PMID- 28861051 TI - Host Ecology Rather Than Host Phylogeny Drives Amphibian Skin Microbial Community Structure in the Biodiversity Hotspot of Madagascar. AB - Host-associated microbiotas of vertebrates are diverse and complex communities that contribute to host health. In particular, for amphibians, cutaneous microbial communities likely play a significant role in pathogen defense; however, our ecological understanding of these communities is still in its infancy. Here, we take advantage of the fully endemic and locally species-rich amphibian fauna of Madagascar to investigate the factors structuring amphibian skin microbiota on a large scale. Using amplicon-based sequencing, we evaluate how multiple host species traits and site factors affect host bacterial diversity and community structure. Madagascar is home to over 400 native frog species, all of which are endemic to the island; more than 100 different species are known to occur in sympatry within multiple rainforest sites. We intensively sampled frog skin bacterial communities, from over 800 amphibians from 89 species across 30 sites in Madagascar during three field visits, and found that skin bacterial communities differed strongly from those of the surrounding environment. Richness of bacterial operational taxonomic units (OTUs) and phylogenetic diversity differed among host ecomorphs, with arboreal frogs exhibiting lower richness and diversity than terrestrial and aquatic frogs. Host ecomorphology was the strongest factor influencing microbial community structure, with host phylogeny and site parameters (latitude and elevation) explaining less but significant portions of the observed variation. Correlation analysis and topological congruency analyses revealed little to no phylosymbiosis for amphibian skin microbiota. Despite the observed geographic variation and low phylosymbiosis, we found particular OTUs that were differentially abundant between particular ecomorphs. For example, the genus Pigmentiphaga (Alcaligenaceae) was significantly enriched on arboreal frogs, Methylotenera (Methylophilaceae) was enriched on aquatic frogs, and Agrobacterium (Rhizobiaceae) was enriched on terrestrial frogs. The presence of shared bacterial OTUs across geographic regions for selected host genera suggests the presence of core microbial communities which in Madagascar, might be driven more strongly by a species' preference for specific microhabitats than by the physical, physiological or biochemical properties of their skin. These results corroborate that both host and environmental factors are driving community assembly of amphibian cutaneous microbial communities, and provide an improved foundation for elucidating their role in disease resistance. PMID- 28861052 TI - EXPOSE-R2: The Astrobiological ESA Mission on Board of the International Space Station. AB - On July 23, 2014, the Progress cargo spacecraft 56P was launched from Baikonur to the International Space Station (ISS), carrying EXPOSE-R2, the third ESA (European Space Agency) EXPOSE facility, the second EXPOSE on the outside platform of the Russian Zvezda module, with four international astrobiological experiments into space. More than 600 biological samples of archaea, bacteria (as biofilms and in planktonic form), lichens, fungi, plant seeds, triops eggs, mosses and 150 samples of organic compounds were exposed to the harsh space environment and to parameters similar to those on the Mars surface. Radiation dosimeters distributed over the whole facility complemented the scientific payload. Three extravehicular activities later the chemical samples were returned to Earth on March 2, 2016, with Soyuz 44S, having spent 588 days in space. The biological samples arrived back later, on June 18, 2016, with 45S, after a total duration in space of 531 days. The exposure of the samples to Low Earth Orbit vacuum lasted for 531 days and was divided in two parts: protected against solar irradiation during the first 62 days, followed by exposure to solar radiation during the subsequent 469 days. In parallel to the space mission, a Mission Ground Reference (MGR) experiment with a flight identical Hardware and a complete flight identical set of samples was performed at the premises of DLR (German Aerospace Center) in Cologne by MUSC (Microgravity User Support Center), according to the mission data either downloaded from the ISS (temperature data, facility status, inner pressure status) or provided by RedShift Design and Engineering BVBA, Belgium (calculated ultra violet radiation fluence data). In this paper, the EXPOSE-R2 facility, the experimental samples, mission parameters, environmental parameters, and the overall mission and MGR sequences are described, building the background for the research papers of the individual experiments, their analysis and results. PMID- 28861053 TI - Enhanced Biocide Treatments with D-amino Acid Mixtures against a Biofilm Consortium from a Water Cooling Tower. AB - Different species of microbes form mixed-culture biofilms in cooling water systems. They cause microbiologically influenced corrosion (MIC) and biofouling, leading to increased operational and maintenance costs. In this work, two D-amino acid mixtures were found to enhance two non-oxidizing biocides [tetrakis hydroxymethyl phosphonium sulfate (THPS) and NALCO 7330 (isothiazoline derivatives)] and one oxidizing biocide [bleach (NaClO)] against a biofilm consortium from a water cooling tower in lab tests. Fifty ppm (w/w) of an equimass mixture of D-methionine, D-leucine, D-tyrosine, D-tryptophan, D-serine, D-threonine, D-phenylalanine, and D-valine (D8) enhanced 15 ppm THPS and 15 ppm NALCO 7330 with similar efficacies achieved by the 30 ppm THPS alone treatment and the 30 ppm NALCO 7330 alone treatment, respectively in the single-batch 3-h biofilm removal test. A sequential treatment method was used to enhance bleach because D-amino acids react with bleach. After a 4-h biofilm removal test, the sequential treatment of 5 ppm bleach followed by 50 ppm D8 achieved extra 1-log reduction in sessile cell counts of acid producing bacteria, sulfate reducing bacteria, and general heterotrophic bacteria compared with the 5 ppm bleach alone treatment. The 10 ppm bleach alone treatment showed a similar efficacy with the sequential treatment of 5 ppm bleach followed by 50 ppm D8. The efficacy of D8 was found better than that of D4 (an equimass mixture of D-methionine, D-leucine, D-tyrosine, and D-tryptophan) in the enhancement of the three individual biocides against the biofilm consortium. PMID- 28861054 TI - Screening of TB Actives for Activity against Nontuberculous Mycobacteria Delivers High Hit Rates. AB - The prevalence of lung disease due to infections with nontuberculous mycobacteria (NTM) has been increasing and surpassed tuberculosis (TB) in some countries. Treatment outcomes are often unsatisfactory, highlighting an urgent need for new anti-NTM medications. Although NTM in general do not respond well to TB specific drugs, the similarities between NTM and Mycobacterium tuberculosis at the molecular and cell structural level suggest that compound libraries active against TB could be leveraged for NTM drug discovery. Here we tested this hypothesis. The Pathogen Box from the Medicines for Malaria Venture (MMV) is a collection of 400 diverse drug-like compounds, among which 129 are known to be active against M. tuberculosis. By screening this compound collection against two NTM species, Mycobacterium abscessus and Mycobacterium avium, we showed that indeed the hit rates for NTM among TB active compounds is significantly higher compared to compounds that are not active against TB. MIC/dose response confirmation identified 10 top hits. Bactericidal activity determination demonstrated attractive potency for a subset of the confirmed hits. In vivo pharmacokinetic profiling showed that some of the compounds present reasonable starting points for medicinal chemistry programs. Three of the top hits were oxazolidinones, suggesting the potential for repositioning this class of protein synthesis inhibitors to replace linezolid which suffers from low potency. Two hits were inhibitors of the trehalose monomycolate transporter MmpL3, suggesting that this transmembrane protein may be an attractive target for NTM. Other hits are predicted to target a range of functions, including cell division (FtsZ), DNA gyrase (GyrB), dihydrofolate reductase, RNA polymerase and ABC transporters. In conclusion, our study showed that screening TB active compounds for activity against NTM resulted in high hit rates, suggesting that this may be an attractive approach to kick start NTM drug discovery projects. In addition, the work identified a series of novel high value NTM hits with associated candidate targets which can be followed up in hit-to-lead projects for the discovery of new NTM antibiotics. PMID- 28861055 TI - Genomic Characteristics of Bifidobacterium thermacidophilum Pig Isolates and Wild Boar Isolates Reveal the Unique Presence of a Putative Mobile Genetic Element with tetW for Pig Farm Isolates. AB - Genomic analysis was performed on seven strains of Bifidobacterium thermacidophilum, a Sus-associated Bifidobacterium. Three strains from the feces of domestic pigs (Sus scrofa domesticus) and four strains from the rectal feces of free-range Japanese wild boars (S. s. scrofa) were compared. The phylogenetic position of these isolates suggested by genomic analyses were not concordant with that suggested by 16S rRNA sequence. There was biased distribution of genes for virulence, phage, metabolism of aromatic compounds, iron acquisition, cell division, and DNA metabolism. In particular four wild boar isolates harbored fiber-degrading enzymes, such as endoglucanase, while two of the pig isolates obtained from those grown under an intensive feeding practice with routine use of antimicrobials, particularly tetracycline harbored a tetracycline resistance gene, which was further proved functional by disk diffusion test. The tetW gene is associated with a serine recombinase of an apparently non-bifidobacterial origin. The insertion site of the tetW cassette was precisely defined by analyzing the corresponding genomic regions in the other tetracycline-susceptible isolates. The cassette may have been transferred from some other bacteria in the pig gut. PMID- 28861056 TI - Identification of Novel Conjugative Plasmids with Multiple Copies of fosB that Confer High-Level Fosfomycin Resistance to Vancomycin-Resistant Enterococci. AB - To further characterize the fosB-carrying plasmids of 19 vancomycin-resistant enterococci, the complete sequences of the fosB- and vanA-containing plasmids of Enterococcus faecium (pEMA120) and E. avium (pEA19081) were obtained by single molecule, real-time sequencing. We found that these two plasmids are essentially identical (99.99% nucleotide sequence identity), which proved the possibility of interspecies transmission. Comparative analysis of the plasmids revealed that the backbone of pEMA120 is 99% similar to a conjugative fosB-negative E. faecium plasmid, pZB18. There is a traE disrupted in the transfer region of pEMA120, in comparison to pZB18 with an intact traE. The difference of their transfer frequencies between pEMA120 and pZB18 suggests this interruption of traE might affect conjugative transfer. Two copies of the fosB gene linked to a tnpA gene, forming an ISL3-like transposon, were found at separate locations within pEMA120, which had not been reported previously. These two fosB-carrying transposons were confirmed to form circular intermediates by inverse PCR. The hybridization of plasmid DNA digested by BsaI, having restriction site within the fosB sequence, demonstrated that the presence of multiple copies of fosB per plasmid is common. The total copy number of the fosB gene as revealed by qRT-PCR did not correlate with fosfomycin MICs or growth rates at sub-MICs of fosfomycin in different transconjugants. From susceptibility tests, the fosB gene, regardless of the copy number, conferred high fosfomycin MICs that ranged from 16384 to 65536 MUg/ml. This first complete nucleotide sequence of a plasmid carrying two copies of fosB in VRE suggests that the fosB gene can transfer to multiple loci of plasmids by the ISL3 family transposase TnpA, possibly in the form of circular intermediates, leading to the dissemination of high fosfomycin resistance in VRE. PMID- 28861058 TI - Editorial: Management of Fusarium Species and their Mycotoxins in Cereal Food and Feed. PMID- 28861057 TI - The Complete Genome Sequence of the Fish Pathogen Tenacibaculum maritimum Provides Insights into Virulence Mechanisms. AB - Tenacibaculum maritimum is a devastating bacterial pathogen of wild and farmed marine fish with a broad host range and a worldwide distribution. We report here the complete genome sequence of the T. maritimum type strain NCIMB 2154T. The genome consists of a 3,435,971-base pair circular chromosome with 2,866 predicted protein-coding genes. Genes encoding the biosynthesis of exopolysaccharides, the type IX secretion system, iron uptake systems, adhesins, hemolysins, proteases, and glycoside hydrolases were identified. They are likely involved in the virulence process including immune escape, invasion, colonization, destruction of host tissues, and nutrient scavenging. Among the predicted virulence factors, type IX secretion-mediated and cell-surface exposed proteins were identified including an atypical sialidase, a sphingomyelinase and a chondroitin AC lyase which activities were demonstrated in vitro. PMID- 28861059 TI - Characterization of Full-Length and Truncated Recombinant kappa-Carrageenase Expressed in Pichia pastoris. AB - kappa-Carrageenase belongs to glycoside hydrolase family 16 and cleaves the beta (1->4) linkages of kappa-carrageenan. In this study, genes encoding the full length (cgkZ), Por secretion tail-truncated (cgkZDeltaPst) and carbohydrate binding domain-truncated (cgkZDeltaCBM) kappa-carrageenase proteins were expressed in Pichia pastoris. The copy numbers of gene cgkZ, cgkZDeltaPst and cgkZDeltaCBM were 7, 7 and 6, respectively. The enzymatic activities of recombinant enzymes cgkZ, cgkZDeltaPst and cgkZDeltaCBM reached 4.68, 5.70, and 3.02 U/mL, respectively, after 120 h of shake flask fermentation at 22 degrees C and pH 6 in the presence of 1 % (v/v) methanol. The molecular weights of recombinant cgkZ, cgkZDeltaPst, and cgkZDeltaCBM were approximately 65, 45, and 40 kDa; their Km values were 2.07, 1.85, and 1.04 mg/mL; and they exhibited optimal activity at 45-50 degrees C and pH 6-7. All the recombinant enzymes were stimulated by Na+, Mg2+, Ca2+, and dithiothreitol. The end-products of enzymatic hydrolysis were mainly composed of kappa-carrageenan tetrasaccharide and hexasaccharide. The removal of the Por secretion tail of kappa-carrageenase promoted the transcription of kappa-carrageenase gene, enhancing the specific activity of kappa-carrageenase without significantly changing its catalytic properties. Although the transcription level of kappa-carrageenase gene after the removal of the carbohydrate binding domain was relatively high, the specific activity of the recombinant enzyme significantly decreased. The comprehensive application of the P. pastoris expression system combined with the rational modification of genes may provide a novel approach for the heterologous expression of various marine enzymes with high activities. PMID- 28861060 TI - CRISPR-Cas Systems Features and the Gene-Reservoir Role of Coagulase-Negative Staphylococci. AB - The claimed role of gene reservoir of coagulase-negative staphylococci (CoNS) could be contradicted by estimates that CRISPR/Cas systems are found in the genomes of 40-50% of bacteria, as these systems interfere with plasmid uptake in staphylococci. To further correlate this role with presence of CRISPR, we analyzed, by computational methods, 122 genomes from 15 species of CoNS. Only 15% of them harbored CRISPR/Cas systems, and this proportion was much lower for S. epidermidis and S. haemolyticus, the CoNS most frequently associated with opportunistic infections in humans. These systems are of type II or III, and at least two of them are located within SCCmec, a mobile genetic element of Staphylococcus bacterial species. An analysis of the spacers of these CRISPRs, which come from exogenous origin, allowed us to track the transference of the SCCmec, which was exchanged between different strains, species and hosts. Some of the spacers are derived from plasmids described in Staphylococcus species that are different from those in which the CRISPR are found, evidencing the attempt (and failure) of plasmid transference between them. Based on the polymorphisms of the cas1 gene in CRISPRs of types II and III, we developed a multiplex polymerase chain reaction (PCR) suitable to screen and type CRISPR systems in CoNS. The PCR was tested in 59 S. haemolyticus strains, of which only two contained a type III cas1. This gene was shown to be expressed in the exponential growth, stationary phase and during biofilm formation. The low abundance of CRISPRs in CoNS is in accordance with their role as gene reservoirs, but when present, their spacers sequence evidence and give an insight on the dynamics of horizontal genetic transfer among staphylococci. PMID- 28861061 TI - Small, Enigmatic Plasmids of the Nosocomial Pathogen, Acinetobacter baumannii: Good, Bad, Who Knows? AB - Acinetobacter baumannii is a Gram-negative nosocomial pathogen that has become a serious healthcare concern within a span of two decades due to its ability to rapidly acquire resistance to all classes of antimicrobial compounds. One of the key features of the A. baumannii genome is an open pan genome with a plethora of plasmids, transposons, integrons, and genomic islands, all of which play important roles in the evolution and success of this clinical pathogen, particularly in the acquisition of multidrug resistance determinants. An interesting genetic feature seen in majority of A. baumannii genomes analyzed is the presence of small plasmids that usually ranged from 2 to 10 kb in size, some of which harbor antibiotic resistance genes and homologs of plasmid mobilization genes. These plasmids are often overlooked when compared to their larger, conjugative counterparts that harbor multiple antibiotic resistance genes and transposable elements. In this mini-review, we will examine our current knowledge of these small A. baumannii plasmids and look into their genetic diversity and phylogenetic relationships. Some of these plasmids, such as the Rep-3 superfamily group and the pRAY-type, which has no recognizable replicase genes, are quite widespread among diverse A. baumannii clinical isolates worldwide, hinting at their usefulness to the lifestyle of this pathogen. Other small plasmids especially those from the Rep-1 superfamily are truly enigmatic, encoding only hypothetical proteins of unknown function, leading to the question of whether these small plasmids are "good" or "bad" to their host A. baumannii. PMID- 28861063 TI - Variation of Oxygenation Conditions on a Hydrocarbonoclastic Microbial Community Reveals Alcanivorax and Cycloclasticus Ecotypes. AB - Deciphering the ecology of marine obligate hydrocarbonoclastic bacteria (MOHCB) is of crucial importance for understanding their success in occupying distinct niches in hydrocarbon-contaminated marine environments after oil spills. In marine coastal sediments, MOHCB are particularly subjected to extreme fluctuating conditions due to redox oscillations several times a day as a result of mechanical (tide, waves and currents) and biological (bioturbation) reworking of the sediment. The adaptation of MOHCB to the redox oscillations was investigated by an experimental ecology approach, subjecting a hydrocarbon-degrading microbial community to contrasting oxygenation regimes including permanent anoxic conditions, anoxic/oxic oscillations and permanent oxic conditions. The most ubiquitous MOHCB, Alcanivorax and Cycloclasticus, showed different behaviors, especially under anoxic/oxic oscillation conditions, which were more favorable for Alcanivorax than for Cycloclasticus. The micro-diversity of 16S rRNA gene transcripts from these genera revealed specific ecotypes for different oxygenation conditions and their dynamics. It is likely that such ecotypes allow the colonization of distinct ecological niches that may explain the success of Alcanivorax and Cycloclasticus in hydrocarbon-contaminated coastal sediments during oil-spills. PMID- 28861062 TI - Evolutionary Genetic Analysis Uncovers Multiple Species with Distinct Habitat Preferences and Antibiotic Resistance Phenotypes in the Stenotrophomonas maltophilia Complex. AB - The genus Stenotrophomonas (Gammaproteobacteria) has a broad environmental distribution. Stenotrophomonas maltophilia is its best known species because it is a globally emerging, multidrug-resistant (MDR), opportunistic pathogen. Members of this species are known to display high genetic, ecological and phenotypic diversity, forming the so-called S. maltophilia complex (Smc). Heterogeneous resistance and virulence phenotypes have been reported for environmental Smc isolates of diverse ecological origin. We hypothesized that this heterogeneity could be in part due to the potential lumping of several cryptic species in the Smc. Here we used state-of-the-art phylogenetic and population genetics methods to test this hypothesis based on the multilocus dataset available for the genus at pubmlst.org. It was extended with sequences from complete and draft genome sequences to assemble a comprehensive set of reference sequences. This framework was used to analyze 108 environmental isolates obtained in this study from the sediment and water column of four rivers and streams in Central Mexico, affected by contrasting levels of anthropogenic pollution. The aim of the study was to identify species in this collection, defined as genetically cohesive sequence clusters, and to determine the extent of their genetic, ecological and phenotypic differentiation. The multispecies coalescent, coupled with Bayes factor analysis was used to delimit species borders, together with population genetic structure analyses, recombination and gene flow estimates between sequence clusters. These analyses consistently revealed that the Smc contains at least 5 significantly differentiated lineages: S. maltophilia and Smc1 to Smc4. Only S. maltophilia was found to be intrinsically MDR, all its members expressing metallo-beta-lactamases (MBLs). The other Smc lineages were not MDR and did not express MBLs. We also obtained isolates related to S. acidaminiphila, S. humi and S. terrae. They were significantly more susceptible to antibiotics than S. maltophilia. We demonstrate that the sympatric lineages recovered display significantly differentiated habitat preferences, antibiotic resistance profiles and beta-lactamase expression phenotypes, as shown by diverse multivariate analyses and robust univariate statistical tests. We discuss our data in light of current models of bacterial speciation, which fit these data well, stressing the implications of species delimitation in ecological, evolutionary and clinical research. PMID- 28861064 TI - Screening and Characterization of Potentially Suppressive Soils against Gaeumannomyces graminis under Extensive Wheat Cropping by Chilean Indigenous Communities. AB - Wheat production around the world is severely compromised by the occurrence of "take-all" disease, which is caused by the soil-borne pathogen Gaeumannomyces graminis var. tritici (Ggt). In this context, suppressive soils are those environments in which plants comparatively suffer less soil-borne pathogen diseases than expected, owing to native soil microorganism activities. In southern Chile, where 85% of the national cereal production takes place, several studies have suggested the existence of suppressive soils under extensive wheat cropping. Thus, this study aimed to screen Ggt-suppressive soil occurrence in 16 locations managed by indigenous "Mapuche" communities, using extensive wheat cropping for more than 10 years. Ggt growth inhibition in vitro screenings allowed the identification of nine putative suppressive soils. Six of these soils, including Andisols and Ultisols, were confirmed to be suppressive, since they reduced take-all disease in wheat plants growing under greenhouse conditions. Suppressiveness was lost upon soil sterilization, and recovered by adding 1% of the natural soil, hence confirming that suppressiveness was closely associated to the soil microbiome community composition. Our results demonstrate that long-term extensive wheat cropping, established by small Mapuche communities, can generate suppressive soils that can be used as effective microorganism sources for take-all disease biocontrol. Accordingly, suppressive soil identification and characterization are key steps for the development of environmentally-friendly and efficient biotechnological applications for soil borne disease control. PMID- 28861065 TI - Effect of Pre-weaning Diet on the Ruminal Archaeal, Bacterial, and Fungal Communities of Dairy Calves. AB - At birth, calves display an underdeveloped rumen that eventually matures into a fully functional rumen as a result of solid food intake and microbial activity. However, little is known regarding the gradual impact of pre-weaning diet on the establishment of the rumen microbiota. Here, we employed next-generation sequencing to investigate the effects of the inclusion of starter concentrate (M: milk-fed vs. MC: milk plus starter concentrate fed) on archaeal, bacterial and anaerobic fungal communities in the rumens of 45 crossbred dairy calves across pre-weaning development (7, 28, 49, and 63 days). Our results show that archaeal, bacterial, and fungal taxa commonly found in the mature rumen were already established in the rumens of calves at 7 days old, regardless of diet. This confirms that microbiota colonization occurs in the absence of solid substrate. However, diet did significantly impact some microbial taxa. In the bacterial community, feeding starter concentrate promoted greater diversity of bacterial taxa known to degrade readily fermentable carbohydrates in the rumen (e.g., Megasphaera, Sharpea, and Succinivribrio). Shifts in the ruminal bacterial community also correlated to changes in fermentation patterns that favored the colonization of Methanosphaera sp. A4 in the rumen of MC calves. In contrast, M calves displayed a bacterial community dominated by taxa able to utilize milk nutrients (e.g., Lactobacillus, Bacteroides, and Parabacteroides). In both diet groups, the dominance of these milk-associated taxa decreased with age, suggesting that diet and age simultaneously drive changes in the structure and abundance of bacterial communities in the developing rumen. Changes in the composition and abundance of archaeal communities were attributed exclusively to diet, with more highly abundant Methanosphaera and less abundant Methanobrevibacter in MC calves. Finally, the fungal community was dominated by members of the genus SK3 and Caecomyces. Relative anaerobic fungal abundances did not change significantly in response to diet or age, likely due to high inter animal variation and the low fiber content of starter concentrate. This study provides new insights into the colonization of archaea, bacteria, and anaerobic fungi communities in pre-ruminant calves that may be useful in designing strategies to promote colonization of target communities to improve functional development. PMID- 28861066 TI - Unraveling the Fecal Microbiota and Metagenomic Functional Capacity Associated with Feed Efficiency in Pigs. AB - Gut microbiota plays fundamental roles in energy harvest, nutrient digestion, and intestinal health, especially in processing indigestible components of polysaccharides in diet. Unraveling the microbial taxa and functional capacity of gut microbiome associated with feed efficiency can provide important knowledge to improve pig feed efficiency in swine industry. In the current research, we studied the association of fecal microbiota with feed efficiency in 280 commercial Duroc pigs. All experimental pigs could be clustered into two enterotype-like groups. Different enterotypes showed the tendency of association with the feed efficiency (P = 0.07). We further identified 31 operational taxonomic units (OTUs) showing the potential associations with porcine feed efficiency. These OTUs were mainly annotated to the bacteria related to the metabolisms of dietary polysaccharides. Although we did not identify the RFI associated bacterial species at FDR < 0.05 level, metagenomic sequencing analysis did find the distinct function capacities of gut microbiome between the high and low RFI pigs (FDR < 0.05). The KEGG orthologies related to nitrogen metabolism, amino acid metabolism, and transport system, and eight KEGG pathways including glycine, serine, and threonine metabolism were positively associated with porcine feed efficiency. We inferred that gut microbiota might improve porcine feed efficiency through promoting intestinal health by the SCFAs produced by fermenting dietary polysaccharides and improving the utilization of dietary protein. The present results provided important basic knowledge for improving porcine feed efficiency through modulating gut microbiome. PMID- 28861067 TI - Transcriptomic Analyses Reveal Differential Gene Expression of Immune and Cell Death Pathways in the Brains of Mice Infected with West Nile Virus and Chikungunya Virus. AB - West Nile virus (WNV) and chikungunya virus (CHIKV) are arboviruses that are constantly (re-)emerging and expanding their territory. Both viruses often cause a mild form of disease, but severe forms of the disease can consist of neurological symptoms, most often observed in the elderly and young children, respectively, for which the mechanisms are poorly understood. To further elucidate the mechanisms responsible for end-stage WNV and CHIKV neuroinvasive disease, we used transcriptomics to compare the induction of effector pathways in the brain during the early and late stage of disease in young mice. In addition to the more commonly described cell death pathways such as apoptosis and autophagy, we also found evidence for the differential expression of pyroptosis and necroptosis cell death markers during both WNV and CHIKV neuroinvasive disease. In contrast, no evidence of cell dysfunction was observed, indicating that cell death may be the most important mechanism of disease. Interestingly, there was overlap when comparing immune markers involved in neuroinvasive disease to those seen in neurodegenerative diseases. Nonetheless, further validation studies are needed to determine the activation and involvement of these effector pathways at the end stage of disease. Furthermore, evidence for a strong inflammatory response was found in mice infected with WNV and CHIKV. The transcriptomics profile measured in mice with WNV and CHIKV neuroinvasive disease in our study showed strong overlap with the mRNA profile described in the literature for other viral neuroinvasive diseases. More studies are warranted to decipher the role of cell inflammation and cell death in viral neuroinvasive disease and whether common mechanisms are active in both neurodegenerative and brain infectious diseases. PMID- 28861068 TI - Protein-Protein Interactions in Virus-Host Systems. AB - To study virus-host protein interactions, knowledge about viral and host protein architectures and repertoires, their particular evolutionary mechanisms, and information on relevant sources of biological data is essential. The purpose of this review article is to provide a thorough overview about these aspects. Protein domains are basic units defining protein interactions, and the uniqueness of viral domain repertoires, their mode of evolution, and their roles during viral infection make viruses interesting models of study. Mutations at protein interfaces can reduce or increase their binding affinities by changing protein electrostatics and structural properties. During the course of a viral infection, both pathogen and cellular proteins are constantly competing for binding partners. Endogenous interfaces mediating intraspecific interactions-viral-viral or host-host interactions-are constantly targeted and inhibited by exogenous interfaces mediating viral-host interactions. From a biomedical perspective, blocking such interactions is the main mechanism underlying antiviral therapies. Some proteins are able to bind multiple partners, and their modes of interaction define how fast these "hub proteins" evolve. "Party hubs" have multiple interfaces; they establish simultaneous/stable (domain-domain) interactions, and tend to evolve slowly. On the other hand, "date hubs" have few interfaces; they establish transient/weak (domain-motif) interactions by means of short linear peptides (15 or fewer residues), and can evolve faster. Viral infections are mediated by several protein-protein interactions (PPIs), which can be represented as networks (protein interaction networks, PINs), with proteins being depicted as nodes, and their interactions as edges. It has been suggested that viral proteins tend to establish interactions with more central and highly connected host proteins. In an evolutionary arms race, viral and host proteins are constantly changing their interface residues, either to evade or to optimize their binding capabilities. Apart from gaining and losing interactions via rewiring mechanisms, virus-host PINs also evolve via gene duplication (paralogy); conservation (orthology); horizontal gene transfer (HGT) (xenology); and molecular mimicry (convergence). The last sections of this review focus on PPI experimental approaches and their limitations, and provide an overview of sources of biomolecular data for studying virus-host protein interactions. PMID- 28861069 TI - Vertical Transmission of H9N2 Avian Influenza Virus in Goose. AB - During a study on high mortality cases of goose embryo in Shandong Province, China (2014-2015), we isolated an H9N2 avian influenza virus (AIV) strain (A/goose/Shandong/DP01/2014, DP01), which was supposedly the causative agent for goose embryo death. Sequence analysis revealed that DP01 shared 99.9% homology in the HA gene with a classic immune suppression strain SD06. To study the potential vertical transmission ability of the DP01 strain in breeder goose, a total of 105 Taizhou breeder geese, which were 360 days old, were equally divided into five groups (A, B, C, D, and E) for experimental infection. H9N2 AIV (DP01) was used for inoculating through intravenous (group A), intranasal instillation (group B), and throat inoculation (group C) routes, respectively. The geese in group D were inoculated with phosphate buffer solution (PBS) and those in group E were the non treated group. At 24 h post inoculation, H9N2 viral RNA could be detected at vitelline membrane, embryos, and allantoic fluid of goose embryos from H9N2 inoculated groups. Furthermore, the HA gene of H9N2 virus from vitelline membrane, embryo, allantoic fluid, and gosling shared almost 100% homology with an H9N2 virus isolated from the ovary of breeder goose, which laid these eggs, indicating that H9N2 AIV can be vertically transmitted in goose. The present research study provides evidence that vertical transmission of H9N2 AIV from breeding goose to goslings is possible. PMID- 28861070 TI - Environmental Pollutant Benzo[a]Pyrene Impacts the Volatile Metabolome and Transcriptome of the Human Gut Microbiota. AB - Benzo[a]pyrene (B[a]P) is a ubiquitous, persistent, and carcinogenic pollutant that belongs to the large family of polycyclic aromatic hydrocarbons. Population exposure primarily occurs via contaminated food products, which introduces the pollutant to the digestive tract. Although the metabolism of B[a]P by host cells is well known, its impacts on the human gut microbiota, which plays a key role in health and disease, remain unexplored. We performed an in vitro assay using 16S barcoding, metatranscriptomics and volatile metabolomics to study the impact of B[a]P on two distinct human fecal microbiota. B[a]P exposure did not induce a significant change in the microbial structure; however, it altered the microbial volatolome in a dose-dependent manner. The transcript levels related to several metabolic pathways, such as vitamin and cofactor metabolism, cell wall compound metabolism, DNA repair and replication systems, and aromatic compound metabolism, were upregulated, whereas the transcript levels related to the glycolysis gluconeogenesis pathway and bacterial chemotaxis toward simple carbohydrates were downregulated. These primary findings show that food pollutants, such as B[a]P, alter human gut microbiota activity. The observed shift in the volatolome demonstrates that B[a]P induces a specific deviation in the microbial metabolism. PMID- 28861071 TI - Tetrathionate and Elemental Sulfur Shape the Isotope Composition of Sulfate in Acid Mine Drainage. AB - Sulfur compounds in intermediate valence states, for example elemental sulfur, thiosulfate, and tetrathionate, are important players in the biogeochemical sulfur cycle. However, key understanding about the pathways of oxidation involving mixed-valance state sulfur species is still missing. Here we report the sulfur and oxygen isotope fractionation effects during the oxidation of tetrathionate (S4O62-) and elemental sulfur (S degrees ) to sulfate in bacterial cultures in acidic conditions. Oxidation of tetrathionate by Acidithiobacillus thiooxidans produced thiosulfate, elemental sulfur and sulfate. Up to 34% of the tetrathionate consumed by the bacteria could not be accounted for in sulfate or other intermediate-valence state sulfur species over the experiments. The oxidation of tetrathionate yielded sulfate that was initially enriched in 34S (epsilon34SSO4-S4O6) by +7.90/00, followed by a decrease to +1.40/00 over the experiment duration, with an average epsilon34SSO4-S4O6 of +3.5 +/- 0.20/00 after a month of incubation. We attribute this significant sulfur isotope fractionation to enzymatic disproportionation reactions occurring during tetrathionate decomposition, and to the incomplete transformation of tetrathionate into sulfate. The oxygen isotope composition of sulfate (delta18OSO4) from the tetrathionate oxidation experiments indicate that 62% of the oxygen in the formed sulfate was derived from water. The remaining 38% of the oxygen was either inherited from the supplied tetrathionate, or supplied from dissolved atmospheric oxygen (O2). During the oxidation of elemental sulfur, the product sulfate became depleted in 34S between -1.8 and 00/00 relative to the elemental sulfur with an average for epsilon34SSO4-S0 of -0.9 +/- 0.20/00 and all the oxygen atoms in the sulfate derived from water with an average normal oxygen isotope fractionation (epsilon18OSO4-H2O) of -4.40/00. The differences observed in delta18OSO4 and the sulfur isotope composition of sulfate (delta34SSO4), acid production, and mixed valence state sulfur species generated by the oxidation of the two different substrates suggests a metabolic flexibility in response to sulfur substrate availability. Our results demonstrate that microbial processing of mixed-valence state sulfur species generates a significant sulfur isotope fractionation in acidic environments and oxidation of mixed-valence state sulfur species may produce sulfate with characteristic sulfur and oxygen isotope signatures. Elemental sulfur and tetrathionate are not only intermediate-valence state sulfur compounds that play a central role in sulfur oxidation pathways, but also key factors in shaping these isotope patterns. PMID- 28861073 TI - Epithelial Cell Damage Activates Bactericidal/Permeability Increasing-Protein (BPI) Expression in Intestinal Epithelium. AB - As the first line of defense against invading pathogen, intestinal epithelium produces various antimicrobial proteins (AMP) that help in clearance of pathogen. Bactericidal/permeability-increasing protein (BPI) is a 55 kDa AMP that is expressed in intestinal epithelium. Dysregulation of BPI in intestinal epithelium is associated with various inflammatory diseases like Crohn's Disease, Ulcerative colitis, and Infectious enteritis's. In this paper, we report a direct correlation between intestinal damage and BPI expression. In Caco-2 cells, we see a significant increase in BPI levels upon membrane damage mediated by S. aureus infection and pore-forming toxins (Streptolysin and Listeriolysin). Cells detect changes in potassium level as a Danger-associated molecular pattern associated with cell damage and induce BPI expression in a p38 dependent manner. These results are further supported by in vivo findings that the BPI expression in murine intestinal epithelium is induced upon infection with bacteria which cause intestinal damage (Salmonella Typhimurium and Shigella flexneri) whereas mutants that do not cause intestinal damage (STM DeltafliC and STM DeltainvC) did not induce BPI expression. Our results suggest that epithelial damage associated with infection act as a signal to induce BPI expression. PMID- 28861072 TI - UroPathogenic Escherichia coli (UPEC) Infections: Virulence Factors, Bladder Responses, Antibiotic, and Non-antibiotic Antimicrobial Strategies. AB - Urinary tract infections (UTIs) are one of the most common pathological conditions in both community and hospital settings. It has been estimated that about 150 million people worldwide develop UTI each year, with high social costs in terms of hospitalizations and medical expenses. Among the common uropathogens associated to UTIs development, UroPathogenic Escherichia coli (UPEC) is the primary cause. UPEC strains possess a plethora of both structural (as fimbriae, pili, curli, flagella) and secreted (toxins, iron-acquisition systems) virulence factors that contribute to their capacity to cause disease, although the ability to adhere to host epithelial cells in the urinary tract represents the most important determinant of pathogenicity. On the opposite side, the bladder epithelium shows a multifaceted array of host defenses including the urine flow and the secretion of antimicrobial substances, which represent useful tools to counteract bacterial infections. The fascinating and intricate dynamics between these players determine a complex interaction system that needs to be revealed. This review will focus on the most relevant components of UPEC arsenal of pathogenicity together with the major host responses to infection, the current approved treatment and the emergence of resistant UPEC strains, the vaccine strategies, the natural antimicrobial compounds along with innovative anti adhesive and prophylactic approaches to prevent UTIs. PMID- 28861074 TI - The Probiotic Combination of Bifidobacterium longum subsp. infantis CECT 7210 and Bifidobacterium animalis subsp. lactis BPL6 Reduces Pathogen Loads and Improves Gut Health of Weaned Piglets Orally Challenged with Salmonella Typhimurium. AB - Probiotics have been demonstrated to be useful to enhance gut health and prevent gastrointestinal infections in humans. Additionally, some multi-strain probiotic combinations have been suggested to have greater efficacy than single strains. The objective of this study is to demonstrate the potential of a combination of the probiotic strains: Bifidobacterium longum subsp. infantis CECT 7210 (brand name B. infantis IM1(r)) and B. animalis subsp. lactis BPL6 to enhance gut health and to ameliorate the outcome of a Salmonella challenge using a weaning piglet model. Seventy-two 28-day-old weanling piglets, 7.7 (+/-0.28) kg of body-weight, were distributed in a 2 * 2 factorial design; treated or not with the probiotic combination and challenged or not with the pathogen. Animals were orally challenged after an adaptation period (Day 8) with a single dose (5 * 108 cfu) of Salmonella Typhimurium. One animal per pen was euthanized on Day 12 (Day 4 post inoculation [PI]) and Day 16 (Day 8 PI). All parameters responded to the challenge and 4 deaths were registered, indicating a severe but self-limiting challenge. Improvements registered in the challenged animals due to the probiotic were: increased voluntary feed-intake (P probiotic * challenge = 0.078), reduced fecal excretion of Salmonella (P = 0.028 at Day 1 PI and P < 0.10 at Days 3 and 5 PI), decreased rectal temperature (P probiotic * day = 0.048) and improvements in the villous:crypt ratio (P probiotic * challenge < 0.001). Moreover, general probiotic benefits were observed in both challenged and non-challenged groups: decreased diarrhea scores of the PI period (P = 0.014), improved fermentation profiles on Day 8 PI (increased ileal acetic acid [P = 0.008] and a tendency to lower colonic ammonia concentrations [P = 0.078]), stimulation of intestinal immune response by increasing villous intraepithelial lymphocytes (P = 0.015 on Day 8 PI) and an improved villous:crypt ratio (P = 0.011). In conclusion, the multi-strain probiotic had a positive effect on reducing pathogen loads and alleviating animals in a Salmonella challenge. In addition, enhanced gut health and immunity was recorded in all animals receiving the probiotic, indicating an improvement in the post-weaning outcome. PMID- 28861075 TI - Ebola Virus Glycoprotein Induces an Innate Immune Response In vivo via TLR4. AB - Ebola virus (EBOV), a member of the Filoviridae family, causes the most severe form of viral hemorrhagic fever. Although no FDA licensed vaccine or treatment against Ebola virus disease (EVD) is currently available, Ebola virus glycoprotein (GP) is the major antigen used in all candidate Ebola vaccines. Recent reports of protection as quickly as within 6 days of administration of the rVSV-based vaccine expressing EBOV GP before robust humoral responses were generated suggests that the innate immune responses elicited early after vaccination may contribute to the protection. However, the innate immune responses induced by EBOV GP in the absence of viral vectors or adjuvants have not been fully characterized in vivo. Our recent studies demonstrated that immunization with highly purified recombinant GP in the absence of adjuvants induced a robust IgG response and partial protection against EBOV infection suggesting that GP alone can induce protective immunity. In this study we investigated the early immune response to purified EBOV GP alone in vitro and in vivo. We show that GP was efficiently internalized by antigen presenting cells and subsequently induced production of key inflammatory cytokines. In vivo, immunization of mice with EBOV GP triggered the production of key Th1 and Th2 innate immune cytokines and chemokines, which directly governed the recruitment of CD11b+ macrophages and CD11c+ dendritic cells to the draining lymph nodes (DLNs). Pre-treatment of mice with a TLR4 antagonist inhibited GP-induced cytokine production and recruitment of immune cells to the DLN. EBOV GP also upregulated the expression of costimulatory molecules in bone marrow derived macrophages suggesting its ability to enhance APC stimulatory capacity, which is critical for the induction of effective antigen-specific adaptive immunity. Collectively, these results provide the first in vivo evidence that early innate immune responses to EBOV GP are mediated via the TLR4 pathway and are able to modulate the innate-adaptive interface. These mechanistic insights into the adjuvant-like property of EBOV GP may help to develop a better understanding of how optimal prophylactic efficacy of EBOV vaccines can be achieved as well as further explore the potential post-exposure use of vaccines to prevent filoviral disease. PMID- 28861076 TI - Case of Meningitis in a Neonate Caused by an Extended-Spectrum-Beta-Lactamase Producing Strain of Hypervirulent Klebsiella pneumoniae. AB - Klebsiella pneumoniae is one of the most important infectious agents among neonates. This pathogen has a potential to develop an increased antimicrobial resistance and virulence. The classic non-virulent strain of K. pneumoniae, producing an extended-spectrum beta-lactamases (ESBL), is associated with nosocomial infection mainly in preterm neonates. Hypervirulent K. pneumoniae strains are associated with invasive infection among previously healthy ambulatory patients, and most of them exhibit antimicrobial susceptibility. During the last few years, several cases of diseases caused by hypervirulent K. pneumoniae producing ESBL have been registered in different geographical regions of the world. However, reports of such cases in neonates are rare. Here, we reported that this pathogen can cause pyogenic meningitis in full-term neonate with poor prognosis. A previously healthy, full-term, 12-day-old neonate was admitted to the infectious diseases hospital with suspected meningitis. The clinical symptoms included loss of appetite, irritability, fever, seizures, and a bulging anterior fontanelle. The analysis of the cerebrospinal fluid confirmed the diagnosis of meningitis. Blood and cerebrospinal fluid cultures were positive for K. pneumoniae, producing ESBL. K. pneumoniae isolates were resistant to aminopenicillins, 3rd generation cephalosporins but were sensitive to imipenem and meropenem. The "string test" was positive. The study of the virulence factors of K. pneumoniae by PCR revealed the presence of the rmpA gene. A combination of K. pneumoniae virulence and drug resistance complicated by cerebral oedema led to the death of the neonate. We concluded that both the risk of developing severe forms of infection and the outcome of the disease due to K. pneumonia are associated with the phenotypic features of the pathogen such as its antibiotic susceptibility and virulence factors. Emergence of the ESBL-producing strain of hypervirulent K. pneumoniae could represent a new serious threat to public health, suggesting an urgent need to enhance clinical awareness and epidemiological surveillance. PMID- 28861077 TI - Identification of a New Target slr0946 of the Response Regulator Sll0649 Involving Cadmium Tolerance in Synechocystis sp. PCC 6803. AB - Survival of photosynthetic cyanobacteria is challenged by environmental contaminations like heavy metals. Among them, deciphering the regulatory mechanisms for cadmium (Cd) in cyanobacteria would facilitate the construction of Cd-resistant strains. In this study, the DNA-Affinity-Purified-chromatin immunoprecipitation assay was employed to identify the direct targets of Sll0649, which was a Cd2+-related response regulator identified in our previous work in model cyanobacteria Synechocystis sp. PCC 6803. As a result, the promoter region of slr0946 encoding the arsenate reductase was enriched fourfolds by quantitative real time PCR analysis. Further, deletion of slr0946 led to a sensitive phenotype to Cd2+ stress compared with the wild type (WT) and the sensitive phenotype of Deltaslr0946 could be rescued by complementation assay via introducing slr0946 back into Deltaslr0946. Finally, individually overexpression of slr0946 as well as two Cd2+-related genes identified priviously (i.e., sll1598 and slr0798) in WT could significantly improve the tolerance of Synechocystis sp. PCC 6803 to Cd2+. This study provided a better understanding of the tolerance mechanism to Cd2+ in cyanobacteria and also feasible strategies for tolerance modifications to heavy metals in the future. PMID- 28861078 TI - Increased Innate Lymphoid Cells in Periodontal Tissue of the Murine Model of Periodontitis: The Role of AMP-Activated Protein Kinase and Relevance for the Human Condition. AB - Innate lymphoid cells (ILCs) are master regulators of immune and inflammatory responses, but their own regulatory mechanisms and functional roles of their subtypes (i.e., ILC1s-ILC3s) remain largely unresolved. Interestingly, AMP activated protein kinase (AMPK), influences inflammatory responses, but its role in modulation of ILCs is not known. Periodontitis is a prevalent disorder with impairment of immune and inflammatory responses contributing importantly to its pathogenesis; however, neither the role of ILCs nor AMPK has been explored in this condition. We tested the hypotheses that (a) periodontitis increases ILCs and expression of relevant cytokines thereby contributing to inflammation and (b) knockdown of AMPK worsens indices of periodontitis in association with further increases in subtypes of ILCs and cytokine expression. The studies utilized wild type (WT) and AMPK knockout (KO) mice, subjected to ligature-induced periodontitis or sham operation, in association with the use of micro-CT for assessment of bone loss, immunogold electron microscopy to show presence of ILCs in periodontal tissues, flow cytometry for quantitative assessment of subtypes of ILCs and RT-polymerase chain reaction analyses to measure mRNA expression of several relevant cytokines. The results for the first time show (a) presence of each subtype of ILCs in periodontal tissues of sham control and periodontitis animals, (b) that periodontitis is associated with increased frequencies of ILC1s ILC3s with the effect more marked for ILC2s and differential phenotypic marker expression for ILC3s, (c) that AMPK KO mice display exacerbation of indices of periodontitis in association with further increases in the frequency of subtypes of ILCs with persistence of ILC2s effect, and (d) that periodontitis increased mRNA for interleukin (IL)-33, but not IL-5 or IL-13, in WT mice but expression of these cytokines was markedly increased in AMPK KO mice with periodontitis. Subsequently, we showed that human periodontitis is associated with increases in each ILCs subtype with the effect more marked for ILC2s and that mRNA expressions for IL-33 and IL-5 are markedly greater for sites affected by periodontitis than healthy sites. Collectively, these novel observations indicate a pivotal role for ILCs in pathogenesis of periodontitis and that AMPK is a regulator of their phenotype expression in this condition. PMID- 28861079 TI - Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation. AB - Tocilizumab, a humanized anti-IL-6 receptor alpha (IL-6Ralpha) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other inflammatory diseases in close future. Dendritic cells (DCs) appear to be deeply involved in the immunopathology of these diseases, yet the effects of tocilizumab on these cells were poorly studied. In this study, we explored the effect of tocilizumab on the regulation of IL-6R subunits [gp130, soluble form of IL 6Ralpha (sIL-6Ralpha), and mIL-6Ralpha] in human monocyte-derived DCs. Human DCs were derived from CD14+ monocytes purified with beads with IL-4 and granulocyte macrophage colony-stimulating factor. Ex vivo cultures of DCs were performed in the presence of tocilizumab. Using lipopolysaccharide (LPS) maturation of DCs, we demonstrated that tocilizumab did not inhibit IL-6 secretion, enhanced mIL 6Ralpha expression, and largely increased sIL-6Ralpha secretion. MAPK modulated STAT3 phosphorylation and surface expression of IL-6Ralpha in LPS-DCs. Tocilizumab had no impact on STAT3 phosphorylation in LPS-DCs while both LPS and IL-6 increased its activation. Tocilizumab modulated the regulation of IL-6R subunits leading to an inflammatory status of DCs and a massive secretion of IL 6Ralpha. Our results demonstrate that DCs acquire a pro-inflammatory profile following tocilizumab treatment, becoming a major source of IL-6 trans-signaling activation that might explain the poor clinical benefit in some RA patients. PMID- 28861080 TI - Isolation of Single-Domain Antibody Fragments That Preferentially Detect Intact (146S) Particles of Foot-and-Mouth Disease Virus for Use in Vaccine Quality Control. AB - Intact (146S) foot-and-mouth disease virus (FMDVs) can dissociate into specific (12S) viral capsid degradation products. FMD vaccines normally consist of inactivated virions. Vaccine quality is dependent on 146S virus particles rather than 12S particles. We earlier isolated two llama single-domain antibody fragments (VHHs) that specifically recognize 146S particles of FMDV strain O1 Manisa and shown their potential use in quality control of FMD vaccines during manufacturing. These 146S-specific VHHs were specific for particular O serotype strains and did not bind strains from other FMDV serotypes. Here, we describe the isolation of 146S-specific VHHs against FMDV SAT2 and Asia 1 strains by phage display selection from llama immune libraries. VHHs that bind both 12S and 146S particles were readily isolated but VHHs that bind specifically to 146S particles could only be isolated by phage display selection using prior depletion for 12S particles. We obtained one 146S-specific VHH-M332F-that binds to strain Asia 1 Shamir and several VHHs that preferentially bind 146S particles of SAT2 strain SAU/2/00, from which we selected VHH M379F for further characterization. Both M332F and M379F did not bind FMDV strains from other serotypes. In a sandwich enzyme-linked immunosorbent assay (ELISA) employing unlabeled and biotinylated versions of the same VHH M332F showed high specificity for 146S particles but M379F showed lower 146S-specificity with some cross-reaction with 12S particles. These ELISAs could detect 146S particle concentrations as low as 2.3-4.6 ug/l. They can be used for FMD vaccine quality control and research and development, for example, to identify virion stabilizing excipients. PMID- 28861081 TI - 14 Years after Discovery: Clinical Follow-up on 15 Patients with Inducible Co Stimulator Deficiency. AB - BACKGROUND: Inducible co-stimulator (ICOS) deficiency was the first monogenic defect reported to cause common variable immunodeficiency (CVID)-like disease in 2003. Since then, 16 patients have been reported worldwide with an increasing range of clinical phenotypes. OBJECTIVE: We sought to compare the clinical and immunological phenotype and provide clinical follow-up and therapeutic approaches for treating ICOS-deficient patients. METHODS: We describe the clinical and laboratory data of 15 patients with available clinical data. Previous publications and clinical assessment were used as data sources. RESULTS: The observed ICOS gene mutations were all deletions leading to undetectable protein expression. The clinical phenotype of ICOS deficiency is much broader than initially anticipated and includes not only CVID-like disease but an increased susceptibility to viral and opportunistic infections, as well as cancer. Impaired B-cell development led to decreased memory B-cells in all patients, and hypogammaglobulinemia in all but one patient. Circulating CXCR5+ CD4+ follicular T-helper-cell numbers were also reduced in all patients. Treatment included immunoglobulin replacement, regular antibiotic prophylaxis, corticosteroids, and steroid-sparing agents. Three patients underwent hematopoietic stem cell transplantation; one of them died due to capillary leak syndrome on day 5 posttransplantation. CONCLUSION: The disease spectrum of ICOS deficiency is expanding from solely B-cell to combined B- and T-cell immunodeficiency, suggesting genetic and environmental modifiers. Genetic diagnosis is the only tool to distinguish ICOS deficiency from other immunological defects. Patients with antibody deficiency, autoimmunity, and combined immunodeficiency should be screened for ICOS mutations. PMID- 28861082 TI - Polyvinylpyrrolidone-Capped Silver Nanoparticle Inhibits Infection of Carbapenem Resistant Strain of Acinetobacter baumannii in the Human Pulmonary Epithelial Cell. AB - Acinetobacter baumannii, an opportunistic ESKAPE pathogen, causes respiratory and urinary tract infections. Its prevalence increases gradually in the clinical setup. Pathogenicity of Acinetobacter is significantly influenced by its ability to infect and survive in human pulmonary cells. Therefore, it is important to study the infection of A. baumannii in human pulmonary host cell (A-549), monitoring surface interacting and internalized bacteria. It was found that during infection of A. baumannii, about 40% bacteria adhered to A-549, whereas 20% got internalized inside pulmonary cell and induces threefold increase in the reactive oxygen species production. We have synthesized polyvinylpyrrolidone (PVP)-capped AgNPs using chemical methods and tested its efficacy against carbapenem-resistant strain of A. baumannii. PVP-capped silver nanoparticles (PVP AgNPs) (30 uM) have shown antibacterial activity against carbapenem-resistant strain of A. baumannii and this concentration does not have any cytotoxic effect on the human pulmonary cell line (IC50 is 130 uM). Similarly, PVP-AgNPs treatment decreases 80% viability of intracellular bacteria, decreases adherence of A. baumannii to A-549 (40 to 2.2%), and decreases intracellular concentration (20 to 1.3%) of A. baumannii. This concludes that PVP-AgNPs can be developed as a substitute for carbapenem to control the infection caused by carbapenem-resistant A. baumannii. PMID- 28861083 TI - d(-) Lactic Acid-Induced Adhesion of Bovine Neutrophils onto Endothelial Cells Is Dependent on Neutrophils Extracellular Traps Formation and CD11b Expression. AB - Bovine ruminal acidosis is of economic importance as it contributes to reduced milk and meat production. This phenomenon is mainly attributed to an overload of highly fermentable carbohydrate, resulting in increased d(-) lactic acid levels in serum and plasma. Ruminal acidosis correlates with elevated acute phase proteins in blood, along with neutrophil activation and infiltration into various tissues leading to laminitis and aseptic polysynovitis. Previous studies in bovine neutrophils indicated that d(-) lactic acid decreased expression of L selectin and increased expression of CD11b to concentrations higher than 6 mM, suggesting a potential role in neutrophil adhesion onto endothelia. The two aims of this study were to evaluate whether d(-) lactic acid influenced neutrophil and endothelial adhesion and to trigger neutrophil extracellular trap (NET) production (NETosis) in exposed neutrophils. Exposure of bovine neutrophils to 5 mM d(-) lactic acid elevated NET release compared to unstimulated neutrophil negative controls. Moreover, this NET contains CD11b and histone H4 citrullinated, the latter was dependent on PAD4 activation, a critical enzyme in DNA decondensation and NETosis. Furthermore, NET formation was dependent on d(-) lactic acid plasma membrane transport through monocarboxylate transporter 1 (MCT1). d(-) lactic acid enhanced neutrophil adhesion onto endothelial sheets as demonstrated by in vitro neutrophil adhesion assays under continuous physiological flow conditions, indicating that cell adhesion was a NET- and a CD11b/ICAM-1-dependent process. Finally, d(-) lactic acid was demonstrated for the first time to trigger NETosis in a PAD4- and MCT1-dependent manner. Thus, d( ) lactic acid-mediated neutrophil activation may contribute to neutrophil-derived pro-inflammatory processes, such as aseptic laminitis and/or polysynovitis in animals suffering acute ruminal acidosis. PMID- 28861084 TI - Autoantibody Repertoire in APECED Patients Targets Two Distinct Subgroups of Proteins. AB - High titer autoantibodies produced by B lymphocytes are clinically important features of many common autoimmune diseases. APECED patients with deficient autoimmune regulator (AIRE) gene collectively display a broad repertoire of high titer autoantibodies, including some which are pathognomonic for major autoimmune diseases. AIRE deficiency severely reduces thymic expression of gene-products ordinarily restricted to discrete peripheral tissues, and developing T cells reactive to those gene-products are not inactivated during their development. However, the extent of the autoantibody repertoire in APECED and its relation to thymic expression of self-antigens are unclear. We here undertook a broad protein array approach to assess autoantibody repertoire in APECED patients. Our results show that in addition to shared autoantigen reactivities, APECED patients display high inter-individual variation in their autoantigen profiles, which collectively are enriched in evolutionarily conserved, cytosolic and nuclear phosphoproteins. The APECED autoantigens have two major origins; proteins expressed in thymic medullary epithelial cells and proteins expressed in lymphoid cells. These findings support the hypothesis that specific protein properties strongly contribute to the etiology of B cell autoimmunity. PMID- 28861085 TI - Neurotrophin Receptor p75NTR Regulates Immune Function of Plasmacytoid Dendritic Cells. AB - Plasmacytoid dendritic cells (pDCs) regulate innate and adaptive immunity. Neurotrophins and their receptors control the function of neuronal tissue. In addition, they have been demonstrated to be part of the immune response but little is known about the effector immune cells involved. We report, for the first time, the expression and immune-regulatory function of the low affinity neurotrophin receptor p75 neurotrophin receptor (p75NTR) by the antigen presenting pDCs, mediated by toll-like receptor (TLR) 9 activation and differential phosphorylation of interferon regulatory factor 3 and 7. The modulation of p75NTR on pDCs significantly influences disease progression of asthma in an ovalbumin-induced mouse model mediated by the TLR9 signaling pathway. p75NTR activation of pDCs from patients with asthma increased allergen specific T cell proliferation and cytokine secretion in nerve growth factor concentration-dependent manner. Further, p75NTR activation of pDCs delayed the onset of autoimmune diabetes in RIP-CD80GP mice and aggravated graft-versus-host disease in a xenotransplantation model. Thus, p75NTR signaling on pDCs constitutes a new and critical mechanism connecting neurotrophin signaling and immune response regulation with great therapeutic potential for a variety of immune disorders. PMID- 28861087 TI - Alanine Mutagenesis in the Complementarity Determining Region 3 of the MTB and HIV-1 Peptide-Bispecific T Cell Receptor Beta Chain Affects Ligand Recognition. AB - Mycobacterium tuberculosis/human immunodeficiency virus (MTB/HIV) coinfection presents a special challenge to the prevention and treatment of tuberculosis and HIV/AIDS. Adoptive transfer of high-affinity T cell receptor (TCR) gene-modified T cells against MTB and HIV antigens is a promising approach to treating MTB/HIV coinfected patients whose cellular immunity is obviously disordered. We have previously successfully identified that a bispecific TCR screened out from peripheral blood mononuclear cells of a HLA-A*0201+ healthy individual using the complementarity determining region 3 (CDR3) spectratype analysis recognizes both MTB Ag85B199-207 and HIV-1 Env120-128 peptide. However, it has not been known how residues on CDR3 loops, which have been shown to play a leading role in antigen binding and specificity contribute to the bispecific TCR contact with the peptide major histocompatibility complex (MHC) complexes. In this study, we provided an extensive investigation of residues in the predicted CDR3 of the bispecific TCR beta (beta) chain using alanine scanning mutagenesis. Our data showed that three of the five substituted residues (G115A, T116A, A117G) in CDR3beta of the bispecific TCR caused a significantly diminished T cell response to antigen, whereas the remaining two substituted residues (D114A, S118A) resulted in completely eliminated response, thus identifying the two residues that were particularly critical for the recognition of peptide-MHC in the bispecific TCR. These findings will provide an imperative foundation for generating an improved high-affinity bispecific TCR for use in T cell adoptive immunotherapy for MTB/HIV coinfected individuals. PMID- 28861086 TI - Immunobiography and the Heterogeneity of Immune Responses in the Elderly: A Focus on Inflammaging and Trained Immunity. AB - Owing to its memory and plasticity, the immune system (IS) is capable of recording all the immunological experiences and stimuli it was exposed to. The combination of type, dose, intensity, and temporal sequence of antigenic stimuli that each individual is exposed to has been named "immunobiography." This immunological history induces a lifelong continuous adaptation of the IS, which is responsible for the capability to mount strong, weak or no response to specific antigens, thus determining the large heterogeneity of immunological responses. In the last years, it is becoming clear that memory is not solely a feature of adaptive immunity, as it has been observed that also innate immune cells are provided with a sort of memory, dubbed "trained immunity." In this review, we discuss the main characteristics of trained immunity as a possible contributor to inflammaging within the perspective of immunobiography, with particular attention to the phenotypic changes of the cell populations known to be involved in trained immunity. In conclusion, immunobiography emerges as a pervasive and comprehensive concept that could help in understanding and interpret the individual heterogeneity of immune responses (to infections and vaccinations) that becomes particularly evident at old age and could affect immunosenescence and inflammaging. PMID- 28861088 TI - The Unresolved Role of Interferon-lambda in Asthma Bronchiale. AB - Asthma bronchiale is a disease of the airways with increasing incidence, that often begins during infancy. So far, therapeutic options are mainly symptomatic and thus there is an increasing need for better treatment and/or prevention strategies. Human rhinoviruses (HRVs) are a major cause of asthma exacerbations and might cause acute wheezing associated with local production of pro inflammatory mediators resulting in neutrophilic inflammatory response. Viral infections induce a characteristic activation of immune response, e.g., TLR3, 4, 7, 8, 9 in the endosome and their downstream targets, especially MyD88. Moreover, other cytoplasmic pattern recognition molecules (PRMs) like RIG1 and MDA5 play important roles in the activation of interferons (IFNs) of all types. Depending on the stimulation of the different PRMs, the levels of the IFNs induced might differ. Recent studies focused on Type I IFNs in samples from control and asthma patients. However, the administration of type I IFN-alpha was accompanied by side effects, thus this possible therapy was abandoned. Type III IFN-lambda acts more specifically, as fewer cells express the IFN-lambda receptor chain 1. In addition, it has been shown that asthmatic mice treated with recombinant or adenoviral expressed IFN-lambda2 (IL-28A) showed an amelioration of symptoms, indicating that treatment with IFN-lambda might be beneficial for asthmatic patients. PMID- 28861089 TI - Black Raspberries Enhance Natural Killer Cell Infiltration into the Colon and Suppress the Progression of Colorectal Cancer. AB - Natural killer (NK) cells are an essential component of innate immunity against cancer development. Many studies have been conducted to evaluate immune modulating effects using dietary compounds. Our laboratory has been investigating the chemopreventive potential of black raspberries (BRBs) and previously demonstrated their beneficial modulation of genetic and epigenetic biomarkers in patients with colorectal cancer (CRC). The current study investigated their potential on modulating NK cells. To avoid the excessive inflammation caused by the dextran sulfate sodium (DSS) treatment that leads to colitis, we treated the mice with overnight DSS so that it would slightly irritate the colon but still promote colon carcinogenesis with 100% incidence in both the ApcMin/+ mice and azoxymethane (AOM)-treated mice. A significant decrease of tissue-infiltrating NK cells along the progression of microadenoma-to-adenoma and adenoma-to adenocarcinoma was observed in the ApcMin/+ /DSS and AOM/DSS mice, respectively. Depletion of NK cells significantly promoted the development of CRC, suggesting a critical role of NK cells in combating CRC progression. BRBs significantly suppressed the CRC progression and increased the number of tissue-infiltrating NK cells in both mouse models. Moreover, we further determined BRBs' effects on NK cells in the human biopsy specimens collected from our previously completed clinical trial, in which CRC patients consumed BRBs for an average of 4 weeks during a presurgical window. We observed an increased number and an enhanced cytotoxicity of NK cells by BRB intervention. The current study provides evidence that BRBs have the potential to enhance the tumor immunesurveillance of NK cells that can be beneficial in the setting of CRC prevention and treatment. PMID- 28861090 TI - Dynamics of Natural Killer Cells Cytotoxicity in Microwell Arrays with Connecting Channels. AB - Natural killer (NK) cells serve an important role in immune system by recognizing and killing the potentially malignant cells without antigen sensitization, and could be promising in cancer therapy. We have designed and fabricated microwell arrays with microchannel connections in polydimethylsiloxane (PDMS) substrates to study the interaction dynamics of NK-92MI cells with MCF7 breast cancer cells using time-lapse imaging by fluorescence microscopy for 15 h. Although cell seeding density was the same, NK cell cytotoxicity was found to be higher in larger microwells, which is manifested as increased target death ratio from 13.7 +/- 3.1 to 46.3 +/- 3.3% and shorter triggering time of first target lysis from 502 +/- 49 to 391 +/- 63 min in 150 MUm * 150 MUm microwells comparing to 50 MUm * 50 MUm wells in 15 h. Mirochannel connection between adjacent microwells of the same size increased the overall target death ratio by >10%, while connection between microwells of different sizes led to significantly increased target death ratio and delayed first target lysis in smaller microwells. Our findings reveal unique cell interaction dynamics, such as initiation and stimulation, of NK cell cytotoxicity in a confined microenvironment, which is different from population based study, and the results could lead to a better understanding of the dynamics of NK cell cytotoxicity. PMID- 28861091 TI - Insufficient Chilling Effects Vary among Boreal Tree Species and Chilling Duration. AB - Insufficient chilling resulting from rising winter temperatures associated with climate warming has been an area of particular interest in boreal and temperate regions where a period of cool temperatures in fall and winter is required to break plant dormancy. In this study, we examined the budburst and growth of trembling aspen (Populus tremuloides Michx.), balsam poplar (Populus balsamifera L.), white birch (Betula papyrifera Marsh.), black spruce (Picea mariana (Mill.) B.S.P.), white spruce (Picea glauca (Moench) Voss), jack pine (Pinus banksiana Lamb.), and lodgepole pine (Pinus contorta Dougl. ex. Loud.) seedlings subjected to typical northern Ontario, Canada, spring conditions in climate chambers after different exposures to natural chilling. Results indicate that chilling requirements (cumulative weighted chilling hours) differed substantially among the seven species, ranging from 300 to 500 h for spruce seedlings to more than 1100 h for trembling aspen and lodgepole pine. Only spruce seedlings had fulfilled their chilling requirements before December 31, whereas the other species continued chilling well into March and April. Species with lower chilling requirements needed more heat accumulation for budburst and vice versa. Insufficient chilling delayed budburst but only extremely restricted chilling hours (<400) resulted in abnormal budburst and growth, including reduced needle and shoot expansion, early budburst in lower crowns, and erratic budburst on lower stems and roots. Effects, however, depended on both the species' chilling requirements and the chilling-heat relationship. Among the seven tree species examined, trembling aspen is most likely to be affected by reduced chilling accumulation possible under future climate scenarios, followed by balsam poplar, white birch, lodgepole pine, and jack pine. Black and white spruce are least likely to be affected by changes in chilling hours. PMID- 28861092 TI - Testing the Hypothesis of Multiple Origins of Holoparasitism in Orobanchaceae: Phylogenetic Evidence from the Last Two Unplaced Holoparasitic Genera, Gleadovia and Phacellanthus. AB - Orobanchaceae is the largest family among the parasitic angiosperms. It comprises non-parasites, hemi- and holoparasites, making this family an ideal test case for studying the evolution of parasitism. Previous phylogenetic analyses showed that holoparasitism had arisen at least three times from the hemiparasitic taxa in Orobanchaceae. Until now, however, not all known genera of Orobanchaceae were investigated in detail. Among them, the unknown phylogenetic positions of the holoparasites Gleadovia and Phacellanthus are the key to testing how many times holoparasitism evolved. Here, we provide clear evidence for the first time that they are members of the tribe Orobancheae, using sequence data from multiple loci (nuclear genes ITS, PHYA, PHYB, and plastid genes rps2, matK). Gleadovia is an independent lineage whereas Phacellanthus should be merged into genus Orobanche section Orobanche. Our results unambiguously support the hypothesis that there are only three origins of holoparasitism in Orobanchaceae. Divergence dating reveals for the first time that the three origins of holoparasitism were not synchronous. Our findings suggest that holoparasitism can persist in specific clades for a long time and holoparasitism may evolve independently as an adaptation to certain hosts. PMID- 28861093 TI - The Phenylpropanoid Pathway and Lignin in Defense against Ganoderma boninense Colonized Root Tissues in Oil Palm (Elaeis guineensis Jacq.). AB - Basal stem rot, caused by the basidiomycete fungus, Ganoderma boninense, is an economically devastating disease in Malaysia. Our study investigated the changes in lignin content and composition along with activity and expression of the phenylpropanoid pathway enzymes and genes in oil palm root tissues during G. boninense infection. We sampled control (non-inoculated) and infected (inoculated) seedlings at seven time points [1, 2, 3, 4, 8, and 12 weeks post inoculation (wpi)] in a randomized design. The expression profiles of phenylalanine ammonia lyase (PAL), cinnamyl alcohol dehydrogenase (CAD), and peroxidase (POD) genes were monitored at 1, 2, and 3 wpi using real-time quantitative polymerase chain reaction. Seedlings at 4, 8, and 12 wpi were screened for lignin content, lignin composition, enzyme activities (PAL, CAD, and POD), growth (weight and height), and disease severity (DS). Gene expression analysis demonstrated up-regulation of PAL, CAD, and POD genes in the infected seedlings, relative to the control seedlings at 1, 2, and 3 wpi. At 2 and 3 wpi, CAD showed highest transcript levels compared to PAL and POD. DS increased progressively throughout sampling, with 5, 34, and 69% at 4, 8, and 12 wpi, respectively. Fresh weight and height of the infected seedlings were significantly lower compared to the control seedlings at 8 and 12 wpi. Lignin content of the infected seedlings at 4 wpi was significantly higher than the control seedlings, remained elicited with no change at 8 wpi, and then collapsed with a significant reduction at 12 wpi. The nitrobenzene oxidation products of oil palm root lignin yielded both syringyl and guaiacyl monomers. Accumulation of lignin in the infected seedlings was in parallel to increased syringyl monomers, at 4 and 8 wpi. The activities of PAL and CAD enzymes in the infected seedlings at DS = 5-34% were significantly higher than the control seedlings and thereafter collapsed at DS = 69%. PMID- 28861094 TI - On Being the Right Size as an Animal with Plastids. AB - Plastids typically reside in plant or algal cells-with one notable exception. There is one group of multicellular animals, sea slugs in the order Sacoglossa, members of which feed on siphonaceous algae. The slugs sequester the ingested plastids in the cytosol of cells in their digestive gland, giving the animals the color of leaves. In a few species of slugs, including members of the genus Elysia, the stolen plastids (kleptoplasts) can remain morphologically intact for weeks and months, surrounded by the animal cytosol, which is separated from the plastid stroma by only the inner and outer plastid membranes. The kleptoplasts of the Sacoglossa are the only case described so far in nature where plastids interface directly with the metazoan cytosol. That makes them interesting in their own right, but it has also led to the idea that it might someday be possible to engineer photosynthetic animals. Is that really possible? And if so, how big would the photosynthetic organs of such animals need to be? Here we provide two sets of calculations: one based on a best case scenario assuming that animals with kleptoplasts can be, on a per cm2 basis, as efficient at CO2 fixation as maize leaves, and one based on 14CO2 fixation rates measured in plastid-bearing sea slugs. We also tabulate an overview of the literature going back to 1970 reporting direct measurements or indirect estimates of the CO2 fixing capabilities of Sacoglossan slugs with plastids. PMID- 28861095 TI - Overexpression of CtCHS1 Increases Accumulation of Quinochalcone in Safflower. AB - Carthami flos, the dried petal of safflower (Carthamus tinctorius L.) has been widely used in traditional Chinese medicine to treat cardiovascular and cerebrovascular diseases, in which quinochalcone glucosides such as hydrosafflower yellow A (HSYA), carthamin are uniquely present and have been identified as active compounds. In the present study, through sequencing of a safflower floret cDNA library and subsequent microarray analysis, we found 23 unigenes (5 PALs, 1 C4Hs, 5 4CLs, 6 CHSs, 2 CHIs, 2 DFRs, 2 FLSs) involved in flavonoid pathway, of which 4 were up-regulated differentially during quinochalcone glucosides accumulation with the floret developing stage. The up regulated genes were verified by PCR methods. Considering chalcone synthase are entry enzyme in flavonoid biosynthesis, CHS1 was focused on target gene to verify its function furtherly. Bioinformation analysis showed that CHS1 shared 86.94% conserved residues with CHS from other plants. Subcellular localization showed that CtCHS1 was localized in cytoplasm in onion epidermal cells. The transgenic safflower plant with overexpression CtCHS1 by Agrobacterium-mediated pollen-tube pathway method was firstly generated. The results present that expression of PAL2, PAL3, CHS1, CHS4, CHS6 increased and expression of CHI1 and CHI2 decreased in the transgenic plant floret. Meanwhile, the accumulation of quinochalcone glucosides increased by ~20-30% and accumulation of quercetin-3-beta-D-glucoside and quercetin decreased by 48 and 63% in the transgenic plant floret. These results suggested that CtCHS1 played an important role in quinochalcone glucosides biosynthesis rather than flavonol biosynthesis. These results also demonstrated that the pollen-tube pathway method was an efficient method for gene transformation in safflower. Our study will provide a deep understanding of potential synthetic genes involved in quinochalcone biosynthetic pathway. PMID- 28861096 TI - Effects of Cultivar and Maternal Environment on Seed Quality in Vicia sativa. AB - Production of high quality seeds is of fundamental importance for successful crop production. However, knowledge of the effects of increased temperature resulting from global warming on seed quality of alpine species is limited. We investigated the effect of maternal environment on seed quality of three cultivars of the leguminous forage species Vicia sativa, giving particular attention to temperature. Plants of each cultivar were grown at 1700 and 3000 m a.s.l., and mass, germination, electrical conductivity (EC) of leakage and longevity were determined for mature seeds. Seeds of all three cultivars produced at the low elevation had a significantly lower mass and longevity but higher EC of leachate than those produced at the high elevation, suggesting that increased temperatures decreased seed quality. However, seed viability did not differ between elevations. The effects of maternal environment on seed germination strongly depended on cultivar and germination temperature. At 10 and 15 degrees C, seeds of "Lanjian 3" produced at high elevation germinated to higher percentages and rates than those produced at low elevation, but the opposite trend was observed at 20 degrees C. However, for seeds of "Lanjian 1" and "Lanjian 2," no significant effect of elevation was observed in germination percentage. Our results indicate that the best environment for the production of high quality seeds (e.g., high seed mass, low EC, high seed longevity) of V. sativa is one in which temperatures are relatively low during seed development. PMID- 28861097 TI - Editorial: Grassland-Invertebrate Interactions: Plant Productivity, Resilience and Community Dynamics. PMID- 28861098 TI - Development of an Efficient Protein Extraction Method Compatible with LC-MS/MS for Proteome Mapping in Two Australian Seagrasses Zostera muelleri and Posidonia australis. AB - The availability of the first complete genome sequence of the marine flowering plant Zostera marina (commonly known as seagrass) in early 2016, is expected to significantly raise the impact of seagrass proteomics. Seagrasses are marine ecosystem engineers that are currently declining worldwide at an alarming rate due to both natural and anthropogenic disturbances. Seagrasses (especially species of the genus Zostera) are compromised for proteomic studies primarily due to the lack of efficient protein extraction methods because of their recalcitrant cell wall which is rich in complex polysaccharides and a high abundance of secondary metabolites in their cells. In the present study, three protein extraction methods that are commonly used in plant proteomics i.e., phenol (P); trichloroacetic acid/acetone/SDS/phenol (TASP); and borax/polyvinyl polypyrrolidone/phenol (BPP) extraction, were evaluated quantitatively and qualitatively based on two dimensional isoelectric focusing (2D-IEF) maps and LC MS/MS analysis using the two most abundant Australian seagrass species, namely Zostera muelleri and Posidonia australis. All three tested methods produced high quality protein extracts with excellent 2D-IEF maps in P. australis. However, the BPP method produces better results in Z. muelleri compared to TASP and P. Therefore, we further modified the BPP method (M-BPP) by homogenizing the tissue in a modified protein extraction buffer containing both ionic and non-ionic detergents (0.5% SDS; 1.5% Triton X-100), 2% PVPP and protease inhibitors. Further, the extracted proteins were solubilized in 0.5% of zwitterionic detergent (C7BzO) instead of 4% CHAPS. This slight modification to the BPP method resulted in a higher protein yield, and good quality 2-DE maps with a higher number of protein spots in both the tested seagrasses. Further, the M-BPP method was successfully utilized in western-blot analysis of phosphoenolpyruvate carboxylase (PEPC-a key enzyme for carbon metabolism). This optimized protein extraction method will be a significant stride toward seagrass proteome mining and identifying the protein biomarkers to stress response of seagrasses under the scenario of global climate change and anthropogenic perturbations. PMID- 28861100 TI - Editorial: Aquaporins: Dynamic Role and Regulation. PMID- 28861101 TI - Functional Disruption of a Chloroplast Pseudouridine Synthase Desensitizes Arabidopsis Plants to Phosphate Starvation. AB - Phosphate (Pi) deficiency is a common nutritional stress of plants in both agricultural and natural ecosystems. Plants respond to Pi starvation in the environment by triggering a suite of biochemical, physiological, and developmental changes that increase survival and growth. The key factors that determine plant sensitivity to Pi starvation, however, are unclear. In this research, we identified an Arabidopsis mutant, dps1, with greatly reduced sensitivity to Pi starvation. The dps1 phenotypes are caused by a mutation in the previously characterized SVR1 (SUPPRESSION OF VARIAGATION 1) gene, which encodes a chloroplast-localized pseudouridine synthase. The mutation of SVR1 results in defects in chloroplast rRNA biogenesis, which subsequently reduces chloroplast translation. Another mutant, rps5, which contains a mutation in the chloroplast ribosomal protein RPS5 and has reduced chloroplast translation, also displayed decreased sensitivity to Pi starvation. Furthermore, wild type plants treated with lincomycin, a chemical inhibitor of chloroplast translation, showed similar growth phenotypes and Pi starvation responses as dps1 and rps5. These results suggest that impaired chloroplast translation desensitizes plants to Pi starvation. Combined with previously published results showing that enhanced leaf photosynthesis augments plant responses to Pi starvation, we propose that the decrease in responses to Pi starvation in dps1, rps5, and lincomycin-treated plants is due to their reduced demand for Pi input from the environment. PMID- 28861099 TI - New Biotechnological Tools for the Genetic Improvement of Major Woody Fruit Species. AB - The improvement of woody fruit species by traditional plant breeding techniques has several limitations mainly caused by their high degree of heterozygosity, the length of their juvenile phase and auto-incompatibility. The development of new biotechnological tools (NBTs), such as RNA interference (RNAi), trans-grafting, cisgenesis/intragenesis, and genome editing tools, like zinc-finger and CRISPR/Cas9, has introduced the possibility of more precise and faster genetic modifications of plants. This aspect is of particular importance for the introduction or modification of specific traits in woody fruit species while maintaining unchanged general characteristics of a selected cultivar. Moreover, some of these new tools give the possibility to obtain transgene-free modified fruit tree genomes, which should increase consumer's acceptance. Over the decades biotechnological tools have undergone rapid development and there is a continuous addition of new and valuable techniques for plant breeders. This makes it possible to create desirable woody fruit varieties in a fast and more efficient way to meet the demand for sustainable agricultural productivity. Although, NBTs have a common goal i.e., precise, fast, and efficient crop improvement, individually they are markedly different in approach and characteristics from each other. In this review we describe in detail their mechanisms and applications for the improvement of fruit trees and consider the relationship between these biotechnological tools and the EU biosafety regulations applied to the plants and products obtained through these techniques. PMID- 28861102 TI - Comparative Transcriptome Analyses of Gene Expression Changes Triggered by Rhizoctonia solani AG1 IA Infection in Resistant and Susceptible Rice Varieties. AB - Rice sheath blight, caused by Rhizoctonia solani, is one of the most devastating diseases for stable rice production in most rice-growing regions of the world. Currently, studies of the molecular mechanism of rice sheath blight resistance are scarce. Here, we used an RNA-seq approach to analyze the gene expression changes induced by the AG1 IA strain of R. solani in rice at 12, 24, 36, 48, and 72 h. By comparing the transcriptomes of TeQing (a moderately resistant cultivar) and Lemont (a susceptible cultivar) leaves, variable transcriptional responses under control and infection conditions were revealed. From these data, 4,802 differentially expressed genes (DEGs) were identified. Gene ontology and pathway enrichment analyses suggested that most DEGs and related metabolic pathways in both rice genotypes were common and spanned most biological activities after AG1 IA inoculation. The main difference between the resistant and susceptible plants was a difference in the timing of the response to AG1 IA infection. Photosynthesis, photorespiration, and jasmonic acid and phenylpropanoid metabolism play important roles in disease resistance, and the relative response of disease resistance-related pathways in TeQing leaves was more rapid than that of Lemont leaves at 12 h. Here, the transcription data include the most comprehensive list of genes and pathway candidates induced by AG1 IA that is available for rice and will serve as a resource for future studies into the molecular mechanisms of the responses of rice to AG1 IA. PMID- 28861103 TI - Integrated RNA Sequencing and QTL Mapping to Identify Candidate Genes from Oryza rufipogon Associated with Salt Tolerance at the Seedling Stage. AB - Soil salinity is a common abiotic stress affecting crop productivity. To identify favorable alleles from wild rice (Oryza rufipogon Griff.) that enhance salinity tolerance of rice (O. sativa L.), a set of introgression lines (ILs) were developed. The ILs were derived from an O. rufipogon accession collected from Chaling (Hunan Province, China) as the donor, and a widely grown O. sativa indica cultivar 93-11 as the recipient. Through evaluating the salt tolerance of 285 ILs at the seedling stage, a total of 10 quantitative trait loci (QTLs) related to salt tolerance were identified on chromosomes 1, 5, 7 and 9-12, with individual QTLs explaining 2-8% of phenotypic variance. The O. rufipogon-derived alleles at four QTLs improved salt tolerance in the 93-11 background. At the same time, a salt-tolerant IL, 9L136, was identified and characterized. Compared with the recipient parent 93-11, a total of 1,391 differentially expressed genes (DEGs) were detected specifically in 9L136 between salt stress and normal condition through genome-wide expression analysis. Of these, four DEGs located in the QTL regions carried by 9L136, suggesting that the four genes might be candidates associated with salt tolerance. Both the highly salt-tolerant ILs and the favorable O. rufipogon-derived QTLs identified in the present study will provide new genetic resources for improving the resistance of cultivated rice against salinity stress using molecular breeding strategies in the future. PMID- 28861104 TI - Identification of Genes under Positive Selection Reveals Differences in Evolutionary Adaptation between Brown-Algal Species. AB - Brown algae are an important taxonomic group in coastal ecosystems. The model brown algal species Ectocarpus siliculosus and Saccharina japonica are closely related lineages. Despite their close phylogenetic relationship, they vary greatly in morphology and physiology. To obtain further insights into the evolutionary forces driving divergence in brown algae, we analyzed 3,909 orthologs from both species to identify Genes Under Positive Selection (GUPS). About 12% of the orthologs in each species were considered to be under positive selection. Many GUPS are involved in membrane transport, regulation of homeostasis, and sexual reproduction in the small sporophyte of E. siliculosus, which is known to have a complex life cycle and to occupy a wide range of habitats. Genes involved in photosynthesis and cell division dominated the group of GUPS in the large kelp of S. japonica, which might explain why this alga has evolved the ability to grow very rapidly and to form some of the largest sporophytes. A significant number of molecular chaperones (e.g., heat-shock proteins) involved in stress responses were identified to be under positive selection in both species, potentially indicating their important roles for macroalgae to cope with the relatively variable environment of coastal ecosystems. Moreover, analysis of previously published microarray data of E. siliculosus showed that many GUPS in E. siliculosus were responsive to stress conditions, such as oxidative and hyposaline stress, whereas our RNA-seq data of S. japonica showed that GUPS in this species were most highly expressed in large sporophytes, which supports the suggestion that selection largely acts on different sets of genes in both marcoalgal species, potentially reflecting their adaptation to different ecological niches. PMID- 28861105 TI - Interplay between Light and Plant Hormones in the Control of Arabidopsis Seedling Chlorophyll Biosynthesis. AB - Chlorophyll biosynthesis is one of the most important cellular processes and is essential for plant photosynthesis. After germination under the soil, dark-grown seedlings are etiolated and accumulate the chlorophyll precursor protochlorophyllide (Pchlide) in cotyledons. Upon exposure to light, Pchlide is rapidly converted to chlorophyll to initiate photoautotrophic growth. In this light-regulated de-etiolation process, multiple endogenous phytohormones are also involved. Although the co-regulation of seedling greening by light and hormones has long been observed, recent studies greatly advanced our understanding of their interplay by identifying the key components connecting these pathways. The integrators, such as PHYTOCHROME-INTERACTING FACTORs, ELONGATED HYPOCOTYL 5, ETHYLENE INSENSTIVE 3 and DELLA proteins, are key transcription regulators in light or hormone signaling pathways. This review focuses on these integrators and illustrates the regulatory networks of light and hormone interactions in chlorophyll biosynthesis. PMID- 28861106 TI - Unraveling Salt Tolerance Mechanisms in Halophytes: A Comparative Study on Four Mediterranean Limonium Species with Different Geographic Distribution Patterns. AB - We have performed an extensive study on the responses to salt stress in four related Limonium halophytes with different geographic distribution patterns, during seed germination and early vegetative growth. The aims of the work were twofold: to establish the basis for the different chorology of these species, and to identify relevant mechanisms of salt tolerance dependent on the control of ion transport and osmolyte accumulation. Seeds were germinated in vitro, in the presence of increasing NaCl concentrations, and subjected to "recovery of germination" tests; germination percentages and velocity were determined to establish the relative tolerance and competitiveness of the four Limonium taxa. Salt treatments were also applied to young plants, by 1-month irrigation with NaCl up to 800 mM; then, growth parameters, levels of monovalent and divalent ions (in roots and leaves), and leaf contents of photosynthetic pigments and common osmolytes were determined in control and stressed plants of the four species. Seed germination is the most salt-sensitive developmental phase in Limonium. The different germination behavior of the investigated species appears to be responsible for their geographical range size: L. narbonense and L. virgatum, widespread throughout the Mediterranean, are the most tolerant and the most competitive at higher soil salinities; the endemic L. santapolense and L. girardianum are the most sensitive and more competitive only at lower salinities. During early vegetative growth, all taxa showed a strong tolerance to salt stress, although slightly higher in L. virgatum and L. santapolense. Salt tolerance is based on the efficient transport of Na+ and Cl- to the leaves and on the accumulation of fructose and proline for osmotic adjustment. Despite some species-specific quantitative differences, the accumulation patterns of the different ions were similar in all species, not explaining differences in tolerance, except for the apparent activation of K+ transport to the leaves at high external salinity, observed only in the most tolerant L. narbonense and L. virgatum. This specific response may be therefore relevant for salt tolerance in Limonium. The ecological implications of these results, which can contribute to a more efficient management of salt marshes conservation/regeneration programs, are also discussed. PMID- 28861107 TI - PIWI-like protein, HIWI2 is aberrantly expressed in retinoblastoma cells and affects cell-cycle potentially through OTX2. AB - Retinoblastoma (RB), a childhood cancer, is caused by biallelic mutation of the RB1 gene, but its development is not clearly understood. Furthermore, the presence of a cancer stem cell subpopulation in RB might impact its treatment. PIWI protein, known for its role in stem cell self-renewal, is aberrantly expressed in cancers. We examined the role of the PIWI-like protein HIWI2 in RB and its effect on the stem cell markers in cells of the RB line, Y79. The expression of HIWI2 is significantly increased in Y79 compared with its level in HeLa and ARPE19 cells. The stem cell markers Oct-3/4, Nanog and Sox-2 were not altered upon HIWI2 knockdown in Y79 cells. Interestingly, OTX2 was significantly downregulated in the absence of HIWI2. Otx2 transcripts also decreased in HIWI2 silenced Y79 and ARPE19 cells. Moreover, silencing HIWI2 in Y79 accumulated the cells at G2-M phase and reduced the levels of proliferating cell nuclear antigen (PCNA) and the tumor suppressor, p16. Our results demonstrate that HIWI2 is aberrantly expressed in Y79 cells and silencing of HIWI2 downregulates OTX2, suggesting that HIWI2 might play a role in the progression of RB. PMID- 28861109 TI - Serum free IgE guided dose reduction of omalizumab: a case report. AB - BACKGROUND: Omalizumab is a human IgG1 antibody against IgE used as a therapy for sever asthmatic patients with asthma. According to the guidelines of the Global Initiative for Asthma, omalizumab is an add-on drug at treatment step 5 that is used for severe asthma patients who are allergic to perennial allergens. The effects of omalizumab for severe asthma therapy have been validated in multiple clinical studies. However, the long-term effects of omalizumab on IgE production and possibility of resetting of administration dose of omalizumab remain unknown. CASE PRESENTATION: The serum total and free IgE levels were measured over time in a 63-year-old female patient with allergic asthma who was administered 375 mg omalizumab biweekly for 36 months. Her symptoms did not worsen and clinical course remained favorable after reducing the dose to 375 mg per month. The serum free IgE levels temporarily increased following a dose reduction of omalizumab. The serum free IgE trough level temporarily increased at 4 weeks after capable to reduce the dosage; however, thereafter, the serum free IgE level decreased to desired levels (below 30 ng/mL). CONCLUSIONS: The present case shows the possibility of reducing the dose following the long-term use of omalizumab. Considering the high medical cost of omalizumab, the dose reduction may be a viable option. It may be useful to measure the serum free IgE level to appropriately identify patients in whom the dose can be reduced, and to carefully monitor the clinical course. PMID- 28861108 TI - Gene functioning and storage within a folded genome. AB - In mammals, genomic DNA that is roughly 2 m long is folded to fit the size of the cell nucleus that has a diameter of about 10 MUm. The folding of genomic DNA is mediated via assembly of DNA-protein complex, chromatin. In addition to the reduction of genomic DNA linear dimensions, the assembly of chromatin allows to discriminate and to mark active (transcribed) and repressed (non-transcribed) genes. Consequently, epigenetic regulation of gene expression occurs at the level of DNA packaging in chromatin. Taking into account the increasing attention of scientific community toward epigenetic systems of gene regulation, it is very important to understand how DNA folding in chromatin is related to gene activity. For many years the hierarchical model of DNA folding was the most popular. It was assumed that nucleosome fiber (10-nm fiber) is folded into 30-nm fiber and further on into chromatin loops attached to a nuclear/chromosome scaffold. Recent studies have demonstrated that there is much less regularity in chromatin folding within the cell nucleus. The very existence of 30-nm chromatin fibers in living cells was questioned. On the other hand, it was found that chromosomes are partitioned into self-interacting spatial domains that restrict the area of enhancers action. Thus, TADs can be considered as structural-functional domains of the chromosomes. Here we discuss the modern view of DNA packaging within the cell nucleus in relation to the regulation of gene expression. Special attention is paid to the possible mechanisms of the chromatin fiber self-assembly into TADs. We discuss the model postulating that partitioning of the chromosome into TADs is determined by the distribution of active and inactive chromatin segments along the chromosome. This article was specially invited by the editors and represents work by leading researchers. PMID- 28861110 TI - Chorioamnionitis: Is a major player in the development of bronchopulmonary dysplasia? AB - Chorioamnionitis is an inflammation in the fetal membranes or placenta. When chorioamnionitis develops, fetal lungs are exposed to inflammatory cytokines and mediators via amniotic fluid. Because inflammation plays a pivotal role in the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, fetal lung inflammation induced by chorioamnionitis has been considered to be one of the major pathogenetic factors for BPD. Although there have been a number of studies that demonstrated the relationship between chorioamnionitis and BPD, there are still controversies on this issue. The controversies on the relationship between chorioamnionitis and BPD arise from not unified definitions of chorioamnionitis and BPD, different study populations, and the proportion of contribution between inflammation and infectious microorganisms. The publication bias also contributes to the controversies. Clinical trials targeting chorioamnionitis or microorganisms that cause chorioamnionitis will answer on the actual relationship between chorioamnionitis and BPD and provide a novel prophylactic strategy against BPD based on that relationship. PMID- 28861111 TI - Association of Toll-like receptor 2-positive monocytes with coronary artery lesions and treatment nonresponse in Kawasaki disease. AB - PURPOSE: Activation of Toll-like receptor 2 (TLR2) present on circulating monocytes in patients with Kawasaki disease (KD) can lead to the production of proinflammatory cytokines and interleukin-10 (IL-10). We aimed to determine the association of the frequency of circulating TLR2+/CD14+ monocytes (FTLR2%) with the outcomes of KD, as well as to compare FTLR2% to the usefulness of sIL-10. METHODS: The FTLR2% in patients with KD was measured by flow cytometry. Serum levels of IL-10 (sIL-10) were determined in 31 patients with KD before the initial treatment with intravenous immunoglobulin (IVIG) and in 21 febrile controls by using enzyme-linked immunosorbent assay. Patients were classified as having coronary artery lesions (CALs) based on the maximal internal diameters of the proximal right coronary artery and proximal left anterior descending coronary artery one month after the initial diagnosis. RESULTS: We found that FTLR2% greater than 92.62% predicted CALs with 80% sensitivity and 68.4% specificity, whereas FTLR2% more than 94.61% predicted IVIG resistance with 66.7% sensitivity and 71.4% specificity. Moreover, sIL-10 more than 15.52 pg/mL predicted CALs and IVIG resistance with 40% and 66.7% sensitivity, respectively, and 73.7% and 76.2% specificity, respectively. CONCLUSION: We showed that measuring FTLR2% before the initial treatment could be useful in predicting CAL development with better sensitivity than sIL-10 and with results comparable to sIL-10 results for the prediction of IVIG resistance in patients with KD. However, further studies are necessary to validate FTLR2% as a marker of prognosis and severity of KD. PMID- 28861112 TI - Relationship between vitamin D levels and intravenous immunoglobulin resistance in Kawasaki disease. AB - PURPOSE: Vitamin D is associated with various pathological conditions such as cardiovascular diseases and cancer. We investigated the relationship between vitamin D and Kawasaki disease (KD). METHODS: We performed a retrospective review of the medical records of patients with KD between February 2013 and March 2016 in Daegu Fatima Hospital. Study participants were grouped according to vitamin D serum concentration. Group 1 included patients with 25(OH)-vitamin D >=20 ng/mL. Group 2 included patients with 25(OH)-vitamin D <20 ng/mL. We analyzed the clinical characteristics and laboratory data of the 2 groups. RESULTS: Of the 91 patients, 52 were included in group 1, and 39 in group 2. Group 1 patients had significantly higher levels of calcium, phosphate, albumin and sodium than group 2 patients did. There were no differences in clinical characteristics, but the proportion of patients with polymorphic rash was significantly higher in group 2. Resistance to intravenous immunoglobulin was more frequent in group 2 (P=0.023). No significant difference in the incidence of coronary artery complications was observed. CONCLUSION: Low vitamin D levels are associated with resistance to intravenous immunoglobulin therapy in KD. Vitamin D deficiency might be a risk factor for immunoglobulin resistance in KD. PMID- 28861113 TI - Uropathogenic Escherichia coli ST131 in urinary tract infections in children. AB - PURPOSE: Escherichia coli sequence type (ST) 131, a multidrug-resistant clone causing extraintestinal infections, has rapidly become prevalent worldwide. However, the epidemiological and clinical features of pediatric infections are poorly understood. We aimed to explore the characteristics of ST131 Escherichia coli isolated from Korean children with urinary tract infections. METHODS: We examined 114 uropathogenic E. coli (UPEC) isolates from children hospitalized at Chung-Ang University Hospital between 2011 and 2014. Bacterial strains were classified into STs by partial sequencing of seven housekeeping genes (adk, fumC, gyrB, icd, mdh, purA, and recA). Clinical characteristics and antimicrobial susceptibility were compared between ST131 and non-ST131 UPEC isolates. RESULTS: Sixteen UPEC isolates (14.0%) were extended-spectrum beta-lactamase (ESBL) producers; 50.0% of ESBL-producers were ST131 isolates. Of all the isolates tested, 13.2% (15 of 114) were classified as ST131. There were no statistically significant associations between ST131 and age, sex, or clinical characteristics, including fever, white blood cell counts in urine and serum, C-reactive protein, radiologic abnormalities, and clinical outcome. However, ST131 isolates showed significantly lower rates of susceptibility to cefazolin (26.7%), cefotaxime (40.0%), cefepime (40.0%), and ciprofloxacin (53.3%) than non-ST131 isolates (65.7%, 91.9%, 92.9%, and 87.9%, respectively; P<0.001 for all). ESBL was more frequently produced in ST131 (53.3%) than in non-ST131 (8.1%) isolates (P<0.01). CONCLUSION: ST131 E. coli isolates were prevalent uropathogens in children at a single medical center in Korea between 2011 and 2014. Although ST131 isolates showed higher rates of antimicrobial resistance, clinical presentation and outcomes of patients were similar to those of patients infected with non-ST131 isolates. PMID- 28861114 TI - Effects of low-dose topiramate on language function in children with migraine. AB - PURPOSE: This study aimed to verify the safety of low-dose topiramate on language development in pediatric patients with migraine. METHODS: Thirty newly diagnosed pediatric patients with migraine who needed topiramate were enrolled and assessed twice with standard language tests, including the Test of Language Problem Solving Abilities (TOPs), Receptive and Expressive Vocabulary Test, Urimal Test of Articulation and Phonology, and computerized speech laboratory analysis. Data were collected before treatment, and topiramate as monotherapy was sustained for at least 3 months. The mean follow-up period was 4.3+/-2.7 months. The mean topiramate dosage was 0.9 mg/kg/day. RESULTS: The patient's mean age was 144.1+/ 42.3 months (male-to-female ratio, 9:21). The values of all the language parameters of the TOPs were not changed significantly after the topiramate treatment as follows: Determine cause, from 15.0+/-4.4 to 15.4+/-4.8 (P>0.05); making inference, from 17.6+/-5.6 to 17.5+/-6.6 (P>0.05); predicting, from 11.5+/ 4.5 to 12.3+/-4.0 (P>0.05); and total TOPs score, from 44.1+/- 13.4 to 45.3+/ 13.6 (P>0.05). The total mean length of utterance in words during the test decreased from 44.1+/-13.4 to 45.3+/-13.6 (P<0.05). The Receptive and Expressive Vocabulary Test results decreased from 97.7+/-22.1 to 96.3+/-19.9 months, and from 81.8+/-23.4 to 82.3+/-25.4 months, respectively (P>0.05). In the articulation and phonology validation in both groups, speech pitch and energy were not significant, and all the vowel test results showed no other significant values. CONCLUSION: No significant difference was found in the language-speaking ability between the patients; however, the number of vocabularies used decreased. Therefore, topiramate should be used cautiously for children with migraine. PMID- 28861115 TI - A pediatric case of relapsed pulmonary alveolar proteinosis despite successful whole lung lavage. AB - Pulmonary alveolar proteinosis (PAP) is a rare disease in children characterized by intra-alveolar accumulation of surfactant proteins, which severely reduces gaseous exchange. Whole lung lavage (WLL) is the preferred technique for the treatment of severe PAP. Herein, we present a pediatric case of PAP treated with WLL. An 11-year-old boy was admitted with the chief complaint of a dry cough lasting 6 months. He developed symptoms of dyspnea on exertion and had difficulty in climbing stairs. He was ultimately diagnosed with PAP through video-assisted thoracoscopic lung biopsy. As first-line of treatment for PAP, he underwent therapeutic WLL for each of his lungs on separate days. After a brief recovery, his symptoms gradually worsened; therefore, he underwent a second WLL. This is the first pediatric case of PAP relapse despite successful WLL in Korea. PMID- 28861116 TI - Enabling a genetically informed approach to cancer medicine: evaluation of the impact of comprehensive tumor sequencing. AB - "The role of next-generation sequencing to determine appropriateness of anti PD1/PD-L1 therapy needs further investigation, but has shown promise in predicting response and survival in melanoma and urothelial carcinoma." PMID- 28861117 TI - Quantification of seed-soil contact of sugar beet (Beta vulgaris) using X-ray Computed Tomography. AB - BACKGROUND: Seed-soil contact is important to ensure successful germination, however, there is a paucity of reported studies that have quantified the microstructure at and around this critical interface, mainly due to the opacity of soil. RESULTS: Here we describe a novel methodology to non-destructively calculate the seed-soil contact area using X-ray Computed Tomography. Under controlled conditions, we observed that seed-soil contact was strongly influenced by the size and type of seed, with a seed-soil contact of ca. 15% for naked sugar beet seeds compared to ca. 32% for pelleted and coated seeds. Similar results were obtained for seeds sampled from the field albeit with a higher spatial variability. CONCLUSIONS: By application of this new quantification method it is hoped seed enhancement technologies can be optimised and ultimately seedbed preparation improved to ensure better germination. PMID- 28861118 TI - Biologically feasible gene trees, reconciliation maps and informative triples. AB - BACKGROUND: The history of gene families-which are equivalent to event-labeled gene trees-can be reconstructed from empirically estimated evolutionary event relations containing pairs of orthologous, paralogous or xenologous genes. The question then arises as whether inferred event-labeled gene trees are biologically feasible, that is, if there is a possible true history that would explain a given gene tree. In practice, this problem is boiled down to finding a reconciliation map-also known as DTL-scenario-between the event-labeled gene trees and a (possibly unknown) species tree. RESULTS: In this contribution, we first characterize whether there is a valid reconciliation map for binary event labeled gene trees T that contain speciation, duplication and horizontal gene transfer events and some unknown species tree S in terms of "informative" triples that are displayed in T and provide information of the topology of S. These informative triples are used to infer the unknown species tree S for T. We obtain a similar result for non-binary gene trees. To this end, however, the reconciliation map needs to be further restricted. We provide a polynomial-time algorithm to decide whether there is a species tree for a given event-labeled gene tree, and in the positive case, to construct the species tree and the respective (restricted) reconciliation map. However, informative triples as well as DTL-scenarios have their limitations when they are used to explain the biological feasibility of gene trees. While reconciliation maps imply biological feasibility, we show that the converse is not true in general. Moreover, we show that informative triples neither provide enough information to characterize "relaxed" DTL-scenarios nor non-restricted reconciliation maps for non-binary biologically feasible gene trees. PMID- 28861120 TI - Edaravone: a baby in the bathwater? PMID- 28861119 TI - Evaluation of a multimodal pain therapy concept for chronic pain after total knee arthroplasty: a pilot study in 21 patients. AB - BACKGROUND: In spite of the improvement of many aspects around Total knee arthroplasty (TKA), there is still a group of 10% to 34% of patients who is not satisfied with the outcome. The therapy of chronic pain after TKA remains a medical challenge that requires an interdisciplinary therapy concept. The aim of this prospective pilot study was to evaluate the efficacy of a multimodal pain therapy in chronic complaints after TKA. METHODS: In a prospective cohort pilot study, we included patients with chronic pain after TKA who obtained in-patient care, especially multimodal pain therapy (MMPT), for at least 10 days. Essential elements of this therapy concept were physiotherapy, pain medication therapy, topical application of ketamine, local infiltration and Traditional Chinese Medicine. Patients with varying causes of complaints were excluded in advance. Before the start of the study all test persons were informed and gave their written consent. Moreover, each patient was examined and questioned at hospital admission, discharge and at its first as well as second follow-up. Additionally, knee joint mobility and stability were investigated at all examination times. RESULTS: From 03/07/2016 to 07/14/2016, 21 patients were included in the pilot study. 52% of the considered population were female (11 persons). The median age was 65 years (45-79 years) and the median stay in hospital amounted 9 days (8-14 days). The first follow-up was scheduled after six weeks (median: 38 days, 30-112 days) and the second one after six months (median: 8 months, 7-12 months). The number of patients of the first follow-up was 17 out of 21 (19% drop out). The drop out of the last follow-up accounted for 33%. All patients benefit from the presented applications and therapies with regard to pain, function and range of motion. Especially, during the period of in-patient treatment, nearly all patients have improved in all terms. However, during the first follow-up clear deteriorations occurred in all areas, which stagnated up to the second follow-up. The range of motion has even worsened slightly. CONCLUSIONS: With the presented pilot study on multimodal in-patient therapy of chronic complaints due to TKA, the improvement of pain, function and mobility could be verified, especially during the stationary stay. Even though the results deteriorate during the follow up period, they did never relapse to their initial level. In order to ensure an effective treatment, a clear diagnostic algorithm is essential, by which treatable causes, such as low-grade infections or loosenings, are safely excluded. Further prospective studies are necessary to obtain precise statements on prospects of success of our therapy plan. PMID- 28861121 TI - Tacrolimus in the treatment of myasthenia gravis in patients with an inadequate response to glucocorticoid therapy: randomized, double-blind, placebo-controlled study conducted in China. AB - BACKGROUND: To determine the efficacy of low-dose, immediate-release tacrolimus in patients with myasthenia gravis (MG) with inadequate response to glucocorticoid therapy in a randomized, double-blind, placebo-controlled study. METHODS: Eligible patients had inadequate response to glucocorticoids (GCs) after ?6 weeks of treatment with prednisone ?0.75 mg/kg/day or 60-100 mg/day. Patients were randomized to receive 3 mg tacrolimus or placebo daily (orally) for 24 weeks. Concomitant glucocorticoids and pyridostigmine were allowed. Patients continued GC therapy from weeks 1-4; from week 5, the dose was decreased at the discretion of the investigator. The primary efficacy outcome measure was a reduction, relative to baseline, in quantitative myasthenia gravis (QMG) score assessed using a generalized linear model; supportive analyses used alternative models. RESULTS: Of 138 patients screened, 83 [tacrolimus (n = 45); placebo (n = 38)] were enrolled and treated. The change in adjusted mean QMG score from baseline to week 24 was -4.9 for tacrolimus and -3.3 for placebo (least squares mean difference: -1.7, 95% confidence interval: -3.5, -0.1; p = 0.067). A post hoc analysis demonstrated a statistically significant difference for QMG score reduction of ?4 points in the tacrolimus group (68.2%) versus the placebo group (44.7%; p = 0.044). Adverse event profiles were similar between treatment groups. CONCLUSIONS: Tacrolimus 3 mg treatment for patients with MG and inadequate response to GCs did not demonstrate a statistically significant improvement in the primary endpoint versus placebo over 24 weeks; however, a post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ?4 points in the tacrolimus group versus the placebo group. This study was limited by the low number of patients, the absence of testing for acetylcholine receptor antibody and the absence of stratification by disease duration (which led to a disparity between the two groups). ClinicalTrials.gov identifier: NCT01325571. PMID- 28861122 TI - The role of natalizumab in the treatment of multiple sclerosis: benefits and risks. AB - Natalizumab, a monoclonal antibody that blocks lymphocyte infiltration in the central nervous system, is a valuable tool in the treatment of relapsing forms of multiple sclerosis (MS). In a phase III clinical trial comparing natalizumab with placebo over 2 years, natalizumab reduced annualized relapse rate by 68%, 12-week confirmed disability progression by 42%, and reduced contrast-enhancing lesions by 92%. In post hoc analyses, natalizumab treatment was associated with 37% of patients achieving no evidence of disease activity (versus 7% on placebo) and 30% achieving sustained disability improvement (versus 19% on placebo). Natalizumab did not achieve a statistically significant primary composite disability outcome in a trial of 887 patients with secondary progressive MS, but it did demonstrate a benefit on a prespecified component of the 9-Hole Peg Test. The greatest risk of natalizumab treatment is progressive multifocal leukoencephalopathy (PML), with a 23% mortality rate. Risk stratification on the basis of immunosuppressant exposure, natalizumab treatment duration and anti-John Cunningham virus (JCV) antibody status and index has greatly improved clinical decision making. Other potential serious natalizumab-associated risks reported in clinical trials and postmarketing settings include infusion reactions, hepatotoxicity and rare, serious opportunistic infections. With more than a decade of continuous postmarketing experience, natalizumab remains a very effective option for patients with relapsing forms of MS. To optimize appropriate selection of natalizumab for patients with relapsing MS, however, a thorough understanding of individual patient risk factors for PML or other adverse events is also required. PMID- 28861123 TI - An explorative qualitative study to determine the footwear needs of workers in standing environments. AB - BACKGROUND: Many work places require standing for prolonged periods of time and are potentially damaging to health, with links to musculoskeletal disorders and acute trauma from workplace accidents. Footwear provides the only interaction between the body and the ground and therefore a potential means to impact musculoskeletal disorders. However, there is very limited research into the necessary design and development of footwear based on both the physical environmental constraints and the personal preference of the workers. Therefore, the purpose of this study was to explore workers needs for footwear in the 'standing' workplace in relation to MSD, symptoms, comfort and design. METHOD: Semi-structured interviews were conducted with participants from demanding work environments that require standing for high proportions of the working day. Thematic analysis was used to analyse the results and gain an exploratory understanding into the footwear needs of these workers. RESULTS: Interviews revealed the environmental demands and a very high percentage of musculoskeletal disorders, including day to day discomfort and chronic problems. It was identified that when designing work footwear for standing environments, the functionality of the shoe for the environment must be addressed, the sensations and symptoms of the workers taken into account to encourage adherence and the decision influencers should be met to encourage initial footwear choice. Meeting all these criteria could encourage the use of footwear with the correct safety features and comfort. Development of the correct footwear and increased education regarding foot health and footwear choice could help to reduce or improve the effect of the high number of musculoskeletal disorders repeatedly recorded in jobs that require prolonged periods of standing. CONCLUSION: This study provides a unique insight into the footwear needs of some workers in environments that require prolonged standing. This user based enquiry has provided information which is important to workplace footwear design. PMID- 28861124 TI - Forest disturbances under climate change. AB - Forest disturbances are sensitive to climate. However, our understanding of disturbance dynamics in response to climatic changes remains incomplete, particularly regarding large-scale patterns, interaction effects and dampening feedbacks. Here we provide a global synthesis of climate change effects on important abiotic (fire, drought, wind, snow and ice) and biotic (insects and pathogens) disturbance agents. Warmer and drier conditions particularly facilitate fire, drought and insect disturbances, while warmer and wetter conditions increase disturbances from wind and pathogens. Widespread interactions between agents are likely to amplify disturbances, while indirect climate effects such as vegetation changes can dampen long-term disturbance sensitivities to climate. Future changes in disturbance are likely to be most pronounced in coniferous forests and the boreal biome. We conclude that both ecosystems and society should be prepared for an increasingly disturbed future of forests. PMID- 28861125 TI - ABC classification of posterior shoulder instability. AB - Posterior glenohumeral instability (PGHI) is a commonly under- and misdiagnosed pathology owing to its variety of clinical presentations. In order to facilitate diagnosis and treatment, the simple yet comprehensive ABC classification for PGHI is based on the underlying pathomechanical principles and current standard of treatment. Three main groups of PGHI are distinguished based on the type of instability: A (first time), B (dynamic), C (static). Two subtypes further differentiate these groups in terms of their specific pathomechanism and provide a guideline in the choice of appropriate treatment: A (1, subluxation; 2, dislocation), B (1, functional; 2, structural), C (1, constitutional; 2, acquired). While conservative treatment is warranted in most patients with type 1 PGHI (A1, B1, C1), surgical treatment should be considered on an individual basis in patients with type 2 PGHI (A2, B2, C2), while keeping in mind that the different groups and subtypes can overlap, co-exist, or even progress from one to another over time. Of course the necessity for surgical treatment depends on the extent of the structural defects, on the severity of symptoms, on the chronicity, as well as on patient-specific functional demand, age, and health status. Nonetheless, the ABC classification helps to correctly diagnose the type of PGHI and provides a guideline for the generally recommended type of treatment. PMID- 28861126 TI - Soft tissue-based surgical techniques for treatment of posterior shoulder instability. AB - Posterior shoulder instability is a rare clinical condition that encompasses different degrees of severity including various possible pathologies involving the labrum, capsule, bony lesions, and even locked posterior dislocation. When focusing on soft tissue involvement, the diagnosis of posterior instability may be difficult to make because frequently patients report vague symptoms not associated with a clear history of traumatic shoulder dislocation. Pathological soft tissue conditions associated with posterior instability in most cases are related to posterior labral tear and/or posterior capsular detensioning/tear. The diagnosis can be facilitated by physical examination using specific clinical tests (i. e., jerk test, Kim test, and reinterpreted O'Brien test) together with appropriate imaging studies (i. e., magnetic resonance arthrography). Arthroscopy may help in a complete evaluation of the joint and allows for the treatment of soft tissue lesions in posterior instability. Caution is warranted in the case of concomitant posterior glenoid chondral defect as a potential cause of poor outcome after soft tissue repair in posterior instability. PMID- 28861127 TI - Multi-parameter comparison of a standardized mixed meal tolerance test in healthy and type 2 diabetic subjects: the PhenFlex challenge. AB - BACKGROUND: A key feature of metabolic health is the ability to adapt upon dietary perturbations. Recently, it was shown that metabolic challenge tests in combination with the new generation biomarkers allow the simultaneous quantification of major metabolic health processes. Currently, applied challenge tests are largely non-standardized. A systematic review defined an optimal nutritional challenge test, the "PhenFlex test" (PFT). This study aimed to prove that PFT modulates all relevant processes governing metabolic health thereby allowing to distinguish subjects with different metabolic health status. Therefore, 20 healthy and 20 type 2 diabetic (T2D) male subjects were challenged both by PFT and oral glucose tolerance test (OGTT). During the 8-h response time course, 132 parameters were quantified that report on 26 metabolic processes distributed over 7 organs (gut, liver, adipose, pancreas, vasculature, muscle, kidney) and systemic stress. RESULTS: In healthy subjects, 110 of the 132 parameters showed a time course response. Patients with T2D showed 18 parameters to be significantly different after overnight fasting compared to healthy subjects, while 58 parameters were different in the post-challenge time course after the PFT. This demonstrates the added value of PFT in distinguishing subjects with different health status. The OGTT and PFT response was highly comparable for glucose metabolism as identical amounts of glucose were present in both challenge tests. Yet the PFT reports on additional processes, including vasculature, systemic stress, and metabolic flexibility. CONCLUSION: The PFT enables the quantification of all relevant metabolic processes involved in maintaining or regaining homeostasis of metabolic health. Studying both healthy subjects and subjects with impaired metabolic health showed that the PFT revealed new processes laying underneath health. This study provides the first evidence towards adopting the PFT as gold standard in nutrition research. PMID- 28861128 TI - Pyrosequencing quantified methylation level of miR-124 predicts shorter survival for patients with myelodysplastic syndrome. AB - BACKGROUND: Aberrant CpG island methylation has been increasingly recognized as a common event in myelodysplastic syndrome (MDS). To date, most of the previous studies of miR-124 in MDS have focused on epigenetic changes and little is known about the underlying mechanism through which miR-124 regulates CDK6 expression. RESULTS: In the present study, we employed pyrosequencing analysis to quantify the methylation levels of upstream regions of the miR-124 genes (miR-124-1, miR 124-2 and miR-124-3) in 56 primary MDS patients. We found the three miR-124 genes were methylated in MDS patients. Univariate analysis revealed that the World Health Organization (WHO) classification, marrow blast count, karyotype, International Prognostic Scoring System (IPSS), mean corpuscular volume, as well as high methylation of miR-124-1, miR-124-2 and miR-124-3 were significantly related to overall survival. In leukaemia-free survival, patients who were older and had an advanced WHO classification, high marrow blast counts, high IPSS risk and high methylation of miR-124-1 and miR-124-2 progressed rapidly to acute myeloid leukaemia. Multivariate analysis demonstrated that high methylation of miR-124-3 was an independent factor of overall survival. Median survival of patients with high miR-124-3 methylation was significantly shorter (7.6 months) than patients with low methylation (32.7 months; P = 0.010). A functional study revealed that silencing of miR-124 resulted in upregulation of its target gene, cyclin dependent kinase CDK6, which in turn promoted cell proliferation in the MDS cell line SKM-1. CONCLUSIONS: High methylation of miR-124-3 predicts shorter survival for patients with MDS, which may be a useful prognostic marker in MDS. PMID- 28861130 TI - Using Expectancy Value Theory as a Framework to Reduce Student Resistance to Active Learning: A Proof of Concept. AB - There has been a national movement to transition college science courses from passive lectures to active learning environments. Active learning has been shown to be a more effective way for students to learn, yet there is concern that some students are resistant to active learning approaches. Although there is much discussion about student resistance to active learning, few studies have explored this topic. Furthermore, a limited number of studies have applied theoretical frameworks to student engagement in active learning. We propose using a theoretical lens of expectancy value theory to understand student resistance to active learning. In this study, we examined student perceptions of active learning after participating in 40 hours of active learning. We used the principal components of expectancy value theory to probe student experience in active learning: student perceived self-efficacy in active learning, value of active learning, and potential cost of participating in active learning. We found that students showed positive changes in the components of expectancy value theory and reported high levels of engagement in active learning, which provide proof of concept that expectancy value theory can be used to boost student perceptions of active learning and their engagement in active learning classrooms. From these findings, we have built a theoretical framework of expectancy value theory applied to active learning. PMID- 28861129 TI - Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome. AB - BACKGROUND: Werner syndrome is a progeroid disorder characterized by premature age-related phenotypes. Although it is well established that autosomal recessive mutations in the WRN gene is responsible for Werner syndrome, the molecular alterations that lead to disease phenotype remain still unidentified. RESULTS: To address whether epigenetic changes can be associated with Werner syndrome phenotype, we analysed genome-wide DNA methylation profile using the Infinium MethylationEPIC BeadChip in the whole blood from three patients affected by Werner syndrome compared with three age- and sex-matched healthy controls. Hypermethylated probes were enriched in glycosphingolipid biosynthesis, FoxO signalling and insulin signalling pathways, while hypomethylated probes were enriched in PI3K-Akt signalling and focal adhesion pathways. Twenty-two out of 47 of the differentially methylated genes belonging to the enriched pathways resulted differentially expressed in a publicly available dataset on Werner syndrome fibroblasts. Interestingly, differentially methylated regions identified CERS1 and CERS3, two members of the ceramide synthase family. Moreover, we found differentially methylated probes within ITGA9 and ADAM12 genes, whose methylation is altered in systemic sclerosis, and within the PRDM8 gene, whose methylation is affected in dyskeratosis congenita and Down syndrome. CONCLUSIONS: DNA methylation changes in the peripheral blood from Werner syndrome patients provide new insight in the pathogenesis of the disease, highlighting in some cases a functional correlation of gene expression and methylation status. PMID- 28861131 TI - Unique Down to Our Microbes-Assessment of an Inquiry-Based Metagenomics Activity. AB - Metagenomics is an important method for studying microbial life. However, undergraduate exposure to metagenomics is hindered by associated software, computing demands, and dataset access. In this inquiry-based activity designed for introductory life science majors and nonmajors, students perform an investigation of the bacterial communities inhabiting the human belly button and associated metagenomics data collected through a citizen science project and visualized using an open-access bioinformatics tool. The activity is designed for attainment of the following student learning outcomes: defining terms associated with metagenomics analyses, describing the biological impact of the microbiota on human health, formulating a hypothesis, analyzing and interpreting metagenomics data to compare microbiota, evaluating a specific hypothesis, and synthesizing a conceptual model as to why bacterial populations vary. This activity was implemented in six introductory biology and biotechnology courses across five institutions. Attainment of student learning outcomes was assessed through completion of a quiz and students' presentations of their findings. In presentations, students demonstrated their ability to develop novel hypotheses and analyze and interpret metagenomic data to evaluate their hypothesis. In quizzes, students demonstrated their ability to define key terms and describe the biological impact of the microbiota on human health. Student learning gains assessment also revealed that students perceived gains for all student learning outcomes. Collectively, our assessment demonstrates achievement of the learning outcomes and supports the utility of this inquiry-based activity to engage undergraduates in the scientific process via analyses of metagenomics datasets and associated exploration of a microbial community that lives on the human body. PMID- 28861132 TI - Hands-On Assembly of DNA Sequencing Reads as a Gateway to Bioinformatics. PMID- 28861133 TI - Microbial Murders Crime Scene Investigation: An Active Team-Based Learning Project that Enhances Student Enthusiasm and Comprehension of Clinical Microbial Pathogens. AB - Microbial disease knowledge is a critical component of microbiology courses and is beneficial for many students' future careers. Microbiology courses traditionally cover core concepts through lectures and labs, but specific instruction on microbial diseases varies greatly depending on the instructor and course. A common project involves students researching and presenting a disease to the class. This method alone is not very effective, and course evaluations have consistently indicated that students felt they lacked adequate disease knowledge; therefore, a more hands-on and interactive disease project was developed called Microbial Murders. For this team-based project, a group of students chooses a pathogen, researches the disease, creates a "mugshot" of the pathogen, and develops a corresponding "crime scene," where a hypothetical patient has died from the microbe. Each group gives a presentation introducing the microbial pathogen, signs/symptoms, treatments, and overall characteristics. The students then visit each other's crime scenes to match the pathogen with the correct crime scene by critically thinking through the clues. This project has shown remarkable success. Surveys indicate that 73% of students thought the project helped them understand the material and 84% said it was worth their time. Student participation, excitement, understanding, and application of microbial disease knowledge have increased and are evident through an increase in course evaluations and in student assessment scores. This project is easy to implement and can be used in a wide variety of biology, microbiology, or health classes for any level (middle school through college). PMID- 28861134 TI - Introducing Mammalian Cell Culture and Cell Viability Techniques in the Undergraduate Biology Laboratory. AB - Undergraduate students learn about mammalian cell culture applications in introductory biology courses. However, laboratory modules are rarely designed to provide hands-on experience with mammalian cells or teach cell culture techniques, such as trypsinization and cell counting. Students are more likely to learn about cell culture using bacteria or yeast, as they are typically easier to grow, culture, and manipulate given the equipment, tools, and environment of most undergraduate biology laboratories. In contrast, the utilization of mammalian cells requires a dedicated biological safety cabinet and rigorous antiseptic techniques. For this reason, we have devised a laboratory module and method herein that familiarizes students with common cell culture procedures, without the use of a sterile hood or large cell culture facility. Students design and perform a time-efficient inquiry-based cell viability experiment using HeLa cells and tools that are readily available in an undergraduate biology laboratory. Students will become familiar with common techniques such as trypsinizing cells, cell counting with a hemocytometer, performing serial dilutions, and determining cell viability using trypan blue dye. Additionally, students will work with graphing software to analyze their data and think critically about the mechanism of death on a cellular level. Two different adaptations of this inquiry-based lab are presented-one for non-biology majors and one for biology majors. Overall, these laboratories aim to expose students to mammalian cell culture and basic techniques and help them to conceptualize their application in scientific research. PMID- 28861135 TI - Implementing an Expressive Writing Intervention for Test Anxiety in a Large College Course. PMID- 28861136 TI - A Hands-On Activity to Demonstrate the Central Dogma of Molecular Biology Via a Simulated VDJ Recombination Activity. PMID- 28861137 TI - Modeling and Visualizing Bacterial Colony Purification Without the Use of Bacteria or Laboratory Equipment. PMID- 28861138 TI - New Changes for JMBE: A Look Forward. PMID- 28861139 TI - Education is the Only Business Where the Customer is Satisfied with Less of the Product. PMID- 28861140 TI - Microbiology Education in Nursing Practice. AB - Nurses must have sufficient education and training in microbiology to perform many roles within clinical nursing practice (e.g., administering antibiotics, collecting specimens, preparing specimens for transport and delivery, educating patients and families, communicating results to the healthcare team, and developing care plans based on results of microbiology studies and patient immunological status). It is unclear whether the current microbiology courses required of nursing students in the United States focus on the topics that are most relevant to nursing practice. To gauge the relevance of current microbiology education to nursing practice, we created a confidential, web-based survey that asked nurses about their past microbiology education, the types of microbiology specimens they collect, their duties that require knowledge of microbiology, and how frequently they encounter infectious diseases in practice. We used the survey responses to develop data-driven recommendations for educators who teach microbiology to pre-nursing and nursing students. Two hundred ninety-six Registered Nurses (RNs) completed the survey. The topics they deemed most relevant to current practice were infection control, hospital-acquired infections, disease transmission, and collection and handling of patient specimens. Topics deemed least relevant were the Gram stain procedure and microscope use. In addition, RNs expressed little interest in molecular testing methods. This may reflect a gap in their understanding of the uses of these tests, which could be bridged in a microbiology course. We now have data in support of anecdotal evidence that nurses are most engaged when learning about microbiology topics that have the greatest impact on patient care. Information from this survey will be used to shift the focus of microbiology courses at our university to topics more relevant to nursing practice. Further, these findings may also support an effort to evolve national recommendations for microbiology education in pre-nursing and nursing curricula. PMID- 28861141 TI - Multi-Institutional, Multidisciplinary Study of the Impact of Course-Based Research Experiences. AB - Numerous national reports have called for reforming laboratory courses so that all students experience the research process. In response, many course-based research experiences (CREs) have been developed and implemented. Research on the impact of these CREs suggests that student benefits can be similar to those of traditional apprentice-model research experiences. However, most assessments of CREs have been in individual courses at individual institutions or across institutions using the same CRE model. Furthermore, which structures and components of CREs result in the greatest student gains is unknown. We explored the impact of different CRE models in different contexts on student self-reported gains in understanding, skills, and professional development using the Classroom Undergraduate Research Experience (CURE) survey. Our analysis included 49 courses developed and taught at seven diverse institutions. Overall, students reported greater gains for all benefits when compared with the reported national means for the Survey of Undergraduate Research Experiences (SURE). Two aspects of these CREs were associated with greater student gains: 1) CREs that were the focus of the entire course or that more fully integrated modules within a traditional laboratory and 2) CREs that had a higher degree of student input and results that were unknown to both students and faculty. PMID- 28861142 TI - Integration of RCR and Ethics Education into Course-Based Undergraduate Research Experiences in the Biological Sciences: A Needed Discussion. AB - Course-based undergraduate research experiences (CUREs) have been identified as a promising vehicle to broaden novices' participation in authentic scientific opportunities. While recent studies in the bioeducation literature have focused on the influence of CUREs on cognitive and non-cognitive student outcomes (e.g., attitudes and motivation, science process skills development), few investigations have examined the extent to which the contextual features inherent in such experiences affect students' academic and professional growth. Central among these factors is that of ethics and the responsible conduct of research (RCR) essential cornerstones of the scientific enterprise. In this article, we examine the intersectionality of ethics/RCR instruction within CURE contexts through a critical review of existing literature that details mechanisms for the integration of ethics/RCR education into undergraduate laboratory experiences in the science domains. Building upon this foundation, we propose a novel, evidence based framework that seeks to illustrate posited interactions between core ethics/RCR principles and unique dimensions of CUREs. It is our intent that this framework will inform and encourage open dialogue around an often-overlooked aspect of CURE instruction-how to best prepare ethically responsible scholars for entrance into the global scientific workforce. PMID- 28861143 TI - Artificial Urine for Teaching Urinalysis Concepts and Diagnosis of Urinary Tract Infection in the Medical Microbiology Laboratory. AB - Dipstick urinalysis is an informative, quick, cost-effective and non-invasive diagnostic tool that is useful in clinical practice for the diagnosis of urinary tract infections (UTIs), kidney diseases, and diabetes. We used dipstick urinalysis as a hands-on microbiology laboratory exercise to reinforce student learning about UTIs with a particular focus on cystitis, which is a common bacterial infection. To avoid exposure to potentially contaminated human urine samples, we prepared artificial urine using easily acquired and affordable ingredients, which allowed less-experienced students to perform urinalysis without the risk of exposure to pathogenic organisms and ensured reliable availability of the urine samples. This practical class taught medical students how to use urinalysis data in conjunction with medical history to diagnose diseases from urine samples and to determine a treatment plan for clinical scenarios. PMID- 28861144 TI - Design and Revision of an Open-Educational Resource Microbiology Lab Manual Using Student Feedback. PMID- 28861145 TI - Bacterial DNA Extraction Using Individual Enzymes and Phenol/Chloroform Separation. PMID- 28861146 TI - Therapeutic effects of fibroblast growth factor-10 on hyperoxia-induced bronchopulmonary dysplasia in neonatal mice. AB - The survival rate of preterm neonates increases significantly with the development of neonatal care and comprehensive treatment, but more and more high risk preterm neonates suffer from bronchopulmonary dysplasia (BPD). Currently, there is no effective treatment for BPD, thus it is still a major cause of disability and mortality in neonates. Thus, it is imperative to investigate the pathogenesis and treatment of BPD in depth. Fibroblast growth factor-10 (FGF-10) is a paracrine growth factor binding its receptors (FGFR1 and FGFR2) to regulate a lot of biological processes. FGF-10, with mitotic and chemotactic activities, plays an important role in histogenesis during embryonic stage. It can prevent and attenuate mechanical or infection induced inflammation in lung. Results showed lung FGF-10 expression reduced significantly in neonatal mice with BPD, and exogenous FGF-10 was able to promote the growth of pulmonary mesenchymal stem cells and alveolar epithelial cells type II and reduce the expression of pro inflammatory cytokines. We preliminarily explored the relationship between FGF-10 and NF-kappaB in this animal model and found FGF-10 could inhibit NF-kappaB p65 expression as a feedback. Thus, to investigate the protective effects of FGF-10 on hyperoxia induced BPD in neonatal mice will provide a new strategy for the treatment of BPD. PMID- 28861147 TI - MiR-214 inhibits cell migration, invasion and promotes the drug sensitivity in human cervical cancer by targeting FOXM1. AB - OBJECT: MicroRNAs (miRNAs) play key roles in progression of cervical cancer. In the present study, we investigated the role of miR-214 in the process of migration, invasion and drug sensitivity to cisplatin in cervical cancer. METHODS: We detected the differential expression of miR-214 in 19 cases cervical cancer tissues and normal tissues as well as 4 cervical cancer cells and one normal cervical cells by Real-time PCR. Then, wound healing assay, transwell invasion assay and MTT were used to detect the effects of migration, invasion and sensitivity to cisplatin of cervical cancer when miR-214 was overexpressed. Western blot, immunofluorescence and Flow Cytometry were used to detect the mechanism of migration, invasion and sensitivity to cisplatin. Next, bioinformatics analysis was used to find the target of miR-214. Through the luciferase reporter assay, Real-time PCR and western blot, we confirmed the binding relationship of miR-214 and FOXM1. In cervical cancer tissues, the expression of FOXM1 was detected by western blot and Immunohistochemistry. We also knocked down FOXM1 in cervical cancer cells, wound healing assay, transwell invasion assay and MTT were performed to detect the migration, invasion and sensitivity to cisplatin abilities of FOXM1. Western blot and Flow Cytometry were used to detect the mechanism of migration, invasion and sensitivity to cisplatin by FOXM1. Finally, we performed rescue expriments to confirm the function relationship between miR-214 and FOXM1. RESULTS: 1. Our results showed that miR 214 was frequently downregulated in tumor tissues and cancer cells especially in CIN III and cervical cancer stages. 2. Overexpression of miR-214 significantly inhibited migration and invasion of cervical cancer cells and prompted the sensitivity to cisplatin. 3. FOXM1 was identified as a target of miR-214 and down regulated by miR-214. 4. Knocking down FOXM1 could inhibited migration and invasion of cervical cancer cells and prompted the sensitivity to cisplatin. 5. FOXM1 was upregulated in tumor tissues. 6. The mechanism of migration, invasion and sensitivity to cisplatin were the resluts of changes of EMT and apoptosis. 7. The restoration of FOXM1 expression can counteract the effect of miR-214 on cell migration, invasion and sensitivity to cisplatin of cervical cancer cells. CONCLUSIONS: These findings indicate that miR-214 acts as a tumor suppressor during the process of migration, invasion and drug sensitivity through targeting FOXM1, suggesting miR-214 as a potential new diagnostic and therapeutic target for the treatment of cervical cancer. PMID- 28861148 TI - A proteomics-based investigation on the anticancer activity of alisertib, an Aurora kinase A inhibitor, in hepatocellular carcinoma Hep3B cells. AB - Targeted therapy may provide survival benefit for advanced hepatocellular carcinoma (HCC) and Aurora A kinase (AURKA) represents a feasible target in cancer treatment. The purpose of this study is to investigate the anticancer activity of alisertib (ALS) on Hep3B cells based on a proteomic study conducted with the stable-isotope labeling by amino acids in cell culture (SILAC). The proteomic response to ALS was obtained with SILAC-based proteomic study. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy. ALS inhibited the proliferation of Hep3B cells, with IC50 values for 24- and 48-h exposure of 46.8 and 28.0 MUM, respectively. Our SILAC study demonstrated that there were at least 565 proteins responding to ALS treatment, with 256 upregulated, 275 downregulated and 35 stable. Ninety-four signaling pathways, majority of which involved cell proliferation and survival, programmed cell death, and nutrition and energy metabolism, were regulated by ALS. ALS significantly inhibited the phosphorylation of AURKA at Thr288 in a concentration-dependent manner. Subsequent study showed that ALS remarkably arrested Hep3B cells in G2/M phase via regulating the expression of key cell cycle regulators, and induced a marked autophagy via the PI3K/Akt/mTOR axis. Inhibition of autophagy enhanced the anticancer activity of ALS in Hep3B cells. Overall, ALS leads to comprehensive proteomic response, inhibits cellular proliferation, and induces cell cycle arrest and autophagy in Hep3B cells. Further studies are warranted to explore the role of ALS in the treatment of HCC. PMID- 28861150 TI - MicroRNA-130a-3p suppresses cell viability, proliferation and invasion in nasopharyngeal carcinoma by inhibiting CXCL12. AB - Incidence of nasopharyngeal carcinoma (NPC) has remained high worldwide, posing a serious health problem. MicroRNAs (miRNAs) are a family of about 20-23 nucleotides small non-coding molecules, which play a significant role in NPC. In this study, we explored the molecular mechanisms of miR-130a-3p in inhibiting viability, proliferation, migration and invasion of NPC cells by suppressing CXCL12. The relative expression of miR-130a-3p and CXCL12 mRNA expression in tissues and cells was measured by qRT-PCR. NPC cell line CNE-2Z was transfected with miR-130a-3p mimics, CXCL12 siRNA, cDNA-CXCL12 and negative control. Western Blot was performed to detect CXCL12 expression. The MTT assay was performed to study cell viability. The colony formation assay was done to test cell growth. Flow cytometry was conducted to analyze cell cycle and apoptosis. The Transwell assay was used to investigate cell migration and invasion. The results found that the up-regulation of miR-130a-3p or down-regulation of CXCL12 could inhibit viability, proliferation, migration and invasion of CNE-2Z cells. Luciferase reporting system assay was performed to investigate miR-130a-3p could bind to the 3'UTR region of CXCL12 and the overexpression of miR-130a-3p could suppress CXCL12 expression. Collectively, our finding suggested demonstrated that miR-130a 3p could prohibit the progression of NPC by suppressing CXCL12, which might serve as potential therapeutic targets for NPC. PMID- 28861149 TI - Posttranslational modifications of calcium/calmodulin-dependent protein kinase IIdelta and its downstream signaling in human failing hearts. AB - BACKGROUND: In human failing hearts (HF) of different origin (coronary artery disease-CAD, dilated-DCM, restrictive and hypertrophic cardiomyopathy-OTHER), we investigated the active forms of Ca2+/calmodulin-dependent protein kinase IIdelta (p-Thr287-CaMKIIdelta, oxMet281/282-CaMKIIdelta) and their role in phenotypes of the disease. METHODS AND RESULTS: Although basic diagnostic and clinical markers indicating the attenuated cardiac contractility and remodeling were comparable in HF groups, CaMKIIdelta-mediated axis was different. P-Thr287-CaMKIIdelta was unaltered in CAD group, whereas it was upregulated in non-ischemic cardiomyopathic groups. No correlation between the upregulated p-Thr287 CaMKIIdelta and QT interval prolongation was detected. Unlike in DCM, oxMet281/282-CaMKIIdelta did not differ among HF groups. Independently of CaMKIIdelta phosphorylation/oxidation, activation of its downstreams phospholamban and cardiac myosin binding protein-C was significantly downregulated supporting both diminished cardiac lusitropy and inotropy in all hearts. Content of sarcoplasmic reticulum Ca2+-ATPase 2a in all HF was unchanged. Protein phosphatase1beta was upregulated in CAD and DCM only, while 2A did not differ among groups. CONCLUSION: This is the first demonstration that the posttranslational activation of CaMKIIdelta differs in HF depending on etiology. Lower levels of downstream molecular targets of CaMKIIdelta do not correlate with either activation of CaMKIIdelta or the expression of major protein phosphatases in the HF. Thus, it is unlikely that these mechanisms exclusively underlie failing of the heart. PMID- 28861151 TI - microRNA-204 modulates chemosensitivity and apoptosis of prostate cancer cells by targeting zinc-finger E-box-binding homeobox 1 (ZEB1). AB - Epigenetic gene inactivation by microRNAs (miRNAs) is crucial in malignant transformation, prevention of apoptosis, development of drug resistance, and metastasis. miR-204 dysregulation has been reported in prostate cancer (PC). It is considered to exert tumor suppressor functions and is associated with the development of chemoresistance. However, the detailed mechanisms underlying the role of miR-204 in PC, particularly in chemoresistance, remain to be fully elucidated. In this study, analysis using miRNA microarray showed that miR-204 is downregulated in chemoresistant PC tissues with respect to its expression in chemosensitive PC tissues and benign prostatic hyperplasia tissues. Microarray results were validated via qPCR. The changes in miR-204 expression levels were also observed in vitro. Forced overexpression of miR-204 evidently attenuated docetaxel chemoresistance and promoted apoptosis in PC-3-R cells, whereas miR-204 knockdown effectively reduced docetaxel-induced cell death and inhibited cell apoptosis. Mechanistically, miR-204 directly targets the 3'-untranslated region of zinc-finger E-box-binding homeobox 1 (ZEB1) and inhibits its protein expression via translational repression. Furthermore, suppression of ZEB1 could effectively improve miR-204 deficiency-triggered chemoresistance in PC cells. Our results collectively indicate that miR-204 expression is downregulated in chemoresistant PC tissues and cells and that miR-204/ZEB1 could potentially be used as adjunct therapy for patients with advanced/chemoresistant PC. PMID- 28861152 TI - MicroRNA-138 attenuates epithelial-to-mesenchymal transition by targeting SOX4 in clear cell renal cell carcinoma. AB - MicroRNAs (miRNAs) are small, non-coding RNAs which can serve as oncogenes or tumor suppressor genes in human cancers. Herein, the transcriptomic differences of miRNAs in ccRCC were globally assessed using publicly available microarray dataset (GSE71302) from Gene Expression Omnibus (GEO) and we identified miR-138 as a potential onco-suppressive miRNA. We further found that the expression of miR-138 was dramatically decreased in ccRCC cell lines and clinical ccRCC tissue samples, and the low miR-138 expression was closely correlated with tumor progression and prognosis in ccRCC patients. Overexpression of miR-138 inhibited, whereas downregulation of miR-138 promoted, the proliferation, migration and invasion of ccRCC cells in vitro, suggesting that miR-138 may function as a tumor suppressor in ccRCC. Furthermore, for the first time, we identified the EMT related transcription factor SOX4 as a direct target gene of miR-138, evidenced by the direct binding of miR-138 with the 3'UTR of SOX4. Notably, the EMT marker E-cadherin or vimentin was also upregulated or downregulated upon miR-138 overexpression, and these effects were restored by SOX4 overexpression. We have also shown SOX4 overexpression reversed the attenuated migratory and invasive capacities mediated by miR-138. These results revealed that miR-138 functions as a tumor suppressor in ccRCC by targeting SOX4 and the EMT process and might represent a potential target in the treatment of human ccRCC. PMID- 28861153 TI - Peripheral blood Th9 cells reconstitution and its relationship with acute graft versus-host disease after matched-sibling peripheral blood hematopoietic stem cell transplantation. AB - T helper type 9 (Th9) cells have recently been identified as a new effector T cell subset. This study is to analyze the reconstitution of Th9 cell after matched sibling peripheral blood hematopoietic stem cell transplantation (MS PBSCT) and the relationship between Th9 cell and acute graft-versus-host disease (aGVHD). Flow cytometry and ELISA were used to analyze the percentages of Th9 cell, levels of IL-9, TGF-beta, IFN-gamma, and IL-4. The results showed that for patients without aGVHD, Th9 cells recovery started from day 60 after transplantation and reached normal level on day 90. Serum TGF-beta, IL-4, and IFN gamma reached normal levels on day 60, 60, and 90 post transplantation respectively. The serum IL-9 recovery is slower than that of IFN-gamma and IL-4. For patients suffering from aGVHD, they had declined Th9 cell numbers, lower IL-9 and TGF-beta levels, but higher serum IFN-gamma level when compared with those without aGVHD after transplantation. Serum IFN-gamma/IL-9 ratios increased linearly with grades of aGVHD. In conclusion, Th9 cells recovery is delayed after MS-PBSCT in patients with aGVHD but early in patients without aGVHD, indicating quick immune reconstitution of Th9 cells and IL-9 after MS-PBSCT may promote the immune tolerance. PMID- 28861154 TI - Curcumin inhibits human non-small cell lung cancer xenografts by targeting STAT3 pathway. AB - Human non-small cell lung cancer (NSCLC) is the most common cause of cancer related death in men. Signal transducers and activators of transcription 3 (STAT3) is a potential molecular target in angiogenesis-mediated cancer therapy. In this study, we subcutaneously injected athymic nude mice with NCI-H460 cells to induce ectopic xenograft model, and treated the animals with curcumin (100 mg/kg) or vehicle by oral gavage. Tumor size and tumor weight were significantly reduced by curcumin treatment. Besides, curcumin significantly decreased hemoglobin content and mRNA expression of CD31 and CD105 in tumor tissue, suggesting that curcumin could inhibit angiogenesis in NSCLC xenograft. Similarly, we intrathoracally injected athymic nude mice with H1975 cells to induce orthotopic xenograft model, in which curcumin significantly reduced tumor weight as well as improved the survival rate of mice. STAT3 pathway was involved in curcumin-induced tumor inhibition, in which phosphorylation of STAT3 and JAK in ectopic xenograft were both declined after curcumin treatment, and the STAT3 regulated promoter activation of VEGF, Bcl-xL, Cyclin D1 was also significantly reduced after treatment. In in vitro assays, curcumin significantly inhibited cell migration and tube formation of NCI-H460 cells, but transfection with pMXs Stat3C, a dominant active mutant, could abolish the inhibitory effects of curcumin on the cells, suggesting curcumin inhibited tumor angiogenesis of NCI H460 cells through the inactivation of STAT3. All data showed that curcumin could be a potential drug targeting STAT3 to treat NSCLC. PMID- 28861155 TI - Calcitriol promotes survival of experimental random pattern flap via activation of autophagy. AB - Calcitriol can promote random pattern flap survival and increase autophagy activity. However, effect of autophagy on flap survival after calcitriol treatment, along with the underlying mechanism, is undefined. In this study, the "McFarlane flap" model was established in 72 rats divided into control, calcitriol, and calcitriol+3-methyladenine (3MA) groups and injected with saline, calcitriol, and calcitriol plus 3MA, respectively. The percentage flap survival area and tissue water content were tested after 7 days. The extent of autophagy was evaluated by the expression of the autophagy markers LC3-II/I, Beclin1, and p62. Flap angiogenesis was assessed via hematoxylin and eosin (H&E) staining and immunohistochemistry (for CD34 levels). The level of vascular endothelial growth factor (VEGF) protein/mRNA was measured. Oxidative stress was assessed by measuring the activity of tissue superoxide dismutase (SOD) and the contents of glutathione (GSH) and malondialdehyde (MDA). Our results showed that 3MA decreased autophagy in random skin flap treated with calcitriol. Compared with the calcitriol group, the calcitriol+3MA group showed a smaller mean flap survival area and greater tissue edema, had a markedly decreased level of VEGF mRNA/protein and SOD activity, and a significantly higher level of MDA and GSH. H&E staining and immunohistochemistry showed that angiogenesis was inhibited in this group. In conclusion, calcitriol increased angiogenesis and reduced oxidative stress via activation of autophagy, contributing to a significant increase in random skin flap survival. PMID- 28861156 TI - MIR-519d suppresses the gastric cancer epithelial-mesenchymal transition via Twist1 and inhibits Wnt/beta-catenin signaling pathway. AB - MicroRNAs (miRNAs) deregulation is frequent in human gastric cancer (GC). MiR 519d has been reported to function as tumor suppressor microRNA in some tumors. However, the role of miR-519d in GC progression remains unclear. In the study, we demonstrated that the expression of miR-519d was down-regulated in gastric cancer tissues and cell lines, and lower miR-519d expression was associated with distant metastasis, lymph node metastasis and clinical stage for patients with GC. Univariate and multivariate Cox analysis showed that lower miR-519d expression was positively associated with shorter disease-free survival (DFS) and the over survival (OS) time for GC patients and was an independent predictor. Kaplan-Meier curve and log-rank test also demonstrated that lower miR-519d had a poor shorter DFS and OS for GC patients. Function analysis showed that the inhibition of miR 519d expression was able to promote the cell proliferation, migration and invasion and over-expression of miR-519d in GC cells had inhibited effects. Moreover, we demonstrated that over-expression of miR-519d significantly inhibited the process of epithelial mesenchymal transition (EMT) in GC cells and miR-519d can directly target at 3'-untranslation region of Twist1 and regulate its expression. We also demonstrated that miR-519d could suppress the Wnt/beta catenin signaling pathway in GC cells. In vivo, we showed that miR-519d inhibited the tumor growth. Thus, our results suggested that miR-519d functioned as a tumor suppressor in GC and could be a promising therapeutic target for GC. PMID- 28861157 TI - TIM-1 attenuates the protection of ischemic preconditioning for ischemia reperfusion injury in liver transplantation. AB - Ischemic preconditioning (IPC) has been introduced to protect grafts against ischemic reperfusion injury (IRI) during liver transplantation (LT) in recent years. However, the underlying molecular mechanisms of IPC are not fully understood. We aimed to confirm whether the efficacy of IPC is dependent on T cell Immunoglobulin and Mucin domain-containing molecules-1 (TIM-1). Quantitative real-time reverse transcription PCR and western blotting were used to detect the expression of genes of interest. Graft function was assessed using the levels of alanine transaminase (ALT) and aspartate transaminase (AST), percentage of apoptosis cells and pathological examination. IPC treatment alleviated graft function after ischemic reperfusion. AST, ALT, CD68, CD3 positive cells and tissue myeloperoxidase activity were decreased significantly by IPC. IPC decreased the expressions of the cytokines and chemokines. Compared with the IRI group, TIM-1 expression and TIM-1 positive cells were inhibited significantly in the IPC group. TIM-1 blockage abolished the protective effect of IPC on IRI damage. IPC could not further improve graft function and decrease the sequestration of immune cells after blocking TIM-1 signaling. IPC is a convenient therapeutic strategy against IRI during LT. The benefit of IPC depends on TIM-1 signaling. PMID- 28861158 TI - FL118, a novel survivin inhibitor, wins the battle against drug-resistant and metastatic lung cancers through inhibition of cancer stem cell-like properties. AB - Failure of cancer treatment caused by drug resistance and metastasis is mainly due to existence of cancer stem cells (CSCs). Therefore, targeting CSCs to overcome cancers is a challenging issue in clinic. In this report, in view of the important role of survivin in tumor growth and CSCs maintaining, we aimed to confirm that FL118, as a novel survivin inhibitor, may effectively inhibit lung cancer stem cells. We showed that lung cancer stem cells have the obviously higher expression of survivin than their parental cells. After treated with FL118, the survivin level in CSCs was suppressed. Consistently, lung cancer stem cells displayed significantly growth inhibition over time. Here, we compared the antitumor efficacy between FL118 and cisplatin. The data revealed that CSCs are more sensitive to FL118 than cisplatin. To further demonstrate the inhibitory effect of FL118 on CSCs, we found that FL118 down-regulated the expression of CSCs markers (ABCG2, ALDH1A1, Oct4) and drug resistant proteins (P-gp, ERCC1), suggesting that FL118 may change CSCs phenotype and improve drug-sensitivity of tumor cells. Moreover, FL118 effectively decreased the invasive ability of CSCs. These findings expand the uniqueness of FL118 as an attractive therapeutic option for cancers with drug-resistant or metastatic potential. PMID- 28861159 TI - Relationship and mechanism of Kv2.1 expression to ADH secretion in rats with heart failure. AB - OBJECTIVE: To explore the mechanisms of Kv2.1 on the secretion of ADH in rats with heart failure. METHODS: In the animal study, 70 healthy male SD rats were selected. Ligation of coronary heart failure model surgery was performed in 60 rats and sham surgery was performed in the other 10 rats. Q-PCR was used to detect the mRNA expression of Kv2.1 in hypothalamus and heart. The protein expression of Kv2.1 and ADH was detected by western blot. In the cell culture study, hypothalamic neurons were cultured and divided into 7 groups. The mRNA expression of Kv2.1 and ADH was detected by Q-PCR. The protein expression of Kv2.1, CamKII, phosphorylation SynapsinI, dephosphorylation SynapsinI and ADH was detected by western blot. RESULTS: Compared with the control group of heart failure, LVEDD, LVESD, LVEDV and LVESV were significantly decreased (P < 0.01), and LVEF and LVFS were significantly increased (P < 0.01) in the Kv2.1 agonist group; in the Kv2.1 inhibitor group, LVEDD, LVESD, LVEDV and LVESV were significantly increased (P < 0.01), and LVEF and LVFS were significantly decreased (P < 0.01). In cell culture study, after the different concentrations of Kv2.1 inhibitor gradient down the expression of Kv2.1, intracellular Ca2+ concentration gradient increased (P < 0.01), CamKII and phosphorylation of SynapsinI protein expression gradient increased (P < 0.01), dephosphorylation of SynapsinI protein expression gradient decreased (P < 0.01), and the ADH mRNA and protein expression of gradient increased (P < 0.01). CONCLUSIONS: Kv2.1 agonist can prevent the calcium overload by reducing the intracellular Ca2+ concentration, so that the phosphorylation of SynapsinI reduces and exocytosis in hypothalamic neurons is inhibited, which ease the secretion of ADH. PMID- 28861160 TI - Long nonding RNA UCA1 regulates neural stem cell differentiation by controlling miR-1/Hes1 expression. AB - Neural stem cells are able to self-renew and generate glial and neuronal lineages. Neural stem cell may serve as therapeutic method for neurological disorders including spinal cord injuries, Parkinson's disease, Huntington's disease and Alzheimer's disease. Long noncoding RNAs (lncRNAs) are longer than 200 nucleotides with limited protein-coding capacity. Recent studies have demonstreated that lncRNAs play an important role in several cellular processes including cell differentiation, cell development, proliferation, apoptosis, invasion and migration. However, the role of lncRNA human urothelial carcinoma associated 1 (UCA1) in the development of neural stem cells remains unknown. In this study, we showed that the expression of UCA1 was upregulated in the neural stem cell in a time-dependent manner. Knockdown of UCA1 suppressed the neural stem cell proliferation. Inhibition of UCA1 decreased the expression of nestin and the formation of neurosphere. Moreover, knockdown of UCA1 suppressed the neural stem cell differentiation to astrocyte and promoted the neural stem cell differentiation to neuron. Furthermore, we demonstrated that knockdown of UCA1 increased the expression of miR-1 in the neural stem cell and suppressed the expresion of Hes1, which is one target gene of miR-1. In addition, ectopic expression of Hes1 could impair siUCA1-induced neural stem cells proliferation. Overexpression of Hes1 suppressed siUCA1-induced beta-tubulin expression and promoted siUCA1-inhibited GFAP expression in the neural stem cell. These results suggested that UCA1 regulated the neural stem cell proliferation and differentiation through regulating Hes1 expression. PMID- 28861161 TI - miR-320 inhibited ovarian cancer oncogenicity via targeting TWIST1 expression. AB - Ovarian cancer is the most lethal gynecological cancer in most countries. Increasing studies have demonstrated that dysregulation of microRNAs (miRNAs) can contribute to cancer progression. In this study, we showed that miR-320 was underexpressed in ovarian cancer samples compared to their non-tumor tissues. The expression of Twist homolog 1 (TWIST1) in ovarian cancer tissues was upregulated compared with that in the non-tumorous tissues. We found that the expression of TWIST1 was inversely correlated with that of miR-320 in the ovarian cancer. Overexpression of miR-320 suppressed cell proliferation, cell cycle and invasion in ovarian cancer. We identified TWIST1 as a direct target gene of miR-320 in the ovarian cancer cell. Overexpression of TWIST1 promoted the ovarian cancer cell proliferation, cell cycle and invasion. Ectopic expression of TWIST1 restored the effects of miR-320 on cell proliferation, cell cycle and invasion. These findings revealed that miR-320 was a tumor suppressive gene that supressed cell prloferation, cycle and invasion through targeting TWIST1 in ovarian cancer. PMID- 28861162 TI - Suppression of miR-4735-3p in androgen receptor-expressing prostate cancer cells increases cell death during chemotherapy. AB - MicroRNAs (miRNAs) play critical roles in the tumorigenesis of prostate cancer, while the biological function of miR-4735-3p is unknown. Mitogen-activated protein kinase kinase kinase 1 (MEKK1) has been shown to induce androgen receptor (AR)-dependent apoptosis in prostate cancer cells, but the regulation of MEKK1 in prostate cancer cells remains poorly defined. Here, we showed that miR-4735-3p was a MEKK1-targeting miRNA, and was highly expressed in AR+ prostate cancer specimens. Moreover, the levels of miR-4735-3p and MEKK1 inversely correlated. MiR-4735-3p-low subjects had a better overall survival, compared to miR-4735-3p high subjects. MiR-4735-3p targeted the 3'-UTR of MEKK1 mRNA to inhibit its protein translation. Overexpression of miR-4735-3p inhibited MEKK1-mediated cell apoptosis upon docetaxel treatment, while depletion of miR-4735-3p enhanced it. Together, our data suggest that miR-4735-3p may suppress MEKK1-mediated prostate cancer cell apoptosis during chemotherapy. Inhibition of miR-4735-3p may improve the outcome of chemotherapy for some prostate cancers. PMID- 28861163 TI - Image-guided stem cells with functionalized self-assembling peptide nanofibers for treatment of acute myocardial infarction in a mouse model. AB - AIM: To investigate the survival of bone marrow mesenchymal stem cells (BMSCs) and the therapeutic effect for acute myocardial infarction (AMI) after co transplantation with the functionalized self-assembling peptide nanofiber RAD/PRG or RAD/KLT. METHODS: AMI of balb/c mice was induced. Mice were randomly divided into four groups, and received treatment of phosphate buffered saline (PBS) (Group A), GFP/Fluc-BMSCs (Group B), GFP/Fluc-BMSCs + RAD/PRG (Group C), and GFP/Fluc-BMSCs + RAD/KLT (Group D), respectively. Bioluminescence imaging (BLI) was performed on day 1 (d-1), d-4, d-7, d-10, and d-13 after transplantation. Magnetic resonance imaging (MRI) was performed at baseline (d-4 before transplantation) and d-29 after treatment. Mice were euthanized on d-29 following treatment. Paraffin sections were obtained from the top, mid and bottom part of the infarcted region along the long-axis of the heart. Hematoxylin and eosin (HE) staining and immunohistochemical staining were performed. The infarct ratio micro vascular density (MVD) was quantified. RESULTS: There was a significant higher of BLI signal intensity of BMSCs in Group C than that in Group B (d-4, 9713+/-320 vs. 8164+/-378, P=0.0008; d-7, 6489+/-241 vs. 5417+/-361, P=0.0026; d-10, 3768+/ 255 vs. 0, P < 0.0001). The left ventricular ejection fraction (LVEF) via MRI examination was significantly improved in both Group C and Group D. Infarct ratio and MVD were significantly improved in both Group C and Group D. CONCLUSION: Our data highlights BMSCs combining functionalized self-assembling peptide nanofibers RAD/PRG or RAD/KLT as promising therapy for AMI. PMID- 28861164 TI - Danggui buxue tang suppresses high glucose-induced proliferation and extracellular matrix accumulation of mesangial cells via inhibiting lncRNA PVT1. AB - BACKGROUND: Danggui Buxue Tang (DBT), a traditional Chinese medicine decoction, has been proven to have satisfactory effects on treating diabetic nephropathy (DN). In this study, we explored the potential underlying mechanism of DBT in DN treatment. METHODS: The DBT-containning serum was prepared by intragastric administration with DBT for rats. The levels of fibronectin (FN), laminin (LN) and collagen IV (COL IV) and TGF-beta1 protein secreted in cell culture medium were determined by ELISA assay. The mRNA and protein expression of related molecule was measured using qRT-PCR and western blotting. MTT assay was applied to test MCs proliferation. RESULTS: DBT has a negative effect on the high glucose (HG)-induced proliferation and extracellular matrix (ECM) accumulation of mesangial cells (MCs). Further research showed that DBT reduced the acetylation level of histone H3 at the site of PVT1 promoter to promote PVT1 downregulation, which was accompanied by a decrease in TGF-beta and c-myc expression. Moreover, PVT1 overexpression significantly enhanced cell viability and promoted the expression levels of TGF-beta1 and c-myc. Furthermore, PVT1 overexpression significantly reversed the inhibition of DBT on HG-induced cell viability and ECM accumulation and also lifted the effect of DBT on TGF-beta1 and c-myc expression. CONCLUSION: DBT inhibited TGF-beta1 and c-myc expression through downregulating PVT1, and thus attenuated MCs excessive proliferation and ECM accumulation in DN. PMID- 28861165 TI - Association of ECRG4 with PLK1, CDK4, PLOD1 and PLOD2 in esophageal squamous cell carcinoma. AB - Esophageal cancer-related gene 4 (ECRG4) is a tumor suppressor gene associated with the prognosis of esophageal squamous-cell carcinoma (ESCC). Studies have reported that ECRG4 effectively inhibits the proliferation, migration and invasion of ESCC cells. In the current study, ectopic expression of ECRG4 significantly induced ESCC cell apoptosis. To further understand the molecular profile of ECRG4 overexpression in ESCC cells, tandem mass tag (TMT) labeling followed by LC-MS/MS analysis was applied on samples from ECRG4 overexpressed cells and control cells. Among the identified differentially expressed proteins, four up-regulated proteins (PLK1, CDK4, PLOD1 and PLOD2) associated with cell apoptosis, cell cycle and metastasis were chosen for the further investigation. The effects of ECRG4 protein levels on the expression of these four proteins were validated by manipulating the expression of ECRG4 in ESCC cells followed by Western blotting analysis. The immunohistochemical staining results showed a significant decrease in ECRG4 levels and a notable increase in the four proteins in ESCC samples as compared to matched esophageal tissues (n=75). More importantly, the protein levels of ECRG4 had a negative association with those of PLK1, CDK4, PLOD1 and PLOD2. Thus, our data suggested that the tumor-repressor functions of ECRG4 may be associated with PLK1, CDK4, PLOD1 and PLOD2, providing important insights into the molecular mechanisms of esophageal carcinogenesis. PMID- 28861166 TI - YKL-40 promotes the migration and invasion of prostate cancer cells by regulating epithelial mesenchymal transition. AB - OBJECTIVE: This study aims to observe the expression of YKL-40 in prostate cancer and whether YKL-40 can affect the migration and invasion of tumor cells by regulating epithelial mesenchymal transition. METHODS: We collected 14 cases of prostate cancer tissues and adjacent tissues in this study. The expression levels of YKL-40 in the tissues were analyzed by western blotting and immunohistochemical methods. The expression of YKL-40 in human prostate cancer cell line DU145 and PC3 was detected by fluorescence quantitative PCR and western blotting methods. The expression levels of YKL-40 in different cells were up regulated or down- regulated by lentivirus to observe the changes of cell migration and invasion. The expression levels of EMT related genes were analyzed by RT-PCR and Western blotting methods. RESULTS: The expression level of YKL-40 in prostate cancer tissues was significantly higher than that in adjacent tissues (P<0.01), and it was higher in DU145 cells than that in PC3 cells (P<0.05). The expression level of YKL-40 was positively correlated with cell migration and invasion. YKL-40 can regulate the expression of EMT related genes (Twist, Snail, Slug, N-cadherin, Vimentin and E-cadherin). CONCLUSIONS: The expression level of YKL-40 was positively correlated with the migration and invasion of prostate cells, it affects cancer metastasis by regulating EMT. PMID- 28861167 TI - Can rheumatoid arthritis ever cease to exist: a review of various therapeutic modalities to maintain drug-free remission? AB - Therapies for rheumatoid arthritis (RA) were mostly aimed at reducing the pain, stiffness and further progression of joint destruction. However, with the advent of biologic agents that act against specific inflammatory cytokines contributing to RA pathogenesis (treat-to-target strategy), the degree of remission achieved has been remarkably impressive. In particular, inhibition of tumor necrosis factor alpha (TNFalpha), interleukins-1 and -6 and receptor-activator of nuclear kappa B ligand by neutralizing antibodies in early diagnosed RA patients has resulted in lowering of disease activity to levels that enable them to function as in the pre-disease stage. There are other biologic approaches such as depletion of B cells and blocking T-cell co-stimulators that have been included successfully in RA therapy under the class of disease-modifying anti-rheumatic drugs (DMARD). Given the excellent clinical outcomes of biologic DMARDs when initiated early in RA, discontinuation or dose tapering is practised. Because biologic DMARDs are expensive and also known to make users vulnerable to viral infections, dose reduction and drug holiday are reasonable steps when sustained good clinical response has been achieved. Majority clinical studies have been done with TNF inhibitors and data suggest that sustained remission of RA is achieved in several multi-centric studies carried out worldwide. However, high flare rate and reappearance of disease has been reported in several cases. This review critically discusses response predictors of biologic DMARDs, the case for treatment relaxation, strategizing drug tapering considering patient eligibility and timing in light of available clinical practice guidelines of RA. PMID- 28861168 TI - Inhibition of Wnt/beta-catenin by anthelmintic drug niclosamide effectively targets growth, survival, and angiogenesis of retinoblastoma. AB - Retinoblastoma is an angiogenesis-dependent ocular tumor, the clinical management of which remains a challenge. Agents that can target tumor cells and angiogenesis, as well as augment current chemotherapy efficacy, present a promising therapeutic strategy for retinoblastoma. We demonstrated that niclosamide, an FDA-approved anthelmintic drug, is effective against multiple aspects of retinoblastoma. Niclosamide inhibited proliferation via causing cell cycle arrest at the G2/M phase and induced caspase-dependent apoptosis in a panel of retinoblastoma cell lines, including Y79, RB116, and WERI-Rb-1. In addition, niclosamide inhibited retinoblastoma angiogenesis by disrupting capillary network formation, decreasing migration and proliferation, and inducing apoptosis of human primary retinal microvascular endothelial cells. We also demonstrated that niclosamide specifically suppresses the levels of p-LRP6, Dvl2, and beta-catenin, but not p-STAT3, in Y79 cells. It decreased beta-catenin activity and the mRNA expression levels of Wnt/beta-catenin target genes. Stabilization of beta-catenin with the Wnt activator lithium or overexpression of beta-catenin reversed the inhibitory effects of niclosamide in Y79 cells, confirming Wnt/beta-catenin as the molecular target of niclosamide in retinoblastoma cells. Importantly, niclosamide significantly enhanced the in vitro and in vivo efficacy of carboplatin and inhibited Wnt/beta-catenin signaling in a retinoblastoma xenograft mouse model. Our data suggest that niclosamide is a promising candidate for the treatment armamentarium for retinoblastoma. Our work also highlights that targeting Wnt/beta-catenin is a potential therapeutic strategy in retinoblastoma. PMID- 28861169 TI - Knockdown of REGgamma inhibits proliferation by inducing apoptosis and cell cycle arrest in prostate cancer. AB - Prostate cancer (PCa) is the most common malignant tumor and the second leading cause of cancer related death among men in western countries. REGgamma, a proteasome activator, is reported to play important roles in various human cancers. However, the expression patterns and potential roles of REGgamma in prostate cancer have never been reported. In this study, we found for the first time that REGgamma is overexpressed in prostate cancer tissues and cell lines at both protein and mRNA levels. In addition, we demonstrated that knockdown of REGgamma significantly inhibited cell proliferation and induced apoptosis and cell cycle arrest in PCa cell lines PC-3 and DU145. Moreover, we observed that the expressions of P21 were increased while the levels of cycinD1 and bcl-2 were decreased after knockdown of REGgamma in PCa cells. And the stabilization of P21 was enhanced after REGgamma knockdown in PC-3 cells. In summary, our findings suggest that REGgamma may play important roles in prostate cancer and may serve as a novel therapeutic target in the treatment of PCa patients. PMID- 28861170 TI - MiR-663a/MiR-423-5p are involved in the pathogenesis of lupus nephritis via modulating the activation of NF-kappaB by targeting TNIP2. AB - Lupus nephritis (LN) is a kidney disorder resulting from systemic lupus erythematosus (SLE), an autoimmune inflammatory disease. MicroRNAs (miRNAs) have emerged as a new class of therapeutic targets in LN treatment, but how they specifically contribute to the disease development remains unknown. In this study, the expression of miR-663a/miR-423-5p and TNIP2 were compared between human renal biopsy tissues from LN patients and renal cell carcinoma patients. Additionally, the LN mouse model was used to measure the levels of miR-663a/miR 423-5p and TNIP2 in the control group and the experiment group. Dual luciferase reporter assay was used to validate TNIP2 as the target of miR-663a/miR-423-5p. MiR-663a/miR-423-5p were highly expressed in kidney tissues from LN patients as compared to kidney tissues from SLE patients and normal tissues. TNIP2 showed comparatively low expression in tissues from LN patients. In the LN mouse model, the levels of miR-663a/miR-423-5p were improved whereas TNIP2 was reduced in response to renal injury stimulated by pristine. MiR-663a/miR-423-5p mimics and inhibitors triggered decrease and increase of TNIP2 levels, respectively. Dual luciferase assay showed that TNIP2 was a direct target of miR-663a/miR-423-5p. In addition, detection of inflammatory factors confirmed that miR-663a/miR-423-5p and TNIP2 fundamentally contributed to LPS-induced NF-kappaB activation. Our findings suggested the involvement of miR-663a/miR-423-5p-TNIP2-NF-kappaB axis in the development of LN, thereby providing new therapeutic targets for LN treatment. PMID- 28861171 TI - Caragaphenol a induces reactive oxygen species related apoptosis in human gastric cancer cells. AB - Caragaphenol A (CAA) is a novel resveratrol trimer isolated from the roots of Caraganastenophylla. However, the biological activity of CAA is still unknown. In the present study, we investigated the anticancer effects of CAA on gastric cancer cells. CAA selectively inhibited cell growth of human gastric cancer cells. Moreover, CAA potently induced cell cycle arrest at G2/M phase and apoptosis with the increased intracellular reactive oxidative species (ROS) level. Inhibition of ROS could partially rescue CAA-induced cell apoptosis. Additionally, DNA is not the target of CAA. CAA in combination with DDP or 5FU synergistically inhibited the growth of human gastric cancer cells. Altogether, our study provides the evidence for the potential therapeutic application of CAA on human gastric cancer. PMID- 28861172 TI - Hepatocyte growth factor induces breast cancer cell invasion via the PI3K/Akt and p38 MAPK signaling pathways to up-regulate the expression of COX2. AB - Hepatocyte growth factor (HGF) is a multifunctional growth factor that plays important roles in promoting the invasion and metastasis of various tumor cells. However, there are few reports about the exact mechanisms of HGF involved in the regulation of cell invasion via the induction of COX2. In this study, we found that HGF could activate its receptor c-Met and up-regulate COX2 expression in a dose- and time-dependent manner, which resulted in an increase in MMP-9 expression and subsequent invasiveness of the breast cancer cell lines MDA-MB-231 and MCF-7. The HGF-induced expression of COX2 and MMP-9 and cell invasion were partially suppressed by COX2 gene silencing. The PI3K/Akt and p38 MAPK signaling pathways were activated by HGF in both cell lines. However, PI3K/Akt or p38 MAPK specific inhibition alone partially attenuated HGF-induced COX2 and MMP-9 expression and the invasiveness of the two breast cancer cell lines, and these HGF-induced effects were almost completely abolished by simultaneous treatment with both inhibitors. Therefore, we concluded that HGF mediates the up-regulation of COX2 predominantly through the PI3K/Akt and p38 MAPK signaling pathways, leading to MMP-9 expression and the subsequent invasion of two breast cancer cell lines. This study improves our understanding of the signal transduction mechanisms in the HGF-induced invasion and progression of breast cancer. PMID- 28861173 TI - Therapeutic effect of rosuvastatin and propylthiouracil on ameliorating high cholesterol diet-induced fatty liver disease, fibrosis and inflammation in rabbit. AB - This study tested the hypothesis that high-cholesterol diet (HCD)-induced fatty liver disease could be ameliorated by rosuvastatin (Ros) and propylthiouracil (PTU) therapy. Thirty-two Zealand rabbits were equally divided into group 1 (sham control), group 2 (HCD for 8 weeks), group 3 [HCD-Ros (20 mg/kg/day administration after 4-week HFD for 4 weeks)], group 4 [HCD-PTU (0.1% PTU in drinking water) with treatment course as group 3]. Liver weight, fibrosis, collagen deposition area, and serum levels of AST/ALT were highest in group 2, lowest in group 1, and significantly higher in group 4 than group 3 (all P<0.0001). The levels of inflammatory (TNF-alpha/NF-kappaB/IL-1beta/IL-6/MMP 9/VCAM-1/PAI-1/TLR-4, MyD88/IL-12/IFN-gamma), oxidative stress (NOX-1/NOX 2/oxidized protein), apoptotic (Bax/cleaved-capase-3/PARP), fibrotic (Smad-3/TGF beta), and mitochondria-damaged (cytosolic-cytochrome-C) proteins showed an identical pattern, whereas antiapoptotic (Bcl-2), mitochondrial-integrity (mitochondrial-cytochrome-C) and antioxidative (SIRT1/SIRT3) biomarkers exhibited an opposite pattern to fibrosis among the four groups (all P<0.0001). The cellular expressions of inflammatory (Kupffer/CD14/CD44), alpha-fetoprotein positively stained biomarkers, apoptotic nuclei and fat cells displayed an identical pattern to fibrosis (all P<0.0001). In conclusion, Ros-PTU therapy attenuated liver fibrosis, inflammatory reaction and generation of oxidative stress and fatty liver after HCD challenge in rabbits. PMID- 28861174 TI - Protective effect of asiatic acid in an experimental cerulein-induced model of acute pancreatitis in mice. AB - Asiatic acid (AA), a triterpenoid derived from the medicinal plant Centella asiatica, is considered to have anti-inflammatory, anti-fibrotic and anti-tumor effects, but its effects in acute pancreatitis (AP) are unknown. Our purpose of this study was to investigate the effects of AA in a mouse model of cerulein induced pancreatitis. We evaluated AA in an experimental model of AP induced in mice by six hourly intraperitoneal injections of cerulein 50 ug/kg. Mice were pretreated with vehicle or AA 50 mg/kg 2 h before the first cerulein injection. The severity of AP was evaluated histologically and by biochemistry, myeloperoxidase activity, proinflammatory cytokine production, and nuclear factor (NF)-kappaB activity. Administration of AA significantly reduced the severity of AP, and was associated with reduction of serum amylase and lipase levels, decreased pancreatic histological damage, and decreased myeloperoxidase activity. The serum levels and mRNA expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and NF-kappaB activity were reduced. AA also significantly improved the in vitro viability of pancreatic acinar cells induced by cholecystokinin (CCK) and suppressed NF-kappaB activity. AA protected against experimental AP, possibly by reducing production of proinflammatory cytokines via suppression NF-kappaB activation. PMID- 28861175 TI - The STAT3 inhibitor pimozide impedes cell proliferation and induces ROS generation in human osteosarcoma by suppressing catalase expression. AB - Currently, there is a considerable need to develop new treatments for osteosarcoma (OS), a very aggressive bone cancer. The activation of STAT3 signaling is positively associated with poor prognosis and aggressive progression in OS patients. Our previous study reported that the FDA-approved antipsychotic drug pimozide had anti-tumor activity against hepatocellular carcinoma and prostate cancer cells by suppressing STAT3 activity. Therefore, the aim of this study was to investigate the specific effect of pimozide on OS cells and the underlying molecular mechanism. Pimozide inhibited cell proliferation, colony formation, and sphere formation capacities of the OS cells in a dose-dependent manner, inducing G0/G1 phase cell cycle arrest. Pimozide reduced the percentage of side population cells representing cancer stem-like cells and enhanced the sensitivity of OS cells to 5-FU induced proliferative inhibition. In addition, pimozide induced apoptosis of U2OS cells, which showed increased expression of cleaved-PARP, a marker of programmed cell death. Moreover, pimozide suppressed Erk signaling in OS cells. Importantly, pimozide induced ROS generation by downregulating the expression of the antioxidant enzyme catalase (CAT). NAC treatment partially reversed the ROS generation and cytotoxic effects induced by pimozide. CAT treatment attenuated the pimozide-induced proliferation inhibition. The decrease of CAT expression induced by pimozide was potentially mediated through the suppression of cellular STAT3 activity in OS cells. Thus, pimozide may be a novel STAT3 inhibitor that suppresses cellular STAT3 activity to inhibit OS cells or stem-like cells and is a novel potential anti-cancer agent in OS treatment. PMID- 28861176 TI - Prevalence of obesity and diabetes in patients with schizophrenia. AB - AIM: To compare the prevalence of diabetes in patients with schizophrenia treated at a community mental health center with controls in the same metropolitan area and to examine the effect of antipsychotic exposure on diabetes prevalence in schizophrenia patients. METHODS: The study was a comprehensive chart review of psychiatric notes of patients with schizophrenia and schizoaffective disorder treated at a psychosis program in a community mental health center. Data collected included psychiatric diagnoses, diabetes mellitus diagnosis, medications, allergies, primary care status, height, weight, body mass index (BMI), substance use and mental status exam. Local population data was downloaded from the Centers for Disease Control Behavioral Risk Factor Surveillance System. Statistical methods used were chi2 test, Student's t test, general linear model procedure and binary logistic regression analysis. RESULTS: The study sample included 326 patients with schizophrenia and 1899 subjects in the population control group. Demographic data showed control group was on average 7.6 years older (P = 0.000), more Caucasians (78.7% vs 38.3%, P = 0.000), and lower percentage of males (40.7% vs 58.3%, P = 0.000). Patients with schizophrenia had a higher average BMI than the subjects in the population control (32.11, SD = 7.72 vs 27.62, SD = 5.93, P = 0.000). Patients with schizophrenia had a significantly higher percentage of obesity (58.5% vs 27%, P = 0.000) than the population group. The patients with schizophrenia also had a much higher rate of diabetes compared to population control (23.9% vs 12.2%, P = 0.000). After controlling for age sex, and race, having schizophrenia was still associated with increased risk for both obesity (OR = 3.25, P = 0.000) and diabetes (OR = 2.42, P = 0.000). The increased risk for diabetes remained even after controlling for obesity (OR = 1.82, P = 0.001). There was no difference in the distribution of antipsychotic dosage, second generation antipsychotic use or multiple antipsychotic use within different BMI categories or with diabetes status in the schizophrenia group. CONCLUSION: This study demonstrates the high prevalence of obesity and diabetes in schizophrenia patients and indicates that antipsychotics may not be the only contributor to this risk. PMID- 28861177 TI - Age-dependent changes in the association between sleep duration and impaired glucose metabolism. AB - AIM: To investigate whether the association between sleep duration and impaired glucose metabolism varies among younger and older populations. METHODS: We reviewed data of self-reported habitual sleep duration per night, HbA1c levels, and clinically relevant factors in a cross-sectional checkup database of 75472 Japanese from the general population aged 20-79 years (51695 men and 23777 women). Associations of prediabetes (HbA1c >= 5.7% and/or diabetic pharmacotherapy) or diabetes (HbA1c >= 6.5% and/or diabetic pharmacotherapy) with short and long sleep durations compared with a reference sleep duration (7 h) were investigated by multivariate logistic regression analysis. We controlled for potential relevant confounders, including age, sex, and work duration per day according to younger and older subjects. RESULTS: As age advanced, sleep duration became longer and this increase in the 40s and 50s was two times greater in men than in women. This finding was accompanied by a deterioration in HbA1c levels. In subjects aged younger than 40 years (n = 32929), HbA1c levels were inversely and linearly correlated with sleep duration in both sexes. However, in subjects aged 40 years or older (n = 42543), HbA1c levels showed a non-linear relationship against sleep duration with a nadir at 7 h. Multivariate logistic regression analysis showed that in younger subjects, short durations of sleep (<= 5 h and 6 h) were positively associated with prediabetes (both P < 0.001), but a long duration of sleep (>= 8 h) was inversely associated with prediabetes (P < 0.001). These associations remained significant after adjustment for relevant confounders, including age, sex, and work duration per day (ORs = 1.20, 95%CI: 1.05-1.37, P < 0.001; ORs = 1.12, 95%CI: 1.02-1.24, P < 0.05; and ORs = 0.84, 95%CI: 0.72-0.99, P < 0.05, respectively). In contrast, in older subjects, besides an association of prediabetes with a short duration of sleep (<= 5 h) (ORs = 1.12, 95%CI: 1.03-1.21, P < 0.01), diabetes was significantly associated with a long duration of sleep (>= 8 h) (ORs = 1.11, 95%CI: 1.02-1.25, P < 0.05). CONCLUSION: A short sleep duration may be associated with prediabetes throughout life. However, the association between a long sleep duration and glucose metabolism can change with aging. PMID- 28861178 TI - Clinico-epidemiological factors of health related quality of life among people with type 2 diabetes. AB - AIM: To investigate the quality of life (QOL) and its clinical and epidemiological correlates among people with type 2 diabetes. METHODS: This cross sectional study was conducted in Tabriz, Northwest of Iran, including a total of 394 people with type 2 diabetes using convenient sampling method from November 2014 to March 2015. General information including demographic, socioeconomic status and lifestyle factors were collected by trained interviewers. Clinical information was retrieved from clinic's record and QOL was assessed using the 26 item WHOQOL-BRIFE questionnaire. Univariate and multivariate linear regression were performed to assess the related factors and QOL dimensions. RESULTS: The mean of overall health related QOL was 52.11 +/- 11.53 and the maximum and minimum dimensions were respectively seen in psychological (60.38 +/- 14.54) and social (38.32 +/- 16.94) dimensions. The results of multiple linear regression showed a significant overall relationship between HRQOL and age (b = -1.48%, 95%CI: -0.03 and -2.93) level of education (b = 4.12%, 95%CI: 2.73 and 5.5), number of comorbidities (b = -2.41%, 95%CI: -3.89 and -9.41), and level of income (b = 1.98, 95%CI: 0.05 and 3.9), functional limitation (b = -3.59, 95%CI: -2.26 and -4.92) and psychological distress (b = -2.02%, 95%CI: -2.83 and -1.21). Level of education, functional limitation, psychological distress were associated with the score of physical, mental and environmental dimensions, and number of comorbidities was associated with the score of physical and mental dimensions. CONCLUSION: Based on our findings, lifestyle modification and increasing facilities of clinics providing service can be effective steps to improve the QOL among people with type 2 diabetes. PMID- 28861179 TI - Impact on dietary intake of a self-directed, gender-tailored diabetes prevention program in men. AB - AIM: To investigate changes in dietary intake following a 6-mo randomised controlled trial of the self-directed, gender-tailored type 2 diabetes mellitus (T2DM) Prevention Using LifeStyle Education (PULSE) program in men. METHODS: Men aged 18-65 years, with a body mass index (BMI) 25-40 kg/m2, and at high risk for developing T2DM were recruited from the Hunter Region of New South Wales, Australia. Eligible participants were randomised into one of two groups: (1) waitlist control; or (2) PULSE intervention. Dietary intake was assessed at baseline and immediately post-program using the Australian Eating Survey food frequency questionnaire and diet quality measured using the Australian Recommended Food Score (ARFS). RESULTS: One hundred and one participants (n = 48, control; n = 53, intervention, mean age 52.3 +/- 9.7 years, BMI of 32.6 +/- 3.3 kg/m2) commenced the study. Following the active phase, differences between groups were observed for proportion of total energy consumed from healthful (core) foods (+7.6%EI, P < 0.001), energy-dense, nutrient-poor foods (-7.6%EI, P < 0.001), sodium (-369 mg, P = 0.047), and diet quality (ARFS) (+4.3, P = 0.004), including sub-scales for fruit (+1.1, P = 0.03), meat (+0.9, P = 0.004) and non meat protein (+0.5, P = 0.03). CONCLUSION: The PULSE prevention program's nutrition messages led to significant improvements in dietary intake in men at risk of T2DM. PMID- 28861180 TI - Posterior Reversible Encephalopathy in Undiagnosed Systemic Lupus Erythematous: A Case Report. AB - A 33-year old Malay woman with undiagnosed systemic lupus erythematosus (SLE) and other comorbids presented with acute glomerularnephritis, hypertensive emergency and later acute confusional state. Cranial MRI revealed features consistent with posterior reversible encephalopathy syndrome (PRES). PMID- 28861181 TI - Separate Belly and Tendon of Flexor Digitorum Superficialis to the Fifth Digit. AB - Variation in the origin of long flexor tendons in the anterior compartment of forearm is common. During routine cadaveric dissection at Melaka Manipal Medical College (Manipal Campus), we observed a separate muscle belly and tendon of flexor digitorum superficialis (FDS) to the fifth digit in the right upper limb of a 60 year-old male cadaver. The anomalous muscle belly originated from the common flexor tendon from the medial epicondyle of the humerus and continued as a thin tendon at the middle of the forearm to get inserted into the middle phalanx of the fifth digit. This can be considered as a case of split flexor digitorum superficialis. Such muscle variations and knowledge of their frequency, appearance, and location can be helpful for surgeons. PMID- 28861182 TI - Salvage Surgery in Endoscopic Era. AB - Common bile duct stones are usually managed by Gastroenterologists using Endoscopic Retrograde Cholangiopancreaticography (ERCP) and services of Surgeons are required if the stone is large or impacted. But at times, emergency bile duct explorations become mandatory in some unusual complications of ERCP. We describe one such situation of impacted dormia basket during ERCP which required rescue surgery. PMID- 28861183 TI - Small Bowel Obstruction due to Meckel's Diverticulum: A Case Report. AB - Meckel's diverticulum is the most common congenital anomaly of the small intestine. Common complications related to Meckel's diverticulum include hemorrhage, intestinal obstruction and inflammation. Small bowel obstruction due to mesodiverticular band of Meckel's diverticulum is a rare complication. Herein, we report the diagnosis and management of a small bowel obstruction occurring due to the mesodiverticular band of a Meckel's diverticulum. PMID- 28861184 TI - Largest Serous Cystadenoma in the first Trimester treated Laparoscopically: A Case Report. AB - We report the first case of a giant serous cystadenoma approximately 7.5kg in weight in a 28-year old primigravida at 8 weeks of gestation which was successfully excised laparoscopically. Postoperatively, she had a quick recovery and she was discharged on post op day 3 with an intact pregnancy and no complications. This is the largest ovarian cyst in early pregnancy that has been ever reported from our hospital. We also believe this cyst to be the largest cyst in early pregnancy ever reported in the literature that has been managed by Laparoscopy. PMID- 28861185 TI - Primary Ovarian Clear Cell Adenofibroma of Borderline Malignancy. AB - Clear cell adenofibromas of borderline malignancy are extremely rare tumors of ovary. We report a case of ovarian borderline clear cell adenofibroma in a 53 year-old postmenopausal woman. The patient had abdominal hysterectomy and bilateral salpingo-oophorectomy because of left adnexeal mass. The tumor was well demarcated, solid and multinodular mass, measuring 12*10.5*6 cm. Microscopically, the tumor consisted mainly of fibrous stroma and glands composed of cells with eosinophilic or clear cytoplasm. The epithelium focally showed moderate nuclear atypia and mitotic figures. The histopathologic diagnosis was borderline clear cell adenofibroma. The patient is alive and well without signs of recurrence 6 months after the operation. PMID- 28861186 TI - Primary Lymphoepithelioma-like Carcinoma of the Lung in a 13 year old Girl. AB - Lymphoepithelioma-like carcinoma, a large cell carcinoma with pronounced lymphocyte infiltration, is a rare entity mostly seen in the nasopharynx. But primary pulmonary LELC in children & adolescents is extremely rare. Here we present a 13 year old girl with chief complaint of fever, cough, shortness of breath and heaviness in the left side of chest. She underwent left upper lobectomy. Histopathological examination of the biopsy specimen confirmed it to be a case of large cell carcinoma of lung, lymphoepithelioma type, invading pleura (stage pT3N0M0) with high serum titre of anti Epstein-Barr virus IgG antibody. PMID- 28861187 TI - Uterine Artery Embolization in Postpartum Hemorrhage: A Case Report. AB - A case of secondary postpartum hemorrhage was treated by uterine artery embolization with a view to preserve fertility as the patient was of low parity. PMID- 28861188 TI - Exercise Based Cardiac Rehabilitation for Unstable Angina: A Case Report. AB - A 42-year-old male was hospitalized with unstable angina (UA) which had resulted in severe impairment of his daily activities. Coronary angiography revealed a 100% occlusion of the right coronary artery (RCA) and a 50% stenosis within the left anterior descending coronary artery. However, in view of the previously occluded RCA that was supplied by discernible collaterals, medical management was recommended and he was rehabilitated using a progressive exercise regimen to increase his anginal threshold and functional capacity. Following rehabilitation, the patient demonstrated increases in the rate-pressure product of his anginal threshold, as well as his symptom-limited walking distance. At discharge, he was able to negotiate 400 m without angina and was asymptomatic during his daily activities. He was started on a home-based exercise program and followed for 9 months during which time he was functionally independent and walked at least 1 km each day. These findings highlight the benefits of an exercise-based cardiac rehabilitation program among patients with previous UA in whom other treatment options have been exhausted. PMID- 28861189 TI - Dermatofibrosarcoma Protuberans of Male Breast: An Unusual Presentation. AB - Dermatofibrosarcoma protuberans (DFSP) is a rare tumor, which usually presents during early or middle adult life, as erythematous indurated firm subcutaneous nodules. DFSP involving the breast is a rare phenomenon and even rarer in males. We describe a case of a male patient who presented with this tumor in his left breast. PMID- 28861190 TI - Cylindrical Cell Papilloma (Oncocytic Schneiderian Papilloma): Clinicopathological Study of Five Cases. AB - OBJECTIVE: To study the clinicopathological findings of cylindrical cell papilloma (oncocytic schneiderian papilloma) diagnosed among patients at Bahrain Defense Force Hospital with review of literature. METHODS: All cases of cylindrical cell papilloma were retrieved from the pathology register from 2006 2010. The medical records of the cases were studied for age, sex, clinical presentation, and imaging reports along with the histopathological findings. RESULTS: Five cases were found and showed male to female ratio 4:1. Their ages were between 36-71 years with average age of 55 years. The main symptom found was unilateral nasal obstruction mainly involving the left side. All papillomas were removed by endoscopic sinus surgery. Four patients had regular followup with complete recovery, while only one case was lost for followup. CONCLUSION: Cylindrical cell papilloma is a variant of sinonasal schneiderian papilloma. Although most are benign complete excision is the treatment of choice to prevent tumour recurrence as a proportion exhibit unpredictable biological behavior. This study is an important reminder for both clinicians and pathologists to recognize this tumor and to differentiate it from other tumours and rhinosporidiosis. Regular followup is an important strategy for complete recovery and tumour-free surveillance. PMID- 28861191 TI - Porous Femoral Fixation in Total Hip Arthroplasty with Short Anatomical Stem: Radiographic Evaluation. AB - BACKGROUND: Hip prostheses with short anatomical stems were designed for metaphyseal fixation and to spare bone stock. We present a study of a short anatomical femoral stem used in all age groups of patients with Dorr A and B type of femora. METHODS: We reviewed radiographs of 85 hips in 74 patients who had a cementless total hip arthroplasty with a short anatomical 80 mm femoral stem designed to achieve pure metaphyseal fixation. A ream-only technique was used for femoral canal preparation in all patients. At each follow-up, radiological evaluation was performed for stem alignment, proximal metaphyseal fill, subsidence, status of biological fixation of the femoral stem, heterotrophic ossification, radiolucency, osteolysis, and limb length discrepancy of the stem. Acetabular components were evaluated for positioning, acetabular bone coverage, and radiolucent and osteolytic lesions. RESULTS: The final mean alignment of femoral stem was 2 degrees valgus. The average intramedullary fill by the stem at the proximal level of the lesser trochanter was 93% in the coronal plane and 88% in the sagittal plane. No components were considered to be undersized. Thirteen hips (15.2%) presented radiolucent lines (10 hips < 1 mm in width and 3 hips [3.5%] 2 mm in width) and 100% of them were not progressive with respect to the last follow-up radiograph. All of the stems had excellent fixation by demonstrating bone ingrowth at the latest follow-up. At the last follow-up, heterotopic ossification was noted in 5 hips. The mean preoperative limb length discrepancy was 9.3 mm and the mean postoperative discrepancy was 3.8 mm. The mean acetabular component angle of the 85 components was 41.2 degrees with a mean anteversion of 22.1 degrees . At the last follow-up, there were no revisions of the femoral component. One patient, 25 months after the index operation, required an acetabular component revision because of recurrent hip dislocation. There were no radiological signs of loosening in any of the short-stem prostheses at the last examination. CONCLUSIONS: The short, metaphyseal-fitting anatomic cementless femoral stem provided stable fixation without relying on diaphyseal fixation. PMID- 28861192 TI - Comparison of Outcomes of Total Hip Arthroplasty between Patients with Ankylosing Spondylitis and Avascular Necrosis of the Femoral Head. AB - BACKGROUND: The objective of this study was to compare clinical and radiological outcomes of total hip arthroplasty (THA) between ankylosing spondylitis (AS) of the hip joint and avascular necrosis (AVN) of the femoral head. METHODS: Thirty patients (30 hips) underwent cementless THA for AS between 2003 and 2012. They were compared to 30 patients (30 hips) who underwent the same procedure for AVN of the femoral head. Each group was matched for age and gender, and both groups had similar preoperative demographic characteristics. All cases were followed for minimum 4 postoperative years. Clinical evaluation was based on operation time, intraoperative blood loss, quantity of postoperative drainage, Harris Hip Score (HHS), and range of motion (ROM). Radiological results were evaluated by acetabular cup anteversion and inclination, femoral stem orientation, pre- and postoperative leg length discrepancy, and postoperative complications. RESULTS: The operation time was significantly longer in the AS group (120.2 +/- 26.2 min) than in the AVN group (79.5 +/- 11.1 min). The volume of postoperative drainage was significantly greater in the AS group (764.5 +/- 355.4 mL vs. 510.5 +/- 195.6 mL). Preoperative HHS was lower in the AS group (55.6 +/- 13.8 vs. 59.2 +/- 2.8). Similarly, postoperative HHS was significantly lower in the AS group (92.8 +/- 2.7 vs. 97.4 +/- 2.6). The arc of ROM was improved from 146.5 degrees +/- 13.2 degrees preoperatively to 254.7 degrees +/- 17.2 degrees postoperatively in the AS group and from 182.6 degrees +/- 15.5 degrees to 260.4 degrees +/- 13.7 degrees in the AVN group. Implant position and postoperative leg length discrepancy were not different between the groups. However, three cases of heterotopic ossification was observed in the AS group, whereas only 1 case was found in the AVN group. One deep infection and one aseptic stem loosening were found in the AS group, whereas none was observed in the AVN group. CONCLUSIONS: Cementless THA showed satisfactory clinical and radiological results in both groups, despite the longer operation time, larger blood loss volume, and lower HHS score of the AS group. Our findings suggest that cementless THA is an effective and reliable treatment for both AS and AVN. PMID- 28861193 TI - Comparison of Poly-L-Lactic Acid and Poly-L-Lactic Acid/Hydroxyapatite Bioabsorbable Screws for Tibial Fixation in ACL Reconstruction: Clinical and Magnetic Resonance Imaging Results. AB - BACKGROUND: The purpose of this study was to compare the clinical and radiological results of 2 different tibial fixations performed using bioabsorbable screws with added hydroxyapatite (HA) and pure poly-L-lactic acid (PLLA) screws in anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 394 patients who underwent arthroscopic ACL reconstruction between March 2009 and June 2012 were retrospectively reviewed. Of those, 172 patients who took the radiological and clinical evaluations at more than 2 years after surgery were enrolled and divided into 2 groups: PLLA group (n = 86) and PLLA-HA group (n = 86). Both groups were assessed by means of the Lysholm score, International Knee Documentation Committee (IKDC) subjective knee score, and Tegner activity score. Stability was evaluated using the KT-2000 arthrometer. Magnetic resonance imaging was performed to evaluate tibial tunnel widening, screw resorption, osteoingeration, and foreign body reactions. RESULTS: The PLLA-HA group showed significant reduction in the extent of tibial tunnel widening and foreign body reactions and significant increase in screw resorption compared to the pure PLLA group (p < 0.001 for both). In contrast, postoperative Lysholm score, Tegner activity score, IKDC score, and side-to-side difference on the KT-2000 arthrometer showed no significant differences between groups (p = 0.478, p = 0.906, p = 0.362, and p = 0.078, respectively). The PLLA group showed more significant widening in the proximal tibial tunnel than the PLLA-HA group (p = 0.001). In the correlation analysis, proximal tibial tunnel widening revealed a positive correlation with knee laxity (r = 0.866) and a negative correlation with Lysholm score (r = -0.753) (p < 0.01 for both). CONCLUSIONS: The HA added PLLA screws would be advantageous for tibial graft fixation by reducing tibial tunnel widening, improving osteointegration, and lowering foreign body reactions. Even though no clinically significant differences were noted between the pure PLLA group and PLLA-HA group, widening of the proximal area of the tibial tunnel showed a tendency to increase knee laxity measured using the KT-2000 arthrometer. PMID- 28861194 TI - Tibial Base Plate for Total Knee Arthroplasty: Symmetric or Asymmetric? AB - BACKGROUND: Ideal positioning and best coverage of the tibial base plate are essential in total knee arthroplasty. There are 2 types of tibial base plates: symmetric and asymmetric. The superiority of one to the other is still controversial. The aim of this study was to compare symmetric and asymmetric tibial base plates for total knee arthroplasty in terms of rotational alignment and coverage. METHODS: The study was conducted on a total of 80 cadaveric tibial bones. Two surgeons were asked to place 20 symmetric (group 1) and 20 asymmetric (group 2) tibial base plates taking care to ensure the best coverage that they were able to determine. Afterwards, the rotational errors and coverage were assessed with reference to the posterior tibial margin and posterior condylar axis on the three-dimensional computed tomography (3D CT) scan. In the second part of the study, the surgeons were asked to place 20 symmetric (group 3) and 20 asymmetric (group 4) base plates taking care to ensure the best rotational alignment. The rotational errors and the areas uncovered or overstuffed after the application were measured on the 3D CT scan. RESULTS: On the comparison of rotational errors, while there was no significant difference between group 1 and group 2 in terms of coverage (p = 0.624), the mean external rotation error was significantly greater in group 2 (p = 0.034). On the comparison of coverage, while there was no significant difference between group 3 and group 4 in terms of rotation (p = 0.36), the mean ratios of the uncovered tibial surface to the total tibial surface (p = 0.041) and also the overstuffed area to the total base plate surface (p = 0.029) were significantly greater in group 4. CONCLUSIONS: The determination of correct size and rotation of the tibial component is essential for favorable outcomes of total knee arthroplasty. In this study, the symmetric tibial base plate design was more effective than the asymmetric design in providing the ideal tibial rotation and coverage. PMID- 28861195 TI - India-Based Knee Osteoarthritis Evaluation (iKare): A Multi-Centre Cross Sectional Study on the Management of Knee Pain and Early Osteoarthritis in India. AB - BACKGROUND: Access to early knee osteoarthritis treatment in low and middle income nations is often believed to be limited. We conducted a cross-sectional study in India to assess prior access to treatment among patients presenting with knee pain to specialist orthopaedic clinics. METHODS: The multi-centre, cross sectional study included patients presenting with knee pain at 3 hospitals in India. Patients who met the inclusion criteria and provided informed consent completed a questionnaire designed to assess patient demographics, socioeconomic status, knee pain, treatment method, and patient's knowledge on osteoarthritis (OA). Their orthopaedic surgeons also completed a questionnaire on the severity of patient's OA and their recommended treatments. The impact of demographic characteristics on the prescription of treatment options was analyzed using logistic regression. RESULTS: A total of 714 patients met the eligibility criteria and participated in this study. The majority of patients had been experiencing pain for less than 1 year (64.8%) and had previously been prescribed medications (91.6%), supplements (68.6%), and nonpharmacological (81.9%) treatments to manage their knee OA. Current treatment recommendations included oral medications (83.3%), intra-articular injections (29.8%), and surgical intervention (12.7%). Prescription of oral medications was related to younger age, lack of deformities, and lower Kellgren-Lawrence grades (p < 0.01). Patients treated in private hospital settings were more likely to have been previously treated with medications (range, 84.3% to 92.6%; p < 0.01) and physical treatments (range, 61.8% to 84.8%; p < 0.01) than patients treated at government hospitals. CONCLUSIONS: Contrary to the perception, our findings suggest a similar proportion of early knee OA treatment between India and North America. PMID- 28861196 TI - Patellofemoral Joint Arthroplasty: Early Results and Functional Outcome of the Zimmer Gender Solutions Patello-Femoral Joint System. AB - BACKGROUND: Improved knee prosthesis designs have led to an increase in the use of patellofemoral arthroplasty as a primary treatment option in recent times. We report the early results and outcomes of the Zimmer Gender Solutions Patello Femoral Joint (PFJ) system used to treat isolated patellofemoral osteoarthritis (PFA). METHODS: We retrospectively reviewed and analysed data of patients who underwent PFJ replacement (PFJR) at our institution with a minimum follow-up of 2 years. RESULTS: Median Oxford Knee score (OKS) was 38 (interquartile range, 28 to 42) at the latest follow-up with a significant improvement from preoperative scores (p < 0.0005). Median OKS was 40 for unilateral PFJRs and 39 for nonobese patients (body mass index [BMI] < 30 kg/m2). There was no significant difference in OKS between unilateral and bilateral procedures (p = 0.462). Likewise, there was no significant difference in OKS between obese and nonobese patients (p = 0.272). Two knees (4%) were revised for progression of osteoarthritis. No complications were reported related to infectious or thromboembolic causes. CONCLUSIONS: Our study showed good early results of the PFJ system, at least equal to those of other leading brands in the National Joint Registry for England, Wales and Northern Ireland (NJR). There have been no complications related to either the implantation technique or prosthetic design for this new implant. Progression of tibiofemoral arthritis remains a major concern. Our study also suggests that PFJR in obese patients and bilateral procedures can have good results. PMID- 28861197 TI - Comparison of the Effect of Continuous Femoral Nerve Block and Adductor Canal Block after Primary Total Knee Arthroplasty. AB - BACKGROUND: This study aimed to compare the effects of femoral nerve block and adductor canal block on postoperative pain, quadriceps strength, and walking ability after primary total knee arthroplasty. METHODS: Between November 2014 and February 2015, 60 patients underwent primary total knee arthroplasty. Thirty patients received femoral nerve block and the other 30 received adductor canal block for postoperative pain control. Before spinal anesthesia, the patients received nerve block via a catheter (20 mL 0.75% ropivacaine was administered initially, followed by intermittent bolus injection of 10 mL 0.2% ropivacaine every 6 hours for 3 days). The catheters were maintained in the exact location of nerve block in 24 patients in the femoral nerve block group and in 19 patients in the adductor canal block group. Data collection was carried out from these 43 patients. To evaluate postoperative pain control, the numerical rating scale scores at rest and 45 degrees flexion of the knee were recorded. To evaluate quadriceps strength, manual muscle testing was performed. Walking ability was assessed using the Timed Up and Go test. We also evaluated analgesic consumption and complications of peripheral nerve block. RESULTS: No significant intergroup difference was observed in the numerical rating scale scores at rest and 45 degrees flexion of the knee on postoperative days 1, 2, 3, and 7. The adductor canal block group had significantly greater quadriceps strength than did the femoral nerve block group, as assessed by manual muscle testing on postoperative days 1, 2, and 3. The 2 groups showed no difference in walking ability on postoperative day 1, but on postoperative days 2, 3, walking ability was significantly better in the adductor canal block group than in the femoral nerve block group. No significant intergroup difference was observed in analgesic consumption. CONCLUSIONS: The groups showed no difference in postoperative pain control. Adductor canal block was superior to femoral nerve block in preserving quadriceps strength and walking ability. However, adductor canal block was inferior to femoral nerve block in maintaining the exact location of the catheter. PMID- 28861198 TI - Lumbar Single-Level Dynamic Stabilization with Semi-Rigid and Full Dynamic Systems: A Retrospective Clinical and Radiological Analysis of 71 Patients. AB - BACKGROUND: This study compares the clinical and radiological results of three most commonly used dynamic stabilization systems in the field of orthopedic surgery. METHODS: A total of 71 patients underwent single-level posterior transpedicular dynamic stabilization between 2011 and 2014 due to lumbar degenerative disc disease. Three different dynamic systems used include: (1) the Dynesys system; (2) a dynamic screw with a PEEK rod; and (3) a full dynamic system (a dynamic screw with a dynamic rod; BalanC). The mean patient age was 45.8 years. The mean follow-up was 29.7 months. Clinical and radiological data were obtained for each patient preoperatively and at 6, 12, and 24 months of follow-up. RESULTS: Clinical outcomes were significantly improved in all patients. There were no significant differences in the radiological outcomes among the groups divided according to the system used. Screw loosening was detected in 2 patients, and 1 patient developed screw breakage. All patients with screw loosening or breakage underwent revision surgery. CONCLUSIONS: Each procedure offered satisfactory outcome regardless of which system was applied. PMID- 28861199 TI - The Efficacy of Vitamin C on Postoperative Outcomes after Posterior Lumbar Interbody Fusion: A Randomized, Placebo-Controlled Trial. AB - BACKGROUND: Vitamin C has critical features relavant to postoperative pain management and functional improvement; however, no study has yet evaluated the effectiveness of vitamin C on improving the surgical outcomes for spine pathologies. Thus, this study aimed to explore the impact of vitamin C on postoperative outcomes after single-level posterior lumbar interbody fusion (PLIF) for lumbar spinal stenosis in prospectively randomized design. We conducted a 1-year prospective, randomized, placebo-controlled, double-blind study to evaluate the impact of vitamin C on the postoperative outcomes after PLIF surgery. METHODS: A total of 123 eligible patients were randomly assigned to either group A (62 patients with vitamin C) or group B (61 patients with placebo). Patient follow-up was continued for at least 1 year after surgery. The primary outcome measure was pain intensity in the lower back using a visual analogue scale. The secondary outcome measures were: (1) the clinical outcome assessed using the Oswestry Disability Index (ODI); (2) the fusion rate assessed using dynamic radiographs and computed tomography scans; and (3) complications. RESULTS: Pain intensity in the lower back was significantly improved in both groups compared with preoperative pain intensity, but no significant difference was observed between the 2 groups over the follow-up period. The ODI score of group A at the third postoperative month was significantly higher than the score of group B. After the sixth postoperative month, the ODI score of group A was slightly higher than the score of group B; however, this difference was not significant. The fusion rates at 1 year after surgery and the complication rates were not significantly different between the 2 groups. CONCLUSIONS: Postoperative pain intensity, the primary outcome measure, was not significantly different at 1 year after surgery between the 2 groups. However, vitamin C may be associated with improving functional status after PLIF surgery, especially during the first 3 postoperative months. PMID- 28861200 TI - Reverse Shoulder Arthroplasty in Patients with Rheumatoid Arthritis: A Systematic Review. AB - BACKGROUND: There are limited data available regarding the results of reverse shoulder arthroplasty (RSA) in patients with rheumatoid arthritis (RA). We performed a systematic review of the literature to investigate the radiological and clinical outcomes after RSA in patients with RA. METHODS: A literature search for publications between 1987 and 2014 was conducted by 2 independent reviewers using PubMed, Scopus, Embase, and Cochrane Central Register of Controlled Trials. Articles were retrieved by an electronic search using keywords and their combinations. Studies that met inclusion criteria were assessed for pertinent data. RESULTS: Seven studies including 123 shoulders met the inclusion criteria. The mean age of the patients was 67.9 years and the mean follow-up period was 46.6 months. The mean Constant score and American Shoulder and Elbow Surgeons (ASES) score increased from 18.6 and 27.5 preoperatively to 58.6 and 73.7, respectively, at the final follow-up evaluation. The mean active forward flexion, abduction, and external rotation increased from 57.2 degrees , 50.4 degrees , and 11.4 degrees to 127.1 degrees , 116.7 degrees , and 26.4 degrees , respectively. The incidence of scapular notching was 33.7%. Twenty-seven (22.0%) of 123 shoulders had one or more complications, 12 of which (44.4%) had intraoperative or postoperative fractures. Nine shoulders (7.3%) had one or more revision surgeries. CONCLUSIONS: RSA in RA showed similar short- to mid-term results without higher complication rates as compared to RSA in cuff tear arthropathy. Although RSA can be considered a reliable treatment option in patients with RA, further large-scale studies are required to determine the long-term survival of the implant. PMID- 28861201 TI - Arthroscopic Evaluation of Subluxation of the Long Head of the Biceps Tendon and Its Relationship with Subscapularis Tears. AB - BACKGROUND: The purpose of this study was to evaluate the angle between the long head of the biceps tendon (LHBT) and the glenoid during arthroscopic surgery and its correlation with biceps subluxation on magnetic resonance imaging (MRI). Furthermore, we evaluated the relationship of this angle with subscapularis tears and biceps pathologies. METHODS: MRI and arthroscopic images of 270 consecutive patients who had undergone arthroscopic surgery were retrospectively evaluated. On MRI, 60 shoulders with biceps subluxation and 210 shoulders without subluxation were identified. On the arthroscopic view from the posterior portal, the angle between the LHBT and the glenoid (biceps-glenoid angle) was measured. The biceps-glenoid angle, tears of the LHBT, degenerative superior labrum anterior to posterior (SLAP) lesions, and presence of a subscapularis tear were compared according to the presence of biceps subluxation on MRI. RESULTS: In the subluxation group, 51 (85%) had a subscapularis tendon tear and all shoulders showed biceps tendon pathologies. In the non-subluxation group, 116 (55.2%) had a subscapularis tendon tear, 125 (60%) had tears in the biceps tendon, and 191 (91%) had degenerative SLAP lesions. The incidences of subscapularis tears (p < 0.001) and biceps pathologies (p < 0.001) showed significant differences. The mean biceps-glenoid angle was 87.0 degrees (standard deviation [SD], 11.4 degrees ) in the subluxation group and 90.0 degrees (SD, 9.6 degrees ) in the non-subluxation group, showing a statistically significant difference (p = 0.037). CONCLUSIONS: Shoulders with subluxation of the biceps tendon on the preoperative MRI revealed more pathologies in the subscapularis tendon and biceps tendon during arthroscopy. However, the arthroscopically measured biceps-glenoid angle did not have clinical relevance to the determination of subluxation of the LHBT from the bicipital groove. PMID- 28861202 TI - Comparison of Arthroscopically Guided Suprascapular Nerve Block and Blinded Axillary Nerve Block vs. Blinded Suprascapular Nerve Block in Arthroscopic Rotator Cuff Repair: A Randomized Controlled Trial. AB - BACKGROUND: The purpose of this study was to compare the results of arthroscopically guided suprascapular nerve block (SSNB) and blinded axillary nerve block with those of blinded SSNB in terms of postoperative pain and satisfaction within the first 48 hours after arthroscopic rotator cuff repair. METHODS: Forty patients who underwent arthroscopic rotator cuff repair for medium sized full thickness rotator cuff tears were included in this study. Among them, 20 patients were randomly assigned to group 1 and preemptively underwent blinded SSNB and axillary nerve block of 10 mL 0.25% ropivacaine and received arthroscopically guided SSNB with 10 mL of 0.25% ropivacaine. The other 20 patients were assigned to group 2 and received blinded SSNB with 10 mL of 0.25% ropivacaine. Visual analog scale (VAS) score for pain and patient satisfaction score were assessed 4, 8, 12, 24, 36, and 48 hours postoperatively. RESULTS: The mean VAS score for pain was significantly lower 4, 8, 12, 24, 36, and 48 hours postoperatively in group 1 (group 1 vs. group 2; 5.2 vs. 7.4, 4.1 vs. 6.1, 3.0 vs. 5.1, 2.1 vs. 4.2, 0.9 vs. 3.9, and 1.3 vs. 3.3, respectively). The mean patient satisfaction score was significantly higher at postoperative 4, 8, 12, 24, 36, and 48 hours in group 1 (group 1 vs. group 2; 6.7 vs. 3.9, 7.4 vs. 5.1, 8.8 vs. 5.9, 9.2 vs. 6.7, 9.5 vs. 6.9, and 9.0 vs. 7.2, respectively). CONCLUSIONS: Arthroscopically guided SSNB and blinded axillary nerve block in arthroscopic rotator cuff repair for medium-sized rotator cuff tears provided more improvement in VAS for pain and greater patient satisfaction in the first 48 postoperative hours than blinded SSNB. PMID- 28861203 TI - Differences between the Upper Extremity and the Lower Extremity in Reconstruction Using an Anterolateral Thigh Perforator Flap. AB - BACKGROUND: While reconstruction of soft tissue defects is the common purpose, surgical reconstructions of upper extremities and lower extremities have different goals in terms of functional and aesthetic outcomes. The purpose of the current study was to compare and analyze differences between reconstructions of upper extremities and lower extremities using an anterolateral thigh (ALT) flap. METHODS: We analyzed 74 patients who underwent reconstructions of upper extremities and lower extremities using an ALT flap from October 2006 to August 2012 (upper extremities, 45 cases; lower extremities, 29 cases). The study focused on the statistical analysis of patient satisfaction according to the donor site of the ALT flap and the timing of a debulking procedure. RESULTS: On the choice of donor site, in the upper extremity reconstruction, flap elevation from the opposite side of the recipient limb was preferred (p = 0.019) because it causes less inconvenience while walking. In the lower extremity reconstruction, flap elevation from the same side of the recipient limb (p = 0.002) was preferred. The debulking procedure performed on the upper extremities at 4 weeks after reconstruction led to better functional results and enhanced patient satisfaction (p = 0.022). In the case of lower extremities, enhanced satisfaction was noted in patients who underwent the procedure at 6 months after reconstruction (p < 0.001). CONCLUSIONS: Elevation of the flap in reconstruction reduced inconvenience when performed on the same side of the recipient limb for lower extremities and on the opposite side for upper extremities. In addition, debulking resulted in better satisfaction when performed 4 weeks postoperatively in the upper extremities and 6 months postoperatively in the lower extremities. PMID- 28861204 TI - Clinical Outcome of Lateral Wedge Osteotomy of the Radius in Advanced Stages of Kienbock's Disease. AB - BACKGROUND: Radius osteotomies showed favorable clinical outcome in Kienbock's disease. However, few articles have been published on the long-term outcome of lateral wedge osteotomy of the radius in patients with advanced stage Kienbock's disease. METHODS: Eleven patients with Lichtman stage IIIB/IV Kienbock's disease (group A; mean follow-up period, 86.1 months; range, 48 to 163 months) and 14 patients with Lichtman stage IIIA Kienbock's disease (group B; mean follow-up period, 85.1 months; range, 49 to 144 months) underwent radial wedge osteotomy between August 2004 and August 2012. Radiological changes of the lunate and radiocarpal joint were compared between two groups after osteotomy. The wrist flexion/extension angle, grip strength, and Disabilities of the Arm, Shoulder and Hand (DASH) scores were evaluated preoperatively and at the final follow-up. The Nakamura Scoring System (NSSK) was used for comprehensive understanding of radiological and clinical outcomes. RESULTS: Nine patients of group A and 11 patients of group B showed radiological improvement in the lunate regarding sclerosis, cystic changes, or fragmentation. No patients showed progression of arthritic changes in radiocarpal and midcarpal joints. The wrist flexion/extension angle, grip strength, and DASH score were significantly improved in both groups after operation, but intergroup difference was not statistically significant at the final follow-up (p = 0.149, p = 0.267, and p = 0.536, respectively). The mean NSSK was 21.6 (range, 15 to 27) in group A and 21.8 (range, 15 to 26) in group B. CONCLUSIONS: Radial wedge osteotomy yielded excellent radiological and functional outcomes in advanced stages of Kienbock's disease and these results were comparable to those of Lichtman stage IIIA disease. This technique could be a useful alternative to salvage procedures in the treatment of Lichtman stage IIIB/IV Kienbock's disease without severe radiocarpal arthritis. PMID- 28861205 TI - Gait Analysis of Symptomatic Flatfoot in Children: An Observational Study. AB - BACKGROUND: Flatfoot deformity is a lever arm disease that incurs kinetic inefficiency during gait. The purpose of this study was to measure the degree of kinetic inefficiency by comparing the gait analysis data of a flatfoot group with a normal control group. METHODS: The patient group consisted of 26 children (21 males and 5 females) with symptomatic flatfoot. They were examined with gait analysis between May 2005 and February 2014. Exclusion criteria were patients with secondary flatfoot caused by neuromuscular disorders, tarsal coalition, vertical talus, or others. Patients' mean age was 9.5 years (range, 7 to 13 years). The gait analysis data of the study group and the normal control group were compared. RESULTS: The mean vertical ground reaction force (GRF) in the push off phase was 0.99 for the patient group and 1.15 for the control group (p < 0.05). The mean ankle moment in the sagittal plane during the push-off phase was 0.89 for the patient group and 1.27 for the control group (p < 0.05). The mean ankle power in the sagittal plane during the push-off phase was 1.38 for the patient group and 2.52 for the control group (p < 0.05). The aforementioned results show that patients with pes planovalgus had a reduction of moment, power, and GRF in the push-off phase during gait. CONCLUSIONS: Symptomatic flatfeet had a moment inefficiency of 30% and power inefficiency of 45% during gait compared to feet with preserved medial longitudinal arches. PMID- 28861206 TI - Comparison of Pasteurized Autograft-Prosthesis Composite Reconstruction and Resection Hip Arthroplasty for Periacetabular Tumors. AB - BACKGROUND: Because of the high complication rate of anatomical reconstruction after periacetabular resection, the strategy of resection alone has been revisited. However, in terms of complications and functional outcome, whether resection hip arthroplasty (RHA) shows a superior result to that of pelvic ring reconstruction remains controversial. METHODS: We compared 24 RHAs and 16 pasteurized autograft-prosthesis composite (PPC) reconstructions regarding the complication rates, operative time, blood loss, and functional outcome. RESULTS: Compared to 16 PPC hips, 24 RHA hips showed lower major and minor complication rates (p < 0.001), shorter surgical time (p < 0.001), and superior Musculoskeletal Tumor Society scores (p < 0.001). Of the 24 RHA hips, bony neo acetabulum was identified in 7 on computed tomography and partial neo-acetabulum in 9; the remaining 8 had no bony acetabular structure. The average time to bony neo-acetabulum formation was 7 months (range, 4 to 13 months). CONCLUSIONS: RHA for periacetabular tumors can be an excellent alternative to anatomical reconstruction. It offers short surgical time, low complication rates, and functional results comparable to those of other reconstruction methods. However, this procedure is indicated for patients who can accept some limb shortening, and a tumor should be confined to the periacetabular area. PMID- 28861207 TI - Clinical Outcomes in Musculoskeletal Involvement of Burkholderia Pseudomallei Infection. AB - BACKGROUND: Musculoskeletal involvement in melioidosis is often seen in conjunction with a disseminated illness. Recent reports suggest that operative management of musculoskeletal melioidosis has favourable results. The purpose of this study was to review the patient profile and clinical outcomes of Burkholderia pseudomallei infection in the musculoskeletal system. METHODS: Hospital records of 163 patients who were diagnosed to have B. pseudomallei infection between January 2009 and December 2014 were reviewed. Patients underwent surgical and nonsurgical management depending upon the tissue of involvement. Epidata software was used to record the data. The SPSS ver. 17.0 was used for analysis. RESULTS: Eighteen out of 24 patients who had musculoskeletal melioidosis were available for follow-up. Septic arthritis, osteomyelitis, and intramuscular abscess were the common diagnosis, with 6 patients in each group. Twelve patients required surgical intervention. All patients received a full course of parenteral ceftazidime followed by oral doxycycline and co-trimoxazole. Two out of 6 patients (33.3%) died among those who had nonsurgical management as compared to none in the group who had surgical management. This was significant at 10% level of significance (p = 0.098). The rest were followed up for a minimum of 1 year with no evidence of disease recurrence. CONCLUSIONS: This series describing musculoskeletal involvement in melioidosis is the largest such study from a recently recognized 'endemic' region. Of importance are the patterns of musculoskeletal involvement, pitfalls in diagnosis and adequate clinical response with timely diagnosis and appropriate surgical management. PMID- 28861208 TI - Retrograde Intramedullary Nailing for Humerus Fracture in a Supine Position: Performing an Unfamiliar Procedure in a Familiar Position. AB - Intramedullary (IM) nailing for humeral shaft fracture has provided excellent outcomes in terms of fracture biology and cosmetic appearance because of the relatively small incision involved. However, antegrade nailing causes issues such as iatrogenic rotator cuff injury. Retrograde nail fixation method could avoid cuff injury, but has shortcomings such as the need for the prone or lateral decubitus position during surgery. We report that the retrograde IM nail fixation technique performed in a supine position and some ancillary techniques for minimizing scars or complications can provide the advantages of both retrograde nailing and supine position during surgery. PMID- 28861209 TI - Erratum to "Clinical Outcomes and Complications during the Learning Curve for Reverse Total Shoulder Arthroplasty: An Analysis of the First 40 Cases". AB - [This corrects the article on p. 213 in vol. 9, PMID: 28567225.]. PMID- 28861210 TI - Pharmacogenetics and precision medicine: Is inflammation a covert threat to effective genotype-based therapy? PMID- 28861211 TI - Adverse effects of proton-pump inhibitor use in older adults: a review of the evidence. AB - Proton-pump inhibitors (PPIs) are a widely prescribed class of medications used to treat acid-related disorders and use has significantly increased over the last few decades. PPIs are often inappropriately prescribed and since they have been on the market, a number of post-marketing studies have been published demonstrating associations between longer duration of PPI therapy and a number of adverse effects that are a concern in older adults. The objective of this review is to discuss the existing literature of potential adverse effects with long-term PPI use in older adults and to summarize the implications in clinical practice. A PubMed search was conducted to identify studies evaluating the potential long term adverse effects of PPI therapy in older adults, and publications were selected based on relevant criteria. PPIs have been associated with an increased risk of a number of adverse effects including osteoporotic-related fractures, Clostridium difficile infection, community-acquired pneumonia, vitamin B12 deficiency, kidney disease, and dementia, demonstrated by a number of case control, cohort studies, and meta-analyses. Older adults should be periodically evaluated for the need for continued use of PPI therapy given the number of potential adverse effects associated with long-term use. PMID- 28861212 TI - Revised disproportionality analysis of Mirena and benign intracranial hypertension. PMID- 28861213 TI - Idiopathic non-histaminergic acquired angioedema: a case series and discussion of published clinical trials. AB - BACKGROUND: Idiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease for which there are no available laboratory parameters to clearly define the disorder. Therapy is often difficult and various treatment options have been proposed. In this paper, we have evaluated the most effective therapies for InH AAE on the basis of current literature and report the therapeutic effect of omalizumab in three patients with InH-AAE. METHODS: Literature was searched with a combination of MeSH/EMTREE terms and freetext search for angioedema and therapy/omalizumab in the databases Medline (Ovid), PubMed/Premedline, Embase, Cochrane library and Scopus with no time or language restrictions. In three patients affected by InH-AAE the therapeutic effect of omalizumab was demonstrated by clinical outcome. In one patient the FcepsilonRI receptor density on basophils was monitored under therapy with omalizumab. RESULTS: From the review of the current literature, 25 out of 286 publications dealing with relevant therapeutic recommendations for InH-AAE were analyzed. Six publications with 98 patients referred to tranexamic acid, of which 27 had a complete, 70 a partial and 1 no response. In three case reports ecallantide showed 2 patients with a complete and 1 a partial response. In four case reports for Icatibant 2 had a complete and 3 a partial response. When evaluated in three reports, C1-INH found complete and partial responses in 2 patients each. One patient had a complete response to progestin. Omalizumab was described in 6 reports with 20 patients, all of whom showed a complete response. All three patients described in our study responded to omalizumab with a complete remission. Density of FcepsilonRI receptors on basophils, monitored in patient 1 on a long-term course of 31 months, decreased from 74,051.61 to a minimal level of 1907 receptors per cell. CONCLUSIONS: Omalizumab seems to be the most effective therapy in InH-AAE. The continuous decrease of FcepsilonRI-receptor density on basophils under therapy with omalizumab along with clinical improvement observed in one patient, could serve as a new approach for further studies to evaluate FcepsilonRI receptor density as a surrogate marker for therapeutic efficacy and for dosing and determining injection intervals of omalizumab. Trial registration BASEC-Nr. Req-2016-00692. Retrospectively registered 24.11.2016. PMID- 28861214 TI - Phylogeography of a migratory songbird across its Canadian breeding range: Implications for conservation units. AB - The objectives of this study were to describe and evaluate potential drivers of genetic structure in Canadian breeding populations of the Ovenbird, Seiurus aurocapilla. We performed genetic analyses on feather samples of individuals from six study sites using nuclear microsatellites. We also assessed species identity and population genetic structure of quill mites (Acariformes, Syringophilidae). For male Ovenbirds breeding in three study sites, we collected light-level geolocator data to document migratory paths and identify the wintering grounds. We also generated paleohindcast projections from bioclimatic models of Ovenbird distribution to identify potential refugia during the last glacial maximum (LGM, 21,000 years before present) as a factor explaining population genetic structure. Birds breeding in the Cypress Hills (Alberta/Saskatchewan) may be considered a distinct genetic unit, but there was no evidence for genetic differentiation among any other populations. We found relatively strong migratory connectivity in both western and eastern populations, but some evidence of mixing among populations on the wintering grounds. There was also little genetic variation among syringophilid mites from the different Ovenbird populations. These results are consistent with paleohindcast distribution predictions derived from two different global climate models indicating a continuous single LGM refugium, with the possibility of two refugia. Our results suggest that Ovenbird populations breeding in boreal and hemiboreal regions are panmictic, whereas the population breeding in Cypress Hills should be considered a distinct management unit. PMID- 28861215 TI - Historic changes in length distributions of three Baltic cod (Gadus morhua) stocks: Evidence of growth retardation. AB - Understanding how combinations of fishing effort and selectivity affect productivity is central to fisheries research. We investigate the roles of fishing regulation in comparison with ecosystem status for Baltic Sea cod stock productivity, growth performance, and population stability. This case study is interesting because three cod populations with different exploitation patterns and stock status are located in three adjacent but partially, ecologically different areas. In assessing stock status, growth, and productivity, we use survey information and rather basic stock parameters without relying on age readings. Because there is an urgent interest of better understanding of the current development of the Eastern Baltic cod stock, we argue that our approach represents partly a novel way of interpreting monitoring information together with catch data in a simplified yet more informative way. Our study reports how the Eastern and Western Baltic cod have gone toward more truncated size structures between 1991 and 2016, in particular for the Eastern Baltic cod, whereas the Oresund cod show no trend. We suggest that selective fishing may disrupt fish population dynamic stability and that lower natural productivity might amplify the effects of selective fishing. In support of earlier findings on a density-dependent growth of Eastern Baltic cod, management is advised to acknowledge that sustainable exploitation levels for Eastern Baltic cod are much more limited than perceived in regular assessments. Of more general importance, our results emphasize the need to embrace a more realistic view on what ecosystems can produce regarding tractable fish biomass to facilitate a more ecosystem-based fisheries management. PMID- 28861216 TI - Simultaneous estimation of diet composition and calibration coefficients with fatty acid signature data. AB - Knowledge of animal diets provides essential insights into their life history and ecology, although diet estimation is challenging and remains an active area of research. Quantitative fatty acid signature analysis (QFASA) has become a popular method of estimating diet composition, especially for marine species. A primary assumption of QFASA is that constants called calibration coefficients, which account for the differential metabolism of individual fatty acids, are known. In practice, however, calibration coefficients are not known, but rather have been estimated in feeding trials with captive animals of a limited number of model species. The impossibility of verifying the accuracy of feeding trial derived calibration coefficients to estimate the diets of wild animals is a foundational problem with QFASA that has generated considerable criticism. We present a new model that allows simultaneous estimation of diet composition and calibration coefficients based only on fatty acid signature samples from wild predators and potential prey. Our model performed almost flawlessly in four tests with constructed examples, estimating both diet proportions and calibration coefficients with essentially no error. We also applied the model to data from Chukchi Sea polar bears, obtaining diet estimates that were more diverse than estimates conditioned on feeding trial calibration coefficients. Our model avoids bias in diet estimates caused by conditioning on inaccurate calibration coefficients, invalidates the primary criticism of QFASA, eliminates the need to conduct feeding trials solely for diet estimation, and consequently expands the utility of fatty acid data to investigate aspects of ecology linked to animal diets. PMID- 28861217 TI - The evolution of mutualism with modifiers. AB - Mutualisms are widespread, yet their evolution has received less theoretical attention than within-species social behaviors. Here, we extend previous models of unconditional pairwise interspecies social behavior, to consider selection for donation but also for donation-suppressing modifiers. We present conditions under which modifiers that suppress costly donation receive either positive or negative selection; assortment only at the donation locus always leads to selection for donation suppression, as in within-species greenbeard traits. However, genomewide assortment with modifier loci can lead to intermediate levels of donation, and these can differ in the two species even when payoffs from donation are additive and symmetric. When costly donation between species can evolve without being suppressed, we argue that it is most appropriately explained by indirect fitness benefits within the donating species, using partner species as vectors for altruism. Our work has implications for identifying both the stability and the ultimate beneficiaries of social behavior between species. PMID- 28861218 TI - No evidence of nonlinear effects of predator density, refuge availability, or body size of prey on prey mortality rates. AB - Predator density, refuge availability, and body size of prey can all affect the mortality rate of prey. We assume that more predators will lead to an increase in prey mortality rate, but behavioral interactions between predators and prey, and availability of refuge, may lead to nonlinear effects of increased number of predators on prey mortality rates. We tested for nonlinear effects in prey mortality rates in a mesocosm experiment with different size classes of western mosquitofish (Gambusia affinis) as the prey, different numbers of green sunfish (Lepomis cyanellus) as the predators, and different levels of refuge. Predator number and size class of prey, but not refuge availability, had significant effects on the mortality rate of prey. Change in mortality rate of prey was linear and equal across the range of predator numbers. Each new predator increased the mortality rate by about 10% overall, and mortality rates were higher for smaller size classes. Predator-prey interactions at the individual level may not scale up to create nonlinearity in prey mortality rates with increasing predator density at the population level. PMID- 28861219 TI - Disentangling the genetic and morphological structure of Patella candei complex in Macaronesia (NE Atlantic). AB - The uptake of natural living resources for human consumption has triggered serious changes in the balance of ecosystems. In the archipelagos of Macaronesia (NE Atlantic), limpets have been extensively exploited probably since islands were first colonized. This has led to profound consequences in the dynamics of rocky shore communities. The Patella candei complex includes various subspecies of limpets that are ascribed to a particular archipelago and has been the focus of several taxonomic surveys without much agreement. Under a conservational perspective, we apply morphometric and genetic analyses to test subspecies boundaries in P. candei and to evaluate its current population connectivity throughout Macaronesia (Azores, Madeira, and Canaries). A highly significant genetic break between archipelagos following isolation by distance was detected (FST = 0.369, p < .001). Contrastingly, significant genetic differentiation among islands (i.e., Azores) was absent possibly indicating ongoing gene flow via larval exchange between populations. Significant shell-shape differences among archipelagos were also detected using both distance-based and geometric morphometric analyses. Adaptive processes associated with niche differentiation and strong barriers to gene flow among archipelagos may be the mechanisms underlying P. candei diversification in Macaronesia. Under the very probable assumption that populations of P. candei from each archipelago are geographically and/or ecologically isolated populations, the various subspecies within the P. candei complex may be best thought of as true species using the denomination: P. candei in Selvagens, Patella gomesii in Azores, Patella ordinaria in Madeira, and Patella crenata for Canaries. This would be in agreement with stock delimitation and units of conservation of P. candei sensu latu along Macaronesia. PMID- 28861220 TI - The ability to manipulate plant glucosinolates and nutrients explains the better performance of Bemisia tabaci Middle East-Asia Minor 1 than Mediterranean on cabbage plants. AB - The performance of herbivorous insects is greatly affected by host chemical defenses and nutritional quality. Some herbivores have developed the ability to manipulate plant defenses via signaling pathways. It is currently unclear, however, whether a herbivore can benefit by simultaneously reducing plant defenses and enhancing plant nutritional quality. Here, we show that the better performance of the whitefly Bemisia tabaci Middle East-Asia Minor 1 (MEAM1; formerly the "B" biotype) than Mediterranean (MED; formerly the "Q" biotype) on cabbage is associated with a suppression of glucosinolate (GS) content and an increase in amino acid supply in MEAM1-infested cabbage compared with MED infested cabbage. MEAM1 had higher survival, higher fecundity, higher intrinsic rate of increase (rm), a longer life span, and a shorter developmental time than MED on cabbage plants. Amino acid content was higher in cabbage infested with MEAM1 than MED. Although infestation by either biotype decreased the levels of total GS, aliphatic GS, glucoiberin, sinigrin, glucobrassicin, and 4OH glucobrassicin, and the expression of related genes in cabbage, MED infestation increased the levels of 4ME-glucobrassicin, neoglucobrassicin, progoitrin, and glucoraphanin. The GS content and expression of GS-related genes were higher in cabbage infested with MED than with MEAM1. Our results suggest that MEAM1 performs better than MED on cabbage by manipulating host defenses and nutritional quality. PMID- 28861221 TI - Temperature, energy metabolism, and adaptive divergence in two oyster subspecies. AB - Comparisons of related species that have diverse spatial distributions provide an efficient way to investigate adaptive evolution in face of increasing global warming. The oyster subjected to high environmental selections is a model species as sessile marine invertebrate. This study aimed to detect the adaptive divergence of energy metabolism in two oyster subspecies from the genus Crassostrea-C. gigas gigas and C. gigas angulata-which are broadly distributed along the northern and southern coasts of China, respectively. We examined the effects of acute thermal stress on energy metabolism in two oyster subspecies after being common gardened for one generation in identical conditions. Thermal responses were assessed by incorporating physiological, molecular, and genomic approaches. Southern oysters exhibited higher fluctuations in metabolic rate, activities of key energetic enzymes, and levels of thermally induced gene expression than northern oysters. For genes involved in energy metabolism, the former displayed higher basal levels of gene expression and a more pronounced downregulation of thermally induced expression, while the later exhibited lower basal levels and a less pronounced downregulation of gene expression. Contrary expression pattern was observed in oxidative stress gene. Besides, energy metabolic tradeoffs were detected in both subspecies. Furthermore, the genetic divergence of a nonsynonymous SNP (SOD-132) and five synonymous SNPs in other genes was identified and validated in these two subspecies, which possibly affects downstream functions and explains the aforementioned phenotypic variations. Our study demonstrates that differentiations in energy metabolism underlie the plasticity of adaptive divergence in two oyster subspecies and suggest C. gigas angulata with moderate phenotypic plasticity has higher adaptive potential to cope with exacerbated global warming. PMID- 28861222 TI - Supplementary feeding increases nestling feather corticosterone early in the breeding season in house sparrows. AB - Several studies on birds have proposed that a lack of invertebrate prey in urbanized areas could be the main cause for generally lower levels of breeding success compared to rural habitats. Previous work on house sparrows Passer domesticus found that supplemental feeding in urbanized areas increased breeding success but did not contribute to population growth. Here, we hypothesize that supplementary feeding allows house sparrows to achieve higher breeding success but at the cost of lower nestling quality. As abundant food supplies may permit both high- and low-quality nestlings to survive, we also predict that within brood variation in proxies of nestling quality would be larger for supplemental food broods than for unfed broods. As proxies of nestling quality, we considered feather corticosterone (CORT f), body condition (scaled mass index, SMI), and tarsus-based fluctuating asymmetry (FA). Our hypothesis was only partially supported as we did not find an overall effect of food supplementation on FA or SMI. Rather, food supplementation affected nestling phenotype only early in the breeding season in terms of elevated CORT f levels and a tendency for more variable within-brood CORT f and FA. Early food supplemented nests therefore seemed to include at least some nestlings that faced increased stressors during development, possibly due to harsher environmental (e.g., related to food and temperature) conditions early in the breeding season that would increase sibling competition, especially in larger broods. The fact that CORT f was positively, rather than inversely, related to nestling SMI further suggests that factors influencing CORT f and SMI are likely operating over different periods or, alternatively, that nestlings in good nutritional condition also invest in high quality feathers. PMID- 28861223 TI - Populations genetically rifting within a complex geological system: The case of strong structure and low genetic diversity in the migratory freshwater catfish, Bagrus docmak, in East Africa. AB - The complex geological history of East Africa has been a driving factor in the rapid evolution of teleost biodiversity. While there is some understanding of how macroevolutionary drivers have shaped teleost speciation in East Africa, there is a paucity of research into how the same biogeographical factors have affected microevolutionary processes within lakes and rivers. To address this deficiency, population genetic diversity, demography, and structure were investigated in a widely distributed and migratory (potamodromous) African teleost species, Ssemutundu (Bagrus docmak). Samples were acquired from five geographical locations in East Africa within two major drainage basins; the Albertine Rift and Lake Victoria Basin. Individuals (N = 175) were genotyped at 12 microsatellite loci and 93 individuals sequenced at the mitochondrial DNA control region. Results suggested populations from Lakes Edward and Victoria had undergone a severe historic bottleneck resulting in very low nucleotide diversity (pi = 0.004 and 0.006, respectively) and negatively significant Fu values (-3.769 and -5.049; p < .05). Heterozygosity deficiencies and restricted effective population size (NeLD) suggested contemporary exposure of these populations to stress, consistent with reports of the species decline in the East African Region. High genetic structuring between drainages was detected at both historical (phiST = 0.62 for mtDNA; p < .001) and contemporary (microsatellite FST = 0.460; p < .001) levels. Patterns of low genetic diversity and strong population structure revealed are consistent with speciation patterns that have been linked to the complex biogeography of East Africa, suggesting that these biogeographical features have operated as both macro- and micro-evolutionary forces in the formation of the East African teleost fauna. PMID- 28861224 TI - Genomic patterns in Acropora cervicornis show extensive population structure and variable genetic diversity. AB - Threatened Caribbean coral communities can benefit from high-resolution genetic data used to inform management and conservation action. We use Genotyping by Sequencing (GBS) to investigate genetic patterns in the threatened coral, Acropora cervicornis, across the Florida Reef Tract (FRT) and the western Caribbean. Results show extensive population structure at regional scales and resolve previously unknown structure within the FRT. Different regions also exhibit up to threefold differences in genetic diversity (He), suggesting targeted management based on the goals and resources of each population is needed. Patterns of genetic diversity have a strong spatial component, and our results show Broward and the Lower Keys are among the most diverse populations in Florida. The genetic diversity of Caribbean staghorn coral is concentrated within populations and within individual reefs (AMOVA), highlighting the complex mosaic of population structure. This variance structure is similar over regional and local scales, which suggests that in situ nurseries are adequately capturing natural patterns of diversity, representing a resource that can replicate the average diversity of wild assemblages, serving to increase intraspecific diversity and potentially leading to improved biodiversity and ecosystem function. Results presented here can be translated into specific goals for the recovery of A. cervicornis, including active focus on low diversity areas, protection of high diversity and connectivity, and practical thresholds for responsible restoration. PMID- 28861225 TI - Life history constraints explain negative relationship between fish productivity and dissolved organic carbon in lakes. AB - Resource availability constrains the life history strategies available to organisms and may thereby limit population growth rates and productivity. We used this conceptual framework to explore the mechanisms driving recently reported negative relationships between fish productivity and dissolved organic carbon (DOC) concentrations in lakes. We studied populations of bluegill (Lepomis macrochirus) in a set of lakes with DOC concentrations ranging from 3 to 24 mg/L; previous work has demonstrated that primary and secondary productivity of food webs is negatively related to DOC concentration across this gradient. For each population, we quantified individual growth rate, age at maturity, age-specific fecundity, maximum age, length-weight and length-egg size relationships, and other life history characteristics. We observed a strong negative relationship between maximum size and DOC concentration; for instance, fish reached masses of 150 to 260 g in low-DOC lakes but <120 g in high-DOC lakes. Relationships between fecundity and length, and between egg size and length, were constant across the DOC gradient. Because fish in high-DOC lakes reached smaller sizes but had similar fecundity and egg size at a given size, their total lifetime fecundity was as much as two orders of magnitude lower than fish in low-DOC lakes. High DOC concentrations appeared to constrain the range of bluegill life history strategies available; populations in high-DOC lakes always had low initial growth rates and high ages at maturity, whereas populations in low-DOC showed higher variability in these traits. This was also the case for the intrinsic rates of natural increase of these populations, which were always low at the high end of the DOC gradient. The potentially lower capacity for fish populations in high-DOC lakes to recover from exploitation has clear implications for the sustainable management of recreational fisheries in the face of considerable spatial heterogeneity and ongoing temporal change in lake DOC concentrations. PMID- 28861226 TI - Genetic sampling for estimating density of common species. AB - Understanding population dynamics requires reliable estimates of population density, yet this basic information is often surprisingly difficult to obtain. With rare or difficult-to-capture species, genetic surveys from noninvasive collection of hair or scat has proved cost-efficient for estimating densities. Here, we explored whether noninvasive genetic sampling (NGS) also offers promise for sampling a relatively common species, the snowshoe hare (Lepus americanus Erxleben, 1777), in comparison with traditional live trapping. We optimized a protocol for single-session NGS sampling of hares. We compared spatial capture recapture population estimates from live trapping to estimates derived from NGS, and assessed NGS costs. NGS provided population estimates similar to those derived from live trapping, but a higher density of sampling plots was required for NGS. The optimal NGS protocol for our study entailed deploying 160 sampling plots for 4 days and genotyping one pellet per plot. NGS laboratory costs ranged from approximately $670 to $3000 USD per field site. While live trapping does not incur laboratory costs, its field costs can be considerably higher than for NGS, especially when study sites are difficult to access. We conclude that NGS can work for common species, but that it will require field and laboratory pilot testing to develop cost-effective sampling protocols. PMID- 28861227 TI - Human influence on the temporal dynamics and spatial distribution of forest biomass carbon in China. AB - Global carbon cycles are impacted by human activity primarily via fossil fuel combustion and forest carbon budget alterations. In this study, the temporal dynamics and spatial distribution of forest biomass carbon (FBC) stock and density in China were analyzed to assess the large-scale effects of humans on FBC. The results indicated that from 1977 to 2013, the FBC stock increased by 62.9%, from 4,335 to 7,064 Tg C, owing to human-driven forestation and ecological restoration programs. Because of intensive human impacts, 44.2%-54.6% of the FBC stock was concentrated in four provinces (Heilongjiang, Yunnan, Inner Mongolia, and Sichuan) and the FBC density increased from the densely populated southeastern provinces to the sparsely populated northeastern and western provinces. On a spatial scale, the FBC density was significantly negatively related to population density, and the degree of the dependence of the FBC density on population density has been declining since 1998. This improvement in human-forest relations is related to economic development and programs in China that have promoted forestation and reduced deforestation. These results suggest that human impacts, including forestation, deforestation, population density, and economic development, have played significant roles in determining the temporal and spatial variations of FBC in the anthropogenic era. Moreover, our findings have implications for forest management and improvement of the forest carbon sink in China. PMID- 28861228 TI - Resurgence of cucurbit downy mildew in the United States: Insights from comparative genomic analysis of Pseudoperonospora cubensis. AB - Pseudoperonospora cubensis, the causal agent of cucurbit downy mildew (CDM), is known to exhibit host specialization. The virulence of different isolates of the pathogen can be classified into pathotypes based on their compatibility with a differential set composed of specific cucurbit host types. However, the genetic basis of host specialization within P. cubensis is not yet known. Total genomic DNA extracted from nine isolates of P. cubensis collected from 2008 to 2013 from diverse cucurbit host types (Cucumis sativus, C. melo var. reticulatus, Cucurbita maxima, C. moschata, C. pepo, and Citrullus lanatus) in the United States were subjected to whole-genome sequencing. Comparative analysis of these nine genomes confirmed the presence of two distinct evolutionary lineages (lineages I and II) of P. cubensis. Many fixed polymorphisms separated lineage I comprising isolates from Cucurbita pepo, C. moschata, and Citrullus lanatus from lineage II comprising isolates from Cucumis spp. and Cucurbita maxima. Phenotypic characterization showed that lineage II isolates were of the A1 mating type and belonged to pathotypes 1 and 3 that were not known to be present in the United States prior to the resurgence of CDM in 2004. The association of lineage II isolates with the new pathotypes and a lack of genetic diversity among these isolates suggest that lineage II of P. cubensis is associated with the resurgence of CDM on cucumber in the United States. PMID- 28861229 TI - Influence of olfactory and visual cover on nest site selection and nest success for grassland-nesting birds. AB - Habitat selection by animals is influenced by and mitigates the effects of predation and environmental extremes. For birds, nest site selection is crucial to offspring production because nests are exposed to extreme weather and predation pressure. Predators that forage using olfaction often dominate nest predator communities; therefore, factors that influence olfactory detection (e.g., airflow and weather variables, including turbulence and moisture) should influence nest site selection and survival. However, few studies have assessed the importance of olfactory cover for habitat selection and survival. We assessed whether ground-nesting birds select nest sites based on visual and/or olfactory cover. Additionally, we assessed the importance of visual cover and airflow and weather variables associated with olfactory cover in influencing nest survival. In managed grasslands in Oklahoma, USA, we monitored nests of Northern Bobwhite (Colinus virginianus), Eastern Meadowlark (Sturnella magna), and Grasshopper Sparrow (Ammodramus savannarum) during 2015 and 2016. To assess nest site selection, we compared cover variables between nests and random points. To assess factors influencing nest survival, we used visual cover and olfactory-related measurements (i.e., airflow and weather variables) to model daily nest survival. For nest site selection, nest sites had greater overhead visual cover than random points, but no other significant differences were found. Weather variables hypothesized to influence olfactory detection, specifically precipitation and relative humidity, were the best predictors of and were positively related to daily nest survival. Selection for overhead cover likely contributed to mitigation of thermal extremes and possibly reduced detectability of nests. For daily nest survival, we hypothesize that major nest predators focused on prey other than the monitored species' nests during high moisture conditions, thus increasing nest survival on these days. Our study highlights how mechanistic approaches to studying cover informs which dimensions are perceived and selected by animals and which dimensions confer fitness-related benefits. PMID- 28861230 TI - Oxygen minimum zone: An important oceanographic habitat for deep-diving northern elephant seals, Mirounga angustirostris. AB - Little is known about the foraging behavior of top predators in the deep mesopelagic ocean. Elephant seals dive to the deep biota-poor oxygen minimum zone (OMZ) (>800 m depth) despite high diving costs in terms of energy and time, but how they successfully forage in the OMZ remains largely unknown. Assessment of their feeding rate is the key to understanding their foraging behavior, but this has been challenging. Here, we assessed the feeding rate of 14 female northern elephant seals determined by jaw motion events (JME) and dive cycle time to examine how feeding rates varied with dive depth, particularly in the OMZ. We also obtained video footage from seal-mounted videos to understand their feeding in the OMZ. While the diel vertical migration pattern was apparent for most depths of the JME, some very deep dives, beyond the normal diel depth ranges, occurred episodically during daylight hours. The midmesopelagic zone was the main foraging zone for all seals. Larger seals tended to show smaller numbers of JME and lower feeding rates than smaller seals during migration, suggesting that larger seals tended to feed on larger prey to satisfy their metabolic needs. Larger seals also dived frequently to the deep OMZ, possibly because of a greater diving ability than smaller seals, suggesting their dependency on food in the deeper depth zones. Video observations showed that seals encountered the rarely reported ragfish (Icosteus aenigmaticus) in the depths of the OMZ, which failed to show an escape response from the seals, suggesting that low oxygen concentrations might reduce prey mobility. Less mobile prey in OMZ would enhance the efficiency of foraging in this zone, especially for large seals that can dive deeper and longer. We suggest that the OMZ plays an important role in structuring the mesopelagic ecosystem and for the survival and evolution of elephant seals. PMID- 28861231 TI - Habitat predictors of genetic diversity for two sympatric wetland-breeding amphibian species. AB - Population genetic diversity is widely accepted as important to the conservation and management of wildlife. However, habitat features may differentially affect evolutionary processes that facilitate population genetic diversity among sympatric species. We measured genetic diversity for two pond-breeding amphibian species (Dwarf salamanders, Eurycea quadridigitata; and Southern Leopard frogs, Lithobates sphenocephalus) to understand how habitat characteristics and spatial scale affect genetic diversity across a landscape. Samples were collected from wetlands on a longleaf pine reserve in Georgia. We genotyped microsatellite loci for both species to assess population structures and determine which habitat features were most closely associated with observed heterozygosity and rarefied allelic richness. Both species exhibited significant population genetic structure; however, structure in Southern Leopard frogs was driven primarily by one outlier site. Dwarf salamander allelic richness was greater at sites with less surrounding road area within 0.5 km and more wetland area within 1.0 and 2.5 km, and heterozygosity was greater at sites with more wetland area within 0.5 km. In contrast, neither measure of Southern Leopard frog genetic diversity was associated with any habitat features at any scale we evaluated. Genetic diversity in the Dwarf salamander was strongly associated with land cover variables up to 2.5 km away from breeding wetlands, and/or results suggest that minimizing roads in wetland buffers may be beneficial to the maintenance of population genetic diversity. This study suggests that patterns of genetic differentiation and genetic diversity have associations with different habitat features across different spatial scales for two syntopic pond-breeding amphibian species. PMID- 28861232 TI - Modeling the impact of reproductive mode on masting. AB - Masting is defined as the intermittent highly variable production of seed in a plant population. According to reproductive modes, that is, sexual and asexual reproduction, masting species can be separated into three groups, that is, (1) species, for example, bamboo, flower only once before they die; (2) species, for example, Fagus, reproduce sexually; and (3) species, for example, Stipa tenacissima, reproduce both sexually and asexually. Several theories have been proposed to explore the underlying mechanisms of masting. However, to our knowledge, no theory has been found to explain the mechanism of masting species that reproduce both sexually and asexually. Here we refine the Resource Budget Model by considering a trade-off between sexual and asexual reproduction. Besides the depletion efficient (i.e., the ratio of the cost of seed setting and the cost of flowering), other factors, such as the annual remaining resource (i.e., the rest of the resource from the photosynthetic activity after allocating to growth and maintenance), the trade-off between sexual and asexual reproduction, and the reproductive thresholds, also affect masting. Moreover, two potential reproductive strategies are found to explain the mechanisms: (1) When the annual remaining resource is relatively low, plants reproduce asexually and a part of the resource is accumulated as the cost of asexual reproduction is less than the annual remaining resource. Plants flower and set fruits once the accumulated resource exceeds the threshold of sexual reproduction; (2) when the annual remaining resource is relatively high, and the accumulated resource surpasses the threshold of sexual reproduction, masting occurs. Remarkably, under certain depletion efficient, more investigation in sexual reproduction will lead plants to reproduce periodically. Additionally, plants investigate less resource to reproduce periodically when depletion efficient keeps increasing as plants can reproduce efficiently. Overall, our study provides new insights into the interpretation of masting, especially for species that reproduce both sexually and asexually. PMID- 28861233 TI - Assessing the relationships between phylogenetic and functional singularities in sharks (Chondrichthyes). AB - The relationships between diversity and ecosystem functioning have become a major focus of science. A crucial issue is to estimate functional diversity, as it is intended to impact ecosystem dynamics and stability. However, depending on the ecosystem, it may be challenging or even impossible to directly measure ecological functions and thus functional diversity. Phylogenetic diversity was recently under consideration as a proxy for functional diversity. Phylogenetic diversity is indeed supposed to match functional diversity if functions are conservative traits along evolution. However, in case of adaptive radiation and/or evolutive convergence, a mismatch may appear between species phylogenetic and functional singularities. Using highly threatened taxa, sharks, this study aimed to explore the relationships between phylogenetic and functional diversities and singularities. Different statistical computations were used in order to test both methodological issue (phylogenetic reconstruction) and overall a theoretical questioning: the predictive power of phylogeny for function diversity. Despite these several methodological approaches, a mismatch between phylogeny and function was highlighted. This mismatch revealed that (i) functions are apparently nonconservative in shark species, and (ii) phylogenetic singularity is not a proxy for functional singularity. Functions appeared to be not conservative along the evolution of sharks, raising the conservational challenge to identify and protect both phylogenetic and functional singular species. Facing the current rate of species loss, it is indeed of major importance to target phylogenetically singular species to protect genetic diversity and also functionally singular species in order to maintain particular functions within ecosystem. PMID- 28861234 TI - The spitting image of plant defenses: Effects of plant secondary chemistry on the efficacy of caterpillar regurgitant as an anti-predator defense. AB - In the arms race between plants, herbivores, and their natural enemies, specialized herbivores may use plant defenses for their own benefit, and variation in plant traits may affect the benefits that herbivores derive from these defenses. Pieris brassicae is a specialist herbivore of plants containing glucosinolates, a specific class of defensive secondary metabolites. Caterpillars of P. brassicae are known to actively spit on attacking natural enemies, including their main parasitoid, the braconid wasp Cotesia glomerata. Here, we tested the hypothesis that variation in the secondary metabolites of host plants affects the efficacy of caterpillar regurgitant as an anti-predator defense. Using a total of 10 host plants with different glucosinolate profiles, we first studied natural regurgitation events of caterpillars on parasitoids. We then studied manual applications of water or regurgitant on parasitoids during parasitization events. Results from natural regurgitation events revealed that parasitoids spent more time grooming after attack when foraging on radish and nasturtium than on Brassica spp., and when the regurgitant came in contact with the wings rather than any other body part. Results from manual applications of regurgitant showed that all parameters of parasitoid behavior (initial attack duration, attack interruption, grooming time, and likelihood of a second attack) were more affected when regurgitant was applied rather than water. The proportion of parasitoids re-attacking a caterpillar within 15 min was the lowest when regurgitant originated from radish-fed caterpillars. However, we found no correlation between glucosinolate content and regurgitant effects, and parasitoid behavior was equally affected when regurgitant originated from a glucosinolate deficient Arabidopsis thaliana mutant line. In conclusion, host plant affects to a certain extent the efficacy of spit from P. brassicae caterpillars as a defense against parasitoids, but this is not due to glucosinolate content. The nature of the defensive compounds present in the spit remains to be determined, and the ecological relevance of this anti-predator defense needs to be further evaluated in the field. PMID- 28861235 TI - Switching from monoculture to polyculture farming benefits birds in oil palm production landscapes: Evidence from mist netting data. AB - Monoculture farming is pervasive in industrial oil palm agriculture, including those RSPO plantations certified as sustainably managed. This farming practice does not promote the maintenance of farmland biodiversity. However, little scientific attention has been given to polyculture farming in oil palm production landscapes. Polyculture farming is likely to increase the floristic diversity and stand structural complexity that underpins biodiversity. Mist nets were used to sample birds at 120 smallholdings in Peninsular Malaysia. At each site, 12 vegetation structure characteristics were measured. We compared bird species richness, abundance, and composition between monoculture and polyculture smallholdings and used predictive models to examine the effects of habitat quality on avian biodiversity. Bird species richness was significantly greater in polyculture than that of monoculture smallholdings. The number of fallen and standing, dead oil palms were also important positive predictors of species richness. Bird abundance was also strongly increased by standing and dead oil palms and decreased with oil palm stand height. Our results indicate that polyculture farming can improve bird species richness in oil palm production landscapes. In addition, key habitat variables that are closely associated with farming practices, such as the removal of dead trees, should and can be managed by oil palm growers in order to promote biodiversity. To increase the sustainability of oil palm agriculture, it is imperative that stakeholders modify the way oil palms are currently planted and managed. Our findings can guide policy makers and certification bodies to promote oil palm production landscapes that will function more sustainably and increase existing biodiversity of oil palm landscapes. PMID- 28861236 TI - Incorporating thresholds into understanding salinity tolerance: A study using salt-tolerant plants in salt marshes. AB - Although salinity in many ecosystems such as salt marshes can be extremely high, an asymmetry in salinity range between experimental studies (relatively narrow) and field conditions (potentially broad) has strongly affected current understanding of plant salinity tolerance. To improve understanding, it is thus important to examine plant tolerances over a broad range of salinities and identify potential tolerance thresholds. We examine tolerances of two widely distributed marsh plants, Suaeda salsa and Salicornia europaea, to salinities ranging from 0 to 100 g/kg, and determine survival, above- and belowground biomass after 8 weeks of salinity treatment. Both species, Sa. europaea in particular, have much broader salinity tolerances than other plants previously examined, (2) plant survival, above- and belowground biomass have remarkably different responses to salinity, and (3) there is a nonlinear, threshold response of S. salsa to salinity, above which S. salsa survivorship drastically decreases. These results provide multiple important insights. Our study suggests that the potential for using these halophytes to revegetate and restore salt-affected land may be greater than previously thought, and highlights the importance of studying multiple plant responses. Importantly, our study calls for a better integration of thresholds into understanding plant salinity tolerances and their applications. PMID- 28861237 TI - Nonannual tree rings in a climate-sensitive Prioria copaifera chronology in the Atrato River, Colombia. AB - In temperate climates, tree growth dormancy usually ensures the annual nature of tree rings, but in tropical environments, determination of annual periodicity can be more complex. The purposes of the work are as follows: (1) to generate a reliable tree-ring width chronology for Prioria copaifera Griseb. (Leguminoceae), a tropical tree species dwelling in the Atrato River floodplains, Colombia; (2) to assess the climate signal recorded by the tree-ring records; and (3) to validate the annual periodicity of the tree rings using independent methods. We used standard dendrochronological procedures to generate the P. copaifera tree ring chronology. We used Pearson correlations to evaluate the relationship of the chronology with the meteorological records, climate regional indices, and gridded precipitation/sea surface temperature products. We also evaluated 24 high precision 14C measurements spread over a range of preselected tree rings, with assigned calendar years by dendrochronological techniques, before and after the bomb spike in order to validate the annual nature of the tree rings. The tree ring width chronology was statistically reliable, and it correlated significantly with local records of annual and October-December (OND) streamflow and precipitation across the upper river watershed (positive), and OND temperature (negative). It was also significantly related to the Oceanic Nino Index, Pacific Decadal Oscillation, and the Southern Oscillation Index, as well as sea surface temperatures over the Caribbean and the Pacific region. However, 14C high precision measurements over the tree rings demonstrated offsets of up to 40 years that indicate that P. copaifera can produce more than one ring in certain years. Results derived from the strongest climate-growth relationship during the most recent years of the record suggest that the climatic signal reported may be due to the presence of annual rings in some of those trees in recent years. Our study alerts about the risk of applying dendrochronology in species with challenging anatomical features defining tree rings, commonly found in the tropics, without an independent validation of annual periodicity of tree rings. High-precision 14C measurements in multiple trees are a useful method to validate the identification of annual tree rings. PMID- 28861238 TI - Explosive radiation and spatial expansion across the cold environments of the Old World in an avian family. AB - Our objective was to elucidate the biogeography and speciation patterns in an entire avian family, which shows a complex pattern of overlapping and nonoverlapping geographical distributions, and much variation in plumage, but less in size and structure. We estimated the phylogeny and divergence times for all of the world's species of Prunella based on multiple genetic loci, and analyzed morphometric divergence and biogeographical history. The common ancestor of Prunella was present in the Sino-Himalayan Mountains or these mountains and Central Asia-Mongolia more than 9 million years ago (mya), but a burst of speciations took place during the mid-Pliocene to early Pleistocene. The relationships among the six primary lineages resulting from that differentiation are unresolved, probably because of the rapid radiation. A general increase in sympatry with increasing time since divergence is evident. With one exception, species in clades younger than c. 3.7 my are allopatric. Species that are widely sympatric, including the most recently diverged (2.4 mya) sympatric sisters, are generally more divergent in size/structure than allo-/parapatric close relatives. The distributional pattern and inferred ages suggest divergence in allopatry and substantial waiting time until secondary contact, likely due to competitive exclusion. All sympatrically breeding species are ecologically segregated, as suggested by differences in size/structure and habitat. Colonizations of new areas were facilitated during glacial periods, followed by fragmentation during interglacials-contrary to the usual view that glacial periods resulted mainly in fragmentations. PMID- 28861239 TI - A neutral view of the evolving genomic architecture of speciation. AB - Analyses of genomewide polymorphism data have begun to shed light on speciation and adaptation. Genome scans to identify regions of the genome that are unusually different between populations or species, possibly due to divergent natural or sexual selection, are widespread in speciation genomics. Theoretical and empirical work suggests that such outlier regions may grow faster than linearly during speciation with gene flow due to a rapid transition between low and high reproductive isolation. We investigate whether this pattern could be attributed to neutral processes by simulating genomes under neutral evolution with varying amounts and timing of gene flow. Under both neutral evolution and divergent selection, simulations with little or no gene flow, or with a long allopatric period after its cessation, resulted in faster than linear growth of the proportion of the genome lying in outlier regions. Without selection, higher recent gene flow erased differentiation; with divergent selection, these same scenarios produced nonlinear growth to a plateau. Our results suggest that, given a history of gene flow, the growth of the divergent genome is informative about selection during divergence, but that in many scenarios, this pattern does not easily distinguish neutral and non-neutral processes during speciation with gene flow. PMID- 28861240 TI - Habitat selection by Eurasian lynx (Lynx lynx) is primarily driven by avoidance of human activity during day and prey availability during night. AB - The greatest threat to the protected Eurasian lynx (Lynx lynx) in Central Europe is human-induced mortality. As the availability of lynx prey often peaks in human modified areas, lynx have to balance successful prey hunting with the risk of encounters with humans. We hypothesized that lynx minimize this risk by adjusting habitat choices to the phases of the day and over seasons. We predicted that (1) due to avoidance of human-dominated areas during daytime, lynx range use is higher at nighttime, that (2) prey availability drives lynx habitat selection at night, whereas high cover, terrain inaccessibility, and distance to human infrastructure drive habitat selection during the day, and that (3) habitat selection also differs between seasons, with altitude being a dominant factor in winter. To test these hypotheses, we analyzed telemetry data (GPS, VHF) of 10 lynx in the Bohemian Forest Ecosystem (Germany, Czech Republic) between 2005 and 2013 using generalized additive mixed models and considering various predictor variables. Night ranges exceeded day ranges by more than 10%. At night, lynx selected open habitats, such as meadows, which are associated with high ungulate abundance. By contrast, during the day, lynx selected habitats offering dense understorey cover and rugged terrain away from human infrastructure. In summer, land-cover type greatly shaped lynx habitats, whereas in winter, lynx selected lower altitudes. We concluded that open habitats need to be considered for more realistic habitat models and contribute to future management and conservation (habitat suitability, carrying capacity) of Eurasian lynx in Central Europe. PMID- 28861241 TI - Evaluation of an automated protocol for efficient and reliable DNA extraction of dietary samples. AB - Molecular techniques have become an important tool to empirically assess feeding interactions. The increased usage of next-generation sequencing approaches has stressed the need of fast DNA extraction that does not compromise DNA quality. Dietary samples here pose a particular challenge, as these demand high-quality DNA extraction procedures for obtaining the minute quantities of short-fragmented food DNA. Automatic high-throughput procedures significantly decrease time and costs and allow for standardization of extracting total DNA. However, these approaches have not yet been evaluated for dietary samples. We tested the efficiency of an automatic DNA extraction platform and a traditional CTAB protocol, employing a variety of dietary samples including invertebrate whole body extracts as well as invertebrate and vertebrate gut content samples and feces. Extraction efficacy was quantified using the proportions of successful PCR amplifications of both total and prey DNA, and cost was estimated in terms of time and material expense. For extraction of total DNA, the automated platform performed better for both invertebrate and vertebrate samples. This was also true for prey detection in vertebrate samples. For the dietary analysis in invertebrates, there is still room for improvement when using the high-throughput system for optimal DNA yields. Overall, the automated DNA extraction system turned out as a promising alternative to labor-intensive, low-throughput manual extraction methods such as CTAB. It is opening up the opportunity for an extensive use of this cost-efficient and innovative methodology at low contamination risk also in trophic ecology. PMID- 28861242 TI - Genomic and phenotypic signatures of climate adaptation in an Anolis lizard. AB - Integrated knowledge on phenotype, physiology, and genomic adaptations is required to understand the effects of climate on evolution. The functional genomic basis of organismal adaptation to changes in the abiotic environment, its phenotypic consequences, and its possible convergence across vertebrates are still understudied. In this study, we use a comparative approach to verify predicted gene functions for vertebrate thermal adaptation with observed functions underlying repeated genomic adaptations in response to elevation in the lizard Anolis cybotes. We establish a direct link between recurrently evolved phenotypes and functional genomics of altitude-related climate adaptation in three highland and lowland populations in the Dominican Republic. We show that across vertebrates, genes contained in this interactome are expressed within the brain, the endocrine system, and during development. These results are relevant to elucidate the effect of global climate change across vertebrates and might aid in furthering insight into gene-environment relationships under disturbances to homeostasis. PMID- 28861243 TI - Assessing patterns of genetic admixture between sheep breeds: Case study in Algeria. AB - In developing countries, cross-breeding between local breeds and indigene or exotic breeds represents one of the main threats to the livestock diversity, leading to genetic dilution and loss of unique allelic combination underlying essential local adaptive traits. In this study, two Algerian sheep breeds, known to be highly admixed, were considered as a case study, to demonstrate how combination of different methodologies coupled with the use of specific softwares can be efficient to assess the spatial structuration of a hybrid zone, even in a case of extreme admixture. A fine sampling covering distribution areas of both breeds was implemented in order to study the admixture area and adjacent zones from a phenotypic (i.e., 19 quantitative traits were considered) and a genetic point of view (i.e., 21 microsatellites markers were used). Both approaches gave concordant patterns, highlighting areas with sheep most differentiated (or less admixed) for each breed. In detail, the region of Biskra appeared as the most preserved for the Ouled-Djellal breed and the northwest of Laghouat was identified as the most preserved area for the Rembi breed. The approach proposed in the study offers a low-cost solution to identify the most representative flocks of a breed, allowing the implementation of efficient conservation plans. PMID- 28861244 TI - Using a historic drought and high-heat event to validate thermal exposure predictions for ground-dwelling birds. AB - Deviations from typical environmental conditions can provide insight into how organisms may respond to future weather extremes predicted by climate modeling. During an episodic and multimonth heat wave event (i.e., ambient temperature up to 43.4 degrees C), we studied the thermal ecology of a ground-dwelling bird species in Western Oklahoma, USA. Specifically, we measured black bulb temperature (Tbb) and vegetation parameters at northern bobwhite (Colinus virginianus; hereafter bobwhite) adult and brood locations as well as at stratified random points in the study area. On the hottest days (i.e., >=39 degrees C), adults and broods obtained thermal refuge using tall woody cover that remained on average up to 16.51 degrees C cooler than random sites on the landscape which reached >57 degrees C. We also found that refuge sites used by bobwhites moderated thermal conditions by more than twofold compared to stratified random sites on the landscape but that Tbb commonly exceeded thermal stress thresholds for bobwhites (39 degrees C) for several hours of the day within thermal refuges. The serendipitous high heat conditions captured in our study represent extreme heat for our study region as well as thermal stress for our study species, and subsequently allowed us to assess ground-dwelling bird responses to temperatures that are predicted to become more common in the future. Our findings confirm the critical importance of tall woody cover for moderating temperatures and functioning as important islands of thermal refuge for ground dwelling birds, especially during extreme heat. However, the potential for extreme heat loads within thermal refuges that we observed (albeit much less extreme than the landscape) indicates that the functionality of tall woody cover to mitigate heat extremes may be increasingly limited in the future, thereby reinforcing predictions that climate change represents a clear and present danger for these species. PMID- 28861245 TI - Herbivore grazing-or trampling? Trampling effects by a large ungulate in cold high-latitude ecosystems. AB - Mammalian herbivores have important top-down effects on ecological processes and landscapes by generating vegetation changes through grazing and trampling. For free-ranging herbivores on large landscapes, trampling is an important ecological factor. However, whereas grazing is widely studied, low-intensity trampling is rarely studied and quantified. The cold-adapted northern tundra reindeer (Rangifer tarandus) is a wide-ranging keystone herbivore in large open alpine and Arctic ecosystems. Reindeer may largely subsist on different species of slow growing ground lichens, particularly in winter. Lichen grows in dry, snow-poor habitats with frost. Their varying elasticity makes them suitable for studying trampling. In replicated factorial experiments, high-resolution 3D laser scanning was used to quantify lichen volume loss from trampling by a reindeer hoof. Losses were substantial, that is, about 0.3 dm3 per imprint in dry thick lichen, but depended on type of lichen mat and humidity. Immediate trampling volume loss was about twice as high in dry, compared to humid thin (2-3 cm), lichen mats and about three times as high in dry vs. humid thick (6-8 cm) lichen mats, There was no significant difference in volume loss between 100% and 50% wetted lichen. Regained volume with time was insignificant for dry lichen, whereas 50% humid lichen regained substantial volumes, and 100% humid lichen regained almost all lost volume, and mostly within 10-20 min. Reindeer trampling may have from near none to devastating effects on exposed lichen forage. During a normal week of foraging, daily moving 5 km across dry 6- to 8-cm-thick continuous lichen mats, one adult reindeer may trample a lichen volume corresponding to about a year's supply of lichen. However, the lichen humidity appears to be an important factor for trampling loss, in addition to the extent of reindeer movement. PMID- 28861246 TI - Leaf and root litter decomposition is discontinued at high altitude tropical montane rainforests contributing to carbon sequestration. AB - We investigated how altitude affects the decomposition of leaf and root litter in the Andean tropical montane rainforest of southern Ecuador, that is, through changes in the litter quality between altitudes or other site-specific differences in microenvironmental conditions. Leaf litter from three abundant tree species and roots of different diameter from sites at 1,000, 2,000, and 3,000 m were placed in litterbags and incubated for 6, 12, 24, 36, and 48 months. Environmental conditions at the three altitudes and the sampling time were the main factors driving litter decomposition, while origin, and therefore quality of the litter, was of minor importance. At 2,000 and 3,000 m decomposition of litter declined for 12 months reaching a limit value of ~50% of initial and not decomposing further for about 24 months. After 36 months, decomposition commenced at low rates resulting in an average of 37.9% and 44.4% of initial remaining after 48 months. In contrast, at 1,000 m decomposition continued for 48 months until only 10.9% of the initial litter mass remained. Changes in decomposition rates were paralleled by changes in microorganisms with microbial biomass decreasing after 24 months at 2,000 and 3,000 m, while varying little at 1,000 m. The results show that, irrespective of litter origin (1,000, 2,000, 3,000 m) and type (leaves, roots), unfavorable microenvironmental conditions at high altitudes inhibit decomposition processes resulting in the sequestration of carbon in thick organic layers. PMID- 28861247 TI - The components of biodiversity, with a particular focus on phylogenetic information. AB - We present a framework for biodiversity metrics that organizes the growing panoply of metrics. Our framework distinguishes metrics based on the type of information-abundance, phylogeny, function-and two common properties-magnitude and variability. Our new metrics of phylogenetic diversity are based on a partition of the total branch lengths of a cladogram into the proportional share of each species, including: a measure of divergence which standardizes the amount of evolutionary divergence by species richness and time depth of the cladogram; a measure of regularity which is maximal when the tree is perfectly symmetrical so that all species have the same proportional branch lengths; a measure that combines information on the magnitude and variability of abundance with phylogenetic variability, and a measure of phylogenetically weighted effective mean abundance; and indicate how those metrics can be decomposed into alpha and beta components. We illustrate the utility of these new metrics using empirical data on the bat fauna of Manu, Peru. Divergence was greatest in lowland rainforest and at the transition between cloud and elfin forests, and least in upper elfin forests and in cloud forests. In contrast, regularity was greatest in lowland rainforest, dipping to its smallest values in mid-elevation cloud forests, and then increasing in high elevation elfin forests. These patterns indicate that the first species to drop out with increasing elevation are ones that are closely related to other species in the metacommunity. Measures of the effective number of phylogenetically independent or distinct species decreased very rapidly with elevation, and beta-diversity was larger. In contrast, a comparison of feeding guilds shows a different effect of phylogenetic patterning. Along the elevational gradient, each guild generally loses some species from each clade-rather than entire clades-explaining the maintenance of functional diversity as phylogenetic diversity decreases. PMID- 28861248 TI - Growth form evolution and hybridization in Senecio (Asteraceae) from the high equatorial Andes. AB - Changes in growth forms frequently accompany plant adaptive radiations, including paramo-a high-elevation treeless habitat type of the northern Andes. We tested whether diverse group of Senecio inhabiting montane forests and paramo represented such growth form changes. We also investigated the role of Andean geography and environment in structuring genetic variation of this group. We sampled 108 populations and 28 species of Senecio (focusing on species from former genera Lasiocephalus and Culcitium) and analyzed their genetic relationships and patterns of intraspecific variation using DNA fingerprinting (AFLPs) and nuclear DNA sequences (ITS). We partitioned genetic variation into environmental and geographical components. ITS-based phylogeny supported monophyly of a Lasiocephalus-Culcitium clade. A grade of herbaceous alpine Senecio species subtended the Lasiocephalus-Culcitium clade suggesting a change from the herbaceous to the woody growth form. Both ITS sequences and the AFLPs separated a group composed of the majority of paramo subshrubs from other group(s) comprising both forest and paramo species of various growth forms. These morphologically variable group(s) further split into clades encompassing both the paramo subshrubs and forest lianas, indicating independent switches among the growth forms and habitats. The finest AFLP genetic structure corresponded to morphologically delimited species except in two independent cases in which patterns of genetic variation instead reflected geography. Several morphologically variable species were genetically admixed, which suggests possible hybrid origins. Latitude and longitude accounted for 5%-8% of genetic variation in each of three AFLP groups, while the proportion of variation attributed to environment varied between 8% and 31% among them. A change from the herbaceous to the woody growth form is suggested for species of high-elevation Andean Senecio. Independent switches between habitats and growth forms likely occurred within the group. Hybridization likely played an important role in species diversification. PMID- 28861249 TI - Influence of density-dependent competition on foraging and migratory behavior of a subtropical colonial seabird. AB - Density-dependent competition for food resources influences both foraging ecology and reproduction in a variety of animals. The relationship between colony size, local prey depletion, and reproductive output in colonial central-place foragers has been extensively studied in seabirds; however, most studies have focused on effects of intraspecific competition during the breeding season, while little is known about whether density-dependent resource depletion influences individual migratory behavior outside the breeding season. Using breeding colony size as a surrogate for intraspecific resource competition, we tested for effects of colony size on breeding home range, nestling health, and migratory patterns of a nearshore colonial seabird, the brown pelican (Pelecanus occidentalis), originating from seven breeding colonies of varying sizes in the subtropical northern Gulf of Mexico. We found evidence for density-dependent effects on foraging behavior during the breeding season, as individual foraging areas increased linearly with the number of breeding pairs per colony. Contrary to our predictions, however, nestlings from more numerous colonies with larger foraging ranges did not experience either decreased condition or increased stress. During nonbreeding, individuals from larger colonies were more likely to migrate, and traveled longer distances, than individuals from smaller colonies, indicating that the influence of density-dependent effects on distribution persists into the nonbreeding period. We also found significant effects of individual physical condition, particularly body size, on migratory behavior, which in combination with colony size suggesting that dominant individuals remain closer to breeding sites during winter. We conclude that density-dependent competition may be an important driver of both the extent of foraging ranges and the degree of migration exhibited by brown pelicans. However, the effects of density-dependent competition on breeding success and population regulation remain uncertain in this system. PMID- 28861250 TI - Does responsiveness to arbuscular mycorrhizal fungi depend on plant invasive status? AB - Differences in the direction and degree to which invasive alien and native plants are influenced by mycorrhizal associations could indicate a general mechanism of plant invasion, but whether or not such differences exist is unclear. Here, we tested whether mycorrhizal responsiveness varies by plant invasive status while controlling for phylogenetic relatedness among plants with two large grassland datasets. Mycorrhizal responsiveness was measured for 68 taxa from the Northern Plains, and data for 95 taxa from the Central Plains were included. Nineteen percent of taxa from the Northern Plains had greater total biomass with mycorrhizas while 61% of taxa from the Central Plains responded positively. For the Northern Plains taxa, measurable effects often depended on the response variable (i.e., total biomass, shoot biomass, and root mass ratio) suggesting varied resource allocation strategies when roots are colonized by arbuscular mycorrhizal fungi. In both datasets, invasive status was nonrandomly distributed on the phylogeny. Invasive taxa were mainly from two clades, that is, Poaceae and Asteraceae families. In contrast, mycorrhizal responsiveness was randomly distributed over the phylogeny for taxa from the Northern Plains, but nonrandomly distributed for taxa from the Central Plains. After controlling for phylogenetic similarity, we found no evidence that invasive taxa responded differently to mycorrhizas than other taxa. Although it is possible that mycorrhizal responsiveness contributes to invasiveness in particular species, we find no evidence that invasiveness in general is associated with the degree of mycorrhizal responsiveness. However, mycorrhizal responsiveness among species grown under common conditions was highly variable, and more work is needed to determine the causes of this variation. PMID- 28861251 TI - Facing herbivory on the climb up: Lost opportunities as the main cost of herbivory in the wild yam Dioscorea praehensilis. AB - Plants with simple architecture and strong constraints on their growth may offer critical insights into how growth strategies affect the tolerance of plants to herbivory. Although Dioscorea praehensilis, a wild yam of African forests, is perennial, both aerial apparatus and tuber are annually renewed. Each year, the tuber produces a single stem that climbs from the ground to the forest canopy. This stem bears no leaves and no branches until it reaches optimal light conditions. Once in the canopy, the plant's production fuels the filling of a new tuber before the plant dies back to the ground. We hypothesized that if deprived of ant defense, the leafless growth phase is a vulnerable part of the cycle, during which a small amount of herbivory entails a high cost in terms of loss of opportunity. We compared the growth of stems bearing ants or not as well as of intact stems and stems subjected to simulated or natural herbivory. Ants reduce herbivory; herbivory delays arrival to the canopy and shortens the season of production. Artificially prolonging the stem growth to the canopy increased plant mortality in the following year and, in surviving plants, reduced the stem diameter and likely the underground reserves produced. Tuber size is a key variable in plant performance as it affects both the size of the aerial apparatus and the duration of its single season of production. Aerial apparatus and tuber are thus locked into a cycle of reciprocal annual renewal. Costs due to loss of opportunity may play a major role in plant tolerance to herbivory, especially when architectural constraints interact with ecological conditions to shape the plant's growth strategy. PMID- 28861252 TI - Florally rich habitats reduce insect pollination and the reproductive success of isolated plants. AB - Landscape heterogeneity in floral communities has the potential to modify pollinator behavior. Pollinator foraging varies with the diversity, abundance, and spatial configuration of floral resources. However, the implications of this variation for pollen transfer and ultimately the reproductive success of insect pollinated plants remains unclear, especially for species which are rare or isolated in the landscape. We used a landscape-scale experiment, coupled with microsatellite genotyping, to explore how the floral richness of habitats affected pollinator behavior and pollination effectiveness. Small arrays of the partially self-compatible plant Californian poppy (Eschscholzia californica) were introduced across a landscape gradient to simulate rare, spatially isolated populations. The effects on pollinator activity, outcrossing, and plant reproduction were measured. In florally rich habitats, we found reduced pollen movement between plants, leading to fewer long-distance pollination events, lower plant outcrossing, and a higher incidence of pollen limitation. This pattern indicates a potential reduction in per capita pollinator visitation, as suggested by the lower activity densities and richness of pollinators observed within florally rich habitats. In addition, seed production reduced by a factor of 1.8 in plants within florally rich habitats and progeny germination reduced by a factor of 1.2. We show this to be a consequence of self-fertilization within the partially self-compatible plant, E. californica. These findings indicate that locally rare plants are at a competitive disadvantage within florally rich habitats because neighboring plant species disrupt conspecific mating by co opting pollinators. Ultimately, this Allee effect may play an important role in determining the long-term persistence of rarer plants in the landscape, both in terms of seed production and viability. Community context therefore requires consideration when designing and implementing conservation management for plants which are comparatively rare in the landscape. PMID- 28861253 TI - The multigenerational effects of water contamination and endocrine disrupting chemicals on the fitness of Drosophila melanogaster. AB - Water pollution due to human activities produces sedimentation, excessive nutrients, and toxic chemicals, and this, in turn, has an effect on the normal endocrine functioning of living beings. Overall, water pollution may affect some components of the fitness of organisms (e.g., developmental time and fertility). Some toxic compounds found in polluted waters are known as endocrine disruptors (ED), and among these are nonhalogenated phenolic chemicals such as bisphenol A and nonylphenol. To evaluate the effect of nonhalogenated phenolic chemicals on the endocrine system, we subjected two generations (F0 and F1) of Drosophila melanogaster to different concentrations of ED. Specifically, treatments involved wastewater, which had the highest level of ED (bisphenol A and nonylphenol) and treated wastewater from a constructed Heliconia psittacorum wetland with horizontal subsurface water flow (He); the treated wastewater was the treatment with the lowest level of ED. We evaluated the development time from egg to pupa and from pupa to adult as well as fertility. The results show that for individuals exposed to treated wastewater, the developmental time from egg to pupae was shorter in individuals of the F1 generation than in the F0 generation. Additionally, the time from pupae to adult was longer for flies growing in the H. psittacorum treated wastewater. Furthermore, fertility was lower in the F1 generation than in the F0 generation. Although different concentrations of bisphenol A and nonylphenol had no significant effect on the components of fitness of D. melanogaster (developmental time and fertility), there was a trend across generations, likely as a result of selection imposed on the flies. It is possible that the flies developed different strategies to avoid the effects of the various environmental stressors. PMID- 28861254 TI - No obvious genetic erosion, but evident relict status at the westernmost range edge of the Pontic-Pannonian steppe plant Linum flavum L. (Linaceae) in Central Europe. AB - We investigate patterns of genetic variation along an east-west transect of Central European populations of Linum flavum and interpret the Quaternary history of its peripheral populations, especially those at the westernmost isolated range edge, discussing their migrations and possible relict status. We defined our peripheral transect across three study regions from Central Hungary, eastern Austria to southwestern Germany. Using AFLP fingerprinting and cpDNA sequence variation (rpL16 intron, atpI-H), we analyzed 267 and 95 individuals, respectively, representing each study region by four populations. Hierarchical AMOVA (AFLPs) indicated significant variation among study regions (12% of total variance) and moderate differentiation between populations (10%). Population differentiation was high at the westernmost range edge (11.5%, Germany), but also in the east (13.4%, Hungary), compared to the Austrian study region (8.6%). Correspondingly, AFLP diversity was highest in the center of the study transect in eastern Austria. CpDNA haplotypes support a pattern of regional structuring with the strongest separation of the westernmost range edge, and some haplotype sharing among Austrian and Hungarian individuals. Equilibrating nucleotide versus haplotype diversity patterns, the highly diverse populations at the Pannonian range edge (Austria) indicate long-term persistence, while Central Pannonian populations are obviously effected by recent bottlenecks. Intermediate nucleotide, but high haplotype diversity within the westernmost exclave (Swabian Alb), is indicative of a founder bottleneck during its pre-LGM or early postglacial migration history, followed by sufficient time to accumulate cpDNA variation. The not obviously reduced genetic diversity and distinctiveness of L. flavum at the westernmost range edge suggest a long-term persistence (relict status) of populations in this region, where the species has survived probably even the Wurm glaciation in extra-Mediterranean refugia. This genetic relict variation represents an important part of the overall genetic diversity found in the western periphery of this steppe plant and highlights the high conservation priority of respective gene pools. PMID- 28861255 TI - Coevolution of competing Callosobruchus species does not stabilize coexistence. AB - Interspecific resource competition is expected to select for divergence in resource use, weakening interspecific relative to intraspecific competition, thus promoting stable coexistence. More broadly, because interspecific competition reduces fitness, any mechanism of interspecific competition should generate selection favoring traits that weaken interspecific competition. However, species also can adapt to competition by increasing their competitive ability, potentially destabilizing coexistence. We reared two species of bean beetles, the specialist Callosobruchus maculatus and the generalist C. chinensis, in allopatry and sympatry on a mixture of adzuki beans and lentils, and assayed mutual invasibility after four, eight, and twelve generations of evolution. Contrary to the expectation that coevolution of competitors will weaken interspecific competition, the rate of mutual invasibility did not differ between sympatry and allopatry. Rather, the invasion rate of C. chinensis, but not C. maculatus, increased with duration of evolution, as C. chinensis adapted to lentils without experiencing reduced adaptation to adzuki beans, and regardless of the presence or absence of C. maculatus. Our results highlight that evolutionary responses to interspecific competition promote stable coexistence only under specific conditions that can be difficult to produce in practice. PMID- 28861256 TI - Interactions among salt marsh plants vary geographically but not latitudinally along the California coast. AB - The strength of species interactions often varies geographically and locally with environmental conditions. Competitive interactions are predicted to be stronger in benign environments while facilitation is expected to be stronger in harsh ones. We tested these ideas with an aboveground neighbor removal experiment at six salt marshes along the California coast. We determined the effect of removals of either the dominant species, Salicornia pacifica, or the subordinate species on plant cover, aboveground biomass and community composition, as well as soil salinity and moisture. We found that S. pacifica consistently competed with the subordinate species and that the strength of competition varied among sites. In contrast with other studies showing that dominant species facilitate subordinates by moderating physical stress, here the subordinate species facilitated S. pacifica shortly after removal treatments were imposed, but the effect disappeared over time. Contrary to expectations based on patterns observed in east coast salt marshes, we did not see patterns in species interactions in relation to latitude, climate, or soil edaphic characteristics. Our results suggest that variation in interactions among salt marsh plants may be influenced by local-scale site differences such as nutrients more than broad latitudinal gradients. PMID- 28861257 TI - Spatial heterogeneity and scale-dependent habitat selection for two sympatric raptors in mixed-grass prairie. AB - Sympatric predators are predicted to partition resources, especially under conditions of food limitation. Spatial heterogeneity that influences prey availability might play an important role in the scales at which potential competitors select habitat. We assessed potential mechanisms for coexistence by examining the role of heterogeneity in resource partitioning between sympatric raptors overwintering in the southern Great Plains. We conducted surveys for wintering Red-tailed hawk (Buteo jamaicensis) and Northern Harrier (Circus cyanea) at two state wildlife management areas in Oklahoma, USA. We used information from repeated distance sampling to project use locations in a GIS. We applied resource selection functions to model habitat selection at three scales and analyzed for niche partitioning using the outlying mean index. Habitat selection of the two predators was mediated by spatial heterogeneity. The two predators demonstrated significant fine-scale discrimination in habitat selection in homogeneous landscapes, but were more sympatric in heterogeneous landscapes. Red-tailed hawk used a variety of cover types in heterogeneous landscapes but specialized on riparian forest in homogeneous landscapes. Northern Harrier specialized on upland grasslands in homogeneous landscapes but selected more cover types in heterogeneous landscapes. Our study supports the growing body of evidence that landscapes can affect animal behaviors. In the system we studied, larger patches of primary land cover types were associated with greater allopatry in habitat selection between two potentially competing predators. Heterogeneity within the scale of raptor home ranges was associated with greater sympatry in use and less specialization in land cover types selected. PMID- 28861258 TI - Predation risk and abiotic habitat parameters affect personality traits in extremophile populations of a neotropical fish (Poecilia vivipara). AB - Understanding whether and how ambient ecological conditions affect the distribution of personality types within and among populations lies at the heart of research on animal personality. Several studies have focussed on only one agent of divergent selection (or driver of plastic changes in behavior), considering either predation risk or a single abiotic ecological factor. Here, we investigated how an array of abiotic and biotic environmental factors simultaneously shape population differences in boldness, activity in an open field test, and sociability/shoaling in the livebearing fish Poecilia vivipara from six ecologically different lagoons in southeastern Brazil. We evaluated the relative contributions of variation in predation risk, water transparency/visibility, salinity (ranging from oligo- to hypersaline), and dissolved oxygen. We also investigated the role played by environmental factors for the emergence, strength, and direction of behavioral correlations. Water transparency explained most of the behavioral variation, whereby fish from lagoons with low water transparency were significantly shyer, less active, and shoaled less than fish living under clear water conditions. When we tested additional wild-caught fish from the same lagoons after acclimating them to homogeneous laboratory conditions, population differences were largely absent, pointing toward behavioral plasticity as a mechanism underlying the observed behavioral differences. Furthermore, we found correlations between personality traits (behavioral syndromes) to vary substantially in strength and direction among populations, with no obvious associations with ecological factors (including predation risk). Altogether, our results suggest that various habitat parameters simultaneously shape the distribution of personality types, with abiotic factors playing a vital (as yet underestimated) role. Furthermore, while predation is often thought to lead to the emergence of behavioral syndromes, our data do not support this assumption. PMID- 28861259 TI - Spatial models to account for variation in observer effort in bird atlases. AB - To assess the importance of variation in observer effort between and within bird atlas projects and demonstrate the use of relatively simple conditional autoregressive (CAR) models for analyzing grid-based atlas data with varying effort. Pennsylvania and West Virginia, United States of America. We used varying proportions of randomly selected training data to assess whether variations in observer effort can be accounted for using CAR models and whether such models would still be useful for atlases with incomplete data. We then evaluated whether the application of these models influenced our assessment of distribution change between two atlas projects separated by twenty years (Pennsylvania), and tested our modeling methodology on a state bird atlas with incomplete coverage (West Virginia). Conditional Autoregressive models which included observer effort and landscape covariates were able to make robust predictions of species distributions in cases of sparse data coverage. Further, we found that CAR models without landscape covariates performed favorably. These models also account for variation in observer effort between atlas projects and can have a profound effect on the overall assessment of distribution change. Accounting for variation in observer effort in atlas projects is critically important. CAR models provide a useful modeling framework for accounting for variation in observer effort in bird atlas data because they are relatively simple to apply, and quick to run. PMID- 28861261 TI - To forage, mate, or thermoregulate: Influence of resource manipulation on male rattlesnake behavior. AB - Male animals should preferentially allocate their time to performing activities that promote enhancing reproductive opportunity, but the need to acquire resources for growth and survival may compete with those behaviors in the short term. Thus, behaviors which require differing movement patterns such as ambushing prey and actively searching for mates can be mutually exclusive. Consequently, males that succeed at foraging could invest greater time and energy into mate searching. We radio-tracked sixteen male massasauga rattlesnakes (Sistrurus catenatus) and supplemented the diets of half the snakes with mice across an active season. We tested the predictions that reduced foraging needs would allow fed snakes to move (i.e., mate search) more, but that they would consequently be stationary to thermoregulate less, than unfed controls. Contrary to our first prediction, we found no evidence that fed snakes altered their mate searching behavior compared to controls. However, we found controls maintained higher body temperatures than fed snakes during the breeding season, perhaps because fed snakes spent less time in exposed ambush sites. Fed snakes had higher body condition scores than controls when the breeding season ended. Our results suggest the potential costs incurred by devoting time to stationary foraging may be outweighed by the drive to increase mating opportunities. Such instances may be especially valuable for massasaugas and other temperate reptiles that can remain inactive for upwards of half their lives or longer in some cases, and for female rattlesnakes that generally exhibit biennial or more protracted reproductive cycles. PMID- 28861260 TI - Morphological plasticity in a native freshwater fish from semiarid Australia in response to variable water flows. AB - In fishes, alterations to the natural flow regime are associated with divergence in body shape morphology compared with individuals from unaltered habitats. However, it is unclear whether this morphological divergence is attributable to evolutionary responses to modified flows, or is a result of phenotypic plasticity. Fishes inhabiting arid regions are ideal candidates for studying morphological plasticity as they are frequently exposed to extreme natural hydrological variability. We examined the effect of early exposure to flows on the development of body shape morphology in the western rainbowfish (Melanotaenia australis), a freshwater fish that is native to semiarid northwest Australia. Wild fish were collected from a region (the Hamersley Ranges) where fish in some habitats are subject to altered water flows due to mining activity. The offspring of wild-caught fish were reared in replicated fast-flow or slow-flow channels, and geometric morphometric analyses were used to evaluate variation in fish body shape following 3, 6, 9, and 12 months of exposure. Water flows influenced fish morphology after 6 and 9 months of flow exposure, with fish in fast-flow environments displaying a more robust body shape than those in slow-flow habitats. No effect of flow exposure was observed at 3 and 12 months. Fishes also showed significant morphological variation within flow treatments, perhaps due to subtle differences in water flow among the replicate channels. Our findings suggest that early exposure to water flows can induce shifts in body shape morphology in arid zone freshwater fishes. Morphological plasticity may act to buffer arid zone populations from the impacts of anthropogenic activities, but further studies are required to link body shape plasticity with behavioral performance in habitats with modified flows. PMID- 28861262 TI - Assessing the effects of iron enrichment across holobiont compartments reveals reduced microbial nitrogen fixation in the Red Sea coral Pocillopora verrucosa. AB - The productivity of coral reefs in oligotrophic tropical waters is sustained by an efficient uptake and recycling of nutrients. In reef-building corals, the engineers of these ecosystems, this nutrient recycling is facilitated by a constant exchange of nutrients between the animal host and endosymbiotic photosynthetic dinoflagellates (zooxanthellae), bacteria, and other microbes. Due to the complex interactions in this so-called coral holobiont, it has proven difficult to understand the environmental limitations of productivity in corals. Among others, the micronutrient iron has been proposed to limit primary productivity due to its essential role in photosynthesis and bacterial processes. Here, we tested the effect of iron enrichment on the physiology of the coral Pocillopora verrucosa from the central Red Sea during a 12-day experiment. Contrary to previous reports, we did not see an increase in zooxanthellae population density or gross photosynthesis. Conversely, respiration rates were significantly increased, and microbial nitrogen fixation was significantly decreased. Taken together, our data suggest that iron is not a limiting factor of primary productivity in Red Sea corals. Rather, increased metabolic demands in response to iron enrichment, as evidenced by increased respiration rates, may reduce carbon (i.e., energy) availability in the coral holobiont, resulting in reduced microbial nitrogen fixation. This decrease in nitrogen supply in turn may exacerbate the limitation of other nutrients, creating a negative feedback loop. Thereby, our results highlight that the effects of iron enrichment appear to be strongly dependent on local environmental conditions and ultimately may depend on the availability of other nutrients. PMID- 28861263 TI - Nest trampling and ground nesting birds: Quantifying temporal and spatial overlap between cattle activity and breeding redshank. AB - Conservation grazing for breeding birds needs to balance the positive effects on vegetation structure and negative effects of nest trampling. In the UK, populations of Common redshank Tringa totanus breeding on saltmarshes declined by >50% between 1985 and 2011. These declines have been linked to changes in grazing management. The highest breeding densities of redshank on saltmarshes are found in lightly grazed areas. Conservation initiatives have encouraged low-intensity grazing at <1 cattle/ha, but even these levels of grazing can result in high levels of nest trampling. If livestock distribution is not spatially or temporally homogenous but concentrated where and when redshank breed, rates of nest trampling may be much higher than expected based on livestock density alone. By GPS tracking cattle on saltmarshes and monitoring trampling of dummy nests, this study quantified (i) the spatial and temporal distribution of cattle in relation to the distribution of redshank nesting habitats and (ii) trampling rates of dummy nests. The distribution of livestock was highly variable depending on both time in the season and the saltmarsh under study, with cattle using between 3% and 42% of the saltmarsh extent and spending most their time on higher elevation habitat within 500 m of the sea wall, but moving further onto the saltmarsh as the season progressed. Breeding redshank also nest on these higher elevation zones, and this breeding coincides with the early period of grazing. Probability of nest trampling was correlated to livestock density and was up to six times higher in the areas where redshank breed. This overlap in both space and time of the habitat use of cattle and redshank means that the trampling probability of a nest can be much higher than would be expected based on standard measures of cattle density. Synthesis and applications: Because saltmarsh grazing is required to maintain a favorable vegetation structure for redshank breeding, grazing management should aim to keep livestock away from redshank nesting habitat between mid-April and mid-July when nests are active, through delaying the onset of grazing or introducing a rotational grazing system. PMID- 28861264 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/ece3.2528.]. PMID- 28794856 TI - ChemMaps: Towards an approach for visualizing the chemical space based on adaptive satellite compounds. AB - We present a novel approach called ChemMaps for visualizing chemical space based on the similarity matrix of compound datasets generated with molecular fingerprints' similarity. The method uses a 'satellites' approach, where satellites are, in principle, molecules whose similarity to the rest of the molecules in the database provides sufficient information for generating a visualization of the chemical space. Such an approach could help make chemical space visualizations more efficient. We hereby describe a proof-of-principle application of the method to various databases that have different diversity measures. Unsurprisingly, we found the method works better with databases that have low 2D diversity. 3D diversity played a secondary role, although it seems to be more relevant as 2D diversity increases. For less diverse datasets, taking as few as 25% satellites seems to be sufficient for a fair depiction of the chemical space. We propose to iteratively increase the satellites number by a factor of 5% relative to the whole database, and stop when the new and the prior chemical space correlate highly. This Research Note represents a first exploratory step, prior to the full application of this method for several datasets. PMID- 28751970 TI - Service evaluation of the implementation of a digitally-enabled care pathway for the recognition and management of acute kidney injury. AB - Acute Kidney Injury (AKI), an abrupt deterioration in kidney function, is defined by changes in urine output or serum creatinine. AKI is common (affecting up to 20% of acute hospital admissions in the United Kingdom), associated with significant morbidity and mortality, and expensive (excess costs to the National Health Service in England alone may exceed L1 billion per year). NHS England has mandated the implementation of an automated algorithm to detect AKI based on changes in serum creatinine, and to alert clinicians. It is uncertain, however, whether 'alerting' alone improves care quality. We have thus developed a digitally-enabled care pathway as a clinical service to inpatients in the Royal Free Hospital (RFH), a large London hospital. This pathway incorporates a mobile software application - the "Streams-AKI" app, developed by DeepMind Health - that applies the NHS AKI algorithm to routinely collected serum creatinine data in hospital inpatients. Streams-AKI alerts clinicians to potential AKI cases, furnishing them with a trend view of kidney function alongside other relevant data, in real-time, on a mobile device. A clinical response team comprising nephrologists and critical care nurses responds to these AKI alerts by reviewing individual patients and administering interventions according to existing clinical practice guidelines. We propose a mixed methods service evaluation of the implementation of this care pathway. This evaluation will assess how the care pathway meets the health and care needs of service users (RFH inpatients), in terms of clinical outcome, processes of care, and NHS costs. It will also seek to assess acceptance of the pathway by members of the response team and wider hospital community. All analyses will be undertaken by the service evaluation team from UCL (Department of Applied Health Research) and St George's, University of London (Population Health Research Institute). PMID- 28861267 TI - Frequency of antiseptic resistance genes in clinical staphycocci and enterococci isolates in Turkey. AB - BACKGROUND: Disinfectants and antiseptics are biocides widely used in hospitals to prevent spread of pathogens. It has been reported that antiseptic resistance genes, qac's, caused tolerance to a variety of biocidal agents, such as benzalkonium chloride (BAC) and chlorhexidine digluconate (CHDG) in Staphylococcus spp. isolates. We aimed to search the frequency of antiseptic resistance genes in clinical Staphylococcus spp. and Enterococcus spp. isolates to investigate the possible association with antiseptic tolerance and antibiotic resistance. METHODS: Antiseptic resistance genes (qacA/B, smr, qacG, qacH, and qacJ) isolated from Gram-positive cocci (69 Staphylococcus spp. and 69 Enterococcus spp.) were analyzed by PCR method. The minimum inhibitory concentrations (MICs) of BAC and CHDG were determined by agar dilution method, whereas antibiotic susceptibility was analyzed by disk diffusion method according to Clinical and Laboratory Standards Institute (CLSI) criteria. RESULTS: The frequency of antiseptic resistance genes was found to be high (49/69; 71.0%) in our clinical staphylococci isolates but absent (0/69; 0%) in enterococci isolates. The frequency of qacA/B and smr genes was higher (25/40; 62.5% and 7/40; 17.5%, respectively) in coagulase negative staphylococci (CNS) when compared to Staphylococcus aureus strains (3/29; 10.3%, and 4/29; 13.8%, respectively). In contrast, the frequency of qacG and qacJ genes was higher (11/29; 37.9% and 8/29; 27.5%, respectively) in S. aureus than those of CNS (5/40; 12.5%, 10/40; 25.0%) strains. qacH was not identified in none of the strains. We found an association between presence of antiseptic resistance genes and increased MIC values of BAC (>4 MUg/mL) in staphylococci and it was found to be statistically statistically significant (p < 0.01). We also showed that MICs of BAC and CHDG of vancomycin-resistant enterococci (VRE) isolates were significantly higher than those of vancomycin-susceptible enterococci (VSE) isolates (p < 0.01). CONCLUSIONS: For our knowledge, our study is the first to investigate antiseptic resistance genes in enterococci and also qacG, qacH, and qacJ genes in staphylococci isolates in Turkey. Further studies are needed to revise the biocide policy and to support infection control programs to avoid the development of new resistance mechanisms. PMID- 28861268 TI - Diagnostic laparoscopy for pneumatosis intestinalis in a very elderly patient: A case report. AB - INTRODUCTION: Pneumatosis intestinalis is rare but may be associated with life threatening intra-abdominal conditions such as intestinal ischemia or perforation. However, it can be difficult, particularly in the very elderly, to identify candidates for immediate surgical intervention. PRESENTATION OF CASE: A 94-year-old man with abdominal distension underwent abdominal computed tomography, which demonstrated accumulation of air bubbles within the intestinal wall and some free intraperitoneal air, suggestive of pneumatosis intestinalis. His vital signs showed evidence of systemic inflammatory response syndrome, and laboratory examination revealed inflammation and hypoxia. As the patient was frail, with his age and concomitant conditions which may have masked the symptoms and severity of his illness, immediate diagnostic laparoscopy was performed, which confirmed the diagnosis of pneumatosis intestinalis, with multiple gas filled cysts seen within the subserosa of the small intestine. No additional surgical procedure was performed. His symptoms improved postoperatively. DISCUSSION: Optimal management of pneumatosis intestinalis in a timely manner requires a comprehensive evaluation of factors in each individual. In patients with severe symptoms, PI might be a sign of a life-threatening intra-abdominal emergency. Despite the contrast-enhanced CT and prediction markers in previous reports, it considered to be difficult to completely rule out these fatal conditions without surgery, especially in very elderly patients with poor performance status. CONCLUSION: Diagnostic laparoscopy may be a useful option for definitively ruling out the lethal conditions associated with pneumatosis intestinalis in frail elderly patients with severe conditions in the emergency setting. PMID- 28861269 TI - Defunctioning stoma- a prognosticator for leaks in low rectal restorative cancer resection: A retrospective analysis of stoma database. AB - AIMS: Low anterior resection (LAR) has higher risk of anastomotic leak with its attendant morbidity -mortality. De-functioning loop ileostomy (DLI), claimed to mitigate the consequences of anastomotic leak, has been questioned in recent years. This study aims to evaluate the impact of ileostomy on LAR. METHODS: A retrospective analysis of stoma database. 136 patients with stoma (March 2011 July 2015) were assessed. Data was analysed in respect to LAR anastomotic leak rate, impact on morbidity-mortality, short and long-term stoma complications, rate of ileostomy reversal and reasons for non-reversal. RESULTS: 45 patients had loop ileostomy for LAR. Male (28) to female (17) ratio was 1.65:1 with median age of 69 (IQR: 56-75.5). Only 3 anastomotic leaks (3/45, 6.5%) occurred, all treated conservatively with no mortality. 29 had reversal, average reversal time is 10 months (3-24) and 5 awaiting. Reasons for non-reversal included patients' choice (7), death from cardiac cause (1), chemotherapy (1), unfit for surgery (1) and failed reversal (1). Acute complications included high output & reversible AKI (1), bleeding (3) and minor complications (6) as skin excoriation, separation and appliance issues. Parastomal hernia was repaired during reversal (12/15). CONCLUSIONS: De-functioning ileostomy for LAR is a safe procedure with low morbidity. Most stomas are reversible. Series highlights a late reversal contrary to the nationally recommended guidelines. Most interestingly, the study demonstrated de-functioning mitigated clinical consequences of anastomotic leak to an extent that reoperation was avoidable, in keeping with recent meta-analysis indicating a significantly low anastomotic leakage rates and reoperation. Larger study is invaluable to substantiate findings. PMID- 28861270 TI - Phosphate disturbance in critically ill children: Incidence, associated risk factors and clinical outcomes. AB - BACKGROUND: Hypophosphatemia is one of the common disorders that develop in critically ill patients. It has potential complications and is often unrecognized in those patients. OBJECTIVE: Determining the incidence of hypophosphatemia in critically ill children, its association with clinical outcomes and the possible risk factors. METHODS: 50 patients were enrolled in the study. Levels of serum phosphate were measured on day 1 and day 7 of PICU (Pediatric intensive care unit) stay. The following variables were analyzed: age, gender, diagnosis on admission, malnutrition, phosphorus intake, clinical severity score on admission OFI (Organ Failure Index) and daily scores PELOD (Pediatric Logistic Organ Dysfunction), sepsis, use of dopamine, furosemide and steroids and assessment of nutrition by z scores. RESULTS: The incidence of hypophosphatemia on admission was 42%. On seventh day of admission incidence of hypophosphatemia was 62%. Malnutrition was present in 24% of patients, serum phosphorus level was significantly lower in malnourished than in well-nourished children (p value = 0.018). Hypophosphatemia was associated with prolonged PICU length of stay (p < 0.001) but was not associated with increased mortality (p = 0.13). Cases on parenteral nutrition and insufficient oral intake while on mechanical ventilator significantly showed hypophosphatemia (p = 0.017). Hypophosphatemia was associated with the use of furosemide, dopamine, steroids and beta2 agonist. CONCLUSION: Hypophosphatemia was common in the first 7 days of PICU hospitalization and was associated with prolonged PICU stay, Significant association between hypophosphatemia and duration of use of mechanical ventilation, use of furosemide, dopamine, steroids and beta2 agonist. PMID- 28861271 TI - No apparent gain from continuing migration for more than 3000 kilometres: willow warblers breeding in Denmark winter across the entire northern Savannah as revealed by geolocators. AB - BACKGROUND: For most Afro-Palearctic migrants, particularly small songbirds, spatiotemporal migration schedules and migratory connectivity remain poorly understood. We mapped migration from breeding through winter of one of the smallest Afro-Palearctic migrants, the willow warbler Phylloscopus trochilus, using geolocators (n = 15). RESULTS: Birds migrated from North European breeding grounds to West Africa via the Iberian Peninsula following a narrow corridor along the West Coast of Africa. Birds then dispersed across the northern Savannah with termination of migration highly variable among individuals. The termination of migration appeared not to be related to timing, current and previous years' vegetation conditions or biometrics. During winter, most birds moved southwards to improved vegetation. CONCLUSION: The willow warblers showed a large, unexpected longitudinal spread in winter sites of more than 3000 km between individuals breeding within a 500 m range resulting in a low degree of connectivity. The large wintering area may well be related to generalist behaviour in the species. Our findings contribute to understanding the link between breeding and wintering ecology in long-distance migratory birds. PMID- 28861272 TI - Three-dimensional space use during the bottom phase of southern elephant seal dives. AB - BACKGROUND: In marine pelagic ecosystems, the spatial distribution of biomass is heterogeneous and dynamic. At large scales, physical processes are the main driving forces of biomass distribution. At fine scales, both biotic and abiotic parameters are likely to be key determinants in the horizontal and vertical distribution of biomass, with direct consequences on the foraging behaviour of diving predators. However, fine scale three-dimensional (3D) spatial interactions between diving predators and their prey are still poorly known. RESULTS: We reconstructed and examined the patterns of southern elephant seals 3D path during the bottom phase of their dives, and related them to estimated prey encounter density. We found that southern elephant seal tracks at bottom are strongly dominated by a single horizontal direction. In high prey density areas, seals travelled shorter distances but their track remained strongly orientated according to a main linear direction. Horizontal, and more importantly, vertical deviations from this main direction, were related negatively to the estimated prey density. We found that prey encounter density decreased with diving depth but tended to be more predictable. CONCLUSION: Southern elephant seal behaviour during the bottom phase of their dives suggest that the prey are dispersed and distributed into layers in which their density relates to the vertical spread of the layer. The linear trajectories performed by the elephant seals would allow to explore the largest volume of water, maximizing the opportunities of prey encounter, while travelling great horizontal distances. PMID- 28861273 TI - Family Connections versus optimised treatment-as-usual for family members of individuals with borderline personality disorder: non-randomised controlled study. AB - BACKGROUND: Borderline personality disorder (BPD) is challenging for family members who are often required to fulfil multiple roles such as those of advocate, caregiver, coach and guardian. To date, two uncontrolled studies by the treatment developers suggest that Family Connections (FC) is an effective programme to support, educate and teach skills to family members of individuals with BPD. However, such studies have been limited by lack of comparison to other treatment approaches. This study aimed to compare the effectiveness of FC with an optimised treatment-as-usual (OTAU) programme for family members of individuals with BPD. A secondary aim was to introduce a long term follow-up to investigate if positive gains from the intervention would be maintained following programme completion. METHODS: This study was a non-randomised controlled study, with assessment of outcomes at baseline (pre-intervention) and end of programme (post intervention) for both FC and OTAU groups, and at follow-up (3 months post intervention; 12 or 19 months post-intervention) for the FC group. Eighty family members participated in the FC (n = 51) and the OTAU (n = 29) programmes. Outcome measures included burden, grief, depression and mastery. Linear mixed-effects models were used to assess baseline differences in the outcome measures by gender, age group and type of relationship to the individual with BPD. Linear mixed-effects models were also used to estimate the treatment effect (FC versus OTAU) utilising all available data from baseline and end of programme. RESULTS: The FC group showed changes indicating significant improvement with respect to all four outcome measures (p < 0.001). The OTAU group showed changes in the same direction as the intervention group but none of the changes were statistically significant. The intervention effect was statistically significant for total burden (including both subscales; p = .02 for subjective burden and p = .048 for objective burden) and grief (p = 0.013). Improvements were maintained at follow up for FC participants. CONCLUSIONS: The findings of the current study indicate that FC results in statistically significant improvements on key measures while OTAU does not yield comparable changes. Lack of significant change on all measures for OTAU suggests that a three session psycho-education programme is of limited benefit. Further research is warranted on programme components and long term supports for family members. PMID- 28861274 TI - Long-term left ventricular remodelling after revascularisation for ST-segment elevation myocardial infarction as assessed by cardiac magnetic resonance imaging. AB - OBJECTIVE: Left ventricular remodelling following a ST-segment elevated myocardial infarction (STEMI) is an adaptive response to maintain the cardiac output despite myocardial tissue loss. Limited studies have evaluated long term ventricular function using cardiac magnetic resonance imaging (CMR) after STEMI. METHODS: Study population consisted of 155 primary percutaneous coronary intervention treated first STEMI patients. CMR was performed at 4+/-2 days, 4 months and 24 months follow-up. Patients were treated with beta-blockers, ACE inhibitors or AT-II- inhibitors, statins and dual antiplatelet according to current international guidelines. RESULTS: Mean left ventricular ejection fraction (LVEF) at baseline was 44%+/-8%. Twenty-one per cent of the study population had an increase of more than 5.0% after 4 months of follow-up and 21% of the cohort had a decrease of more than 5.0%. Patients with long-term LVEF deterioration have significantly larger end-systolic volumes than patients with improvement of LVEF (61+/-23 mL/m2 compared with 52+/-21 mL/m2, p=0.02) and less wall thickening in the remote zone. Patients with LVEF improvement had significantly greater improvement in wall thickening in the infarct areas and in the non-infarct or remote zone. CONCLUSION: Contrary to previous studies, we demonstrate that myocardial remodelling after STEMI is a long-term process. Long term LVEF deterioration is characterised by an increase in end-systolic volume and less wall thickening in the remote zones. Patients with LVEF improvement exhibit an increase in left ventricular wall thickening both in the infarct as well as in the remote zones. TRIAL REGISTRATION: The HEBE study is registered in The Netherlands Trial Register #NTR166 (www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (https://c-d qn9pqajji.sec.amc.nl). PMID- 28861275 TI - The burning issue of white phosphorus: a case report and review of the literature. AB - BACKGROUND: Burns from white phosphorus are rare and remain a challenge for clinicians. White phosphorus burns are often associated with smaller surface areas and high morbidity rates. Classed as a chemical burn, white phosphorus is used for military purposes and within industry, for the manufacture of fireworks and agricultural products. CASE PRESENTATION: In this report, we discuss the case of a 40 years old female who sustained 2% Total Body Surface Area partial to full thickness burns from white phosphorus. The burns were treated conservatively with mafenide acetate on the medial calf and dorsum of foot and Flaminal Forte was used for the palmar region. The patient was discharged 22 days after admission and followed up in the outpatient clinic. Despite the use of pressure garments, hypertrophic scarring began to develop on the dorsum of her right foot. CONCLUSIONS: During peacetime, white phosphorus possess a significant danger to civilians. Awareness of the unique nature of white phosphorus among military burn clinicians should be emphasized. PMID- 28861276 TI - Red-shift of spectral sensitivity due to screening pigment migration in the eyes of a moth, Adoxophyes orana. AB - BACKGROUND: We have found that the spectral sensitivity of the compound eye in the summer fruit tortrix moth (Adoxophyes orana) differs in laboratory strains originating from different regions of Japan. We have investigated the mechanisms underlying this anomalous spectral sensitivity. METHODS: We applied electrophysiology, light and electron microscopy, opsin gene cloning, mathematical modeling, and behavioral analysis. RESULTS: The ERG-determined spectral sensitivity of dark-adapted individuals of all strains peaks around 520 nm. When light-adapted, the spectral sensitivity of the Nagano strain narrows and its peak shifts to 580 nm, while that in other strains remains unchanged. All tested strains appear to be identical in terms of the basic structure of the eye, the pigment migration in response to light- and dark-adaptation, and the molecular structure of long-wavelength absorbing visual pigments. However, the color of the perirhabdomal pigment clearly differs; it is orange in the Nagano strain and purple in the others. The action spectrum of phototaxis appears to be shifted towards longer wavelengths in the Nagano individuals. CONCLUSIONS: The spectral sensitivities of light-adapted eyes can be modeled under the assumption that this screening pigment plays a crucial role in determining the spectral sensitivity. The action spectrum of phototaxis indicates that the change in the eye spectral sensitivity is behaviorally relevant. PMID- 28861277 TI - Long read reference genome-free reconstruction of a full-length transcriptome from Astragalus membranaceus reveals transcript variants involved in bioactive compound biosynthesis. AB - Astragalus membranaceus, also known as Huangqi in China, is one of the most widely used medicinal herbs in Traditional Chinese Medicine. Traditional Chinese Medicine formulations from Astragalus membranaceus have been used to treat a wide range of illnesses, such as cardiovascular disease, type 2 diabetes, nephritis and cancers. Pharmacological studies have shown that immunomodulating, anti hyperglycemic, anti-inflammatory, antioxidant and antiviral activities exist in the extract of Astragalus membranaceus. Therefore, characterising the biosynthesis of bioactive compounds in Astragalus membranaceus, such as Astragalosides, Calycosin and Calycosin-7-O-beta-d-glucoside, is of particular importance for further genetic studies of Astragalus membranaceus. In this study, we reconstructed the Astragalus membranaceus full-length transcriptomes from leaf and root tissues using PacBio Iso-Seq long reads. We identified 27 975 and 22 343 full-length unique transcript models in each tissue respectively. Compared with previous studies that used short read sequencing, our reconstructed transcripts are longer, and are more likely to be full-length and include numerous transcript variants. Moreover, we also re-characterised and identified potential transcript variants of genes involved in Astragalosides, Calycosin and Calycosin-7-O-beta-d glucoside biosynthesis. In conclusion, our study provides a practical pipeline to characterise the full-length transcriptome for species without a reference genome and a useful genomic resource for exploring the biosynthesis of active compounds in Astragalus membranaceus. PMID- 28861278 TI - Comparing structural and transcriptional drug networks reveals signatures of drug activity and toxicity in transcriptional responses. AB - We performed an integrated analysis of drug chemical structures and drug-induced transcriptional responses. We demonstrated that a network representing three dimensional structural similarities among 5452 compounds can be used to automatically group together drugs with similar scaffolds, physicochemical parameters and mode-of-action. We compared the structural network to a network representing transcriptional similarities among a subset of 1309 drugs for which transcriptional response were available in the Connectivity Map data set. Analysis of structurally similar, but transcriptionally different drugs sharing the same MOA enabled us to detect and remove weak and noisy transcriptional responses, greatly enhancing the reliability of transcription-based approaches to drug discovery and drug repositioning. Cardiac glycosides exhibited the strongest transcriptional responses with a significant induction of pathways related to epigenetic regulation, which suggests an epigenetic mechanism of action for these drugs. Drug classes with the weakest transcriptional responses tended to induce expression of cytochrome P450 enzymes, hinting at drug-induced drug resistance. Analysis of transcriptionally similar, but structurally different drugs with unrelated MOA, led us to the identification of a 'toxic' transcriptional signature indicative of lysosomal stress (lysosomotropism) and lipid accumulation (phospholipidosis) partially masking the target-specific transcriptional effects of these drugs. We found that this transcriptional signature is shared by 258 compounds and it is associated to the activation of the transcription factor TFEB, a master regulator of lysosomal biogenesis and autophagy. Finally, we built a predictive Random Forest model of these 258 compounds based on 128 physicochemical parameters, which should help in the early identification of potentially toxic drug candidates. PMID- 28861279 TI - Computer modeling defines the system driving a constant current crucial for homeostasis in the mammalian cochlea by integrating unique ion transports. AB - The cochlear lateral wall-an epithelial-like tissue comprising inner and outer layers-maintains +80 mV in endolymph. This endocochlear potential supports hearing and represents the sum of all membrane potentials across apical and basolateral surfaces of both layers. The apical surfaces are governed by K+ equilibrium potentials. Underlying extracellular and intracellular [K+] is likely controlled by the "circulation current," which crosses the two layers and unidirectionally flows throughout the cochlea. This idea was conceptually reinforced by our computational model integrating ion channels and transporters; however, contribution of the outer layer's basolateral surface remains unclear. Recent experiments showed that this basolateral surface transports K+ using Na+, K+-ATPases and an unusual characteristic of greater permeability to Na+ than to other ions. To determine whether and how these machineries are involved in the circulation current, we used an in silico approach. In our updated model, the outer layer's basolateral surface was provided with only Na+, K+-ATPases, Na+ conductance, and leak conductance. Under normal conditions, the circulation current was assumed to consist of K+ and be driven predominantly by Na+, K+ ATPases. The model replicated the experimentally measured electrochemical properties in all compartments of the lateral wall, and endocochlear potential, under normal conditions and during blocking of Na+, K+-ATPases. Therefore, the circulation current across the outer layer's basolateral surface depends primarily on the three ion transport mechanisms. During the blockage, the reduced circulation current partially consisted of transiently evoked Na+ flow via the two conductances. This work defines the comprehensive system driving the circulation current. PMID- 28861280 TI - Multicentre phase II study of nivolumab in Japanese patients with advanced or recurrent non-squamous non-small cell lung cancer. AB - OBJECTIVE: Nivolumab is a fully human IgG4 programmed cell death 1 immune checkpoint inhibitor monoclonal antibody approved for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent non squamous NSCLC. METHODS: In this multicentre phase II study, patients with advanced or recurrent non-squamous NSCLC, which had progressed after platinum containing chemotherapy, were treated with nivolumab 3 mg/kg, intravenously every 2 weeks until progressive disease or unacceptable toxicity was observed. The primary end point was independent radiology review committee (IRC) assessed overall response rate (ORR) and the secondary endpoints included ORR (investigator assessed), progression-free survival (PFS), overall survival (OS), duration of response, time to response, best overall response, and safety. RESULTS: 76 patients were enrolled across 19 sites in Japan. The ORR (IRC assessed) was 22.4% (95% CI 14.5% to 32.9%). The median PFS and OS were 2.8 months (95% CI 1.4 to 3.4) and 17.1 months (95% CI 13.3 to 23.0), respectively. The OS rate at 1 year was 68.0% (95% CI 56.2% to 77.3%). Current/former smokers were more responsive to treatment than non-smokers (ORR 29.1% vs 4.8%). Patients with epidermal growth factor receptor (EGFR) mutation wild type/unknown showed higher ORR compared with EGFR mutation-positive patients (ORR 28.6% vs 5.0%) and programmed cell death ligand-1 (PD-L1) expression was likely associated with higher ORR, longer PFS and OS. Treatment-related adverse events of grade 3 or higher were reported in 17 patients; these events resolved or were resolving with appropriate treatment including steroid therapy or discontinuation of nivolumab. CONCLUSIONS: Nivolumab was well tolerated and showed clinical efficacy in Japanese patients with non-squamous NSCLC progressed after platinum-containing chemotherapy, especially in those with a history of smoking, wild type/unknown EGFR mutation status or positive PD-L1 expression. TRIAL REGISTRATION NUMBER: JapicCTI-132073. PMID- 28861281 TI - Comparing intensities and modalities within the sensory attenuation paradigm: Preliminary evidence. AB - It is well-documented that the intensity of a self-generated somatosensory stimulus is perceived to be attenuated in respect to an identical stimulus generated by others. At present, it is not clear whether such a phenomenon, known as somatosensory attenuation, is based not only on feedforward motor signals but also on re-afferences towards the body. To answer this question, in the present pilot investigation on twelve healthy subjects, three types of stimulations (sensory non-nociceptive electrical - ES, nociceptive electrical - NES, and vibrotactile - VTS) and intensities (1 = sensory threshold * 2.5 + 2 mA, 2 = sensory threshold * 2.5 + 3 mA, 3 = sensory threshold * 2.5 + 4 mA for ES and NES; 1 = sensory threshold * 2 Hz, 2 = sensory threshold * 3 Hz, 3 = sensory threshold * 4 Hz for VTS) have been directly compared in a somatosensory attenuation paradigm. The results show that the attenuation effect emerged only with electrical stimuli and that it increased with higher intensities. These pilot findings suggest that, depending on the type and the intensity of stimulation, re-afferences can have a role in somatosensory attenuation. Additionally, it is possible to speculate the effect is present only with electrical stimuli because those stimuli are prospectively judged as potentially dangerous. This, in turn, would optimize planning successful reactions to incoming threatening stimuli. PMID- 28861282 TI - Convective thermal and concentration transfer effects in hydromagnetic peristaltic transport with Ohmic heating. AB - The primary theme of this communication is to employ convective condition of mass transfer in the theory of peristalsis. The magnetohydrodynamic (MHD) peristaltic transport of viscous liquid in an asymmetric channel was considered for this purpose. Effects of Ohmic heating and Soret and Dufour are presented. The governing mathematical model was expressed in terms of closed form solution expressions. Attention has been focused to the analysis of temperature and concentration distributions. The graphical results are presented to visualize the impact of sundry quantities on temperature and concentration. It is visualized that the liquid temperature was enhanced with the enhancing values of Soret Dufour parameters. The liquid temperature was reduced when the values of Biot number were larger. It is also examined that mass transfer Biot number for one wall has no impact on transfer rate. Different mass transfer Biot numbers generate a non-uniform concentration profile throughout the channel cross section. PMID- 28861283 TI - Overview of newly announced clinical data sharing policy from the International Committee of Medical Journal Editors. PMID- 28861284 TI - Alveolar socket preservation with demineralised bovine bone mineral and a collagen matrix. AB - PURPOSE: The aim of the present study was to evaluate the healing of post extraction sockets following alveolar ridge preservation clinically, radiologically, and histologically. METHODS: Overall, 7 extraction sockets in 7 patients were grafted with demineralised bovine bone mineral and covered with a porcine-derived non-crosslinked collagen matrix (CM). Soft tissue healing was clinically evaluated on the basis of a specific healing index. Horizontal and vertical ridge dimensional changes were assessed clinically and radiographically at baseline and 6 months after implant placement. For histological and histomorphometric analysis, bone biopsies were harvested from the augmented sites during implant surgery 6 months after the socket preservation procedure. RESULTS: Clinically, healing proceeded uneventfully in all the sockets. A trend towards reduced horizontal and vertical socket dimensions was observed from baseline to the final examination. The mean width and height of resorption were 1.21 mm (P=0.005) and 0.46 mm (P=0.004), respectively. Histologically, residual xenograft particles (31.97%+/-3.52%) were surrounded by either newly formed bone (16.02%+/ 7.06%) or connective tissue (50.67%+/-8.42%) without fibrous encapsulation. The CM underwent a physiological substitution process in favour of well-vascularised collagen-rich connective tissue. CONCLUSIONS: Socket preservation using demineralised bovine bone mineral in combination with CM provided stable dimensional changes of the alveolar ridge associated with good re epithelialisation of the soft tissues during a 6-month healing period. PMID- 28861285 TI - Pattern analysis of patients with temporomandibular disorders resulting from unilateral mastication due to chronic periodontitis. AB - PURPOSE: The purpose of the present study was to perform a pattern analysis in patients with temporomandibular disorder (TMD) resulting from unilateral mastication due to chronic periodontitis. METHODS: Thirty participants with signs or symptoms of TMD who engaged in unilateral mastication due to periodontitis related discomfort (test group) were selected. Another 30 subjects exhibiting signs or symptoms of TMD resulting from unilateral mastication not due to chronic periodontitis (control group) were also recruited. An interview-based questionnaire was administered, and an examination of the temporomandibular joint (TMJ) with determination of periodontal status was performed. RESULTS: The duration of unilateral mastication was significantly longer in the control group than in the test group. There was a significant negative correlation between the duration of unilateral mastication and the Community Periodontal Index score. Using the Research Diagnostic Criteria for TMD (RDC/TMD) axis I algorithms, all the subjects were assigned to 3 main groups. The test group exhibited significantly a higher diagnostic distribution of group III (arthralgia, osteoarthritis, or osteoarthrosis), and in both the test and control groups, the number of diagnoses was larger for the non-chewing side. The control group showed a significantly higher diagnostic distribution of group I (myofacial pain), and in both the test and control groups, the number of diagnoses was larger for the chewing side. CONCLUSIONS: The results of the present study indicate that unilateral mastication due to chronic periodontitis could induce not only pain but also structural TMJ changes if adequate treatment is not administered and supported within a short time from the onset of the condition. Therefore, immediate treatment of chronic periodontitis is recommended to prevent not only the primary progress of periodontal disease, but also secondary TMJ-related problems. Furthermore, subjects who have suffered chronic long-term periodontitis without treatment should be urged to undergo a TMJ examination. PMID- 28861286 TI - Comparison of periodontitis-associated oral biofilm formation under dynamic and static conditions. AB - PURPOSE: The purpose of this study was to compare the characteristics of single- and dual-species in vitro oral biofilms made by static and dynamic methods. METHODS: Hydroxyapatite (HA) disks, 12.7 mm in diameter and 3 mm thick, were coated with processed saliva for 4 hours. The disks were divided into a static method group and a dynamic method group. The disks treated with a static method were cultured in 12-well plates, and the disks in the dynamic method group were cultured in a Center for Disease Control and Prevention (CDC) biofilm reactor for 72 hours. In the single- and dual-species biofilms, Fusobacterium nucleatum and Porphyromonas gingivalis were used, and the amount of adhering bacteria, proportions of species, and bacterial reduction of chlorhexidine were examined. Bacterial adhesion was examined with scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). RESULTS: Compared with the biofilms made using the static method, the biofilms made using the dynamic method had significantly lower amounts of adhering and looser bacterial accumulation in SEM and CLSM images. The proportion of P. gingivalis was higher in the dynamic method group than in the static method group; however, the difference was not statistically significant. Furthermore, the biofilm thickness and bacterial reduction by chlorhexidine showed no significant differences between the 2 methods. CONCLUSIONS: When used to reproduce periodontal biofilms composed of F. nucleatum and P. gingivalis, the dynamic method (CDC biofilm reactor) formed looser biofilms containing fewer bacteria than the well plate. However, this difference did not influence the thickness of the biofilms or the activity of chlorhexidine. Therefore, both methods are useful for mimicking periodontitis associated oral biofilms. PMID- 28861287 TI - Marginal bone level changes in association with different vertical implant positions: a 3-year retrospective study. AB - PURPOSE: To retrospectively evaluate the relationship between the vertical position of the implant-abutment interface and marginal bone loss over 3 years using radiological analysis. METHODS: In total, 286 implant surfaces of 143 implants from 61 patients were analyzed. Panoramic radiographic images were taken immediately after implant installation and at 6, 12, and 36 months after loading. The implants were classified into 3 groups based on the vertical position of the implant-abutment interface: group A (above bone level), group B (at bone level), and group C (below bone level). The radiographs were analyzed by a single examiner. RESULTS: Changes in marginal bone levels of 0.99+/-1.45, 1.13+/-0.91, and 1.76+/-0.78 mm were observed at 36 months after loading in groups A, B, and C, respectively, and bone loss was significantly greater in group C than in groups A and B. CONCLUSIONS: The vertical position of the implant-abutment interface may affect marginal bone level change. Marginal bone loss was significantly greater in cases where the implant-abutment interface was positioned below the marginal bone. Further long-term study is required to validate our results. PMID- 28861288 TI - Prevalence and risk indicators of peri-implantitis in Korean patients with a history of periodontal disease: a cross-sectional study. AB - PURPOSE: The aim of this study was to analyze the prevalence and risk indicators of peri-implantitis in Korean patients with history of periodontal disease. METHODS: A total of 444 patients with 1,485 implants were selected from patients who had been treated at the Department of Periodontology, Chonbuk National University Dental Hospital between July 2014 and June 2015. A group with a history of peri-implantitis (HP) (370 patients with 1,189 implants) and a group with a current peri-implantitis (CP) (318 patients with 1,004 implants) were created based on the radiographic and clinical assessments of implants. The prevalence of peri-implantitis was calculated at both the patient and implant levels. The influence of risk variables on the occurrence of peri-implantitis was analyzed using generalized estimating equations analysis. RESULTS: The prevalence of peri-implantitis in the HP and CP groups ranged from 6.7% to 19.7%. The cumulative peri-implantitis rate in the HP group estimated with the Kaplan-Meier method was higher than that in the CP group over the follow-up period. Among the patient-related risk variables, supportive periodontal therapy (SPT) was the only significant risk indicator for the occurrence of peri-implantitis in both groups. In the analysis of implant-related variables, implants supporting fixed dental prosthesis (FDP) and implants with subjective discomfort were associated with a higher prevalence of peri-implantitis than single implants and implants without subjective discomfort in the HP group. The presence of subjective discomfort was the only significant implant-related variable predictive of peri-implantitis in the CP group. CONCLUSIONS: Within the limitations of this study, the prevalence of peri-implantitis in Korean patients with a history of periodontal disease was similar to that reported in other population samples. Regular SPT was important for preventing peri-implantitis. Single implants were found to be less susceptible to peri-implantitis than those supporting FDP. Patients' subjective discomfort was found to be a strong risk indicator for peri-implantitis. PMID- 28861289 TI - Effects of implant tilting and the loading direction on the displacement and micromotion of immediately loaded implants: an in vitro experiment and finite element analysis. AB - PURPOSE: The purpose of this study was to investigate the effects of implant tilting and the loading direction on the displacement and micromotion (relative displacement between the implant and bone) of immediately loaded implants by in vitro experiments and finite element analysis (FEA). METHODS: Six artificial bone blocks were prepared. Six screw-type implants with a length of 10 mm and diameter of 4.3 mm were placed, with 3 positioned axially and 3 tilted. The tilted implants were 30 degrees distally inclined to the axial implants. Vertical and mesiodistal oblique (45 degrees angle) loads of 200 N were applied to the top of the abutment, and the abutment displacement was recorded. Nonlinear finite element models simulating the in vitro experiment were constructed, and the abutment displacement and micromotion were calculated. The data on the abutment displacement from in vitro experiments and FEA were compared, and the validity of the finite element model was evaluated. RESULTS: The abutment displacement was greater under oblique loading than under axial loading and greater for the tilted implants than for the axial implants. The in vitro and FEA results showed satisfactory consistency. The maximum micromotion was 2.8- to 4.1-fold higher under oblique loading than under vertical loading. The maximum micromotion values in the axial and tilted implants were very close under vertical loading. However, in the tilted implant model, the maximum micromotion was 38.7% less than in the axial implant model under oblique loading. The relationship between abutment displacement and micromotion varied according to the loading direction (vertical or oblique) as well as the implant insertion angle (axial or tilted). CONCLUSIONS: Tilted implants may have a lower maximum extent of micromotion than axial implants under mesiodistal oblique loading. The maximum micromotion values were strongly influenced by the loading direction. The maximum micromotion values did not reflect the abutment displacement values. PMID- 28861291 TI - Score 3 prostate lesions: a gray zone for PI-RADS v2. AB - Prostate Imaging Reporting and Data System version 2 (PI-RADS v2) does not offer a precise guidance on the clinical management (biopsy or not biopsy) for PI-RADS v2 score 3 lesions. Lesion volume calculated on biparametric MRI (bpMRI) [T2 weighted imaging (T2WI) and diffusion-weighted imaging (DWI)] by introducing a cut-off of 0.5 mL, allows to distinguish the lesions assigned by the multiparametric MRI (mpMRI) to the category PI-RADS v2 score 3 in two subgroups: a) Indolent or low risk lesions with volume <0.5 mL, and b) Significant or high risk lesions with volume >=0.5 mL. For mpMRI lesions assigned to PI-RADS v2 score 3, we suggest the following management: 1) Subgroup a (low-risk lesion): Clinical surveillance (accurate evaluation of age and clinical informations, periodic monitoring of prostate specific antigen value and repeated bpMRI 1 year later); 2) Subgroup b (high-risk lesion): Targeted biopsy. The proposed management would reduce the use of unnecessary biopsies and increase the diagostic yield of significant prostate cancer of approximately 50% and 30% respectively. These approaches encourage the radiologist to adopt MRI lesion volume to improve PI RADS v2 and to optimize the management of PI-RADS v2 score 3 lesions. PMID- 28861290 TI - Mystery and realities of phalloplasty: a systematic review. AB - The neophallus creation is still a mystery and it remains challenging even today. In this article, we performed a comprehensive review of the literature regarding phalloplasty and penile reconstructive surgery between January 2008 and May 2016. In this review, we have included 15 research articles and the results of 276 patients were examined. Studies revealed several indications and when indications were reviewed, 191 patients were female-to-male transgender, 9 patients had disorder of sex development/micropenis, 16 had penile amputation/trauma, 9 had ambiguus genitalia, 40 had exstrophy and/or epispadias, 11 had other problems. As a result of this review, phalloplasty is a reliable and useful operation with good functional and aesthetical results. PMID- 28861292 TI - Update on the novel management and future paternity situation in adolescents with varicocele. AB - Varicocele is a progressive disease, and the incidence of varicocele and varicocele related testicular hypotrophy increases with puberty. This review updates novel management and future paternity potential in adolescents with varicocele. Main goal of treatment of the adolescent varicoceles is preservation of fertility. Current recommendations for adolescent varicocele repair are testicular hypotrophy (>2 mL or >20%) on the affected side and/or impaired spermatogenesis in the post-pubertal period. The best treatment modality for adolescent varicocele should include elimination of the varicocele with lower complication rates. Microsurgical varicocelectomy techniques have been shown to result in fewer recurrences and postoperative complications than conventional varicocelectomy in adolescents. We conducted a meta-analysis, including 2 studies with the control groups, and reporting paternity situation after varicocele treatment. In this meta-analysis, varicocele repair increases paternity rate 2.42 times with a p value of 0.000. Adolescents with varicocele and their families should be counselled in the light of these findings. PMID- 28861293 TI - Erectile dysfunction in the elderly male. AB - Erectile dysfunction (ED) is a health problem which mainly effects elderly men and this problem has become a more important health problem with the increased life expectancy. The basic risk factors of ED are hypertension, dyslipidemia, diabetes mellitus, and atherosclerotic heart disease which also have a higher incidence in the elderly men. The aim of this review article is to highlight the age-related changes in ED together with recommendations for patient evaluation and treatment. PMID- 28861294 TI - Retrograde intrarenal surgery for renal stones - Part 2. AB - Retrograde intrarenal surgery (RIRS) has become an effective and safe treatment modality in the management of urinary system stone disease. Recent developments and innovations in the flexible ureterorenoscope and auxiliary equipment have made this procedure easier and more effective with increased success rates. RIRS can be used as a primary treatment in patients with renal stones smaller than 2 cm, prior unsuccessful shock wave lithotripsy, infundibular stenosis, renoureteral malformation, skeletal-muscular deformity, bleeding diathesis and obese patients. In the second part of this detailed review for RIRS, effect of stone composition on success rate, preoperative assessment of stone-free rate, the cost of this modality, education for RIRS, fluoroscopy use, the current role of RIRS in the treatment of various urolithiasis types and special conditions, and combined treatment methods are discussed with up-to-date literature. PMID- 28861296 TI - Ductal variant of prostate adenocarcinoma harbor Xenotropic murine leukemia virus related virus (XMRV) infection: a novel finding in subtype of prostate cancer. AB - OBJECTIVE: Xenotropic murine leukemia virus related virus (XMRV), is the first gammaretrovirus identified a decade ago, in human tissue bearing adenocarcinoma of prostate, followed by several researches documenting little or no prevalence of XMRV in prostate cancer samples. However, the status of XMRV within subtype of prostate adenocarcinoma has not been investigated yet. In this study, we investigated the relationship between XMRV and broad spectrum morphological entities of prostate adenocarcinoma, including acinar, ductal and other rare subtypes. MATERIAL AND METHODS: The prevalence of XMRV DNA in different histological subtypes of prostate adenocarcinoma was examined after characterizing the tumors into groups, using formalin-fixed, paraffin-embedded tissue samples from newly diagnosed prostate adenocarcinomas and archival prostate cancer tissue from our XMRV case control analysis. Broad-spectrum XMRV DNA amplification was performed by end-point polymerase chain reaction, using commercially available primer set. RESULTS: The study included 100 patients with prostate cancer. XMRV DNA was detected in 4 of 8 (50%) ductal adenocarcinomas, exhibiting papillary and cribriform histological features. XMRV DNA was not detected in any other variant of adenocarcinoma including acinar (0/91) and mucinous carcinomas (0/1). Majority of XMRV positive cases were biologically aggressive and present cancer at an early age upon diagnosis. CONCLUSION: Ductal adenocarcinomas demonstrate a significant association of XMRV DNA while other histological variants of prostate adenocarcinoma seem unrelated to XMRV infection. PMID- 28861295 TI - Evaluation of the diagnostic efficacy of strain elastography in infertile population with normal and abnormal semen parameters. AB - OBJECTIVE: The aim of the present study was to investigate the diagnostic value of strain elastography (SE) of testicular tissues in infertile population. We also evaluated the correlation between SE results with semen parameters and hormone profiles of the patients. MATERIAL AND METHODS: A total of 61 patients and 122 testes were evaluated. Patients who were evaluated in an andrology outpatient clinic with the diagnosis of infertility and referred to radiology department for investigation of reproductive organs between June 2015 and January 2016 were included. Patients were divided into two groups according to semen analyses results as normal (Group 1) and abnormal (Group 2). Hormone profiles, semen analyses, B-mode, coloured Doppler ultrasonography and sonoelastography examinations were performed for each patient. Measurements of testicular volumes, resistive indices (RI) in intraparenchymal arteries, strain, strain ratio (SR) and presence of varicocele were recorded. RESULTS: Mean age of participants was 33.7+/-6.3 years. Mean testicular volumes (Group 1, 19.41+/-4.8 mL, and Group 2, 17.64+/-3.62 mL) were significantly different between groups (p=0.023). Mean SRs were also different between Groups 1 and 2 (0.12+/-0.08 vs. 0.22+/-0.18, p<0.001). Testicular volumes were directly proportional with SRs in Group 1. Strain values had inverse relationship with sperm concentration and total motile sperm counts in Group 2 (p=0.01). SRs were found to be positively correlated with RI and sperm morphology in Group 2 (p<0.05). Although FSH values showed significant difference among groups, any correlation between FSH and elastographic parameters could not be displayed. CONCLUSION: Strain elastography results were found to be significantly different in patients with abnormal sperm counts. This technique may provide promising results, however, further large scale studies may help to clarify the value of this imaging modality in the assessment of male infertility. PMID- 28861297 TI - Maintenance treatment with gemcitabine have a promising activity on metastatic bladder cancer survival. AB - OBJECTIVE: To investigate the effects of gemcitabine maintenance treatment on survival in patients with metastatic bladder cancer. MATERIAL AND METHODS: Gemcitabine maintenance monotherapy was administered following the standard platinum-gemcitabine therapy in patients with metastatic bladder cancer. Patients who had responded to standard treatment received maintenance gemcitabine therapy as 1000 mg/m2 on days 1 and 8 every three weeks until progression or development of unacceptable toxicity. The following clinical factors were noted: performance status, age, sex, stage, site of metastasis, choice of cisplatin-gemcitabine or carboplatin-gemcitabine, response rates to the initial chemotherapy. Progression free survival (PFS) and overall survival (OS) for standard treatment, and following gemcitabine monotreatment and for maintenance gemcitabine therapy were calculated using Kaplan-Meier method. RESULTS: A total of 88 patients with metastatic bladder cancer treated between February 2009 to October 2015 were evaluated retrospectively and 23 patients (26.1%) who had responded to six cycles of platinum-gemcitabine treatment were included in this study. Maintenance gamcitabine was administered for a median of 7 times (range 3-14 times). Grade 3 hematotoxicity according to the criteria of the Common Terminology Criteria of Adverse Events was observed in 7 (30.4%) patients. Median PFS of patients was 46 (range: 30-82) weeks for platinum-based treatment plus maintenance gemcitabine therapy. A higher median PFS was obtained in patients who were <65 year-olds, without organ metastasis with objective response rate, however, it was statistically insignificant. CONCLUSION: Gemcitabine maintenance therapy in metastatic bladder cancer patients who did not shown progression after the standard platinum-gemcitabine treatment contributes to survival and presents low toxicity profile, when compared to historical controls. PMID- 28861298 TI - A pilot study assessing the association between paraoxonase 1 gene polymorphism and prostate cancer. AB - OBJECTIVE: We aimed to show the relationship between paraoxonase 1 (PON1) gene polymorphism and the development of prostate cancer (PCa). MATERIAL AND METHODS: We investigated the association of single nuclotide polymorphisms of PON1 enzyme with the development of PCa risk. A total of 147 male patients were divided into PCa, and control groups. The control group was also divided into two subgroups according to serum prostate specific antigen (PSA) levels as non PCa-high PSA (>4 ng/mL) and non PCa-low PSA (<=4 ng/mL) groups. RESULTS: The mean ages of the patients were 64.81 years, 63.27 years and 64.22 years in PCa group, non PCa-low PSA and non PCa -high PSA groups, respectively. The mean PSA levels were 10.9 ng/mL, 1.16 ng/mL and 6.63 ng/mL for PCa group, non PCa -low PSA and non PCa high PSA groups, respectively. In terms of PON1 polymorphisms and allele frequencies, there were no statistically significant differences between PCa and control groups. There was not a statistically significant difference between PCa and non PCa-high PSA groups as for genotypic and allelic frequencies. As a result of this small sample sized hypothetical study of polymorphism, a relationship could not be detected between PCa development and PON1 gene polymorphism. CONCLUSION: According to the results of this preliminary study, it is thought that more comprehensive future studies are necessary to clarify the possible role of PON1 gene polymorphism in the etiology of PCa. PMID- 28861299 TI - Association between systemic inflammation and serum prostate-specific antigen in a healthy Korean population. AB - OBJECTIVE: Serum prostate-specific antigen (PSA) may be elevated in healthy men with systemic inflammation. We aimed to investigate the association between systemic inflammation markers and serum PSA in a healthy Korean population. MATERIAL AND METHODS: A cohort of 20,151 healthy native Korean men without prostate disease between the ages of 40 and 65 years who underwent medical checkups were studied from January 2007 to December 2013. Serum total PSA and serum C-reactive protein concentrations, neutrophil, lymphocyte, and platelet counts were determined. The neutrophil-lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) were calculated. We checked the correlation between systemic inflammation markers and PSA. RESULTS: Data obtained from 18,800 healthy men were analyzed. The mean age of the study subjects was 50.72+/-7.62 years and the mean NLR was 1.764+/-0.804. Correlation analysis after adjustment for age and body mass index (BMI) revealed that neutrophil count (coefficient = 0.028, p value <0.001), and NLR (coefficient = 0.027, p value <0.001) correlated with PSA. Multivariate analysis using the full model revealed that age, neutrophil count and NLR were positively correlated with PSA (p<0.001, 0.001, and 0.043 respectively). Multivariate analysis using a stepwise model revealed that age, neutrophil count and NLR were positively correlated with PSA (p<0.001, 0.001, and 0.040, respectively) and BMI was negatively correlated with PSA (p<0.001). CONCLUSION: Systemic inflammation markers are useful with a serum PSA in a healthy Korean population. NLR in particular is significantly associated with serum PSA. PMID- 28861300 TI - Low free and bioavailable testosterone levels may predict pathologically-proven high-risk prostate cancer: a prospective, clinical trial. AB - OBJECTIVE: To determine the predictive value of free and bioavailable testosterone levels on the detection of high-grade prostate cancer proven by histopathological examination of transrectal prostate biopsy specimens. MATERIAL AND METHODS: A total of 405 patients who underwent transrectal prostate biopsy due to high prostatic specific antigen (PSA) (>2.5 ng/mL) and/or abnormal findings at digital rectal examination were included in this study. Blood free and bioavailable testosterone levels were calculated by the formula recommended by International Society for the Study of the Aging Male (ISSAM). The patients were stratified according to the D'Amico classification based on PSA levels and histological outcomes of prostate biopsies as benign, low, intermediate and high risk prostate cancer. Patients were also divided into five groups according to the percentage of cancerous cores. RESULTS: Prostate cancer was detected in 160 of 405 (39.5%) patients. Total, free and bioavailable testosterone levels did not differ significantly between the patients with benign or malign histology. However, mean free (6.2 vs. 5.2 ng/dL, p=0.02) and bioavailable (151 vs. 125 ng/dL, p=0.001) testosterone levels were found to be significantly different in men with low-intermediate and high-risk prostate cancer. Moreover, a significant correlation was found between free, and bioavailable testosterone levels and percentage of cores with cancer (p=0.002 for free and p=0.016 for bioavailable testosterone, respectively). CONCLUSION: This prospective clinical study demonstrates that reduced levels of calculated blood free and bioavailable testosterone levels are associated with an increased risk of high-grade prostate cancer. Based on these findings blood free and bioavailable testosterone levels may be be thought to be an adjunctive factor in the prediction of high-risk prostate cancer. PMID- 28861301 TI - Longer biopsy cores do not increase prostate cancer detection rate: A large-scale cohort study refuting cut-off values indicated in the literature. AB - OBJECTIVE: Only a few papers in the literature aimed to evaluate biopsy core lengths. Additionally, studies evaluated the core length with different approaches. We aimed to determine whether prostate cancer (PCa) detection is affected from core lengths according to three different approaches in a large standard cohort and compare our cut-off values with the published cut-offs. MATERIAL AND METHODS: We retrospectively analyzed 1,523 initial consecutive transrectal ultrasound-guided 12-core prostate biopsies. Biopsies were evaluated with respect to total core length (total length of each patients' core) average core length (total core length divided by total number of cores in each patient), and mean core length (mean length of all cores pooled), and compared our cut-off values with the published cut-offs. The prostate volumes were categorized into four groups (<30, 30-59.99, 60-119.99, >=120 cm3) and PCa detection rates in these categories were examined. RESULTS: PCa was found in 41.5% patients. There was no difference between benign and malignant mean core lengths of the pooled cores (p>0.05). Total core length and average core length were not significantly associated with PCa in multivariate logistic regression analyses (p>0.05). The core lengths (mean, average and total core lengths) increased (p<0.001) and PCa rates decreased (p<0.001) steadily with increasing prostate volume categories. PCa percentages decreased in all categories above the utilized cut-offs for mean (p>0.05), average (p<0.05), and total core lengths (p>0.05). CONCLUSION: There was no difference between mean core lengths of benign and malignant cores. Total core length and average core length were not significantly associated with PCa. Contrary to the cut-offs used for mean and average core lengths in the published studies, PCa rates decrease as these core lengths increase. Larger studies are necessary for the determination and acceptance of accurate cut-offs. PMID- 28861302 TI - Factors associated with postoperative pain after retrograde intrarenal surgery for kidney stones. AB - OBJECTIVE: We aimed to investigate factors related to early postoperative pain after retrograde intrarenal surgery (RIRS). MATERIAL AND METHODS: A prospective data analysis of 250 patients who underwent RIRS due to kidney stones was performed. Postoperative pain was evaluated in all patients by using visual analogue scale (VAS). Patients with severe pain (VAS score >=7) were separated and included in Group I (n=46). While patients without pain or with insignificant pain were included in Group II (n=204). The impact of patient-related (age, gender, renal anomalies, shock wave lithotripsy history, preoperative hydronephrosis) stone-related (stone number, side, size, location and opacity) and operation-related (preoperative and postoperative ureteral J-stenting, ureteral injury, postoperative bleeding and fever, stone-free rates, size of access sheath, and sheath indwelling time) factors on early stage postoperative pain (if any) were investigated. RESULTS: Female gender increased the risk for pain 3.6-fold (p<0.05). One millimeter increase in stone diameter increased the risk for postoperative pain 1.15-fold. Prolonged sheath time was another important factor which increased the risk for pain (p<0.05). Patients with high residual fragments were also prone to early postoperative pain. CONCLUSION: According to our results, patient-, stone-and operation-related factors associated with postoperative pain after RIRS were female gender, stone size and sheath time. PMID- 28861303 TI - Flouroscopy-free technique is safe and feasible in retrograde intrarenal surgery for renal stones. AB - OBJECTIVE: The aim of this study was to present outcomes of our patients who had undergone retrograde intrarenal surgery (RIRS) with fluoroscopy-free technique and evaluate the efficacy and safety of the technique. MATERIAL AND METHODS: Between January 2013 and June 2015 the outcomes of 93 patients who had undergone RIRS with fluoroscopy-free technique were retrospectively evaluated. Our RIRS technique involved preoperative assessment of ureter by semi-rigid ureteroscope, inserting guidewire through semi-rigid ureteroscope, inserting ureteral access sheath over the guidewire with the visiual guidance of semi-rigid ureteroscope, passing flexible ureteroscope through the sheath, dusting the stone with holmium laser, rechecking the ureter with semi-rigid ureteroscope and inserting double J stent through semi-rigid ureteroscope. Low-dose computerized tomography scan was performed to all patients in postoperative first month and the results were classified as stone-free (absence of any fragment), clinically insignificant residual fragments (CIRF) (<=4 mm) and residual stone. RESULTS: Study population consisted of 62 (66.6%) male and 31 (33.3%) female patients with a mean age of 47.8+/-14 (range 14-93) years. Mean stone size was 14.7+/-5 (7-32) mm. Median operative time was 72 (30-125) minutes. Stone-free rate was achieved in 65 (69.9%) patients while CIRF was achieved in 13 (13.9%) and residual stones were detected in 15 (16.1%) patients. Five patients (5.37%) had minor complications, including hematuria and fever. No major complications were observed. CONCLUSION: Fluoroscopy-free technique is effective and safe technique in management of renal stone. Furthermore fluoroscopy-free technique can protect the surgeon from the negative effects of radiation. PMID- 28861304 TI - Laparoscopic ureteral reimplantation with Boari flap for the management of long- segment ureteral defect: A case series with review of the literature. AB - OBJECTIVE: The incidence of ureteral stricture is showing a rising trend due to increased use of laparoscopic and upper urinary tract endoscopic procedures. Boari flap is the preferred method of repairing long- segment ureteral defects of 8-12 cm. The procedure has undergone change from classical open (transperitoneal and retroperitoneal) method to laparoscopic surgery and recently robotic surgery. Laparoscopic approach is cosmetically appealing, less morbid and with shorter hospital stay. In this case series, we report our experience of performing laparoscopic ureteral reimplantation with Boari flap in 3 patients. MATERIAL AND METHODS: This prospective study was conducted between January 2011 December 2014. The patients with a long- segment ureteral defect who had undergone laparoscopic Boari flap reconstruction were included in the study. Outcome of laparoscopic ureteral reimplantation with Boari flap for the manangement of long segment ureteral defect was evaluated. RESULTS: The procedure was performed on 3 patients, and male to female ratio was 1:2. One patient had bilateral and other two patient had left ureteral stricture. The mean length of ureteral stricture was 8.6 cm (range 8.2-9.2 cm). The mean operative time was 206 min (190 to 220 min). The average estimated blood loss was 100 mL (range 90-110 mL) and mean hospital stay was 6 days (range 5 to 7 days). The mean follow up was 19 months (range 17-22 months). None of the patients experienced any complication related to the procedure in perioperative period. CONCLUSION: Laparoscopic ureteral reimplantation with Boari flap is safe, feasible and has excellent long term results. However, the procedure is technically challenging, requires extensive experience of intracorporeal suturing. PMID- 28861305 TI - Laparoscopic transperitoneal and retroperitoneal simple nephrectomy: The impact of etiological factors of the results of surgical treatment. AB - OBJECTIVE: This retrospective study compares the perioperative outcomes of laparoscopic simple nephrectomy (LSN) in patients with urinary stone disease (USD) in comparison with LSNs performed for other etiological factors. MATERIAL AND METHODS: 115 LSNs were identified from the two teaching hospitals' database. Depending on the etiological factors, patients were stratified in 2 groups. Group 1 consisted of 63 (mean age 44.8+/-1.7 [21-71] years) patients; where the cause of non-functioning kidney was USD. Meanwhile, Group 2 included 52 (mean age was 43.6+/-2.0 [19-78] years) patients; who underwent LSN because of other benign diseases. In both groups, a standardized transabdominal or retroperitoneal approach was used according to the discretion of the attending surgeon. Two groups were compared statistically in terms of perioperative parameters and standardized surgical complications. RESULTS: The use of transperitoneal approach was higher in Group 1 (69.8% vs. 30.2%) compared to Group 2 (51.9% vs. 48.1%). Elective open conversion was needed in 3 and 2 patients in Groups 1 and 2, respectively. The results for mean operative time (108.9+/-4.0 min vs. 106.7+/ 5.0), estimated blood loss (92.5+/-8.2 vs. 86.8+/-10.1 mL) and length of hospital stay (4.1+/-0.33 vs. 3.85+/-0.42 days) were similar between the groups. Despite intraoperative complications were similar between the groups, overall post operative complications were significantly higher (17.5% vs. 3.8%) in Group 1. However, the rate of significant complications (Clavien 3-5) was similar between the groups. CONCLUSION: The present study revealed that perioperative outcomes of patients undergoing LSN for USD are similar to those seen in patients undergoing LSN for other etiological factors. PMID- 28861306 TI - The predictive value of platelet to lymphocyte and neutrophil to lymphocyte ratio in determining urethral stricture after transurethral resection of prostate. AB - OBJECTIVE: The pathology of urethral stricture disease is still unclear however progressive inflammation may contribute to the development of urethral stricture. The platelet-to- lymphocyte ratio (PLR) is a new and simple marker that indicates inflammation. In this study we aimed to investigate the predictive value of neutrophil to lymphocyte ratio (NLR) and PLR in patients with urethral stricture who underwent transurethral resection of prostate (TURP). MATERIAL AND METHODS: A total of 208 patients who underwent bipolar-TURP were included in this study. Patients who had previously undergone surgery due to any urethral pathology, posterior urethral strictures, previous or ongoing treatment for any cancer, hematologic disorders, presence of an active infection at the time of surgical intervention, and prior blood transfusion were excluded. PLR, NLR and red cell distribution width (RDW) levels were measured. In order to investigate the predictive values of NLR and PLR variables, binary logistic regression analysis was performed. RESULTS: No statistically significant differences were observed between the groups in terms of age, NLR, RDW, prostate size and operative times. Statistically significant differences were presented only in the median PLR- values. For predicting urethral stricture, the optimal cut-off value was 112.5, (sensitivity: 0.84, specificity: 0.64; AUC=0.762, 95% CI 0.684-0.84). CONCLUSION: In this study we showed that PLR can be used to determine urethral stricture as a cost-effective, common, and simple biomarker in patients after TURP. PMID- 28861307 TI - Preliminary feasibility study of a new method of hypothermia in an experimental canine model. AB - OBJECTIVE: To build up a new microcontroller thermoelectric system to achieve renal hypothermia. MATERIAL AND METHODS: Renal hypothermia system was tested under in vivo conditions in the kidneys of ten Mongrel dogs. Ambient temperature was evaluated using two different microcontrollers. In order to ensure hypothermia in the renal parenchyma, selection can be made among 4 modules and sensors which detect the temperature of the area. The temperature range of the system was adjusted between -50 degrees C and +50 degrees C. RESULTS: When single and double poles of the kidney were cooled, initial mean intraperitoneal temperature values were found 37.7 degrees C for rectum and 36.5 degrees C for renal cortex and medulla. After the temperature of the cooling module was set to 12 degrees C, the module was placed on the poles of the kidney. After fifteen minutes, temperature was 15.4 degrees C in the lower pole of the kidney, 28.1 degrees C in the cortex of the other side and 29.2 degrees C in the intramedullary region. The temperature was found to be 15 degrees C in the vicinity and 26.1 degrees C in the cortex across the module. After the system was stabilized, a very slight change was observed in the temperature. CONCLUSION: Hypothermia system developed ensured desired cooling of the targeted part of the kidney; however, it did not cause a change in the temperature of other parts of the kidney or general body temperature. Thus, it was possible to create a long term study area for renal parenchymal surgery. PMID- 28861309 TI - Isolation and in vitro cultivation of human urine-derived cells: an alternative stem cell source. AB - OBJECTIVE: For in vitro tissue engineering in urology, stem cells are commonly isolated from tissue specimens obtained during open or endoscopic surgery. Within the context of the present study our aim was to isolate cells from human urine by an alternative and safe technique rather than using the indicated method. MATERIAL AND METHODS: After human urine samples had been collected from young and healthy donors via urethral catheterization, cells were precipitated by centrifugation and cultured. Following this isolation procedure, cells were characterized by immunocytochemical method using specific antibodies. RESULTS: When these cells were characterized by immunocytochemical methods using specific antibodies some of them were positive for mesenchymal stem cell marker CD90 while the others were labelled with urothelial marker cytokeratin 7. When all these results were taken into consideration, urothelial cells together with stem cells were observed in the urine- derived cell population. CONCLUSION: According to the results obtained from this study human urine may be preferred as an alternative stem cell and urothelial cell source in that this method is and easily reproducible non-invasive method. PMID- 28861308 TI - Giant hydronephrosis: still a reality! AB - OBJECTIVE: Giant hydronephrosis (GH) is a rare entity in both developed and developing countries with less than 500 cases reported in the literature. Delayed diagnosis and management of GH, can result in long-term complications like hypertension, rupture of the kidney, renal failure and malignant change. We aim to highlight the importance of this often neglected entity and build a consensus for its early diagnosis and management. MATERIAL AND METHODS: Patients with GH were thoroughly worked up, managed and followed up between June 2013 and December 2015 and epidemiologic, radiological, perioperative and follow-up data was recorded. RESULTS: A total of 35 patients (adults and children) were reported. Flank pain in adults and abdominal lump in children were the most common clinical presentation. Percutaneous nephrostomy tube was placed in all patients and detailed work up was done to reach final diagnosis. Pelvi-ureteric junction obstruction (PUJO) was the final diagnosis in 32 patients (91.4%). Kidneys were non-functioning in 13 cases (37.1%) so nephrectomies were performed. Reduction pyeloplasty with nephropexy was done in 21 patients (60%) with 81% success and 23.1% complication rates. CONCLUSION: GH requires early diagnosis and management to prevent higher nephrectomy rate along with poor success rate of conservative surgery like pyeloplasty. PMID- 28861310 TI - Does site of buccal mucosa graft for bulbar urethra stricture affect outcome? A comparative analysis of ventral, dorso-lateral and dorsal buccal mucosa graft augmentation urethroplasty. AB - OBJECTIVE: To compare long- term outcomes of buccal mucosa graft (BMG) augmentation urethroplasty for long segment bulbar urethral strictures done by placing the graft ventrally, dorso-laterally and dorsally. MATERIAL AND METHODS: We conducted a single institution retrospective study on 112 who underwent BMG augmentation urethroplasty for non-traumatic bulbar urethral strictures between January 2005 to December 2014. The cases were divided into three groups based on the site of placement of BMG graft i.e. (a) Ventral (n=44), (b) Dorso-lateral (n=48) and (c) Dorsal (n=20). Follow-up period was from one year to five years. Patients with failed outcomes underwent urethroscopy or retrograde urethrogram to note the site of recurrence of stricture. RESULTS: Out of 112 cases 91 (81%) were successful and 21 (19%) failed. The success rates for ventral, dorso-lateral and dorsal BMG augmentation procedures were 89%, 79% and 70%, respectively (p=0.18). Among 21 failed cases, 12 cases (57%) had stricture at proximal anastomotic site, 4 cases (19%) at graft and 5 cases (24%) at distal anastomotic site (p=0.01). CONCLUSION: The overall success rate for BMG augmentation urethroplasty is equal for all techniques. Ventral onlay urethroplasty provides better exposure of proximal anastomotic site thus it is associated with minimum proximal anastomotic site recurrence rates. Patients with extensive spongiofibrosis and long segment strictures had higher rates of failure. PMID- 28861311 TI - Our experiences with robot- assisted laparoscopic surgery in pediatric patients: the first case series from Turkey. AB - OBJECTIVE: Robotic surgery is a leading treatment option for minimally invasive surgery and has an increasing popularity in pediatric population, as well. In this article, we reported our case series of robot-assisted laparoscopic surgery in pediatric population. MATERIAL AND METHODS: We retrospectively reviewed 29 consecutive pediatric patients who underwent robot- assisted procedures between May 2014 and October 2016. Patient demographics, hospitalization time, estimated blood loss, robotic time and total operative and peri-, and post-operative complications were evaluated. RESULTS: A total of 24 ureter units (18 patients) with grade 1-5 vesicoureteral reflux in 13 female and 5 male, 1 male patient with vesicoureteral stenosis were underwent robot- assisted laparoscopic ureteral reimplantation (RALUR). All patients had complete resolution after surgery. Robot assisted laparoscopic pyeloplasty (RALP) was performed in 6 patients with ureteropelvic junction obstruction. All patients had complete resolution after surgery. Completely intracorporeal robotic assisted laparoscopic augmentation ileocystoplasty (RLAIC) was applied to two patients with neurogenic bladder. The symptoms and preoperative hydronephrosis were regressed on the first month of follow-up. Robot-assisted laparoscopic reduction cystoplasty (RALRC) was performed in 14-year-old boy with a bladder diverticula and recurrent urinary tract infection. The last case was eleven- year-old female patient with non functioning kidney. She had recurrent urinary tract infections and was treated with robotic assisted laparoscopic nephrectomy (RALN). CONCLUSION: Robot-assisted laparoscopic surgery is safe and efficient in pediatric population. Although open surgery is still the gold standard for many pediatric diseases, inherent reconstructive advantages of robotic assisted laparoscopy have a chance to change this view. PMID- 28861312 TI - Effective predictors for surgical decision in antenatal hydronephrosis: a prospective multiparameter analysis. AB - OBJECTIVE: The majority of antenatal hydronephrosis disappears spontaneously. In our study, we have investigated the effective predictors for surgical decision in antenatal hydronephrosis. MATERIAL AND METHODS: Forty-four patients found to have renal pelvic anteroposterior (AP) diameter more than 10-mm on antenatal ultrasonograpy were followed after birth. The study groups were divided into two groups: follow-up and surgery group. On follow-up, longitudinal diameter of the kidney, parenchymal thickness of the kidney, AP diameter of renal pelvis, AP diameter of middle calyces on ultrasonograpy, and differential renal function, 20th minute clearance, half-life of radionuclide tracer (T1/2), Tmax, Tmax-T1/2, normalised residual activity (NORA) on diuretic renography were evaluated. Ultrasonograpy and diuretic renography measurements were compared in patients whose hydronephrosis resolve or proceeded to surgery. RESULTS: Forty-four patients were diagnosed as antenatal hydronephrosis, spontaneous resolution occurred in 23 (52%), and surgery was performed in 21 patients (48%). Mean age at operation was 8.5+/-6.5 months (3-24 months). Mean AP diameter of renal pelvis was 29.5+/-14.2 mm for surgery group, 13.6+/-4.2 mm for follow-up group (p<0.001). Univariate analyses showed significance for all ultrasonographic measurements and only the differential renal function by diuretic renography. Multivariate logistic regression analysis showed significance for AP diameter of renal pelvis (odds ratio 1.37; 95% Cl 1.13-1.66), and differential renal function (odds ratio 1.14; 95% Cl 1.01-1.29). CONCLUSION: AP diameter of renal pelvis and differential renal function were the most effective parameters for surgical decision. These parameters can be used for appropriate management of antenatal hydronephrosis. PMID- 28861313 TI - Using negative pressure therapy for improving skin graft taking on genital area defects following Fournier gangrene. AB - OBJECTIVE: Fournier's gangrene is an infective necrotizing fasciitis of the perineal, genital and perianal regions. Treatment includes aggressive surgical debridement that often results in extensive loss of genital skin. Skin grafts may be used for reconstruction but skin grafting of the male genitalia is diffucult because the penis and scrotum are mobile and deformable. A variety of methods are used to secure skin graft to recipient beds. We used negative pressure therapy (NPT) to secure skin grafts and improve skin graft taking. MATERIAL AND METHODS: We used negative pressure therapy for graft fixation in 13 male patients who underwent debridements with the indication of Fournier gangrene, and whose defects formed were reconstructed with grafts between January 2009, and January 2014. Information about age of the patients, sessions of negative pressure therapy applied before, and after reconstruction, duration of hospital stay, and graft losses during postoperative period were recorded. RESULTS: Median age of the patients was 56.15 (46-72) years. NPT was applied to patients for an average of 6.64 sessions (4-12) before and 1 sessions after graft reconstruction. Patients were hospitalized for an average of 26.7 (20-39) days. Any graft loss was not seen after NPT. CONCLUSION: Because of the peculiar anatomy of the genital region, anchoring of grafts is difficult so graft losses are often encountered. Use of NPT for ensuring graft fixation on the genital region prevents skin graft shearing. PMID- 28861314 TI - New surgical technique applied with urological instruments in bilobar multiple hepatolithiasis: Ultra-mini percutaneous hepatolithotomy. AB - Intrahepatic bile duct stones may emerge with manifestations as chronic stomach ache, cholestasis, cholangitis, abscess, post-obstructive atrophy and liver cirrhosis presentation may occur. Thus the treatment of symptomatic hepatolithiasis patients should be provided. Different methods such as biliary decompression, endoscopic, percutaneous or open surgery are recommended for the treatment of patients with intrahepatic gallstones. The aim of the treatment is to extract the stones and regain biliary drainage. But the treatment regimen to be applied should be determined after examining the age, performance condition, general condition of the patient and location of the stone carefully. In this case, we presented a young female patient who had many unsuccessful surgical interventions due to coledochal cyst and congenital malformation in bile ducts, had large stones in right and left intrahepatic bile ducts and in whom we provided complete stone-free condition through Ultra-Mini Percutaneous Hepatolithotomy (UM-PHL) using urological instruments. PMID- 28861315 TI - Renal angiomyoadenomatous tumour. AB - Renal angiomyoadenomatous tumour is a newly described rare neoplasm. This tumour is characterised microscopically by admixture of three components- epithelial cells arranged in tubules and nests, angiomyomatous stroma and capillary sized interconnecting vascular channels in close association with the epithelial cell clusters. Microscopically it has wide range of differential diagnoses which include mixed epithelial and stromal tumour of kidney, angiomyolipoma and clear cell renal cell carcinoma with angiomyolipomatous/angiomyoadenomatous areas. Renal angiomyoadenomatous tumour should be differentiated from these tumours. Till now, only 10 cases have been reported in English medical literature. Here, we are reporting a case of renal angiomyoadenomatous tumour in a 29 year- old female patient who presented with hematuria and low backache and describing its main features so as to differentiate this entity from other renal tumours. To the best of our knowledge, this is the first case to be reported from India. PMID- 28861316 TI - Granular cell tumor of the urinary bladder. AB - Granular cell tumors (GCTs) are extremely rare neoplasms of the bladder. In the literature, there are only a few reported cases. We present a GCT case with clinical, radiological, histomorphological, immunohistochemical findings and its differential diagnosis. PMID- 28861317 TI - Removal of a retroperitoneal foreign body through single port laparoscopy using nephroscope. AB - Foreign bodies are rare and challenging issues leading to symptoms according to the location. Laparoscopy is a popular and minimally invasive method used for removal of foreign bodies in the abdominal cavity or retroperitoneum. We herein report a case with retroperitoneal foreign body that was removed through retroperitoneal single- port laparoscopy using nephroscope. To our knowledge this is the first case of removal of a retroperitoneal foreign body through single- port laparoscopy using nephroscope. PMID- 28861318 TI - DiGeorge Syndrome Associated with Azoospermia: First case in the literature. AB - DiGeorge syndrome (DGS) is one of the most frequently seen chromosomal abnormalities. The major genetic cause of DGS is a microdeletion on chromosome 22q11.2. Majority of the cases are diagnosed during their childhood. DGS is rarely considered and diagnosed in adulthood. Herein, we report the first case of a patient with DGS and azoospermia in the literature. Our patient was a 35-year old male with mild dysmorphic features, hypernasal voice, mental retardation, and azoospermia. His laboratory tests and echocardiographic assessments were normal. Clinical clues to DGS were hypernasal voice and dysmorphic features with mild mental retardation. The diagnosis of DGS was confirmed by fluorescence in situ hybridization (FISH). Negative effects of cognitive disorders on reproductivity are already known; however, we haven't find any studies in the literature that evaluated infertile patients with DGS using semen analysis, apart from these potential unfavourable effectc of cognitive disorders. Coexistence of DGS and azoospermia may be completely coincidental, but azoospermia can be also one of the unknown clinical features of this syndrome. Many patients with a mild phenotype of DGS may be underdiagnosed. DGS should be considered in adults who have mental, behavioral, or psychiatric disorders with mild dysmorphic features, even in the absence of classical features. PMID- 28861320 TI - CS1 (SLAMF7, CD319) is an effective immunotherapeutic target for multiple myeloma. AB - CS1 (also known as CD319, CRACC and SLAMF7) was identified as an NK cell receptor regulating immune functions. It is also expressed on B cells, T cells, Dendritic cells, NK-T cells, and monocytes. CS1 is overexpressed in multiple myeloma and makes it a target for immunotherapy. A humanized anti-CS1 antibody, Elotuzumab or Empliciti has shown promising results in clinical studies. This review focuses on the biology of CS1 in NK and other hematopoietic cells and multiple myeloma. Anti CS1 mAb can activate natural cytotoxicity of NK cells as well as enhance ADCC (antibody-dependent cell-mediated cytotoxicity) and thus makes an effective target for immunotherapy of MM. PMID- 28861321 TI - FoxC1 promotes epithelial-mesenchymal transition through PBX1 dependent transactivation of ZEB2 in esophageal cancer. AB - Esophageal cancer (EC) was one of the most lethal malignancies worldwide with intricate mechanisms. Here we reported that Forkhead box C1 (FoxC1), a member of the forkhead family transcription factors, was up-regulated in EC tissues and cell lines in comparison with controls. FoxC1 levels were negatively correlated with tumor stage, lymph node metastasis and survival status of EC patients. Knockdown of FoxC1 inhibited the proliferation, colony formation and epithelial mesenchymal transition (EMT) of EC cells, while overexpression of FoxC1 promoted these biological behaviors. Mechanically, serial deletion and chromatin immunoprecipitation assays showed that ZEB2, a well-reported transcriptional suppressor of E-cadherin, was a direct transcriptional target of FoxC1. Moreover, FoxC1 was recruited to the ZEB2 promoter by its interaction with the pioneer transcription factor pre-B-cell leukemia homeobox 1 (PBX1). Importantly, significant correlation between levels of FoxC1 and ZEB2 was observed in EC tissues and the two proteins could be used as prognostic biomarkers together. Hence, our results revealed a critical role of FoxC1 in the EMT process of EC and uncovered a novel mechanism for the regulation of ZEB2-E-cadherin axis in EC. PMID- 28861319 TI - Steroid hormone receptors as prognostic markers in breast cancer. AB - Despite the existence of many promising anti-cancer therapies, not all breast cancers are equally treatable, due partly to the fact that focus has been primarily on a few select breast cancer biomarkers- notably ERalpha, PR and HER2. In cases like triple negative breast cancer (ERalpha-, PR-, and HER2-), there is a complete lack of available biomarkers for prognosis and therapeutic purposes. The goal of this review is to determine if other steroid receptors, like ERbeta and AR, could play a prognostic and/or therapeutic role. Data from various in vitro, in vivo, and clinical breast cancer studies were examined to analyze the presence and function of ERbeta, PR, and AR in the presence and absence of ERalpha. Additionally, we focused on studies that examined how expression of the various steroid receptor isoforms affects breast cancer progression. Our findings suggest that while we have a solid understanding of how these receptors work individually, how they interact and behave in the presence and absence of other receptors requires further research. Furthermore, there is an incomplete understanding of how the various steroid receptor isoforms interact and impact receptor function and breast cancer progression, partly due to the difficulty in detecting all the various isoforms. More large-scale clinical studies must be made to analyze systematically the expression of steroid hormone receptors and their respective isoforms in breast cancer patients in order to determine how these receptors interact with each other and in turn affect cancer progression. PMID- 28861322 TI - 14-3-3zeta loss impedes oncogene-induced mammary tumorigenesis and metastasis by attenuating oncogenic signaling. AB - The 14-3-3zeta protein belongs to the 14-3-3 family of regulatory eukaryotic proteins that modulate signaling by binding to wide variety of signaling molecules. 14-3-3zeta expression is amplified in over 40% breast cancer patients and is associated with a poor prognosis. Various in vitro and xenograft models have suggested that attenuating 14-3-3zeta expression may provide therapeutic benefits but there has been no study looking at tumor onset and metastasis in breast cancer mouse models with a targeted deletion of 14-3-3zeta. We generated a 14-3-3zeta knockout mouse model to characterize the role of 14-3-3zeta in breast cancer progression. Crossing 14-3-3zeta-/- mice with MMTV-PyMT and MMTV-Neu transgenic mice revealed that loss of 14-3-3zeta prolonged tumor latency and reduced lung metastasis as compared to MMTV-PyMT and MMTV-Neu mice. Mechanistically, loss of 14-3-3zeta suppressed tumor proliferation and angiogenesis and promoted apoptosis by suppressing the Akt and Erk pathway and upregulated the expression of the tumor suppressor p53. Our results provide evidence showing that attenuating 14-3-3zeta expression/activity in mammary tumors can provide a therapeutic benefit. PMID- 28861323 TI - POU2F1 promotes growth and metastasis of hepatocellular carcinoma through the FAT1 signaling pathway. AB - Increasing evidence suggests that POU domain class 2 transcription factor 1 (POU2F1) participates in carcinogenesis and cancer progression via promotion of cell proliferation and metastasis; however, the functional role of POU2F1 in hepatocellular carcinoma (HCC) is largely unknown. In this study, we determined that POU2F1 was significantly up-regulated in HCC tumor tissue and cell lines. We demonstrated that POU2F1 over-expression promoted HCC cell proliferation, colony formation, migration, and invasion, while silencing of POU2F1 inhibited these malignant phenotypes. In vivo experiments indicated that knockdown of POU2F1 inhibited HCC cell metastasis and xenograft growth, whereas ectopic expression of POU2F1 promoted these cellular functions. Microarray analysis suggests that FAT atypical cadherin 1 (FAT1) can function downstream of POU2F1. Functionally, we demonstrated that POU2F1 knockdown induced growth suppression and metastasis inhibition of HCC cells and inactivated the FAT1 pathway, indicating that POU2F1 is a potential novel therapeutic target in HCC. PMID- 28861324 TI - MicroRNA-1179 inhibits glioblastoma cell proliferation and cell cycle progression via directly targeting E2F transcription factor 5. AB - Glioblastoma multiforme (GBM) is an extraordinary aggressive disease that requires more effective therapeutic options. In the past few years, many microRNAs (miRNAs) have been demonstrated to have important roles in promoting GBM progression. However, little is known about the role of miR-1179 in GBM. In the present study, we found that miR-1179 was significantly downregulated in glioma tissues and cell lines. Functional experiments showed that introduction of miR-1179 dramatically suppressed GBM cell proliferation and cell cycle progression. Importantly, treatment of miR-1179 strongly inhibited tumor growth in a subcutaneous GBM model. Further studies showed that E2F transcription factor 5 (E2F5), a key transcription factor that controls cell cycle transition, was a direct target of miR-1179. Silencing of E2F5 inhibited the proliferative ability of GBM cells and induces cell cycle arrest, which were consistent with the effects of miR-1179 overexpression. More importantly, reintroduction of E2F5 into GBM cells reversed the tumor-suppressive function of miR-1179. Finally, we demonstrated that miR-1179 expression was negatively correlated with E2F5 messenger RNA (mRNA) levels in high-grade gliomas. Our findings provide new insights into the role of miR-1179 in the progression of GBM, and implicate the potential application of miR-1179 in GBM therapy. PMID- 28861325 TI - The efficacy of combination therapy with oncolytic herpes simplex virus HF10 and dacarbazine in a mouse melanoma model. AB - Advanced melanoma has long been treated with chemotherapy using cytotoxic agents like dacarbazine (DTIC), but overall survival rates with these drugs have been generally low. Recently, immunoregulatory monoclonal antibodies and molecularly targeted therapy with a BRAF inhibitor and/or a MEK inhibitor, have been used to treat malignant melanoma and have improved the survival rate of patients with advanced melanoma. However, high prices of these drugs are problematic. In this study, we evaluated the oncolytic efficacy of HF10, an attenuated, replication competent HSV, with DTIC in immunocompetent mice model of malignant melanoma. For in vitro studies, cytotoxicity assays were conducted in clone M3 mouse melanoma cells. For the in vivo studies, subcutaneous melanoma models were prepared in DBA/2 mice with clone M3 cells, and then HF10 was intratumorally inoculated with/without intraperitoneal DTIC injection. The efficacy of the therapies was evaluated by survival, growth of subcutaneous tumor, and histopathological and immunological analyses. Both HF10 infection and DTIC treatment showed cytotoxic effects in melanoma cells, but combination treatment with HF10 and DTIC showed a rapid and strong cytotoxic effect compared with monotherapy. In the subcutaneous melanoma model, intratumoral HF10 inoculation significantly inhibited tumor growth. HF10 also inhibited the growth of non-inoculated contralateral tumors when it was injected into the ipsilateral tumors of mice. In histologic and immunohistochemical analysis, tumor lysis and inflammatory cell infiltration were observed after intratumoral HF10 inoculation. When mice were treated with HF10 and DTIC, the combination therapy induced a robust systemic anti-tumor immune response and prolonged survival. IFN-gamma secretion from splenocytes of the HF10 DTIC combination therapy group showed more IFN-gamma secretion than did the other groups. These data showed the efficacy of HF10 and DTIC combination therapy in a mouse melanoma model. PMID- 28861326 TI - LncRNA SNHG5 regulates imatinib resistance in chronic myeloid leukemia via acting as a CeRNA against MiR-205-5p. AB - Imatinib resistance has become a major obstacle for the treatment of chronic myeloid leukemia (CML). The present study aimed to investigate the effects of the long non-coding RNA, SNHG5 on imatinib resistance in CML and explored the underlying mechanisms. The quantitative real-time PCR results showed that SNHG5 and ABCC2 expressions were up-regulated in the isolated peripheral blood cells of the CML patients when compared with healthy controls, and SNHG5 expression levels was positively correlated with ABCC2 in CML patients. In vitro studies showed that the expressions of SNHG5 and ABCC2 were up-regulated in imatinib resistant cells (K562-R) when compared to K562 cells. Bioinformatics analysis showed the interaction between SNHG5 and miR-205-5p, which was further confirmed by luciferase reporter assay and RNA immune-precipitation in K562 cells. Overexpression of SNHG5 suppressed the expression of miR-205-5p and the expression of SNHG5 was negatively correlated with the miR-205-5p expression in CML patients. In addition, ABCC2 was predicted as a downstream target of miR-205 5p, which was further confirmed by the luciferase reporter assay in K562-R cells, and overexpression of miR-205-5p suppressed the expression of ABCC2 in K562-R cells. In vitro functional assay showed that overexpression of SNHG5 in K562 cells increased imatinib resistance and knock-down of SNHG5 reduced the imatinib resistance in K562-R cells. Further experiments showed that SNHG5 promotes imatinib resistance through regulating ABCC2. Taken together, SNHG5 promotes imatinib resistance in CML via acting as a competing endogenous RNA against miR 205-5p. PMID- 28861327 TI - A human recombinant IL-7/HGFbeta hybrid cytokine enhances antitumor immunity in mice. AB - We purified a hybrid cytokine that contains interleukin-7 (IL-7) and the beta chain of hepatocyte growth factor (HGFbeta) from a unique long-term murine bone marrow culture system. We have cloned and expressed the human form of IL 7/HGFbeta in which the IL-7 and HGFbeta genes are connected by a flexible linker to produce a single-chain recombinant human IL-7/HGFbeta protein (hrIL 7/HGFbeta). To determine whether hrIL-7/HGFbeta has antitumor activity, we injected this hybrid cytokine into melanoma and colon cancer animal models, and then assessed the local tumor growth and tumor metastasis. We show here that in vivo administration of hrIL-7/HGFbeta significantly inhibited the growth and metastasis of malignant melanoma and colon cancer in mice. The antitumor activity was involved in a marked increase in the number of tumor-infiltrating CD4+ and CD8+ T cells and activated dendritic cells. The immunological mechanism by which hrIL-7/HGFbeta inhibits tumor growth was confirmed by its inability to inhibit tumor growth in vitro and in immunodeficient mice. Furthermore, immune cells from hrIL-7/HGFbeta-treated cancer-bearing mice can be adoptively transferred into naive mice to resist same tumor cell challenge. Therefore, hrIL-7/HGFbeta has potential applications in the treatment of cancer patients. PMID- 28861329 TI - MiR-210-3p inhibits the tumor growth and metastasis of bladder cancer via targeting fibroblast growth factor receptor-like 1. AB - Current evidence indicates that microRNAs are widely down-regulated in various tumors including colorectal carcinoma, liver cancer and lung cancer, and function as tumor suppressors through inhibiting cancer cell growth, invasion and migration. Here, we demonstrated that miR-210-3p level was significantly reduced in the bladder cancer compared to paratumor tissues, and attempt to reveal the regulatory role of miR-210-3p in bladder cancer progression. Exogenous overexpression of miR-210-3p inhibited the proliferation, migration and invasion of bladder cancer cells in vitro. In addition, the nude mouse xenograft model showed that miR-210-3p over-expressing inhibited bladder cancer growth and liver metastasis whereas silencing miR-210-3p caused an opposite outcome, which is mainly regulated by targeting fibroblast growth factor receptor-like 1 (FGFRL1). We also demonstrated that the expression of FGFRL1 in bladder cancer specimens were negatively correlated with miR-210-3p level, and FGFRL1 overexpression rescued the cell proliferation and invasion inhibited by ectopic expression of miR-210-3p. Moreover, knockdown of FGFRL1 was able to mimic the cell growth and metastasis effects induced by miR-210-3p over-expressing in bladder cancer cells. Together, these results indicate that miR-210-3p plays an important role in the regulation of bladder cancer growth and metastasis in vitro and in vivo through targeting FGFRL1. PMID- 28861328 TI - Targeting MYC sensitizes malignant mesothelioma cells to PAK blockage-induced cytotoxicity. AB - Clinical management of malignant mesothelioma (MM) is very challenging due to marked resistance of this tumor to chemotherapy. Various mechanisms lead to a less than ideal drug concentration inside of MM cells, diminishing cytotoxicity. Consequently, single cytotoxic drugs achieve very modest response rates in MM patients, and combination regimens using standard and novel therapies have achieved only limited improvement in overall survival. Here, we demonstrate that MYC has either proliferative or pro-survival effects in MM cells during normal or stressed conditions, respectively. A MYC inhibitor 10058-F4 reduced MM cell proliferation via down regulation of cyclin D. Under serum starvation conditions, MM cells became quiescent, and the addition of MYC inhibitors triggered apoptosis in the resting MM cells. We also found that high concentrations of the PAK inhibitor PF3758309 killed MM cells, but the drug had only cytostatic effects at lower concentrations. These quiescent cells underwent apoptosis upon pharmacological inhibition of MYC. A novel MYC inhibitor KJ-Pyr-9 and a newer PAK inhibitor, FRAX597, also demonstrated marked cytotoxic cooperativity. Collectively, these findings demonstrate that targeting of MYC can sensitize MM cells and provide rationale for inhibition of MYC and PAK as a novel combinatory regimen for the treatment of this otherwise therapy-resistant, clinically incurable malignancy. PMID- 28861330 TI - A Plasma Cell Dyscrasia Presenting as Amyloid Cardiomyopathy and Autonomic Dysfunction in a Healthy Patient. AB - Systemic amyloidosis is a rare multisystem disease caused by incorrectly folded proteins that deposit pathologically in different tissues and organs of the human body. It has a very wide spectrum of clinical presentations according to the affected organ(s), and its diagnosis is commonly delayed. Cardiac involvement is the leading cause of morbidity and mortality and carries a poor prognosis, especially in primary light chain amyloidosis. Therefore any delay in the diagnosis can result in devastating outcomes for the patient. We report the case of a 65-year-old man who presented with dizziness and lightheadedness. He was found to have orthostatic hypotension and further investigations revealed the diagnosis of amyloid cardiomyopathy complicating a plasma cell dyscrasia. What is worth noting, in this case, is that the patient had cardiac amyloidosis presenting primarily as autonomic dysfunction and orthostatic hypotension, without any cardiac-specific symptoms such as heart failure or angina. This is a very unusual presentation of advanced-stage cardiac amyloidosis. This article highlights the variety of clinical presentations of cardiac amyloidosis, and focuses on the recent progress such as novel diagnostic and surveillance approaches using imaging, biomarkers, and new histological typing techniques. Current and future promising treatment options are also discussed, including methods directly targeting the amyloid deposits. PMID- 28861331 TI - Alteration of Interneuron Immunoreactivity and Autophagic Activity in Rat Hippocampus after Single High-Dose Whole-Brain Irradiation. AB - The effects of high dose gamma radiation on brain tissue are poorly understood, with both limited and major changes reported. The present study compared the effects of gamma irradiation on the expression of interneuron markers within the hippocampal cornu ammonis 1 (CA1) region with expression in control matched rats. This area was chosen for study because of its well-characterized circuitry. Male Sprague-Dawley rats were exposed to 60 Gy of whole brain gamma radiation and after 24 or 48 hours, the brains were removed, fixed and sectioned to quantitate expression of parvalbumin (PV), calbindin-D28K (CB), reelin, neuropeptide-Y (NPY), and somatostatin. All of these markers increased in expression over the first 48 hours, except NPY, which decreased. This provides novel information on changes in gene expression in the hippocampal interneurons following radiation. Staining for Beclin 1, a marker of autophagy, increased most strongly in the subgranular zone (SGZ) of the dentate gyrus (DG). Overall, the results are consistent with the hypothesis that increased intracellular calcium follows irradiation, leading to an increased expression of calcium binding proteins. Increased autophagy occurs in the neurogenic zone of the dentate hilus, consistent with reduced effective neurogenesis after irradiation. PMID- 28861332 TI - EML4-ALK-positive lung adenocarcinoma presenting an unusual metastatic pattern in a 29-year-old woman who is alive and well in her third year follow up:A case report. AB - : Non-small cell lung cancer (NSCLC) is a frequent tumor entity with high mortality. Although several newly discovered chromosomal translocations and mutations opened new horizons for targeted therapy, literature still lacks large series of NSCLC with chromosomal abberations and their correlations with histological and clinical features. We present a case of echinoderm microtubule associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation positive adenocarcinoma of the lung with an unusual metastatic pattern in a 29 year-old young woman. CONCLUSION: Young adult non-smoker female patients with an unexplained pleural effusion and signs of metastatic disease should alert the physicians straight away for all types of malignancies including lung cancer. Any skin lesions should be evaluated carefully, biopsies should be done to exclude metastasis in urgency. On the other hand, an uncommon clinical presentation of a lung cancer requires corresponding molecular testing rapidly in order to offer the best treatment option. PMID- 28861333 TI - Successful treatment of limited-stage small-cell lung cancer in the right mainstem bronchus by a combination of chemotherapy and argon plasma coagulation. AB - The current standard-of-care treatment for patients with limited-stage small-cell lung cancer (SCLC) is concurrent chemoradiotherapy for local and systemic control. However, standard-of-care treatment strategies have not been established for those with limited-stage SCLC who have a history of thoracic radiotherapy due to concerns with complications associated with radiation overdose. A 37-year-old male developed an aspergilloma in the postoperative left thoracic space after he was treated with concurrent chemoradiotherapy for mediastinal type lung adenocarcionoma and subsequent left upper lobectomy for heterochronous dual adenocarcinoma. Fiberoptic bronchoscopy was performed to examine the status of the suspected bronchopleural fistula when a polypoid mass was observed in the right mainstem bronchus. A histological examination showed that the mass was SCLC at a clinical stage of cTisN0M0, stageIA, without local invasion. Since thoracic radiotherapy was not an option due to a previous history of thoracic irradiation, a combination treatment of carboplatin and etoposide was administered for 4 cycles and resulted in good partial response. In addition, argon plasma coagulation (APC) was performed as an alternative to curative radiotherapy on day 22 of the 4th cycle. The 5th cycle was administered 7 days after APC at which the anticancer therapy was completed. The patient remains disease-free 60 months after the completion of treatment, which suggests that this combination therapy may resolve very early-stage SCLC. PMID- 28861334 TI - Severe pneumocystis jiroveci pneumonia in a patient on temozolomide therapy: A case report and review of literature. AB - A 66 year old man was diagnosed with CNS diffuse large B-cell lymphoma, and underwent treatment with Temozolomide, Dexamethasone, Rituximab, and radiation therapy, and prolonged steroid taper with Dexamethasone. Approximately one month after this, he presented with severe acute hypoxemic respiratory failure, and was admitted to the Medical Intensive Care Unit. Imaging showed diffuse ground glass opacities. Patient underwent diagnostic bronchoalveolar lavage which was positive for Pneumocystis jiroveci. He did not respond well to appropriate therapy and was transitioned to comfort care per his family's wishes, and expired. Pneumocystis jiroveci should always be included in the differential diagnosis of pneumonia in patients treated with Temozolomide, especially when this agent is used in combination with long term, high dose corticosteroids and radiation therapy. PMID- 28861335 TI - Diffusion tensor image segmentation of the cerebrum provides a single measure of cerebral small vessel disease severity related to cognitive change. AB - Cerebral small vessel disease (SVD) is the primary cause of vascular cognitive impairment and is associated with decline in executive function (EF) and information processing speed (IPS). Imaging biomarkers are needed that can monitor and identify individuals at risk of severe cognitive decline. Recently there has been interest in combining several magnetic resonance imaging (MRI) markers of SVD into a unitary score to describe disease severity. Here we apply a diffusion tensor image (DTI) segmentation technique (DSEG) to describe SVD related changes in a single unitary score across the whole cerebrum, to investigate its relationship with cognitive change over a three-year period. 98 patients (aged 43-89) with SVD underwent annual MRI scanning and cognitive testing for up to three years. DSEG provides a vector of 16 discrete segments describing brain microstructure of healthy and/or damaged tissue. By calculating the scalar product of each DSEG vector in reference to that of a healthy ageing control we generate an angular measure (DSEG theta) describing the patients' brain tissue microstructural similarity to a disease free model of a healthy ageing brain. Conventional MRI markers of SVD brain change were also assessed including white matter hyperintensities, cerebral atrophy, incident lacunes, cerebral-microbleeds, and white matter microstructural damage measured by DTI histogram parameters. The impact of brain change on cognition was explored using linear mixed-effects models. Post-hoc sample size analysis was used to assess the viability of DSEG theta as a tool for clinical trials. Changes in brain structure described by DSEG theta were related to change in EF and IPS (p < 0.001) and remained significant in multivariate models including other MRI markers of SVD as well as age, gender and premorbid IQ. Of the conventional markers, presence of new lacunes was the only marker to remain a significant predictor of change in EF and IPS in the multivariate models (p = 0.002). Change in DSEG theta was also related to change in all other MRI markers (p < 0.017), suggesting it may be used as a surrogate marker of SVD damage across the cerebrum. Sample size estimates indicated that fewer patients would be required to detect treatment effects using DSEG theta compared to conventional MRI and DTI markers of SVD severity. DSEG theta is a powerful tool for characterising subtle brain change in SVD that has a negative impact on cognition and remains a significant predictor of cognitive change when other MRI markers of brain change are accounted for. DSEG provides an automatic segmentation of the whole cerebrum that is sensitive to a range of SVD related structural changes and successfully predicts cognitive change. Power analysis shows DSEG theta has potential as a monitoring tool in clinical trials. As such it may provide a marker of SVD severity from a single imaging modality (i.e. DTIs). PMID- 28861336 TI - A whole-brain computational modeling approach to explain the alterations in resting-state functional connectivity during progression of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common dementia with dramatic consequences. The research in structural and functional neuroimaging showed altered brain connectivity in AD. In this study, we investigated the whole-brain resting state functional connectivity (FC) of the subjects with preclinical Alzheimer's disease (PAD), mild cognitive impairment due to AD (MCI) and mild dementia due to Alzheimer's disease (AD), the impact of APOE4 carriership, as well as in relation to variations in core AD CSF biomarkers. The synchronization in the whole-brain was monotonously decreasing during the course of the disease progression. Furthermore, in AD patients we found widespread significant decreases in functional connectivity (FC) strengths particularly in the brain regions with high global connectivity. We employed a whole-brain computational modeling approach to study the mechanisms underlying these alterations. To characterize the causal interactions between brain regions, we estimated the effective connectivity (EC) in the model. We found that the significant EC differences in AD were primarily located in left temporal lobe. Then, we systematically manipulated the underlying dynamics of the model to investigate simulated changes in FC based on the healthy control subjects. Furthermore, we found distinct patterns involving CSF biomarkers of amyloid-beta (Abeta1 - 42) total tau (t-tau) and phosphorylated tau (p-tau). CSF Abeta1 - 42 was associated to the contrast between healthy control subjects and clinical groups. Nevertheless, tau CSF biomarkers were associated to the variability in whole-brain synchronization and sensory integration regions. These associations were robust across clinical groups, unlike the associations that were found for CSF Abeta1 - 42. APOE4 carriership showed no significant correlations with the connectivity measures. PMID- 28861337 TI - Clinical neuroimaging in the preterm infant: Diagnosis and prognosis. AB - Perinatal care advances emerging over the past twenty years have helped to diminish the mortality and severe neurological morbidity of extremely and very preterm neonates (e.g., cystic Periventricular Leukomalacia [c-PVL] and Germinal Matrix Hemorrhage - Intraventricular Hemorrhage [GMH-IVH grade 3-4/4]; 22 to < 32 weeks of gestational age, GA). However, motor and/or cognitive disabilities associated with mild-to-moderate white and gray matter injury are frequently present in this population (e.g., non-cystic Periventricular Leukomalacia [non cystic PVL], neuronal-axonal injury and GMH-IVH grade 1-2/4). Brain research studies using magnetic resonance imaging (MRI) report that 50% to 80% of extremely and very preterm neonates have diffuse white matter abnormalities (WMA) which correspond to only the minimum grade of severity. Nevertheless, mild-to moderate diffuse WMA has also been associated with significant affectations of motor and cognitive activities. Due to increased neonatal survival and the intrinsic characteristics of diffuse WMA, there is a growing need to study the brain of the premature infant using non-invasive neuroimaging techniques sensitive to microscopic and/or diffuse lesions. This emerging need has led the scientific community to try to bridge the gap between concepts or ideas from different methodologies and approaches; for instance, neuropathology, neuroimaging and clinical findings. This is evident from the combination of intense pre-clinical and clinicopathologic research along with neonatal neurology and quantitative neuroimaging research. In the following review, we explore literature relating the most frequently observed neuropathological patterns with the recent neuroimaging findings in preterm newborns and infants with perinatal brain injury. Specifically, we focus our discussions on the use of neuroimaging to aid diagnosis, measure morphometric brain damage, and track long-term neurodevelopmental outcomes. PMID- 28861338 TI - Increased default-mode variability is related to reduced task-performance and is evident in adults with ADHD. AB - Insufficient suppression and connectivity of the default mode network (DMN) is a potential mediator of cognitive dysfunctions across various disorders, including attention deficit/hyperactivity disorder (ADHD). However, it remains unclear if alterations in sustained DMN suppression, variability and connectivity during prolonged cognitive engagement are implicated in adult ADHD pathophysiology, and to which degree methylphenidate (MPH) remediates any DMN abnormalities. This randomized, double-blinded, placebo-controlled, cross-over clinical trial of MPH (clinicaltrials.gov/ct2/show/NCT01831622) explored large-scale brain network dynamics in 20 adults with ADHD on and off MPH, compared to 27 healthy controls, while performing a reward based decision-making task. DMN task-related activation, variability, and connectivity were estimated and compared between groups and conditions using independent component analysis, dual regression, and Bayesian linear mixed models. The results show that the DMN exhibited more variable activation patterns in unmedicated patients compared to healthy controls. Group differences in functional connectivity both between and within functional networks were evident. Further, functional connectivity between and within attention and DMN networks was sensitive both to task performance and case control status. MPH altered within-network connectivity of the DMN and visual networks, but not between-network connectivity or temporal variability. This study thus provides novel fMRI evidence of reduced sustained DMN suppression in adults with ADHD during value-based decision-making, a pattern that was not alleviated by MPH. We infer from multiple analytical approaches further support to the default mode interference hypothesis, in that higher DMN activation variability is evident in adult ADHD and associated with lower task performance. PMID- 28861339 TI - Spatio-temporal source cluster analysis reveals fronto-temporal auditory change processing differences within a shared autistic and schizotypal trait phenotype. AB - Social Disorganisation (SD) is a shared autistic and schizotypal phenotype that is present in the subclinical population. Auditory processing deficits, particularly in mismatch negativity/field (MMN/F) have been reported across both spectrum disorders. This study investigates differences in MMN/F cortical spatio temporal source activity between higher and lower quintiles of the SD spectrum. Sixteen low (9 female) and 19 high (9 female) SD subclinical adults (18-40years) underwent magnetoencephalography (MEG) during an MMF paradigm where standard tones (50ms) were interrupted by infrequent duration deviants (100ms). Spatio temporal source cluster analysis with permutation testing revealed no difference between the groups in source activation to the standard tone. To the deviant tone however, there was significantly reduced right hemisphere fronto-temporal and insular cortex activation for the high SD group (p= 0.038). The MMF, as a product of the cortical response to the deviant minus that to the standard, did not differ significantly between the high and low Social Disorganisation groups. These data demonstrate a deficit in right fronto-temporal processing of an auditory change for those with more of the shared SD phenotype, indicating that right fronto-temporal auditory processing may be associated with psychosocial functioning. PMID- 28861340 TI - Multivariate pattern analysis strategies in detection of remitted major depressive disorder using resting state functional connectivity. AB - Understanding abnormal resting-state functional connectivity of distributed brain networks may aid in probing and targeting mechanisms involved in major depressive disorder (MDD). To date, few studies have used resting state functional magnetic resonance imaging (rs-fMRI) to attempt to discriminate individuals with MDD from individuals without MDD, and to our knowledge no investigations have examined a remitted (r) population. In this study, we examined the efficiency of support vector machine (SVM) classifier to successfully discriminate rMDD individuals from healthy controls (HCs) in a narrow early-adult age range. We empirically evaluated four feature selection methods including multivariate Least Absolute Shrinkage and Selection Operator (LASSO) and Elastic Net feature selection algorithms. Our results showed that SVM classification with Elastic Net feature selection achieved the highest classification accuracy of 76.1% (sensitivity of 81.5% and specificity of 68.9%) by leave-one-out cross-validation across subjects from a dataset consisting of 38 rMDD individuals and 29 healthy controls. The highest discriminating functional connections were between the left amygdala, left posterior cingulate cortex, bilateral dorso-lateral prefrontal cortex, and right ventral striatum. These appear to be key nodes in the etiopathophysiology of MDD, within and between default mode, salience and cognitive control networks. This technique demonstrates early promise for using rs-fMRI connectivity as a putative neurobiological marker capable of distinguishing between individuals with and without rMDD. These methods may be extended to periods of risk prior to illness onset, thereby allowing for earlier diagnosis, prevention, and intervention. PMID- 28861341 TI - Blockade of angiopoietin-2/Tie2 signaling pathway specifically promotes inflammation-induced angiogenesis in mouse cornea. AB - AIM: To investigate angiopoietin-2 (Ang-2)/Tie2 signaling pathway involving in inflammatory angiogenesis. METHODS: Three interrupted 11-0 nylon sutures were placed into the corneal stroma of BALB/c mice (6wk old) to induce inflammatory neovascularization. Expression of Ang-2 and Tie2 protein on neovascularization were examined by immunofluorescence. The dynamic expression of Ang-2 mRNA on neovascularization was examined by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Finally, the mouse model of suture-induced corneal neovascularization was used to assess the role of Ang-2/Tie2 signaling pathway in inflammatory angiogenesis by systemic application of L1-10, an Ang-2 specific inhibitor. Mouse corneal hemangiogenesis were evaluated by whole mount immunofluorescence. RESULTS: Both Ang-2 and Tie2 were expressed on newly generated blood vessels in inflammatory cornea. Ang-2 expression was gradually upregulated around 2wk following injury, which was concurrent with an increased number of blood vessels. Blockade of Ang-2/Tie2 signaling pathway obviously promoted angiogenesis in inflammatory cornea. CONCLUSION: Ang-2/Tie2 signaling pathway seems to play an important role during angiogenesis in inflammatory cornea. This may open new therapeutic applications in pathological processes such as corneal graft survival, wound healing and carcinogenesis. PMID- 28861342 TI - MiR-200c suppresses the migration of retinoblastoma cells by reversing epithelial mesenchymal transition. AB - AIM: To analyze the relationship between clinical features and epithelial mesenchymal transition (EMT) in retinoblastoma (RB), further to investigate whether miR-200c regulates the EMT and migration of RB cells. METHODS: Expression of EMT-related markers and tumor-related factors were detected by immuno histochemistry analysis in RB tissue from 29 cases. Correlations between their expression and clinical characteristics were analyzed. The regulation effects of miR-200c on EMT-related markers, tumor-related factors were observed in mRNA level and protein level by real-time polymerase chain reaction (PCR) and Western blot, respectively, in Y79 and Weri-rb1 cells. Its effects on migration force of these RB cell lines were also detected with Transwell test. RESULTS: Lower expression of E-cadherin was present in the cases with malignant prognosis. MiR 200c promoted the expression of E-cadherin and decreased the expression of Vimentin and N-cadherin in Y79 and Weri-rb1 cells. Migration force of RB cells could be inhibited by miR-200c. CONCLUSION: EMT might be associated with bad prognosis in RB. MiR-200c suppresses the migration of retinoblastomatous cells by reverse EMT. PMID- 28861344 TI - Inhibitory effect of tenomodulin versus ranibizumab on in vitro angiogenesis. AB - AIM: To evaluate anti-angiogenic effect of tenomodulin (TNMD) and ranibizumab on cell proliferation and capillary-like morphogenesis of vascular endothelial cells under the stimulation of vascular endothelial growth factor (VEGF) in vitro. METHODS: The effects of TNMD and ranibizumab on VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) were evaluated by MTT assay, and the effects of TNMD and ranibizumab on capillary-like structures formed by HUVECs under the stimulation of VEGF were examined in culture. Capillary-like morphogenesis of HUVECs was quantitatively evaluated, and total lengths of tube like structures per field were measured in a masked way. RESULTS: HUVECs with both ranibizumab and TNMD protein showed MTT reduction in VEGF-stimulated cell proliferation as expected, while MTT absorbance in the HUVECs with TNMD was significantly declined than that with ranibizumab (P<0.01). The capillary-like structures formed by HUVECs were markedly impaired by the presence of both TNMD and ranibizumab in the culture medium. The total length of the capillary-like structures per field was significantly shorter in the medium with TNMD than that of ranibizumab (P<0.01). The inhibitory effect of TNMD on tube formation in vitro angiogenesis was significantly stronger than that of ranibizumab. CONCLUSION: TNMD may have stronger inhibitory effect than ranibizumab on in vitro angiogenesis. PMID- 28861343 TI - Aralia elata inhibits neurodegeneration by downregulating O-GlcNAcylation of NF kappaB in diabetic mice. AB - AIM: To investigate the role of O-GlcNAcylation of nuclear factor-kappa B (NF kappaB) in retinal ganglion cell (RGC) death and analysedthe effect of Aralia elata (AE) on neurodegeneration in diabetic mice. METHODS: C57BL/6mice with streptozotocin-induced diabetes were fed daily with AE extract or control (CTL) diet at the onset of diabetes mellitus (DM). Two months after injection of streptozotocin or saline, the degree of cell death and the expression of O-GlcNAc transferase (OGT), N-acetyl-b-D-glucosaminidase (OGA), O-GlcNAcylated proteins, and O-GlcNAcylation of NF-kappaB were examined. RESULTS: AE did not affect the metabolic status of diabetic mice. The decrease in the inner retinal thickness (P<0.001 vs CTL, P<0.01 vs DM) and increases in RGCs with terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (P<0.001 vs CTL, P<0.0001 vs DM), glial activation, and active caspase-3 (P<0.0001 vs CTL, P<0.0001 vs DM) were blocked in diabetic retinas of AE extract-fed mice. Expression levels of protein O-GlcNAcylation and OGT were increased in diabetic retinas (P<0.0001 vs CTL), and the level of O-GlcNAcylation of the NF-kappaB p65 subunit was higher in diabetic retinas than in controls (P<0.0001 vs CTL). AE extract downregulated O-GlcNAcylation of NF-kappaB and prevented neurodegeneration induced by hyperglycemia (P<0.0001 vs DM). CONCLUSION: O GlcNAcylation of NF-kappaB is concerned in neuronal degeneration and that AE prevents diabetes-induced RGC apoptosis via downregulation of NF-kappaB O GlcNAcylation. Hence, O-GlcNAcylation may be a new object for the treatment of DR, and AE may have therapeutic possibility to prevent diabetes-induced neurodegeneration. PMID- 28861345 TI - Possible role of sialylation of retinal protein glycans in the regulation of electroretinogram response in mice. AB - AIM: To evaluate if the nature, degree and extent of Siaalpha2-3-/Siaalpha2-6 sialylation of retinal protein glycans plays a possible role in the development and regulation of electroretinogram response (ERG) in mice. METHODS: Proteins extracted, from retinae of postnatal day 2 (PN2), PN7, and PN14 wild type (wt) and retinal degeneration 1 (rd1) mice were quantified, labeled and used for lectin-microarray profiling with immobilized lectins which recognize a wide range of N-/O-glycans. Net fluorescence intensities of lectin-ligand complexes were measured and images of fluorescent lectin-microarrays were acquired. From the binding curves between each lectin and protein extracts from PN14 wt and PN14 rd1 mice retinae, the protein concentration was selected to determine optimum signal intensity for lectin-ligand binding. Mean+/-SEM values of proteins and fluorescence-intensities of lectin-ligand-complexes between 45 lectins and 36 protein extracts from wt and rd1 mice retinae were compared for significance of differences. RESULTS: Comparison of the progressive relative changes in the sialylated glycans of retinal proteins from wt and rd1 mice showed that Siaalpha2 3Galbeta1-4GlcNAc-glycans (but not Siaalpha2-6-glycans) were detectable and quantifiable from the retinal-proteins of PN7 and PN14 wt and rd1 mice. Siaalpha2 3-sialylation of retinal-protein Gal/alpha-linked-Gal-glycans was significantly increased with age in PN7 and PN14 wt and less so in PN14 rd1 mice. Siaalpha2-3 /Siaalpha2-6-sialylation of retinal-protein Gal/alpha-linked-Gal-glycans was absent in PN2 wt and rd1 mice. Comparison of published ERG responses of wt and rd1 mice retinae with degree of Siaalpha2-3-sialylation of retinal-protein glycans showed that PN2 wt and rd1 mice lack both the ERG response and Siaalpha2 3-/Siaalpha2-6-sialylation of retinal-protein Gal/alpha-linked-Gal-glycans; rd1 mice with relatively lower Siaalpha2-3-sialylation of retinal-protein Gal/alpha linked-Gal-glycans showed aberrant ERG response; and wt mice with significantly higher Siaalpha2-3-sialylation of retinal-protein Gal/alpha-linked-Gal-glycans showed normal ERG response. CONCLUSION: Degree of Siaalpha2-3-sialylation of glycans possibly regulates ERG function in mice. PMID- 28861346 TI - Identification of rare paired box 3 variant in strabismus by whole exome sequencing. AB - AIM: To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS: A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS: Whole exome sequencing and filtering identified a nonsynonymous mutation c.434G-T transition in paired box 3 (PAX3) in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION: Our results report that the c.434G-T mutation (p.R145L) in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder. PMID- 28861347 TI - Association of the macrophage migration inhibitory factor promoter polymorphisms with benign lymphoepithelial lesion of lacrimal gland. AB - AIM: To identify the association of the macrophage migration inhibitory factor (MIF) gene polymorphism with the susceptibility of benign lymphoepithelial lesions (BLEL) of the lacrimal gland. METHODS: A total of 40 BLEL of lacrimal gland cases were matched with 40 healthy subjects (HS). Extraction the plasma and whole blood DNA of patients of lacrimal gland BLEL and HS. Elisa and polymerase chain reaction was used to determine in plasma contents of MIF and MIF gene SNP 173G>C and STR -794 CATT(5-8) polymorphism, respectively. RESULTS: The MIF levels in plasma were significantly higher in patients with lacrimal gland BLEL versus HS (P<0.001). The -173 G>C MIF polymorphism was significantly associated with lacrimal gland BLEL, with a significantly higher frequency of the C allele in lacrimal gland BLEL patients compared with HS (OR=2.38, 95% CI=1.07-5.31, P=0.032), and the -173 C/x is more frequent in patients than in HS, P=0.037. Besides, we found that the carriage rate of the MIF -173C/x is associated with higher plasma levels of MIF in the BLEL of lacrimal gland. CONCLUSION: MIF 173G/C variants play an insidious role in susceptibility of BLEL of lacrimal gland. Otherwise, there is no statistically significant correlation exists between MIF-794 CATT (5-8) and BLEL of lacrimal gland. PMID- 28861348 TI - Diurnal macular choroidal area fluctuation in normal and primary open angle glaucoma groups. AB - AIM: To assess and compare the diurnal macular choroidal area fluctuation in normal and primary open angle glaucoma (POAG) groups using enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: Twenty-eight normal and 27 POAG eyes were enrolled in this study. EDI-OCT was used to measure the macular choroidal area every 3h from 9:00 a.m. to 21:00 p.m. RESULTS: Significant diurnal fluctuations of macular choroidal area were observed in both normal (P=0.003) and POAG groups (P<0.001). But no significant macular choroidal area difference has been found between the two groups at all the five measurement time-points (512778+/-166242 vs 455079+/-207278 um2, P=0.195 at 9:00 a.m.; 501526+/-168953 vs 447846+/-211147 um2, P=0.245 at 12:00 a.m.; 501982+/-173158 vs 448024+/-206653 um2, P=0.239 at 15:00 p.m.; 508912+/-174589 vs 457783+/-207081 um2, P=0.252 at 18:00 p.m.; 503787+/-171241 vs 453230+/-205955 um2, P=0.274 at 21:00 p.m.; respectively). Furthermore, neither the fluctuation manners nor the change in macular choroidal area between the two adjacent measurement time points showed significant difference between normal and POAG groups (all P>0.05). In the meantime, significant diurnal intraocular pressure fluctuations were also observed in normal and POAG groups (both P<0.001). CONCLUSION: In diurnal time, the macular choroidal area in both normal and POAG groups fluctuated significantly; moreover, neither the value of macular choroidal area, nor the fluctuation of macular choroidal area in POAG group is significantly different from that in normal group. PMID- 28861349 TI - The change of anterior segment parameters after cataract surgery in normal tension glaucoma. AB - AIM: To investigate the change of anterior chamber angle morphology and intraocular pressure (IOP) reduction after cataract surgery in patients with normal-tension glaucoma (NTG) using swept-source optical coherence tomography (SS OCT). METHODS: This prospective, comparative, observational study recruited patients into two groups. Group 1 was the control group including normal subjects except those with cataracts (cataract group, n=67 eyes of 67 patients), and group 2 was NTG group including patients who were diagnosed with NTG and cataracts (n=43 eyes of 43 patients), which were treated with phacoemulsification and intraocular lens implantation. Before surgery, and at postoperative 1 and 6mo, anterior chamber angles were evaluated by SS-OCT under dark conditions using three-dimensional angle analysis scan protocol. Angle opening distance (AOD), angle recess area (ARA), and trabecular-iris surface area (TISA) at four quadrants (temporal, nasal, superior, and inferior) were calculated automatically by SS-OCT, after the observer marked scleral spurs. RESULTS: A total of 106 patients (54 males and 52 females) were enrolled in the study. Angle parameters, AOD, ARA, and TISA were increased after surgery in both groups. However, changes of angle parameters were only significant in group 2. In group 2, preoperative IOP was 13.2+/-2.9 mm Hg, and postoperative IOP at 1 and 6mo were 10.5+/-3.0 and 10.7+/-2.8 mm Hg, respectively. In group 1, preoperative IOP was 12.4+/-2.8 mm Hg, and postoperative IOP at 1 and 6mo were 11.6+/-2.5 and 12.0+/-2.8 mm Hg, respectively. After cataract surgery, angle parameters changed significantly while IOP significantly reduced and was maintained in group 2 (P<0.001). The changes in angle parameters (DeltaAOD500, DeltaTISA500 at temporal; DeltaAOD500, DeltaARA500 at nasal) were linearly correlated with postoperative IOP changes. CONCLUSION: Cataract surgery may have improved anterior chamber angle parameters and decreased IOP in NTG patients. PMID- 28861350 TI - Refractive errors and biometry of primary angle-closure disease in a mixed Malaysian population. AB - AIM: To assess the refractive status, anterior chamber depth (ACD) and axial length (AL) of patients with primary angle-closure disease (PACD). METHODS: Retrospective cohort. Data was collected from charts of all PACD patients treated from April 2013 to December 2015. Analysis was done on 137 patient charts with complete biometric data. Patient demographics, PACD type, refractive status (spherical equivalent), ACD and AL were studied. RESULTS: The median age of 137 subjects [53 with primary angle-closure suspects (PACS), 27 with primary angle closure (PAC) and 57 with primary angle-closure glaucoma (PACG)] was 68y (range 21-88y). The majority was Chinese (n=68; 49.6%) and most of them were women (n=75; 54.7%). The distribution of myopia (n=51; 37.2%) and hyperopia (n=49; 35.8%) was similar. The ACD was shallower in myopes compared to hyperopes (P=0.02) and emmetropia (P=0.049) but the AL was not significantly different between groups. There were no patients blind from PACG. CONCLUSION: Both myopia and hyperopia can occur in PACD. Despite a shallower ACD in angle closure myopes, the AL was not different between groups. PMID- 28861351 TI - Efficacy and safety of bimatoprost in glaucoma and ocular hypertension in non responder patients. AB - AIM: To establish the efficacy and safety of bimatoprost 0.03% monotherapy in glaucoma and ocular hypertension (OHT) patients with inadequate intraocular pressure (IOP)on current therapy. METHODS: Pre- and post-switch IOPs were analyzed for 59 consecutive patients who were switched from current therapy to bimatoprost monotherapy between 2011-2015. Demographic information, diagnosis, and any adverse events were recorded. Change in IOP post-pre switch was analyzed using a 2-sided Student's paired t-test at the 5% significance level. RESULTS: There was a statistically significant mean reduction in IOP at the first follow up visit, which was maintained at subsequent follow up visits for patients regardless of diagnosis, or pre-switch treatment (P<0.001). Subgroup analysis also demonstrated a statistically significant mean reduction in IOP when looking at OHT patients only, as well as patients with any diagnosis switched from latanoprost monotherapy to bimatoprost monotherapy (P<0.001). CONCLUSION: This is the largest independent data set which supports switching glaucoma patients with poor response to current treatment onto bimatoprost monotherapy before considering other adjuvant medical or more invasive therapy. PMID- 28861352 TI - Area and volume ratios for prediction of visual outcome in idiopathic macular hole. AB - AIM: To predict the visual outcome in patients undergoing macular hole surgery by two novel three-dimensional morphological parameters on optical coherence tomography (OCT): area ratio factor (ARF) and volume ratio factor (VRF). METHODS: A clinical case series was conducted, including 54 eyes of 54 patients with an idiopathic macular hole (IMH). Each patient had an OCT examination before and after surgery. Morphological parameters of the macular hole, such as minimum diameter, base diameter, and height were measured. Then, the macular hole index (MHI), tractional hole index (THI), and hole form factor (HFF) were calculated. Meanwhile, novel postoperative macular hole (MH) factors, ARF and VRF were calculated by three-dimensional morphology. Bivariate correlations were performed to acquire asymptotic significance values between the steady best corrected visual acuity (BCVA) after surgery and 2D/3D arguments of MH by the Pearson method with two-tailed test. All significant factors were analyzed by the receiver operating characteristic (ROC) curve analysis of SPSS software which were responsible for vision recovery. ROC curves analyses were performed to further discuss the different parameters on the prediction of visual outcome. RESULTS: The mean and standard deviation values of patients' age, symptoms duration, and follow-up time were 64.8+/-8.9y (range: 28-81), 18.6+/-11.5d (range: 2-60), and 11.4+/-0.4mo (range: 6-24), respectively. Steady-post-BCVA analyzed with bivariate correlations was found to be significantly correlated with base diameter (r=0.521, P<0.001), minimum diameter (r=0.514, P<0.001), MHI (r=-0.531, P<0.001), THI (r=-0.386, P=0.004), HFF (r=-0.508, P<0.001), and ARF (r=-0.532, P<0.001). Other characteristic parameters such as age, duration of surgery, height, diameter hole index, and VRF were not statistically significant with steady-post-BCVA. According to area under the curve (AUC) values, values of ARF, MHI, HFF, minimum diameter, THI, and base diameter are 0.806, 0.772, 0.750, 0.705, 0.690, and 0.686, respectively. However, Steady-post-BCVA analysis with bivariate correlations for VRF was no statistical significance. Results of ROC curve analysis indicated that the MHI value, HFF, and ARF was greater than 0.427, 1.027 and 1.558 respectively which could correlate with better visual acuity. CONCLUSION: Compared with MHI and HFF, ARF could effectively express three dimensional characteristics of macular hole and achieve better sensitivity and specificity. Thus, ARF could be the most effective parameter to predict the visual outcome in macular hole surgery. PMID- 28861353 TI - Role of short-wavelength filtering lenses in delaying myopia progression and amelioration of asthenopia in juveniles. AB - AIM: To evaluate the positive effects of blue-violet light filtering lenses in delaying myopia and relieving asthenopia in juveniles. METHODS: Sixty ametropia juveniles (aged range, 11-15y) were randomized into two groups: the test group (30 children, 60 eyes), wearing blue-violet light filtering lenses; and the control group (30 children, 60 eyes), wearing ordinary aspherical lenses. Baseline refractive power of the affected eyes and axial length of the two groups was recorded. After 1-year, the patients underwent contrast sensitivity (glare and non-glare under bright and dark conditions), accommodation-related testing, asthenopia questionnaire assessment, and adverse reaction questionnaire assessment. RESULTS: After 1y of wearing the filtering lenses, changes in refractive power and axial length were not significantly different between the two groups (P>0.05). Under bright conditions, the contrast sensitivities at low and medium-frequency grating (vision angles of 6.3 degrees , 4.0 degrees , and 2.5 degrees ) with glare in the test group were significantly higher than in the control group (P<0.05), while the contrast sensitivity at low-frequency grating (vision angles of 6.3 degrees and 4.0 degrees ) in the absence of glare in the test group was higher than in the control group (P<0.05). Under glare and non glare dark conditions, the contrast sensitivities of various frequencies in the test group did not show significant differences compared with those in the control group (P>0.05). In the test group, the amplitude of accommodation, accommodative lag, and accommodative sensitivity of patients wearing glasses for 6 and 12mo were significantly elevated (P<0.05), while the asthenopia gratings were significantly decreased (P<0.05). Nevertheless, in the control group, the amplitude of accommodation, accommodative lag, and accommodative sensitivity after 12mo were not significantly altered compared with baseline (P>0.05), and the asthenopia grating was not significantly decreased (P>0.05). In addition, after wearing glasses for 6 to 12mo, the asthenopia grating of patients in the test group decreased significantly compared with the control group (P<0.05). At 12mo, the constituent ratio of adverse reactions did not show significant difference between the two groups (P>0.05). CONCLUSION: A 1-year follow-up reveal that compare with ordinary glasses, short-wavelength filtering lenses (blue/violet-light filters) increase the low- and medium-frequency contrast sensitivity under bright conditions and improved accommodation. They effectively relieved asthenopia without severe adverse reactions, suggesting potential for clinical application. However, no significant advantages in terms of refractive power or axial length progression were found compared with ordinary aspheric lenses. PMID- 28861354 TI - Epstein-Barr virus-encoded small RNAs in idiopathic orbital inflammatory pseudotumor tissues: a comparative case series. AB - AIM: To investigate the positive rate and types of cells that express Epstein Barr virus-encoded small RNAs (EBERs) and to determine the distribution of EBER expressing cells in idiopathic orbital inflammatory pseudotumor (IOIP) tissues. METHODS: We retrospectively examined 40 archived paraffin specimens from two teaching hospitals in Southern China between January 2007 and January 2015 that were pathologically determined to exhibit IOIP. Eleven concurrent paraffin specimens of thyroid-associated ophthalmopathy (TAO) composed the control group. In situ hybridization was performed to detect EBERs. Immunohistochemistry was employed to detect CD3, CD20, Vimentin, and smooth muscle actin (SMA), and the positive rate, types of positive cells, and distribution and location of EBERs were evaluated. RESULTS: The positive expression rate of EBERs was 47.5% (19/40) in the IOIP group, which was significantly higher than that in the TAO group [0 (0/11), P=0.011]. In the IOIP group, the lymphocyte infiltrative subtype, fibrotic subtype, and mixed subtype exhibited EBER-positive rates of 57.1% (12/21), 12.5% (1/8), and 54.5% (6/11), respectively, and no significant differences were found between these subtypes (P=0.085). Positive signals of EBERs were mainly present in medium-small lymphocytes between or around follicles and in the nuclei of activated immunoblasts (14/19). CONCLUSION: The positive rate, types, and distribution of EBER-expressing cells in IOIP have been documented. These findings are conducive for a better understanding of the underlying mechanisms of Epstein-Barr virus infection in IOIP pathogenesis. PMID- 28861355 TI - Prevalence of retinopathy of prematurity in Iran: a systematic review and Meta analysis. AB - AIM: To estimate overall prevalence of retinopathy of prematurity (ROP) in Iran using a systematic review and Meta-analysis. METHODS: A systematic review and Meta-analysis was performed of all published studies pertaining to prevalence of ROP using international and national electronic databases (ISI Web of Sciences, PubMed, Scopus, Google Scholar, SID, MagIran, and IranMedex) from their inception until May 2016 with standard keywords. Begg and Egger tests were used to examine the publication bias and Cochran test and I2 statistics were used to evaluate the statistical heterogeneity. Pooled estimate of the prevalence of ROP were calculated using random effects Meta-analysis. RESULTS: The publication bias assumption was rejected by Egger tests with P-value equal to 0.024. The results of Cochran test and I2 statistics revealed substantial heterogeneity (Q=1099.02, df=25, I2=97.7%, P=0.001). The overall prevalence of ROP using the random effect model in Iran was 26.1% (95% CI: 20.3%-31.8%). CONCLUSION: The prevalence of ROP is relatively high in Iran. Low birth weight and gestational age are significant risk factors for the disease. Improved care, including oxygen delivery and monitoring, for preterm babies in all facility settings would reduce the number of babies affected with ROP. PMID- 28861356 TI - Combined therapy versus anti-vascular endothelial growth factor monotherapy for polypoidal choroidal vasculopathy: a Meta-analysis. AB - AIM: To evaluate the efficacy and safety of anti-vascular endothelial growth factor (VEGF) combined with photodynamic therapy (PDT) versus anti-VEGF monotherapy for polypoidal choroidal vasculopathy (PCV). METHODS: We conducted a Meta-analysis of 9 studies to compare the efficacy and safety between combined therapy and anti-VEGF monotherapy for PCV. The programs of RevMan 5.3 and Stata 12.0 were used to analyze data. RESULTS: The best corrected visual acuity (BCVA) in combined therapy group were significantly better than those of anti-VEGF monotherapy group at 6, 24 and 36mo, with pooled weighted means differences (WMDs) of 0.12 (0.06, 0.18), 0.25 (0.12, 0.38) and 0.28 (0.13, 0.43), respectively. The central retinal thickness (CRT) reductions in combined therapy group were higher than that in anti-VEGF monotherapy group at 1, 3, 6 and 9mo, with pooled WMDs of 63.90 (20.41, 107.38), 33.47 (4.69, 62.24), 30.57 (0.12, 60.01) and 28.00 (2.51, 53.49), respectively. The regression rate of polyps in combined therapy group was much higher than that in anti-VEGF monotherapy group [RD: 0.47 (0.26, 0.68); P<0.0001]. The adverse event retinal hemorrhage did not differ significantly between the two groups. CONCLUSION: Our findings clearly document that anti-VEGF combined with PDT is a more effective therapy for PCV compared with anti-VEGF monotherapy. Furthermore, combined therapy does not increase the incidence of retinal hemorrhage. PMID- 28861357 TI - The evolution of refractive status in Chinese infants during the first year of life and its affected factors. AB - AIM: To study the evolution of the refractive status and examine the affected factors in infants during the first year of life in a large sample size in China. METHODS: A total of 1258 babies (2516 eyes) aged 32wk gestational age to 1y participated in the study, including 766 premature and 492 full-term infants. First, each baby received an orthoptic examination, slit-lamp checking and fundus imaging. Patients with diseases which might affect refractive status were excluded from the cohort. The cycloplegia retinoscopy was performed. Their neonatal histories were reviewed. Each measurement contained the refractive status and calculation of the spherical equivalent (SE). RESULTS: Refractive state showed an average hyperopia of +0.94+/-1.63 D at early ages, followed by a trend toward more hyperopia. The refractive state reached the top (+2.43+/-1.46 D) at the age of one to two months. Then gliding till one year old when the refractive state reached +0.59+/-1.41 D. The prevalence of astigmatism was 42.17% in the study, being 2.82% myopic astigmatism and 39.35% hyperopic astigmatism. The 94.1% of hyperopic astigmatism was with-the-rule astigmatism and 71.83% of myopic astigmatism was with-the-rule astigmatism. Refractive state between boys and girls was different. The mean SE of boys was +1.97+/-1.57 D, while that of girls was +1.79+/-1.46 D, and the difference was significant. CONCLUSION: Before one year old, the change of refractive status is associated with checking age and sex. At the age of one to two months, the degree of hyperopia reaches the top. Boys have more hyperopic degree than girls, and with-the-rule astigmatism is predominant. Excluding premature infants with advanced retinopathy of prematurity, premature and full-term children have same refraction status. PMID- 28861358 TI - Epidemiologic characteristics and outcomes of open globe injury in Shanghai. AB - AIM: To investigate the epidemiologic characteristics and outcomes of open globe injury in Shanghai. METHODS: A retrospective study was conducted for 148 unilateral open globe injury cases presenting to a tertiary referral hospital of Shanghai. Electronic medical records were reviewed and phone surveys were conducted to collect and analyze 1) background of patient; 2) setting of injury and clinical signs at presentation; 3) treatment procedure and outcome; 4) quality of life after injury. RESULTS: There were more male patients (77.03%) than females (22.97%), more temporary habitants (79.05%) than residents (20.95%). The subjects in this study presented a significantly lower constitutional status of education than that of the whole Shanghai population (P<0.001). Occupational injury was the first cause of injuries (39.86%), followed by home accident (20.27%), road accident (16.89%), violent behavior (16.89%) and outdoor injury (6.08%). The 143 subjects (96.62%) were not wearing spectacles at the time of injury. Of all patients, 77 subjects (52.03%) had the outcome of no vision (including enucleation). The classification and regression tree (CART) prognosis presents 59.58% sensitivity to predict visual survival correctly and 80.19% specificity to predict no vision correctly. The patients whose injured eye had no vision reported more reduction of life quality. CONCLUSION: We found that male subject, temporary habitants, low educational status and no eyewear are risk factors of open globe injury in Shanghai. Occupational injury is the leading cause. CART analysis presents a certain agreement to the actual visual outcome. The injury imposes negative impact on quality of life especially in no vision cases. The education of eye protection may help to avoid the injury. PMID- 28861359 TI - Intraocular lymphoma. AB - Intraocular lymphoma (IOL) is a rare lymphocytic malignancy which contains two main distinct forms. Primary intraocular lymphoma (PIOL) is mainly a sub-type of primary central nervous system lymphoma (PCNSL). Alternatively, IOL can originate from outside the central nervous system (CNS) by metastasizing to the eye. These tumors are known as secondary intraocular lymphoma (SIOL). The IOL can arise in the retina, uvea, vitreous, Bruch's membrane and optic nerve. There are predominantly of B-cell origin; however there are also rare T-cell variants. Diagnosis remains challenging for ophthalmologists and pathologists, due to its ability to masquerade as noninfectious or infectious uveitis, white dot syndromes, or occasionally as other metastatic cancers. Laboratory tests include flow cytometry, immunocytochemistry, interleukin detection (IL-10: IL-6, ratio >1), and polymerase chain reaction (PCR) amplification. Methotrexate-based systemic chemotherapy with external beam radiotherapy and intravitreal chemotherapy with methotrexate are useful for controlling the disease, but the prognosis remains poor. Therefore, it is important to make an early diagnose and treatment. This review is focused on the clinical manifestations, diagnosis, treatment and prognosis of the IOL. PMID- 28861362 TI - A case of non-Acanthamoeba keratitis with radial keratoneuritis. PMID- 28861360 TI - Metalloproteinases as mediators of inflammation and the eyes: molecular genetic underpinnings governing ocular pathophysiology. AB - There are many vision threatening diseases of the eye affecting millions of people worldwide. In this article, we are summarizing potential role of various matrix metalloproteinases (MMPs); the Zn (2+)-dependent endoproteases in eye health along with pathogenesis of prominent ocular diseases such as macular degeneration, diabetic retinopathy, and glaucoma via understanding MMPs regulation in affected patients, interactions of MMPs with their substrate molecules, and key regulatory functions of tissue inhibitor of metalloproteinases (TIMPs) towards maintaining overall homeostasis. PMID- 28861361 TI - Cysticercosis of the eye. AB - Cysticercosis is a preventable and eradicable cause of blindness endemic in the Indian subcontinent, South-East Asia and other developing countries. Ocular and orbital cysticercosis has varied presentations depending upon the site of involvement, number of lesion and the host immune response. In this article we present a review of the various clinical manifestations, diagnosis and management protocol for orbital and ocular cysticercosis. Owing to its varied presentation, cysticercosis may pose a diagnostic challenge to the health professionals. Early diagnosis and management can prevent the vision loss and optimize visual outcomes. PMID- 28861363 TI - Optical coherence tomography-angiography of juxtapapillary hamartoma. PMID- 28861364 TI - Spectral-domain optical coherence tomography dynamic changes and steroid response in multiple evanescent white dot syndrome. PMID- 28861365 TI - Comment on "Comparison of 45-degree Kelman and 45-degree balanced phaco tip designs in torsional microcoaxial phacoemulsification". PMID- 28861366 TI - Serum phosphorus values for early prediction of hypocalcemia in total thyroidectomy. PMID- 28861367 TI - Safety of same-day thyroidectomy: meta-analysis and systematic review. AB - BACKGROUND: Performance of thyroid surgery as a same day surgery procedure has been a controversial topic. This study aimed to compare the safety and efficacy of outpatient thyroid surgery with inpatient thyroid surgery by meta-analysis of current literature. METHODS: Articles were identified from the following keyword searches: outpatient thyroidectomy/thyroid surgery, same day thyroidectomy/thyroid surgery. Outcomes included perioperative complications including recurrent laryngeal nerve (RLN) injury, hypocalcemia, and readmissions. Data were extracted following review of appropriate studies by authors and random effects models were used. RESULTS: 34 potentially relevant publications were identified and 14 studies fulfilled the predetermined inclusion criteria, totaling 10,478 patients, 4,565 of whom were discharged the same day following thyroid surgery. There was no difference in malignancy rate between the two groups (95% CI, 0.84-2.31; P=0.196). Inpatient group were 2.23 times (95% CI, 1.36-3.36; P=0.001) more likely to develop transient RLN injury and 2.32 times (95% CI, 1.06-5.06; P=0.034) more likely to have documented transient hypocalcemia compared to outpatients. Inpatient groups were 2.10 times (95% CI, 1.33-3.33; P=0.002) more likely to have documented other complications. The two groups also had similar readmission rates (95% CI, 0.71-1.41; P=1.000). CONCLUSIONS: Our meta-analysis suggests that discharging selective patients the same day after a thyroid surgery is as safe, feasible, and efficacious as admitting them for observation. Admitting patients after thyroid surgery is associated with higher reported risk of complications. PMID- 28861368 TI - Can magnetic resonance imaging obviate the need for biopsy for microcalcifications? AB - BACKGROUND: Although microcalcifications detected with mammography (MG) are usually biopsied, biopsies cannot be performed in all cases. We sought to determine if magnetic resonance imaging (MRI) findings could indicate whether stereotactic vacuum-assisted biopsy (SVAB) is necessary. METHODS: Patients with mammographically detected Breast Imaging-Reporting and Data System (BI-RADS) 3, 4, and 5 microcalcifications were analyzed from April 2012 to September 2014. All patients underwent MRI. All patients with enhancing lesions in the region of the microcalcifications underwent SVAB. Non-enhancing lesions were followed or biopsied, depending on the patient's preferences. MRI findings were classified as either malignant-suspicious or benign-suspicious ("none" or "nonspecific"), and we evaluated the positive predictive value (PPV) and negative predictive value (NPV) of these classifications for predicting malignancy. RESULTS: A total of 87 patients underwent both MRI and SVAB. The NPV of MRI was 100% in the group with no enhancement. In BI-RADS category 3, there were 57 benign-suspicious lesions on MRI, of which eight were malignant (NPV of MRI: 85.0%). CONCLUSIONS: It may be possible to omit SVAB for microcalcifications if there is no enhancement on MRI; however, any kind of enhancement indicates the need for biopsy in cases of BI RADS 3 calcifications on MG. PMID- 28861369 TI - Microsurgical dissection of facial nerve in parotidectomy: a discussion of techniques and long-term results. AB - BACKGROUND: Parotidectomy has well-documented post-operative complications. Dissection of the facial nerve branches can be challenging even under loupe magnification, and partial, or complete injury of the nerve branches can occur during surgery. To reduce this risk and the associated complications, we propose a number of microsurgical best practices, which can be performed during parotidectomy. METHODS: A retrospective survey was conducted on 109 patients (45 males and 64 females, average age 46.2 years, range of 6 to 74 years) who underwent parotidectomy in two different institutions. RESULTS: Our data showed no permanent injury to the facial nerve, and 17% of neuroapraxia that had resolved with time. Post-operative complications have occurred in 33 cases (30% rate). In the superficial parotidectomy cohort (78 patients), the number of complications was 17 (21%). In the total parotidectomy cohort (31 patients), the number of complications was 16 (51%). CONCLUSIONS: Based on our results, we believe that the use of microsurgical techniques during parotidectomy may represent a useful tool in improving accuracy and minimising local tissue trauma that can affect nerve recovery. This is particularly true in situations such as tumor recurrence, tissue fibrosis or in case of sizeable tumors around the facial nerve branches. We believe that the decreased risk of facial nerve post-operative symptoms outweigh the disadvantage of increased operative time of this procedure. PMID- 28861370 TI - Increased risk of recurrence associated with certain risk factors in breast cancer patients after DIEP-flap reconstruction and lipofilling-a matched cohort study with 200 patients. AB - BACKGROUND: Lipofilling is performed in breast cancer patients to optimize the aesthetic outcome following breast reconstruction after mastectomy. Despite its common usage worldwide, little is known about the interaction of the lipoaspirate and dormant cancer cells. Up to date, no risk factors that increase the risk for cancer recurrence have been established. This study aims to identify risk factors for lipofilling candidates after breast cancer and questions the oncological safety of lipofilling in lymph node positive disease. METHODS: Matched retrospective cohort study: the disease-free survival (DFS) between 100 breast cancer patients undergoing a lipofilling after their DIEP-flap reconstruction and 100 matched control patients with no subsequent lipofilling was analyzed. Further, patients were subdivided according to risk factors, which were categorized as patient-dependent factors (PDFs) and tumor-dependent factors (TDFs). DFS and hazard ratios (HR) were compared to identify potential risk factors that may increase cancer recurrence. RESULTS: Median follow-up was 76.5 months from the mastectomy, and 31 months from the startpoint to the end of follow-up. Seven and eleven patients had recurrence in the lipofilling and control group, respectively, presenting with comparable DFS rates and an insignificant HR =0.57, 95% confidence interval (CI): 0.22-1.47, P=0.24. According to subgroup survival analysis, lipofilling increased the risk of recurrence in women with a positive nodal status (P=0.035) and a high-grade neoplasia (P=0.049). CONCLUSIONS: No general increased recurrence risk was observed between the lipofilling and control group. The subgroup analysis identified high-grade neoplasia and positive nodal status to be a risk factor for cancer recurrence. Patients with a known node positive disease have an increased risk of occult micrometastases in their lymph nodes. Further studies are necessary to clarify whether dormant breast cancer cells in form of micrometastases in the lymph nodes can be reactivated by the factors secreted by adipose derived stem cells. PMID- 28861371 TI - Laparoscopic versus open 1-stage resection of synchronous liver metastases and primary colorectal cancer. AB - BACKGROUND: The aim of this study is to compare the perioperative and oncologic outcomes of open and laparoscopic approaches for concomitant resection of synchronous colorectal cancer and liver metastases. METHODS: Between 2006 and 2015, all patients undergoing combined resection of primary colorectal cancer and liver metastases were included in the study (n=43). Laparoscopic and open groups were compared regarding clinical, perioperative and oncologic outcomes. RESULTS: There were 29 patients in the open group and 14 patients in the laparoscopic group. The groups were similar regarding demographics, comorbidities, histopathological characteristics of the primary tumor and liver metastases. Postoperative complication rate (44.8% vs. 7.1%, P=0.016) was higher, and hospital stay (10 vs. 6.4 days, P=0.001) longer in the open compared to the laparoscopic group. Overall survival (OS) was comparable between the groups (P=0.10); whereas, disease-free survival (DFS) was longer in laparoscopic group (P=0.02). CONCLUSIONS: According to the results, in patients, whose primary colorectal cancer and metastatic liver disease was amenable to a minimally invasive resection, a concomitant laparoscopic approach resulted in less morbidity without compromising oncologic outcomes. This suggests that a laparoscopic approach may be considered in appropriate patients by surgeons with experience in both advanced laparoscopic liver and colorectal techniques. PMID- 28861372 TI - Estimation of tumor size in breast cancer comparing clinical examination, mammography, ultrasound and MRI-correlation with the pathological analysis of the surgical specimen. AB - BACKGROUND: To evaluate the best method in our center to measure preoperative tumor size in breast tumors, using as reference the tumor size in the postoperative surgical specimen. We compared physical examination vs. mammography vs. resonance vs. ultrasound. There are different studies in the literature with disparate results. METHODS: This is a retrospective study. All the included patients have been studied by clinical examination performed by gynecologist or surgeon specialists in senology, and radiological tests (mammography, ultrasound and magnetic resonance imaging). The correlation of mammary examination, ultrasound, mammography and resonance with pathological anatomy was studied using the Pearson index. Subsequently, the results of such imaging tests were compared with the tumor size of the infiltrating component measured by anatomopathological study using a student's t test for related variables. The level of significance was set at 95%. Statistical package R. was used. RESULTS: A total of 73 cases were collected from October 2015 to July 2016 with diagnosis of infiltrating breast carcinoma. Twelve cases of carcinoma in situ and seven cases of neoadjuvant carcinoma are excluded. Finally, a total of 56 cases were included in the analysis. The mean age of the patients is 57 years. The histology is of infiltrating ductal carcinoma in 46 patients (80.7%), lobular in 8 (14%) and other carcinomas in 3 cases (5.2%). We verified the relationship between preoperative tumor size by physical examination, mammography, ultrasound (US) and magnetic resonance imaging (MRI), and the final size of the surgical specimen by applying a Pearson correlation test. A strong correlation was found between the physical examination results 0.62 (0.43-0.76 at 95% CI), ultrasound 0.68 (0.51 0.8 at 95% CI), mammography 0.57 (0.36-0.72 at 95% CI) and RM 0.51 (0.29-0.68 at 95% CI) with respect to pathological anatomy. The mean tumor size of the surgical specimen was 16.1 mm. Mean of tumor size by physical examination was 12.1 mm (P<0.05), by 14 mm US (P<0.05), by mammography of 14.3 (P<0.05) and by MRI of 22.53 mm (P>0.05). CONCLUSIONS: Ultrasonography is the best predictor of tumor size in breast cancer, compared with clinical examination, mammography, and resonance. Our work could help the decision-making process such as the type of conservative surgery, the possible need for oncoplastic surgery or the decision to start treatment with neoadjuvant therapy, in patients with unifocal tumors. PMID- 28861373 TI - Staged approach to partial breast reconstruction to avoid mastectomy in women with breast cancer. AB - BACKGROUND: The lateral chest wall perforator flaps (CWPF) offer an excellent option for partial breast reconstruction (PBR) in women undergoing breast conservation surgery (BCS) for laterally placed tumours in small to moderate non ptotic breasts. METHODS: A total of 20 patients underwent PBR with lateral CWPF over the last 4 years, as two-stage approach. This approach was undertaken for patients with high tumour to breast ratio (>30% predicted resection) in an attempt to avoid mastectomy. The reconstruction was carried out 2-4 weeks after wide local excision in order to ensure clear margins prior to undertaking PBR. RESULTS: Twenty-three women were selected for attempt at BCS with 2-stage approach. Three patients had extensive disease so they were then counseled for mastectomy after the first surgery and 20 patients had successful BCS. Out of 20 patients, 13 were symptomatic and 7 were screen-detected with mean age of 49 years. The median tumour size on pre-op imaging was 43 mm (23-75 mm). A percentage of 50% women with unifocal cancers undergoing primary surgery had disease overestimated on pre-op imaging. The complication rate was low. Good to excellent aesthetic outcomes were reported in 90% cases. Patients reported high satisfaction scores. CONCLUSIONS: We recommend considering two-stage approach in selected women with high tumour-breast ratio to ensure successful BCS prior to PBR. This approach facilitates BCS and avoids mastectomy in borderline cases, particularly lobular cancers, DCIS, bifocal cancers and post neoadjuvant chemotherapy where pre-operative disease estimation could be challenging. Our small series has shown that this approach results in safe oncological surgery with good aesthetic outcomes in the selected group of women. PMID- 28861374 TI - Oncoplastic round block technique has comparable operative parameters as standard wide local excision: a matched case-control study. AB - BACKGROUND: Although oncoplastic breast surgery is used to resect larger tumors with lower re-excision rates compared to standard wide local excision (sWLE), criticisms of oncoplastic surgery include a longer-albeit, well concealed-scar, longer operating time and hospital stay, and increased risk of complications. Round block technique has been reported to be very suitable for patients with relatively smaller breasts and minimal ptosis. We aim to determine if round block technique will result in operative parameters comparable with sWLE. METHODS: Breast cancer patients who underwent a round block procedure from 1st May 2014 to 31st January 2016 were included in the study. These patients were then matched for the type of axillary procedure, on a one to one basis, with breast cancer patients who had undergone sWLE from 1st August 2011 to 31st January 2016. The operative parameters between the 2 groups were compared. RESULTS: 22 patients were included in the study. Patient demographics and histologic parameters were similar in the 2 groups. No complications were reported in either group. The mean operating time was 122 and 114 minutes in the round block and sWLE groups, respectively (P=0.64). Length of stay was similar in the 2 groups (P=0.11). Round block patients had better cosmesis and lower re-excision rates. A higher rate of recurrence was observed in the sWLE group. CONCLUSION: The round block technique has comparable operative parameters to sWLE with no evidence of increased complications. Lower re-excision rate and better cosmesis were observed in the round block patients suggesting that the round block technique is not only comparable in general, but may have advantages to sWLE in selected cases. PMID- 28861375 TI - The role of laparoscopic resection of metastases to adrenal glands. AB - BACKGROUND: The potential role of the laparoscopic approach for metastases to the adrenal gland is debated. We review here a series of patients consecutively submitted to laparoscopic adrenalectomy (LA) for suspected adrenal metastasis (AM). METHODS: Retrospective study (consecutive series) of LA for AM. We measured parameters associated to primary tumor and metastasis. Statistical analysis: stepwise regression model. RESULTS: Thirty-seven LA were performed on 36 patients. The mean age was 62.1 yrs. The side was right in 13 cases. Primary tumor was in the lung (n=22), breast (n=4), colon-rectum (n=4), kidney (n=3), thyroid, melanoma and ovary (n=1 each). Thirty-three out of 37 were confirmed to be AM (mean diameter 50 mm). Twenty-five were single metastasis. One LA was converted due to cava vein infiltration. Mean operative time was 142 min', median p.o. hospital stay was 3 days. After a mean follow-up of 33 months, 9 patients (25%) were alive free of disease, 6 (17%) were alive with disease. Mean post adrenalectomy DFI was 19 months (range, 0-97 months), and it was the most predictive variable for survival (P<0.001). CONCLUSIONS: The dimensions and absence of invasion on imaging, the evolutive status of the disease and the performance status of the patient are key factors for LA, which is associated with adequate oncologic results, a quicker postoperative recovery, and potential survival benefits. PMID- 28861377 TI - Concomitant thyroid disease and primary hyperparathyroidism in patients undergoing parathyroidectomy or thyroidectomy. AB - BACKGROUND: Thyroid abnormalities have been found intraoperatively during parathyroidectomy and have resulted in concomitant thyroidectomy. The identification of concomitant disease is important prior to primary operation in order to minimize reoperations. This study investigates the incidence of concomitant primary hyperparathyroidism (PHPT) and thyroid nodular disease in patients undergoing thyroidectomy or parathyroidectomy. METHODS: We performed a retrospective review of prospectively gathered data for 621 patients who underwent thyroidectomy, parathyroidectomy, or both at Tulane Medical Center. Information obtained included initial referral, initial thyroid stimulating hormone (TSH), initial parathyroid hormone (PTH), fine needle aspiration (FNA) results, ultrasound results, type of operation performed, final diagnosis, and final pathology. RESULTS: Among the 400 patients referred primarily for thyroid disease, 13.50% underwent a thyroidectomy and parathyroidectomy (PTX) simultaneously and 10.75% received a final diagnosis of thyroid and concomitant parathyroid disease. Among the 103 patients referred primarily for parathyroid disease, 26.21% underwent a PTX and thyroidectomy and 24.27% received a final diagnosis of both thyroid and parathyroid disease. Patients referred primarily for parathyroid disease were more likely to receive a final diagnosis of both parathyroid and thyroid disease and were more likely to undergo a combined operation. CONCLUSIONS: Concomitant thyroid and parathyroid disease occur and preoperative analysis is important to avoid increased complications from reoperations. PMID- 28861376 TI - Patient determinants as independent risk factors for postoperative complications of breast reconstruction. AB - BACKGROUND: Breast reconstruction is an essential component in the treatment of breast cancer. Postoperative complications after breast reconstruction are common and affect patient satisfaction. Determining independent risk factors using patient characteristics could be advantageous for patient assessment and counseling. METHODS: We retrospectively enrolled 623 consecutive patients who underwent reconstruction with a deep inferior epigastric perforator flap (DIEP), latissimus dorsi flap (LD), lateral thoracodorsal flap (LTDF), or tissue expander with a secondary implant (EXP) in this study. Information on demographic and perioperative factors was collected, as well as information on all postoperative complications. Logistic regression was used to analyze associations between possible patient-related risk factors and postoperative complications. RESULTS: Smoking was associated with the highest number of early overall complications [odds ratio (OR) 2.05, 95% confidence interval (CI) 1.25-3.37, P=0.0005], followed by body mass index (BMI) (OR 1.07, 95% CI 1.01-1.13, P=0.017). High BMI was associated with the highest number of late overall postoperative complications (OR 1.06, 95% CI 1.00-1.11, P=0.042), followed by history of radiotherapy (OR 1.66, 95% CI 1.01-2.74, P=0.046). When the risk factors were combined, the risk for postoperative complications rose exponentially. CONCLUSIONS: Our results provide evidence that patients should cease smoking and overweight patients should lose weight before undergoing breast reconstruction. Additionally, if the patient has received radiotherapy, the reconstruction method should be carefully chosen. High BMI, history of radiotherapy, and smoking are independent risk factors for many types of both early and late postoperative complications in breast reconstructive surgery. Combining these risk factors multiplies the risk of postoperative complications. PMID- 28861378 TI - Microsurgical refinements with the use of internal mammary (IM) perforators as recipient vessels in transverse upper gracilis (TUG) autologous breast reconstruction. AB - BACKGROUND: The transverse upper gracilis (TUG) flap is the senior authors' second choice for autologous breast reconstruction when the DIEP flap is not available. It provides durable, pliable tissue with well hidden scars. The main criticism of this flap is the limited volume, donor site complications, short pedicle and vessel mismatch depending on which recipient vessels are used. We described methods of reducing vessel mismatch, complications of venous coupler and refinements to help give a more superior aesthetic outcome. METHODS: We describe several maneuvers to help reduce vessel mismatch with the use of the internal mammary (IM) perforator vessels with a modification of the Harashina fish-mouth technique or the use of a vessel bifurcation to increase vessel diameter. We also describe the optimum method of perforator preparation and potential methods to prevent palpable venous couplers. The author's describe their case series of 14 TUG flaps to reconstruct 13 breasts in 12 patients. RESULTS: Eight unilateral, 2 partial breast reconstruction, 1 bilateral and 1 bilateral TUG flap for a unilateral reconstruction was carried out. All flaps survived with one partial flap necrosis, one donor site seroma and two cases of palpable/tender venous couplers. The mean reconstructed breast was 320 grams. CONCLUSIONS: The TUG flap is a reconstructive challenge, but with correct planning a good aesthetic outcome is possible. The IM perforator is our first choice recipient vessel in TUG breast reconstructions. With meticulous preparation and by overcoming vessel mismatch the use of this recipient vessel is a reliable option. PMID- 28861379 TI - The current status of robotic transaxillary thyroidectomy in the United States: an experience from two centers. AB - BACKGROUND: Few studies exist regarding the state of robotic transaxillary thyroidectomy (RT) and its outcomes at high-volume institutions. METHODS: Eighty nine patients underwent RT between January 2009 and September 2015 at two tertiary centers. Data were collected from prospectively-maintained IRB-approved databases. Patient demographic and clinical data, and trends were evaluated. RESULTS: Indications for RT included biopsy-proven or suspicion for malignancy in 20.2%, atypical cells or follicular neoplasm in 27.7%, multinodular goiter in 26.6%, thyrotoxicosis in 8.5%, need for completion thyroidectomy in 5.3%, and non diagnostic FNA in 3.2%. 56% underwent total thyroidectomy and 44% lobectomy. Operative time (OT) was 153.5 minutes for lobectomies and 192.6 minutes for total thyroidectomy. The complication rate was 11.7%: temporary RLN neuropraxia in 2 patients, permanent hypoparathyroidism in 1 patient, temporary hypoparathyroidism in 6 patients, flap seroma in 1 patient, and flap hematoma in 1 patient. Pathology showed malignancy in 43 patients. At a mean follow-up of 31.9 months, there were no recurrences. Since 2013, the number of RTs performed has risen. The number of out-of-state patients increased from 18% to 37% after 2011. CONCLUSIONS: RT was performed without compromising outcomes in selected patients. There remains interest among patients seeking this procedure in expert centers. PMID- 28861380 TI - Smoking and mortality in women diagnosed with breast cancer-a systematic review with meta-analysis based on 400,944 breast cancer cases. AB - BACKGROUND: It is evident that smoking is causing disease and increased mortality in general. Recently published data are now suggesting that smoking might increase both the overall mortality in women diagnosed with breast cancer but also increase their risk of dying from their breast cancer. METHODS: A systematic review and meta-analysis on smoking status in women diagnosed with breast cancer, their mortality rate and cause of death. Based on all cohort studies published within the last ten years. RESULTS: Twelve studies met our inclusion criteria, and 400,944 women diagnosed with primary invasive breast cancer was included. Hazard ratio (HR) for breast cancer associated death in former smokers was 1.02 (0.93, 1.12) and for current smokers 1.28 (1.17, 1.41) when compared to never smokers. For all-cause death, the HR for former smokers was 1.12 (1.04, 1.19), and for current smokers 1.52 (1.32, 1.76) when compared to never smokers. CONCLUSIONS: This large systematic review and meta-analysis found a 28% increase in breast cancer-associated mortality in those who were current smokers compared to never smokers. The mortality in former smokers was equal to the one found in never smokers. This indicates that breast cancer patients ceasing to smoke can lower their risk of dying from their breast cancer disease dramatically, and possibly regain the risk of a never smoker. PMID- 28861381 TI - Use of acellular dermal matrix (ADM) in nipple reconstruction: the 'central pillar technique'. AB - Nipple reconstructions are prone to a variable and unpredictable degree of flattening, which in some cases lead to secondary reconstruction. The use of an acellular dermal matrix (ADM) augmentation may be appropriate in cases with very thin dermis that are particularly prone to flattening or in revision cases where the first procedure has already failed. The authors present a series of 13 nipple reconstructions in ten cases. Average projection at 12 months was 51% in primary cases and 46% in secondary revision cases. This represents a better than expected long term result in a difficult cohort of patients. PMID- 28861382 TI - Minimalist breast conserving surgical approaches for inferiorly sited cancers. AB - Contemporary data suggests that breast conservation treatment (BCT) may confer a survival advantage when compared to mastectomy. Hence, it would be logical to adopt strategies which increase eligibility of successful BCT without compromising oncologic principles or cosmetic outcome. With respect to achieving good aesthetics, inferiorly sited breast cancers pose a particular technical challenge. A vast array of techniques, collectively referred to as oncoplastic breast surgery (OBS) have been developed to minimise post treatment distortion. The purported advantages of these approaches are the acquisition of wider margins and reduced re-excision rates. However, to date, there is a lack of data demonstrating significant reduction in local recurrence and overall survival when compared with less extensive procedures. In this review, "minimalist" procedures are described where strict oncologic criteria of clear margins are fulfilled and acceptable cosmesis are simultaneously achieved. These techniques offer less tissue loss, less extensive parenchymal mobilisation and shorter operating times without compromising margin status and aesthetics. They involve the combination of innovative incision designs and certain parenchymal resection patterns. Incision designs include the boomerang, golf-tee, anchor and arrowhead incisions which have been previously described but not widely used. Parenchymal resection patterns follow the "sick lobe hypothesis". These techniques, termed "reductionist", or "minimalist" comprising approaches where breast conserving surgery is condensed to its irreducible elements, offer alternatives which align with contemporary objectives of surgery where optimal survival outcomes are achieved through individualised procedures resulting in reduced iatrogenic impact. This logically allows scope for de-escalation of surgical therapy for breast cancer. PMID- 28861383 TI - Robotic transaxillary parathyroidectomy. AB - We recently reported on the safety and feasibility of robotic transaxillary approaches for parathyroid surgeries with benefit of avoiding a visible cervical scar. Herein, we demonstrate our technique with utilization of intraoperative nerve monitoring and indocyanine green (ICG) imaging. The patient was discharged a few hours after the surgery. PMID- 28861384 TI - A rare presentation of malignant phyllodes tumor with bloody nipple discharge report of a case. AB - Phyllodes tumor of the breast is a rare neoplasm, particularly in young women. It is usually presented as a unilateral palpable mass and nipple discharge presented as a symptom is rare. We reported a 22-year-old Taiwanese woman in our hospital for right breast tumor with nipple discharge. Preoperative diagnosis was intraductal papilloma but the histological examination showed a malignant phyllodes tumor with intraductal growth. Symptom of nipple discharge and intraductal growth in phyllodes tumor are rare presentations. Therefore, the management and the biological behavior of this uncommon tumor are discussed in this patient. PMID- 28861385 TI - IPTH cost-effectiveness in thyroid surgery. PMID- 28861386 TI - Less postoperative pain in patients receiving trans-oral vestibular endoscopic thyroidectomy: a plausible finding? PMID- 28861387 TI - Erratum to Professor Hoon Yub Kim: Transoral Robotic Thyroidectomy shows promising results with ideal outcomes. AB - [This corrects the article DOI: 10.21037/gs.2016.12.10.]. PMID- 28861388 TI - Reader's Forum. PMID- 28861389 TI - Cone-beam computed tomographic evaluation of the temporomandibular joint and dental characteristics of patients with Class II subdivision malocclusion and asymmetry. AB - OBJECTIVE: Treating Class II subdivision malocclusion with asymmetry has been a challenge for orthodontists because of the complicated characteristics of asymmetry. This study aimed to explore the characteristics of dental and skeletal asymmetry in Class II subdivision malocclusion, and to assess the relationship between the condyle-glenoid fossa and first molar. METHODS: Cone-beam computed tomographic images of 32 patients with Class II subdivision malocclusion were three-dimensionally reconstructed using the Mimics software. Forty-five anatomic landmarks on the reconstructed structures were selected and 27 linear and angular measurements were performed. Paired-samples t-tests were used to compare the average differences between the Class I and Class II sides; Pearson correlation coefficient (r) was used for analyzing the linear association. RESULTS: The faciolingual crown angulation of the mandibular first molar (p < 0.05), sagittal position of the maxillary and mandibular first molars (p < 0.01), condylar head height (p < 0.01), condylar process height (p < 0.05), and angle of the posterior wall of the articular tubercle and coronal position of the glenoid fossa (p < 0.01) were significantly different between the two sides. The morphology and position of the condyle-glenoid fossa significantly correlated with the three dimensional changes in the first molar. CONCLUSIONS: Asymmetry in the sagittal position of the maxillary and mandibular first molars between the two sides and significant lingual inclination of the mandibular first molar on the Class II side were the dental characteristics of Class II subdivision malocclusion. Condylar morphology and glenoid fossa position asymmetries were the major components of skeletal asymmetry and were well correlated with the three dimensional position of the first molar. PMID- 28861390 TI - Biomechanical analysis of distalization of mandibular molars by placing a mini plate: A finite element study. AB - OBJECTIVE: The objective of this study was to analyze the patterns of tooth movements when distalization of mandibular molars using a mini-plate took place. A finite element analysis was applied to analyze patterns of tooth movements. METHODS: The model of the mandible and teeth were used to build a finite element analysis model, and a mini-plate was inserted in the mandibular ramus. Two different orthodontic forces were established for displacement of mandibular molars. Orthodontic forces were applied at the level of the bracket and at the level of the cemento-enamel junction in the mandibular canine respectively. RESULTS: orthodontic forces at the level of the cemento-enamel junction resulted in a greater biomechanical bodily movement in distalization of the mandibular molars compared to when the orthodontic forces were applied at the level of the bracket. Applying orthodontic forces to the cemento-enamel junction also resulted in unwanted greater extrusive movements in distalization of the mandibular molars compared to the bracket level. CONCLUSIONS: With considering the mode of orthodontic teeth movement, applying different vertical orthodontic forces for distalization of mandibular molars can lead to more effective distalization of teeth. PMID- 28861391 TI - Time series analysis of patients seeking orthodontic treatment at Seoul National University Dental Hospital over the past decade. AB - OBJECTIVE: This paper describes changes in the characteristics of patients seeking orthodontic treatment over the past decade and the treatment they received, to identify any seasonal variations or trends. METHODS: This single center retrospective cohort study included all patients who presented to Seoul National University Dental Hospital for orthodontic diagnosis and treatment between January 1, 2005 and December 31, 2015. The study analyzed a set of heterogeneous variables grouped into the following categories: demographic (age, gender, and address), clinical (Angle Classification, anomaly, mode of orthodontic treatment, removable appliances for Phase 1 treatment, fixed appliances for Phase 2 treatment, orthognathic surgery, extraction, mini-plate, mini-implant, and patient transfer) and time-related variables (date of first visit and orthodontic treatment time). Time series analysis was applied to each variable. RESULTS: The sample included 14,510 patients with a median age of 19.5 years. The number of patients and their ages demonstrated a clear seasonal variation, which peaked in the summer and winter. Increasing trends were observed for the proportion of male patients, use of non-extraction treatment modality, use of ceramic brackets, patients from provinces outside the Seoul region at large, patients transferred from private practitioners, and patients who underwent orthognathic surgery performed by university surgeons. Decreasing trends included the use of metal brackets and orthodontic treatment time. CONCLUSIONS: Time series analysis revealed a seasonal variation in some characteristics, and several variables showed changing trends over the past decade. PMID- 28861392 TI - The effect of fluoride-containing oral rinses on the corrosion resistance of titanium alloy (Ti-6Al-4V). AB - OBJECTIVE: The purpose of this study was to examine the effect of commercially available fluoride-containing oral rinses on the corrosion behavior of titanium alloys, which are the main components of orthodontic miniscrews. METHODS: Four commercially available oral rinses (solution A, pH 4.46/260 ppm fluoride; solution B, pH 4.41/178 ppm fluoride; solution C, pH 6.30/117 ppm fluoride; and solution D, pH 4.17/3.92 ppm fluoride) were tested on titanium alloy (Ti-6Al-4V) circular plates, and saline was used as the control. The open-circuit potential and potentiodynamic polarization of these materials were measured. Thereafter, all samples were evaluated under a field-emission scanning electron microscope. RESULTS: Among the tested oral rinses, except solution D, the more the fluoride content was, the greater was the corrosion potential downtrend; the corrosion resistance of the titanium alloy sample was also lowered significantly (p < 0.05). Field-emission scanning electron microscopic analysis of the surface morphology of the titanium alloy samples revealed that all samples had some defects, crevices, or pitting after exposure to the oral rinses than before treatment. In particular, the samples in solution A showed the most changes. CONCLUSIONS: Commercially available oral rinses having a high fluoride concentration and a low pH may reduce the corrosion resistance of titanium alloys used in dental appliances such as orthodontic titanium miniscrews and brackets. PMID- 28861393 TI - Stability of dental, alveolar, and skeletal changes after miniscrew-assisted rapid palatal expansion. AB - OBJECTIVE: Miniscrew-assisted rapid palatal expansion (MARPE) is a means for expanding the basal bone without surgical intervention in young adults. Here, we assessed the differences in dental, alveolar, and skeletal measurements taken before (T0), immediately after (T1), and 1 year after (T2) MARPE. METHODS: Twenty four patients (mean age, 21.6 years) who had undergone MARPE and cone-beam computed tomography at T0, T1, and T2 were included. Changes in the following parameters were compared using paired t-tests: intercusp, interapex, alveolar, nasal floor, and nasal cavity widths; inclination of the first molar (M1) and its alveolus; and thickness and height of the alveolar bone. A linear mixed-effects model was used to determine variables that affected periodontal changes in the M1. RESULTS: MARPE produced significant increases in most measurements during T0 T2, despite relapse of some measurements during T1-T2. The alveolar thickness decreased on the buccal side, but increased on the palatal side. The alveolar crest level at the first premolar moved apically. Changes in the thickness and height of the alveolar bone were affected by the corresponding initial values. CONCLUSIONS: MARPE can be used as an effective tool for correcting maxillomandibular transverse discrepancy, showing stable outcomes 1 year after expansion. PMID- 28861394 TI - Long-term survival of retained deciduous mandibular second molars and maxillary canine incorporated into final occlusion. AB - Orthodontic treatment of a complex case that involves retained deciduous mandibular second molars with missing permanent successors is challenging. Usually, congenitally missing teeth are manifested with other dental anomalies that further complicate orthodontic treatment, such as retained deciduous teeth, impactions, transpositions and peg-shaped lateral incisors. Even though the long term prognosis of the retained deciduous tooth is not fully predictable, if the teeth are in good condition, the patient and clinician may incline towards a decision to preserve the deciduous teeth as long as possible. This case report demonstrates that deciduous teeth, in this case the mandibular second molars and maxillary canine, can be incorporated into final occlusion with clinically stable long-term results. PMID- 28861395 TI - Teeth discoloration during orthodontic treatment. AB - OBJECTIVE: Teeth discoloration is a rare orthodontic complication. The aim of this study was to report the clinical progression of discoloration during orthodontic treatment. METHODS: Discolored teeth, detected during orthodontic treatment between January 2003 and December 2012 by a single dentist using similar techniques and appliances, were analyzed. RESULTS: The total number of teeth that showed discoloration was 28. Progression of discoloration was evaluated in only 24 teeth that were observed without any treatment. During the observation period, the discoloration "improved" in 8 of the 24 teeth (33.3%) and was "maintained" in 16 (66.6%). The electric pulp test performed at the time of initial detection of discoloration showed 14.3% positivity, which improved to 21.4% at the final follow-up. None of the initial and final follow-up radiographic findings showed any abnormalities. CONCLUSIONS: When teeth discoloration is detected during orthodontic treatment, observation as an initial management is recommended over immediate treatments. PMID- 28861396 TI - The Role of OmpR in the Expression of Genes of the KdgR Regulon Involved in the Uptake and Depolymerization of Oligogalacturonides in Yersinia enterocolitica. AB - Oligogalacturonide (OGA)-specific porins of the KdgM family have previously been identified and characterized in enterobacterial plant pathogens. We found that deletion of the gene encoding response regulator OmpR causes the porin KdgM2 to become one of the most abundant proteins in the outer membrane of the human enteropathogen Yersinia enterocolitica. Reporter gene fusion and real-time PCR analysis confirmed that the expression of kdgM2 is repressed by OmpR. We also found that kdgM2 expression is subject to negative regulation by KdgR, a specific repressor of genes involved in the uptake and metabolism of pectin derivatives in plant pathogens. The additive effect of kdgR and ompR mutations suggested that KdgR and OmpR regulate kdgM2 expression independently. We confirmed that kdgM2 occurs in an operon with the pelP gene, encoding the periplasmic pectate lyase PelP. A pectinolytic assay showed strong upregulation of PelP production/activity in a Y. enterocolitica strain lacking OmpR and KdgR, which corroborates the repression exerted by these regulators on kdgM2. In addition, our data showed that OmpR is responsible for up regulation of the kdgM1 gene encoding the second specific oligogalacturonide porin KdgM1. This indicates the involvement of OmpR in the reciprocal regulation of both KdgM1 and KdgM2. Moreover, we demonstrated the negative impact of OmpR on kdgR transcription, which might positively affect the expression of genes of the KdgR regulon. Binding of OmpR to the promoter regions of the kdgM2-pelP-sghX operon, and kdgM1 and kdgR genes was confirmed using the electrophoretic mobility shift assay, suggesting that OmpR can directly regulate their transcription. We also found that the overexpression of porin KdgM2 increases outer membrane permeability. Thus, OmpR-mediated regulation of the KdgM porins may contribute to the fitness of Y. enterocolitica in particular local environments. PMID- 28861398 TI - Extensive Metabolic Remodeling Differentiates Non-pathogenic and Pathogenic Growth Forms of the Dimorphic Pathogen Talaromyces marneffei. AB - Fungal infections are an increasing public health problem, particularly in immunocompromised individuals. While these pathogenic fungi show polyphyletic origins with closely related non-pathogenic species, many undergo morphological transitions to produce pathogenic cell types that are associated with increased virulence. However, the characteristics of these pathogenic cells that contribute to virulence are poorly defined. Talaromyces marneffei grows as a non-pathogenic hyphal form at 25 degrees C but undergoes a dimorphic transition to a pathogenic yeast form at 37 degrees C in vitro and following inhalation of asexual conidia by a host. Here we show that this transition is associated with major changes in central carbon metabolism, and that these changes are correlated with increased virulence of the yeast form. Comprehensive metabolite profiling and 13C-labeling studies showed that hyphal cells exhibited very active glycolytic metabolism and contain low levels of internal carbohydrate reserves. In contrast, yeast cells fully catabolized glucose in the mitochondrial TCA cycle, and store excess glucose in large intracellular pools of trehalose and mannitol. Inhibition of the yeast TCA cycle inhibited replication in culture and in host cells. Yeast, but not hyphae, were also able to use myo-inositol and amino acids as secondary carbon sources, which may support their survival in host macrophages. These analyses suggest that T. marneffei yeast cells exhibit a more efficient oxidative metabolism and are capable of utilizing a diverse range of carbon sources, which contributes to their virulence in animal tissues, highlighting the importance of dimorphic switching in pathogenic yeast. PMID- 28861399 TI - Overexpression of Adenylyl Cyclase Encoded by the Mycobacterium tuberculosis Rv2212 Gene Confers Improved Fitness, Accelerated Recovery from Dormancy and Enhanced Virulence in Mice. AB - Earlier we demonstrated that the adenylyl cyclase (AC) encoded by the MSMEG_4279 gene plays a key role in the resuscitation and growth of dormant Mycobacterium smegmatis and that overexpression of this gene leads to an increase in intracellular cAMP concentration and prevents the transition of M. smegmatis from active growth to dormancy in an extended stationary phase accompanied by medium acidification. We surmised that the homologous Rv2212 gene of M. tuberculosis (Mtb), the main cAMP producer, plays similar physiological roles by supporting, under these conditions, the active state and reactivation of dormant bacteria. To test this hypothesis, we established Mtb strain overexpressing Rv2212 and compared its in vitro and in vivo growth characteristics with a control strain. In vitro, the AC-overexpressing pMindRv2212 strain demonstrated faster growth in a liquid medium, prolonged capacity to form CFUs and a significant delay or even prevention of transition toward dormancy. AC-overexpressing cells exhibited easier recovery from dormancy. In vivo, AC-overexpressing bacteria demonstrated significantly higher growth rates (virulence) in the lungs and spleens of infected mice compared to the control strain, and, unlike the latter, killed mice in the TB-resistant strain before month 8 of infection. Even in the absence of selecting hygromycin B, all pMindRv2212 CFUs retained the Rv2212 insert during in vivo growth, strongly suggesting that AC overexpression is beneficial for bacteria. Taken together, our results indicate that cAMP supports the maintenance of Mtb cells vitality under unfavorable conditions in vitro and their virulence in vivo. PMID- 28861397 TI - Modulation of Host Immunity by Human Respiratory Syncytial Virus Virulence Factors: A Synergic Inhibition of Both Innate and Adaptive Immunity. AB - The Human Respiratory Syncytial Virus (hRSV) is a major cause of acute lower respiratory tract infections (ARTIs) and high rates of hospitalizations in children and in the elderly worldwide. Symptoms of hRSV infection include bronchiolitis and pneumonia. The lung pathology observed during hRSV infection is due in part to an exacerbated host immune response, characterized by immune cell infiltration to the lungs. HRSV is an enveloped virus, a member of the Pneumoviridae family, with a non-segmented genome and negative polarity-single RNA that contains 10 genes encoding for 11 proteins. These include the Fusion protein (F), the Glycoprotein (G), and the Small Hydrophobic (SH) protein, which are located on the virus surface. In addition, the Nucleoprotein (N), Phosphoprotein (P) large polymerase protein (L) part of the RNA-dependent RNA polymerase complex, the M2-1 protein as a transcription elongation factor, the M2 2 protein as a regulator of viral transcription and (M) protein all of which locate inside the virion. Apart from the structural proteins, the hRSV genome encodes for the non-structural 1 and 2 proteins (NS1 and NS2). HRSV has developed different strategies to evade the host immunity by means of the function of some of these proteins that work as virulence factors to improve the infection in the lung tissue. Also, hRSV NS-1 and NS-2 proteins have been shown to inhibit the activation of the type I interferon response. Furthermore, the hRSV nucleoprotein has been shown to inhibit the immunological synapsis between the dendritic cells and T cells during infection, resulting in an inefficient T cell activation. Here, we discuss the hRSV virulence factors and the host immunological features raised during infection with this virus. PMID- 28861400 TI - Entamoeba histolytica EhCP112 Dislocates and Degrades Claudin-1 and Claudin-2 at Tight Junctions of the Intestinal Epithelium. AB - During intestinal invasion, Entamoeba histolytica opens tight junctions (TJs) reflected by transepithelial electrical resistance (TEER) dropping. To explore the molecular mechanisms underlying this, we studied in vitro and in vivo the damage produced by the recombinant E. histolytica cysteine protease (rEhCP112) on TJ functions and proteins. rEhCP112 reduced TEER in Caco-2 cells in a dose- and time-dependent manner; and EhCP112-overexpressing trophozoites provoked major epithelial injury compared to control trophozoites. rEhCP112 penetrated through the intercellular space, and consequently the ion flux increased and the TJs fence function was disturbed. However, macromolecular flux was not altered. Functional in vitro assays revealed specific association of rEhCP112 with claudin 1 and claudin-2, that are both involved in regulating ion flux and fence function. Of note, rEhCP112 did not interact with occludin that is responsible for regulating macromolecular flux. Moreover, rEhCP112 degraded and delocalized claudin-1, thus affecting interepithelial adhesion. Concomitantly, expression of the leaky claudin-2 at TJ, first increased and then it was degraded. In vivo, rEhCP112 increased intestinal epithelial permeability in the mouse colon, likely due to apical erosion and claudin-1 and claudin-2 degradation. In conclusion, we provide evidence that EhCP112 causes epithelial dysfunction by specifically altering claudins at TJ. Thus, EhCP112 could be a potential target for therapeutic approaches against amoebiasis. PMID- 28861403 TI - Acotiamide hydrochloride hydrate added to combination treatment with an alpha blocker and a cholinergic drug improved the QOL of women with acute urinary retention: case series. AB - Acute urinary retention is the most common urological emergency. To resolve this emergency, urethral catheterization is performed. If the procedure fails and permanent transurethral catheterization is required, the patient's quality of life is significantly affected. Therefore, catheter-free treatment is the ideal goal of therapy for patients with acute urinary retention. Especially, for women, placement of a catheter poses a cosmetic problem. Therefore, the aim of this study was to treat female patients who had already received urapidil/distigmine bromide with acotiamide. Acotiamide was administered at a dose of 100 mg three times daily for 2 weeks, and the outcome of trial without catheter was evaluated. Only female patients were enrolled for this study. Treatment proved successful and all patients become catheter free. PMID- 28861401 TI - Micropathogen Community Analysis in Hyalomma rufipes via High-Throughput Sequencing of Small RNAs. AB - Ticks are important vectors in the transmission of a broad range of micropathogens to vertebrates, including humans. Because of the role of ticks in disease transmission, identifying and characterizing the micropathogen profiles of tick populations have become increasingly important. The objective of this study was to survey the micropathogens of Hyalomma rufipes ticks. Illumina HiSeq2000 technology was utilized to perform deep sequencing of small RNAs (sRNAs) extracted from field-collected H. rufipes ticks in Gansu Province, China. The resultant sRNA library data revealed that the surveyed tick populations produced reads that were homologous to St. Croix River Virus (SCRV) sequences. We also observed many reads that were homologous to microbial and/or pathogenic isolates, including bacteria, protozoa, and fungi. As part of this analysis, a phylogenetic tree was constructed to display the relationships among the homologous sequences that were identified. The study offered a unique opportunity to gain insight into the micropathogens of H. rufipes ticks. The effective control of arthropod vectors in the future will require knowledge of the micropathogen composition of vectors harboring infectious agents. Understanding the ecological factors that regulate vector propagation in association with the prevalence and persistence of micropathogen lineages is also imperative. These interactions may affect the evolution of micropathogen lineages, especially if the micropathogens rely on the vector or host for dispersal. The sRNA deep sequencing approach used in this analysis provides an intuitive method to survey micropathogen prevalence in ticks and other vector species. PMID- 28861402 TI - Ixodes scapularis Tick Cells Control Anaplasma phagocytophilum Infection by Increasing the Synthesis of Phosphoenolpyruvate from Tyrosine. AB - The obligate intracellular pathogen, Anaplasma phagocytophilum, is the causative agent of life-threatening diseases in humans and animals. A. phagocytophilum is an emerging tick-borne pathogen in the United States, Europe, Africa and Asia, with increasing numbers of infected people and animals every year. It is increasingly recognized that intracellular pathogens modify host cell metabolic pathways to increase infection and transmission in both vertebrate and invertebrate hosts. Recent reports have shown that amino acids are central to the host-pathogen metabolic interaction. In this study, a genome-wide search for components of amino acid metabolic pathways was performed in Ixodes scapularis, the main tick vector of A. phagocytophilum in the United States, for which the genome was recently published. The enzymes involved in the synthesis and degradation pathways of the twenty amino acids were identified. Then, the available transcriptomics and proteomics data was used to characterize the mRNA and protein levels of I. scapularis amino acid metabolic pathway components in response to A. phagocytophilum infection of tick tissues and ISE6 tick cells. Our analysis was focused on the interplay between carbohydrate and amino acid metabolism during A. phagocytophilum infection in ISE6 cells. The results showed that tick cells increase the synthesis of phosphoenolpyruvate (PEP) from tyrosine to control A. phagocytophilum infection. Metabolic pathway analysis suggested that this is achieved by (i) increasing the transcript and protein levels of mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), (ii) shunting tyrosine into the tricarboxylic acid (TCA) cycle to increase fumarate and oxaloacetate which will be converted into PEP by PEPCK-M, and (iii) blocking all the pathways that use PEP downstream gluconeogenesis (i.e., de novo serine synthesis pathway (SSP), glyceroneogenesis and gluconeogenesis). While sequestering host PEP may be critical for this bacterium because it cannot actively carry out glycolysis to produce PEP, excess of this metabolite may be toxic for A. phagocytophilum. The present work provides a more comprehensive view of the major amino acid metabolic pathways involved in the response to pathogen infection in ticks, and provides the basis for further studies to develop novel strategies for the control of granulocytic anaplasmosis. PMID- 28861404 TI - Effectiveness of percutaneous tibial nerve stimulation in the treatment of overactive bladder syndrome. AB - Overactive bladder syndrome (OAB) is a common condition affecting adults and children worldwide, resulting in a substantial economic and psychological burden. Percutaneous tibial nerve stimulation (PTNS) is derived from acupuncture used in Chinese traditional medicine and was first described in the early 1980s. It is a neuromodulation technique used to modulate bladder function and facilitate storage. Being a minimally invasive, easily applicable, but time-consuming treatment, future developments with implantable devices might be the solution for the logistical problems and economic burden associated with PTNS on the long term. This nonsystematic review provides a current overview on PTNS and its effectiveness in the treatment of OAB for both adults and children. PMID- 28861405 TI - Procedural techniques and multicenter postmarket experience using minimally invasive convective radiofrequency thermal therapy with Rezum system for treatment of lower urinary tract symptoms due to benign prostatic hyperplasia. AB - OBJECTIVE: This report evaluates clinical experience with the Rezum system after US Food and Drug Administration clearance in consecutive cases accrued by multiple community urologists for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Treatment techniques for transurethral convective radiofrequency water-vapor thermal therapy and outcomes with up to 12 months' follow-up are presented. MATERIALS AND METHODS: A total of 131 patients with moderate-severe LUTS were included in a retrospective analysis of BPH procedures with the Rezum system. Pre- and postprocedure assessments included International Prostate Symptom Score (IPSS), quality of life, peak urinary flow rate, voided volume, and postvoid residual urine volume. Urologists used their own discretion for patient selection, with variable prostate sizes, LUTS severity, urinary retention, or presence of an obstructing median lobe. Safety signals and surgical retreatment rates were monitored prospectively. RESULTS: Men aged 47-96 years with prostates 13-183 cm3 showed significant improvement in IPSS, quality of life, and postvoid residual volume durable through 12 months after thermal therapy. Patients with either moderate (IPSS 8-19) or severe (IPSS 20-35) symptoms achieved significantly improved scores. Postprocedure adverse events normally anticipated and related to endoscopic instrumentation were transient and mild-moderate in nature. No de novo erectile or ejaculatory dysfunction was reported. CONCLUSION: This study corroborates prior published pilot and randomized controlled trial results indicating significant relief of urinary symptoms and reproducibility of responses to thermal therapy. Convective radiofrequency thermal therapy with the Rezum system warrants consideration as a first-line treatment for LUTS/BPH as an alternative to the use of pharmaceutical agents. PMID- 28861406 TI - Erratum to: Usefulness and capability of three-dimensional, full high-definition movies for surgical education. AB - [This corrects the article DOI: 10.1186/s40902-017-0107-3.]. PMID- 28861408 TI - A Latent Markov Model with Covariates to Study Unobserved Heterogeneity among Fertility Patterns of Couples Employing Natural Family Planning Methods. AB - PURPOSE: We use the historical data from the European Study of Daily Fecundability and we develop an algorithm to determine the fertile window in a woman's cycle according to the rules of the C.A.Me.N. symptothermal method proposed by the Centro Ambrosiano Metodi Naturali. Our aim is to identify variables acting on the probability of conception by considering the fertile window and factors that cannot be explained by employing the observed covariates of individuals and couples. METHODS: We adopt the latent Markov model with covariates tailored for data collected at times when a latent process detects the dependence across fertile periods of each woman's cycle. We consider measurement errors, transitions between conception and non-conception, and the prediction of conception rate over the fertile windows. CONCLUSION: We find that the conception pattern is mainly related to sexual intercourse behavior during the fertile window and to previous pregnancies. For the cohort under study, we predict a steep decline in the average conception rate across fertile windows. PMID- 28861407 TI - Alterations in Cerebral Blood Flow after Resuscitation from Cardiac Arrest. AB - Greater than 50% of patients successfully resuscitated from cardiac arrest have evidence of neurological disability. Numerous studies in children and adults, as well as in animal models have demonstrated that cerebral blood flow (CBF) is impaired after cardiac arrest. Stages of cerebral perfusion post-resuscitation include early hyperemia, followed by hypoperfusion, and finally either resolution of normal blood flow or protracted hyperemia. At the level of the microcirculation the blood flow is heterogeneous, with areas of no flow, low flow, and increased flow. CBF directed therapies in animal models of cardiac arrest improved neurological outcome, and therefore, the alterations in CBF after cardiac arrest likely contribute to the development of hypoxic ischemic encephalopathy. Current intensive care after cardiac arrest is centered upon maintaining systemic oxygenation, normal blood pressure values for age, maintaining general homeostasis, and avoiding hyperthermia. Assessment of CBF and oxygenation is not routinely performed after cardiac arrest. Currently available and underutilized techniques to assess cerebral perfusion include transcranial doppler, near-infrared spectroscopy, and arterial spin labeling magnetic resonance imaging. Limited clinical studies established the role of CBF and oxygenation monitoring in prognostication after cardiac arrest and few studies suggest that guiding critical care post-resuscitation to mean arterial pressures above the minimal autoregulatory range might improve outcome. Important knowledge gaps thus remain in cerebral monitoring and CBF and oxygen goal-directed therapies post-resuscitation from cardiac arrest. PMID- 28861409 TI - Editorial: The Impact of School Food Consumption on Children's Cognition, Educational Attainment and Social Development. PMID- 28861410 TI - Psychosocial Hazard Analysis in a Heterogeneous Workforce: Determinants of Work Stress in Blue- and White-Collar Workers of the European Steel Industry. AB - The European steel industry's workforce is highly heterogeneous and consists of various occupational groups, presumably facing different psychosocial stressors. The few existing studies on the subject mainly focused on physical constraints of blue-collar workers, whereas the supposable psychosocial workload received only little research attention. This is remarkable considering the challenges associated with statutory required risk assessment of psychosocial hazards. Valid measures of hazard analysis must account for various stressors and reliably identify them, also between occupational groups. The present study, based on a sample of blue- and white-collar workers (N = 124) from the European steel industry, aims to provide a first insight into psychosocial stressors and strain at work in this rarely researched industrial sector. Furthermore, two well-known theoretical roadmaps in job analysis are examined regarding their utility for risk assessment in heterogeneous workforces: the German standard version of the Copenhagen Psychosocial Questionnaire (COPSOQ) and the short version of the effort-reward imbalance questionnaire. Hierarchical multiple regression analyses revealed that the COPSOQ was better suited to predict various strain indices in the present sample. Especially stressors relating to socioemotional aspects, such as work-privacy conflict, revealed a reasonable impact, indicating the need for comprehensive solutions at the organizational level instead of solutions focusing on single workplaces. To conclude, a broadly diversified and validated approach in psychosocial risk assessment is needed to adequately assess the variety of psychosocial factors at work and in different occupational groups. PMID- 28861411 TI - Reduction and Alkylation of Proteins in 2D Gel Electrophoresis: Before or after Isoelectric Focusing? PMID- 28861412 TI - Stable Production of the Antimalarial Drug Artemisinin in the Moss Physcomitrella patens. AB - Malaria is a real and constant danger to nearly half of the world's population of 7.4 billion people. In 2015, 212 million cases were reported along with 429,000 estimated deaths. The World Health Organization recommends artemisinin-based combinatorial therapies, and the artemisinin for this purpose is mainly isolated from the plant Artemisia annua. However, the plant supply of artemisinin is irregular, leading to fluctuation in prices. Here, we report the development of a simple, sustainable, and scalable production platform of artemisinin. The five genes involved in artemisinin biosynthesis were engineered into the moss Physcomitrella patens via direct in vivo assembly of multiple DNA fragments. In vivo biosynthesis of artemisinin was obtained without further modifications. A high initial production of 0.21 mg/g dry weight artemisinin was observed after only 3 days of cultivation. Our study shows that P. patens can be a sustainable and efficient production platform of artemisinin that without further modifications allow for industrial-scale production. A stable supply of artemisinin will lower the price of artemisinin-based treatments, hence become more affordable to the lower income communities most affected by malaria; an important step toward containment of this deadly disease threatening millions every year. PMID- 28861414 TI - Continuous Spinal Anesthesia for Obstetric Anesthesia and Analgesia. AB - The widespread use of continuous spinal anesthesia (CSA) in obstetrics has been slow because of the high risk for post-dural puncture headache (PDPH) associated with epidural needles and catheters. New advances in equipment and technique have not significantly overcome this disadvantage. However, CSA offers an alternative to epidural anesthesia in morbidly obese women, women with severe cardiac disease, and patients with prior spinal surgery. It should be strongly considered in parturients who receive an accidental dural puncture with a large bore needle, on the basis of recent work suggesting significant reduction in PDPH when intrathecal catheters are used. Small doses of drug can be administered and extension of labor analgesia for emergency cesarean delivery may occur more rapidly compared to continuous epidural techniques. PMID- 28861413 TI - Paying the Toll in Nuclear Reprogramming. AB - The ability to reverse lineage-committed cells toward pluripotent stem cells or to another cell type is one of the ultimate goals in regenerative medicine. We recently discovered that activation of innate immunity, through Toll-like receptor 3, is required during this conversion of cell fate by causing global changes in the expression and activity of epigenetic modifiers. Here we discuss, in a comprehensive manner, the recent studies on the role of innate immunity in nuclear reprogramming and transdifferentiation, the underlying mechanisms, and its role in regenerative medicine. PMID- 28861415 TI - More Haste, Less Speed: Could Public-Private Partnerships Advance Cellular Immunotherapies? AB - Cellular immunotherapies promise to transform cancer care. However, they must overcome serious challenges, including: (1) the need to identify and characterize novel cancer antigens to expand the range of therapeutic targets; (2) the need to develop strategies to minimize serious adverse events, such as cytokine release syndrome and treatment-related toxicities; and (3) the need to develop efficient production/manufacturing processes to reduce costs. Here, we discuss whether these challenges might better be addressed through forms of public-private research collaborations, including public-private partnerships (PPPs), or whether these challenges are best addressed by way of standard market transactions. We reviewed 14 public-private relationships and 25 underlying agreements for the clinical development of cancer cellular immunotherapies in the US. Most were based on bilateral research agreements and pure market transactions in the form of service contracts and technology licenses, which is representative of the commercialization focus of the field. We make the strategic case that multiparty PPPs may better advance cancer antigen discovery and characterization and improved cell processing/manufacturing and related activities. In the rush toward the competitive end of the translational continuum for cancer cellular immunotherapy and the attendant focus on commercialization, many gaps have appeared in our understanding of cellular biology, immunology, and bioengineering. We conclude that the model of bilateral agreements between leading research institutions and the private sector may be inadequate to efficiently harness the interdisciplinary skills and knowledge of the public and private sectors to bring these promising therapies to the clinic for the benefit of cancer patients. PMID- 28861416 TI - Etiology of intracranial stenosis in young patients: a high-resolution magnetic resonance imaging study. AB - BACKGROUND: Using high-resolution magnetic resonance imaging (HRMRI), we sought to investigate the underlying etiology of intracranial stenosis in young patients. METHODS: We retrospectively studied 122 Chinese young adult patients (from 18 to 45 years old, mean age 36.2+/-7.5 years) with unilateral middle cerebral artery (MCA) stenosis based on a prospectively established HRMRI database. The eccentricity, degree of stenosis, and remodeling types of MCA lesions were analyzed. The MCA lesions were classified as eccentric (presumed atherosclerosis) or concentric stenosis (presumed non-atherosclerosis). The clinical data and vessel wall properties were compared between the patients >35 years old and the patients <=35 years old. RESULTS: Eccentric stenosis was observed in 98 (80.3%) patients and concentric stenosis in 24 (19.7%) patients. The patients with eccentric stenosis were older (37.5+/-6.8 vs. 31.4+/-8.4 years old, P<0.001) and more likely had atherosclerosis risk factors (56.1% vs. 25.0%, P=0.006). The patients >35 years old had higher prevalence (90.1% vs. 66.7%, P=0.001) of eccentric stenosis and atherosclerosis factors (60.6% vs. 35.3%, P=0.006) than the patients <=35 years old. Most of the patients with concentric stenosis were <=35 years old (17/24, 70.8%) and were female (16/24, 66.7%). Binary Logistic analysis suggested smoking (OR =3.171; 95% CI, 1.210-8.314) and remodeling ratio (OR =1.625; 95% CI, 1.001-2.636) were independent predictive factors for symptomatic stenosis. CONCLUSIONS: Atherosclerosis is the most common cause of intracranial stenosis in Chinese young patients. Non-atherosclerosis disease is an important etiology in young female, especially in the patients aged 35 years old or younger. PMID- 28861417 TI - Impact of diverticular inflammation and complication assessment classification on the burden of medical therapies in preventing diverticular disease complications in Italy. AB - BACKGROUND: Several treatments are currently advised to manage diverticular disease (DD) patients, but their impact on the burden of the disease is unknown. Our aim was to assess the economic analysis of using the recent Diverticular Inflammation and Complication Assessment (DICA) endoscopic classification on the burden of medical therapies prescribed in preventing DD complications occurrence in Italy. METHODS: We assessed retrospectively the cost/year of treatments in estimated DICA 1, DICA 2 and DICA 3 population. Analysis of diverticulosis prevalence was estimated according to data population provided by Italian Institute of Statistics (ISTAT). Cost of treatments calculated according to data on drugs' consumption collected during the DICA study. RESULTS: We estimated that >8 million of Italian people >60 years may have diverticulosis, and that about 75% of diverticular population are on DICA 1, about 30% on DICA 2, and about 13% on DICA 3. We estimated that >387 million of euros could be spent in DICA 1 population, >203 million of euros in DICA 2 population, and >88 million of euros in DICA 3 population. Since medical treatments did not show any significant advantage when treating DICA 1 and DICA 3 people in terms of prevention of acute diverticulitis occurrence/recurrence and surgery occurrence, we can estimated that >475 million of euros could be spent in Italy without any significant benefit in preventing DD complications occurrence. CONCLUSIONS: DICA endoscopic classification may have a significant impact on the burden of DD in Italy, because it helps to select DD people who effectively need treatments in terms of prevention of acute diverticulitis occurrence/recurrence and surgery occurrence. PMID- 28861418 TI - Incidence of postoperative delirium in patients undergoing total knee arthroplasty-an Asian perspective. AB - BACKGROUND: Very little is known in the literature with regards to the incidence of postoperative delirium following total knee arthroplasty (TKA) in Asians and the associated surgical factors. We conducted a retrospective study on incidence of postoperative delirium following TKA in Asians. METHODS: One thousand sixteen knees of 954 consecutive patients who underwent TKA by the senior author of this study in the year 2006 were included in this review. All written and electronic medical records for patients were screened. Delirium was recorded to be present based on clinical entry onto the patients' inpatient hospital notes and a diagnosis made by psychiatrist based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). All statistical analysis was performed using SPSS v.18.0 (IBM Corp., Armonk, NY, USA). RESULTS: The incidence of postoperative delirium in our patients undergoing TKA was 0.59%. Six patients had a confirmed diagnosis of delirium postoperatively. We noted an association between a higher mean age (P<0.0001), a lower body mass index (P<0.0001), Chinese ethnicity (P=0.002), male gender (P=0.002) and chronic opioid use (P<0.0001) with incidence of post-operative delirium. We also noted a higher proportion of post operative DVT (P<0.0001) and wound infection (P<0.0001) in the delirium group. CONCLUSIONS: The incidence of postoperative delirium in Asians undergoing TKA in our institution is very low at 0.59%. Advanced age, lower body mass index, Chinese ethnicity, male gender and preoperative chronic opioid use may be associated with developing postoperative delirium. PMID- 28861419 TI - Direct oral anticoagulants: analysis of worldwide use and popularity using Google Trends. AB - BACKGROUND: Four direct oral anticoagulants (DOACs) have been approved for clinical use by many medicines regulatory agencies around the world. Due to increasing use of these drugs in routine practice, we planned an original study to investigate their worldwide diffusion using a popular Web-search engine. METHODS: Two electronic searches were performed using Google Trends, the former using the keywords "warfarin" AND "heparin" AND "fondaparinux", and the latter using the keywords "warfarin" AND "dabigatran" AND "rivaroxaban" AND "apixaban" AND "edoxaban", both using the search criterion "prescription drug". No language restriction was applied, and the searches were carried out from the first date available in Google Trends (January 1st, 2004) to present time (June 1st, 2017). RESULTS: The median Google Trends score of warfarin (i.e., 86) was consistently higher than that of heparin (54; P<0.001), fondaparinux (6; P<0.001), dabigatran (11; P<0.001), rivaroxaban (5; P<0.001), apixaban (1; P<0.001) and edoxaban (1; P<0.001). Specific analysis of the trends shows that the score of warfarin exhibits a highly significant decrease over time (r=-0.40; P<0.001), whilst that of heparin has remained virtually unchanged (r=0.12; P=0.127), and that of fondaparinux has marginally increased (r=0.16; P=0.038). As regards DOACs, the scores of these drugs significantly increased during the search period (dabigatran, r=0.79; rivaroxaban, r=0.99; apixaban, r=0.98; edoxaban, r=0.78; all P<0.001). When the analysis was limited to the past five years, the dabigatran score significantly decreased (r=-0.57; P<0.001), whereas that of the other DOACs exhibited an even sharper increase. Most Google searches for DOACs were performed in North America, central-eastern Europe and Australia. CONCLUSIONS: The results of our analysis suggest that the popularity of DOACs is constantly increasing around the world, whereas that of warfarin has exhibited a constant and inexorable decline. PMID- 28861420 TI - Balanced versus isotonic saline resuscitation-a systematic review and meta analysis of randomized controlled trials in operation rooms and intensive care units. AB - BACKGROUND: Fluid resuscitation is the cornerstone in treatment of shock, and intravenous fluid administration is the most frequent intervention in operation rooms and intensive care units (ICUs). The composition of fluids used for fluid resuscitation gained interest over the past decade, with recent focus on whether balanced solutions should be preferred over isotonic saline. METHODS: Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing fluid resuscitation with a balanced solution versus isotonic saline in adult patients in operation room or ICUs. Primary outcome was in-hospital mortality, secondary outcomes included occurrence of acute kidney injury (AKI) and need for renal replacement therapy (RRT). RESULTS: The search identified 11 RCTs involving 2,703 patients; 8 trials were conducted in operation room and 3 in ICU. In-hospital mortality, as well as the occurrence of AKI and need for RRT was not different between resuscitation with balanced solutions versus isotonic saline, neither in operation room nor in ICU patients. Serum chloride levels, but not arterial pH, were significantly lower in patients resuscitated with balanced solutions. CONCLUSIONS: Currently evidence insufficiently supports the use of balanced over isotonic saline for fluid resuscitation to improve outcome of operation room and ICU patients. PMID- 28861421 TI - The role of reactive oxygen species in myocardial redox signaling and regulation. AB - Reactive oxygen species (ROS) are subcellular messengers in gene regulatory and signal transduction pathways. In pathological situations, ROS accumulate due to excessive production or insufficient degradation, leading to oxidative stress (OS). OS causes oxidation of DNA, membranes, cellular lipids, and proteins, impairing their normal function and leading ultimately to cell death. OS in the heart is increased in response to ischemia/reperfusion, hypertrophy, and heart failure. The concentration of ROS is determined by their rates of production and clearance by antioxidants. Increases in OS in heart failure are primarily a result of the functional uncoupling of the respiratory chain due to inactivation of complex I. However, increased ROS in the failing myocardium may also be caused by impaired antioxidant capacity, such as decreased activity of Cu/Zn superoxide dismutase (SOD) and catalase (CAT) or stimulation of enzymatic sources, including, cyclooxygenase, xanthine oxidase (XO), nitric oxide synthase, and nonphagocytic NAD(P)H oxidases (Noxs). Mitochondria are the main source of ROS during heart failure and aging. Increased production of ROS in the failing heart leads to mitochondrial permeability transition, which results in matrix swelling, outer membrane rupture, a release of apoptotic signaling molecules, and irreversible injury to the mitochondria. Alterations of "redox homeostasis" leads to major cellular consequences, and cellular survival requires an optimal regulation of the redox balance. PMID- 28861422 TI - Is "symmetric" gap balancing still the gold standard in primary total knee arthroplasty? AB - A rectangular and symmetrical gap in flexion as well as in extension is mandatory to achieve good outcomes and good long-term results in total knee arthroplasty (TKA) using classical designs. Recently, as showed in several fluoroscopic studies, different modern designs (medial congruent or sagittally stable implants) have been demonstrated to better reproduce the more physiological medial pivoting (MP) biomechanics of the normal knee when compared to classical postero-stabilized (PS) and cruciate-retaining (CR) designs. These modern designs, characterized by different level of conformity, might require adopting a different surgical technique in terms of soft tissue balancing technique for primary TKA. In such cases, the current authors suggest to reproduce a slightly asymmetric extension and flexion gaps with a tighter medial then lateral compartment to re-establish the MP kinematics of the normal knee. PMID- 28861424 TI - Cystic adventitial disease-case series and review of literature. AB - Cystic adventitial disease (CAD) is a rare vascular disorder that involves the arteries and rarely the veins, most commonly found in the popliteal artery of male patients. Etiology of CAD is uncertain and currently without a consensus agreement. Clinically, the most common presenting symptom is claudication. Diagnosis requires a strong clinical suspicion in patients with intermittent claudication, but without other risk factors for atherosclerotic disease. Angiography, ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) can all be used for diagnosis. Treatment of CAD can be done via surgical resection or percutaneous intervention such as aspiration. CAD can rarely recur after treatment. PMID- 28861423 TI - The role of reactive oxygen species in the pathophysiology of cardiovascular diseases and the clinical significance of myocardial redox. AB - Acute and chronic excessive intracellular increase of reactive oxygen species (ROS) is involved in the development and progression of cardiovascular diseases. ROS are by-products of various oxidative physiological and biochemical processes. Sources of ROS are mitochondrial respiration, NADH/NADPH oxidase, xanthine oxidoreductase or the uncoupling of nitric oxide synthase (NOS) in vascular cells. ROS mediate various signaling pathways that underlie cardiovascular pathophysiology. The delicate equilibrium between free-radical generation and antioxidant defense is altered in favor of the former, thus leading to redox imbalance, oxidative stress, and increased cellular injury. An understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of cardiovascular diseases. PMID- 28861425 TI - Single-incision video-assisted thoracoscopic evaluation and emergent surgery for severe lung and chest wall injury after thoracic trauma in a water park. AB - Thoracic trauma is a challenging situation with potential severe chest wall and intrathoracic organ injuries. We present a case of emergent surgery in a 23-year old man with hemorrhagic shock due to massive lung and chest wall injury after thoracic trauma in a water slide. We performed a SI-VATS approach in order to define intrathoracic and chest wall injuries, and once checked the extension of the chest wall injury, we added a middle size thoracotomy just over the affected area in order to stabilize rib fractures with Judet plates, that had caused massive laceration in left lower lobe (LLL) and injured the pericardium causing myocardical tear. After checking bronchial and vascular viability of LLL we suggested a lung parenchyma preserving technique with PTFE protected pulmonary primary suture in order to avoid a lobectomy. Chest tubes were removed on 3rd postoperative day and patient was discharged on 14th postoperative day. He has already recovered his normal activity 6 months after surgery. PMID- 28861426 TI - The gender paradox in TAVR. PMID- 28861427 TI - Sex differences in outcomes with transcatheter aortic valve replacement. PMID- 28861428 TI - Ethical challenges and terminal deactivation of left ventricular assist device. PMID- 28861429 TI - Favorable outcomes for female patients undergoing transcatheter aortic valve replacement? PMID- 28861430 TI - Evolving treatment options for valve and aortic disease with bicuspid aortic valve. PMID- 28861431 TI - Another passenger for the TAVR speeding train. PMID- 28861432 TI - CBT-I and the short sleep duration insomnia phenotype: a comment on Bathgate, Edinger and Krystal. PMID- 28861433 TI - Is it time to get some SHUT-i? PMID- 28861434 TI - Exosomes may play a crucial role in HIV dendritic cell immunotherapy. PMID- 28861435 TI - Markers of increased risk in primary mitral regurgitation. PMID- 28861436 TI - Low levels of interleukin-10 in patients with transfusion-related acute lung injury. PMID- 28861438 TI - Crystallographic anomalous diffraction data for the experimental phasing of two myelin proteins, gliomedin and periaxin. AB - We present datasets that can be used for the experimental phasing of crystal structures of two myelin proteins. The structures were recently described in the articles "Periaxin and AHNAK nucleoprotein 2 form intertwined homodimers through domain swapping" (H. Han, P. Kursula, 2014) [1] and "The olfactomedin domain from gliomedin is a beta-propeller with unique structural properties" (H. Han, P. Kursula, 2015) [2]. Crystals of periaxin were derivatized with tungsten and xenon prior to data collection, and diffraction data for these crystals are reported at 3 and 1 wavelengths, respectively. Crystallographic data for two different pressurizing times for xenon are provided. Gliomedin was derivatized with platinum, and data for single-wavelength anomalous dispersion are included. The data can be used to repeat the phasing experiments, to analyze heavy atom binding sites in proteins, as well as to optimize future derivatization experiments of protein crystals with these and other heavy-atom compounds. PMID- 28861437 TI - Saccular Kommerell aneurysm, a potential pitfall on MDCT imaging - A review of imaging features and potential mimics. AB - Saccular Kommerell aneurysm represents a potential pitfall on Multidetector CT (MDCT) imaging, mimicking conditions such as saccular aneurysm of the thoracic aorta, ductus diverticulum and dilated Kommerell diverticulum. Accurate diagnosis of this condition is critical in the management of this potentially fatal condition. This paper reviews the MDCT imaging features of Kommerell aneurysms and its mimics and demonstrates how to make an accurate diagnosis through a series of four cases. MDCT features of Kommerell aneurysms, either saccular or fusiform types arising from a Kommerell diverticulum with atherosclerotic plaque and mural thrombus are discussed. PMID- 28861439 TI - Data on the power of the creatinine to uromodulin ratio in serum to predict cardiovascular events in coronary patients. AB - Uromodulin is a protein which is produced by the tubular cells of the thick ascending limb in the kidneys and the creatinine to uromodulin ratio in serum recently has attracted interest as a marker of kidney disease. Whether this ratio also is associated with cardiovascular event risk is unknown. This article provides additional data on the association of the creatinine to uromodulin ratio with its power to predict cardiovascular events and major cardiovascular events in coronary patients. In addition, this data article demonstrates the performance of the creatinine to uromodulin ratio as a biomarker using c-statistics. Analyzed data was derived from 529 coronary patients. Uromodulin and creatinine were measured and cardiovascular events were recorded for up to 8 years. This data article is related to a research article titled "Serum Uromodulin is a predictive biomarker for cardiovascular events and overall mortality in coronary patients" [1]. PMID- 28861440 TI - Description of long-term climate data in Eastern and Southeastern Ethiopia. AB - This article presents long-term analyzed climate data from nine weather stations in eastern and southeastern parts of Ethiopia. At the outset of this data process, unrefined meteorological data was obtained from National Meteorological Agency (NMA) of Ethiopia for the analysis. The analyzed data in this article shows patterns of rainfall variability, frequency of drought years, seasonal concentration of precipitation and temperature conditions. As issues related to climate conditions are very intricate, different techniques and indices were applied to analyze and refine the data. The analysis reveals that eastern and southeastern parts Ethiopia are severely affected by recurrent droughts, erratic rainfall, and high and increasing temperature conditions. The long-term (1981 2009) mean annual total rainfall had been fluctuating between about 850 mm and 1350 mm. Most stations receive maximum rainfall in summer (June, July and August) except Gode which gets over 50% of its rainfall in spring season (March, April and May). The inter-annual rainfall difference was found to be very high. The Precipitation Concentration Index (PCI) is greater than 11 for all the stations showing that rainfall is concentrated in a few months. PCI is extremely high (greater than 20) for very dry stations such as Gode. Food production and consumer price index were found to be fluctuating with rainfall patters. PMID- 28861441 TI - Statistical analyses on Si microwire solar cells. AB - In this data, the statistical analyses of silicon microwire (SiMW) solar cells are presented for the research article entitled "Electrical and optical properties of Si microwire solar cells" (H.-S. Kim, D. B. Patel, H. Kim, M. Patel, K. R. Chauhan, W. Park, and J. Kim) [1]. This article shows the statistical analyses on performances of the various SiMW solar cells. The accuracy of solar cell parameters is discussed on the basis of data sets. PMID- 28861442 TI - Development of Au nanowire injector system to deliver plasmid into mouse embryo. AB - In this data article, we developed a Au nanowire injector (Au NWI) for directly delivering plasmid into the 1-cell stage of the mouse embryos designed to successfully attach and detach the plasmid on the Au NWI, highly minimizing physical and chemical damage on the embryos. This data presents that a Au NWI system does not induce detrimental damages on development of embryos and efficiently express the green fluorescence protein in vitro. The data provided herein is in association with the research article related to reduce the occurrence of mosaicism by a Au NWI," Suppressing Mosaicism by Au Nanowire Injector-driven Direct Delivery of Plasmids into Mouse Embryos" (Park et al., 2017 [1]). PMID- 28861443 TI - Biochemical characteristics of a free cyanide and total nitrogen assimilating Fusarium oxysporum EKT01/02 isolate from cyanide contaminated soil. AB - Sustainability of nutrient requirements for microbial proliferation on a large scale is a challenge in bioremediation processes. This article presents data on biochemical properties of a free cyanide resistant and total nitrogen assimilating fungal isolate from the rhizosphere of Zeamays (maize) growing in soil contaminated with a cyanide-based pesticide. DNA extracted from this isolate were PCR amplified using universal primers; TEF1-alpha and ITS. The raw sequence files are available on the NCBI database. Characterisation using biochemical data was obtained using colorimetric reagents analysed with VITEK(r) 2 software version 7.01. The data will be informative in selection of biocatalyst for environmental engineering application. PMID- 28861444 TI - Estimates of average energy requirements in Bangladesh: Adult Male Equivalent values for use in analyzing household consumption and expenditure surveys. AB - This dataset contains Adult Male Equivalent (AME) values for use in Bangladesh. These were constructed using prescriptive nutritional constructs adapted to the actual growth and weight pattern seen in Bangladesh. This dataset provides a common base to facilitate for future work with household consumption and expenditure data in Bangladesh while updating the average energy requirements for infants and young children for the WHO 2006 growth standards and 2007 growth reference curves. PMID- 28861445 TI - Data regarding the growth of Lactobacillus acidophilus NCFM on different carbohydrates and recombinant production of elongation factor G and pyruvate kinase. AB - The present study describes the growth of the very well-known probiotic bacterium Lactobacillus acidophilus NCFM on different carbohydrates. Furthermore, recombinant production of putative moonlighting proteins elongation factor G and pyruvate kinase from this bacterium is described. For further and detailed interpretation of the data presented here, please see the research article "Mucin and carbohydrate-stimulated adhesion and subproteome changes of the probiotic bacterium Lactobacillus acidophilus NCFM" (Celebioglu et al., 2017) [1]. PMID- 28861447 TI - Input data for mathematical modeling and numerical simulation of switched reluctance machines. AB - The modeling and simulation of Switched Reluctance (SR) machine and drives is challenging for its dual pole salient structure and magnetic saturation. This paper presents the input data in form of experimentally obtained magnetization characteristics. This data was used for computer simulation based model of SR machine, "Selecting Best Interpolation Technique for Simulation Modeling of Switched Reluctance Machine" [1], "Modeling of Static Characteristics of Switched Reluctance Motor" [2]. This data is primary source of other data tables of co energy and static torque which are also among the required data essential for the simulation and can be derived from this data. The procedure and experimental setup for collection of the data is presented in detail. PMID- 28861446 TI - Raw data of the effects of Chlorogenic acid in 3-Nitropropionic acid induced toxicity and genotoxicity. AB - The raw data showed in this article comes from the published research article entitled "Protective effects of Chlorogenic acid in 3-Nitropropionic acid induced toxicity and genotoxicity" Food Chem Toxicol. 2017 May 3. pii: S0278 6915(17)30226-0. DOI:10.1016/j.fct.2017.04.048. [1]. Data illustrates antitoxic and antigenotoxic effects of Chlorogenic acid (CGA) on toxicity and genotoxicity produced by the in vivo treatment with mitochondria toxin 3-Nitropropionic acid (3-NP) in mice. Toxicity and genotoxicity was evaluated in erythrocytes of peripheral blood through the micronuclei assay. Data was share at the Elsevier repository under the reference number FCT9033. PMID- 28861448 TI - Modeling and performance analysis dataset of a CIGS solar cell with ZnS buffer layer. AB - This article represents the baseline data of the several semiconductor materials used in the model of a CIGS thin film solar cell with an inclusion of ZnS buffer layer. As well, input parameters, contact layer data and operating conditions for CIGS solar cell simulation with ZnS buffer layer have been described. The schematic diagram of photovoltaic solar cell has been depicted. Moreover, the most important performance measurement graph, J-V characteristic curve, resulting from CIGS solar cell simulation has been analyzed to estimate the optimum values of fill factor and cell efficiency. These optimum results have been obtained from the open circuit voltage, short circuit current density, and the maximum points of voltage and current density generated from the cell. PMID- 28861449 TI - Data of added-value lipid production, Arachidonic acid, among other lipids by Mortierella elongata, using low cost simulated wastewater. AB - This article presented an innovative data of feasibility to produce Arachidonic acid (ARA), as added-value Polyunsaturated Fatty Acids (PUFA), among other lipids from Mortierella elongata, using simulated low cost sugarcane wastewater, vinasse, as a carbon source. Data from lipids quantification by total lipids extraction and by lipid classes was presented. M. elongata was able to produce 156.45mg of ARA per g of total lipids. PMID- 28861450 TI - Data describing IFNgamma-mediated viral clearance in an adult mouse model of respiratory syncytial virus (RSV). AB - The data presented here are related to the research article entitled "Age predicts cytokine kinetics and innate immune cell activation following intranasal delivery of IFNgamma and GM-CSF in a mouse model of RSV infection" (Eichinger et al., 2017) [1]. The cited manuscript demonstrated that the macrophage-stimulating cytokine, interferon gamma (IFNgamma), but not granulocyte macrophage-colony stimulating factor (GM-CSF), effectively enhanced viral clearance in infant mice infected with respiratory syncytial virus (RSV) following intranasal delivery. This article describes the immune response and viral clearing effects of intranasal IFNgamma in RSV-infected adult BALB/c mice demonstrating delayed production of endogenous IFNgamma. The dataset is made publicly available to extrapolate the role of IFNgamma in RSV-infected adult mice. PMID- 28861451 TI - Data on heavy metal levels (Cd, Co, and Cu) in wheat grains cultured in Dashtestan County, Iran. AB - Due to importance of wheat as the most popular food, in this data article, we determined the accumulation of heavy metal levels including Cd, Co, and Cu in wheat grains in Dashtestan county, Iran. The concentration levels of heavy metals in wheat grains cultured were determined by Flame Atomic Absorption Spectrometry (FAAS). PMID- 28861452 TI - RNA-seq assembly and analysis of Garcinia mangostana transcriptome during seed germination. AB - Garcinia mangostana is a tropical fruit plant rich in antioxidant and bears recalcitrant seeds. The extent of water loss and low temperature tolerable by recalcitrant seed varies from regular orthodox seeds. Present study generates transcriptome resources for G. mangostana to postulate potential transcriptome differences between recalcitrant and orthodox seeds during seed germination process. Raw reads of pooled samples used for the assembly have been deposited in genbank accession SRR5412332. PMID- 28861453 TI - Data on the effect of oral feeding of Arachidonic acid or Docosahexanoic acid on haematopoiesis in mice. AB - Stem cells have peculiar property to self-renew and differentiate. It is important to control their fate in safe and effective ways for their therapeutic use. The mediators of essential polyunsaturated fatty acids (PUFAs) namely Arachidonic acid (AA) and Docosahexanoic acid (DHA) are known to play a role in haematopoiesis via various metabolic pathways [1]. However the direct effect of purified AA or DHA on haematopoiesis has not been well investigated yet. We have reported that oral administration of PUFAs enhanced haematopoiesis in mice [2]. Signaling Leukocyte Antigen Molecule (SLAM) (CD48-CD150+) phenotype consists of pure population of haematopoietic stem cells (HSCs). Herein we observed higher percentage of SLAM (CD48-CD150+) phenotype in the bone marrow (BM) cells of mice fed with AA or DHA compared to PBS fed control mice. Data from engraftment study depicts that BM from AA/DHA-fed mice showed higher absolute number of donor cells in recipient mice compared to control. The enhanced hematopoiesis observed in AA/DHA-fed mice was returned to normal when the mice were kept on normal diet for six weeks (after ten days of oral feeding). We confirmed GCMS (Gas Chromatography Mass Spectroscopy) retention times of AA and DHA by co-injecting fatty acid extract from AA or DHA fed mice with purified AA or DHA standards respectively. Representative flow cytometry profile of Lin-Sca-1+c-kit+(LSK) cells showed higher expression of CXCR4 protein and ligands of Wnt, Notch1 signaling in BM of AA/DHA-fed mice. PMID- 28861454 TI - Hemodynamic response function parameters obtained from resting-state functional MRI data in soldiers with trauma. AB - Functional magnetic resonance imaging (fMRI) is an indirect measure of brain activity, i.e. it is a convolution of the latent (unmeasured) neural signal and the hemodynamic response function (HRF). As such, the HRF has been shown to vary across brain regions and individuals. The shape of the HRF is controlled by both neural and non-neural factors. The shape of the HRF can be characterized by three parameters (response height, time-to-peak and full-width at half-max). The data presented here provides the three HRF parameters at every voxel, obtained from U.S. Army soldiers (N=87) diagnosed with posttraumatic stress disorder (PTSD), with comorbid PTSD and mild-traumatic brain injury (mTBI), and matched healthy combat controls. Findings from this data and further interpretations are available in our recent research study (Rangaprakash et al., 2017) [1]. This data is a valuable asset in studying the impact of HRF variability on fMRI data analysis, specifically resting state functional connectivity. PMID- 28861455 TI - Baseline characteristics and event rates among anticoagulated patients with atrial fibrillation in practice and pivotal NOAC trials. AB - The data report details the baseline characteristics and observed outcomes among patients included in a large US administrative claims database (Optum Labs Data Warehouse) and those enrolled in the pivotal phase III clinical trials examining apixaban, dabigratan, edoxaban and rivaroxaban versus warfarin for the prevention of cardio embolism (Granger et al., 2011; Cannolly et al., 2009; Patel et al., 2011; Giugliano et al., 2013) [1], [2], [3], [4]. These data are to be interpreted in the context of the linked publication (Noseworthy et al., 2017) [5]. These data illustrate baseline characteristics in patients treated in routine practice and those enrolled in clinical trials. For instance, patients treated with apixaban in practice tended to be slightly older and we more likely to be female than those enrolled in the apixaban clinical trial. Patient treated with rivaroxaban in practice tended to have lower CHADS2 scores than those included in the rivaroxaban clinical trial. Overall, and stratified by baseline CHADS2 scores, patients treated with NOACs in routine practice had comparable or slightly lower stroke risks than those in the clinical trials. Patients treated with NOACs in routine practice had slightly higher bleeding risk in practice, particularly in high-risk patients with CHADS2 >= 3, compared to those in the clinical trials. These data may serve as a benchmark for realized outcomes among anticoagulated patients with atrial fibrillation in the United States and may serve as a useful comparison to other datasets or countries. PMID- 28861456 TI - Atomoxetine in abstinent cocaine users: Sex differences. AB - Data presented are from a sex-differences secondary analysis of a human laboratory investigation of single doses of atomoxetine (40 mg and 80 mg) versus placebo in abstinent individuals with cocaine use disorders (CUD). Subjective drug effects, cognitive performance and cardiovascular measures were assessed. The primary atomoxetine dose analyses (which do not consider sex as a factor) are reported in full elsewhere (DeVito et al., 2017) [1]. PMID- 28861457 TI - Data and material of the Safe-Range-Inventory: An assistance tool helping to improve the charging infrastructure for electric vehicles. AB - The Safe-Range-Inventory (SRI) was constructed in order to help public authorities to improve the charging infrastructures for electric vehicles [1; 10.1016/j.trf.2017.04.011]. Specifically, the impact of fast (vs slow) charging stations on people's range anxiety was examined. Ninety-seven electric vehicle users from Germany (81 male; Mage=46.3 years, SD=12.1) were recruited to participate in the experimental design. Statistical analyses were conducted using ANOVA for repeated measures to test for interaction effects of available charging stations and remaining range with the dependent variable range anxiety. The full data set is publicly available via https://osf.io/bveyw/ (Carbon and Gebauer, 2017) [2]. PMID- 28861458 TI - XRD and spectral dataset of the UV-A stable nanotubes of 3,5 bis(trifluoromethyl)benzylamine derivative of tyrosine. AB - The data presented in this article are related to the research entitled of UV-A stable nanotubes. The nanotubes have been prepared from 3,5 bis(trifluoromethyl)benzylamine derivative of tyrosine (BTTP). XRD data reveals the size of the nanotubes. As-synthesized nanotubes (BTTPNTs) are characterized by UV-vis optical absorption studies [1] and photo physical degradation kinetics. The resulted dataset is made available to enable critical or extended analyzes of the BTTPNTs as an excellent light resistive materials. PMID- 28861459 TI - Development of a comprehensive and sustainable gynecologic oncology training program in western Kenya, a low resource setting. AB - To provide information on the development of a gynecologic oncology training program in a low-resource setting in Kenya. This is a review of a collaboration between Kenyan and North American physicians who worked together to develop a gynecologic oncology training in Kenya. We review the published data on the increase of cancer incidence in sub-Saharan Africa and outline the steps that were taken to develop this program. The incidence of cervical cancer in Kenya is very high and is the leading cause of cancer mortality in Kenya. WHO identifies cancer as a new epidemic affecting countries in sub-Saharan Africa. In Kenya, a country of 45 million, there is limited resources to diagnose and treat cancer. In 2009 in western Kenya, at Moi University there was no strategy to manage oncology in the Reproductive Health department. There was only 1 gynecologic oncologists in Kenya in 2009. A collaboration between Canadian and Kenya physicians resulted in development of a gynecologic oncology clinical program and initiation of fellowship training in Kenya. In the past 4 years, five fellows have graduated from a 2 year fellowship training program. Integration of data collection on all the patients as part of this program provided opportunities to do clinical research and to acquire peer reviewed grants. This is the first recognized fellowship training program in sub-Saharan Africa outside of South Africa. It is an example of a collaborative effort to improve women's health in a low-resource country. This is a Kenyan managed program through Moi University. These subspecialty trained doctors will also provide advice that will shape health care policy and provide sustainable expertise for women diagnosed with a gynecologic cancer. PMID- 28861460 TI - Incidental fallopian tube mesothelioma diagnosed at time of elective bilateral salpingectomy for sterilisation: A case report. AB - *Incidental finding of a fallopian tube lesion at the time of bilateral salpingectomy*Histopathological appearance not consistent with mucinous or serous carcinoma, appearance of mesothelioma*Very rare known primary neoplasm of tubal mesothelium, favours an indolent course*Recommendation for prophylactic hysterectomy and bilateral oophorectomy*If nil further spread, generally nil further treatment is required. PMID- 28861461 TI - Verifying Heisenberg's error-disturbance relation using a single trapped ion. AB - Heisenberg's uncertainty relations have played an essential role in quantum physics since its very beginning. The uncertainty relations in the modern quantum formalism have become a fundamental limitation on the joint measurements of general quantum mechanical observables, going much beyond the original discussion of the trade-off between knowing a particle's position and momentum. Recently, the uncertainty relations have generated a considerable amount of lively debate as a result of the new inequalities proposed as extensions of the original uncertainty relations. We report an experimental test of one of the new Heisenberg's uncertainty relations using a single 40Ca+ ion trapped in a harmonic potential. By performing unitary operations under carrier transitions, we verify the uncertainty relation proposed by Busch, Lahti, and Werner (BLW) based on a general error-trade-off relation for joint measurements on two compatible observables. The positive operator-valued measure, required by the compatible observables, is constructed by single-qubit operations, and the lower bound of the uncertainty, as observed, is satisfied in a state-independent manner. Our results provide the first evidence confirming the BLW-formulated uncertainty at a single-spin level and will stimulate broad interests in various fields associated with quantum mechanics. PMID- 28861462 TI - Nonlinear climate sensitivity and its implications for future greenhouse warming. AB - Global mean surface temperatures are rising in response to anthropogenic greenhouse gas emissions. The magnitude of this warming at equilibrium for a given radiative forcing-referred to as specific equilibrium climate sensitivity (S)-is still subject to uncertainties. We estimate global mean temperature variations and S using a 784,000-year-long field reconstruction of sea surface temperatures and a transient paleoclimate model simulation. Our results reveal that S is strongly dependent on the climate background state, with significantly larger values attained during warm phases. Using the Representative Concentration Pathway 8.5 for future greenhouse radiative forcing, we find that the range of paleo-based estimates of Earth's future warming by 2100 CE overlaps with the upper range of climate simulations conducted as part of the Coupled Model Intercomparison Project Phase 5 (CMIP5). Furthermore, we find that within the 21st century, global mean temperatures will very likely exceed maximum levels reconstructed for the last 784,000 years. On the basis of temperature data from eight glacial cycles, our results provide an independent validation of the magnitude of current CMIP5 warming projections. PMID- 28861463 TI - Marine plastic debris emits a keystone infochemical for olfactory foraging seabirds. AB - Plastic debris is ingested by hundreds of species of organisms, from zooplankton to baleen whales, but how such a diversity of consumers can mistake plastic for their natural prey is largely unknown. The sensory mechanisms underlying plastic detection and consumption have rarely been examined within the context of sensory signals driving marine food web dynamics. We demonstrate experimentally that marine-seasoned microplastics produce a dimethyl sulfide (DMS) signature that is also a keystone odorant for natural trophic interactions. We further demonstrate a positive relationship between DMS responsiveness and plastic ingestion frequency using procellariiform seabirds as a model taxonomic group. Together, these results suggest that plastic debris emits the scent of a marine infochemical, creating an olfactory trap for susceptible marine wildlife. PMID- 28861465 TI - Incorporating explicit geospatial data shows more species at risk of extinction than the current Red List. AB - The IUCN (International Union for Conservation of Nature) Red List classifies species according to their risk of extinction, informing global to local conservation decisions. Unfortunately, important geospatial data do not explicitly or efficiently enter this process. Rapid growth in the availability of remotely sensed observations provides fine-scale data on elevation and increasingly sophisticated characterizations of land cover and its changes. These data readily show that species are likely not present within many areas within the overall envelopes of their distributions. Additionally, global databases on protected areas inform how extensively ranges are protected. We selected 586 endemic and threatened forest bird species from six of the world's most biodiverse and threatened places (Atlantic Forest of Brazil, Central America, Western Andes of Colombia, Madagascar, Sumatra, and Southeast Asia). The Red List deems 18% of these species to be threatened (15 critically endangered, 29 endangered, and 64 vulnerable). Inevitably, after refining ranges by elevation and forest cover, ranges shrink. Do they do so consistently? For example, refined ranges of critically endangered species might reduce by (say) 50% but so might the ranges of endangered, vulnerable, and nonthreatened species. Critically, this is not the case. We find that 43% of species fall below the range threshold where comparable species are deemed threatened. Some 210 bird species belong in a higher-threat category than the current Red List placement, including 189 species that are currently deemed nonthreatened. Incorporating readily available spatial data substantially increases the numbers of species that should be considered at risk and alters priority areas for conservation. PMID- 28861464 TI - Organic electronics for high-resolution electrocorticography of the human brain. AB - Localizing neuronal patterns that generate pathological brain signals may assist with tissue resection and intervention strategies in patients with neurological diseases. Precise localization requires high spatiotemporal recording from populations of neurons while minimizing invasiveness and adverse events. We describe a large-scale, high-density, organic material-based, conformable neural interface device ("NeuroGrid") capable of simultaneously recording local field potentials (LFPs) and action potentials from the cortical surface. We demonstrate the feasibility and safety of intraoperative recording with NeuroGrids in anesthetized and awake subjects. Highly localized and propagating physiological and pathological LFP patterns were recorded, and correlated neural firing provided evidence about their local generation. Application of NeuroGrids to brain disorders, such as epilepsy, may improve diagnostic precision and therapeutic outcomes while reducing complications associated with invasive electrodes conventionally used to acquire high-resolution and spiking data. PMID- 28861466 TI - Molecular structure of bottlebrush polymers in melts. AB - Bottlebrushes are fascinating macromolecules that display an intriguing combination of molecular and particulate features having vital implications in both living and synthetic systems, such as cartilage and ultrasoft elastomers. However, the progress in practical applications is impeded by the lack of knowledge about the hierarchic organization of both individual bottlebrushes and their assemblies. We delineate fundamental correlations between molecular architecture, mesoscopic conformation, and macroscopic properties of polymer melts. Numerical simulations corroborate theoretical predictions for the effect of grafting density and side-chain length on the dimensions and rigidity of bottlebrushes, which effectively behave as a melt of flexible filaments. These findings provide quantitative guidelines for the design of novel materials that allow architectural tuning of their properties in a broad range without changing chemical composition. PMID- 28861467 TI - There are many ways to spin a photon: Half-quantization of a total optical angular momentum. AB - The angular momentum of light plays an important role in many areas, from optical trapping to quantum information. In the usual three-dimensional setting, the angular momentum quantum numbers of the photon are integers, in units of the Planck constant h. We show that, in reduced dimensions, photons can have a half integer total angular momentum. We identify a new form of total angular momentum, carried by beams of light, comprising an unequal mixture of spin and orbital contributions. We demonstrate the half-integer quantization of this total angular momentum using noise measurements. We conclude that for light, as is known for electrons, reduced dimensionality allows new forms of quantization. PMID- 28861468 TI - Rapid identification of health care-associated infections with an integrated fluorescence anisotropy system. AB - Health care-associated infections (HAIs) and drug-resistant pathogens have become a major health care issue with millions of reported cases every year. Advanced diagnostics would allow clinicians to more quickly determine the most effective treatment, reduce the nonspecific use of broad-spectrum antimicrobials, and facilitate enrollment in new antibiotic treatments. We present a new integrated system, polarization anisotropy diagnostics (PAD), for rapid detection of HAI pathogens. The PAD uses changes of fluorescence anisotropy when detection probes recognize target bacterial nucleic acids. The technology is inherently robust against environmental noise and economically scalable for parallel measurements. The assay is fast (2 hours) and performed on-site in a single-tube format. When applied to clinical samples obtained from interventional procedures, the PAD determined the overall bacterial burden, differentiated HAI bacterial species, and identified drug resistance and virulence status. The PAD system holds promise as a powerful tool for near-patient, rapid HAI testing. PMID- 28861469 TI - An electromechanical Ising Hamiltonian. AB - Solving intractable mathematical problems in simulators composed of atoms, ions, photons, or electrons has recently emerged as a subject of intense interest. We extend this concept to phonons that are localized in spectrally pure resonances in an electromechanical system that enables their interactions to be exquisitely fashioned via electrical means. We harness this platform to emulate the Ising Hamiltonian whose spin 1/2 particles are replicated by the phase bistable vibrations from the parametric resonances of multiple modes. The coupling between the mechanical spins is created by generating two-mode squeezed states, which impart correlations between modes that can imitate a random, ferromagnetic state or an antiferromagnetic state on demand. These results suggest that an electromechanical simulator could be built for the Ising Hamiltonian in a nontrivial configuration, namely, for a large number of spins with multiple degrees of coupling. PMID- 28861470 TI - A strongly robust type II Weyl fermion semimetal state in Ta3S2. AB - Weyl semimetals are of great interest because they provide the first realization of the Weyl fermion, exhibit exotic quantum anomalies, and host Fermi arc surface states. The separation between Weyl nodes of opposite chirality gives a measure of the robustness of the Weyl semimetal state. To exploit the novel phenomena that arise from Weyl fermions in applications, it is crucially important to find robust separated Weyl nodes. We propose a methodology to design robust Weyl semimetals with well-separated Weyl nodes. Using this methodology as a guideline, we search among the material parameter space and identify by far the most robust and ideal Weyl semimetal candidate in the single-crystalline compound tantalum sulfide (Ta3S2) with new and novel properties beyond TaAs. Crucially, our results show that Ta3S2 has the largest k-space separation between Weyl nodes among known Weyl semimetal candidates, which is about twice larger than the measured value in TaAs and 20 times larger than the predicted value in WTe2. Moreover, all Weyl nodes in Ta3S2 are of type II. Therefore, Ta3S2 is a type II Weyl semimetal. Furthermore, we predict that increasing the lattice by <4% can annihilate all Weyl nodes, driving a novel topological metal-to-insulator transition from a Weyl semimetal state to a topological insulator state. The robust type II Weyl semimetal state and the topological metal-to-insulator transition in Ta3S2 are potentially useful in device applications. Our methodology can be generally applied to search for new Weyl semimetals. PMID- 28861472 TI - Microscale spatial heterogeneity of protein structural transitions in fibrin matrices. AB - Following an injury, a blood clot must form at the wound site to stop bleeding before skin repair can occur. Blood clots must satisfy a unique set of material requirements; they need to be sufficiently strong to resist pressure from the arterial blood flow but must be highly flexible to support large strains associated with tissue movement around the wound. These combined properties are enabled by a fibrous matrix consisting of the protein fibrin. Fibrin hydrogels can support large macroscopic strains owing to the unfolding transition of alpha helical fibril structures to beta sheets at the molecular level, among other reasons. Imaging protein secondary structure on the submicrometer length scale, we reveal that another length scale is relevant for fibrin function. We observe that the protein polymorphism in the gel becomes spatially heterogeneous on a micrometer length scale with increasing tensile strain, directly showing load bearing inhomogeneity and nonaffinity. Supramolecular structural features in the hydrogel observed under strain indicate that a uniform fibrin hydrogel develops a composite-like microstructure in tension, even in the absence of cellular inclusions. PMID- 28861471 TI - Mimosa Origami: A nanostructure-enabled directional self-organization regime of materials. AB - One of the innate fundamentals of living systems is their ability to respond toward distinct stimuli by various self-organization behaviors. Despite extensive progress, the engineering of spontaneous motion in man-made inorganic materials still lacks the directionality and scale observed in nature. We report the directional self-organization of soft materials into three-dimensional geometries by the rapid propagation of a folding stimulus along a predetermined path. We engineer a unique Janus bilayer architecture with superior chemical and mechanical properties that enables the efficient transformation of surface energy into directional kinetic and elastic energies. This Janus bilayer can respond to pinpoint water stimuli by a rapid, several-centimeters-long self-assembly that is reminiscent of the Mimosa pudica's leaflet folding. The Janus bilayers also shuttle water at flow rates up to two orders of magnitude higher than traditional wicking-based devices, reaching velocities of 8 cm/s and flow rates of 4.7 MUl/s. This self-organization regime enables the ease of fabricating curved, bent, and split flexible channels with lengths greater than 10 cm, demonstrating immense potential for microfluidics, biosensors, and water purification applications. PMID- 28861473 TI - Introduction to Cannabis and Cannabinoid Research. PMID- 28861474 TI - Expression of Cannabinoid Receptors in Human Osteoarthritic Cartilage: Implications for Future Therapies. AB - Introduction: Cannabinoids have shown to reduce joint damage in animal models of arthritis and reduce matrix metalloproteinase expression in primary human osteoarthritic (OA) chondrocytes. The actions of cannabinoids are mediated by a number of receptors, including cannabinoid receptors 1 and 2 (CB1 and CB2), G protein-coupled receptors 55 and 18 (GPR55 and GPR18), transient receptor potential vanilloid-1 (TRPV1), and peroxisome proliferator-activated receptors alpha and gamma (PPARalpha and PPARgamma). However, to date very few studies have investigated the expression and localization of these receptors in human chondrocytes, and expression during degeneration, and thus their potential in clinical applications is unknown. Methods: Human articular cartilage from patients with symptomatic OA was graded histologically and the expression and localization of cannabinoid receptors within OA cartilage and underlying bone were determined immunohistochemically. Expression levels across regions of cartilage and changes with degeneration were investigated. Results: Expression of all the cannabinoid receptors investigated was observed with no change with grade of degeneration seen in the expression of CB1, CB2, GPR55, PPARalpha, and PPARgamma. Conversely, the number of chondrocytes within the deep zone of cartilage displaying immunopositivity for GPR18 and TRPV1 was significantly decreased in degenerate cartilage. Receptor expression was higher in chondrocytes than in osteocytes in the underlying bone. Conclusions: Chondrocytes from OA joints were shown to express a wide range of cannabinoid receptors even in degenerate tissues, demonstrating that these cells could respond to cannabinoids. Cannabinoids designed to bind to receptors inhibiting the catabolic and pain pathways within the arthritic joint, while avoiding psychoactive effects, could provide potential arthritis therapies. PMID- 28861475 TI - Adherence to Medical Cannabis Among Licensed Patients in Israel. AB - Objectives: To evaluate adherence among Israeli patients who are licensed to use medical cannabis and to identify factors associated with adherence to medical cannabis. Methods: Ninety-five novice licensed patients were interviewed for this cross-sectional study. The questionnaire measured demographics, the perceived patient-physician relationship, and the level of patients' active involvement in their healthcare. In addition, patients were queried about adverse effect(s) and about their overall satisfaction from this medical treatment. Results: Eighty percent (n=76) has been identified as adherent to medical cannabis use. Variables found associated with adherence were "country of origin" (immigrant status), "type of illness" (cancer vs. non-cancer), and "experiencing adverse effect(s)." Three predictors of adherence were found significant in a logistic regression model: "type of illness" (odds ratio [OR] 0.101), patient-physician relationship (OR 1.406), and level of patient activation (OR 1.132). 71.5% rated themselves being "completely satisfied" or "satisfied" from medical cannabis use. Conclusions: Our findings show a relatively high adherence rate for medical cannabis, as well as relative safety and high satisfaction among licensed patients. Additionally indicated is the need to develop and implement standardized education about this evolving field-to both patients and physicians. PMID- 28861477 TI - Tackling the Pharmaceutical Frontier: Regulation of Cannabinoid-Based Medicines in Postwar Japan. AB - Background: The valley of death, which refers to the gap due to the lack of support for the translation of basic research to related clinical studies, exists in the field of translational cannabinoid research in Japan owing to regulations. Article 4 of the Cannabis Control Act (CCA) of 1948 prohibits the use of Cannabis based medicines. Objectives: This study aimed to explore the history of the establishment of regulations on the medical use of Cannabis-based medicines and discuss the current status of cannabinoid research and its regulation in Japan. Methods: We conducted a literature review of nationally archived official documents from the end of World War II in 1945 to 1948, which is the year the CCA was established. The documents were examined, specifically focusing on the sequence of events. Results: We found three memoranda related to the establishment of the CCA. The establishment of law on controlling narcotics was instructed by the general headquarters (GHQ)/Supreme Commander for the Allied Powers (SCAP) during the period of occupation after World War II. However, the Japanese Government decided to regulate Cannabis separately from other narcotics. Item (ii) of article 4 in the CCA, which prohibits medical application of Cannabis, was included to protect farmers growing Cannabis for the hemp content. Conclusion: Current Japanese regulations prohibiting clinical research in phytocannabinoids were instituted during the postwar era of World War II. Scientific discoveries have advanced cannabinoid research and have led positive reforms of the regulation of Cannabis in other countries. Therefore, there is ample motivation and opportunity for Japanese stakeholders to revise article 4 of the CCA for the benefit of patients. PMID- 28861476 TI - Allosteric Modulators of the CB1 Cannabinoid Receptor: A Structural Update Review. AB - In 2005, the first evidence of an allosteric binding site at the CB1R was provided by the identification of three indoles of the company Organon that were allosteric enhancers of agonist binding affinity and, functionally, allosteric inhibitors of agonist activity. Since then, structure-activity relationships of indoles as CB1R modulators have been reported. Targeting the allosteric site on CB1R, new families structurally based on urea and on 3-phenyltropane analogs of cocaine have been discovered as CB1R-negative allosteric modulators (NAMs), respectively, by Prosidion and by the Research Triangle Park. Endogenous allosteric ligands of different nature have been identified more recently. Thus, the therapeutic neuroprotection application of lipoxin A4, an arachidonic acid derivative, as an allosteric enhancer of CB1R activity has been confirmed in vivo. It was also the case of the steroid hormone, pregnenolone, whose negative allosteric effects on Delta9-tetrahydrocannabinol (Delta9-THC) were reproduced in vivo in a behavioral tetrad model and in food intake and memory impairment assays. Curiously, the peroxisome proliferator-activated receptor-gamma agonist fenofibrate or polypeptides such as pepcan-12 have been shown to act on the endocannabinoid system through CB1R allosteric modulation. The mechanistic bases of the effects of the phytocannabinoid cannabidiol (CBD) are still not fully explained. However, there is evidence that CBD behaves as an NAM of Delta9-THC- and 2-AG. Allosteric modulation at CB1R offers new opportunities for therapeutic applications. Therefore, further understanding of the chemical features required for allosteric modulation as well as their orthosteric probe dependence may broaden novel approaches for fine-tuning the signaling pathways of the CB1R. PMID- 28861478 TI - Cannabinoids in Medical Practice. AB - Many patients with chronic medical illnesses use cannabinoids. There are two FDA approved cannabinoid products, whereas medical marijuana purchased at legal dispensaries is not FDA regulated and may contain uncertain concentrations of various compounds. Cannabinoids have shown efficacy in treating chemotherapy related nausea and vomiting, poor appetite in advanced HIV, some pain states, and multiple sclerosis-associated spasticity. Recreational cannabinoid use has many known potential serious harms. Physicians should be knowledgeable about cannabinoids and should inquire with their patients about cannabinoid use. Practical suggestions for clinical approaches are included. PMID- 28861479 TI - The Cannabis sativa Versus Cannabis indica Debate: An Interview with Ethan Russo, MD. AB - Dr. Ethan Russo, MD, is a board-certified neurologist, psychopharmacology researcher, and Medical Director of PHYTECS, a biotechnology company researching and developing innovative approaches targeting the human endocannabinoid system. Previously, from 2003 to 2014, he served as Senior Medical Advisor and study physician to GW Pharmaceuticals for three Phase III clinical trials of Sativex(r) for alleviation of cancer pain unresponsive to optimized opioid treatment and studies of Epidiolex(r) for intractable epilepsy. He has held faculty appointments in Pharmaceutical Sciences at the University of Montana, in Medicine at the University of Washington, and as visiting Professor, Chinese Academy of Sciences. He is a past President of the International Cannabinoid Research Society and former Chairman of the International Association for Cannabinoid Medicines. He serves on the Scientific Advisory Board for the American Botanical Council. He is the author of numerous books, book chapters, and articles on Cannabis, ethnobotany, and herbal medicine. His research interests have included correlations of historical uses of Cannabis with modern pharmacological mechanisms, phytopharmaceutical treatment of migraine and chronic pain, and phytocannabinoid/terpenoid/serotonergic/vanilloid interactions. PMID- 28861480 TI - Legal or Illegal, Cannabis Is Still Addictive. PMID- 28861481 TI - Endocannabinoids and Immunity. AB - Over the last 10 years, a great boost of knowledge accumulated on the immunomodulatory and anti-inflammatory properties of endocannabinoids (eCBs). In this scenario, these bioactive lipids, which are produced by most immune cells along with a set of receptors and enzymes that regulate their synthesis and degradation, act as secondary modulators and increase or decrease a plethora of immune functions. In this review, the manifold immunomodulatory effects of the main eCBs in different compartments of innate and adaptive immunity will be discussed, suggesting that they could be considered as master regulators of innate-adaptive immune axis and as potent immunoresolvents. PMID- 28861482 TI - Medicinal Cannabis in California: An Interview with Igor Grant, MD. AB - Dr. Igor Grant, MD, is distinguished professor and chair of psychiatry and director of the HIV Neurobehavioral Research Program and the Center for Medicinal Cannabis Research at the University of California, San Diego. Dr. Grant is a neuropsychiatrist who graduated from the University of British Columbia School of Medicine (1966), and received specialty training in psychiatry at the University of Pennsylvania (1967-1971), and additional training in neurology at the Institute of Neurology (1980-1981), London, U.K. Dr. Grant's academic interests focus on the effects of various diseases on brain and behavior, with an emphasis on translational studies in HIV, and drugs of abuse. He has contributed to ~700 scholarly publications and is principal investigator of several NIH studies, including an NIDA P50 (Translational Methamphetamine AIDS Research Center-TMARC), and is codirector of the HIV Neurobehavioral Research Center (HNRC). PMID- 28861483 TI - Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism Related Social Impairment. AB - Introduction: We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD-social impairment-we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1-/- (model of Fragile X Syndrome). Methods: We used the established three-chambered social approach test. We specifically increased the activity of anandamide by administering the compound URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH), the hydrolytic enzyme for anandamide. Results: Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice. These results were likely independent of effects on anxiety, as FAAH inhibition did not alter the performance of BTBR mice in the elevated plus maze. Conclusions: The results suggest that increasing anandamide activity at CB1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD. PMID- 28861484 TI - Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy. AB - Cannabidiol (CBD), the main nonpsychoactive constituent of Cannabis sativa, has shown a wide range of therapeutically promising pharmacological effects either as a sole drug or in combination with other drugs in adjunctive therapy. However, the targets involved in the therapeutic effects of CBD appear to be elusive. Furthermore, scarce information is available on the biological activity of its human metabolites which, when formed in pharmacologically relevant concentration, might contribute to or even account for the observed therapeutic effects. The present overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD in humans, reviews studies on the biological activity of CBD metabolites either in vitro or in vivo, and discusses relevant drug-drug interactions. To facilitate further research in the area, the reported syntheses of CBD metabolites are also catalogued. PMID- 28861485 TI - Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid. AB - Introduction: In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Delta9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quantitative exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF). Methods: Materials included synthetic CBD, Delta8 THC, and Delta9-THC. Linearity was demonstrated for each component over the concentration range used in this study. CBD was spiked into media containing 1% sodium dodecyl sulfate (SDS). Samples were analyzed using chromatography with UV and mass spectrometry detection. An assessment time of 3 h was chosen as representative of the maximal duration of exposure to gastric fluid. Results: CBD in SGF with 1% SDS was degraded about 85% after 60 min and more than 98% at 120 min. The degradation followed first-order kinetics at a rate constant of -0.031 min-1 (R2=0.9933). The major products formed were Delta9-THC and Delta8-THC with less significant levels of other related cannabinoids. CBD in physiological buffer performed as a control did not convert to THC. Confirmation of THC formation was demonstrated by comparison of mass spectral analysis, mass identification, and retention time of Delta9-THC and Delta8-THC in the SGF samples against authentic reference standards. Conclusions: SGF converts CBD into the psychoactive components Delta9-THC and Delta8-THC. The first-order kinetics observed in this study allowed estimated levels to be calculated and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiological response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored. PMID- 28861487 TI - Furthering Cannabis Research and Education: An Interview with Fundacion CANNA. AB - Fundacion CANNA is a nonprofit initiative of CANNA, a multinational company producing high-quality fertilizers for fast growing plants. The Foundation carries out studies and conducts research on cannabis and its active compounds. Fundacion CANNA supports different congresses, initiatives, and scientific studies to push forward the knowledge about cannabinoids as a medicine. PMID- 28861486 TI - Cannabinoid Regulation of Acute and Anticipatory Nausea. AB - Chemotherapy-induced nausea is one of the most distressing symptoms reported by patients undergoing treatment, and even with the introduction of newer antiemetics such as ondansetron and aprepitant, nausea remains problematic in the clinic. Indeed, when acute nausea is not properly managed, the cues of the clinic can become associated with this distressing symptom resulting in anticipatory nausea for which no effective treatments are available. Clinical trials exploring the potential of exogenous or endogenous cannabinoids to reduce chemotherapy induced nausea are sparse; therefore, we must rely on the data from pre-clinical rat models of nausea. In this review, we explore the human and pre-clinical animal literature examining the potential for exogenous and endogenous cannabinoid treatments to regulate chemotherapy-induced nausea. The pre-clinical evidence points to a compelling need to evaluate the antinausea potential of cannabidiol, cannabidiolic acid, and treatments that boost the functioning of the endocannabinoid system in human clinical trials. PMID- 28861488 TI - Can You Pass the Acid Test? Critical Review and Novel Therapeutic Perspectives of Delta9-Tetrahydrocannabinolic Acid A. AB - Delta9-tetrahydrocannabinolic acid A (THCA-A) is the acidic precursor of Delta9 tetrahydrocannabinol (THC), the main psychoactive compound found in Cannabis sativa. THCA-A is biosynthesized and accumulated in glandular trichomes present on flowers and leaves, where it serves protective functions and can represent up to 90% of the total THC contained in the plant. THCA-A slowly decarboxylates to form THC during storage and fermentation and can further degrade to cannabinol. Decarboxylation also occurs rapidly during baking of edibles, smoking, or vaporizing, the most common ways in which the general population consumes Cannabis. Contrary to THC, THCA-A does not elicit psychoactive effects in humans and, perhaps for this reason, its pharmacological value is often neglected. In fact, many studies use the term "THCA" to refer indistinctly to several acid derivatives of THC. Despite this perception, many in vitro studies seem to indicate that THCA-A interacts with a number of molecular targets and displays a robust pharmacological profile that includes potential anti-inflammatory, immunomodulatory, neuroprotective, and antineoplastic properties. Moreover, the few in vivo studies performed with THCA-A indicate that this compound exerts pharmacological actions in rodents, likely by engaging type-1 cannabinoid (CB1) receptors. Although these findings may seem counterintuitive due to the lack of cannabinoid-related psychoactivity, a careful perusal of the available literature yields a plausible explanation to this conundrum and points toward novel therapeutic perspectives for raw, unheated Cannabis preparations in humans. PMID- 28861489 TI - A Cross-Sectional Survey of Medical Cannabis Users: Patterns of Use and Perceived Efficacy. AB - Background: The political climate around Cannabis as a medicine is rapidly changing. Legislators are adopting policies regarding appropriate medical applications, while the paucity of research may make policy decisions around conditions for which Cannabis is an effective medicine difficult. Methods: An anonymous online survey was developed to query medical Cannabis users about the conditions they use Cannabis to treat, their use patterns, perception of efficacy, and physical and mental health. Participants were recruited through social media and Cannabis dispensaries in Washington State. Results: A total of 1429 participants identified as medical Cannabis users. The most frequently reported conditions for which they used Cannabis were pain (61.2%), anxiety (58.1%), depression (50.3%), headache/migraine (35.5%), nausea (27.4%), and muscle spasticity (18.4%). On average, participants reported an 86% reduction in symptoms as a result of Cannabis use; 59.8% of medical users reported using Cannabis as an alternative to pharmaceutical prescriptions. Global health scores were on par with the general population for mental health and physical health. Conclusions: While patient-reported outcomes favor strong efficacy for a broad range of symptoms, many medical users are using Cannabis without physician supervision and for conditions for which there is no formal research to support the use of Cannabis (e.g., depression and anxiety). Future research and public policy should attempt to reduce the incongruence between approved and actual use. PMID- 28861490 TI - Maintenance of Blinding in Clinical Trials and the Implications for Studying Analgesia Using Cannabinoids. AB - The design of analgesic clinical trials invariably involves a comparison between placebo and active study medication. An assumption is made that treatment effects can be approximated by subtracting the response to placebo from that attained with the use of active study medication. However, the psychoactivity of cannabinoids may unmask their presence and lead to an expectation and/or conditioning of pain relief. For example, study participants biased toward the belief that cannabis is beneficial for their condition might be more inclined to report positive effects if they were to accurately identify the active treatment because of its psychoactivity. This may lead to incorrect assumptions regarding the efficacy of a cannabinoid. Methodologies designed to counteract unmasking need to be implemented in the design phase of a study. During the clinical trial, it is also important to query participants as to which treatment they believe they have received. Blinding can be considered to be preserved when the accuracy of treatment guesses is not considerably different than random guessing, which is estimated to be correct 50% of the time. After a study has been completed, the use of statistical methodologies such as regression and mediation analysis are worthy of consideration to see whether psychoactive effects biased the results. PMID- 28861491 TI - Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes. AB - Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS. PMID- 28861492 TI - Sex Differences in Cannabis Use and Effects: A Cross-Sectional Survey of Cannabis Users. AB - Introduction: Despite known sex differences in the endocannabinoid system of animals, little attention has been paid to sex differences in human's cannabis use patterns and effects. The purpose of the present study was to examine sex differences in cannabis use patterns and effects in a large sample of recreational and medical cannabis users. Methods: A large sample (n=2374) of cannabis users completed an anonymous, online survey that assessed their cannabis use practices and experiences, including the short-term acute effects of cannabis and withdrawal effects. A subsample of 1418 medical cannabis users further indicated the medical conditions for which they use cannabis and its perceived efficacy. Results: The results indicated that men reported using cannabis more frequently and in higher quantities than did women. Men were more likely to report using joints/blunts, vaporizers, and concentrates, while women were more likely to report using pipes and oral administration. Men were more likely than women to report increased appetite, improved memory, enthusiasm, altered time perception, and increased musicality when high, while women were more likely than men to report loss of appetite and desire to clean when high. Men were more likely than women to report insomnia and vivid dreams during periods of withdrawal, while women were more likely than men to report nausea and anxiety as withdrawal symptoms. Sex differences in the conditions for which medical cannabis is used, and its efficacy, were trivial. Conclusions: These results may be used to focus research on biological and psychosocial mechanisms underlying cannabis related sex differences, to inform clinicians treating individuals with cannabis use disorders, and to inform cannabis consumers, clinicians, and policymakers about the risks and benefits of cannabis for both sexes. PMID- 28861493 TI - Increased Renal 2-Arachidonoylglycerol Level Is Associated with Improved Renal Function in a Mouse Model of Acute Kidney Injury. AB - Background: Acute kidney injury (AKI) is associated with a significantly increased risk of morbidity and mortality. Ischemia-reperfusion injury (IRI) is a major cause of AKI. In this study, we investigated the role of the endocannabinoid (EC) system in renal IRI using a well-established mouse model. Materials and Methods: Renal ischemia was induced in male C57BL/6 mice by clamping both kidney pedicles for 30 min followed by 24 h of reperfusion. To increase renal 2-arachidonoylglycerol (2-AG) levels, mice were pretreated with JZL184 (16 mg/kg), 30 min before IRI. Serum creatinine and blood urea nitrogen (BUN), renal tubular damage, renal content of ECs and renal expression of markers of inflammation and oxidative stress were measured. Results: Renal IRI was associated with significantly increased serum BUN and creatinine, increased tubular damage score, increased expression of renal markers of inflammation and oxidative stress and elevated renal 2-AG content. Pretreatment with JZL184 was associated with a significant increase in renal 2-AG content and there was also improved serum BUN, creatinine and tubular damage score. However, renal expression of inflammation and oxidative stress markers remained unchanged. Conclusions: This is the first report documenting that renal IRI is associated with an increase in kidney 2-AG content. Further enhancement of 2-AG levels using JZL184 improved indices of renal function and histology, but did not lower renal expression of markers of inflammation and oxidative stress. Further studies are needed to determine the mechanisms responsible for the effects observed and the potential value of 2-AG as a therapeutic target in renal IRI. PMID- 28861494 TI - The Name of Cannabis: A Short Guide for Nonbotanists. AB - The genus Cannabis (Family Cannabaceae) is probably indigenous to wet habitats of Asiatic continent. The long coexistence between mankind and Cannabis led to an early domestication of the plant, which soon showed an amazing spectrum of possible utilizations, as a source of textile fibers, as well as narcotic and psychoactive compounds. Nowadays, the specie(s) belonging to the genus Cannabis are represented by myriads of cultivated varieties, often with unstable taxonomic foundations. The nomenclature of Cannabis has been the object of numerous nomenclatural treatments. Linnaeus in Species Plantarum (1753) described a single species of hemp, Cannabis sativa, whereas Lamarck (1785) proposed two species of Cannabis: C. sativa, the species largely cultivated in Western Continent, and Cannabis indica, a wild species growing in India and neighboring countries. The dilemma about the existence of the species C. indica considered distinct from C. sativa continues up to present days. Due to their prevalent economic interest, the nomenclatural treatment is particularly important as far as it concerns the cultivated varieties of Cannabis. In this context, we propose to avoid the distinction between sativa and indica, suggesting a bimodal approach: when a cultivar has been correctly established. It could be advisable to apply a nomenclature system based on the International Code of Nomenclature for Cultivated Plants (ICNCP): it is not necessary to use the species epithets, sativa or indica, and a combination of the genus name and a cultivar epithet in any language and bounded by single quotation marks define an exclusive name for each Cannabis cultivar. In contrast, Cannabis varieties named with vernacular names by medical patients and recreational users, and lacking an adequate description as required by ICNCP, should be named as Cannabis strain, followed by their popularized name and without single quotation marks, having in mind that their names have no taxonomical validity. PMID- 28861495 TI - Cannabis Users' Recommended Warnings for Packages of Legally Sold Cannabis: An Australia-Centered Study. AB - Introduction: Although cannabis use creates health risks, governments have recently been legalizing either medical use or leisure use. These governments can mandate health warnings on cannabis packages. Prior research examined recommended warnings of cannabis experts. The aim of this study was to obtain suggested cannabis health and safety warnings from cannabis users. Methods: We used a media release, Facebook postings, and announcements in university classes to seek individuals who had used cannabis at least once according to their own report. Using online data collection software that keeps participants anonymous, we asked the individuals to suggest a warning that governments could mandate on cannabis packages. Results: In total, 288 users suggested warnings. Categorizing the warnings into content categories led to six warning topics: (1) risk of harm to mental health and psychological functioning; (2) risk of operating machinery while under the influence; (3) short-term physical side effects; (4) responsible use; (5) long-term negative physical effects; and (6) dependence, addiction, or abuse. The user-suggested warnings overlapped with six expert-recommended warnings identified in prior survey research and included two content areas that did not feature in expert-recommended warnings: short-term physical side effects and the importance of responsible use. Conclusions: The results are consistent with prior findings that some youths perceive cannabis use as potentially harmful. The current findings provide possible new content for warnings on cannabis packages. PMID- 28861496 TI - Training and Practices of Cannabis Dispensary Staff. AB - Introduction: The proliferation of cannabis dispensaries within the United States has emerged from patient demand for the legalization of cannabis as an alternative treatment for a number of conditions and symptoms. Unfortunately, nothing is known about the practices of dispensary staff with respect to recommendation of cannabis strains/concentrations for specific patient ailments. To address this limitation, the present study assessed the training and practices of cannabis dispensary staff. Materials and Methods: Medical and nonmedical dispensary staff (n=55) were recruited via e-mail and social media to complete an online survey assessing their demographic characteristics, dispensary features, patient characteristics, formal training, and cannabis recommendation practices. Results: Fifty-five percent of dispensary staff reported some formal training for their position, with 20% reporting medical/scientific training. A majority (94%) indicated that they provide specific cannabis advice to patients. In terms of strains, dispensary staff trended toward recommendations of Indica for anxiety, chronic pain, insomnia, nightmares, and Tourette's syndrome. They were more likely to recommend Indica and hybrid plants for post-traumatic stress disorder (PTSD)/trauma and muscle spasms. In contrast, staff were less likely to recommend Indica for depression; hybrid strains were most often recommended for amyotrophic lateral sclerosis (ALS). In terms of cannabinoid concentrations, dispensary staff were most likely to recommend a 1:1 ratio of delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) for patients suffering from anxiety, Crohn's disease, hepatitis C, and PTSD/trauma, while patients seeking appetite stimulation were most likely to be recommended THC. Staff recommended high CBD for arthritis and Alzheimer's disease and a high CBD or 1:1 ratio for ALS, epilepsy, and muscle spasms. Conclusions: Although many dispensary staff are making recommendations consistent with current evidence, some are recommending cannabis that has either not been shown effective for, or could exacerbate, a patient's condition. Findings underscore the importance of consistent, evidence-based, training of dispensary staff who provide specific recommendations for patient medical conditions. PMID- 28861498 TI - Decarboxylation Study of Acidic Cannabinoids: A Novel Approach Using Ultra-High Performance Supercritical Fluid Chromatography/Photodiode Array-Mass Spectrometry. AB - Introduction: Decarboxylation is an important step for efficient production of the major active components in cannabis, for example, Delta9-tetrahydrocannabinol (Delta9-THC), cannabidiol (CBD), and cannabigerol (CBG). These cannabinoids do not occur in significant concentrations in cannabis but can be formed by decarboxylation of their corresponding acids, the predominant cannabinoids in the plant. Study of the kinetics of decarboxylation is of importance for phytocannabinoid isolation and dosage formulation for medical use. Efficient analytical methods are essential for simultaneous detection of both neutral and acidic cannabinoids. Methods:C. sativa extracts were used for the studies. Decarboxylation conditions were examined at 80 degrees C, 95 degrees C, 110 degrees C, 130 degrees C, and 145 degrees C for different times up to 60 min in a vacuum oven. An ultra-high performance supercritical fluid chromatography/photodiode array-mass spectrometry (UHPSFC/PDA-MS) method was used for the analysis of acidic and neutral cannabinoids before and after decarboxylation. Results: Decarboxylation at different temperatures displayed an exponential relationship between concentration and time indicating a first-order or pseudo-first-order reaction. The rate constants for Delta9 tetrahydrocannabinolic acid-A (THCA-A) were twice those of the cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA). Decarboxylation of THCA-A was forthright with no side reactions or by-products. Decarboxylation of CBDA and CBGA was not as straightforward due to the unexplained loss of reactants or products. Conclusion: The reported UHPSFC/PDA-MS method provided consistent and sensitive analysis of phytocannabinoids and their decarboxylation products and degradants. The rate of change of acidic cannabinoid concentrations over time allowed for determination of rate constants. Variations of rate constants with temperature yielded values for reaction energy. PMID- 28861497 TI - Preliminary Development of a Brief Cannabis Use Disorder Screening Tool: The Cannabis Use Disorder Identification Test Short-Form. AB - Introduction: Rates of cannabis use disorder (CUD) among vulnerable populations have increased in recent years, highlighting a need to equip providers with an efficient screening tool. Materials and Methods: A short form of the Cannabis Use Disorder Identification Test-Revised (CUDIT-R) was developed by using item response theory and traditional statistical methods, with data from two community samples of cannabis users representing two countries. Four item selection methods (Rasch regression, test characteristic curve, logistic regression, discriminant function analysis) were employed to identify the optimal three-item shortened version. The diagnostic ability of the short form was evaluated by using receiver operating characteristic curves. Results: Using a cut score of 2, the 3-item CUDIT-Short Form (CUDIT-SF; reliability alpha=0.66, Sample 1; 0.80, Sample 2) identified 78.26% of participants in Sample 1 and 78.31% of participants in Sample 2 who met DSM-5 criteria for CUD, with 98% agreement in Sample 1 and 93% agreement in Sample 2 with the full CUDIT-R on CUD classifications using a cut score of 13. Specificity was 76.70 and 78.00 in Samples 1 and 2, respectively. Conclusions: The CUDIT-SF may be useful in busy clinical settings for a stepwise screening. Further validation of this shortened version with larger samples and in different settings is warranted. PMID- 28861499 TI - Even High Doses of Oral Cannabidol Do Not Cause THC-Like Effects in Humans: Comment on Merrick et al. Cannabis and Cannabinoid Research 2016;1(1):102-112; DOI: 10.1089/can.2015.0004. AB - This short communication examines the question whether the experimental data presented in a study by Merrick et al. are of clinical relevance. These authors found that cannabidiol (CBD), a major cannabinoid of the cannabis plant devoid of psychotropic effects and of great interest for therapeutic use in several medical conditions, may be converted in gastric fluid into the psychoactive cannabinoids delta-8-THC and delta-9-THC to a relevant degree. They concluded that "the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a positive physiological response." They issued a warning concerning oral use of CBD and recommend the development of other delivery methods. However, the available clinical data do not support this conclusion and recommendation, since even high doses of oral CBD do not cause psychological, psychomotor, cognitive, or physical effects that are characteristic for THC or cannabis rich in THC. On the contrary, in the past decades and by several groups, high doses of oral CBD were consistently shown to cause opposite effects to those of THC in clinical studies. In addition, administration of CBD did not result in detectable THC blood concentrations. Thus, there is no reason to avoid oral use of CBD, which has been demonstrated to be a safe means of administration of CBD, even at very high doses. PMID- 28861500 TI - Conversion of Cannabidiol Following Oral Administration: Authors' Response to Grotenhermen et al. DOI: 10.1089/can.2016.0036. AB - In a commentary, Grotenhermen, Russo, and Zuardi questioned not only the clinical relevance but also the conclusions of a recently published study by Merrick et al. on the conversion of cannabidiol (CBD) to delta-8 and delta-9 tetrahydrocannabinol (THC) in simulated gastric fluid. In response, this article aims to provide a thorough review of the in vitro and in vivo studies of gastric CBD conversion as well as potential consequences resulting from such conversion. Findings highlight (1) consistent evidence over the past half century of gastric conversion of CBD, (2) evidence from human studies, indicating the importance of testing for THC metabolites as well as a number of other cannabinoids in the detection of such conversion, and (3) THC-like effects after administration of oral CBD in humans that may not only stem from CBD's conversion to THC, but also its conversion to 9alpha-hydroxy-hexahydrocannabinol and 8alpha-hydroxy-iso hexahydrocannabinol. These findings, coupled with a number of limitations in the existing literature, point to the need for large-scale human studies, specifically designed to explore gastric conversion and potential THC-like side effects after oral administration of CBD. PMID- 28861501 TI - Palmitoylethanolamide Modulates GPR55 Receptor Signaling in the Ventral Hippocampus to Regulate Mesolimbic Dopamine Activity, Social Interaction, and Memory Processing. AB - Introduction: The GPR55 receptor has been identified as an atypical cannabinoid receptor and is implicated in various physiological processes. However, its functional role in the central nervous system is not currently understood. The presence of GPR55 receptor in neural regions such as the ventral hippocampus (vHipp), which is critical for cognition, recognition memory, and affective processing, led us to hypothesize that intra-vHipp GPR55 transmission may modulate mesolimbic activity states and related behavioral phenomena. The vHipp is involved in contextual memory and affective regulation through functional interactions with the mesolimbic dopamine system. Materials and Methods: Using a combination of in vivo electrophysiology and behavioral pharmacological assays in rats, we tested whether intra-vHipp activation of GPR55 receptor transmission with the fatty acid amide, palmitoylethanolamide (PEA), a lipid neuromodulator with agonist actions at the GPR55 receptor, may modulate mesolimbic dopaminergic activity states. We further examined the potential effects of intra-vHipp PEA in affective, cognitive and contextual memory tasks. Discussion: We report that intra-vHipp PEA produces a hyper-dopaminergic state in the mesolimbic system characterized by increased firing and bursting activity of ventral tegmental area dopaminergic neuron populations. Furthermore, while PEA-induced activation of GPR55 transmission had no effects on opiate-related reward-related memory formation, we observed strong disruptions in social interaction and recognition memory, spatial location memory, and context-independent associative fear memory formation. Finally, the effects of intra-vHipp PEA were blocked by a selective GPR55 receptor antagonist, CID160 and were dependent upon NMDA receptor transmission, directly in the vHipp. Conclusions: The present results add to a growing body of evidence demonstrating important functional roles for GPR55 signaling in cannabinoid-related neuronal and behavioral phenomena and underscore the potential for GPR55 signaling in the mediation of cannabinoid-related effects independently of the CB1/CB2 receptor systems. PMID- 28861503 TI - Identification of Terpenoid Chemotypes Among High (-)-trans-Delta9- Tetrahydrocannabinol-Producing Cannabis sativa L. Cultivars. AB - Introduction: With laws changing around the world regarding the legal status of Cannabis sativa (cannabis) it is important to develop objective classification systems that help explain the chemical variation found among various cultivars. Currently cannabis cultivars are named using obscure and inconsistent nomenclature. Terpenoids, responsible for the aroma of cannabis, are a useful group of compounds for distinguishing cannabis cultivars with similar cannabinoid content. Methods: In this study we analyzed terpenoid content of cannabis samples obtained from a single medical cannabis dispensary in California over the course of a year. Terpenoids were quantified by gas chromatography with flame ionization detection and peak identification was confirmed with gas chromatography mass spectrometry. Quantitative data from 16 major terpenoids were analyzed using hierarchical clustering analysis (HCA), principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA). Results: A total of 233 samples representing 30 cultivars were used to develop a classification scheme based on quantitative data, HCA, PCA, and OPLS-DA. Initially cultivars were divided into five major groups, which were subdivided into 13 classes based on differences in terpenoid profile. Different classification models were compared with PLS-DA and found to perform best when many representative samples of a particular class were included. Conclusion: A hierarchy of terpenoid chemotypes was observed in the data set. Some cultivars fit into distinct chemotypes, whereas others seemed to represent a continuum of chemotypes. This study has demonstrated an approach to classifying cannabis cultivars based on terpenoid profile. PMID- 28861502 TI - Cannabinoids in Parkinson's Disease. AB - The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (gamma-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2). In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies. A number of preclinical studies in different experimental Parkinson's disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results from clinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies. PMID- 28861504 TI - Cannabinoid CB1 and CB2 Receptor Signaling and Bias. AB - An agonist that acts through a single receptor can activate numerous signaling pathways. Recent studies have suggested that different ligands can differentially activate these pathways by stabilizing a limited range of receptor conformations, which in turn preferentially drive different downstream signaling cascades. This concept, termed "biased signaling" represents an exciting therapeutic opportunity to target specific pathways that elicit only desired effects, while avoiding undesired effects mediated by different signaling cascades. The cannabinoid receptors CB1 and CB2 each activate multiple pathways, and evidence is emerging for bias within these pathways. This review will summarize the current evidence for biased signaling through cannabinoid receptor subtypes CB1 and CB2. PMID- 28861505 TI - The Use of Cannabis for Headache Disorders. AB - Headache disorders are common, debilitating, and, in many cases, inadequately managed by existing treatments. Although clinical trials of cannabis for neuropathic pain have shown promising results, there has been limited research on its use, specifically for headache disorders. This review considers historical prescription practices, summarizes the existing reports on the use of cannabis for headache, and examines the preclinical literature exploring the role of exogenous and endogenous cannabinoids to alter headache pathophysiology. Currently, there is not enough evidence from well-designed clinical trials to support the use of cannabis for headache, but there are sufficient anecdotal and preliminary results, as well as plausible neurobiological mechanisms, to warrant properly designed clinical trials. Such trials are needed to determine short- and long-term efficacy for specific headache types, compatibility with existing treatments, optimal administration practices, as well as potential risks. PMID- 28861507 TI - A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans. AB - Cannabidiol (CBD), a major cannabinoid of hemp, does not bind to CB1 receptors and is therefore devoid of psychotomimetic properties. Under acidic conditions, CBD can be transformed to delta9-tetrahydrocannabinol (THC) and other cannabinoids. It has been argued that this may occur also after oral administration in humans. However, the experimental conversion of CBD to THC and delta8-THC in simulated gastric fluid (SGF) is a highly artificial approach that deviates significantly from physiological conditions in the stomach; therefore, SGF does not allow an extrapolation to in vivo conditions. Unsurprisingly, the conversion of oral CBD to THC and its metabolites has not been observed to occur in vivo, even after high doses of oral CBD. In addition, the typical spectrum of side effects of THC, or of the very similar synthetic cannabinoid nabilone, as listed in the official Summary of Product Characteristics (e.g., dizziness, euphoria/high, thinking abnormal/concentration difficulties, nausea, tachycardia) has not been observed after treatment with CBD in double-blind, randomized, controlled clinical trials. In conclusion, the conversion of CBD to THC in SGF seems to be an in vitro artifact. PMID- 28861506 TI - The Clinical Significance of Endocannabinoids in Endometriosis Pain Management. AB - Introduction: Patients with endometriosis often suffer from diffuse and poorly localized severe pain. The current pain management strategies include medical and hormonal therapy, as well as surgery. Medical management of pain is often insufficient and is associated with high rate of recurrence. Better pain management is therefore of urgent need. Methods: Among the various candidates, the endocannabinoid system (ECS) has recently emerged as a relevant pharmacological target for the management of endometriosis-related pain. A computerized literature search was performed to identify relevant studies combining the keywords "endometriosis," "endocannabinoid," "cannabinoid receptor," "THC," and "pain mechanisms." Conclusions: This review describes the multiple and complex pain mechanisms associated with endometriosis. Current data and theories concerning the link between the ECS and pain management for endometriosis patients are presented. Finally, we will discuss which aspects of endometriosis-associated pain can be targeted by modulation of the ECS. PMID- 28861508 TI - Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two. AB - Introduction:Cannabis biosynthesizes Delta9-tetrahydrocannabinolic acid (THCA-A), which decarboxylates into Delta9-tetrahydrocannabinol (THC). There is growing interest in the therapeutic use of THCA-A, but its clinical application may be hampered by instability. THCA-A lacks cannabimimetic effects; we hypothesize that it has little binding affinity at cannabinoid receptor 1 (CB1). Materials and Methods: Purity of certified reference standards were tested with high performance liquid chromatography (HPLC). Binding affinity of THCA-A and THC at human (h) CB1 and hCB2 was measured in competition binding assays, using transfected HEK cells and [3H]CP55,940. Efficacy at hCB1 and hCB2 was measured in a cyclic adenosine monophosphase (cAMP) assay, using a Bioluminescence Resonance Energy Transfer (BRET) biosensor. Results: The THCA-A reagent contained 2% THC. THCA-A displayed small but measurable binding at both hCB1 and hCB2, equating to approximate Ki values of 3.1MUM and 12.5MUM, respectively. THC showed 62-fold greater affinity at hCB1 and 125-fold greater affinity at hCB2. In efficacy tests, THCA-A (10MUM) slightly inhibited forskolin-stimulated cAMP at hCB1, suggestive of weak agonist activity, and no measurable efficacy at hCB2. Discussion: The presence of THC in our THCA-A certified standard agrees with decarboxylation kinetics (literature reviewed herein), which indicate contamination with THC is nearly unavoidable. THCA-A binding at 10MUM approximated THC binding at 200nM. We therefore suspect some of our THCA-A binding curve was artifact-from its inevitable decarboxylation into THC-and the binding affinity of THCA-A is even weaker than our estimated values. We conclude that THCA-A has little affinity or efficacy at CB1 or CB2. PMID- 28861510 TI - Cannabidiol Does Not Dampen Responses to Emotional Stimuli in Healthy Adults. AB - Introduction: Cannabidiol (CBD) is a nonpsychoactive constituent of whole plant cannabis that has been reported to reduce anxiety-like behaviors in both pre clinical and human laboratory studies. Yet, no controlled clinical studies have demonstrated its ability to reduce negative mood or dampen responses to negative emotional stimuli in humans. The objective of this study was to investigate the effects of CBD on responses to negative emotional stimuli, as a model for its potential anxiety-reducing effects. Materials and Methods: The study used a double-blind, placebo (PLB)-controlled, within-subjects design in which 38 healthy, drug-free participants consumed oral CBD (300, 600, and 900 mg) or PLB before completing several behavioral tasks selected to assess reactivity to negative stimuli. Dependent measures included emotional arousal to negative and positive visual stimuli, perceptual sensitivity to emotional facial expressions, attentional bias toward emotional facial expressions, and feelings of social rejection. In addition, subjective drug effects and physiological data were also gathered during each experimental session to assess drug effects. Discussion: CBD did not dampen responses to negative emotional stimuli and did not affect feelings of social rejection. The high dose of CBD (900 mg) marginally reduced attentional bias toward happy and sad facial expressions, and produced a slight increase in late-session heart rate. CBD did not produce detectable subjective effects or alterations in mood or anxiety. Conclusion: These findings indicate that CBD has minimal behavioral and subjective effects in healthy volunteers, even when they are presented with emotional stimuli. Further research into the behavioral and neural mechanisms of CBD and other phytocannabinoids is needed to ascertain the clinical function of this drug. PMID- 28861509 TI - Cannabis and Pain: A Clinical Review. AB - Introduction: Cannabis has been used for medical purposes across the world for centuries. As states and countries implement medical and recreational cannabis policies, increasing numbers of people are using cannabis pharmacotherapy for pain. There is a theoretical rationale for cannabis' efficacy for pain management, although the subjective pain relief from cannabis may not match objective measurements of analgesia. As more patients turn to cannabis for pain relief, there is a need for additional scientific evidence to evaluate this increase. Materials and Methods: Research for this review was performed in the PubMed/National Library of Medicine database. Discussion: Preclinical studies demonstrate a narrow therapeutic window for cannabis as pharmacotherapy for pain; the body of clinical evidence for this indication is not as extensive. A recent meta-analysis of clinical trials of cannabis and cannabinoids for pain found modest evidence supporting the use of cannabinoid pharmacotherapy for pain. Recent epidemiological studies have provided initial evidence for a possible reduction in opioid pharmacotherapy for pain as a result of increased implementation of medical cannabis regimens. Conclusion: With increased use of medical cannabis as pharmacotherapy for pain comes a need for comprehensive risk benefit discussions that take into account cannabis' significant possible side effects. As cannabis use increases in the context of medical and recreational cannabis policies, additional research to support or refute the current evidence base is essential to attempt to answer the questions that so many healthcare professionals and patients are asking. PMID- 28861511 TI - Explorative Placebo-Controlled Double-Blind Intervention Study with Low Doses of Inhaled Delta9-Tetrahydrocannabinol and Cannabidiol Reveals No Effect on Sweet Taste Intensity Perception and Liking in Humans. AB - Introduction: The endocannabinoid system (ECS) plays an important role in food reward. For example, in humans, liking of palatable foods is assumed to be modulated by endocannabinoid activity. Studies in rodents suggest that the ECS also plays a role in sweet taste intensity perception, but it is unknown to what extent this can be extrapolated to humans. Therefore, this study aimed at elucidating whether Delta9-tetrahydrocannabinol (THC) or cannabidiol (CBD) affects sweet taste intensity perception and liking in humans, potentially resulting in alterations in food preferences. Materials and Methods: In a randomized placebo-controlled, double-blind crossover study, 10 healthy males participated in three test sessions that were 2 weeks apart. During the test sessions, participants received THC-rich, CBD-rich, or placebo Cannabis by inhalation divided over two doses (4 + 1 mg THC; 25 + 10 mg CBD). Participants tasted seven chocolate milk-like drinks that differed in sugar concentration and they rated sweet taste intensity and liking of the drinks. They were then asked to rank the seven drinks according to how much they liked the drinks and were offered ad libitum access to their favorite drink. In addition, they completed a computerized food preference task and completed an appetite questionnaire at the start, midway, and end of the test sessions. Results: Inhalation of the Cannabis preparations did not affect sweet taste intensity perception and liking, ranking order, or ad libitum consumption of the favorite drink. In addition, food preferences were not influenced by the interventions. Reported fullness was lower, whereas desire to eat was higher throughout the THC compared to the CBD condition. Conclusions: These results suggest that administration of Cannabis preparations at the low doses tested does not affect sweet taste intensity perception and liking, nor does it influence food preferences in humans. PMID- 28861512 TI - Identification of a Widespread Palmitoylethanolamide Contamination in Standard Laboratory Glassware. AB - Introduction: Fatty acid ethanolamides (FAEs) are a family of lipid mediators that participate in a host of biological functions. Procedures for the quantitative analysis of FAEs include organic solvent extraction from biological matrices (e.g., blood), followed by purification and subsequent quantitation by liquid chromatography-mass spectrometry (LC/MS) or gas chromatography-mass spectrometry. During the validation process of a new method for LC/MS analysis of FAEs in biological samples, we observed unusually high levels of the FAE, palmitoylethanolamide (PEA), in blank samples that did not contain any biological material. Materials and Methods: We investigated a possible source of this PEA artifact via liquid chromatography coupled to tandem mass spectrometry, as well as accurate mass analysis. Results: We found that high levels of a contaminant indistinguishable from PEA is present in new 5.75" glass Pasteur pipettes, which are routinely used by laboratories to carry out lipid extractions. This artifact might account for discrepancies found in the literature regarding PEA levels in human blood serum and other tissues. Conclusions: It is recommended to take into account this pitfall by analyzing potential contamination of the disposable glassware during the validation process of any method used for analysis of FAEs. PMID- 28861513 TI - Prevalence and Correlates of Cannabis Use in Outpatients with Serious Mental Illness Receiving Treatment for Alcohol Use Disorders. AB - Introduction: People with serious mental illness (SMI) use cannabis more than any other illicit drug. Cannabis use is associated with increased psychotic symptoms and is highly comorbid with alcohol use disorders (AUDs). Despite the national trend toward decriminalization, little is known about the prevalence, correlates, and impact of cannabis use on those with SMI receiving treatment for substance use disorders, a group at high risk for the negative effects of cannabis use. Methods: In this secondary data analysis, cannabis use prevalence, correlates, and impact on treatment outcomes were examined in 121 adults with cooccurring SMI and AUDs receiving outpatient addiction treatment in a randomized trial of contingency management (CM) for alcohol. Prevalence and frequency of cannabis use were calculated across the 7-month study period using self-report and urine tests. Cannabis users were compared with nonusers by SMI diagnosis, psychiatric symptoms, medical problems, legal problems, and HIV-risk behavior. The relationship between cannabis use and longest duration of alcohol abstinence in participants randomized to CM (n=40) was assessed. Results: Fifty-seven (47%) of participants submitted at least one cannabis-positive urine sample during the study. Out of the 2834 total samples submitted, 751 (27%) were positive for cannabis. Cannabis users were 2.2 times more likely to submit an alcohol-positive sample, and 2.5 times more likely to submit a cocaine-positive sample at baseline, relative to noncannabis users (p=0.01). Cannabis users were more likely to engage in risky sexual behavior (p=0.01) and to report being homeless (p=0.03) than nonusers. When controlling for pretreatment alcohol use, the relationship between comorbid cannabis use and alcohol abstinence during CM was not significant (p=0.77). Conclusion: Rates of comorbid cannabis use were high in this sample of adults with SMI and AUDs. Cannabis use was correlated with recent alcohol and cocaine use, risky sexual behavior, and homelessness, but not with alcohol abstinence during CM. PMID- 28861515 TI - A Guide to the National Academy of Science Report on Cannabis: An Exclusive Discussion with Panel Members. PMID- 28861514 TI - An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. AB - Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs. Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients' compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam's side effects. Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking. PMID- 28861516 TI - Cannabis as a Substitute for Opioid-Based Pain Medication: Patient Self-Report. AB - Introduction: Prescription drug overdoses are the leading cause of accidental death in the United States. Alternatives to opioids for the treatment of pain are necessary to address this issue. Cannabis can be an effective treatment for pain, greatly reduces the chance of dependence, and eliminates the risk of fatal overdose compared to opioid-based medications. Medical cannabis patients report that cannabis is just as effective, if not more, than opioid-based medications for pain. Materials and Methods: The current study examined the use of cannabis as a substitute for opioid-based pain medication by collecting survey data from 2897 medical cannabis patients. Discussion: Thirty-four percent of the sample reported using opioid-based pain medication in the past 6 months. Respondents overwhelmingly reported that cannabis provided relief on par with their other medications, but without the unwanted side effects. Ninety-seven percent of the sample "strongly agreed/agreed" that they are able to decrease the amount of opiates they consume when they also use cannabis, and 81% "strongly agreed/agreed" that taking cannabis by itself was more effective at treating their condition than taking cannabis with opioids. Results were similar for those using cannabis with nonopioid-based pain medications. Conclusion: Future research should track clinical outcomes where cannabis is offered as a viable substitute for pain treatment and examine the outcomes of using cannabis as a medication assisted treatment for opioid dependence. PMID- 28861517 TI - The Microtubule-Stabilizing Protein CLASP1 Associates with the Theileria annulata Schizont Surface via Its Kinetochore-Binding Domain. AB - Theileria is an apicomplexan parasite whose presence within the cytoplasm of a leukocyte induces cellular transformation and causes uncontrolled proliferation and clonal expansion of the infected cell. The intracellular schizont utilizes the host cell's own mitotic machinery to ensure its distribution to both daughter cells by associating closely with microtubules (MTs) and incorporating itself within the central spindle. We show that CLASP1, an MT-stabilizing protein that plays important roles in regulating kinetochore-MT attachment and central spindle positioning, is sequestered at the Theileria annulata schizont surface. We used live-cell imaging and immunofluorescence in combination with MT depolymerization assays to demonstrate that CLASP1 binds to the schizont surface in an MT independent manner throughout the cell cycle and that the recruitment of the related CLASP2 protein to the schizont is MT dependent. By transfecting Theileria infected cells with a panel of truncation mutants, we found that the kinetochore binding domain of CLASP1 is necessary and sufficient for parasite localization, revealing that CLASP1 interaction with the parasite occurs independently of EB1. We overexpressed the MT-binding domain of CLASP1 in parasitized cells. This exhibited a dominant negative effect on host MT stability and led to altered parasite size and morphology, emphasizing the importance of proper MT dynamics for Theileria partitioning during host cell division. Using coimmunoprecipitation, we demonstrate that CLASP1 interacts, directly or indirectly, with the schizont membrane protein p104, and we describe for the first time TA03615, a Theileria protein which localizes to the parasite surface, where it has the potential to participate in parasite-host interactions. IMPORTANCET. annulata, the only eukaryote known to be capable of transforming another eukaryote, is a widespread parasite of veterinary importance that puts 250 million cattle at risk worldwide and limits livestock development for some of the poorest people in the world. Crucial to the pathology of Theileria is its ability to interact with host microtubules and the mitotic spindle of the infected cell. This study builds on our previous work in investigating the host and parasite molecules involved in mediating this interaction. Because it is not possible to genetically manipulate Theileria schizonts, identifying protein interaction partners is critical to understanding the function of parasite proteins. By identifying two Theileria surface proteins that are involved in the interaction between CLASP1 and the parasite, we provide important insights into the molecular basis of Theileria persistence within a dividing cell. PMID- 28861518 TI - Butyrate Supplementation at High Concentrations Alters Enteric Bacterial Communities and Reduces Intestinal Inflammation in Mice Infected with Citrobacter rodentium. AB - Butyrate is a short-chain fatty acid by-product of the microbial fermentation of dietary fermentable materials in the large intestine; it is the main energy source for enterocyte regeneration, modulates the enteric microbial community, and contributes to increasing host health via mechanisms that are relatively poorly defined. Limited research has examined the therapeutic potential of butyrate using models of enteric inflammation incited by pathogenic organisms. We used Citrobacter rodentium to incite acute Th1/Th17 inflammation to ascertain the impact of butyrate on the host-microbiota relationship. Rectal administration of 140 mM butyrate to mice increased fecal concentrations of butyrate and increased food consumption and weight gain in mice infected with C. rodentium. Histological scores of colonic inflammation were lower in infected mice administered 140 mM butyrate. Expression of Il10, Tgfbeta, and Muc2 was elevated in noninfected mice administered butyrate in comparison to mice not administered butyrate. Infected mice administered butyrate displayed elevated expression of genes necessary for pathogen clearance (i.e., Il17A and Il1beta) and of genes involved in epithelial barrier repair and restoration (i.e., Relmbeta, Tff3, and Myd88). Butyrate supplemented to inflamed colons increased the abundances of Proteobacteria and Lachnospiraceae and reduced the abundance of Clostridiaceae species. Mice with enteritis that were administered butyrate also exhibited an increased abundance of mucus-associated bacteria. In summary, rectal administration of butyrate increased feed consumption and weight gain, ameliorated C. rodentium-induced cell injury through enhanced expression of immune regulation and tissue repair mechanisms, and increased the abundance of butyrate-producing bacteria in mice with enteritis. IMPORTANCE The study findings provide evidence that administration of butyrate in a dose-dependent manner can increase weight gain in infected mice, enhance clearance of the infection, reduce inflammation through altered cytokine expression, and enhance tissue repair and mucus secretion. Moreover, butyrate treatment also affected the abundance of bacterial populations in both noninflamed and inflamed intestines. Notably, this investigation provides foundational information that can be used to determine the effects of prebiotics and other functional foods on the production of butyrate by enteric bacteria and their impact on intestinal health and host well-being. PMID- 28861519 TI - An Aptamer-Based Biosensor for the Azole Class of Antifungal Drugs. AB - This technical report describes the development of an aptamer for sensing azole antifungal drugs during therapeutic drug monitoring. Modified synthetic evolution of ligands through exponential enrichment (SELEX) was used to discover a DNA aptamer recognizing azole class antifungal drugs. This aptamer undergoes a secondary structural change upon binding to its target molecule, as shown through fluorescence anisotropy-based binding measurements. Experiments using circular dichroism spectroscopy revealed a unique G-quadruplex structure that was essential and specific for binding to the azole antifungal target. Aptamer functionalized graphene field effect transistor (GFET) devices were created and used to measure the strength of binding of azole antifungals to this surface. In total, this aptamer and the supporting sensing platform provide a valuable tool for therapeutic drug monitoring of patients with invasive fungal infections. IMPORTANCE We have developed the first aptamer directed toward the azole class of antifungal drugs and a functional biosensor for these drugs. This aptamer has a unique secondary structure that allows it to bind to highly hydrophobic drugs. The aptamer works as a capture component of a graphene field effect transistor device. These devices can provide a quick and easy assay for determining drug concentrations. These will be useful for therapeutic drug monitoring of azole antifungal drugs, which is necessary to deal with the complex drug dosage profiles. PMID- 28861520 TI - Arginine Exposure Decreases Acidogenesis in Long-Term Oral Biofilm Microcosms. AB - Arginine is an important pH-elevating agent in the oral cavity. It has been incorporated in oral hygiene formulations to mitigate sensitivity and to prevent caries. In this investigation, the effects of sustained arginine dosing of dental plaque microcosms on bacteriological composition and pH were evaluated under controlled conditions. Plaque microcosms were established in constant-depth film fermentors (CDFFs) using salivary inocula and fed continuously with artificial saliva. To simulate resting and cariogenic states, the CDFFs were supplemented with sterile water or 5% sucrose, respectively. Plaques were then dosed twice daily with a dentifrice with 1.5% arginine arginine added (DA) or without arginine (DN). This regimen continued for over 3 weeks, after which fermentors were maintained without dosing. Microcosms were analyzed by differential viable counting, with a pH microelectrode, and by eubacterial DNA profiling. Sucrose dosing was associated with significantly (P < 0.001) decreased pH, significantly (P < 0.05) increased counts of total aerobes, Gram-negative anaerobes, aciduric species, acidogenic species, arginine utilizing species, bifidobacteria, lactobacilli and streptococci, and significant (P < 0.05) changes in DNA profiles. Plaques dosed with DA had a significantly (P < 0.001) higher pH than those dosed with DN, with or without sucrose supplementation. Dosing with DA but not DN significantly (P < 0.05) decreased counts of all functional bacterial groups apart from the total anaerobes in cariogenic plaques, and in resting plaques, dosing with DA significantly (P < 0.05) decreased counts of streptococci, lactobacilli, bifidobacteria, and acidogenic bacteria. In summary, sustained exposure of oral microcosms to arginine in formulation significantly increased plaque pH and significantly reduced the viability of cariogenic bacterial species. IMPORTANCE Arginine is used in dental health formulations to help prevent dental cavities. This study assessed the effects of the long-term dosing of laboratory dental plaques with an arginine dentifrice. Data indicate that the addition of arginine dentifrice during sucrose challenge significantly increased plaque pH, thus potentially mitigating cariogenesis. Counts of several functional groups of bacteria associated with tooth decay were significantly decreased in the laboratory plaques during exposure to the arginine dentifrice. PMID- 28861521 TI - Options for Synthetic DNA Order Screening, Revisited. AB - Gene synthesis providers affiliated with the International Gene Synthesis Consortium (IGSC) voluntarily screen double-stranded DNA (dsDNA) synthesis orders over 200 bp to check for matches to regulated pathogens and to screen customers. Questions have been raised, however, about the continuing feasibility and effectiveness of screening. There are technical challenges (e.g., oligonucleotides and tracts of DNA less than 200 bp are not screened) and corporate challenges (e.g., the costs of screening are high, but other costs are dropping, so screening is an increasing portion of operating costs). In this article, we describe tangible actions that should be taken to (i) preserve the effectiveness of DNA order screening as a security tool and (ii) develop additional mechanisms to increase the safety and security of DNA synthesis technologies. Screening is not a perfect solution to DNA synthesis security challenges, but we believe it is still a valuable addition to security, and it can remain effective for some time. PMID- 28861522 TI - A Serendipitous Mutation Reveals the Severe Virulence Defect of a Klebsiella pneumoniae fepB Mutant. AB - Klebsiella pneumoniae is considered a significant public health threat because of the emergence of multidrug-resistant strains and the challenge associated with treating life-threatening infections. Capsule, siderophores, and adhesins have been implicated as virulence determinants of K. pneumoniae, yet we lack a clear understanding of how this pathogen causes disease. In a previous screen for virulence genes, we identified a potential new virulence locus and constructed a mutant (smr) with this locus deleted. In this study, we characterize the smr mutant and show that this mutation renders K. pneumoniae avirulent in a pneumonia model of infection. The smr mutant was expected to have a deletion of three genes, but subsequent genome sequencing indicated that a much larger deletion had occurred. Further analysis of the deleted region indicated that the virulence defect of the smr mutant could be attributed to the loss of FepB, a periplasmic protein required for import of the siderophore enterobactin. Interestingly, a DeltafepB mutant was more attenuated than a mutant unable to synthesize enterobactin, suggesting that additional processes are affected. As FepB is highly conserved among the members of the family Enterobacteriaceae, therapeutic targeting of FepB may be useful for the treatment of Klebsiella and other bacterial infections. IMPORTANCE In addition to having a reputation as the causative agent of several types of hospital-acquired infections, Klebsiella pneumoniae has gained widespread attention as a pathogen with a propensity for acquiring antibiotic resistance. It is capable of causing a range of infections, including urinary tract infections, pneumonia, and sepsis. Because of the rapid emergence of carbapenem resistance among Klebsiella strains, there is a dire need for a better understanding of virulence mechanisms and identification of new drug targets. Here, we identify the periplasmic transporter FepB as one such potential target. PMID- 28861523 TI - Monodeuterated Methane, an Isotopic Tool To Assess Biological Methane Metabolism Rates. AB - Biological methane oxidation is a globally relevant process that mediates the flux of an important greenhouse gas through both aerobic and anaerobic metabolic pathways. However, measuring these metabolic rates presents many obstacles, from logistical barriers to regulatory hurdles and poor precision. Here we present a new approach for investigating microbial methane metabolism based on hydrogen atom dynamics, which is complementary to carbon-focused assessments of methanotrophy. The method uses monodeuterated methane (CH3D) as a metabolic substrate, quantifying the aqueous D/H ratio over time using off-axis integrated cavity output spectroscopy. This approach represents a nontoxic, comparatively rapid, and straightforward approach that supplements existing radiotopic and stable carbon isotopic methods; by probing hydrogen atoms, it offers an additional dimension for examining rates and pathways of methane metabolism. We provide direct comparisons between the CH3D procedure and the well-established 14CH4 radiotracer method for several methanotrophic systems, including type I and II aerobic methanotroph cultures and methane-seep sediment slurries and carbonate rocks under anoxic and oxic incubation conditions. In all applications tested, methane consumption values calculated via the CH3D method were directly and consistently proportional to 14C radiolabel-derived methane oxidation rates. We also employed this method in a nontraditional experimental setup, using flexible, gas-impermeable bags to investigate the role of pressure on seep sediment methane oxidation rates. Results revealed an 80% increase over atmospheric pressure in methanotrophic rates the equivalent of ~900-m water depth, highlighting the importance of this parameter on methane metabolism and exhibiting the flexibility of the newly described method. IMPORTANCE Microbial methane consumption is a critical component of the global carbon cycle, with wide-ranging implications for climate regulation and hydrocarbon exploitation. Nonetheless, quantifying methane metabolism typically involves logistically challenging methods and/or specialized equipment; these impediments have limited our understanding of methane fluxes and reservoirs in natural systems, making effective management difficult. Here, we offer an easily implementable, precise method using monodeuterated methane (CH3D) that advances three specific aims. First, it allows users to directly compare methane consumption rates between different experimental treatments of the same inoculum. Second, by empirically linking the CH3D procedure with the well established 14C radiocarbon approach, we determine absolute scaling factors that facilitate rate measurements for several aerobic and anaerobic systems of interest. Third, CH3D represents a helpful tool in evaluating the relationship between methane activation and full oxidation in methanotrophic metabolisms. The procedural advantages, consistency, and novel research questions enabled by the CH3D method should prove useful in a wide range of culture-based and environmental microbial systems to further elucidate methane metabolism dynamics. PMID- 28861524 TI - Deep Sequencing of RNA from Blood and Oral Swab Samples Reveals the Presence of Nucleic Acid from a Number of Pathogens in Patients with Acute Ebola Virus Disease and Is Consistent with Bacterial Translocation across the Gut. AB - In this study, samples from the 2013-2016 West African Ebola virus outbreak from patients in Guinea with Ebola virus disease (EVD) were analyzed to discover and classify what other pathogens were present. Throat swabs were taken from deceased EVD patients, and peripheral blood samples were analyzed that had been taken from patients when they presented at the treatment center with acute illness. High throughput RNA sequencing (RNA-seq) and bioinformatics were used to identify the potential microorganisms. This approach confirmed Ebola virus (EBOV) in all samples from patients diagnosed as acute positive for the virus by quantitative reverse transcription-PCR in deployed field laboratories. Nucleic acid mapping to Plasmodium was also used on the patient samples, confirming results obtained with an antigen-based rapid diagnostic test (RDT) conducted in the field laboratories. The data suggested that a high Plasmodium load, as determined by sequence read depth, was associated with mortality and influenced the host response, whereas a lower parasite load did not appear to affect outcome. The identifications of selected bacteria from throat swabs via RNA-seq were confirmed by culture. The data indicated that the potential pathogens identified in the blood samples were associated with translocation from the gut, suggesting the presence of bacteremia, which transcriptome data suggested may induce or aggravate the acute phase response observed during EVD. Transcripts mapping to different viruses were also identified, including those indicative of lytic infections. The development of high-resolution analysis of samples from patients with EVD will help inform care pathways and the most appropriate general antimicrobial therapy to be used in a resource-poor setting. IMPORTANCE Our results highlight the identification of an array of pathogens in the blood of patients with Ebola virus disease (EVD). This has not been done before, and the data have important implications for the treatment of patients with EVD, particularly considering antibiotic stewardship. We show that EVD patients who were also infected with Plasmodium, particularly at higher loads, had more adverse outcomes than patients with lower levels of Plasmodium. However, the presence of Plasmodium did not influence the innate immune response, and it is likely that the presence of EBOV dominated this response. Several viruses other than EBOV were identified, and bacteria associated with sepsis were also identified. These findings were indicative of bacterial translocation across the gut during the acute phase of EVD. PMID- 28861525 TI - Impacts of Penicillin Binding Protein 2 Inactivation on beta-Lactamase Expression and Muropeptide Profile in Stenotrophomonas maltophilia. AB - Penicillin binding proteins (PBPs) are involved in peptidoglycan synthesis, and their inactivation is linked to beta-lactamase expression in ampR-beta-lactamase module-harboring Gram-negative bacteria. There are seven annotated PBP genes, namely, mrcA, mrcB, pbpC, mrdA, ftsI, dacB, and dacC, in the Stenotrophomonas maltophilia genome, and these genes encode PBP1a, PBP1b, PBP1c, PBP2, PBP3, PBP4, and PBP6, respectively. In addition, S. maltophilia harbors two beta-lactamase genes, L1 and L2, whose expression is induced via beta-lactam challenge. The impact of PBP inactivation on L1/L2 expression was assessed in this study. Inactivation of mrdA resulted in increased L1/L2 expression in the absence of beta-lactam challenge, and the underlying mechanism was further elucidated. The roles of ampNG, ampDI (the homologue of Escherichia coli ampD), nagZ, ampR, and creBC in L1/L2 expression mediated by a DeltamrdA mutant strain were assessed via mutant construction and beta-lactamase activity determinations. Furthermore, the strain DeltamrdA-mediated change in the muropeptide profile was assessed using liquid chromatography mass spectrometry (LC-MS). The mutant DeltamrdA-mediated L1/L2 expression relied on functional AmpNG, AmpR, and NagZ, was restricted by AmpDI, and was less related to the CreBC two-component system. Inactivation of mrdA significantly increased the levels of total and periplasmic N acetylglucosaminyl-1,6-anhydro-N-acetylmuramyl-l-alanyl-d-glutamyl-meso diamnopimelic acid-d-alanine (GlcNAc-anhMurNAc tetrapeptide, or M4N), supporting that the critical activator ligands for mutant strain DeltamrdA-mediated L1/L2 expression are anhMurNAc tetrapeptides. IMPORTANCE Inducible expression of chromosomally encoded beta-lactamase(s) is a key mechanism for beta-lactam resistance in Enterobacter cloacae, Citrobacter freundii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. The muropeptides produced during the peptidoglycan recycling pathway act as activator ligands for beta-lactamase(s) induction. The muropeptides 1,6-anhydromuramyl pentapeptide and 1,6 anhydromuramyl tripeptide are the known activator ligands for ampC beta-lactamase expression in E. cloacae. Here, we dissected the type of muropepetides for L1/L2 beta-lactamase expression in an mrdA deletion mutant of S. maltophilia. Distinct from the findings with the ampC system, 1,6-anhydromuramyl tetrapeptide is the candidate for DeltamrdA-mediated beta-lactamase expression in S. maltophilia. Our work extends the understanding of beta-lactamase induction and provides valuable information for combating the occurrence of beta-lactam resistance. PMID- 28861527 TI - Gender Variance Among Youth with Autism Spectrum Disorders: A Retrospective Chart Review. AB - Purpose: Increasing clinical evidence suggests an overrepresentation of gender variance (GV) among patients with autism spectrum disorders (ASDs). This retrospective chart review aims to contribute to the existing literature on co occurring ASD and gender dysphoria (GD). We compare the rate of parent-reported GV in patients with an ASD diagnosis to that of parent-reported GV in a normative nonreferred data set. Methods: Child Behavior Checklist (CBCL) charts were collected from 492 children and adolescents (409 natal males and 83 natal females) aged 6-18 years who have received a diagnosis of ASD at the New York University Child Study Center. Parent-reported GV was determined through endorsement of CBCL sex item 110, which assesses the presence of gender-related issues. We calculated the odds ratio of endorsement of item 110 between our ASD sample and the CBCL sample data. Results: The subjects diagnosed with ASD were 7.76 times more likely to report GV than the CBCL sample. This finding was statistically significant. About 5.1% of the patients in the ASD group and 0.7% of the CBCL nonreferred group endorsed sex item 110. 5.1% of natal males and 4.8% of natal females endorsed sex item 110. Neither gender nor age influenced the rate of endorsement. Conclusion: This finding supports the growing research suggesting a heightened co-occurrence rate of ASD and GD. Focus should be placed upon improving our understanding of the nature of this co-occurrence and on gender identity development within the atypical development of ASD. PMID- 28861526 TI - Metabolic Network Analysis and Metatranscriptomics Reveal Auxotrophies and Nutrient Sources of the Cosmopolitan Freshwater Microbial Lineage acI. AB - An explosion in the number of available genome sequences obtained through metagenomics and single-cell genomics has enabled a new view of the diversity of microbial life, yet we know surprisingly little about how microbes interact with each other or their environment. In fact, the majority of microbial species remain uncultivated, while our perception of their ecological niches is based on reconstruction of their metabolic potential. In this work, we demonstrate how the "seed set framework," which computes the set of compounds that an organism must acquire from its environment (E. Borenstein, M. Kupiec, M. W. Feldman, and E. Ruppin, Proc Natl Acad Sci U S A 105:14482-14487, 2008, https://doi.org/10.1073/pnas.0806162105), enables computational analysis of metabolic reconstructions while providing new insights into a microbe's metabolic capabilities, such as nutrient use and auxotrophies. We apply this framework to members of the ubiquitous freshwater actinobacterial lineage acI, confirming and extending previous experimental and genomic observations implying that acI bacteria are heterotrophs reliant on peptides and saccharides. We also present the first metatranscriptomic study of the acI lineage, revealing high expression of transport proteins and the light-harvesting protein actinorhodopsin. Putative transport proteins complement predictions of nutrients and essential metabolites while providing additional support of the hypothesis that members of the acI are photoheterotrophs. IMPORTANCE The metabolic activity of uncultivated microorganisms contributes to numerous ecosystem processes, ranging from nutrient cycling in the environment to influencing human health and disease. Advances in sequencing technology have enabled the assembly of genomes for these microorganisms, but our ability to generate reference genomes far outstrips our ability to analyze them. Common approaches to analyzing microbial metabolism require reconstructing the entirety of an organism's metabolic pathways or performing targeted searches for genes involved in a specific process. This paper presents a third approach, in which draft metabolic reconstructions are used to identify compounds through which an organism may interact with its environment. These compounds can then guide more-intensive metabolic reconstruction efforts and can also provide new hypotheses about the specific contributions that microbes make to ecosystem-scale metabolic processes. PMID- 28861528 TI - Policy Perspective: Ensuring Comprehensive Care and Support for Gender Nonconforming Children and Adolescents. AB - Despite recent notable advances in societal equality for lesbian, gay, bisexual, and transgender (LGBT) individuals, youth who identify as trans* or gender nonconforming, in particular, continue to experience significant challenges accessing the services they need to grow into healthy adults. This policy perspective first offers background information describing this population, their unique healthcare needs, and obstacles when seeking care, including case study examples. The authors then provide recommendations for medical education, health systems, and insurance payers, as well as recommendations for school systems and broader public policy changes to improve the health and well-being of gender nonconforming youth. PMID- 28861529 TI - Multidisciplinary Care for Gender-Diverse Youth: A Narrative Review and Unique Model of Gender-Affirming Care. AB - Heightened public awareness about gender diversity in childhood and adolescence has resulted in more youth and families seeking medical and mental health services. In response to these needs, there has been nationwide growth in specialized multidisciplinary clinics treating gender-diverse and transgender youth. Despite general agreement that comprehensive treatment is best delivered through a multidisciplinary team by both medical and mental health clinicians with gender-related expertise and familiarity with child and adolescent development, there is currently no consensus regarding the best approach to clinical care with gender-diverse and transgender youth. In this article, we provide a narrative review of the gender affirmative model guiding our clinical practice and describe the development of our unique model of affirming care within the Gender and Sex Development Program at the Ann & Robert H. Lurie Children's Hospital of Chicago. PMID- 28861530 TI - A Comparison of HIV-Related Risk Factors Between Black Transgender Women and Black Men Who Have Sex with Men. AB - Purpose: Rates of HIV infection among transgender women (TW) are higher than rates observed among men who have sex with men (MSM), and black or African American individuals are at a disproportionately higher risk for HIV than individuals of other races. Limited information, however, is available regarding the needs of black TW and their risk for HIV. Numerous scholarly works and surveillance reports have combined TW with MSM, which has stymied our ability to understand the unique needs of black TW. Methods: To identify patterns of HIV risk among black TW and black MSM, the current study utilized a cross-sectional, convenience sample to compare sociodemographic risk factors, HIV prevention tools, HIV-related risk factors, and psychosocial and sexual risk factors in a sample of 58 black TW and 764 black MSM. Participants were recruited between 2012 and 2014 from Atlanta, GA. Results: Findings demonstrated that black TW were significantly more likely to report lower educational attainment (odds ratio [OR]=0.60, 95% confidence interval [CI]: 0.42-0.85, p=0.005), greater likelihood of being homeless (OR=2.49, 95% CI: 1.30-4.78, p=0.006), lower HIV testing knowledge (OR=0.66, 95% CI: 0.52-0.83, p=0.001), and higher likelihood of having engaged in transactional sex (OR=1.95, 95% CI: 0.99-3.83, p=0.052) compared to black MSM. Conclusions: These findings highlight the need to understand how risk factors for HIV present themselves similarly and differently for both black TW and black MSM, and for HIV prevention programs and interventions to incorporate evidence-based content for each group. PMID- 28861531 TI - The Association Between Geographic Location and Anxiety and Depression in Transgender Individuals: An Exploratory Study of an Online Sample. AB - Purpose: Research has demonstrated associations between discrimination and mental health in lesbian, gay, bisexual, and transgender populations. However, little is known about the influence of geographic location on psychological distress in these populations, particularly among transgender people. Methods: This secondary analysis conducted on a national sample of transgender individuals (N=414) offers a preliminary understanding of the effects of geographic location on psychological distress (i.e., anxiety and depression). A univariate analysis of variance was calculated to determine this relationship. Results: The West South Central division (i.e., Arkansas, Louisiana, Oklahoma, and Texas) revealed highest psychological distress. Conclusion: Results suggest an urgent need for transgender-competent healthcare in this division. PMID- 28861532 TI - Perceptions of Barriers to and Facilitators of Participation in Health Research Among Transgender People. AB - Purpose: Although transgender people may be at increased risk for a range of health problems, they have been the subject of relatively little health research. An important step toward expanding the evidence base is to understand and address the reasons for nonparticipation and dropout. The aim of this study was to explore the perceptions of barriers to and facilitators of participation in health research among a sample of transgender people in San Francisco, CA, and Atlanta, GA. Methods: Twelve in-person focus groups (FGs) were conducted; six (three with transwomen, three with transmen) were conducted in San Francisco and six FGs were conducted in Atlanta (three with transwomen and three with transmen). FGs were audiorecorded, transcribed, and uploaded to MaxQDA software for analysis. A codebook was used to code transcripts; new codes were added iteratively as they arose. All transcripts were coded by at least 2 of the 4 researchers and, after each transcript was coded, the researchers met to discuss any discrepancies, which were resolved by consensus. Results: Among 67 FG participants, 37 (55%) identified as transmen and 30 (45%) identified as transwomen. The average age of participants was ~41 years (range 18-67) and the majority (61%) were non-Hispanic Whites. Several barriers that can hinder participation in health research were identified, including logistical concerns, issues related to mistrust, a lack of awareness about participation opportunities, and psychosocial/emotional concerns related to being "outed." A broad range of facilitators were also identified, including the opportunity to gain knowledge, access medical services, and contribute to the transgender community. Conclusion: These findings provide insights about the perceived barriers to and facilitators of research participation and offer some guidance for researchers in our ongoing effort to engage the transgender community in health research. PMID- 28861533 TI - Fertility-Related Care for Gender and Sex Diverse Individuals: A Provider Needs Assessment Survey. AB - Twelve providers (eight institutions) participating in a Gender and Sex Diversity Fertility Working Group completed a survey assessing their hospital's transgender, disorders/differences of sex development (DSD), and fertility healthcare teams. Participants also prioritized the development of a: (1) Provider Assessment Tool (questionnaire assessing knowledge/feelings about future fertility), or (2) decision aid (DA). Healthcare team presence by institution: transgender (6/8; 75%), DSD (75%), and fertility preservation (75%). Two-thirds of providers reported that the DA was most needed. Respondents recommended the DA to: help manage complex information, have a take-home reference, and provide neutral information. Other identified resource needs included: fertility specialists in clinic and financial resources. PMID- 28861534 TI - Scalp Hair Regrowth in Hormone-Treated Transgender Woman. AB - Evidence of androgenetic alopecia, or male pattern baldness, can be distressing for transgender women. Here we present the case of a transgender woman with scalp hair regrowth after ~6 months on oral estradiol and spironolactone therapy achieving testosterone levels within normal female range. PMID- 28861535 TI - Patient Perspectives on Gender Identity Data Collection in Electronic Health Records: An Analysis of Disclosure, Privacy, and Access to Care. AB - Purpose: In 2015, the Centers for Medicare and Medicaid Services ruled that health organizations comply with additional requirements for electronic health records (EHRs), known as "Meaningful Use," and develop the capacity to collect gender identity data. Research has established effectiveness of a two-step gender identity question to collect these data. This study examines transgender patient perspectives on the use of a two-step question and experiences with privacy and sensitive disclosures in EHRs and healthcare settings. Methods: Four focus groups (N=30) were conducted in Chicago, Illinois in 2014-2015. Participants were asked to compare two intake forms-one with a two-step question and one with a single question-and discuss experiences with gender identity disclosure, privacy, and access to care. Narratives were transcribed verbatim to identify patterns and themes; the extended case method was used and grounded the data analysis process in the concept of intersectionality. Results: Participants expressed appreciation for improved reliability and competencies that the two-part question may afford. Narratives reveal concerns related to patient privacy, safety, and access because of the contexts in which these data are collected and transmitted. Virtually all participants described situations whereby sensitive gender identity information had been involuntarily disclosed, misinterpreted, or abused, and safety and care were compromised. Conclusion: Participants recognized the potential of the two part question as a measurement and competency tool, but anticipated new privacy violations and involuntary disclosures. Narratives indicate that effects of sensitive disclosures may vary intersectionally, whereby white participants experienced lesser harms than their immigrant, HIV-positive, and black trans feminine counterparts. Discrimination and privacy violations may occur regardless of a two-part or one-part gender identity question, but increasing these sensitive disclosures within expanding EHR infrastructures may require a range of mechanisms that have flexibility across contexts to safeguard sensitive information and access to care. PMID- 28861536 TI - Opportunities and Gaps in Primary Care Preventative Health Services for Transgender Patients: A Systemic Review. AB - Purpose: Transgender people face barriers to accessing healthcare, resulting in population-level disparities in health outcomes. Little research is available to better understand the receipt of primary healthcare among transgender patients or how the rate of receipt of preventive care may differ among transgender populations. Methods: The medical literature regarding U.S. adult transgender primary healthcare was reviewed using a keyword search strategy: transgender OR transsexual OR transvestite OR gender nonconforming for articles published between January 1, 2001 and June 15, 2015. Studies addressing the following topics as assessed by the Behavioral Risk Factor Surveillance System were extracted for qualitative review: colorectal cancer screenings, mammography or chest/breast tissue examinations, cholesterol and blood pressure screenings, tobacco use and smoking cessation, cervical cancer or human papillomavirus (HPV) screenings, human immunodeficiency virus (HIV), annual flu shot, and insurance coverage. Results: The search identified 1304 eligible records, of which 41 discussed transgender primary or preventive care. The majority of studies discussed HIV rates or risk behaviors, while fewer articles addressed pelvic examinations, tobacco use, insurance coverage, and cholesterol screenings. No studies addressed mammography or chest/breast tissue examinations, colorectal screenings, or flu shots. Conclusions: Findings from articles addressing five topics are discussed: HIV, cholesterol screenings, tobacco use, pelvic health, and insurance coverage. Gaps in the extant literature, including the lack of studies of nonbinary people, transgender men of color, and transgender people living outside of large coastal urban centers, are discussed. This review, coincident with other health disparity findings, suggests an urgent need for research that addresses the primary care needs of all transgender and gender nonconforming people. PMID- 28861537 TI - An Exploratory Study of Transgender New Yorkers' Use of Sexual Health Services and Interest in Receiving Services at Planned Parenthood of New York City. AB - Purpose: Transgender individuals experience barriers to healthcare, including discrimination in care provision and lack of knowledge about transgender health. We assessed New York City (NYC) transgender and gender nonconforming individuals' sexual and reproductive health (SRH) needs, access to services, and interest in receiving services from Planned Parenthood of NYC (PPNYC). Methods: We conducted an anonymous Internet-based survey of transgender individuals residing in NYC from September to December 2014 by using snowball sampling. Results: Data were analyzed from 113 surveys. Although 74% (71/96) of respondents avoided or delayed healthcare in the past year, most respondents adhered to medically indicated SRH screenings. In the past year, 64% (45/70) and 67% (46/69) of respondents were tested for HIV and other sexually transmitted infections, respectively. In the past 3 years, 80% (39/49) of respondents received clinical breast/chest examinations and 83% (35/42) of eligible individuals received Pap tests. Respondents most often received care at LGBT specialty clinics (35% [37/105]) or at private doctors' offices (31% [32/105]). Eighteen percent (19/107) had ever been to a Planned Parenthood health center. On a four-point scale, respondents rated the following factors as most influential on whether they would seek care at PPNYC: assurance that staff received transsensitivity training (mean 3.8), the existence of gender identity nondiscrimination policies (mean 3.7), and the availability of transgender-specific services, such as hormone therapy (mean 3.7). Conclusions: Although the majority of transgender individuals in our sample received recommended SRH screenings, respondents reported barriers to accessing needed medical care. Healthcare organizations interested in better serving the transgender community should ensure a high level of training around transsensitivity and explore the provision of transgender-specific services. PMID- 28861538 TI - Exploring Healthcare Experiences of Transgender Individuals. AB - Purpose: It has been widely noted that existing healthcare systems do not always function effectively for the transgender population. Despite existing healthcare barriers, however, transgender individuals have been shown to have positive healthcare experiences. This study explored a cohort of transgender individuals who had positive healthcare experiences, and those who were involved in creating a positive healthcare experience for transgender individuals. Methods: A single case study was conducted, which included 10 interviews with transgender individuals, healthcare providers, and friends/family/significant others of transgender individuals. Data were analyzed through thematic analysis. Results: Seven key themes emerged within macro levels (large-scale system), meso levels (local/interpersonal), and micro levels (individual/internal) of healthcare system support. At a macro level, few system strengths were shown, with hope for change in the future. On a meso level, both external supports and informal networking emerged as key factors in positive healthcare experiences. At the micro level, self-navigation, characteristics for success, and personal strategy development were important for achieving positive experiences. Conclusion: Factors that contribute to positive healthcare experiences for transgender individuals were outlined in this study, showing that meso and micro level support compensate for large-scale healthcare system deficits. PMID- 28861539 TI - Identifying the Transgender Population in the Medicare Program. AB - Purpose: To identify and describe the transgender population in the Medicare program using administrative data. Methods: Using a combination of International Classification of Diseases ninth edition (ICD-9) codes relating to transsexualism and gender identity disorder, we analyzed 100% of the 2013 Centers for Medicare & Medicaid Services (CMS) Medicare Fee-For-Service (FFS) "final action" claims from both institutional and noninstitutional providers (~1 billion claims) to identify individuals who may be transgender Medicare beneficiaries. To confirm, we developed and applied a multistage validation process. Results: Four thousand ninety-eight transgender beneficiaries were identified, of which ~90% had confirmatory diagnoses, billing codes, or evidence of a hormone prescription. In general, the racial, ethnic, and geographic distribution of the Medicare transgender population tends to reflect the broader Medicare population. However, age, original entitlement status, and disease burden of the transgender population appear substantially different. Conclusions: Using a variety of claims information, ranging from claims history to additional diagnoses, billing modifiers, and hormone prescriptions, we demonstrate that administrative data provide a valuable resource for identifying a lower bound of the Medicare transgender population. In addition, we provide a baseline description of the diversity and disease burden of the population and a framework for future research. PMID- 28861540 TI - High Willingness to Use HIV Pre-Exposure Prophylaxis Among Transgender Women in Argentina. AB - Purpose: In Argentina, transgender women face a disproportionately high prevalence of HIV infection (34%). Although not currently approved in Argentina, pre-exposure prophylaxis (PrEP) may offer a potential effective HIV prevention tool for this population. In this study, we assessed the willingness to use PrEP among transgender women in Argentina. Methods: Data were drawn from a nationwide cross-sectional survey conducted among transgender women in 2013. Using multivariable logistic regression, we assessed the prevalence of and factors associated with willingness to use PrEP among transgender women with negative or unknown HIV status. Results: This study included 337 transgender women (278 HIV negative and 59 with unknown HIV status), most of whom had a history of sex work involvement (81.8%). Overall, 301 (89.3%) expressed willingness to use PrEP. In a multivariable analysis, having casual sexual partners was positively associated with willingness to use PrEP (adjusted odds ratio [AOR]=4.26, 95% confidence interval [CI] 1.73-10.51), while discrimination by healthcare workers was negatively associated (AOR=0.33, 95% CI 0.12-0.88). Conclusion: We found high levels of willingness to use PrEP among transgender women in Argentina, suggesting that there is high perception of HIV risk in this population. However, discrimination by healthcare workers was a strong negative correlate of willingness to use PrEP, suggesting that multilevel interventions that address gender-based stigma in healthcare settings will be critical for the success of PrEP as an HIV prevention strategy in this population. PMID- 28861541 TI - Rumination as a Marker of Psychological Improvement in Transsexual Women Postoperative. AB - Purpose: This study aimed to analyze rumination levels of transsexual women before and after gender affirmation surgery (GAS). Rumination scores may represent a broader measure of GAS success and an alternative to patient-reported satisfaction, quality of life, well-being, or the presence of "caseness" for anxiety or depression as previously established in the literature. Methods: Thirty-nine transsexual women were recruited. The participants completed the rumination scale of the Response Styles Questionnaire (RSQ) and were divided into three subsets according to the treatment time. Results: The rumination scores were lower in the transsexual women who had undergone surgical procedures on primary sexual characteristics and gradually decreased with each additional procedure completed with respect to secondary sexual characteristics. Conclusion: Rumination appears to comprise an important marker of improvement in post-GAS transsexual women. PMID- 28861542 TI - Psychosocial Disparities Among Racial/Ethnic Minority Transgender Young Adults and Young Men Who Have Sex with Men Living in Detroit. AB - Purpose: Transgender populations in the United States experience unique inequities in health and social well-being; however, they continue to be categorized with men who have sex with men (MSM) in HIV surveillance. To illustrate the differences in the lived realities of young MSM and transgender youth, we compare psychosocial outcomes across a sample of transgender and MSM youth from Detroit. Methods: Data for this study come from a community-based cross-sectional survey of young adults (ages 18-29) living in Detroit who identify as transgender and/or as cisgender young men who have sex with men (YMSM). Using participants' geographic location within the city of Detroit, we matched transgender participants (N=26) to YMSM (N=123) living in the same area, and compared the prevalence in risk and resilience indicators across the two groups. Results: Transgender participants were more likely than YMSM to experience socioeconomic vulnerability across several indicators, including lower educational attainment and workforce participation, greater residential instability, and higher lifetime experiences of transactional sex. Transgender participants were more likely than YMSM to report poorer health status, higher symptoms of depression and anxiety, and greater experiences of daily hassles and gender-related discrimination. Transgender participants did not differ from YMSM peers on health-promotive factors, including self-esteem, coping mastery, purpose in life, or social support. Conclusions: Our findings underscore the importance of addressing the social and economic inequities experienced by transgender young adults. Local- and national-level programmatic and policy interventions are recommended to alleviate the psychosocial vulnerability experienced by transgender young adults and to improve their health and social well-being. PMID- 28861543 TI - Interviews with Patients and Providers on Transgender and Gender Nonconforming Health Data Collection in the Electronic Health Record. AB - Purpose: Meaningful use (MU) and Uniform Data Systems (UDSs) are calling for the collection of gender identity (GI) in electronic health record (EHR) systems; however, many transgender and nonconforming (TGNC) patients may not feel safe disclosing their GI and the data collection is not designed to guide care provision. This study explores the complexities surrounding the inclusion of GI in EHR data collection and how it can best serve patients and providers. Methods: Using a semistructured interview format, TGNC patients (n=7) and providers (n=5) who care for TGNC patients were asked about data collection procedures and the use of these data within community health centers in Oregon. Using a constant comparative data analysis methodology, interview transcripts were coded for emergent concepts until overlapping themes were identified. Results: Both patients and providers expressed a need for the EHR to expand upon MU and UDS recommended fields to include current pronouns and name and gender identifiers in a forward-facing display to prevent misgendering by clinic staff and providers. Furthermore, they both cited the need for a broader range of birth-assigned sex and gender options. TGNC patients and providers disagreed on the scope of health information to be collected as well as who should be tasked with the data collection. Conclusion: These interviews offer us a glimpse into the structural difficulties of creating an EHR system that serves the needs of clinicians while providing safe and culturally competent care to TGNC patients. PMID- 28861544 TI - Transgender and Gender Nonconforming in Emergency Departments: A Qualitative Report of Patient Experiences. AB - Background: Individuals who have a transgender or gender nonconforming (TGGNC) experience belong to a marginalized segment of the U.S. population, and healthcare can be difficult for them to navigate. Although emergency departments (EDs) traditionally serve as healthcare "safety nets" for vulnerable populations, quantitative studies outside the United States have found that TGGNC-experienced persons tend to avoid EDs and/or have negative experiences. This qualitative study primarily describes the ED experiences of people with a TGGNC history; furthermore, the study explores reasons why this population avoids U.S. EDs and their recommendations for improvements to ED care. Methods: This qualitative study used data about TGGNC-historied persons' experiences in U.S. EDs from retrospective, anonymous, written surveys (paper or web based). National data collection took place from June 2012 through December 2014. Participant responses (n=240) were examined using thematic analysis. Results: Using a framework that recognized positive and negative responses, the themes of Self-Efficacy and Power Inequity surfaced. These themes exposed the tension between patients with TGGNC experiences and clinicians who were perceived to lack training in this area, resulting in negative patient experiences. When practitioners had specific training about this population, participants reported positive care experiences. Conclusions: This study indicates that many TGGNC-historied persons who use U.S. EDs have negative experiences, largely due to lack of provider sensitivity toward and training about this patient population. Data from this investigation suggest that training of U.S. ED providers and institutional support would help improve care for this marginalized group. PMID- 28861545 TI - Transgender Noninclusive Healthcare and Delaying Care Because of Fear: Connections to General Health and Mental Health Among Transgender Adults. AB - Purpose: There are many barriers to reliable healthcare for transgender people that often contribute to delaying or avoiding needed medical care. Yet, few studies have examined whether noninclusive healthcare and delaying needed medical care because of fear of discrimination are associated with poorer health among transgender adults. This study aims to address these gaps in the knowledge base. Methods: This study analyzed secondary data from a statewide survey of 417 transgender adults in the Rocky Mountain region of the United States. Independent variables included noninclusive healthcare from a primary care provider (PCP) and delay of needed medical care because of fear of discrimination. Dependent variables assessed general health and mental health. Results: Transgender individuals who delayed healthcare because of fear of discrimination had worse general health in the past month than those who did not delay or delayed care for other reasons (B=-0.26, p<0.05); they also had 3.08 greater odds of having current depression, 3.81 greater odds of a past year suicide attempt, and 2.93 greater odds of past year suicidal ideation (p<0.001). After controlling for delayed care because of fear of discrimination, having a noninclusive PCP was not significantly associated with either general health or mental health. Conclusion: This study suggests a significant association between delaying healthcare because of fear of discrimination and worse general and mental health among transgender adults. These relationships remain significant even when controlling for provider noninclusivity, suggesting that fear of discrimination and consequent delay of care are at the forefront of health challenges for transgender adults. The lack of statistical significance for noninclusive healthcare may be related to the measurement approach used; future research is needed to develop an improved tool for measuring transgender noninclusive healthcare. PMID- 28861546 TI - Addressing the Needs of Transgender Military Veterans: Better Access and More Comprehensive Care. AB - Purpose: There is a gap in social science literature addressing issues of access and quality of care for transgender military veterans. Psychologists, medical doctors, and other health professionals are beginning to address some of the barriers present in the Department of Veterans Affairs (VA) system that affect veterans who are also transgender and intersex. Over a 7-year period, between 2006 and 2013, 2600 transgender veterans were served by the VA. Data from several surveys revealed that most transgender veterans perceive the Veterans Health Administration (VHA) to be less than accommodating for their special needs. The goal of this study was to investigate the experiences of a sample of transgender veterans with regard to their experiences with healthcare services provided by the VHA. Methods: Using snowball sampling techniques, we were able to recruit 22 transgender military veterans to participate in our study. A combination of telephone interviews and questionnaires provided data from veterans in various branches of the military throughout the United States. Results: Findings indicate that even though the VHA is working to address issues of inequality for transgender veterans, our participants indicated that there are still some problems with administration of care, proper training of staff and physicians, and availability of comprehensive services for the unique healthcare needs of transgender individuals. Conclusion: Since our data were collected, the VA has worked to bridge the gap by focusing on increased training for VHA providers and staff and establishing LGBT programs at VA facilities. However, we suggest that one key area of importance should continue to focus on how mental health and medical providers and ancillary staff are trained to interact with and provide care for their transgender patients. PMID- 28861547 TI - A Systematic Review of Interventions to Reduce Problematic Substance Use Among Transgender Individuals: A Call to Action. AB - Persons who are transgender (i.e., individuals who are assigned one sex at birth, but who do not identify with that sex) are at elevated risk for developing problematic substance use. Recent studies indicate that transgender persons have high rates of alcohol use, illicit drug use, and nonmedical use of prescription drugs and evince more severe misuse of these substances compared with nontransgender individuals. Despite the high rates of substance use among transgender persons and the multiple conceptual and narrative recommendations for substance use treatments, there is a lack of consensus or awareness of empirically tested interventions and programs effective for this population. Thus, it is critical to examine current substance use interventions for transgender individuals to identify gaps in the field and to immediately put forth efforts to reduce problematic substance use. This systematic review is the first to attempt a comprehensive identification and synthesis of the available evidence on interventions for reducing problematic substance use among transgender persons. Reflective of the state of the field regarding transgender care for substance use, we found a deficiency of studies to include in this systematic review (n=2). Perhaps the most important conclusion of this review is that well-designed, theoretically informed culturally sensitive research focused on developing and rigorously testing interventions for substance use among transgender individuals is alarmingly scarce. This review discusses barriers to intervention design and synthesizes treatment recommendations for future work. PMID- 28861549 TI - Overrepresentation of Adopted Adolescents at a Hospital-Based Gender Dysphoria Clinic. AB - Purpose: We have noted a greater than expected prevalence of adopted children presenting to our multidisciplinary gender program for evaluation of gender dysphoria. Methods: A retrospective review of 184 patient charts was conducted to assess the prevalence of adopted children presenting to gender clinic. Results: Fifteen of 184 patients seen were living with adoptive families (8.2%). This is significantly higher than expected based on U.S. census data. Conclusion: Adopted children are referred to our gender program more than would be expected based on the percentage of adopted children in our state and the United States at large. This may be due to a true increased risk of gender dysphoria in adopted children, or could represent presentation bias. Gender programs should be prepared to provide assessments for adopted children. Further work is needed to understand the relationship between adopted status and gender development. PMID- 28861550 TI - Transgender Health Accepted for Indexing in PubMed Central and Inclusion in PubMed. PMID- 28861548 TI - Varied Reports of Adult Transgender Suicidality: Synthesizing and Describing the Peer-Reviewed and Gray Literature. AB - Purpose: This article reports on the findings of a meta-synthesis undertaken on published gray transgender suicidality literature, to determine the average rate of suicidal ideation and attempts in this population. Methods: Studies included in this synthesis were restricted to the 42 that reported on 5 or more Canadian or U.S. adult participants, as published between 1997 and February 2016 in either gray or peer-reviewed health literature. Results: Across these 42 studies an average of 55% of respondents ideated about and 29% attempted suicide in their lifetimes. Within the past year, these averages were, respectively, 51% and 11%, or 14 and 22 times that of the general public. Overall, suicidal ideation was higher among individuals of a male-to-female (MTF) than female-to-male (FTM) alignment, and lowest among those who were gender non-conforming (GNC). Conversely, attempts occurred most often among FTM individuals, then decreased for MTF individuals, followed by GNC individuals. Conclusion: These findings may be useful in creating targeted interventions that take into account both the alarmingly high rate of suicidality in this population, and the relatively differential experience of FTM, MTF, and GNC individuals. Future research should examine minority stress theory and suicidality protection/resilience factors, particularly transition, on this population. PMID- 28861551 TI - Access to Medical and Mental Health Services Across the HIV Care Continuum Among Young Transgender Women: A Qualitative Study. AB - Purpose: (1) To describe psychosocial, medical, and mental health outcomes of young transgender women (YTW) living with or at risk for HIV infection and (2) to explore barriers and facilitators to medical and mental health services across the HIV care continuum. Methods: We conducted a cross-sectional observational study of YTW aged 16-24 years who were at risk for contracting or living with HIV. Participants were recruited from an adolescent HIV clinic and local community-based organizations that serve YTW. The single study visit included: a computer-assisted self-interview of demographics, medical and mental health measures, a qualitative semi-structured interview, optional rapid HIV testing for HIV-negative/status-unknown participants, and a chart review to determine rates of antiretroviral therapy (ART) prescription and viral suppression among HIV+ participants. Descriptive statistics were used for quantitative data, and a modified-grounded theory approach was used for qualitative analysis. Results: Participants (n=25) had a mean age of 21.2 years; the majority were non-white (76%), had less than a college education (76%), were unemployed (52%), and had an income <$12,000/year (80%). More than one-third were unstably housed (36%) and uninsured (36%), and 28% reported having transactional sex. A majority had taken gender-affirming hormones (72%), but 17% obtained them from a source other than their doctor. Among HIV+ participants (n=8), 50% were prescribed ART and all four participants achieved viral suppression. Qualitative themes included lack of respect for or misunderstanding of gender identity, mismatch of mental health needs with available provider skills, challenges in finding HIV prevention services during adolescence or when transitioning to adult care, and importance of workforce diversity, including representation of transgender women in care teams. Conclusion: This study identified significant unmet mental health needs and several barriers and facilitators to engaging in healthcare for YTW across the HIV care continuum. Our data suggest an urgent need for provider competency training in gender-affirming care and integration of appropriate mental health and gender-affirming treatment with HIV prevention and treatment services for this population. PMID- 28861552 TI - Internal Medicine Resident Attitudes, Prior Education, Comfort, and Knowledge Regarding Delivering Comprehensive Primary Care to Transgender Patients. AB - Transgender patients face a multitude of health disparities and often a lack of understanding by healthcare professionals. A survey was undertaken of internal medicine residents in a large urban academic training program to determine prior education, attitudes, comfort, and knowledge in providing care for transgender individuals in a primary care setting. Total N=67 respondents (52% of those eligible). A full 97% of residents believe transgender medical issues are relevant to their practice, but only 45% had prior education about the care of transgender patients. Less than one-third of respondents felt comfortable describing hormonal/surgical therapy options or referring to another physician to meet these patient needs. HIV, gonorrhea, and chlamydia risk was underestimated for the trans woman population. Most medical residents did not feel up to date with screening guidelines. In contrast, most residents correctly identified higher rates of depression/suicidality in transgender individuals, as well as lower adherence to human papillomavirus screening recommendations for trans men. PMID- 28861553 TI - MANOTA: a promising bifunctional chelating agent for copper-64 immunoPET. AB - Improved bifunctional chelating agents (BFC) are required for copper-64 radiolabelling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific imaging agents. Four different bifunctional chelating agents (BFC) were evaluated for Fab (Fragment antigen binding) conjugation and radiolabelling with copper-64. Two DOTA- (1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid) and two NOTA- (1,4,7-triazacyclononane-1,4,7-triacetic acid) derivatives bearing a p-benzyl-isothiocyanate group were conjugated to Fab trastuzumab - which targets the HER2/neu receptor - and the average number of chelators attached ranged from 2.4 to 4.3 macrocycles per Fab. Labelling of the immunoconjugate with copper-64 was achieved in high radiochemical yields after 45 min at 37 degrees C, and the radiochemical purity of each 64Cu-BFC-Fab trastuzumab reached 97% after purification. The affinity of each 64Cu-BFC-Fab trastuzumab ranged between 10 and 50 nM as evaluated by in vitro saturation assays using the HCC1954 breast cancer cell line. PET-MR imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumours were clearly visualized on PET images at 4 and 24 hours post-injection. The tumour uptake of 64Cu-BFC-Fab-trastuzumab reached 8.9 to 12.8% ID g-1 24 hours post-injection and significant differences in non specific liver uptake were observed depending on the BFC conjugated, the lowest being observed with MANOTA. These results show that MANOTA is a valuable tool for copper-64 radiolabelling. PMID- 28861554 TI - Giant lattice expansion by quantum stress and universal atomic forces in semiconductors under instant ultrafast laser excitation. AB - Femtosecond lasers (fs) can cause a disparity between electronic and lattice temperatures in the very short period after irradiation. In this relatively cool lattice regime, the material properties can differ drastically from those under thermal equilibrium. In particular, first-principles calculations reveal two general mechanical effects on semiconductors. Firstly, the excitation can induce a negative pressure on the lattice, causing a >10% expansion, even for superhard diamond. Secondly, it induces inhomogeneous local forces on the atoms, for both perfect and distorted lattices. In the case of phase-change-memory for Ge2Sb2Te5 and GeTe alloys, such random forces cause a simultaneous phase transition from crystalline to amorphous, which enables faster data writing. These excitation effects are further supported by the time-dependent density functional theory. This work could be an important step in advancing fs laser techniques for the atomic-level control of structures, rather than relying on traditional melting or ablation approaches which often apply to much larger and non-atomic scales. PMID- 28861555 TI - Cranberry Proanthocyanidins - Protein complexes for macrophage activation. AB - In this work we characterize the interaction of cranberry (Vaccinium macrocarpon) proanthocyanidins (PAC) with bovine serum albumin (BSA) and hen egg-white lysozyme (HEL) and determine the effects of these complexes on macrophage activation and antigen presentation. We isolated PAC from cranberry and complexed the isolated PAC with BSA and HEL. The properties of the PAC-protein complexes were studied by matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS), gel electrophoresis and zeta-potential. The effects of PAC-BSA complexes on macrophage activation were studied in RAW 264.7 macrophage like cells after treatment with lipopolysaccharide (LPS). Fluorescence microscopy was used to study the endocytosis of PAC-BSA complexes. The effects of the PAC complexes on macrophage antigen presentation were studied in an in vitro model of HEL antigen presentation by mouse peritoneal mononuclear cells to a T cell hybridoma. The mass spectra of the PAC complexes with BSA and HEL differed from the spectra of the proteins alone by the presence of broad shoulders on the singly and doubly charged protein peaks. Complexation with PAC altered the electrophoretic mobility shift assay in native agarose gel and the electrophoretic mobility (zeta-potential) values. These results indicate that the PAC-protein complexes are stable and alter the protein structure without precipitating the protein. Fluorescence microscopy showed that the RAW 264.7 macrophages endocytosed BSA and PAC-BSA complexes in discrete vesicles that surrounded the nucleus. Macrophages treated with increasing amounts of PAC-BSA complexes had significantly reduced COX-2 and iNOS expression in response to treatment with lipopolysaccharide (LPS) in comparison to the controls. The PAC HEL complexes modulated antigen uptake, processing and presentation in murine peritoneal macrophages. After 4 h of pre-incubation, only trace amounts of IL-2 were detected in the co-cultures treated with HEL alone, whereas the PAC-HEL complex had already reached the maximum IL-2 expression. Cranberry PAC may increase the rate of endocytosis of HEL and subsequent expression of IL-2 by the T-cell hybridomas. These results suggest that PAC-protein complexes modulate aspects of innate and acquired immune responses in macrophages. PMID- 28861556 TI - Frontiers of solvent-free functional molecular liquids. AB - The chemistry of functional molecular liquids (FMLs) is a recently developed research area that describes the unique properties of the liquid physical state of the materials under solvent-free conditions. FMLs are generally composed of uncharged molecular units and exist in free-flowing as well as amorphous states in nature under ambient conditions. Attachment of flexible and bulky alkyl chains to a pi-conjugated chromophore is the most common method for producing such molecular liquids. FMLs exhibit many uncommon phenomena, including inherent molecular properties which have rarely been observed for conventional organic condensed materials. In the last decade, these optoelectronically active alkylated-pi liquids have attracted significant attention because of their applicability to flexible/foldable electronic devices with high stability towards photo-oxidation and thermal decomposition, as well as facile processability into devices. Besides these pi-conjugated chromophore-based liquids, a few other types of fluidic materials such as liquid biomaterials and liquid metals also exhibit many attractive functions in their solvent-free state. The breakthrough of FMLs in cutting-edge research and their fundamental liquid features on the basis of intermolecular architectures are highlighted in this Feature Article. It is expected that this Feature Article will encourage the understanding of liquid properties as a consequence of intermolecular interactions and inspire the development of molecular architectures that could be useful for designing more attractive FMLs with specific functions in the future. PMID- 28861557 TI - Diesel particulate matter and polycyclic aromatic hydrocarbons in fire stations. AB - Firefighters are known to be exposed to a wide variety of combustion products during operational and training firefighting activities. However, the potential for exposure to diesel exhaust emissions, recently classified as carcinogenic to humans by the International Agency for Research on Cancer, also exists within the fire station environment. In this study, concentrations of diesel particulate matter and polycyclic aromatic hydrocarbons have been measured in the engine bays, duty offices and dormitory areas of eight fire stations in Queensland, Australia. Operation of fire appliances and mechanical equipment during start of shift checks were found to contribute more strongly to overall engine bay diesel particulate matter concentrations than the number of fire appliance departures and returns. Polycyclic aromatic hydrocarbons were found to be transported further into fire station living environments than diesel particulate matter. This study highlights a number of potential strategies for reducing firefighter exposures to components of diesel engine exhaust in the fire station environment. PMID- 28861558 TI - O-O bond formation in ruthenium-catalyzed water oxidation: single-site nucleophilic attack vs. O-O radical coupling. AB - In this review we discuss at the mechanistic level the different steps involved in water oxidation catalysis with ruthenium-based molecular catalysts. We have chosen to focus on ruthenium-based catalysts to provide a more coherent discussion and because of the availability of detailed mechanistic studies for these systems but many of the aspects presented in this review are applicable to other systems as well. The water oxidation cycle has been divided in four major steps: water oxidative activation, O-O bond formation, oxidative activation of peroxide intermediates, and O2 evolution. A significant portion of the review is dedicated to the O-O bond formation step as the key step in water oxidation catalysis. The two main pathways to accomplish this step, single-site water nucleophilic attack and O-O radical coupling, are discussed in detail and compared in terms of their potential use in photoelectrochemical cells for solar fuels generation. PMID- 28861559 TI - Dietary fucoidan of Acaudina molpadioides alters gut microbiota and mitigates intestinal mucosal injury induced by cyclophosphamide. AB - Cyclophosphamide (cy) is a widely used cancer drug. Many researchers have focused on the prevention and alleviation of its side effects, particularly damage to the intestinal mucosal barrier. In this study, we examined the effects of fucoidan, isolated from Acaudina molpadioides, on mice with intestinal mucosal damage induced by cyclophosphamide. Our results showed that fucoidan intervention could relieve injury such as decreasing inflammation and increasing the expression of tight junction proteins, and 50 kDa fucoidan significantly increased the abundance of short chain fatty acid (SCFA) producer Coprococcus, Rikenella, and Butyricicoccus (p < 0.05, p < 0.001, and p < 0.05, respectively) species within the intestinal mucosa compared with the cyclophosphamide group, as determined by 16S rDNA gene high-throughput sequencing. In addition, SCFAs, particularly propionate, butyrate, and total SCFAs, were increased in the feces, and SCFA receptors were upregulated in the small intestine. The protective effects of fucoidan on cyclophosphamide treatment may be associated with gut microflora, and 50 kDa fucoidan had superior effects. Therefore, fucoidan may have applications as an effective supplement to protect against intestinal mucosal barrier damage during chemotherapy. PMID- 28861560 TI - Pushing to the low limits: tetraazaanthracenes with very low-lying LUMO levels and near-infrared absorption. AB - Here we propose the combination of the 4-alkoxythiazole donor motif with highly photostable tetraazaanthracenes as electron-acceptor units. The segregated frontier orbitals in these dyes afford optical band gaps of 1.4-1.1 eV. Cyclic voltammetry confirmed the very low-lying LUMO levels that are attributed to the highly electron-deficient tetraazaanthracene moiety. PMID- 28861561 TI - The influence of water content in a proton-conducting ionic liquid on the double layer properties of the Pt/PIL interface. AB - The influence of the water content of 2-sulfoethylmethylammonium trifluoromethanesulfonate [2-Sema][TfO] on the double layer properties of the interface of platinum and the proton conducting ionic liquid (PIL) is investigated by means of impedance spectroscopy and cyclic voltammetry. By fitting the impedance spectra as complex capacitances, up to four differential double layer capacitances and corresponding time constants are obtained, depending on the potential (U = 0-1.6 V/RHE), water content (0.7-6.1 wt%) and temperature (T = 70-110 degrees C). Within the whole potential range investigated, a high frequency capacitance, C1, and a low frequency capacitance, C2, can be calculated. In the potential region of hydrogen underpotential deposition (HUPD), C1 can be separated into two parts, C1a and C1b. Whereas the high frequency capacitive processes can mainly be attributed to ion transport processes in the double layer, the low frequency process is ascribed to changes in the interfacial layer, including ad-/desorption and Faradaic processes. Alternative interpretations regarding the reorientation of ions, reconstruction of the metal surface and partial electron transfer between anions and Pt are considered. PMID- 28861562 TI - Tumour-vessel-on-a-chip models for drug delivery. AB - Nanocarriers for drug delivery have great potential to revolutionize cancer treatment, due to their enhanced selectivity and efficacy. Despite this great promise, researchers have had limited success in the clinical translation of this approach. One of the main causes of these difficulties is that standard in vitro models, typically used to understand nanocarriers' behaviour and screen their efficiency, do not provide the complexity typically encountered in living systems. In contrast, in vivo models, despite being highly physiological, display serious bottlenecks which threaten the relevancy of the obtained data. Microfluidics and nanofabrication can dramatically contribute to solving this issue, providing 3D high-throughput models with improved resemblance to in vivo systems. In particular, microfluidic models of tumour blood vessels can be used to better elucidate how new nanocarriers behave in the microcirculation of healthy and cancerous tissues. Several key steps of the drug delivery process such as extravasation, immune response and endothelial targeting happen under flow in capillaries and can be accurately modelled using microfluidics. In this review, we will present how tumour-vessel-on-a-chip systems can be used to investigate targeted drug delivery and which key factors need to be considered for the rational design of these materials. Future applications of this approach and its role in driving forward the next generation of targeted drug delivery methods will be discussed. PMID- 28861563 TI - Metal-based magnetic fluids with core-shell structure FeB@SiO2 amorphous particles. AB - FeB@SiO2 amorphous particles were firstly introduced into Ga85.8In14.2 alloys to prepare metal-based magnetic fluids. The morphology of the FeB amorphous particles is spherical with an average particle size of about 190 nm. The shape of the particles is regular and the particle size is homogeneous. Stable core shell structure SiO2 modified FeB amorphous particles are obtained and the thickness of the SiO2 coatings is observed to be about 40 nm. The results of VSM confirm that the saturation magnetization of the FeB amorphous particles is 131.5 emu g-1, which is almost two times higher than that of the Fe3O4 particles. The saturation magnetization of the FeB@SiO2 amorphous particles is 106.9 emu g-1, an approximate decrease of 18.7% due to the non-magnetic SiO2 coatings. The results from the torsional oscillation viscometer show that the metal-based magnetic fluids with FeB amorphous particles exhibit a desirable high temperature performance and are ideal candidates for high temperature use. PMID- 28861565 TI - Surface effects on converse piezoelectricity of crystals. AB - The contribution of surface units to bulk properties are often neglected in theoretical and computational studies of crystalline systems. We demonstrate that this assumption has to be made with caution in the case of (electric field) polarization. As a generalization of an earlier work on quasi-one-dimensional systems [Springborg, et al., Phys. Rev. B: Condens. Matter Mater. Phys., 2010, 82, 165442], it is shown that the polarization for 2D and 3D systems contains a surface contribution that can, in principle, take any value (within physical limits) and has consequences for converse piezoelectric responses. Subsequently, we determine the surface effects quantitatively for a group of ferroelectric perovskite structures. Our results indicate that such contributions can be substantial. PMID- 28861564 TI - Selective reduction of carboxylic acids to aldehydes with hydrosilane via photoredox catalysis. AB - The direct reduction of carboxylic acids to aldehydes with hydrosilane was achieved through visible light photoredox catalysis. The combination of both single electron transfer and hydrogen atom transfer steps offers a novel and convenient approach to selective reduction of carboxylic acids to aldehydes. The method also features mild conditions, high yields, broad substrate scope, and good functional group tolerance, such as alkyne, ester, ketone, amide and amine groups. PMID- 28861566 TI - Microfluidic generation of aqueous two-phase-system (ATPS) droplets by oil droplet choppers. AB - Existing approaches for droplet generation with an ultra-low interfacial tension using aqueous two-phase systems, ATPS, are either constricted by a narrow range of flow conditions using passive methods or subjected to complex chip fabrication with the integration of external components using active actuation. To address these issues, we present a simple approach to produce uniform ATPS droplets facilitated by oil-droplet choppers in microfluidics. Our solution counts on the synchronized formation of high-interfacial-tension oil-in-water and low interfacial-tension water-in-water droplets, where the ATPS interface is distorted by oil droplets and decays into water-in-water droplets. In the synchronization regime, the size and generation frequency of ATPS droplets can be controlled independently by tuning the flow rates of the dispersed aqueous and oil phases, respectively. Our method demonstrates high uniformity of droplets (coefficient of variation between 0.75% and 2.45%), a wide range of available droplet size (droplet radius from 5 MUm to 180 MUm), and a maximum generation frequency of about 2.1 kHz that is nearly two orders of magnitude faster than that in existing methods. We develop theoretical models to precisely predict the minimum and maximum frequencies of droplet generation and the droplet size. The produced ATPS droplets and oil choppers are separated in the channel using density difference. Our method would boost emulsion-based biological applications such as cell encapsulation, biomolecule delivery, bioreactors, and biomaterials synthesis with ATPS droplets. PMID- 28861568 TI - Asymmetric conjugate addition of alkylzirconium reagents to alpha,beta unsaturated thioesters: access to fragrances and acyclic stereochemical arrays. AB - Copper-catalyzed asymmetric conjugate addition of alkylzirconium species to alpha,beta-unsaturated thioesters is reported. A variety of functionalized alkyl nucleophiles were introduced with yields around 70% and ee's over 92%. The method was applied to the straightforward syntheses of the commercially important fragrances phenoxanol (both enantiomers 97% ee), and hydroxycitronellal (98% ee). The 1,4-addition products can be converted to enantiomerically enriched linear building blocks bearing a terminal functional group. Formation of further alpha,beta-unsaturated thioesters provides an iterative route for the stereocontrolled synthesis of functionalized acyclic arrays and we demonstrate almost complete catalyst control in the formation of additional stereocentres. PMID- 28861567 TI - How the electron-deficient cavity of heterocalixarenes recognizes anions: insights from computation. AB - We have quantum chemically analyzed the bonding mechanism behind the affinity of various heterocalixarenes for anions with a range of geometries and net charges, using modern dispersion-corrected density functional theory (DFT-D3BJ). The purpose is to better understand the physical factors that are responsible for the computed affinities and thus to develop principles for a more rational design of anion receptors. Our model systems comprise heterocalixarenes 1-4 as hosts, which are characterized by different bridging heteroatoms (O, N, S) as well as the anionic guests Cl-, Br-, I-, BF4-, CH3CO2-, H2PO4-, HSO4-, NCS-, NO3-, PF6-, and SO42-. We use various analysis schemes (EDA, NCI, and NBO) to elucidate the interactions between the calixarene cavity and the anions to probe the importance of the different bonding modes (anion-pi, lone-pair electron-pi, sigma-complexes, hydrogen bonds, and others) of the interactions. Electrostatic interactions appear to be dominant for heterocalixarenes with oxygen bridges whereas orbital interactions prevail in the case of nitrogen and sulfur bridges. Dispersion interactions are however in all cases non-negligible. PMID- 28861569 TI - A naked-eye colorimetric sensor for Hg2+ monitoring with cascade signal amplification based on target-induced conjunction of split DNAzyme fragments. AB - A colorimetric sensor for the visual detection of Hg2+ with cascade signal amplification has been successfully constructed using split DNAzyme subunits as sensing elements and gold nanoparticles as signal reporters. The biosensor is ultrasensitive, enabling the visual detection of trace levels of Hg2+ as low as 10 pM without instrumentation. PMID- 28861570 TI - NIR-emissive PEG-b-TCL micelles for breast tumor imaging and minimally invasive pharmacokinetic analysis. AB - Motivated by the goal of developing a fully biodegradable optical contrast agent with translational clinical potential, a nanoparticle delivery vehicle was generated from the self-assembly of poly(ethylene-glycol)-block-poly(trimethylene carbonate-co-caprolactone) (PEG-b-TCL) copolymers. Cryogenic transmission electron microscopy verified that PEG-b-TCL-based micelles were formed at low solution temperatures (~38 degrees C). Detailed spectroscopic experiments validated facile loading of large quantities of the high emission dipole strength, tris(porphyrin)-based fluorophore PZn3 within their cores, and the micelles displayed negligible in vitro and in vivo toxicities in model systems. The pharmacokinetics and biodistribution of PZn3-loaded PEG-b-TCL-based micelles injected intravenously were determined via ex vivo near-infrared (NIR) imaging of PZn3 emission in microcapillary tubes containing minute quantities of blood, to establish a novel method for minimally invasive pharmacokinetic monitoring. The in vivo circulatory half-life of the PEG-b-TCL-based micelles was found to be ~19.6 h. Additionally, longitudinal in vivo imaging of orthotopically transplanted breast tumors enabled determination of micelle biodistribution that correlated to ex vivo imaging results, demonstrating accumulation predominantly within the tumors and livers of mice. The PEG-b-TCL-based micelles quickly extravasated within 4T1 orthotopic mammary carcinomas, exhibiting peak accumulation at ~48 h following intravenous tail-vein injection. In summary, PEG b-TCL-based micelles demonstrated favorable characteristics for further development as in vivo optical contrast agents for minimally invasive imaging of breast tumors. PMID- 28861572 TI - 1,5-Electrocyclization of conjugated azomethine ylides derived from 3-formyl chromene and N-alkyl amino acids/esters. AB - A novel strategy has been developed for the synthesis of chromeno[3,4-b]pyrrol 4(3H)-one and substituted pyrrole derivatives through 1,5-electrocyclization of conjugated azomethine ylides. This is the first example of the preparation of highly substituted pyrrole derivatives from chromene-3-carboxaldehydes (non enolizable aldehydes) and N-alkyl amino acids/esters. This method is simple and applicable to a diverse range of substrates. PMID- 28861571 TI - Synthetic approach to tailored physical associations in peptide polyurea/polyurethane hybrids. AB - Nature has achieved diverse functionality via hierarchical organization driven by physical interactions such as hydrogen bonding. Synthetically, polymer-peptide hybrids have been utilized to achieve these architectural arrangements and obtain diverse mechanical properties, stimuli responsiveness, and bioactivity. Here, we explore the impact of peptide ordering and soft/hard phase interactions in PEG based non-chain extended and chain extended peptidic polyurea (PU) and polyurea/polyurethane (PUU) hybrids towards tunable mechanics. Increasing the peptide content of poly(epsilon-carbobenzyloxy-l-lysine) (PZLY) revealed an increase in alpha-helical formation and modulation in amine/ether hydrogen bonding, suggesting enhanced intermolecular hydrogen bonding between peptide segments and soft/hard blocks. A balance of phase mixing and microphase segregation was observed depending on competitive hydrogen bonding and the hybrid architecture. This phase behaviour strongly modulated the mechanical response, particularly modulus and extensibility. We anticipate that this solid-state, synthetic framework will expand the reach of our peptide hybrids into biointerfacing materials, including scaffolds and responsive actuators via peptide selection. PMID- 28861573 TI - Anisotropic permeability in deterministic lateral displacement arrays. AB - We uncover anisotropic permeability in microfluidic deterministic lateral displacement (DLD) arrays. A DLD array can achieve high-resolution bimodal size based separation of microparticles, including bioparticles, such as cells. For an application with a given separation size, correct device operation requires that the flow remains at a fixed angle to the obstacle array. We demonstrate via experiments and lattice-Boltzmann simulations that subtle array design features cause anisotropic permeability. Anisotropic permeability indicates the microfluidic array's intrinsic tendency to induce an undesired lateral pressure gradient. This can cause an inclined flow and therefore local changes in the critical separation size. Thus, particle trajectories can become unpredictable and the device useless for the desired separation task. Anisotropy becomes severe for arrays with unequal axial and lateral gaps between obstacle posts and highly asymmetric post shapes. Furthermore, of the two equivalent array layouts employed with the DLD, the rotated-square layout does not display intrinsic anisotropy. We therefore recommend this layout over the easier-to-implement parallelogram layout. We provide additional guidelines for avoiding adverse effects of anisotropy on the DLD. PMID- 28861574 TI - Direct, efficient NHC-catalysed aldehyde oxidative amidation: in situ formed benzils as unconventional acylating agents. AB - A new N-heterocyclic carbene-catalysed oxidative amidation of aldehydes has been developed which converts the aldehyde to a benzil acylating agent in situ. The process uses an air-recyclable oxidant and a nucleophilic co-catalyst and does not require the use of a large excess of either one coupling partner or catalyst. PMID- 28861576 TI - Unusually low and density-insensitive thermal conductivity of three-dimensional gyroid graphene. AB - Graphene has excellent mechanical, thermal and electrical properties. However, there are limitations in utilizing monolayers of graphene for mechanical engineering applications due to its atomic thickness and lack of bending rigidity. Synthesizing graphene aerogels or foams is one approach to utilize graphene in three-dimensional bulk forms. Recently, graphene with a gyroidal geometry has been proposed. A gyroid is a triply periodic minimal surface that allows graphene sheets to form a three-dimensional structure. Its light weight and high mechanical strength suggests that the graphene that constitutes this geometry can synergistically contribute to the mechanics of the bulk material. However, it is not clear whether gyroid graphene can preserve the high thermal conductivity of pristine graphene sheets. Here, we investigate the thermal conductivities of gyroid graphene with different porosities by using full-atom molecular dynamics simulations. In contrast to its excellent mechanical properties, we find that the thermal conductivity of gyroid graphene is more than 300 times lower than that of pristine graphene, with a bulk density of only about one-third of that of graphene. We derive a scaling law showing that the thermal conductivity does not vary much with different bulk densities, which contrasts the behavior of conventional porous materials. Our analysis shows that the poor thermal conductivity of gyroid graphene can be attributed to defects and curvatures of graphene, which increase with the density, resulting in the reduction of a phonon mean free path by phonon scattering. Our study shows that three-dimensional porous graphene has potential that may be utilized in designing new lightweight structural materials with low and density-insensitive thermal properties and superior mechanical strength. PMID- 28861575 TI - Investigation into the energy storage behaviour of layered alpha-V2O5 as a pseudo capacitive electrode using operando Raman spectroscopy and a quartz crystal microbalance. AB - alpha-V2O5 nanowires with a layered structure have been fabricated through a two step procedure. When measured as a pseudo-capacitive electrode with a three electrode configuration in 1 M Na2SO4 aqueous solutions, alpha-V2O5 exhibits ideal capacitive characteristics with a specific capacitance of ~238 F g-1 at a high current of 2 A g-1, but poor cycling stability with a continuous drop in the first 2000 cycles before it is maintained. To find possible solutions towards this problem, the energy storage behavior of the alpha-V2O5 electrode has been carefully investigated. In situ Raman analysis suggests that it is electrolytic hydrated cations [Na(H2O)n]+ rather than anions (SO42-) that are involved in the energy storage process through reversible adsorption/desorption on the surface or intercalation/deintercalation at the interlayer of the (001) planes accompanied by interlayer spacing expansion/contraction. Moreover, the electrochemical quartz crystal microbalance results indicate that, besides a reversible mass change, there is a continuous mass loss that may originate from slow dissolution of V2O5, which should bear the main responsibility for the poor stability (initial dramatic drop). Hence, how to inhibit dissolution, such as by coating or adding additives in the electrolyte, is found to be the key approach to improve the stability of V2O5 based electrodes. PMID- 28861577 TI - Anion photoelectron spectroscopy of free [Au25(SC12H25)18]. AB - Previous theoretical studies have shown that the thiolated gold cluster compound [Au25(SR)18]- can be viewed as a prototypical superatom with a closed electronic structure. The quantized electronic structure of [Au25(SR)18]- has been experimentally demonstrated by optical and electrochemical methods in the dispersed state. Nevertheless, no direct information is available on the energy levels and densities of occupied states. Here, we report the photoelectron spectrum of [Au25(SC12H25)18]- isolated under vacuum for the first time. The spectrum exhibits two distinct peaks, corresponding to electron detachment from the superatomic 1P orbitals and Au 5d orbitals of the Au13 core. The adiabatic electron affinity of [Au25(SC12H25)18]0 was experimentally determined to be 2.2 eV, which is significantly smaller than that of [Au25(SCH3)18]0 predicted theoretically. PMID- 28861578 TI - A multiplex microplatform for the detection of multiple DNA methylation events using gold-DNA affinity. AB - We report a new multiplexed strategy for the electrochemical detection of regional DNA methylation across multiple regions. Using the sequence dependent affinity of bisulfite treated DNA towards gold surfaces, the method integrates the high sensitivity of a micro-fabricated multiplex device comprising a microarray of gold electrodes, with the powerful multiplexing capability of multiplex-PCR. The synergy of this combination enables the monitoring of the methylation changes across several genomic regions simultaneously from as low as 500 pg MUl-1 of DNA with no sequencing requirement. PMID- 28861579 TI - mRNA-miRNA bipartite network reconstruction to predict prognostic module biomarkers in colorectal cancer stage differentiation. AB - Biomarker detection is one of the most important and challenging problems in cancer studies. Recently, non-coding RNA based biomarkers such as miRNA expression levels have been used for early diagnosis of many cancer types. In this study, a systems biology approach was used to detect novel miRNA based biomarkers for CRC diagnosis in early stages. The mRNA expression data from three CRC stages (Low-grade Intraepithelial Neoplasia (LIN), High-grade Intraepithelial Neoplasia (HIN) and Adenocarcinoma) were used to reconstruct co-expression networks. The networks were clustered to extract co-expression modules and detected low preserved modules among CRC stages. Then, the experimentally validated mRNA-miRNA interaction data were applied to reconstruct three mRNA miRNA bipartite networks. Twenty miRNAs with the highest degree (hub miRNAs) were selected in each bipartite network to reconstruct three bipartite subnetworks for further analysis. The analysis of these hub miRNAs in the bipartite subnetworks revealed 30 distinct important miRNAs as prognostic markers in CRC stages. There are two novel CRC related miRNAs (hsa-miR-190a-3p and hsa-miR-1277-5p) in these 30 hub miRNAs that have not been previously reported in CRC. Furthermore, a drug gene interaction network was reconstructed to detect potential candidate drugs for CRC treatment. Our analysis shows that the hub miRNAs in the mRNA-miRNA bipartite network are very essential in CRC progression and should be investigated precisely in future studies. In addition, there are many important target genes in the results that may be critical in CRC progression and can be analyzed as therapeutic targets in future research. PMID- 28861580 TI - Oxidative C-H functionalization of N-carbamoyl 1,2-dihydroquinolines. AB - A modular and efficient method for the synthesis of alpha-substituted 1,2 dihydroquinolines is described. Under mild metal-free conditions, readily available N-carbamoyl 1,2-dihydroquinolines undergo oxidative C-H alkynylation, alkenylation, and allylation with a range of potassium trifluoroborates using TEMPO oxoammonium salt as an oxidant. PMID- 28861581 TI - A microfluidic device for the batch adsorption of a protein on adsorbent particles. AB - A microfluidic platform or "microfluidic batch adsorption device" is presented, which performs two sets of 9 parallel protein incubations with/without adsorbent particles to achieve an adsorption isotherm of a protein in a single experiment. The stepwise concentration gradient of a target protein was created by the integration of microvalves into the device. The nanoliter-scale reactor (41 nl) allows about 5000 times reduction of sample consumption and fast analysis compared with a conventional 96 well plate. The integration of two sets of parallel reactors as reference reactors and adsorption reactors, respectively, in a single microfluidic format has many advantages, such as the exclusion of the influence of undesired experimental fluctuations, and the possibility of real time tracing of adsorption processes. We performed batch adsorption of albumin fluorescein isothiocyanate conjugate (FITC-BSA) on polymeric particles (Source 15Q) to obtain an adsorption isotherm. The obtained on-chip parameters maximum adsorption amount (Qmax) and adsorption constant (Keq) were 0.33 +/- 0.03 ng per particle and 0.97 +/- 0.22 L g-1, respectively, which are in good agreement with off-chip values (Qmax = 0.34 +/- 0.01 ng per particle and Keq = 0.81 +/- 0.10 L g 1). On-chip adsorption isotherms of FITC-BSA at various concentrations of sodium chloride (NaCl) were measured to evaluate the effect of this salt on the adsorption capability of Source 15Q. The microfluidic device serves as a new analytical tool, useful in biotechnological and industrial applications, where the adsorption behavior of (bio)molecules on commercial adsorbent particles plays critical roles, such as protein separation and purification, detection of analytes and biomarkers, and solid-phase immunoassays. PMID- 28861583 TI - Tunable emergent structures and traveling waves in mixtures of passive and contact-triggered-active particles. AB - We investigate emergent behavior in binary mixtures comprised of passive particles and contact-triggered active particles (CAPs), where a propulsion force is applied on CAPs towards passive particles when the two are in contact. We show that such mixtures phase separate into distinct dense and dilute phases with as few as 10% CAPs. Furthermore, the structure of the dense phase can be tuned by varying the fraction of CAPs and the strength of their propulsion force. The dense phase is classified into seven structure types, which includes both 6-fold and 4-fold ordered crystals, and kinetically arrested gels and clusters. Mixtures with fewer than 35% CAPs exhibit traveling density waves such that one end of the dense phase recedes while the other propagates. This phenomenon results from the spontaneous symmetry breaking of particle flux at the dense-dilute interface. We show that contact-triggered activity can be employed to develop materials with a wide range of structures and dynamics. PMID- 28861582 TI - A systems biology approach to identify microRNAs contributing to cisplatin resistance in human ovarian cancer cells. AB - Cisplatin (CDDP)-based chemotherapy is a standard first-line therapy for ovarian cancer. However, drug resistance remains a major obstacle to its efficacy. Recently, increasing evidence suggested that the aberrant expression of microRNAs (miRNAs) may contribute to drug resistance. Here, we proposed a systems biology analysis strategy to identify the novel miRNAs potentially involved in CDDP resistance in human ovarian cancer cells. Firstly, we identified the candidate miRNAs associated with CDDP resistance using NCI-60 data. Next, the differentially expressed genes (DEGs) in the CDDP-resistant ovarian cancer cell line OVCAR-8R were obtained. After mapping the DEGs to a human protein-protein interaction network, a CDDP resistance-related sub-network for ovarian cancer was constructed, and subsequently the functional gene modules were identified. Then, based on the experimentally validated miRNA regulations to target genes, 4 candidate miRNAs (miR-24-3p, miR-192-5p, miR-139-5p and miR-155-5p) were identified to potentially contribute to ovarian cancer cell chemoresistance to CDDP through mediating OVCAR-8R cell CDDP resistance-related gene modules, which participated in functions that were closely related to "apoptosis", "cell cycle" and "adhesion". In addition, we predicted the therapeutic drugs that might reduce or reverse CDDP resistance by targeting these 4 identified miRNAs. This study revealed the underlying mechanism of CDDP resistance, and provided novel potential drug targets and therapeutics for CDDP-resistant ovarian cancer patients. PMID- 28861584 TI - Synthetic route to chiral indolines via Cu(OAc)2-catalyzed ring-opening/C(sp2)-H activation of activated aziridines. AB - A simple strategy for the synthesis of highly functionalized indolines via Lewis acid catalyzed ring-opening of activated aziridines with various nucleophiles followed by Cu(OAc)2-mediated intramolecular C-H amination in one-pot has been developed with excellent enantio- and diastereospecificity (ee 99%; de >99%). The reaction proceeds via Cu(OAc)2-catalyzed SN2-type ring-opening of 2-phenyl-N-(2 pyridinesulfonyl)aziridine with alcohols and arene, followed by copper-mediated pyridine-2-sulfonamide directed intramolecular C(sp2)-H activation/cyclization in a stepwise fashion to furnish the indoline derivatives in excellent yields (up to 91%). PMID- 28861585 TI - A model derived from hydrodynamic simulations for extracting the size of spherical particles from the quartz crystal microbalance. AB - One challenging aspect of quartz crystal microbalance (QCM) measurements is the characterization of adsorbed particles as the change in resonance frequency (Deltaf) is proportional not only to the inertia of the adsorbed layer but also to that of the hydrodynamically coupled fluid. Herein, by solving numerically the Navier-Stokes equations, we scrutinize Deltaf for sparsely deposited, rigid spherical particles that are firmly attached to an oscillating surface. The analysis is shown to be applicable to adsorbed, small unilamellar vesicles (SUVs) of controlled size under experimental conditions in which adhesion-induced vesicle deformation is negligible. The model supports a hydrodynamic explanation for the overtone dependence of Deltaf, and was fitted to experimental data concerning three monodisperse populations of SUVs with different average sizes ranging between 56 and 114 nm diameter. Using this procedure, we determined the average size of adsorbed vesicles to be within 16% of the size that was measured by dynamic light scattering experiments in bulk solution. In conclusion, this model offers a means to extract the particle size from QCM-D measurement data, with applications to biological and synthetic nanoparticles. PMID- 28861586 TI - Cu(ii)-Mediated keto C(sp3)-H bond alpha-acyloxylation of N,N-dialkylamides with aromatic carboxylic acids. AB - The selective oxidative coupling of aromatic carboxylic acids with the C(sp3)-H bond adjacent to the keto group of alkylamides has been developed by employing a low cost copper source. This provides an efficient approach for synthesis of O benzoylglycolamides. The protocol displayed good functional group tolerance. A broad range of benzoic acids directly coupled with alkylamides to afford a variety of O-benzoylglycolamides in moderate to good yields. In addition, a reasonable radical mechanism was proposed based on EPR experiments. PMID- 28861587 TI - Electronic effects on a one-pot aromatization cascade involving alkynyl-Prins cyclization, Friedel-Crafts alkylation and dehydration to tricyclic benzo[f]isochromenes. AB - A three-step domino reaction between 1-aryl-3-hexyne-2,6-diol derivatives and aldehydes is used to construct tricyclic 1,4-dihydro-2H-benzo[f]isochromenes. The cascade is initiated by BF3.OEt2 and involves alkynyl-Prins cyclization, Friedel Crafts alkenylation, and dehydration/aromatization to create a new, central aromatic ring and eliminate 2 equiv. of water. Electron-donating substituents on the aryl ring of the 1-aryl-3-hexyne-2,6-diols significantly increase overall yields as do electron-rich aldehyde reaction partners. For 2,4-disubstituted 2H benzo[f]isochromene products, diastereoselectivities in the alkynyl-Prins reaction are ~1.4 : 1 in favor of the cis-diastereomer. The stereochemistry of one cis-product was verified by X-ray crystallographic analysis and a second structure was also verified by X-ray analysis. PMID- 28861588 TI - Efficient genome-wide association in biobanks using topic modeling identifies multiple novel disease loci. AB - Biobanks and national registries represent a powerful tool for genomic discovery, but rely on diagnostic codes that may be unreliable and fail to capture the relationship between related diagnoses. We developed an efficient means of conducting genome-wide association studies using combinations of diagnostic codes from electronic health records (EHR) for 10845 participants in a biobanking program at two large academic medical centers. Specifically, we applied latent Dirichilet allocation to fit 50 disease topics based on diagnostic codes, then conducted genome-wide common-variant association for each topic. In sensitivity analysis, these results were contrasted with those obtained from traditional single-diagnosis phenome-wide association analysis, as well as those in which only a subset of diagnostic codes are included per topic. In meta-analysis across three biobank cohorts, we identified 23 disease-associated loci with p<1e-15, including previously associated autoimmune disease loci. In all cases, observed significant associations were of greater magnitude than for single phenome-wide diagnostic codes, and incorporation of less strongly-loading diagnostic codes enhanced association. This strategy provides a more efficient means of phenome wide association in biobanks with coded clinical data. PMID- 28861589 TI - Erratum to: CT-Guided Percutaneous Trans-scapular Lung Biopsy in the Diagnosis of Peripheral Pulmonary Lesion Nodules of the Superior Lobes Using Large Needles. PMID- 28861590 TI - [Botulinum toxin in otorhinolaryngology - an update]. AB - During recent decades, the clinical use of botulinum toxin has become increasingly well established. In the field of otorhinolaryngology there are many indications for which botulinum toxin can improve patients' quality of life. These include applications in the region of the head and neck muscles and the autonomic nervous system in patients suffering from movement disorders of special muscles and secretory disorders (salivary, lacrimal, and sweat glands). The present article presents an overview of well-established and new indications for application of botulinum toxin in the head and neck region. PMID- 28861591 TI - Multianalyte quantitative competitive PCR on optically encoded microspheres for an eight-gene panel related to prostate cancer. AB - Nucleic acid-based tests have a profound impact in every medical discipline. Because multigene tests offer higher diagnostic accuracy and lower overall cost than single assays, they are especially useful for diseases, like prostate cancer, that present variability at the molecular level and diversity of available therapeutic interventions. We have developed a quantitative competitive PCR for an eight-gene panel, related to prostate cancer, that includes five genes of the human tissue kallikrein family (KLKs), prostate-specific membrane antigen (PSMA), prostate cancer antigen 3 (PCA3), and HPRT1 as a reference gene. Using PCR as a synthetic tool, a competitor was prepared for each target sequence containing the same primer binding sites as the target but differing in a short segment to enable discrimination by hybridization. The assay involves multiplex amplification of targets and competitors followed by a multiplex hybridization assay for the 16 amplification products. The assay was performed on optically encoded microspheres with oligonucleotide probes attached to their surface. The microspheres were analyzed rapidly (1 min) by flow cytometry. The signal ratio of the target and cognate competitor is a function of the target copy number in the sample prior to amplification. The multiplexing potential of the proposed method is much higher than real-time PCR and other end-point methods since there are 100 sets of commercially available microspheres. PMID- 28861592 TI - Increased alertness, better than posture prioritization, explains dual-task performance in prosthesis users and controls under increasing postural and cognitive challenge. AB - Sensorimotor impairments after limb amputation impose a threat to stability. Commonly described strategies for maintaining stability are the posture first strategy (prioritization of balance) and posture second strategy (prioritization of concurrent tasks). The existence of these strategies was examined in 13 below knee prosthesis users and 15 controls during dual-task standing under increasing postural and cognitive challenge by evaluating path length, 95% sway area, and anterior-posterior and medial-lateral amplitudes of the center of pressure. The subjects stood on two force platforms under usual (hard surface/eyes open) and difficult (soft surface/eyes closed) conditions, first alone and while performing a cognitive task without and then with instruction on cognitive prioritization. During standing alone, sway was not significantly different between groups. After adding the cognitive task without prioritization instruction, prosthesis users increased sway more under the dual-task than single-task standing (p <= 0.028) during both usual and difficult conditions, favoring the posture second strategy. Controls, however, reduced dual-task sway under a greater postural challenge (p <= 0.017), suggesting the posture first strategy. With prioritization of the cognitive task, sway was unchanged or reduced in prosthesis users, suggesting departure from the posture second strategy, whereas controls maintained the posture first strategy. Individual analysis of dual tasking revealed that greater postural demand in controls and greater cognitive challenge in prosthesis users led to both reduced sway and improved cognitive performance, suggesting cognitive motor facilitation. Thus, activation of additional resources through increased alertness, rather than posture prioritization, may explain dual-task performance in both prosthesis users and controls under increasing postural and cognitive challenge. PMID- 28861593 TI - Effects of Elevated Ozone on Polka Dot Plant (Hypoestes phyllostachya) with Variegated Leaves. AB - In this study, impacts of O3 on four cultivars ('Rose', 'Pink', 'Blush' and 'White') of the polka dot plant with variegated leaves were investigated for the first time. Ozone fumigation [(120 +/- 20 ppb) for 14 days (8 h day-1, from 8:30 to 16:30)] resulted in visible foliar injuries, decreased contents of pigments (chlorophyll a and b, and carotenoid), the inhibition of photosynthesis, the increase of quantum yield of non-regulated heat dissipation and fluorescence emission (Y(NO)), and the damage of cell membrane. Elevated O3 increased the content of anthocyanin (Ant). 'White' showed the highest, and 'Rose' the lowest amount of injured leaf area, indicating that the former was the most sensitive, and the latter the most tolerant to O3 stress. After O3 exposure, the highest Ant content was found in 'Rose', followed by 'Pink', 'Blush', and 'White'. Levels of Ant were likely responsible for the different sensitivities to O3 due to their roles in photoprotection. PMID- 28861594 TI - [Corticosteroids compromise survival in glioblastoma patients after radio- and chemotherapy]. PMID- 28861595 TI - Oxysterols Versus Cholesterol in Model Neuronal Membrane. I. The Case of 7 Ketocholesterol. The Langmuir Monolayer Study. AB - Oxysterols are products of cholesterol oxidation. They can be formed endogenously (in both enzymatic and non-enzymatic reactions) as well as exogenously (delivered with food). Recent studies clearly demonstrate cytotoxic properties of these compounds, being mainly due to their incorporation into natural lipid bilayers. This process can influence mechanical and physicochemical properties of biomembrane-mainly by modifying the interactions between its components, which may result in the disruption of proper functioning of cell membrane and could lead to its degradation. Therefore, it can be assumed that oxysterols may affect the initiation of neurodegenerative diseases, including Alzheimer's disease. However, the mode of action of these molecules at the molecular level is not fully known. To get a better understanding of the role of oxysterols in neurodegeneration, it is of great importance to examine mutual interactions between oxysterols and neuronal membrane components. One of the most promising techniques that can be used to analyze such interactions is the Langmuir monolayer technique. In this work, we have prepared an artificial neuronal membrane modeled as multicomponent Langmuir monolayer built up with cholesterol, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and sphingomyelin (SM). To examine whether there are any changes in the membrane properties under oxidative stress, in this paper we have investigated the impact of the representative ring-oxidized oxysterol: 7-ketocholesterol (7-KC). Our results show that replacing cholesterol with 7-KC increases the interaction between molecules in the model membrane. PMID- 28861597 TI - Single high dose versus repeated bone-targeted radionuclide therapy. PMID- 28861596 TI - Effects of lesions in different nuclei of the amygdala on conditioned taste aversion. AB - Conditioned taste aversion (CTA) is an adaptive learning that depends on brain mechanisms not completely identified. The amygdala is one of the structures that make up these mechanisms, but the involvement of its nuclei in the acquisition of CTA is unclear. Lesion studies suggest that the basolateral complex of the amygdala, including the basolateral and lateral amygdala, could be involved in CTA. The central amygdala has also been considered as an important nucleus for the acquisition of CTA in some studies. However, to the best of our knowledge, the effect of lesions of the basolateral complex of the amygdala on the acquisition of CTA has not been directly compared with the effect of lesions of the central and medial nuclei of the amygdala. The aim of this study is to compare the effect of lesions of different nuclei of the amygdala (the central and medial amygdala and the basolateral complex) on the acquisition of taste aversion in male Wistar rats. The results indicate that lesions of the basolateral complex of the amygdala reduce the magnitude of the CTA when compared with lesions of the other nuclei and with animals without lesions. These findings suggest that the involvement of the amygdala in the acquisition of CTA seems to depend particularly on the integrity of the basolateral complex of the amygdala. PMID- 28861598 TI - Screening and Characterization of Phytases from Bacteria Isolated from Chilean Hydrothermal Environments. AB - Phytases are enzymes involved in organic phosphorus cycling in nature and widely used as feed additives in animal diets. Thermal tolerance is a desired property of phytases. The objectives of this study were to screen and characterize bacterial phytases from Chilean hydrothermal environments. In this study, 60% (30 of 63) of screened thermophilic (60 degrees C) isolates showed phytase activity in crude protein extracts. The characterization of phytase from two selected isolates (9B and 15C) revealed that both isolates produce phytases with a pH optimum at 5.0. The temperature optimum for phytate dephosphorylation was determined to be 60 and 50 degrees C for the phytases from the isolates 9B and 15C, respectively. Interestingly, the phytase from the isolate 15C showed a residual activity of 46% after incubation at 90 degrees C for 20 min. The stepwise dephosphorylation of phytate by protein extracts of the isolates 9B and 15C was verified by HLPC analysis. Finally, the isolates 9B and 15C were identified by partial sequencing of the 16S rRNA gene as members of the genera Bacillus and Geobacillus, respectively. PMID- 28861599 TI - Interleukin-6 in idiopathic multicentric Castleman's disease after long-term tocilizumab. PMID- 28861600 TI - Imaging Findings of Atypical Type II Endoleak Through Vasa Vasorum After Abdominal Endovascular Aneurysm Repair. AB - A type II endoleak (T2EL) is the most common endoleak after endovascular aneurysm repair (EVAR), and a persistent T2EL has been occasionally associated with aneurysmal enlargement. Typical findings of a T2EL consist of an endoleak cavity with inflow and outflow arteries of aortic branch vessels. However, an atypical T2EL, in which hypertrophied vasa vasorum and enlargement of a thrombosed aneurysm are observed, has no endoleak cavity. We have seen three cases of continuous aortic aneurysmal growth after EVAR caused by atypical T2ELs without endoleak cavities through developed vasa vasorum. In this report, the imaging findings of selective angiography and dynamic computed tomography of these cases are reviewed. PMID- 28861602 TI - Episodic future thinking improves children's prospective memory performance in a complex task setting with real life task demands. AB - Research on children's prospective memory (PM) shows an increase of performance across childhood and provides first evidence that encoding strategies such as episodic future thinking (EFT; i.e., engaging in a vivid prospection of oneself performing future tasks) may improve performance. The present study aimed at testing whether the beneficial effects of EFT extend from typical lab-based tasks to more complex tasks with real life demands. Further, it was tested whether children's ability to project themselves into different perspectives (i.e., self projection) moderates the effects of EFT encoding on PM. Overall, 56 children (mean age: M = 10.73 years) were included in this study who were randomly assigned to either an EFT or control condition. Children participated in a 'sightseeing tour' (ongoing activity) inside the lab with various socially relevant and neutral PM tasks embedded. Results showed significantly higher PM performance in the EFT compared to the control group. There was no difference between neutral and social PM tasks and no interaction between type of PM tasks with encoding condition. Further, self-projection did not moderate the effects of EFT encoding on PM. Results suggest that EFT is an effective strategy to improve children's everyday PM. These beneficial effects seem to occur independent from children's general ability to change perspectives and for different types of PM tasks. PMID- 28861601 TI - The role of high-risk human papillomavirus infections in laryngeal squamous cell carcinoma. AB - The contribution of human papillomavirus (HPV) to the development and clinical outcome of oropharyngeal cancers has been well documented. The association of HPV in laryngeal squamous cell carcinoma (LSCC) has been examined in several studies, but controversy exists regarding its role in carcinogenesis, the outcome of the patients and thus, clinical significance of HPV testing in LSCC. In this review, we give an update of known associations between HPV-positive testing and carcinogenesis in laryngeal cancer. In an early study, the HPV-DNA detection rate in LSCC was documented being 24.0% with significant regional differences. Non-HPV 16 types were more often detected in LSCC when compared to the oropharynx. Later, single institution case series revealed markedly fewer amounts (<10%) of HPV DNA in LSCC and the results suggested that high-risk HPV infections seem to be biologically irrelevant in most LSCC. The significance of p16INK4a (p16) expression as a surrogate marker towards high-risk HPV infection and the outcome in LSCC is doubtful, since only few p16-positive LSCC samples are HPV RNA positive and accordingly there was poor correlation of p16-test results towards the outcome in LSCC. Recent meta-analysis (n = 2739) and large case series (n = 1042) of LSCC revealed the true rate of HPV-driven LSCC being 8.6%, respectively, <5%. In the latter the rate of DNA-, DNA/RNA-, DNA/p16, and DNA/RNA/p16 positivity was 5.7, 3.1, 1.9, and 1.5%, respectively. These results indicate relevant amounts of insignificant/transient HPV infection in LSCC specimen. However, in the same study the rate of transforming HPV infections increased since 2000, and younger patients had higher amounts of HPV-driven LSCC. Serologic testing of E6/E7 antibodies additionally revealed odds ratios between 2 and 5 as a hint for a weak contribution of high-risk HPV infection and the development of LSCC. The contribution of HPV for the development of LSCC needs future investigations, to date, routine HPV testing of LSCC specimen is not warranted. PMID- 28861603 TI - Pleasantness of olfactory and trigeminal stimulants in different Italian regions. AB - Although individuals categorize odors according to their pleasantness, experience may also influence odor perception-a phenomenon that partially explains why different populations perceive odors differently. Italy, which comprises 20 regions, is characterized by very different cultures. In the present study, we investigated for the first time how Italian regional differences can affect odor perception. 254 healthy volunteers coming from northern, central, southern Italy, and Sicily, one of the two major Italian islands, were recruited in Padua, Rome, Naples, and Syracuse, respectively. Olfactory function was tested with Sniffin' Sticks identification subtest. Subjects who had a score in the range within the mean identification value +/- 1 SD, in accordance with the age classes identified in the literature, were asked to judge the odor pleasantness of 20 substances. The hedonic tone of the odorants was categorized as pleasant, neutral, unpleasant, and very unpleasant. Some odorants were appreciated more in northern Italy than in the other parts of the country, whereas others were appreciated more in the south and in Sicily than in the north. Unpleasant odorants were judged less unpleasant in central Italy. Some odorants such as strawberry and vanilla were perceived similarly in all the regional areas. Our study indicates that in Italy, hedonic perception of odorants differs probably in relation with genetic, cultural, and environmental factors. Further investigation is needed to delve deeper into the factors that influence the quality odor perception amongst humans. PMID- 28861605 TI - [Sepsis and mortality after severe infections : How epidemiological data confirm results of animal experiments]. PMID- 28861604 TI - Cardiac optogenetics: using light to monitor cardiac physiology. AB - Our current understanding of cardiac excitation and its coupling to contraction is largely based on ex vivo studies utilising fluorescent organic dyes to assess cardiac action potentials and signal transduction. Recent advances in optogenetic sensors open exciting new possibilities for cardiac research and allow us to answer research questions that cannot be addressed using the classic organic dyes. Especially thrilling is the possibility to use optogenetic sensors to record parameters of cardiac excitation and contraction in vivo. In addition, optogenetics provide a high spatial resolution, as sensors can be coupled to motifs and targeted to specific cell types and subcellular domains of the heart. In this review, we will give a comprehensive overview of relevant optogenetic sensors, how they can be utilised in cardiac research and how they have been applied in cardiac research up to now. PMID- 28861606 TI - Attention capacity in European adolescents: role of different health-related factors. The HELENA study. AB - : We compared the level of attention capacity between adolescents from the center and south of Europe. The study included 627 European adolescents (54% girls), aged 12.5-17.5 years, who participated in the HELENA Study. The d2 Test of Attention was administered to assess attention capacity. The main results showed that adolescents from the south of Europe had significantly higher score in attention capacity compared with adolescents from central Europe (score + 8.1; 95%CI, 2.44-13.61) after adjustment for age, sex, socioeconomic indicators, body mass index, cardiorespiratory fitness and diet quality index (p = 0.012). CONCLUSION: Adolescents from the south of Europe had higher levels of attention capacity than their counterparts from central Europe independently of sociodemographic and health-related factors. These differences should be taken into account by educational institutions when promoting new approaches for putting into the practice student's capacities. What is Known? * Attention is a crucial capacity during adolescence. * Several health-related factors (i.e., physical activity, fitness or fatness) may influence attention capacity in adolescents. What is New? * Adolescents from the south of Europe had higher levels of attention capacity than their counterparts from the center, after accounting for socioeconomic factors, fitness, fatness and quality of diet. * These differences should be taken into account by educational institutions when promoting new approaches for putting into the practice student's capacities. PMID- 28861607 TI - Glomerular and tubular effects of nitric oxide (NO) are regulated by angiotensin II (Ang II) in an age-dependent manner through activation of both angiotensin receptors (AT1Rs and AT2Rs) in conscious lambs. AB - Renin-angiotensin (RAS) and nitric oxide (NO) systems and the balance and interaction between them are considered of primary importance in maintaining fluid and electrolyte homeostasis. It has been suggested that the effects of NO may be modulated at least in part by the angiotensin (Ang) II, yet the roles of angiotensin receptor type 1 (AT1R) and type 2 (AT2R) are not well understood. Even though both Ang II and NO are elevated at birth and during the newborn period, their contribution to the adaptation of the newborn to life after birth as well as their physiological roles during development are poorly understood. The aim of this study was to determine if NO regulation of renal function during postnatal maturation is modulated by Ang II through activation of AT1R or AT2R or both receptors. Glomerular and tubular effects of either AT1R selective antagonist ZD 7155, AT2R selective antagonist PD 123319, and both antagonists ZD 7155 plus PD 123319, were measured in 1- (N = 9) and 6-week-old (N = 13) conscious, chronically instrumented lambs before and after removal of endogenous NO with L-arginine analogue, L-NAME. Two-way analysis of variance (ANOVA) procedures for repeated measures over time with factors age and treatment were used to compare the effects of the treatments on several glomerular and tubular variables in both groups. This study showed that L-NAME infusion after pre treatment with ATR antagonists did not alter glomerular function in 1- or 6-week old lambs. NO effects on electrolytes handling along the nephron during postnatal development were modulated by Ang II through AT1R and AT2R in an age-dependent manner. Selective inhibition of AT1R and AT2R increased excretion of Na+, K+, and Cl- in 6- but not in 1-week-old lambs. In 6-week-old lambs, urinary flow rate increased by 200%, free water clearance increased by 50%, and urine osmolality decreased by 40% after L-NAME was added to the pre-treatment with ZD 7155 plus PD 123319. When L-NAME was added either to ZD 7155 or PD 123319, the same trend in the alterations of these variables was observed, albeit to a lower degree. In conclusion, in conscious animals, during postnatal maturation, Ang II modulates the effects of NO on glomerular function, fluid, and electrolyte homeostasis through AT1Rs and AT2Rs in an age-dependent manner. Under physiological conditions, AT2Rs may potentiate the effects of AT1R, providing evidence of a crosstalk between ATRs in modulating NO effects on fluid and electrolyte homeostasis during postnatal maturation. This study provides new insights on the regulation of renal function during early postnatal development showing that, compared with later in life, newborns have impaired capacity to regulate glomerular function, water, and electrolyte balance. PMID- 28861608 TI - Donepezil effects on cholesterol and oxysterol plasma levels of Alzheimer's disease patients. AB - Cholesterol is an essential component in the structure and function of cell membranes and has been associated with the major pathological signatures of Alzheimer's disease (AD). To maintain brain cholesterol homeostasis, it is converted into 24(S)-hydroxycholesterol (24OHC) which can be driven through the blood-brain barrier. Several studies have already described a decrease in 24OHC and an increase of 27(S)-hydroxycholesterol (27OHC) in AD, as a reflection of disease burden, the loss of metabolically active neurons and the degree of structural atrophy. It is also well known that peripheral cholesterol is altered in AD patients. However, there are no data regarding effects of AD treatment in this cholesterol pathway. Since a study from our group indicated a significant increase in membrane phospholipid metabolism by donepezil, the aim of this study was to evaluate the effect of short- and long-term donepezil treatment on cholesterol and metabolites 24OHC and 27OHC in plasma of AD patients and in healthy volunteers. At baseline, we found a decrease of 24OHC (p = 0.003) in AD patients. Cholesterol levels increased with donepezil treatment (p = 0.04) but no differences were observed regarding 24OHC and 27OHC. However, these results confirm and extend previous studies demonstrating disturbed cholesterol turnover in Alzheimer's disease. PMID- 28861609 TI - MiR-375 and YAP1 expression profiling in medullary thyroid carcinoma and their correlation with clinical-pathological features and outcome. AB - Medullary thyroid cancer (MTC) is a tumor marked by an indolent growth for which few prognostic factors and therapeutic strategies are actually available. Different studies have recently appraised well-differentiated thyroid cancers are characterized by a dysregulation in different microRNA sets; however, only few of them investigated the role of miRNA expression in MTCs. In this study, we have assessed the miR-375 expression in a series of 130 MTCs (104 are sporadic and 26 familial) with a median follow-up of 39 months (range 1-138) and then we have correlated our results with the clinical-pathological features and the patients' outcome.Moreover, we have appraised YAP1 (Yes-associated protein 1) immunohistochemical expression in the same MTC series and in 5 C-cells hyperplasia (CCH) samples as well. We observed a significant upregulation of miR 375 in all MTCs, when compared to the normal thyroid tissues. Besides, miR-375 expression was found to be closely linked to neoplastic size, a chance of thyroid capsule infiltration, the risk of lymph node metastasis, and the staging of the tumor. At the end of follow-up, only 10% (13/130) showed a tumor progression and a higher miR-375 expression was found to be closely linked to a worst patient' outcome. On the contrary, YAP1 immunohistochemical expression was sharply downregulated in tumors, whereas it was weakly expressed in CCHs. Our results suggest miR-375 plays a central role in MTC progression and, therefore, we seek following the idea that miR-375 pathway may be an effective target in novel MTC therapeutic strategies. PMID- 28861610 TI - Inhibitors of the proteasome stimulate the epithelial sodium channel (ENaC) through SGK1 and mimic the effect of aldosterone. AB - The epithelial sodium channel (ENaC) marks the tightly regulated, rate-limiting step of sodium re-absorption in the aldosterone-sensitive distal nephron (ASDN). Stimulation of ENaC activity by aldosterone involves the serum and glucocorticoid induced kinase 1 (SGK1) and is mediated via complex mechanisms including inhibition of channel retrieval. Retrieved channels may be recycled or degraded, e.g. by the proteasomal pathway. The aim of the present study was to investigate whether inhibitors of the proteasome affect ENaC activity and surface expression, and to explore a possible involvement of SGK1. Short circuit current (I SC) measurements were performed on confluent mCCDcl1 murine cortical collecting duct cells to investigate the effect of two distinct proteasomal inhibitors, MG132 and bortezomib, on amiloride-sensitive ENaC-mediated I SC. Both inhibitors robustly stimulated amiloride-sensitive I SC. The time course and magnitude of the stimulatory effect of the proteasomal inhibitors on I SC were similar to those of aldosterone. Both, MG132 and aldosterone, significantly increased the abundance of beta-ENaC at the cell surface. SGK1 activity was assessed by monitoring the phosphorylation of a downstream target, NDRG1, and was found to be increased by MG132. Importantly, inhibiting SGK1 activity prevented not only the stimulatory effect of aldosterone but also that of proteasomal inhibition. In conclusion, these data suggest that ENaC stimulation following proteasomal inhibition is due to an accumulation of active SGK1 resulting in increased expression of ENaC at the cell surface. Thus, inhibition of the proteasome mimics SGK1-dependent stimulation of ENaC by aldosterone. PMID- 28861611 TI - The maize WRKY transcription factor ZmWRKY17 negatively regulates salt stress tolerance in transgenic Arabidopsis plants. AB - MAIN CONCLUSION: We cloned and characterized the ZmWRKY17 gene from maize. Overexpression of ZmWRKY17 in Arabidopsis led to increased sensitivity to salt stress and decreased ABA sensitivity through regulating the expression of some ABA- and stress-responsive genes. The WRKY transcription factors have been reported to function as positive or negative regulators in many different biological processes including plant development, defense regulation and stress response. This study isolated a maize WRKY gene, ZmWRKY17, and characterized its role in tolerance to salt stress by generating transgenic Arabidopsis plants. Expression of the ZmWRKY17 was up-regulated by drought, salt and abscisic acid (ABA) treatments. ZmWRKY17 was localized in the nucleus with no transcriptional activation in yeast. Yeast one-hybrid assay showed that ZmWRKY17 can specifically bind to W-box, and it can activate W-box-dependent transcription in planta. Heterologous overexpression of ZmWRKY17 in Arabidopsis remarkably reduced plant tolerance to salt stress, as determined through physiological analyses of the cotyledons greening rate, root growth, relative electrical leakage and malondialdehyde content. Additionally, ZmWRKY17 transgenic plants showed decreased sensitivity to ABA during seed germination and early seedling growth. Transgenic plants accumulated higher content of ABA than wild-type (WT) plants under NaCl condition. Transcriptome and quantitative real-time PCR analyses revealed that some stress-related genes in transgenic seedlings showed lower expression level than that in the WT when treated with NaCl. Taken together, these results suggest that ZmWRKY17 may act as a negative regulator involved in the salt stress responses through ABA signalling. PMID- 28861612 TI - Molecular characterization of Enterocytozoon bieneusi isolates in laboratory macaques in north China: zoonotic concerns. AB - The significance of wild and zoo nonhuman primates (NHPs) as potential sources of human Enterocytozoon bieneusi infections has been increasingly appreciated, while the role of laboratory NHPs in zoonotic transmission of microsporidiosis remains elusive. In this study, the infection rate, genetic characteristic, and zoonotic potential of E. bieneusi were investigated for 205 laboratory macaques in Beijing, north China. The parasite was identified in 37 (18.0%) animals by nested PCR and sequencing of the ribosomal internal transcribed spacer (ITS), with an infection rate of 25.6% in Macaca fascicularis (34/133) and 4.2% in Macaca mulatta (3/72). The differences in infection rate between the two species of macaques and between young macaques aged <= 5 years (29.6%, 32/108) and adults aged > 5 years (5.2%, 5/97) were significant (p < 0.01). Analysis of the ITS sequence polymorphisms recognized eight known genotypes (CC4, CM1, CM2, D, Peru8, Peru11, Type IV, and WL21) and two new genotypes (named as CMB1 and CMB2), with well-known human-pathogenic genotypes (D, Peru8, Peru11, and Type IV) most frequently detected. The rest genotypes (CC4, CM1, CM2, WL21, CMB1, and CMB2) were clustered into zoonotic group 1 in phylogenetic analysis. The high diversity and widespread presence of the human-pathogenic or group 1 E. bieneusi genotypes in laboratory NHPs, notably M. fascicularis and the young animals, suggest potential of zoonotic transmission. These findings imply that laboratory rhesus macaques could be significant reservoirs for human microsporidiosis. PMID- 28861613 TI - First mortality analysis in the French cohort of uranium millers (F-Millers), period 1968-2013. AB - PURPOSE: Epidemiological studies in cohorts of uranium millers can be informative to improve knowledge of the health effects of uranium, but are very rare. The aim of this study was to analyze, for the first time, mortality in a French cohort of uranium millers. METHODS: The F-Millers cohort includes permanent contract workers employed at least 6 months at French uranium milling plants. Vital status and causes of death were obtained from national registries between 1968 and 2013, in order to perform comparisons with French national and local mortality rates by computing standardized mortality ratios (SMRs) with 95% confidence intervals (95% CI). RESULTS: The cohort includes 1291 workers. The average duration of follow-up is 32.1 years. At the end of follow-up, 448 workers were deceased and 13 lost to follow-up. We observed a significant deficit of mortality for all causes combined when the national reference was considered (SMR 0.81; 95% CI [0.74;0.89]), but no significant difference when the local reference was considered (SMR 0.97; 95% CI [0.88;1.07]). Significant excesses were observed only in a subgroup of 552 workers hired at the manufacturing unit, mainly when the local reference was considered. CONCLUSION: No significant excess of mortality was observed at the scale of the full cohort. The cause-specific excesses of mortality observed in the subgroup of workers hired at the manufacturing unit were based on small number of cases, but would warrant further investigations. Undertaking analytical studies and combined analyses of cohorts of uranium millers would help to study the influence of potential risk factors and obtain more precise results. PMID- 28861614 TI - Gender differences in SCRABBLE performance and associated engagement in purposeful practice activities. AB - In two studies, the SCRABBLE skill of male and female participants at the National SCRABBLE Championship was analyzed and revealed superior performance for males. By collecting increasingly detailed information about the participants' engagement in practice-related activities, we found that over half of the variance in SCRABBLE performance was accounted for by measures of starting ages and the amount of different types of practice activities. Males and females did not differ significantly in the benefits to their performance derived from engagement in SCRABBLE-specific practice alone (purposeful practice). However, gender differences in performance were fully mediated by lower engagement in purposeful practice by females and by their rated preference for playing games of SCRABBLE-an activity where more extended engagement is not associated with increased SCRABBLE performance. General implications from our account of gender differences in skill acquisition are discussed, and future research is proposed for how the duration of engagement in effective deliberate practice can be experimentally manipulated. PMID- 28861615 TI - About MET expression and other biomarkers in non-small cell lung cancer. PMID- 28861616 TI - 9th International Conference on Pediatric Continuous Renal Replacement Therapy. PMID- 28861617 TI - Novel Therapeutic Approaches to Atopic Dermatitis. AB - Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. The number of people affected by AD is relatively high and seems to be rising. Although mild and moderate forms of the disease can be well controlled by the use of emollients, topical corticosteroids, and topical calcineurin inhibitors, treatment of severe is still a huge challenge. The new hope is biologic drugs, magic bullets in allergy, targeted at different points of the complex pathomechanism of inflammation in AD. In this review, novel biologic therapies are discussed, including recombinant monoclonal antibodies directed against various interleukin pathways (such as IL-4, IL-13, TSLP, IL-31, and IL-12/23), on immunoglobulin E, molecules acting as T cells, B cells, etc. Of biological drugs, the most promising seems to be anti-IL-4/IL-13 therapy (dupilumab-the biological agent) and phosphodiesterase-4 inhibitor (crisaborole-a small molecule). A deep understanding of the AD pathomechanism provides a new perspective for tailor-made treatment of severe atopic dermatitis. PMID- 28861618 TI - Why do people participate in health-related studies? PMID- 28861619 TI - Efficacy and economic analysis of two treatment regimens using toltrazuril in lambs naturally infected with Eimeria spp. on pasture. AB - This study evaluated the efficacy and the economic viability of two anticoccidial treatment regimens tested in lambs naturally exposed to Eimeria spp. re infections in a grazing system during a 140-day period. Twenty-four suckling lambs were distributed into three groups based on the individual count of oocysts per gram of feces (OPG) and body weight. Animals were treated with toltrazuril 5% (20 mg/kg) at 14- (GI) or 21-day (GII) intervals, and GIII was kept as untreated control. A cost-benefit analysis of each treatment regimen was calculated. Additionally, economic analysis was performed on four hypothetical scenarios, in which lambs could be having 10, 25, 50, or 85% decrease in their expected body weight gain due to clinical. Efficacy of toltrazuril against Eimeria spp. was 96.9-99.9% (GI) and 74.2-99.9% (GII). E. ovinoidalis was most frequently identified, but no clinical signs of coccidiosis were observed in lambs. There were no differences in weight gain among the groups. The cost of treatment per lamb was $13.09 (GI) and $7.83 (GII). The estimation model showed that the cost benefit ratio favored treatment with toltrazuril when lambs fail to gain weight. In the studied flock, the break-even point for toltrazuril administered at 14-day intervals was reached with 85% decrease in mean weight gain. In conclusion, toltrazuril can be used at 14-day intervals to control Eimeria spp. (re) infection in lambs raised on pasture. This treatment regimen was not economically feasible for subclinical coccidiosis; however, it may be feasible when used to prevent weight loss caused by clinical coccidiosis. PMID- 28861620 TI - Nationwide survey of hereditary pancreatitis in Japan. AB - BACKGROUND: Hereditary pancreatitis (HP) is a rare cause of chronic pancreatitis. We here report a nationwide survey to clarify the epidemiological, genetic, and clinical features of HP in Japan. METHODS: Target subjects were patients with HP and their family members who had visited selected hospitals between 2005 and 2014. This study consisted of two-stage surveys; patients with HP were identified by the first questionnaire and their clinical features were assessed by the second questionnaire. RESULTS: Two hundred seventy-one patients (153 males and 118 females) in 100 families diagnosed based on the Japanese criteria or 231 patients (131 males and 100 females) patients in 80 families based on the EUROPAC criteria were reported. Of the families undertaking genetic tests, 41% had the PRSS1 mutations (p.R122H 33%, p.N29I 8%) and 36% had the SPINK1 mutations (p.N34S 22%, c.194+2T>C 14%, p.P45S 1%). The mean age at symptom onset was 17.8 years. The cumulative rates of pancreatic exocrine insufficiency and diabetes mellitus were 16.1 and 5.5% at 20 years old, and 45.3 and 28.2% at 40 years, respectively. Forty-four percent of the patients underwent endoscopic treatment and/or surgery. The cumulative rate of pancreatic cancer diagnosis was 2.8% at 40 years old, 10.8% at 60 years, and 22.8% at 70 years. CONCLUSIONS: HP was characterized by early disease onset, frequent development of pancreatic exocrine insufficiency and diabetes mellitus, requirement of endoscopic treatment and/or surgery, and increased risk of pancreatic cancer. PRSS1 and SPINK1 mutations serve as genetic background for HP in Japan. PMID- 28861621 TI - Enteroviruses in blood of patients with type 1 diabetes detected by integrated cell culture and reverse transcription quantitative real-time PCR. AB - AIMS: Enteroviruses (EV) have been associated with type 1 diabetes (T1D), but EV RNA detection has been reported in only a small proportion of T1D patients. We studied whether integrated cell culture and reverse transcription real-time PCR could improve EV detection in blood samples from patients with T1D. METHODS: Blood was collected from 13 patients with T1D. The presence of EV RNA in blood was investigated by using real-time RT-PCR. In addition, plasma and white blood cells (WBC) were inoculated to BGM and Vero cell line cultures. Culture supernatants and cells collected on day 7 and day 14 were tested for EV RNA by real-time RT-PCR. Enterovirus identification was performed through sequencing of the VP4/VP2 region. RESULTS: Enterovirus RNA was detected in blood by using real time RT-PCR in only one out of 13 patients. The detection of EV RNA in cultures inoculated with clinical samples (plasma and/or WBC) gave positive results in five other patients. The viral loads were low, ranging from 45 to 4420 copies/ng of total RNA. One isolate was successfully identified as coxsackievirus B1. CONCLUSIONS: Integrated cell culture and reverse transcription real-time PCR can improve the detection rate of EV in blood samples of patients with T1D and can be useful to investigate further the relationship between EV and the disease. PMID- 28861622 TI - Perfusion magnetic resonance imaging in pediatric brain tumors. AB - PURPOSE: The use of DSC-MR imaging in pediatric neuroradiology is gradually growing. However, the number of studies listed in the literature remains limited. We propose to assess the perfusion and permeability parameters in pediatric brain tumor grading. METHODS: Thirty children with a brain tumor having benefited from a DSC-MR perfusion sequence have been retrospectively explored. Relative CBF and CBV were computed on the ROI with the largest lesion coverage. Assessment of the lesion's permeability was also performed through the semi-quantitative PSR parameter and the K2 model-based parameter on the whole-lesion ROI and a reduced ROI drawn on the permeability maps. A statistical comparison of high- and low grade groups (HG, LG) as well as a ROC analysis was performed on the histogram based parameters. RESULTS: Our results showed a statistically significant difference between LG and HG groups for mean rCBV (p < 10-3), rCBF (p < 10-3), and for PSR (p = 0.03) but not for the K2 factor (p = 0.5). However, the ratio K2/PSR was shown to be a strong discriminating factor between the two groups of lesions (p < 10-3). For rCBV and rCBF indicators, high values of ROC AUC were obtained (> 0.9) and mean value thresholds were observed at 1.07 and 1.03, respectively. For K2/PSR in the reduced area, AUC was also superior to 0.9. CONCLUSIONS: The implementation of a dynamic T2* perfusion sequence provided reliable results using an objective whole-lesion ROI. Perfusion parameters as well as a new permeability indicator could efficiently discriminate high-grade from low-grade lesions in the pediatric population. PMID- 28861623 TI - Arthroscopic management of snapping scapula syndrome improves pain and functional outcomes, although a high rate of residual symptoms has been reported. AB - PURPOSE: To investigate the use of arthroscopy in the management of patients with snapping scapula syndrome, including aetiology, surgical decision-making, outcomes, complications, effectiveness of arthroscopy, and quality of evidence of the existing literature. METHODS: Three databases (PubMed, Ovid [MEDLINE], and EMBASE) were searched independently and in duplicate to systematically screen the literature. The Preferred Reporting Items for Systematic Reviews and Meta analyses (PRISMA) checklist guided the reporting and data abstraction. Methodological quality of all included papers was assessed using the MINORS criteria. The results are presented in a narrative summary fashion using descriptive statistics including means, proportions, and ranges. RESULTS: Overall, 18 studies (5 case reports and 13 case series; all level IV evidence) were identified, including 201 patients (203 shoulders). The mean follow-up period was 32.7 months (range 1-154 months). Surgical decision-making for the use of arthroscopy was most commonly based on a failed trial of initial non-operative management in 17 studies (94%). Overall, 21% of cases achieved complete resolution of pre-operative symptoms, including pain, crepitus, and range of motion, while 68% of cases obtained some clinical improvement, but reported some residual symptoms (persistent crepitus [12%] and persistent scapulothoracic pain [4%]). Moreover, poor outcomes were reported 11% of cases and the most common complication was scapular oedema (6%). CONCLUSION: Arthroscopic management of snapping scapula syndrome yields improvement in pain, crepitus, and range of motion in a majority of patients; however, most patients experience residual symptoms. Further studies are needed to compare the outcomes of shoulder arthroscopy with other available treatment options for snapping scapula syndrome. Shoulder arthroscopy for snapping scapula can improve patients' symptoms; however, patients must be informed about the high likelihood of persistent symptoms post-operatively. LEVEL OF EVIDENCE: Systematic review of Level IV studies. PMID- 28861625 TI - The hydroxyapatite Turkish Delight: a technical note. AB - Nasal dorsum augmentation is commonly performed using autologous cartilage grafts, also in the Turkish Delight technique. The aim of this study was to describe a modification of the Turkish Delight technique for dorsal augmentation consisting of small hydroxyapatite-calcium carbonate granules (0.5-1 mm) that were wrapped in layers of oxidized cellulose and glued with 1-2-cm3 fibrin sealant and to compare its utility with that of other techniques. Clinically stable and satisfactory results were achieved in the four cases examined. Cone beam computerized tomography (CBCT) imaging revealed that there was no degradation of the graft up to 2 years after surgery. The use of a modified Turkish Delight method using hydroxyapatite granules promises to be a valuable option for the correction of nasal dorsum deficiency. PMID- 28861624 TI - Docking-assisted 3D-QSAR studies on xanthones as alpha-glucosidase inhibitors. AB - Recently, a series of xanthone analogues has been identified as alpha-glucosidase inhibitors. To provide deeper insight into the three-dimensional (3D) structural requirements for the activities of these molecules, CoMFA and CoMSIA approaches were employed on 54 xanthones to construct 3D-QSAR models. Their bioactive conformations were first investigated by docking studies and optimized by subsequent molecular dynamics (MD) simulations using the homology modeled structure of the target protein. Based on the docking/MD-determined conformers, 3D-QSAR studies generated several significant models in terms of 47 molecules as the training set. The best model (CoMSIA-SHA) yielded q 2 of 0.713, r 2 of 0.967 and F of 140.250. The robustness of the model was further externally confirmed by a test set of the remaining molecules (q 2 = 0.793, r 2 = 0.902, and k = 0.905). Contour maps provided much information for future design and optimization of new compounds with high inhibitory activities towards alpha-glucosidase. Graphical Abstract CoMSIA/SHA contour map of xanthone alpha-glucosidase inhibitor. PMID- 28861626 TI - Alanyl-glutamine but not glycyl-glutamine improved the proliferation of enterocytes as glutamine substitution in vitro. AB - The synthetic dipeptides alanyl-glutamine (Ala-Gln) and glycyl-glutamine (Gly Gln) are used as Gln substitution to provide energy source in the gastrointestinal tract due to their high solubility and stability. This study aimed to investigate the effects of Gln, Ala-Gln and Gly-Gln on mitochondrial respiration and protein turnover of enterocytes. Intestinal porcine epithelial cells (IPEC-J2) were cultured for 2 days in Dulbecco's modified Eagle's-F12 Ham medium (DMEM-F12) containing 2.5 mM Gln, Ala-Gln or Gly-Gln. Results from 5 ethynyl-2'-deoxyuridine incorporation and flow cytometry analysis indicated that there were no differences in proliferation between free Gln and Ala-Gln-treated cells, whereas Gly-Gln treatment inhibited the cell growth compared with Gln treatment. Significantly lower mRNA expressions of Sp1 and PepT1 were also observed in Gly-Gln-treated cells than that of Ala-Gln treatment. Ala-Gln treatment increased the basal respiration and ATP production, compared with free Gln and Gly-Gln treatments. There were no differences in protein turnover between free Gln and Ala-Gln-treated cells, but Gly-Gln treatment reduced protein synthesis and increased protein degradation. Ala-Gln treatment stimulated mTOR activation whereas Gly-Gln decreased mTOR phosphorylation and increased the UB protein expression compared with free Gln treatment. These results indicate that Ala-Gln has the very similar functional profile to free Gln in porcine enterocytes in vitro and can be substituted Gln as energy and protein sources in the gastrointestinal tract. PMID- 28861627 TI - Is the addition of a neurokinin-1 receptor antagonist beneficial in moderately emetogenic chemotherapy?-a systematic review and meta-analysis. AB - PURPOSE: This systematic review evaluates the efficacy of neurokinin-1 receptor antagonists (NK1RAs) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy (MEC) excluding anthracycline-cyclophosphamide-based regimens. METHODS: A systematic review of MEDLINE (via PubMed and OVID) and Central databases, plus major oncology conferences, identified randomized trials evaluating NK1RAs in combination with a 5-HT3 RA plus a glucocorticoid for management of CINV. Efficacy endpoints were complete response (CR), no emesis and no nausea rates. Data were analyzed using a random effects model. RESULTS: Sixteen trials (3848 patients) were identified. Results were separately analyzed for (a) pure MEC regimens (excluding regimens containing carboplatin or oxaliplatin), (b) carboplatin-based regimens, and (c) oxaliplatin-based regimens. (a) Two trials (abstracts) enrolled 715 patients. The odds ratio for overall CR with the addition of an NK1-RA was 1.46 (95% 1.06-2.02; p = 0.02) with an absolute risk difference (RD) of 8%. (b) Nine trials (1790 patients) were identified. The OR for achieving an overall CR was 1.96 (95% CI 1.57-2.45; p < 0.00001) in favor of the NK1RA containing regimen with an RD of 15%. (c) Three trials (1190 patients) were identified. The OR for achieving an overall CR was 1.34 (95% CI 0.88-2.04; p = 0.17) not reaching statistical significance with a RD of 4%. CONCLUSION: Clear clinically significant benefit was seen with the addition of NK1RAs in carboplatin-based chemotherapy. A global benefit of an NK1RA containing regimen for the whole MEC category cannot be attested yet and warrants more randomized trials exclusively testing pure MEC regimens without carboplatin. PMID- 28861628 TI - HSV-2 encephalitis presenting as multifocal ischemic stroke. PMID- 28861629 TI - Predicting medical practices using various risk attitude measures. AB - This paper investigates the predictive power of several risk attitude measures on a series of medical practices. We elicit risk preferences on a sample of 1500 French general practitioners (GPs) using two different classes of tools: scales, which measure GPs' own perception of their willingness to take risks between 0 and 10; and lotteries, which require GPs to choose between a safe and a risky option in a series of hypothetical situations. In addition to a daily life risk scale that measures a general risk attitude, risk taking is measured in different domains for each tool: financial matters, GPs' own health, and patients' health. We take advantage of the rare opportunity to combine these multiple risk attitude measures with a series of self-reported or administratively recorded medical practices. We successively test the predictive power of our seven risk attitude measures on eleven medical practices affecting the GPs' own health or their patients' health. We find that domain-specific measures are far better predictors than the general risk attitude measure. Neither of the two classes of tools (scales or lotteries) seems to perform indisputably better than the other, except when we concentrate on the only non-declarative practice (prescription of biological tests), for which the classic money-lottery test works well. From a public health perspective, appropriate measures of willingness to take risks may be used to make a quick, but efficient, profiling of GPs and target them with personalized communications, or interventions, aimed at improving practices. PMID- 28861631 TI - Unenhanced magnetic resonance imaging immediately after radiofrequency ablation of liver malignancy: preliminary results. AB - PURPOSE: To assess the accuracy of unenhanced magnetic resonance imaging (MRI) immediately after the percutaneous ultrasound-guided radiofrequency ablation (RFA) of liver malignancy in predicting treatment efficacy at CT follow-up. MATERIALS AND METHODS: Percutaneous ablation was prospectively performed in 23 liver malignancies (20 hepatocarcinomas and 3 metastases). After the procedure in the same day all patients were studied with unenhanced MRI. The best sequence to detect the coagulative necrosis was visually established. Pre-RFA CT and post-RFA MRI were registered with non-rigid transformation algorithm. Manual segmentation of lesions and ablated areas in pre-RFA CT, post-RFA MRI, and follow-up CT were obtained. Sensitivity, specificity, positive predictive value (PPV), negative predicitve value (NPV), and accuracy of MRI in predicting the correct centering and the complete treatment of the lesion were calculated in respect to the 1 month follow-up CT. RESULTS: Fat-saturated T1-weighted (fs T1-w) was the sequence in which the best conspicuity of the ablated area was depicted. Coagulative necrosis was hyperintense in fs T1-w sequence in 17/23 (74%). In respect to follow-up CT, MRI predicted the correct centering of the lesions in 19/20 lesions with sensitivity, specificity, PPV, NPV, and accuracy of 100%, 75%, 95%, 100%, and 100%, respectively. MRI predicted the complete treatment of the lesions in 17/17 lesions with sensitivity, specificity, PPV, NPV, and accuracy of 100%. CONCLUSION: MRI with the single fs T1-w sequence was highly accurate in predicting the treatment efficacy of percutaneous ablation of liver malignancies in comparison to follow-up CT control. Unnecessary CT in case of incomplete treatment can be therefore easily avoided. PMID- 28861630 TI - An integrated inverse model-experimental approach to determine soft tissue three dimensional constitutive parameters: application to post-infarcted myocardium. AB - Knowledge of the complete three-dimensional (3D) mechanical behavior of soft tissues is essential in understanding their pathophysiology and in developing novel therapies. Despite significant progress made in experimentation and modeling, a complete approach for the full characterization of soft tissue 3D behavior remains elusive. A major challenge is the complex architecture of soft tissues, such as myocardium, which endows them with strongly anisotropic and heterogeneous mechanical properties. Available experimental approaches for quantifying the 3D mechanical behavior of myocardium are limited to preselected planar biaxial and 3D cuboidal shear tests. These approaches fall short in pursuing a model-driven approach that operates over the full kinematic space. To address these limitations, we took the following approach. First, based on a kinematical analysis and using a given strain energy density function (SEDF), we obtained an optimal set of displacement paths based on the full 3D deformation gradient tensor. We then applied this optimal set to obtain novel experimental data from a 1-cm cube of post-infarcted left ventricular myocardium. Next, we developed an inverse finite element (FE) simulation of the experimental configuration embedded in a parameter optimization scheme for estimation of the SEDF parameters. Notable features of this approach include: (i) enhanced determinability and predictive capability of the estimated parameters following an optimal design of experiments, (ii) accurate simulation of the experimental setup and transmural variation of local fiber directions in the FE environment, and (iii) application of all displacement paths to a single specimen to minimize testing time so that tissue viability could be maintained. Our results indicated that, in contrast to the common approach of conducting preselected tests and choosing an SEDF a posteriori, the optimal design of experiments, integrated with a chosen SEDF and full 3D kinematics, leads to a more robust characterization of the mechanical behavior of myocardium and higher predictive capabilities of the SEDF. The methodology proposed and demonstrated herein will ultimately provide a means to reliably predict tissue-level behaviors, thus facilitating organ-level simulations for efficient diagnosis and evaluation of potential treatments. While applied to myocardium, such developments are also applicable to characterization of other types of soft tissues. PMID- 28861632 TI - Margination and adhesion of micro- and nanoparticles in the coronary circulation: a step towards optimised drug carrier design. AB - Obstruction of left anterior descending artery (LAD) due to the thrombosis or atherosclerotic plaques is the leading cause of death worldwide. Targeted delivery of drugs through micro- and nanoparticles is a very promising approach for developing new strategies in clot-busting or treating restenosis. In this work, we modelled the blood flow characteristics in a patient-specific reconstructed LAD artery by the fluid-solid interaction method and based on physiological boundary conditions. Next, we provided a Lagrangian description of micro- and nanoparticles dynamics in the blood flow considering their Brownian motion and the particle-particle interactions. Our results state that the number of spherical particles migrating towards the region of lumen with potential of thrombus existence (PTE) rises by increasing the particle size. Also, an optimum scope of particle size in which the adhesive probability parameter reaches its maximum was determined. We acquired an optimum scope for a specific degree of particle sphericity in which the thrombus surfaces experience the maximum density of interaction with particles. We learned that the ligand-receptor mechanism based drug carriers are better choices for treating LAD arterial diseases when the addressees are patients with low haematocrit-related diseases. While due to the amount of shear stress exerting on the diseased area, generally exploiting nanoshear-activated drug carriers would be the more effective option when it comes to the thrombolytic therapies of patients with high haematocrit-related diseases. PMID- 28861633 TI - Efficacy of pedobarographic analysis to evaluate proximal medial gastrocnemius recession in patients with gastrocnemius tightness and metatarsalgia. AB - PURPOSE: Proximal medial gastrocnemius recession (PMGR) is a surgical procedure performed in patients with gastrocnemius tightness (GT). The purpose of this study is to evaluate the efficacy of pedobarographic analysis on PMGR in patients with GT and metatarsalgia. METHODS: This prospective study included 52 patients diagnosed with GT treated surgically with PMGR and 49 non-operated upon patients (control group). A total of 55 PMGRs (three bilateral) were performed as an isolated or combined procedure in the treatment group. Passive ankle dorsiflexion with knee flexion and extension was evaluated in all patients. In addition, pedobarographic analysis was performed before and after surgery. RESULTS: Median preoperative ankle dorsiflexion was -10.0 degrees (equinus) with extended knee and 10.0 degrees with flexed knee and postoperative differences in median ankle dorsiflexion was 12.5 degrees (extended knee) (p = 0.000) and 5.0 degrees (flexed knee) (p = 0.002). After the PMGR, the median area of the contact surface (-3.0 cm2) (p = 0.009), the maximum (-13,239.0 Pa) (p = 0.019) and mean pressure (-2,942.0 Pa) and the forefoot force (-70.0 N) (p = 0.000) decreased. An increase in hindfoot force (20.0 N), hindfoot bearing time (4.0 ms) (p = 0.005), and forefoot bearing time (1.0 ms) was also observed. CONCLUSIONS: Pedobarographic analysis is an efficient tool to evaluate surgical procedures that assess metatarsal overload. PMGR is an effective surgical procedure to improve passive ankle range of motion and decrease forefoot plantar overload. PMID- 28861634 TI - Novel one-pot ATP regeneration system based on three-enzyme cascade for industrial CTP production. AB - OBJECTIVES: To develop a new one-pot polyphosphate kinase (PPK) system with low cost and high efficiency for ATP regeneration in industrial CTP production. RESULTS: We developed a new one-pot PPK system by applying a three-enzyme cascade (CMK, NDK and PPK) with an in vitro polyP-based ATP regeneration system. The PPK was selected from twenty sources, and was made solvable by fusion expressing with soluble protein and constructing polycistronic plasmids, or co-expressing with molecular chaperones GroES/EL. Activities of other enzymes were optimized by employing fusion expression, tac-pBAD system, Rosetta host and codon optimization. After 24 h, the concentration of CDP and CTP reached 3.8 +/- 0.2 and 6.9 +/- 0.3 mM l-1 respectively with a yield of approximately 79%. The molar conversion rate of CTP was 51%, and its yield and conversion rate increased 100% from the traditional system. CONCLUSIONS: A new one-pot ATP regeneration system applying polyphosphate kinase for CTP production was developed. PMID- 28861635 TI - Diffusion-weighted imaging of the pericholecystic hepatic parenchyma for distinguishing acute and chronic cholecystitis. AB - PURPOSE: The purpose of this study is to measure the performance of restricted diffusion of the pericholecystic hepatic parenchyma for distinguishing between acute and chronic cholecystitis. METHODS: The institutional review board approved this HIPAA-compliant retrospective study. Two hundred sixty-six patients presenting with acute right upper quadrant pain between 10/3/2010 and 11/28/2012 undergoing MR within 48 h of equivocal utility of ultrasound (US) were included. Diffusion-weighted imaging (DWI) sequences (b = 0, 600 s/mm2, apparent diffusion coefficient (ADC) maps) were reviewed and graded in a blinded fashion by two abdominal fellowship-trained radiologists for the presence of restricted diffusion in the pericholecystic hepatic parenchyma and the gallbladder wall. Sensitivity, specificity, and inter-observer agreement for individual imaging signs were calculated using surgical pathology as the reference standard for acute cholecystitis. RESULTS: Of the 266 patients, 113 were treated conservatively and 153 underwent cholecystectomy. Restricted diffusion of the pericholecystic hepatic parenchyma showed low sensitivity (reviewer 1, 40%; reviewer 2, 30%) and moderately high specificity (reviewer 1, 84%; reviewer 2, 75%) for distinguishing acute and chronic cholecystitis. Restricted diffusion in the gallbladder wall showed low sensitivity (reviewer 1, 30%; reviewer 2, 7%) and high specificity (reviewer 1, 93%; reviewer 2, 97%) for distinguishing acute and chronic cholecystitis. CONCLUSION: Diffusion-weighted imaging of the pericholecystic hepatic parenchyma shows moderately high specificity for distinguishing between acute and chronic cholecystitis. PMID- 28861638 TI - Why critical appraisal is so important these days. PMID- 28861636 TI - Self-perception of fracture risk: what can it tell us? AB - : In this study, we report that self-perception of fracture risk captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is associated with improved medication uptake. It suggests that adequate appreciation of fracture risk may be beneficial and lead to greater healthcare engagement and treatment. INTRODUCTION: This study aimed to assess how well self-perception of fracture risk, and fracture risk as estimated by the fracture prediction tool FRAX, related to fracture incidence and uptake and persistence of anti-osteoporosis medication among women participating in the Global Longitudinal study of Osteoporosis in Women (GLOW). METHODS: GLOW is an international cohort study involving 723 physician practices across 10 countries in Europe, North America and Australia. Aged >= 55 years, 60,393 women completed baseline questionnaires detailing medical history, including co-morbidities, fractures and self-perceived fracture risk (SPR). Annual follow-up included self reported incident fractures and anti-osteoporosis medication (AOM) use. We calculated FRAX risk without bone mineral density measurement. RESULTS: Of the 39,241 women with at least 1 year of follow-up data, 2132 (5.4%) sustained an incident major osteoporotic fracture over 5 years of follow-up. Within each SPR category, risk of fracture increased as the FRAX categorisation of risk increased. In GLOW, only 11% of women with a lower baseline SPR were taking AOM at baseline, compared with 46% of women with a higher SPR. AOM use tended to increase in the years after a reported fracture. However, women with a lower SPR who were fractured still reported lower AOM rates than women with or without a fracture but had a higher SPR. CONCLUSIONS: These results suggest that SPR captures some aspect of fracture risk not currently measured using conventional fracture prediction tools and is also associated with improved medication uptake. PMID- 28861637 TI - Impact of repeat HER2 testing after initial equivocal HER2 FISH results using 2013 ASCO/CAP guidelines. AB - PURPOSE: The updated 2013 American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing have made some major changes in HER2 fluorescence in situ hybridization (FISH) interpretation criteria with additional FISH equivocal cases. Repeat HER2 testing is recommended after initial HER2 FISH equivocal results; however, little is known about its impact on final HER2 status. The aim of this study is to investigate whether reflex test clarifies HER2 status, and to characterize clinicopathological features of the newly defined HER2 equivocal group. METHODS: A total of 886 consecutive cases of primary invasive breast cancer conducted with dual-probe HER2 FISH testing between November 2013 and December 2015 were reviewed. HER2 immunohistochemistry (IHC) and FISH testing were performed on a different tissue block or a new specimen after initial HER2 FISH equivocal results. RESULTS: Compared to 2007 guideline, 85 (9.6%) cases changed their category by using 2013 guideline. The major change of the 85 cases is that 57 (6.4%) cases in HER2 FISH-negative category changed to equivocal, and the equivocal category cases increased from 36 to 67. HER2 FISH equivocal was significantly associated with HER2 IHC equivocal (2+) and chromosome 17 polysomy (P < 0.01). Repeat testing by IHC and FISH clarified HER2 status in 33 and 42% of HER2 equivocal cases, respectively. Overall 32 (48%) initial HER2 equivocal cases stayed HER2 equivocal after repeat FISH and or IHC testing. These tumors were ER/PR+, with high KI-67 index. CONCLUSION: New guidelines classify more HER2 FISH equivocal cases. Repeat HER2 testing clarifies HER2 status in about 50% of initial HER2 FISH equivocal cases. In addition, HER2 equivocal cases merit further study as there is limited information about prognosis and optimal treatment strategy for this population. PMID- 28861639 TI - Repositioning of proton pump inhibitors in cancer therapy. AB - Drug repositioning, as a smart way to exploit new molecular targets of a known drug, has been gaining increasing attention in the discovery of anti-cancer drugs. Proton pump inhibitors (PPIs) as benzimidazole derivatives, which are essentially H+-K+-ATPases inhibitors, are commonly used in the treatment of acid related diseases such as gastric ulcer. In recent years, exploring the new application of PPIs in anti-cancer field has become a hot research topic. Interestingly, cancer cells display an alkaline intracellular pH and an acidic extracellular pH. The extracellular acidity of tumors can be corrected by PPIs that are selectively activated in an acid milieu. It is generally believed that PPIs might provoke disruption of pH homeostasis by targeting V-ATPase on cancer cells, which is the theoretical basis for PPIs to play an anti-cancer role. Numerous studies have shown specialized effects of the PPIs on tumor cell growth, metastasis, chemoresistance, and autophagy. PPIs may really represent new anti cancer drugs due to better safety and tolerance, the potential selectivity in targeting tumor acidity, and the ability to inhibit mechanism pivotal for cancer homeostasis. In this review, we focus on the new therapeutic applications of PPIs in multiple cancers, explaining the rationale behind this approach and providing practical evidence. PMID- 28861640 TI - Bone Mineral Density in Boys Diagnosed with Autism Spectrum Disorder: A Case Control Study. AB - This study compared bone mineral density (BMD) of the spine obtained by dual energy X-ray absorptiometry (DEXA), nutritional status, biochemical markers, and gastrointestinal (GI) symptoms in 4-8 year old boys with Autism Spectrum Disorder (ASD) with a group of age-matched, healthy boys without ASD. Boys with ASD had significantly lower spine BMD compared to controls but this was not correlated with any biochemical markers, dietary intake of calcium and vitamin D, elimination diet status, or GI symptomology. Reduced BMD in 4-8 year old boys with ASD appears to involve factors other than nutrient intake and GI status, and requires further study. PMID- 28861642 TI - Chronic pain and other symptoms among breast cancer survivors: prevalence, predictors, and effects on quality of life. AB - PURPOSE: To investigate prevalence and risk factors associated with self-reported chronic pain, and other symptoms related to breast cancer or its treatment among breast cancer survivors (BCS). METHODS: A cross-sectional study of a random sample of 410 female BCS, members of "Leumit" healthcare fund, diagnosed with primary nonmetastatic invasive breast cancer in the years 2002-2012. The study questionnaire included questions on health-related quality of life, pain symptoms, and was completed by all women contacted. RESULTS: A total of 305 BCS (74%), with a median of 7.4 years since diagnosis reported chronic pain, of whom 84% had moderate pain, and 97% experienced pain at least 1-3 days/week. Other symptoms were paresthesia (63%), allodynia (48%), and phantom sensations (15%). Report of pain symptoms, alone or combined, was significantly associated with poorer quality of life. In multivariable analyses, chronic pain was positively associated with mastectomy compared to breast-conserving surgery [Odds ratio (OR), 3.54; 95% confidence interval (CI) 1.46-8.59; P = 0.005], radiotherapy compared to non-radiotherapy (OR 2.96; 95% CI 1.43-6.12; P = 0.003), breast cancer stage at diagnosis-regional versus localized (OR 3.63; 95% CI 2.00-6.57; P < 0.001), and inversely with age (OR per one-year increment, 0.96; 95% CI 0.94 0.99; P = 0.002), and with time since diagnosis (OR per one-year increment, 0.82; 95% CI 0.75-0.90; P < 0.001). CONCLUSIONS: With the increasing incidence of detected breast cancer and the improvements in treatment and consequently survival, knowledge about prevalence, and factors related to treatment late effects of chronic pain is highly relevant for potential prevention or management without negatively impacting quality of life. PMID- 28861641 TI - Medicinal plant extracts modulate respiratory burst and proliferation activity of rainbow trout (Oncorhynchus mykiss) leukocytes. AB - The present study was designed to investigate the immunomodulatory effects of Aloe vera, Curcuma longa, Echinacea purpurea, Lavandula officinalis, Origanum vulgare, Panax ginseng, and Rheum officinale extracts on leukocytes purified from rainbow trout (Oncorhynchus mykiss) head kidney. The cells were cultured in a medium containing increasing doses of extracts; afterwards, they were tested for reactive oxygen species production after stimulation with phorbol myristate acetate (PMA) and proliferation in the presence or absence of phytohemagglutinin from Phaseolus vulgaris (PHA-P). After a 2-h exposure, the extracts of L. officinalis, O. vulgare, and R. officinale strongly reduced the oxidative burst activity of PMA-stimulated leukocytes, in a dose-dependent manner (P <= 0.05). A. vera, C. longa, E. purpurea, and P. ginseng extracts reduced this response with lower efficacy and especially at lower concentrations. On the contrary, the highest concentration of ginseng extract stimulated the respiratory burst of leukocytes compared to untreated control cells. After a 72-h exposure, the extracts of L. officinalis, R. officinale, C. longa, E. purpurea, and P. ginseng had a clear dose-dependent stimulatory effect on leukocyte proliferation (P <= 0.05). The results suggest that these medicinal plants can be considered as reliable sources of new antioxidants or immunostimulants to be used in aquaculture. PMID- 28861643 TI - N-acetylcysteine manipulation fails to elicit an increase in glutathione in a teleost model. AB - Levels of oxidative stress can be affected by a range of compounds including toxins and pharmaceuticals. Antioxidants are important protective compounds which counteract the damaging effects of oxidative stress. Glutathione (GSH) is one of the main antioxidants for many organisms and can be synthesized from administered N-acetylcysteine (NAC). NAC has therefore often been used in a wide range of taxa to manipulate levels of GSH. Our objective was to validate this approach in a wild temperate teleost fish model, the brown trout (Salmo trutta). We used intracoelomic injections of NAC in saline and vegetable shortening, at two different concentrations (100 and 400 mg/kg), with the appropriate controls and shams, under controlled laboratory settings. We found that NAC failed to elicit an increase in GSH over three time periods and concluded that NAC is not an effective method to enhance GSH levels in teleost fish using the concentrations and vehicles tested here. We emphasize the importance of validation studies across all new species/taxa when possible and suggest that more investigation is required with regard to NAC manipulation in fish if this approach is to be used. PMID- 28861644 TI - Epistemological rehabilitation of "shoe leather" epidemiology: the lesson of cholera in Haiti. PMID- 28861646 TI - Nanocomposite particles with improved microstructure for 3D culture systems and bone regeneration. AB - Nano-apatite and gelatin-alginate hydrogel microparticles have been prepared by a one-step synthesis combined with electrostatic bead generation, for the reconstruction of bone defects. Based on the analysis of bone composition, architecture and embryonic intramembranous ossification, a bio-inspired fabrication has been developed. Accordingly, the mineral phase has been in situ synthesized, calcifying the hydrogel matrix while the latter was crosslinked, finally generating microparticles that can assemble into a bone defect to ensure interconnected pores. Although nano-apatite-biopolymer composites have been widely investigated, microstructural optimization to provide improved distribution and stability of the mineral is rarely achieved. The optimization of the developed method progressively resulted in two types of formulations (15P and 7.5P), with 15 and 7.5 (wt%) phosphate content in the initial precursor. The osteolytic potential was investigated using differentiated macrophages. A commercially available calcium phosphate bone graft substitute (Eurocer 400) was incorporated into the hydrogel, and the obtained composites were in vitro tested for comparison. The cytocompatibility of the microparticles was studied with mouse osteoblast-like cell line MC3T3-E1. Results indicated the best in vitro performance have been obtained for the sample loaded with 7.5P. Preliminary evaluation of biocompatibility into a critical size (3 mm) defect in rabbits showed that 7.5P nanocomposite is associated with newly formed bone in the proximity of the microparticles, after 28 days. PMID- 28861647 TI - Fiber-type distribution and expression of myosin heavy chain isoforms in newborn heterozygous myostatin-knockout pigs. AB - OBJECTIVES: To explore the effects of heterozygous myostatin-knockout (MSNT+/-) on muscle characteristics, specifically fiber-type distribution and expression of myosin heavy chain isoforms in pigs. RESULTS: The fiber cross-sectional area of the semitendinosus and semimembranosus muscles were much larger in MSTN+/- pigs at birth than in wild-type (WT) pigs. MSTN+/- pigs had a higher proportion of fast-type fibers and lower succinate dehydrogenase activity in muscles than WT pigs. The myosin heavy chain IIB mRNA level in both two muscles was ~ threefold higher in MSTN+/- pigs compared with WT pigs. CONCLUSION: MSTN+/- pigs exhibit a disproportionate increase in muscle mass and can have a higher body weight due to fiber hypertrophy, a change in the fiber-type distribution, and alteration of myosin heavy chain isoforms levels, leading to more fast glycolytic fibers. PMID- 28861648 TI - The Role of Secondary Calciprotein Particles in the Mineralisation Paradox of Chronic Kidney Disease. AB - Mineralisation paradox is prevalent in chronic kidney disease and ageing where increased vascular calcification is accompanied by reduced bone mineralisation and osteopenia. Secondary calciprotein particles (CPP2), colloidal nanoparticles containing hydroxyapatite crystal stabilised by a protein shell, have been implicated in vascular calcification in chronic kidney disease. Here, we describe the effect of CPP2 on osteoblasts and vascular smooth muscle cells (VSMC) mineralisation in an in vitro model system. The mineralisation paradox can be simulated in vitro by the addition of phosphate ions (Pi, 3 mM) and CPP2 (10 ug/ml of Ca equivalent). Pi alone induced osteoblast mineralisation but had no effect on VSMC mineralisation. CPP2 alone had no effect on mineralisation in either cell line, but when combined with elevated Pi, reduced osteoblast-like mineralisation (P < 0.001) whilst induced VSMC mineralisation (P < 0.001). These results suggest that in an in vitro system the synergistic interaction between Pi and CPP2 could mimic the mineralisation paradox, and may provide a potential mechanistic link to explain these clinical observations. PMID- 28861649 TI - Parents Suggest Which Indicators of Progress and Outcomes Should be Measured in Young Children with Autism Spectrum Disorder. AB - Evaluation of interventions for children with autism spectrum disorder (ASD) is hampered by the multitude of outcomes measured and tools used. Measurement in research with young children tends to focus on core impairments in ASD. We conducted a systematic review of qualitative studies of what matters to parents. Parent advisory groups completed structured activities to explore their perceptions of the relative importance of a wide range of outcome constructs. Their highest ranked outcomes impacted directly on everyday life and functioning (anxiety, distress, hypersensitivity, sleep problems, happiness, relationships with brothers and sisters, and parent stress). Collaboration between professionals, researchers and parents/carers is required to determine an agreed core set of outcomes to use across evaluation research. PMID- 28861650 TI - Optimal timing of drug sensitivity testing for patients on first-line tuberculosis treatment. AB - Effective treatment for tuberculosis (TB) patients on first-line treatment involves triaging those with drug-resistant (DR) TB to appropriate treatment alternatives. Patients likely to have DR TB are identified using results from repeated inexpensive sputum-smear (SS) tests and expensive but definitive drug sensitivity tests (DST). Early DST may lead to high costs and unnecessary testing; late DST may lead to poor health outcomes and disease transmission. We use a partially observable Markov decision process (POMDP) framework to determine optimal DST timing. We develop policy-relevant structural properties of the POMDP model. We apply our model to TB in India to identify the patterns of SS test results that should prompt DST if transmission costs remain at status-quo levels. Unlike previous analyses of personalized treatment policies, we take a societal perspective and consider the effects of disease transmission. The inclusion of such effects can significantly alter the optimal policy. We find that an optimal DST policy could save India approximately $1.9 billion annually. PMID- 28861645 TI - [Guideline for "rhinosinusitis"-long version : S2k guideline of the German College of General Practitioners and Family Physicians and the German Society for Oto-Rhino-Laryngology, Head and Neck Surgery]. PMID- 28861651 TI - Parent-Mediated Intervention for One-Year-Olds Screened as At-Risk for Autism Spectrum Disorder: A Randomized Controlled Trial. AB - Theoretically, interventions initiated with at-risk infants prior to the point in time a definitive autism spectrum disorder (ASD) diagnosis can be made will improve outcomes. Pursuing this idea, we tested the efficacy of a parent-mediated early intervention called Adapted Responsive Teaching (ART) via a randomized controlled trial with 87 one-year-olds identified by community screening with the First Year Inventory as at-risk of later ASD diagnoses. We found minimal evidence for main effects of ART on child outcomes. However, ART group parents showed significantly greater increases in responsiveness to their infants than control group parents. Further, significant indirect (mediation) effects of assignment group on multiple child outcomes through changes in parent responsiveness supported our theory of change. PMID- 28861652 TI - Mental Wellbeing of Family Members of Autistic Adults. AB - Family members are often the primary caregiver for autistic adults and this responsibility may impact on the carer's wellbeing and quality of life. 109 family members of autistic adults completed an online survey assessing their wellbeing relating to their caring role for their autistic relative. Family members who were supporting an autistic relative with co-occurring mental health difficulties and who they reported as unprepared for the future, self-reported higher levels of worry, depression, anxiety and stress, and poorer quality of life. These findings emphasise the importance of support for family members of autistic adults, whether through external services to support their relative or individual mental health support for the carer. PMID- 28861654 TI - Breast Cancer Screening for Patients of Rural Accountable Care Organization Clinics: A Multi-Level Analysis of Barriers and Facilitators. AB - Not all women 50-74 years received biennial mammography and the situation is worse in rural areas. Accountable care organizations (ACO) emphasize coordinated care, use of electronic health system, and preventive quality measures and these practices may improve their patients' breast cancer screening rate. Using medical record data of 8,347 women patients aged 50-74 years from eight rural ACO clinics in Nebraska, this study examined patient-, provider-, and county-level barriers and facilitators for breast cancer screening. A generalized estimating equations model was used to account for the correlation among patients from the same provider and county. The multi-level logistic regression results suggest that uninsured non-Hispanic Black patients were less likely to meet the biennial mammography screening guideline. Patients whose preferred language being English, having a preventive visit in the past 12 months, having one or more chronic conditions were more likely to meet the biennial mammography screening guideline. Patients with a primary care provider (PCP) that was male, without a medical doctor degree were less likely to screen biennially. Patients with a PCP that reviewed performance report quarterly, or manually checked patients' mammography screening status during visits were more likely to screen biennially. Interestingly, patients whose PCP reported being reminded by a care coordination team were less likely to screen biennially. Patients living in counties with more PCPs were also more likely to screen biennially. The study findings suggest that efforts targeting individual and practice-level barriers could be most effective in improving mammography screening for these rural ACO patients. PMID- 28861653 TI - Behavioral Phenotype of ASD Preschoolers with Gastrointestinal Symptoms or Food Selectivity. AB - This study investigated the prevalence and type of gastrointestinal (GI) and food selectivity (FS) symptoms in 163 preschoolers with ASD, and their possible links with core ASD features and emotional/behavioural problems. 40.5% of children with ASD had at least one severe GI symptom or FS. Preschoolers with and without GI symptoms and with and without FS were significantly different on several emotional/behavioural problems and restrictive/repetitive behaviours, whereas they did not differ significantly on performance IQ and autistic severity. The GI plus FS group presented with Sleep Problems, Self-injurious Behaviors and Anxiety Problems. Results indicated the need for early identification of GI disturbances and FS in order to design tailored intervention for these symptoms frequently associated to challenging behaviours in ASD. PMID- 28861655 TI - Inhaled anesthetic agent sedation in the ICU and trace gas concentrations: a review. AB - There is a growing interest in the use of volatile anesthetics for inhalational sedation of adult critically ill patients in the ICU. Its safety and efficacy has been demonstrated in various studies and technical equipment such as the anaesthetic conserving device (AnaConDaTM; Sedana Medical, Uppsala, Sweden) or the MIRUSTM system (Pall Medical, Dreieich, Germany) have significantly simplified the application of volatile anesthetics in the ICU. However, the personnel's exposure to waste anesthetic gas during daily work is possibly disadvantageous, because there is still uncertainty about potential health risks. The fact that average threshold limit concentrations for isoflurane, sevoflurane and desflurane either differ significantly between countries or are not even defined at all, leads to raising concerns among ICU staff. In this review, benefits, risks, and technical aspects of inhalational sedation in the ICU are discussed. Further, the potential health effects of occupational long-term low concentration agent exposure, the staffs' exposure levels in clinical practice, and strategies to minimize the individual gas exposure are reviewed. PMID- 28861656 TI - An opportune and unique research to evaluate the public health impact of electronic cigarettes. AB - In response to the growing public health concern regarding the risks or benefits of electronic cigarettes (e-cig) use relative to smoking, the National Institute on Drug Abuse (NIDA) has recently introduced the first standardized- and well- characterized e-cig device to the research community (see, https://www.drugabuse.gov/funding/supplemental-information-nida-e-cig ). E-cig are promoted as safe alternatives to conventional tobacco cigarettes and/or as aides to smoking cessation. E-cig are highly popular among cigarette smokers who are unable/unwilling to quit but are willing to switch to putatively less-harmful tobacco substitutes. E-cig are also becoming increasingly popular among youth who have never experimented with combustible cigarettes. However, chemical analyses of e-cig juices (both in liquid form and after being heated into vapor) have shown that many carcinogens present in cigarette smoke are also found in a range of e-cig products. To date, the cancer-causing potential of e-cig has not been investigated in e-cig users (i.e., vapers). Use of e-cig without a prior history of smoking is currently a rare phenomenon in adults, but is increasingly common among youth. Consequently, investigating the carcinogenic potential of e-cig in nonsmoking youth provides a unique opportunity to verify the health impact of e cig use, without the confounding effects of cigarette smoking. Within this context, the availability of the NIDA Standard Research e-cig offers a unique research opportunity with tremendous public health implications. Comparing and contrasting the cancer-causing potentials of standard vaping and smoking in youth will help determine the health risks or benefits of e-cig use relative to cigarette smoking. This information will be instrumental in making scientifically based decisions on the development and evaluation of policies and regulations on e-cig manufacture, marketing, and distribution. Ultimately, evidence-based guidelines and legislations on e-cig will help reduce the burden of tobacco related diseases, particularly on minors and vulnerable populations. PMID- 28861658 TI - BMI change and abdominal circumference are risk factors for breast cancer, even in Asian women. AB - PURPOSE: We investigated the association between breast cancer incidence and obesity among Asian women. METHODS: We used data from 30,109 women who had undergone medical check-ups and opportunistic breast cancer screening at least twice at the St. Luke's International Hospital Affiliated Clinic, Center for Preventive Medicine, between April 1, 2005 and March 31, 2014. This study evaluated obesity through body mass index (BMI) at age 18-20 years (BMI18-20y), BMI at research entry (entry BMI), change of BMI from age 18-20 to research entry (DeltaBMI), abdominal circumference at research entry (AC), and HbA1c [N] at research entry (HbA1c). We used a multivariate Cox proportional hazard model to evaluate hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: Of the 30,109 women, 325 were initially diagnosed with breast cancer over 131,657 person-years. Postmenopausal women whose BMI increased >=+5.0 were significantly more likely to develop breast cancer (HR 1.902, 95% CI 1.202-3.009) than were the stable BMI group (DeltaBMI: -2.5 to +2.5). Postmenopausal women with AC >=90 cm were significantly likelier to develop breast cancer than were those with AC <70 cm (HR 2.500, 95% CI 1.091-5.730). Among postmenopausal women whose BMI18-20y was >=20, those with high (>=6.5) HbA1c were more likely to develop breast cancer than those with low (<5.5) HbA1c (HR 3.325, 95% CI 1.307-8.460). CONCLUSIONS: Breast cancer incidence and obesity are positively associated in postmenopausal Asian women. PMID- 28861659 TI - The Influence of Static and Dynamic Intrapersonal Factors on Longitudinal Patterns of Peer Victimization through Mid-adolescence: a Latent Transition Analysis. AB - Using 6 cycles (grade 5 through grade 10) of data obtained from a large prospective sample of Canadian school children (N = 700; 52.6% girls), we replicated previous findings concerning the empirical definition of peer victimization (i.e., being bullied) and examined static and dynamic intrapersonal factors associated with its emergence and experiential continuity through mid adolescence. Latent class analyses consistently revealed a low victimization and an elevated victimization class across time, supporting previous work suggesting peer victimization was defined by degree rather than by type (e.g., physical). Using latent transition analyses (LTA), we found that child sex, parent-perceived pubertal development, and internalizing symptoms influenced the probability of transitioning from the low to the elevated victimization class across time. Higher-order extensions within the LTA modeling framework revealed a lasting effect of grade 5 victimization status on grade 10 victimization status and a large effect of chronic victimization on later parent-reported youth internalizing symptoms (net of prior parent-reported internalizing symptoms) in later adolescence (grade 11). Implications of the current findings for the experience of peer victimization, as well as the application of latent transition analysis as a useful approach for peer victimization research, are discussed. PMID- 28861657 TI - The interplay of psychosis and victimisation across the life course: a prospective study in the general population. AB - PURPOSE: Psychosis has been associated with adult victimisation. However, it remains unclear whether psychosis predicts incident adult victimisation, or whether adult victimisation predicts incident psychosis. Furthermore, a moderating effect of childhood victimisation on the association between psychosis and adult victimisation has not been investigated. METHODS: The longitudinal association between baseline psychotic experiences and six-year incidence of adult victimisation was assessed in a prospective general population cohort of 6646 adults using logistic regression analysis. The association between baseline adult victimisation and six-year incidence of psychotic experiences was examined as well. Furthermore, the moderating effect of childhood victimisation on these bidirectional associations was analysed. RESULTS: Psychotic experiences and childhood victimisation were both associated with an increased risk of incident adult victimisation. However, this was through competing pathways, as suggested by a negative interaction between psychotic experiences and childhood victimisation. Baseline adult victimisation and childhood victimisation both independently increased the risk of incident psychotic experiences, but there was no interaction between adult victimisation and childhood victimisation. CONCLUSIONS: Psychosis and victimisation are interconnected throughout the life course. Childhood victimisation is connected to psychosis through two pathways: one direct and one indirect through adult victimisation. In individuals without childhood victimisation, psychosis and adult victimisation bidirectionally impact on each other. PMID- 28861660 TI - Shape memory activation can affect cell seeding of shape memory polymer scaffolds designed for tissue engineering and regenerative medicine. AB - The ability of a three-dimensional scaffold to support cell seeding prior to implantation is a critical criterion for many scaffold-based tissue engineering and regenerative medicine strategies. Shape memory polymer functionality may present important new opportunities and challenges in cell seeding, but the extent to which shape memory activation can positively or negatively affect cell seeding has yet to be reported. The goal of this study was to determine whether shape memory activation can affect cell seeding. The hypothesis was that shape memory activation of porous scaffolds during cell seeding can affect both the number of cells seeded in a scaffold and the distribution (in terms of average infiltration distance) of cells following seeding. Here, we used a porous shape memory foam scaffold programmed to expand when triggered to study cell number and average cell infiltration distance following shape memory activation. We found that shape memory activation can affect both the number of cells and the average cell infiltration distance. The effect was found to be a function of rate of shape change and scaffold pore interconnectivity. Magnitude of shape change had no effect. Only reductions in cell number and infiltration distance (relative to control and benchmark) were observed. The findings suggest that strategies for tissue engineering and regenerative medicine that involve shape memory activation in the presence of a cell-containing medium in vitro or in vivo should consider how recovery rate and scaffold pore interconnectivity may ultimately impact cell seeding. PMID- 28861661 TI - Brief Report: Social Support, Depression and Suicidal Ideation in Adults with Autism Spectrum Disorder. AB - Adults with autism spectrum disorder (ASD) are at increased risk of suicide compared to the general population. Research has yet to identify the mechanisms underlying this increased risk. This study examined perceived social support as a potential protective factor for depressive symptoms and suicidal ideation in 76 adults with ASD. Twenty-five percent of participants were in the clinical range for depression, and 20% reported recent suicidal ideation. Social support in the form of appraisal and belonging was not associated with depression or ideation; however the perceived availability of tangible (material) support indirectly acted on ideation through depression. The findings suggest that tangible support, but not appraisal or belonging, may act as an indirect protective factor against suicidality in ASD. PMID- 28861663 TI - Environmental risk assessment of cobalt and manganese from industrial sources in an estuarine system. AB - A total of 74 samples of soil, sediment, industrial sludge, and surface water were collected in a Mediterranean estuarine system in order to assess the potential ecological impact of elevated concentrations of Co and Mn associated with a Terephthalic (PTA) and Isophthalic (PIPA) acids production plant. Samples were analyzed for elemental composition (37 elements), pH, redox potential, organic carbon, and CaCO3 content, and a group of 16 selected samples were additionally subjected to a Tessier sequential extraction. Co and Mn soil concentrations were significantly higher inside the industrial facility and around its perimeter than in background samples, and maximum dissolved Co and Mn concentrations were found in a creek near the plant's discharge point, reaching values 17,700 and 156 times higher than their respective background concentrations. The ecological risk was evaluated as a function of Co and Mn fractionation and bioavailability which were controlled by the environmental conditions generated by the advance of seawater into the estuarine system during high tide. Co appeared to precipitate near the river mouth due to the pH increase produced by the influence of seawater intrusion, reaching hazardous concentrations in sediments. In terms of their bioavailability and the corresponding risk assessment code, both Co and Mn present sediment concentrations that result in medium to high ecological risk whereas water concentrations of both elements reach values that more than double their corresponding Secondary Acute Values. PMID- 28861662 TI - Extracellular Expression in Aspergillus niger of an Antibody Fused to Leishmania sp. Antigens. AB - Nucleoside hydrolase and sterol 24-c-methyltransferase, two antigenic proteins of Leishmania sp., were expressed in Aspergillus niger. Genetic transformation of conidia was achieved using underwater shock waves. scFv antibody addressed to DEC205, a receptor of dendritic cells, was fused to two proteins of Leishmania sp. Receptor 205 has a relevant role in the immune system in mammals; it can modulate T cell response to different antigens. Extracellular expression strategy of recombinant antibody was achieved using a fragment of native glucoamylase A (514 aa) as a carrier. Fermentations in shake flasks showed that the recombinant protein (104 kDa) was expressed and secreted only when maltose was used as carbon source; on the contrary, the expression was highly repressed in presence of xylose. Noteworthy, recombinant protein was secreted without glucoamylase-carrier and accumulation at intracellular level was not observed. The results presented here demonstrate the high value of Aspergillus niger as biotechnological platform for recombinant antibodies against Leishmania sp. at low cost. To the best of our knowledge, this is the first report about the recombinant expression of antigenic proteins of Leishmania sp. in filamentous fungi. The protein obtained can be used to explore novel strategies to induce immunity against Leishmania sp. or it can be employed in diagnostic kits to detect this neglected disease. PMID- 28861664 TI - The Associations of Area-Level Violent Crime Rates and Self-Reported Violent Crime Exposure with Adolescent Behavioral Health. AB - The effects of witnessing and experiencing crime have seldom been disaggregated. Little research has assessed the effect of multiple exposures to crime. We assess independent contributions of self-reported crime and area-level crime to adolescent behavioral health outcomes. Cross sectional data on 5519 adolescents from the Comprehensive Community Mental Health Services for Children and their Families Program was linked to FBI crime rate data to assess associations of mutually exclusive categories of self-reported crime exposure and area-level crime rates with mental health and substance abuse. Self-reported crime exposure was significantly associated with poorer behavioral health. Violent victimization had the largest association with all outcomes except internalizing scores. All self-reported crime variables were significantly associated with three of the outcomes. Area-level crime rates were associated with one mental health outcome. Providers should assess direct and indirect crime exposure rather than only focusing on violent victimization. PMID- 28861665 TI - Non-visualized sentinel nodes in breast cancer patients; prevalence, risk factors, and prognosis. AB - BACKGROUND: Evidence and consensus is lacking in international guidelines regarding axillary treatment recommendations for patients in whom a sentinel lymph node (SLN) cannot be visualized (non-vSLN) during the sentinel node procedure. In this study we aimed to determine the prevalence of non-vSLNs in a Dutch population of breast cancer patients and to examine predictors and survival rate for non-vSLN. METHODS: A nationwide, retrospective, population-based study was performed including 116,920 patients with invasive breast cancer who underwent a SLN procedure in the Netherlands between January 2005 and December 2013. RESULTS: Of the 76,472 clinically negative patients who underwent a SLN procedure, 1924 patients (2.5%) had a non-vSLN, of whom 1552 (80.7%) underwent an ALND. Multivariate analysis showed predictive factors for non-vSLN: older age (p < 0.001), diagnosis in the period 2005-2009 (p < 0.001), larger tumor size (p = 0.003), and extensive nodal involvement (p < 0.001). Multivariate survival analysis showed a significantly worse survival (HR 1.18, 95% CI 1.03-1.34, p = 0.015) for non-vSLNs patients. However, in the non-vSLN group, an ALND was not statistically significantly associated with a better survival (HR 0.96, 95% CI 0.53-1.75, p = 0.891). CONCLUSION: Patients with non-vSLNs had less favorable disease characteristics and a worse survival compared to patients with a visualized SLN. Performing an ALND was not associated with a significantly better survival in patients with non-vSLNs. However, further research on the necessity of axillary treatment in this specific patient group is required. PMID- 28861667 TI - Workplace Social System and Sustained Return-to-Work: A Study of Supervisor and Co-worker Supportiveness and Injury Reaction. AB - Objective To examine the impact of the social workplace system on sustained return-to-work (SRTW). Methods A random sample of workers' compensation claimants was recruited to complete a survey following claim acceptance (baseline), and 6 months later (time 2). SRTW, at baseline and time 2, was classified as those reporting being back at work for >28 days. Co-worker and supervisor support were assessed using five and seven items, respectively, and total scores were produced. A list of potential supervisory and co-worker reactions were presented to participants who were asked whether the reaction applied to them; response were coded as positive or non-positive. Demographic and injury characteristics, and work context factors were collected. Baseline and at time 2 multivariable models were conducted to examine the impact of supervisory and coworker support and injury reaction on SRTW. Results 551 (baseline) and 403 (time 2) participants from the overall cohort met study eligibility criteria. At baseline, 59% of all participants indicated SRTW; 70% reported SRTW at time 2. Participants reported moderate support from their supervisor (mean = 8.5 +/- 3.9; median = 8.2; range = 5-15) and co-workers (mean = 10.2 +/- 4.5; median = 10.3; range = 5-25). Over half reported a positive supervisor (59%) or co-worker injury reaction (71%). Multivariable models found that a positive supervisor injury reaction was significantly associated with SRTW at baseline (OR 2.3; 95% CI 1.4-3.9) and time 2 (OR 1.6; 95% CI 1.1-2.3). Conclusions Promoting supervisor positivity towards an injured worker is an important organizational work disability management strategy. PMID- 28861666 TI - Epidemiology of glioma: clinical characteristics, symptoms, and predictors of glioma patients grade I-IV in the the Danish Neuro-Oncology Registry. AB - In this national population-based study of glioma, we present epidemiologic data on incidence, demographics, survival, clinical characteristics and symptoms, and evaluate the association of specific indicators with the grade of glioma. We included 1930 patients registered in the Danish Neuro-Oncology Registry (DNOR) from 2009 to 2014. DNOR is a large-scale national population-based database including all adult glioma patients in Denmark. The age-adjusted annual incidence of histologic verified glioma was 7.3 cases pr. 100,000 person-years. High-grade gliomas were present in 85% and low-grade glioma in 15%. The overall male:female ratio was 3:2 and the mean age at onset was 60 years. Data for WHO grade I, II, III and IV glioma showed several important differences regarding age and sex distribution and symptomatology at presentation. The mean age increased with the grade of glioma and males predominated in all grades. Focal deficits were the most frequent presenting symptom, but among patients with glioma, grade II epileptic seizures were the most frequent symptom. Headache was a rare mono symptomatic onset symptom. At presentation, higher age, focal deficits and cognitive change for <3 months duration, and headache <1 month were significant independent indicators of high-grade gliomas. Younger age and epileptic seizures for more than 3 months were indicative for low-grade gliomas. Survival rates for glioma grade I-IV showed decreasing survival with increasing grade. Glioma grade I-IV showed high diversity regarding several demographic and clinical characteristics emphasizing the importance of individually tailored disease treatments and support. PMID- 28861668 TI - Neuroprotective Activities of Spirulina platensis in the 6-OHDA Model of Parkinson's Disease Are Related to Its Anti-Inflammatory Effects. AB - Spirulina platensis (SPI) is a cyanobacterium, presenting anti-inflammatory and antioxidant actions. Considering the importance of inflammation and oxidative stress in Parkinson's disease (PD), SPI neuroprotective effects were evaluated in a model of PD. Male Wistar rats were divided into: sham-operated (SO), untreated 6-OHDA and 6-OHDA treated with SPI (25 and 50 mg/kg, p.o.). The 6-OHDA was injected into the right striata and SPI treatments started 24 h later for 2 weeks. The SO and untreated 6-OHDA-lesioned groups were administered with distilled water, for the same period. Afterwards, the animals were subjected to the apomorphine-induced rotational test and euthanized for striatal measurements of DA and DOPAC, nitrite and TBARS and immunohistochemistry assays for TH, DAT, iNOS and COX-2. SPI reduced the apomorphine-induced rotational behavior, DA and DOPAC depletions and nitrite and TBARS increases, at its high dose. Furthermore, TH and DAT immunoreactivities in the lesioned striatum of the untreated 6-OHDA lesioned group were attenuated by SPI. Similarly, immunoreactivities for iNOS and COX-2 were also decreased after SPI treatments. In conclusion, we showed that behavioral and neurochemical alterations in hemiparkinsonian rats were partly reversed by SPI, characterizing the neuroprotective potential of Spirulina and stimulating translational studies focusing on its use as an alternative treatment for PD. PMID- 28861669 TI - Reproducibility of the Pleth Variability Index in premature infants. AB - The aim was to assess the reproducibility of the Pleth Variability Index (PVI), developed for non-invasive monitoring of peripheral perfusion, in preterm neonates below 32 weeks of gestational age. Three PVI measurements were consecutively performed in stable, comfortable preterm neonates in the first 48 h of life. On each occasion, pulse oximeter sensors were attached to two different limbs for 5 min. Reproducibility was assessed with the intra-class correlation coefficient (ICC) and Bland-Altman analysis. A total of 25 preterm neonates were included. Inter-limb comparison showed fair to moderate ICC's with 95%-confidence intervals (95%-CI). Left hand-right hand ICC = 0.498, 95%-CI (0.119-0.753); right foot-right hand ICC = 0.314 (-0.088-0.644); right foot-left foot ICC = 0.315 ( 0.089-0.628). Intra-limb comparison showed fair to moderate ICC for right foot right foot ICC = 0.380 (-0.014-0.677); and good ICC for right hand-right hand ICC = 0.646 (0.194-0.852). Bland-Altman plots showed moderate reproducibility of measurements between different limbs and of the same limb in consecutive time periods, with large biases and wide limits of agreement. The findings from this study indicate that PVI measurement is poorly reproducible when measured on different limbs and on the same limb in stable and comfortable preterm neonates. PMID- 28861671 TI - Intensive care medicine in 2050: vasopressors in sepsis. PMID- 28861670 TI - Anthranilic acid, the new player in the ensemble of aromatic residue labeling precursor compounds. AB - The application of metabolic precursors for selective stable isotope labeling of aromatic residues in cell-based protein overexpression has already resulted in numerous NMR probes to study the structural and dynamic characteristics of proteins. With anthranilic acid, we present the structurally simplest precursor for exclusive tryptophan side chain labeling. A synthetic route to 13C, 2H isotopologues allows the installation of isolated 13C-1H spin systems in the indole ring of tryptophan, representing a versatile tool to investigate side chain motion using relaxation-based experiments without the loss of magnetization due to strong 1JCC and weaker 2JCH scalar couplings, as well as dipolar interactions with remote hydrogens. In this article, we want to introduce this novel precursor in the context of hitherto existing techniques of in vivo aromatic residue labeling. PMID- 28861672 TI - Use of Traditional Healing Practices in Two Ontario First Nations. AB - Colonization has negatively impacted Canada's Aboriginal people, with one of the consequences being loss of traditional knowledge, beliefs and practices, including traditional healing practices. In a study of two Ontario First Nations, the objectives of this research were to examine: (1) the extent of use of traditional healing practices, including traditional medicines and healers; (2) factors associated with their use and people's desire to use them; and (3) reasons for not using them among those who want to use them, but currently do not. Registered Band Members and volunteers from two First Nations communities (N = 613) participated in a well-being survey. About 15% of participants used both traditional medicines and healers, 15% used traditional medicines only, 3% used a traditional healer only, and 63% did not use either. Of those who did not use traditional healing practices, 51% reported that they would like to use them. Use was more common among men, older people, and those with more than high school education. Those who used traditional healing practices were found to have a stronger First Nations identity, better self-reported spiritual health, higher scores on historical loss and historical loss symptoms and higher levels of anxiety compared with people who did not use them. Common reasons for not using traditional practices were: not knowing enough about them, not knowing how to access or where to access them. These findings may be useful for promoting the use of traditional healing practices for the purpose of improving the health of First Nations people. PMID- 28861674 TI - [Ocular involvement in rheumatoid arthritis, connective tissue diseases and vasculitis]. AB - There are many interfaces between ophthalmologists and rheumatologists. On the one hand ophthalmologists face the question if an inflammation of the eye is caused by systemic inflammatory rheumatic diseases and on the other hand rheumatologists have to consider that ocular manifestations are relatively common in some inflammatory rheumatic diseases. Furthermore, these ocular manifestations may influence therapeutic decisions of the rheumatologist. This article summarizes which ocular inflammations can be associated with rheumatoid arthritis, connective tissue diseases and vasculitides. The description of acute anterior uveitis in spondyloarthritis and in juvenile idiopathic arthritis is omitted in this article but will be dealt with elsewhere in this issue. PMID- 28861673 TI - SOD1 Mutations Causing Familial Amyotrophic Lateral Sclerosis Induce Toxicity in Astrocytes: Evidence for Bystander Effects in a Continuum of Astrogliosis. AB - Astrocytes contribute to the death of motor neurons via non-cell autonomous mechanisms of injury in amyotrophic lateral sclerosis (ALS). Since mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) underlie the neuropathology of some forms of familial ALS, we explored how expression of mutant SOD1 protein A4V SOD1-EGFP affected the biology of secondary murine astrocytes. A4V SOD1-EGFP expressing astrocytes (72 h after transfection) displayed decreased mitochondrial activity (~45%) and L-glutamate transport (~25%), relative to cells expressing wild-type SOD1-EGFP. A4V SOD1-EGFP altered F-actin and Hoechst staining, indicative of cytoskeletal and nuclear changes, and altered GM130 labelling suggesting fragmentation of Golgi apparatus. SOD1 inclusion formation shifted from discrete to "punctate" over 72 h with A4V SOD1-EGFP more rapidly producing inclusions than G85R SOD1-EGFP, and forming more punctate aggregates. A4V, not wild-type SOD1-EGFP, exerted a substantial, time-dependent effect on GFAP expression, and ~60% of astrocytes became stellate and hypertrophic at 72 h. Spreading toxicity was inferred since at 72 h ~80% of bystander cells exhibited hypertrophy and stellation. This evidence favours mutant SOD1-containing astrocytes releasing destructive species that alter the biology of adjacent astrocytes. This panoply of mutant SOD1-induced destructive events favours recruitment of astrocytes to non-cell autonomous injury in ALS. PMID- 28861675 TI - Kinetics of Radiological Response of Thoracic Invasive Fungal Disease in Chronic Granulomatous Disease. PMID- 28861676 TI - Machete injuries to the upper extremity. AB - PURPOSE: We intend to describe and analyze the spectrum of upper extremity injuries that arises from both accidental and intentional machete injuries with a focus on associated complications and comorbidities. This review is the first from a United States institution, and the only from a designated level 1 trauma center. METHODS: A retrospective review of machete related upper extremity injuries admitted to a level 1 trauma center from 2008 to 2016. The following data was collected on admitted patients: demographics, mechanism of injury, surgical management, and complications. We assessed the data with Pearson Chi square analysis. RESULTS: This cohort consisted of 48 patients (mean = 42 +/- 13 years old); the majority were men (96%) involved in an assault (81%). These patients had a high rate of documented psychiatric history, substance and tobacco abuse, and being underinsured. Patient follow-up was extremely variable: 75% of patients presented for follow-up care (mean = 149 +/- 344 days; range 8-1846 days). 44% had complications (i.e., infection, tendon rupture, nerve palsy). We identified no associations when examining follow-up rates or complication rates regarding patient comorbidities, insurance status, mechanism of injury, or the need for a nerve, artery, or tendon repair. Patients with current tobacco use did have an increased risk for infection. The majority (52%) of injuries occurred on the ulnar side of the forearm and to the non-dominant extremity (66%). Patients assaulted by machetes are significantly more likely to have a history of psychiatric illness, substance abuse, tobacco use, and are more likely to be underinsured compared to those with accidental machete injuries. CONCLUSIONS: While machete injuries may be uncommon in most areas of the United States, physicians should give special attention to the patient comorbidities as many of these patients have complex medical and social issues which could complicate attempts of appropriate treatment. LEVEL OF EVIDENCE: IV; Prognostic Study. PMID- 28861677 TI - Seroepidemiological survey on Leptospira spp. infection in wild and domestic mammals in two distinct areas of the semi-arid region of northeastern Brazil. AB - Leptospirosis is a bacterial zoonotic disease that causes severe reproductive problems in livestock and generates economic losses for farmers. This study aimed to determine the seroprevalence of anti-Leptospira antibodies in small mammals, both wild and domestic, in two distinct areas of the semi-arid region of northeastern Brazil: the National Park of Serra das Confusoes (NPSC), state of Piaui, a preserved area; and rural areas in the municipalities of Petrolina and Lagoa Grande, state of Pernambuco, non-preserved areas. Serum samples were evaluated using the microscopic agglutination test (MAT). Approximately 4% (6/152) of the wild animals were positive, all of them in the non-preserved area. Overall, the seroprevalence rates among goats and sheep were 13.4 (77/576) and 4.6% (24/518), respectively, confirmed in both areas. The seroprevalence rates in dogs and cats were 5.6 (10/180) and 4.7% (2/43) and were determined only in the non-preserved area. The risk factors associated with Leptospira spp. infection were as follows: ages of 1-3 and > 3 years for goats and sheep, region (preserved area) for goats, intensive management system for sheep, and region (non-preserved area) for dogs and wildlife. The present study confirmed the presence of circulation of Leptospira spp. in both of these areas of the Caatinga biome, as well as a variety of serotypes in these areas. PMID- 28861678 TI - Perioperative serum creatinine changes and ureteral injury. AB - PURPOSE: To illustrate a simple method that screens for ureteral injury in the acute postoperative period after urogynecologic surgeries. METHODS: Serum creatinine measurements in the preoperative (baseline) and postoperative periods of urogynecologic surgeries were determined and the correlation of the change to ureteral injury and/or obstruction analyzed. The sample size calculation showed 7 cases and 28 controls were sufficient to detect significant changes in creatinine. Each of the seven cases was matched for age and type of surgery with a control patient in a 1:4 ratio following standard protocol. RESULTS: Chart review of patients (273 cases) undergoing urogynecologic surgeries from October 2009 to June 2014 were undertaken. There were 7 cases of ureteral injury and 28 matching control cases. All cases had intraoperative cystoscopy confirming bilateral ureteral flow. In the ureteral injury group, blockage of ureter was confirmed by CT scan with IV contrast. There was a 59.8% increase in serum creatinine levels postoperative in the ureteral injury group versus a 3.8% decrease in controls. A difference of creatinine levels greater than or equal to 0.3 mg/dL over baseline was evident in ureteral injury cases. CONCLUSION: A small change in serum creatinine level over baseline after urogynecologic surgery alerted the possibility of ureteral injury or obstruction. A simple and inexpensive evaluation of perioperative creatinine levels can promptly diagnose ureteral damage in the acute postoperative period for gynecologic reconstructive surgeries. PMID- 28861679 TI - Acclimation of Swedish and Italian ecotypes of Arabidopsis thaliana to light intensity. AB - This study addressed whether ecotypes of Arabidopsis thaliana from Sweden and Italy exhibited differences in foliar acclimation to high versus low growth light intensity, and compared CO2 uptake under growth conditions with light- and CO2 saturated intrinsic photosynthetic capacity and leaf morphological and vascular features. Differential responses between ecotypes occurred mainly at the scale of leaf architecture, with thicker leaves with higher intrinsic photosynthetic capacities and chlorophyll contents per leaf area, but no difference in photosynthetic capacity on a chlorophyll basis, in high light-grown leaves of the Swedish versus the Italian ecotype. Greater intrinsic photosynthetic capacity per leaf area in the Swedish ecotype was accompanied by a greater capacity of vascular infrastructure for sugar and water transport, but this was not associated with greater CO2 uptake rates under growth conditions. The Swedish ecotype with its thick leaves is thus constructed for high intrinsic photosynthetic and vascular flux capacity even under growth chamber conditions that may not permit full utilization of this potential. Conversely, the Swedish ecotype was less tolerant of low growth light intensity than the Italian ecotype, with smaller rosette areas and lesser aboveground biomass accumulation in low light-grown plants. Foliar vein density and stomatal density were both enhanced by high growth light intensity with no significant difference between ecotypes, and the ratio of water to sugar conduits was also similar between the two ecotypes during light acclimation. These findings add to the understanding of the foliar vasculature's role in plant photosynthetic acclimation and adaptation. PMID- 28861680 TI - Image Retrieval Based on Local Mesh Vector Co-occurrence Pattern for Medical Diagnosis from MRI Brain Images. AB - In modern health-care, for evidence-based diagnosis, there is a requirement for an efficient image retrieval approach to retrieve the cases of interest that have similar characteristics from the large image databases. This paper presents a feature extraction approach that aims at extracting texture features present in the medical images using Local Pattern Descriptor (LPD) and Gray-level Co occurrence Matrix (GLCM). As a main contribution, a novel local pattern named Local Mesh Vector Co-occurrence Pattern (LMVCoP) has been proposed by concatenating the Local Mesh Co-occurrence Pattern (LMCoP) and the Local Vector Co-occurrence Pattern (LVCoP). The fusion of GLCM with the Local Mesh Pattern (LMeP) and the Local Vector Pattern (LVP) produces LMCoP and LVCoP respectively. The LMVCoP method has been investigated on the Open Access Series of Imaging Studies (OASIS): a Magnetic Resonance Imaging (MRI) brain image database. LMVCoP descriptor achieves 87.57% of ARP and 53.21% of ARR which are higher than the existing methods of LTCoP, PVEP, LBDP, LMeP and LVP. The LMVCoP method enhances the retrieval results of LMeP/LVP from 81.36%/83.52% to 87.57% in terms of ARP on OASIS MRI brain database. PMID- 28861682 TI - Chemotherapeutic dosing implicated by pharmacodynamic modeling of in vitro cytotoxic data: a case study of paclitaxel. AB - Conventional maximum tolerated doses (MTD) in chemotherapy are recently challenged by an alternative dosing method with low doses and high dosing frequency (LDHF). Still, it remains unclear which chemotherapies would potentially benefit from LDHF. The pharmacokinetic (PK) differences between MTD and LDHF are drug exposure magnitude (concentration) and exposure duration (time), two fundamental PK elements that are associated with the pharmacodynamics (PD) of chemotherapies. Here we hypothesized that quantitatively analyzing the contribution of each PK element to the overall cytotoxic effects would provide insights to the selection of the preferred chemotherapeutic dosing. Based on in vitro cytotoxic data, we developed a cellular PD model, which assumed that tumor cells were generally comprised of two subpopulations that were susceptible to either concentration- or time-dependent cytotoxicity. The developed PD model exhibited high flexibility to describe diverse patterns of cell survival curves. Integrated with a PK model, the cellular PD model was further extended to predict and compare the anti-tumor effect of paclitaxel in two dosing regimens: multiple MTD bolus and continuous constant infusion (an extreme LDHF). Our simulations of paclitaxel in treatment of three types of cancers were consistent with clinical observations that LDHF yielded higher patient efficacy than MTD. Our further analysis suggested that the ratio between drug steady-state concentrations and its cytotoxic sensitivity (C ss /KC 50 ) was a critical factor that largely determines favored dosing regimen. LDHF would produce higher efficacy when the ratio C ss /KC 50 is greater than 1. Otherwise MTD was favored. The developed PD model presented an approach simply based on in vitro cytotoxic data to predict the potentially favored chemotherapeutic dosing between MTD and LDHF. PMID- 28861681 TI - In vivo estimation of normal amygdala volume from structural MRI scans with anatomical-based segmentation. AB - PURPOSE: Literature includes a number of studies using structural MRI (sMRI) to determine the volume of the amygdala, which is modified in various pathologic conditions. The reported values vary widely mainly because of different anatomical approaches to the complex. This study aims at estimating of the normal amygdala volume from sMRI scans using a recent anatomical definition described in a study based on post-mortem material. METHODS: The amygdala volume has been calculated in 106 healthy subjects, using sMRI and anatomical-based segmentation. The resulting volumes have been analyzed for differences related to hemisphere, sex, and age. RESULTS: The mean amygdalar volume was estimated at 1.42 cm3. The mean right amygdala volume has been found larger than the left, but the difference for the raw values was within the limits of the method error. No intersexual differences or age-related alterations have been observed. CONCLUSION: The study provides a method for determining the boundaries of the amygdala in sMRI scans based on recent anatomical considerations and an estimation of the mean normal amygdala volume from a quite large number of scans for future use in comparative studies. PMID- 28861683 TI - Neuroendocrine Response to School Load in Prepubertal Children: Focus on Trait Anxiety. AB - At the time of school-age, the most frequent stress stimuli are related to school environment and educational process. Anxiety may play a big role in coping with stressful situations associated with school load. To approach this issue, we performed a real-life study at school during the classwork. The sample consisted of 36 healthy children aged 10 years, which were divided to low and high trait anxiety group based on the median value of the anxiety score. The investigations were carried out in the classroom during a stress condition (final exams) and non stress condition (without any exam). In the whole sample, the condition with exam was associated with higher cortisol and lower testosterone concentrations in saliva compared to the condition without exam. The activity of salivary alpha amylase increased at the end of the exam. Anxious children showed higher concentrations of aldosterone and lower activity of alpha-amylase compared to children with low trait anxiety. Cortisol levels were higher in anxious children in the first morning samples before starting the lessons. Children with high and low trait anxiety did not differ in extraversion, neuroticism, as well as non verbal intelligence and school success. Thus, the anxious children at school showed a more rapid decrease of anticipatory stress-induced cortisol concentrations, higher aldosterone levels, and lower alpha-amylase activities compared to non-anxious children. These changes, particularly high concentrations of aldosterone in children with high trait anxiety, may have an impact on their psychophysiological development. PMID- 28861685 TI - Bayesian Estimation of the DINA Q matrix. AB - Cognitive diagnosis models are partially ordered latent class models and are used to classify students into skill mastery profiles. The deterministic inputs, noisy "and" gate model (DINA) is a popular psychometric model for cognitive diagnosis. Application of the DINA model requires content expert knowledge of a Q matrix, which maps the attributes or skills needed to master a collection of items. Misspecification of Q has been shown to yield biased diagnostic classifications. We propose a Bayesian framework for estimating the DINA Q matrix. The developed algorithm builds upon prior research (Chen, Liu, Xu, & Ying, in J Am Stat Assoc 110(510):850-866, 2015) and ensures the estimated Q matrix is identified. Monte Carlo evidence is presented to support the accuracy of parameter recovery. The developed methodology is applied to Tatsuoka's fraction-subtraction dataset. PMID- 28861686 TI - Bell's phenomenon in thyroid-associated inferior rectus myopathy. AB - PURPOSE: To examine Bell's phenomenon in patients with unilateral thyroid associated inferior rectus myopathy and changes in this phenomenon after inferior rectus muscle recession. METHODS: This prospective interventional study included 12 patients who underwent inferior rectus muscle recession with or without nasal transposition. Bell's phenomenon was examined before and 3 months after surgery. The upper eyelid was held open by a finger to prevent complete eyelid closure. Then, the distance of upward excursion of the inferior corneal limbus or the corneal light reflex was measured during voluntary maximum forced eyelid closure. The pre- and postoperative distances of upward excursion on the affected side were statistically compared with the preoperative distance on the unaffected side using the Mann-Whitney U test, and the pre- and postoperative distances on the affected side were statistically compared using paired t-test. The relationships among postoperative changes of Bell's phenomenon, patient age, the amount of recession and nasal transposition of the inferior rectus muscle, postoperative angle of ocular deviation, and reduction in the angle after surgery were analyzed using stepwise multiple regression analyses. RESULTS: The preoperative measurement of Bell's phenomenon was significantly shorter on the affected side (1.6 +/- 1.6 mm) than the unaffected side (4.3 +/- 1.6 mm; P = 0.001). However, the distance on the affected side significantly increased after surgery (4.1 +/- 1.9 mm; P < 0.001), compared to the preoperative distance on the unaffected side (P = 0.843). Using a stepwise method, all variables were deleted from the regression equation. CONCLUSIONS: Bell's phenomenon decreased on the affected side, which improved after inferior rectus muscle recession. PMID- 28861684 TI - Curcumin revitalizes Amyloid beta (25-35)-induced and organophosphate pesticides pestered neurotoxicity in SH-SY5Y and IMR-32 cells via activation of APE1 and Nrf2. AB - Amyloid beta (Abeta) peptide deposition is the primary cause of neurodegeneration in Alzheimer's disease (AD) pathogenesis. Several reports point towards the role of pesticides in the AD pathogenesis, especially organophosphate pesticides (OPPs). Monocrotophos (MCP) and Chlorpyrifos (CP) are the most widely used OPPs. In this study, the role of MCP and CP in augmenting the Abeta-induced oxidative stress associated with the neurodegeneration in AD has been assessed in human neuroblastoma IMR-32 and SH-SY5Y cell lines. From the cell survival assay, it was observed that MCP and CP reduced cell survival both dose- and time-dependently. Nitro blue tetrazolium (NBT) based assay for determination of intracellular reactive oxygen species (ROS) demonstrated that Abeta(25-35), MCP or CP produce significant oxidative stress alone or synergistically in IMR-32 and SH-SY5Y cells, while pretreatment of curcumin reduced ROS levels significantly in all treatment combinations. In this study, we also demonstrate that treatment of Abeta(25-35) and MCP upregulated inducible nitric oxide synthase (iNOS/NOS2) whereas, no change was observed in neuronal nitric oxide synthase (nNOS/NOS1), but down-regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) level was observed. While curcumin pretreatment resulted in upregulation of iNOS and Nrf2 proteins. Also, the expression of key DNA repair enzymes APE1, DNA polymerase beta (Pol beta), and PARP1 were found to be downregulated upon treatment with MCP, Abeta(25-35) and their combinations at 24 h and 48 h time points. In this study, pretreatment of curcumin to the SH-SY5Y cells enhanced the expression of DNA repair enzymes APE1, pol beta, and PARP1 enzymes to counter the oxidative DNA base damage via base excision repair (BER) pathway, and also activated the antioxidant element (ARE) via Nrf2 upregulation. Furthermore, the immunofluorescent confocal imaging studies in SH-SY5Y and IMR-32 cells treated with Abeta(25-35) and MCP-mediated oxidative stress and their combinations at different time periods suggesting for cross-talk between the two proteins APE1 and Nrf2. The APE1's association with Nrf2 might be associated with the redox function of APE1 that might be directly regulating the ARE-mediated neuronal survival mechanisms. PMID- 28861687 TI - Conservation of the Notch antagonist Hairless in arthropods: functional analysis of the crustacean Daphnia pulex Hairless gene. AB - The Notch signaling pathway is highly conserved in all animal metazoa: upon Notch receptor activation, transcription of Notch target genes is turned on by an activator complex that centers on the transcription factor CSL. In the absence of signal, CSL assembles transcriptional repression complexes that display remarkable evolutionary diversity. The major antagonist of Notch signaling in insects named Hairless was originally identified in Drosophila melanogaster. It binds to the Drosophila CSL homologue Suppressor of Hairless [Su(H)] and recruits the two general co-repressors, Groucho and C-terminal binding protein. Whereas the majority of Notch signaling components is conserved between insects and vertebrates, Hairless is found only in insects. Here, we present the analysis of the Hairless gene from Daphnia pulex and, hence, for the first time from a crustacean. Daphnia and Drosophila Hairless protein sequences are highly diverged. Known functional domains, however, the Su(H), Groucho and the C terminal binding protein interactions domains, are well conserved. Moreover, direct binding of the Daphnia Hairless protein and the respective Drosophila interaction partners was detected, demonstrating the conservation at the molecular level. In addition, interaction between Daphnia Hairless and Drosophila Su(H) was demonstrated in vivo, as co-overexpression of the respective genes during Drosophila development resulted in the expected downregulation of Notch activity in the fly. Structural models show that the Hairless-Su(H) repressor complexes from Daphnia and Drosophila are almost indistinguishable from one another. Amino acid residues in direct contact within the Hairless-Su(H) complex are at absolutely identical positions in the two homologues. PMID- 28861688 TI - Predicting Major Adverse Kidney Events among Critically Ill Adults Using the Electronic Health Record. AB - Prediction of major adverse kidney events in critically ill patients may help target therapy, allow risk adjustment, and facilitate the conduct of clinical trials. In a cohort comprised of all critically ill adults admitted to five intensive care units at a single tertiary care center over one year, we developed a logistic regression model for the outcome of Major Adverse Kidney Events within 30 days (MAKE30), the composite of persistent renal dysfunction, new renal replacement therapy (RRT), and in-hospital mortality. Proposed risk factors for the MAKE30 outcome were selected a priori and included age, race, gender, University Health System Consortium (UHC) expected mortality, baseline creatinine, volume of isotonic crystalloid fluid received in the prior 24 h, admission service, intensive care unit (ICU), source of admission, mechanical ventilation or receipt of vasopressors within 24 h of ICU admission, renal replacement therapy prior to ICU admission, acute kidney injury, chronic kidney disease as defined by baseline creatinine value, and renal failure as defined by the Elixhauser index. Among 10,983 patients in the study population, 1489 patients (13.6%) met the MAKE30 endpoint. The strongest independent predictors of MAKE30 were UHC expected mortality (OR 2.32 [95%CI 2.06-2.61]) and presence of acute kidney injury at ICU admission (OR 4.98 [95%CI 4.12-6.03]). The model had strong predictive properties including excellent discrimination with a bootstrap corrected area-under-the-curve (AUC) of 0.903, and high precision of calibration with a mean absolute error prediction of 1.7%. The MAKE30 composite outcome can be reliably predicted from factors present within 24 h of ICU admission using data derived from the electronic health record. PMID- 28861689 TI - Superactive human leptin antagonist (SHLA), triple Lan1 and quadruple Lan2 leptin mutein as a promising treatment for human folliculoma. AB - PURPOSE: There are no data showing a direct correlation between obesity and increased blood leptin levels with folliculoma. Moreover, folliculoma is not the best studied among other ovarian cancer types. We investigated whether oestradiol can modulate ObR expression in some oestrogen-responsive tissues and that leptin exerts its activity not only via the leptin receptor but also through cross talk with other signalling systems. We hypothesise that blocking ObR expression could be a novel treatment for gonadal ovarian cancer. METHODS: We evaluated the effect of SHLA, Lan1 and Lan2 blockers on cell proliferation (BrdU incorporation assay), ObR and ERalpha/beta gene expression (qPCR), oestradiol secretion (ELISA) and cell cycle protein expression (Western blot) in the non-cancerous cell line HGrC1 and two granulosa cancer cell lines: the juvenile form (COV434) and the adult form (KGN). RESULTS: ObR gene expression in cancer cell lines was 50% higher than in the non-cancer cells. Lan-1 and Lan-2 decreased ObR expression in COV434, while it had no effect in KGN cells. Higher ERbeta expression in non-cancer and higher ERalpha expression in both cancer cell lines was noted. SHLA and Lan-1 changed the ratio towards greater expression of ERbeta, characteristic of non cancer granulosa cells. All ObR antagonists in HCrC1 and KGN but only Lan-2 in COV434 reversed leptin-stimulated proliferation. In both non-cancer and cancer granulosa cells, leptin acts as a cyclinD/cdk4, cyclin A/cdk2 and E2F inhibitor. CONCLUSION: These results indicate that SHLA and Lan2 are promising leptin receptor inhibitors that can eliminate the negative effects of leptin. These compounds should be considered in further ex vivo studies on the cancer microenvironment. PMID- 28861690 TI - Sexual Minority Stress, Coping, and Physical Health Indicators. AB - Sexual minorities experience higher rates of several physical health problems compared to their heterosexual counterparts. The present study uses Meyer's Minority Stress Model (Psychological Bulletin, 129(5): 674-697, 2003) to examine physical health indicators among 250 adults who identified as sexual minorities. Study hypotheses include that sexual minority stress is predictive of two physical health indicators (i.e., engagement in a health-promoting lifestyle and number of physical health problems) and that planning (i.e., problem-focused) and social support coping will partially mediate the relationship between sexual minority stress and each physical health indicator. Results showed that as level of sexual minority stress increased, engagement in a health-promoting lifestyle decreased and the number of physical health problems increased. Planning and social support coping did not mediate these relationships; however, as levels of coping increased, engagement in a health-promoting lifestyle increased. These findings have implications for researchers and healthcare professionals in their efforts to promote the physical health of sexual minorities. PMID- 28861692 TI - Highly selective capture of phosphate ions from water by a water stable metal organic framework modified with polyethyleneimine. AB - In this work, a series of polyethyleneimine (PEI) impregnated metal-organic framework (UiO-66) with varying PEI loadings were prepared and applied as sorbents to capture phosphate ions from water. As indicated by SEM and XRD analysis, PEI was dispersed on the outer surface and the inner pores of UiO-66. At 9.45% PEI loadings (UiO-66-3), the saturated adsorption capacity of phosphate reached 73.15 mg P/g at 298 K, which is superior to most sorbents ever reported. UiO-66-3 could sequestrate phosphate over a wide pH range from 2.0 to 7.0 with high efficiency. The sorption toward phosphate reached equilibrium in 50 min. Unlike commercial anion exchanger IRA-900, UiO-66-3 still exhibited high removal toward phosphate even large amount of coexisted anions were present. Successive sorption assay demonstrated that the removal efficiency of UiO-66-3 toward phosphate remained constant after six cyclic runs. All the above results indicated the great potential of UiO-66-3 as a promising sorbent for the decontamination of water from phosphate. PMID- 28861691 TI - Post-prostatectomy radiotherapy adversely affects urinary continence irrespective of radiotherapy regime. AB - PURPOSE: To investigate the influence of different postoperative radiotherapy (RT) regimes on post-prostatectomy continence and QoL. METHODS: Men after prostatectomy (RP) and RT were assigned in adjuvant (ART), early salvage (ESRT) and salvage radiotherapy (SRT) groups depending on time of initiation, indication and pre-RT-PSA (<=/>0.5 ng/ml). Continence and QoL outcomes were evaluated by validated questionnaire. Statistical analysis included students t test, Chi square, Fisher's test, ROC- and McNemar-Bowker-Analyses. RESULTS: The mean follow up was 5.1 years. 33.5, 38.2 and 28.3% received ART, ESRT and SRT, respectively. Mean time to RT was 0.3 (+/-0.4), 1.8 (+/-2.5) and 3.3 (+/-3.6) years respectively. Differences in age at RP (p = 0.54) and RT (p = 0.47) between groups were not significant. Mean-RT-dose was similar (p = 0.70). Differences in continence distribution between groups before (p = 0.56) and after RT (p = 0.38) were not significant. No significant differences were observed for frequency (p = 0.58) or amount (p = 0.88) of urine loss, impact on QoL (p = 0.13) and ICIQ-SF scores (p = 0.69) between groups. Even though no significant difference in post RT-continence (p = 0.89) was observed in the direct comparison between groups, a significant worsening of long-term continence was observed in all groups (p < 0.001). We found no cutoff and no time-point after RP at which this negative effect of RT on continence became insignificant (AUC = 0.474). A subgroup with apparent local recurrence showed no differences for ICIQ-SF-score (p = 0.155), QoL (0.077), incontinence grade (p = 0.387), frequency (p = 0.182) and amount (p = 0.415) of urine loss. Proportionally more men in this subgroup remembered deterioration of continence after RT (p = 0.029). CONCLUSION: Postoperative RT adversely affects long-term continence; this negative effect is irrespective of time of initiation or indication for RT. These results suggest a need for innovative strategies of prostate cancer therapy with lasting oncological, functional and QoL outcomes. PMID- 28861693 TI - Mixed reality ultrasound guidance system: a case study in system development and a cautionary tale. AB - PURPOSE: Real-time ultrasound has become a crucial aspect of several image-guided interventions. One of the main constraints of such an approach is the difficulty in interpretability of the limited field of view of the image, a problem that has recently been addressed using mixed reality, such as augmented reality and augmented virtuality. The growing popularity and maturity of mixed reality has led to a series of informal guidelines to direct development of new systems and to facilitate regulatory approval. However, the goals of mixed reality image guidance systems and the guidelines for their development have not been thoroughly discussed. The purpose of this paper is to identify and critically examine development guidelines in the context of a mixed reality ultrasound guidance system through a case study. METHODS: A mixed reality ultrasound guidance system tailored to central line insertions was developed in close collaboration with an expert user. This system outperformed ultrasound-only guidance in a novice user study and has obtained clearance for clinical use in humans. A phantom study with 25 experienced physicians was carried out to compare the performance of the mixed reality ultrasound system against conventional ultrasound-only guidance. Despite the previous promising results, there was no statistically significant difference between the two systems. RESULTS: Guidelines for developing mixed reality image guidance systems cannot be applied indiscriminately. Each design decision, no matter how well justified, should be the subject of scientific and technical investigation. Iterative and small-scale evaluation can readily unearth issues and previously unknown or implicit system requirements. CONCLUSIONS: We recommend a wary eye in development of mixed reality ultrasound image guidance systems emphasizing small-scale iterative evaluation alongside system development. Ultimately, we recommend that the image guided intervention community furthers and deepens this discussion into best practices in developing image-guided interventions. PMID- 28861695 TI - Pharmacometrics models with hidden Markovian dynamics. AB - The aim of this paper is to provide an overview of pharmacometric models that involve some latent process with Markovian dynamics. Such models include hidden Markov models which may be useful for describing the dynamics of a disease state that jumps from one state to another at discrete times. On the contrary, diffusion models are continuous-time and continuous-state Markov models that are relevant for modelling non observed phenomena that fluctuate continuously and randomly over time. We show that an extension of these models to mixed effects models is straightforward in a population context. We then show how the forward backward algorithm used for inference in hidden Markov models and the extended Kalman filter used for inference in diffusion models can be combined with standard inference algorithms in mixed effects models for estimating the parameters of the model. The use of these models is illustrated with two applications: a hidden Markov model for describing the epileptic activity of a large number of patients and a stochastic differential equation based model for describing the pharmacokinetics of theophyllin. PMID- 28861694 TI - Effects of sex on the levels of metals and metalloids in the hair of a group of healthy Spanish adolescents (13 to 16 years old). AB - Human biomonitoring can be a reliable tool to protect the health of the citizens of major urban environments. Human hair may be an invaluable specimen to determine chronic exposure to any environmental contaminant in an individual, especially in the young population. However, different factors including a lack of studies that have established reference values for metals and metalloids (trace elements) in human scalp hair make the use of this matrix controversial. A monitoring study was performed to establish possible normal or tentative reference values of Al, As, Be, Cd, Cr, Cu, Hg, Mn, Pb, Sn, Ti, Tl and Zn in adolescents' (aged 13-16) hair who have lived since birth in Alcala de Henares, Madrid region (Spain). Strict inclusion criteria were followed to study the effect of sex on the hair metal content, and the levels of the above contaminants were also studied in park topsoils from Alcala de Henares. Scalp hair samples were collected from 96 healthy adolescents (28 boys and 68 girls), and reference values were calculated following the recommendations of the International Union of Pure and Applied Chemistry. The levels of Cd, Cu, Pb, Sn and Zn in hair of adolescents from Alcala de Henares show a sex dependency, being significantly higher in female participants. Sex should be a factor taken into account when developing future reference values and hair metal content. Soil metal contamination was not correlated with the levels found in hair. To conclude, the values of metals and metalloids here analysed and discussed could be considered as tentative reference values for Spanish adolescents aged 13-16 years living in the Madrid region, and may be used to identify the level of exposure of adolescents in this Spanish region to the various metals and metalloids. PMID- 28861696 TI - Treatment of Vitamin and Mineral Deficiencies After Biliopancreatic Diversion With or Without Duodenal Switch: a Major Challenge. AB - BACKGROUND: Vitamin and mineral deficiencies are a major concern after biliopancreatic diversion (BPD) and BPD with duodenal switch (BPD/DS). Evidence based guidelines how to prevent or how to treat deficiencies in these patients are currently lacking. The aim of the current study is to give an overview of postsurgical deficiencies and how to prevent and treat these deficiencies. METHODS: Retrospective evaluation of a 1-year structured monitoring and treatment schedule for various deficiencies in 34 patients after BPD or BPD/DS. RESULTS: Patients were introduced into the program 12-90 months after surgery. Vitamin B1, B6, B9, and B12 deficiencies could be prevented by mean daily doses of 2.75 mg, 980 MUg, 600 MUg, and 350 MUg, respectively. However, many patients continued to develop deficiencies of vitamin A, D, iron, calcium, and zinc despite major dose adjustments. Current observations suggest that at least total daily doses of 200 mg Fe in premenopausal women and 100 mg in men, 100 mg of Zinc, 3000 mg of calcium, and weekly doses of at least 50,000 IU solubilized vitamin A and vitamin D are needed to prevent the occurrence of major deficiencies. CONCLUSION: Exceptionally high supplementation doses are needed to prevent and treat vitamin and mineral deficiencies in patients after BPD or BPD/DS. Further refinement and simplification of treatment schedules is needed. Focus on improvement of compliance to treatment is recommended. PMID- 28861697 TI - Optical coherence tomography angiography in acute arteritic and non-arteritic anterior ischemic optic neuropathy. AB - PURPOSE: The purpose of our study was to describe the feature of acute non arteritic or arteritic anterior ischemic optic neuropathy (NA-AION and A-AION) using optical coherence tomography angiography (OCT-A) and to compare it with fluorescein angiography (FA) and indocyanine green angiography (ICGA). METHODS: In this retrospective, observational case-control study four NA-AION patients and one A-AION patient were examined by FA, ICGA and OCT-A within 2 weeks from disease presentation. The characteristics of the images were analyzed. Optic nerve head (ONH) and radial peripapillary capillaries (RPC) vessel densities (VDs) were compared between NA-AION and controls. RESULTS: In two of four NA-AION cases and in the A-AION patient, OCT-A clearly identified the boundary of the ischemic area at the level of the optic nerve head, which was comparable to optic disc filling defects detected by FA. In the other two NA-AION cases, a generalized leakage from the disc was visible with FA, yet OCT-A still demonstrated sectorial peripapillary capillary network reduction. Both ONH and RPC VDs were reduced in NA-AION patients, when compared to controls. CONCLUSIONS: OCT-A was able to identify microvascular defects and VD reduction in cases of acute optic disc edema due to NA-AION and A-AION. OCT-A provides additional information in ischemic conditions of the optic nerve head. PMID- 28861698 TI - Polyester Preserves the Highest Breaking Point After Prolonged Incubation in Pancreatic Juice. AB - BACKGROUND: The impact of suture materials on the development of pancreatic fistula after pancreaticoduodenectomy remains unclear. Thus, their choice among pancreatic surgeons is still mostly experience-based. Aim of the present study is to assess what is the best suture material to be used for pancreaticojejunostomy. MATERIALS AND METHODS: The force needed to reach the breaking point of five widely used suture materials (polypropylene, polyester, polydioxanone, silk, and polyglactin 910) has been determined through a digital precision dynamometer at baseline and after 5 and 20 days of incubation in pancreatic juice, bile, or a mixture of both. RESULTS: Regardless of the condition, polyglactin 910 has retained only 10% of its baseline force. Silk has maintained almost 90% of its initial force showing a very low baseline value of force. In pancreatic juice, polypropylene has lost less force compared to polyester (0.25 vs. 0.93 N; p = 0.03) and polydioxanone (0.25 vs. 3.67 N; p = 0.04). Polyester and polydioxanone have showed similar values of force. However, polydioxanone has lost a significant amount of force in pancreatic juice when compared to polyester (0.93 vs. 3.67 N; p = 0.03). Polyester has showed the highest value of force needed to reach the breaking point after 20 days of incubation in pancreatic juice. CONCLUSIONS: After incubation in pancreaticobiliary secretions, polyglactin 910 loses almost all its force. Polypropylene preserves its characteristic, but polydioxanone and polyester show absolute higher breaking points, with polyester retaining the highest value of force needed to reach its breaking point after incubation in pancreatic juice. PMID- 28861699 TI - Effects of solar photovoltaic technology on the environment in China. AB - Among the various types of renewable energy, solar photovoltaic has elicited the most attention because of its low pollution, abundant reserve, and endless supply. Solar photovoltaic technology generates both positive and negative effects on the environment. The environmental loss of 0.00666 yuan/kWh from solar photovoltaic technology is lower than that from coal-fired power generation (0.05216 yuan/kWh). The negative effects of solar photovoltaic system production include wastewater and waste gas pollutions, the representatives of which contain fluorine, chromium with wastewater and hydrogen fluoride, and silicon tetrachloride gas. Solar panels are also a source of light pollution. Improper disposal of solar cells that have reached the end of their service life harms the environment through the stench they produce and the damage they cause to the soil. So, the positive and negative effects of green energy photovoltaic power generation technology on the environment should be considered. PMID- 28861700 TI - A method for going from 2D laparoscope to 3D acquisition of surface landmarks by a novel computer vision approach. AB - PURPOSE: This paper presents a method to use the Smart Trocars-our new surgical instrument recognition system-or any accurate localization system of surgical instrument for acquiring intraoperative surface data. Complex laparoscopic surgeries need a proper guidance system which requires registering the preoperative data from a CT or MRI scan to the intraoperative patient state. The Smart Trocar can be used to localize the instruments when it comes to contact with the soft tissue surface. METHOD: Two successive views through the laparoscope at different angles with the 3D localization of a fixed tool at one single location using the Smart Trocars can point out visible features during the surgery and acquire their location in 3D to provide a depth map in the region of interest. In other words, our method transforms a standard laparoscope system into a system with three-dimensional registration capability. RESULT: This method was initially tested on a simulation for uncertainty assessment and then on a rigid model for verification with an accuracy within 2 mm distance. In addition, an in vivo experiment on pig model was also conducted to investigate how the method might be used during a physiologic respiratory cycle. CONCLUSION: This method can be applied in a large number of surgical applications as a guidance system on its own or in conjunction with other navigation techniques. Our work encourages further testing with realistic surgical applications in the near future. PMID- 28861701 TI - Heat stress differentially modifies ethylene biosynthesis and signaling in pea floral and fruit tissues. AB - KEY MESSAGE: Ethylene biosynthesis is regulated in reproductive tissues in response to heat stress in a manner to optimize resource allocation to pollinated fruits with developing seeds. High temperatures during reproductive development are particularly detrimental to crop fruit/seed production. Ethylene plays vital roles in plant development and abiotic stress responses; however, little is known about ethylene's role in reproductive tissues during development under heat stress. We assessed ethylene biosynthesis and signaling regulation within the reproductive and associated tissues of pea during the developmental phase that sets the stage for fruit-set and seed development under normal and heat-stress conditions. The transcript abundance profiles of PsACS [encode enzymes that convert S-adenosyl-L-methionine to 1-aminocyclopropane-1-carboxylic acid (ACC)] and PsACO (encode enzymes that convert ACC to ethylene), and ethylene evolution were developmentally, environmentally, and tissue-specifically regulated in the floral/fruit/pedicel tissues of pea. Higher transcript abundance of PsACS and PsACO in the ovaries, and PsACO in the pedicels was correlated with higher ethylene evolution and ovary senescence and pedicel abscission in fruits that were not pollinated under control temperature conditions. Under heat-stress conditions, up-regulation of ethylene biosynthesis gene expression in pre pollinated ovaries was also associated with higher ethylene evolution and lower retention of these fruits. Following successful pollination and ovule fertilization, heat-stress modified PsACS and PsACO transcript profiles in a manner that suppressed ovary ethylene evolution. The normal ethylene burst in the stigma/style and petals following pollination was also suppressed by heat-stress. Transcript abundance profiles of ethylene receptor and signaling-related genes acted as qualitative markers of tissue ethylene signaling events. These data support the hypothesis that ethylene biosynthesis is regulated in reproductive tissues in response to heat stress to modulate resource allocation dynamics. PMID- 28861702 TI - Simulation of facial expressions using person-specific sEMG signals controlling a biomechanical face model. AB - PURPOSE: Functional inoperability in advanced oral cancer is difficult to assess preoperatively. To assess functions of lips and tongue, biomechanical models are required. Apart from adjusting generic models to individual anatomy, muscle activation patterns (MAPs) driving patient-specific functional movements are necessary to predict remaining functional outcome. We aim to evaluate how volunteer-specific MAPs derived from surface electromyographic (sEMG) signals control a biomechanical face model. METHODS: Muscle activity of seven facial muscles in six volunteers was measured bilaterally with sEMG. A triple camera set up recorded 3D lip movement. The generic face model in ArtiSynth was adapted to our needs. We controlled the model using the volunteer-specific MAPs. Three activation strategies were tested: activating all muscles [Formula: see text], selecting the three muscles showing highest muscle activity bilaterally [Formula: see text]-this was calculated by taking the mean of left and right muscles and then selecting the three with highest variance-and activating the muscles considered most relevant per instruction [Formula: see text], bilaterally. The model's lip movement was compared to the actual lip movement performed by the volunteers, using 3D correlation coefficients [Formula: see text]. RESULTS: The correlation coefficient between simulations and measurements with [Formula: see text] resulted in a median [Formula: see text] of 0.77. [Formula: see text] had a median [Formula: see text] of 0.78, whereas with [Formula: see text] the median [Formula: see text] decreased to 0.45. CONCLUSION: We demonstrated that MAPs derived from noninvasive sEMG measurements can control movement of the lips in a generic finite element face model with a median [Formula: see text] of 0.78. Ultimately, this is important to show the patient-specific residual movement using the patient's own MAPs. When the required treatment tools and personalisation techniques for geometry and anatomy become available, this may enable surgeons to test the functional results of wedge excisions for lip cancer in a virtual environment and to weigh surgery versus organ-sparing radiotherapy or photodynamic therapy. PMID- 28861703 TI - Robotic-assisted vs. laparoscopic donor nephrectomy: a retrospective comparison of perioperative course and postoperative outcome after 1 year. AB - Safety is of utmost importance in live donor nephrectomies. In this study, we describe our initial experience with robot-assisted laparoscopic donor nephrectomy (RDN) in comparison with the standard laparoscopic donor nephrectomy (LDN). We retrospectively reviewed 95 patients who either underwent RDN or LDN performed by a single surgeon from 2011 to 2016 at a tertiary institution. Donor perioperative course and postoperative outcome along with recipient outcomes were compared. Of the 95 cases, 73 were classified as LDN and 22 were classified as RDN. There were no significant differences between the two groups in age, sex, BMI, race, and ASA status. Operative times (p < 0.001) were longer in the RDN group, but eventually approached LDN times. Warm ischemia (p = 0.002) and extraction times (p = 0.05) were also longer in the RDN cohort. The donor length of hospital stay, complication rates, and postoperative change in eGFR from baseline were similar in both cohorts up to 1 year. Recipient outcomes, including delayed graft function, graft failure, and renal function up to 1 year, were also comparable. In this study, we compared the longest postoperative course so far in both donors and recipients between RDN and LDN. Up to 1 year, RDN does not negatively impact outcomes. Proficiency with RDN also quickly improved to match LDN, making it a suitable procedure for newer surgeons. PMID- 28861704 TI - Multimodal image registration based on binary gradient angle descriptor. AB - PURPOSE: Multimodal image registration plays an important role in image-guided interventions/therapy and atlas building, and it is still a challenging task due to the complex intensity variations in different modalities. METHODS: The paper addresses the problem and proposes a simple, compact, fast and generally applicable modality-independent binary gradient angle descriptor (BGA) based on the rationale of gradient orientation alignment. The BGA can be easily calculated at each voxel by coding the quadrant in which a local gradient vector falls, and it has an extremely low computational complexity, requiring only three convolutions, two multiplication operations and two comparison operations. Meanwhile, the binarized encoding of the gradient orientation makes the BGA more resistant to image degradations compared with conventional gradient orientation methods. The BGA can extract similar feature descriptors for different modalities and enable the use of simple similarity measures, which makes it applicable within a wide range of optimization frameworks. RESULTS: The results for pairwise multimodal and monomodal registrations between various images (T1, T2, PD, T1c, Flair) consistently show that the BGA significantly outperforms localized mutual information. The experimental results also confirm that the BGA can be a reliable alternative to the sum of absolute difference in monomodal image registration. The BGA can also achieve an accuracy of [Formula: see text], similar to that of the SSC, for the deformable registration of inhale and exhale CT scans. Specifically, for the highly challenging deformable registration of preoperative MRI and 3D intraoperative ultrasound images, the BGA achieves a similar registration accuracy of [Formula: see text] compared with state-of-the-art approaches, with a computation time of 18.3 s per case. CONCLUSIONS: The BGA improves the registration performance in terms of both accuracy and time efficiency. With further acceleration, the framework has the potential for application in time-sensitive clinical environments, such as for preoperative MRI and intraoperative US image registration for image-guided intervention. PMID- 28861705 TI - Multistep translation and cultural adaptation of the Penn acoustic neuroma quality-of-life scale for German-speaking patients. AB - BACKGROUND: Monitoring the health-related quality of life (HRQOL) for patients with vestibular schwannoma (VS) has garnered increasing interest. In German speaking countries, there is no disease-specific questionnaire available similar to the "Penn Acoustic Neuroma Quality-of-life Scale" (PANQOL). METHOD: We translated the PANQOL for German-speaking patients based on a multistep protocol that included not only a forward-backward translation but also linguistic and sociocultural adaptations. The process consists of translation, synthesis, back translation, review by an expert committee, administration of the prefinal version to our patients, submission and appraisal of all written documents by our research team. The required multidisciplinary team for translation comprised head and neck surgeons, language professionals (German and English), a professional translator, and bilingual participants. A total of 123 patients with VS underwent microsurgical procedures via different approaches at our clinic between January 2007 and January 2017. Among these, 72 patients who underwent the translabyrinthine approach participated in the testing of the German-translated PANQOL. RESULT: The first German version of the PANQOL questionnaire was created by a multistep translation process. The responses indicate that the questionnaire is simple to administer and applicable to our patients. CONCLUSION: The use of a multistep process to translate quality-of-life questionnaires is complex and time consuming. However, this process was performed properly and resulted in a version of the PANQOL for assessing the quality of life of German-speaking patients with VS. PMID- 28861706 TI - Xerostomia Quality of Life Scale (XeQoLS) questionnaire: validation of Italian version in head and neck cancer patients. AB - AIM: To translate the Xerostomia Quality-of-Life Scale (XeQoLS) into Italian language (XeQoLS-IT). Xerostomia is the most relevant acute and late toxicity in patients with head and neck cancer treated with radiotherapy (RT). Patient reported outcome (PRO) instruments are subjective report on patient perception of health status. The XeQoLS consists of 15 items and measures the impact of salivary gland dysfunction and xerostomia on the four major domains of oral health-related QoL. METHODS: The XeQoLS-IT was created through a linguistic validation multi-step process: forward translation (TF), backward translation (TB) and administration of the questionnaire to 35 Italian patients with head and neck cancer. Translation was independently carried out by two radiation oncologists who were Italian native speakers. The two versions were compared and adapted to obtain a reconciled version, version 1 (V1). V1 was translated back into English by an Italian pro skilled in teaching English. After review of discrepancies and choice of the most appropriate wording for clarity and similarity to the original, version 2 (V2) was reached by consensus. To evaluate version 2, patients completed the XeQoLS-IT questionnaire and also underwent a cognitive debriefing. RESULTS: The questionnaire was considered simple by the patients. The clarity of the instructions and the easiness to answer questions had a mean value of 4.5 (+/- 0.71) on a scale from 1 to 5. CONCLUSION: A valid multi-step process led to the creation of the final version of the XeQoLS-IT, a suitable instrument for the perception of xerostomia in patients treated with RT. PMID- 28861708 TI - Breast cancer cell nuclei classification in histopathology images using deep neural networks. AB - PURPOSE: Cell nuclei classification in breast cancer histopathology images plays an important role in effective diagnose since breast cancer can often be characterized by its expression in cell nuclei. However, due to the small and variant sizes of cell nuclei, and heavy noise in histopathology images, traditional machine learning methods cannot achieve desirable recognition accuracy. To address this challenge, this paper aims to present a novel deep neural network which performs representation learning and cell nuclei recognition in an end-to-end manner. METHODS: The proposed model hierarchically maps raw medical images into a latent space in which robustness is achieved by employing a stacked denoising autoencoder. A supervised classifier is further developed to improve the discrimination of the model by maximizing inter-subject separability in the latent space. The proposed method involves a cascade model which jointly learns a set of nonlinear mappings and a classifier from the given raw medical images. Such an on-the-shelf learning strategy makes obtaining discriminative features possible, thus leading to better recognition performance. RESULTS: Extensive experiments with benign and malignant breast cancer datasets are conducted to verify the effectiveness of the proposed method. Better performance was obtained when compared with other feature extraction methods, and higher recognition rate was achieved when compared with other seven classification methods. CONCLUSIONS: We propose an end-to-end DNN model for cell nuclei and non nuclei classification of histopathology images. It demonstrates that the proposed method can achieve promising performance in cell nuclei classification, and the proposed method is suitable for the cell nuclei classification task. PMID- 28861709 TI - A nociceptive stress model of adolescent physical abuse induces contextual fear and cingulate nociceptive neuroplasticities. AB - Adolescent physical abuse impairs emotional development and evokes cingulate pathologies, but its neuronal and circuit substrates are unknown. Conditioning adolescent rabbits with noxious colorectal distension for only 2 h over 3 weeks simulated the human child abuse in amplitude, frequency, and duration. Thermal withdrawal thresholds were unchanged suggesting that sensitized spinal mechanisms may not be operable. Unchanged weight, stools, colorectal histology, and no evidence of abdominal pain argue against tissue injury or irritable bowel syndrome. Contextual fear was amplified as they avoided the site of their abuse. Conditioning impacted anterior cingulate and anterior midcingulate (ACC, aMCC) neuron excitability: (1) more neurons responded to cutaneous and visceral (VNox) noxious stimuli than controls engaging latent nociception (present but not manifest in controls). (2) Rear paw stimulation increased responses over forepaws with shorter onsets and longer durations, while forepaw responses were of higher amplitude. (3) There were more VNox responses with two excitatory phases and longer durations. (4) Some had unique three-phase excitatory responses. (5) Long duration VNox stimuli did not inhibit neurons as in controls, suggesting the release of an inhibitory circuit. (6) aMCC changes in cutaneous but not visceral nociception confirmed its role in cutaneous nociception. For the first time, we report neuroplasticities that may be evoked by adolescent physical abuse and reflect psychogenic pain: i.e., no ongoing peripheral pain and altered ACC nociception. These limbic responses may be a cognitive trace of abuse and may shed light on impaired human emotional development and sexual function. PMID- 28861707 TI - The Impact of a Required Longitudinal Stress Management and Resilience Training Course for First-Year Medical Students. AB - BACKGROUND: Although psychological distress is common among medical students, little remains known about effective interventions. One promising individual focused approach is mindfulness-based stress management interventions; however, studies to date have relied on volunteers. OBJECTIVE: To determine whether a required longitudinal stress management and resilience course improves well-being among first-year medical students. DESIGN: A quasi-experimental study. PARTICIPANTS: Two cohorts of medical students who participated in a required stress management and resilience course and completed pre and post questionnaires. MAIN MEASURES: Validated instruments were used to examine the effects on burnout, quality of life (QOL), stress, resilience, happiness, and empathy. Paired analysis was conducted to explore changes from baseline. KEY RESULTS: On paired analysis of individual students, mean mental QOL and happiness declined (mental QOL: -5.63 [P < 0.001] and -5.15 [P = 0.015] and happiness: 0.31 [P = 0.02] and -0.4 [P = 0.01], cohorts 1 and 2, respectively) over the course of the year. Similarly, stress scores increased by 4.22 (P < 0.0001) and 3.62 (P = 0.03) in cohorts 1 and 2, respectively. Cognitive and emotive empathy declined in both cohorts but was only statistically significant for cohort 1 ( 1.64 and -2.07, P < 0.01). No statistically significant differences in burnout or resilience were seen. CONCLUSIONS: The required longitudinal mindfulness-based stress management course tested in first-year medical students did not lead to measurable improvements in medical student well-being or empathy. These findings contrast with those of studies using volunteer medical students or physicians, which suggested a reduction in burnout and stress using a similar curriculum. Medical schools should consider offering a variety of effective options so that students can select activities they want to engage in. PMID- 28861710 TI - Healing of root and surrounding periodontium after root damage with miniscrew implants: a histomorphologic study in dogs. AB - OBJECTIVES: The main purpose of this study was to investigate the detailed healing process of the roots and surrounding periodontium [cementum, periodontal ligament (PDL), and bone] at different time points after intentional root damage with miniscrew implants (MSIs). MATERIALS AND METHODS: After cone-beam computed tomography examination and measurement, a total of 78 premolar and molar roots from five beagle dogs were intentionally damaged by implanting miniscrews in the interradicular region. MSIs were immediately removed, and the histological morphology was observed at days 0 and 3 and at weeks 1, 2, 3, 4, 6, 8, and 12 after root injury using haematoxylin and eosin and fluorescence stainings (fluorescence staining was performed at days 28 and 56). RESULTS: An early new attachment of PDL adhering on to the damaged root surface was found at week 2 after root injury. Tissue differentiation of newly formed bone tissue, PDL, and cementum began at week 3. Moreover, the newly formed cementum and bone were constantly forming and mineralising at weeks 4, 6, 8, and 12, and the width of PDL gradually narrowed until close to the normal width at week 12. CONCLUSIONS: This study demonstrated the complete healing process of the roots and surrounding periodontium after root damage with MSIs in dogs when the damage was limited to the cementum or dentin. CLINICAL RELEVANCE: The findings of this study may help provide a better understanding of the detailed healing process in roots and PDLs damaged by MSIs. PMID- 28861711 TI - Variations in Physicochemical Properties and Bioconversion Efficiency of Ulva lactuca Polysaccharides After Different Biomass Pretreatment Techniques. AB - Green macroalgae are an abundant and undervalued biomass with a specific cell wall structure. In this context, different pretreatments, namely ethanol organosolv (Org), alkaline, liquid hot water (LHW), and ionic liquid (IL) pretreatments, were applied to the green macroalgae Ulva lactuca biomass and then evaluated. Their effects on chemical composition, biomass crystallinity, enzymatic digestibility, and theoretical ethanol potential were studied. The chemical composition analysis showed that the Org and LHW pretreatments allowed the highest glucan recovery (80.8 +/- 3.6 and 62.9 +/- 4.4 g/100 g DM, respectively) with ulvan (80.0 and 99.1%) and hemicellulose (55.0 and 42.3%) removal. These findings were in agreement with both thermogravimetric analysis and scanning electron microscopy results that confirm significant structural changes of the pretreated biomasses. It was found that the employed pretreatments did not significantly affect the cellulose crystallinity; however, they both increased the whole crystallinity and the enzymatic digestibility. This later reached 97.5% in the case of LHW pretreatment. Our results showed high efficiency saccharification of Ulva lactuca biomass that will constitute the key step of the implementation of a biorefinery process. PMID- 28861712 TI - Robot-assisted laparoscopic extravascular stent for nutcracker syndrome. AB - Minimally invasive treatment options are a safe and feasible alternative for treatment of nutcracker syndrome. Endovascular stenting has shown promising long term resolution of symptoms but can be complicated by stent migration or thrombosis. Laparoscopic extravascular stent placement has shown promising results with the potential to avoid these complications. We report the first case of extravascular stent placement using the robotic approach for the treatment of nutcracker syndrome. PMID- 28861713 TI - LncRNA ZEB1-AS1 contributes to STAT3 activation by associating with IL-11 in B lymphoblastic leukemia. AB - OBJECTIVE: To investigate the role of lncRNA ZEB1-AS1 in B-lineage acute lymphoblastic leukemia (B-ALL). RESULTS: ZEB1-AS1 levels were aberrantly up regulated in B-ALL. All correlated with STAT3 activation and IL-11 production. Moreover, a high level of ZEB1-AS1 predicted poor prognosis of B-ALL patients. Mechanistically, ZEB1-AS1 could bind to IL-11 and promote IL-11 stability. Down regulation of ZEB1-AS1 decreased IL-11 production of human bone marrow stromal cells (BMSCs), which led to suppressed proliferation and inhibited IL-11/STAT3 pathway in BALL-1 cells. CONCLUSIONS: ZEB1-AS1 promotes the activation of IL 11/STAT3 signaling pathway by associating with IL-11 in B-ALL. PMID- 28861716 TI - Fish Oil Finishing Diet Maintains Optimal n-3 Long-Chain Fatty Acid Content in European Whitefish (Coregonus lavaretus). AB - This study examined the effect of substituting vegetable oil for fish oil in feed, with subsequent re-introduction of fish oil-rich feed (finishing feeding) in late stages of growth, on the fatty acids of cultivated European whitefish (Coregonus lavaretus). Restorative finishing feeding with fish oil-rich feed for 15 and 25 weeks was sufficient to change the total content of nutritionally valuable long-chain n-3 fatty acids, eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3), to correspond to that of fish fed the fish oil rich feed throughout their lifespan. Under natural conditions, 15 and 25 weeks correspond to weight gains of 75% and 100% (i.e. doubling), respectively. Also, the fatty acid profile of the fish was restored after finishing periods of 15 and 25 weeks. Limiting the use of fish oil by lowering the overall fat content of the feed (no vegetable oil added) resulted in a decrease in the long-chain n-3 fatty acids. Based on the results, after receiving a vegetable oil-rich diet, restorative fish oil-rich feeding in the last stages of growth in European whitefish is nutritionally justified in order to balance nutritional gain for consumers with sustainable use of finite marine oils. The results encourage commercial efforts to further utilize and optimize finishing feeding practices. PMID- 28861715 TI - The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington's disease. AB - Activating transcription factor-5 (ATF5) is a stress-response transcription factor induced upon different cell stressors like fasting, amino-acid limitation, cadmium or arsenite. ATF5 is also induced, and promotes transcription of anti apoptotic target genes like MCL1, during the unfolded protein response (UPR) triggered by endoplasmic reticulum stress. In the brain, high ATF5 levels are found in gliomas and also in neural progenitor cells, which need to decrease their ATF5 levels for differentiation into mature neurons or glia. This initially led to believe that ATF5 is not expressed in adult neurons. More recently, we reported basal neuronal ATF5 expression in adult mouse brain and its neuroprotective induction during UPR in a mouse model of status epilepticus. Here we aimed to explore whether ATF5 is also expressed by neurons in human brain both in basal conditions and in Huntington's disease (HD), where UPR has been described to be partially impaired due to defective ATF6 processing. Apart from confirming that ATF5 is present in human adult neurons, here we report accumulation of ATF5 within the characteristic polyglutamine-containing neuronal nuclear inclusions in brains of HD patients and mice. This correlates with decreased levels of soluble ATF5 and of its antiapoptotic target MCL1. We then confirmed the deleterious effect of ATF5 deficiency in a Caenorhabditis elegans model of polyglutamine-induced toxicity. Finally, ATF5 overexpression attenuated polyglutamine-induced apoptosis in a cell model of HD. These results reflect that decreased ATF5 in HD-probably secondary to sequestration into inclusions-renders neurons more vulnerable to mutant huntingtin-induced apoptosis and that ATF5 increasing interventions might have therapeutic potential for HD. PMID- 28861714 TI - The immune response to secondary necrotic cells. AB - When apoptotic cells are not cleared in an efficient and timely manner, they progress to secondary necrosis and lose their membrane integrity. This results in a leakage of immunostimulatory, danger associated molecular patterns (DAMPs), similar to accidental (or primary) necrosis. However, primary necrosis is a sudden event with an inadvertent release of almost unmodified DAMPs. Secondary necrotic cells, in contrast, have gone through various modifications during the process of apoptosis. Recent research revealed that the molecules released from the cytoplasm or exposed on the cell surface differ between primary necrosis, secondary necrosis, and regulated necrosis such as necroptosis. This review gives an overview of these differences and focusses their effects on the immune response. The implications to human physiology and diseases are manifold and will be discussed in the context of cancer, neurodegenerative disorders and autoimmunity. PMID- 28861717 TI - Estimates of Heritability for Growth and Shell Color Traits and Their Genetic Correlations in the Black Shell Strain of Pacific Oyster Crassostrea gigas. AB - The Pacific oyster Crassostrea gigas has been introduced widely and massively and became an economically important aquaculture species on a global scale. We estimated heritabilities of growth and shell color traits and their genetic correlations in black shell strain of C. gigas. Analyses were performed on 22 full-sib families in a nested mating design including 410 individuals at harvest (24 months of age). The parentage assignment was inferred based on four panels of multiplex PCR markers including 10 microsatellite loci and 94.9% of the offspring were unambiguously assigned to single parent pairs. The Spearman correlation test (r = - 0.992, P < 0.001) demonstrated the high consistency of the shell pigmentation (SP) and L* and their same efficacy in shell color measurements. The narrow-sense heritability estimated under the animal model analysis was 0.18 +/- 0.12 for shell height, 0.25 +/- 0.16 for shell length, 0.10 +/- 0.09 for shell width, 0.42 +/- 0.20 for total weight, 0.32 +/- 0.18 for shell weight, and 0.68 +/- 0.16 for L*, 0.69 +/- 0.16 for shell pigmentation, respectively. The considerable additive genetic variation in growth and shell color traits will make it feasible to produce genetic improvements for these traits in selective breeding program. High genetic and phenotypic correlations were found among growth traits and among shell color traits. To optimize a selection strategy for both fast growth and pure dark shell strain of C. gigas, it is proposed to take both total weight and black shell as joint objective traits in selective breeding program. Our study offers an important reference in the process of selective breeding in black shell color stain of C. gigas and will facilitate to develop favorable breeding strategies of genetic improvements for this economically important strain. PMID- 28861719 TI - Lanthanum exerts acute toxicity and histopathological changes in gill and liver tissue of rare minnow (Gobiocypris rarus). AB - We evaluated the acute toxicity effects of lanthanum (La(III)) on gill and liver of rare minnow (Gobiocypris rarus). The median lethal concentration of La (III) at 96 h was 1.92 mg L-1. Rare minnow were reared in freshwater and exposed to 0.04, 0.08, 0.16, 0.32 and 0.80 mg L-1 La (III) for 21 d. Gill and liver samples were analyzed by light microscopy. The main histopathological changes induced by La (III) in gills were epithelial lifting, filamentary epithelial proliferation,edema, lamellar fusion, desquamation, and necrosis. Histopathological changes induced by La (III) in the liver included dilation of sinusoids, focal congestion, pyknotic nuclei, karyohexis and karyolysis, vacuolar degeneration, and numerous necrosis areas. Hypsometric analysis indicated significant changes in the measures of gill dimensions (average length, width, area), suggesting metabolic disturbance (gas exchange) upon La (III) exposure. The result showed that La (III) severely affects fish gill and liver. PMID- 28861718 TI - Repeated Forced Swim Exacerbates Methamphetamine-Induced Neurotoxicity: Neuroprotective Effects of Nanowired Delivery of 5-HT3-Receptor Antagonist Ondansetron. AB - The possibility that stress associated with chronic forced swim (FS) may exacerbate methamphetamine (METH) neurotoxicity was examined in a rat model. Rats were subjected to FS in a pool (30 degrees C) for 15 min daily for 8 days. Control rats were kept at room temperature. METH was administered (9 mg/kg, s.c.) in both control and FS rats and allowed to survive 4 h after the drug injection. METH in FS rats exacerbated BBB breakdown to Evans blue albumin (EBA) by 150 to 220% and [131]-Iodine by 250 to 380% as compared to naive rats after METH. The METH-induced BBB leakage was most pronounced in the cerebral cortex followed by the hippocampus, cerebellum, thalamus, and hypothalamus in both FS and naive rats. The regional BBB changes were associated with a reduction in the local cerebral blood flow (CBF). Brain edema was also higher by 2 to 4% in FS rats after METH than in naive animals. Neuronal and glial cell injuries were aggravated by threefold to fivefold after METH in FS than the control group. Pretreatment with ondansetron (1 mg/kg, i.p.) 30 min before METH injection in naive rats reduced the brain pathology and improved the CBF. However, TiO2 nanowired delivery of ondansetron (1 mg/kg, i.p.) was needed to reduce METH induced brain damage, BBB leakage, reduction in CBF, and edema formation in FS. Taken together, these observations are the first to show that METH exacerbates BBB breakdown leading to neurotoxicity in FS animals. This effect of METH-induced BBB breakdown and brain pathology in naive and FS rats is attenuated by ondansetron treatment indicating an involvement of 5-HT3 receptors, not reported earlier. PMID- 28861720 TI - Accurate Identification of Fatty Liver Disease in Data Warehouse Utilizing Natural Language Processing. AB - INTRODUCTION: Natural language processing is a powerful technique of machine learning capable of maximizing data extraction from complex electronic medical records. METHODS: We utilized this technique to develop algorithms capable of "reading" full-text radiology reports to accurately identify the presence of fatty liver disease. Abdominal ultrasound, computerized tomography, and magnetic resonance imaging reports were retrieved from the Veterans Affairs Corporate Data Warehouse from a random national sample of 652 patients. Radiographic fatty liver disease was determined by manual review by two physicians and verified with an expert radiologist. A split validation method was utilized for algorithm development. RESULTS: For all three imaging modalities, the algorithms could identify fatty liver disease with >90% recall and precision, with F-measures >90%. DISCUSSION: These algorithms could be used to rapidly screen patient records to establish a large cohort to facilitate epidemiological and clinical studies and examine the clinic course and outcomes of patients with radiographic hepatic steatosis. PMID- 28861722 TI - Preoperative Assessment for Ambulatory Surgery. AB - PURPOSE OF REVIEW: Ambulatory surgery has grown in recent decades in volume and represents a significant number of anesthetics delivered throughout the USA. Preoperative anesthetic assessment in the ambulatory setting has become important because patients with numerous complex comorbidities are now commonplace in this arena. Disease states involving the lungs, the heart, the kidneys, and subpopulations including those who are obese and the elderly commonly receive anesthetics in an ambulatory setting. RECENT FINDINGS: This review presents key aspects of current thinking with regard to preoperative assessment and considerations for different critical disease states and subpopulations that are now being managed under ambulatory surgery. Same day surgery centers require patient safety, and expectations are high for patient satisfaction. Advancements in surgical and anesthetic technique have allowed for more complex patients to partake in ambulatory surgery. Anesthesiologists must be familiar with guidelines, state-of-the-art pain management, and standards of preoperative patient evaluation to accurately stratify patient risk and to advocate for patient safety. PMID- 28861721 TI - Influence of Parasitic Worm Infections on Allergy Diagnosis in Sub-Saharan Africa. AB - Epidemiological studies from Sub-Saharan Africa indicate that allergies are on the rise in this region especially in urban compared to rural areas. This increase has been linked to improved hygiene, lifestyle changes, and lower exposure to pathogens in childhood. Reduced exposure to parasitic worm (helminth) infections and allergy outcomes has been the focus of a number of population studies over the years. Paradoxically, there are parallels in the immune responses to helminths and to allergies. Both conditions are associated with elevated levels of immunoglobulin E, high numbers of T helper 2 cells, eosinophils, and mast cells. These immune parallels have meant that the diagnosis of allergies in parts of the world where helminths are endemic can be hampered. The aim of this review is to examine observations from population studies conducted in Sub-Saharan Africa that demonstrate how helminth infections influence the parameters used to diagnose allergy outcomes in this region. We explore specifically how helminth infections hinder the in vitro diagnosis of allergic sensitization, influence the clinical manifestations of allergy, and also the effect of anthelmintic treatment on allergy outcomes. Advancing our understanding of how helminths influence allergy diagnosis is imperative for the development of improved tools to assess, diagnose, and treat allergic disorders in both helminth-endemic and non-endemic countries worldwide. PMID- 28861723 TI - Health risk assessment of heavy metal variability in sachet water sold in Ado-Odo Ota, South-Western Nigeria. AB - The sales of sachet water (SW), also known as "pure water" (PW), in Nigeria is a lucrative business. It serves many people, especially low-income earners, by providing a more affordable access to safe drinking water when compared with table water. However, some of the producers of SW do not effectively treat raw water before packaging them for sale. This study investigates the presence and concentrations of heavy metals, such as chromium (Cr), iron (Fe), manganese (Mn), copper (Cu), aluminum (Al), and zinc (Zn) in some samples of SW sold within Ota, Ogun State, Nigeria. Samples of SW from nine different producers were purchased for four consecutive weeks and analyzed to determine the concentrations of these heavy metals in them. Furthermore, health risk indicators, such as chronic daily intake (CDI) and health risk indices (HRI) for children and adults, were calculated separately. The metal concentrations were compared with allowable limits set by the World Health Organization (WHO), Nigerian Industrial Standard (NIS), and the United States Environmental Protection Agency (US EPA). High concentrations of Cr, Fe, and Al were found in all the nine samples and exceeded the maximum allowable limits (MAL) of all the standards considered. However, the concentrations of Zn, Mn, and Cu were within permissible limits. The HRIs of heavy metals were in the order of Cu > Fe > Zn > Mn > Al > Cr, but since the standard limits set for some metals were exceeded, proper and effective treatment is required to safeguard the health of consumers. PMID- 28861724 TI - Role of the Hippocampus in Distinct Memory Traces: Timing of Match and Mismatch Enhancement Revealed by Intracranial Recording. AB - A previous functional magnetic resonance imaging study reported evidence for parallel memory traces in the hippocampus: a controlled match signal detecting matches to internally-generated goal states and an automatic mismatch signal identifying unpredicted perceptual novelty. However, the timing information in this process is unknown. In the current study, facilitated by the high spatial and temporal resolution of intracranial recording from human patients, we confirmed that the left posterior hippocampus played an important role in the goal match enhancement effect, in which combinations of object identity and location were involved. We also found that this effect happened within 520 ms to 735 ms after the probe onset, ~150 ms later than the perceptual mismatch enhancement found bilaterally in both the anterior and posterior hippocampus. More specifically, the latency of the perceptual mismatch enhancement effect of the right hippocampus was positively correlated with the performance accuracy. These results suggested that the hippocampus is crucial in working memory if features binding with location are involved in the task and the goal match enhancement effect happens after perceptual mismatch enhancement, implying the dissociation of different components of working memory at the hippocampus. Moreover, single trial decoding results suggested that the intracranial field potential response in the right hippocampus can classify the match or switch task. This is consistent with the findings that the right hippocampal activity observed during the simulation of the future events may reflect the encoding of the simulation into memory. PMID- 28861725 TI - Proposal for the creation of a national strategy for precision medicine in cancer: a position statement of SEOM, SEAP, and SEFH. AB - Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. Precision medicine is transforming clinical and biomedical research, as well as health care itself from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical-legal, regulatory, organizational, and knowledge-related challenges. Without a national strategy, precision medicine, which will be implemented one way or another, could take place without the appropriate planning that can guarantee technical quality, equal access of all citizens to the best practices, violating the rights of patients and professionals, and jeopardizing the solvency of the healthcare system. With this paper from the Spanish Societies of Medical Oncology, Pathology, and Hospital Pharmacy, we highlight the need to institute a consensual national strategy for the development of precision medicine in our country, review the national and international context, comment on the opportunities and challenges for implementing precision medicine, and outline the objectives of a national strategy on precision medicine in cancer. PMID- 28861726 TI - A Day at the Office: What if "Later" Never Comes? Four Tips for Volunteering Abroad Now. PMID- 28861727 TI - Managing Idiopathic Pulmonary Fibrosis: Which Drug for Which Patient? AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Two novel antifibrotic agents, pirfenidone and nintedanib, have received licences for use in IPF in recent years. Phase III, multinational, randomised control trials have provided evidence that both drugs reduce decline in forced vital capacity (FVC) over time, while further post hoc studies have suggested that both pirfenidone and nintedanib can be efficacious, regardless of age and severity of baseline lung function. Both therapeutic agents have manageable side effect profiles. In the absence of head-to-head data, decisions regarding which agent to choose when starting treatment for IPF should take into consideration joint decision making between patients and clinicians based on accurate information in the decision-making process. Questions remain as to the role of combination antifibrotic therapy as a future treatment option. PMID- 28861728 TI - Off-clamp robot-assisted partial nephrectomy does not benefit short-term renal function: a matched cohort analysis. AB - In the interest of renal functional preservation, partial nephrectomy has supplanted radical nephrectomy as the preferred treatment for T1 renal masses. This procedure usually involves the induction of renal warm ischemia by clamping the hilar vessels prior to tumor excision. Performing robot-assisted partial nephrectomy (RAPN) "off-clamp" can theoretically prevent renal functional loss associated with warm ischemia. We describe our institutional experience and compare perioperative and renal functional outcomes using a propensity score matched cohort. We conducted a retrospective comparison from a prospectively maintained database of all patients who underwent RAPN from 2009 to 2015. Of those patients, 143 underwent off-clamp RAPN. Fifty off-clamp RAPN patients were propensity score matched with fifty clamped RAPN patients based on renal function, tumor size, and R.E.N.A.L. nephrometry score. The cohorts were compared across demographics, operative information, perioperative outcomes, and renal functional outcomes. For all off-clamp RAPN patients, mean nephrometry score was 7.1, mean estimated blood loss (EBL) was 236.9 mL, perioperative complication rate was 7.7%, and mean decrease in estimated glomerular filtration rate (eGFR) was 7.1% at a median follow-up of 9.2 months. In the propensity score matched cohorts, off-clamp RAPN resulted in a shorter mean operative time (172.0 versus 196.0 min, p = 0.025) and a lower mean EBL (179.7 versus 283.2 mL, p = 0.046). A lower complication rate of 6.0% in the off-clamp group compared with 20.0% in the clamped group approached significance (p = 0.071). Mean preoperative eGFR was similar in both cohorts. Importantly, there was no significant difference in decrease in eGFR between the clamped cohort (9.8%) and off-clamp cohort (11.9%) at a median follow-up of 9.0 months (p = 0.620). Off-clamp RAPN did not result in improved renal functional preservation in our experience. Surprisingly, the off clamp cohort experienced lower intraoperative blood loss, shorter operative times, and fewer complications. PMID- 28861729 TI - A preliminary randomized clinical trial comparing diode laser and scalpel periosteal incision during implant surgery: impact on postoperative morbidity and implant survival. AB - The aim of this preliminary randomized clinical trial was to compare: (1) post operative morbidity after application of laser or scalpel incision for flap advancement during implant surgery and bone grafting and (2) implant survival rate following flap advancement with laser or scalpel incision after 6 months of loading. Eighteen patients who were scheduled for dental implant placement and simultaneous bone grafting were randomly assigned to test or control groups. Diode laser (810 nm, 2 W, pulse interval 200 MUs; pulse length 100 MUs, 400-MUm initiated fiber tip), or scalpel (control) was used to sever the periosteum to create a tension-free flap. Visual analogue scale (VAS) pain score, rate of nonsteroid anti-inflammatory drug (NSAID) consumption, intensity of swelling, and ecchymosis were measured for the six postsurgical days. Six months after loading, implant survival was assessed. VAS pain score (during the first four postoperative days), rate of NSAID consumption (during the first three postoperative days), and intensity of swelling (during the first five postoperative days) were significantly lower in the test group compared to the control group (All P values < 0.05). One patient in the control group experienced ecchymosis. All implants were successful in function. Application of laser for performing periosteal releasing incision reduced the incidence and severity of postoperative morbidity of the patients undergone implant surgery in conjunction with bone augmentation procedure. We did not find any detrimental effect of laser incision on the implant survival within 6 months of loading. PMID- 28861730 TI - Do Male Patients Benefit from Laparoscopic Adjustable Gastric Banding More than Female Patients? A Retrospective Cohort Study. AB - BACKGROUND: Clinical trials in the field of bariatrics, and specifically laparoscopic adjustable gastric banding (LAGB), have frequently been gender imbalanced, with males representing only 20% of examinees. Long-term gender oriented results, and specifically quality of life (QOL) parameters, have not been addressed sufficiently. The aim of our study was to examine the long-term gender association with outcome of LAGB including the impact on QOL. METHODS: A retrospective cohort study of patients who underwent LAGB between 2006 and 2014 by a single surgeon was conducted. Data were collected from the hospital registry and a telephone interview that included a standardized questionnaire. Outcomes including BMI reduction, evolution of comorbidities, complications, reoperations, and QOL were compared according to the Bariatric Analysis and Reporting Outcome System (BAROS). RESULTS: Included were 114 males and 127 females, with a mean age of 38.2 years at surgery, and an average post-surgery follow-up of 6.5 years. Similar BMI reduction (p = 0.68) and perioperative complication rates (p = 0.99) were observed. Males had a greater improvement in comorbidities (p < 0.001), less band slippage (p = 0.006), underwent fewer reoperations (p = 0.02), and reported higher QOL scores (p = 0.02) than females. The total BAROS score was significantly higher for males than females (p < 0.001). CONCLUSIONS: LAGB surgery results in better outcomes for male than female patients as measured by the BAROS, despite a similar BMI reduction. Gender-specific outcomes should be taken into consideration in optimizing patient selection and preoperative patient counseling. PMID- 28861731 TI - Adaptation of Intestinal and Bile Acid Physiology Accompany the Metabolic Benefits Following Ileal Interposition in the Rat. AB - PURPOSE: Ileal interposition recapitulates many of the metabolic improvements similar to Roux-en-Y gastric bypass. We aimed to determine whether the metabolic improvements seen following ileal interposition were conferred solely by the interposed segment by examining changes in neighboring intestinal segments as well as the composition of the bile acid pool. MATERIALS AND METHODS: Adult male rats were treated with either sham or ileal interposition surgeries. Glucose tolerance tests, body composition analysis, polymer chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were done after the surgeries. RESULTS: This study showed that ileal interposition improved glucose tolerance and enhanced both fasting and glucose-stimulated GLP-1 secretion in diabetic rats. Total bile acid pool was similar between groups but the composition favored glycine-conjugation in rats with ileal interposition. Insulin secretion was highly correlated with the 12-alpha-hydroxylase index of activity. The interposed ileum exhibited an increase in mRNA for preproglucagon and peptide YY; however, the bile acid transporter, apical sodium bile acid transporter, was dramatically reduced compared to sham rats. The interposed segment becomes jejunized in its new location as indicated by an increase in Glut2 and Pepck mRNA, genes predominantly synthesized within the jejunum. CONCLUSION: Ileal relocation alone can significantly alter the bile acid pool to favor a more insulin-sensitive metabolism in association with intestinal wide alterations in mRNA for a variety of genes. Ileal interposition may confer metabolic improvement via both the interposed segment and the associated intestinal changes in all segments of the intestine, including the colon. PMID- 28861732 TI - Autism Spectrum Disorders and Low Mental Age: Diagnostic Stability and Developmental Outcomes in Early Childhood. AB - Some children with autism spectrum disorders (ASDs) exhibit low mental age (Low MA; i.e., cognitive functioning below 12 months). We examined diagnosis, symptom severity, and development in children with ASD-low MA (n = 25), autistic disorder (n = 111), and PDD-NOS (n = 82) at ages two and four. We predicted that some ASD low MA children would demonstrate just intellectual impairment and not autism symptoms on follow-up, with social deficits at age two attributable to global delays. Instead, most ASD-low MA children (96%) had an ASD at follow-up, compared to children initially diagnosed with autistic disorder (86.5%) or PDD-NOS (73.2%). They showed the least developmental progress and highest symptom severity. Results support diagnosing ASDs in children functioning below a 12 month level. PMID- 28861733 TI - Patterns of uveitis in children at the apex institute for eye care in India: analysis and review of literature. AB - AIM: To study patterns of uveitis in Indian children and compare with data sets published earlier in the literature. METHODS: Consecutive patients below 16 years of age presenting to the uvea clinic of a tertiary eye care center were included prospectively through the period of July 2009-August 2013. Children with retinal vasculitis, exogenous endophthalmitis and masquerade syndromes were excluded from analysis. Uveitis was classified as per the nomenclature system adopted by the International Uveitis Study Group. Hemogram, Mantoux test and chest X-ray were done for each patient, along with tailored investigations and pediatric review as per clinical profile. Clinical pattern and etiology were the main outcome measures. RESULTS: One hundred and thirty-four children were analyzed. Anterior uveitis (40%) was the commonest pattern followed by intermediate uveitis (25%), panuveitis (18%) and posterior uveitis (17%). Bilateral disease was present in 54%, 15% had infectious uveitis, 10% had granulomatous uveitis and 54% had idiopathic uveitis. Complications were present in half of the patients. Juvenile idiopathic arthritis (22), followed by toxoplasmosis (10) and tuberculosis (5), was the commonest etiology. Intermediate uveitis, non-granulomatous inflammation and older onset of disease had the high odds ratio of having idiopathic disease. CONCLUSION: Patterns of pediatric uveitis can vary between regions from even within the same geopolitical region. Anterior uveitis is commonest, and juvenile idiopathic arthritis and toxoplasmosis are the most frequent etiologies. Diagnosis of pediatric ocular tuberculosis is more difficult than in adults and needs better and well-defined criteria. PMID- 28861734 TI - Inhibitory effects of sesamin on human osteoclastogenesis. AB - The promotional nature of sesamin on human osteoblast differentiation has been proven. Here, the effect of sesamin on human osteoclasts was investigated in terms of differentiation and function in M-CSF and RANKL induced human PBMCs. Sesamin treatment significantly decreased the number of differentiated osteoclasts observed by TRAP staining; however, sesamin inhibition did not result from the alteration of precursor cell proliferation. Sesamin did not decrease NFATc1 gene expression, which opposed the decreasing trend of CathK and TRAP expression. DC-STAMP, but not Atp6v0d2, also significantly decreased in the presence of 14 uM sesamin. Expressions of CCR2b and CCR4 as chemokine receptors were significantly down-regulated. Sesamin might mediate the inhibition of human osteoclast differentiation, the recruitment of precursor cells and F-actin formation. Decrease in the area of the resorption pits and the collagen released from the bone slices under sesamin treatment emphasized the inhibitory effects on both the differentiation and function of osteoclasts. Sesamin is a promising phytochemical agent inhibiting osteoclast differentiation and function. PMID- 28861735 TI - Dementia, identity and the role of friends. AB - Ronald Dworkin (1993) introduced the example of Margo, who was so severely demented that she could not recognise any family or friends, and could not remember anything of her life. At the same time, however, she seemed full of childish delight. Dworkin also imagines that, before her dementia, Margo signed an advance refusal of life-saving treatment. Now severely demented, she develops pneumonia, easy to treat, but lethal if untreated. Dworkin argues that the advance refusal ought to be heeded and Margo be allowed to die of that pneumonia, on the basis that the prior refusal expresses her true wishes (her 'critical interests'). In this paper I want to challenge Dworkin's understanding of identity and his conclusion about advance refusals, and I develop my argument in two directions. First, I argue that the demented Margo is not some 'lesser' version of the 'true' Margo, but instead that the present Margo's wishes should take precedence over those of the past Margo, on the grounds that all of us are entitled to change our minds. Second, I argue for a stronger role for friends and family members in sustaining the demented Margo's identity through her years of decline. Based on this, I argue for a presumption against the advance refusal, but I allow that in extreme cases (which I describe), a friend might have the authority to demand that it be heeded. PMID- 28861736 TI - Identification and fine mapping of a new gene, BPH31 conferring resistance to brown planthopper biotype 4 of India to improve rice, Oryza sativa L. AB - BACKGROUND: Rice (Oryza sativa L.) is the staple food for more than 3.5 billion people, mainly in Asia. Brown planthopper (BPH) is one of the most destructive insect pests of rice that limits rice production. Host-plant resistance is one of the most efficient ways to overcome BPH damage to the rice crop. RESULTS: BPH bioassay studies from 2009 to 2015 conducted in India and at the International Rice Research Institute (IRRI), Philippines, revealed that the cultivar CR2711-76 developed at the National Rice Research Institute (NRRI), Cuttack, India, showed stable and broad-spectrum resistance to several BPH populations of the Philippines and BPH biotype 4 of India. Genetic analysis and fine mapping confirmed the presence of a single dominant gene, BPH31, in CR2711-76 conferring BPH resistance. The BPH31 gene was located on the long arm of chromosome 3 within an interval of 475 kb between the markers PA26 and RM2334. Bioassay analysis of the BPH31 gene in CR2711-76 was carried out against BPH populations of the Philippines. The results from bioassay revealed that CR2711-76 possesses three different mechanisms of resistance: antibiosis, antixenosis, and tolerance. The effectiveness of flanking markers was tested in a segregating population and the InDel type markers PA26 and RM2334 showed high co-segregation with the resistance phenotype. Foreground and background analysis by tightly linked markers as well as using the Infinium 6 K SNP chip respectively were applied for transferring the BPH31 gene into an indica variety, Jaya. The improved BPH31-derived Jaya lines showed strong resistance to BPH biotypes of India and the Philippines. CONCLUSION: The new BPH31 gene can be used in BPH resistance breeding programs on the Indian subcontinent. The tightly linked DNA markers identified in the study have proved their effectiveness and can be utilized in BPH resistance breeding in rice. PMID- 28861738 TI - A surgical case of radiotherapy induced esophageal perforation accompanying pyogenic spondylodiscitis: a case report. AB - BACKGROUND: Stereotactic body radiotherapy has been a treatment choice for lung cancer, especially in medically inoperable patients. However, the acute and late toxicity to adjacent organs have been reported as an uncommon but severe adverse effect. CASE PRESENTATION: A 65-year-old male was presented with his back pain and pyrexia. He had been followed up for non-small-cell lung cancer, which was treated by the stereotactic body radiotherapy 4 years prior to the current visit. The endoscopy revealed an esophageal perforation on its left side in the upper thoracic locus. Because of his poor lung function, he was managed by the conservative treatment. After 3 months, his back pain recurred with developing paraplegia in the lower extremities. The MRI revealed an abscess formation at the posterior side of the upper thoracic esophagus which destroyed the vertebral body and compressed the spinal cord. Laminectomy and two-stage operation-the first stage, nontransthoracic esophagectomy, cervical and transhiatal approach using mediastinoscope and laparoscope, and the second stage, esophageal reconstruction were performed. CONCLUSION: This complex disease status was successfully managed by the orthopedic surgery followed by a two-stage esophagectomy without transthoracic approach. PMID- 28861739 TI - Acculturation and a Potential Relationship with Oral Health Outcomes Among Somali Refugees in Massachusetts. AB - This paper explores the relationship between acculturation and oral health in a study of Somali refugees. This cross-sectional survey included structured surveys and dental examinations of a convenience sample of 439 Somali adults living in Massachusetts. Associations between an acculturation scale and: (1) lifetime history of caries and (2) access to oral health services were calculated. In bivariate analyses, many individual questions in the scale were associated with outcomes. In multivariate analysis, speaking English (OR 0.5, CI 0.28-0.84) was associated with better access to, and utilization of, dental health services while reading American books and newspapers in English was associated with increased lifetime history of dental disease (OR 2.6, CI 1.1-6.0). As specific elements of acculturation have different relationships with oral health among Somali refugees, a summary acculturation scale may have limited utility. Ongoing efforts to remove language barriers may improve oral health. PMID- 28861740 TI - Gut microbiota and physiologic bowel 18F-FDG uptake. AB - BACKGROUND: We investigated the association between physiologic bowel FDG uptake and gut microbiota. FDG uptake in the normal large and small intestine is widely variable both in distribution and intensity. The etiology of physiologic bowel 18F-FDG activity remains unknown. RESULTS: We included 63 healthy male subjects. After overnight fasting, blood samples and 18F-FDG PET/CT scans were taken. Fecal samples were collected, and gut microbiota were analyzed by 16S rRNA gene pyrosequencing. The physiologic bowel FDG uptake was classified into three groups by visual assessment and measured using the maximum and mean standardized uptake value. We used the total bowel to liver uptake ratio (TBRmax and TBRmean). There was no significant difference in age, BMI, or lipid profiles between groups. To identify specific microbial taxa associated with the bowel FDG uptake while accounting for age and BMI, we performed a generalized linear model. At the genus level, the group with focal or intense FDG uptake in the intestine was associated with low abundance of unclassified Clostridiales. The group with intestinal FDG uptake lower than the liver was associated with high abundance of Klebsiella. TBRmax and TBRmean were negatively associated with abundance of unclassified Enterobacteriaceae. CONCLUSION: We cautiously speculate that physiologic bowel FDG activity might be caused by an increase in intestinal permeability and may reflect an impaired barrier function in the intestine. PMID- 28861741 TI - Probiotics and the Gut Immune System: Indirect Regulation. AB - The gastrointestinal tract (GIT) represents the largest interface between the human organism and the external environment. In the lumen and upper part of the mucus layer, this organ hosts an enormous number of microorganisms whose composition affects the functions of the epithelial barrier and the gut immune system. Consequentially, the microorganisms in the GIT influence the health status of the organism. Probiotics are living microorganisms which, in specific conditions, confer a health benefit to the host. Among others, probiotics have immunomodulatory properties that usually act directly by (a) increasing the activity of macrophages or natural killer cells, (b) modulating the secretion of immunoglobulins or cytokines, or indirectly by (c) enhancing the gut epithelial barrier, (d) altering the mucus secretion, and (e) competitive exclusion of other (pathogenic) bacteria. This review focuses on specific bacteria strains with indirect immunomodulatory properties. Particularly, we describe here the mechanisms through which specific probiotics enhance the gut epithelial barrier and modulate mucus production. Moreover, we describe the antimicrobial properties of specific bacteria strains. Recent data suggest that multiple pathologies are associated with an unbalanced gut microflora (dysbiosis). Although the cause effect relationship between pathology and gut microflora is not yet well established, consumption of specific probiotics may represent a powerful tool to re-establish gut homeostasis and promote gut health. PMID- 28861742 TI - Current situation in gynecological oncology training in Spain: where we are and where we want to go. AB - BACKGROUND: It is important to know what a young gynecologic oncologist perceives as a need to achieve a good training in gynecologic oncology. OBJECTIVE: This study aims to evaluate the level of training in gynecologic oncology in Spain. METHODS: A Web-based anonymous questionnaire was sent via e-mail to Spanish trainees listed in European Network of Young Gynecological Oncology (ENYGO). The survey was developed in four sections: (1) general training in gynecologic oncology, (2) distribution of current clinical activity, (3) surgical training, and (4) perspective future gynecologic oncology. It contained 51 questions, with multiple-choice answers that had to be answered by the ENYGO members. RESULTS: The questionnaire was sent to 64 people listed in the ENYGO database. Of these, 37 members responded (response rate of 58%). Overall, more training in surgery is necessary, to perform radical oncological surgeries. It is claimed a sub specialty recognition, to ensure an equalitarian and homogeneous training. PMID- 28861743 TI - Feasibility and safety of exercise stress testing using an anti-gravity treadmill with Tc-99m tetrofosmin single-photon emission computed tomography (SPECT) myocardial perfusion imaging: A pilot non-randomized controlled study. AB - BACKGROUND: Exercise is the AHA/ACC guideline-recommended stress modality for myocardial perfusion imaging, but many patients are unable to exercise to target heart rate on a conventional treadmill. We examined the feasibility and safety of stress imaging using an anti-gravity treadmill in patients with perceived poor exercise capacity. METHODS AND RESULTS: 49 patients were recruited for stress testing by anti-gravity treadmill (n = 29) or to a regadenoson control group (n = 20). Seventeen anti-gravity test patients (59%) reached target heart rate obviating the need for a pharmacologic stress agent. Adverse effects of the anti gravity treadmill were limited to minor muscle aches in 5 subjects. Stress myocardial perfusion image quality judged by 3 blinded readers on a 5-point scale was comparable for the anti-gravity treadmill (4.30 +/- SD 0.87) vs pharmacologic stress (4.28 +/- SD 0.66). CONCLUSION: Stress testing using an anti-gravity treadmill is feasible and may help some patients safely achieve target heart rate. PMID- 28861737 TI - Chronic MPTP administration regimen in monkeys: a model of dopaminergic and non dopaminergic cell loss in Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically characterized by cardinal motor deficits including bradykinesia, tremor, rigidity and postural instability. Over the past decades, it has become clear that PD symptoms extend far beyond motor signs to include cognitive, autonomic and psychiatric impairments, most likely resulting from cortical and subcortical lesions of non-dopaminergic systems. In addition to nigrostriatal dopaminergic degeneration, pathological examination of PD brains, indeed, reveals widespread distribution of intracytoplasmic inclusions (Lewy bodies) and death of non dopaminergic neurons in the brainstem and thalamus. For that past three decades, the MPTP-treated monkey has been recognized as the gold standard PD model because it displays some of the key behavioral and pathophysiological changes seen in PD patients. However, a common criticism raised by some authors about this model, and other neurotoxin-based models of PD, is the lack of neuronal loss beyond the nigrostriatal dopaminergic system. In this review, we argue that this assumption is largely incorrect and solely based on data from monkeys intoxicated with acute administration of MPTP. Work achieved in our laboratory and others strongly suggest that long-term chronic administration of MPTP leads to brain pathology beyond the dopaminergic system that displays close similarities to that seen in PD patients. This review critically examines these data and suggests that the chronically MPTP-treated nonhuman primate model may be suitable to study the pathophysiology and therapeutics of some non-motor features of PD. PMID- 28861744 TI - Bond durability of universal adhesive to bovine enamel using self-etch mode. AB - OBJECTIVES: The purpose of this study was to examine the enamel bond durability of universal adhesives in the self-etch mode under 2-year water storage and thermal cycling conditions. MATERIALS AND METHODS: Three commercially available universal adhesives and a gold standard two-step self-etch adhesive were used. Ten specimens of bovine enamel were prepared per test group, and shear bond strength (SBS) was measured to determine the bonding durability after thermal cycling (TC) or long-term water storage (WS). The bonded specimens were divided into three groups: (1) specimens subjected to TC, where the bonded specimens were stored in 37 degrees C distilled water for 24 h before being subjected to 3000, 10,000, 20,000 or 30,000 TC; (2) specimens stored in 37 degrees C distilled water for 3 months, 6 months, 1 year or 2 year; and (3) specimens stored in 37 degrees C distilled water for 24 h, serving as a baseline. RESULTS: The two-step self-etch adhesive showed significantly higher SBS than the universal adhesives tested, regardless of the type of degradation method. All universal adhesives showed no significant enamel SBS reductions in TC and WS, when compared to baseline and the other degradation conditions. CONCLUSIONS: Compared to the bond strengths obtained with the two-step self-etch adhesive, significantly lower bond strengths were obtained with universal adhesives. However, the enamel bond durability of universal adhesives was relatively stable under both degradation conditions tested. CLINICAL RELEVANCE: The present data indicate that the enamel bond durability of universal adhesives in the self-etch mode might be sufficient for clinical use. PMID- 28861745 TI - Promising Practices for Making Recreation Programming Matter for People who Experience Mental Illness. AB - There is merit in understanding how recreation-oriented programs for adults living with mental illness address barriers to participation and how programming is structured to create safe and inclusive environments, resulting in programming that amplifies the benefits of recreation for mental well-being. Following an environmental scan of programs targeting adults living with mental illness in Canada, ten coordinators in community mental health settings were interviewed. Four themes were constructed to reflect characteristics deemed to be 'promising practices' related to recreation-oriented programming: (a) barriers and solutions to individual participation, (b) characteristics of welcoming and supportive environments, PMID- 28861746 TI - Trigemino-gustatory interactions: a randomized controlled clinical trial assessing the effects of selective anesthesia of dental afferents on taste thresholds. AB - OBJECTIVES: This study aimed at analyzing the effect of the temporary removal of trigeminal dental afferents on electrogustometric thresholds (EGMt). MATERIAL AND METHODS: EGMt were measured in 300 healthy subjects randomized in three groups, in nine loci on the right and left side (RS, LS) of the tongue surface before and after anesthesia. Group IAN (n = 56 RS, n = 44 LS) received intraosseous local anesthesia of the inferior alveolar nerve (IAN). Group MdN received mandibular nerve (MdN) block targeting IAN before its entrance into the mandibular foramen (n = 60, RS, and n = 40, LS); group MxN receiving maxillary nerve (MxN) anesthesia (n = 56 RS and n = 44 LS) was the control group. Differences between mean EGMt were analyzed with the Wilcoxon test; correlation between type of anesthesia and EGMt was performed with Spearman's rho, all with a level of significance set at p <= 0.05. RESULTS: Significant EGMt (MUA) differences before and after anesthesia were found in all loci with MdN and IAN on the ipsilateral side (p < 0.05), but not with MxN. Anesthesia of the MdN was positively correlated with the increase in EGMt (p < 0.001). Selective anesthesia of IAN was positively correlated only with the increase in EGMt measured at posterior and dorsal loci of the tongue surface (p < 0.01). CONCLUSION: The increase in EGMt following IAN anesthesia suggests a participation of dental afferents in taste perception. CLINICAL RELEVANCE: Extraction of teeth may impair food intake not only due to impaired masticatory ability but also to alteration of neurological trigemino-gustatory interactions. TRIAL REGISTRATION NUMBER: PACTR201602001452260. PMID- 28861747 TI - Correspondence regarding: Post-traumatic headache: the use of the sport concussion assessment tool (SCAT-3) as a predictor of post-concussion recovery. AB - This article consists of a Letter to the Editor regarding Post-traumatic headache: the use of the sport concussion assessment tool (SCAT-3) as a predictor of post-concussion recovery, recently published in The Journal of Headache and Pain, along with a response from the original authors. PMID- 28861748 TI - Physiological and molecular responses of seedlings of an upland rice ('Tung Lu 3') to total submergence compared to those of a submergence-tolerant lowland rice ('FR13A'). AB - BACKGROUND: Understanding the responses of rice to environmental stresses such as unscheduled submergence is of pressing important owing to increasing severity of weather thought to arise from global climate change. When rice is completely submerged, different types adopt either a quiescence survival strategy (i.e., minimal shoot elongation) or an escape strategy (i.e., enhanced shoot elongation). Each strategy can prolong survival depending on the circumstances. While submergence responses have been studied in rice typical of lowland and flood-prone areas, few studies have explored the physiological and molecular properties of upland rice under submergence. Here, we use seedlings of the upland rice 'Tung Lu 3' ('TL3') to analyze physiological and molecular responses to submergence. We compare them with those of 'FR13A', a lowland rice that tolerates submergence by adopting the quiescence strategy. RESULTS: Plant height and distance between leaf sheaths, increased rapidly in 'TL3' under submergence. Although this indicated a strong escape strategy the seedlings remained totally underwater for the duration of the experiments. In contrast, 'FR13A' elongated much less. Consequently, after 4 days complete submergence followed by drainage, 'TL3' lodged much more severely than 'FR13A'. After 10 d complete submergence, 55% of 'TL3' seedlings survived compared to 100% in 'FR13A'. Chlorophyll a, b and total chlorophyll concentrations of the 2nd oldest leaves of 'TL3' were also significantly above those of 'FR13A' (but were lower than 'FR13A' in the 3rd oldest leaves) and less hydrogen peroxide accumulated in 'TL3'. Peroxidase activity in submerged 'TL3' was also greater than in 'FR13A' 1 day after submergence. Quantitative RT-PCR showed increased expression of sucrose synthase 1 and alcohol dehydrogenases 1 after 2 days complete submergence with significantly higher levels in 'TL3' compared to 'FR13A'. Expression was also higher in 'TL3' under non-submerged conditions. CONCLUSIONS: The upland rice line 'TL3' gave a stronger elongation response than 'FR13A' to complete submergence. This escape strategy is widely considered to prejudice survival when the plant remains totally submerged. However, contrary to expectations, 'TL3' survival rates were substantial although below those for 'FR13A' while physiological, biochemical and molecular parameters linked to adaptation differed in detail but appeared to be broadly comparable. These findings highlight that submergence tolerance is determine not only by the adoption of quiescence or escape strategies but maybe by metabolic and physiological properties unrelated to the underwater elongation rate. PMID- 28861749 TI - Taking the hassle out of wellness: Do peers and health matter? AB - Despite substantial financial incentives provided by the Affordable Care Act and employers, employee enrollment in wellness programs is low. This paper studies enrollment in a wellness program offered along an employer-provided health insurance plan. Two factors are considered in the choice of health plan with wellness: the effect of peer choices and family health on plan choice. Using exclusively obtained data of health insurance plan choice and utilization, this paper compares similar plans and focuses on a subsample of new employees. Result show that peers affect own choice of health insurance: a 10 percentage point rise in the share of colleagues enrolled in Aetna Wellness increases the probability of own enrollment in the plan by up to 3.9 percentage points. This result suggests that lack of experience with a wellness program are key to employee reluctance to enroll. Health effect on probability of enrollment in Aetna Wellness ranges from a 3 percentage point decline to a 3 percentage point rise depending on the measure, suggesting that while wellness programs appeal to low- to medium-intensity users of medical services, they do not appeal to individuals with more severe medical conditions which might benefit most from better coordinated medical care. PMID- 28861750 TI - Isolation, purification and characterization of a pH tolerant and temperature stable proteinaceous protease inhibitor from marine Pseudomonas mendocina. AB - OBJECTIVES: An extracellular protease inhibitor (BTPI-301) of trypsin was purified and characterized from an isolate of Pseudomonas mendocina. RESULTS: BTPI-301was purified to homogeneity by (NH4)2SO4, precipitation, DEAE Sepharose and CNBr-activated Sepharose chromatography. Homogeneity was proved by native PAGE and SDS-PAGE. The intact molecular mass was 11567 Da by MALDI-TOF analysis. BTPI-301was a competitive inhibitor with a Ki of 3.5 * 10-10 M. It was stable and active at pH 4-12 and also at 4-90 degrees C for 1 h. Peptide mass fingerprinting by MALDI revealed that the BTPI-301 is a new inhibitor not reported so far with protease inhibitory activity. The pI of the inhibitor was 3.8. The stoichiometry of trypsin-BTPI-301 interaction is 1:1. The inhibitor was specific towards trypsin. CONCLUSION: A pH tolerant and thermostable protease inhibitor BTPI-301 active against trypsin was purified and characterized from P. mendocina that could be developed and used as biopreservative as well as biocontrol agent. PMID- 28861751 TI - Bias and ignorance in demographic perception. AB - When it comes to knowledge of demographic facts, misinformation appears to be the norm. Americans massively overestimate the proportions of their fellow citizens who are immigrants, Muslim, LGBTQ, and Latino, but underestimate those who are White or Christian. Previous explanations of these estimation errors have invoked topic-specific mechanisms such as xenophobia or media bias. We reconsidered this pattern of errors in the light of more than 30 years of research on the psychological processes involved in proportion estimation and decision-making under uncertainty. In two publicly available datasets featuring demographic estimates from 14 countries, we found that proportion estimates of national demographics correspond closely to what is found in laboratory studies of quantitative estimates more generally. Biases in demographic estimation, therefore, are part of a very general pattern of human psychology-independent of the particular topic or demographic under consideration-that explains most of the error in estimates of the size of politically salient populations. By situating demographic estimates within a broader understanding of general quantity estimation, these results demand reevaluation of both topic-specific misinformation about demographic facts and topic-specific explanations of demographic ignorance, such as media bias and xenophobia. PMID- 28861752 TI - Ground reaction forces during walking with different load and slope combinations in rats. AB - BACKGROUND: Treadmill animal models are commonly used to study effects of exercise on bone. Since mechanical loading induces bone strain, resulting in bone formation, exercise that induces higher strains is likely to cause more bone formation. Our aim was to investigate the effect of slope and additional load on limb bone strain. METHODS: Horizontal and vertical ground reaction forces on left fore-limb (FL) and hind-limb (HL) of twenty 23-week old female Wistar rats (weight 279 +/- 26 g) were measured for six combinations of SLOPE (-10 degrees , 0 degrees , +10 degrees ) and LOAD (0 to 23% of body mass). Peak force (Fmax), rate of force rise (RC), stance time (Tstance) and impulse (Fint) on FLs and HLs were analyzed. RESULTS: For the FL, peak ground reaction forces and rate of force rise were highest when walking downward -10 degrees with load (Fmax = 2.09+/ 0.05 N, FLRC = 34+/-2 N/s) For the HL, ground reaction forces and rate of force rise were highest when walking upward +10 degrees , without load (Fmax = 2.20+/ 0.05 N, HLRC = 34+/-1 N/s). Load increased stance time. Without additional load, estimates for the highest FL loading (slope is -10 degrees ) were larger than for the highest HL loading (slope is +10 degrees ) relative to level walking. CONCLUSIONS: Thus, walking downward has a higher impact on FL bones, while walking upward is a more optimal HL exercise. Additional load may have a small effect on FL loading. PMID- 28861755 TI - Clarithromycin decreases rhinovirus replication and cytokine production in nasal epithelial cells from subjects with bronchial asthma: effects on IL-6, IL-8 and IL-33. AB - Rhinoviral infection is associated with an increased risk of asthma attacks. The macrolide clarithromycin decreases cytokine production in nasopharyngeal aspirates from patients with wheezing, but the effects of macrolides on cytokine production in nasal epithelial cells obtained from asthmatic subjects remain unclear. Here, human nasal epithelial cells were infected with type-14 rhinovirus (RV14), a major RV group. Titers and RNA of RV14 and cytokine concentrations, including IL-1beta and IL-6, were higher in the supernatants of the cells obtained from subjects with bronchial asthma (asthmatic group) than in those from the non-asthmatic group. Pretreatment with clarithromycin decreased RV14 titers, viral RNA and cytokine concentrations, and susceptibility to RV14 infection. Pretreatment with clarithromycin also decreased IL-33 production, which was detected after infection. Pretreatment with clarithromycin decreased the expression of intercellular adhesion molecule-1, the receptor for RV14, after infection, the number and fluorescence intensity of the acidic endosomes through which RV RNA enters the cytoplasm, and the activation of nuclear factor kappa-B proteins in nuclear extracts. These findings suggested that RV replication and cytokine production may be enhanced in nasal epithelial cells obtained from subjects with bronchial asthma and may be modulated by clarithromycin. PMID- 28861753 TI - Healthy lifestyle impact on breast cancer-specific and all-cause mortality. AB - PURPOSE: While several studies have evaluated the association of combined lifestyle factors on breast cancer-specific mortality, few have included Hispanic women. We constructed a "healthy behavior index" (HBI) and evaluated its associations with mortality in non-Hispanic White (NHW) and Hispanic women diagnosed with breast cancer from the southwestern U.S. METHODS: Diet and lifestyle questionnaires were analyzed for 837 women diagnosed with invasive breast cancer (1999-2004) in New Mexico as part of the 4-Corners Women's Health Study. An HBI score ranging from 0 to 12 was based on dietary pattern, physical activity, smoking, alcohol consumption, and body size and shape, with increasing scores representing less healthy characteristics. Hazard ratios for mortality over 14 years of follow-up were estimated for HBI quartiles using Cox proportional hazards models adjusting for education and stratified by ethnicity and stage at diagnosis. RESULTS: A significant increasing trend was observed across HBI quartiles among all women, NHW women, and those diagnosed with localized or regional/distant stage of disease for all-cause (AC) mortality (p trend = 0.006, 0.002, 0.03, respectively). AC mortality was increased >2-fold for all women and NHW women in HBI Q4 versus Q1 (HR = 2.18, 2.65, respectively). The association was stronger in women with regional/distant than localized stage of disease (HR = 2.62, 1.94, respectively). Associations for Hispanics or breast cancer-specific mortality were not significant. CONCLUSIONS: These findings indicate the associations between the HBI and AC mortality, which appear to differ by ethnicity and stage at diagnosis. Interventions for breast cancer survivors should address the combination of lifestyle factors on prognosis. PMID- 28861754 TI - Estrogen Receptor beta Mediated Neuroprotective Efficacy of Cicer microphyllum Seed Extract in Global Hypoxia. AB - Hypoxia induced oxidative stress and neurodegeneration in the hippocampus has been implicated for memory impairment in conditions like stroke, ischemia and hypobaric hypoxia. The present study, aimed at investigating the potential of ethanolic extract of Cicer microphyllum seeds (CSE) for amelioration of global hypoxia induced neurodegeneration in CA1 region of hippocampus. CSE supplementation considerably reduced neurodegeneration and dendritic atrophy in CA1 neurons along with improvement of memory in hypoxic rats. This effect of CSE was partly attributed to its antioxidant activity resulting in reduction of lipid peroxidation, protein oxidation and DNA damage during exposure to chronic hypoxia. CSE also promoted dendritic arborization through activation of estrogen receptor beta (ERbeta) and phosphorylation of extracellular signal regulated kinase (ERK1/2) which was independent of brain derived neurotrophic factor (BDNF) mediated signalling mechanisms. Extra nuclear activation of ERK1/2 by ERbeta resulted in phosphorylation of cyclic AMP response element binding protein (CREB) leading to increased expression of PSD-95.These molecular alterations translated to behavioural changes in CSE administered hypoxic animals that performed better in Morris Water Maze Task as compared to vehicle treated hypoxic animals. Toxicological studies show NOEAL > 2000 mg/kg b.w. for oral administration of CSE indicating its safety for consumption. Our findings not only suggest the neuroprotective potential of CSE in hypoxia but also provide evidence for involvement of estrogen receptor and pCREB mediated nootropic effect of the extract. PMID- 28861756 TI - Management of Supraventricular Tachycardia in Infants. AB - Supraventricular tachycardia is the most common tachyarrhythmia encountered in infants. In older children and adults, definitive treatment of the supraventricular tachycardia substrate with catheter ablation is a common approach to management. However, in infants, the risks of catheter ablation are significantly higher, and the patients often outgrow the potential to experience episodes. Therefore, antiarrhythmic medications are often utilized to minimize the likelihood of experiencing episodes. This article reviews the common arrhythmia mechanisms encountered in infants and the medications used to treat these patients. PMID- 28861758 TI - Venous thromboembolism prophylaxis for ambulatory cancer patients, can we do better? AB - Patients with cancer are at a much higher risk of thromboembolic events. Such events are occasionally associated with significant complications that can negatively affect patients' quality of life. Thromboprophylaxis is widely practiced, but much of the emphasis is given for those admitted with acute medical illnesses or following major surgical procedures. However, a significant percentage of thrombotic events encountered in routine clinical practice are among ambulatory patients where current guidelines do not recommend routine thromboprophylaxis. PMID- 28861757 TI - Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer's Disease. AB - Alzheimer's disease (AD) is one of the leading causes for disability and death affecting millions of people worldwide. Thus, novel therapeutic strategies are needed to reduce brain pathology associated with AD. In view of increasing awareness regarding involvement of histaminergic pathways in AD, we explored the role of one H3 receptor inverse agonist BF 2649 and one selective H3 receptor antagonist with partial H4 agonist activity in amyloid beta peptide (AbetaP) infusion-induced brain pathology in a rat model. AD-like pathology was produced by administering AbetaP (1-40) intracerebroventricular (i.c.v.) in the left lateral ventricle (250 ng/10 MUl, once daily) for 4 weeks. Control rats received saline. In separate group of rats, either BF 2649 (1 mg/kg, i.p.) or clobenpropit (1 mg/kg, i.p.) was administered once daily for 1 week after 3 weeks of AbetaP administration. After 30 days, blood-brain barrier (BBB) breakdown, edema formation, neuronal, glial injuries, and AbetaP deposits were examined in the brain. A significant reduction in AbetaP deposits along with marked reduction in neuronal or glial reactions was seen in the drug-treated group. The BBB breakdown to Evans blue albumin and radioiodine in the cortex, hippocampus, hypothalamus, and cerebellum was also significantly reduced in these drug-treated groups. Clobenpropit showed superior effects than the BF2649 in reducing brain pathology in AD. Taken together, our observations are the first to show that blockade of H3 and stimulation of H4 receptors are beneficial for the treatment of AD pathology, not reported earlier. PMID- 28861760 TI - Non-small cell lung cancer: miR-30d suppresses tumor invasion and migration by directly targeting NFIB. AB - OBJECTIVE: To evaluate the role and the molecular mechanism of miR-30d in non small cell lung cancer (NSCLC). RESULTS: qRT-PCR was used to detect miR-30d expression in NSCLC tissues and cell lines. miR-30d was frequently down-regulated in NSCLC and its expression was associated with clinicopathological features of NSCLCC patients. Over-expression of miR-30d notably inhibited cell migration and invasion in NSCLC cell lines. miR-30d could negatively regulate Nuclear factor I B (NFIB) by directly targeting its 3'-UTR, which was confirmed by luciferase assay. NFIB also reversed miR-30d-mediated suppression on the migration and invasion in NSCLC cell lines. CONCLUSION: miR-30d suppressed cell migration and invasion by directly targeting NFIB in NSCLC, and NFIB could partially abrogated the inhibition of biological functions by miR-30d. PMID- 28861759 TI - Diffusion, outcomes and implementation of minimally invasive liver surgery: a snapshot from the I Go MILS (Italian Group of Minimally Invasive Liver Surgery) Registry. AB - The Italian Group of MILS (I Go MILS) prospective registry was established in 2014 with the goals to create a hub for data and projects on a national basis and to promote the diffusion and implementation of MILS programs on a national scale. The primary endpoint of the present study is to give a snapshot of the real diffusion and outcomes of MILS in Italy, while analyzing the role of the registry in the implementation of MILS programs nationwide. The I Go MILS Registry is a prospective and intention-to-treat registry opened to any Italian center performing MILS, without restriction criteria based on number of procedures. The Registry is developed through the eClinical, an electronic platform for the management of clinical trials and is based on 34 clinical variables, regarding indication, intra- and postoperative course. Clinical outcomes and data regarding implementation of MILS activity have been analyzed for the aim of the study. Between November 2014 and June 2017, data from 1678 MILS performed in 48 centers have been collected (mean number of procedures per center 35, range 1-302). 22% of procedures were performed for benign and 78% for malignant disease (HCC constituted the 49.1% and CRLM the 31.2% of malignant tumors). Major liver resections (>3 liver segments), including right and left hepatectomies, trisectionectomies and ALPPS procedures were 10% of the series. Mean blood loss was 200 +/- 230 mL Morbidity rate was 20.5% and mortality was 0.3%. 10.4% of cases were converted to open approach. Median length of stay was 5 days. MILS/total resections ratio in 13 experienced centers increased from 14 to 30% after Registry establishment. MILS programs are well established in Italy, with progressive increase both in the number of cases and in the numerosity of centers. The I Go MILS Registry is playing a crucial role in monitoring the development of MILS in the real world on a national basis while giving a significant contribution to the implementation of MILS programs. PMID- 28861761 TI - Tobacco smoking and breast cancer: a life course approach. PMID- 28861762 TI - Stillness (in 5 minutes). PMID- 28861763 TI - Prediction of vulnerability to bipolar disorder using multivariate neurocognitive patterns: a pilot study. AB - Bipolar disorder (BD) is a common disorder with high reoccurrence rate in general population. It is critical to have objective biomarkers to identify BD patients at an individual level. Neurocognitive signatures including affective Go/No-go task and Cambridge Gambling task showed the potential to distinguish BD patients from health controls as well as identify individual siblings of BD patients. Moreover, these neurocognitive signatures showed the ability to be replicated at two independent cohorts which indicates the possibility for generalization. Future studies will examine the possibility of combining neurocognitive data with other biological data to develop more accurate signatures. PMID- 28861764 TI - Oil refinery wastewater treatment in the Niger Delta, Nigeria: current practices, challenges, and recommendations. AB - The extensive oil exploration has led to a series of environmental issues in the Niger Delta, Nigeria, over the years. Aside from oil spill, insufficient wastewater treatment of oil refineries and the discharged effluents become another potential source of pollution that has not received enough attention from the government and the public. Through reviewing the current oil refinery wastewater treatment processes and the discharge standards of wastewater effluents in Nigeria, we aimed to raise the awareness of the shortcomings of the current wastewater treatment technology and to discuss the consequences of insufficient treatment to the environment. This article further discussed the use of nanotechnology as a potential upgrade to the conventional treatment technologies as it has shown its capacity of removing persistent organic pollutants (POPs) or converting hazardous components to environmentally friendly derivatives. It should also prove beneficial to the key stakeholders involved in the exploration of crude oil in the region to consider optimization of oil refinery wastewater treatment processes through integration of emerging technologies. PMID- 28861766 TI - In Vitro Probiotic Properties of Lactobacillus salivarius MG242 Isolated from Human Vagina. AB - Vulvovaginal candidiasis (VVC) is a very common infection worldwide that is mainly caused by Candida albicans. In a previous study, we showed that Lactobacillus salivarius MG242 has anti-Gardnerella vaginalis activity. In this study, we investigated the potential of using L. salivarius MG242 for biocontrol of C. albicans. In line with the results from a spot overlay assay, MG242 inhibited the growth of C. albicans by 99.99 +/- 0.01% in co-culture, suggesting that L. salivarius MG242 has the potential to be developed into a probiotic formula to treat or prevent VVC. Accelerated storage tests using dehydrated live cell powder at 50, 60, and 70 degrees C were performed, and the results showed that immobilization with 10% skim milk effectively increased the thermal resistance of entrapped microorganisms, resulting in sevenfold longer shelf-life than the control (in PBS). Lower storage temperatures also increased the shelf life up to 8.31 months. PMID- 28861765 TI - Multifunctional decoration of alpha-tocopheryl succinate-based NP for cancer treatment: effect of TPP and LTVSPWY peptide. AB - Active targeting not only of a specific cell but also a specific organelle maximizes the therapeutic activity minimizing adverse side effects in healthy tissues. The present work describes the synthesis, characterization, and in vitro biological activity of active targeting nanoparticles (NP) for cancer therapy based on alpha-tocopheryl succinate (alpha-TOS), a well-known mitocan, that selectively induces apoptosis of cancer cells and proliferalting endothelial cells. Human epidermal growth factor receptor 2 (HER2) targeting peptide LTVSPWY (PEP) and triphenylphosphonium lipophilic cation (TPP) were conjugated to a previously optimized RAFT block copolymer that formed self-assembled NP of appropriate size for this application and low polydispersity by self-organized precipitation method. PEP and TPP were included in order to target not only HER2 positive cancer cells, but also the mitochondria of these cancer cells, respectively. The in vitro experiments demonstrated the faster incorporation of the active-targeting NP and the higher accumulation of TPP-bearing NP in the mitochondria of MDA-MB-453 HER2 positive cancer cells compared to non-decorated NP. Moreover, the encapsulation of additional alpha-TOS in the hydrophobic core of the NP was achieved with high efficiencies. The loaded NP presented higher cytotoxicity than unloaded NP but preserved their selectivity against cancer cells in a range of tested concentrations. PMID- 28861767 TI - Placental growth factor signaling regulates isoform splicing of vascular endothelial growth factor A in the control of lung cancer cell metastasis. AB - Vascular endothelial growth factor (VEGF) family members play critical and complex roles in the regulation of cancer vascularization and metastasis. The exact molecular control of lung cancer metastasis by VEGF family members is not completely understood. Here, we showed that specimens from non-small cell lung cancer (NSCLC) contained significantly higher levels of placental growth factor (PlGF) than paired non-cancer tissue (p < 0.05, N = 25). Moreover, higher levels of PlGF were detected in NSCLC specimens from the patients who had distal metastases than those who had not. High-PlGF levels appeared to be associated with poor patient survival. In vitro, PlGF dose-dependently increased the ratio of pro-angiogenic VEGF isoform (VEGF165) versus anti-angiogenic VEGF isoform (VEGF165b), seemingly through induction of expression of splicing regulatory factor SRp40, resulting in the enhancement of the cancer cell metastatic potential. Higher levels of SRp40 were detected in NSCLC specimens, compared to paired non-cancer tissue (p < 0.05, N = 25). Finally, a strong correlation was detected between the levels of PlGF and SRp40 in NSCLC specimens (r = 0.83, p < 0.0001, N = 25). Together, these data suggest that PlGF may increase NSCLC metastasis through SRp40-mediated mRNA splicing of VEGF. PMID- 28861768 TI - Capsaicin Protects Against Oxidative Insults and Alleviates Behavioral Deficits in Rats with 6-OHDA-Induced Parkinson's Disease via Activation of TRPV1. AB - Increasing evidence suggests that capsaicin may play a role in modulating neuronal function and controlling motor behavior. However, the underlying mechanism is still unclear and the activation of transient receptor potential vanilloid 1 (TRPV1) might be involved in. This study investigated the potential neuroprotective role of capsaicin in a rat model of 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD). Capsaicin was treated intraperitoneally for the 6-OHDA induced PD rats and the locomotor activity and abnormal involuntary movements were found alleviated. Besides, brain oxidative stress (lipid peroxidation, superoxide dismutase and catalase) was also assessed, and oxidative insults were investigated relieved. Both the expression of tyrosine hydroxylase and TRPV1 were increased in the striatal and substantia nigra areas of 6-OHDA induced rats after the treatment of capsaicin by the semi-quantitative analysis of Western Blot. And the immunostaining of substantia nigra further suggested that capsaicin might protect against dopaminergic neuronal loss. Our results showed that TRPV1 might be a novel therapeutic target for PD. PMID- 28861769 TI - Erratum to: Obstetric antiphospholipid syndrome and long term arterial thrombosis risk. PMID- 28861770 TI - Economic Considerations in the Use of Novel Targeted Therapies for Lung Cancer: Review of Current Literature. AB - Lung cancer remains the leading cause of cancer-related death and economic burden worldwide. Despite the heavy toll of lung cancer, multiple new advances have improved patient outcomes, largely through precision medicine and targeted therapy. The associated rising economic burden however may impact the uptake of novel therapeutic agents in lung cancer, thereby limiting patient access. This article identifies and reviews economic evaluations of targeted agents in lung cancer in the era of precision medicine. Articles evaluating biomarker-directed test-and-treat strategies are also reviewed to evaluate the cost impact of novel therapeutic agents at a population level. The Quality of Health Economic Studies instrument is applied to assess the quality of included studies. Forty-six studies are reviewed and encompass studies of epidermal growth factor receptor inhibitors and monoclonal antibodies, anaplastic lymphoma kinase inhibitors, vascular endothelial growth factor and vascular endothelial growth factor receptor inhibitors and immunotherapy (programmed death-1 inhibitors). Key factors influencing results of economic analyses include comparators chosen, perspective used, magnitude of clinical benefit, utility weighting of outcomes and drug acquisition costs. Biomarker-driven decision making should be integrated into cost evaluations given the important role of molecular testing for individualising treatment for non-small-cell lung cancer. We conclude that despite major clinical advances in lung cancer therapeutics, cost remains an important consideration in the adoption of novel therapies. PMID- 28861771 TI - Recombinant rabies virus expressing IL-15 enhances immunogenicity through promoting the activation of dendritic cells in mice. AB - Rabies remains a public health threat that kills approximately 59,000 people worldwide each year, most of which are from the developing countries of Africa and Asia where dog rabies are endemic. Therefore, developing an affordable and efficacious vaccine is crucial for rabies control in these countries. Interleukin (IL)-15, an immunoregulatory cytokine, is a pluripotent molecule with therapeutic potential, which targets many cell types and links the innate and adaptive immune system. In this study, IL-15 gene was cloned and inserted into the genome of a recombinant rabies virus (RABV) strain LBNSE (designated as LBNSE-IL15), and the effect of over-expression of IL-15 on the immunogenicity of RABV was investigated. It was found that mice vaccinated with LBNSE-IL15 could induce significantly higher level of virus-neutralizing antibody (VNA) than those immunized with LBNSE, resulting in the higher protection after challenge. Further investigation was performed to find out the possible role of IL-15 plays in the process of antibody induction, and it was found that LBNSE-IL15 could enhance the maturation of dendritic cells (DCs) in immunized mice. Furthermore, the mice immunized with LBNSE-IL15 could promote the TFH cells differentiation and the generation of germinal center B cells and plasma cells. Together, these data indicated that IL-15 could be a potential adjuvant in enhancing the immunogenicity of RABV, contributing to the development of more-efficacious rabies vaccines. PMID- 28861772 TI - Oral Health May Affect the Performance of mRNA-Based Saliva Biomarkers for Oral Squamous Cell Cancer. AB - Oral squamous cell carcinoma (OSCC) has a dismal 50% five-year survival rate, emphasizing the need to develop reliable and sensitive tools for early diagnosis. In this study we evaluated the performance of 7 previously identified, potential mRNA biomarkers of OSCC in saliva samples of Hungarian patients. Expression of the putative OSCC biomarkers (DUSP1, OAZ1, H3F3A, IL1B, IL8, SAT and S100P), 2 biomarkers of inflammation (IL6 and TNFalpha) and 8 putative normalizing genes was quantified from each sample using real-time quantitative PCR. In contrast with previous studies, the expression pattern of the 7 mRNA biomarkers was similar between OSCC patients and age-matched control patients in the Hungarian patient population. On the other hand, 5 of the 7 mRNA biomarkers were present at significantly higher levels in saliva samples of OSCC patients when compared to young control patients. The best biomarker combination could distinguish only the OSCC vs. young control patients, but not the OSCC vs. age-matched control patients. In conclusion, the significant differences between our results and previous studies, and the clinical characteristics of the patients suggest that inflammatory processes in the oral cavity may affect the performance of the 7 putative salivary mRNA biomarkers. Lastly, since IL6 mRNA was quantifiable in the majority of OSCC cases, but only in a few control samples, salivary IL6 mRNA may be utilized as part of a biomarker combination to detect OSCC. PMID- 28861773 TI - Biodegradation of pulp and paper mill effluent by co-culturing ascomycetous fungi in repeated batch process. AB - The competence of novel fungal consortium, consisting of Nigrospora sp. LDF00204 (accession no. KP732542) and Curvularia lunata LDF21 (accession no. KU664593), was investigated for the treatment of pulp and paper mill effluent. Fungal consortium exhibited enhanced biomass production under optimized medium conditions, i.e., glucose as carbon (C), sodium nitrate as nitrogen (N), C/N 1.5:0.5, pH 5, temperature 30 degrees C, and agitation 140 rpm, and significantly reduced biochemical oxygen demand (85.6%), chemical oxygen demand (80%), color (82.3%), and lignin concentration (76.1%) under catalytic enzyme activity; however, unutilized ligninolytic enzymes, such as laccase (Lac), manganese peroxidase (MnP), and lignin peroxidase (LiP), were observed to be 13.5, 11.4, and 9.4 U/ml after the third cycle of effluent treatment in repeated batch process. Scanning electron microscopy (SEM) of fungal consortium revealed their compatibility through intermingled hyphae and spores, while the FTIR spectra confirmed the alteration of functional groups ensuring structural changes during the effluent treatment. Gas chromatography/mass spectroscopy (GC-MS) analysis showed the reduction of complex compounds and development of numerous low-molecular-weight metabolites, such as 1-3-dimethyl benzene, 2-chloro-3-methyl butane, pentadecanoic acid, and 1-2-benzene dicarboxylic acid, during the treatment, demonstrating the massive potential of the novel fungal consortium to degrade recalcitrant industrial pollutants. PMID- 28861775 TI - Elastic and dielectric properties of ferroelectric nanoparticles/bent-core nematic liquid crystal blend. AB - Bent-core liquid crystals present the first evidence of forming polar superstructures from achiral molecules. The nematic phase is the newest member of the bent-core family and turns out to be extremely interesting owing to its distinct features compared to its calamitic counterpart. Here the investigation of one achiral unsymmetrical 2-methyl-3-amino-benzoic acid (2,6-substituted toluene)-derived four-ring bent-core nematic (BCN) liquid crystals (11-2M-F) is presented after nanodispersion. Ferroelectric nanoparticles significantly affect the phase transition temperature, threshold voltage, dielectric permittivity, elastic constants and splay viscosity of the pristine BCN. In most bent-core nematic liquid crystals the bent elastic constant (K33) is usually lower than the splay elastic constant (K11) owing to the presence of short-range smectic-C-like correlations in the nematic phase. Thus the elastic anisotropy ([Formula: see text]) is usually negative in bent-core nematics unlike in rod-like nematic liquid crystals where K33 is always greater than K11. Here we report a short-core bent-shaped nematic liquid crystal whose negative elastic anisotropy was turned to positive by minute addition of ferroelectric nanoparticles. PMID- 28861774 TI - Doxycycline Used for Control of Transgene Expression has its Own Effects on Behaviors and Bcl-xL in the Rat Hippocampus. AB - Doxycycline (Dox)-inducible transgenic approach is used to examine the neural mechanisms of anxiety and depression; however, its own effects on related behaviors are not clear. To address this, in the present study, we tested the anxiety- and depression-like behaviors in rats treated with Dox in drinking water (2 mg/ml) in the elevated plus-maze (EPM; on day 5) and forced swim (FST; on day 8) tests, respectively. In addition, the levels of mRNAs and proteins of brain derived neurotrophic factor (BDNF) and anti-apoptotic protein Bcl-xL in the hippocampus (HIPP) and frontal cortex (FC) were also analyzed. Consumption of Dox for 4 days induced an anxiogenic-like phenotype that was manifested by the decreased percentages of open arm entries and time spent on the open arms of the EPM. After Dox for 7 days, animals demonstrated more active behavior in the FST than control rats as evidenced by the increase in climbing time. When assessed after the FST, expression of Bcl-xL was increased in the hippocampus of Dox treated animals. Furthermore, hippocampal Bcl-xL content correlated positively with the duration of climbing in the test. This study is the first to find that Dox in treatment regime used to control transgene expression can affect anxiety- and depression-like behaviors in rats. Dox-induced increase in Bcl-xL expression in the hippocampus may be involved in the moderate activation of FST behavior. PMID- 28861776 TI - Gamma irradiation-induced decomposition of sulfamethoxazole in aqueous solution: the influence of additives, biological inhibitory, and degradation mechanisms. AB - Sulfamethoxazole (SMX) was decomposed by using gamma irradiation in the presence of different additives such as NO3-, NO2-, Cr(VI), 2-propanol, and tert-butanol. The results demonstrated that NO3-, NO2-, 2-propanol, and tert-butanol inhibited SMX radiolytic removal. However, there existed a synergetic effect for radiolytic removal of the mixture containing SMX and Cr(VI). At an absorbed dose of 150 Gy, the removal percentages of SMX and Cr(VI) in the mixture were 73.5 and 84.6%, respectively, which was higher than the removal percentages of 70.6 and 4.1% for the single component of SMX and Cr(VI). This provides us an insight into treating the combined pollution in micro-polluted water. The SMX radiolytic removal followed a pseudo first-order reaction kinetic model, and the rate constant ratios of .OH, eaq-, and H. towards SMX radiolysis were 10.4:1:2.9. In addition, 24-h bio-inhibitory to the macroalgae of SMX solution during gamma irradiation reached the maximum of 0.85 at an adsorbed dose of 100 Gy, then gradually decreased with the increasing adsorbed dose. Based on LC-MS analysis and quantum chemical calculation, the degradation intermediates were determined and concluded that SMX radiolytic removal was mainly via .OH radical attack and direct decomposition of SMX molecule by gamma ray. PMID- 28861777 TI - Benign esophageal schwannoma: a brief overview and our experience with this rare tumor. AB - BACKGROUND: Benign esophageal tumors are uncommon, comprising approximately 2% of esophageal tumors. Esophageal schwannomas constitute an even rarer entity, with few cases reported in the literature. CASE PRESENTATION: We present a 66-year-old male who was referred for dysphagia. A computed tomography scan showed a well demarcated, enhancing, and homogenous esophageal tumor measuring 50 mm. The tumor was hypermetabolic on positron emission tomography, and an endoscopic ultrasound guided fine needle aspiration demonstrated the presence of benign spindle cells. We performed an uncomplicated, simple, tumor enucleation through a cervical approach. Histology revealed spindle-shaped cells in a fasciculated, disarrayed pattern. Immunohistochemistry demonstrated positive staining for S-100 protein and negative staining for KIT, CD34, desmin, and alpha-smooth muscle actin. These findings were consistent with a benign esophageal schwannoma. CONCLUSIONS: We report our experience with esophageal schwannoma, a rare but benign diagnosis of the esophagus. PMID- 28861778 TI - Purification and Fibrillation of Full-Length Recombinant PrP. AB - Misfolding and aggregation of prion protein are related to several neurodegenerative diseases in humans such as Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Straussler-Scheinker disease. A growing number of applications in the prion field including assays for detection of PrPSc and methods for production of PrPSc de novo require recombinant prion protein (PrP) of high purity and quality. Here, we report an experimental procedure for expression and purification of full-length mammalian prion protein. This protocol has been proved to yield PrP of extremely high purity that lacks PrP adducts, oxidative modifications, or truncation, which is typically generated as a result of spontaneous oxidation or degradation. We also describe methods for preparation of amyloid fibrils from recombinant PrP in vitro. Recombinant PrP fibrils can be used as a noninfectious synthetic surrogate of PrPSc for development of prion diagnostics including generation of PrPSc-specific antibody. PMID- 28861779 TI - Method for Folding of Recombinant Prion Protein to Soluble beta-Sheet Secondary Structure. AB - A key event in the pathogenesis of prion diseases is the change in structure of the normal cellular form of the prion protein from a predominantly alpha-helix form to the beta-sheet-rich prion protein found in disease-associated tissue. To allow more detailed structural research into PrP misfolding, it is necessary to have techniques which enable enrichment of the beta-sheet content in recombinant PrP.This method describes the procedure for inducing beta-folding of recombinant PrP to resemble a disease-associated structure and ultimately produce soluble beta-folded recombinant PrP. PMID- 28861780 TI - Analysis of Prion Protein Conformation Using Circular Dichroism Spectroscopy. AB - According to the protein-only hypothesis of prion propagation, the pathogenesis of prion disease is due to the misfolding of cellular PrP (PrPC) which gives rise to disease-associated PrPSc. This misfolding results in the predominantly alpha helix secondary structure of PrP becoming increasingly beta-sheet. Prion protein researchers often employ circular dichroism (CD) spectroscopy to rapidly analyze and identify the degree of alpha-helix and beta-sheet content in their recombinant protein and peptide samples. CD is a nondestructive method of determining protein secondary structure and can be used to monitor the protein structural changes in various environments, e.g., pH and temperature. CD can also be used to investigate kinetic and thermodynamic characteristics of proteins and peptides. PMID- 28861781 TI - Analysis of Prion Protein Structure Using Nuclear Magnetic Resonance Spectroscopy. AB - Nuclear magnetic resonance (NMR) spectroscopy is a powerful experimental tool for obtaining information on three-dimensional (3D) structures of proteins at atomic resolution. In inherited forms of prion diseases, misfolding of cellular prion protein, PrPC, into its pathological form, PrPSc, is caused by mutations in the human prion protein gene (PRNP). Understanding of the earliest stages of the conformational changes leading to spontaneous generation of prions in inherited forms of prion diseases may benefit from detailed structural analysis of different human (Hu) PrP variants. Here, we describe the protocol for structure determination of HuPrP variants by NMR spectroscopy in solution that consists of preparation of NMR samples, acquisition of NMR data, NMR resonance assignments, and structure calculation. PMID- 28861782 TI - Immunodetection of PrPSc Using Western Immunoblotting Techniques. AB - Western immunoblotting is a workhorse technique used in the prion field to analyze disease-associated forms of the prion protein, termed PrPSc. The biochemical stability of PrPSc aggregates combined with the increased resistance of prion infectivity to inactivation by various treatments that inactivate most other pathogens complicates the use of Western immunoblotting as a means to characterize PrPSc samples. In this chapter, we describe a method for Western immunoblot analysis of PrPSc with an emphasis on precautions to address the biochemical and biosafety considerations associated with this procedure. PMID- 28861784 TI - Cell Biology Approaches to Studying Prion Diseases. AB - During the course of prion infection, the normally soluble and protease-sensitive mammalian prion protein (PrPC) is refolded into an insoluble, partially protease resistant, and infectious form called PrPSc. The conformational conversion of PrPC to PrPSc is a critical event during prion infection and is essential for the production of prion infectivity. This chapter briefly summarizes the ways in which cell biological approaches have enhanced our understanding of how PrP contributes to different aspects of prion pathogenesis. PMID- 28861783 TI - Analysis of miRNA Signatures in Neurodegenerative Prion Disease. AB - Prion diseases or transmissible spongiform encephalopathies are disorders of the central nervous system that affect both humans and animals. The underlying cause of prion diseases is the formation and propagation of the infectious prion protein. Prion diseases are difficult to diagnose and treat due to a prolonged asymptomatic incubation period prior to the onset of clinical symptoms. MicroRNAs (miRNAs) are small noncoding RNA species and have been identified as potential biomarkers that also function to regulate disease-specific pathways and proteins in several neurodegenerative disorders, including prion diseases. Here we describe the quantitative analysis of miRNA isolated from neuronal cells infected with a strain of mouse-adapted human prions. These methods can also be adapted to the discovery of miRNA biomarkers in extracellular vesicles, tissue, and noninvasive biological fluids. PMID- 28861785 TI - Expression of Heterologous PrP and Prion Propagation in RK13 Cells. AB - Cultured cells are valuable models to study prion infections at the cellular level. Unfortunately, the vast majority of cell lines are resistant to the propagation of prion agents. The rabbit epithelial RK13 cell line is among the few cell lines permissive to prion infection. When genetically engineered to express heterologous PrP proteins, RK13 cells become permissive to several strains of prions from various animal species. Here, we describe the generation of stable RK13 cell clones expressing a heterologous PrP protein in an inducible manner, the establishment and maintenance of chronically infected cultures, and the selection of cell clones suitable for cell-based titration of prions. PMID- 28861786 TI - Generation of Infectious Prions and Detection with the Prion-Infected Cell Assay. AB - Cell lines propagating prions are an efficient and useful means for studying the cellular and molecular mechanisms implicated in prion disease. Utilization of cell-based models has led to the finding that PrPC and PrPSc are released from cells in association with extracellular vesicles known as exosomes. Exosomes have been shown to act as vehicles for infectivity, transferring infectivity between cell lines and providing a mechanism for prion spread between tissues. Here, we describe the methods for generating a prion-propagating cell line with prion infected brain homogenate, cell lysate, conditioned media, and exosomes and also detection of protease-resistant PrP with the prion-infected cell assay. PMID- 28861787 TI - Analysis of Cellular Prion Protein Endoproteolytic Processing. AB - Like numerous proteins of various structural and functional classes, the glycosylphosphatidylinositol (GPI)-anchored cellular prion protein (PrPC) has been recognized to undergo endoproteolytic processing for decades, a phenomenon observed in various cultured cell lines, as well as human and several animal tissue extracts. Despite this, the physiological significance of PrPC proteolytic cleavage has not yet been entirely elucidated. Experimental evidence suggests independent normal biological functions of the full-length and truncated PrPC species, as well as probable links of endoproteolysis to prion disease transmission susceptibility, pathogenesis, and toxicity. The accurate characterization of constitutive PrPC processing, through the method outlined in this chapter, is therefore an important tool in order to investigate the biological relevance of the alternative cleavage events. PMID- 28861788 TI - Cellular Analysis of Adult Neural Stem Cells for Investigating Prion Biology. AB - Traditional primary and secondary cell cultures have been used for the investigation of prion biology and disease for many years. While both types of cultures produce highly valid and immensely valuable results, they also have their limitations; traditional cell lines are often derived from cancers, therefore subject to numerous DNA changes, and primary cultures are labor intensive and expensive to produce requiring sacrifice of many animals. Neural stem cell (NSC) cultures are a relatively new technology to be used for the study of prion biology and disease. While NSCs are subject to their own limitations they are generally cultured ex vivo in environments that artificially force their growth-they also have their own unique advantages. NSCs retain the ability for self-renewal and can therefore be propagated in culture similarly to secondary cultures without genetic manipulation. In addition, NSCs are multipotent; they can be induced to differentiate into mature cells of central nervous system (CNS) linage. The combination of self-renewal and multipotency allows NSCs to be used as a primary cell line over multiple generations saving time, costs, and animal harvests, thus providing a valuable addition to the existing cell culture repertoire used for investigation of prion biology and disease. Furthermore, NSC cultures can be generated from mice of any genotype, either by embryonic harvest or harvest from adult brain, allowing gene expression to be studied without further genetic manipulation. This chapter describes a standard method of culturing adult NSCs and assays for monitoring NSC growth, migration, and differentiation and revisits basic reactive oxygen species detection in the context of NSC cultures. PMID- 28861789 TI - Neurotoxicity of Prion Peptides on Cultured Cerebellar Neurons. AB - Prion neurotoxicity has been modeled in vitro using synthetic peptides derived from the PrPC sequence. The major region of neurotoxicity has been localized to the hydrophobic domain located in the middle of the PrP protein. Neurotoxicity assays are typically performed on cultured mouse cerebellar neurons derived from neonatal pups, and cell viability can be monitored by assays including MTT or MTS, cell death by LDH release, or apoptosis by caspase cleavage assays. These neurotoxicity studies have been useful in identifying cofactors, such as PrPC and metals, as modulators of PrP peptide-mediated neurotoxicity. Given the biosafety issues associated with handling and purifying infectious prions, the use of synthetic peptides, which display a dependence upon PrPC expression for toxicity, as per the PrPSc agent for infectivity, supports the relevance of using these synthetic peptides for understanding PrP-mediated neurotoxicity. PMID- 28861790 TI - Methods of Protein Misfolding Cyclic Amplification. AB - Protein misfolding cyclic amplification (PMCA) amplifies infectious prions in vitro. Over the past decade, PMCA has become an essential tool in prion research. The current chapter describes in detail the PMCA format with beads (PMCAb) and several methods that rely on PMCAb for assessing strain-specific prion amplification rates, for selective amplification of subtypes of PrPSc from a mixture, and a PMCAb approach that can replace animal titration of scrapie material. Development of PMCAb-based methodology is important for addressing a number of research topics including prion strain evolution, selection and adaptation, strain-typing, prion detection, and biochemical requirements for prion replication. PMID- 28861791 TI - RT-QuIC Assays for Prion Disease Detection and Diagnostics. AB - In coping with prion diseases, it is important to have tests that are practical enough for routine applications in medicine, agriculture, wildlife biology, and research, yet sensitive enough to detect minimal amounts of infectivity. Real time quaking-induced conversion (RT-QuIC) assays have evolved to the point where they fulfill these criteria in applications to various human and animal prion diseases. For example, RT-QuIC assays of cerebrospinal fluid and nasal brushings allow for highly sensitive (77-97%) and specific (99-100%) identification of human sCJD patients. Recent improvements have markedly enhanced sensitivity and reduced the assay time required for many samples to a matter of hours rather than days. By combining analyses of cerebrospinal fluid and nasal brushings, diagnostic sensitivities and specificities of nearly 100% can be achieved. RT QuIC assays are based on prion-seeded amyloid fibril formation by recombinant prion protein (rPrPSen) in multiwell plates using a Thioflavin T fluorescence readout. Here we describe our current RT-QuIC methodologies as well as technical considerations in executing, troubleshooting, and adapting the assay to new strains of prions and sample types. PMID- 28861792 TI - A Quick Method to Evaluate the Effect of the Amino Acid Sequence in the Misfolding Proneness of the Prion Protein. AB - Prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases where the misfolding of the prion protein (PrP) is a crucial event. Based on studies in TSE-affected humans and the generation of transgenic mouse models overexpressing different mutated versions of the PrP, we conclude that both wild-type and mutated PrPs exhibit differential propensity to misfold in vivo. Here, we describe a new method in vitro to assess and quantify the PrP misfolding phenomenon in order to better understand the molecular mechanisms involved in this process. PMID- 28861794 TI - In Vivo-Near Infrared Imaging of Neurodegeneration. AB - In vivo near-infrared (NIR) imaging of molecular processes at the preclinical stage promises to provide more valuable mechanistic information about pathological pathways involved in neurodegeneration. NIR imaging has the potential to improve in vivo therapeutic screening protocols by enabling noninvasive monitoring of presymptomatic responses to treatment. We have developed new NIR fluorescent contrast agents conjugated to markers of cell death, and using these agents we have identified molecular pathways associated with prion-induced neurodegeneration and determined the optimal window for meaningful therapeutic intervention in prion disease. This chapter provides a description of the synthesis and purification of our NIR cell Death (NIRD) contrast agent and the application of in vivo NIRD (iNIRD) imaging to a prion model of neurodegeneration. PMID- 28861795 TI - Strain Typing of Prion Diseases Using In Vivo Mouse Models. AB - Transmissible spongiform encephalopathies (TSE) or prion diseases exhibit strain variation, a phenomenon that has been studied extensively in mouse bioassays. Despite the introduction of many rapid in vitro systems, bioassays remain a key tool in defining prion strains and their ability to transmit disease in vivo. Prion strains can be characterized by a range of phenotypic characteristics such as incubation period, vacuolar pathology, and distribution of the abnormal form of PrP following experimental transmission of the agent into a panel of mice (transgenic or wild type). Interpretation of these characteristics requires considerable experience and an understanding of the procedures used to define them. This chapter reviews the techniques used in strain typing of prion diseases from inoculum preparation and pathological studies to data interpretation alongside an extensive troubleshooting guide. PMID- 28861796 TI - Preparation and Immunostaining of the Myenteric Plexus of Prion-Infected Mice. AB - Intracerebral inoculation of mice with the M1000 strain of mouse-adapted human prions results in the consistent accumulation of PrPSc in the ileum of the gastrointestinal tract (GIT) of mice with clinical signs of prion disease. The accumulation of PrPSc in the ileum is accompanied by caspase activation and loss of immunoreactivity in subpopulations of neurons in the enteric nervous system. This suggests that like neurons in the central nervous system, cells in the enteric nervous system are also susceptible to prion-induced toxicity. In this chapter we describe the immunostaining of cells in myenteric plexus preparations of whole mounts prepared from the gastrointestinal tract of prion-infected mice. PMID- 28861797 TI - Cell Culture Methods for Screening of Prion Therapeutics. AB - It is currently difficult to predict the number of asymptomatic prion carriers who will potentially go on to develop a prion disease or who will unknowingly transmit the prion agent to another individual. As prion therapeutic clinical trials have lacked success, there is a continuous need for novel therapeutics that have the potential to prevent, as for inherited prion disorders; slow, as for all prion disorders; and ultimately stop disease progression. Prion-infected cell models provide an ideal tool to search for new treatment avenues. This chapter describes the use of prion cell culture systems in the identification of prion therapeutics. It also deals with the methods required to validate the potential of an antiprion agent through cell viability and impact on cell growth rate. PMID- 28861793 TI - Insights into Mechanisms of Transmission and Pathogenesis from Transgenic Mouse Models of Prion Diseases. AB - Prions represent a new paradigm of protein-mediated information transfer. In the case of mammals, prions are the cause of fatal, transmissible neurodegenerative diseases, sometimes referred to as transmissible spongiform encephalopathies (TSEs), which frequently occur as epidemics. An increasing body of evidence indicates that the canonical mechanism of conformational corruption of cellular prion protein (PrPC) by the pathogenic isoform (PrPSc) that is the basis of prion formation in TSEs is common to a spectrum of proteins associated with various additional human neurodegenerative disorders, including the more common Alzheimer's and Parkinson's diseases. The peerless infectious properties of TSE prions, and the unparalleled tools for their study, therefore enable elucidation of mechanisms of template-mediated conformational propagation that are generally applicable to these related disease states. Many unresolved issues remain including the exact molecular nature of the prion, the detailed cellular and molecular mechanisms of prion propagation, and the means by which prion diseases can be both genetic and infectious. In addition, we know little about the mechanism by which neurons degenerate during prion diseases. Tied to this, the physiological role of the normal form of the prion protein remains unclear and it is uncertain whether or not loss of this function contributes to prion pathogenesis. The factors governing the transmission of prions between species remain unclear, in particular the means by which prion strains and PrP primary structure interact to affect interspecies prion transmission. Despite all these unknowns, advances in our understanding of prions have occurred because of their transmissibility to experimental animals, and the development of transgenic (Tg) mouse models has done much to further our understanding about various aspects of prion biology. In this review, we will focus on advances in our understanding of prion biology that occurred in the past 8 years since our last review of this topic. PMID- 28861798 TI - Real-Time Quaking-Induced Conversion for Diagnosis of Prion Disease. AB - Sporadic human prion diseases are defined on the basis of clinical features, with periodic sharp discharge (PSD) on electroencephalograms (EEG), a positive 14-3-3 protein assay of CSF samples, and abnormal signals on cerebral cortex on diffusion-weighted (DWI) MR images. It is essential to detect the abnormal prion protein in neuropathological or immunochemical detection of brain tissues when we diagnose definite cases for human prion disease. We performed definite diagnosis of sporadic human prion disease in alive patients. Recently, testing of CSF with a new in vitro abnormal prion protein amplification technology, designated real time quaking-induced conversion (RT-QUIC), has shown considerable promise as a highly specific diagnostic test for human prion disease. PMID- 28861799 TI - Methods for Molecular Diagnosis of Human Prion Disease. AB - Human prion diseases are associated with a range of clinical presentations, and they are classified by both clinicopathological syndrome and etiology, with subclassification according to molecular criteria. Here, we describe updated procedures that are currently used within the MRC Prion Unit at UCL to determine a molecular diagnosis of human prion disease. Sequencing of the PRNP open reading frame to establish the presence of pathogenic mutations is described, together with detailed methods for immunoblot or immunohistochemical determination of the presence of abnormal prion protein in the brain or peripheral tissues. PMID- 28861800 TI - Molecular Subtyping of PrPres in Human Sporadic CJD Brain Tissue. AB - Across the spectrum of sporadic human prion diseases (also known as transmissible spongiform encephalopathies: TSE), there is considerable phenotypic diversity. Cumulative scientific evidence supports that prions, the infectious agents of prion diseases, are constituted predominantly, if not exclusively, by misfolded, typically protease-resistant, disease-associated isoforms of the prion protein (PrPres). Consequently, tissue deposition of PrPres is considered a hallmark of prion disease pathology, and this can be visualized by Western blotting after tissue homogenization and treatment with proteinases, particularly proteinase K (PK). Indeed, Western blot profiles of PrPres are utilized as one marker of different prion strains, with such strains thought to contribute to at least part of the phenotypic variation observed in sporadic human prion disease. Typically, Western blotting of PrPres demonstrates three bands of different electrophoretic mobility, depicting the di-glycosylated, mono-glycosylated and unglycosylated species although further subclassification and the delineation of novel sporadic disease subtypes, such as variably protease-sensitive prionopathy, has contributed greater complexity. Nevertheless, it is the mobility of the unglycosylated PrPres band, the relative abundance of the two glycosylated bands or overall profile of the banding post-PK, in combination with the prion protein gene (PRNP) codon 129 genotype that allows the categorisation of molecular subtypes of sporadic human prion disease. These subtypes appear to correlate with distinct clinico-pathological profiles of sporadic Creutzfeldt-Jakob disease. PMID- 28861801 TI - Intercellular Prion-Like Conversion and Transmission of Cu/Zn Superoxide Dismutase (SOD1) in Cell Culture. AB - The prion hypothesis has extended to the fatal motor neuron disease, amyotrophic lateral sclerosis (ALS), as a means to explain the spatiotemporal spread of pathology from one or more focal points through the neuroaxis. About 20% of inheritable cases of ALS are due to mutation in the gene encoding the Cu/Zn superoxide dismutase (SOD1), causing the protein to misfold and form neurotoxic aggregates. Mutant SOD1 has been shown to impart its misfold onto natively folded wild-type SOD1 in living cells. Furthermore, misfolded wild-type SOD1 can itself induce further rounds of propagated SOD1 misfolding. Finally, this prion-like mechanism of propagated SOD1 misfolding can be transmitted from cell to cell in human cell culture. Here, we describe a protocol for the induction of wild-type SOD1 misfolding inside living cells and its subsequent transmission from cell to cell in a prion-like fashion. PMID- 28861802 TI - Distinct Recurrence Risk Factors for Intrahepatic Metastasis and Multicenter Occurrence After Surgery in Patients with Hepatocellular Carcinoma: What Is More Is About Different Therapeutic Strategies. PMID- 28861803 TI - Electro-acupuncture treatment for internet addiction: Evidence of normalization of impulse control disorder in adolescents. AB - OBJECTIVE: To observe the impacts of electro-acupuncture (EA) and psychological intervention (PI) on impulsive behavior among internet addiction (IA) adolescents. METHODS: Thirty-two IA adolescents were allocated to either EA (16 cases) or PI (16 cases) group by a randomized digital table. Subjects in the EA group received EA treatment and subjects in the PI group received cognition and behavior therapy. All adolescents underwent 45-d intervention. Sixteen healthy volunteers were recruited into a control group. Barratt Impulsiveness Scale (BIS 11) scores, Young's Internet Addiction Test (IAT) as well as the ratio of brain N acetyl aspartate (NAA) to creatine (NAA/Cr) and choline (Cho) to creatine (Cho/Cr) were recorded by magnetic resonance spectroscopy before and after intervention respectively. RESULTS: The IAT scores and BIS-11 total scores in both EA and PI group were remarkably decreased after treatment (P<0.05), while EA group showed more significant decrease in certain BIS-11 sub-factors (P<0.05). Both NAA/Cr and Cho/Cr were significantly improved in EA group after treatment (P<0.05); however, there were no significant changes of NAA/Cr or Cho/Cr in PI group after treatment (P>0.05). CONCLUSIONS: Both EA and PI had significantly positive effect on IA adolescents, especially in the aspects of psychological experiences and behavioral expressions, EA might have an advantage over PI in terms of impulsivity control and brain neuron protection. The mechanism underlying this advantage might be related to the increased NAA and Cho levels in prefrontal and anterior cingulate cortices. PMID- 28861805 TI - Recurrent coronary restenosis treated with Chinese medicine: A case report. PMID- 28861804 TI - Therapeutic Benefits of Natural Ingredients for Atopic Dermatitis. AB - Although a variety of regimens are available for the treatment of atopic dermatitis (AD), severe adverse reactions and unpopular costs often limit their usage. In contrast, certain inexpensive, naturally-occurring ingredients are proven effective for AD with fewer side effects. The beneficial effects of these ingredients can be attributed to inhibition of cytokine and chemokine expression, IgE production, inflammatory cell infiltration, histamine release, and/or the enhancement of epidermal permeability barrier function. Since herbal medicines are widely available, inexpensive and generally safe, they could be valuable alternatives for the treatment of AD, particularly for those patients who are not suitable for the utilization of immune modulators. In this review, we summarize the therapeutic benefits of natural ingredients for the treatment of AD and the mechanisms of their actions. PMID- 28861806 TI - Rutaecarpine Inhibits Intimal Hyperplasia in A Balloon-Injured Rat Artery Model. AB - OBJECTIVE: To investigate the effect and potential mechanisms of rutaecarpine (Rut) in a rat artery balloon-injury model. METHODS: The intimal hyperplasia model was established by rubbing the endothelia with a balloon catheter in the common carotid artery (CCA) of rats. Fifty rats were randomly divided into five groups, ie. sham, model, Rut (25, 50 and 75 mg/kg) with 10 rats of each group. The rats were treated with or without Rut (25, 50, 75 mg/kg) by intragastric administration for 14 consecutive days following injury. The morphological changes of the intima were evaluated by hematoxylin-eosin staining. The expressions of proliferating cell nuclear antigen (PCNA) and smooth muscle (SM) alpha-actin in the ateries were assayed by immunohistochemical staining. The mRNA expressions of c-myc, extracellular signal-regulated kinase 2 (ERK2), MAPK phosphatase-1 (MKP-1) and endothelial nitric oxide synthase (eNOS) were determined by real-time reverse transcription-polymerase chain reaction. The protein expressions of MKP-1 and phosphorylated ERK2 (p-ERK2) were examined by Western blotting. The plasma contents of nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) were also determined. RESULTS: Compared with the model group, Rut treatment significantly decreased intimal thickening and ameliorated endothelial injury (P<0.05 or P<0.01). The positive expression rate of PCNA was decreased, while the expression rate of SM alpha-actin obviously increased in the vascular wall after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01). Furthermore, the mRNA expressions of c-myc, ERK2 and PCNA were downregulated while the expressions of eNOS and MKP-1 were upregulated (P<0.05 or P<0.01). The protein expressions of MKP-1 and the phosphorylation of ERK2 were upregulated and downregulated after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01), respectively. In addition, Rut dramatically reversed balloon injury-induced decrease of NO and cGMP in the plasma (P<0.05 or P<0.01). CONCLUSION: Rut could inhibit the balloon injury-induced carotid intimal hyperplasia in rats, possibly mediated by promotion of NO production and inhibiting ERK2 signal transduction pathways. PMID- 28861807 TI - Oral Secretions Affect HIPVs Induced by Generalist (Mythimna loreyi) and Specialist (Parnara guttata) Herbivores in Rice. AB - Plants synthesize variable mixtures of herbivore-induced plant volatiles (HIPVs) as part of their evolutionary conserved defense. To elucidate the impact of chewing herbivores with different level of adaptation on HIPV profiles in rice, we measured HIPVs released from rice seedlings challenged by either the generalist herbivore Mythimna loreyi (MYL) or the specialist Parnara guttata (PAG). Both herbivores markedly elicited the emission of HIPVs, mainly on the second and third days after attack compared to control plants. In addition, side by-side HIPV comparisons using MYL and PAG caterpillars revealed that generalist feeding induced comparably more HIPVs relative to specialist, particularly on day two as highlighted by multivariate analysis (PLS-DA) of emitted HIPVs, and further confirmed in mimicked herbivory experiments. Here, mechanically wounded plants treated with water (WW) released more VOCs than untreated controls, and on top of this, oral secretions (OS) from both herbivores showed differential effects on volatile emissions from the wounded plants. Similar to actual herbivory, MYL OS promoted higher amounts of HIPVs relative to PAG OS, thus supporting disparate induction of rice indirect defenses in response to generalist and specialist herbivores, which could be due to the differential composition of their OS. (196 words). PMID- 28861808 TI - A Review of Thoracic and Mediastinal Cytoreductive Techniques in Advanced Ovarian Cancer: Extending the Boundaries. AB - The aim of this study was to review the surgical and clinical outcomes of intrathoracic and mediastinal surgical cytoreduction in stage IV epithelial ovarian cancer (EOC). Relevant articles were identified from MEDLINE and EMBASE. Only analyses or reports that described actual intrathoracic cytoreduction via pleurectomy and/or resection of cardiophrenic/mediastinal lymph nodes were included. Imaging articles that merely described thoracic tumor patterns were excluded. A total of nine studies were identified, the oldest originating in 2007. Procedures described were transdiaphragmatic resection of cardiophrenic lymph nodes and pleural disease (n = 5) and video-assisted thoracoscopic and mediastinal tumorectomies including pleurectomy (n = 4). The number of operated patients ranged between 1 and 30 with complete cytoreduction rates ranging between 68 and 100%. No surgical deaths directly related to the thoracic cytoreduction were reported and only one patient (1/30) experienced a postoperative complication in terms of a pneumothorax. None of the studies presented a direct comparison of survival to patients with thoracic disease who did not undergo thoracic cytoreduction, and therefore the survival benefit of thoracic cytoreduction could not be quantified. In conclusion, thoracic cytoreduction in advanced EOC seems feasible and with acceptable morbidity while offering a better understanding of the extent of disease and hence allowing the tailoring of intraabdominal resections. Nevertheless, its direct impact on patients' survival by a potential overruling of a more adverse tumor biology remains to be established in larger-scale prospective and ideally randomized trials. PMID- 28861809 TI - Negative Impact of Skeletal Muscle Wasting After Neoadjuvant Chemotherapy Followed by Surgery on Survival for Patients with Thoracic Esophageal Cancer. AB - BACKGROUND: Skeletal muscle wasting during curative treatment is an important issue faced by esophageal cancer patients. However, it has not been clarified whether skeletal muscle change during neoadjuvant chemotherapy followed by surgery adversely affects prognosis. This study aimed to determine the relation between skeletal muscle change and survival for patients with advanced esophageal cancer who underwent neoadjuvant chemotherapy followed by surgery. METHODS: This study retrospectively analyzed 66 patients with thoracic esophageal cancer who had undergone neoadjuvant chemotherapy followed by esophagectomy. The study investigated the correlation between the change in the total muscle cross sectional area at the third lumbar vertebra before and 4 months after surgery as well as the postoperative recurrence and overall survival (OS). RESULTS: Of the 66 patients, 39 (59%) showed a skeletal muscle decrease from baseline to 4 months after esophagectomy. The change in the skeletal muscle index from baseline to 4 months after surgery was -1.2 cm2/m2. Multivariable analysis showed that nonsquamous cell carcinoma subtype (hazard ratio [HR] 2.57; p = 0.029), pathologic stage (HR 5.73; p < 0.01), and skeletal muscle wasting (HR per 1 unit decrease in skeletal muscle index, 1.16; p = 0.015) were the independent prognostic factors associated with worse OS. Additionally, pathologic stage (HR 6.03; p < 0.01) and skeletal muscle wasting (HR per 1 unit decrease in skeletal muscle index, 1.11; p = 0.048) also were found to be independent prognostic factors associated with worse recurrence-free survival. CONCLUSIONS: The study findings suggest that skeletal muscle wasting from baseline has a negative impact on cancer recurrence and survival. PMID- 28861810 TI - Profiling methyl jasmonate-responsive transcriptome for understanding induced systemic resistance in whitebark pine (Pinus albicaulis). AB - KEY MESSAGE: RNA-seq analysis on whitebark pine needles demonstrated that methyl jasmonate (MeJA)-triggered transcriptome re-programming substantially overlapped with defense responses against insects and fungal pathogens in Pinus species, increasing current knowledge regarding induced systemic resistance (ISR) to pathogens and pests in whitebark pine. Many whitebark pine populations are in steep decline due to high susceptibility to mountain pine beetle and the non native white pine blister rust (WPBR). Resistance, including induced systemic resistance (ISR), is not well characterized in whitebark pine, narrowing the current options for increasing the success of restoration and breeding programs. Exogenous jasmonates are known to trigger ISR by activating the plant's immune system through regulation of gene expression to produce chemical defense compounds. This study reports profiles of whitebark pine needle transcriptomes, following methyl jasmonate (MeJA) treatment using RNA-seq. A MeJA-responsive transcriptome was de novo assembled and transcriptome profiling identified a set of differentially expressed genes (DEGs), revealing 1422 up- and 999 down regulated transcripts with at least twofold change (FDR corrected p < 0.05) in needle tissues in response to MeJA application. GO analysis revealed that these DEGs have putative functions in plant defense signalling, transcription regulation, biosyntheses of secondary metabolites, and other biological processes. Lineage-specific expression of defense-related genes was characterized through comparison with MeJA signalling in model plants. In particular, MeJA triggered transcriptome re-programming substantially overlapped with defense responses against WPBR and insects in related Pinus species, suggesting that MeJA may be used to improve whitebark pine resistance to pathogens/pests. Our study provides new insights into molecular mechanisms and metabolic pathways involved in whitebark pine ISR. DEGs identified in this study can be used as candidates to facilitate identification of genomic variation contributing to host resistance and aid in breeding selection of elite genotypes with better adaptive fitness to environmental stressors in this endangered tree species. PMID- 28861812 TI - Review of Ordering Don't Resuscitate in Iranian Dying Patients. AB - Making decision on not to resuscitate is a confusing, conflicting and complex issue and depends on each country's culture and customs. Therefore, each country needs to take action in accordance with its cultural, ethical, religious and legal contexts to develop guidelines in this regard. Since the majority of Iran's people are Muslims, and in Islam, the human life is considered sacred, based on the values of the community, an Iranian Islamic agenda needs to be developed not taking measures about resuscitation of dying patients. It is necessary to develop an Iranian Islamic guidelines package in order to don't resuscitate in dying patients. PMID- 28861811 TI - Differential Effects of Antiretroviral Drugs on Neurons In Vitro: Roles for Oxidative Stress and Integrated Stress Response. AB - Mounting evidence suggests that antiretroviral drugs may contribute to the persistence of HIV-associated neurocognitive disorders (HAND), which impact 30% 50% of HIV-infected patients in the post-antiretroviral era. We previously reported that two first generation HIV protease inhibitors, ritonavir and saquinavir, induced oxidative stress, with subsequent neuronal death in vitro, which was reversed by augmentation of the endogenous antioxidant response by monomethyl fumarate. We herein determined whether two newer-generation PIs, darunavir and lopinavir, were deleterious to neurons in vitro. Further, we expanded our assessment to include three integrase strand transfer inhibitors, raltegravir, dolutegravir, and elvitegravir. We found that only lopinavir and elvitegravir were neurotoxic to primary rat neuroglial cultures as determined by the loss of microtubule-associated protein 2 (MAP2). Intriguingly, lopinavir but not elvitegravir led to oxidative stress and induced the endogenous antioxidant response (EAR). Furthermore, neurotoxicity of lopinavir was blocked by pharmacological augmentation of the endogenous antioxidant heme oxygenase-1 (HO 1), expanding our previous finding that protease inhibitor-induced neurotoxicity was mediated by oxidative stress. Conversely, elvitegravir but not lopinavir led to increased eIF2alpha phosphorylation, indicating the activation of a common adaptive pathway termed the integrated stress response (ISR), and elvitegravir mediated neurotoxicity was partially alleviated by the ISR inhibitor trans-ISRIB, suggesting ISR as a promoter of elvitegravir-associated neurotoxicity. Overall, we found that neurotoxicity was induced only by a subset of protease inhibitors and integrase strand transfer inhibitors, providing evidence for class- and drug specific neurotoxic effects of antiretroviral drugs. Future in vivo studies will be critical to confirm the neurotoxicity profiles of these drugs for incorporation of these findings into patient management. The EAR and ISR pathways are potential access points for the development of adjunctive therapies to complement antiretroviral therapies and limit their contribution to HAND persistence. PMID- 28861813 TI - An Overview of Protein Secretion in Yeast and Animal Cells. AB - Protein secretion mediated by the secretory transport pathway is an important cellular process in eukaryotic cells. In the conventional secretory transport pathway, newly synthesized proteins pass through several endomembrane compartments en route to their specific destinations. Transport of secretory proteins between different compartments is shuttled by small, membrane-enclosed vesicles. To ensure the fidelity of transport, eukaryotic cells employ elaborate molecular machineries to accurately sort newly synthesized proteins into specific transport vesicles and precisely deliver these transport vesicles to distinct acceptor compartments. In this review, we summarize the molecular machineries that regulate each step of vesicular transport in the secretory transport pathway in yeast and animal cells. PMID- 28861814 TI - An Overview of Protein Secretion in Plant Cells. AB - The delivery of proteins to the apoplast or protein secretion is an essential process in plant cells. Proteins are secreted to perform various biological functions such as cell wall modification and defense response. Conserved from yeast to mammals, both conventional and unconventional protein secretion pathways have been demonstrated in plants. In the conventional protein secretion pathway, secretory proteins with an N-terminal signal peptide are transported to the extracellular region via the endoplasmic reticulum-Golgi apparatus and the subsequent endomembrane system. By contrast, multiple unconventional protein secretion pathways are proposed to mediate the secretion of the leaderless secretory proteins. In this review, we summarize the recent findings and provide a comprehensive overview of protein secretion pathways in plant cells. PMID- 28861815 TI - Bioinformatics Analysis of Protein Secretion in Plants. AB - In sessile plants, the dynamic protein secretion pathways orchestrate the cellular responses to internal signals and external environmental changes in almost every aspect of plant developmental events. The cohort of plant proteins, secreted from the plant cells into the extracellular matrix, has been annotated as plant secretome. Therefore, the identification and characterization of secreted proteins will discover novel secretory potentials and establish the functional connection between cellular protein secretion and plant physiological phenomena. Noteworthy, an increasing number of bioinformatics databases and tools have been developed for computational predictions on either secreted proteins or secretory pathways. This chapter summarizes current accessible databases and tools for protein secretion analysis in Arabidopsis thaliana and higher plants, and provides feasible methodologies for bioinformatics analysis of secretome studies for the plant research community. PMID- 28861816 TI - Proteomic Analysis of Secreted Proteins from Cell Microenvironment. AB - Cell microenvironment consists of various types of cells which communicate with each other by vast number of secreted proteins. An unbiased profiling of these secreted proteins on a global scale is often critical for understanding the intercellular signaling in an autocrine or paracrine manner. Mass spectrometry based proteomics has become one of the most popular technology for characterization of the secreted proteins. In this chapter, we discuss the standard workflow for secreted proteins characterization, including harvesting secreted proteins from conditioned media, digesting the obtained proteins, liquid chromatography-mass spectrometry analysis, and downstream data analysis. PMID- 28861817 TI - Using Homology Modeling to Understand the Structural Basis of Specific Interaction of a Plant-Specific AtSar1a-AtSec23a Pair Involved in Protein ER Export. AB - Homology modeling allows the prediction of a protein structure based on sequence similarity to a known structure of homologous proteins. In this chapter, we use a plant-specific AtSar1a-Atsec23a pair of proteins as a case study to illustrate how to use homology modeling to understand the specificity of the pairwise interaction between AtSar1a and AtSec23a. The detailed procedures described here are also useful in structure prediction of other protein complexes. PMID- 28861818 TI - Analysis of Golgi-Mediated Protein Traffic in Plant Cells. AB - In plant secretory pathways, the Golgi apparatus serves as the major sorting hub to receive de novo synthesized protein from the endoplasmic reticulum for further sorting to post-Golgi compartments or for residence in the cisternae of Golgi stacks. Meanwhile, Golgi functions as a pivotal biochemical factory to make modifications of N-glycans and to produce mature glycoproteins. Fluorescent tag based confocal microscopy in combination with the brefeldin A drug or the genetic tools to disturb Golgi function have been shown as powerful approaches to analyze Golgi-mediated protein traffic in transiently expressed plant protoplasts or in stably expressed transgenic plants. Various endoglycosidases like Endo H and PNGase F have been widely used to monitor Golgi-mediated glycosylation of secretory proteins. Here, using fluorescently tagged Golgi-resident proteins and known glycosylated proteins as examples, we describe detailed protocols to analyze Golgi-mediated protein traffic and glycosylation in transiently expressed protoplasts derived from Arabidopsis suspension culture cells and in stably expressed transgenic plants. PMID- 28861819 TI - Analysis of Membrane Protein Topology in the Plant Secretory Pathway. AB - Topology of membrane proteins provides important information for the understanding of protein function and intermolecular associations. Integrate membrane proteins are generally transported from endoplasmic reticulum (ER) to Golgi and downstream compartments in the plant secretory pathway. Here, we describe a simple method to study membrane protein topology along the plant secretory pathway by transiently coexpressing a fluorescent protein (XFP)-tagged membrane protein and an ER export inhibitor protein, ARF1 (T31N), in tobacco BY-2 protoplast. By fractionation, microsome isolation, and trypsin digestion, membrane protein topology could be easily detected by either direct confocal microscopy imaging or western-blot analysis using specific XFP antibodies. A similar strategy in determining membrane protein topology could be widely adopted and applied to protein analysis in a broad range of eukaryotic systems, including yeast cells and mammalian cells. PMID- 28861820 TI - Semiautomatic Segmentation of Plant Golgi Stacks in Electron Tomograms Using 3dmod. AB - Electron tomography is a powerful tool for visualizing subcellular organelles. With the advances in cryo-fixation techniques, it is now possible to reconstruct complex structures in cells preserved close to their native states in three dimension (3D) using electron tomography. In order to better visualize these objects, 3D models are made from outlines of organelles in individual tomographic slices, which can be used to display morphological features and quantify structural parameters. While outlines of simple organelles can be drawn by hand fairly quickly, it is possible to accelerate 3D modeling of more complex organelles by means of semiautomatic segmentation. In this chapter, we use the example of reconstructing Golgi cisternae of a plant cell into 3D models using the semiautomatic protocol. PMID- 28861821 TI - 3D Printing of Plant Golgi Stacks from Their Electron Tomographic Models. AB - Three-dimensional (3D) printing is an effective tool for preparing tangible 3D models from computer visualizations to assist in scientific research and education. With the recent popularization of 3D printing processes, it is now possible for individual laboratories to convert their scientific data into a physical form suitable for presentation or teaching purposes. Electron tomography is an electron microscopy method by which 3D structures of subcellular organelles or macromolecular complexes are determined at nanometer-level resolutions. Electron tomography analyses have revealed the convoluted membrane architectures of Golgi stacks, chloroplasts, and mitochondria. But the intricacy of their 3D organizations is difficult to grasp from tomographic models illustrated on computer screens. Despite the rapid development of 3D printing technologies, production of organelle models based on experimental data with 3D printing has rarely been documented. In this chapter, we present a simple guide to creating 3D prints of electron tomographic models of plant Golgi stacks using the two most accessible 3D printing technologies. PMID- 28861822 TI - Transient Expression of Chimeric Fluorescent Reporter Proteins in Pollen Tubes to Study Protein Polar Secretion and Dynamics. AB - Transient expression of chimeric fluorescent reporter proteins by biolistic bombardment is a quick and useful procedure for studying subcellular protein localization and dynamics in plants. It is especially beneficial in specific plant cells which are not suitable for protoplast-based and Agrobacterium mediated protein transient expression. Polar protein secretion and vesicular trafficking play essential functions for cell polarization and tip growth. The growing pollen tube is regarded as an ideal model plant cell system to study the machinery and regulation of polar protein trafficking and targeting. A large amount of newly synthesized proteins are packed and polarly transported to the apical region to support the rapid and highly polarized tip growth. Here, we described a detailed step-by-step protocol for the transient expression of chimeric fluorescent reporter proteins in growing Arabidopsis and tobacco pollen tubes to study polar transportation logistics and mechanisms. In addition, we have optimized the Arabidopsis and tobacco in vitro pollen germination medium and the conditions to maximize the efficiency of protein expression. As a proof of concept, we have used this protocol to express actin microfilament and late endosomal fluorescent markers in Arabidopsis and tobacco pollen tubes. PMID- 28861823 TI - Analysis of Actin-Based Intracellular Trafficking in Pollen Tubes. AB - Underlying rapid and directional pollen tube growth is the active intracellular trafficking system that carries materials necessary for cell wall synthesis and membrane expansion to the expanding point of the pollen tube. The actin cytoskeleton has been shown to control various intracellular trafficking events in the pollen tube, but the underlying cellular and molecular mechanisms remain poorly understood. To better understand how the actin cytoskeleton is involved in the regulation of intracellular trafficking events, we need to establish assays to visualize and quantify the distribution and dynamics of organelles, vesicles, or secreted proteins. In this chapter, we introduce methods regarding the visualization and quantification of the distribution and dynamics of organelles or vesicles in pollen tubes. PMID- 28861824 TI - Analysis of Phragmoplast Kinetics During Plant Cytokinesis. AB - In plants, the partitioning of daughter cells during cytokinesis is achieved via physical insertion of a membranous cell plate within the dividing parent cell. It is a cellular process of extensive protein secretion and membrane trafficking toward the plane of cell division and the cytoskeleton is an important facilitator of this process. A specialized cytoskeletal array termed phragmoplast expands centrifugally throughout cytokinesis and directs, mostly Golgi-derived vesicles that ultimately fuse to form the developing cell plate. The function of the phragmoplast in guiding cell plate synthesis has strongly motivated many scientists to monitor its dynamic behavior. In this chapter, we present an overview of basic principles and methods concerning the live imaging of cytokinetic plant cells using confocal laser scanning microscopy (CLSM) and the analysis of phragmoplast expansion. PMID- 28861825 TI - Immunofluorescence Analysis of Membrane-Associated Proteins for Clathrin-Mediated Endocytosis in Plant Root Cells. AB - The root is an ideal model system for studying subcellular localization and dynamic trafficking of important membrane-associated proteins in plants. Immunofluorescence analysis is necessary to reveal subcellular localization and intracellular trafficking of endogenous proteins as epitope tags or fluorescent proteins may cause mislocation of fusion proteins. Here, we describe a rapid and reliable immunodetection protocol for whole-mount in situ localization of membrane-associated proteins involved in clathrin-mediated endocytosis (CME) in Arabidopsis root cells. The whole procedure includes five basic steps: tissue fixation, tissue permeation, blocking, primary antibody incubation, and secondary antibody incubation. PMID- 28861826 TI - In Vivo Interaction Studies by Measuring Forster Resonance Energy Transfer Through Fluorescence Lifetime Imaging Microscopy (FRET/FLIM). AB - Combinations of multiple fluorescent fusion proteins are commonly generated and used for colocalization studies in live cell imaging but also biochemical analysis of protein-protein interactions by co-immunoprecipitation in vitro. Advanced microscopy techniques like Forster resonance energy transfer through fluorescence lifetime imaging microscopy (FRET/FLIM) nowadays enable the combination of both approaches. This opens up the possibility to perform a location-specific protein-protein interaction analysis in vivo. To this end, the nonradiant energy transfer from a donor to an acceptor fluorophore (FRET) is harnessed to test for close proximity as an indicator for interaction, while the spectromicroscopical measurement of the fluorescence lifetime by FLIM serves as a readout.Here, we describe FRET/FLIM measurements performed with a Leica TCS SP8/PicoHarp 300 combination to demonstrate the interaction between a RFP-tagged GFP-nanobody and its epitope, GFP, in the cytoplasm of tobacco mesophyll protoplasts. PMID- 28861827 TI - Analysis of Nanobody-Epitope Interactions in Living Cells via Quantitative Protein Transport Assays. AB - Over the past few decades, quantitative protein transport analyses have been used to elucidate the sorting and transport of proteins in the endomembrane system of plants. Here, we have applied our knowledge about transport routes and the corresponding sorting signals to establish an in vivo system for testing specific interactions between soluble proteins.Here, we describe the use of quantitative protein transport assays in tobacco mesophyll protoplasts to test for interactions occurring between a GFP-binding nanobody and its GFP epitope. For this, we use a secreted GFP-tagged alpha-amylase as a reporter together with a vacuolar-targeted RFP-tagged nanobody. The interaction between these proteins is then revealed by a transport alteration of the secretory reporter due to the interaction-triggered attachment of the vacuolar sorting signal. PMID- 28861828 TI - A Secretion System for Cargo Protein Identification of Vacuolar Sorting Receptors. AB - Vacuolar sorting receptors (VSRs) are type I integral membrane family proteins in plant cells that can sort cargo proteins at the late Golgi or trans-Golgi network (TGN) for vacuolar transport via the prevacuolar compartment (PVC). However, little is known about VSR cargo proteins in plants. Here, we describe a new method for the identification of VSR cargos, which is based on the premise that the expressed N-terminus of VSRs will be secreted into the culture media along with their corresponding cargo proteins. The protocol described here should be applicable to all VSRs and should be also useful for other receptor cargo identification and protein-protein interaction in vivo. PMID- 28861829 TI - Identifying Novel Regulators of Vacuolar Trafficking by Combining Fluorescence Imaging-Based Forward Genetic Screening and In Vitro Pollen Germination. AB - Subcellular targeting of vacuolar proteins depends on cellular machinery regulating vesicular trafficking. Plant-specific vacuolar trafficking routes have been reported. However, regulators mediating these processes are obscure. By combining a fluorescence imaging-based forward genetic approach and in vitro pollen germination system, we show an efficient protocol of identifying regulators of plant-specific vacuolar trafficking routes. PMID- 28861830 TI - Measuring Plant Protein Secretion. AB - Fluorescent protein fusions are widely used for visualizing the subcellular localization and mobility of intercellular proteins. There is now a variety of colors, expression vectors, and photoactivated molecules to choose from, each with their own strengths and limitations. In this chapter, the methodologies for expressing and quantifying protein secretion with fluorescent protein fusion constructs using two separate protocols-one in which the retention of a transiently expressed fluorescent marker is measured in seedling roots to quantify a block in secretion, and one in which the secretion of a fluorescent marker into the space of the apoplast is measured to quantify secretion in plant leaves-are described. In the first protocol, seedling roots are transiently transformed with multicistronic constructs; and in the second protocol, markers can be stably expressed and controlled under an inducible promoter in mature plants. Both methods provide tools for quantifying protein secretion and visualizing defects in secretion pathways in Arabidopsis. PMID- 28861831 TI - Transient Secretory Enzyme Expression in Leaf Protoplasts to Characterize SNARE Functional Classes in Conventional and Unconventional Secretion. AB - Despite a long case history, the use of protoplasts in cell biology research still divides scientists but their weaknesses can be exploited as strengths. Transient expression in protoplasts can saturate protein-protein interactions very efficiently, inhibiting the process of interest more efficiently than other approaches at gene expression level. The method described here consists of an assay providing a functional characterization of SNARE proteins in a heterogeneous population of cells, by the comparison of native and dominant negative mutant forms. In particular, it allows for discriminating between t SNARE and i-SNARE functional classes. PMID- 28861833 TI - Analysis of Exocyst-Positive Organelle (EXPO)-Mediated Unconventional Protein Secretion (UPS) in Plant Cells. AB - Unconventional protein secretion (UPS) together with conventional protein secretion (CPS) is responsible for protein secretion in plants. We have previously identified a novel UPS pathway in plants, which is mediated by exocyst positive organelle-EXPO. Here, we describe detailed protocols to study UPS in plants by using Arabidopsis protoplasts or transgenic suspension cells, expressing the EXPO marker Exo70E2-XFP, as materials. Via drug and osmotic treatment plus secretion assay, we illustrate several major methods to analyze EXPO-mediated UPS in plant cells, which also supplys mining tools for similar study. PMID- 28861832 TI - The Organelle pH Estimate and Measurement in Plant Secretory Pathway. AB - The maintenance of pH in the intracellular compartments is essential for the viability of cells. Several genetically encoded fluorescent pH sensors have been developed for noninvasive in vivo analysis. Here, we describe the methods using PEpHluorin (plant-solubility-modified ecliptic pHluorin) and PRpHluorin (plant solubility-modified ratiometric pHluorin) as pH sensors for in vivo visualization and quantification organelle pH of in plant secretory pathway. PMID- 28861834 TI - Isolation of the Plant Exocyst Complex. AB - The exocyst, conserved from yeast to plants to mammals, is a hetero-octameric complex that mediates tethering of secretory vesicles to designated sites on the plasma membrane during polarized exocytosis. Because structural studies of the intact exocyst complex have been greatly limited by the low yields of purified proteins, many aspects of the exocyst functions remain poorly understood. Here, we present the protocols for the isolation and purification of the recombinant and the native plant exocyst complex. Given the known diversification of the exocyst subunits in plants, our protocols will likely open the possibility of unraveling the functional significance of these subunits in the context of the fully assembled exocyst complex. PMID- 28861835 TI - Using Microscopy Tools to Visualize Autophagosomal Structures in Plant Cells. AB - Macroautophagy (hereafter as autophagy), is a metabolic process for sequestration of cytoplasmic cargos into a double membrane structure named as autophagosome. In plants, autophagy is required for nutrition mobilization/recycling and clearance of protein aggregates or damaged organelles during starvation or other unfavorable conditions, as well as for plant immunity during pathogen infection. Multiple experimental approaches have been developed to elucidate the autophagic activity. To facilitate further investigations on the potential involvement of autophagy in protein secretion process in plant cells, here we describe detailed protocols to measure the autophagic activity in model plant Arabidopsis. Using the autophagosome marker ATG8 and a novel autophagic regulator SH3P2 as examples, we illustrate the major cell biology tools and methods using microscopy to analyze the autophagosomal structures in plant cells, including BTH-induced autophagic response, transient expression and colocalization analysis, as well as immuno-EM labeling. PMID- 28861836 TI - Analysis of Plant Autophagy. AB - Autophagy is an intercellular degradation/recycling system by which cytoplasmic components are sequestered in autophagic vesicles (autophagosomes) and delivered to the vacuole for breakdown. During the last decade, plant studies have revealed that autophagy is employed as a major route to recycle nutrients needed for plant growth and development, and to combat with a wide range of biotic and abiotic stresses. Another important outcome of these studies was the development and optimization of methods and techniques for monitoring autophagy activity in plants. In this chapter, methods frequently used in plant autophagy study, from physiological to biochemical and microscopical analyses, are discussed. PMID- 28861837 TI - Cardiovascular Effects of the MEK Inhibitor, Trametinib: A Case Report, Literature Review, and Consideration of Mechanism. AB - The MEK inhibitor trametinib was approved in 2013 for the treatment of unresectable or metastatic melanoma with a BRAF V600E mutation, the most common pathogenic mutation in melanoma. Trametinib blocks activation of ERK1/2, inhibiting cell proliferation in melanoma. ERK1/2 also protects against multiple types of cardiac insult in mouse models. Trametinib improves survival in melanoma patients, but evidence of unanticipated cardiotoxicity is emerging. Here we describe the case of a patient with metastatic melanoma who developed acute systolic heart failure after trametinib treatment and present the results of the literature review prompted by this case. A patient with no cardiac history presented with a 6.5-mm skin lesion and was found to have metastatic BRAF V600E melanoma. Combination treatment with trametinib and the BRAF inhibitor, dabrafenib, was initiated. The patient's pre-treatment ejection fraction was 55 60%. His EF declined after 13 days and that was 40% 1 month after treatment. Two months after initiating trametinib, he developed dyspnea and fatigue. We conducted a chart review in the electronic medical record. We conducted a PubMed search using trametinib/adverse effects AND ("heart failure" OR "left ventricular dysfunction" OR hypertension OR cardiotoxicity OR mortality). We also queried the FDA Adverse Events Reporting System for reports of cardiomyopathy, ejection fraction decrease, and left ventricular dysfunction associated with trametinib between January 1, 2013, and July 20, 2017. The literature search retrieved 19 articles, including clinical trials and case reports. Early clinical experience with the MEK inhibitor trametinib suggests that its clinical efficacy may be compromised by cardiotoxicity. Further studies in humans and animals are required to determine the extent of this adverse effect, as well as its underlying mechanisms. PMID- 28861838 TI - Metal concentrations in American oyster Crassotrea virginica and adjacent sediments from harvestable and non-harvestable sites in the Southeastern USA. AB - Human population growth in coastal areas continues to threaten estuarine ecosystems and resources. Populations of Crassostrea virginica have declined across the USA due to water quality degradation, disease pressure, alteration of habitat, and other changes related to anthropogenic impacts. Metals that may be present in estuarine habitats can bioaccumulate in oysters, with potential consequences to the health of oysters and humans consumers. This study (1) evaluated the occurrence and relationships of metal concentrations in oyster tissue versus estuarine sediments, (2) examined oyster tissue concentrations in relation to state water quality designations, and (3) evaluated the potential risk for humans from oyster consumption related to metal concentrations from harvestable waters. Results indicated metal concentrations in sediments and oysters along coastal South Carolina remain low compared to other areas and that concentrations in oyster tissue and adjacent sediments were not highly correlated with each other. However, high concentrations of some metals occurred in oysters sampled from areas designated as Approved for Harvesting. This is important because most harvest area designation systems rely on regular bacterial monitoring when evaluating the safety of consumption. Others safety measurements may be necessary as part of routine monitoring. PMID- 28861839 TI - Factors controlling groundwater quality in the Yeonjegu District of Busan City, Korea, using the hydrogeochemical processes and fuzzy GIS. AB - The hydrogeochemical processes and fuzzy GIS techniques were used to evaluate the groundwater quality in the Yeonjegu district of Busan Metropolitan City, Korea. The highest concentrations of major ions were mainly related to the local geology. The seawater intrusion into the river water and municipal contaminants were secondary contamination sources of groundwater in the study area. Factor analysis represented the contamination sources of the mineral dissolution of the host rocks and domestic influences. The Gibbs plot exhibited that the major ions were derived from the rock weathering condition. Piper's trilinear diagram showed that the groundwater quality was classified into five types of CaHCO3, NaHCO3, NaCl, CaCl2, and CaSO4 types in that order. The ionic relationship and the saturation mineral index of the ions indicated that the evaporation, dissolution, and precipitation processes controlled the groundwater chemistry. The fuzzy GIS map showed that highly contaminated groundwater occurred in the northeastern and the central parts and that the groundwater of medium quality appeared in most parts of the study area. It suggested that the groundwater quality of the study area was influenced by local geology, seawater intrusion, and municipal contaminants. This research clearly demonstrated that the geochemical analyses and fuzzy GIS method were very useful to identify the contaminant sources and the location of good groundwater quality. PMID- 28861840 TI - Author response to: Stereotactic accuracy must be as high as possible in stereoelectroencephalography procedures. PMID- 28861841 TI - The first serological evidence for Rift Valley fever infection in the camel, goitered gazelle and Anatolian water buffaloes in Turkey. AB - Rift valley fever (RVF), a vector-borne zoonotic disease, is caused by a phlebovirus (family Bunyaviridae). The virus was initially characterized approximately 80 years ago in Kenya and disseminated to many countries in the continental Africa, Saudi Arabia, and Yemen. The infection has not been reported in Turkey. In this study, blood serum samples collected from camel (Camelus dromedairus), goitered gazelle (Gazella subgutturosa subgutturosa), and buffaloes (Bubalus bubalis linneaus) from 2000 to 2006 were investigated for RVF using C ELISA. Camel samples (n = 72) were obtained from private small enterprises in Aydin province in theAegean region. Gazella samples (82) were taken from the biggest captive gazelle herd in Sanliurfa province in the southeast Anatolia. Buffalo samples were collected mostly from small private family type farms in Afyon (168), Amasya (80), Samsun (69), Ankara (35), Sivas (21), Tokat (19), Konya (10), and Elazig (8) provinces in the central, north, west, and east Anatolia. All of the gazella samples were negative; whereas, one of the 71 camel samples (1.3%) was positive for RVF-specific antibodies. Buffalos from Sivas, Tokat, Konya, and Elazig provinces were negative. However, 35 of the 410 samples (8.5%) from rural areas in the following four provinces were positive: Amasya (12/80, 15%), Ankara (5/35, 14.2%), Samsun (8/69, 11.5%), and Afyon (10/168, 5.9%). To our knowledge, this is the first report of presence of RVF infection in Turkey. PMID- 28861843 TI - Brain motor functional changes after somatosensory discrimination training. AB - Somatosensory discrimination training may modulate cognitive processes, such as movement planning and monitoring, which can be useful during active movements. The aim of the study was to assess the effect of somatosensory discrimination training on brain functional activity using functional magnetic resonance imaging (fMRI) during motor and sensory tasks in healthy subjects. Thirty-nine healthy young subjects were randomized into two groups: the experimental group underwent somatosensory discrimination training consisting of shape, surface and two-point distance discrimination; and the control group performed a simple object manipulation. At baseline and after 2 weeks of training, subjects underwent sensorimotor evaluations and fMRI tasks consisting of right-hand tactile stimulation, manipulation of a simple object, and complex right-hand motor sequence execution. Right-hand dexterity improved in both groups, but only the experimental group showed improvements in all manual dexterity tests. After training, the experimental group showed: decreased activation of the ipsilateral sensorimotor areas during the tactile stimulation task; increased activation of the contralateral postcentral gyrus and thalamus bilaterally during the manipulation task; and a reduced recruitment of the ipsilateral pre/postcentral gyri and an increased activation of the basal ganglia and cerebellum contralaterally during the complex right-hand motor task. In healthy subjects, sensory discrimination training was associated with lateralization of brain activity in sensorimotor areas during sensory and motor tasks. Further studies are needed to investigate the usefulness of this training in motor rehabilitation of patients with focal lesions in the central nervous system. PMID- 28861845 TI - Face-to-face vs. online peer support groups for prostate cancer: A cross sectional comparison study. AB - BACKGROUND: As social media are evolving rapidly online support groups (OSG) are becoming increasingly important for patients. Therefore, the aim of our study was to compare the users of traditional face-to-face support groups and OSG. PATIENTS AND METHODS: We performed a cross-sectional comparison study of all regional face to-face support groups and the largest OSG in Germany. By applying validated instruments, the survey covered sociodemographic and disease-related information, decision-making habits, psychological aspects, and quality of life. RESULTS: We analyzed the complete data of 955 patients visiting face-to-face support groups and 686 patients using OSG. Patients using OSG were 6 years younger (65.3 vs. 71.5 years; p < 0.001), had higher education levels (47 vs. 21%; p < 0.001), and had higher income. Patients using OSG reported a higher share of metastatic disease (17 vs. 12%; p < 0.001). Patients using OSG reported greater distress. There were no significant differences in anxiety, depression, and global quality of life. In the face-to-face support groups, patient ratings were better for exchanging information, gaining recognition, and caring for others. Patients using OSG demanded a more active role in the treatment decision-making process (58 vs. 33%; p < 0.001) and changed their initial treatment decision more frequently (29 vs. 25%; p < 0.001). CONCLUSIONS: Both modalities of peer support received very positive ratings by their users and have significant impact on treatment decision-making. IMPLICATIONS FOR CANCER SURVIVORS: Older patients might benefit more from the continuous social support in face-to-face support groups. OSG offer low-threshold advice for acute problems to younger and better educated patients with high distress. TRIAL REGISTRATION: www.germanctr.de , number DRKS00005086. PMID- 28861844 TI - Physical activity and advanced cancer: the views of oncology and palliative care physicians in Ireland. AB - BACKGROUND: Physical activity (PA) levels play an important role in maintaining the quality of life and enhancing the physical function of advanced cancer patients. A brief exercise prompt by physicians can increase PA levels of patients diagnosed with cancer. AIMS: This study explores the views of Irish oncology and palliative care physicians towards PA for patients with advanced cancer. METHODS: A web-based survey with closed- and open-ended questions was used to explore physicians' views. The survey presented a Likert-style questionnaire and open text responses to two patient case studies. Quantitative data were analysed using descriptive statistics, and qualitative data were analysed using content analysis. RESULTS: Forty participants completed the study, a response rate of 41%. Responding physicians acknowledged the importance of physical activity for patients with advanced cancer. Twenty-six physicians (67%) agreed that patients look to them for PA recommendations and 30 physicians (77%) indicated a need for more information on providing PA recommendations. Case study responses highlighted concerns relating to PA prescription for patients with bone metastases including the aggravation of symptom control and increased fracture risk. CONCLUSIONS: The results of this study identify a need for physician education on providing PA recommendations for patients with advanced cancer. Concerns over the prescription of PA to patients with bone metastases highlight the need to disseminate the evidence on the benefits of PA for patients with metastatic cancer to healthcare professionals. PMID- 28861846 TI - Generalizing from Case Studies: A Commentary. AB - This commentary responds to the articles assembled for the thematic issue Self identity on the move: methodological elaborations (IPBS, 51 (2), June 2017). The issue points in two directions. Firstly, the articles investigate the way individual self-identity develops in changing social and cultural environments, specifically in the contexts of family, youth and migration. Secondly, the special issue is also interested in methodological elaboration, more specifically the question of how one can generalize from individual case studies, especially when looking at complex, multiscale, semiotic processes. This commentary particularly addresses the second point and uses the various cases in this issue (i) to better understand something of the larger intellectual debate around the question of 'generalizing from case studies', and (ii) to reflect on writing as a tool for indexing generalization. The commentary highlights five textual moves the authors use to make their findings relevant beyond the specifics of the local study. PMID- 28861842 TI - Myeloma and Bone Disease. AB - PURPOSE OF REVIEW: Bone disease is a defining characteristic of multiple myeloma (MM) and the major cause of morbidity. It manifests as lytic lesions or osteopenia and is often associated with severe pain, pathological fracture, spinal cord compression, vertebral collapse, and hypercalcemia. Here, we have reviewed recent data on understanding its biology and treatment. RECENT FINDINGS: The imbalance between bone regeneration and bone resorption underlies the pathogenesis of osteolytic bone disease. Increased osteoclast proliferation and activity accompanied by inhibition of bone-forming osteoblasts leads to progressive bone loss and lytic lesions. Although tremendous progress has been made, MM remains an incurable disease. Novel agents targeting bone disease are under investigation with the goal of not only preventing bone loss and improving bone quality but also harnessing MM tumor growth. Current data illustrate that the interactions between MM cells and the tumor-bone microenvironment contribute to the bone disease and continued MM progression. A better understanding of this microenvironment is critical for novel therapeutic treatments of both MM and associated bone disease. PMID- 28861847 TI - Population Pharmacokinetics of Mycophenolic Acid: An Update. AB - The most recent comprehensive reviews on the population pharmacokinetics of mycophenolic acid (MPA) were published in 2014. Since then, several population pharmacokinetic studies on MPA have been published. The majority of literature is still focused on the kidney transplant population, although studies have also been conducted in liver and lung transplantation, autoimmune diseases, and hematopoietic stem cell transplant. While the majority of the model building is still based on parametric non-linear mixed-effects modeling, recent studies suggest the suitability of other methodologies. Additionally, instead of just focusing on pharmacokinetic modeling, a trend toward describing the relationships between pharmacokinetic and pharmacodynamic parameters is observed. Given the importance of enterohepatic recirculation (EHR) in the pharmacokinetics of MPA, more authors have attempted to characterize this process in their models. Overall, the recent models have become more sophisticated and incorporate EHR, pharmacodynamic relationships, and metabolites while maintaining many of the population values and covariates identified previously. However, the number of MPA population pharmacokinetic models describing the enteric-coated formulation of MPA (EC-MPA) is still limited. Given the increasing use of EC-MPA, more studies are needed to fill this literature gap. In addition, few studies are yet available characterizing free MPA concentration or MPA metabolites. Given the extensive protein binding, low to intermediate extraction, and intrinsic clearance characteristics of MPA in humans, including these variables would improve the population structural models. PMID- 28861848 TI - Update of HIV-Associated Sensory Neuropathies. AB - PURPOSE OF REVIEW: HIV-sensory neuropathy (HIV-SN) remains a common complication of HIV infection and may be associated with significant morbidity due to neuropathic pain. The overall purpose of this review is to discuss trends in the changing epidemiology in HIV-SN, new data regarding the pathophysiology of the condition, and discuss approaches to management. RECENT FINDINGS: While HIV-SN has been historically considered the most common neurological complication of HIV infection, improved accessibility to effective combination antiretroviral therapy (cART), use of less neurotoxic antiretroviral medication regimens, and trends towards earlier introduction of treatment have impacted the condition: overall incident HIV-SN is likely decreased compared to prior rates and patients afflicted by HIV-SN may more frequently have asymptomatic or subclinical disease. Traditional predictors of HIV-SN have also changed, as traditional indices of severe immune deficiency such as low CD4 count and high viral load no longer predict HIV-SN. Emerging evidence supports the contention that both peripheral and central mechanisms underlying the generation as well as persistence of neuropathic pain in HIV-SN exist. It is important to recognize that even mild neuropathic pain in this clinical population is associated with meaningful impairment in quality of life and function, which emphasizes the clinical importance of recognizing and treating the condition. The general approach to management of neuropathic pain in HIV-SN is the introduction of symptomatic analgesic therapy. There exist, however, few evidence-based analgesic options for HIV-SN based on available clinical data. Symptomatic treatment trials are increasingly recognized to have been potentially confounded by more robust placebo response than that observed in other neuropathic pain conditions. In the authors' experience, use of analgesic therapies with proven efficacy in other neuropathic pain conditions is appropriate, bearing in consideration potential pharmacokinetic interactions with the cART regimen. Combination analgesic regimens may also achieve meaningful analgesic responses, particularly when drugs with differing mechanisms of action are utilized. It is paramount that the patient is appropriately counseled regarding expectations and the anticipated benefit of analgesic therapy, as pain relief is often incomplete but clinically meaningful improvement in pain and function can be achieved. PMID- 28861850 TI - Novel simulator for robotic surgery. AB - Surgical simulation avoids practicing skills in patients, allowing trainees to learn in a safe, controlled, and standardized environment. Current robotic surgical simulators available include virtual reality simulators, human cadavers, and live animals. The use of cadavers has the highest possible fidelity available to practice entire operations. Nevertheless, their cost, availability, tissue compliance, and infection risk outweigh the advantages of cadaver models. Drawbacks of using live animals include anatomical differences with humans, high costs due to their housing and handling requirements, and ethical concerns. We designed a novel robotic surgical simulator based on porcine perfused tissue blocks that allows the simulation of entire surgical procedures. Our simulation allows trainees to increase familiarity with the robotic console and its controls, as well as with the docking process. It provides an opportunity to learn not only universal skills needed in robotic surgery, such as camera and instrument targeting, but also to perform complete surgical procedures such as an antireflux procedure. The adoption of robotic simulation curricula with realistic models will decrease overall operative time while increasing resident participation. PMID- 28861849 TI - Internal Carotid Artery Occlusion: Pathophysiology, Diagnosis, and Management. AB - PURPOSE OF REVIEW: Acute internal carotid artery occlusion (ICAO) is associated with large infarcts and poor clinical outcomes and contributes to morbidity and mortality worldwide. In this review, we discuss various etiologies and pathophysiology of clinical presentations of ICAO, different radiographic patterns, and management of patients with ICAO. RECENT FINDINGS: Recanalization rates remain suboptimal with systemic thrombolysis amongst patients with acute ICAO. Recent success of endovascular therapy for vessel occlusion in anterior circulation has expanded the horizons; however, few patients with cervical dissections and ICAO were included in these landmark trials. Acute ICAO responds poorly to intravenous thrombolysis and portends worse clinical outcomes. Extracranial and intracranial ICAOs have varied clinical course and imaging patterns, with discrete cervical ICAO usually associated with better clinical outcomes while tandem occlusions predispose poor outcomes. Diagnostic catheter based angiogram is often required since appearances of ICAO using non-invasive neuroimaging modalities are often deceiving. Repeated vascular imaging in acute to subacute phase to determine recanalization of ICAO is critical for secondary prevention. Recent success of endovascular procedures will continue to expand the horizons to improve the management of ICAO. PMID- 28861851 TI - A comparison between two double-button endoscopically assisted surgical techniques for the treatment acute acromioclavicular dislocations. AB - PURPOSE: To compare clinical and radiological outcomes between two endoscopically assisted double-button techniques in high-grade acute acromioclavicular separations. METHODS: A retrospective single-center study was conducted in patients with acute acromioclavicular joint dislocation Rockwood types III and V, from 2009 to 2014. All were treated endoscopically, with a 1-year minimum follow up. Two consecutive series were conducted; the first (TR group) received the TightRope(r) system, whereas last series (DB group) was treated with the Dog Bone(r) button technology (Arthrex, Naples, FL, USA). Primary endpoints were last follow-up values of Constant score (CS) and Quick-DASH (QD) score. Moreover, the posttraumatic displacement and its evolution were assessed on bilateral Zanca radiographs. A displacement of 5 mm or greater the day after surgery was considered as a lack of reduction; the same difference on last follow-up X-rays was considered as a loss of reduction. RESULTS: Forty patients were reviewed: 22 in the TR group and 18 in the DB group. After a mean follow-up of 27.7 +/- 8.3 months, CS and QD averaged, respectively, 94.3 +/- 4.4 and 2.0 +/- 2.6 in the TR series, whereas they averaged, respectively, 95 +/- 6.1 and 3.4 +/- 3.3 in the DB series after a mean follow-up of 24.1 +/- 5 months (PCS = 0.16, PQDS = 0.08). Lack of reduction and loss of reduction rates were significantly higher in the DB group, with P = 0.0005 and P < 0.0001, respectively. CONCLUSIONS: Both techniques provided good to excellent functional outcomes. However, considering inferior radiological results using the Dog Bone(r) device, we would prefer the TightRope(r) device in acute acromioclavicular dislocations. LEVEL OF EVIDENCE: IV: Therapeutic study-cases series. PMID- 28861852 TI - Antithrombin deficiency and decreased protein C activity in a young man with venous thromboembolism: a case report. AB - Antithrombin and protein C are two crucial members in the anticoagulant system and play important roles in hemostasis. Mutations in SERPINC1 and PROC lead to deficiency or dysfunction of the two proteins, which could result in venous thromboembolism (VTE). Here, we report a Chinese 22-year-old young man who developed recurrent and serious VTE in cerebral veins, visceral veins, and deep veins of the lower extremity. Laboratory tests and direct sequencing of PROC and SERPINC1 were conducted for the patient and his family members. Coagulation tests revealed that the patient presented type I antithrombin deficiency combined with decreased protein C activity resulting from a small insertion mutation c.848_849insGATGT in SERPINC1 and a short deletion variant c.572_574delAGA in PROC. This combination of the two mutations was absent in 400 healthy subjects each from southern and northern China. Then, we summarized all the mutations of the SERPINC1 and PROC gene reported in the Chinese Han population. This study demonstrates that the combination of antithrombin deficiency and decreased protein C activity can result in severe VTE and that the coexistence of different genetic factors may increase the risk of VTE. PMID- 28861853 TI - CORR Insights(r): How Long Does Antimycobacterial Antibiotic-loaded Bone Cement Have In Vitro Activity for Musculoskeletal Tuberculosis? PMID- 28861854 TI - Characteristics of tropical human-modified forests after 20 years of natural regeneration. AB - BACKGROUND: Abandoned human-modified forests are refuges for remnant biodiversity. However, there are very few studies on the biodiversity and regeneration of native species in human-modified forests which are rich in exotic trees. Our research aim is to evaluate the regeneration status and biodiversity of two adjacent human-modified forests. The two forests have distinct overstorey exotic species richness prior to abandonment: one is an exotic tree plantation low in species richness, and the other is an exotic arboretum high in species richness. The original management practices of the two forests have been neglected for more than 20 years. A primary forest was selected as a reference forest to compare their diversity and regeneration status. We asked: (1) Is there a structural difference among the three forests? (2) What are the proportions of native saplings in the human-modified forests? (3) Are the introduced exotic species able to naturalize? RESULTS: We recorded 1316 individuals from 88 species, belonging to 69 genera and 34 families in the three forests [each sampled 16 quadrats (10 m * 5 m)]. Both human-modified forests were similar in their height structure, diameter structure, and sapling density, but differed in species diversity (characterized by rarefaction curves) and floristic composition (indicated by a quantitative similarity index). In the arboretum, only 50% of the sapling individuals were native. Surprisingly, when sampling efforts were standardized, the arboretum had higher native sapling species richness than the exotic species-poor plantation. Moreover, both human-modified forests had conserved a few rare and endemic species. Nevertheless, some exotic species in the arboretum had escaped to the nearby plantation. CONCLUSIONS: After 20 years of abandonment, the two human-modified forests had converged in structure, but not in diversity patterns of native saplings. This could be due to that the diversity of exotic overstorey composition can influence the natural regeneration of understorey plants. Our study also raised concerns about conserving native species and managing naturalized exotic species in these human-modified forests. PMID- 28861855 TI - Provider-controlled virtual reality experience may adjust for cognitive load during vascular access in pediatric patients. PMID- 28861857 TI - 1H, 13C and 15N resonance assignment of human guanylate kinase. AB - Human guanylate kinase (hGMPK) is a critical enzyme that, in addition to phosphorylating its physiological substrate (d)GMP, catalyzes the second phosphorylation step in the conversion of anti-viral and anti-cancer nucleoside analogs to their corresponding active nucleoside analog triphosphates. Until now, a high-resolution structure of hGMPK is unavailable and thus, we studied free hGMPK by NMR and assigned the chemical shift resonances of backbone and side chain 1H, 13C, and 15N nuclei as a first step towards the enzyme's structural and mechanistic analysis with atomic resolution. PMID- 28861856 TI - Role of sentinel node in differentiated thyroid cancer: a prospective study comparing patent blue injection technique, lymphoscintigraphy and the combined technique. AB - PURPOSE: The purpose of the present study was to evaluate the feasibility and reproducibility of the sentinel lymph node (SLNs) biopsy in differentiated thyroid cancer using patent blue injection, lymphoscintigraphy and the combined techniques. METHODS: Between January 2011 and January 2013, 82 consecutive patients were enrolled in our prospective multicentre study. Inclusion criteria were 18 years of age, preoperative diagnosis of differentiated thyroid carcinoma, no evidence of lymph node enlargement and multifocal neoplasm. To investigate the benefits of each procedure, all patients underwent total thyroidectomy plus central compartment lymphadenectomy, and in all cases, the SLN was identified via one of three techniques using the same protocol. RESULTS: Lymphoscintigraphy was used in five patients, patent blue injection was used in 40 patients, and a combined technique was used in 40 patients to identify sentinel lymph nodes (SLN). SLNs were identified in 61 cases. In the patent blue injection technique, the sensitivity, specificity and false negative rates were 88.9, 94.4 and 3.8%, respectively. In the lymphoscintigraphy technique, the percentages of sensitivity and specificity were 100%, and the percentage false negative was 0%. For the combined techniques, the corresponding values were, respectively, 69.2, 90, and 17.4%. Metastases were detected in nine cases of lateral-cervical nodes, ipsilateral tumour metastases were observed in eight cases, and contralateral tumour metastasis was observed in one case. CONCLUSION: Additional well-designed randomized studies are needed to validate and further optimize the SLN biopsy in patients with differentiated thyroid cancer. PMID- 28861859 TI - Sodium hydroxide as a sclerosing agent in patients with neoplastic pleural effusion non-candidates for VATS: results of a minimally invasive protocol. AB - Symptomatic neoplastic pleural effusion (SNPE) is a significant cause of morbidity in patients with advanced neoplastic disease. These patients often present a deteriorated general condition which prevents them from undergoing pleurodesis with video-assisted thoracic surgery (VATS). We developed a minimally invasive therapeutic protocol specially designed for this population, achieved by combining chemical pleurodesis with placement of small-bore pleural catheters (PC), which resulted in early hospital discharge, low morbimortality and good therapeutic results. This study reports the safety and efficacy of administration of sodium hydroxide (NaOH) through PC in 60 patients diagnosed with SNPE who were admitted to Hospital Italiano de Buenos Aires between January 2012 and December 2015. Successful pleurodesis was achieved in 96% of procedures. Recurrence occurred in 25% of patients during follow-up, with recurrence occurring earlier than 30 days after pleurodesis in 8% of patients. There were no reports of major morbidity or associated mortality. In total, 44% of patients were discharged within 48 h of pleurodesis. Administration of NaOH through a small-bore PC represents an effective and safe method of pleurodesis in patients who are not candidates for talc pleurodesis by VATS. PMID- 28861860 TI - Interaction of Lead with Calcium, Iron, and Zinc in the Biological Samples of Malnourished Children. AB - Interaction between toxic and essential elements is of particular interest, because the deficiency of essential element can dramatically increase the absorption rate of toxic metals inside the body. This study was conducted to evaluate the possible correlation of lead (Pb) with calcium (Ca), iron (Fe), and zinc (Zn) in biological samples (whole blood and scalp hair) of malnourished children (MNC). For comparative purposes, age-matched, well-nourished children (WNC) were selected. The concentrations of understudy elements were analyzed by atomic absorption spectrophotometry after microwave acid digestion. The accuracy of the methodology, as well as its its validity and efficiency, was checked through certified reference material of whole blood and scalp hair. The result indicates that the MNC have a twofold higher level of Pb, while the levels of essential elements (Ca, Fe, and Zn) were onefold to twofold lower as compared to the WNC (p < 0.05). Significant negative correlations of Pb with Ca, Fe, and Zn were found in the studied malnourished population at p < 0.05. Further research studies are required to elucidate the role of these metals and the mechanism of interaction inside the body. PMID- 28861861 TI - GATE Monte Carlo simulation of dose distribution using MapReduce in a cloud computing environment. AB - The GATE Monte Carlo simulation platform has good application prospects of treatment planning and quality assurance. However, accurate dose calculation using GATE is time consuming. The purpose of this study is to implement a novel cloud computing method for accurate GATE Monte Carlo simulation of dose distribution using MapReduce. An Amazon Machine Image installed with Hadoop and GATE is created to set up Hadoop clusters on Amazon Elastic Compute Cloud (EC2). Macros, the input files for GATE, are split into a number of self-contained sub macros. Through Hadoop Streaming, the sub-macros are executed by GATE in Map tasks and the sub-results are aggregated into final outputs in Reduce tasks. As an evaluation, GATE simulations were performed in a cubical water phantom for X ray photons of 6 and 18 MeV. The parallel simulation on the cloud computing platform is as accurate as the single-threaded simulation on a local server and the simulation correctness is not affected by the failure of some worker nodes. The cloud-based simulation time is approximately inversely proportional to the number of worker nodes. For the simulation of 10 million photons on a cluster with 64 worker nodes, time decreases of 41* and 32* were achieved compared to the single worker node case and the single-threaded case, respectively. The test of Hadoop's fault tolerance showed that the simulation correctness was not affected by the failure of some worker nodes. The results verify that the proposed method provides a feasible cloud computing solution for GATE. PMID- 28861864 TI - 13 Body Parts. PMID- 28861862 TI - Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study. AB - BACKGROUND: Eribulin is a nontaxane microtubule inhibitor with activity in patients with metastatic breast cancer (MBC). We conducted a phase I dose-finding study of eribulin and capecitabine in patients with MBC pretreated with anthracycline and taxane. METHODS: Women with MBC aged <=70 years were enrolled. A 3 + 3 dose escalation design was used: level 0 dosing, eribulin (1.4 mg/m2 intravenously on days 1 and 8) plus capecitabine [825 mg/m2 orally twice daily (BID)]; 2-weeks-on, 1-week-off in a 21-day cycle. If there were no dose-limiting toxicities (DLTs), level 1 capecitabine dose was 1000 mg/m2 BID. The primary objective was to determine maximum tolerated dose, DLTs, and recommended dose (RD). Secondary objectives included pharmacokinetics, safety, and best overall response rate. RESULTS: Nine women with MBC were enrolled; six at level 0, three at level 1. One patient had grade 4 DLTs at level 0 (serum creatinine 7.65 mg/dL and uric acid 13.4 mg/dL), considered associated with study drugs. Level 1 dosing was taken as the RD. Neutropenia was the most common >=grade 3 toxicity. Pharmacokinetic parameters of eribulin were not influenced by co-administration of capecitabine. Of three patients in level 1, one achieved partial response and one had prolonged stable disease. CONCLUSION: Eribulin with capecitabine in the level 1 dosing schedule was associated with manageable toxicities and promising clinical activity. This combination is recommended for phase II investigation. PMID- 28861863 TI - Protective ventilation reduces Pseudomonas aeruginosa growth in lung tissue in a porcine pneumonia model. AB - BACKGROUND: Mechanical ventilation with positive end expiratory pressure and low tidal volume, i.e. protective ventilation, is recommended in patients with acute respiratory distress syndrome. However, the effect of protective ventilation on bacterial growth during early pneumonia in non-injured lungs is not extensively studied. The main objectives were to compare two different ventilator settings on Pseudomonas aeruginosa growth in lung tissue and the development of lung injury. METHODS: A porcine model of severe pneumonia was used. The protective group (n = 10) had an end expiratory pressure of 10 cm H2O and a tidal volume of 6 ml x kg 1. The control group (n = 10) had an end expiratory pressure of 5 cm H2O and a tidal volume of 10 ml x kg-1. 1011 colony forming units of Pseudomonas aeruginosa were inoculated intra-tracheally at baseline, after which the experiment continued for 6 h. Two animals from each group received only saline, and served as sham animals. Lung tissue samples from each animal were used for bacterial cultures and wet-to-dry weight ratio measurements. RESULTS: The protective group displayed lower numbers of Pseudomonas aeruginosa (p < 0.05) in the lung tissue, and a lower wet-to-dry ratio (p < 0.01) than the control group. The control group deteriorated in arterial oxygen tension/inspired oxygen fraction, whereas the protective group was unchanged (p < 0.01). CONCLUSIONS: In early phase pneumonia, protective ventilation with lower tidal volume and higher end expiratory pressure has the potential to reduce the pulmonary bacterial burden and the development of lung injury. PMID- 28861865 TI - Even low doses of dexmedetomidine produced obstructive apnea during spinal anesthesia. PMID- 28861866 TI - Erratum to: Obesity in International Migrant Populations. PMID- 28861867 TI - Urine glucose levels are disordered before blood glucose level increase was observed in Zucker diabetic fatty rats. AB - Many patients with diabetes are not diagnosed at all or are diagnosed too late to be effectively treated, resulting in nonspecific symptoms and a long period of incubation of the disease. Pre-diabetes is an early warning signal of diabetes, and the change of urine glucose in this period has been ignored even though urine has long been related with diabetes. In this study, Zucker diabetic fatty (ZDF) rats were used to test if there were changes in urine glucose before blood glucose increases. Six 8-week-old male ZDF rats (fa/fa) and Zucker lean (ZL) rats (fa/+) were fed with Purina 5008 high-fat diet and tested for fasting blood glucose and urine glucose. After 12 weeks of feeding, the urine glucose values of the ZL rats were normal (0-10 mmol L-1), but the values of the ZDF model rats increased 10 weeks before their blood glucose levels elevated. The urine glucose values of the ZDF model rats showed a state of disorder that was frequently elevated (>10 mmol L-1) and occasionally normal (0-10 mmol L-1). This finding may provide an easy early screening for diabetes by long-term monitoring of urine glucose levels: pre-diabetes may be revealed by frequently disordered urine glucose levels over a period. PMID- 28861868 TI - Photoperiodic refractoriness in energy balance: a specific pattern in Mongolian gerbils (Meriones unguiculatus). PMID- 28861869 TI - A comparative study of distant hybridization in plants and animals. AB - Distant hybridization refers to crosses between two different species, genera, or higher-ranking taxa, which can break species limits, increase genetic variation, and combine the biological characteristics of existing species. It is an important way of creating genetic variation, fertile strains, and excellent characteristics in new strains and populations. Combining analyses and summaries from many inter-related documents in plants and animals, both domestic and international, including examples and long-standing research on distant hybridization in fish from our laboratory, we summarize and compare the similarities and differences in plant and animal distant hybridization. In addition, we analyze and review the biological characteristics of their different ploidy progenies and the possible causes of disparity in survival rates. Mechanisms of sterility in animal and plant distant hybrids are also discussed, and research methods for the study of biological characteristics of hybrids, including morphology, cytology, and molecular cytogenetics are presented. This paper aims to provide comprehensive research materials and to systematically compare the general and specific characteristics of plant and animal hybrids with regards to reproduction, genetics, growth traits, and other biological characteristics. It is hoped that this paper will have great theoretical and practical significance for the study of genetic breeding and biological evolution of plant and animal distant hybridization. PMID- 28861871 TI - Combinatorial Therapies in Melanoma: MAPK Inhibitors and Beyond. AB - Melanoma is the most aggressive of the skin cancers, with historically high rates of morbidity and mortality due to its resistance to traditional cytotoxic therapies. Recently, however, breakthroughs in new therapies have dramatically changed clinical outcomes of this disease. These advances emerged from an improved understanding of tumor oncogenesis and the interacting tumor microenvironment. Small molecules that target the oncogenic mitogen-activated protein kinase (MAPK) pathway, specifically the tyrosine kinase BRAF and its downstream signaling partner MEK, have demonstrated an improved overall survival and progression-free survival for BRAF-mutant melanoma. Additionally, manipulation of tumor immune surveillance by inhibitors of the immune suppressive programmed cell death 1 receptor (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathways have recently demonstrated durable responses in various cancers by promoting an anti-tumor immune response. Application of these targeted and immune-modulatory therapies has shown promising outcomes in melanoma. Combinations of these therapies may hold promise to enhance responses further. In this review, we will discuss the current targeted therapies and immunotherapies, and review the results of combination studies and speculate on future treatment paradigms. PMID- 28861872 TI - Intermale aggression in mice, selected for the cognitive trait. AB - The data are presented on intermale aggression in mice which were selected for high scores of cognitive trait (the ability for extrapolation of movement direction) in comparison to the data of control mice performance. The changes in aggression level in the course of selection are presumably connected with anxiety level which also changed during selection generations. PMID- 28861873 TI - Role of the pregnancy-specific glycoprotein in regulation of the cytokine and chemokine profiles of intact mononuclear cells. AB - The effect of human pregnancy-specific glycoprotein (PSG) on the cytokine and chemokine production in vitro by intact mononuclear cells was studied by the method of flow fluorimetry. PSG inhibited production of the proinflammatory cytokines IL-6, IL-8, IL-17, IFN-gamma, and TNF-alpha and chemokines CCL3/MIP 1alpha, CCL4/MIP-1beta, CCL2/MCP-1; at the same time, PSG stimulated IL-12(p70) production. Simultaneously with increasing the VEGF level, PSG inhibited production of IL-9, IL-13, G-CSF, and GM-CSF. The PSG effect discovered can be interpreted as a contribution into the immune tolerance formation during pregnancy. PMID- 28861870 TI - Dopamine Agonists and Impulse Control Disorders: A Complex Association. AB - Impulse control disorders (ICDs) are a well-known adverse effect of dopamine agonists (DAAs). This critical review aims to summarize data on the prevalence and factors associated with the development of an ICD simultaneous to DAA use. A search of two electronic databases was completed from inception to July 2017. The search terms were medical subject headings (MeSH) terms including "dopamine agonists" AND "disruptive disorders", "impulse control disorders", or "conduct disorders". Articles had to fulfill the following criteria to be included: (i) the target problem was an ICD; (ii) the medication was a dopaminergic drug; and (iii) the article was an original article. Of the potential 584 articles, 90 met the criteria for inclusion. DAAs were used in Parkinson's disease (PD), restless legs syndrome (RLS) or prolactinoma. The prevalence of ICDs ranged from 2.6 to 34.8% in PD patients, reaching higher rates in specific PD populations; a lower prevalence was found in RLS patients. We found only two studies about prolactinoma. The most robust findings relative to the factors associated with the development of an ICD included the type of DAA, the dosage, male gender, a younger age, a history of psychiatric symptoms, an earlier onset of disease, a longer disease duration, and motor complications in PD. This review suggests that DAA use is associated with an increased risk in the occurrence of an ICD, under the combined influence of various factors. Guidelines to help prevent and to treat ICDs when required do exist, although further studies are required to better identify patients with a predisposition. PMID- 28861874 TI - Cytokine production by the tumor from patients with breast cancer in different age groups. AB - Dependence of cytokine pattern in the tumor supernatant obtained after cultivation of biopsy samples-on the patients' age was evaluated among patients with invasive ductal carcinoma of the breast. An increase in VEGF and IL-6 production in a group of younger patients was observed. An increase only in interferon gamma concentration was revealed in the supernatants of the tumor after addition of polyclonal activators to the culture medium. This result indicates likely secretion of interferon gamma in younger patients. The relation among the production of angiogenic factors by tumor cells, age of the patients, and presence or absence of lymph node metastases shows that in such studies, patients have to be stratified by age. PMID- 28861875 TI - Age-related adaptive responses of mitochondria of the retinal pigment epithelium to the everyday blue LED lighting. AB - The effect of everyday blue light (lambda = 440-460 nm) on mitochondria of the retinal pigment epithelium of different age groups of Japanese quail was studied using electron microscopy, morphometric methods, and biochemical analysis. We have found a significant increase in the number of mitochondria, including those modified, mainly in young birds. In addition, cell metabolic activity increased in response to blue lighting. These changes are assumed to reflect an adaptive response of mitochondria aimed at neutralizing the phototoxic effect of blue light caused by accumulation of lipofuscin granules. PMID- 28861876 TI - Isolation of primary osteoblast cell lines from adult rat and rat embryos and their use as models for in vitro biocompatibility tests of nanostructured titanium-based implants. AB - Methods for obtaining osteoblast cultures from the calvaria of adult Wistar rats and 12-day-old embryos of these rats have been adapted for studying the biocompatibility and ossointegration of titanium-based implants. The osteoblast morphology and their differentiation into osteocytes on a titanium matrix with specially treated surface have been studied. It has been confirmed that two cultures of diploid rat cells obtained in the study can serve as efficient models for preclinical in vitro testing of nanostructured titanium implants for biocompatibility and osseointegration. PMID- 28861877 TI - New data on the effect of ionizing radiation on the growth of the aquatic plant Elodea canadensis in the laboratory. AB - Toxicological experiments with radioactive bottom sediments and extrinsic gamma irradiation have demonstrated that the growth of common elodea roots is suppressed by irradiation at doses several times lower than the established threshold dose. The effect of gamma-irradiation on the growth of elodea stems has not been observed at any dose used. The data obtained show that elodea could be recommended for use as an indicator of biological effects of radiation in the range of low radiation doses. PMID- 28861878 TI - Regulation of the peritoneal macrophage functional activity by the MP-5 and MP-6 myelopeptides under stress. AB - In mice, two-hour immobilization stress inhibited zymosan-induced production by macrophages of the oxygen radicals and cytokine IL-1beta. After myelopeptides MP 5 and MP-6 were administered into mice, the stress-induced inhibition of the reactive oxygen species (ROS) and IL-1beta was abrogated. MP-5 peptide stimulated spontaneous ROS production by macrophages and reduced IL-10 production under stress. Thus, under in vivo conditions and under stress, the effect of MP-5 and MP-6 myelopeptides modulates the peritoneal macrophage activity. PMID- 28861879 TI - Comparative analysis of the nervous system structure of polymorphic zooids in marine bryozoans. AB - The nervous system structure was compared for the first time in avicularia and vibracula in seven species of the cheilostome bryozoans from six families by immunohistochemical methods and confocal scanning microscopy. Regardless of significant differences in heterozooid shape, size, and position in a colony, their muscular and nervous systems have a common structure, which suggests their parallel evolution. PMID- 28861880 TI - Unconsidered sporadic sources of carbon dioxide emission from soils in taiga forests. AB - Long-term monitoring in the Russian taiga zone has shown that all known extreme destructive effects resulting in the weakening and death of tree stands (windfalls, pest attacks, drought events, etc.) can be sporadic, but significant sources of CO2 soil emission. Among them are (i) a recently found effect of the multiyear CO2 emission from soil at the bottom of deadwood of spruce trees that died due to climate warming and subsequent pest outbreaks, (ii) increased soil CO2 emissions due to to the fall of tree trunks during massive windfalls, and (iii) pulse CO2 emission as a result of the so-called Birch effect after drought events in the taiga zone. According to the modeling, while depending on the spatial and temporal scales of their manifestation, the impact of these sporadic effects on the regional and global soil respiration fluxes could be significant and should be taken into consideration. This is due to continuing Climate Change, and further increase of local, regional and Global human impacts on the atmospheric greenhouse gases balance, and land use, as well. PMID- 28861881 TI - Inactivation of proteolytic enzymes by cestodes. AB - Inhibitor activity of cestodes from intestines of different hosts (sea birds, salt-water fish, and freshwater fish) was investigated. Alcataenia larina, Arctotaenia tetrabothrioides, Tetrabothrius erostris, T. minor, Wardium cirrosa, Bothriocephalus scorpii, Eubothrium rugosum, and Triaenophorus nodulosus were able to inhibit the activity of the commercial trypsin and activity of proteinase homogenates of the intestinal mucosa of the hosts. It was suggested that the inhibitor produced by the cestodes is specific for trypsin and protects them from the digestive enzymes of the host. PMID- 28861882 TI - Sucrose-enriched diet during maturation increases ethanol preference in rats. AB - In the present study we used a diet enriched with 10% sucrose, which was consumed by adolescent animals of the experimental group for one month. We found that consumption of sweet food during sexual maturation affected alcohol preference, anxiety, and locomotor and exploratory activity in the adult rats. Our data show that easily available tasty food during adolescence probably impairs the reward system and serves as a trigger of future alcohol preference. PMID- 28861883 TI - Nervous system and musculature of the parasitic turbellarian Notentera ivanovi (Plathelminthes, Fecampiida). AB - The article reports the first description of the architecture of the musculature and cholinergic nervous system of the parasitic turbellarian Notentera ivanovi from the White Sea using histochemistry and confocal scanning laser microscopy. It has been demonstrated that the body wall is composed of layers of circular and longitudinal muscles between which there are diagonal muscles described here for the first time. The nervous system is of the regular closely spaced orthogon type with pronounced radiality. In order to make it clear whether the orthogon of this type is a phylogenetic characteristic of this group of worms or its shape is associated with the flat rounded body, the study of other representatives of the Fecampiida group is required. PMID- 28861884 TI - Cross-cultural Differences in Mental Health, Quality of Life, Empathy, and Burnout between US and Brazilian Medical Students. AB - OBJECTIVE: This study aimed to compare mental health, quality of life, empathy, and burnout in medical students from a medical institution in the USA and another one in Brazil. METHODS: This cross-cultural study included students enrolled in the first and second years of their undergraduate medical training. We evaluated depression, anxiety, and stress (DASS 21), empathy, openness to spirituality, and wellness (ESWIM), burnout (Oldenburg), and quality of life (WHOQOL-Bref) and compared them between schools. RESULTS: A total of 138 Brazilian and 73 US medical students were included. The comparison between all US medical students and all Brazilian medical students revealed that Brazilians reported more depression and stress and US students reported greater wellness, less exhaustion, and greater environmental quality of life. In order to address a possible response bias favoring respondents with better mental health, we also compared all US medical students with the 50% of Brazilian medical students who reported better mental health. In this comparison, we found Brazilian medical students had higher physical quality of life and US students again reported greater environmental quality of life. Cultural, social, infrastructural, and curricular differences were compared between institutions. Some noted differences were that students at the US institution were older and were exposed to smaller class sizes, earlier patient encounters, problem-based learning, and psychological support. CONCLUSION: We found important differences between Brazilian and US medical students, particularly in mental health and wellness. These findings could be explained by a complex interaction between several factors, highlighting the importance of considering cultural and school-level influences on well-being. PMID- 28861885 TI - Erratum to: Clinical Impact of the 2016 Update to the WHO Lymphoma Classification. PMID- 28861886 TI - Insights of Chinese medicine on ventricular remodeling: Multiple-targets, individualized-treatment. AB - Ventricular remodeling (VR) can be induced by myocardial injury, leading to progressive cardiac dysfunction and heart failure, and is associated with high morbidity and mortality. Despite being studied for more than 3 decades, current therapeutic strategies still remain unsatisfactory in effificacy, expensive, and with side effects and drug resistances. Chinese medicine (CM) has been used to treat heart diseases for thousands of years. This article reviews the published studies on the mechanisms and therapeutic applications of CM in VR. The major aspects include: mechanistic studies of VR, molecular biology and myocardial functional studies of CM therapies on VR, and mechanism of CM therapies on VR. PMID- 28861887 TI - Combination of quercetin, cinnamaldehyde and hirudin protects rat dorsal root ganglion neurons against high glucose-induced injury through Nrf-2/HO-1 activation and NF-kappaB inhibition. AB - OBJECTIVE: To examine the effects of the combination of quercetin (Q), cinnamaldehyde (C) and hirudin (H), a Chinese medicine formula on high glucose (HG)-induced apoptosis of cultured dorsal root ganglion (DRG) neurons. METHODS: DRG neurons exposed to HG (45 mmol/L) for 24 h were employed as an in vitro model of diabetic neuropathy. Cell viability, reactive oxygen species (ROS) level and apoptosis were determined. The expression of nuclear factor of Kappa B (NF kappaB), inhibitory kappa Balpha(IkappaBalpha), phosphorylated IkappaBalpha and Nf-E2 related factor 2 (Nrf2) were examined using reverse transcription polymerase chain reaction (RT-PCR) and Western blot assay. The expression of hemeoxygenase-1 (HO-1), interleukin-6 (IL-6), tumor necrosis factor (TNF-alpha) and caspase-3 were also examined by RT-PCR and Western blot assay. RESULTS: HG treatment markedly increased DRG neuron apoptosis via increasing intracellular ROS level and activating the NF-kappaB signaling pathway (P<0.05). Co-treatment with Q, C, H and their combination decreased HG-induced caspase-3 activation and apoptosis (P<0.05 or P<0.01). The expressions of NF-kappaB, IL-6 and TNF-alpha were down-regulated, and Nrf2/HO-1 expression was up-regulated (P<0.05 or P<0.01). QCH has better effect in scavenging ROS, activating Nrf-2/HO-1, and down regulating the NF-kappaB pathway than other treatment group. CONCLUSIONS: DRG neurons' apoptosis was increased in diabetic conditions, which was reduced by QCH formula treatment. The possible reason could be activating Nrf-2/HO-1 pathway, scavenging ROS, and inhibition of NF-kappaB activation. The effect of QCH combination was better than each monomer or the combination of the two monomers. PMID- 28861888 TI - Effect of Qingfei Mixture () on pediatric mycoplasma pneumoniae pneumonia with phlegm heat obstructing Fei (Lung) syndrome. AB - OBJECTIVE: To explore the effect and mechanism of Qingfei Mixture (), a Chinese medicine, in treating mycoplasma pneumonia (MP) in MP patients and rat model METHODS: A total of 46 MP children with phlegm heat obstructing Fei (Lung) syndrome were randomly assigned to two groups by the method of random number table, with 23 children in each group. The control group was treated with intravenous infusion of azithromycin; the treatment group received intravenous infusion of azithromycin and oral administration of Qingfei Mixture. The treatment course was 7 days. Major symptoms and minor symptoms were observed and scored before and after treatments. A rat model of MP was also established. A total of 120 wistar rats were randomly divided into 5 groups: a normal group, infection group, Qingfei Mixture treatment group, azithromycin treatment group, and Qingfei Mixture + azithromycin treatment group. Each group contained 24 rats, from which every 6 were euthanatized 1, 3, 7 and 14 days after infection. MP DNA in pulmonary tissue homogenates was detected using real-time fluorescence quantitative polymerase chain reaction. Pathology was assessed after hematoxylin (HE) staining and lung tissue pathology scores were determined in pulmonary tissue. Transmission electron microscopic detection and electronic image analysis were performed on lung tissue 3 days after infection. Interleukin (IL)-17 was detected in serum using enzymelinked immunosorbent assay (ELISA) 7 days after infection. RESULTS: In the clinical study, both control and the treatment group showed improved results on removing symptoms of phlegm heat syndrome compared to the control group (P<0.05). In animal experiments, On the 7th day after MP infection, as detected by electron microscopy, the pulmonary capillary basement membranes of the azithromycin + Qingfei Mixture treatment group were much thinner than those of the azithromycin or Qingfei mixture treatment groups (P<0.05). The level of serum IL-17 in the azithromycin + Qingfei Mixture treatment group was lower than that in the azithromycin or Qingfei Mixture groups (P<0.01). CONCLUSION: Both Qingfei Mixture and azithromycin have therapeutic effects on mycoplasma pneumoniae pneumonia, but the combination of both agents had the greatest effect. PMID- 28861889 TI - Red yeast rice prevents atherosclerosis through regulating inflammatory signaling pathways. AB - OBJECTIVE: To observe the effects of red yeast rice (RYR) on blood lipid levels, aortic atherosclerosis (AS), and plaque stability in apolipoprotein E gene knockout (ApoE-/-) mice. METHODS: Twenty-four ApoE-/- mice were fed with a high fat diet starting from 6 weeks of age. Mice were randomized into three groups (n = 8 in each group): model group (ApoE-/- group), RYR group (ApoE-/- + RYR group), and simvastatin group (ApoE-/- + simvastatin group). Eight 6-week-old C57BL/6 mice were assigned as the control group and fed with a basic diet. After 36 weeks, plasma lipids and inflflammatory factors were measured. Aortic atherosclerotic lesions by microscope, scanning electron microscope and transmission electron microscope were observed. Plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured with enzyme linked immunosorbent assay. The level of high sensitivity C-reaction protein (Hs CRP) was detected by the scattering immunoturbidimetric assay. Protein expression of matrix metalloproteinase-9 (MMP-9) and nuclear factor kappaB (NF-kappaB) in aorta were tested by immunohistochemistry. RESULTS: Compared with the model group, treatment with RYR significantly decreased the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, lipoprotein (a), and apolipoprotein B100 in ApoE-/- mice (P<0.01). Compared with the model group, treatment with RYR decreased the levels of Hs-CRP, IL-6, and TNF-alpha (P<0.01). RYR also reduced the protein levels of NF-kappaB and MMP-9 of the aorta. CONCLUSIONS: RYR has the anti-atherosclerotic and stabilizing unstable plaque effects. The mechanism might be related to the inflflammatory signaling pathways. PMID- 28861890 TI - High-grade renal cell carcinoma with emperipolesis: Clinicopathological, immunohistochemical and molecular-genetic analysis of 14 cases. AB - Emperipolesis has recently been described as a constant feature of "biphasic squamoid" papillary renal cell carcinoma (BPRCC). We also noticed this in some high-grade (HG) RCC, which promoted the present study to estimate the incidence of emperipolesis in RCCs and to describe them in further detail. 14 cases of HGRCC showing emperipolesis were retrieved from our registry. Microscopic examination of filed slides was supplemented with immunohistochemical and molecular-genetic analyses using paraffin embedded tissue. 12 of 14 patients were males with a mean age of 58.6 years (range 41-72 years). Tumor size ranged from 6 16.5 cm (mean of 8.8 cm). Follow up data were available for 8/14 patients (range 0.5-10 years). Metastases were documented in 6 cases. All tumors showed solid alveolar growth patterns with focal pseudopapillary features, and were composed of large cells with bizarre nuclei and eosinophilic rhabdoid-like cytoplasm. Emperipolesis was a constant and prominent feature in large bizarre cells. All cases were positive for OSCAR, CANH 9, vimentin, cyclin D1, INI-1, and myoD1, while negative for melanocytic markers, CK 7, myoglobin, cathepsin K, and TFE3. VHL gene abnormalities were found in 6/9 analyzable cases, of which 2 demonstrated polysomy of chromosomes 7, 17. Emperipolesis is a rare histomorphologic feature which can be seen not only in BPRCCs but also in highgrade CCRCCs. All RCC cases with prominent emperipolesis fulfilled both morphologic and immunohistochemical diagnostic criteria of high-grade CCRCC. The majority of patients with available follow up information developed metastases. PMID- 28861891 TI - Improving power of association tests using multiple sets of imputed genotypes from distributed reference panels. AB - The accuracy of genotype imputation depends upon two factors: the sample size of the reference panel and the genetic similarity between the reference panel and the target samples. When multiple reference panels are not consented to combine together, it is unclear how to combine the imputation results to optimize the power of genetic association studies. We compared the accuracy of 9,265 Norwegian genomes imputed from three reference panels-1000 Genomes phase 3 (1000G), Haplotype Reference Consortium (HRC), and a reference panel containing 2,201 Norwegian participants from the population-based Nord Trondelag Health Study (HUNT) from low-pass genome sequencing. We observed that the population-matched reference panel allowed for imputation of more population-specific variants with lower frequency (minor allele frequency (MAF) between 0.05% and 0.5%). The overall imputation accuracy from the population-specific panel was substantially higher than 1000G and was comparable with HRC, despite HRC being 15-fold larger. These results recapitulate the value of population-specific reference panels for genotype imputation. We also evaluated different strategies to utilize multiple sets of imputed genotypes to increase the power of association studies. We observed that testing association for all variants imputed from any panel results in higher power to detect association than the alternative strategy of including only one version of each genetic variant, selected for having the highest imputation quality metric. This was particularly true for lower frequency variants (MAF < 1%), even after adjusting for the additional multiple testing burden. PMID- 28861892 TI - Sociodemographic, clinical, and functional long-term outcomes in adolescents and young adults with mental disorders. AB - OBJECTIVE: To examine unfavorable sociodemographic, clinical, and functional long term outcomes for a range of adolescent mental disorders. METHODS: A total number of 2210 adolescents and young adults (14-24 years at baseline, T0) from a representative community sample were prospectively followed up (T1-T3) over 10 years. DSM-IV mental disorders, sociodemographic, clinical, and functional outcomes were assessed using the DIA-X/M-CIDI and its embedded assessment modules. RESULTS: In (multinomial) logistic regressions adjusted for sex, age, other baseline disorders and sociodemographics, baseline anxiety, affective, substance use, somatoform and eating disorders (lifetime) predicted various unfavorable sociodemographic, clinical, and functional outcomes at T3. Particularly, strong associations were found between baseline disorders and adverse clinical outcomes at T3 (12-month diagnosis of the same/other disorder(s), drug use, suicide attempts, and help-seeking due to psychological problems). While substance use disorders were primarily associated with unfavorable sociodemographic and educational outcomes, anxiety and eating disorders were associated with unfavorable interpersonal outcomes, affective disorders with pregnancy-/childbirth-related complications and financial issues, and somatoform disorders with unfavorable educational/occupational and interpersonal outcomes. The risk of unfavorable outcomes increased with clinical severity, especially a higher number of baseline diagnoses. CONCLUSIONS: Our findings emphasize the importance of effective treatment of mental disorders to prevent unfavorable long-term outcomes in various life domains. PMID- 28861893 TI - Glitazone use associated with reduced risk of Parkinson's disease. AB - BACKGROUND: Whether antidiabetic glitazone drugs protect against Parkinson's disease remains controversial. Although a single clinical trial showed no evidence of disease modulation, retrospective studies suggest that a disease preventing effect may be plausible. The objective of this study was to examine if the use of glitazone drugs is associated with a lower incidence of PD among diabetic patients. METHODS: We compared the incidence of PD between individuals with diabetes who used glitazones, with or without metformin, and individuals using only metformin in the Norwegian Prescription Database. This database contains all prescription drugs dispensed for the entire Norwegian population. We identified 94,349 metformin users and 8396 glitazone users during a 10-year period and compared the incidence of PD in the 2 groups using Cox regression survival analysis, with glitazone exposure as a time-dependent covariate. RESULTS: Glitazone use was associated with a significantly lower incidence of PD compared with metformin-only use (hazard ratio, 0.72; 95% confidence interval, 0.55-0.94; P = 0.01). CONCLUSIONS: The use of glitazones is associated with a decreased risk of incident PD in populations with diabetes. Further studies are warranted to confirm and understand the role of glitazones in neurodegeneration. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 28861895 TI - Temperature-shuffled parallel cascade selection molecular dynamics accelerates the structural transitions of proteins. AB - Parallel cascade selection molecular dynamics (PaCS-MD) is an enhanced conformational sampling method for searching structural transition pathways from a given reactant to a product. Recently, a temperature-aided PaCS-MD (Vinod et al., Eur. Biophys. J. 2016, 45, 463) has been proposed as its extension, in which the temperatures were introduced as additional parameters in conformational resampling, whereas the temperature is fixed in the original PaCS-MD. In the present study, temperature-shuffled PaCS-MD is proposed as a further extension of temperature-aided PaCS-MD in which the temperatures are shuffled among different replicas at the beginning of each cycle of conformational resampling. To evaluate their conformational sampling efficiencies, the original, temperature-aided, and temperature-shuffled PaCS-MD were applied to a protein-folding process of Trp cage, and their minimum computational costs to identify the native state were addressed. Through the evaluation, it was confirmed that temperature-shuffled PaCS-MD remarkably accelerated the protein-folding process of Trp-cage compared with the other methods. (c) 2017 Wiley Periodicals, Inc. PMID- 28861894 TI - Sex differences in the glutamate signaling pathway in juvenile rats. AB - Females have been found to be at lower risk for the development of neurodevelopmental disorders than males. The greater neuroprotection in females is mostly due to female sex hormones. Estrogen is hypothesized to provide neuroprotection by suppressing the neuro-excitotoxicity induced by glutamate (Glu). This study was conducted to understand the effect of sex in modulating Glu signaling in juvenile rats. Brain tissue homogenate of 15 Wistar albino rats (9 males, 6 females) weighing 60 to 80 g and aged approximately 28 days was used. Biochemical parameters related to Glu signaling, such as the absolute and relative concentrations of Glu, gamma aminobutyric acid (GABA), and glutamine, as well as glutamate transporter 1 (GLT1), glutamine synthetase (GS), glutaminase (GLN), and glutamate decarboxylase-67 (GAD-67), were measured by ELISA. The data obtained demonstrated that compared with the levels in males, female rats exhibited significantly lower levels of Glu (p = .001) and GLN/GS (p = .021). The Glu/GABA and Glu/GLT1 ratios as well as the levels of GAD-67 were also lower in female rats, although the difference was not significant. The GLN/GAD-67 ratio (p = .027) and levels of GS (p = .019) were significantly higher in female rats than in males. Multiple regression analysis confirmed the role of GLN/GS, together with the much higher affinity of GLT1 to Glu, in avoiding excitotoxicity in females. In conclusion, there was a significant difference in Glu signaling between female and male rats. The females exhibited a lower susceptibility to develop Glu-induced excitotoxicity, an etiological mechanism for multiple neurodevelopmental disorders. PMID- 28861896 TI - Sleep difficulties and academic performance in Norwegian higher education students. AB - BACKGROUND: Sleep difficulties are common among university students and may detrimentally affect academic outcomes. Despite this, remarkably little information is currently available during this critical developmental period of early adulthood, and thus, the direct effect on measurable domains of academic ability and proficiency is equivocal. AIMS: To evaluate the associations between difficulties initiating and maintaining sleep (DIMS) and subjective and objective academic performance in a large sample of university students. SAMPLE: A total of 12,915 students who participated in large student survey in Norway from 24 February 2014 to 27 March 2014. DIMS was assessed by the Hopkins Symptoms Checklist (HSCL-25), and academic outcomes included failed examinations, delayed study progress, and school-related self-efficacy (General Self-Efficacy Scale). RESULTS: Difficulties initiating and maintaining sleep was independently associated with increased odds for poor school performance for all academic outcomes. Reporting 'extreme' DIMS was associated with increased odds of reporting delayed study progress (adjusted odds ratio [OR] = 1.25, 95% CI 1.01 1.57, p < .05), increased odds for having failed several examinations (adjusted OR = 1.91, 95% CI 1.56-2.34, p < .001), and being in the lowest self-efficacy quartile (adjusted OR = 4.94, 95% CI: 4.04-6.03, p < .001). CONCLUSIONS: Self reported sleep difficulties are associated with poorer objective markers of academic outcomes as well as poorer self-rated academic proficiency among higher education students. Amelioration of sleep difficulties may improve overall academic performance and health outcomes in affected students. PMID- 28861897 TI - Beyond mean allelic effects: A locus at the major color gene MC1R associates also with differing levels of phenotypic and genetic (co)variance for coloration in barn owls. AB - The mean phenotypic effects of a discovered variant help to predict major aspects of the evolution and inheritance of a phenotype. However, differences in the phenotypic variance associated to distinct genotypes are often overlooked despite being suggestive of processes that largely influence phenotypic evolution, such as interactions between the genotypes with the environment or the genetic background. We present empirical evidence for a mutation at the melanocortin-1 receptor gene, a major vertebrate coloration gene, affecting phenotypic variance in the barn owl, Tyto alba. The white MC1R allele, which associates with whiter plumage coloration, also associates with a pronounced phenotypic and additive genetic variance for distinct color traits. Contrarily, the rufous allele, associated with a rufous coloration, relates to a lower phenotypic and additive genetic variance, suggesting that this allele may be epistatic over other color loci. Variance differences between genotypes entailed differences in the strength of phenotypic and genetic associations between color traits, suggesting that differences in variance also alter the level of integration between traits. This study highlights that addressing variance differences of genotypes in wild populations provides interesting new insights into the evolutionary mechanisms and the genetic architecture underlying the phenotype. PMID- 28861899 TI - Modified method for applying Mohs' paste. PMID- 28861898 TI - Irrigated-tip catheters for radiofrequency ablation of right-sided accessory pathways in adolescents. AB - BACKGROUND: Catheter ablation of right-sided accessory pathways (APs) has lower success and higher recurrence rates compared to left-sided substrates. Irrigated tip catheter (ITC) ablation might offer an advantage in this setting but data about its use in patients below 18 years are scarce. The aim of this study was to compare an ITC approach to conventional catheter ablation. METHODS: A retrospective analysis of all patients <18 years undergoing radiofrequency ablation (RFA) for right-sided APs from 2004 to 2014 at our institution was performed. Patients either underwent an ITC approach in combination with 3-D mapping (Group 1; n = 53) or a conventional non-ITC approach (Group 2; n = 52). Study endpoints were acute procedural success, safety, and recurrence rate. A total of 105 mostly adolescent patients (56.2% male; median age 14 years) with 107 right-sided APs were included. RESULTS: The prevailing anatomic AP locations were right posteroseptal (44.9%), right anterior/anterolateral (24.3%), and right lateral (13.1%). Acute success (94.3% vs 94.2%) did not differ between the groups. One major complication (pericardial effusion) occurred in the non-ITC group. Overall, freedom from AP recurrence was 94% at 4 years in the ITC group, and 81% at 4 years in the non-ITC group (P = 0.04). CONCLUSIONS: The use of ITCs in combination with 3-D mapping system for ablation of right-sided APs in adolescents has a high acute success rate, is safe, and associated with a significantly reduced recurrence rate compared to a non-ITC/conventional approach. It might be considered as alternative approach in this age group. PMID- 28861900 TI - Does persisting fear sustain catatonia? AB - OBJECTIVE: To examine the psychological substrate of catatonia. METHOD: Reviewing the historical descriptions and explanations of catatonic behaviours by clinicians from its delineation in the 19th century to the present. RESULTS: Patients with catatonia are often haunted by fears and terrors; this has not been widely appreciated, and certainly was lost from view in the days when catatonia was considered a subtype of schizophrenia. The report contributes to resolving a major question in catatonia: is the mind in stupor inactive, as the blank state that we picture in anesthetized patients, or is the mind active, so preoccupied as to exclude all other influences. THE MAIN FINDING: Persistent fear occupies the mind of catatonic patients. CONCLUSION: The signs of catatonia are adaptations to persistent fear, akin to tonic immobilization. The relief afforded by sedation supports this interpretation. PMID- 28861901 TI - eHealth literacy: How to choose quality Internet electrophysiology patient resources. PMID- 28861902 TI - Age effects in eating disorder baseline risk factors and prevention intervention effects. AB - OBJECTIVE: Examine the impact of age on baseline eating disorder symptoms/risk factors and on the effects of completing three variants of an eating disorder prevention program. METHOD: Six hundred and eighty women (60% White) were randomized to clinician-led Body Project groups, peer-led Body Project groups, an Internet-based version of the Body Project (eBodyProject), or educational video control condition. Participants, who were on average 22.2 years old (SD = 7.1, range 17-64, median = 19), were assessed at pretest, posttest, and 6-month follow up. RESULTS: Two of the seven baseline variables were significantly associated with age, indicating that older age was associated with lower reported dieting (r = -.12) and better psychosocial functioning (r = -.13). Interactions indicated that age moderated the intervention effects, such that group-based programs were superior to the Internet-delivered version in terms of eating disorder symptom reductions for women up to age 20, whereas the Internet-delivered program was superior to group-based interventions, particularly in terms of BMI reduction, for women over approximately age 25. None of the four tests examining whether age moderated the effects of delivering Body Project groups by mental health clinicians versus undergraduate peer educators were significant. DISCUSSION: Results suggest that group-based versions of the Body Project should be implemented with young women up to the age of 20, as they produce larger eating disorder symptom reductions, whereas the Internet version of the Body Project should be implemented with women aged 25 or older, as it produces superior weight loss/gain prevention effects. PMID- 28861903 TI - Patterns and biases of climate change threats in the IUCN Red List. AB - International Union for Conservation of Nature (IUCN) Red List assessments rely on published data and expert inputs, and biases can be introduced where underlying definitions and concepts are ambiguous. Consideration of climate change threat is no exception, and recently numerous approaches to assessing the threat of climate change to species have been developed. We explored IUCN Red List assessments of amphibians and birds to determine whether species listed as threatened by climate change display distinct patterns in terms of habitat occupied and additional nonclimatic threats faced. We compared IUCN Red List data with a published data set of species' biological and ecological traits believed to infer high vulnerability to climate change and determined whether distributions of climate change-threatened species on the IUCN Red List concur with those of climate change-threatened species identified with the trait-based approach and whether species possessing these traits are more likely to have climate change listed as a threat on the IUCN Red List. Species in some ecosystems (e.g., grassland, shrubland) and subject to particular threats (e.g., invasive species) were more likely to have climate change as a listed threat. Geographical patterns of climate change-threatened amphibians and birds on the IUCN Red List were incongruent with patterns of global species richness and patterns identified using trait-based approaches. Certain traits were linked to increases or decreases in the likelihood of a species being threatened by climate change. Broad temperature tolerance of a species was consistently related to an increased likelihood of climate change threat, indicating counterintuitive relationships in IUCN assessments. To improve the robustness of species assessments of the vulnerability or extinction risk associated with climate change, we suggest IUCN adopt a more cohesive approach whereby specific traits highlighted by our results are considered in Red List assessments. To achieve this and to strengthen the climate change-vulnerability assessments approach, it is necessary to identify and implement logical avenues for further research into traits that make species vulnerable to climate change (including population-level threats). PMID- 28861904 TI - Equity trade-offs in conservation decision making. AB - Conservation decisions increasingly involve multiple environmental and social objectives, which result in complex decision contexts with high potential for trade-offs. Improving social equity is one such objective that is often considered an enabler of successful outcomes and a virtuous ideal in itself. Despite its idealized importance in conservation policy, social equity is often highly simplified or ill-defined and is applied uncritically. What constitutes equitable outcomes and processes is highly normative and subject to ethical deliberation. Different ethical frameworks may lead to different conceptions of equity through alternative perspectives of what is good or right. This can lead to different and potentially conflicting equity objectives in practice. We promote a more transparent, nuanced, and pluralistic conceptualization of equity in conservation decision making that particularly recognizes where multidimensional equity objectives may conflict. To help identify and mitigate ethical conflicts and avoid cases of good intentions producing bad outcomes, we encourage a more analytical incorporation of equity into conservation decision making particularly during mechanistic integration of equity objectives. We recommend that in conservation planning motivations and objectives for equity be made explicit within the problem context, methods used to incorporate equity objectives be applied with respect to stated objectives, and, should objectives dictate, evaluation of equity outcomes and adaptation of strategies be employed during policy implementation. PMID- 28861906 TI - Aquatic exposures of chemical mixtures in urban environments: Approaches to impact assessment. AB - Urban regions of the world are expanding rapidly, placing additional stress on water resources. Urban water bodies serve many purposes, from washing and sources of drinking water to transport and conduits for storm drainage and effluent discharge. These water bodies receive chemical emissions arising from either single or multiple point sources, diffuse sources which can be continuous, intermittent, or seasonal. Thus, aquatic organisms in these water bodies are exposed to temporally and compositionally variable mixtures. We have delineated source-specific signatures of these mixtures for diffuse urban runoff and urban point source exposure scenarios to support risk assessment and management of these mixtures. The first step in a tiered approach to assessing chemical exposure has been developed based on the event mean concentration concept, with chemical concentrations in runoff defined by volumes of water leaving each surface and the chemical exposure mixture profiles for different urban scenarios. Although generalizations can be made about the chemical composition of urban sources and event mean exposure predictions for initial prioritization, such modeling needs to be complemented with biological monitoring data. It is highly unlikely that the current paradigm of routine regulatory chemical monitoring alone will provide a realistic appraisal of urban aquatic chemical mixture exposures. Future consideration is also needed of the role of nonchemical stressors in such highly modified urban water bodies. Environ Toxicol Chem 2018;37:703-714. (c) 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 28861907 TI - Teacher spatial skills are linked to differences in geometry instruction. AB - BACKGROUND: Spatial skills have been linked to better performance in mathematics. AIM: The purpose of this study was to examine the relationship between teacher spatial skills and their instruction, including teacher content and pedagogical knowledge, use of pictorial representations, and use of gestures during geometry instruction. SAMPLE: Fifty-six middle school teachers participated in the study. METHODS: The teachers were administered spatial measures of mental rotations and spatial visualization. Next, a single geometry class was videotaped. RESULT: Correlational analyses revealed that spatial skills significantly correlate with teacher's use of representational gestures and content and pedagogical knowledge during instruction of geometry. Spatial skills did not independently correlate with the use of pointing gestures or the use of pictorial representations. However, an interaction term between spatial skills and content and pedagogical knowledge did correlate significantly with the use of pictorial representations. Teacher experience as measured by the number of years of teaching and highest degree did not appear to affect the relationships among the variables with the exception of the relationship between spatial skills and teacher content and pedagogical knowledge. CONCLUSION: Teachers with better spatial skills are also likely to use representational gestures and to show better content and pedagogical knowledge during instruction. Spatial skills predict pictorial representation use only as a function of content and pedagogical knowledge. PMID- 28861905 TI - Treatable inherited rare movement disorders. AB - There are many rare movement disorders, and new ones are described every year. Because they are not well recognized, they often go undiagnosed for long periods of time. However, early diagnosis is becoming increasingly important. Rapid advances in our understanding of the biological mechanisms responsible for many rare disorders have enabled the development of specific treatments for some of them. Well-known historical examples include Wilson disease and dopa-responsive dystonia, for which specific and highly effective treatments have life-altering effects. In recent years, similarly specific and effective treatments have been developed for more than 30 rare inherited movement disorders. These treatments include specific medications, dietary changes, avoidance or management of certain triggers, enzyme replacement therapy, and others. This list of treatable rare movement disorders is likely to grow during the next few years because a number of additional promising treatments are actively being developed or evaluated in clinical trials. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28861908 TI - Issues in vaccinology: Present challenges and future directions. AB - Vaccination is a principal and highly cost-effective means of controlling infectious diseases, providing direct protection against pathogens by conferring long-lasting immunological memory and inducing population-level herd immunity. Despite rapid ongoing progress in vaccinology, there remain many obstacles to the development and deployment of novel or improved vaccines; these include the underlying science of how to induce and sustain appropriate protective immune responses as well as bureaucratic, logistic and socio-political hurdles. The failure to distribute and administer existing vaccines to at-risk communities continues to account for a large proportion of infant mortality worldwide: almost 20 million children do not have access to basic vaccines and several million still die each year as a result. While emerging epidemic or pandemic diseases pose a significant threat to global health and prosperity, there are many infectious diseases which provide a continuous or cyclical burden on healthcare systems which also need to be addressed. Gaps in knowledge of the human immune system stand in the way of developing technologies to overcome individual and pathogenic variation. The challenges in tackling infectious disease and directions that the field of preventive medicine may take to improve the current picture of global health are the focus of this review. PMID- 28861909 TI - Major trauma and the need for massive transfusion. PMID- 28861910 TI - Vertebral Fracture Risk in Diabetic Elderly Men: The MrOS Study. AB - Type 2 diabetes (T2DM) is associated with a significant increase in risk of nonvertebral fractures, but information on risk of vertebral fractures (VFs) in subjects with T2DM, particularly among men, is lacking. Furthermore, it is not known whether spine bone mineral density (BMD) can predict the risk of VF in T2DM. We sought to examine the effect of diabetes status on prevalent and incident vertebral fracture, and to estimate the effect of lumbar spine BMD (areal and volumetric) as a risk factor for prevalent and incident morphometric vertebral fracture in T2DM (n = 875) and nondiabetic men (n = 4679). We used data from the Osteoporotic Fractures in Men (MrOS) Study, which enrolled men aged >=65 years. Lumbar spine areal BMD (aBMD) was measured with dual-energy X-ray absorptiometry (DXA), and volumetric BMD (vBMD) by quantitative computed tomography (QCT). Prevalence (7.0% versus 7.7%) and incidence (4.4% versus 4.5%) of VFs were not higher in T2DM versus nondiabetic men. The risk of prevalent (OR, 1.05; 95% CI, 0.78 to 1.40) or incident vertebral-fracture (OR, 1.28; 95% CI, 0.81 to 2.00) was not higher in T2DM versus nondiabetic men in models adjusted for age, clinic site, race, BMI, and aBMD. Higher spine aBMD was associated with lower risk of prevalent VF in T2DM (OR, 0.55; 95% CI, 0.48 to 0.63) and nondiabetic men (OR, 0.66; 95% CI, 0.5 to 0.88) (p for interaction = 0.24) and of incident VF in T2DM (OR, 0.50; 95% CI, 0.41 to 0.60) and nondiabetic men (OR, 0.54; 95% CI, 0.33 to 0.88) (p for interaction = 0.77). Results were similar for vBMD. In conclusion, T2DM was not associated with higher prevalent or incident VF in older men, even after adjustment for BMI and BMD. Higher spine aBMD and vBMD are associated with lower prevalence and incidence of VF in T2DM as well as nondiabetic men. (c) 2017 American Society for Bone and Mineral Research. PMID- 28861911 TI - Automated and efficient quantum chemical determination and energetic ranking of molecular protonation sites. AB - We present an automated quantum chemical protocol for the determination of preferred protonation sites in organic and organometallic molecules containing up to a few hundred atoms. It is based on the Foster-Boys orbital localization method, whereby we automatically identify lone pairs and pi orbitals as possible protonation sites. The method becomes efficient in conjunction with the robust and fast GFN-xTB semiempirical method proposed recently (Grimme et al., J. Chem. Theory Comput. 2017, 13, 1989). The protonated isomers that are found within a few seconds to minutes of computational wall-time on a standard desktop computer are then energetically refined using density functional theory (DFT), where we use a high-level double-hybrid reference method to benchmark GFN-xTB and low-cost DFT approaches. The proposed DFT/GFN-xTB/LMO composite protocol is generally applicable to almost arbitrary molecules including transition metal complexes. Importantly it is found that even in electronically complicated cases, the GFN xTB optimized protomer structures are reasonable and can safely be used in single point DFT calculations. Corrections from energy to free energy mostly have a small effect on computed protomer populations. The resulting protomer equilibrium is valuable, for example, in the context of electrospray ionization mass spectrometry where it may help identify the ionized species and assist the interpretation of the experiment. (c) 2017 Wiley Periodicals, Inc. PMID- 28861912 TI - Diagnosis checking of statistical analysis in RCTs indexed in PubMed. AB - BACKGROUND: Statistical analysis is essential for reporting of the results of randomized controlled trials (RCTs), as well as evaluating their effectiveness. However, the validity of a statistical analysis also depends on whether the assumptions of that analysis are valid. OBJECTIVE: To review all RCTs published in journals indexed in PubMed during December 2014 to provide a complete picture of how RCTs handle assumptions of statistical analysis. METHODS: We reviewed all RCTs published in December 2014 that appeared in journals indexed in PubMed using the Cochrane highly sensitive search strategy. The 2014 impact factors of the journals were used as proxies for their quality. The type of statistical analysis used and whether the assumptions of the analysis were tested were reviewed. RESULTS: In total, 451 papers were included. Of the 278 papers that reported a crude analysis for the primary outcomes, 31 (27.2%) reported whether the outcome was normally distributed. Of the 172 papers that reported an adjusted analysis for the primary outcomes, diagnosis checking was rarely conducted, with only 20%, 8.6% and 7% checked for generalized linear model, Cox proportional hazard model and multilevel model, respectively. Study characteristics (study type, drug trial, funding sources, journal type and endorsement of CONSORT guidelines) were not associated with the reporting of diagnosis checking. CONCLUSION: The diagnosis of statistical analyses in RCTs published in PubMed-indexed journals was usually absent. Journals should provide guidelines about the reporting of a diagnosis of assumptions. PMID- 28861914 TI - A novel MAs(III)-selective ArsR transcriptional repressor. AB - Microbial expression of genes for resistance to heavy metals and metalloids is usually transcriptionally regulated by the toxic ions themselves. Arsenic is a ubiquitous, naturally occurring toxic metalloid widely distributed in soil and groundwater. Microbes biotransform both arsenate (As(V)) and arsenite (As(III)) into more toxic methylated metabolites methylarsenite (MAs(III)) and dimethylarsenite (DMAs(III)). Environmental arsenic is sensed by members of the ArsR/SmtB family. The arsR gene is autoregulated and is typically part of an operon that contains other ars genes involved in arsenic detoxification. To date every identified ArsR is regulated by inorganic As(III). Here we described a novel ArsR from Shewanella putrefaciens selective for MAs(III). SpArsR orthologs control expression of two MAs(III) resistance genes, arsP that encodes the ArsP MAs(III) efflux permease, and arsH encoding the ArsH MAs(III) oxidase. SpArsR has two conserved cysteine residues, Cys101 and Cys102. Mutation of either resulted in loss of MAs(III) binding, indicating that they form an MAs(III) binding site. SpArsR can be converted into an As(III)-responsive repressor by introduction of an additional cysteine that allows for three-coordinate As(III) binding. Our results indicate that SpArsR evolved selectivity for MAs(III) over As(III) in order to control expression of genes for MAs(III) detoxification. PMID- 28861913 TI - Identification and functional analysis of CORIN variants in hypertensive patients. AB - Corin is a serine protease that activates atrial natriuretic peptide (ANP). CORIN gene variants have been reported in patients with hypertension. To date, however, the prevalence of CORIN variants in hypertensive patients remains unknown. To understand the prevalence and functional significance of CORIN variants in hypertension, we sequenced CORIN exons in 300 normal and 401 hypertensive individuals in a Chinese population and identified nine nonsynonymous variants, of which eight were not characterized previously. Among them, variants c.131A > G (p.Tyr13Cys), c.376G > T (p.Asp95Tyr), c.1094T > G (p.Leu334Trp), and c.1667G > A (p.Arg525His) occurred similarly in both normal and hypertensive individuals. Variants c1139G > A (p.Arg349His), c.2689C > T (p.Pro866Ser), and c.2864C > T (p.Thr924Met) were found once each in hypertensive individuals. Variant c.1683G > T (p.Arg530Ser) occurred preferentially in hypertensive individuals [10/401 (2.5%) vs. 1/300 (0.3%) in normal individuals; P = 0.023], which was confirmed in another independent cohort [9/368 (2.44%) in hypertensive and 2/377 (0.53%) in normal individuals; P = 0.033]. In biochemical and cell-based functional studies, variants p.Arg530Ser and p.Thr924Met, but not p.Tyr13Cys, p.Asp95Tyr, p.Leu334Trp, p.Arg349His, p.Arg525His, and p.Pro866Ser, exhibited reduced pro-ANP processing activity, which was caused by endoplasmic reticulum retention and poor zymogen activation, respectively. These results indicate that genetic variants impairing corin function are not uncommon in general populations and that such variants may be an important contributing factor in hypertension. PMID- 28861915 TI - Patients Visiting Multiple Emergency Departments: Patterns, Costs, and Risk Factors. AB - OBJECTIVES: We sought to characterize the population of patients seeking care at multiple emergency departments (EDs) and to quantify the proportion of all ED visits and costs accounted for by these patients. METHODS: We performed a retrospective, cohort study of deidentified insurance claims for privately insured patients with one of more ED visits between 2010 and 2016. We measured the number of EDs visited by each patient and determined the overall proportion of all ED visits and ED costs accounted for by patients who visit multiple EDs. We identified factors associated with visiting multiple EDs. RESULTS: A total of 8,651,716 patients made 16,390,676 ED visits over the study period, accounting for $26,102,831,740 in ED costs. A significant minority (20.5%) of patients visited more than one ED over the study period. However, these patients accounted for a disproportionate amount of all ED visits (41.4%) and all ED costs (39.2%). A small proportion (0.4%) of patients visited five or more EDs but accounted for 2.8% of ED visits and costs. Among patients with two ED visits within 30 days, 32% were to different EDs. Having at least one ED visit for mental health or substance abuse-related diagnosis was associated with increased odds of visiting multiple EDs. CONCLUSIONS: A substantial minority of patients visit multiple EDs, but account for a disproportionate burden of overall ED utilization and costs. Future work should evaluate the impact of visiting multiple EDs on care utilization and outcomes and explore systems for improving access to patient records across care centers. PMID- 28861916 TI - Risking existence: The experience and handling of depression. AB - AIMS AND OBJECTIVES: To gain insight into how people suffering from depression experience and manage life. BACKGROUND: Depression is the leading cause of incapacitation and constitutes the second largest healthcare burden worldwide, causing considerable discomfort for depression sufferers and their significant others. Depression must be understood against the backdrop of a person's context as well as biological, psychological and social factors. While various studies have been conducted on the process of depression, only a few studies have examined its existential aspects. DESIGN: A classical grounded theory methodology employing open and selective coding was used to identify the participants' main concern and the strategies they used to handle it. METHOD: Data were collected in 2015-2016 during 18 in-depth interviews with people with current or former moderate depression. The data were analysed through constant comparisons until the grounded theory emerged. RESULTS/FINDINGS: The main concern of the participants was Longing for belonging, and they handled their depression through a process named Risking existence. The process comprised four phases: (i) Ungraspable processing; (ii) Giving clues; (iii) Daring dependence; and (iv) Courage to be. The process of risking existence was accompanied from beginning to end by three essentials: to hope, to endure and shame. CONCLUSION: Working in mental health care involves encountering the pain, suffering and despair that humans endure. This challenges nurses to go beyond the symptoms and to listen for their meaning to each individual person. RELEVANCE TO CLINICAL PRACTICE: The grounded theory of risking existence provides a model by which nurses can orient themselves when working with people who are depressed. Each phase describes different strategies that patients use that can help the nurse recognise what is going on, thus enabling him or her to understand and guide his or her patients. PMID- 28861917 TI - Feto- and utero-placental vascular adaptations to chronic maternal hypoxia in the mouse. AB - KEY POINTS: Chronic fetal hypoxia is one of the most common complications of pregnancy and is known to cause fetal growth restriction. The structural adaptations of the placental vasculature responsible for growth restriction with chronic hypoxia are not well elucidated. Using a mouse model of chronic maternal hypoxia in combination with micro-computed tomography and scanning electron microscopy, we found several placental adaptations that were beneficial to fetal growth including capillary expansion, thinning of the interhaemal membrane and increased radial artery diameters, resulting in a large drop in total utero placental vascular resistance. One of the mechanisms used to achieve the rapid increase in capillaries was intussusceptive angiogenesis, a strategy used in human placental development to form terminal gas-exchanging villi. These results contribute to our understanding of the structural mechanisms of the placental vasculature responsible for fetal growth restriction and provide a baseline for understanding adaptive physiological responses of the placenta to chronic hypoxia. ABSTRACT: The fetus and the placenta in eutherian mammals have a unique set of compensatory mechanisms to respond to several pregnancy complications including chronic maternal hypoxia. This study examined the structural adaptations of the feto- and utero-placental vasculature in an experimental mouse model of chronic maternal hypoxia (11% O2 from embryonic day (E) 14.5-E17.5). While placental weights were unaffected by exposure to chronic hypoxia, using micro-computed tomography, we found a 44% decrease in the absolute feto-placental arterial vascular volume and a 30% decrease in total vessel segments in the chronic hypoxia group compared to control group. Scanning electron microscopy imaging showed significant expansion of the capillary network; consequently, the interhaemal membrane was 11% thinner to facilitate maternal-fetal exchange in the chronic hypoxia placentas. One of the mechanisms for the rapid capillary expansion was intussusceptive angiogenesis. Analysis of the utero-placental arterial tree showed significant increases (24%) in the diameter of the radial arteries, resulting in a decrease in the total utero-placental resistance by 2.6 fold in the mice exposed to chronic maternal hypoxia. Together these adaptations acted to preserve placental weight whereas fetal weight was decreased. PMID- 28861919 TI - Newborn screening for severe combined immunodeficiency: Evaluation of a commercial T-cell receptor excision circle-based method in Victorian dried blood spots. AB - AIM: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency and is fatal in infancy if untreated. As early diagnosis is associated with improved outcomes, SCID is an ideal condition to consider for inclusion in a newborn screening (NBS) programme in Australia. In this feasibility study, we evaluated the EnLite Neonatal TREC kit for detection of T cell receptor excision circles (TRECs) from NBS dried blood spots for the identification of known SCID patients in Victoria. METHODS: TREC copies/MUL were measured retrospectively in 14 children diagnosed with SCID or complete DiGeorge syndrome (CDGS) from 2005 to 2015 at the Royal Children's Hospital, Melbourne. In addition, TREC copies/MUL were measured for 501 prospective de-identified NBS cards. RESULTS: Of 14 known SCID or CDGS samples, 11 were correctly identified as presumptive positive samples with low or undetectable TREC on duplicate testing. The remaining three samples also had low or undetectable TREC on duplicate testing but were considered invalid due to insufficient beta-actin DNA amplification. Of the 501 prospective NBS samples, none were identified as presumptive positive samples on duplicate testing. CONCLUSIONS: The EnLite Neonatal TREC kit correctly identified known SCID or CDGS patients as presumptive positive samples, and initial cut-offs for TREC and beta-actin in the Victorian NBS population were determined. A larger pilot study is required to confirm these proposed cut-offs and to evaluate the cost and implementation of this screening programme in Victoria, Australia. Overall, this study provides preliminary data to support the introduction of this assay to the NBS programme in Victoria. PMID- 28861918 TI - Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases. AB - The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits. PMID- 28861920 TI - Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. AB - Li-Fraumeni syndrome (LFS) is an autosomal-dominant cancer predisposition disorder associated with pathogenic germline variants in TP53, with a high penetrance over an individual's lifetime. The actual population prevalence of pathogenic germline TP53 mutations is still unclear, most likely due to biased selection of cancer affected families. The aim of this study was to estimate the population prevalence of potentially pathogenic TP53 exonic variants in three sequencing databases, totaling 63,983 unrelated individuals. Potential pathogenicity was defined using an original algorithm combining bioinformatic prediction tools, suggested clinical significance, and functional data. We identified 34 different potentially pathogenic TP53 variants in 131 out of 63,983 individuals (0.2%). Twenty-eight (82%) of these variants fell within the DNA binding domain of TP53, with an enrichment for specific variants that were not previously identified as LFS mutation hotspots, such as the p.R290H and p.N235S variants. Our findings reveal that the population prevalence of potentially pathogenic TP53 variants may be up to 10 times higher than previously estimated from family-based studies. These results point to the need for further studies aimed at evaluating cancer penetrance modifiers as well as the risk associated between cancer and rare TP53 variants. PMID- 28861921 TI - The Functional Response of Mesenchymal Stem Cells to Electron-Beam Patterned Elastomeric Surfaces Presenting Micrometer to Nanoscale Heterogeneous Rigidity. AB - Cells directly probe and respond to the physicomechanical properties of their extracellular environment, a dynamic process which has been shown to play a key role in regulating both cellular adhesive processes and differential cellular function. Recent studies indicate that stem cells show lineage-specific differentiation when cultured on substrates approximating the stiffness profiles of specific tissues. Although tissues are associated with a range of Young's modulus values for bulk rigidity, at the subcellular level, tissues are comprised of heterogeneous distributions of rigidity. Lithographic processes have been widely explored in cell biology for the generation of analytical substrates to probe cellular physicomechanical responses. In this work, it is shown for the first time that that direct-write e-beam exposure can significantly alter the rigidity of elastomeric poly(dimethylsiloxane) substrates and a new class of 2D elastomeric substrates with controlled patterned rigidity ranging from the micrometer to the nanoscale is described. The mechanoresponse of human mesenchymal stem cells to e-beam patterned substrates was subsequently probed in vitro and significant modulation of focal adhesion formation and osteochondral lineage commitment was observed as a function of both feature diameter and rigidity, establishing the groundwork for a new generation of biomimetic material interfaces. PMID- 28861922 TI - Site-specific accumulation and dynamic change of flavonoids in Apocyni Veneti Folium. AB - Site-specific accumulation of flavonoids in Apocyni Veneti Folium was determined by laser scanning confocal microscope (LSCM) and the localization of catechins also was observed via vanillin-HCl staining under the conventional optical microscope. The contents of five flavonoids in Apocyni Veneti Folium from different harvest times and growth parts were measured using HPLC method. LSCM observation showed that flavonoids are accumulated in cuticle of epidermal cells and vessel walls, especially in protoplasts and nucleolus of the collenchyma cells and the epidermal cells. Catechins are localized in the palisade parenchyma cells and vessel walls, particularly in the laticifers found in the phloem. On the basis of the difference of the maximal emission wavelength between quercetin and kaempferol derivatives which have fluorescence behavior by appropriate treatment, kaempferol and its derivatives are localized exclusively in the cuticle. Results showed that the content of astragalin in Apocyni Veneti Folium from different parts revealed the decreasing trend, while hyperin and isoquercitrin were higher in June and July analyzed by HPLC. In summary, the site specific accumulation of flavonoids in Apocyni Veneti Folium can be determined by LSCM and vanillin-HCl staining. The contents of flavonoids in Apocyni Veneti Folium are correlated with harvest times and growth parts. PMID- 28861923 TI - Unravelling hypothyroidism in AL amyloidosis: Authors' reply. PMID- 28861924 TI - Highly Concentrated, Ultrathin Nickel Hydroxide Nanosheet Ink for Wearable Energy Storage Devices. AB - Solution-based techniques are considered as a promising strategy for scalable fabrication of flexible electronics owing to their low-cost and high processing speed. The key to the success of these techniques is dominated by the ink formulation of active nanomaterials. This work successfully prepares a highly concentrated two dimensional (2D) crystal ink comprised of ultrathin nickel hydroxide (Ni(OH)2 ) nanosheets with an average lateral size of 34 nm. The maximum concentration of Ni(OH)2 nanosheets in water without adding any additives reaches as high as 50 mg mL-1 , which can be printed on arbitrary substrates to form Ni(OH)2 thin films. As a proof-of-concept application, Ni(OH)2 nanosheet ink is coated on commercialized carbon fiber yarns to fabricate wearable energy storage devices. The thus-fabricated hybrid supercapacitors exhibit excellent flexibility with a capacitance retention of 96% after 5000 bending-unbending cycles, and good weavability with a high volumetric capacitance of 36.3 F cm-3 at a current density of 0.4 A cm-3 , and an energy density of 11.3 mWh cm-3 at a power density of 0.3 W cm-3 . As a demonstration of practical application, a red light emitting diode can be lighted up by three hybrid devices connected in series. PMID- 28861925 TI - Standard and reduced doses of dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: a nationwide cohort study. AB - BACKGROUND: Comparative data of non-vitamin K antagonist oral anticoagulants (NOAC) are lacking in patients with atrial fibrillation (AF). OBJECTIVE: We compared effectiveness and safety of standard and reduced dose NOAC in AF patients. METHODS: Using Danish nationwide registries, we included all oral anticoagulant-naive AF patients who initiated NOAC treatment (2012-2016). Outcome specific and mortality-specific multiple Cox regressions were combined to compute average treatment effects as 1-year standardized differences in stroke and bleeding risks (g-formula). RESULTS: Amongst 31 522 AF patients, the distribution of NOAC/dose was as follows: dabigatran standard dose (22.4%), dabigatran-reduced dose (14.0%), rivaroxaban standard dose (21.8%), rivaroxaban reduced dose (6.7%), apixaban standard dose (22.9%), and apixaban reduced dose (12.2%). The 1-year standardized absolute risks of stroke/thromboembolism were 1.73-1.98% and 2.51 2.78% with standard and reduced NOAC dose, respectively, without statistically significant differences between NOACs for given dose level. Comparing standard doses, the 1-year standardized absolute risk (95% CI) for major bleeding was for rivaroxaban 2.78% (2.42-3.17%); corresponding absolute risk differences (95% CI) were for dabigatran -0.93% (-1.45% to -0.38%) and apixaban, -0.54% (-0.99% to 0.05%). The results for major bleeding were similar for reduced NOAC dose. The 1 year standardized absolute risk (95% CI) for intracranial bleeding was for standard dose dabigatran 0.19% (0.22-0.50%); corresponding absolute risk differences (95% CI) were for rivaroxaban 0.23% (0.06-0.41%) and apixaban, 0.18% (0.01-0.34%). CONCLUSIONS: Standard and reduced dose NOACs, respectively, showed no significant risk difference for associated stroke/thromboembolism. Rivaroxaban was associated with higher bleeding risk compared with dabigatran and apixaban and dabigatran was associated with lower intracranial bleeding risk compared with rivaroxaban and apixaban. PMID- 28861926 TI - Bis(aryl) Tetrasulfides as Cathode Materials for Rechargeable Lithium Batteries. AB - An organotetrasulfide consists of a linear chain of four sulfur atoms that could accept up to 6 e- in reduction reactions, thus providing a promising high capacity electrode material. Herein, we study three bis(aryl) tetrasulfides as cathode materials in lithium batteries. Each tetrasulfide exhibits two major voltage regions in the discharge. The high voltage slope region is governed by the formation of persulfides and thiolates, and the low voltage plateau region is due to the formation of Li2 S2 /Li2 S. Based on theoretical calculations and spectroscopic analysis, three reduction reaction processes are revealed, and the discharge products are identified. Lithium half cells with tetrasulfide catholytes deliver high specific capacities over 200 cycles. The effects of the functional groups on the electrochemical characteristics of tetrasulfides are investigated, which provides guidance for developing optimum aryl polysulfides as cathode materials for high energy lithium batteries. PMID- 28861927 TI - Half-Metallic Behavior in 2D Transition Metal Dichalcogenides Nanosheets by Dual Native-Defects Engineering. AB - Two-dimensional transition metal dichalcogenides (TMDs) have been regarded as one of the best nonartificial low-dimensional building blocks for developing spintronic nanodevices. However, the lack of spin polarization in the vicinity of the Fermi surface and local magnetic moment in pristine TMDs has greatly hampered the exploitation of magnetotransport properties. Herein, a half-metallic structure of TMDs is successfully developed by a simple chemical defect engineering strategy. Dual native defects decorate titanium diselenides with the coexistence of metal-Ti-atom incorporation and Se-anion defects, resulting in a high-spin-polarized current and local magnetic moment of 2D Ti-based TMDs toward half-metallic room-temperature ferromagnetism character. Arising from spin polarization transport, the as-obtained T-TiSe1.8 nanosheets exhibit a large negative magnetoresistance phenomenon with a value of -40% (5T, 10 K), representing one of the highest negative magnetoresistance effects among TMDs. It is anticipated that this dual regulation strategy will be a powerful tool for optimizing the intrinsic physical properties of TMD systems. PMID- 28861928 TI - Octahedral [Pd6 L8 ]12+ Metallosupramolecular Cages: Synthesis, Structures and Guest-Encapsulation Studies. AB - Four planar tripyridyl ligands (Ltripy ), 1,3,5-tris(pyridin-3-ylethynyl)benzene 1 a, 1,3,5-tris[4-(3-pyridyl)phenyl]benzene 2 a, and the hexyloxy chain functionalized derivatives 1,3,5-tris[(3-hexyloxy-5-pyridyl)ethynyl]benzene 1 b, and 1,3,5-tris[4-(3-hexyloxy-5-pyridyl)phenyl]benzene 2 b, were synthesized and used to generate a family of [Pd6 (Ltripy )8 ](BF4 )12 octahedral cages (Ltripy =1 a, b or 2 a, b). The ligands and cages were characterized using a combination of 1 H, 13 C, and DOSY nuclear magnetic resonance (NMR) spectroscopy, high resolution electrospray mass spectrometry (HR-ESI-MS), infrared (IR) spectroscopy, elemental analysis, and in three cases, X-ray crystallography. The molecular recognition properties of the cages with neutral and anionic guests were examined, in dimethyl sulfoxide (DMSO), using NMR spectroscopy, mass spectrometry and molecular modeling. No binding was observed with simple aliphatic and aromatic guest molecules. However, anionic sulfonates were found to interact with the octahedral cages and the binding interaction was size selective. The smaller [Pd6 (1 a, b)8 ]12+ cages were able to interact with three p-toluenesulfonate guest molecules while the larger [Pd6 (2 a, b)8 ]12+ systems could host four of the anionic guest molecules. To probe the importance of the hydrophobic effect, a mixed water-DMSO (1:1) solvent system was used to reexamine the binding of the neutral organic guests adamantane, anthracene, pyrene and 1,8 naphthalimide within the cages. In this solvent system all the guests except adamantane were observed to bind within the cavities of the cages. NMR spectroscopy and molecular modeling indicated that the cages bind multiple copies of the individual guests (between 3-6 guest molecules per cage). PMID- 28861929 TI - Myelin content changes in probable Alzheimer's disease and mild cognitive impairment: Associations with age and severity of neuropsychiatric impairment. AB - BACKGROUND: Existing indices of white matter integrity such as fractional anisotropy and magnetization transfer ratio may not provide optimal specificity to myelin content. In contrast, myelin water fraction (MWF) derived from the multiecho T2 relaxation time technique may serve as a more direct measure of myelin content. PURPOSE/HYPOTHESIS: The goal of the present study was to identify markers of regional demyelination in patients with probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) in relation to age and severity of neuropsychiatric impairment. POPULATION: The sample included patients diagnosed with probable AD (n = 25) or MCI (n = 43), and cognitively intact elderly controls (n = 33). FIELD STRENGTH/SEQUENCE ASSESSMENT: Long T2 , short T2 , and MWF values were measured with a 1.5T scanner in periventricular and deep normal appearing white matter (NAWM), serving as indices of intra/extracellular water content and myelin content. A comprehensive neuropsychological and neuropsychiatric assessment was administered to all participants. STATISTICAL TESTS, RESULTS: AD patients displayed higher age-adjusted long and short T2 values and reduced MWF values in left temporal/parietal and bilateral periventricular NAWM than controls and MCI patients (P < 0.004; one-way analysis of covariance [ANCOVA] tests). Short T2 /MWF values in temporal, frontal, and periventricular NAWM of controls and/or MCI patients were significantly associated with episodic and semantic memory performance and depressive symptomatology (P < 0.004; partial correlation indices). The impact of age on memory performance was significantly (P < 0.01; mediated linear regression analyses) mediated by age-related changes in short T2 and MWF values in these regions. DATA CONCLUSION: Age-related demyelination is associated with memory impairment (especially in prodromal dementia states) and symptoms of depression in an anatomically specific manner. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1359-1372. PMID- 28861930 TI - Electrical pulse stimulation: an in vitro exercise model for the induction of human skeletal muscle cell hypertrophy. A proof-of-concept study. AB - NEW FINDINGS: What is the central question of this study? Is electrical pulse stimulation (EPS) an in vitro exercise model able to elicit the hypertrophy of human muscle cells? What is the main finding and its importance? The addition of a restitution period of 8 h after EPS induces the enlargement of human muscle cells, a major physiological end-point to resistance exercise. This is supported by downregulation of myostatin, a negative regulator of muscle mass, and increased phosphorylated mTOR and 4E-BP1, key factors in the growth cascade. This proof-of-concept study provides a model of physiologically mediated muscle growth, which will be the basis for future studies aiming to depict molecular events governing the hypertrophy of human muscle cells. Electrical pulse stimulation (EPS) of muscle cells has previously been used as an in vitro exercise model. The present study aimed to establish an EPS protocol promoting the hypertrophy of human muscle cells, which represents a major physiological end point to resistance exercise in humans. We hypothesized that adding a resting period after EPS would be crucial for the occurrence of the morphological change. Myoblasts obtained from human muscle biopsies (n = 5) were differentiated into multinucleated myotubes and exposed to 8 h of EPS consisting of 2 ms pulses at 12 V, with a frequency of 1 Hz. Myotube size was assessed using immunohistochemistry immediately, 4 and 8 h after completed EPS. Gene expression and phosphorylation status of selected markers of hypertrophy were assessed using RT-PCR and Western blotting, respectively. Release of the myokine interleukin-6 in culture medium was measured using enzyme-linked immunosorbent assay. We demonstrated a significant increase (31 +/- 14%; P = 0.03) in the size of myotubes when EPS was followed by an 8 h resting period, but not immediately or 4 h after completion of EPS. The response was supported by downregulation (P = 0.04) of the gene expression of myostatin, a negative regulator of muscle mass, and an increase in phosphorylated mTOR (P = 0.03) and 4E-BP1 (P = 0.01), which are important factors in the cellular growth signalling cascade. The present work demonstrates that EPS is an in vitro exercise model promoting the hypertrophy of human muscle cells, recapitulating a major physiological end-point to resistance exercise in human skeletal muscle. PMID- 28861931 TI - The ubiquitin ligase TRIM25 inhibits hepatocellular carcinoma progression by targeting metastasis associated 1 protein. AB - Metastasis associated 1 protein (MTA1) is one of the prime facilitators of metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the underlying regulatory mechanism of MTA1 expression in HCC is not clear. In this study, we evaluated MTA1 transcript and protein expression in HCC and normal hepatic cell lines. The results revealed that MTA1 protein expression had a significantly increase in HCC cell line, HuH6, compared with that in normal hepatic cell line, THLE-2. Determination of protein half-life using cycloheximide (CHX) treatment did not reveal any statistically significant difference in protein turn-over rates between THLE-2 (3.3 +/- 0.25 h) and HuH6 (3.6 +/- 0.15 h) cell lines. MTA1 protein level was stabilized in THLE-2 cells after treatment with MG-132 to levels similar to those observed in HuH6 cells. Mass spectrometric analysis of FLAG immunoprecipitates of FLAG-MTA1 transfected THLE-2 cells after MG-132 treated revealed candidate ubiquitin ligases that were interacting with MTA1. RNAi-mediated silencing of each prospective ubiquitin ligase in THLE-2 cells indicated that knockdown of TRIM25 resulted in stabilization of MTA1 protein, indicating TRIM25 as a putative E3 ligase for MTA1. Coimmunoprecipitation of FLAG-tagged MTA1, but not IgG, in MG-132 treated and untreated THLE-2 cells cotransfected with either FLAG-MTA1 or Myc-TRIM25 revealed robust polyubiquitinated MTA1, confirming that the TRIM25 is the ubiquitin ligase for MTA1 degradation. Overexpression of TRIM25 in HuH6 and RNAi mediated silencing of TRIM25 in THLE-2 cells inhibited and increased the cell migration and invasion, respectively. Analysis of The Cancer Genome Atlas data for assessment of TRIM25 transcript level and MTA1 protein expression in 25 HCC patients confirmed an inverse correlation between the expression of TRIM25 and MTA1. Cumulatively, our data reveal a novel mechanism of post-translational to regulate MTA1 expression in normal hepatic cells, which is repressed in HCC. (c) 2017 IUBMB Life, 69(10):795-801, 2017. PMID- 28861932 TI - Ion Mobility-Enhanced Data-Independent Acquisitions Enable a Deep Proteomic Landscape of Oligodendrocytes. AB - Oligodendrocytes are a type of neuroglia that provide trophic support and insulation to axons in the central nervous system. The genesis and maturation of oligodendrocytes are essential processes for myelination and the course of CNS development. Using ion mobility-enhanced, data-independent acquisitions and 2D nanoUPLC fractionation operating at nanoscale flow rates, we established a comprehensive data set of proteins expressed by the human oligodendroglia cell line MO3.13. The final dataset incorporating all fractions comprised 223 531 identified peptides assigned to 10 390 protein hits, an improvement of 4.5 times on identified proteins described previously by our group using the same cell line. Identified proteins play pivotal roles in many biological processes such as cell growth and development and energy metabolism, providing a rich resource for future studies on oligodendrocyte development, myelination, axonal support, and the regulation of such process. Our results can help further studies that use MO3.13 cells as a tool of investigation, not only in relation to oligodendrocyte maturation, but also to diseases that have oligodendrocytes as key players. All MS data have been deposited in the ProteomeXchange with identifier PXD004696. PMID- 28861934 TI - Indirect MRI of 17 o-labeled water using steady-state sequences: Signal simulation and preclinical experiment. AB - BACKGROUND: Few studies have been reported for T2 -weighted indirect 17 O imaging. PURPOSE/HYPOTHESIS: To evaluate the feasibility of steady-state sequences for indirect 17 O brain imaging. STUDY TYPE: Signal simulation, phantom measurements, and prospective animal experiments were performed in accordance with the institutional guidelines for animal experiments. POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: Signal simulations of balanced steady-state free precession (bSSFP) were performed for concentrations of 17 O ranging from 0.037-1.600%. Phantom measurements with concentrations of 17 O water ranging from 0.037-1.566% were also conducted. Six healthy beagle dogs were scanned with intravenous administration of 20% 17 O-labeled water (1 mL/kg). FIELD STRENGTH/SEQUENCE: Dynamic 3D-bSSFP scans were performed at 3T MRI. 17 O labeled water was injected 60 seconds after the scan start, and the total scan duration was 5 minutes. ASSESSMENT: Based on the result of signal simulation and phantom measurement, signal changes in the beagle dogs were measured and converted into 17 O concentrations. STATISTICAL TESTS: The 17 O concentrations were averaged for every 15 seconds, and compared to the baseline (30-45 sec) with Dunnett's multiple comparison tests. RESULTS: Signal simulation revealed that the relationships between 17 O concentration and the natural logarithm of relative signals were linear. The intraclass correlation coefficient between relative signals in phantom measurement and signal simulations was 0.974. In the animal experiments, significant increases in 17 O concentration (P < 0.05) were observed 60 seconds after the injection of 17 O. At the end of scanning, mean respective 17 O concentrations of 0.084 +/- 0.026%, 0.117 +/- 0.038, 0.082 +/- 0.037%, and 0.049 +/- 0.004% were noted for the cerebral cortex, cerebellar cortex, cerebral white matter, and ventricle. DATA CONCLUSION: Dynamic steady-state sequences were feasible for indirect 17 O imaging, and absolute quantification was possible. This method can be applied for the measurement of permeability and blood flow in the brain, and for kinetic analysis of cerebrospinal fluid. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1373-1379. PMID- 28861935 TI - Children with autism spectrum disorder who improve with fever: Insights from the Simons Simplex Collection. AB - : Literature indicates that some children with ASD may show behavioral improvements during fever; however, little is known about the behavioral profiles of these children. This study aims to (a) investigate the subset of children who show parent-reported behavioral improvements associated with fever and (b) compare the demographic, behavioral, and genetic characteristics of this subset of children to children whose parents report no change during fever. Parents of 2,152 children from the Simons Simplex Collection provided information about whether and in which areas their child improved during fever. Children were randomly assigned into discovery or replication samples. In discovery analyses, children who reportedly improved with fever (Improve Group) were compared to those who reportedly did not improve (No Improve Group) on demographics, medical history, ASD symptoms, adaptive skills, and presence of de novo ASD-associated mutations. Significant and marginal results from discovery analyses were tested in the replication sample. Parent reports of 17% of children indicated improvements during fever across a range of domains. Discovery and replication analyses revealed that the Improve Group had significantly lower non-verbal cognitive skills (NVIQ) and language levels and more repetitive behaviors. Groups did not differ on demographic variables, parent-report of current ASD symptoms or the presence of de novo mutations. Understanding the profiles of children who improve during episodes of fever may provide insights into innovative treatments for ASD. Autism Res 2018, 11: 175-184. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study explored characteristics of children with ASD who are reported to improve during fever. Parents of 17% of children with ASD report improvements across a range of domains during fever including cognition, communication, repetitive behaviors, social interaction, and behavior. Children who are reported to improve during fever have significantly lower non-verbal cognitive skills and language levels and more repetitive behaviors. Understanding the profiles of children who improve during episodes of fever may provide insights into new treatments for ASD. PMID- 28861933 TI - Desmosterol accumulation in users of amiodarone. AB - BACKGROUND: Amiodarone is an effective and widely used antiarrhythmic drug with many possible adverse effects including hypercholesterolaemia and hepatotoxicity. OBJECTIVE: Our aim was to evaluate how long-term amiodarone treatment affects cholesterol metabolism. METHODS: The study population consisted of 56 cardiac patients, of whom 20 were on amiodarone (amiodarone + group) and 36 did not use the drug (amiodarone - group). We also studied a control group of 124 individuals selected randomly from the population. Cholesterol metabolism was evaluated by analysis of serum noncholesterol sterols by gas-liquid chromatography and gas chromatography-mass spectrometry. RESULTS: Comparisons of serum lipids and noncholesterol sterols across the three groups showed increased serum triglyceride in users of amiodarone but no statistically significant group differences in total, LDL or HDL cholesterol or serum proprotein convertase subtilisin/kexin type 9 concentrations. Nor did the groups differ in the ratios of cholestanol or plant sterols to cholesterol in serum, suggesting that cholesterol absorption was unaltered. However, all users of amiodarone had very markedly elevated serum desmosterol concentrations: the desmosterol-to cholesterol ratio (102 * MUmol mmol-1 ) averaged 1030.7 +/- 115.7 (mean +/- SE) in the amiodarone + group versus 82.7 +/- 3.4 and 75.9 +/- 1.4 in the amiodarone and the population control groups (P < 0.001), respectively. CONCLUSION: Use of amiodarone was associated with on average 12-fold serum desmosterol concentrations compared with the control groups. This observation is fully novel and suggests that amiodarone interferes with the conversion of desmosterol to cholesterol in the cholesterol synthesis pathway. Whether accumulation of desmosterol plays a role in amiodarone-induced hepatotoxicity deserves to be studied in the future. PMID- 28861936 TI - Pivotal response treatment for preschoolers with autism spectrum disorder: Defining a predictor profile. AB - : Behavioral characteristics of children with autism spectrum disorder (ASD) who respond positively to Pivotal Response Treatment (PRT) have been described previously, based on single-subject design research. The present study examined several such characteristics, as well as positive affect, as predictors of expressive language (EL) gains in a representative sample of preschoolers with ASD (n = 57) enrolled in a PRT-based community early intervention program. Children's cognitive ability, positive affect, and levels of appropriate toy contact measured at the start of intervention each contributed significantly to the prediction of EL outcomes. Together these variables accounted for 40% of the total outcome variance. In addition, a profile of increased EL ability, positive affect and appropriate toy contact, and decreased social avoidance and stereotyped and repetitive vocalizations was associated with greater gains during intervention. Results are discussed in relation to their implications for understanding both the variable treatment response documented in children with ASD and how to tailor treatment to optimize individual benefit. Autism Res 2018, 11: 153-165. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The study examined behavior of 57 preschoolers who made the greatest and least gains from 1 year of a community Pivotal Response Treatment program. Using pre-treatment videos, we saw that children who made the most progress showed more language, positive affect, and appropriate interactions with toys, also less avoidance of people and fewer repetitive vocalizations. Behavior profiles can be used to match treatment to individual children's needs. PMID- 28861937 TI - Engineered Fluorine Metabolism and Fluoropolymer Production in Living Cells. AB - Fluorine has become an important element for the design of synthetic molecules for use in medicine, agriculture, and materials. Despite the many advantages provided by fluorine for tuning key molecular properties, it is rarely found in natural metabolism. We seek to expand the molecular space available for discovery through the development of new biosynthetic strategies that cross synthetic with natural compounds. Towards this goal, we engineered a microbial host for organofluorine metabolism and show that we can achieve the production of the fluorinated diketide 2-fluoro-3-hydroxybutyrate at approximately 50 % yield. This fluorinated diketide can be used as a monomer in vivo to produce fluorinated poly(hydroxyalkanoate) (PHA) bioplastics with fluorine substitutions ranging from around 5-15 %. This system provides a platform to produce mm flux through the key fluoromalonyl coenzyme A (CoA) building block, thereby offering the potential to generate a broad range of fluorinated small-molecule targets in living cells. PMID- 28861938 TI - Diagnostic accuracy of a new algorithm to detect atrial fibrillation in a home blood pressure monitor. AB - The authors evaluated a new algorithm for detecting atrial fibrillation (AF) using a home blood pressure monitor. Three serial blood pressure values were measured by the monitor in 16 patients with AF and 20 patients with sinus rhythm. The authors defined "monitor AF in irregular pulse peak (IPP) 25" as follows: (1) IPP: |interval of pulse peak - the average of the interval of the pulse peak| >= the average of the interval of the pulse peak *25%; (2) irregular heart beat: beats of IPP >= total pulse *20%; and (3) monitor AF: two or more irregular heart beats of the three blood pressure measurements. Cutoff IPP values were set at 20% (IPP20) and 15% (IPP15). The monitor's AF specificity was 1.0 in IPP25, IPP20, and IPP15, and its sensitivity was 0.88 in IPP25, 0.94 in IPP20, and 1.0 in IPP15. The new algorithm had high diagnostic accuracy for detecting AF and a low false-positive rate. PMID- 28861939 TI - Boosting the Catalytic Performance of Metal-Organic Frameworks for Steroid Transformations by Confinement within a Mesoporous Scaffold. AB - Solid-state crystallization achieves selective confinement of metal-organic framework (MOF) nanocrystals within mesoporous materials, thereby rendering active sites more accessible compared to the bulk-MOF and enhancing the chemical and mechanical stability of MOF nanocrystals. (Zr)UiO-66(NH2 )/SiO2 hybrid materials were tested as efficient and reusable heterogeneous catalysts for the synthesis of steroid derivatives, outperforming the bulk (Zr)UiO-66(NH2 ) MOF. A clear correlation between the catalytic activity of the dispersed Zr sites present in the confined MOF, and the loading of the mesoporous SiO2 , is demonstrated for steroid transformations. PMID- 28861940 TI - Mapping the Spatial Proteome of Metastatic Cells in Colorectal Cancer. AB - Colorectal cancer (CRC) is the second deadliest cancer worldwide. Here, we aimed to study metastasis mechanisms using spatial proteomics in the KM12 cell model. Cells were SILAC-labeled and fractionated into five subcellular fractions corresponding to: cytoplasm, plasma, mitochondria and ER/golgi membranes, nuclear, chromatin-bound and cytoskeletal proteins and analyzed with high resolution mass spectrometry. We provide localization data of 4863 quantified proteins in the different subcellular fractions. A total of 1318 proteins with at least 1.5-fold change were deregulated in highly metastatic KM12SM cells respect to KM12C cells. The protein network organization, protein complexes and functional pathways associated to CRC metastasis was revealed with spatial resolution. Although 92% of the differentially expressed proteins showed the same deregulation in all subcellular compartments, a subset of 117 proteins (8%) showed opposite changes in different subcellular localizations. The chaperonin CCT, the Eif2 and Eif3 initiation of translation and the oxidative phosphorylation complexes together with an important number of guanine nucleotide binding proteins, were deregulated in abundance and localization within the metastatic cells. Particularly relevant was the relationship of deregulated protein complexes with exosome secretion. The knowledge of the spatial proteome alterations at subcellular level contributes to clarify the molecular mechanisms underlying colorectal cancer metastasis and to identify potential targets of therapeutic intervention. PMID- 28861941 TI - Early follow-up of lung disease in infants with cystic fibrosis using the raised volume rapid thoracic compression technique and computed tomography during quiet breathing. AB - BACKGROUND: Among the different techniques used to monitor lung disease progression in infants with CF diagnosed by Newborn screening (NBS), raised volume-rapid thoracic compression (RVRTC) remains a promising tool. However, the need of sedation and positive pressure ventilation considerably limits its clinical use. We recently described a semi-quantitative method to evaluate air trapping by chest tomography during quite breathing without sedation (CTqb score). This parameter is the radiological sign of airway obstruction and could be also used for lung disease follow-up in infants with CF. However, its discriminative power compared with RVRTC and correlation with lung function parameters are not known. OBJECTIVES: To compare the discriminative powers of the CTqb score and RVRTC parameters and to determine their correlation during the first year of life of infants with CF. METHODS: In this multicenter longitudinal study, infants with CF diagnosed by NBS underwent RVRTC and CT during quite breathing at 10 +/- 4 weeks (n = 30) and then at 13 +/- 1 months of age (n = 28). RESULTS: All RVRTC parameters and the CTqb score remained stable between evaluations. The CTqb score showed a higher discriminative power than forced expiratory volume in 0.5 s (FEV0.5 ; the main RVRTC parameter) at both visits (66% and 50% of abnormal values vs 30% and 28%, respectively). No correlation was found between CTqb score and, the different RVRTC parameters or the plethysmographic functional residual capacity, indicating that they evaluate different aspect of CF lung disease. PMID- 28861942 TI - Cobalt Phosphide Coupled with Heteroatom-Doped Nanocarbon Hybrid Electroctalysts for Efficient, Long-Life Rechargeable Zinc-Air Batteries. AB - Metal phosphides and heteroatom-doped carbons have been regarded as promising candidates as bifunctional catalysts for oxygen evolution reaction (OER) and oxygen reduction reaction (ORR). However, both have suffered from stability issues during repeated ORR and OER operations in zinc-air batteries (ZABs). Herein, this study reports a versatile cobalt-based hybrid catalyst with a 1D structure by integrating the metal-organic framework-derived conversion approach and an in situ crosslinking method. Among them, the 1D hybrid catalyst composed of ultrasmall cobalt phosphide nanoparticles supported by nitrogen-, sulfur-, phosphorus-doped carbon matrix shows remarkable bifunctional activity close to that of the benchmark precious-metal catalysts along with an excellent durability in the full potential range covering both the OER and ORR. The overall overpotential of the rechargeable ZABs can be greatly reduced with this bifunctional hybrid catalyst as an air-electrode, and the cycling stability outperforms the commercial Pt/C catalyst. It is revealed that the cobalt phosphide nanoparticles are in situ converted to cobalt oxide under the accelerated conditions during OER (and/or ORR) of the ZABs and reduces the anodic current applied to the carbon. This contributes to the stability of the carbon material and in maintaining the high initial catalytic properties of the hybrid catalyst. PMID- 28861944 TI - A novel application of cultural consensus models to evaluate conservation education programs. AB - Conservation professionals recognize the need to evaluate education initiatives with a flexible approach that is culturally appropriate. Cultural-consensus theory (CCT) provides a framework for measuring the extent to which beliefs are communally held and has long been applied by social scientists. In a conservation education context, we applied CCT and used free lists (i.e., a list of items on a topic stated in order of cultural importance) and domain analysis (analysis of how free lists go together within a cultural group) to evaluate a conservation education program in which we used a children's picture book to increase knowledge about and empathy for a critically endangered mammal, the Javan slow loris (Nycticebus javanicus). We extracted free lists of keywords generated by students (n = 580 in 18 schools) from essays they wrote before and after the education program. In 2 classroom sessions conducted approximately 18 weeks apart, we asked students to write an essay about their knowledge of the target species and then presented a book and several activities about slow loris ecology. Prior to the second session, we asked students to write a second essay. We generated free lists from both essays, quantified salience of terms used, and conducted minimal residuals factor analysis to determine presence of cultural domains surrounding slow lorises in each session. Students increased their use of words accurately associated with slow loris ecology and conservation from 43% in initial essays to 76% in final essays. Domain coherence increased from 22% to 47% across schools. Fifteen factors contributed to the domain slow loris. Between the first and second essays, factors that showed the greatest change were feeding ecology and slow loris as a forest protector, which increased 7-fold, and the humancentric factor, which decreased 5-fold. As demonstrated by knowledge retention and creation of unique stories and conservation opinions, children achieved all six levels of Bloom's taxonomy of learning domains. Free from the constraints of questionnaires and surveys, CCT methods provide a promising avenue to evaluate conservation education programs. PMID- 28861943 TI - Surface-Engineering of Red Blood Cells as Artificial Antigen Presenting Cells Promising for Cancer Immunotherapy. AB - The development of artificial antigen presenting cells (aAPCs) to mimic the functions of APCs such as dendritic cells (DCs) to stimulate T cells and induce antitumor immune responses has attracted substantial interests in cancer immunotherapy. In this work, a unique red blood cell (RBC)-based aAPC system is designed by engineering antigen peptide-loaded major histocompatibility complex-I and CD28 activation antibody on RBC surface, which are further tethered with interleukin-2 (IL2) as a proliferation and differentiation signal. Such RBC-based aAPC-IL2 (R-aAPC-IL2) can not only provide a flexible cell surface with appropriate biophysical parameters, but also mimic the cytokine paracrine delivery. Similar to the functions of matured DCs, the R-aAPC-IL2 cells can facilitate the proliferation of antigen-specific CD8+ T cells and increase the secretion of inflammatory cytokines. As a proof-of-concept, we treated splenocytes from C57 mice with R-aAPC-IL2 and discovered those splenocytes induced significant cancer-cell-specific lysis, implying that the R-aAPC-IL2 were able to re-educate T cells and induce adoptive immune response. This work thus presents a novel RBC-based aAPC system which can mimic the functions of antigen presenting DCs to activate T cells, promising for applications in adoptive T cell transfer or even in direct activation of circulating T cells for cancer immunotherapy. PMID- 28861945 TI - Copper-Catalyzed Intermolecular Heck-Like Coupling of Cyclobutanone Oximes Initiated by Selective C-C Bond Cleavage. AB - The first example of intermolecular olefination of cyclobutanone oximes with alkenes via selective C-C bond cleavage leading to the synthesis of nitriles in the presence of a cheap copper catalyst is reported. The procedure is distinguished by mild and safe reaction conditions that avoid ligand, oxidant, base, or toxic cyanide salt. A wide scope of cyclobutanones and olefin coupling components can be used without compromising efficiency and scalability. The alternative visible-light-driven photoredox process for this coupling reaction was also uncovered. PMID- 28861946 TI - Ultrathin Colloidal Quantum Dot Films for Optical Amplification: The Role of Modal Confinement and Heat Dissipation. AB - We demonstrate optical pumping lasers based on colloidal quantum dots, with a very thin geometry consisting of a ~20 nm thick film. Obstacles in ultrasmall laser devices come from the limitation of gain materials and the size of cavities for lasing modes, which requires a minimum thickness of the gain media (typically greater than 50-100 nm). Here we introduce dielectric waveguide structures with a high refractive index, in order to reduce the thickness of quantum dot gain media as well as their threshold energy (~39 % compared to the original gain medium). Finite-difference time-domain simulations show that the modal confinement factor of thinner quantum dot films can be improved by the presence of an adjacent waveguide layer. We also discuss the possible role of dielectric waveguide layers for efficient heat dissipation during optical pumping. Integrating an extremely thin colloidal quantum dot gain medium into optical waveguides is a promising platform for downscaling on-chip photonic integrated devices, as well as investigating extreme interactions between light and matter such as surface plasmon-photon coupling. PMID- 28861947 TI - Intravenous lobular capillary haemangioma (pyogenic granuloma): A case report and a review of imaging findings as reported in the literature. AB - INTRODUCTION: Intravenous lobular capillary haemangioma (IVLCH) is a rare benign lesion with minimal published reports containing a description of its appearance at medical imaging. We present the ultrasound and MRI images of a histologically proven IVLCH and provide the first review of the imaging findings reported in the literature. METHODS: The imaging findings of a case of IVLCH are presented. A PubMed search of English language articles was performed from 1966 to October 2016, and all relevant papers were reviewed. Imaging findings from those papers are summarised. RESULTS: Key features on ultrasound are of a well-defined, usually hypoechoic, mass which is highly vascular. The host vein is usually apparent. MRI imaging usually shows T1 signal isointense to muscle and variable T2 signal, either isointense or of high signal relative to the vein. The lesions enhance with gadolinium. CONCLUSION: Intravenous lobular capillary haemangioma has distinctive ultrasound but less consistent MRI features although radiological diagnosis should usually be possible. Review of reported cases shows that a previously described gender bias is incorrect. PMID- 28861948 TI - Corrigendum for: Pregnancy-related Listeriosis. PMID- 28861949 TI - Corrigendum for: Congenital Lung Agenesis: Incidence and Outcome in the North of England. PMID- 28861950 TI - Coherent synthesis of genomic associations with phenotypes and home environments. AB - Local adaptation is often studied via (i) multiple common garden experiments comparing performance of genotypes in different environments and (ii) sequencing genotypes from multiple locations and characterizing geographic patterns in allele frequency. Both approaches aim to characterize the same pattern (local adaptation), yet the complementary information from each has not yet been coherently integrated. Here, we develop a genome-wide association model of genotype interactions with continuous environmental gradients (G * E), that is reaction norms. We present an approach to impute relative fitness, allowing us to coherently synthesize evidence from common garden and genome-environment associations. Our approach identifies loci exhibiting environmental clines where alleles are associated with higher fitness in home environments. Simulations show our approach can increase power to detect loci causing local adaptation. In a case study on Arabidopsis thaliana, most identified SNPs exhibited home allele advantage and fitness trade-offs along climate gradients, suggesting selective gradients can maintain allelic clines. SNPs exhibiting G * E associations with fitness were enriched in genic regions, putative partial selective sweeps and associations with an adaptive phenotype (flowering time plasticity). We discuss extensions for situations where only adaptive phenotypes other than fitness are available. Many types of data may point towards the loci underlying G * E and local adaptation; coherent models of diverse data provide a principled basis for synthesis. PMID- 28861951 TI - Encapsulation of Hydrophilic and Hydrophobic Peptides into Hollow Mesoporous Silica Nanoparticles for Enhancement of Antitumor Immune Response. AB - Codelivery of combinational antigenic peptides and adjuvant to antigen presenting cells is expected to amplify tumor specific T lymphocytes immune responses while minimizing the possibility of tumor escaping and reducing immune tolerance to single antigenic peptide. However, the varied hydrophobicities of these multivariant derived short antigenic peptides limit their codelivery efficiency in conventional delivery systems. Here, a facile yet effective route is presented to generate monodisperse and stable hollow mesoporous silica nanoparticles (HMSNs) for codelivering of HGP10025-33 and TRP2180-188 , two melanoma-derived peptides with varied hydrophobicities. The HMSNs with large pore size can improve the encapsulation efficiency of both HGP100 and TRP2 after ?NH2 modification on the inner hollow core and ?COOH modification in the porous channels. HGP100 and TRP2 loaded HMSNs (HT@HMSNs) are further enveloped within monophosphoryl lipid A adjuvant entrapped lipid bilayer (HTM@HMLBs), for improved stability/biocompatibility and codelivery efficiency of multiple peptides, adjuvant, and enhanced antitumor immune responses. HTM@HMLBs increase uptake by dendritic cells (DCs) and stimulate DCs maturation efficiently, which further induce the activation of both tumor specific CD8+ and CD4+ T lymphocytes. Moreover, HTM@HMLBs can significantly inhibit tumor growth and lung metastasis in murine melanoma models with good safety profiles. HMSNs enveloped with lipid bilayers (HMLBs) are believed to be a promising platform for codelivery of multiple peptides, adjuvant, and enhancement of antitumor efficacy of conventional vaccinations. PMID- 28861952 TI - Use of sodium-glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus. AB - AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long-term use of SGLT2 inhibitors in older patients with diabetes. METHODS: A total of 117 older patients with type 2 diabetes who were given SGLT2 inhibitors were enrolled from April 2014 to March 2016. RESULTS: The mean age of the patients was 73.7 +/- 10.0 years. During the follow-up period (mean 289.3 days), there was no event associated with oral administration of SGLT2 inhibitors. These drugs significantly lowered fasting blood glucose and glycosylated hemoglobin levels at 6 months, and did not affect the creatinine level, blood urea nitrogen/creatinine ratio or estimated glomerular filtration rate during treatment. Although the treatment significantly increased hemoglobin and hematocrit levels, it did not affect the ultrasonographically determined diameter of the inferior vena cava, and no signs of intravascular collapse were observed. Changes in brain natriuretic peptide levels during the follow-up period were assessed in 78 patients with a brain natriuretic peptide level exceeding the normal upper limit before treatment with SGLT2 inhibitors. The brain natriuretic peptide levels significantly decreased after 6 months of treatment. CONCLUSIONS: In older Japanese patients with diabetes, treatment with SGLT2 inhibitors for 6 months exerted a favorable hypoglycemic effect, while no sign of dehydration was observed. Geriatr Gerontol Int 2018; 18: 108-114. PMID- 28861953 TI - FEN1 promotes tumor progression and confers cisplatin resistance in non-small cell lung cancer. PMID- 28861954 TI - Accurate viscosity measurements of flowing aqueous glucose solutions with suspended scatterers using a dynamic light scattering approach with optical coherence tomography. AB - The viscosity of turbid colloidal glucose solutions has been accurately determined from spectral domain optical coherence tomography (OCT) M-mode measurements and our recently developed OCT dynamic light scattering model. Results for various glucose concentrations, flow speeds, and flow angles are reported. The relative "combined standard uncertainty" uc(eta) on the viscosity measurements was +/-1% for the no-flow case and +/-5% for the flow cases, a significant improvement in measurement robustness over previously published reports. The available literature data for the viscosity of pure water and our measurements differ by 1% (stagnant case) and 1.5% (flow cases), demonstrating good accuracy; similar agreement is seen across the measured glucose concentration range when compared to interpolated literature values. The developed technique may contribute toward eventual noninvasive glucose measurements in medicine. PMID- 28861955 TI - Evaluating biomechanical properties of murine embryos using Brillouin microscopy and optical coherence tomography. AB - Embryogenesis is regulated by numerous changes in mechanical properties of the cellular microenvironment. Thus, studying embryonic mechanophysiology can provide a more thorough perspective of embryonic development, potentially improving early detection of congenital abnormalities as well as evaluating and developing therapeutic interventions. A number of methods and techniques have been used to study cellular biomechanical properties during embryogenesis. While some of these techniques are invasive or involve the use of external agents, others are compromised in terms of spatial and temporal resolutions. We propose the use of Brillouin microscopy in combination with optical coherence tomography (OCT) to measure stiffness as well as structural changes in a developing embryo. While Brillouin microscopy assesses the changes in stiffness among different organs of the embryo, OCT provides the necessary structural guidance. PMID- 28861956 TI - [Discussion on present situation of study on pesticide residues in Chinese herbal medicines]. AB - Pesticide residues in traditional Chinese medicine has attracted widespread attention at home and abroad. This paper analyzed the pollution present situation and existing problems of pesticide residue for Chinese herbal medicines, explicited the analytical methods of pesticide residues in Chinese herbal medicines. Meanwhile, the commonly used pesticide residue degradation and application in Chinese herbal medicines were discussed. Moreover, on the basis of analysis of pesticide residue standards, this paper proposed the necessity and urgency of the limit standard of pesticide residues in Chinese herbal medicines, and provided a scientific references for deepening research and developing safe, green medicines. PMID- 28861957 TI - [Current researches and prospects of seedling propagation and cultivation modes of Jinxianlian]. AB - In the wake of on-the-spot investigation into Chinese major production bases in Fujian, Zhejiang, Jiangxi, Taiwan, Guangxi and Yunnan provinces, and based on relevant literature, the paper systematically elaborates the current researches of botanical origin, major cultivation type, seedling propagation technique as well as cultivation mode of Jinxianlian. The way of seedling breeding mainly includes aseptic seed culture, in vitro propagation, artificial seed and bioreactor propagation, etc. And the planting model mainly includes protected cultivation modes, bionic wild cultivation modes and pot cultivation modes, etc. Further discussions have also been conducted to tackle significant problems existing in the production process of Jinxianlian, based on personal studies of the authors. It has made considerable contributions for the betterment of Jinxianlian's development and improvement. PMID- 28861958 TI - [Research progress of structures and pharmacological activities of phthalides from Angelica sinensis]. AB - Angelica sinensis(Umbelliferae)is a worldwide-known medicinal plant and also a famous traditional Chinese medicinal herb. It is recorded to possess the efficacy of enriching the blood and invigorating the circulation of blood of the individual.Danggui was extensively applied to the treatment of gynecological disorders. Modern researches indicate that phthalides are main chemical components related to the bioactivities of A.sinensis, such as anti-tumor, analgesic and neuroprotective effect.The advances in studies on the structures and pharmacological activities of phthalides from A.sinensis are reviewed to provide references for further researches and utilization of their medicinal value. PMID- 28861959 TI - [Quality evaluation method for Chinese medicine based on color grading]. AB - Traditional identification method is an effective approach to evaluate the quality for Chinese herbal medicine (CHM). Color is one of the important indicators for quality evaluation due to high correlation with quality. Therefore, a new theory of quality control for CHM based on color grading was discussed in this article. The scientific nature of this theory was illustrated by investigating the relation between CHM color, medicinal properties and active compound contents. The effect of origins, collecting time, processing, and storage on the CHM color was also analyzed. To overcome the drawback of the traditional identification method, the novel objective color evaluation methods such as spectrocolorimeter and machine vision technology were reviewed, including the application, advantages and disadvantages in Chinese medicine field, and the significance of color sense digitalization was illustrated finally. PMID- 28861960 TI - [Recent advances in anti-aging study of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D glucopyranoside--a main component of Polygonum multiflorum]. AB - Aging is an inevitable process of life caused by a combination of organs and tissues events which manifests as loss of structure and function. It is accompanied with organ hypofunction, decline in defense against stress and energy metabolism, and lots of age-related diseases. Therefore, it is critical to understand the mechanism of aging, as well as to discover new drugs to slow aging. Polygonum multiflorum has long been recognized in traditional Chinese medicine as anti-aging medicine. Interestingly, its extract has been shown to prolong lifespan in drosophila and elegans. Tetrahydroxystilbene glucoside (TSG), the main ingredient of P. multiflorum, shares a strong structural similarity with resveratrol, a well-known anti-aging natural product. This review summarized up to-date literature reports and our laboratory findings on the mechanism of TSG anti-aging efficiency and function against age-related disease. It could provide reference for searching for anti-aging tradition Chinese medicine. PMID- 28861961 TI - [Resource investigation of wild Codonopsis pilosula in Tanchang county of Gansu]. AB - Tanchang county is the distribution of wild medicinal plant resource-rich region, in order to ascertain Tanchang county Codonopsis pilosula wild resources and reserves of the status quo, according to the fourth national Chinese medicine resources survey technology solutions, using sets of plots and investigating combined route survey method, the county wild C. pilosula var. modesta and C. pilosula resources were investigated by a comprehensive survey designed to reveal the distribution of the county's wildlife resources and herbs C. pilosula reserves. The results showed that in Tanchang county seven ecological zones 53 plots, wild C. pilosula distributed in there were 6 ecological zones 11 plots, accounting for 85.71% of the survey area, wild C. pilosula var. modesta was found only in an ecoregions plots, overlapping with C. pilosula region, accounting for 14.29% of the survey area. C. pilosula herbs reserves were calculated as about 461.85 t, economic capacity of 254.02 t, annual amount of acceptance 25.40 t. C. pilosula var. modesta herbs reserves were calculated as 67.75 t, economic capacity of 36.16 t, acceptance annual amount 3.62 t. The total ash C. pilosula was 3.25%, alcohol-soluble extract was 63.86%, while the C. pilosula var. modesta total ash was 3.69%, alcohol-soluble extract was 68.32%. C. pilosula is suitable for broad range, but wild resource is scarce, C. pilosula var. modesta is suitable for relatively narrow scope, and wild resource is scarce, it is recommended to strengthen the protection of wild resources and the rational development and utilization. PMID- 28861962 TI - [Construction and expression of prokaryotic vector of AsJAZ1 gene from Aquilaria sinensis]. AB - The full-length coding sequence (cds) of jasmonate-zim-domain protein (AsJAZ1) gene was cloned from Aquilaria sinensis, the prokaryotic vector was constructed and the recombinant proteins expression was induced to provide the basic material for interactive proteins screen and gene function research. In this study, with the total RNA isolated from A. sinensis leave as template, the full-length cds of AsJAZ1 gene was amplified using RT-PCR method and subcloned into pET-28a vector. The recombinant plasmid identified by restriction enzyme digestion and nucleotide sequencing was transformed into E. coli BL21(DE3). Inducing with 0.5 mmol*L-1 IPTG at 37 C for 4 hours, a fusion protein about 39 kDa was maximumly obtained. AsJAZ1 fusion protein had been expressed successfully mainly in the form of inclusion bodies and only a very small amount was secreted into the cytoplasm in the supernatant. PMID- 28861963 TI - [Effect of exogenous brassinolide on morphological characters and contents of seven chemical constituents of Glycyrrhiza uralensis]. AB - The transplants of the two-year-old Glycyrrhiza uralensis were subjected to four concentration of brassinolide (BR 0.1, 0.4, 0.7, 1.0 mg*L-1) in July. The morphological characters ( plant height, stem diameter, nodes number, internode length and root length , root thick, root fresh weight and root dry weight ) were measured and seven kinds of chemical constituents (glycyrrhizic acid, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, liquiritin apioside, isoliquiritin apioside) were determined by HPLC with the aim of increasing sinter output and improving quality of G. uralensis. Then the long-term dynamic changes of these morphological characters and chemical compositions' content were analyzed. The results showed that morphological characters of plant height, stem diameter, root length , root thick, root fresh weight and root dry weight increased remarkably with the 0.7 mg*L-1 BR stimulating 2 months later,the increase rates were: 15.09%,6.15%,16.52%,8.46%,21.90%,29.41%, respectively. The content of glycyrrhizic acid, liquiritin, isoliquiritin, liquiritigenin, liquiritin apioside, isoliquiritin apioside were increased 20.16%,45.31%,53.56%,27.66%,23.54%,8.46% with the 0.7 mg*L-1 BR stimulating 2 months later. The best effects were achieved in 2 months after brassinolide stimulating. The conclusions prove that morphological characters and the main chemical constituents accumulation of G. uralensis could be effected by exogenous BR stimulation in certain case. PMID- 28861964 TI - [Variation and correlation analysis on phenotypic traits of Scutellaria baicalensis from different strains]. AB - To research the differences and correlation between Scutellaria baicalensis about phenotypic traits of different strains, 10 aboveground traits and 6 root traits of S. baicalensis in two-year-transplanted plants from 14 different strains were compared respectively, and the SPSS 17.0 statistical software was used for data analysis. It showed that phenotypic traits variation of different S. baicalensis strains was rich and the F value ranged from 3.169 to 71.58. The difference was significant between each other and germplasm 15 performs the most outstanding characters. Correlation analysis showed that there existed a significant correlation between the characters except for lateral root number, root diameter and length. The correlation coefficient between the fresh weight of root and the reed head diameter was up to 0.877. Principal component analysis showed that the average of overall yield per plant and root diameter could be used as the comprehensive reference index for germplasm evaluation. The differences and correlations in phenotypic traits of different S. baicalensis strains, provide theoretical basis for distinguishing germplasm and breeding good varieties of S. baicalensis. PMID- 28861965 TI - [Authentication of Cuscutae Semen, Raphani Semen and their adulterants by rapid PCR]. AB - To establish an accurate, rapid and efficient method for authenticating Cuscutae Semen and Raphani Semen by using rapid PCR amplification. The samples of Cuscutae Semen, Raphani Semen and their adulterants were collected. The total DNA of the samples has been extracted, and ITS sequence from Cuscutae Semen, Raphani Semen and their adulterants was amplified by PCR and sequenced directionally. These sequences were aligned by using Clustal W. Specific primers were designed and amplified by two-steps PCR amplification method. The rapid PCR methods for authenticating Cuscutae Semen and Raphani Semen were established by optimizing the denatured and annealing temperature, cycle numbers, and etc. When 100 * SYBR Green I was added in the PCR product, strong green fluorescence was visualized under 365 nm UV lamp whereas adulterants showed no florescence. The results indicated that the rapid PCR method can identify Cuscutae Semen and Raphani Semen rapidly. This study provides the technical support for authentication of Chinese medicinal materials. PMID- 28861966 TI - [Intestinal toxicity of n-BuOH fraction from Phytolacca Radix before and after being processed with vinegar]. AB - To research the intestinal toxicity of n-BuOH fraction in Phytolacca Radix before and after being processed with vinegar. Toxic n-BuOH fractions were separated from Phytolacca Radix. In the animal model, the level of intestinal edema, water content of intestine and stool, IC50 values of HT-29 and IEC-6 were detected with MTT method to compare the changes in toxicity of n-BuOH fractions from Phytolacca Radix before and after being processed with vinegar. n-BuOH fractions of Phytolacca Radix could cause intestinal edema in mice, increase the edema of duodenum, jejunum and the water content in stool, inhibit the proliferation of HT 29 cells and IEC-6 cells, indicating its intestinal toxicity, with HT-29 IC50 at 14.59 mg*L-1 and IEC-6 IC50 at 43.77 mg*L-1. After being processed with vinegar, the level of intestinal edema, edema of duodenum and jejunum and the water content in stool and inhibition ratio of cells line were reduced, with HT-29 IC50 at 58.51 mg*L-1 and IEC-6 IC50 at 84.37 mg*L-1. After being processed with vinegar, the toxicity of n-BuOH fractions from Phytolacca Radix decreased obviously. PMID- 28861967 TI - [Response surface optimization of purification process for pigment from Coreopsis tinctoria by macroporous resins]. AB - To optimize the purification process of pigments from Coreopsis tinctoria with macroporous resins by establishing second regression model with response surface methodology. The experiment showed that XDA-7 resin had the best purification effect for pigments from C. tinctoria. The optimal absorption conditions for pigments from C. tinctoria were determined as follows: concentration of pigments solution 2.7 g*L-1, flow rate 6 mL*min-1, pH 6. Under these conditions, the absorption rate of pigments was up to 94.16%. Optimal desorption conditions were as follows: ethanol concentration 64%, flow rate 5 mL*min-1, elution dosage 4 BV. Under these conditions, pigment desorption rate was as high as 98.72%. PMID- 28861968 TI - [Extraction and purification process of total fatty acid in Brassica campestris pollen]. AB - This study was aimed to optimize the extraction (CO2 supercritical extraction) process and purification (ethanol washing and decontaminating) process of total fatty acid in Brassica campestris pollen. With the extraction yield of total fatty acid as index, CO2 supercritical extraction of total fatty acid in B. campestris polle was optimized by central composite design-response surface methodology. Ethanol washing and decontaminating was done for the extract through orthogonal design with content of total fatty acid (linolenic acid amide, linolenic acid glyceride, linolenic acid and palmitic acid) as the indexes. The optimum parameters of CO2 supercritical extraction technology were as follows: extraction pressure of 35 MPa, extraction temperature of 60 Cand extraction time of 3 h. When extract of supercritical fluid was purified by 50 times of 80% ethanol for 1.5 h, the content of total fatty acid can reach 60%. In addition, this process was stable and steady, provided reliable basis for production. PMID- 28861969 TI - [Chemical constituents of Chinese red ginseng]. AB - The chemical constituents of the Chinese red ginseng were systematically investigated by using various column chromatographic methods including D-101 macroporous adsorptive resins and open silica gel column chromatographies as well as high-performance liquid chromatography.Their chemical structures were identified by physico-chemical properties and spectral analyses.Fifty-two compounds were isolated from Chinese red ginseng decoction and identified as 20(S)-ginsenoside Rh1 (1), 20(R)-ginsenoside Rh1 (2), ginsenoside Rg6 (3), 20(22) E-ginsenoside F4 (4), ginsenoside Rk3 (5), 20(22) E-ginsenoside Rh4 (6), ginsenoside Rg1 (7), 20(S)-ginsenoside Rf-1a(8), 20(S)-ginsenoside Rf(9), 20(R) ginsenoside Rf(10),20(S)-notoginsenoside R2 (11),20(R)-notoginsenoside R2 (12), 20(S)-ginsenoside Rg2 (13), 20(R)-ginsenoside Rg2 (14), ginsenoside Rs2 (15),ginsenoside Rs1 (16),ginsenoside Rd(17),notoginsenoside R1 (18),ginsenoside Re2 (19), ginsenoside Re(20), 20-gluco-ginsenoside Rf(21),quinquenoside-R1 (22),ginsenoside Ro methyl ester(23),ginsenoside Ro(24),ginsenoside Rb1 (25),ginsenoside Rc(26),ginsenoside Rb2 (27),ginsenoside Ra2 (28),ginsenoside Ra3 (29),ginsenoside Rb3 (30),20(22)Z-ginsenoside Rh4 (31),chikusetsusaponin IVa butyl ester(32), 20(22)Z-ginsenoside Rs4 (33),ginsenoside Rs5 (34),20(22)E ginsenoside Rs4 (35),zingibroside R1-6'-butyl ester(36), chikusetsusaponin IVa methyl ester(37),20(S)-ginsenoside Rs3 (38),20(R)-ginsenoside Rs3 (39),zingibroside R1-6'-methyl ester(40),ginsenoside Rz1 (41),ginsenoside Rk1 (42),ginsenoside Rg5 (43),23-O-methylginsenoside-Rg1 1 (44),12beta,25 dihydroxydammar-20(22)E-ene-3-O-beta-D-glucopyranosyl-(1->2)-O-beta-D glucopyranoside(45), 20(22)Z-ginsenoside F4 (46),3beta,12beta-dihydroxydammar 20(22)E,24-diene-6-O-beta-D-xylopyranosyl-(1->2)-O-beta-D-glucopyranoside(47), 20(S)-ginsenoside Rg3 (48),20(R)-ginsenoside Rg3 (49),20(22)E-ginsenoside Rg9 (50),ginsenoside-Ro-6'-butyl ester(51), and polyacetyleneginsenoside Ro(52). Compounds 8, 12, 31-33, 36, 37, 44, 45, 47 and 51 were isolated from the P. ginseng, and compounds 19, 23 and 46 were isolated from Chinese red ginseng for the first time. PMID- 28861970 TI - [Simultaneous determination of 4 diterpenoids in Rabdosia japonica var.glaucocalyx by HPLC-ESI-MS/MS and cluster analysis]. AB - A quick HPLC-ESI-MS/MS method was established for simultaneous determination of four major diterpenoids in Rabdosia japonica var.glaucocalyx, including glaucocalyxin A, oridonin, hebeirubesensin and enmenol. Analysis was performed on an Agilent ZORBAX SB-C18(4.6 mm*250 mm, 5 MUm ) column eluted in a gradient program with methanol and water. The flow rate was 0.8 mL*min-1. Multiple reaction monitoring (MRM) scanning mode was performed in negative ion switching mode to apply for the quantitative determination. The calibration curves for the above four compounds were linear in corresponding injection amount. The average recoveries of the compounds ranged from 92.40% to 105.9%, with RSDs of 1.7%-6.5%. The method is simple, rapid, accurate with good repeatability, which can provide a reference for overcalling evaluation the quality of R. japonica var.glaucocalyx. The result of cluster analysis- showed that the quality of R. japonica glaucocalyx var. greatly varied between areas and parts. PMID- 28861971 TI - [Study on composition of essential oils in three different origins' Curcumae Rhizoma by AMDIS and retention index]. AB - To compare the differences of essential oils extracted from Curcumae Rhizoma with different origins. The TIC of the essential oils of Curcumae Rhizoma from three different origins recorded by CP(2010) , were investigated by GC-MS combined with automated mass spectral deconvolution and identification system(AMDIS),steps as follow: firstly, overlapped peaks were resolved by AMDIS,secondly, NIST11.L standard MS spectral database combined with retention index were used to assist qualitative analysis, thirdly, the peak area of each split peak were determined by choosing the characteristic fragment ion peak, finally, the relative percentage contents of each compounds were determined through peak area normalization method. The results showed that the components of the essential oils of Curcumae Rhizoma from three origins were different from each other at various degree. In conclusion, the types and content of essential oils could be an indicator to evaluate the quality of Curcumae Rhizoma from different origins and its geoherbalism. PMID- 28861972 TI - [Discovery of potential ATP-sensitive potassium channel openers with potential hypotensive activity from Chinese herbs based on molecular simulation]. AB - In this research, a combined method of ligand-based pharmacophore (LBP), structure-based pharmacophore (SBP), and molecular docking was applied for virtual screening potential ATP-sensitive potassium channel (KATP) openers from Chinese herbs. LBP models were generated by 3D-QSAR pharmacophore(hypogen) program, based on the training set composed of 48 KATP agonists. The best LBP model consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one hydrophobic feature, one aromatic ring and five excluded volumes. Besides, the correlation coefficient of training set and test set, N, and CAI value of the model were 0.876 4, 0.705 8, 3.304, and 2.616 respectively. Meanwhile, SBP models were also generated based on a 3D structure of KATP (PMID: PM0079770). The best SBP model consisted of six hydrogen-bond acceptors, eight hydrogen-bond donors, seven hydrophobic features and eighteen excluded volumes. The corresponding N and CAI value were 2.200 and 2.017. Then, the best LBP model and SBP model were applied to identify potential KATP openers from Traditional Chinese Medicine Database(TCMD), respectively. 349 hits were obtained after analyzed by drug likeness rules. Moreover, 12 compounds with high docking scores were reserved after molecular docking evaluation. Interestingly, part of the results had been verified as hypotensive active ingredients by literatures. Therefore, this study uncovers a specific target effect contained in TCMD, and provides candidates for new KATP openers' research. PMID- 28861973 TI - [Prescription of Jingdan Yimin for treatment of metabolic syndrome]. AB - Based on the theory of traditional Chinese medicine, modern methods for drug investigation such as molecular targets in vitro and effects in vivo were used to study the prescription of Jingdan Yimin(JD), including selection of raw materials, composition, proportion, and effective dose of the compounds for treatment of metabolic syndrome. The IRF mice models, characterized by insulin resistance and hypercholesterolemia, were induced by high fat diet. The insulin sensitivity was estimated with insulin tolerance test(ITT) and glucose tolerance test(GTT); the levels of blood glucose and total cholesterol(TC), and the activities of alpha-glucosidase, protein tyrosine phosphatase 1B(PTP1B), and fructose phosphate amide transferase(GFAT)were measured with biochemical methods, respectively. The sample H13(h) extracted from Rhodiola crenulata, Y12(y) from Cordyceps militaris, and D(d) from Rheum palmatum were selected according to the inhibition activity on both PTP1B and alpha-glucosidase in vitro, regulation on hypercholesterolemia in IRF mice, and effects on GFAT activity, respectively; their synergistic effects on the treatment of metabolic syndrome were determined in IRF mice; composition proportion of h?y?d was measured in accordance with the results of L8(27) orthogonal experiments targeting on the inhibition of both PTP1B and alpha-glucosidase; finally, the effective dose was assessed based on the effects on IGT and hypercholesterolemia, respectively, in IRF mice. In conclusion, the prescription JD is composed by R. crenulata, C. militaris, and R. palmatum with the rate of 20?1?1, and its effective oral dose is 200 mg*kg-1 for treatment of metabolic syndrome; its main mechanism is to inhibit the targets PTP1B and alpha-glucosidase. Monarch drug, R. crenulata, can clear away the lung heat, tonify Qi, resolve stasis and nourish the heart. Adjuvant drug, C. militaris, can tonify the lung Qi and the kidney essence, strengthen waist and knee, accompanied with R. crenulata to enhance the function of invigorating lung and kidney. Assistant drug, rhubarb, can clear heat, detoxify, and remove blood stasis. These three herbs are compatible to show the effects of tonifying Qi, nourishing essence, clearing heat, reducing phlegm and resolving masses for the treatment of metabolic syndrome. PMID- 28861974 TI - [Effect of schisantherin A inhibit liver sinusoid endothelial cell function and action against liver fibrosis relating to angiogenesis]. AB - To investigate the effect of schisantherin A on liver sinusoid endothelial cell function and angiogenesis. Different dosages (0-40 MUmol*L-1) of schisantherin A were incubated 24 h with SK-HEP-1 cells, and the toxicity of SK-HEP-1 cells was assayed by MTT method. The proliferation of SK-HEP-1 cells were induced by the vascular endothelial growth factor (VEGF), with receptor tyrosine kinase inhibitor sorafenib as the control, at the same time, set up the control group, 2, 20 MUmol*L-1 schisantherin A were incubated with SK-HEP-1 cells, cell proliferation was analyzed by EdU DNA cell proliferation kit. Fluorescence probe method was used to assay the intracellular NO levels and NOS activity. Tube formation was observed using cell migration and a matrigel tube formation assay. Rat aortic ring assay was performed to observe the sprouting vessels from aortic ring. The fluorescence vessels, the number of functional blood vessels, and intersegmental vessel changes of transgenic zebrafish were also observed. Compared with control group, the proliferation of SK-HEP-1 cells induced by VEGF increased and and the level of NO and NOS activity induced; compared with model group, 2, 20 MUmol*L-1 schisantherin A and sorafenib inhibited the proliferation of SK-Hep-1 cells induced by VEGF, and reduced the level of NO and NOS activity. At the dosage of 20 MUmol*L-1, schisantherin A attenuated the migration and tube formation of SK-HEP-1 cells induced by VEGF, and also inhibition the formation of rat aortic rings and intersegmental vessel changes of transgenic zebrafish, and significantly reduce the number of vessels in zebrafish. Schisantherin A has potential effects on function of endothelial cell proliferation and angiogenesis. PMID- 28861975 TI - [Quantitative determination of seven major absorbed volatile constituents in mice brain, liver and blood after intragastric administration of Asari Radix et Rhizoma suspension by headspace-solid phase microextraction-gas chromatography mass spectrometry]. AB - A headspace-solid phase microextraction-gas chromatography-mass spectrometry method(HS-SPME-GC-MS) was adopted for the quantitative study of 4-allylanisole, methyl eugenol, 2,3,5-trimethoxytoluene, 3,4,5-trimethoxytoluene, sarisan, 3,5 dimethoxytoluene and safrole in mice brain, liver tissues and blood after intragastric administration of Asari Radix et Rhizoma. A VF-WAXms (30 m*0.25 mm, 0.25 MUm film thickness) capillary column and SPME fiber coated with 65 MUm polydimethylsiloxane/divinylbenzene (PDMS/DVB) were used. The calibration curves of seven volatile constituents were established to validate the method's stability (RSD<15%), repeatability (RSD<9.5%), accuracy (RSD<22%), relative recovery (87.0%-108%) and extraction recovery (74.9%-102%). The validated HS-SPME GC-MS assay was applied to determine the concentrations of seven constituents in liver, brain and blood. The detected contents were 0.22,0.14 MUg*g-1,0.25 mg*L-1 (4-allylanisole), 1.1, 0.39 MUg*g-1, 0.69 mg*L-1 (methyl eugenol), 0.45, 0.13 MUg*g-1, 0.54 mg*L-1 (2,3,5-trimethoxytoluene), 0.51, 0.15 MUg*g-1, 0.45 mg*L-1 (3,4,5-trimethoxytoluene), 0.48, 0.039 MUg*g-1, 0.69 mg*L -1 (sarisan), 2.2, 1.2 MUg*g-1, 1.5 mg*L-1 (3,5-dimethoxytoluene) and 1.3, 0.67 MUg*g-1, 1.1 mg*L-1 (safrole) respectively. This HS-SPME-GC-MS method is rapid and convenient, with a small sample size, and applicable for the analysis and determination of volatile constituents in traditional Chinese medicines, which provides scientific data for further studies on effective substances and toxic substances in Asari Radix et Rhizoma. PMID- 28861976 TI - [Effects of different penetration enhancers on pharmacokinetics of active components in Xiangfu Siwu transdermal patches]. AB - To study the effect of different penetration enhancers on the pharmacokinetic characters of six active components in Xiangfu Siwu transdermal patch (XBW) and optimize the best penetration enhancers. During the experiment, the patches containing different penetration enhancers were stuck on the rat's skin, and then the blood samples were acquired at different time points. Six active components in plasma were determined by UPLC-MS/MS. The main pharmacokinetic parameters were calculated with DAS software package. The total factor scores (F) of the plasma concentrations of six components at every time point in different groups were calculated using principle component analysis, and the areas under F versus time curves (AUCF-t) were employed to be the indexes for selecting penetration enhancers. The results demonstrated that compared with the control group, the AUCF-t from other groups increased prominently and furthermore, 5% menthol manifested the best effect. In this research, 5% menthol could remarkably promote the percutaneous penetration effect of the six active compounds in XBW, and it could provide a scientific basis for the preparation research of XBW. PMID- 28861977 TI - [Effect of salvianolic acid B on nasal absorption in rats in situ]. AB - This experiment focused on the effect of salvianolic acid B's nasal absorption characteristics in rats. In the study, HPLC determination of salvianolic acid B(SalB) in perfusion liquid was established to examine the SalB nasal irritation in different pH buffers and stability in nasal perfusion solution, and systematically study in vivo nasal absorption characteristics of SalB. Improved rats were adopted to establish the in situ nasal perfusion model to measure the release of total protein and lactate dehydrogenase in perfusion fluid, quantitatively evaluate the nasal irritation and the stability in perfusion liquid of pH 4.0, 5.0, 6.0 SalB phosphate buffer, compare the absorption of SalB in pH 5.0 buffer solution with low, medium and high concentrations (200, 400, 800 mg*L-1). According to the results, nasal irritation: pH 4.0>pH 5.0>pH 6.0, RSD of pH 6.0 SalB buffer solution within 24 h was 3.1%, stability was poor. PH 5.0 SalB buffer solution had a smaller irritation and good stability. According to the nose perfusion test in rats, the nasal absorption of SalB fitted the first-order process and could be considered as passive absorption based on concentration gradient. SalB buffer solution of pH 5.0 had also a small nasal irritation and good stability, with a good absorption in rat nasal perfusion test, which therefore had a certain significance for the development of SalB nasal formulation. PMID- 28861978 TI - [In vitro and In vivo effects of six Coptidis alkaloids on liver microsomes UGTs and UGT1A1 activities in rats and mice]. AB - In the present study, the effects of six Coptidis alkaloids (berberine, epiberberine, coptisine, jatrorrhizine, palmatine and magnoflorine) on liver microsomes UGTs and UGT1A1 activities in rats and mice were investigated in vitro and in vivo to study the mechanism of metabolic drug-drug interactions of Coptidis Rhizoma with other drugs. In vitro rat and mice liver microsomal incubation systems combined with UDPGA were applied, as well as mice liver microsomes after administration of six Coptidis alkaloids. 4-Nitrophenol and beta estradiol were selected as substrates to determine activities of UGTs and UGT1A1 by UV and HPLC, respectively. According to the in vitro rat study, berberine, epiberberine, coptisine and jatrorrhizine significantly inhibited rat liver microsome UGTs activity, particularly epiberberine showed the strongest inhibition. UGT1A1 activity was lowly inhibited by jatrorrhizine, with IC50 at about 227 MUmol*L-1, whereas coptisine and magnoflorine significantly activated UGT1A1. According to the in vitro mice study, berberine, coptisine, jatrorrhizine and palmatine significantly inhibited mice liver microsome UGTs activity, and the six alkaloids all significantly activated UGT1A1. According to the in vivo mice study, UGTs activity was significantly activated only in berberine group, while UGT1A1 activity was significantly activated only in jatrorrhizine group. In conclusion, the effects of Coptidis alkaloids on UGT activity showed significant differences in species and between in vitro and in vivo. Meanwhile, the changes in structures of Coptidis alkaloids also have a big impact on UGT activity, which may be one of the causes for the drug-drug interactions between Coptidis Rhizoma and other drugs. PMID- 28861979 TI - [Analysis on traditional Chinese medicine prescriptions treating cancer-related anorexia syndrome based on grey system theory combined with multivariate analysis method and discovery of new prescriptions]. AB - Cancer-related anorexia syndrome (CACS) is one of the main causes for death at present as well as a syndrome seriously harming patients' quality of life, treatment effect and survival time. In current clinical researches, there are fewer reports about empirical traditional Chinese medicine(TCM) prescriptions and patent prescriptions treating CACS, and prescription rules are rarely analyzed in a systematic manner. As the hidden rules are not excavated, it is hard to have an innovative discovery and knowledge of clinical medication. In this paper, the grey screening method combined with the multivariate statistical method was used to build the "CACS prescriptions database". Based on the database, totally 359 prescriptions were selected, the frequency of herbs in prescription was determined, and commonly combined drugs were evolved into 4 new prescriptions for different syndromes. Prescriptions of TCM in treatment of CACS gave priority to benefiting qi for strengthening spleen, also laid emphasis on replenishing kidney essence, dispersing stagnated liver-qi and dispersing lung-qi. Moreover, interdependence and mutual promotion of yin and yang should be taken into account to reflect TCM's holism and theory for treatment based on syndrome differentiation. The grey screening method, as a valuable traditional Chinese medicine research-supporting method, can be used to subjectively and objectively analyze prescription rules; and the new prescriptions can provide reference for the clinical use of TCM for treating CACS and the drug development. PMID- 28861980 TI - [Effects of Gushen Antai pills combined with progestin on serum beta-HCG, P, E2 and CA125 in patients with threatened abortion]. AB - To investigate the clinical effect of Gushen Antai pills and progesterone in the treatment of threatened abortion, in order to provide references for early clinical intervention with threatened abortion. The 112 cases of patients with threatened abortion were randomly divided into the control group and the observation group. 56 cases in each group. Patients in the control group was injected with progesterone, the observation group was treated with Gushen Antai pills in addition to the therapy of the control group. Both groups were treated by drugs for two weeks. Their venous bloods (5 mL) were collected before treatment and in 1, 2 weeks after treatment to determine serum levels of beta HCG, P, E2 and CA125. The differences between the two groups after treatment were compared. The total effective rate of the control group and the observation group were 79% and 91.9% respectively, with a statistically significant difference between the two groups (P<0.05). Two weeks after the treatment, the serum levels of P and E2 in the observation group were significantly higher than before treatment, but the serum CA125 levels decreased significantly after treatment (P<0.05). These indicators showed statistically significant difference compared with that of the control group (P<0.05). After treatment, the serum beta-HCG levels of the two groups were significantly higher than before treatment (P<0.05), but there was no statistically significant difference between the two groups. Gushen Antai pills and progesterone had a better clinical curative effect in treatment threatened abortion, which could significantly raise serum beta-HCG, P and E2, reduce serum CA125 and increase the tocolysis efficiency, and so it was worth promoted in clinic. PMID- 28861981 TI - [Meta-analysis on efficacy and safety of Brucea javanica oil emulsion injection combined with chemotherapy for patients with advanced gastric carcinoma]. AB - Eligible studies were searched in Cochrane library, Pubmed, Medline, CBM, CNKI and VIP databases from establishment to June 2014. Two researchers independently identified 7 randomized controlled trials (RCTs) and extracted data of Brucea javanica oil emulsion injection combined with chemotherapy. Based on the published studies, the researchers analyzed them by RevMan 5.2 software and investigated the efficacy and safety of Brucea javanica oil emulsion injection combined with chemotherapy for patients with advanced gastric cancer by Meta analysis. Meta analysis showed that, compared with the simple chemotherapy, Brucea javanica oil emulsion injection combined with chemotherapy could increase objective response rate by 43%(RR=1.43, P<0.001). In addition, the incidence of neutropenia (RR=0.56, P<0.001), thrombocytopenia (RR=0.64, P=0.02), nausea, vomit (RR=0.66, P=0.002) decreased in these patients. However, the quality of life was not improved significantly in gastric carcinoma patients with combined therapy (RR=1.36, P=0.07). The paper suggested Brucea javanica oil emulsion injection combined with chemotherapy could increase efficacy and safety, which might be a promising therapy for patients with advanced gastric cancer. PMID- 28861982 TI - [Investigation of potential toxic factors for fleece-flower root: from perspective of processing methods evolution]. AB - In recent years, the rapid growth of reports on fleece-flower root-caused liver damages has drawn wide attention of both at home and abroad, however, there were rare literature on toxicology of fleece-flower root in ancient Chinese medicine. But why there are so many reports on toxicology of fleece-flower root now compared with the ancient literature? As a typical tonic medicine, the clinical utility of fleece-flower root was largely limited by its standardization and reliability of processing methods in ancient Chinese medicine. The ancient processing methods of fleece-flower root emphasized nine times of steaming and nine times of drying, while the modern processes have been simplified into one time of steaming. Whether the differences between ancient and modern processing methods are the potential cause of the increased events of fleece-flower root caused liver damages. We will make deep analysis and provide new clues and perspectives for the research on its toxicity. This article, therefore, would discuss the affecting factors and key problems in toxicity attenuation of fleece flower root on the basis of sorting out the processing methods of fleece-flower root in ancient medical books and modern standards, in order to provide the reference for establishing specification for toxicity attenuation of fleece flower root. PMID- 28861983 TI - [Reduction of ADRs of essential traditional Chinese medicines]. AB - The essential traditional Chinese medicines (ETCM) are the characteristics of our National Essential Medicine List (NEML) and we should give full play to its unique advantage. The essential medicines of ETCM are specific, but also have dual characters, namely efficacy and ADRs. Although ADRs cannot be avoided, we can make efforts to control some conditions to minimize the possibility of ADRs. It is significant to give suggestions to reduce ADRs of ETCM under the ETCM system by analyzing the possibility of ADRs during ETCM selection, production distribution and use. This research focuses on ETCM, and the conclusion is also applicable to common traditional Chinese medicines. PMID- 28861984 TI - [Impact of "imprinting templates" characteristics of traditional Chinese medicine injection supramolecules on (anaphylactoid) hypersensibility]. AB - The (anaphylactoid) hypersensibility mechanism of "imprinting templates" characteristics of traditional Chinese medicine (TCM) injection supramolecules was clarified to lay the foundation to build safety evaluation method. Based on the previous publication on special impact of Chinese medicine theories on supramolcular chemistry, combined with the natural origination of (anaphylactoid) hypersensitized special rules as well as the sensitization phenomenon of cordate houttuynia injection, the impact of the structure characteristics of "imprinting templates" in TCM injection supramolecules on its (anaphylactoid) hypersensibility was clarified. In Chinese medicine injections, the supramolecular structures can independently be generated, showing overall apparent (anaphylactoid) hypersensibility nature, and their structure characteristics were dependent on the strength. In addition, (anaphylactoid) hypersensitive critical supramolecular structure was present. When it was administrated by "injection", it's structure was not easy to be destroyed, often showing apparent immunogenicity, whereas if it was administrated by "oral", the structure would be destroyed by the gastrointestinal tract, showing weaker or no apparent immunogenicity. Therefore, there are differences in (anaphylactoid) hypersensibility between "injection" and "oral" administration of TCM. TCM injections would produce the supramolecules between "molecular society" by independent reaction of supramolecular "imprinting template" (chemical determinants), showing apparent immune process of recognition, copying, and storage. Single molecule is a special example for this. The screening of anaphylactoid (sensitinogen) includes the single ingredients and their forming supramolecules for TCM injection. This is the unique feature for safety evaluation of Chinese medicine injection. PMID- 28861985 TI - [Construction and practice on rational medication model of Chinese patent medicine for orthopedics based on "symdrome-dosage-toxicity differentiation" theory]. AB - Chinese patent medicines for orthopedics are among the hotspot and difficulty in the rational medication of traditional Chinese medicine (TCM), because they mostly contain toxic medicinal herbs and oriented to special patients. According to the hospital pharmacy practices and the therapeutic theories of TCM, this paper focused on a novel model of rational drug use of Chinese patent medicine for orthopedics based on the principles of "syndrome-dosage-toxicity differentiation". We also proposed relevant specifications for guiding their clinical use. Firstly, we proposed a list of the primary clinical application characteristics for rational drug use of orthopedic TCMs, including the syndromes of patient, the dosage of medicine and the toxic ingredients in medicine. Secondly, a database was established for recording the package inserts of all of the 81 orthopedic patent medicines in our hospital, and 2 000 retrospective recipes were analyzed for looking for the high-frequency medicines and common irrational factors. Then clinical case reports involving the adverse reactions and side effects of related drugs were searched from CNKI, VIP and WanFang databases. Then the key information for rational application of each medicine was extracted from these resources and some survey questionnaires. Finally, we established a guide named instructions for clinical use of orthopedic Chinese patient medicines (ICUOCPM) after the discusstion with experts. According to the effect after the practice in hospital for 2 months, the proposed principles of "syndrome-dosage-toxicity differentiation" in this paper were believed to be the core elements and the most important clinical monitoring points in TCM for orthopedic patents. It would provide innovative ideas, theoretical guarantee and data support for the development of TCM clinical pharmacy. PMID- 28861986 TI - Global leprosy update, 2016: accelerating reduction of disease burden. PMID- 28861987 TI - Eulogy for Kristian Fauchald (1 July 1935 - 4 April 2015). PMID- 28861988 TI - [Role of mammals on seed dispersal and predation processes of Mauritia flexuosa (Arecaceae)in the Colombian Amazon]. AB - Mammals and palms are important elements of fauna and flora in the Neotropics,and their interactions, such as fruit consumption and seed dispersal, are one of the most important ecologicalrelationships in these ecosystems. The main objective of this study was to identify the relative importance ofmammals in the dispersal and predation of Mauritia flexuosa palm fruits. We installed camera-traps in front ofpalm fallen seeds and clusters with fruits. A catalog of species was prepared with the recorded videos and theforaging behaviors exhibited were classified and identified. In addition, two exclusion treatments with three repetitions each were used. In the semi-open treatment, a plot was fenced with metal mesh leaving four open-ings in order to allow access only to small and medium sized mammals, while in the open treatment, the small, medium and large sized mammals had free access. In both cases, seed removal was evaluated. We recorded atotal of 19 species of mammals, nine of which fed on palm fruits and the other five were seed dispersers. Wereported for the first time the consumption of Mauritia flexuosa fruits by Atelocynus microtis. The specieswith the highest relative importance was Dasyprocta fuliginosa, which showed the highest percentage of seeddispersal (63.5%) compared to the other species. Tayassu peccary was identified as an in situ consumer, eating45.3% of seeds without dispersing them. The number of seeds consumed in situ in the open treatment showedsignificant differences regarding the semi-open treatment, suggesting greater involvement of large mammals in this process. In conclusion, the fruits of M. flexuosa are an important food source for the local mammal com-munity. Additionally, the consumption of seeds under the canopy of the mother palm is proportionally greater than their dispersion. Generally, the pressure of frugivorous species over seeds may determine the reproductivestrategies of plants. However, research on effective dispersion, dispersal distances and demographic impactshould be conducted to determine the specific role of medium and large sized mammals in the ecology of thispalm. PMID- 28861989 TI - Biogeography and areas of endemism of Prepops Reuter (Heteroptera: Miridae). AB - The Miridae (Hemiptera: Heteroptera) are one of the most species rich families of insects, with about11 100 described species. Mirinae is the largest subfamily and its endemism becomes evident at the tribal leveland below. Mirines of the tribe Restheniini are found throughout America, with most of the diversity confined to the Neotropics. Prepops Reuter is the largest genus in Restheniini with 198 described species and its geographi-cal range is similar to that of the tribe. The study of the distribution and areas of endemism in Miridae are scarce and non existent for Prepops. We analyzed all the geographic records of Prepops (707 records for 181 species) inorder to identify diversity patterns and areas of endemism, using network analysis. Locality data were assignedusing museum specimens and geographic records in the literature. Additionally we used spatial data to proposehabitat preferences and geoclimatic variables important for each group of co-occurring species. The results indicate high species richness in subtropical regions, while the tropical belt and high latitudes appear impover ished. The Neotropical region contains 86% of the species, and the Nearctic about 11 % (but with larger species ranges); the Andean region is sparingly represented. Twenty-three areas of endemism (and two diads), formed by 2 or more endemic species, are distributed in the Nearctic (3), Mexican Transition Zone and Caribbean sub-region (5), South American Transition Zone and Amazonian, Chacoan and Paranaense subregions (15). Overlap between some of the areas indicates regions with high species richness and complex history. The lack of records from the Andean region (except for P. nigrus in Southern Patagonia) and dominance of strictly Neotropical spe-cies (86 %) supports the hypothesis of a Neotropical origin for the tribe Restheniini. The general arrangement of the units of co occurrence of Prepops species shows a close correlation with known biogeographic regions andsubregions. Broad physiographic characteristics most commonly associated with Prepops geographical recordsare, in order of importance: broad leaf forests (wet and dry), grasslands and xeric habitats. PMID- 28861990 TI - Changes in body size spectra of benthic caridean shrimps (Decapoda: Caridea) and snails (Gastropoda)as response to seasonal variability AB - Ecologists have been largely interested in the description and understanding of the power scalingrelationships between body size and abundance of organisms. Many studies have focused on estimating theexponents of these functions across taxonomic groups and spatial scales, to draw inferences about the processesunderlying this pattern. The exponents of these functions usually approximate -3/4 at geographical scales, butthey deviate from this value when smaller spatial extensions are considered. This has led to propose that bodysize abundance relationships at small spatial scales may reflect the impact of environmental changes. Thisstudy tests this hypothesis by examining body size spectra of benthic shrimps (Decapoda: Caridea) and snails (Gastropoda) in the Tamiahua lagoon, a brackish body water located in the Eastern coast of Mexico. We mea-sured water quality parameters (dissolved oxygen, salinity, pH, water temperature, sediment organic matter and chemical oxygen demand) and sampled benthic macrofauna during three different climatic conditions of theyear (cold, dry and rainy season). Given the small size of most individuals in the benthic macrofaunal samples,we used body volume, instead of weight, to estimate their body size. Body size-abundance relationships of bothtaxonomic groups were described by tabulating data from each season into base-2 logarithmic body size bins.In both taxonomic groups, observed frequencies per body size class in each season were standardized to yielddensities (i.e., individuals/m(3)). Nonlinear regression analyses were separately performed for each taxonomicgroup at each season to assess whether body size spectra followed power scaling functions. Additionally, foreach taxonomic group, multiple regression analyses were used to determine whether these relationships variedamong seasons. Our results indicated that, while body size-abundance relationships in both taxonomic groupsfollowed power functions, the parameters defining the shape of these relationships varied among seasons. Thesevariations in the parameters of the body size-abundance relationships seems to be related to changes in theabundance of individuals within the different body size classes, which seems to follow the seasonal changes that occur in the environmental conditions of the lagoon. Thus, we propose that these body size-abundance relation-ships are influenced by the frequency and intensity of environmental changes affecting this ecosystem. PMID- 28861991 TI - Rhodium(III)-Catalyzed Oxadiazole-Directed Alkenyl C-H Activation for Synthetic Access to 2-Acylamino and 2-Amino Pyridines. AB - We report herein a Rh(III)-catalyzed alkenyl C-H activation protocol for the coupling of oxadiazoles with alkynes and synthesis of 2-acylamino and 2-amino pyridines, an important heterocyclic scaffold for various naturals products and synthetic pharmaceuticals bearing a readily reacting functional group. The selective protection/deprotection of amino groups through simple solvent switching, good functional group compatibility, superior product yield, and high regioselectivity are some of the notable synthetic features witnessed in this reaction protocol. PMID- 28861992 TI - Flow Injection Photochemical Vapor Generation Coupled with Miniaturized Solution Cathode Glow Discharge Atomic Emission Spectrometry for Determination and Speciation Analysis of Mercury. AB - A novel, compact, and green method was developed for the determination and speciation analysis of mercury, based on flow injection photochemical vapor generation (PVG) coupled with miniaturized solution cathode glow discharge-atomic emission spectroscopy (SCGD-AES). The SCGD was generated between a miniature hollow titanium tube and a solution emerging from a glass capillary. Cold mercury vapor (Hg(0)) was generated by PVG and subsequently delivered to the SCGD for excitation, and finally the emission signals were recorded by a miniaturized spectrograph. The detection limits (DLs) of Hg(II) and methylmercury (MeHg) were both determined to be 0.2 MUg L-1. Moreover, mercury speciation analysis could also be performed by using different wavelengths and powers from the UV lamp and irradiation times. Both Hg(II) and MeHg can be converted to Hg(0) for the determination of total mercury (T-Hg) with 8 W/254 nm UV lamp and 60 s irradiation time; while only Hg(II) can be reduced to Hg(0) and determined selectively with 4 W/365 nm UV lamp and 20 s irradiation time. Then, the concentration of MeHg can be calculated by subtracting the Hg(II) from the T-Hg. Because of its similar sensitivity and DL at 8 W/254 nm, the simpler and less toxic Hg(II) was used successfully as a primary standard for the quantification of T-Hg. The novel PVG-SCGD-AES system provides not only a 365-fold improvement in the DL for Hg(II) but also a nonchromatographic method for the speciation analysis of mercury. After validating its accuracy, this method was successfully used for mercury speciation analysis of water and biological samples. PMID- 28861993 TI - Fabrication of Stable and Luminescent Copper Nanocluster-Based AIE Particles and Their Application in beta-Galactosidase Activity Assay. AB - Thiolated copper nanoclusters (CuNCs) with aggregation-induced emission characteristic are becoming a novel luminescent material, but it is still a challenging task to retain its bright luminescence in a neutral solution. In this work, we report a new copper nanocluster with aggregation-induced emission (AIE) enhancement property using a hydrophobic molecule as the protecting ligand, and brightly luminescent AIE particles of copper nanocluster were prepared via hydrophobic interaction. These CuNCs AIE particles possess uniform rod-like shapes, with sizes in hundreds of nanometer, and an intense luminescence; more importantly, its luminescence remains stable in neutral and alkaline solutions. It is found that 4-nitrophenol is able to effectively quench the luminescence of CuNC AIE particles through strong hydrophobic interaction and electron transfer between them. This strong quenching effect was adopted to develop a luminescent assay for beta-galactosidase at physiological condition. This work presents a demonstration of preparing CuNC AIE particles with bright luminescence at neutral condition and gives an example of the use of AIE particles in monitoring the enzyme activity. PMID- 28861994 TI - On-Demand Drug Release from Dual-Targeting Small Nanoparticles Triggered by High Intensity Focused Ultrasound Enhanced Glioblastoma-Targeting Therapy. AB - Glioblastoma is one of the most challenging and intractable tumors with the difficult treatment and poor prognosis. Unsatisfactory traditional systemic chemotherapies for glioblastoma are mainly attributed to the insufficient and nonspecific drug delivery into the brain tumors as well as the incomplete drug release at the tumor sites. Inspired by the facts that angiopep-2 peptide is an acknowledged dual-targeting moiety for brain tumor-targeting delivery and high intensity focused ultrasound (HIFU) is an ideal trigger for drug release with an ultrahigh energy and millimeter-sized focus ability, in the present study, a novel HIFU-responsive angiopep-2-modified small poly(lactic-co-glycolic acid) (PLGA) hybrid nanoparticle (NP) drug delivery system holding doxorubicin/perfluorooctyl bromide (ANP-D/P) was designed to increase the intratumoral drug accumulation, further trigger on-demand drug release at the glioblastoma sites, and enhance glioblastoma therapy. It was shown that the ANP D/P was stable and had a small size of 41 nm. The angiopep-2 modification endowed the ANP-D/P with improved blood-brain barrier transportation and specific accumulation in glioblastoma tissues by 17 folds and 13.4 folds compared with unmodified NPs, respectively. Under HIFU irradiation, the ANP-D/P could release 47% of the drug within 2 min and induce the apoptosis of most tumor cells. HIFU triggered instantaneous drug release at the glioblastoma sites eventually enabled the ANP-D/P to achieve the strongest antiglioblastoma efficacy with the longest median survival time (56 days) of glioblastoma-bearing mice and the minimum vestiges of tumor cells in the pathological slices among all groups. In conclusion, the HIFU-responsive ANP-D/P in this study provided a new way for glioblastoma therapy with a great potential for clinical applications. PMID- 28861995 TI - Chemo-, Regio-, and Stereoselective N-Alkenylation of Pyrazoles/Benzpyrazoles Using Activated and Unactivated Alkynes. AB - Transition-metal-free chemo-, regio-, and stereoselective synthesis of (Z) and (E) styryl pyrazoles and benzpyrazoles by the addition of N-heterocycles onto functionalized terminal and internal alkynes using a super basic solution of KOH/DMSO has been described. The stereochemical outcome of the reaction was governed by time and quantity of the base. The reaction of pyrazoles and benzpyrazoles onto alkynes takes place chemoselectively without affecting the free -NH2 group of pyrazoles and -OH group of alkynes. The designed protocol was well implemented on alkynes bearing long alkyl chain, an alicyclic ring, hydroxy, ether, and ester functionality, which offer the N-alkenylated products in good yields. This developed methodology also provides easy access for the synthesis of bis-vinylated heterocycles. The presence of free -NH2, -OH, -COOR, and halo group in styryl pyrazoles, could be further utilized for synthetic elaboration, which is advantageous for biological evaluation. For the first time, we have disclosed the base-mediated conversion of (Z)-styryl pyrazoles to (E)-styryl pyrazoles in KOH/DMSO system. The cis-trans isomerization was supported by the control experiments and deuterium labeling studies. PMID- 28861996 TI - Transition-Metal-Free [3+2] Cycloaddition of Dehydroaminophosphonates and N Tosylhydrazones: Access to Aminocyclopropanephosphonates with Adjacent Quaternary Tetrasubstituted Carbon Centers. AB - A novel one-step strategy for the synthesis of aminocyclopropanephosphonates containing adjacent quaternary-tetrasubstituted carbon centers under transition metal-free catalysis via [3+2] cycloaddition process has been developed. A series of aminocyclopropanephosphonates with adjacent quaternary-tetrasubstituted carbon centers including spirocyclopropyl adducts were obtained in moderate to excellent yields under mild reaction conditions. This protocol would find the potential applications in biochemistry and medicinal chemistry. PMID- 28861997 TI - Profiling B-Type Natriuretic Peptide Cleavage Peptidoforms in Human Plasma by Capillary Electrophoresis with Electrospray Ionization Mass Spectrometry. AB - B-type Natriuretic Peptide (BNP) is a biologically active circulating hormone. Plasma concentrations of BNP are routinely used in the diagnosis of heart failure, and the intravenous infusion of recombinant BNP can be used for heart failure treatment. Like many bioactive polypeptides, multiple plasma enzymes are known to cleave circulating BNP, and as part of the CVD-B/D-HPP mandate, we sought to develop a technique capable of profiling these catabolic processes in plasma. We used a neutral-coated capillary electrophoresis-electrospray ionization (CESI) separation system coupled with high-resolution mass spectrometry to profile the proteolysis of exogenous recombinant BNP1-32 in plasma. Our method utilizes electrokinetic injection of minimally processed plasma samples to simultaneously monitor the dynamic generation and breakdown of at least five BNP peptidoforms in plasma. By integrating multisegment injection, our method can produce a multipoint BNP proteolytic profile for one sample within an hour. We envision applying this method to assess the potential relation between plasma-based BNP proteolysis and heart failure as well as a means of monitoring BNP bioavailability after therapeutic infusion. PMID- 28861999 TI - Self-Etching of Metal-Organic Framework Templates during Polydopamine Coating: Nonspherical Polydopamine Capsules and Potential Intracellular Trafficking of Metal Ions. AB - Traditionally, containers made from steel or other metals are not good for making tea, probably due to the fact that polyphenol components in tea can chelate with metal ions. A similar reason might stand behind the observations as reported herein. During the coating of well-defined metal-organic framework (MOF) crystalline particles with polydopamine (PDA) via pH-induced self-polymerization of dopamine, we found that MOF templates automatically etch off during the coating, giving rise to nonspherical PDA capsules that inherit the morphologies of the templates. Such self-etching of MOF templates is ascribed to the chelation of the metal nodes of the MOFs by the catechol moieties in the PDA layer. In addition, the self-etching of the zeolitic imidazolate framework-8 (ZIF-8) with a truncated cubic shape probably follows a crystalline facet-dependent fashion, resulting in intermediate yolk-shell structures with ZIF-8 cargos of various shapes inside a highly biocompatible PDA shell. Incubation of such intermediate hybrid particles with the cancerous HeLa cell line leads to pronounced cytotoxicity, which is tentatively connected with the cellular internalization of the ZIF@PDA nanoparticles because of the cell affinity of the PDA layer. Subsequently, the continuous release of Zn2+ by the self-etching of the encapsulated ZIF-8 inside the cell increases intracellular Zn2+ to a harmful level. Therefore, intracellular delivery of metal ions is probably realized, which might offer a novel way for cancer therapy. PMID- 28861998 TI - Comparative Proteomics Enables Identification of Nonannotated Cold Shock Proteins in E. coli. AB - Recent advances in mass spectrometry-based proteomics have revealed translation of previously nonannotated microproteins from thousands of small open reading frames (smORFs) in prokaryotic and eukaryotic genomes. Facile methods to determine cellular functions of these newly discovered microproteins are now needed. Here, we couple semiquantitative comparative proteomics with whole-genome database searching to identify two nonannotated, homologous cold shock-regulated microproteins in Escherichia coli K12 substr. MG1655, as well as two additional constitutively expressed microproteins. We apply molecular genetic approaches to confirm expression of these cold shock proteins (YmcF and YnfQ) at reduced temperatures and identify the noncanonical ATT start codons that initiate their translation. These proteins are conserved in related Gram-negative bacteria and are predicted to be structured, which, in combination with their cold shock upregulation, suggests that they are likely to have biological roles in the cell. These results reveal that previously unknown factors are involved in the response of E. coli to lowered temperatures and suggest that further nonannotated, stress regulated E. coli microproteins may remain to be found. More broadly, comparative proteomics may enable discovery of regulated, and therefore potentially functional, products of smORF translation across many different organisms and conditions. PMID- 28862000 TI - Quantitative Proteomics for the Comprehensive Analysis of Stress Responses of Lactobacillus paracasei subsp. paracasei F19. AB - Lactic acid bacteria are broadly employed as starter cultures in the manufacture of foods. Upon technological preparation, they are confronted with drying stress that amalgamates numerous stress conditions resulting in losses of fitness and survival. To better understand and differentiate physiological stress responses, discover general and specific markers for the investigated stress conditions, and predict optimal preconditioning for starter cultures, we performed a comprehensive genomic and quantitative proteomic analysis of a commonly used model system, Lactobacillus paracasei subsp. paracasei TMW 1.1434 (isogenic with F19) under 11 typical stress conditions, including among others oxidative, osmotic, pH, and pressure stress. We identified and quantified >1900 proteins in triplicate analyses, representing 65% of all genes encoded in the genome. The identified genes were thoroughly annotated in terms of subcellular localization prediction and biological functions, suggesting unbiased and comprehensive proteome coverage. In total, 427 proteins were significantly differentially expressed in at least one condition. Most notably, our analysis suggests that optimal preconditioning toward drying was predicted to be alkaline and high pressure stress preconditioning. Taken together, we believe the presented strategy may serve as a prototypic example for the analysis and utility of employing quantitative-mass-spectrometry-based proteomics to study bacterial physiology. PMID- 28862001 TI - Wearable Sweatband Sensor Platform Based on Gold Nanodendrite Array as Efficient Solid Contact of Ion-Selective Electrode. AB - As chemical sensors are in great demand for portable and wearable analytical applications, it is highly desirable to develop an all-solid-state ion-selective electrode (ISE) and reference electrode (RE) platform with simplicity and stability. Here we propose a wearable sensor platform with a new type of all solid-state ISE based on a gold nanodendrite (AuND) array electrode as the solid contact and a poly(vinyl acetate)/inorganic salt (PVA/KCl) membrane-coated all solid-state RE. A simple and controllable method was developed to fabricate the AuNDs on a microwell array patterned chip by one-step electrodeposition without additional processing. For the first time, the AuND electrodes with different real surface area and double layer capacitance were developed as solid contact of the Na+-ISE to investigate the relationship between performance of the ISE and surface area. As-prepared AuND-ISE with larger surface area (~7.23 cm2) exhibited enhanced potential stability compared to those with smaller surface area (~1.85 cm2) and to bare Au ISE. Important as the ISE, the PVA/KCl membrane-coated Ag/AgCl RE exhibited highly stable potential even after 3 months' storage. Finally, a wearable sweatband sensor platform was developed for efficient sweat collection and real-time analysis of sweat sodium during indoor exercise. This all-solid-state ISE and RE integrated sensor platform provided a very simple and reliable way to construct diverse portable and wearable devices for healthcare, sports, clinical diagnosis, and environmental analysis applications. PMID- 28862002 TI - Visible-Light Mediated Oxidative C-H/N-H Cross-Coupling between Tetrahydrofuran and Azoles Using Air. AB - Tetrahydrofuran is a privileged structural moiety in many important organic compounds. In this work, we have developed a simple and mild catalytic oxidative amination of tetrahydrofuran mediated by visible-light catalysis. The C(sp3)-H bond of tetrahydrofuran was activated using molecular oxygen as a benign oxidant. Besides, a variety of azoles could be tolerated, providing a green route for N substituted azoles. PMID- 28862003 TI - Light-Regulated Electrochemical Sensor Array for Efficiently Discriminating Hazardous Gases. AB - Inadequate detection limit and unsatisfactory discrimination features remain the challenging issues for the widely applied electrochemical gas sensors. Quite recently, we confirmed that light-regulated electrochemical reaction significantly enhanced the electrocatalytic activity, and thereby can potentially extend the detection limit to the parts per billion (ppb) level. Nevertheless, impact of the light-regulated electrochemical reaction on response selectivity has been discussed less. Herein, we systematically report on the effect of illumination on discrimination features via design and fabrication of a light regulated electrochemical sensor array. Upon illumination (light on), response signal to the examined gases (C3H6, NO, and CO) is selectively enhanced, resulting in the sensor array demonstrating disparate response patterns when compared with that of the sensor array operated at light off. Through processing all the response patterns derived from both light on and light off with a pattern recognition algorithm, a satisfactory discrimination feature is observed. In contrast, apparent mutual interference between NO and CO is found when the sensor array is solely operated without illumination. The impact mechanism of the illumination is studied and it is deduced that the effect of the illumination on the discriminating features can be mainly attributed to the competition of electrocatalytic activity and gas-phase reactivity. If the enhanced electrocatalytic activity (to specific gas) dominates the whole sensing progress, enhancements in the corresponding response signal would be observed upon illumination. Otherwise, illumination gives a negligible impact. Hence, the response signal to part of the examined gases is selectively enhanced by illumination. Conclusively, light-regulated electrochemical reaction would provide an efficient approach to designing future smart sensing devices. PMID- 28862005 TI - [Newborn hearing screening - importance, current state in the Czech Republic]. AB - The importance of early detection of hearing impairment in newborns and children and the early rehabilitation of hearing disorder with hearing aid or cochlear implant was demonstrated in a number of papers. As a result, newborn hearing screening was introduced in many countries around the world. The incidence of congenital hearing impairment has been underestimated for a long time, empirically determined incidence was 1:1000 neonates. Thanks to newborn hearing screening was revealed that incidence of congenital hearing impairment is 3 times higher. One out of 300 newborns has profound hearing loss (deafness) and 1 in 300 newborns has mild to moderate hearing loss. Moreover, in 1 out of 300 children hearing impairment would develop before the age of 18. In the Czech Republic, the screening of all newborns is still systematical and multilevel conducted in only three regions (Moravskoslezsky, Kralovehradecky, Pardubicky). In these regions, statistics as well as assessments of individual stages of screening are carried out. In other regions, records of the number of screened children, number of rescreened children and detailed statistics of hearing impairment is missing. The authors summarize the basic information about the importance of screening, the history of screening and its organization. Provided information is based on experience with the gradual introduction of screening over recent years in the regions in which they work. Newborn hearing screening should be organized in several stages (1 - screening at maternity hospitals, 2 - rescreening on collaborating otolaryngology/phoniatric workplaces and 3 - detailed hearing examination in centers in children whose screening was negative). The authors focus on problems related to the organization of screening and offer practical advice (e.g. implementation of screening coordinators). They consider it is essential to have statistical evidence of examination at all levels. Introducing of newborn hearing screening is not a short-term task but a long-term (many years) challenge. PMID- 28862004 TI - Single Molecule Trapping and Sensing Using Dual Nanopores Separated by a Zeptoliter Nanobridge. AB - There is a growing realization, especially within the diagnostic and therapeutic community, that the amount of information enclosed in a single molecule can not only enable a better understanding of biophysical pathways, but also offer exceptional value for early stage biomarker detection of disease onset. To this end, numerous single molecule strategies have been proposed, and in terms of label-free routes, nanopore sensing has emerged as one of the most promising methods. However, being able to finely control molecular transport in terms of transport rate, resolution, and signal-to-noise ratio (SNR) is essential to take full advantage of the technology benefits. Here we propose a novel solution to these challenges based on a method that allows biomolecules to be individually confined into a zeptoliter nanoscale droplet bridging two adjacent nanopores (nanobridge) with a 20 nm separation. Molecules that undergo confinement in the nanobridge are slowed down by up to 3 orders of magnitude compared to conventional nanopores. This leads to a dramatic improvement in the SNR, resolution, sensitivity, and limit of detection. The strategy implemented is universal and as highlighted in this manuscript can be used for the detection of dsDNA, RNA, ssDNA, and proteins. PMID- 28862006 TI - [30 years of the cochlear implantations in the Czech Republic]. AB - Cochlear implant is the unique sensory neuroprosthesis and still the only one used in clinical praxis. The function of the inner ear is replaced with direct electrical stimulation of the cochlear nerve. It is 30 years since the first cochlear implantation has been performed with the Czech single-channel cochlear neuroprosthesis. There are more than one thousand users of cochlear implants in the Czech Republic nowadays. Cochlear implants have become a standard of care of patients with severe hearing loss. It allows user inclusion to the society with only a minimum of obstacles.Key words: cochlear implant, history, neuroprosthesis, severe hearing loss. PMID- 28862007 TI - [Speech intelligibility in noise at presbycusis]. AB - Evaluation of speech recognition is possible by presenting testing material in sentence form with presence of competitive noise. We developed new test of sentence intelligibility in noise in the Czech language. This article demonstrates results of the influence of the babble noise on sentence intelligibility in hearing impaired listeners with presbycusis. The time characteristics of babble noise are similar to human voice. That is the reason why this noise masking is more enhanced at the central hearing level than any other noise masking. A group of 423 persons was divided into younger group (age from 40 to 65 years, N = 191, mean age 55.8 years.) and older group (age from 66 to 85 years, N = 232, mean age 75.4 years). For these two age groups, we compared the test performance in the subgroups stratified by the speech audiometry in silence. We demonstrate a statistically significant worse understanding of sentences in the older group against the younger group listening to sentences at level 65 dB SPL in competitive noise at level 65 dB SPL (p = 0.05). The development of the sentence intelligibility in noise test increased the possibilities of audiological examination by another test, which was up to now missing in the Czech language. PMID- 28862008 TI - [Olfactory function in patients undergoing FESS for chronic rhinosinusitis]. AB - Patients with chronic rhinosinusitis (CRS) often suffer from loss of olfactory function. Rhinosinusitis can be treated either by medical therapy or surgically (FESS). Postoperative outcome in terms of improving sense of smell has been controversial so far. The aim of our study was to determine the patients who would have better postoperative outcomes in terms of improving olfactory function. We collected data of patients undergoing FESS for chronic rhinosinusitis (either with or without nasal polyps) at our department during the years 2012-2015. These patients had their olfactory function examined with Odorized markers test (OMT) up to 24 hours before surgery. After that we chose the best result in OMT found out in visits from 4 weeks to 4 months after surgery. We were comparing individual risk factors out of the patients' anamnesis, CT scan and physical examination. 51 patients were enrolled in this study. 25 % of patients showed improvement of their olfactory function, no change was recorded in 55 % of patients and 20 % of patients showed deterioration of olfaction. Before surgery we found out statistically significant difference in results of OMT between the patients with and without nasal polyps and with and without asthma (p = 0,0016, resp. p = 0,04). After surgery the difference was no longer statistically significant (p = 0,17, resp. p = 0,12). Correlation with age and Lund-Mackay score showed changes after surgery. No statistically significant difference in results of OMT was found out before and after surgery in other observed risk factors (oral corticosteroids before surgery, smoking, revision surgery and middle turbinate resection). Changes in olfactory function in patients with chronic rhinosinusitis after surgery are hard to predict. Our results show that nasal polyps, asthma, lower age and higher Lund-Mackay score are factors which predict better postoperative outcome. PMID- 28862009 TI - [Endoscopic optical imaging methods in the diagnostics of the laryngeal cancer]. AB - Endoscopic optical imaging methods for the detection of mucosal lesions in the ENT area have been developed for better and earlier detection of these changes. They can be divided into horizontal methods group - showing the surface of the mucous membrane (autofluorescence, photodynamic diagnosis, Narrow Band Imaging, magnifying and contact endoscopy) and vertical methods group - visualizing different layers of the mucosa (optical coherence tomography and confocal endomicroscopy). Some of them are routinely used in practice, others are used in experimental mode and their introduction into practice may be a matter of the near future. The authors present a comprehensive overview of available endoscopic optical imaging methods. PMID- 28862010 TI - [Sleep-related breathing disorders in children and adults from the aspect of the otorhinolaryngology]. AB - Sleep medicine is multidisciplinary branch with significant role of the otorhinolaryngologist especially in the area of sleep related breathing disorders. Snoring and sleep apnea are topics that have recently become more popular in lay as well as in professionals. The authors present a basic overview of pathophysiology, correct diagnosis and therapy in adult and pediatric patients. Although the awareness of sleep medicine improves, we still encounter incorrect procedures that can harm the patient. The physician who deals with sleep disturbances should have at least basic education in somnology. PMID- 28862011 TI - [Sore throat treatment]. AB - The article deals with sore throat, gives definition of acute and chronic pain and describes their causes. Further describes possibilities of diagnosis with regard to differential diagnosis. Special attention is focused on differentiation between viral and streptococcal infection. Accented is the necessity of causal treatment and possibilities of supportive local treatment.Key words: sore throat, sore throat causes, sore throat diagnosis, causal treatment, local supportive treatment. PMID- 28862012 TI - [American healthcare system and the uncertain future of the Obamas reform]. AB - The United States differs from other developed countries in health care system which does not guarantee health care for the entire population. The right to health care is not considered a part of the basic human rights. There is much more emphasis on individual responsibility in insurance of health services that are essentially commercial in nature. The aim of this article is to inform on US health system and the measures underlying the recently introduced health reform, whose future development cannot be predicted at present. PMID- 28862013 TI - Influence of Direct Oral Anticoagulants on Anti-Factor Xa Measurements Utilized for Monitoring Heparin. AB - BACKGROUND: Unanticipated drug-laboratory interactions may occur between direct oral anticoagulants (DOACs) and anti-factor Xa (AXA) levels used to monitor parenteral heparin infusions. Characterization of the extent and duration of DOAC effect on AXA levels may reduce complications with transition to heparin infusions. OBJECTIVE: To evaluate the impact of oral factor Xa inhibitors on AXA levels with and without concurrent heparin. METHODS: This retrospective descriptive study was approved by institutional review board waiver and included patients with AXA levels drawn on a heparin calibrated assay who had received a factor Xa inhibitor. Participants were divided on the basis of whether AXA levels were drawn with concurrent parenteral heparin. If transitioned to heparin, number of AXA draws required until AXA level was within therapeutic range was recorded. RESULTS: A total of 50 patients (60% rivaroxaban, 40% apixaban) met inclusion criteria. When AXA levels were drawn within 12 hours of apixaban without concurrent heparin (n = 7), 71% were greater than 1 IU/mL, and 29% were below suggested trough levels (0.7-1.1 IU/mL). For AXA levels drawn within 24 hours of rivaroxaban without concurrent heparin (n = 11), 55% were greater than 1 IU/mL, 9% were within suggested trough (0.6-1 IU/mL), and 36% were below 0.6 IU/mL. In patients (n = 28) who were initiated on heparin infusion prior to AXA monitoring, administration of the DOAC within the prior 72 hours resulted in supratherapeutic initial AXA levels 69% of the time. CONCLUSION: DOACs may cause elevations in heparin-calibrated AXA assays; this creates problematic challenges in using the AXA level to optimize heparin management. PMID- 28862014 TI - Persistent physical activity translating to persistent reduction in mortality. PMID- 28862015 TI - Why various wines reduce the risks of heart diseases. PMID- 28862016 TI - Health promotion in children and adolescents - a global challenge. PMID- 28862017 TI - Health status, food insecurity, and time allocation patterns of patients with AIDS receiving antiretroviral treatment in South Africa. AB - For patients with AIDS receiving antiretroviral treatment (ART) in South Africa via public clinics, improvements in nutritional status and economic productivity are likely to depend on adherence to drug regimen and quality of diet reflected in protein and micronutrient intakes. This study randomized 643 patients receiving ART from public clinics in the Free State Province into a Control group, a treatment group receiving adherence support, and a treatment group receiving adherence support and a nutritious food supplement. The data on food insecurity levels and time spent on various activities were analyzed for assessing the impact of the intervention programs. The main results were, first, changes between survey rounds 1 and 3 were significant at the 5% level for outcomes such as food insecurity levels and CD4 cell counts. Moreover, there was a significant reduction in food insecurity levels of patients with BMI less than 25 who received the nutritious food supplement. Second, the estimated parameters from models for patients' food insecurity levels showed that household incomes were significantly associated with lower food insecurity levels. Third, patients' BMI was a significant predictor of time spent on sedentary, moderate and overall activity levels, and it was important to separately evaluate the effects of BMI for under-weight and over-weight patients. Overall, the results indicated the need for reducing food insecurity levels, and for designing different interventions for under-weight and over-weight patients with AIDS for enhancing their labor productivity. PMID- 28862018 TI - Quantitative Micro-Raman Spectroscopy for Partial Pressure Measurement in Small Volumes. AB - We demonstrate the quantitative capabilities of Raman confocal microscopy as a nondestructive method to measure the partial pressure of molecular gases in mm3 range sealed volume having an optical access. Thanks to a calibration procedure, we apply this technique for the characterization of the absolute nitrogen partial pressure inside buffered micro electromechanical system (MEMS) atomic vapor cells developed for atomic clocks. Our results are compared with measurements obtained by rubidium hyperfine frequency spectroscopy and a good agreement is demonstrated between the two methods, with a three-sigma detection limit below 10 mbar for a 1 h integration time, using a 33 mW 532 nm excitation laser. These results prove the potential of confocal micro-Raman spectroscopy as a simple and nondestructive method for small-scale pressure measurements. PMID- 28862020 TI - Angiotensin-converting enzyme inhibitors reduce mortality compared to angiotensin receptor blockers: Systematic review and meta-analysis. AB - Background There are few reviews comparing the long-term outcomes of the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in a hypertensive population because both are effective in reducing blood pressure. None of them compared angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers with a placebo group in patients with essential hypertension, because few studies exist with this design. Methods A systematic search of PUBMED, LILACS, SCIELO, ICTRP, Cochrane, EMBASE and ClinicalTrials.gov from 1 January 2000 until 31 December 2015 selected prospective studies that reported an association between the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in the following cardiovascular outcomes: heart failure/hospitalisation, stroke, acute myocardial infarction, total cardiovascular deaths, total deaths and total outcomes. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were combined by using a fixed-effects model. Results Seventeen studies ( n = 73,761) were included of which 12 studies were randomly assigned to angiotensin II receptor blocker therapy ( n = 24,697) and five to angiotensin-converting enzyme inhibitors ( n = 12,170). Angiotensin converting enzyme inhibitors proved to be significant in reducing total deaths (OR 0.85, 95% CI 0.78-0.93) and cardiovascular deaths (OR 0.77, 95% CI 0.69 0.87). Angiotensin II receptor blocker therapy did not show a reduction in total deaths (OR 1.02, 95% CI 0.96-1.09) or cardiovascular deaths (OR 0.95, 95% CI 0.86 1.06). For acute myocardial infarction, stroke and heart failure/hospitalisation, the reductions were significant for both classes. Conclusion Angiotensin converting enzyme inhibitor or angiotensin II receptor blocker use is similar in preventing major cardiovascular outcomes regarding acute myocardial infarction, stroke and heart failure/hospitalisation. However, the use of angiotensin converting enzyme inhibitors is more effective in reducing total deaths and cardiovascular deaths than angiotensin II receptor blockers. PMID- 28862021 TI - Data Processing Algorithm for Diagnostics of Combustion Using Diode Laser Absorption Spectrometry. AB - A new algorithm for the evaluation of the integral line intensity for inferring the correct value for the temperature of a hot zone in the diagnostic of combustion by absorption spectroscopy with diode lasers is proposed. The algorithm is based not on the fitting of the baseline (BL) but on the expansion of the experimental and simulated spectra in a series of orthogonal polynomials, subtracting of the first three components of the expansion from both the experimental and simulated spectra, and fitting the spectra thus modified. The algorithm is tested in the numerical experiment by the simulation of the absorption spectra using a spectroscopic database, the addition of white noise, and the parabolic BL. Such constructed absorption spectra are treated as experimental in further calculations. The theoretical absorption spectra were simulated with the parameters (temperature, total pressure, concentration of water vapor) close to the parameters used for simulation of the experimental data. Then, spectra were expanded in the series of orthogonal polynomials and first components were subtracted from both spectra. The value of the correct integral line intensities and hence the correct temperature evaluation were obtained by fitting of the thus modified experimental and simulated spectra. The dependence of the mean and standard deviation of the evaluation of the integral line intensity on the linewidth and the number of subtracted components (first two or three) were examined. The proposed algorithm provides a correct estimation of temperature with standard deviation better than 60 K (for T = 1000 K) for the line half-width up to 0.6 cm-1. The proposed algorithm allows for obtaining the parameters of a hot zone without the fitting of usually unknown BL. PMID- 28862022 TI - Is CHA2DS2-VASc Score Related to Inflammation in Patients With In-Stent Restenosis? PMID- 28862023 TI - What is the most suitable MR signal index for quantitative evaluation of placental function using Half-Fourier acquisition single-shot turbo spin-echo compared with T2-relaxation time? AB - Background Half-Fourier acquisition single-shot turbo spin-echo (HASTE) imaging is now widely used for placental and fetal imaging because of its rapidity and low sensitivity to fetal movement. If placental dysfunction is also predicted by quantitative value obtained from HASTE image, then it might be beneficial for evaluating placental wellbeing. Purpose To ascertain the most suitable magnetic resonance (MR) signal indexes reflecting placental function using HASTE imaging. Material and Methods This retrospective study included 37 consequent patients who had given informed consent to MR imaging (MRI) examinations. All had undergone MRI examinations between February 2014 and June 2015. First, the correlation between T2-relaxation time of normal placenta and gestational age (GA) was examined. Second, correlation between signal intensity ratios (SIRs) using HASTE imaging and placental T2-relaxation time were assessed. The SIRs were calculated using placental signal intensity (SI) relative to the SI of the amniotic fluid, fetal ocular globes, gastric fluid, bladder, maternal psoas major muscles, and abdominal subcutaneous adipose tissue. Results Among the 37 patients, the correlation between T2-relaxation time of the 25 normal placentas and GA showed a moderately strong correlation (Spearman rho = -0.447, P = 0.0250). The most significant correlation with placental T2-relaxation time was observed with the placental SIR relative to the maternal psoas major muscles (SIRpl./psoas muscle) (Spearman rho = -0.531, P = 0.0007). Conclusion This study revealed that SIRpl./psoas muscle showed the best correlation to placental T2-relaxation time. Results show that SIRpl./psoas muscle might be optimal as a clinically available quantitative index of placental function. PMID- 28862024 TI - Differentiation of grade II and III oligodendrogliomas from grade II and III astrocytomas: a histogram analysis of perfusion parameters derived from dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) MRI. AB - Background Since oligodendroglial tumors are sensitive to chemotherapy and have a better prognosis, the differentiation of oligodendroglial tumors (OT) from astrocytic tumors (AT) is important. Purpose To investigate the perfusion and permeability parameters that differentiate grade II and III OT from AT, using dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI). Material and Methods We retrospectively reviewed the DCE and DSC MRIs of 39 patients with OT (OTs, n = 19; grade II, n = 12 and grade III, n = 7) and AT (ATs, n = 20; grade II, n = 7 and grade III, n = 13). Glioblastomas were not included. Various histogram parameters of relative cerebral blood volume, volume transfer constant (Ktrans), flux rate constant (Kep), plasma volume fraction (Vp), and extravascular extracellular volume fraction (Ve) from DSC and DCE MRI, were compared between the two groups. Univariable and multivariable logistic regression were used to distinguish OT from AT. Receiver operating characteristic (ROC) curve analysis was performed. Results On the results of DCE MRI, most of the histogram parameters of Ktrans, Kep, and Ve showed tendencies toward higher values in OT than AT. Multivariable logistic regression revealed that the 50th Kep and 95th Ktrans were the most significant parameters predictive of OT, with an odds ratio of 3.7 and 2.5, respectively ( P = 0.004 and 0.03). The area under the curve from the ROC curve analysis for the 50th Kep and the 95th Ktrans were 0.81 and 0.80, respectively. Conclusion The DCE MRI-derived parameters of Ktrans and Kep could facilitate differentiation of OT from AT. PMID- 28862025 TI - Freehand 3T MR-guided vacuum-assisted breast biopsy (VAB): a five-year experience. AB - Background Magnetic resonance (MR) permits the detection of some malignant lesions that cannot be identified with mammography or ultrasonography. The characterization of these MR-only detectable lesions often requires a biopsy. Purpose To evaluate the technique, the feasibility and the accuracy of freehand 3T MR-guided VAB for the characterization of suspicious, MR-only detectable lesions and to compare VAB results with surgical pathology and follow-up imaging results. Material and Methods During 2010-2015, 118 women who were referred for MR-guided VAB were retrospectively reviewed. All BI-RADS MR 4 and 5 lesions and some BI-RADS MR 3 lesions (according to clinical context and patient anxiety) were scheduled to undergo biopsy. Results A total of 123 suspicious lesions were retrospectively selected. Technical failures occurred in only two cases (1.6%) due to the location of the lesions. Histopathological results revealed 59 benign lesions (48%), 27 high-risk lesions (22%), and 35 malignant lesions (28.4%). Surgical pathology results led to the reclassification of eight B3 lesions: one proved to be a ductal carcinoma in situ, while seven presented with invasive features. B3 underestimation also occurred in 29% of the cases. MR follow-up was achieved for all the benign lesions and no false-negative cases were observed. No complications, 3T-related artefacts, or difficulties were observed. Conclusion Freehand 3T MR-guided VAB was found to be a valid, safe, fast, and inexpensive alternative to surgical histology. PMID- 28862026 TI - The Challenges of Collecting and Using Patient Care Data From Diverse Care Systems: Lessons From COMPASS. AB - The ability to aggregate clinical data across multiple diverse organizations and to use it for performance measurement, quality improvement, evaluation, and research is rapidly becoming a national necessity, but there are few examples of how to do that. This article uses lessons from a national effort to implement the collaborative care management model for patients with both depression and diabetes or heart disease across 8 partner organizations, 18 medical groups, and more than 170 clinics in 8 states to identify the challenges and provide experience-based recommendations for those tasks. The challenges are divided into those needed for (1) collecting similar data, (2) aggregating those data across care systems, and (3) using the data to both improve and evaluate care. Start with agreement on goals, methods, transparency, and a data system integrated into the electronic medical record while promptly addressing all the legal, regulatory, and human subject requirements. PMID- 28862027 TI - The Experience of Management of High-Alert Medications. PMID- 28862030 TI - Eliminating Critical Incident Tracking Network Patient Safety Events at a Veterans Affairs Institution Through Crew Resource Management Training. AB - The objective of this study was to determine whether rates of Critical Incident Tracking Network (CITN) patient safety adverse events change after implementation of crew resource management (CRM) training at a Veterans Affairs (VA) hospital. CRM training was conducted for all surgical staff at a VA hospital. Compliance with briefing and debriefing checklists was assessed for all operating room procedures. Tracking of adverse patient safety events utilizing the VA CITN events was performed. There was 100% adherence to performance of briefings and debriefings after initiation of CRM training. There were 3 CITN events in the year prior to implementation of CRM training; following CRM training, there have been zero CITN events. Following CRM training, CITN events were eliminated, and this has been sustained for 2.5 years. This is the first study to demonstrate the impact of CRM training on CITN events, specifically, in a VA medical center. PMID- 28862031 TI - Benefits of lifelong exercise training on left ventricular function after myocardial infarction. AB - Background Endurance exercise training induces cardio-protective effects, but athletes are not exempted from a myocardial infarction. Evidence from animal studies suggests that exercise training attenuates pathological left ventricular remodelling following myocardial infarction. We tested the hypothesis that lifelong exercise training is related to attenuated pathological left ventricular remodelling after myocardial infarction as evidenced by better left ventricular systolic function in veteran athletes compared to sedentary peers. Design This was a cross-sectional study. Methods Sixty-five males (60 +/- 6 years) were included and allocated to four groups based on lifelong exercise training volumes: (a) athletes ( n = 18), (b) post-myocardial infarction athletes (athletes + myocardial infarction, n = 20), (c) sedentary controls ( n = 13), and (d) post-myocardial infarction controls (sedentary controls + myocardial infarction, n = 14). Athletes were lifelong (>=20 years) highly physically active (>=30 metabolic equivalent of task (MET)-h/week), whereas sedentary controls did not meet the exercise guidelines (<10 MET-h/week) for the past 20 years. left ventricular systolic function, diastolic function and wall strain were measured using echocardiography. Results Cardiac enzyme markers (creatine-kinase, creatinine, aspartate transaminase and lactate dehydrogenase) following myocardial infarction and infarct location did not differ between athletes + myocardial infarction and sedentary controls + myocardial infarction. Left ventricular ejection fraction was significantly higher in athletes (61% +/- 4), athletes + myocardial infarction (58% +/- 4) and sedentary controls (57% +/- 6) compared to sedentary controls + myocardial infarction (51% +/- 7; p < 0.01). Left ventricular circumferential strain was superior in athletes (-19% (-21% to 17%), athletes + myocardial infarction (-16% (-20% to -12%)), and sedentary controls (-15% (-18% to -14%) compared to sedentary controls + myocardial infarction (-13% (-15% to -8%), p < 0.01). Diastolic function parameters did not differ across groups. Conclusion These findings suggest that lifelong exercise training may preserve left ventricular systolic function and possibly attenuates or minimises the deleterious effects of pathological post-myocardial infarction left ventricular remodelling in veteran athletes. PMID- 28862032 TI - Heparin pre-treatment in patients with ST-segment elevation myocardial infarction and the risk of intracoronary thrombus and total vessel occlusion. Insights from the TASTE trial. AB - BACKGROUND: Pre-treatment with unfractionated heparin is common in ST-segment elevation myocardial infarction (STEMI) protocols, but the effect on intracoronary thrombus burden is unknown. We studied the effect of heparin pre treatment on intracoronary thrombus burden and Thrombolysis in Myocardial Infarction (TIMI) flow prior to percutaneous coronary intervention in patients with STEMI. METHODS: The Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial angiographically assessed intracoronary thrombus burden and TIMI flow, prior to percutaneous coronary intervention, in patients with STEMI. In this observational sub-study, patients pre-treated with heparin were compared with patients not pre-treated with heparin. Primary end points were a visible intracoronary thrombus and total vessel occlusion prior to percutaneous coronary intervention. Secondary end points were in-hospital bleeding, in-hospital stroke and 30-day all-cause mortality. RESULTS: Heparin pre treatment was administered in 2898 out of 7144 patients (41.0%). Patients pre treated with heparin less often presented with an intracoronary thrombus (61.3% vs. 66.0%, p<0.001) and total vessel occlusion (62.9% vs. 71.6%, p<0.001). After adjustments, heparin pre-treatment was independently associated with a reduced risk of intracoronary thrombus (odds ratio (OR) 0.73, 95% confidence interval (CI)=0.65-0.83) and total vessel occlusion (OR 0.64, 95% CI=0.56-0.73), prior to percutaneous coronary intervention. There were no significant differences in secondary end points of in-hospital bleeding (OR 0.84, 95% CI=0.55-1.27), in hospital stroke (OR 1.17, 95% CI=0.48-2.82) or 30-day all-cause mortality (hazard ratio 0.88, 95% CI=0.60-1.30). CONCLUSIONS: Heparin pre-treatment was independently associated with a lower risk of intracoronary thrombus and total vessel occlusion before percutaneous coronary intervention in patients with STEMI, without evident safety concerns, in this large multi-centre observational study. PMID- 28862033 TI - Random Forest-Based Evaluation of Raman Spectroscopy for Dengue Fever Analysis. AB - This work presents the evaluation of Raman spectroscopy using random forest (RF) for the analysis of dengue fever in the infected human sera. A total of 100 dengue suspected blood samples, collected from Holy Family Hospital, Rawalpindi, Pakistan, have been used in this study. Out of these samples, 45 were dengue positive based on immunoglobulin M (IgM) capture enzyme-linked immunosorbent assay (ELISA) tests. For highlighting the spectral differences between normal and infected samples, an effective machine learning system is developed that automatically learns the pattern of the shift in spectrum for the dengue compared to normal cases and thus is able to predict the unknown class based on the known example. In this connection, dimensionality reduction has been performed with the principal component analysis (PCA), while RF is used for automatic classification of dengue samples. For the determination of diagnostic capabilities of Raman spectroscopy based on RF, sensitivity, specificity, and accuracy have been calculated in comparison to normally performed IgM capture ELISA. According to the experiment, accuracy of 91%, sensitivity of 91%, and specificity of 91% were achieved for the proposed RF-based model. PMID- 28862035 TI - The Effect of Moderate Temperatures on Latent Fingerprint Chemistry. AB - The effect of moderate temperatures (25-75 C) on latent fingerprints over a five hour period was examined using Fourier transform infrared (FT-IR) microspectroscopy. The aim of the study was to detect changes in IR spectra due to any changes in fingerprint chemistry; these results were then compared to pure compounds found in sebum that was subjected to 75 C for 5 h. Latent fingerprints deposited on CaF2 microscope slides and placed on a Peltier pump heating stage showed that higher temperatures significantly reduced the quantity of sebaceous compounds after 5 h, whereas temperatures below 45 C had little effect on the quantity of these compounds over the same time period. Fourier transform infrared microspectroscopy allowed for the real-time detection of changes to the IR spectra and demonstrated an increase in the OH stretch band (3250 cm-1) over 5 h at all temperatures investigated, suggesting various oxidation processes were taking place. Pure samples analyzed included squalene, fatty acids, wax esters, and mixed triglycerides. Unsaturated lipids showed a similar increase in the OH stretch band to the latent fingerprints whereas saturated compounds showed no change over time. This information is required to better understand the effect of moderate temperatures on latent fingerprints and how these temperatures could affect aged print composition. PMID- 28862036 TI - Origin of Analyte-Induced Porous Silicon Photoluminescence Quenching. AB - We report on gaseous analyte-induced photoluminescence (PL) quenching of porous silicon, as-prepared (ap-pSi) and oxidized (ox-pSi). By using steady-state and emission wavelength-dependent time-resolved intensity luminescence measurements in concert with a global analysis scheme, we find that the analyte-induced quenching is best described by a three-component static quenching model. In the model, there are blue, green, and red emitters (associated with the nanocrystallite core and surface trap states) that each exhibit unique analyte emitter association constants and these association constants are a consequence of differences in the pSi surface chemistries. PMID- 28862037 TI - The Relationship Between Osteomyelitis Complication and Drug-Resistant Infection Risk in Diabetic Foot Ulcer: A Meta-analysis. AB - In this study, we aimed to investigate the relationship between osteomyelitis complications and drug-resistant infection risk in diabetic foot ulcer. Searches of MEDLINE and ISI databases were performed for the studies. Odds ratios (ORs) for drug-resistant infection incidence were calculated for diabetic foot ulcer patients with or without osteomyelitis complications. Eleven studies (12 cohorts) with 1526 patients were included in this study. Meta-analysis showed that the summary OR was 3.343 (95% CI = 2.355-4.745; Z = 6.75, P < .00001) when compared with osteomyelitis group and without osteomyelitis group. Significant publication bias was found. Sensitivity analysis by only pooled the adjusted ORs showed that the result was robust (the summary OR = 4.081, 95% CI = 2.471-6.739). Subgroup analysis by drug-resistant type showed that the summary OR was 4.391 (95% CI = 2.287-8.394) for methicillin-resistant infection subgroup, and 2.693 (95% CI = 1.882-3.851) for multidrug-resistant infection subgroup. The meta-regression showed that drug-resistant incidence ( t = -0.90, P = .389) and published year ( t = -0.11, P = .913) were not related with the OR changes. In conclusion, our meta-analysis indicates that osteomyelitis complications are related with drug resistant infection risk in diabetic foot ulcer. We suggest bone culture-based narrow-spectrum antibiotic therapy for osteomyelitis for prevention drug resistant infection in diabetic foot ulcer. PMID- 28862038 TI - Novel methods of self-poisoning: repeated cardenolide poisoning after accessing Cerbera odollam seeds via the internet. PMID- 28862039 TI - Application of the American society of clinical oncology frameworks to compare tyrosine kinase inhibitors used in first line treatment of metastatic renal cell carcinoma: had we solved the mystery? AB - INTRODUCTION: The approval of multiple biological therapies as a first line treatment for metastatic renal cell carcinoma (mRCC) in the last decade have made the selection of the best treatment between these drugs, especially tyrosine kinase inhibitors (TKIs), a great challenge to oncologists and patients. The four TKIs recommended by the National Comprehensive Cancer Network guidelines in this setting have a relatively similar mechanism of action and analogical adverse events. Areas covered: In this article, the two published American Society of Clinical Oncology frameworks are applied to calculate the net health benefits of the four TKIs used as the first line in mRCC and this was balanced against their monthly cost. The available clinical data that is present for each drug has been displayed and compared to the use of the ASCO frameworks. Expert commentary: There is an urgent need to develop a comprehensive model incorporating all relevant aspects of each drug together. Oncologists should consider all data available for the drugs in order to give the patients an informed opportunity to select the best drug fitting for them. PMID- 28862040 TI - Lymphoplasmacyte-Rich Meningioma With Atypical Angiomatous Feature and an Increased Deposition of IgG4-Positive Plasma Cells: An Unusual Case Report. AB - Lymphoplasmacyte-rich meningioma (LPRM) is an extremely rare variant of meningioma, and a small percentage of LPRM may be associated with IgG4-related disease. To date, the coexistence of 2 rare meningioma variants consisting of LPRM and angiomatous meningioma within one neoplasm has not been reported in the literature. A 56-year-old woman presented with episodes of frequent and severe epistaxis that began 4 months ago. Initial magnetic resonance imaging showed localized, heterogeneous, and intermediate to high signal lesion at the odontoid process and clivus. In subsequent magnetic resonance images, the mass grew to the posterior nasopharyngeal wall, and compression to the medulla, and a suspicious enhancement of both distal vertebral arteries became evident even though there was 3 times of partial resection over 17 years. The tumor showed regional and temporal heterogeneity, and atypical features such as mitoses and a high proliferative index were also identified in the area of angiomatous meningioma in addition to LPRM with an increased deposition of IgG4-positive plasma cells within the neoplasm. PMID- 28862041 TI - The use of free non-dementia-specific Apps on iPad to conduct group communication exercises for individuals with Alzheimer's disease (Innovative Practice). AB - This study examined the use of various iPad Apps to conduct group cognitive exercises for clients with mild or early stage dementia of Alzheimer's type. A list of free non-dementia-specific Apps suitable for group sessions was compiled. The procedures in choosing these Apps and determining the most successful ones for group exercises were discussed. Based on participants' and professionals' responses to the use of these Apps, the results would render practitioners useful guidelines in replicating and running technology-based training for individuals with dementia. PMID- 28862042 TI - The Component Timed-Up-and-Go test: the utility and psychometric properties of using a mobile application to determine prosthetic mobility in people with lower limb amputations. AB - OBJECTIVE: Using a custom mobile application to evaluate the reliability and validity of the Component Timed-Up-and-Go test to assess prosthetic mobility in people with lower limb amputation. DESIGN: Cross-sectional design. SETTING: National conference for people with limb loss. SUBJECTS: A total of 118 people with non-vascular cause of lower limb amputation participated. Subjects had a mean age of 48 (+/-13.7) years and were an average of 10 years post amputation. Of them, 54% ( n = 64) of subjects were male. INTERVENTION: None. MAIN MEASURE: The Component Timed-Up-and-Go was administered using a mobile iPad application, generating a total time to complete the test and five component times capturing each subtask (sit to stand transitions, linear gait, turning) of the standard timed-up-and-go test. The outcome underwent test-retest reliability using intraclass correlation coefficients (ICCs) and convergent validity analyses through correlation with self-report measures of balance and mobility. RESULTS: The Component Timed-Up-and-Go exhibited excellent test-retest reliability with ICCs ranging from .98 to .86 for total and component times. Evidence of discriminative validity resulted from significant differences in mean total times between people with transtibial (10.1 (SD: +/-2.3)) and transfemoral (12.76 (SD: +/-5.1) amputation, as well as significant differences in all five component times ( P < .05). Convergent validity of the Component Timed-Up-and-Go was demonstrated through moderate correlations with the PLUS-M ( rs = -.56). CONCLUSION: The Component Timed-Up-and-Go is a reliable and valid clinical tool for detailed assessment of prosthetic mobility in people with non-vascular lower limb amputation. The iPad application provided a means to easily record data, contributing to clinical utility. PMID- 28862043 TI - Study of the Safety of Extracorporeal Cardiac Shock Wave Therapy: Observation of the Ultrastructures in Myocardial Cells by Transmission Electron Microscopy. AB - Extracorporeal cardiac shock wave therapy (CSWT) has been used to treat patients with severe coronary heart disease and cardiac failure with good results; however, the safety of this treatment is still controversial. Its safety in clinical setting and on microstructures has been confirmed, but the influence of shock wave on the ultrastructures of myocardial cells is not clear. In this study, 12 Sprague-Dawley rats were randomly divided into control (NC) and CSWT therapy (NC+SW) groups. The heart rate, blood pressure, serum troponin I (TNI), and cardiac ultrasound were evaluated, and the myocardial inflammatory responses and fibrosis changes were compared. The samples were observed by transmission electron microscopy to evaluate the changes in myocardial tissue ultrastructure. The CSWT had no significant influence on rat hemodynamics indices and serum TNI, did not affect left ventricular function, and did not cause myocardial inflammatory response and fibrosis changes. The scores of myocardial ultrastructure damage in the NC and NC+SW groups were 1.39 +/- 0.982 and 2.42 +/- 1.009, respectively ( P = .103). The CSWT did not cause significant additional damage to myocardial ultrastructures. The safety of CWST has been preliminarily proved at the clinical, microstructure, and ultrastructure levels, but its long term safety needs further exploration. PMID- 28862044 TI - Acute lamotrigine overdose: a systematic review of published adult and pediatric cases. AB - CONTEXT: Lamotrigine is a broad-spectrum anticonvulsant commonly used to treat seizure and bipolar mood disorders. Evidence from case series and retrospective studies indicate that lamotrigine overdose is usually benign. However, there are reported cases of cardiac arrest and mortality following lamotrigine overdose. We undertook a systematic review of the literature on lamotrigine overdoses to better understand the clinical severity, the relevance of serum concentrations, and therapeutic interventions for overdose. OBJECTIVES: To characterize manifestations of acute lamotrigine overdose, determine if serum concentrations predict poisoning severity, and evaluate the effectiveness of overdose management interventions. METHODS: We performed a literature search across eight databases, including Medline, EMBASE, and the Cochrane Library, from database inception to April 2014. Major bibliographic databases were updated on 31 May 2017. Articles were eligible if they described acute or acute on chronic lamotrigine overdose. At least one serum lamotrigine concentration had to be reported for inclusion. Reports on chronic poisoning, studies describing adverse effects of therapeutic use, and animal studies were excluded. RESULTS: We retrieved 6238 records; 48 (51 cases) met the inclusion criteria. Cases primarily involved adults (70.6%). Potentially life-threatening symptoms of overdose included seizures (55%), Glasgow Coma Scale <=8 (20%), hypotension (12%), and wide complex tachycardia (WCT) and cardiac arrest (6%). Among the 25 cases exposed to lamotrigine alone (13 adult; 12 pediatric), 2 adult fatalities occurred (4 g and 7.5 g ingested) and 8 pediatric cases experienced seizures (all children <=3.5-years-old, 75% without an underlying seizure disorder, >= 525 mg ingested). The lowest seizure associated serum concentration was 3.8 mg/L and 25.6 mg/L for pediatric and adult patients, respectively, suggesting children may be more susceptible to CNS toxicity. Cardiovascular toxicities occurred primarily in adult patients (threshold >25 mg/L). Overdose interventions included benzodiazepines (53%), propofol or barbiturates (14%), NaHCO3 (20%), lipid therapy (12%), and extracorporeal elimination (10%). NaHCO3 yielded no response in four of nine cases with conduction delays; however, two of the four cases subsequently responded with lipid therapy. CONCLUSIONS: Most cases reporting lamotrigine exposures observed mild or no toxicity; however, large exposures were associated with severe CNS depression, seizures, cardiac conduction delays, wide complex tachycardia, and death. In adults with a serum concentration >25 mg/L, severe toxicity may occur. In patients <=3.5 years of age, ingestions of >=525 mg may produce severe CNS depression and seizures. PMID- 28862045 TI - Developing a case mix classification for child and adolescent mental health services: the influence of presenting problems, complexity factors and service providers on number of appointments. AB - BACKGROUND: Case-mix classification is a focus of international attention in considering how best to manage and fund services, by providing a basis for fairer comparison of resource utilization. Yet there is little evidence of the best ways to establish case mix for child and adolescent mental health services (CAMHS). AIM: To develop a case mix classification for CAMHS that is clinically meaningful and predictive of number of appointments attended and to investigate the influence of presenting problems, context and complexity factors and provider variation. METHOD: We analysed 4573 completed episodes of outpatient care from 11 English CAMHS. Cluster analysis, regression trees and a conceptual classification based on clinical best practice guidelines were compared regarding their ability to predict number of appointments, using mixed effects negative binomial regression. RESULTS: The conceptual classification is clinically meaningful and did as well as data-driven classifications in accounting for number of appointments. There was little evidence for effects of complexity or context factors, with the possible exception of school attendance problems. Substantial variation in resource provision between providers was not explained well by case mix. CONCLUSION: The conceptually-derived classification merits further testing and development in the context of collaborative decision making. PMID- 28862046 TI - Glucose metabolism and metabolic flexibility in cultured skeletal muscle cells is related to exercise status in young male subjects. AB - We hypothesised that skeletal muscles of healthy young people have a large variation in oxidative capacity and fibre-type composition, and aimed therefore to investigate glucose metabolism in biopsies and myotubes isolated from musculus vastus lateralis from healthy males with varying degrees of maximal oxygen uptake. Trained and intermediary trained subjects showed higher carbohydrate oxidation in vivo. Fibre-type distribution in biopsies and myotubes did not differ between groups. There was no correlation between fibre-type I expression in biopsies and myotubes. Myotubes from trained had higher deoxyglucose accumulation and fractional glucose oxidation (glucose oxidation relative to glucose uptake), and were also more sensitive to the suppressive action of acutely added oleic acid to the cells. Despite lack of correlation of fibre types between skeletal muscle biopsies and cultured cells, myotubes from trained subjects retained some of their phenotypes in vitro with respect to enhanced glucose metabolism and metabolic flexibility. PMID- 28862047 TI - New surgical approaches for clinically high-risk or metastatic prostate cancer. AB - INTRODUCTION: A considerable number of individuals with prostate cancer (PCa) still harbor locally-advanced and metastatic disease. Although such men were initially not considered eligible for local treatment, the role of radical prostatectomy (RP) has been recently reassessed. Areas covered: This review analyses currently published evidences regarding new surgical approaches for clinically high-risk PCa individuals, as well as the role of cytoreductive surgery in the metastatic setting. The role of robot-assisted radical prostatectomy (RARP) and extended pelvic lymph node dissection will be evaluated with regards to perioperative, oncologic, as well as functional outcomes. Expert commentary: RARP is a feasible approach in PCa patients regardless of the presence of high-risk disease features and can achieve optimal short-term oncologic outcomes and acceptable short/intermediate-term functional outcomes, that are comparable to those reported for open RP. Extended pelvic lymph node dissection can be performed in this setting and should be recommended for all high-risk PCa patients. The overall rate of complications in contemporary men treated with RARP for high-risk disease is not negligible. Cytoreduction in the oligo-metastatic setting is feasible and relatively safe, although evidence is scarce to recommend its widespread adoption. In consequence, longer follow-up data and, ideally, randomized controlled trials are needed. PMID- 28862048 TI - A Precious Diagnostic "Pearl": The Necklace Pattern in Germ Cell Tumors of the Testis. AB - Diffuse embryoma is a rare pattern of nonseminomatous germ cell tumor of the testis originally described in 1983. We report a case with this predominant pattern in an 18-year-old male with a painless palpable testicular mass. Although it is relatively common to see a diffuse embryoma pattern focally in mixed nonseminomatous germ cell tumors of the testis, it is rarely the predominant pattern and can represent a diagnostic pitfall on routine hematoxylin and eosin stain. We emphasize the importance of recognizing the individual components within the diffuse embryoma pattern, review the literature, and briefly discuss the ancillary immunohistochemical stains that may be utilized to help support the diagnosis. PMID- 28862049 TI - Pulmonary Adenocarcinoma, Intra-alveolar Variant: A Rare Entity Mimicking Desquamative Interstitial Pneumonia. AB - Exclusive discohesive tumor cells within intra-alveolar spaces is a rare pattern of involvement of primary and metastatic lung tumors. In the absence of a tumoral mass, this pattern closely mimics desquamative interstitial pneumonia (DIP) clinically, radiologically, and histologically. However, a secondary DIP pattern may be seen adjacent to a tumor mass not infrequently. Here, we describe a case of a 64-year-old woman status post bilateral lung transplantation, who was radiologically thought to have an interstitial lung disease. The autopsy lung specimen revealed extensive involvement by intra-alveolar adenocarcinoma, with a cytomorphology mimicking alveolar macrophages as seen in DIP in the absence of a tumoral mass. The presence of subtle clustering with signet ring cell features and rare micropapillae were an important clue to the diagnosis. The tumor cells were positive for CK7, napsin-A, and TTF-1, and negative for CD68. This case represents an unusual variant of pulmonary adenocarcinoma with a pure intra alveolar pattern of involvement, mimicking DIP. To the best of our knowledge, excluding biopsy specimens, only one similar case has been reported in the literature and none in the posttransplant setting. PMID- 28862050 TI - Synthetic cannabinoid "Black Mamba" infidelity in patients presenting for emergency stabilization in Colorado: a P SCAN Cohort. AB - BACKGROUND: Use of new psychoactive substances (NPS) has increased over the last decade. During this period, variability of both clinical presentations and chemical compositions of these compounds has increased. Synthetic cannabinoids (SCs) are the most commonly used NPS and there are more than 100 documented unique molecules in this class. "Black Mamba", often associated to ADB-FUBINACA, is the most commonly used SC in Colorado. It has been linked to kidney injury, myocardial toxicity, seizures, and death. OBJECTIVES: We aim to identify the chemical constituents and quantification of eight cases of reported "Black Mamba" use in order to further understand the clinical variability in patients presenting for emergency stabilization. METHODS: We report data from eight cases of reported "Black Mamba" use prospectively captured through the Colorado site of the Psychoactive Surveilance Consortium and Analysis Network (P SCAN). P SCAN is a geographically representative group of academic hospitals that capture clinical presentation, outcome, and biologic samples from patients that present for emergency stabilization following NPS use. Serum and urine samples were analyzed and quantified by liquid chromatography-quadrupole time-of-flight mass spectrometry after a qualitative screen for over 600 unique NPS compounds. RESULTS: In the reported eight cases, the median age was 28 years old. There were four male and four females. Four patients had agitation/delirium and four patients had chest pain. Normal saline, benzodiazepines and ondansetron were the common treatment provided in the emergency department (ED). Two patients were discharged from the ED and six patients being admitted for emergency observation with a median length of stay (LOS) of six hours. No deaths were reported. Confirmatory testing revealed that only five patients (62.5%) had SCs found in blood or urine samples. Cocaine, NRG-3, 3-methoxyphencyclidine hydrochloride (MeO PCP), and methamfetamine were identified in other presentations. CONCLUSIONS: The wide range of clinical presentations from "Black Mamba" use may be explained by the wide variability of chemical constituents found by laboratory analysis. PMID- 28862051 TI - The projected public health and economic impact of vitamin D fortified dairy products for fracture prevention in France. AB - BACKGROUND: There is a paucity of research that projects the public health and economic impact of healthcare interventions in the future. In this study, we aimed to estimate the public health and economic impact of vitamin D fortified dairy products for the years 2020, 2030, 2040, 2050 and 2060. METHODS: We used a previously validated Markov microsimulation model that was designed to assess the public health and economic impact of dairy products for fracture prevention in the French general population aged over 60 years in the year 2015. RESULTS: The expected benefit (in terms of fractures prevented) of the recommended intake of dairy products compared to the absence of appropriate intake is expected to increase by 63% in 2040 and by 85% in 2060. The cost per quality-adjusted life years gained of the appropriate intake of dairy products is expected to decrease from ?58,244 in 2015 to ?42,616 in 2060. CONCLUSION: The potential public health and economic benefits of vitamin D fortified dairy products is expected to substantially increase in the future, especially in the population aged over 80 years. Decision makers should be aware of the current and future potential benefits of dairy products to protect bone fractures. PMID- 28862052 TI - Proteomic analysis of mitochondria: biological and clinical progresses in cancer. AB - INTRODUCTION: Mitochondria play important roles in regulating multiple biological processes and signalling pathways in eukaryotic cells, and mitochondrial dysfunction may result in a wide range of serious diseases, including cancer. With improvements in the identification of mitochondrial proteins, mitochondrial proteomics has made great achievements. In particular, this approach has been widely used to compare tumour cells at different stages of malignancy. Therefore, there is an urgent need to identify and characterize the function of mitochondrial proteins in cancer progression and to determine the involved mechanisms. Areas covered: We provide an overview of recent progress related to mitochondrial proteomics in cancer and the application of comparative mitochondrial proteomics in various biological processes, including apoptosis, necroptosis, autophagy and metastasis, as well as clinical progress in cancer. Proteomics-related reports were found using PubMed and Google Scholar databases. Expert commentary: Understanding both post-translational modification and post translational processing is important in the comprehensive characterization of protein function. The application of comparative mitochondrial proteomics to investigate clinical samples and cancer cells will contribute to our understanding of the molecular interplay of mitochondrial proteins in the development of cancer. This approach will mine more biomarkers for diagnosis and prognosis and improve therapeutic outcomes among cancer patients. PMID- 28862053 TI - Turning the spotlight on lasers. PMID- 28862054 TI - Lysosomal targeting strategies for design and delivery of bioactive for therapeutic interventions. AB - Lysosomes are of particular interest for the design and delivery of pH-dependent pro-drugs, enhancing selectivity and developing strategies to inhibit drug degradation inside the cells. There is great potential to bring intracellular drug delivery and distribution using nanotherapeutic approaches to target lysosomes for therapeutic interventions. Lysosomal targeting strategies involve two contrasting facets. One aspect is to directly target therapeutics to the lysosome through receptor-mediated endocytosis and the other facet involves strategies, which ensure escape from the lysosome in order to prevent their degradation, so that therapeutics may remain intact and available in the cytosol for their further action. It provides a unique opportunity to explore novel treatment strategies and design future drugs for the effective treatment of lysosome-related diseases especially lysosomal storage disorders (LSD), cancer, inflammatory, neurodegenerative conditions (Parkinson's, Alzheimer's and Huntington's diseases) and autoimmune diseases. In this review, we illustrate the fundamentals of membrane trafficking, subcellular organisation, strategies to target lysosomes and its implications for the advance design of efficient drug delivery vectors for safe and effective therapies. PMID- 28862055 TI - Elastotic Lesions of Intestinal Subserosal Fat: Report of Two Cases. AB - We report 2 unusual elastotic lesions of intestinal subserosal fat. The first arose in the small bowel subserosa of a 64-year-old woman with volvulus. It was undetected macroscopically and consisted of a relatively circumscribed focus of elastosis, with essentially no evidence of fibrosis or blood vessel walls within. The second arose in the subserosa of the sigmoid colon in a 46-year-old woman with recurrent diverticulitis. It was also undetected macroscopically and consisted of a well-circumscribed nodule of elastic fibers surrounding prominent veins and arteries. Both patients had unremarkable postoperative courses. These lesions likely represent localized response to injury and are probably underrecognized. PMID- 28862056 TI - The Use of Engineered Bilayered Skin (MyDermTM) in the Management of Massive Skin Defect in Grade III Gustilo-Anderson Open Fracture. AB - Open fracture Gustilo-Anderson grade IIIC is associated with higher risk of infection and problems with soft tissue coverage. Various methods have been used for soft tissue coverage in open fractures with large skin defect. We report a case of a patient who had grade IIIC open fracture of the tibia with posterior tibial artery injury. The patient underwent external fixation and reduction. Because of potential compartment syndrome after vascular repair, fasciotomy of the posterior compartment was performed. This wound, however, became infected and because of further debridement, gave rise to a large skin defect. A tissue engineered skin construct, MyDermTM was employed to cover this large defect. Complete wound closure was achieved 35 days postimplantation. The patient then underwent plating of the tibia for nonunion with no adverse effect to the grafted site. The tibia eventually healed 5 months postplating, and the cosmetic appearance of the newly formed skin was satisfactory. PMID- 28862057 TI - Biological characteristics of Edgeworthia tomentosa (Thunb.) Nakai flowers and antimicrobial properties of their essential oils. AB - Edgeworthia tomentosa (Thunb.) Nakai belongs to Thymelaeaceae family, its alabastrum is used as the traditional Chinese medicine 'Buddleja Officinalis Maxim'. The present study was to elucidate the ultrastructure characteristics of the flower, the phytochemical composition of the aroma essential oils (EOs) and the relevant antimicrobial properties. There were exclusive characters of calyx, ovule, anther and pollen grain of the flowers under scanning electron microscopy. A total of 40 phytochemical components representing 98% of the EOs were successfully identified: monoterpenes and sesquiterpenes were the dominant terpenoids according to Kovats retention index and MS database. EOs exhibited a broad spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria, the best bacteriostatic effect was against Diplococcus pneumonia with MIC and MBC values ranging between 7.8 and 62.5 and 26.0-71.0 MUg/mL, respectively. These results demonstrate that the surface microscopic morphological characteristics of Edgeworthia chrysantha Lindl. flowers, are full scale chemical composition and antimicrobial properties of the EOs. PMID- 28862058 TI - A new cyclic dipeptide from cultures of Coprinus plicatilis. AB - Three cyclic dipeptides (1-3), including one new compound (1) were isolated from cultures of the basidiomycetes Coprinus plicatilis. Their structures were elucidated by spectroscopic methods, including extensive 2D NMR techniques. At the same time, all compounds were tested for their cytotoxicities against five human cancer cell lines. PMID- 28862059 TI - Monitoring a municipal wastewater treatment process using a trend analysis. AB - New monitoring methods are required to enhance the operation of a wastewater treatment process and to meet the constantly tightening regulations for the effluent discharges. An on-line optical monitoring device, that analyses the morphological parameters of the flocs, has been shown to be a potential tool for assessing the wastewater quality and the state of the activated sludge process. In this paper, the earlier presented trend analysis method is applied to the operating conditions, the treatment results and the optical monitoring variables of a full-scale biological wastewater treatment process. The trend episodes and the deviation indices resulted from the trend analysis provide warning of the changes in the monitored variables and the received information can be used as assistance in the treatment process operation and avoiding harmful environmental risks. PMID- 28862060 TI - Best-worst scaling to assess the most important barriers and facilitators for the use of health technology assessment in Austria. AB - BACKGROUND: Although Health Technology Assessment (HTA) is increasingly used to support evidence-based decision-making in health care, several barriers and facilitators for the use of HTA have been identified. This best-worst scaling (BWS) study aims to assess the relative importance of selected barriers and facilitators of the uptake of HTA studies in Austria. METHODS: A BWS object case survey was conducted among 37 experts in Austria to assess the relative importance of HTA barriers and facilitators. Hierarchical Bayes estimation was applied, with the best-worst count analysis as sensitivity analysis. Subgroup analyses were also performed on professional role and HTA experience. RESULTS: The most important barriers were 'lack of transparency in the decision-making process', 'fragmentation', 'absence of appropriate incentives', 'no explicit framework for decision-making process', and 'insufficient legal support'. The most important facilitators were 'transparency in the decision-making process', 'availability of relevant HTA research for policy makers', 'availability of explicit framework for decision-making process', 'sufficient legal support', and 'appropriate incentives'. CONCLUSION: This study suggests that HTA barriers and facilitators related to the context of decision makers, especially 'policy characteristics' and 'organization and resources' are the most important in Austria. A transparent and participatory decision-making process could improve the adoption of HTA evidence. PMID- 28862061 TI - Pulmonary Metastasis of Undifferentiated Uterine Sarcoma Forming Fluid-Containing Cyst. AB - Undifferentiated uterine sarcoma (UUS) is a high-grade sarcoma with no specific differentiation; however, it exhibits variable positivity for CD10 as an immunohistochemical marker of endometrial stroma, suggesting immunohistochemical differentiation into endometrial stroma. It has been reported that some low-grade endometrial stromal sarcoma pulmonary metastatic foci show cystic changes; however, whether pulmonary metastatic UUS foci are solid or cystic remains undescribed. A 63-year-old woman underwent a hysterectomy. The subsequent pathologic diagnosis was UUS. After the operation, she was treated with chemotherapy; however, pulmonary solitary shadow was radiologically detected. Eight months after the gynecologic operation, her pulmonary lesion was surgically resected. Pathologically, the lesion consisted of a cyst containing serous fluid with thick whitish wall composed of tumor cells, which led to the diagnosis of metastatsis of UUS. The cyst seemed to be formed via secondary degeneration. She remains healthy without recurrence 28 months after her first visit to our hospital. PMID- 28862062 TI - Methyl-cellulose powder for prevention and management of nasal symptoms. AB - INTRODUCTION: HPMC-p, an inert micronized powder form of hydroxy-propyl-methyl cellulose, when insufflated nasally, provides a natural barrier against pollen allergens and noxious agents. This overview assesses the efficacy and safety of this patented powder product and delivery system without an analogue among the cellulose derivatives. Areas covered: Twenty-six studies with HPMC-p were critically appraised to obtain an updated characteristic of the product. Most studies assessed the efficacy of HPMC-p as a nasal barrier enforcing measure: one experimental setup evaluated its ability to prevent or delay the diffusion of allergen through it, two clinical studies used allergen provocation tests, and the remaining relied on clinical criteria in open real world or placebo controlled designs. Two studies checked if HPMC-p could enhance the efficacy of drugs applied nasally to treat local symptoms. The studies, using either nasal allergen challenge or natural exposure of patients to environmental allergen, support the hypothesis that HPMC-p possesses barrier enforcing properties. Also, acute and clinical experiments indicated that intra-nasal application of HPMC-p following local relief medications enhances their ability to suppress symptoms and reduces their long-term use. Expert commentary: Nasal insufflation of HPMC-p provides a mucosal barrier, reducing the nasal symptoms and enhancing the effects of local relief medications. PMID- 28862063 TI - The safety of edoxaban for treating atrial fibrillation. AB - INTRODUCTION: Atrial Fibrillation (AF) has a worldwide increasing incidence and prevalence, putting patients at risk for atrial thrombus formation and consecutive thromboembolic events. Morbidity and mortality have become a significant global public health care burden. Thus, there is increasing need for safe and effective medical prophylaxis of thromboembolic events. Edoxaban is the fourth approved non-vitamin K oral anticoagulant (NOAC) that has been introduced into the market for the prophylaxis of stroke or systemic embolism in non valvular AF patients after dabigatran, rivaroxaban, and apixaban. The pivotal phase III clinical trial evaluating safety and efficacy of edoxaban included more than 21,000 patients. Areas covered: The aim of this expert opinion drug safety review is to introduce edoxaban as a compound, to discuss its development, and its pharmacologic properties. Furthermore, efficacy and safety data of edoxaban - with emphasis on a comparison to oral anticoagulation with warfarin and the other currently available NOACs - are discussed. Ongoing studies that further evaluate edoxaban in special patient populations and disease entities are summarized. Expert opinion: Concerning safety and efficacy, medical compliance, adherence and concomitant diseases like renal impairment are of utmost importance in daily clinical practice, why in the expert opinion part of this review emphasis is put on that issue. PMID- 28862064 TI - Time and change in health care. AB - Purpose The purpose of this paper is to explore the dimensions of temporality that are rarely considered in the literature on leading change. Design/methodology/approach The analysis is informed by Adams' (1995) social theory of time encompassing temporality, timing and tempo. This will illustrate the complexities of time as they relate to the individual, teams and organisation. Findings This paper demonstrates the multidimensional nature of time: temporality, timing and tempo, and how each of these can contribute to our understanding of the temporal nature and complexity of change within the health system. A framework to inform much-needed research in the area of time and change is presented. Practical implications Challenging assumptions that there is only one common time, that is clock time, can provide opportunities for further discussion and understanding of how various people view time and the influence this has on leading and participating in change in health care. Originality/value There is limited literature on the temporal dimensions of change at an organisational, team and individual level. The perspective offered in this paper presents the multidimensional nature of time and the influence this has on understanding the temporal nature of change and critically identifies some key areas for future research. PMID- 28862065 TI - Adiposity, but not Obesity, Is Associated With Arterial Stiffness in Young Nulliparous Women. AB - Subclinical vascular dysfunction is increasingly recognized as an independent risk factor for cardiovascular events and adverse pregnancy outcomes. The evidence linking indices of obesity and vascular dysfunction is mixed. As an example, some data suggest that adiposity may be a better predictor of endothelial dysfunction than body mass index (BMI). The aim of the current study is to compare the association of obesity, as evaluated by BMI, and a direct measure of body fat to biophysical parameters of vascular function including flow mediated vasodilation and pulse wave velocity (PWV) in healthy nulliparous reproductive-age women. This is a secondary analysis of data collected as a prospective study of prepregnancy physiology in healthy, nulliparous women. Body mass index was calculated as weight (kg)/height (m2). Total and android body fat were calculated by dual-energy X-ray absorptiometry. Brachial PWV and flow mediated vasodilation were assessed ultrasonographically. Seventy-nine women were evaluated. Mean BMI was 24.4 (5.4) kg/m2, and 15% of women were obese (BMI >= 30 kg/m2). In contrast, 39% were considered to have excess adiposity, with >=39% android body fat. Brachial PWV was associated with increased adiposity, but not obesity. We found no differences in flow-mediated dilation associated with either BMI or body fat. Adiposity may be superior to BMI in identifying women with vascular dysfunction at increased risk of adverse pregnancy outcome and cardiovascular disease. Proper identification may allow implementation of prevention strategies to improve perinatal outcomes and maternal health. PMID- 28862066 TI - Solitary Neurofibroma of the Breast, and "The Man From Istanbul" Syndrome. PMID- 28862067 TI - Pushing the envelope: a treat and repair strategy for patients with advanced pulmonary hypertension associated with congenital heart disease. AB - Pulmonary arterial hypertension (PAH) is a frequent complication of congenital heart disease as a consequence of altered pulmonary hemodynamics with increased pulmonary blood flow and pressure. The development of pulmonary vascular disease (PVD) in this patient population is an important concern in determining operative strategy. Early, definitive surgical repair, when possible, is the best therapy to prevent and treat PVD. However, this is not possible in some patients because they either presented late, after the development of PVD, or they have complex lesions not amenable to one-step surgical correction, including patients with single ventricle physiology, who have a continuing risk of developing PVD. These patients represent an important, high-risk subgroup and many have been considered inoperable. We present a case series of two patients with complex congenital heart disease and advanced PVD who successfully underwent a treat and repair strategy with aggressive PAH therapies before surgical correction. Both patients had normalization of pulmonary vascular resistance prior to surgical correction. Caution is warranted in applying this strategy broadly and long-term follow-up for these patients is crucial. However, this treat and repair strategy may allow for favorable outcomes among some patients who previously had no therapeutic options. PMID- 28862068 TI - Novel transparent collagen film patch derived from duck's feet for tympanic membrane perforation. AB - To increase healing rate of tympanic membrane (TM) perforations, patching procedure has been commonly conducted. Biocompatible, biodegradable patching materials which is not limited across cultures is needed. The authors evaluated the effectiveness of novel transparent duck's feet collagen film (DCF) patch in acute traumatic TM perforation. This procedure was compared with spontaneous healing and paper patching. Cell proliferation features were observed in paper and DCF patches. Forty-eight TMs of 24 rats were used for animal experiment, perforations were made on each TMs, and divided into three groups according to treatment modality. Sixteen were spontaneously healed, 16 were paper patched and 16 were DCF patched. The gross and histological healing results were analyzed. Both paper and DCF patch showed no cytotoxicity, but cell proliferations were more active in DCF than paper in early stage. In animal study, the healing of TM perforations were completed within 14 days in all three groups, but found to be faster in DCF patch group than paper patch or spontaneous healing group. The DCF patches were transparent and size of DCF patches were gradually decreased, so there were no need to remove the DCF patches to check the wound status or after the completion of healing. According to this result, authors concluded that DCF patch is transparent, biocompatible and biodegradable material, and can induce fast healing in acute traumatic TM perforations. PMID- 28862069 TI - Patient-related risk factors for requiring surgical intervention following a failed injection for the treatment of medial and lateral epicondylitis. AB - OBJECTIVES: To identify risk factors for failure of a therapeutic injection leading to operative management of both medial and lateral epicondylitis. METHODS: A national database was used to query Medicare Standard Analytic Files from 2005-2012 for patients treated with therapeutic injections for medial or lateral epicondylitis using CPT codes for injections associated with corresponding ICD-9 diagnostic codes (726.31 and 726.32, respectively). Those who subsequently underwent surgical treatment following injection were identified. A multivariate binomial logistic regression analysis was utilized to evaluate patient-related risk factors for requiring surgery within 2 years after therapeutic injection. RESULTS: 1,837 patients received therapeutic injections for medial epicondylitis. 52 (2.8%) required ipsilateral surgery at a mean of 429 +/- 28 days post-injection. Risk factors for requiring surgical intervention included age <65, obesity, and morbid obesity. 6,561 patients received therapeutic injections for lateral epicondylitis. 201 (3.1%) required subsequent surgery at a mean of 383 +/- 128 days' post-injection. Risk factors included age <65, tobacco use, diabetes mellitus and peripheral vascular disease. CONCLUSION: The incidence of surgical intervention following a failed therapeutic injection for medial or lateral epicondylitis is low (~3%). Risk factors for failing a therapeutic injection include age <65 years and obesity (BMI > 30) for medial epicondylitis and age <65 years, smoking, diabetes mellitus and peripheral vascular disease for lateral epicondylitis. Patients with these identified risk factors presenting with medial or lateral epicondylitis should be cautioned that they carry a higher risk of subsequent surgical treatment. LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28862070 TI - Comparative study on turbulence models simulating inorganic particle removal in a Pista grit chamber. AB - Numerical simulations and experimental validations were conducted to determine grit removal efficiency and separation processes for inorganic suspended solids (ISS) with different particle sizes in a vortex-type grit chamber (Pista). The Euler-Lagrange method was used to simulate solid-liquid two-phase flow; the Unsteady Discrete Model was used to simulate the solid phase; and the Renormalization Group k-epsilon (RNG k-epsilon), Realizable k-epsilon (Real k epsilon), and Shear Stress Transmission k-omega (SST k-omega) models were used to simulate the liquid phase. Results of the RNG k-epsilon model agreed well with the experimental results for particles with d <= 200 um, with an average error of 7.10% (d < 100 um) and 6.78% (100 um <= d <= 200 um). When particle size exceeded 200 um, the Real k-epsilon model had the minimum average error (4.16%). Bed load transport and suspended load transport of the different size ISS particles presented in the grit chamber were important factors influencing grit removal efficiency. Pressure gradient and turbulence intensity distributions simulated by the three turbulence models were significantly different. Particles with diverse sizes reacted distinctly to the disturbance effect caused by pressure difference, which impacted on the accuracy and reliability of simulation results. PMID- 28862071 TI - Work environment investments: outcomes from three cases. AB - Work environment investments are important in order to create a healthy and safe workplace. This article presents findings from a seven-step interventions process aimed at examining and following-up work environment investments in small and medium-sized enterprises (SMEs), with a particular focus on air contaminants. Three different cases were analyzed and included in the study: (a) an educational center for welding; (b) a paint station in furniture manufacturing; (c) a joinery in furniture manufacturing. The results show that the work environment investments were highly appreciated by the employees and managers, but at the same time the investment could be optimized through markedly decreased exposure levels for the worker. Factors such as follow-ups of the investment, education and training in how to use the equipment, worker involvement in the process and leadership engagement are important in order to optimize work environment investments. PMID- 28862072 TI - Intranasal delivery of tapentadol hydrochloride-loaded chitosan nanoparticles: formulation, characterisation and its in vivo evaluation. AB - The aim of the present investigation was to formulate tapentadol hydrochloride loaded chitosan nanoparticles (CS-NPs) for nose to brain delivery. Chitosan nanoparticles were prepared using ionotropic gelation technique. Optimisation of the formulation and process parameters was done using Box-Behnken Design. The entrapment efficiency, drug loading, Z-average size and zeta potential of the optimised batch were 63.49 +/- 1.61%, 17.25 +/- 1.38%w/w, 201.2 +/- 1.5 nm and +49.3 mV, respectively. In-vitro release study showed 84.04 +/- 1.53% drug release after 28 h, while ex vivo studies indicated higher permeation of CS-NPs through nasal mucosa. The nanoparticles exhibited good mucoadhesiveness, haemocompatibility and safety as evidenced by histopathology. The results of the pharmacodynamic study revealed prolongation of the analgesic activity. The intranasal instillation of CS-NPs resulted in the higher concentrations in brain compared to the drug solution and intravenous administration of CS-NPs. In a nutshell, intranasal administration of tapentadol hydrochloride-loaded CS-NPs is a promising approach for effective pain management. PMID- 28862073 TI - Mental health risks and stressors faced by urban refugees: Perceived impacts of war and community adversities among Somali refugees in Nairobi. AB - BACKGROUND: There is a gap in understanding of refugee mental health risks unique to urban areas of low-income countries. MATERIAL: A qualitative rapid appraisal using focus group interviews with community stakeholders explored main stressors pervasive by Somali refugees in Nairobi, Kenya. DISCUSSION: This study identified the intersection of war trauma and daily stressors that affect both functional and structural challenges and risk of mental health issues among Somali urban refugees. CONCLUSION: Findings underscore the importance of understanding mental health in the broader context of community adversities, suggesting development of contextually informed interventions responsive to complex needs of urban refugees. PMID- 28862074 TI - The regulatory effects of L. plantarum peptidoglycan microspheres on innate and humoral immunity in mouse. AB - OBJECTIVE: To study the effects of Lactobacillus Plantarum cell wall peptidoglycan (LPG) microspheres on mouse intestinal flora changes, peptidoglycan recognitions protein (PGRP) and cytokines expression levels. METHOD: Plate counting was used for enumeration of the intestinal flora. Real-time PCR was used for quantification PGRP in different tissues. Cytokines content were determined by ELISA kits. RESULT: The mouse administered orally with LPG microspheres showed significantly higher number of Lactobacillus and Bifidobacterium in caecum contents (p < 0.01). The amount of PGRP expression in different organs was highest in LPG microspheres-treated group. IL-4, 12, IFN-gamma, TNF-alpha contents in serum from LPG microspheres-treated mouse were significantly higher than those in normal saline-treated group (p < 0.01). CONCLUSIONS: This study shows that the LPG microspheres can regulate intestinal flora imbalance and improve systemic immunity, improve both Th1 and Th2 immune response, which provide some basis for the use of LPG as potential adjuvants. PMID- 28862075 TI - Shedding light on designing potential meprin beta inhibitors through ligand-based robust validated computational approaches: A proposal to chemists! AB - Human meprin (EC 3.4.24.18) is a member of the metzincin superfamily. It correlates with matrix metalloproteinases and ADAMs (a disintegrin and metalloproteinase). Overexpression of meprin beta is implicated in fibrosis, inflammatory diseases and cancers. However, selective meprin beta inhibition is crucial to reduce cancer metastasis and adverse effects in inflammation. It also plays critical roles in modulating several interleukins and growth factors. Moreover, meprin beta cleaves amyloid precursor protein, thought to be involved in the progression of Alzheimer's disease. Therefore, meprin beta inhibitors are considered to be emerging therapeutics with paramount importance in the treatment of kidney failure, fibrosis, inflammatory bowel diseases and cancer. Despite its crucial implication in several diseases, no meprin beta inhibitors are available as drug candidates till date. Therefore, it is an urgent need to identify new potential meprin beta inhibitors as prospective therapeutics. In this article, a series of meprin beta inhibitors has been analysed through multiple molecular modelling studies as the first initiative to get an idea about their structural, physicochemical and pharmacophoric requirements for higher activity. All in silico approaches performed here are statistically validated and subsequently adjudicated each other. Compounds with p-carboxylic acid substituted arylsulphonamide moiety attached with m-carboxylic acid substituted benzyl group along with a methylene hydroxamate function may be crucial for imparting potential meprin beta inhibition. Depending on the results obtained, 14 molecules have been proposed by QSAR model that predicted a minimum of 4-fold higher activity compared to these compounds of the current study. PMID- 28862076 TI - Timing the Microbes: The Circadian Rhythm of the Gut Microbiome. AB - The mammalian circadian clock system, which includes the master clock and peripheral clocks, times different biological processes in reaction to external cues, such as the light-dark cycle. However, the chronobiology of prokaryotic cells is less well understood, except for in cyanobacteria. The recent blooming of gut microbiome research has revealed a critical role for the trillions of microbes residing in the vertebrate gut in determining both health and disease in the host. The question of whether the gut microbiome exhibits circadian oscillation and how it synchronizes with the host circadian clock has attracted considerable interest. In this review, we discuss the time-of-day-dependent compositional and functional structure within the gut microbial community, how it is regulated by the host, and how it reciprocally influences the host circadian clock. PMID- 28862077 TI - Disinfection of Mycobacterium avium subspecies hominissuis in drinking tap water using ultraviolet germicidal irradiation. AB - Nontuberculous mycobacteria are resistant to conventional water treatments, and are opportunistic human pathogen, particularly in hospitalized patients. The aim of this investigation was to assess the effectiveness of an ultraviolet UV-C lamp treatment against Mycobacterium avium subspecies hominissuis in drinking tap water. Ultraviolet treatments (0-192 mJ/cm2) were performed using UV lamp immerged onto cylindrical glass tubes containing artificially contaminated water. The results showed that susceptibility to UV varied considerably according to the strains and the diameter of the tube. With a dose of 32 mJ/cm2, a significant inactivation (p < .05) of 3 log (99.9%) or more was obtained in only 5 of the 14 strains. To obtain a complete inactivation of all strains an irradiation of 192 mJ/cm2 was needed, a dose that is much higher than the limits recommended by the international standards for UV disinfection of drinking water. In conclusion, it may be difficult to standardize a UV dose for the elimination of waterborne mycobacteria. PMID- 28862078 TI - Emotion regulation choice: the role of environmental affordances. AB - Which emotion regulation strategy one uses in a given context can have profound affective, cognitive, and social consequences. It is therefore important to understand the determinants of emotion regulation choice. Many prior studies have examined person-specific, internal determinants of emotion regulation choice. Recently, it has become clear that external variables that are properties of the stimulus can also influence emotion regulation choice. In the present research, we consider whether reappraisal affordances, defined as the opportunities for re interpretation of a stimulus that are inherent in that stimulus, can shape individuals' emotion regulation choices. We show that reappraisal affordances have stability across people and across time (Study 1), and are confounded with emotional intensity for a standardised set of picture stimuli (Study 2). Since emotional intensity has been shown to drive emotion regulation choice, we construct a context in which emotional intensity is separable from reappraisal affordances (Study 3) and use this context to show that reappraisal affordances powerfully influence emotion regulation choice even when emotional intensity and discrete emotions are taken into account (Study 4). PMID- 28862079 TI - Sense of community, organizational commitment and quality of services. AB - Purpose The purpose of this paper is to examine how factors associated with a sense of community in the workplace are connected with organizational commitment and the quality of services among frontline managers and middle managers in social and health care services in Finland. Design/methodology/approach A questionnaire designed specifically for this research was sent to 241 lower-level and middle-level managers in social and health care services in central Finland. A total of 136 managers completed the questionnaire (response rate 56 per cent). The results were analyzed using descriptive statistics, exploratory factor analysis, Spearman's rank-order correlation coefficient and multiple linear regression analyses. Findings The study showed that feeling a sense of belonging, mutual trust and appreciation, and open interaction among colleagues were connected to organizational commitment for frontline managers and middle managers in social and health care services in Finland. Correspondingly, an open flow of information in the organization, job meaningfulness and appreciation received from managers' superiors were connected to the quality of services. Originality/value This study provides information on the factors that influence social and health care managers' organizational commitment and on items connected to their experience of the quality of services. PMID- 28862080 TI - Evaluation of brain-targeted chitosan nanoparticles through blood-brain barrier cerebral microvessel endothelial cells. AB - The blood-brain barrier (BBB) is the major problem for the treatment of central nervous system diseases. A previous study from our group showed that the brain targeted chitosan nanoparticles-loaded with large peptide moieties can rapidly cross the barrier and provide neuroprotection. The present study aims to determine the efficacy of the brain-targeted chitosan nanoparticles' uptake by the human BBB cerebral microvessel endothelial cells (hCMECs) and to investigate the underlying mechanisms for enhanced cellular entry. Fluorescently labelled nanoparticles either conjugated with antibodies recognising human transferrin receptor (anti-TfR mAb) or not were prepared, characterised and their interaction with cerebral endothelial cells was evaluated. The antibody decoration of chitosan nanoparticles significantly increased their entry into hCMEC/D3 cell line. Inhibition of cellular uptake by chlorpromazine indicated that the anti-TfR mAb-conjugated nanoparticles were preferentially cell internalised through receptor-mediated endocytosis pathway. Alternatively, as primarily observed with control chitosan nanoparticles, aggregation of nanoparticles may also have induced macropinocytosis. PMID- 28862081 TI - A Matter of Mushroom. PMID- 28862082 TI - Intergenerational Similarity of Religiosity Over the Family Life Course. AB - OBJECTIVES: Research consistently shows that parents influence children's religiosity. However, few studies acknowledge that there is within-group variation in the intergenerational transmission of religiosity. In this article, we examine whether and how congruence in religiosity between generations changes over the family life course and identifies unique parent-child trajectory classes. METHOD: We used eight waves of data from the Longitudinal Study of Generations, including 1,084 parent-child dyads beginning in 1971 when the children were adolescents and young adults, followed up to 2005. Growth mixture models (GMM) were tested. RESULTS: GMM revealed four temporal patterns: stable similar, child weakens, child strengthens, and child returns. Results showed that children who were married were more likely to be members of the child-returns class than members of the stable-similar class. DISCUSSION: Results are discussed in terms of the utility of the separation-individuation process and the life course framework for understanding intergenerational differences and their stability over time. PMID- 28862083 TI - Detection of Salmonella spp. in veterinary samples by combining selective enrichment and real-time PCR. AB - Rapid screening for enteric bacterial pathogens in clinical environments is essential for biosecurity. Salmonella found in veterinary hospitals, particularly Salmonella enterica serovar Dublin, can pose unique challenges for culture and testing because of its poor growth. Multiple Salmonella serovars including Dublin are emerging threats to public health given increasing prevalence and antimicrobial resistance. We adapted an automated food testing method to veterinary samples and evaluated the performance of the method in a variety of matrices including environmental samples ( n = 81), tissues ( n = 52), feces ( n = 148), and feed ( n = 29). A commercial kit was chosen as the basis for this approach in view of extensive performance characterizations published by multiple independent organizations. A workflow was established for efficiently and accurately testing veterinary matrices and environmental samples by use of real time PCR after selective enrichment in Rappaport-Vassiliadis soya (RVS) medium. Using this method, the detection limit for S. Dublin improved by 100-fold over subculture on selective agars (eosin-methylene blue, brilliant green, and xylose lysine-deoxycholate). Overall, the procedure was effective in detecting Salmonella spp. and provided next-day results. PMID- 28862084 TI - Diagnostic Overshadowing of the Psychiatric Population in the Emergency Department: Physiological Factors Identified for an Early Warning System. AB - BACKGROUND: Many people with mental disorders in the United States remain either medically untreated or inadequately treated, which is often attributed to diagnostic overshadowing, a common occurrence across the nation in emergency departments. OBJECTIVE: The aim of this research is to create a tool that supports accurate assessment and distinguishing behavioral symptoms between psychiatric illness and coexisting medical conditions in the emergency department, thus leading to appropriate care and placement. DESIGN: Retrospective cohort design of 133 psychiatric admissions were reviewed between the years 2011 and 2015. RESULTS: Logistic regression retained three factors: age greater than 70 years (odds ratio [OR] = 6.575, 95% confidence interval [CI] = 2.58-16.76), abnormal heart rate (OR = 8.48, 95% CI = 3.39-28.42), and abnormal temperature (OR = 9.82, 95% CI = 3.91-18.40). The three factors were then placed into a screening tool. The presence of each factor equaled 1 point. If the total score was greater than 2, the sensitivity of the tool was 68.7% and the specificity of the tool was 85.8%. CONCLUSIONS: Coexisting medical conditions in the psychiatric population may present as behavioral symptoms; however, the use of a tool that focuses assessment toward medical factors such as abnormal heart rate, abnormal temperature, and advanced age can direct further investigation of behavioral symptoms. PMID- 28862085 TI - Value-based healthcare as a trigger for improvement initiatives. AB - Purpose This study explores four pilot teams' experiences of improvements resulting from the implementation of value-based healthcare (VBHC) at a Swedish University Hospital. The aim of this study is to gain a deeper understanding of VBHC when used as a management strategy to improve patients' health outcomes. Design/methodology/approach An exploratory design was used and qualitative interviews were undertaken with 20 team members three times each, during a period of two years. The content of the interviews was qualitatively analysed. Findings VBHC worked as a trigger for initiating improvements related to processes, measurements and patients' health outcomes. An example of improvements related to patients' health outcomes was solving the problem of patients' nausea. Improvement related to processes was developing care planning and increasing the number of contact nurses. Improvement related to measurements was increasing coverage ratio in the National Quality Registers used, and the development of a new coding system for measurements. VBHC contributed a structure for measurement and for identification of the need for improvements, but this structure on its own was not enough. To implement and sustain improvements, it is important to establish awareness of the need for improvements and to motivate changes not just among managers and clinical leaders directly involved in VBHC projects but also engage all other staff providing care. Originality/value This study shows that although the VBHC management strategy may serve as an initiator for improvements, it is not enough for the sustainable implementation of improvement initiatives. Regardless of strategy, managers and clinical leaders need to develop increased competence in change management. PMID- 28862086 TI - Activating attachment representations impact how we retrieve autobiographical memories. AB - Although much research indicates that proximity to attachment figures confers many psychological benefits, there is little evidence pertaining to how attachment activation may impact autobiographical memory retrieval. Following a negative mood induction to elicit overgeneral autobiographical retrieval, participants (N = 70) were administered an induction in which they imagined a person who is a strong attachment figure or an acquaintance. Participants then completed an autobiographical memory task to retrieve memories in response to neutral and negative cue words. Attachment priming resulted in less distress, increased retrieval of specific memories, and reduced retrieval of categoric memories. These findings indicate that activation of mental representations of attachment figures can impact on the specificity of autobiographical memory retrieval, and extends prevailing models of autobiographical memory by integrating them with attachment theory. PMID- 28862087 TI - Workplace Violence: Not Part of the Job. PMID- 28862088 TI - Advancing Situation Awareness Research. PMID- 28862091 TI - A Feasible and Effective Model for Personal Electronic Usage in Inpatient Psychiatry. PMID- 28862089 TI - Assessment of DNA damage in blood lymphocytes of bakery workers by comet assay. AB - The comet assay is widely used in screening and identification of genotoxic effects of different substances on people in either their working or living environment. Exposure to fuel smoke leads to DNA damage and ultimately different types of cancer. Using a comet assay, the present study aimed to assess peripheral blood lymphocyte DNA damage in people working in bakeries using natural gas, kerosene, diesel, or firewood for fuel compared to those in the control group. The subjects of this study were 55 people in total who were divided into four experimental groups, each of which comprised of 11 members (based on the type of fuel used), and one control group comprised of 11 members. Using CometScore, the subjects' peripheral blood lymphocytes were examined for DNA damage. All bakers, that is, experimental subjects, showed significantly greater peripheral blood lymphocyte DNA damage compared to the individuals in the control group. There was greater peripheral blood lymphocyte DNA damage in bakers who had been using firewood for fuel compared to those using other types of fuel to such an extent that tail moments (um) for firewood-burning bakers was 4.40 +/- 1.98 versus 1.35 +/- 0.84 for natural gas, 1.85 +/- 1.33 for diesel, and 2.19 +/- 2.20 for kerosene. The results indicated that burning firewood is the greatest inducer of peripheral blood lymphocytes DNA damage in bakers. Nonetheless, there was no significant difference in peripheral blood lymphocyte DNA damage among diesel and kerosene burning bakers. PMID- 28862092 TI - Flexible Assertive Community Treatment. PMID- 28862090 TI - Barriers in Case Managers' Roles: A Qualitative Systematic Review. AB - The challenges faced by case managers when implementing case management have received little focus. Several qualitative studies have been published that may be able to shed light on those challenges. This study is a systematic review of qualitative literature to identify barriers case managers have when implementing case management. Five electronic bibliographic databases were systematically searched, and 10 qualitative studies were identified for inclusion in the review which were published from 2007 to 2016. Through thematic synthesis of findings, five themes were identified as barriers to case management implementation: unclear scope of practice, diverse and complex case management activities, insufficient training, poor collaboration with other health-care providers, and client relationship challenges. This review study suggested that standardized evidence-based practical protocols and certification programs may help overcome case managers' barriers and improve case management practices. Health policymakers, case management associations, and health-care management researchers should develop educational and practical supports for case managers. PMID- 28862093 TI - Mental Disorders as a Basis for Physician-Assisted Death. PMID- 28862094 TI - Performance Measures: From Proliferation to Implementation. PMID- 28862096 TI - Suggesting a Medical-Psychiatric Cohort for ACT Treatment: In Reply. PMID- 28862095 TI - Suggesting a Medical-Psychiatric Cohort for ACT Treatment. PMID- 28862097 TI - Mental Disorders as a Basis for Physician-Assisted Death: In Reply. PMID- 28862098 TI - Yoga in the Yard. PMID- 28862099 TI - Association of killer cell immunoglobulin-like receptor (KIR) genes and their HLA ligands with susceptibility to Behcet's disease. AB - OBJECTIVES: Behcet's disease (BD) is a systemic inflammatory disorder with remissions and exacerbations. It is thought that defects in the natural killer (NK) cell repertoire may be involved in BD through killer cell immunoglobulin like receptors (KIRs). This study aimed to evaluate KIR and HLA genes, their interactions in BD patients, and their associations with clinical manifestations. METHOD: The presence or absence of KIR and HLA alleles and genotypes was analysed by polymerase chain reaction sequence-specific primer on genomic DNA of 397 BD patients and 300 healthy controls. RESULTS: None of the KIR genes showed significant effects on BD susceptibility. HLA-C1Asn80 showed a protective effect against BD, whereas HLA-C2Lys80, HLA-B-Bw4Ile80, HLA-B5, and HLA-B51 were associated with a susceptibility risk for BD. In the combination of KIR and HLA genes, the frequencies of HLA genotypes no. 2, 3, 5, and 8, and inhibitory KIR no. 4 were significantly higher in patients than in controls. The frequencies of KIR genotype no. 3 and HLA genotypes no. 1, 4, 6, 7, and 9 were significantly lower in patients than in controls. There were many associations between KIR and HLA genes with clinical features of BD. CONCLUSION: Differences in the frequency of HLA genes, KIR-HLA interactions, and genotypes between BD and healthy controls and their associations with clinical manifestations indicate that NK cells are involved in BD pathogenesis. The observed differences indicated an NK cell activity imbalance in BD patients, and suggest a role of the KIR-HLA repertoire in the development of BD. PMID- 28862100 TI - Arthroscopy-assisted versus standard intramedullary nail fixation in diaphyseal fractures of the humerus. AB - PURPOSE: The aim of this study was to assess applicability of arthroscopic technique in intramedullary nail fixation of humerus shaft fractures and to compare with conventional nailing in terms of its effects on perioperative and postoperative intra-articular complication rates as well as on clinical and functional outcomes. METHODS: This prospective randomized controlled clinical trial included 40 patients (12 females and 28 males) indicated for surgery between either undergo arthroscopy-assisted (Arthroscopy-assisted intramedullary nailing [AIMN]; n = 20) or conventional (Intramedullary nailing [IMN]; n = 20) anterograde intramedullary nailing. Two groups were compared in terms of mean number of fluoroscopic shootings until the guide wire was inserted, time for union, length of hospital stay, and complication rates. Shoulder functions were assessed by Constant and American Shoulder and Elbow Surgeons (ASES) score. RESULTS: Groups did not significantly differ in terms of age, gender, and mechanism of injury, length of hospital stay, union rate, and mean union time ( p > 0.05). Mean ASES and Constant scores were found to be statistically significantly higher in AIMN group than that in IMN group ( p = 0.000 and p = 0.002, respectively). Mean number of fluoroscopic shootings until the guide wire was inserted was 2.15 in AIMN group, which was significantly lower compared to 4.2 of IMN group ( p = 0.000). CONCLUSIONS: Arthroscopy-assisted technique may be an applicable and safe method owing to its cosmetic advantages and more satisfactory postoperative shoulder functions subsequent to less injury to deltoid, rotator cuff, and other soft tissue, as compared to conventional anterograde approach. PMID- 28862101 TI - Efficient use of a limited resource femoral head allograft: A comparison of allograft preparation methods. AB - PURPOSE: The purpose of the study was to compare the yield and compressed volume of femoral head allograft prepared by either hand morselization or a bone mill. METHODS: Twenty human femoral head allografts were donated from a bone bank and morselized by two different methods. The heads were divided in half and split into two sample groups. One group underwent hand morselization with large bone nibblers, while the other was prepared using a bone mill. The volume of graft produced was measured. Ten-gram aliquots of each sample then underwent 30 impactions in a contained cavity, with the volume of graft compression measured. RESULTS: Bone milling yielded approximately 31% more usable graft than hand morselization (81% to 50%; p = 0.0001). There was no difference between the compressed volume of graft prepared by either method ( p = 0.14). CONCLUSION: This study demonstrates the efficacy of preparation of allograft with a bone mill and assists the clinician in determining the yield of graft by the weight of femoral head, thereby potentially minimizing excessive ordering and wastage. PMID- 28862102 TI - Shoulder motion assistance using a single-joint Hybrid Assistive Limb(r) robot: Evaluation of its safety and validity in healthy adults. AB - PURPOSES: To evaluate the feasibility of using the single-joint Hybrid Assistive Limb(r) robot (HAL) to assist with shoulder flexion-extension in healthy adults, and to assess the capacity of the HAL to analyze the bioelectrical signals of muscle activity for shoulder flexion-extension. METHODS: This cross-sectional feasibility study included six healthy adult men with no impairment in shoulder motion. The single-joint HAL was fixed to a custom-designed platform and upper arm attachment, and aligned 3 cm below the acromion process. Vital signs, shoulder fatigue, and shoulder pain were evaluated before and after the shoulder elevation exercise performed with and without the HAL. Activity of selected muscles of the shoulder was recorded using a wireless superficial electromyography device. Shoulder movement was captured using a three-dimensional motion analysis system. RESULTS: The HAL supported smooth flexion-extension of the arm at the shoulder joint, with no negative effects on vital signs, shoulder fatigue, and shoulder pain. The HAL decreased muscle activity levels, with a 55% decrease in trapezius muscle activity. The upward rotation angle of the scapula was significantly lower with the HAL at 120 degrees of shoulder flexion. CONCLUSION: The single-joint HAL provided safe and effective assistance to scapular plane shoulder flexion-extension among healthy adults. PMID- 28862103 TI - View-Dependent Prosopometamorphopsia after Stroke. PMID- 28862104 TI - Regulatory Framework for Conducting Clinical Research in Canada. AB - Research in human subjects is at the core of achieving improvements in health outcomes. For clinical trials, in addition to the peer review of the results before publication, it is equally important to consider whether the trial will be conducted in a manner that generates data of the highest quality and provides a measure of safety for the participating subjects. In Canada, there is no definitive legislation that governs the conduct of research involving human subjects, but a network of regulations at different levels does provide a framework for both principal investigators and sponsors. In this paper, we provide an overview of the federal, provincial and institutional legislation, guidelines and policies that will inform readers about the requirements for clinical trial research. This includes a review of the role of the Food and Drug Regulations under the Food and Drugs Act and the Tri-Council Policy Statement (TCPS2), an overview of provincial legislation across the country, and a focus on selected policies from institutional research ethics boards and public health agencies. Many researchers may find navigation through regulations frustrating, and there is a paucity of information that explains the interrelationship between the different regulatory agencies in Canada. Better understanding the process, we feel, will facilitate investigators interested in clinical trials and also enhance the long-term health of Canadians. PMID- 28862105 TI - Prevalence of Convergence Insufficiency-Type Symptomatology in Parkinson's Disease. AB - BACKGROUND: Individuals with Parkinson's disease (PD) often present with visual symptoms (e.g., difficulty in reading, double vision) that can also be found in convergence insufficiency (CI). Our objective was to estimate the prevalence of CI-type visual symptomatology in individuals with PD, in comparison with controls. METHODS: Participants >=50 years with (n=300) and without (n=300) PD were recruited. They were administered the Convergence Insufficiency Symptom Survey (CISS-15) over the phone. A score of >=21 on the CISS-15, considered positive for CI-type symptomatology, served as the cutoff. Data from individuals (n=87 with, n=94 without PD) who were approached but who reported having a known oculovisual condition were analysed separately. Student's t test and chi-square at the 0.05 level were employed for statistical significance. RESULTS: A total of 29.3% of participants with versus 7.3% without PD presented with a score of >=21 on the CISS-15 (p=0.001). Of the participants having a known oculovisual condition, 39.1% with versus 19.1% without PD presented with a score of >=21 on the CISS-15 (p=0.01). CONCLUSIONS: The prevalence of CI-type visual symptoms is higher in individuals with versus without PD whether or not they have a coexisting oculovisual condition. These results suggest that PD per se places individuals with the disease at greater risk of visual symptomatology. These results further underline the importance of providing regular eye exams for individuals with PD. PMID- 28862106 TI - Efficacy of Vagal Nerve Stimulation for Drug-Resistant Epilepsy: Is it the Stimulation or Medication? AB - BACKGROUND: Vagus nerve stimulation (VNS) therapy has been widely recognized as an alternative for the treatment of drug-resistant epilepsy, although modification of antiepileptic drugs (AEDs) during VNS treatment could explain the improvement in patients. METHODS: We retrospectively assessed the efficacy of VNS in 30 adult patients with epilepsy treated with >6 months of follow-up. The criteria for implantation were the following: (1) not a candidate for resective epilepsy surgery, (2) drug-resistant epilepsy, (3) impairment of quality of life, (4) no other option of treatment, and (5) patients with idiopathic generalized epilepsy who fail to be controlled with appropriate AEDs. We assessed sociodemographics, seizure etiology, seizure classification, and AEDs used during treatment with VNS. We assessed adverse effects and efficacy. Responder rate was defined as >50% seizure improvement from baseline. RESULTS: Thirty patients (females, 18; males, 12; age, 35.1+/-13.3 years) were included. After 6, 12, 24, and 36 months of follow-up, the response rates were: 13/30 (43%), 13/27 (48%), 9/22 (41%), and 8/16 (50%), respectively; none was seizure free. Fifty-seven percent, 33%, 59%, and 81% of patients had changes of medication type or dose at 6, 12, 24, and 36 months respectively. In the majority of patients, the change of medication consisted of an increase in the dose of AEDs. CONCLUSIONS: Our study shows that VNS is an effective therapy, although significant changes in medications were done along with the therapy; therefore, the real effect of VNS could be controversial. PMID- 28862107 TI - Collateral Scoring on CT Angiogram Must Evaluate Phase and Regional Pattern. AB - PURPOSE: We measured anterior cerebral artery (ACA)-middle cerebral artery (MCA) and posterior cerebral artery (PCA)-MCA pial filling on single-phase computed tomography angiograms (sCTAs) in acute ischemic stroke and correlate with the CTA based Massachusetts General Hospital (MGH) and digital subtraction angiography (DSA)-based American Society of Interventional and Therapeutic Neuroradiology (ASITN) score. METHODS: Patients with acute stroke and M1 MCA+/-intracranial internal carotid artery occlusion on baseline CTA were included. Baseline sCTA was assessed for phase of image acquisition. An evaluator assessed collaterals using the Calgary Collateral (CC) Score (measures pial arterial filling in ACA MCA and PCA-MCA regions separately), the CTA-based MGH score, and on DSA using the ASITN score. Infarct volumes were measured on 24- to 48-hour magnetic resonance imaging/ computed tomography. RESULTS: Of 106 patients, baseline sCTA was acquired in early arterial phase in 9.9%, peak arterial in 50.7%, equilibrium in 32.4%, early venous in 5.6%, and late venous in 1.4%. Variance in ACA-MCA collaterals explained only 32% of variance in PCA-MCA collaterals on the CC score (Spearman's correlation coefficient rho [rho]=0.56). Correlation between ACA-MCA collaterals and the MGH score was strong (rho=0.8); correlation between PCA-MCA collaterals and this score was modest (rho=0.54). Correlation between ACA-MCA collaterals and the ASITN score was modest (n=53, rho=0.43); and correlation between PCA-MCA collaterals and ASITN score was poor (rho=0.33). Of the CTA-based scores, the CC Score (Akaike [AIC] 1022) was better at predicting follow-up infarct volumes than was the MGH score (AIC 1029). CONCLUSION: Collateral assessments in acute ischemic stroke are best done using CTA with temporal resolution and by assessing regional variability. ACA-MCA and MCA-PCA collaterals should be evaluated separately. PMID- 28862108 TI - Review of the Incidence of Traumatic Brain Injury. PMID- 28862109 TI - Video Head Impulse Test for Early Diagnosis of Vestibular Neuritis Among Acute Vertigo. AB - BACKGROUND: This study assesses the value of the video head impulse test (vHIT) for early diagnosis of vestibular neuritis (VN) among acute vertigo. METHODS: Thirty-three cases of vestibular neuritis (VN), 96 patients with other acute vertigo (AV), and 50 cases of normal controls used vHIT to quantitatively test a pair of horizontal vestibulo-ocular reflection (VOR) gains, two pairs of vertical VOR gains, and the corresponding three pairs of VOR gain asymmetry. The peculiarity of VOR gains in VN and the differences between VN and other AV, normal controls by vHIT, were collected and analyzed. RESULTS: There were statistically significant differences in the three pairs of VOR gains asymmetry between VN and other AV, and normal controls (P<0.01). The sensitivity was 87.9% and specificity was 94.3% in differentiating VN from normal and other acute vertigo by vHIT. CONCLUSIONS: This study shows vHIT has advantages in the diagnosis of VN in acute vertigo with good sensitivity and specificity and indicates a widespread clinical application. PMID- 28862110 TI - Severe Cerebral Vasospasm and Infarction After Minor Head Trauma. PMID- 28862111 TI - How Can We Improve Education of Breast Surgeons Across Europe? AB - : The proposed global curriculum developed by the American Society of Surgical Oncology (SSO) and the European Society of Surgical Oncology (ESSO) and the textbook: provides a state-of- the- art of breast cancer surgery, complements the syllabus and curriculum of the Union Europeenne des Medecins Specialistes (UEMS) examination in breast surgery/ European Board of Surgery Qualification in Breast Surgery (EBSQinBS) administered by ESSO (1) Knowledge and understanding of the principles of breast cancer incidence, aetiology, risk factors, genetics, premalignant and high-risk lesions, pathology, prognostic and predictive factors, risk prediction models, screening, diagnosis and imaging, breast cancer, oncoplastic, reconstructive breast surgery, axillary surgery and future perspective for this, radiation therapy, neoadjuvant and adjuvant systemic treatment- endocrine-, immuno- and chemotherapy, side effects and toxicities of treatment, locoregional recurrence, follow-up, locally advanced breast cancer, metastatic breast cancer, breast cancer in young and elderly patients, survivor issues, lymphedema, palliative care, chroni pain, body image and sexuality, fertility issues, cognitive functions, etc.) (1) ESSO fellowships: for instance BSSO (Brazilian Society of Surgical Oncology)-ESSO fellowship, ESSO members are being offered the opportunity by the BSSO to apply for a visiting observership in Brazil; ESSO fellowship in Breast Surgery- the fellowship provides further specialised training in the multi-modality clinical care specific to the breast cancer patient and a deeper training in breast cancer research; training fellowships- to allow young surgeons to visit a specialist breast unit in Europe, to help them to expand their experience and learn new techniques; congress fellowships- for each ESSO congress the ESSO Scientific Committee awards a number of fellowship grantsto participants from low-income countries to attend the congress; EYSAC (ESSO Young Surgeons and Alumni Club) research fellowship; SSO/ ESSO fellowshipthrough its partnership with ESSO, SSO provides a grant to attend the SSO Annual Symposium; Reciprocal International Exchange Programmes with Japan, Latin America and North America (2). ESSO courses and masterclasses: expanded portfolio of courses, in- and outside Europe, basic and advanced, international faculty, multidisciplinary approach, learning methods: hands-on with human cadavers, workshops in small groups, live and case demonstrations, interactive sessions, 3D videos (for instance in 2017 ESSO course on ultrasound of breast in Barcelona, advanced course on oncoplastic surgery in Barcelona, advanced course on breast cancer surgery in Naples) (2). Trials: Interantional Nipple- Sparing Mastectomy Registry (INSPIRE), EURECCA (European Cancer Audit) project. The aim of INSPIRE is to provide pooled evidence derived from a prospective collaborative high-quality registry between international centers, oncological safety, patient- reported outcome measures, launched in March, 2016, European Breast Cancer Conference EBCC 10, Amsterdam (2). EXAMINATION: European Board of Surgery Qualification in Breast Surgery (EBSQ in BS): phase 1 eligibility assessment (CV, logbook, references); phase 2- test; phase 3- oral examination with 2 clinical cases and 1 critical review of academic paper. The applicant must hold a current license to practice as a surgeon (general or plastic or gynaecologist), demonstrate work for one year in a breast surgery unit with at least 150 new primary breast cancer cases per year, attended at least one national/ international training course in breast surgery and has attended at least one well recognized international congress. The applicant should present a signed log book for breast surgery with application; published either one paper or book chapter on breast disease Conclusions 1. The need for certified breast units: Standardised techniques by specialist breast surgeons across Europe should be the aim. 2. No man'?s land. Across Europe oncoplastic reconstruction is performed by specialist breast, general or plastic surgeons, sometimes in collaboration with each other. There may be dispute as who should or should not be involved. This needs to be addressed. 3. Oncoplastic reconstruction technique expansion. Significant expansion in number, variety and complexity of available techniques is a fact. A good example would be a 6-fold increase together with a low rate of complications in some Eastern European countries over the last decade 4. CME. European breast surgeons want to improve their skills, as evidenced by fully or overbooked ESSO-endorsed breast surgery courses and other high quality workshops. Applications for the European Examination in Breast Surgery (EBSQBS) continue to increase. PMID- 28862112 TI - Indications of the Magnetic Resonance Method in Breast Pathology. AB - The high incidence of breast cancer is a known fact. The 5-year survival rate for women with correctly treated breast cancer is 90% around the world, and 50% in Romania, respectively. Correct diagnostic evaluation of the breasts allows for a competent therapeutic management. The primary diagnosis of breast cancer includes clinical examination of the breasts, breast ultrasound and mammography. Magnetic resonance imaging (MRI) examination is not a first line type of investigation, but targeted to selected patient groups. MRI exam is indicated in: screening of breast cancer in women at high risk for breast cancer, in cases with equivocal diagnosis or with contradictory diagnoses at mammography-ultrasound examinations, and in patients with mammographically dense breasts. Mammary MRI exam is the best imaging method in assessing the real dimensions of the initial tumour, in the detection of multifocal and multicentric lesions and of nodular axillary post lumpectomy lesions. Also, MRI exam is recommended for preoperative breast cancer staging, for assessment of the breast operated on, and for evaluating chemotherapy. Preoperative MRI assessment of the breast reduces the number of surgical interventions required to obtain surgical negative resection margins, decreases breast cancer recurrence rates, and increases long-term life expectancy (survival). MRI is a potential method for monitoring early responses during neoadjuvant therapy, identifying chemoresistant tumours, and allowing guided re excision, as well as identifying residual tumours after completion of the neoadjuvant therapy course. The exam is very useful in diagnosing mammary pathology in men and is recommended prior to augmentation or reconstructive breast surgery, to appreciate the integrity of the breast implant. PMID- 28862113 TI - Immediate Versus Delayed Breast Reconstruction for Postmastectomy Patients. Controversies and Solutions. AB - When considering breast reconstruction, two main decisions have to be made: optimal timing and appropriate reconstruction technique,that would best suit each patient, while also taking into consideration the complications and risks that these decisions might lead to. By careful patient selection and individualized breast reconstruction approach, the risks and complications of the procedure can be minimized, while attaining successful aesthetic outcomes and high patient satisfaction. Breast reconstruction can be performed in three different settings: immediate reconstruction - at the time of mastectomy; delayed reconstruction " after the completion of the adjuvant treatment and in a delayed-immediate setting that uses both previous methods" includes tissue expansion at the time of mastectomy and definitive reconstruction performed after completion of the adjuvant treatment. The strategies perfected for decades in breast reconstructive surgery have now made breast reconstruction more possible than ever, thus offering patients the chance to recover after a mastectomy procedure with a new reconstructed breast. Although, the choice of breast reconstruction is not adressed by all breast cancer patients, rates are gradually expanding while new and improved techniques are rapidly developing. PMID- 28862114 TI - Immediate-DElayed AutoLogous (IDEAL) Breast Reconstruction with the DIEP Flap. AB - : Background: The most common cancer worldwide in women is breast cancer. The increasing number of cases each year, requires a novel curative approach that can combine oncological treatments and breast reconstruction yielding a pleasing and aesthetic breast that is a definitive and long lasting solution. Thus, the Immediate-DElayed AutoLogous (IDEAL) breast reconstruction principle was created to hold up to the standards of the needs of contemporary women. METHOD: The IDEAL protocol for breast reconstruction was developed in our department in cooperation with our breast surgery unit and describes a two-stage approach that implicates neoadjuvant radio-/ chemotherapy treatment regimes and tumor staging before the mastectomy in order to avoid post-mastectomy radiation. In a second step the breast is then reconstructed with autologous tissue for optimal and natural results. CONCLUSION: More and more patients decide to undergo breast reconstruction after breast cancer. The IDEAL concept offers a life-long and safe solution with a low rate of late complications. PMID- 28862115 TI - New Language and Old Problems in Breast Cancer Radiotherapy. AB - New developments in breast cancer radiotherapy make possible new standards in treatment recommandations based on international guidelines. Developments in radiotherapy irradiation techniques from 2D to 3D-Conformal RT and to IMRT (Intensity Modulated Arc Therapy) make possible to reduce the usual side effects on the organs at risk as: skin, lung, miocard, bone, esophagus and brahial plexus. Dispite of all these progresses acute and late side effects are present. Side effects are as old as the radiotherapy was used. New solutions are available now by improving irradiation techniques. New techniques as sentinel node procedure (SNP) or partial breast irradiation (PBRT) and immediate breast reconstruction with silicon implants (IBRIS) make necessary new considerations regarding the target volume delineations. A new language for definition of gross tumor volume (GTV), clinical target volume (CTV) based on the new diagnostic methods as PET/CT,nonaparticle MRI will have real impact on target delineation and irradiation techniques. "The new common language in breast cancer therapy" would be the first step to improve the endresults and finally the quality of life of the patients. PMID- 28862116 TI - Radiation Therapy Following Breast Conserving Surgery for Ductal Carcinoma in situ: Yes or No? AB - Ductal carcinoma in situ (DCIS) is a non-invasive precursor to breast cancerand represents a heterogenous group of lesions with different malignant potential. Despite several randomized trials, there is still controversy regarding the optimal local treatment for DCIS patients. The addition of radiotherapy after breast conserving surgery approximately halves the local recurrence risk but has no impact on long-term survival. Clinical studies failed to identify a low risk subgroup of DCIS patients treated with breast conserving surgery in whom radiotherapy can be safely omitted. Results of clinical trials of breast conserving surgery radiotherapy are summarized. Treatment decision making in low risk DCIS and current tendencies in the radiotherapy for DCIS are other issues addressed in this paper. PMID- 28862117 TI - Hormone Therapy in Breast Cancer. AB - Hormonal therapy is mandatory for all patients with hormonereceptor- positive breast neoplasms. It is active both in adjuvant and metastatic disease. The only active adjuvant hormonal therapy in pre- and postmenopause is Tamoxifen. The adjuvant treatment duration influences disease-free survival, the risk of a contralateral breast cancer apparition and overall survival. The aromatase inhibitors: Anastrozol, Letrozol, Exemestan are only used in postmenopause. Fulvestrant is used in recurrent disease after or during treatment with Tamoxifen. LHRH analogues are used in premenopausal patients in adjuvantcy and sometimes in case of recurrences. Around 50% of hormonereceptor- positive breast neoplasms are or become resistant to hormone therapy. Some molecules involved in some tumour cellular growth pathways reverse the resistance to hormone therapy (Palbociclib, Everolimus). PMID- 28862118 TI - Review on Practical Approach in Multiple Breast Carcinomas: Does Each Focus Matter? AB - Breast carcinoma is the most frequent form of cancer encountered in women worldwide. In the routine practice, most of breast carcinomas are diagnosed as unifocal, however, a variable proportion is represented by multiple tumor foci. Since data regarding the incidence, definition, morphological and molecular profile, treatment and prognosis of multiple breast carcinomas are currently contradictory we are presenting a practical approach for pathologists dealing with such a lesion, which may display morphological and molecular heterogeneity among multiple foci with an impact on management and prognosis. Multiple tumor foci should be reported separately and taken into account when establishing the treatment. PMID- 28862119 TI - Management of Breast Cancer Locoregional Recurrence. AB - Breast cancer recurrence represents a challenge for clinicians because the management is not standardized and usually requires a multidisciplinary approach. This is the key for a good long term disease control and for a management with curative intent. The local recurrence in breast cancer appears after breast conserving treatment (BCT) or after mastectomy, and the regional recurrence involves the ipsilateral axillary, internal mammary or supraclavicular lymph nodes. Local recurrence prognosis after BCT seems to be better than after mastectomy regarding distant metastases occurrence and overall survival. Prognosis of axillary recurrence is better than prognosis of supraclavicular and internal mammary recurrence. Locoregional recurrence in breast cancer represents rather a marker for the appearance of distant metastases than a determinant factor for them. Management options for locoregional recurrence of cancer require multidisciplinary input decision making and for this reason the multidisciplinary tumor-board (MTD) is very important. Each patient should receive the best individualized oncologic treatment. PMID- 28862120 TI - Does the Surgical Management of the Intercostobrachial Nerve Influence the Postoperatory Paresthesia of the Upper Limb and Life Quality in Breast Cancer Patients? AB - : The aim of our study was to evaluate the extent to which the preservation or the section of the intercostobrachial nerve (ICBN) influences the development of postoperatoryparesthesia and to assess whether the development of paresthesiamay change the patient's life quality after surgical treatment for breast carcinoma. MATERIAL AND METHODS: We performed a nonrandomized retrospective study including 100 patients who underwent axillary lymph node dissection for infiltrating breast carcinoma associated with axillary lymph node metastases. Using a questionnaire we studied the patients general life quality in the postoperative period. For the statistical analysis we used GraphPad Prism, Fisher'?s exact test and Chi square test. Results: 100 patients were included in our study with a mean age of 59.7 years. In 50 cases, the ICBN was preserved (Group 1),while in the remaining 50 cases the ICBN was sectioned during surgery (Group 2). Significantly more patients from Group 2 complained about postoperative paresthesia (p=0.026). In our series, the management of the ICBN cannot be significantly correlated with the impairment of the patients daily activities (p=0.2), sleeping cycle (p=0.2), and general life quality after surgery (p=0.67). We can conclude that the management of ICBN has a great influence on the development of postoperative paresthesia. Although the paresthesia does not have a negative effect on the patient'?s life quality in the postoperative period, in our opinion it is important to preserve the ICBN in order to prevent postoperative paresthesia. PMID- 28862121 TI - Elucidation of a Conserved Proteomic Pattern of Breast Cancer Tissue and Metastatic Axillary Lymph Node. AB - OBJECTIVE: Breast cancer is one of the most devastating cancer types affecting women. For critical decision making regarding the fate of cancerous breast tissue, the assessment of axillary lymph node (ALN) involvement is required. However, such ALN involvement is difficult to predict without surgical intervention. Therefore, an easy predictive test using protein markers may be a desirable approach. In this study, we performed a whole proteome analysis to reveal the presence of a putative biomarker panel using primary breast tumor tissue. Materials and Methods: Proteins were extracted from tumor tissues and were subjected to two dimensional (2D) gel electrophoresis. The resulting gel images were used for inter-gel spot comparisons using PDQuest Advance software. The paterns thus obtained were used for differentiating invasive tumor types from non-invasive ones. Results: The analysis of 2D gel images revealed the presence of 24 conserved protein spots whose intensities were moderately regulated high on the gels. Those protein spots were used to create a conserved 2D pattern spanning a pH range of 4 to 8. CONCLUSION: Protein spots generating a preserved model among pattern between primary breast cancer and its axillary lymph node indicated that a robust and highly reliable proteomic approach, e.g., 2DE may be used to differentiate metastatic forms of breast cancer from non-metastatic ones. PMID- 28862122 TI - Improvement of Breast Cancer Patient Pathway Using EUSOMA Standards and European Guidelines. AB - Queues in hospitals are directly affecting the quality of human life, which should have priority compared to other types of queues. The aim of this paper is to design a future value stream map of the system and patient pathway in terms of quality improvement in order to decrease the non-value added activities for breast cancer patients, doctors and nurses for a radiology unit in a Training and Research University Hospital based in Kocaeli, Turkey. Nowadays, the increased demand versus insufficient sources affect healthcare services due to poor quality with long queues during the diagnosis and treatment processes. For this paper, data were collected from personal observations, information technologies units and authorized employees. Moreover, data tracking and keeping systems are too poor for revealing the current situation. This paper provides an example of a current and future value stream map showing step by step where the bottlenecks are and how it can be improved and what specific benefits it will bring to the healthcare system. In consideration of all these outcomes, it is highly suggested that the hospital apply European Guidelines for quality assurance in breast cancer screening and diagnosis together with the mentioned above improvement suggestions using lean applications. PMID- 28862123 TI - Results of 1-year Diet and Exercise Interventions for ER+/PR+/-/HER2- Breast Cancer Patients Correlated with Treatment Type. AB - PURPOSE: Many breast cancer patients gain weight during chemotherapy and antiestrogenic treatment increasing recurrence, oncologic specific and all-cause mortality risks. Patients and Methods: 165 ER+/PR+/-/HER2- breast cancer patients under antiestrogenic treatment were randomly assigned to follow an at-home diet based on food naturally high in proteins, calcium, probiotics and prebiotics (D), or this diet and 4' isometric exercises (D+Ex) for 1 year. We measured weight (W), body (BF) and visceral fat (VF) using a multi-frequency bioelectrical impedance scale on the 6th and 12th month and we correlated results with chemotherapy, surgery and antiestrogenic medication type. Results were analysed using the Friedman Test, then with Wilcoxon signed-rank tests if Friedman Test was significant. Results: Overall, the patients 1-year results show that both D+Ex and D patients obtained statistically significant weight loss and fat loss. D patients lost 3.3 kg, 3.2% BF and 1% visceral fat. D+Ex patients lost 6.5 kg, 3.3% BF and 2% visceral fat. D+Ex patients obtained statistically significance for W, BF and VF regardless of chemotherapy, surgery or antiestrogenic treatment type. D patients with mastectomy or with aromatase inhibitors lost W, BF and VF. D patients with conservatory surgery, adjuvant or both neoadjuvant and adjuvant chemotherapy and those on Tamoxifen only lost W. D patients with neoadjuvant chemotherapy also lost VF. CONCLUSION: This diet is effective for ER+/PR+/-/HER2- breast cancer patients on antiestrogenic medication. Adding at least a minimal exercise protocol improves patients chances of counteracting sarcopenic obesity. PMID- 28862124 TI - 3D Ultrasound and Virtual Touch(r) in Breast Tumors - Two Clinical Cases. AB - Visualization of infraclinical malignant lesions using 3D breast ultrasound, and differentiation of benign and malignant lesions using ARFI Virtual Touch(r) technology in two patients. 3D ultrasound is useful in early detection of architectural distortions, even in the soft tissue of the breast, and Virtual Touch(r) ARFI differentiates more accurately malignant vs. benign lesions, allowing the patient to be regraded in the BiRADS score (increasing or decreasing the BiRADS score, depending on the situation). PMID- 28862125 TI - Solitary Adrenal Metastases from Breast Invasive Ductal Carcinoma. AB - The usual neoplastic dissease involving suprarenal glands are adrenal metastaes. The majority of suprarenal metastatic disease arise from lung cancer, followed by the stomach and colon cancer, oesophagus, the liver/bile ducts cancer and renal cell carcinoma. Invasive mammary carcinoma usually spreads to the bones, lungs, lymph nodes, liver and the brain. Adrenal gland metastases from invasive no special type carcinoma represents an extremly low rate number of cases. We discuss about a 66 year old patient who presented with a solitary adrenal metastases from triple negative breast invasive carcinoma. The patient underwent total left adrenalectomy in June 2016. No further adjuvants therapies were performed. At the time of writing the patient is in good condition, without any evidence of recurrence. The role of surgical and adjuvant therapy in treating adrenal metastases after breast cancer in survival rate will be determined in future studies. PMID- 28862126 TI - Diffuse Large B Cell Lymphoma in a Male Breast - A Rare Case Report. AB - Primary breast diffuse large B cell lymphoma (PBL) in male patients represents a rare clinical phenomenon and can imitate a breast carcinoma in its clinical presentation, so, therefore, the initial treatment for most patients remains surgery. Prompt diagnosis associating subsequent treatment combining chemotherapy and radiotherapy are of the utmost importance. We herein report a 56 years old male patient diagnosed with diffuse large B cell lymphoma, after clinically presenting with a visible tumor in the left breast and showing no axillary lymphadenopathy. Following clinical diagnosis we performed a breast biopsy with subsequent immunohistochemistry testing. The results showed that the malignant cells stained positive for CD 20, CD 10, and negative for BCL 2, myc and BCL 6, ER/PR with a high proliferation index (Ki 67 90%). The immunohistochemical tests were suggestive for primary large B cell lymphoma of the breast, germinal center type. The patient was submitted to three cycles of R-CHOP (cyclophosphamide, adryamicin, vincristine and prednisolone) and rituximab chemotherapy. Primary diffuse large B cell lymphoma is an extremely unique disease that involves a rather difficult differential diagnosis with a breast carcinoma. A strong index of clinical suspicion is necessary with early diagnosis and treatment. PMID- 28862127 TI - Breast Recurrent Hydatid Cyst Disease. AB - : Introduction: Hydatid cyst is a zoonotic disease seen in endemic areas. It is an important health problem in our country and especially in our Eastern and South-eastern Anatolia Region. Involvement of isolated breast tissue is very rare in hydatid cystdisease. As far as we know, isolated recurrent breast cyst hydatidosis has not been found in the literature. CASE REPORT: We aimed to present the case of a patient who was diagnosed with recurrent isolated cyst hydatid in the same breast, operated on because of hydatid cyst in the right breast 9 years ago. CONCLUSION: A hydatid cyst should be considered, particularly in endemic regions, in the differential diagnosis of cystic masses of the breast. If the patient has previously undergone surgery for breast cyst hydatid disease, recurrent cyst hydatid disease should be considered at the differential diagnosis. PMID- 28862128 TI - Breast Cancer Surgery in Images. AB - As a picture speaks more than a thousand words, we tried to reflect, at least in part, on our surgical day-to-day practice on the 2nd Oncological Surgery Department of "Prof. Dr. Al. Trestioreanu" Bucharest Institute of Oncology in the field of breast cancer. And how could we not talk about imaging in breast cancer, when one of the reasons for low breast cancer mortality at present is early detection, which is performed through imaging investigations. Mammographic screening is recognized as a success in this area (Fig. 1), but moreover, mammary ultrasound, a newer addition to this domain, also allows the detection of infraclinical cancers (Fig. 2). The localization of these infraclinical lesions can be obtained preoperatively by mammographic technique using a harpoon (Fig. 3). Under ultrasound guidance we can not only puncture cysts (Fig. 4), but also perform mammary biopsies for suspicious lesions. PMID- 28862130 TI - Unusual association of ADPKD and bullous emphysema: a case report and literature review. PMID- 28862129 TI - Duration of intravenous antibiotic therapy for children with acute osteomyelitis or septic arthritis: a feasibility study. AB - BACKGROUND: There is little current consensus regarding the route or duration of antibiotic treatment for acute osteomyelitis (OM) and septic arthritis (SA) in children. OBJECTIVE: To assess the overall feasibility and inform the design of a future randomised controlled trial (RCT) to reduce the duration of intravenous (i.v.) antibiotic use in paediatric OM and SA. DESIGN: (1) A prospective service evaluation (cohort study) to determine the current disease spectrum and UK clinical practice in paediatric OM/SA; (2) a prospective cohort substudy to assess the use of targeted polymerase chain reaction (PCR) in diagnosing paediatric OM/SA; (3) a qualitative study to explore families' views and experiences of OM/SA; and (4) the development of a core outcome set via a systematic review of literature, Delphi clinician survey and stakeholder consensus meeting. SETTING: Forty-four UK secondary and tertiary UK centres (service evaluation). PARTICIPANTS: Children with OM/SA. INTERVENTIONS: PCR diagnostics were compared with culture as standard of care. Semistructured interviews were used in the qualitative study. RESULTS: Data were obtained on 313 cases of OM/SA, of which 218 (61.2%) were defined as simple disease and 95 (26.7%) were defined as complex disease. The epidemiology of paediatric OM/SA in this study was consistent with existing European data. Children who met oral switch criteria less than 7 days from starting i.v. antibiotics were less likely to experience treatment failure (9.6%) than children who met oral switch criteria after 7 days of i.v. therapy (16.1% when switch was between 1 and 2 weeks; 18.2% when switch was > 2 weeks). In 24 out of 32 simple cases (75%) and 8 out of 12 complex cases (67%) in which the targeted PCR was used, a pathogen was detected. The qualitative study demonstrated the importance to parents and children of consideration of short- and long-term outcomes meaningful to families themselves. The consensus meeting agreed on the following outcomes: rehospitalisation or recurrence of symptoms while on oral antibiotics, recurrence of infection, disability at follow-up, symptom free at 1 year, limb shortening or deformity, chronic OM or arthritis, amputation or fasciotomy, death, need for paediatric intensive care, and line infection. Oral switch criteria were identified, including resolution of fever for >= 48 hours, tolerating oral food and medicines, and pain improvement. LIMITATIONS: Data were collected in a 6-month period, which might not have been representative, and follow-up data for long term complications are limited. CONCLUSIONS: A future RCT would need to recruit from all tertiary and most secondary UK hospitals. Clinicians have implemented early oral switch for selected patients with simple disease without formal clinical trial evidence of safety. However, the current criteria by which decisions to make the oral switch are made are not clearly established or evidence based. FUTURE WORK: A RCT in simple OM and SA comparing shorter- or longer-course i.v. therapy is feasible in children randomised after oral switch criteria are met after 7 days of i.v. therapy, excluding children meeting oral switch criteria in the first week of i.v. therapy. This study design meets clinician preferences and addresses parental concerns not to randomise prior to oral switch criteria being met. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28862131 TI - Three cases of type-1 complex regional pain syndrome after elective total hip replacement. AB - Complex regional pain syndrome (CRPS) constitutes an atypical cause of pain after orthopaedic procedures. To our knowledge, there is a paucity of literature reporting this syndrome after total hip arthroplasty (THR), since only two case reports have been published. We thenceforth describe the clinical outcome of three cases of type-1 CRPS developed after elective THR, two of them initially diagnosed with secondary osteoarthritis whereas the remaining one presented a sequel of a failed osteosynthesis that required conversion to THR. Remission of disease was found at an average seven months (range: 4-9). Medical treatment involved a combined therapy of pain management, bisphosphonates and intense physical therapy. One patient was additionally treated with a corticosteroid blockade of his right sympathetic lumbar ganglia. None of the patients required surgical treatment. At final follow-up, physical examinations and imaging were negative for disease. PMID- 28862133 TI - Treatment patterns and outcomes for patients with locally advanced basal cell carcinoma before availability of Hedgehog pathway inhibitors: a retrospective chart review. AB - : Understanding the molecular basis of basal cell carcinoma (BCC) has led to development of Hedgehog pathway inhibitors (HPIs) for patients with advanced forms of BCC (aBCC). A practical definition of aBCC as a distinct disease entity is unavailable, and epidemiological information is limited. To conduct the RONNIE study to describe characteristics, treatment patterns, and outcomes of patients with aBCC during the period preceding HPI introduction, as well as results from patients with locally advanced BCC (laBCC). A retrospective chart review was conducted using data from adult patients with a new diagnosis of laBCC between 1st January 2005 and 31st December 2010. The study period was 1st January 2005 to 31st December 2011 to allow for inclusion of at least 12 months of follow-up information for all patients. RESULTS: Treatment data were available for 106/117 patients. Radiation and excisional surgery were the most common first-line treatment options (43.4% and 23.5% of patients, respectively). Patients typically received multiple subsequent treatments; no apparent trend or pattern was observed. Complete visual response, partial visual response, and stable disease were obtained in 51.9%, 25.9%, and 11.1% of patients, respectively, after first line surgery, and in 53.7%, 22.0%, and 9.8%, respectively, after first-line radiation. Median progression-free survival after first-line treatment was 32.1 months. Median overall survival was 78.8 months. These data represent a baseline for laBCC before HPIs became part of the treatment algorithm. The observed heterogeneity of treatment patterns highlights the lack of an established standard treatment for laBCC before HPIs were available. PMID- 28862132 TI - The complex relationship of exposure to new Plasmodium infections and incidence of clinical malaria in Papua New Guinea. AB - : The molecular force of blood-stage infection (molFOB) is a quantitative surrogate metric for malaria transmission at population level and for exposure at individual level. Relationships between molFOB, parasite prevalence and clinical incidence were assessed in a treatment-to-reinfection cohort, where P.vivax (Pv) hypnozoites were eliminated in half the children by primaquine (PQ). Discounting relapses, children acquired equal numbers of new P. falciparum (Pf) and Pv blood stage infections/year (Pf-molFOB = 0-18, Pv-molFOB = 0-23) resulting in comparable spatial and temporal patterns in incidence and prevalence of infections. Including relapses, Pv-molFOB increased >3 fold (relative to PQ treated children) showing greater heterogeneity at individual (Pv-molFOB = 0-36) and village levels. Pf- and Pv-molFOB were strongly associated with clinical episode risk. Yearly Pf clinical incidence rate (IR = 0.28) was higher than for Pv (IR = 0.12) despite lower Pf-molFOB. These relationships between molFOB, clinical incidence and parasite prevalence reveal a comparable decline in Pf and Pv transmission that is normally hidden by the high burden of Pv relapses. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02143934. PMID- 28862134 TI - Adult female acne treated with spironolactone: a retrospective data review of 70 cases. AB - The prevalence of acne in the adult population is increasing, particularly in women. Spironolactone regulates sebaceous gland activity by blocking androgen receptor. To evaluate retrospectively the efficacy of spironolactone in women with acne. Data from 70 women of at least 20 years, treated for their acne between 2010 and 2015 with low-dose spironolactone (<=150 mg/day), were analysed. Remission was defined by the number of retentional lesions inferior or equal to five and inflammatory lesions inferior or equal to two on the face. Variables influencing the response were studied using the Cox model. The mean age was 31.3 years; 39 (56%) women had prior courses of isotretinoin and 53 (76%) had an oral contraception prior to treatment. Remission data from a median treatment period of six months (95% CI: 4-9) were obtained from 47 (71%) women. Markers for a positive response to spironolactone were a high number of inflammatory lesions at inclusion (OR: 1.08; 95% CI: 1.03-1.13; p = 0.001) and relapse with previous isotretinoin (OR: 2.46; 95% CI: 1.09-5.54; p = 0.03). The marker for a negative response was an association with oral contraceptives containing first or second generation progestin (OR: 2.77; 95% CI: 1.35-5.71; p = 0.005). This retrospective data analysis confirms that the use of low doses of spironolactone is a valuable alternative in women with acne in whom oral isotretinoin has failed. Moreover, the analysis shows that first and second-generation oral contraceptives decrease the efficacy of spironolactone, confirming the interest of using two third or fourth-generation oral contraceptives. PMID- 28862136 TI - Serum anti-oxidative reserves during cellulitis: a pilot study. PMID- 28862137 TI - Editorial: What's new this month? PMID- 28862138 TI - Dermpath & Clinic: Giant trichoblastoma of the leg. PMID- 28862139 TI - And next... Adnexa: Subungual lipoma. PMID- 28862140 TI - sQuiz your knowledge: Chronic ulceration of the palm. PMID- 28862141 TI - sQuiz your knowledge: Extensive facial scarring: an unusual presentation in a neuropsychiatric patient. PMID- 28862142 TI - Cancer screening for older people: to screen or not to screen. AB - In this scoping review, the evidence of the benefits of screening older people for the five most common types of cancer in Hong Kong, namely colorectal, lung, breast, liver, and prostate cancers, is discussed. Although cancer treatments can be extensive and a good prognosis is less likely if cancer is diagnosed at a late stage, screening programmes for older people in primary care remain a matter of contention. The general recommendation for the screening of older people is to adopt an individualised approach that takes account of not only age but also co morbidity, life expectancy, harms and benefits, and patient's preference. PMID- 28862144 TI - Beating 'Guangdong cancer': a review and update on nasopharyngeal cancer. AB - Once endemic in southern China, nasopharyngeal cancer is becoming less prevalent in Hong Kong. This is probably due to a better understanding of the risk factors associated with the disease, its genomic landscape, advances in radiotherapy technology, and development of effective systemic agents. More specifically, the close relationship between Epstein-Barr virus and nasopharyngeal cancer opens up the possibility of using Epstein-Barr virus DNA as a biomarker for early detection and monitoring of the disease. On the other hand, the looming genomic data for nasopharyngeal cancer aid in the development of powerful biomarkers and promising targeted therapy. Clinical use of a combination of radiotherapy and chemotherapy continues to increase, while the development of immunotherapy, such as checkpoint inhibitors, offers hope in improving treatment outcome. PMID- 28862143 TI - Immunoglobulin G4-related disease in Hong Kong: clinical features, treatment practices, and its association with multisystem disease. AB - INTRODUCTION: Immunoglobulin G4-related disease remains an under-recognised and evolving disease. Local data are sparse and previous publications have been limited to individual case reports or case series only. We conducted this study to review the clinical features, treatment practices, and factors associated with multisystem involvement in Hong Kong. We described the clinical features and treatment modalities of the largest cohort of immunoglobulin G4-related disease in our locality thus far. METHODS: We retrospectively evaluated all patients with immunoglobulin G4-related disease between January 2003 and December 2015 in Queen Mary Hospital and combined this with patient data extracted from previous local publications. We analysed the clinical features, treatment practices, and factors associated with the number of organ systems involved. RESULTS: A total of 104 patients (55 from Queen Mary Hospital and 49 from literature review) were identified. Patients were predominantly older men (mean [standard deviation] age, 61.9 [12.7] years; male-to-female ratio=3:1) and 94.4% had elevated pre-treatment serum immunoglobulin G4 levels. Hepatobiliary and pancreatic system (40.4%), salivary gland (33.7%), lymph node (29.8%), and eye (19.2%) were the most common organ systems involved. Lymphadenopathy was associated with glucocorticoid use (odds ratio=2.65; 95% confidence interval, 1.08-6.54; P=0.034). Pre-treatment serum immunoglobulin G4 levels correlated with the number of organ systems involved (beta=0.347; P=0.004) and, specifically, more associated with patients having salivary gland involvement than those without (mean, 1109 mg/dL vs 599 mg/dL; P=0.012). CONCLUSION: We identified pre-treatment serum immunoglobulin G4 to be associated with multisystem disease, especially with salivary gland involvement, highlighting its potential for disease prognostication and monitoring. Increased physician awareness and multidisciplinary efforts are required for early diagnosis and optimal management of this masquerading disease. PMID- 28862145 TI - Expanded newborn metabolic screening programme in Hong Kong: a three-year journey. AB - INTRODUCTION: No universal expanded newborn screening service for inborn errors of metabolism is available in Hong Kong despite its long history in developed western countries and rapid development in neighbouring Asian countries. To increase the local awareness and preparedness, the Centre of Inborn Errors of Metabolism of the Chinese University of Hong Kong started a private inborn errors of metabolism screening programme in July 2013. This study aimed to describe the results and implementation of this screening programme. METHODS: We retrieved the demographics of the screened newborns and the screening results from July 2013 to July 2016. These data were used to calculate quality metrics such as call-back rate and false-positive rate. Clinical details of true-positive and false negative cases and their outcomes were described. Finally, the call-back logistics for newborns with positive screening results were reviewed. RESULTS: During the study period, 30 448 newborns referred from 13 private and public units were screened. Of the samples, 98.3% were collected within 7 days of life. The overall call-back rate was 0.128% (39/30 448) and the false-positive rate was 0.105% (32/30 448). Six neonates were confirmed to have inborn errors of metabolism, including two cases of medium-chain acyl-coenzyme A dehydrogenase deficiency, one case of carnitine-acylcarnitine translocase deficiency, and three milder conditions. One case of maternal carnitine uptake defect was diagnosed. All patients remained asymptomatic at their last follow-up. CONCLUSION: The Centre of Inborn Errors of Metabolism has established a comprehensive expanded newborn screening programme for selected inborn errors of metabolism. It sets a standard against which the performance of other private newborn screening tests can be compared. Our experience can also serve as a reference for policymakers when they contemplate establishing a government-funded universal expanded newborn screening programme in the future. PMID- 28862146 TI - Analytic approach to magneto-strain tuning of electronic transport through a graphene nanobubble: perspectives for a strain sensor. AB - We consider the scattering of Dirac particles in graphene due to the superposition of an external magnetic field and mechanical strain. As a model for a graphene nanobubble, we find exact analytical solutions for single-particle states inside and outside a circular region submitted to the fields. Finally, we obtain analytical expressions for the scattering cross-section, as well as for the Landauer current through the circular region. Our results provide a fully analytical treatment for electronic transport through a graphene nanobubble, showing that a combination of a physical magnetic field and strain leads to valley polarization and filtering of the electronic current. Moreover, our analytical model provides an explicit metrology principle to measure strain by performing conductance experiments under a controlled magnetic field imposed over the sample. PMID- 28862147 TI - Experimental investigation of biomimetic self-pumping and self-adaptive transpiration cooling. AB - Transpiration cooling is an effective way to protect high heat flux walls. However, the pumps for the transpiration cooling system make the system more complex and increase the load, which is a huge challenge for practical applications. A biomimetic self-pumping transpiration cooling system was developed inspired by the process of trees transpiration that has no pumps. An experimental investigation showed that the water coolant automatically flowed from the water tank to the hot surface with a height difference of 80 mm without any pumps. A self-adaptive transpiration cooling system was then developed based on this mechanism. The system effectively cooled the hot surface with the surface temperature kept to about 373 K when the heating flame temperature was 1639 K and the heat flux was about 0.42 MW m-2. The cooling efficiency reached 94.5%. The coolant mass flow rate adaptively increased with increasing flame heat flux from 0.24 MW m-2 to 0.42 MW m-2 while the cooled surface temperature stayed around 373 K. Schlieren pictures showed a protective steam layer on the hot surface which blocked the flame heat flux to the hot surface. The protective steam layer thickness also increased with increasing heat flux. PMID- 28862148 TI - Frequency upconversion and fluorescence intensity ratio method in Yb3+-ion sensitized Gd2O3:Er3+-Eu3+ phosphors for display and temperature sensing. AB - Near infrared (NIR) to visible frequency upconversion emission studies in Er3+ Eu3+/Er3+-Eu3+-Yb3+ co-doped/tri-doped Gd2O3 phosphors prepared by the co precipitation technique have been explored under 980 nm laser diode radiation. The developed phosphors were characterized with the help of XRD, FE-SEM and FTIR analysis. No upconversion (UC) emission was found in the Eu3+-doped Gd2O3 phosphor. UC emission from Eu3+ ions along with Er3+ ions was observed in Er3+ Eu3+ and Er3+-Eu3+-Yb3+ co-doped/tri-doped phosphors. The UC emission arising from the Er3+ and Eu3+ ions was enhanced several times due to the incorporation of Yb3+ ions. The processes involved in the UC emission were obtained on the basis of the effect of energy transfer/sensitization through the Yb3+ -> Er3+ -> Eu3+ process. The red/green intensity ratio was improved from 0.16 to 1.50 and 1.01 to 1.50 for Er3+-Eu3+-Yb3+ tri-doped phosphors as compared to the Er3+-doped and Er3+-Yb3+ co-doped phosphors, respectively, at a fixed pump power density. A UC fluorescence intensity ratio (FIR)-based temperature sensing study was performed in the prepared Er3+-Eu3+-Yb3+ tri-doped Gd2O3 phosphors for green upconversion emission bands in the 300 K-443 K temperature range. A maximum sensor sensitivity of about ~0.0043 K-1 at 300 K was achieved for the synthesized tri-doped phosphors upon excitation with a 980 nm laser diode. The colour coordinates lying in the green-yellow region are invariant, with variation in pump power density and temperature. The observed results support the utility of the prepared tri-doped phosphors in optical temperature sensing, display devices and NIR to visible upconverters. PMID- 28862149 TI - Electrical and thermoelectric transport properties of two-dimensional fermionic systems with k-cubic spin-orbit coupling. AB - We investigate effect of k-cubic spin-orbit interaction on electrical and thermoelectric transport properties of two-dimensional fermionic systems. We obtain exact analytical expressions of the inverse relaxation time (IRT) and the Drude conductivity for long-range Coulomb and short-range delta scattering potentials. The IRT reveals that the scattering is completely suppressed along the three directions theta = (2n+1)pi/3 with n=1,2,3. We also obtain analytical results of the thermopower and thermal conductivity at low temperature. The thermoelectric transport coefficients obey the Wiedemann-Franz law, even in the presence of k-cubic Rashba spin-orbit interaction (RSOI) at low temperature. In the presence of quantizing magnetic field, the signature of the RSOI is revealed through the appearance of the beating pattern in the Shubnikov de Haas (SdH) oscillations of thermopower and thermal conductivity in low magnetic field regime. The empirical formulae for the SdH oscillation frequencies accurately describe the locations of the beating nodes. The beating pattern in magnetothermoelectric measurement can be used to extract the spin-orbit coupling constant. PMID- 28862150 TI - Sonogashira cross-coupling over Au(1 1 1): from UHV to ambient pressure. AB - We have studied the reaction of phenylacetylene (PA) with chloro-, bromo-, and iodobenzene on the Au(1 1 1) surface as a model system for the gold-catalysed Sonogashira cross-coupling. Both ultrahigh vacuum-based and ambient pressure x ray photoelectron spectroscopy show that iodo- and chlorobenzene (IB and CB) undergo the cross-coupling reaction towards diphenylacetylene. Bromobenzene (BB), in contrast, does not react in the UHV experiments. Further, at ambient pressure signs are found for poisoning of the Au(1 1 1) surface by a carbon species formed in the reaction. The understanding obtained in the reaction experiments are based on a thorough investigation of the adsorption of PA, IB, CB, and BB on the Au(1 1 1) surface by soft x-ray absorption spectroscopy and temperature-dependent x-ray photoelectron spectroscopy. In particular, the experiments provide the orientation of the intact adsorbates with respect to the surfaces at liquid nitrogen temperature. Dissociation in the temperature regime between -80 and 15 degrees C is observed for iodo- and chlorobenzene, but not for BB, in agreement with that only IB and CB, but not BB, react with PA to form diphenylacetylene. The difference is tentatively attributed to a difference in surface orientation of the different halobenzenes. PMID- 28862151 TI - Relaxation dynamics of a driven two-level system coupled to a Bose-Einstein condensate: application to quantum dot-dipolar exciton gas hybrid systems. AB - We develop a microscopic theory for the relaxation dynamics of an optically pumped two-level system (TLS) coupled to a bath of weakly interacting Bose gas. Using Keldysh formalism and diagrammatic perturbation theory, expressions for the relaxation times of the TLS Rabi oscillations are derived when the boson bath is in the normal state and the Bose-Einstein condensate (BEC) state. We apply our general theory to consider an irradiated quantum dot coupled with a boson bath consisting of a two-dimensional dipolar exciton gas. When the bath is in the BEC regime, relaxation of the Rabi oscillations is due to both condensate and non condensate fractions of the bath bosons for weak TLS-light coupling and pre dominantly due to the non-condensate fraction for strong TLS-light coupling. Our theory also shows that a phase transition of the bath from the normal to the BEC state strongly influences the relaxation rate of the TLS Rabi oscillations. The TLS relaxation rate is approximately independent of the pump field frequency and monotonically dependent on the field strength when the bath is in the low temperature regime of the normal phase. Phase transition of the dipolar exciton gas leads to a non-monotonic dependence of the TLS relaxation rate on both the pump field frequency and field strength, providing a characteristic signature for the detection of BEC phase transition of the coupled dipolar exciton gas. PMID- 28862152 TI - Tumour control in ion beam radiotherapy with different ions in the presence of hypoxia: an oxygen enhancement ratio model based on the microdosimetric kinetic model. AB - Few attempts have been made to include the oxygen enhancement ratio (OER) in treatment planning for ion beam therapy, and systematic studies to evaluate the impact of hypoxia in treatment with the beam of different ion species are sorely needed. The radiobiological models used to quantify the OER in such studies are mainly based on the dose-averaged LET estimates, and do not explicitly distinguish between the ion species and fractionation schemes. In this study, a new type of OER modelling, based on the microdosimetric kinetic model, taking into account the specificity of the different ions, LET spectra, tissues and fractionation schemes, has been developed. The model has been benchmarked with published in vitro data, HSG, V79 and CHO cells in aerobic and hypoxic conditions, for different ion irradiation. The model has been included in the simulation of treatments for a clinical case (brain tumour) using proton, lithium, helium, carbon and oxygen ion beams. A study of the tumour control probability (TCP) as a function of oxygen partial pressure, dose per fraction and primary ion type has been performed. The modelled OER depends on both the LET and ion type, also showing a decrease for an increased dose per fraction with a slope that depends on the LET and ion type, in good agreement with the experimental data. In the investigated clinical case, a significant increase in TCP has been found upon increasing the ion charge. Higher OER variations as a function of dose per fraction have also been found for low-LET ions (up to 15% varying from 2 to 8 Gy(RBE) for protons). This model could be exploited in the identification of treatment condition optimality in the presence of hypoxia, including fractionation and primary particle selection. PMID- 28862153 TI - Zirconia based Ho3+-Yb3+ codoped upconverting nanophosphors for green light emitting devices applications. AB - Photoluminescence study of the Ho3+-Yb3+ codoped ZrO, AlZrO and YZrO nanophosphors, synthesized by chemical co-precipitation method, upon excitation at 450 and 980 nm radiations have been performed. An improvement of about ~4.5 times in the downconversion emission intensity of green band corresponding to the 5F4, 5S2 -> 5I8 transition for codoped YZrO nanophosphors compared to ZrO codoped nanophosphors has been observed. On varying the pump power density upon 980 nm excitation the colour tunability in the codoped YZrO nanophosphors has been observed. UC emission intensity of the green band arising from the Ho3+ ion in the codoped YZrO nanophosphors is enhanced about ~22 times compared to that of the codoped ZrO nanophosphors. The absorption and UC emission study for the codoped YZrO nanophosphors dispersed in different biologically compatible solvents viz. water, methanol, ethanol and dimethyl sulfoxide (DMSO) has been performed. The green UC emission intensity of about ~1.3 and ~1.7 times for the efficient codoped YZrO nanophosphors dispersed in methanol compared to that dispersed in water and DMSO respectively has been observed. The absorption spectra of an efficient upconverting YZrO nanophosphors dispersed in methanol exhibit no change with the passage of time. PMID- 28862154 TI - Stalk-length-dependence of the contractility of Vorticella convallaria. AB - Vorticella convallaria is a sessile protozoan of which the spasmoneme contracts on a millisecond timescale. Because this contraction is induced and powered by the binding of calcium ions (Ca2+), the spasmoneme showcases Ca2+-powered cellular motility. Because the isometric tension of V. convallaria increases linearly with its stalk length, it is hypothesized that the contractility of V. convallaria during unhindered contraction depends on the stalk length. In this study, the contractile force and energetics of V. convallaria cells of different stalk lengths were evaluated using a fluid dynamic drag model which accounts for the unsteadiness and finite Reynolds number of the water flow caused by contracting V. convallaria and the wall effect of the no-slip substrate. It was found that the contraction displacement, peak contraction speed, peak contractile force, total mechanical work, and peak power depended on the stalk length. The observed stalk-length-dependencies were simulated using a damped spring model, and the model estimated that the average spring constant of the contracting stalk was 1.34 nN um-1. These observed length-dependencies of Vorticella's key contractility parameters reflect the biophysical mechanism of the spasmonemal contraction, and thus they should be considered in developing a theoretical model of the Vorticella spasmoneme. PMID- 28862155 TI - Osteogenesis effects of strontium-substituted hydroxyapatite coatings on true bone ceramic surfaces in vitro and in vivo. AB - To develop bioactive bone graft materials that can induce rapid bone regeneration, a novel biomaterial was synthesized by coating true bone ceramic (TBC) substrates with strontium-substituted nano-hydroxyapatites (SrHA) (Sr concentrations of 0%, 10%, 40%, 100%) through a sol-gel dip-coating approach. All coated TBC scaffolds retained the inherent natural trabecular structure, porosity, compressive strength and simultaneously possessed a micro/nanotopography SrHA layer on the substrate surface. The dimension of the deposited crystal increased and the density of the deposited apatite particles became sparse with increasing Sr content, but a unique HA crystalline phase was observed under all conditions. The modified TBC scaffolds significantly enhanced the adhesion, proliferation, and osteogenic differentiation of MC3T3-E1 osteoblasts in vitro. Particularly, the Sr10-TBC group (10 mol% Sr2+ in apatite coating) revealed the highest osteogenic efficacy over the other groups. Three dimensional CT imaging and histological evaluations on a bilateral critical-sized rabbit radial defect model for 12 weeks showed significant bone formation in the Sr10-TBC implants. The new bone area ratios of the Sr10-TBC group were significantly higher than that of the TBC group. Additionally, Sr10-TBC implants showed faster degradability compared with raw TBC implants during the 12 weeks of implantation. The results indicate that TBC modification with 10% SrHA coating stimulated osteogenesis and could be a promising biomaterial for future bone defect regeneration. PMID- 28862156 TI - Manipulation of native point defect behavior in rutile TiO2 via surfaces and extended defects. AB - Semiconductor surfaces offer efficient pathways for exchanging native point defects with the underlying bulk. For rutile TiO2(1 1 0), isotopic self-diffusion studies of oxygen have suggested that the surface may act as a source for Oi while simultaneously acting as a sink for titanium interstitials Tii. Through self-diffusion measurements with labeled Ti as well as O, the present work develops a more complete picture of the diffusion-reaction network involving Oi and Tii, complete with the surface acting as a source for whichever elements are available from the gas phase and a sink for elements that are not. The picture points to the importance of extended defects such as platelets and crystallographic shear planes as reservoirs of Oi and Tii, acting as net sources or sinks of these species depending upon specific conditions. The results exemplify the combined roles of surfaces and extended defects in regulating point defect behavior even in macroscopic metal oxide crystals, and point to specific strategies for manipulating that behavior intentionally. PMID- 28862157 TI - Modelling the collective response of heterogeneous cell populations to stationary gradients and chemical signal relay. AB - The directed motion of cell aggregates toward a chemical source occurs in many relevant biological processes. Understanding the mechanisms that control this complex behavior is of great relevance for our understanding of developmental biological processes and many diseases. In this paper, we consider a self propelled particle model for the movement of heterogeneous subpopulations of chemically interacting cells towards an imposed stable chemical gradient. Our simulations show explicitly how self-organisation of cell populations (which could lead to engulfment or complete cell segregation) can arise from the heterogeneity of chemotactic responses alone. This new result complements current theoretical and experimental studies that emphasise the role of differential cell cell adhesion on self-organisation and spatial structure of cellular aggregates. We also investigate how the speed of individual cell aggregations increases with the chemotactic sensitivity of the cells, and decreases with the number of cells inside the aggregates. PMID- 28862158 TI - Facile modification of electrospun fibrous structures with antifouling zwitterionic hydrogels. AB - Electrospinning technology can easily produce different shaped fibrous structures, making them highly valuable to various biomedical applications. However, surface contamination of biomolecules, cells, or blood has emerged as a significant challenge to the success of electrospun devices, especially artificial blood vessels, catheters and wound dressings etc. Many efforts have been made to resist the surface non-specific biomolecules or cells adsorption, but most of them require complex pre-treatment processes, hard-to-remove metal catalysts or rigorous reaction conditions. In addition, the stability of antifouling coatings, especially in complex conditions, is still a major concern. In this work, inspired by the interpenetrating polymer network and reinforced concrete structure, an efficient and facile strategy for modifying hydrophobic electrospun meshes and tubes with antifouling zwitterionic hydrogels has been introduced. The resulting products could efficiently resist the adhesion of proteins, cells, or even fresh whole blood. Meanwhile, they could maintain the shapes and mechanical strength of the original electrospun structures. Furthermore, the hydrogel structures could retain stable in a physiological condition for at least 3 months. This paper provided a general antifouling and hydrophilicity surface modification strategy for various fibrous structures, and could be of great value for many biomedical applications where antifouling properties are critical. PMID- 28862160 TI - Construction of MoS2/Si nanowire array heterojunction for ultrahigh-sensitivity gas sensor. AB - Few-layer MoS2 thin films were synthesized by a two-step thermal decomposition process. In addition, MoS2/Si nanowire array (SiNWA) heterojunctions exhibiting excellent gas sensing properties were constructed and investigated. Further analysis reveals that such MoS2/SiNWA heterojunction devices are highly sensitive to nitric oxide (NO) gas under reverse voltages at room temperature (RT). The gas sensor demonstrated a minimum detection limit of 10 ppb, which represents the lowest value obtained for MoS2-based sensors, as well as an ultrahigh response of 3518% (50 ppm NO, ~50% RH), with good repeatability and selectivity of the MoS2/SiNWA heterojunction. The sensing mechanisms were also discussed. The performance of the MoS2/SiNWA heterojunction gas sensors is superior to previous results, revealing that they have great potential in applications relating to highly sensitive gas sensors. PMID- 28862161 TI - Epitaxial strain driven crossover from Drude to Drude-Smith terahertz conductivity dynamics in LaNiO3 thin films. AB - We investigate the hetero-epitaxial strain driven low-energy charge dynamics in compressive and tensile strained LaNiO3 thin films employing terahertz (THz) time domain spectroscopy. The complex THz conductivity exhibits a crossover from Drude type metallic behavior for the compressive film to a Drude-Smith type disordered behavior for the tensile film. This demonstration of strain driven crossover in THz conductivity dynamics, while the two films have qualitatively similar dc conductivities, (i) brings out the potential of THz technology in distinguishing between similar dc electronic phases and (ii) suggests that LaNiO3 under compressive strain is a better candidate for applications as electrodes in oxides electronics. PMID- 28862162 TI - Philip Coppens (1930-2017). PMID- 28862163 TI - Davide Viterbo (1939-2017). PMID- 28862164 TI - Close-packed structure dynamics with finite-range interaction: computational mechanics with individual layer interaction. AB - This is the second contribution in a series of papers dealing with dynamical models in equilibrium theories of polytypism. A Hamiltonian introduced by Ahmad & Khan [Phys. Status Solidi B (2000), 218, 425-430] avoids the unphysical assignment of interaction terms to fictitious entities given by spins in the Hagg coding of the stacking arrangement. In this paper an analysis of polytype generation and disorder in close-packed structures is made for such a Hamiltonian. Results are compared with a previous analysis using the Ising model. Computational mechanics is the framework under which the analysis is performed. The competing effects of disorder and structure, as given by entropy density and excess entropy, respectively, are discussed. It is argued that the Ahmad & Khan model is simpler and predicts a larger set of polytypes than previous treatments. PMID- 28862165 TI - Mathematical aspects of molecular replacement. IV. Measure-theoretic decompositions of motion spaces. AB - In molecular-replacement (MR) searches, spaces of motions are explored for determining the appropriate placement of rigid-body models of macromolecules in crystallographic asymmetric units. The properties of the space of non-redundant motions in an MR search, called a 'motion space', are the subject of this series of papers. This paper, the fourth in the series, builds on the others by showing that when the space group of a macromolecular crystal can be decomposed into a product of two space subgroups that share only the lattice translation group, the decomposition of the group provides different decompositions of the corresponding motion spaces. Then an MR search can be implemented by trading off between regions of the translation and rotation subspaces. The results of this paper constrain the allowable shapes and sizes of these subspaces. Special choices result when the space group is decomposed into a product of a normal Bieberbach subgroup and a symmorphic subgroup (which is a common occurrence in the space groups encountered in protein crystallography). Examples of Sohncke space groups are used to illustrate the general theory in the three-dimensional case (which is the relevant case for MR), but the general theory in this paper applies to any dimension. PMID- 28862166 TI - The wavevector substar group in reciprocal space and its representation. AB - A new concept of the wavevector substar group is established which, in the study of translational symmetry breaking of a crystal, only considers the particular arms of the wavevector star taking part in the phase transition; this is in contrast with the traditional Landau theory which considers all of the arms of the wavevector star. It is shown that this new concept can be used effectively to investigate the interesting physical properties of crystals associated with translational symmetry breaking. It is shown that studies on complicated phase transitions related to reducible representations, such as those in perovskite KMnF3 multiferroics and the high-temperature superconductor La2/3Mg1/2W1/2O3 (La4Mg3W3O18), are much simplified by the new concept. The theory of the wavevector substar group and its representation is a powerful mathematical tool for the study of various symmetry-breaking phenomena in solid-state crystals. PMID- 28862167 TI - Real-time detection and resolution of atom bumping in crystallographic models. AB - A basic principle in crystal structure determination is that there should be proper distances between adjacent atoms. Therefore, detection of atom bumping is of fundamental significance in structure determination, especially in the direct space method where crystallographic models are just randomly generated. Presented in this article is an algorithm that detects atom bonding in a unit cell based on the sweep and prune algorithm of axis-aligned bounding boxes and running in the O(n log n) time bound, where n is the total number of atoms in the unit cell. This algorithm only needs the positions of individual atoms in the unit cell and does not require any prior knowledge of existing bonds, and is thus suitable for modelling of inorganic crystals where the bonding relations are often unknown a priori. With this algorithm, computation routines requiring bonding information, e.g. anti-bumping and computation of coordination numbers and valences, can be performed efficiently. As an example application, an evaluation function for atom bumping is proposed, which can be used for real-time elimination of crystallographic models with unreasonably short bonds during the procedure of global optimization in the direct-space method. PMID- 28862168 TI - Accelerated scattering of convex polyhedra. AB - The formulas for the minimum (minn) and maximum (maxn) names in the classes of convex n-acra (i.e. n-vertex polyhedra) are found for any n. The asymptotic behaviour (as n -> infinity) for maxn+1/maxn, minn+1/minn, minn+1/maxn and maxn/minn is established. They characterize in detail the accelerated scattering of [minn, maxn] ranges on a real line. PMID- 28862169 TI - Three-dimensional Intralunate Arteries Visualization with Red Lead (Pb3O4) Angiography. AB - BACKGROUND: The etiology of Kienbock's disease is controversial, and the blood supply is a possible pathogenic factor. The red lead (Pb3O4) angiography with micro-computed tomography (micro-CT) of lunate to investigate intralunate arteries has rarely been reported. This study aimed to investigate a new, reasonable, and simplified technique to study the intraosseous arterial pattern of normal lunates. METHODS: This study investigated the intraosseous arterial pattern of six normal cadaveric lunates through Pb3O4injection and three dimensional reconstruction with micro-CT. The intraosseous arteries of all specimens were clearly enhanced. The data of enhanced arteries and nutrient foramina were shown as median (Q1, Q3) and analyzed with Wilcoxon signed-rank test. RESULTS: The mean number of total nutrient foramina was 2.00 (1.75, 2.00) on the palmar side and 3.50 (2.50, 4.25) on the dorsal side. The number with enhanced arteries on the palmar side was 1.00 (0.75, 2.00) and on the dorsal side was 3.50 (1.75, 4.00). There were no significant differences between the number of nutrient foramina on the palmar and dorsal sides of the lunates, no matter the total number or enhanced arteries. The intraosseous arterial pattern in normal lunates can be classified into three types: the dominate stems from the palmar side, from the dorsal side, and from both sides with anastomosis. CONCLUSIONS: The Pb3O4angiography with micro-CT is a simplified, quicker, and reliable method to study intraosseous arteries. PMID- 28862170 TI - Lumbar Scoliosis Induction in Juvenile Dogs by Three-dimensional Modulation of Spinal Growth Using Nickel-Titanium Coil Springs. AB - BACKGROUND: Current treatments for scoliosis have some defects and complications. To study spinal deformities and test novel scoliosis treatments, many animal models of scoliosis have been developed. These models applied a single load to the spine and could not precisely modulate the spinal growth in different dimensions. In this study, we applied posterior tethering in various directions with the application of nickel-titanium (NT) coil springs in dog's spine to modulate spinal growth in the coronal, sagittal, and transverse planes and create a scoliosis model possess curves that mimic adolescent idiopathic scoliosis (AIS) three dimensionally. METHODS: Scoliosis was surgically induced in eight 8-week old female dogs (weight: 1.95-2.30 kg) using bone screws and NT coil springs. The deformity was induced through the placement of posterior NT coil springs that tethered the spine by bone screw fixation. All dogs were monitored with serial radiographs to document changes in deformities. RESULTS: All experimental animals developed scoliotic curves convex to the left in the lumbar segment. The mean coronal Cobb angle was 18.0 degrees immediately postoperatively and 54.5 degrees at 22 weeks. The mean lordosis increased from 6.2 degrees postoperatively to 35.0 degrees at final follow-up. Apical axial rotation increased from 4.5 degrees postoperatively to 31.2 degrees at 22 weeks. CONCLUSIONS: With the application of NT springs in dogs that allowed posterior tethering in various directions, lumbar spinal deformity was achieved in three planes: coronal, sagittal, and transverse planes. Notably, the lumbar spine in surgically treated dogs developed lordoscoliosis with obvious rotation and the curves mimic AIS three dimensionally well. This method allows lumbar scoliosis to develop without deep dissection of muscle and maintains the essential anatomical elements along the spinal curve. Moreover, the spinal growth modulation technique could yield information that would provide a basis for developing novel early-stage treatments for children with scoliosis. PMID- 28862171 TI - Depression: Why to talk? PMID- 28862172 TI - Do we need better hepatitis B vaccines? PMID- 28862173 TI - When treating rheumatoid arthritis be vigilant for influenza (& pneumonia): Don't ignore, don't neglect. PMID- 28862174 TI - Genital tuberculosis in females. AB - The morbidity and mortality due to tuberculosis (TB) is high worldwide, and the burden of disease among women is significant, especially in developing countries. Mycobacterium tuberculosis bacilli reach the genital tract primarily by haematogenous spread and dissemination from foci outside the genitalia with lungs as the common primary focus. Genital TB in females is a chronic disease with low grade symptoms. The fallopian tubes are affected in almost all cases of genital TB, and along with endometrial involvement, it causes infertility in patients. Many women present with atypical symptoms which mimic other gynaecological conditions. A combination of investigations is needed to establish the diagnosis of female genital TB (FGTB). Multidrug anti-TB treatment is the mainstay of management and surgery may be required in advanced cases. Conception rates are low among infertile women with genital TB even after multidrug therapy for TB, and the risk of complications such as ectopic pregnancy and miscarriage is high. More research is needed on the changing trends in the prevalence and on the appropriate methods for diagnosis of FGTB. PMID- 28862175 TI - Methylenetetrahydrofolate reductase A1298C genetic variant& risk of schizophrenia: A meta-analysis. AB - BACKGROUND & OBJECTIVES: Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate metabolism, whose role in schizophrenia is debatable. Numerous case-control studies have investigated the association of MTHFR A1298C polymorphism with schizophrenia, but results are controversial. The aim of the present study was to find the association between MTHFR A1298C gene polymorphism and schizophrenia. METHODS: PubMed, Google Scholar, Science Direct and Springer link databases were searched for case-control association studies in which MTHFR A1298C polymorphism was investigated as a risk factor for schizophrenia. In all, 19 studies with 4049 cases and 5488 controls were included in this meta-analysis. Odds ratios (ORs) with 95 per cent confidence intervals (CIs) were used as an association measure. RESULTS: The results of meta-analysis reported a significant association between A1298C polymorphism and schizophrenia risk in overall comparisons in all genetic models (C vs. A: OR=1.13, 95% CI=1.01-1.27, P=0.02; CC vs. AA: OR=1.20, 95% CI=1.03-1.39, P=0.02; AC vs. AA: OR=1.13, 95% CI=1.03-1.23, P=0.009; AC+CC vs. AA: OR=1.14, 95% CI=1.02-1.24, P=0.002; CC vs. AA+AC: OR=1.17, 95% CI=1.01-1.35, P=0.04). INTERPRETATION & CONCLUSIONS: MTHFR A1298C polymorphism was found to be a risk factor for schizophrenia and might have played a significant role in the pathogenesis of schizophrenia. PMID- 28862176 TI - Index-TB guidelines: Guidelines on extrapulmonary tuberculosis for India. AB - Extrapulmonary tuberculosis (EPTB) is frequently a diagnostic and therapeutic challenge. It is a common opportunistic infection in people living with HIV/AIDS and other immunocompromised states such as diabetes mellitus and malnutrition. There is a paucity of data from clinical trials in EPTB and most of the information regarding diagnosis and management is extrapolated from pulmonary TB. Further, there are no formal national or international guidelines on EPTB. To address these concerns, Indian EPTB guidelines were developed under the auspices of Central TB Division and Directorate of Health Services, Ministry of Health and Family Welfare, Government of India. The objective was to provide guidance on uniform, evidence-informed practices for suspecting, diagnosing and managing EPTB at all levels of healthcare delivery. The guidelines describe agreed principles relevant to 10 key areas of EPTB which are complementary to the existing country standards of TB care and technical operational guidelines for pulmonary TB. These guidelines provide recommendations on three priority areas for EPTB: (i) use of Xpert MTB/RIF in diagnosis, (ii) use of adjunct corticosteroids in treatment, and (iii) duration of treatment. The guidelines were developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, which were evidence based, and due consideration was given to various healthcare settings across India. Further, for those forms of EPTB in which evidence regarding best practice was lacking, clinical practice points were developed by consensus on accumulated knowledge and experience of specialists who participated in the working groups. This would also reflect the needs of healthcare providers and develop a platform for future research. PMID- 28862177 TI - Effect of disease-modifying antirheumatic drug therapy on immune response to trivalent influenza vaccine in rheumatoid arthritis. AB - BACKGROUND & OBJECTIVES: Patients with autoimmune rheumatic diseases may be at an increased risk of infection due to disease and use of disease-modifying antirheumatic drug (DMARD) therapy. The present study was done to evaluate the immune response to influenza vaccination in patients with rheumatoid arthritis (RA). METHODS: Fifty one RA patients on stable methotrexate (MTX) therapy (>=15 mg/wk), 51 newly diagnosed DMARD-naive RA patients and 45 healthy controls received a single dose of inactivated seasonal trivalent influenza vaccine. Blood samples were collected just prior to and four weeks after vaccination. Pre- and post-vaccination antibody titres against the three virus strains were measured by hemagglutination inhibition assay. The impact of age, gender, DMARD treatment and pre-vaccination seroprotection on response to the vaccine was assessed by binary logistic regression analysis for each of the virus strains. RESULTS: Pre vaccination antibody titres were found to be high in the three study groups for all influenza strains, except for Yamagata strain, the titres for which were low in healthy controls. Trivalent influenza vaccination was found to be safe and stimulated a good antibody response in all study groups. On regression analysis, there was no association of age, gender or MTX therapy with vaccine response, except for Yamagata strain where healthy controls had higher positive immune response (P=0.008; odds ratio - 3.37, 95% confidence interval: 1.36-8.32). INTERPRETATION & CONCLUSIONS: Our results indicated that influenza vaccination was safe in RA patients with no detrimental effect on disease activity. MTX therapy at a dose >=15 mg/wk did not affect the vaccine response. Presence of high pre-vaccination seroprotective antibody levels in the study population indicates the need for re-examination of recommended annual influenza vaccination in such subgroups of population. PMID- 28862178 TI - Spectrum of prenatally detected central nervous system malformations: Neural tube defects continue to be the leading foetal malformation. AB - BACKGROUND & OBJECTIVES: Prenatal diagnosis of malformations is an important method of prevention and control of congenital anomalies with poor prognosis. Central nervous system (CNS) malformations amongst these are the most common. The information about the prevalence and spectrum of prenatally detected malformations is crucial for genetic counselling and policymaking for population based preventive programmes. The objective of this study was to study the spectrum of prenatally detected CNS malformations and their association with chromosomal abnormalities and autopsy findings. METHODS: This retrospective study was conducted in a tertiary care hospital in north India from January 2007 to December 2013. The details of cases with prenatally detected CNS malformations were collected and were related with the foetal chromosomal analysis and autopsy findings. RESULTS: Amongst 6044 prenatal ultrasonographic examinations performed; 768 (12.7%) had structural malformations and 243 (31.6%) had CNS malformations. Neural tube defects (NTDs) accounted for 52.3 per cent of CNS malformations and 16.5 per cent of all malformations. The other major groups of prenatally detected CNS malformations were ventriculomegaly and midline anomalies. Chromosomal abnormalities were detected in 8.2 per cent of the 73 cases studied. Foetal autopsy findings were available for 48 foetuses. Foetal autopsy identified additional findings in eight foetuses and the aetiological diagnosis changed in two of them (4.2%). INTERPRETATION & CONCLUSIONS: Amongst prenatally detected malformations, CNS malformations were common. NTD, which largely is a preventable anomaly, continued to be the most common group. Moreover, 60 per cent of malformations were diagnosed after 20 weeks, posing legal issues. Chromosomal analysis and foetal autopsy are essential for genetic counselling based on aetiological diagnosis. PMID- 28862179 TI - Influence of single photon emission computed tomography (SPECT) reconstruction algorithm on diagnostic accuracy of parathyroid scintigraphy: Comparison of iterative reconstruction with filtered backprojection. AB - BACKGROUND & OBJECTIVES: Preoperative localization of parathyroid lesions is essential for improving the results in patients with primary hyperparathyroidism. The purpose of this study was to evaluate retrospectively the value of technetium 99m (Tc-99m) methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) and to compare the diagnostic accuracy of iterative reconstruction (IR) and filtered backprojection (FBP) reconstruction algorithms about localization of parathyroid lesions. METHODS: Forty four patients with primary hyperparathyroidism, in whom histopathological correlation could be performed, were included in the study. Dual-phase Tc-99m parathyroid scintigraphy was performed 20 and 120 min after injection of 740 MBq Tc-99m MIBI in all patients. Tomographic images were acquired 120 min after the administration of radiopharmaceutical. The SPECT data were evaluated using an IR as well as a FBP algorithm. In 23 of 44 patients, SPECT acquisitions were performed in 64*64 matrix; in the remaining 21 patients, tomographic data were collected in 128*128 matrix. The imaging results were compared with pathological findings and sensitivities of both reconstruction algorithms, and planar views were calculated. RESULTS: Using planar MIBI scans, abnormal parathyroid glands were correctly localized in 75 per cent of the cases. Sensitivity increased to 77 per cent using SPECT with FBP and to 84 per cent with IR. When the sensitivities were calculated according to the acquisition matrix, these were 95 per cent (20/21) and 85 per cent (18/21) for IR and FBP, respectively in patients in whom 128*128 matrix was used. The sensitivities were lower in patients who were imaged with 64*64 matrix; these were calculated as 74 per cent (17/23) and 70 per cent (16/23) with IR and FBP, respectively. INTERPRETATION & CONCLUSIONS: Our findings showed that compared to planar scintigraphy, Tc-99m MIBI SPECT was more sensitive diagnostic modality in the detection of abnormal parathyroid tissues. Image quality and sensitivity may be improved further when larger matrices with IR are used instead of FBP algorithm. PMID- 28862180 TI - Red cell alloimmunization & role of advanced immunohaematological support in liver transplantation. AB - BACKGROUND & OBJECTIVES: Transfusion support forms an integral part of liver transplantation programme. Advanced immunohaematology services are required to deal with complex serological problems that can complicate transfusion therapy in these patients. Here, we report on red cell alloimmunization and presence of alloimmunization in donors and patients undergoing liver transplantation in a tertiary care hospital in north India. METHODS: Records of 1433 liver transplants performed from January 2009 to March 2015 were retrieved and reviewed. Antibody screening was performed both for liver donors, and recipients and antibody identification was performed for the screen-positive patients. RESULTS: Of the 1433 liver recipients, 32 (2.3%) developed antibodies. Seventeen patients had one or more alloantibodies, five had autoantibodies with an underlying alloantibody and 10 had only autoantibodies in their plasma. The overall alloimmunization rate was 1.5 per cent with 25 alloantibodies identified in 22 patients. Anti-E was the most common specificity identified. INTERPRETATION & CONCLUSIONS: The presence of alloantibodies can complicate transfusion therapy in patients undergoing liver transplantation, who are already at a high risk of being heavily transfused owing to the nature of surgery and the haemostatic dysfunction from chronic liver disease. Therefore, screening for irregular red cell alloantibodies combined with a rational blood transfusion policy may be essential for these patients. PMID- 28862182 TI - Does endoscopic thoracic sympathectomy through clipping procedure have early effects on electrocardiographic parameters? AB - BACKGROUND & OBJECTIVES: Hyperhidrosis is a pathologic condition of excessive sweating in amounts greater than physiologic needs. Endoscopic thoracic sympathectomy (ETS) is a globally accepted treatment modality for primary palmar and axillary hyperhidrosis. ETS also has distinctive effects on the heart, circulatory and respiratory systems. In this study early effects of ETS on electrocardiographic (ECG) parameters of hyperhidrosis patients were evaluated. METHODS: Twelve-lead ECGs were performed on 72 patients who were free from cardiovascular, metabolic, neurological and pulmonary diseases and underwent planned ETS because of hyperhidrosis, before and after the procedure within the first 24 h. Heart rate (HR), PR, QT, corrected QT (QTc), QTc/Tpeak-Tend (TpTe) intervals, P-wave and QTc/TpTe dispersions were compared by ECG. RESULTS: A total of 72 patients (24.1+/-6.0 yr, 17 female) were included in the study. The pre operative HR of patients was significantly higher than post-operative HR of patients (73.8+/-12.8 vs. 68.1+/-12.6 beats/ min; P<0.001). The QTc dispersion (QTcd) durations of pre-operative patients were significantly longer than those of post-operative patients (51.5+/-6.3 vs. 44.9+/-5.6 msec; P<0.01). The TpTe dispersion value of pre-operative patients was significantly (P<0.001) higher than that of post-operative patients. INTERPRETATION & CONCLUSIONS: Our study showed that ETS through clipping procedure had positive effects on the mechanisms of arrhythmia by reducing HR, QTcd, TpTe and TpTe dispersion parameters of ECG in early periods in hyperhidrosis patients. PMID- 28862181 TI - Identification of a novel homozygous mutation in transmembrane channel like 1 (TMC1) gene, one of the second-tier hearing loss genes after GJB2 in India. AB - BACKGROUND & OBJECTIVES: Hearing impairment is a common and heterogeneous sensory disorder in humans. Among about 90 genes, which are known to be associated with hearing impairment, mutations in the GJB2 (gap junction protein beta 2) gene are the most prevalent in individuals with hereditary hearing loss. Contribution of the other deafness-causing genes is relatively poorly understood. Here, we present our findings on two families with transmembrane channel like 1 (TMC1) gene variants of the 47 families with nonsyndromic hearing loss (NSHL) studied. METHODS: Forty seven families including 26 consanguineous families with at least two hearing impaired children and one normal hearing child and 21 non consanguineous families having at least three hearing impaired children and one normal hearing child were enrolled for this study. Genetic linkage studies were carried out in 41 families that were GJB2 (Connexin 26) negative. Seven polymorphic short tandem repeat markers at the DFNB7/11 locus were studied employing fluorescently labelled markers. RESULTS: A novel homozygous missense mutation c.1283C>A (p.Ala428Asp) was identified co-segregating with hearing loss. This change results in substitution of a highly conserved polar alanine to a charged aspartic acid and is predicted to be deleterious. In addition, a previously reported nonsense mutation, p.R34X in TMC1, was found. INTERPRETATION & CONCLUSIONS: While mutations in TMC1 are not as common a cause of NSHL as those in GJB2, TMC1 should be considered for diagnostic investigations in cases of NSHL in GJB2-negative families. PMID- 28862183 TI - Acute effects on cardiovascular oscillations during controlled slow yogic breathing. AB - BACKGROUND & OBJECTIVES: Breathing exercises are believed to modulate the cardiovascular oscillations in the body. To assess the validity of the assumption and understand the underlying mechanism, the key autonomic regulatory parameters such as heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity (BRS) were recorded during controlled slow yogic breathing. Alternate nostril breathing (ANB) was selected as the yogic manoeuvre. METHODS: Twelve healthy volunteers (age 30+/-3.8 yr) participated in the study. ANB was performed at a breathing frequency of 5 breaths per minute (bpm). In each participant, the electrocardiogram, respiratory movements, beat-to-beat BP and end-tidal carbon dioxide were recorded for five minutes each: before, during and after ANB. The records were analyzed for HRV, BPV and BRS. RESULTS: During ANB, HRV analysis showed significant increase in the standard deviation of all NN intervals, low-frequency (LF) component, LF/HF (low frequency/high frequency) ratio and significant decrease in the HF component. BPV analysis showed a significant increase in total power in systolic BPV (SBPV), diastolic BPV (DBPV) and mean BPV. BRS analysis showed a significant increase in the total number of sequences in SBPV and DBPV and significant augmentation of alpha-LF and reduction in alpha-HF. The power spectrum showed a dominant peak in HRV at 0.08 Hz (LF component) similar to the respiratory frequency. The acute short-term change in circulatory control system declined immediately after the cessation of slow yogic breathing (ANB) and remained elevated in post-ANB stage as compared to the pre ANB. INTERPRETATION & CONCLUSIONS: Significant increase in cardiovascular oscillations and baroreflex recruitments during-ANB suggested a dynamic interaction between respiratory and cardiovascular system. Enhanced phasic relationship with some delay indicated the complexity of the system. It indicated that respiratory and cardiovascular oscillations were coupled through multiple regulatory mechanisms, such as mechanical coupling, baroreflex and central cardiovascular control. PMID- 28862184 TI - Ocular distribution of antioxidant enzyme paraoxonase & its alteration in cataractous lens & diabetic retina. AB - BACKGROUND & OBJECTIVES: The enzyme paraoxonase (PON), an antioxidant enzyme that has both arylesterase and thiolactonase activity, is well studied in cardiovascular diseases. Although a few studies have shown altered PON activity in ocular diseases such as age-related macular degeneration and diabetic retinopathy, but the tissue-wise expression of PON in its three gene forms has not been studied. This study was conducted to see the ocular distribution of PON for any altered expression in ocular pathologies such as in cataract and diabetes mellitus. METHODS: Immunohistochemistry (IHC) of the ocular tissues was done for localizing all three forms of the PON in the human donor eyeballs. The PON arylesterase (PON-AREase) and thiolactonase (PON-HCTLase) activities were determined by spectrophotometry in kinetic mode, and the mRNA expression of the PON genes (PON1-3) was determined by reverse transcription-polymerase chain reaction. RESULTS: IHC showed the presence of both PON1 and 2 in all the ocular tissues and PON3 was seen only in retina. The mRNA expression analysis showed that PON2 and PON3 were present in all the tissues, whereas PON1 was seen only in ciliary and retina. Both the PON-AREase and PON-HCTLase activities were detected in all ocular tissues and was in the order of lens>retina>choroid>ciliary body>iris. The expression and activity were studied in cataractous lens and in diabetic retina of the donor eyes. A significant decrease in PON-AREase activity was seen in cataractous lens (P<0.05) but not in diabetic retina, and there was an increase in PON- HCTLase activity (P<0.05) only in diabetic retina. Bioinformatic studies and in vitro experiments indicated that advanced glycation end products (AGE) such as carboxymethyl -lysine might decrease the PON- AREase activity of the PON. INTERPRETATION & CONCLUSIONS: Distribution of PON enzyme and its activity in ocular tissues is reported here. The study revealed maximal PON activity in lens and retina, which are prone to higher oxidative stress. Differential activities of PON were observed in the lens and retinal tissues from cataractous and diabetic patients, respectively. PMID- 28862185 TI - Health-related quality of life in Indian children: A community-based cross sectional survey. AB - BACKGROUND & OBJECTIVES: There are limited data on health-related quality of life (HRQOL) related to Indian children. The objective of this study was to construct a generic HRQOL reference for children aged 2-18 yr from a community setting. METHODS: The study was a community-based cross-sectional survey. A total of 719 children/adolescents in the age group of 2-18 yr were enrolled using stratified random cluster sampling. A total of 40 clusters (cluster size 18) were selected for the study. The data contained child self-report and parent proxy report from healthy children and their parents/caretakers. The Pediatric Quality of Life Inventory 4.0 (PedsQL4.0) Generic Core Scale was used to collect HRQOL data. Questionnaires were self-administered for parents and children aged 8-18 yr. In the age group of five to seven years, parents assisted the children in filling questionnaires. RESULTS: The mean HRQOL total scores from child self-report and parent proxy report were 87.50+/-11.10 and 90.10+/-9.50 respectively, for children aged 2-18 yr. Social functioning had the highest scores and emotional functioning had the lowest scores for the entire sample and subgroups. The mean values for HRQOL in the current study were significantly different from the reference study for both child (87.39 vs. 83.91, P<0.001) and parent proxy reports (90.03 vs. 82.29, P<0.001) when compared between children aged 2-16 yr. INTERPRETATION & CONCLUSIONS: The study provided reference values for HRQOL in healthy children and adolescents from Kerala, India, that appeared to be different from existing international reference. Similar studies need to be done in different parts of India to generate a country-specific HRQOL reference for Indian children. PMID- 28862186 TI - Food significantly reduces plasma concentrations of first-line anti-tuberculosis drugs. AB - BACKGROUND & OBJECTIVES: Concomitant feeding and anti-tuberculosis (TB) drug administration are likely to reduce nausea and enhance compliance to treatment. However, food could lower plasma drug concentrations. This study was undertaken to examine the effect of food on two-hour plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA), and pharmacokinetics of these drugs in adult TB patients. METHODS: Newly diagnosed adult TB patients were recruited from the Revised National Tuberculosis Control Programme (RNTCP) treatment centres in Chennai Corporation, Chennai, India. Two-hour post-dosing plasma concentrations were determined in 25 patients, and a semi-intensive pharmacokinetic study was undertaken in six patients. RMP, INH and PZA concentrations were determined by high-performance liquid chromatography. RESULTS: The geometric mean two-hour concentrations with food and under fasting conditions were 2.2 and 5.5 MUg/ml for RMP (P<0.001), 3.9 and 11.3 MUg/ml for INH (P<0.001), and 18.0 and 28.2 MUg/ml for PZA (P<0.001), respectively. Drug administration with food caused the plasma concentration to decrease by 50, 45 and 34 per cent for RMP, INH and PZA, respectively. Significant decreases in peak concentrations and exposures of drugs and delay in time to attain peak concentrations of drugs when taken with food were also observed. INTERPRETATION & CONCLUSIONS: Our findings showed that food lowered anti-TB drug concentrations significantly and delayed absorption. Patients may be explained the beneficial effects of taking anti-TB drugs in a fasting state and advised to do so. There is a need for more research on optimization of dosing to maximize efficacy and safety of currently used drugs. PMID- 28862187 TI - Seroprevalence of transplacentally acquired measles antibodies in HIV-exposed versus HIV-unexposed infants at six months of age. AB - BACKGROUND & OBJECTIVES: Measles infection is reported to be more severe, prolonged and associated with a higher complication rate in children with HIV infection. Reports indicate that infants born to HIV-infected women [HIV exposed infants (HEI)] may be more vulnerable to measles. The World Health Organization recommends measles vaccination starting at six months of age in these infants who may be HIV-infected themselves. However, in India, they are given measles vaccination at nine months of age like all other infants. In this study, the seroprevalence of transplacentally acquired measles antibodies was compared in HEI and unexposed infants (HUnI) at six months of age and the proportion of HEI undergoing seroconversion after immunization with measles vaccine was assessed. METHODS: In this prospective longitudinal study, measles IgG antibodies were estimated in serum of 49 HEI and 50 HUnI aged 6-7 months. Measles vaccine was then administered to HEI. Assessment for measles IgG antibodies was repeated 8-12 wk post-immunization. RESULTS: Measles IgG antibodies were detected in two of 49 (4.1%) HEI and 16 of 50 (32%) HUnI. HEI were 11 times more likely to lack measles antibodies as compared to HUnI (odds ratio=11.05, 95% confidence interval=2.989 40.908). Post-vaccination, seroprevalence of measles antibodies increased to 38.5 per cent (PInterpretation & conclusions: Most HEI lacked measles antibodies at six months age and were, therefore, more vulnerable to measles than HUnI. Seroconversion in response to a single dose of measles vaccine administered at six months age was low in these infants, signifying the need of additional dose(s) of measles/measles-containing vaccine. PMID- 28862188 TI - Interferon-gamma-inducible protein-10 in chronic hepatitis C: Correlations with insulin resistance, histological features & sustained virological response. AB - BACKGROUND & OBJECTIVES: One of the multiple factors contributing to virological response in chronic hepatitis C (CHC) is interferon-gamma-inducible protein-10 (IP-10). Its level reflects the status of interferon-stimulated genes, which in turn is associated with virological response to antiviral therapy. The aim of this study was to evaluate the role of serum IP-10 levels on sustained virological response (SVR) and the association of this parameter with insulin resistance (IR) and liver histology. METHODS: Two hundred and three consecutive biopsy proven CHC patients were included in the study. Serum levels of IP-10 were determined using ELISA method. IR was evaluated by homeostasis model assessment IR (HOMA-IR). Histological features were assessed invasively by liver biopsy and noninvasively using FibroTest, ActiTest and SteatoTest. Predictive factors for SVR and their interrelations were assessed. RESULTS: A cut-off value for IP-10 of 392 pg/ml was obtained to discriminate between responders and non-responders. SVR was obtained in 107 patients (52.70%). Area under the receiver operating characteristic curve for SVR was 0.875 with a sensitivity of 91.6 per cent, specificity 74.7 per cent, positive predictive value 80.3 per cent and negative predictive value 88.7 per cent. Higher values of IP-10 were associated with increasing stages of fibrosis (P<0.01) and higher grades of inflammation (P=0.02, P=0.07) assessed morphologically and noninvasively through FibroTest and ActiTest. Significant steatosis and IR were also associated with increased levels of IP-10 (P=0.01 and P=0.02). In multivariate analysis, IP-10 levels and fibrosis stages were independently associated with SVR. INTERPRETATION & CONCLUSIONS: Our findings showed that the assessment of serum IP-10 level could be a predictive factor for SVR and it was associated with fibrosis, necroinflammatory activity, significant steatosis and IR in patients with chronic HCV infection. PMID- 28862189 TI - Typical & atypical enteropathogenic Escherichia coli in diarrhoea & their role as carrier in children under five. AB - BACKGROUND & OBJECTIVES: Multidrug-resistant enteropathogenic Escherichia coli (EPEC) is responsible for a large number of cases of infantile diarrhoea in developing countries, causing failure in treatment with consequent health burden and resulting in a large number of deaths every year. This study was undertaken to determine the proportion of typical and atypical EPEC in under five children with diarrhoea and controls, their function as a carriage and to identify virulent genes associated with them. METHODS: During the study period, 120 stool samples including 80 from controls children were collected and analyzed for the presence of EPEC using standard bacteriological methods. Isolates were subjected to antimicrobial testing by disc diffusion method. Isolates confirmed as E. coli by phenotypic method were further tested for the presence of attaching and effacing (eae) and bundle-forming pilus (bfpA) genes by real-time SYBR Green based polymerase chain reaction. RESULTS: All isolates were tested for the presence of EPEC. The frequency of typical EPEC was 20 and 16.25 per cent whereas the frequency of atypical EPEC strains was 5 and 23.75 per cent in patients and controls, respectively (PbfpA was seen in 45 and 18.75 per cent isolates of diarrhoeal patients and controls, respectively. INTERPRETATION & CONCLUSIONS: Our results showed that typical EPEC was a common cause of diarrhoea, but at the same time, atypical EPEC was emerging as colonizers in the intestine of children with and without diarrhoea in and around Delhi. Children can be considered asymptomatic carriers of these pathogens and can transmit them to other susceptible children. Adequate steps need to be taken to stop these strains from developing and spreading further. PMID- 28862190 TI - Seroprevalence of cytomegalovirus in donors & opportunistic viral infections in liver transplant recipients. AB - BACKGROUND & OBJECTIVES: Opportunistic virus infections are common in liver transplant (LT) recipients. There is a risk of developing infection with cytomegalovirus (CMV) and herpes-related viruses such as herpes simplex virus-1 and 2 (HSV-1 & 2), Epstein-Barr virus (EBV) and Varicella Zoster virus (VZV), reactivation of infection and recurrent infection. This study was conducted to determine CMV seropositivity in donors and its influence on LT recipients and seropositivity of CMV, HSV-1 and 2, EB viral capsid antigen (EBVCA) and VZV in LT recipients and their reactivation. METHODS: Pre-transplant data for IgG and IgM for CMV (and donor), HSV-1 and -2, EB viral capsid antigen (VCA) and VZV were available for 153 recipients. All recipients were on ganciclovir or valganciclovir prophylaxis for three months after LT. For reactivation rates, findings of post-transplant CMV quantitative reverse transcription polymerase chain reaction (CMV qRT-PCR) assay were associated with pre-transplant serological profile. RESULTS: Of the 153 LT recipients, 131 were men (85.6%). The median age of LT was 46 yr (range 9 months-71 yr). Overall exposure to CMV was 71.8 per cent followed by EB VCA (61.4%) and VZV (49.6%). Susceptibility to both HSV-1 and -2 was high across all decades (P<0.001). Seropositivity of CMV in donor was 90.9 per cent (100 out of 110). Post-transplant CMV qRT- PCR was positive in 17 (26.6%; 3 in recipient negative) of 64 samples tested. qRT-PCR assay was positive in one out of four (25%) tested for HSV-1 and nine out of 19 (47.4%) tested for EBV. Two recipients tested for HSV-2 and one for VZV were negative. There were three deaths in recipients (D+ R+) who were also positive for CMV qRT PCR. There was one death due to HSV-1 pneumonia. One patient with EBV reactivation developed post-transplant lymphoproliferative disorder two years after transplant. INTERPRETATION & CONCLUSIONS: Transplant recipient were at highest risk of acquiring HSV-1 and -2 more so for HSV-2. CMV exposure in transplant recipients and donors were very high and at greatest risk for recipient reactivation rate. Despite this, death related to CMV reactivation was low. PMID- 28862191 TI - Heterologous expression of porcine elongase 6 (ELOVL6) gene in a human cell line. PMID- 28862192 TI - Underutilization of antenatal services among tribal women. PMID- 28862193 TI - Authors' Response. PMID- 28862194 TI - Choice of criterion used in the receiver operating characteristic analysis. PMID- 28862195 TI - Authors' Response. PMID- 28862196 TI - Freely moving right ventricular thrombus in a patient with acute pulmonary embolism. PMID- 28862197 TI - Prospects of cytological cervical cancer screening in India: Exploring adjuvant approaches. PMID- 28862198 TI - Physical activity influences the immune system of breast cancer patients. AB - It has been suggested that physical activity in breast cancer patients can not only improve quality of life. Influences on physical and psychological levels have been evaluated, but effects on the immune system of breast cancer patients are hardly known. A PubMed search identified relevant trials and meta-analyses from 1970 to 2013. This review summarizes the results of international studies and the current discussion of effects of physical activity on the immune system of breast cancer patients. Highlighted are effects of physical activity on the immune system. Seven original articles and 14 reviews included in this review. Two original and the review articles includes other tumor entities besides breast cancer.Evaluated methods such as dose-response relationships for exercise in oncology, hardly exist. Increased immunological anti-cancer activity due to physical activity is probably mediated via an increase in number and cytotoxicity of monocytes and natural killer cells and cytokines. PMID- 28862199 TI - An update on studies on etiological factors, disease progression, and malignant transformation in oral submucous fibrosis. AB - Worldwide estimates of oral submucous fibrosis (OSMF) show a confinement to Indians and Southeast Asians. In India, the prevalence of OSMF has increased over the past four decades from 0.03% to 6.42%. The condition is well recognized for its malignant potential rate of 7-30%. The condition has a multifactorial etiology and may remain either stationary or become severe, leaving an individual physically challenged both physically and psychologically. Hence, the study aims at reviewing studies done on various etiological factors leading to its onset. Their analysis may serve as an adjunct in defining the broad spectrum of the causation of this potentially malignant disorder. PMID- 28862200 TI - Lactate - A new frontier in the immunology and therapy of prostate cancer. AB - Prostate cancer, one of the most common male malignancies with an increasing incidence in the recent years, requires the development of new methods of treatment. One of the most debated subjects is the tumor-associated macrophages (TAM). Although, the pathophysiological mechanisms are still a subject of intense research, TAM acts as procarcinogenic factors. It was also demonstrated that hypoxia-inducible factor 1 (HIF1) induces the expression of TAM genes involved in prostate carcinogenesis. Furthermore, it should be noted that the stromal extracellular lactate, the result of tumoral glycolysis process is one of the HIF1 activators. In addition, lactate inhibits the differentiation of monocytes and dendritic cells and also induces the inactivation of the cytotoxic T lymphocytes. Through an analysis of recent studies, we conclude that lactate is a vital component of several ways of modulating the immune response at the stromal prostatic adenocarcinoma including TAM activation and cytotoxic T lymphocytes immunosuppression. Our review focuses on the impact of lactate on prostatic adenocarcinoma progression in terms of its immunology, and how this influences the therapy of this condition and the clinical outcome. PMID- 28862201 TI - Spindle cell lesions: A review on immunohistochemical markers. AB - The intriguing array of spindle cell lesions occurring, especially in the head and neck region, poses a critical diagnostic challenge not only to the histopathologist but also ultimately to the clinicians for planning an appropriate treatment protocol. Overlapping spectrum of clinico-radiographic and microscopic features further compounds this problem. In such situations, the aid of ancillary techniques such as immunohistochemistry (IHC) is sought to clinch the diagnosis. This study aims to review the spindle cell neoplasms of the oral cavity with emphasis on IHC. PMID- 28862202 TI - Optical computed tomography in PRESAGE(r) three-dimensional dosimetry: Challenges and prospective. AB - With the advent of new complex but precise radiotherapy techniques, the demands for an accurate, feasible three-dimensional (3D) dosimetry system have been increased. A 3D dosimeter system generally should not only have accurate and precise results but should also feasible, inexpensive, and time consuming. Recently, one of the new candidates for 3D dosimetry is optical computed tomography (CT) with a radiochromic dosimeter such as PRESAGE(r). Several generations of optical CT have been developed since the 90s. At the same time, a large attempt has been also done to introduce the robust dosimeters that compatible with optical CT scanners. In 2004, PRESAGE(r) dosimeter as a new radiochromic solid plastic dosimeters was introduced. In this decade, a large number of efforts have been carried out to enhance optical scanning methods. This article attempts to review and reflect on the results of these investigations. PMID- 28862203 TI - Utility of cell block to detect malignancy in fluid cytology: Adjunct or necessity? AB - AIM OF THE STUDY: Cell block (CB) technique when supplemented with conventional smear, provides increased cellularity, preservation of architectural pattern with excellent morphology, and a clear background. We compare the utility of CB technique compared to conventional smear in detection of malignancy in serous effusions. MATERIALS AND METHODS: An institution-based observational and analytical study was carried out over 1 year on 50 patients with effusions. The residual amount of centrifuged deposit after preparation of conventional smear was mixed with 10% alcohol-formalin solution, and CBs were prepared. Calretinin and cytokeratin 5 were used for reactive mesothelial cells and Wilms tumor 1, thyroid transcription factor 1, CDX2, and estrogen receptor were used to confirm the adenocarcinoma cells. RESULTS: Maximum patients belonged to the age group of 61-70 years. Male:female ratio 1:1.17. Most common cause of malignant peritoneal effusion was due to ovarian malignancies in females and adenocarcinoma of stomach in males while, in case of pleural effusion, it was breast carcinoma in females and lung carcinoma in males. Thirteen suspicious cases were subjected to immunohistochemistry (IHC). In 70% cases, CB findings were consistent with the findings of conventional smears. In 20% cases, the conventional smears were suspicious for malignancy, and malignancy was confirmed by CB technique, whereas in 10% cases, both smears and CB were suspicious for malignancy and the original nature of the lesion was confirmed by the IHC. Sensitivity and specificity of CB compared to conventional smear were 88.88% and 86.98%, respectively. CONCLUSION: CB produced significantly better results (P = 0.0271) while detecting malignant lesions and reducing suspicious results (P = 0.0226). PMID- 28862204 TI - Epidemiological profile of head and neck cancer patients in Western Uttar Pradesh and analysis of distributions of risk factors in relation to site of tumor. AB - BACKGROUND: Head and neck cancers (HNCs) are a major form of cancers in India. The spectrum varies from place to place within the country because of significant diversified risk factors. AIMS AND OBJECTIVE: To study, epidemiology and risk factors of HNC patients from Western Uttar Pradesh and to find out the correlation between risk factors and different anatomical regions involved. MATERIALS AND METHODS: All patients with histologically confirmed diagnoses of HNC between January 2011 and December 2013 were selected from hospital records. Data regarding age, gender, addiction habits, site of tumor, and other details were obtained from their clinical records, and statistical analysis was done. RESULTS AND CONCLUSION: HNC accounts for 21.2% of total body malignancy and 47% of all malignancies in males and 2.5% in females. Squamous cell carcinoma was the most common histological type (97%). Maximum incidence of HNC (>60%) was in 40-60 year of age. Male:female ratio was 16:1. Oral cancers were most common HNC in patients below 40 year age group, whereas carcinoma oropharynx and larynx were more common in patients above 40 year age group. Tobacco smoking was a most prevalent risk factor for carcinoma oropharynx, larynx, and hypopharynx. Tobacco chewing was a most prevalent risk factor in females, young males, and carcinoma buccal mucosa patients. Habit of tobacco consumption in HNC patients was much higher than their normal counterpart. Alcohols drinking alone was observed in <1% patient as a risk factor. In oral tongue cancer, smoking and tobacco chewing were equally prevalent. Habit of tobacco chewing and alcohol were significantly higher in carcinoma buccal mucosa than other HNC suggesting synergistic effect specific to this site. PMID- 28862206 TI - Lysosomal storage disorders: Morphologic appraisal in Indian population. AB - BACKGROUND: Lysosomal storage disorders (LSDs) comprise a group of at least 50 distinct genetic diseases, each one resulting from the deficiency of a particular lysosomal enzyme involved in metabolism. We attempt to study and further subclassify pediatric LSDs into Gaucher's and non-Gaucher's category based on the morphologic variables seen in the bone marrow aspiration smears and trephine biopsy sections. MATERIALS AND METHODS: Pediatric (<12 years age) cases of LSDs diagnosed by bone marrow aspiration and trephine biopsy specimens, in the last 12 years period, were retrieved. The archival material and the relevant clinical as well as hematologic parameters were reviewed. RESULTS: From January 1997 to December 2008, 55 cases were diagnosed as LSDs. Based on bone marrow morphology, 56% (n = 31) cases were diagnosed as non-Gaucher's and the remaining 44% (n = 24) cases as Gaucher's disease, the ratio being 1.29:1. Anemia and thrombocytopenia were more commonly observed in Gaucher's disease (91.67 and 62.5%) as compared to non-Gaucher's group (74.19 and 19.35%). Neurologic symptoms and signs were more frequently present in non-Gaucher's cases (45.16%) as compared to Gaucher's group (29.17%). CONCLUSION: LSDs can be classified into Gaucher's and non-Gaucher's subtypes based on the characteristic cytomorphology of the storage cells in Giemsa-stained bone marrow aspiration smears and on hematoxylin and eosin-stained trephine biopsy sections. This approach would be fairly adequate for therapeutic and prognostic purposes in resource.constrained settings, where enzyme studies and mutational analysis may not be easily available. PMID- 28862205 TI - Mathematical formulation of 125I seed dosimetry parameters and heterogeneity correction in lung permanent implant brachytherapy. AB - OBJECTIVES: Precise determination of dose distribution around low-energy brachytherapy sources as well as considering tissue heterogeneity is crucial for optimized treatment planning. This study is aimed at determination and mathematically formulation of American Association of Physicists in Medicine Task Group No. 43 (AAPM TG-43) dosimetry parameters of 125I seed (model 6711) and calculation of dose difference caused by neglecting lung heterogeneity in permanent implant brachytherapy. MATERIALS AND METHODS: Using MCNPX 2.6.0 code, 125I seed (model 6711) was simulated in a cubic water environment, and its dosimetry parameters mentioned in AAPM TG-43 protocol were obtained. After benchmarking of parameters and comparison with prior studies, mathematical equations were fitted to the data, and a specific set of 125I seeds was simulated on a plane in simulated lung and water environments. Appropriate photon histories were considered to achieve data with maximum accuracy (max error 1%). In the end, isodose curves, profiles, depth dose, and dose difference between lung and water environments were obtained. RESULTS: For 125I seed (model 6711), radial dose function and anisotropy functions were obtained precisely with R2 > 0.99, all in good agreement with previous studies and protocol. In addition, percentage dose difference between inhomogeneous lung and homogenous water environments in a 5 cm distance was calculated and presented as D (r) function with R2 > 0.99. CONCLUSIONS: Considering practical difficulties in dose calculations, 125I seed dosimetry parameters and lung heterogeneity corrections can be obtained precisely by MCNPX. Equations presented in this study are recommended to be considered in future studies based on lung permanent implantation. PMID- 28862207 TI - Effectiveness of intraperitoneal or intrapleural administration of triamcinolone acetonide for the control of malignant ascites and pleural effusion (Kansai Clinical Oncology Group-G1102 study). AB - OBJECTIVES: We conducted a retrospective multi-institutional study to evaluate the efficacy and toxicity of intraperitoneal or intrapleural triamcinolone acetonide (TA), a slowly metabolized corticosteroid administration for the management of malignant ascites or pleural effusion. MATERIALS AND METHODS: The medical records of patients with gynecologic cancer who were treated with paracentesis or thoracocentesis followed by administration of 400 mg of TA between 2005 and 2014 were reviewed. RESULTS: The median age of the 74 eligible patients was 59 years. An Eastern Cooperative Oncology Group performance status 3 4 was present in 53 patients (73%), and 52 patients (70%) had ovarian cancer. Paracentesis followed by TA administration was performed in 65 patients (88%), and 37 patients (50%) were treated in a palliative setting. Chemotherapy or surgery after TA administration was performed in 37 patients (50%) in an aggressive setting, of which 14 patients (19%) were treated at the primary phase and 23 patients (31%) were treated at recurrent phase. The time interval of serial drainage was prolonged in 15 of 19 assessable patients, resulting in a response rate of 79% (95% confidence interval [95% CI]: 54-94%). Median overall survival after TA therapy in a palliative setting was 36 days (95% CI: 19-58 days). After TA therapy in a palliative setting, one patient complained of mild abdominal pain, two patients with advanced peritonitis carcinomatosis experienced bowel perforation, and three patients died within 7 days owing to disease progression. CONCLUSIONS: Intraperitoneal and intrapleural TA administration were feasible and effective in symptomatic control of ascites and pleural effusion. PMID- 28862208 TI - Diagnostic accuracy of fine-needle aspiration cytology of thyroid gland lesions: A study of 200 cases in Himalayan belt. AB - AIMS: The study is undertaken to correlate the fine-needle aspiration cytology (FNAC) findings with histopathology in a spectrum of thyroid lesions and to find the diagnostic accuracy of fine-needle aspiration (FNA) so that unnecessary thyroidectomies can be avoided in benign lesions. MATERIALS AND METHODS: This study was carried out over the period of 1-year (May 1, 2012-April, 30 2013). FNA specimens obtained from 200 patients were analyzed. Of these, only 40 patients underwent surgery and their thyroid specimens were subjected to histopathological examination. RESULTS: The age of the patients ranged from 9 to 82 years with mean age being 43 years. There was female preponderance, with male to female ratio being 1:7. On cytology out of 200 cases, 148 (74%) were benign, 25 (12.5%) were malignant, 16 (8%) were indeterminate, and 11 (5.5%) were nondiagnostic. Only 40 patients underwent surgery. On histopathology, 21 (52.5%) cases were benign and 19 (47.5%) were malignant. The statistical analysis of cytohistological correlation for both benign and malignant lesions revealed sensitivity, specificity, and diagnostic accuracy of 84%, 100% and 90%, respectively. CONCLUSION: FNAC is a minimally invasive, highly accurate and cost-effective procedure for the assessment of patients with thyroid lesions and has high sensitivity and specificity. It acts as a good screening test and avoids unnecessary thyroidectomies. PMID- 28862209 TI - Accelerator driven neutron source design via beryllium target and 208Pb moderator for boron neutron capture therapy in alternative treatment strategy by Monte Carlo method. AB - AIMS: The reactor has increased its area of application into medicine especially boron neutron capture therapy (BNCT); however, accelerator-driven neutron sources can be used for therapy purposes. The present study aimed to discuss an alternative method in BNCT functions by a small cyclotron with low current protons based on Karaj cyclotron in Iran. MATERIALS AND METHODS: An epithermal neutron spectrum generator was simulated with 30 MeV proton energy for BNCT purposes. A low current of 300 MUA of the proton beam in spallation target concept via 9Be target was accomplished to model neutron spectrum using 208Pb moderator around the target. The graphite reflector and dual layer collimator were planned to prevent and collimate the neutrons produced from proton interactions. Neutron yield per proton, energy distribution, flux, and dose components in the simulated head phantom were estimated by MCNPX code. RESULTS: The neutron beam quality was investigated by diverse filters thicknesses. The maximum epithermal flux transpired using Fluental, Fe, Li, and Bi filters with thicknesses of 7.4, 3, 0.5, and 4 cm, respectively; as well as the epithermal to thermal neutron flux ratio was 161. Results demonstrated that the induced neutrons from a low energy and low current proton may be effective in tumor therapy using 208Pb moderator with average lethargy and also graphite reflector with low absorption cross section to keep the generated neutrons. CONCLUSIONS: Combination of spallation-based BNCT and proton therapy can be especially effective, if a high beam intensity cyclotron becomes available. PMID- 28862210 TI - Pulmonary toxicity following bleomycin use: A single-center experience. AB - BACKGROUND: Bleomycin-induced pulmonary (BIP) toxicity is a notorious entity and cropped up in roughly 10% of cases. The aim of the study is to evaluate BIP at our tertiary care cancer center. PATIENTS AND METHODS: This is a retrospective, analytical study conducted at a tertiary care center from January 1998 to December 2012. Records of all the patients who were offered bleomycin chemotherapy as an integral part of adriamycin, bleomycin, vinblastine, and dacarbazine or bleomycin, etoposide, and cisplatin regimen in Hodgkin disease (HD) or germ cell tumor (GCT) were studied for the study inclusion criteria. Twenty-two patients treated with bleomycin who had respiratory symptoms and/or abnormal high-resolution computed tomography (HRCT) findings, suggestive of bleomycin-induced lung injury were included in this study. Results and Statistical Analysis: A total of 22 patients met the inclusion criteria for the study cohort. Of 22 patients, 8 were of HD and 14 were of GCT (nonseminomatous GCT [NSGCT] = 10 and seminomatous GCT = 4). Of 22 patients, 14 had symptoms of nonproductive cough, dyspnea and showed HRCT findings of ground glass opacities, diffuse alveolar damage, extensive reticular markings, traction bronchiectasis, and/or nodular densities. Two patients had fever and pleuritic pain. Eight patients were asymptomatic. Symptomatic patients were treated with prednisone at the dose of 0.75-1 mg/kg 4-8 weeks then gradually tapered. Four patients required noninvasive ventilatory support and managed with oxygen, nebulization, and antibiotics. Two patients required mechanical ventilatory support (HD = 1 and NSGCT = 1) and developed multiorgan failure subsequently succumbed to death. CONCLUSION: BIP is noteworthy lung toxicity as subsequent mortality ranges from 10% to 20% and shrinks survival rate in patients with highly curable malignant conditions. Physicians should be vigilant concerning this impending side effect. PMID- 28862211 TI - Diosmin reduces cell viability of A431 skin cancer cells through apoptotic induction. AB - OBJECTIVES: Aim of the present study was to evaluate the in vitro cytotoxic potential of the diosmin in A431 skin cancer cells. MATERIALS AND METHODS: The cytotoxic (anti-cell proliferative) potential of diosmin in A431 cells was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (cell viability), dual staining (apoptotic induction), dichloro-dihydro fluorescein diacetate assay (reactive oxygen species [ROS] generation), DNA fragmentation study, Western blotting analysis (apoptotic markers expression) and flow cytometry (cell cycle arrest). RESULTS: Diosmin reduced the cell viability of A431 cells in a dose-dependent fashion and the inhibitory concentration 50% value was attained at 45 MUg/ml using MTT assay. Diosmin at a concentration of 45 MUg/ml generated excessive ROS in A431 cells, as compared to untreated cells. Diosmin treated A431 cells also revealed multiple DNA fragments than the untreated cells. Diosmin upregulated the expression of p53, caspases 3 and 9 and downregulated the expression of Bcl-2, matrix metalloproteinases-2 and 9 in A431 cells. CONCLUSION: The cytotoxic or anti-cell proliferative potential of diosmin is due to its ROS-mediated apoptotic induction potential, as well as due to its role in the inhibition of invasion in the A431 cells. PMID- 28862212 TI - Target genes prediction and functional analysis of microRNAs differentially expressed in gastric cancer stem cells MKN-45. AB - CONTEXT: Since mechanisms of microRNAs (miRNAs) in gastric cancer stem cells (CSCs) and their signaling pathways remain unknown, our aim was to predict the miRNA target genes that differentially expressed in gastric CSCs. SUBJECTS AND METHODS: Using miRanda, PicTar, and TargetScan algorithm, target genes of miRNAs differentially expressed in gastric CSCs versus parental cells were predicted. Afterward, signaling pathways and biological functions of miRNAs in gastric CSCs were analyzed by the Database for Annotation, Visualization and Integrated Discovery (DAVID) database and DIANA tools. RESULTS: Gene ontology (GO) tool indicated that most of miRNA target genes involved in regulation of cell cycle, apoptosis, cell migration, vasculogenesis, angiogenesis, etc. Some of miRNA target genes are connected to pivotal signaling pathways of the "stem cell genes," such as Notch, Wnt/beta-catenin. CONCLUSIONS: Bioinformatics analysis such as DAVID database, GO biological process, GO molecular function, Kyoto encyclopedia of genes and genomes pathways, BioCarta pathway, Panther pathway, and Reactome pathway revealed that target genes of differentially expressed miRNAs in gastric CSCs were connected to pivotal biological pathways that involved in cell cycle regulation, stemness properties, and differentiation. PMID- 28862213 TI - Profile of eyelid malignancy in a Tertiary Health Care Center in North India. AB - CONTEXT: The eyelids are affected by wide spectrum of benign and malignant lesions. Basal cell carcinoma (BCC) is the most common malignancy encountered while other malignant lesions such as sebaceous cell carcinoma and squamous cell carcinoma are rare. Data regarding geographical variation in trends of malignant eyelid tumors are presented in the current study. SETTINGS AND DESIGN: Prospective, longitudinal, observational study was conducted from December 2011 to October 2013. SUBJECTS AND METHODS: Patients with mass or growth involving eyelid managed by surgical intervention were selected for the study. Excised tissue masses were sent for histopathological examination. RESULTS: Fifty-two cases of extraocular tumors were operated during the study period, out of which 25 cases (48%) were of eyelids. Sixteen cases (64%) were benign, and remaining 9 cases (36%) were malignant eyelid neoplasms. Benign lesions exhibited female preponderance with male:female ratio of 1:2.25. No significant difference was noted in cases of malignant lesions with male:female ratio of 1:1.25. Most common benign tumor observed was sebaceous cyst. Sebaceous gland carcinoma (4 cases) was the most common malignant neoplasm followed by squamous cell carcinoma (2 cases) and BCC, orbital melanoma, and adenocarcinoma (1 case each). CONCLUSIONS: Sebaceous gland carcinoma is more common in North India as compared to BCC and squamous cell carcinoma. PMID- 28862214 TI - Respiratory cancer database: An open access database of respiratory cancer gene and miRNA. AB - AIMS: Respiratory cancer database (RespCanDB) is a genomic and proteomic database of cancer of respiratory organ. It also includes the information of medicinal plants used for the treatment of various respiratory cancers with structure of its active constituents as well as pharmacological and chemical information of drug associated with various respiratory cancers. MATERIALS AND METHODS: Data in RespCanDB has been manually collected from published research article and from other databases. Data has been integrated using MySQL an object-relational database management system. MySQL manages all data in the back-end and provides commands to retrieve and store the data into the database. The web interface of database has been built in ASP. RESULTS AND CONCLUSIONS: RespCanDB is expected to contribute to the understanding of scientific community regarding respiratory cancer biology as well as developments of new way of diagnosing and treating respiratory cancer. Currently, the database consist the oncogenomic information of lung cancer, laryngeal cancer, and nasopharyngeal cancer. Data for other cancers, such as oral and tracheal cancers, will be added in the near future. The URL of RespCanDB is http://ridb.subdic-bioinformatics-nitrr.in/. PMID- 28862215 TI - Small field depth dose profile of 6 MV photon beam in a simple air-water heterogeneity combination: A comparison between anisotropic analytical algorithm dose estimation with thermoluminescent dosimeter dose measurement. AB - AIM OF STUDY: To establish trends of estimation error of dose calculation by anisotropic analytical algorithm (AAA) with respect to dose measured by thermoluminescent dosimeters (TLDs) in air-water heterogeneity for small field size photon. MATERIALS AND METHODS: TLDs were irradiated along the central axis of the photon beam in four different solid water phantom geometries using three small field size single beams. The depth dose profiles were estimated using AAA calculation model for each field sizes. The estimated and measured depth dose profiles were compared. RESULTS: The over estimation (OE) within air cavity were dependent on field size (f) and distance (x) from solid water-air interface and formulated as OE = - (0.63 f + 9.40) x2+ (-2.73 f + 58.11) x + (0.06 f2 - 1.42 f + 15.67). In postcavity adjacent point and distal points from the interface have dependence on field size (f) and equations are OE = 0.42 f2 - 8.17 f + 71.63, OE = 0.84 f2 - 1.56 f + 17.57, respectively. CONCLUSION: The trend of estimation error of AAA dose calculation algorithm with respect to measured value have been formulated throughout the radiation path length along the central axis of 6 MV photon beam in air-water heterogeneity combination for small field size photon beam generated from a 6 MV linear accelerator. PMID- 28862216 TI - A study to evaluate resource draining "no shows". AB - INTRODUCTION: Waiting lists are problems that plague all government radiation therapy centers across the country, leading to disease progression, and reduced treatment efficacy. No shows for appointments create artificial access issues, reduce revenues, waste staff time, and negatively affect patient care. METHODOLOGY: A Retrospective analysis of 180 patients, who were given an appointment and were to be started for radiation therapy at the Department of Radiation Therapy and Oncology, at our institute from May 1, 2013 to July 31, 2013, was done. Patients were divided into two Groups; Group A (n = 104, 57.8%) that complied for treatment and Group B (n = 76, 42.2%) that did not comply for treatment on the scheduled date. The Group B ("no shows") patients were contacted telephonically and were evaluated for the primary reasons for their failure to comply for treatment through a preformed questionnaire. RESULTS: The mean age, gender distribution and patient's habitat in both the groups were comparable. On Group B analysis, the average waiting period for the appointment was 74 days; 31.4% had died within an average of 31 days; 37.1% said they were better; 10% said their condition was the same; 18.6% said their disease had progressed. Patients were also evaluated for various factors responsible for their not reporting for treatment at the institute. CONCLUSION: Better communication and constant reminders between patients and the departmental staff can go a long way in helping to curb the problem of no shows and mitigate the artificial access issues. This would lead to better patient care and better resource utilization. PMID- 28862217 TI - Evaluation of the accuracy of various dose calculation algorithms of a commercial treatment planning system in the presence of hip prosthesis and comparison with Monte Carlo. AB - PURPOSE: High atomic number elements are commonly used in a hip prosthesis which can cause uncertainty in accurate dose calculations in radiation therapy. The aim of this study is to assess the accuracy of the three various algorithms of ISOgray treatment planning system in the presence of hip prosthesis by Monte Carlo (MC). MATERIALS AND METHODS: A MC model of Siemens PRIMUS linear accelerator has been built and verified by the measured data of the different algorithms of ISOgray treatment planning systems (TPS) in 6 and 15 MV photon beam energies. Two types of hip prosthesis have been used: stainless steel and titanium. The accuracy of mentioned dose calculation algorithms in the presence of hip prosthesis was evaluated. RESULTS: There were 24.78%, 27.68%, and 27.72% errors in fast Fourier transform (FFT) Convolution, collapsed cone (CC), and superposition in 6 MV photon beam and 26.45%, 30.45%, and 28.63% in 15 MV photon beam for titanium type, respectively. However, there were 32.84%, 35.89%, and 35.57% in 6 MV photon beam and 38.81%, 47.31%, and 39.91% errors in 15 MV photon beam in steel type, respectively. In addition, the ISOgray TPS algorithms are not able to predict the dose enhancement and reduction at the proximal and distal prosthesis interfaces, respectively. CONCLUSIONS: Hip prosthesis creates a considerable disturbance in dose distribution which cannot be predicted accurately by the FFT convolution, CC, and superposition algorithms. It is recommended to use of MC-based TPS for the treatment fields including the hip prosthesis. PMID- 28862218 TI - Docetaxel plus cisplatin plus fluorouracil versus carboplatin plus fluorouracil cetuximab in first-line setting in patients with recurrent or metastatic head and neck squamous cell cancer who did not previously receive neoadjuvant or adjuvant chemotherapy, which is standard? AB - BACKGROUND: The prognosis of recurrent or metastatic head and neck squamous cell cancer (HNSCC) is very poor. In the present retrospective study, we compared the impact of docetaxel plus cisplatin plus fluorouracil (TCF), and cisplatin plus fluorouracil plus cetuximab (CF-Ctx) regimens on the prognosis of patients with recurrent or metastatic HNSCC in first-line. MATERIALS AND METHODS: A total of 70 patients were evaluated as two groups, according to treatment protocol: TCF (n: 47) and CF-Ctx (n: 23). The groups were compared regarding survival. RESULTS: The median progression-free survival was 7.3 and 8.3 months, TCF and CF-Ctx groups, respectively, (P = 0.280). The median overall survival (OS) was 15.6 and 9.3 months for TCF and CF-Ctx groups, respectively, (P = 0.029). The dose reduction and using of granulocyte colony stimulating factor were significantly higher in TCF group (P = 0.048 and P = 0.018, respectively). CONCLUSION: In first-line setting, TCF regimen is superior to CF-Ctx regimen in terms of OS in patients with recurrent or metastatic HNSCC, who did not previously receive neoadjuvant or adjuvant chemotherapy. PMID- 28862219 TI - Assessment of nutritional status using abridged scored patient-generated subjective global assessment in cancer patient. AB - CONTEXT: Malnutrition is a common problem among cancer patients, usually occurs due to poor appetite, low food intake, and changes in body metabolism. AIMS: The aim of this study is to determine the prevalence of malnutrition in patients receiving chemotherapy on an outpatient basis. SETTINGS AND DESIGN: This cross sectional study conducted on 300 cancer patients referred to hospital. SUBJECTS AND METHODS: The prevalence of malnutrition among patients was assessed using the abridged scored patient-generated subjective global assessment (abPG-SGA) standard questionnaire. Moreover, patient's weight and 24 h dietary recall were measured. STATISTICAL ANALYSIS USED: Descriptive statistics were used to present characteristics of patients and dietary recalls. For revealing the correlation, Spearman correlation was used. RESULTS: The average abPG-SGA score was 7.6 (standard deviation [SD] = 5.4) and 60.7% of patients were malnourished and required nutritional intervention. Patients mean age and mean duration of illness were 54.2 (SD = 14.7(years, 25 months, respectively. The most common complaint of patients included fatigue (51.3%), anorexia (43.3%), and dry mouth (41%). Reduction in food intake in past month was reported by 41.7% of patients. CONCLUSION: According to the high prevalence of cancers and increasing growth of them in recent years with regard to outpatient treatment development for cancer patients, using the abPG-SGA standard questionnaire by nutritionist or nurses can be effective to detect malnourished patients and reduce complications caused by disease. PMID- 28862220 TI - The impact of patient positioning and use of belly board on small bowel toxicity in patients receiving pelvic radiotherapy for gynecological malignancies. AB - AIM: To determine the efficacy of belly board device in patients receiving postoperative radiation for gynecological malignancies in terms of setup error and acute small bowel toxicity. MATERIALS AND METHODS: Patients requiring postoperative radiation for gynecological malignancies were prospectively randomized to either treatment with supine position (supine arm) or prone position using belly board (prone arm). Each patient underwent computed tomography simulation in the assigned treatment position, and a three-dimensional conformal radiation was planned. Weekly two to three treatment sessions were verified using portal imaging and setup errors were noted. All patients were reviewed weekly to assess for symptoms and toxicity using a structured format. The systematic and random errors were calculated along the three axes. RESULTS: Twenty-four patients were randomized and 22 patients were available for the final analysis. The systematic error in supine arm versus prone arm was 3.9 versus 3.5 mm, 2.1 versus 4.8 mm and 3.1 versus 3.1 mm along lateral, antero-posterior (AP) and cranio-caudal (CC) direction. The random error in supine arm versus prone arm was 5 versus 3.9 mm, 2.9 mm versus 4.4 mm and 4.3 versus 3.4 mm along lateral, AP and CC direction. The calculated planning target volume margin for supine arm was 1.3, 0.7, and 1.0 cm and margin for prone arm was 1.1, 1.5, and 1.0 cm along lateral, AP, and CC direction, respectively. One patient in supine arm developed Grade 3 toxicity. CONCLUSION: The systematic error and random error is more along AP direction for prone position. The acute small bowel toxicity was less using belly board. PMID- 28862221 TI - Pelvic radiotherapy does not deteriorate the quality of life of women with gynecologic cancers in long-term follow-up: A 2 years prospective single-center study. AB - PURPOSE: To evaluate the emotional, sexual and health-related quality of life (HRQoL) concerns of the women with gynecologic malignancy treated with curative radiotherapy (RT). PATIENTS AND METHODS: A 100 women with diagnosis of gynecologic malignancy were prospectively enrolled. HRQoL at baseline, at the end of RT and during follow-up was assessed using European Organization for Research and Treatment of Cancer QoL Questionnaire-C30 (EORTC QLQ-C30), EORTC QLQ-cervical cancer module 24, and Hospital Anxiety and Depression Scale. RESULTS: The appetite loss, diarrhea, fatigue, dyspnea, insomnia, nausea and vomiting, pain scores, and sexual activity and sexual enjoyment scores were deteriorated after RT (P = 0.02 for pain scores and P < 0.001 for all other). Body image scores were higher in patients with endometrial cancer (P < 0.01). The emotional function, nausea and vomiting, body image and symptom experience scores were higher in patients who underwent chemotherapy (P = 0.04 and P = 0.01). All the complaints of patients improved during follow-up period. The global health status scores and the level of depression deteriorated in patients with locoregional recurrent disease and distant metastasis. The anxiety (P = 0.001) and depression (P = 0.007) levels were higher in basal and after-RT visits but then decreased through the subsequent follow-up visits. CONCLUSION: Although pelvic RT deteriorated HRQoL in patients with gynecologic malignancy, HRQoL improved during the follow up period. The progressive disease had a negative impact on HRQoL. PMID- 28862222 TI - Efficiency of combined blocking of aerobic and glycolytic metabolism pathways in treatment of N1-S1 hepatocellular carcinoma in a rat model. AB - BACKGROUND/AIM: The aim of this study was to determine whether the addition of bumetanide (BU), a glycolytic metabolism pathway inhibitor, to arterial embolization improves tumor necrosis of N1-S1 hepatocellular carcinoma in a rat model. MATERIALS AND METHODS: N1-S1 tumors were surgically implanted in the liver of 14 Sprague-Dawley rats. The rats were divided into three groups: In control group (n = 5), 1 ml of normal saline was injected intra-arterially. The tumor in the transarterial embolization group (TAE, n = 4) was embolized using 10 mg of 50 150 MU polyvinyl alcohol (PVA) particles and embolization plus BU group (TAE + BU, n = 5) were embolized with 10 mg of PVA plus 0.04 mg/kg of BU. Tumor volume was measured using two-dimensional ultrasound before intervention and twice a week afterward. Relative tumor volume after the intervention was calculated as the percentage of preinterventional tumor volume. After 4 weeks of observation, the rats were sacrificed for histopathological evaluation. RESULTS: No statistically significant difference was detected in the preintervention tumor sizes between the three groups (P > 0.05). In the control group, the relative tumor volume increased to 142.5% larger than baseline measurements. In the TAE group, the tumor volume decreased by 18.2 +/- 12.2%. The tumor volume in the TAE + BU group decrease by 90.4 +/- 10.2%, which was 72.2% more than in TAE only group (P < 0.0001). Histopathological evaluation demonstrated no residual tumor in the TAE + BU group. CONCLUSION: Tumor necrosis significantly increased in N1 S1 tumor that received BU at the time of TAE when compared to TAE alone. PMID- 28862223 TI - Effect of various dental restorations on dose distribution of 6 MV photon beam. AB - AIM: The purpose of this study is to evaluate the effect of various dental restoration materials on dose distribution in radiotherapy of head and neck cancer with 6 MV photon beam of a medical linac. SETTING AND DESIGN: The dental restorations include tooth, tooth with amalgam, tooth with Ni-Cr alloy, and tooth with Ceramco. Dose perturbation due to the dental restorations on 6 MV beam of Siemens Primus linac was calculated by MCNPX Monte Carlo code. These dental materials were separately simulated in a cubic water phantom. MATERIALS AND METHODS: Photon percentage dose change in the presence of tooth, tooth with amalgam, tooth with Ni-Cr alloy, and tooth with Ceramco was calculated at various depths on the central axis of the beam relative to the dose in water. In another evaluation, the absolute dose (cGy) for water, tooth, tooth with amalgam, tooth with Ni-Cr alloy, and tooth with Ceramco was obtained by calculating 100 cGy dose at 0.75 cm depth in the water phantom. RESULTS: Based on the calculations performed, maximum percentage dose change due to backscattering was 11%, 8%, 6%, and 4% for amalgam, Ni-Cr alloy, Ceramco and tooth at depth of 0.75 cm, respectively. The maximum dose perturbation by amalgam is due to its higher mass density and atomic number. CONCLUSION: Ignoring the effect of dental restoration compositions on dose distribution causes discrepancy in clinical treatment planning system calculations. PMID- 28862224 TI - Honey bee venom combined with 1,25-dihydroxyvitamin D3as a highly efficient inducer of differentiation in human acute myeloid leukemia cells. AB - PURPOSE: Most cancer cells exhibit a defect in their capacity to mature into nonreplicating adult cells and existing in a highly proliferating state. Differentiation therapy by agents such as 1,25-dihydroxyvitamin D3(1,25-(OH)2 VD3) represents a useful approach for the treatment of cancer including acute myeloid leukemia. Human myeloid leukemia cell lines are induced to terminal differentiation into monocyte lineage by 1,25-(OH)2 VD3. However, usage of these findings in the clinical trials is limited by calcemic effects of 1,25-(OH)2 VD3. Attempts to overcome this problem have focused on a combination of low concentrations 1,25-(OH)2 VD3 with other compounds to induce differentiation of HL-60 cells. In this study, the effect of honey bee venom (BV) and 1,25-(OH)2 VD3, individually and in combination, on proliferation and differentiation of human myeloid leukemia HL-60 cells were assayed. MATERIALS AND METHODS: In this in vitro study, toxic and nontoxic concentrations of BV and 1,25-(OH)2 VD3 were tested using Trypan blue stained cell counting and (3[4, 5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide) assay. In addition, differentiation of cells was assayed using a Wright-Giemsa staining and nitroblue tetrazolium reduction test. Data were analyzed by a one-way analysis of the variance test using SPSS software. RESULTS: Our findings showed that both the BV and 1,25-(OH)2 VD3, in a dose and time-dependent manner, caused cell death at high concentrations and inhibited cell proliferation at lower concentrations. About 5 nM of 1,25-(OH)2 VD3 induced differentiation of HL-60 cells to monocytes after 72 h. 2.5 MUg/ml of BV suppressed proliferation of HL-60 cells but had not any effects on their differentiation, whereas in combination with 5 nM of 1,25-(OH)2 VD3, it enhanced antiproliferative and differentiation potency of 1,25-(OH)2 VD3. CONCLUSIONS: These results indicate that BV potentiates the 1,25-(OH)2 VD3-induced HL-60 cell differentiation into monocytes. PMID- 28862225 TI - Estimation of serum ferritin level in potentially malignant disorders, oral squamous cell carcinoma, and treated cases of oral squamous cell carcinoma. AB - INTRODUCTION: Serum ferritin is the best indicator of iron stores in the body. The level of serum ferritin was found to be elevated in number of malignancies. Serum ferritin is also been established as prognostic marker for malignant lymphoma, cervical cancer, breast cancer, etc. AIMS AND OBJECTIVE: The aim of this study is to evaluate the level of serum ferritin in patients with pretreatment and posttreatment of squamous cell carcinoma and to determine the significance of serum ferritin as prognostic marker for oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Blood samples of 15 normal, thirty potentially malignant lesions, and thirty patients of squamous cell carcinoma were taken and analyzed for serum ferritin using ELISA. Of thirty patients, 15 patients were followed up till 6 months after their treatment and serum ferritin was again determined. RESULTS: The average serum ferritin of 30 potentially malignant disorders was 62.70 ng/ml, and thirty patients with squamous cell carcinoma were found to be 162.47 ng/dl. After 6 months of the treatment, the mean fall in serum ferritin with nonrecurrence patients was 84 ng/dl and increase in the serum ferritin in recurrence cases was 13.4 ng/dl. CONCLUSION: Determining serum ferritin is a convenient and nonexpensive method to determine the outcome of the treatment of the cases with OSCC. Its potential as prognostic marker could not be overlooked. PMID- 28862226 TI - Serum metabolomics in oral leukoplakia and oral squamous cell carcinoma. AB - CONTEXT: Metabolomics is a core discipline of system biology focusing on the study of low molecular weight compounds in biological system. Analysis of human metabolome, which is composed of diverse group of metabolites, can aid in diagnosis and prognosis of oral squamous cell carcinoma (OSCC). AIM: The aim of the present study is to analyze and identify serum metabolites in oral leukoplakia and OSCC as a potential diagnostic biomarker and a predictor for malignant transformation of oral leukoplakia. SUBJECTS AND METHODS: Serum metabolomic profile of patients diagnosed with oral leukoplakia (n = 21) and OSCC (n = 22) was compared with normal controls (n = 18) using quadrupole time of flight-liquid chromatography-mass spectrometry. MassHunter profile software was used for metabolite identification, and statistical analysis to assess the variation of the metabolites was performed using Mass Profiler Professional software. Statistical significance between the three groups was expressed using ANOVA (P < 0.05), and intergroup comparison was done using Student's t-test (P < 0.05). RESULTS: Significant upregulation of estradiol-17-beta-3-sulfate, L carnitine, 5-methylthioadenosine (MTA), 8-hydroxyadenine, 2-methylcitric acid, putrescine, and estrone-3-sulfate was seen in oral leukoplakia and OSCC than in normal controls. Furthermore, significant upregulation of 5,6-dihydrouridine, 4 hydroxypenbutolol glucuronide, 8-hydroxyadenine, and putrescine was evident in OSCC group than in oral leukoplakia. CONCLUSION: Upregulation of L-carnitine, lysine, 2-methylcitric acid, putrescine; 8-hydroxyadenine; 17-estradiol; 5,6 dihydrouridine; and MTA suggests their diagnostic potential in oral leukoplakia and OSCC. Further, a significant upregulation of putrescine, 8-hydroxyadenine, and 5,6-dihydrouridine in OSCC than in oral leukoplakia indicates their potential role in predicting the malignant transformation of oral leukoplakia. PMID- 28862227 TI - Tumor size distribution of invasive breast cancers and the sensitivity of screening methods in the Canadian National Breast Screening Study. AB - INTRODUCTION: This study set out to explore if breast cancers of different sizes are detected with varying sensitivity. In addition, we attempt to determine the effect of tumor size on screening detectability. SUBJECTS AND METHODS: Data arising from the Canadian National Breast Screening Study (CNBSS) was used to perform all analyses. The CNBSS consists of two randomized controlled trials, which includes data on detection methods, age, and allocation groups. We stratified tumor size by 5 mm; age into 40-49 and 50-59 years age groups; and cancer detection or presentation methods into mammography only, physical breast examination only, both mammography and physical breast examination, interval cancers, and incident cancers. RESULTS: This study revealed that a difference in tumor size exists for age (smaller tumor sizes are found in older women) and breast cancer detection or presentation modes. More specifically, breast cancers detected by mammography screening are statistically smaller than those detected by physical breast examination or those presenting as incident or interval cancers. This study also found that tumor size affects screening detectability for women in their 50's but not in their forties. That is, a statistically significant difference between mammography screening alone and physical examination alone was observed for women between the ages of 50-59 for tumor sizes up to 20 mm, including prevalent cases, and up to 15 mm when prevalent cases were excluded. CONCLUSION: The results of this study suggest that smaller breast cancers are more likely to be detected among women in their 50s. PMID- 28862228 TI - A study of the distribution of B-cell lymphoma/leukemia-2 in odontogenic cyst and tumors: Histochemical study. AB - INTRODUCTION: The odontogenic keratocyst is known for its aggressiveness, high recurrence rate, and transformation of keratinized epithelia to nonkeratinized squamous epithelium for which inflammation has been suggested to be responsible. B-cell lymphoma/leukemia-2 (Bcl-2) an anti-apoptotic protein, prolongs the life span of epithelial cells and allows proliferation, differentiation, and morphogenesis. MATERIALS AND METHODS: Study was carried out comprising of 90 cases; (30 ameloblastoma, 30 keratocystic odontogenic tumor (KCOT), and 30 radicular cyst). Bcl-2 expression was determined with respect to localization, area (percentage) and intensity of stained cells in epithelium, and connective tissue stroma by counting the endothelial, round, and fusiform cells. RESULTS: In epithelium bcl-2 expression in KCOTs was higher followed by ameloblastoma and lowest in the radicular cyst. Whereas, in connective tissue stroma bcl-2 expression was higher in KCOT and radicular cyst than ameloblastoma cases. Solid variants showed statistically higher expression as compared to the unicystic variants of ameloblastoma (P = 0.009, 0.033, 0.011, and 0.041). CONCLUSION: High expression of bcl-2 in KCOT supports the general agreement that some features of KCOT are those of a neoplasia. The bcl-2 expression in connective tissue cells suggests that these cells may also be important as epithelial cells in the biological behavior odontogenic keratocyst. PMID- 28862229 TI - Prevalence of tobacco in Darbhanga district: A hospital-based cross-sectional study. AB - INTRODUCTION: Chewing tobacco, smoking, and consumption of alcoholic beverages have become common social habits in India. No study has been conducted so far in this part of Bihar regarding the prevalence of tobacco. The aim of this study was to estimate the prevalence of tobacco use, its influences, triggers, and associated oral lesions. MATERIALS AND METHODS: A hospital-based cross-sectional study was conducted. Patients who consume tobacco in any form were selected and were interviewed through a pretested structured questionnaire in relation to their tobacco habits, its influences, and triggers. In addition, clinical examination was carried out to check for any tobacco-related oral lesions. RESULTS: The overall prevalence of tobacco use was 16.69%, out of which 14.48% were males and 2.21% were females. The most affected age group was from 19 to 50 years. 13.45% were below 18 years of age. 43.40% males and 77.42% females having the tobacco habit were illiterates. The majority of individuals were addicted due to peer pressure and friends, some acquired it, due to loneliness, stress, and for adapting themselves in the work place. Females frequently used smokeless for cleaning teeth. The most common oral mucosal lesion in both males (53.26%) and females (18.55%) was tobacco hyperkeratosis. CONCLUSION: The present study reflects the high prevalence rates of tobacco use among various sections of society. Apart from mass against tobacco products, authorities should focus on strict enforcement of law and promote research for creating new and harmless replacement products. PMID- 28862230 TI - Intratumoral granulomatous reaction in recurrent pituitary adenoma: A unique presentation. AB - Pituitary adenoma is one of the most common intracranial neoplasms, usually presenting with endocrinopathies or visual field defects. Granulomatous hypophysitis, one of the subtypes of primary hypophysitis, is a rare neurological entity presenting as a sellar lesion with mass effect symptoms and endocrinological dysfunction. Majority of cases of primary hypophysitis are misdiagnosed as pituitary adenomas preoperatively, and histopathology is required for a definitive diagnosis. Granulomatous hypophysitis can be primary/idiopathic or secondary to a variety of causes such as infection, foreign body reactions, and systemic inflammatory conditions. The presence of tumoral microgranulomas in pituitary adenoma is exceedingly rare, having been documented only twice previously. We present a unique case of recurrent pituitary macroadenoma in a 59 year-old woman with histopathological features of idiopathic intratumoral noncaseating granulomatous inflammation. The presence of a granulomatous response in the absence of a systemic infectious or inflammatory disorder is suggestive of a local tumoral response to an as-yet unidentified antigen. PMID- 28862231 TI - Neurofibromatosis and breast cancer: Do we need to revise the mammographic screening schedule in patients of neurofibromatosis? AB - Neurofibromatosis type 1 (NF-1) is a neurocutaneous syndrome with autosomal dominant mode of inheritance and has a high propensity to develop benign and malignant nervous system tumors. Although uncommon, case reports describing the association of NF-1 and breast cancer are available in the literature. We illustrate one such case of NF-1, with no family history of the disorder and presenting with multifocal invasive carcinoma of the right breast, in an attempt to describe the association between these two entities. We also attempt to extensively review the current literature on the subject. Since patients with NF 1 are at an increased risk of developing breast cancer, we recommend strict adherence to careful clinical breast examination and annual screening mammographic examination starting at 40 years of age in all patients of NF-1. PMID- 28862232 TI - Giant cell tumour of distal ulna. AB - Giant cell tumor (GCT) of distal end epiphysis ulna is a rare presentation, and only few cases are reported in the scientific literature. We report a case of GCT of distal end epiphysis ulna treated at our Tertiary Care Hospital, Mumbai. PMID- 28862233 TI - Radiation treatment for chemotherapy-resistant non-Hodgkin's lymphoma in the left thigh. AB - Extranodal non-Hodgkin lymphomas (NHLs) arising in soft tissue is rare. This study describes a rare case of chemo-resistant large B-cell NHL of skeletal muscle, characterized by voluminous swelling in the thigh which responded well to radiotherapy. In this patient, recurrent NHL showed refractoriness to various chemotherapy regimens and was treated with radiation therapy repeatedly with excellent local response and no evidence of disease for 18 months. Most of the published literature describes surgery or chemotherapy as treatment for NHL soft tissue. This is the first case report describing the durable response with radiation without in-field recurrence in chemo-resistant large B-cell NHL skeletal muscle. PMID- 28862234 TI - Metaplastic breast carcinoma presenting as benign breast lump. AB - A 38-year-old female presented with the left breast lump for 6 months. Physical examination revealed 11 cm * 7 cm mobile lump in the left breast without any axillary or supraclavicular lymphadenopathy. Mammographically it appeared as benign breast lump (breast imaging reporting and Data System-II). Fine needle aspiration cytology and Tru-cut biopsy were not able to differentiate between benign or malignant nature of this breast lump. For better characterization of this lesion, lumpectomy was performed, which revealed malignant tumor with squamous differentiation along with areas of ductal carcinoma in situ and the inferior margin was not free. For proper locoregional control, left modified radical mastectomy was performed. Postoperative period was uneventful. Final biopsy report of the mastectomy specimen was negative for any residual tumor, and axillary lymph nodes were not involved. PMID- 28862235 TI - Forgotten dimension of cancer caregivers and patients: Psychosocial perspective. PMID- 28862236 TI - Comment on: Survey of cervical cancer survivors regarding quality of life and sexual function. PMID- 28862237 TI - Metastatic adenocarcinoma of unknown primary presenting with cervical lymphadenopathy: A diagnostic challenge. PMID- 28862238 TI - Erratum: Oral cryotherapy for preventing chemotherapy-induced oral mucositis: An effective but yet neglected strategy. AB - [This corrects the article DOI: 10.4103/0973-1482.188301.]. PMID- 28862240 TI - Acute myocardial infarction in yellow oleander poisoning. AB - Self-harm by consuming yellow oleander seeds has become more frequent in South Asian countries, especially Sri Lanka and in southern parts of India. Yellow oleander poisoning usually presents with gastrointestinal, cardiovascular, and neurological manifestations as well as electrolyte abnormalities. Cardiac effects can manifest as nearly any type of dysrhythmia and sudden death with very few premonitory signs. To our knowledge yellow oleander poisoning related acute myocardial infarction has not yet been reported. We report a 37-year-old man with yellow oleander poisoning who had normal sinus rhythm at presentation but within few hours developed acute ST-segment myocardial infarction. PMID- 28862239 TI - Insomnia and risk of nonalcoholic fatty liver disease: A systematic review and meta-analysis. AB - AIM: This sudy aims to investigate the association between insomnia or excessive daytime sleepiness (EDS) and risk of nonalcoholic fatty liver disease (NAFLD). METHODS: We searched published studies indexed in MEDLINE and EMBASE database from inception to December 2015. Studies that reported odds ratios (ORs), risk ratios, hazard ratios or standardized incidence ratio with 95% confidence intervals (CI) comparing the risk of NAFLD among participants who had insomnia or EDS versus those without insomnia or EDS were included. Pooled ORs and 95% CI were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. Cochran's Q test and I2 statistic were used to determine the between-study heterogeneity. RESULTS: Our search strategy yielded 2117 potentially relevant articles (781 articles from MEDLINE and 1336 articles from EMBASE). After comprehensive review, seven studies (three cross-sectional studies and four case-control studies) were found to be eligible and were included in the meta-analysis. The risk of NAFLD in participants who had insomnia was significantly higher with the pooled OR of 1.13 (95% CI, 1.00-1.27). The statistical heterogeneity was moderate with an I2 of 62%. Elevated risk of NAFLD was also observed among participants with EDS even though the 95% CI was wider and did not reach statistical significance (pooled OR 2.21; 95% CI, 0.84-5.82). The statistical heterogeneity was moderate with an I2 of 62%. CONCLUSIONS: Our study demonstrated an increased risk of NAFLD among participants who had insomnia or EDS. Whether this association is causal needs further investigations. PMID- 28862241 TI - Is rule of halves still an occurrence in South India: Findings from community based survey in a selected urban area of Puducherry. AB - BACKGROUND: The objective of the present study was to assess the applicability of the rule of halves in an urban population of Puducherry, South India. We also aimed to find the correlates associated with undiagnosed hypertension to facilitate targeted screening. METHODOLOGY: We derive our observation from a community-based cross-sectional study conducted using the World Health Organization STEPwise approach to surveillance in urban slum of Puducherry during 2014-15. Blood pressure (BP) was measured for all the study subjects (n = 2399), and the subjects were classified as hypertensive using Joint National Committee 8 criteria, systolic BP (SBP) >=140 mm Hg and/or diastolic BP (DBP) >=90 mmHg and/or known hypertensives and/or treatment with antihypertensive drugs. Controlled hypertension was defined as SBP <140 mmHg and DBP <90 mmHg. RESULTS: Of 2399, 799 (33.3%; 95% confidence interval [CI]: 31.4%-35.2%) adults were found to have raised BP by any means (known and unknown hypertensives). Of the 799, 367 (15.3%; 95%CI: 13.9%-16.8%) of study participants were known hypertensives. Of the known hypertensives, 74.7% (274/367) were put on treatment (drugs and or lifestyle modification), and 80% (218/274) were on regular treatment. Higher proportions of men were found to have undiagnosed hypertension compared to women (26.1 vs. 19.8%, P < 0.001). Similarly, adult from below poverty line (23.8 vs. 20%, P < 0.001), unskilled laborer (26.6 vs. 20%, P < 0.001), and literacy less than middle school (12.3 vs. 23%, P < 0.001) had more undiagnosed hypertension. CONCLUSION: In the selected urban area of Puducherry around one-third of the adult populations are having hypertension, including the 54% of undiagnosed hypertension. Adults from the vulnerable subgroups such as lower level of literacy, below poverty line, and unskilled work are found to have higher proportions of undiagnosed hypertension. PMID- 28862242 TI - Unusual presentation of chondroblastoma mimicking Trevor's disease. PMID- 28862243 TI - Association of anti-CLIC2 and anti-HMGB1 autoantibodies with higher disease activity in systemic lupus erythematosus patients. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by numerous autoantibodies. In this study, we investigated the presence of anti-chloride intracellular channel 2 (anti-CLIC2) and anti-high mobility group box 1 (anti-HMGB1) autoantibodies in SLE patients (n = 43) versus healthy controls ([HCs] n = 43), and their association with serological parameters (antinuclear antibody [ANA], anti-double-stranded DNA [anti-dsDNA], and C-reactive protein [CRP]) and disease activity using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (active or inactive). SETTINGS AND DESIGN: Case-control study at Rheumatology Clinic of Universiti Sains Malaysia Hospital. SUBJECTS AND METHODS: The sera of SLE patients and HCs were tested for the presence of anti-CLIC2 and anti-HMGB1 autoantibodies using human recombinant proteins and ELISA methodologies. Other serological parameters were evaluated according to routine procedures, and patients' demographic and clinical data were obtained. STATISTICAL ANALYSIS: Mann-Whitney U-test, Chi square test, Fisher's exact test, and receiver operating characteristic analysis. RESULTS: Anti-CLIC2 autoantibody levels were significantly higher in SLE patients compared to HCs (P = 0.0035), whereas anti-HMGB1 autoantibody levels were not significantly elevated (P = 0.7702). Anti-CLIC2 and anti-HMGB1 autoantibody levels were not associated with ANA pattern, anti-dsDNA, and CRP. Interestingly, SLEDAI score (>=6) was associated with anti-CLIC2 (P = 0.0046) and with anti HMGB1 (P = 0.0091) autoantibody levels. CONCLUSION: Our findings support the potential of using anti-CLIC2 autoantibodies as a novel biomarker for SLE patients. Both anti-CLIC2 and anti-HMGB1 autoantibody levels demonstrated potential in monitoring SLE disease activity. PMID- 28862244 TI - Isolated left-sided pulmonary artery agenesis with left lung hypoplasia: A report of two cases. AB - Unilateral absence of pulmonary artery or pulmonary artery agenesis (UAPA) is a rare congenital malformation that can present as an isolated lesion or in association with other cardiac anomalies. Though congenital, presentation in adults are also reported. Most common presentation in adults is of exercise intolerance. The developing lung on the affected side is hypoplastic. Diagnosis of UAPA is established by imaging methods like CT and MRI . There is no specific treatment for this condition. Treatment depends on patients symptomatology, presence of pulmonary hypertension and collateral circulation. Presence of pulmonary hypertension carries a bad prognosis. We present two adult patients with isolated left sided unilateral pulmonary artery agenesis with ipsilateral lung hypoplasia. The diagnosis was confirmed by CT chest and perfusion scan. PMID- 28862245 TI - Novel use of levodopa in human immunodeficiency virus encephalopathy-mediated parkinsonism in an adult. AB - We report a case of a 36-year-old man with a medical history of human immunodeficiency virus (HIV) infection who presented with hypomimia, hypophonia, bradykinesia, rigidity, and freezing of gait. His clinical presentation and magnetic resonance imaging were consistent with HIV encephalopathy with involvement of the bilateral basal ganglia and diffuse leukoencephalopathy. We initiated a trial of carbidopa-levodopa. The dose was escalated to 1050 mg levodopa daily. Amantadine was also started. The patient was closely monitored for behavioral, neurological, or systemic side effects. He tolerated therapy well without adverse effects. The patient's neurological status significantly improved with levodopa, including hypomimia, hypophonia, bradykinesia, and fluidity of gait. This case demonstrates that carbidopa-levodopa can be safely utilized to manage parkinsonism in an adult patient with HIV encephalopathy. PMID- 28862246 TI - Hypereosinophilia: A rare presentation of acute lymphoblastic leukaemia. AB - Acute lymphoblastic leukaemia (ALL) presenting as peripheral blood hypereosinophilia is very rare and the incidence is <1%. The characteristic feature of patients with ALL and hypereosinophilia is the absence of blasts in peripheral blood, and this might lead to misdiagnosis of ALL. It is important for clinicians and pathologists to be aware of this uncommon initial presentation of ALL to avoid delay in diagnosis. We report a 37-year-old man who presented with fever and respiratory symptoms and was found to have hypereosinophilia in peripheral blood. His bone marrow and lymph node biopsies were diagnostic of ALL. PMID- 28862247 TI - Ectopic adrenocorticotropic hormone syndrome in a case of duodenal neuroendocrine tumor presenting with liver metastasis. AB - Ectopic adrenocorticotropic hormone (ACTH) syndrome is an uncommon disorder and comprises about 15% of all patients with Cushing's syndrome (CS). Duodenal carcinoids are rare, indolent tumors usually associated with a benign progression. We hereby report a rare case of CS resulting from ectopic ACTH secretion from a duodenal neuroendocrine tumor (NET) presenting with liver metastasis. A 37-year-old female presented with abdominal discomfort and dyspepsia of 1-month duration. Ultrasound abdomen suggested a well-defined hypoechoic lesion in the left lobe of the liver, suggestive of neoplasia. On clinical examination, she had Cushingoid features and persistent hypokalemia. Midnight ACTH and cortisol levels were grossly elevated at 1027 pg/ml (n < 46 pg/ml) and 87.56 MUg/dl (n < 7.5 MUg/ml), respectively. Both overnight and high dose dexamethasone suppression test confirmed nonsuppressed cortisol levels - 86.04 and 84.42 MUg/dl (n < 1.8 MUg/ml), respectively. Magnetic resonance imaging brain showed a structurally normal pituitary gland. Computed tomography scan of the abdomen revealed hepatic lesion with bilateral adrenal enlargement. A diagnosis of ectopic ACTH-dependent CS was made. Intraoperatively, a duodenal lesion of 0.5 cm * 0.5 cm was identified alongside an 8 cm * 6 cm exophytic lesion in segment IV of the liver. Frozen section of the duodenal lesion was positive for NET. She underwent a Whipple's surgery, cholecystectomy, and left hepatic lobectomy. Postoperatively, she showed clinical and biochemical remission. Herewith, we report the third case of duodenal carcinoid tumor presenting as ectopic ACTH syndrome and the first with liver metastasis. PMID- 28862248 TI - The Allan Burns mummies: A history and future prospect of an anatomical collection. AB - Acquiring adequate resources for anatomy education has represented a challenge throughout the discipline's long history. A significant number of collections housed in anatomy departments contain human tissue of unknown provenance with some obtained in morally dubious ways. This paper outlines the history and future prospects of one such anatomical assemblage - the Burns Anatomical Collection, currently housed at the University of Maryland (UM). The collection originally contained more than 1000 anatomically prepared mummified human remains. They were produced by the renowned Scottish anatomist Allan Burns in Glasgow in the late eighteenth and early nineteenth centuries. The prepared cadavers became a commodity and after Burns' death, were acquired by his pupil Granville Pattison, who later sold them to the UM. While the origin of these human remains is unknown, historical data suggests that most of the cadavers for the collection were obtained through grave robbing. While intensely used in anatomy teaching in the nineteenth century, specimens from the collection should now be treated primarily as historical artifacts, appropriate only for teaching medical history and ethics. Other perspectives may include repatriating and reburying the human remains and providing a memorial service. Most importantly, this collection and others similar to it should initiate dialog and reflection on the ethical aspects of the past and present medical practice. PMID- 28862249 TI - Mechanisms of Action of MicroRNAs in Infantile Hemangioma Tissue and Vascular Endothelial Cells in Different Periods. PMID- 28862251 TI - Prefrontal Cortex Deep Brain Stimulation Improves Fear and Anxiety-Like Behavior and Reduces Basolateral Amygdala Activity in a Preclinical Model of Posttraumatic Stress Disorder. AB - Deep brain stimulation (DBS) is being investigated for a number of psychiatric indications, including posttraumatic stress disorder (PTSD). Preclinical studies continue to be a cornerstone for the development of new DBS applications. We investigate whether DBS delivered to the infralimbic cortex (IL), a region involved in mechanisms of stress resiliency, may counter behavioral abnormalities in rats that present persistent extinction deficits and long-term anxiety after exposure to fear conditioning. Rats undergoing fear conditioning/extinction were segregated into weak and strong extinction groups (WE >70% or SE <30% of freezing during extinction). Following 2 weeks of DBS, animals were exposed to novel recall sessions and tested in the open field, novelty-suppressed feeding, and elevated plus maze. zif268 expression was measured in structures involved in mechanisms of fear and stress. In vivo electrophysiology was used to record activity from the basolateral amygdala (BLA). We found that DBS improved extinction deficits and anxiety-like behavior in WE animals, having no significant effects in SE rats. No major differences in absolute zif268 levels were recorded across groups. However, correlation between zif268 expression in the IL and BLA was disrupted in WE animals, a deficit that was countered by DBS treatment. Electrophysiology experiments have shown that DBS reduced BLA firing of both putative principal cells and interneurons in WE rats, with no significant differences being detected between SE and SE DBS animals. In summary, IL DBS mitigated fear, partially improved anxiety-like behavior, reversed neurocircuitry abnormalities, and reduced BLA cell firing in a preclinical model of PTSD. PMID- 28862253 TI - Risk of intraocular hemorrhage with oral anticoagulants in ocular surgery. PMID- 28862250 TI - CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity. AB - Endocannabinoids (eCBs) are amongst the most ubiquitous signaling molecules in the nervous system. Over the past few decades, observations based on a large volume of work, first examining the pharmacological effects of exogenous cannabinoids, and then the physiological functions of eCBs, have directly challenged long-held and dogmatic views about communication, plasticity and behavior in the central nervous system (CNS). The eCBs and their cognate cannabinoid receptors exhibit a number of unique properties that distinguish them from the widely studied classical amino-acid transmitters, neuropeptides, and catecholamines. Although we now have a loose set of mechanistic rules based on experimental findings, new studies continue to reveal that our understanding of the eCB system (ECS) is continuously evolving and challenging long-held conventions. Here we will briefly summarize findings on the current canonical view of the 'ECS' and will address novel aspects that reveal how a nearly ubiquitous system can determine highly specific functions in the brain. In particular, we will focus on findings that push for an expansion of our ideas around long-held beliefs about eCB signaling that, while clearly true, may be contributing to an oversimplified perspective on how cannabinoid signaling at the microscopic level impacts behavior at the macroscopic level. PMID- 28862252 TI - Genome-wide identification of histone H2A and histone variant H2A.Z-interacting proteins by bPPI-seq. AB - H2A is a nucleosome core subunit involved in organizing DNA into a chromatin structure that is often inaccessible to regulatory enzymes. Replacement of H2A by its variant H2A.Z renders chromatin accessible at enhancers and promoters. However, it remains unclear how H2A.Z functions so differently from canonical H2A. Here we report the genome-wide identification of proteins that directly interact with H2A and H2A.Z in vivo using a novel strategy, bPPI-seq. We show that bPPI-seq is a sensitive and robust technique to identify protein-protein interactions in vivo. Our data indicate that H2A.Z-interacting proteins and H2A interacting proteins participate in distinct biological processes. In contrast to H2A-interacting proteins, the H2A.Z-interacting proteins are involved in transcriptional regulation. We found that the transcription factor Osr1 interacts with H2A.Z both in vitro and in vivo. It also mediates H2A.Z incorporation to a large number of target sites and regulates gene expression. Our data indicate that bPPI-seq can be widely applied to identify genome-wide interacting proteins under physiological conditions. PMID- 28862254 TI - One-year result of XEN45 implant for glaucoma: efficacy, safety, and postoperative management. AB - PurposeTo report the efficacy, safety profile, and postoperative management of XEN45 implant at 12-month follow-up.Patients and methodsThis was a retrospective, non-randomised interventional case series involving patients who underwent XEN45 implantation by a single, experienced glaucoma specialist in a tertiary centre. Primary outcome measures were the intraocular pressure (IOP) and the number of medications at 1-year follow-up visit. Two IOP criteria were chosen to measure success: IOP <=21 mm Hg and >=20% reduction from baseline (criteria one); and IOP <=15 mm Hg and >=30% reduction from baseline (criteria two).ResultsAll 39 eyes completed 1-year follow-up. The mean preoperative IOP was 24.9+/-7.8 mm Hg on three drops, which reduced to 14.5+/-3.4 mm Hg at month 12 (P<0.005) on 0.7 drops (P<0.005). On the basis of criteria one, the cumulative probability of success at 1 year was 87.0% without medication and 92.0% with medication. On the basis of criteria two, cumulative probability of success was 62.0% without medication and 64.0% with medication. Bleb intervention with a median of 2 (range 1-4) was required for 51.3% of eyes. Implant was obstructed by iris tissue in three eyes (7.7%); one eye (2.6%) developed hyphaema; eight eyes (20.5%) had numerical hypotony (IOP<=5 mm Hg) at day 1, of which all spontaneously resolved by week 4 apart from one eye.ConclusionsThe XEN45 implant proved to be an effective treatment with a good safety profile at 1-year follow-up period. The high rate of postoperative bleb intervention does not make XEN45 a 'fit-and-forget' procedure and therefore the procedure should ideally be performed by surgeons experienced in bleb management. PMID- 28862255 TI - Response to: 'Unmet needs of cataract blind children in special schools in Southeast Nigeria'. PMID- 28862256 TI - Rhegmatogenous retinal detachment in paediatric patients after pars plana vitrectomy and sutured scleral-fixated intraocular lenses. AB - PurposeTo report the incidence rate, management, and surgical outcomes of rhegmatogenous retinal detachment (RRD) in children who underwent pars plana vitrectomy (PPV) with sutured scleral-fixated intraocular lens implantation (SSFIOL).Patients and methodsOf the 279 eyes of 230 children who underwent PPV with SSFIOL at a tertiary eye care centre, 16 eyes of 15 children developed RRD. Retrospective analysis of the surgical details of RRD, the structural and functional outcomes was done.ResultsOf the 279 eyes of 230 children who underwent PPV with SSFIOL, RRD was seen in 5.7% of the eyes. Average age was 10.7 years (range 4-15 years). Indication for SSFIOL implantation was congenital subluxation of lens (8 eyes) and traumatic aphakia or lens subluxation (4 eyes each). PPV was done in 15 of the 16 eyes, and 1 patient underwent scleral buckling. Retina was attached at the last follow-up visit in 87.5% of the eyes with median number of surgeries being 1. BCVA at the time of retinal detachment, multiple surgeries, and PVR at presentation were associated with poor visual outcome.ConclusionSurgery for SSFIOL in our series of paediatric eyes was complicated by vision-threatening RRD in 5.7% of cases. Surgical outcome in eyes with RRD without PVR was better (100%) than that in those, where PVR had already set in (75%). Need for regular follow-up and self-monitoring of vision should be emphasized and discussed with the parents before surgical intervention. PMID- 28862257 TI - Outcomes of lower eyelid retractor recession and lateral horn lysis in lower eyelid elevation for facial nerve palsy. AB - PurposeTo report outcomes and complications of lower eyelid retractor recession and lateral horn lysis (RR) for lower eyelid elevation in patients with facial nerve palsy (FNP).Patients and methodsRetrospective review. Patients with FNP undergoing RR alone (group 1) or with adjunctive procedures (canthal suspension group 2, tarsorrhaphy-group 3, and full-thickness skin graft-group 4) during a 5 year period were included. Patient demographics, lagophthalmos, occurrence of eyelid malpositions, recurrent retraction, and repeat procedures were noted from medical records. Measures of lower eyelid height (LEH) and lid lag on downgaze were obtained from standard photographs.ResultsForty-two patients (23 females, mean age was 59 years) were included. Mean follow-up was 24 months (range 6-77). Median improvement in LEH following surgery was significant in Group 1 (0.90 mm, IQR: 0.37-0.91, P=0.20) and in Group 2 (0.51 mm, IQR: 0.30-1.37, P<0.001), respectively. Median improvement in blink lagophthalmos was 3.00 mm (IQR: 3.00 3.50, P=0.02) in Group 1 and 3.50 mm (IQR: 1.75-5.00, P<0.001) in Group 2. Median improvement in lagophthalmos on gentle eye closure was 2.00 mm (IQR: 1.50-3.00, P=0.02) in Group 1 and 1.00 mm (IQR: 0-2.13, P=0.006) in Group 2. No new cases of ectropion were noted. 23.5% of patients required a repeat RR at a mean interval of 20 (range 1-70) months and a further 9.8% required a third procedure at a mean interval of 21 (range 18-29) months.ConclusionRR improves lower eyelid retraction and lagophthalmos in FNP either alone or when combined as an adjunctive procedure. It does not aggravate paralytic ectropion although repeated retractor recessions may be required to improve retraction. PMID- 28862258 TI - Unmet needs of cataract blind children in special schools in Southeast Nigeria. PMID- 28862259 TI - Lateral canthotomy orbitotomy: a rapid approach to the orbit. AB - PurposeThe lateral compartment of the orbit can readily be accessed through a horizontal lateral canthotomy without the need to swing the lid or remove bone. In this paper the technique, accessible orbital territory, and duration of surgery are presented.Patients and methodsRetrospective, non-interventional descriptive case series for patients who underwent a lateral canthotomy to access pathology within the lateral orbit.ResultsA series of 18 patients are included, all presenting with pathology lateral to, or within, the optic nerve. Pathologies included amyloidosis (1), lymphoma (4), metastatic adenocarcinoma within the optic nerve (1), idiopathic lateral rectus muscle mysositis (4), meningothelial meningioma of the optic nerve (1), intraconal orbital meningioma (1), reactive lymphoid hyperplasia (1), optic nerve glioma (3), optic nerve meningioma (1), and cavernous haemangioma (1). The median surgical time was 36 min (range 23-75 min). No patient required detachment of the lower lid, the technique leaving both upper and lower 'arms' of the lateral canthal tendon attached to Whitnall's tubercle.ConclusionsThe lateral canthotomy approach orbitotomy is a rapid, safe, and minimally disruptive approach for accessing pathology in the lateral orbit and optic nerve. The lateral canthal tendon is split along the horizontal raphe without detachment of either limb from Whitnall's tubercle, no bone is removed, and the post-operative recovery is rapid with minimal associated inflammation or chemosis. This approach is also flexible, permitting the clinician to increase exposure to the orbit peroperatively by swinging the lower lid if required. PMID- 28862260 TI - A paracentesis to save time and money with re-bubbling after descemets membrane endothelial keratoplasty. PMID- 28862261 TI - Molecular testing for the clinical diagnosis of fibrolamellar carcinoma. AB - Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1 PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone. PMID- 28862262 TI - Centrilobular ductular reaction correlates with fibrosis stage and fibrosis progression in non-alcoholic steatohepatitis. AB - There is increasing interest in the role of ductular reaction as part of the pathogenesis and characteristic histology of non-alcoholic steatohepatitis. However, earlier studies did not separately assess the contribution of periportal and centrilobular zone ductular reaction over the spectrum of non-alcoholic steatohepatitis, and their clinical significance remains unclear. We herein analyzed the character of ductular reaction in each hepatic zone in non-alcoholic steatohepatitis biopsies and for the first time evaluated the prognostic value of ductular reaction in baseline biopsies as a predictor of progression of fibrosis in subsequent biopsies. A total of 90 non-alcoholic steatohepatitis liver biopsies were included in the cohort. The relationships among ductular reaction, grade, stage, and other common histopathologic findings in non-alcoholic steatohepatitis were analyzed in a cross-sectional manner. Among these patients, a total of 47 patients underwent sequential liver biopsies in the absence of effective treatment. The frequency of ductular reaction and the other histopathologic parameters in the initial biopsies were analyzed as predictors of progression of fibrosis in the second biopsies in a longitudinal analysis. Centrilobular ductular reaction was identified in 90% of patients and 38% of centrilobular zones. The prevalence of centrilobular ductular reaction increased as non-alcoholic steatohepatitis grade increased (P=0.0002) and also as stage of fibrosis increased (P<0.0001) in the cross-sectional study. In the longitudinal study, the frequency of centrilobular ductular reaction in the initial biopsies was significantly higher in the group of progressors and correlated with the rate of fibrosis progression (P=0.02). Centrilobular ductular reaction is common in non-alcoholic steatohepatitis and its presence correlates significantly with increasing necroinflammatory activity and fibrosis stage. Development of centrilobular ductular reaction appears to predict progression of fibrosis in subsequent biopsies. PMID- 28862263 TI - Neurofibromin C terminus-specific antibody (clone NFC) is a valuable tool for the identification of NF1-inactivated GISTs. AB - An increasing body of evidence supports the involvement of NF1 mutations, constitutional or somatic, in the pathogenesis of gastrointestinal stromal tumors (GISTs). Due to the large size of the NF1 locus, the existence of multiple pseudogenes and the wide spectrum of mechanisms of gene inactivation, the analysis of NF1 gene status is still challenging for most laboratories. Here we sought to assess the efficacy of a recently developed neurofibromin-specific antibody (NFC) in detecting NF1-inactivated GISTs. NFC reactivity was analyzed in a series of 98 GISTs. Of these, 29 were 'NF1-associated' (17 with ascertained NF1 mutations and 12 arising in the context of clinically diagnosed Neurofibromatosis type 1 syndrome and thus considered bona fine NF1 inactivated); 38 were 'NF1 unrelated' (either wild-type or carrying non-pathogenic variants of NF1). Thirty one additional GISTs with no available information on NF1 gene status or with NF1 gene variants of uncertain pathogenic significance were also included in the analysis. Cases were scored as NFC negative when, in the presence of NFC positive internal controls, no cytoplasmic staining was detected in the neoplastic cells. NFC immunoreactivity was lost in 24/29 (83%) NF1-associated GISTs as opposed to only 2/38 (5%) NF1-unrelated GISTs (P=3e-11). NFC staining loss significantly correlated (P=0.007) with the presence of biallelic NF1 inactivation, due essentially to large deletions or truncating mutations. NFC reactivity was instead retained in two cases in which the NF1 alteration was heterozygous and in one case where the pathogenic NF1 variant, although homo/hemizygous, was a missense mutation predicted not to affect neurofibromin half-life. Overall this study provides evidence that NFC is a valuable tool for identifying NF1 inactivated GISTs, thus serving as a surrogate for molecular analysis. PMID- 28862264 TI - SOX2-silenced squamous cell carcinoma: a highly malignant form of esophageal cancer with SOX2 promoter hypermethylation. AB - This study originally aimed to investigate whether the overexpression of SOX2 is associated with the poor prognosis of patients with squamous cell carcinoma of the esophagus. However, we unexpectedly found that esophageal squamous cell carcinomas completely lacking SOX2 expression showed distinct pathologic features and highly aggressive clinical courses. The study cohort consisted of 113 consecutive patients with esophageal squamous cell carcinoma who underwent surgical resection without neoadjuvant therapy. Immunostaining on tissue microarrays and whole sections revealed that 8/113 (7%) cases were entirely negative for this transcriptional factor. SOX2-negative cancers were histologically less differentiated (P=0.002) and showed higher pT and pStages (P=0.003 and 0.007, respectively) than SOX2-positive cases. A remarkable finding was widespread lymphatic infiltration distant from the primary invasive focus, which was observed in 4 SOX2-negative cancers (50%), but none of the SOX2 positive cases. All separate dysplastic lesions observed in SOX2-negative cases were also SOX2-negative. The negative expression of SOX2 appeared to be an independent poor prognostic factor (OR=7.05, 95% CI=1.27-39.0). No mutations were identified in the coding or non-coding regions of SOX2. Fluorescent in situ hybridization did not show any copy-number variations in this gene. Since the SOX2 promoter contains an extensive CpG island, SOX2-negative cases underwent methylation-specific PCR, which disclosed promoter hypermethylation in all cases. In conclusion, SOX2-silenced squamous cell carcinomas of the esophagus appear to be a minor, but distinct form of malignancy characterized by extensive lymphatic invasion, a poor prognosis, and potential association with multiple SOX2-negative neoplastic lesions. The hypermethylation of the promoter region is seemingly a critical epigenetic event leading to SOX2 silencing. PMID- 28862265 TI - Anaplastic sarcomas of the kidney are characterized by DICER1 mutations. AB - Anaplastic sarcoma of the kidney is a rare tumor (<=25 reported cases) characterized by the presence of cysts, and solid areas composed of bundles of undifferentiated spindle cells, showing marked cellular anaplasia (usually accompanied by TP53 overexpression). These tumors often feature prominent areas of cartilage or chondroid material. Germline mutations in DICER1, encoding the microRNA (miRNA) processor DICER1, cause an eponymous syndrome. Recent reports suggest that anaplastic sarcoma of the kidney should be included in DICER1 syndrome as germline DICER1 mutations are associated with the occurrence of such tumors. Therefore, we sought to determine the following: (1) what proportion of anaplastic sarcoma of the kidney have DICER1 mutations; (2) whether the identified mutations affect both alleles of DICER1 (ie, are biallelic); (3) whether somatic missense mutations in the DICER1 RNase IIIb domain impact miRNA generation; and (4) whether TP53 alteration always occurs in these tumors. DICER1 mutations were evaluated by Sanger sequencing and next-generation sequencing in nine tumor/normal pairs. Impact of DICER1 mutations on miRNA generation was evaluated via an in vitro DICER1 cleavage assay. TP53 status was assessed by immunohistochemistry and next-generation sequencing. Eight of the nine cases had at least one RNase IIIb DICER1 mutation that impacted the generation of miRNAs. There were six tumors with truncating DICER1 mutations and in four of them, the mutation found in the tumor was also detected in adjacent normal tissue, and therefore was likely to be either mosaic or germline in origin. Analysis of mutation phase revealed that two of three tumors had biallelic DICER1 mutations. Six of nine anaplastic sarcomas of the kidney had aberrant TP53 immunohistochemisty with damaging TP53 mutations identified in three cases. Taken together, these data suggest that the great majority of anaplastic sarcomas of the kidney have DICER1 mutations and confirm that these tumors are part of the DICER1 syndrome. PMID- 28862267 TI - Diabetes: Risk of T2DM in children - influence of sleep duration. PMID- 28862268 TI - Diabetes: Peripheral Abeta linked to pathogenesis of T2DM. PMID- 28862270 TI - Multiple sclerosis: Microstructural pathology imaged in MS. PMID- 28862269 TI - Obesity: Obesity and cardiometabolic disease - more than meets the eye. PMID- 28862266 TI - Genomic and epigenomic mechanisms of glucocorticoids in the brain. AB - Following the discovery of glucocorticoid receptors in the hippocampus and other brain regions, research has focused on understanding the effects of glucocorticoids in the brain and their role in regulating emotion and cognition. Glucocorticoids are essential for adaptation to stressors (allostasis) and in maladaptation resulting from allostatic load and overload. Allostatic overload, which can occur during chronic stress, can reshape the hypothalamic-pituitary adrenal axis through epigenetic modification of genes in the hippocampus, hypothalamus and other stress-responsive brain regions. Glucocorticoids exert their effects on the brain through genomic mechanisms that involve both glucocorticoid receptors and mineralocorticoid receptors directly binding to DNA, as well as by non-genomic mechanisms. Furthermore, glucocorticoids synergize both genomically and non-genomically with neurotransmitters, neurotrophic factors, sex hormones and other stress mediators to shape an organism's present and future responses to a stressful environment. Here, we discuss the mechanisms of glucocorticoid action in the brain and review how glucocorticoids interact with stress mediators in the context of allostasis, allostatic load and stress-induced neuroplasticity. PMID- 28862271 TI - Precision medicine: a matter of regulation or collaboration? PMID- 28862272 TI - Impact of uterus transplant on fetuses and resulting children: a response to Daar and Klipstein. PMID- 28862273 TI - Controlling the supramolecular assembly of nucleosomes asymmetrically modified on H4. AB - In stem cells, H4 proteins carrying different modifications coexist within single nucleosomes. For functional studies, we report the synthesis of such asymmetric nucleosomes. Asymmetry is achieved by transiently crosslinking H4 by a traceless, protease-removable tag introduced via an isopeptide linkage. These nucleosomes are used to study Set8 activity, a key methyltransferase. PMID- 28862274 TI - High-purity capture and release of circulating exosomes using an exosome-specific dual-patterned immunofiltration (ExoDIF) device. AB - We present a microfluidic device for the capture and release of circulating exosomes from human blood. The exosome-specific dual-patterned immunofiltration (ExoDIF) device is composed of two distinct immuno-patterned layers, and is capable of enhancing the chance of binding between the antibody and exosomes by generating mechanical whirling, thus achieving high-throughput exosome isolation with high specificity. Moreover, follow-up recovery after the immuno-affinity based isolation, via cleavage of a linker, enables further downstream analysis. We verified the performance of the present device using MCF-7 secreted exosomes and found that both the concentration and proportion of exosome-sized vesicles were higher than in the samples obtained from the conventional exosome isolation kit. We then isolated exosomes from the human blood samples with our device to compare the exosome level between cancer patients and healthy donors. Cancer patients show a significantly higher exosome level with higher selectivity when validating the exosome-sized vesicles using both electron microscopy and nanoparticle tracking analysis. The captured exosomes from cancer patients also express abundant cancer-associated antigens, the epithelial cell adhesion molecule (EpCAM) on their surface. Our simple and rapid exosome recovery technique has huge potential to elucidate the function of exosomes in cancer patients and can thus be applied for various exosome-based cancer research studies. PMID- 28862275 TI - Facile cyclometallation of a mesitylsilylene: synthesis and preliminary catalytic activity of iridium(iii) and iridium(v) iridasilacyclopentenes. AB - Reactions of the mesityl-amidinato-silylene Si(tBu2bzam)Mes (1; tBu2bzam = N,N' bis(tert-butyl)benzamidinato; Mes = mesityl) with three different iridium precursors led, at room temperature, to two iridium(iii) and one iridium(v) complexes featuring one (IrIII) or two (IrV) cyclometallated silylene ligands. The iridium(iii) complexes are active catalyst precursors for H/D exchange and dehydrogenative borylation of arene C-H bonds. PMID- 28862276 TI - A new insight into the thermodynamical criterion for the preparation of semiconductor and metal nanocrystals using a polymerized complexing method. AB - This work reports the intrinsic thermodynamical criterion for the preparation of metal and semiconductor nanocrystals using a polymerized complexing method. The basic principle of this method is the formation of a polymerized complexing structure between mono-, binary-, or ternary-metallic ions and bonding agents in aqueous or ethylene glycol solutions by evaporation of the solvents. Heat treatment of the complexing structure under N2 atmosphere produces H2 and CH4 gases, which can reduce the oxide crystalline nuclei to semiconductor and metallic nanocrystals. Experimental results show that Te, CdTe, Ag2Te, CuTe, NiTe1.5, CoTe1.5, Bi2Te3, Sb2Te3, Bi-Sb, In2Te3, Ni2.9SnTe2, CuGaTe2, and CuInS2 semiconductors and Bi, Sb, Ag, Cu, and Ni metallic nanocrystals can be prepared by this method. Transmission electron microscopy observations show that the obtained Bi, Ag2Te, Bi2Te3, Sb2Te3, CdTe, and NiTe1.5 nanocrystals have grain sizes in the nanometer range. The types of metallic and semiconductor phase that can be obtained by this method are explained by the thermodynamical criterion based on calculations of the Gibbs free energy and electrode potential. It is proposed that the crystalline phase of the final product is controlled by the change of the Gibbs free energies of the reactions of the metal oxide with reducing gases and the metal oxide redox electrode potentials, not the metal redox standard electrode potentials and electronegativities of the elements. Furthermore, a prediction is presented for the preparation of other kinds of binary and ternary compound based on the thermodynamical criterion. Our results provide new insight into facile and green preparation of semiconductor and metal nanocrystals. PMID- 28862277 TI - Graphene oxide as a catalyst for the diastereoselective transfer hydrogenation in the synthesis of prostaglandin derivatives. AB - Modification of GO by organic molecules changes its catalytic activity in the hydrogen transfer from i-propanol to enones, affecting the selectivity to allyl alcohol and diastereoselectivity to the resulting stereoisomers. It is noteworthy the system does not contain metals and is recyclable. PMID- 28862278 TI - Correction: Rapid determination of the tumour stroma ratio in squamous cell carcinomas with desorption electrospray ionization mass spectrometry (DESI-MS): a proof-of-concept demonstration. AB - Correction for 'Rapid determination of the tumour stroma ratio in squamous cell carcinomas with desorption electrospray ionization mass spectrometry (DESI-MS): a proof-of-concept demonstration' by Michael Woolman et al., Analyst, 2017, 142, 3250-3260. PMID- 28862279 TI - Synthesis of 4-benzylpyridines via Pd-catalyzed CH3-arylation of 4-picoline. AB - A highly efficient synthesis of 4-benzylpyridines was developed via Pd-catalyzed C(sp3)-H arylation between 4-picoline and aryl halides. It was found that the best yields were achieved with a simple Pd(PPh3)4 catalyst and Cs2CO3 as the base. Compared with the known methods, our reaction does not require the use of a strong organometallic reagent as the base. PMID- 28862280 TI - The templation effect as a driving force for the self-assembly of hydrogen-bonded peptidic capsules in competitive media. AB - Peptide-based cavitands (resorcin[4]arenes substituted with histidine and glutamine hydrazides) exist as monomeric species in polar solvents (DMSO and methanol). Upon complexation of fullerenes, the cavitands wrap around the hydrophobic guests forming dimeric capsular shells (as evidenced by DOSY). The self-assembly of the cavitands is based on the formation of beta-sheet-like binding motifs around the hydrophobic core. In a polar environment, these hydrogen bonded structures are kinetically stable and highly ordered as manifested by a 100-fold increase of intensity of circular dichroism bands, as well as a separate set of signals and substantial differences in chemical shifts in NMR spectra. This behavior resembles a protein folding process at the molten globule stage with non-specific hydrophobic interactions creating a protective and favourable local environment for the formation of secondary structures of proteins. PMID- 28862281 TI - The role of the secondary structure of helical poly(phenylacetylene)s in the formation of nanoparticles from polymer-metal complexes (HPMCs). AB - The great importance of the secondary structure (compressed/stretched) of helical poly(phenylacetylene)s (PPAs) in the formation of nanostructures (nanospheres and nanotoroids) by complexation with metal ions of diverse valences is demonstrated. PPAs bearing the same chelating units [anilide of (R)-methoxyphenylacetic acid] but displaying different helical scaffolds show great differences in their nanostructuration due to the different secondary structures of their helices despite the analogous ways in which their mono- and divalent metal ions form complexes. This key 3-D structural feature has not been taken into account previously when studying the nanostructuration of helical polymer-metal complexes (HPMCs). PMID- 28862282 TI - Hybrid mesoporous silica nanocarriers with thermovalve-regulated controlled release. AB - Mesoporous silica nanoparticles (MSNs) are excellent nanocarriers, featuring very high cargo capacity due to their large surface area and pore volume. The particle and pore dimensions can be accurately tuned, and both the internal and external surfaces allow versatile functionalization. We developed hybrid MSNs with diameters around 140 nm, with the external surface selectively modified with a temperature-responsive biocompatible copolymer to control cargo release. The nanoparticles feature either a polymer brush or a gel-like responsive shell, produced by grafting from RAFT polymerization of PEG-acrylate macromonomers. The hybrid nanoparticles have fluorescent molecules incorporated into the inorganic network providing excellent optical properties for traceability and imaging. The cargo release profiles are explained by a temperature-controlled "pumping" mechanism: at low temperature (ca. 20 degrees C) the polymer shell is hydrophilic and expanded, opposing cargo diffusion out of the shell and retaining the molecules released from the mesopores; above room temperature (ca. 40-50 degrees C) the polymer network becomes more hydrophobic and collapses onto the silica surface, releasing the cargo by a sponge-like squeezing effect. The release kinetics depends on the polymer shell type, with better results obtained for the gel-coated nanoparticles. Our proof-of-concept system shows that by modulating the temperature, it is possible to achieve a pumping regime that increases the release rate in a controlled way. PMID- 28862283 TI - Controlling the photochemical reaction of an azastilbene derivative in water using a water-soluble pillar[6]arene. AB - Photochemistry plays an important role in our lives. It has also been a common tool in the laboratory to construct complicated systems from small molecules. Supramolecular chemistry provides an opportunity to solve some of the problems in controlling photochemical reactions via non-covalent interactions. By using confining media and weak interactions between the medium and the reactant molecule, the excited state behavior of molecules has been successfully manipulated. Pillararenes, a new class of macrocyclic hosts, have rarely been used in the field of photochemical investigations, such as the controlling of photo-induced reactions. Herein, we explore a synthetic macrocyclic host, a water soluble pillar[6]arene, as a controlling tool to manipulate the photo-induced reactions (hydration) in water. A host-guest system in water based on a water soluble pillar[6]arene and an azastilbene derivative, (E)-4,4'-dimethyl-4,4' diazoniastilbene diiodide, has been constructed. Then this water-soluble pillar[6]arene was successfully employed to control the photohydration of the azastilbene derivative in water as a "protective agent". PMID- 28862284 TI - Detection of atrial fibrillation in patients with embolic stroke of undetermined source by prolonged monitoring with implantable loop recorders. AB - Recently, the clinical entity embolic stroke of undetermined source (ESUS) has been defined for patients with ischemic strokes, where neither a cardioembolic nor a non-cardiac source can be detected. These patients may suffer from asymptomatic atrial fibrillation (AF), terminating spontaneously and thus eluding detection. Implantable loop recorders (ILR) with automatic AF detection algorithms can detect short-lasting, subclinical AF. The aim of this study was to prospectively assess and predict AF detection in patients with ESUS using ILR with daily remote interrogation. Patients with acute ESUS received an ILR, were seen every 6 months and additionally interrogated their ILR daily using remote monitoring. The incidence of AF detection was assessed and parameters which might predict AF detection (clinical and from magnetic resonance tomography) were analysed. ILR implantation was performed in 123 patients on average 20 days after stroke. During a mean follow-up of 12.7+/-5.5 months, AF was documented and manually confirmed in 29 of 123 patients (23.6 %). First AF detection occurred on average after 3.6+/-3.4 months of monitoring. Patients with AF were on average older, had a higher CHA2DS2-VASc score and more often cerebral microangiopathy. In conclusion, AF can be documented in approximately 25 % of patients with the diagnosis of ESUS after careful work-up within a year of monitoring by an ILR and daily remote interrogation. This had important therapeutic consequences (initiation of anticoagulation for secondary stroke prevention) in these patients. PMID- 28862285 TI - Accumulating data on rivaroxaban for venous thromboembolism in clinical practice. PMID- 28862286 TI - Electrospun Nanofibrous Polyacrylonitrile/calixarene Mats: an Excellent Adsorbent for the Removal of Chromate Ions from Aqueous Solutions. AB - Herein, calixarene molecules containing piperidine units at lower rim or upper rim of calix skeleton was turned into a water resistant composite nanofiber adsorbent using polyacrylonitrile (PAN) polymeric support via electrospinning process. The PAN based calixarene nanofibrous adsorbents showed an excellent adsorption capacity toward the toxic chromate anions in aqueous solution. Furthermore, this new nanofiber mats would be promising filter materials for drinking water purification. PMID- 28862287 TI - Use of Differential Scanning Calorimetry and Immunoaffinity Chromatography to Identify Disease Induced Changes in Human Blood Plasma Proteome. AB - Differential scanning calorimetry provides unique signatures of blood plasma samples. Plasma samples from diseased individuals yield specific thermograms, which differ from each other and from plasma samples of healthy individuals. Thermograms from individuals suffering from chronic lymphocytic leukemia, multiple myeloma and acute myeloid leukemia were measured with DSC. To obtain additional information about thermal behaviour of plasma proteins immunoaffinity chromatography was introduced. An immunoextraction of HSA using a chromatographic column with immobilized anti-HSA was carried out in order to enrich less abundant plasma proteins, which could provide a further insight into disease development. Efficiency of HSA depletion and protein composition of fractionated plasma was validated by SDS-PAGE. PMID- 28862288 TI - Preliminary Evaluation of Animal Bone Char as Potential Metal Stabilization Agent in Metal Contaminated Soil. AB - The aim of this study was to evaluate the potential effect of animal bone char (ABC) addition on metal mobility in mine tailings. The mobility of metals after addition of ABC to tailings at four different application rates (0.6 g, 1.2 g, 1.8 g and 3.6 g ABC per 100 g of tailings) was evaluated by Toxicity Characteristic Leaching Procedure (TCLP) one step extraction. The obtained results indicated that the mobility of Pb, Cr and Cd gradually decreased with increasing quantity of added ABC. According to the TCLP, mobile concentrations of Pb in tailings exceeded threshold values for almost eight times. After ABC addition, Pb TCLP-extractable concentrations decreased from 39 mg L-1 in tailings to lower than the TCLP limit values of 5 mg L-1 at all ABC application rates, except in mixtures with the lowest addition of ABC. We concluded that ABC could be a successful metal stabilization agent for multi-metal contaminated soil, although attention should be paid at highly As contaminated soil. PMID- 28862289 TI - Lipid Droplet Formation in HeLa Cervical Cancer Cells Depends on Cell Density and the Concentration of Exogenous Unsaturated Fatty Acids. AB - Cytosolic lipid droplets (LDs) store excess fatty acids (FAs) in the form of neutral lipids and prevent starvation-induced cancer cell death. Here we studied the ability of mono- and polyunsaturated FAs to affect LD formation and survival in HeLa cervical cancer cells. We found that the LD content in HeLa cells increases with cell density, but it decreases in MDA-MB-231 breast cancer cells. Exogenously-added unsaturated FAs, including oleic (OA), linoleic (LA), arachidonic (AA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) displayed a similar ability to alter LD formation in HeLa cells. There was a dual, concentration-dependent effect on neutral lipid accumulation: low micromolar concentrations of LA, AA and DHA reduced, while all FAs induced LD formation at higher concentrations. In serum starved He-La cells, OA stimulated LD formation, but, contrary to expectations, it promoted cell death. Our results reveal a link between cell population density and LD formation in HeLa cells and show that unsaturated FAs may both suppress or stimulate LD formation. This dynamic regulation of LD content must be accounted for when studying the effects of lipids and lipid metabolism-targeting drugs on LD metabolism in HeLa cells. PMID- 28862290 TI - Cold Plasma and Acid Treatment Modification Effects on Phonolite. AB - A sample of phonolite was treated by cold plasma and hydrochloric acid diluted in water to study the change of its structure and acid properties. The phonolite and treated samples were analysed by XRD, elemental analysis XRF, specific surface area BET, TPD-NH3 and FT-IR spectroscopy. They were also tested in the adsorption of Ca, K, Mg, P and Na impurities present in waste cooking oil. Plasma treated sample presented almost the same structure with some surface differences respect to the original phonolite. However, acid treated sample presented bigger total surface compared to the other samples, different structure, composition and acid properties. PMID- 28862291 TI - Trans-Activation Response Element RNA is Detectable in the Plasma of a Subset of Aviremic HIV-1-Infected Patients. AB - Determining the HIV-1 reservoir size in infected individuals is of great importance for improvement of their treatment. Plasma trans-activation response element (TAR) RNA has been suggested as one of the possible biomarkers. TAR RNA is produced during non-processive transcription in HIV-1 productively infected and latent T cells. Here, plasma samples and paired exosome samples of 55 subjects from the observational SCOPE cohort were analysed for the presence of TAR RNA. First, a PCR-based assay was optimized, which provided 100% specificity and 100% sensitivity in differentiating HIV-1 infected non-controllers from uninfected individuals. Next, TAR RNA was detected in the plasma of 63% of aviremic HIV-1-infected patients, who were either treated with antiretroviral therapy or were elite controllers. Although TAR RNA levels did not correlate with patient gender, age, CD4 levels, CD8 levels, they tended to correlate with CD4/CD8 ratio (P = 0.047). This study is the first to investigate plasma TAR RNA in a relatively large cohort of HIV-1-infected patients. We additionally show that the TAR RNA molecules in the plasma of aviremic patients are not limited to exosomes. PMID- 28862293 TI - Bismuth(III) Complexes with Bis(dimethylphenyl) Dithiophosphates: Synthesis, Characterization and Crystal Structure of [{(3,5-CH3)2C6H3O}2PS2]3Bi. AB - This work presents four complexes with general formula [(ArO)2PS23Bi] (1-4), where Ar = 2,4-(CH3)2C6H3, 2,5-(CH3)2C6H3, 3,4-(CH3)2C6H3 and 3,5-(CH3)2C6H3, respectively. Reaction of [(ArO)2PS2Na] with Bi(NO3)3 . 5H2O in toluene in 3:1 molar stoichiometry afforded the complexes [(ArO)2PS23Bi]. These newly synthesized complexes have been characterized by elemental analysis, FT-IR and multinuclear NMR (1H, 13C and 31P) NMR. The crystal structure of [(3,5 CH3)2C6H3O2PS2]3Bi (4) has been determined by X-ray crystallography. The compound crystallizes in monoclinic P21/c space group and Bi(III) centre is surrounded by six sulfur atoms from three symmetrically chelating bidentate diphenyl dithiophosphate ligands in a distorted octahedron environment. Screening these complexes for their antifungal activity against Pencillium chrysogenum gave positive results. PMID- 28862292 TI - Chemometric Characterization of Slovenian Red Wines. AB - Total phenolic (TPC), flavonoid (TFC) and tannin (TTC) contents, total SO2, total acids, pH, and reducing sugars were measured in twenty five Slovenian red wines from three key wine producing regions, Podravje, Posavje and Primorska. The results were chemometrically analysed and the wines were classified according to wine growing region and vine variety. Principal component analysis proved that TPC, TFC and TTC contents were primarily responsible for variation in the wines. Additionally, linear discriminant analysis (LDA) was performed and resulted in the satisfactory classification of samples by both vine variety and region. PMID- 28862294 TI - Design, Preparation and Characterization of MoO3H-functionalized Fe3O4@SiO2 Magnetic Nanocatalyst and Application for the One-pot Multicomponent Reactions. AB - Molybdic acid-functionalized silica-based Fe3O4 nanoparticles (Fe3O4@SiO2-MoO3H) are found to be a powerful and magnetically recyclable nanocatalyst. The morphology and structure of this nanocatalyst were investigated by Fourier transform infrared spectroscopy (FT-IR), energy dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), thermo gravimetric analyses (TGA), X-ray diffraction (XRD) and vibrating sample magnetometer (VSM) techniques. The high catalytic activity of this catalyst was investigated in the synthesis of pyrano[2,3-c]chromenes, representing potent biologically active compounds. The catalyst can be readily separated by applying an external magnet device and recycled up to 8 times without significant decrease in its catalytic activity, which makes it highly beneficial to address the industrial needs and environmental concerns. Fe3O4@SiO2 MoO3H has many advantages, such as low cost, low toxicity, ease of preparation, good stability, high reusability and operational simplicity. PMID- 28862295 TI - Synthesis of Some Substituted 6-Phenyl Purine Analogues and Their Biological Evaluation as Cytotoxic Agents. AB - A series of 6-(4-substituted phenyl)-9-(tetrahydropyran-2-yl)purines 3-9, 6-(4 substituted phenyl)purines 10-16, 9-((4-substituted phenyl)sulfonyl)-6-(4 substituted phenyl)purines 17-32 were prepared and screened initially for their in vitro anticancer activity against selected human cancer cells (liver Huh7, colon HCT116, breast MCF7). 6-(4-Phenoxyphenyl) purine analogues 9, 16, 30-32, had potent cytotoxic activities. The most active purine derivatives 5-9, 14, 16, 18, 28-32 were further screened for their cytotoxic activity in hepatocellular cancer cells. 6-(4-Phenoxyphenyl)-9-(tetrahydropyran-2-yl)-9H-purine (9) had better cytotoxic activity (IC50 5.4 MUM) than the well-known nucleobase analogue 5-FU and known nucleoside drug fludarabine on Huh7 cells. The structure-activity relationship studies reported that the substitution at C-6 positions in purine nucleus with the 4-phenoxyphenyl group is responsible for the anti-cancer activity. PMID- 28862296 TI - Disintegrins from the Venom of Vipera ammodytes ammodytes Efficiently Inhibit Migration of Breast Cancer Cells. AB - Integrins are plasma membrane proteins, whose dysfunction frequently results in cancer pathology, and therefore they represent important targets of anti-tumour therapy. Snake venoms are a rich source of disintegrins (Dis), proteins that specifically bind integrins and thus interfere with their functions. In an attempt to discover new molecules for treatment of breast cancer, the major type of cancer in women, we isolated a dimeric Dis (Vaa-Dis) from the venom of the nosehorned viper. By cell viability testing we demonstrated that 50 nM and higher concentrations of Vaa-Dis were toxic to highly invasive human breast adenocarcinoma cell line MDA-MB-231. Wound-healing assay revealed that already at one order of magnitude lower concentrations Vaa-Dis efficiently inhibited MDA-MB 231 cell migration. This exposed a promising anti-metastatic potential of Vaa-Dis and a good perspective of these natural snake venom proteins for further research and development towards the application in breast cancer treatment. PMID- 28862297 TI - Synthesis, Antimicrobial Activity and in silico Studies on Thymol Esters. AB - Derivatisation of parent structure in terpenoids often results in enhancement of biological activity of newly obtained compounds. Thymol, a naturally occurring phenol biosynthesized through the terpene pathway, is a well known biocide with strong antimicrobial attributes and diverse therapeutic activities. We have aimed our study on a single modification of phenolic functionality in thymol in order to obtain a small focused library of twenty thymyl esters, ten of which were new compounds. All compounds were involved in in vitro antimicrobial testing. Another important aspect of current study was implementation of in silico calculation of physico-chemical, pharmacokinetic and toxicological properties, which could be helpful by giving an additional guidance in further research. PMID- 28862298 TI - Effectiveness of Student Learning during Experimental Work in Primary School. AB - The aim of the research was to optimize the effectiveness of student learning based on experimental work in chemistry classes in Slovenian primary schools. To obtain evidence about how experimental work is implemented during regular chemistry classes, experimental work was videotaped during 19 units of chemistry lessons at 12 Slovenian primary schools from the pool of randomly selected schools. Altogether 332 eight-grade students were involved in the investigation, with an average age of 14.2 years. Students were videotaped during chemistry lessons, and their worksheets were collected afterward. The 12 chemistry teachers, who conducted lessons in these schools, were interviewed before the lessons; their teaching plans were also collected. The collected data was analyzed using qualitative methods. The results indicate that many teachers in Slovenian primary schools are not fully aware of the potential of experimental work integrated into chemistry lessons for the development of students' experimental competence. Further research of the value of different kinds of training to support teachers for the use of experimental work in chemistry teaching is needed. PMID- 28862299 TI - N,N,N',N'-Tetrabutyl-1,10-phenanthroline-2,9-dicarboxamide as Very Effective Extraction Agent for Trivalent Europium and Americium. AB - Solvent extraction of microamounts of Eu3+ and Am3+ from water into nitrobenzene by means of a mixture of hydrogen dicarbollylcobaltate (H+B-) and N,N,N',N' tetrabutyl-1,10-phenanthroline-2,9-dicarboxamide (L) was studied. The equilibrium data were explained assuming that the species HL+, H2L2+, HL+2, ML3+2, and ML3+3 (M3+ = Eu3+, Am3+; L = N,N,N',N'-tetrabutyl-1,10-phenanthroline-2,9 dicarboxamide) are extracted into the nitrobenzene phase. Extraction and stability constants of the cationic complex species in nitrobenzene saturated with water were determined and discussed. From the experimental results it is evident that this effective N,N,N',N'-tetrabutyl-1,10-phenanthroline-2,9 dicarboxamide receptor for the Eu3+ and Am3+ cations could be considered as a potential extraction agent for nuclear waste treatment. PMID- 28862300 TI - Interaction of PER2 with the Constitutive Androstane Receptor Possibly Links Circadian Rhythms to Metabolism. AB - Period 2 (PER2) is an important factor in daily oscillations called circadian rhythms, which are emerging as one of the most important regulatory networks, responsible for homeostasis and transcriptional regulation of a number of genes. Our work shows that PER2 could act as a co-activator of the constitutive androstane receptor (CAR), a key nuclear receptor (NR) that regulates the metabolism of endobiotics and xenobiotics. Bioinformatic analysis shows that PER2 and CAR possess structural elements that could enable them to interact which was confirmed experimentally by CoIP experiment. Co-transfection of mouse hepatocarcinoma cells with plasmids overexpressing Per2 and Car increases expression of Bmal1, a potential CAR target gene, more than transfections with Car only. This is the first report indicating the interaction of PER2 and CAR. PMID- 28862301 TI - Synthesis and Properties of two CuI Complexes Involving Tetrathia-fulvalene-Fused Phenanthroline Ligand. AB - Two CuI complexes based on the pi-conjugated tetrathiafulvalene-annulated phenanthroline ligands (TTF-Phen, L1 and L2), [CuI(Xantphos)(L1)]BF4 (1, Xantphos = 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene) and [CuI(Binap)(L2)]BF4 (2, Binap = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), have been synthesized. They have been fully characterized, and their photophysical and electrochemical properties are reported together with those of L1 and L2 for comparison. Both CuI complexes show metal-to-ligand charge transfer (MLCT) absorption bands, whereas the 3MLCT luminescence is strongly quenched. PMID- 28862302 TI - Magnetite-Containing Sulfonated Polyacrylamide as a Nanocatalyst for the Preparation of Biscoumarins. AB - Magnetite-containing sulfonated polyacrylamide was easily prepared through polymerization of the corresponding monomers followed by the reaction with Fe3O4 nanoparticles. The characterization of the obtained catalyst was performed by Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), and vibrating sample magnetometer (VSM). The acidic SO3H moiety was found to be 1.1 mmol per gram of the obtained polymer. The catalytic activity of the polymer was examined for the synthesis of biscoumarin derivatives by two-component one-pot domino Knoevenagel-type condensation/Michael reaction between aldehydes and 4-hydroxycoumarin. Biscoumarins were obtained in high to excellent yields in short time. The work-up procedure of this reaction was very simple. The catalyst is stable (as a bench top catalyst) with easy-handling and it can be used again. PMID- 28862303 TI - Adsorption of Cr(III) from Aqueous Solution using Borax Sludge. AB - Borax sludge is the waste produced by a trommel sieve in the borax production process and is used as an adsorbent for Cr(III) removal. The effects of various parameters, including pH, initial Cr(III) concentration and contact time were investigated for batch adsorption of Cr(III). The experimental results obtained were applied to different adsorption isotherms and kinetic models. The results indicated that the Temkin isotherm (R2 = 0.9749) was most suitable to explain the adsorption characteristics of borax sludge, and the removal of Cr(III) was achieved by a physisorption process. The overall kinetic data fitted the pseudo second order rate model (R2 = 0.9990). According to thermodynamic studies, which were carried out at different temperatures, changes in enthalpy (DeltaH) and entropy (DeltaS) values for Cr(III) adsorption by borax sludge were determined to be 69.395 kJ/mol and 0.276 kJ/mol K, respectively. The study implied that borax sludge could be used as an alternative adsorbent in the adsorption of Cr(III) from aqueous solutions. PMID- 28862304 TI - Surface Modification of Alumina Nanoparticles: A Dispersion Study in Organic Media. AB - The alumina nanoparticles (NPs) have been synthesized from reaction between alum with ammonia and then calcined the precipitate at 1200 degrees C for 4 h. Its surface was modified by oleic acid (OA) and trimethoxyvinylsilane (TMVS) in o xylene at 50 degrees C. The alumina NPs and its modified were characterized by XRD, FT-IR, SEM, EDX and TGA. The TGA analysis indicated that the grafting amount of OA and TMVS were 10.5 and 8.0% respectively. The dispersion of modified NPs was determined in monomers such as methyl methacrylate (MMA), butyl acrylate (BuA) and styrene (St) and in solvents such as ethanol, hexane and acetone. The experimental results showed that the highest dispersion was happened NPs modified by oleic acid in n-hexane, while the highest dispersion was observed NPs modified by TMVS in acetone. The results indicate that NPs modified by oleic acid formed a stable dispersion in MMA and BuA. The highest amount of dispersion happened NPs modified by oleic acid in MMA and BuA in initial weight of 5 and 2.5% respectively, while stable dispersion is formed in styrene when TMVS is used as modifier. The highest amount of dispersion was happened NPs modified by TMVS in styrene in initial weight of 2.5%. PMID- 28862305 TI - In vitro assessment of potential bladder papillary neoplasm treatment with functionalized polyethyleneimine coated magnetic nanoparticles. AB - Normal porcine urothelial cells have been shown to have a much lower rate of endocytosis than urothelial papillary neoplasm cells. This could be used as a mechanism for selective delivery of toxic compounds, such as polyethyleneimine coated nanoparticles (NPs). However, these NPs induce nonselective toxicity through direct membrane disruption. This toxicity can be reduced by functionalization of NPs with L-glutathione reduced or bovine serum albumin by reducing their surface charge. Functionalization was confirmed with Fourier Transform Infrared Spectroscopy, Dynamic Light Scattering and zeta potential measurements. Viability assays showed that bovine serum albumin coating reduced NPs cytotoxicity immediately after 3 h exposure and that such NPs were more toxic to urothelial papillary neoplasm cells compared to normal porcine urothelial cells at 50 MUg/ml NPs concentration. However, 24 h after exposure, bovine serum albumin functionalized NPs had similar effect on viability of both cell lines. NPs showed some selective toxicity towards urothelial papillary neoplasm cells compared to normal cells after 3 h, however this was not confirmed after 24 h. PMID- 28862307 TI - Synthesis of Hetero- and Homo-multinuclear Complexes with a Tetracyanonickelate Anion: Structural Characterization [Cu(bcen)Ni(CN)4]2. AB - Two new complexes [Cu(bcen)Ni(CN)4]2 (1) and [Ni(bcen)Ni(CN)4] (2) where bcen is 4,7-diazadecanediamide, were synthesized by reaction of equimolar amounts of M(NO3)2 (M = Cu and Ni), bcen ligand and K2[Ni(CN)4]. Single-crystal X-ray diffraction analysis of compound 1, shows that the bcen ligand acts as a tridentate chelate, coordinating to the Cu(II) ion via the two nitrogen atoms of the amine groups and one oxygen atom of one amide group, and the other amide unit is left uncoordinated. The coordination geometry around the Cu(II) ions is five coordinate with a distorted square pyramid geometry, comprising two nitrogen atoms and one oxygen atom belonging to the bcen ligand and two nitrogen atoms of the cyano groups of two Ni(CN)4 2- units. The distance between the copper ion and the amide oxygen of the dangling arm of an adjacent tetranuclear species is within the expected range for an axial Cu-O bond, and hence suggests that the amide oxygen of an adjacent tetranuclear complex may weakly coordinate to the copper ion in an axial position. These contacts link the tetranuclear species into infinite chain polymers. PMID- 28862306 TI - Novel HPLC-UV Method for Simultaneous Determination of Fat-soluble Vitamins and Coenzyme Q10 in Medicines and Supplements. AB - A precise, accurate and rapid HPLC-UV method for simultaneous determination of fat-soluble vitamins (vitamin D3, E-acetate, K1, beta-carotene, A-palmitate) and coenzyme Q10 was developed and validated according to ICH guidelines. Optimal chromatographic separation of the analytes in minimal analysis time (8 min) was achieved on a Luna C18 150 * 4.6 mm column using a mixture of acetonitrile, tetrahydrofuran and water (50:45:5, v/v/v). The described reversed phase HPLC method is the first published for quantification of these five fat-soluble vitamins and coenzyme Q10 within a single chromatographic run. The method was further applied for quantification of the analytes in selected liquid and solid dosage forms, registered as nutritional supplements and prescription medicines, which confirmed its suitability for routine analysis. PMID- 28862308 TI - Synthesis, X-ray Structural Characterization, and DFT Calculations of Binuclear Mixed-ligand Copper(II) Complexes Containing Diamine, Acetate and Methacrylate Ligands. AB - The dinuclear Cu(II) complexes [Cu(en)(MAA)(MU-CH3COO)]2 (1) and [Cu(pn)(MAA)(MU CH3COO)]2 (2) where MAA, en and pn are methacrylate, ethylendiamine and 1,3 propylendiamine, respectively, have been synthesized and characterized by elemental analysis, FT-IR and UV-Vis spectroscopy. The structures of the complexes have been determined by single-crystal X-ray diffraction analyses. In the dinuclear complexes 1 and 2 the two copper centers are five-coordinated and exhibit distorted square pyramidal geometries. The theoretical geometries of the studied compounds have been calculated by means of density functional theory (DFT) at the B3LYP/6-311+G(d,p)/LanL2DZ level considering effective core potential (ECP). PMID- 28862309 TI - Ionic Liquid-Assisted Liquid-Liquid Microextraction based on the Solidification of Floating Organic Droplet in Sample Preparation for Simultaneous Determination of Herbicide Residues in Fruits. AB - An ionic liquid-assisted liquid-liquid microextraction based on the solidification of floating organic droplet (ILSFODLLME) was investigated for analysis of four herbicide residues (i.e. simazine, atrazine, propazine, and linuron) by high performance liquid chromatography. For ILSFOD-LLME, the optimal extraction conditions were 5% w/v Na2SO4, 30 MUL [C4MIM][PF6]RTIL, 100 MUL of 1 octanol, ultrasonication time 30 s and centrifugation at 5000 rpm for 5 min. Under the optimal conditions, linearity was obtained within the range of 0.1-1000 MUg kg-1, with the correlation coefficients greater than 0.999. The high enrichment factors of the target analytes were in the range of 64.5-139.9 and low limit of detection could be obtained. A modified QuEChERS was applied for fruit sample preparation before analysis. Matrix effects were also investigated using matrix matched standards for construction of the calibration graph. The proposed method has been successfully applied for extraction and preconcentration of herbicide residues in fruit samples, and good recoveries in the range of 87.32% to 99.93% were obtained. PMID- 28862310 TI - Modelling the Correlation Between Molecular Electrostatic Potential and pKa on Sets of Carboxylic Acids, Phenols and Anilines. AB - Calculations of molecular electrostatic potential were correlated with experimental pKa values for different sets of acidic molecules (carboxylic acids, phenols, and anilines) to obtain linear relationships of variable quality. A single tri-parameter model function was constructed to describe the pKa dependence on MEP maxima together with two automatically generated molecular descriptors, namely the counts of carboxylic acid and amine functional groups. PMID- 28862311 TI - A Dansyl-Rhodamine Based Fluorescent Probe for Detection of Hg2+ and Cu2. AB - A novel fluorescent probe based on dansyl-appended rhodamine B was developed. The probe can selectively recognize and sense Hg2+ and Cu2+ from other common metal ions by showing unique fluorescence and absorption characteristics. In MeCN/HEPES buffer solution, the probe gives a ratiometric fluorescent response to Hg2+, which was ascribed to the fluorescence resonance energy transfer from dansyl moiety to the ring-opened rhodamine B moiety, while the presence of Cu2+ causes fluorescence quenching. Beside the fluorescence change, the presence of Cu2+ and Hg2+ can induce intensive absorption at about 555 nm, which resulted in a color change from colorless to pink. PMID- 28862312 TI - Synthesis of 2,4,5-Trisubstituted Phenanthroimidazole Derivatives using SBA-Pr SO3H as a Nanocatalyst. AB - An efficient one-pot approach for the preparation of 2,4,5-trisubstituted phenanthroimidazole derivatives is described. The three-component reaction between 9,10-phenanthraquinone, benzaldehyde derivatives, and ammonium acetate proceeds in the presence of SBA-Pr-SO3H as a nanoporous solid acid catalyst in short reaction times and good to excellent yields. PMID- 28862313 TI - Measurement properties of maximal cardiopulmonary exercise tests protocols in persons after stroke: A systematic review. AB - OBJECTIVE: To systematically review and critically appraise the literature on measurement properties of cardiopulmonary exercise test protocols for measuring aerobic capacity, VO2max, in persons after stroke. DATA SOURCES: PubMed, Embase and Cinahl were searched from inception up to 15 June 2016. A total of 9 studies were identified reporting on 9 different cardiopulmonary exercise test protocols. STUDY SELECTION: VO2max measured with cardiopulmonary exercise test and open spirometry was the construct of interest. The target population was adult persons after stroke. We included all studies that evaluated reliability, measurement error, criterion validity, content validity, hypothesis testing and/or responsiveness of cardiopulmonary exercise test protocols. DATA EXTRACTION: Two researchers independently screened the literature, assessed methodological quality using the COnsensus-based Standards for the selection of health Measurement INstruments checklist and extracted data on measurement properties of cardiopulmonary exercise test protocols. DATA SYNTHESIS: Most studies reported on only one measurement property. Best-evidence synthesis was derived taking into account the methodological quality of the studies, the results and the consistency of the results. CONCLUSION: No judgement could be made on which protocol is "best" for measuring VO2max in persons after stroke due to lack of high-quality studies on the measurement properties of the cardiopulmonary exercise test. PMID- 28862314 TI - Working capacity after a subarachnoid haemorrhage: A six-year follow-up. AB - OBJECTIVE: Subarachnoid haemorrhage can lead to long-term disabilities. It is a major health issue for the patient and can affect work capacity. The aim of this study was to investigate working capacity after subarachnoid haemorrhage from a long-term perspective, using data from national sick leave records. In addition, factors associated with working capacity were analysed. DESIGN: A retrospective cohort study. SUBJECTS/PATIENTS: A consecutive total sample of 38 working-age participants with first-ever subarachnoid haemorrhage was included. Working capacity of the 30 participants not on early retirement prior to the subarachnoid haemorrhage was analysed. METHODS: Working capacity was defined as no longer being registered on sick leave or early retirement in the Social Insurance Agency and not being age retired or deceased. RESULTS: Regain of working capacity continued until 2.5 years post-subarachnoid haemorrhage and 73% of the participants were deemed to have working capacity. Functional independence at discharge from hospital, and higher responsiveness at admittance were the main factors associated with an earlier regain of working capacity. CONCLUSION: Nearly three-quarters of subjects were deemed to have working capacity within 2.5 years post-subarachnoid haemorrhage with a non-self-reported outcome. This information will help to individualize rehabilitation for affected persons. PMID- 28862315 TI - Effectiveness of postoperative home-exercise compared with usual care on kinesiophobia and physical activity in spondylolisthesis: A randomized controlled trial. AB - OBJECTIVE: To study the effectiveness of a 12-month exercise therapy on kinesiophobia and physical activity in patients with spondylolisthesis after lumbar spine fusion. DESIGN: Randomized controlled trial. SUBJECTS: Patients (n = 98) with spondylolisthesis who had undergone lumbar spine fusion. METHODS: All patients (mean age 59 years) had received lumbar spine fusion surgery and identical postoperative instructions. Three months postoperatively, they were randomized into an exercise group (n = 48) or usual care group (n = 50). The exercise group received 12-month progressive home-based training with regular booster sessions, and the usual care group a single session of physiotherapy instruction. Kinesiophobia was assessed with the Tampa Scale for Kinesiophobia (TSK) and physical activity by the International Physical Activity Questionnaire (IPAQ) preoperatively, 3 months after lumbar spine fusion, and at the end of the 12-month intervention. RESULTS: Before the intervention, the median (first quartile; third quartile) of TSK was 32.5 (29.0; 37.0) in the exercise group and 30.0 (25.8; 36.0) in the usual care group, changing to 30.0 (25; 36) in the exercise group and to 30.5 (24; 36.3) in the usual care group (between-group p = 0.17). IPAQ metabolic equivalent minutes per week increased from 1,863 (1,040; 3,042) to 3,190 (1,634; 6,485) in the exercise group and from 2,569 (1,501; 4,075) to 3,590 (1,634; 6,484) in the usual care group (between-group p = 0.92). CONCLUSION: Progressive 12-month home-exercise starting 3 months postoperatively was not superior to usual care in decreasing kinesiophobia or increasing physical activity in spondylolisthesis. PMID- 28862316 TI - Reliability and concurrent validity of standardized walking obstacle course test in people with stroke. AB - OBJECTIVES: To investigate: (i) the intra-rater, inter-rater and test-retest reliabilities of completion times and step counts on the Standardized Walking Obstacle Course test (SWOC); (ii) correlations between SWOC scores and stroke specific impairments; (iii) the cut-off SWOC completion times and step counts for distinguishing differences in obstacle negotiation ability in people with chronic stroke and healthy older adults. DESIGN: Cross-sectional study. SETTING: University-based rehabilitation centre. SUBJECTS: Twenty-nine people with stroke and 30 healthy older adults. METHODS: SWOC completion times and step counts were measured under 3 conditions: (i) normal walking; (ii) walking with a tray; and (iii) walking with dark-glasses. The Fugl-Meyer Assessment of lower extremity, the Five-Times-Sit-to-Stand Test, the Berg Balance Scale, the Timed Up and Go Test (TUG), and the Community Integration Measure questionnaire, were also administered. RESULTS: SWOC completion times and step counts showed very satisfactory to excellent reliabilities (intraclass correlation coefficient; ICC = 0.851-0.993). TUG times correlated significantly with SWOC completion times and step counts under the 3 conditions (r = 0.586-0.815, p < 0.001). SWOC completion times of 14.73-16.00 s and step counts of 23.06-24.13, depending on different walking conditions, were able to discriminate between stroke survivors and healthy older adults. CONCLUSION: The SWOC is a reliable clinical tool for assessing obstacle negotiation ability in people with stroke. PMID- 28862317 TI - Is prolongation of corrected QT interval associated with seizures induced by electroconvulsive therapy reduced by atropine sulfate? AB - BACKGROUND: Electrocardiogram abnormalities have been reported during electroconvulsive therapy (ECT). A corrected QT interval (QTc) prolongation indicates delayed ventricular repolarization, which can trigger ventricular arrhythmias such as torsade de pointes (TdP). We examined the QTc changes during generalized tonic-clonic seizures induced by ECT, and the effects of atropine sulfate on these QTc changes. METHODS: We analyzed heart rate, QT interval, and QTc in 32 patients with depression who underwent ECT (25 women, 67.4 +/- 8.7 years of age). The QTc from -30 to 0 seconds prestimulation was used as baseline, which was compared with QTc at 20-30 seconds and 140-150 seconds poststimulus onset. RESULTS: QTc was significantly prolonged at 20-30 seconds poststimulus, then significantly decreased at 140-150 seconds poststimulus, compared with baseline. QTc prolongation induced by ECT was significantly decreased by atropine sulfate. CONCLUSIONS: These data suggest that the risk of TdP may be enhanced by ECT. Further, the risk of cardiac ventricular arrhythmias, including TdP, may be reduced by administration of atropine sulfate. PMID- 28862318 TI - Case of bullous pemphigoid accompanied by collagenous gastroenteritis. PMID- 28862320 TI - Case of toxic shock syndrome triggered by negative-pressure wound therapy. PMID- 28862321 TI - Expression of HLA-DRA and CD74 mRNA in whole blood during the course of complicated and uncomplicated Staphylococcus aureus bacteremia. AB - To improve management of Staphylococcus aureus bacteremia (SAB), better understanding of host-pathogen interactions is needed. In vitro studies have shown that S. aureus bacteria induce dose-dependent immunosuppression that is evidenced by reduced expression of major histocompatibility complex (MHC) class II on antigen presenting cells. Thus, the aim of this study was to determine whether expression of the MHC class II-related genes HLA-DRA and CD74 is more greatly reduced in complicated SAB, with its probable higher loads of S. aureus, than in uncomplicated SAB. Adult patients with SAB were prospectively included and blood samples taken on the day of confirmation of SAB (Day 1) and on Days 2, 3, 5 and 7. HLA-DRA and CD74 mRNA expression was determined by quantitative reverse transcription PCR. Sepsis was defined according to the Sepsis-3 classification and SAB was categorized as complicated in patients with deep seated infection and/or hematogenous seeding. Twenty patients with SAB were enrolled and samples obtained on all assessment days. HLA-DRA and CD74 expression did not differ significantly between patients with SAB and sepsis (n = 13) and those without sepsis (n = 7) on any assessment day. However, patients with complicated SAB (n = 14) had significantly weaker HLA-DRA expression on all five assessment days than patients with uncomplicated SAB (n = 6). Additionally, they tended to have weaker CD74 expressions. Neutrophil, monocyte and leukocyte counts did not differ significantly between complicated and uncomplicated SAB. In conclusion, patients with complicated SAB show weaker HLA-DRA expression than those with uncomplicated SAB during the first week of bacteremia. PMID- 28862322 TI - Squamous cell carcinoma of neck metastasized to the lung and cervical lymph nodes, successfully treated with systemic docetaxel and local radiation therapy to the neck in a renal transplant patient. PMID- 28862323 TI - A comparative study of quality and safety of Atlantic cod (Gadus morhua) fillets during cold storage, as affected by different thawing methods of pre-rigor frozen headed and gutted fish. AB - BACKGROUND: The catch of marine whitefish is typically seasonal, whereas the land based processing industry has a need for all-year stable supply of raw materials. This challenge can be met by applying fish frozen at sea. When using frozen fish, the methods employed for thawing may influence the safety and quality of the final product. This study aimed to investigate the applicability of novel thawing strategies in order to provide an all-year supply of high-quality and safe cod products. RESULTS: Comparative investigations of quality and safety factors after thawing in water, with and without air circulation, and contact thawing were performed. The parameters included water-holding capacity, thawing loss, drip loss, cooking yield, sensory evaluation and microbiological analyses (including total volatile bases nitrogen). Water thawing with air circulation provided faster thawing than water thawing without air circulation and contact thawing. For all three methods, the quality of the thawed fish was acceptable and the shelf life of the fillets during chilled storage was between 10 and 14 days post filleting. CONCLUSION: The results show that controlled freezing of cod, followed by appropriate thawing, may provide the processing industry with an all-year delivery of raw materials, without compromising quality and safety of the final product. (c) 2017 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 28862324 TI - Do sleep problems mediate the link between adverse childhood experiences and delinquency in preadolescent children in foster care? AB - BACKGROUND: Adverse childhood experiences (ACEs) are associated with multiple mental and physical health problems. Yet, mechanisms by which ACEs confer risk for specific problems are largely unknown. Children in foster care typically have multiple ACEs and high rates of negative sequelae, including delinquent behaviors. Mechanisms explaining this link have not been explored in this population. Impaired sleep has been identified as a potential mechanism by which ACEs lead to delinquency in adolescents, because inadequate sleep may lead to poor executive function and cognitive control - known risk factors for delinquency. METHODS: Interviews were conducted with 516 maltreated children in foster care, ages 9-11 years, and their caregivers regarding child exposure to ACEs, sleep problems, engagement in delinquent acts, symptoms of posttraumatic stress disorder, and current psychotropic medication use. ACEs data were also obtained from child welfare case records. RESULTS: After controlling for age, gender, race/ethnicity, placement type (residential, kin, foster), length of time in placement, posttraumatic stress symptoms, and current psychotropic medication use, sleep partially mediated the association between ACEs and delinquency. CONCLUSIONS: Although delinquency is likely multiply determined in this population, improving sleep may be one important strategy to reduce delinquency. PMID- 28862325 TI - Platelet-rich fibrin/aspirin complex promotes alveolar bone regeneration in periodontal defect in rats. AB - BACKGROUND AND OBJECTIVES: The efficacy and outcomes of aspirin in local defects and the use of platelet-rich fibrin (PRF) in periodontal defects were investigated. Whether the PRF/aspirin complex is a suitable scaffold and delivery system to carry sustained-release aspirin/salicylic acid to promote periodontal bone regeneration was determined. MATERIAL AND METHODS: PRF and PRF/aspirin complex were prepared. The concentrations of aspirin/salicylic acid released from the PRF/aspirin complex were calculated at 37 degrees C. Periodontal ligament mesenchymal cells were cultured on six-well plates with PRF or PRF/aspirin complex gel to analyze proliferation and migration. The alveolar bone between the inferior buccal mesial root and anterior buccal distal root of the first maxillary molar was removed in 15 rats randomly divided into three groups: no treatment, PRF or PRF/aspirin complex. Twelve weeks post-transplantation, 2D/3D micro-computed tomography and histomorphometric technique were used for quantitative analyses. RESULTS: The PRF/aspirin complex provided a sustained release aspirin/salicylic acid. Peak concentrations occurred 4 hours after transplantation and were sustained to 48 hours at 37 degrees C; the total concentration of released aspirin/salicylic acid was 83.5 mg/mL, respectively. The sustained-release promoted the proliferation and migration of periodontal ligament mesenchymal cells. Micro-computed tomography and histological data showed that both the PRF and PRF/aspirin complex enhanced periodontal bone formation (P<.05). Moreover, the new bone formation was two times greater in the PRF/aspirin complex group than the PRF group. CONCLUSION: Aspirin/salicylic acid could be sustained-released from PRF/aspirin complex, which could inhibit inflammation and improve the function of mesenchymal cells. The data might provide a new safe and easy clinical therapeutic strategy to promote periodontal bone reparation. PMID- 28862326 TI - Physicochemical characterization of actomyosin-paramyosin from giant squid mantle (Dosidicus gigas). AB - BACKGROUND: The giant squid (Dosidicus gigas) has been proposed as raw material to obtain myofibrillar protein concentrates. However, it has been observed that colloidal systems formed from squid proteins have limited stability. Therefore, the isolation and characterization of the actomyosin-paramyosin isolated (API) complex were performed, because they are the main proteins to which functionality has been attributed. RESULTS: Densitogram analysis revealed 45% of actin, 38% of myosin and 17% of paramyosin. The amino acid profile indicates a higher proportion of acidic amino acids, which gives a higher negative charge; this was supported by the zeta potential. Total sulfhydryl (TSH) content was lower compared with proteins of other aquatic species. CONCLUSION: The higher percentage of actin in relation to myosin, the presence of paramyosin, as well as the low content of sulfhydryl groups, could comprise the main causes of the low technological functional property of proteins from D. gigas mantle. (c) 2017 Society of Chemical Industry. PMID- 28862327 TI - Chemical composition, water vapor permeability, and mechanical properties of yuba film influenced by soymilk depth and concentration. AB - BACKGROUND: Yuba is a soy protein-lipid film formed during heating of soymilk. This study described yuba as an edible film by analyzing its chemical composition, water vapor permeability (WVP), and mechanical properties. Three yuba films were prepared by using different concentrations and depths of soymilk: HS (86 g kg-1 and 2.3 cm), LS (70 g kg-1 and 2.3 cm), and LD (70 g kg-1 and 3.0 cm). RESULTS: As yuba was successively skimmed, the protein, lipid, and ?SH content decreased, but carbohydrate and ?S?S? content increased. Though both the initial concentration and the depth of soymilk affect the properties of the films, the depth of soymilk influences WVP and tensile strength (TS) more. The WVP of the HS and LS changed the least (13-17 g mm kPa-1 m-2 day1 ), while that of the LD changed the most (13-35 g mm kPa-1 m-2 day-1 ). There were no differences (P > 0.05) in the TS between the HS and LS. LD had the greatest decrease of TS and the lowest TS among the groups. The earlier the yuba films were collected, the greater the elongation of the films was: 129% (HS), 113% (LS), and 155% (LD). CONCLUSION: The initial concentration and the depth of soymilk changed the chemical composition and structure of the yuba films. The LS yuba produced more uniform edible films with good mechanical properties. (c) 2017 Society of Chemical Industry. PMID- 28862328 TI - An allosteric gating model recapitulates the biophysical properties of IK,L expressed in mouse vestibular type I hair cells. AB - KEY POINTS: Vestibular type I and type II hair cells and their afferent fibres send information to the brain regarding the position and movement of the head. The characteristic feature of type I hair cells is the expression of a low voltage-activated outward rectifying K+ current, IK,L , whose biophysical properties and molecular identity are still largely unknown. In vitro, the afferent nerve calyx surrounding type I hair cells causes unstable intercellular K+ concentrations, altering the biophysical properties of IK,L . We found that in the absence of the calyx, IK,L in type I hair cells exhibited unique biophysical activation properties, which were faithfully reproduced by an allosteric channel gating scheme. These results form the basis for a molecular and pharmacological identification of IK,L . ABSTRACT: Type I and type II hair cells are the sensory receptors of the mammalian vestibular epithelia. Type I hair cells are characterized by their basolateral membrane being enveloped in a single large afferent nerve terminal, named the calyx, and by the expression of a low-voltage activated outward rectifying K+ current, IK,L . The biophysical properties and molecular profile of IK,L are still largely unknown. By using the patch-clamp whole-cell technique, we examined the voltage- and time-dependent properties of IK,L in type I hair cells of the mouse semicircular canal. We found that the biophysical properties of IK,L were affected by an unstable K+ equilibrium potential (Veq K+ ). Both the outward and inward K+ currents shifted Veq K+ consistent with K+ accumulation or depletion, respectively, in the extracellular space, which we attributed to a residual calyx attached to the basolateral membrane of the hair cells. We therefore optimized the hair cell dissociation protocol in order to isolate mature type I hair cells without their calyx. In these cells, the uncontaminated IK,L showed a half-activation at -79.6 mV and a steep voltage dependence (2.8 mV). IK,L also showed complex activation and deactivation kinetics, which we faithfully reproduced by an allosteric channel gating scheme where the channel is able to open from all (five) closed states. The 'early' open states substantially contribute to IK,L activation at negative voltages. This study provides the first complete description of the 'native' biophysical properties of IK,L in adult mouse vestibular type I hair cells. PMID- 28862329 TI - Virgin coconut oil reverses hepatic steatosis by restoring redox homeostasis and lipid metabolism in male Wistar rats. AB - BACKGROUND: Hepatosteatosis, a form of nonalcoholic fatty liver disease (NAFLD), is being increasingly recognized as a major health burden worldwide. Insulin resistance, dyslipidemia and imbalances in adipokine/cytokine interplay are reported to be involved in the onset and progression of this disease. Use of dietary nutraceuticals in prevention and treatment of NAFLD is emerging. Virgin coconut oil (VCO), a fermented product of fresh coconut kernel, has been shown to impede the development of hepatosteatosis in rats. This study analyzes the potential of VCO to reverse the already developed hepatosteatosis condition. RESULTS: Hyperglycemia, reduced glucose tolerance, dyslipidemia, and hepatic macrovesicles in high-fructose-diet-fed rats (4 weeks) confirmed the development of hepatosteatosis. Natural reversion in these parameters was observed upon shifting to normal diet in untreated control animals. Administration of VCO, however, increased this natural reversion by improving high-density lipoprotein cholesterol level (53.5%) and reducing hepatic and serum triacylglycerols (78.0 and 51.7%). Increased hepatic glutathione level (P < 0.01), antioxidant enzyme activities (P < 0.05) and reduced lipid peroxidation were also noticed in these animals. These observations were in concordance with reduced liver enzyme activities (P < 0.01) and restoration of altered hepatic architecture. CONCLUSION: The study indicates that VCO can be used as a nutraceutical against hepatosteatosis. (c) 2017 Society of Chemical Industry. PMID- 28862319 TI - Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research-practice gaps, challenges, and insights. AB - To date, five cancer treatment modalities have been defined. The three traditional modalities of cancer treatment are surgery, radiotherapy, and conventional chemotherapy, and the two modern modalities include molecularly targeted therapy (the fourth modality) and immunotherapy (the fifth modality). The cardiotoxicity associated with conventional chemotherapy and radiotherapy is well known. Similar adverse cardiac events are resurging with the fourth modality. Aside from the conventional and newer targeted agents, even the most newly developed, immune-based therapeutic modalities of anticancer treatment (the fifth modality), e.g., immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy, have unfortunately led to potentially lethal cardiotoxicity in patients. Cardiac complications represent unresolved and potentially life threatening conditions in cancer survivors, while effective clinical management remains quite challenging. As a consequence, morbidity and mortality related to cardiac complications now threaten to offset some favorable benefits of modern cancer treatments in cancer-related survival, regardless of the oncologic prognosis. This review focuses on identifying critical research-practice gaps, addressing real-world challenges and pinpointing real-time insights in general terms under the context of clinical cardiotoxicity induced by the fourth and fifth modalities of cancer treatment. The information ranges from basic science to clinical management in the field of cardio-oncology and crosses the interface between oncology and onco-pharmacology. The complexity of the ongoing clinical problem is addressed at different levels. A better understanding of these research-practice gaps may advance research initiatives on the development of mechanism-based diagnoses and treatments for the effective clinical management of cardiotoxicity. PMID- 28862330 TI - Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control. AB - KEY POINTS: The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart. The neural fulcrum is defined as the operating point, based on frequency-amplitude-pulse width, where a null heart rate response is reproducibly evoked during the on phase of VNS. Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus. Beta-receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS. While muscarinic cholinergic blockade prevented the VNS induced bradycardia, clinically relevant doses of ACE inhibitors, beta-blockade and the funny channel blocker ivabradine did not alter the VNS chronotropic response. While there are qualitative differences in VNS heart control between awake and anaesthetized states, the physiological expression of the neural fulcrum is maintained. ABSTRACT: Vagus nerve stimulation (VNS) is an emerging therapy for treatment of chronic heart failure and remains a standard of therapy in patients with treatment-resistant epilepsy. The objective of this work was to characterize heart rate (HR) responses (HRRs) during the active phase of chronic VNS over a wide range of stimulation parameters in order to define optimal protocols for bidirectional bioelectronic control of the heart. In normal canines, bipolar electrodes were chronically implanted on the cervical vagosympathetic trunk bilaterally with anode cephalad to cathode (n = 8, 'cardiac' configuration) or with electrode positions reversed (n = 8, 'epilepsy' configuration). In awake state, HRRs were determined for each combination of pulse frequency (2-20 Hz), intensity (0-3.5 mA) and pulse widths (130-750 MUs) over 14 months. At low intensities and higher frequency VNS, HR increased during the VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation were balanced, a null HRR was evoked (defined as 'neural fulcrum') during which HRR ~ 0. As intensity increased further, HR was reduced during the active phase of VNS. While qualitatively similar, VNS delivered in the epilepsy configuration resulted in more pronounced HR acceleration and reduced HR deceleration during VNS. At termination, under anaesthesia, transection of the vagi rostral to the stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent-mediated suppressing effect on electrical and mechanical function of the heart. In conclusion, VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy. PMID- 28862332 TI - Response to Dr. Serkan Cay comment on "Various approaches to reach the pericardial space for arrhythmia mapping and ablation". PMID- 28862331 TI - Selection and use of indigenous mixed starter cultures for mustard leaves fermentation and the improvement of cuocai characteristics. AB - BACKGROUND: To improve the characteristics and safety of traditional cuocai, the selection and use of mixed starter cultures is important. This study aimed to isolate the main indigenous lactic acid bacteria (LABs) and yeast species from spontaneous fermented mustard leaves, and they were used as starter cultures to ferment mustard leaves. RESULTS: Five predominant LABs, namely Q-1 (Enterococcus faecalis), G-1 (Lactobacillus plantarum), G-3 (Lactobacillus pentosus), and G-2 and G-4 (Lactobacillus buchneri) strains, and the two yeast strains J-1 (Issatchenkia orientalis) and J-2 (Issatchenkia occidentalis) were isolated from cuocai. From the results, Lb. plantarum and I. orientalis strains exhibited strong growth ability, fast acidification, and potent low-pH tolerance. Therefore, they were chosen as the mixed starter cultures to ferment mustard leaves. During the process of culture-dependent fermented mustard leaves, the changes of acidity, total crude protein, and total sugar were similar to those of culture-independent fermented mustard leaves, while the nitrite content of culture-dependent fermented mustard leaves was significantly lower than that of culture-independent fermented cuocai. According to gas chromatography-mass spectrometry analysis, the main volatile flavor compounds of fermented mustard leaves were alcohols, aldehydes, esters, and sulfides. There was no significant difference of volatile flavor compounds between the processes of culture dependent and culture-independent fermentations. CONCLUSION: Therefore, it was suggested that Lb. plantarum and I. orientalis strains could be used to ferment cuocai instead of the traditional ferment method to control the quality and shelf safety of cuocai. (c) 2017 Society of Chemical Industry. PMID- 28862333 TI - The effect of ultrasound on the alkali extraction of proteins from eggshell membranes. AB - BACKGROUND: Eggshell contains two layers formed by a dense network of fibrous proteins. These proteins are highly insoluble in a broad variety of solvents, but their composition makes them suitable for a broad range of applications. In this study, in order to extract and solubilise these proteins, the eggshell membranes were treated in an alkali solution. A Box-Behnken design was employed to determine the influence of the treatment variables on the amount of protein solubilised. Furthermore, the effect of ultrasound on the protein recovery yield was also evaluated and compared with the unmodified process. RESULTS: A solubilised protein yield close to 100% of the total eggshell membrane protein was obtained. The optimal conditions could be set at 70 degrees C in a 1.0 mol L 1 NaOH solution for 60 min. However, when ultrasound was applied, it was possible to decrease the time of reaction by half. In the two processes, the temperature was found to be the most important independent variable evaluated. Finally, the antioxidant properties of the proteins obtained in each case were similar. CONCLUSIONS: Ultrasound favours the detachment of big clumps of proteins from the eggshell membrane, facilitating the solubilisation of its compounds. The ultrasound had no effect on the protein properties tested in this study. (c) 2017 Society of Chemical Industry. PMID- 28862334 TI - SKUP3 : 6 and 24 months follow-up of changes in respiration and sleepiness after modified UPPP. AB - OBJECTIVE: Our previous randomized controlled trial of patients with obstructive sleep apnea syndrome (OSAS) showed that modified uvulopalatopharyngoplasty (UPPP), including tonsillectomy, significantly improved nocturnal respiration, daytime sleepiness, and quality of life in the intervention group compared to controls who had delayed surgery after 6 months. This is the continuous report with the 6- and 24-month postoperative results. STUDY DESIGN: Single-center prospective cohort study. METHODS: Sixty-five patients with apnea-hypopnea index (AHI) >= 15, body mass index (BMI) < 36, Epworth Sleepiness Scale (ESS) >= 8, and Friedman stage I or II underwent UPPP after failing nonsurgical treatment. The results from polysomnography and ESS at 6 and 24 months were compared to baseline. RESULTS: Eight percent and 20% dropped out from the 6- and 24-month follow-ups, respectively. The AHI value decreased significantly from mean (standard deviation) 52.9 (20.5) at baseline to 23.6 (20.2) after 6 months, and to 24.1 (20.9) after 24 months (P < 0.001). Patients with tonsil size 2, and 3 to 4, had significant reductions in the AHI after both follow-ups. The median ESS score decreased significantly from 13 (range 8-21) to 6.5 (1-18) after 6 months, and to 5 (2-17) after 24 months (P < 0.001). The BMI remained unchanged. There were significant modest correlations for the reductions in AHI and ESS after 24 months. CONCLUSION: Modified UPPP was effective in improving nocturnal respiration and daytime sleepiness in OSAS patients at both 6- and 24-month follow-up. Patients with tonsil size 2, and 3 to 4, benefitted similarly from surgery with improved respiration. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:1238 1244, 2018. PMID- 28862335 TI - Interventions to improve hand hygiene compliance in patient care. AB - BACKGROUND: Health care-associated infection is a major cause of morbidity and mortality. Hand hygiene is regarded as an effective preventive measure. This is an update of a previously published review. OBJECTIVES: To assess the short- and long-term success of strategies to improve compliance to recommendations for hand hygiene, and to determine whether an increase in hand hygiene compliance can reduce rates of health care-associated infection. SEARCH METHODS: We conducted electronic searches of the Cochrane Register of Controlled Trials, PubMed, Embase, and CINAHL. We conducted the searches from November 2009 to October 2016. SELECTION CRITERIA: We included randomised trials, non-randomised trials, controlled before-after studies, and interrupted time series analyses (ITS) that evaluated any intervention to improve compliance with hand hygiene using soap and water or alcohol-based hand rub (ABHR), or both. DATA COLLECTION AND ANALYSIS: Two review authors independently screened citations for inclusion, extracted data, and assessed risks of bias for each included study. Meta-analysis was not possible, as there was substantial heterogeneity across studies. We assessed the certainty of evidence using the GRADE approach and present the results narratively in a 'Summary of findings' table. MAIN RESULTS: This review includes 26 studies: 14 randomised trials, two non-randomised trials and 10 ITS studies. Most studies were conducted in hospitals or long-term care facilities in different countries, and collected data from a variety of healthcare workers. Fourteen studies assessed the success of different combinations of strategies recommended by the World Health Organization (WHO) to improve hand hygiene compliance. Strategies consisted of the following: increasing the availability of ABHR, different types of education for staff, reminders (written and verbal), different types of performance feedback, administrative support, and staff involvement. Six studies assessed different types of performance feedback, two studies evaluated education, three studies evaluated cues such as signs or scent, and one study assessed placement of ABHR. Observed hand hygiene compliance was measured in all but three studies which reported product usage. Eight studies also reported either infection or colonisation rates. All studies had two or more sources of high or unclear risks of bias, most often associated with blinding or independence of the intervention.Multimodal interventions that include some but not all strategies recommended in the WHO guidelines may slightly improve hand hygiene compliance (five studies; 56 centres) and may slightly reduce infection rates (three studies; 34 centres), low certainty of evidence for both outcomes.Multimodal interventions that include all strategies recommended in the WHO guidelines may slightly reduce colonisation rates (one study; 167 centres; low certainty of evidence). It is unclear whether the intervention improves hand hygiene compliance (five studies; 184 centres) or reduces infection (two studies; 16 centres) because the certainty of this evidence is very low.Multimodal interventions that contain all strategies recommended in the WHO guidelines plus additional strategies may slightly improve hand hygiene compliance (six studies; 15 centres; low certainty of evidence). It is unclear whether this intervention reduces infection rates (one study; one centre; very low certainty of evidence).Performance feedback may improve hand hygiene compliance (six studies; 21 centres; low certainty of evidence). This intervention probably slightly reduces infection (one study; one centre) and colonisation rates (one study; one centre) based on moderate certainty of evidence.Education may improve hand hygiene compliance (two studies; two centres), low certainty of evidence.Cues such as signs or scent may slightly improve hand hygiene compliance (three studies; three centres), low certainty of evidence.Placement of ABHR close to point of use probably slightly improves hand hygiene compliance (one study; one centre), moderate certainty of evidence. AUTHORS' CONCLUSIONS: With the identified variability in certainty of evidence, interventions, and methods, there remains an urgent need to undertake methodologically robust research to explore the effectiveness of multimodal versus simpler interventions to increase hand hygiene compliance, and to identify which components of multimodal interventions or combinations of strategies are most effective in a particular context. PMID- 28862336 TI - Editorial: Emerging Principles of Practice in Couple and Family therapy. PMID- 28862337 TI - Case of neutrophilic dermatosis as erythema nodosum migrans-like eruption with pustulosis in a patient with Crohn's disease. PMID- 28862338 TI - Automated Tracking of Cell Migration with Rapid Data Analysis. AB - Cell migration is essential for many biological processes including development, wound healing, and metastasis. However, studying cell migration often requires the time-consuming and labor-intensive task of manually tracking cells. To accelerate the task of obtaining coordinate positions of migrating cells, we have developed a graphical user interface (GUI) capable of automating the tracking of fluorescently labeled nuclei. This GUI provides an intuitive user interface that makes automated tracking accessible to researchers with no image-processing experience or familiarity with particle-tracking approaches. Using this GUI, users can interactively determine a minimum of four parameters to identify fluorescently labeled cells and automate acquisition of cell trajectories. Additional features allow for batch processing of numerous time-lapse images, curation of unwanted tracks, and subsequent statistical analysis of tracked cells. Statistical outputs allow users to evaluate migratory phenotypes, including cell speed, distance, displacement, and persistence, as well as measures of directional movement, such as forward migration index (FMI) and angular displacement. (c) 2017 by John Wiley & Sons, Inc. PMID- 28862339 TI - Determination of Membrane Protein Distribution on the Nuclear Envelope by Single Point Single-Molecule FRAP. AB - Nuclear envelope transmembrane proteins (NETs) are synthesized on the endoplasmic reticulum and then transported from the outer nuclear membrane (ONM) to the inner nuclear membrane (INM) in eukaryotic cells. The abnormal distribution of NETs has been associated with many human diseases. However, quantitative determination of the spatial distribution and translocation dynamics of NETs on the ONM and INM is still very limited in currently existing approaches. Here we demonstrate a single point single-molecule fluorescence recovery after photobleaching (FRAP) microscopy technique that enables quick determination of distribution and translocation rates for NETs in vivo. (c) 2017 by John Wiley & Sons, Inc. PMID- 28862340 TI - In Vitro Reconstitution of the Endoplasmic Reticulum. AB - Reconstitution of cellular organelles in vitro offers the possibility to perform quantitative and qualitative experiments in a controlled environment that cannot be done with the same accuracy in living cells. Following a previous report, the subsequent list of protocols describes how to reconstitute and quantify a tubular ER network in vitro based on purified microsomes from culture cells and cytosol from Xenopus laevis egg extracts. Biological material preparation and reconstitution assays require mostly basic laboratory instrumentation and chemicals, and can be executed without any specific training, making them appealing to a wide range of laboratories. Moreover, to promote conditions that are markedly more reflective of in vivo environments, this method describes for the first time in the literature, the purification of microsomes from HeLa cells in some detail. Basic Protocol 1 in this article describes the reconstitution process on different substrates including the associated fluorescence imaging process. Purification of ER microsomes and cytosol, both of which are needed for this approach, are described in detail in Support Protocols 1 and 2, respectively. Coating of surfaces with polyacrylamide gels is described in Support Protocol 3. Basic Protocol 2 outlines how to segment and skeletonize fluorescence images of ER networks, and how to quantify segment lengths between the network's branching points. The described quantitative evaluation provides a meaningful approach to analyze the topology and geometry of organelle structures. (c) 2017 by John Wiley & Sons, Inc. PMID- 28862341 TI - Centrifugation-Free Magnetic Isolation of Functional Mitochondria Using Paramagnetic Iron Oxide Nanoparticles. AB - Subcellular fractionation techniques are essential for cell biology and drug development studies. The emergence of organelle-targeted nanoparticle (NP) platforms necessitates the isolation of target organelles to study drug delivery and activity. Mitochondria-targeted NPs have attracted the attention of researchers around the globe, since mitochondrial dysfunctions can cause a wide range of diseases. Conventional mitochondria isolation methods involve high-speed centrifugation. The problem with high-speed centrifugation-based isolation of NP loaded mitochondria is that NPs can pellet even if they are not bound to mitochondria. We report development of a mitochondria-targeted paramagnetic iron oxide nanoparticle, Mito-magneto, that enables isolation of mitochondria under the influence of a magnetic field. Isolation of mitochondria using Mito-magneto eliminates artifacts typically associated with centrifugation-based isolation of NP-loaded mitochondria, thus producing intact, pure, and respiration-active mitochondria. (c) 2017 by John Wiley & Sons, Inc. PMID- 28862342 TI - Lectin-Array Blotting. AB - Aberrant protein glycosylation is a hallmark of cancer, infectious diseases, and autoimmune or neurodegenerative disorders. Unlocking the potential of glycans as disease markers will require rapid and unbiased glycoproteomics methods for glycan biomarker discovery. The present method is a facile and rapid protocol for qualitative analysis of protein glycosylation in complex biological mixtures. While traditional lectin arrays only provide an average signal for the glycans in the mixture, which is usually dominated by the most abundant proteins, our method provides individual lectin binding profiles for all proteins separated in the gel electrophoresis step. Proteins do not have to be excised from the gel for subsequent analysis via the lectin array but are transferred by contact diffusion from the gel to a glass slide presenting multiple copies of printed lectin arrays. Fluorescently marked glycoproteins are trapped by the printed lectins via specific carbohydrate-lectin interactions and after a washing step their binding profile with up to 20 lectin probes is analyzed with a fluorescent scanner. The method produces the equivalent of 20 lectin blots in a single experiment, giving detailed insight into the binding epitopes present in the fractionated proteins. (c) 2017 by John Wiley & Sons, Inc. PMID- 28862343 TI - Cellular Detection of G-Quadruplexes by Optical Imaging Methods. AB - G-quadruplexes (G4s) are higher-order nucleic acid structures that fold from guanine (G)-rich DNA and RNA strands. This field of research gains traction as a major chemical biology area since it aims at uncovering many key cellular mechanisms in which quadruplexes are involved. The wealth of knowledge acquired over the past three decades strongly supports pivotal roles of G4 in the regulation of gene expression at both transcriptional (DNA quadruplexes) and translational levels (RNA quadruplexes). Recent biochemical discoveries uncovered myriad of additional G4 actions: from chromosomal stability to the firing of replication origins, from telomere homeostasis to functional dysregulations underlying genetic diseases (including cancers and neurodegeneration). Here, we listed a repertoire of protocols that we have developed over the past years to visualize quadruplexes in cells. These achievements were made possible thanks to the discovery of a novel family of versatile quadruplex-selective fluorophores, the twice-as-smart quadruplex ligands named TASQ (for template-assembled synthetic G-quartet). The versatility of this probe allows for multiple imaging techniques in both fixed and live cells, including the use of the multiphoton microscopy, confocal microscopy, and real-time fluorescent image collection. (c) 2017 by John Wiley & Sons, Inc. PMID- 28862344 TI - Proximal nail plate destruction in subungual melanoma could be a possible predictor of invasiveness thicker than 1.25 mm. AB - Various patterns of nail plate destruction are common features in subungual melanoma (SUM), but there has been no reports regarding their clinical significance according to the pattern of nail plate destruction in terms of tumor thickness. We tried to find a relationship between dermal invasion of SUM and proximal nail plate destruction (PNPD). Clinical information of patients with SUM was reviewed retrospectively from seven dermatology training hospitals in Korea. The PNPD was defined as a visible loss of full thickness of nail plate touching the eponychium at the most proximal part of it. We evaluated whether there are correlations between patients' age, sex, location of SUM, Breslow thickness (BT) and the presence of PNPD. Among 93 patients with SUM, 36 (38.7%) showed PNPD. Sex and BT showed significant correlations with the presence of PNPD in univariate analysis (P < 0.05). BT, age and sex showed significant correlations with the presence of PNPD in multivariate analysis (P < 0.05). Among them, BT showed the strongest correlation with the presence of PNPD (area under the curve, 0.722) and the cut-off value was 1.25 mm. In conclusion, we suggest that PNPD in SUM could be a possible predictor of invasiveness of more than 1.25 mm BT. PMID- 28862346 TI - Dual-Pore Carbon Shells for Efficient Removal of Humic Acid from Water. AB - A template-mediated process for the preparation of mesoporous carbon shells with high surface area, dual-pore structure, and excellent performance in the adsorption of humic acid is reported. Their synthesis involves templating phenolic resin against wrinkled silica nanospheres, subsequent carbonization under Ar atmosphere, and final release of dual-pore mesoporous carbon shells by etching the silica templates. An additional silica layer was used to protect the phenolic resin from aggregation during carbonization, and its subsequent removal gives the carbon shells a hydrophilic surface, which significantly improves their dispersity in aqueous media. When used as adsorbents for humic acid removal, the as-prepared dual-pore mesoporous carbon shells show superior adsorption performance to activated carbon. PMID- 28862345 TI - Subgroups in language trajectories from 4 to 11 years: the nature and predictors of stable, improving and decreasing language trajectory groups. AB - BACKGROUND: Little is known about the nature, range and prevalence of different subgroups in language trajectories extant in a population from 4 to 11 years. This hinders strategic targeting and design of interventions, particularly targeting those whose difficulties will likely persist. METHODS: Children's language abilities from 4 to 11 years were investigated in a specialist language longitudinal community cohort (N = 1,910). Longitudinal trajectory latent class modelling was used to characterise trajectories and identify subgroups. Multinomial logistic regression was used to identify predictors associated with the language trajectories children followed. RESULTS: Three language trajectory groups were identified: 'stable' (94% of participants), 'low-decreasing' (4%) and 'low-improving' (2%). A range of child and family factors were identified that were associated with following either the low-improving or low-increasing language trajectory; many of them shared. The low-improving group was associated with mostly environmental risks: non-English-speaking background, social disadvantage and few children's books in the home. The low-decreasing group was associated with mainly biological risks: low birth weight, socioemotional problems, lower family literacy and learning disability. CONCLUSIONS: By 4 years, services can be confident that most children with low language will remain low to 11 years. Using rigid cut-points in language ability to target interventions is not recommended due to continued individual variability in language development. Service delivery models should incorporate monitoring over time, targeting according to language abilities and associated risks and delivery of a continuum of interventions across the continuum of need. PMID- 28862347 TI - Effects of Hydroxyethyl Starch 130/0.4 on Serum Creatinine Concentration and Development of Acute Kidney Injury in Nonazotemic Cats. AB - BACKGROUND: Hydroxyethyl-starch (HES) solutions might have renal adverse effects in humans and dogs. OBJECTIVE: To determine if administration of 6% HES-130/0.4 is associated with an increase in serum creatinine concentration and development of acute kidney injury (AKI) in nonazotemic cats. ANIMALS: A total of 62 critically ill cats; 26 HES exposed and 36 unexposed. METHODS: Retrospective cohort study (2012-2015). Serum creatinine concentrations were recorded and changes in serum creatinine concentrations before exposure (baseline) and 2-10 and 11-90 days, respectively, were determined. Development of AKI was defined as a > 150% increase or >26 MUmol/L increase in serum creatinine concentration from baseline. Risk factors, such as HES administration, cumulative volume of HES (mL/kg) and number of days of HES administration leading to development of AKI, and change in serum creatinine were analyzed. RESULTS: Cats in the HES cohort received a mean volume of 98.5 +/- 76.2 mL/kg (range, 8-278 mL/kg) HES over a median of 4 (range, 1-11) days, resulting in a median dose of 20.1 (range, 8 40.5) mL/kg per day. Short-term %change in serum creatinine concentration (P = 0.40) and development of AKI (P = 0.32) were not significantly different between cohorts. Multivariable logistic regression did not identify HES dose in mL/kg (P = 0.33) and number of days of HES application (P = 0.49) as a risk factor for development of AKI. CONCLUSION AND CLINICAL IMPORTANCE: Hydroxyethyl-starch administration to critically ill nonazotemic cats seems to be safe. A larger prospective study is required to determine the effect of HES administration at higher dosages and for prolonged time periods. PMID- 28862348 TI - Immunophenotype of Peripheral Blood Lymphocytes in Dogs with Inflammatory Bowel Disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is common in dogs. Despite the known importance of intestinal lymphocytes in its pathogenesis, little is known about the role of peripheral blood lymphocytes (PBLs) in IBD. OBJECTIVES: The aims of this study were (1) comparison of PBLs analyzed by flow cytometry (FCM) in IBD dogs and healthy controls and (2) comparison of PBLs in IBD dogs at the time of diagnosis and in dogs in clinical remission. ANIMALS: Whole blood samples of 19 IBD dogs at the time of diagnosis and blood samples of 6 dogs in clinical remission were collected. Ten healthy dogs served as controls. METHODS: In this prospective observational study, PBLs were analyzed with multicolor FCM by staining with a panel of anticanine and cross-reactive monoclonal antibodies against T- and B-cell differentiation antigens, including CD45, CD3, CD4, CD8alpha, CD8beta, TCRalphabeta, TCRgammadelta, CD79alphacy, and CD21. RESULTS: The IBD patients' PBLs had significantly decreased percentages of TCRgammadelta+ T lymphocytes (median: healthy dogs, 3.32; IBD dogs, 0.97; P = 0.03) and CD21+ B cells (median: healthy dogs, 27.61; IBD dogs, 17.26; P = 0.04). There were no significant differences in PBLs between pretreatment and follow-up samples. CONCLUSIONS AND CLINICAL IMPORTANCE: The differences between PBLs in healthy and IBD dogs analyzed by FCM indicate an imbalance of lymphocytes with different immunologic functions and emphasize the potential value of this technique in a larger cohort of dogs. The PBLs did not differ between IBD dogs before treatment and clinically well-controlled dogs after treatment. PMID- 28862349 TI - Z-spectrum appearance and interpretation in the presence of fat: Influence of acquisition parameters. AB - PURPOSE: Chemical exchange saturation transfer (CEST) MRI is increasingly evolving from brain to body applications. One of the known problems in the body imaging is the presence of strong lipid signals. Although their influence on the CEST effect is acknowledged, there was no study that focuses on the interplay among echo time, fat fraction, and Z-spectrum. This study strives to address these points, with the emphasis on the application in the breast. METHODS: Z spectra were simulated in phase and out of phase of the main fat peak at -3.4 ppm, with the fat fraction varying from 0 to 100%. The magnetization transfer ratio asymmetry in two ranges, centering at the exchanging pool and at 3.5 ppm approximately opposite the nonexchanging fat pool, were calculated and were plotted against fat fraction. The results were verified in phantoms and in vivo. RESULTS: The results demonstrate the combined influence of fat fraction and echo time on the Z-spectrum for gradient echo based CEST acquisitions. The influence is straightforward in the in-phase images, but it is more complicated in the out of-phase images, potentially leading to erroneous CEST contrast. CONCLUSIONS: This study provides a basis for understanding the origin and appearance of lipid artifacts in CEST imaging, and lays the foundation for their efficient removal. Magn Reson Med 79:2731-2737, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28862350 TI - Reconstruction by calibration over tensors for multi-coil multi-acquisition balanced SSFP imaging. AB - PURPOSE: To develop a rapid imaging framework for balanced steady-state free precession (bSSFP) that jointly reconstructs undersampled data (by a factor of R) across multiple coils (D) and multiple acquisitions (N). To devise a multi acquisition coil compression technique for improved computational efficiency. METHODS: The bSSFP image for a given coil and acquisition is modeled to be modulated by a coil sensitivity and a bSSFP profile. The proposed reconstruction by calibration over tensors (ReCat) recovers missing data by tensor interpolation over the coil and acquisition dimensions. Coil compression is achieved using a new method based on multilinear singular value decomposition (MLCC). ReCat is compared with iterative self-consistent parallel imaging (SPIRiT) and profile encoding (PE-SSFP) reconstructions. RESULTS: Compared to parallel imaging or profile-encoding methods, ReCat attains sensitive depiction of high-spatial frequency information even at higher R. In the brain, ReCat improves peak SNR (PSNR) by 1.1 +/- 1.0 dB over SPIRiT and by 0.9 +/- 0.3 dB over PE-SSFP (mean +/- SD across subjects; average for N = 2-8, R = 8-16). Furthermore, reconstructions based on MLCC achieve 0.8 +/- 0.6 dB higher PSNR compared to those based on geometric coil compression (GCC) (average for N = 2-8, R = 4-16). CONCLUSION: ReCat is a promising acceleration framework for banding-artifact-free bSSFP imaging with high image quality; and MLCC offers improved computational efficiency for tensor-based reconstructions. Magn Reson Med 79:2542-2554, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28862351 TI - Chemical shift encoding (CSE) for sensitive fluorine-19 MRI of perfluorocarbons with complex spectra. AB - PURPOSE: To implement a fluorine-19 (19 F) chemical shift encoding (CSE) approach for the sensitive imaging of molecules with multi-resonance spectra to remove their chemical shift displacement (CSD) artifacts, and to characterize its sensitivity versus established pulse sequences. METHODS: The feasibility of CSE spoiled gradient echo (GRE) and balanced steady-state free precession (bSSFP) was first demonstrated in a phantom study. The dependence of the sensitivity of CSE bSSFP on several pulse sequence parameters was then established, after which the occurrence of out-of-plane excitation was assessed for 2D and 3D techniques. Next, the sensitivity (in mm-3 s-0.5 ) of both CSE techniques was compared to bSSFP ultrashort echo time (bSSFP-UTE) imaging and multi-chemical-shift-selective turbo spin echo (MCSS-TSE) in a second phantom study. Finally, the sensitivity of the CSE-bSSFP, bSSFP-UTE, and MCSS-TSE pulse sequences was compared in a preliminary in vivo mouse study. RESULTS: Both CSE approaches were successfully implemented and resulted in negligible residual CSD artifacts, while large-volume 3D acquisitions should be considered to reduce problems related to out-of-plane excitation. CSE-bSSFP was shown to have a higher sensitivity than the bSSFP-UTE and MCSS-TSE pulse sequences (15.8 +/- 1.3 vs. 11.7 +/- 1.0 vs. 13.3 +/- 0.9 mm-3 s-0.5 , respectively, P < 0.001), whereas CSE-GRE technique had a lower sensitivity (4.8 +/- 1.1 mm-3 s-0.5 ). CONCLUSION: CSE 19 F MR imaging enables the unambiguous visualization of compounds with complex spectra, and provides high sensitivity both in vitro and in vivo. Magn Reson Med 79:2724-2730, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28862352 TI - Geometric distortion correction in prostate diffusion-weighted MRI and its effect on quantitative apparent diffusion coefficient analysis. AB - PURPOSE: To evaluate the effect of correction for B0 inhomogeneity-induced geometric distortion in echo-planar diffusion-weighted imaging on quantitative apparent diffusion coefficient (ADC) analysis in multiparametric prostate MRI. METHODS: Geometric distortion correction was performed in echo-planar diffusion weighted images (b = 0, 50, 400, 800 s/mm2 ) of 28 patients, using two b0 scans with opposing phase-encoding polarities. Histology-matched tumor and healthy tissue volumes of interest delineated on T2 -weighted images were mapped to the nondistortion-corrected and distortion-corrected data sets by resampling with and without spatial coregistration. The ADC values were calculated on the volume and voxel level. The effect of distortion correction on ADC quantification and tissue classification was evaluated using linear-mixed models and logistic regression, respectively. RESULTS: Without coregistration, the absolute differences in tumor ADC (range: 0.0002-0.189 mm2 /s*10-3 (volume level); 0.014-0.493 mm2 /s*10-3 (voxel level)) between the nondistortion-corrected and distortion-corrected were significantly associated (P < 0.05) with distortion distance (mean: 1.4 +/- 1.3 mm; range: 0.3-5.3 mm). No significant associations were found upon coregistration; however, in patients with high rectal gas residue, distortion correction resulted in improved spatial representation and significantly better classification of healthy versus tumor voxels (P < 0.05). CONCLUSIONS: Geometric distortion correction in DWI could improve quantitative ADC analysis in multiparametric prostate MRI. Magn Reson Med 79:2524-2532, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28862353 TI - The effect of CCR5Delta32 on the risk of grade 3-4 acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis. AB - OBJECTIVE: Many studies have showed that CCR5 was involved in the pathological process of acute graft-versus-host disease (aGVHD). However, the relationship between CCR5Delta32, a frameshift mutation, and grade 3-4 acute GVHD risk has not been well established. We performed a meta-analysis to explore the effects of CCR5 gene polymorphisms on grade 3-4 aGVHD. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched to collect relevant articles. Studies about association between CCR5 genotype in recipients or donors of allo-HSCT and aGVHD risk were included. All pooled analyses were based on fixed effects models. The effects were assessed from odd ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of three studies comprising 937 recipients and 914 donors of allo-HSCT met the inclusion criteria. Compared with the wild-type CCR5 homozygotes, the pooled odd ratios (ORs) for CCR5Delta32 mutation (both homozygous and heterozygous) was 0.71 (95% CI, 0.40-1.26; P = .24) for donors, and 0.79 (95% CI, 0.35-1.81; P = .58) for recipients. No relationship was found between the presence of the CCR5Delta32 mutation and grade 3-4 aGVHD. Larger clinical investigations and retrospective studies are needed to explore the association of CCR5 gene polymorphisms with aGVHD risk as well as the outcome of HSCT. PMID- 28862354 TI - Feline Differential Leukocyte Count with ProCyte Dx: Frequency and Severity of a Neutrophil-Lymphocyte Error and How to Avoid It. AB - BACKGROUND: Erroneous neutrophil and lymphocyte counts from analysis of feline blood samples were transferred directly into the hospital information system from the ProCyte Dx hematology instrument in our after-hours laboratory. Errors usually were not detected by the users. HYPOTHESIS/OBJECTIVES: To quantify the frequency and severity of errors associated with the ProCyte Dx analyzer and to identify methods to avoid the errors. ANIMALS: One-hundred six EDTA blood samples routinely submitted from feline hospital patients were analyzed. METHODS: ProCyte differential leukocyte counts were compared to 2 reference methods: Advia 2120 hematology instrument and manual enumeration. Limits for unacceptable deviation from the reference methods were defined as 18 for % lymphocytes and 23 for % neutrophils. RESULTS: Fourteen of 106 samples had unacceptable errors for both lymphocytes and neutrophils compared to both reference methods. Median % lymphocytes in those 14 samples were 11.2, 15.0, and 53.0% for Advia, manual, and ProCyte, respectively. Median % neutrophils were 85.4, 81.5, and 34.2% for Advia, manual, and ProCyte, respectively. All errors were avoided by rejecting automated ProCyte differential leukocyte results whenever the dot plot appeared clearly incorrect, but only 9 of these 14 samples had a ProCyte WBC distribution error flag. CONCLUSIONS AND CLINICAL IMPORTANCE: Results reported by ProCyte had markedly falsely increased lymphocyte and decreased neutrophil counts in 13% of feline patient samples. Users must reject automated differential leukocyte count results when the WBC dot plot appears overtly incorrect. Rejection based only on ProCyte WBC error flag was insufficient. PMID- 28862355 TI - Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel sulfate. AB - While insoluble nickel subsulfide (Ni3 S2 ) was carcinogenic in the lung in a 2 year rat bioassay, soluble nickel sulfate hexahydrate (NiSO4* 6H2 O) was not. To investigate whether differences in the cellular responses to these two nickel compounds could underlie their differential activities, we conducted parallel studies to determine the gene expression changes in micro-dissected lung distal airway cells from Fischer 344 rats following inhalation of the two compounds for one and four weeks (6 hr per day, 5 days per week). The results of the Ni3 S2 study have been reported previously; this paper reports the results for NiSO4 and provides a comparative analysis. The cellular responses to NiSO4 were highly similar to those previously reported for Ni3 S2 , and a set of genes was identified whose expression could be used as biomarkers for comparing cellular nickel effects from in vitro or in vivo studies with soluble NiSO4 and particulate Ni3 S2 . Evaluation of the genomic concentration-responses for the two compounds suggests that the highest inhaled concentration in the tumor bioassay for NiSO4 , which was limited by toxicity, may not have achieved the Ni concentrations at which tumors were observed in the Ni3 S2 bioassay. However, several key differences in the immune responses to NiSO4 and Ni3 S2 were identified that may result from the differential intracellular disposition of Ni from NiSO4 entering the cell as an ion rather than as a slowly soluble Ni3 S2 particle. These differences may also contribute to the observation of tumors in the bioassay for Ni3 S2 but not NiSO4 . Environ. Mol. Mutagen. 58:607-618, 2017. (c) 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. PMID- 28862356 TI - Health survey and assessment of the polymorphisms BRCA1/P871L, BRCA1/Q356R, and BRCA2/N372H in female gas station workers in Rio de Janeiro. AB - Gas station workers are exposed to chemicals known to be carcinogenic, especially benzene. The objective was to analyze the health problems of female gas station workers by means of sociodemographic and clinical questionnaires, and laboratorial exams. We performed the genotyping of the polymorphisms BRCA1/P871L and BRCA1/Q356R by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism, and of variant allele BRCA2/N372H through direct sequencing. The female workers showed a higher concentration of monocytes (P = 0.039); a greater number of spontaneous abortions (P = 0.025, OR = 4.977, 95% CI = 1.135-30.669); higher tobacco consumption (P = 0.013); and higher alcohol consumption (P = 0.05). The statistical analysis of the polymorphisms associated with the variables monocyte concentration and miscarriage number did not reveal a significant relationship, and smoking and spontaneous abortion were not statistically associated either. Environ. Mol. Mutagen. 58:730-734, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28862357 TI - High early post-operative complication rate after elective aseptic orthopedic implant removal of upper and lower limb. AB - The necessity of orthopedic implant removal is under intense discussion and even if it is performed as an elective procedure, the risk of complications is present. Aim of the study was to identify parameters responsible for an increased risk of early post-operative complications after elective aseptic orthopedic implant removal. We reviewed 1,545 cases of aseptic and elective orthopedic implant removal between 2009 and 2011. The patients demographic data, time and duration of operation, patients comorbidities, and presence of complications in the first 4 weeks after implant removal were evaluated. Patients with signs of infection at the time of the surgical procedure were excluded from this study. 579 women and 966 men who underwent elective aseptic orthopedic implant removal were identified. Mean age at implant removal was 42 years and mean duration of the surgical procedure was 37 min. In this cohort, 70 patients (4.5%) underwent elective aseptic implant removal after 6pm. 52 patients (3.37%) operated on during daytime suffered from complications post-operatively and five patients (0.3%) who were operated on during the night experienced complications. The parameters age, sex, BMI, and surgeon showed no statistically significant differences for the risk of post-operative complications. Patients' comorbidities such as diabetes seem to have influence but were not statistically significant either. Patients with revision surgery since their first operation, nocturnal surgery and longer duration of the procedure showed a statistically significant higher risk for complications, especially in the lower leg. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1035-1039, 2018. PMID- 28862358 TI - Anti-apoptosis endothelial cell-secreted microRNA-195-5p promotes pulmonary arterial smooth muscle cell proliferation and migration in pulmonary arterial hypertension. AB - In the pathological mechanism of pulmonary arterial hypertension, the role of apoptosis-resistant pulmonary microvascular endothelial cells (PVECs/AR) has been emphasized on the pulmonary vascular remodeling. In the present study, we investigated whether PVECs/AR can promote the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), and to study the role of miR-195 5p in the crosstalk between these two types of cells. We confirmed that PVECs/AR can promote the proliferation and migration of PASMCs in a co-culture system of AR/PVECs and PASMCs. Additionally, after exposure to hypoxia for 12 or 24 h, AR/PVECs had a higher mature miR-195-5p level than PVECs (P < 0.05, 12 and 24 h). Luciferase reporter assays were used to validate indications of the existence of an HRE in the miR-195-5p promoter. Knocking down Smad7 can reverse the inhibition of Lv-S195 on TGF-beta1-induced PASMCs remodeling. TGF-beta1 promoted cell growth in PASMCs, and the supernatant of PVECs/AP infected with Lv-S195 inhibited TGF beta1 enhanced proliferation in PASMCs, which was also blocked by Lv-shRNA-Smad7. The result of this experiment confirmed the specificity of the HIF-1a/miR 195/Smad7 pathway. Our data indicate the possible function of PVECs/AR in the process of pulmonary vascular remodeling. MiRNA-195-5p played a role as an interacting paracrine factor between PVECs/AR and PASMC, which seemed to function through the HIF-1a/miRNA-195-5p/Smad7 pathway. PMID- 28862359 TI - Novel A178P mutation in SLC16A2 in a patient with Allan-Herndon-Dudley syndrome. PMID- 28862360 TI - Mechanically stimulated biomarkers signal cartilage changes over 5 years consistent with disease progression in medial knee osteoarthritis patients. AB - Using serum biomarkers to assess osteoarthritis (OA) disease state and risks of progression remain challenging. This study tested the hypothesis that changes to serum biomarkers in response to a mechanical stimulus in patients with medial knee OA signal cartilage thickness changes 5 years later. Specifically, serum concentrations of a collagen degradation marker (C1,2C) and a chondroitin sulfate synthesis marker (CS846) were measured 0.5 and 5.5 hours after a 30-min walk in 16 patients. Regional cartilage thickness changes measured from magnetic resonance images obtained at study entry and at 5-year follow-up were tested for correlations with baseline biomarker changes after mechanical stimulus, and for differences between groups stratified based on whether biomarker levels increased or decreased. Results showed that an increase in the degradation biomarker C1,2C correlated with cartilage thinning of the lateral tibia (R = -0.63, p = 0.009), whereas an increase in the synthesis marker CS846 correlated with cartilage thickening of the lateral femur (R = 0.76, p = 0.001). Changes in C1,2C and CS846 were correlated (R2 = 0.28, p = 0.037). Subjects with increased C1,2C had greater (p = 0.05) medial tibial cartilage thinning than those with decreased C1,2C. In conclusion, the mechanical stimulus appeared to metabolically link the biomarker responses where biomarker increases signaled more active OA disease states. The findings of medial cartilage thinning for patients with increases in the degradation marker and correlation of cartilage thickening in the less involved lateral femur with increases in the synthetic marker were consistent with progression of medial compartment OA. Thus, the mechanical stimulus facilitated assessing OA disease states using serum biomarkers. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:891-897, 2018. PMID- 28862361 TI - Accumulation of advanced-glycation end products (AGEs) accelerates arthrogenic joint contracture in immobilized rat knee. AB - Joint mobility decreases in the elderly and in diabetics, this process is thought to be caused by accumulation of advanced-glycation end products (AGEs). Here, we aimed to elucidate the role of AGEs in joint contracture formation in rat knees. Rats were injected with ribose or saline into the knees twice weekly for 8 weeks. Pentosidine (AGE) levels were measured in the knee-joint tissues. After serial injections, rats were subjected to unilateral knee-joint immobilization in a flexion position for various periods. At day 21, the passive knee ranges of motions (ROMs) were measured. Knee joint histopathology were assessed, and the expression of fibrotic genes in the posterior joint capsules was examined using real-time PCR. Ribose injection induced a 7.0-fold increase in pentosidine levels relative to saline injection. Joint immobilization resulted in equal myogenic ROM restriction in both groups. Arthrogenic ROM restriction was greater with ribose injection in the immobilized joints (p < 0.05), but was not affected in nonimmobilized joints. Type-I (COL1A1) and type-III (COL3A1) collagen gene expression increased significantly in immobilized joints relative to nonimmobilized joints in the ribose group, but was not affected in the saline group. Ribose injection increased COL1A1 expression slightly and COL3A1 expression significantly in immobilized joints. Histologically, inflammatory changes appeared at day 3 of immobilization and peaked at day 7. These responses trended to be more severe and prolonged in the ribose group than in the saline group. Our data provide evidence for a causal relationship between AGEs and joint contracture formation following immobilization. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:854-863, 2018. PMID- 28862362 TI - Controlling the object phase for g-factor reduction in phase-Constrained parallel MRI using spatially selective RF pulses. AB - PURPOSE: Parallel imaging generally entails a reduction in the signal-to-noise ratio of the final image. Phase-constrained methods aim to improve reconstruction quality by using symmetry properties of k-space. Noise amplification in phase constrained reconstruction depends heavily on the object background phase. The purpose of this work is to present a new approach of using tailored radiofrequency pulses to optimize the object phase distribution in order to maximize the benefit of phase-constrained reconstruction, and to minimize the noise amplification. METHODS: Intrinsic object phase and coil sensitivity profiles are measured in a prescan. Optimal phase distribution is computed to maximize signal-to-noise ratio in the given setup. Tailored radiofrequency pulses are designed to introduce the optimal phase map in the following accelerated acquisitions, subsequently reconstructed by phase-constrained methods. The potential of the method is demonstrated in vivo with in-plane accelerated (8x) and simultaneous multislice (3x) acquisitions. RESULTS: Mean g-factors are reduced by up to a factor of 2 compared with conventional techniques when an appropriate phase-constrained reconstruction is applied to phase-optimized acquisitions, enhancing the signal-to-noise ratio of the final images and the visibility of small details. CONCLUSIONS: Combining phase-constrained reconstruction and phase optimization by tailored radiofrequency pulses can provide notable improvement in the signal-to-noise ratio and reconstruction quality of accelerated MRI. Magn Reson Med 79:2113-2125, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28862363 TI - Selective Utilization of the Methoxy Group in Lignin to Produce Acetic Acid. AB - Selective transformation of lignin into a valuable chemical is of great importance and challenge owing to its complex structure. Herein, we propose a strategy for the transformation of methoxy group (-OCH3 ) which is abundant in lignin into pure highly valuable chemicals. As an example to apply this strategy, a route to produce acetic acid with high selectivity by conversion of methoxy group of lignin was developed. It was demonstrated that the methoxy group in lignin could react with CO and water to generate acetic acid over RhCl3 in the presence of a promoter. The conversions of methoxy group in the kraft lignin and organosolv lignin reached 87.5 % and 80.4 %, respectively, and no by-product was generated. This work opens the way to produce pure chemicals using lignin as the feedstock. PMID- 28862364 TI - Gold Catalysis for Heterocyclic Chemistry: A Representative Case Study on Pyrone Natural Products. AB - 2-Pyrones and 4-pyrones are common structural motifs in bioactive natural products. However, traditional methods for their synthesis, which try to emulate the biosynthetic pathway of cyclization of a 1,3,5-tricarbonyl precursor, are often harsh and, therefore, not particularly suitable for applications to polyfunctionalized and/or sensitive target compounds. pi-Acid catalysis, in contrast, has proved to be better for a systematic exploration of the pyrone estate. To this end, alkynes are used as stable ketone surrogates, which can be activated under exceedingly mild conditions due to the pronounced carbophilicity of [LAu]+ fragments (L=two electron donor ligand); attack of a tethered ester carbonyl group onto the transient alkyne-gold complex then forges the pyrone ring in a fully regiocontrolled manner. PMID- 28862365 TI - Further Insight into Crystal Structures of Escherichia coli IspH/LytB in Complex with Two Potent Inhibitors of the MEP Pathway: A Starting Point for Rational Design of New Antimicrobials. AB - IspH, also called LytB, a protein involved in the biosynthesis of isoprenoids through the methylerythritol phosphate pathway, is an attractive target for the development of new antimicrobial drugs. Here, we report crystal structures of Escherichia coli IspH in complex with the two most potent inhibitors: (E)-4 mercapto-3-methylbut-2-en-1-yl diphosphate (TMBPP) and (E)-4-amino-3-methylbut-2 en-1-yl diphosphate (AMBPP) at 1.95 and 1.7 A resolution, respectively. The structure of the E. coli IspH:TMBPP complex exhibited two conformers of the inhibitor. This unexpected feature was exploited to design and evolve new antimicrobial candidates in silico. PMID- 28862366 TI - Redirecting Killer T Cells through Incorporation of Azido Sugars for Tethering Ligands. AB - The genetic expression of chimeric antigen receptors (CARs) on the surfaces of T cells enables the redirection of T cell specificity. To enhance the versatility of T cells as tumor-specific killers, we developed a nongenetic approach by which azide-containing sialic acids were metabolically incorporated into T cells to modify cellular sialyl glycans. After successful display of these moieties on the T cells, small-molecule ligands such as RGD and folate (as proof-of-concept, rather than supersized antibodies) were clicked orthogonally, leading to highly selective time- and dose-dependent cytotoxicity to integrin alphav beta3 - and folate-receptor-positive cells, respectively. This chemical approach provides a facile platform for rational design of tumor-specific cytotoxic T cells for targeted immunotherapy. PMID- 28862367 TI - Auxiliary-Directed C(sp3 )-H Arylation by Synergistic Photoredox and Palladium Catalysis. AB - Herein we describe the auxiliary-directed arylation of unactivated C(sp3 )-H bonds with aryldiazonium salts, which proceeds under synergistic photoredox and palladium catalysis. The site-selective arylation of aliphatic amides with alpha quaternary centres is achieved with high selectivity for beta-methyl C(sp3 )-H bonds. This operationally simple method is compatible with carbocyclic amides, a range of aryldiazonium salts and proceeds at ambient conditions. PMID- 28862368 TI - Convergent Evolution of Ergothioneine Biosynthesis in Cyanobacteria. AB - Biosynthesis of N-alpha-trimethyl-2-thiohistidine (ergothioneine) is a frequent trait in cyanobacteria. This sulfur compound may provide essential relief from oxidative stress related to oxygenic photosynthesis. The central steps in ergothioneine biosynthesis are catalyzed by a histidine methyltransferase and an iron-dependent sulfoxide synthase. In this report, we present evidence that some cyanobacteria recruited and adapted a sulfoxide synthase from a different biosynthetic pathway to make ergothioneine. The discovery of a second origin of ergothioneine production underscores the physiological importance of this metabolite and highlights the evolutionary malleability of the thiohistidine biosynthetic machinery. PMID- 28862369 TI - Consideration of the haplotype diversity at nonallelic homologous recombination hotspots improves the precision of rearrangement breakpoint identification. AB - Precise characterization of nonallelic homologous recombination (NAHR) breakpoints is key to identifying those features that influence NAHR frequency. Until now, analysis of NAHR-mediated rearrangements has generally been performed by comparison of the breakpoint-spanning sequences with the human genome reference sequence. We show here that the haplotype diversity of NAHR hotspots may interfere with breakpoint-mapping. We studied the transmitting parents of individuals with germline type-1 NF1 deletions mediated by NAHR within the paralogous recombination site 1 (PRS1) or paralogous recombination site 2 (PRS2) hotspots. Several parental wild-type PRS1 and PRS2 haplotypes were identified that exhibited considerable sequence differences with respect to the reference sequence, which also affected the number of predicted PRDM9-binding sites. Sequence comparisons between the parental wild-type PRS1 or PRS2 haplotypes and the deletion breakpoint-spanning sequences from the patients (method #2) turned out to be an accurate means to assign NF1 deletion breakpoints and proved superior to crude reference sequence comparisons that neglect to consider haplotype diversity (method #1). The mean length of the deletion breakpoint regions assigned by method #2 was 269-bp in contrast to 502-bp by method #1. Our findings imply that paralog-specific haplotype diversity of NAHR hotspots (such as PRS2) and population-specific haplotype diversity must be taken into account in order to accurately ascertain NAHR-mediated rearrangement breakpoints. PMID- 28862370 TI - Atmosphere-Controlled Chemoselectivity: Rhodium-Catalyzed Alkylation and Olefination of Alkylnitriles with Alcohols. AB - The chemoselective alkylation and olefination of alkylnitriles with alcohols have been developed by simply controlling the reaction atmosphere. A binuclear rhodium complex catalyzes the alkylation reaction under argon through a hydrogen borrowing pathway and the olefination reaction under oxygen through aerobic dehydrogenation. Broad substrate scope is demonstrated, permitting the synthesis of some important organic building blocks. Mechanistic studies suggest that the alkylation product may be formed through conjugate reduction of an alkene intermediate by a rhodium hydride, whereas the formation of olefin product may be due to the oxidation of the rhodium hydride complex with molecular oxygen. PMID- 28862371 TI - Amine-Mediated Enzymatic Carboxylation of Phenols Using CO2 as Substrate Increases Equilibrium Conversions and Reaction Rates. AB - A variety of strategies is applied to alleviate thermodynamic and kinetic limitations in biocatalytic carboxylation of metabolites in vivo. A key feature to consider in enzymatic carboxylations is the nature of the cosubstrate: CO2 or its hydrated form, bicarbonate. The substrate binding and activation mechanism determine what the actual carboxylation agent is. Dihydroxybenzoic acid (de)carboxylases catalyze the reversible regio-selective ortho-(de)carboxylation of phenolics. These enzymes have attracted considerable attention in the last 10 years due to their potential in substituting harsh conditions typical of chemical carboxylations (100-200 degrees C, 5-100 bar) with, ideally, greener ones (20-40 degrees C, 1 bar). They are reported to use bicarbonate as substrate, needed in large excess to overcome thermodynamic and kinetic limitations. Therefore, CO2 can be used as substrate by these enzymes only if it is converted into bicarbonate in situ. In this contribution, we report the simultaneous amine mediated conversion of CO2 into bicarbonate and the ortho-carboxylation of different phenolic molecules catalyzed by 2,3-dihydroxybenzoic acid (de)carboxylase from Aspergillus oryzae. Our results show that under the newly developed conditions a significant thermodynamic (up to twofold increase in conversion) and kinetic improvement (up to approx. fivefold increase in rate) of the biocatalytic carboxylation of catechol is achieved. PMID- 28862372 TI - Correlation of CD4 count with cariogenic oral flora indicators and dental caries in HIV-seropositive children undergoing antiretroviral therapy in Mangaluru, South India. AB - AIM: The aim of the present study was to compare the association of CD4 count with cariogenic oral flora indicators and dental caries in HIV-seropositive children receiving antiretroviral therapy (ART). METHODS: A descriptive study was conducted among HIV-seropositive children receiving ART at Snehasadan Camillian Care and Support Center HIV/AIDS in Mangaluru, India. Demographic details and r recent CD4 counts were recorded. For dental caries, the Decayed, Missing, Filled Teeth (DMFT)/decayed, missing, filled/decayed, extracted, filled index was used. Data were analyzed using SPSS version 22. Spearman's correlation was used to correlate CD4 count with dental caries and cariogenic oral flora indicators (mutans streptococci and lactobacilli). RESULTS: The study population comprised 35 patients. Dental caries prevalence was 54.1% in deciduous teeth and 41.2% in permanent teeth. Age and DMFT showed a significant, positive correlation; age and dmft showed a negative correlation (P < .05). A weak, negative correlation was found between age and Streptococcus mutans (S. mutans), and also CD4 count; S. mutans and CD4 count and dmft were not found to be statistically significant (P < .05). CONCLUSION: No statistically-significant correlation was found between CD4 count and cariogenic oral flora indicators in HIV-positive patients. The presence of a minimum number of restored teeth compared to decayed teeth suggests a lack of dental care being given to HIV-positive patients. PMID- 28862373 TI - Sociodemographic profile and oral health status of thalassemic patients attending the National Thalassaemia Centre, Kurunegala, Sri Lanka. AB - AIM: The aim of the present study was to investigate the sociodemographic profile and oral health status (Decayed, Missing, Filled Teeth [DMFT] and periodontal health) of thalassemic patients compared to healthy individuals. METHODS: The data were collected by means of an interviewer-administered, pretested, and validated questionnaire, followed by oral examination. Patients attending the outpatient department, who were age and sex matched, but without any diagnosed or suspected long-term illnesses, were considered for the control group. Both groups were compared in terms of facial profile, skeletal pattern, facial angles, DMFT, and periodontal health (plaque index, bleeding on probing, and probing pocket depth). RESULTS: The association of convex facial profile and class II skeletal pattern with Thalassemic status was statistically significant when compared to healthy individuals. Decayed, missing, and filled teeth in the permanent and deciduous dentition, plaque index, and probing pocket depths of the control group were significantly higher compared with the thalassemic group. Surprisingly, 67.8% of thalassemic patients did not show bleeding on probing. CONCLUSION: Families of the thalassemic patients attending the National Thalassaemia Centre are from a low socioeconomic background. Their DMFT and periodontal health are significantly better than those of healthy individuals. PMID- 28862374 TI - Controlled Synthesis of 3D Flower-like Ni2 P Composed of Mesoporous Nanoplates for Overall Water Splitting. AB - Developing efficient non-noble metal and earth-abundant electrocatalysts with tunable microstructures for overall water splitting is critical to promote clean energy technologies for a hydrogen economy. Herein, novel three-dimensional (3D) flower-like Ni2 P composed of mesoporous nanoplates with controllable morphology and high surface area was prepared by a hydrothermal method and low-temperature phosphidation as efficient electrocatalysts for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). Compared with the urchin-like Nix Py , the 3D flower-like Ni2 P with a diameter of 5 MUm presented an efficient and stable catalytic performance in 0.5 m H2 SO4 , with a small Tafel slope of 79 mV dec-1 and an overpotential of about 240 mV at a current density of 10 mA cm-2 with a mass loading density of 0.283 mg cm-2 . In addition, the catalyst also exhibited a remarkable performance for the OER in 1.0 m KOH electrolyte, with an overpotential of 320 mV to reach a current density of 10 mA cm-2 and a small Tafel slope of 72 mV dec-1 . The excellent catalytic performance of the as prepared Ni2 P may be ascribed to its novel 3D morphology with unique mesoporous structure. PMID- 28862375 TI - Analysis of IN.PACT DEEP trial on the association between changes in perfusion from pre- to postrevascularization and clinical outcomes in critical limb ischemia. AB - OBJECTIVES: To quantify changes in ankle and toe pressure from pre- to post endovascular revascularization for critical limb ischemia (CLI) and examine their association with major adverse limb events (MALE). BACKGROUND: Despite societal guidelines recommendation of routine hemodynamic surveillance following revascularization, little is known about hemodynamic assessment in CLI. METHODS: Among the 358 patients with CLI from the international multicenter IN.PACT DEEP trial, ankle and toe pressures measurements were available at both baseline and after intervention in 270 and 44 patients, respectively. The change in ankle and toe pressures in response to endovascular revascularization and its association with 1-year MALE (target limb revascularization, amputation, or death) were examined using Kaplan-Meier curves and multivariable Cox proportional hazard analyses. Corresponding optimal cutoff points were also identified. RESULTS: The mean increase in ankle and toe pressures following revascularization was 33 and 13 mmHg, respectively. Patients with an improvement of ankle pressure >73 mmHg or toe pressure >1 mmHg had similarly the lowest incidence of MALE (23%), while the highest rate of MALE (50%) was found in those whose toe pressure failed to improve by at least 1 mmHg following intervention. In addition, an increase in ankle pressure >73 mmHg was numerically protective against MALE, and more importantly, an increase in toe pressure of >1 mmHg provided statistically significant protection from MALE (adjusted HR = 0.15, 95% CI: 0.04-0.57, P = 0.005). CONCLUSIONS: Improvements in toe pressure post revascularization are incremental and rarely normalize. Toe pressure, compared to ankle pressure, is more useful in CLI and predicts future MALE. PMID- 28862376 TI - Rationale and design of a global registry to evaluate real-world clinical outcomes in patients with atrial fibrillation and high risk of stroke treated with left atrial appendage occlusion using the AMPLATZER amulet device Perspective of available/ongoing registries of catheter-based LAA occlusion. AB - OBJECTIVES: To describe the rationale and design of a global prospective registry on catheter-based left atrial appendage (LAA) occlusion using the second generation AMPLATZER Amulet LAA occlusion device and to provide a comprehensive perspective on available/ongoing registries for catheter-based LAA occlusion. BACKGROUND: Given the increasing clinical application of catheter-based LAA occlusion, there is an important need for prospective real-world clinical data regarding this cardiac intervention. METHODS: The Global Amplatzer Amulet LAA registry aims to provide prospective real-world data from an all-comer population of atrial fibrillation (AF) patients undergoing catheter-based LAA occlusion for stroke prevention. This observational, prospective, multicenter registry will provide peri-procedural and long-term clinical outcome data for catheter-based LAA occlusion using a second generation LAA occlusion device. The global registry will enroll 1,000 patients at up to 75 institutions. Patients will be followed for 2 years after implantation. Primary endpoints will report procedural and long term data on ischemic stroke, systemic embolism, cardiovascular death and major bleeding. The study will involve independent event adjudication and echocardiographic core laboratory evaluation. Long-term follow-up data are expected in 2018. RESULTS: The Global Amplatzer Amulet LAA registry will collect safety and efficacy information on catheter-based LAA occlusion. Characteristics of available and ongoing catheter-based LAA occlusion registries are described. CONCLUSIONS: There is an important need for prospective real-world clinical data of catheter-based LAA occlusion given the increasing application of this intervention. The present global real-world registry will expand our knowledge on peri-procedural and long-term outcome of catheter-based LAA occlusion using a second generation occlusion device. PMID- 28862377 TI - Biosynthesis of 2-Hydroxyacid-Containing Polyhydroxyalkanoates by Employing butyryl-CoA Transferases in Metabolically Engineered Escherichia coli. AB - The authors previously reported the production of polyhydroxyalkanoates (PHAs) containing 2-hydroxyacid monomers by expressing evolved Pseudomonas sp. 6-19 PHA synthase and Clostridium propionicum propionyl-CoA transferase in engineered microorganisms. Here, the authors examined four butyryl-CoA transferases from Roseburia sp., Eubacterium hallii, Faecalibacterium prausnitzii, and Anaerostipes caccae as potential CoA-transferases to support synthesis of polymers having 2HA monomer. In vitro activity analyses of the four butyryl-CoA transferases suggested that each butyryl-CoA transferase has different activities towards 2 hydroxybutyrate (2HB), 3-hydroxybutyrate (3HB), and lactate (LA). When Escherichia coli XL1-Blue expressing Pseudomonas sp. 6-19 PhaC1437 along with one butyryl-CoA transferase is cultured in chemically defined MR medium containing 20 g L-1 of glucose, 2 g L-1 of sodium 3-hydroxybutyrate, and various concentrations of sodium 2-hydroxybutyrate, PHAs consisting of 3HB, 2HB, and LA are produced. The monomer composition of PHAs agreed well with the substrate specificities of butyryl-CoA transferases from E. hallii, F. prausnitzii, and A. caccae, but not Roseburia sp. When E. coli XL1-Blue expressing PhaC1437 and E. hallii butyryl-CoA transferase is cultured in MR medium containing 20 g L-1 of glucose and 2 g L-1 of sodium 2-hydroxybutyrate, P(65.7 mol% 2HB-co-34.3 mol% LA) is produced with the highest PHA content of 30 wt%. Butyryl-CoA transferases also supported the production of P(3HB-co-2HB-co-LA) from glucose as the sole carbon source in E. coli XL1-Blue strains when one of these bct genes is expressed with phaC1437, cimA3.7, leuBCD, panE, and phaAB genes. Butyryl-CoA transferases characterized in this study can be used for engineering of microorganisms that produce PHAs containing novel 2-hydroxyacid monomers. PMID- 28862378 TI - Why are we not prescribing more valaciclovir for herpes infections of the eye? Is it time for a change of practice in New Zealand? PMID- 28862379 TI - Recent Developments in Lanthanide Single-Molecule Magnets. AB - Single-molecule magnets (SMMs) exhibiting slow relaxation of magnetization of purely molecular origin are highly attractive owing to their potential applications in spintronic devices, high-density information storage, and quantum computing. In particular, lanthanide SMMs have been playing a major role in the advancement of this field because of the large intrinsic magnetic anisotropy of lanthanide metal ions. Herein, some recent breakthroughs that are changing the perspective of the field are highlighted, with special emphasis on synthetic strategies towards the design of high-performance SMMs. PMID- 28862381 TI - A systematic review of reported cases of combined transcatheter aortic and mitral valve interventions. AB - OBJECTIVES: To summarize the published data of combined transcatheter aortic and mitral valve intervention (CTAMVI). BACKGROUND: CTAMVI, a combination of either transcatheter aortic valve replacement (TAVR) or transcatheter aortic valve-in valve (TAViV) and transcatheter mitral valve replacement (TMVR), transcatheter mitral valve-in-valve/valve-in-ring (TMViV/ViR), or percutaneous mitral valve repair (PMVR) is an attractive alternative in high-surgical risk patients with combined aortic and mitral valve disease. However, its procedural details and clinical outcomes have not been well described. METHODS: We performed a systematic review of all the published articles from PUBMED and EMBASE. RESULTS: A total of 37 studies with 60 patients were included. The indication for CTAMVI was high or inoperable surgical risk and symptomatic severe aortic stenosis (92%) or severe aortic regurgitation (8%) combined with moderate to severe/severe mitral stenosis (30%) or moderate/severe mitral regurgitation (65%) or both (5%). In majority of the cases, aortic valve intervention was performed prior to the mitral valve. Mortality rate were 25% for TAVR + TMVR (range 42 days to 10 months), 17% for TAVR + TMViV/ViR (range 13 days to 6 months), 0% for TAViV + TMViV/ViR (range 6-365 days), and 15% for TAVR/ViV + PMVR (range 17 days to 419 days). Significant (more than moderate) paravalvular regurgitation post-procedure was rare. CONCLUSIONS: CTAMVI appears to confer reasonable clinical outcome. Further large study is warranted to clarify the optimal strategy, procedural details and clinical outcomes in the future. PMID- 28862380 TI - Fetal Bone Marrow-Derived Mesenchymal Stem/Stromal Cells Enhance Humanization and Bone Formation of BMP7 Loaded Scaffolds. AB - Tissue engineered constructs built with human cells capable of generating a bone like organ within the mouse have attracted considerable interest over the past decade. Here, we aimed to compare the utility of human mesenchymal stem/stromal cells (MSC) isolated from fetal term placenta (fPL-MSC) and fetal first trimester bone marrow (fBM-MSC) in a polycaprolactone scaffold/BMP7-based model in nude mice. Furthermore, fPL-MSC were co-seeded with fetal placenta-derived endothelial colony forming cells (ECFC) to assess the impact of ECFC on fPL-MSC osteogenesis. X-ray radiography and micro computed tomography analyses showed enhanced bone formation in all BMP7 groups; however there was no difference after 2 months in bone formation between scaffolds seeded with fPL-MSC alone or combination of ECFC and fPL-MSC. Of interest, fBM-MSC showed the highest level of bone formation. Additionally, endochondral ossification contributed in generation of bone in fBM MSC. Histological analysis showed the primary role of BMP in generation of cortical and trabecular bone, and the recruitment of hematopoietic cells to the scaffolds. Current in vivo engineered bone organs can potentially be used for drug screening or as models to study bone tissue development in combination with haematopoiesis. PMID- 28862382 TI - Tunable SERS Platforms from Small Nanoparticle 3D Superlattices: A Comparison between Gold, Silver, and Copper. AB - Herein we present new substrates for surface-enhanced Raman spectroscopy (SERS). The synthesis of colloidal nanoparticles through an organometallic route allowed us to obtain gold, silver, or copper nanoparticles with well-controlled shapes and sizes (5-12 nm in diameter). The organization of these nanoparticles into large-scale 3D superlattices produces a very large number of "hot spots" at the origin of the signal enhancement. Each superlattice was studied individually to correlate its optical and SERS properties to the thickness, the nanoparticle sizes, and the interparticle distance. This experimental and theoretical study provides insights for the optimization and tuning of the SERS activity. Indeed, significant SERS amplification could be observed regardless of the nature of the metal. In addition, the SERS signal was homogeneous at the surface of the superlattices, which opens the route for a new approach in analytical SERS detection. PMID- 28862383 TI - Serum Aspergillus fumigatus-specific IgG antibody decreases after antifungal treatment in chronic pulmonary aspergillosis patients. PMID- 28862384 TI - Atrial septostomy with a predefined diameter using a novel occlutech atrial flow regulator improves symptoms and cardiac index in patients with severe pulmonary arterial hypertension. AB - OBJECTIVES: A novel Occlutech atrial flow regulator (AFR) implantation gives an atrial septal predefined predictable fenestration. BACKGROUND: Atrial septostomy relieves syncope in pulmonary arterial hypertension (PAH) by improving left heart filling, cardiac output and systemic oxygen transport despite hypoxia. Symptoms recur when small fenestrations close spontaneously. METHODS: AFR was implanted after informed consent in patients with severe PAH presenting with syncope and right heart failure. Symptoms, hemodynamics, echocardiographic parameters, brain natriuretic peptide (BNP) levels and device patency were serially documented. RESULTS: Twelve patients aged 28.3 +/- 8.5 years with severe PAH underwent AFR implantation. All procedures were successful without any major complications. All patients had relief of syncope and 6-min walk distance improved significantly from 377.3 +/- 33.2 to 423 +/- 31.32 m. The cardiac index (2.36 +/- 0.52 to 2.89 +/- 0.56 L/min/m2 ) and systemic oxygen transport (367.5 +/- 75.5 to 428.0 +/- 67.1 ml/min/m2 ) also showed a significant improvement. Inferior caval vein congestion and pericardial effusion reduced due to improvement in heart failure, but other echocardiographic parameters of right ventricular function did not show significant change. The reduction in BNP levels too did not reach statistical significance. The device was patent in all patients at a median follow-up of 189 days (range 10-296 days) resulting in a significant reduction of oxygen saturations from 98 +/- 0.18 to 85.26 +/- 2.86% after exercise. CONCLUSIONS: AFR implantation was feasible and safe in all patients with PAH. There was a significant improvement of symptoms, six-minute walk distance, cardiac index and systemic oxygen transport. The device maintained patency in short-term follow-up and the resultant hypoxia was tolerated well. PMID- 28862385 TI - Tailoring stents to fit the anatomy of unique vascular stenoses in congenital heart disease. AB - BACKGROUND: Unique and small anatomical features often preclude the use of available vascular stents in pediatric patients with congenital heart disease (CHD). OBJECTIVES: To report our experience and outcomes tailoring stents to fit unique anatomy, particularly in small children and infants with CHD. METHODS: Stent tailoring techniques included trimming, folding, and flaring. Patients receiving a tailored stent November 2002 to February 2015 were included in a retrospective analysis. RESULTS: Forty-one tailored stents were implanted in 30 patients with median age and weight of 0.8 years (6 days to 17 years) and 8.1 kg (2.9-47.9 kg). Thirty stents were placed intraoperatively and 11 percutaneously. Sites included branch pulmonary arteries (BPA; n = 32), pulmonary veins (n = 6), SVC (n = 1), and the ventricular septum (n = 2). Twenty-three (56%) stents were trimmed with or without folding to avoid jailing of side branches, 16 (39%) stents were folded or flared with or without trimming to avoid excessive proximal protrusion, and two (5%) stents were folded back at both ends for implantation in ventricular septal defects. Final stent lengths were 6-15 mm. Minimal vessel diameters increased from 2.8 +/- 1.4 mm to 6.7 +/- 2.6 mm (P < 0.001). Complications included two intraoperative BPA tears, three pinhole balloon leaks, two intraoperative stent dislodgements, one transient heart block, and one lung reperfusion injury. Follow-up catheterization included 36 re-dilations and implantation of four additional stents over a median of 4.1 years. In-stent restenosis was the indication in 25 (69.4%) re-interventions. CONCLUSION: Tailored stents can be safely implanted to fit unique anatomy in small patients. Re-interventions can effectively treat restenosis and accommodate ongoing vessel growth. PMID- 28862386 TI - Use of antidepressive agents as a possibility in the management of periodontal diseases: A systematic review of experimental studies. AB - Antidepressant agents have anti-inflammatory functions that could be interesting as adjuvants in periodontal therapy. The aim of the present study was to analyze the effect of antidepressive drugs in the management of periodontal disease. The MEDLINE, Scopus, Embase, LILACS, and SciELO databases were searched. To be included, the studies had to be experimental studies; randomized, controlled; double-blinded; or blinded studies. A total of 565 articles were initially searched, of which five were selected for the systematic review. All studies used rats, and three different drugs were evaluated: tianeptine, venlafaxine, and fluoxetine. Two of these studies evaluated the effect of antidepressive agents in rats submitted to both ligature-induced periodontitis and depression models, showing that depressive rats had greater alveolar bone loss (ABL). Only the venlafaxine study was not able to find any significant ABL reduction in the group that used this antidepressive drug. The other four studies showed statistically significant differences, favoring the group with the antidepressant agent. Treatments that are able to modulate the brain-neuroendocrine-immune system could be used as an adjuvant to periodontal disease management. However, studies on humans and animals are scarce, limiting the conclusion of a positive effect in the present systematic review. PMID- 28862387 TI - Symptom evaluation during the methacholine test: Does it add to the interpretation of the test results based on the PC20FEV1? AB - PURPOSE: Conventionally, symptoms occurring during the methacholine test are not taken into account when interpreting the test results. We examined whether the evaluation of methacholine-induced symptoms (MIS) added to the test interpretation based on the PC20FEV1 by assessing their prevalence, their similarity with symptoms justifying referral and their relationship with airway responsiveness. METHODS: Eighty-two patients with suspected asthma completed a questionnaire of symptoms and underwent bronchial challenge with methacholine. Based on MIS and airway responsiveness (responders = PC20FEV1 < 8 mg/mL), subjects were classified as asymptomatic non-responders (ANRs), asymptomatic responders (ARs), symptomatic non-responders (SNRs) and symptomatic responders (SRs). Airway responsiveness for all subjects, including non-responders (ie, fall in FEV1 < 20%), was assessed by the methacholine concentration response-slope (MCRS) obtained using all points of the curve. RESULTS: ARs (n = 6) were poor perceivers of bronchoconstriction. SNRs (n = 16) did not differ from SRs (n = 34) in any clinical parameter, including the proportion of subjects (~80%) whose methacholine test reproduced symptoms justifying referral. In turn, SNRs differed significantly from ANRs (n = 26) by having lower baseline FEV1 (P = .005), more physician-diagnosed asthma (P < .001), more use of respiratory medication (P = .032), and relatively greater responsiveness as manifested by a steeper MCRS (P < .001). CONCLUSIONS: The occurrence of asthma-like symptoms during the methacholine test was associated with milder airway hyperresponsiveness that would go unnoticed by the PC20FEV1. This finding suggests that SNRs should not be merely classified as having normal responsiveness, as currently recommended, but further assessed for airway inflammation. Our results helped planning a longitudinal study to investigate the prognostic validity of this approach. PMID- 28862388 TI - Visible-light Homogeneous Photocatalytic Conversion of CO2 into CO in Aqueous Solutions with an Iron Catalyst. AB - An iron-substituted tetraphenyl porphyrin bearing positively charged trimethylammonio groups at the para position of each phenyl ring catalyzes the photoinduced conversion of CO2 . This complex is water soluble and acts as a molecular catalyst to selectively reduce CO2 into CO under visible-light irradiation in aqueous solutions (acetonitrile/water=1:9 v/v) with the assistance of purpurin, a simple organic photosensitizer. CO is produced with a catalytic selectivity of 95 % and turnover number up to 120, illustrating the possibility of photocatalyzing the reduction of CO2 in aqueous solution by using visible light, a simple organic sensitizer coupled to an amine as a sacrificial electron donor, and an earth-abundant metal-based molecular catalyst. PMID- 28862389 TI - The role of high expectations of self and social desirability in emotional processing in individuals with irritable bowel syndrome: A qualitative study. AB - OBJECTIVES: Although high levels of distress are associated with the onset and severity of Irritable bowel syndrome (IBS), it is unclear how this relates to emotional processing, particularly in relation to maintenance of symptoms and treatment outcome. This qualitative study embedded within a randomized controlled trial aimed to explore how individuals with refractory IBS experience, express, and manage their emotions after either therapist-delivered cognitive behavioural therapy (TCBT) or Web-based CBT (WBCBT) compared to treatment as usual (TAU). DESIGN: Cross-sectional qualitative study. METHODS: Fifty-two semi-structured interviews were conducted at post-treatment with 17 TCBT, 17 WBCBT, and 18 TAU participants. The transcripts were analysed using inductive thematic analysis with grounded theory elements. NVivo 11 was used to compare themes across groups. RESULTS: Across all groups, high expectations of self was a recurring reason for how participants experienced and expressed their emotions. Three themes with subthemes captured how high expectations related to specific aspects of emotional processing: perceived causes of emotions, strategies for coping with emotions (bottling up, avoiding emotions, and active coping strategies), and the perceived interplay between emotions and IBS symptoms. CONCLUSIONS: Patients recognized that their IBS symptoms both triggered and were triggered by negative emotions. However, there was a tendency to bottle up or avoid negative emotions for reasons of social desirability regardless of whether patients had CBT for IBS or not. Future psychological interventions in IBS may benefit from addressing negative beliefs about expressing emotions, promoting assertive emotional expression, and encouraging the experience of positive emotions. Statement of contribution What is already known on this subject? High levels of distress are consistently associated with both the onset and maintenance of IBS symptoms. Little is known about how this relates to the concept of emotional processing. Preliminary findings suggest a positive correlation between poor emotional processing and IBS. However, further studies need to confirm its role in relation to aetiology, maintenance of symptoms, and response to treatment. What does this study add? High expectations of self and social desirability seem to be important aspects shaping the way individuals with IBS experience, express, and manage their emotions. Emotional avoidance and bottling up were reported as key strategies to cope with negative emotions. The study revealed that bottling up is not perceived as an all-or-nothing strategy but can be applied selectively depending on the context. Psychological interventions in IBS may benefit from addressing not only illness-related causes of negative emotions but also personal and social triggers of distress. PMID- 28862390 TI - Correction. PMID- 28862391 TI - Dental extractions for preradiation dental clearance and incidence of osteoradionecrosis in patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. AB - AIM: The aims of the present retrospective study were to evaluate the outcomes of dental extractions in nasopharyngeal carcinoma patients who had undergone dental clearance pre- and post-radiotherapy (RT) with intensity-modulated RT, and to report on the incidence and timing of osteoradionecrosis (ORN) in these patients. METHODS: A total of 231 patients were seen pre-, mid-, and postradiation therapy. Information on patient demographics, smoking history, staging, treatment modalities, dental extraction indications, and number and site of dental extractions was gathered. Wilcoxon two-sample tests and Fisher's exact test were used to test the association between groups for patient variables. RESULTS: The mean number of teeth removed was 4.1 teeth per patient. A total of 334 (35.2%) teeth were removed for periodontal reasons, 322 (34.03%) were removed prophylactically, and the remaining teeth were removed because of deep caries, retained roots, partial impaction, endodontic lesions, and prosthodontic reasons. Patients had an average of 19.6 teeth remaining after dental clearance, and only 97 (42%) required prosthetic intervention. The statistical analysis showed that there was no correlation between dental extractions pre- or post-RT and the development of ORN. CONCLUSIONS: No specific parameter was directly associated with dental extractions, although smoking and increased number of teeth removed preradiation seemed to be prevalent in patients who developed ORN. PMID- 28862392 TI - Minimizing exposure to radiation in invasive cardiology using modern dose reduction technology: Evaluation of the real-life effects. AB - OBJECTIVES: We aimed to measure the reduction in the estimated dose of radiation received by patients that can be achieved using dose-reduction technology (ClarityIQ, Philips Healthcare, The Netherlands), among all patients undergoing invasive cardiology procedures. BACKGROUND: Medical procedures remain the primary source of exposure to ionizing radiation in the general population. METHODS: The study population comprised all patients (without exclusion criteria) undergoing invasive coronary procedures over a 1-year study period in a large referral centre equipped with two catheterization laboratories (cathlabs). Both cathlabs (A and B) were equipped with the Allura Xper FD10 imaging system (Philips Healthcare, The Netherlands), but only Cathlab B was equipped with ClarityIQ technology. The primary endpoint was the estimated total dose of radiation received by the patient, as assessed by Air Kerma (AK) and dose area product (DAP). RESULTS: In total, 2095 invasive coronary procedures were analyzed. The patients who underwent procedures in Cathlab B received an average estimated dose that was 23% (AK) and 43% (DAP) lower than the dose received by patients undergoing procedures in Cathlab A (P < .0001). The reduction remained significant by multivariate analysis after adjustment for total X-ray time, body mass index, arterial approach, PCI of at least one lesion, sex, and patient age. CONCLUSION: In our study, the ClarityIQ technology reduced the estimated radiation dose received by patients by 23-43%, according to the method of measurement. PMID- 28862393 TI - Microheterogeneity of Recombinant Antibodies: Analytics and Functional Impact. AB - Antibodies are typical examples of biopharmaceuticals which are composed of numerous, almost infinite numbers of potential molecular entities called variants or isoforms, which constitute the microheterogeneity of these molecules. These variants are generated during biosynthesis by so-called posttranslational modification, during purification or upon storage. The variants differ in biological properties such as pharmacodynamic properties, for example, Antibody Dependent Cellular Cytotoxicity, complement activation, and pharmacokinetic properties, for example, serum half-life and safety. Recent progress in analytical technologies such as various modes of liquid chromatography and mass spectrometry has helped to elucidate the structure of a lot of these variants and their biological properties. In this review the most important modifications (glycosylation, terminal modifications, amino acid side chain modifications, glycation, disulfide bond variants and aggregation) are reviewed and an attempt is made to give an overview on the biological properties, for which the reports are often contradictory. Even though there is a deep understanding of cellular and molecular mechanism of antibody modification and their consequences, the clinical proof of the effects observed in vitro and in vivo is still not fully rendered. For some modifications such as core-fucosylation of the N-glycan and aggregation the effects are clear and should be monitored, but with others such as C-terminal lysine clipping the reports are contradictory. As a consequence it seems too early to tell if any modification can be safely ignored. PMID- 28862394 TI - Efficacy and safety of a calcium sensitizer, levosimendan, in patients with right heart failure due to pulmonary hypertension. AB - BACKGROUND: Despite using vasoactive and pulmonary hypertension (PH) specific therapies, the in-hospital mortality of severe PH with right heart failure (RHF) is high. We conducted a prospective analysis evaluating the efficacy and safety of levosimendan in PH patients with severe acute RHF. METHODS: Forty-five PH patients hospitalized between January 2016 and November 2016 were recruited into a single arm, prospective, open-label study. Levosimendan was administered at the rate of .05-0.1 MUg/kg/min, up to a total dose of 12.5 mg. The primary endpoints were changes of World Health Organization Function Class (WHO-FC) and Borg dyspnoea scores. Secondary endpoints included changes in 6-min walk distance (6 MWD), biochemical markers and right heart structure and function together with adverse events on day 7 and incidence of major cardiovascular events (death or readmission due to RHF) on day 30. RESULTS: Forty-five PH patients were enrolled. On the 7th day after levosimendan infusion, seven out of 13 PH patients with WHO FC IV improved by one class (P = .008). Borg dyspnoea scores, 6-MWD and NT-proBNP improved significantly (P < .001). Compared with baseline, the right atrial transverse dimension, end-systolic eccentricity index and tricuspid annular plane systolic excursion improved significantly (58.8 +/- 13.1 mm vs 53.7 +/- 12.4 mm; 1.50 +/- 0.27 vs 1.38 +/- 0.23; 15.0 (13.0, 16.0) mm vs 15.8 (14.0, 17.4) mm, P < .005, respectively). One patient occurred sudden death after discharge during follow-up. CONCLUSIONS: Intravenous levosimendan can effectively improve severe RHF of PH patients in hospital and well tolerated. PMID- 28862396 TI - Association between lung function, physical activity level and postural evaluation variables in adult patients with cystic fibrosis. AB - INTRODUCTION: With the evolution of the cystic fibrosis (CF) disease, the decline of lung function associated with metabolic disorders and malnutrition, causes alterations in respiratory mechanics, musculoskeletal disorders and thoracic deformities, bringing injury to the individual's quality of life. OBJECTIVE: To verify the association between lung function, physical activity level and postural evaluation variables in adults with CF. METHODS: All patients underwent clinical evaluation and spirometry. The International Physical Activity Questionnaire (IPAQ) and an accelerometer were used to verify the physical activity level (PA). Photogrammetry was used with the aid of the Software of postural evaluation (SAPO) and, for complementary comparisons, the 6-minute walk test (6MWT) was used. RESULTS: Twenty-eight adult subjects with CF, mean age of 25.1 +/- 6.3 years and mean expiratory volume in the first second (FEV1 ) of 47.1 +/- 20.9% of the predicted group participated in the study. The FEV1 correlated with the parameters obtained by the accelerometer (r = 0.723, P = .000), postural evaluation (r = -0.483, P = .005) and 6MWT (r = 0.439, P = .019), but there was no correlation with the data obtained by IPAQ (r = -0.282; P = .073). The time in which each individual remained in moderate to vigorous physical activity correlated with parameters of postural evaluation (thoracic kyphosis r = -0.484, P = .031, cervical lordosis r = 0.531, P = .016), 6MWT (r = 0.564; P = .010) and with the total METS obtained by IPAQ (r = 0.451, P = .046). CONCLUSIONS: Lung function in patients with CF disease is associated with higher thoracic kyphosis, shorter time in moderate and vigorous PA, and shorter distance covered in 6MWT. The accelerometer has been shown to be the best instrument for assessing PA in this public. PMID- 28862395 TI - Phelan-McDermid syndrome data network: Integrating patient reported outcomes with clinical notes and curated genetic reports. AB - The heterogeneity of patient phenotype data are an impediment to the research into the origins and progression of neuropsychiatric disorders. This difficulty is compounded in the case of rare disorders such as Phelan-McDermid Syndrome (PMS) by the paucity of patient clinical data. PMS is a rare syndromic genetic cause of autism and intellectual deficiency. In this paper, we describe the Phelan-McDermid Syndrome Data Network (PMS_DN), a platform that facilitates research into phenotype-genotype correlation and progression of PMS by: a) integrating knowledge of patient phenotypes extracted from Patient Reported Outcomes (PRO) data and clinical notes-two heterogeneous, underutilized sources of knowledge about patient phenotypes-with curated genetic information from the same patient cohort and b) making this integrated knowledge, along with a suite of statistical tools, available free of charge to authorized investigators on a Web portal https://pmsdn.hms.harvard.edu. PMS_DN is a Patient Centric Outcomes Research Initiative (PCORI) where patients and their families are involved in all aspects of the management of patient data in driving research into PMS. To foster collaborative research, PMS_DN also makes patient aggregates from this knowledge available to authorized investigators using distributed research networks such as the PCORnet PopMedNet. PMS_DN is hosted on a scalable cloud based environment and complies with all patient data privacy regulations. As of October 31, 2016, PMS_DN integrates high-quality knowledge extracted from the clinical notes of 112 patients and curated genetic reports of 176 patients with preprocessed PRO data from 415 patients. PMID- 28862398 TI - JCD Editorial - September, 2017. PMID- 28862397 TI - EMPIRE Registry, Czech Part: Impact of demographics, pulmonary function and HRCT on survival and clinical course in idiopathic pulmonary fibrosis. AB - INTRODUCTION: Prognostic factors of idiopathic pulmonary fibrosis (IPF) currently recognized include changes in vital capacity and radiologic findings. However, most of the prognostic studies in IPF are based on clinical studies with preselected IPF populations. Therefore, we decided to analyze the factors influencing IPF prognosis based on the real-practice data from our IPF registry. METHODS: Data of 514 subjects consecutively entered since 2012 into Czech EMPIRE IPF registry were analyzed. RESULTS: Median age of our patient cohort was 67 years (50-82). Median overall survival (OS) of the cohort was 63.1 months. The clinical course of IPF according to FVC (forced vital capacity) changes was stabilized in 32.8% of patients (29.7% according to DLCO [diffuse lung capacity] changes), slowly progressive in 39.5% (45%), rapidly progressive in 23.5% (20.7%); and 1.7% patients had at least one acute exacerbation during follow-up. Deterioration in FVC of >=10% at month 12 and in DLCO of >=15% at months 12, 18, and 24 influenced the OS significantly. The fast progressors defined by the DLCO decline rate had higher risk of death compared to those defined by the FVC change over time. In multivariate analysis, age >=70 years, interstitial HRCT scores >=3, and change in DLCO of >=15% at month 12 were confirmed as factors negatively influencing OS. CONCLUSIONS: DLCO changes over time were shown as a better predictor of mortality compared with FVC changes in our study. In our opinion it is necessary to implement the DLCO analysis into clinical trials and routine practice. PMID- 28862399 TI - The Bex-Nikaidoh operation for dextro-transposition of the great arteries with a ventricular septal defect and pulmonary stenosis using an 'oversized' conduit. AB - We report a case of a 4-month-old infant with dextro (d)-transposition of the great arteries, ventricular septal defect (VSD) and left ventricular outflow tract obstruction previously palliated with a systemic-to-pulmonary shunt. He underwent repair by aortic root translocation with an arterial switch procedure and coronary artery reimplantation (modified Bex-Nikaidoh operation). This case demonstrates that aortic translocation results in a more normal anatomic repair compared with the Rastelli operation. As shown, it is always possible to place an oversized conduit (homograft) and there is no risk of sternal compression of the conduit. This is especially important for children under 1 year, when there are contraindications for the Rastelli operation. Placement of oversized pulmonary ventricle-pulmonary artery conduits is performed to decrease conduit failure in the future. The postoperative course was uneventful. At 6 months, he was asymptomatic with tomographic images and echocardiography showing no residual lesions. PMID- 28862400 TI - Carotid artery cannulation in aortic surgery. AB - The common carotid artery is not widely used for arterial return in cardiovascular surgery with the use of extracorporeal circulation; however, in our opinion, it is an artery that most ideally fits several criteria for cannulation use. It is easy and very fast to access, even in obese patients, and it is large and strong enough to provide a sufficient arterial return. Moreover, the risk of local injuries and wound infection is extremely low, and finally, the use of the common carotid artery for cannulation is very advantageous for cerebral perfusion in many pathologies of the aortic arch and its branches. PMID- 28862401 TI - Aspergillus and Penicillium (Eurotiales: Trichocomaceae) in soils of the Brazilian tropical dry forest: diversity in an area of environmental preservation. AB - Soil is a complex biological system that plays a key role for plants and animals, especially in dry forests such as the Caatinga. Fungi from soils, such as Aspergillus and Penicillium, can be used as bioindica-tors for biodiversity conservation. The aim of this study was to isolate and identify species of Aspergillus and Penicillium in soil, from the municipalities of Tupanatinga and Ibimirim, with dry forests, in the CatimbauNational Park. Five collections were performed in each area during the drought season of 2012, totaling 25soil samples per area. Fungi were isolated by suspending soil samples in sterile distilled water and plating onSabouraud Agar media plus Chloramphenicol and Rose Bengal, and Glycerol Dicloran Agar. Isolates wereidentified by morphological taxonomy in the Culture Collection Laboratory and confirmed by sequencing ofthe Internal Transcribed Spacer of rDNA. A total of 42 species were identified, of which 22 belong to the genusAspergillus and 20 to Penicillium. Penicillium isolates showed uniform distribution from the collecting area inTupanatinga, and the evenness indices found were 0.92 and 0.88 in Tupanatinga and Ibimirim, respectively.Among isolates of Aspergillus evenness, the value found in Tupanatinga (0.85) was very close to that found in Ibimirim (0.86). High diversity and low dominance of fungi in soil samples was observed. These results con-tributed to the estimation of fungal diversity in dry environments of the Caatinga, where diversity is decreasing in soils that have undergone disturbance. PMID- 28862402 TI - Reproductive system, mating behavior and basic ecology of an extremely rare tropical snail: Drymaeus tripictus(Stylommatophora: Bulimulidae) AB - Very little is known about the ecology and biology of Drymaeus tripictus, an extremely rare andendemic land snail species from Costa Rican highlands. I studied the ecology and reproductive biology of D. tripictusfrom April 2009 through June 2010 in an old forest, a young forest and a Cupressus lusitanica plantationin central Costa Rica. Every three months I visited each habitat and collected specimens in 20 random samplingplots (3x3 m2 each). I observed the snail's activity and microhabitat preference in the field, and in the laboratoryI recorded high definition videos of its mating behavior and analyzed reproductive morphology with lightmicroscopy. The snail is more abundant in the old forest (0.017 ind./m(2)) and prefers leaves with little epiphyllouscover (0-25 % cover, chi-square test, p <0.0001). During the dry season the snails become active between 20:00pm and 8:00 am (chi-square = 22.65, df=3, p < 0.0001); they are inactive mainly during the afternoon (11:00 amto 16:59 pm). I found active individuals mostly on the upper side of leaves, where they feed (Chi-square =6.76,df=1, p = 0.0093). Mating is unilateral, by shell mounting, with cryptic phallus intromission and without roleswitching or multiple mating. Its reproductive system is morphologically similar to that of Drymaeus costaricensis.Mating behavior is as expected for snails with high-spired shells, except for the lack of role switching.The density of D. tripictus is low even when compared with other endangered bulimulids. PMID- 28862403 TI - Population structure and reproductive biology of Astyanax gymnodontus(Characiformes: Characidae), a poorly known endemic fish of the Iguacu River basin, Brazil. AB - Success in fish breeding depends on reproduction intensity, periodicity and the place where it occurs.Information about fish species reproduction is important to assist managers, and to determine conservation andmanagement strategies. The fish assemblage of the Iguacu River basin is already known for its high endemism,and despite this privilege, the large number of dams built along it, threat this particular biodiversity. Astyanaxgymnodontus is an endemic fish species and studies on its population structure and reproductive biology areimportant, since they represent the first step for further community studies. Our objective was to evaluate someaspects of the population structure and reproductive biology of A. gymnodontus in the influence area of SaltoSantiago dam, Iguacu River, Parana State, Brazil. Sampling was made monthly from July 2003 to June 2005, andbimonthly from July 2005 to March 2013, at five sites in the influence area of Salto Santiago dam. Fishes werecollected using 10 m length gillnets with meshes ranging from 2.5 to 6.0 cm between non-adjacent knots andtrammel nets with inner meshes of 6.0 cm between non-adjacent knots. Nets were arranged on surface, bottomand margins of each site, exposed for 24 h. Additional drags on littoral areas were performed from January toMarch and October to December from 2009 to 2011, with 50.0 m nets, 0.5 cm mesh size, for juveniles capture.We captured and analyzed 21 932 individuals, being 9 249 females and 12 683 males, representing 42.2 % and57.8 %, respectively. The average body length was 8.8 cm for females and 8.3 cm for males. The average weightwas 18.8 g for females and 16.0 g for males. Sex ratio calculated for the entire period was 1.8 males/female.Males were more abundant than females in 73.2 % of samples and significant differences were observed in 35.3% of samples. The estimated length at first maturity (SL(50)) was 6.4 cm for females and 6.2 cm for males. We suggestthat sexual differences in body length and weight, and sex ratio occurred as a result of sexual differences inenergy allocation. Females spend more energy on body growth, which means more eggs production and higherfecundity. As an integrated response, males spend more energy on sperm production, in competition with othermales, leading to a smaller body size. Differences in estimated SL(50) might be an indicator of this sexual differencein energy allocation. The reproduction period was from September to February, with greater intensity at thebeginning of this period, and the sites of highest reproductive intensity were those immediate downstream fromdams, and therefore with more riverine characteristics. PMID- 28862404 TI - Coral communities condition in varying wave exposure: the gulf of Cazones, Cuba. AB - Wave exposure can influence community structure and distribution of shallow coral reefs, by affectingorganisms both directly and indirectly. To assess the current stony coral community condition under differentdegrees of wave exposure at a marine protected area of the Gulf of Cazones (SW Cuba), two expeditions werecarried out in May 2010 and June 2012. Four sampling sites were sampled at reef crests (1.5 m deep), and twelveat fore-reefs, at 10, 15 and 20 m deep in four geographic locations. Live coral cover, species richness and composition,colony density, and maximum diameter were assessed using the AGRRA 2001 methodology. Multivariateand non-parametric statistics were applied to compare sites. The coral community structure within reef crestswas not homogenous. The observed variability of indicators apparently was determined by great coral mortalityevents resulting from natural disturbances that occurred in the past (hurricanes, bleaching and diseases). Forereefcoral communities displayed better condition and lower coral mortality than reef crests. Species richnessand coral composition varied, while multivariate and statistical methods did not reveal site grouping with regardto wave exposure. The remaining biological condition indicators were similar among sites, except in the mostexposed one, where coral cover and coral size were slightly lower. Wave exposure in the gulf of Cazones seemednot to have a significant influence on differences in condition and structure of the assessed coral communities. PMID- 28862405 TI - Can anthropic fires affect epigaeic and hypogaeic Cerrado ant (Hymenoptera: Formicidae) communities in the same way? AB - Fire occurrences are a common perturbation in Cerrado ecosystems, and may differently impact thelocal biodiversity. Arthropods are one of the taxa affected by fires, and among them, ants are known as goodbioindicators. We aimed to evaluate the effect of anthropic fires on epigaeic and hypogaeic ant communities(species richness and composition) in Cerrado areas with different post-fire event recovery periods. We conductedthe study in four Cerrado areas during two weeks of 2012 dry season: one unburned and three at differentpost-fire times (one month, one and two years). We sampled ants with pitfall traps in epigaeic and hypogaeicmicrohabitats. We collected 71 ant morpho-species from 25 genera. In the epigaeic microhabitat we sampled56 morpho-species and 42 in the hypogaeic microhabitat. The area with the shortest recovery time presentedlower epigaeic ant species richness (4.3 +/- 2.00) in comparison to the other areas (8.1 +/- 2.68 species on oneyear area; 10.3 +/- 2.66 species on two years area; 10.4 +/- 2.31 species on control area), but recovery time did notaffect hypogaeic ant species richness. Regarding ant species composition, fire did not directly affect hypogaeicant species, which remained the same even one month after fire event. However, two years were not enough toreestablish ant species composition in both microhabitats in relation to our control group samples. Our studyis the first to assess anthropic fire effects upon epigaeic and hypogaeic ants communities; highlighting theimportance of evaluating different microhabitats, to more accurately detect the effects of anthropic disturbancesin biological communities. We concluded that ant communities are just partially affected by fire occurrences,and epigaeic assemblages are the most affected ones in comparison to hypogaeic ants. Furthermore the studyprovides knowledge to aid in the creation of vegetation management programs that allow Cerrado conservation. PMID- 28862406 TI - Effect of NaCl + Chitosan 3% vs. NaCl on high blood pressure parameters of healthy volunteers with prehypertension. AB - BACKGROUND: Because of the impressive increase in the risk of cardiovascular complications associated with levels of BP previously considered to be normal, the JNC 7 report has introduced a new classification that includes the term "prehypertension" for those with blood pressures (BPs) ranging from 120-139 mmHg systolic and/or 80-89 mmHg diastolic. In the framework of a salt reduction as recommended by health authorities, this trial evaluates if the use of Symbiosal(r) reduces more prehypertension than standard table marine salt (NaCl). METHODS: Study design: monocenter, randomized, double blind, controlled trial comparing the marine salt NaCl + Chitosan 3% according a specific patent Symbiosal and the standard table marine salt NaCl. The study has been conducted in 2 parallel arms design: every subject received, according to the randomization Symbiosal or NaCl. STUDY OBJECTIVES: The main objective of this clinical trial was to demonstrate a higher reduction of systolic BP (SBP) with Symbiosal than with NaCl in the framework of a table salt reduction to a maximum of 3 g per day in prehypertensive patients RESULTS: Twenty-two subjects were included in the Symbiosal group and 19 in the NaCl group according randomization. The two groups have the same salt consumption: a daily intake of respectively 2.2+/-1.1 g/day vs. 2.5+/-1.2 g/day (P=0.3621). The SBP was measured by the investigators at D0 and D56. It significantly (P<0.0001) decreased more in the Symbiosal group from 133.8+/-5.7 mmHg to 126.1+/-6.5 mmHg which correspond to a reduction of 7.7+/-5.9 mmHg while it slightly increased in the group NaCl from 136.6+/-10.3 mmHg to 140.4+/-8.3 mmHg which corresponds to an increase of 3.7+/-6 mmHg (main criteria). The proportion of subjects whose SBP was under 130 mmHg strongly and significantly more important in the Symbiosal group =77.3% vs. 10.5% in the NaCl group (P<0.0001). CONCLUSIONS: This controlled randomized double-blind trial comparing Symbiosal to standard salt in the framework of a salt reduction demonstrate the efficiency of Symbiosal to prevent hypertension by controlling the BP rising in subject presenting prehypertensive status which is the target population of that food supplement. PMID- 28862407 TI - A handbook for the clinical cardiologist about CRT/ICD. A practical guide about how to survive during an on call shift. AB - Cardiac resynchronization therapies (CRTs) have been demonstrated to improve the clinical management and prognosis of selected patients with heart failure. CRT devices include both CRT pacemakers (CRT-P) and CRT defibrillators (CRT-D), with the latter being used to treat life-threatening ventricular arrhythmias. A significant advantage of CRTs is the ability to monitor several vital parameters which, thanks to advanced technology, may be remotely assessed. Personalized programming options allow patients to receive the maximum benefit from these treatments. In this review we report the main diagnostic and therapeutic algorithms used in clinical practice. PMID- 28862408 TI - Benefits of electroanatomic ablation of conventional cardiac arrhytmias: from fluoroscopy to zero X-ray mapping. AB - Electrophysiology procedures are traditionally performed under fluoroscopic guidance. Nowadays a growing interest in the radiation risk associated to these procedures has been cultivated, since radiation exposure has non-negligible stochastic and deterministic effects on health. A correlation between radiation exposure and lifetime malignancy effect is difficult to establish and the threshold of a completely safe exposure dose is unknown. Thus, electrophisiologists have become aware of the use of fluoroscopy and they have tried to use all the complementary imaging technologies available in order to reduce the radiological exposure. This review is aimed at evaluating the radiation exposure risk, both for the patients and the operators. We describe electroanatomical mapping systems and technologies, which allow the reduction of radiation exposure. We review the main literature based on different catheter ablation procedures with the use of the abovementioned technologies, specifically focusing on feasibility, safety, and radiation exposure. Finally, we highlight the necessity of increasing the radiological risk awareness among operators and cardiological scientific societies. PMID- 28862409 TI - [The tolerance of ten diatom species (Bacillariophyceae) to water's physico chemical factors inthe Sarapiqui River, Costa Rica]. AB - Benthic diatoms are the periphyton component most studied in Costa Ricanrivers, yet there is still much to be known about their ecology. This study aims to contribute to this knowledge.Periphyton samples from six locations along the middle reach of Sarapiqui river and some of its tributarieswere taken and analyzed from 2010 to 2012. A total count of 400 frustules was performed in each sample toobtain relative abundances of each species. Ten species, which were easily recognized at the light microscope,were analyzed here: Achnanthidium exiguum, Coconneis placentula, Cymbella tumida, Luticola goeppertiana,Luticola ventricosa, Navicula symmetrica, Nitzchia clausii, Nupela praecipua, Reimeria sinuata and Synedragoulardi. Their abundance was related to physico chemical data at each site for every sampling date (dissolvedoxygen, temperature, conductivity, total suspended solids, turbidity, pH and alkalinity) with a canonical correspondenceanalysis (CCA) that allowed distinguishing three sectors along the river according to altitude.These sectors differed by substrate, riparian vegetation cover, and physic-chemical parameters, all of whichresulted in differences in diatom species composition among them. Optimum values and tolerances form eachenvironmental parameter were calculated for each species. Our results showed that A. exiguum, R. sinuata, L.ventricosa and C. tumida, were dominant in clean and well oxygenated waters with low temperatures. The speciesN. praecipua, S. goulardi, C. placentula, L. goeppertiana, N. clausii and N. symmetrica inhabited warmwaters with high turbidity and low oxygen. The species A. exiguum, R. sinuata were dominant in sites with lowalkalinity and conductivity, whereas species like N. symmetrica, C. tumida and L. ventricosa showed a positiverelationship with conductivity and pH. The studied species showed good characteristics of their value as waterquality indicators, yet due to different interpretations by several authors, it is necessary to perform further studiesat more river basins in the country. PMID- 28862410 TI - [Temperature and daily emergence of seven genera of Ephemeroptera (Insecta) in a cloud forest stream of tropical Andes]. AB - Daily emergence of mayflies in Neotropical rivers and their causes have been poorly studied. In temperate zones, this process is better known and attributed to several factors. In this work, we studied the daily emergence of subimagines of several Ephemeroptera genera in La Picon River of a Venezuelan Andean cloud forest and its relation with changes of environmental temperature. Four emergence traps were placed along a reach of 50 m of the stream, each one was examined each two hours in a 24 hr cycle to capture the newly emerged subimagos. This procedure was repeated for eight dates between November-2007 and February-2008 for a total of 32 observations in each sampling hour. The subimagos were reared to adults and identified to genus. The relative density of emergence per trap was calculated for each genus and sampling hour. Water and air temperature were measured each hour during the daily cycle of observation, and the averages of temperature and hour-degrees of air and water were calculated for each hour from the eight dates studied. Seven genera were identified: Leptohyphes Eaton, 1882 and Haplohyphes Allen 1966 (Leptophlebiidae); Prebaetodes Lugo-Ortiz and McCafferty, 1996, Andesiops Lugo-Ortiz and McCafferty, 1999, Baetodes Needham and Murphy, 1924 and Americabaetis Kluge, 1992 (Baetidae); and Thraulodes Ulmer, 1920 (Leptophlebiidae); being the more abundant Leptohyphes (38.4 %) and Thraulodes (20.5 %). The emergence occurred between 11:00 am and 23:00 pm showing the following: a) an emergence initiated during daylight hours by organisms of Leptohyphes, Prebaetodes and Haplohyphes; b) a nocturnal emergence, in Thraulodes, Andesiops, Baetodes and Americabaetis; and c) two peaks: one diurnal produced by Leptohyphes and other nocturnal with predominance of Thraulodes. These results are the first records on the diurnal daily emergence in Andesiops, Prebaetodes, Americabaetis, Haplohyphes, and Leptohyphes, as well as the nocturnal emergence in Thraulodes. It was evidenced that Leptohyphes, with small nymphs (average head width = 1.05 mm) needed to accumulate less hour-degrees to initiate the emergence than those required by Thraulodes whose nymphs are larger (average head width = 2.01 mm). This disparity in the emergence energy requirements must be consequence of differences between the sizes of mature nymphs of both genera; facts which rely on the constancy of sizes shown by these taxa along an altitudinal-thermal gradient and the little daily and seasonal variability of water temperature in La Picon River. In the daily lapse when the emergence occurred, the air and water average temperatures were higher than those registered in the no-emergence lapse; therefore; it is suggested that during the daily lapse, when this process occurs, the environment is thermally favorable for the emergence of subimagos and their survival out of water. PMID- 28862411 TI - [Biological parameters of Pseudocurimata boulengeri (Characiformes: Curimatidae) inhabiting the Chongon dam, Ecuador]. AB - Pseudocurimata boulengeri is an endemic species of Ecuador, which sustains a large group of fisher families. The biological data of this species correspond to reports from lotic systems of Los Rios province; nevertheless, their trend in a lentic system is not yet known. This paper describes the sex ratio, length-weight relationship, gonad development, spawning season and size at reproductive maturity of P. boulengeri, inhabiting the lentic system of Chongon dam, Ecuador. Fish were caught between 2003 and 2009 using gill nets (2.5"). The total length (Lt) of caught specimens ranged from 10.5 to 35.5 cm, spawning occurred between the months of October and March, and size at first maturity for females was estimated at 17.9 cm (Lt) and 20.0 cm (Lt) for males. Between May and October male and female ratios were as expected (1:1), whereas for May, November and April, females ratios were higher than males, situation that coincided with the spawning season. The limnetic conditions and high production characteristics of Chongon dam, have promoted the availability of a great amount of food for this species, which may have allowed P. boulengeri to have a more extended reproductive season in this favorable environment. PMID- 28862412 TI - [Bibliometry of collaboration and impact of the Revista de Biologia Tropical (Web of Science 2003-2012)]. AB - The activity analysis of a scientific journal is relevant to know the evolution of its characteristics over time. In this paper, results of a bibliometric study of the Revista de Biologia Tropical/International Journal of Tropical Biology and Conservation (Costa Rica) are presented. The goal of this study was to describe the main characteristics of its scientific production, and analyze its level of collaboration and its impact between the years 2003-2012. Data was derived from the Web of Science (Thomson-Reuters), and the relationship among authors and coauthors, institutions and countries, and their links with the citations received were analyzed for that period. Descriptive statistics about production (number of documents per year, institution and country), collaboration (authorship index, collaboration among institutions and countries) and impact (IF, position in JCR and number of citations received) were collected. Results showed that the journal has published 1 473 papers in this period, in similar proportions English and Spanish. Mexico, Costa Rica, Venezuela and Colombia are the most common countries of origin, with the Universidad of Costa Rica, Universidad Autonoma de Mexico and the University of Puerto Rico as the most common leader institutions. Collaboration between authors, institutions and countries has shown an increasing trend over the last decade. The co-author index was 3.07 per document, 63 % of publications included 2 or more institutions, and 22 % of the papers were product of international collaboration. The most common collaboration link was between Costa Rica and the United States of America. The impact factor has been oscillating during this last decade, reaching a maximum in 2012 (IF JCR = 0.553). Besides, 10 % of the most cited papers concentrated half of the citations received by the journal, and have a very high number of citations, compared with the journal mean. The main countries that cite the journal were USA, Brazil, Mexico, Argentina and Costa Rica. Data showed an increasing collaboration between authors, institutions and countries, and a direct relationship between the increase of this collaboration and the received impact. PMID- 28862413 TI - [Which factors determine the altitudinal distribution of tropical Andean riverine fishes]? AB - Altitudinal gradients represent an appropriate system to assess whether there is a relationship between richness patterns, environmental variables, and the ecological processes that determine the species type and number inhabiting a given area. In mountain streams freshwater fishes, the most prevalent relationship is a monotonic decrease in species richness with elevation. The objective of this study was to evaluate four hypotheses that can explain the negative relationship between local fish species richness and altitude, 1) the hypothesis of decreasing energy availability, 2) the hypothesis of increasing climate severity, 3) the hypothesis of habitat diversity, and 4) the hypothesis of isolation by physical severity of the environment. Fish and macro invertebrates were collected following standard methods from 83 sites (between 200-4 000 meters) of two river basins in the Bolivian Amazon. The first hypothesis was tested by analyzing relationships between the density of macro invertebrates, the richness of invertivorous fish species and altitude; while the second and third hypotheses were assessed by a multiple regression analysis (GLM) between fish species richness and several local and regional factors. Besides, assemblage dissimilarity between sites along the altitudinal gradient was analyzed using betasim and betaness indices. Fish richness decreases linearly with increasing altitude. The density of macro-invertebrates tends to increase at higher altitudes, contrary to invertivorous fish species richness, suggesting that energy availability is not a limiting factor for fish species colonization. The GLM explained 86 % of the variation in fish species richness, with a significant contribution of water temperature, maximum slope in the river mainstem, and stream width. There is a higher species turnover (betasim) between sites at low elevation. Inversely, betaness shows higher values in the upper parts, corresponding to change in assemblages mainly due to species loss. Taken together, these results suggest that climatic and physical severities create strong barriers to colonization, further explaining the decrease in fish richness along the altitudinal gradient. PMID- 28862414 TI - Asthma-COPD overlap syndrome: recent advances in diagnostic criteria and prognostic significance. AB - The term asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) has been proposed for individuals with features of both asthma and COPD. Several attempts have been done to define ACOS on the basis of medical history, symptoms, and functional findings. The main diagnostic criteria include airflow obstruction with a strong although incomplete reversibility to bronchodilation tests, a significant exposure to cigarette or biomass smoke, and a history of atopy or asthma. Additional diagnostic elements include eosinophilic airway and systemic inflammation, a good response to corticosteroid treatment, and a high concentration of exhaled nitric oxide. ACOS should be distinguished from asthma with not fully reversible bronchial obstruction due to airway remodeling, thus the lack of smoking exposure should exclude the diagnosis of ACOS. In patients without a documented history of asthma before 40 years of age, an increase in FEV1 after bronchodilator >400 mL should be required to diagnose ACOS. ACOS has been found to be associated with impaired physical performance, functional ability, and health-related quality of life. The prevalence of ACOS increases with aging, then it is relatively stable in elderly individuals (>65 years). Long term mortality of subjects with ACOS is similar to COPD, and worse than asthma and healthy controls. Future research is still needed to improve the understanding and management of ACOS. PMID- 28862415 TI - Exploring adjuvant epidermal growth factor receptor inhibition in non-small cell lung cancer. AB - Lung cancer is among the most important causes of death worldwide. Despite the relevant progresses in the personalized approach to lung cancer, patients' survival is still poor. Only a minor fraction of patients can be addressed to surgery for radical tumor removal. Adjuvant chemotherapy is currently recommended for resected stages II and III patients although it is known that it can modestly contribute to survival prolongation. A better identification of molecular markers, predictive of adjuvant chemo response is now mandatory, in order to reduce useless toxicities and identify those patients who could really benefit. Here we present and analyze a recent paper by Huang et al. aimed at evaluating the prognostic role of epidermal growth factor receptor (EGFR) activation in adjuvant setting in order to determine whether the administration of EGFR tyrosine-kinase inhibitors could improve the outcomes of patients affected by NSCLC undergoing complete resection. Moreover we provide an exhaustive literature revision that could be helpful for a proper management of that small cohort of EGFR-mutated resected NSCLC. PMID- 28862416 TI - Role and challenges of severe asthma services: insights from the UK registry. AB - Severe bronchial asthma affects at least 5% of the asthmatic population and remains a clinical challenge. Data from the UK National Registry for Severe Asthma suggest that dedicated centers may improve asthma control, quality of life, reduce healthcare use and oral steroid burden. A multidisciplinary approach through complete lung function evaluation, optimization of adherence to treatment and immunological characterization are key issues to improve patients' care. In this paper, we provide an overview of the challenges of managing patients with severe asthma and the role of dedicated services. PMID- 28862417 TI - Two-year temporal response of benthic macrofauna and sediments to hypoxia in a tropical semi-enclosed bay (Cienfuegos, Cuba). AB - Hypoxia is the depletion of dissolved oxygen below 2 mg O(2)/L. Relatively few studies on hypoxia and its effects on benthic macrofauna have been done in tropical marine ecosystems. This study describes the temporal response of the water column, sediments and macrofauna to seasonal hypoxia in a semi-enclosed bay (Cienfuegos, Caribbean Sea). The Calisito site was sampled monthly from June 2010 until February 2012, yielding 21 sampling times. At each sampling event water and sediment samples were collected for measuring the abiotic variables (temperature, salinity, dissolved oxygen, nutrients, redox potential discontinuity, silt/clay and organic matter content) and macrofauna (abundance and species richness). Temperature and surface salinity followed a typical temporal pattern during the summer/rainy and the winter/dry periods. Salinity stratification occurred in the rainy period, lasting three months in 2010 and six months in 2011. The bottom water dissolved oxygen indicated hypoxic and anoxic events during the wet periods of 2010 and 2011 associated with salinity stratification, low hydrodynamics and oxidation of the accumulated organic matter. Over the study period, 817 individuals were collected and identified. Polychaetes were the dominant group in terms of abundance (57 % of total) followed by mollusks (41%). Hypoxia (and occasionally anoxia) caused strong deleterious effects on the abundance and species richness of macrofaunal communities in the study site. The most abundant polychaetes were opportunistic species with high tolerance to hypoxic conditions: Prionospio steenstrupi, Polydora sp.and Paraprionospio pinnata. Most of them colonized relatively fast once hypoxia ended. Persistent species such as Caecum pulchellum and Parvanachis obesa were present during hypoxia with fluctuating densities and apparently recover to higher abundances when normoxic conditions are re-established. Macoma tenta and Tellina consobrina colonized approximately 1 2 months later than the first polychaete peak during normoxia. Probably, the deleterious effects of hypoxia on the macrofauna were intensified by negative interspecific relationships such as competition by suitable space and predation. The recolonization of macrofauna depended possibly on local transport by currents within the bay because the connection with the Caribbean Sea is relatively limited. In summary, seasonal hypoxia in Cienfuegos Bay influences the water and sediment geochemistry and reduces both the abundance and diversity of macrofauna. PMID- 28862418 TI - Morphological distinction between estuarine polychaetes: Laeonereis culveri and L. nota (Phyllodocida: Nereididae). AB - The family Nereididae includes more than 500 polychaete species described worldwide, and includes species common in many benthic environments, but some other species may tolerate freshwater or can even thrive in humid substrates in tropical forests. In estuarine environments, nereidid polychaetes can be abundant and relevant as a food source for resident or migratory birds. Laeonereis culveri (Webster, 1879) is a common estuarine species found in tropical and subtropical Atlantic American shores and was described from New Jersey; its median and posterior parapodia have upper notopodial ligules usually longer than the lower ones, and the latter are parallel to the notaciculae throughout the body. L. culveri distribution is from Connecticut to central Argentina; however, this wide distribution might be due to the inclusion of several other species as junior synonyms, despite that some morphological differences were found between them. One of such species is L. nota (Treadwell, 1941), that was described from Texas; its parapodia have notopodial ligules of about the same size, and the lower ones are oblique to the notaciculae. In order to clarify the differences between these two species, and to define which inhabits the Northwestern Caribbean region, topotype materials from these two species and specimens from Chetumal Bay were collected, and their morphological features were compared. Our results indicated that L. culveri and L. nota are different species and that the latter is found in Chetumal Bay. On the basis of mature specimens, L. culveri is hereby restricted to the Northern Gulf of Mexico and Northwestern Atlantic Ocean, and L. nota are reinstated and its distribution extends from Texas, in the Gulf of Mexico to Chetumal Bay, in the Northwestern Caribbean Sea. A key to identify all species in Laeonereis Hartman (1945) is also included. PMID- 28862419 TI - Occurrence and toxicity of Microcystis aeruginosa (Cyanobacteria) in the Parana River, downstream of the Yacyreta dam (Argentina). AB - Cyanobacteria constitute the main toxin producers in inland water ecosystems and have extensiveglobal distribution. The presence of hepatotoxins in aquatic environments is hazardous to human and animalhealth; even though the presence and identification of hepatotoxic microcystins in rivers and reservoirs of theworld have been confirmed by several studies in the last few years. Herein, we studied the abundance and toxicityof Microcystis aeruginosa in the Argentine section of the Parana River at the beginning of the Middle Parana(Corrientes Hydrometer), near Corrientes city (27o28' S - 58o51' W) and approximately 220 km downstream ofthe Yacyreta dam (High Parana). The Parana River basin, with a drainage area of 3.1 x 10(6) km(2) and 3 965 km inlength, is the second largest catchment of South America, after that of the Amazon. The Parana River is the mainsource of drinking water supply for the Northeastern Argentine region. Phytoplankton samples were collectedand environmental variables were measured in a monthly basis (exceptionally fortnightly), from March 2004 toJune 2008. Fifty-eight samples were analyzed for phytoplankton density and biomass. Five samples were usedfor toxicity testing; the latter were obtained during the cyanobacteria blooms from 2005 to 2008. Phytoplanktoncounts were performed with an inverted microscope, and biomass was expressed as biovolume. Bioassays withmice and high-performance liquid chromatography (HPLC) analysis were performed to evaluate the presenceof cyanotoxins. Phytoplankton mainly consisted of Cryptophyta, Chlorophyta and Bacillariophyta. Microcystisaeruginosa was identified during the warmer months each year (November to March). Density varied between189 and 25 027 cells/mL (1 10 colonies/mL) and biomass from 0.34 to 44 mm(3)/L. Taking into account thenumber of cells, the highest abundance occurred in April 2004 (25 027 cells/mL), coinciding with the largestbiovolume (44 mm(3)/L). All mice subjected to intraperitoneal injections with samples obtained during bloomepisodes showed positive results for the presence of hepatotoxins. Three microcystins variants: LR, RR and[D-Leu(1)] Mcyst-LR were detected by analysis with semi-preparative high-performance liquid chromatographywith diode array detector system (HPLC PDA). This constitutes the first report of microcystins recorded duringM. aeruginosa blooms in the Argentine stretch of the Parana River at the beginning of the Middle Parana(Corrientes Hydrometer), approximately 220 km downstream of the Yacyreta dam (High Parana). PMID- 28862420 TI - Effects of different forms of nitrogen on rhizosphere microbial community structure of Eichhornia crassipes (Pontederiaceae). AB - Rhizosphere microbial communities are important for phytoremediation, plant nutrition, health and metabolism. Many factors, including plant species, pH and nutritional factors influence rhizosphere micro-biology. In this study, we analysed the effects of different forms of nitrogen on the structures of rhizosphere microbial communities of E. crassipes. Using a conventional culture method with special media, bacteria, acti-nobacteria and molds were cultured. We found that the numbers of bacteria were largely similar across the three culture conditions, while the numbers of actinobacteria and molds from the rhizosphere of E. crassipes culturedin NH4Cl solution were two orders of magnitude higher than those from the rhizospheres of plants cultured indistilled water and KNO3 solution. Using a culture-independent method of polymerase chain reaction denaturinggradient gel electrophoresis (PCR-DGGE) of 16S rDNA, we found that the form of nitrogen could influence thecomponents of the rhizosphere microbial community. Pseudoxanthomonas, Enterobacter and Citrobacter werepresent in all of the samples cultured under the three different experimental conditions. The genus Reyranellawas found only in samples cultured in KNO(3) solution; Acinetobacter and Streptomyces were unique to samplescultured in NH(4)Cl solution, and Pseudomonas, Pseudacidovorax and Methylosinus were found only in samplescultured in distilled water. Pseudoxanthomonas and Acidovorax were the dominant genera in the rhizospheremicrobial community of E. crassipes cultured in KNO(3) solution, while Novosphingobium was the dominantgenus in the sample cultured in a nitrogen deficient medium. Our results provide a theoretical foundation forusing E. crassipes as a phytoremediation plant and controlling the widespread distribution of E. crassipes aroundthe world using principles of nutrient metabolism. PMID- 28862421 TI - [Relative abundance of the gray fox Urocyon cinereoargenteus (Carnivora: Canidae) in Veracruz central area, Mexico]. AB - The gray fox, Urocyon cinereoargenteus, is a medium-size canid widely distributed in Mexico. Most studies on this species focus on habitat use, home range, diet, intraguild competence, and lanscape distribution between urban and rural sites. In central Veracruz, gray foxes are present in fragments of cloud forest and in shaded coffee plantations; nevertheless, its abundance has not yet been compared among other vegetation types found in the area, such as sugarcane plantations. In this study we described gray foxes abundance variations using 500 m transects, among sugarcane plantations, shaded coffee plantations, and cloud forest fragments throughout eight months, by scat counting in three sites of each cover type. We reported the relative abundance index for each cover type and each month, and evaluated its relationship with four landscape features: (a) shade percent, (b) trail density, (c) human population density, and (d) habitat juxtaposition, in influence areas of 450 ha around sampling sites. Abundance comparison among cover types showed lower abundances in cloud forest fragments and higher abundances in coffee and sugarcane plantations. No significant differences were found throughout months (p = 0.476). We proposed that higher abundances in plantations may be related to the presence of rodent plagues and fruit trees which offer food resources to gray foxes. The evaluation of landscape features showed that only medium-impact trail density and human population density were positively correlated with gray fox abundance; fact that demonstrates that this canid can coexist with humans in rural sites. We highlight the gray fox capacity to take advantage of heterogeneous landscapes. PMID- 28862422 TI - Elaboration on the Distribution of Hydrophobic Segments in the Chains of Amphiphilic Cationic Polymers for Small Interfering RNA Delivery. AB - Hydrophobization of cationic polymers, as an efficient strategy, had been widely developed in the structure of cationic polymer micelles to improve the delivery efficiency of nucleic acids. However, the distribution of hydrophobic segments in the polymer chains is rarely considered. Here, we have elaborated three types of hydrophobized polyethylene glycol (PEG)-blocked cationic polymers with different distributions of the hydrophobic segments in the polymer chains PEG-PAM-PDP (E-A D), PEG-PDP-PAM (E-D-A), and PEG-P(AM/DP) (E-(A/D)), which were synthesized by reversible addition-fragmentation chain transfer polymerization of methoxy PEG, cationic monomer aminoethyl methacrylate, and pH-sensitive hydrophobic monomer 2 diisopropylaminoethyl methacrylate, respectively. In aqueous solution, all of the three copolymers, E-A-D, E-D-A, and E-(A/D), were able to spontaneously form nanosized micelles (100-150 nm) (ME-A-D, ME-D-A, and ME-(A/D)) and well incorporated small interfering RNA (siRNA) into complex micelles (CMs). The effect of distributions of the hydrophobic segments on siRNA delivery had been evaluated in vitro and in vivo. Compared with ME-D-A and ME-(A/D), ME-A-D showed the best siRNA binding capacity to form stable ME-A-D/siRNA CMs less than 100 nm, mediated the best gene-silencing efficiency and inhibition effect of tumor cell growth in vitro, and showed better liver gene-silencing effect in vivo. In the case of ME-(A/D) with a random distribution of cationic and hydrophobic segments, a gene-silencing efficiency higher than Lipo2000 but lesser than ME-A-D and ME-D A was obtained. As the mole ratio of positive and negative charges increased, ME D-A/siRNA and ME-A-D/siRNA showed similar performances in size, zeta potential, cell uptake, and gene silencing, but ME-(A/D)/siRNA showed reversed performances. In addition, ME-A-D as the best siRNA carrier was evaluated in the tumor tissue in the xenograft murine model and showed good anticancer capacity. Obviously, the distribution of the hydrophobic segments in the amphiphilic cationic polymer chains should be seriously considered in the design of siRNA vectors. PMID- 28862423 TI - Why I'm Not a Cognitive Psychologist... or a Behaviorist... or a Biologist. AB - "Science" is under increasing amounts of scrutiny. Concerns about reproducibility, reduced institutional support, and intensified competition has been highlighted in recent years, but segregated science endangers scientific discovery above all. Segregated science can be interdisciplinary (biology vs psychology) or intradisciplinary (behaviorism vs cognitive psychology). The advancement of science and public knowledge depends on the unification of all disciplines to better understand the phenomena scientists study. We suggest that engendering collaborations across scientific disciplines produces better-designed research and appropriate interpretations, and increases career-long success. I am not a cognitive psychologist, behaviorist, or biologist because I am a neuroscientist. PMID- 28862424 TI - Injectable Macroporous Ferrogel Microbeads with a High Structural Stability for Magnetically Actuated Drug Delivery. AB - Macroporous hydrogels are an attractive material platform that can provide shortened interfacial diffusion pathways and high biomacromolecule loading. Recently, macroporous ferrogels have shown high potential for use in the on demand delivery of bioactive molecules, resulting from their reversible and large volumetric deformation upon magnetic stimulation. However, these macroporous ferrogels require surgical placement in the body due to their large size; an injectable form of macroporous ferrogels has not yet been reported. In this study, injectable macroporous ferrogel microbeads loaded with iron oxide nanoparticles have been prepared on the basis of alginate microbeads for on demand drug release. A simple solvent exchange and subsequent covalent cross linking of the alginate chains in hydrogel microbeads induced a high polymer density on the hydrogel network and led to enhanced mechanical properties even after the generation of macropores in the microbeads. The macroporous ferrogel microbeads exhibited good mechanical stability and were stable during needle injection. The increased loading of large biomolecules due to the macroporosity of the microbeads and their large reversible volumetric deformation response to the external magnetic field enabled their potential for use in the on-demand delivery of drugs of assorted sizes by magnetic actuation. As a result of their structural stability, injectable size, and ability for on-demand drug delivery, ferrogel microbeads have promising potential for application in many biomedical fields. PMID- 28862426 TI - Digitally Controlled Procedure for Assembling Fully Drawn Paper-Based Electroanalytical Platforms. AB - A simple, reliable, and low-cost fabrication method is proposed here for assembling paper-based electrochemical devices (PEDs) using a commercial desktop digitally controlled plotter/cutter, together with ordinary writing tools. Permanent markers (tips of 1 mm) were used to create effective hydrophobic barriers on paper, while micromechanical pencils (mounting 4B graphite leads, 0.5 mm in diameter) were adopted for automatically drawn precise reference, counter, and working carbon electrodes. Fabrication parameters, such as writing pressure and speed, were first optimized, and the electrochemical performance of these devices was then evaluated by using potassium hexacyanoferrate(II) as redox probe. The good interdevice reproducibility (4.8%) displayed by the relevant voltammetric responses confirmed that this strategy can be profitably adopted to easily assemble paper-based electrochemical devices in a highly flexible manner. The simplicity of the instrumentation used and the low cost of each single device (about $0.04), together with the speed of fabrication (about 2 min), are other important features of the proposed strategy. Finally, to confirm the effectiveness of this prototyping method for the analysis of real samples and rapid controls, PEDs assembled by this simple approach were successfully exploited for the analysis of vitamin B6 in food supplements. PMID- 28862425 TI - BTN3A1 Discriminates gammadelta T Cell Phosphoantigens from Nonantigenic Small Molecules via a Conformational Sensor in Its B30.2 Domain. AB - Human Vgamma9/Vdelta2 T-cells detect tumor cells and microbial infections by recognizing small phosphorylated prenyl metabolites termed phosphoantigens (P Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P-Ag-mediated activation of Vgamma9/Vdelta2 T-cells; however, the molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P-Ag's are discriminated from nonantigenic small molecules. Here, we utilized NMR and X-ray crystallography to probe P-Ag sensing by BTN3A1. Whereas the BTN3A1 immunoglobulin variable domain failed to bind P-Ag, the intracellular B30.2 domain bound a range of negatively charged small molecules, including P-Ag, in a positively charged surface pocket. However, NMR chemical shift perturbations indicated BTN3A1 discriminated P-Ag from nonantigenic small molecules by their ability to induce a specific conformational change in the B30.2 domain that propagated from the P-Ag binding site to distal parts of the domain. These results suggest BTN3A1 selectively detects P-Ag intracellularly via a conformational antigenic sensor in its B30.2 domain and have implications for rational design of antigens for Vgamma9/Vdelta2-based T-cell immunotherapies. PMID- 28862427 TI - Clay, Water, and Salt: Controls on the Permeability of Fine-Grained Sedimentary Rocks. AB - The ability to predict the permeability of fine-grained soils, sediments, and sedimentary rocks is a fundamental challenge in the geosciences with potentially transformative implications in subsurface hydrology. In particular, fine-grained sedimentary rocks (shale, mudstone) constitute about two-thirds of the sedimentary rock mass and play important roles in three energy technologies: petroleum geology, geologic carbon sequestration, and radioactive waste management. The problem is a challenging one that requires understanding the properties of complex natural porous media on several length scales. One inherent length scale, referred to hereafter as the mesoscale, is associated with the assemblages of large grains of quartz, feldspar, and carbonates over distances of tens of micrometers. Its importance is highlighted by the existence of a threshold in the core scale mechanical properties and regional scale energy uses of shale formations at a clay content Xclay ~ 1/3, as predicted by an ideal packing model where a fine-grained clay matrix fills the gaps between the larger grains. A second important length scale, referred to hereafter as the nanoscale, is associated with the aggregation and swelling of clay particles (in particular, smectite clay minerals) over distances of tens of nanometers. Mesoscale phenomena that influence permeability are primarily mechanical and include, for example, the ability of contacts between large grains to prevent the compaction of the clay matrix. Nanoscale phenomena that influence permeability tend to be chemomechanical in nature, because they involve strong impacts of aqueous chemistry on clay swelling. The second length scale remains much less well characterized than the first, because of the inherent challenges associated with the study of strongly coupled nanoscale phenomena. Advanced models of the nanoscale properties of fine-grained media rely predominantly on the Derjaguin Landau-Verwey-Overbeek (DLVO) theory, a mean field theory of colloidal interactions that accurately predicts clay swelling in a narrow range of conditions (low salinity, low compaction, Na+ counterion). An important feature of clay swelling that is not predicted by these models is the coexistence, in most conditions of aqueous chemistry and dry bulk density, of two types of pores between parallel smectite particles: mesopores with a pore width of >3 nm that are controlled by long-range interactions (the osmotic swelling regime) and nanopores with a pore width <1 nm that are controlled by short-range interactions (the crystalline swelling regime). Nanogeochemical characterization and simulation techniques, including coarse-grained and all-atom molecular dynamics simulations, hold significant promise for the development of advanced constitutive relations that predict this coexistence and its dependence on aqueous chemistry. PMID- 28862428 TI - Nanowire Morphology of Mono- and Bidoped alpha-MnO2 Catalysts for Remarkable Enhancement in Soot Oxidation. AB - In the present work, nanowire morphologies of alpha-MnO2, cobalt monodoped alpha MnO2, Cu and Co bidoped alpha-MnO2, and Ni and Co bidoped alpha-MnO2 samples were prepared by a facile hydrothermal synthesis. The structural, morphological, surface, and redox properties of all the as-prepared samples were investigated by various characterization techniques, namely, scanning electron microscopy (SEM), transmission and high resolution electron microscopy (TEM and HR-TEM), powder X ray diffraction (XRD), N2 sorption surface area measurements, X-ray photoelectron spectroscopy (XPS), hydrogen-temperature-programmed reduction (H2-TPR), and oxygen-temperature-programmed desorption (O2-TPD). The soot oxidation performance was found to be significantly improved via metal mono- and bidoping. In particular, Cu and Co bidoped alpha-MnO2 nanowires showed a remarkable improvement in soot oxidation performance, with its T50 (50% soot conversion) values of 279 and 431 degrees C under tight and loose contact conditions, respectively. The soot combustion activation energy for the Cu and Co bidoped MnO2 nanowires is 121 kJ/mol. The increased oxygen vacancies, greater number of active sites, facile redox behavior, and strong synergistic interaction were the key factors for the excellent catalytic activity. The longevity of Cu and Co bidoped alpha-MnO2 nanowires was analyzed, and it was found that the Cu/Co bidoped alpha-MnO2 nanowires were highly stable after five successive cycles and showed an insignificant decrease in soot oxidation activity. Furthermore, the HR TEM analysis of a spent catalyst after five cycles indicated that the (310) crystal plane of alpha-MnO2 interacts with the soot particles; therefore, we can assume that more-reactive exposed surfaces positively affect the reaction of soot oxidation. Thus, the Cu and Co bidoped alpha-MnO2 nanowires provide promise as a highly effective alternative to precious metal based automotive catalysts. PMID- 28862429 TI - Electrostatic Self-Assembly of Sandwich-Like CoAl-LDH/Polypyrrole/Graphene Nanocomposites with Enhanced Capacitive Performance. AB - A novel sandwich-like composite with ultrathin CoAl-layered double hydroxide (LDH) nanoplates electrostatically assembled on both sides of two-dimensional polypyrrole/graphene (PG) substrate has been successfully fabricated using facile hydrothermal techniques. The PG not only serves as an excellent conductive and structural scaffold to enhance the transmission of electrons and prevent aggregation of CoAl-LDH nanoplates but also contributes to the enhancement of the specific capacitance. Owing to the homogeneous dispersion of CoAl-LDH nanoplates and its intimate interaction with PG substrate, the resulting CoAl-LDH/PG nanocomposite material exhibits excellent capacitive performance, for example, enhanced gravimetric specific capacitance (864 F g-1 at 1 A g-1 ), high rate performance (75% retention at 20 A g-1), and excellent cycle life (almost no degradation in supercapacitor performance after 5000 cycles) in aqueous KOH solution. Furthermore, the assembled asymmetric capacitor is able to deliver a superhigh energy density of 46.8 Wh kg-1 at 1.2 kW kg-1 and maintain 90.1% of its initial capacitance after 10 000 cycles. These results indicate a rational assembly strategy toward a high-performance pseudocapacitive electrode material with excellent rate performance, high specific capacitance, and outstanding cycle stability. PMID- 28862430 TI - Conformation Manipulation and Motion of a Double Paddle Molecule on an Au(111) Surface. AB - The molecular conformation of a bisbinaphthyldurene (BBD) molecule is manipulated using a low-temperature ultrahigh-vacuum scanning tunneling microscope (LT-UHV STM) on an Au(111) surface. BBD has two binaphthyl groups at both ends connected to a central durene leading to anti/syn/flat conformers. In solution, dynamic nuclear magnetic resonance indicated the fast interexchange between the anti and syn conformers as confirmed by density functional theory calculations. After deposition in a submonolayer on an Au(111) surface, only the syn conformers were observed forming small islands of self-assembled syn dimers. The syn dimers can be separated into syn monomers by STM molecular manipulations. A flat conformer can also be prepared by using a peculiar mechanical unfolding of a syn monomer by STM manipulations. The experimental STM dI/dV and theoretical elastic scattering quantum chemistry maps of the low-lying tunneling resonances confirmed the flat conformer BBD molecule STM production. The key BBD electronic states for a step by-step STM inelastic excitation lateral motion on the Au(111) are presented requiring no mechanical interactions between the STM tip apex and the BBD. On the BBD molecular board, selected STM tip apex positions for this inelastic tunneling excitation enable the flat BBD to move controllably on Au(111) by a step of 0.29 nm per bias voltage ramp. PMID- 28862432 TI - Engineered Fabrication of Hierarchical Frameworks with Tuned Pore Structure and N,O-Co-Doping for High-Performance Supercapacitors. AB - A series of multiheteroatom porous carbon frameworks (MPCFs) is prepared successfully from the trimerization of cyano groups of our designed and synthesized 4,4'-(4-oxophthalazine-1,3(4H)-diyl)dibenzonitrile monomers and subsequent ionothermal synthesis. Benefiting from the molecular engineering strategy, the obtained MPCFs framework show a homogeneous distribution of nitrogen and oxygen heteroatoms at the atomic level, confirmed by the transmission electron microscopy mapping intuitively, thereby ensuring the stability of electrical properties. The supercapacitor with the obtained MPCFs@700 as the electrode exhibits a high energy density of 65 Wh kg-1 at 0.1 A g-1, with excellent long cycle life and cycle stability (98% capacitance retention for 10 000 cycles in 1-butyl-3-methylimidazolium tetrafluoroborate). Another two electrolyte systems employed also demonstrate the delightful results, showing a 112% capacitance retention for 30 000 cycles in 1 M H2SO4 and a 95% capacitance retention for 30 000 cycles in tetraethylammonium tetrafluoroborate in an acetonitrile solution. Moreover, the successful preparation of MPCFs provides new insights into the fabrication of electrode materials intrinsically containing nitrogen and oxygen in the frameworks for readily available components through a facile routine. PMID- 28862431 TI - The Medicinal Chemistry of Natural and Semisynthetic Compounds against Parkinson's and Huntington's Diseases. AB - Among the diseases affecting the central nervous system (CNS), neurodegenerations attract the interest of both the clinician and the medicinal chemist. The increasing average age of population, the growing number of patients, and the lack of long-term effective remedies push ahead the quest for novel tools against this class of pathologies. We present a review on the state of the art of the molecules (or combination of molecules) of natural origin that are currently under study against two well-defined pathologies: Parkinson's disease (PD) and Huntington's disease (HD). Nowadays, very few tools are available for preventing or counteracting the progression of such diseases. Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and where available, papers reporting in vivo data were preferred. A literature search for peer-reviewed articles using PubMed, Scopus, and Reaxys databases was performed, exploiting different keywords and logical operators: 91 papers were considered (preferentially published after 2015). The review presents a brief overview on the etiology of the studied neurodegenerations and the current treatments, followed by a detailed discussion of the natural and semisynthetic compounds dividing them in different paragraphs considering their several mechanisms of action. PMID- 28862433 TI - Role of Ligand Protonation in Dihydrogen Evolution from a Pentamethylcyclopentadienyl Rhodium Catalyst. AB - Recent work has shown that Cp*Rh(bpy) [Cp* = pentamethylcyclopentadienyl, bpy = 2,2'- bipyridine] undergoes endo protonation at the [Cp*] ligand in the presence of weak acid (Et3NH+; pKa = 18.8 in MeCN). Upon exposure to stronger acid (e.g., DMFH+; pKa = 6.1), hydrogen is evolved with unity yield. Here, we study the mechanisms by which this catalyst evolves dihydrogen using density functional theory (M06) with polarizable continuum solvation. The calculations show that the complex can be protonated by weak acid first at the metal center with a barrier of 3.2 kcal/mol; this proton then migrates to the ring to form the detected intermediate, a rhodium(I) compound bearing endo eta4-Cp*H. Stronger acid is required to evolve hydrogen, which calculations show happens via a concerted mechanism. The acid approaches and protonates the metal, while the second proton simultaneously migrates from the ring with a barrier of ~12 kcal/mol. Under strongly acidic conditions, we find that hydrogen evolution can proceed through a traditional metal-hydride species; protonation of the initial hydride to form an H-H bond occurs before migration of the hydride (in the form of a proton) to the [Cp*] ring (i.e., H-H bond formation is faster than hydride-proton tautomerization). This work demonstrates the role of acid strength in accessing different mechanisms of hydrogen evolution. Calculations also predict that modification of the bpy ligand by a variety of functional groups does not affect the preference for [Cp*] protonation, although the driving force for protonation changes. However, we predict that exchange of bpy for a bidentate phosphine ligand will stabilize a rhodium(III) hydride, reversing the preference for bound [Cp*H] found in all computed bpy derivatives and offering an appealing alternative ligand platform for future experimental and computational mechanistic studies of H2 evolution. PMID- 28862434 TI - Iron-Catalyzed Asymmetric Haloazidation of alpha,beta-Unsaturated Ketones: Construction of Organic Azides with Two Vicinal Stereocenters. AB - Organic azides play important roles in synthetic chemistry, chemical biology, drug discovery, and material science. Azido-functionalization of alkenes is one of the most efficient procedures for rapid introduction of azide group into organic compounds. But only a few examples have been documented in the catalytic asymmetric version of the azidation of alkenes. Herein, we report an unprecedented highly diastereo- and enantioselective bromoazidation of alpha,beta unsaturated ketones catalyzed by chiral N,N'-dioxide/Fe(OTf)2 complexes. An array of aryl, heteroaryl, and alkyl substituted alpha,beta-unsaturated ketones were transformed to the corresponding alpha-bromo-beta-azido ketones in high yields with excellent diastereo- and enantioselectivities. The catalytic system was also applicable for chloroazidation and iodoazidation of chalcone. Kinetic studies and some control experiments suggested that the reaction might proceed via a 1,4 addition/halogenation pathway. PMID- 28862435 TI - A Luminescent 3d-4f-4d MOF Nanoprobe as a Diagnosis Platform for Human Occupational Exposure to Vinyl Chloride Carcinogen. AB - A luminescent nanoprobe based on a lanthanide-transition heterometallic metal organic framework (MOF) is first designed for specific detection of urinary thiodiglycolic acid (TDGA) which is the biomarker of carcinogenic vinyl chloride monomer (VCM) and represents the internal dose of human exposure to VCM. The nanoprobe demonstrates high selectivity to TDGA with about 27.5-fold luminescence enhancement. It also displays excellent sensitivity with a detection limit as low as 89 ng.mL-1 and fast response to TDGA within 4 min, while refraining from the interference of other coexisting species in urine. Such good sensing performance enables the nanoprobe to practically monitor TDGA levels in human urine. Moreover, a portable urine dipstick based on the sensor is developed to conveniently evaluate individuals' intoxication degree of VCM. This fast, sensitive, and selective nanoprobe has promising potential to be a useful tool for point-of-care diagnosis of disease associated with VCM exposure. PMID- 28862436 TI - Induced-Dipole-Directed, Cooperative Self-Assembly of a Benzotrithiophene. AB - A benzotrithiophene derivative possessing phenylisoxazoles self-assembled to form stacks. The molecule isodesmically self-assembled in chloroform, whereas it self assembled in a cooperative fashion in decalin and in methylcyclohexane. Thermodynamic studies based on isodesmic, van der Schoot, and Goldstein-Stryer mathematical models revealed that the self-assembly processes are enthalpically driven and entropically opposed. An enthalpy-entropy compensation plot indicates that the assembly processes in chloroform, decalin, and methylcyclohexane are closely related. The enthalpic gains in less-polar solvents are greater than those in more-polar solvents, resulting in the formation of large assemblies in decalin and in methylcyclohexane. The formation of large assemblies leads to cooperative assemblies. The elongation process is enthalpically more favored than the nucleation process, which drives the cooperativity of the self-assembly. DFT calculations suggested that a hexameric assembly is more stable than tetrameric or dimeric assemblies. Cooperative self-assemblies based on intermolecular interactions other than hydrogen bonding have rarely been reported. It is demonstrated herein that van der Waals interactions, including induced dipole dipole interactions, can drive the cooperative assembly of planar pi-conjugated molecules. PMID- 28862437 TI - Form Follows Function: Nanoparticle Shape and Its Implications for Nanomedicine. AB - This review is a comprehensive description of the past decade of research into understanding how the geometry and size of nanoparticles affect their interaction with biological systems: from single cells to whole organisms. Recently, there has been a great deal of effort to use both the shape and the size of nanoparticles to target specific cellular uptake mechanisms, biodistribution patterns, and pharmacokinetics. While the successes of spherical lipid-based nanoparticles have heralded marked changes in chemotherapy worldwide, the history of asbestos-induced lung disease casts a long shadow over fibrous materials to date. The impact of particle morphology is known to be intertwined with many physicochemical parameters, namely, size, elasticity, surface chemistry, and biopersistence. In this review, we first highlight some of the morphologies observed in nature as well as shapes available to us through synthetic strategies. Following this we discuss attempts to understand the cellular uptake of nanoparticles through various theoretical models before comparing this with observations from in vitro and in vivo experiments. In addition, we consider the impact of nanoparticle shape at different size regimes on targeting, cytotoxicity, and cellular mechanics. PMID- 28862438 TI - Correction to Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors. PMID- 28862439 TI - Thermal and Structural Aspects of the Hydride-Conducting Oxyhydride La2LiHO3 Obtained via a Halide Flux Method. AB - Oxyhydrides, in which oxide and hydride anions share the same anionic lattice, are relatively rare compounds. La2LiHO3 belongs to this family. We report the synthesis of La2LiHO3 by means of an alkali halide flux method, which allows the production of larger quantities of material relative to the usually adopted synthesis routes. Powder X-ray and neutron diffraction studies show that La2LiHO3 adopts an n = 1 Ruddlesden-Popper (RP)-type structure with an orthorhombic distortion (Immm) due to hydride and oxide anion ordering. No sign of polymorphism is observed. La2LiHO3 is seen to decompose in an oxygen atmosphere at ~450 degrees C into La2LiO3.5. We show that the high mobility of hydride anions close to the decomposition temperature is likely the main factor in inducing the oxidation. The crystal structure of La2LiO3.5 is also determined and takes an n = 1 RP-type structure with an orthorhombic distortion (Fmmm). This newly reported large-scale synthesis approach, combined with the proven high thermal stability, is a key factor for potential practical applications of this oxyhydride in real devices. PMID- 28862440 TI - Comparative Evaluation of Key Aroma-Active Compounds in Raw and Cooked Red Mullet (Mullus barbatus) by Aroma Extract Dilution Analysis. AB - Raw red mullet (Mullus barbatus) and its cooked samples, obtained from steam and oven cooking, were subjected to aroma and key odorant analysis for the first time using GC-MS-O. The extraction of the aroma compounds was carried out by the direct solvent extraction-solvent assisted flavor evaporation (DSE-SAFE) method. Principal component analysis (PCA) was used to determine the relations between cooking processes and fish aroma compounds. By applying the aroma extract dilution analysis (AEDA), 8 and 13 aroma-active compounds were detected in raw and cooked fish samples, respectively. The most prominent differences between raw and cooked fish samples were as follows: 3-hydroxybutan-2-one, 2,3-octadienone, (E,E)-2,4-heptadienal, linalool, gamma-butyrolactone, 1-methylpyrrolidin-2-one, 2H-furan-5-one and pyrrolidin-2-one were only detected in cooked samples while hexanal and 2-phenoxyethanol in only raw fish samples. GC-MS-O results clearly indicated that cooking process results in the development of characteristics and pleasant aroma of red mullet samples due to the lipid oxidation. The most dominant aroma-active compound in the cooked fish samples was the 1-octen-3-ol which is responsible for the mushroom-like odor. PMID- 28862441 TI - Reaction of Ynamides with Iminoiodinane-Derived Nitrenes: Formation of Oxazolones and Polyfunctionalized Oxazolidinones. AB - This article describes the reaction of ynamides with metallanitrenes generated in the presence of an iodine(III) oxidant. N-(Boc)-Ynamides are converted to oxazolones via a cyclization reaction. The reaction is mediated by a catalytic dirhodium-bound nitrene species that first behaves as a Lewis acid. The oxazolones can be converted in a one pot manner to functionalized oxazolidinones following a regio- and stereoselective oxyamination reaction with the same nitrene reagent generated in stoichiometric amounts. PMID- 28862442 TI - meso-Tetraphenylporphyrin Iron Chloride Catalyzed Selective Oxidative Cross Coupling of Phenols. AB - A novel catalytic system for oxidative cross-coupling of readily oxidized phenols with poor nucleophilic phenolic partners based on an iron meso tetraphenylporphyrin chloride (Fe[TPP]Cl) complex in 1,1,1,3,3,3-hexafluoropropan 2-ol (HFIP) was developed. The unique chemoselectivity of this reaction is attributed to the coupling between a liberated phenoxyl radical with an iron ligated phenolic coupling partner. The conditions are scalable for preparing a long list of unsymmetrical biphenols assembled from a less reactive phenolic unit substituted with alkyl or halide groups. PMID- 28862443 TI - Open-Framework Manganese(II) and Cobalt(II) Borophosphates with Helical Chains: Structures, Magnetic, and Luminescent Properties. AB - Two borophosphates, (NH4)1-2xM1+x(H2O)2(BP2O8).yH2O with M = Mn (I) and Co (II), synthesized hydrothermally crystallize in enantiomorphous space groups P6522 and P6122 with a = 9.6559(3) and 9.501(3) A, c = 15.7939(6) and 15.582(4) A, and V = 1275.3(1) and 1218.2(8) A3 for I and II, respectively. Both compounds feature helical chains composed of vertex-sharing tetrahedral PO4 and BO4 groups that are connected through O atoms to transition-metal cations, Mn2+ and Co2+, respectively. For the two crystallographically distinct transition-metal cation sites present in the structure, this results in octahedral coordination with different degrees of distortion from the ideal symmetry. The crystal-field parameters, calculated from the corresponding absorption spectra, indicate that Mn2+ and Co2+ ions are located in a weak octahedral-like crystal field and suggest that the Co-ligand interactions are more covalent than the Mn-ligand ones. Luminescence measurements at room temperature reveal an orange emission that red-shifts upon lowering of the temperature to 77 K for I, while II is not luminescent. The luminescence lifetimes of I are 33.4 MUs at room temperature and 1.87 ms at 77 K. Both compounds are Curie-Weiss paramagnets with negative Weiss constants and effective magnetic moments expected for noninteracting Mn2+ and Co2+ cations but no clear long-range magnetic order above 2 K. PMID- 28862444 TI - Manual and Flow-Injection Detection/Quantification of Polyquaterniums via Fully Reversible Polyion-Sensitive Polymeric Membrane-Based Ion-Selective Electrodes. AB - The detection of four different polyquaterniums (PQs) using a fully reversible potentiometric polyion sensor in three different detection modes is described. The polyion sensing "pulstrodes" serve as the detector for direct dose-response experiments, beaker titrations, and in a flow-injection analysis (FIA) system. Direct polycation response toward PQ-2, PQ-6, PQ-10, and poly(2 methacryloxyethyltrimethylammonium) chloride (PMETAC) yields characteristic information about each PQ species (e.g., relative charge densities, etc.) via syringe pump addition of each PQ species to a background electrolyte solution. Quantitative titrations are performed using a syringe pump to deliver heparin as the polyanion titrant to quantify all four PQs at MUg/mL levels. Both the direct and indirect methods incorporate the use of a three-electrode system including counter, double junction reference, and working electrodes. The working electrode possesses a plasticized poly(vinyl chloride) (PVC) membrane containing the neutral lipophilic salt of dinonylnaphthalenesulfonate (DNNS-) tridodecylmethylammonium (TDMA+). Further, the titration method is shown to be useful to quantify PQ-6 levels in recreational swimming pool water collected in Ann Arbor, MI. Finally, a FIA system equipped with a pulstrode detector is used to demonstrate the ability to potentially quantify PQ levels via a more streamlined and semiautomated testing platform. PMID- 28862445 TI - "Cationic" Suzuki-Miyaura Coupling with Acutely Base-Sensitive Boronic Acids. AB - Fast, base-promoted protodeboronation of polyfluoroaryl and heteroaryl boronic acids complicates their use in Suzuki-Miyaura coupling (SMC) because a base is generally required for catalysis. We report a "cationic" SMC method using a PAd3 Pd catalyst that proceeds at rt in the absence of a base or metal mediator. A wide range of sensitive boronic acids, particularly polyfluoroaryl substrates that are poorly compatible with classic SMC conditions, undergo clean coupling. Stoichiometric experiments implicate the intermediacy of organopalladium cations, which supports a long-postulated cationic pathway for transmetalation in SMC. PMID- 28862446 TI - From Vegetable Waste to New Agents for Potential Health Applications: Antioxidant Properties and Effects of Extracts, Fractions and Pinocembrin from Glycyrrhiza glabra L. Aerial Parts on Viability of Five Human Cancer Cell Lines. AB - Glycyrrhiza glabra cultivation and harvesting produces substantial quantities of aerial parts as waste. With the aim to prospect an innovative valorization of these byproducts, the aerial parts were harvested in May and October and analyzed for their chemical profile, antioxidant properties, and effects on viability of five cancer cell lines. Pinocembrin was the main constituent. A significant protection of lipid peroxidation was observed with the May total extract (IC50 of 4.2 +/- 0.4 MUg/mL at 30 min of incubation). The effects on viability of HeLa, MCF-7, MDA-MB-231, Caco-2, and PC3 human cancer cells were investigated. All samples shown a remarkable activity with IC50 values below 25 MUg/mL. Samples from plants harvested in May exhibited greater activity than those harvested in October. MCF-7 and HeLa were the most sensitive cells with IC50 in the range 2.73 3.01 and 3.28-5.53 MUg/mL, respectively. G. glabra aerial parts represent a good source of valuable products. PMID- 28862447 TI - Comparison of Translocation and Transformation from Soil to Rice and Metabolism in Rats for Four Arsenic Species. AB - Arsenic (As) is ubiquitously present in the environment. The toxicity of As is related to its forms. This study was designed to compare the translocation and transformation of four As species from soil to rice, and metabolism in rats for four arsenic species. A set of 26550 data was obtained from pot experiments of rice plants grown in soil fortified with four As species, and 4050 data were obtained from rat experiments in which 81 rats were administered with the four As species. The total As in grain from the methyl arsenate fortified soil was 6.1, 4.9, and 5.2 times that from As(III), As(V), and dimethyl arsenate fortified soil, respectively. The total As in husk was 1.2-7.8 times greater than that in grain. After oral administration of each As species to rats, 83-96% was accumulatively excreted via feces and urine, while 0.1-16% was detected in blood. The translocation, transformation, and metabolism of different forms of arsenic vary greatly. PMID- 28862448 TI - Photoinduced Nickel-Catalyzed Chemo- and Regioselective Hydroalkylation of Internal Alkynes with Ether and Amide alpha-Hetero C(sp3)-H Bonds. AB - A direct hydroalkylation of disubstituted alkynes with unfunctionalized ethers and amides was achieved in an atom-efficient and additive-free manner through the synergistic combination of photoredox and nickel catalysis. The protocol was effective with a wide range of internal alkynes, providing products in a highly selective fashion. Notably, the observed regioselectivity is complementary to conventional radical addition processes. Mechanistic investigations suggest that the photoexcited iridium catalyst facilitated the nickel activation via single electron transfer. PMID- 28862449 TI - Structures of a DNA Polymerase Inserting Therapeutic Nucleotide Analogues. AB - Members of the nucleoside analogue class of cancer therapeutics compete with canonical nucleotides to disrupt numerous cellular processes, including nucleotide homeostasis, DNA and RNA synthesis, and nucleotide metabolism. Nucleoside analogues are triphosphorylated and subsequently inserted into genomic DNA, contributing to the efficacy of therapeutic nucleosides in multiple ways. In some cases, the altered base acts as a mutagen, altering the DNA sequence to promote cellular death; in others, insertion of the altered nucleotide triggers DNA repair pathways, which produce lethal levels of cytotoxic intermediates such as single and double stranded DNA breaks. As a prerequisite to many of these biological outcomes, the modified nucleotide must be accommodated in the DNA polymerase active site during nucleotide insertion. Currently, the molecular contacts that mediate DNA polymerase insertion of modified nucleotides remain unknown for multiple therapeutic compounds, despite decades of clinical use. To determine how modified bases are inserted into duplex DNA, we used mammalian DNA polymerase beta (pol beta) to visualize the structural conformations of four therapeutically relevant modified nucleotides, 6-thio-2'-deoxyguanosine-5' triphosphate (6-TdGTP), 5-fluoro-2'-deoxyuridine-5'-triphosphate (5-FdUTP), 5 formyl-deoxycytosine-5'-triphosphate (5-FodCTP), and 5-formyl-deoxyuridine-5' triphosphate (5-FodUTP). Together, the structures reveal a pattern in which the modified nucleotides utilize Watson-Crick base pairing interactions similar to that of unmodified nucleotides. The nucleotide modifications were consistently positioned in the major groove of duplex DNA, accommodated by an open cavity in pol beta. These results provide novel information for the rational design of new therapeutic nucleoside analogues and a greater understanding of how modified nucleotides are tolerated by polymerases. PMID- 28862450 TI - A One-Pot Construction of Halogenated Trifluoromethylated Pyrroles through NXS (X = Br, I) Triggered Cascade. AB - An easy two-step, one-pot synthesis of halogenated trifluoromethylated pyrroles is realized by sequential intermolecular hydroamination reaction of 2 trifluoromethyl-1,3-enynes with aliphatic primary amines under mild reaction conditions, and NXS mediated oxidative cyclization of the hydroamination product. The salient features of this method include mild conditions, readily available starting materials, general substrate scope, high efficiency and synthetic utility of the products. PMID- 28862451 TI - Cation Effect on Hot Carrier Cooling in Halide Perovskite Materials. AB - Organic-inorganic lead-halide perovskites have received a revival of interest in the past few years as a promising class of materials for photovoltaic applications. Despite recent extensive research, the role of cations in defining the high photovoltaic performance of these materials is not fully understood. Here, we conduct nonadiabatic molecular dynamics simulations to study and compare nonradiative hot carrier relaxation in three lead-halide perovskite materials: CH3NH3PbI3, HC(NH2)2PbI3, and CsPbI3. It is found that the relaxation of hot carriers to the band edges occurs on the ultrafast time scale and displays a strong quantitative dependence on the nature of the cations. The obtained results are explained in terms of electron-phonon couplings, which are strongly affected by the atomic displacements in the Pb-I framework triggered by the cation dynamics. PMID- 28862452 TI - Phototriggered Dehydration Condensation Using an Aminocyclopropenone. AB - A phototriggered dehydration condensation using an aminocyclopropenone has been developed. The UV irradiation of an aminocyclopropenone generated a highly reactive ynamine in situ and the dehydration condensation of a carboxylic acid and an amine coexisting in the reaction solution smoothly proceeded to afford an amide. This reaction is completely controllable by the ON/OFF states of a UV lamp. PMID- 28862453 TI - Aziridination of Cyclic Nitrones Targeting Constrained Iminosugars. AB - Rare C-7-substituted aziridinyl iminosugars can be synthesized through a short reaction sequence involving 1,3-cycloaddition of cyclic nitrones with alkynes and a Baldwin rearrangement of isoxazolines into bicyclic 2-acylaziridines. The method is efficient and completely diastereoselective, producing stable aziridinyl iminosugars in high yields. PMID- 28862454 TI - Unusual Electronic Structure of the Donor-Acceptor Cocrystal Formed by Dithieno[3,2-a:2',3'-c]phenazine and 7,7,8,8-Tetracyanoquinodimethane. AB - Mixed cocrystals derived from electron-rich donor (D) and electron-deficient acceptor (A) molecules showcase electronic, optical, and magnetic properties of interest for a wide range of applications. We explore the structural and electronic properties of a cocrystal synthesized from dithieno[3,2-a:2',3' c]phenazine (DTPhz) and 7,7,8,8-tetracyanoquinodimethane (TCNQ), which has a mixed-stack packing arrangement of the (pi-electronic) face-to-face stacks in a 2:1 D:A stoichiometry. Density functional theory investigations reveal that the primary electronic characteristics of the cocrystal are not determined by electronic interactions along the face-to-face stacks, but rather they are characterized by stronger electronic interactions orthogonal to these stacks that follow the edge-to-edge donor-donor or acceptor-acceptor contacts. These distinctive electronic characteristics portend semiconducting properties that are unusual for semiconducting mixed cocrystals and suggest further potential to design organic semiconductors with orthogonal transport characteristics for different charge carriers. PMID- 28862455 TI - Nickel-Mediated Asymmetric Allylic Alkylation between Nitroallylic Acetates and Acyl Imidazoles. AB - A nickel-mediated asymmetric allylic alkylation reaction between imidazole modified ketones and nitroallylic acetates is presented. This reaction is catalyzed by a simple chiral diamine-nickel catalyst under mild conditions and leads to a series of novel enantioenriched alpha-allylic adducts in moderate to good yields with excellent enantioselectivities. Furthermore, transformation of the allylic adducts could smoothly lead to chiral gamma-nitro-esters containing three continuous stereocenters in good yields. PMID- 28862456 TI - Controlling Protein Orientation in Vacuum Using Electric Fields. AB - Single-particle imaging using X-ray free-electron lasers is an emerging technique that could provide high-resolution structures of macromolecules in the gas phase. One of the largest difficulties in realizing this goal is the unknown orientation of the individual sample molecules at the time of exposure. Preorientation of the molecules has been identified as a possible solution to this problem. Using molecular dynamics simulations, we identify a range of electric field strengths where proteins become oriented without losing their structure. For a number of experimentally relevant cases we show that structure determination is possible only when orientation information is included in the orientation-recovery process. We conclude that nondestructive field orientation of intact proteins is feasible and that it enables a range of new structural investigations with single particle imaging. PMID- 28862457 TI - Reaction Paths and Chemical Activation Reactions of 2-Methyl-5-Furanyl Radical with 3O2. AB - Interest in high-energy substituted furans has been increasing due to their occurrence in biofuel production and their versatility in conversion to other useful products. Methylfurans are the simplest substituted furans and understanding their reaction pathways, thermochemical properties, including intermediate species stability, and chemical kinetics would aid in the study of larger furans. Furan ring C-H bonds have been shown to be extremely strong, approximately 120 kcal mol-1, due in part to the placement of the oxygen atom and aromatic-like resonance, both within the ring. The thermochemistry and kinetics of the oxidation of 2-methyfuran radical at position 5 of the furan ring, 2 methyl-5-furanyl radical (2MF5j), is analyzed. The resulting chemically activated species, 2MF5OOj radical, has a well depth of 51 kcal mol-1 below the 2MF5j + O2 reactants; this is 4-5 kcal mol-1 deeper than that of phenyl and vinyl radical plus O2, with both of these reactions known to undergo chain branching. Important, low-energy reaction pathways include chain branching dissociations, intramolecular abstractions, group transfers, and radical oxygen additions. Enthalpies of formation, entropies, and heat capacities for the stable molecules, radicals, and transition-state species are analyzed using computational methods. Calculated DeltaH degrees f 298 values were determined using an isodesmic work reaction from the CBS-QB3 composite method. Elementary rate parameters are from saddle point transition-state structures and compared to variational transition state analysis for the barrierless reactions. Temperature- and pressure-dependent rate constants which are calculated using QRRK and master equation analysis is used for falloff and stabilization. PMID- 28862458 TI - Fluorescent Phase-Pure Zero-Dimensional Perovskite-Related Cs4PbBr6 Microdisks: Synthesis and Single-Particle Imaging Study. AB - Quantum-confined perovskites are a new class of promising materials in optoelectronic applications. In this context, a zero-dimensional perovskite related substance, Cs4PbBr6, having high exciton binding energy can be an important candidate, but its photoluminescence (PL) is a topic of recent debate. Herein, we report an ambient condition controlled synthesis of Cs4PbBr6 microdisks of different shapes and dimensions which exhibit fairly strong green PL (quantum yield up to 38%, band gap ~2.43 eV) in the solid state. Using confocal fluorescence microscopy imaging of the single particles, we show that the fluorescence of Cs4PbBr6 microdisks is inherent to these particles. Fluorescence intensity and lifetime imaging of the microdisks reveals significant spatial heterogeneity with a bright central area and somewhat dimmer edges. This intensity and lifetime distribution is attributed to enhanced trap-mediated nonradiative deactivation at the edges compared to the central region of the microdisks. Our results, which unambiguously establish the PL of these Cs4PbBr6 and suggest its possible origin, brighten the potential of these materials in photon-emitting applications. PMID- 28862459 TI - Adsorption of CO on the Fe3O4(001) Surface. AB - The interaction of CO with the Fe3O4(001)-(?2 * ?2)R45 degrees surface was studied using temperature-programmed desorption (TPD), scanning tunneling microscopy (STM), and X-ray photoelectron spectroscopy (XPS), the latter both under ultrahigh vacuum (UHV) conditions and in CO pressures up to 1 mbar. In general, the CO-Fe3O4 interaction is found to be weak. The strongest adsorption occurs at surface defects, leading to small TPD peaks at 115, 130, and 190 K. Desorption from the regular surface occurs in two distinct regimes. For coverages up to two CO molecules per (?2 * ?2)R45 degrees unit cell, the desorption maximum shows a large shift with increasing coverage, from initially 105 to 70 K. For coverages between 2 and 4 molecules per (?2 * ?2)R45 degrees unit cell, a much sharper desorption feature emerges at ~65 K. Thermodynamic analysis of the TPD data suggests a phase transition from a dilute 2D gas into an ordered overlayer with CO molecules bound to surface Fe3+ sites. XPS data acquired at 45 K in UHV are consistent with physisorption. Some carbon-containing species are observed in the near-ambient-pressure XPS experiments at room temperature but are attributed to contamination and/or reaction with CO with water from the residual gas. No evidence was found for surface reduction or carburization by CO molecules. PMID- 28862460 TI - Electrophilic Cyclization and Intermolecular Acetalation of 2-(4-Hydroxybut-1-yn 1-yl)benzaldehydes: Synthesis of Diiodinated Diepoxydibenzo[c,k][1,9]dioxacyclohexadecines. AB - An expedient strategy for the preparation of diiodinated diepoxydibenzo[c,k][1,9]dioxacyclohexadecines from readily available 2-(4 hydroxybut-1-yn-1-yl)benzaldehydes through electrophile-triggered tandem cyclization/intermolecular acetalation sequence has been presented. The electrophilic macrocyclization can be performed under mild conditions and in up to gram quantities. Moreover, palladium-catalyzed coupling and reduction reactions of the resulting iodides could efficiently afford oxa-macrocycles. PMID- 28862461 TI - Effects of an Extreme Flood on Trace Elements in River Water-From Urban Stream to Major River Basin. AB - Major floods adversely affect water quality through surface runoff, groundwater discharge, and damage to municipal water infrastructure. Despite their importance, it can be difficult to assess the effects of floods on streamwater chemistry because of challenges collecting samples and the absence of baseline data. This study documents water quality during the September 2013 extreme flood in the South Platte River, Colorado, USA. Weekly time-series water samples were collected from 3 urban source waters (municipal tap water, streamwater, and wastewater treatment facility effluent) under normal-flow and flood conditions. In addition, water samples were collected during the flood at 5 locations along the South Platte River and from 7 tributaries along the Colorado Front Range. Samples were analyzed for 54 major and trace elements. Specific chemical tracers, representing different natural and anthropogenic sources and geochemical behaviors, were used to compare streamwater composition before and during the flood. The results differentiate hydrological processes that affected water quality: (1) in the upper watershed, runoff diluted most dissolved constituents, (2) in the urban corridor and lower watershed, runoff mobilized soluble constituents accumulated on the landscape and contributed to stream loading, and (3) flood-induced groundwater discharge mobilized soluble constituents stored in the vadose zone. PMID- 28862462 TI - Growth Behavior of Pristine and Potassium Doped Coronene Thin Films on Substrates with Tuned Coupling Strength. AB - The growth of polycyclic aromatic hydrocarbon (PAH) molecular coronene film on various substrates and the subsequent doping of potassium under ultrahigh vacuum (UHV) conditions have been systematically investigated by low-temperature scanning tunneling microscopy and spectroscopy (STM/STS). The crystalline structures and molecular orientations of coronene thin films are both thickness dependent and substrate-sensitive due to the competition between molecule substrate interaction and intermolecular interaction. In mono- or bilayer films, coronene molecules are flat-lying on the surface with hexagonal lattice, whereas in multilayer films, the topmost molecules are in a standing-up but tilted configuration with rectangular lattice. In particular, a 2 * 1 superstructure with respect to that of bulk coronene is formed on thick KCl film. Furthermore, we have studied the potassium doped coronene monolayer and multilayer on Ag(100) and KCl/Ag(100) surface. For K-doped coronene monolayer, at certain doping ratio x = 3, the lowest unoccupied molecular orbital (LUMO) of coronene film moves to the Fermi level, and a splitting of the LUMO state is observed. Increased potassium doping would result in a filled LUMO state below the Fermi level. By contrast, no well-ordered structures are obtained in the K-doped coronene multilayers which are vulnerable to rather moderate annealing processes owing to their relatively weak bonding with the supporting substrates, implying a big challenge of growth of PAH thick films in vacuum. The differences in the crystal structures of coronene thin films compared with that in bulk crystals might shed insight on the controversies in the experimental results on the electronic properties of alkali-metal-doped PAHs. PMID- 28862463 TI - Digital Photographic Procedure for Comprehensive Two-Dimensional Tooth Shade Analysis. AB - Current commercially available restorative materials vary in their esthetic properties, depending on brand and shade. Variations are related not only to basic color parameters such as hue, chroma, and value, but also to other important properties that affect the overall esthetic restorative outcome, such as opalescence, fluorescence, translucency, and metamerism. Fluorescence and bluish opalescence, though associated with the ingredients and chemical composition of the material, may be controlled and refined by a proper layering technique if that pretreatment analysis has been performed with the aid of appropriate photographic techniques. Digital cameras and dental photography have long been imperative tools for clinicians in their daily practice. Traditionally, digital photography has been used for recordkeeping, documentation, presentation, and informing patients of their oral status before and after treatment. Today, evolved techniques facilitate clinicians' ability to compare the esthetic properties of restorative materials with those of natural teeth for delivery of natural-looking restorations. Moreover, documentation obtained before and after restoration may be used for more comprehensive information for the patient. PMID- 28862464 TI - Use of CBCT Imaging, Open-Source Modeling Software, and Desktop Stereolithography 3D Printing to Duplicate a Removable Dental Prosthesis-A Proof of Concept. AB - This article describes an alternative computer-aided design/computer-aided manufacturing (CAD/CAM) technique that uses cone-beam computed tomography (CBCT) imaging, open-source 3-dimensional (3D) modeling software, and a desktop stereolithography (SLA) 3D printer to duplicate an existing complete removable dental prosthesis (CRDP). Intended to offer a proof of concept, this proposed technique provides dental clinicians who have access to a CBCT imaging unit and a desktop SLA 3D printer an option to manufacture a duplicated prosthesis in office. The 3D model of the CRDP can be preserved indefinitely, and the CAD/CAM process makes it possible to manufacture the CRDP multiple times with ease, when necessary. Different materials can be selected for the SLA 3D printer, and the duplicated prosthesis could be used for a variety of clinical and laboratory indications, such as a custom tray, a trial prosthesis, a reference record for a definitive prosthesis in laboratory procedures, or a radiographic template. Clinicians should select and use 3D software, printers, and materials with proper biocompatibility and classification and clearance from respective medical device regulatory bodies (such as US Food & Drug Administration) in different intended applications. PMID- 28862465 TI - Lateral Access Pouch Technique to Treat Implants With Gingival Recession. AB - Connective tissue grafting is a means of developing stable and natural-looking soft-tissue architecture. The use of a subepithelial connective tissue graft (SCTG) has been successful in achieving root coverage and augmenting tissue thickness. Tunnel techniques enable root coverage with results that appear natural. These techniques can be applied to the treatment of dental implants with gingival recession. The purpose of this article is to demonstrate the use of a SCTG and a lateral access pouch in the treatment of multiple gingival recession defects affecting adjacent implants. PMID- 28862466 TI - Evaluating the Clinical Efficacy of Tooth Powder on Plaque-Induced Gingivitis: A Randomized Controlled Trial. AB - Toothpastes and tooth powders are common oral care products used to control plaque and other deposits from tooth surfaces, thereby reducing gingivitis. This study was conducted to evaluate the efficacy of tooth powder in controlling dental plaque and gingivitis. A double-blind, parallel-arm, randomized controlled trial was conducted on 154 participants, aged 33 to 40 years, having at least 20 teeth with a full-mouth gingival index (GI) score >= 1.04 and fulfilling other inclusion/exclusion criteria. The plaque index (PI) and GI scores were used as measures of oral hygiene. Outcome variables of gingivitis and dental plaque were evaluated in test and control groups randomized with 1:1 ratio at 4, 12, and 24 weeks of follow-up. Repeated measure analysis of variance (ANOVA), t test, and paired t test were used for statistical analysis with a significance level of <= 0.050. One hundred and thirty-seven (N = 137) participants completed the study. Demographic and oral clinical parameters showed no statistical difference between the test group and the control group at baseline. A statistically significant difference (P <= .033) between the test group and the control group was observed for dental PI and GI scores at follow-up examinations. The repeated measure ANOVA also revealed a significant group interaction (P <= .01) for a reduction in outcome variables. From the current study, it may be concluded that tooth powder has been shown to be statistically superior to toothpastes in controlling dental plaque and gingivitis. PMID- 28862468 TI - Palliative Care Dentistry: Focusing on Quality of Life. AB - Palliative care dentistry is the management of patients with progressive, far advanced disease for whom the oral cavity has been compromised either by disease or by treatment. The focus of care is on the immediate quality of life. Typically, the palliative care team neglects to include a dentist despite many patients under its care, including those with cancer, exhibiting oral problems such as xerostomia, candidiasis, mucositis, and loss of masticatory function. This article will discuss the oral care of patients with terminal illnesses, many of whom have oral maladies that negatively impact quality of life. Treatment options for these patients will be outlined. PMID- 28862467 TI - Clinical, Imaging, and Laboratory Findings in Sjogren's Syndrome. AB - Sjogren's syndrome (SS) is a rare condition characterized by structural damage and secretory dysfunction of the lacrimal and salivary glands that leads to dryness, particularly xerophthalmia (eyes) and xerostomia (mouth). No cure is known; however, the effects of the disease are manageable and symptoms may be reduced. Although the salivary damage is irreversible, the dental decay and oral infections may be prevented, which highlights the importance that the clinician plays in the diagnosis and management of SS. The cardinal features of this disease are summarized through the case report of primary SS in a 23-year-old woman who received an early diagnosis based on clinical features, laboratory investigations, lower lip biopsy, and imaging findings. PMID- 28862469 TI - Clinical Applications of an Atraumatic Osteotome. AB - Osteotomes have long been used in the formation of osteotomies for the placement of dental implants. Their ability to manipulate and compress existing bone without generating heat makes them particularly useful for expanding narrow ridges, elevating delicate sinus membrane, and increasing relative bone density around the osteotomy. Common concerns with these devices include the traumatic force communicated to the patient during use and difficulty controlling force vectors. A new type of osteotome has been developed that is designed to enable the clinician to eliminate the concerns found with traditional osteotomes yet it preserves the best qualities and functionality of this class of device. This article will present several case reports that illustrate the usefulness of this instrumentation in clinical settings. PMID- 28862470 TI - Treatment Considerations for a Full-Mouth Reconstruction of a Transgender Patient. AB - A transgender patient presenting as a female sought dental care with her primary concern being a desire to change the appearance of her teeth. Open initial communication regarding the patient's gender status helped enable the clinician to gain a more thorough understanding of how medications taken by the patient could affect dental treatment. In this case, estradiol taken in constant doses impeded necessary orthodontic movement of the teeth, and the dosing, therefore, was modified to enhance treatment. The case report describes a full-mouth reconstruction for the transgender patient. PMID- 28862471 TI - Ten Myths of Guided Implant Surgery. AB - Since their introduction, guided dental implant planning and surgery procedures, like most new techniques in medicine and dentistry, have undergone many modifications and advances. While some practitioners were early adopters, most dental surgeons have been cautious regarding this methodology. Despite more than a decade of literature, podium presentations, advances in instrumentation and technique, and successful cases, questions remain within the dental surgical community. This article attempts to address some of these by outlining common but erroneous beliefs about this technology and procedure. PMID- 28862472 TI - Bone Grafting Opportunities, Options in Implant Dentistry. PMID- 28862473 TI - From phytoremediation of soil contaminants to phytomanagement of ecosystem services in metal contaminated sites. AB - Since the emergence of phytoremediation, much research has focused on its development for (i) the removal of metals from soil and/or (ii) the reduction of metal bioavailability, mobility, and ecotoxicity in soil. Here, we review the lights and shades of the two main strategies (i.e., phytoextraction and phytostabilization) currently used for the phytoremediation of metal contaminated soils, irrespective of the level of such contamination. Both strategies face limitations to become successful at commercial scale and, then, often generate skepticism regarding their usefulness. Recent innovative approaches and paradigms are gradually establishing these phytoremediation strategies as suitable options for the management of metal contaminated soils. The combination of these phytotechnologies with a sustainable and profitable site use (a strategy called phytomanagement) grants value to the many benefits that can be obtained during the phytoremediation of metal contaminated sites, such as, for instance, the restoration of important ecosystem services, e.g. nutrient cycling, carbon storage, water flow regulation, erosion control, water purification, fertility maintenance, etc. PMID- 28862474 TI - Tympanic membrane temperature decreases during head up tilt: relation to frontal lobe oxygenation and middle cerebral artery mean blood flow velocity. AB - INTRODUCTION: Changes in blood flow influence temperature of surrounding tissues. Since the internal carotid artery (ICA) and internal jugular vein (IJV) neighbor the tympanic membrane, changes in their blood flow most likely determine changes in tympanic membrane temperature (TMT). We sought to evaluate the relationship between changes during a head-up tilt (HUT) induced reduction in cerebral blood flow (CBF) and TMT. METHODS: Ten male subjects (age 19-28 years) underwent 50 degrees HUT until presyncope. A non-contact infrared sensor in the ear canal targeted the tympanic membrane. Changes in CBF were monitored by transcranial Doppler which determined the mean blood flow velocity in the middle cerebral artery (MCA Vmean) and by near infrared spectroscopy assessed frontal lobe oxygenation (ScO2), while skin blood flow (SkBF) was evaluated by laser Doppler flowmetry. RESULTS: During HUT, TMT decreased by 0.6 degrees C (median; range 0.2 to 1.6 degrees C) related to a decrease in MCA Vmean (51.0 +/- 6.7 to 34.3 +/- 5.8 cm/sec (mean +/- SD); r = 0.518, p = .002) and ScO2 (78.6 +/- 5.4% to 69.0 +/- 5.7%; r = 0.352, p = .043), but not to SkBF (120 +/- 78 to 69 +/- 37 PU; r = 0.245, p = .142). CONCLUSION: During an orthostatic challenge TMT decreases and the decrease is related to a reduction in CBF as indicated by MCA Vmean and ScO2, but not to SkBF. We consider TMT holds potential for non-invasive assessment of changes in cerebral perfusion. PMID- 28862475 TI - A survey of Canadian interprofessional student-run free clinics. AB - Student-run free clinics (SRFCs) have existed in Canada since 1971, providing interprofessional healthcare to underserved populations. SRFCs are seen as vehicles for socially accountable health professional education. Literature on how Canadian SRFC function is lacking. Web-based surveys were sent to student leaders from Canadian SRFCs regarding their 2014 activities. All six fully functioning SRFCs responded reporting on the following: services provided, professions involved, governing structure, funding sources, clients seen, types of care sought, students and preceptors involved, as well as perceived strengths, weaknesses, opportunities and threats. In 2014, 2,159 clients were provided clinical care at Canadian SRFCs. The most common reasons for visiting included pain and infection. Strengths identified include autonomy, ability to adapt to client needs, serving the underserved, and real-world interprofessional teamwork. Weaknesses reported include high student and preceptor turnover. Threats include securing funding and liability coverage. Since there is little literature on Canadian SRFCs, we compared our results with United States (US) based SRFCs. Canadian SRFCs share core values with US-based SRFCs and report similar strengths and challenges. However, Canadian SRFCs differ in scope and appear to provide care for more acute concerns. Data from studies of US-based SRFCs may not be immediately applicable to Canadian SRFCs. Studies evaluating Canadian SRFCs are needed. PMID- 28862476 TI - Olaratumab for the treatment of advanced soft tissue sarcoma. AB - INTRODUCTION: Olaratumab, a human monoclonal antibody against platelet derived growth factor receptor alpha (PDGFR- alpha), is the first drug that in combination with doxorubicin for the treatment of patients with advanced/metastatic soft tissue sarcoma (STS) that has showed an improved overall survival compared to doxorubicin alone. These initial results are exciting and have the potential to change the landscape of treatment for patients with STS. Areas covered: This article reviews the development of olaratumab for oncology use by reviewing articles in PubMed for 'platelet derived growth factor' and 'receptor' and 'soft tissue sarcoma'. We provide an overview of the published studies to date for olaratumab and specifically the use in soft tissue sarcoma. Expert commentary: Olaratumab is a well-tolerated drug that, when combined with doxorubicin, has shown an improved overall survival compared to doxorubicin alone and the phase III confirmatory study is eagerly awaited. PMID- 28862477 TI - New national curricula guidelines that support the use of interprofessional education in the Brazilian context: An analysis of key documents. AB - The National Curricular Guidelines (NCGs) are important documents for understanding the history of academic health professions education in Brazil. Key policies within the NCGs have helped to reorient health professions education and have stimulated curricular changes, including active learning methodologies and more integrated teaching-service environments, and, more recently, have introduced interprofessional education (IPE) in both undergraduate and postgraduate sectors. This article presents the findings of a study that examined the NCGs for nursing, dentistry, and medicine courses as juridical foundations for adopting strategies that promote IPE across higher education institutions in Brazil. We employed a comparative and exploratory documentary analysis to understand the role of IPE and collaborative practices in NCGs for the three largest professions in Brazil. Following a thematic analysis of these texts, four key themes emerged: faculty development; competencies for teamwork; curricular structure; and learning metrics. Key findings related to each of these themes are presented and discussed in relation to the wider interprofessional literature. The article goes on to argue that the statements contained in the NCGs about adoption of IPE and collaborative practices will have an important influence in shaping the future of health professions education in Brazil. PMID- 28862478 TI - Pyoderma gangrenosum affecting the eye, orbit, and adnexa. A review. AB - While pyoderma gangrenosum (PG) most commonly affects the skin it can also involve other organs. It rarely affects the eye, orbit, or adnexa. Its early recognition and proper management with prompt initiation of immunosuppressive therapy are essential for the preservation of the eye and, in turn, vision, in these cases. Here, we review the limited literature already published regarding ocular involvement in PG. PMID- 28862479 TI - Cost-effectiveness analysis of dabigatran versus rivaroxaban for stroke prevention in patients with non-valvular atrial fibrillation using real-world evidence in elderly US Medicare beneficiaries. AB - OBJECTIVE: Dabigatran and rivaroxaban have been approved by the US FDA to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients. Newly published real-world evidence based on the US population found that elderly Medicare patients with NVAF treated with rivaroxaban experienced statistically significant increases in intracranial hemorrhage (ICH) and major extracranial bleeding, and statistically nonsignificant decreases in thromboembolic stroke and acute myocardial infarction (AMI) compared with dabigatran. This study assessed the cost-effectiveness of dabigatran vs. rivaroxaban for the treatment of US Medicare NVAF patients. METHODS: A previously published Markov model was adapted to compare dabigatran and rivaroxaban. The model considered thromboembolic stroke, bleeding events, and AMI based on the published real-world event risks. Model outputs included clinical event rates, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Dabigatran patients experienced fewer ICH and major extracranial bleeding events than rivaroxaban patients, but more stroke and AMI events. Dabigatran was found to yield lower costs and higher QALYs than rivaroxaban, with incremental costs of -$3534 and incremental QALYs of 0.004. Results remained consistent in sensitivity analyses, with a positive net monetary benefit (willingness-to-pay thresholds of $50,000 and $100,000 per QALY) for dabigatran over rivaroxaban for all model inputs tested. CONCLUSIONS: In this study using US Medicare real-world data, dabigatran was found to dominate rivaroxaban. The analyses were limited by the short follow-up period of the real world data and results may not be generalizable to other patient populations. PMID- 28862480 TI - National Characteristics of Emergency Medical Services Responses for Older Adults in the United States. AB - OBJECTIVE: Older adults, those aged 65 and older, frequently require emergency care. However, only limited national data describe the Emergency Medical Services (EMS) care provided to older adults. We sought to determine the characteristics of EMS care provided to older adults in the United States. METHODS: We used data from the 2014 National Emergency Medical Services Information System (NEMSIS), encompassing EMS response data from 46 States and territories. We excluded EMS responses for children <18 years, interfacility transports, intercepts, non emergency medical transports, and standby responses. We defined older adults as age >=65 years. We compared patient demographics (age, sex, race, primary payer), response characteristics (dispatch time, location type, time intervals), and clinical course (clinical impression, injury, procedures, medications) between older and younger adult EMS emergency 9-1-1 responses. RESULTS: During the study period there were 20,212,245 EMS emergency responses. Among the 16,116,219 adult EMS responses, there were 6,569,064 (40.76%) older and 9,547,155 (59.24%) younger adults. Older EMS patients were more likely to be white and the EMS incident to be located in healthcare facilities (clinic, hospital, nursing home). Compared with younger patients, older EMS patients were more likely to present with syncope (5.68% vs. 3.40%; OR 1.71; CI: 1.71-1.72), cardiac arrest/rhythm disturbance (3.27% vs. 1.69%; OR 1.97; CI: 1.96-1.98), stroke (2.18% vs. 0.74%; OR 2.99; CI: 2.96-3.02) and shock (0.77% vs. 0.38%; OR 2.02; CI: 2.00-2.04). Common EMS interventions performed on older persons included intravenous access (32.02%), 12-lead ECG (14.37%), CPR (0.87%), and intubation (2.00%). The most common EMS drugs administered to older persons included epinephrine, atropine, furosemide, amiodarone, and albuterol or ipratropium. CONCLUSION: One of every three U.S. EMS emergency responses involves older adults. EMS personnel must be prepared to care for the older patient. PMID- 28862481 TI - Utilization of the Impella for hemodynamic support during percutaneous intervention and cardiogenic shock: an insight. AB - INTRODUCTION: Impella is a catheter-based micro-axial flow pump placed across the aortic valve, and it is currently the only percutaneous left ventricular assist device approved for high-risk percutaneous coronary intervention and cardiogenic shock. Areas Covered: Even though several studies have repeatedly demonstrated the excellent hemodynamic profile of Impella in high-risk settings, it remains underutilized. Here we aim to provide an up-to-date summary of the available literature on Impellas use in High risk settings as well as the practical aspects of its usage. Expert Commentary: Percutaneous coronary interventions in high rsk settings have always been challenging for a physician. Impella 2.5 and CP, have been proven safe, cost effective and feasible in High Risk Percutaneous coronary Interventions with an excellent hemodynamic profile. PMID- 28862482 TI - Pseudoprogression after glioma therapy: an update. AB - INTRODUCTION: Initial diagnostics and follow-up of gliomas is usually based on contrast-enhanced MRI. However, the capacity of standard MRI to differentiate neoplastic tissue from posttherapeutic effects such as pseudoprogression is limited. Advanced neuroimaging methods may provide relevant additional information, which allow for a more accurate diagnosis especially in clinically equivocal situations. This review article focuses predominantly on PET using radiolabeled amino acids and advanced MRI techniques such as perfusion-weighted imaging (PWI) and summarizes the efforts of these methods regarding the identification of pseudoprogression after glioma therapy. Areas covered: The current literature on pseudoprogression in the field of brain tumors, with a focus on gliomas is summarized. A literature search was performed using the terms 'pseudoprogression', 'temozolomide', 'glioblastoma', 'PET', 'PWI', 'radiochemotherapy', and derivations thereof. Expert commentary: The present literature provides strong evidence that PWI MRI and amino acid PET can be of great value by providing valuable additional diagnostic information in order to overcome the diagnostic challenge of pseudoprogression. Despite various obstacles such as the still limited availability of amino acid PET and the lack of standardization of PWI, the diagnostic improvement probably results in relevant benefits for brain tumor patients and justifies a more widespread use of these diagnostic tools. PMID- 28862484 TI - A population-based study of prognosis and survival in patients with second primary thyroid cancer after Hodgkin lymphoma. AB - Hodgkin lymphoma (HL) survivors are at increased risk of thyroid cancer (TC). We sought to determine whether increased risks of high-risk pathology or mortality are seen with thyroid cancer after HL (HL-TC) compared with first primary thyroid cancer (TC-1). From the Surveillance, Epidemiology and End Results (SEER) registry, we compared patient and tumor characteristics as well as survival outcomes between HL-TC and TC-1 and fit a multivariable Cox model to assess for a possible association between HL history and overall survival after TC. Among 139,297 TC-1 and 174 HL-TC patients, history of HL was not associated with anaplastic or sarcoma TC. Multivariable analyzes showed that history of HL was not associated with a difference in risk of death after TC (hazard ratio: 0.96, 95% confidence interval: (0.81, 1.13), p = .61). Despite a significantly increased risk of TC among HL survivors, prior HL is not associated with more aggressive pathologic subtypes or worse prognosis. PMID- 28862483 TI - PrEP Chicago: A randomized controlled peer change agent intervention to promote the adoption of pre-exposure prophylaxis for HIV prevention among young Black men who have sex with men. AB - BACKGROUND/AIMS: Advances in biomedical prevention strategies such as pre exposure prophylaxis (PrEP) represent a new opportunity for reducing HIV incidence among young Black men who have sex with men, for whom the number of new HIV infections continues to rise. However, studies have documented low rates of PrEP uptake in this community. Research suggests that the peer networks of young Black men who have sex with men play important roles in their sexual health decisions. PrEP Chicago is a randomized controlled trial network intervention designed to increase PrEP uptake among young Black men who have sex with men living in Chicago. The aims of this study are twofold. Aim 1 is to estimate the effectiveness of a peer change agent intervention for (1) increasing the number of referrals made to a PrEP information line, (2) increasing the rate of PrEP adoption among non-participant peers, and (3) increasing PrEP knowledge, attitudes, and intentions among participants. Aim 2 is to determine the individual and network variables that explain peer change agent effectiveness. METHODS: PrEP Chicago is a social network intervention that utilizes the influence of peer change agents to link young Black men who have sex with men in Chicago to PrEP. Young Black men who have sex with men were recruited using respondent-driven sampling. Once screened for eligibility, participants were randomly assigned to either one of two treatment sequences: (1) intervention treatment in Year 1 followed by a minimal contact attention control in Year 2 or (2) the minimal contact attention control in Year 1 followed by treatment in Year 2. The treatment consists of a PrEP/peer change agent training workshop followed by booster calls for 12 months. The attention control consists of a sex diary activity designed to help participants assess sexual risk. Psychosocial, sexual health, and network data are collected from all participants at baseline and at 12- and 24-month follow-ups. RESULTS: In total, 423 participants aged 18-35 have been enrolled (more than 100% target enrollment) and have completed baseline data collection. A majority of participants in both intervention and control groups reported having heard of PrEP before enrolling in the study, yet also reported having had no current or prior experience taking PrEP. Statistical analyses await completion of Year 1 of the trial in March 2018. CONCLUSION: PrEP Chicago addresses a gap in HIV prevention research and intervention design by utilizing the existing social networks among young Black men who have sex with men as mechanisms for information diffusion, behavioral influence, social support, and empowerment. Therefore, interventions that leverage peer influence processes to facilitate PrEP uptake are promising strategies to improve sexual health engagement and overcome disparities in outcomes among this at-risk population. PMID- 28862485 TI - High expression of Parkin predicts easier recurrence of patients with adjuvant transarterial chemoembolization. AB - AIM: To investigate the clinical significance of E3 ubiquitin ligase Parkin in patients with adjuvant transarterial chemoembolization after curative resection of hepatocellular carcinoma. METHODS: Parkin expression of hepatocellular carcinomas was detected and its correlation with clinicopathological factors was analyzed with chi2 test. The significance of Parkin in prognosis and recurrence was analyzed with log-rank test and the Cox-regression model. RESULTS: High expression of Parkin could result in lower recurrence-free survival rate instead of overall survival rate. Larger tumor size, positive tumor recurrence, advanced T, N, M and TNM stage were significantly associated with poorer prognosis. Larger tumor size, advanced T and TNM stage could lead to higher recurrence. CONCLUSION: High Parkin expression could predict easier recurrence to patients with adjuvant transarterial chemoembolization. PMID- 28862486 TI - Student experiences of interprofessional simulation: Findings from a qualitative study. AB - Interprofessional simulation provides healthcare profession students an opportunity to collaborate in a team. The purpose of this study was to examine student perspectives of an interprofessional simulation experience within the fields of nursing, physical therapy, nutrition, and social work. An exploratory case study design was employed, using open-ended interview questions post simulation to generate information about the student's perceptions of the experience. Based on the content analysis of reflection articles submitted by 100 students across professions, three themes emerged from the data: increased understanding of the role of other professionals, increased sense of confidence and ability to improve patient outcomes, and increased appreciation for inter professional simulation as a valuable learning experience. Participants felt a sense of comfort in working as a team, which in turn fostered confidence in their own role. This is an important finding, as confidence in one's own role in conjunction with increased willingness to work in a team is a powerful force for changing the ways in which professions interact with one another. Interprofessional simulation is a teaching strategy that shows great promise for promoting teamwork among the healthcare professions. PMID- 28862487 TI - Association between high sensitivity C-reactive protein levels with abdominal aortic aneurysms: fact or fiction? PMID- 28862488 TI - Some lectin binding properties of the tongue of the mole rat, Nannospalax xanthodon. AB - We investigated carbohydrate residues on the epithelial surface, in the epithelial cells and in gland cells of the tongue of the mole rat using histochemical methods. We used horseradish peroxidase-conjugated lectins from Helix pomatia (HPA), Arachishypogaea (PNA), Ulexeuropaeus (UEA I), Canavaliaensiformis (Con A). The most intense reactivity was observed in the keratin layer with HPA, UEA I and Con A, and in the epithelial cells with UEA I and Con A. In the glands, we found strong reactivity in serous cells with HPA and Con A, and in mucous cells with HPA and UEA I. PNA did not bind to epithelial or gland cells. Consequently, GlcNAc, fucose and alpha-D-mannose terminal glycoconjugates are distributed widely; GalNAc terminal glycoconjugates appeared in small amounts. PMID- 28862489 TI - Subcellular distribution, chemical forms and thiol synthesis involved in cadmium tolerance and detoxification in Siegesbeckia orientalis L. AB - Siegesbeckia orientalis L. is a promising species for cadmium (Cd) phytoextraction with large biomass and fast growth rate, while little information about their intracellular mechanisms involved in Cd tolerance and detoxification has been explored. A soil pot experiment with total target Cd concentrations of 0, 10, 50, 100, and 150 mg kg-1 were designed to investigate the subcellular distribution, chemical forms and thiol synthesis characteristics of Cd in S. orientalis. More than 90% of Cd was bound to the soluble fractions (48.4-76.5%) and cell walls (19.9-46.3%). Increasing soil Cd concentrations enhanced Cd sequestration into the cell walls. Most of the Cd (69.8-82.7%) in the plant organ was mainly in the forms of pectate and protein integrated Cd and undissolved Cd phosphate, while a minor portion (6.8-20.9%) was in the forms of the inorganic Cd and the water soluble Cd. Nonprotein thiols and phytochelatins significantly increased with increasing soil Cd treatment levels, while glutathione concentrations had no obvious change trends. Therefore, intracellular detoxification mechanisms of Cd in S. orientalis mainly rely on formation of less toxic Cd chemical forms, store of a large amount of Cd in cell wall and synthesis of thiol compounds. PMID- 28862490 TI - Phytoextraction potential of water fern (Azolla pinnata) in the removal of a hazardous dye, methyl violet 2B: Artificial neural network modelling. AB - This study investigated the potential of Azolla pinnata (AP) in the removal of toxic methyl violet 2B (MV) dye wastewater using the phytoextraction approach with the inclusion of an Artificial Neural Network (ANN) modelling. Parameters examined included the effects of dye concentration, pH and plant dosage. The highest removal efficiency was 93% which was achieved at a plant dosage of 0.8 g (dye volume = 200 mL, initial pH = 6.0, initial dye concentration = 10 mg L-1). A significant decrease in relative frond number (RFN), a growth rate estimator, observed at a dye concentration of 20 mg L-1 MV indicated some toxicity, which coincided with the plant pigments studies where the chlorophyll a content was lower than the control. There were little differences in the plant pigment contents between the control and those in the presence of dye (5 to 15 mg L-1) indicating the tolerance of AP to MV at lower concentrations. A three-layer ANN model was optimized (6 neurons in the hidden layer) and successfully predicted the phytoextraction of MV (R = 0.9989, RMSE = 0.0098). In conclusion, AP proved to be a suitable plant that could be used for the phytoextraction of MV while the ANN modelling has shown to be a reliable method for the modelling of phytoextraction of MV using AP. PMID- 28862491 TI - Eye-gaze control technology for children, adolescents and adults with cerebral palsy with significant physical disability: Findings from a systematic review. AB - PURPOSE: The primary objective of this systematic review was to examine the effectiveness of eye-gaze control technology for facilitating communication across different social contexts for people with cerebral palsy and significant physical disability. METHODS: Systematic review. RESULTS: The search identified 756 potentially eligible articles, of which two, low level articles were eligible. One study reported positive results for achieving communication goals for children with cerebral palsy. The second concluded that eye-gaze control technology resulted in greater quality of life and less depression for adults with late stage amyotrophic lateral sclerosis when compared to non-users. DISCUSSION: Research regarding the effectiveness of eye-gaze control technology used to access a laptop, tablet or computer on communication outcomes, participation, quality of life and self-esteem in children, adolescents and adults with cerebral palsy and significant physical disability is sparse. A scoping review to fully identify issues to inform clinical practice and future research is required. PMID- 28862492 TI - Three-dimensional positional assessment of glenoid fossae and mandibular condyles in patients with Class II subdivision malocclusion. AB - OBJECTIVES: To test the null hypotheses that the positions of the glenoid fossae and mandibular condyles are identical on the Class I and Class II sides of patients with Class II subdivision malocclusion. MATERIALS AND METHODS: Retrospective three-dimensional (3D) assessments of the positions of the glenoid fossae and mandibular condyles were made in patients with Class II malocclusion. Relative to a fiducial reference at the anterior cranial base, distances from the glenoid fossae and condyles were calculated in pretreatment cone beam computed tomographic scans of 82 patients: 41 with Class II and 41 with Class II subdivision malocclusions. The 3D distances from glenoid fossae to sella turcica in the X (right-left), Y (anterior-posterior), Z (inferior-superior) projections were calculated. RESULTS: Patients with Class II malocclusion displayed a symmetric position of the glenoid fossae and condyles with no statistically significant differences between sides (P > .05), whereas patients with Class II subdivision showed asymmetry in the distance between the glenoid fossae and anterior cranial base or sella turcica (P < .05), with distally and laterally positioned glenoid fossae on the Class II side. (P < .05). Male patients had greater distances between glenoid fossae and anterior cranial fossae (P < .05). The condylar position relative to the glenoid fossae did not differ between the two malocclusion groups nor between males and females (P > .05). CONCLUSIONS: The null hypotheses were rejected. Patients with Class II subdivision malocclusion displayed asymmetrically positioned right- and left-side glenoid fossae, with a distally and laterally positioned Class II side, although the condyles were symmetrically positioned within the glenoid fossae. PMID- 28862494 TI - Going with the Flow: Saddle Pulmonary Embolism Complicated by Severe Hypoxemia without Shock. PMID- 28862496 TI - Tracheobronchomalacia in Neonates: The "New Bronchopulmonary Dysplasia" Is Not Just about the Alveoli. PMID- 28862493 TI - An Official American Thoracic Society Workshop Report: Presentations and Discussion of the Sixth Jack Pepys Workshop on Asthma in the Workplace. AB - The Sixth Jack Pepys Workshop on Asthma in the Workplace focused on six key themes regarding the recognition and assessment of work-related asthma and airway diseases: (1) cleaning agents and disinfectants (including in swimming pools) as irritants and sensitizers: how to evaluate types of bronchial reactions and reduce risks; (2) population-based studies of occupational obstructive diseases: use of databanks, advantages and pitfalls, what strategies to deal with biases and confounding?; (3) damp environments, dilapidated buildings, recycling processes, and molds, an increasing problem: mechanisms, how to assess causality and diagnosis; (4) diagnosis of occupational asthma and rhinitis: how useful are recombinant allergens (component-resolved diagnosis), metabolomics, and other new tests?; (5) how does exposure to gas, dust, and fumes enhance sensitization and asthma?; and (6) how to determine probability of occupational causality in chronic obstructive pulmonary disease: epidemiological and clinical, confirmation, and compensation aspects. A summary of the presentations and discussion is provided in this proceedings document. Increased knowledge has been gained in each topic over the past few years, but there remain aspects of controversy and uncertainty requiring further research. PMID- 28862495 TI - Fluid Management in Acute Respiratory Distress Syndrome: Do We Have All the FACTTs to Determine the Effect of Race? PMID- 28862497 TI - Another Brick in the Wall: Lung Clearance Index and Lower Airways Pathology in Preschool Cystic Fibrosis. PMID- 28862498 TI - Shedding Light on Incidental Findings on Low-Dose Lung Cancer Screening Chest Computed Tomography. PMID- 28862499 TI - Suspect the Unexpected: A 45-Year-Old Man with Fevers, Rash, and Multiorgan Failure. PMID- 28862500 TI - Satori: Awakening to Outcomes That Matter: The Impact of Social Support in Chronic Obstructive Pulmonary Disease. PMID- 28862501 TI - Clarity on Endpoints for Clinical Trials in Idiopathic Pulmonary Fibrosis. PMID- 28862502 TI - A 53-Year-Old Woman with Severe Carbon Monoxide Poisoning. PMID- 28862503 TI - Chronic Rhinosinusitis and Structural Remodeling. PMID- 28862504 TI - Breaking Steroid Resistance: Effect of Vitamin D on IL-23. PMID- 28862506 TI - Aiding and Abetting the Enemy: Nicotine Impairs the Macrophage Defense against Mtb. PMID- 28862507 TI - A "GLI-tch" in Alveolar Myofibroblast Differentiation. PMID- 28862508 TI - Vulnerability and Genetic Susceptibility to Cigarette Smoke-Induced Emphysema in Mice. PMID- 28862509 TI - Partially Assisted Ventilation-induced Lung Injury in Early Acute Respiratory Distress Syndrome. When Real Life Is Different from Classical Physiology. PMID- 28862510 TI - Autophagy Traps Neutrophils into a Protective Alliance during Sepsis. PMID- 28862511 TI - What Is Menthol? PMID- 28862512 TI - EDITORIAL. PMID- 28862513 TI - Relationship between glucocorticoid dose and adverse events in systemic lupus erythematosus: data from a randomized clinical trial. AB - OBJECTIVE: The aim was to obtain a better understanding of the relationship between exposure to glucocorticoids (GCs) and adverse events (AEs) reported in a randomized controlled trial (RCT) in systemic lupus erythematosus (SLE) patients. METHOD: We used data from the BLISS-76 trial on belimumab. The data were accessed through an agreement under the SHARE mechanism. AEs were grouped according to medical relevance, i.e. based on similarity of symptoms and pathophysiology. We studied the relationship between AEs and exposure to GCs at baseline and at any time-point, and compared the frequencies of each AE and groups of AEs between tertiles of cumulative GC dose. RESULTS: In total, 991 AEs were reported in the 819 patients of the trial. The frequencies of anaemia, pyrexia, oral herpes, and malaise were significantly higher (p < 0.05) in patients who were on GCs at baseline than in those who were not. The frequencies of several other AEs, including nausea, seasonal allergy, bacterial sinusitis, and viral upper respiratory infection, were significantly higher in patients without GCs. For cumulative GCs, tachycardia and proteinuria were significantly more frequent in the highest tertile than in the lowest tertile, but other AEs and groups of AEs were significantly more frequent in the lowest tertile. CONCLUSION: This study highlights the feasibility of post-hoc analyses of RCTs using the SHARE mechanism and demonstrates the association of GCs with various AEs. Contrary to expectations, there were also associations between lower cumulative GC dose and several other AEs. PMID- 28862514 TI - Characteristics of organic acid profiles in 16 species of wild growing edible mushrooms. AB - The aim of study was to determine 9 organic acids in nine aboveground and seven wood-growing wild edible mushroom species originated from an area under the direct influence of a busy trunk road in Poland. The organic acids in the extracts of samples were identified by reversed-phase column liquid chromatography (RPLC). The presented results show that all the mushroom species were characterized by high variation in the profile and content of the analyzed acids. Each of mushroom species contained oxalic acid, the profiles of the other acids strictly depended on mushroom species. Among aboveground species, the highest total content of organic acids was found in Lepista gilva (267.5 +/- 26.6 mg g-1 dry weight (DW)), while Laccaria amethystina was characterized by the lowest content (37.7 +/- 6.5 mg g-1 DW). Within wood-growing species, the highest content of organic acids was determined in Flammulina velutipes (171.9 +/- 26.7 mg g-1 DW), whereas the lowest content (34.2 +/- 2.9 mg g-1 DW) of the studied acids was observed in Grifola frondosa. PMID- 28862515 TI - Study of the factors at admission predicting the outcome in patients with attempted suicidal hanging. AB - Our study sought to identify factors at presentation which can predict the outcome after an attempted hanging. A retrospective analysis of patients over a 12-year period was carried out. A poor outcome was found in 17.8% and this could be predicted by the presence of myoclonus, a Glasgow coma motor score of <=3 or an abnormal chest radiograph. PMID- 28862516 TI - Breast enlargement in newborns: a folkloric-medical dilemma. PMID- 28862517 TI - Letter to the Editor. Ventriculoperitoneal shunts after abdominal surgery. PMID- 28862518 TI - Optimal stimulation parameters for intraoperative bulbocavernosus reflex in infants. AB - OBJECTIVE The aim of this study was to establish optimal electric stimulation parameters for intraoperatively monitoring the bulbocavernosus reflexes (BCRs) in infants. METHODS The authors retrospectively reviewed the medical records of all infants (age < 24 months) who had undergone an untethering operation for tethered cord syndrome between May 2013 and February 2014 at a single institution and whose baseline BCR had been elicited during surgery. Using different combinations of stimulation parameters-number of stimulation pulses: 4 or 8 pulses, interpulse interval: 1, 2, or 5 msec, and polarity of stimulation: biphasic or monophasic the authors compared the relative mean amplitude of 10 BCR responses (rmaBCRs) to each combination of parameters. RESULTS The rmaBCRs were larger with the 8-pulse stimulations than with the 4-pulse stimulations (p < 0.0001). There was a tendency, though not statistically significant, for larger rmaBCRs to be obtained with the longer interpulse interval in the 8-pulse stimulation (p = 0.1289). The biphasic stimulation produced larger rmaBCRs than the monophasic stimulation (p = 0.0005). CONCLUSIONS Biphasic 8-pulse stimulations with 5-msec or 2-msec intervals yield the largest BCR responses. Considering that an 8-pulse stimulation with 5-msec intervals may overlap the onset of the BCR, a biphasic 8 pulse stimulation with 2-msec intervals is recommended as the optimal stimulation paradigm to monitor intraoperative BCRs in infants. PMID- 28862519 TI - Novel insights into symptomatology of moyamoya disease in pediatric patients: survey of symptoms suggestive of orthostatic intolerance. AB - OBJECTIVE A specific population of young patients with moyamoya disease (MMD) persistently experience physical symptoms not attributable to focal ischemia. These symptoms, highly suggestive of orthostatic intolerance (also termed "orthostatic dysregulation"), were investigated and reported as potential determinants of quality of life in young MMD patients. METHODS Forty-six patients (6-30 years of age) were selected from a group of 122 patients who were diagnosed with MMD before 18 years of age. The authors administered a structured questionnaire consisting of 11 items based on screening checklists published in the Japanese clinical guidelines for juvenile orthostatic dysregulation in young patients. The results were tabulated, and correlations with clinical data were explored. RESULTS Thirty-seven (80%) patients (mean age 15.9 years) responded to the questionnaire. Frequent headache, vertigo/dizziness on standing, fatigue, difficulty with getting out of bed, and motion sickness were the top 5 symptoms, resulting in 57% of patients being unable to attend school. Forty-three percent of the patients demonstrated multiple symptoms suggestive of orthostatic intolerance, even as long as 5 years after revascularization surgery. The number of symptoms was inversely associated with the number of years after surgery (p = 0.028). The number of symptoms was not associated with a history of surgery, clinical presentations, vascular involvement, cerebral perfusion, brain lesions, or history of transient ischemic attacks. CONCLUSIONS The present study provided novel insight into the symptomatology of young patients with MMD. Failure to notice nonfocal physical symptoms can significantly impair quality of life in young patients with MMD even years after successful revascularization surgery. These symptoms may serve as independent clinical markers used to assess disease outcome, although the underlying mechanisms of this disease are, as of yet, unclear. PMID- 28862520 TI - Non-communicable disease prevention in Nepal: systemic challenges and future directions. AB - Developing countries such as Nepal are experiencing a double burden of communicable and non-communicable diseases (NCDs) resulting in social and economic losses. In Nepal, more than half of the disease burden is due to NCDs. The major NCDs in Nepal are cardiovascular diseases, cancers, chronic respiratory diseases and diabetes. Behavioural factors such as tobacco use, alcohol consumption, physical inactivity and unhealthy diet are driving the epidemic of NCDs, which are further influenced by social, economic and environmental determinants. The health system of Nepal has not been able to address the ever increasing burden of NCDs. With the formulation of the Multisectoral Action Plan for Prevention and Control of NCDs 2014-2020, there has been some hope for tackling the NCDs and their social determinants in Nepal through a primary prevention approach. This paper discusses the systemic challenges and recommends two key actions for the prevention and control of NCDs in Nepal. PMID- 28862521 TI - Repeated faecal occult blood testing is associated with decreased advanced colorectal cancer risk: A population-based study. AB - OBJECTIVE: To evaluate the association between repeated faecal occult blood testing and advanced colorectal cancer risk at population level in Canada. METHODS: A retrospective cohort study of all Ontario residents aged 56-74 diagnosed with colorectal cancer from 1 April 2007 to 31 March 2010, identified using health administrative data. The primary outcome was stage IV colorectal cancer, and primary exposure was faecal occult blood testing use within five years prior to colorectal cancer diagnosis. Patients were categorized into four mutually exclusive groups based on their exposure to faecal occult blood testing in the five years prior to colorectal cancer diagnosis: none, pre-diagnostic, repeated, and sporadic. Logistic regression was utilized to adjust for confounders. RESULTS: Of 7753 patients (median age 66, interquartile range 61-70, 62% male) identified, 1694 (22%) presented with stage I, 2056 (27%) with stage II, 2428 (31%) with stage III, and 1575 (20%) with stage IV colorectal cancer. There were 4092 (53%) with no record of prior faecal occult blood testing, 1485 (19%) classified as pre-diagnostic, 1693 (22%) as sporadic, and 483 (6%) as repeated faecal occult blood testing. After adjusting for confounders, patients who had repeated faecal occult blood testing were significantly less likely to present with stage IV colorectal cancer at diagnosis (Odds ratio 0.46, 95% Confidence Interval 0.34-0.62) than those with no prior faecal occult blood testing. CONCLUSIONS: Repeated faecal occult blood testing is associated with a decreased risk of advanced colorectal cancer. Our findings support the use of organized screening programmes that employ repeated faecal occult blood testing to improve colorectal cancer outcomes at population level. PMID- 28862522 TI - The social context of hormone and silicone injection among Puerto Rican transwomen. AB - This paper draws on ethnographic, qualitative and survey data with transwomen in Puerto Rico to examine the social and political-economic context of lay injection with hormone and silicone - common practices within this community. We describe specific practices of hormone and silicone injection, the actors that govern them, the market for the sale and distribution of syringes and the networks of lay specialists who provide services to a population that is neglected by and largely excluded from biomedical settings. Our data derive from ethnographic observations, sociodemographic questionnaires, surveys and semi-structured interviews conducted with a diverse group of transwomen in metropolitan San Juan, Puerto Rico. Our analysis focuses on four overlapping social domains or processes that shape the practices of lay silicone and hormone injection among transwomen: (1) the circulation of gender transitioning technologies within local and global markets; (2) the tension between the social exclusion of transwomen and their resilient sub-cultural responses; (3) the cultural meanings that shape transwomen's attitudes about injection; and (4) the perceived consequences of injection. We conclude with a discussion of the kinds of intervention and policy changes that would respond to the factors that most endanger transwomen's health. PMID- 28862523 TI - L- and T-type calcium channel blockers protect against the inhibitory effects of mipafox on neurite outgrowth and plasticity-related proteins in SH-SY5Y cells. AB - Some organophosphorus compounds (OP), including the pesticide mipafox, produce late onset distal axonal degeneration, known as organophosphorus-induced delayed neuropathy (OPIDN). The underlying mechanism involves irreversible inhibition of neuropathy target esterase (NTE) activity, elevated intracellular calcium levels, increased activity of calcium-activated proteases and impaired neuritogenesis. Voltage-gated calcium channels (VGCC) appear to play a role in several neurologic disorders, including OPIDN. Therefore, this study aimed to examine and compare the neuroprotective effects of T-type (amiloride) and L-type (nimodipine) VGCC blockers induced by the inhibitory actions of mipafox on neurite outgrowth and axonal proteins of retinoic-acid-stimulated SH-SY5Y human neuroblastoma cells, a neuronal model widely employed to determine the neurotoxicity attributed to OP. Both nimodipine and amiloride significantly blocked augmentation of intracellular calcium levels and activity of calpains, as well as decreased neurite length, number of differentiated cells, and lowered concentrations of growth-associated protein 43 (GAP-43) and synapsin induced by mipafox. Only nimodipine inhibited reduction of synaptophysin levels produced by mipafox. These findings demonstrate a role for calcium and VGCC in the impairment of neuronal plasticity mediated by mipafox. Data also demonstrated the neuroprotective potential of T-type and L type VGCC blockers to inhibit OP-mediated actions, which may be beneficial to counteract cases of pesticide poisoning. PMID- 28862524 TI - Effect of anaesthetic and choice of neuromuscular blocker on vagal control of heart rate under laboratory animal experimental conditions. AB - Neuromuscular-blocking agents are commonly used in laboratory animal research settings. Due to actions of cholinergic receptors at locations other than the motor end-plate, these agents have a strong propensity to modulate autonomic outflow and may therefore not be desirable in studies examining autonomic function. This study aimed to compare the effect of two non-depolarizing neuromuscular-blocking agents, pancuronium and cisatracurium, on blood pressure, heart rate and non-invasive indices of autonomic function (heart rate variability, systolic blood pressure variability and baroreflex sensitivity) under two different types of anaesthesia in Lewis rats. Pancuronium produced a profound vagolytic response characterized by tachycardia, reduction in heart rate variability and baroreflex sensitivity under urethane anaesthesia, and with minimal effect under isoflurane anaesthesia. Conversely, cisatracurium produced no evidence of vagolytic action under either urethane or isoflurane anaesthesia. Therefore, for studies interested in examining autonomic function, particularly baroreflex or vagal function, neuromuscular blockade would be best achieved using cisatracurium. PMID- 28862526 TI - Time-dependent ROC analysis for censored biomarker data due to limit of detection. AB - Receiver operating characteristic (ROC) curve is a well-established analysis method to evaluate biomarker's discrimination accuracy for binary outcomes. When the endpoint of interest is time to event outcome such as time to cancer recurrence, a biomarker's time-varying discriminatory performance is often assessed by time-dependent ROC analysis. In practice, biomarkers are often imprecisely measured due to the limitation of assay sensitivity. The values below the limit of detection are not detectable. Ignorance of such data characteristic may lead to inaccurate estimation of marker's potential discriminatory power. The objective of this article is to extend time-dependent ROC method to censored biomarker data by using parameter estimates from the Cox regression model that accommodates censored biomarker measurements. In the simulation study, the proposed methods are shown to outperform the simple substitution method that has been conventionally adopted for handling censored data. Application data are also given to illustrate our methods. PMID- 28862527 TI - Agency, lapse in condom use and relationship intimacy among female sex workers in Jamaica. AB - This paper explores barriers to consistent condom use among female sex workers in Jamaica in a qualitative study using grounded theory. Multiple perspectives were sought through 44 in-depth interviews conducted with female sex workers, clients, the partners of sex workers and facilitators of sex work. Poverty and lack of education or skills, severely limited support systems as well as childhood abuse served to push the majority of participants into sex work and created vulnerability to HIV and other STIs. Despite these constraints, women found ways to exercise agency, ensure condom use, adopt protective measures and gain economic advantage in various aspects of the Jamaican sex trade. Perceived relationship intimacy between sex workers and their clients and/or their main partners emerged as the main factor contributing to reduced risk perception and inconsistent condom use. Relationship intimacy, with associated trust and affirmation of self, is the most important factor influencing sexual decision making with respect to lapse in condom use among female sex workers in Jamaica. Study findings provide important insights that can enhance individual psychosocial, interpersonal and community-based interventions as well as inform environmental, structural and policy interventions to reduce risk and vulnerability among female sex workers. PMID- 28862528 TI - Infectious complications in HIV-infected kidney transplant recipients. AB - Renal transplantation is now a viable alternative for dialysis in HIV-infected patients who achieve good immunovirological control with current antiretroviral therapy regimens available. However, there are few studies that analyze the incidence of post-transplant infections in this population. In this study, a retrospective analysis of data files of 24 HIV-infected kidney transplant (KT) recipients was undertaken, matched to 21 non-infected controls. All patients received induction with anti-interleukin-2 antibodies and were followed in the Pitie-Salpetriere Hospital in Paris, France. The rate of incidence of post transplant infections was 23.58 and 26.98/100 patient-years, in HIV-infected and HIV-negative groups (relative risk [RR]: 0.90; 95% confidence interval [CI]: 0.58 1.39; p = 0.63). In HIV-infected KT recipients, bacterial infections were the most frequent (67.7%), followed by viral (14.7%) and fungal and parasitic infections (8.8%). Similar trends were seen in the control group. Incidence of opportunistic infections was similar in HIV-infected KT recipients and controls (38.2 vs. 26.5%; p = 0.44). There were three post-transplant HIV reactivations in two patients, secondary to poor adherence to medication. HIV status did not influence survival, but infections increased the risk of unfavorable outcome. Incidence of post-transplant infections was similar in HIV-infected KT recipients and controls. Infections, but not HIV status, had adverse effects on patient and graft survival. PMID- 28862529 TI - An algorithmic approach to rehabilitation following arthroscopic surgery for arthrofibrosis of the knee. AB - BACKGROUND AND PURPOSE: Loss of knee range of motion (ROM) has been reported as the most common complication following anterior cruciate ligament reconstruction (ACLR). Arthrofibrosis of the knee, or specifically Cyclops syndrome, has been described as the formation of a scar tissue nodule adjacent to the tibial tunnel of the anterior cruciate ligament (ACL) graft. This lesion often results in loss of knee extension ROM, pain, and impaired function. CASE DESCRIPTIONS: Three consecutive patients were referred to physical therapy following arthroscopic knee surgery for lysis of adhesions of a Cyclops lesion from a previous ACLR. Arthroscopic debridement was performed between 3 and 12 months post ACLR. An algorithmic progression of extension ROM was the initial focus of physical therapy, which then advanced to strengthening, neuromuscular reeducation, and sport specific training. OUTCOME: Following knee surgery for debridement of the Cyclops lesion, mean knee joint ROM at the initial physical therapy evaluation was 7.0 degrees +/- 8.6 degrees to 118.3 degrees +/- 7.6 degrees that progressed to -1.0 degrees +/- 1.7 degrees to 127 degrees +/- 2.6 degrees at discharge. Mean numeric pain rating improved from 3.0 +/- 1.0 at the evaluation to 0.7 +/- 1.1 at discharge. Mean Lower Extremity Functional Scale (LEFS) improved from 56.3 +/- 13.6 to 77.0 +/- 4.3 at discharge. DISCUSSION: Arthroscopic debridement of knee joint arthrofibrosis after ACLR in conjunction with a postoperative physical therapy algorithmic approach to maximizing knee joint extension ROM can be beneficial in gaining symmetrical knee extension range of motion and improved function. Further studies may help to understand the optimal mode, frequency, and duration of stretching to achieve full symmetrical knee extension in this population. PMID- 28862531 TI - Unisensory and multisensory Self-referential stimulation of the lower limb: An exploratory fMRI study on healthy subjects. AB - BACKGROUND: The holistic view of the person is the essence of the physiotherapy. Knowledge of approaches that develop the whole person promotes better patient outcomes. Multisensory Self-referential stimulation, more than a unisensory one, seems to produce a holistic experience of the Self ("Core-Self"). OBJECTIVES: (1) To analyze the somatotopic brain activation during unisensory and multisensorial Self-referential stimulus; and (2) to understand if the areas activated by multisensorial Self-referential stimulation are the ones responsible for the "Core-Self." METHODS: An exploratory functional magnetic resonance imaging (fMRI) study was performed with 10 healthy subjects, under the stimulation of the lower limbs with three Self-referential stimuli: unisensory auditory-verbal, unisensory tactile-manual, and multisensory, applying the unisensory stimuli simultaneously. RESULTS: Unisensory stimulation elicits bilateral activations of the temporoparietal junction (TPJ), of the primary somatosensory cortex (S1), of the primary motor cortex (BA4), of the premotor cortex (BA6) and of BA44; multisensory stimulation also elicits activity in TPJ, BA4, and BA6, and when compared with unisensory stimuli, activations were found in: (1) Cortical and subcortical midline structures-BA7 (precuneus), BA9 (medial prefrontal cortex), BA30 (posterior cingulated), superior colliculum and posterior cerebellum; and (2) Posterior lateral cortex-TPJ, posterior BA13 (insula), BA19, and BA37. Bilateral TPJ is the one that showed the biggest activation volume. CONCLUSION: This specific multisensory stimulation produces a brain activation map in regions that are responsible for multisensory Self-processing and may represent the Core Self. We recommend the use of this specific multisensory stimulation as a physiotherapy intervention strategy that might promote the Self-reorganization. PMID- 28862530 TI - Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice. AB - Exercise reduces the risk of inflammatory disease by modulating a variety of tissue and cell types, including those within the gastrointestinal tract. Recent data indicates that exercise can also alter the gut microbiota, but little is known as to whether these changes affect host function. Here, we use a germ-free (GF) animal model to test whether exercise-induced modifications in the gut microbiota can directly affect host responses to microbiota colonization and chemically-induced colitis. Donor mice (n = 19) received access to a running wheel (n = 10) or remained without access (n = 9) for a period of six weeks. After euthanasia, cecal contents were pooled by activity treatment and transplanted into two separate cohorts of GF mice. Two experiments were then conducted. First, mice were euthanized five weeks after the microbiota transplant and tissues were collected for analysis. A second cohort of GF mice were colonized by donor microbiotas for four weeks before dextran-sodium-sulfate was administered to induce acute colitis, after which mice were euthanized for tissue analysis. We observed that microbial transplants from donor (exercised or control) mice led to differences in microbiota beta-diversity, metabolite profiles, colon inflammation, and body mass in recipient mice five weeks after colonization. We also demonstrate that colonization of mice with a gut microbiota from exercise-trained mice led to an attenuated response to chemical colitis, evidenced by reduced colon shortening, attenuated mucus depletion and augmented expression of cytokines involved in tissue regeneration. Exercise-induced modifications in the gut microbiota can mediate host-microbial interactions with potentially beneficial outcomes for the host. PMID- 28862533 TI - Improvements in cardiometabolic risk markers, aerobic fitness, and functional performance following a physical therapy weight loss program. AB - OBJECTIVE: The objectives of this study were to determine the efficacy of a current physical therapy and weight loss program model on exercise performance, physical function, and cardiometabolic risk factors in obese patients. DESIGN: Retrospective pre-post design. SUBJECTS: A total of 192 patients who previously underwent testing of anthropometric measurements, cardiovascular biomarkers, and lower extremity function scale (LEFS) were included. RESULTS: There was a significant reduction in body weight [5.91 +/- 3.47 (95% CI, 5.4 to 6.4) kg; p < 0.001; n = 187] and waist circumference [7.1 +/- 5 (95% CI, 6.3 to 7.9) cm; p < 0.001; n = 187]. Submaximal exercise capacity (VO2ex) increased by [5.29 +/- 4.74 (95% CI, 4.38 to 6.19) ml/kg/min; p < 0.001; n = 107], and lower extremity functional scale (LEFS) improved by [9 +/- 11 (95% CI, 7 to 12) scale points; p < 0.001; n = 75]. Both systolic (pre SBP: 125.7 +/- 15 vs. post SBP: 118.4 +/- 12 mmHg; p < 0.001; n = 150) and diastolic (pre DBP: 78.5 +/- 10 vs. post DBP: 74 +/ 8.5 mmHg; p < 0.001; n = 150) blood pressures as well as fasting blood glucose (pre FBG: 112.8 +/- 37 vs. post FBG: 99 +/- 18 mg/dL; p < 0.001; n = 132) were significantly reduced. CONCLUSIONS: This study indicates the importance and significance of weight loss in improving physical function and cardiometabolic risk profiles across a cohort of outpatient physical therapy patients. Our study also suggests that weight loss can be achieved in a comprehensive exercise intensive physical therapy program for obese patients. PMID- 28862534 TI - A Novel Model for Teaching Primary Care in a Community Practice Setting: Tufts at Tech Community Veterinary Clinic. AB - Providing veterinary students with opportunities to develop clinical skills in a realistic, hands-on environment remains a challenge for veterinary education. We have developed a novel approach to teaching clinical medicine to fourth-year veterinary students and technical high school students via development of a primary care clinic embedded within a technical high school. The primary care clinic targets an underserved area of the community, which includes many of the participating high school students. Support from the veterinary community for the project has been strong as a result of communication, the opportunity for veterinarians to volunteer in the clinic, and the careful targeting of services. Benefits to veterinary students include the opportunity to build clinical competencies and confidence, as well as the exposure to a diverse client population. The financial model of the clinic is described and initial data on outcomes for case load, clinic income, veterinary student evaluations, and high school students' success in passing the veterinary assisting examination are reported. This clinical model, involving a partnership between a veterinary school and a technical high school, may be adoptable to other clinical teaching situations. PMID- 28862535 TI - Discipline-Specific Compared to Generic Training of Teachers in Higher Education. AB - A recurrent theme arising in the higher education sector is the suitability and effectiveness of generic versus discipline-specific training of university teachers, who are often recruited based on their disciplinary specialties to become teachers in higher education. We compared two groups of participants who had undergone training using a generic post-graduate certificate in higher education (PGCertGeneric) versus a discipline-specific course in veterinary education (PGCertVetEd). The study was conducted using a survey that allowed comparison of participants who completed PGCertGeneric (n=21) with PGCertVetEd (n=22). Results indicated that participants from both PGCertGeneric and PGCertVetEd considered teaching to be satisfying and important to their careers, valued the teaching observation component of the course, and identified similar training needs. However, the participants of the PGCertVetEd felt that the course made them better teachers, valued the relevance of the components taught, understood course design better, were encouraged to do further courses/reading in teaching and learning, changed their teaching as a result of the course, and were less stressed about teaching as compared to the PGCertGeneric participants (p<.05). It is likely that the PGCertVetEd, which was designed and developed by veterinarians with a wider understanding of the veterinary sector, helped the participants perceive the training course as suited to their needs. PMID- 28862536 TI - Investigation of a Brazilian tannery effluent by means of zebra fish (Danio rerio) embryo acute toxicity (FET) test. AB - Tannery effluents consist of a complex chemical composition not only limited to primary pollutants, which also require biological detection as these compounds may produce adverse effects. The fish embryo toxicity (FET) test with Danio rerio is an alternative method in hazard and risk assessment for determination of chemical-mediated effects. The aim of this investigation was to use the FET test to detect compounds and consequent effects in Brazilian tannery effluents. Samples were collected from the inlet and outlet of the effluent treatment plant at a tannery located in Restinga, Sao Paulo, Brazil. The toxicological effects were assessed using FET assay for a period of 144 hr using indices such as (1) coagulation of fertilized eggs, (2) lack of detachment of tail-bud from yolk sac, (3) absence of spontaneous movement, (4) yolk sack edema, (5) malformation of the tail, (6) scoliosis, and (7) deformation of swim bladder in the embryos. Data showed that effluent treatment plant exposure produced acute toxicity in D. rerio embryos as evidenced by coagulation of fertilized eggs in up to 5% of all diluted samples 24 hr post fertilization for inlet effluent samples compared to 100% coagulation for outlet samples. Results demonstrated that these effects may not be attributed to metals, but to other non-detected components, such as dyes, pigments, biocides, carriers, surfactants, or other organic compounds that might be present in these complex mixtures. The use of D. rerio embryos was found to be useful as an additional tool for ecotoxicity testing to assess the potential environmental acute toxicity influence of tannery effluents. PMID- 28862537 TI - Signaling through reactive oxygen and nitrogen species is differentially modulated in sunflower seedling root and cotyledon in response to various nitric oxide donors and scavengers. AB - Sodium nitroprusside (SNP), diethylenetriamine NONOate (DETA), S-nitroso-n-acetyl D,L- penicillamine (SNAP), and 4-(p-methoxyphenyl)-1,3,2- Oxathiazolylium-5-olate (CAY) exhibit differential NO releasing ability in aqueous solution and hemoglobin is a more efficient NO quencher than cPTIO in solution. DETA releases 16% more NO compared with SNP in solution. Various NO donors (SNP, DETA, SNAP, and CAY) also bring about a differential but concentration-dependent increase in endogenous NO in seedling cotyledons and roots. Two-day old, dark-grown seedling roots exhibit 95%, 77%, 59% and 45% increase in NO content in presence of each of 500 uM of DETA, SNAP, CAY and SNP, respectively, relative to control. NO accumulation in the tissue system as a response to NO donors is reflected in terms of corresponding peroxynitrite accumulation. Release of cyanide and free iron as byproducts of SNP dissociation in solution limits its usefulness as an NO donor. SNP leads to profuse ROS generation in sunflower seedling roots. Light is not a pre-requisite for NO generation from SNP. Present work also demonstrates the usefulness of hemoglobin over cPTIO as NO scavenger. Hemoglobin brings about increasing NO quenching with its increasing concentration from 2.5 to 10 uM. Greater sensitivity of the root system to the NO donor/scavenger treatments is evident, it being in direct contact with the molecules in the incubation/ growth medium. This differential effect does not seem to be significantly transmitted to the cotyledons (long-distance signaling). PMID- 28862538 TI - Postoperative continuous catheter-infused local anesthetic reduces pain scores and narcotic use after lower extremity revascularization. AB - Objective Postoperative pain following lower extremity revascularization procedures is traditionally controlled with narcotic administration. However, this may not adequately control the pain and puts the patient at risk for complications from opiate use. Here we report an alternative strategy for pain management using a continuous catheter-infused local anesthetic into the operative limb. Design Retrospective case-control study. Methods Patients undergoing lower extremity revascularization procedures using continuous catheter infused local anesthetic were compared to similar patients undergoing similar procedures during the same time period who did not receive continuous catheter infused local anesthetic. Records were reviewed for pain scores, narcotics consumption, length of stay, need for postoperative chest X-ray, supplemental oxygen use, wound complications, and 30-day readmission. Results There were 153 patients (mean age 69.5 years) from September 2011 to December 2014 who underwent common femoral artery procedures, femoral-popliteal bypass, femoral-tibial bypass, popliteal aneurysm repair, popliteal to pedal bypass, popliteal artery thrombo-embolectomy, sapheno-popliteal venous bypass, or ilio-femoral bypass. There were no significant differences between the continuous catheter-infused local anesthetic ( n=57) and control ( n=96) groups regarding age, body mass index, cardiac history, diabetes, hypertension, and procedures performed. The continuous catheter-infused local anesthetic group showed better cumulative average pain scores, better high pain scores on postoperative days 1-3, and better average pain scores on postoperative days 2-3 ( P<0.03). The continuous catheter-infused local anesthetic group had lower median narcotics consumption on postoperative days 1-2 ( P=0.02). No differences were found in postoperative length of stay, urinary catheter use, number of postoperative chest X-rays, oxygen use, mobilization, or fever. Wound complications occurred in 8.8% of the continuous catheter-infused local anesthetic group and in 11.5% of controls (P=0.79). Readmission rates were 23% (continuous catheter-infused local anesthetic) and 21% (controls; P=0.84). Conclusion Postoperative continuous catheter-infused local anesthetic reduces pain scores and pain medication use compared to standard opiate therapy in these patients, without increasing wound complication or readmission rates. Continuous catheter-infused local anesthetic appeared to have no effect on the incidence of pulmonary complications, mobilization, or fever. PMID- 28862539 TI - Lead (Pb) exposure induces disturbances in epigenetic status in workers exposed to this metal. AB - Previous studies showed that lead (Pb) exposure may modulate gene expression by changes in the epigenetic status. However, little is known about the impact of Pb exposure and alterations on DNA methylation patterns in humans exposed to this metal. The aim of this study was to assess the consequences of exposure to Pb on DNA global methylation, in order to gain a better understanding of the interactions between Pb exposure and epigenetic effects. The study included 100 male workers employed in automotive battery factories from Parana State, Brazil. Concentrations of Pb in blood (B-Pb) and plasma (P-Pb) were determined by ICP-MS, the percentage (%) of global DNA methylation was determined by quantification of 5-methylcytosine using indirect ELISA, and sociodemographic data collected by questionnaire by trained interviewers. The mean age was 37 +/- 10 (18-67 years); 18% of participants were smokers, while 32% reported consumption of alcoholic beverages. The B-Pb and P-Pb levels were 20 +/- 11 and 0.56 +/- 0.64 ug/dl, respectively; % global DNA methylation was 2.8 +/- 1.1% (ranging from 1.1 to 6.5%). B-Pb and P-Pb concentrations were significantly correlated. Furthermore, a marked association was noted between Pb biomarkers and DNA global methylation. Taken together, our data demonstrated that Pb exposure induced alterations on DNA global methylation in workers who were exposed to the metal and consequently may result in disturbances in the regulation of gene expression, leading to potentially several health adverse effect outcomes. PMID- 28862540 TI - Characterizing cytotoxic and estrogenic activity of Arctic char tissue extracts in primary Arctic char hepatocytes. AB - Contaminants from various anthropogenic activities are detected in the Arctic due to long-range atmospheric transport, ocean currents, and living organisms such as migrating fish or seabirds. Although levels of persistent organic pollutants (POPs) in Arctic fish are generally low, local hot spots of contamination were found in freshwater systems such as Lake Ellasjoen at Bjornoya (Bear Island, Norway). Higher concentrations of organic halogenated compounds (OHC), and higher levels of cytochrome P450 and DNA-double strand breaks were reported in Arctic char (Salvelinus alpinus) from this lake compared to fish from other lakes on Bjornoya. Although several of the measured contaminants are potential endocrine disrupters, few studies have investigated potential endocrine disruptive effects of the contaminant cocktail in this fish population. The aim of this study was to compare acutely toxic and estrogenic potency of the cocktail of pollutants as evidenced by cytotoxic and/or estrogenic effects in vitro using extracts of Arctic char livers from contaminated Lake Ellasjoen with those from less contaminated Lake Laksvatn at Bjornoya. This was performed by in situ sampling and contaminant extraction from liver tissue, followed by chemical analysis and in vitro testing of the following contaminated tissue extracts: F1-nonpolar OHC, F2-polar pesticides and metabolites of OHC, and F3-polar OHC. Contaminant levels were highest in extracts from Ellasjoen fish. The F2 and F3 extracts from Lake Laksvatn and Lake Ellasjoen fish reduced in vitro cell viability at a concentration ratio of 0.03-1 relative to tissue concentration in Arctic char. Only the F3 liver extract from Ellasjoen fish increased in vitro vitellogenin protein expression. Although compounds such as estrogenic OH-PCBs were quantified in Ellasjoen F3 extracts, it remains to be determined which compounds were inducing estrogenic effects. PMID- 28862542 TI - Letter to the Editor. Magnetic resonance-guided focused ultrasound thalamotomy for Parkinson's disease. PMID- 28862541 TI - Anatomy and white matter connections of the orbitofrontal gyrus. AB - OBJECTIVE The orbitofrontal cortex (OFC) is understood to have a role in outcome evaluation and risk assessment and is commonly involved with infiltrative tumors. A detailed understanding of the exact location and nature of associated white matter tracts could significantly improve postoperative morbidity related to declining capacity. Through diffusion tensor imaging-based fiber tracking validated by gross anatomical dissection as ground truth, the authors have characterized these connections based on relationships to other well-known structures. METHODS Diffusion imaging from the Human Connectome Project for 10 healthy adult controls was used for tractography analysis. The OFC was evaluated as a whole based on connectivity with other regions. All OFC tracts were mapped in both hemispheres, and a lateralization index was calculated with resultant tract volumes. Ten postmortem dissections were then performed using a modified Klingler technique to demonstrate the location of major tracts. RESULTS The authors identified 3 major connections of the OFC: a bundle to the thalamus and anterior cingulate gyrus, passing inferior to the caudate and medial to the vertical fibers of the thalamic projections; a bundle to the brainstem, traveling lateral to the caudate and medial to the internal capsule; and radiations to the parietal and occipital lobes traveling with the inferior fronto-occipital fasciculus. CONCLUSIONS The OFC is an important center for processing visual, spatial, and emotional information. Subtle differences in executive functioning following surgery for frontal lobe tumors may be better understood in the context of the fiber-bundle anatomy highlighted by this study. PMID- 28862544 TI - Letter to the Editor. Infraorbital nerve as a surgical landmark. PMID- 28862543 TI - Delayed facial palsy after microvascular decompression for hemifacial spasm: friend or foe? AB - OBJECTIVE The authors investigated the incidence, clinical course, and predisposing factors associated with delayed facial palsy (DFP) following microvascular decompression (MVD). METHODS The authors reviewed the records of 310 patients (311 cases) who were followed after MVD for hemifacial spasm (HFS). Of these patients, 45 (14.5%) developed DFP after MVD. The clinical characteristics and predisposing factors of the patients with HFS were investigated to identify prognostic factors that predicted the development of DFP after MVD. Log-rank tests were used to compare times to symptom disappearance, and a logistic regression analysis was performed to compare clinical characteristics between patients who developed DFP and those who did not. RESULTS HFS was completely resolved immediately after MVD in 158 cases (50.8%), and HFS eventually disappeared in 289 (92.9%) of the cases. Of the 45 patients with DFP, 17 were men and 28 were women. DFP occurred between postoperative Days 1 and 44 (mean 9.67 days). Finally, 44 patients (97.8%) completely recovered. The average time to recovery was 3.9 months (range 1-24 months). Patients who had experienced an immediate disappearance of HFS experienced a significantly higher occurrence of DFP than those who did not (odds ratio 0.383, 95% confidence interval 0.183 0.802; p = 0.011). In addition, preoperative botulinum neurotoxin injections negatively influenced the occurrence of DFP (p = 0.016). CONCLUSIONS In this study, the incidence rate of DFP was slightly higher than previously reported values. Moreover, DFP can occur even when spasms disappear immediately after MVD, but the patients with DFP can fully recover within weeks. PMID- 28862545 TI - Sex differences in delayed cerebral ischemia after subarachnoid hemorrhage. AB - OBJECTIVE In this study the authors sought to investigate the sex differences in the risk of delayed cerebral ischemia (DCI), delayed cerebral infarction, and the role of hormonal status. METHODS Ten studies included in the SAHIT (SAH International Trialists) repository were analyzed using a fitting logistic regression model. Heterogeneity between the studies was tested using I2 statistics, and the results were pooled using a random-effects model. Multivariable analysis was adjusted for the effects of neurological status and fixed effect of study. An additional model was examined in which women and men were split into groups according to an age cut point of 55 years, as a surrogate to define hormonal status. RESULTS A pooled cohort of 6713 patients was analyzed. The risk of DCI was statistically significantly higher in women than in men (OR 1.29, 95% CI 1.12-1.48); no difference was found with respect to cerebral infarction (OR 1.17, 95% CI 0.98-1.40). No difference was found in the risk of DCI when comparing women <= 55 and > 55 years (OR 0.87, 95% CI 0.74-1.02; p = 0.08) or when comparing men <= 55 and > 55 years (p = 0.38). Independent predictors of DCI were World Federation of Neurosurgical Societies (WFNS) grade, Fisher grade, age, and sex. Independent predictors of infarction included WFNS grade, Fisher grade, and aneurysm size. CONCLUSIONS Female sex is associated with a higher risk of DCI. Sex differences may play a role in the pathogenesis of DCI but are not associated with menopausal status. The predictors of DCI and cerebral infarction were identified in a very large cohort and reflect experience from multiple institutions. PMID- 28862546 TI - Angioarchitecture of arteriovenous fistulas at the craniocervical junction: a multicenter cohort study of 54 patients. AB - OBJECTIVE The aim of this retrospective multicenter cohort study was to assess the details of the angioarchitecture of arteriovenous fistulas (AVFs) at the craniocervical junction (CCJ) and to determine the associations between the angiographic characteristics and the clinical presentations and outcomes. METHODS The authors analyzed angiographic and clinical data for patients with CCJ AVFs from 20 participating centers that are members of the Japanese Society for Neuroendovascular Therapy (JSNET). Angiographic findings (feeding artery, location of AV shunt, draining vein) and patient data (age, sex, presentation, treatment modality, outcome) were tabulated and stratified based on the angiographic types of the lesions, as diagnosed by a member of the CCJ AVF study group, which consisted of a panel of 6 neurointerventionalists and 1 spine neurosurgeon. RESULTS The study included 54 patients (median age 65 years, interquartile range 61-75 years) with a total of 59 lesions. Five angiographic types were found among the 59 lesions: Type 1, dural AVF (22 [37%] of 59); Type 2, radicular AVF (17 [29%] of 59); Type 3, epidural AVF (EDAVF) with pial feeders (8 [14%] of 59); Type 4, EDAVF (6 [10%] of 59); and Type 5, perimedullary AVF (6 [10%] of 59). In almost all lesions (98%), AV shunts were fed by radiculomeningeal arteries from the vertebral artery that drained into intradural or epidural veins through AV shunts on the dura mater, on the spinal nerves, in the epidural space, or on the spinal cord. In more than half of the lesions (63%), the AV shunts were also fed by a spinal pial artery from the anterior spinal artery (ASA) and/or the lateral spinal artery. The data also showed that the angiographic characteristics associated with hemorrhagic presentations-the most common presentation of the lesions (73%)-were the inclusion of the ASA as a feeder, the presence of aneurysmal dilatation on the feeder, and CCJ AVF Type 2 (radicular AVF). Treatment outcomes differed among the angiographic types of the lesions. CONCLUSIONS Craniocervical junction AVFs commonly present with hemorrhage and are frequently fed by both radiculomeningeal and spinal pial arteries. The AV shunt develops along the C-1 or C-2 nerve roots and can be located on the spinal cord, on the spinal nerves, and/or on the inner or outer surface of the dura mater. PMID- 28862548 TI - Reoperation for growth hormone-secreting pituitary adenomas: report on an endonasal endoscopic series with a systematic review and meta-analysis of the literature. AB - OBJECTIVE Surgery is generally the first-line therapy for acromegaly. For patients with residual or recurrent tumors, several treatment options exist, including repeat surgery, medical therapy, and radiation. Reoperation for recurrent acromegaly has been associated with poor results, with hormonal control usually achieved in fewer than 50% of cases. Extended endonasal endoscopic approaches (EEAs) may potentially improve the results of reoperation for acromegaly by providing increased visibility and maneuverability in parasellar areas. METHODS A database of all patients treated in the authors' center between July 2004 and February 2016 was reviewed. Cases involving patients with acromegaly secondary to growth hormone (GH)-secreting adenomas who underwent EEA were selected for chart review and divided into 2 groups: first-time surgery and reoperation. Disease control was defined by 2010 guidelines. Clinical and radiological characteristics and outcome data were extracted. A systematic review was done through a MEDLINE database search (2000-2016) to identify studies on the surgical treatment of acromegaly. Using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, the included studies were reviewed for surgical approach, tumor size, cavernous sinus invasion, disease control, and complications. Cases were divided into reoperation or first-time surgery for comparative analysis. RESULTS A total of 44 patients from the authors' institution were included in this study. Of these patients, 2 underwent both first-time surgery and reoperation during the study period and were therefore included in both groups. Thus data from 46 surgical cases were analyzed (35 first-time operations and 11 reoperations). The mean length of follow-up was 70 months (range 6-150 months). The mean size of the reoperated tumors was 14.8 +/- 10.0 mm (5 micro- and 6 macroadenomas). The patients' mean age at the time of surgery was younger in the reoperation group than in the first-time surgery group (34.3 +/- 12.8 years vs 49.1 +/- 15.7 years, p = 0.007) and the mean preoperative GH level was also lower (7.7 +/- 13.1 MUg/L vs 25.6 +/- 36.8 MUg/L, p = 0.04). There was no statistically significant difference in disease control rates between the reoperation (7 [63.6%] of 11) and first-time surgery (25 [71.4%] of 33) groups (p = 0.71). Univariate analysis showed that older age, smaller tumor size, lower preoperative GH level, lower preoperative IGF-I level, and absence of cavernous sinus invasion were associated with higher chances of disease control in the first-time surgery group, whereas only absence of cavernous sinus invasion was associated with disease control in the reoperation group (p = 0.01). There was 1 case (9%) of transient diabetes insipidus and hypogonadism and 1 (9%) postoperative nasal infection after reoperation. The systematic review retrieved 29 papers with 161 reoperation and 2189 first-time surgery cases. Overall disease control for reoperation was 46.8% (95% CI 20%-74%) versus 56.4% (95% CI 49%-63%) for first-time operation. Reoperation and first-time surgery had similar control rates for microadenomas (73.6% [95% CI 32%-98%] vs 77.6% [95% CI 68%-85%]); however, reoperation was associated with substantially lower control rates for macroadenomas (27.5% [95% CI 5%-57%] vs 54.3% [95% CI 45%-62%]) and tumors invading the cavernous sinus (14.7% [95% CI 4%-29%] vs 38.5% [95% CI 27%-50%]). CONCLUSIONS Reoperative EEA for acromegaly had results similar to those for first time surgery and rates of control for macroadenomas that were better than historical rates. Cavernous sinus invasion continues to be a negative prognostic indicator for disease control; however, results with EEA show improvement compared with results reported in the prior literature. PMID- 28862547 TI - The Treatment of Brain AVMs Study (TOBAS): an all-inclusive framework to integrate clinical care and research. AB - OBJECTIVE The management of brain arteriovenous malformations (bAVMs) remains controversial. The Treatment of Brain AVMs Study (TOBAS) was designed to manage patients with bAVMs within a clinical research framework. The objective of this study was to study trial feasibility, recruitment rates, patient allocation to the various management groups, and compliance with treatment allocation. METHODS TOBAS combines two randomized care trials (RCTs) and a registry. Designed to be all-inclusive, the study offers randomized allocation of interventional versus conservative management to patients eligible for both options (first RCT), a second RCT testing the role of preembolization as an adjunct to surgery or radiotherapy, and a registry of patients managed using clinical judgment alone. The primary outcome of the first RCT is death from any cause or disabling stroke (modified Rankin Scale score > 2) at 10 years. A pilot phase was initiated at one center to test study feasibility, record the number and characteristics of patients enrolled in the RCTs, and estimate the frequency of crossovers. RESULTS All patients discussed at the multidisciplinary bAVM committee between June 2014 and June 2016 (n = 107) were recruited into the study; 46 in the randomized trials (23 in the first RCT with 21 unruptured bAVMs, 40 in the second RCT with 17 unruptured bAVMs, and 17 in both RCTs), and 61 patients in the registry. Three patients crossed over from surgery to observation (first RCT). CONCLUSIONS Clinical research was successfully integrated with normal practice using TOBAS. Recruitment rates in a single center are encouraging. Whether the trial will provide meaningful results depends on the recruitment of a sufficient number of participating centers. Clinical trial registration no.: NCT02098252 (clinicaltrials.gov). PMID- 28862549 TI - Outcomes of stereotactic radiosurgery for foramen magnum meningiomas: an international multicenter study. AB - OBJECTIVE Meningiomas are the most common benign extramedullary lesions of the foramen magnum; however, their optimal management remains undefined. Given their location, foramen magnum meningiomas (FMMs) can cause significant morbidity, and complete microsurgical removal can be challenging. Anterior and anterolateral FMMs carry greater risks with surgery, but they comprise the majority of these lesions. As an alternative to resection, stereotactic radiosurgery (SRS) has been used to treat FMMs in small case series. To more clearly define the outcomes of SRS and to delineate a rational management paradigm for these lesions, the authors analyzed the safety and efficacy of SRS for FMM in an international multicenter trial. METHODS Seven medical centers participating in the International Gamma Knife Research Foundation (IGKRF) provided data for this retrospective cohort study. Patients who were treated with Gamma Knife radiosurgery and whose clinical and radiological follow-up was longer than 6 months were eligible for study inclusion. Data from pre- and post-SRS radiological and clinical evaluations were analyzed. Stereotactic radiosurgery treatment variables were recorded. RESULTS Fifty-seven patients (39 females and 18 males, with a median age of 64 years) met the study inclusion criteria. Thirty two percent had undergone prior microsurgical resection. Patients most frequently presented with cranial neuropathy (39%), headache (35%), numbness (32%), and ataxia (30%). Median pre-SRS tumor volume was 2.9 cm3. Median SRS margin dose was 12.5 Gy (range 10-16 Gy). At the last follow-up after SRS, 49% of tumors were stable, 44% had regressed, and 7% had progressed. Progression-free survival rates at 5 and 10 years were each 92%. A greater margin dose was associated with a significantly increased likelihood of tumor regression, with 53% of tumors treated with > 12 Gy regressing. Fifty-two percent of symptomatic patients noted some clinical improvement. Adverse radiation effects were limited to hearing loss and numbness in 1 patient (2%). CONCLUSIONS Stereotactic radiosurgery for FMM frequently results in tumor control or tumor regression, as well as symptom improvement. Margin doses > 12 Gy were associated with increased rates of tumor regression. Stereotactic radiosurgery was generally safe and well tolerated. Given its risk-benefit profile, SRS may be particularly useful in the management of small- to moderate-volume anterior and anterolateral FMMs. PMID- 28862550 TI - Voxel-based lesion mapping of meningioma: a comprehensive lesion location mapping of 260 lesions. AB - OBJECTIVE In the present study the authors aimed to determine preferred locations of meningiomas by avoiding descriptive analysis and instead using voxel-based lesion mapping and 3D image-rendering techniques. METHODS Magnetic resonance images obtained in 248 treatment-naive meningioma patients with 260 lesions were retrospectively and consecutively collected. All images were registered to a 1-mm isotropic, high-resolution, T1-weighted brain atlas provided by the Montreal Neurological Institute (the MNI152), and a lesion frequency map was created, followed by 3D volume rendering to visualize the preferred locations of meningiomas in 3D. RESULTS The 3D lesion frequency map clearly showed that skull base structures such as parasellar, sphenoid wing, and petroclival regions were commonly affected by the tumor. The middle one-third of the superior sagittal sinus was most commonly affected in parasagittal tumors. Substantial lesion accumulation was observed around the leptomeninges covering the central sulcus and the sylvian fissure, with very few lesions observed at the frontal, parietal, and occipital convexities. CONCLUSIONS Using an objective visualization method, meningiomas were shown to be located around the middle third of the superior sagittal sinus, the perisylvian convexity, and the skull base. These observations, which are in line with previous descriptive analyses, justify further use of voxel-based lesion mapping techniques to help understand the biological nature of this disease. PMID- 28862551 TI - Isolated abducens nerve palsy associated with subarachnoid hemorrhage: a localizing sign of ruptured posterior inferior cerebellar artery aneurysms. AB - OBJECTIVE Compressive cranial nerve syndromes can be useful bedside clues to the diagnosis of an enlarging intracranial aneurysm and can also guide subsequent evaluation, as with an acute oculomotor nerve (cranial nerve [CN] III) palsy that is presumed to be a posterior communicating artery aneurysm and a surgical emergency until proven otherwise. The CN VI has a short cisternal segment from the pontomedullary sulcus to Dorello's canal, remote from most PICA aneurysms but in the hemodynamic pathway of a rupturing PICA aneurysm that projects toward Dorello's canal. The authors describe a cranial nerve syndrome for posterior inferior cerebellar artery (PICA) aneurysms that associates subarachnoid hemorrhage (SAH) and an isolated abducens nerve (CN VI) palsy. METHODS Clinical and radiological data from 106 surgical patients with PICA aneurysms (66 ruptured and 40 unruptured) were retrospectively reviewed. Data from a group of 174 patients with other aneurysmal SAH (aSAH) were analyzed in a similar manner to control for nonspecific effects of SAH. Univariate statistical analysis compared incidence and risk factors associated with CN VI palsy in subarachnoid hemorrhage. RESULTS Overall, 13 (4.6%) of 280 patients had CN VI palsy at presentation, and all of them had ruptured aneurysms (representing 13 [5.4%] of the 240 cases of ruptured aneurysms). CN VI palsies were observed in 12 patients with ruptured PICA aneurysms (12/66 [18.1%]) and 1 patient with other aSAH (1/174 [0.1%], p < 0.0001). PICA aneurysm location in ruptured aneurysms was an independent predictor for CN VI palsy on multivariate analysis (p = 0.001). PICA aneurysm size was not significantly different in patients with or without CN VI palsy (average size 4.4 mm and 5.2 mm, respectively). Within the PICA aneurysm cohort, modified Fisher grade (p = 0.011) and presence of a thick cisternal SAH (modified Fisher Grades 3 and 4) (p = 0.003) were predictors of CN VI palsy. In all patients with ruptured PICA aneurysms and CN VI palsy, dome projection and presumed direction of rupture were directed toward the ipsilateral and/or contralateral Dorello's canal, in agreement with laterality of the CN palsy. In patients with bilateral CN VI palsies, a medial projection with extensive subarachnoid blood was observed near bilateral canals. CONCLUSIONS This study establishes a localizing connection between an isolated CN VI palsy, SAH, and an underlying ruptured PICA aneurysm. CN VI palsy is an important clinical sign in aSAH and when present on initial clinical presentation may be assumed to be due to ruptured PICA aneurysms until proven otherwise. The deficit may be ipsilateral, contralateral, or bilateral and is determined by the direction of the aneurysm dome projection and extent of subarachnoid bleeding toward Dorello's canal, rather than by direct compression. PMID- 28862552 TI - Cavernous sinus compartments from the endoscopic endonasal approach: anatomical considerations and surgical relevance to adenoma surgery. AB - OBJECTIVE Tumors with cavernous sinus (CS) invasion represent a neurosurgical challenge. Increasing application of the endoscopic endonasal approach (EEA) requires a thorough understanding of the CS anatomy from an endonasal perspective. In this study, the authors aimed to develop a surgical anatomy-based classification of the CS and establish its utility for preoperative surgical planning and intraoperative guidance in adenoma surgery. METHODS Twenty-five colored silicon-injected human head specimens were used for endonasal and transcranial dissections of the CS. Pre- and postoperative MRI studies of 98 patients with pituitary adenoma with intraoperatively confirmed CS invasion were analyzed. RESULTS Four CS compartments are described based on their spatial relationship with the cavernous ICA: superior, posterior, inferior, and lateral. Each compartment has distinct boundaries and dural and neurovascular relationships: the superior compartment relates to the interclinoidal ligament and oculomotor nerve, the posterior compartment bears the gulfar segment of the abducens nerve and inferior hypophyseal artery, the inferior compartment contains the sympathetic nerve and distal cavernous abducens nerve, and the lateral compartment includes all cavernous cranial nerves and the inferolateral arterial trunk. Twenty-nine patients had a single compartment invaded, and 69 had multiple compartments involved. The most commonly invaded compartment was the superior (79 patients), followed by the posterior (n = 64), inferior (n = 45), and lateral (n = 23) compartments. Residual tumor rates by compartment were 79% in lateral, 17% in posterior, 14% in superior, and 11% in inferior. CONCLUSIONS The anatomy-based classification presented here complements current imaging-based classifications and may help to identify involved compartments both preoperatively and intraoperatively. PMID- 28862553 TI - Transorbital endoscopic eyelid approach for resection of sphenoorbital meningiomas with predominant hyperostosis: report of 2 cases. AB - Sphenoorbital meningiomas (SOMs) are slow-growing tumors that originate from the sphenoidal wing and are associated with visual deterioration, extrinsic ocular movement disorders, and proptosis caused by hyperostosis of the lateral wall of the orbit. In some cases, the intracranial component is quite small or "en plaque," and the majority of the symptoms arise from adjacent hyperostosis. Craniotomy has traditionally been the standard of care, but new minimally invasive multiportal endoscopic approaches offer an alternative. In the current study, the authors to present their experience with the transorbital endoscopic eyelid approach for the treatment of 2 patients with SOMs and sphenoid wing hyperostosis. Clinical and radiological data for patients with SOMs who underwent a transorbital endoscopic eyelid approach were retrospectively reviewed. Surgical technique and clinical and radiographic outcomes were analyzed. The authors report the cases of 2 patients with SOMs and proptosis due to sphenoid wing hyperostosis. One patient underwent prior craniotomy to debulk the intracranial portion of the tumor, and the other had a minimal intracranial component. Both patients were discharged 2 days after surgery. MR images and CT scans demonstrated a large debulking of the hyperostotic bone. Postoperative measurement of the proptosis with the aid of an exophthalmometer demonstrated significant reduction of the proptosis in one of the cases. Persistence of intraconal tumor in the orbital apex limited the efficacy of the procedure in the other case. A review of the literature revealed 1 publication with 3 reports of the transorbital eyelid approach for SOMs. No measure of relief of proptosis after this surgery had been previously reported. The transorbital endoscopic approach, combined with endonasal decompression of the medial orbit, may be a useful minimally invasive alternative to craniotomy in a subset of SOMs with a predominantly hyperostotic orbital wall and minimal intracranial bulky or merely en plaque disease. In these cases, relief of proptosis and optic nerve compression are the primary goals of surgery, rather than gross-total resection, which may have high morbidity or be unachievable. In cases with significant residual intraconal tumor, orbital bone removal alone may not be sufficient to reduce proptosis. PMID- 28862554 TI - Peculiar Archaea Found in Japanese Paddy Soils?. AB - Archaeal 16S rDNA clones retrieved from paddy soil DNA were sequenced. Among 100 clones, 88 clones were assigned to methanogens and nine clones were assigned to crenarchaeota. However, three of the nine clones were phylogenetically far from the cultured crenarchaeota and closely related to marine planktonic archaea. The other three clones showed extremely novel 16S rDNA sequences and were phylogenetically far from both Crenarchaeota and Euryarchaeota. This paper reports the ubiquitous presence of crenarchaeotal and extremely novel clones in paddy soils. PMID- 28862555 TI - New Dihydroquinolinone Toxic to Artemia salina Produced by Penicillium sp. NTC 47. AB - Penicillium sp. NTC-47, which had been isolated from a soil sample, produced novel dihydroquinolinones when cultured with okara (the insoluble residue of whole soybean). These metabolites, 1 and 2, were crystalline products with molecular formulas of C17H17NO5 and C17H17NO4, respectively. The structure of 1 was established to be 3-methoxy-4,5-dihydroxy-4-(4'-methoxyphenyl)-quinolinone by spectroscopic evidence and by an X-ray crystal-lographic analysis. Spectral data indicated the structure of 2 to be 5-deoxy-l. Compound 1 demonstrated toxicity against brine shrimp with an LC50 value of 20MUg/ml, but 2 exhibited no activity at a dose of 100 MUg/ml. PMID- 28862556 TI - Action of a Thermostable Trehalose Synthase from Thermus aquaticus on Sucrose. AB - A thermostable trehalose synthase from Thermus aquaticus ATCC 33923, which catalyzes the interconversion between maltose and trehalose by intramolecular transglucosylation, converted sucrose into trehalulose (1-O-alpha-d glucopyranosyl-d-fructose). The trehalulose-forming activity of the enzyme was very low compared with that of maltose and trehalose. Kinetic studies showed that sucrose competitively inhibited the interconversion activity between maltose and trehalose. Consequently, these three substrates, maltose, trehalose, and sucrose, are thought to bind the same active site of trehalose synthase. PMID- 28862557 TI - Occurrence of Cobalamin Coenzymes in the Photosynthetic Green Alga, Chlorella vulgaris. AB - To analyze cobalamin metabolism in photosynthetic green algae, the effects of cobalamin on growth of Chlorella vulgaris C-30 were studied and the algal cobalamin contents were assayed. Cobalamin significantly stimulated growth of the Chlorella cells, but biologically inactive cobalamin analogues did not. Chlorella grown in a cobalamin-free medium (control) contained cobalamin coenzymes, 5' deoxyadenosylcobalamin (7.95 +/- 0.31 ng/g wet weight) and methylcobalamin (2.72 +/- 0.45 ng/g wet weight), of which the levels were increased significantly in cobalamin-supplemented cells. These results indicate that the alga has ability to take up exogenous cobalamin and synthesize the coenzyme forms. PMID- 28862558 TI - Protoplast Formation from Schizophyllum commune by a Culture Filtrate of Bacillus circulans KA-304 Grown on a Cell-wall Preparation of S. commune as a Carbon Source. AB - From microorganisms growing on a cell-wall preparation (CWP) of Schizophyllum commune as a carbon source, Bacillus circulans KA-304 was isolated on the bases of activities in culture filtrate to decrease turbidity of the CWP-suspension and to form protoplasts from S. commune. The culture filtrate was also active in hydrolyzing p-nitrophenyl (p-NP)-alpha-d-glucoside, p-NP-beta-d-glucoside, and p NuRho-beta-d-Nu-acetylglucosaminide. The protoplast-forming and the p-NP glycoside-hydrolyzing activities were increased by the addition of CWP of S. commune to the culture medium, and this was not observed for other bacteria tested (15 genera, 80 species). B. circulans KA-304 was shown on gel filtration to produce at least two enzyme species for hydrolyzing both p-NP-alpha-d glucoside and p-NP-alpha-d-glucoside. The protoplast-forming activity was retained for at least 6 months at 5 degrees C as an ammonium sulfate (90% saturation) precipitate or at -20 degrees C as a freeze-dried preparation (KA preparation). The activity was stable at pH 6.5-7.0, and remained after 10 min of treatment at 40 degrees C. Protoplast formation proceeded optimally at pH 6.5 with 50 mm potassium phosphate buffer and 0.5 m mannitol as an osmotic stabilizer. B. circulans KA-304 seems to be a suitable strain producing enzyme(s) to prepare protoplasts from S. commune. PMID- 28862559 TI - Preparation of Glutaraldehyde Cross-linked Complex from Support. AB - A glutaraldehyde (GA) spacer complex on enzyme immobilization was cleaved from the support introduced Nalpha-9-fluorenylmethyl-oxycarbonylglycine. By the 1H-NMR spectroscopic measurement of the desired complex, glycine-GA-phenethylamine (GGP), GA was thought to be involved in enzyme immobilization as a heteropolymer with the molecular weight range of about 600 to 1300. PMID- 28862560 TI - In Vitro and in Vivo Anti-platelet Effects of Enzymatic Hydrolysates of Collagen and Collagen-related Peptides. AB - Collagen-related peptides, Gly-Pro-Arg and its analogues, were examined for their inhibitory effects on platelet aggregation induced by the addition of ADP. Human platelet aggregation was suppressed by more than 50% with each of Gly-Pro-Arg and such Gly-Pro-Arg-containing peptides as Gly-Pro-Arg-Gly, Gly-Pro-Arg-Gly-Pro, Gly Pro-Arg-Pro-Pro, and Gly-Pro-Arg-Pro-Pro-Pro at a concentration of 0.3 mm. The inhibitory effects of these peptides were about 10 times higher in human PRP than in rat PRP. Other Gly-Pro-Arg analogues such as Sar-Pro-Arg, Gly-Pro-Lys, Gly-Ala Arg, and Ala-Gly-Pro-Arg had no inhibitory effect at a concentration from 0.1 to 0.8 mm even in human PRP. Intravenous and oral administrations of Gly-Pro-Arg and enzymatic hydrolysates of collagen suppressed the decrease in platelet count for endotoxin-induced DIC in rats. Collagen itself has been regarded as a potent inducer of platelet aggregation, but these findings suggest that collagen-related peptides and enzymatic hydrolysates of collagen prevent platelet aggregation. PMID- 28862561 TI - Expression of Gene Encoding Endo-1,4-beta-glucanase in Suspension-cultured Poplar (Poplus alba L.) Cells?. AB - The level of mRNA for endo-1,4-beta-glucanase was increased before the exponential phase of growth and decreased rapidly during the exponential phase in suspension-cultured poplar cells. The level of mRNA was increased for a short period after the addition of either 2,4-D or sucrose to the culture medium at the stationary phase. The level was increased to the maximal level when both 2,4-D and sucrose were provided together, but one did not increase the effect of the other. These findings suggest that expression of gene encoding poplar endo-1,4 beta-glucanase is controlled during cell growth by independent systems activated by auxin and sucrose. PMID- 28862562 TI - Synthesis of 24a-Substituted Milbemycin A4 Derivatives and Their Acaricidal Activity against Tetranychus uvticae. AB - A series of 24a-substituted milbemycin A4 derivatives were synthesized from 24a hydroxymilbemycin A4, which had been obtained by the microbial oxidation of milbemycin A4. The acaricidal activity of each synthesized derivative against Tetranychus urticae was tested and some of the derivatives showed higher activity than parent milbemycin A4. Among them, 24a-methylmilbemycin A4 (22) was the most active derivative, with 100% mortality of the mite at a concentration of 1 ppm and 50% mortality at a concentration of 0.1 ppm. PMID- 28862563 TI - Inhibition of Glucan Synthesis by Flavipin-crosslinked Casein Polymers. AB - Mutastein, a casein polymer that inhibits insoluble glucan synthesis by Streptococcus sobrinus, was produced when Aspergillus terreus was grown in a medium containing alpha-casein. In these experiments, it was shown that flavipin (3,4,5-trihydroxy-6-methyl-o-phthalaldehyde) isolated from cultures of A. terreus caused polymerization of alpha-casein. Like mutastein, the polymerization products were active in inhibiting insoluble glucan synthesis by S. sobrinus. PMID- 28862564 TI - Occurrence of Free N-Glycans in Pea (Pisum sativum, L) Seedlings?. AB - Free N-glycans have been found in pea seedlings. These free N-glycans were coupled with 2-aminopyridine and purified by gel filtration, Con Alpha-Sepharose affinity chromatography, and size fractionation HPLC. These structures of pyridylaminated free N-glycans were analyzed by exomannosidase digestions and ion spray tandem mass spectrometry. The structural analyses showed that the several oligomannose-type sugar chains having one GlcNAc residue at the reducing-end side occur in the seedlings, suggesting the endo-beta-N-acetylgIucosaminidase PS [Y. Kimura et al., Biosci. Biotech. Biochem., 60, 228-232 (1996)] should be involved in the release of oligomannose-type N-glycans from the storage glycoproteins [Y. Kimura et al., Biosci. Biotech. Biochem., 60, 1841-1850 (1996)] during the germination of pea seeds. PMID- 28862566 TI - Grandinal, a New Phloroglucinol Dimer from Eucalyptus grandis. AB - Grandinal, a new dimeric phloroglucinol compound, was isolated from Eucalyptus grandis and characterized by spectral techniques. Tautomeric structures 1, 2, and 3 were assigned to grandinal. Biogenetically, 1 is proposed to be formed from intermediates derived from grandinol and jensenone. PMID- 28862565 TI - Enzymatic Synthesis of Mannosyl-cyclodextrin by alpha-Mannosidase from Jack Bean. AB - Mannosylated derivatives of cyclodextrins (CDs), mannosyl-alpha, beta, and gammaCD were synthesized from a mixture of mannose and alpha, beta, and gammaCD by the reverse action of alpha-mannosidase from jack bean, respectively. Their structures were analyzed by FAB-MS and 13C-NMR spectroscopies, and they were identified as 6-O-alpha-d-mannosyl-alpha, beta, and gammaCD. The optimum conditions for the production of 6-O-alpha-d-mannosyl-alphaCD by alpha mannosidase were examined. Optimum pH and temperature were pH 4.5 and 60 degrees C, respectively. Yield of mannosyl-alphaCD increased with increasing mannose concentration and reached more than 35% (mol/mol) at the concentration of 2 m mannose and 0.4 m alphaCD. PMID- 28862567 TI - Incorporation of Farnesyl Pyrophosphate Derivertives into Abscisic Acid and Its Biosynthetic Intermediates in Cevcospova cruenta. AB - To investigate the transformation from (2E,6E)-farnesyl pyrophosphate to (2Z,4E) gamma-ionylideneethanol in the abscisic acid-producing fungi, Cercospora cruenta, plausible [2-14C]-C15 intermediates were prepared and fed. Substrates such as (2E,6E)-farnesyl pyrophosphate, (2Z,4E)-gamma-ionylideneethanol and its pyrophosphate were incorporated into ABA and its known biosynthetic precursors. It is suggested that (2E,6E>farnesyl pyrophosphate is converted to (2Z,4E)-gamma ionylideneethanol in four consecutive steps: dehydrogenation, isomerization, cyclization and hydrolysis. PMID- 28862569 TI - Isolation and Partial Amino Add Sequence of Bacteriocins Produced by Lactobacillus acidophilus. AB - Bacteriocins produced by Lactobacillus acidophilus JCM 1023, JCM 1028, JCM 1021, JCM 1229, and JCM 5342 were active against closely related lactobacilli. These bacteriocins were purified and partial sequenced. Bacteriocin activities of L. acidophilus JCM 1023 and JCM 1028 were associated with two components. On the basis of N-terminal amino acid sequencing and the molecular masses, it is interpreted that these two-component bacteriocins are identical to acidocin J1132, a bacteriocin from L. acidophilus JCM 1132 [Tahara et al., Appl. Environ. Microbiol., 62, 892-897 (1996)]. Other bacteriocins were single-peptide bacteriocins. PMID- 28862568 TI - Effects of Ethylene and Gibberellins on the Elongation of Rice Seedlings (Oryza sativa L.). AB - Three-day-old rice seedlings treated with ethylene showed elongation of the 2nd and 3rd leaves. This ethylene-stimulated elongation was not observed in the presence of uniconazole-P or prohexadione, both gibberellin (GA) biosynthesis inhibitors, suggesting that GA was involved in the response. An analysis of endogenous GAs by GC-MS revealed that the GA1 level was reduced in the 3rd leaf in response to ethylene. Dose-response experiments showed that the responsiveness to GA1 was enhanced by ethylene. Feeding experiments of 14C-GA1 with ethylene treated seedlings showed that ethylene may increase the conversion of GA1 to GA8. These results suggest that, in young seedlings of rice, ethylene stimulates leaf elongation by increasing the responsiveness to GA1 and the turnover of GA1. PMID- 28862570 TI - Absolute Configurations of Some Hydroxy-fatty Acids Produced by the Insect Genus Laccifer. AB - The absolute configurations of some hydroxy-fatty acids were examined by the modified Mosher's method proposed by Ohtani et al. The absolute configurations of the major components were determined from NMR data of their MUTauRhoAlpha esters and 2-NuMUAlpha esters. The application of Mosher's method for the anti-glycol is discussed. PMID- 28862571 TI - Utility of intraoperative rotational thromboelastometry in thoracolumbar deformity surgery. AB - OBJECTIVE Blood loss during surgery for thoracolumbar scoliosis often requires blood product transfusion. Rotational thromboelastometry (ROTEM) has enabled the more targeted treatment of coagulopathy, but its use in deformity surgery has received limited study. The authors investigated whether the use of ROTEM reduces transfusion requirements in this case-control study of thoracolumbar deformity surgery. METHODS Data were prospectively collected on all patients who received ROTEM-guided blood product management during long-segment (>= 7 levels) posterior thoracolumbar fusion procedures at a single institution from April 2015 to February 2016. Patients were matched with a group of historical controls who did not receive ROTEM-guided therapy according to age, fusion segments, number of osteotomies, and number of interbody fusion levels. Demographic, intraoperative, and postoperative transfusion requirements were collected on all patients. Univariate analysis of ROTEM status and multiple linear regression analysis of the factors associated with total in-hospital transfusion volume were performed, with p < 0.05 considered to indicate statistical significance. RESULTS Fifteen patients who received ROTEM-guided therapy were identified and matched with 15 non-ROTEM controls. The mean number of fusion levels was 11 among all patients, with no significant differences between groups in terms of fusion levels, osteotomy levels, interbody fusion levels, or other demographic factors. Patients in the non-ROTEM group required significantly more total blood products during their hospitalization than patients in the ROTEM group (8.5 +/- 4.2 units vs 3.71 +/- 2.8 units; p = 0.001). Multiple linear regression analysis showed that the use of ROTEM (p = 0.016) and a lower number of fused levels (p = 0.022) were associated with lower in-hospital transfusion volumes. CONCLUSIONS ROTEM use during thoracolumbar deformity correction is associated with lower transfusion requirements. Further investigation will better define the role of ROTEM in transfusion during deformity surgery. PMID- 28862572 TI - Laminoplasty versus laminectomy with posterior spinal fusion for multilevel cervical spondylotic myelopathy: influence of cervical alignment on outcomes. AB - OBJECTIVE Cervical curvature is an important factor when deciding between laminoplasty and laminectomy with posterior spinal fusion (LPSF) for cervical spondylotic myelopathy (CSM). This study compares outcomes following laminoplasty and LPSF in patients with matched postoperative cervical lordosis. METHODS Adults undergoing laminoplasty or LPSF for cervical CSM from 2011 to 2014 were identified. Matched cohorts were obtained by excluding LPSF patients with postoperative cervical Cobb angles outside the range of laminoplasty patients. Clinical outcomes and radiographic results were compared. A subgroup analysis of patients with and without preoperative pain was performed, and the effects of cervical curvature on pain outcomes were examined. RESULTS A total of 145 patients were included: 101 who underwent laminoplasty and 44 who underwent LPSF. Preoperative Nurick scale score, pain incidence, and visual analog scale (VAS) neck pain scores were similar between the two groups. Patients who underwent LPSF had significantly less preoperative cervical lordosis (5.8 degrees vs 10.9 degrees , p = 0.018). Preoperative and postoperative C2-7 sagittal vertical axis (SVA) and T-1 slope were similar between the two groups. Laminoplasty cases were associated with less blood loss (196.6 vs 325.0 ml, p < 0.001) and trended toward shorter hospital stays (3.5 vs 4.3 days, p = 0.054). The perioperative complication rate was 8.3%; there was no significant difference between the groups. LPSF was associated with a higher long-term complication rate (11.6% vs 2.2%, p = 0.036), with pseudarthrosis accounting for 3 of 5 complications in the LPSF group. Follow-up cervical Cobb angle was similar between the groups (8.8 degrees vs 7.1 degrees , p = 0.454). At final follow-up, LPSF had a significantly lower mean Nurick score (0.9 vs 1.4, p = 0.014). Among patients with preoperative neck pain, pain incidence (36.4% vs 31.3%, p = 0.629) and VAS neck pain (2.1 vs 1.8, p = 0.731) were similar between the groups. Similarly, in patients without preoperative pain, there was no significant difference in pain incidence (19.4% vs 18.2%, p = 0.926) and VAS neck pain (1.0 vs 1.1, p = 0.908). For laminoplasty, there was a significant trend for lower pain incidence (p = 0.010) and VAS neck pain (p = 0.004) with greater cervical lordosis, especially when greater than 20 degrees (p = 0.011 and p = 0.018). Mean follow-up was 17.3 months. CONCLUSIONS For patients with CSM, LPSF was associated with slightly greater blood loss and a higher long-term complication rate, but offered greater neurological improvement than laminoplasty. In cohorts of matched follow-up cervical sagittal alignment, pain outcomes were similar between laminoplasty and LPSF patients. However, among laminoplasty patients, greater cervical lordosis was associated with better pain outcomes, especially for lordosis greater than 20 degrees . Cervical curvature (lordosis) should be considered as an important factor in pain outcomes following posterior decompression for multilevel CSM. PMID- 28862573 TI - The sagittal spinal profile type: a principal precondition for surgical decision making in patients with lumbar spinal stenosis. AB - OBJECTIVE Microsurgical decompression (MD) in patients with lumbar spinal stenosis (LSS) shows good clinical results. Nevertheless, 30%-40% of patients do not have a significant benefit after surgery-probably due to different anatomical preconditions. The sagittal profile types (SPTs 1-4) defined by Roussouly based on different spinopelvic parameters have been shown to influence spinal degeneration and surgical results. The aim of this study was to investigate the influence of the SPT on the clinical outcome in patients with LSS who were treated with MD. METHODS The authors retrospectively investigated 100 patients with LSS who received MD. The patients were subdivided into 4 groups depending on their SPT, which was determined from preoperative lateral spinal radiographs. The authors analyzed pre- and postoperative outcome scales, including the visual analog scale (VAS), walking distance, Oswestry Disability Index, Roland-Morris Disability Questionnaire, Odom's criteria, and the 36-Item Short Form Health Survey score. RESULTS Patients with SPT 1 showed a significantly worse clinical outcome concerning their postoperative back pain (VASback-SPT 1 = 5.4 +/- 2.8; VASback-SPT 2 = 2.6 +/- 1.9; VASback-SPT 3 = 2.9 +/- 2.6; VASback-SPT 4 = 1.5 +/- 2.5) and back pain-related disability. Only 43% were satisfied with their surgical results, compared with 70%-80% in the other groups. CONCLUSIONS A small pelvic incidence with reduced compensation mechanisms, a distinct lordosis in the lower lumbar spine with a high load on dorsal structures, and a long thoracolumbar kyphosis with a high axial load might lead to worse back pain after MD. Therefore, the indication for MD should be provided carefully, fusion can be considered, and other possible reasons for back pain should be thoroughly evaluated and treated. PMID- 28862575 TI - Proceedings of the Experimental Psychology Society 2017. PMID- 28862574 TI - Steady-state pharmacokinetics of hydroxychloroquine in patients with cutaneous lupus erythematosus. AB - Background Hydroxychloroquine (HCQ), a 4-aminoquinolone antimalarial, is regarded as the oral therapy of choice for cutaneous and systemic lupus erythematosus (SLE). It is also licensed for rheumatoid arthritis (RA). Studies of HCQ-treated patients with SLE or RA have demonstrated a positive correlation between whole blood HCQ levels and clinical response. Such studies have involved measuring whole-blood concentrations at any given time point after HCQ ingestion assuming that steady-state concentrations would undergo limited fluctuation over a daily interval because HCQ has a long half-life. This approach might not sufficiently take into account the potential intra-patient variation in HCQ blood levels that can occur over a 24-hour period. Such variation, if significant, could affect the credibility of any concentration-response relationship provided from these previous studies. Objectives The objectives of this report are to: (a) investigate the intra-patient variation in HCQ whole-blood levels and (b) suggest an optimum time for sampling patients for future studies. Methods Six patients were recruited with cutaneous lupus erythematosus who had each been on HCQ 200 mg twice daily for at least six months, so that they were at steady-state. Each patient was fasted overnight and had standardized meals and dosing schedule. Whole blood was sampled at seven time points over 24 hours. Whole-blood HCQ levels were measured with high-performance liquid chromatography using gradient elution, fluorimetric detection and chloroquine as an internal standard. The assay had a mean inter- and intra-day coefficient of variation of 10% and 5% respectively and a limit of detection of 5ng/ml. Results HCQ levels appeared to follow a biphasic pattern over the sampling period. Maximum levels were noted a median of four hours (range 2-6) after ingestion. Median intra-patient variation between trough and peak levels, 'Cmax' ((peak - trough)/trough * 100%), was 27% (range 8-150%). Conclusions This study demonstrated that whole-blood HCQ levels vary 27% (median, range 8-150%) within an individual over a 12-hour period. Drug levels might differ between individuals because of multiple factors, including variable adherence to medication. Measuring HCQ levels for assessment of drug adherence could be valuable in the 'real-world' clinical setting. This could be assessed by taking a blood sample at any time following HCQ ingestion. If patients were found to have very low or undetectable levels of HCQ, non-adherence to HCQ should be suspected. PMID- 28862578 TI - Missed opportunity. PMID- 28862577 TI - Website design for the dental practice. PMID- 28862579 TI - Addressing the emerging public health crisis of narcotic overdose. PMID- 28862580 TI - Drug shortages: how do we run out of salt water? PMID- 28862581 TI - "I didn't sign up for this!" PMID- 28862582 TI - Gingival mass and Blue lesion of palate. PMID- 28862583 TI - Dentin desensitizing agents: too many options. AB - As the number of dentin desensitizing products has grown, it has become more difficult for the dental clinician to make the correct choice. This literature review seeks to clearly explain the different modes of action of current desensitizing agents, including the clinical trial outcomes of different materials and products in the market. A better understanding of the prevalence, pain physiology, diagnosis, and different methods of management of dentinal hypersensitivity is imperative for proper pain management. PMID- 28862584 TI - A root volume study of the adult dentition for ridge preservation purposes. AB - Ridge preservation has become a common practice to preserve the remaining alveolar bone volume after tooth extraction. The most common volume of graft material in commercially available vials is between 0.50 and 1.00 mL. The clinician must estimate how much grafting material is needed after extracting a tooth. The aim of this study is to provide the clinician with a volumetric guide for selection of graft material for ridge preservation after tooth extraction. Fifteen sets of permanent teeth, each representing a full adult dentition excluding the third molars, were selected at random from a collection of extracted teeth. Teeth were submerged in a polyvinyl siloxane impression material to record the negative impression of the root. Water was then used to fill this space and measure the root volume. For the majority of the teeth, 0.50 mL of graft material was adequate for grafting the socket. A volume greater than 0.50 mL was required to preserve the maxillary and mandibular first molars. Overestimation or underestimation of the amount of grafting material necessary postextraction may result in unnecessary expense. PMID- 28862585 TI - Oral health considerations in anorexia and bulimia nervosa. 2. Multidisciplinary management and personalized dental care. AB - This article outlines a comprehensive, multidisciplinary strategy for treatment of patients with anorexia and bulimia nervosa. In this approach, primary medical intervention and emergency dental care are followed by the staging of treatment phases that integrate medical care, psychotherapy, nutritional counseling, and dental management, which may encompass various treatment options for repair of damaged dentition. Emphasis is placed on prevention of further tissue damage during all phases of management and following completion of the treatment course. PMID- 28862586 TI - Success rates of Hall technique crowns in primary molars: a retrospective pilot study. AB - The purpose of this retrospective observational study was to assess success rates, both clinical and radiographic, of stainless steel crowns (SSCs) placed on primary molars using the Hall technique. A retrospective analysis was performed on recorded data of patients with any primary molar treated with an SSC that was placed using the Hall technique at the University of Iowa College of Dentistry during 2011-2015. The primary outcome measure was the success or failure of the SSCs placed with the Hall technique. These outcomes were categorized as either clinical and radiographic success or failure. Clinical failure was defined as the need for pulp therapy or extraction following crown placement. Radiographic failure was defined as the presence of any pathological condition-including external or internal root resorption, bifurcation radiolucency, widened periodontal ligament, or ectopic eruption of permanent first molar adjacent to the Hall crown-following crown placement. Records indicated that 100 boys received a total of 179 crowns (61.1% of all Hall crowns placed), and 64 girls received 114 crowns. The mean age of the patients was 5.1 years (SD, 2.4 years). Of 293 SSCs included in the study, 180 received at least 1 follow-up examination after a mean of 9.9 months (SD, 6.5 months). At the first follow-up visit, 178 (98.9%) of 180 SSCs placed using the Hall technique were clinically successful. Of 87 crowns with radiographs available, 85 (97.7%) were radiographically successful. At the second follow-up visit (after a mean of 20.1 months), 74 of 76 (97.4%) were rated as clinically successful, and 37 of 39 (94.9%) were radiographically successful. Results of this study provide evidence of high clinical and radiographic success rates for SSCs placed on primary molars with the Hall technique. PMID- 28862587 TI - Modified PEEK as an alternative crown framework material for weak abutment teeth: a case report. AB - This case report describes the fabrication of 3 single crowns for a patient with weakened abutment teeth. The patient exhibited nocturnal bruxism and clenching but refused to use an occlusal appliance. The abutment teeth were endodontically treated and presented with loss of tooth structure and thin axial walls. The patient was seeking a metal-free restoration, and all-ceramic restorations were contraindicated because of the potential for abrasion of the opposing teeth and direct force transmission to the weak abutment teeth. The restoration of choice was a modified polyetheretherketone (PEEK) framework material veneered with an indirect light-cured composite resin. This approach offered characteristics such as biocompatibility, protection of opposing teeth, a cushioning effect, abrasion resistance almost equal to that of dentin, ease of intraoral repair in case of chipping, and a high level of comfort. The use of PEEK frameworks veneered with indirect light-cured composite resin could be a viable alternative for the treatment of weakened abutment teeth in patients with parafunctional habits. PMID- 28862588 TI - Phantom bite: a real or a phantom diagnosis? A case report. AB - This case report describes computer-guided occlusal therapy in a patient who met the unified diagnostic criteria for phantom bite. After a review of the patient's medical history, along with a diagnostic work-up that included cone beam computed tomography, temporomandibular joint vibration analysis, and digital occlusal analysis, problematic dental components were discovered (including prolonged disclusion time and imbalanced bite force). A digital occlusal analyzer evaluated the patient's occlusion and systematically guided the necessary changes. After reduction of the disclusion time and correction of the occlusal force imbalance, the patient reported significant improvement in comfort. The results suggest that phantom bite could be an abnormal occlusal condition and not a psychological or neurologic somatoform disorder. PMID- 28862589 TI - Review of techniques for the intact removal of a permanently cemented restoration. AB - The safest and least traumatic means of removing a cemented restoration is to cut a slot and pry the crown or retainer loose, sacrificing the restoration. However, various techniques and instruments for intact removal of permanently cemented cast restorations have been described in the literature. This literature review explores conservative and semiconservative techniques that are useful for preserving permanently cemented restorations during removal. Richwil resin, ultrasonic energy, and crown tractors can be considered preferred methods for removal of temporarily cemented restorations. Patients should be informed regarding the risks and benefits before removal of a cemented restoration. PMID- 28862590 TI - The compression dome concept: the restorative implications. AB - Evidence now supports the concept that the enamel on a tooth acts like a compression dome, much like the dome of a cathedral. With an overlying enamel compression dome, the underlying dentin is protected from damaging tensile forces. Disruption of a compression system leads to significant shifts in load pathways. The clinical restorative implications are significant and far-reaching. Cutting the wrong areas of a tooth exposes the underlying dentin to tensile forces that exceed natural design parameters. These forces lead to crack propagation, causing flexural pain and eventual fracture and loss of tooth structure. Improved understanding of the microanatomy of tooth structure and where it is safe to cut teeth has led to a revolution in dentistry that is known by several names, including microdentistry, minimally invasive dentistry, biomimetic dentistry, and bioemulation dentistry. These treatment concepts have developed due to a coalescence of principles of tooth microanatomy, material science, adhesive dentistry, and reinforcing techniques that, when applied together, will allow dentists to repair a compromised compression dome so that it more closely replicates the structure of the healthy tooth. PMID- 28862591 TI - Double mesiodens: a review and report of 2 cases. AB - Mesiodentes are the most frequently encountered supernumerary teeth. Recently, reports of double mesiodens have increased, which may be due to the availability of better diagnostic methods. This article discusses 2 cases of double mesiodens with varying clinical presentations. In addition, the literature related to the etiology, clinical presentation, diagnosis, and management of mesiodentes is reviewed. PMID- 28862592 TI - What every dentist should know about statins. AB - Statins are well known for their ability to combat cardiovascular disease. There is new evidence that statins can influence a variety of cellular pathways, suggesting that their benefits may extend beyond lowering cholesterol. This review will explore potential new therapeutic roles for statins in medical and dental settings. PMID- 28862593 TI - Prosthetic rehabilitation in a pediatric patient with hypohidrotic ectodermal dysplasia: a case report. AB - Hypohidrotic ectodermal dysplasia (HED) is a rare ectodermal disease with a systemic expression. Oral abnormalities are common and may include hypodontia and shape irregularities in the primary and permanent dentitions. Rehabilitation of the dental arches in pediatric patients with HED is a challenge because HED is a multifactorial disease that demands a complicated treatment approach and most dentists have limited experience or training in the necessary treatment. In addition, pediatric patients often lack the patience or ability to cooperate with complex prosthetic treatment. This case report describes a simplified technique used to fabricate complete dentures for a 4-year-old HED patient in 4 sessions. PMID- 28862594 TI - Use of antimicrobial photodynamic therapy for treatment of deep caries in the primary dentition: a step-by-step technique report. AB - Antimicrobial photodynamic therapy (aPDT) is increasingly used in dentistry to treat a number of diseases. The procedure involves the activation of a photosensitizer by a visible light source to induce chemical reactions that create cytotoxic reactive oxygen species, cause oxidative stress, and result in inactivation of pathogenic microorganisms. The use of aPDT has been proven to reduce microorganisms present in dentin and therefore may be effective for treatment of deep caries. This case report describes the use of aPDT as an adjuvant therapy in the treatment of deep caries in the primary molar of a 7-year old boy. The case also highlights the preservation of pulpal vitality-in accordance with the concepts of minimal intervention-as well as the reduction of chair time achieved by resolving the case in a single session, a factor that is important for the treatment of children. PMID- 28862595 TI - Effect of bleaching on color stability and roughness of composite resins aged in staining beverage. AB - Composite resin properties can be affected by contact with gel during bleaching procedures; however, there is no consensus about the effect of this contact on resin susceptibility to color change. This study aimed to evaluate staining susceptibility and surface roughness changes in 2 composite resins (Filtek Z250 XT and Filtek Z350 XT) after application of bleaching peroxides and storage in different media. Forty-two disc-shaped specimens of each composite were made, polished, and divided into 3 groups according to treatment type (35% hydrogen peroxide, 16% carbamide peroxide, or deionized water as a control group). These groups were subdivided into 2 groups according to immersion media (n = 7): deionized water or red wine. Color and average roughness (Ra) measurements were taken 24 hours after specimen preparation (T0), immediately after bleaching procedures (T1), and immediately after aging (staining; T2). Statistical analyses were performed using 2-way analyses of variance for repeated measurements and the Tukey test (P < 0.05). Bleaching resulted in minimal color change (DeltaE* < 1) in all groups. Filtek Z350 XT specimens presented greater mean values of color change. The Ra values did not increase significantly after bleaching procedures or aging (staining) in all groups. Thus, bleaching agents did not significantly change the color or roughness of the composite resins used in this study. PMID- 28862596 TI - Noninvasive approach to esthetic rehabilitation of conoid anterior teeth. AB - Several factors, including anomalies of shape, color, or size, or positioning of the teeth, may interfere with smile esthetics. A 26-year-old woman was dissatisfied with the esthetics of her maxillary lateral incisors, which had defective composite resin restorations with alterations of color and shape. The aim of this article is to present a step-by-step description of the technique used to fabricate esthetic restorations for the conoid maxillary lateral incisors with a minimum of dental preparation. The successful outcome demonstrates the importance of correct planning for successful restorations. PMID- 28862597 TI - Influence of custom adaptation on the characteristics of fiber posts. AB - In this in vitro study, 3 experiments were conducted to evaluate the influence of customizing the apical portion on the characteristics of fiber posts. In the first experiment, 4 fiber posts were submitted to different custom adaptations (no customization, industrial shaping tool, diamond bur, or paper disc) and were observed with a scanning electron microscope to evaluate the micromorphologic changes. In the second experiment, 60 posts of different sizes were divided into 6 groups (n = 10): 0 (No. 0.5), 1 (No. 1), 2 (No. 2), 3 (No. 3), 4 (No. 4), and 5 (paper disc-remodeled No. 4). The posts were submitted to a 3-point bending test. In the third experiment, the crowns of 20 extracted, healthy permanent human canines were removed, and the teeth were endodontically treated, embedded in acrylic resin, and divided into 2 groups (n = 10): I (control), No. 4 posts cemented into post spaces prepared with a No. 4 drill; and II (test), remodeled No. 4 posts cemented into root spaces prepared with No. 2 and 4 drills. The posts were cemented with self-adhesive dual resin cement, and the specimens received direct resin crowns. Fracture strength was measured with a universal testing machine at 45 degrees until fracture. Results were submitted to analysis of variance (P <= 0.05). Customization of fiber posts with diamond burs or paper discs produced acceptable micromorphologic changes. Custom adaptation of fiber posts reduced their flexural strength, which remained at acceptable values. Teeth restored with customized fiber posts had greater fracture strength than those restored with intact posts. The results of this study indicated that post remodeling is a safe means to facilitate adaptation to root walls and preserve tooth structure. PMID- 28862598 TI - [Correction of the oxidant-antioxidant balance in lungs during hyperoxia by liposomal alpha-tocopherol and retinoids in the experiment]. AB - The influence of inhaled liposomes, containing dipalmitoyl phosphatidylcholine and a-tocopherol, and liposomes containing dipalmitoyl phosphatidylcholine, retinol and retinoic acid, on parameters of the oxidantantioxidant system in lungs of newborn guinea pigs exposed to hyperoxia during 3 and 14 days has been studied. Administration of both types of liposomes under conditions of prolonged hyperoxia (14 days) results in normalization of glutathione peroxidase activity and prevents elevation of the levels of lipid and protein peroxidation products in bronchoalveolar lavage fluid. Unlike liposomes with a-tocopherol, administration of liposomes containing retinoids did not cause the normalizing effect on the content of nonprotein SH-compounds in the bronchoalveolar fluid and contributed to significant reduction of the a-tocopherol level in lung tissues. PMID- 28862600 TI - [Differences in adrenal steroid hormones production in pubertal rats exposed to low doses of endocrine disruptor DDT during prenatal and postnatal development]. AB - Production of adrenal steroid hormones in pubertal male Wistar rats exposed to low doses of DDT during both prenatal and postnatal and only postnatal development was evaluated. Altered production of all types of steroid hormones and serum steroid profile with opposite changes in rats exposed prenatally and postnatally, and only postnatally was found. The study showed that daily exposure to low doses of DDT enhanced conversion of progesterone to 17OH-progesterone and did not exert selective antiandrogenic or proestrogenic action unlike effect of toxic and subtoxic doses. Impaired morphogenesis of the adrenal cortex and circulatory disorders in zona glomerulosa contributed to reduced aldosterone and sex steroid hormones production. PMID- 28862599 TI - [Induction of apoptotic endonuclease EndoG with DNA-damaging agents initiates alternative splicing of telomerase catalytic subunit hTERT and inhibition of telomerase activity hTERT in human CD4+ and CD8+ T-lymphocytes]. AB - Activity of telomerase catalytic subunit hTERT (human Telomerase Reverse Transcriptase) can be regulated by alternative splicing of its mRNA. At present time exact mechanism of hTERT splicing is not fully understood. Apoptotic endonuclease EndoG is known to participate this process. EndoG expression is induced by DNA damages. The aim of this work was to investigate the ability of DNA-damaging agents with different mechanism of action to induce EndoG expression and inhibit telomerase activity due to the activation of hTERT alternative splicing in normal activated human CD4+ and CD8+ T-lymphocytes. All investigated DNA-damaging agents were able to induce EndoG expression. Cisplatin, a therapeutic compound, producing DNA cross-links induced the highest level of DNA damages and EndoG expression. Incubation of CD4+ and CD8+ T-cells with cisplatin caused the changes in proportion of hTERT splice variants and inhibition of telomerase activity. PMID- 28862601 TI - [Comparative analysis of expression of genes encoding enzymes of catecholamine catabolism and renalase in tissues of normotensive and hypertensive rats]. AB - Comparative analysis of expression of genes encoding enzymes of catecholamine catabolism (monoaminbe oxidases A and B (MAO A and MAO B) and catechol-O-methyl transferase (COMT)) and renalase has been carried out in tissues of normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Among investigated tissues the highest level of mRNA of genes encoding key enzymes of catecholamine catabolism (MAO A, MAO B, COMT) was found in the heart of WKY rats. In SHR the mRNA levels of these genes were lower (p<0.05-0.01), however, no similar changes were observed in the tissues studied in dependence of hypertension. The relative mRNA levels of the studied genes normalized versus actin mRNA significantly varied. In heart and kidney the relative level of COMT mRNA significantly exceeded the relative levels of both MAO A mRNA and MAO B mRNA. In the brain differences in mRNAs of MAOA, MAOB, and COMT were less pronounced. However, in all examined tissue the renalase mRNA level was much (at least 10-20-fold) lower than any other mRNA studied. Taking into consideration known correlations between mRNAs and corresponding protein products reported in the literature for many genes these results suggest that in the case of any catalytic scenarios proposed or even proved for renalase this protein cannot contribute to catecholamine degradation. It is also unlikely that the products of renalase reaction, b-NAD(P)+ and hydrogen peroxide, can exhibit a hypotensive effect due to low expression of the renalase encoding gene. PMID- 28862602 TI - [The effect of neurotoxin MPTP administration to mice on the proteomic profile of brain isatin-binding proteins]. AB - Isatin (indole-2,3-dione) is an endogenous indole found in the mammalian brain, peripheral organs and body fluids. It acts as a neuroprotector, which decreases manifestation of locomotor impairments in animal models of Parkinson's disease. A wide range of biological activity of isatin is associated with interaction of this regulator with numerous isatin-binding proteins. The aim of this study was to investigate the profile of brain isatin-binding proteins in mice with MPTP induced Parkinsonism (90 min and seven days after administration of this neurotoxin). A single dose administration of MPTP (30 mg/kg, ip.) was accompanied by locomotor impairments in the open field test 90 min after administration; seven days after MPTP administration locomotor activity of mice significantly improved but did not reach the control level. Five independent experiments on proteomic profiling of isatin-binding proteins resulted in confident identification of 96+/-12 proteins. Development of MPTP-induced locomotor impairments was accompanied by a significant decrease in the number of isatin binding proteins (63+/-6; n=5; p<0.01). Seven days after MPTP administration the total number of identified proteins increased and reached the control level (132+/-34; n=4). The profiles of isatin-binding proteins were rather specific for each group of mice: in the control group these proteins (which were not found in both groups of MPTP-treated mice) represented more than 70% of total proteins. In the case of MPTP treated mice this parameter was 60% (90 min after MPTP administration) and >82% (seven days after MPTP administration). The major changes were found in the groups of isatin-binding proteins involved into cytoskeleton formation and exocytosis, regulation of gene expression, cell division and differentiation and also proteins involved in signal transduction. PMID- 28862603 TI - [The activity of redox-regulatory systems in the primary and recurrence tumors in vulvar cancer]. AB - The activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione transferase (GST), the content of reduced glutathione (GSH) and malondialdehyde (MDA) were investigated in the samples of the tumor, peritumoral zone and healthy tissue, taken at the line of resection, were obtained from 14 patients with primary squamous cell carcinoma of the vulva, and 13 patients with local recurrence appeared in the period from 3 months to 7 years. by conventional spectrophotometric methods. The content of GSH and the activity of SOD, GPx, GR, GST were significantly increased, while MDA was decreased in the tissue of the primary carcinoma of the vulva in compared with the healthy tissue. Differences in the functioning of the investigated system of enzymes in the peritumoral zone were also revealed in the primary and recurrent tumoral process. Similar but much less pronounced changes were also observed in the recurrent tumor. It is suggested that such dynamics of activity of the studied system with the progression of cancer process can be the result of adaptation to changes in the local biochemical status of healthy (nonmalignant) tissue of the organ carrying the tumor and reflect the metabolic features of the recurrent tumor. PMID- 28862604 TI - [High resolution respirometry in diagnostic of mitochondrial disorders caused by mitochondrial complex I deficiency]. AB - Complex I (CI) deficiency is one of the most common defects in the OXPHOS system; it represents more than 30% cases of mitochondrial diseases. The group is characterized by clinical and genetic heterogeneity and comprise several nosological forms. The most prevalent phenotypes for CI are LHON and Leigh syndrome. In this study we have analyzed skin fibroblasts from 11 patients with mutations in mtDNA, which cause LHON or Leigh-like phenotypes: m.11778 G>A (n=3), m.3460 A>G (n=2), m.3635 G>A (n=1), m.3308 T>G (n=2), m.3472 T>C (n=1) and 2 patients with earlier unknown substitutions m.3945 C>A and m.14441T>C. High resolution respirometry (HRR) on the Oxygraph-2k instrument ("Oroboros corp.", Austria) was performed for complex analysis of the mitochondrial respiratory function in intact and permeabilized fibroblasts of patients and healthy controls. Flux control rations in intact cells R/E, (R-L)/E (p<0.05) were raised compared to the control. Rates of R, E, L normalized on the CS were statistically varied between patients and controls. In permeabilized fibroblasts we observed differences in CII/E, Rot/E, R/CII, CI/CII (p<0.05) between groups. These data highlight the dysfunction of the OXPHOS system and particularly CI. Increased citrate synthase level and decreased CI/CII ratio indicate compensatory metabolic response to respiratory chain dysfunction. Our results show applicability of HRR in revealing the biochemical abnormalities of complex I in fibroblasts of patients with LHON and Leigh-like syndrome. We also suggest HRR to be a useful method for inspection of other mutations causing complex I deficiency. PMID- 28862605 TI - [Influence of cultivation conditions on the proteomic profile of Mycobacterium tuberculosis H37RV]. AB - Comparative proteomic profiling of M. tuberculosis H37Rv strains cultured on two different nutrient media, Levenstein-Jensen and Middlebrook 7H11, was performed using a label-free LC-MS/MS approach. It was shown that results obtained from two media possessed high convergence. The only difference was observed in the representation of fumarate reductase FrdB, its abundance was higher in the mycobacterial cells cultured on Levenstein-Jensen medium. The correlation analysis of biological repeats revealed the high convergence of the results obtained from Middlebrook 7H11 medium. Thus, we can conclude that the use of the Middlebrook 7H11 medium is most appropriate in the scientific laboratory. PMID- 28862606 TI - [Use of de novo sequencing for proteins identification]. AB - Three de novo sequencing programs (Novor, PEAKS and PepNovo+) have been used for identification of 48 individual human proteins constituting the Universal Proteomics Standard Set 2 (UPS2) ("Sigma-Aldrich", USA). Experimental data have been obtained by tandem mass spectrometry. The MS/MS was performed using pure UPS2 and UPS2 mixtures with E. coli extract and human plasma samples. Protein detection was based on identification of at least two peptides of 9 residues in length or one peptide containing at least 13 residues. Using these criteria 13 (Novor), 20 (PEAKS) and 11 (PepNovo+) proteins were detected in pure UPS2 sample. Protein identifications in mixed samples were comparable or worse. Better results (by ~20%) were obtained using prediction included high quality identified fragment (TAG) containing at least 7 residues and unidentified additional masses at N- and C-termini (PepNovo+). The latter approach confidently recognized mass spectrometric artefacts (and probably PTM). Atypical mass changes missed in UNIMOD DB were found (PepNovo+) to be statistically significant at the C-terminus (+23.02, +26.04 and +27.03). Using peptides containing these modifications and milder detection threshold 41 of 48 UPS2 proteins were identified. PMID- 28862607 TI - [Protective action of fish muscle extracts against cellular senescence induced by oxidative stress]. AB - Muscle extracts of some fish species, i.e. pike (Esox lucius), sterlet (Acipenser ruthenus), pink salmon (Oncorhynchus gorbuscha) and, to a lesser extent, perch (Perca fluviatilis) and Russian sturgeon, (Acipenser gueldenstaedtii) prevent the development of premature senescence of the human embryonic fibroblasts induced by the sublethal concentration of H2O2. Muscle extracts of other fish species tested, i.e. coho salmon (Oncorhynchus kisutch) and zander (Sander lucioperca), have not demonstrated this feature. Cell proliferation increased after the action of the senescence-inhibiting muscle extracts. Possible mechanisms of the action of nature biologically active compounds that interfere with the development of stress-induced cell senescence are discussed. PMID- 28862609 TI - Gutzwiller variational approach to the two-impurity Anderson model for a metallic host at particle-hole symmetry. AB - We study Gutzwiller-correlated wave functions as variational ground states for the two-impurity Anderson model (TIAM) at particle-hole symmetry as a function of the impurity separation [Formula: see text]. Our variational state is obtained by applying the Gutzwiller many-particle correlator to a single-particle product state. We determine the optimal single-particle product state fully variationally from an effective non-interacting TIAM that contains a direct electron transfer between the impurities as variational degree of freedom. For a large Hubbard interaction U between the electrons on the impurities, the impurity spins experience a Heisenberg coupling proportional to [Formula: see text] where V parameterizes the strength of the on-site hybridization. For small Hubbard interactions we observe weakly coupled impurities. In general, for a three dimensional simple cubic lattice we find discontinuous quantum phase transitions that separate weakly interacting impurities for small interactions from singlet pairs for large interactions. PMID- 28862608 TI - [Quaternary structures of human cytoplasmic and nuclear PCNA are the same]. AB - Properties and mechanisms of PCNA (proliferating cell nuclear antigen) functions have been investigated for a long time and are studied in great detail. As follows from its name, most known PCNA functions (DNA replication, DNA repair, DNA recombination and others) are connected with cell proliferation and localization of this protein in nuclei. In addition, there is good reason to believe that PCNA also performs some functions in the cytoplasm. However, the possible role and mechanisms of PCNA action in the cytoplasm require careful study and clarification. Interestingly, such cells as neutrophils differ in that they are non-dividing on one hand and on the other hand contain a rather large amount of PCNA, which is localized only in the cytoplasm, that is, they are an ideal model for the study of cytoplasmic PCNA. Using cross-linkages with formaldehyde, we showed that this cytoplasmic PCNA is cross-linked in a similar way, that is, organized in the same way as the nuclear PCNA that is present in the proliferating cells. Previously, we showed that PCNA in such cells is organized into a dynamic complex of double trimer on the basis of the back-to back principle (Naryzhny S.N. et al. (2005) J. Biol. Chem., 280, 13888). Apparently, such organization of this hub-protein allows it to better coordinate the processes taking place in the cytoplasm as well. PMID- 28862610 TI - Seventy years of publications. PMID- 28862611 TI - Phase-merging enhanced harmonic generation free-electron laser with a normal modulator. AB - A phase-merging enhanced harmonic generation free-electron laser (FEL) was proposed to increase the harmonic conversion efficiency of seeded FELs and promote the radiation wavelength towards the X-ray spectral region. However, this requires a specially designed transverse gradient undulator (TGU) as the modulator to couple the transverse and longitudinal phase space of the electron beam. In this paper, the generation of the phase-merging effect is explored using the natural field gradient of a normal planar undulator. In this method, a vertical dispersion on the electron beam is introduced and then the dispersed beam travels through a normal modulator in a vertical off-axis orbit where the vertical field gradient is selected properly in terms of the vertical dispersion strength and modulation amplitude. The phase-merging effect will be generated after passing through the dispersive chicane. Theoretical analysis and numerical simulations for a seeded soft X-ray FEL based on parameters of the Shanghai Soft X-ray FEL project are presented. Compared with a TGU modulator, using the natural gradient of a normal planar modulator has the distinct advantage that the gradient can be conveniently tuned in quite a large range by adjusting the beam orbit offset. PMID- 28862612 TI - Electron-bunch lengthening on higher-harmonic oscillations in storage-ring free electron lasers. AB - The influence of higher-harmonic free-electron laser (FEL) oscillations on an electron beam have been studied by measuring its bunch length at the NIJI-IV storage ring. The bunch length and the lifetime of the electron beam were measured, and were observed to have become longer owing to harmonic lasing, which is in accord with the increase of the FEL gain. It was demonstrated that the saturated FEL power could be described by the theory of bunch heating, even for the harmonic lasing. Cavity-length detuning curves were measured for the harmonic lasing, and it was found that the width of the detuning curve was proportional to a parameter that depended on the bunch length. These experimental results will be useful for developing compact resonator-type FELs by using higher harmonics in the extreme-ultraviolet and the X-ray regions. PMID- 28862613 TI - Refurbishment of a used in-vacuum undulator from the National Synchrotron Light Source for the National Synchrotron Light Source-II ring. AB - The National Synchrotron Light Source (NSLS) ceased operation in September 2014 and was succeeded by NSLS-II. There were four in-vacuum undulators (IVUs) in operation at NSLS. The most recently constructed IVU for NSLS was the mini-gap undulator (MGU-X25, to be renamed IVU18 for NSLS-II), which was constructed in 2006. This device was selected to be reused for the New York Structural Biology Consortium Microdiffraction beamline at NSLS-II. At the time of construction, IVU18 was a state-of-the-art undulator designed to be operated as a cryogenic permanent-magnet undulator. Due to the more stringent field quality and impedance requirements of the NSLS-II ring, the transition region was redesigned. The control system was also updated to NSLS-II specifications. This paper reports the details of the IVU18 refurbishment activities including additional magnetic measurement and tuning. PMID- 28862614 TI - Simulated sample heating from a nanofocused X-ray beam. AB - Recent developments in synchrotron brilliance and X-ray optics are pushing the flux density in nanofocusing experiments to unprecedented levels, which increases the risk of different types of radiation damage. The effect of X-ray induced sample heating has been investigated using time-resolved and steady-state three dimensional finite-element modelling of representative nanostructures. Simulations of a semiconductor nanowire indicate that the heat generated by X-ray absorption is efficiently transported within the nanowire, and that the temperature becomes homogeneous after about 5 ns. The most important channel for heat loss is conduction to the substrate, where the heat transfer coefficient and the interfacial area are limiting the heat transport. While convective heat transfer to air is significant, the thermal radiation is negligible. The steady state average temperature in the nanowire is 8 K above room temperature at the reference parameters. In the absence of heat transfer to the substrate, the temperature increase at the same flux reaches 55 K in air and far beyond the melting temperature in vacuum. Reducing the size of the X-ray focus at constant flux only increases the maximum temperature marginally. These results suggest that the key strategy for reducing the X-ray induced heating is to improve the heat transfer to the surrounding. PMID- 28862615 TI - Observation of an optical vortex beam from a helical undulator in the XUV region. AB - The observation of an optical vortex beam at 60 nm wavelength, produced as the second-harmonic radiation from a helical undulator, is reported. The helical wavefront of the optical vortex beam was verified by measuring the interference pattern between the vortex beam from a helical undulator and a normal beam from another undulator. Although the interference patterns were slightly blurred owing to the relatively large electron beam emittance, it was possible to observe the interference features thanks to the helical wavefront of the vortex beam. The experimental results were well reproduced by simulation. PMID- 28862616 TI - Estimating the absolute flux distribution for a synchrotron X-ray beam using ionization-chamber measurements with various filters. AB - It is shown that an extensive set of accurate ionization-chamber measurements with a primary polychromatic synchrotron X-ray beam transmitted through various filter combinations/thicknesses can be used to quite effectively estimate the absolute flux distribution. The basic technique is simple but the 'inversion' of the raw data to extract the flux distribution is a fundamentally ill-posed problem. It is demonstrated, using data collected at the Imaging and Medical Beamline (IMBL) of the Australian Synchrotron, that the absolute flux can be quickly and reliably estimated if a suitable choice of filters is made. Results are presented as a function of the magnetic field (from 1.40 to 4.00 T) of the superconducting multi-pole wiggler insertion device installed at IMBL. A non linear least-squares refinement of the data is used to estimate the incident flux distribution and then comparison is made with calculations from the programs SPECTRA, XOP and spec.exe. The technique described is important not only in estimating flux itself but also for a variety of other, derived, X-ray properties such as beam quality, power density and absorbed-dose rate. The applicability of the technique with a monochromatic X-ray beam for which there is significant harmonic contamination is also demonstrated. Whilst absolute results can also be derived in this monochromatic beam case, relative (integrated) flux values are sufficient for our primary aim of establishing reliable determinations of the percentages of the various harmonic components. PMID- 28862617 TI - Mutual optical intensity propagation through non-ideal mirrors. AB - The mutual optical intensity (MOI) model is extended to include the propagation of partially coherent radiation through non-ideal mirrors. The propagation of the MOI from the incident to the exit plane of the mirror is realised by local ray tracing. The effects of figure errors can be expressed as phase shifts obtained by either the phase projection approach or the direct path length method. Using the MOI model, the effects of figure errors are studied for diffraction-limited cases using elliptical cylinder mirrors. Figure errors with low spatial frequencies can vary the intensity distribution, redistribute the local coherence function and distort the wavefront, but have no effect on the global degree of coherence. The MOI model is benchmarked against HYBRID and the multi-electron Synchrotron Radiation Workshop (SRW) code. The results show that the MOI model gives accurate results under different coherence conditions of the beam. Other than intensity profiles, the MOI model can also provide the wavefront and the local coherence function at any location along the beamline. The capability of tuning the trade-off between accuracy and efficiency makes the MOI model an ideal tool for beamline design and optimization. PMID- 28862618 TI - The EIGER detector for low-energy electron microscopy and photoemission electron microscopy. AB - EIGER is a single-photon-counting hybrid pixel detector developed at the Paul Scherrer Institut, Switzerland. It is designed for applications at synchrotron light sources with photon energies above 5 keV. Features of EIGER include a small pixel size (75 um * 75 um), a high frame rate (up to 23 kHz), a small dead-time between frames (down to 3 us) and a dynamic range up to 32-bit. In this article, the use of EIGER as a detector for electrons in low-energy electron microscopy (LEEM) and photoemission electron microscopy (PEEM) is reported. It is demonstrated that, with only a minimal modification to the sensitive part of the detector, EIGER is able to detect electrons emitted or reflected by the sample and accelerated to 8-20 keV. The imaging capabilities are shown to be superior to the standard microchannel plate detector for these types of applications. This is due to the much higher signal-to-noise ratio, better homogeneity and improved dynamic range. In addition, the operation of the EIGER detector is not affected by radiation damage from electrons in the present energy range and guarantees more stable performance over time. To benchmark the detector capabilities, LEEM experiments are performed on selected surfaces and the magnetic and electronic properties of individual iron nanoparticles with sizes ranging from 8 to 22 nm are detected using the PEEM endstation at the Surface/Interface Microscopy (SIM) beamline of the Swiss Light Source. PMID- 28862619 TI - Temperature-dependent thermal properties of Ru/C multilayers. AB - Multilayers made of Ru/C are the most promising candidates when working in the energy region 8-20 keV. The stability of its thermal properties, including thermal expansion and thermal conduction, needs to be considered for monochromator or focusing components. Ru/C multilayers with periodic thicknesses of 3, 4 and 5 nm were investigated in situ by grazing-incidence X-ray reflectometry and diffuse scattering in order to study their thermal expansion characteristics as a function of annealing temperature up to 400 degrees C. The thermal conductivity of multilayers with the same structure was also measured by the transient hot-wire method and compared with bulk values. PMID- 28862620 TI - Characterization of individual stacking faults in a wurtzite GaAs nanowire by nanobeam X-ray diffraction. AB - Coherent X-ray diffraction was used to measure the type, quantity and the relative distances between stacking faults along the growth direction of two individual wurtzite GaAs nanowires grown by metalorganic vapour epitaxy. The presented approach is based on the general property of the Patterson function, which is the autocorrelation of the electron density as well as the Fourier transformation of the diffracted intensity distribution of an object. Partial Patterson functions were extracted from the diffracted intensity measured along the [000?bar{1}] direction in the vicinity of the wurtzite 00?bar{1}?bar{5} Bragg peak. The maxima of the Patterson function encode both the distances between the fault planes and the type of the fault planes with the sensitivity of a single atomic bilayer. The positions of the fault planes are deduced from the positions and shapes of the maxima of the Patterson function and they are in excellent agreement with the positions found with transmission electron microscopy of the same nanowire. PMID- 28862621 TI - Flyscan opportunities in medicine: the case of quantum rattle based on gold quantum dots. AB - The new rapid scan method, Flyscan mode, implemented on the DiffAbs beamline at Synchrotron SOLEIL, allows fast micro-X-ray fluorescence data acquisition. It paves the way for applications in the biomedical field where a large amount of data is needed to generate meaningful information for the clinician. This study presents a complete set of data acquired after injection of gold-cluster-enriched mesoporous silica nanospheres, used as potential theranostic vectors, into rats. While classical X-ray fluorescence investigations (using step-by-step acquisitions) are based on a limited number of samples (approximately one per day at the DiffAbs beamline), the Flyscan mode has enabled gathering information on the interaction of nanometer-scale vectors in different organs such as liver, spleen and kidney at the micrometer scale, for five rats, in only a single five day synchrotron shift. Moreover, numerous X-ray absorption near-edge structure spectra, which are beam-time-consuming taking into account the low concentration of these theranostic vectors, were collected. PMID- 28862622 TI - Confocal depth-resolved fluorescence micro-X-ray absorption spectroscopy for the study of cultural heritage materials: a new mobile endstation at the Beijing Synchrotron Radiation Facility. AB - A confocal fluorescence endstation for depth-resolved micro-X-ray absorption spectroscopy is described. A polycapillary half-lens defines the incident beam path and a second polycapillary half-lens at 90 degrees defines the probe sample volume. An automatic alignment program based on an evolutionary algorithm is employed to make the alignment procedure efficient. This depth-resolved system was examined on a general X-ray absorption spectroscopy (XAS) beamline at the Beijing Synchrotron Radiation Facility. Sacrificial red glaze (AD 1368-1644) china was studied to show the capability of the instrument. As a mobile endstation to be applied on multiple beamlines, the confocal system can improve the function and flexibility of general XAS beamlines, and extend their capabilities to a wider user community. PMID- 28862623 TI - In operando quantitation of Li concentration for a commercial Li-ion rechargeable battery using high-energy X-ray Compton scattering. AB - Compton scattering is one of the most promising probes for quantitating Li under in operando conditions, since high-energy X-rays, which have high penetration power, are used as the incident beam and the Compton-scattered energy spectrum has specific line-shapes for each element. An in operando quantitation method to determine the Li composition in electrodes has been developed by using line-shape (S-parameter) analysis of the Compton-scattered energy spectrum. In this study, S parameter analysis has been applied to a commercial coin cell Li-ion rechargeable battery and the variation of the S-parameters during the charge/discharge cycle at the positive and negative electrodes has been obtained. By using calibration curves for Li composition in the electrodes, the change in Li composition of the positive and negative electrodes has been determined using the S-parameters simultaneously. PMID- 28862624 TI - Local structure around In atoms in coherently grown m-plane InGaN film. AB - The local structure around In atoms in an m-plane In0.06Ga0.94N film coherently grown on a freestanding m-plane GaN substrate was investigated by polarization dependent X-ray absorption fine-structure. A step-by-step fitting procedure was proposed for the m-plane wurtzite structure. The interatomic distance for the first nearest neighbour In-N atomic pairs was almost isotropic. For the second nearest In-Ga pairs, the interatomic distances along the m- and a-axes were longer and shorter, respectively, than that in strain-free virtual crystals as expected for the m-plane compressive strain. In contrast, the In-Ga interatomic distance in the c-direction was elongated in spite of the compressive strain, which was explained in terms of the anisotropic atomic structure on the m-plane. The local strain in the m-plane film was more relaxed than that in coherently grown c-plane single quantum wells. A few In atoms were atomically localized in all directions, and thus localized excitonic emission is expected as in the case of c-plane InGaN. PMID- 28862625 TI - Investigation of nanoparticulate silicon as printed layers using scanning electron microscopy, transmission electron microscopy, X-ray absorption spectroscopy and X-ray photoelectron spectroscopy. AB - The presence of native oxide on the surface of silicon nanoparticles is known to inhibit charge transport on the surfaces. Scanning electron microscopy (SEM) studies reveal that the particles in the printed silicon network have a wide range of sizes and shapes. High-resolution transmission electron microscopy reveals that the particle surfaces have mainly the (111)- and (100)-oriented planes which stabilizes against further oxidation of the particles. X-ray absorption spectroscopy (XANES) and X-ray photoelectron spectroscopy (XPS) measurements at the O 1s-edge have been utilized to study the oxidation and local atomic structure of printed layers of silicon nanoparticles which were milled for different times. XANES results reveal the presence of the +4 (SiO2) oxidation state which tends towards the +2 (SiO) state for higher milling times. Si 2p XPS results indicate that the surfaces of the silicon nanoparticles in the printed layers are only partially oxidized and that all three sub-oxide, +1 (Si2O), +2 (SiO) and +3 (Si2O3), states are present. The analysis of the change in the sub oxide peaks of the silicon nanoparticles shows the dominance of the +4 state only for lower milling times. PMID- 28862626 TI - A protocol for searching the most probable phase-retrieved maps in coherent X-ray diffraction imaging by exploiting the relationship between convergence of the retrieved phase and success of calculation. AB - Coherent X-ray diffraction imaging (CXDI) is a technique for visualizing the structures of non-crystalline particles with size in the submicrometer to micrometer range in material sciences and biology. In the structural analysis of CXDI, the electron density map of a specimen particle projected along the direction of the incident X-rays can be reconstructed only from the diffraction pattern by using phase-retrieval (PR) algorithms. However, in practice, the reconstruction, relying entirely on the computational procedure, sometimes fails because diffraction patterns miss the data in small-angle regions owing to the beam stop and saturation of the detector pixels, and are modified by Poisson noise in X-ray detection. To date, X-ray free-electron lasers have allowed us to collect a large number of diffraction patterns within a short period of time. Therefore, the reconstruction of correct electron density maps is the bottleneck for efficiently conducting structure analyses of non-crystalline particles. To automatically address the correctness of retrieved electron density maps, a data analysis protocol to extract the most probable electron density maps from a set of maps retrieved from 1000 different random seeds for a single diffraction pattern is proposed. Through monitoring the variations of the phase values during PR calculations, the tendency for the PR calculations to succeed when the retrieved phase sets converged on a certain value was found. On the other hand, if the phase set was in persistent variation, the PR calculation tended to fail to yield the correct electron density map. To quantify this tendency, here a figure of merit for the variation of the phase values during PR calculation is introduced. In addition, a PR protocol to evaluate the similarity between a map of the highest figure of merit and other independently reconstructed maps is proposed. The protocol is implemented and practically examined in the structure analyses for diffraction patterns from aggregates of gold colloidal particles. Furthermore, the feasibility of the protocol in the structure analysis of organelles from biological cells is examined. PMID- 28862627 TI - Analysis of the microvascular morphology and hemodynamics of breast cancer in mice using SPring-8 synchrotron radiation microangiography. AB - Tumor vasculature is characterized by morphological and functional abnormalities. However, analysis of the dynamics in blood flow is still challenging because of limited spatial and temporal resolution. Synchrotron radiation (SR) microangiography above the K-edge of the iodine contrast agent can provide high contrast imaging of microvessels in time orders of milliseconds. In this study, mice bearing the human breast cancer cell lines MDAMB231 and NOTCH4 overexpression in MDAMB231 (MDAMB231NOTCH4+) and normal mice were assessed using SR microangiography. NOTCH is transmembrane protein that has crucial roles for vasculogenesis, angiogenesis and tumorigenesis, and NOTCH4 is considered to be a cause of high-flow arteriovenous shunting. A subgroup of mice received intravenous eribulin treatment, which is known to improve intratumor core circulation (MDAMB231_eribulin). Microvessel branches from approximately 200 um to less than 20 um in diameter were observed within the same visual field. The mean transition time (MTT) was measured as a dynamic parameter and quantitative analysis was performed. MTT in MDAMB231 was longer than that in normal tissue, and MDAMB231NOTCH4+ showed shorter MTT [5.0 +/- 1.4 s, 3.6 +/- 1.0 s and 3.6 +/- 1.1 s (mean +/- standard deviation), respectively]. After treatment, average MTT was correlated to tumor volume (r = 0.999) in MDAMB231_eribulin, while in contrast there was no correlation in MDAMB231 (r = -0.026). These changes in MTT profile are considered to be driven by the modulation of intratumoral circulation dynamics. These results demonstrate that a SR microangiography approach enables quantitative analysis of morphological and dynamic characteristics of tumor vasculature in vivo. Further studies will reveal new findings concerning vessel function in tumors. PMID- 28862628 TI - Micro-beam Laue alignment of multi-reflection Bragg coherent diffraction imaging measurements. AB - Multi-reflection Bragg coherent diffraction imaging has the potential to allow three-dimensional (3D) resolved measurements of the full lattice strain tensor in specific micro-crystals. Until now such measurements were hampered by the need for laborious, time-intensive alignment procedures. Here a different approach is demonstrated, using micro-beam Laue X-ray diffraction to first determine the lattice orientation of the micro-crystal. This information is then used to rapidly align coherent diffraction measurements of three or more reflections from the crystal. Based on these, 3D strain and stress fields in the crystal are successfully determined. This approach is demonstrated on a focused ion beam milled micro-crystal from which six reflections could be measured. Since information from more than three independent reflections is available, the reliability of the phases retrieved from the coherent diffraction data can be assessed. Our results show that rapid, reliable 3D coherent diffraction measurements of the full lattice strain tensor in specific micro-crystals are now feasible and can be successfully carried out even in heavily distorted samples. PMID- 28862629 TI - Characterization of enamel caries lesions in rat molars using synchrotron X-ray microtomography. AB - Dental caries is a ubiquitous infectious disease with a nearly 100% lifetime prevalence. Rodent caries models are widely used to investigate the etiology, progression and potential prevention or treatment of the disease. To explore the suitability of these models for deeper investigations of intact surface zones during enamel caries, the structures of early-stage carious lesions in rats were characterized and compared with previous reports on white spot enamel lesions in humans. Synchrotron X-ray microcomputed tomography non-destructively mapped demineralization in carious rat molar specimens across a range of caries severity, identifying 52 lesions across the 30 teeth imaged. Of these lesions, 13 were shown to have intact surface zones. Depth profiles of fractional mineral density were qualitatively similar to lesions in human teeth. However, the thickness of the surface zone in the rat model ranges from 10 to 58 um, and is therefore significantly thinner than in human enamel. These results indicate that a fraction of lesions in rat caries possess an intact surface zone and are qualitatively similar to human lesions at the micrometer scale. This suggests that rat caries models may be a suitable analog through which to investigate the structure of surface zone enamel and its role during dental caries. PMID- 28862630 TI - Insight into 3D micro-CT data: exploring segmentation algorithms through performance metrics. AB - Three-dimensional (3D) micro-tomography (u-CT) has proven to be an important imaging modality in industry and scientific domains. Understanding the properties of material structure and behavior has produced many scientific advances. An important component of the 3D u-CT pipeline is image partitioning (or image segmentation), a step that is used to separate various phases or components in an image. Image partitioning schemes require specific rules for different scientific fields, but a common strategy consists of devising metrics to quantify performance and accuracy. The present article proposes a set of protocols to systematically analyze and compare the results of unsupervised classification methods used for segmentation of synchrotron-based data. The proposed dataflow for Materials Segmentation and Metrics (MSM) provides 3D micro-tomography image segmentation algorithms, such as statistical region merging (SRM), k-means algorithm and parallel Markov random field (PMRF), while offering different metrics to evaluate segmentation quality, confidence and conformity with standards. Both experimental and synthetic data are assessed, illustrating quantitative results through the MSM dashboard, which can return sample information such as media porosity and permeability. The main contributions of this work are: (i) to deliver tools to improve material design and quality control; (ii) to provide datasets for benchmarking and reproducibility; (iii) to yield good practices in the absence of standards or ground-truth for ceramic composite analysis. PMID- 28862631 TI - Strategies for high-throughput focused-beam ptychography. AB - X-ray ptychography is being utilized for a wide range of imaging experiments with a resolution beyond the limit of the X-ray optics used. Introducing a parameter for the ptychographic resolution gain Gp (the ratio of the beam size over the achieved pixel size in the reconstructed image), strategies for data sampling and for increasing imaging throughput when the specimen is at the focus of an X-ray beam are considered. The tradeoffs between large and small illumination spots are examined. PMID- 28862632 TI - Non-uniform nanosecond gate-delay of hybrid pixel detectors. AB - A simple experiment to characterize the gating properties of X-ray area detectors using pulsed X-ray sources is presented. For a number of time-resolved experiments the gating uniformity of area detectors is important. Relative gating delays between individual modules and readout chips of PILATUS2 series area X-ray detectors have been observed. For three modules of a PILATUS 300K-W unit the maximum gating offset between the modules is found to be as large as 30 ns. On average, the first photosensor module is found to be triggered 15 ns and 30 ns later than the second and the third modules, respectively. PMID- 28862633 TI - Nanosecond pump-probe device for time-resolved serial femtosecond crystallography developed at SACLA. AB - X-ray free-electron lasers (XFELs) have opened new opportunities for time resolved X-ray crystallography. Here a nanosecond optical-pump XFEL-probe device developed for time-resolved serial femtosecond crystallography (TR-SFX) studies of photo-induced reactions in proteins at the SPring-8 Angstrom Compact free electron LAser (SACLA) is reported. The optical-fiber-based system is a good choice for a quick setup in a limited beam time and allows pump illumination from two directions to achieve high excitation efficiency of protein microcrystals. Two types of injectors are used: one for extruding highly viscous samples such as lipidic cubic phase (LCP) and the other for pulsed liquid droplets. Under standard sample flow conditions from the viscous-sample injector, delay times from nanoseconds to tens of milliseconds are accessible, typical time scales required to study large protein conformational changes. A first demonstration of a TR-SFX experiment on bacteriorhodopsin in bicelle using a setup with a droplet type injector is also presented. PMID- 28862634 TI - Artifact reduction in the CSPAD detectors used for LCLS experiments. AB - The existence of noise and column-wise artifacts in the CSPAD-140K detector and in a module of the CSPAD-2.3M large camera, respectively, is reported for the L730 and L867 experiments performed at the CXI Instrument at the Linac Coherent Light Source (LCLS), in low-flux and low signal-to-noise ratio regime. Possible remedies are discussed and an additional step in the preprocessing of data is introduced, which consists of performing a median subtraction along the columns of the detector modules. Thus, we reduce the overall variation in the photon count distribution, lowering the mean false-positive photon detection rate by about 4% (from 5.57 * 10-5 to 5.32 * 10-5 photon counts pixel-1 frame-1 in L867, cxi86715) and 7% (from 1.70 * 10-3 to 1.58 * 10-3 photon counts pixel-1 frame-1 in L730, cxi73013), and the standard deviation in false-positive photon count per shot by 15% and 35%, while not making our average photon detection threshold more stringent. Such improvements in detector noise reduction and artifact removal constitute a step forward in the development of flash X-ray imaging techniques for high-resolution, low-signal and in serial nano-crystallography experiments at X-ray free-electron laser facilities. PMID- 28862635 TI - Atomic pair distribution function at the Brazilian Synchrotron Light Laboratory: application to the Pb1-xLaxZr0.40Ti0.60O3 ferroelectric system. AB - This work reports the setting up of the X-ray diffraction and spectroscopy beamline at the Brazilian Synchrotron Light Laboratory for performing total scattering experiments to be analyzed by atomic pair distribution function (PDF) studies. The results of a PDF refinement for Al2O3 standard are presented and compared with data acquired at a beamline of the Advanced Photon Source, where it is common to perform this type of experiment. A preliminary characterization of the Pb1-xLaxZr0.40Ti0.60O3 ferroelectric system, with x = 0.11, 0.12 and 0.15, is also shown. PMID- 28862636 TI - WIFIP: a web-based user interface for automated synchrotron beamlines. AB - The beamline control software, through the associated graphical user interface (GUI), is the user access point to the experiment, interacting with synchrotron beamline components and providing automated routines. FIP, the French beamline for the Investigation of Proteins, is a highly automatized macromolecular crystallography (MX) beamline at the European Synchrotron Radiation Facility. On such a beamline, a significant number of users choose to control their experiment remotely. This is often performed with a limited bandwidth and from a large choice of computers and operating systems. Furthermore, this has to be possible in a rapidly evolving experimental environment, where new developments have to be easily integrated. To face these challenges, a light, platform-independent, control software and associated GUI are required. Here, WIFIP, a web-based user interface developed at FIP, is described. Further than being the present FIP control interface, WIFIP is also a proof of concept for future MX control software. PMID- 28862637 TI - In situ beamline analysis and correction of active optics. Erratum. AB - A correction to one of the equations in the paper by Sutter et al. (2012). [J. Synchrotron Rad. 19, 960-968] is made. PMID- 28862639 TI - Oligodendroglia: metabolic supporters of neurons. AB - Oligodendrocytes are glial cells that populate the entire CNS after they have differentiated from oligodendrocyte progenitor cells. From birth onward, oligodendrocytes initiate wrapping of neuronal axons with a multilamellar lipid structure called myelin. Apart from their well-established function in action potential propagation, more recent data indicate that oligodendrocytes are essential for providing metabolic support to neurons. Oligodendrocytes transfer energy metabolites to neurons through cytoplasmic "myelinic" channels and monocarboxylate transporters, which allow for the fast delivery of short-carbon chain energy metabolites like pyruvate and lactate to neurons. These substrates are metabolized and contribute to ATP synthesis in neurons. This Review will discuss our current understanding of this metabolic supportive function of oligodendrocytes and its potential impact in human neurodegenerative disease and related animal models. PMID- 28862638 TI - Microglia in Alzheimer's disease. AB - Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an "activated state"). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer's disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed. PMID- 28862641 TI - The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes. PMID- 28862642 TI - Isolated polycystic liver disease genes define effectors of polycystin-1 function. AB - Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases. PMID- 28862640 TI - Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. AB - Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems. PMID- 28862643 TI - A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. PMID- 28862644 TI - Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM). AB - Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis. We list other attractive potential targets for CAR T cell therapy for MPM, and discuss augmentation strategies of CAR T cell therapy with other forms of immunotherapy in this disease. PMID- 28862645 TI - A Sub-30 mpH Resolution Thin Film Transistor-Based Nanoribbon Biosensing Platform. AB - We present a complete biosensing system that comprises a Thin Film Transistor (TFT)-based nanoribbon biosensor and a low noise, high-performance bioinstrumentation platform, capable of detecting sub-30 mpH unit changes, validated by an enzymatic biochemical reaction. The nanoribbon biosensor was fabricated top-down with an ultra-thin (15 nm) polysilicon semiconducting channel that offers excellent sensitivity to surface potential changes. The sensor is coupled to an integrated circuit (IC), which combines dual switched-capacitor integrators with high precision analog-to-digital converters (ADCs). Throughout this work, we employed both conventional pH buffer measurements as well as urea urease enzymatic reactions for benchmarking the overall performance of the system. The measured results from the urea-urease reaction demonstrate that the system can detect urea in concentrations as low as 25 MUM, which translates to a change of 27 mpH, according to our initial pH characterisation measurements. The attained accuracy and resolution of our system as well as its low-cost manufacturability, high processing speed and portability make it a competitive solution for applications requiring rapid and accurate results at remote locations; a necessity for Point-of-Care (POC) diagnostic platforms. PMID- 28862646 TI - Locomotion Inhibition of Cimex lectularius L. Following Topical, Sublethal Dose Application of the Chitin Synthesis Inhibitor Lufenuron. AB - To date, few studies have evaluated chitin synthesis inhibitors against bed bugs, although they would provide an alternative mode of action to circumvent insecticide resistance. Acute and sublethal effects of lufenuron were evaluated against two strains of the common bed bug. Combined acute and sublethal effects were used to calculate effective doses. The dose that was effective against 50% of Harlan strain bed bugs was 0.0081% (w/v), and was much higher against Bradenton strain bed bugs (1.11% w/v). Sublethal doses were chosen to determine the effect that leg abnormalities had on pulling force. Both Harlan and Bradenton strain bed bugs had significantly lower locomotion ability (p < 0.0001) following topical application of lufenuron. The observed sublethal effects that limit locomotion could prevent bed bugs from moving within a domicile and taking a blood meal, subsequently reducing a bed bug population over time. PMID- 28862647 TI - Bio-Corrosion of Magnesium Alloys for Orthopaedic Applications. AB - Three Mg alloys, Mg-1.34% Ca-3% Zn (MCZ), Mg-1.34% Ca-3% Zn-0.2% Sr (MCZS), and Mg-2% Sr (MS), were examined to understand their bio-corrosion behavior. Electrochemical impedance spectroscopy and polarization scans were performed after 6 days of immersion in cell culture medium, and ion release and changes in media pH were tracked over a 28 day time period. Scanning electron microscopy (SEM) of alloy microstructure was performed to help interpret the results of the electrochemical testing. Results indicate that corrosion resistance of the alloys is as follows: MCZ > MCZS > MS. PMID- 28862648 TI - Bioactive Steroids with Methyl Ester Group in the Side Chain from a Reef Soft Coral Sinularia brassica Cultured in a Tank. AB - A continuing chemical investigation of the ethyl acetate (EtOAc) extract of a reef soft coral Sinularia brassica, which was cultured in a tank, afforded four new steroids with methyl ester groups, sinubrasones A-D (1-4) for the first time. In particular, 1 possesses a beta-D-xylopyranose. The structures of the new compounds were elucidated on the basis of spectroscopic analyses. The cytotoxicities of compounds 1-4 against the proliferation of a limited panel of cancer cell lines were assayed. The anti-inflammatory activities of these new compounds 1-4 were also evaluated by measuring their ability to suppress superoxide anion generation and elastase release in N-formyl-methionyl-leucyl phenylalanine/cytochalasin B (fMLP/CB)-induced human neutrophils. Compounds 2 and 3 were shown to exhibit significant cytotoxicity, and compounds 3 and 4 were also found to display attracting anti-inflammatory activities. PMID- 28862650 TI - Pharmacokinetics of Jaspine B and Enhancement of Intestinal Absorption of Jaspine B in the Presence of Bile Acid in Rats. AB - We aimed to investigate the pharmacokinetics and the underlying mechanisms of the intestinal absorption, distribution, metabolism, and excretion of Jaspine B in rats. The oral bioavailability of Jaspine B was 6.2%, but it decreased to 1.6% in bile-depleted rats and increased to 41.2% (normal) and 23.5% (bile-depleted) with taurocholate supplementation (60 mg/kg). Consistent with the increased absorption in the presence of bile salts, rat intestinal permeability of Jaspine B also increased in the presence of 10 mM taurocholate or 20% bile. Further studies demonstrated that the enhanced intestinal permeability with bile salts was due to increased lipophilicity and decreased membrane integrity. Jaspine B was designated as a highly tissue-distributed compound, because it showed large tissue to plasma ratios in the brain, kidney, heart, and spleen. Moreover, the recovery of Jaspine B from the feces and urine after an intravenous administration was about 6.3%, suggesting a substantial metabolism of Jaspine B. Consistent with this observation, 80% of the administered Jaspine B was degraded after 1 h incubation with rat liver microsomes. In conclusion, the facilitated intestinal permeability in the presence of bile salts could significantly increase the bioavailability of Jaspine B and could lead to the development of oral formulations of Jaspine B with bile salts. Moreover, the highly distributed features of Jaspine B in the brain, kidney, heart, and spleen should be carefully considered in the therapeutic effect and toxicity of this compound. PMID- 28862651 TI - 3D Microstructure Inhibits Mesenchymal Stem Cells Homing to the Site of Liver Cancer Cells on a Microchip. AB - The cell microenvironment consists of multiple types of biophysical and biochemical factors, and represents a complex integrated system that is variable in both time and space. Studies show that changes in biochemical and biophysical factors in cell microenvironments result in significant changes in cellular forms and functions, especially for stem cells. Mesenchymal stem cells (MSCs) are derived from adult stem cells of the mesoderm and play an important role in tissue engineering, regenerative medicine and even cancer therapy. Furthermore, it is found that MSCs can interact with multiple types of tumor cells. The interaction is reflected as two totally different aspects. The negative aspect is that MSCs manifest as tumor-associated fibroblasts and could induce migration of cancer cells and promote tumor formation. On the other hand, MSCs can home to sites of the tumor microenvironment, directionally migrate toward tumor cells and cause tumor cell apoptosis. In this study, we designed and made a simple microfluidic chip for cell co-culture, and studied stem cell homing behavior in the interaction between MSCs and liver cancer cells. Moreover, by etching a three dimensional microstructure on the base and adding transforming growth factor-beta (TGF-beta) in the co-culture environment, we studied the impact of biophysical and biochemical factors on stem cell homing behavior, and the causes of such impact. PMID- 28862652 TI - The Effect of Concentration Factor on Membrane Fouling. AB - Bench-scale systems are often used to evaluate pretreatment methods and operational conditions that can be applied in full-scale ultrafiltration (UF) systems. However, the membrane packing density is substantially different in bench and full-scale systems. Differences in concentration factor (CF) at the solution-membrane interface as a result of packing density may impact the mass transfer and fouling rate and the applicability of bench-scale systems. The present study compared membrane resistance when considering raw water (CF = 1) and reject water (also commonly referred to as concentrate water) (CF > 1) as feed in UF systems operated in deposition (dead-end) mode. A positive relationship was observed between the concentration of the organic matter in the solution being filtered and resistance. Bench-scale trials conducted with CF = 1 water were more representative of full-scale operation than trials conducted with elevated CFs when considering membrane resistance and permeate quality. As such, the results of this study indicate that the use of the same feed water as used at full-scale (CF = 1) is appropriate to evaluate fouling in UF systems operated in deposition mode. PMID- 28862649 TI - Immune Evasion Strategies during Chronic Hepatitis B and C Virus Infection. AB - Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are a major global healthcare problem with more than 240 million and 70 million infected, respectively. Both viruses persist within the liver and result in progressive liver disease, resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma. Strikingly, this pathogenesis is largely driven by immune responses, unable to clear an established infection, rather than by the viral pathogens themselves. Even though disease progression is very similar in both infections, HBV and HCV have evolved distinct mechanisms, by which they ensure persistence within the host. Whereas HCV utilizes a cloak-and-dagger approach, disguising itself as a lipid-like particle and immediately crippling essential pattern recognition pathways, HBV has long been considered a "stealth" virus, due to the complete absence of innate immune responses during infection. Recent developments and access to improved model systems, however, revealed that even though it is among the smallest human-tropic viruses, HBV may, in addition to evading host responses, employ subtle immune evasion mechanisms directed at ensuring viral persistence in the absence of host responses. In this review, we compare the different strategies of both viruses to ensure viral persistence by actively interfering with viral recognition and innate immune responses. PMID- 28862653 TI - The Starvation Symptom Inventory: Development and Psychometric Properties. AB - Background: Starvation symptoms are common in patients with anorexia nervosa, and according to the transdiagnostic cognitive behavioural theory for eating disorders, they contribute to maintaining the eating disorder psychopathology. The aim of this study was therefore to describe the design and validation of the Starvation Symptoms Inventory (SSI); a self-report questionnaire that examines the symptoms of starvation in underweight patients with eating disorders. Methods: 150 female patients with anorexia nervosa were recruited, as well as 341 healthy control subjects, 30 not-underweight patients with an eating disorder, and 15 patients with bipolar depressive episodes. The 150 patients completed the Eating Disorder Examination Questionnaire and the Brief Symptom Inventory. All participants rated their starvation symptoms on a continuous Likert-type scale (0 6), and reported the number of days in which they had experienced them in the previous 28 days. Results: Principal component analysis identified a single factor, 15-item scale, which demonstrated good internal consistency (alpha = 0.91) and test-retest reliability (r = 0.90). The SSI global score was significantly correlated with eating disorder and general psychopathology, demonstrating good convergent validity. SSI scores were significantly higher in the anorexia nervosa sample than in the healthy control, not-underweight eating disorder and bipolar depressive episode samples. Conclusions: These findings suggest that the SSI is a valid self-report questionnaire that may provide important clinical information regarding symptoms of starvation in patients with anorexia nervosa. PMID- 28862655 TI - Characterization and Discrimination of Gram-Positive Bacteria Using Raman Spectroscopy with the Aid of Principal Component Analysis. AB - Raman scattering and its particular effect, surface-enhanced Raman scattering (SERS), are whole-organism fingerprinting spectroscopic techniques that gain more and more popularity in bacterial detection. In this work, two relevant Gram positive bacteria species, Lactobacillus casei (L. casei) and Listeria monocytogenes (L. monocytogenes) were characterized based on their Raman and SERS spectral fingerprints. The SERS spectra were used to identify the biochemical structures of the bacterial cell wall. Two synthesis methods of the SERS-active nanomaterials were used and the recorded spectra were analyzed. L. casei and L. monocytogenes were successfully discriminated by applying Principal Component Analysis (PCA) to their specific spectral data. PMID- 28862657 TI - Personalized Computational Models as Biomarkers. AB - Biomarkers are cornerstones of clinical medicine, and personalized medicine, in particular, is highly dependent on reliable and highly accurate biomarkers for individualized diagnosis and treatment choice. Modern omics technologies, such as genome sequencing, allow molecular profiling of individual patients with unprecedented resolution, but biomarkers based on these technologies often lack the dynamic element to follow the progression of a disease or response to therapy. Here, we discuss computational models as a new conceptual approach to biomarker discovery and design. Being able to integrate a large amount of information, including dynamic information, computational models can simulate disease evolution and response to therapy with high sensitivity and specificity. By populating these models with personal data, they can be highly individualized and will provide a powerful new tool in the armory of personalized medicine. PMID- 28862654 TI - Antioxidant Therapeutic Strategies for Cardiovascular Conditions Associated with Oxidative Stress. AB - Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability to scavenge these ROS by endogenous antioxidant systems, where ROS overwhelms the antioxidant capacity. Excessive presence of ROS results in irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases related to hypoxia, cardiotoxicity and ischemia-reperfusion. Here, we describe the participation of OS in the pathophysiology of cardiovascular conditions such as myocardial infarction, anthracycline cardiotoxicity and congenital heart disease. This review focuses on the different clinical events where redox factors and OS are related to cardiovascular pathophysiology, giving to support for novel pharmacological therapies such as omega 3 fatty acids, non-selective betablockers and microRNAs. PMID- 28862656 TI - Bromopropane Compounds Increase the Stemness of Colorectal Cancer Cells. AB - Bromopropane (BP) compounds, including 1-bromopropane, 2-bromopropane, and 1,2 dibromopropane, are used in industry for various purposes, and their deleterious effects on human health are becoming known. In this study, we examined the effects of BP compounds on the stemness of colorectal cancer cells. At low, non cytotoxic concentrations, BP compounds significantly increased spheroid formation in CSC221, DLD1, Caco2, and HT29 cells. In addition, the levels of cancer stem cell markers, such as aldehyde dehydrogenase-1, cluster of differentiation 133 (CD133), CD44, Lgr5, Musashi-1, Ephrin receptor, and Bmi-1 increased after exposure to BP compounds. BP compounds increased the transcriptional activity of the TOPflash and glioma-associated oncogene homolog zinc finger protein (Gli) promoters in reporter assays and increased the expression of Gli-1, Gli-2, Smoothened (SMO), and beta-catenin by RT-PCR. These results demonstrate for the first time that BP compounds have the potential to promote cancer stemness. PMID- 28862658 TI - Multi-Mode GF-3 Satellite Image Geometric Accuracy Verification Using the RPC Model. AB - The GaoFen-3 (GF-3) satellite is the first C-band multi-polarization synthetic aperture radar (SAR) imaging satellite with a resolution up to 1 m in China. It is also the only SAR satellite of the High-Resolution Earth Observation System designed for civilian use. There are 12 different imaging models to meet the needs of different industry users. However, to use SAR satellite images for related applications, they must possess high geometric accuracy. In order to verify the geometric accuracy achieved by the different modes of GF-3 images, we analyze the SAR geometric error source and perform geometric correction tests based on the RPC model with and without ground control points (GCPs) for five imaging modes. These include the spotlight (SL), ultra-fine strip (UFS), Fine Strip I (FSI), Full polarized Strip I (QPSI), and standard strip (SS) modes. Experimental results show that the check point residuals are large and consistent without GCPs, but the root mean square error of the independent checkpoints for the case of four corner control points is better than 1.5 pixels, achieving a similar level of geometric positioning accuracy to that of international satellites. We conclude that the GF-3 satellite can be used for high-accuracy geometric processing and related industry applications. PMID- 28862660 TI - Dynamic Response of Graphitic Flakes in Nematic Liquid Crystals: Confinement and Host Effect. AB - Electric field-induced reorientation of suspended graphitic (GP) flakes and its relaxation back to the original state in a nematic liquid crystal (NLC) host are of interest not only in academia, but also in industrial applications, such as polarizer-free and optical film-free displays, and electro-optic light modulators. As the phenomenon has been demonstrated by thorough observation, the detailed study of the physical properties of the host NLC (the magnitude of dielectric anisotropy, elastic constants, and rotational viscosity), the size of the GP flakes, and cell thickness, are urgently required to be explored and investigated. Here, we demonstrate that the response time of GP flakes reorientation associated with an NLC host can be effectively enhanced by controlling the physical properties. In a vertical field-on state, higher dielectric anisotropy and higher elasticity of NLC give rise to quicker reorientation of the GP flakes (switching from planar to vertical alignment) due to the field-induced coupling effect of interfacial Maxwell-Wagner polarization and NLC reorientation. In a field off-state, lower rotational viscosity of NLC and lower cell thickness can help to reduce the decay time of GP flakes reoriented from vertical to planar alignment. This is mainly attributed to strong coupling between GP flakes and NLC originating from the strong pi-pi interaction between benzene rings in the honeycomb-like graphene structure and in NLC molecules. The high-uniformity of reoriented GP flakes exhibits a possibility of new light modulation with a relatively faster response time in the switching process and, thus, it can show potential application in field-induced memory and modulation devices. PMID- 28862659 TI - Fever in Children: Pearls and Pitfalls. AB - Fever in children is a common concern for parents and one of the most frequent presenting complaints in emergency department visits, often involving non pediatric emergency physicians. Although the incidence of serious infections has decreased after the introduction of conjugate vaccines, fever remains a major cause of laboratory investigation and hospital admissions. Furthermore, antipyretics are the most common medications administered to children. We review the epidemiology and measurement of fever, the meaning of fever and associated clinical signs in children of different ages and under special conditions, including fever in children with cognitive impairment, recurrent fevers, and fever of unknown origin. While the majority of febrile children have mild, self resolving viral illness, a minority may be at risk of life-threatening infections. Clinical assessment differs markedly from adult patients. Hands-off evaluation is paramount for a correct evaluation of breathing, circulation and level of interaction. Laboratory markers and clinical prediction rules provide limited help in identifying children at risk for serious infections; however, clinical examination, prudent utilization of laboratory tests, and post-discharge guidance ("safety netting") remain the cornerstone of safe management of febrile children. PMID- 28862661 TI - The Effect of Taichi Practice on Attenuating Bone Mineral Density Loss: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Objective: The purpose of this study was to determine the effects of practicing Taichi on attenuating bone mineral density (BMD) loss. Methods: Both electronic and manual searches were performed for randomized controlled trials (RCTs) examining Taichi for bone health. Two review authors independently performed study selection and data extraction according to inclusion criteria. A third party (Lin Luo) emerged to discuss with the two review authors and resolve a disagreement. Results: Twenty RCTs were found to meet the inclusion criteria and used for meta-analysis with a total effective sample of 1604. The aggregated results from this systematic review have shown significant benefits in favour of Taichi on BMD at lumbar spine (Standard Mean Difference, SMD) = 0.29; 95% CI 0.15 to 0.43; p < 0.0001), femur neck (SMD = 0.56; 95% CI 0.38 to 0.75; p < 0.00001), femur trochanter (SMD = 0.04; 95% CI 0.01 to 0.07; p = 0.007), total hip BMD (SMD = 0.46; 95% CI 0.16 to 0.76; p = 0.003). Conclusions: The aggregated results from this systematic review suggests that Taichi is effective on attenuating BMD loss at the regions of lumbar spine and proximal femur neck in special populations (e.g., older adults, perimenopausal and postmenopausal women, people with osteoarthritis, and cancer survivors). Researchers should further examine the effect of Taichi on the proximal femur trochanter and total hip so that a more definitive claim can be made regarding the beneficial effects for attenuating BMD loss in these musculoskeletal regions. PMID- 28862662 TI - SNORAP: A Device for the Correction of Impaired Sleep Health by Using Tactile Stimulation for Individuals with Mild and Moderate Sleep Disordered Breathing. AB - Sleep physiology and sleep hygiene play significant roles in maintaining the daily lives of individuals given that sleep is an important physiological need to protect the functions of the human brain. Sleep disordered breathing (SDB) is an important disease that disturbs this need. Snoring and Obstructive Sleep Apnea Syndrome (OSAS) are clinical conditions that affect all body organs and systems that intermittently, repeatedly, with at least 10 s or more breathing stops that decrease throughout the night and disturb sleep integrity. The aim of this study was to produce a new device for the treatment of patients especially with position and rapid eye movement (REM)-dependent mild and moderate OSAS. For this purpose, the main components of the device (the microphone (snore sensor), the heart rate sensor, and the vibration motor, which we named SNORAP) were applied to five volunteer patients (male, mean age: 33.2, body mass index mean: 29.3). After receiving the sound in real time with the microphone, the snoring sound was detected by using the Audio Fingerprint method with a success rate of 98.9%. According to the results obtained, the severity and the number of the snoring of the patients using SNORAP were found to be significantly lower than in the experimental conditions in the apnea hypopnea index (AHI), apnea index, hypopnea index, in supine position's AHI, and REM position's AHI before using SNORAP (Paired Sample Test, p < 0.05). REM sleep duration and nocturnal oxygen saturation were significantly higher when compared to the group not using the SNORAP (Paired Sample Test, p < 0.05). PMID- 28862663 TI - Novelty Detection Classifiers in Weed Mapping: Silybum marianum Detection on UAV Multispectral Images. AB - In the present study, the detection and mapping of Silybum marianum (L.) Gaertn. weed using novelty detection classifiers is reported. A multispectral camera (green-red-NIR) on board a fixed wing unmanned aerial vehicle (UAV) was employed for obtaining high-resolution images. Four novelty detection classifiers were used to identify S. marianum between other vegetation in a field. The classifiers were One Class Support Vector Machine (OC-SVM), One Class Self-Organizing Maps (OC-SOM), Autoencoders and One Class Principal Component Analysis (OC-PCA). As input features to the novelty detection classifiers, the three spectral bands and texture were used. The S. marianum identification accuracy using OC-SVM reached an overall accuracy of 96%. The results show the feasibility of effective S. marianum mapping by means of novelty detection classifiers acting on multispectral UAV imagery. PMID- 28862665 TI - Wearable Devices for Classification of Inadequate Posture at Work Using Neural Networks. AB - Inadequate postures adopted by an operator at work are among the most important risk factors in Work-related Musculoskeletal Disorders (WMSDs). Although several studies have focused on inadequate posture, there is limited information on its identification in a work context. The aim of this study is to automatically differentiate between adequate and inadequate postures using two wearable devices (helmet and instrumented insole) with an inertial measurement unit (IMU) and force sensors. From the force sensors located inside the insole, the center of pressure (COP) is computed since it is considered an important parameter in the analysis of posture. In a first step, a set of 60 features is computed with a direct approach, and later reduced to eight via a hybrid feature selection. A neural network is then employed to classify the current posture of a worker, yielding a recognition rate of 90%. In a second step, an innovative graphic approach is proposed to extract three additional features for the classification. This approach represents the main contribution of this study. Combining both approaches improves the recognition rate to 95%. Our results suggest that neural network could be applied successfully for the classification of adequate and inadequate posture. PMID- 28862666 TI - Detection of Interfacial Debonding in a Rubber-Steel-Layered Structure Using Active Sensing Enabled by Embedded Piezoceramic Transducers. AB - Rubber-steel-layered structures are used in many engineering applications. Laminated rubber-steel bearing, as a type of seismic isolation device, is one of the most important applications of the rubber-steel-layered structures. Interfacial debonding in rubber-steel-layered structures is a typical failure mode, which can severely reduce their load-bearing capacity. In this paper, the authors developed a simple but effective active sensing approach using embedded piezoceramic transducers to provide an in-situ detection of the interfacial debonding between the rubber layers and steel plates. A sandwiched rubber-steel layered specimen, consisting of one rubber layer and two steel plates, was fabricated as the test specimen. A novel installation technique, which allows the piezoceramic transducers to be fully embedded into the steel plates without changing the geometry and the surface conditions of the plates, was also developed in this research. The active sensing approach, in which designed stress waves can propagate between a pair of the embedded piezoceramic transducers (one as an actuator and the other one as a sensor), was employed to detect the steel rubber debonding. When the rubber-steel debonding occurs, the debonded interfaces will attenuate the propagating stress wave, so that the amplitude of the received signal will decrease. The rubber-steel debonding was generated by pulling the two steel plates in opposite directions in a material-testing machine. The changes of the received signal before and after the debonding were characterized in a time domain and further quantified by using a wavelet packet-based energy index. Experiments on the healthy rubber-steel-layered specimen reveal that the piezoceramic-induced stress wave can propagate through the rubber layer. The destructive test on the specimen demonstrates that the piezoceramic-based active sensing approach can effectively detect the rubber-steel debonding failure in real time. The active sensing approach is often used in structures with "hard" materials, such as steel, concrete, and carbon fiber composites. This research lays a foundation for extending the active sensing approach to damage detection of structures involving "soft" materials, such as rubber. PMID- 28862664 TI - Brassica-Derived Plant Bioactives as Modulators of Chemopreventive and Inflammatory Signaling Pathways. AB - A high consumption of vegetables belonging to the Brassicaceae family has been related to a lower incidence of chronic diseases including different kinds of cancer. These beneficial effects of, e.g., broccoli, cabbage or rocket (arugula) intake have been mainly dedicated to the sulfur-containing glucosinolates (GLSs) secondary plant compounds nearly exclusively present in Brassicaceae-and in particular to their bioactive breakdown products including isothiocyanates (ITCs). Overall, the current literature indicate that selected Brassica-derived ITCs exhibit health-promoting effects in vitro, as well as in laboratory mice in vivo. Some studies suggest anti-carcinogenic and anti-inflammatory properties for ITCs which may be communicated through an activation of the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) that controls the expression of antioxidant and phase II enzymes. Furthermore, it has been shown that ITCs are able to significantly ameliorate a severe inflammatory phenotype in colitic mice in vivo. As there are studies available suggesting an epigenetic mode of action for Brassica-derived phytochemicals, the conduction of further studies would be recommendable to investigate if the beneficial effects of these compounds also persist during an irregular consumption pattern. PMID- 28862667 TI - Epigenetic Alterations in Human Papillomavirus-Associated Cancers. AB - Approximately 15-20% of human cancers are caused by viruses, including human papillomaviruses (HPVs). Viruses are obligatory intracellular parasites and encode proteins that reprogram the regulatory networks governing host cellular signaling pathways that control recognition by the immune system, proliferation, differentiation, genomic integrity, and cell death. Given that key proteins in these regulatory networks are also subject to mutation in non-virally associated diseases and cancers, the study of oncogenic viruses has also been instrumental to the discovery and analysis of many fundamental cellular processes, including messenger RNA (mRNA) splicing, transcriptional enhancers, oncogenes and tumor suppressors, signal transduction, immune regulation, and cell cycle control. More recently, tumor viruses, in particular HPV, have proven themselves invaluable in the study of the cancer epigenome. Epigenetic silencing or de-silencing of genes can have cellular consequences that are akin to genetic mutations, i.e., the loss and gain of expression of genes that are not usually expressed in a certain cell type and/or genes that have tumor suppressive or oncogenic activities, respectively. Unlike genetic mutations, the reversible nature of epigenetic modifications affords an opportunity of epigenetic therapy for cancer. This review summarizes the current knowledge on epigenetic regulation in HPV-infected cells with a focus on those elements with relevance to carcinogenesis. PMID- 28862668 TI - Origin and Formation Mechanism Investigation of Compound Precipitation from the Traditional Chinese Prescription Huang-Lian-Jie-Du-Tang by Isothermal Titration Calorimetry. AB - Previous studies have shown that compounds in the form of precipitate (CFP) from Huang-Lian-Jie-Du-Tang (HLJDT) were stable, and the CFP content reached 2.63% of the whole decoction and had good neuroprotective effects. However, there has been no research on their specific source. In this study, it was found that HLJDT CFP mainly came from the reaction of Scutellaria baicalensis and Coptis chinensis by studying the separated prescription components (accounting for 81.33% of HLJDT CFP). Unlike previous studies on HLJDT CFP, in this research the chemical composition of Scutellaria baicalensis-Coptis chinensis (SB-CC) CFP was identified by high performance liquid chromatography coupled with mass spectrometry (HPLC-MSn), which further proved that the main source of HLJDT CFP was Scutellaria baicalensis-Coptis chinensis CFP compared with previous HLJDT CFP studies. To explain the reaction mechanism between the decoctions of Scutellaria baicalensis and Coptis chinensis, isothermal titration calorimetry (ITC) was used to analyze their binding heat and the thermodynamic parameters (DeltaH, DeltaS, DeltaG, n, Ka) of the reaction between baicalin and berberine, which are the main components of Scutellaria baicalensis and Coptis chinensis, respectively. The results showed that the reaction between decoctions of Scutellaria baicalensis and Coptis chinensis was exothermic and the reaction between baicalin and berberine was a spontaneous and enthalpy-driven chemical reaction, the binding ratio being 1:1. In addition, HLJDT CFP (EC50 = 14.71 +/- 0.91 ug/mL) and SB-CC CFP (EC50 = 6.11 +/- 0.12 ug/mL) showed similar protective activities on PC12 cells injured by cobalt chloride (CoCl2). This study provided a new angle to research on the main chemical components and therapeutic values of CFP in Traditional Chinese Medicine compounds. PMID- 28862670 TI - Catalytic Behavior of Chromium Oxide Supported on Nanocasting-Prepared Mesoporous Alumina in Dehydrogenation of Propane. AB - Mesoporous alumina with narrow pore size distribution centered in the range of 4.4-5.0 nm and with a specific surface area as high as 270 m2.g-1 was prepared via the nanocasting approach using a CMK-3 carbon replica as a hard template. Based on this support, a series of catalysts containing 1, 5, 10, 20 and 30 wt % of chromium was prepared by incipient wetness impregnation, characterized, and studied in the dehydrogenation of propane to propene (PDH). Cr species in three oxidation states-Cr(III), Cr(V) and Cr(VI)-were found on the oxidized surface of the catalysts. The concentration of these species varied with the total Cr loading. Temperature-programmed reduction (H2-TPR) and UV-Vis diffuse reflectance spectroscopy (UV-Vis-DRS) studies revealed that Cr(VI) species dominated at the lowest Cr content. An increase in the Cr loading resulted in an appearance of an increasing amount of Cr(III) oxide. UV-Vis-DRS measurements performed in situ during the PDH process showed that at the beginning of the catalytic test Cr(VI) species were reduced to Cr(III) redox species. A crucial role of the redox species in the PDH process over the catalysts with the low Cr content was confirmed. The stability test for the catalyst containing 20 wt % of Cr showed that this sample exhibited the reproducible catalytic performance after the first four regeneration-dehydrogenation cycles. Moreover, this catalyst had higher resistance on deactivation during the PDH process as compared to the reference catalyst with the same Cr loading, but was supported on commercially available alumina. PMID- 28862669 TI - Antimicrobial Susceptibility of Staphylococcus aureus Isolated from Recreational Waters and Beach Sand in Eastern Cape Province of South Africa. AB - Background: Resistance of Staphylococcus aureus to commonly used antibiotics is linked to their ability to acquire and disseminate antimicrobial-resistant determinants in nature, and the marine environment may serve as a reservoir for antibiotic-resistant bacteria. This study determined the antibiotic sensitivity profile of S.aureus isolated from selected beach water and intertidal beach sand in the Eastern Cape Province of South Africa. Methods: Two hundred and forty-nine beach sand and water samples were obtained from 10 beaches from April 2015 to April 2016. Staphylococcus aureus was isolated from the samples using standard microbiological methods and subjected to susceptibility testing to 15 antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA) was detected by susceptibility to oxacillin and growth on Brilliance MRSA II agar. Antibiotic resistance genes including mecA, femA rpoB, blaZ, ermB, ermA, ermC, vanA, vanB, tetK and tetM were screened. Results: Thirty isolates (12.3%) were positive for S. aureus by PCR with over 50% showing phenotypic resistance to methicillin. Resistance of S. aureus to antibiotics varied considerably with the highest resistance recorded to ampicillin and penicillin (96.7%), rifampicin and clindamycin (80%), oxacillin (73.3%) and erythromycin (70%). S.aureus revealed varying susceptibility to imipenem (96.7%), levofloxacin (86.7%), chloramphenicol (83.3%), cefoxitin (76.7%), ciprofloxacin (66.7%), gentamycin (63.3%), tetracycline and sulfamethoxazole-trimethoprim (56.7%), and vancomycin and doxycycline (50%). All 30 (100%) S. aureus isolates showed multiple antibiotic resistant patterns (resistant to three or more antibiotics). The mecA, femA, rpoB, blaZ, ermB and tetM genes were detected in 5 (22.7%), 16 (53.3%), 11 (45.8%), 16 (55.2%), 15 (71.4%), and 8 (72.7%) isolates respectively; Conclusions: Results from this study indicate that beach water and sand from the Eastern Cape Province of South Africa may be potential reservoirs of antibiotic resistant S. aureus which could be transmitted to exposed humans and animals. PMID- 28862671 TI - Delay Discounting as an Index of Sustainable Behavior: Devaluation of Future Air Quality and Implications for Public Health. AB - Poor air quality and resulting annual deaths represent significant public health concerns. Recently, rapid delay discounting (the devaluation of future outcomes) of air quality has been considered a potential barrier for engaging in long term, sustainable behaviors that might help to reduce emissions (e.g., reducing private car use, societal support for clean air initiatives). Delay discounting has been shown to be predictive of real world behavior outside of laboratory settings, and therefore may offer an important framework beyond traditional variables thought to measure sustainable behavior such as importance of an environmental issue, or environmental attitudes/values, although more research is needed in this area. We examined relations between discounting of air quality, respiratory health, and monetary gains and losses. We also examined, relations between discounting and self-reported importance of air quality and respiratory health, and nature relatedness. Results showed rapid delay discounting of all outcomes across the time frames assessed, and significant positive correlations between delay discounting of air quality, respiratory health, and monetary outcomes. Steeper discounting of monetary outcomes relative to air quality and respiratory health outcomes was observed in the context of gains; however, no differences in discounting were observed across losses of monetary, air quality, and respiratory health. Replicating the sign effect, monetary outcomes were discounted more steeply than monetary losses. Importance of air quality, respiratory health and nature relatedness were significantly and positively correlated with one another, but not with degree of delay discounting of any outcome, demonstrating the need for more comprehensive measures that predict pro-environmental behaviors that might benefit individuals and public health over time. These results add to our understanding of decision-making, and demonstrate alarming rates of delay discounting of air quality and health. These results implicate a major public health concern and potential barriers to individual and societal behavior that reduce pollution and emissions for conservation of clean air. PMID- 28862672 TI - Stress and Depressive Symptoms in Cancer Survivors and Their Family Members: Korea Community Health Survey, 2012. AB - This study examined the prevalence of perceived stress and depressive symptoms in cancer survivors and their family members compared with subjects without cancer and without family members with cancer. The subjects of this cross-sectional study were adults >=19 years old who participated in the 2012 Korea Community Health Survey. Stress and depressive symptoms in cancer survivors and their family members were assessed and compared to symptoms in control groups by chi square tests and multiple logistic regression analyses. Of the 6783 cancer survivors, 26.9% and 8.7% reported having stress and depressive symptoms, respectively, and 27.7% and 5.9% of family members of cancer survivors reported having stress and depressive symptoms, respectively. Cancer survivors showed higher adjusted odds ratio (aOR) for stress (aOR = 1.26, 95% confidence interval (CI) = 1.16-1.37) and depressive symptoms (aOR = 1.82, 95% CI = 1.57-2.11) than subjects without cancer history. Family members of cancer survivors showed a higher OR for stress and depressive symptoms than subjects without a family member who survived cancer. Cancer survivors and family members of cancer survivors had more stress and depressive symptoms than controls. Careful management for cancer patients and their family members should include screening for stress and depression to improve mental health associated with cancer survivorship. PMID- 28862673 TI - IGF-1 Attenuates Hypoxia-Induced Atrophy but Inhibits Myoglobin Expression in C2C12 Skeletal Muscle Myotubes. AB - Chronic hypoxia is associated with muscle wasting and decreased oxidative capacity. By contrast, training under hypoxia may enhance hypertrophy and increase oxidative capacity as well as oxygen transport to the mitochondria, by increasing myoglobin (Mb) expression. The latter may be a feasible strategy to prevent atrophy under hypoxia and enhance an eventual hypertrophic response to anabolic stimulation. Mb expression may be further enhanced by lipid supplementation. We investigated individual and combined effects of hypoxia, insulin-like growth factor (IGF)-1 and lipids, in mouse skeletal muscle C2C12 myotubes. Differentiated C2C12 myotubes were cultured for 24 h under 20%, 5% and 2% oxygen with or without IGF-1 and/or lipid treatment. In culture under 20% oxygen, IGF-1 induced 51% hypertrophy. Hypertrophy was only 32% under 5% and abrogated under 2% oxygen. This was not explained by changes in expression of genes involved in contractile protein synthesis or degradation, suggesting a reduced rate of translation rather than of transcription. Myoglobin mRNA expression increased by 75% under 5% O2 but decreased by 50% upon IGF-1 treatment under 20% O2, compared to control. Inhibition of mammalian target of rapamycin (mTOR) activation using rapamycin restored Mb mRNA expression to control levels. Lipid supplementation had no effect on Mb gene expression. Thus, IGF-1-induced anabolic signaling can be a strategy to improve muscle size under mild hypoxia, but lowers Mb gene expression. PMID- 28862674 TI - Biological and Chemical Diversity of Bacteria Associated with a Marine Flatworm. AB - The aim of this research is to explore the biological and chemical diversity of bacteria associated with a marine flatworm Paraplanocera sp., and to discover the bioactive metabolites from culturable strains. A total of 141 strains of bacteria including 45 strains of actinomycetes and 96 strains of other bacteria were isolated, identified and fermented on a small scale. Bioactive screening (antibacterial and cytotoxic activities) and chemical screening (ultra performance liquid chromatography-mass spectrometry (UPLC-MS)) yielded several target bacterial strains. Among these strains, the ethyl acetate (EA) crude extract of Streptomyces sp. XY-FW47 fermentation broth showed strong antibacterial activity against methicillin-resistant Staphylococcus aureus ATCC43300 (MRSA ATCC43300) and potent cytotoxic effects on HeLa cells. The UPLC MS spectral analysis of the crude extract indicated that the strain XY-FW47 could produce a series of geldanamycins (GMs). One new geldanamycin (GM) analog, 4,5 dihydro-17-O-demethylgeldanamycin (1), and three known GMs (2-4) were obtained. All of these compounds were tested for antibacterial, cytotoxic, and antifungal activities, yet only GM (3) showed potent cytotoxic (HeLa cells, EC50 = 1.12 MUg/mL) and antifungal (Setosphaeria turcica MIC = 2.40 MUg/mL) activities. Their structure-activity relationship (SAR) was also preliminarily discussed in this study. PMID- 28862675 TI - Prediction-Based Energy Saving Mechanism in 3GPP NB-IoT Networks. AB - The current expansion of the Internet of things (IoT) demands improved communication platforms that support a wide area with low energy consumption. The 3rd Generation Partnership Project introduced narrowband IoT (NB-IoT) as IoT communication solutions. NB-IoT devices should be available for over 10 years without requiring a battery replacement. Thus, a low energy consumption is essential for the successful deployment of this technology. Given that a high amount of energy is consumed for radio transmission by the power amplifier, reducing the uplink transmission time is key to ensure a long lifespan of an IoT device. In this paper, we propose a prediction-based energy saving mechanism (PBESM) that is focused on enhanced uplink transmission. The mechanism consists of two parts: first, the network architecture that predicts the uplink packet occurrence through a deep packet inspection; second, an algorithm that predicts the processing delay and pre-assigns radio resources to enhance the scheduling request procedure. In this way, our mechanism reduces the number of random accesses and the energy consumed by radio transmission. Simulation results showed that the energy consumption using the proposed PBESM is reduced by up to 34% in comparison with that in the conventional NB-IoT method. PMID- 28862676 TI - Problems in Classifying Mild Cognitive Impairment (MCI): One or Multiple Syndromes? AB - As the conceptual, methodological, and technological advances applied to dementias have evolved the construct of mild cognitive impairment (MCI), one problem encountered has been its classification into subtypes. Here, we aim to revise the concept of MCI and its subtypes, addressing the problems of classification not only from the psychometric point of view or by using alternative methods, such as latent class analysis, but also considering the absence of normative data. In addition to the well-known influence of certain factors on cognitive function, such as educational level and cultural traits, recent studies highlight the relevance of other factors that may significantly affect the genesis and evolution of MCI: subjective memory complaints, loneliness, social isolation, etc. The present work will contemplate the most relevant attempts to clarify the issue of MCI categorization and classification, combining our own data with that from recent studies which suggest the role of relevant psychosocial factors in MCI. PMID- 28862677 TI - Simulation of Food Folate Digestion and Bioavailability of an Oxidation Product of 5-Methyltetrahydrofolate. AB - Generating bioavailability data from in vivo studies is time-consuming and expensive. In vitro simulation can help to investigate factors influencing bioavailability or facilitate quantifying the impact of such factors. For folates, an efficient deconjugation of polyglutamates to the corresponding monoglutamates is crucial for bioavailability and highly dependent on the food matrix. Therefore, the bioaccessibility of folates of different foodstuffs was examined using a simulated digestion model with respect to folate stability and the efficiency of deconjugation. For realistic simulated deconjugation, porcine brush border membrane was used during the phase of the simulated digestion in the small intestine. For a better understanding of folate behaviour during digestion, single folate monoglutamates were also investigated with this in vitro digestion model. The results for bioaccessibility were compared with data from a human bioavailability study. They support the idea that both stability and deconjugation have an influence on bioaccessibility and thus on bioavailability. Tetrahydrofolate is probably lost completely or at least to a high extent and the stability of 5-methyltetrahydrofolate depends on the food matrix. Additionally, 5 methyltetrahydrofolate can be oxidised to a pyrazino-s-triazine (MeFox), whose absorption in the human intestinal tract was shown tentatively. PMID- 28862679 TI - Research on the Mechanism of In-Plane Vibration on Friction Reduction. AB - A modified model for predicting the friction force between drill-string and borehole wall under in-plane vibrations was developed. It was found that the frictional coefficient in sliding direction decreased significantly after applying in-plane vibration on the bottom specimen. The friction reduction is due to the direction change of friction force, elastic deformation of surface asperities and the change of frictional coefficient. Normal load, surface topography, vibration direction, velocity ratio and interfacial shear factor are the main influence factors of friction force in sliding direction. Lower driving force can be realized for a pair of determinate rubbing surfaces under constant normal load by setting the driving direction along the minimum arithmetic average attack angle direction, and applying intense longitudinal vibration on the rubbing pair. The modified model can significantly improve the accuracy in predicting frictional coefficient under vibrating conditions, especially under the condition of lower velocity ratio. The results provide a theoretical gist for friction reduction technology by vibrating drill-string, and provide a reference for determination of frictional coefficient during petroleum drilling process, which has great significance for realizing digitized and intelligent drilling. PMID- 28862680 TI - The Effect of Precipitate Evolution on Austenite Grain Growth in RAFM Steel. AB - To study the effects of various types of precipitates and precipitate evolution behavior on austenite (size and phase fraction) in reduced activation ferritic/martensitic (RAFM) steel, RAFM steel was heated to various austenitizing temperatures. The microstructures of specimens were observed using optical microscopy (OM) and transmission electron microscopy (TEM). The results indicate that the M23C6 and MX precipitates gradually coarsen and dissolve into the matrix as the austenitizing temperatures increase. The M23C6 precipitates dissolve completely at 1100 degrees C, while the MX precipitates dissolve completely at 1200 degrees C. The evolution of two types of precipitate has a significant effect on the size of austenite. Based on the Zener pinning model, the effect of precipitate evolution on austenite grain size is quantified. It was found that the coarsening and dissolution of M23C6 and MX precipitates leads to a decrease in pinning pressure on grain boundaries, facilitating the rapid growth of austenite grains. The austenite phase fraction is also affected by the coarsening and dissolution of precipitates. PMID- 28862678 TI - Rosemary Extract as a Potential Anti-Hyperglycemic Agent: Current Evidence and Future Perspectives. AB - Type 2 diabetes mellitus (T2DM), a disease on the rise and with huge economic burden to health care systems around the globe, results from defects in insulin action (termed insulin resistance) combined with impaired insulin secretion. Current methods of prevention and treatments for insulin resistance and T2DM are lacking in number and efficacy and, therefore, there is a need for new preventative measures and targeted therapies. In recent years, chemicals found in plants/herbs have attracted attention for their use as functional foods or nutraceuticals for preventing and treating insulin resistance and T2DM. Rosemary is an evergreen shrub indigenous to the Mediterranean region and South America, which contains various polyphenols. Rosemary extract and its polyphenolic constituents have been reported to have antioxidant, anti-inflammatory, anticancer, and anti-hyperglycemic properties. The current review summarizes the existing in vitro and in vivo studies examining the anti-diabetic effects of rosemary extract and its polyphenolic components and highlights the known mechanism of action. PMID- 28862681 TI - Comparison of Efficiency of BG-Sentinel Traps Baited with Mice, Mouse-Litter, and CO2 Lures for Field Sampling of Male and Female Aedes albopictus Mosquitoes. AB - Determining the abundance and distribution of male mosquitoes in the wild and establishing species seasonality in candidate pilot sites is of particular interest with respect to the use of the sterile-male technique. With the knowledge that using mice as bait in BG-Sentinel traps effectively enhances Aedes albopictus male and female trapping success, the present study was designed to determine whether attractants derived from mouse odour blend could be a viable substitute for live mice to lure Ae. albopictus mosquitoes into traps. The effects of baiting BG-Sentinel traps with mice, carbon dioxide (CO2), and attractants derived from litter mouse odours (mouse litter (ML)) and a mouse odour blend (MOB) on the efficiency of trapping Ae. albopictus males and females were tested using a Latin square design. The BG-Sentinel trap baited with CO2 + ML caught a significantly larger number of mosquitoes compared to traps baited with mice only. The BG-Sentinel traps containing only CO2 or CO2 + MOB, however, did not catch significantly more mosquitoes compared to the other traps. The proportions of males caught in the BG-Sentinel traps did not differ significantly between the respective attractants. The results from this study confirm that CO2 bait is efficient to provide a reliable estimation method for Ae. albopictus adult male abundance in the wild, and suggest that mouse litter baits in combination with CO2 could be used to enhance Aedes trapping success in BG Sentinel traps. PMID- 28862682 TI - Public Health Services Utilization and Its Determinants among Internal Migrants in China: Evidence from a Nationally Representative Survey. AB - There have been obstacles for internal migrants in China in accessing local public health services for some time. This study aimed to estimate the utilization of local public health services and its determinants among internal migrants. Data were from the 2014 and 2015 nationally representative cross sectional survey of internal migrants in China. Multivariate logistic regressions were used to estimate the relationship between socioeconomic, migration, and demographic characteristics and public health services utilization. Our results showed that internal migrants in more developed eastern regions used less public health services. Those with higher socioeconomic status were more likely to use public health services. The years of living in the city of residence were positively associated with the utilization of public health services. Compared to migration within the city, migration across provinces significantly reduced the probability of using health records (OR = 0.88, 95% CI: 0.86-0.90), health education (OR = 0.97, 95% CI: 0.94-1.00), and health education on non communicable diseases (OR = 0.92, 95% CI: 0.89-0.95) or through the Internet (OR = 0.96, 95% CI: 0.94-0.99). This study concludes that public health services coverage for internal migrants has seen great improvement due to government subsidies. Internal migrants with lower socioeconomic status and across provinces need to be targeted. More attention should be given to the local government in the developed eastern regions in order to narrow the regional gaps. PMID- 28862684 TI - Position Fingerprint-Based Beam Selection in Millimeter Wave Heterogeneous Networks. AB - The traditional beam selection algorithms determine the optimal beam direction by feeding back the perfect channel state information (CSI) in a millimeter wave (mmWave) massive Multiple-Input Multiple-Output (MIMO) system. Popular beam selection algorithms mostly focus on the methods of feedback and exhaustive search. In order to reduce the extra computational complexity coming from the redundant feedback and exhaustive search, a position fingerprint (PFP)-based mmWave multi-cell beam selection scheme is proposed in this paper. In the proposed scheme, the best beam identity (ID) and the strongest interference beam IDs from adjacent cells of each fingerprint spot are stored in a fingerprint database (FPDB), then the optimal beam and the strongest interference beams can be determined by matching the current PFP of the user equipment (UE) with the PFP in the FPDB instead of exhaustive search, and the orthogonal codes are also allocated to the optimal beam and the strongest interference beams. Simulation results show that the proposed PFP-based beam selection scheme can reduce the computational complexity and inter-cell interference and produce less feedback, and the system sum-rate for the mmWave heterogeneous networks is also improved. PMID- 28862683 TI - Mechanochemical Synthesis and Biological Evaluation of Novel Isoniazid Derivatives with Potent Antitubercular Activity. AB - A series of isoniazid derivatives bearing a phenolic or heteroaromatic coupled frame were obtained by mechanochemical means. Their pH stability and their structural (conformer/isomer) analysis were checked. The activity of prepared derivatives against Mycobacterium tuberculosis cell growth was evaluated. Some compounds such as phenolic hydrazine 1a and almost all heteroaromatic ones, especially 2, 5 and 7, are more active than isoniazid, and their activity against some M. tuberculosis MDR clinical isolates was determined. Compounds 1a and 7 present a selectivity index >1400 evaluated on MRC5 human fibroblast cells. The mechanism of action of selected hydrazones was demonstrated to block mycolic acid synthesis due to InhA inhibition inside the mycobacterial cell. PMID- 28862685 TI - Alumina Concentration Detection Based on the Kernel Extreme Learning Machine. AB - The concentration of alumina in the electrolyte is of great significance during the production of aluminum. The amount of the alumina concentration may lead to unbalanced material distribution and low production efficiency and affect the stability of the aluminum reduction cell and current efficiency. The existing methods cannot meet the needs for online measurement because industrial aluminum electrolysis has the characteristics of high temperature, strong magnetic field, coupled parameters, and high nonlinearity. Currently, there are no sensors or equipment that can detect the alumina concentration on line. Most companies acquire the alumina concentration from the electrolyte samples which are analyzed through an X-ray fluorescence spectrometer. To solve the problem, the paper proposes a soft sensing model based on a kernel extreme learning machine algorithm that takes the kernel function into the extreme learning machine. K fold cross validation is used to estimate the generalization error. The proposed soft sensing algorithm can detect alumina concentration by the electrical signals such as voltages and currents of the anode rods. The predicted results show that the proposed approach can give more accurate estimations of alumina concentration with faster learning speed compared with the other methods such as the basic ELM, BP, and SVM. PMID- 28862686 TI - Identification of Polar Constituents in the Decoction of Juglans mandshurica and in the Medicated Egg Prepared with the Decoction by HPLC-Q-TOF MS2. AB - As a folk medicinal plant, Juglans mandshurica has been used for the treatment of cancer in China and Korea. Traditionally, J. mandshurica is decocted together with chicken eggs. Both the decoction and medicated eggs possess anti-tumor properties. Clarifying the constituents of the decoction and absorbed by the medicated eggs is essential for the investigation of the active principles of J. mandshurica. Herein, the medicated eggs were prepared by decocting raw chicken eggs, having unbroken shells, with the decoction of J. mandshurica. A systematic investigation of the chemical profile of the J. mandshurica decoction and the medicated egg extraction was conducted by HPLC-Q-TOF-MS2. In total, 93 peaks, including 45 tannins, 14 naphthalene derivatives, 17 organic acids, 3 diarylheptanoids, 4 lignans, 3 anthraquinones, 1 flavonoid glycoside, 3 amino acids, and 3 nitrogenous compounds, were tentatively identified in the decoction. In the medicated egg extraction, 44 peaks including 11 organic acids, 3 amino acids, 3 nitrogenous compounds, 8 naphthalene derivatives, 3 diarylheptanoids, 15 tannins, and 1 lignan were tentatively identified. The chemical profile presented provided a detailed overview of the polar chemical constituents in J. mandshurica and useful information for the research of bioactive compounds of this plant. PMID- 28862687 TI - Changes in Tannin Composition of Syrah Grape Skins and Seeds during Fruit Ripening under Contrasting Water Conditions. AB - Tannin accumulation and composition were determined in skins and seeds isolated from Vitis vinifera cv. Syrah grapes submitted to contrasting water regimes under semiarid climatic conditions. Three irrigation treatments were conducted, starting at berry set through harvest of two growing seasons, 2011 and 2012: irrigation at 100% of crop evapotranspiration ETc (FI), irrigation at 50% of ETc (DI) and non-irrigated (NI). Seed total tannins did not vary with maturity but those of skins underwent a progressive decline (especially in 2011), expressed both on a fresh weight and on a per berry basis. Skin total tannin concentration and content per berry were increased under NI and DI conditions, mainly in 2012. In contrast, seed total tannins (in 2012) and flavan-3-ol monomers and tannin oligomers (both years) were higher in the fully irrigated vines (FI). Skin polymer size increased during ripening, NI and DI skins showing higher mean degree of polymerization (mDP) compared to FI at harvest. NI was also associated with a lower percentage of galloylation (%G) in skin oligomeric fraction (in 2012) and a lower percentage of prodelphinidins in the skin polymeric fraction (both years) at harvest. The mDP and %G of seed extracts did not vary during ripening and were higher in NI but only in 2012. According to the results, management of vine water status was shown to influence tannin amount and composition of Syrah grapes grown under semiarid conditions. PMID- 28862688 TI - Constituents of the Fruits of Citrus medica L. var. sarcodactylis and the Effect of 6,7-Dimethoxy-coumarin on Superoxide Anion Formation and Elastase Release. AB - Investigation of the chemical constituents from the fruits of Citrus medica L. var. sarcodactylis Swingle has led to the characterization of a new sesquiterpene 1 along with thirty-two known compounds. The structure of 1 was established on the basis of 2D NMR spectroscopic and mass spectrometric analyses, and the known compounds were identified by comparison of their physical and spectroscopic data with those reported in the literature. In addition, most of the isolated compounds were evaluated for the activity assayed by the in vitro inhibition of superoxide anion generation and elastase release by human neutrophils. The results showed that only 6,7-dimethoxycoumarin (5) exhibited significant inhibition of superoxide anion generation, with IC50 value of 3.8 +/- 1.4 MUM. PMID- 28862689 TI - The Efficacy of Electron Beam Irradiated Bacterial Cellulose Membranes as Compared with Collagen Membranes on Guided Bone Regeneration in Peri-Implant Bone Defects. AB - Bacterial cellulose (BC) is a natural polysaccharide produced by some bacteria, and consists of a linear polymer linked by beta-(1,4) glycosidic bonds. BC has been developed as a material for tissue regeneration purposes. This study was conducted to evaluate the efficacy of resorbable electron beam irradiated BC membranes (EI-BCMs) for guided bone regeneration (GBR). The electron beam irradiation (EI) was introduced to control the biodegradability of BC for dental applications. EI-BCMs had higher porosity than collagen membranes (CMs), and had similar wet tensile strengths to CMs. NIH3T3 cell adhesion and proliferation on EI-BCMs were not significantly different from those on CMs (p > 0.05). Micro computed tomography (MUCT) and histometric analysis in peri-implant dehiscence defects of beagle dogs showed that EI-BCMs were non-significantly different from CMs in terms of new bone area (NBA; %), remaining bone substitute volume (RBA; %) and bone-to-implant contact (BIC; %) (p > 0.05). These results suggest resorbable EI-BCMs can be used as an alternative biomaterial for bone tissue regeneration. PMID- 28862691 TI - Peg-in-Hole Assembly Based on Two-phase Scheme and F/T Sensor for Dual-arm Robot. AB - This paper focuses on peg-in-hole assembly based on a two-phase scheme and force/torque sensor (F/T sensor) for a compliant dual-arm robot, the Baxter robot. The coordinated operations of human beings in assembly applications are applied to the behaviors of the robot. A two-phase assembly scheme is proposed to overcome the inaccurate positioning of the compliant dual-arm robot. The position and orientation of assembly pieces are adjusted respectively in an active compliant manner according to the forces and torques derived by a six degrees-of freedom (6-DOF) F/T sensor. Experiments are conducted to verify the effectiveness and efficiency of the proposed assembly scheme. The performances of the dual-arm robot are consistent with those of human beings in the peg-in-hole assembly process. The peg and hole with 0.5 mm clearance for round pieces and square pieces can be assembled successfully. PMID- 28862690 TI - Variations in the Rate of Infestations of Dogs with Zoonotic Nematodes and the Contamination of Soil in Different Environments. AB - Companion animals are an important aspect in human life. However, they may also be considered a source of pathogens. An example of zoonotic parasitoses is toxocarosis or cutaneous larva migrans (CLM). The aim of the study was to detect zoonotic nematodes of dogs living in different areas and the intensity of contamination in parasite polluted environments that are hazardous to human health. The fecal samples were examined using standard flotation and decantation methods as well as McMaster's quantitative technique. The soil samples in urban and rural areas were examined using a modified flotation method as described by Quinn et al. Statistical analyses were performed by IBM SPSS Statistics Version 23. The overall prevalence of parasites in dogs was 38%, 17.02% and 56.60% from urban and rural areas, respectively. The percentage values of nematodes important for human health (Toxocaracanis, Ancylostomatidae, Trichurisvulpis) remained at the same level (16%). The infected dogs were dominated by a single parasite species, the main was T.canis (28.95%). In total, 54.30% of the soil samples were contaminated with parasite eggs. The contamination of urban and rural sandpits was 40% and 60%, respectively. The molecular examinations of soil samples using LAMP (loop-mediated isothermal amplification) confirmed the presence of nematode eggs of the species T.canis in all samples previously classified as positive. PMID- 28862692 TI - Characteristics and Outcomes of Dogs Admitted into Queensland RSPCA Shelters. AB - Over 200,000 stray and surrendered dogs are admitted to shelters and municipal facilities in Australia each year, and approximately 20% are euthanized. Contemporary, comprehensive data on the characteristics and outcomes of dogs entering shelters are required to reduce shelter admissions and euthanasia. However, there are currently limited up-to-date data published on dog admission into shelters. A retrospective single cohort study was conducted to describe the characteristics and outcomes of the dog population entering Royal Society for Prevention of Cruelty to Animals, Queensland (RSPCA-QLD) shelters in 2014 (n = 11,967). The majority of dog admissions were strays from the public (24%) or from municipal councils (34%). Just over a quarter of admissions were puppies, 18% of adults (>6 months) were desexed, and the majority of admissions were crossbred dogs (92%). The majority of owner surrenders (86%) were due to human-related reasons. Most dogs were reclaimed (32%) or adopted (43%) and aggression was the most common reason for euthanasia of adult dogs (45%). Low-cost or free desexing and identification programs targeted to areas and breeds contributing to high intake, and increased support services for owners at risk of surrendering their dog, should be trialed to determine their cost effectiveness in reducing shelter admissions and euthanasia. PMID- 28862694 TI - An Assessment of the Food and Nutrition Security Status of Weaned 7-12 Months Old Children in Rural and Peri-Urban Communities of Gauteng and Limpopo Provinces, South Africa. AB - This study assessed the food and nutrition security status of children receiving complementary food in rural and peri-urban communities. A group of 106 mothers from Lebowakgomo village and Hammanskraal Township, respectively, participated in the survey. Additionally, six focus group discussions were conducted per study area to assess the mothers' perceptions about children's food access. The Children's Food Insecurity Access Scale (CFIAS) was used to assess the food security status (access) of the children. The Individual Dietary Diversity Score (IDDS) together with the unquantified food consumption frequency survey were used as a proxy measure of the nutritional quality of the children's diets. The age and weight of the children obtained from the children's clinic health cards were used to calculate Weight-for-Age Z scores (WAZ) in order to determine the prevalence of underweight children. The findings showed that a large percentage of children were severely food-insecure, 87% and 78%, in rural and peri-urban areas, respectively. Additionally, Lebowakgomo children (23.6%) and Hammanskraal children (17.9%) were severely underweight. Overall, children's diets in both study areas was characterized by nutrient-deficient complementary foods. Cheaper foods with a longer stomach-filling effect such as white maize meal and sugar were the most commonly purchased and used. Hence, the children consumed very limited amounts of foods rich in proteins, minerals, and vitamins, which significantly increased the risk of their being malnourished. PMID- 28862695 TI - Quantifying the Performance of P-Type Transparent Conducting Oxides by Experimental Methods. AB - Screening for potential new materials with experimental and theoretical methods has led to the discovery of many promising candidate materials for p-type transparent conducting oxides. It is difficult to reliably assess a good p-type transparent conducting oxide (TCO) from limited information available at an early experimental stage. In this paper we discuss the influence of sample thickness on simple transmission measurements and how the sample thickness can skew the commonly used figure of merit of TCOs and their estimated band gap. We discuss this using copper-deficient CuCrO 2 as an example, as it was already shown to be a good p-type TCO grown at low temperatures. We outline a modified figure of merit reducing thickness-dependent errors, as well as how modern ab initio screening methods can be used to augment experimental methods to assess new materials for potential applications as p-type TCOs, p-channel transparent thin film transistors, and selective contacts in solar cells. PMID- 28862693 TI - Pro-Inflammatory Versus Anti-Inflammatory Effects of Dendrimers: The Two Faces of Immuno-Modulatory Nanoparticles. AB - Dendrimers are soft matter, hyperbranched, and multivalent nanoparticles whose synthesis theoretically affords monodisperse compounds. They are built from a core on which one or several successive series of branches are engrafted in an arborescent way. At the end of the synthesis, the tunable addition of surface groups gives birth to multivalent nano-objects which are generally intended for a specific use. For these reasons, dendrimers have received a lot of attention from biomedical researchers. In particular, some of us have demonstrated that dendrimers can be intrinsically drug-candidate for the treatment of inflammatory disorders, amongst others, using relevant preclinical animal models. These anti inflammatory dendrimers are innovative in the pharmaceutical field. More recently, it has appeared that some dendrimers (even among those which have been described as anti-inflammatory) can promote inflammatory responses in non diseased animals. The main corpus of this concise review is focused on the reports which describe anti-inflammatory properties of dendrimers in vivo, following which we review the few recent articles that show pro-inflammatory effects of our favorite molecules, to finally discuss this duality in immuno modulation which has to be taken into account for the preclinical and clinical developments of dendrimers. PMID- 28862696 TI - Zeamide, a Glycosylinositol Phosphorylceramide with the Novel Core Arap(1beta >6)Ins Motif from the Marine Sponge Svenzea zeai. AB - Glycosylinositol phosphorylceramides (GIPCs) show a great structural diversity, but all share a small number of core structures, with a glucosamine, a mannose, or a glucuronic acid as the first sugar linked to the inositol. The Caribbean sponge Svenzea zeai was shown to consistently contain zeamide (1), the first example of a new class of GIPCs, in which the inositol is glycosylated by a d arabinose. The structure of zeamide was determined by spectroscopic analysis (NMR, MS, ECD) and microscale chemical degradation. The 6-O-beta-d arabinopyranosyl-myo-inositol (d-Arap(1beta->6)Ins) core motif of zeamide is unprecedented not only among GIPCs, but also in any natural glycoconjugate. PMID- 28862697 TI - Identification of a Group's Physiological Synchronization with Earth's Magnetic Field. AB - A new analysis technique for the evaluation of the degree of synchronization between the physiological state of a group of people and changes in the Earth's magnetic field based on their cardiac inter-beat intervals was developed and validated. The new analysis method was then used to identify clusters of similar synchronization patterns in a group of 20 individuals over a two-week period. The algorithm for the identification of slow wave dynamics for every person was constructed in order to determine meaningful interrelationships between the participants and the local magnetic field data. The results support the hypothesis that the slow wave rhythms in heart rate variability can synchronize with changes in local magnetic field data, and that the degree of synchronization is affected by the quality of interpersonal relationships. PMID- 28862698 TI - Prognostic implications of abnormalities of chromosome 13 and the presence of multiple cytogenetic high-risk abnormalities in newly diagnosed multiple myeloma. AB - Fluorescence in situ hybridization evaluation is essential for initial risk stratification in multiple myeloma. While the presence of specific cytogenetic high-risk abnormalities (HRA) is known to confer a poor prognosis, less is known about the cumulative effect of multiple HRA. We studied 1181 patients with newly diagnosed multiple myeloma who received novel agents as first-line therapy. High risk abnormalities were defined as t(4;14), t(14;16), t(14;20) and del(17p). There were 884 patients (75%) without any HRA and 297 patients (25%) with HRA, including 262 (22%) with one HRA and 35 (3%) with two HRA. The presence of one HRA (versus zero, hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.32-2.05, p<0.001) and the presence of two HRA (versus zero, HR 3.15, 95% CI 2.00-4.96, p<0.001) were of prognostic significance after adjusting for other prognostic factors. Abnormalities of chromosome 13 were of prognostic significance independent of the established HRA: Monosomy 13 (HR 1.27, 95% CI 1.04-1.56, P=0.022) and del(13q) (HR 0.48, 95% CI 0.28-0.81, P=0.006) with opposite effects. Patients with HRA experienced worse overall survival suggesting a cumulative adverse effect of multiple HRA. Abnormalities of chromosome 13 were of prognostic significance after adjusting for other prognostic factors. PMID- 28862699 TI - CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients. AB - Although the introduction of tyrosine kinase inhibitors (TKIs) has improved overall survival of patients with chronic myeloid leukemia (CML), about half of the patients eventually relapse after cessation of TKIs. In contrast, the remainder of the patients maintain molecular remission without TKIs, indicating that the patients' immune system could control proliferation of TKI-resistant leukemic stem cells (LSCs). However, the precise mechanism of immunity against CML-LSCs is not fully understood. We have identified a novel immune target, CXorf48, expressed in LSCs of CML patients. Cytotoxic T cells (CTLs) induced by the epitope peptide derived from CXorf48 recognized CD34+CD38- cells obtained from the bone marrow of CML patients. We detected CXorf48-specific CTLs in the peripheral blood mononuclear cells from CML patients who have discontinued imatinib after maintaining complete molecular remission for more than 2 years. Significantly, the relapse rate of CXorf48-specific CTL-negative patients was 63.6%, compared to 0% in CXorf48-specific CTL-positive patients. These results indicate that CXorf48 could be a promising therapeutic target of LSCs for immunotherapy to obtain durable treatment-free remission in CML patients. PMID- 28862700 TI - Differences in genomic patterns and clinical outcomes between African-American and White patients with myelodysplastic syndromes. PMID- 28862701 TI - Deletion of Nedd4-2 results in progressive kidney disease in mice. AB - NEDD4-2 (NEDD4L), a ubiquitin protein ligase of the Nedd4 family, is a key regulator of cell surface expression and activity of the amiloride-sensitive epithelial Na+ channel (ENaC). While hypomorphic alleles of Nedd4-2 in mice show salt-sensitive hypertension, complete knockout results in pulmonary distress and perinatal lethality due to increased cell surface levels of ENaC. We now show that Nedd4-2 deficiency in mice also results in an unexpected progressive kidney injury phenotype associated with elevated ENaC and Na+Cl- cotransporter expression, increased Na+ reabsorption, hypertension and markedly reduced levels of aldosterone. The observed nephropathy is characterized by fibrosis, tubule epithelial cell apoptosis, dilated/cystic tubules, elevated expression of kidney injury markers and immune cell infiltration, characteristics reminiscent of human chronic kidney disease. Importantly, we demonstrate that the extent of kidney injury can be partially therapeutically ameliorated in mice with nephron-specific deletions of Nedd4-2 by blocking ENaC with amiloride. These results suggest that increased Na+ reabsorption via ENaC causes kidney injury and establish a novel role of NEDD4-2 in preventing Na+-induced nephropathy. Contrary to some recent reports, our data also indicate that ENaC is the primary in vivo target of NEDD4 2 and that Nedd4-2 deletion is associated with hypertension on a normal Na+ diet. These findings provide further insight into the critical function of NEDD4-2 in renal pathophysiology. PMID- 28862702 TI - The emerging role of RNAs in DNA damage repair. AB - This corrects the article DOI: 10.1038/cdd.2017.16. PMID- 28862704 TI - Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. PMID- 28862706 TI - Covalent self-assembly of the specific RSSR isomer of 14-membered tetrakisphosphine. AB - The first representative of the specific RSSR isomer of 14-membered tetrakisphosphine has been obtained instead of the RRRR/SSSS isomer predicted according to the empirical rule formulated recently. The geometry of the obtained 14-P4N2 is preorganized for the dicopper complex formation with the unique coordination mode in the row of P4N2 corands. PMID- 28862703 TI - Fine-tuning and autoregulation of the intestinal determinant and tumor suppressor homeobox gene CDX2 by alternative splicing. AB - On the basis of phylogenetic analyses, we uncovered a variant of the CDX2 homeobox gene, a major regulator of the development and homeostasis of the gut epithelium, also involved in cancer. This variant, miniCDX2, is generated by alternative splicing coupled to alternative translation initiation, and contains the DNA-binding homeodomain but is devoid of transactivation domain. It is predominantly expressed in crypt cells, whereas the CDX2 protein is present in crypt cells but also in differentiated villous cells. Functional studies revealed a dominant-negative effect exerted by miniCDX2 on the transcriptional activity of CDX2, and conversely similar effects regarding several transcription-independent functions of CDX2. In addition, a regulatory role played by the CDX2 and miniCDX2 homeoproteins on their pre-mRNA splicing is displayed, through interactions with splicing factors. Overexpression of miniCDX2 in the duodenal Brunner glands leads to the expansion of the territory of these glands and ultimately to brunneroma. As a whole, this study characterized a new and original variant of the CDX2 homeobox gene. The production of this variant represents not only a novel level of regulation of this gene, but also a novel way to fine-tune its biological activity through the versatile functions exerted by the truncated variant compared to the full-length homeoprotein. This study highlights the relevance of generating protein diversity through alternative splicing in the gut and its diseases. PMID- 28862705 TI - Membrane and genomic DNA dual-targeting of citrus flavonoid naringenin against Staphylococcus aureus. AB - The antimicrobial mechanism of naringenin, one of the citrus antibacterial flavonoids against food-borne Staphylococcus aureus ATCC 6538, was investigated in this study. Analysis of gas chromatography-mass spectrometry (GC-MS) and fluorescence showed that relatively low concentrations of naringenin caused perturbations in the membrane fatty acid composition and the conformation of membrane proteins through changing the microenvironment of phenylalanine, tyrosine, and tryptophan residues. Exposure of naringenin at higher levels significantly increased membrane permeability and changed the morphology of S. aureus cells. The genomic DNA-binding of naringenin was also quantitatively monitored using UV-vis spectra in combination with multivariate curve resolution alternating least squares (MCR-ALS) analysis, and the concentration and pure spectra profiles for the three reaction species (DNA, naringenin, and DNA naringenin) were obtained. Moreover, the thermal behavior of DNA and docking studies revealed that naringenin preferentially bound to the A-T base pair regions of genomic DNA via groove binding, and atomic force microscopy and circular dichroism showed that naringenin induced mild secondary structure and obvious morphological variations of this biomacromolecule. These results suggested that naringenin exerting its antibacterial effects might be connected with disruption of the cytoplasmic membrane and DNA targeting effects in Staphylococcus aureus. PMID- 28862708 TI - Non-planar PDMS microfluidic channels and actuators: a review. AB - This review examines the state of the art for manufacturing non-planar miniature channels and actuators from PDMS, where non-planar structures are defined here as those beyond simple extrusions of 2D designs, either with rounded or variable cross sections or with an emergence of the channel trajectory out-of-plane. The motivation for 3D PDMS structures and advances in their fabrication are described, focusing on geometries that were previously unachievable through conventional microfabrication. The motivation for non-planar microfluidic channels and actuators is first discussed and the existing literature is grouped into general fabrication themes and described. The structures are organized by their method of fabrication and evaluated based on their relevant properties, including the capability of producing structures with complex geometry, automation of the fabrication process, and minimum feature size. Additional properties are included for work in the more recently emerging field of non planar PDMS actuators, where the feature size, actuation stroke, and actuation method are the key parameters of interest. In particular, this review considers the impact from recent advances in additive manufacturing, which now allow creation of truly arbitrary 3D structures down to ~100 MUm size scales. PMID- 28862707 TI - Synthesis and in vivo anticancer evaluation of poly(organo)phosphazene-based metallodrug conjugates. AB - Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed unselective activity in vivo. Different organometallic complexes were attached to a degradable poly(organo)phosphazene macromolecule, prepared via controlled polymerization techniques. The conjugation to hydrophilic polymers was designed to increase the aqueous solubility of the typically poorly soluble metal-based half-sandwich compounds with the aim of a controlled, pH-triggered release of the active metallodrug. The synthesized conjugates and their characteristics have been thoroughly studied by means of 31P NMR and UV-Vis spectroscopy, ICP-MS analyses and SEC coupled to ICP-MS. In order to assess their potential as possible anticancer drug candidates, the complexes, as well as their respective macromolecular prodrug formulations were tested against three different cancer cell lines in cell culture. Subsequently, the anticancer activity and organ distribution of the poly(organo)phosphazene drug conjugates were explored in vivo in mice bearing CT-26 colon carcinoma. Our investigations revealed a beneficial influence of this macromolecular prodrug by a significant reduction of adverse effects compared to the free metallodrugs. PMID- 28862709 TI - Different effects of aging and gender on the temporal resolution in attentional tracking. AB - The current study examined the role of temporal resolution of attention in the decline in multiple object tracking abilities with healthy aging. The temporal resolution of attention is known to limit attentional tracking of one and multiple targets (Holcombe & Chen, 2013). Here, we examined whether aging is associated with a lower temporal resolution of attention when tracking one target, the efficiency of splitting attention across multiple targets, or both. Stimuli comprised three concentric rings containing five or 10 equally spaced dots. While maintaining central fixation, younger and older participants tracked a target dot on one, two, or three rings while the rings rotated around fixation in random directions for 5 s. Rotational speed was varied to estimate speed or temporal frequency thresholds in six conditions. Results showed that younger and older participants had similar temporal frequency thresholds for tracking one target, but the addition of one and two more targets reduced thresholds more in the older group compared to the younger group. Gender also affected performance, with men having higher temporal frequency thresholds than women, independently of the number of targets. These findings indicate that the temporal resolution of attention for a single target depends on gender but is not affected by aging, whereas aging specifically affects the efficiency of dividing attention across multiple targets. PMID- 28862710 TI - Letter and symbol identification: No evidence for letter-specific crowding mechanisms. AB - It has been proposed that letters, as opposed to symbols, trigger specialized crowding processes, boosting identification of the first and last letters of words. This hypothesis is based on evidence that single-letter accuracy as a function of within-string position has a W shape (the classic serial position function [SPF] in psycholinguistics) whereas an inverted V shape is obtained when measured with symbols. Our main goal was to test the robustness of the latter result. Our hypothesis was that any letter/symbol difference might result from short-term visual memory processes (due to the partial report [PR] procedures used in SPF studies) rather than from crowding. We therefore removed the involvement of short-term memory by precueing target-item position and compared SPFs with precueing and postcueing. Perimetric complexity was stringently matched between letters and symbols. In postcueing conditions similar to previous studies, we did not reproduce the inverted V shape for symbols: Clear-cut W shapes were observed with an overall smaller accuracy for symbols compared to letters. This letter/symbol difference was dramatically reduced in precueing conditions in keeping with our prediction. Our results are not consistent with the claim that letter strings trigger specialized crowding processes. We argue that PR procedures are not fit to isolate crowding processes. PMID- 28862711 TI - Influence of transcutaneous electrical nerve stimulation on spasticity, balance, and walking speed in stroke patients: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the influence of transcutaneous electrical nerve stimulation in patients with stroke through a systematic review and meta analysis. METHODS: PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases were searched systematically. Randomized controlled trials assessing the effect of transcutaneous electrical nerve stimulation vs placebo transcutaneous electrical nerve stimulation on stroke were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. The primary outcome was modified Ashworth scale (MAS). Meta-analysis was performed using the random-effect model. RESULTS: Seven randomized controlled trials were included in the meta-analysis. Compared with placebo transcutaneous electrical nerve stimulation, transcutaneous electrical nerve stimulation supplementation significantly reduced MAS (standard mean difference (SMD) = -0.71; 95% confidence interval (95% CI) = -1.11 to -0.30; p = 0.0006), improved static balance with open eyes (SMD = -1.26; 95% CI = -1.83 to 0.69; p<0.0001) and closed eyes (SMD = -1.74; 95% CI = -2.36 to -1.12; p < 0.00001), and increased walking speed (SMD = 0.44; 95% CI = 0.05 to 0.84; p = 0.03), but did not improve results on the Timed Up and Go Test (SMD = -0.60; 95% CI=-1.22 to 0.03; p = 0.06). CONCLUSION: Transcutaneous electrical nerve stimulation is associated with significantly reduced spasticity, increased static balance and walking speed, but has no influence on dynamic balance. PMID- 28862712 TI - Enhanced liver fibrosis test as a reliable tool for assessing fibrosis in nonalcoholic fatty liver disease in a clinical setting. AB - BACKGROUND: Liver fibrosis is the main determinant and predictor of the clinical course of nonalcoholic fatty liver disease (NAFLD). To date, a liver biopsy is still considered the gold standard for staging fibrosis. The aim of this study was to investigate the diagnostic accuracy of the commercial enhanced liver fibrosis (ELF) test manufacturer's cutoff value (>=9.8) in identifying severe fibrosis for adult patients with histologically confirmed NAFLD. METHODS: We tested the ELF test in a clinical practice, prospective cohort of 82 consecutive patients who consecutively underwent percutaneous liver biopsy. RESULTS: All stages of liver fibrosis were represented in our cohort, and severe fibrosis was present in 15 of 82 patients (18.3%). The stage of fibrosis was significantly associated with ELF score (Spearman's rho = 0.483, p<0.001). The commercial ELF test manufacturer's cutoff identified severe fibrosis with good sensitivity (86.7%; 95% confidence interval [95% CI], 0.69-1.04) and high specificity (92.5%; 95% CI, 0.86-0.99), with a positive predictive value of 72% and negative predictive value of 97%. CONCLUSIONS: Our data could support the use of the ELF test in clinical practice. PMID- 28862713 TI - Meta-analysis of microRNAs as potential biomarkers for detecting esophageal carcinoma in Asian populations. AB - BACKGROUND:: An Increasing number of studies in the literature have shown that microRNAs (miRNAs) can be used as early diagnostic markers for esophageal carcinoma (EC), but their conclusions remain controversial. Hence, we performed this meta-analysis to evaluate the diagnostic accuracy of using miRNAs in EC and to provide an experimental basis for early diagnosis of the disease. METHODS:: This meta-analysis included 39 Asian studies from 18 articles, which covered 3,708 EC patients and 2,689 healthy controls. We used a bivariate random-effects model, the chi-square test and the I2 test to assess sensitivity and heterogeneity. RESULTS:: Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of miRNAs for diagnosis of EC in Asians reached 0.798, 0.785, 3.705, 0.257 and 14.391, respectively. Additionally, the area under the summary receiver operating characteristic curve was 0.86. Subgroup analysis based on research country (China vs. Japan), sample types (plasma vs. serum) and miRNAs (single vs. multiple; singly reported miRNAs vs. repeatedly reported miRNAs) showed no significant difference in accuracy of diagnosis for each subgroup. CONCLUSIONS:: MiRNAs can distinguish EC patients from healthy controls. Blood-based miRNAs have better diagnostic value in detecting EC than saliva-based miRNAs, whereas both serum and plasma are recommended for clinical specimens for miRNA detection. PMID- 28862714 TI - Serum albumin levels in relation to tumor parameters in hepatocellular carcinoma patients. AB - BACKGROUND: Serum albumin levels have been shown to have prognostic significance in hepatocellular carcinoma (HCC), as part of an inflammatory index. The aim of this study was to examine the possible relationship of serum albumin levels to parameters of HCC aggressiveness. METHODS: A large HCC patient cohort was retrospectively examined, and the possible relationships of albumin levels to tumor diameter, multifocality, portal vein thrombosis (PVT) and alpha-fetoprotein levels were examined. RESULTS: HCC patients with lower serum albumin levels had significantly larger maximum tumor diameters, greater prevalence of PVT, increased tumor multifocality and higher alpha-fetoprotein levels, than HCC patients with higher albumin levels. A correlation was found between levels of these tumor parameters and serum albumin levels. CONCLUSIONS: These results indicate that low serum albumin levels correlate with increased parameter measures of HCC aggressiveness, in addition to their role as a monitor of systemic inflammation. Decreased serum albumin might have a role in HCC aggressiveness. PMID- 28862715 TI - Prognostic role of EZH2 in gliomas: a meta-analysis. AB - BACKGROUND: The aim of this study was to elucidate the clinicopathological significance of enhancer of zeste homolog 2 (EZH2) expression in gliomas, including its incidence and prognostic role. In addition, we investigated the concordance between immunohistochemistry and polymerase chain reaction for determining the presence or absence of EZH2 in these tumors. METHODS: The current meta-analysis included 1,049 gliomas with various WHO tumor grades from 12 eligible studies, which were analyzed for positivity of EZH2 and correlation between EZH2 expression and prognosis. Subgroup analyses were performed based on detection methods and WHO tumor grades. RESULTS: We found the estimated positive rate of EZH2 in gliomas to be 0.663 (95% confidence interval [95% CI], 0.549 0.761). There was no difference between immunohistochemistry and polymerase chain reaction in determination of EZH2 positivity (0.706, 95% CI, 0.539-0.831 vs. 0.673, 95% CI, 0.472-0.825). The positive rate of EZH2 increased by increasing WHO tumor grade. EZH2 expression was significantly correlated with worse overall and progression-free survival (hazard ratio [HR] = 2.436, 95% CI, 1.350-4.393, and HR = 4.071, 95% CI, 1.325-12.508, respectively). The overall concordance rate between immunohistochemistry and polymerase chain reaction was 0.885 (95% CI, 0.300-0.993). CONCLUSIONS: EZH2 positivity was significantly correlated with WHO tumor grade and worse prognosis in gliomas. PMID- 28862716 TI - Role of PSA response as a marker for efficacy of patients with castration resistant prostate cancer treated with novel hormonal therapies. PMID- 28862717 TI - An original valveless artificial heart providing pulsatile flow tested in mock circulatory loops. AB - PURPOSE: We present the test bench results of a valveless total artificial heart that is potentially compatible with the pediatric population. METHODS: The RollingHeart is a valveless volumetric pump generating pulsatile flow. It consists of a single spherical cavity divided into 4 chambers by 2 rotating disks. The combined rotations of both disks produce changes in the volumes of the 4 cavities (suction and ejection). The blood enters/exits the spherical cavity through 4 openings that are symmetrical to the fixed rotation axis of the first disk.Mock circulatory system: The device pumps a 37% glycerin solution through 2 parallel circuits, simulating the pulmonary and systemic circulations. Flow rates are acquired with a magnetic inductive flowmeter, while pressure sensors collect pressure in the left and right outflow and inflow tracts.In vitro test protocol: The pump is run at speeds ranging from 20 to 180 ejections per minute. The waveform of the pressure generated at the inflow and outflow of the 4 chambers and the flow rate in the systemic circulation are measured. RESULTS: At an ejection rate of 178 min-1, the RollingHeart pumps 5.3 L/min for a systemic maximal pressure gradient of 174 mmHg and a pulmonary maximal pressure gradient of 75 mmHg. The power input was 14 W, corresponding to an efficiency of 21%. CONCLUSIONS: The RollingHeart represents a new approach in the domain of total artificial heart. This preliminary study endorses the feasibility of a single valveless device acting as a total artificial heart. PMID- 28862719 TI - Kinematic analysis of new and used reciprocating endodontic motors in 2 different modes. AB - PURPOSE: The actual reciprocating angles of endodontic motors might differ from the manufacturers' set values. This study analyzed the effect of clinical usage on the kinematics of reciprocating endodontic motors with 2 different reciprocal modes. METHODS: 1 new and 3 used reciprocating endodontic motors (X-Smart Plus, Dentsply Maillefer) with 2 different reciprocating modes, WaveOne mode (W-mode) or Reciproc mode (R-mode), were analyzed. An angle measurement disc was inserted into a contra-angle. Reciprocating motions were recorded with a high-speed camera at 1,200 fps and analyzed on a computer. The following kinematic parameters were calculated: duration of each reciprocating motion, engaging and disengaging angles, cycle rotational speeds, engaging and disengaging rotational speeds, net cycle angle, total cycle angle, and number of cycles to complete full rotation. One-way ANOVA and Kruskal-Wallis test followed by multiple comparison tests were used for statistical analysis (p = 0.05). RESULTS: In W-mode, the actual engaging angles of all used and new motors were different from the manufacturer's set values (p<0.0001), whereas there was no difference between actual engaging angles among the motors (p>0.05). In R-mode, the actual engaging angles of all used and new motors were similar to the manufacturers' set values (p>0.05). There was no difference between the actual engaging angles among motors (p>0.05). Both the W mode and R-mode showed statistically different values of actual disengaging angles for all used and new motors when compared with the manufacturers' set value (p<0.0001). CONCLUSIONS: This study confirmed that the actual kinematics of reciprocating endodontic motors differ from the manufacturers' set values. Some kinematic parameters were influenced by the clinical usage of the motors. PMID- 28862718 TI - Clinical impact of regional citrate anticoagulation in continuous renal replacement therapy in critically ill patients. AB - BACKGROUND: Regional citrate anticoagulation (RCA) is being used increasingly in continuous renal replacement therapy (CRRT) as a safer alternative to heparin. However, complex metabolic control to avoid side effects have generated discrepancies about its introduction into everyday practice. We aimed to compare both anticoagulation techniques in terms of efficacy, safety and feasibility. METHODS: Observational retrospective study performed in 3 specialized ICUs in patients receiving CVVHDF with RCA between January 2013 and May 2016. Heparin treated patients matched by age, sex and disease severity treated in the preceding year were selected as historic controls. Filter lifetime, number of filters used, haemorrhagic complications and metabolic complications were recorded. RESULTS: 54 patients (27 treated with RCA and 27 with heparin) were included in the study. Filter lifetimes in the first 72 hours were 55.1 +/- 21.8 hours in the RCA group compared to 38.8 +/- 24.8 hours in the heparin group, (p = 0.004). In addition, the number of filters used in the first 72 hours was significantly higher in the heparin group (2.4 +/- 1.3 vs. 1.5 +/- 0.7; p = 0.004). There was a trend toward a lower incidence of bleeding in the RCA group, with a significantly lower red blood cell transfusion rate (p = 0.027) in the citrate group. No clinically significant metabolic disturbances were observed in the RCA group. Regarding outcomes, there were no significant differences between groups. CONCLUSIONS: These results suggest that the implementation of CVVHDF with RCA using concentrated citrate solutions prolongs filter lifetime, achieves a longer effective hemodiafiltration time and is a safe and feasible method. PMID- 28862720 TI - Effect of the different implant protocols on peri-implant bone: a 6-month prospective study in beagle dogs. AB - OBJECTIVE: To compare the effects of different implant placement and loading protocols on the marginal bone loss (MBL) in beagles by intraoral radiography. METHODS AND MATERIALS: 61 dental implants were inserted on 9 beagle dogs at bilateral lower posteriors according to 8 different protocols: immediate implant placement and immediate loading for 3 months (IIP + IL3) or 6 months (IIP + IL6) and unloading (IIP + UL), immediate implant placement and delayed loading for 3 months (IIP + DL3) or 6 months (IIP + DL6), delayed implant placement and immediate loading for 3 months (DIP + IL3) or delayed loading for 3 months (DIP + DL3) and unloading (DIP + UL). Intraoral radiography was performed to analyze the MBL during each surgery, before and after the implant placement and at 3-month intervals after the procedure. RESULTS: In total, 57 samples were included. There was less MBL (p<0.05) in the IIP + IL3 group (1.22 +/- 0.63 mm) compared to the DIP + IL3 group (1.89 +/- 0.9 mm). The longer the loading time, the more bone loss appeared in the IIP + IL group; however, the results were reversed in the IIP + DL group. The MBL during the latter 3-month period was dramatically decreased compared to the former 3-month period in the IIP + DL3 group (p<0.05). CONCLUSIONS: The IIP + IL group seems superior to the DL protocol and the MBL changed significantly during the first three months and thereafter became stable. PMID- 28862721 TI - In vitro benchmark of cytokine removal by dialyzers with various permeability profiles. AB - PURPOSE: Removal of cytokines is relevant for dialysis patients as they are suspected to promote cardiovascular complications. The objective of this study was to benchmark membranes with different permeability profiles under standardized in vitro test conditions using miniaturized devices with respect to their ability to remove cytokines from human serum and to lower cell activating potential. METHODS: In vitro dialysis was used to dialyze cytokine enriched serum in 3 independent experiments per tested membrane. IL-6 in the serum and dialysate was measured at defined times by enzyme-linked immunosorbent assay. IL-8, IL 1beta, IL-6 and TNF-alpha in dialysate were measured by immunoassay. Dialysate samples were subjected to cultured tubular epithelial cells or human fibroblasts to study cell activation via IL-6 generation. Dialysate samples were added to human whole blood with subsequent analysis of granulocyte and monocyte activation by detection of CD11b. RESULTS: IL-6 decreased in serum and increased in dialysate during in vitro dialysis. IL-8, IL-1beta, and TNF-alpha were identified in dialysate. Dialysate added to cell cultures increased IL-6 concentration in culture medium or increased expression of CD11b. High cut-off membranes showed the strongest transfer of cytokines, albumin and total proteins from serum to dialysate and led to strongest cell activation. This effect was lower for medium cut-off membranes and lowest for conventional high-flux membranes. CONCLUSIONS: This study demonstrated an in vitro test by which membranes were benchmarked with respect to cytokine and cell activation removal capacity. Cell activation levels could be influenced by the choice of membrane by altering cytokine concentration levels. PMID- 28862723 TI - Experimental investigation on the mechanical behavior of polyurethane PICCs after long-term conservation in in vivo-like conditions. AB - INTRODUCTION: In a previous paper, the authors investigated the mechanical behavior of several commercial polyurethane peripherally inserted central venous catheters (PICCs) in their 'brand new' condition. The present study represents a second step of the research activity and aims to investigate possible modifications of the PICC mechanical response, induced by long-term conservation in in vivo-like conditions, particularly when used to introduce oncologic drugs. METHODS: Eight 5 Fr single-lumen catheters from as many different vendors, were examined. Several specimens were cut from each of them and kept in a bath at 37 degrees C for 1, 2, 3 and 6 months. Two fluids were used to simulate in vivo-like conditions, i.e. ethanol and Ringer-lactate solutions, the first being chosen in order to reproduce a typical chemical environment of oncologic drugs. The test plan included swelling analyses, uniaxial tensile tests and dynamic mechanical thermal analysis (DMTA). RESULTS AND CONCLUSIONS: All tested samples were chemically and mechanically stable in the studied conditions, as no significant weight variation was observed even after six months of immersion in ethanol solution. Uniaxial tensile tests confirmed such a response. For each PICC, very similar curves were obtained from samples tested after different immersion durations in the two fluid solutions, particularly for strains lower than 10%. PMID- 28862724 TI - Abstracts from the American Society of Diagnostic and Interventional Nephrology 13th Annual Scientific Meeting. AB - Abstracts from the American Society of Diagnostic and Interventional Nephrology 13th Annual Scientific Meeting, 10-12 February 2017, New Orleans, USA. PMID- 28862722 TI - Associations of physical activity energy expenditure with nutritional inflammatory markers in hemodialysis patients. AB - BACKGROUND: Sedentariness, high inflammation status and malnutrition are highly prevalent in end-stage kidney disease patients on maintenance hemodialysis (MHD). This study investigated associations of weekly physical activity energy expenditure (PAEE) with clinical and anthropometric markers of nutrition and inflammation. METHODS: The analysis was performed using baseline cross-sectional data of 640 patients enrolled in the prospective cohort "The Prospective Study of the Prognosis of Patients Treated Chronically by Hemodialysis" (PROHEMO) developed in Salvador, BA, Brazil. The long version of the International Physical Activity Questionnaire was used to determine a summary measure of PAEE, the metabolic equivalent of task (MET), taking into account physical activities related to occupation, recreation, travel, sports, and housework. PAEE was the predictor variable. To assess associations of PAEE with outcomes, the sex-age specific median MET was used. The malnutrition-inflammation score (MIS) with range of 0 to 30 (higher is worse), conicity index as indicator of abdominal adiposity and C-reactive protein (CRP) were the nutritional-inflammatory outcomes. RESULTS: The mean age of the patients was 48.9 +/- 13.8 y, 60.3% were males, 16.7% diabetic, 88.1% nonwhite. In multivariable logistic regression models with adjustments for sociodemographic variables and comorbidities, PAEE <=median was associated with MIS >=6 (odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.08, 2.29), conicity index >=1.3 (OR = 1.52, 95% CI = 1.03, 2.23) and CRP >1.30 mg/dL (OR = 1.69, 95% CI = 1.08, 2.84). CONCLUSIONS: Greater physical activity assessed by PAEE was associated with indicators of better nutritional and inflammation status. These results indicate opportunities for improving outcomes in MHD patients by counseling and treatment intervention. PMID- 28862725 TI - Longitudinal dialysis adequacy and clinical performance of the VectorFlow hemodialysis catheter: a prospective study. AB - PURPOSE: To report clinical performance and longitudinal assessment of hemodialysis adequacy with the Arrow-Clark VectorFlow catheter, a symmetrical-tip device with a distal lumen configuration designed to reduce platelet shear stress and catheter thrombosis. METHODS AND MATERIALS: We prospectively enrolled patients who required de novo placement of a chronic tunneled catheter for hemodialysis or exchange of a dysfunctional catheter as part of an Institutional Review Board (IRB)-approved protocol. Catheter patency, Kt/V, mean blood-flow (Qb), and pump pressures were obtained at baseline and at monthly intervals to 90 days. RESULTS: Forty-six subjects were enrolled into the study. During the 90-day observation period, maximum blood-flow rate averaged 355-398 mL/minute; mean Qb averaged 333-392 mL/minute. Mean Kt/V values were consistently >=1.5. Dwell-time was 15-114 days, for a total of 2997 catheter days (mean 71.4 days). Excluding patients who died during the study and those receiving surgical access, overall intervention-free catheter patency rate was 94.9%, 92.2% and 88.8% at days 30, 60, 90, respectively. There were no acute complications. During the follow-up period, three patients developed complications (6.5%). Two catheter infections occurred (0.7/1000 catheter days) and one catheter malfunctioned; a rate of 1.0/ 1000 catheter days for all complications. CONCLUSIONS: The VectorFlow catheter produced safe, effective hemodialysis with Kt/V >=1.5. A single catheter occlusion occurred and a low rate of infection was seen. Results support the hypothesis that the VectorFlow design reduces thrombogenic risk during clinical performance. PMID- 28862726 TI - The therapeutic approach to different forms of cystitis: impact on public health. AB - Interstitial cystitis/bladder pain syndrome, recurrent urinary tract infections and other forms of cystitis significantly impact the quality of life of patients with chronic bladder disorders and impose a considerable economic burden on health systems. Effective management is essential to provide symptom relief and to reduce the negative impact of chronic bladder disorders. Identifying the appropriate pharmacological or non-pharmacological approach is essential, and there is a growing evidence base for the use of intravesical hyaluronic acid and chondroitin sulfate in several bladder conditions, including recurrent urinary tract infections. PMID- 28862727 TI - Bladder pain: the patient perspective. AB - Patients with chronic pain, discomfort and other urinary symptoms related to bladder pain syndrome or urinary tract infections may experience severely diminished quality of life and psychological and social problems, including depression, anxiety, and a sense of helplessness and hopelessness. These patients require empathy, understanding and practical support to allow them to cope with their chronic bladder disorder. PMID- 28862728 TI - Value of triphasic MDCT in the differentiation of small renal cell carcinoma and oncocytoma. AB - INTRODUCTION: Although differentiation between benign and malignant small renal tumors (<=4 cm) is still difficult, it is a demand for decision making and determining the treatment strategy. Our aim is to evaluate the role of multidetector row computed tomography (MDCT) in the differentiation of small renal clear cell carcinoma (RCC) and renal oncocytoma (RO). METHODS: We reviewed triphasic computed tomographic (CT) scans performed in 43 patients diagnosed with RCC (n = 23) and RO (n = 21). After an unenhanced CT phase of the upper abdomen, triple-phase acquisition included a cortico-medullary phase (CMP), a nephrographic phase (NP), and a pyelographic phase (PP), and lesions were evaluated both qualitatively and quantitatively. RESULTS: RCCs were hypervascular in 13 cases and hypovascular in 10 cases, while ROs were hypervascular in nine cases and hypovascular in 12 cases. Mean attenuation values (MAVs) for hypervascular RCCs and hypervascular ROs on unenhanced examination were 34.0 +/- 7.1 and 31.3 +/- 8.1 HU, respectively. Enhancement in CMP was 173.1 +/- 45.2 HU for RCCs and 151.1 +/- 36.0 HU for ROs and a gradual wash-out in NP (148.8 +/- 34.3 and 137.1 +/- 33.9 HU for RCCs and ROs, respectively) and in PP (98.2 +/- 36.0 HU for RCCs and 79.4 +/- 21.5 HU for ROs) was observed. MAV for hypovascular RCCs and hypovascular ROs on unenhanced examination were 32.4 +/- 12.0 and 28.9 +/- 8.0 HU, respectively. Both hypovascular RCCs and ROs showed a statistically significant difference in each post contrastographic phase. CONCLUSIONS: Absolute attenuation and the quantitative amount of the enhancement were not strong predictors for RO and RCC differentiation. PMID- 28862729 TI - ls clinical practice aligned with the latest scientific evidence on GAG therapy? AB - The role of glycosaminoglycans (GAGs) as key components of the protective bladder barrier is well accepted. Replenishment of the GAG layer could restore the normal protective barrier function of the damaged bladder urothelium and re-establish normal permeability. A number of bladder diseases, including interstitial cystitis/bladder pain syndrome, recurrent urinary tract infections, radiation cystitis, and other forms of cystitis may benefit from GAG therapy. PMID- 28862730 TI - Intravesical glycosaminoglycan therapy - overall conclusions. PMID- 28862731 TI - Cystitis and pelvic pain management: guidelines versus real-world practice. AB - Clinical practice guidelines for the management of bladder pain syndrome/chronic pelvic pain aim to help guide clinicians in diagnosing and treating patients they see on a day-to-day basis in the clinic. However, the approaches suggested by current clinical guidelines may not always align with the practicalities of routine clinical practice, where patient expectations must also be taken into consideration. PMID- 28862732 TI - Preparation, bioactivity and mechanism of nano-hydroxyapatite/sodium alginate/chitosan bone repair material. AB - BACKGROUND: As the major inorganic component of natural bone, nano-hydroxyapatite (n-HA) on its own is limited in its use in bone repair, due to its brittleness. Chitosan (CS) and sodium alginate (SAL) are used to reduce its brittleness and tendency to degradation. However, the compressive strength of the composite is still low, and its biological performance needs further study. METHODS: Nano hydroxyapatite/sodium alginate/chitosan (n-HA/SAL/CS) composite was prepared via an in situ synthesis method. Further, we prepared the n-HA/SAL/CS self-setting bone repair material by mixing n-HA/SAL/CS powder with a curing liquid (20 wt.% citric acid). In addition, the in vitro bioactivity and cell cytotoxicity were also explored. RESULTS: Transmission electron microscopy photos revealed that the n-HA crystals were uniformly distributed throughout the polymer matrix. Infrared IR spectroscopy indicated that the HA interacted with the COO- of SAL and NH2- of CS. The compressive strength of the n-HA/SAL/CS bone cement was 34.3 MPa and matched the demands of weight-bearing bones. Soaking in vitro in simulated body fluid demonstrated that the composite material had reasonably good bioactivity, while cytotoxicity tests indicated that the n-HA/SAL/CS cement could promote cell proliferation and was biocompatible. CONCLUSIONS: Compressive strength of n HA/SAL/CS can satisfy the needs of cancellous bone, and in vitro bioactivity and cytotoxicity tests results indicated that the n-HA/SAL/CS composite could act as an optimal bone repair material. PMID- 28862733 TI - Load-bearing capacity and fracture behavior of glass fiber-reinforced composite cranioplasty implants. AB - BACKGROUND: Glass fiber-reinforced composites (FRCs) have been adapted for routine clinical use in various dental restorations and are presently also used in cranial implants. The aim of this study was to measure the load-bearing capacity and failure type of glass FRC implants during static loading with and without interconnective bars and with different fixation modes. METHODS: Load bearing capacities of 2 types of FRC implants with 4 different fixation modes were experimentally tested. The sandwich-like FRC implants were made of 2 sheets of woven FRC fabric, which consisted of silanized, woven E-glass fiber fabrics impregnated in BisGMA-TEGDMA monomer resin matrix. The space between the outer and inner surfaces was filled with glass particles. All FRC implants were tested up to a 10-mm deflection with load-bearing capacity determined at 6-mm deflection. The experimental groups were compared using nonparametric Kruskal Wallis analysis with Steel-Dwass post hoc test. RESULTS: FRC implants underwent elastic and plastic deformation until 6-mm deflection. The loading test did not demonstrate any protrusions of glass fibers or cut fiber even at 10-mm deflection. An elastic and plastic deformation of the implant occurred until the FRC sheets were separated from each other. In the cases of the free-standing setup (no fixation) and the fixation with 6 screws, the FRC implants with 2 interconnective bars showed a significantly higher load-bearing capacity compared with the implant without interconnective bars. CONCLUSIONS: FRC implants used in this study showed a load-bearing capacity which may provide protection for the brain after cranial bone defect reconstruction. PMID- 28862734 TI - Utility of Bruch membrane opening-based optic nerve head parameters in myopic subjects. AB - PURPOSE: To evaluate whether the new rim analysis software with spectral-domain optical coherence tomography (SD-OCT) shows advantages over the retinal nerve fiber layer (RNFL) thickness in patients with moderate myopia. METHODS: In this prospective cross-sectional study, we studied 65 healthy subjects, 37 with spherical refractive errors in the range of -3 to -6 D (moderate, G1) and 28 with less than -3 D (low/non-myopic, G0). All patients were examined with Heidelberg Spectralis SD-OCT, including Glaucoma Premium Module Edition (GPME) software. With GPME, we analyzed the neuroretinal rim (Bruch membrane opening-minimum rim width [BMO-MRW]) and RNFL. RESULTS: The average age of subjects was 30.2 +/- 9.3 years for G0 and 29.9 +/- 7.1 years for G1 (p = 0.903). Mean sphere was -0.5 +/- 0.3 D (-1.25 to 0 D) G0 and -3.9 +/- 0.3 D (-6.00 to -3 D) G1 (p<0.001). The RNFL thickness comparison between G0 and G1 showed a significantly lower thickness in G1 (p = 0.018). The BMO-MRW measurements were similar in both groups (p = 0.331). With the BMO-MRW examination, the number of sectors classified as pathologic per subject in G1 were significantly lower compared to RNFL analysis (p = 0.023). CONCLUSIONS: Ring analysis based on BMO-MRW measurements shows a lower rate of false-positives compared to RNFL thickness when studying healthy moderate myopic eyes and it would be advisable to take this into consideration when analyzing these patients. PMID- 28862735 TI - Author's Reply to Comments to: Real-World Outcomes of Anti-VEGF Treatment for Retinal Vein Occlusion in Portugal. PMID- 28862736 TI - Long-term results of pars plana vitrectomy as an anti-inflammatory therapy of pediatric intermediate uveitis resistant to standard medical treatment. AB - PURPOSE: To evaluate the efficacy of pars plana vitrectomy (PPV) as an anti inflammatory therapy in pediatric recurrent intermediate uveitis. METHODS: A retrospective study evaluated the long-term results of PPV indicated for intermediate uveitis with a mean observation period of 10.3 years (range 7-15.6 years) in 6 children (mean age 8 years, range 6-12 years). Pars plana vitrectomy was performed on 10 eyes in the standard manner and was initiated by vitreous sampling for laboratory examination. Data recorded were perioperative or postoperative vitrectomy complications, anatomic and functional results of PPV, and preoperative and postoperative best-corrected Snellen visual acuity. RESULTS: No perioperative or postoperative complications were observed. Bacteriologic, virologic, mycotic, and cytologic analysis of the vitreous was negative in all tested children. Five eyes were subsequently operated on for posterior subcapsular cataracts. An average preoperative visual acuity of 0.32 improved to an average postoperative visual acuity of 0.8. CONCLUSIONS: In the case of systemic immunosuppressive treatment failure in pediatric uveitis, particularly in eyes with cystoid macular edema, we recommend PPV relatively early. PMID- 28862737 TI - Primary bone lymphoma of the talus: a challenging diagnosis. AB - PURPOSE: Diagnostic challenges are common in clinical practice and diagnostic or classification criteria for musculoskeletal conditions cannot overshadow clinical skills. METHODS: We present the case of a young man who complained of prolonged articular pain and mild swelling of the right ankle in the absence of other remarkable data. Apparently fulfilling the Budapest diagnostic criteria for complex regional pain syndrome, the patient was treated accordingly, but the pain increased over time. Then the patient underwent an additional diagnostic workup including synovial and bone biopsies in 2 separate occasions with the second one demonstrating diffuse lymphoid infiltrate compatible with lymphoma. RESULTS: The conclusive diagnosis of primary diffuse large B-cell lymphoma of the talus was made and adequate treatment initiated. CONCLUSIONS: The diagnostic difficulties as well as the importance of a multidisciplinary approach for complex cases are highlighted in this report. PMID- 28862738 TI - Doppler-based fetal heart rate analysis markers for the detection of early intrauterine growth restriction. AB - INTRODUCTION: One indicator for fetal risk of mortality is intrauterine growth restriction (IUGR). Whether markers reflecting the impact of growth restriction on the cardiovascular system, computed from a Doppler-derived heart rate signal, would be suitable for its detection antenatally was studied. MATERIAL AND METHODS: We used a cardiotocography archive of 1163 IUGR cases and 1163 healthy controls, matched for gestation and gender. We assessed the discriminative power of short-term variability and long-term variability of the fetal heart rate, computed over episodes of high and low variation aiming to separate growth restricted fetuses from controls. Metrics characterizing the sleep state distribution within a trace were also considered for inclusion into an IUGR detection model. RESULTS: Significant differences in the risk markers comparing growth-restricted with healthy fetuses were found. When used in a logistic regression classifier, their performance for identifying IUGR was considerably superior before 34 weeks of gestation. Long-term variability in active sleep was superior to short-term variability [area under the receiver operator curve (AUC) of 72% compared with 71%]. Most predictive was the number of minutes in high variation per hour (AUC of 75%). A multivariate IUGR prediction model improved the AUC to 76%. CONCLUSION: We suggest that heart rate variability markers together with surrogate information on sleep states can contribute to the detection of early-onset IUGR. PMID- 28862739 TI - Functional role of Lys residues of Psb31 in electrostatic interactions with diatom photosystem II. AB - We recently revealed that positively charged amino acids of Psb31, an extrinsic subunit found in diatom photosystem II (PSII), are involved in electrostatic interactions with PSII intrinsic subunits. However, the molecular interactions of Psb31 with PSII remain unclear. Here, we report the functional contribution of Lys residues in the binding of Psb31 to PSII using site-directed mutants of Psb31. Each of the K33A, K39A, K54A, K56A, K57A, and K69A mutants exhibits decreased binding affinities to PSII concomitantly with decreases in the O2 evolution activity. Conversely, each of the K24A, K76A, K80A, and K117A mutants functionally binds to PSII in a manner similar to wild-type Psb31. These results provide evidence that some Lys residues of Psb31 are responsible for electrostatic interactions with PSII. PMID- 28862740 TI - Dynamics of M1 macrophages in oral mucosal lesions during the development of acute graft-versus-host disease in rats. AB - The role of macrophage infiltrates in oral mucosal acute graft-versus-host disease (AGVHD) remains unclear, although clinical studies suggest that macrophage infiltration correlates directly with the severity of AGVHD. In this study, we investigated the role of M1 macrophage infiltration in the oral mucosa of rats with AGVHD. Lewis rat spleen cells were injected into (Lewis * Brown Norway) F1 rats to induce systemic GVHD. Tongue samples were evaluated using histology, immunohistochemistry, dual immunofluorescence, real-time reverse transcription-polymerase chain reaction, Transwell migration assays and Stamper Woodruff binding assays. At the onset of oral mucosal AGVHD, dual immunofluorescence and migration assays revealed that M1 macrophages had accumulated in the basement membrane (BM) region via the laminin/CD29 beta1 integrin pathway. Macrophage-secreted matrix metalloproteinase-2 was related to BM degradation. The adhesion of macrophages to the oral epithelium could be inhibited by pretreating macrophages with a CC chemokine receptor 2 (CCR2) antibody and/or pretreating lesion sections with monocyte chemoattractant protein 1 (MCP-1) antibody. Our data show that the migration and adhesion of M1 macrophages are associated with oral mucosal AGVHD, which is mediated in part by both laminin/CD29 beta 1 intern and MCP-1/CCR2 pathways. Therefore, our study provides additional support for the contribution of macrophage infiltrate to the development of oral mucosal AGVHD. PMID- 28862742 TI - Transcription factor retention on mitotic chromosomes: regulatory mechanisms and impact on cell fate decisions. AB - During mitosis, gene transcription stops, and the bulk of DNA-binding proteins are excluded from condensed chromosomes. While most gene-specific transcription factors are largely evicted from mitotic chromosomes, a subset remains bound to specific and non-specific DNA sites. Here, we review the current knowledge on the mechanisms leading to the retention of a subset of transcription factors on mitotic chromosomes and discuss the implications in gene expression regulation and their potential as an epigenetic mechanism controlling stem cell self-renewal and differentiation. PMID- 28862743 TI - Negative pressure therapy versus passive open abdominal drainage for the treatment of septic peritonitis in dogs: A randomized, prospective study. AB - OBJECTIVE: To compare passive open abdominal drainage (POAD) and negative pressure abdominal drainage (NPAD) using the ABTheraTM system in the treatment of septic peritonitis. STUDY DESIGN: Randomized prospective clinical trial. ANIMALS: Dogs (n = 16) with septic peritonitis. METHODS: Dogs with septic peritonitis were randomly assigned to one of two treatment protocols: NPAD versus POAD. Anesthesia time, operating time, duration of drainage, costs, survival, and complications were compared between techniques. Hematological and biochemical parameters in blood and abdominal fluid, and histopathological findings of omentum and abdominal wall tissue samples were compared between NPAD and POAD at time of initial surgery and at time of closure. RESULTS: Overall survival was 81%. Treatment costs, anesthesia and operating time, drainage time, survival, and postoperative complications were similar between techniques. Loss of total plasma protein and decreased inflammation-related factors in abdominal fluid at time of closure were noted in all patients. Neutrophilic inflammation was greater in abdominal wall samples after NPAD. POAD patients showed discomfort during bandage changes and had frequent leakage of abdominal fluid outside of the bandage. CONCLUSION: NPAD is an effective alternative to POAD for treatment of septic peritonitis, based on costs and survival. NPAD resulted in less abdominal fluid leakage, and evidence of superior healing on histological evaluation of abdominal tissues. PMID- 28862741 TI - Radial glia in the ventral telencephalon. AB - The ventral telencephalon is the developmental origin of the basal ganglia and the source of neuronal and glial cells that integrate into developing circuits in other areas of the brain. Radial glia in the embryonic subpallium give rise to an enormous diversity of mature cell types, either directly or through other transit amplifying progenitors. Here, we review current knowledge about these subpallial neural stem cells and their progeny, focusing on the period of neurogenesis. We describe their cell biological features and the extrinsic and intrinsic molecular codes that guide their fate specification in defined temporal and spatial sequences. We also discuss the role of clonal lineage in the organization and specification of mature neurons. PMID- 28862745 TI - Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease. AB - Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels. PMID- 28862746 TI - Extended specificity studies of mRNA assays used to infer human organ tissues and body fluids. AB - Messenger RNA (mRNA) profiling is a technique increasingly applied for the forensic identification of body fluids and skin. More recently, an mRNA-based organ typing assay was developed which allows for the inference of brain, lung, liver, skeletal muscle, heart, kidney, and skin tissue. When applying this organ typing system in forensic casework for the presence of animal, rather than human, tissue is an alternative scenario to be proposed, for instance that bullets carry cell material from a hunting event. Even though mRNA profiling systems are commonly in silico designed to be primate specific, physical testing against other animal species is generally limited. In this study, human specificity of the organ tissue inferring system was assessed against organ tissue RNAs of various animals. Results confirm human specificity of the system, especially when utilizing interpretation rules considering multiple markers per cell type. Besides, we cross-tested our organ and body fluid mRNA assays against the target types covered by the other assay. Marker expression in the nontarget organ tissues and body fluids was observed to a limited extent, which emphasizes the importance of involving the case-specific context of the forensic samples in deciding which mRNA profiling assay to use and when for interpreting results. PMID- 28862744 TI - Increased metabolite production by deletion of an HDA1-type histone deacetylase in the phytopathogenic fungi, Magnaporthe oryzae (Pyricularia oryzae) and Fusarium asiaticum. AB - : Histone deacetylases (HDACs) play an important role in the regulation of chromatin structure and gene expression. We found that dark pigmentation of Magnaporthe oryzae (anamorph Pyricularia oryzae) DeltaMohda1, a mutant strain in which an orthologue of the yeast HDA1 was disrupted by double cross-over homologous recombination, was significantly stimulated in liquid culture. Analysis of metabolites in a DeltaMohda1 mutant culture revealed that the accumulation of shunt products of the 1,8-dihydroxynaphthalene melanin and ergosterol pathways were significantly enhanced compared to the wild-type strain. Northern blot analysis of the DeltaMohda1 mutant revealed transcriptional activation of three melanin genes that are dispersed throughout the genome of M. oryzae. The effect of deletion of the yeast HDA1 orthologue was also observed in Fusarium asiaticum from the Fusarium graminearum species complex; the HDF2 deletion mutant produced increased levels of nivalenol-type trichothecenes. These results suggest that histone modification via HDA1-type HDAC regulates the production of natural products in filamentous fungi. SIGNIFICANCE AND IMPACT OF THE STUDY: Natural products of fungi have significant impacts on human welfare, in both detrimental and beneficial ways. Although HDA1-type histone deacetylase is not essential for vegetative growth, deletion of the gene affects the expression of clustered secondary metabolite genes in some fungi. Here, we report that such phenomena are also observed in physically unlinked genes required for melanin biosynthesis in the rice blast fungus. In addition, production of Fusarium trichothecenes, previously reported to be unaffected by HDA1 deletion, was significantly upregulated in another Fusarium species. Thus, the HDA1 inactivation strategy may be regarded as a general approach for overproduction and/or discovery of fungal metabolites. PMID- 28862748 TI - Inflammasome-mediated inflammation and fibrosis: It is more than just the IL 1beta. PMID- 28862747 TI - Saccharomyces cerevisiae vineyard strains have different nitrogen requirements that affect their fermentation performances. AB - : In this work the fermentation performances of seven vineyard strains, together with the industrial strain EC1118, have been investigated at three differing yeast assimilable nitrogen (YAN) concentrations (300 mg N l-1 , 150 mg N l-1 and 70 mg N l-1 ) in synthetic musts. The results indicated that the response to different nitrogen levels is strain dependent. Most of the strains showed a dramatic decrease of the fermentation at 70 mg N l-1 but no significant differences in CO2 production were found when fermentations at 300 mg N l-1 and 150 mg N l-1 were compared. Only one among the vineyard strains showed a decrease of the fermentation when 150 mg N l-1 were present in the must. These results contribute to shed light on strain nitrogen requirements and offer new perspectives to manage the fermentation process during winemaking. SIGNIFICANCE AND IMPACT OF THE STUDY: Selected vineyard Saccharomyces cerevisiae strains can improve the quality and the complexity of local wines. Wine quality is also influenced by nitrogen availability that modulates yeast fermentation activity. In this work, yeast nitrogen assimilation was evaluated to clarify the nitrogen requirements of vineyard strains. Most of the strains needed high nitrogen levels to express the best fermentation performances. The results obtained indicate the critical nitrogen levels. When the nitrogen concentration was above the critical level, the fermentation process increased, but if the level of nitrogen was further increased no effect on the fermentation was found. PMID- 28862749 TI - Characterization of a polypeptide-binding site in the DEAD Motor of the SecA ATPase. AB - We coupled peptides from a CNBr digest of signal-sequenceless maltose-binding protein (MBP) to a surface plasmon resonance chip. SecA-N95, SecA-N68, and SecA DM (which consists of only the DEAD Motor domains NBD1 and NBD2) bound to the immobilized peptides; ADP weakened the binding. SecA-DM, which lacks the 'preprotein cross-linking domain' (PPXD), displayed the most extensive binding, while an MBP-PPXD chimera showed no binding, demonstrating that the PPXD does not contribute to the binding. We characterized the sequence specificity using oriented peptide libraries; these results enabled synthesis of a 20-residue peptide that was used to recapitulate the results obtained with MBP-derived peptides. This study shows that there is a promiscuous and nucleotide-modulated peptide-binding site in the DEAD Motor domains of SecA. PMID- 28862750 TI - Erratum: Meta-Analysis Reveals Significant Association of the 3'-UTR VNTR in SLC6A3 With Alcohol Dependence. PMID- 28862752 TI - Thyroid-stimulating hormone and risk of sudden cardiac death, total mortality and cardiovascular morbidity. AB - BACKGROUND: Previous data on the association of thyroid function with total mortality, cardiovascular disease (CVD) outcomes and sudden cardiac death (SCD) are conflicting or limited. We investigated associations of thyroid-stimulating hormone (TSH) with these outcomes in a nationwide population-based prospective cohort study. METHODS: We examined 5211 participants representative of the Finnish population aged >=30 years in 2000-2001 and followed them for a median of 13.2 years. Using Cox proportional hazards regression models adjusted for baseline age, gender, smoking, diabetes, systolic blood pressure and total and high-density lipoprotein cholesterol, we assessed the associations of continuous baseline TSH and TSH categories (low [<0.4 mU/L], reference range [0.4-3.4 mU/L] and high [>3.4 mU/L]) with incident total mortality, SCD, coronary heart disease events, stroke, CVD, major adverse cardiac events and atrial fibrillation. RESULTS: High TSH at baseline was related to a greater risk of total mortality (HR 1.34, 95% CI 1.02-1.76) and SCD (HR 2.28, 95% CI 1.13-4.60) compared with TSH within the reference range. High TSH was not associated with the other outcomes (P >= .51), whereas low TSH was not associated with any of the outcomes (P >= .09). TSH at baseline over the full range did not have a linear relation with any of the outcomes (P >= .17). TSH showed a U-shaped association with total mortality after a restricted cubic spline transformation (P = .01). CONCLUSIONS: Thyroid function abnormalities could be linked with higher risks of total mortality and SCD. Large-scale randomized studies are needed for evidence-based recommendations regarding treatment of mild thyroid failure. PMID- 28862753 TI - Geometrical characterization of fluorescently labelled surfaces from noisy 3D microscopy data. AB - Modern fluorescence microscopy enables fast 3D imaging of biological and inert systems alike. In many studies, it is important to detect the surface of objects and quantitatively characterize its local geometry, including its mean curvature. We present a fully automated algorithm to determine the location and curvatures of an object from 3D fluorescence images, such as those obtained using confocal or light-sheet microscopy. The algorithm aims at reconstructing surface labelled objects with spherical topology and mild deformations from the spherical geometry with high accuracy, rather than reconstructing arbitrarily deformed objects with lower fidelity. Using both synthetic data with known geometrical characteristics and experimental data of spherical objects, we characterize the algorithm's accuracy over the range of conditions and parameters typically encountered in 3D fluorescence imaging. We show that the algorithm can detect the location of the surface and obtain a map of local mean curvatures with relative errors typically below 2% and 20%, respectively, even in the presence of substantial levels of noise. Finally, we apply this algorithm to analyse the shape and curvature map of fluorescently labelled oil droplets embedded within multicellular aggregates and deformed by cellular forces. PMID- 28862754 TI - Single particle raster image analysis of diffusion for particle mixtures. AB - Recently we complemented the raster image correlation spectroscopy (RICS) method of analysing raster images via estimation of the image correlation function with the method single particle raster image analysis (SPRIA). In SPRIA, individual particles are identified and the diffusion coefficient of each particle is estimated by a maximum likelihood method. In this paper, we extend the SPRIA method to analyse mixtures of particles with a finite set of diffusion coefficients in a homogeneous medium. In examples with simulated and experimental data with two and three different diffusion coefficients, we show that SPRIA gives accurate estimates of the diffusion coefficients and their proportions. A simple technique for finding the number of different diffusion coefficients is also suggested. Further, we study the use of RICS for mixtures with two different diffusion coefficents and investigate, by plotting level curves of the correlation function, how large the quotient between diffusion coefficients needs to be in order to allow discrimination between models with one and two diffusion coefficients. We also describe a minor correction (compared to published papers) of the RICS autocorrelation function. PMID- 28862755 TI - Surface relaxation of strained Ga(P,As)/GaP heterostructures investigated by HAADF STEM. AB - The surfaces of thin transmission electron microscopy (TEM) specimens of strained heterostructures can relax. The resulting bending of the lattice planes significantly influences high-angle annular dark field (HAADF) measurements. We investigate the impact by evaluating the intensities measured at the atomic columns as well as their positions in high-resolution HAADF images. In addition, the consequences in the diffraction plane will be addressed by simulated position averaged convergent beam electron diffraction (PACBED) patterns. The experimental column intensities and positions acquired from a strained Ga(P,As) quantum well (QW) embedded in a in a GaP matrix agree very well with frozen phonon contrast simulations, if the surface relaxation is taken into account by finite element relaxation. Neglecting the surface relaxation the As content of the QW can be significantly underestimated. Taking the effects into account correctly, we find that the lower interface of the investigated Ga(P,As) QW is atomically abrupt whereas the upper one is smeared out. PMID- 28862756 TI - hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells. AB - Recently, understanding of protein targeting to the endoplasmic reticulum (ER) was expanded by the discovery of multiple pathways that function in parallel to the signal recognition particle (SRP). Guided entry of tail-anchored proteins and SRP independent (SND) are two such targeting pathways described in yeast. So far, no human SND component is functionally characterized. Here, we report hSnd2 as the first constituent of the human SND pathway able to support substrate-specific protein targeting to the ER. Similar to its yeast counterpart, hSnd2 is assumed to function as a membrane-bound receptor preferentially targeting precursors carrying C-terminal transmembrane domains. Our genetic and physical interaction studies show that hSnd2 is part of a complex network of targeting and translocation that is dynamically regulated. PMID- 28862758 TI - Fremanezumab as Add-On Treatment for Patients Treated With Other Migraine Preventive Medicines. AB - BACKGROUND: Fremanezumab (formerly TEV-48125) is a monoclonal antibody directed against calcitonin-gene-related peptide (CGRP), a validated target for migraine preventive therapy. In two previous phase 2 studies, fremanezumab administered once every 28 days for 12 weeks was found to be effective and safe as a preventive treatment for patients suffering from episodic migraine (EM) and chronic migraine (CM). OBJECTIVE: To evaluate the efficacy and safety of fremanezumab as an add-on preventive therapy in individuals with EM and CM who are on stable doses of preventive migraine medications. METHODS: Two randomized placebo-controlled studies tested once-monthly subcutaneous injections of various dosing regimens of fremanezumab versus placebo in EM and CM. Headache information was captured daily using an electronic headache diary. For these post hoc analyses, data were pooled from patients who were on stable preventive medications and taking fremanezumab doses of 225 mg or 675/225 mg, or placebo. RESULTS: The sample consisted of 133 patients, (67 fremanezumab and 66 placebo). Total reduction in migraine days for the duration of the study was 12.4 for fremanezumab and 7.4 for placebo (P = .0321). There were also decreases in moderate/severe headache days (12.5 vs 7.1, P = .0058), and days using acute medication for headaches relative to placebo (11.6 vs 7.5, P = .0414). Treatment emergent adverse events were generally mild and transient, and no serious adverse events were considered to be treatment-related by the site investigators. CONCLUSIONS: The findings from these post hoc analyses suggest that fremanezumab is a safe and effective add-on treatment for migraine patients being concomitantly treated with other migraine preventive medications. Trials are registered at Clinicaltrials.gov NCT02025556 and NCT02021773. PMID- 28862757 TI - The CCCTC-binding factor (CTCF)-forkhead box protein M1 axis regulates tumour growth and metastasis in hepatocellular carcinoma. AB - CCCTC-binding factor (CTCF) is a DNA-binding protein that interacts with a large number of highly divergent target sequences throughout the genome. It is implicated in a variety of functions, including chromatin organization and transcriptional control. The functional role of CTCF in tumour pathogenesis remains elusive. We showed that CTCF is frequently upregulated in a subset of primary hepatocellular carcinomas (HCCs) as compared with non-tumoural liver. Overexpression of CTCF was associated with shorter disease-free survival of patients. Short hairpin RNA (shRNA)-mediated suppression of CTCF inhibited cell proliferation, motility and invasiveness in HCC cell lines; these effects were correlated with prominent reductions in the expression of telomerase reverse transcriptase (TERT), the shelterin complex member telomerase repeat-binding factor 1, and forkhead box protein M1 (FOXM1). In contrast, upregulation of CTCF was positively correlated with FOXM1 and TERT expression in clinical HCC biopsies. Depletion of CTCF resulted in reduced motility and invasiveness in HCC cells that could be reversed by ectopic expression of FOXM1, suggesting that FOXM1 is one of the important downstream effectors of CTCF in HCC. Reporter gene analysis suggested that depletion of CTCF is associated with reduced FOXM1 and TERT promoter activity. Chromatin immunoprecipitation (ChIP)-polymerase chain reaction (PCR) analysis further revealed occupancy of the FOXM1 promoter by CTCF in vivo. Importantly, depletion of CTCF by shRNA significantly inhibited tumour progression and metastasis in HCC mouse models. Our work uncovered a novel functional role of CTCF in HCC pathogenesis, which suggests that targeting CTCF could be further explored as a potential therapeutic strategy for HCC. (c) 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 28862759 TI - [Potential distribution and geographic characteristics of wild populations of Vanilla planifolia (Orchidaceae) Oaxaca, Mexico]. AB - Wild specimens of Vanilla planifolia represent a vital part of this resource primary gene pool, and some plants have only been reported in Oaxaca, Mexico. For this reason, we studied its geographical distribution within the state, to locate and describe the ecological characteristics of the areas where they have been found, in order to identify potential areas of establishment. The method comprised four stages: 1) the creation of a database with herbarium records, 2) the construction of the potential distribution based on historical herbarium records for the species, using the model of maximum entropy (MaxEnt) and 22 bioclimatic variables as predictors; 3) an in situ systematic search of individuals, based on herbarium records and areas of potential distribution in 24 municipalities, to determine the habitat current situation and distribution; 4) the description of the environmental factors of potential ecological niches generated by MaxEnt. A review of herbarium collections revealed a total of 18 records of V. planifolia between 1939 and 1998. The systematic search located 28 plants distributed in 12 sites in 95 364 Km(2). The most important variables that determined the model of vanilla potential distribution were: precipitation in the rainy season (61.9 %), soil moisture regime (23.4 %) and precipitation during the four months of highest rainfall (8.1 %). The species potential habitat was found to be distributed in four zones: wet tropics of the Gulf of Mexico, humid temperate, humid tropical, and humid temperate in the Pacific. Precipitation oscillated within the annual ranges of 2 500 to 4 000 mm, with summer rains, and winter precipitation as 5 to 10 % of the total. The moisture regime and predominating climate were udic type I (330 to 365 days of moisture) and hot humid (Am/A(C) m). The plants were located at altitudes of 200 to 1 190 masl, on rough hillsides that generally make up the foothills of mountain systems, with altitudes of 1 300 to 2 500 masl. In natural conditions, distribution of the species is not limited to high evergreen forests, since it was also found in mountain mesophyll and tropical evergreen forests. The location of new specimens of V. planifolia in its wild condition reduces the potential distribution area by 66 %. This area is fragmented into three geographically separated areas. Habitat reduction was due to the increased number of located plants that define the environmental conditions into a more accurate level. Conservation actions can thus be designed and implemented, focusing on more specific areas within the state of Oaxaca, Mexico. PMID- 28862761 TI - Effects of pulse duration on muscle fatigue during electrical stimulation inducing moderate-level contraction. AB - INTRODUCTION: Neuromuscular electrical stimulation (NMES) is used to prevent muscle atrophy. However, the effect of pulse duration modulation for reducing muscle fatigue and pain is unknown. METHODS: Two 2-minute stimulation protocols were applied to the knee extensors of 10 healthy individuals. In 1 session, a long pulse duration (1,000 MUs) and a low current amplitude (LL), set to evoke 25% maximal voluntary contraction at 30 Hz, were applied. The other session was identical except that a short pulse duration (200 MUs) and a high current amplitude (SH) were used. RESULTS: Muscle fatigue was lower for LL than for SH (P < 0.01). Force recovery rate was higher for LL than for SH (P < 0.05). Pain scores were also lower for LL than for SH (P < 0.05). DISCUSSION: The use of 1-ms pulse durations reduces fatigue and pain during NMES for moderate-level contractions compared with 200-MUs durations. Muscle Nerve 57: 642-649, 2018. PMID- 28862760 TI - Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma. AB - Aberrant c-Met activity has been implicated in the development of hepatocellular carcinoma (HCC), suggesting that c-Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c-Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This lack of observed efficacy is likely due to several factors, including trial design, lack of patient selection according to tumor c-Met status, and the prevalent off-target activity of these agents, which may indicate that c-Met inhibition is incomplete. In contrast, selective c-Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve complete inhibition of tumor c-Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c-Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child-Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c-Met inhibition compared with standard therapy in patients with HCC that were selected based on tumor c-Met status. Thus, c-Met inhibition continues to be an active area of research in HCC, with well-designed trials in progress to investigate the benefit of selective c-Met inhibitors. (Hepatology 2018;67:1132-1149). PMID- 28862762 TI - Quadricuspid aortic valve infective endocarditis. AB - Infective endocarditis complicating a quadricuspid aortic valve (QAV) is rare. Previous reports highlight the increased risk for complications, including progressive aortic regurgitation, decompensated heart failure, and valve perforation. Thus, cardiologists must be able to quickly identify QAVs to guide rapid evaluation and treatment. We report a case of infective endocarditis in a QAV identified on echocardiography and effectively managed with medical therapy alone without complications over an 8-year follow-up period. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:145-148, 2018. PMID- 28862763 TI - Technical quality of root canal treatment performed by undergraduate students using hand instrumentation: a meta-analysis. AB - The technical quality of root canal treatment (RCT) may impact on the outcome. The quality of education received during undergraduate school may be linked to the quality of treatment provided in general dental practice. In this context, the aim of this systematic review was to answer the following focused questions: (i) What is the frequency of acceptable technical quality of root fillings, assessed radiographically, performed by undergraduate students? (ii) What are the most common errors assessed radiographically and reported in these treatments? For this purpose, articles that evaluated the quality of root fillings performed by undergraduate students were selected. Data were collected based on predetermined criteria. The key features from the included studies were extracted. GRADE-tool assessed the quality of the evidence. MAStARI evaluated the methodological quality, and a meta-analysis on all studies was conducted. At the end of the screening, 24 articles were identified. Overall frequency of acceptable technical quality of root fillings was 48%. From this total, 52% related to anterior teeth, 49% to premolars and 26% to molars. The main procedural errors reported were ledge formation, furcation perforation, apical transportation and apical perforation. The heterogeneity amongst the studies was high (84-99%). Five studies had a high risk of bias, eight had a moderate risk, and 11 had low risk. The overall quality of evidence identified was very low. The conclusion was that technical quality of root fillings performed by undergraduate students is low, which may reveal that endodontic education has limited achievement at undergraduate level. A plan to improve the quality of root fillings, and by extrapolation the overall quality of root canal treatment, should be discussed by the staff responsible for endodontic education and training. PMID- 28862764 TI - Testing a linear time invariant model for skin conductance responses by intraneural recording and stimulation. AB - Skin conductance responses (SCR) are increasingly analyzed with model-based approaches that assume a linear and time-invariant (LTI) mapping from sudomotor nerve (SN) activity to observed SCR. These LTI assumptions have previously been validated indirectly, by quantifying how much variance in SCR elicited by sensory stimulation is explained under an LTI model. This approach, however, collapses sources of variability in the nervous and effector organ systems. Here, we directly focus on the SN/SCR mapping by harnessing two invasive methods. In an intraneural recording experiment, we simultaneously track SN activity and SCR. This allows assessing the SN/SCR relationship but possibly suffers from interfering activity of non-SN sympathetic fibers. In an intraneural stimulation experiment under regional anesthesia, such influences are removed. In this stimulation experiment, about 95% of SCR variance is explained under LTI assumptions when stimulation frequency is below 0.6 Hz. At higher frequencies, nonlinearities occur. In the intraneural recording experiment, explained SCR variance is lower, possibly indicating interference from non-SN fibers, but higher than in our previous indirect tests. We conclude that LTI systems may not only be a useful approximation but in fact a rather accurate description of biophysical reality in the SN/SCR system, under conditions of low baseline activity and sporadic external stimuli. Intraneural stimulation under regional anesthesia is the most sensitive method to address this question. PMID- 28862765 TI - An FMEA evaluation of intensity modulated radiation therapy dose delivery failures at tolerance criteria levels. AB - PURPOSE: The objective of this work was to assess both the perception of failure modes in Intensity Modulated Radiation Therapy (IMRT) when the linac is operated at the edge of tolerances given in AAPM TG-40 (Kutcher et al.) and TG-142 (Klein et al.) as well as the application of FMEA to this specific section of the IMRT process. METHODS: An online survey was distributed to approximately 2000 physicists worldwide that participate in quality services provided by the Imaging and Radiation Oncology Core - Houston (IROC-H). The survey briefly described eleven different failure modes covered by basic quality assurance in step-and shoot IMRT at or near TG-40 (Kutcher et al.) and TG-142 (Klein et al.) tolerance criteria levels. Respondents were asked to estimate the worst case scenario percent dose error that could be caused by each of these failure modes in a head and neck patient as well as the FMEA scores: Occurrence, Detectability, and Severity. Risk probability number (RPN) scores were calculated as the product of these scores. Demographic data were also collected. RESULTS: A total of 181 individual and three group responses were submitted. 84% were from North America. Most (76%) individual respondents performed at least 80% clinical work and 92% were nationally certified. Respondent medical physics experience ranged from 2.5 to 45 yr (average 18 yr). A total of 52% of individual respondents were at least somewhat familiar with FMEA, while 17% were not familiar. Several IMRT techniques, treatment planning systems, and linear accelerator manufacturers were represented. All failure modes received widely varying scores ranging from 1 to 10 for occurrence, at least 1-9 for detectability, and at least 1-7 for severity. Ranking failure modes by RPN scores also resulted in large variability, with each failure mode being ranked both most risky (1st) and least risky (11th) by different respondents. On average MLC modeling had the highest RPN scores. Individual estimated percent dose errors and severity scores positively correlated (P < 0.01) for each FM as expected. No universal correlations were found between the demographic information collected and scoring, percent dose errors or ranking. CONCLUSIONS: Failure modes investigated overall were evaluated as low to medium risk, with average RPNs less than 110. The ranking of 11 failure modes was not agreed upon by the community. Large variability in FMEA scoring may be caused by individual interpretation and/or experience, reflecting the subjective nature of the FMEA tool. PMID- 28862767 TI - Modification of growth anisotropy and cortical microtubule dynamics in Arabidopsis hypocotyls grown under microgravity conditions in space. AB - We carried out a space experiment, denoted as Aniso Tubule, to examine the effects of microgravity on the growth anisotropy and cortical microtubule dynamics in Arabidopsis hypocotyls, using lines in which microtubules are visualized by labeling tubulin or microtubule-associated proteins (MAPs) with green fluorescent protein (GFP). In all lines, GFP-tubulin6 (TUB6)-, basic proline-rich protein1 (BPP1)-GFP- and spira1-like3 (SP1L3)-GFP-expressing using a constitutive promoter, and spiral2 (SPR2)-GFP- and GFP-65 kDa MAP-1 (MAP65-1) expressing using a native promoter, the length of hypocotyls grown under microgravity conditions in space was longer than that grown at 1 g conditions on the ground. In contrast, the diameter of hypocotyls grown under microgravity conditions was smaller than that of the hypocotyls grown at 1 g. The percentage of cells with transverse microtubules was increased under microgravity conditions, irrespective of the lines. Also, the average angle of the microtubules with respect to the transverse cell axis was decreased in hypocotyls grown under microgravity conditions. When GFP fluorescence was quantified in hypocotyls of GFP-MAP65-1 and SPR2-GFP lines, microgravity increased the levels of MAP65-1, which appears to be involved in the maintenance of transverse microtubule orientation. However, the levels of SPR2 under microgravity conditions were comparable to those at 1 g. These results suggest that the microgravity-induced increase in the levels of MAP65-1 is involved in increase in the transverse microtubules, which may lead to modification of growth anisotropy, thereby developing longer and thinner hypocotyls under microgravity conditions in space. PMID- 28862766 TI - Genomic profiles of lung cancer associated with idiopathic pulmonary fibrosis. AB - Little is known about the pathogenesis or molecular profiles of idiopathic pulmonary fibrosis-associated lung cancer (IPF-LC). This study was performed to investigate the genomic profiles of IPF-LC and to explore the possibility of defining potential therapeutic targets in IPF-LC. We assessed genomic profiles of IPF-LC by using targeted exome sequencing (OncoPanel version 2) in 35 matched tumour/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling was performed with GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively. Copy number analysis was conducted with CNVkit, with focal events determined by Genomic Identification of Significant Targets in Cancer 2.0, and pathway analysis (KEGG) with DAVID. Germline mutations in TERT (rs2736100, n = 33) and CDKN1A (rs2395655, n = 27) associated with idiopathic pulmonary fibrosis risk were detected in most samples. A total of 410 somatic mutations were identified, with an average of 11.7 per tumour, including 69 synonymous, 177 missense, 17 nonsense, 1 nonstop and 11 splice-site mutations, and 135 small coding indels. Spectra of the somatic mutations revealed predominant C > T transitions despite an extensive smoking history in most patients, suggesting a potential association between APOBEC-related mutagenesis and the development of IPF-LC. TP53 (22/35, 62.9%) and BRAF (6/35, 17.1%) were found to be significantly mutated in IPF-LC. Recurrent focal amplifications in three chromosomal loci (3q26.33, 7q31.2, and 12q14.3) and 9p21.3 deletion were identified, and genes associated with the JAK-STAT signalling pathway were significantly amplified in IPF-LC (P = 0.012). This study demonstrates that IPF LC is genetically characterized by the presence of somatic mutations reflecting a variety of environmental exposures on the background of specific germline mutations, and is associated with potentially targetable alterations such as BRAF mutations. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28862769 TI - Histamine and Migraine. AB - BACKGROUND: Histamine is an ancient "tissue amine" preceding multicellular organisms. In the central nervous system (CNS), its fibers originate solely from the tuberomammillary nucleus and travel throughout the brain. It is mainly responsible for wakefulness, energy homeostasis, and memory consolidation. Recently, several studies suggest a potential role of histamine in migraine pathogenesis and management. METHODS: Narrative review of current literature regarding histamine and migraine. RESULTS: Histamine plays a crucial role in migraine pathogenesis: sustaining the neurogenic inflammation pathway. Interaction between mast cells (MC) and calcitonin-gene related protein (CGRP) results in sensitization of trigeminal afferents and trigeminal ganglia (TG). Histamine binds with differing affinities to four different histaminergic G protein coupled receptors, activating protein kinases, or triggering calcium release with subsequent mode of actions. Histamine 1 receptor (H1 R) and histamine 2 receptor (H2 R) antagonists are frequently used for the treatment of allergy and gastric acid secretion, respectively, but their antagonism is probably ineffective for migraine. Histamine 3 receptor (H3 R) and histamine 4 receptor (H4 R) have a threefold higher affinity than H1 R/H2 R for histamine and are found almost exclusively on neurons and immune tissues, respectively. H3 R acts as an autoreceptor or as a heteroreceptor, lowering the release of histamine and other neurotransmitters. This is a potential target for anti-nociception and anti-neurogenic inflammation. To date, several small clinical trials using low dose histamine or Nalpha -methylhistamine have demonstrated migraine prophylactic efficacy, probably via H3 R or other undetermined pathways. CONCLUSION: The histamine system interacts with multiple regions in the CNS and may hypothetically modulate the migraine response. Low dose histamine may be a promising option for migraine prevention. PMID- 28862768 TI - Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c. AB - Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c-/ ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c /- mice with AAD also had reduced numbers of alpha-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3 positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28862772 TI - Parallel ridge dermoscopic pattern in plantar atypical Spitz nevus. PMID- 28862770 TI - Glucosamine oral administration as an adjunct to hyaluronic acid injection in treating temporomandibular joint osteoarthritis. AB - OBJECTIVE: To investigate the therapeutic effect of oral glucosamine (GS) as an adjunct to hyaluronic acid (HA) injection on patients with temporomandibular joint osteoarthritis (TMJ OA). METHODS: In this clinical trial, 136 participants, diagnosed as TMJ OA clinically and radiographically, were enrolled and randomized into two groups (group GS + HA: oral GS + HA injection; group placebo + HA: oral placebo + HA injection). Pain, maximum interincisal mouth opening (MMO), the levels of IL-1beta, IL-6, and TGF-beta in TMJ synovial were defined as the outcome measurements and conducted before operation, and at 1-month and 1-year follow-up. RESULTS: In both groups, pain scores were decreased and MMOs were increased at 1-month and 1-year follow-up, the changes at 1-year follow-up showed statistically significant intergroup differences. At 1-month follow-up, only IL-6 concentration was lower in group GS + HA than that in group placebo + HA. One year later, TGF-beta concentration was higher and IL-6 and IL-1beta concentrations were lower in group GS + HA than those in group placebo + HA. CONCLUSIONS: Both strategies alleviated symptoms in short term, but the patients treated with GS benefited more than those with placebo in long term, which may be due to the suppression of IL-1beta and IL-6 and the stimulation of TGF-beta. PMID- 28862771 TI - Oral melanoma and other pigmentations: when to biopsy? AB - Oral pigmentations (OPs) are often neglected, although a meticulous examination of the oral cavity is important not only in the diagnosis of oral melanoma, but also for the detection of important clinical findings that may indicate the presence of a systemic disease. OPs may be classified into two major groups on the basis of their clinical appearance: focal and diffuse pigmentations, even though this distinction may not appear so limpid in some cases. The former include amalgam tattoo, melanocytic nevi, melanoacanthoma and melanosis, while the latter include physiological/racial pigmentations, smoker's melanosis, drug induced hyperpigmentations, postinflammatory hyperpigmentations and OPs associated with systemic diseases. We will discuss the most frequent OPs and the differential diagnosis with oral mucosal melanoma (OMM), underlining the most frequent lesions that need to undergo a bioptic examination and lesions that could be proposed for a sequential follow-up. PMID- 28862773 TI - Trends in outcomes of very preterm infants in Romania: A tale of three cities. AB - BACKGROUND: Although survival of preterm infants has improved, prematurity remains the second most frequent cause of death before 5 years of age in Romania. Data on the changing mortality of Romanian preterm infants born before 29 weeks of gestation have not been available. METHODS: Outcomes of infants of gestational age 25-28 weeks born in 2007-2010 (n = 247) were compared with those born in 2011 2014 (n = 235). Data were analyzed from three tertiary neonatal intensive care centers. Mortality rates and major morbidities were compared between these two epochs. RESULTS: Infants in the later epoch were more likely to have been born by cesarean section and had higher 1 and 5 min Apgar scores. Mortality rate decreased significantly with increasing gestational age at birth. Between the two epochs, the in-hospital mortality rate decreased from 65.6% to 29.4% (P < 0.001); death in the first 48 h decreased from 30.0% to 8.5% (P < 0.001); and prevalence of severe intraventricular hemorrhage decreased from 52.2% to 11.9% (P < 0.001). There were significant increases in the rates of necrotizing enterocolitis and bronchopulmonary dysplasia among survivors but no change in the rate of retinopathy of prematurity. The rate of antenatal corticosteroid use did not change and was only 47% in the more recent epoch (2011-2014). CONCLUSIONS: Overall mortality is decreasing, and infants admitted in the later epoch had substantially different rates of mortality and several serious morbidities. The low rate of antenatal corticosteroid use provides an opportunity for further reductions in mortality and morbidity among very preterm infants born in Romania. PMID- 28862774 TI - Deinococcus radiodurans DR1088 is a novel RecF-interacting protein that stimulates single-stranded DNA annealing. AB - RecF, together with the recombination mediators RecO and RecR, is required in the RecFOR homologous recombination repair pathway in bacteria. In this study, a recF dr1088 operon, which is highly conserved in the Deinococcus-Thermus phylum, was identified in Deinococcus radiodurans. Interaction between DRRecF and DR1088 was confirmed by yeast two-hybrid and pull-down assays. DR1088 exhibited some RecO like biochemical properties including single/double-stranded DNA binding activity, ssDNA binding protein (SSB) replacement ability and ssDNA (with or without SSB) annealing activity. However, unlike other recombination proteins, dr1088 is essential for cell viability. These results indicate that DR1088 might play a role in DNA replication and DNA repair processes. PMID- 28862775 TI - Implicit Association with Suicide as Measured by the Suicide Affect Misattribution Procedure (S-AMP) Predicts Suicide Ideation. AB - The identification of indirect markers of suicide that do not rely on explicit self-report of suicide ideation is vital, as research indicates that a significant number of individuals who die by suicide do not discuss or explicitly deny thoughts of suicide with a provider in their last health care interaction. The current study tests whether a new measure of implicit association with suicide, a modified version of the Affect Misattribution Procedure (AMP), predicts suicide ideation in participants oversampled for the experience of suicide ideation. Results indicated that implicit associations with suicide related images were positively correlated with levels of suicide ideation and predicted suicide ideation when entered as a simultaneous predictor with symptoms of depression, thwarted belongingness, and perceived burdensomeness. Implicit associations with positive and negative images were unrelated to thoughts of suicide. The modified version of the AMP may be a particularly useful indirect measure of suicide ideation that can be easily included in suicide risk assessment paradigms in clinical practice and research studies. PMID- 28862776 TI - Catalytic Enantioselective Synthesis of Highly Functionalized Difluoromethylated Cyclopropanes. AB - The first catalytic asymmetric synthesis of highly functionalized difluoromethylated cyclopropanes is described. The method, based on a rhodium catalyzed cyclopropanation of difluoromethylated olefins, gives access to a broad range of cyclopropanes bearing ester, ketone, or nitro functional groups. By using Rh2 ((S)-BTPCP)4 as a catalyst, the corresponding products were obtained in high yields and high diastereo- and enantioselectivities (up 20:1 d.r. and 99 % ee). This methodology allowed preparation of enantioenriched difluoromethylcyclopropanes for the first time. PMID- 28862777 TI - Reduced Oxygenated g-C3 N4 with Abundant Nitrogen Vacancies for Visible-Light Photocatalytic Applications. AB - A novel g-C3 N4 photocatalyst (RCNO) with abundant nitrogen vacancies and oxygen containing electron-withdrawing groups was prepared. Oxygen was gradually introduced into the g-C3 N4 structure by a hydrothermal hydrolysis/condensation process, and nitrogen vacancies were produced with H2 reduction. The presence of nitrogen vacancies reduced the conduction band energy of g-C3 N4 from -0.75 to 0.5 eV and introduced plenty of defect levels in the band gap (just below the conductive band with a width of 0.45 eV). The oxygenation of g-C3 N4 induced the formation of oxygen-containing functional groups, such as C=O and C-O, as well as effectively enhancing the separation efficiency of photogenerated carriers and reducing the valence band energy from 2.05 to 2.30 eV. Therefore, the photocatalytic activity and photocurrent responses of RCNO were about nine and eight times higher than that of g-C3 N4 , respectively. PMID- 28862778 TI - Evidence of genomic adaptation to climate in Eucalyptus microcarpa: Implications for adaptive potential to projected climate change. AB - Understanding whether populations can adapt in situ or whether interventions are required is of key importance for biodiversity management under climate change. Landscape genomics is becoming an increasingly important and powerful tool for rapid assessments of climate adaptation, especially in long-lived species such as trees. We investigated climate adaptation in Eucalyptus microcarpa using the DArTseq genomic approach. A combination of FST outlier and environmental association analyses were performed using >4200 genomewide single nucleotide polymorphisms (SNPs) from 26 populations spanning climate gradients in southeastern Australia. Eighty-one SNPs were identified as putatively adaptive, based on significance in FST outlier tests and significant associations with one or more climate variables related to temperature (70/81), aridity (37/81) or precipitation (35/81). Adaptive SNPs were located on all 11 chromosomes, with no particular region associated with individual climate variables. Climate adaptation appeared to be characterized by subtle shifts in allele frequencies, with no consistent fixed differences identified. Based on these associations, we predict adaptation under projected changes in climate will include a suite of shifts in allele frequencies. Whether this can occur sufficiently rapidly through natural selection within populations, or would benefit from assisted gene migration, requires further evaluation. In some populations, the absence or predicted increases to near fixation of particular adaptive alleles hint at potential limits to adaptive capacity. Together, these results reinforce the importance of standing genetic variation at the geographic level for maintaining species' evolutionary potential. PMID- 28862779 TI - Gaps in physician knowledge are associated with under-referral for evidence-based implantable cardioverter defibrillator therapy: How can we improve care? PMID- 28862780 TI - Re: Are electromagnetic fields in incubators a risk factor for autism? PMID- 28862781 TI - Effects of lateral olfactory tract stimulation on Fos immunoreactivity in vasopressin neurones of the rat piriform cortex. AB - In the main olfactory system, odours are registered at the main olfactory epithelium and are then processed at the main olfactory bulb (MOB) and, subsequently, by the anterior olfactory nucleus (AON), the piriform cortex (PC) and the cortical amygdala. Previously, we reported populations of vasopressin neurones in different areas of the rat olfactory system, including the MOB, accessory olfactory bulb (AOB) and the AON and showed that these are involved in the coding of social odour information. Utilising immunohistochemistry and a transgenic rat in which an enhanced green fluorescent protein reporter gene is expressed in vasopressin neurones (eGFP-vasopressin), we now show a population of vasopressin neurones in the PC. The vasopressin neurones are predominantly located in the layer II of the PC and the majority co-express the excitatory transmitter glutamate. Furthermore, there is no sex difference in the number of neurones expressing vasopressin. Electrical stimulation of the lateral olfactory tract leads to a significant increase in the number of Fos-positive nuclei in the PC, MOB, AOB, dorsal AON and supraoptic nucleus (SON). However, there was only a significant increase in Fos expression in vasopressin cells of the PC and SON. Thus, functionally distinct populations of vasopressin cells are implicated in olfactory processing at multiple stages of the olfactory pathway. PMID- 28862782 TI - Mycorrhizal fungi enhance plant nutrient acquisition and modulate nitrogen loss with variable water regimes. AB - Climate change will alter both the amount and pattern of precipitation and soil water availability, which will directly affect plant growth and nutrient acquisition, and potentially, ecosystem functions like nutrient cycling and losses as well. Given their role in facilitating plant nutrient acquisition and water stress resistance, arbuscular mycorrhizal (AM) fungi may modulate the effects of changing water availability on plants and ecosystem functions. The well-characterized mycorrhizal tomato (Solanum lycopersicum L.) genotype 76R (referred to as MYC+) and the mutant mycorrhiza-defective tomato genotype rmc were grown in microcosms in a glasshouse experiment manipulating both the pattern and amount of water supply in unsterilized field soil. Following 4 weeks of differing water regimes, we tested how AM fungi affected plant productivity and nutrient acquisition, short-term interception of a 15NH4+ pulse, and inorganic nitrogen (N) leaching from microcosms. AM fungi enhanced plant nutrient acquisition with both lower and more variable water availability, for instance increasing plant P uptake more with a pulsed water supply compared to a regular supply and increasing shoot N concentration more when lower water amounts were applied. Although uptake of the short-term 15NH4+ pulse was higher in rmc plants, possibly due to higher N demand, AM fungi subtly modulated NO3- leaching, decreasing losses by 54% at low and high water levels in the regular water regime, with small absolute amounts of NO3- leached (<1 kg N/ha). Since this study shows that AM fungi will likely be an important moderator of plant and ecosystem responses to adverse effects of more variable precipitation, management strategies that bolster AM fungal communities may in turn create systems that are more resilient to these changes. PMID- 28862783 TI - A novel red pigment from marine Arthrobacter sp. G20 with specific anticancer activity. AB - AIMS: Bacterial pigments are promising compounds in the prevention and treatment of various cancers. In the current study, the antioxidant, cytotoxic and antimicrobial effects of a red pigment obtained from a marine bacterial strain were investigated. METHODS AND RESULTS: Optimization of the pigment production by the marine strain was conducted using the one-factor-at-a-time approach. Chemical identification of the pigment was achieved by UV-visible, FTIR and HPLC analyses. The biological activities of the pigment were evaluated by DPPH, MTT and microbroth dilution assays. The strain was identified as Arthrobacter, and its pigment was related to carotenoids. The EC50 antioxidant activity of the pigment was evaluated as 4.5 mg ml-1 . It showed moderate anticancer effects on an oesophageal cancer cell line, KYSE30, while no inhibition was observed on normal HDF (human dermal fibroblasts) cells. The pigment had no antibacterial effects on the four tested strains. CONCLUSION: The antitumour activity of a carotenoid related pigment from Arthrobacter sp. was reported for the first time. SIGNIFICANCE AND IMPACT OF THE STUDY: Marine environments are interesting sources for the identification of novel bioproducts. The identification of carotenoid pigments from marine bacteria with remarkable antioxidant and anticancer activities would result in better insights into the potential pharmaceutical applications of carotenoids and marine environments. PMID- 28862784 TI - "Isolated" DyO+ Embedded in a Ceramic Apatite Matrix Featuring Single-Molecule Magnet Behavior with a High Energy Barrier for Magnetization Relaxation. AB - Meeting the challenges of Moore's Law, predicting ambitious miniaturization rates of integrated circuits, requires to go beyond the traditional top-down approaches, and to employ synthetic chemistry methods, to use bottom-up techniques. During the recent decades, it has been shown that open-shell coordination compounds may exhibit intramolecular spontaneous magnetization, thus offering promising prospects for storage and processing of digital information. Against this background we regarded it rewarding to implement similar magnetic centers into a ceramic material, which would provide better long-term mechanical and chemical durability. Here we present new robust inorganic compounds containing separate DyO+ ions in an apatite matrix, which behave like single molecule magnets. The materials exhibit a blocking temperature of 11 K and an energy barrier for spin reversal of a thousand inverse centimeters which is among the highest values ever achieved. PMID- 28862785 TI - History rather than hybridization determines population structure and adaptation in Populus balsamifera. AB - Hybridization between species is known to greatly affect their genetic diversity and, therefore, their evolution. Also, within species, there may be genetic clusters between which gene flow is limited, which may impact natural selection. However, few studies have looked simultaneously at the influence of among-species and within-species gene flow. Here, we study the influence of hybridization between Populus balsamifera and Populus trichocarpa on population structure and adaptation in P. balsamifera. We did this by sampling a total of 1517 individuals from across the ranges of these two species, and by genotyping them using a combination of 93 nuclear and 17 cpDNA SNPs. We found that hybridization is mostly limited to the contact zone where the species' distributions overlap. Within P. balsamifera, we found multiple levels of population structure. Interestingly, the border between the Eastern and Central clusters is very sharp, whereas the border between the Central and Western clusters is diffuse. Outlier analysis revealed that three loci associated with the sharp border were also associated with climate. We hypothesize that the observed clusters derive from three refugia during the Pleistocene ice ages. Between the Central and Western clusters, post-glacial long-distance gene flow has led to the diffusion of their border. In the Eastern cluster, we hypothesize that endogenous genomic barriers have developed, leading to the sharp border and a spurious climate association. We conclude that the large-scale genetic structure of P. balsamifera is mostly shaped by historical factors and the influence of interspecific hybridization is limited. PMID- 28862786 TI - Characterization of fungal communities of developmental stages in table grape grown in the northern region of South Africa. AB - AIMS: To determine fungal communities that characterize table grapes during berry development. METHODS AND RESULTS: Two agro-ecologically different table grape commercial farms (site A and B) were used in this study. Samples were collected at full bloom, pea size and mature stages, from three positions (inside centre, eastern and western peripheral ends) per site. Total DNA extraction, Illumina sequencing and analysis of 18 pooled samples for fungal diversity targeting ITS1 2 generated a total of 2 035 933 high-quality sequences. The phylum Ascomycota (77.0%) and Basidiomycota (23.0%) were the most dominant, while the genera, Alternaria (33.1%) and Cladosporium (24.2%) were the overall dominant postharvest decay causing fungi throughout the developmental stages. Inside centre of site A were more diverse at full bloom (3.82) than those at the peripheral ends (<3.8), while at site B, the peripheral ends showed better diversity, particularly the eastern part at both full bloom (3.3) and pea size (3.7). CONCLUSION: Fungal population diversity varies with different phenological table grape growth stages and is further influenced by site and vine position within a specific vineyard. SIGNIFICANCE AND IMPACT OF THE STUDY: The information on fungal diversity and succession in table grapes during preharvest growth stages is critical in the development of a more targeted control strategy, to improve postharvest quality of table grapes. PMID- 28862787 TI - Panoramic atrial mapping with basket catheters: A quantitative analysis to optimize practice, patient selection, and catheter choice. AB - INTRODUCTION: Panoramic mapping with basket catheters has been used to map atrial fibrillation (AF). However, the limited tissue contact and coverage achieved has raised concerns. METHODS AND RESULTS: Patients undergoing catheter ablation for atrial tachycardia (AT) and persistent AF were recruited. Unipolar signals were recorded with the Constellation or FIRMap catheters. The proportion and distribution of anatomical coverage by the catheters was determined and tissue contact achieved measured. The impact of catheter position, left atrium (LA) size, and bipolar voltage were evaluated. Forty patients were recruited (20 Constellation and 20 FIRMap). The LA coverage achieved with the FIRMap catheter compared to the Constellation catheter was greater (76.9 +/- 12.9% vs. 50.8 +/- 10.3%; P < 0.001), with better septal coverage (66.8 +/- 20.9% vs. 15.5 +/- 12.0%; P < 0.001). A greater number of electrodes recorded peak-to-peak electrogram amplitude of >=0.5 mV (84.2% vs. 62.8%; P < 0.001). Positioning the catheter tip at or posterior to LA appendage ridge gave better coverage than a more anterior position (P = 0.001). Increasing LA area correlated inversely with coverage (P < 0.001) and contact (P = 0.002) despite patient-specific basket catheter sizing. An LA area of >30 cm2 and mean bipolar voltage of <0.3 mV was associated with reduction in coverage and contact (both P < 0.001). There was a significant difference in AT/AF freedom during follow-up in the FIRMap versus Constellation group (13/13 vs. 8/12; P = 0.04). CONCLUSIONS: The FIRMap is superior to the Constellation catheter in terms of LA coverage and contact. Optimizing catheter position and appropriate patient selection based on no more than moderately dilated or scarred atria will also facilitate mapping with basket catheters. PMID- 28862789 TI - Creating a Strain Relief Loop during S1 Transforaminal Lead Placement for Dorsal Root Ganglion Stimulation for Foot Pain: A Technical Note. AB - Chronic neuropathic pain is often refractory to conventional medical treatments and leads to significant disability and socio-economic burden. Dorsal root ganglion (DRG) stimulation has recently emerged as a treatment for persistent neuropathic pain, but creating a strain relief loop at the S1 level has thus far been a challenging technical component of DRG lead placement. We describe a refined technique for strain relief loop formation at the S1 level using a transforaminal approach that we employed in a 45-year-old patient with intractable foot pain. We successfully placed a strain relief loop in the sacral space in a predictable and easily reproducible manner using a transforaminal anchorless approach. The patient experienced a decrease in visual analog pain score (85%), and improvement in function during the trial period, and proceeded with permanent implantation. The described sacral transforaminal strain relief loop formation technique appears to be a more reliable and predictable technique of DRG lead placement in the sacrum than those previously documented. PMID- 28862788 TI - Factors related to diagnostic delay of oral squamous cell carcinoma in southern Thailand: Revisited. AB - OBJECTIVES: To evaluate the impact of more open access to health services by Thailand's universal health coverage (UHC) on diagnostic delay of oral squamous cell carcinomas (OSCC) by comparing results with our previous study prior to the UHC. Reasons for delay in attending healthcare professional (HCP) consultation were also investigated. METHODS: A structure questionnaire was employed to interview 154 OSCC consecutive patients. Variables were included for Cox proportional regression models to conclude the hazard ratio of each delay. RESULTS: Regarding patient delay, those who had more than 12-year education showed less delay (HR 0.46, 95% CI: 0.21-1.01) while longer delay was found in farmers (HR 1.49, 95% CI: 1.05-2.11). Compared with the previous study, there was no association between herbal medication and patient delay, herbal medication and total delay, nor religion and total delay. Professional delay showed no association with any variable. Only half of the patients received initial proper HCP management in both studies. Patient delay was mostly (89.9%) due to unawareness of the lesion severity. CONCLUSIONS: Open access to the healthcare system had an influence on diagnostic delay. Public education and precise clinical acumen by HCPs in OSCC diagnosis are needed for early detection. PMID- 28862790 TI - Abstracts From the 33rd Annual Meeting of the Histiocyte Society Singapore October 3-4, 2017. PMID- 28862791 TI - Efficacy of the Volatile Oil from Water Celery (Helosciadium nodiflorum, Apiaceae) against the Filariasis Vector Culex quinquefasciatus, the Housefly Musca domestica, and the African Cotton Leafworm Spodoptera littoralis. AB - Water celery (Helosciadium nodiflorum, Apiaceae) is a common and invasive hydrophyte occurring in rivers and slow waters of Europe. In the past, it was consumed as a vegetable and spices, but currently it has mostly been abandoned. As a result, this plant produces an unexploited biomass occluding rivers and slow waters. With the aim to valorise water celery as an important biomass source for the development of botanical insecticides, in this work, we investigated the inhibitory effects of the essential oil hydrodistilled from its aerial parts against larvae of the filariasis vector Culex quinquefasciatus, adults of the housefly Musca domestica, and larvae of the African cotton leafworm Spodoptera littoralis. The essential oil, which was characterized by the insecticidal limonene (39.8%) and myristicin (35.3%), exerted important toxic effects on 3rd instar larvae of C. quinquefasciatus and S. littoralis and on adults of M. domestica, with LD50 of 50.4 MUl l-1 , 116.7 MUg larva-1 , and 45.1 (male) and 70.1 (female) MUg adult-1 , respectively. The oil did not show any noticeable inhibitory activity on the acetylcholinesterase enzyme. Our findings add scientific evidences highlighting water celery as an important biomass source to be used for the control of insect pests and vectors of high economic importance. PMID- 28862792 TI - A novel patient-centered "intention-to-treat" metric of U.S. lung transplant center performance. AB - Despite the importance of pretransplantation outcomes, 1-year posttransplantation survival is typically considered the primary metric of lung transplant center performance in the United States. We designed a novel lung transplant center performance metric that incorporates both pre- and posttransplantation survival time. We performed an ecologic study of 12 187 lung transplant candidates listed at 56 U.S. lung transplant centers between 2006 and 2012. We calculated an "intention-to-treat" survival (ITTS) metric as the percentage of waiting list candidates surviving at least 1 year after transplantation. The median center level 1-year posttransplantation survival rate was 84.1%, and the median center level ITTS was 66.9% (mean absolute difference 19.6%, 95% limits of agreement 4.3 to 35.1%). All but 10 centers had ITTS values that were significantly lower than 1-year posttransplantation survival rates. Observed ITTS was significantly lower than expected ITTS for 7 centers. These data show that one third of lung transplant candidates do not survive 1 year after transplantation, and that 12% of centers have lower than expected ITTS. An "intention-to-treat" survival metric may provide a more realistic expectation of patient outcomes at transplant centers and may be of value to transplant centers and policymakers. PMID- 28862793 TI - Fine-needle aspiration biopsy of lytic bone lesions: An institution's experience. AB - OBJECTIVES: Fine needle aspiration (FNAB) is an effective, minimally-invasive, inexpensive, diagnostic technique. The objective of this study was to evaluate the accuracy of FNAB in the diagnosis of bone lesions. METHODS: FNABs of bone lesions diagnosed at our institution over a 2-year period were retrospectively analyzed. RESULTS: 241 samples were reviewed. Patients included 121 males and 120 females, with ages ranging from 4-95 years (mean = 66 years). Of these 241 cases, 43.2% had FNAB and 56.8% had FNAB with core needle biopsy (CNB). The cytologic diagnoses were categorized as nondiagnostic, benign, atypical, suspicious, and positive for malignant cells. Total of 84.3% of FNABs were diagnostic. Of the malignant cases, 78.5% were metastases from nonosseous primary sites, 17.1% were lymphoproliferative lesions, and 4.4% were primary bone tumors. The most common site of metastasis was the pelvic bones (43.5%) followed by the vertebral column (38.7%). Breast (21%), lung (12.7%), and prostate (11.3%) were the most common identifiable primary site in metastatic cases. FNA smears and cell blocks allowed identification of metastatic lesions in 94.3% cases with immunohistochemistry (IHC). Obtaining a concomitant CNB did not result in a statistically significant increase in overall diagnostic yields (P = .20), ascertaining presence of metastatic lesion (P = .96) or ability to identify site of primary tumor in cases of metastasis (P = .53) compared to FNAB alone. Diagnostic accuracy was improved by reviewing clinical history, performing cell block, and IHC. CONCLUSIONS: FNAB is a reliable tool for diagnosis of bone lesions with comparable diagnostic sensitivity to CNB. PMID- 28862794 TI - Open dialogue between professionals with different opinions builds the best policy. PMID- 28862795 TI - Techniques for the analysis of pentacyclic triterpenoids in medicinal plants. AB - Triterpenes are a major class of chemical compounds found in natural plants and can be categorized into acyclic triterpenoids, monocyclic triterpenoids, tricyclic triterpenoids, tetracyclic triterpenoids, and pentacyclic triterpenoids. Among them, pentacyclic triterpenoids have gained more extensive attention due to their biological activities, including anti-inflammation, antibacterial, antioxidation, antitumor, anti-HIV, hepatoprotection, and immunological adjuvant properties. In this review, we summarize the extraction and analytical methods for pentacyclic triterpenoids, where more than 56 triterpenes from 49 kinds of plants were involved. The analysis methods include gas chromatography, liquid chromatography, capillary electrophoresis, thin-layer chromatography, supercritical fluid chromatography, NMR spectroscopy, and X-ray spectroscopy. This review provides valuable reference for the determination of pentacyclic triterpenoids in medicinal plants. PMID- 28862796 TI - Donor-derived hepatitis C transmission from NAT negative donors-Still an unexpected event! PMID- 28862797 TI - 2017 Annual Meeting American College of Clinical Pharmacology. PMID- 28862799 TI - Initiating therapy in patients newly diagnosed with type 2 diabetes: Combination therapy vs a stepwise approach. AB - There is clear evidence that achieving glycaemic targets reduces the risk of developing complications as a result of type 2 diabetes (T2D). Many patients, however, continue to have suboptimal glycaemic control because of issues that include unclear advice on how to achieve these targets as well as clinical inertia. The two management approaches recommended for patients newly diagnosed with T2D are stepwise and combination therapy, each of which has advantages and disadvantages. Stepwise therapy may result in good patient adherence and allow greater individualization of therapy, and minimization of side effects and cost, and so may be appropriate for patients who are closer to goal. Stepwise therapy, however, may also lead to frequent delays in achieving glycaemic goals and longer exposure to hyperglycaemia. Combination therapy, which is now emerging as an important therapy option, has a number of potential advantages over stepwise therapy, including reduction in clinical inertia and earlier and more frequent achievement of glycated haemoglobin goals by targeting multiple pathogenic mechanisms simultaneously, which may more effectively delay disease progression. Compared with stepwise therapy, the disadvantages of combination therapy include reduced patient adherence resulting from complex, multi-drug regimens, difficulty determining the cause of poor efficacy and/or side effects, patient refusal to accept disease, and higher cost. Fixed-dose and fixed-ratio combinations are novel therapeutic approaches which may help address several issues of treatment complexity and patient burden associated with combination therapy comprising individual drugs. The choice of which drugs to administer and the decision to use stepwise vs combination therapy, however, should always be made on an individualized basis. PMID- 28862798 TI - Grading effect of abnormal glucose status on arterial stiffness and a new threshold of 2-h post-load glucose based on a Chinese community study. AB - AIMS/INTRODUCTION: To investigate the relationship between various glucose metabolic status and arterial stiffness, and further explore the threshold of blood glucose indices for the risk of arterial stiffness. MATERIALS AND METHODS: The present cross-sectional study included 4,851 individuals from a Chinese community. Overnight fasting blood glucose and 2-h post-load glucose were sampled. Arterial stiffness was measured as brachial-ankle pulse wave velocity. The association was examined using generalized linear regression models. The threshold effect was explored using two piecewise linear regression models by the smoothing plot. RESULTS: After adjustment for covariates, isolated impaired fasting glucose, isolated impaired glucose tolerance, combined glucose intolerance and newly diagnosed diabetes mellitus were associated with a greater risk of arterial stiffness compared with normal glucose tolerance (B = 18.09, 95% confidence interval [CI] 0.42-35.76, P = 0.045; B = 28.51, 95% CI: 3.40-53.62, P = 0.026; B = 60.70, 95% CI: 38.37-83.04, P < 0.001; B = 95.06, 95% CI: 71.88 118.25, P < 0.001, respectively). Furthermore, there was a non-linear relationship between 2-h post-load glucose and arterial stiffness. A threshold for 2-h post-load glucose of 6.14 mmol/L was observed for the risk of arterial stiffness. CONCLUSIONS: Impaired fasting glucose, impaired glucose tolerance, combined glucose intolerance and newly diagnosed diabetes mellitus were related to a greater risk of arterial stiffness compared with normal glucose levels. A threshold for 2-h post-load glucose of 6.14 mmol/L probably exists for the risk of arterial stiffness. PMID- 28862800 TI - Neurological and Neurophysiological Findings in Workers with Chronic 2,3,7,8 Tetrachlorodibenzo-p-Dioxin Intoxication 50 Years After Exposure. AB - : The last eight survivors of 80 workers accidentally exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) during production of herbicides based on trichlorophenoxyacetic acid in 1965-1967 in a chemical factory were followed. All were men, mean age 72.4 +/- 1.3 years. Their current median TCDD blood level was 112 (46-390) pg/g lipids. Neurological examination revealed central nervous system impairment in all individuals and signs of polyneuropathy in 87.5%, which was confirmed by a nerve conduction study (NCS) in 75%. A Lanthony test demonstrated acquired dyschromatopsia in 87.5% of the patients, with deterioration of mean colour confusion index (CCI) from 1.52 +/- 0.39 in 2010 to 1.73 +/- 0.41 in 2016. Single-photon emission computer tomography (SPECT) of the brain showed focal reduction of perfusion in various brain locations in all patients and worsening in six patients. Visual-evoked potentials (VEP) was abnormal in 62.6% of individuals. Most patients complained of psychological problems. The neuropsychological test battery showed most positive impairments in the Trail Making Test evaluating processing speed (average level in the range of mild neurocognitive impairment), which correlated with mean CCI (p < 0.05). CONCLUSION: Fifty years after exposure, blood levels of TCDD are still 10 times higher than the general population. NCS, VEP, Lanthony test and SPECT findings deteriorated from examination of these patients in 2004 and in 2010. The total of abnormal tests per patient in 2016 is very high. Minor differences among patients and their reduced count may explain why the number of impairments in 2016 does not correlate with TCDD blood level. PMID- 28862801 TI - Better glycaemic control and less hypoglycaemia with insulin glargine 300 U/mL vs glargine 100 U/mL: 1-year patient-level meta-analysis of the EDITION clinical studies in people with type 2 diabetes. AB - AIMS: To investigate the efficacy and safety of insulin glargine 300 U/mL (Gla 300) vs insulin glargine 100 U/mL (Gla-100) over 12 months in a patient-level meta-analysis, using data from the EDITION studies in people with type 2 diabetes (T2DM). METHODS: EDITION 1, 2 and 3 were multicentre, randomized, open-label, 2 arm, parallel-group, treat-to-target phase IIIa studies. Similar study designs and endpoints enabled a meta-analysis to be conducted. RESULTS: Reductions in glycated haemoglobin (HbA1c) were better sustained over 12 months with Gla-300 than with Gla-100 (least squares [LS] mean difference in change from baseline: 0.10 % [95% confidence interval {CI} -0.18 to -0.02] or -1.09 mmol/mol [95% CI 2.01 to -0.20]; P = .0174). Risk of confirmed (<=3.9 mmol/L) or severe hypoglycaemia was 15% lower with Gla-300 vs Gla-100 at night (relative risk 0.85 [95% CI 0.77-0.92]) and 6% lower at any time of day (relative risk 0.94 [95% CI 0.90-0.98]). Rates of hypoglycaemia were 18% lower with Gla-300 vs Gla-100 at night (rate ratio 0.82 [95% CI 0.67-0.99]), but comparable at any time of day. HbA1c <7.0 % without nocturnal hypoglycaemia was achieved by 24% more participants with Gla-300 than with Gla-100 (relative risk 1.24 [95% CI 1.03 1.50]). Severe hypoglycaemia was rare; in both treatment groups the incidence of events at any time of day was <=3.6%, while rates were <=0.08 events per participant-year. CONCLUSIONS: In a broad population of people with T2DM over 12 months, use of Gla-300 provided more sustained glycaemic control and significantly lower hypoglycaemia risk at night and at any time of day compared with Gla-100. PMID- 28862802 TI - Cytological and cytomorphometric characteristics of buccal mucosa cells from smokeless tobacco users. AB - BACKGROUND: Use of smokeless tobacco (ST) is increasing in many communities. We investigated whether ST alters the cytological and cytomorphometric features of buccal mucosa cells. METHODS: Twenty male participants who had used Nicotiana rustica Linn.-containing ST (Maras powder) for at least 10 years, and 20 healthy male controls who did not use ST, were included in this study. After rinsing the mouth with water, samples were taken using a toothbrush from the buccal mucosa of subjects in both groups. Samples were gently spread over a glass slide. After applying a cytofixative spray, the Papanicolaou method was used to stain the slides. The presence of dysplasia, dyskeratosis, parakeratosis, hyperkeratosis, hypergranulosis, karyorrhexis, and pyknosis was evaluated by light microscopy, as were the increment amount of candida, cocco-bacillus, and Leptotrichia buccalis. Cytomorphometric analysis was performed and at least 20 cells with well-defined borders were evaluated from each slide, and the cellular diameter (CD), nuclear diameter (ND), and nucleus/cytoplasm (N/C) ratio of the cells were analyzed using a 60* objective. RESULTS: Other than the presence of dysplasia and candida, all measured cytological parameters were significantly higher in the ST users than in the non-ST users. Furthermore, CD was lower while nuclear/cytoplasmic ratio was higher in the ST users than in those non-ST users. CONCLUSION: Cytological changes associated with the use of ST, include dyskeratosis, parakeratosis, hyperkeratosis, hypergranulosis, karyorrhexis, pyknosis together with increase in the bacterial population of cocco-bacillus and L. buccalis. There were no significant differences in patients with dysplasia in spite of reduction of CD, increased nuclear size and N/C ratio. PMID- 28862803 TI - Patient- and Cell Type-Specific Heterogeneity of Metformin Response. AB - Most FDA-approved drugs are not equally effective in all patients, suggesting that identification of biomarkers to predict responders to a chemoprevention agent will be needed to stratify patients and achieve maximum benefit. The goal of this study was to investigate both patient-specific and cell context-specific heterogeneity of metformin response, using fibroblast cell lines and induced pluripotent stem cells differentiated into lung epithelial lineages. We performed cell survival analysis, transcriptome and whole exome sequencing analysis on both patient-derived cell lines and cancer cell lines to assess differential metformin response and identify response genes. We found differences in response to metformin treatment across a variety of cell lines and cellular contexts, suggesting that heterogeneity may be patient- and cell type-specific. Gene expression profiling and analysis of metformin-sensitive and metformin-resistant cells identified differentially expressed genes that may be able to stratify patients into metformin responders and non-responders. Sequencing analysis found genomic alterations that correlated with metformin response. These results suggest that the identification of genomic biomarkers for patients who may respond to metformin treatment can provide an opportunity for individualizing metformin chemoprevention in the clinical setting. PMID- 28862804 TI - People should not be banned from transplantation only because of their country of origin. PMID- 28862805 TI - Vitamin D status of gastrostomy-fed children with special needs: a cross sectional pilot study. AB - AIM: To assess the vitamin D status of gastrostomy-fed children. METHODS: Vitamin D status was measured in 32 children aged five to 16 years recruited from special schools in Manchester, UK (53 degrees 48' N). All children were receiving a nutritionally complete, commercially prepared enteral feed via gastrostomy, and had been established on this regimen for over 12 months. Serum concentrations of 25-hydroxyvitamin D (25OHD) were measured at the end of winter. Children with serum concentrations of 25OHD >50 nmol/L were considered to be sufficient, and those with concentrations <25 nmol/L were considered to be deficient. RESULTS: Approximately 83% of subjects had sufficient concentrations of serum 25OHD (>50 nmol/L). One subject was vitamin D deficient (serum 25OHD <25 nmol/L), and four were vitamin D insufficient (serum 25OHD >25 nmol/L - <50 nmol/L). The median vitamin D derived from enteral feeds was 9.45 MUg/day; range 3.5-30; 13 children (41%) received less than 10 MUg of vitamin D per day from their enteral feed. CONCLUSION: Nutritionally complete gastrostomy feeds may be protective against vitamin D deficiency in the majority of children with special needs. We recommend that all children over 1 year of age receive 10 MUg (400 IU) of vitamin D, as recommended by the Scientific Advisory Committee on Nutrition (SACN). PMID- 28862806 TI - Initial experience of a novel mapping system combined with remote magnetic navigation in the catheter ablation of atrial fibrillation. AB - BACKGROUND: There have been advancements of sophisticated mapping systems used for ablation procedures over the last decade. Utilization of these novel mapping systems in combination with remote magnetic navigation (RMN) needs to be established. We investigated the new EnSite Precision mapping system (St. Jude Medical, Inc., St. Paul, MN, USA), which collects magnetic data for checking navigation field stability and is built on an open platform, allowing physicians to choose diagnostic and ablation catheters. We address its compatibility with RMN. OBJECTIVE: To assess the clinical utility of a novel 3D mapping system (EnSite Precision mapping system) combined with RMN (Niobe ES, Stereotaxis, Inc., St. Louis, MO, USA) for atrial fibrillation (AF) ablation. METHODS: In this prospective nonrandomized study, two groups of patients were treated in our center for drug refractory AF. Patients were consecutively enrolled in each group. Group A (n = 35, 14 persistent AF [PsAF]) was treated using the novel 3D mapping system combined with RMN. Group B (n = 38, 16 PsAF) was treated using Carto(r) 3 (Biosense Webster, Inc., Diamond Bar, CA, USA) combined with RMN. In Group A, the left atrium (LA) was mapped with a circular magnetic catheter manually and was then replaced by a RMN ablation catheter. At the end of the procedures in Group A, the circular catheter was used for confirming field stability. In Group B, an ablation catheter was controlled by RMN to perform both LA mapping and ablation. All patients underwent pulmonary vein antrum isolation. Additional complex fractionated atrial electrograms (CFAEs) ablation was performed for PsAF. Procedural, ablation, and fluoroscopy times were recorded and complications were assessed. RESULTS: Electrophysiological end points were achieved in all patients. Using the novel mapping system, LA mapping time was fast (308 +/- 60 seconds) with detailed anatomy points (178,831 +/- 70,897) collected and magnetic points throughout LA. At the end of the procedures in Group A, the LA model was confirmed to be stable and its location was within the distance threshold (1 mm). Procedure time (117.9 +/- 29.6 minutes vs. 119.2 +/- 29.7 minutes, P = 0.89), fluoroscopy time (6.1 +/- 2.4 minutes vs. 4.8 +/- 2.2 minutes, P = 0.07), and ablation time (28.0 +/- 12.9 minutes vs. 27.9 +/- 15.8 minutes, P = 0.98) were similar in Group A versus Group B, respectively. No complications occurred in either group. CONCLUSIONS: LA mapped by the novel system is stable and reliable. Combined with RMN, it could be effectively used for AF ablation without impacting overall procedural times. PMID- 28862807 TI - Clinical, pathological and dermoscopic characteristics of cutaneous lesions in LEOPARD syndrome. PMID- 28862808 TI - Comparative effectiveness of once-weekly glucagon-like peptide-1 receptor agonists with regard to 6-month glycaemic control and weight outcomes in patients with type 2 diabetes. AB - A retrospective cohort study was conducted in patients with type 2 diabetes in an electronic medical record database to compare real-world, 6-month glycated haemoglobin (HbA1c) and weight outcomes for exenatide once weekly with those for dulaglutide and albiglutide. The study included 2465 patients: exenatide once weekly, n = 2133; dulaglutide, n = 201; and albiglutide, n = 131. The overall mean (standard deviation [s.d.]) age was 60 (11) years and 54% were men; neither differed among the comparison groups. The mean (s.d.) baseline HbA1c was similar in the exenatide once-weekly (8.3 [1.7]%) and dulaglutide groups (8.5 [1.5]%; P = .165), but higher in the albiglutide group (8.7 [1.7]%; P < .001). The overall mean (s.d.) HbA1c change was -0.5 (1.5)% (P < .001) and this did not differ among the comparison groups in either adjusted or unadjusted analyses. The mean (s.d.) weight change was -1.4 (4.7) kg for exenatide once weekly and -1.6 (3.7) kg for albiglutide (P = .579), but was greater for dulaglutide, at -2.7 (5.7) kg (P = .001). Outcomes were similar in subsets of insulin-naive patients with baseline HbA1c >=7.0% or >=9.0%. All agents significantly reduced HbA1c at 6 months, with no significant differences among agents or according to baseline HbA1c in insulin naive subgroups. PMID- 28862809 TI - Novel luciferase-opsin combinations for improved luminopsins. AB - Previous work has demonstrated that fusion of a luciferase to an opsin, to create a luminescent opsin or luminopsin, provides a genetically encoded means of manipulating neuronal activity via both chemogenetic and optogenetic approaches. Here we have expanded and refined the versatility of luminopsin tools by fusing an alternative luciferase variant with high light emission, Gaussia luciferase mutant GLucM23, to depolarizing and hyperpolarizing channelrhodopsins with increased light sensitivity. The combination of GLucM23 with Volvox channelrhodopsin-1 produced LMO4, while combining GLucM23 with the anion channelrhodopsin iChloC yielded iLMO4. We found efficient activation of these channelrhodopsins in the presence of the luciferase substrate, as indicated by responses measured in both single neurons and in neuronal populations of mice and rats, as well as by changes in male rat behavior during amphetamine-induced rotations. We conclude that these new luminopsins will be useful for bimodal opto and chemogenetic analyses of brain function. PMID- 28862810 TI - A follow-up study on thyroid aspirates reported as atypia of undetermined significance/follicular lesion of undetermined significance and follicular neoplasm/suspicious for follicular neoplasm: A multicenter study from the Arabian Gulf region. AB - OBJECTIVE: This is a multicenter study which was conducted to evaluate the follow up on thyroid aspirate cases with atypia of undetermined significance/follicular cells of undetermined significance (AUS/FLUS) and follicular neoplasm or suspicious for follicular neoplasm (FN/SFN) using the Bethesda system for reporting thyroid cytology (TBSRTC). MATERIALS AND METHODS: The archival materials of all thyroid fine-needle aspirates over a 5-year period were retrieved from 3 institutions in the Arabian Gulf Region. All cytology slides and follow-up material for cases interpreted as AUS/FLUS and FN/SFN were reviewed. The revised diagnoses and follow-up were recorded. Analysis of risk of malignancy was calculated for the 2 entities. RESULTS: A total number of 2592 thyroid fine needle aspirates were performed, out of which AUS/FLUS was found in 115 (4.4%) while FN/SFN in 39 (1.5%). Follow-up by surgery or repeat FNA was conducted on 42 (27%) and 10 (7%) patients on these 2 categories, respectively. The risk of malignancy was found to be 29% and 45%, respectively. CONCLUSION: The risk of malignancy for AUS/FLUS and FN/SFN are 29% and 45%, respectively. This risk of malignancy in our study is on the higher range of that reported in the literature. PMID- 28862811 TI - Role of population genetics in guiding ecological responses to climate. AB - Population responses to climate were assessed using 3-7 years height growth data gathered for 266 populations growing in 12 common gardens established in the 1980s as part of five disparate studies of Pinus contorta var. latifolia. Responses are interpreted according to three concepts: the ecological optimum, the climate where a population is competitively exclusive and in which, therefore, it occurs naturally; the physiological optimum, the climate where a population grows best but is most often competitively excluded; and growth potential, the innate capacity for growth at the physiological optimum. Statistical analyses identified winter cold, measured by the square root of negative degree-days calculated from the daily minimum temperature (MINDD01/2 ), as the climatic effect most closely related to population growth potential; the colder the winter inhabited by a population, the lower its growth potential, a relationship presumably molded by natural selection. By splitting the data into groups based on population MINDD01/2 and using a function suited to skewed normal distributions, regressions were developed for predicting growth from the distance in climate space (MINDD01/2 ) populations had been transferred from their native location to a planting site. The regressions were skewed, showing that the ecological optimum of most populations is colder than the physiological optimum and that the discrepancy between the two increases as the ecological optimum becomes colder. Response to climate change is dependent on innate growth potential and the discrepancy between the two optima and, therefore, is population-specific, developing out of genotype-environment interactions. Response to warming in the short-term can be either positive or negative, but long term responses will be negative for all populations, with the timing of the demise dependent on the amount of skew. The results pertain to physiological modeling, species distribution models, and climate-change adaptation strategies. PMID- 28862812 TI - Performance of individually measured vs population-based C-peptide kinetics to assess beta-cell function in the presence and absence of acute insulin resistance. AB - AIMS: To compare the performance of population-based kinetics with that of directly measured C-peptide kinetics when used to calculate beta-cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population-based kinetics apply to all conditions where beta-cell function is measured. METHODS: Somatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C-peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics. RESULTS: There were marked differences in the exchange variables (k 12 and k 21 ) of the model describing C peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment (k 01 ), obtained from population-based estimates compared with experimental measurement. Because it is predominantly influenced by k 01 , DI estimated using individual kinetics correlated well with DI estimated using population-based kinetics. CONCLUSIONS: These data support the use of population-based measures of C-peptide kinetics to estimate beta-cell function during an OGTT. PMID- 28862813 TI - Polyamine is a critical determinant of Pseudomonas chlororaphis O6 for GacS dependent bacterial cell growth and biocontrol capacity. AB - The Gac/Rsm network regulates, at the transcriptional level, many beneficial traits in biocontrol-active pseudomonads. In this study, we used Phenotype MicroArrays, followed by specific growth studies and mutational analysis, to understand how catabolism is regulated by this sensor kinase system in the biocontrol isolate Pseudomonas chlororaphis O6. The growth of a gacS mutant was decreased significantly relative to that of the wild-type on ornithine and arginine, and on the precursor of these amino acids, N-acetyl-l-glutamic acid. The gacS mutant also showed reduced production of polyamines. Expression of the genes encoding arginine decarboxylase (speA) and ornithine decarboxylases (speC) was controlled at the transcriptional level by the GacS sensor of P. chlororaphis O6. Polyamine production was reduced in the speC mutant, and was eliminated in the speAspeC mutant. The addition of exogenous polyamines to the speAspeC mutant restored the in vitro growth inhibition of two fungal pathogens, as well as the secretion of three biological control-related factors: pyrrolnitrin, protease and siderophore. These results extend our knowledge of the regulation by the Gac/Rsm network in a biocontrol pseudomonad to include polyamine synthesis. Collectively, our studies demonstrate that bacterial polyamines act as important regulators of bacterial cell growth and biocontrol potential. PMID- 28862814 TI - Prevalence of lipohypertrophy in insulin-treated diabetes patients: A systematic review and meta-analysis. AB - AIMS/INTRODUCTION: Insulin-treated diabetes patients are at high risk for lipohypertrophy (LH), but this clinical problem has been overlooked by some medical professionals. In addition, studies differed from each other significantly in regard to the prevalence of LH. The present systematic review aimed to determine pooled prevalence levels of LH among insulin-injecting diabetes patients. MATERIALS AND METHODS: Four electronic databases (PubMed, EMBASE, The Cochrane Library and Scopus) were searched for eligible studies from their inception until April 2017, and reference lists were searched manually to identify additional studies. Studies containing data on LH in patients with diabetes mellitus were included. Meta-analysis was carried out with a random effects model. RESULTS: A total of 26 studies with a total of 12,493 participants met the inclusion criteria. Meta-analysis showed that the pooled prevalence of LH was 38% (95% confidence interval [CI] 29-46%, I2 = 99.1%). The main influence on LH was the type of diabetes mellitus. The pooled prevalence of LH among patients with type 2 diabetes mellitus was higher than patients with type 1 diabetes mellitus (49%, 95% CI 23-74% vs 34%, 95% CI 19-49%). The pooled prevalence of LH of studies involving a mixed type of diabetes mellitus was 37% (95% CI 25-48%, I2 = 98.3%). CONCLUSION: The prevalence of LH was high in insulin-treated diabetes patients. It showed that diabetes nurses should screen for LH regularly in their patients, and teach them how to prevent LH in their daily management of diabetes mellitus. PMID- 28862816 TI - Lentinula edodes based GIS mapping, biometabolites and antiinflamatory activity of wild edible mushroomsfrom tropical 'sacred grove' forests of Meghalaya, India. AB - The biodiversity rich state of Meghalaya, India located in the realms of mega biodiversity hotspots, is home tonumerous species of wild edible macrofungi that are used extensively by the mycophillic ethnic population, asa part of their traditional cuisine and medicine systems. However, habitat loss, due to deforestation and climatechange, is destroying the natural population of these mushrooms, depleting their availability to the local communities.In the present investigation, a GIS guided habitat search, using Lentinula edodes as a representativespecies, was used in mapping the habitats of wild edible macrofungi of the study region. Sampling of around4 000 specimens per distinct morphological type available in the traditional markets and "sacred grove" forestsindicated presence of ten common genera, belonging to nine different families of wild edible mushrooms.Nutritional profiling of the representative species Lentinula edodes was carried out by evaluation of its moisture,total fat, crude protein and carbohydrates contents by standard methods. Similarly, bioactive components determinationwas performed by estimation of total phenols, flavonoids, ascorbic acid, beta-carotene and lycopenes.Bioactivity of the mushrooms extracts was studied using the DPPH radical scavenging and Human Red BloodCell (HRBC) membrane stabilization assays. The present investigation successfully attempted to explore remotesensing technologies and GIS (Geographic Information System) based system to predict the natural habitats ofwild edible mushrooms of Meghalaya, India which we believe will lead to the generation of a mushroom specificnon-wood forest resource mapping system in the near future. Results of nutritional profiling and biologicalactivity studies on the representative species of wild edible mushrooms from the studied region revealed that itis a rich source of essential nutrients and antioxidants. PMID- 28862817 TI - [Spatial and temporal mangrove litter production in Barra de Navidad lagoon, Jalisco, Mexico]. AB - Barra de Navidad lagoon is a coastal wetland of international importance (Ramsar site) and it is included among the 81 Mexican mangrove priority sites. One of the most valued characteristics of this lagoon is the presence of mangrove forest in a good conservation state. The goal of our research was the measurement of mangrove litter production and environmental factors influencing its dynamics. The mangrove area was divided into seven zones and litterfall was monthly sampled from November 2011 to October 2012 using 0.25 m(2) square collectors made with mosquito mesh (1 mm) and positioned at 1.3 m above the ground. Abiotic variables of the interstitial water were measured simultaneously at each zone in permanent plots using a multi-parameter probe, YSI-556-M. Total mean value of litterfall production, weighted by zone surface, was 19.12 +/- 1.23 gPS/m(2).mo (2.29 t/ha.year). This low productivity is a consequence of the region's dry climate and low tide range. The species Avicennia germinans and Laguncularia racemosa produced more than 80 % of total litterfall, while Rhizophora mangle contributed only 16 % and Conocarpus erectus < 4 %. A significant correlation between litterfall production and abiotic variables was found (e.g. salinity and interstitial water depth). We concluded that there are significant spatial variations in soil abiotic variables which are correlated with differences in mangrove species composition, and produce, together with the life cycles stages of those species, significant variations in the quantity and composition of litterfall. Future research will be focused on quantifying spatial variations in forest structure and their relationship with litterfall production. PMID- 28862815 TI - Enantioselective Total Synthesis of (-)-Deoxoapodine. AB - The first enantioselective total synthesis of (-)-deoxoapodine is described. Our synthesis of this hexacyclic aspidosperma alkaloid includes an efficient molybdenum-catalyzed enantioselective ring-closing metathesis reaction for the desymmetrization of an advanced intermediate that introduces the C5-quaternary stereocenter. After C21-oxygenation, the pentacyclic core was accessed by electrophilic C19-amide activation and transannular spirocyclization. A biogenetically inspired dehydrative C6-etherification reaction proved highly effective to secure the F-ring and the fourth contiguous stereocenter of (-) deoxoapodine with complete stereochemical control. PMID- 28862818 TI - Life cycles of dominant mayflies (Ephemeroptera) on a torrent of the high Bolivian Andes AB - The mayflies of the temperate and cold zones have well-synchronized life cycles, distinct cohorts,short emergence and flight periods. In contrast, aquatic insects from the tropical zones are characterized bymultivoltine life cycles, "non discernible cohorts" and extended flight periods throughout the year. This reportis the first observation of life cycle patterns made of two species of mayflies on a torrent in the high elevationBolivian Andes. The samples were taken from four sites and four periods during a hydrological season. The lifecycle of each species was examined using size-class frequency analysis and a monthly modal progression model(von Bertalanffy's model) to infer the life cycle synchrony type. These first observations showed a moderatelysynchronized univoltine life cycle for Andesiops peruvianus (Ulmer, 1920), whereas Meridialaris tintinnabulaPescador and Peters (1987), had an unsynchronized multivoltine life cycle. These results showed that the generalizationof all aquatic insects as unsynchronized multivoltine species in the Andean region may not be entirelyaccurate since there is still a need to further clarify the life cycle patterns of the wide variety of aquatic insectsliving in this high elevation tropical environment. PMID- 28862819 TI - [Morphoecology guild in beetles (Coleoptera: Passalidae) along an altitudinal gradient in oak forests of the Eastern Cordillera, Colombia]. AB - Bess beetles are important components on tropical forest dead wood nutrient cycling, since they act as direct consumers and ease the consumption by another organism (indirect). Studies of bess beetle ecology are scarce and have focused on communities responses to environmental changes on alimentary resources. We characterized the bess beetles guild composition in an elevation gradient, according to their differential use of resources (microhabitat) and morphological traits quantification (geometric and lineal), as a potential tool to improve our understanding on resource use and functional ecology of beetles. Three guilds (underbark, sapwood-heartwood and generalists feeders), five species and 198 familiar groups were recognized; their richness decreased as elevation increased. Changes in linear morphometric measures were influenced by elevation; morphogeometrical measures were not associated with the elevation gradient, only grouping at guild level were observed. Morphological markers analysis (morphometric) provided information to guild delimitation. Body and metatibiae shape contributed with the best information to guild grouping. Quantification of those structural markers proved the relationship between resource repartition, because they are involved in movement on wood galleries and wood consumption, this fact allowed to propose specific functional roles. The identified patterns have contributed on the understanding of functional processes in Passalidae communities and their role in ecosystem function. PMID- 28862820 TI - Leaf morphological strategies of seedlings and saplings of Rhizophora mangle (Rhizophoraceae), Laguncularia racemosa (Combretaceae) andAvicennia schaueriana (Acanthaceae) from Southern Brazil. AB - The initial phase of a plant life cycle is a short and critical period, when individuals are more vulnerableto environmental factors. The morphological and anatomical study of seedlings and saplings leaf typeenables the understanding of species strategies of fundamental importance in their establishment and survival.The objective of this study was to analyze the structure of seedlings and saplings leaf types of three mangrovespecies, Avicennia schaueriana, Laguncularia racemosa, Rhizophora mangle, to understand their early life adaptivestrategies to the environment. A total of 30 fully expanded cotyledons (A. schaueriana and L. racemosa), 30leaves of seedlings, and 30 leaves of saplings of each species were collected from a mangrove area in GuaratubaBay, Parana State, Brazil. Following standard methods, samples were prepared for morphological (leaf dry mass,density, thickness) and anatomical analysis (epidermis and sub-epidermal layers, stomata types, density of saltsecretion glands, palisade and spongy parenchyma thickness). To compare leaf types among species one-wayANOVA and Principal Component Analysis were used, while Cluster Analysis evaluated differences betweenthe species. We observed significant structural differences among species leaf types. A. schaueriana showedthe thickest cotyledons, while L. racemosa presented a dorsiventral structure. Higher values of the specific leafarea were observed for seedlings leaves of A. schaueriana, cotyledons of L. racemosa and saplings leaves of A.schaueriana and R. mangle. Leaf density was similar to cotyledons and seedlings leaves in A. schaueriana andL. racemosa, while R. mangle had seedlings leaves denser than saplings. A. schaueriana and R. mangle showedhypostomatic leaves, while L. racemosa amphistomatic; besides, A. chaueriana showed diacytic stomata, whileL. racemosa anomocytic, and R. mangle ciclocytic. Seedling leaves were thicker in R. mangle (535 MUm) andL. racemosa (520 MUm) than in A. schaueriana (470.3 MUm); while saplings leaves were thicker in L. racemosa(568.3 MUm) than in A. schaueriana seedlings (512.4 MUm) and R. mangle (514.6 MUm). Besides, seedlings leavespalisade parenchyma showed increasing thickness in L. racemosa (119.2 MUm) < A. schaueriana (155.5 MUm) 48msec had a sensitivity of 90% and specificity of 55% in predicting death and QTcD >48msec was also associated with worse overall survival (months) (mean +/- SD: 26 +/- 1.0 vs. 30 +/- 0.7, p = 0.001). CONCLUSION: QTcD >=48msec is associated with increased mortality. Further research is required to better understand this association and potentially identify reversible factors that if appropriately addressed, may ultimately improve the prognosis of patients with COPD. PMID- 28862874 TI - Tracheal Foreign Body Removal Using Flexible Bronchoscope in a Pediatric Patient. A Novel Approach. PMID- 28862875 TI - Preponderance of High-Grade Histologic Subtype in Autologous Metastases in Lung Adenocarcinoma. PMID- 28862876 TI - Quantification of cotinine in dried blood spots as a biomarker of exposure to tobacco smoke. AB - OBJECTIVE: We present an ultra-sensitive, minimally-invasive method for quantifying cotinine in dried blood spot (DBS) samples as a biomarker of exposure to tobacco smoke that can be collected using a simple heel or finger prick to obtain blood samples. METHODS: Cotinine levels were measured in matched plasma and reconstituted DBS samples from smokers and nonsmokers to evaluate assay parameters. In addition, we applied this new method to finger-prick DBS samples that were collected from infants, children and young adults ages 1-21 to estimate exposure to tobacco smoke. Partitioning of cotinine across red blood cells and haematocrit effects were investigated. RESULTS: Cotinine levels measured in matched plasma and reconstituted DBS samples from smokers and nonsmokers were found to be highly correlated (R2=0.94), with 100% sensitivity and 94% specificity to differentiate reported smokers from nonsmokers. With this method, the LOQ is <0.25 ng/mL using a single 3.2 mm punch of a DBS, and haematocrit effects are negligible. CONCLUSIONS: This sensitive, high-throughput and minimally-invasive method for quantifying cotinine in DBS samples provides a simple and cost effective means for estimating exposure to tobacco smoke in population based studies, and has particular advantages in studies involving infants and children. PMID- 28862878 TI - Turner syndrome - growing pressure for more multidisciplinary clinics for adults and earlier diagnosis in children. PMID- 28862877 TI - Mepolizumab Attenuates Airway Eosinophil Numbers, but Not Their Functional Phenotype, in Asthma. AB - RATIONALE: Mepolizumab, an IL-5-blocking antibody, reduces exacerbations in patients with severe eosinophilic asthma. Mepolizumab arrests eosinophil maturation; however, the functional phenotype of eosinophils that persist in the blood and airway after administration of IL-5 neutralizing antibodies has not been reported. OBJECTIVES: To determine the effect of anti-IL-5 antibody on the numbers and phenotypes of allergen-induced circulating and airway eosinophils. METHODS: Airway inflammation was elicited in participants with mild allergic asthma by segmental allergen challenge before and 1 month after a single intravenous 750-mg dose of mepolizumab. Eosinophils were examined in blood, bronchoalveolar lavage, and endobronchial biopsies 48 hours after challenge. MEASUREMENTS AND MAIN RESULTS: Segmental challenge without mepolizumab induced a rise in circulating eosinophils, bronchoalveolar lavage eosinophilia, and eosinophil peroxidase deposition in bronchial mucosa. IL-5 neutralization before allergen challenge abolished the allergen-induced rise in circulating eosinophils and expression of IL-3 receptors, whereas airway eosinophilia and eosinophil peroxidase deposition were blunted but not eliminated. Before mepolizumab treatment, bronchoalveolar lavage eosinophils had more surface IL-3 and granulocyte-monocyte colony-stimulating factor receptors, CD69, CD44, and CD23 and decreased IL-5 and eotaxin receptors than blood eosinophils. This activation phenotype indicated by bronchoalveolar lavage eosinophil surface markers, as well as the release of eosinophil peroxidase by eosinophils in the bronchial mucosa, was maintained after mepolizumab. CONCLUSIONS: Mepolizumab reduced airway eosinophil numbers but had a limited effect on airway eosinophil activation markers, suggesting that these cells retain functionality. This observation may explain why IL-5 neutralization reduces but does not completely eradicate asthma exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT00802438). PMID- 28862879 TI - Chronic Obstructive Pulmonary Disease in Hispanics. A 9-Year Update. PMID- 28862880 TI - Club cell protein (CC16) in plasma, bronchial brushes, BAL and urine following an inhaled allergen challenge in allergic asthmatics. AB - BACKGROUND: Club cell protein (CC16) is a pneumoprotein secreted by epithelial club cells. CC16 possesses anti-inflammatory properties and is a potential biomarker for airway epithelial damage. We studied the effect of inhaled allergen on pulmonary and systemic CC16 levels. METHODS: Thirty-four subjects with allergic asthma underwent an inhaled allergen challenge. Bronchoscopy with bronchoalveolar lavage (BAL) and brushings was performed before and 24 h after the challenge. CC16 was quantified in BAL and CC16 positive cells and CC16 mRNA in bronchial brushings. CC16 was measured in plasma and urine before and repeatedly after the challenge. Thirty subjects performed a mannitol inhalation challenge prior to the allergen challenge. RESULTS: Compared to baseline, CC16 in plasma was significantly increased in all subjects 0-1 h after the allergen challenge, while CC16 in BAL was only increased in subjects without a late allergic response. Levels of CC16 in plasma and in the alveolar fraction of BAL correlated significantly after the challenge. There was no increase in urinary levels of CC16 post-challenge. Mannitol responsiveness was greater in subjects with lower baseline levels of CC16 in plasma. CONCLUSIONS: The increase in plasma CC16 following inhaled allergen supports the notion of CC16 as a biomarker of epithelial dysfunction. PMID- 28862881 TI - Deficient Immune Response to Viral Infections in Children Predicts Later Asthma Persistence. PMID- 28862884 TI - Opioid Prescribing Patterns by Obstetrics and Gynecology Residents in the United States. AB - BACKGROUND: Despite the opioid epidemic in the U.S., little data exist to guide postoperative opioid prescribing in Obstetrics & Gynecology (Ob/Gyn). OBJECTIVE: To describe Ob/Gyn resident opioid prescription patterns in the U.S. and assess influential factors. METHODS: An anonymous survey was emailed to Ob/Gyn residents in the U.S. between January-February 2015. Respondents reported the typical number of discharge narcotic tablets prescribed following six common procedures. Responses to questions addressed potential factors influencing prescription practices and knowledge about opioid abuse in the U.S. Residents who prescribed a number of discharge narcotic tablets in the top quartile were compared to those who never did. Logistic regression was used to identify factors associated with top quartile prescribers. RESULTS: 267 residents responded. Median number of discharge narcotics prescribed following cesarean section was 30 (IQR 28, 40) and after laparoscopic hysterectomy was 29 (IQR 20, 30). Factors associated with increased odds of prescribing in the top quartile included training in the West (aOR 3.15, 95% CI 1.05-9.45, p = 0.04) and agreeing with: "I prescribe postoperative narcotics to avoid getting reprimanded by attendings" (aOR 2.72, 95% CI 1.20-6.15, p = 0.02). Factors associated with decreased odds of prescribing in the top quartile included training in a community-based program (aOR 0.33, 95% CI 0.15-0.71, p = 0.005) and agreeing with: "I am conservative with the number of narcotics I prescribe after surgery" (aOR 0.34, 95% CI 0.17 0.71, p = 0.004). Conclusions/Importance: Opioid prescribing practices of Ob/Gyn residents are influenced by region of country, program-type, and factors related to hospital culture and personal insight. PMID- 28862883 TI - Randomized Phase II Study of R-CHOP With or Without Bortezomib in Previously Untreated Patients With Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma. AB - Purpose To evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). Patients and Methods After real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m2 intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP). Results After a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2 year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade >= 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%). Conclusion Outcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib. PMID- 28862882 TI - Myeloid-derived Suppressor Cells Are Necessary for Development of Pulmonary Hypertension. AB - Pulmonary hypertension (PH) complicates the care of patients with chronic lung disease, such as idiopathic pulmonary fibrosis (IPF), resulting in a significant increase in morbidity and mortality. Disease pathogenesis is orchestrated by unidentified myeloid-derived cells. We used murine models of PH and pulmonary fibrosis to study the role of circulating myeloid cells in disease pathogenesis and prevention. We administered clodronate liposomes to bleomycin-treated wild type mice to induce pulmonary fibrosis and PH with a resulting increase in circulating bone marrow-derived cells. We discovered that a population of C-X-C motif chemokine receptor (CXCR) 2+ myeloid-derived suppressor cells (MDSCs), granulocytic subset (G-MDSC), is associated with severe PH in mice. Pulmonary pressures worsened despite improvement in bleomycin-induced pulmonary fibrosis. PH was attenuated by CXCR2 inhibition, with antagonist SB 225002, through decreasing G-MDSC recruitment to the lung. Molecular and cellular analysis of clinical patient samples confirmed a role for elevated MDSCs in IPF and IPF with PH. These data show that MDSCs play a key role in PH pathogenesis and that G-MDSC trafficking to the lung, through chemokine receptor CXCR2, increases development of PH in multiple murine models. Furthermore, we demonstrate pathology similar to the preclinical models in IPF with lung and blood samples from patients with PH, suggesting a potential role for CXCR2 inhibitor use in this patient population. These findings are significant, as there are currently no approved disease specific therapies for patients with PH complicating IPF. PMID- 28862885 TI - Educational interventions to enhance competencies for interprofessional collaboration among nurse and physician managers: An integrative review. AB - Collaborative leadership and management structures are critical to transforming care delivery. Both nurse and physician managers are uniquely positioned to co lead. However, little is known on how to prepare and support individuals for these co-leader arrangements. The re-design of healthcare professional education focuses on interprofessional collaboration, mutual learning, and a competency based approach. While competencies for interprofessional collaboration have been delineated, competencies for collaborative management practice have yet to be addressed. An integrative review of empirical studies on existing educational interventions was conducted to critically appraise and synthesise the results regarding collaborative competence among nurse and physician leaders. We reviewed how these interventions have been designed, implemented, and evaluated within workplace settings in order to inform our understanding of what components are effective or ineffective for the future development of an educational programme. This review reports on key characteristics of nine empirical studies and emphasises that: a uniprofessional approach to leadership development is predominant within educational programmes and that the assessment of shared learning experiences are not addressed; there are inconsistency in terms used to describe competencies by individual researchers and limitations within the competency frameworks used in the studies reviewed; and there is a lack of suitable instruments available to assess whether competencies have been achieved through the educational programmes. None of the studies discussed the process of how individuals learned specific competencies or whether learning outcome were achieved. Educational programmes were developed based on a perceived lack of leadership preparation and orientation programmes for leaders in formal management positions and used multiple interventions. Only two of the programmes involved organisational or systems level competencies. Interprofessional co leading requires enhanced capabilities and capacity for managers. There is a need for developing an in-action education intervention that addresses the unique learning needs of co-leader arrangements particularly among nurses and physicians who are new to their role. PMID- 28862886 TI - The future of diagnosing NASH - could a simple blood test be the key? PMID- 28862887 TI - The weight of networks: the role of social ties and ethnic media in mitigating obesity and hypertension among Latinas. AB - OBJECTIVES: Latinos have a disproportionately high risk for obesity and hypertension. The current study analyzes survey data from Latin American women to detect differences in rates of obesity and hypertension based on their number of health-related social ties. Additionally, it proposes individuals' health-related media preference (ethnic/ mainstream) as a potential moderator. DESIGN: The dataset includes 364 Latinas (21-50 years old) from the greater Los Angeles metropolitan area, who responded to a series of sociodemographic, physiological, health-related, and media-related questions. RESULTS: Controlling for various sociodemographic and health variables, each additional health-related tie in a Latina's social network significantly decreased her likelihood of being obese OR = .79, p = .041, 95% CI [.66, .95], but did not affect hypertension. Further, the analysis revealed a significant interaction between media preference and health related social ties, such that exposure to ethnic media tended to compensate for the absence of social ties for the likelihood of obesity OR = .75, p = .041, 95% CI [.52, .97], as well as hypertension OR = .79, p = .045, 95% CI [.55, .98]. CONCLUSION: In concurrence with the literature, increases in health-related ties reduced the likelihood of obesity in this population. Moreover, ethnic media preference may play an important role in mitigating the likelihood of obesity and hypertension among Latinas. PMID- 28862888 TI - Aquatic bird bornavirus 1 infection in a captive Emu (Dromaius novaehollandiae): presumed natural transmission from free-ranging wild waterfowl. AB - An adult female emu (Dromaius novaehollandiae) presented with anorexia, maldigestion, weight loss, and various subtle nervous deficits. After four months of unrewarding diagnostics, treatments, and supportive care, the emu was euthanized due to lack of clinical improvement and progressive weight loss. Gross pathology revealed a very narrow pylorus and multiple flaccid diverticula of the small intestines. Histopathological findings included severe lymphoplasmacytic encephalomyelitis and multifocal lymphocytic neuritis associated with the gastrointestinal tract. Immunohistochemistry and polymerase chain reaction on the brain were positive for an avian bornavirus (ABV), and partial sequencing of the matrix gene identified aquatic bird bornavirus-1 (ABBV-1), 100% identical to viruses circulating in wild Canada geese (Branta canadensis). As wild geese frequently grazed and defaecated in the emu's outdoor exhibit, natural transmission of ABBV-1 from free-ranging waterfowl to the emu was presumed to have occurred. PMID- 28862889 TI - Best practice interprofessional stroke care collaboration and simulation: The student perspective. AB - Interprofessional practice (IPP) is the accepted standard of care for clients following a stroke. A brief, embedded and evidence-based IPP team simulation was designed to address stroke care knowledge and IPP competencies for students within limited curriculum space. Each team was required to construct a collaborative care plan for their patient during the simulation and submit the care plan for evaluation of best practice stroke care knowledge and implementation with evidence of interprofessional collaboration (IPC). A total of 302 students (274 on-site, 28 by distance technology) representing four professions comprised of 55 teams took part in this experience. Post-simulation, voluntary and anonymous programme evaluations were completed using the standardised interprofessional collaborative competency assessment scale (ICCAS) and open-ended free-text responses to five questions. There was a significant improvement for all pre-post ratings on the ICCAS regardless of profession or previous interprofessional experience. Additionally, the open-ended responses indicated perceived changes to role clarification, communication, and teamwork. The combined interpretation of the programme evaluation results supports interprofessional team simulation as an effective and efficient learning experience for students regardless of previous interprofessional experience, and demonstrated positive changes in stroke best-practice knowledge and IPC competencies. PMID- 28862890 TI - Treating highly exuding wounds in the community setting. PMID- 28862891 TI - Apex Pro-care mattress: How can this advanced mattress assist in prevention of pressure injuries? AB - Avalon Nursing Home is fully aware of the potential for pressure ulcers in immobile residents and were keen to undertake an evaluation to ensure their residents have the most appropriate care possible. They selected Apex Pro-care to evaluate as there were concerns for residents heels in those with any arterial insufficiency. The Apex Pro-care mattress has a heel section where one or more of the bottom five cells can be deflated under the patient's heel to create a void, which will enable the heel to "float" so that there is no pressure in contact with the heel area. The mattress would reduce the cost of nursing care as repositioning times can be optimised according to need. The three residents who agreed to evaluate the mattress found it to be extremely comfortable and they remained free of any pressure injury. PMID- 28862893 TI - Woundcare4Heroes update. PMID- 28862892 TI - Chronic leg ulcers disrupt patients' lives: A study of leg ulcer-related life changes and quality of life. AB - Chronic leg ulcers have a profound impact on patients' physical, functional, and psychological status, which may result in several life changes and a significant decline in quality of life (QoL). We aimed to study what changed in patients' lives after developing a chronic leg ulcer, including QoL, patients' comprehension of the disease and related feelings. A cross-sectional study, using an anonymous questionnaire and the Dermatology Life Quality Index (DLQI) was performed. Chronic leg ulcers were life changing events, causing abandonment of work in almost 80% of the patients and important limitations in daily activities and autonomy. Familial relationships changed in more than half of the patients. Almost 15% hid or would like to hide their disease from others, especially patients with a shorter duration of disease. QoL was very or extremely affected in 18.2% of the participants completing the DLQI. PMID- 28862894 TI - A reflection on the EWMA conference 2017. PMID- 28862895 TI - How to prevent and avoid common mistakes in skin tear management in the home setting. AB - Skin tears are acute wounds, often mismanaged and misdiagnosed that can convert to chronic wounds, representing a common but relevant burden to both the individual and the health care system. The implementation of prevention protocols and training programs is essential to manage these wounds in the community. Managing a skin tear-related problem at home represents a challenge, due to some critical issues and specific conditions. A multifaceted prevention programme should consider the involvement of relatives, caregivers and personal care aides in order to promote patients' safety, to minimise the risk of trauma and to improve patients' outcomes following a skin injury. PMID- 28862896 TI - Keeping up with wound care in the community setting. PMID- 28862897 TI - Venous leg ulcers: An evidence review. PMID- 28862898 TI - Wound management should not be a pain. AB - Pain is a complex sensation with a variety of qualities rather than a single sensation varying in intensity. People find it difficult to describe their pain mainly because its nature and intensity vary so much, not only between individuals but also for a person over time. This article provides an overview of wound pain, its causes and assessment, with a focus on the procedure of dressing change itself. The wound care industry has manufactured dressings to assist in reducing the pain experience and it is incumbent on health care professionals to make the most appropriate dressing selection for the individual patient and wound, rather than a 'one type of dressing fits all' approach. The choice of primary product is important and is the aspect of focus for this discussion. This paper discusses the use of Flaminal (an enzyme alginogel) to assist practitioners in managing painful wounds. PMID- 28862899 TI - How to combat infection in Leg Clubs: Is sterility necessary? PMID- 28862902 TI - Consider the Alternative. PMID- 28862903 TI - Medication-Assisted Treatment for Opioid Addiction in the United States: Critique and Commentary. AB - In the United States, buprenorphine products (namely buprenorphine/naloxone combination) and methadone are the primary forms of medication-assisted treatment (MAT) that are authorized for addressing opioid addiction. Although treatment ideologies differentiate MAT programs, much of the provision in the US reflects a model of "high threshold, low tolerance." This model is discussed with a focus on structural and programmatic barriers that shape access to and retention in MAT. The critique continues with a discussion of multifaceted stigma that reinforces spoiled identities and diffuses into treatment settings. The social control mechanisms that are imposed in MAT are strikingly similar to those reflected in criminal justice settings, namely probation, parole and community corrections more generally. Parallels are drawn between the "addict" and the "felon" and how they are monitored, tracked, and controlled. These factors have major implications for recovery. PMID- 28862904 TI - Infection control when delivering intravenous therapy in the community setting. PMID- 28862900 TI - Physiotherapy clinical educators' perspectives on a fitness to practice initiative. AB - CONTEXT: Health practitioner registration boards require health professionals to evaluate and maintain "fitness to practice" (FTP). This encompasses the professional behavior, clinical competence, and freedom from impairment required for safe and effective service provision. We developed and implemented policies to promote student self-assessment and support of FTP that were pre-emptive and designed to be helpful and sought clinician feedback on this initiative. METHOD: An innovative student-centered FTP approach was devised with consideration of defensible ethico-legal practice. A survey explored clinical educators' perceptions of the FTP policy and the associated education and support. Closed and open survey questions were analyzed using descriptive statistics, qualitative evaluation, and thematic analysis. RESULTS: Seventy-nine physiotherapy clinical educators from 34 sites across eight Australian health services returned surveys. Educators had positive perceptions of policy components, particularly incorporating professionalism as a hurdle requirement and the attendance and incident reporting policies. CONCLUSIONS: The benefits of a student-centered FTP approach included clarity and consistency in managing FTP issues and facilitation of student awareness through active engagement in maintaining their FTP. To our knowledge, this paper is the first to report a comprehensive approach to the range of FTP issues incorporating student self-declaration of issues that may affect desirable progression through clinical placements. The policy and program of education and support are likely to be generalizable to health professional training programs that utilize workplace training. PMID- 28862905 TI - Community nursing middle management: 'dealing with different people in different time zones on both sides'. AB - The overall aim of the investigation was to redress a knowledge gap by exploring community nursing middle managers' (CNMMs') experiences of role enactment through change within Community Health Partnerships (CHPs) in Scotland-now further evolved into Health and Social Care Partnerships (HSCPs). HSCPs play a key role in shifting care from the acute to the primary care/community setting. However, a literature review demonstrated there has been very little research into the role of CNMMs within the changing primary care context. This concept was considered important in understanding how CNMMs enacted their roles to implement service change. A qualitative longitudinal interpretative phenomenological analysis (IPA) ( Smith, 1996 ) study was conducted in four distinct phases, comprising the reflexive, foundational, recursive and expansive, from 2008-2011. Some 35 semi structured interviews were conducted with 26 participants. CNMMs perceived that their responsibilities had increased, become more complex and wider ranging. Maintaining an implicit connection with service users was a primary motivation for CNMMs. They were proud to be members of the nursing profession aligning their identity with their career history. A small but significant proportion resigned during the study and some were considering leaving the NHS. The study addresses a gap in literature, contributes to the understanding of NHS community nursing, middle management, role, change and gives a voice to CNMMs in Scotland. They are the lynchpins in taking change forward and maintaining quality services. Much more attention needs to be paid to the needs, constitution and sustenance of middle managers in Scottish community nursing-which has policy, practice, education, and research and retention implications. PMID- 28862907 TI - Predicting dying in palliative care. PMID- 28862906 TI - Criminal liability for spreading sexually transmitted infections. AB - Last month's article considered capacity to consent to sexual activity. This month's article reviews the case of a man from Nottingham who was jailed for 7 years for infecting two former lovers with HIV and considers whether those who act recklessly put others at risk of infection during sexual activity should be held criminally liable and prosecuted for their actions. PMID- 28862908 TI - Vitamin D: Get it while it's hot and even when it's not. PMID- 28862910 TI - How to address compassion fatigue in the community nurse. PMID- 28862909 TI - What are community nurses experiences of assessing frailty and assisting in planning subsequent interventions? AB - With an ageing population and increasing focus on community care, this study aimed to explore the experiences of community nurses in assessing frailty and planning interventions around frailty. Six community nurses were recruited for face-to-face semi-structured interviews as part of this qualitative study which was underpinned by a competence framework ( Royal College of Nursing, 2009 ). Thematic analysis was used and frailty was identified as an emerging topic within practice. Participants discussed several aspects associated with frailty; however, some uncertainty around the concept of frailty and its definition was noted, particularly for staff who had received limited frailty training. Participants had a growing awareness of frailty in practice, but challenges including time constraints and staffing within some roles, a perception of limited services to support older people, and for some a lack of confidence and training-presented barriers to frailty assessment. The Rockwood frailty scale was used by participants within practice, but evidence suggested it was felt to lack validity within the community setting. PMID- 28862911 TI - Safely administering and storing vaccines in the community setting. PMID- 28862912 TI - Lest we forget the carers' contribution. PMID- 28862913 TI - Assessment and management of refractory breathlessness in interstitial lung disease. AB - Interstitial lung disease (ILD) refers to a cluster of fibroinflammatory conditions. There are limited treatment options and most patients have severe dyspnoea. The prognosis is poor. This study aims to evaluate current literature on the assessment and management of refractory breathlessness in ILD. Few tools are available to assess dyspnoea in advanced respiratory disease. Holistic assessment requires a combination of tools but there are few disease specific tools. The role of opioids is well established in the reduction of breathlessness, but there is insufficient evidence that benzodiazepines are beneficial. Non-pharmcolological breathlessness intervention services can give patients mastery of their disease, reduced distress due to breathlessness and were more cost effective. More research on holistic interventions for use in advanced disease needs to be done. Patient-reported outcome measures could elicit valuable evidence to describe the benefit of breathlessness management services in advanced respiratory disease. PMID- 28862914 TI - Oliver Sacks (1933-2015): A belated obituary. PMID- 28862915 TI - Introduction of Vasyl V. Tkach, Recipient of the Henry Baldwin Ward Medal for 2017. PMID- 28862916 TI - Supporting female survivors of intimate partner violence with disabilities: Recommendations for social workers in the emergency department. AB - Intimate partner violence (IPV) is a pervasive problem with grave consequences. Women with disabilities are among the most vulnerable groups disproportionately affected, with higher IPV rates than either women without disabilities or men with disabilities. The emergency department (ED) in particular affords a gateway into health services for female survivors of IPV, placing ED social workers in a prime position to observe potential signs of IPV and connect survivors to further assistance. This article explores the critical role ED social workers can fill in addressing the needs of female survivors of IPV with disabilities. We begin by providing background on the characteristics of IPV among women with disabilities, followed by a discussion of the opportunities and challenges inherent to assessing and intervening with survivors. We conclude by outlining recommendations for working with female survivors of IPV with disabilities in EDs, using our previous research on the topic as a guide. PMID- 28862917 TI - Preparing the workforce for integrated healthcare: A systematic review. AB - Integrated healthcare is recommended to deliver care to individuals with co occurring medical and mental health conditions. This literature review was conducted to identify the knowledge and skills required for behavioral health consultants in integrated settings. A review from 1999 to 2015 identified 68 articles. Eligible studies examined care to the U.S. adult population at the highest level of integration. The results provide evidence of specific knowledge of medical and mental health diagnoses, screening instruments, and intervention skills in integrated primary care, specialty medical, and specialty mental health. Further research is required to identify methods to develop knowledge/skills in the workforce. PMID- 28862918 TI - Pudicinae (Nematoda: Heligmonellidae) Parasitic in Endemic Chilean Rodents (Caviomorpha: Octodontidae and Abrocomidae): Description of a New Species and Emended Description of Pudica degusi (Babero and Cattan) n. comb. AB - We report the finding of 2 species of Pudica (Nematoda: Heligmonellidae: Pudicinae) in 2 rodents endemic to Chile, the common degu Octodon degus (Octodontidae) and the Bennett's chinchilla rat Abrocoma bennettii (Abrocomidae). Pudica degusi ( Babero and Cattan, 1975 ) n. comb., originally described as a species of Longistriata (Heligmosomidae), was found in the common degu; through the study of its synlophe, the species is reassigned to the Heligmonellidae: Pudicinae and the genus Pudica, and it is revalidated through comparison with the remaining species of the genus. Pudica cattani n. sp. is described from both O. degus and A. bennettii. It is characterized by its large body size, bursal pattern of type 1-3-1 on right lobe, 1-3-1 tending to 1-4 on left lobe, synlophe with 11 ridges including a careen, dorsal ray of the bursa dividing proximally and bursal rays 9 and 10 relatively short. Pudica degusi n. comb. and Pudica cattani n. sp. were found in the same host species but not as coparasitic in the same individuals. The common degu is confirmed as the sole and primary host of Pudica degusi n. comb. It is unlikely that it is the primary host for Pudica cattani n. sp., whose host affinities are less clear mainly due to the scarcity of data. Pudica cattani n. sp. is the first helminth reported from the Bennett's chinchilla rat. Both findings enlarge the host range of the Pudicinae to the families Octodontidae and Abrocomidae, i.e., 9 out of the 11 extant families of caviomorphs, thereby establishing the presence of this nematode subfamily as typical parasites of the Neotropical Hystricognathi. PMID- 28862919 TI - The Science and Practice of Self-Control. AB - In 2005, we discovered that self-control "outdoes" talent in predicting academic success during adolescence. Since then, a surfeit of longitudinal evidence has affirmed the importance of self-control to achieving everyday goals that conflict with momentary temptations. In parallel, research that has "lumped" self-control with other facets of Big Five conscientiousness has shown the superior predictive power of this broad family of individual differences for diverse life outcomes. Self-control can also be "split" from related traits that in certain contexts demonstrate superior predictive power for achievement. Most important, both the "lumping" and "splitting" traditions have enhanced our understanding of the underlying mechanisms and antecedents of self-control. Collectively, progress over the past decade and a half suggests a bright future for the science and practice of self-control. PMID- 28862920 TI - Social Cognitive Factors, Physical Activity, and Mobility Impairment in Adults with Multiple Sclerosis. AB - Among those with multiple sclerosis (MS), mobility impairment is common and significantly affects independent functioning and quality of life. The purpose of the study was to examine the role of physical activity in mobility impairment in individuals with MS and explore the social cognitive factors of social support, outcome expectations, and self-efficacy that facilitate physical activity among those with the disease. A sample of 319 individuals with MS were assessed on the following: family and friend social support, self-efficacy, and physical and social outcome expectations. Self-reported physical activity, perceived ambulation disability, balance confidence, and fall history were also measured. The structural model fit the data (chi2 (29) = 24.49, p = 0.70; Root Mean Square Error of Approximation < 0.01; Comparative Fit Index = 1.0; Normed Fit Index = 0.96; Goodness of Fit Index = 0.98; Standardized Root Mean Square Residual = 0.03). The primary findings of the study revealed that physical activity was strongly linked to mobility impairment (path coefficient, -0.43), such that increasing levels of physical activity were associated with less mobility impairment. The most important predictors of health-promoting levels of physical activity were self-efficacy (path coefficient, 0.48) and social support (path coefficient, 0.38), with support from friends being a stronger indicator of social support than support from family. It may be prudent to design interventions aimed at increasing physical activity, especially in regard to helping individuals become more efficacious and building larger social networks, as this may serve to forestall advancing mobility impairment in those with MS. PMID- 28862921 TI - Sex-differences in elite-performance track and field competition from 1983 to 2015. AB - The purpose of this study was to assess the veracity of the Court of Arbitration for Sport's assertion that sex-differences in athletic performance in elite standard track and field competition is of the order of 10-12%. Exponential curves were fitted to the data of selected track and field events of the finals of all IAAF World Championships and Olympic Games from 1983 to 2016. For each curve, the coefficient of determination R2 was calculated, in combination the corresponding 95% confidence intervals for the curve constants. Sex-differences were evaluated via differences in the fitted curves between men and women. Mean performances of winners, as well as overall performance means of all participants, were also analyzed. The calculated sex-difference was 8.2 +/- 1.0% 11.8 +/- 2.1% for sprints, 10.3 +/- 3.3% - 12.8 +/- 4.0% for middle and long distance events, 9.7 +/- 2.9% - 13.1 +/- 2.9% for relays and 14.2 +/- 2.2% - 25.0 +/- 4.4% for jumps. This study therefore confirms that the percentage difference accepted by the CAS is appropriate for elite-standard track and field events. PMID- 28862922 TI - Adherence to Dietary Approaches to Stop Hypertension (DASH) Dietary Pattern in Relation to Chronic Obstructive Pulmonary Disease (COPD): A Case-Control Study. AB - OBJECTIVE: This case-control study was designed to investigate the association between adherences to the Dietary Approaches to Stop Hypertension (DASH) diet in patients with chronic obstructive pulmonary disease (COPD) in comparison to subjects without COPD. DESIGN: This is a case-control study. Usual dietary intake was assessed using a validated food frequency questionnaire. Lung function was evaluated with spirometry testing, and one of the researchers inquired about other respiratory symptoms, including chronic cough, sputum, and breathlessness. Adherence to the DASH dietary pattern was assessed according to the Fung method. SETTING: This study was conducted at Alzahra University Hospital of Isfahan, Iran, in 2015. SUBJECTS: Eight-four patients with COPD and 80 subjects without a history of COPD participated in study. RESULTS: The mean age of participants was 57 years. Average smoking in the case group was about 27.5 pack-years. Spirometry tests including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC were significantly lower in patients with COPD (p = 0.0001). Among COPD symptoms, cough was significantly decreased across tertiles of DASH score (p = 0.03). Significant differences were found for DASH score between patients with COPD and control subjects (19.82 + 3.63 vs 21.13 + 3.82, p = 0.02). Vitamin C, vitamin E, and dietary fiber intake were lower in patients with COPD (144.32 + 70.51 vs 166.97 + 71.88, p = 0.04, 7.49 + 3.91 vs 8.72 + 3.21, p = 0.02 and 19.34 + 7.05 vs 22.19 + 7.87, p = 0.01, respectively). CONCLUSION: We observed that adherence to a DASH dietary pattern among patients with COPD was significantly lower compared to the control group. Cough was significantly decreased by increments in adherence to a DASH dietary pattern. PMID- 28862923 TI - Representing Color Ensembles. AB - Colors are rarely uniform, yet little is known about how people represent color distributions. We introduce a new method for studying color ensembles based on intertrial learning in visual search. Participants looked for an oddly colored diamond among diamonds with colors taken from either uniform or Gaussian color distributions. On test trials, the targets had various distances in feature space from the mean of the preceding distractor color distribution. Targets on test trials therefore served as probes into probabilistic representations of distractor colors. Test-trial response times revealed a striking similarity between the physical distribution of colors and their internal representations. The results demonstrate that the visual system represents color ensembles in a more detailed way than previously thought, coding not only mean and variance but, most surprisingly, the actual shape (uniform or Gaussian) of the distribution of colors in the environment. PMID- 28862924 TI - Sex differences in jealousy: the (lack of) influence of researcher theoretical perspective. AB - The sex difference in jealousy is an effect that has generated significant controversy in the academic literature (resulting in two meta-analyses that reached different conclusions on the presence or absence of the effect). In this study, we had a team of researchers from different theoretical perspectives use identical protocols to test whether the sex difference in jealousy would occur across many different samples (while testing whether mate value would moderate the effect). In our samples, we found the sex difference in jealousy to occur using both forced choice and continuous measures, this effect appeared in several different settings, and, we found that mate value moderated participant responses. The results are discussed in light of the controversy surrounding the presence of the effect. PMID- 28862925 TI - Erratum. PMID- 28862926 TI - Alirocumab Treatment and Achievement of Non-High-Density Lipoprotein Cholesterol and Apolipoprotein B Goals in Patients With Hypercholesterolemia: Pooled Results From 10 Phase 3 ODYSSEY Trials. AB - BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (apo) B are better predictors of atherosclerotic cardiovascular disease risk than low-density lipoprotein cholesterol alone. US and European lipid management guidelines support non-HDL-C and apoB as targets for lipid lowering therapy. METHODS AND RESULTS: This analysis evaluated the efficacy of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, on non-HDL C and apoB. Data were derived from 4983 patients enrolled in 10 randomized, placebo- or ezetimibe-controlled Phase 3 ODYSSEY trials. Primary end point for this pooled analysis was percent reduction in non-HDL-C and apoB at Week 24; secondary end points included the percentage of patients achieving guideline directed treatment goals (National Lipid Association guidelines: non-HDL-C <100 or <130 mg/dL for patients at very high and high cardiovascular risk, respectively; European Society of Cardiology/European Atherosclerosis Society guidelines: apoB <80 mg/dL for patients at very-high cardiovascular risk). Data were grouped according to comparator, alirocumab starting dose, and concomitant statin use. Compared with controls, alirocumab produced significantly greater reductions in non-HDL-C and apoB at Week 24 (P<0.0001), an effect extending up to 78 weeks. More alirocumab-treated patients achieved levels of non-HDL-C <100 mg/dL and apoB <80 mg/dL (P<=0.0001 versus control). By Week 24, >70% of alirocumab-treated patients on background statin achieved non-HDL-C <100 or <130 mg/dL, and apoB <80 mg/dL. Safety was comparable across pooled groups and in line with previous reports. CONCLUSIONS: Alirocumab produced significant, sustained reductions in non-HDL-C and apoB, allowing more patients to achieve lipid goals compared with placebo or ezetimibe and irrespective of maximally tolerated statin use. PMID- 28862927 TI - Inhibition of Mutant alphaB Crystallin-Induced Protein Aggregation by a Molecular Tweezer. AB - BACKGROUND: Compromised protein quality control causes the accumulation of misfolded proteins and intracellular aggregates, contributing to cardiac disease and heart failure. The development of therapeutics directed at proteotoxicity based pathology in heart disease is just beginning. The molecular tweezer CLR01 is a broad-spectrum inhibitor of abnormal self-assembly of amyloidogenic proteins, including amyloid beta-protein, tau, and alpha-synuclein. This small molecule interferes with aggregation by binding selectively to lysine side chains, changing the charge distribution of aggregation-prone proteins and thereby disrupting aggregate formation. However, the effects of CLR01 in cardiomyocytes undergoing proteotoxic stress have not been explored. Here we assess whether CLR01 can decrease cardiac protein aggregation catalyzed by cardiomyocyte-specific expression of mutated alphaB-crystallin (CryABR120G). METHODS AND RESULTS: A proteotoxic model of desmin-related cardiomyopathy caused by cardiomyocyte-specific expression of CryABR120G was used to test the efficacy of CLR01 therapy in the heart. Neonatal rat cardiomyocytes were infected with adenovirus expressing either wild-type CryAB or CryABR120G. Subsequently, the cells were treated with different doses of CLR01 or a closely related but inactive derivative, CLR03. CLR01 decreased aggregate accumulation and attenuated cytotoxicity caused by CryABR120G expression in a dose-dependent manner, whereas CLR03 had no effect. Ubiquitin-proteasome system function was analyzed using a ubiquitin-proteasome system reporter protein consisting of a short degron, CL1, fused to the COOH-terminus of green fluorescent protein. CLR01 improved proteasomal function in CryABR120G cardiomyocytes but did not alter autophagic flux. In vivo, CLR01 administration also resulted in reduced protein aggregates in CryABR120G transgenic mice. CONCLUSIONS: CLR01 can inhibit CryABR120G aggregate formation and decrease cytotoxicity in cardiomyocytes undergoing proteotoxic stress, presumably through clearance of the misfolded protein via increased proteasomal function. CLR01 or related compounds may be therapeutically useful in treating the pathogenic sequelae resulting from proteotoxic heart disease. PMID- 28862928 TI - Socioeconomic Position Is Associated With Carotid Intima-Media Thickness in Mid Childhood: The Longitudinal Study of Australian Children. AB - BACKGROUND: Lower socioeconomic position (SEP) predicts higher cardiovascular risk in adults. Few studies differentiate between neighborhood and family SEP or have repeated measures through childhood, which would inform understanding of potential mechanisms and the timing of interventions. We investigated whether neighborhood and family SEP, measured biennially from ages 0 to 1 year onward, was associated with carotid intima-media thickness (IMT) at ages 11 to 12 years. METHODS AND RESULTS: Data were obtained from 1477 families participating in the Child Health CheckPoint study, nested within the Longitudinal Study of Australian Children. Disadvantaged family and neighborhood SEP was cross-sectionally associated with thicker maximum carotid IMT in separate univariable linear regression models. Associations with family SEP were not attenuated in multivariable analyses, and associations with neighborhood SEP were attenuated only in models adjusted for family SEP. The difference in maximum carotid IMT between the highest and lowest family SEP quartile measured at ages 10 to 11 years was 10.7 MUm (95% CI, 3.4-18.0; P=0.004), adjusted for age, sex, pubertal status, passive smoking exposure, body mass index, blood pressure, and arterial lumen diameter. In longitudinal analyses, family SEP measured as early as age 2 to 3 years was associated with maximum carotid IMT at ages 11 to 12 years (difference between highest and lowest quartile: 8.5 MUm; 95% CI, 1.3-15.8; P=0.02). No associations were observed between SEP and mean carotid IMT. CONCLUSIONS: We report a robust association between lower SEP in early childhood and carotid IMT in mid-childhood. Further investigation of mechanisms may inform pediatric cardiovascular risk assessment and prevention strategies. PMID- 28862929 TI - Socioeconomic Status and Incidence of Hospitalization With Lower-Extremity Peripheral Artery Disease: Atherosclerosis Risk in Communities Study. AB - BACKGROUND: Compared to coronary heart disease, heart failure, and stroke, the relationship between low socioeconomic status (SES) and peripheral artery disease (PAD) is less well established. We examined the association between SES and incidence of hospitalization with PAD and explored whether this association can be explained by traditional cardiovascular risk factors and healthcare access. METHODS AND RESULTS: A total of 12 517 participants in the Atherosclerosis Risk in Communities (ARIC) Study (1987-1989) with no prior PAD were examined. Individual-level SES was assessed from household income (low <$12 000/year, medium $12 000 to $24 999/year, and high >=$25 000/year [double to approximate to values in 2016]) and educational attainment (high school), and area-level SES from area deprivation index (quintiles). During a median follow-up of 23.6 (Interquartile range 19.6-24.5) years, 433 participants had a hospitalization with PAD. In Cox proportional hazards regression analysis, the demographically adjusted hazard ratio was 2.42 (1.81-3.23) for low household income, 2.08 (1.60-2.69) for low educational attainment, and 2.18 (1.35-3.53) for most deprived neighborhoods, compared to their high-SES counterparts. After adjustment for traditional cardiovascular risk factors and heath care access, the associations were attenuated but remained significant, particularly for income and education. Results were consistent when stratified by race (P-values for interaction >0.2 for all SES parameters). CONCLUSIONS: Low individual- and area level SES are strong predictors of hospitalization with PAD, in part due to increased prevalence of cardiovascular risk factors and poor access to care in these groups. Additional risk factors may also need to be identified and acted on to eliminate SES disparities in PAD hospitalization. PMID- 28862930 TI - Blood Pressure Response to Main Renal Artery and Combined Main Renal Artery Plus Branch Renal Denervation in Patients With Resistant Hypertension. AB - BACKGROUND: Single-electrode ablation of the main renal artery for renal sympathetic denervation showed mixed blood pressure (BP)-lowering effects. Further improvement of the technique seems crucial to optimize effectiveness of the procedure. Because sympathetic nerve fibers are closer to the lumen in the distal part of the renal artery, treatment of the distal main artery and its branches has been shown to reduce variability in treatment effects in preclinical studies and a recent randomized trial. Whether this optimized technique improves clinical outcomes remains uncertain. We report a 2-center experience of main renal artery and combined main renal artery plus branches renal denervation in patients with resistant hypertension using a multielectrode catheter. METHODS AND RESULTS: Twenty-five patients with therapy-resistant hypertension underwent renal sympathetic denervation with combined main renal artery and renal branch ablation and were compared to matched controls undergoing an ablation of the main renal artery only. BP change was assessed by ambulatory measurement at baseline and after 3 months. At baseline, BP was balanced between the groups. After 3 months, BP changed significantly in the combined ablation group (systolic/diastolic 24 hour mean and daytime mean BP -8.5+/-9.8/-7.0+/-10.7 and -9.4+/-9.8/-7.1+/-13.5 mm Hg, P<0.001/0.003 and <0.001/0.016, respectively), but not in patients with main artery treatment (-3.5+/-11.1/-2.0+/-7.6 and -2.8+/-10.9/-1.8+/-7.7 mm Hg, P=0.19/0.20 and 0.19/0.24, respectively). Systolic daytime BP was significantly more reduced in patients with combined ablation than in patients with main artery ablation (P=0.033). CONCLUSIONS: Combined ablation of the main renal artery and branches appears to improve BP-lowering efficacy and should be further investigated. PMID- 28862932 TI - Atrial Fibrillation in Heart Failure US Ambulatory Cardiology Practices and the Potential for Uptake of Catheter Ablation: An National Cardiovascular Data Registry (NCDR(r)) Research to Practice (R2P) Project. AB - BACKGROUND: Atrial fibrillation (AF) and heart failure with reduced ejection fraction frequently coexist. The AATAC (Ablation versus Amiodarone for Treatment of persistent Atrial fibrillation in patients with Congestive heart failure and an implantable device) trial suggests that catheter ablation may benefit these patients. However, applicability to contemporary ambulatory cardiology practice is unknown. METHODS AND RESULTS: Using the outpatient National Cardiovascular Data Registry(r) Practice Innovation and Clinical Excellence Registry, we identified participants meeting AATAC enrollment criteria between 2013 and 2014. Treatment with medications and procedures was assessed at registry inclusion. From 164 166 patients with AF and heart failure, 8483 (7%) patients potentially met AATAC inclusion criteria. Eligible subjects, compared to AATAC trial participants, were older (mean age, 71.2+/-11.4 years) and had greater comorbidity (coronary artery disease 79.2%, hypertension 82.4%, and diabetes mellitus 31.8%). AF was predominantly paroxysmal (65.5%), rather than persistent/permanent (16.7%) or new onset (17.8%), whereas all patients in the AATAC trial had persistent AF. Commonly used atrioventricular-nodal blocking agents were carvedilol (71.2%), digoxin (31.9%), and metoprolol (27.1%). Rhythm control with anti-arrhythmic drugs was reported in 29.0% of AATAC eligible patients (predominantly amiodarone [24.6%]) and 9.3% had undergone catheter ablation. Patients who underwent ablation were more likely to be younger and have less comorbidities than those who did not. CONCLUSIONS: Among the contemporary ambulatory AF/heart failure with reduced ejection fraction population, treatment is predominantly rate control with few catheter ablations. Application of AATAC findings has the potential to markedly increase the use of catheter ablation in this population, although significant differences in clinical profiles might influence ablation outcomes in practice. PMID- 28862931 TI - Cardiovascular Adverse Events in Patients With Cancer Treated With Bevacizumab: A Meta-Analysis of More Than 20 000 Patients. AB - BACKGROUND: The monoclonal antibody bevacizumab effectively inhibits angiogenesis in several types of cancers by blocking vascular endothelial growth factor. However, life-threatening cardiovascular adverse effects could limit its use and may warrant specific follow-up strategies. METHODS AND RESULTS: We systematically searched MEDLINE, Cochrane, EMBASE, and Web of Science for randomized controlled trials published until November 2016 that assessed patients with cancer treated with or without bevacizumab in addition to standard chemotherapy. A total of 20 050 patients with a broad range of cancer types from 22 studies were included in this analysis (10 394 in the bevacizumab group and 9656 in the control group). The risks of arterial and venous adverse events were higher in the bevacizumab groups (relative risk [RR], 1.37; 95% CI, 1.10-1.70 [P=0.004] and RR, 1.29; 95% CI, 1.12-1.47 [P<0.001], respectively), and more arterial adverse events occurred in patients taking high-dose bevacizumab regimens. Bevacizumab treatment was associated with the highest risk of cardiac and cerebral ischemia in the high dose bevacizumab groups (RR, 4.4; 95% CI, 1.59-12.70 [P=0.004] and RR, 6.67; 95% CI, 2.17-20.66 [P=0.001], respectively). In addition, the risk of bleeding and arterial hypertension were higher in the bevacizumab groups (RR, 2.74; 95% CI, 2.38-3.15 [P<0.001] and RR, 4.73; 95% CI, 4.15-5.39 [P<0.00001], respectively), with higher values for patiens taking high-dose regimens. CONCLUSIONS: Treatment with bevacizumab increases the risk of arterial adverse events, particularly cardiac and cerebral ischemia, venous adverse events, bleeding, and arterial hypertension. This risk is additionally increased with high doses of bevacizumab. Further studies should determine the appropriate options for cardio-oncology management. CLINICAL TRIAL REGISTRATION: URL: https://www.crd.york.ac.uk. Unique identifier: PROSPERO(CRD42016054305). PMID- 28862933 TI - Quality of Care of the Initial Patient Cohort of the Diabetes Collaborative Registry(r). AB - BACKGROUND: Although guidelines and performance measures exist for patients with diabetes mellitus, achievement of these metrics is not well known. The Diabetes Collaborative Registry(r) (DCR) was formed to understand the quality of diabetes mellitus care across the primary and specialty care continuum in the United States. METHODS AND RESULTS: We assessed the frequency of achievement of 7 diabetes mellitus-related quality metrics and variability across the Diabetes Collaborative Registry(r) sites. Among 574 972 patients with diabetes mellitus from 259 US practices, median (interquartile range) achievement of the quality metrics across the practices was the following: (1) glycemic control: 19% (5-47); (2) blood pressure control: 80% (67-88); (3) angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in patients with coronary artery disease: 62% (51-69); (4) nephropathy screening: 62% (53-71); (5) eye examination: 0.7% (0.0-79); (6) foot examination: 0.0% (0.0-2.3); and (7) tobacco screening/cessation counseling: 86% (80-94). In hierarchical, modified Poisson regression models, there was substantial variability in meeting these metrics across sites, particularly with documentation of glycemic control and eye and foot examinations. There was also notable variation across specialties, with endocrinology practices performing better on glycemic control and diabetes mellitus foot examinations and cardiology practices succeeding more in blood pressure control and use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. CONCLUSIONS: The Diabetes Collaborative Registry(r) was established to document and improve the quality of outpatient diabetes mellitus care. While target achievement of some metrics of cardiovascular risk modification was high, achievement of others was suboptimal and highly variable. This may be attributable to fragmentation of care, lack of ownership among various specialists concerning certain domains of care, incomplete documentation, true gaps in care, or a combination of these factors. PMID- 28862934 TI - Impact of Spontaneous Extracranial Bleeding Events on Health State Utility in Patients with Atrial Fibrillation: Results from the ENGAGE AF-TIMI 48 Trial. AB - BACKGROUND: The impact of different types of extracranial bleeding events on health-related quality of life and health-state utility among patients with atrial fibrillation is not well understood. METHODS AND RESULTS: The ENGAGE AF TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) Trial compared edoxaban with warfarin with respect to the prevention of stroke or systemic embolism in atrial fibrillation. Data from the EuroQol-5D (EQ-5D-3L) questionnaire, prospectively collected at 3-month intervals for up to 48 months, were used to estimate the impact of different categories of bleeding events on health-state utility over 12 months following the event. Longitudinal mixed-effect models revealed that major gastrointestinal bleeds and major nongastrointestinal bleeds were associated with significant immediate decreases in utility scores (-0.029 [ 0.044 to -0.014; P<0.001] and -0.029 [-0.046 to -0.012; P=0.001], respectively). These effects decreased in magnitude over time, and were no longer significant for major nongastrointestinal bleeds at 9 months, but remained borderline significant for major gastrointestinal bleeds at 12 months. Clinically relevant nonmajor and minor bleeds were associated with smaller but measurable immediate impacts on utility (-0.010 [-0.016 to -0.005] and -0.016 [-0.024 to -0.008]; P<0.001 for both), which remained relatively constant and statistically significant over the 12 months following the bleeding event. CONCLUSIONS: All categories of bleeding events were associated with negative impacts on health state utility in patients with atrial fibrillation. Major bleeds were associated with relatively large immediate decreases in utility scores that gradually diminished over 12 months; clinically relevant nonmajor and minor bleeds were associated with smaller immediate decreases in utility that persisted over 12 months. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391. PMID- 28862935 TI - What Is the Relationship Between Dairy Intake and Blood Pressure in Black and White Children and Adolescents Enrolled in a Weight Management Program? AB - BACKGROUND: The DASH (Dietary Approaches to Stop Hypertension) clinical trials and other studies have demonstrated a relationship between diet and cardiovascular outcomes in adults, yet little is known of this relationship in children. Childhood obesity has reached epidemic proportions in the United States, with similar increases in hypertension among this population. The purpose of our study was to examine the association between dairy intake and blood pressure (BP) in a cohort of children and adolescents (aged 4-17 years) enrolled in a weight management program. METHODS AND RESULTS: Dietary intake was assessed using the Block Kids 2004 food frequency questionnaire in a cross-sectional sample of participants enrolled in the Pediatric Metabolic Syndrome Study at the Children's Hospital (Charleston, SC). BP and other anthropometrics were obtained at baseline. Only children with complete baseline data and food frequency questionnaires were included in this analysis (n=117). Associations between food group/nutrient intake and BP were examined across race and sex using ANOVA and Pearson correlations. Linear regression models were controlled for body mass index and age. In the total sample, a significant inverse relationship was found between the intake of dairy and systolic BP (r=-0.24, P=0.009). The effect of dairy on systolic BP, however, differed by race. We observed a decrease of 11.2 mm Hg for each serving of dairy consumed by white children, and no decrease in systolic BP in black children (P=0.001 for the race-dairy serving interaction). CONCLUSIONS: Nutrition professionals must consider nonnutrition factors contributing to childhood hypertension, as current dietary recommendations appear to have differential outcomes across races. PMID- 28862936 TI - Prevalence and Characteristics of Carotid Artery High-Risk Atherosclerotic Plaques in Chinese Patients With Cerebrovascular Symptoms: A Chinese Atherosclerosis Risk Evaluation II Study. AB - BACKGROUND: Carotid atherosclerotic plaque rupture is an important source of ischemic stroke. However, the prevalence of high-risk plaque (HRP) defined as plaques with luminal surface disruption, a lipid-rich necrotic core occupying >40% of the wall, or intraplaque hemorrhage in Chinese population remains unclear. This study uses carotid magnetic resonance imaging (CMRI) to investigate HRP prevalence in carotid arteries of Chinese patients with cerebrovascular symptoms. METHODS AND RESULTS: Patients with cerebral ischemic symptoms in the anterior circulation within 2 weeks and carotid plaque determined by ultrasound were recruited and underwent CMRI. The HRP features were identified and compared between symptomatic and asymptomatic arteries. Receiver-operating-characteristic analysis was used to calculate area-under-the-curve (AUC) of stenosis and maximum wall thickness for discriminating presence of HRP. In 1047 recruited subjects, HRP detected by CMRI was nearly 1.5 times more prevalent than severe stenosis (>=50%) in this cohort (28% versus 19%, P<0.0001). Approximately two thirds of HRPs were found in arteries with <50% stenosis. The prevalence of HRP in symptomatic carotid arteries was significantly higher than that of the contralateral asymptomatic carotid arteries (23.0% versus 16.4%, P=0.001). Maximum wall thickness was found to be a stronger discriminator than stenosis for HRP (AUC: 0.93 versus 0.81, P<0.0001). CONCLUSIONS: There are significantly more high-risk carotid plaques than carotid arteries with >=50% stenosis in symptomatic Chinese patients. A substantial number of HRPs were found in arteries with lower grade stenosis and maximum wall thickness was a stronger indicator for HRP than luminal stenosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02017756. PMID- 28862937 TI - Predictors of Intramyocardial Hemorrhage After Reperfused ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Findings from recent studies show that microvascular injury consists of microvascular destruction and intramyocardial hemorrhage (IMH). Patients with ST-segment elevation myocardial infarction (STEMI) with IMH show poorer prognoses than patients without IMH. Knowledge on predictors for the occurrence of IMH after STEMI is lacking. The current study aimed to investigate the prevalence and extent of IMH in patients with STEMI and its relation with periprocedural and clinical variables. METHODS AND RESULTS: A multicenter observational cohort study was performed in patients with successfully reperfused STEMI with cardiovascular magnetic resonance examination 5.5+/-1.8 days after percutaneous coronary intervention. Microvascular injury was visualized using late gadolinium enhancement and T2-weighted cardiovascular magnetic resonance imaging for microvascular obstruction and IMH, respectively. The median was used as the cutoff value to divide the study population with presence of IMH into mild or extensive IMH. Clinical and periprocedural parameters were studied in relation to occurrence of IMH and extensive IMH, respectively. Of the 410 patients, 54% had IMH. The presence of IMH was independently associated with anterior infarction (odds ratio, 2.96; 95% CI, 1.73-5.06 [P<0.001]) and periprocedural glycoprotein IIb/IIIa inhibitor treatment (odds ratio, 2.67; 95% CI, 1.49-4.80 [P<0.001]). Extensive IMH was independently associated with anterior infarction (odds ratio, 3.76; 95% CI, 1.91-7.43 [P<0.001]). Presence and extent of IMH was associated with larger infarct size, greater extent of microvascular obstruction, larger left ventricular dimensions, and lower left ventricular ejection fraction (all P<0.001). CONCLUSIONS: Occurrence of IMH was associated with anterior infarction and glycoprotein IIb/IIIa inhibitor treatment. Extensive IMH was associated with anterior infarction. IMH was associated with more severe infarction and worse short-term left ventricular function in patients with STEMI. PMID- 28862938 TI - Microstructural Alterations and Oligodendrocyte Dysmaturation in White Matter After Cardiopulmonary Bypass in a Juvenile Porcine Model. AB - BACKGROUND: Newly developed white matter (WM) injury is common after cardiopulmonary bypass (CPB) in severe/complex congenital heart disease. Fractional anisotropy (FA) allows measurement of macroscopic organization of WM pathology but has rarely been applied after CPB. The aims of our animal study were to define CPB-induced FA alterations and to determine correlations between these changes and cellular events after congenital heart disease surgery. METHODS AND RESULTS: Normal porcine WM development was first assessed between 3 and 7 weeks of age: 3-week-old piglets were randomly assigned to 1 of 3 CPB-induced insults. FA was analyzed in 31 WM structures. WM oligodendrocytes, astrocytes, and microglia were assessed immunohistologically. Normal porcine WM development resembles human WM development in early infancy. We found region-specific WM vulnerability to insults associated with CPB. FA changes after CPB were also insult dependent. Within various WM areas, WM within the frontal cortex was susceptible, suggesting that FA in the frontal cortex should be a biomarker for WM injury after CPB. FA increases occur parallel to cellular processes of WM maturation during normal development; however, they are altered following surgery. CPB-induced oligodendrocyte dysmaturation, astrogliosis, and microglial expansion affect these changes. FA enabled capturing CPB-induced cellular events 4 weeks postoperatively. Regions most resilient to CPB-induced FA reduction were those that maintained mature oligodendrocytes. CONCLUSIONS: Reducing alterations of oligodendrocyte development in the frontal cortex can be both a metric and a goal to improve neurodevelopmental impairment in the congenital heart disease population. Studies using this model can provide important data needed to better interpret human imaging studies. PMID- 28862939 TI - Left Atrial Size and Long-Term Risk of Recurrent Stroke After Acute Ischemic Stroke in Patients With Nonvalvular Atrial Fibrillation. AB - BACKGROUND: Among patients with ischemic stroke and atrial fibrillation, which ones are at high risk of recurrent stroke is unclear. This study aimed to determine whether left atrial size was associated with long-term risk of stroke recurrence in patients with nonvalvular atrial fibrillation. METHODS AND RESULTS: In this multicenter prospective cohort study, nonvalvular atrial fibrillation patients hospitalized for acute ischemic stroke were enrolled and followed up after discharge. Indexed-left atrial diameter was obtained by dividing left atrial diameter by body surface area. Cause-specific and subdistribution hazard ratios of recurrent stroke were estimated by Cox proportional hazards and Fine Gray models, respectively. Risk prediction was evaluated by integrated discrimination improvement and net reclassification improvement. In total, 1611 patients (77.8+/-10.2 [mean+/-SD] years, 44.5% female) were included. During follow-up for 2.40+/-1.63 (mean+/-SD) years, 251 patients had recurrent stroke and 514 patients died. An increased indexed-left atrial diameter (per 1 cm/m2) was significantly associated with elevated risk of stroke recurrence (hazard ratio 1.60, 95% CI 1.30-1.98). The association was maintained when death was regarded as the competing risk and in 1464 patients who were treated with anticoagulants (hazard ratio 1.59, 95% CI 1.27-2.00). Risk prediction for recurrent stroke was significantly improved by adding indexed-left atrial diameter to the baseline model composed of the factors in the CHADS2 score or those in the CHA2DS2-VASc score. CONCLUSION: These findings suggest that left atrial enlargement is associated with an increased risk of recurrent stroke in nonvalvular atrial fibrillation patients with ischemic stroke. PMID- 28862940 TI - Childhood Age and Associations Between Childhood Metabolic Syndrome and Adult Risk for Metabolic Syndrome, Type 2 Diabetes Mellitus and Carotid Intima Media Thickness: The International Childhood Cardiovascular Cohort Consortium. AB - BACKGROUND: There is paucity of knowledge concerning the specific age in youth when the associations of metabolic syndrome (MetS) begin to be operative. Thus, we investigated the relation of age to the associations of childhood MetS with adult MetS, type 2 diabetes mellitus and high carotid intima-media thickness. METHODS AND RESULTS: Five thousand eight-hundred three participants were analyzed in 4 cohort studies (Cardiovascular Risk in Young Finns, Bogalusa Heart Study, Princeton Lipid Research Study, Insulin Study). International cutoffs and previously used 75th percentile cutoffs were used for children to define MetS and its components. Mean follow-up period was 22.3 years. Logistic regression was used to calculate risk ratios and 95% confidence intervals. Childhood MetS and overweight were associated with over 2.4-fold risk for adult MetS from the age of 5 years onward. Risk for type 2 diabetes mellitus was increased from the age of 8 (risk ratio, 2.6-4.1; 95% confidence interval, 1.35-6.76 and 1.12-7.24, respectively) onward for the 2 childhood MetS criteria based on international cut off values and for childhood overweight. Risk for high carotid intima-media thickness was significant at ages 11 to 18 years in relation to childhood MetS or overweight (risk ratio, 2.44-4.22; 95% confidence interval, 1.55-3.55 and 2.55 5.66, respectively). Continuous childhood MetS score was associated with adult MetS from the age of 5, with type 2 diabetes mellitus from the age of 14 and with high carotid intima-media thickness from the age of 11 years onward. CONCLUSIONS: Adult MetS was predicted by MetS in childhood beginning at age 5. However, adult type 2 diabetes mellitus and subclinical atherosclerosis were not predicted by childhood data until after age 8. Body mass index measurement alone at the same age points provided similar findings. PMID- 28862941 TI - Prognostic Value of the CHADS2 Score for Adverse Cardiovascular Events in Coronary Artery Disease Patients Without Atrial Fibrillation-A Multi-Center Observational Cohort Study. AB - BACKGROUND: The CHADS2 score has mainly been used to predict the likelihood of cerebrovascular accidents in patients with atrial fibrillation. However, increasing attention is being paid to this scoring system for risk stratification of patients with coronary artery disease. We investigated the value of the CHADS2 score in predicting cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. METHODS AND RESULTS: This was a multicenter, observational cohort study. The subjects had been admitted to one of the participating institutions with coronary artery disease requiring percutaneous coronary intervention. We calculated the CHADS2 scores for 7082 patients (mean age, 69.7 years; males, 71.9%) without clinical evidence of atrial fibrillation. Subjects were subdivided into low- (0-1), intermediate- (2-3), and high-score (4-6) groups and followed for 1 year. The end point was a composite of cardiovascular/cerebrovascular death, nonfatal myocardial infarction, and ischemic stroke at 1-year follow-up. Rates of triple-vessel/left main trunk disease correlated positively with CHADS2 score categories. CHADS2 scores among single, double, and triple-vessel/left main trunk groups were 2 (1-2), 2 (1-3), and 2 (2-3), respectively (P<0.001). A total of 194 patients (2.8%) had a cardiovascular/cerebrovascular event, and Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular/cerebrovascular events in proportion to a higher CHADS2 score (log-rank test, P<0.001). Multivariate Cox hazard analysis identified CHADS2 score (per 1 point) as an independent predictor of cardiovascular/cerebrovascular events (hazard ratio, 1.31; 95% CI, 1.17-1.47; P<0.001). CONCLUSIONS: This large cohort study indicated that the CHADS2 score is useful for the prediction of cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. PMID- 28862942 TI - Physiological Assessment of Ventricular Myocardial Voltage Using Omnipolar Electrograms. AB - BACKGROUND: Characterization of myocardial health by bipolar electrograms are critical for ventricular tachycardia therapy. Dependence of bipolar electrograms on electrode orientation may reduce reliability of voltage assessment along the plane of arrhythmic myocardial substrate. Hence, we sought to evaluate voltage assessment from orientation-independent omnipolar electrograms. METHODS AND RESULTS: We mapped the ventricular epicardium of 5 isolated hearts from each species-healthy rabbits, healthy pigs, and diseased humans-under paced conditions. We derived bipolar electrograms and voltage peak-to-peak (Vpps) along 2 bipolar electrode orientations (horizontal and vertical). We derived omnipolar electrograms and Vpps using omnipolar electrogram methodology. Voltage maps were created for both bipoles and omnipole. Electrode orientation affects the bipolar voltage map with an average absolute difference between horizontal and vertical of 0.25+/-0.18 mV in humans. Vpps provide larger absolute values than horizontal and vertical bipolar Vpps by 1.6 and 1.4 mV, respectively, in humans. Bipolar electrograms with the largest Vpps from either along horizontal or vertical orientation are highly correlated with omnipolar electrograms and with Vpps values (0.97+/-0.08 and 0.94+/-0.08, respectively). Vpps values are more consistent than bipoles, in both beat-by-beat (CoV, 0.28+/-0.19 versus 0.08+/ 0.13 in human hearts) and rhythm changes (0.55+/-0.21 versus 0.40+/-0.20 in porcine hearts). CONCLUSIONS: Omnipoles provide physiologically relevant and consistent voltages that are along the maximal bipolar direction on the plane of the myocardium. PMID- 28862943 TI - Inter-Relations of Orthostatic Blood Pressure Change, Aortic Stiffness, and Brain Structure and Function in Young Adults. AB - BACKGROUND: Relations of orthostatic change in blood pressure with brain structure and function have not been studied thoroughly, particularly in younger, healthier individuals. Elucidation of factors that contribute to early changes in brain integrity may lead to development of interventions that delay or prevent cognitive impairment. METHODS AND RESULTS: In a sample of the Framingham Heart Study Third Generation (N=2119; 53% women; mean age+/-SD, 47+/-8 years), we assessed orthostatic change in mean arterial pressure (MAP), aortic stiffness (carotid-femoral pulse wave velocity), neuropsychological function, and markers of subclinical brain injury on magnetic resonance imaging. Multivariable regression analyses were used to assess relations between orthostatic change in MAP and brain structural and neuropsychological outcomes. Greater orthostatic increase in MAP on standing was related to better Trails B-A performance among participants aged <49 years (beta+/-SE, 0.062+/-0.029; P=0.031) and among participants with carotid-femoral pulse wave velocity <6.9 m/s (beta+/-SE, 0.063+/-0.026; P=0.016). This relation was not significant among participants who were older or had stiffer aortas. Conversely, greater orthostatic increase in MAP was related to larger total brain volume among older participants (beta+/-SE, 0.065+/-0.029; P=0.023) and among participants with carotid-femoral pulse wave velocity >=6.9 m/s (beta+/-SE, 0.078+/-0.031; P=0.011). CONCLUSIONS: Blunted orthostatic increase in MAP was associated with smaller brain volume among participants who were older or had stiffer aortas and with poorer executive function among persons who were younger or who had more-elastic aortas. Our findings suggest that the brain is sensitive to orthostatic change in MAP, with results dependent on age and aortic stiffness. PMID- 28862944 TI - Exposure to Violence and Carotid Artery Intima-Media Thickness in Mexican Women. AB - BACKGROUND: Violence against women has become a global public health threat. Data on the potential impact of exposure to violence on cardiovascular disease are scarce. METHODS AND RESULTS: We evaluated the association between exposure to violence and subclinical cardiovascular disease in 634 disease-free women from the Mexican Teachers' Cohort who responded to violence-related items from the Life Stressor Checklist and underwent measures of carotid artery intima-media thickness in 2012 and 2013. We defined exposure to violence as having ever been exposed to physical and/or sexual violence. Intima-media thickness was log transformed, and subclinical carotid atherosclerosis was defined as intima-media thickness >=0.8 mm or plaque. We used multivariable linear and logistic regression models adjusted for several potential confounders. Mean age was 48.9+/ 4.3 years. Close to 40% of women reported past exposure to violence. The lifetime prevalence of sexual violence was 7.1%, and prevalence of physical violence was 23.5% (7.7% reported both sexual and physical violence). Relative to women with no history of violence, exposure to violence was associated with higher intima media thickness (adjusted mean percentage difference=2.4%; 95% confidence interval 0.5, 4.3) and subclinical atherosclerosis (adjusted odds ratio=1.60; 95% confidence interval 1.10, 2.32). The association was stronger for exposure to physical violence, especially by mugging or physical assault by a stranger (adjusted mean % difference=4.6%; 95% confidence interval 1.8, 7.5, and odds ratio of subclinical carotid atherosclerosis=2.06; 95% confidence interval 1.22, 3.49). CONCLUSIONS: Exposure to violence, and in particular assault by a stranger, was strongly associated with subclinical cardiovascular disease in Mexican middle-aged women. PMID- 28862945 TI - Effect of Multifactorial Treatment Targets and Relative Importance of Hemoglobin A1c, Blood Pressure, and Low-Density Lipoprotein-Cholesterol on Cardiovascular Diseases in Chinese Primary Care Patients With Type 2 Diabetes Mellitus: A Population-Based Retrospective Cohort Study. AB - BACKGROUND: The relative effect of hemoglobin A1c, blood pressure, and low density lipoprotein-cholesterol (LDL-C) ("ABC" factors) on the prevention of cardiovascular diseases (CVD) among patients with type 2 diabetes mellitus is poorly understood. This study aimed to evaluate the association of key clinical parameters on CVD risk using a multifactorial optimal control approach in Chinese primary care patients with type 2 diabetes mellitus. METHODS AND RESULTS: A population-based retrospective cohort study was conducted on 144 271 Chinese type 2 diabetes mellitus primary care patients, aged 18 to 79 and without prior clinical diagnosis of CVD in 2008-2011. Cox regressions were conducted to examine the association between the combinations of ABC targets (hemoglobin A1c <7%, blood pressure <130/90 mm Hg, and LDL-C <2.6 mmol/L) and risks of CVD (overall), coronary heart disease, stroke, and heart failure. Achieving more ABC targets incrementally reduced the incidence of total CVD and individual disease including coronary heart disease, stroke, and heart failure, irrespective of other patient characteristics. Compared with suboptimal control in all ABC levels, achieving any 1, 2, and all 3 ABC targets reduced the relative risk of CVD by 13% to 42%, 31% to 52%, and 55%, respectively. Among those achieving only 1 ABC target, LDL-C reduction was associated with the greatest CVD risk reduction (42%), followed by blood pressure reduction (18%), and hemoglobin A1c reduction (13%). CONCLUSIONS: To achieve the greatest risk reduction for the incidence of CVD, the ultimate goal of treatment should be to achieve target control of hemoglobin A1c, blood pressure, and LDL-C. If it is not possible to achieve all 3 targets, efforts should be prioritized on treating the LDL-C to minimize CVD risk. PMID- 28862946 TI - alpha1-Adrenergic Receptors Function Within Hetero-Oligomeric Complexes With Atypical Chemokine Receptor 3 and Chemokine (C-X-C motif) Receptor 4 in Vascular Smooth Muscle Cells. AB - BACKGROUND: Recently, we provided evidence that alpha1-adrenergic receptors (ARs) in vascular smooth muscle are regulated by chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor 3 (ACKR3). While we showed that CXCR4 controls alpha1-ARs through formation of heteromeric receptor complexes in human vascular smooth muscle cells (hVSMCs), the molecular basis underlying cross-talk between ACKR3 and alpha1-ARs is unknown. METHODS AND RESULTS: We show that ACKR3 agonists inhibit inositol trisphosphate production in hVSMCs on stimulation with phenylephrine. In proximity ligation assays and co-immunoprecipitation experiments, we observed that recombinant and endogenous ACKR3 form heteromeric complexes with alpha1A/B/D-AR. While small interfering RNA knockdown of ACKR3 in hVSMCs reduced alpha1B/D-AR:ACKR3, CXCR4:ACKR3, and alpha1B/D-AR:CXCR4 complexes, small interfering RNA knockdown of CXCR4 reduced alpha1B/D-AR:ACKR3 heteromers. Phenylephrine-induced inositol trisphosphate production from hVSMCs was abolished after ACKR3 and CXCR4 small interfering RNA knockdown. Peptide analogs of transmembrane domains 2/4/7 of ACKR3 showed differential effects on heteromerization between ACKR3, alpha1A/B/D-AR, and CXCR4. While the transmembrane domain 2 peptide interfered with alpha1B/D-AR:ACKR3 and CXCR4:ACKR3 heteromerization, it increased heteromerization between CXCR4 and alpha1A/B-AR. The transmembrane domain 2 peptide inhibited ACKR3 but did not affect alpha1b-AR in beta-arrestin recruitment assays. Furthermore, the transmembrane domain 2 peptide inhibited phenylephrine-induced inositol trisphosphate production in hVSMCs and attenuated phenylephrine-induced constriction of mesenteric arteries. CONCLUSIONS: alpha1-ARs form hetero-oligomeric complexes with the ACKR3:CXCR4 heteromer, which is required for alpha1B/D-AR function, and activation of ACKR3 negatively regulates alpha1-ARs. G protein-coupled receptor hetero oligomerization is a dynamic process, which depends on the relative abundance of available receptor partners. Endogenous alpha1-ARs function within a network of hetero-oligomeric receptor complexes. PMID- 28862947 TI - Role of Volume Redistribution in the Congestion of Heart Failure. PMID- 28862948 TI - Improving Outcomes of Witnessed Out-of-Hospital Cardiac Arrest After Implementation of International Liaison Committee on Resuscitation 2010 Consensus: A Nationwide Prospective Observational Population-Based Study. AB - BACKGROUND: The International Liaison Committee on Resuscitation (ILCOR) periodically updates the consensus recommendations for cardiopulmonary resuscitation to improve the outcomes of out-of-hospital cardiac arrest (OHCA). However, little is known about the differences in outcomes of witnessed OHCA following the publication of the ILCOR 2010 and the ILCOR 2005 recommendations. METHODS AND RESULTS: We enrolled 241 990 adults who experienced witnessed OHCA between 2007 and 2013 from a prospective, nation-wide, population-based cohort database in Japan. We compared neurologically favorable 1-month survival and 1 month survival rates post-OHCA by dividing the study period into 2 categories: the ILCOR 2005 period and ILCOR 2010 period. The associations between guideline periods and outcomes were estimated using multivariable logistic regression analysis and reported as adjusted odds ratio and 95% CI. Among 241 990 patients examined in this study, OHCA was witnessed in 44 706 patients (18%) by emergency medical service personnel and in 197 284 patients (82%) by citizens. Compared with the ILCOR 2005 period, the neurologically favorable 1-month survival rate improved from 4.6% to 5.2% (adjusted odds ratio, 1.54; 95% CI, 1.42-1.67; P<0.001), and the 1-month survival rate improved from 9.0% to 9.7% (adjusted odds ratio, 1.34; 95% CI, 1.27-1.42; P<0.001) in the ILCOR 2010 period. These improvements were also shown in patients receiving conventional versus compression-only cardiopulmonary resuscitation. CONCLUSIONS: Outcomes of witnessed OHCA were better in the ILCOR 2010 period than those in the ILCOR 2005 period. Our results can provide baseline data for many future prospective studies. PMID- 28862949 TI - High Perforin-Positive Cardiac Cell Infiltration and Male Sex Predict Adverse Long-Term Mortality in Patients With Inflammatory Cardiomyopathy. AB - BACKGROUND: The authors analyzed the effects of perforin-dependent infiltration on long-term mortality in patients with inflammatory cardiomyopathy (CMi). We previously demonstrated that left ventricular function deteriorates and progresses to substantial cardiac dysfunction in patients with perforin-positive cardiac cell infiltration. METHODS AND RESULTS: Between 2003 and 2013, 2389 consecutive patients with clinically suspected CMi who underwent endomyocardial biopsies were enrolled. Endomyocardial biopsies were performed at first admission after exclusion of ischemic or valvular heart disease, and CMi was confirmed in 1717 patients. Follow-up was up to 10.1 years (median 0.47 years; interquartile range, 0.03-2.56 years) and information on vital status was obtained from official resident data files. Multivariable statistical analysis was conducted for all patients with CMi regarding significant predictors of all-cause mortality or need for heart transplantation. Multiple Cox regression analysis revealed perforin above the calculated cutoff point of 2.9 cells/mm2 as a strong predictor of impaired survival with a hazard ratio of 1.881 (95% confidence interval, 1.177 3.008; P=0.008), independent of left ventricular function and other myocardial inflammation markers (CD3, macrophage-1 antigen, leukocyte function-associated antigen-1, human leukocyte antigen-1, and intercellular cell adhesion molecule 1). Unexpectedly, male sex emerged as another strong adverse predictor of survival in CMi (hazard ratio, 1.863; confidence interval, 1.096-3.168 [P=0.022]). Whereas left ventricular ejection fraction course is adversely affected by myocardial perforin, multivariate analysis indicates that left ventricular ejection fraction explains only part of the observed overall mortality. CONCLUSIONS: High perforin-positive cardiac cell infiltration and male sex are independent adverse predictors of long-term mortality in CMi. Furthermore, exact quantification of immunohistochemically detected infiltrates is necessary to assess the prognosis. PMID- 28862950 TI - Cardiac Adaptations to High-Intensity Aerobic Training in Premenopausal and Recent Postmenopausal Women: The Copenhagen Women Study. AB - BACKGROUND: We examined the role of menopause on cardiac dimensions and function and assessed the efficacy of exercise training before and after menopause. METHODS AND RESULTS: Two groups of healthy premenopausal (n=36, 49.4+/-0.3 years) and postmenopausal (n=37, 53.5+/-0.5 years) women with no history of cardiovascular disease and with a mean age difference between groups of only 4 years were studied. Cardiac dimensions and systolic and diastolic function were determined by transthoracic echocardiography with tissue Doppler imaging and 2 dimensional speckle tracking. Measurements were performed at baseline and after a 12-week period of high-intensity aerobic cycle training. LV internal diastolic diameter and LV mass were similar in the 2 groups at baseline and increased by ~2% to 8% (P=0.04-0.0007) with training in both groups. Left atrial end-diastolic and end-systolic volumes were similar for both groups and increased by 23% to 36% (P=0.0006-0.0001) with training. Systolic function assessed by mean global strain was similar in both groups at baseline and increased by ~8% (P=0.0004) with training in the postmenopausal group. LV displacement increased by ~3% (P=0.04) in the premenopausal women only. Diastolic function assessed by E/A ratio was similar at baseline and increased by ~7% (P=0.01) in the premenopausal group and 11% (P=0.0001) in the postmenopausal group with training. CONCLUSIONS: These results suggest that training-induced cardiac adaptations are preserved in the early postmenopausal phase. Furthermore, the hormonal changes associated with the menopausal transition do not appear to affect cardiac dimensions and function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02135575. PMID- 28862951 TI - Serum Neprilysin and Recurrent Admissions in Patients With Heart Failure. AB - BACKGROUND: Our aim was to evaluate the association between the soluble form of neprilysin (sNEP) levels and long-term all-cause, cardiovascular, and acute heart failure (AHF) recurrent admissions in an ambulatory cohort of patients with heart failure. sNEP has emerged as a new biomarker with promising implications for prognosis and therapy in patients with heart failure. Reducing the recurrent admission rate of heart failure patients has become an important target of public health planning strategies. METHODS AND RESULTS: We measured sNEP levels in 1021 consecutive ambulatory heart failure patients. End points were the number of all cause, cardiovascular, and AHF hospitalizations during follow-up. We used covariate-adjusted incidence rate ratios to identify associations. At a median follow-up of 3.4 years (interquartile range: 1.8-5.7), 391 (38.3%) patients died, 477 (46.7%) patients had 1901 all-cause admissions, 324 (31.7%) patients had 770 cardiovascular admissions, and 218 (21.4%) patients had 488 AHF admissions. The medians for sNEP and amino-terminal pro-brain natriuretic peptide were 0.64 ng/mL (interquartile range: 0.39-1.22) and 1248 pg/mL (interquartile range: 538-2825), respectively. In a multivariate setting, the adjusted incidence rate ratios for the top (>1.22 ng/mL) versus the bottom (<=0.39 ng/mL) quartiles of sNEP were 1.37 (95% confidence interval: 1.03-1.82), P=0.032; 1.51 (95% confidence interval: 1.10-2.06), P=0.010; and 1.51 (95% confidence interval: 1.05-2.16), P=0.026 for all-cause, cardiovascular, and AHF admissions, respectively. CONCLUSIONS: Elevated sNEP levels predicted an increased risk of recurrent all cause, cardiovascular, and AHF admissions in ambulatory patients with heart failure. PMID- 28862953 TI - International Collaboration With Dedicated Local Implementation Improves Survival From Out-of-Hospital Cardiac Arrest. PMID- 28862952 TI - Sex-Specific Associations of Oral Anticoagulant Use and Cardiovascular Outcomes in Patients With Atrial Fibrillation. AB - BACKGROUND: Sex-specific effectiveness of rivaroxaban (RIVA), dabigatran (DABI), and warfarin in reducing myocardial infarction (MI), heart failure (HF), and all cause mortality among patients with atrial fibrillation are not known. We assessed sex-specific associations of RIVA, DABI, or warfarin use with the risk of MI, HF, and all-cause mortality among patients with atrial fibrillation. METHODS AND RESULTS: Medicare beneficiaries (men: 65 734 [44.8%], women: 81 135 [55.2%]) with atrial fibrillation who initiated oral anticoagulants formed the study cohort. Inpatient admissions for MI, HF, and all-cause mortality were compared between the 3 drugs separately for men and women using 3-way propensity matched samples. In men, RIVA use was associated with a reduced risk of MI admissions compared with warfarin use (hazard ratio [95% confidence interval (CI): 0.59 [0.38-0.91]), with a trend towards reduced risk compared with DABI use (0.67 [0.44-1.01]). In women, there were no significant differences in the risk of MI admissions across all 3 anticoagulants. In both sexes, RIVA use and DABI use were associated with reduced risk of HF admissions (men: RIVA; 0.75 [0.63 0.89], DABI; 0.81 [0.69-0.96]) (women: RIVA; 0.64 [0.56-0.74], DABI; 0.73 [0.63 0.83]) and all-cause mortality (men: RIVA; 0.66 [0.53-0.81], DABI; 0.75 [0.61 0.93]) (women: RIVA; 0.76 [0.63-0.91], DABI; 0.77 [0.64-0.93]) compared with warfarin use. CONCLUSIONS: RIVA use and DABI use when compared with warfarin use was associated with a reduced risk of HF admissions and all-cause mortality in both sexes. However, reduced risk of MI admissions noted with RIVA use appears to be limited to men. PMID- 28862954 TI - A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy. AB - BACKGROUND: Heart failure preceded by hypertrophy is a leading cause of death, and sex differences in hypertrophy are well known, although the basis for these sex differences is poorly understood. METHODS AND RESULTS: This study used a systems biology approach to investigate mechanisms underlying sex differences in cardiac hypertrophy. Male and female mice were treated for 2 and 3 weeks with angiotensin II to induce hypertrophy. Sex differences in cardiac hypertrophy were apparent after 3 weeks of treatment. RNA sequencing was performed on hearts, and sex differences in mRNA expression at baseline and following hypertrophy were observed, as well as within-sex differences between baseline and hypertrophy. Sex differences in mRNA were substantial at baseline and reduced somewhat with hypertrophy, as the mRNA differences induced by hypertrophy tended to overwhelm the sex differences. We performed an integrative analysis to identify mRNA networks that were differentially regulated in the 2 sexes by hypertrophy and obtained a network centered on PPARalpha (peroxisome proliferator-activated receptor alpha). Mouse experiments further showed that acute inhibition of PPARalpha blocked sex differences in the development of hypertrophy. CONCLUSIONS: The data in this study suggest that PPARalpha is involved in the sex-dimorphic regulation of cardiac hypertrophy. PMID- 28862955 TI - Sex Differences in Associations of Arterial Compliance With Coronary Artery Plaque and Calcification Burden. AB - BACKGROUND: Coronary artery disease is a leading killer of women. Arterial stiffness predicts myocardial infarction, and postmenopausal women have lower arterial compliance (AC) than men. We hypothesized that lower AC would be associated with greater burden of coronary artery plaque and calcification, and that these associations would be stronger in women than men. METHODS AND RESULTS: We evaluated 3639 consecutive adults without coronary artery disease history who had coronary computed tomography between 2006 and 2014. Coronary artery calcification was calculated using the Agatston method. Plaque extent was assessed by the number of arterial segments with visible plaque divided by the number of visualized segments *100 (percent plaque score). Indexed AC was calculated as stroke volume index/central pulse pressure. We used step-wise multivariable linear regression to assess associations of log indexed AC with log (percent plaque score+1) and log (coronary artery calcification+1). Sex-specific models were performed if the interaction sex*AC was significant. Mean age was 57+/-11 years, 53% were men, and 71% were hypertensive. Interaction term sex*AC was significant for both models (P=0.008 for percent plaque score and 0.022 for coronary artery calcification). Lower indexed AC was associated with higher percent plaque score and coronary artery calcification in women (beta+/-SE: 0.231+/-0.113, P=0.042 and -0.334+/-0.166, P=0.044, respectively), but not in men (beta+/-SE: -0.062+/-0.104, P=0.551 and 0.114+/-0.173, P=0.510, respectively). CONCLUSIONS: Lower AC is associated with greater burden of coronary artery plaque and calcification in women, but not in men. Our findings highlight low AC as a correlate of more-advanced coronary artery disease and as a potential link to the worse cardiovascular outcomes in women. PMID- 28862956 TI - Sirtuin 3 Deficiency Accelerates Hypertensive Cardiac Remodeling by Impairing Angiogenesis. AB - BACKGROUND: Emerging evidence indicates that impaired angiogenesis may contribute to hypertension-induced cardiac remodeling. The nicotinamide adenine dinucleotide dependent deacetylase Sirtuin 3 (SIRT3) has the potential to modulate angiogenesis, but this has not been confirmed. As such, the aim of this study was to examine the relationship between SIRT3-mediated angiogenesis and cardiac remodeling. METHODS AND RESULTS: Our experiments were performed on SIRT3 knockout and age-matched wild-type mice infused with angiotensin II (1400 ng/kg per minute) or saline for 14 days. After angiotensin II infusion, SIRT3 knockout mice developed more severe microvascular rarefaction and functional hypoxia in cardiac tissues compared with wild-type mice. These events were concomitant with mitochondrial dysfunction and enhanced collagen I and collagen III expression, leading to cardiac fibrosis. Silencing SIRT3 facilitated angiotensin II-induced aberrant Pink/Parkin acetylation and impaired mitophagy, while excessive mitochondrial reactive oxygen species generation limited angiogenic capacity in primary mouse cardiac microvascular endothelial cells. Moreover, SIRT3 overexpression in cardiac microvascular endothelial cells enhanced Pink/Parkin mediated mitophagy, attenuated mitochondrial reactive oxygen species generation, and restored vessel sprouting and tube formation. In parallel, endothelial cell specific SIRT3 transgenic mice showed decreased fibrosis, as well as improved cardiac function and microvascular network, compared with wild-type mice with similar stimuli. CONCLUSIONS: Collectively, these findings suggest that SIRT3 could promote angiogenesis through attenuating mitochondrial dysfunction caused by defective mitophagy. PMID- 28862958 TI - Paradox of Appropriate Implantable Cardioverter-Defibrillator Therapy: Saving Lives But Revealing an Increased Mortality Risk. PMID- 28862957 TI - Mortality Implications of Appropriate Implantable Cardioverter Defibrillator Therapy in Secondary Prevention Patients: Contrasting Mortality in Primary Prevention Patients From a Prospective Population-Based Registry. AB - BACKGROUND: We sought to examine the mortality impact of appropriate implantable cardioverter defibrillator (ICD) therapy between patients who received ICD for primary versus secondary prevention purposes. METHODS AND RESULTS: From a prospective, population-based registry, we identified 7020 patients who underwent de novo ICD implantation between February 2007 and May 2012 in Ontario, Canada. The primary outcome was all-cause mortality. We used multivariable Cox proportional hazard modeling to adjust for differences in baseline characteristics and analyzed the mortality impact of first appropriate ICD therapy (shock and antitachycardia pacing [ATP]) as a time-varying covariate. There were 1929 (27.5%) patients who received ICDs for secondary prevention purposes. The median follow-up period was 5.02 years. Compared with those with secondary prevention ICDs, patients with primary prevention ICDs had more medical comorbidities, and lower ejection fraction. Patients who experienced appropriate ICD shock or ATP had greater risk of death compared with those who did not, irrespective of implant indication. In the primary prevention group, the adjusted hazard ratios of death for appropriate shock and ATP were 2.00 (95% CI: 1.72 2.33) and 1.73 (95% CI: 1.52-1.97), respectively. In the secondary prevention group, the adjusted hazard ratios of death for appropriate ICD shock and ATP were 1.46 (95% CI: 1.20-1.77) and 1.38 (95% CI: 1.16-1.64), respectively. CONCLUSIONS: Despite having a more favorable clinical profile, occurrence of appropriate ICD shock or ATP in patients with secondary prevention ICDs was associated with similar magnitudes of mortality risk as those with primary prevention ICDs. A heightened degree of care is warranted for all patients who experience appropriate ICD shock or ATP therapy. PMID- 28862959 TI - Hypo-Attenuated Leaflet Thickening and Reduced Leaflet Motion in Sutureless Bioprosthetic Aortic Valves. AB - BACKGROUND: The prevalence of hypo-attenuated leaflet thickening (HALT) and reduced leaflet motion (RLM) is unknown in surgically implanted bioprostheses because systematic investigation of HALT and/or RLM is limited to a few catheter based valves. The aim of this study was to investigate the prevalence of HALT and RLM by cardiac computed tomography in patients who underwent surgical aortic valve replacement and received a Perceval sutureless aortic valve bioprosthesis. METHODS AND RESULTS: This was a single-center prospective observational study that included 47 patients (83.5% of the total number of implantations) who underwent surgical aortic valve replacement with implantation of the Perceval sutureless bioprosthesis (LivaNova PLC, London, UK) at Karolinska University Hospital in Stockholm, Sweden from 2012 to 2016 and were studied by cardiac computed tomography. Cardiac computed tomography was performed at a median of 491 days (range 36-1247 days) postoperatively. HALT was found in 18 (38%) patients and RLM in 13 (28%) patients. All patients with RLM had HALT. Among patients with HALT, 5 out of 18 patients (28%) were treated with anticoagulation (warfarin or any novel oral anticoagulant) at the time of cardiac computed tomography. Among patients with RLM, 3 out of 13 patients (23%) were treated with anticoagulation. CONCLUSIONS: HALT and RLM were prevalent in the surgically implanted Perceval sutureless aortic valve bioprosthesis. Both HALT and RLM were found in patients with ongoing anticoagulation treatment. Whether these findings are associated with adverse events needs further study. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02671474. PMID- 28862960 TI - Selection of Stent Type in Patients With Atrial Fibrillation Presenting With Acute Myocardial Infarction: An Analysis From the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry-Get With the Guidelines. AB - BACKGROUND: Patients receiving oral anticoagulation in addition to dual antiplatelet therapy are known to be at high risk for bleeding events; thus, the selection of a drug-eluting stent (DES) versus a bare metal stent (BMS) can have important implications for patients with atrial fibrillation (AF) presenting with acute myocardial infarction (MI). METHODS AND RESULTS: From the National Cardiovascular Data Registry ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry-Get With the Guidelines, we identified 14 427 AF patients presenting with acute MI undergoing percutaneous coronary intervention from 2008 to 2014. Temporal trends and hospital variation in DES use were examined, as were patterns of use by stroke risk (CHA2DS2-VASc) and bleeding risk ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation). Among patients with linked Medicare data (n=2844), multivariable Cox regression modeling was used to compare risks for a composite outcome (all-cause mortality, readmission for stroke, or MI), readmission for stroke, revascularization, and major bleeding at 1 year. A DES was used in 8414 (58.9%) MI patients with AF, increasing from 47.1% in 2008 to 67.9% in 2014, with wide variation among hospitals. DES placement was more common than BMS placement among patients at high stroke risk (CHA2DS2-VASc >=2) and high bleeding risk (ATRIA >=4). Although aspirin and a P2Y12 inhibitor were prescribed for >95% of all patients regardless of stent type at discharge, warfarin was prescribed less frequently among patients receiving a DES than a BMS (31% versus 39%, P<0.001). The composite outcome was similar between patients with a DES or BMS at 1 year (22% versus 26%; adjusted hazard ratio: 0.88; 95% confidence interval [CI], 0.76-1.03). CONCLUSIONS: Use of DESs among MI patients with AF has increased over time, but substantial hospital-level variation was observed. Patients with AF meeting indications for anticoagulation are more likely to receive a DES than a BMS, even among those at high predicted risk of both stroke and bleeding. PMID- 28862961 TI - Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study. AB - BACKGROUND: Sudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Women's Ischemia Syndrome Evaluation) study. METHODS AND RESULTS: Overall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and as SCD or non-SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person-hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P<0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively (P value not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression (P=0.018) and longer corrected QT interval (P=0.023) were independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD (P=0.033). CONCLUSIONS: SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women. PMID- 28862962 TI - Inspiratory Muscle Training Is Associated With Improved Inspiratory Muscle Strength, Resting Cardiac Output, and the Ventilatory Efficiency of Exercise in Patients With a Fontan Circulation. AB - BACKGROUND: Patients with a Fontan circulation have reduced exercise capacity and respiratory muscle strength. Inspiratory muscle training (IMT) improves exercise capacity and quality of life in adults with heart failure. We assessed whether 6 weeks of a home-based program of IMT improves inspiratory muscle strength and the ventilatory efficiency of exercise in adolescent patients with a Fontan circulation. METHODS AND RESULTS: Twenty-three adolescent participants (aged 16+/ 2 years) with a Fontan circulation underwent 6 weeks of IMT for 30 minutes daily. Respiratory muscle strength (maximal inspiratory pressure and expiratory pressure), lung function, and exercise capacity (cardiopulmonary exercise testing) were assessed. Fourteen of 23 participants also underwent exercise cardiac magnetic resonance imaging to examine the effects of IMT on cardiac output and systemic and pulmonary blood flow. Six weeks of IMT improved maximal inspiratory pressure by 36+/-24 cm H2O (61+/-46%) with no change in maximal expiratory pressure. Ventilatory efficiency of exercise improved after 6 weeks of IMT (from 34.2+/-7.8 to 32.2+/-5.6, P=0.04). In those who underwent exercise cardiac magnetic resonance imaging, IMT increased resting cardiac output (from 4.2+/-1.2 to 4.5+/-1.0 L/min, P=0.03) and ejection fraction (from 50.1+/-4.3 to 52.8+/-6.1%, P=0.03). CONCLUSIONS: Six weeks of IMT is associated with improved inspiratory muscle strength, ventilatory efficiency of exercise, and resting cardiac output in young Fontan patients. IMT may be a simple beneficial addition to the current management of Fontan patients, potentially reducing exercise intolerance and long-term morbidity and mortality. PMID- 28862963 TI - Delayed Care and Mortality Among Women and Men With Myocardial Infarction. AB - BACKGROUND: Women with ST-segment-elevation myocardial infarction (STEMI) have higher mortality rates than men. We investigated whether sex-related differences in timely access to care among STEMI patients may be a factor associated with excess risk of early mortality in women. METHODS AND RESULTS: We identified 6022 STEMI patients who had information on time of symptom onset to time of hospital presentation at 41 hospitals participating in the ISACS-TC (International Survey of Acute Coronary Syndromes in Transitional Countries) registry (NCT01218776) from October 2010 through April 2016. Patients were stratified into time-delay cohorts. We estimated the 30-day risk of all-cause mortality in each cohort. Despite similar delays in seeking care, the overall time from symptom onset to hospital presentation was longer for women than men (median: 270 minutes [range: 130-776] versus 240 minutes [range: 120-600]). After adjustment for baseline variables, female sex was independently associated with greater risk of 30-day mortality (odds ratio: 1.58; 95% confidence interval, 1.27-1.97). Sex differences in mortality following STEMI were no longer observed for patients having delays from symptom onset to hospital presentation of <=1 hour (odds ratio: 0.77; 95% confidence interval, 0.29-2.02). CONCLUSIONS: Sex difference in mortality following STEMI persists and appears to be driven by prehospital delays in hospital presentation. Women appear to be more vulnerable to prolonged untreated ischemia. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01218776. PMID- 28862964 TI - Hospital Practice of Direct-Home Discharge and 30-Day Readmission After Transcatheter Aortic Valve Replacement in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry. AB - BACKGROUND: Nearly 17% of patients are readmitted within 30 days of discharge after transcatheter aortic valve replacement. Selected patients are discharged to skilled nursing facilities, yet the association between a hospital's practice to discharge home versus to skilled nursing facilities, and readmission remains unclear. METHODS AND RESULTS: The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry was used to evaluate readmissions among patients undergoing transcatheter aortic valve replacement (2011-2015). Hospitals were divided into quartiles (Q1-Q4) based on the percentage of patients discharged directly home. We assessed patient and hospital level characteristics and used hierarchical logistic regression to analyze the association of discharge disposition with 30-day readmission. Our cohort included 18 568 transcatheter aortic valve replacement patients at 329 US hospitals, of whom 69% were discharged directly home. Hospitals in the highest quartile of direct home discharge (Q4) compared with hospitals in the lowest (Q1) were more likely to use femoral access (75.2% versus 60.1%, P<0.001), had fewer patients receiving transfusion (26.4% versus 40.9%, P<0.001), and were more likely to be located in the Southern United States (48.8% versus 18.3%, P<0.001). Median 30-day readmission rate was 17.9%. There was no significant difference in 30-day readmissions among quartiles (P=0.14), even after multivariable adjustment (odds ratio Q4 versus Q1=0.89, 95%CI 0.76-1.04; P=0.15). Factors most strongly associated with 30-day readmission were glomerular filtration rate, in-hospital stroke or transient ischemic attack, and nonfemoral access. CONCLUSIONS: There was no statistically significant association between hospital practice of direct home discharge post-transcatheter aortic valve replacement and 30-day readmission. Further research is needed to understand regional variations and optimum strategies for postdischarge care. PMID- 28862965 TI - Subclinical Valve Thrombosis in Sutureless Bioprosthetic Valves. PMID- 28862966 TI - Are Drug Eluting Stents Worth Triple Therapy? PMID- 28862967 TI - In Touch But Out of Time: Aggressive Hospital Discharge and Readmissions After Transcatheter Aortic Valve Replacement. PMID- 28862968 TI - Myocardial Perfusion Imaging Versus Computed Tomography Angiography-Derived Fractional Flow Reserve Testing in Stable Patients With Intermediate-Range Coronary Lesions: Influence on Downstream Diagnostic Workflows and Invasive Angiography Findings. AB - BACKGROUND: Data on the clinical utility of coronary computed tomography angiography-derived fractional flow reserve (FFRCT) are sparse. In patients with intermediate (40-70%) coronary stenosis determined by coronary computed tomography angiography, we investigated the association of replacing standard myocardial perfusion imaging with FFRCT testing with downstream utilization of invasive coronary angiography (ICA) and the diagnostic yield of ICA (rate of no obstructive disease, and rate of revascularization). METHODS AND RESULTS: This was a single-center observational study of symptomatic patients with suspected coronary artery disease referred to coronary computed tomography angiography between 2013 and 2015. Patients were divided into 3 historical groups based on the adjunctive functional testing approach: myocardial perfusion imaging (n=1332) or FFRCT "implementation" (n=800) or "clinical use" (n=1391). Propensity score matching was used to estimate the average period effect on outcomes. Patients in the FFRCT clinical use group versus the myocardial perfusion imaging group were older and had higher pretest probability of obstructive disease. After adjusting for baseline risk characteristics, there was a reduction in downstream ICA utilization (absolute risk difference: -4.2; 95% CI, -6.9 to -1.6; P=0.002). In patients referred to ICA, findings of no obstructive coronary artery disease decreased (-12.8%; 95% CI, -22.2 to -3.4; P=0.008) and rate of coronary revascularization increased (14.1%; 95% CI, 3.3-24.9; P=0.01), as did availability of functional information for guidance of revascularization (27.8%; 95% CI, 11.3-44.4; P<0.001) after clinical adoption of FFRCT. CONCLUSIONS: Replacing adjunctive myocardial perfusion imaging with FFRCT testing for functional assessment of intermediate stenosis determined by coronary computed tomography angiography in stable coronary artery disease was associated with less ICA utilization, and a higher ICA diagnostic yield. The findings in this observational study needs confirmation in prospective, randomized trials. PMID- 28862969 TI - Three-dimensional Integrated Functional, Structural, and Computational Mapping to Define the Structural "Fingerprints" of Heart-Specific Atrial Fibrillation Drivers in Human Heart Ex Vivo. AB - BACKGROUND: Structural remodeling of human atria plays a key role in sustaining atrial fibrillation (AF), but insufficient quantitative analysis of human atrial structure impedes the treatment of AF. We aimed to develop a novel 3-dimensional (3D) structural and computational simulation analysis tool that could reveal the structural contributors to human reentrant AF drivers. METHODS AND RESULTS: High resolution panoramic epicardial optical mapping of the coronary-perfused explanted intact human atria (63-year-old woman, chronic hypertension, heart weight 608 g) was conducted during sinus rhythm and sustained AF maintained by spatially stable reentrant AF drivers in the left and right atrium. The whole atria (107*61*85 mm3) were then imaged with contrast-enhancement MRI (9.4 T, 180*180*360-MUm3 resolution). The entire 3D human atria were analyzed for wall thickness (0.4-11.7 mm), myofiber orientations, and transmural fibrosis (36.9% subendocardium; 14.2% midwall; 3.4% subepicardium). The 3D computational analysis revealed that a specific combination of wall thickness and fibrosis ranges were primarily present in the optically defined AF driver regions versus nondriver tissue. Finally, a 3D human heart-specific atrial computer model was developed by integrating 3D structural and functional mapping data to test AF induction, maintenance, and ablation strategies. This 3D model reproduced the optically defined reentrant AF drivers, which were uninducible when fibrosis and myofiber anisotropy were removed from the model. CONCLUSIONS: Our novel 3D computational high-resolution framework may be used to quantitatively analyze structural substrates, such as wall thickness, myofiber orientation, and fibrosis, underlying localized AF drivers, and aid the development of new patient-specific treatments. PMID- 28862972 TI - Improved Precision of Initial Chest Pain Evaluation With Fractional Flow Reserve Computed Tomography. PMID- 28862970 TI - Clinical Outcomes of Deferred Lesions With Angiographically Insignificant Stenosis But Low Fractional Flow Reserve. AB - BACKGROUND: Data are limited regarding outcomes of deferred lesions in patients with angiographically insignificant stenosis but low fractional flow reserve (FFR). We investigated the natural history of angiographically insignificant stenosis with low FFR among patients who underwent routine 3-vessel FFR measurement. METHODS AND RESULTS: From December 2011 to March 2014, 1136 patients with 3298 vessels underwent routine 3-vessel FFR measurement (3V FFR-FRIENDS study, ClinicalTrials.gov identifier NCT01621438), and this study analyzed the 2 year clinical outcomes of 1024 patients with 2124 lesions with angiographically insignificant stenosis (percentage of diameter stenosis <50%), in which revascularization was deferred. All lesions were classified according to FFR values, using a cutoff of 0.80 (high FFR >0.80 versus low FFR <=0.80). The primary end point was outcome of major adverse cardiovascular events (a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization) at 2 years. Mean angiographic percentage of diameter stenosis and FFR of total lesions were 32.5+/-10.3% and 0.91+/-0.08%, respectively. Among the total lesions with angiographically insignificant stenosis, 8.7% showed low FFR (185 lesions). The incidence of lesions with low FFR was 2.5%, 3.8%, 9.0%, and 15.1% in categories of percentage of diameter stenosis <20%, 20% to 30%, 30% to 40%, and 40% to 50%, respectively. At 2-year follow-up, the low-FFR group showed a significantly higher risk of major adverse cardiovascular events compared with the high FFR group (3.3% versus 1.2%, hazard ratio: 3.371; 95% CI, 1.346-8.442; P=0.009). In multivariable analysis, low FFR was the most powerful independent predictor of future MACE in deferred lesions with angiographically insignificant stenosis (adjusted hazard ratio: 2.617; 95% CI, 1.026-6.679; P=0.044). CONCLUSIONS: In deferred angiographically insignificant stenosis, lesions with low FFR showed significantly higher event rates than those with high FFR. FFR was an independent predictor of future major adverse cardiovascular events in lesions with angiographically insignificant stenosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01621438. PMID- 28862971 TI - Self-Reported Health and Outcomes in Patients With Stable Coronary Heart Disease. AB - BACKGROUND: The major determinants and prognostic importance of self-reported health in patients with stable coronary heart disease are uncertain. METHODS AND RESULTS: The STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial randomized 15 828 patients with stable coronary heart disease to treatment with darapladib or placebo. At baseline, 98% of participants completed a questionnaire that included the question, "Overall, how do you feel your general health is now?" Possible responses were excellent, very good, good, average, and poor. Adjudicated major adverse cardiac events, which included cardiovascular death, myocardial infarction, and stroke, were evaluated by Cox regression during 3.7 years of follow-up for participants who reported excellent or very good health (n=2304), good health (n=6863), and average or poor health (n=6361), before and after adjusting for 38 covariates. Self-reported health was most strongly associated with geographic region, depressive symptoms, and low physical activity (P<0.0001 for all). Poor/average compared with very good/excellent self-reported health was independently associated with major adverse cardiac events (hazard ratio [HR]: 2.30 [95% confidence interval (CI), 1.92-2.76]; adjusted HR: 1.83 [95% CI, 1.51-2.22]), cardiovascular mortality (HR: 4.36 [95% CI, 3.09-6.16]; adjusted HR: 2.15 [95% CI, 1.45-3.19]), and myocardial infarction (HR: 1.87 [95% CI, 1.46-2.39]; adjusted HR: 1.68 [95% CI, 1.25-2.27]; P<0.0002 for all). CONCLUSIONS: Self-reported health is strongly associated with geographical region, mood, and physical activity. In a global coronary heart disease population, self-reported health was independently associated with major cardiovascular events and mortality beyond what is measurable by established risk indicators. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00799903. PMID- 28862973 TI - Fractional Flow Reserve in Angiographically Insignificant Stenoses: Unmasking the Lesion or Creating Disease? PMID- 28862974 TI - Clostridial Collagenase for the Management of Diabetic Foot Ulcers: Results of Four Randomized Controlled Trials. AB - BACKGROUND: Despite major treatment advances, diabetic foot ulcers (DFUs) remain a frequent and debilitating complication of diabetes mellitus and a major cause of significant morbidity and mortality. OBJECTIVE: This study evaluates and compares clinical effectiveness of clostridial collagenase ointment (CCO) with standard care (SC) in patients with DFUs, with the goal to define best clinical criteria under which to use CCO in the DFU population. MATERIALS AND METHODS: This is a pooled data analysis of 4 randomized controlled trials that compared clinical effectiveness of CCO to SC. A total of 174 adult patients with 1 target DFU each who underwent treatment with CCO (n = 88) or SC (n = 86) for 4 or 6 weeks were evaluated. Assessments included wound area reduction, wound bed status, and time to closure. RESULTS: Statistically significant mean percentage change in wound area from baseline was numerically greater for CCO than SC at the end of study (EOS) following 6 or 8 weeks of treatment; these values were -56% and -10%, respectively, in the subgroup of plantar surface ulcers (P = .05) and wounds assessed as "low necrosis" (<= 25% necrotic) at baseline (-64% vs. -20%). When rapidly healing ulcers were excluded from the analysis, the difference in ulcer area reduction was even greater for CCO compared with SC at EOS (-53% vs. 7%; P = .05). CONCLUSIONS: Active CCO therapy was associated with a nonstatistically greater reduction in wound size than any of the passive or mechanical SC modalities at end of treatment. This was statistically significant when used in conjunction with sharp debridement and for slow healing ulcers, larger sized wounds, or plantar surface wounds. PMID- 28862976 TI - Sarcoidosis and Wound Healing After Cellulitis of the Lower Limb: Is Methotrexate Responsible for Skin Graft Failure? AB - The authors report the case of a 53-year-old man with diffuse cutaneous and mediastinal pulmonary sarcoidosis and well-controlled steroid-induced diabetes. He was hospitalized for cellulitis of his left leg. His standard treatment for sarcoidosis consisted of prednisone and methotrexate. Prednisone was stopped at his admission. He received antibiotics for 4 weeks to treat the cellulitis. In parallel, the leg wound was treated with daily silver sulfadiazine applications until necrosis removal, then by skin autografting. Four successive procedures were performed, but all failed despite lack of surgical problem or local infection. Methotrexate was stopped after the fourth grafting procedure failed; the fifth, and final, autografting procedure was successfully performed. PMID- 28862975 TI - G Protein-coupled Receptors and Proopiomelanocortin Expression After Light Emitting Diode Irradiation in Diabetic Wound Healin. AB - OBJECTIVE: The purpose of this study is to investigate whether light-emitting diode (LED) light at different wavelengths can improve wound healing in both diabetic and normal fibroblasts. MATERIALS AND METHODS: Both diabetic and normal fibroblast cell lines were cultured and artificial wounds were created on the cultured cells in petri dishes as a streak line with pipette tips. Then, both cells were separately irradiated with 635 nm (red), 520 nm (green), and 465 nm (blue) LED lights at 0.67 J/cm2 for 10 minutes. Immediately after LED irradiation, messenger ribonucleic acid samples of each cell line were isolated for microarray analysis. RESULTS: The investigator found that G protein-coupled receptors (GPR) class A, a rhodopsin-like structure gene, were significantly upregulated in all treated groups by transferring the signal to proopiomelanocortin (POMC) genes in diabetic cells. In addition, for normal cell groups, the expression of other genes relevant to viral defense responses markedly increased. However, in diabetic cells, genes relating to acute inflammatory response and mitotic cell cycle were highly expressed. The investigator also found that diabetic cells responded significantly better to wound healing attempts than normal cells because inflammatory response, cell migration, cell proliferation, cell adhesion, and regulation of mitosis pathways could be instantly activated by red and green LED lights. CONCLUSIONS: These lights activate the expression of GPR class A gene, which receives photons and transfers this signal to other downstream pathways inside the cell, specifically to the POMC gene, which will recover the wound-healing process to the normal stage. PMID- 28862977 TI - Healing Rate of Chronic and Subacute Lower Extremity Ulcers Treated With Contact Ultrasound Followed by Noncontact Ultrasound Therapy: The VIP Ultrasound Protocol. AB - BACKGROUND: Contact and noncontact ultrasounds are types of low-frequency ultrasonic treatments for wound care. OBJECTIVE: The purpose of this research was to collect data in order to see if healing rates are accelerated when both forms of ultrasound therapies are utilized. MATERIALS AND METHODS: The Viana-Pompeo (VIP) Ultrasound Protocol consists of high-intensity, low-frequency, contact ultrasound therapy followed by low-intensity, low-frequency, noncontact ultrasound therapy. A total of 11 subjects with a total of 24 chronic or subacute lower extremity wounds were enrolled in the study. Of the 11 subjects, 6 finished the protocol (12 wounds). All subjects started with contact ultrasound for debridement at a frequency of 25 kHz and at the maximum intensity the subject could tolerate (equipment range, 20%-100% of 1.0 W/cm2). Once the wound was sufficiently clean with <= 20% of necrotic tissue or adherent slough, therapy was switched to noncontact, low-frequency ultrasound (NLFU) for cellular stimulation at 40 kHz and intensities of 0.1 W/cm2 to 0.5 W/cm2. Subjects received ultrasound treatment 3 times weekly for the 12-week study. Progress was analyzed based on reductions in wound area, volume, and slough and increases in granulation and epithelialization. Wounds were divided into 2 groups: group A, wound duration between 4 and 21 weeks; and group B, wound duration >= 47 weeks. There were no wounds between 21 and 47 weeks. RESULTS: In group A (4 wounds), all wounds improved in wound area and epithelialization; 75% achieved an improvement of > 99% before or at 12 weeks of treatment. In addition, all wounds saw a wound volume reduction of 93% to 100%. Granulation in group A was 100%, and by visit 10 of 36, all wounds had 0% slough or eschar. In group B (8 wounds), 50% of wounds improved with a wound volume reduction of 50%; all wounds increased in granulation, with 50% achieving 75% to 100% granulation. Sixty-two percent of wounds in group B saw an increase in epithelialization, and 75% of wounds had 85% to 100% reduction in slough and eschar by the last visit (end of week 12). There was a strong positive correlation between wound age and healing time (r = 0.94). CONCLUSIONS: Both groups benefited from the VIP Protocol, which promoted wound closure or wound bed preparation for graft. The results seem to favor an earlier start of the protocol for best outcomes and indicate that contact and noncontact ultrasound therapies are not exclusionary but rather complementary. PMID- 28862979 TI - Negative Pressure Wound Therapy for a Giant Wound Secondary to Malignancy-induced Necrotizing Fasciitis: Case Report and Review of the Literature. AB - BACKGROUND: Necrotizing fasciitis (NF) is a life-threatening condition in which rapid diagnosis, debridement of nonviable tissue, and broad-spectrum antibiotics are critical to effective treatment. The debridement required can be extensive, resulting in large wounds that can sometimes be covered with split-thickness skin grafts (STSGs) with the help of negative pressure wound therapy (NPWT), or vacuum assisted closure, to decrease the wound size. CASE REPORT: The authors report a rare case of NF due to malignancy-associated bowel perforation with a giant lower extremity wound secondary to debridement that involved 20% of the total body surface area (TBSA) in a 64-year-old, previously healthy, nonsmoking man. The wound was surgically debrided twice and packed before NPWT was applied. Based on the authors' literature search, this case is 1 of the single largest wounds successfully managed with a STSG and NPWT. CONCLUSIONS: Rapid diagnosis of NF is critical to guide surgical management and administration of antibiotics. It is important to be mindful of the origin of certain necrotizing infections, and clinicians should have a greater index of suspicion for NF when assessing skin infections in unwell patients with concomitant bowel perforation secondary to gastrointestinal malignancy. PMID- 28862980 TI - Management of Chronic Wounds: Diagnosis, Preparation, Treatment, and Follow-up. AB - Management of chronic wounds remains challenging in terms of prevalence and complexity. Considerable progress has been made in understanding the science of wound healing during the past decade, sparking volumes of publications and the development of hundreds of dressing and therapy options. There is a need for a simpli ed overview of evidence-based criteria to assist in the accurate diagnosis and appropriate management of chronic wounds in all care settings. An expert panel of 11 wound healing specialists experienced in various care settings convened to discuss best practices and recommended guidelines for managing major chronic wound types. Prior to the meeting, panel members reviewed 8 preselected peer-reviewed articles and 1 white paper containing treatment algorithms for all major chronic wound types. During the meeting, each panelist presented current evidence-based guidelines regarding a specific chronic wound type and case studies to illustrate concepts in the guidelines. This publication is a result of the panel discussion and presents an overview of literature- and experience- based criteria to help guide chronic wound diagnosis, assessment, treatment, and follow-up. A cycle of steps is presented as a framework to guide holistic care for all patients with chronic wounds, including de- hisced surgical wounds, diabetic foot ulcers, venous leg ulcers, arterial insu ciency ulcers, and pressure ulcers/injuries. Emphasis is placed on criteria to assist accurate diagnosis and dressing/therapy selection, holistic elements of patient and wound bed preparation, interventions to achieve patient adherence to a care plan, and follow-up to help prevent wound recurrence. PMID- 28862981 TI - Need for pharmacogenetic studies on the prevalence of MTHFR mutations in Puerto Ricans and Hispanics. AB - Methylenetetrahydrofolate reductase (MTHFR) mutations have been linked to many diseases. Evidence has been provided to prove that we need to perform pharmacogenetic studies regarding the prevalence of MTHFR mutations and diseases, risks, and the impact on folate requirement in general, but little has been published about Puerto Ricans. A multi center cross-sectional retrospective review study or a prospective pharmacogenetic study of valid genotypes and phenotypes of MTHFR mutations within the different populations of Puerto Ricans and Hispanics are recommended, because differences within them and within the general population are expected. PMID- 28862982 TI - Effects of the genetic variants of organic cation transporters 1 and 3 on the pharmacokinetics of metformin in Jordanians. AB - BACKGROUND: Human response to the antidiabetic metformin is influenced by some factors, such as genetic variants in the SLC22A genes. This study aimed to determine the frequency of main SLC22A1 and SLC22A3 genetic variants and their influence on metformin pharmacokinetics among healthy unrelated Arab Jordanians. PATIENTS AND METHODS: The SLC22A1 and SLC22A3 genes were genotyped by DNA sequencing of exons 1, 3, 7, and 9 in the SLC22A1 gene and exons 6, 7, and 9 in the SLC22A3 gene. Then, a clinical pharmacokinetic study was conducted on 26 healthy volunteers. The pharmacokinetic parameters were calculated using non compartmental model analysis. The study was an open-label, randomized study with single 1000 mg metformin administration. RESULTS: Results showed that volunteers with SLC22A3 rs8187722 variant had higher (chi2, p<0.05) metformin Cmax and AUC values than the wild SLC22A3 volunteers, whereas T1/2 and Kel were not affected. In addition, volunteers with the heterozygote SLC22A3 rs2292334 variant had significantly higher (chi2, p<0.05) metformin Cmax and AUC and lower Kel values than the wild-type SLC22A3 genotype. CONCLUSIONS: The SLC22A3 rs8187722 and rs2292334 genetic variants affected metformin pharmacokinetics among a clinical sample of Jordanians. The findings may increase our understanding of the inter individual and inter-ethnic variations in metformin response. PMID- 28862983 TI - The association of NOV/CCN3 with obstructive sleep apnea (OSA): preliminary evidence of a novel biomarker in OSA. AB - Obstructive sleep apnea (OSA) has a strong association with cardiovascular and metabolic abnormalities, although the mechanism driving this association is not well established. NOV/CCN3, a multifunctional extracellular matrix protein, may play a mechanistic and/or prognostic role in these associations. We hypothesized that patients with OSA, which primarily affects obese individuals, will have increased levels of NOV, and that NOV can serve as a biomarker in patients to predict OSA as well as metabolic and cardiac risk. Ten morbidly obese and 10 healthy lean subjects underwent overnight polysomnography (PSG) and clinical evaluation. Blood samples were analyzed for NOV levels, adiponectin and IL-6. OSA was found in nine obese subjects and three lean subjects. NOV levels were significantly higher in the OSA vs. no OSA group (2.1 +/- 0.9 vs. 1.3 +/- 0.8, p < 0.03). NOV levels were significantly higher in the obese vs. lean group (2.2 +/ 0.3 vs. 1.4 +/- 0.2-fold change, p < 0.03). Among lean subjects, NOV levels were significantly higher in the OSA vs. no OSA group (2.1 +/- 0.9 vs. 1.0 +/- 0.4, p < 0.05). NOV and AHI were positively correlated (rho = 0.49, p = 0.033). IL-6 and adiponectin differences in obese vs. lean and OSA vs. no OSA were consistent with an inflammatory phenotype in obese subjects and OSA subjects. NOV is a novel biomarker of the presence and severity of OSA and a potential marker of future cardiovascular and metabolic disease in OSA patients. PMID- 28862984 TI - Physiological regulation and metabolic role of browning in white adipose tissue. AB - Great progress has been made in our understanding of the browning process in white adipose tissue (WAT) in rodents. The recognition that i) adult humans have physiologically inducible brown adipose tissue (BAT) that may facilitate resistance to obesity and ii) that adult human BAT molecularly and functionally resembles beige adipose tissue in rodents, reignited optimism that obesity and obesity-related diabetes type 2 can be battled by controlling the browning of WAT. In this review the main cellular mechanisms and molecular mediators of browning of WAT in different physiological states are summarized. The relevance of browning of WAT in metabolic health is considered primarily through a modulation of biological role of fat tissue in overall metabolic homeostasis. PMID- 28862985 TI - Critical review of beige adipocyte thermogenic activation and contribution to whole-body energy expenditure. AB - Beige (or brite, "brown in white") adipocytes are uncoupling protein 1 (UCP1) positive cells residing in white adipose depots that, depending on the conditions, behave either as classic white adipocytes, storing energy as lipids, or as brown adipocytes, dissipating energy from oxidative metabolism as heat through non-shivering thermogenesis. Because of their thermogenic potential and, therefore, possible usage to treat metabolic diseases such as obesity and type 2 diabetes, beige cells have attracted the attention of many scientists worldwide aiming to develop strategies to safely recruit and activate their thermogenic activity. Indeed, in recent years, a large variety of conditions, molecules (including nutrients) and signaling pathways were reported to promote the recruitment of beige adipocytes. Despite of those advances, the true contribution of beige adipocyte thermogenesis to whole-body energy expenditure is still not completely defined. Herein, we discuss some important aspects that should be considered when studying beige adipocyte biology and the contribution to energy balance and whole-body metabolism. PMID- 28862986 TI - Digital Biomass Accumulation Using High-Throughput Plant Phenotype Data Analysis. AB - Biomass is an important phenotypic trait in functional ecology and growth analysis. The typical methods for measuring biomass are destructive, and they require numerous individuals to be cultivated for repeated measurements. With the advent of image-based high-throughput plant phenotyping facilities, non destructive biomass measuring methods have attempted to overcome this problem. Thus, the estimation of plant biomass of individual plants from their digital images is becoming more important. In this paper, we propose an approach to biomass estimation based on image derived phenotypic traits. Several image-based biomass studies state that the estimation of plant biomass is only a linear function of the projected plant area in images. However, we modeled the plant volume as a function of plant area, plant compactness, and plant age to generalize the linear biomass model. The obtained results confirm the proposed model and can explain most of the observed variance during image-derived biomass estimation. Moreover, a small difference was observed between actual and estimated digital biomass, which indicates that our proposed approach can be used to estimate digital biomass accurately. PMID- 28862987 TI - MODY in Ukraine: genes, clinical phenotypes and treatment. AB - BACKGROUND: Maturity-onset diabetes of the young (MODY) has not been previously studied in Ukraine. We investigated the genetic etiology in a selected cohort of patients with diabetes diagnosed before 18 years of age, and in their family members. METHODS: Genetic testing of the most prevalent MODY genes (GCK, HNF1A, HNF4A, HNF1B and INS) was undertaken for 36 families (39 affected individuals) by Sanger or targeted next generation sequencing. RESULTS: A genetic diagnosis of MODY was made in 15/39 affected individuals from 12/36 families (33%). HNF1A and HNF4A MODY were the most common subtypes, accounting for 9/15 of MODY cases. Eight patients with HNF1A or HNF4A MODY and inadequate glycemic control were successfully transferred to sulfonylureas. Median HbA1c decreased from 67 mmol/mol (range 58-69) to 47 mmol/mol (range 43-50) (8.3% [7.5-8.5] to 6.4% [6.1 6.7]) 3 months after transfer (p=0.006). CONCLUSIONS: Genetic testing identified pathogenic HNF1A and HNF4A variants as the most common cause of MODY in Ukraine. Transfer to sulfonylureas substantially improved the glycemic control of these patients. PMID- 28862988 TI - Feto-maternal osmotic balance at term. A prospective observational study. AB - OBJECTIVE: We performed the present study to investigate the feto-maternal osmotic relationship at term with the hypothesis that, in contrast to the literature, maternal plasma osmolality is lower than fetal levels. In a previous study, we found that maternal plasma sodium at delivery was consistently lower than the sodium in the umbilical artery. Our aim was to corroborate these results with analysis of osmolality. METHODS: Blood was sampled from 30 women immediately before cesarean section and from the umbilical artery and vein before cord clamping and osmolality, sodium and albumin were analyzed. RESULTS: Maternal osmolality was (mean; 95% confidence interval) 287.0 (285.8-288.2) mOsmkg/kg, arterial cord osmolality was 289.4 (287.9-291.0) mOsm/kg and venous cord osmolality was 287.3 (286.0-288.5) mOsm/kg. The paired difference between maternal and umbilical arterial osmolality was mean (SD) -2.4 (3.3) mOsm/kg (P<0.001), between maternal and umbilical vein -0.3 (3.0) mOsm/kg (P=0.63) and between umbilical artery and vein -2.1 (2.8) mOsm/kg (P<0.001). CONCLUSION: Maternal osmolality was significantly lower than arterial cord osmolality confirming our previous results. The feto-maternal osmotic gradient favors water transport from the mother to the fetus and may increase the fetal risk of water intoxication when the mother ingests or is administered large volumes of electrolyte free solutions. PMID- 28862990 TI - Response to the Letter to the Editor, "Risk factors of uterine rupture with a special interest to uterine fundal pressure: methodological issues". PMID- 28862992 TI - Bayesian comparison of protein structures using partial Procrustes distance. AB - An important topic in bioinformatics is the protein structure alignment. Some statistical methods have been proposed for this problem, but most of them align two protein structures based on the global geometric information without considering the effect of neighbourhood in the structures. In this paper, we provide a Bayesian model to align protein structures, by considering the effect of both local and global geometric information of protein structures. Local geometric information is incorporated to the model through the partial Procrustes distance of small substructures. These substructures are composed of beta-carbon atoms from the side chains. Parameters are estimated using a Markov chain Monte Carlo (MCMC) approach. We evaluate the performance of our model through some simulation studies. Furthermore, we apply our model to a real dataset and assess the accuracy and convergence rate. Results show that our model is much more efficient than previous approaches. PMID- 28862991 TI - Confidence intervals for heritability via Haseman-Elston regression. AB - Heritability is the proportion of phenotypic variance in a population that is attributable to individual genotypes. Heritability is considered an important measure in both evolutionary biology and in medicine, and is routinely estimated and reported in genetic epidemiology studies. In population-based genome-wide association studies (GWAS), mixed models are used to estimate variance components, from which a heritability estimate is obtained. The estimated heritability is the proportion of the model's total variance that is due to the genetic relatedness matrix (kinship measured from genotypes). Current practice is to use bootstrapping, which is slow, or normal asymptotic approximation to estimate the precision of the heritability estimate; however, this approximation fails to hold near the boundaries of the parameter space or when the sample size is small. In this paper we propose to estimate variance components via a Haseman Elston regression, find the asymptotic distribution of the variance components and proportions of variance, and use them to construct confidence intervals (CIs). Our method is further developed to obtain unbiased variance components estimators and construct CIs by meta-analyzing information from multiple studies. We demonstrate our approach on data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). PMID- 28862993 TI - A statistical test for detecting parent-of-origin effects when parental information is missing. AB - Genomic imprinting is an epigenetic mechanism that leads to differential contributions of maternal and paternal alleles to offspring gene expression in a parent-of-origin manner. We propose a novel test for detecting the parent-of origin effects (POEs) in genome wide genotype data from related individuals (twins) when the parental origin cannot be inferred. The proposed method exploits a finite mixture of linear mixed models: the key idea is that in the case of POEs the population can be clustered in two different groups in which the reference allele is inherited by a different parent. A further advantage of this approach is the possibility to obtain an estimation of parental effect when the parental information is missing. We will also show that the approach is flexible enough to be applicable to the general scenario of independent data. The performance of the proposed test is evaluated through a wide simulation study. The method is finally applied to known imprinted genes of the MuTHER twin study data. PMID- 28862994 TI - FC1000: normalized gene expression changes of systematically perturbed human cells. AB - The systematic study of transcriptional responses to genetic and chemical perturbations in human cells is still in its early stages. The largest available dataset to date is the newly released L1000 compendium. With its 1.3 million gene expression profiles of treated human cells it offers many opportunities for biomedical data mining, but also data normalization challenges of new dimensions. We developed a novel and practical approach to obtain accurate estimates of fold change response profiles from L1000, based on the RUV (Remove Unwanted Variation) statistical framework. Extending RUV to a big data setting, we propose an estimation procedure, in which an underlying RUV model is tuned by feedback through dataset specific statistical measures, reflecting p-value distributions and internal gene knockdown controls. Applying these metrics - termed evaluation endpoints - to disjoint data splits and integrating the results to select an optimal normalization, the procedure reduces bias and noise in the L1000 data, which in turn broadens the potential of this resource for pharmacological and functional genomic analyses. Our pipeline and normalization results are distributed as an R package (nelanderlab.org/FC1000.html). PMID- 28862996 TI - Low-temperature thermal transport and thermopower of monolayer transition metal dichalcogenide semiconductors. AB - We study the low temperature thermal conductivity of single-layer transition metal dichalcogenides (TMDCs). In the low temperature regime where heat is carried primarily through transport of electrons, thermal conductivity is linked to electrical conductivity through the Wiedemann-Franz law (WFL). Using a k.p Hamiltonian that describes the [Formula: see text] and [Formula: see text] valley edges, we compute the zero-frequency electric (Drude) conductivity using the Kubo formula to obtain a numerical estimate for the thermal conductivity. The impurity scattering determined transit time of electrons which enters the Drude expression is evaluated within the self-consistent Born approximation. The analytic expressions derived show that low temperature thermal conductivity (1) is determined by the band gap at the valley edges in monolayer TMDCs and (2) in presence of disorder which can give rise to the variable range hopping regime, there is a distinct reduction. Additionally, we compute the Mott thermopower and demonstrate that under a high frequency light beam, a valley-resolved thermopower can be obtained. A closing summary reviews the implications of results followed by a brief discussion on applicability of the WFL and its breakdown in context of the presented calculations. PMID- 28862995 TI - Intracranial EEG fluctuates over months after implanting electrodes in human brain. AB - OBJECTIVE: Implanting subdural and penetrating electrodes in the brain causes acute trauma and inflammation that affect intracranial electroencephalographic (iEEG) recordings. This behavior and its potential impact on clinical decision making and algorithms for implanted devices have not been assessed in detail. In this study we aim to characterize the temporal and spatial variability of continuous, prolonged human iEEG recordings. APPROACH: Intracranial electroencephalography from 15 patients with drug-refractory epilepsy, each implanted with 16 subdural electrodes and continuously monitored for an average of 18 months, was included in this study. Time and spectral domain features were computed each day for each channel for the duration of each patient's recording. Metrics to capture post-implantation feature changes and inflexion points were computed on group and individual levels. A linear mixed model was used to characterize transient group-level changes in feature values post-implantation and independent linear models were used to describe individual variability. MAIN RESULTS: A significant decline in features important to seizure detection and prediction algorithms (mean line length, energy, and half-wave), as well as mean power in the Berger and high gamma bands, was observed in many patients over 100 d following implantation. In addition, spatial variability across electrodes declines post-implantation following a similar timeframe. All selected features decreased by 14-50% in the initial 75 d of recording on the group level, and at least one feature demonstrated this pattern in 13 of the 15 patients. Our findings indicate that iEEG signal features demonstrate increased variability following implantation, most notably in the weeks immediately post-implant. SIGNIFICANCE: These findings suggest that conclusions drawn from iEEG, both clinically and for research, should account for spatiotemporal signal variability and that properly assessing the iEEG in patients, depending upon the application, may require extended monitoring. PMID- 28862997 TI - A novel optically transparent RF shielding for fully integrated PET/MRI systems. AB - Preclinical imaging benefits from simultaneous acquisition of high-resolution anatomical and molecular data. Additionally, PET/MRI systems can provide functional PET and functional MRI data. To optimize PET sensitivity, we propose a system design that fully integrates the MRI coil into the PET system. This allows positioning the scintillators near the object but requires an optimized design of the MRI coil and PET detector. It further requires a new approach in realizing the radiofrequency (RF) shielding. Thus, we propose the use of an optically transparent RF shielding material between the PET scintillator and the light sensor, suppressing the interference between both systems. We evaluated two conductive foils (ITO, 9900) and a wire mesh. The PET performance was tested on a dual-layer scintillator consisting of 12 * 12 LSO matrices, shifted by half a pitch. The pixel size was 0.9 * 0.9 mm2; the lengths were 10.0 mm and 5.0 mm, respectively. For a light sensor, we used a 4 * 4 SiPM array. The RF attenuation was measured from 320 kHz to 420 MHz using two pick-up coils. MRI compatibility and shielding effect of the materials were evaluated with an MRI system. The average FWHM energy resolution at 511 keV of all 144 crystals of the layer next to the SiPM was deteriorated from 15.73 +/- 0.24% to 16.32 +/- 0.13%, 16.60 +/- 0.25%, and 19.16 +/- 0.21% by the ITO foil, 9900 foil, mesh material, respectively. The average peak-to-valley ratio of the PET detector changed from 5.77 +/- 0.29 to 4.50 +/- 0.39, 4.78 +/- 0.48, 3.62 +/- 0.16, respectively. The ITO, 9900, mesh attenuated the scintillation light by 11.3 +/- 1.6%, 11.0 +/- 1.8%, 54.3 +/- 0.4%, respectively. To attenuate the RF from 20 MHz to 200 MHz, mesh performed better than copper. The results show that an RF shielding material that is sufficiently transparent for scintillation light and is MRI compatible can be obtained. This result enables the development of a fully integrated PET detector and MRI coil assembly. PMID- 28862989 TI - Fetal death: an extreme manifestation of maternal anti-fetal rejection. AB - OBJECTIVE: The aim of this study was to determine the association between chronic placental inflammation and amniotic fluid (AF) markers of maternal anti-fetal rejection as well as the presence of microorganisms in the AF fluid of patients with fetal death. STUDY DESIGN: This cohort study included 40 patients with fetal death whose placentas were examined for chronic inflammatory lesions and whose AF chemokine ligand (CXCL)10 and interleukin (IL)-6 concentrations were determined by immunoassays. AF was processed for bacteria, mycoplasmas and viruses using cultivation and molecular microbiologic techniques (i.e. PCR-ESI/MS). RESULTS: (1) The most prevalent placental findings were maternal vascular underperfusion (63.2%, 24/38), followed by chronic inflammatory lesions (57.9%, 22/38); (2) chronic chorioamnionitis (18/38) was three times more frequent than villitis of unknown etiology (6/38); (3) an elevated AF CXCL10 concentration (above the 95th centile) was present in 60% of the cases, and a receiver operating characteristics (ROC)-derived cut-off of 2.9 ng/mL had a sensitivity of 73% and a specificity of 75% in the identification of chronic placental inflammatory lesions; (4) only five cases had microbial invasion of the amniotic cavity, and the presence of microorganisms did not correlate with chronic placental inflammation. CONCLUSION: In women with unexplained fetal death, there is an association between elevated AF CXCL10 and chronic placental inflammatory lesions. Therefore, we conclude that a subset of patients with fetal death may have endured a breakdown of maternal-fetal tolerance, which cannot be attributed to microorganisms in the amniotic cavity. PMID- 28862998 TI - A sequential solution for anisotropic total variation image denoising with interval constraints. AB - We show that two problems involving the anisotropic total variation (TV) and interval constraints on the unknown variables admit, under some conditions, a simple sequential solution. Problem 1 is a constrained TV penalized image denoising problem; problem 2 is a constrained fused lasso signal approximator. The sequential solution entails finding first the solution to the unconstrained problem, and then applying a thresholding to satisfy the constraints. If the interval constraints are uniform, this sequential solution solves problem 1. If the interval constraints furthermore contain zero, the sequential solution solves problem 2. Here uniform interval constraints refer to all unknowns being constrained to the same interval. A typical example of application is image denoising in x-ray CT, where the image intensities are non-negative as they physically represent linear attenuation coefficient in the patient body. Our results are simple yet seem unknown; we establish them using the Karush-Kuhn Tucker conditions for constrained convex optimization. PMID- 28862999 TI - Innovation in microbiome-based strategies for promoting metabolic health. AB - PURPOSE OF REVIEW: Update on the development of microbiome-based interventions and dietary supplements to combat obesity and related comorbidities, which are leading causes of global mortality. RECENT FINDINGS: The role of intestinal dysbiosis, partly resulting from unhealthy diets, in the development of obesity and metabolic disorders, is well documented by recent translational research. Human experimental trials with whole-faecal transplants are ongoing, and their results will be crucial as proof of concept that interventions intended to modulate the microbiome composition and function could be alternatives for the management of obesity and related comorbidities. Potential next-generation probiotic bacteria (Akkermansia, Bacteroides spp., Eubacterium halli) and microbiota-derived molecules (e.g. membrane proteins, short-chain fatty acids) are being evaluated in preclinical and clinical trials to promote the development of innovative dietary supplements. The fact that live or inactivated bacteria and their products can regulate pathways that increase energy expenditure, and reduce energy intake, and absorption and systemic inflammation make them attractive research targets from a nutritional and clinical perspective. SUMMARY: Understanding which are the beneficial bacteria and their bioactive products is helping us to envisage innovative microbiome-based dietary interventions to tackle obesity. Advances will likely result from future refinements of these strategies according to the individual's microbiome configuration and its particular response to interventions, thereby progressing towards personalized nutrition. PMID- 28863000 TI - Osteogenesis imperfecta: diagnosis and treatment. AB - PURPOSE OF REVIEW: Here we summarize the diagnosis of osteogenesis imperfecta, discuss newly discovered genes involved in osteogenesis imperfecta, and review the management of this disease in children and adults. RECENT FINDINGS: Mutations in the two genes coding for collagen type I, COL1A1 and COL1A2, are the most common cause of osteogenesis imperfecta. In the past 10 years, defects in at least 17 other genes have been identified as responsible for osteogenesis imperfecta phenotypes, with either dominant or recessive transmission. Intravenous bisphosphonate infusions are the most widely used medical treatment. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures. However, bisphosphonates are less effective for preventing long-bone fractures. At the moment, new therapies are under investigation. SUMMARY: Despite advances in the diagnosis and treatment of osteogenesis imperfecta, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice. PMID- 28863001 TI - Arytenoid neuromas are a recognized feature of SOS1 mutations causing pure mucosal neuroma syndrome. PMID- 28863002 TI - Histamine H3 receptor antagonists ameliorate attention deficit/hyperactivity disorder-like behavioral changes caused by neonatal habenula lesion. AB - A partial agonist and a full antagonist of the histamine H3 receptor have been suggested to have therapeutic effects on cognitive deficits in psychiatric disorders. We have previously shown that neonatal habenula lesion (NHL) induces behavioral deficits that resemble the symptoms of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the effects of three H3 antagonists on ADHD-like behavioral changes caused by NHL in rats. Behavioral tests and administration of the H3 receptor antagonists were performed in juvenile rats with NHL. H3 antagonist administration to juvenile rats dose dependently improved NHL-induced hyperlocomotion, impulsive behavior, and attention deficit. These results suggest that histamine H3 antagonists may be used as alternative therapeutic drugs for the treatment of ADHD. PMID- 28863004 TI - Dexamethasone impairs encoding and expression of aversive conditioning promoted by pentylenetetrazole. AB - Behavioral and neuroendocrine responses following threatening situations promote the release of corticosterone, which is known to modulate trauma-related learning and memory process. However, it remains unknown whether the aversive learning generated by interoceptive fear conditioning is affected by glucocorticoid modulation. Therefore, the present study aimed to investigate the role of dexamethasone suppression in encoding and expression of pentylenetetrazole induced olfactory fear conditioning (OFC) and in contextual second-order conditioning promoted by the conditioned odor. Adult male Long-Evans rats were treated with dexamethasone 60 min before the encoding or the expression in both OFC and contextual second-order conditioning. Dexamethasone treatment impaired encoding and expression of the OFC, but failed to impair encoding and expression of the contextual second-order conditioning. Altogether, our results show that although OFC and thereafter contextual second-order conditioning may allow the study of traumatic memories, each order of conditioning seems to present specific features related to their pharmacological modulation. These findings highlight the importance of addressing the role of neuromodulatory systems in first-order and second-order conditioning to gain a better understanding of these phenomena and support future therapies related to traumatic memories. PMID- 28863003 TI - Varenicline and GZ-793A differentially decrease methamphetamine self administration under a multiple schedule of reinforcement in rats. AB - Methamphetamine is a potent psychostimulant with high abuse rates. Currently, there is no Food and Drug Administration-approved pharmacotherapy for methamphetamine addiction. Ideally, a pharmacotherapy should selectively decrease methamphetamine self-administration without affecting responding for other reinforcers. One way to test this is with the use of a multiple schedule of reinforcement, in which drug and food are available in alternating components within a session. The present study evaluated GZ-793A, a vesicular monoamine transporter-2 inhibitor, and varenicline, a partial agonist at alpha4beta2 and full agonist at alpha7 nicotinic acetylcholine receptors, for their ability to decrease methamphetamine and food self-administration using a multiple schedule of reinforcement. Male Sprague-Dawley rats self-administered methamphetamine (0.03 mg/kg/intravenous infusion) and food pellets under a multiple schedule of reinforcement. GZ-793A or varenicline was administered before multiple schedule sessions. GZ-793A (5 and 20 mg/kg) significantly decreased methamphetamine intake compared with saline and did not alter food-maintained responding. In contrast, varenicline decreased methamphetamine intake less specifically across time. The results suggest that vesicular monoamine transporter-2 inhibition may be a viable pharmacological target for the treatment of methamphetamine-use disorders. PMID- 28863005 TI - HIV and contraception. AB - PURPOSE OF REVIEW: Contraception is a vital component of medical care for women with HIV or at high risk of acquiring HIV. Over the last several years, there has been emerging evidence regarding the safety and effectiveness of various contraceptive methods, ultimately leading to a revision in the WHO Medical Eligibility Criteria for contraceptive use. RECENT FINDINGS: Progestogen-only injectables may be associated with an increased risk of HIV acquisition and its use has been revised to category 2 from category 1. Etonogestrel and levonorgestrel levels are lower in women who concurrently use contraceptive implant and efavirenz-based antiretroviral therapy. Multipurpose technology, aimed at providing antiretroviral medication and contraception, is an area of ongoing research but is not yet clinically available. SUMMARY: It is important for providers who care for women with HIV or at high risk of HIV to inquire about pregnancy intentions. If contraception is desired, these women should be offered all available methods, with counseling regarding possible risks of contraceptive failure or HIV acquisition. PMID- 28863007 TI - Intraoperative Neurophysiologic Monitoring for Prediction of Postoperative Neurological Improvement in a Child With Chiari Type I Malformation. AB - INTRODUCTION: Although many surgical treatment strategies for Chiari malformation type I (CM-I) have been reported, the most appropriate surgical technique remains controversial. It is wholly ascribable to the complicacy of pathological condition in CM-I. Recently, intraoperative neurophysiologic monitoring (INM) is becoming prevalent in spinal surgery. Indeed, motor-evoked potentials (MEPs) monitoring and somatosensory-evoked potentials (SSEPs) monitoring are standard tools to minimize the risk of neurologic injury and postoperative deficits. The most recent study suggested that multimodality INM can be beneficial in foramen magnum decompression surgery for CM-I patients for surgical positioning and planning. Various authors have investigated the consistency of intraoperative evoked potential changes that might aid the surgeon to determine the appropriate extent of decompression required for an individual patient. PATIENT DESCRIPTION: The authors report the case of a 7-year-old boy who had the signs of medullary and cerebellar dysfunction, clumsy hands, and ataxic gait. He underwent a surgery of foramen magnum decompression with tonsillectomy and duraplasty for CM-I with cervicomedullary compression. His intraoperative MEPs improved (indicated increased-amplitude and shortened-latency) both after craniotomy and durotomy, whereas SSEPs improved only after durotomy. Those results were correlated well with a functional improvement that was apparent in the immediate postoperative hospitalization. CONCLUSIONS: The authors' data provides 1 possible interpretation of INM for safety aspect, but also which degree of decompression in each patient will require. The improvement in MEPs and SSEPs observed during decompression procedure may be a good indicator for the prediction of the clinical improvement seen postoperatively. PMID- 28863006 TI - Intervertebral Disc Degeneration in a Percutaneous Mouse Tail Injury Model. AB - OBJECTIVES: Intervertebral disc (IVD) degenerates progressively with age and after injuries. In this study, we aimed to characterize early molecular events underlying disc degeneration using a mouse tail IVD injury model. DESIGN: We have established a transcutaneous minimally invasive approach to induce mouse tail IVD injury under fluoroscopic guidance. Morphological and molecular changes in the injured IVDs are compared with the baseline features of adjacent intact levels. RESULTS: After needle puncture, tail IVDs exhibited time-dependent histological changes. The aggrecan neoepitope VDIPEN was evident from 2 days to 4 wks after injury. A disintegrin and metalloproteinase domain-containing protein 8 (adam8) is a surface protease known to cleave fibronectin in the IVD. Gene expression of adam8 was elevated at all time points after injury, whereas the increase of C-X-C motif chemokine ligand (cxcl)-1 gene expression was statistically significant at 2 days and 2 wks after injury. Type 1 collagen gene expression decreased initially at day 2 but increased at 2 wks after injury, whereas no significant change in type 2 collagen gene expression was observed. The extracellular matrix gene expression pattern is consistent with fibrocartilage formation after injury. CONCLUSIONS: Mouse tail IVDs degenerate after needle puncture, as demonstrated by histological changes and aggrecan degradation. The minimally invasive tail IVD injury model should prove useful to investigators studying mechanisms of IVD degeneration and repair. PMID- 28863008 TI - Olfactory Dysfunction Associated With Neuro-Behcet Disease. AB - INTRODUCTION: Neurologic involvement associated with Behcet disease (BD) is defined as a different entity: Neuro-Behcet disease (NBD). Behcet disease presents with olfactory dysfunction. It is not known whether this is the consequence of mucosal involvement or neurologic involvement. OBJECTIVE: The aim of this study was to investigate whether olfactory dysfunction was further aggravated as the result of neurologic involvement. METHODS: Sixteen patients diagnosed with NBD and 16 healthy control patients with similar demographic characteristics were recruited as the healthy control group. Expanded Disability Status Scale (EDSS) scoring was used for quantification of neurological disability. All diagnoses were confirmed and categorized with magnetic resonance imaging studies in all patients individually: parenchymal or nonparenchymal. A well-established test of orthonasal olfaction developed at the CCCRC was used. Correlation analysis was carried out. RESULTS: The mean CCCRC score of NBD patients was 4.60 out of 7, and this group was diagnosed to be moderately hyposmic, whereas the average score of the control group was 6.5; the difference was significant (P < 0.0001). CCCRC scores of NBD patients were significantly lower compared both healthy control patients and those of BD patients reported in the literature. Mean EDSS score of NBD patients was 1.75 +/- 1.0 out of 10 (0-no neurologic disability and 10-worst neurologic disability). Magnetic resonance imaging of NBD patients revealed 4 nonparenchymal and 12 parenchymal patients. Neuro-Behcet disease patients with parenchymal involvement presented with (worse) EDSS scores. Mean olfactory CCCRC score of this group was 4.38 whereas the average olfactory score of the vascular group was 5.25 out 7. Average EDSS score of vascular group was 0.75, much better compared to higher average neurologic disability score of 2.08 for the parenchymal group. Significant correlation existed between the duration of NBD and both olfactory and neurologic dysfunction scores. CONCLUSION: Neuro-Behcet disease present with aggravated olfactory dysfunction compared to BD. Neurologic involvement-especially parenchymal involvement-seems to deteriorate the olfactory dysfunction. Duration of disease is correlated with this severity of dysfunction. PMID- 28863009 TI - Methadone and the QTc Interval: Paucity of Clinically Significant Factors in a Retrospective Cohort. AB - OBJECTIVE: Methadone is associated with prolongation of the electrocardiographic QTc interval. QTc prolongation may be linked to cardiac dysrhythmia and sudden cardiac death. The rate of these events is unknown in methadone-maintained patients. METHODS: This retrospective cohort study of 749 patients with opioid use disorder receiving methadone maintenance therapy through a single safety-net hospital, queried the electronic health record for electrocardiogram results, demographics, methadone dose, and diagnostic codes consistent with cardiac conduction disorder (International Classification of Disease, Ninth Revision [ICD 9] 426) and cardiac dysrhythmia (ICD-9 427). Factors associated with QTc interval were explored; Cox proportional-hazards regression models were used to analyze time to an event that may predispose to sudden cardiac death. RESULTS: One hundred thirty-four patients had an electrocardiogram while on methadone, 404 while off methadone, and 211 both while on and off methadone. Mean QTc interval while on methadone (436 ms, SD 36) was significantly greater than while off methadone (423 ms, SD 33). Age and methadone dose were weakly associated with increased QTc interval (P < 0.01 and P < 0.0005, respectively, adjusted R = 0.05). There were 44 ICD-9 426 and 427 events over 7064 patient-years (6.3 events/1000 patient-yrs). Having a QTc greater than sex-specific cut-off values was significantly associated with time to event (hazard ratio 3.32, 95% confidence interval 1.25-8.81), but being on methadone was not. CONCLUSIONS: Methadone is associated with QTc prolongation in a nonclinically significant dose related manner. Cardiac events were rare and the sudden cardiac death rate was below that of the general population. Current recommendations for cardiac risk assessment in methadone-maintained patients should be reconsidered. PMID- 28863010 TI - Faecal microbiota transplantation: establishment of a clinical application framework. AB - BACKGROUND: Faecal microbiota transplantation (FMT) is currently being established as a second-line treatment for recurrent Clostridium difficile infection. FMT is further being considered for other infectious and inflammatory conditions. Safe and reproducible methods for donor screening, laboratory processing and clinical application of FMT are warranted. METHODS: Here, we describe the development of a complete clinical application framework for FMT. The framework has been developed to comply with the European Tissue Act, thus considering donor faeces for FMT comparable to a human tissue and not a drug. RESULTS: Recruitment and screening of potential faeces donors took place in the public blood donor setting and consisted of questionnaires, blood sampling and faecal sample analysis. Once approved, and following their written informed consent, eligible donors were invited for voluntary faecal donation. Laboratory processing protocols describe the initial handling, cryopreservation and thawing for clinical application. The clinical FMT procedures took place in a gastroenterological setting using a nasojejunal tube or colonoscopy, and follow ups were performed at 1, 8 and 26 weeks after FMT. Complete traceability of essential equipment, faecal samples and donor-recipient matching data will be maintained and secured for 30 years. CONCLUSION: A clinical FMT service should be consolidated by a complete documentation system that complies with the European Tissue Act. In this paper, we provide a description of such a framework. PMID- 28863011 TI - Sedation and Mobilization During Venovenous Extracorporeal Membrane Oxygenation for Acute Respiratory Failure: An International Survey. AB - OBJECTIVES: To characterize sedation, analgesia, delirium, and mobilization practices in patients supported with venovenous extracorporeal membrane oxygenation for severe acute respiratory failure. DESIGN: Cross-sectional electronic survey administered January 2016 to March 2016. SETTING: Three-hundred ninety-four extracorporeal membrane oxygenation centers registered with the Extracorporeal Life Support Organization. SUBJECTS: Extracorporeal membrane oxygenation medical directors and program coordinators. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed responses from 209 respondents (53%), mostly from academic centers (63%); 41% respondents provide venovenous extracorporeal membrane oxygenation to adults exclusively. Following venovenous extracorporeal membrane oxygenation initiation, 97% respondents administer sedative/analgesic infusions, and the sedation target was "sedated" or "very sedated" for 59%, "calm and cooperative" for 25%, and "unarousable" for 16%. Use of daily sedation interruption and a sedation/analgesia protocol was reported by 51% and 39%, respectively. Midazolam (48%) and propofol (19%) were reported as the most frequently used sedatives; fentanyl (44%) and morphine (20%) the most frequent opioids. Use of a delirium scale was reported by 55% respondents. Physical therapy was reported by 84% respondents, with 41% initiating it within 72 hours after cannulation. Mobilization goals varied from range of motion exercises (81%) to ambulation (22%). The most frequently perceived barriers to mobilization were hemodynamic instability, hypoxemia, and dependency on venovenous extracorporeal membrane oxygenation support. CONCLUSIONS: The majority of respondents reported targeting moderate to deep sedation following cannulation, with the use of sedative and opioid infusions. There is considerable variability surrounding early physical therapy and mobilization goals for patients with acute respiratory failure supported by venovenous extracorporeal membrane oxygenation. PMID- 28863012 TI - Critical Care Organizations: Business of Critical Care and Value/Performance Building. AB - OBJECTIVE: New, value-based regulations and reimbursement structures are creating historic care management challenges, thinning the margins and threatening the viability of hospitals and health systems. The Society of Critical Care Medicine convened a taskforce of Academic Leaders in Critical Care Medicine on February 22, 2016, during the 45th Critical Care Congress to develop a toolkit drawing on the experience of successful leaders of critical care organizations in North America for advancing critical care organizations (Appendix 1). The goal of this article was to provide a roadmap and call attention to key factors that adult critical care medicine leadership in both academic and nonacademic setting should consider when planning for value-based care. DESIGN: Relevant medical literature was accessed through a literature search. Material published by federal health agencies and other specialty organizations was also reviewed. Collaboratively and iteratively, taskforce members corresponded by electronic mail and held monthly conference calls to finalize this report. SETTING: The business and value/performance critical care organization building section comprised of leaders of critical care organizations with expertise in critical care administration, healthcare management, and clinical practice. MEASUREMENTS AND MAIN RESULTS: Two phases of critical care organizations care integration are described: "horizontal," within the system and regionalization of care as an initial phase, and "vertical," with a post-ICU and postacute care continuum as a succeeding phase. The tools required for the clinical and financial transformation are provided, including the essential prerequisites of forming a critical care organization; the manner in which a critical care organization can help manage transformational domains is considered. Lastly, how to achieve organizational health system support for critical care organization implementation is discussed. CONCLUSIONS: A critical care organization that incorporates functional clinical horizontal and vertical integration for ICU patients and survivors, aligns strategy and operations with those of the parent health system, and encompasses knowledge on finance and risk will be better positioned to succeed in the value-based world. PMID- 28863014 TI - Antiviral Therapy in Patients With Chronic Hepatitis C-related Hepatocellular Carcinoma Responding to Palliative Treatment. AB - BACKGROUND/AIM: Advances in hepatitis C virus (HCV) treatment offer high sustained virologic response rates with minimal side-effects. However, benefits of eradicating HCV in hepatocellular carcinoma (HCC) patients whose life expectancies are hard to be determined after palliative therapy still needs to be assessed. This study sought to evaluate prognostic factors for survival in HCV related HCC patients that responded to the palliative HCC treatment to speculate whether treating HCV would be beneficial in these patients. MATERIALS AND METHODS: In this retrospective cohort study, the medical records of 97 patients that showed complete or partial response to the initial HCC treatment were included. RESULTS: Receiving HCV treatment [hazard ratio (HR), 0.244; 95% confidence interval (CI), 0.075-0.788; P=0.018] increased the survival, whereas partial response to the initial HCC treatment (HR, 1.795; 95% CI, 1.071-3.008; P=0.026) and increased Child-Turcotte-Pugh score (HR, 2.017; 95% CI, 1.196-3.403; P=0.009) reduced the survival. From 97 patients, 16 patients were eventually treated for HCV. The mean time from the last HCC therapy to HCV treatment was 16.9+/-13.9 months. The median time of follow-up after HCV treatment was 10.0 months (range, 3 to 47 mo). Among the HCV-treated patients 3 patients had HCC recurred. The time to progression in HCV-treated patients were significantly longer than those untreated for HCV (P=0.032). CONCLUSIONS: Although treating HCV in HCC patient that undergo noncurative HCC treatment is still debatable, this study results carefully suggest that HCV-related HCC patients that responded to the initial HCC palliative treatment might benefit from HCV treatment. PMID- 28863015 TI - Heart failure in persons living with HIV infection. AB - PURPOSE OF REVIEW: To discuss presentation, pathophysiology, complications, and treatment of heart failure in persons living with HIV (PLWHIV) in the antiretroviral therapy (ART) era. RECENT FINDINGS: Since the advent of effective ART and improved longevity, heart failure has become more chronic and insidious and is often characterized by preserved ejection fraction, diastolic dysfunction, and left ventricular (LV) hypertrophy. The mechanism underlying heart failure in the setting of HIV infection remains unknown. A high burden of coronary risk factors is often present in PLWHIV, and clinical manifestations of coronary disease appear at a younger age compared with uninfected persons. Heart failure is more common in the year following myocardial infarction in HIV-infected compared with uninfected patients. Epidemiological data suggest the incidence of atrial fibrillation in PLWHIV is increasing, likely due to advancing age and increasing rates of LV hypertrophy in this population. The treatment of heart failure in PLWHIV is extrapolated from treatment of uninfected patients, as clinical trials have not been done specifically in HIV. SUMMARY: Symptoms of heart failure or echocardiographic evidence of cardiomyopathy increase the risk of death in PLWHIV. Additional studies are needed to ascertain if HIV-specific issues such as newer ART, chronic inflammation/immune activation, illicit drug use, and early initiation of ART are implicated in heart failure pathogenesis. PMID- 28863016 TI - Oligometastatic prostate cancer: shaping the definition with molecular imaging and an improved understanding of tumor biology. AB - PURPOSE OF REVIEW: The aim of this review is to discuss how novel imaging modalities and molecular markers are shaping the definition of oligometastatic prostate cancer. RECENT FINDINGS: To effectively classify a patient as having oligometastatic prostate cancer, diagnostic tests must be sensitive enough to detect subtle sites of metastatic disease. Conventional imaging modalities can readily detect widespread polymetastatic disease but do not have the sensitivity necessary to reliably classify patients as oligometastatic. Molecular imaging using both metabolic- and molecularly-targeted radiotracers has demonstrated great promise in aiding in our ability to define the oligometastatic state. Perhaps the most promising data to date have been generated with radiotracers targeting prostate-specific membrane antigen. In addition, early studies are beginning to define biologic markers in the oligometastatic state that may be indicative of disease with minimal metastatic potential. SUMMARY: Recent developments in molecular imaging have allowed for improved detection of metastatic prostate cancer allowing for more accurate staging of patients with oligometastatic disease. Future development of biologic markers may assist in defining the oligometastatic state and determining prognosis. PMID- 28863013 TI - Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass. AB - OBJECTIVES: To determine the relationship between the production of cell-free plasma hemoglobin and acute kidney injury in infants and children undergoing cardiopulmonary bypass for cardiac surgery. DESIGN: Prospective observational study. SETTING: Twelve-bed cardiac ICU in a university-affiliated children's hospital. PATIENTS: Children were prospectively enrolled during their preoperative outpatient appointment with the following criteria: greater than 1 month to less than 18 years old, procedures requiring cardiopulmonary bypass, no preexisting renal dysfunction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma and urine were collected at baseline (in a subset), the beginning and end of cardiopulmonary bypass, and 2 hours and 24 hours after cardiopulmonary bypass in 60 subjects. Levels of plasma hemoglobin increased during cardiopulmonary bypass and were associated (p < 0.01) with cardiopulmonary bypass duration (R = 0.22), depletion of haptoglobin at end and 24 hours after cardiopulmonary bypass (R = 0.12 and 0.15, respectively), lactate dehydrogenase levels at end cardiopulmonary bypass (R = 0.27), and change in creatinine (R = 0.12). Forty-three percent of patients developed acute kidney injury. There was an association between plasma hemoglobin level and change in creatinine that varied by age (overall [R = 0.12; p < 0.01]; in age > 2 yr [R = 0.22; p < 0.01]; and in < 2 yr [R = 0.03; p = 0.42]). Change in plasma hemoglobin and male gender were found to be risk factors for acute kidney injury (odds ratio, 1.02 and 3.78, respectively; p < 0.05). CONCLUSIONS: Generation of plasma hemoglobin during cardiopulmonary bypass and male gender are associated with subsequent renal dysfunction in low-risk pediatric patients, especially in those older than 2 years. Further studies are needed to determine whether specific subgroups of pediatric patients undergoing cardiopulmonary bypass would benefit from potential treatments for hemolysis and plasma hemoglobin-associated renal dysfunction. PMID- 28863017 TI - Debate position: cognition and mood are not improved in men administered exogenous testosterone therapy. AB - PURPOSE OF REVIEW: The purpose of this article is to provide an overview of the increasing evidence suggesting that exogenous testosterone therapy is not associated with improvements in cognition or mood. This article is part of a series, in this issue, in which authors are assigned opinion pieces on controversial topics pertaining to testosterone replacement. RECENT FINDINGS: Testosterone is increasingly being prescribed. Particularly in the setting of recent data suggestive of possible cardiovascular risk associated with its use; a clear understanding of the domains of health that improve with exogenous testosterone use is important. Data on endogenous and exogenous testosterone with cognition and mood are mixed, likely partly related to methodological differences of type of testosterone, patient population, and dosing. SUMMARY: Overall, available data are not suggestive of a clear benefit of testosterone supplementation in multiple domains of cognition and in mood. Supraphysiologic testosterone has been associated with adverse psychological outcomes, albeit not uniformly in studies. PMID- 28863018 TI - Reflecting on the PA profession's 50th anniversary. PMID- 28863019 TI - Pediatric Anesthesiology Fellows' Perception of Quality of Attending Supervision and Medical Errors. AB - BACKGROUND: Appropriate supervision has been shown to reduce medical errors in anesthesiology residents and other trainees across various specialties. Nonetheless, supervision of pediatric anesthesiology fellows has yet to be evaluated. The main objective of this survey investigation was to evaluate supervision of pediatric anesthesiology fellows in the United States. We hypothesized that there was an indirect association between perceived quality of faculty supervision of pediatric anesthesiology fellow trainees and the frequency of medical errors reported. METHODS: A survey of pediatric fellows from 53 pediatric anesthesiology fellowship programs in the United States was performed. The primary outcome was the frequency of self-reported errors by fellows, and the primary independent variable was supervision scores. Questions also assessed barriers for effective faculty supervision. RESULTS: One hundred seventy-six pediatric anesthesiology fellows were invited to participate, and 104 (59%) responded to the survey. Nine of 103 (9%, 95% confidence interval [CI], 4%-16%) respondents reported performing procedures, on >1 occasion, for which they were not properly trained for. Thirteen of 101 (13%, 95% CI, 7%-21%) reported making >1 mistake with negative consequence to patients, and 23 of 104 (22%, 95% CI, 15% 31%) reported >1 medication error in the last year. There were no differences in median (interquartile range) supervision scores between fellows who reported >1 medication error compared to those reporting <=1 errors (3.4 [3.0-3.7] vs 3.4 [3.1-3.7]; median difference, 0; 99% CI, -0.3 to 0.3; P = .96). Similarly, there were no differences in those who reported >1 mistake with negative patient consequences, 3.3 (3.0-3.7), compared with those who did not report mistakes with negative patient consequences (3.4 [3.3-3.7]; median difference, 0.1; 99% CI, 0.2 to 0.6; P = .35). CONCLUSIONS: We detected a high rate of self-reported medication errors in pediatric anesthesiology fellows in the United States. Interestingly, fellows' perception of quality of faculty supervision was not associated with the frequency of reported errors. The current results with a narrow CI suggest the need to evaluate other potential factors that can be associated with the high frequency of reported errors by pediatric fellows (eg, fatigue, burnout). The identification of factors that lead to medical errors by pediatric anesthesiology fellows should be a main research priority to improve both trainee education and best practices of pediatric anesthesia. PMID- 28863020 TI - Validating the Physiologic Model HumMod as a Substitute for Clinical Trials Involving Acute Normovolemic Hemodilution. AB - BACKGROUND: Blood conservation strategies and transfusion guidelines remain a heavily debated clinical topic. Previous investigational trials have shown that acute isovolemic hemodilution does not limit adequate oxygen delivery; however, a true critical hemoglobin level has never been investigated or defined due to safety concerns for human volunteers. Validated physiologic modeling may be useful to investigate hemodilution at critical hemoglobin levels without the ethical or safety hazards of clinical trials. Our hypothesis is that HumMod, an integrative physiological model, can replicate the cardiovascular and metabolic findings of previous clinical studies of acute isovolemic hemodilution and use coronary blood flow and coronary oxygen delivery in extreme hemodilution to predict a safety threshold. METHODS: By varying cardiovascular and sizing parameters, unique individuals were generated to simulate a population using HumMod, an integrative mathematical model of human physiology. Hemodilution was performed by simultaneously hemorrhaging 500 mL aliquots of blood while infusing equal volumes of hetastarch, 5% albumin balanced salt solution, or triple volumes of lactated Ringer's solution over 10 minutes. Five hemodilution protocols reported over 3 studies were directly replicated with HumMod to compare and validate essential cardiovascular and metabolic responses to hemodilution in moderately healthy, awake adults. Cardiovascular parameters, mental status, arterial and mixed venous oxygen content, and oxyhemoglobin saturation were recorded after the removal of each aliquot. The outputs of this simulation were considered independent variables and were stratified by hemoglobin concentration at the time of measurement to assess hemoglobin as an independent predictor of hemodynamic and metabolic behavior. RESULTS: The published reports exhibited discrepancies: Weiskopf saw increased heart rate and cardiac index, while Jones and Ickx saw no change in these variables. In HumMod, arterial pressure was maintained during moderate hemodilution due to decreases in peripheral resistance opposing increases in cardiac index. HumMod showed preserved ventilation through moderate hemodilution, compensated for by an increased oxygen extraction similar to the studies of Jones and Ickx. The simulation results qualitatively followed the clinical studies, but there were statistical differences. In more extreme hemodilution, HumMod had a lesser increase in cardiac index, which led to deficiencies in oxygen delivery and low venous saturation. In the simulations, coronary blood flow and oxygen delivery increase up to a critical hemoglobin threshold of 55-75 g/L in HumMod. In this range, coronary blood flow and oxygen delivery fell, leading to cardiac injury. The allowable amount of hemodilution before reaching the critical point is most closely correlated with nonmuscle mass (r = 0.69) and resting cardiac output (r = 0.67). CONCLUSIONS: There were significant statistical differences in the model population and the clinical populations, but overall, the model responses lay within the clinical findings. This suggests our model is an effective replication of hemodilution in conscious, healthy adults. A critical hemoglobin range of 5.5-7.5 g/L was predicted and found to be highly correlated with nonmuscle mass and resting cardiac output. PMID- 28863022 TI - Transesohageal Echocardiographic-Guided Transapical Neochord Implantation. PMID- 28863021 TI - The Effect of Head Position on the Cross-Sectional Area of the Subclavian Vein. AB - In 41 healthy volunteers, we investigated the cross-sectional area (CSA) of the subclavian vein (SCV) in the following head positions: neutral and 30 degrees head rotation toward the contralateral or ipsilateral sides. Significant differences were observed in the CSA of the SCV at 3 different head positions: contralateral 30 degrees versus neutral, -0.05 cm (95% confidence interval, 0.08 to -0.03); contralateral 30 degrees versus ipsilateral 30 degrees , -0.15 cm (-0.19 to -0.12); neutral versus ipsilateral 30 degrees , -0.10 cm (-0.13 to 0.07); all Pcorrected< .001). For SCV catheterization, 30 degrees head rotation to the ipsilateral side provided significant improvements in the CSA compared with the other head positions. PMID- 28863023 TI - Evaluation of the Augmented Infant Resuscitator: A Monitoring Device for Neonatal Bag-Valve-Mask Resuscitation. AB - BACKGROUND: Annually, 6 million newborns require bag-valve-mask resuscitation, and providing live feedback has the potential to improve the quality of resuscitation. The Augmented Infant Resuscitator (AIR), a real-time feedback device, has been designed to identify leaks, obstructions, and inappropriate breath rates during bag-valve-mask resuscitation. However, its function has not been evaluated. METHODS: The resistance of the AIR was measured by attaching it between a ventilator and a ventilator tester. To test the device's reliability in training and clinical-use settings, it was placed in-line between a ventilation bag or ventilator and a neonatal manikin and a clinical lung model simulator. The lung model simulator simulated neonates of 3 sizes (2, 4, and 6 kg). Leaks, obstructions, and respiratory rate alterations were introduced. RESULTS: At a flow of 5 L/min, the pressure drop across the AIR was only 0.38 cm H2O, and the device had almost no effect on ventilator breath parameters. During the manikin trials, it was able to detect all leaks and obstructions, correctly displaying an alarm 100% of the time. During the simulated clinical trials, the AIR performed best on the 6-kg neonatal model, followed by the 4-kg model, and finally the 2-kg model. Over all 3 clinical models, the prototype displayed the correct indicator 73.5% of the time, and when doing so, took 1.6 +/- 0.9 seconds. CONCLUSIONS: The AIR is a promising innovation that has the potential to improve neonatal resuscitation. It introduces only marginal resistance and performs well on neonatal manikins, but its firmware should be improved before clinical use. PMID- 28863024 TI - Neurologic Injury With Severe Adult Respiratory Distress Syndrome in Patients Undergoing Extracorporeal Membrane Oxygenation: A Single-Center Retrospective Analysis. AB - This retrospective single-center study investigated the incidence of neurologic injury as determined by autopsy or cerebral imaging in 74 patients undergoing extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome. Seventy-three percent of patients were treated with venovenous and 27% with venoarterial ECMO. ECMO-associated intracerebral hemorrhage was diagnosed in 10.8% of patients. There were no cases of ischemic stroke. Clinical characteristics did not differ between patients with and without neurologic injury. Six-month survival was 13% (Wilson confidence interval, 2%-47%) in patients with severe intracerebral hemorrhage compared to an overall survival rate of 57% (Wilson confidence interval, 45%-67%). PMID- 28863025 TI - Women and Leadership in Anesthesiology: Can We "Lean In" Further? PMID- 28863026 TI - Transfusion of Older Red Blood Cells Increases the Risk of Acute Kidney Injury After Orthotopic Liver Transplantation: A Propensity Score Analysis. AB - BACKGROUND: Acute kidney injury (AKI) is a common and serious complication of orthotopic liver transplantation (OLT). Transfusion of older red blood cells (RBCs) has been implicated in poor outcomes in trauma, cardiac surgery, and critically ill patients. However, whether transfusion of older RBCs plays any role in post-OLT AKI remained unknown. The aim of this study was to investigate the effect of the age of transfused RBCs on post-OLT AKI. METHODS: The clinical data of consecutive adult patients who received donation after cardiac death and underwent OLT from December 2011 to December 2015 were analyzed. These patients were divided into 2 groups: the newer blood group, who received exclusively RBCs that had been stored for <14 days; and the older blood group, who received RBCs that had been stored for 14 days or more. The incidence of post-OLT AKI, severe AKI, lengths of intensive care unit and hospital stay, and in-hospital mortality after OLT were analyzed. RESULTS: Postoperative AKI occurred in 65.1% of patients in the older blood group and 40.5% of patients in the newer blood group (P < .01). The incidence of severe AKI after OLT was significantly higher, and the duration of intensive care unit stay was significantly longer, in the older blood group. After adjustment by the multivariable regression logistic analysis, transfusion of older blood was independently associated with post-OLT AKI (odds ratio [OR] = 2.47 [95% confidence interval {CI}, 1.13-5.41]; P = .024) and severe AKI (OR = 5.88 [95% CI, 2.06-16.80]; P = .001). After adjustment by the inverse probability of treatment weighting analysis, patients in the older blood group still had significantly higher incidences of postoperative AKI (OR = 2.13 [95% CI, 1.07-4.22]; P = .030) and severe AKI (OR = 3.34 [95% CI, 1.47-7.60]; P = .003) than those in the newer blood group. CONCLUSIONS: Transfusion of older RBCs significantly increased the risk of postoperative AKI in liver transplant recipients. PMID- 28863028 TI - Associations of Plasma Nitrite, L-Arginine and Asymmetric Dimethylarginine With Morbidity and Mortality in Patients With Necrotizing Soft Tissue Infections. AB - BACKGROUND: The nitric oxide system could play an important role in the pathophysiology related to necrotizing soft tissue infection (NSTI). Accordingly, we investigated the association between plasma nitrite level at admission and the presence of septic shock in patients with NSTI. We also evaluated the association between nitrite, asymmetric dimethylarginine (ADMA), L-arginine, L-arginine/ADMA ratio, and outcome. METHODS: We analyzed plasma from 141 NSTI patients taken upon hospital admission. The severity of NSTI was assessed by the presence of septic shock, Simplified Acute Physiology Score (SAPS) II, Sepsis-Related Organ Failure Assessment (SOFA) score, use of renal replacement therapy (RRT), amputation, and 28-day mortality. RESULTS: No difference in nitrite levels was found between patients with and without septic shock (median 0.82 MUmol/L [interquartile range (IQR) 0.41-1.21] vs. 0.87 MUmol/L (0.62-1.24), P = 0.25). ADMA level was higher in patients in need of RRT (0.64 MUmol/L (IQR 0.47-0.90) vs. (0.52 MUmol/L (0.34 0.70), P = 0.028), and ADMA levels correlated positively with SAPS II (rho = 0.32, P = 0.0002) and SOFA scores (rho = 0.22, P = 0.01). In a logistic regression analysis, an L-arginine/ADMA ratio below 101.59 was independently associated with 28-day mortality, odds ratio 6.03 (95% confidence interval, 1.41 25.84), P = 0.016. None of the other analyses indicated differences in the NO system based on differences in disease severity. CONCLUSIONS: In patients with NSTI, we found no difference in baseline nitrite levels according to septic shock. High baseline ADMA level was associated with the use of RRT and patients with a low baseline L-arginine/ADMA ratio were at higher risk of dying within 28 days after hospital admission. PMID- 28863029 TI - Requirements for trial registration and adherence to reporting guidelines in critical care journals: a meta-epidemiological study of journals' instructions for authors. AB - BACKGROUND: The purpose of this study was to investigate the policies of critical care journals with regard to guideline adoption and clinical trial registration to understand the extent to which journals use these mechanisms to improve reporting practices. METHODS: The current study's sample comprised 37 critical care journals cataloged in the Expanded Science Citation Index of the 2015 Journal Citation Reports and Google Scholar Metrics h5-index critical care subcategory. A web-based data abstraction was performed to identify which journals required, recommended, or made no mention of 17 different reporting guidelines. We also extracted whether journals required or recommended trial registration. Authors were blinded to one another's ratings until completion of the data validation. Cross tabulations and descriptive statistics were calculated by using STATA 13. RESULTS: Of the 37 critical care journals, 15 (15/37, 40.5%) did not mention a single guideline within their instructions for authors, whereas the remaining 22 (22/37, 59.5%) mentioned one or more guidelines. The Quality of Reporting of Meta-analyses statement and Standards for Reporting Qualitative Research were not mentioned by any journals, whereas the International Committee of Medical Journal Editors Uniform Requirements for Manuscripts (26/37, 70.3%) and Consolidated Standards of Reporting Trials statement (17/37, 45.9%) were mentioned most often. Of the 37 critical care journals, 21 (21/37, 56.8%) did not mention trial or review registration, but the remaining 16 (16/37, 43.2%) mentioned at least one of the two. Trial registration through ClinicalTrials.gov was mentioned by six (6/37, 16.2%) journals, whereas the WHO registry was mentioned by five (5/37, 13.5%). Sixteen (16/37, 43.2%) journals mentioned trial registration through a registry platform. CONCLUSION: Nearly half of the journals in our sample did not mention a reporting guideline, and only a small percentage of journals required the registration of clinical trials as a condition for publication. Implementing these two mechanisms may limit bias, and their adoption should be considered by journal editors in critical care. TRIAL REGISTRATION: UMIN000024081. PMID- 28863030 TI - Persistent Super-Utilization of Acute Care Services Among Subgroups of Veterans Experiencing Homelessness. AB - BACKGROUND: Acute health care utilization often occurs among persons experiencing homelessness. However, knowing which individuals will be persistent super utilizers of acute care is less well understood. OBJECTIVE: The objective of the study was to identify those more likely to be persistent super-utilizers of acute care services. RESEARCH DESIGN: We conducted a latent class analysis of secondary data from the Veterans Health Administration Corporate Data Warehouse, and Homeless Operations Management and Evaluation System. The study sample included 16,912 veterans who experienced homelessness and met super-utilizer criteria in any quarter between July 1, 2014 and December 31, 2015. The latent class analysis included veterans' diagnoses and acute care utilization. RESULTS: Medical, mental health, and substance use morbidity rates were high. More than half of the sample utilized Veterans Health Administration Homeless Programs concurrently with their super-utilization of acute care. There were 7 subgroups of super-utilizers, which varied considerably on the degree to which their super-utilization persisted over time. Approximately a third of the sample met super-utilizer criteria for >=3 quarters; this group was older and disproportionately male, non-Hispanic white, and unmarried, with lower rates of post-9/11 service and higher rates of rural residence and service-connected disability. They were much more likely to be currently homeless with more medical, mental health, and substance use morbidity. CONCLUSION: Only a subset of homeless veterans were persistent super-utilizers, suggesting the need for more targeted interventions. PMID- 28863031 TI - Association between Intrapartum Magnesium Administration and the Incidence of Maternal Fever: A Retrospective Cross-sectional Study. AB - BACKGROUND: Intrapartum maternal fever is associated with several adverse neonatal outcomes. Intrapartum fever can be infectious or inflammatory in etiology. Increases in interleukin 6 and other inflammatory markers are associated with maternal fever. Magnesium has been shown to attenuate interleukin 6-mediated fever in animal models. We hypothesized that parturients exposed to intrapartum magnesium would have a lower incidence of fever than nonexposed parturients. METHODS: In this study, electronic medical record data from all deliveries at Northwestern Memorial Hospital (Chicago, Illinois) between 2007 and 2014 were evaluated. The primary outcome was intrapartum fever (temperature at or higher than 38.0 degrees C). Factors associated with the development of maternal fever were evaluated using a multivariable logistic regression model. Propensity score matching was used to reduce potential bias from nonrandom selection of magnesium administration. RESULTS: Of the 58,541 women who met inclusion criteria, 5,924 (10.1%) developed intrapartum fever. Febrile parturients were more likely to be nulliparous, have used neuraxial analgesia, and have been delivered via cesarean section. The incidence of fever was lower in women exposed to magnesium (6.0%) than those who were not (10.2%). In multivariable logistic regression, women exposed to magnesium were less likely to develop a fever (adjusted odds ratio = 0.42 [95% CI, 0.31 to 0.58]). After propensity matching (N = 959 per group), the odds ratio of developing fever was lower in women who received magnesium therapy (odds ratio = 0.68 [95% CI, 0.48 to 0.98]). CONCLUSIONS: Magnesium may play a protective role against the development of intrapartum fever. Future work should further explore the association between magnesium dosing and the incidence of maternal fever. PMID- 28863032 TI - Large Intracranial Aneurysms in a 2-month-old Female: A Rare Occurrence with Serious Anesthetic Challenges. PMID- 28863033 TI - Increased blood pressure and aortic stiffness among abusers of anabolic androgenic steroids: potential effect of suppressed natriuretic peptides in plasma? AB - BACKGROUND: Abuse of anabolic androgenic steroids (AAS) is prevalent among recreational athletes and adverse effects on blood pressure (BP) and arterial stiffness could be substantial. Testosterone decreases natriuretic peptides which are key components in BP-regulation and may impair BP-homeostasis in AAS abusers. OBJECTIVE: To investigate BP and aortic stiffness in relation to natriuretic peptides among current AAS abusers, former AAS abusers and controls. METHODS: In this cross-sectional study, 37 current AAS abusers, 33 former AAS abusers and 30 controls were included. All participants were men involved in recreational strength training. We used 24-h BP monitoring, assessed proximal aorta distensibility index (ADI) by MRI and obtained overnight fasting blood samples to measure: midregional proatrial natriuretic peptide (MR-proANP), aldosterone, noradrenaline and copeptin. RESULTS: Current AAS abusers exhibited higher mean (95% confidence interval) 24-h systolic BP than controls [132 (129; 135) versus 124 (120; 128) mmHg, P = 0.005] and systolic hypertension was more frequent among current AAS abusers than controls (51 versus 17%, P = 0.009). ADI was lower among both current and former AAS abusers suggesting higher aortic stiffness; % difference (95% confidence interval) from controls: -21% (-35; -5) and -21% (-36; -4), P < 0.05. Plasma MR-proANP was decreased, whereas aldosterone and noradrenaline were increased among current AAS abusers compared with former AAS abusers and controls. Decreased MR-proANP was independently associated with increased systolic BP and reduced ADI in multivariate linear regressions. CONCLUSION: Current AAS abusers displayed increased 24-h systolic BP and decreased plasma MR-proANP. Both current and former AAS abusers exhibited higher aortic stiffness. PMID- 28863034 TI - The Effect of Signal to Noise Ratio on Cortical Auditory-Evoked Potentials Elicited to Speech Stimuli in Infants and Adults With Normal Hearing. AB - OBJECTIVES: Identification and discrimination of speech sounds in noisy environments is challenging for adults and even more so for infants and children. Behavioral studies consistently report maturational differences in the influence that signal to noise ratio (SNR) and masker type have on speech processing; however, few studies have investigated the neural mechanisms underlying these differences at the level of the auditory cortex. In the present study, we investigated the effect of different SNRs on speech-evoked cortical auditory evoked potentials (CAEPs) in infants and adults with normal hearing. DESIGN: A total of 10 adults (mean age 24.1 years) and 15 infants (mean age 30.7 weeks), all with normal hearing, were included in the data analyses. CAEPs were evoked to /m/ and /t/ speech stimuli (duration: 79 ms) presented at 75 dB SPL in the sound field with a jittered interstimulus interval of 1000-1200 ms. Each of the stimuli were presented in quiet and in the presence of white noise (SNRs of 10, 15, and 20 dB). Amplitude and latency measures were compared for P1, N1, and P2 for adults and for the large positivity (P) and following negativity (N: N250 and/or N450) for infants elicited in quiet and across SNR conditions. RESULTS: Infant P N responses to /t/ showed no statistically significant amplitude and latency effects across SNR conditions; in contrast, infant CAEPs to /m/ were greatly reduced in amplitude and delayed in latency. Responses were more frequently absent for SNRs of 20 dB or less. Adult P1-N1-P2 responses were present for all SNRs for /t/ and most SNRs for /m/ (two adults had no responses to /m/ for SNR 10); significant effects of SNR were found for P1, N1, and P2 amplitude and latencies. CONCLUSIONS: The findings of the present study support that SNR effects on CAEP amplitudes and latencies in infants cannot be generalized across different types of speech stimuli and cannot be predicted from adult data. These findings also suggest that factors other than energetic masking are contributing to the immaturities in the SNR effects for infants. How these CAEP findings relate to an infant's capacity to process speech-in-noise perceptually has yet to be established; however, we can be confident that the presence of CAEPs to a speech stimulus in noise means that the stimulus is detected at the level of the auditory cortex. The absence of a response should be interpreted with caution as further studies are needed to investigate a range of different speech stimuli and SNRs, in conjunction with behavioral measures, to confirm that infant CAEPs do indeed reflect functional auditory capacity to process speech stimuli in noise. PMID- 28863035 TI - Same or Different: The Overlap Between Children With Auditory Processing Disorders and Children With Other Developmental Disorders: A Systematic Review. AB - OBJECTIVES: Children diagnosed with auditory processing disorders (APD) experience difficulties in auditory functioning and with memory, attention, language, and reading tasks. However, it is not clear whether the behavioral characteristics of these children are distinctive from the behavioral characteristics of children diagnosed with a different developmental disorder, such as specific language impairment (SLI), dyslexia, attention-deficit hyperactivity disorder (ADHD), learning disorder (LD), or autism spectrum disorder. This study describes the performance of children diagnosed with APD, SLI, dyslexia, ADHD, and LD to different outcome measurements. The aim of this study was to determine (1) which characteristics of APD overlap with the characteristics of children with SLI, dyslexia, ADHD, LD, or autism spectrum disorder; and (2) if there are characteristics that distinguish children diagnosed with APD from children diagnosed with other developmental disorders. DESIGN: A systematic review. Six electronic databases (Pubmed, CINAHL, Eric, PsychINFO, Communication & Mass Media Complete, and EMBASE) were searched to find peer-reviewed studies from 1954 to May 2015. The authors included studies reporting behaviors and performance of children with (suspected) APD and children diagnosed with a different developmental disorder (SLI, Dyslexia, ADHD, and LD). Two researchers identified and screened the studies independently. Methodological quality of the included studies was assessed with the American Speech-Language Hearing Association's levels-of-evidence scheme. RESULTS: In total, 13 studies of which the methodological quality was moderate were included in this systematic review. In five studies, the performance of children diagnosed with APD was compared with the performance of children diagnosed with SLI: in two with children diagnosed with dyslexia, one with children diagnosed with ADHD, and in another one with children diagnosed with LD. Ten of the studies included children who met the criteria for more than one diagnosis. In four studies, there was a comparison made between the performances of children with comorbid disorders. There were no studies found in which the performance of children diagnosed with APD was compared with the performance of children diagnosed with autism spectrum disorder. Children diagnosed with APD broadly share the same characteristics as children diagnosed with other developmental disorders, with only minor differences between them. Differences were determined with the auditory and visual Duration Pattern Test, the Children's Auditory Processing Performance Scale questionnaire, and the subtests of the Listening in Spatialized Noise Sentences test, in which noise is spatially separated from target sentences. However, these differences are not consistent between studies and are not found in comparison to all groups of children with other developmental disorders. CONCLUSIONS: Children diagnosed with APD perform equally to children diagnosed with SLI, dyslexia, ADHD, and LD on tests of intelligence, memory or attention, and language tests. Only small differences between groups were found for sensory and perceptual functioning tasks (auditory and visual). In addition, children diagnosed with dyslexia performed poorer in reading tasks compared with children diagnosed with APD. The result is possibly confounded by poor quality of the research studies and the low quality of the used outcome measures. More research with higher scientific rigor is required to better understand the differences and similarities in children with various neurodevelopmental disorders. PMID- 28863037 TI - Talking to cancer survivors about dyspareunia and self-management. PMID- 28863036 TI - Clinical activity of eribulin in advanced desmoplastic small round-cell tumor. AB - Desmoplastic small round-cell tumor is a rare but highly aggressive tumor occurring mainly in adolescents and young adults. Prolonged progression-free survival has been documented in patients who have undergone aggressive multimodality therapy - that is, multiagent intensive chemotherapy, debulking surgery, and radiation therapy. Eribulin is a microtubule-dynamics inhibitor, and it has recently been shown to be active in liposarcomas. In preclinical models, eribulin activities have also been shown to occur in Ewing's sarcoma cell lines, rhabdomyosarcomas and osteosarcomas. In this study, we report three cases of male patients suffering from desmoplastic small round-cell tumor and the clinical response to eribulin in two of them. PMID- 28863038 TI - Long-Term Durability Test for the Left Ventricular Assist System EVAHEART under the Physiologic Pulsatile Load. AB - The EVAHEART Left Ventricular Assist System (LVAS) was designed for the long-term support of a patient with severe heart failure. It has an original water lubrication system for seal and bearing and wear on these parts was considered one of its critical failure modes. A durability test focusing on wear was designed herein. We developed a mock loop, which generates a physiologic pulsatile flow and is sufficiently durable for a long-term test. The pulsatile load and the low fluid viscosity enable the creation of a severe condition for the mechanical seal. A total of 18 EVAHEART blood pumps completed 2 years of operation under the pulsatile condition without any failure. It indicated the EVAHEART blood pump had a greater than 90% reliability with a 88% confidence level. The test was continued with six blood pumps and achieved an average of 8.6 years, which was longer than the longest clinical use in Japan. The test result showed that no catastrophic, critical, marginal, or minor failures of the blood pump or their symptoms were observed. The seal performance was maintained after the test. Moreover, the surface roughness did not change, which showed any burn or abnormal wear occurred. The original water lubrication system equipped in EVAHEART LVAS prevent severe wear on the seal and the bearing, and it can be used in the bridge to transplant and destination therapy. PMID- 28863039 TI - Extracorporeal Membrane Oxygenation for End-Stage Interstitial Lung Disease With Secondary Pulmonary Hypertension at Rest and Exercise: Insights From Simulation Modeling. AB - Interstitial lung disease (ILD) represents a collection of lung disorders with a lethal trajectory with few therapeutic options with the exception of lung transplantation. Various extracorporeal membrane oxygenation (ECMO) configurations have been used for bridge to transplant (BTT), yet no optimal configuration has been clearly demonstrated. Using a cardiopulmonary simulation, we assessed different ECMO configurations for patients with end-stage ILD to assess the physiologic deficits and help guide the development of new long-term pulmonary support devices. A cardiopulmonary ECMO simulation was created, and changes in hemodynamics and blood gases were compared for different inflow and outflow anatomic locations and for different sweep gas and blood pump flow rates. The system simulated the physiologic response of patients with severe ILD at rest and during exercise with central ECMO, peripheral ECMO, and with no ECMO. The output parameters were total cardiac output (CO), mixed venous oxygen (O2) saturation, arterial pH, and O2 delivery (DO2)/O2 utilization (VO2) at different levels of exercise. The model described the physiologic state of progressive ILD and showed the relative effects of using various ECMO configurations to support them. It elucidated the optimal device configurations and required physiologic pump performance and provided insight into the physiologic demands of exercise in ILD patients. The simulation program was able to model the pathophysiologic state of progressive ILD with PH and demonstrate how mechanical support devices can be implemented to improve cardiopulmonary function at rest and during exercise. The information generated from simulation can be used to optimize ECMO configuration selection for BTT patients and provide design guidance for new devices to better meet the physiologic demands of exercise associated with normal activities of daily living. PMID- 28863040 TI - Del Nido Cardioplegia for Myocardial Protection in Adult Cardiac Surgery: A Systematic Review and Meta-Analysis. AB - Cardioplegia is an important strategy for myocardial protection during cardiac surgery. This meta-analysis was to compare the effects of del Nido and conventional cardioplegia in adult patients. Systematic searches were performed to identify studies using PubMed, Embase, the Cochrane Library, and the International Clinical Trials Registry Platform. A total of nine studies were included. Cardiopulmonary bypass and cross-clamp time were significantly shorter in the del Nido than conventional cardioplegia (mean difference [MD]: -7.52, 95% confidence interval [95% CI]: -14.76 to -0.29, p = 0.04; MD: -5.74, 95% CI: 10.14 to -1.34, p = 0.01). During the operation, cardioplegia volume and blood glucose level were lower in the del Nido group (MD: -522.53, 95% CI: -926.68 to 118.37, p = 0.01; standardized mean difference [SMD]: -1.11, 95% CI: -1.74 to 0.48, p = 0.0006). Ventilation time and length of intensive care unit were decreased significantly with del Nido cardioplegia (MD: -1.05, 95% CI: -1.79 to 0.31, p = 0.006; MD: -0.65, 95% CI: -0.92 to -0.38, p < 0.00001). There were no differences in myocardial enzyme, postoperative inotropic support, atrial fibrillation, hospital, and mortality between the two groups. In adult cardiac surgery, myocardial protection used with the del Nido or conventional cardioplegia solution yield similar short-term clinical outcomes. PMID- 28863041 TI - Decellularized Rat Lung Scaffolds Using Sodium Lauryl Ether Sulfate for Tissue Engineering. AB - Perfusion decellularization with detergents is effective to maintain the architecture and proteins of extracellular matrix (ECM) for use in the field of lung tissue engineering (LTE). However, it is unclear which detergent is ideal to produce an acellular lung scaffold. In this study, we obtained two decellularized rat lung scaffolds using a novel detergent sodium lauryl ether sulfate (SLES) and a conventional detergent sodium dodecyl sulfate (SDS). Both decellularized lung scaffolds were assessed by histology, immunohistochemistry, scanning electron microscopy, DNA quantification, sulfated glycosaminoglycans (GAGs) quantification and western blot. Subsequently, the scaffolds were implanted subcutaneously in rats for 6 weeks and were evaluated via hematoxylin and eosin staining and Masson staining. Results indicated that SLES was effective to remove cells; moreover, lungs decellularized with SLES showed better preservation of sulfated GAGs, lung architecture, and ECM proteins than SDS. After 6 weeks, SLES scaffolds demonstrated a significantly greater potential for cell infiltration and blood vessel formation compared with SDS scaffolds. Taken together, we conclude that SLES is a promising detergent to produce an acellular scaffold using LTE for eventual transplantation. PMID- 28863042 TI - The Bioengineered Cardiac Left Ventricle. AB - Left ventricle and aortic valve underdevelopment are presentations in the congenital cardiac condition hypoplastic left heart syndrome (HLHS); current clinical treatments involve right ventricle refunctionalization. Cardiac organoid models provide simplified open chambers engineered into a flow loop, to ameliorate ventricle-type function. Complete bioengineered ventricle development presents a significant advancement in cardiac organoids. This study provides the foundation for bioengineered complete ventricle (BECV) fabrication. Bioengineered trileaflet valve (BETV) molds and chitosan scaffolds were developed to emulate human neonate aortic valve geometry. Bioengineered complete ventricle were fabricated by fitting BETV into a bioengineered open ventricle (BEOV); the chamber was cellularized using a two-stage cellularization strategy, and BETV were passively seeded with rat neonatal cardiac fibroblasts and perfusion cultured for 3 days. Average pressure generated ranged from 0.06 to 0.12 mm Hg; average biopotential output was 1.02 mV. Histologic assessment displayed syncytial-type cardiomyocyte aggregates at the BECV chamber surface; BETV displayed randomly oriented, diffusely distributed cardiac fibroblasts. The fabrication of this novel BECV may aid in developing a functional engineered left ventricle for clinical application in HLHS. PMID- 28863043 TI - Pediatric Tandem Therapeutic Apheresis: A Multidisciplinary Approach. AB - The epidemiology, safety, and efficacy of pediatric multiple tandem extracorporeal therapies are not well understood. We conducted a retrospective chart review of therapeutic apheresis (TA) from January 1, 2012 to October 31, 2015. We collected procedural/clinical demographics, American Society for Apheresis (ASFA) indication, complications, and mortality. One hundred eighty tandem TA procedures were performed in 53 patients. Median age was 9 years (range: 2 months to 21 years) with a median weight of 28 kg (range: 6-170.3 kg) with nine patients weighing < 10 kg. Forty-five percent of patients were in tandem with continuous veno-venous hemofiltration (CVVH), 21% cardiopulmonary bypass (CPB), 4% extracorporeal membrane oxygenation (ECMO), and 11% had multiple extracorporeal therapies (CVVH and ECMO). Common indications were solid organ transplant (50% cardiac, 13% renal) and sepsis-induced thrombocytopenia associated multiple organ failure (26%). Equipment (4%) and patient (4%) complications occurred, with rare failure (1%) and no procedure-related mortality. Tandem procedures are used in critically ill pediatric patients with higher morbidity and mortality (21%) than typical TA patients. The high percentage of patients outside of category I or II (83%) underscores the emerging nature of tandem extracorporeal therapies and need for further investigation. PMID- 28863044 TI - Changing Patterns of Foreigner Transplants in Korea and Overseas Organ Transplants Among Koreans. AB - BACKGROUND: This study aimed to estimate the numbers of foreign patients seeking organ transplantation (OT) in Korea and to examine the relationship between the trend of deceased donors in Korea and number of Korean patients seeking OT overseas since 2000. METHODS: Data on foreigners who received a transplant in Korea were obtained from the Korean Network for Organ Sharing. Data on overseas transplants were obtained from 42 transplant centers surveyed through transplant coordinators. RESULTS: A total of 336 foreigners underwent OT (kidney transplantation [KT], 174; liver transplantation [LT], 162) in Korea between 2006 and 2016. The Mongolians were the most common foreigners who undergo KTs (32%), followed by the Chinese (18%), Americans (9%), and Emiratis (7%). Among foreigners undergoing LTs, the most common country of origin was Mongolia (39%), followed by United Arab Emirates (23%), China (13%), and the United States (6%). A total of 2206 Korean patients underwent overseas OT (KT, 977; LT, 1229) between 2000 and 2016. In 97% of overseas KT cases (n = 942) and 98% (n = 1205) of overseas LT cases, the transplantations were performed in China. The relationship between the number of deceased donors in Korea and the number of overseas transplants after 2006 indicates a highly negative correlation. (rho = -0.988, P < 0.001). CONCLUSIONS: This analysis of trends in Korean patients seeking OT overseas demonstrates the importance of multilateral approaches to address organ trafficking. National effort to achieve self-sufficiency by increasing activities for organ donations is one of the fundamental solutions to transplant tourism. PMID- 28863045 TI - Perineal Talc Use and Ovarian Cancer: A Systematic Review and Meta-Analysis. AB - BACKGROUND: It has been posited that there is an association between perineal talc use and the incidence of ovarian cancer. To date, this has only been explored in observational studies. OBJECTIVES: To perform a meta-analysis to evaluate the association between perineal talc use and risk of ovarian cancer. METHODS: Studies were identified using six electronic databases. Observational studies involving at least 50 cases of ovarian cancer were eligible for inclusion. We analyzed the association between ovarian cancer, including specific types, and any perineal talc use, long-term (>10 years) use, total lifetime applications, and use on diaphragms or sanitary napkins. A subgroup analysis was performed, stratifying by study design and population. RESULTS: We identified 24 case-control (13,421 cases) and three cohort studies (890 cases, 181,860 person years). Any perineal talc use was associated with increased risk of ovarian cancer (OR = 1.31; 95% CI = 1.24, 1.39). More than 3600 lifetime applications (OR = 1.42; 95% CI = 1.25, 1.61) were slightly more associated with ovarian cancer than <3600 (OR = 1.32; 95% CI = 1.15, 1.50). An association with ever use of talc was found in case-control studies (OR = 1.35; 95% CI = 1.27, 1.43), but not cohort studies (OR = 1.06; 95% CI = 0.90, 1.25). However, cohort studies found an association between talc use and invasive serous type ovarian cancer (OR = 1.25; 95% CI = 1.01, 1.55). We found an increased risk of serous and endometrioid, but not mucinous or clear cell subtypes. CONCLUSIONS: In general, there is a consistent association between perineal talc use and ovarian cancer. Some variation in the magnitude of the effect was found when considering study design and ovarian cancer subtype. PMID- 28863046 TI - Cognitive Aging in Black and White Americans: Cognition, Cognitive Decline, and Incidence of Alzheimer Disease Dementia. AB - BACKGROUND: US-based studies have reported that older blacks perform worse than older whites on cognitive tests and have higher risk of Alzheimer disease dementia (AD). It is unclear whether these findings reflect differences in cognitive decline. METHODS: The Chicago Health and Aging Project followed individuals, 65+ years old (64% black, 36% white), for up to 18 years. Participants underwent triennial cognitive assessments; stratified randomized samples underwent assessments for AD. We compared black and white participants' cognitive performance, cognitive decline rate (N = 7,735), and AD incidence (N = 2,144), adjusting for age and sex. RESULTS: Black participants performed worse than white participants on the cognitive tests; 441 participants developed AD. Black participants' incident AD risk was twice that of whites (RR = 1.9; 95% CI, 1.4, 2.7), with 58 excess cases/1,000 occurring among blacks (95% CI, 28, 88). Among noncarriers of APOE epsilon4, blacks had 2.3 times the AD risk (95% CI, 1.5, 3.6), but among carriers, race was not associated with risk (RR = 1.1; 95% CI, 0.6, 2.0; Pinteraction = 0.05). However, cognitive decline was not faster among blacks: the black-white difference in 5-year change in global cognitive score was 0.007 standard unit (95% CI, -0.034, 0.047). Years of education accounted for a sizable portion of racial disparities in cognitive level and AD risk, in analyses using a counterfactual approach. CONCLUSIONS: The higher risk of AD among blacks may stem from lower level of cognitive test performance persisting throughout the observation period rather than faster rate of late-life cognitive decline. Disparities in educational attainment may contribute to these performance disparities. See video abstract at, http://links.lww.com/EDE/B299. PMID- 28863048 TI - Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. AB - PURPOSE OF REVIEW: This review highlights the current literature on both infectious and noninfectious diarrhea in renal transplant recipients and provides a diagnostic algorithm for the evaluation of posttransplant diarrhea. RECENT FINDINGS: Renal transplant recipients share certain predisposing characteristics for the development of posttransplant diarrhea, including a generalized immunosuppressed state and exposure to polypharmacy, most notably broad-spectrum antimicrobial therapy. The main causes of diarrhea after transplantation are infections, immunosuppressive drugs, antibiotics and other drugs. As the cause of posttransplant diarrhea varies greatly depending on several factors, recommending a single optimal diagnostic algorithm is extremely difficult. SUMMARY: Physicians should be familiar with common causes that result in posttransplant diarrhea. A directed approach to diagnosis and treatment will not only help to resolve diarrhea, but also prevent potentially life-threatening consequences, such as loss of the graft. Prospective studies are needed to better assess true prevalence, risk factors and complications of diarrhea by norovirus, rotavirus and adenovirus in kidney transplant patients. PMID- 28863049 TI - Nursing Roles and Substance Use Disorders. PMID- 28863047 TI - Aspirin Use and Mortality in Two Contemporary US Cohorts. AB - BACKGROUND: Daily aspirin use has been recommended for secondary prevention of cardiovascular disease, but its use for primary prevention remains controversial. METHODS: We followed 440,277 men and women from the NIH-AARP Diet and Health Study (ages 50-71) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (ages 55-74) for mortality for 13 years on average. Frequency of aspirin use was ascertained through self-report, and cause of death by death certificates. We calculated multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality using Cox proportional hazards models for each cohort and combined by meta-analysis. RESULTS: We found a consistent U-shaped relationship between aspirin use and mortality in both studies, with differential risk patterns for cardiovascular mortality by disease history. Among individuals with a history of cardiovascular disease, daily aspirin use was associated with reduced cardiovascular mortality [HR = 0.78 (95% CI, 0.74, 0.82)]. However, among those without a previous history, we observed no protection for daily aspirin users [HR = 1.06 (1.02, 1.11)], and elevated risk of cardiovascular mortality for those taking aspirin twice daily or more [HR = 1.29 (1.19, 1.39)]. Elevated risk persisted even among participants who lived beyond 5 years of follow-up and used aspirin without other nonsteroidal antiinflammatory drugs [HR = 1.31 (1.17, 1.47)]. CONCLUSIONS: Results from these 2 large population-based US cohorts confirm the utility of daily aspirin use for secondary prevention of cardiovascular mortality; however, our data suggest that caution should be exercised in more frequent use, particularly among individuals without a history of cardiovascular disease. PMID- 28863050 TI - Nursing Roles in the Care of Patients With Substance Use Disorders. PMID- 28863051 TI - Developing an Addictions Nursing Competency Framework Within a Canadian Context. AB - Clients with substance use disorders access care in all areas of the health care system, yet the Canadian nursing literature lacks content on the knowledge, skills, and judgment needed by nurses who work with this population. To address this literature gap, two Advanced Practice Nurses adapted the Canadian Centre on Substance Abuse's Technical Competencies for Canada's Substance Abuse Workforce to include nursing content and theory. This article describes the adaptation process and validation method used by the Advanced Practice Nurses at a large, Canadian urban teaching hospital and includes discussion about actual and potential opportunities for practical application of the adapted framework. PMID- 28863052 TI - Perspectives on a Home Telehealth Care Management Program for Veterans With Posttraumatic Stress Disorder Who Smoke. AB - BACKGROUND: Individuals with posttraumatic stress disorder (PTSD) have high rates of smoking and low quit rates. We conducted a qualitative evaluation of an integrated smoking cessation randomized controlled trial (RCT) that used home telehealth and motivational interviewing (MI) to change smoking behaviors among individuals with PTSD. METHOD: Using a convenience sample sourced from the original RCT, intervention and control group participants were invited to participate in a qualitative evaluation. Semistructured interview guides were used to assess the effectiveness of study components, make recommendations for future interventions, and identify facilitators/barriers to smoking cessation. We analyzed these data using an inductive and deductive, team-based content analysis approach. RESULTS: We interviewed 32 study participants (intervention: n = 15, control: n = 17) who completed the original RCT within the previous 6 months. Respondents were highly satisfied with home telehealth and MI counseling. The intervention group respondents found MI counseling to be supportive, nonjudgmental, and informative. Control group respondents felt that they had received smoking cessation assistance. Respondents from both groups desired more information about PTSD and smoking, relied on smoking as a coping mechanism for PTSD, and believed that quitting was an individual choice. CONCLUSION: Respondents reported that home telehealth and MI were acceptable ways to provide smoking cessation assistance to individuals with PTSD. The support and increased awareness of smoking behaviors were perceived as helpful. Future investigations should focus on increasing support and information about stress management, smoking, PTSD, and the relationship between them for individuals with PTSD who smoke. PMID- 28863053 TI - Preparing Nursing Students to Work With Patients With Alcohol or Drug-Related Problems. AB - Stigma and insufficient training for addressing alcohol or drug problems in clinical settings are two significant barriers to earlier identification and access to care for patients with alcohol or drug (AOD)-related problems. Nurses are crucial players in this strategy, yet nurses often report poor motivation and insufficient training for working with AOD-affected patients. This article describes and reports preliminary evaluation results of an educational experience that integrated AOD curriculum into a community/public health nursing clinical practicum. The purpose of the intervention was to meet the required objectives for our university's community/public health nursing clinical course, improve students' attitudes and therapeutic commitment for working with AOD-affected patients, and prepare students for providing high-quality nursing care for individuals with AOD-related problems. PMID- 28863054 TI - Topics of Addiction in Turkish Nursing Programs: A Summary. AB - Addiction is a serious health issue. The measured rates of substance abuse in Turkey are lower than those in Western countries; however, recent studies show a significant increase in the prevalence of substance abuse and that the age of onset of substance abuse has decreased. There is a lack of literature about the topic of addiction in the undergraduate nursing programs in Turkey. Therefore, the aim of this current study was to examine the presence of addiction content in nursing education in Turkey among state and foundation universities.A descriptive, survey research design was used in this study. One hundred twelve state universities and 64 foundation universities that provide undergraduate education in Turkey were screened using the database of the Council of Higher Education. Researchers found that 89.09% of the state universities and all the foundation universities included the topic of addiction and/or substance addiction somewhere in their undergraduate nursing programs. The courses were primarily elective courses, and availability of the coursework varied. Given the impact of substance and process addictions, the authors conclude with a recommendation that the topic of addiction be offered as a discrete, mandatory course in the undergraduate nursing curricula of all universities offering nursing programs. PMID- 28863055 TI - The Last State to Grant Nurse Practitioners DEA Licensure: An Education Improvement Initiative on the Florida Prescription Drug Monitoring Program. AB - Nurse practitioners (NPs) now have prescriptive authority for controlled substances in all 50 states in the United States. Florida, the last state to grant NPs DEA licensure, has been wrought with prescription diversion practices for a number of years as pill mills, doctor shopping, and overprescribing proliferated. Prescription Drug Monitoring Programs (PDMPs) help curb drug diversion activity and play a key role in reducing the abuse of controlled substances. The primary objective of this education improvement initiative was to increase knowledge of actively licensed NPs in the state of Florida regarding the state's PDMP. The main themes included the drug abuse problem, description and progression of the PDMP, and how to use the Florida PDMP. Upon approval from the institutional review board, this education improvement initiative gauged NP knowledge of the PDMP and main themes before and after an educational PowerPoint intervention. A pretest/posttest questionnaire was administered for assessment of all knowledge questions. One hundred forty-five NPs with active advanced registered NP licenses in Florida completed both the pretest and posttest questionnaires. Descriptive statistics and paired t tests were used for statistical significance testing. Knowledge of the PDMP and the main themes of the education improvement initiative significantly increased (p < .001) from pretest to posttest results. This education improvement initiative had positive effects for NPs on the knowledge of the Florida PDMP and the main themes. This indicated that Florida NPs are able to acquire greater comprehension of the PDMP by an education intervention. PMID- 28863056 TI - Preparing Nursing and Social Work Students to Care for Patients in Acute Alcohol Withdrawal. AB - Alcohol and other drug abuse has become a national crisis with approximately 26% of general medical patients having alcohol-related problems. New nurses and social workers are often not prepared to care for patients with severe alcohol withdrawal symptoms because they lack experience in actual crisis situations. The purpose of this study was to prepare nursing and social work students to care for a patient undergoing an acute alcohol withdrawal process. Nine groups of 8-10 students participated in a 2.5-hour simulation event that included an alcohol withdrawal seizure, team meeting, and discharge of the patient. Students recognized the importance of all the professional roles and how each professional benefits patient care. Before the simulation, students thought they were prepared to care for patients experiencing alcohol withdrawal; however, the crisis of an alcohol seizure decreased the student's ability to perform skills and communicate effectively. These findings suggest that new nurses and social workers may not be prepared to care for the acute alcohol withdrawal patient. PMID- 28863057 TI - Nursing Fellowship in Addiction Medicine: A Novel Program in a Canadian Setting. PMID- 28863058 TI - Brief Report: First World Health Organization Forum on Alcohol Drugs and Addictive Behaviors: Enhancing Public Health Actions Through Partnerships and Collaboration. PMID- 28863059 TI - Recovery Beyond Buprenorphine: Nurse-Led Group Therapy. AB - It has taken the tragedy of swelling opioid overdoses to raise addictions to national attention. This past year, a new law called the Comprehensive Addictions Recovery Act has helped to open doors for nurse practitioners and physician assistants to prescribe buprenorphine. Although this medication can assist those dependent on opioids in finding needed stability, medication-assisted treatment is only the beginning. Addiction and psychiatric nurses must play a larger role in providing various therapies that coincide with medication-assisted treatment to support ongoing recovery. One treatment option is group therapy, which is effective for individuals with substance use as well as other co-occurring disorders to develop needed skills to remain in recovery. The purpose of this review is to explore the nursing role in group therapy for substance use as well as encourage addictions and psychiatric nurse practitioners to offer recovery focused group therapy to this population. PMID- 28863060 TI - Socialized Risk and Privatized Profit: What Addictions Nurses Need to Know About the Potential Repeal of the Affordable Care Act. AB - The aim of this column is to provide an overview of the positive impacts of the Patient Protection and Affordable Care Act of 2010 (ACA) on improved health care access, quality, and outcomes for individuals with substance use disorders (SUDs), including opioid use disorders and opioid overdose deaths. Addictions nurses should be alerted to the serious, often lethal consequences that individuals with SUDs will experience if the ACA is repealed. Proposed legislation to reverse major provisions of the ACA include the American Health Care Act of 2017 (H. R. 1628), passed by the U.S. House of Representatives on May 4, 2017, and the Better Care Reconciliation Act of 2017 (H. R. 1628, Senate Amendment, June 26, 2017), which was made public just before this writing, amid much secrecy and lack of transparency. This column focuses on ACA-related Medicaid expansion and the impact that future cuts to Medicaid and other insurance coverage would have on individuals in need of SUD treatment. Finally, this column addresses the moral, ethical, and professional obligations of nurses and others involved in health care and health policy. Intensified advocacy efforts are required to ensure that recent ACA-related gains in insurance coverage and access to quality behavioral health treatment are not only preserved but also expanded. Access to health insurance coverage and health care, especially among vulnerable, high-risk populations, including those at elevated risk for opioid overdose and other SUD-related morbidity and mortality risks, is one of the most important social justice issues of our time. PMID- 28863061 TI - Nursing Roles in Addiction Care. PMID- 28863063 TI - Preparing Nursing Students to Work with Patients with Alcohol or Drug-Related Problems. PMID- 28863062 TI - Strategic Development of an Alternative-to-Discipline Program in Hawaii. PMID- 28863064 TI - Mixed Tumor, Eccrine Type: So What If it's Vulval! PMID- 28863065 TI - Ovarian Leydig Cells (OLC): About their Heterotopia or Eutopia. PMID- 28863066 TI - Inflammatory Pseudotumor Presenting as a Mesosalpingeal Mass. AB - We describe a case in which the clinical and pathologic features of a mesosalpingeal mass led to a diagnosis of inflammatory pseudotumor, an unusual tumor found in a rare location. The differential diagnosis is rather broad and includes lesions ranging from Castleman disease to an immunoglobulin G4-related fibrosclerosing tumor. The patient is alive and well at last follow-up. PMID- 28863067 TI - Cervical Carcinoma With Divergent Neuroendocrine and Gastrointestinal Differentiation. AB - Neuroendocrine carcinomas of the uterine cervix are rare tumors with aggressive behavior. They comprise <4% of cervical carcinomas. They may coexist with both adenocarcinoma and squamous cell carcinoma of cervix. Signet ring carcinoma of cervix is a rarer entity and less than 20 cases have been described in the literature. We present a case of a 34-year-old female who presented with systemic thrombosis, splenic mass and a cervical mass which on biopsy showed divergent differentiation of primitive large cell neuroendocrine carcinoma with signet ring cells. The cervical tumor was positive for human papilloma virus 16/18 by in situ hybridization, confirming cervical origin of the tumor. This unusual presentation and morphology needs to be recognized and appropriately evaluated when patients present with tumors of unknown origin in metastatic sites. PMID- 28863068 TI - Test Characteristics of Specific p16 Clones in the Detection of High-grade Squamous Intraepithelial Lesions (HSIL). AB - p16 immunohistochemistry is recommended by the CAP-ASCCP Lower Anogenital Squamous Terminology (LAST) Standardization Project for human papillomavirus associated Lesions as an adjunct to morphologic assessment in the diagnosis of high-grade squamous intraepithelial lesion. This study evaluates the performance of different p16 clones as compared with E6H4 (CINtec) in detecting high-grade squamous intraepithelial lesion. The 54 high-quality articles addressing the performance of p16 identified by work group 4 of the LAST Project were evaluated for: specific p16 clone, scoring method, number of cases, anatomic site, and histologic diagnoses. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each clone. Two-proportion z tests (pooled) were used to evaluate significance. In total, 32 of the 54 studies met the inclusion criteria. The most commonly used clone was E6H4 (17 studies, 3507 cases) with smaller numbers (1-4) of studies evaluating the following: 16P04, JC8, 16P07, G175-405, K5334, K5336, and 7962. p16 clones 16P04 and JC8 performed better than E6H4 with 16P04 exhibiting statistically significant higher sensitivity (94% vs. 87% for E6H4), specificity (94% vs. 81%), and positive predictive value (96% vs. 69%) while JC8 exhibited higher specificity (91% vs. 81%) and positive predictive value (88% vs. 69%). 16P07 performed similarly to E6H4 and the other 4 clones did not perform as well as E6H4. p16 clones 16P04, JC8, and 16P07 clones perform as well or better than the widely used p16 clone E6H4 (CINtec). However, further studies are indicated to determine the reproducibility of these findings and the impact of interlaboratory variation on test performance. PMID- 28863070 TI - Evaluation of Microscopic Changes in Fallopian Tubes of BRCA Mutation Carriers by Morphometric Analysis of Histologic Slides: A Preliminary Pilot Study. AB - Mutations in BRCA genes increase the risk of ovarian cancer, yet no method for early diagnosis is available. Some serous ovarian tumors are hypothesized to stem from cells of the fallopian tube fimbria. Using a novel method of computerized morphometry of the fimbrial epithelium, this study aimed to detect morphologic differences in noncancerous fimbriae between BRCA mutation carriers and noncarriers, and between healthy and serous ovarian cancer patients. Twenty-four fimbriae from healthy women (13 BRCA+, 11 BRCA-) and 21 fimbriae from women with serous ovarian cancer (10 BRCA+, 11 BRCA-), all reported as "normal" by hematoxylin and eosin examination, were subjected to computerized histomorphometric analysis. A Fast Fourier Transformation was applied to images of fimbrial epithelium and the Fast Fourier Transformation 2-dimensional frequency maps were subsequently quantified for nuclear orientation and planar distribution by a cooccurrence matrix analysis. Additional analysis of nuclear contour was applied to the fimbriae of the healthy women. Among the healthy women, significant differences were found in morphometric characteristics between the BRCA mutation carriers and noncarriers. Among the women with ovarian cancer, no significant differences were found between BRCA mutation carriers and noncarriers. Between healthy women and those with ovarian cancer, significant differences were detected, regardless of BRCA mutational status. A novel method, which combined Fast Fourier Transformation with cooccurrence matrix analysis, demonstrated differences in morphometric characteristics in the fimbriae between healthy and ovarian cancer patients, and between BRCA mutation carriers and noncarriers. The clinical significance of these observations should be investigated. PMID- 28863069 TI - Fibroepithelial Stromal Polyp of the Vulva: Case Report and Review of Potential Histologic Mimickers. AB - Vulvar tumors arising from submucosal connective tissue, some of which exhibit hormonal responsiveness, have many clinical and histologic overlapping characteristics. We present a case of a fibroepithelial stromal polyp arising from the vulva of a 22-year-old female. We review the differential diagnosis with an emphasis on distinguishing features of these uncommon neoplasms. Accurate diagnosis is essential as the extent of surgical resection and risk of local recurrence varies for these tumors. PMID- 28863071 TI - An Ovarian Adenocarcinoma With Combined Low-grade Serous and Mesonephric Morphologies Suggests a Mullerian Origin for Some Mesonephric Carcinomas. AB - Mesonephric carcinomas are rare adenocarcinomas of the female genital tract that occur most commonly in the uterine cervix. They are classically thought to arise from benign mesonephric remnants, and are rarely reported at other sites in the gynecologic tract. Here we present an interesting biphenotypic ovarian adenocarcinoma with intimately associated but distinct components of both low grade serous carcinoma and mesonephric-like carcinoma. A serous borderline tumor was present adjacent to the invasive carcinoma, and no benign mesonephric precursors were identified. Numerous invasive peritoneal metastases were present, including multiple metastases with both low-grade serous and mesonephric-like elements. Consistent with recent reports, foci of mesonephric-like carcinoma were morphologically and immunohistochemically identical to classic mesonephric carcinoma of the cervix. On molecular analysis, the serous borderline tumor, primary and metastatic low-grade serous carcinoma, and primary and metastatic mesonephric-like carcinoma each harbored a shared NRAS p.Q61R hotspot mutation, shared gains in chromosome 1q and 18p, and shared losses in chromosomes 1p, 18q, and 22. These shared molecular features indicate a clonal relationship between all morphologic elements of this ovarian adenocarcinoma, suggesting that at least some mesonephric carcinomas may arise from Mullerian precursors. PMID- 28863072 TI - YWHAE Rearrangement in a Purely Conventional Low-grade Endometrial Stromal Sarcoma that Transformed Over Time to High-grade Sarcoma: Importance of Molecular Testing. AB - Low and high-grade endometrial stromal sarcomas (ESS) can be distinguished on a morphologic basis. Low-grade ESS is composed of oval cells that resemble normal proliferative-phase endometrial stroma, while the well-known high-grade ESS is composed of round cells growing in nests separated by delicate sinusoidal vasculature. Recurrent JAZF1 rearrangements have been reported to be most frequent in low-grade stromal sarcomas (up to 60%), while YWHAE rearrangements are characteristic of high-grade ESS. Herein, we report a case of a 45-yr-old woman with stage IA typical low-grade ESS who developed multiple abdominopelvic recurrences and lung metastases 15 mo after her primary tumor was resected. The unusual morphology (without high-grade areas) as well as the aggressive behavior of the tumor prompted molecular testing which showed YWHAE rearrangement in her abdominopelvic recurrence and her primary tumor. Five years after her primary tumor was resected, she developed scalp metastases with a typical morphology of a high-grade ESS associated with t(10;17) and died of her disease. Our case highlights the potential value of molecular testing in all low-grade ESS at time of initial diagnosis to stratify patients at higher risk for developing high grade ESS with the goal of offering closer follow-up for early detection and treatment if transformation occurs. PMID- 28863073 TI - Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei. AB - Leiomyoma with bizarre nuclei (LM-BN), is a variant of uterine smooth muscle tumor with atypical histologic features. Although some LM-BN share several significant genetic alterations with leiomyosarcoma, including p16 and p53, the underlying tumorigenesis of LM-BN remains largely unknown. As we previously reported, LM-BN can be divided into 2 subtypes, type I and type II, based on different nuclear features. Type I LM-BN have similar histologic features as uterine smooth muscle tumors with fumarate hydratase (FH) alterations. In this study, we examined FH expression and FH mutations in 77 LM-BN (40 type I cases and 37 type II cases). FH expression was examined by immunohistochemistry using S (2-succino)-cysteine antibodies (2SC, a protein modification associated with FH inactivation and subsequent fumarate accumulation) and FH antibodies (FH gene products). Seventy-two LM-BN tumors underwent Sanger sequencing to detect FH mutations. We found that 51% (39/77) of LM-BN showed FH alterations detected by immunohistochemistry with both 2SC and FH. Mutational analysis showed that 21% (15/72) of LM-BN harbored FH gene mutations. Further analysis revealed that 85% (34/40) of those with FH alterations were type I LM-BN while 19% (7/37) were type II LM-BN. Our findings suggest that over half of histologically diagnosed LM-BN may be related to FH alterations or FH mutations and the majority of these have the characteristic histologic features of type I LM-BN. PMID- 28863074 TI - Interval Walking Training and Nutritional Intake to Increase Plasma Volume in Elderly. AB - PURPOSE: Aerobic training-induced plasma volume (PV) expansion improves thermoregulation, and carbohydrate (CHO) + whey protein supplementation enhanced the effects in older people; however, these were suggested by studies on gym based cycling training but not on home-based interval walking training (IWT). Moreover, long-term walking training effects on PV remain unknown. METHODS: Seventeen male and 10 female subjects (~69 yr), having performed IWT for >=24 months before the study, were used. After pre-intervention measurement (PRE) of PV, plasma albumin content (Albcont), fasting glucose concentration ([Glc]f), and HbA1c, the subjects were randomly divided into two groups: CHO and Pro-CHO, either consuming CHO (22.5 g) alone or CHO (15 g) + whey protein (10 g), respectively, during additional 5-month IWT from May to November, 2009. After the additional IWT, we measured the same variables again (postintervention measurement). RESULTS: The baseline PV and Albcont were significantly correlated with the number of IWT days for the 12 months preceding PRE (r = 0.716, P < 0.001 and r = 0.671, P < 0.001, respectively). In postintervention, PV and Albcont marginally decreased in CHO from the baselines (P = 0.081 and P = 0.130, respectively) with increased HbA1c (P < 0.001) after correction for the baseline [Glc]f by ANCOVA, but these values remained unchanged in Pro-CHO (both, P > 0.74), with significant differences in the changes between groups (P = 0.020, P = 0.041, and P = 0.018 respectively). CONCLUSIONS: PV was proportional to the number of IWT days for 12 months and a CHO + whey protein supplementation during the 5-month IWT prevented PV reduction for the period of no supplementation, which might be partially linked with blood glucose control mechanisms. PMID- 28863075 TI - Hyperthermia-induced Neural Alterations Impair Proprioception and Balance. AB - PURPOSE: Hyperthermia has been shown to affect both central and peripheral nervous systems. However, the consequences of these alterations on the proprioceptive mechanisms underlying human movement control remain unclear. The aim of this study was to investigate the effect of passive hyperthermia on various measures of proprioception and balance, two key components of injury prevention and movement efficiency. METHODS: After a familiarization session, 14 volunteers (8 males, 6 females) completed two experimental sessions in temperate (CON, 24 degrees C) and hot (HOT, 44 degrees C-50 degrees C) conditions, in a counterbalanced order. Participants were tested for neural function (electrically evoked M-wave and Hoffman reflex, Soleus), active movement discrimination (five positions, 50 trials, dorsiflexion), dynamic balance (Star Excursion Balance Test, three directions), and static balance (single-leg stance). RESULTS: Both rectal (39.0 degrees C +/- 0.3 degrees C vs 36.9 degrees C +/- 0.6 degrees C) and mean skin (37.9 degrees C +/- 1.0 degrees C vs 32.0 degrees C +/- 2.7 degrees C) temperatures were significantly higher in HOT than CON (P < 0.05). Hyperthermia significantly reduced the Hoffman reflex (P < 0.05) but not the M-wave (P > 0.05) amplitudes, increased the mean error for active movement discrimination (0.58 degrees +/- 0.13 degrees vs 0.50 degrees +/- 0.11 degrees , +17%, P < 0.05), decreased the average distance reached in the posteromedial direction during dynamic balance (88.6 +/- 7.9 cm vs 90.9 +/- 6.1 cm, P < 0.05), and increased the contact area of the foot (126 +/- 14 cm vs 122 +/- 13 cm, +2.7%, P < 0.05) and the center of pressure excursion (64 +/- 14 vs 57 +/- 9 cm, +11.1%, P < 0.10) during single-leg stance. CONCLUSIONS: The current study suggests that hyperthermia impairs the proprioception and balance parameters measured. These observations might be due to heat-induced alterations in efferent and afferent signals to and from the muscle. PMID- 28863077 TI - Undifferentiated Endometrial Carcinomas Show Frequent Loss of Core Switch/Sucrose Nonfermentable Complex Proteins. AB - Undifferentiated endometrial carcinoma is an aggressive type of endometrial carcinoma that typically presents with advanced stage disease and rapid clinical progression. In contrast to dedifferentiated endometrial carcinoma, undifferentiated carcinoma lacks a concurrent differentiated (typically low-grade endometrioid) carcinoma component, though the undifferentiated component of dedifferentiated carcinoma is similar histologically and immunophenotypically to pure undifferentiated carcinoma. We recently identified 3 mutually exclusive mechanisms of switch/sucrose nonfermentable (SWI/SNF) complex inactivation (BRG1 inactivation, INI1 inactivation or ARID1A/ARID1B co-inactivation) that are associated with histologic dedifferentiation in the majority of dedifferentiated endometrial carcinoma. In the current study, we aimed to determine by immunohistochemistry whether these patterns of SWI/SNF inactivation also occur in undifferentiated endometrial carcinomas. Of the 34 undifferentiated carcinomas examined, 17 (50%) exhibited SWI/SNF complex inactivation, with 11 tumors showing complete loss of both ARID1A and ARID1B, 5 showing complete loss of BRG1 and 1 showing complete loss of INI1. Ten of the remaining 17 undifferentiated carcinomas showed the following alterations: 5 tumors (15%) showed loss of ARID1A only with intact ARID1B, BRG1, and INI1 expression, 4 tumors (12%) showed mutated patterns of p53 staining with intact SWI/SNF protein expression, and 1 tumor (3%) harbored a POLE exonuclease domain mutation (P286R). SWI/SNF complex-inactivated tumors presented more frequently with extrauterine disease spread than those with intact expression (88% vs. 41%, respectively). In addition, patients with SWI/SNF complex-inactivated tumors had a significantly worse disease-specific survival (P=0.02). The findings here demonstrate frequent SWI/SNF complex inactivation in undifferentiated endometrial carcinomas, which has future implications regarding therapies that target chromatin remodelling and epigenetic control. PMID- 28863076 TI - Histologic Correlates of Clinical and Endoscopic Severity in Children Newly Diagnosed With Ulcerative Colitis. AB - To characterize rectal histology in an inception cohort of children newly diagnosed with ulcerative colitis (UC) and to explore its relationship with clinical indices of disease severity. The PROTECT (Predicting Response to Standardized Pediatric Colitis Therapy) Study enrolled children 17 years of age and younger newly diagnosed with UC. Baseline rectal biopsies were evaluated for acute and chronic inflammation, eosinophilic inflammation (peak eosinophil count > 32 eosinophils/high powered field, eosinophilic cryptitis or abscesses), and architectural/nonarchitectural chronic changes. Correlation with clinical indices including Mayo endoscopy subscore and Pediatric Ulcerative Colitis Activity Index was performed. Rectal biopsies from 369 patients (mean age, 12.9+/-3.1 y, 50% female) were reviewed. Cryptitis was found in 89%, crypt abscesses in 25%, and eosinophilic inflammation in 58%. Crypt distortion/atrophy was present in 98% of specimens. Higher grades of acute and chronic inflammation were associated with the presence of basal plasmacytosis (P<0.0001), basal lymphoid aggregates (P<0.0001), and surface villiform changes (P<0.0001). A severe Mayo endoscopy subscore was most common among those with severe acute and chronic inflammation, although this relationship was not linear. Severe Pediatric Ulcerative Colitis Activity Index scores were associated with the absence of or only mild eosinophilic inflammation (<32 eosinophils/high powered field) (P<0.03) and the presence of surface villiform changes (P<0.005). Acute and chronic inflammation, eosinophilic inflammation and chronic changes are common in children newly diagnosed with UC. The clinical and biological implication of low to absent eosinophilic inflammation and the presence of surface villiform changes requires further study. PMID- 28863079 TI - Medical Challenges and Advances in the American Civil War. PMID- 28863078 TI - The prevalence of chronic deep venous thrombosis in trauma: Implications for hospitals and patients. AB - INTRODUCTION: Deep venous thrombosis (DVT) is considered a preventable complication in trauma patients. Hospitals risk financial penalties for DVT rates above accepted benchmarks. These penalties do not apply to chronic DVT, which develops before admission. Lower-extremity duplex ultrasound (LEDUS) can detect characteristics of thrombus chronicity, allowing differentiation of chronic from acute DVT. The objective of this study was to determine the prevalence of chronic DVT in hospitalized trauma patients. METHODS: We performed a retrospective review of trauma patients admitted to our Level I trauma center between July 1, 2006 and October 31, 2016 who had a DVT on initial screening LEDUS. Our center utilizes screening and surveillance LEDUS for patients admitted more than 48 hours. Definitions for chronic and acute DVT were extracted from existing literature. Patients with DVT on initial LEDUS underwent review of that LEDUS to assess clot chronicity and were classified as having acute DVT, chronic DVT, or DVT of indeterminate age. Demographic data, medical history, and injury characteristics were collected. Patients with acute DVT and those with chronic DVT were compared. RESULTS: The prevalence of chronic DVT among patients with a DVT on initial LEDUS was 29.9%. Chronic DVT occurred in patients who were older and less severely injured. An above-knee component was significantly more common in chronic DVT (65%). Only 34 (41%) of those with chronic DVT reported a history of DVT. Among the patients with chronic DVT, 44 (53%) had a subsequent LEDUS, of whom 4 (9%) showed thrombus progression and 6 (14%) formed a new DVT. CONCLUSION: Lower extremity duplex ultrasound can identify chronic DVT, which represents nearly 30% of all DVT found on initial screening LEDUS in trauma patients. Those with chronic DVT should receive pharmacologic and mechanical prophylaxis because of the incidence of progression and new acute DVT. They should also be counseled regarding the possibilities of recurrence and chronic venous insufficiency. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 28863080 TI - Loop ileostomy for Clostridium difficile infection: Know thy enemy. PMID- 28863081 TI - Twelve-month results of laparoscopic lavage in perforated acute diverticulitis Update of meta-analysis results. New evidences, which perspectives? PMID- 28863082 TI - Chemoprophylaxis for venous thromboembolism prevention in spine surgery patients. PMID- 28863084 TI - An impending tension pneumomediastinum. PMID- 28863083 TI - For the patient-Evolution in the management of vascular trauma. AB - There has been an evolution in the diagnosis and management of vascular trauma over the past 100 years. The primary stimulus to these changes has been the increased volume of patients with cervical, truncal, and peripheral vascular injuries during military conflicts and in civilian life. Patients with "hard" signs of a vascular injury are taken to surgery emergently with a few exceptions to be described. In contrast, patients with "soft" signs of a vascular injury undergo a careful physical examination including measurement of vascular index to determine if radiologic imaging is necessary. Computed tomography arteriography has become the most commonly used method of imaging, whereas duplex ultrasonography is used in some centers. Nonoperative management is now common for nonocclusive injuries diagnosed on computed tomography arteriography. Proximal tourniquets are commonly used to control exsanguinating hemorrhage from injuries to extremities, whereas balloons can be used to control hemorrhage from difficult to expose areas at operation. Temporary intraluminal shunts are now used in 3% to 9% of arterial injuries. Operative techniques of repair have been refined and contribute to the excellent results noted in modern trauma centers. PMID- 28863086 TI - Common Versus Unique Findings on Processing-Based Task Performance in Korean Speaking Children With Cochlear Implants. AB - HYPOTHESIS: To better understand individual variability by examining overall neurocognitive underlying features in children with cochlear implants (CIs), and to investigate whether previous findings hold constant in Asian-language users. BACKGROUND: Studies have tried to explain the individual variability in children with CIs. However, performance on experience-dependent tasks does not seem to be sensitive enough to explain the underlying reason why children have language difficulties even after the surgical procedure. Thus, this current research has focused on underlying neurocognitive functions to better explain the reason for the wide variability in this population. METHODS: Using a separate univariate analysis paradigm, performance on processing-based tasks was compared between children with CIs and children with normal hearing. A total of 34 children ranging from 10 to 12 years old participated in the study. There were two different categories of processing-based tasks tapping processing capacity and processing speed. This study used nonword repetition (NWR), competing language processing task (CLPT), and counting span (CS) for examining processing capacity, while rapid naming (RAN) in color, shape, and color shape were used to investigate processing speed. RESULTS: Children with NH outperformed children with CIs on all processing-capacity tasks, except CS. Children with CIs performed similarly to children with NH on processing speed tasks. CONCLUSIONS: We found children with CIs still experienced difficulties with processing capacity. Due to cross-linguistic features, we also discovered some interesting findings that differed from previous studies. Lastly, we found processing speed was fairly intact in children with CIs, which is a new finding. PMID- 28863085 TI - Early chemoprophylaxis is associated with decreased venous thromboembolism risk without concomitant increase in intraspinal hematoma expansion after traumatic spinal cord injury. AB - BACKGROUND: After traumatic spinal cord injury (SCI), there is increased risk of venous thromboembolism (VTE), but chemoprophylaxis (PPX) may cause expansion of intraspinal hematoma (ISH). METHODS: Single-center retrospective study of adult trauma patients from 2012 to 2015 with SCI. EXCLUSION CRITERIA: VTE diagnosis, death, or discharge within 48 hours. Patients were dichotomized based on early (<=48 hours) heparinoid and/or aspirin PPX. Intraspinal hematoma expansion was diagnosed intraoperatively or by follow-up radiology. We used multivariable Cox proportional hazards to estimate the effect of PPX on risk of VTE and ISH expansion controlling for age, injury severity score (ISS), complete SCI, and mechanism as static covariates and operative spine procedure as a time-varying covariate. RESULTS: Five hundred one patients with SCI were dichotomized into early PPX (n = 260 [52%]) and no early PPX (n = 241 [48%]). Early PPX patients were less likely blunt injured (91% vs 97%) and had fewer operative spine interventions (65% vs 80%), but age (median, 43 vs 49 years), ISS (median 24 vs 21), admission ISH (47% vs 44%), and VTE (5% vs 9%) were similar. Cox analysis found that early heparinoids was associated with reduced VTE (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16-0.84) and reduced pulmonary embolism (PE) (HR, 0.20; 95% CI, 0.06-0.69). The estimated number needed to treat with heparinoids was 10 to prevent one VTE and 13 to prevent one PE at 30 days. Early aspirin was not associated with reduced VTE or PE. Seven patients (1%) had ISH expansion, of which four were on PPX at the time of expansion. Using heparinoid and aspirin as time-varying covariates, neither heparinoids (HR, 1.90; 95% CI, 0.32-11.41) nor aspirin (HR, 3.67; 95% CI, 0.64-20.88) was associated with ISH expansion. CONCLUSION: Early heparinoid therapy was associated with decreased VTE and PE risk in SCI patients without concomitant increase in ISH expansion. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 28863087 TI - Framework of care: communicating the structure and processes of care. AB - AIM: This article attempts to present a 'macro view' of the role and nature of an organization's Framework of Care (FrOC). This 'view' arises from a critical reflection on the available literature and the combined professional experience of the authors, who have worked in a variety of healthcare systems and settings in Australia, North America, United Kingdom, and the Middle East. BACKGROUND: FrOC can be defined as the systems and processes within an organization that structure the delivery of care. These systems and processes are made evident in a series of documents, such as the Mission and Vision statement, Policies and Procedures, Standards of Care, Clinical Practice Guidelines, Clinical Pathways, and Protocols. These frameworks can provide structure for important organizational activities such as clinical audits, quality management and clinical information system (CIS) 'decision support', thereby supporting clinicians in their efforts to deliver high-quality, evidence-based care. How a healthcare organization structures its systems and processes of care directly impacts the patient and caregiver experience - made evident in patient and staff satisfaction with the services provided. RECOMMENDATIONS: Mapping out and understanding an organization's FrOC is a critical first step for interprofessional teams attempting to implement evidence into practice and/or accreditation teams and expert consultants critiquing the performance of an organization. PMID- 28863088 TI - Early Death From Pediatric Severe Sepsis: Still a Problem and a Mandate for Future Clinical Research. PMID- 28863089 TI - Dexmedetomidine in the PICU: Can We Get More for Less? PMID- 28863090 TI - Acute Respiratory Compromise Leading to Cardiac Arrest. PMID- 28863091 TI - Pushing the ECMO Envelope for Children With Genetic Conditions. PMID- 28863092 TI - Mothers' Milk-Can We Improve the Neonatal Immunity Response With the Oldest Recipe in the Mammal's Cookbook? PMID- 28863093 TI - Does Birth at Early-Term Gestation Increase Mortality for Neonates on Extracorporeal Life Support After Cardiac Surgery? PMID- 28863094 TI - Augmented Renal Clearance in Critically Ill Pediatric Patients: Does It Impact the Outcome of Pharmacotherapy? PMID- 28863095 TI - How Can We Optimize Antibiotic Use in the PICU? PMID- 28863096 TI - Thomas Jefferson, Steroids, and Sepsis. PMID- 28863097 TI - Caring for Long Length of Stay Patients in the Neonatal ICU and PICU: How Do We Ensure Coherent Decisions When the Physicians Are Continuously Rotating? PMID- 28863098 TI - Nebulized Fluticasone for Preventing Postextubation Stridor-Is It Really Effective? PMID- 28863099 TI - The authors reply. PMID- 28863100 TI - High-Flow Nasal Cannula Weaning Protocol: Is It Relevant? PMID- 28863101 TI - The authors reply. PMID- 28863102 TI - The Silk Road to Modern Times: An Exchange of Education, Culture, and Knowledge for the Best Patient Quality of Life. PMID- 28863103 TI - The Excellence of Graduate Medical Education in China: the New Door to Open for the Future of Young Surgeons. PMID- 28863104 TI - Meet Dr Kilner at the Hunterian Museum. PMID- 28863105 TI - The Current Challenge For Plastic and Reconstructive Surgery In China, The Biggest Developing Country. PMID- 28863106 TI - Decompressive Craniectomy With Bifrontal Coronal Incision in the Management of Fronto-Temporal Contusion and Laceration for Early Cranioplasty. AB - The present study aims to explore the effectiveness of decompressive craniectomy with bifrontal coronal incision in the management of severe contusion and laceration of bilateral fronto-temporal lobes, as well as the outcomes of early cranioplasty. The authors performed the bifrontal decompressive craniectomy on 56 patients with contusion and laceration of bilateral frontal and temporal lobes, and their follow-up treatment outcomes were tracked within 6 months using Glasgow Outcome Scale. The results showed that 33 patients (out of 56, 58.9%) have recovered, 12 patients (out of 56, 21.4%) have moderate defects, 5 patients (out of 56, 8.9%) have severe defects, 3 patients (out of 56, 5.3%) stayed in persistent vegetative status, and the remaining 3 patients (out of 56, 5.3%) have been dead. There was no persistent temporal hollowing. No patients required revision surgery with modified titanium mesh in this study. Particularly, 28 patients have successfully accepted the early cranioplasty with bone flap or computer-assisted design titanium mesh, and showed good recovery. These results together indicated that the decompressive craniectomy with bifrontal coronal incision in the management of severe contusion and laceration of bilateral fronto temporal lobes can significantly relieve the comorbidity of intracranial hypertension, and improve the prognosis obviously, thus finally increasing the probability of successful rescue and decreasing the probability of mortality and disability. PMID- 28863107 TI - Surgical Approach to Foreign Material Within the Mandibular Canal Due to Iatrogenic Factors. AB - This clinical report describes a relatively infrequent patient with inferior alveolar nerve damage caused by foreign material within the mandibular canal, which is one of the most severe complications of endodontic therapy. Although the circumstance is uncommon, it can have extremely unfavorable consequences for patients, such as anesthesia and paresthesia. In the present case, a patient suffered pain and severe paresthesia in the corresponding area after routine endodontic therapy. Several treatments were conducted to relieve the patient's symptoms, ranging from medication to tooth extraction, but all were of no avail. Ultimately, surgical exploration and debridement were performed with assistance of a customized surgical template. Once the foreign material was excavated, the exacerbation of condition was terminated and gradually reverted. This patient illustrates that special attention is required when undertaking intracanal procedures of lower posterior teeth so as to avoid iatrogenic damage to inferior alveolar nerve. Even more significant, when above-mentioned condition occurs, prompt surgical intervention is essential for recovery of sensation. It also demonstrates the advantages of applying surgical template and piezosurgery in removal of foreign material within the mandibular canal. PMID- 28863108 TI - Application of Computer-Aided Design and Customized Implants in the Reconstruction of Pyriform Aperture Defects Secondary to Unilateral Cleft Lip and Palate. AB - PURPOSE: To design and develop customized implants with the rapid prototyping (RP) technique in order to reconstruct the defected pyriform aperture. METHODS: A 3-dimensional digital model was reconstructed with the software proplan CMF based on the computed tomography data of the patient's skeleton. Then an individualized implant was designed by computer-aided design (CAD) and prepared with the RP technique. A total of 5 patients (3 males and 2 females) with unilateral secondary nasal deformities received the customized implants in this study. RESULTS: All the implants closely matched the surface of the defects. During the 12- to 24-month follow-up period, all the patients reported satisfactory outcomes except for 1 patient where exposure of the implant was observed and had to be removed 3 months after the surgery. CONCLUSION: With high precision and matching degree, individualized implants designed by CAD and prepared with the RP technique can be used to overcome the limitations of ready-made materials and improve the accuracy of the surgical procedure in reconstructing the defected pyriform aperture. PMID- 28863109 TI - Surgical Landmark of Mandible Angle in the Identification of Cervical Spinal Level. AB - Mandible angle is considered to be a consistently palpable external landmark for the identification of cervical spinal level by a radiographic study. But this anatomical study aimed to determine the positional relationship between mandible angle and cervical spinal level in cadavers. In this study, the cervical spine of 10 adult cadavers with intact head and neck structure, including 6 males and 4 females, was dissected, and the position of mandible angle (MA) relative to the corresponding cervical spinal level was measured when the head was fixed in the flexion, anatomy position, and extension. The difference between the genders and the sides was analyzed. On the basis of the study of the corpse samples, the reference level of cervical spine was approximated to C2/3 intervertebral disc. The result has confirmed MA as a consistent and convenient landmark in the identification of cervical spinal level. Given some external landmarks do not consistently correspond to the exact level of the cervical spine, MA provides the relatively consistent reference point: C2/3 intervertebral disc. The authors hold that MA is a superior external landmark, which can help surgeons to localize the skin incision before anterior cervical spine surgery. PMID- 28863110 TI - Relative Location of Fundus Meatus Acustici Interni Via Porus Acusticus Internus in Facial Nerve Decompression. AB - Facial neural edema is the pathophysiological base of Bell's palsy. The middle cranial fossa approach is used to relieve the oppression of facial nerve at its most narrow course in the facial canal. In this research, the authors mainly discussed the internal auditory canal segment of facial nerve, completely in the shadow of the bony structure, which is inconvenient for transmastoid decompression. Therefore, the objective was to explore the definite position of the fundus meatus acustici interni from internal acoustic pore. Two hundred persons (age 22-60, 100 men and 100 women), presenting with healthy facial nerve, ear, and internal auditory canal, were investigated by computed tomography 3 dimensional reconstruction. Using statistical method to analyze, the authors obtained the definite position of the fundus meatus acustici interni, regarding the internal acoustic pore as the origin of coordinates. Our data provided more significant information for medical workers to improve the efficiency of operation and to prevent complications of surgery. PMID- 28863111 TI - The Endoscopic Prelacrimal Recess Approach to the Pterygopalatine Fossa and Infratemporal Fossa. AB - PURPOSE: The authors studied the anatomic importance of the endoscopic prelacrimal recess approach (PLRA) to the pterygopalatine fossa (PPF) and infratemporal fossa (ITF). METHODS: Ten adult heads (20 sides) from cadavers fixed in formalin were dissected using the PLRA. Anatomic dissections were detailed and several crucial landmarks measured. RESULTS: Identification of the infraorbital neurovascular bundle is the crucial step for the detection of other branches of the maxillary artery. The distance from the base of columella to inferior orifice of the nasolacrimal duct, sphenopalatine foramen, pterygold canal, foramen rotundum, foramen ovale was (32.97 +/- 3.44), (63.93 +/- 4.52), (66.81 +/- 3.44), (68.13 +/- 4.43), and (85.23 +/- 6.25) mm, respectively. The PLRA can be used to expose the entire maxillary sinus and PPF, most parts of the ITF (lateral pterygoid muscle, foramen ovale, mandibular division of the trigeminal nerve, and its divisions), maxillary artery and its branches, and the superior part of the medial pterygoid muscle (upon the floor of the maxillary sinus). The lateral boundary can be reached to visualize the temporomandibular joint and vertically oriented temporalis muscle. CONCLUSION: Use of the PLRA to the PPF and ITF offers a clear visual field, wide range of exposure, as well as preservation of the integrity of nasal structures. PMID- 28863112 TI - Disruption of Hedgehog Signaling by Vismodegib Leads to Cleft Palate and Delayed Osteogenesis in Experimental Design. AB - The function of hedgehog signaling has previously been shown to be crucial for craniofacial development. In this study, we treated C57/BL6J mice with the hedgehog pathway inhibitor vismodegib by oral gavage to establish a stable vismodegib-induced cleft palate model. At E10.5 and E12.5, mice in the experimental group were treated with 100 mg/kg of vismodegib, whereas mice in the control group were treated with solvent. The treated pregnant mice were sacrificed on E13.5, E14.5, E15.5, and E16.5. Palatal shelf growth was evaluated via histological and immunohistochemical analyses as well as palatal organ culture. Immunohistochemical staining was performed to examine the expression of osteogenic proteins in the palatal tissue. A high proportion of the mice administered 2 doses of 100 mg/kg of vismodegib displayed a cleft palate. Histologic examination revealed severely retarded palatal shelf growth and thickened epithelium in the experimental group. Vismodegib exposure induced complete cleft palate, which was attributed to a reduced cell proliferation rate in the palatal mesenchyme along the anterior-posterior axis. Moreover, this model also showed delayed ossification in the region of palatine bone with downregulation of Indian hedgehog (Ihh) protein. Our results suggest that vismodegib can be used to inhibit hedgehog signaling to affect palatal morphogenesis. Under treatment with this exogenous inhibitor, the cell proliferation rate of the palatal shelves and the osteogenic potential of the hard palate were decreased, which likely contributed to the complete cleft palate. PMID- 28863113 TI - The Distribution of Transplanted Umbilical Cord Mesenchymal Stem Cells in Large Blood Vessel of Experimental Design With Traumatic Brain Injury. AB - The authors aim to track the distribution of human umbilical cord mesenchymal stem cells (MSCs) in large blood vessel of traumatic brain injury -rats through immunohistochemical method and small animal imaging system. After green fluorescent protein (GFP) gene was transfected into 293T cell, virus was packaged and MSCs were transfected. Mesenchymal stem cells containing GFP were transplanted into brain ventricle of rats when the infection rate reaches 95%. The immunohistochemical and small animal imaging system was used to detect the distribution of MSCs in large blood vessels of rats. Mesenchymal stem cells could be observed in large vessels with positive GFP expression 10 days after transplantation, while control groups (normal group and traumatic brain injury group) have negative GFP expression. The vascular endothelial growth factor in transplantation group was higher than that in control groups. The in vivo imaging showed obvious distribution of MSCs in the blood vessels of rats, while no MSCs could be seen in control groups. The intravascular migration and homing of MSCs could be seen in rats received MSCs transplantation, and new angiogenesis could be seen in MSCs-transplanted blood vessels. PMID- 28863115 TI - Treatment of Posterior Inferior Cerebellar Artery Adhesion on Petrous Bone During Microvascular Decompression Procedure for Hemifacial Spasm: Technique Note. AB - Hemifacial spasm is a hyperactive cranial nerve disease mainly characterized by unilateral facial muscles paroxysmal, involuntary, irregular and clonic convulsion. Standard microvascular decompression is currently the most effective solution. During operation, it is pivotal to conduct a sharp dissection of arachnoid membrane around the caudal cranial nerves and facial, auditory nerves for fully exposure of pontomedullary sulcus, and lateral pontine region. In this article, the authors demonstrate a hemifacial spasm patient who underwent microvascular decompression successfully in their department. But the authors encountered a serious barrier to the exploration of facial nerve and its offending vessels before decompression and found that posterior inferior cerebellar artery tightly adhered to petrous bone and closely attached to a petrosal vein on cerebellar surface at the same time. The petrosal vein was also seriously stuck to petrous bone. To solve this practical difficulty, the authors employed sharp point knife blade and microsurgical scissors boldly to separate posterior inferior cerebellar artery from the dura mater of petrous bone bidirectionally and bipolar coagulation for effective hemostasis. And then the authors moderately dealt with the surface adhesion of cerebellum for smooth exploration instead of processing the petrosal vein attached to petrous bone because the authors did not want to sacrifice this vein. Relative to the routine microvascular decompression for hemifacial spasm, treatments of the adhensions before decompression were the key technology of this operation. PMID- 28863116 TI - An Aesthetic Orbicularis Oculi Myectomy Technique for Blepharospasm: Use of Topical 5-Fluorouracil and Fibrin Sealant. AB - PURPOSE: To describe a modified technique of orbicularis oculi myectomy for refractory blepharospasm. This technique includes removal of orbicularis muscle, reformation of the eyelid crease and pretarsal platform using fibrin sealant (Tisseel), and topical 5-fluorouracil to reduce scar formation and improve aesthetic outcome. METHODS: Retrospective chart review of 7 patients who underwent bilateral orbicularis oculi myectomy with our technique from 2013 to 2016. Outcome measures were postoperative botulinum toxin dose, frequency, duration between treatments, the amount of lagophthalmos, severity of dry eye, and patient satisfaction with aesthetic and functional outcome. RESULTS: Patients who underwent the aesthetic myectomy technique had significantly decreased botulinum toxin use with relief of symptoms postoperatively. Only 1 of 7 patients experienced mild dry eye symptoms postoperatively, managed with artificial tears. All patients were satisfied with the aesthetic and functional outcome. CONCLUSIONS: The aesthetic myectomy technique provides effective treatment for blepharospasm with good functional and aesthetic outcome. PMID- 28863117 TI - Rituximab Monotherapy Is Effective in Treating Orbital Necrobiotic Xanthogranuloma. AB - The authors report a case of a patient with bilateral orbital necrobiotic xanthogranuloma and no associated systemic paraproteinemia. Orbital biopsy showed strong expression of CD20-positive cells. The patient was treated with systemic rituximab monotherapy, with excellent clinical response and marked regression of the orbital lesions on imaging. At the time of writing, the patient has been treated with bimonthly rituximab maintenance therapy for 22 months and has stable clinical and imaging findings with sustained response to treatment and no reported side effects. To the authors' knowledge, this is the first reported case of orbital necrobiotic xanthogranuloma successfully treated with rituximab monotherapy. They hope that this well-documented case will encourage clinicians to consider rituximab monotherapy as a possible treatment option, albeit one entailing an off-label use of this drug, for patients with necrobiotic xanthogranuloma of the orbit. PMID- 28863118 TI - Peri-Punctal Lymphangioma Treated With Bleomycin. PMID- 28863119 TI - Effect of Optic Nerve Disinsertion During Evisceration on Nonporous Implant Migration: A Comparative Case Series and a Review of Literature. AB - AIM: To determine whether evisceration with optic nerve disinsertion and nonporous implant placement increases the risk of implant migration. METHODS: This was a single-center, retrospective consecutive comparative interventional case series including patients undergoing evisceration with nonporous implant between January and December 2014. Patients were grouped into 2 groups: group I where the optic nerve was not disinserted (n = 37) and group II with optic nerve disinsertion (n = 50). Implant migration was assessed clinically and on patient photographs. Migration was subclassified as decentration that did not affect the prosthetic outcome and displacement that affected the prosthetic outcome. The secondary outcome measures were the mean implant diameter, volume of the custom ocular prosthesis, and implant-related complications like exposure and extrusion between the 2 groups. RESULTS: At a mean follow up of 12.5 months, none of the sockets in group I and 3 (6%) sockets in group II (p = 0.35) had evidence of implant decentration. There were no cases of implant displacement in both groups. The mean implant diameter in group I was 16.97 mm +/- 0.65 mm and in group II 19.2 mm +/- 0.83 mm (p = 0.0001). Implant extrusion was not different between the 2 groups. The mean custom ocular prosthesis volume in group I was 3.86 ml +/- 0.52 ml and in group II 2.50 ml +/- 0.68 ml (p < 0.0001). CONCLUSIONS: The rate of nonporous implant migration due to optic nerve disinsertion is not statistically or clinically significant in evisceration with optic nerve disinsertion, allowing placement of a larger implant and fabrication of a custom ocular prosthesis with an ideal weight. PMID- 28863120 TI - Assessing the Accuracy of Eyelid Measurements Utilizing the Volk Eye Check System and Clinical Measurements. AB - PURPOSE: The purpose of this study was to validate the accuracy of marginal reflex distance 1 (MRD1) measurements obtained by the Volk Eye Check system, a modified smartphone that measures MRD1 automatically, relative to clinical and digital measurements. METHODS: In this prospective observational study of adults with normal eyelids and ptosis, MRD1 was measured clinically, digitally, and automatically with the Volk device. Eyes were divided into successful versus unsuccessful Volk trial groups; successful eyes were then subdivided into control and ptosis subgroups. The primary outcome measures were mean MRD1 obtained by the 3 modalities. Secondary outcome measures included the success rate of the device and the prevalence of ptosis within the successful and unsuccessful groups. RESULTS: In the overall sample of 88 eyes, clinical and digital MRD1 were not significantly different. Among eyes with successful Volk trials, significant differences in MRD1 measured by the 3 modalities were as follows: in the successful group, Volk MRD1 (3.05 mm) was significantly (p < 0.01) higher than digital MRD1 (2.68 mm); in the ptosis subgroup, Volk MRD1 (2.47 mm) was significantly higher than clinical (2.05 mm; p < 0.05) and digital MRD1 (1.91 mm; p < 0.01). Eyes in the successful group (66% of attempted collections) demonstrated significantly higher MRD1 (mean difference, 1.21 mm; p < 0.01) and were significantly less likely to demonstrate ptosis (2.7*; p < 0.05) than those in the unsuccessful group. CONCLUSIONS: The Volk device measures MRD1 well in normal patients but overestimates MRD1 in patients with ptosis. It may be most appropriate in assessing patients with normal or elevated eyelid position. Clinical and digital MRD1 measurements were not different than each other. PMID- 28863121 TI - Haberland Syndrome Associated With Calvarial Exostosis. PMID- 28863122 TI - A novel molecular agent for glioma angiogenesis imaging. AB - BACKGROUND: Gliomas are rich in blood vessels and are the most primary and malignant type of brain tumor affecting the central nervous system. A few fluorine-18 (F)-labeled imaging agents can be used for imaging of tumor angiogenesis. In the current study, F-labeled recombinant human endostatin (rh endostatin) was developed and evaluated as a probe for PET imaging of tumor angiogenesis. MATERIALS AND METHODS: F-fluorobenzoyl-endostatin (F-FB-endostatin) was synthesized from radiolabeling of rh-endostatin with N-succinimidyl-4-F fluorobenzoate produced by a facile module-assisted radiosynthesis procedure. Blocking studies were used to measure the relative affinities of F-FB-endostatin to human glioblastoma U87MG cells in tumor tissues rich with vessels. In addition, biodistribution, metabolic stability, and small-animal PET imaging studies were carried out with F-FB-endostatin using Institute of Cancer Research and U87MG tumor-bearing mice. RESULTS: Noninvasive small-animal PET imaging indicated that F-FB-endostatin showed rapid and good tumor uptake. The probe was rapidly cleared from the blood and most organs, resulting in excellent tumor-to normal tissue contrasts. Tumor uptake and rapid clearance were further confirmed with biodistribution studies. Metabolite assays showed that the probe was highly stable, making it suitable for in-vivo applications. CONCLUSION: F-FB-endostatin shows promising in-vivo properties. Therefore, the promising properties of F-FB endostatin indicate that this probe can be a powerful tool to evaluate the antiangiogenic therapy for gliomas and thus warrants further investigation as a novel PET probe for imaging of tumor angiogenesis. PMID- 28863123 TI - Orbital flourine-18-fluorodeoxyglucose positron emission tomography in patients with Graves' disease for evaluation of active inflammation. AB - OBJECTIVE: Prediction and early diagnosis of orbitopathy is needed in patients with Graves' disease, especially when radioiodine therapy is planned. Positron emission tomography/computerized tomography (PET/CT) using flourine-18 fluorodeoxyglucose (FDG) is an effective imaging modality in detection of inflammation, however, its ability to detect orbital inflammation has not been well studied. The aim of our study is to determine the ability of FDG PET/CT to detect orbital inflammation related with Graves' disease, identify active orbitopathy, predict the radioiodine-triggered orbitopathy, and find out the effects of radioiodine on orbital inflammation. MATERIALS AND METHODS: Total 31 Graves' disease patients and 17 controls were included. All Graves' disease patients underwent cranial FDG PET/CT imaging prior therapy. Radioiodine therapy and post-treatment PET/CT study was applied to 21 patients. PET/CT images of all examinees were evaluated, measuring extraocular muscle maximum standard uptake value (SUVmax) and muscle thickness. RESULTS: FDG uptake was increased in the majority of extraocular muscles in Graves' disease patients in comparison to controls and this increase was found to be irrelevant from muscle thickness. Extraocular muscle SUVmax values did not increase in Graves' orbitopathy patients who received radioiodine under corticosteroid prophylaxis. SUVmax level of all orbital rectus muscles were increased after radioiodine therapy in nonsmokers, whereas no increase was detected in smokers. CONCLUSION: FDG PET/CT may be helpful in detection of extraocular muscle inflammation and it may show ongoing orbitopathy in early stages of inflammation before anatomical changes occur. PMID- 28863124 TI - Quantification and reduction of respiratory induced artifacts in positron emission tomography/computed tomography using the time-of-flight technique. AB - OBJECTIVE: The aim of this study was to investigate the impact of time-of-flight (TOF) on quantification and reduction of respiratory artifacts. PATIENTS AND METHODS: The National Electrical Manufacturers Association phantom was used for optimization of reconstruction parameters. Twenty seven patients with lesions located in the diaphragmatic region were evaluated. The PET images were retrospectively reconstructed using non-TOF (routine protocol in our department) and TOF algorithms with different reconstruction parameters. Maximum standardized uptake value, estimated maximum tumor diameter, coefficient of variation, signal to-noise ratio, and lesion-to-background-ratio were also evaluated. RESULTS: On the basis of phantom experiments, TOF algorithms with two iterations, 18 subsets, and 5.4 mm and 6.4 mm postsmoothing filter reduced the noise by 3.1 and 12.6% in phantom with 2 : 1 activity ratio, and 3.0 and 13.1% in phantom with 4 : 1 activity ratio. The TOF algorithm with two iterations, 18 subsets, and 6.4 mm postsmoothing filter had the highest signal-to-noise value, and was selected as the optimal TOF reconstruction. Mean relative difference for signal-to-noise between non-TOF and optimal TOF in phantom with 2 : 1 and 4 : 1 activity ratio were 11.6 and 18.7%, respectively. In clinical data, the mean relative difference for estimated maximum tumor diameter and maximum standardized uptake value between routine protocol and optimal TOF algorithm were -6.3% (range: -20.4 to 0.6%) and 13.2% (range: 0.3-57.6%), respectively. CONCLUSION: Integration of TOF in reconstruction algorithm remarkably improved the white band artifact in the diaphragmatic region. This technique affected the quantification accuracy and resulted in smaller tumor size and higher standardized uptake value in tumors located in/near the diaphragmatic region. PMID- 28863125 TI - Ethical Considerations on Disclosure When Medical Error Is Discovered During Medicolegal Death Investigation. AB - In the course of fulfilling their statutory role, physicians performing medicolegal investigations may recognize clinical colleagues' medical errors. If the error is found to have led directly to the patient's death (missed diagnosis or incorrect diagnosis, for example), then the forensic pathologist has a professional responsibility to include the information in the autopsy report and make sure that the family is appropriately informed. When the error is significant but did not lead directly to the patient's demise, ethical questions may arise regarding the obligations of the medical examiner to disclose the error to the clinicians or to the family. This case depicts the discovery of medical error likely unrelated to the cause of death and describes one possible ethical approach to disclosure derived from an ethical reasoning model addressing ethical principles of respect for persons/autonomy, beneficence, nonmaleficence, and justice. PMID- 28863126 TI - A Histological Analysis of Visceral Organs to Evaluate the Effect of Duration of Heating From Refrigeration to Core Body Temperature for Ballistics Investigations. AB - Animal organs have been used in ballistics research to investigate the effects on human organs. Such organs are refrigerated until the investigation to minimize autolytic degradation and at times have been reheated to the human core body temperature to simulate the in situ environment. The aim of this investigation was to study the microstructural changes that may occur in fresh chilled visceral organs of the thorax and abdomen (ie, heart, lung, liver, and kidney) during the period of reheating to 37 degrees C. Fifty-millimeter cubes of porcine heart, lung, liver, and kidney were taken rapidly after slaughter, chilled overnight, and the next morning were reheated to core body temperature (37 degrees C). Histological changes occurring in the tissues during the reheating phase were investigated. The findings indicated that no cytoplasmic or nuclear changes occurred in any of the tissues during the period of reheating. Therefore, reheating of animal organs to the human core body temperature is not necessary, if the organs are refrigerated. PMID- 28863127 TI - Analysis of Tractor-Associated Fatalities. AB - INTRODUCTION AND OBJECTIVE: Tractor is regarded as a key equipment in agriculture, and it is also used for transportation and transfer purposes in addition to its agricultural use. Accidents resulting in death in farmlands are frequently encountered. Tractor-related fatalities are the most common ones among the deaths after farm accidents. This study aimed to evaluate the characteristics of tractor-related deaths and to discuss the measures that could be taken to prevent these deaths. METHODS: In this study, 42 cases who underwent postmortem examination and/or autopsy because of tractor fatalities in the province of Elazig between January 2005 and December 2016 were examined retrospectively with such variables as sex, age, month and season of incident, cause of incident, location of incident, position of case, and injured region. RESULTS: Of the cases, 36 (85.7%) were male, and 6 (14.3%) were female. The youngest case was 2 years old, and the oldest case was 83 years old; the mean age was 43.3 +/- 25.0 years. Examining the deaths regarding the cause of incident showed that tractor rollover was the most common cause (42.9%). This was followed by being run over by the tractor (19.0%). Of the cases, 24 (57.1%) were drivers, 10 (23.8%) were passengers, and 8 (19.0%) were pedestrians. CONCLUSIONS: Tractor-related fatalities due to tractor rollover are most often seen. To reduce the deaths caused by this reason, drivers should have special training and technical support, use helmets and seatbelts in the tractor, and have a health check at certain intervals (especially the drivers at advanced age). PMID- 28863128 TI - Effects of epsilon-Polylysine on Pseudomonas Aeruginosa and Aspergillus Fumigatus Biofilm In Vitro. AB - BACKGROUND The antimicrobial mechanisms of epsilon-polylysine (EPL) against Pseudomonas aeruginosa and Aspergillus fumigatus biofilm were investigated. MATERIAL AND METHODS We assessed the changes in electric conductivity of broth and total sugar concentration, as well as changes in phosphorous metabolism and protein expression, of the 2 organisms before and after treatment with EPL. RESULTS The experimental results showed that EPL has antimicrobial activity against Pseudomonas aeruginosa and Aspergillus fumigatus, but the activity was much stronger for the former. After treatment with EPL, the electric conductivity and total sugar concentration of microbial broth increased, suggesting that EPL damages the cell membrane structure, which increases permeability of the cell membrane and release of cell components. CONCLUSIONS The consumption of phosphorous decreased in the EPL-treated organisms, which seriously affected the synthesis of important cell components such as nucleic acid and phospholipid, as well as energy metabolism. PMID- 28863129 TI - Insulin-like growth factor type 1 and its relation with neuropsychiatric disorders. AB - The study of different neurotrophic factors, including insulin-like growth factor 1 (IGF-1), has become relevant in recent years because of its role in brain activity and its potential therapeutic applications. This article reviews IGF-1 in relation to neuropsychiatric disorders such as autism, anxiety, depression, post-traumatic stress disorder and Alzheimer's disease. An exhaustive search of different original articles, clinical, experimental, and review studies was carried out in MEDLINE/PubMed and ScienceDirect databases, selecting 80 high impact post-2000 publications. It is concluded that despite the many functions of IGF-1 in the developing nervous system as well as in the adult brain that have been studied, especially with animal models, their role in the human brain with neuropsychiatric disorders is not completely understood, yielding contradictory data in highly prevalent disorders such as mood disorders. However, greater implications are encountered with neurodegenerative disorders. In addition, its high potential as a therapeutic resource in difficult-to-approach neuropsychiatric disorders, such as autism and Alzheimer's disease, is pointed out, but more research is needed at both basic and clinical levels, to fully understand its relevance in these disorders. PMID- 28863130 TI - Is device-modified trabeculectomy better than classic surgery for treatment of glaucoma? AB - Several techniques have emerged as complement or replacement for trabeculectomy, the standard surgery for glaucoma. Device-modified trabeculectomy is a recently developed technique whose results compared to the classical technique have not been fully defined. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified eight systematic reviews including 34 studies overall. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded device-modified trabeculectomy probably leads to greater overall success rate and may decrease intraocular pressure more than classical surgery. In addition, this technique would probably have a better safety profile than standard trabeculectomy. PMID- 28863131 TI - Do textured breast implants decrease the rate of capsular contracture compared to smooth implants? AB - The use of breast implants for aesthetic and reconstructive purposes has become one of the most common procedures performed by plastic surgeons. Several breast implants models exist. They differ in their size, filling, shape and characteristic of the shell, which can be smooth or textured. Capsular contracture is one of the main complications of breast implants. It has been suggested that the use of textured implants could reduce the incidence of capsular contracture. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified 15 studies overall, of which 13 were randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded the use of textured breast implants probably decreases the risk of capsular contracture, however, they might be associated to an increased risk of anaplastic large cell lymphoma. PMID- 28863133 TI - Spatial distribution and risk factors of Schistosoma haematobium and hookworm infections among schoolchildren in Kwale, Kenya. AB - BACKGROUND: Large-scale schistosomiasis control programs are implemented in regions with diverse social and economic environments. A key epidemiological feature of schistosomiasis is its small-scale heterogeneity. Locally profiling disease dynamics including risk factors associated with its transmission is essential for designing appropriate control programs. To determine spatial distribution of schistosomiasis and its drivers, we examined schoolchildren in Kwale, Kenya. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional study of 368 schoolchildren from six primary schools. Soil-transmitted helminths and Schistosoma mansoni eggs in stool were evaluated by the Kato-Katz method. We measured the intensity of Schistosoma haematobium infection by urine filtration. The geometrical mean intensity of S. haematobium was 3.1 eggs/10 ml urine (school range, 1.4-9.2). The hookworm geometric mean intensity was 3.2 eggs/g feces (school range, 0-17.4). Heterogeneity in the intensity of S. haematobium and hookworm infections was evident in the study area. To identify factors associated with the intensity of helminth infections, we utilized negative binomial generalized linear mixed models. The intensity of S. haematobium infection was associated with religion and socioeconomic status (SES), while that of hookworm infection was related to SES, sex, distance to river and history of anthelmintic treatment. CONCLUSIONS/SIGNIFICANCE: Both S. haematobium and hookworm infections showed micro-geographical heterogeneities in this Kwale community. To confirm and explain our observation of high S. haematobium risk among Muslims, further extensive investigations are necessary. The observed small scale clustering of the S. haematobium and hookworm infections might imply less uniform strategies even at finer scale for efficient utilization of limited resources. PMID- 28863132 TI - A novel rapid and reproducible flow cytometric method for optimization of transfection efficiency in cells. AB - Transfection is one of the most frequently used techniques in molecular biology that is also applicable for gene therapy studies in humans. One of the biggest challenges to investigate the protein function and interaction in gene therapy studies is to have reliable monospecific detection reagents, particularly antibodies, for all human gene products. Thus, a reliable method that can optimize transfection efficiency based on not only expression of the target protein of interest but also the uptake of the nucleic acid plasmid, can be an important tool in molecular biology. Here, we present a simple, rapid and robust flow cytometric method that can be used as a tool to optimize transfection efficiency at the single cell level while overcoming limitations of prior established methods that quantify transfection efficiency. By using optimized ratios of transfection reagent and a nucleic acid (DNA or RNA) vector directly labeled with a fluorochrome, this method can be used as a tool to simultaneously quantify cellular toxicity of different transfection reagents, the amount of nucleic acid plasmid that cells have taken up during transfection as well as the amount of the encoded expressed protein. Finally, we demonstrate that this method is reproducible, can be standardized and can reliably and rapidly quantify transfection efficiency, reducing assay costs and increasing throughput while increasing data robustness. PMID- 28863135 TI - Correction: TDRD6 mediates early steps of spliceosome maturation in primary spermatocytes. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006660.]. PMID- 28863134 TI - Invasive lobular carcinoma of the breast: A special histological type compared with invasive ductal carcinoma. AB - The clinical outcomes and therapeutic strategies for infiltrating ductal carcinoma (IDC) and infiltrating lobular carcinoma (ILC) are not uniform. The primary objectives of this study were to identify the differences in the clinical characteristics and prognoses between ILC and IDC, and identify the high-risk population based on the hormone receptor status and metastasis sites. The Surveillance, Epidemiology, and End Results Program database was searched and patients diagnosed with ILC or IDC from 1990 to 2013 were identified. In total,796,335 patients were analyzed, including 85,048 withILC (10.7%) and 711,287 withIDC (89.3%). The ILC group was correlatedwith older age, larger tumor size, later stage, lower grade, metastasis disease(M1) disease, and greater counts ofpositive lymph nodesandestrogen-receptor-positive (ER)/progesterone receptor-positive (PR) positive nodes. The overall survival showed an early advantage for ILC but a worse outcome after 5 years. Regarding the disease specific survival, the IDC cohort had advantages over the ILC group, both during the early years and long-term. In hormone status and metastasis site subgroup analyses, the ER+/PR+ subgroup had the best survival, while the ER+/PR- subgroup had the worst outcome, especially the ILC cohort. ILC and IDC had different metastasis patterns. The proportion of bone metastasis was higher in the ILC group (91.52%) than that in the IDC (76.04%), and the ILC group was more likely to have multiple metastasis sites. Survival analyses showed patients with ILC had a higher risk of liver metastasis (disease-specific survival[DSS]; P = 0.046), but had a better overall survival than the bone metastasis group (P<0.0001). We concluded that the long-term prognosis for ILC was poorer than that for IDC, and the ER+/PR- subgroup had the worst outcome. Therefore, the metastasis pattern and prognosis must be seriously evaluated, and a combination of endocrine therapy and chemotherapy should be considered. PMID- 28863136 TI - Differential receptive field organizations give rise to nearly identical neural correlations across three parallel sensory maps in weakly electric fish. AB - Understanding how neural populations encode sensory information thereby leading to perception and behavior (i.e., the neural code) remains an important problem in neuroscience. When investigating the neural code, one must take into account the fact that neural activities are not independent but are actually correlated with one another. Such correlations are seen ubiquitously and have a strong impact on neural coding. Here we investigated how differences in the antagonistic center-surround receptive field (RF) organization across three parallel sensory maps influence correlations between the activities of electrosensory pyramidal neurons. Using a model based on known anatomical differences in receptive field center size and overlap, we initially predicted large differences in correlated activity across the maps. However, in vivo electrophysiological recordings showed that, contrary to modeling predictions, electrosensory pyramidal neurons across all three segments displayed nearly identical correlations. To explain this surprising result, we incorporated the effects of RF surround in our model. By systematically varying both the RF surround gain and size relative to that of the RF center, we found that multiple RF structures gave rise to similar levels of correlation. In particular, incorporating known physiological differences in RF structure between the three maps in our model gave rise to similar levels of correlation. Our results show that RF center overlap alone does not determine correlations which has important implications for understanding how RF structure influences correlated neural activity. PMID- 28863137 TI - Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA. AB - Cystic Fibrosis is an autosomal recessive disorder caused by mutations in the CFTR gene. CRISPR mediated, template-dependent homology-directed gene editing has been used to correct the most common mutation, c.1521_1523delCTT / p.Phe508del (F508del) which affects ~70% of individuals, but the efficiency was relatively low. Here, we describe a high efficiency strategy for editing of three different rare CFTR mutations which together account for about 3% of individuals with Cystic Fibrosis. The mutations cause aberrant splicing of CFTR mRNA due to the creation of cryptic splice signals that result in the formation of pseudoexons containing premature stop codons c.1679+1634A>G (1811+1.6kbA>G) and c.3718 2477C>T (3849+10kbC>T), or an out-of-frame 5' extension to an existing exon c.3140-26A>G (3272-26A>G). We designed pairs of Cas9 guide RNAs to create targeted double-stranded breaks in CFTR either side of each mutation which resulted in high efficiency excision of the target genomic regions via non homologous end-joining repair. When evaluated in a mini-gene splicing assay, we showed that targeted excision restored normal splicing for all three mutations. This approach could be used to correct aberrant splicing signals or remove disruptive transcription regulatory motifs caused by deep-intronic mutations in a range of other genetic disorders. PMID- 28863140 TI - Crumble analysis of the historic sympatric distribution between Dendrortyx macroura and D. barbatus (Aves: Galliformes). AB - In Mexico, the Long-tailed Wood-Partridge (Dendrortyx macroura) is distributed in the mountains of the Trans-Mexican Volcanic Belt, Sierra Madre del Sur and Sierra Norte de Oaxaca; while the Bearded Wood-Partridge (D. barbatus) is distributed in the Sierra Madre Oriental (SMO). There is a controversial overlap in distribution (sympatry) between these two species (on the Cofre de Perote and Pico de Orizaba volcanoes, SMO and Sierra Norte de Oaxaca), based on the ambiguity and current lack of information regarding the distribution of these two species. In order to disentangle the possible presence of both species in the area of sympatry, we conducted a crumble analysis of the historic knowledge regarding the geographic distribution of both species, based on a review of scientific literature, database records, the specimen examination (in ornithological collections), field work and a reconstruction of the distribution range based on Ecological Niche Modeling. Our results support the presence of only one of these two species in the overlapping area, rejecting the existence of such an area of sympatry between the two species. We discuss alternative hypotheses that could explain the historically reported distribution pattern: 1) an error in the single existing historical record; 2) a possible local extinction of the species and 3) the past existence of interspecific competition that has since been resolved under the principle of competitive exclusion. We propose that the Santo Domingo River in northern Oaxaca and western slope of the Sierra Madre Oriental, mark the distribution limits between these species. PMID- 28863139 TI - Gut microbiome in ADHD and its relation to neural reward anticipation. AB - BACKGROUND: Microorganisms in the human intestine (i.e. the gut microbiome) have an increasingly recognized impact on human health, including brain functioning. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with abnormalities in dopamine neurotransmission and deficits in reward processing and its underlying neuro-circuitry including the ventral striatum. The microbiome might contribute to ADHD etiology via the gut-brain axis. In this pilot study, we investigated potential differences in the microbiome between ADHD cases and undiagnosed controls, as well as its relation to neural reward processing. METHODS: We used 16S rRNA marker gene sequencing (16S) to identify bacterial taxa and their predicted gene functions in 19 ADHD and 77 control participants. Using functional magnetic resonance imaging (fMRI), we interrogated the effect of observed microbiome differences in neural reward responses in a subset of 28 participants, independent of diagnosis. RESULTS: For the first time, we describe gut microbial makeup of adolescents and adults diagnosed with ADHD. We found that the relative abundance of several bacterial taxa differed between cases and controls, albeit marginally significant. A nominal increase in the Bifidobacterium genus was observed in ADHD cases. In a hypothesis-driven approach, we found that the observed increase was linked to significantly enhanced 16S-based predicted bacterial gene functionality encoding cyclohexadienyl dehydratase in cases relative to controls. This enzyme is involved in the synthesis of phenylalanine, a precursor of dopamine. Increased relative abundance of this functionality was significantly associated with decreased ventral striatal fMRI responses during reward anticipation, independent of ADHD diagnosis and age. CONCLUSIONS: Our results show increases in gut microbiome predicted function of dopamine precursor synthesis between ADHD cases and controls. This increase in microbiome function relates to decreased neural responses to reward anticipation. Decreased neural reward anticipation constitutes one of the hallmarks of ADHD. PMID- 28863138 TI - 5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells. AB - Mammalian genomes contain several dozens of large (>0.5 Mbp) lineage-specific gene loci harbouring functionally related genes. However, spatial chromatin folding, organization of the enhancer-promoter networks and their relevance to Topologically Associating Domains (TADs) in these loci remain poorly understood. TADs are principle units of the genome folding and represents the DNA regions within which DNA interacts more frequently and less frequently across the TAD boundary. Here, we used Chromatin Conformation Capture Carbon Copy (5C) technology to characterize spatial chromatin interaction network in the 3.1 Mb Epidermal Differentiation Complex (EDC) locus harbouring 61 functionally related genes that show lineage-specific activation during terminal keratinocyte differentiation in the epidermis. 5C data validated by 3D-FISH demonstrate that the EDC locus is organized into several TADs showing distinct lineage-specific chromatin interaction networks based on their transcription activity and the gene rich or gene-poor status. Correlation of the 5C results with genome-wide studies for enhancer-specific histone modifications (H3K4me1 and H3K27ac) revealed that the majority of spatial chromatin interactions that involves the gene-rich TADs at the EDC locus in keratinocytes include both intra- and inter-TAD interaction networks, connecting gene promoters and enhancers. Compared to thymocytes in which the EDC locus is mostly transcriptionally inactive, these interactions were found to be keratinocyte-specific. In keratinocytes, the promoter-enhancer anchoring regions in the gene-rich transcriptionally active TADs are enriched for the binding of chromatin architectural proteins CTCF, Rad21 and chromatin remodeler Brg1. In contrast to gene-rich TADs, gene-poor TADs show preferential spatial contacts with each other, do not contain active enhancers and show decreased binding of CTCF, Rad21 and Brg1 in keratinocytes. Thus, spatial interactions between gene promoters and enhancers at the multi-TAD EDC locus in skin epithelial cells are cell type-specific and involve extensive contacts within TADs as well as between different gene-rich TADs, forming the framework for lineage-specific transcription. PMID- 28863141 TI - Assessment of tilt and decentration of crystalline lens and intraocular lens relative to the corneal topographic axis using anterior segment optical coherence tomography. AB - PURPOSE: To investigate the tilt and decentration of the crystalline lens and the intraocular lens (IOL) relative to the corneal topographic axis using anterior segment ocular coherence tomography (AS-OCT). METHODS: A sample set of 100 eyes from 49 subjects (41 eyes with crystalline lenses and 59 eyes with IOLs) were imaged using second generation AS-OCT (CASIA2, TOMEY) in June and July 2016 at Okayama University. Both mydriatic and non-mydriatic images were obtained, and the tilt and decentration of the crystalline lens and the IOL were quantified. The effects of pupil dilation on measurements were also assessed. RESULTS: The crystalline lens showed an average tilt of 5.15 degrees towards the inferotemporal direction relative to the corneal topographic axis under non mydriatic conditions and 5.25 degrees under mydriatic conditions. Additionally, an average decentration of 0.11 mm towards the temporal direction was observed under non-mydriatic conditions and 0.08 mm under mydriatic conditions. The average tilt for the IOL was 4.31 degrees towards the inferotemporal direction relative to the corneal topographic axis under non-mydriatic conditions and 4.65 degrees in the same direction under mydriatic conditions. The average decentration was 0.05 mm towards the temporal direction under non-mydriatic conditions and 0.08 mm in the same direction under mydriatic conditions. A strong correlation was found between the average tilt and decentration values of the crystalline lens and the IOL under both non-mydriatic and mydriatic conditions (all Spearman correlation coefficients, r >= 0.800; all P < 0.001). CONCLUSION: When measured using second generation AS-OCT, both the crystalline lens and the IOL showed an average tilt of 4-6 degrees toward the inferotemporal direction relative to the corneal topographic axis and an average decentration of less than 0.12 mm towards the temporal direction. These results were not influenced by pupil dilation and they showed good repeatability. PMID- 28863142 TI - Assessing the accuracy of blood RNA profiles to identify patients with post concussion syndrome: A pilot study in a military patient population. AB - Mild traumatic brain injury (mTBI) is a complex, neurophysiological condition that can have detrimental outcomes. Yet, to date, no objective method of diagnosis exists. Physical damage to the blood-brain-barrier and normal waste clearance via the lymphatic system may enable the detection of biomarkers of mTBI in peripheral circulation. Here we evaluate the accuracy of whole transcriptome analysis of blood to predict the clinical diagnosis of post-concussion syndrome (PCS) in a military cohort. Sixty patients with clinically diagnosed chronic concussion and controls (no history of concussion) were recruited (retrospective study design). Male patients (46) were split into a training set comprised of 20 long-term concussed (> 6 months and symptomatic) and 12 controls (no documented history of concussion). Models were validated in a testing set (control = 9, concussed = 5). RNA_Seq libraries were prepared from whole blood samples for sequencing using a SOLiD5500XL sequencer and aligned to hg19 reference genome. Patterns of differential exon expression were used for diagnostic modeling using support vector machine classification, and then validated in a second patient cohort. The accuracy of RNA profiles to predict the clinical diagnosis of post concussion syndrome patients from controls was 86% (sensitivity 80%; specificity 89%). In addition, RNA profiles reveal duration of concussion. This pilot study shows the potential utility of whole transcriptome analysis to establish the clinical diagnosis of chronic concussion syndrome. PMID- 28863143 TI - Genotypic characterization directly applied to sputum improves the detection of Mycobacterium africanum West African 1, under-represented in positive cultures. AB - BACKGROUND: This study aimed to compare the prevalence of Mycobacterium tuberculosis complex (MTBc) lineages between direct genotyping (on sputum) and indirect genotyping (on culture), to characterize potential culture bias against difficult growers. METHODOLOGY/PRINCIPAL FINDINGS: Smear-positive sputa from consecutive new tuberculosis patients diagnosed in Cotonou, (Benin) were included, before patients had started treatment. An aliquot of decontaminated sputum was used for direct spoligotyping, and another aliquot was cultured on Lowenstein Jensen (LJ) medium (90 days), for indirect spoligotyping. After DNA extraction, spoligotyping was done according to the standard method for all specimens, and patterns obtained from sputa were compared versus those from the derived culture isolates. From 199 patient's sputa, 146 (73.4%) yielded a positive culture. In total, direct spoligotyping yielded a pattern in 98.5% (196/199) of the specimens, versus 73.4% (146/199) for indirect spoligotyping on cultures. There was good agreement between sputum- and isolate derived patterns: 94.4% (135/143) at spoligotype level and 96.5% (138/143) at (sub)lineage level. Two of the 8 pairs with discrepant pattern were suggestive of mixed infection in sputum. Ancestral lineages (Lineage 1, and M. africanum Lineages 5 and 6) were less likely to grow in culture (OR = 0.30, 95%CI (0.14 to 0.64), p = 0.0016); especially Lineage 5 (OR = 0.37 95%CI (0.17 to 0.79), p = 0.010). Among modern lineages, Lineage 4 was over-represented in positive-culture specimens (OR = 3.01, 95%CI (1.4 to 6.51), p = 0.005). CONCLUSIONS/ SIGNIFICANCE: Ancestral lineages, especially M. africanum West African 1 (Lineage 5), are less likely to grow in culture relative to modern lineages, especially M. tuberculosis Euro American (Lineage 4). Direct spoligotyping on smear positive sputum is effective and efficient compared to indirect spoligotyping of cultures. It allows for a more accurate unbiased determination of the population structure of the M. tuberculosis complex. TRIAL REGISTRATION: ClinicalTrials.gov NCT02744469. PMID- 28863144 TI - Latency modulation of collicular neurons induced by electric stimulation of the auditory cortex in Hipposideros pratti: In vivo intracellular recording. AB - In the auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from the lower auditory nuclei, contralateral IC, and auditory cortex (AC), and then uploads these inputs to the thalamus and cortex. Meanwhile, the AC modulates the sound signal processing of IC neurons, including their latency (i.e., first-spike latency). Excitatory and inhibitory corticofugal projections to the IC may shorten and prolong the latency of IC neurons, respectively. However, the synaptic mechanisms underlying the corticofugal latency modulation of IC neurons remain unclear. Thus, this study probed these mechanisms via in vivo intracellular recording and acoustic and focal electric stimulation. The AC latency modulation of IC neurons is possibly mediated by pre-spike depolarization duration, pre-spike hyperpolarization duration, and spike onset time. This study suggests an effective strategy for the timing sequence determination of auditory information uploaded to the thalamus and cortex. PMID- 28863146 TI - Involvement of the anterior cingulate cortex in time-based prospective memory task monitoring: An EEG analysis of brain sources using Independent Component and Measure Projection Analysis. AB - OBJECTIVE: Time-based prospective memory (PM), remembering to do something at a particular moment in the future, is considered to depend upon self-initiated strategic monitoring, involving a retrieval mode (sustained maintenance of the intention) plus target checking (intermittent time checks). The present experiment was designed to explore what brain regions and brain activity are associated with these components of strategic monitoring in time-based PM tasks. METHOD: 24 participants were asked to reset a clock every four minutes, while performing a foreground ongoing word categorisation task. EEG activity was recorded and data were decomposed into source-resolved activity using Independent Component Analysis. Common brain regions across participants, associated with retrieval mode and target checking, were found using Measure Projection Analysis. RESULTS: Participants decreased their performance on the ongoing task when concurrently performed with the time-based PM task, reflecting an active retrieval mode that relied on withdrawal of limited resources from the ongoing task. Brain activity, with its source in or near the anterior cingulate cortex (ACC), showed changes associated with an active retrieval mode including greater negative ERP deflections, decreased theta synchronization, and increased alpha suppression for events locked to the ongoing task while maintaining a time-based intention. Activity in the ACC was also associated with time-checks and found consistently across participants; however, we did not find an association with time perception processing per se. CONCLUSION: The involvement of the ACC in both aspects of time-based PM monitoring may be related to different functions that have been attributed to it: strategic control of attention during the retrieval mode (distributing attentional resources between the ongoing task and the time based task) and anticipatory/decision making processing associated with clock checks. PMID- 28863145 TI - Associations between endothelial dysfunction and clinical and laboratory parameters in children and adolescents with sickle cell anemia. AB - BACKGROUND: Hematological changes can drive damage of endothelial cells, which potentially lead to an early endothelial dysfunction in patients with sickle cell anemia (SCA). An association may exist between endothelial dysfunction and several clinical manifestations of SCA. The present study aims to evaluate the links between changes in endothelial function and clinical and laboratory parameters in children and adolescents with SCA. METHODS: This study included 40 children and adolescents with stable SCA as well as 25 healthy children; aged 6 18 years. All study subjects were evaluated for endothelial function using Doppler ultrasonography. In addition, a number of laboratory assays were performed, including reticulocyte and leukocyte counts as well as measurement of circulating levels of total bilirubin, C-reactive protein (CRP), glucose, lipoproteins and peripheral oxyhemoglobin saturation. These parameters were also compared between SCA patients who were undertaking hydroxyurea (HU) and those who were not. RESULTS: Flow-mediated vasodilation (FMD) values were found to be reduced in SCA patients compared with those detected in healthy controls. SCA individuals with lower FMD values exhibited higher number of hospital admissions due to vaso-occlusive events. Additional analyses revealed that patients who had decreased FMD values exhibited higher odds of acute chest syndrome (ACS) episodes. A preliminary analysis with limited number of individuals failed to demonstrate significant differences in FMD values between SCA individuals who were treated with HU and those who were not. CONCLUSIONS: Children and adolescents with SCA exhibit impaired endothelial function. Reductions in FMD values are associated with ACS. These findings underline the potential use of FMD as screening strategy of SCA patients with severe prognosis at early stages. PMID- 28863147 TI - Short-term imaging response after drug-eluting embolic trans-arterial chemoembolization delivered with the Surefire Infusion System(r) for the treatment of hepatocellular carcinoma. AB - PURPOSE: To review the initial imaging responses after drug-eluting embolic trans arterial chemoembolization (DEE-TACE) delivered with the Surefire Infusion System (r) for the treatment of hepatocellular carcinoma (HCC). METHODS: Single center retrospective evaluation of patients who underwent DEE-TACE for HCC, delivered with SIS. Information was gathered from available medical records. Treatment response rates were assessed using the modified Response Evaluation Criteria in Solid Tumors criteria. Assessment of adverse events was categorized per Common Terminology Criteria for Adverse Events version 4.03. RESULTS: Twenty-two patients with 39 hepatocellular carcinoma lesions were treated with the surefire infusion system. Complete response was demonstrated in 32% of patients and 54% of lesions after a single treatment session. Overall disease response was demonstrated in 91% of patients and 85% of lesions after a single treatment. No grade 3 or higher elevations in liver function tests were demonstrated in the short-term. CONCLUSION: SIS delivered DEE-TACE leads to a higher than expected initial response in patients with HCC. PMID- 28863148 TI - A conceptual and computational framework for modelling and understanding the non equilibrium gene regulatory networks of mouse embryonic stem cells. AB - The capacity of pluripotent embryonic stem cells to differentiate into any cell type in the body makes them invaluable in the field of regenerative medicine. However, because of the complexity of both the core pluripotency network and the process of cell fate computation it is not yet possible to control the fate of stem cells. We present a theoretical model of stem cell fate computation that is based on Halley and Winkler's Branching Process Theory (BPT) and on Greaves et al.'s agent-based computer simulation derived from that theoretical model. BPT abstracts the complex production and action of a Transcription Factor (TF) into a single critical branching process that may dissipate, maintain, or become supercritical. Here we take the single TF model and extend it to multiple interacting TFs, and build an agent-based simulation of multiple TFs to investigate the dynamics of such coupled systems. We have developed the simulation and the theoretical model together, in an iterative manner, with the aim of obtaining a deeper understanding of stem cell fate computation, in order to influence experimental efforts, which may in turn influence the outcome of cellular differentiation. The model used is an example of self-organization and could be more widely applicable to the modelling of other complex systems. The simulation based on this model, though currently limited in scope in terms of the biology it represents, supports the utility of the Halley and Winkler branching process model in describing the behaviour of stem cell gene regulatory networks. Our simulation demonstrates three key features: (i) the existence of a critical value of the branching process parameter, dependent on the details of the cistrome in question; (ii) the ability of an active cistrome to "ignite" an otherwise fully dissipated cistrome, and drive it to criticality; (iii) how coupling cistromes together can reduce their critical branching parameter values needed to drive them to criticality. PMID- 28863149 TI - The neural correlates of biomechanical constraints in hand laterality judgment task performed from other person's perspective: A near-infrared spectroscopy study. AB - Previous studies, mainly using a first-person perspective (1PP), have shown that the judgments of the hand laterality judgment (HLJ) task are dependent on biomechanical constraints (BC). Specifically, differing reaction times (RT) for hand pictures rotated medially or laterally around the mid sagittal plane are attributed to the BC effect on motor imagery. In contrast, we investigated whether the HLJ task is also subject to BC when performed from a third-person perspective (3PP) as well as 1PP using near-infrared spectroscopy (NIRS) to measure the brain activity of prefrontal cortex (PFC) in right-handed participants assigned to 1PP or 3PP groups. The 1PP group judged whether a presented hand was their own left or right hand, and the 3PP group whether it was the other's left or right hand. Using their HLJ task error rates, the 1PP and 3PP groups were subdivided into an Error Group (EG) and No Error Group (NEG). For the 1PP group, both EG and NEG showed a significant Hand Laterality * Orientation interaction for RT, indicating the BC effect on motor imagery. For the 3PP group, however, neither EG nor NEG showed the interaction, even though EG showed a significantly longer RT than NEG. These results suggest that the 3PP EG appropriately followed the 3PP task instruction, while the NEG might have taken 1PP. However, the 3PP EG NIRS profile of left PFC showed a significant Hand Laterality * Orientation interaction, while the 1PP EG did not. More noteworthy is that the left PFC activation of EG showed an interaction between the 1PP and 3PP groups when the left hand was presented. Furthermore, in the NEG, the PFC activation was not influenced by the BC in either the 1PP or 3PP condition. These results indicate that BC interferes with the HLJ task performed from the 1PP and 3PP. PMID- 28863150 TI - A single Markov-type kinetic model accounting for the macroscopic currents of all human voltage-gated sodium channel isoforms. AB - Modelling ionic channels represents a fundamental step towards developing biologically detailed neuron models. Until recently, the voltage-gated ion channels have been mainly modelled according to the formalism introduced by the seminal works of Hodgkin and Huxley (HH). However, following the continuing achievements in the biophysical and molecular comprehension of these pore-forming transmembrane proteins, the HH formalism turned out to carry limitations and inconsistencies in reproducing the ion-channels electrophysiological behaviour. At the same time, Markov-type kinetic models have been increasingly proven to successfully replicate both the electrophysiological and biophysical features of different ion channels. However, in order to model even the finest non-conducting molecular conformational change, they are often equipped with a considerable number of states and related transitions, which make them computationally heavy and less suitable for implementation in conductance-based neurons and large networks of those. In this purely modelling study we develop a Markov-type kinetic model for all human voltage-gated sodium channels (VGSCs). The model framework is detailed, unifying (i.e., it accounts for all ion-channel isoforms) and computationally efficient (i.e. with a minimal set of states and transitions). The electrophysiological data to be modelled are gathered from previously published studies on whole-cell patch-clamp experiments in mammalian cell lines heterologously expressing the human VGSC subtypes (from NaV1.1 to NaV1.9). By adopting a minimum sequence of states, and using the same state diagram for all the distinct isoforms, the model ensures the lightest computational load when used in neuron models and neural networks of increasing complexity. The transitions between the states are described by original ordinary differential equations, which represent the rate of the state transitions as a function of voltage (i.e., membrane potential). The kinetic model, developed in the NEURON simulation environment, appears to be the simplest and most parsimonious way for a detailed phenomenological description of the human VGSCs electrophysiological behaviour. PMID- 28863152 TI - The Boston Marathon versus the World Marathon Majors. AB - PURPOSE: To compare finish times across WMM races for Boston, London, Berlin, Chicago and New York Marathons. METHODS: Race times of the top 10 male and 10 female finishers were analyzed from 2005 to 2014 using the high-performance mixed linear model procedure in the Statistical Analysis System. Venue-to-venue comparisons, as well as comparisons between Boston and other WMM races, with and without factors of temperature, humidity and altitude change were examined. RESULTS: Performance from 2005 to 2014 in the WMM races was found to improve at a rate of ~1% each 7 years. Despite its higher variability, comparison between Boston's estimated mean finishing time and all other venues revealed moderate positive differences, indicating the Boston event to be typically slower than other venues. CONCLUSIONS: Across the 10-year study period, performance times improved ~1% each 7 years for both genders for the WMM, with the Boston Marathon being slower on average than other WMM venues. Weather rather than course metrics appeared to impact performance times most. PMID- 28863151 TI - Perinatal outcomes after induced termination of pregnancy by methods: A nationwide register-based study of first births in Finland 1996-2013. AB - BACKGROUND: Women with previous terminations of pregnancy (TOPs) before their first birth have been associated with poorer perinatal outcomes. However, previous studies on the perinatal outcomes by the method in previous TOPs are inconsistent. OBJECTIVE: To examine the perinatal outcomes of the first-time mothers with singleton births, by the method of previous TOP (medical and surgical vs no TOP, and surgical vs medical). METHOD: This is a nationwide register-based study including 419,879 first-time Finnish mothers with singleton birth during the time period 1996-2013. Mothers having their first birth were identified from the Medical Birth Register and linked to the Abortion Register by their identification numbers. Multinomial logistic regression analysis was performed to examine the risk for preterm birth, low birth weight, small for gestational age and perinatal death by the method in previous TOPs. RESULTS: Among the first-time mothers, 87.0% had no history of TOPs, 3.2% had a history of medical TOP(s), 9.2% had a history of surgical TOP(s) and 0.6% had a history of both (medical and surgical) TOP(s). No significant differences in perinatal outcomes were found among the women with surgical TOPs, compared to the women with no TOPs. In unadjusted analysis, increased odds for preterm birth and low birth weight were found when comparing women having previous surgical TOPs with medical TOPs. Even after the adjustment of potential confounders, odds for preterm birth < 37 weeks (OR = 1.19, 95% CI = 1.04-1.36) and low birth weight < 2500 g (OR = 1.16, 95% CI = 1.00-1.35) remained significant. After restricting data to the single TOP, the results were similar; OR for both preterm birth and low birth weight was 1.18 (95% CIs = 1.02-1.36 and 1.01-1.38). CONCLUSION: Perinatal outcomes did not differ among the mothers with surgical TOPs compared to the mothers with no TOPs, while the outcomes were poorer after surgical TOP(s) than after medical TOP(s). PMID- 28863153 TI - Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation and plasmablast/plasma cell differentiation pathways. AB - OBJECTIVES: This study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients. While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action. We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown. METHODS: Paired synovial biopsy samples from early RA patients before and after 6 months of tDMARD therapy were collected by arthroscopy (n = 19). These biopsies as well as those from subjects with normal synovium (n = 28) were profiled by total RNA sequencing. RESULTS: Large differences in gene expression between RA and control biopsies (over 5000 genes) were identified. Despite clinical efficacy, the expression of a restricted set of less than 300 genes was reversed after 6 months of treatment. Many genes remained elevated, even in patients who achieved low disease activity. Interestingly, tDMARD downregulated genes included those involved in T cell activation and signaling and plasmablast/plasma cell differentiation and function. CONCLUSIONS: We have identified transcriptomic signatures that characterize synovial tissue from RA patients with early disease. Analysis after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to T cell activation and plasmablast/plasma cell differentiation. These results provide novel insight into the biology of early RA and the mechanism of tDMARD action and may help identify novel drug targets to improve rates of treatment-induced disease remission. PMID- 28863154 TI - The impact of HIV infection and socioeconomic factors on the incidence of gonorrhea: A county-level, US-wide analysis. AB - BACKGROUND: Gonorrhea is the second most commonly reported identifiable disease in the United States (U.S.). Importantly, more than 25% of gonorrheal infections demonstrate antibiotic resistance, leading the Centers for Disease Control and Prevention (CDC) to classify gonorrhea as an "urgent threat". METHODS: We examined the association of gonorrhea infection rates with the incidence of HIV and socioeconomic factors. A county-level multivariable model was then constructed. RESULTS: Multivariable analysis demonstrated that HIV incidence [Coefficient (Coeff): 1.26, 95% Confidence Interval (CI): 0.86, 1.66, P<0.001] exhibited the most powerful independent association with the incidence of gonorrhea and predicted 40% of the observed variation in gonorrhea infection rates. Sociodemographic factors like county urban ranking (Coeff: 0.12, 95% CI: 0.03, 0.20, P = 0.005), percentage of women (Coeff: 0.41, 95% CI: 0.28, 0.53, P<0.001) and percentage of individuals under the poverty line (Coeff: 0.45, 95% CI: 0.32, 0.57, P<0.001) exerted a secondary impact. A regression model that incorporated these variables predicted 56% of the observed variation in gonorrhea incidence (Pmodel<0.001, R2 model = 0.56). CONCLUSIONS: Gonorrhea and HIV infection exhibited a powerful correlation thus emphasizing the benefits of comprehensive screening for sexually transmitted infections (STIs) and the value of pre-exposure prophylaxis for HIV among patients visiting an STI clinic. Furthermore, sociodemographic factors also impacted gonorrhea incidence, thus suggesting another possible focus for public health initiatives. PMID- 28863155 TI - Electrophysiological characteristics of pressure overload-induced cardiac hypertrophy and its influence on ventricular arrhythmias. AB - OBJECTIVE: To explore the cardiac electrophysiological characteristics of cardiac hypertrophy and its influence on the occurrence of ventricular tachyarrhythmias. METHODS: Adult C57BL6 mice were randomly divided into a surgery group and a control group. Thoracic aortic constriction was performed on mice in the surgery group, and cardiac anatomical and ultrasonic evaluations were performed to confirm the success of the cardiac hypertrophy model 4 weeks after the operation. Using the Langendorff method of isolated heart perfusion, monophasic action potentials (MAPs) and the effective refractory period (ERP) at different parts of the heart (including the epi- and endo-myocardium of the left and right ventricles) were measured, and the induction rate of ventricular tachyarrhythmias was observed under programmed electrical stimulus (PES) and burst stimulus. Whole cell patch-clamp was used to obtain the I-V characteristics of voltage-gated potassium channels in cardiomyocytes of different parts of the heart (including the epi- and endo-myocardium of the left and right ventricles) as well as the channels' properties of steady-state inactivation and recovery from inactivation. RESULTS: The ratio of heart weight to body weight and the ratio of left ventricular weight to body weight in the surgery group were significantly higher than those in the control group (P < 0.05). Ultrasonic evaluation revealed that both interventricular septal diameter (IVSD) and left ventricle posterior wall diameter (LVPWD) in the surgery group were significantly larger than those in the control group (P < 0.05). Under PES and burst stimuli, the induction rates of arrhythmias in the surgery group significantly increased, reaching 41.2% and 23.5%, respectively. Both the QT interval and action potential duration (APD) in the surgery group were significantly longer than in the control group (P<0.01), and the changes showed obvious spatial heterogeneity. Whole-cell patch-clamp recordings demonstrated that the surgery group had significantly lower potassium current densities (IPeak, Ito, IKur, Iss, and IK1) at different parts of the heart than the control group (P < 0.01), and there were significant differences in the half-inactivation voltage (V1/2) and the inactivation-recovery time constant (tau) of Ito and IKur at different parts of the heart (P < 0.01) between the surgery group and the control group. In addition, the surgery group had significantly lower densities of IPeak, Ito, and IKur in cells of the endo myocardium (P < 0.05), and the changes showed obvious spatial heterogeneity. CONCLUSION: Changes in the current density and function of potassium channels contributed to irregular repolarization in cardiac hypertrophy, and the spatially heterogeneous changes of the channels may increase the occurrence of ventricular arrhythmias that accompany cardiac hypertrophy. PMID- 28863157 TI - Evaluating the impacts of grades on vehicular speeds on interstate highways. AB - Grade variation on interstate highways affects the roadway geometric design, vehicle performance and driver behavior, thus possibly exerting an unexpected effect on vehicular speed. Hence, determining the internal relationship between grade and speed is important and useful for drivers, traffic regulators and other traffic participants. However, the problem with performing this research is the lack of large-scale gradient and speed data. Google Earth (GE) provides an application programming interface for extracting elevation data worldwide. The elevation dataset from GE can be easily converted to grade data. In addition, our team has collected and stored speed series data for different freeways over several years. Based on the above obtainable grade and speed datasets, we conducted research on the effect of grades on free flow speeds from two perspectives. First, the influence of grades on speed was analyzed from both quantitative and qualitative aspects. The analysis of the distributions of four typical types of speeds demonstrated a decreasing tendency as the speed increased. Steeper grades generated a more intense speed fluctuation in terms of the four types of speeds. Second, a model based on the Student's t-test was developed to evaluate the level of significant difference among speed series under neighboring grades. The Student's t-test demonstrated that adjacent grades do not significantly influence the speeds. In summary, speeds under different grades showed obviously different tendencies. The findings of this study can help transport authorities set more reasonable speed limits and improve the geometric design of interstates with grade variation constraints. PMID- 28863156 TI - Molecular characterization and epidemic history of hepatitis C virus using core sequences of isolates from Central Province, Saudi Arabia. AB - The source of HCV transmission in Saudi Arabia is unknown. This study aimed to determine HCV genotypes in a representative sample of chronically infected patients in Saudi Arabia. All HCV isolates were genotyped and subtyped by sequencing of the HCV core region and 54 new HCV isolates were identified. Three sets of primers targeting the core region were used for both amplification and sequencing of all isolates resulting in a 326 bp fragment. Most HCV isolates were genotype 4 (85%), whereas only a few isolates were recognized as genotype 1 (15%). With the assistance of Genbank database and BLAST, subtyping results showed that most of genotype 4 isolates were 4d whereas most of genotype 1 isolates were 1b. Nucleotide conservation and variation rates of HCV core sequences showed that 4a and 1b have the highest levels of variation. Phylogenetic analysis of sequences by Maximum Likelihood and Bayesian Coalescent methods was used to explore the source of HCV transmission by investigating the relationship between Saudi Arabia and other countries in the Middle East and Africa. Coalescent analysis showed that transmissions of HCV from Egypt to Saudi Arabia are estimated to have occurred in three major clusters: 4d was introduced into the country before 1900, the major 4a clade's MRCA was introduced between 1900 and 1920, and the remaining lineages were introduced between 1940 and 1960 from Egypt and Middle Africa. Results showed that no lineages seem to have crossed from Egypt to Saudi Arabia in the last 15 years. Finally, sequencing and characterization of new HCV isolates from Saudi Arabia will enrich the HCV database and help further studies related to treatment and management of the virus. PMID- 28863158 TI - c-FLIP and the NOXA/Mcl-1 axis participate in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells. AB - Choroidal melanoma is the most common primary malignant intraocular tumor, and very few effective therapies are available to treat it. Our study aimed to understand whether pemetrexed plus cisplatin exerts a beneficial synergistic effect in human choroidal melanoma cells and to delineate the underlying molecular mechanism. To accomplish these aims, we treated choroidal melanoma cells with pemetrexed and cisplatin and assessed cell survival with SRB and MTT assays. Proteins were detected using western blotting analysis. NOXA and CHOP were knocked down with siRNA. We found that pemetrexed or cisplatin alone inhibited survival and induced apoptosis in human choroidal melanoma cells. Furthermore, the expression levels of c-FLIP, an anti-apoptotic protein in the extrinsic apoptosis pathway, and Mcl-1, an anti-apoptotic protein in the intrinsic apoptosis pathway, were decreased by pemetrexed or cisplatin respectively, while the expression of a pro-apoptotic protein in the intrinsic apoptosis pathway, NOXA, was up-regulated. Moreover, pemetrexed or cisplatin alone increased the protein expression of the endoplasmic reticulum stress markers IRE1alpha, Bip and CHOP. Silencing CHOP expression reduced NOXA expression. These findings suggest that the pemetrexed or cisplatin induced intrinsic apoptosis via activation of the ER stress response. Importantly, combining the two compounds more strongly induced apoptosis. Following the cotreatment, CHOP and NOXA expression increased, while c-FLIP and Mcl-1 expression decreased, and these effects were more pronounced than when using either compound alone. This result suggests that pemetrexed and cisplatin synergistically activate ER stress response-induced apoptosis in choroidal melanoma cells. To summarize, the c-FLIP and NOXA/Mcl-1 axis participated in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells. Intrinsic apoptosis was induced via activation of the ER stress response. Our study provides important mechanistic insights into potential cancer treatment with pemetrexed plus cisplatin and enriches our understanding of human choroidal melanoma. PMID- 28863159 TI - Building test data from real outbreaks for evaluating detection algorithms. AB - Benchmarking surveillance systems requires realistic simulations of disease outbreaks. However, obtaining these data in sufficient quantity, with a realistic shape and covering a sufficient range of agents, size and duration, is known to be very difficult. The dataset of outbreak signals generated should reflect the likely distribution of authentic situations faced by the surveillance system, including very unlikely outbreak signals. We propose and evaluate a new approach based on the use of historical outbreak data to simulate tailored outbreak signals. The method relies on a homothetic transformation of the historical distribution followed by resampling processes (Binomial, Inverse Transform Sampling Method-ITSM, Metropolis-Hasting Random Walk, Metropolis-Hasting Independent, Gibbs Sampler, Hybrid Gibbs Sampler). We carried out an analysis to identify the most important input parameters for simulation quality and to evaluate performance for each of the resampling algorithms. Our analysis confirms the influence of the type of algorithm used and simulation parameters (i.e. days, number of cases, outbreak shape, overall scale factor) on the results. We show that, regardless of the outbreaks, algorithms and metrics chosen for the evaluation, simulation quality decreased with the increase in the number of days simulated and increased with the number of cases simulated. Simulating outbreaks with fewer cases than days of duration (i.e. overall scale factor less than 1) resulted in an important loss of information during the simulation. We found that Gibbs sampling with a shrinkage procedure provides a good balance between accuracy and data dependency. If dependency is of little importance, binomial and ITSM methods are accurate. Given the constraint of keeping the simulation within a range of plausible epidemiological curves faced by the surveillance system, our study confirms that our approach can be used to generate a large spectrum of outbreak signals. PMID- 28863160 TI - High rates of loss to follow-up during the first year of pre-antiretroviral therapy for HIV patients at sites providing pre-ART care in Nigeria, 2004-2012. AB - BACKGROUND: With about 3.4 million HIV-infected persons, Nigeria has the second highest number of people living with HIV (PLHIV) in the world. However, antiretroviral treatment (ART) coverage in Nigeria remains low with only 748,846 (22%) of PLHIV on ART by the end of 2014. Retention of HIV-infected patients in pre-ART care is essential to ensure timely ART initiation. We assessed outcomes of patients enrolled in Nigeria's pre-ART program during 2004-2012. METHODS: We conducted a nationally representative retrospective cohort study among adults (>=15 years old), enrolling in pre-ART programs supported by the U.S. President's Emergency Plan for AIDS Relief in Nigeria. A total of 35 sites enrolling >=50 patients in pre-ART were selected using probability proportional-to-size sampling; 2,415 eligible medical records at these sites were randomly selected for abstraction. Determinants of loss to follow-up (LTFU) and mortality during pre-ART care were estimated using Cox proportional hazards regression models. RESULTS: The median age at enrollment was 32 years (interquartile range (IQR) 27 40). A total of 1,216 (51.4%) initiated ART by the time of data abstraction. Among the remaining 1,199 patients, 898 (74.9%) had been LTFU, 180 (15.0%) were alive and in pre-ART care, 71 (5.9%) had died, 50 (4.2%) had transferred out or stopped care. Baseline markers of advanced disease, including weight <45 kg (adjusted hazard ration (AHR) = 4.23; 95% confidence interval (CI): 1.51-15.58) and more advanced WHO disease stage, were predictive of pre-ART mortality. Compared with patients aged 15-24, patients aged 35-44 (AHR = 0.67; 95% CI: 1.0.47-0.95) and age 45-54 (AHR = 0.66; 95% CI: 0.48-0.91) had lower LTFU rates. Compared with attending facilities in North Central geopolitical zone, attending facility locations in South East (AHR = 0.44; 95% CI: 0.24-0.83) was protective against LTFU. CONCLUSIONS: About half of patients enrolling in HIV program during 2004-2012 in Nigeria had not initiated ART by 2013. Key strategies to improve early ART initiation among pre-ART enrollees include implementation of the WHO test and treat guidelines, earlier HIV testing, and better monitoring to improve ART initiation rates. Further research to understand regional variations in pre ART outcomes is warranted. PMID- 28863161 TI - Diffusion weighted imaging in patients with rectal cancer: Comparison between Gaussian and non-Gaussian models. AB - PURPOSE: The purpose of this study was to compare the performance of four diffusion models, including mono and bi-exponential both Gaussian and non Gaussian models, in diffusion weighted imaging of rectal cancer. MATERIAL AND METHODS: Nineteen patients with rectal adenocarcinoma underwent MRI examination of the rectum before chemoradiation therapy including a 7 b-value diffusion sequence (0, 25, 50, 100, 500, 1000 and 2000 s/mm2) at a 1.5T scanner. Four different diffusion models including mono- and bi-exponential Gaussian (MG and BG) and non-Gaussian (MNG and BNG) were applied on whole tumor volumes of interest. Two different statistical criteria were recruited to assess their fitting performance, including the adjusted-R2 and Root Mean Square Error (RMSE). To decide which model better characterizes rectal cancer, model selection was relied on Akaike Information Criteria (AIC) and F-ratio. RESULTS: All candidate models achieved a good fitting performance with the two most complex models, the BG and the BNG, exhibiting the best fitting performance. However, both criteria for model selection indicated that the MG model performed better than any other model. In particular, using AIC Weights and F-ratio, the pixel-based analysis demonstrated that tumor areas better described by the simplest MG model in an average area of 53% and 33%, respectively. Non-Gaussian behavior was illustrated in an average area of 37% according to the F-ratio, and 7% using AIC Weights. However, the distributions of the pixels best fitted by each of the four models suggest that MG failed to perform better than any other model in all patients, and the overall tumor area. CONCLUSION: No single diffusion model evaluated herein could accurately describe rectal tumours. These findings probably can be explained on the basis of increased tumour heterogeneity, where areas with high vascularity could be fitted better with bi-exponential models, and areas with necrosis would mostly follow mono-exponential behavior. PMID- 28863162 TI - Effect of continuous positive airway pressure on carotid intima-media thickness in patients with obstructive sleep apnea: A meta-analysis. AB - OBJECTIVE: Obstructive sleep apnea (OSA) is associated with increased carotid intima-media thickness (IMT), an early marker of atherosclerosis. Continuous positive airway pressure (CPAP) is the first-line treatment for OSA. A meta analysis was performed to determine whether CPAP therapy could decrease carotid IMT. METHODS: The PubMed, Embase, Web of Science, and Cochrane library were searched before March, 2017. Weighted mean difference (WMD) was calculated to estimate the treatment effects of pre and post-CPAP therapy. Seven studies were examined and the meta-analysis was performed using STATA 12.0. RESULTS: There was no change of carotid IMT before and after CPAP treatment in OSA patients (WMD = 0.052, 95% confidence interval (CI) = -0.002 to 0.105, z = 1.90, p = 0.057). Meanwhile, meta-analysis of the two RCTs showed that carotid IMT was not changed in CPAP group when compared with control group (WMD = 0.002 95% CI = -0.125 to 0.129, z = 0.03, p = 0.976). Subgroup analyses indicated that carotid IMT was significantly decreased after CPAP use in more severe OSA patients (AHI>=50) (WMD = 0.073, 95% CI = 0.022 to 0.124, z = 2.80, p = 0.005) and patients with therapeutic duration >=6 months (WMD = 0.121, 95% CI = 0.019 to 0.223, z = 2.32, p = 0.021). CONCLUSIONS: CPAP had no impact on carotid IMT in OSA patients. However, carotid IMT was significantly decreased after CPAP treatment in more severe OSA patients and patients with longer CPAP usage. PMID- 28863163 TI - The complete chloroplast genome sequence of Aconitum coreanum and Aconitum carmichaelii and comparative analysis with other Aconitum species. AB - Aconitum species (belonging to the Ranunculaceae) are well known herbaceous medicinal ingredients and have great economic value in Asian countries. However, there are still limited genomic resources available for Aconitum species. In this study, we sequenced the chloroplast (cp) genomes of two Aconitum species, A. coreanum and A. carmichaelii, using the MiSeq platform. The two Aconitum chloroplast genomes were 155,880 and 157,040 bp in length, respectively, and exhibited LSC and SSC regions separated by a pair of inverted repeat regions. Both cp genomes had 38% GC content and contained 131 unique functional genes including 86 protein-coding genes, eight ribosomal RNA genes, and 37 transfer RNA genes. The gene order, content, and orientation of the two Aconitum cp genomes exhibited the general structure of angiosperms, and were similar to those of other Aconitum species. Comparison of the cp genome structure and gene order with that of other Aconitum species revealed general contraction and expansion of the inverted repeat regions and single copy boundary regions. Divergent regions were also identified. In phylogenetic analysis, Aconitum species positon among the Ranunculaceae was determined with other family cp genomes in the Ranunculales. We obtained a barcoding target sequence in a divergent region, ndhC-trnV, and successfully developed a SCAR (sequence characterized amplified region) marker for discrimination of A. coreanum. Our results provide useful genetic information and a specific barcode for discrimination of Aconitum species. PMID- 28863164 TI - Seasonal dynamics and spatial distribution pattern of Parapoynx crisonalis (Lepidoptera: Crambidae) on water chestnuts. AB - Parapoynx crisonalis (Walker, 1859) (Lepidoptera: Crambidae) is a major pest of aquatic vegetables and aquatic landscape plants. It has been responsible for causing considerable economic damage to water chestnut (Trapa natans) plants. In the Changsha vicinity of China, P. crisonalis has five generations a year. Populations of P. crisonalis were relatively low in April and began to rapidly rise at the beginning of May. At the end of July and early August, the population dropped dramatically. A rebound occurred at the end of August and early September, which was referred to as the second population peak. From then, until early November, the P. crisonalis population steadily diminished in preparation for overwintering. The primary factors influencing the seasonal dynamics of P. crisonalis were the climatic conditions, especially the temperature, and secondarily precipitation. Between May and October, the P. crisonalis adults were evenly distributed in the pond. In May and June, the eggs of P. crisonalis were present in an aggregate distribution, due to the effects of environmental heterogeneity. In July and August, however, they were found to be in a uniform distribution. PMID- 28863165 TI - Comprehensive analysis of amino acid sequence diversity at the F protein cleavage site of Newcastle disease virus in fusogenic activity. AB - Newcastle disease virus (NDV) is a contagious agent of Newcastle disease in avian species and seriously affects the poultry industry. The cleavage site of the viral F protein (Fcs) is a key determinant of membrane fusion and viral virulence. In this study, we investigated the precise effect of variable amino acid sequences of the Fcs on fusogenic activity. Based on viral pathogenicity, the Fcs sequences of natural isolates (n = 1572) are classified into eight types of virulent Fcs (VFcs) with the motif "G/R/K-R-Q/R/K-R/K-R?F" and ten types of the avirulent Fcs (AFcs) with the motif "G/R/E-R/K/Q-Q-G/E-R?L". The VFcs is only found in the Class II cluster of viral classification and not in Class I. The AFcs exists in both Class I and II isolates. The VFc and AFc types present an evolutionary relationship with temporal distribution and host species. Using a fusion assay in vitro, VFcs-1 "RRQKR?F" and VFcs-2 "RRQRR?F" show the highest efficiency in triggering membrane fusion. The neutral residue Q at the P3 position of the VFcs plays an enhancing role compared to effect of the basic residues R and K. A single residue K at P3 or P5 is less efficient of the fusogenic activity in the VFcs with all basic residues. Moreover, the cleavage efficiencies of F0 proteins with different types of Fcs motifs do not appear to affect membrane fusion. Our findings offer insight into the effect of amino acid variation of the Fcs on the fusion triggered by NDV. PMID- 28863166 TI - The novel Lyme borreliosis vaccine VLA15 shows broad protection against Borrelia species expressing six different OspA serotypes. AB - We have previously shown that the Outer surface protein A (OspA) based Lyme borreliosis vaccine VLA15 induces protective immunity in mice. Herein, we report the induction of protective immunity by VLA15 with mouse models using ticks infected with B. burgdorferi (OspA serotype 1), B. afzelii (OspA serotype 2) and B. bavariensis (OspA serotype 4) or with in vitro grown B. garinii (OspA serotype 5 and 6) for challenge. For B. garinii (OspA serotype 3), we have developed a growth inhibition assay using chicken complement and functional antibodies targeting B. garinii (OspA serotype 3) could be demonstrated after immunization with VLA15. Furthermore, following three priming immunizations, a booster dose was administered five months later and the induction of immunological memory could be confirmed. Thus, the antibody titers after the booster dose were increased considerably compared to those after primary immunization. In addition, the half-lives of anti-OspA serotype specific antibodies after administration of the booster immunization were longer than after primary immunization. Taken together, we could show that VLA15 induced protection in mice against challenge with four different clinically relevant Borrelia species (B. burgdorferi, B. afzelii, B. garinii and B. bavariensis) expressing five of the six OspA serotypes included in the vaccine. The protection data is supported by functional assays showing efficacy against spirochetes expressing any of the six OspA serotypes (1 to 6). To our knowledge, this is the first time a Lyme borreliosis vaccine has been able to demonstrate such broad protection in preclinical studies. These new data provide further promise for the clinical development of VLA15 and supports our efforts to provide a new Lyme borreliosis vaccine available for global use. PMID- 28863167 TI - The development and validation of an easy to use automatic QT-interval algorithm. AB - BACKGROUND: To evaluate QT-interval dynamics in patients and in drug safety analysis, beat-to-beat QT-interval measurements are increasingly used. However, interobserver differences, aberrant T-wave morphologies and changes in heart axis might hamper accurate QT-interval measurements. OBJECTIVE: To develop and validate a QT-interval algorithm robust to heart axis orientation and T-wave morphology that can be applied on a beat-to-beat basis. METHODS: Additionally to standard ECG leads, the root mean square (ECGRMS), standard deviation and vectorcardiogram were used. QRS-onset was defined from the ECGRMS. T-wave end was defined per individual lead and scalar ECG using an automated tangent method. A median of all T-wave ends was used as the general T-wave end per beat. Supine standing tests of 73 patients with Long-QT syndrome (LQTS) and 54 controls were used because they have wide ranges of RR and QT-intervals as well as changes in T wave morphology and heart axis orientation. For each subject, automatically estimated QT-intervals in three random complexes chosen from the low, middle and high RR range, were compared with manually measured QT-intervals by three observers. RESULTS: After visual inspection of the randomly selected complexes, 21 complexes were excluded because of evident noise, too flat T-waves or premature ventricular beats. Bland-Altman analyses of automatically and manually determined QT-intervals showed a bias of <4ms and limits of agreement of +/-25ms. Intra-class coefficient indicated excellent agreement (>0.9) between the algorithm and all observers individually as well as between the algorithm and the mean QT-interval of the observers. CONCLUSION: Our automated algorithm provides reliable beat-to-beat QT-interval assessment, robust to heart axis and T-wave morphology. PMID- 28863168 TI - A novel polyepitope vaccine elicited HIV peptide specific CD4+ T cell responses in HLA-A2/DRB1 transgenic mice. AB - Human immunodeficiency (HIV) infection is a leading global health problem that causes approximately one million deaths each year. Although antiretroviral therapy can slow down the disease progression and improve the quality of life of infected individuals, it cannot eradicate the virus. A successful vaccine is one of the most cost-effective alternatives to control the incidence and mortality of HIV infection. CD4+ T cells play a key role in orchestrating other forms of human immune responses, therefore, an HIV vaccine that includes a component capable of eliciting CD4+ T cell responses is highly desirable. To this end, we have previously designed a polypeptide vaccine comprised of multiple CD4+ T cell epitopes. In the current study, we tested the immunogenicity of this vaccine in mouse models by using IFN-gammaELISPOT and intracellular cytokine staining assays. We found that several epitopes in this vaccine elicited CD4+ T cell immune responses in both congenic mice and human HLA-A2/DRB1 transgenic mice. These new epitopes may be further tested for their ability to augment immune responses elicited by other forms of HIV vaccines. PMID- 28863169 TI - Effects of small-molecule amyloid modulators on a Drosophila model of Parkinson's disease. AB - Alpha-synuclein (aS) amyloid formation is involved in Parkinson's disease (PD); therefore, small molecules that target aS and affect its aggregation are of interest as future drug candidates. We recently reported modified ring-fused 2 pyridones that modulate aS amyloid formation in vitro. Here, we describe the effects of such molecules on behavioral parameters of a Drosophila model of PD (i.e., flies expressing human aS), using a new approach (implemented in a commercially available FlyTracker system) to quantify fly mobility. FlyTracker allows for automated analysis of walking and climbing locomotor behavior, as it collects large sequences of data over time in an unbiased manner. We found that the molecules per se have no toxic or kinetic effects on normal flies. Feeding aS expressing flies with the amyloid-promoting molecule FN075, remarkably, resulted in increased fly mobility at early time points; however, this effect switched to reduced mobility at later time points, and flies had shorter life spans than controls. In contrast, an amyloid inhibitor increased both fly kinetics and life span. In agreement with increased aS amyloid formation, the FN075-fed flies had less soluble aS, and in vitro aS-FN075 interactions stimulated aS amyloid formation. In addition to a new quantitative approach to probe mobility (available in FlyTracker), our results imply that aS regulates brain activity such that initial removal (here, by FN075-triggered assembly of aS) allows for increased fly mobility. PMID- 28863170 TI - Intuitive intellectual property law: A nationally-representative test of the plagiarism fallacy. AB - Studies with convenience samples have suggested that the lay public's conception of intellectual property laws, including how the laws should regulate and why they should exist, are largely incommensurate with the actual intended purpose of intellectual property laws and their history in the United States. In this paper, we test whether these findings generalize to a more diverse and representative sample. The major findings from past work were replicated in the current study. When presented with several potential reasons for IP protection, the lay public endorsed plagiarism and felt that acknowledging the original source of a creative work should make copying that work permissible-viewpoints strongly divergent from lawmakers' intent and the law itself. In addition, we replicate the finding that lay people know remarkably little about intellectual property laws more generally and report little experience as users or creators of creative works. PMID- 28863171 TI - Studies of wolf x coyote hybridization via artificial insemination. AB - Following the production of western gray wolf (Canis lupus) x western coyote (Canis latrans) hybrids via artificial insemination (AI), the present article documents that the hybrids survived in captivity for at least 4 years and successfully bred with each other. It further reports that backcrossing one of the hybrids to a male gray wolf by AI also resulted in the birth of live pups that have survived for at least 10 months. All male hybrids (F1 and F2) produced sperm by about 10 months of age, and sperm quality of the F1 males fell within the fertile range for domestic dogs, but sperm motility and morphology, in particular, were low in F2 males at 10 months but improved in samples taken at 22 months of age. These studies are relevant to a long-standing controversy about the identity of the red wolf (Canis rufus), the existence of a proposed new species (Canis lycaon) of gray wolf, and to the role of hybridization in mammalian evolution. PMID- 28863173 TI - Portfolio optimization for seed selection in diverse weather scenarios. AB - The aim of this work was to develop a method for selection of optimal soybean varieties for the American Midwest using data analytics. We extracted the knowledge about 174 varieties from the dataset, which contained information about weather, soil, yield and regional statistical parameters. Next, we predicted the yield of each variety in each of 6,490 observed subregions of the Midwest. Furthermore, yield was predicted for all the possible weather scenarios approximated by 15 historical weather instances contained in the dataset. Using predicted yields and covariance between varieties through different weather scenarios, we performed portfolio optimisation. In this way, for each subregion, we obtained a selection of varieties, that proved superior to others in terms of the amount and stability of yield. According to the rules of Syngenta Crop Challenge, for which this research was conducted, we aggregated the results across all subregions and selected up to five soybean varieties that should be distributed across the network of seed retailers. The work presented in this paper was the winning solution for Syngenta Crop Challenge 2017. PMID- 28863172 TI - Regulation of xanthine dehydrogensase gene expression and uric acid production in human airway epithelial cells. AB - INTRODUCTION: The airway epithelium is a physical and immunological barrier that protects the pulmonary system from inhaled environmental insults. Uric acid has been detected in the respiratory tract and can function as an antioxidant or damage associated molecular pattern. We have demonstrated that human airway epithelial cells are a source of uric acid. Our hypothesis is that uric acid production by airway epithelial cells is induced by environmental stimuli associated with chronic respiratory diseases. We therefore examined how airway epithelial cells regulate uric acid production. MATERIALS AND METHODS: Allergen and cigarette smoke mouse models were performed using house dust mite (HDM) and cigarette smoke exposure, respectively, with outcome measurements of lung uric acid levels. Primary human airway epithelial cells isolated from clinically diagnosed patients with asthma and chronic obstructive pulmonary disease (COPD) were grown in submerged cultures and compared to age-matched healthy controls for uric acid release. HBEC-6KT cells, a human airway epithelial cell line, were grown under submerged monolayer conditions for mechanistic and gene expression studies. RESULTS: HDM, but not cigarette smoke exposure, stimulated uric acid production in vivo and in vitro. Primary human airway epithelial cells from asthma, but not COPD patients, displayed elevated levels of extracellular uric acid in culture. In HBEC-6KT, production of uric acid was sensitive to the xanthine dehydrogenase (XDH) inhibitor, allopurinol, and the ATP Binding Cassette C4 (ABCC4) inhibitor, MK-571. Lastly, the pro-inflammatory cytokine combination of TNF-alpha and IFN-gamma elevated extracellular uric acid levels and XDH gene expression in HBEC-6KT cells. CONCLUSIONS: Our results suggest that the active production of uric acid from human airway epithelial cells may be intrinsically altered in asthma and be further induced by pro-inflammatory cytokines. PMID- 28863174 TI - Handgrip strength and its prognostic value for mortality in Moscow, Denmark, and England. AB - BACKGROUND: This study compares handgrip strength and its association with mortality across studies conducted in Moscow, Denmark, and England. MATERIALS: The data collected by the Study of Stress, Aging, and Health in Russia, the Study of Middle-Aged Danish Twins and the Longitudinal Study of Aging Danish Twins, and the English Longitudinal Study of Ageing was utilized. RESULTS: Among the male participants, the age-standardized grip strength was 2 kg and 1 kg lower in Russia than in Denmark and in England, respectively. The age-standardized grip strength among the female participants was 1.9 kg and 1.6 kg lower in Russia than in Denmark and in England, respectively. In Moscow, a one-kilogram increase in grip strength was associated with a 4% (hazard ratio [HR] = 0.96, 95% confidence interval [CI]: 0.94, 0.99) reduction in mortality among men and a 10% (HR = 0.90, 95%CI: 0.86, 0.94) among women. Meanwhile, a one-kilogram increase in grip strength was associated with a 6% (HR = 0.94, 95%CI: 0.93, 0.95) and an 8% (HR = 0.92, 95%CI: 0.90, 0.94) decrease in mortality among Danish men and women, respectively, and with a 2% (HR = 0.98, 95%CI: 0.97, 0.99) and a 3% (HR = 0.97, 95%CI: 0.95, 0.98) reduction in mortality among the English men and women, respectively. CONCLUSION: The study suggests that, although absolute grip strength values appear to vary across the Muscovite, Danish, and English samples, the degree to which grip strength is predictive of mortality is comparable across national populations with diverse socioeconomic and health profiles and life expectancy levels. PMID- 28863175 TI - The modeling of attraction characteristics regarding passenger flow in urban rail transit network based on field theory. AB - Aimed at the complicated problems of attraction characteristics regarding passenger flow in urban rail transit network, the concept of the gravity field of passenger flow is proposed in this paper. We establish the computation methods of field strength and potential energy to reveal the potential attraction relationship among stations from the perspective of the collection and distribution of passenger flow and the topology of network. As for the computation methods of field strength, an optimum path concept is proposed to define betweenness centrality parameter. Regarding the computation of potential energy, Compound Simpson's Rule Formula is applied to get a solution to the function. Taking No. 10 Beijing Subway as a practical example, an analysis of simulation and verification is conducted, and the results shows in the following ways. Firstly, the bigger field strength value between two stations is, the stronger passenger flow attraction is, and the greater probability of the formation of the largest passenger flow of section is. Secondly, there is the greatest passenger flow volume and circulation capacity between two zones of high potential energy. PMID- 28863177 TI - Identification of sero-reactive antigens for the early diagnosis of Johne's disease in cattle. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne's disease (JD), a chronic intestinal inflammatory disease of cattle and other ruminants. JD has a high herd prevalence and causes serious animal health problems and significant economic loss in domesticated ruminants throughout the world. Since serological detection of MAP infected animals during the early stages of infection remains challenging due to the low sensitivity of extant assays, we screened 180 well-characterized serum samples using a whole proteome microarray from Mycobacterium tuberculosis (MTB), a close relative of MAP. Based on extensive testing of serum and milk samples, fecal culture and qPCR for direct detection of MAP, the samples were previously assigned to one of 4 groups: negative low exposure (n = 30, NL); negative high exposure (n = 30, NH); fecal positive, ELISA negative (n = 60, F+E-); and fecal positive, ELISA positive (n = 60, F+E+). Of the 740 reactive proteins, several antigens were serologically recognized early but not late in infection, suggesting a complex and dynamic evolution of the MAP humoral immune response during disease progression. Ordinal logistic regression models identified a subset of 47 candidate proteins with significantly different normalized intensity values (p<0.05), including 12 in the NH and 23 in F+E- groups, suggesting potential utility for the early detection of MAP infected animals. Next, the diagnostic utility of four MAP orthologs (MAP1569, MAP2942c, MAP2609, and MAP1272c) was assessed and reveal moderate to high diagnostic sensitivities (range 48.3% to 76.7%) and specificity (range 96.7% to 100%), with a combined 88.3% sensitivity and 96.7% specificity. Taken together, the results of our analyses have identified several candidate MAP proteins of potential utility for the early detection of MAP infection, as well individual MAP proteins that may serve as the foundation for the next generation of well-defined serological diagnosis of JD in cattle. PMID- 28863178 TI - PROTAX-Sound: A probabilistic framework for automated animal sound identification. AB - Autonomous audio recording is stimulating new field in bioacoustics, with a great promise for conducting cost-effective species surveys. One major current challenge is the lack of reliable classifiers capable of multi-species identification. We present PROTAX-Sound, a statistical framework to perform probabilistic classification of animal sounds. PROTAX-Sound is based on a multinomial regression model, and it can utilize as predictors any kind of sound features or classifications produced by other existing algorithms. PROTAX-Sound combines audio and image processing techniques to scan environmental audio files. It identifies regions of interest (a segment of the audio file that contains a vocalization to be classified), extracts acoustic features from them and compares with samples in a reference database. The output of PROTAX-Sound is the probabilistic classification of each vocalization, including the possibility that it represents species not present in the reference database. We demonstrate the performance of PROTAX-Sound by classifying audio from a species-rich case study of tropical birds. The best performing classifier achieved 68% classification accuracy for 200 bird species. PROTAX-Sound improves the classification power of current techniques by combining information from multiple classifiers in a manner that yields calibrated classification probabilities. PMID- 28863176 TI - iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease. AB - Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent. PMID- 28863179 TI - The feasibility of a heart block with an electron compensation as an alternative whole breast radiotherapy technique in patients with underlying cardiac or pulmonary disease. AB - PURPOSE: We aimed to evaluate the feasibility of the heart block with electron compensation (HBE) technique, based on three-dimensional conformal radiotherapy (3D-CRT) in left-sided breast cancer patients with underlying cardiac or pulmonary disease. METHODS: Twenty patients with left-sided breast cancer who were treated with whole breast radiotherapy (WBRT) were included in this study. Intensity-modulated radiotherapy (IMRT), 3D-CRT, and HBE treatment plans were generated for each patient. Based on the 3D-CRT plan, the HBE plan included a heart block from the medial tangential field to shield the heart and added an electron beam to compensate for the loss in target volume coverage. The dosimetric parameters for the heart and lung and the target volume between the three treatment types were compared. RESULTS: Of the three plans, the HBE plan yielded the most significant reduction in the doses received by the heart and lung (heart Dmean: 5.1 Gy vs. 12.9 Gy vs. 4.0 Gy and lung Dmean: 11.4 Gy vs. 13.2 Gy vs. 10.5 Gy, for 3D-CRT, IMRT, and HBE, respectively). Target coverage with all three techniques was within the acceptable range (Dmean 51.0 Gy vs. 51.2 Gy vs. 50.6 Gy, for 3D-CRT, IMRT, and HBE, respectively). CONCLUSIONS: The HBE plan effectively reduced the amount of radiation exposure to the heart and lung. It could be beneficial for patients who are vulnerable to radiation-related cardiac or pulmonary toxicities. PMID- 28863180 TI - A non-invasive specimen collection method and a novel simian foamy virus (SFV) DNA quantification assay in New World primates reveal aspects of tissue tropism and improved SFV detection. AB - Simian foamy viruses (SFVs) co-evolved with a wide range of Old World and New World primates (OWPs and NWPs, respectively) and occasionally transmit to humans. Previous studies of OWPs showed that the predominant site of SFV replication is the oral mucosa. However, very little is known about SFV viral loads (VLs) in the oral mucosa or blood of NWPs. NWPs have smaller body sizes, limiting collection of sufficient whole blood volumes to molecularly detect and quantify SFV. Our study evaluated the use of noninvasively collected buccal swabs to detect NWP SFV compared with detection in blood using a new NWP SFV quantitative PCR (qPCR) assay. Buccal and blood samples were collected from 107 captive NWPs in Brazil comprising eleven distinct genera at the Primate Center of Rio de Janeiro (n = 58) and at Fundacao Jardim Zoologico da Cidade do Rio Janeiro (n = 49). NWP SFV western blot (WB) testing was performed on a subset of animals for comparison with PCR results. The qPCR assay was validated using distinct SFV polymerase sequences from seven NWP genera (Callithrix, Sapajus, Saimiri, Ateles, Alouatta, Cacajao and Pithecia). Assay sensitivity was 20 copies/106 cells, detectable in 90% of replicates. SFV DNA VLs were higher in buccal swabs (5 log copies/106 cells) compared to peripheral blood mononuclear cells (PBMCs) (3 log copies/106 cells). The qPCR assay was also more sensitive than nested PCR for detection of NWP SFV infection and identified an additional 27 SFV-infected monkeys of which 18 (90%) were WB-positive and three that were WB-negative. We show the utility of using both blood and buccal swabs and our new qPCR assay for detection and quantification of diverse NWP SFV, which will assist a better understanding of the epidemiology of SFV in NWPs and any potential zoonotic infection risk for humans exposed to NWPs. PMID- 28863181 TI - BRCA1 protein expression and subcellular localization in primary breast cancer: Automated digital microscopy analysis of tissue microarrays. AB - PURPOSE: Mutations in BRCA1 are associated with familial as well as sporadic aggressive subtypes of breast cancer, but less is known about whether BRCA1 expression or subcellular localization contributes to progression in population based settings. METHODS: We examined BRCA1 expression and subcellular localization in invasive breast cancer tissues from an ethnically diverse sample of 286 patients and 36 normal breast tissue controls. Two different methods were used to label breast cancer tissues for BRCA1: (1) Dual immunofluoresent staining with BRCA1 and cytokeratin 8/18 and (2) immunohistochemical staining using the previously validated MS110 mouse monoclonal antibody. Slides were visualized and quantified using the VECTRA Automated Multispectral Image Analysis System and InForm software. RESULTS: BRCA1 staining was more intense in normal than in invasive breast tissue for both cytoplasmic (p<0.0001) and nuclear (p<0.01) compartments. BRCA1 nuclear to cytoplasmic ratio was higher in breast cancer cells than in normal mammary epithelial cells. Reduced BRCA1 expression was associated with high tumor grade and negative hormone receptors (estrogen receptor, progesterone receptor and Her2). On the other hand, high BRCA1 expression correlated with basal-like tumors (high CK5/6 and EGFR), and high nuclear androgen receptor staining. Lower nuclear to cytoplasmic ratio of BRCA1 correlated significantly with high Ki67 labeling index (p< 0.05) and family history of breast cancer (p = 0.001). CONCLUSION: Findings of this study indicate that alterations in BRCA1 protein expression and subcellular localization in breast cancer correlate with poor prognostic markers and aggressive tumor features. Further large-scale studies are required to assess the potential relevance of BRCA1 protein expression and localization in routine classification of breast cancer. PMID- 28863182 TI - Immune response to hepatitis B vaccination in HIV-positive individuals with isolated antibodies against hepatitis B core antigen: Results of a prospective Italian study. AB - BACKGROUND AND AIM: Antibodies against hepatitis B core antigen (anti-HBc) are found in 14-44% of patients with HIV infection, but it is still unclear whether hepatitis B virus (HBV) vaccination should be recommended for HIV-positive subjects with isolated anti-HBc (IAHBc). We examined the rate of anamnestic and primary responses (ARs and PRs) and associated factors in a group of HIV-infected patients with an IAHBc profile. METHODS: This prospective study recruited 25 HIV positive patients with anti-HBc alone who were vaccinated against HBV infection. Those without an AR (anti-hepatitis B envelope antigen [anti-HBs] levels of <10 U/L) or who were hypo-responsiveness (anti-HBs levels of >10 but <100 U/L) four weeks after the first dose of vaccine underwent a full course of vaccinations. Their clinical and virological data, including the presence of occult hepatitis B infection (OBI), were evaluated in accordance with the vaccination schedule. RESULTS: Six of the 25 patients (24%) showed an AR, four of whom had anti-HBs levels of <100 U/L. Ten of 19 (52.6%) remaining patients became seroprotected after the third dose. OBI was detected in four of the six patients with an AR, two of the 10 patients with a PR, and none of the nine patients who did not respond. Multivariate analysis showed that an AR was associated with the presence of OBI (P = 0.0162), and a PR was associated with HCV antibody status. (P = 0.0191). CONCLUSIONS: Our data suggest that testing for anti-HBc alone may not be a reliable means of assessing protection from HBV infection in HIV-positive patients. OBI-positive patients may benefit from a single vaccine dose. Anti-HCV serostatus may affect PRs. PMID- 28863183 TI - Increased microcirculatory heterogeneity in patients with obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is the most common form of sleep disordered breathing and has been associated with major cardiovascular comorbidities. We hypothesized that the microcirculation is impaired in patients with OSA and that the magnitude of impairment correlates to OSA severity. METHODS: Subjects were consecutive patients scheduled for routine diagnostic polysomnography (PSG). OSA was defined by paradoxical rib cage movements together with abdominal excursions and by the apnea-hypopnea index (AHI) (events/hour; no apnea AHI<5; mild apnea 5<=AHI<15; moderate apnea 15<=AHI<30; severe apnea AHI >=30). Sidestream darkfield imaging was used to assess the sublingual microcirculation. Recordings of sublingual microcirculation (5 random sites) were performed before and after overnight PSG. Data are summarized as mean (+/-SD); p values <0.05 were considered statistically significant. RESULTS: Thirty-three consecutive patients were included. OSA was diagnosed in 16 subjects (4 moderate, 12 severe). There was no significant difference in microcirculation between subjects with moderate OSA and without OSA. However, compared to subjects without OSA, subjects with severe OSA (AHI>=30) showed a significant decrease of microvascular flow index (-0.07+/-0.17 vs. 0.08+/-0.14; p = 0.02) and increase of microvascular flow index heterogeneity (0.06+/-0.15 vs. -0.06+/-0.11; p = 0.02) overnight. Multiple regression analysis (adjusted for age and gender) showed both decrease of flow and increase of flow heterogeneity associated with AHI (b = 0.41; F = 1.8; p = 0.04 and b = 0.43; F = 1.9; p = 0.03, respectively). CONCLUSION: Acute overnight microcirculatory changes are observed in subjects with severe OSA characterized by decreased flow and increased flow heterogeneity. PMID- 28863184 TI - Insertion of the voltage-sensitive domain into circularly permuted red fluorescent protein as a design for genetically encoded voltage sensor. AB - Visualization of electrical activity in living cells represents an important challenge in context of basic neurophysiological studies. Here we report a new voltage sensitive fluorescent indicator which response could be detected by fluorescence monitoring in a single red channel. To the best of our knowledge, this is the first fluorescent protein-based voltage sensor which uses insertion into-circular permutant topology to provide an efficient interaction between sensitive and reporter domains. Its fluorescent core originates from red fluorescent protein (FP) FusionRed, which has optimal spectral characteristics to be used in whole body imaging techniques. Indicators using the same domain topology could become a new perspective for the FP-based voltage sensors that are traditionally based on Forster resonance energy transfer (FRET). PMID- 28863185 TI - Loop-mediated isothermal amplification (LAMP) assay-A rapid detection tool for identifying red fox (Vulpes vulpes) DNA in the carcasses of harbour porpoises (Phocoena phocoena). AB - Carcasses of wild animals are often visited by different scavengers. However, determining which scavenger caused certain types of bite marks is particularly difficult and knowledge thereof is lacking. Therefore, a loop-mediated isothermal amplification (LAMP) assay (target sequence cytochrome b) was developed to detect red fox DNA in carcasses of harbour porpoises. The MSwabTM method for direct testing without prior DNA isolation was validated. As a detection device, the portable real-time fluorometer Genie(r) II was used, which yields rapid results and can be used in field studies without huge laboratory equipment. In addition to in vitro evaluation and validation, a stranded and scavenged harbour porpoise carcass was successfully examined for red fox DNA residues. The developed LAMP method is a valuable diagnostic tool for confirming presumable red fox bite wounds in harbour porpoises without further DNA isolation steps. PMID- 28863186 TI - Fusion of Taq DNA polymerase with single-stranded DNA binding-like protein of Nanoarchaeum equitans-Expression and characterization. AB - DNA polymerases are present in all organisms and are important enzymes that synthesise DNA molecules. They are used in various fields of science, predominantly as essential components for in vitro DNA syntheses, known as PCR. Modern diagnostics, molecular biology and genetic engineering need DNA polymerases which demonstrate improved performance. This study was aimed at obtaining a new NeqSSB-TaqS fusion DNA polymerase from the Taq DNA Stoffel domain and a single-stranded DNA binding-like protein of Nanoarchaeum equitans in order to significantly improve the properties of DNA polymerase. The DNA coding sequence of Taq Stoffel DNA polymerase and the nonspecific DNA-binding protein of Nanoarchaeum equitans (NeqSSB-like protein) were fused. A novel recombinant gene was obtained which was cloned into the pET-30 Ek/LIC vector and introduced into E. coli for expression. The recombinant enzyme was purified and its enzymatic properties including DNA polymerase activity, PCR amplification rate, thermostability, processivity and resistance to inhibitors, were tested. The yield of the target protein reached approximately 18 mg/l after 24 h of the IPTG induction. The specific activity of the polymerase was 2200 U/mg. The recombinant NeqSSB-TaqS exhibited a much higher extension rate (1000 bp template in 20 s), processivity (19 nt), thermostability (half-life 35 min at 95 degrees C) and higher tolerance to PCR inhibitors (0.3-1.25% of whole blood, 0.84-13.5 MUg of lactoferrin and 4.7-150 ng of heparin) than Taq Stoffel DNA polymerase. Furthermore, our studies show that NeqSSB-TaqS DNA polymerase has a high level of flexibility in relation to Mg2+ ions (from 1 to 5 mM) and KCl or (NH4)2SO4 salts (more than 60 mM and 40 mM, respectively). Using NeqSSB-TaqS DNA polymerase instead of the Taq DNA polymerase could be a better choice in many PCR applications. PMID- 28863188 TI - Correction: On the evolutionary origins of equity. AB - [This corrects the article DOI: 10.1371/journal.pone.0173636.]. PMID- 28863187 TI - Innate activation of human primary epithelial cells broadens the host response to Mycobacterium tuberculosis in the airways. AB - Early events in the human airways determining whether exposure to Mycobacterium tuberculosis (Mtb) results in acquisition of infection are poorly understood. Epithelial cells are the dominant cell type in the lungs, but little is known about their role in tuberculosis. We hypothesised that human primary airway epithelial cells are part of the first line of defense against Mtb-infection and contribute to the protective host response in the human respiratory tract. We modelled these early airway-interactions with human primary bronchial epithelial cells (PBECs) and alveolar macrophages. By combining in vitro infection and transwell co-culture models with a global transcriptomic approach, we identified PBECs to be inert to direct Mtb-infection, yet to be potent responders within an Mtb-activated immune network, mediated by IL1beta and type I interferon (IFN). Activation of PBECs by Mtb-infected alveolar macrophages and monocytes increased expression of known and novel antimycobacterial peptides, defensins and S100 family members and epithelial-myeloid interactions further shaped the immunological environment during Mtb-infection by promoting neutrophil influx. This is the first in depth analysis of the primary epithelial response to infection and offers new insights into their emerging role in tuberculosis through complementing and amplifying responses to Mtb. PMID- 28863189 TI - Opposing effects of in vitro differentiated macrophages sub-type on epithelial wound healing. AB - Inappropriate repair responses to pulmonary epithelial injury have been linked to perturbation of epithelial barrier function and airway remodelling in a number of respiratory diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. We developed an in vitro mechanical scratch injury model in air-liquid interface differentiated primary human small airway epithelial cells that recapitulates many of the characteristics observed during epithelial wound injury in both human tissue and small animal models. Wound closure was initially associated with de-differentiation of the differentiated apical cells and rapid migration into the wound site, followed by proliferation of apical cells behind the wound edge, together with increases in FAK expression, fibronectin and reduction in PAI-1 which collectively facilitate cell motility and extracellular matrix deposition. Macrophages are intimately involved in wound repair so we sought to investigate the role of macrophage sub-types on this process in a novel primary human co-culture model. M1 macrophages promoted FAK expression and both M1 and M2 macrophages promoted epithelial de-differentiation. Interestingly, M2a macrophages inhibited both proliferation and fibronectin expression, possibly via the retinoic acid pathway, whereas M2b and M2c macrophages prevented fibronectin deposition, possibly via MMP expression. Collectively these data highlight the complex nature of epithelial wound closure, the differential impact of macrophage sub-types on this process, and the heterogenic and non-delineated function of these macrophages. PMID- 28863190 TI - Transcriptome analysis of the pectoral muscles of local chickens and commercial broilers using Ribo-Zero ribonucleic acid sequencing. AB - BACKGROUND: The molecular mechanisms underlying meat quality and muscle growth are not clear. The meat quality and growth rates of local chickens and commercial broilers are very different. The Ribo-Zero RNA-Seq technology is an effective means of analyzing transcript groups to clarify molecular mechanisms. The aim of this study was to provide a reference for studies of the differences in the meat quality and growth of different breeds of chickens. RESULTS: Ribo-Zero RNA-Seq technology was used to analyze the pectoral muscle transcriptomes of Gushi chickens and AA broilers. Compared with AA broilers, 1649 genes with annotated information were significantly differentially expressed (736 upregulated and 913 downregulated) in Gushi chickens with Q<=0.05 (Q is the P-value corrected by multiple assumptions test) at a fold change >=2 or <=0.5. In addition, 2540 novel significantly differentially expressed (SDE) genes (1405 upregulated and 1135 downregulated) were discovered. The results showed that the main signal transduction pathways that differed between Gushi chickens and AA broilers were related to amino acid metabolism. Amino acids are important for protein synthesis, and they regulate key metabolic pathways to improve the growth, development and reproduction of organisms. CONCLUSION: This study showed that differentially expressed genes in the pectoral tissues of Gushi chickens and AA broilers were related to fat metabolism, which affects meat. Additionally, a large number of novel genes were found that may be involved in fat metabolism and thus may affect the formation of meat, which requires further study. The results of this study provide a reference for further studies of the molecular mechanisms of meat formation. PMID- 28863191 TI - Anti-cancer stem cell activity of a sesquiterpene lactone isolated from Ambrosia arborescens and of a synthetic derivative. AB - New regimens are constantly being pursued in cancer treatment, especially in the context of treatment-resistant cancer stem cells (CSCs) that are assumed to be involved in cancer recurrence. Here, we investigated the anti-cancer activity of sesquiterpene lactones (SLs) isolated from Ambrosia arborescens and of synthetic derivatives in breast cancer cell lines, with a specific focus on activity against CSCs. The breast cancer cell lines MCF-7, JIMT-1, and HCC1937 and the normal-like breast epithelial cell line MCF-10A were treated with the SLs damsin and coronopilin, isolated from A. arborescens, and with ambrosin and dindol-01, synthesized using damsin. Inhibitory concentration 50 (IC50) values were obtained from dose-response curves. Based on IC50 values, doses in the MUM range were used for investigating effects on cell proliferation, cell cycle phase distribution, cell death, micronuclei formation, and cell migration. Western blot analysis was used to investigate proteins involved in cell cycle regulation as well as in the NF-kappaB pathway since SLs have been shown to inhibit this transcription factor. Specific CSC effects were investigated using three CSC assays. All compounds inhibited cell proliferation; however, damsin and ambrosin were toxic at single digit micromolar ranges, while higher concentrations were required for coronopilin and dindol-01. Of the four cell lines, the compounds had the least effect on the normal-like MCF-10A cells. The inhibition of cell proliferation can partly be explained by downregulation of cyclin-dependent kinase 2. All compounds inhibited tumour necrosis factor-alpha-induced translocation of NF-kappaB from the cytoplasm to the nucleus. Damsin and ambrosin treatment increased the number of micronuclei; moreover, another sign of DNA damage was the increased level of p53. Treatment with damsin and ambrosin decreased the CSC subpopulation and inhibited cell migration. Our results suggest that these compounds should be further investigated to find efficient CSC-inhibiting compounds. PMID- 28863192 TI - E2/ER beta inhibit ISO-induced cardiac cellular hypertrophy by suppressing Ca2+ calcineurin signaling. AB - Cardiovascular incidences are markedly higher in men than in pre-menstrual women. However, this advantage in women declines with aging and therefore can be correlated with the sex hormone 17beta-Estradiol (E2) which is reported to protect heart cells by acting though estrogen receptors (ERs). In this study we have determined the effect of E2/ERbeta against ISO induced cellular hypertrophy in H9c2 cardiomyoblast cells. The results confirm that ISO induced cardiac hypertrophy by elevating the levels of hypertrophy associated proteins, ANP and BNP and further by upregulating p-CaMKII, calcineurin, p-GATA4 and NFATc3 which was correlated with a significant enlargement of the H9c2 cardiomyoblast. However, overexpression of ERbeta and/or administration of E2 inhibited ISO induced hypertrophy in H9c2 cells. In addition, E2/ERbeta also inhibited ISO induced NFATc3 translocation, and reduced the protein level of downstream marker, BNP. Furthermore, by testing with the calcineurin inhibitor (CsA), it was confirmed that calcineurin acted as a key mediator for the anti-hypertrophic effect of E2/ERbeta. In cells treated with calcium blocker (BATPA), the inhibitory effect of E2/ERbeta on ISO-induced Ca2+ influx and hypertrophic effects were totally blocked suggesting that E2/ERbeta inhibited calcineurin activity to activate I-1 protein and suppress PP1, then induce PLB protein phosphorylation and activation, resulting in Ca2+ reuptake into sarcoplasmic reticulum through SR Ca2+ cycling modification. In conclusion, E2/ERbeta suppresses the Ca2+ influx and calcineurin activity induced by ISO to enhance the PLB protein activity and SR Ca2+ cycling. PMID- 28863194 TI - Correction: The Dkk3 gene encodes a vital intracellular regulator of cell proliferation. AB - [This corrects the article DOI: 10.1371/journal.pone.0181724.]. PMID- 28863193 TI - A refined model of claudin-15 tight junction paracellular architecture by molecular dynamics simulations. AB - Tight-junctions between epithelial cells of biological barriers are specialized molecular structures that regulate the flux of solutes across the barrier, parallel to cell walls. The tight-junction backbone is made of strands of transmembrane proteins from the claudin family, but the molecular mechanism of its function is still not completely understood. Recently, the crystal structure of a mammalian claudin-15 was reported, displaying for the first time the detailed features of transmembrane and extracellular domains. Successively, a structural model of claudin-15-based paracellular channels has been proposed, suggesting a putative assembly that illustrates how claudins associate in the same cell (via cis interactions) and across adjacent cells (via trans interactions). Although very promising, the model offers only a static conformation, with residues missing in the most important extracellular regions and potential steric clashes. Here we present detailed atomic models of paracellular single and double pore architectures, obtained from the putative assembly and refined via structural modeling and all-atom molecular dynamics simulations in double membrane bilayer and water environment. Our results show an overall stable configuration of the complex with a fluctuating pore size. Extracellular residue loops in trans interaction are able to form stable contacts and regulate the size of the pore, which displays a stationary radius of 2.5-3.0 A at the narrowest region. The side-by-side interactions of the cis configuration are preserved via stable hydrogen bonds, already predicted by cysteine crosslinking experiments. Overall, this work introduces an improved version of the claudin-15-based paracellular channel model that strengthens its validity and that can be used in further computational studies to understand the structural features of tight-junctions regulation. PMID- 28863195 TI - Risk factors for 14-day rehospitalization following trauma with new traumatic spinal cord injury diagnosis: A 10-year nationwide study in Taiwan. AB - OBJECTIVES: Fourteen-day rehospitalization with new traumatic spinal cord injury (tSCI) diagnosis is used as an indicator for the diagnostic quality of the first hospitalization. In this nationwide population-based cohort study, we identified risk factors for this indicator. METHODS: We conducted a nested case-control study by using the data of patients who received a first hospitalization for trauma between 2001 and 2011. The data were retrieved from Taiwan's National Health Insurance Research Database. Variables including demographic and trauma characteristics were compared between patients diagnosed with tSCI at the first hospitalization and those receiving a 14-day rehospitalization with new tSCI diagnosis. RESULTS: Of the 23 617 tSCI patients, 997 had 14-day rehospitalization with new tSCI diagnosis (incidence rate, 4.22%). The risk of 14-day rehospitalization with new tSCI diagnosis was significantly lower in patients with severe (injury severity score [ISS] = 16-24; odds ratio [OR], 0.17; 95% confidence interval [CI], 0.13-0.21) and profound (ISS > 24; OR, 0.11; 95% CI, 0.07-0.18) injuries. Interhospital transfer (OR, 8.20; 95% CI, 6.48-10.38) was a significant risk factor, along with injuries at the thoracic (OR, 1.62; 95% CI, 1.21-2.18), lumbar (OR, 1.30; 95% CI, 1.02-1.65), and multiple (OR, 3.23; 95% CI, 1.86-5.61) levels. Brain (OR, 2.82), chest (OR, 2.99), and abdominal (OR, 2.74) injuries were also identified as risk factors. In addition, the risk was higher in patients treated at the orthopedic department (OR, 2.26; 95% CI, 1.78-2.87) and those of other surgical disciplines (OR, 1.89; 95% CI, 1.57-2.28) than in those treated at the neurosurgery department. CONCLUSIONS: Delayed tSCI diagnoses are not uncommon, particularly among trauma patients with ISSs < 16 or those who are transferred from lower-level hospitals. Further validation and implementation of evidence-based decision rules is essential for improving the diagnostic quality of traumatic thoracolumbar SCI. PMID- 28863198 TI - Skip the antidepressant when the patient has chronic disease? AB - It makes sense to think that treating patients who have congestive heart failure and depression with an antidepressant would be effective. But common sense is not always supported by empiric observation or evidence. PMID- 28863197 TI - Complete chloroplast genome of green tide algae Ulva flexuosa (Ulvophyceae, Chlorophyta) with comparative analysis. AB - Ulva flexuosa, one kind of green tide algae, has outbroken in the Yellow Sea of China during the past ten years. In the present study, we sequenced the chloroplast genome of U. flexuosa followed by annotation and comparative analysis. It indicated that the chloroplast genomes had high conservation among Ulva spp., and high rearrangement outside them. Though U. flexuosa was closer to U. linza than U. fasciata in phylogenetic tree, the average Ka/Ks between U. flexuosa and U. linza assessed by 67 protein-coding genes was higher than those between U. flexuosa and other species in Ulva spp., due to the variation of psbZ, psbM and ycf20. Our results laid the foundation for the future studies on the evolution of chloroplast genomes of Ulva, as well as the molecular identification of U. flexuosa varieties. PMID- 28863196 TI - Impact of INR monitoring, reversal agent use, heparin bridging, and anticoagulant interruption on rebleeding and thromboembolism in acute gastrointestinal bleeding. AB - BACKGROUND: Anticoagulant management of acute gastrointestinal bleeding (GIB) during the pre-endoscopic period has not been fully addressed in American, European, or Asian guidelines. This study sought to evaluate the risks of rebleeding and thromboembolism in anticoagulated patients with acute GIB. METHODS: Baseline, endoscopy, and outcome data were reviewed for 314 patients with acute GIB: 157 anticoagulant users and 157 age-, sex-, and important risk matched non-users. Data were also compared between direct oral anticoagulants (DOACs) and warfarin users. RESULTS: Between anticoagulant users and non-users, of whom 70% underwent early endoscopy, no endoscopy-related adverse events or significant differences were found in the rate of endoscopic therapy need, transfusion need, rebleeding, or thromboembolism. Rebleeding was associated with shock, comorbidities, low platelet count and albumin level, and low-dose aspirin use but not HAS-BLED score, any endoscopic results, heparin bridge, or international normalized ratio (INR) >= 2.5. Risks for thromboembolism were INR >= 2.5, difference in onset and pre-endoscopic INR, reversal agent use, and anticoagulant interruption but not CHA2DS2-VASc score, any endoscopic results, or heparin bridge. In patients without reversal agent use, heparin bridge, or anticoagulant interruption, there was only one rebleeding event and no thromboembolic events. Warfarin users had a significantly higher transfusion need than DOACs users. CONCLUSION: Endoscopy appears to be safe for anticoagulant users with acute GIB compared with non-users. Patient background factors were associated with rebleeding, whereas anticoagulant management factors (e.g. INR correction, reversal agent use, and drug interruption) were associated with thromboembolism. Early intervention without reversal agent use, heparin bridge, or anticoagulant interruption may be warranted for acute GIB. PMID- 28863200 TI - Autonomic dysfunction: A guide for FPs. AB - Impotence, bladder dysfunction, GI symptoms, and orthostatic hypotension can signal autonomic dysfunction. Here's what you'll see and how to respond. PMID- 28863199 TI - Hypertension treatment strategies for older adults. AB - This evidence-based review illustrates how to adjust treatment for comorbidities and incorporate frailty and cognitive impairment into the equation. PMID- 28863201 TI - Cervical artery dissection related to chiropractic manipulation: One institution's experience. AB - PURPOSE: The purpose of this study was to determine the frequency of patients seen at a single institution who were diagnosed with a cervical vessel dissection related to chiropractic neck manipulation. METHODS: We identified cases through a retrospective chart review of patients seen between April 2008 and March 2012 who had a diagnosis of cervical artery dissection following a recent chiropractic manipulation. Relevant imaging studies were reviewed by a board-certified neuroradiologist to confirm the findings of a cervical artery dissection and stroke. We conducted telephone interviews to ascertain the presence of residual symptoms in the affected patients. RESULTS: Of the 141 patients with cervical artery dissection, 12 had documented chiropractic neck manipulation prior to the onset of the symptoms that led to medical presentation. The 12 patients had a total of 16 cervical artery dissections. All 12 patients developed symptoms of acute stroke. All strokes were confirmed with magnetic resonance imaging or computerized tomography. We obtained follow-up information on 9 patients, 8 of whom had residual symptoms and one of whom died as a result of his injury. CONCLUSION: In this case series, 12 patients with newly diagnosed cervical artery dissection(s) had recent chiropractic neck manipulation. Patients who are considering chiropractic cervical manipulation should be informed of the potential risk and be advised to seek immediate medical attention should they develop symptoms. PMID- 28863202 TI - Immigrant with stomach pain, distension, nausea, and fever . Dx? AB - A 34-year-old Eritrean man presented to the emergency department with complaints of diffuse abdominal pain and distention. He had emigrated to the United States 3 months earlier, following 5 years in a refugee camp in Ethiopia. Two weeks earlier, the patient sought care at his primary care clinic and was diagnosed with post-operative urinary retention and constipation following a recent hemorrhoidectomy. A Foley catheter was inserted and provided a short period of relief. Following the visit, however, his abdominal pain worsened. He also experienced increasing abdominal distention, a declining appetite, and persistent nausea. The patient said that he was unable to urinate and had not had a bowel movement in 6 days. He also described fevers, drenching night sweats, chills, and a 4-kg weight loss over 2 months. PMID- 28863203 TI - PURLs: SSRIs for depression/heart failure patients? Not so fast. AB - This study should put to rest the practice of starting SSRIs in depressed patients with heart failure in an attempt to affect CVD outcomes. PMID- 28863204 TI - Latest recommendations for the 2017-2018 flu season. AB - This season's vaccine has a new H1N1 component and any vaccine, except the live attenuated virus formulation, is suitable for pregnant women. PMID- 28863205 TI - Bruises on the ears and body. AB - Over the course of a month, this 34-year-old woman had sought care at our facility--and another--on 3 separate occasions for painful bruises (visits #1 and #3) and deep vein thrombosis (visit #2). The bruises first appeared acutely on her arms, prompting her first visit to our ED and leading to a hospital stay. Several weeks later, the patient developed new bruise-like lesions on her earlobes, face, trunk, and lower extremities. In between these 2 visits, the patient was seen in another ED (and admitted) for right upper extremity DVT and was started on enoxaparin, followed by warfarin. The patient had no history of trauma, but did have a 7-year history of cocaine abuse. The initial bruises appeared one week after using cocaine from a different dealer. On her most recent visit, her vitals and physical examination were unremarkable, apart from the skin findings. Her complete blood count, complete metabolic panel, and urinalysis were unremarkable. On her previous admissions, the patient's urine drug test had been positive for cocaine. She'd also tested positive for cytoplasmic antineutrophil cytoplasmic antibodies, antinuclear antibodies, anti-double stranded DNA, and anticardiolipin IgM. WHAT IS YOUR DIAGNOSIS? HOW WOULD YOU TREAT THIS PATIENT? PMID- 28863206 TI - Periorbital ecchymoses and breathlessness. AB - A 54-year-old man presented at our facility with a 3-month history of exertional breathlessness and purple blotches around his eyes. Examination revealed bilateral periorbital and perioral ecchymosis, purpuric spots along his waist, and waxy papules on his eyelids. In addition, the patient had macroglossia with nodular infiltration and irregular indentations at the lateral margin of his tongue. The patient also had a raised jugular venous pressure and prominent atrial and ventricular waves. Further examination revealed a fourth heart sound over the left ventricular apex, as well as bilateral basal rales. All other systems were normal except for mild hepatomegaly. Routine hematologic and biochemical lab work was unremarkable. X-rays of the spine and skull were normal, but a chest x-ray showed mild cardiomegaly. An electrocardiogram showed a QS complex from leads V1 to V4 (a pseudo-infarction pattern). An echocardiogram showed biatrial enlargement, left ventricular hypertrophy with a left ventricular ejection fraction of 48%, a speckled pattern on the myocardium, a thickened interatrial septum, and mild pericardial effusion. A color Doppler revealed mild mitral and tricuspid regurgitation with a restrictive pattern of mitral valve flow. Serum protein electrophoresis was normal. WHAT IS YOUR DIAGNOSIS? HOW WOULD YOU TREAT THIS PATIENT? PMID- 28863207 TI - Does treating obstructive sleep apnea improve control of Tx-resistant hypertension? AB - Maybe. Treating obstructive sleep apnea with continuous positive airway pressure is associated with decreases in both systolic and diastolic blood pressure of 3 to 5 mm Hg in patients with treatment-resistant hypertension. The clinical significance of this small decrease hasn't been evaluated, however. PMID- 28863208 TI - Individualizing immunization for international travelers. AB - Take into account routine childhood vaccinations, those that are mandatory for specific destinations, and these highly recommended immunizations. PMID- 28863209 TI - D-loop haplotype diversity in Brazilian horse breeds. AB - The first horses were brought to Brazil by the colonizers after 1534. Over the centuries, these animals evolved and adapted to local environmental conditions usually unsuitable for exotic breeds, thereby originating locally adapted Brazilian breeds. The present work represents the first description of maternal genetic diversity in these horse breeds based on D-loop sequences. A D-Loop HSV-I fragment of 252 bp, from 141 horses belonging to ten Brazilian breeds / genetic groups (locally adapted and specialized breeds) were analysed. Thirty-five different haplotypes belonging to 18 haplogroups were identified with 33 polymorphic sites. Haplotype diversity (varying from 0.20 to 0.96) and nucleotide diversity (varying from 0.0039 to 0.0239) was lower for locally adapted than for specialized breeds, with the same pattern observed for FST values. Haplogroups identified in Brazilian breeds are in agreement with previous findings in South American samples. The low variability observed mainly in locally adapted breeds, indicates that, to ensure conservation of these breeds, careful reproductive management is needed. Additional genetic characterization studies are required to support accurate decision-making. PMID- 28863210 TI - Alternatively spliced MEFV transcript lacking exon 2 and its protein isoform pyrin-2d implies an epigenetic regulation of the gene in inflammatory cell culture models. AB - The function of gene body DNA methylation in alternative splicing, and its relation to disease pathogenesis is not fully elucidated. The gene for familial Mediterranean fever (MEFV) encodes the pyrin protein and contains a 998 bp CpG island, covering the second exon, which is differentially methylated in FMF patients compared to healthy controls. Our further observation of increased exon 2-spliced MEFV transcript in leukocytes of FMF patients provoked us to test the role of exon methylation in alternative splicing using inflammatory cell culture models. First, in vitro exon methylation triggered an increased level of exon 2 exclusion using a splicing cassette in a promyelocytic leukemia cell line (HL 60). HL-60 cells subjected to methylating and demethylating agents, as well as cells differentiated to neutrophil-like cells, exhibited different levels of spliced/unspliced transcripts. We observed increased levels of spliced transcripts in neutrophil-like (p = 0.0005), activated (p = 0.0034) and methylated cells (p < 0.0001), whereas decreased levels in demethylated cells (p = 0.0126) compared to control untreated HL-60 cells. We also showed that the protein isoform of pyrin lacking the exon 2 has an adverse subcellular localization in neutrophil-like cells. Therefore, it remains in the cytoplasm rather than the nucleus. This may point to an epigenetic involvement in an important inflammatory gene. PMID- 28863211 TI - Exome sequencing identifies a novel mutation of the GDI1 gene in a Chinese non syndromic X-linked intellectual disability family. AB - X-linked intellectual disability (XLID) has been associated with various genes. Diagnosis of XLID, especially for non-syndromic ones (NS-XLID), is often hampered by the heterogeneity of this disease. Here we report the case of a Chinese family in which three males suffer from intellectual disability (ID). The three patients shared the same phenotype: no typical clinical manifestation other than IQ score <= 70. For a genetic diagnosis for this family we carried out whole exome sequencing on the proband, and validated 16 variants of interest in the genomic DNA of all the family members. A missense mutation (c.710G > T), which mapped to exon 6 of the Rab GDP-Dissociation Inhibitor 1 (GDI1) gene, was found segregating with the ID phenotype, and this mutation changes the 237th position in the guanosine diphosphate dissociation inhibitor (GDI) protein from glycine to valine (p. Gly237Val). Through molecular dynamics simulations we found that this substitution results in a conformational change of GDI, possibly affecting the Rab-binding capacity of this protein. In conclusion, our study identified a novel GDI1 mutation that is possibly NS-XLID causative, and showed that whole exome sequencing provides advantages for detecting novel ID-associated variants and can greatly facilitate the genetic diagnosis of the disease. PMID- 28863212 TI - A Young Seedling Stripe2 phenotype in rice is caused by mutation of a chloroplast localized nucleoside diphosphate kinase 2 required for chloroplast biogenesis. AB - Chloroplast development and chlorophyll (Chl) biosynthesis in plants are regulated by many genes, but the underlying molecular mechanisms remain largely elusive. We isolated a rice mutant named yss2 (young seedling stripe2) with a striated seedling phenotype beginning from leaf 2 of delayed plant growth. The mutant developed normal green leaves from leaf 5, but reduced tillering and chlorotic leaves and panicles appeared later. Chlorotic yss2 seedlings have decreased pigment contents and impaired chloroplast development. Genetic analysis showed that the mutant phenotype was due to a single recessive gene. Positional cloning and sequence analysis identified a single nucleotide substitution in YSS2 gene causing an amino acid change from Gly to Asp. The YSS2 allele encodes a NDPK2 (nucleoside diphosphate kinase 2) protein showing high similarity to other types of NDPKs. Real-time RT-PCR analysis demonstrated that YSS2 transcripts accumulated highly in L4 sections at the early leaf development stage. Expression levels of genes associated with Chl biosynthesis and photosynthesis in yss2 were mostly decreased, but genes involved in chloroplast biogenesis were up-regulated compared to the wild type. The YSS2 protein was associated with punctate structures in the chloroplasts of rice protoplasts. Our overall data suggest that YSS2 has important roles in chloroplast biogenesis. PMID- 28863213 TI - Type 2 diabetes associated variants of KCNQ1 strongly confer the risk of cardiovascular disease among the Saudi Arabian population. AB - Genome-wide association studies have identified several loci associated with an increased risk for cardiovascular disease (CVD) and type 2 diabetes (T2D). Polymorphisms within the KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) gene are consistently associated with T2D in a number of populations. The current study was undertaken to evaluate the association of 3 polymorphisms of KCNQ1 (rs2237892, rs151290 and rs2237895) with T2D and/or CVD. Patients diagnosed with either T2D (320 patients), CVD (250 patients) or both (60 patients) and 516 healthy controls were genotyped by TaqMan assay run on a real time PCR thermocycler. A statistically significant association was found for SNPs rs151290 (OR = 1.76; 95%CI = 1.02-3.05; p = 0.0435) and rs2237895 (OR = 2.49; 95%CI = 1.72-3.61; p < 0.0001) with CVD. SNP rs151290 (OR = 7.43; 95%CI = 1.00 55.22; p = 0.0499) showed a strong association in patients with both T2D and CVD. None of the SNPs showed any significant association with T2D. Haploview analysis showed that the ACC (rs151290, rs2237892 and rs2237895) haplotype is the most significant risk allele combination for CVD, while CCA is the most significant risk haplotype for co-morbidity with T2D. KCNQ1 polymorphism at SNPs rs151290 and rs2237895 is strongly associated with CVD in this population, but presented no association with T2D. PMID- 28863215 TI - Multifocal Visual Evoked Potential in Eyes With Temporal Hemianopia From Chiasmal Compression: Correlation With Standard Automated Perimetry and OCT Findings. AB - Purpose: To verify whether multifocal visual evoked potential (mfVEP) can differentiate eyes with temporal hemianopia due to chiasmal compression from healthy controls. To assess the relationship between mfVEP, standard automated perimetry (SAP), and Fourier domain-optical coherence tomography (FD-OCT) macular and peripapillary retinal nerve fiber layer (RNFL) thickness measurements. Methods: Twenty-seven eyes with permanent temporal visual field (VF) defects from chiasmal compression on SAP and 43 eyes of healthy controls were submitted to mfVEP and FD-OCT scanning. Multifocal visual evoked potential was elicited using a stimulus pattern of 60 sectors and the responses were averaged for the four quadrants and two hemifields. Optical coherence tomography macular measurements were averaged in quadrants and halves, while peripapillary RNFL thickness was averaged in four sectors around the disc. Visual field loss was estimated in four quadrants and each half of the 24-2 strategy test points. Multifocal visual evoked potential measurements in the two groups were compared using generalized estimated equations, and the correlations between mfVEP, VF, and OCT findings were quantified. Results: Multifocal visual evoked potential-measured temporal P1 and N2 amplitudes were significantly smaller in patients than in controls. No significant difference in amplitude was observed for nasal parameters. A significant correlation was found between mfVEP amplitudes and temporal VF loss, and between mfVEP amplitudes and the corresponding OCT-measured macular and RNFL thickness parameters. Conclusions: Multifocal visual evoked potential amplitude parameters were able to differentiate eyes with temporal hemianopia from controls and were significantly correlated with VF and OCT findings, suggesting mfVEP is a useful tool for the detection of visual abnormalities in patients with chiasmal compression. PMID- 28863214 TI - Regulation of Noncoding Transcriptome in Developing Photoreceptors by Rod Differentiation Factor NRL. AB - Purpose: Transcriptome analysis by next generation sequencing allows qualitative and quantitative profiling of expression patterns associated with development and disease. However, most transcribed sequences do not encode proteins, and little is known about the functional relevance of noncoding (nc) transcriptome in neuronal subtypes. The goal of this study was to perform a comprehensive analysis of long noncoding (lncRNAs) and antisense (asRNAs) RNAs expressed in mouse retinal photoreceptors. Methods: Transcriptomic profiles were generated at six developmental time points from flow-sorted Nrlp-GFP (rods) and Nrlp-GFP;Nrl-/- (S cone like) mouse photoreceptors. Bioinformatic analysis was performed to identify novel noncoding transcripts and assess their regulation by rod differentiation factor neural retina leucine zipper (NRL). In situ hybridization (ISH) was used for validation and cellular localization. Results: NcRNA profiles demonstrated dynamic yet specific expression signature and coexpression clusters during rod development. In addition to currently annotated 586 lncRNAs and 454 asRNAs, we identified 1037 lncRNAs and 243 asRNAs by de novo assembly. Of these, 119 lncRNAs showed altered expression in the absence of NRL and included NRL binding sites in their promoter/enhancer regions. ISH studies validated the expression of 24 lncRNAs (including 12 previously unannotated) and 4 asRNAs in photoreceptors. Coexpression analysis demonstrated 63 functional modules and 209 significant antisense-gene correlations, allowing us to predict possible role of these lncRNAs in rods. Conclusions: Our studies reveal coregulation of coding and noncoding transcripts in rod photoreceptors by NRL and establish the framework for deciphering the function of ncRNAs during retinal development. PMID- 28863217 TI - Assisted Death and the Public Good. PMID- 28863216 TI - Hyaluronan Rich Microenvironment in the Limbal Stem Cell Niche Regulates Limbal Stem Cell Differentiation. AB - Purpose: Limbal epithelial stem cells (LSCs), located in the basal layer of the corneal epithelium in the corneal limbus, are vital for maintaining the corneal epithelium. LSCs have a high capacity of self-renewal with increased potential for error-free proliferation and poor differentiation. To date, limited research has focused on unveiling the composition of the limbal stem cell niche, and, more important, on the role the specific stem cell niche may have in LSC differentiation and function. Our work investigates the composition of the extracellular matrix in the LSC niche and how it regulates LSC differentiation and function. Methods: Hyaluronan (HA) is naturally synthesized by hyaluronan synthases (HASs), and vertebrates have the following three types: HAS1, HAS2, and HAS3. Wild-type and HAS and TSG-6 knockout mice-HAS1-/-;HAS3-/-, HAS2Delta/DeltaCorEpi, TSG-6-/--were used to determine the importance of the HA niche in LSC differentiation and specification. Results: Our data demonstrate that the LSC niche is composed of a HA rich extracellular matrix. HAS1-/-;HAS3-/ , HAS2Delta/DeltaCorEpi, and TSG-6-/- mice have delayed wound healing and increased inflammation after injury. Interestingly, upon insult the HAS knock-out mice up-regulate HA throughout the cornea through a compensatory mechanism, and in turn this alters LSC and epithelial cell specification. Conclusions: The LSC niche is composed of a specialized HA matrix that differs from that present in the rest of the corneal epithelium, and the disruption of this specific HA matrix within the LSC niche leads to compromised corneal epithelial regeneration. Finally, our findings suggest that HA has a major role in maintaining the LSC phenotype. PMID- 28863218 TI - Commentary on "Assisted Death and the Public Good". PMID- 28863219 TI - Discussing Advance Care Planning and Directives in the General Population. AB - The concept of end-of-life planning, along with medical and legal issues, has been discussed and has evolved over several years. The 1990 Patient Self Determination Act and individual states' Department of Health Advance Directive forms helped overcome past problems. Patients with terminal and chronic illness are now able to have their wishes recognized for their future care. Any healthy individual's decision during an advance care planning (ACP) discussion can be adversely affected by various factors; however, multiple barriers-religion, culture, education, and family dynamics-can influence the process. Healthcare professionals' reluctance to initiate the conversation may result from limited training during medical school and residency programs. These limitations hinder both the initiation and productiveness of an ACP conversation. We explored ACP issues to provide guidance to healthcare professionals on how best to address this planning process with a healthy adult. PMID- 28863220 TI - Commentary on "Discussing Advance Care Planning and Directives in the General Population". PMID- 28863221 TI - Resident Workshop Standardizes Patient Handoff and Improves Quality, Confidence, and Knowledge. AB - OBJECTIVES: Residency programs are required to instruct residents in handoff; however, a handoff curriculum endorsed by the Accreditation Council for Graduate Medical Education does not exist. Although curricula are available, we preferred to use a curriculum that could be taught quickly, was easy to implement, and used a mnemonic that resembled current practices at our institution. We designed and implemented a novel handoff educational workshop intended to improve resident confidence and performance. METHODS: In this observational study, pediatric residents across postgraduate training years during winter 2014-spring 2015 participated in two study segments: a handoff workshop with questionnaires and handoff observations. Co-investigators developed and led an interactive workshop for residents that emphasized a standardized approach using the SIGNOUT mnemonic (see text for definition). The effect of workshop participation on handoff abilities was evaluated using a validated, handoff evaluation tool administered before and after the workshop. Qualitative feedback was obtained from residents using pre- and postworkshop surveys. RESULTS: Forty-three residents participated in the workshop; 41 residents completed handoff observations. Improvements were noted in clinical judgment (P = 0.02) and organization/communication (P = 0.005). Pre- and postworkshop surveys demonstrated self-perceived increases in confidence, comfort, and knowledge (P < 0.001). CONCLUSIONS: Improvements in handoffs, particularly in clinical judgment and organization/communication domains, suggest that a more standardized handoff approach is beneficial, especially for postgraduate year 1 residents. The novel, interactive workshop we developed can be taught quickly, is easy to implement, is appropriate for all resident training levels, and improves resident confidence and skill. This workshop can be implemented by training programs across all disciplines, possibly leading to improved patient safety. PMID- 28863222 TI - Chronic Kidney Disease in Pregnancy. AB - With the increasing prevalence of chronic kidney disease (CKD) worldwide, the number of pregnant women with various degrees of renal dysfunction is expected to increase. There is a bidirectional relation between CKD and pregnancy in which renal dysfunction negatively affects pregnancy outcomes, and the pregnancy can have a deleterious impact on various aspects of kidney disease. It has been shown that even mild renal dysfunction can increase considerably the risk of adverse maternal and fetal outcomes. Moreover, data suggest that a history of recovery from acute kidney injury is associated with adverse pregnancy outcomes. In addition to kidney dysfunction, maternal hypertension and proteinuria predispose women to negative outcomes and are important factors to consider in preconception counseling and the process of risk stratification. In this review, we provide an overview of the physiologic renal changes during pregnancy as well as available data regarding CKD and pregnancy outcomes. We also highlight the important management strategies in women with certain selected renal conditions that are seen commonly during the childbearing years. We call for future research on underexplored areas such as the concept of renal functional reserve to develop a potential clinical tool for prognostication and risk stratification of women at higher risk for complications during pregnancy. PMID- 28863223 TI - Management of Metastatic Spinal Cord Compression. AB - Cancer metastasis is a key event in tumor progression associated not only with mortality but also significant morbidity. Metastatic disease can promote end organ dysfunction and even failure through mass effect compression of various vital organs including the spinal cord. In such cases, prompt medical attention is needed to restore neurological function, relieve pain, and prevent permanent damage. The three therapeutic approaches to managing metastatic spinal cord compression include corticosteroids, surgery, and radiation therapy. Although each may improve patients' symptoms, their combination has yielded the best outcome. In cancer patients with clinical suspicion of spinal cord compression, dexamethasone should be initiated followed by surgical decompression, when possible, and radiation. The latter becomes the preferred treatment in patients with inoperable disease. PMID- 28863225 TI - Commentary on "Hospital Discharge Disposition of Stroke Patients in the State of Tennessee". PMID- 28863224 TI - Hospital Discharge Disposition of Stroke Patients in Tennessee. AB - OBJECTIVES: Early determination of hospital discharge disposition status at an acute admission is extremely important for stroke management and the eventual outcomes of patients with stroke. We investigated the hospital discharge disposition of patients with stroke residing in Tennessee and developed a predictive tool for clinical adoption. Our investigational aims were to evaluate the association of selected patient characteristics with hospital discharge disposition status and predict such status at the time of an acute stroke admission. METHODS: We analyzed 127,581 records of patients with stroke hospitalized between 2010 and 2014. Logistic regression was used to generate odds ratios with 95% confidence intervals to examine the factor outcome association. An easy-to-use clinical predictive tool was built by using integer-based risk scores derived from coefficients of multivariable logistic regression. RESULTS: Among the 127,581 records of patients with stroke, 86,114 (67.5%) indicated home discharge and 41,467 (32.5%) corresponded to facility discharge. All considered patient characteristics had significant correlations with hospital discharge disposition status. Patients were at greater odds of being discharged to another facility if they were women; older; black; patients with a subarachnoid or intracerebral hemorrhage; those with the comorbidities of diabetes mellitus, heart disease, hypertension, chronic kidney disease, arrhythmia, or depression; those transferred from another hospital; or patients with Medicare as the primary payer. A predictive tool had a discriminatory capability with area under the curve estimates of 0.737 and 0.724 for derivation and validation cohorts, respectively. CONCLUSIONS: Our investigation revealed that the hospital discharge disposition pattern of patients with stroke in Tennessee was associated with the key patient characteristics of selected demographics, clinical indicators, and insurance status. These analyses resulted in the development of an easy-to-use predictive tool for early determination of hospital discharge disposition status. PMID- 28863226 TI - Idiopathic Thrombocytopenic Purpura in Individuals Older than 75 Years: A Rare Series. PMID- 28863227 TI - On "Direct to Physician Journal Marketing". PMID- 28863228 TI - Evolutionary origin of synapses and neurons - Bridging the gap. AB - The evolutionary origin of synapses and neurons is an enigmatic subject that inspires much debate. Non-bilaterian metazoans, both with and without neurons and their closest relatives already contain many components of the molecular toolkits for synapse functions. The origin of these components and their assembly into ancient synaptic signaling machineries are particularly important in light of recent findings on the phylogeny of non-bilaterian metazoans. The evolution of synapses and neurons are often discussed only from a metazoan perspective leaving a considerable gap in our understanding. By taking an integrative approach we highlight the need to consider different, but extremely relevant phyla and to include the closest unicellular relatives of metazoans, the ichthyosporeans, filastereans and choanoflagellates, to fully understand the evolutionary origin of synapses and neurons. This approach allows for a detailed understanding of when and how the first pre- and postsynaptic signaling machineries evolved. PMID- 28863229 TI - Ambient Asbestos Fiber Concentrations and Long-Term Trends in Pleural Mesothelioma Incidence between Urban and Rural Areas in the United States (1973 2012). AB - Over the past 40 years, measured ambient asbestos concentrations in the United States have been higher in urban versus rural areas. The purpose of this study was to determine whether variations in ambient asbestos concentrations have influenced pleural mesothelioma risk in females (who generally lacked historic occupational asbestos exposure relative to males). Male pleural mesothelioma incidence trends were analyzed to provide perspective for female trends. Annual age-adjusted incidence rates from 1973 to 2012 were obtained from the SEER 9, 13, and 18 databases for urban and rural locations, and standardized rate ratios were calculated. Female rural rates exceeded urban rates in almost half of the years analyzed, although the increases were not statistically significant, which is in line with expectations if there was no observable increased risk for urban locations. In contrast, male urban rates were elevated over rural rates for nearly all years examined and were statistically significantly elevated for 22 of the 40 years. Trend analyses demonstrated that trends for females remained relatively constant over time, whereas male urban and rural incidence increased into the 1980s and 1990s, followed by a decrease/leveling off. Annual female urban and rural incidence rates remained approximately five- to six-fold lower than male urban and rural incidence rates on average, consistent with the comparatively increased historical occupational asbestos exposure for males. The results suggest that differences in ambient asbestos concentrations, which have been reported to be 10-fold or greater across regions in the United States, have not influenced the risk of pleural mesothelioma. PMID- 28863230 TI - Dorsal and ventral parts of thalamic nucleus submedius project to different areas of rat orbitofrontal cortex: A single neuron-tracing study using virus vectors. AB - The rodent orbitofrontal cortex is involved in a variety of cognitive and behavioral functions that require thalamic input to be successfully expressed. Although the thalamic nucleus submedius (Sm) is a major source of afferents to the orbitofrontal cortex, thalamocortical projection from the Sm has not been fully elucidated. In the present study, we first divided the rat Sm into dorsal and ventral parts according to the distribution of vesicular glutamate transporter 2-immunoreactive varicosities, which were somatosensory afferents from the brain stem. Subsequently we investigated dendritic and axonal arborizations of individual dorsal and ventral Sm neurons by visualizing the processes with Sindbis virus vectors expressing membrane-targeted fluorescent proteins. The number of dendritic processes of ventral Sm neurons was greater than that of dorsal Sm neurons. In the cerebral cortex, all the reconstructed Sm neurons sent axons primarily to layers 2-5. Interestingly, dorsal Sm neurons formed a single axon arbor exclusively within the ventrolateral orbital area, whereas ventral Sm neurons made two axon arbors in the lateral orbital and ventral orbital areas simultaneously. The spread of each axon arbor was 500-1000 um in diameter in the direction tangential to the cortical surface. These results indicate that the dorsal and ventral Sm comprise two distinct thalamocortical pathways. The dorsal Sm pathway relay somatosensory information to the ventrolateral orbital area and may be involved in emotional and aversive aspects of nociceptive information processing, whereas the ventral Sm pathway seems to co activate distant orbitofrontal cortical areas, and may link their functions under certain circumstances. PMID- 28863232 TI - Body Piercing. PMID- 28863231 TI - Design, Synthesis, and Pharmacological Screening of Pyridazinone Hybrids as Anticonvulsant Agents. AB - A series of new hybrid benzimidazole containing pyridazinones derivatives were designed and synthesized in accordance with the pharmacophoric requirements essential for the anticonvulsant activity. The synthesized compounds were evaluated for anticonvulsant activity on mice by the gold standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models. Among the compounds tested, SS-4F showed significant anticonvulsant activity in both the screens with ED50 values of 25.10 and 85.33 mg/kg in the MES and scPTZ screens, respectively. Compound SS-4F emerged as safer and effective anticonvulsant due to its several-fold higher protective indices. Further, the gamma-aminobutyric acid (GABA) estimation result showed a marked increase in the GABA level (1.7-fold) as compared to the control, which was further confirmed by good binding properties with the GABAA receptor. PMID- 28863233 TI - The promise and peril of CRISPR gene drives: Genetic variation and inbreeding may impede the propagation of gene drives based on the CRISPR genome editing technology. AB - Gene drives are selfish genetic elements that use a variety of mechanisms to ensure they are transmitted to subsequent generations at greater than expected frequencies. Synthetic gene drives based on the clustered regularly interspersed palindromic repeats (CRISPR) genome editing system have been proposed as a way to alter the genetic characteristics of natural populations of organisms relevant to the goals of public health, conservation, and agriculture. Here, we review the principles and potential applications of CRISPR drives, as well as means proposed to prevent their uncontrolled spread. We also focus on recent work suggesting that factors such as natural genetic variation and inbreeding may represent substantial impediments to the propagation of CRISPR drives. PMID- 28863234 TI - Biodegradable Microparticles for Simultaneous Detection of Counterfeit and Deteriorated Edible Products. AB - In an era of globalized trade relations where food and pharmaceutical products cross borders effortlessly, consumers face counterfeit and deteriorated products at elevated rates. This paper presents multifunctional, biodegradable hydrogel microparticles that can provide information on the authenticity and the potential deterioration of the tagged food or pharmaceutical formulations. These microparticles integrate spatially patterned authenticity code with two sensors the first one detects possible presence of pathogenic microbes through monitoring pH while the second one identifies products stored above optimal temperatures via optical monitoring of the microparticle degradation. Particles are synthesized from a biocompatible polymer and a photoinitiator, dextran modified with 2 hydroxyethylmethacrylate and riboflavin, respectively, using a continuous, high throughput method stop-flow lithography. The proposed synthesis approach also enables crosslinking with visible light bringing about additional flexibility to flow lithography. Model liquid and solid food and pharmaceutical products are successfully labeled with microparticles and the functionality of the sensors in aqueous solutions is demonstrated. PMID- 28863236 TI - Recent Advances in Conjugated Furans. AB - Thiophene is one of the most ubiquitous moieties in organic conjugated materials; however, furan, its oxygen congener, and furan derivatives have received comparatively less attention. This is primarily due to the intrinsic instability of furan and its tendency to decompose in the presence of oxygen and light. Incorporating furan into conjugated systems can confer many benefits, including increases in conjugation, improved solubility, and better transport properties. In this Concept Article, advances in furan-containing conjugated materials are presented. The impact of furan on the properties of conjugated materials is discussed, recent advances in synthetic methods are overviewed, and strategies for improving the stability of conjugated furans are detailed. PMID- 28863235 TI - Therapeutic potential of alpha-lipoic acid derivative, sodium zinc histidine dithiooctanamide, in a mouse model of allergic rhinitis. AB - BACKGROUND: Oxidative stress is involved in various diseases, including allergies. Several studies have pointed to the preventive and therapeutic potential of antioxidants in allergic disorders. However, little is known about the immunomodulatory effects of antioxidants in type I hypersensitivity. In this study we aimed to explore the impact of a water-soluble antioxidant and alpha lipoic acid derivative, sodium zinc histidine dithiooctanamide (DHL-HisZn), on mast-cell- and T-cell-mediated allergic and immune responses both in vitro and in vivo. METHODS: The therapeutic impact of DHL-HisZn on mast-cell-mediated type I hypersensitivity was evaluated by a mast-cell degranulation assay using bone marrow-derived mast cells and by a mouse model of ovalbumin (OVA)-induced allergic rhinitis. The effect of DHL-HisZn on the proportion of regulatory T cells (Tregs) was evaluated using flow cytometry. RESULTS: During the course of OVA-induced allergic rhinitis in mice, serum nitrate was elevated, suggesting the involvement of oxidative stress in allergic responses. DHL-HisZn not only suppressed mast-cell degranulation but also ameliorated OVA-induced nasal hypersensitivity, with significant suppression of serum nitrate. DHL-HisZn treatment significantly suppressed OVA-specific immunoglobulin E (IgE) but enhanced OVA-specific IgG2a in OVA-sensitized and nasal-challenged mice. Furthermore, DHL-HisZn treatment suppressed interleukin-17 production in OVA stimulated splenocytes. Finally, we demonstrated the induction of Tregs by DHL HisZn in concanavalin A blasts. CONCLUSIONS: These findings suggest that DHL HisZn may regulate mast-cell-, T-helper 2 (Th2)-, and Th17-mediated allergic and immune responses by induction of Tregs. PMID- 28863237 TI - A prospective analysis evaluating tissue biopsy location and its clinical relevance in chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) has a high propensity for recurrence. Studies suggest that eosinophilia influences disease severity and surgical outcomes, but the selection of sinonasal site for measuring eosinophilia has not been examined. The aim of this study was to investigate how region-specific tissue eosinophilia affects radiographic severity, comorbidity prevalence, and polyp recurrence risk following sinus surgery. METHODS: Eosinophil cationic protein (ECP) levels in uncinate tissue (UT) and nasal polyp (NP) homogenates from 116 CRSwNP patients were measured using enzyme-linked immunosorbent assay (ELISA). Clinical history, radiographic severity, and time to polyp recurrence were obtained from electronic health records. The correlations between baseline Lund-Mackay scores and comorbidities were compared between UT and NP ECP levels. Cox regression and Kaplan-Meier analysis were then performed to assess whether UT or NP ECP better predicted recurrence. Censoring occurred at 4 years or at last follow-up if there was no endoscopic diagnosis of recurrent polyps. RESULTS: Lund-Mackay scores were significantly correlated with UT and NP ECP (r = 0.46 and 0.26 respectively, p < 0.05). UT but not NP ECP was significantly higher in patients with asthma (p < 0.01) and aspirin-exacerbated respiratory disease (AERD) (p < 0.05). Polyp recurrence risk was only significantly higher for patients with eosinophilic UT tissue (hazard ratio [HR] = 2.84, p = 0.025). When measured in NP, eosinophilia did not predict recurrence. CONCLUSION: Although ECP in NP was higher than in UT tissue, eosinophilia in UT tissue was a more clinically coherent biomarker of baseline radiographic severity, comorbid asthma and AERD, and prospective polyp recurrence risk than NP eosinophilia. PMID- 28863239 TI - Ribbon-like Foldamers for Cellular Uptake and Drug Delivery. AB - Different intracellular delivery systems of bioactive compounds have been developed, including cell-penetrating peptides. Although usually nontoxic and biocompatible, these vectors share some of the general drawbacks of peptides, notably low bioavailability and susceptibility to protease degradation, that limit their use. Herein, the conversion of short peptide sequences into poly alpha-amino-gamma-lactam foldamers that adopt a ribbon-like structure is investigated. This template is used to distribute critical cationic and/or hydrophobic groups on both sides of the backbone, leading to potent short, cell permeable foldamers with a low positive-charge content. The lead compound showed dramatically improved protease resistance and was able to efficiently deliver a biologically relevant cargo inside cells. This study provided a simple strategy to convert short peptide sequences into efficient protease-resistant cell penetrating foldamers. PMID- 28863240 TI - Mesoscopic-Functionalization of Silk Fibroin with Gold Nanoclusters Mediated by Keratin and Bioinspired Silk Synapse. AB - Silk fibroin (SF) offers great opportunities in manufacturing biocompatible/partially biodegradable devices with environmental benignity and biomedical applications. To obtain active SF devices of next generation, this work is to demonstrate a new functionalization strategy of the mesoscopic functionalization for soft materials. Unlike the atomic functionalization of solid materials, the meso-functionalization is to incorporate meso-dopants, i.e., functional molecules or nanomaterials, quantum dots, into the mesoscopic networks of soft materials. In this work, wool keratin (WK) molecules were adopted as mediating molecules to incorporate gold nanoclusters (AuNCs), into the mesoscopic networks of SF. It follows from our analyses that the beta-crystallites between WK and SF molecules establish the binding between WK@AuNCs and the SF networks. The incorporated WK@AuNCs are electron rich and serve as electronically charged nano particles to bridge the growth of Ag filaments in bio-degradable WK@AuNCs-SF memristors. The meso-functionalization can greatly enhance the performance of SF materials and endows them with new functionalities. This can be highlighted by biocompatible/partly degradable WK@AuNCs functionalized SF resistive random access memories, having the enhanced resistive switching memory performance, and the unique synapse characteristics and the capability of synapse learning compared with neat SF devices, and of great importance in nonvolatile memory, analog circuits, and neuromorphic applications. PMID- 28863241 TI - Editorial for the discussion papers on the p-value controversy. PMID- 28863242 TI - Argon-Plasma Reinforced Superamphiphobic Fabrics. AB - A novel method for preparing durable superamphiphobic fabrics is reported, which involves preapplying a solution consisting of perfluoroalkyl acrylate, epoxide containing silane, and silica nanoparticles onto fabric and subsequent argon plasma treatment. The coated fabrics show superphobic to both water and oil fluids (surface tension >21.5 mN m-1 ). The coating is durable to withstand repeated laundries and multicycles of abrasion without apparently altering the superamphiphobicity. The coating is also very stable in boiling water, strong acid, and base, but has little effect on the fabric handle and air permeability. The argon-plasma-enhanced coating may offer a facile way to prepare durable superamphiphobic fabrics. PMID- 28863244 TI - Abstracts From the 49th Congress of the International Society of Paediatric Oncology (SIOP) Washington, DC, USA October 12-15, 2017. PMID- 28863243 TI - One-Pot Multicomponent Synthesis of Glycopolymers through a Combination of Host Guest Interaction, Thiol-ene, and Copper-Catalyzed Click Reaction in Water. AB - There is a common phenomenon that the heterogeneity of natural oligosaccharides contains various sugar units, which can be used to enhance affinity and selectivity toward a specific receptor, so the synthesis of heterogeneous glycopolymers is always an important issue in the glycopolymer field. Herein, this study conducts a one-pot method to prepare polyrotaxane-based heteroglycopolymers anchored with different sugar units and fluorescent moieties via the combination of host-guest interaction, thiol-ene, and copper-catalyzed click chemistry in water. Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, gel permeation chromatography, X-ray diffraction, and Ellman's assay test are used in the paper to characterize the compounds. Quartz crystal microbalance-dissipation (QCD-D) experiments and bacterial adhesion assay are utilized to study the interactions of polyrotaxane based heteroglycopolymers with Con A and Escherichia coli. The results reveal that polyrotaxanes (PRs) with mannose and glucose present better specificity toward Con A and E. coli than PRs with glucose due to synergistic effects. PMID- 28863245 TI - Ultrasensitive and Fast All-Inorganic Perovskite-Based Photodetector via Fast Carrier Diffusion. AB - Low trap-state density, high carrier mobility, and efficient charge carrier collection are key parameters for photodetectors with high sensitivity and fast response time. This study demonstrates a simple solution growth method to prepare CsPbBr3 microcrystals (MCs) with low trap-state density. Time-dependent photoluminescence study with one-photon excitation (OPE) and two-photon excitation (TPE) indicates that CsPbBr3 MCs exhibit fast carrier diffusion with carrier mobility over 100 cm2 V-1 S-1 . Furthermore, CsPbBr3 MC-based photodetectors with high charge carriers' collection efficiency are fabricated. Such photodetectors show ultrahigh responsivity (R) up to 6 * 104 A W-1 with OPE and high R up to 6 A W-1 with TPE. The R for OPE is over one order of magnitude higher (the R for TPE is three orders of magnitude higher) than that of previously reported all-inorganic perovskite-based photodetectors. Moreover, the photodetectors exhibit fast response time of ~1 ms, which corresponds to a gain ~105 and a gain- bandwidth product of 108 Hz for OPE (a gain ~103 and a gain bandwidth product of 106 Hz for TPE). PMID- 28863246 TI - FLCRM: Functional linear cox regression model. AB - We consider a functional linear Cox regression model for characterizing the association between time-to-event data and a set of functional and scalar predictors. The functional linear Cox regression model incorporates a functional principal component analysis for modeling the functional predictors and a high dimensional Cox regression model to characterize the joint effects of both functional and scalar predictors on the time-to-event data. We develop an algorithm to calculate the maximum approximate partial likelihood estimates of unknown finite and infinite dimensional parameters. We also systematically investigate the rate of convergence of the maximum approximate partial likelihood estimates and a score test statistic for testing the nullity of the slope function associated with the functional predictors. We demonstrate our estimation and testing procedures by using simulations and the analysis of the Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Our real data analyses show that high-dimensional hippocampus surface data may be an important marker for predicting time to conversion to Alzheimer's disease. Data used in the preparation of this article were obtained from the ADNI database (adni.loni.usc.edu). PMID- 28863247 TI - Self-Powered Pulse Sensor for Antidiastole of Cardiovascular Disease. AB - Cardiovascular diseases are the leading cause of death globally; fortunately, 90% of cardiovascular diseases are preventable by long-term monitoring of physiological signals. Stable, ultralow power consumption, and high-sensitivity sensors are significant for miniaturized wearable physiological signal monitoring systems. Here, this study proposes a flexible self-powered ultrasensitive pulse sensor (SUPS) based on triboelectric active sensor with excellent output performance (1.52 V), high peak signal-noise ratio (45 dB), long-term performance (107 cycles), and low cost price. Attributed to the crucial features of acquiring easy-processed pulse waveform, which is consistent with second derivative of signal from conventional pulse sensor, SUPS can be integrated with a bluetooth chip to provide accurate, wireless, and real-time monitoring of pulse signals of cardiovascular system on a smart phone/PC. Antidiastole of coronary heart disease, atrial septal defect, and atrial fibrillation are made, and the arrhythmia (atrial fibrillation) is indicative diagnosed from health, by characteristic exponent analysis of pulse signals accessed from volunteer patients. This SUPS is expected to be applied in self-powered, wearable intelligent mobile diagnosis of cardiovascular disease in the future. PMID- 28863248 TI - Controllable Microfluidic Fabrication of Microstructured Materials from Nonspherical Particles to Helices. AB - This work reports on a facile and flexible strategy based on the deformation of encapsulated droplets in fiber-like polymeric matrices for template synthesis of controllable microstructured materials from nonspherical microparticles to complex 3D helices. Monodisperse droplets generated from microfluidics are encapsulated into crosslinked polymeric networks via an interfacial crosslinking reaction in microchannel to in situ produce the droplet-containing, fiber-like matrices. By stretching and twining the dried fiber-like matrices, the encapsulated droplets can be flexibly engineered into versatile shapes for template synthesis of controllable nonspherical microparticles and helices. Moreover, magnetic helices can be fabricated by simply dispersing magnetic Fe3 O4 nanoparticles in the droplets to achieve rotational and translational motion under a rotated magnetic field. This work provides a simple and versatile strategy for the template synthesis of advanced functional microstructured materials with flexible shapes. PMID- 28863249 TI - Bio-Inspired Synthesis of an Ordered N/P Dual-Doped Porous Carbon and Application as an Anode for Sodium-Ion Batteries. AB - Carbonaceous materials are one of the most promising anode materials for sodium ion batteries, because of their abundance, stability, and safe usage. However, the practical application of carbon materials is hindered by poor specific capacity and low initial Coulombic efficiency. The design of porous structure and doping with heteroatoms are two simple and effective methods to promote the sodium storage performance. Herein, the N, P co-doped porous carbon materials are fabricated using renewable and biodegradable gelatin as carbon and nitrogen resource, phosphoric acid as phosphorus precursor and polystyrene nanospheres as a template. The product can deliver a reversible capacity of 230 mA h g-1 at a current density of 0.2 A g-1 , and even a high capacity of 113 mA h g-1 at 10 Ag 1 . The enhanced sodium storage performance is attributed to the synergistic effect of the porosity and the dual-doping of nitrogen and phosphorus. PMID- 28863250 TI - 2017 Scholars Day Symposium Abstracts. PMID- 28863251 TI - CYP2D6 and Tamoxifen: Lessons Learned. PMID- 28863252 TI - A Fish Mouth Appearing Perforation of the Native Aortic Valve Due to Streptococcus infantarius subspecies coli. AB - Infective endocarditis due to Streptococcus infantarius with the subspecies (subsp.) coli is infrequently encountered in healthy humans. This entity is associated with hepatobiliary malignancies and colorectal neoplasia. Here, we report on a unique case of endocarditis associated with S. infantarius subsp. coli in an 80-year-old male with no known risk factors of the infective endocarditis. PMID- 28863253 TI - Tick Talk: Tick-borne Diseases of South Dakota. AB - In addition to being a nuisance, ticks can carry disease. This article presents a brief review of ticks and associated tick-borne disease relevant to South Dakota and surrounding regions. Tick-borne diseases of special relevance in South Dakota include tularemia, Rocky Mountain spotted fever, and Lyme disease. A number of others may also be encountered in the state as well. Prompt treatment of suspected cases is important to ensure a successful recovery, and tick-avoidance measures can reduce the risks of acquiring them. Most of these conditions are nationally reportable infectious diseases. PMID- 28863254 TI - "How Did You Get to This Appointment?" The First Step in Assessing the Older Driver in Your Primary Care Clinic. PMID- 28863255 TI - Think About Ramifications Before Taking Away Right to Choose. PMID- 28863256 TI - Bezlotoxumab for Preventing Recurrent Clostridium difficile Infections. PMID- 28863257 TI - Care Transition: Returning Patients Home Safely and Reducing Readmissions. PMID- 28863258 TI - Using Particle Lithography to Tailor the Architecture of Au Nanoparticle Plasmonic Nanoring Arrays. AB - The facile assembly of metal nanostructured arrays is a fundamental step in the design of plasmon enhanced chemical sensing and solar cell architectures. Here we have investigated methods of creating controlled formations of two-dimensional periodic arrays comprised of 20 nm Au nanoparticles (NPs) on a hydrophilic polymer surface using particle lithography. To direct the assembly process, capillary force and NP concentration both play critical roles on the resulting nanostructured arrays. As such, tuning these experimental parameters can directly be used to modify the nature of the nanostructures formed. To explore this, two different concentrations of Au NP solutions (~7 * 1011 or 4 * 1012 NPs/mL) were used in conjunction with a fixed concentration of polystyrene microspheres (PS MS, ~6 * 109 PS MS/mL). Assembly at a relative humidity (RH) of 45% with the higher concentration resulted in the formation of well-defined Au nanorings of ca. 23 nm in height and 881 nm in diameter with a pitch of 2.5 MUm. Assembly at 65% RH with the lower concentration of NPs resulted in Au nanodonut arrays comprised of isolated single Au NPs. To explore the extent of coupling in the well-defined structures, dark field scattering spectra were collected and showed a broad localized surface plasmon resonance (LSPR) peak with a shoulder, which full-wave electrodynamics modeling (finite-difference time domain (FDTD) method) attributed to be a result of pronounced particle-particle coupling along the circumference of the nanoring array. PMID- 28863259 TI - Stereoselective Analysis and Degradation of Pyrisoxazole in Cabbage, Pakchoi, and Pepper by Liquid Chromatography Tandem Mass Spectrometry. AB - Pyrisoxazole is a chiral fungicide with high sterilizing activity to the plant pathogenic bacteria and thus can be used for protecting the vegetables from gray mold, powdery mildew, and brown rot. The present work aimed to explore its stereoselective degradation in cabbage, pakchoi, and pepper samples. The enantioseparation and analysis on chiral column Lux Cellulose-3 based on liquid chromatography tandem mass spectrometry was developed coupled to the QuEChERS method. The recoveries of the stereoisomers in various vegetables ranged from 72.6 to 124% with RSD lower than 5.0%. Enantioselective dissipation of pyrisoxazole in vegetables displayed that (-)-A-pyrisoxazole was preferentially degraded versus (+)-A-pyrisoxazole in all the vegetables. (+)-B-pyrisoxazole was preferentially degraded in cabbage, while there was no obvious enantioselectivity in pakchoi and pepper. Meanwhile, stereoselectivity analysis demonstrated that (+/-)-A-pyrisoxazole was degraded faster than (+/-)-B-pyrisoxazole in pakchoi and pepper, while there was no stereoselective degradation in cabbages. PMID- 28863260 TI - Interfacial Assembly and Jamming Behavior of Polymeric Janus Particles at Liquid Interfaces. AB - The self-assembly and interfacial jamming of spherical Janus nanoparticles (JNPs) at the water/oil interface were investigated. Polymeric JNPs, made by cross linking polystyrene-block-polybutadiene-block-poly(methyl methacrylate) (PS-PB PMMA), with a high interfacial activity assemble at the water/oil interface. During the self-assembly at the interface, the interfacial energy was reduced and a dynamic interlayer was observed that is responsive to the pH of the aqueous phase. Unlike hard particles, the JNPs are composed of polymer chains that can spread at the liquid-liquid interface to maximize coverage at relatively low areal densities. In a pendant drop geometry, the interfacial area of a water droplet in oil was significantly decreased and the JNPs were forced to pack more closely. Entangling of the polymer chains causes the JNPs to form a solid-like interfacial assembly, resulting in the formation of wrinkles when the interfacial area is decreased. The wrinkling behavior, the retention of the wrinkles, or the slow relaxation of the liquid drop back to its original equilibrium shape was found to depend upon the pH. PMID- 28863261 TI - Characterization of Hsp90 Co-Chaperone p23 Cleavage by Caspase-7 Uncovers a Peptidase-Substrate Interaction Involving Intrinsically Disordered Regions. AB - Caspases are cysteinyl peptidases involved in inflammation and apoptosis during which hundreds of proteins are cleaved by executioner caspase-3 and -7. Despite the fact that caspase-3 has a higher catalytic activity, caspase-7 is more proficient at cleaving poly(ADP ribose) polymerase 1 (PARP1) because it uses an exosite within its N-terminal domain (NTD). Here, we demonstrate that molecular determinants also located in the NTD enhance the recognition and proteolysis of the Hsp90 co-chaperone p23. Structure-activity relationship analyses using mutagenesis of the caspase-7 NTD and kinetics show that residues 36-45 of caspase 7, which overlap with residues necessary for efficacious PARP1 cleavage, participate in p23 recognition. We also demonstrate using chimeric and truncated proteins that the caspase-7 NTD binds close to the cleavage site in the C terminal tail of p23. Moreover, because p23 is cleaved at a site bearing a P4 Pro residue (PEVD142?G), which is far from the optimal sequence, we tested all residues at that position and found notable differences in the preference of caspase-7 and magnitude of differences between residues compared to the results of studies that have used small peptidic substrate libraries. Finally, bioinformatics shows that the regions we identified in caspase-7 and p23 are intrinsically disordered regions that contain molecular recognition features that permit a transient interaction between these two proteins. In summary, we characterized the binding mode for a caspase that is tailored to the specific recognition and cleavage of a substrate, highlighting the importance of studying the peptidase-substrate pair to understand the modalities of substrate recognition by caspases. PMID- 28863262 TI - Spatiotemporal Analysis of K-Ras Plasma Membrane Interactions Reveals Multiple High Order Homo-oligomeric Complexes. AB - Self-assembly of plasma membrane-associated Ras GTPases has major implications to the regulation of cell signaling. However, the structural basis of homo oligomerization and the fractional distribution of oligomeric states remained undetermined. We have addressed these issues by deciphering the distribution of dimers and higher-order oligomers of K-Ras4B, the most frequently mutated Ras isoform in human cancers. We focused on the constitutively active G12V K-Ras and two of its variants, K101E and K101C/E107C, which respectively destabilize and stabilize oligomers. Using raster image correlation spectroscopy and number and brightness analysis combined with fluorescence recovery after photobleaching, fluorescence correlation spectroscopy and electron microscopy in live cells, we show that G12V K-Ras exists as a mixture of monomers, dimers and larger oligomers, while the K101E mutant is predominantly monomeric and K101C/E107C is dominated by oligomers. This observation demonstrates the ability of K-Ras to exist in multiple oligomeric states whose population can be altered by interfacial mutations. Using molecular modeling and simulations we further show that K-Ras uses two partially overlapping interfaces to form compositionally and topologically diverse oligomers. Our results thus provide the first detailed insight into the multiplicity, structure, and membrane organization of K-Ras homomers. PMID- 28863264 TI - Folate-Targeted Dendrimers Selectively Accumulate at Sites of Inflammation in Mouse Models of Ulcerative Colitis and Atherosclerosis. AB - Folate-receptor-positive activated macrophages are critical for the development and maintenance of many chronic inflammatory and autoimmune diseases. Previously, small-molecule folate-targeted conjugates were found to specifically bind to these activated macrophages in vitro and selectively accumulate at sites of inflammation in vivo. While these small-molecule conjugates have shown promise, the use of a folate-targeted, higher cargo capacity nanovehicle may prove superior in delivering imaging or therapeutic agents in vivo. This nanoparticle strategy has been demonstrated in oncology, where targeted dendrimers have shown superior delivery capabilities; however, little research has been pursued in the area of folate-targeted dendrimers for inflammation and autoimmune diseases. Therefore, we endeavored to create a folate-decorated dendrimer to explore its uptake in mouse models of ulcerative colitis and atherosclerosis. We demonstrate that our final poly(ethylene glycol)-coated, acetic-anhydride-capped, folate targeted poly(amidoamine) dendrimer exhibits no discernible cytotoxicity in vitro, specifically binds to a folate-receptor-expressing macrophage cell line in vitro, and selectively accumulates in areas of inflammation in vivo. PMID- 28863263 TI - Single-Nanoparticle Plasmonic Electro-optic Modulator Based on MoS2 Monolayers. AB - The manipulation of light in an integrated circuit is crucial for the development of high-speed electro-optic devices. Recently, molybdenum disulfide (MoS2) monolayers generated broad interest for the optoelectronics because of their huge exciton binding energy, tunable optical emission, direct electronic band-gap structure, etc. Miniaturization and multifunctionality of electro-optic devices further require the manipulation of light-matter interaction at the single nanoparticle level. The strong exciton-plasmon interaction that is generated between the MoS2 monolayers and metallic nanostructures may be a possible solution for compact electro-optic devices at the nanoscale. Here, we demonstrate a nanoplasmonic modulator in the visible spectral region by combining the MoS2 monolayers with a single Au nanodisk. The narrow MoS2 excitons coupled with broad Au plasmons result in a deep Fano resonance, which can be switched on and off by applying different gate voltages on the MoS2 monolayers. A reversible display device that is based on this single-nanoparticle modulator is demonstrated with a heptamer pattern that is actively controlled by the external gates. Our work provides a potential application for electro-optic modulation on the nanoscale and promotes the development of gate-tunable nanoplasmonic devices in the future. PMID- 28863265 TI - Structure-Property Relationships in Sodium Muricholate Derivative (Bile Salts) Micellization: The Effect of Conformation of Steroid Skeleton on Hydrophobicity and Micelle Formation-Pattern Recognition and Potential Membranoprotective Properties. AB - It is known that beta-muricholic acid anions prevent membrane toxicity of hydrophobic bile acids, which are being used in therapy for solubilization of the cholesterol type bile stone. Better knowledge of these derivative micelles is very important for understanding their physiological and pharmacological effects. beta-Axial (a) oriented hydroxyl group from the steroid skeleton decreases the hydrophobic surface of the convex side of the steroid skeleton. Therefore, the critical micellization concentration (CMC) for steroid surfactants with beta-a-OH group should increase, but in the case of OH groups of different orientations forming H-bonds in the hydrophobic phase of the micelle, it has the opposite effect; the CMC decreses, and aggregation is more favored. The set of muricholic acids (MCs) is composed by alpha-MC, beta-MC, gamma-MC, and omega-MC, where alpha MC and beta-MC have beta-axial-OH groups. The aggregation numbers (n) are determined using the Moroi-Matsuoka-Sugioka thermodynamic method. CMC, enthalpy of demicellization, and DeltaCp are determined by isothermal titration calorimetry (ITC). This report pioneers in the study of MC derivatives micellization. Micelles of beta-MC and gamma-MC belong to the linear congeneric group (LCG) and their micelles above 85 mM have constant aggregation numbers n = 4-5. Micelles of alpha-MC and omega-MC are outliers in relation to the LCG, their aggregation number constantly increases; at 85 mM n = 6.8 (alpha-MC) and 6.5 (omega-MC). In micelles of derivatives beta-MC and gamma-MC, there is a low probability for the existence of hydrogen bonds. A micelle of alpha-MC probably has hydrogen bonds in its hydrophobic domain. PMID- 28863266 TI - Development of a Systems Science Curriculum to Engage Rural African American Teens in Understanding and Addressing Childhood Obesity Prevention. AB - Engaging youth from racial and ethnic minority communities as leaders for change is a potential strategy to mobilize support for addressing childhood obesity, but there are limited curricula designed to help youth understand the complex influences on obesity. Our aim was to develop and pilot test a systems science curriculum to elicit rural African American youth perspectives on childhood obesity and enhance their understanding of and support for obesity prevention solutions. The curriculum was designed so it could be integrated with existing positive youth development curricula that help youth advocate for and implement identified solutions. We conducted four workshop sessions with youth that engaged them in systems learning activities such as guided systems diagramming activities. The participants ( n = 21) completed validated surveys presession and postsession that assessed their causal attributions of obesity and support for obesity prevention policies. The youths' perception that environmental factors cause obesity increased ( p < .05), and perceptions that individual behavior and biology cause obesity did not change. Their support for policies that addressed food access and food pricing significantly increased ( p < .05). The youths' system diagrams elucidated links between multilevel factors such as personal attitudes, social influence, and the built environment, which provides important information for designing synergistic solutions. The changes we observed in youths' perceptions of obesity and support for policy changes have important implications for youths' interest and willingness to advocate for social and environmental changes in their community. The strategies have a promising role in supporting community mobilization to address childhood obesity. PMID- 28863267 TI - Obesity as a Predictor of Delayed Lactogenesis II. AB - BACKGROUND: Lactogenesis II is the onset of copious milk production. A delay in this has been associated with an increased risk of formula supplementation and early cessation of breastfeeding. Prepregnancy obesity has also been associated with decreased breastfeeding rates and early cessation. Research aim: This study aimed to evaluate the effect of prepregnancy obesity on self-reported delayed lactogenesis II. METHODS: We conducted a prospective observational cohort study of 216 women with a singleton pregnancy and who planned to breastfeed. We compared the onset of lactogenesis II between women with a body mass index (BMI) < 30 kg/m2 and women with a BMI >= 30 kg/m2. Using multivariate logistic regression analyses, we assessed the relationship between maternal BMI and delay of lactogenesis II. RESULTS: The prevalence of delayed lactogenesis II among women with prepregnancy BMI < 30 kg/m2 and BMI >= 30 kg/m2 was 46.4% and 57.9%, respectively. Delayed lactogenesis II occurred more frequently among women who were obese at the time of delivery ( p < .05). After controlling for the covariates, age, prepregnancy BMI, and gestational weight gain were positively associated with delayed lactogenesis II. CONCLUSION: Prepregnancy obesity and excessive gestational weight gain are associated with an increased risk of delayed lactogenesis II. Women who are at risk for delay in lactogenesis II and early breastfeeding cessation will need targeted interventions and support for them to achieve their personal breastfeeding goals. PMID- 28863268 TI - Two years' outcome of thread lifting with absorbable barbed PDO threads: Innovative score for objective and subjective assessment. AB - BACKGROUND: Thread-lifting rejuvenation procedures have evolved again, with the development of absorbable threads. Although they have gained popularity among plastic surgeons and dermatologists, very few articles have been written in literature about absorbable threads. This study aims to evaluate two years' outcome of thread lifting using absorbable barbed threads for facial rejuvenation. METHODS: Prospective comparative stud both objectively and subjectively and follow-up assessment for 24 months. RESULTS: Thread lifting for face rejuvenation has significant long-lasting effects that include skin lifting from 3-10 mm and high degree of patients' satisfaction with less incidence rate of complications, about 4.8%. Augmented results are obtained when thread lifting is combined with other lifting and rejuvenation modalities. CONCLUSION: Significant facial rejuvenation is achieved by thread lifting and highly augmented results are observed when they are combined with Botox, fillers, and/or platelet rich plasma (PRP) rejuvenations. PMID- 28863269 TI - Bacteriophages: the possible solution to treat infections caused by pathogenic bacteria. AB - Since their discovery in 1915, bacteriophages have been used to treat bacterial infections in animals and humans because of their unique ability to infect their specific bacterial hosts without affecting other bacterial populations. The research carried out in this field throughout the 20th century, largely in Georgia, part of USSR and Poland, led to the establishment of phage therapy protocols. However, the discovery of penicillin and sulfonamide antibiotics in the Western World during the 1930s was a setback in the advancement of phage therapy. The misuse of antibiotics has reduced their efficacy in controlling pathogens and has led to an increase in the number of antibiotic-resistant bacteria. As an alternative to antibiotics, bacteriophages have become a topic of interest with the emergence of multidrug-resistant bacteria, which are a threat to public health. Recent studies have indicated that bacteriophages can be used indirectly to detect pathogenic bacteria or directly as biocontrol agents. Moreover, they can be used to develop new molecules for clinical applications, vaccine production, drug design, and in the nanomedicine field via phage display. PMID- 28863270 TI - Mindfulness-based forgiveness groups for older adults. AB - Interventions that enable individuals to be more forgiving toward themselves and others are important for older adults. This article describes a group intervention for adults aged 60 or older that integrates forgiveness-related skills with a mindfulness approach. The Mindfulness-based Forgiveness Group was designed to meet for eight sessions. The skills taught included: recognizing one's own expectations and unenforceable rules, broadening one's perspectives about the context of the transgression, and discovering positive intentions through exercises as well as a variety of meditations to cultivate mindfulness, self-compassion and forgiveness. Data from five Mindfulness-Based Forgiveness Groups were collected. Based on pre- and post-test measures, analyses indicate that participants improved significantly in relation to forgiveness, mindfulness/self-compassion, and mental health. Using qualitative post-test data from participants, we identify elements of the intervention that appear to be helpful. Suggestions are provided for social workers seeking to replicate and build upon this promising intervention. PMID- 28863271 TI - Feasibility and acceptability of shared decision-making to promote alcohol behavior change among women Veterans: Results from focus groups. AB - BACKGROUND: Although rates of unhealthy drinking are high among women Veterans with mental health comorbidities, most women Veterans with mental comorbidities who present to primary care with unhealthy drinking do not receive alcohol related care. Barriers to alcohol-related treatment could be reduced through patient-centered approaches to care, such as shared decision-making. AIMS: We assessed the feasibility and acceptability of a telephone-delivered shared decision-making intervention for promoting alcohol behavior change in women Veterans with unhealthy drinking and co-morbid depression and/or probable post traumatic stress disorder. METHODS: We used 3, 2-hour focus group discussions with 19 women Veterans to identify barriers and solicit recommendations for using the intervention with women Veterans who present to primary care with unhealthy drinking and mental health comorbidities. Transcripts from the focus groups were qualitatively analyzed using template analysis. RESULTS: Although participants perceived that the intervention was feasible and acceptable for the targeted patient population, they identified the treatment delivery modality, length of telephone sessions, and some of the option grid content as potential barriers. Facilitators included strategies for enhancing the telephone-delivered shared decision-making sessions and diversifying the treatment options contained in the option grids. Focus group feedback resulted in preliminary adaptations to the intervention that are mindful of women Veterans' individual preferences for care and realistic in the everyday context of their busy lives. PMID- 28863272 TI - Recombinant protein rMBP-NAP restricts tumor progression by triggering antitumor immunity in mouse metastatic lung cancer. AB - Recombinant Helicobacter pylori neutrophil-activating protein fused with maltose binding protein (rMBP-NAP), a potential TLR2 ligand, was reported to possess immunomodulatory effects on in situ tumors in our previous study. In the present work, we attempt to elucidate the effect of rMBP-NAP at the local immune modulation in B16-F10-induced metastatic lung cancer. Our results demonstrated that growth of B16-F10 melanoma metastases in the lung was significantly arrested after rMBP-NAP treatment, along with marked reduction in metastatic lung nodules and significant increase in survival. The treatment induced both local and systemic immune responses, which were associated with higher influx of CD4+/CD8+ T cells and drove toward Th1-like and cytotoxic immune environment. Moreover, rMBP-NAP also showed significant anti-angiogenic activity by reducing vascularization in lung tumor sections. rMBP-NAP could induce antitumor immunity through activating Th1 cells and producing pro-inflammatory cytokines, which are responsible for the effective cytotoxic immune response against cancer progression. Our findings indicate that rMBP-NAP might be a novel antitumor therapeutic strategy. PMID- 28863273 TI - 2,3,4',5-tetrahydroxystilbene-2-O-beta-d-glycoside attenuates atherosclerosis in apolipoprotein E-deficient mice: role of reverse cholesterol transport. AB - The aim of this study was to evaluate the potential effects of 2,3,4',5 tetrahydroxystilbene-2-O-beta-d-glucoside (TSG) on the development of atherosclerotic plaque in ApoE-/- mice, and explore the mechanisms involved. Our data showed that after 8 weeks of treatment, TSG ameliorated serum levels of total cholesterol, triglyceride, and low density lipoprotein cholesterol, and increased serum levels of high density lipoprotein cholesterol in ApoE-/- mice. TSG suppressed hepatic steatosis, the formation of atherosclerotic lesions, and the formation of macrophage foam cells in ApoE-/- mice. Moreover, TSG improved the expressions of hepatic SR-BI, ABCG5, and CYP7A1, and up-regulated the protein expressions of aortic ABCA1 and ABCG1. An in-vitro study showed that TSG promoted macrophage cholesterol efflux and increased the protein expressions of ABCA1 and ABCG1. Our findings provide evidence for a positive role of TSG in preventing atherosclerosis by promoting reverse cholesterol transport. These effects may be achieved by stimulating cholesterol efflux through ABCA1 and ABCG1, promoting SR BI-mediated cholesterol uptake in the liver, increasing secretion of cholesterol into bile by ABCG5, and improving cholesterol metabolism by the CYP7A1 pathway. In addition, antioxidative and anti-inflammatory effects of TSG may also contribute to its inhibitory effects on atherosclerosis. Further study is needed to investigate whether other potential mechanisms are involved in TSG-mediated atheroprotection. PMID- 28863274 TI - Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans. PMID- 28863275 TI - Mutations in TSPAN12 Cause Autosomal-Dominant Familial Exudative Vitreoretinopathy. PMID- 28863276 TI - Immobilization of methotrexate anticancer drug onto the graphene surface and interaction with calf thymus DNA and 4T1 cancer cells. AB - Immobilization of methotrexate (MTX) anticancer drug onto the graphene surface is reported through three methods, including either covalent linkage via (a) EDC/NHS organic activators and (b) electrografting of MTX diazonium salt, or (c) noncovalent bonding, resulting in three different systems. To evaluate the interaction ability of the immobilized MTX with biological species, calf thymus DNA (ctDNA), mouse 4T1 breast tumor, and Human foreskin fibroblast (hFF) cells as models of the primary intracellular target of anticancer drugs, cancer and normal cells, respectively, are examined. The features of the constructed systems and their interactions with ctDNA are followed by surface analysis techniques and electrochemical methods. The results indicate that (i) the amount of the immobilized MTX on the graphene surface is affected by type of the immobilization method; and a maximum value of (Gamma=9.3+/-0.9pmolcm-2) is found via electrografting method, (ii) graphene-modified-MTX has high affinity for ctDNA in a wide dynamic range of concentrations, and (iii) the nature of the interaction is of electrostatic and/or hydrogen bonding type, formed most probably between OH, NH and CO groups of MTX and different DNA functions. Finally, electrochemical impedance spectroscopy results approved the high affinity of the systems for 4T1 cancer cells. PMID- 28863277 TI - Insights into genetic diversity and biological propensities of potentially zoonotic avian influenza H9N2 viruses circulating in Egypt. AB - Low pathogenic avian influenza (LPAI) H9N2 viruses have established endemic status in Egyptian poultry populations since 2012. Recently, four cases of human H9N2 virus infections in Egypt demonstrated the zoonotic potential of these viruses. Egyptian H9N2 viruses obtained from 2011 to 2014 phylogenetically grouped into three clusters (1-3) within subclade B of the G1 lineage. Antigenically, a close clustering of the Egyptian H9N2 viruses with other recent G1-B like H9N2 strains and a significant antigenic distance from viruses outside the G1-B lineage was evident. Recent Egyptian LPAIV H9N2 showed a tendency to increased binding with erythrocytes expressing alpha 2,6-linked sialic acid which correlated with the Q226L amino acid substitution at the receptor binding unit of the hemagglutinin (Q234L, H9 numbering). Sequence analyses of the N2 neuraminidase (NA) revealed substitutions in the NA hemadsorption site similar to the N2 of prepandemic H3N2/1968, but no distinct antigenic or functional characteristics of the H9N2 NA associated with increased zoonotic potential could be identified. PMID- 28863278 TI - On the use of SEM correlative tools for in situ mechanical tests. AB - In situ SEM mechanical tests are key to study crystal plasticity. In particular, imaging and diffraction (EBSD) allow microstructure and surface kinematics to be monitored all along the test. However, to get a full benefit from different modalities, it is necessary to register all images and crystallographic orientation maps from EBSD into the same frame. Different correlative approaches tracking either Pt surface markings, crystal orientations or grain boundaries, allow such registrations to be performed and displacement as well as rotation fields to be measured, a primary information for crystal plasticity identification. However, the different contrasts that are captured in different modalities and unavoidable stage motions also give rise to artifacts that are to be corrected to register the different information onto the same material points. The same image correlation tools reveal very powerful to correct such artifacts. Illustrated by an in situ uniaxial tensile test performed on a bainitic-ferritic steel sample, recent advances in image correlation techniques are reviewed and shown to provide a comprehensive picture of local strain and rotation maps. PMID- 28863279 TI - Strain measurement of 3D structured nanodevices by EBSD. AB - We present a new methodology to accurately measure strain magnitudes from 3D nanodevices using Electron Backscatter Diffraction (EBSD). Because the dimensions of features on these devices are smaller than the interaction volume for backscattered electrons, EBSD patterns from 3D nanodevices will frequently be the superposition of patterns from multiple material regions simultaneously. The effect of this superposition on EBSD strain measurement is demonstrated, along with an approach to separate EBSD patterns from these devices via subtraction. The subtraction procedure is applied to 33 nm wide SiGe lines, and it provides accurate strain magnitudes where the traditional EBSD strain analysis method undervalues the strain magnitude by an order of magnitude. The approach provides a strain measurement technique for nanoscale 3D structures that is high spatial resolution, nondestructive, and accurate. PMID- 28863280 TI - Molar absorption coefficients and stability constants of Zincon metal complexes for determination of metal ions and bioinorganic applications. AB - : Zincon (ZI) is one of the most common chromophoric chelating probes for the determination of Zn2+ and Cu2+ ions. It is also known to bind other metal ions. However, literature data on its binding properties and molar absorption coefficients are rather poor, varying among publications or determined only in certain conditions. There are no systematic studies on Zn2+ and Cu2+ affinities towards ZI performed under various conditions. However, this widely commercially available and inexpensive agent is frequently the first choice probe for the measurement of metal binding and release as well as determination of affinity constants of other ligands/macromolecules of interest. Here, we establish the spectral properties and the stability of ZI and its complexes with Zn2+, Cu2+, Cd2+, Hg2+, Co2+, Ni2+ and Pb2+ at multiple pH values from 6 to 9.9. The obtained results show that in water solution the MZI complex is predominant, but in the case of Co2+ and Ni2+, M(ZI)2 complexes are also formed. The molar absorption coefficient at 618 nm for ZnZI and 599nm for CuZI complexes at pH7.4 in buffered (I=0.1M) water solutions are 24,200 and 26,100M-1cm-1, respectively. Dissociation constants of those complexes are 2.09*10-6 and 4.68*10-17M. We also characterized the metal-assisted Zincon decomposition. Our results provide new and reassessed optical and stability data that are applicable to a wide range of chemical and bioinorganic applications including metal ion detection, and quantification and affinity studies of ligands of interest. SYNOPSIS: Accurate values of molar absorption coefficients of Zincon complex with Zn2+, Cd2+, Hg2+, Co2+, Ni2+, Cu2+, and Pb2+ for rapid metal ion quantification are provided. Zincon stability constants with Zn2+ and Cu2+ in a wide pH range were determined. PMID- 28863281 TI - Aging-related decline in the induction of Nrf2-regulated antioxidant genes in human bronchial epithelial cells. AB - Evidence from animal studies suggests that stress-induced increases in Nrf2 regulated antioxidant gene expression, a critical mechanism of cellular protection, declines with aging. This study examined whether this also occurs in humans. We measured the basal and inducible levels of Nrf2-regulated antioxidant genes in human bronchial epithelial (HBE) cells from subjects of young adult (21 29 years) and older (60-69 years) non-smokers, and explored factors affecting expresion. The basal expression of three representative Nrf2-regulated genes, the catalytic and modulator subunits of glutamate cysteine ligase (GCLC and GCLM, respectively), and NAD(P)H quinone oxidoreductase 1 (NQO1), was higher in cells from the older donors compared with cells from the young adult donors. Upon exposure to the Nrf2 activator, sulforaphane (SF), the expression of these antioxidant genes was increased in cells from both the young adults and the older donors; however, the induction by SF in older donor cells was significantly less than that seen in young adult cells. In addition, the activation of an EpRE driven reporter by SF was lower in cells from older donors compared to cells from young adults. The basal expression of Nrf2 protein was also lower in cells from older donors than cells from young adults. Furthermore, we found that the basal expression of both Bach1 and c-Myc, two Nrf2 suppressors, was higher in cells from older adults than from young adult donors. In summary, our data suggest that, as in other species, basal expression of Nrf2-regulated genes increases with aging, while inducibility declines with aging. The increased expression of Nrf2 suppressors such as Bach1 and c-Myc may contribute to the impaired inducibility of the Nrf2-regulated antioxidant genes with aging in human bronchial epithelial cells. PMID- 28863282 TI - Factor structure and psychometric properties of a Romanian translation of the Body Appreciation Scale-2. AB - We examined the psychometric properties of a Romanian translation of the 10-item Body Appreciation Scale-2 (BAS-2). A total of 453 university students from Romania completed the BAS-2, along with measures of disordered eating, self esteem, satisfaction with life, and subjective happiness. In addition, a separate sample of university students (N=109) completed only the BAS-2 at two time-points three weeks apart. Principal-axis factor analysis indicated that BAS-2 scores had a one-dimensional factor structure in both women and men. Confirmatory factor analysis indicated that this factor structure had adequate fit, but invariance across sex was not supported. Further analyses indicated that BAS-2 scores evidenced internal consistency, convergent validity, and test-retest reliability in both women and men. These results suggest that BAS-2 scores reduce to one dimension in Romanian adults, but the lack of sex invariance may indicate that the same latent construct is not being measured in women and men. PMID- 28863283 TI - The role of propionic acid at diagnosis predicts mortality in patients with septic shock. AB - PURPOSE: This study aims to assess the diagnostic and prognostic value of propionic acid in patients with septic shock on a medical intensive care unit (ICU). METHODS: Serum propionic acid and clinical common cytokines levels were measured within 24h after the diagnosis of sepsis, and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, and Mortality were recorded in ICU. A 28-day and 90-day follow-up was performed for all patients. RESULTS: A total of 118 septic patients were enrolled in this study. The propionic acid was higher in patients with septic shock compared with sepsis. Multivariate logistic regression analysis showed that propionic acid was independent predictor of sepsis (odds ratio: 1.279; 95% confidence interval: 1.069-1.530; P=0.007) and septic shock (odds ratio: 1.859; 95% confidence interval: 1.342-2.576; P<0.001) and ICU mortality (odds ratio: 1.331; 95% confidence interval: 1.107-1.600; P=0.002), 28-day mortality (odds ratio: 1.259; 95% confidence interval: 1.046-1.514; P=0.015) and 90-day mortality (odds ratio: 1.304; 95% confidence interval: 1.092-1.558; P=0.003). The receiver operating characteristic curve (AUC) analysis showed the areas under of propionic acid on ICU admission day for predicting sepsis and septic shock were 0.773 and 0.85 respectively, the areas under of propionic acid for predicting ICU mortality, 28-d and 90-d mortality were 0.779, 0.739 and 0.809 respectively. Using a PA cutoff of 0.053 and 0.095 for predicting sepsis and septic shock respectively, the sensitivity was 97.62% and 85.5%, and the specificity was 58% and 83.5%, respectively. Using a PA cutoff of 0.139 for predicting ICU mortality, 28- and 90-day mortality, the sensitivity was 69.39%, 67.44% and 69.09% respectively, and the specificity was 78.26%, 73.33% and 82.54% respectively. CONCLUSIONS: Propionic acid showed diagnostic capacity to diagnose septic shock and revealed prognostic information for mortality. PMID- 28863284 TI - Establishing objective volume-outcome measures for anterior and posterior cervical spine fusion. AB - OBJECTIVES: There is a growing literature on the relationship between provider volume and patient outcomes, specifically within joint arthroplasty and lumbar spine surgery. Such benchmarks have yet to be established for many other spinal procedures, including cervical fusion. We sought to determine whether outcomes based volume measures for both surgeons and hospitals can be established for cervical spine fusion procedures. PATIENTS AND METHODS: This was a retrospective review of patient data in the Florida Statewide Inpatient Dataset (SID; 2011-14). Patients identified in the Florida SID who underwent either anterior or posterior cervical fusion were identified along with the operative surgeons and the hospitals where the procedures were performed. Socio-demographic data, as well as medical and surgical characteristics were obtained, as were the development of complications and readmissions up to 90days following hospital discharge. Surgeon and hospital volume were plotted separately against the number of complications and readmissions in an adjusted spline analysis. Multivariable logistic regression analysis was subsequently performed to assess the effect of surgeon and hospital volume on post-operative complications and readmissions. RESULTS: There were 8960 patients with posterior cervical fusion and 57,108 anterior cervical fusions (total=66,068) identified for inclusion in the analysis. The patients of low-volume surgeons were found to have an increased (OR 1.83; 95% CI 1.65, 2.02) likelihood of complications following anterior and posterior (OR 1.45; 95% CI 1.24, 1.69) cervical fusion. Low-volume surgeons demonstrated increased likelihood of readmission, irrespective of anterior (OR 1.37; 95% CI 1.29, 1.47) or posterior (OR 1.31; 95% CI 1.16, 1.48) approach. No clinically meaningful differences in the likelihood of complications or readmissions were detected between high- and low-volume hospitals. CONCLUSIONS: This study demonstrates objective volume-outcome measures for surgeons who perform anterior and posterior cervical fusions. Our results have immediate applicability to clinical practice and may be used to benchmark procedural volume. Findings with respect to hospitals speak against the need for healthcare regionalization in this specific clinical context. PMID- 28863285 TI - Endovascular treatment of acute ischemic stroke in octogenarians: A meta-analysis of observational studies. AB - OBJECTIVES: The aim of this study is to compare procedural outcomes after endovascular treatment (EVT) according to age (>=80 years vs. <80 years) and to examine treatment outcomes after mechanical thrombectomy using a stent retriever between the different age groups. PATIENTS AND METHODS: A systemic literature review of an online database of articles published from January 2004 to February 2017 was conducted. The primary outcome was successful recanalization in the final angiogram and symptomatic intracranial hemorrhage (S-ICH) after EVT. The secondary outcome was good clinical outcome and mortality at 3 months. A random effect model was used in cases of heterogeneity over 50%. RESULTS: Eight articles including 1711 patients compared outcomes according to age. Successful recanalization did not differ significantly between the two groups (>=80 years, n=214 (70.6%);<80years, n=1035 (73.5%); OR: 0.797; 95% CI: 0.599-1.060). Age >=80 years did not significantly increase the risk of S-ICH (OR: 1.271; 95% CI: 0.784 2.060). Octogenarians showed lower good clinical outcome at 3 months (OR: 0.323; 95% CI: 0.233-0.448) and higher mortality (OR: 2.689; 95% CI: 2.050-3.527). Three studies including 670 patients (>=80 years, n=140;<80years, n=530) assessed outcomes after mechanical thrombectomy using a stent retriever. Successful recanalization (OR: 0.786; 95% CI: 0.507-1.218) and S-ICH (OR: 1.679; 95% CI: 0.918-3.071) did not significantly differ between the two groups. CONCLUSIONS: Procedural outcomes such as successful recanalization and S-ICH after EVT in octogenarians are comparable to those seen in patients <80years. EVT is technically feasible to treat hyperacute stroke in octogenarians. Further large scale studies dealing with various factors, such as occlusion site, stroke severity, comorbidities, and concomitant use of endovascular devices are required. PMID- 28863286 TI - Flow diversion with the pipeline embolization device for patients with intracranial aneurysms and antiplatelet therapy: A systematic literature review. AB - Flow diversion with the Pipeline Embolization Device (PED) is reported as a safe and efficient treatment for patients with intracranial aneurysms; however, literature discussing the antiplatelet (APT) regimen used before and after the PED is limited. Our aim was to systematically review and summarize available data regarding the APT regimen and the platelet function test (PFT) that was used. We also sought to provide an overview of the aneurysm morphologies and adverse event rates associated with the PED use. This systematic review was conducted according to the PRISMA statement and eligible studies were identified through search of the PubMed and Cochrane databases. We reviewed 28 studies, involving 1556 patients that underwent aneurysm treatment with the PED. The preprocedural aspirin (ASA) 300- 325mg (2-14days) combined with clopidogrel 75mg (3 to >10days) were used as a treatment strategy in 61.7% of patients and ASA 81mg with clopidogrel 75mg for 5-10days for 27%. Patients who received low versus high dose pre-PED ASA, were at less risk for a hemorrhagic event (0.7% versus 3.3%, p=0.053); however no statistical significance was reached. There was also lack of relationship between patients that received low versus high preprocedural ASA in terms of thromboembolic events. Regarding postprocedural APT, ASA (>6months) and clopidogrel (3- 12 months) was the regimen of choice for 93% of patients. Most studies conducted at least one PFT, most common being the VerifyNow. The most frequently reported target P2Y12 Reaction unit (PRU) and Aspirin Reaction Unit (ARU) values were <230 and <550 respectively. There was no statistically demonstrable difference in regards to thrombotic events between centers that conducted at least one PFT and centers that did not test their patients with a PFT. The overall rates of symptomatic thrombotic episodes were 6.6% and hemorrhagic were 3%. The pre- and post-PED APT dose and duration varies across different institutions. More prospective studies are needed to compare the efficacy of different APT agents and reach conclusions regarding use of PFT and platelet reaction values in order to decrease hemorrhagic and thromboembolic complications associated with the PED. PMID- 28863287 TI - Proving of a Mathematical Model of Cell Calculation Based on Apparent Diffusion Coefficient. AB - OBJECTIVES: Recently, Atuegwu et al. proposed a mathematical model based on ADCmean and ADCmin to calculation of cellularity. Our purpose was to compare the calculated cellularity according to the formula with the estimated cell count by histopathology in different tumors. METHODS: For this study, we re-analyzed our previous data regarding associations between ADC parameters and histopathological findings. Overall, 134 patients with different tumors were acquired for the analysis. For all tumors, the number of tumor cells was calculated according to Atuegwu et al. 2013. We performed a correlation analysis between the calculated and estimated cellularity. Thereby, Pearson's correlation coefficient was used and P < .05 was taken to indicate statistical significance in all instances. RESULTS: The estimated and calculated cellularity correlated well together in HNSCC (r=0.701, P=.016) and lymphomas (r=0.661, P=.001), and moderately in rectal cancer (r=0.510, P=.036). There were no statistically significant correlations between the estimated and calculated cellularity in uterine cervical cancer, meningiomas, and in thyroid cancer. CONCLUSION: The proposed formula for cellularity calculation does not apply for all tumors. It may be used for HNSCC, cerebral lymphomas and rectal cancer, but not for uterine cervical cancer, meningioma, and thyroid cancer. Furthermore, its usefulness should be proved for other tumors. PMID- 28863288 TI - Radiation and criticality safety analyses for the highly-enriched uranium core removal from a research reactor. AB - Analysis was performed to estimate radiation levels during removal and packaging of the highly-enriched uranium core of the JM-1 SLOWPOKE-2 research reactor. Due to severe limitations of space in and around the reactor pool, the core could not be removed in the conventional manner as was done for previous SLOWPOKE defuelling operations. A transfer shield, with a balance between shielding efficacy, volume and weight was designed. Fuel depletion, Monte Carlo shielding and criticality calculations were performed. Comparisons of measured and calculated dose rates as well as results of the criticality safety assessment are presented. The designed transfer shield reduced the calculated unshielded dose rate from 29Sv/h to 8mSv/h. The maximum calculated effective neutron multiplication factor of approximately 0.89 was below the 0.91 upper subricital limit. PMID- 28863289 TI - Accounting for the impact of parent internalizing symptoms on Parent Training benefits: The role of positive parenting. AB - Parent Training (PT) is not as effective for parents with histories of internalizing symptoms as it is for other parents. This study aimed to determine which dimensions of parenting, notably parenting efficacy, positive parenting, inconsistent discipline, and poor supervision, mediate the association between parent lifetime internalizing symptoms and post-PT child emotional and behavioral difficulties. One hundred fourteen parents (82% biological mothers) of children aged 9-12 years received PT at an urban children's mental health clinic. Parents reported their lifetime internalizing symptoms, pre- and post- PT parenting skills, and pre- and post- PT child difficulties. Positive parenting fully mediated the relation between parent lifetime internalizing symptoms and elevated child post-PT emotional and behavioral difficulties. Specifically, parents higher in internalizing symptoms reported lower positive parenting post-PT, which in turn predicted more child difficulties post-PT. Findings suggest that fostering positive parenting in PT may be particularly important for parents with histories of internalizing symptoms. PMID- 28863290 TI - Zinc-arsenic interactions in soil: Solubility, toxicity and uptake. AB - Arsenic (As) and zinc (Zn) are common co-contaminants in mining impacted soils. Their interaction on solubility and toxicity when present concurrently is not well understood in natural systems. The aim of this study was to observe their interaction in solubility (soil-solution), bioaccumulation (shoot uptake) and toxicity to cucumber (Cucumis sativa L) conducting 4 weeks pot study in 5 different soils spiked with As (0, 2, 4, 8 to 1024 mg kg-1) individually and with Zn at two phytotoxic doses. The As pore-water concentration was significantly reduced (df = 289, Adjusted R2 = 0.84, p < 0.01) in the presence of Zn in the whole dataset, whereas Zn and Zn2+ activity in pore-water was reduced significantly only in the two alkaline soils. This outcome may be due to adsorption/surface precipitation or tertiary bridging complexation. No homogenous precipitation of zinc arsenate could be established using electron microscopy, XRD or even equilibrium calculations. For bioaccumulation phase, no significant effect of Zn on As uptake was observed except acidic MG soil whereas, Zn uptake was significantly reduced (p < 0.05) by As in whole dataset. However, an additive response was observed mostly except acidic MG soil. The synergistic response (more than additive) was predominant in this soil for a wide range of inhibition concentration (0-80%) at both Zn EC10 and EC50 levels. Since additive response is mostly considered in risk assessment for mixtures, precautions should be implemented for assessment of toxicity for As-Zn mixture in acidic soil due to their synergistic response in some soils. PMID- 28863291 TI - Comparison of methods for determination of total oil sands-derived naphthenic acids in water samples. AB - There are several established methods for the determination of naphthenic acids (NAs) in waters associated with oil sands mining operations. Due to their highly complex nature, measured concentration and composition of NAs vary depending on the method used. This study compared different common sample preparation techniques, analytical instrument methods, and analytical standards to measure NAs in groundwater and process water samples collected from an active oil sands operation. In general, the high- and ultrahigh-resolution methods, namely high performance liquid chromatography time-of-flight mass spectrometry (UPLC-TOF-MS) and Orbitrap mass spectrometry (Orbitrap-MS), were within an order of magnitude of the Fourier transform infrared spectroscopy (FTIR) methods. The gas chromatography mass spectrometry (GC-MS) methods consistently had the highest NA concentrations and greatest standard error. Total NAs concentration was not statistically different between sample preparation of solid phase extraction and liquid-liquid extraction. Calibration standards influenced quantitation results. This work provided a comprehensive understanding of the inherent differences in the various techniques available to measure NAs and hence the potential differences in measured amounts of NAs in samples. Results from this study will contribute to the analytical method standardization for NA analysis in oil sands related water samples. PMID- 28863292 TI - Oxidation of clofibric acid in aqueous solution using a non-thermal plasma discharge or gamma radiation. AB - In this work, we study degradation of clofibric acid (CFA) in aqueous solution using either ionizing radiation from a60Co source or a non-thermal plasma produced by discharges in the air above the solution. The results obtained with the two technologies are compared in terms of effectiveness of CFA degradation and its by-products. In both cases the CFA degradation follows a quasi exponential decay in time well modelled by a kinetic scheme which considers the competition between CFA and all reaction intermediates for the reactive species generated in solution as well as the amount of the end product formed. A new degradation law is deduced to explain the results. Although the end-product CO2 was detected and the CFA conversion found to be very high under the studied conditions, HPLC analysis reveals several degradation intermediates still bearing the aromatic ring with the chlorine substituent. The extent of mineralization is rather limited. The energy yield is found to be higher in the gamma radiation experiments. PMID- 28863293 TI - Dynamic arsenic aging processes and their mechanisms in nine types of Chinese soils. AB - Although specific soil properties controlling the arsenic (As) aging process have been studied extensively, few investigations have attempted to determine how soil types influence As bioavailability and fractionations in soils. Nine types of soil were selected from typical grain producing areas in China, and the bioavailability and fractionations of As during aging were measured. Results showed that available As in all soils rapidly decreased in the first 30 days and slowly declined thereafter. In spiked soils, As easily became less available and less toxic in low pH soils compared to high pH soils, demonstrating the importance of soil pH on As availability. Results from fitting kinetic equations revealed that the pseudo-second-order model described the As aging processes well in all soils (R2 = 0.945-0.999, P < 0.01, SE = 0.09-4.25), implying that the mechanism for As aging combined adsorption, external diffusion, and internal diffusion. Fe oxides were more important than Al oxides for determining the As aging rate (|k|). Based on these results, we are the first to propose the approximate aging equilibrium time (T) for As, which was mainly influenced by soil clay content. The shortest time for approximate stabilization of As aging was 28 d in latosol soils (LS), while the longest approximate equilibrium time was 169 d in cinnamon soils (CS). Individual soil properties controlling the variation in different As fractionations further confirmed that the influences of soil types on As aging were the result of the combined effects of soil properties and a time-consuming redistribution process. PMID- 28863294 TI - Chlorine decay and trihalomethane formation following ferrate(VI) preoxidation and chlorination of drinking water. AB - This paper presents the effect of preoxidation with ferrate(VI) (FeVIO42-, Fe(VI)) prior to chlorination on chlorine decay and formation of disinfection by products in filtered raw water from a full-scale drinking water treatment plant. The rate of chlorine decay became significantly faster as the concentration of ferrate(VI) increased. Chlorine degradation followed two first-order decay reactions with rate constants k1 and k2 for fast and slow decay, respectively. Kinetic modeling established the relationships between k1 and k2 and varying dosages of chlorine and ferrate(VI). When ferrate(VI) was used as a pre-oxidant, the levels of trihalomethanes (trichloromethane (TCM), dichlorobromomethane (DCBM), dibromochloromethane (DBCM), and tribromomethane (TBM)) in water samples decreased as the ferrate(VI) concentration increased. The concentrations of these trihalomethanes followed the order TCM > DCBM ~ DBCM > TBM. PMID- 28863295 TI - Enhanced chiral recognition by beta-cyclodextrin at liquid/liquid interfaces as revealed by chromatographic and interfacial tension measurements. AB - The chiral selectivity of beta-cyclodextrin (beta-CD) in the water/hexane (3.0% THF) two-phase system is studied with chromatography and interfacial tension measurements. Chromatography using silica gel impregnated with aqueous beta-CDas the stationary phase reveals that the chiral selectivity of this system is higher than that predicted from the beta-CD complexation that occurs in bulk water. The retention of the solutes and chiral selectivity can be explained by the adsorption of beta-CD at the interface between the aqueous phase (AP) and hexane (3.0% THF) phase. The interfacial tension measurements suggest that beta-CD molecules forms a monolayer at this interface. The interfacial complexation constants are larger than the corresponding bulk water constants by at least one order of magnitude. The beta-CD molecules adsorbed at the interface are preferably oriented for the formation of inclusion complexes, and thereby solute molecules are directly accommodated in the CD cavity at the interface without partitioning into the AP. The present chromatography-based method probes the interfacial phenomena that are not accessible by other methods. Hence, the liquid/liquid interface is a new field for molecular recognition that does not occur in bulk solution phases. PMID- 28863296 TI - Associations of prolonged standing with musculoskeletal symptoms-A systematic review of laboratory studies. AB - While prolonged standing has shown to be detrimentally associated with musculoskeletal symptoms, exposure limits and underlying mechanisms are not well understood. We systematically reviewed evidence from laboratory studies on musculoskeletal symptom development during prolonged (>=20min) uninterrupted standing, quantified acute dose-response associations and described underlying mechanisms. Peer-reviewed articles were systematically searched for. Data from included articles were tabulated, and dose-response associations were statistically pooled. A linear interpolation of pooled dose-response associations was performed to estimate the duration of prolonged standing associated with musculoskeletal symptoms with a clinically relevant intensity of >=9 (out of 100). We included 26 articles (from 25 studies with 591 participants), of which the majority examined associations of prolonged standing with low back and lower extremity symptoms. Evidence on other (e.g., upper limb) symptoms was limited and inconsistent. Pooled dose-response associations showed that clinically relevant levels of low back symptoms were reached after 71min of prolonged standing, with this shortened to 42min in those considered pain developers. Regarding standing related low back symptoms, consistent evidence was found for postural mechanisms (i.e., trunk flexion and lumbar curvature), but not for mechanisms of muscle fatigue and/or variation in movement. Blood pooling was the most consistently reported mechanism for standing-related lower extremity symptoms. Evidence suggests a detrimental association of prolonged standing with low back and lower extremity symptoms. To avoid musculoskeletal symptoms (without having a-priori knowledge on whether someone will develop symptoms or not), dose-response evidence from this study suggests a recommendation to refrain from standing for prolonged periods >40min. Interventions should also focus on underlying pain mechanisms. PMID- 28863297 TI - Clinical gait evaluation of patients with knee osteoarthritis. AB - Knee osteoarthritis (KOA) is the most common osteoarthritis in lower limbs, and gait measurement is important to evaluate walking function of KOA patients before and after treatment. The third generation Intelligent Device for Energy Expenditure and Activity (IDEEA3) is a portable gait analysis system to evaluate gaits. This study is to evaluate the accuracy and reliability of IDEEA3 for gait measurement of KOA patients. Meanwhile, gait differences between KOA patients and healthy subjects are examined. Twelve healthy volunteers were recruited for measurement comparison of gait cycle (GC), cadence, step length, velocity and step counts between a motion analysis system and a high-speed camera (GoPro Hero3). Twenty-three KOA patients were recruited for measurement comparison of former five parameters between GoPro Hero3 and IDEEA3. Paired t-test, Concordance Correlation Coefficient (CCC) and Intraclass Correlation Coefficient (ICC) were used for data analysis. All p-values of paired t-tests for GC, cadence, step length and velocity were greater than 0.05 while all CCC and ICC results were above 0.95. The measurements of GC, cadence, step length, velocity and step counts by motion analysis system are highly consistent with the measurements by GoPro Hero3. The measurements of former parameters by GoPro Hero3 are not statistically different from the measurements by IDEEA3. IDEEA3 can be effectively used for the measurement of GC, cadence, step length, velocity and step counts in KOA patients. The KOA patients walk with longer GC, lower cadence, shorter step length and slower speed compared with healthy subjects in natural speed with flat shoes. PMID- 28863298 TI - Effectiveness of assertive case management on repeat self-harm in patients admitted for suicide attempt: Findings from ACTION-J study. AB - BACKGROUND: Self-harm is an important risk factor for subsequent suicide and repetition of self-harm, and a common cause of emergency department presentations. However, there still remains limited evidence on intervention in emergency department settings for individuals who self-harm. METHODS: This multicentre, randomised controlled trial was conducted at 17 general hospitals in Japan. In total, 914 adult patients admitted to emergency departments for a suicide attempt and had a DSM-IV-TR axis I disorder were randomly assigned to two groups, to receive either assertive case management (intervention) or enhanced usual care (control). Assertive case management was introduced by the case manager during emergency department admissions for suicide attempts, and continued after discharge. Interventions were provided until the end of the study period (for at least 18 months and up to 5 years). RESULTS: The number of overall self-harm episodes per person-year was significantly lower in the intervention group (adjusted incidence risk ratio (IRR) 0.88, 95%CI 0.80-0.96, p=0.0031). Subgroup analysis showed a greater reduction of overall self-harm episodes among patients with no previous suicide attempt at baseline (adjusted IRR 0.73, 95% CI 0.53-0.98, p=0.037). LIMITATIONS: Patients younger than 20 years and patients who self-harmed but were not admitted to an emergency department were excluded. CONCLUSIONS: The present study showed that assertive case management following emergency admission for a suicide attempt reduced the incident rate of repeat overall self-harm. PMID- 28863299 TI - Sensory profiles as potential mediators of the association between hypomania and hopelessness in 488 major affective outpatients. AB - INTRODUCTION: Extreme sensory processing patterns may contribute to the pathophysiology of major affective disorders. We aimed to examine whether significant correlations exist between sensory profiles, hypomania, self-reported depression, and hopelessness and whether sensory profiles may be potential mediators of the association between hypomania and depression/hopelessness. METHODS: The sample consisted of 488 euthymic affective disorder patients of which 283 diagnosed with unipolar and 162 with bipolar disorder with an age ranging from 18 to 65 years (mean = 47.82 +/- 11.67). RESULTS: Lower registration of sensory input and sensory sensitivity significantly correlated with elevated self-reported depression, hopelessness, and irritable/risk-taking hypomania while sensation seeking and avoiding significantly correlated with elevated depression and hopelessness but not with irritable/risk-taking hypomania. Moreover, individuals with lower ability to register sensory input and higher hypomania showed higher self-reported depression than those with good registration of sensory information. According to SEM analyses, there was both a direct/indirect effect of irritable/risk-taking on depression-hopelessness with the mediation model explaining 48% of the variance in depression-hopelessness. LIMITATIONS: The relatively small sample size and the cross-sectional nature of the study design do not allow the generalization of the main findings. CONCLUSION: Low registration was associated with enhanced depressed mood and hopelessness while sensory seeking may be considered a resilient factor. PMID- 28863300 TI - Affective reactivity to daily life stress: Relationship to positive psychotic and depressive symptoms in a general population sample. AB - INTRODUCTION: Increased affective reactivity to daily life stress has been found in individuals with psychosis and depression, and in those at risk for these conditions. Because depressive and psychotic symptoms often co-occur, increased affective reactivity in these disorders may be explained by the presence of depressive symptoms, psychotic symptoms, or both. Therefore, we examined whether affective reactivity to daily stress is related to positive psychotic symptoms, independently of depressive symptoms, and vice versa. METHODS: We used data from an intensive sampling study in the general population (n = 411), with three measurements a day (t = 90). The following subjective stressors were assessed: appraisal of activities, appraisal of social interactions, and experienced physical discomfort. Affective reactivity was conceptualized as both the positive affect (PA) and negative affect (NA) response to these stressors. By means of mixed model analyses, it was examined whether affective reactivity was independently related to depressive and/or positive psychotic symptoms. RESULTS: The PA response to activities and NA response to social interactions were negatively and positively related to depressive symptoms, respectively, independent of psychotic symptoms. In contrast, no (in)dependent association was found between positive psychotic symptoms and affective reactivity to any of the daily life stressors. These findings were confirmed in a subsample with increased symptoms. LIMITATIONS: The prevalence of positive psychotic symptoms was relatively low in this general population sample. CONCLUSIONS: Increased affect reactivity predicts depressive symptoms, but not positive psychotic symptoms. Affective reactivity may still facilitate the development of psychotic symptomatology via its impact on depressive symptoms. PMID- 28863301 TI - Long-term atmospheric visibility trends in megacities of China, India and the United States. AB - Millions of premature deaths worldwide every year mostly in China and India are contributed by the poor air quality. The atmospheric visibility is a proven indicator of the ambient air quality. In this study, nine megacities were selected, including Beijing, Shanghai and Guangzhou from China, Chicago, Los Angeles (LA) and New York City (NYC) from the United States, and Mumbai, Chennai and Jaipur from India. The data of visibility, aerosol optical depth (AOD), and meteorological factors from 1973 to 2015 were collected. The temporal variations of annual and monthly percentages of bad days (visibility < 5km) and good days (visibility > 15km) were evaluated. Visibility of Chicago, LA and NYC gradually improved during the past 43 years and has reached a very good level (good day percentages: 75-88%; bad day percentages: 0 - 4%). Conversely, visibility in Mumbai, Chennai and Jaipur continued deteriorating and suffered an extremely poor visibility situation in recent years (good day percentages: 0; bad day percentages: 6-100%). Likewise, visibility in Beijing, Shanghai and Guangzhou has experienced the worsening period during the industrial development from 1970s and turned better after the 1990s. A strong seasonal pattern of bad day percentages of each year were observed in most cities, especially in the winter, which is caused by the fossil fuel combustion for heating, relatively high relative humidity, and other unfavorable meteorological conditions. The low visibility events occurred more frequently in days with low wind speeds and specific wind directions, further explaining the seasonal patterns of visibility. With population growth from the period of 2000-2010 to the period of 2011-2015, AOD and bad day percentages both increased in Mumbai, Chennai, Jaipur and Beijing while others were relatively stable. This study demonstrated that the macro control of pollution emissions could effectively reduce air deterioration. The relationships among visibility variation, meteorological, pollutant and population factors provide valuable scientific support for public health researches, air quality managements (monitoring and forecasting), and clean energy initiatives. PMID- 28863302 TI - Beyond the Normalized Difference Vegetation Index (NDVI): Developing a Natural Space Index for population-level health research. AB - BACKGROUND: Natural spaces can provide psychological benefits to individuals, but population-level epidemiologic studies have produced conflicting results. Refining current exposure-assessment methods is necessary to advance our understanding of population health and to guide the design of health-promoting urban forms. OBJECTIVES: The aim of this study was to develop a comprehensive Natural Space Index that robustly models potential exposure based on the presence, form, accessibility, and quality of multiple forms of greenspace (e.g., parks and street trees) and bluespace (e.g., oceans and lakes). MATERIAL AND METHODS: The index was developed for greater Vancouver, Canada. Greenness presence was derived from remote sensing (NDVI/EVI); forms were extracted from municipal and private databases; and accessibility was based on restrictions such as private ownership. Quality appraisals were conducted for 200 randomly sampled parks using the Public Open Space Desktop Appraisal Tool (POSDAT). Integrating these measures in GIS, exposure was assessed for 60,242 postal codes using 100- to 1,600-m buffers based on hypothesized pathways to mental health. A single index was then derived using principal component analysis (PCA). RESULTS: Comparing NDVI with alternate approaches for assessing natural space resulted in widely divergent results, with quintile rankings shifting for 22-88% of postal codes, depending on the measure. Overall park quality was fairly low (mean of 15 on a scale of 0-45), with no significant difference seen by neighborhood-level household income. The final PCA identified three main sets of variables, with the first two components explaining 68% of the total variance. The first component was dominated by the percentages of public and private greenspace and bluespace and public greenspace within 250m, while the second component was driven by lack of access to bluespace within 1 km. CONCLUSIONS: Many current approaches to modeling natural space may misclassify exposures and have limited specificity. The Natural Space Index represents a novel approach at a regional scale with application to urban planning and policy-making. PMID- 28863303 TI - Low doses and non-targeted effects in environmental radiation protection; where are we now and where should we go? AB - The field of low dose radiobiology has advanced considerably in the last 30 years from small indications in the 1980's that all was not simple, to a paradigm shift which occurred during the 1990's, which severely dented the dose-driven models and DNA centric theories which had dominated until then. However while the science has evolved, the application of that science in environmental health protection has not. A reason for this appears to be the uncertainties regarding the shape of the low dose response curve, which lead regulators to adopt a precautionary approach to radiation protection. Radiation protection models assume a linear relationship between dose (i.e. energy deposition) and effect (in this case probability of an adverse DNA interaction leading to a mutation). This model does not consider non-targeted effects (NTE) such as bystander effects or delayed effects, which occur in progeny cells or offspring not directly receiving energy deposition from the dose. There is huge controversy concerning the role of NTE with some saying they reflect "biology" and that repair and homeostatic mechanisms sort out the apparent damage while others consider them to be a class of damage which increases the size of the target. One thing which has recently become apparent is that NTE may be very critical for modelling long-term effects at the level of the population rather than the individual. The issue is that NTE resulting from an acute high dose such as occurred after the A-bomb or Chernobyl occur in parallel with chronic effects induced by the continuing residual effects due to radiation dose decay. This means that if ambient radiation doses are measured for example 25 years after the Chernobyl accident, they only represent a portion of the dose effect because the contribution of NTE is not included. PMID- 28863304 TI - Is therapist evaluation of Social Anxiety/Avoidance traits associated with patient-reported attachment style? AB - The Social Anxiety/Avoidance Scale was recently added to the Shedler Westen Assessment Procedure (SWAP), and requires independent validation. This study used data drawn from a larger ongoing project in order to retrospectively examine its convergent validity with two self-report attachment measures: Relationship Questionnaire (RQ) and Experiences in Close Relationships Questionnaire-Revised (ECR-R). Fifty-two patients completed the RQ and the ECR-R before beginning psychotherapy treatment. Clinicians rated the patients on the SWAP after six sessions. The SWAP Social Anxiety/Avoidance Scale (SWAP-SAAS) was negatively related to the RQ secure attachment prototype scale and positively related to the ECR-R attachment anxiety scale. Our findings provide initial support for the use of the SWAP-SAAS as a therapist-rated measure associated with lower patient reported levels of fit with a secure attachment prototype and with higher patient reported levels of attachment anxiety. Implications and suggestions for future research on the SWAP-SAAS, as well as for clinical work with socially anxious and avoidant patients, are discussed. PMID- 28863305 TI - Diterpenoids from the roots of Croton dichogamus Pax. AB - Four previously undescribed diterpenoids including two crotofolanes, crotodichogamoin A and B, and two halimanes, crothalimene A and B, a new sesquiterpenoid, and fifteen previously reported compounds, including the crotofolane, crotohaumanoxide, the casbane, depressin, a further seven furanohalimane diterpenoids, three patchoulane and two further cadinane sesquiterpenoids and aleuritolic acid were isolated from the root of Croton dichogamus. Crotodichogamoin B is an important biosynthetic intermediate of the crotofolane class and this is the first report of patchoulene sesquiterpenoids from the genus. Compounds were tested at one concentration, 1 * 10-5 M, in the NCI59 cell one-dose screen but did not show significant activity snd were also evaluated for their cytotoxicity against Caco-2 cell lines using the neutral red assay. 10-epi-Maninsigin D reduced Caco-2 cell viability at 10, 30 and 100 MUM, with values of decreased viability of 28%, 48% and 43% respectively. None of the other tested compounds showed significant activity. PMID- 28863306 TI - The study of flavonolignan association patterns in fruits of diverging Silybum marianum (L.) Gaertn. chemotypes provides new insights into the silymarin biosynthetic pathway. AB - Silymarin is the phytochemical with medicinal properties extracted from Silybum marianum (L.) Gaertn. fruits. Yet, little information is available about silymarin biosynthesis. Moreover, the generally accepted pathway, formulated thus far, is not in agreement with actual experimental measurements on flavonolignan contents. The present work analyses flavonolignan and taxifolin content in 201 S. marianum samples taking into consideration a wide phenotypic variability. Two stable chemotypes were identified: one characterized by both high silychristin and silybin content (chemotype A) and another by a high silydianin content (chemotype B). Through the correlation analysis of samples divided according to chemotype, it was possible to construct a simplified silymarin biosynthetic pathway that is sufficiently versatile in explaining experimental results responding to the actually unresolved questions about this process. The proposed pathway highlights that three separate and equally sized metabolite pools exist, namely: diastereoisomers A (silybin A plus isosilybin A), diastereoisomers B (silybin B plus isosilybin B) and silychristin. In both A and B diastereoisomers pools, isosilybin A and isosilybin B always represent a given amount of the metabolite flux through the specific metabolite pool suggesting the possible involvement of dirigent protein-like enzymes. We suggest that chemotype B possesses a complete silymarin biosynthetic pathway in which silydianin biosynthesis is enzymatically controlled. On the contrary, chemotype A is probably a natural mutant unable to biosynthesize silydianin. The present simplified pathway for silymarin biosynthesis will constitute an important tool for the further understanding of the reactions that drive flavonolignan biosynthesis in S. marianum. PMID- 28863307 TI - Transcriptomic characterization of bovine primary cultured hepatocytes; a cross comparison with a bovine liver and the Madin-Darby bovine kidney cells. AB - Bovine primary cultured hepatocytes (CHs) are widely used in vitro models for liver toxicity testing. However, little is known about their whole-transcriptome profile and its resemblance to the normal liver tissue. In the present study, we profiled - by microarray - the whole-transcriptome of bovine CHs (n=4) and compared it with the transcriptomic landscape of control liver samples (n=8), as well the Madin-Darby bovine kidney (MDBK) cells (n=4). Compared with liver tissue, the bovine CHs relatively expressed (fold change >2, P<0.05) about 2155 and 2073 transcripts at a lower and higher abundance, respectively. Of those expressed at a lower abundance, many were drug biotransformation enzyme-coding genes, such as the cytochrome P450 family (CYPs), sulfotransferases, methyltransferases, and glutathione S-transferases. Also, several drug transporters and solute carriers were expressed at a lower abundance in bovine CHs. 'Drug metabolism', 'PPAR signaling', and 'metabolism of xenobiotics by CYPs' were among the most negatively-enriched pathways in bovine CHs compared with liver. A qPCR cross-validation using 8 selected genes evidenced a high correlation (r=0.95, P=0.001) with the corresponding microarray results. Although from a kidney origin, and albeit to a lower extent compared to bovine CHs, the MDBK cells showed a basal expression of many CYP-coding genes. Our study provides a whole-transcriptome-based evidence for the bovine CHs and hepatic tissue resemblance. Overall, the bovine CHs' transcriptomic profile might render it unreliable as an in vitro model to study drug metabolism. PMID- 28863308 TI - Clickable and imageable multiblock polymer micelles with magnetically guided and PEG-switched targeting and release property for precise tumor theranosis. AB - Targeted delivery of therapeutics and diagnostics using nanotechnology holds great promise to minimize the side effects of conventional chemotherapy and enable specific and real-time detection of diseases. To realize this goal, we report a clickable and imageable nanovehicle assembled from multiblock polyurethanes (MPUs). The soft segments of the polymers are based on detachable poly(ethylene glycol) (PEG) and degradable poly(epsilon-caprolactone) (PCL), and the hard segments are constructed from lysine- and cystine-derivatives bearing reduction-responsive disulfide linkages and click-active alkynyl moieties, allowing for post-conjugation of targeting ligands via a click chemistry. It was found that the cleavage of PEG corona bearing a pH-sensitive benzoic-imine linkage (BPEG) could act as an on-off switch, which is capable of activating the clicked targeting ligands under extracellular acidic condition, followed by triggering the core degradation and payload release within tumor cells. In combination with superparamagnetic iron oxide nanoparticles (SPION) clustered within the micellar core, the MPUs exhibit excellent magnetic resonance imaging (MRI) contrast effects and T2 relaxation in vitro, as well as magnetically guided MR imaging and multimodal targeting of therapeutics to tumor precisely, leading to significant inhibition of cancer with minimal side effect. This work provides a safe and versatile platform for the further development of smart theranostic systems for potential magnetically-targeted and imaging-guided personalized medicine. PMID- 28863309 TI - Polymeric nanoparticles of siRNA prepared by a double-emulsion solvent-diffusion technique: Physicochemical properties, toxicity, biodistribution and efficacy in a mammary carcinoma mice model. AB - siRNA-loaded nanoparticles (NPs) administered systemically can overcome the poor stability and rapid elimination of free double-stranded RNA in circulation, resulting in increased tumor accumulation and efficacy. siRNA against osteopontin (siOPN), a protein involved in breast cancer development, was encapsulated in poly(D,L-lactic-co-glycolic acid) NPs by a double emulsion solvent diffusion (DESD) technique. We also compared the effect of polyethylenimine (PEI) molecular weight (800 Da and 25 kDa), used as the counter-ion for siRNA complexation, on the physicochemical properties of the NPs, cytotoxicity, and cellular uptake. NPs prepared by the DESD technique were obtained at the desired size (~170 nm) using both types of PEIs, and were characterized with a neutral surface charge, high encapsulation yield (up to ~60%), siOPN concentration of 5.6-8.4 MUg/mg, stability in physiologic conditions in vitro and in vivo, and long-term shelf life stability (> 3 years). The NPs prepared using both PEIs exhibited no cytotoxicity in primary smooth muscle culture, and no detrimental effect on mice liver enzymes following their IV administration. Following cellular uptake and biodistribution studies, the therapeutic potential of the NPs was demonstrated by a significant decrease of tumor progression and size in an ectopic xenograft model of mammary carcinoma in mice. PMID- 28863310 TI - Altered patterns of resting-state functional connectivity between the caudate and other brain regions in medication-naive children with attention deficit hyperactivity disorder. AB - BACKGROUND: Structural and functional alterations occur in the caudate of patients with attention-deficit/hyperactivity disorder (ADHD). Here we aimed to investigate the functional connectivity between the dorsal caudate and other brain regions in ADHD children. METHODS: Resting-state functional connectivity from 30 ADHD and 33 age- and gender-matched "normal" children were measured by functional Magnetic Resonance Imaging. RESULTS: Positive connectivity with dorsal caudate was observed in the prefrontal areas, cingulate cortex and temporal lobe. Negative functional connectivity was observed in the precuneus, occipital cortices and cerebellum. The connectivity of left dorsal caudate to left inferior frontal gyrus was correlated with severity of ADHD. CONCLUSIONS: Connectivity of dorsal caudate with several brain regions was identified in ADHD children. PMID- 28863311 TI - Approach-avoidance responses to infant facial expressions in nulliparous women: Associations with early experience and mood induction. AB - Infant expressions are important signals for eliciting caregiving behaviors in parents. The present study sought to test if infant expressions affect adults' behavioral response, taking into account the role of a mood induction and childhood caregiving experiences. A modified version of the Approach Avoidance Task (AAT) was employed to study nulliparous female university students' implicit responses to infant faces with different expressions. Study 1 showed that sad, neutral and sleepy expressions elicit a tendency for avoidance, while no tendency for approach or avoidance was found for happy faces. Notably, differences between approach and avoidance response latencies for sad faces and participants' negative caregiving experiences were positively correlated (r=0.30, p=0.04, Bonferroni corrected), indicating that individuals who experienced insensitive parental care show more bias toward sad infant faces. In Study 2, we manipulated participants' current mood (inducing sad and happy mood by asking to recall a happy or sad event of their recent life) before the AAT. Results showed that sad mood enhanced the bias toward sad faces that is buffered by positive mood induction. In conclusion, these findings indicate that implicit approach avoidance behaviors in females depend on the emotional expression of infant faces and are associated with childhood caregiving experiences and current mood. PMID- 28863312 TI - Healthcare cost of HER2-positive and negative breast tumors in the United States (2012-2035). AB - BACKGROUND: In this study, we estimated the current and future costs related to the use of targeted agents in patients with HER2-positive and negative advanced breast cancer (BC), aimed at identifying the subgroup associated with the higher cost in the coming years. METHODS: We calculated the patient cost considering an ideal patient who received therapeutic sequences including all approved agents for HER2-positive or negative BC. The duration of treatment was estimated by the median Progression-Free Survival (PFS) reported in the phase III trials which have led to the approval of these drugs by the US Food and Drug Administration. The estimated number of BC patients in the US from 2012 to 2035 refers to data published by the World Health Organization. RESULTS: The per patient cost was $292,155 for HER2-positive and $224,955 for negative tumors, respectively. The total cost for HER2-positive patients was estimated for 2012 at $2,719,542,347, with an annual increase ranged from 4.3 (for 2035) to 7.7% (for 2020), leading to a total expense of $3,648,232,975 in 2035. Otherwise, the total cost for HER2 negative patients in 2012 was estimated as $8,376,028,459, with an increase of more than $2.5 billion from 2012 to 2035. The estimated cost for HER2-negative patients was $5.6 billion higher that for HER2-positive tumors, raising to $7.6 billion to 2035. CONCLUSIONS: Our data strongly suggest that cost-analyses should be carefully evaluated in the coming years, in particular in patients with HER2 negative tumors. PMID- 28863313 TI - Duration of adjuvant trastuzumab in HER2 positive breast cancer: Overall and disease free survival results from meta-analyses of randomized controlled trials. AB - BACKGROUND: One year of trastuzumab, chosen empirically, improves survival of women with early-stage, HER2-positive breast cancer but also adds substantially to cost, toxicity, and inconvenience. Longer treatment does not improve outcomes, but potentiates toxicities. METHODS: Medline, Embase, and major conference proceedings were searched systematically in June 2017 to identify Randomized Controlled Trials (RCTs) comparing one year versus shorter durations of trastuzumab in adjuvant treatment of breast cancer. Reported Hazard-Ratios (HR) for Overall Survival (OS) and Disease-Free Survival (DFS), and Odds-Ratio for cardiac events, with respective 95% Confidence Intervals (CI) from each study was weighted using generic inverse-variance, and pooled in a meta-analysis. Inter study heterogeneity and sub-group difference (based on hormone-receptors and node positivity) were assessed using I2, and chi2 statistics, respectively. RESULTS: Four studies (n=7614) satisfied inclusion criteria. Individual RCTs had diverse pre-specified upper-limits of 95% CI for declaring non-inferiority (range: <1.15 to <1.53). Pooled results demonstrated significant improvements in OS (HR 1.28, p=0.04), and DFS (HR 1.24, p=0.005) with 1year of trastuzumab compared to shorter durations. Absence of multiplicity argument allowed for declaring superiority of 1year of trastuzumab based on our results despite non-inferiority designs of individual trials. No influence on overall effect by duration of trastuzumab in experimental arm (9weeks versus 6months) was noted. No statistical interaction by hormone-receptor status and node-positivity on overall results was noticed [p(sub group difference) 0.73, and 0.52, respectively]. Odds-Ratio for cardiac events was 2.65 (p<0.001) favoring shorter duration. CONCLUSION: One year of trastuzumab prolongs overall, and disease-free survivals in women with early-stage HER2 positive breast cancer compared to shorter durations and this should remain as the standard of care. Cardiotoxicity increased significantly with the 1-year treatment. PMID- 28863314 TI - When do you know what you know? The emergence of memory monitoring. AB - Recent research on comparative metacognition shows that animals, like humans, can differentiate between what they know and what they do not know. However, not much is known about the metacognitive behaviors of human children during their early years. To explore the emergence of memory-monitoring skills, two experiments were conducted using nonverbal tasks adapted from the work of Kornell, Son, and Terrace (2007) and Hampton (2001). Experiment 1 endeavored to determine when children began to show the ability to monitor their memories retrospectively. Experiment 2 aimed to reveal when young children knew what they knew by assessing their prospective monitoring. The results suggested that 4- to 5-year-olds had the ability to judge retrospectively their accuracy in a serial position task, whereas 3- to 4-year-olds did not. In contrast, 4.5- to 5-year-olds could discern items present in and absent from their memory before recognition, whereas 4- to 4.5-year-olds could not. In conclusion, 4-year-olds began to make accurate confidence judgments retrospectively, and children who are approximately 4.5years old began to demonstrate prospective memory-monitoring skills. PMID- 28863315 TI - A biosocial cognitive model of cannabis use in emerging adulthood. AB - OBJECTIVES: The aim of this study was to test a new theoretical model of cannabis use incorporating biologically-based personality traits and social cognition. This biosocial cognitive theory (bSCT) has robust support in alcohol studies, but has not been applied to cannabis. The model proposes two pathways linking dimensions of impulsivity to cannabis use. The first predicts that the association between Reward Sensitivity (SR) and cannabis use is mediated by positive outcome expectancies. The second predicts that the relationship between Rash Impulsiveness (RI) and cannabis use is mediated by cannabis refusal self efficacy. An extended version of this model was also tested and included a third pathway linking Punishment Sensitivity (SP) to cannabis use via higher negative outcome expectancies. METHOD: Participants were 252 18-to-21-year-olds who completed questionnaires assessing cannabis use, personality and social cognition. Theoretical models were tested using structural equation modeling. RESULTS: The bSCT model provided a good fit to the data (CFI=0.95; RMSEA=0.07; SRMR=0.06). Positive cannabis expectancies and refusal self-efficacy partially mediated the association between SR and cannabis use (p<0.05). Cannabis refusal self-efficacy fully mediated the relationship between RI and cannabis use (p<0.05). The addition of a third SP pathway did not improve model fit. CONCLUSIONS: Consistent with alcohol studies, the association between impulsivity and cannabis use is largely mediated by social cognition. The bSCT may provide novel insights to inform prevention and treatment of problematic cannabis use. PMID- 28863316 TI - Use of hormonal contraceptives and smoking cessation: A preliminary report. AB - Although endogenous sex hormones influence smoking-related outcomes, little is known about the effect of exogenous sex hormones. Therefore, the goal of this preliminary study was to examine differences in withdrawal symptoms and cessation between women using hormonal contraceptives (HC), women not using hormonal contraceptives (no-HC) and men. Utilizing data from two recently completed smoking cessation randomized clinical trials, we selected participants who were between the ages of 18-35years old. Participants were classified based on use of hormonal contraceptives and gender, then matched based on pharmacotherapy randomization assignment and baseline cigarettes per day. Participants provided self-reported assessments on withdrawal, craving and negative affect, and smoking status was assessed for 52weeks after quit date. Participants (N=130) were 28.7+/ 0.4years old and smoked 16.8+/-0.6 cigarettes/day. Compared to both no-HC and men, the HC group had significantly greater withdrawal one week prior to the quit date, on the quit date and one week after the quit date. During the first week of attempted abstinence, craving declined in HC and in men, but increased in no-HC. At end of treatment, the HC group was at 3.73 times higher odds of being abstinent compared to men (95% confidence interval: 1.12-12.40). There were no group differences in abstinence rates at Week 26 or 52. These data suggest that HC users may experience more adverse levels of withdrawal, though may be more likely to achieve short-term abstinence. Future research is needed to replicate our observations and explore mechanisms of action. PMID- 28863317 TI - Mediator or moderator? The role of mindfulness in the association between child behavior problems and parental stress. AB - BACKGROUND: Raising a child with intellectual disability (ID) may be stressful for parents. Previous studies have suggested the mediating role of mindfulness in the association between child behavior problems and parental stress. AIMS: The present study examined whether this mediating role is a result of parents' self report bias. It also explored whether mindfulness has a moderating role instead when child behavior problems are reported by teachers. METHODS: In a questionnaire survey, 271 Chinese parents of children with ID in 6 Hong Kong special schools reported their levels of stress and mindfulness, as well as their children's behavior problems. The latter was also reported by teachers. RESULTS: When child behavior problems were reported by parents, parental mindfulness was a mediator between child behavior problems and parental stress. In contrast, when child behavior problems were reported by teachers, parental mindfulness was a moderator between child behavior problems and parental stress. CONCLUSION: The mediation role of mindfulness maybe an artifact of measurement. The findings provide an encouraging message that parenting a child with ID and behavior problems does not necessarily mean more stress among all parents. Parents with a high level of mindfulness may experience less stress than those with a low level of mindfulness. WHAT THIS PAPER ADDS: Parents of children with intellectual disability (ID) tend to report high psychological stress. Previous self-report studies have identified mindfulness as a mediator in the association between child behavior problems and parental stress. The present study differs from previous studies by including third-party's reports. It has contributed to the existing body of knowledge in two respects. First, it examined whether the mediation effect resulted from parent self-report bias. Second, it tested an alternative hypothesis of the moderation effect by using teachers' reports to measure child behavior problems. The results showed that when child behavior problems were measured by parents' reports, parental mindfulness was a mediator between child behavior problems and parental stress. The more the parents reported that their children had behavior problems, the less they reported being mindful, which in turn the more stressful they were. However, when child behavior problems were measured by teachers' reports, parental mindfulness was a moderator instead, moderating the association between child behavior problems and parental stress. The association was ameliorated when parents reported high levels of mindfulness. These findings reveal another possible role of mindfulness and shed light on the support for parents of children with ID. PMID- 28863318 TI - Therapeutic effect of carnosine in rat model of experimental liver carcinogenesis. AB - The possible anticancer effect of carnosine versus doxorubicin was investigated against hepatocellular carcinoma (HCC) induced by trichloroacetic acid (TCA) (500mg/kg/day, p.o., for 5days) in rats. Following induction of HCC, rats treated with either carnosine (10mg/kg/day, i.p.), or doxorubicin (2.5mg/kg, i.p., once weekly), for 2 weeks. Carnosine significantly decreased serum alanine aminotransferase, and hepatic lipid peroxidation, nitric oxide, tumor necrosis factor-alpha, and nuclear factor-kappaB p65 unit, and significantly increased liver total antioxidant status in TCA-challenged rats. The effects of doxorubicin on oxidative, nitrative, and inflammatory biomarkers were less significant than carnosine. However, both carnosine and doxorubicin significantly induced liver tissue apoptotic biomarkers, Bax, cytosolic cytochrome C, and caspase-3, in a comparable manner. Additionally, carnosine and doxorubicin reduced the histopathological dysplastic changes, and alpha-fetoprotein expression in liver of rats with HCC. It was concluded that carnosine significantly protected against TCA-induced liver carcinogenesis in rats, through its antioxidant, antinitrative, and anti-inflammatory effects, and induction of apoptosis. PMID- 28863319 TI - Comparison of mechanical compressive properties of commercial and autologous fibrin glues for tissue engineering applications. AB - BACKGROUND: Fibrin glues are widely used in orthopedic surgery as adhesives and hemostatic agents. We evaluated the compressive properties of selected fibrin glues in order to identify which are appropriate for tissue regeneration applications subject to compression. METHODS: Uniaxial unconfined compression tests were performed on fibrin gels prepared from commercial and autologous products: (1) Evicel (Ethicon), (2) Tisseel (Baxter), (3) Angel (Arthrex), and (4) ProPlaz (Biorich). Cyclic loads were applied from 0 to 30% strain for 100cycles at 0.5Hz. Following cyclic testing, specimens were subjected to ramp displacement of 1% strain per second to 80% strain. FINDINGS: Throughout cyclic loading, Evicel and Tisseel deformed (shortened) less than Angel at all but one time point, and deformed less than ProPlaz at cycles 10 and 20. The dynamic moduli, peak stress, and strain energy were significantly greater in Tisseel than all other groups. Evicel displayed significantly greater dynamic moduli, peak stress, and strain energy than Angel and ProPlaz. Following cyclic testing, Tisseel and Evicel were significantly less deformed than Angel. No specimens exhibited gross failure during ramp loading to 80% strain. Ramp loading trends mirrored those of cyclic loading. INTERPRETATION: The tested commercial glues were significantly more resistant to compression than the autologous products. The compressive properties of Tisseel were approximately twice those of Evicel. All preparations displayed moduli multiple orders of magnitude less than that of native articular cartilage. We conclude that in knee surgeries requiring fibrin glue to undergo compression of daily activity, commercial products are preferable to autologous preparations from platelet-poor plasma, though both will deform significantly. PMID- 28863320 TI - NTRK2 (TrkB gene) variants and temporal lobe epilepsy: A genetic association study. AB - OBJECTIVE: The NTRK2 gene encodes a member of the neurotrophic tyrosine kinase receptor family known as TrkB. It is a membrane-associated receptor with signaling and cellular differentiation properties that has been involved in neuropsychiatric disorders, including epilepsy. We report here the frequencies of NTRK2 allele variants in patients with temporal lobe epilepsy (TLE) compared to controls without epilepsy and explore the impact of these polymorphisms on major clinical variables in TLE. METHODS: A case-control study comparing the frequencies of the NTRK2 gene polymorphisms beween 198 TLE Caucasian patients and 200 matching controls without epilepsy. In a second step, the impact of allelic variation on major clinical and electroencephalographic epilepsy variables was evaluated in the group of TLE patients. The following polymorphisms were determined by testing different regions of the NTRK2 gene: rs1867283, rs10868235, rs1147198, rs11140800, rs1187286, rs2289656, rs1624327, rs1443445, rs3780645, and rs2378672. To correct for multiple correlations the level of significance was set at p<0.01. RESULTS: Patients with TLE showed a statistical trend for increase of the T/T genotype in rs10868235 compared to control (O.R.=1.90; 95%CI=1.17-3.09; p=0.01). Homozygous patients for the A allele in rs1443445 had earlier mean age at onset of seizures, p=0.009 (mean age of 16.6 versus 22.4years). We also observed that the T allele in rs3780645 was more frequent in patients who needed polytheraphy for seizure control than in patients on monotherapy, (O.R.=4.13; 95%CI=1.68-10.29; p=0.001). This finding may reflect an increased difficulty to obtain seizure control in this group of patients. No additional differences were observed in this study. CONCLUSIONS: Patients with epilepsy showed a trend for a difference in rs10868235 allelic distribution compared to controls without epilepsy. NTRK2 variability influenced age at seizure onset and the pharmacological response to seizure control. As far as we know, this is the first study showing an association between NTKR2 allelic variants in human epilepsy. We believe that further studies in this venue will shade some light on the molecular mechanisms involved in epileptogenesis and in the clinical characteristics of epilepsy. PMID- 28863321 TI - The role of necroptosis in status epilepticus-induced brain injury in juvenile rats. AB - PURPOSE: To study the role of necroptosis in status epilepticus (SE)-induced injury in the developing brain and the possible associations of necroptosis with epileptogenesis and cognitive dysfunction. METHODS: The lithium-pilocarpine epilepsy model was reproduced in male rats at postnatal day 25. Propidium iodide (PI) staining was used to detect cell death after SE. Transmission electron microscopy (TEM) was performed to observe morphological changes in injured neurons. Western blot and immunofluorescence (IF) staining were used to investigate the expression of receptor interacting protein kinase-3 (RIP3), mixed lineage kinase domain-like (MLKL), and p-MLKL after SE. EEG was monitored during the chronic epileptic period. The Morris water maze test was performed to evaluate spatial learning and memory in juvenile rats after SE. RESULTS: Massive PI-positive (PI+) neurocytes were observed mainly in the amygdala and piriform cortex 24h to 7days after SE, with the most prominent changes observed after 72h. Injured neurons observed via TEM exhibited necroptotic morphological features, including loss of ribosomes, autophagosome formations, deformed nuclei with condensed and marginated chromatin, and disruptive cell membranes. The expression of RIP3 and p-MLKL increased after 24h, peaked at 72h, and decreased 7days after SE. In addition, IF staining revealed that MLKL was expressed in cell plasma membranes present in the amygdala and piriform cortex. This finding was concomitant with the fact that MLKL is involved in executing necroptosis by binding and disrupting the plasma membrane. During the chronic epileptic period, spontaneous recurrent seizures were observed behaviorally and interictal spikes and sharp waves were recorded by EEG in the SE group. The Morris water maze test revealed that in the place navigation test, the escape latency of the SE group was longer than that of the control group (p<0.05). In the spatial probe test, the number of times the rats in the SE group passed through the original platform site was lesser than that of the rats in the control group (p<0.05). CONCLUSION: SE-induced brain injury leads to neuronal necroptosis in juvenile rats. MLKL may play a significant role in the execution of SE-induced necroptosis. Further studies are required to determine whether inhibiting necroptosis can prevent chronic epileptogenesis and improve cognitive ability for juvenile rats. PMID- 28863322 TI - IL-17 contributes to the pathogenesis of obliterative bronchiolitis via regulation of M1 macrophages polarization in murine heterotopic trachea transplantation models. AB - Acute allograft rejection is a principal conundrum in lung obliterative bronchiolitis (OB). Monocytes/macrophages infiltration has been proved to be the main reason for acute rejection. IL-17 contributes to the recruitment and function of macrophages. However, the mechanism of IL-17 underlying OB progression remains elusive. In the present study, we showed that the deficiency of IL-17 attenuated the pathology of murine heterotopic trachea allografts. Compared to WT recipients, IL-17-/- mice displayed higher frequency of CD206+ cells and lower ratio of CD86+ cells among F4/80+ macrophages in allografts and spleens on day 7 post heterotopic trachea transplantation. Moreover, mRNA levels of pro-inflammatory cytokines including IL-6, TNF-alpha, and IL-1beta decreased in allografts of IL-17-/- recipients, but these of MRC1 and Arg-1 increased in comparison with WT. IL-17 deficiency can inhibit LPS induced M1 while promote IL 4 induced M2 polarization of bone marrow-derived macrophages. Further data demonstrated that the deficiency of IL-17 suppressed the lipopolysaccharide induced M1 polarization and function through prevention of phosphorylation of both STAT3 and STAT5. Therefore, IL-17 contributes to OB pathogenesis through regulating macrophages function, thereby it may unravel part of the complexity of IL-17 in OB and enhance future therapeutic development. PMID- 28863323 TI - Ethyl pyruvate reverses development of Pseudomonas aeruginosa pneumonia during sepsis-induced immunosuppression. AB - Sepsis is characterized by an innate immune response and the following immune dysfunction which can increase the emergence of secondary infections. Ethyl pyruvate (EP) has multiple immunoregulation functions in several serious illnesses, such as burn injury, severe sepsis and acute respiratory syndrome. However, little data was shown the effect of EP administration on immunosuppression post-CLP and the following secondary infection. The cecal ligation and puncture (CLP) followed by the induction of Pseudomonas aeruginosa (PA) was used as a clinically relevant two-hit model of sepsis. We assessed the survival rate, lung damage and lung bacterial clearance in vehicle or EP treatment group to demonstrate the lung response to Pseudomonas aeruginosa of septic mice. Then cytokines including lung IL-6, IL-1beta, IL-10 and plasma HMGB1, apoptosis of splenic immune cells and Foxp3 level on regulatory T cells (Tregs) were studied to demonstrate the mechanisms of EP administration on two hit mice. We found that the susceptibility of septic mice to Secondary Pseudomonas aeruginosa pneumonia could be down-regulated by ethyl pyruvate treatment and the protective effects of EP may via decreasing lung IL-10 and plasma HMGB1 expression, inhibiting the function of Tregs and relieving the apoptosis of splenic immune cells. The "immune paralysis" post-sepsis still remains a rigorous challenge for curing sepsis, our study may aid in the development of new therapeutic strategies to this problem. PMID- 28863324 TI - Quantification of viable and non-viable Legionella spp. by heterogeneous asymmetric recombinase polymerase amplification (haRPA) on a flow-based chemiluminescence microarray. AB - Increasing numbers of legionellosis outbreaks within the last years have shown that Legionella are a growing challenge for public health. Molecular biological detection methods capable of rapidly identifying viable Legionella are important for the control of engineered water systems. The current gold standard based on culture methods takes up to 10 days to show positive results. For this reason, a flow-based chemiluminescence (CL) DNA microarray was developed that is able to quantify viable and non-viable Legionella spp. as well as Legionella pneumophila in one hour. An isothermal heterogeneous asymmetric recombinase polymerase amplification (haRPA) was carried out on flow-based CL DNA microarrays. Detection limits of 87 genomic units (GU) uL-1 and 26GUuL-1 for Legionella spp. and Legionella pneumophila, respectively, were achieved. In this work, it was shown for the first time that the combination of a propidium monoazide (PMA) treatment with haRPA, the so-called viability haRPA, is able to identify viable Legionella on DNA microarrays. Different proportions of viable and non-viable Legionella, shown with the example of L. pneumophila, ranging in a total concentration between 101 to 105GUuL-1 were analyzed on the microarray analysis platform MCR 3. Recovery values for viable Legionella spp. were found between 81% and 133%. With the combination of these two methods, there is a chance to replace culture-based methods in the future for the monitoring of engineered water systems like condensation recooling plants. PMID- 28863325 TI - Recent advances and future prospects in molecularly imprinted polymers-based electrochemical biosensors. AB - Molecularly imprinted polymers (MIPs)-based electrochemical biosensors (ECBSs) have many advantages from MIPs and ECBSs, such as high selectivity and sensitivity, chemical/mechanical stability, reusability, low limit of detection, facile preparation and low cost. MIPs-based ECBSs attract much attention in medical diagnose, biological analysis, environmental monitoring, food safety evaluation, etc. Due to the capacity of highly specific recognition for target biomolecules, MIPs-based ECBSs have been smartly designed and extensively used for electrochemical sensing applications in recent years, exhibiting obvious superiority over other analytical techniques. In this review, firstly we systematically summarize the recent advances of MIPs-based ECBSs reported in recent years, referring to the preparation, structures and components of sensing systems. Secondly, we highlight the sensing applications for various significant biomolecules (proteins, antibiotics, pesticide, neurotransmitter, hormone, etc.), and demonstrate the sensing mechanism and detection performance. Finally, the rational summaries, present challenges and future prospects in the field of MIPs based ECBSs have been discussed reasonably. PMID- 28863326 TI - Confocal epifluorescence sensor with an arc-shaped aperture for slide-based PCR quantification. AB - The increasing needs of point-of-care diagnostics, quarantine of epidemic pathogens, and prevention of terrorism's bio-attacks have promised the future of portable real-time quantitative polymerase chain reaction (qPCR) sensors. This work aims at developing a highly sensitive and low-cost light emitting diode (LED)-based epifluorescence sensor module for qPCR sensor development and relevant bioassay applications. Inspired by the light stop design and dark-field detection of microscopes, this paper first reports a compact confocal LED epifluorescence sensor using a light stop with an arc-shaped aperture for enhancing the flexibility of quick DNA and PCR detection. The sensor features the advantages of the dichroic mirror-free and confocal (shared-focus) characteristics, which benefits size reduction and minimal optics used. It also allows extension to integrate with in situ real-time PCR thermal cycling since the sample slide is placed apart from the epi-sensing module. The epifluorescence sensor can detect as low as sub-ng/MUL standard DNA and 101 copies of Salmonella typhimurium InvA gene sequences (cloned in E. coli and after 30-cycle PCR) with SYBR(r) Green I from non-purified culture samples, having highly sensitive and specific signal responses comparable with that of a commercial qPCR instrument. PMID- 28863327 TI - A specific nanoprobe for cysteine based on nitrogen-rich fluorescent quantum dots combined with Cu2. AB - As a new member of the carbon quantum-dot family, fluorescent nitrogen-rich quantum dots (NRQDs) were prepared by a mixed solvothermal method using 2 azidoimidazole and aqueous ammonia as reactants. These NRQDs are rich in nitrogen up to 40.2%, which are endowed with high fluorescence quantum yield, good photostability, water-solubility and favourable biocompatibility. We further explored the use of NRQDs combined with Cu2+ as a nanoprobe for sensing fluorescently of cysteine (Cys) in complex biological samples. In this sensing system, the fluorescence is significantly quenched via energy transfer from NRQDs to Cu2+ for the coordination of amino-containing groups with Cu2+. The strong affinity between Cu 2+ and Cys leads to the formation of Cu2+-Cys complexes and cause the detachment of Cu2+ from the surface of NRQDs, thus the fluorescence of NRQDs recover. This nanoprobe allows analysis of Cys by modulating the switch of the fluorescence of NRQDs with a detection limit of 5.3nM. As expected, the proposed NRQDs-Cu2+complex-based nanoprobes were successfully applied for the determination of Cys in human serum and plasma samples with recoveries ranging from 97.2% to 105.7%. The probe ensemble was also successfully applied to imaging of Cys in living cells with satisfactory results, which shows strong potential for clinical diagnosis. PMID- 28863328 TI - Effects of age, gender and statin dose on lipid levels: Results from the VOYAGER meta-analysis database. AB - BACKGROUND AND AIMS: The effectiveness of statins in the treatment of dyslipidaemia and reduction of cardiovascular risk is well established. However, the association of statin-mediated lipid effects with age and gender is unclear. This study aimed to determine whether age and gender are associated with statin mediated changes in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and non-HDL-C. METHODS: Individual patient data (n = 32,258) were obtained from VOYAGER. Least-squares mean percentage change from baseline in LDL-C, non-HDL-C and HDL-C with atorvastatin 10-80 mg, rosuvastatin 5-40 mg or simvastatin 10-80 mg was estimated in women aged <70 years, women aged >=70 years, men aged <70 years and men aged >=70 years. RESULTS: All statins and doses gave significant dose-dependent reductions in LDL C and non-HDL-C, and increases in HDL-C, in all four patient groups. A 2.1% greater reduction in LDL-C was observed in women, compared with men (p < 0.0001). Patients aged >=70 years experienced a 2.7% greater reduction in LDL-C compared with younger patients (p < 0.0001). Similar results were also observed for statin mediated changes in non-HDL-C. Men experienced a significantly greater increase in HDL-C than women, and patients aged >=70 years achieved a significantly greater increase than younger patients (both p = 0.001). CONCLUSIONS: While statins improve the lipid profile in all gender and age groups analysed, the improvements are greater in women than in men and in those aged >=70 years compared with those aged <70 years. PMID- 28863329 TI - Both Notch1 and its ligands in B cells promote antibody production. AB - Notch1 signaling regulates B and T lymphocyte development and also in vitro promotes antibody secretion upon B cell activation. However, it is still unclear about the role of Notch1 in antibody production upon in vitro and in vivo mixture lymphocytes activation. We first showed that Notch1 expressed in LPS-activated CD19hi B cells and CD19cre mediated Notch1 knock-down in LPS-activated B cells. Furthermore, we demonstrated that Notch1 knock-down in B cells reduced antibody production in LPS-stimulated B cells but did not affect antibody production in LPS-stimulated splenocytes and in experimental allergic encephalomyelitis (EAE) mice. Importantly, Notch1 ligands Dll1 and Jag1 expressed in B cells and pre coated Notch1 protein promotes Notch1-knocked down B cells to produce antibody in LPS-stimulated B cells suggesting that Notch1 in other cells may promote antibody production by binding its ligands Dll1 and Jag1 in B cells. Together, our results suggest that both Notch1 and its ligands in B cells play an important role in antibody production. PMID- 28863330 TI - 18F-Labeled perfluorocarbon droplets for positron emission tomography imaging. AB - INTRODUCTION: Nanoscale perfluorocarbon (PFC) droplets have been used to create imaging agents and drug delivery vehicles. However, development and characterization of new formulations of PFC droplets are hindered because of the lack of simple methods for quantitative and sensitive assessment of whole body tissue distribution and pharmacokinetics of the droplets. To address this issue, a general-purpose method for radiolabeling the inner core of nanoscale perfluorocarbon droplets with a hydrophobic and lipophobic fluorine-18 compound was developed, so that positron emission tomography (PET) and quantitative biodistribution studies can be employed to evaluate PFC nanodroplets in vivo. METHODS: A robust method to produce [18F]CF3(CF2)7(CH2)3F from a tosylate precursor using [18F]F- was developed. The product's effectiveness as a general label for different PFCs and its ability to distinguish the in vivo behavior of different PFC droplet formulations was evaluated using two types of PFC nanodroplets: fluorosurfactant-stabilized perfluorohexane (PFH) nanodroplets and lipid-stabilized perfluorooctylbromide (PFOB) nanodroplets. In vivo assessment of the 18F-labeled PFH and PFOB nanodroplets were conducted in normal mice following intravenous injection using small animal PET imaging and gamma counting of tissues and fluids. RESULTS: [18F]CF3(CF2)7(CH2)3F was produced in modest yield and was stable with respect to loss of fluoride in vitro. The labeled fluorocarbon was successfully integrated into PFH nanodroplets (~175 nm) and PFOB nanodroplets (~260 nm) without altering their mean sizes, size distributions, or surface charges compared to their non-radioactive analogues. No leakage of the radiolabel from the nanodroplets was detected after droplet formation in vitro. PET imaging and biodistribution data for the two droplet types tested showed significantly different tissue uptake and clearance patterns. CONCLUSION: A convenient method for producing 18F-labeled PFC droplets was developed. The results highlight the potential utility of the strategy for pre-clinical evaluation of different PFC droplet formulations through direct PFC core labeling using a fluorinated radiolabel. PMID- 28863331 TI - Grip strength is not associated with incident type 2 diabetes mellitus in healthy adults: The CoLaus study. AB - AIMS: We examined the association of grip strength with incident type 2 diabetes mellitus (T2DM) in healthy subjects initially aged 50 to 75years after a follow up of 5.5years and 10.7years. METHODS: This was a prospective, population-based study derived from the CoLaus (Cohorte Lausannoise) study including 2318 participants (aged 60.2y; 1354 women) free from T2DM at baseline. Grip strength was assessed using a handheld dynamometer. The effect of grip strength on the incidence of T2DM was analyzed by logistic regression. RESULTS: After a follow-up of 5.5years, 190 (8.2%) T2DM cases were identified. In bivariate analysis, participants who developed T2DM had a higher absolute grip strength (35.3+/-10.6 versus 33.2+/-10.7kg, P=0.013). Analysis between grip strength expressed in 5kg increment and incident TD2M showed a negative association when adjusted for age and sex [ORs (95% CI): 0.88 (0.79, 0.98)], or for age, sex and body mass index (BMI) [ORs (95% CI): 0.87 (0.78, 097)]. After a follow-up of 10.7years, 131 supplemental (7.3%) T2DM cases were identified, but there was no association between grip strength and incident T2DM in bivariate and multivariable analysis, potentially due to a lack of statistical power. CONCLUSIONS: In non elderly healthy adults, the risk of incident T2DM is overall not associated with grip strength over a maximum follow-up of 10.7years. Future studies are warranted to better assess the association between grip strength and incident T2DM in bigger and even younger cohorts. PMID- 28863332 TI - Screening for gestational diabetes in Tuscany, Italy. A population study. AB - AIMS: According to current Italian guidelines, only women at higher risk of gestational diabetes (GDM) are eligible for receiving a glucose tolerance test (OGTT) during pregnancy. This study evaluates the compliance to national guidelines, additionally proposing an algorithm able to identify women with GDM. METHODS: The study included 23,270 pregnant women aged >15yr, resident in Tuscany, a region in central Italy, delivering in year 2015, identified by certificates of care at delivery. Eligibility to screening was evaluated by fulfillment to regional guidelines recommending a 2-h-75g-OGTT only in presence of risk factors. Additionally, a validated algorithm is proposed to diagnose GDM from regional administrative databases. RESULTS: Glucose tolerance was tested in 79.2% of women. Eligibility criteria were fulfilled in 55.6% of OGTT performers and in 40.2% of those who didn't perform any OGTT. Performers' rate increased with age, body weight, higher education degree and in those followed by a well defined clinical setting. Housewives and students had a lower chance of receiving an OGTT. Algorithm identified GDM in 11% of women, ranging from 14% among eligible and 7% among non-eligible ones. CONCLUSION: Selective screening for GDM is not being currently applied in Tuscany. Despite the percentage of eligible women by national guidelines was 55%, the rate of those who performed the screening was about 80%, with a 40% of low risk women continuing to be screened. Moreover, GDM rate, calculated by algorithm, was relatively large (7%) among non eligible women, suggesting the need of universal glucose screening to adequately capture all GDM cases. PMID- 28863333 TI - Reverse phase HPLC method for detection and quantification of lupin seed gamma conglutin. AB - A simple, selective and accurate reverse phase HPLC method was developed for detection and quantitation of gamma-conglutin from lupin seed extract. A linear gradient of water and acetonitrile containing trifluoroacetic acid (TFA) on a reverse phase column (Agilent Zorbax 300SB C-18), with a flow rate of 0.8ml/min was able to produce a sharp and symmetric peak of gamma-conglutin with a retention time at 29.16min. The identity of gamma-conglutin in the peak was confirmed by mass spectrometry (MS/MS identification) and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The data obtained from MS/MS analysis was matched against the specified database to obtain the exact match for the protein of interest. The proposed method was validated in terms of specificity, linearity, sensitivity, precision, recovery and accuracy. The analytical parameters revealed that the validated method was capable of selectively performing a good chromatographic separation of gamma-conglutin from the lupin seed extract with no interference of the matrix. The detection and quantitation limit of gamma-conglutin were found to be 2.68MUg/ml and 8.12MUg/ml respectively. The accuracy (precision and recovery) analysis of the method was conducted under repeatable conditions on different days. Intra-day and inter-day precision values less than 0.5% and recovery greater than 97% indicated high precision and accuracy of the method for analysis of gamma-conglutin. The method validation findings were reproducible and can be successfully applied for routine analysis of gamma-conglutin from lupin seed extract. PMID- 28863334 TI - Molecularly imprinted polymer-sol-gel tablet toward micro-solid phase extraction: II. Determination of amphetamine in human urine samples by liquid chromatography tandem mass spectrometry. AB - Amphetamine selective molecularly imprinted sol-gel polymer tablets, MIP-tablets, for solid-phase microextraction of biofluid samples were prepared. An acetonitrile solution of deuterated amphetamine template and silane precursor, 3 (propylmethacrylate) trimethoxysilane, was soaked into the pores of polyethylene tablet substrates and polymerized by an acid-catalysed sol-gel process. Application of the resultant MIP-tablets to extract amphetamine from human urine samples followed by LC-MS/MS analysis was investigated. The extraction protocol was optimised with respect to pH of sample, addition of sodium chloride, extraction time, desorption solvent and desorption time. The final analysis method determined amphetamine in human urine with a limit of detection (LOD) of 1.0ng/mL and a lower limit of quantification (LLOQ) of 5ng/mL. Validation demonstrated accuracy of the method was 91.0-104.0% and inter-assay precision was 4.8-8.5% (RSD). Extraction recovery was 80%. The MIP-tablets could be re-used and the same tablet could be employed for more than twenty extractions. PMID- 28863335 TI - An efficient analytical method for determination of S-phenylmercapturic acid in urine by HPLC fluorimetric detector to assessing benzene exposure. AB - Benzene is an important occupational and environmental contaminant, naturally present in petroleum and as by-product in the steel industry. Toxicological studies showed pronounced myelotoxic action, causing leukemic and others blood cells disorders. Assessing of benzene exposure is performed by biomarkers as trans, trans-muconic acid (AttM) and S-phenylmercapturic acid (S-PMA) in urine. Due to specificity of S-PMA, this biomarker has been proposed to asses lower levels of benzene in air. The aim of this study was to validate an analytical method for the quantification of S-PMA by High-Performance Liquid Chromatography with fluorometric detector. The development of an analytical method of S-PMA in urine was carried out by solid phase extraction (SPE) using C-18 phase. The eluated were submitted to water bath at 75 degrees C and nitrogen to analyte concentration, followed by alkaline hydrolysis and derivatization with monobromobimane. The chromatography conditions were reverse phase C-18 column (240mm, 4mm and 5MUm) at 35 degrees C; acetonitrile and 0.5% acetic acid (50:50) as mobile phase with a flow of 0.8mL/min. The limits of detection and quantification were 0.22MUg/L and 0.68MUg/L, respectively. The linearity was verified by simple linear regression, and the method exhibited good linearity in the range of 10-100MUg/L. There was no matrix effect for S-PMA using concentrations of 40, 60, 80 and 100MUg/L. The intra- and interassay precision showed coefficient of variation of less than 10% and the recovery ranged from 83.4 to 102.8% with an average of 94.4%. The stability of S-PMA in urine stored at -20 degrees C was of seven weeks. The conclusion is that this method presents satisfactory results per their figures of merit. This proposed method for determining urinary S-PMA showed adequate sensitivity for assessment of occupational and environmental exposure to benzene using S-PMA as biomarker of exposure. PMID- 28863336 TI - Patient-provider communication, maternal anxiety, and self-care in pregnancy. AB - RATIONALE: Favorable relationships with health care providers predict greater patient satisfaction and adherence to provider recommendations. However, the specific components of patient-provider relationships that account for these benefits have not been identified. The potential benefits of strong patient provider relationships in pregnancy may be especially important, as care providers have frequent, intimate interactions with pregnant women that can affect their emotions and behaviors. In turn, prenatal emotions and health behaviors have potent effects on birth outcomes. OBJECTIVE: This study investigated whether pregnant women's relationships with their midwives predicted better self-care. Specific components of the patient-provider relationship (communication, integration, collaboration, and empowerment) were examined. We also investigated a mechanism through which these relationship components may be associated with salutary health behaviors: by alleviating women's anxiety. METHODS: In total, 139 low-risk patients of a university-affiliated midwifery practice in the northeastern United States completed well-validated measures assessing their relationship with midwives, state anxiety, and prenatal health behaviors in late pregnancy; state anxiety was also assessed in mid-pregnancy. RESULTS: Women's perceptions of better communication, collaboration, and empowerment from their midwives were associated with more frequent salutary health behavior practices in late pregnancy. Controlling for mid-pregnancy anxiety, lower anxiety in late pregnancy mediated associations of communication and collaboration with health behavior practices, indicating that these associations were attributable to reductions in anxiety from mid- to late pregnancy. CONCLUSION: Results substantiate that benefits of patient-provider relationships in pregnancy may extend beyond providing medical expertise. Some aspects of patient-provider relationships may offer direct benefits to pregnant women in promoting better health practices; other aspects of these relationships may indirectly contribute to better health practices by alleviating negative emotions. The benefits of strong midwife relationships may derive from the reassurance, comfort, and warmth these relationships offer, as well as the information and education that midwives provide to their patients. PMID- 28863337 TI - 'Being' a ventricular assist device recipient: A liminal existence. AB - Ventricular assist devices (VADs) are playing an increasing role in the management of heart failure. VADs are mechanical circulatory devices that support or replace the function of a failing heart. Currently, VADs are only offered in theUnited Kingdom (UK) to patients waiting for a heart transplant; however, the use of these devices is likely to increase in the near future. Presently, there is a dearth of literature exploring the day-to-day realities of living with a VAD, which will become increasingly important as the role of VADs is increased. This paper adopts an interpretive phenomenological approach to uncover the experience of 'Being' a VAD recipient. Semi-structured interviews were conducted with 20 VAD recipients. The overarching theme is that life with a VAD is a liminal existence. This comprised four subthemes: the first examines how the VAD imposes limitations on recipients' lives that can precipitate a loss of identity; the second focuses on temporal disruptions, recipients' sense of time changes from authentic to inauthentic; the third explores how the VAD itself is liminal, it is positioned as temporary rather than as the 'answer' to the condition; and finally, we discuss VAD recipients' projections to the future and the possibility of an end to the experience of liminality. PMID- 28863338 TI - Perceptions of incentives offered in a community-based malaria diagnosis and treatment program in the Highlands of Papua New Guinea. AB - What motivates community-based health workers to provide care in rural and remote areas, often on a voluntary or casual basis, is a key question for program managers and public health officials. This paper examines how a range of incentives offered as part of the Marasin Stoa Kipa program, a community-based malaria diagnosis and treatment program that has been implemented since 2007 within a major oil and gas development area in Papua New Guinea, are perceived and critiqued by community-based health workers. Nineteen interviews and seven focus group discussions with the workers who deliver services and members of the communities served by the program, conducted between November 4 and 25, 2015, reveal a pattern of mixed motivations and changes in motivation over time. This can be attributed partly to the unique social and economic circumstances in which the program is operating. Changes in the burden of disease as well as in global and national health services policy with implications for local level program operations also had an impact, as did the nature of relationships between program managers, community-based health workers, and program beneficiaries. Overall, the findings suggest that while financial and in-kind incentives can be a useful tool to motivate voluntary or minimally-compensated community-based health workers, they must be carefully structured to align with local social, economic, and epidemiological realities over the long-term. PMID- 28863339 TI - Treatments of asbestos containing wastes. AB - Since the second half of the twentieth century, many studies have indicated inhalation of asbestos fibers as the main cause of deadly diseases including fibrosis and cancer. Consequently, since the beginning of the 80s, many countries started banning production and use of asbestos containing products (ACP), although still present in private and public buildings. Due to some extraordinary catastrophic events and/or the aging of these products, people's health and environmental risk associated with the inhalation of asbestos fibers keeps being high even in those countries where it was banned. For these reasons, many communities are developing plans for an environmental and sanitary safe asbestos removal and management. Asbestos containing wastes (ACW) are usually disposed in controlled landfills, but this practice does not definitively eliminate the problems related with asbestos fiber release and conflicts with the ideas of sustainable land use, recycling, and closing material cycles. Consequently, many scientific papers and patents proposed physical, chemical, and biological treatments aimed to the detoxification of ACW (or the reduction of their health effects) and looking for the adoption of technologies, which allow the reuse of the end-products. By including recent relevant bibliography, this report summarizes the status of the most important and innovative treatments of ACW, providing main operating parameters, advantages, and disadvantages. PMID- 28863340 TI - Assessing the long-term effects of land use changes on runoff patterns and food production in a large lake watershed with policy implications. AB - Effects of land use development on runoff patterns are salient at a hydrological response unit scale. However, quantitative analysis at the watershed scale is still a challenge due to the complex spatial heterogeneity of the upstream and downstream hydrological relationships and the inherent structure of drainage systems. This study aims to use the well-calibrated Soil and Water Assessment Tool (SWAT) to assess the response of hydrological processes under different land use scenarios in a large lake watershed (Lake Dongting) in the middle Yangtze River basin in China. Based on possible land use changes, scale-dependent land use scenarios were developed and parameters embedded in SWAT were calibrated and validated for hydrological systems analysis. This approach leads to the simulation of the land use change impacts on the hydrological cycle. Results indicated that evapotranspiration, surface runoff, groundwater flow, and water yield were affected by the land use change scenarios in different magnitudes. Overall, changes of land use and land cover have significant impacts on runoff patterns at the watershed scale in terms of both the total water yield (i.e., groundwater flow, surface runoff, and interflow, minus transmission losses) and the spatial distribution of runoff. The changes in runoff distribution were resulted in opposite impacts within the two land use scenarios including forest and agriculture. Water yield has a decrease of 1.8 percent in the forest-prone landscape scenario and an increase of 4.2 percent in the agriculture-rich scenario during the simulated period. Surface runoff was the most affected component in the hydrological cycle. Whereas surface runoff as part of water yield has a decrease of 8.2 percent in the forest- prone landscape scenario, there is an increase of 8.6 percent in the agriculture-rich landscape scenario. Different runoff patterns associated with each land use scenario imply the potential effect on flood or drought mitigation policy. Based on the results, key areas were identified to show that hydrological extreme mitigation and flood control can be coordinated by some land use regulations. PMID- 28863341 TI - Acetic acid bacteria in fermented foods and beverages. AB - Although acetic acid bacteria (AAB) are commonly found in spontaneous or backslopped fermented foods and beverages, rather limited knowledge about their occurrence and functional role in natural food fermentation ecosystems is available. Not only is their cultivation, isolation, and identification difficult, their cells are often present in a viable but not culturable state. Yet, they are promising starter cultures either to better control known food fermentation processes or to produce novel fermented foods and beverages. This review summarizes the most recent findings on the occurrence and functional role of AAB in natural food fermentation processes such as lambic beer, water kefir, kombucha, and cocoa. PMID- 28863342 TI - Molecular transformation of natural and anthropogenic dissolved organic matter under photo-irradiation in the presence of nano TiO2. AB - Photochemical transformation of dissolved organic matter (DOM) plays a very important role in the cycling of organic carbon in aquatic systems. Increasing release of photoactive nanoparticles such as titanium dioxide nanoparticles (nano TiO2) into surface water may impact this process. The present study employed Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) to examine the molecular transformation of natural DOM (peat DOM, DOMp) and anthropogenic DOM (sludge-derived DOM, DOMs) under photo-irradiation as affected by nano TiO2. Differences in molecular components between DOMp and DOMs were observed. DOMs contained more heteroatom formulas (76%) with low aromaticity and low carbon oxidation state than did DOMp (22%). The presence of nano TiO2 resulted in significant decreases in both DOM content and molecular diversity under photo-irradiation. Consistent alterations were observed between DOMp and DOMs such that high molecular weight compounds, high aromaticity and/or heteroatom S-containing compounds were more easily photodegraded in the presence of nano TiO2; whereas the average carbon oxidation state decreased in DOMp but increased in DOMs, likely due to the significant differences in O abundance, especially in the contents of carboxyl moieties, between DOMp and DOMs. The findings of the present study suggest that the release of nano TiO2 into aquatic environment will accelerate the consumption of dissolved organic carbon and the attenuation of molecular diversity for both DOM in waters. PMID- 28863343 TI - Activation of peroxymonosulfate by phenols: Important role of quinone intermediates and involvement of singlet oxygen. AB - In this study, the kinetics of reactions of peroxymonosulfate (PMS) with ten model phenols (including phenol, methylphenols, methoxyphenols, and dihydroxybenzenes) were examined. The oxidation kinetics of these phenols by PMS except for catechol and resorcinol showed autocatalysis in alkaline conditions (pH 8.5 and 10), due to the contribution of singlet oxygen (1O2) produced from PMS activation by quinone intermediates formed from their phenolic parents. The oxidation rates of ortho- and meta-substituted methylphenols and methoxyphenols by PMS were much higher than their para-substituted counterparts under similar conditions. This was attributed to the relatively low yields of quinone intermediates from para-substituted phenols. SMX could be efficiently degraded by PMS in the presence of phenols which showed great autocatalysis when they individually reacted with PMS, and the addition of methanol in excess had negligible influence suggesting that 1O2 rather than hydroxyl radical and sulfate radical played an important role. Transformation of SMX by 1O2 underwent three pathways including hydroxylation of aniline ring, oxidation of aromatic amine group to generate nitro-SMX, and oxidative coupling to generate azo-SMX and hydroxylated azo-SMX. These results obtained in this work improve the understanding of in situ chemical oxidation using PMS for remediation of subsurface, where phenolic and quinonoid moieties are ubiquitous. PMID- 28863344 TI - Elimination of antibiotic-resistance bacterium and its associated/dissociative blaTEM-1 and aac(3)-II antibiotic-resistance genes in aqueous system via photoelectrocatalytic process. AB - The ubiquity of antibiotic-resistance bacteria (ARB) and antibiotic-resistance genes (ARGs) in various environmental matrices is a potential threat to human and ecological health. Therefore, the inactivation of ARB E. coli S1-23 and the elimination of its associated ARGs, blaTEM-1 and aac(3)-II, were investigated using the photoelectrocatalytic (PEC) process. Results indicate that the ARB E. coli S1-23 (1 * 108 cfu mL-1) and its ARGs (extracellular and intracellular) could be fully inactivated within 10 and 16 h PEC treatment, respectively. In contrast, photocatalytic (PC) and electrochemical (EC) treatments displayed no obvious effect; however, ARG-containing DNA extracted from E. coli S1-23, which was used as a model for dissociative naked ARGs, could be completely decomposed within a few minutes through these three treatments. Further analyses, including PCR, AFM and HPLC, proved that the structural integrity and surface topography of naked ARGs are damaged during treatment and can be completely eliminated. Furthermore, there is no generation of cytosine, guanine, adenine or thymine intermediates during the PEC, PC, and EC treatments. This study is the first report to propose the PEC treatment as a promising method for complete decomposition of ARB and ARGs in aqueous systems. PMID- 28863345 TI - The Stromal Microenvironment Modulates Mitochondrial Oxidative Phosphorylation in Chronic Lymphocytic Leukemia Cells. AB - Peripheral blood chronic lymphocytic leukemia (CLL) cells are replicationally quiescent mature B-cells. In short-term cultures, supporting stromal cells provide a survival advantage to CLL cells by inducing transcription and translation without promoting proliferation. We hypothesized that the stromal microenvironment augments malignant B cells' metabolism to enable the cells to cope with their energy demands for transcription and translation. We used extracellular flux analysis to assess the two major energy-generating pathways, mitochondrial oxidative phosphorylation (OxPhos) and glycolysis, in primary CLL cells in the presence of three different stromal cell lines. OxPhos, measured as the basal oxygen consumption rate (OCR) and maximum respiration capacity, was significantly higher in 28 patients' CLL cells cocultured with bone marrow derived NK.Tert stromal cells than in CLL cells cultured alone (P = .004 and <.0001, respectively). Similar OCR induction was observed in CLL cells cocultured with M2-10B4 and HS-5 stromal lines. In contrast, heterogeneous changes in the extracellular acidification rate (a measure of glycolysis) were observed in CLL cells cocultured with stromal cells. Ingenuity Pathway Analysis of CLL cells' metabolomics profile indicated stroma-mediated stimulation of nucleotide synthesis. Quantitation of ribonucleotide pools showed a significant two-fold increase in CLL cells cocultured with stromal cells, indicating that the stroma may induce CLL cellular bioenergy and the RNA building blocks necessary for the transcriptional requirement of a prosurvival phenotype. The stroma did not impact the proliferation index (Ki-67 staining) of CLL cells. Collectively, these data suggest that short-term interaction (<=24 hours) with stroma increases OxPhos and bioenergy in replicationally quiescent CLL cells. PMID- 28863346 TI - The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma. AB - In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201. Treatment decreased cellular viability and induced apoptosis in myeloma cell lines, with IC50 values of 1 to 1.5 MUM, even in those with high risk features or TP53 loss. ONC201 increased levels of the pro-apoptotic protein Bim in myeloma cells, resulting from decreased phosphorylation of degradation-promoting Bim Ser69 by ERK1/2. In addition, myeloma cell lines made resistant to several standard-of care agents (by chronic exposure) were equally sensitive to ONC201 as their drug naive counterparts, and combinations of ONC201 with proteasome inhibitors had synergistic anti-myeloma activity. Overall, these findings demonstrate that ONC201 kills myeloma cells regardless of resistance to standard-of-care therapies, making it promising for clinical testing in relapsed/refractory myeloma. PMID- 28863347 TI - Deletion of Dlk2 increases the vulnerability to anxiety-like behaviors and impairs the anxiolytic action of alprazolam. AB - The purpose of this study was to evaluate the role of the non-canonical DLK2 NOTCH ligand in the regulation of emotional behavior. To this aim, anxiety and depressive-like behaviors were examined in Dlk2 knock-out (Dlk2-/-) and its corresponding wild-type (WT) mice. Furthermore, relative gene expression analyses of corticotropin releasing hormone (Crh) in the paraventricular nucleus (PVN), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5) in the hippocampus (HIPP), and the transcription factors Hes1, Hes5 and Hey1 in the PVN, HIPP and amygdala (AMY) were carried out in Dlk2-/- and WT mice under basal conditions and after exposure to restraint stress. The anxiolytic action of alprazolam and the relative gene expression levels of the GABA-A alpha 2 and gamma 2 receptor subunits (Gabra2 and Gabrg2) were also evaluated in the HIPP and AMY of WT and Dlk2-/- mice. The results reveal that deletion of Dlk2 increased anxiety and depressive-like behaviors and altered the vulnerability to restraint stress on Crh gene expression in the PVN, Nr3c1 and Fkbp5 gene expression in the HIPP, and Hes1, Hes5 and Hey1 gene expression in the PVN, HIPP and AMY. Interestingly, the administration of alprazolam failed to produce an anxiolytic action in Dlk2-/- mice. Indeed, Gabra2 and Gabrg2 gene expression levels were significantly affected under basal conditions and after stress exposure in Dlk2-/ mice compared with WT mice. In conclusion, the results suggest that DLK2 plays an important role in the regulation of emotional behaviors and relevant targets of the stress axis, NOTCH pathway and GABAergic neurotransmission. In addition, the deletion of Dlk2 blocked the anxiolytic response to alprazolam. Future studies are needed to determine the relevance of DLK2 as a potential therapeutic target for the treatment of neuropsychiatric disorders with anxiety or depressive like behaviors. PMID- 28863348 TI - Biological and perceived stress in motor functional neurological disorders. AB - BACKGROUND: Current models explaining motor functional neurological disorders (FND) integrate both the neurobiological mechanisms underlying symptoms production and the role of psychosocial stressors. Imaging studies have suggested abnormal motor control linked to impaired emotional and stress regulation. However, little is known on the biological stress regulation in FND. Our aim was to study the biological and perceived response to stress in patients with motor FND. METHODS: Sixteen patients with motor FND (DSM-5 criteria) and fifteen healthy controls underwent the Trier Social Stress Test. Hypothalamo-pituitary adrenal axis (HPA) response was evaluated with salivary cortisol and autonomous sympathetic response with salivary alpha-amylase. Area under the curve was computed to reflect background levels (AUCg) and change over time (AUCi). Life adversities and perceived subjective stress on a visual analog scale (VAS) were correlated with biological responses. RESULTS: FND patients had significantly higher background levels (AUCg) of both stress markers (cortisol and amylase) than controls. The biological response (AUCi) to stress did not differ between groups for both markers but the subjective response showed an interaction effect with patients reporting higher levels of stress than controls. After stress, controls showed a strong correlation between subjective and objective sympathetic values (amylase) but not patients. The number and subjective impact of adverse life events correlated with cortisol AUCg in patients only. CONCLUSION: This study confirms a baseline HPA-axis and sympathetic hyperarousal state in motor FND related to life adversities. During a social stress, dissociation between perceived stress and biological markers was observed in patients only, reflecting a dysregulation of interoception capacity, which might represent an endophenotype of this disorder. PMID- 28863349 TI - Effect of bovine somatotropin injection in late pregnant Holstein heifers on metabolic parameters and steroidogenic potential of the first postpartum dominant follicle. AB - The aim of this study was to determine the effect of pre-partum injections of bovine somatotropin (bST) in dairy heifers on metabolic markers and the steroidogenic potential of the first postpartum dominant follicle. Heifers were assigned to two groups: bST (ST; n = 29), that received two doses of bST (500 mg/dose) at -28 and -14 days relative to calving; and control (CTL; n = 30), that did not received bST. Follicular development was monitored via ultrasound every 3 days starting at 8 days in milk (DIM) in a subset of 20 heifers until the day the first large follicle reached a diameter of 16 mm. From these cows follicular fluid was aspirated and the follicular cells recovered (ST; n = 8 and CTL; n = 10). Blood samples were collected weekly for all heifers. Follicular fluid IGF-I concentrations of the first postpartum dominant follicle was higher (P = 0.05) in ST (87.1 +/- 7.7 mg/mL) than CTL cows (64.3 +/- 6.8 mg/mL). Also, E2 concentration in the follicular fluid was higher (P = 0.02) for ST (199.7 +/- 55.9 ng/mL) than CTL cows (74.5 +/- 37.7 ng/mL). The expression of LHCGR and STAR mRNA in follicular cells was higher (P < 0.05) in ST than CTL cows. Nonetheless, HSD3B, P450scc, P450c17, IGFr and CYP19A1 mRNA expression was not different between groups (P > 0.05). Serum IGF-I concentration was higher in ST treated heifers during the pre-partum period (P = 0.01) and no difference was observed in the postpartum period (P = 0.19). In conclusion, pre-partum bST treatment in dairy heifers increased intrafollicular IGF-I and expression of LHCGR and STAR mRNA in follicular cells of the first postpartum dominant follicle. These changes were associated to increased intrafollicular and serum E2 concentration, which can potentially increase the chance of ovulation of the first follicular wave. PMID- 28863350 TI - Ice nucleating agents allow embryo freezing without manual seeding. AB - Embryo slow freezing protocols include a nucleation induction step called manual seeding. This step is time consuming, manipulator dependent and hard to standardize. It requires access to samples, which is not always possible within the configuration of systems, such as differential scanning calorimeters or cryomicroscopes. Ice nucleation can be induced by other methods, e.g., by the use of ice nucleating agents. Snomax is a commercial preparation of inactivated proteins extracted from Pseudomonas syringae. The aim of our study was to investigate if Snomax can be an alternative to manual seeding in the slow freezing of mouse embryos. The influence of Snomax on the pH and osmolality of the freezing medium was evaluated. In vitro development (blastocyst formation and hatching rates) of fresh embryos exposed to Snomax and embryo cryopreserved with and without Snomax was assessed. The mitochondrial activity of frozen-thawed blastocysts was assessed by JC-1 fluorescent staining. Snomax didn't alter the physicochemical properties of the freezing medium, and did not affect embryo development of fresh embryos. After cryopreservation, the substitution of manual seeding by the ice nucleating agent (INA) Snomax did not affect embryo development or embryo mitochondrial activity. In conclusion, Snomax seems to be an effective ice nucleating agent for the slow freezing of mouse embryos. Snomax can also be a valuable alternative to manual seeding in research protocols in which manual seeding cannot be performed (i.e., differential scanning calorimetry and cryomicroscopy). PMID- 28863351 TI - Mexican consumers at the point of meat purchase. Pork choice. AB - Use of within-consumer preference replication and systematic image manipulation in surveying showed that consumers in four cities across Mexico had similar strategies for pork choice. New surveying tools also determined preferred levels of the characteristics used in the decision-making process. The most important choice criteria were colour (31% chose dark and 21% light red), and fat cover (42% chose lean and 8% fatty). Marbling and drip were less used, but are nevertheless important given that 21% of consumers used three or four characteristics to make their choice. Split colour and marbling preferences and a range of acceptable limits for both, and a preference for the leanest fat cover available were observed. Preferences within the normal range of pork colour, fat cover achieved through trimming and drip countered by an absorbent pad all favour industry practice. Unfortunately, preferences for minimal or no marbling and fat cover likely result in a compromised gustative experience for many Mexican consumers. PMID- 28863352 TI - The circumstances, orientations, and impact locations of falls in community dwelling older women. AB - OBJECTIVE: We sought to characterize the circumstances, orientations, and impact locations of falls in community-dwelling, ambulatory, older women. METHODS: For this longitudinal, observational study, 125 community-dwelling women age>=65years were recruited. Over 12-months of follow-up, fall details were recorded using twice-monthly questionnaires. RESULTS: More than half (59%) of participants fell, with 30% of participants falling more than once (fall rate=1.3 falls per person year). Slips (22%) and trips (33%) accounted for the majority of falls. Approximately 44% of falls were forward in direction, while backward falls accounted for 41% of falls. About a third of all falls were reported to have lateral (sideways) motion. Subjects reported taking a protective step in response to 82% of forward falls and 37% of backward falls. Of falls reporting lateral motion, a protective step was attempted in 70% of accounts. Common impact locations included the hip/pelvis (47% of falls) and the hand/wrist (27%). Backwards falls were most commonly reported with slips and when changing direction, and increased the risk of hip/pelvis impact (OR=12.6; 95% CI: 4.7 33.8). Forward falls were most commonly reported with trips and while hurrying, and increased the risk of impact to the hand/wrist (OR=2.6; 95% CI: 1.2-5.9). CONCLUSION: Falls in older ambulatory women occur more frequently than previously reported, with the fall circumstance and direction dictating impact to common fracture locations. Stepping was a common protective recovery strategy and that may serve as an appropriate focus of interventions to reduce falls in this high risk population. PMID- 28863354 TI - Domain-general neural computations underlying prosociality during infancy and early childhood. AB - A mounting body of neuroscience research in the social and moral evaluative abilities of infants and young children suggests the coopting of three domain general processes involved in attention allocation, approach/avoidance, and intention and action understanding. Electrophysiological investigations demonstrate children's preference for prosocial others, that children's individual differences in moral evaluation predict prosocial behaviors, and that parental values may already influence neural sociomoral computations at quite young ages. This review highlights the importance of a developmental neuroscience approach in clarifying our understanding of early prosocial preference and behavior. PMID- 28863353 TI - Predicting 3-year mortality and admission to acute-care hospitals, skilled nursing facilities, and long-term care facilities in Medicare beneficiaries. AB - PURPOSE: The ability to predict mortality and admission to acute care hospitals, skilled nursing facilities (SNFs), and long-term care (LTC) facilities in the elderly and how it varies by activity of daily living (ADL) and instrumental ADL (IADL) status could be useful in measuring the success or failure of economic, social, or health policies aimed at disability prevention and management. We sought to derive and assess the predictive performance of rules to predict 3-year mortality and admission to acute care hospitals, SNFs, and LTC facilities among Medicare beneficiaries with differing ADL and IADL functioning levels. METHODS: Prospective cohort using Medicare Current Beneficiary Survey data from the 2001 to 2007 entry panels. In all, 23,407 community-dwelling Medicare beneficiaries were included. Multivariable logistic models created predicted probabilities for all-cause mortality and admission to acute care hospitals, SNFs, and LTC facilities, adjusting for sociodemographics, health conditions, impairments, behavior, and function. RESULTS: Sixteen, 22, 14, and 14 predictors remained in the final parsimonious model predicting 3-year all-cause mortality, inpatient admission, SNF admission, and LTC facility admission, respectively. The C statistic for predicting 3-year all-cause mortality, inpatient admission, SNF admission, and LTC facility admission was 0.779, 0.672, 0.753, and 0.826 in the ADL activity limitation stage development cohorts, respectively, and 0.788, 0.669, 0.748, and 0.799 in the ADL activity limitation stage validation cohorts, respectively. CONCLUSIONS: Parsimonious models can identify elderly Medicare beneficiaries at risk of poor outcomes and can aid policymakers, clinicians, and family members in improving care for older adults and supporting successful aging in the community. PMID- 28863355 TI - Design, synthesis and preliminary biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine/thiourea hybrids as antiproliferative agents. AB - A series of new [1,2,3]triazolo[4,5-d]pyrimidine/thiourea hybrids were designed and synthesized through the scaffold replacement/ring cleavage strategy. SARs studies revealed that the N-heteroarene moiety attached to the thiourea is preferred over the phenyl ring for the R2 substituents, while the hydrophobic aromatic group is beneficial for improving the activity. Among these compounds, compound 5r significantly inhibited cell growth of lung cancer cell lines H1650 and A549 (IC50 = 1.91, 3.28 MUM, respectively), but was less toxic against the normal cell line GES-1 (IC50 = 27.43 MUM). Mechanistic studies showed that compound 5r could remarkably inhibit the colony formation of H1650 cells, induced apoptosis possibly through the intrinsic apoptotic pathways, and arrested the cell cycle at G2/M phase. Our studies suggest that the [1,2,3]triazolo[4,5 d]pyrimidine/thiourea hybrids are a new class of chemotypes possessing interesting antiproliferative activity against lung cancer cells and could be potentially utilized for designing new antitumor agents. PMID- 28863356 TI - Glycine-replaced derivatives of [Pro3,DLeu9]TL, a temporin L analogue: Evaluation of antimicrobial, cytotoxic and hemolytic activities. AB - In this study we designed and synthesized a new library of antimicrobial peptides correlated to [Pro3,DLeu9]TL 1, a temporin L derivative devoid of cytolytic effects in vitro, and investigated the correlation between the alpha-helical content of the compounds and their antibacterial, cytotoxic and hemolytic activities. We systematically replaced Gly in position 10 of reference peptide with several amino acids. Structure-activity relationship studies of these analogues were performed by means of antimicrobial and cytotoxicity assays along with CD spectroscopy analyses. NMR analysis was also accomplished for compound 10. As well, the most promising peptides were additionally evaluated for their activity against some clinical strains isolated from human skin and for their mechanism of action by studying the kinetics of membrane perturbation of some representative microbial strains. We identified novel analogues with interesting properties that make them attractive lead compounds for potential topical applications. PMID- 28863357 TI - Dual Inhibition of Mnk2 and FLT3 for potential treatment of acute myeloid leukaemia. AB - The discovery of novel anti-AML therapeutic agents is urgently needed, but the complex heterogeneity of the disease has so far hampered the development of a curative treatment. FLT3 inhibitors have shown therapeutic potential in clinical trials; but a monotherapy regimen has been associated with resistance mediated by the activation of parallel signalling circuitry, including MAPK and mTOR. Therefore, inhibiting a nexus of the two signalling pathways along with inhibition of FLT3 might be advantageous. Herein, we propose that a dual inhibition of FLT3 and Mnk would provide a better clinical option for AML patients compared to targeting FLT3 alone. Thus, a series of N-phenyl-4-(thiazol 5-yl)pyrimidin-2-amines and 4-(indol-3-yl)-N-phenylpyrimidin-2-amines were prepared. Potent Mnk2 inhibitors, FLT3 inhibitors, and dual inhibitors of Mnk2 and FLT3 were identified and their anti-proliferative activities assessed against MV4-11 AML cell lines. Dual inhibition of FLT3 and Mnk2 caused the increased apoptotic cell death of MV4-11 cells compared to inhibition of FLT3 or Mnk2 alone. PMID- 28863358 TI - From dual binding site acetylcholinesterase inhibitors to allosteric modulators: A new avenue for disease-modifying drugs in Alzheimer's disease. AB - The lack of an effective treatment for Alzheimer' disease (AD), an increasing prevalence and severe neurodegenerative pathology boost medicinal chemists to look for new drugs. Currently, only acethylcholinesterase (AChE) inhibitors and glutamate antagonist have been approved to the palliative treatment of AD. Although they have a short-term symptomatic benefits, their clinical use have revealed important non-cholinergic functions for AChE such its chaperone role in beta-amyloid toxicity. We propose here the design, synthesis and evaluation of non-toxic dual binding site AChEIs by hybridization of indanone and quinoline heterocyclic scaffolds. Unexpectely, we have found a potent allosteric modulator of AChE able to target cholinergic and non-cholinergic functions by fixing a specific AChE conformation, confirmed by STD-NMR and molecular modeling studies. Furthermore the promising biological data obtained on human neuroblastoma SH-SY5Y cell assays for the new allosteric hybrid 14, led us to propose it as a valuable pharmacological tool for the study of non-cholinergic functions of AChE, and as a new important lead for novel disease modifying agents against AD. PMID- 28863359 TI - Novel chemotypes targeting tubulin at the colchicine binding site and unbiasing P glycoprotein. AB - Retrospective validation studies carried out on three benchmark databases containing a small fraction (that is 2.80%) of known tubulin binders permitted us to develop a computational platform very effective in selecting easier manageable subsets showing by far higher percentages of actives (about 25%). These studies relied on the hierarchical application of multilayer in silico screenings employing filters implying molecular shape similarity; a structure-based pharmacophore model and molecular docking campaigns. Building on this validated approach, we performed intensive prospective studies to screen a large chemical collection, including up to 3.7 millions of commercial compounds, to across an unexplored and patent space in the search of novel colchicine binding site inhibitors. Our investigation was successful in identifying a pool of 31 initial hits showing new molecular scaffolds (such as 4,5-dihydro-1H-pyrrolo[3,4 c]pyrazol-6-one and pyrazolo[1,5-a]pyrimidine). This panel of new hits resulted antiproliferative activity in the low MUM range towards MCF-7 human breast cancer, HepG2 human liver cancer, HeLa human ovarian cancer and SHSY5Y human glioblastoma cell lines as well as interesting concentration-dependent inhibition of tubulin polymerization assessed through fluorescence polymerization assays. Unlike typical tubulin inhibitors, a satisfactorily low sensitivity towards P-gp was also measured in bi-directional transport studies across MDCKII-MDR1 cells for a selected subset of seven compounds. PMID- 28863360 TI - Idiopathic intracranial hypertension: Ocular vestibular evoked myogenic potentials as a new evaluation tool. PMID- 28863361 TI - Evaluating brain-computer interface performance using color in the P300 checkerboard speller. AB - OBJECTIVE: Current Brain-Computer Interface (BCI) systems typically flash an array of items from grey to white (GW). The objective of this study was to evaluate BCI performance using uniquely colored stimuli. METHODS: In addition to the GW stimuli, the current study tested two types of color stimuli (grey to color [GC] and color intensification [CI]). The main hypotheses were that in a checkboard paradigm, unique color stimuli will: (1) increase BCI performance over the standard GW paradigm; (2) elicit larger event-related potentials (ERPs); and, (3) improve offline performance with an electrode selection algorithm (i.e., Jumpwise). RESULTS: Online results (n=36) showed that GC provides higher accuracy and information transfer rate than the CI and GW conditions. Waveform analysis showed that GC produced higher amplitude ERPs than CI and GW. Information transfer rate was improved by the Jumpwise-selected channel locations in all conditions. CONCLUSIONS: Unique color stimuli (GC) improved BCI performance and enhanced ERPs. Jumpwise-selected electrode locations improved offline performance. SIGNIFICANCE: These results show that in a checkerboard paradigm, unique color stimuli increase BCI performance, are preferred by participants, and are important to the design of end-user applications; thus, could lead to an increase in end-user performance and acceptance of BCI technology. PMID- 28863362 TI - The location of late night bars and alcohol-related crashes in Houston, Texas. AB - A study in the City of Houston, Texas, related the location of establishments primarily serving alcohol ("bars") after midnight to late night alcohol-related motor vehicle crashes. There were three data sets for 2007-09: 1) 764bars that were open after midnight; 2) 1660 alcohol-related crashes that occurred within the City of Houston between midnight and 6 am; and 3) 4689 modeling network road segments to which bars and alcohol-related crashes were assigned. Forty-five percent of the late night alcohol-related crashes were within a quarter mile of a late night bar. The bars were highly concentrated in 17 small bar clusters. Using the modeling network, Poisson-Gamma-CAR and Poisson-Lognormal-CAR spatial regression models showed a positive exponential relationship between late night alcohol-related crashes and the number of late nights bars and bar clusters, and a negative exponential relationship to distance to the nearest late night bar controlling for the type of road segment (freeway, principal arterial, minor arterial). A more general model dropped the bar cluster variable. Further, the Poisson-Gamma-CAR model appeared to produce a better representation than the Poisson-Lognormal-CAR model though the errors were different. The general Poisson Gamma-CAR model showed that each late night bar increased the frequency of alcohol-related crashes on a segment by approximately 190%. For each mile closer a segment was to a late night bar, the likelihood increased by 42%. PMID- 28863363 TI - Operating conditions influence microbial community structures, elimination of the antibiotic resistance genes and metabolites during anaerobic digestion of cow manure in the presence of oxytetracycline. AB - The way that antibiotic residues in manure follow is one of the greatest concerns due to its potential negative impacts on microbial communities, the release of metabolites and antibiotic resistant genes (ARGs) into the nature and the loss of energy recovery in anaerobic digestion (AD) systems. This study evaluated the link between different operating conditions, the biodegradation of oxytetracycline (OTC) and the formation of its metabolites and ARGs in anaerobic digesters treating cow manure. Microbial communities and ARGs were determined through the use of quantitative real-time PCR. The biodegradation of OTC and occurrence of metabolites were determined using UV-HPLC and LC/MS/MS respectively. The maximum quantity of resistance genes was also examined at the beginning of AD tests and concentration was in the order of: tetM >tetO. The numbers of ARGs were always higher at high volatile solids (VS) content and high mixing rate. The results of the investigation revealed that relationship between mixing rate and VS content plays a crucial role for elimination of ARGs, OTC and metabolites. This can be attributed to high abundance of microorganisms due to high VS content and their increased contact with elevated mixing rate. An increased interaction between microorganisms triggers the promotion of ARGs. PMID- 28863364 TI - High-energy breakfast based on whey protein reduces body weight, postprandial glycemia and HbA1C in Type 2 diabetes. AB - Acute studies show that addition of whey protein at breakfast has a glucose lowering effect through increased incretin and insulin secretion. However, whether this is a long-term effect in Type 2 diabetes is unknown. Fifty-six Type 2 diabetes participants aged 58.9+/-4.5 years, BMI 32.1+/-0.9 kg/m2 and HbA1C 7.8+/-0.1% (61.6+/-0.79 mmol/mol) were randomized to one of 3 isocaloric diets with similar lunch and dinner, but different breakfast: 1) 42 g total protein, 28 g whey (WBdiet, n=19); 2) 42 g various protein sources (PBdiet, n=19); or 3) high carbohydrate breakfast, 17 g protein from various sources (CBdiet, n=18). Body weight and HbA1C were examined after 12 weeks. All participants underwent three all-day meal challenges for postprandial glycemia, insulin, C-peptide, intact glucagon-like peptide 1 (iGLP-1), ghrelin and hunger and satiety scores. Overall postprandial AUCglucose was reduced by 12% in PBdiet and by 19% in WBdiet, compared with CBdiet (P<.0001). Compared with PBdiet and CBdiet, WBdiet led to a greater postprandial overall AUC for insulin, C-peptide, iGLP-1 and satiety scores, while postprandial overall AUC for ghrelin and hunger scores were reduced (P<.0001). After 12 weeks, HbA1C was reduced after WBdiet by 0.89+/-0.05% (11.5+/ 0.6 mmol/mol), after PBdiet by 0.6+/-0.04% (7.1+/-0.31 mmol/mol) and after CBdiet by 0.36+/-0.04% (2.9+/-0.31 mmol/mol) (P<.0001). Furthermore, the participants on WBdiet lost 7.6+/-0.3 kg, PBdiet 6.1+/-0.3 kg and CBdiet 3.5+/-0.3 kg (P<.0001). Whey protein-based breakfast is an important adjuvant in the management of Type 2 diabetes. PMID- 28863365 TI - A polyphenolic extract from green tea leaves activates fat browning in high-fat diet-induced obese mice. AB - Fat browning has emerged as an attractive target for the treatment of obesity and related metabolic disorders. Its activation leads to increased energy expenditure and reduced adiposity, thus contributing to a better energy homeostasis. Green tea extracts (GTEs) were shown to attenuate obesity and low-grade inflammation and to induce the lipolytic pathway in the white adipose tissue (WAT) of mice fed a high-fat diet. The aim of the present study was to determine whether the antiobesity effect of an extract from green tea leaves was associated with the activation of browning in the WAT and/or the inhibition of whitening in the brown adipose tissue (BAT) in HF-diet induced obese mice. Mice were fed a control diet or an HF diet supplemented with or without 0.5% polyphenolic GTE for 8 weeks. GTE supplementation significantly reduced HF-induced adiposity (WAT and BAT) and HF induced inflammation in WAT. Histological analysis revealed that GTE reduced the adipocyte size in the WAT and the lipid droplet size in the BAT. Markers of browning were induced in the WAT upon GTE treatment, whereas markers of HF induced whitening were reduced in the BAT. These results suggest that browning activation in the WAT and whitening reduction in the BAT by the GTE could participate to the improvement of metabolic and inflammatory disorders mediated by GTE upon HF diet. Our study emphasizes the importance of using GTE as a nutritional tool to activate browning and to decrease fat storage in all adipose tissues, which attenuate obesity. PMID- 28863366 TI - Fat-enriched rather than high-fructose diets promote whitening of adipose tissue in a sex-dependent manner. AB - Adipose tissue is a critical regulator of energy metabolism and an effector organ of excessive caloric intake. We studied the effects of high-fructose (HFruD), high-fat (HFD) and mixed high-sucrose and high-fat diet (HFHSD) on adipocyte morphology and biology and consecutive metabolic effects in male and female C57BL/6 mice. Forty male and 40 female mice were randomly assigned to one of four dietary groups and fed for 10 weeks ad libitum. After 10 weeks of feeding, mice were analyzed in regard to glucose metabolism, insulin sensitivity and alteration in adipocyte morphology and function. Weight gain and diminished insulin sensitivity in HFD- and HFHSD-fed mice were accompanied by increased adipocyte size and a shift in size distribution towards larger adipocytes in all mice. The latter effect was also found but less pronounced in HFruD-fed mice, while insulin sensitivity and body weight remained unaffected. In male mice, expansion of white adipocytes along with decreased uncoupling protein 1 (UCP-1) expression and alterations of mitochondrial biogenesis was found after HFD and HFHSD feeding, while in female mice, UCP-1 expression was also reduced in the HFruD dietary group. Diet-induced cellular alterations were less pronounced in female mice. Our data demonstrate that high-fat rather than high fructose consumption drives metabolically disadvantageous alterations of adipocyte differentiation involving whitening and insulin resistance in a sex-dependent manner with most deleterious effects seen upon administration of combined sucrose and fat-enriched diet in male mice. PMID- 28863367 TI - Monomeric cocoa catechins enhance beta-cell function by increasing mitochondrial respiration. AB - A hallmark of type 2 diabetes (T2D) is beta-cell dysfunction and the eventual loss of functional beta-cell mass. Therefore, mechanisms that improve or preserve beta-cell function could be used to improve the quality of life of individuals with T2D. Studies have shown that monomeric, oligomeric and polymeric cocoa flavanols have different effects on obesity, insulin resistance and glucose tolerance. We hypothesized that these cocoa flavanols may have beneficial effects on beta-cell function. INS-1 832/13-derived beta-cells and primary rat islets cultured with a monomeric catechin-rich cocoa flavanol fraction demonstrated enhanced glucose-stimulated insulin secretion, while cells cultured with total cocoa extract and with oligomeric or polymeric procyanidin-rich fraction demonstrated no improvement. The increased glucose-stimulated insulin secretion in the presence of the monomeric catechin-rich fraction corresponded with enhanced mitochondrial respiration, suggesting improvements in beta-cell fuel utilization. Mitochondrial complex III, IV and V components are up-regulated after culture with the monomer-rich fraction, corresponding with increased cellular ATP production. The monomer-rich fraction improved cellular redox state and increased glutathione concentration, which corresponds with nuclear factor, erythroid 2 like 2 (Nrf2) nuclear localization and expression of Nrf2 target genes including nuclear respiratory factor 1 (Nrf1) and GA binding protein transcription factor alpha subunit (GABPA), essential genes for increasing mitochondrial function. We propose a model by which monomeric cocoa catechins improve the cellular redox state, resulting in Nrf2 nuclear migration and up regulation of genes critical for mitochondrial respiration, glucose-stimulated insulin secretion and ultimately improved beta-cell function. These results suggest a mechanism by which monomeric cocoa catechins exert their effects as an effective complementary strategy to benefit T2D patients. PMID- 28863369 TI - Application of ozone micro-nano-bubbles to groundwater remediation. AB - Ozone is widely used for water treatment because of its strong oxidation ability. However, the efficiency of ozone in groundwater remediation is limited because of its relatively low solubility and rapid decomposition in the aqueous phase. Methods for increasing the stability of ozone within the subsurface are drawing increasing attention. Micro-nano-bubbles (MNBs), with diameters ranging from tens of nanometres to tens of micrometres, present rapid mass transfer rates, persist for a relatively long time in water, and transport with groundwater flow, which significantly improve gas concentration and provide a continuous gas supply. Therefore, MNBs show a considerable potential for application in groundwater remediation. In this study, the characteristics of ozone MNBs were examined, including their size distribution, bubble quantity, and zeta potential. The mass transfer rate of ozone MNBs was experimentally investigated. Ozone MNBs were then used to treat organics-contaminated water, and they showed remarkable cleanup efficiency. Column tests were also conducted to study the efficiency of ozone MNBs for organics-contaminated groundwater remediation. Based on the laboratory tests, field monitoring was conducted on a trichloroethylene (TCE)-contaminated site. The results showed that ozone MNBs can greatly improve remediation efficiency and represent an innovative technology for in situ remediation of organics-contaminated groundwater. PMID- 28863370 TI - Cognitive flexibility and its electrophysiological correlates in Gilles de la Tourette syndrome. AB - Motor symptoms in Gilles de la Tourette syndrome (GTS) have been related to changes in frontostriatal brain networks. These changes may also give rise to alterations in cognitive flexibility. However, conclusive evidence for altered cognitive flexibility in patients with GTS is still lacking. Here, we meta analyzed data from 20 neuropsychological studies that investigated cognitive flexibility in GTS using the Wisconsin Card Sorting Test (WCST). Results revealed medium-sized GTS-related performance deficits, which were significantly modulated by age: Whilst being substantial in children and adolescents with GTS, WCST deficits seem to dissolve in adult patients with GTS. This age-related normalization of WCST performance might result from the compensatory recruitment of cognitive control in adult patients with GTS. We addressed this possibility by examining neural correlates of proactive and reactive cognitive control in an event-related potential (ERP) study. We analyzed cue- and target-locked ERPs from 23 adult patients with GTS and 26 matched controls who completed a computerized version of the WCST. Compared to controls, patients with GTS showed a marked increase in parietal cue-locked P3 activity, indicating enhanced proactive cognitive control. We conclude that the additional recruitment of proactive cognitive control might ensure flexible cognitive functioning in adult patients with GTS. PMID- 28863368 TI - Postprandial effect to decrease soluble epoxide hydrolase activity: roles of insulin and gut microbiota. AB - Epoxides of free fatty acids (FFAs), especially epoxyeicosatrienoic acids (EETs), are lipid mediators with beneficial effects in metabolic and cardiovascular (CV) health. FFA epoxides are quickly metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EET levels, improves glucose homeostasis and CV health and is proposed as an effective strategy for the treatment of diabetes and CV diseases. Here, we show evidence that sEH activity is profoundly reduced in postprandial states in rats; plasma levels of 17 sEH products (i.e., FFA diols), detected by targeted oxylipin analysis, all decreased after a meal. In addition, the ratios of sEH product to substrate (sEH P/S ratios), which may reflect sEH activity, decreased ~70% on average 2.5 h after a meal in rats (P<.01). To examine whether this effect was mediated by insulin action, a hyperinsulinemic-euglycemic clamp was performed for 2.5 h, and sEH P/S ratios were assessed before and after the clamp. The clamp resulted in small increases rather than decreases in sEH P/S ratios (P<.05), indicating that insulin cannot account for the postprandial decrease in sEH P/S ratios. Interestingly, in rats treated with antibiotics to deplete gut bacteria, the postprandial effect to decrease sEH P/S ratios was completely abolished, suggesting that a gut bacteria-derived factor(s) may be responsible for the effect. Further studies are warranted to identify such a factor(s) and elucidate the mechanism by which sEH activity (or sEH P/S ratio) is reduced in postprandial states. PMID- 28863371 TI - Modelling CO2 emissions from water surface of a boreal hydroelectric reservoir. AB - To quantify CO2 emissions from water surface of a reservoir that was shaped by flooding the boreal landscape, we developed a daily time-step reservoir biogeochemistry model. We calibrated the model using the measured concentrations of dissolved organic and inorganic carbon (C) in a young boreal hydroelectric reservoir, Eastmain-1 (EM-1), in northern Quebec, Canada. We validated the model against observed CO2 fluxes from an eddy covariance tower in the middle of EM-1. The model predicted the variability of CO2 emissions reasonably well compared to the observations (root mean square error: 0.4-1.3gCm-2day-1, revised Willmott index: 0.16-0.55). In particular, we demonstrated that the annual reservoir surface effluxes were initially high, steeply declined in the first three years, and then steadily decreased to ~115gCm-2yr-1 with increasing reservoir age over the estimated "engineering" reservoir lifetime (i.e., 100years). Sensitivity analyses revealed that increasing air temperature stimulated CO2 emissions by enhancing CO2 production in the water column and sediment, and extending the duration of open water period over which emissions occur. Increasing the amount of terrestrial organic C flooded can enhance benthic CO2 fluxes and CO2 emissions from the reservoir water surface, but the effects were not significant over the simulation period. The model is useful for the understanding of the mechanism of C dynamics in reservoirs and could be used to assist the hydro-power industry and others interested in the role of boreal hydroelectric reservoirs as sources of greenhouse gas emissions. PMID- 28863372 TI - Are organosilicon surfactants safe for bees or humans? AB - Organosilicon surfactants are the most potent adjuvants available for formulating and applying agricultural pesticides and fertilizers, household cleaning and personal care products, dental impressions and medicines. Risk assessment of pesticides, drugs or personal care products that takes into account only active ingredients without the other formulation ingredients and adjuvants commonly used in their application will miss important toxicity outcomes detrimental to non target species including pollinators and humans. Over a billion pounds of organosilicon surfactants from all uses are produced globally per year, making this a major component of the chemical landscape to which bees and humans are exposed. These silicones, like most "inerts", are generally recognized as safe, have no mandated tolerances, and their residues are largely unmonitored. Lack of their public disclosure and adequate analytical methods constrains evaluation of their risk. Organosilicon surfactants, the most super-spreading and -penetrating adjuvants available, at relevant exposure levels impair honey bee learning, are acutely toxic, and in combination with bee viruses cause synergistic mortality. Organosilicon surfactants need to be regulated as a separate class of "inerts" from the more common silicones. In turn, impacts of organosilicon surfactant exposures on humans need to be evaluated. Silicones in their great diversity probably represent the single most ubiquitous environmental class of global synthetic pollutants. Do honey bees, a model environmental indicator organism, forewarn of hidden risks to humans of ubiquitous silicone exposures? PMID- 28863373 TI - Plastics in soil: Analytical methods and possible sources. AB - At least 300 Mio t of plastic are produced annually, from which large parts end up in the environment, where it persists over decades, harms biota and enters the food chain. Yet, almost nothing is known about plastic pollution of soil; hence, the aims of this work are to review current knowledge on i) available methods for the quantification and identification of plastic in soil, ii) the quantity and possible input pathways of plastic into soil, (including first preliminary screening of plastic in compost), and iii) its fate in soil. Methods for plastic analyses in sediments can potentially be adjusted for application to soil; yet, the applicability of these methods for soil needs to be tested. Consequently, the current data base on soil pollution with plastic is still poor. Soils may receive plastic inputs via plastic mulching or the application of plastic containing soil amendments. In compost up to 2.38-1200mg plastic kg-1 have been found so far; the plastic concentration of sewage sludge varies between 1000 and 24,000 plastic items kg-1. Also irrigation with untreated and treated wastewater (1000-627,000 and 0-125,000 plastic items m-3, respectively) as well as flooding with lake water (0.82-4.42 plastic items m-3) or river water (0-13,751 items km-2) can provide major input pathways for plastic into soil. Additional sources comprise littering along roads and trails, illegal waste dumping, road runoff as well as atmospheric input. With these input pathways, plastic concentrations in soil might reach the per mill range of soil organic carbon. Most of plastic (especially >1MUm) will presumably be retained in soil, where it persists for decades or longer. Accordingly, further research on the prevalence and fate of such synthetic polymers in soils is urgently warranted. PMID- 28863374 TI - Uptake of the natural radioactive gas radon by an epiphytic plant. AB - Radon (222Rn) is a natural radioactive gas and the major radioactive contributor to human exposure. The present effective ways to control Rn contamination are ventilation and adsorption with activated carbon. Plants are believed to be negligible in reducing airborne Rn. Here, we found epiphytic Tillandsia brachycaulos (Bromeliaceae) was effective in reducing airborne Rn via the leaves. Rn concentrations in the Rn chamber after Tillandsia plant treatments decreased more than those in the natural situation. The specialized foliar trichomes densely covering Tillandsia leaves play a major role in the uptake of Rn because the amplified rough leaf surface area facilitates deposition of Rn progeny particles and the powdery epicuticular wax layer of foliar trichomes uptakes liposoluble Rn. The results provide us a new ecological strategy for Rn contamination control, and movable epiphytic Tillandsia plants can be applied widely in Rn removal systems. PMID- 28863375 TI - Detoxification mechanisms, defense responses, and toxicity threshold in the earthworm Eisenia foetida exposed to ciprofloxacin-polluted soils. AB - The widespread application of antibiotics poses health risks for agro-ecosystems. This study examined the effects of ciproflaxin (CIP)-polluted soils (0 51.2mgCIP/kg) on the earthworm Eisenia foetida. The enhanced activities and isozyme levels of superoxide dismutase (SOD) and ascorbate peroxidase after 15days of CIP exposure suggested reactive oxygen species overproduction and thus the generation of oxidatively damaged proteins (e.g., carbonylated proteins) in the earthworms. Under mild CIP stress, the 20S proteasome was capable of degrading most of the damaged proteins independent of ubiquitin. Under severe stress, proteases and endoproteases were up-regulated and maintained the proteolysis as 20S proteasome activity diminished. These observations suggested that, together with glutathione S-transferases, which also participated in the detoxification, 20S proteasome, proteases, endoproteases, and antioxidant enzymes constituted a detoxification and defense system in the earthworms. The biphasic dose responses of these cellular components confirmed that the dose range tested was reasonable for the bioassay of CIP-polluted soils. Our results also demonstrated the potential utility of SOD and ubiquitin as highly sensitive biomarkers in the early bioassay of CIP-polluted soils. Bases on the results, a toxicity threshold for CIP-polluted soils of 3.2-6.4mgCIP/kg soil can be proposed. PMID- 28863376 TI - Reducing mortality risk by targeting specific air pollution sources: Suva, Fiji. AB - Health implications of air pollution vary dependent upon pollutant sources. This work determines the value, in terms of reduced mortality, of reducing ambient particulate matter (PM2.5: effective aerodynamic diameter 2.5MUm or less) concentration due to different emission sources. Suva, a Pacific Island city with substantial input from combustion sources, is used as a case-study. Elemental concentration was determined, by ion beam analysis, for PM2.5 samples from Suva, spanning one year. Sources of PM2.5 have been quantified by positive matrix factorisation. A review of recent literature has been carried out to delineate the mortality risk associated with these sources. Risk factors have then been applied for Suva, to calculate the possible mortality reduction that may be achieved through reduction in pollutant levels. Higher risk ratios for black carbon and sulphur resulted in mortality predictions for PM2.5 from fossil fuel combustion, road vehicle emissions and waste burning that surpass predictions for these sources based on health risk of PM2.5 mass alone. Predicted mortality for Suva from fossil fuel smoke exceeds the national toll from road accidents in Fiji. The greatest benefit for Suva, in terms of reduced mortality, is likely to be accomplished by reducing emissions from fossil fuel combustion (diesel), vehicles and waste burning. PMID- 28863377 TI - A rare case report of an adenomatoid odontogenic tumor associated with odontoma in the maxilla. AB - INTRODUCTION: The adenomatoid odontogenic tumor (AOT) associated with odontoma has been described as a new entity with overlapping features of adenomatoid-like structures and odontoma. Presentation of the case: We report the second case of AOT associated with odontoma in the posterior maxillary region. A 22-year-old patient presented expansion of the vestibular and palatine cortical wall of maxilla. Radiographic examination and computed tomography confirmed erosion of maxillary walls, root resorption, displacement of a neighboring tooth and radiopacities within the lesion. Histopathological analysis showed a cystic cavity lined by odontogenic epithelium, organized as duct like structures and tubular dentin. The diagnosis established was AOT associated with odontoma. DISCUSSION: As fewer cases have been described, the aim of this study is to report clinical behavior and evolution of adenomatoid odontogenic tumor associated with odontoma, as it have not yet been described and its origin is not completely established. The hamartomatous or neoplastic origin of this tumor is under debate. CONCLUSIONS: Therefore, it is necessary similar cases to be published to increase the knowledge about the clinical behavior and evolution of this tumor, to enable such lesions to be more clearly defined in the next classification of odontogenic tumors. PMID- 28863378 TI - Right hepatectomy after spontaneous hepatic rupture in a patient with preeclampsia: A case report. AB - INTRODUCTION: Spontaneous hepatic rupture associated with preecalmpsia or HELLP syndrome is a rare and life threatining event, only 200 cases have been reported in the literature. PRESENTATION OF CASE: We present a case of a 31 year old female with 28 weeks of gestation that presented with acute abdominal pain, elevated blood pressure and altered liver enzymes an abdominal ultrasound that showed a subcapsular hematoma occupying the whole right lobe and free abdominal fluid, she required emergent laparotomy, C-section, hepatic packing, followed by angioembolization and finally right hepatectomy. DISCUSSION AND CONSLUSION: Spontaneous hepatic rupture due to preeclampsia or HELLP syndrome is a medical emergency, it requires a prompt and decisive treatment. Multiple treatment modalities are available, from simple hepatic packing to endovascular embolization, but in extreme situations a formal hepatectomy might be required. PMID- 28863379 TI - Cassia auriculata flower extract attenuates hyperlipidemia in male Wistar rats by regulating the hepatic cholesterol metabolism. AB - Hyperlipidemia in the male albino Wistar rats was induced by Triton WR - 1339. The treatment of the hyperlipidemic animals with the ethanol extract of Cassia auriculata flower (Et-CAF) exhibited a dose dependent reduction in serum triacylglycerol, total cholesterol, low density lipoprotein (LDL), very low density lipoprotein (VLDL) similar to the hyperlipidemic animals treated with standard drug atorvastatin. Hyperlipidemia altered the protein and mRNA expression levels of the key genes (SREBP-1c, ACC1, SREBP-2, HMGR, HMGS, CYP7A1, and ABCA1) in lipid metabolism and the treatment with Et-CAF (300mg/kg b. wt) reverted these levels similar to that observed with atorvastatin treated hyperlipidemic animals. These results revealed that Et-CAF extract served as an efficient anti-hyperlipidemic drug. PMID- 28863380 TI - Effect of two andrographolide derivatives on cellular and rodent models of non alcoholic fatty liver disease. AB - The prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) is increasing and there is an increasing interest in natural products to treat NAFLD. This study aimed to evaluate the hepatoprotective effect of andrographolide and two of its derivatives; in one the OH group at C-14 was removed and in the other OH groups at C-3 and C-19 were protected. Andrographolide (AN) was isolated from the aerial parts of Andrographis paniculata Wall. Isoandrographolide (IAN) and 3,19 acetonylidene andrographolide (ANA) were derivatized from AN. Drug likeness of the compounds was studied using DataWarrior. The effect of the compounds in ameliorating hepatic steatosis and lipotoxicity was assessed using palmitate oleate induced steatotic HepG2 cell lines. In vivo efficacy of the compounds was assessed by using HFD fed rats. IAN showed comparatively high drug score and low irritability than AN. MTT assay indicated that the treatment with IAN had comparatively less toxicity than AN and ANA to HepG2 cells. The treatment with IAN significantly reduced the lipid accumulation and the leakage of LDH and transaminases, while the treatments with AN and ANA did not prohibit the leakage. In the in vivo experiment, the treatment with IAN showed comparatively better hepatoprotection by reducing the serum lipid, transaminases and ALP levels than with AN and ANA. Our results showed that IAN could be a promising lead to treat NAFLD with comparatively low toxicity and improved efficacy. PMID- 28863381 TI - Natural killer T cells in Preeclampsia: An updated review. AB - Preeclampsia (PE), as a pregnancy-specific syndrome, has become one of the main causes of maternal and fetal mortality worldwide and is known as a major risk factor for preterm birth. PE is typically characterized by hypertension, significant proteinuria, and an excessive maternal systemic inflammatory response. Recent evidences provide support for the notion that Natural killer T (NKT) cells (a small, but significant immunoregulatory T cell subset of human peripheral blood lymphocytes) play pivotal roles in pregnancy. NKT cells with unique transcriptional and cytokine profiles exist in different peripheral tissues acting as mediators between the innate and adaptive immune systems. NKT cells secrete Interleukin-4 (IL-4) and Interferon-gamma (IFN-gamma) which might regulate the balance between Type 1T helper (Th1) and Type 2T helper (Th2) responses. During pregnancy, maternal immunity is biased towards type II cytokine production to inhibit the function of type I cytokines that could be harmful for the developing fetus. This shift to type II cytokines does not occur in preeclamptic patients. In this review, we discuss the numbers, phenotype, changes, and the functional activity of Natural killer T (NKT) cells during normal pregnancy and preeclampsia. PMID- 28863382 TI - Design and synthesis of conjugated azo-hydrazone analogues using nano BF3.SiO2 targeting ROS homeostasis in oncogenic and vascular progression. AB - Disrupted redox balance is implicated in multiple pathologies including malignant progression and tumor angiogenesis. In this investigation, we report the design and development of novel and effective ROS detoxifying azo-hydrazone molecules targeting malignant pathologies and neoangiogenesis. A series of azo-derivatives conjugated to hydrazones moieties (9a-j) were synthesized using Nano BF3.SiO2. The compounds (9a-j) were screened for in-vitro antioxidant and lipid peroxidation inhibitory activity. Among the series 9a-j, compound 9f potently quenched biologically relevant radicals such as superoxide and hydrogen peroxide which emerged as the lead ROS detoxifying molecules. Compound 9f potently inhibited the proliferative capability of Daltons Lymphoma Ascites (DLA) tumor cells in-vivo in dose dependent manner. Regressed tumor progression was correlated with pronounced endogenous antioxidant enzyme superoxide dismutase and catalase in-vivo. Also, ROS levels were severely suppressed in 9f treated mice as assessed by lapsed lipid peroxidation. Altered enzymic and ROS levels in-vivo by 9f were implicated in suppressed VEGF secretion leading to regressed tumor neovasculature and tumor growth. Considering together, it is evident that the synthetic azo-hydrazone analogue 9f with potent ROS scavenging efficacy inhibits tumor progression and neo-angiogenesis. PMID- 28863383 TI - Acetylenic derivative of betulin induces apoptosis in endometrial adenocarcinoma cell line. AB - Since betulin (Bet) and its acetylenic derivative, 28-O-propynoylbetulin (proBet) were shown to induce apoptosis in several cancer cell lines, we studied the mechanism of this process in human endometrial adenocarcinoma cells (EA). Previous studies suggested that this group of compounds affect prolidase activity (proline releasing enzyme from imidodipeptides) and collagen biosynthesis (proline utilizing process) providing substrate (proline) for proline oxidase (POX) dependent apoptosis. Here we provide evidence that Bet and proBet exhibit prolidase-inducing activity in EA cell line. However, in contrast to Bet, proBet inhibited collagen biosynthesis, increased intracellular proline concentration and induced apoptosis in EA cells, as detected by caspase-3, and -9 expressions and annexin V staining. Although POX expression was not affected by both compounds, the process of apoptosis was accompanied by increase in cytoplasmic level of proline. The mechanism for proBet-induced prolidase activity was found at the level of beta1 integrin signaling. The inhibition of collagen biosynthesis was due to up-regulation of NF-kappaB p65, an inhibitor of collagen type I gene transcription. Although Bet and proBet induced expression of pro-apoptotic p53 in EA cells, the effect of proBet on the processes was much stronger. In contrast to proBet, Bet strongly induced expression of pro-survival factors, HIF-1alpha and VEGF. The data suggest that massive production of proline by proBet-dependent activation of prolidase and inhibition of proline utilization for collagen biosynthesis may represent mechanism for POX-dependent apoptosis in EA cells. PMID- 28863384 TI - Therapeutical strategies for anxiety and anxiety-like disorders using plant derived natural compounds and plant extracts. AB - Anxiety and anxiety-like disorders describe many mental disorders, yet fear is a common overwhelming symptom often leading to depression. Currently two basic strategies are discussed to treat anxiety: pharmacotherapy or psychotherapy. In the pharmacotherapeutical clinical approach, several conventional synthetic anxiolytic drugs are being used with several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being sought by researchers. The results of a plethora experimental studies demonstrated that dietary phytochemicals like alkaloids, terpenes, flavonoids, phenolic acids, lignans, cinnamates, and saponins or various plant extracts with the mixture of different phytochemicals possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms of anxiolytics action include interaction with gamma-aminobutyric acid A receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5 hydrodytryptamine receptors, noradrenergic and dopaminergic systems, glutamate receptors, and cannabinoid receptors. This review focuses on the use of both plant-derived natural compounds and plant extracts with anxiolytic effects, describing their biological effects and clinical application. PMID- 28863385 TI - Tumour radiosensitivity is associated with immune activation in solid tumours. AB - PURPOSE: Our goal was to determine whether tumour radiosensitivity is associated with activation of the immune system across all tumour types as measured by two gene expression signatures (GESs). METHODS: We identified 10,240 genomically profiled distinct solid primary tumours with gene expression analysis available from an institutional de-identified database. Two separate GESs were included in the analysis, the radiosensitivity index (RSI) GES (a 10-gene GES as a measure of radiosensitivity) and the 12-chemokine (12-CK) signature (a 12-gene GES as a measure of immune activation). We tested whether the RSI and 12-CK were associated with each other across all tumour samples and, in an exploratory analysis, their prognostic significance in predicting distant metastasis-free survival (DMFS) among a well-characterised, independent cohort of 282 early-stage breast cancer cases treated with surgery and post-operative radiation alone without systemic therapy. The lower the RSI score, the higher the tumour radiosensitivity; whereas, the higher the 12-CK score the higher the immune activation. RESULTS: Using an RSI cut-point of <=0.3745, RSI-low tumours (n = 4,291, 41.9%) had a significantly higher median 12-CK GES value (0.54 [-0.136, 1.095]) compared with RSI-high tumours (-0.17 [-0.82, 0.42]; p < 0.001) across all tumour samples, indicating that radiosensitivity is associated with immune activation. In an exploratory analysis of early-stage breast cancer cases, a multivariable model with patient age, RSI and 12-CK provided a strong composite model for DMFS (p = 0.02), with RSI (hazard ratio [HR] 0.63 [95% confidence interval 0.36, 1.09]) and 12-CK (HR 0.66 [0.41, 1.04]) each providing comparable contributions. CONCLUSIONS: Tumour radiosensitivity is associated with immune activation as measured by the two GESs. PMID- 28863387 TI - Autophagy inhibition of immature oocytes during vitrification-warming and in vitro mature activates apoptosis via caspase-9 and -12 pathway. AB - OBJECTIVE: The aim of this study is to determine the role of autophagy in the immature oocytes during vitrification-warming and in vitro maturation (IVM); the correlations among autophagy, apoptosis, and the activities of caspase in the immature oocytes during vitrification-warming and IVM were also explored. STUDY DESIGN: Immature oocytes from mice were vitrified-warmed and IVM. An autophagy inhibitor (3-methyladenine) was supplemented in cryopreservation solutions and warming solutions. The expression of beclin-1 (an autophagy marker), caspase-3, 8, -9, and -12 were measured. Moreover, the viability of vitrified-warmed immature oocytes and their subsequent developmental competence were measured. RESULTS: The levels of beclin-1 expression in both mRNA and protein in oocytes experienced vitrification-warming and IVM were significantly higher than that in fresh immature oocytes experienced IVM. The levels of caspase-3, -9, -12 expression in both mRNA and protein in oocytes vitrified with 3-methyladenine were significantly higher than that vitrified without 3-methyladenine. However, the differences in the caspase-8 expression in both mRNA and protein between the oocytes vitrified with 3-methyladenine and that vitrified without 3-methyladenine were not significant. CONCLUSION: Immature oocyte cryopreservation exhibits autophagic activation. Autophagy inhibition of the immature oocytes during vitrification-warming and IVM activates apoptosis via caspase-9 and -12 pathway. PMID- 28863386 TI - From the statistics of connectivity to the statistics of spike times in neuronal networks. AB - An essential step toward understanding neural circuits is linking their structure and their dynamics. In general, this relationship can be almost arbitrarily complex. Recent theoretical work has, however, begun to identify some broad principles underlying collective spiking activity in neural circuits. The first is that local features of network connectivity can be surprisingly effective in predicting global statistics of activity across a network. The second is that, for the important case of large networks with excitatory-inhibitory balance, correlated spiking persists or vanishes depending on the spatial scales of recurrent and feedforward connectivity. We close by showing how these ideas, together with plasticity rules, can help to close the loop between network structure and activity statistics. PMID- 28863388 TI - Children's exposure to brominated flame retardants in indoor environments - A review. AB - The aim of this review is to present up-to-date research on children's exposure to brominated flame retardants (BFRs) in indoor environments. Large geographical variations were observed for all BFRs [polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCDD), tetrabromobisphenol A (TBBPA)], with the highest concentrations of PBDEs measured in North America (BDE-47) and Europe (BDE-209), where higher concentrations of PBDEs are present in dust from houses, daycare centers and primary schools. In Asia the highest PBDE concentrations were measured in China, near e-waste recycling areas. In the Middle East, Australia and Africa BFR levels were low in most indoor spaces. Asian countries also have the highest concentrations of TBBPA and HBCDD, followed by European countries. Fewer studies have been conducted measuring novel and emerging BFRs (NBFRs or EBFRs), of which decabromodiphenylethane (DBDPE) has the highest concentration in indoor environments, especially in China. The vast majority of children's exposure studies have been conducted in houses, sampling either dust or air, and considerably fewer in schools, daycare centers, cars and public facilities, despite BFR levels being comparable to (or sometimes even higher than) house dust. Relatively fewer studies focused on children's tissues such as serum, and only two studied exposure via mouthing toys. Alternative noninvasive sampling matrices that may act as surrogates for exposure to BFRs such as handwipes and silicone wristbands have recently started to gain momentum, because of the ease of sampling, faster collection time and better correlations to serum than house dust. Feces sampling is another promising alternative to children's serum that warrants further research. While many studies have associated different indoor environment characteristics, there is a knowledge gap on the association between children's behaviour and activity patterns and their exposure to BFRs, as well as data on infant exposure to BFRs via baby products. Results from the studies showed that dust ingestion was the dominant exposure pathway for most studied BFRs compared to indoor air inhalation and dermal contact, especially for infants and toddlers who have higher exposures than older children. PMID- 28863389 TI - A role of low dose chemical mixtures in adipose tissue in carcinogenesis. AB - The Halifax project recently hypothesized a composite carcinogenic potential of the mixture of low dose chemicals which are commonly encountered environmentally, yet which are not classified as human carcinogens. A long neglected but important fact is that adipose tissue is an important exposure source for chemical mixtures. In fact, findings from human studies based on several persistent organic pollutants in general populations with only background exposure should be interpreted from the viewpoint of chemical mixtures because serum concentrations of these chemicals can be seen as surrogates for chemical mixtures in adipose tissue. Furthermore, in conditions such as obesity with dysfunctional adipocytes or weight loss in which lipolysis is increased, the amount of the chemical mixture released from adipose tissue to circulation is increased. Thus, both obesity and weight loss can enhance the chance of chemical mixtures reaching critical organs, however paradoxical this idea may be when fat mass is the only factor considered. The complicated, interrelated dynamics of adipocytes and chemical mixtures can explain puzzling findings related to body weight among cancer patients, including the obesity paradox. The contamination of fat in human diet with chemical mixtures, occurring for reasons similar to contamination of human adipose tissue, may be a missing factor which affects the association between dietary fat intake and cancer. The presence of chemical mixtures in adipose tissue should be considered in future cancer research, including clinical trials on weight management among cancer survivors. PMID- 28863390 TI - More than clean air and tranquillity: Residential green is independently associated with decreasing mortality. AB - Green space may improve health by enabling physical activity and recovery from stress or by decreased pollution levels. We investigated the association between residential green (greenness or green space) and mortality in adults using the Swiss National Cohort (SNC) by mutually considering air pollution and transportation noise exposure. To reflect residential green at the address level, two different metrics were derived: normalised difference vegetation index (NDVI) for greenness, and high resolution land use classification data to identify green spaces (LU-green). We used stratified Cox proportional hazard models (stratified by sex) to study the association between exposure and all natural cause mortality, respiratory and cardiovascular disease (CVD), including ischemic heart disease, stroke and hypertension related mortality. Models were adjusted for civil status, job position, education, neighbourhood socio-economic position (SEP), geographic region, area type, altitude, air pollution (PM10), and transportation noise. From the nation-wide SNC, 4.2 million adults were included providing 7.8years of follow-up and respectively 363,553, 85,314 and 232,322 natural cause, respiratory and CVD deaths. Hazard ratios (and 95%-confidence intervals) for NDVI [and LU-green] per interquartile range within 500m of residence were highly comparable: 0.94 (0.93-0.95) [0.94 (0.93-0.95)] for natural causes; 0.92 (0.91-0.94) [0.92 (0.90-0.95)] for respiratory; and 0.95 (0.94-0.96) [0.96 (0.95-0.98)] for CVD mortality. Protective effects were stronger in younger individuals and in women and, for most outcomes, in urban (vs. rural) and in the highest (vs. lowest) SEP quartile. Estimates remained virtually unchanged after incremental adjustment for air pollution and transportation noise, and mediation by these environmental factors was found to be small. We found consistent evidence that residential green reduced the risk of mortality independently from other environmental exposures. This suggests the protective effect goes beyond the absence of pollution sources. Environmental public health measures should not only aim at reducing pollutant exposure, but additionally maintain existing and increase residential green in areas where lacking. PMID- 28863391 TI - A precision medicine approach for psychiatric disease based on repeated symptom scores. AB - For psychiatric diseases, rich information exists in the serial measurement of mental health symptom scores. We present a precision medicine framework for using the trajectories of multiple symptoms to make personalized predictions about future symptoms and related psychiatric events. Our approach fits a Bayesian hierarchical model that estimates a population-average trajectory for all symptoms and individual deviations from the average trajectory, then fits a second model that uses individual symptom trajectories to estimate the risk of experiencing an event. The fitted models are used to make clinically relevant predictions for new individuals. We demonstrate this approach on data from a study of antipsychotic therapy for schizophrenia, predicting future scores for positive, negative, and general symptoms, and the risk of treatment failure in 522 schizophrenic patients with observations over 8 weeks. While precision medicine has focused largely on genetic and molecular data, the complementary approach we present illustrates that innovative analytic methods for existing data can extend its reach more broadly. The systematic use of repeated measurements of psychiatric symptoms offers the promise of precision medicine in the field of mental health. PMID- 28863393 TI - Child maltreatment characteristics as predictors of heterogeneity in internalizing symptom trajectories among children in the child welfare system. AB - This study investigated heterogeneity in the developmental trajectories of internalizing symptoms among 541 children who were involved with the child welfare system and examined child maltreatment characteristics, including types, level of harm, and timing, as predictors of internalizing trajectory patterns. Secondary longitudinal research was conducted using data from the National Survey of Child and Adolescent Well-Being-I, collected from 1999 to 2007 in the United States. Three distinct trajectory groups were identified: high-decreasing; low increasing; and low-stable Sexual abuse, emotional abuse, neglect, and more severe levels of harm from maltreatment predicted membership in two maladaptive groups compared to the low-stable group. The findings of the study suggest the importance of providing a thorough assessment of the type and severity of maltreatment experiences and continued monitoring of internalizing symptoms for children with child welfare involvement. PMID- 28863392 TI - Mindfulness mediates the physiological markers of stress: Systematic review and meta-analysis. AB - Meditation is a popular form of stress management, argued to mediate stress reactivity. However, many studies in this field commonly fail to include an active control group. Given the frequency with which people are selecting meditation as a form of self-management, it is important to validate if the practice is effective in mediating stress-reactivity using well-controlled studies. Thus, we aimed to conduct a meta-analysis investigating the neurobiological effects of meditation, including focused attention, open monitoring and automatic self-transcending subtypes, compared to an active control, on markers of stress. In the current meta-analysis and systematic review, we included randomised controlled trials comparing meditation interventions compared to an active control on physiological markers of stress. Studied outcomes include cortisol, blood pressure, heart-rate, lipids and peripheral cytokine expression. Forty-five studies were included. All meditation subtypes reduced systolic blood pressure. Focused attention meditations also reduced cortisol and open monitoring meditations also reduced heart rate. When all meditation forms were analysed together, meditation reduced cortisol, C - reactive protein, blood pressure, heart rate, triglycerides and tumour necrosis factor-alpha. Overall, meditation practice leads to decreased physiological markers of stress in a range of populations. PMID- 28863394 TI - Physical violence against children with hearing loss by parents: A pilot study in Beijing, China. AB - This study aims to examine the rate and risk factors for physical violence (PV) by parents against hearing loss children in Beijing, China. Cross-sectional study was carried out among 86 couples of parents of hearing loss children from two special education schools in Beijing. Parents' self-reporting questionnaires were used to collect information about parental PV behaviors during the past 12 months, definition of child abuse, attitudes towards the use of corporal punishment to discipline children, parents' childhood experience of PV victimization, and demographic characteristics. Descriptive statistics and logistic regression analyses were conducted. The rates of minor PV and severe PV reported by parents were 44.8% and 15.7%, respectively. Results from logistic regression analyses indicated that the risk factors of PV were: lower educational attainment, favorable or tolerant attitudes towards the use of corporal punishment to discipline children, parents' experiences of PV victimization in childhood, and younger children. PV by parents against hearing loss children was common in Beijing. It is urgent to develop prevention programs to improve parents' parenting skills and protect children with hearing loss from PV. PMID- 28863395 TI - Comparison of repeated applications of aPDT with amoxicillin and metronidazole in the treatment of chronic periodontitis: A short-term study. AB - AIM: The aim of this study was to compare the clinical effects of Metronidazole (MTZ) combined with Amoxicillin (AMX) and repeated applications of antimicrobial photodynamic therapy (aPDT) as an adjuvant for the treatment of chronic periodontitis. METHODS: A double-blind controlled and randomized clinical trial was conducted in 34 patients. All of the patients were treated with scaling and root planing (SRP) and separated into 2 groups: the MTZ+AMX Group (n=17), who received SRP and the systemic use of MTZ (400mg 3*per day for 7days) and AMX (500mg 3*per day for 7days), and the aPDT Group (n=17), who received SRP and three aPDT applications at all sites with a probing depth>=5mm immediately, at 48 and 96h after scaling and placebo pills over the span of 7days. Clinical examinations were performed at baseline and 90days post-therapy. The clinical parameters of bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL) were measured. The aPDT was conducted using methylene blue and a low-level laser (GaAlAs 660nm, 100mW, 48s, and 160J/cm2) in all sites with a probing depth>=5mm. A statistical analysis was also performed (alpha=5%). RESULTS: There was a significant improvement in CAL only in the intermediate pocket in the aPDT group compared to the MTZ+AMX group between baseline and 90days post-treatment (p=0.01). There was a reduction of both BOP and the percentage of residual pockets at 90days after treatment compared with baseline in both groups (p<0.05). CONCLUSION: Both proposed adjuvant therapies associated with conventional mechanical treatment in patients with chronic periodontitis were equally effective in terms of the gain of clinical insertion, control of inflammation and elimination of residual pockets. PMID- 28863396 TI - Proximity effects in chromosome aberration induction by low-LET ionizing radiation. AB - Although chromosome aberrations are known to derive from distance-dependent mis rejoining of chromosome fragments, evaluating whether a certain model describes such "proximity effects" better than another one is complicated by the fact that different approaches have often been tested under different conditions. Herein, a biophysical model ("BIANCA", i.e. BIophysical ANalysis of Cell death and chromosome Aberrations) was upgraded, implementing explicit chromosome-arm domains and two new models for the dependence of the rejoining probability on the fragment initial distance, r. Such probability was described either by an exponential function like exp(-r/r0), or by a Gaussian function like exp( r2/2sigma2), where r0 and sigma were adjustable parameters. The second, and last, parameters was the yield of "Cluster Lesions" (CL), where "Cluster Lesion" defines a critical DNA damage producing two independent chromosome fragments. The model was applied to low-LET-irradiated lymphocytes (doses: 1-4Gy) and fibroblasts (1-6.1Gy). Good agreement with experimental yields of dicentrics and centric rings, and thus their ratio ("F-ratio"), was found by both the exponential model (with r0=0.8MUm for lymphocytes and 0.7MUm for fibroblasts) and the Gaussian model (with sigma=1.1MUm for lymphocytes and 1.3MUm for fibroblasts). While the former also allowed reproducing dose-responses for excess acentric fragments, the latter substantially underestimated the experimental curves. Both models provided G-ratios (ratio of acentric to centric rings) higher than those expected from randomness, although the values calculated by the Gaussian model were lower than those calculated by the exponential one. For lymphocytes the calculated G-ratios were in good agreement with the experimental ones, whereas for fibroblasts both models substantially underestimated the experimental results, which deserves further investigation. This work suggested that, although both models performed better than a step model (which previously allowed reproducing the F-ratio but underestimated the G-ratio), an exponential function describes proximity effects better than a Gaussian one. PMID- 28863397 TI - Widespread legacy brine contamination from oil production reduces survival of chorus frog larvae. AB - Advances in drilling techniques have facilitated a rapid increase in hydrocarbon extraction from energy shales, including the Williston Basin in central North America. This area overlaps with the Prairie Pothole Region, a region densely populated with wetlands that provide numerous ecosystem services. Historical (legacy) disposal practices often released saline co-produced waters (brines) with high chloride concentrations, affecting wetland water quality directly or persisting in sediments. Despite the potential threat of brine contamination to aquatic habitats, there has been little research into its ecological effects. We capitalized on a gradient of legacy brine-contaminated wetlands in northeast Montana to conduct laboratory experiments to assess variation in survival of larval Boreal Chorus Frogs (Pseudacris maculata) reared on sediments from 3 local wetlands and a control source. To help provide environmental context for the experiment, we also measured chloride concentrations in 6 brine-contaminated wetlands in our study area, including the 2 contaminated sites used for sediment exposures. Survival of frog larvae during 46- and 55-day experiments differed by up to 88% among sediment sources (Site Model) and was negatively correlated with potential chloride exposure (Chloride Model). Five of the 6 contaminated wetlands exceeded the U.S. EPA acute benchmark for chloride in freshwater (860 mg/L) and all exceeded the chronic benchmark (230 mg/L). However, the Wetland Site model explained more variation in survival than the Chloride Model, suggesting that chloride concentration alone does not fully reflect the threat of contamination to aquatic species. Because the profiles of brine-contaminated sediments are complex, further surveys and experiments are needed across a broad range of conditions, especially where restoration or remediation actions have reduced brine-contamination. Information provided by this study can help quantify potential ecological threats and help land managers prioritize conservation strategies as part of responsible and sustainable energy development. PMID- 28863398 TI - Anti epileptic drug trials for patients with drug resistant idiopathic generalised epilepsy: A meta-analysis. AB - PURPOSE: Determine the impact of anti-epileptic drugs (AED) for drug resistant patients with idiopathic generalised epilepsy. METHODS: A systematic search of Medline, Cumulative Index to Nursing an Allied Health Literature (CINAHL), Cochrane Epilepsy Group Central Specialised Register, Cochrane Central Register of controlled Trials (CENTRAL), Embase and Lenus was performed. Nine randomised controlled trials were included. All trials compared antiepileptic drugs to placebo. Outcome measures assessed were 50% or greater reduction in seizure, seizure freedom and adverse events. RESULTS: Seven trials report a 50% or greater reduction in seizure frequency. This was statistically significant (p=<0.00001) with a narrow confidence interval implying that the overall this meta-analysis has reasonable power to detect an effect. It demonstrated a significant statistical difference of seizure freedom occurring in the drug treatment group compared to placebo. Adverse events were identified with each drug and are reported. There were however methodological issues with the trials included. Quality appraisal was undertaken using the risk of bias assessment from Rev Man 5.3 tool for all randomised controlled trials retrieved. CONCLUSION: This systematic review demonstrated efficacy of adjunctive anti-epileptic drugs with regard to 50% reduction and seizure freedom. Adverse events are identified in all of the studies in the drug treatment groups but are consistent with previous studies of these drugs. Additional adequately powered studies with long term follow up needs to be conducted to unequivocally establish the long term efficacy and tolerability of anti-epileptic drug's for patients with drug resistant idiopathic generalised epilepsy. PMID- 28863399 TI - High recoverable strain tailoring by Zr adjustment of sintered Ti-13Nb-(0-6)Zr biomedical alloys. AB - Ti-13Nb-(0-6)Zr alloys were fabricated by conventional powder metallurgy sintering method. Their microstructure, phase transformation temperature and mechanical properties were investigated by optical microscopy, scanning electron microscope, X-ray diffraction, differential scanning calorimetry and compression test. It was found that with more Zr addition, the content of beta phase increased while the content of precipitated alpha phase reduced. With 1 at% Zr increase, the Ms of Ti-13Nb-(0~6)Zr alloys decreased linearly by around 10 degrees C. The compression test results revealed that sintered Ti-13Nb-2Zr owned a recoverable strain as high as 3.7% at room temperature, and Ti-13Nb-4Zr and Ti 13Nb-6Zr exhibited a remarkable recoverable strain of 4.4% at their Ms temperature which was lower than room temperature, indicating that these two alloys have a higher intrinsic recoverable strain and may be further optimized. PMID- 28863400 TI - Looped ends versus open ends braided stent: A comparison of the mechanical behaviour using analytical and numerical methods. AB - The present study has two major purposes: firstly, to investigate whether the analytical model proposed by Jedwab and Clerc for assessing the mechanical behaviour of an open ends metallic braided stent is applicable to the looped ends stent design and secondly, to compare the response of the two stent designs subjected to radial compression. We use finite element analysis to evaluate the performance of the two braided stents emulating well established designs: WALLSTENT and WallFlex. We validate the WALLSTENT model analytically. We perform a radial crimping simulation and evaluate the radial forces and stresses induced. This study confirms the validity of using the analytical model in the biomechanical analysis of the WALLSTENT design. However, in case of the WallFlex design, a major difference in the results can be observed in the levels of radial forces and wire peak stresses, justifying the decision of using a different alloy in the fabrication of the WallFlex design. PMID- 28863401 TI - Hydrogen bonding recognition and colorimetric detection of isoprenaline using 2 amino-5-mercapto-1,3,4-thiadiazol functionalized gold nanoparticles. AB - In this paper, we describe a rapid, low-cost and highly sensitive colorimetric method for the detection of isoprenaline, based on 2-amino-5-mercapto-1,3,4 thiadiazol (AMTD) functionalized gold nanoparticles (AMTD-AuNPs) as a sensing element. Hydrogen bonding interaction between isoprenaline and AMTD resulted in the aggregation of AuNPs and a consequent color change of AuNPs from red to blue. The concentration of isoprenaline could be detected with the naked eye or a UV visible spectrometer. Results showed that the absorbance ratio (A650/A524) was linear with isoprenaline concentrations in the range of 0.2 to 2.6MUM (R=0.997). The detection limit of this method was 0.08MUM. The proposed method is simple, without using complicated instruments and adding salts for enhancing sensitivity. This probe could be successfully applied to the determination of isoprenaline in human serum samples and urine samples after deproteinization. PMID- 28863402 TI - Sexual assault and general body injuries: A detailed cross-sectional Australian study of 1163 women. AB - OBJECTIVES: To describe the frequency and severity of general body injury in women alleging recent sexual assault and then identify demographic and assault characteristics associated with injury severity. DESIGN: Cross-sectional study. SETTING: Sexual Assault Resource Centre (SARC), Western Australia. PARTICIPANTS: Total of 1163 women attending SARC from Jan-2009 to Mar-2015. METHODS: Women underwent a standardised medical examination and data collection by forensically trained doctors. Multivariate ordinal logistic regression analyses were performed. An algorithm was used to classify general body injuries as mild, moderate or severe. RESULTS: General body injury was observed in 71% of women; 52%, 17% and 2% were classified as having respectively, mild, moderate and severe injuries. Moderate or severe injury was observed in 30.4% of women assaulted by intimate partners, 16.4% of women assaulted by strangers and 14.9% of women assaulted by friends/acquaintances. In regression analysis, an interaction between mental illness and assailant type existed after adjusting for age, intellectual disability, time-to-examination, number of assailants and location. Mental illness was an independent predictor for lower injury severity (adjusted odds ratio=0.5, 95% CI 0.3, 0.9) in women assaulted by strangers and higher injury severity in women assaulted by a friend/acquaintance (adjusted odds ratio=2.4, 95% CI 1.6, 3.6). While women assaulted by intimate partners had more frequent moderate-to-severe injuries than other women their current mental illness status was not associated with risk of injury severity. CONCLUSION: This study highlights the increased injury severity in women assaulted by intimate partners. The risk of moderate/severe injury for women with mental illness assaulted by their acquaintances was unexpected and requires further investigation. PMID- 28863403 TI - Preface. PMID- 28863404 TI - An examination of the spatial distribution of the tissue fragments created during a single explosive attack. AB - Throughout the course of a forensic investigation following an explosive attack, the identification and recovery of tissue fragments is of extreme importance. There are few universally accepted methods to achieve this end. This project aims to explore this issue through the examination of the spatial distribution of the tissue fragments resulting from an explosive event. To address this, a two stage pilot study was conducted: first, a series of controlled explosions on porcine carcases was undertaken. Second, the data produced from these explosions were used to chart the spatial distribution of the tissue debris. In the controlled explosions, 3kg military grade explosive was chosen to create the maximum amount of fragmentation; this level of explosive also prevented the complete disappearance of forensic evidence through evaporation. Additionally, the blast created by military grade explosive is highly powerful and would mean that the maximum possible distance was achieved and would therefore allow the recorded distances and pattern spread to be a guideline for forensic recovery of associated with an explosive amount of an unknown size and quality. A total station was employed to record the location of the resulting forensic evidence, with the collected data analysed using R Studio. The observed patterns suggested that the distribution of remains is fairly consistent in trials under similar environmental conditions. This indicates potential for some general guidelines for forensic evidence collection (for example, the distance from the explosion that a search should cover). PMID- 28863405 TI - Phantom study evaluating detection of simulated upper airway occlusion using piezoelectric ultrasound transducers. AB - : Obstructive sleep apnea/hypopnea syndrome (OSAHS) is characterized by repetitive narrowing or full collapse of the upper airway concomitant with continued respiratory effort during sleep lasting 10s or more. OSAHS is the most prevalent form of sleep-disordered breathing, affecting more than 17% of the middle-aged U.S. POPULATION: Hence, many individuals need to be tested for having OSAHS. Currently, detection of airway occlusion due to OSAHS is achieved by indirect measurements, often requiring multiple sensor types, such as a flow transducer combined with chest and abdomen plethysmography. The need for the use of multiple sensors in the current OSAHS detection systems adds to the cost and complexity of the current systems and associated procedures. Development of a simple sensor system that allows direct detection of airway occlusion is advantageous, as it simplifies detection of OSAHS and paves the way for home diagnosis of OSAHS. The utilization of ultrasonic transducers is attractive, as it is non-invasive and non-ionizing. We present a new ultrasound sensing system for direct detection of the occlusion in the upper airway in OSAHS patients during sleep. The system takes into consideration the constraints arising from the location of probing and the acoustic requirements for transducers. The physiological and theoretical backgrounds are presented for using ultrasonic pulses to detect the presence and degree of occlusion in the airway. The proposed methodology for creating an anthropomorphically-correct neck and airway phantoms to test the hypothesis and the results of the tests are presented. HYPOTHESIS: An ultrasonic signal transmitted through or reflected from an open airway will have different features compared to those associated with a partially or fully occluded airway. METHODOLOGY: A system, comprising a phantom model of the airway and neck with the approximate anatomical-correct dimensions and acoustic properties of the airway, is designed and built. It allows simulating fully open airway as well as hypopnea and apnea events. Further, it facilitates probing using multiple ultrasonic frequencies and transducer configurations for use with different neck sizes. Ultrasound waves are generated using a piezoelectric source to the model of the airway and received by piezoelectric receivers on the opposite side. Energy, the area under the curve, and the peak value of the received signal, are used to detect the airway occlusion. RESULTS: The amount of reflected ultrasonic energy from the phantom model of the airway back to the transmitting transducer reduces as the airway model occlusion increases. Also, transmitted signal through the airway model increases as the amount occlusion of the airway model increases. CONCLUSIONS: The results of this study support the hypothesis that it is feasible to use ultrasonic pulses to detect partial and full upper airway occlusion. PMID- 28863406 TI - A Role for Calcium-Activated Adenylate Cyclase and Protein Kinase A in the Lens Src Family Kinase and Na,K-ATPase Response to Hyposmotic Stress. AB - Purpose: Na,K-ATPase activity in lens epithelium is subject to control by Src family tyrosine kinases (SFKs). Previously we showed hyposmotic solution causes an SFK-dependent increase in Na,K-ATPase activity in the epithelium. Here we explored the role of cAMP in the signaling mechanism responsible for the SFK and Na,K-ATPase response. Methods: Intact porcine lenses were exposed to hyposmotic Krebs solution (200 mOsm) then the epithelium was assayed for cAMP, SFK phosphorylation (activation) or Na,K-ATPase activity. Results: An increase of cAMP was observed in the epithelium of lenses exposed to hyposmotic solution. In lenses exposed to hyposmotic solution SFK phosphorylation in the epithelium approximately doubled as did Na,K-ATPase activity and both responses were prevented by H89, a protein kinase A inhibitor. The magnitude of the SFK response to hyposmotic solution was reduced by a TRPV4 antagonist HC067047 added to prevent TRPV4-mediated calcium entry, and by a cytoplasmic Ca2+ chelator BAPTA AM. The Na,K-ATPase activity response in the epithelium of lenses exposed to hyposmotic solution was abolished by BAPTA-AM. As a direct test of cAMP-dependent SFK activation, intact lenses were exposed to 8-pCPT-cAMP, a cell-permeable cAMP analog. 8-pCPT-cAMP caused robust SFK activation. Using Western blot, two calcium activated adenylyl cyclases, ADCY3 and ADCY8, were detected in lens epithelium. Conclusions: Calcium-activated adenylyl cyclases are expressed in the lens epithelium and SFK activation is linked to a rise of cAMP that occurs upon hyposmotic challenge. The findings point to cAMP as a link between TRPV4 channel mediated calcium entry, SFK activation, and a subsequent increase of Na,K-ATPase activity. PMID- 28863407 TI - High Symmetry of Visual Acuity and Visual Fields in RPGR-Linked Retinitis Pigmentosa. AB - Purpose: Mutations in retinitis pigmentosa GTPase regulator (RPGR) cause 70% to 90% of X-linked retinitis pigmentosa (XLRP3) cases, making this gene a high-yield target for gene therapy. This study analyzed the utility of relevant clinical biomarkers to assess symmetry and rate of progression in XLRP3. Methods: A retrospective, cross-sectional analysis of 50 XLRP3 patients extracted clinical data including visual acuity (VA), visual fields (I4e and III4e targets), foveal thickness, and ERG data points alongside molecular genetic data. Symmetry was assessed by using linear regression analysis. Kaplan-Meier survival curves (KMCs) and generalized linear mixed model calculations were used to describe disease progression. Results: Ninety-six percent of patients exhibited a rod-cone phenotype, and 4% a cone-rod phenotype. Open reading frame 15 (ORF15) was confirmed as a mutational hotspot within RPGR harboring 73% of exonic mutations. Significant variability, but no clear genotype-phenotype relationship, could be shown between mutations located in exons 1-14 versus ORF15. All biomarkers suggested a high degree of symmetry between eyes but demonstrated different estimates of disease progression. VA and foveal thickness, followed by perimetry III4e, were the most useful endpoints to evaluate progression. KMC estimates predicted a loss of 6/6 vision at a mean of 34 years (+/-2.9; 95% confidence interval). Conclusions: XLRP3 affects retinal structure and function symmetrically, supporting the use of the fellow eye as an internal control in interventional trials. VA and kinetic visual fields (III4e) seem promising functional outcome measures to assess disease progression. KMC analysis predicted the most severe decline in vision between the third and fourth decade of life. PMID- 28863408 TI - Polarization-Sensitive Optical Coherence Tomographic Documentation of Choroidal Melanin Loss in Chronic Vogt-Koyanagi-Harada Disease. AB - Purpose: Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder that affects organs with melanocytes. The sunset glow fundus (SGF) in VKH disease was evaluated with polarization-sensitive optical coherence tomography (PS-OCT). Methods: The study involved 28 eyes from 14 patients with chronic VKH disease, 21 eyes from 21 age-matched controls, and 22 eyes from 22 high-myopic patients with a tessellated fundus. VKH eyes were grouped into sunset or non-sunset groups on the basis of color fundus images. The presence of melanin in the choroid was determined by using the degree of polarization uniformity (DOPU) obtained by PS OCT. The sunset glow index (SGI) was calculated by using color fundus images. Presence of an SGF was evaluated by using DOPU, SGI, subfoveal choroidal thicknesses, near-infrared images, and autofluorescence images at 488 nm (SW-AF) and 785 nm (NIR-AF). Results: There were 16 eyes in the sunset group and 12 eyes in the non-sunset group. For all eyes in the sunset group, the disappearance of choroidal melanin was clearly detected with PS-OCT. Percentage areas of low DOPU in the choroidal interstitial stroma of the sunset group were significantly lower than those of other groups and showed no overlap with other groups. The distribution of choroidal thicknesses and SGI in the sunset group substantially overlapped with other groups. The subjective analyses of the sunset and non sunset groups, using near infrared, SW-AF, or NIR-AF, showed substantial inconsistencies with the PS-OCT results. Conclusions: PS-OCT provides an in vivo objective evaluation of choroidal melanin loss of the SGF in chronic VKH disease. PMID- 28863409 TI - Effects of Lexical Variables on Silent Reading Comprehension in Individuals With Aphasia: Evidence From Eye Tracking. AB - Purpose: Previous eye-tracking research has suggested that individuals with aphasia (IWA) do not assign syntactic structure on their first pass through a sentence during silent reading comprehension. The purpose of the present study was to investigate the time course with which lexical variables affect silent reading comprehension in IWA. Three lexical variables were investigated: word frequency, word class, and word length. Methods: IWA and control participants without brain damage participated in the experiment. Participants read sentences while a camera tracked their eye movements. Results: IWA showed effects of word class, word length, and word frequency that were similar to or greater than those observed in controls. Conclusions: IWA showed sensitivity to lexical variables on the first pass through the sentence. The results are consistent with the view that IWA focus on lexical access on their first pass through a sentence and then work to build syntactic structure on subsequent passes. In addition, IWA showed very long rereading times and low skipping rates overall, which may contribute to some of the group differences in reading comprehension. PMID- 28863410 TI - Appearance of Abnormal Cardiothoracic Ratio of Fetuses with Hemoglobin Bart's Disease: Life Table Analysis. AB - Objective To determine the timeline of the first appearance of an increased CT ratio of fetuses with hemoglobin (Hb) Bart's disease. Materials and Methods A prospective longitudinal study was conducted on pregnancies at risk for fetal Hb Bart's disease. Sonographic markers including cardiothoracic (CT) ratio and middle cerebral artery peak systolic velocity (MCA-PSV) were serially assessed and recorded from the first trimester. The definite diagnosis of fetal Hb Bart's disease based on DNA analysis (CVS), or fetal Hb typing (HPLC; cordocentesis) was performed at the first appearance of an increased CT ratio. Results Of 275 pregnancies at risk, 64 fetuses were finally proven to be affected and life table analysis was performed. Most affected fetuses showed an increased CT ratio in late first trimester and early second trimester, with median time of the first appearance at 13 weeks and all affected fetuses were detected at 23 weeks or less. The CT ratio yielded a sensitivity of 100 % at a gestational age of 23 weeks with a false-positive rate of 8 %. MCA-PSV appeared later than CT ratio. Only 9.4 % of affected cases developed abnormal MCA-PSV before an increased CT ratio. Conclusion The timeline of the first appearance of an increased CT ratio of fetuses with Hb Bart's disease was established. This may help us identify Hb Bart's disease among fetuses at risk in earlier gestation and proper schedules for serial ultrasound could be made more effectively. PMID- 28863411 TI - Sirtuin 1 Levels in Recurrent Implantation Failure. AB - Sirtuin 1 has an important role in cellular processes, including apoptosis and cellular stress. The purpose of this study was to assess serum sirtuin 1 levels in women with recurrent implantation failure (RIF). In this cross-sectional study, we included 28 women with RIF, 29 healthy women who had conceived by in vitro fertilization (IVF), and 30 women with a 1-cycle failure of IVF as controls. Human serum nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin-1 (SIRT1/SIRT2L1) levels were detected using a commercial colorimetric kit. Recurrent implantation failure patients have higher sirtuin 1 levels than non-pregnant women and healthy pregnant women, but this difference did not reach statistical significance due to the low number of patients in our study. These higher sirtuin 1 levels may result from the inflammation imbalance of RIF patients. The only statistically significant correlation found was between age and sirtuin (r = 0.277, p = 0.009). PMID- 28863412 TI - ? PMID- 28863413 TI - White Paper: Interventional MRI: Current Status and Potential for Development Considering Economic Perspectives, Part 2: Liver and Other Applications in Oncology. AB - Background MRI is attractive for guiding and monitoring interventional procedures due to its high intrinsic soft tissue contrast and the possibility to measure flow and cardiac function. Methods Technical solutions have been developed for all procedural steps including imaging guidance, MR-safe catheters and instruments and patient monitoring. This has led to widening of the clinical applications. Interventional MRI is becoming increasingly important for the treatment of patients suffering from malignant diseases. The detectability of masses and consequently their accessibility for biopsy is higher, compared to other modalities, due to the high intrinsic soft tissue contrast of MRI. Temperature-dependent sequences allow for minimally invasive and tissue-sparing ablation (A-0 ablation). Conclusion Interventional MRI has become established in the clinical routine for a variety of indications, including biopsies and tumor ablation. Since the economic requirement of covering costs by reimbursement is met and interventional MRI decreases the mortality and morbidity of interventional procedures, broader application of interventional MRI can be expected in the clinical routine in the future. Key points . Particularly for the treatment of oncological patients, interventional MRI is superior to other methods with respect to minimal invasiveness and tissue protection due to the ability to exactly determine tumor borders and to visualize and control the size of the ablation area on the basis of MR temperature measurement.. . Due to the better visualization of targets and the effects of ablation in tissue, interventional MRI can lower the mortality and morbidity associated with these interventions for many indications.. . The complex comparison of costs and reimbursement shows that this application can be performed in a cost-covering manner and broader application can be expected in the future.. Citation Format . Barkhausen J, Kahn T, Krombach GA et al. White Paper: Interventional MRI: Current Status and Potential for Development Considering Economic Perspectives, Part 2: Liver and Other Applications in Oncology. Fortschr Rontgenstr 2017; 189: 1047 - 1054. PMID- 28863415 TI - Oncofertility. PMID- 28863416 TI - Acute Generalized Exanthematous Pustulosis Secondary to Nifedipine. PMID- 28863414 TI - Influence of Age, BMI, Gender and Lumbar Level on T1rho Magnetic Resonance Imaging of Lumbar Discs in Healthy Asymptomatic Adults. AB - PURPOSE: To assess the T1rho range of lumbar intervertebral discs in healthy asymptomatic individuals at 1.5 T and to investigate the influence of age, body mass index (BMI), gender, and lumbar level on T1rho relaxation. MATERIALS AND METHODS: In a prospective study, a total of 81 volunteers aged 20 - 80 years were included in this study and divided into three age groups (A: 20 - 39y; B: 40 - 59y; C: 60 - 80y). All of the volunteers underwent magnetic resonance imaging (MRI) at 1.5 T with acquisition of sagittal T1rho images. The calculated T1rho relaxation times were correlated with age, BMI, gender, and lumbar level relative to the total disc, the annulus fibrosus, and the nucleus pulposus. RESULTS: Age had a significant influence on T1rho relaxation times at all lumbar levels, with increasing age being associated with reduced relaxation times. There was also a significant difference between age groups A vs. C and B vs. C (P = 0.0008 and P = 0.0149, respectively). No significant differences in T1rho relaxation time were observed between men and women (P > 0.05). BMI showed a significant negative correlation with T1rho relaxation times (P < 0.0001). Analysis of the lumbar level revealed a significant decrease in relaxation times from L1/2 to L5 / S1 (P = 0.0013). CONCLUSION: Increasing age correlated significantly with advanced lumbar disc degeneration in asymptomatic individuals, particularly in those aged 60 or older. Increasing BMI correlated significantly with increasing degeneration. The lower discs showed more degeneration than the upper ones. KEY POINTS: . Increasing age significantly reduces the T1rho relaxation time in the intervertebral discs (P < 0.05). . Gender does not significantly influence T1rho relaxation times (P > 0.05). . BMI shows a significant negative correlation with T1rho relaxation times (P < 0.01). . Significantly shorter relaxation times in lower lumbar spine vs. upper lumbar spine (P < 0.01). CITATION FORMAT: . Gubitz R, Lange T, Gosheger G et al. Influence of Age, BMI, Gender and Lumbar Level on T1rho Magnetic Resonance Imaging of Lumbar Discs in Healthy Asymptomatic Adults. Fortschr Rontgenstr 2018; 190: 144 - 151. PMID- 28863417 TI - Permanent Central Diabetes Insipidus as a Complication of S. pneumoniae Meningitis in the Pediatric Population. AB - Diabetes insipidus is a rare but recognized complication of meningitis. The occurrence of diabetes insidipus has been previously attributed to Streptococcus pneumoniae (S. pneumoniae) in a handful of patients and only once within the pediatric subpopulation. We present the clinical course of a previously healthy 2 year, 8-month-old male child ultimately diagnosed with central diabetes insipidus (CDI) secondary to S. pneumoniae meningitis. Permanent CDI following S. pneumoniae meningitis is unique to our case and has not been previously described. Following the case presentation, we describe the etiology, pathophysiology, diagnosis, and treatment of CDI. The mechanism proposed for this clinical outcome is cerebral herniation for a sufficient duration and subsequent ischemia leading to the development of permanent CDI. Providers should be aware of CDI resulting from S. pneumoniae meningitis as prompt diagnosis and management may decrease the risk of permanent hypothalamo-pituitary axis damage. PMID- 28863418 TI - Hereditary Pyropoikilocytosis: A Rare But Not Uncommon Disease. PMID- 28863419 TI - Evaluating Symptom Distress in Cancer Patients. AB - BACKGROUND: Distress in cancer patients negatively affects emotions and coping abilities and can reduce treatment adherence, quality of life, and survival rates. The prevalence of distress in cancer patients has been reported at 35.1 percent and 37.8 percent, but is frequently undiagnosed. Previous studies have produced conflicting results regarding reported symptoms.This study aims to help health care providers identify symptoms correlated with distress to improve recognition and treatment. METHODS: A cross-sectional study was performed via medical record review of 40 adult cancer patients at the Avera Cancer Institute. Responses were compared using Pearson's chi-square test and the t-test. RESULTS: The average age of participants was 56.8 +/- 12.0, and 65 percent had breast cancer. The mean overall score for distress was 4.6 +/- 2.7 points on a 0-10 scale (95 percent CI 3.71 - 5.45). Twenty-four patients (60 percent) reported clinically significant distress. Females were more likely to report sadness. Specific symptoms with a statistically significant association with a higher overall distress included: fears, depression, sleep, worry, fatigue, nervousness, eating, and loss of interest in normal activities. CONCLUSIONS: Although our sample size was small and homogeneous, the results demonstrated statistically significant associations between overall distress and the symptoms of fears, depression, sleep, worry, fatigue, nervousness, eating, and loss of interest in normal activities. These findings can increase awareness of symptoms associated with distress and allow clinicians to recommend specific interventions. Though many oncology clinics screen for distress, distress remains an important factor affecting quality of life and warrants further investigation. PMID- 28863420 TI - Peripartum Cardiomyopathy: Literature Review. AB - Peripartum cardiomyopathy (PPCM) is a rare cause of heart failure that affects women during the last month of pregnancy to the first five months after delivery. The disease occurs in about one in 1,000 births in the U.S. Risk factors include advanced age, multiparity, twin pregnancy, African origin, preeclampsia or preexisting hypertension, and severe anemia. Heart failure in PPCM is treated similarly to heart failure from other causes, bearing in mind the pregnancy and lactation status. In this review article, we discuss the background, etiology, clinical evaluation, treatment, and natural history of peripartum cardiomyopathy, with a major emphasis on treatment. PMID- 28863421 TI - So You Want To Be An Author: A Primer On Writing For Publication In The Medical Literature Part II: Manuscript Submission. AB - Completing a draft of a manuscript that demonstrates the impact of your research within the current literature is the first step toward publication. The next step involves a review process that will allow your peers to provide feedback on the written document, with the goal of improving the presentation of your work. To complete this process, an author will have to be willing to accept constructive criticism of his or her work, as presented, and to modify the manuscript based on the feedback received. This peer-review process will ultimately shape the final draft of your manuscript, and here we provide some points to consider as you navigate the submission and review process. PMID- 28863422 TI - Are you ready for antimicrobial stewardship? PMID- 28863423 TI - Quality Focus: Transforming Clinical Practice Initiative. PMID- 28863424 TI - [Presentation of the Colombian Guidelines for the use of immunoglobulins]. PMID- 28863425 TI - [Colombian Guidelines of clinical practice for the use of immunoglobulins in the treatment of replacement and immunomodulation]. AB - Immunoglobulins are heterodimeric proteins composed of 2 heavy chains and 2 light chains. Human immunoglobulin G (IgG) is a plasma derivative and contains more than 95% of IgG. The composition of IgG subclasses is similar to that of normal human plasma. Immunoglobulin therapy was first introduced more than 50 years ago, and its use has been described in numerous diseases. In Colombia, the importance of this immunomodulatory resource prompted the need for clinical practice guidelines to be available for its use. For this reason, a multidisciplinary group of experts was brought together and distributed in working groups, by specialties, in order to develop an initial manuscript. Systematic literature searches were undertaken; identified evidences were evaluated and classified to support a preliminary draft that was discussed, analyzed and amended. Recommendations were issued on the use of intravenous immunoglobulin in pathologies that include primary and secondary immunodeficiencies, autoimmune diseas es, neurological disorders, infections, transplants and miscellaneous conditions; grades were assigned to each one of them according to the GRADE system. The final result translated into recommendations that are put forth with the purpose to inform, guide and support on optimal use of this immunomodulatory resource. PMID- 28863427 TI - Metabolic control, anticoagulation, and gender aspects. PMID- 28863426 TI - Metabolic engineering of Klebsiella pneumoniae J2B for co-production of 3 hydroxypropionic acid and 1,3-propanediol from glycerol: Reduction of acetate and other by-products. AB - Production of 3-hydroxypropionic acid (3-HP) or 1,3-propanediol (1,3-PDO) production from glycerol is challenging due to the problems associated with cofactor regeneration, coenzyme B12 synthesis, and the instability of pathway enzymes. To address these complications, simultaneous production of 3-HP and 1,3 PDO, instead of individual production of each compound, was attempted. With over expression of an aldehyde dehydrogenase, recombinant Klebsiella pneumoniae could co-produce 3-HP and 1,3-PDO successfully. However, the production level was unsatisfactory due to excessive accumulation of many by-products, especially acetate. To reduce acetate production, we attempted; (i) reduction of glycerol assimilation through the glycolytic pathway, (ii) increase of glycerol flow towards co-production, and (iii) variation of aeration rate. These efforts were partially beneficial in reducing acetate and improving co-production: 21g/L of 1,3-PDO and 43g/L of 3-HP were obtained. Excessive acetate (>150mM) was still produced at the end of bioreactor runs, and limited co-production efficiency. PMID- 28863428 TI - The future of computers in cardiology: 'the connected patient'? PMID- 28863430 TI - Obesity protects during cardiac surgery?: Professor Gavin Murphy speaks to Mark Nicholls about a study that could turn conventional thinking of a patient's weight, cardiac health, and surgery, on its head. PMID- 28863429 TI - Biotherapies and biomarkers for cardiovascular diseases: A 15-year journey at the ICREC (Heart Failure and Cardiac Regeneration) Research Laboratory in Barcelona, Spain. PMID- 28863431 TI - NSAIDs and cardiac arrest: Non-steroidal anti-inflammatory drug use is associated with increased risk of Out-of-hospital Cardiac Arrest: A nationwide Case-Time Control study. PMID- 28863432 TI - Perseverance versus Pedigree: Ankur Kalra, MD, a foreign medical graduate, discusses how determination and perseverance overcame 'pedigree' in his quest for a successful academic cardiology career in America. Determination was the ingredient to success. PMID- 28863433 TI - Modern prevention: genetic testing, vascular imaging, machine learning, and drug safety. PMID- 28863434 TI - Interaction between kisspeptin and adenylate cyclase-activating polypeptide 1 on the expression of pituitary gonadotropin subunits: a study using mouse pituitary lbetaT2 cells. AB - We examined direct effect of kisspeptin on pituitary gonadotrophs. Kisspeptin-10 (KP10) significantly increased the promoter activities of the gonadotropin subunits, common alpha-glycoprotein (Cga), luteinizing hormone beta (Lhb), and follicle-stimulatinghormone beta (Fshb) in LbetaT2 cells overexpressing kisspeptin receptor (Kiss1r). KP10 and gonadotropin-releasing hormone (GnRH) increased gonadotropin subunit levels to similar degrees and combined treatment with GnRH and KP10 did not potentiate their individual effects. Adenylate cyclase activating polypeptide 1 (ADCYAP1) also stimulates all three gonadotropin subunits. When cells were stimulated with both KP10 and ADCYAP1, expression of gonadotropin subunits was further increased compared to KP10 or ADCYAP1 alone. KP10 and GnRH dramatically increased serum response element (Sre) promoter levels but only slightly increased cAMP response element (Cre) promoter levels. Combined stimulation with KP10 and GnRH further increased Sre promoter levels. In contrast, ADCYAP1 slightly increased Sre promoter expression but did not modify the effect of KP10. However, ADCYAP1 increased Cre promoter to greater levels than KP10 alone, and combined treatment with KP10 and ADCYAP1 further increased Cre promoter expression. KP10 increased the expression of ADCYAP1 type I receptor (Adcyap1r) and the basal activity of the Cga promoter was increased at a higher Adcyap1r transfection level. The KP10-induced fold increase in all three gonadotropin subunit promoters was not altered by transfection with a higher amount of Adcyap1r vector. Our findings using model cells show that distinct signaling activation by ADCYAP1 potentiates the action of KP10. We also found that KP10 increases Adcyap1r expression. PMID- 28863435 TI - Erratum to: Gonadotropin-releasing hormone, kisspeptin, and gonadal steroids directly modulate nucleobindin-2/nesfatin-1 in murine hypothalamic gonadotropin releasing hormone neurons and gonadotropes. PMID- 28863436 TI - Erratum to: Reactive Oxygen Stimulation of Interleukin-6 Release in the Human Trophoblast Cell Line HTR-8/SVneo by the Trichlorethylene Metabolite S-(1,2 Dichloro)-l-Cysteine. PMID- 28863438 TI - The role of perivascular adipose tissue-derived sensory nerves in influencing vascular regulation. PMID- 28863439 TI - Ventricular-arterial coupling in heart failure with preserved ejection fraction: the devil is in the details. PMID- 28863440 TI - Embracing the complexity of RNA regulatory networks: layer by layer. PMID- 28863437 TI - Serotonin and catecholamines in the development and progression of heart valve diseases. AB - Heart valve diseases (HVDs) arise from a number of different processes that affect both the structure and function of the valve apparatus. Despite diverse aetiologies, treatments for HVDs are limited to percutaneous or surgical interventions. The search for medical therapies to prevent or slow the progression of HVDs has been hampered by our poor understanding of the progression from subclinical to symptomatic phases, and our limited knowledge of the molecular signals that control the susceptibility of valve interstitial cells to pathological remodeling. Clinical evidence has suggested a link between certain neurotransmitters and valvular diseases of the heart. The fenfluramine phentermine appetite suppressants popular in the 1980s were linked to mitral valve dysfunction, and ergot-derived dopamine agonists for Parkinson's disease have been associated with an increased risk of mitral and aortic valve regurgitation. The effect does not appear to be limited to medications, as valvular pathologies have also been observed in patients with carcinoid tumours of serotonin-producing enterochromaffin cells. The role of neurotransmitter molecules in valve pathology has not been adequately characterized and may represent a target for future medical therapies. Here we present current evidence from both clinical and basic science suggesting a link between neurotransmitters and HVDs, opening the door to future research in this area. PMID- 28863441 TI - Dr Fauconnier talks to genomics expert, Prof. McCarthy. PMID- 28863442 TI - PCSK9 inhibition and clinical cardiovascular outcomes in patients with atherosclerotic cardiovascular disease. PMID- 28863443 TI - The estimates of 5-year colorectal cancer prevalence in adult population in 2012. PMID- 28863445 TI - Erratum. PMID- 28863444 TI - Can Analysis of Routine Viral Testing Provide Accurate Estimates of Respiratory Syncytial Virus Disease Burden in Adults? AB - Respiratory syncytial virus (RSV) is increasingly recognized as a significant cause of adult respiratory illness. We evaluated routine viral testing and discharge diagnoses for identifying RSV and influenza burden. Polymerase chain reaction results performed in adults during emergency room visits or hospitalizations were reviewed. Peak RSV activity preceded influenza activity by 8 weeks. The ratio of total number of viral tests performed divided by total number of respiratory visits was higher during influenza than RSV peaks (1.31 vs 0.72; P = .0001). Influenza and RSV were listed primary diagnoses in 56 (30%) vs 7 (6%), respectively (P < .0001). Routine viral testing to estimate adult RSV disease burden has limitations. PMID- 28863446 TI - Erratum. PMID- 28863447 TI - Erratum. PMID- 28863448 TI - Burnout among young European oncologists: a call for action. PMID- 28863450 TI - Contrasting Patterns of Gene Flow for Amazonian Snakes That Actively Forage and Those That Wait in Ambush. AB - Knowledge of genetic structure, geographic distance and environmental heterogeneity can be used to identify environmental features and natural history traits that influence dispersal and gene flow. Foraging mode is a trait that might predict dispersal capacity in snakes, because actively foragers typically have greater movement rates than ambush predators. Here, we test the hypothesis that 2 actively foraging snakes have higher levels of gene flow than 2 ambush predators. We evaluated these 4 co-distributed species of snakes in the Brazilian Amazon. Snakes were sampled along an 880 km transect from the central to the southwest of the Amazon basin, which covered a mosaic of vegetation types and seasonal differences in climate. We analyzed thousands of single nucleotide polymorphisms to compare patterns of neutral gene flow based on isolation by geographic distance (IBD) and environmental resistance (IBR). We show that IBD and IBR were only evident in ambush predators, implying lower levels of dispersal than the active foragers. Therefore, gene flow was high enough in the active foragers analyzed here to prevent any build-up of spatial genotypic structure with respect to geographic distance and environmental heterogeneity. PMID- 28863452 TI - Erratum. PMID- 28863451 TI - Intensive Management and Natural Genetic Variation in Red Deer (Cervus elaphus). AB - The current magnitude of big-game hunting has outpaced the natural growth of populations, making artificial breeding necessary to rapidly boost hunted populations. In this study, we evaluated if the rapid increase of red deer (Cervus elaphus) abundance, caused by the growing popularity of big-game hunting, has impacted the natural genetic diversity of the species. We compared several genetic diversity metrics between 37 fenced populations subject to intensive management and 21 wild free-ranging populations. We also included a historically protected population from a national park as a baseline for comparisons. Contrary to expectations, our results showed no significant differences in genetic diversity between wild and fenced populations. Relatively lower genetic diversity was observed in the protected population, although differences were not significant in most cases. Bottlenecks were detected in both wild and fenced populations, as well as in the protected population. Assignment tests identified individuals that did not belong to their population of origin, indicating anthropogenic movement. We discuss the most likely processes, which could have led to the observed high levels of genetic variability and lack of differentiation between wild and fenced populations and suggest cautionary points for future conservation. We illustrate our comparative approach in red deer. However, our results and interpretations can be largely applicable to most ungulates subject to big-game hunting as most of them share a common exploitation recovery history as well as many ecological traits. PMID- 28863449 TI - Glioblastoma targeted therapy: updated approaches from recent biological insights. AB - Glioblastoma (WHO grade IV astrocytoma) is the most frequent primary brain tumor in adults, representing a highly heterogeneous group of neoplasms that are among the most aggressive and challenging cancers to treat. An improved understanding of the molecular pathways that drive malignancy in glioblastoma has led to the development of various biomarkers and the evaluation of several agents specifically targeting tumor cells and the tumor microenvironment. A number of rational approaches are being investigated, including therapies targeting tumor growth factor receptors and downstream pathways, cell cycle and epigenetic regulation, angiogenesis and antitumor immune response. Moreover, recent identification and validation of prognostic and predictive biomarkers have allowed implementation of modern trial designs based on matching molecular features of tumors to targeted therapeutics. However, while occasional targeted therapy responses have been documented in patients, to date no targeted therapy has been formally validated as effective in clinical trials. The lack of knowledge about relevant molecular drivers in vivo combined with a lack of highly bioactive and brain penetrant-targeted therapies remain significant challenges. In this article, we review the most promising biological insights that have opened the way for the development of targeted therapies in glioblastoma, and examine recent data from clinical trials evaluating targeted therapies and immunotherapies. We discuss challenges and opportunities for the development of these agents in glioblastoma. PMID- 28863453 TI - PML Nuclear Bodies Are Altered in Adult-Onset Neuronal Intranuclear Hyaline Inclusion Disease. AB - Neuronal intranuclear hyaline inclusion disease (NIHID) is a neurodegenerative disorder characterized by the presence of eosinophilic nuclear inclusions (NIs) in diverse cell lines in systemic organs. Adult-onset NIHID typically manifests with dementia associated with leukoencephalopathy. The detection of NIs in skin biopsies is useful for an antemortem diagnosis. A previous analysis suggested that NIs in NIHID originated from nuclear bodies (NBs), an important nuclear domain related to the ubiquitin-p62-mediated protein degradation system. In this study, we analyzed skin samples from 5 NIHID and 5 control cases immunohistochemically and electron microscopically. In the control cases, small but significant amounts of ubiquitin- and p62-positive intranuclear structures were found. These structures were consistently colocalized with promyelocytic leukemia protein (PML), an essential component of NBs, in particular when activated. The p62- and PML-positive structures were more frequently found in NIHID cases. Activated NBs, having a core and a shell, were observed by electron microscopy in control but not in NIHID cases. Instead, immature and mature filamentous NIs were found only in the NIHID cases. Our results indicate that NBs could not be normally activated in the NIHID, and an abnormal alteration of NBs might be related to the pathogenesis of NIHID. PMID- 28863454 TI - Autobiography Series: From Sleep-Wake Mechanisms to Prion Diseases. PMID- 28863455 TI - Characterization of 2 Novel Ependymoma Cell Lines With Chromosome 1q Gain Derived From Posterior Fossa Tumors of Childhood. AB - Ependymoma (EPN) is a common brain tumor of childhood that, despite standard surgery and radiation therapy, has a relapse rate of 50%. Clinical trials have been unsuccessful in improving outcome by addition of chemotherapy, and identification of novel therapeutics has been hampered by a lack of in vitro and in vivo models. We describe 2 unique EPN cell lines (811 and 928) derived from recurrent intracranial metastases. Both cell lines harbor the high-risk chromosome 1q gain (1q+) and a derivative chromosome 6, and both are classified as molecular group A according to transcriptomic analysis. Transcriptional enrichment of extracellular matrix-related genes was a common signature of corresponding primary tumors and cell lines in both monolayer and 3D formats. EPN cell lines, when cultured in 3D format, clustered closer to the primary tumors with better fidelity of EPN-specific transcripts than when grown as a monolayer. Additionally, 3D culture revealed ependymal rosette formation and cilia-related ontologies, similar to in situ tumors. Our data confirm the validity of the 811 and 928 cell lines as representative models of intracranial, posterior fossa 1q+ EPN, which holds potential to advance translational science for patients affected by this tumor. PMID- 28863456 TI - Multiplex Detection of Pediatric Low-Grade Glioma Signature Fusion Transcripts and Duplications Using the NanoString nCounter System. AB - Previous studies identified recurrent fusion and duplication events in pediatric low-grade glioma (pLGG). In addition to their role in diagnosis, the presence of these events aid in dictating therapy and predicting patient survival. Clinically, BRAF alterations are most commonly identified using fluorescent in situ hybridization (FISH). However, this method is costly, labor-intensive and does not identify nonBRAF events. Here, we evaluated the NanoString nCounter gene expression system for detecting 32 of the most commonly reported fusion/duplication events in pLGG. The assay was validated on 90 pLGG samples using FISH as the gold standard and showed sensitivity and specificity of 97% and 98%, respectively. We next profiled formalin-fixed paraffin-embedded preserved biopsy specimens from 429 pLGG cases. 171 (40%) of the cases within our cohort tested positive for a fusion or duplication event contained within our panel. These events, in order of prevalence, were KIAA1549-BRAF 16;9 (89/171, 52.0%), KIAA1549-BRAF 15;9 (42/171, 24.6%), KIAA1549-BRAF 16;11 (14/171, 8.2%), FGFR1 TACC1 17;7 (13/171, 7.6%), MYBL1 duplication (5/171, 2.9%), KIAA1549-BRAF 18;10 (4/171, 2.3%), KIAA1549-BRAF 15;11 (2/171, 1.2%), FAM131B-BRAF 2;9 (1/171, 0.6%), and RNF130-BRAF 3;9 (1/171, 0.6%). This work introduces NanoString as a viable clinical replacement for the detection of fusion and duplication events in pLGG. PMID- 28863458 TI - ESC Professional Membership: An asset for all. PMID- 28863457 TI - Bortezomib-Induced Muscle Toxicity in Multiple Myeloma. AB - Multiple myeloma (MM) accounts for ~13% of all hematologic malignancies. Bortezomib treatment is effective in MM, but can be complicated with neurological side effects. We describe a patient with symptomatic MM who had a reversible metabolic myopathy associated with bortezomib administration and pathologically characterized by excessive storage of lipid droplets together with mitochondrial abnormalities. In a single-center prospective study, 14 out of 24 patients with symptomatic MM were treated with bortezomib and, among these, 7 developed muscular signs and/or symptoms. The myopathy was characterized by a proximal muscle weakness involving lower limbs and was an early complication. Complete resolution of muscle weakness occurred after treatment discontinuation. Conversely, none of the patients who received a treatment without bortezomib developed muscular symptoms. Experimental studies demonstrate that in primary human myoblasts bortezomib at low concentrations leads to excessive storage of lipid droplets together with structural mitochondrial abnormalities, recapitulating the pathologic findings observed in patient's muscle. Our data suggest that patients treated with bortezomib should be monitored for muscular signs and/or symptoms and muscle weakness should alert the clinician to the possibility of myopathy. Bortezomib-induced metabolic myopathy is a potentially reversible entity with important implications for management and treatment of patients with MM. PMID- 28863459 TI - Barbara Casadei MD, DPhil, FRCP, FESC. PMID- 28863460 TI - Big Data in Cardiovascular Disease. PMID- 28863461 TI - Big Data in Cardiology. PMID- 28863462 TI - Fractional Flow ReserveCT (FFRCT). PMID- 28863463 TI - The electronic cigarette, do we need to worry? PMID- 28863464 TI - Sniffing and gasping to prevent syncope? PMID- 28863465 TI - Risk factors for chronic heart failure: obesity, renal dysfunction, arteriovenous fistulas, and amyloid deposition. PMID- 28863466 TI - Characterization of Dengue Virus Infections Among Febrile Children Clinically Diagnosed With a Non-Dengue Illness, Managua, Nicaragua. AB - Background: We sought to characterize dengue virus (DENV) infections among febrile children enrolled in a pediatric cohort study who were clinically diagnosed with a non-dengue illness ("C cases"). Methods: DENV infections were detected and viral load quantitated by real-time reverse transcription-polymerase chain reaction in C cases presenting between January 2007 and January 2013. Results: One hundred forty-one of 2892 C cases (4.88%) tested positive for DENV. Of all febrile cases in the study, DENV-positive C cases accounted for an estimated 52.0% of patients with DENV viremia at presentation. Compared with previously detected, symptomatic dengue cases, DENV-positive C cases were significantly less likely to develop long-lasting humoral immune responses to DENV, as measured in healthy annual serum samples (79.7% vs 47.8%; P < .001). Humoral immunity was associated with viral load at presentation: 40 of 43 patients (93.0%) with a viral load >=7.0 log10 copies/mL serum developed the expected rise in anti-DENV antibodies in annual samples versus 13 of 68 (19.1%) patients with a viral load below this level (P < .001). Conclusions: Antibody responses to DENV-positive C cases differ from responses to classic symptomatic dengue. These findings have important implications for DENV transmission modeling, immunology, and epidemiologic surveillance. PMID- 28863467 TI - Suppressor Cell-Depleting Immunotherapy With Denileukin Diftitox is an Effective Host-Directed Therapy for Tuberculosis. AB - Host-directed therapies that augment host immune effector mechanisms may serve as important adjunctive therapies for tuberculosis treatment. We evaluated the activity of denileukin diftitox in an acute mouse model of tuberculosis (TB) infection and analyzed the cellular composition and bacterial burden in lungs and spleens. These in vivo studies show that denileukin diftitox potentiates standard TB treatment in the mouse model, an effect which may be due to depletion of T regulatory and myeloid-derived suppressor cells during TB infection. Our results indicate that denileukin diftitox and other suppressor cell-depleting therapies may be useful adjunctive, host-directed therapies for TB. PMID- 28863468 TI - Effect of Prepregnancy Pertussis Vaccination in Young Infants. AB - Background: Maternal antibodies to pertussis can hamper infant immune responses to pertussis vaccines. The effect a maternal tetanus, diphtheria, acellular pertussis (Tdap) vaccine booster between 2 consecutive pregnancies is investigated. Methods: A prospective study was conducted in Belgium during 2008 2014 on the kinetics of maternal pertussis antibodies in unvaccinated women and their infants (group A; 86 mother-infant pairs) and in siblings born after the women received Tdap vaccine (group B; 58 mother-infant pairs). Levels of antibody to pertussis toxin, antibody to filamentous hemagglutinin, and antibody to pertactin were measured in maternal blood before and after vaccination and at both deliveries, in cord blood from both siblings, and in infants before and after they received a priming series of acellular pertussis containing vaccines. Results: Levels of pertussis antibodies in all group B siblings at birth were significantly higher than those in their siblings at birth, even as the interval since maternal vaccination increased. Blunting of the infant pertussis vaccine response was detected in group B siblings. We estimated the maximum interval between repeat Tdap vaccine doses in adult women that would yield a beneficial effect for the consecutive infant. Conclusions: Prepregnancy Tdap vaccination significantly increases maternal antibody concentrations in consecutive infants. However, similar to the effect of Tdap vaccination during pregnancy, immune responses of later-born infants born to mothers who received a prepregnancy immunization, are blunted. PMID- 28863469 TI - Parasites Causing Cerebral Falciparum Malaria Bind Multiple Endothelial Receptors and Express EPCR and ICAM-1-Binding PfEMP1. AB - Background: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates the binding and accumulation of infected erythrocytes (IE) to blood vessels and tissues. Specific interactions have been described between PfEMP1 and human endothelial proteins CD36, intercellular adhesion molecule-1 (ICAM-1), and endothelial protein C receptor (EPCR); however, cytoadhesion patterns typical for pediatric malaria syndromes and the associated PfEMP1 members are still undefined. Methods: In a cohort of 94 hospitalized children with malaria, we characterized the binding properties of IE collected on admission, and var gene transcription using quantitative polymerase chain reaction. Results: IE from patients with cerebral malaria were more likely to bind EPCR and ICAM-1 than IE from children with uncomplicated malaria (P = .007). The level of transcripts encoding CIDRalpha1.4 and CIDRalpha1.5 domain subclasses was higher in patients with severe disease (P < .05). IE populations exhibiting binding to all 3 receptors had higher levels of transcripts encoding PfEMP1 with CIDRalpha1.4 and Duffy binding-like (DBL)-beta3 domains than parasites, which only bound CD36. Conclusions: These results underpin the significance of EPCR binding in pediatric malaria patients that require hospital admission, and support the notion that complementary receptor interactions of EPCR binding PfEMP1with ICAM-1 amplifies development of severe malaria symptoms. PMID- 28863470 TI - Effects of Aging on Parasite Biomass, Inflammation, Endothelial Activation, Microvascular Dysfunction and Disease Severity in Plasmodium knowlesi and Plasmodium falciparum Malaria. AB - Background: In populations pauci-immune to malaria, risk of severe malaria increases with age. This is particularly apparent in Plasmodium knowlesi malaria. However, pathophysiological mechanisms underlying knowlesi malaria, and of the age-related increase in risk of severe malaria in general, are poorly understood. Methods: In Malaysian patients aged >=12 years with severe (n = 47) and nonsevere (n = 99) knowlesi malaria, severe (n = 21) and nonsevere (n = 109) falciparum malaria, and healthy controls (n = 50), we measured parasite biomass, systemic inflammation (interleukin 6 [IL-6]), endothelial activation (angiopoietin-2), and microvascular function, and evaluated the effects of age. Results: Plasmodium knowlesi parasitemia correlated with age (Spearman's correlation coefficient [rs] = 0.36; P < .0001). In knowlesi malaria, IL-6, angiopoietin-2, and microvascular dysfunction were increased in severe compared to nonsevere disease, and all correlated with age, independent of parasitemia. In falciparum malaria, angiopoietin-2 increased with age, independent of parasite biomass (histidine rich protein 2 [HRP2]). Independent risk factors for severe malaria included parasitemia and angiopoietin-2 in knowlesi malaria, and HRP2, angiopoietin-2, and microvascular dysfunction in falciparum malaria. Conclusions: Parasite biomass, endothelial activation, and microvascular dysfunction are associated with severe disease in knowlesi malaria and likely contribute to pathogenesis. The association of each of these processes with aging may account for the greater severity of malaria observed in older adults in low-endemic regions. PMID- 28863471 TI - Moving Lassa Fever Research and Care Into the 21st Century. PMID- 28863473 TI - Targeting Type IV Secretion System Proteins to Combat Multidrug-Resistant Gram positive Pathogens. AB - For many gram-positive pathogens, conjugative plasmid transfer is an important means of spreading antibiotic resistance . Therefore, the search for alternative treatments to fight and prevent infections caused by these bacteria has become of major interest. In the present study, we evaluated the protein TraM, from the conjugative plasmid pIP501, as a potential vaccine candidate. Anti-TraM antiserum mediated in vitro opsonophagocytic killing of the strain harboring the pIP501 plasmid and also proved to be cross-reactive against other clinically relevant enterococcal and staphylococcal strains. Specificity of antibodies toward TraM was confirmed by results of an opsonophagocytic inhibition assay and Western blot. In addition, conjugative transfer experiments proved that TraM is essential for the transfer of pIP501. Finally, immunization with either TraM or anti-TraM antiserum reduced significantly the colony counts in mice livers, demonstrating that TraM is a promising vaccine candidate against enterococci and other gram positive pathogens. PMID- 28863472 TI - A Case of Human Lassa Virus Infection With Robust Acute T-Cell Activation and Long-Term Virus-Specific T-Cell Responses. AB - A nurse who acquired Lassa virus infection in Togo in the spring of 2016 was repatriated to the United States for care at Emory University Hospital. Serial sampling from this patient permitted the characterization of several aspects of the innate and cellular immune responses to Lassa virus. Although most of the immune responses correlated with the kinetics of viremia resolution, the CD8 T cell response was of surprisingly high magnitude and prolonged duration, implying prolonged presentation of viral antigens. Indeed, long after viremia resolution, there was persistent viral RNA detected in the semen of the patient, accompanied by epididymitis, suggesting the male reproductive tract as 1 site of antigen persistence. Consistent with the magnitude of acute T-cell responses, the patient ultimately developed long-term, polyfunctional memory T-cell responses to Lassa virus. PMID- 28863474 TI - Marginal Emission Factors Considering Renewables: A Case Study of the U.S. Midcontinent Independent System Operator (MISO) System. AB - Estimates of marginal emission factors (MEFs) for the electricity sector have focused on emitting sources only, assuming nonemitting renewables rarely contribute to marginal generation. However, with increased penetration and improved dispatch of renewables, this assumption may be outdated. Here, we improve the methodology to incorporate renewables in MEF estimates and demonstrate a case study for the Midcontinent Independent System Operator (MISO) system where wind has been commonly dispatched on the margin. We also illustrate spatiotemporal variations of MEFs and explore implications for energy storage technologies. Results show that because the share of renewables in MISO is still relatively low (6.34%), conventional MEFs focused on emitting sources can provide a good estimate in MISO overall, as well as in the Central and South subregions. However, in the MISO North subregion where wind provides 22.5% of grid generation, neglecting nonemitting sources can overestimate MEFs for CO2, SO2, and NOx by about 30%. The application of expanded MEFs in this case also reveals heightened emission increases associated with load shifting of storage technologies. Our study highlights the importance of expanded MEFs in regions with high and growing renewables penetration, particularly as renewable energy policy seeks to incorporate demand-side technologies. PMID- 28863475 TI - Modeling the Self-Assembly of Bolaamphiphiles under Nanoconfinement by Coarse Grained Molecular Dynamics. AB - Novel and complex nanostructures of amphiphiles assemblies facilitate realizing of many practical applications in nanotechnologies. Under different physical conditions, amphiphiles can form various morphologies. In this article, the self assembly of bolaamphiphiles was investigated under the cylindrical confinement of carbon nanotubes by coarse-grained molecular dynamics simulation. We found that bolaamphiphiles inside a carbon nanotube with a relatively large diameter tended to self-assemble into curved cylindrical micelles, and further some of these micelles can form double helix structures which were not observed in bulk solutions. We develop an effective method to characterize different morphologies. Our analysis results showed that the formation of double helix and other amorphous morphologies of micelles in carbon nanotubes is not induced by the conformational variation of bolaamphiphiles. Moreover, through examining the potential energies of different structures, we infer that it is entropy which leads micelles to bend even to form double stranded helix structures. In addition, we analyzed the sizes of micelles and find the scission and recombination of micelles during the double helix formation process. This work indicates that the confinement of carbon nanotube is an available method to produce complex nanostructures and provides some new insights of the self assembly of bolaamphiphiles. PMID- 28863476 TI - Multi-dark-dark solitons of the integrable repulsive AB system via the determinants. AB - We investigate the integrable repulsive AB system and construct its Darboux transformation using the loop group method. The associated N-fold Darboux transformation is found in terms of simple determinants. Moreover, we derive multi-dark-dark solitons of the repulsive AB system with a non-vanishing background through the Darboux transformation with a limit procedure. Particularly, we exhibit the one-, two-, and three-dark-dark solitons. The results will be meaningful for the study of vector multi-dark solitons in many physical systems such as geophysical fluid dynamics and nonlinear optics. PMID- 28863478 TI - Bifurcations of a periodically forced microbial continuous culture model with restrained growth rate. AB - A three dimensional microbial continuous culture model with a restrained microbial growth rate is studied in this paper. Two types of dilution rates are considered to investigate the dynamic behaviors of the model. For the unforced system, fold bifurcation and Hopf bifurcation are detected, and numerical simulations reveal that the system undergoes degenerate Hopf bifurcation. When the system is periodically forced, bifurcation diagrams for periodic solutions of period-one and period-two are given by researching the Poincare map, corresponding to different bifurcation cases in the unforced system. Stable and unstable quasiperiodic solutions are obtained by Neimark-Sacker bifurcation with different parameter values. Periodic solutions of various periods can occur or disappear and even change their stability, when the Poincare map of the forced system undergoes Neimark-Sacker bifurcation, flip bifurcation, and fold bifurcation. Chaotic attractors generated by a cascade of period doublings and some phase portraits are given at last. PMID- 28863477 TI - Resilience of epidemics for SIS model on networks. AB - Epidemic propagation on complex networks has been widely investigated, mostly with invariant parameters. However, the process of epidemic propagation is not always constant. Epidemics can be affected by various perturbations and may bounce back to its original state, which is considered resilient. Here, we study the resilience of epidemics on networks, by introducing a different infection rate lambda2 during SIS (susceptible-infected-susceptible) epidemic propagation to model perturbations (control state), whereas the infection rate is lambda1 in the rest of time. Noticing that when lambda1 is below lambdac, there is no resilience in the SIS model. Through simulations and theoretical analysis, we find that even for lambda2 < lambdac, epidemics eventually could bounce back if the control duration is below a threshold. This critical control time for epidemic resilience, i.e., cdmax, seems to be predicted by the diameter (d) of the underlying network, with the quantitative relation cdmax ~ dalpha. Our findings can help to design a better mitigation strategy for epidemics. PMID- 28863479 TI - Ag fractal structures in electroless metal deposition systems with and without magnetic field. AB - Metal electrodeposition systems display tree-like structures with extensive ramification and a fractal character. Electrolysis is not a necessary route for the growth of such dendritic metal deposits. We can grow beautiful ramification patterns via a simple redox reaction. We present here a study of silver (Ag) deposits from the reduction of Ag+ in (AgNO3) solution by metallic copper. The experiments are carried out in discotic geometry, in a Petri dish hosting a thin AgNO3 solution film. A variety of deposited structures and patterns is obtained at different Ag+ concentrations, yet with essentially the same fractal dimension averaged at 1.64, typical of diffusion-limited aggregation (DLA). A linear magnetic field of low induction (0.50-1.0 T) applied across the medium causes a notable transformation in the morphology of the deposits. In both the field off and the field on cases, the effect of vertical (hence 3D) heaving seems to be dominant, perhaps explaining the nearly constant fractal dimension. PMID- 28863480 TI - Superregular breathers in a complex modified Korteweg-de Vries system. AB - We study superregular (SR) breathers (i.e., the quasi-Akhmediev breather collision with a certain phase shift) in a complex modified Korteweg-de Vries equation. We demonstrate that such SR waves can exhibit intriguing nonlinear structures, including the half-transition and full-suppression modes, which have no analogues in the standard nonlinear Schrodinger equation. In contrast to the standard SR breather formed by pairs of quasi-Akhmediev breathers, the half transition mode describes a mix of quasi-Akhmediev and quasi-periodic waves, whereas the full-suppression mode shows a non-amplifying nonlinear dynamics of localized small perturbations associated with the vanishing growth rate of modulation instability. Interestingly, we show analytically and numerically that these different SR modes can be evolved from an identical localized small perturbation. In particular, our results demonstrate an excellent compatibility relation between SR modes and the linear stability analysis. PMID- 28863481 TI - Stationary distribution of a stochastic SIS epidemic model with double diseases and the Beddington-DeAngelis incidence. AB - In this paper, a stochastic Susceptible-Infected-Susceptible (SIS) epidemic model with double diseases and the Beddington-DeAngelis incidence is proposed and studied. Sufficient conditions for the existence of an ergodic stationary distribution of the positive solutions to the model are obtained via the Lyapunov function method. The existence of stationary distribution implies stochastic stability to some extent. PMID- 28863482 TI - Network analysis of chaotic systems through unstable periodic orbits. AB - A chaotic motion can be considered an irregular transition process near unstable periodic orbits embedded densely in a chaotic set. Therefore, unstable periodic orbits have been used to characterize properties of chaos. Statistical quantities of chaos such as natural measures and fractal dimensions can be determined in terms of unstable periodic orbits. Unstable periodic orbits that can provide good approximations to averaged quantities of chaos or turbulence are also known to exist. However, it is not clear what type of unstable periodic orbits can capture them. In this paper, a model for an irregular transition process of a chaotic motion among unstable periodic orbits as nodes is constructed by using a network. We show that unstable periodic orbits which have lots of links in the network tend to capture time averaged properties of chaos. A scale-free property of the degree distribution is also observed. PMID- 28863483 TI - Long-period clocks from short-period oscillators. AB - We analyze repulsively coupled Kuramoto oscillators, which are exposed to a distribution of natural frequencies. This source of disorder leads to closed orbits of repetitive temporary patterns of phase-locked motion, providing clocks on macroscopic time scales. The periods can be orders of magnitude longer than the periods of individual oscillators. By construction, the attractor space is quite rich. This may cause long transients until the deterministic trajectories find their stationary orbits. The smaller the width of the distribution about the common natural frequency, the longer are the emerging time scales on average. Among the long-period orbits, we find self-similar sequences of temporary phase locked motion on different time scales. The ratio of time scales is determined by the ratio of widths of the distributions. The results illustrate a mechanism for how simple systems can provide rather flexible dynamics, with a variety of periods even without external entrainment. PMID- 28863484 TI - Uncovering low dimensional macroscopic chaotic dynamics of large finite size complex systems. AB - In the last decade, it has been shown that a large class of phase oscillator models admit low dimensional descriptions for the macroscopic system dynamics in the limit of an infinite number N of oscillators. The question of whether the macroscopic dynamics of other similar systems also have a low dimensional description in the infinite N limit has, however, remained elusive. In this paper, we show how techniques originally designed to analyze noisy experimental chaotic time series can be used to identify effective low dimensional macroscopic descriptions from simulations with a finite number of elements. We illustrate and verify the effectiveness of our approach by applying it to the dynamics of an ensemble of globally coupled Landau-Stuart oscillators for which we demonstrate low dimensional macroscopic chaotic behavior with an effective 4-dimensional description. By using this description, we show that one can calculate dynamical invariants such as Lyapunov exponents and attractor dimensions. One could also use the reconstruction to generate short-term predictions of the macroscopic dynamics. PMID- 28863485 TI - Detecting dynamical changes in time series by using the Jensen Shannon divergence. AB - Most of the time series in nature are a mixture of signals with deterministic and random dynamics. Thus the distinction between these two characteristics becomes important. Distinguishing between chaotic and aleatory signals is difficult because they have a common wide band power spectrum, a delta like autocorrelation function, and share other features as well. In general, signals are presented as continuous records and require to be discretized for being analyzed. In this work, we introduce different schemes for discretizing and for detecting dynamical changes in time series. One of the main motivations is to detect transitions between the chaotic and random regime. The tools here used here originate from the Information Theory. The schemes proposed are applied to simulated and real life signals, showing in all cases a high proficiency for detecting changes in the dynamics of the associated time series. PMID- 28863486 TI - Autapse-induced multiple stochastic resonances in a modular neuronal network. AB - This study investigates the nontrivial effects of autapse on stochastic resonance in a modular neuronal network subjected to bounded noise. The resonance effect of autapse is detected by imposing a self-feedback loop with autaptic strength and autaptic time delay to each constituent neuron. Numerical simulations have demonstrated that bounded noise with the proper level of amplitude can induce stochastic resonance; moreover, the noise induced resonance dynamics can be significantly shaped by the autapse. In detail, for a specific range of autaptic strength, multiple stochastic resonances can be induced when the autaptic time delays are appropriately adjusted. These appropriately adjusted delays are detected to nearly approach integer multiples of the period of the external weak signal when the autaptic strength is very near zero; otherwise, they do not match the period of the external weak signal when the autaptic strength is slightly greater than zero. Surprisingly, in both cases, the differences between arbitrary two adjacent adjusted autaptic delays are always approximately equal to the period of the weak signal. The phenomenon of autaptic delay induced multiple stochastic resonances is further confirmed to be robust against the period of the external weak signal and the intramodule probability of subnetwork. These findings could have important implications for weak signal detection and information propagation in realistic neural systems. PMID- 28863487 TI - A new chaotic oscillator with free control. AB - A novel chaotic system is explored in which all terms are quadratic except for a linear function. The slope of the linear function rescales the amplitude and frequency of the variables linearly while its zero intercept allows offset boosting for one of the variables. Therefore, a free-controlled chaotic oscillation can be obtained with any desired amplitude, frequency, and offset by an easy modification of the linear function. When implemented as an electronic circuit, the corresponding chaotic signal can be controlled by two independent potentiometers, which is convenient for constructing a chaos-based application system. To the best of our knowledge, this class of chaotic oscillators has never been reported. PMID- 28863488 TI - Detection of coupling delay: A problem not yet solved. AB - Nonparametric detection of coupling delay in unidirectionally and bidirectionally coupled nonlinear dynamical systems is examined. Both continuous and discrete time systems are considered. Two methods of detection are assessed-the method based on conditional mutual information-the CMI method (also known as the transfer entropy method) and the method of convergent cross mapping-the CCM method. Computer simulations show that neither method is generally reliable in the detection of coupling delays. For continuous-time chaotic systems, the CMI method appears to be more sensitive and applicable in a broader range of coupling parameters than the CCM method. In the case of tested discrete-time dynamical systems, the CCM method has been found to be more sensitive, while the CMI method required much stronger coupling strength in order to bring correct results. However, when studied systems contain a strong oscillatory component in their dynamics, results of both methods become ambiguous. The presented study suggests that results of the tested algorithms should be interpreted with utmost care and the nonparametric detection of coupling delay, in general, is a problem not yet solved. PMID- 28863489 TI - Scaling laws for diffusion on (trans)fractal scale-free networks. AB - Fractal (or transfractal) features are common in real-life networks and are known to influence the dynamic processes taking place in the network itself. Here, we consider a class of scale-free deterministic networks, called (u, v)-flowers, whose topological properties can be controlled by tuning the parameters u and v; in particular, for u > 1, they are fractals endowed with a fractal dimension df, while for u = 1, they are transfractal endowed with a transfractal dimension df. In this work, we investigate dynamic processes (i.e., random walks) and topological properties (i.e., the Laplacian spectrum) and we show that, under proper conditions, the same scalings (ruled by the related dimensions) emerge for both fractal and transfractal dimensions. PMID- 28863490 TI - Mathematical model of chaotic oscillations and oscillatory entrainment in glycolysis originated from periodic substrate supply. AB - We study the influence of periodic influx on a character of glycolytic oscillations within the forced Selkov system. We demonstrate that such a simple system demonstrates a rich variety of dynamical regimes (domains of entrainment of different order (Arnold tongues), quasiperiodic oscillations, and chaos), which can be qualitatively collated with the known experimental data. We determine detailed dynamical regimes exploring the map of Lyapunov characteristic exponents obtained in numerical simulations of the Selkov system with periodic influx. In addition, a special study of the chaotic regime and the scenario of its origin in this system was evaluated and discussed. PMID- 28863491 TI - Experimental phase synchronization detection in non-phase coherent chaotic systems by using the discrete complex wavelet approach. AB - Phase synchronization may emerge from mutually interacting non-linear oscillators, even under weak coupling, when phase differences are bounded, while amplitudes remain uncorrelated. However, the detection of this phenomenon can be a challenging problem to tackle. In this work, we apply the Discrete Complex Wavelet Approach (DCWA) for phase assignment, considering signals from coupled chaotic systems and experimental data. The DCWA is based on the Dual-Tree Complex Wavelet Transform (DT-CWT), which is a discrete transformation. Due to its multi scale properties in the context of phase characterization, it is possible to obtain very good results from scalar time series, even with non-phase-coherent chaotic systems without state space reconstruction or pre-processing. The method correctly predicts the phase synchronization for a chemical experiment with three locally coupled, non-phase-coherent chaotic processes. The impact of different time-scales is demonstrated on the synchronization process that outlines the advantages of DCWA for analysis of experimental data. PMID- 28863492 TI - Power-functional network. AB - Power grids and their properties have been studied broadly in many aspects. In this paper, we propose a novel concept, power-flow-based power grid, as a typical power-functional network, based on the calculation of power flow distribution from power electrical engineering. We compare it with structural networks based on the shortest path length and effective networks based on the effective electrical distance and study the relationship among these three kinds of networks. We find that they have roughly positive correlations with each other, indicating that in general any close nodes in the topological structure are actually connected in function. However, we do observe some counter-examples that two close nodes in a structural network can have a long distance in a power functional network, namely, two physically connected nodes can actually be separated in function. In addition, we find that power grids in the structural network tend to be heterogeneous, whereas those in the effective and power functional networks tend to be homogeneous. These findings are expected to be significant not only for power grids but also for various other complex networks. PMID- 28863493 TI - Amplitude death in a ring of nonidentical nonlinear oscillators with unidirectional coupling. AB - We study the collective behaviors in a ring of coupled nonidentical nonlinear oscillators with unidirectional coupling, of which natural frequencies are distributed in a random way. We find the amplitude death phenomena in the case of unidirectional couplings and discuss the differences between the cases of bidirectional and unidirectional couplings. There are three main differences; there exists neither partial amplitude death nor local clustering behavior but an oblique line structure which represents directional signal flow on the spatio temporal patterns in the unidirectional coupling case. The unidirectional coupling has the advantage of easily obtaining global amplitude death in a ring of coupled oscillators with randomly distributed natural frequency. Finally, we explain the results using the eigenvalue analysis of the Jacobian matrix at the origin and also discuss the transition of dynamical behavior coming from connection structure as the coupling strength increases. PMID- 28863494 TI - Taming stochastic bifurcations in fractional-order systems via noise and delayed feedback. AB - The dynamics in fractional-order systems have been widely studied during the past decade due to the potential applications in new materials and anomalous diffusions, but the investigations have been so far restricted to a fractional order system without time delay(s). In this paper, we report the first study of random responses of fractional-order system coupled with noise and delayed feedback. Stochastic averaging method has been utilized to determine the stationary probability density functions (PDFs) by means of the principle of minimum mean-square error, based on which stochastic bifurcations could be identified through recognizing the shape of the PDFs. It has been found that by changing the fractional order the shape of the PDFs can switch from unimodal distribution to bimodal one, or from bimodal distribution to unimodal one, thus announcing the onset of stochastic bifurcation. Further, we have demonstrated that by merely modulating the time delay, the feedback strengths, or the noise intensity, the shapes of PDFs can transit between a single peak and a double peak. Therefore, it provides an efficient candidate to control, say, induce or suppress, the stochastic bifurcations in fractional-order systems. PMID- 28863495 TI - On the limits of probabilistic forecasting in nonlinear time series analysis II: Differential entropy. AB - In a previous paper, the authors studied the limits of probabilistic prediction in nonlinear time series analysis in a perfect model scenario, i.e., in the ideal case that the uncertainty of an otherwise deterministic model is due to only the finite precision of the observations. The model consisted of the symbolic dynamics of a measure-preserving transformation with respect to a finite partition of the state space, and the quality of the predictions was measured by the so-called ignorance score, which is a conditional entropy. In practice, though, partitions are dispensed with by considering numerical and experimental data to be continuous, which prompts us to trade off in this paper the Shannon entropy for the differential entropy. Despite technical differences, we show that the core of the previous results also hold in this extended scenario for sufficiently high precision. The corresponding imperfect model scenario will be revisited too because it is relevant for the applications. The theoretical part and its application to probabilistic forecasting are illustrated with numerical simulations and a new prediction algorithm. PMID- 28863496 TI - Andronov-Hopf bifurcation with and without parameter in a cubic memristor oscillator with a line of equilibria. AB - The model of a memristor-based oscillator with cubic nonlinearity is studied. The considered system has infinitely many equilibrium points, which build a line of equilibria in the phase space. Numerical modeling of the dynamics is combined with the bifurcational analysis. It has been shown that the oscillation excitation has distinctive features of the supercritical Andronov-Hopf bifurcation and can be achieved by changing of a parameter value as well as by variation of initial conditions. Therefore, the considered bifurcation is called Andronov-Hopf bifurcation with and without parameter. PMID- 28863497 TI - Distinguishability notion based on Wootters statistical distance: Application to discrete maps. AB - We study the distinguishability notion given by Wootters for states represented by probability density functions. This presents the particularity that it can also be used for defining a statistical distance in chaotic unidimensional maps. Based on that definition, we provide a metric d- for an arbitrary discrete map. Moreover, from d-, we associate a metric space with each invariant density of a given map, which results to be the set of all distinguished points when the number of iterations of the map tends to infinity. Also, we give a characterization of the wandering set of a map in terms of the metric d-, which allows us to identify the dissipative regions in the phase space. We illustrate the results in the case of the logistic and the circle maps numerically and analytically, and we obtain d- and the wandering set for some characteristic values of their parameters. Finally, an extension of the metric space associated for arbitrary probability distributions (not necessarily invariant densities) is given along with some consequences. The statistical properties of distributions given by histograms are characterized in terms of the cardinal of the associated metric space. For two conjugate variables, the uncertainty principle is expressed in terms of the diameters of the associated metric space with those variables. PMID- 28863498 TI - Analysis and application of opinion model with multiple topic interactions. AB - To reveal heterogeneous behaviors of opinion evolution in different scenarios, we propose an opinion model with topic interactions. Individual opinions and topic features are represented by a multidimensional vector. We measure an agent's action towards a specific topic by the product of opinion and topic feature. When pairs of agents interact for a topic, their actions are introduced to opinion updates with bounded confidence. Simulation results show that a transition from a disordered state to a consensus state occurs at a critical point of the tolerance threshold, which depends on the opinion dimension. The critical point increases as the dimension of opinions increases. Multiple topics promote opinion interactions and lead to the formation of macroscopic opinion clusters. In addition, more topics accelerate the evolutionary process and weaken the effect of network topology. We use two sets of large-scale real data to evaluate the model, and the results prove its effectiveness in characterizing a real evolutionary process. Our model achieves high performance in individual action prediction and even outperforms state-of-the-art methods. Meanwhile, our model has much smaller computational complexity. This paper provides a demonstration for possible practical applications of theoretical opinion dynamics. PMID- 28863499 TI - Cycle flows and multistability in oscillatory networks. AB - We study multistability in phase locked states in networks of phase oscillators under both Kuramoto dynamics and swing equation dynamics-a popular model for studying coarse-scale dynamics of an electrical AC power grid. We first establish the existence of geometrically frustrated states in such systems-where although a steady state flow pattern exists, no fixed point exists in the dynamical variables of phases due to geometrical constraints. We then describe the stable fixed points of the system with phase differences along each edge not exceeding pi/2 in terms of cycle flows-constant flows along each simple cycle-as opposed to phase angles or flows. The cycle flow formalism allows us to compute tight upper and lower bounds to the number of fixed points in ring networks. We show that long elementary cycles, strong edge weights, and spatially homogeneous distribution of natural frequencies (for the Kuramoto model) or power injections (for the oscillator model for power grids) cause such networks to have more fixed points. We generalize some of these bounds to arbitrary planar topologies and derive scaling relations in the limit of large capacity and large cycle lengths, which we show to be quite accurate by numerical computation. Finally, we present an algorithm to compute all phase locked states-both stable and unstable-for planar networks. PMID- 28863500 TI - Implementation of dynamic dual input multiple output logic gate via resonance in globally coupled Duffing oscillators. AB - We have used a system of globally coupled double-well Duffing oscillators under an enhanced resonance condition to design and implement Dual Input Multiple Output (DIMO) logic gates. In order to enhance the resonance, the first oscillator in the globally coupled system alone is excited by two forces out of which one acts as a driving force and the other will be either sub-harmonic or super-harmonic in nature. We report that for an appropriate coupling strength, the second force coherently drives and enhances not only the amplitude of the weak first force to all the coupled systems but also drives and propagates the digital signals if any given to the first system. We then numerically confirm the propagation of any digital signal or square wave without any attenuation under an enhanced resonance condition for an amplitude greater than a threshold value. Further, we extend this idea for computing various logical operations and succeed in designing theoretically DIMO logic gates such as AND/NAND, OR/NOR gates with globally coupled systems. PMID- 28863501 TI - Large deviation induced phase switch in an inertial majority-vote model. AB - We theoretically study noise-induced phase switch phenomena in an inertial majority-vote (IMV) model introduced in a recent paper [Chen et al., Phys. Rev. E 95, 042304 (2017)]. The IMV model generates a strong hysteresis behavior as the noise intensity f goes forward and backward, a main characteristic of a first order phase transition, in contrast to a second-order phase transition in the original MV model. Using the Wentzel-Kramers-Brillouin approximation for the master equation, we reduce the problem to finding the zero-energy trajectories in an effective Hamiltonian system, and the mean switching time depends exponentially on the associated action and the number of particles N. Within the hysteresis region, we find that the actions, along the optimal forward switching path from the ordered phase (OP) to disordered phase (DP) and its backward path show distinct variation trends with f, and intersect at f = fc that determines the coexisting line of the OP and DP. This results in a nonmonotonic dependence of the mean switching time between two symmetric OPs on f, with a minimum at fc for sufficiently large N. Finally, the theoretical results are validated by Monte Carlo simulations. PMID- 28863502 TI - Delay-induced locking in bursting neuronal networks. AB - In this paper, the collective behaviors for ring structured bursting neuronal networks with electrical couplings and distance-dependent delays are studied. Each neuron is modeled by the Hindmarsh-Rose neuron. Through changing time delays between connected neurons, different spatiotemporal patterns are obtained. These patterns can be explained by calculating the ratios between the bursting period and the delay which exhibit clear locking relations. The holding and the failure of the lockings are investigated via bifurcation analysis. In particular, the bursting death phenomenon is observed for large coupling strengths and small time delays which is in fact the result of the partial amplitude death in the fast subsystem. These results indicate that the collective behaviors of bursting neurons critically depend on the bifurcation structure of individual ones and thus the variety of bifurcation types for bursting neurons may create diverse behaviors in similar neuronal ensembles. PMID- 28863503 TI - Evolution of initial discontinuities in the Riemann problem for the Kaup Boussinesq equation with positive dispersion. AB - We consider the space-time evolution of initial discontinuities of depth and flow velocity for an integrable version of the shallow water Boussinesq system introduced by Kaup. We focus on a specific version of this "Kaup-Boussinesq model" for which a flat water surface is modulationally stable, we speak below of "positive dispersion" model. This model also appears as an approximation to the equations governing the dynamics of polarisation waves in two-component Bose Einstein condensates. We describe its periodic solutions and the corresponding Whitham modulation equations. The self-similar, one-phase wave structures are composed of different building blocks, which are studied in detail. This makes it possible to establish a classification of all the possible wave configurations evolving from initial discontinuities. The analytic results are confirmed by numerical simulations. PMID- 28863504 TI - Proliferation of stability in phase and parameter spaces of nonlinear systems. AB - In this work, we show how the composition of maps allows us to multiply, enlarge, and move stable domains in phase and parameter spaces of discrete nonlinear systems. Using Henon maps with distinct parameters, we generate many identical copies of isoperiodic stable structures (ISSs) in the parameter space and attractors in phase space. The equivalence of the identical ISSs is checked by the largest Lyapunov exponent analysis, and the multiplied basins of attraction become riddled. Our proliferation procedure should be applicable to any two dimensional nonlinear system. PMID- 28863505 TI - Semi-rational solutions of the third-type Davey-Stewartson equation. AB - General dark solitons and mixed solutions consisting of dark solitons and breathers for the third-type Davey-Stewartson (DS-III) equation are derived by employing the bilinear method. By introducing the two differential operators, semi-rational solutions consisting of rogue waves, breathers, and solitons are generated. These semi-rational solutions are given in terms of determinants whose matrix elements have simple algebraic expressions. Under suitable parametric conditions, we derive general rogue wave solutions expressed in terms of rational functions. It is shown that the fundamental (simplest) rogue waves are line rogue waves. It is also shown that the multi-rogue waves describe interactions of several fundamental rogue waves, which would generate interesting curvy wave patterns. The higher order rogue waves originate from a localized lump and retreat back to it. Several types of hybrid solutions composed of rogue waves, breathers, and solitons have also been illustrated. Specifically, these semi rational solutions have a new phenomenon: lumps form on dark solitons and gradual separation from the dark solitons is observed. PMID- 28863506 TI - Free energy models for ice VII and liquid water derived from pressure, entropy, and heat capacity relations. AB - We present equations of state relevant to conditions encountered in ramp and multiple-shock compression experiments of water. These experiments compress water from ambient conditions to pressures as high as about 14 GPa and temperatures of up to several hundreds of Kelvin. Water may freeze into ice VII during this process. Although there are several studies on the thermodynamic properties of ice VII, an accurate and analytic free energy model from which all other properties may be derived in a thermodynamically consistent manner has not been previously determined. We have developed such a free energy model for ice VII that is calibrated with pressure-volume-temperature measurements and melt curve data. Furthermore, we show that liquid water in the pressure and temperature range of interest is well-represented by a simple Mie-Gruneisen equation of state. Our liquid water and ice VII equations of state are validated by comparing to sound speed and Hugoniot data. Although they are targeted towards ramp and multiple-shock compression experiments, we demonstrate that our equations of state also behave reasonably well at pressures and temperatures that lie somewhat beyond those found in the experiments. PMID- 28863507 TI - The dynamics of nucleation and growth of a particle in the ternary alloy melt with anisotropic surface tension. AB - The dynamics of nucleation and growth of a particle affected by anisotropic surface tension in the ternary alloy melt is studied. The uniformly valid asymptotic solution for temperature field, concentration field, and interface evolution of nucleation and particle growth is obtained by means of the multiple variable expansion method. The asymptotic solution reveals the critical radius of nucleation in the ternary alloy melt and an inward melting mechanism of the particle induced by the anisotropic effect of surface tension. The critical radius of nucleation is dependent on isotropic surface tension, temperature undercooling, and constitutional undercooling in the ternary alloy melt, and the solute diffusion melt decreases the critical radius of nucleation. Immediately after a nucleus forms in the initial stage of solidification, the anisotropic effect of surface tension makes some parts of its interface grow inward while some parts grow outward. Until the inward melting attains a certain distance (which is defined as "the melting depth"), these parts of interface start to grow outward with other parts. The interface of the particle evolves into an ear-like deformation, whose inner diameter may be less than two times the critical radius of nucleation within a short time in the initial stage of solidification. The solute diffusion in the ternary alloy melt decreases the effect of anisotropic surface tension on the interface deformation. PMID- 28863508 TI - Influence of thermalization on thermal conduction through molecular junctions: Computational study of PEG oligomers. AB - Thermalization in molecular junctions and the extent to which it mediates thermal transport through the junction are explored and illustrated with computational modeling of polyethylene glycol (PEG) oligomer junctions. We calculate rates of thermalization in the PEG oligomers from 100 K to 600 K and thermal conduction through PEG oligomer interfaces between gold and other materials, including water, motivated in part by photothermal applications of gold nanoparticles capped by PEG oligomers in aqueous and cellular environments. Variation of thermalization rates over a range of oligomer lengths and temperatures reveals striking effects of thermalization on thermal conduction through the junction. The calculated thermalization rates help clarify the scope of applicability of approaches that can be used to predict thermal conduction, e.g., where Fourier's law breaks down and where a Landauer approach is suitable. The rates and nature of vibrational energy transport computed for PEG oligomers are compared with available experimental results. PMID- 28863510 TI - Depositing nanoparticles on a silicon substrate using a freeze drying technique. AB - For the microscopic observation of nanoparticles, an adequate sample preparation is an essential part of this task. Much research has been performed for usable preparation methods that will yield aggregate-free samples. A freeze drying technique, which only requires a -80 degrees C freezer and a freeze dryer, is shown to provide an on-substrate dispersion of mostly isolated nanoparticles. The particle density could be made sufficiently high for efficient observations using atomic force microscopy. Since this sandwich method is purely physical, it could be applied to deposit various nanoparticles independent of their surface chemical properties. Suspension film thickness, or the dimensionality of the suspension film, was shown to be crucial for the isolation of the particles. Silica nanoparticles were dispersed on a silicon substrate using this method and the sample properties were examined using atomic force microscopy. PMID- 28863509 TI - The nature of three-body interactions in DFT: Exchange and polarization effects. AB - We propose a physically motivated decomposition of density functional theory (DFT) 3-body nonadditive interaction energies into the exchange and density deformation (polarization) components. The exchange component represents the effect of the Pauli exclusion in the wave function of the trimer and is found to be challenging for density functional approximations (DFAs). The remaining density-deformation nonadditivity is less dependent upon the DFAs. Numerical demonstration is carried out for rare gas atom trimers, Ar2-HX (X = F, Cl) complexes, and small hydrogen-bonded and van der Waals molecular systems. None of the tested semilocal, hybrid, and range-separated DFAs properly accounts for the nonadditive exchange in dispersion-bonded trimers. By contrast, for hydrogen bonded systems, range-separated DFAs achieve a qualitative agreement to within 20% of the reference exchange energy. A reliable performance for all systems is obtained only when the monomers interact through the Hartree-Fock potential in the dispersion-free Pauli blockade scheme. Additionally, we identify the nonadditive second-order exchange-dispersion energy as an important but overlooked contribution in force-field-like dispersion corrections. Our results suggest that range-separated functionals do not include this component, although semilocal and global hybrid DFAs appear to imitate it in the short range. PMID- 28863511 TI - Delocalization and stretch-bend mixing of the HOH bend in liquid water. AB - Liquid water's rich sub-picosecond vibrational dynamics arise from the interplay of different high- and low-frequency modes evolving in a strong yet fluctuating hydrogen bond network. Recent studies of the OH stretching excitations of H2O indicate that they are delocalized over several molecules, raising questions about whether the bending vibrations are similarly delocalized. In this paper, we take advantage of an improved 50 fs time-resolution and broadband infrared (IR) spectroscopy to interrogate the 2D IR lineshape and spectral dynamics of the HOH bending vibration of liquid H2O. Indications of strong bend-stretch coupling are observed in early time 2D IR spectra through a broad excited state absorption that extends from 1500 cm-1 to beyond 1900 cm-1, which corresponds to transitions from the bend to the bend overtone and OH stretching band between 3150 and 3550 cm-1. Pump-probe measurements reveal a fast 180 fs vibrational relaxation time, which results in a hot-ground state spectrum that is the same as observed for water IR excitation at any other frequency. The fastest dynamical time scale is 80 fs for the polarization anisotropy decay, providing evidence for the delocalized or excitonic character of the bend. Normal mode analysis conducted on water clusters extracted from molecular dynamics simulations corroborate significant stretch-bend mixing and indicate delocalization of deltaHOH on 2-7 water molecules. PMID- 28863512 TI - Contact angles from Young's equation in molecular dynamics simulations. AB - We propose a method to calculate the equilibrium contact angle of heterogeneous 3 phase solid/fluid/fluid systems using molecular dynamics simulations. The proposed method, which combines the phantom-wall method [F. Leroy and F. Muller Plathe, J. Chem. Phys. 133, 044110 (2010)] and Bennett's acceptance ratio approach [C. H. Bennett, J. Comput. Phys. 22, 245 (1976)], is able to calculate the solid/fluid surface tension relative to the solid surface energy. The calculated relative surface tensions can then be used in Young's equation to estimate the equilibrium contact angle. A fluid droplet is not needed for the proposed method, in contrast to the situation for direct simulations of contact angles. In addition, while prior free-energy based methods for contact angles mainly focused on the wetting of fluids in coexistence with their vapor on solid surfaces, the proposed approach was designed to study the contact angles of fluid mixtures on solid surfaces above the fluid saturation pressures. Using the proposed approach, the contact angles of binary Lennard-Jones fluid mixtures on a non-polar solid substrate were calculated at various interaction parameters and the contact angle of water in equilibrium with CO2 on a hydrophilic polar silica surface was obtained. For both non-polar and polar systems, the calculated contact angles from the proposed method were in agreement with those obtained from the geometry of a cylindrical droplet. The computational cost of the proposed method was found to be comparable to that of simulations that use fluid droplets, but the new method provides a way to calculate the contact angle directly from Young's equation without ambiguity. PMID- 28863513 TI - Pair 2-electron reduced density matrix theory using localized orbitals. AB - Full configuration interaction (FCI) restricted to a pairing space yields size extensive correlation energies but its cost scales exponentially with molecular size. Restricting the variational two-electron reduced-density-matrix (2-RDM) method to represent the same pairing space yields an accurate lower bound to the pair FCI energy at a mean-field-like computational scaling of O(r3) where r is the number of orbitals. In this paper, we show that localized molecular orbitals can be employed to generate an efficient, approximately size-extensive pair 2-RDM method. The use of localized orbitals eliminates the substantial cost of optimizing iteratively the orbitals defining the pairing space without compromising accuracy. In contrast to the localized orbitals, the use of canonical Hartree-Fock molecular orbitals is shown to be both inaccurate and non size-extensive. The pair 2-RDM has the flexibility to describe the spectra of one electron RDM occupation numbers from all quantum states that are invariant to time-reversal symmetry. Applications are made to hydrogen chains and their dissociation, n-acene from naphthalene through octacene, and cadmium telluride 2 , 3-, and 4-unit polymers. For the hydrogen chains, the pair 2-RDM method recovers the majority of the energy obtained from similar calculations that iteratively optimize the orbitals. The localized-orbital pair 2-RDM method with its mean-field-like computational scaling and its ability to describe multi reference correlation has important applications to a range of strongly correlated phenomena in chemistry and physics. PMID- 28863514 TI - An ab initio chemical reaction model for the direct simulation Monte Carlo study of non-equilibrium nitrogen flows. AB - A new ab initio based chemical model for a Direct Simulation Monte Carlo (DSMC) study suitable for simulating rarefied flows with a high degree of non equilibrium is presented. To this end, Collision Induced Dissociation (CID) cross sections for N2+N2->N2+2N are calculated and published using a global complete active space self-consistent field-complete active space second order perturbation theory N4 potential energy surface and quasi-classical trajectory algorithm for high energy collisions (up to 30 eV). CID cross sections are calculated for only a selected set of ro-vibrational combinations of the two nitrogen molecules, and a fitting scheme based on spectroscopic weights is presented to interpolate the CID cross section for all possible ro-vibrational combinations. The new chemical model is validated by calculating equilibrium reaction rate coefficients that can be compared well with existing shock tube and computational results. High-enthalpy hypersonic nitrogen flows around a cylinder in the transition flow regime are simulated using DSMC to compare the predictions of the current ab initio based chemical model with the prevailing phenomenological model (the total collision energy model). The differences in the predictions are discussed. PMID- 28863515 TI - Novel tilt-curvature coupling in lipid membranes. AB - On mesoscopic scales, lipid membranes are well described by continuum theories whose main ingredients are the curvature of a membrane's reference surface and the tilt of its lipid constituents. In particular, Hamm and Kozlov [Eur. Phys. J. E 3, 323 (2000)] have shown how to systematically derive such a tilt-curvature Hamiltonian based on the elementary assumption of a thin fluid elastic sheet experiencing internal lateral pre-stress. Performing a dimensional reduction, they not only derive the basic form of the effective surface Hamiltonian but also express its emergent elastic couplings as trans-membrane moments of lower-level material parameters. In the present paper, we argue, though, that their derivation unfortunately missed a coupling term between curvature and tilt. This term arises because, as one moves along the membrane, the curvature-induced change of transverse distances contributes to the area strain-an effect that was believed to be small but nevertheless ends up contributing at the same (quadratic) order as all other terms in their Hamiltonian. We illustrate the consequences of this amendment by deriving the monolayer and bilayer Euler Lagrange equations for the tilt, as well as the power spectra of shape, tilt, and director fluctuations. A particularly curious aspect of our new term is that its associated coupling constant is the second moment of the lipid monolayer's lateral stress profile-which within this framework is equal to the monolayer Gaussian curvature modulus, kappa-m. On the one hand, this implies that many theoretical predictions now contain a parameter that is poorly known (because the Gauss-Bonnet theorem limits access to the integrated Gaussian curvature); on the other hand, the appearance of kappa-m outside of its Gaussian curvature provenance opens opportunities for measuring it by more conventional means, for instance by monitoring a membrane's undulation spectrum at short scales. PMID- 28863516 TI - Ground state in E ? e Jahn-Teller and Renner-Teller systems: Account of nonadiabaticity. AB - The ground and lower excited states of an E?e Jahn-Teller system with linear and quadratic vibronic coupling are considered, taking nonadiabaticity into account. Our calculations confirm a common opinion that in the case of a weak quadratic coupling, the ground state is doubly degenerate and the first excited state is nondegenerate for any linear coupling. However, with increasing quadratic coupling for weak linear coupling, the nondegenerate state becomes the ground state. The values of vibronic parameters are found at which the ground state changes. PMID- 28863517 TI - Terahertz induced optical birefringence in polar and nonpolar liquids. AB - The terahertz induced optical birefringence in liquids with polar (acetone, chloroform) and nonpolar (benzene, carbon tetrachloride) molecules has been investigated. Fast and slow responses were extracted from the experimental data and compared with previous studies of the femtosecond optical Kerr effect. Terahertz Kerr constants were found and compared with known DC and optical constants. Analysis of the results obtained showed that, in contrast to the optical excitation, the interaction of a permanent dipole moment of molecules with a THz field makes a significant contribution to the transient birefringence and Kerr constants. This conclusion fully agrees with the direct comparison of the femtosecond optical and THz Kerr effects reported by Sajadi et al. [Nat. Commun. 8, 14963 (2017)]. PMID- 28863518 TI - Helical paths, gravitaxis, and separation phenomena for mass-anisotropic self propelling colloids: Experiment versus theory. AB - The self-propulsion mechanism of active colloidal particles often generates not only translational but also rotational motion. For particles with an anisotropic mass density under gravity, the motion is usually influenced by a downwards oriented force and an aligning torque. Here we study the trajectories of self propelled bottom-heavy Janus particles in three spatial dimensions both in experiments and by theory. For a sufficiently large mass anisotropy, the particles typically move along helical trajectories whose axis is oriented either parallel or antiparallel to the direction of gravity (i.e., they show gravitaxis). In contrast, if the mass anisotropy is small and rotational diffusion is dominant, gravitational alignment of the trajectories is not possible. Furthermore, the trajectories depend on the angular self-propulsion velocity of the particles. If this component of the active motion is strong and rotates the direction of translational self-propulsion of the particles, their trajectories have many loops, whereas elongated swimming paths occur if the angular self-propulsion is weak. We show that the observed gravitational alignment mechanism and the dependence of the trajectory shape on the angular self-propulsion can be used to separate active colloidal particles with respect to their mass anisotropy and angular self-propulsion, respectively. PMID- 28863519 TI - Ab initio potential energy surface and microwave spectra for the H2-HCCCN complex. AB - We present a four-dimensional ab initio potential energy surface of the H2-HCCCN complex at the coupled-cluster singles and doubles with noniterative inclusion of connected triples [CCSD(T)]-F12 level with a large basis set including an additional set of bond functions. The artificial neural networks method was extended to fit the intermolecular potential energy surface. The complex has a planar linear global minimum with the well depth of 199.366 cm-1 located at R = 5.09 A, phi = 0 degrees , theta1 = 0 degrees , and theta2 = 180 degrees . An additional planar local minimum is also found with a depth of 175.579 cm-1 that is located at R = 3.37 A, phi = 0 degrees , theta1 = 110 degrees , and theta2 = 104 degrees . The radial discrete variable representation/angular finite basis representation and the Lanczos algorithm were employed to calculate the rovibrational energy levels for four species of H2-HCCCN (pH2-HCCCN, oH2-HCCCN, pD2-HCCCN, and oD2-HCCCN). The rotational frequencies and spectroscopic parameters were also determined for four complexes, which agree well with the experimental values. PMID- 28863520 TI - A quasi-classical study of energy transfer in collisions of hyperthermal H atoms with SO2 molecules. AB - A deep understanding of energy transfer processes in molecular collisions is at central attention in physical chemistry. Particularly vibrational excitation of small molecules colliding with hot light atoms, via a metastable complex formation, has shown to be an efficient manner of enhancing reactivity. A quasi classical trajectory study of translation-to-vibration energy transfer (T-V ET) in collisions of hyperthermal H(2S) atoms with SO2(X1A') molecules is presented here. For such a study, a double many-body expansion potential energy surface previously reported for HSO2(2A) is used. This work was motivated by recent experiments by Ma et al. studying collisions of H + SO2 at the translational energy of 59 kcal/mol [J. Ma et al., Phys. Rev. A 93, 040702 (2016)]. Calculations reproduce the experimental evidence that during majority of inelastic non-reactive collision processes, there is a metastable intermediate formation (HOSO or HSO2). Nevertheless, the analysis of the trajectories shows that there are two distinct mechanisms in the T-V ET process: direct and indirect. Direct T-V processes are responsible for the high population of SO2 with relatively low vibrational excitation energy, while indirect ones dominate the conversion from translational energy to high values of the vibrational counterpart. PMID- 28863521 TI - Quantum dynamics of H2 in a carbon nanotube: Separation of time scales and resonance enhanced tunneling. AB - Quantum confinement effects are known to affect the behavior of molecules adsorbed in nanostructured materials. In order to study these effects on the transport of a single molecule through a nanotube, we present a quantum dynamics study on the diffusion of H2 in a narrow (8,0) carbon nanotube in the low pressure limit. Transmission coefficients for the elementary step of the transport process are calculated using the flux correlation function approach and diffusion rates are obtained using the single hopping model. The different time scales associated with the motion in the confined coordinates and the motion along the nanotube's axis are utilized to develop an efficient and numerically exact approach, in which a diabatic basis describing the fast motion in the confined coordinate is employed. Furthermore, an adiabatic approximation separating the dynamics of confined and unbound coordinates is studied. The results obtained within the adiabatic approximation agree almost perfectly with the numerically exact ones. The approaches allow us to accurately study the system's dynamics on the picosecond time scale and resolve resonance structures present in the transmission coefficients. Resonance enhanced tunneling is found to be the dominant transport mechanism at low energies. Comparison with results obtained using transition state theory shows that tunneling significantly increases the diffusion rate at T < 120 K. PMID- 28863522 TI - Non-equilibrium surface tension of the vapour-liquid interface of active Lennard Jones particles. AB - We study a three-dimensional system of self-propelled Brownian particles interacting via the Lennard-Jones potential. Using Brownian dynamics simulations in an elongated simulation box, we investigate the steady states of vapour-liquid phase coexistence of active Lennard-Jones particles with planar interfaces. We measure the normal and tangential components of the pressure tensor along the direction perpendicular to the interface and verify mechanical equilibrium of the two coexisting phases. In addition, we determine the non-equilibrium interfacial tension by integrating the difference of the normal and tangential components of the pressure tensor and show that the surface tension as a function of strength of particle attractions is well fitted by simple power laws. Finally, we measure the interfacial stiffness using capillary wave theory and the equipartition theorem and find a simple linear relation between surface tension and interfacial stiffness with a proportionality constant characterized by an effective temperature. PMID- 28863523 TI - Vibrational relaxation beyond the linear damping limit in two-dimensional optical spectra of molecular aggregates. AB - We present a computational model for the spectra of molecular aggregates with signatures of vibronic progression. Vibronic dynamics is implemented by coupling the dynamics of Frenkel excitons with underdamped vibrations. Vibrational dynamics includes linear damping resulting in the exponential decay and quadratic damping inducing subexponential or power law relaxation and increasing vibrational decoherence as demonstrated on lineshapes of the absorption spectrum. Simulations of the third-order coherent response account for bath reorganization during excitonic transport, which allows us to study the line-shape evolution of cross peaks of 2D spectra. PMID- 28863524 TI - Nuclear magnetic relaxation by the dipolar EMOR mechanism: Multi-spin systems. AB - In aqueous systems with immobilized macromolecules, including biological tissues, the longitudinal spin relaxation of water protons is primarily induced by exchange-mediated orientational randomization (EMOR) of intra- and intermolecular magnetic dipole-dipole couplings. Starting from the stochastic Liouville equation, we have previously developed a rigorous EMOR relaxation theory for dipole-coupled two-spin and three-spin systems. Here, we extend the stochastic Liouville theory to four-spin systems and use these exact results as a guide for constructing an approximate multi-spin theory, valid for spin systems of arbitrary size. This so-called generalized stochastic Redfield equation (GSRE) theory includes the effects of longitudinal-transverse cross-mode relaxation, which gives rise to an inverted step in the relaxation dispersion profile, and coherent spin mode transfer among solid-like spins, which may be regarded as generalized spin diffusion. The GSRE theory is compared to an existing theory, based on the extended Solomon equations, which does not incorporate these phenomena. Relaxation dispersion profiles are computed from the GSRE theory for systems of up to 16 protons, taken from protein crystal structures. These profiles span the range from the motional narrowing limit, where the coherent mode transfer plays a major role, to the ultra-slow motion limit, where the zero field rate is closely related to the strong-collision limit of the dipolar relaxation rate. Although a quantitative analysis of experimental data is beyond the scope of this work, it is clear from the magnitude of the predicted relaxation rate and the shape of the relaxation dispersion profile that the dipolar EMOR mechanism is the principal cause of water-1H low-field longitudinal relaxation in aqueous systems of immobilized macromolecules, including soft biological tissues. The relaxation theory developed here therefore provides a basis for molecular-level interpretation of endogenous soft-tissue image contrast obtained by the emerging low-field magnetic resonance imaging techniques. PMID- 28863525 TI - Effect of stochastic gating on channel-facilitated transport of non-interacting and strongly repelling solutes. AB - Ligand- or voltage-driven stochastic gating-the structural rearrangements by which the channel switches between its open and closed states-is a fundamental property of biological membrane channels. Gating underlies the channel's ability to respond to different stimuli and, therefore, to be functionally regulated by the changing environment. The accepted understanding of the gating effect on the solute flux through the channel is that the mean flux is the product of the flux through the open channel and the probability of finding the channel in the open state. Here, using a diffusion model of channel-facilitated transport, we show that this is true only when the gating is much slower than the dynamics of solute translocation through the channel. If this condition breaks, the mean flux could differ from this simple estimate by orders of magnitude. PMID- 28863526 TI - Neural network based coupled diabatic potential energy surfaces for reactive scattering. AB - An approach for the construction of vibronically coupled potential energy surfaces describing reactive collisions is proposed. The scheme utilizes neural networks to obtain the elements of the diabatic potential energy matrix. The training of the neural network employs a diabatization by the Ansatz approach and is solely based on adiabatic electronic energies. Furthermore, no system-specific symmetry consideration is required. As the first example, the H2+Cl->H+HCl reaction, which shows a conical intersection in the entrance channel, is studied. The capability of the approach to accurately reproduce the adiabatic reference energies is investigated. The accuracy of the fit is found to crucially depend on the number of data points as well as the size of the neural network. 5000 data points and a neural network with two hidden layers and 40 neurons in each layer result in a fit with a root mean square error below 1 meV for the relevant geometries. The coupled diabatic potential energies are found to vary smoothly with the coordinates, but the conical intersection is erroneously represented as a very weakly avoided crossing. This shortcoming can be avoided if symmetry constraints for the coupling potential are incorporated into the neural network design. PMID- 28863527 TI - Bond dissociation energies of TiSi, ZrSi, HfSi, VSi, NbSi, and TaSi. AB - Predissociation thresholds have been observed in the resonant two-photon ionization spectra of TiSi, ZrSi, HfSi, VSi, NbSi, and TaSi. It is argued that because of the high density of electronic states at the ground separated atom limit in these molecules, the predissociation threshold in each case corresponds to the thermochemical bond dissociation energy. The resulting bond dissociation energies are D0(TiSi) = 2.201(3) eV, D0(ZrSi) = 2.950(3) eV, D0(HfSi) = 2.871(3) eV, D0(VSi) = 2.234(3) eV, D0(NbSi) = 3.080(3) eV, and D0(TaSi) = 2.999(3) eV. The enthalpies of formation were also calculated as Deltaf,0KH degrees (TiSi(g)) = 705(19) kJ mol-1, Deltaf,0KH degrees (ZrSi(g)) = 770(12) kJ mol-1, Deltaf,0KH degrees (HfSi(g)) = 787(10) kJ mol-1, Deltaf,0KH degrees (VSi(g)) = 743(11) kJ mol-1, Deltaf,0KH degrees (NbSi(g)) = 879(11) kJ mol-1, and Deltaf,0KH degrees (TaSi(g)) = 938(8) kJ mol-1. Using thermochemical cycles, ionization energies of IE(TiSi) = 6.49(17) eV and IE(VSi) = 6.61(15) eV and bond dissociation energies of the ZrSi- and NbSi- anions, D0(Zr-Si-) <= 3.149(15) eV, D0(Zr--Si) <= 4.108(20) eV, D0(Nb-Si-) <= 3.525(31) eV, and D0(Nb--Si) <= 4.017(39) eV, have also been obtained. Calculations on the possible low-lying electronic states of each species are also reported. PMID- 28863529 TI - Potential energy and dipole moment surfaces of the triplet states of the O2(X3Sigmag-) - O2(X3Sigmag-,a1Deltag,b1Sigmag+) complex. AB - We compute four-dimensional diabatic potential energy surfaces and transition dipole moment surfaces of O2-O2, relevant for the theoretical description of collision-induced absorption in the forbidden X3Sigmag- -> a1Deltag and X3Sigmag- -> b1Sigmag+ bands at 7883 cm-1 and 13 122 cm-1, respectively. We compute potentials at the multi-reference configuration interaction (MRCI) level and dipole surfaces at the MRCI and complete active space self-consistent field (CASSCF) levels of theory. Potentials and dipole surfaces are transformed to a diabatic basis using a recent multiple-property-based diabatization algorithm. We discuss the angular expansion of these surfaces, derive the symmetry constraints on the expansion coefficients, and present working equations for determining the expansion coefficients by numerical integration over the angles. We also present an interpolation scheme with exponential extrapolation to both short and large separations, which is used for representing the O2-O2 distance dependence of the angular expansion coefficients. For the triplet ground state of the complex, the potential energy surface is in reasonable agreement with previous calculations, whereas global excited state potentials are reported here for the first time. The transition dipole moment surfaces are strongly dependent on the level of theory at which they are calculated, as is also shown here by benchmark calculations at high symmetry geometries. Therefore, ab initio calculations of the collision induced absorption spectra cannot become quantitatively predictive unless more accurate transition dipole surfaces can be computed. This is left as an open question for method development in electronic structure theory. The calculated potential energy and transition dipole moment surfaces are employed in quantum dynamical calculations of collision-induced absorption spectra reported in Paper II [T. Karman et al., J. Chem. Phys. 147, 084307 (2017)]. PMID- 28863528 TI - The dynamics of peptide-water interactions in dialanine: An ultrafast amide I 2D IR and computational spectroscopy study. AB - We present a joint experimental and computational study of the dynamic interactions of dialanine (Ala-Ala) with water, comparing the results of ultrafast 2D IR and infrared transient absorption spectroscopy of its amide I vibration with spectra modeled from molecular dynamics (MD) simulations. The experimental data are analyzed to describe vibrational frequency fluctuations, vibrational energy relaxation, and chemical exchange processes. The origin of these processes in the same underlying fluctuating forces allows a common description in terms of the fluctuations and conformational dynamics of the peptide and associated solvent. By comparing computational spectroscopy from MD simulations with multiple force fields and water models, we describe how the dynamics of water hydrogen bond fluctuations and switching processes act as a source of friction that governs the dephasing and vibrational relaxation, and provide a description of coupled water and peptide motions that give rise to spectroscopic exchange processes. PMID- 28863530 TI - Effects of Cd vacancies and unconventional spin dynamics in the Dirac semimetal Cd3As2. AB - Cd3As2 is a Dirac semimetal that is a 3D analog of graphene. We investigated the local structure and nuclear-spin dynamics in Cd3As2 via 113Cd NMR. The wideline spectrum of the static sample at 295 K is asymmetric and its features are well described by a two-site model with the shielding parameters extracted via Herzfeld-Berger analysis of the magic-angle spinning spectrum. Surprisingly, the 113Cd spin-lattice relaxation time (T1) is extremely long (T1 = 95 s at 295 K), in stark contrast to conductors and the effects of native defects upon semiconductors; but it is similar to that of 13C in graphene (T1 = 110 s). The temperature dependence of 1/T1 revealed a complex bipartite mechanism that included a T2 power-law behavior below 330 K and a thermally activated process above 330 K. In the high-temperature regime, the Arrhenius behavior is consistent with a field-dependent Cd atomic hopping relaxation process. At low temperatures, a T2 behavior consistent with a spin-1/2 Raman-like process provides evidence of a time-dependent spin-rotation magnetic field caused by angular oscillations of internuclear vectors due to lattice vibrations. The observed mechanism does not conform to the conventional two-band model of semimetals, but is instead closer to a mechanism observed in high-Z element ionic solids with large magnetorotation constant [A. J. Vega et al., Phys. Rev. B 74, 214420 (2006)]. PMID- 28863531 TI - Electronic spectrum of the protonated diacetylene cation (H2C4H+). AB - The B1A1<-X1A1 electronic band system of the protonated diacetylene cation (H2C4H+) is measured over the 230-295 nm range by photodissociating H2C4H+ ions stored in a cryogenic ion trap and by photodissociating H2C4H+ tagged with Ar and N2 in a tandem mass spectrometer. The B1A1<-X1A1 band system has an origin at 34 941 cm-1 for H2C4H+, 34 934 cm-1 for H2C4H+-Ar, and 34 920 cm-1 for H2C4H+-N2. The spectra of H2C4H+, H2C4H+-Ar, and H2C4H+-N2 display similar vibronic structure, which is assigned using ab initio calculations to progressions in two symmetric a1 C-C stretch vibrational modes (nu6 and nu4), with band spacings of 860 and 1481 cm-1, respectively. PMID- 28863532 TI - Dissociative recombination of HCl. AB - The dissociative recombination of HCl+, including both the direct and indirect mechanisms, is studied. For the direct process, the relevant electronic states are calculated ab initio by combining electron scattering calculations to obtain resonance positions and autoionization widths with multi-reference configuration interaction calculations of the ion and Rydberg states. The cross section for the direct dissociation along electronic resonant states is computed by solution of the time-dependent Schrodinger equation. For the indirect process, an upper bound value for the cross section is obtained using a vibrational frame transformation of the elements of the scattering matrix at energies just above the ionization threshold. Vibrational excitations of the ionic core from the ground vibrational state, v = 0, to the first three excited vibrational states, v = 1, v = 2, and v = 3, are considered. Autoionization is neglected and the effect of the spin-orbit splitting of the ionic potential energy upon the indirect dissociative recombination cross section is considered. The calculated cross sections are compared to measurements. PMID- 28863534 TI - SERS active self-assembled diphenylalanine micro/nanostructures: A combined experimental and theoretical investigation. AB - Enhancing Raman signatures of molecules by self-assembled metal nanoparticles, nanolithography patterning, or by designing plasmonic nanostructures is widely used for detection of low abundance biological systems. Self-assembled peptide nanostructures provide a natural template for tethering Au and Ag nanoparticles due to its fractal surface. Here, we show the use of L,L-diphenylalanine micro nanostructures (FF-MNSs) for the organization of Ag and Au nanoparticles (Nps) and its potential as surface-enhanced Raman scattering (SERS)-active substrates. The FF-MNSs undergo an irreversible phase transition from hexagonally packed (hex) micro-nanotubes to an orthorhombic (ort) structure at ~150 degrees C. The metal Nps form chains on hex FF-MNSs as inferred from transmission electron microscopy images and a uniform non-aggregated distribution in the ort phase. The high luminescence from the ort FF-MNS phase precludes SERS measurements with AgNps. The calculated Raman spectra using density-functional theory shows a higher intensity from rhodamine 6G (R6G) molecule in the presence of an Ag atom bound to ort FF compared with hex FF. The SERS spectra obtained from R6G bound to FF-MNSs with AuNps clearly show a higher enhancement for the ort phase compared with hex FF, corroborating our theoretical calculations. Our results indicate that FF-MNSs both in the hex and ort phases can be used as substrates for the SERS analysis with different metal nanoparticles, opening up a novel class of optically active bio-based substrates. PMID- 28863533 TI - Primary alpha and secondary beta relaxation dynamics of meta-toluidine in the liquid state investigated by broadband dielectric spectroscopy. AB - We report a broadband dielectric spectroscopic (BDS) study on the clustering fragile glass-former meta-toluidine (m-TOL) from 187 K up to 289 K over a wide frequency range of 10-3-109 Hz with focus on the primary alpha relaxation and the secondary beta relaxation above the glass temperature Tg. The broadband dielectric spectra were fitted by using the Havriliak-Negami (HN) and Cole-Cole (CC) models. The beta process disappearing at Tbeta,disap = 1.12Tg exhibits non Arrhenius dependence fitted by the Vogel-Fulcher-Tamman-Hesse equation with T0betaVFTH in accord with the characteristic differential scanning calorimetry (DSC) limiting temperature of the glassy state. The essential feature of the alpha process consists in the distinct changes of its spectral shape parameter betaHN marked by the characteristic BDS temperatures TB1betaHN and TB2betaHN. The primary alpha relaxation times were fitted over the entire temperature and frequency range by several current three-parameter up to six-parameter dynamic models. This analysis reveals that the crossover temperatures of the idealized mode coupling theory model (TcMCT), the extended free volume model (T0EFV), and the two-order parameter (TOP) model (Tmc) are close to TB1betaHN, which provides a consistent physical rationalization for the first change of the shape parameter. In addition, the other two characteristic TOP temperatures T0TOP and TA are coinciding with the thermodynamic Kauzmann temperature TK and the second change of the shape parameter at around TB2betaHN, respectively. These can be related to the onset of the liquid-like domains in the glassy state or the disappearance of the solid-like domains in the normal liquid state. PMID- 28863535 TI - Dilution effects on combined magnetic and electric dipole interactions: A study of ferromagnetic cobalt nanoparticles with tuneable interactions. AB - Improved understanding of complex interactions between nanoparticles will facilitate the control over the ensuing self-assembled structures. In this work, we consider the dynamic changes occurring upon dilution in the self-assembly of a system of ferromagnetic cobalt nanoparticles that combine magnetic, electric, and steric interactions. The systems examined here vary in the strength of the magnetic dipole interactions and the amount of point charges per particle. Scattering techniques are employed for the characterization of the self-assembly aggregates, and zeta-potential measurements are employed for the estimation of surface charges. Our experiments show that for particles with relatively small initial number of surface electric dipoles, an increase in particle concentration results in an increase in diffusion coefficients; whereas for particles with relatively high number of surface dipoles, no effect is observed upon concentration changes. We attribute these changes to a shift in the adsorption/desorption equilibrium of the tri-n-octylphosphine oxide (TOPO) molecules on the particle surface. We put forward an explanation, based on the combination of two theoretical models. One predicts that the growing concentration of electric dipoles, stemming from the addition of tri-n octylphosphine oxide (TOPO) as co-surfactant during particle synthesis, on the surface of the particles results in the overall repulsive interaction. Secondly, using density functional theory, we explain that the observed behaviour of the diffusion coefficient can be treated as a result of the concentration dependent nanoparticle self-assembly: additional repulsion leads to the reduction in self assembled aggregate size despite the shorter average interparticle distances, and as such provides the growth of the diffusion coefficient. PMID- 28863536 TI - Frequency-domain coherent multidimensional spectroscopy when dephasing rivals pulsewidth: Disentangling material and instrument response. AB - Ultrafast spectroscopy is often collected in the mixed frequency/time domain, where pulse durations are similar to system dephasing times. In these experiments, expectations derived from the familiar driven and impulsive limits are not valid. This work simulates the mixed-domain four-wave mixing response of a model system to develop expectations for this more complex field-matter interaction. We explore frequency and delay axes. We show that these line shapes are exquisitely sensitive to excitation pulse widths and delays. Near pulse overlap, the excitation pulses induce correlations that resemble signatures of dynamic inhomogeneity. We describe these line shapes using an intuitive picture that connects to familiar field-matter expressions. We develop strategies for distinguishing pulse-induced correlations from true system inhomogeneity. These simulations provide a foundation for interpretation of ultrafast experiments in the mixed domain. PMID- 28863537 TI - The isobaric heat capacity of liquid water at low temperatures and high pressures. AB - Isobaric heat capacity for water shows a rather strong anomalous behavior, especially at low temperature. However, almost all experimental studies supporting this statement have been carried out at low pressure; very few experimental data were reported above 100 MPa. In order to explore the behavior of this magnitude for water up to 500 MPa, a new heat flux calorimeter was developed. With the aim of testing the experimental methodology and comparing with water results, isobaric heat capacity was also measured for methanol and hexane. Good agreement with indirect heat capacity estimations from the literature was obtained for the three liquids. Experimental results show large anomalies in water heat capacity. This is especially true as regards its temperature dependence, qualitatively different from that observed for other liquids. Heat capacity versus temperature curves show minima for most studied isobars, whose location decreases with the pressure up to around 100 MPa but increases at higher pressures. PMID- 28863538 TI - Correlation consistent basis sets for actinides. II. The atoms Ac and Np-Lr. AB - New correlation consistent basis sets optimized using the all-electron third order Douglas-Kroll-Hess (DKH3) scalar relativistic Hamiltonian are reported for the actinide elements Ac and Np through Lr. These complete the series of sets reported previously for Th-U [K. A. Peterson, J. Chem. Phys. 142, 074105 (2015); M. Vasiliu et al., J. Phys. Chem. A 119, 11422 (2015)]. The new sets range in size from double- to quadruple-zeta and encompass both those optimized for valence (6s6p5f7s6d) and outer-core electron correlations (valence + 5s5p5d). The final sets have been contracted for both the DKH3 and eXact 2-component (X2C) Hamiltonians, yielding cc-pVnZ-DK3/cc-pVnZ-X2C sets for valence correlation and cc-pwCVnZ-DK3/cc-pwCVnZ-X2C sets for outer-core correlation (n = D, T, Q in each case). In order to test the effectiveness of the new basis sets, both atomic and molecular benchmark calculations have been carried out. In the first case, the first three atomic ionization potentials (IPs) of all the actinide elements Ac-Lr have been calculated using the Feller-Peterson-Dixon (FPD) composite approach, primarily with the multireference configuration interaction (MRCI) method. Excellent convergence towards the respective complete basis set (CBS) limits is achieved with the new sets, leading to good agreement with experiment, where these exist, after accurately accounting for spin-orbit effects using the 4 component Dirac-Hartree-Fock method. For a molecular test, the IP and atomization energy (AE) of PuO2 have been calculated also using the FPD method but using a coupled cluster approach with spin-orbit coupling accounted for using the 4 component MRCI. The present calculations yield an IP0 for PuO2 of 159.8 kcal/mol, which is in excellent agreement with the experimental electron transfer bracketing value of 162 +/- 3 kcal/mol. Likewise, the calculated 0 K AE of 305.6 kcal/mol is in very good agreement with the currently accepted experimental value of 303.1 +/- 5 kcal/mol. The ground state of PuO2 is predicted to be the Sigma0g+5 state. PMID- 28863539 TI - Study of the upper-critical dimension of the East model through the breakdown of the Stokes-Einstein relation. AB - We investigate the dimensional dependence of dynamical fluctuations related to dynamic heterogeneity in supercooled liquid systems using kinetically constrained models. The d-dimensional spin-facilitated East model with embedded probe particles is used as a representative super-Arrhenius glass forming system. We examine the existence of an upper critical dimension in this model by considering decoupling of transport rates through an effective fractional Stokes-Einstein relation, D~tau-1+omega, with D and tau the diffusion constant of the probe particle and the relaxation time of the model liquid, respectively, and where omega>0 encodes the breakdown of the standard Stokes-Einstein relation. To the extent that decoupling indicates non-mean-field behavior, our simulations suggest that the East model has an upper critical dimension at least above d = 10 and argue that it may actually be infinite. This result is due to the existence of hierarchical dynamics in the East model in any finite dimension. We discuss the relevance of these results for studies of decoupling in high dimensional atomistic models. PMID- 28863540 TI - Theoretical investigation of intersystem crossing in the cyanonitrene molecule, 1NCN -> 3NCN. AB - The NCN diradical is an important intermediate of prompt nitric oxide formation in flames. The mechanism of intersystem crossing (ISC) in the NCN molecule formed via pyrolysis or photolysis of NCN3 is of relevance to the interpretation of experiments that utilize NCN3 as a precursor for laboratory studies of NCN kinetics. This mechanism has been investigated by means of multi-reference configuration interaction calculations. From the potential energy surfaces for NCN3 dissociation, it was inferred that both thermal and photo-chemical decomposition initially lead to NCN in its lowest singlet state, a1Deltag, with a possible contribution from the b1Sigmag+ state at low photolysis wavelengths. Direct formation of the triplet ground state X 3Sigmag- is also feasible for the photolytic pathway. An analysis of surface crossings between a or b and the triplet ground state X 3Sigmag- in the absence and presence of a helium atom revealed an ISC channel NCN1(a)->3NCN(X) via a strongly bent structure. However, its barrier of 38 kcal mol-1 relative to the singlet minimum turned out to be much too high to explain the fast ISC observed in experiments. A rigid-bender model including Renner-Teller interactions was used to examine the occurrence of mixed-multiplicity rovibrational states-so-called gateway states-that could enhance collision-induced ISC. The results of this study indicate that a gateway mechanism is probably not operative in the case of the a/X pair of states in NCN. PMID- 28863541 TI - A test for the existence of isomorphs in glass-forming materials. AB - We describe a method to determine whether a material has isomorphs in its thermodynamic phase diagram. Isomorphs are state points for which various properties are invariant in reduced units. Such materials are commonly identified from strong correlation between thermal fluctuations of the potential energy, U, and the virial W, but this identification is not generally applicable to real materials. We show from molecular dynamic simulations of atomic, molecular, and polymeric materials that systems with strong U-W correlation cannot be pressure densified, that is, the density obtained on cooling to the glassy state and releasing the pressure is independent of the pressure applied during cooling. PMID- 28863542 TI - Transport gap renormalization at a metal-molecule interface using DFT-NEGF and spin unrestricted calculations. AB - A method is presented for predicting one-particle energies for a molecule in a junction with one metal electrode, using density functional theory methods. In contrast to previous studies, in which restricted spin configurations were analyzed, we take spin polarization into account. Furthermore, in addition to junctions in which the molecule is weakly coupled, our method is also capable of describing junctions in which the molecule is chemisorbed to the metal contact. We implemented a fully self-consistent scissor operator to correct the highest occupied molecular orbital-lowest unoccupied molecular orbital gap in transport calculations for single molecule junctions. We present results for various systems and compare our results with those obtained by other groups. PMID- 28863543 TI - Line-shape theory of the X3Sigmag-->a1Deltag,b1Sigmag+ transitions in O2-O2 collision-induced absorption. AB - We derive the theory of collision-induced absorption for electronic transitions in the approximation of an isotropic interaction potential. We apply this theory to the spin-forbidden X3Sigmag-->a1Deltag and X3Sigmag-->b1Sigmag+ transitions in O2-O2, which are relevant for calibration in atmospheric studies. We consider two mechanisms for breaking the spin symmetry, either by the intermolecular exchange interaction between paramagnetic collision partners or by the intramolecular spin orbit coupling. The calculations for the exchange-based mechanism employ the diabatic potential energy surfaces and transition dipole moment surfaces reported in Paper I [T. Karman et al., J. Chem. Phys. 147, 084306 (2017)]. We show that the line shape of the theoretical absorption spectra is insensitive to the large uncertainty in the electronic transition dipole moment surfaces. We also perform calculations using a simple model of the alternative mechanism involving intramolecular spin-orbit coupling, which leads to absorption intensities which are well below the experimental results. The relative intensity of this spin orbit-based mechanism may impact the relative contribution to the absorption by collisions with diamagnetic collision partners, such as the atmospherically relevant N2 molecule. We furthermore show that both the line shape and temperature dependence are signatures of the underlying transition mechanism. PMID- 28863544 TI - Molecular dynamics study of the potential of mean force of SDS aggregates. AB - In our previous study, all-atomistic molecular dynamics (MD) calculations have been carried out for the aggregation of ionic sodium dodecyl sulfate in water [S. Kawada et al., Chem. Phys. Lett. 646, 36 (2016)]. Aggregates of 20-30 dodecyl sulfate ions were formed within a short MD run for 10 ns. However, further aggregation did not occur despite a long MD calculation for more than 100 ns. This suggests that strong electrostatic repulsive interactions between the aggregates prevent the fusion of the aggregates. In the present study, mean force and potential of mean force acting between two aggregates with aggregation number N = 30 were evaluated as a function of their separation by MD calculations. The repulsive force becomes strong with decreasing distance between the two aggregates before they merge into one. An origin of the repulsive force is an electric double layer formed by the sulfate group and counter sodium ions. Strength of the repulsive force is in good agreement with the theoretical value given by the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. Once the aggregates establish contact, the force between them turns to be a large attractive force that can be explained by the interfacial tension. In order to form a single micelle from the two aggregates, it is necessary for them to climb over a free energy barrier of 23 kJ/mol. Once, the barrier is overcome, the micelle is stabilized by ~200 kJ/mol. The time constant of aggregation evaluated from the calculated free energy barrier was about 28 MUs at the concentration in our previous study. PMID- 28863545 TI - Photodissociation dynamics of the ortho- and para-xylyl radicals. AB - The photodissociation dynamics of the C8H9 isomers ortho- and para-xylyl are investigated in a free jet. The xylyl radicals are generated by flash pyrolysis from 2-(2-methylphenyl)- and 2-(4-methylphenyl) ethyl nitrite and are excited into the D3 state. REMPI- spectra show vibronic structure and the origin of the transition is identified at 32 291 cm-1 for the para- and at 32 132 cm-1 for the ortho-isomer. Photofragment H-atom action spectra show bands at the same energy and thus confirm H-atom loss from xylyl radicals. To gain further insight into the photodissociation dynamics, velocity map images of the hydrogen atom photofragments are recorded. Their angular distribution is isotropic and the translational energy release is in agreement with a dissociation to products in their electronic ground state. Photodissociation of para-xylyl leads to the formation of para-xylylene (C8H8), while the data for ortho-xylyl agree much better with the isomer benzocyclobutene as the dominant molecular fragment rather than ortho-xylylene. In computations we identified a new pathway for the reaction ortho-xylyl -> benzocyclobutene + H with a barrier of 3.39 eV (27 340 cm-1), which becomes accessible at the employed excitation energy. It proceeds via a combination of scissoring and rotational motion of the -CH2 and -CH3 groups. However, the observed rate constants measured by delaying the excitation and ionization laser with respect to each other are significantly faster than computed ones, indicating intrinsic non-RRKM behaviour. A comparably high value of around 30% of the excess energy is released as translation of the H-atom photofragment. PMID- 28863546 TI - Terahertz absorption of lysozyme in solution. AB - Absorption of radiation by solution is described by its frequency-dependent dielectric function and can be viewed as a specific application of the dielectric theory of solutions. For ideal solutions, the dielectric boundary-value problem separates the polar response into the polarization of the void in the liquid, created by the solute, and the response of the solute dipole. In the case of a protein as a solute, protein nuclear dynamics do not project on significant fluctuations of the dipole moment in the terahertz domain of frequencies and the protein dipole can be viewed as dynamically frozen. Absorption of radiation then reflects the interfacial polarization. Here we apply an analytical theory and computer simulations to absorption of radiation by an ideal solution of lysozyme. Comparison with the experiment shows that Maxwell electrostatics fails to describe the polarization of the protein-water interface and the "Lorentz void," which does not anticipate polarization of the interface by the external field (no surface charges), better represents the data. An analytical theory for the slope of the solution absorption against the volume fraction of the solute is formulated in terms of the cavity field response function. It is calculated from molecular dynamics simulations in good agreement with the experiment. The protein hydration shell emerges as a separate sub-ensemble, which, collectively, is not described by the standard electrostatics of dielectrics. PMID- 28863547 TI - An Ising model for metal-organic frameworks. AB - We present a three-dimensional Ising model where lines of equal spins are frozen such that they form an ordered framework structure. The frame spins impose an external field on the rest of the spins (active spins). We demonstrate that this "porous Ising model" can be seen as a minimal model for condensation transitions of gas molecules in metal-organic frameworks. Using Monte Carlo simulation techniques, we compare the phase behavior of a porous Ising model with that of a particle-based model for the condensation of methane (CH4) in the isoreticular metal-organic framework IRMOF-16. For both models, we find a line of first-order phase transitions that end in a critical point. We show that the critical behavior in both cases belongs to the 3D Ising universality class, in contrast to other phase transitions in confinement such as capillary condensation. PMID- 28863548 TI - Atomistic simulations of cation hydration in sodium and calcium montmorillonite nanopores. AB - During the last four decades, numerous studies have been directed to the swelling smectite-rich clays in the context of high-level radioactive waste applications and waste-liners for contaminated sites. The swelling properties of clay mineral particles arise due to hydration of the interlayer cations and the diffuse double layers formed near the negatively charged montmorillonite (MMT) surfaces. To accurately study the cation hydration in the interlayer nanopores of MMT, solvent solute and solvent-clay surface interactions (i.e., the solvation effects and the shape effects) on the atomic level should be taken into account, in contrast to many recent electric double layer based methodologies using continuum models. Therefore, in this research we employed fully atomistic simulations using classical molecular dynamics (MD) simulations, the software package GROMACS along with the CLAYFF forcefield and the SPC/E water model. We present the ion distributions and the deformation of the hydrated coordination structures, i.e., the hydration shells of Na+ and Ca2+ in the interlayer, respectively, for MMT in the first-layer, the second-layer, the third-layer, the fourth-layer, and the fifth-layer (1W, 2W, 3W, 4W, and 5W) hydrate states. Our MD simulations show that Na+ in Na-MMT nanopores have an affinity to the ditrigonal cavities of the clay layers and form transient inner-sphere complexes at about 3.8 A from clay midplane at water contents less than the 5W hydration state. However, these phenomena are not observed in Ca-MMT regardless of swelling states. For Na-MMT, each Na+ is coordinated to four water molecules and one oxygen atom of the clay basal-plane in the first hydration shell at the 1W hydration state, and with five to six water molecules in the first hydration shell within a radius of 3.1 A at all higher water contents. In Ca-MMT, however each Ca2+ is coordinated to approximately seven water molecules in the first hydration shell at the 1W hydration state and about eight water molecules in the first hydration shell within a radius of 3.3 A at all higher hydration states. Moreover, the MD results show that the complete hydration shells are nearly spherical with an orthogonal coordination sphere. They could only be formed when the basal spacing d001 >= 18.7 A, i.e., approximately, the interlayer separation h >= 10 A. Comparison between DFT and MD simulations shows that DFT failed to reproduce the outer sphere complexes in the Stern-layer (within ~5.0 A from the clay basal-plane), observed in the MD simulations. PMID- 28863549 TI - Lubricant shear thinning behavior correlated with variation of radius of gyration via molecular dynamics simulations. AB - The shear thinning of a lubricant significantly affects lubrication film generation at high shear rates. The critical shear rate, defined at the onset of shear thinning, marks the transition of lubricant behaviors. It is challenging to capture the entire shear-thinning curve by means of molecular dynamics (MD) simulations owing to the low signal-to-noise ratio or long calculation time at comparatively low shear rates (104-106 s-1), which is likely coincident with the shear rates of interest for lubrication applications. This paper proposes an approach that correlates the shear-thinning phenomenon with the change in the molecular conformation characterized by the radius of gyration of the molecule. Such a correlation should be feasible to capture the major mechanism of shear thinning for small- to moderate-sized non-spherical molecules, which is shear induced molecular alignment. The idea is demonstrated by analyzing the critical shear rate for squalane (C30H62) and 1-decene trimer (C30H62); it is then implemented to study the behaviors of different molecular weight poly-alpha olefin (PAO) structures. Time-temperature-pressure superpositioning (TTPS) is demonstrated and it helps further extend the ranges of the temperature and pressure for shear-thinning behavior analyses. The research leads to a relationship between molecular weight and critical shear rate for PAO structures, and the results are compared with those from the Einstein-Debye equation. PMID- 28863550 TI - Categorizing click trains to increase taxonomic precision in echolocation click loggers. AB - Passive acoustic monitoring is an efficient way to study acoustically active animals but species identification remains a major challenge. C-PODs are popular logging devices that automatically detect odontocete echolocation clicks. However, the accompanying analysis software does not distinguish between delphinid species. Click train features logged by C-PODs were compared to frequency spectra from adjacently deployed continuous recorders. A generalized additive model was then used to categorize C-POD click trains into three groups: broadband click trains, produced by bottlenose dolphin (Tursiops truncatus) or common dolphin (Delphinus delphis), frequency-banded click trains, produced by Risso's (Grampus griseus) or white beaked dolphins (Lagenorhynchus albirostris), and unknown click trains. Incorrect categorization rates for broadband and frequency banded clicks were 0.02 (SD 0.01), but only 30% of the click trains met the categorization threshold. To increase the proportion of categorized click trains, model predictions were pooled within acoustic encounters and a likelihood ratio threshold was used to categorize encounters. This increased the proportion of the click trains meeting either the broadband or frequency banded categorization threshold to 98%. Predicted species distribution at the 30 study sites matched well to visual sighting records from the region. PMID- 28863551 TI - Rippling pattern of distortion product otoacoustic emissions evoked by high frequency primaries in guinea pigs. AB - The origin of ripples in distortion product otoacoustic emission (DPOAE) amplitude which appear at specific DPOAE frequencies during f1 tone sweeps using fixed high frequency f2 (>20 kHz) in guinea pigs is investigated. The peaks of the ripples, or local DPOAE amplitude maxima, are separated by approximately half octave intervals and are accompanied by phase oscillations. The local maxima appear at the same frequencies in DPOAEs of different order and velocity responses of the stapes and do not shift with increasing levels of the primaries. A suppressor tone had little effect on the frequencies of the maxima, but partially suppressed DPOAE amplitude when it was placed close to the f2 frequencies. These findings agree with earlier observations that the maxima occur at the same DPOAE frequencies, which are independent of the f2 and the primary ratio, and thus are likely to be associated with DPOAE propagation mechanisms. Furthermore, the separation of the local maxima by approximately half an octave may suggest that the maxima are due to interference of the travelling waves along the basilar membrane at the frequency of the DPOAE. It is suggested that the rippling pattern appears because of interaction between DPOAE reverse travelling waves with standing waves formed in the cochlea. PMID- 28863552 TI - Input matters: Multi-accent language exposure affects word form recognition in infancy. AB - Early language input is far from uniform, even among children learning the same language. For instance, while some children are exposed to a single accent in their linguistic environment, others have routine exposure to multiple accents. Nonetheless, few studies have taken this into account when examining word recognition, and none has examined this issue in infants prior to the emergence of phonological constancy (~18 months). This study demonstrates that daily exposure to multiple accents strongly impacts infants' performance in a laboratory word form recognition task. Accent variability in the input thus needs to be carefully considered when studying speech development. PMID- 28863553 TI - Removal of incoherent noise from an averaged cross-spectral matrix. AB - Measured cross-spectral matrices (CSMs) from a microphone array will in some cases be contaminated by severe incoherent noise signals in the individual channels. A typical example is flow noise generated in the individual microphones when measuring in a wind tunnel. Assuming stationary signals and performing long time averaging, the contamination will be concentrated on the CSM diagonal. When the CSM is used for traditional frequency-domain beamforming, diagonal removal (DR) will avoid use of the diagonal. DR is effective at suppressing the contamination effects, but it also has some side effects. With other beamforming algorithms and in connection with acoustic holography, however, the diagonal of the CSM is needed. The present paper describes a method for removal of incoherent noise contamination from the CSM diagonal. The method formulates the problem as a semidefinite program, which is a convex optimization problem that can be solved very efficiently and with guaranteed convergence properties. A first numerical study investigates the question, whether the semidefinite program formulation will provide in all cases the desired output. A second numerical study investigates the limitations introduced by off-diagonal noise contributions due to finite averaging time. The results of that study are backed up by results from a practical measurement. PMID- 28863554 TI - Complementary empirical data on minimum bow force. AB - The minimum bow force Fmin necessary to maintain Helmholtz motion on stringed instruments was widely believed to be proportional to the bow velocity vB, to the reciprocal of the bridge resistance R, and to the reciprocal of the relative bow bridge distance beta squared [Schelleng, J. Acoust. Soc. Am. 53, 26-41 (1973)]. More recently, a study reported independence from vB and an overproportional reciprocal effect of R while confirming the 1/beta2 proportionality [Schoonderwaldt, Acta Acust. Acust. 94, 604-622 (2008)]. Here, a bowing pendulum is used which facilitates precise control and measurement of related parameters. The string excitation at the contact point is recorded to instantly classify Helmholtz motion (HM) versus non-Helmholtz motion with one (nHM-1) or more additional slips during the stick phase. Monitoring of the classification supports the control of bowing parameters during measurement. These are directed towards the regions of transition between HM and nHM-1 to reveal the parameters related to Fmin. The empirical data gained from cello strings suggest that HM requires a baseline force Fmin,0 even for very low vB. Fmin,0 depends on R and beta. PMID- 28863556 TI - Transverse-to-transverse diffuse ultrasonic scattering. AB - Ultrasonic scattering occurs when elastic waves interact with interfaces within heterogeneous media. Diffuse ultrasonic backscatter measurements are used to capture the effective grain scattering within a polycrystal for extracting microstructural information. Recently, a mode-conversion scattering model was developed to describe the longitudinal-to-transverse ultrasonic scattering within polycrystalline materials and successfully applied to determine the material spatial correlation length L by fitting experimental results with the theoretical model. The mode-conversion model may allow additional microstructural information, such as grain shape, to be assessed. In this article, a theoretical extension of the previous mode-conversion ultrasonic scattering model is presented. The transverse-to-transverse (T-T) scattering can be measured by an experimental configuration with both source and receiving transducers oriented at angles between the first and second critical angles, including pitch-catch and pulse-echo measurements. The model is used to determine the correlation length from a sample of 1040 steel through pulse-echo T-T scattering measurements using 7.5 and 10 MHz transducers. The results show that the derived T-T model works well for lower frequencies but the results for higher frequencies reveal deficiencies in the model. PMID- 28863555 TI - Binaural pitch fusion: Pitch averaging and dominance in hearing-impaired listeners with broad fusion. AB - Both bimodal cochlear implant and bilateral hearing aid users can exhibit broad binaural pitch fusion, the fusion of dichotically presented tones over a broad range of pitch differences between ears [Reiss, Ito, Eggleston, and Wozny. (2014). J. Assoc. Res. Otolaryngol. 15(2), 235-248; Reiss, Eggleston, Walker, and Oh. (2016). J. Assoc. Res. Otolaryngol. 17(4), 341-356; Reiss, Shayman, Walker, Bennett, Fowler, Hartling, Glickman, Lasarev, and Oh. (2017). J. Acoust. Soc. Am. 143(3), 1909-1920]. Further, the fused binaural pitch is often a weighted average of the different pitches perceived in the two ears. The current study was designed to systematically measure these pitch averaging phenomena in bilateral hearing aid users with broad fusion. The fused binaural pitch of the reference pair tone combination was initially measured by pitch-matching to monaural comparison tones presented to the pair tone ear. The averaged results for all subjects showed two distinct trends: (1) The fused binaural pitch was dominated by the lower-pitch component when the pair tone was either 0.14 octaves below or 0.78 octaves above the reference tone; (2) pitch averaging occurred when the pair tone was between the two boundaries above, with the most equal weighting at 0.38 octaves above the reference tone. Findings from two subjects suggest that randomization or alternation of the comparison ear can eliminate this asymmetry in the pitch averaging range. Overall, these pitch averaging phenomena suggest that spectral distortions and thus binaural interference may arise during binaural stimulation in hearing-impaired listeners with broad fusion. PMID- 28863557 TI - Identification of perceptually relevant methods of inter-aural time difference estimation. AB - The inter-aural time difference (ITD) is a fundamental cue for human sound localization. Over the past decades several methods have been proposed for its estimation from measured head-related impulse response (HRIR) data. Nevertheless, inter-method variations in ITD calculation have been found to exceed the known just noticeable differences (JNDs), leading to possible perceptible artifacts in virtual binaural auditory scenes, when personalized HRIRs are being used. In the absence of an objective means for validating ITD estimations, this paper examines which methods lead to the most perceptually relevant results. A subjective lateralization study compared objective ITDs to perceptually evaluated inter aural pure delay offsets. Results clearly indicate the first-onset threshold detection method, using a low relative threshold of -30 dB, applied on 3 kHz low pass filtered HRIRs as consistently the most perceptually relevant procedure across various metrics. Several alternative threshold values and methods based on the maximum or centroid of the inter-aural cross correlation of similarly filtered HRIR or HRIR envelopes also provided reasonable results. On the contrary, phase-based methods employing the integrated relative group delay or auditory model were not found to perform as well. PMID- 28863558 TI - Head movement immune active noise control with head mounted moving microphones. AB - The active headrest is an important application of active noise control (ANC) where the occupant gets a quiet zone during use. However, its performance degrades due to head movement, which is an important issue. Unlike conventional active headrest algorithm, in the present paper, the two error microphones are attached to a head attachment such as a hat or band so that both error microphones can move along with the head, keeping the relative distance of ears and the microphones intact. The two secondary loudspeakers are kept near to the head, facing the ears. The performance of the active headrest was studied through real-time experimentation considering head movement. The innovation in this paper is that the ANC algorithm uses signals of moving error microphones to tune the controller without re-estimating the secondary path transfer functions. Since, the phase error of secondary path estimates at different head positions remains within +/-90 degrees , the secondary paths estimated once, when the head is positioned at the center, can be used for other head positions. This is established through real-time experiments using dSpace 1104 ACE system (dSpace, Germany). PMID- 28863559 TI - Modeling off-frequency binaural masking for short- and long-duration signals. AB - Experimental binaural masking-pattern data are presented together with model simulations for 12- and 600-ms signals. The masker was a diotic 11-Hz wide noise centered on 500 Hz. The tonal signal was presented either diotically or dichotically (180 degrees interaural phase difference) with frequencies ranging from 400 to 600 Hz. The results and the modeling agree with previous data and hypotheses; simulations with a binaural model sensitive to monaural modulation cues show that the effect of duration on off-frequency binaural masking-level differences is mainly a result of modulation cues which are only available in the monaural detection of long signals. PMID- 28863561 TI - Analytical model of mechanically excited piezoelectric unimorph beams. AB - A model is presented of a composite beam with one elastic and one piezoelectric layer. A reduced set of piezoelectric equations of state that has only the longitudinal components of stress and strain and the transverse components of electric field and charge density is consistently used to include the effect of piezoelectric coupling in all the equations. The equi-potential boundary conditions on the electrodes, the open-circuit condition, and the Gauss condition are satisfied. The position of the neutral axis and the dynamic equilibrium equation are derived after including the effect of piezoelectric coupling. All equations are combined to derive an equation of motion that contains only the displacement and the mechanical excitation. The solution to the equation is expressed in terms of a complete set of functions and an auxiliary function that contains the electric potential. The latter is needed to satisfy piezoelectric boundary conditions at the ends of the beam. The electric potential varies along the length of the beam and has a quadratic variation between the electrodes. Analytical expressions for displacement and potential, and numerical results at low frequencies and in the neighborhood of resonance, are presented for certain sets of boundary conditions. PMID- 28863560 TI - Which epenthetic vowel? Phonetic categories versus acoustic detail in perceptual vowel epenthesis. AB - This study aims to quantify the relative contributions of phonetic categories and acoustic detail on phonotactically induced perceptual vowel epenthesis in Japanese listeners. A vowel identification task tested whether a vowel was perceived within illegal consonant clusters and, if so, which vowel was heard. Cross-spliced stimuli were used in which vowel coarticulation present in the cluster did not match the quality of the flanking vowel. Two clusters were used, /hp/ and /kp/, the former containing larger amounts of resonances of the preceding vowel. While both flanking vowel and coarticulation influenced vowel quality, the influence of coarticulation was larger, especially for /hp/. PMID- 28863563 TI - Transient finite element/equivalent sources using direct coupling and treating the acoustic coupling matrix as sparse. AB - Transient structural-acoustic problems can be solved using time stepping procedures with the structure and fluid modeled using finite elements and equivalent sources, respectively. Limitations on the time step size for stable solutions have led to the current popularity of iterative coupling to enforce the boundary conditions at the fluid-structure interface, which also helps to alleviate difficulties caused by the fully populated acoustic coupling matrix. The research presented here examines a monolithic approach using a stabilized equivalent source formulation where the acoustic coupling matrix is either fully diagonal or treated as sparse. In theory, the matrix should be sparse because it relates nodal velocities to nodal acoustic pressure forces during a single time step, and the pressure waves can only travel a distance equal to the sound speed multiplied by the time step. The numerical results demonstrate that for the chosen example problems accurate results are obtained for either diagonal coupling matrices or with a large percentage of the terms set to zero. It is also demonstrated that the formulation adapts well to parallel processing environments and that the times associated with the equivalent source computations are proportional to the number of processors. PMID- 28863562 TI - Uniform theory of diffraction (UTD)-based solution for sound diffraction caused by an array of obstacles. AB - A formulation based on the uniform theory of diffraction (UTD) for the analysis of the multiple-diffraction of a spherical sound wave caused by a series of wedges or knife-edges is hereby presented. The receiver location has to be considered at the same height as the preceding obstacles and at the same inter obstacle distance from the last wedge. The solution, which is based on a UTD physical optics formulation for radio-wave multiple-diffraction and has been validated through comparison with a geometrical theory of diffraction acoustic model, is computationally more efficient than other existing methods thanks to the fact that only single diffractions are involved in the calculations (high order diffraction terms are not considered in the diffraction coefficients), thus allowing for the consideration of a great number of obstacles. In such a way, the proposed solution overcomes the limitations of previous works when multiple acoustic diffraction caused by an array of elements of equal height is to be analyzed. Therefore, the results can be applied in the study of sound propagation in scenarios where multiple-diffraction over a series of edges of equal height and periodical spacing has to be considered, such as the typical audience seating of a concert hall. PMID- 28863564 TI - A one-dimensional search method with stable 1-norm solution for linear prediction. AB - In this paper a simple iterative algorithm that is guaranteed to produce a stable all-pole filter when minimizing the 1-norm of the linear prediction error signal is proposed. The approach works for both the autocorrelation and covariance frameworks, involves only a one-dimensional search at each step, and obviates the need for linear programming based methods. Based on simulation studies, it was observed that the performance of the algorithm is nearly optimal, i.e., very close to the estimates obtained using interior point methods. Moreover, this method also has the ability to constrain the bandwidth of any peak. The proposed method has been applied for vocal tract estimation and, using spectral distortion as the metric, results are presented using synthetic as well as natural speech. PMID- 28863565 TI - Cross-linguistic vowel variation in trilingual speakers of Saterland Frisian, Low German, and High German. AB - The present study compares the acoustic realization of Saterland Frisian, Low German, and High German vowels by trilingual speakers in the Saterland. The Saterland is a rural municipality in northwestern Germany. It offers the unique opportunity to study trilingualism with languages that differ both by their vowel inventories and by external factors, such as their social status and the autonomy of their speech communities. The objective of the study was to examine whether the trilingual speakers differ in their acoustic realizations of vowel categories shared by the three languages and whether those differences can be interpreted as effects of either the differences in the vowel systems or of external factors. Monophthongs produced in a /hVt/ frame revealed that High German vowels show the most divergent realizations in terms of vowel duration and formant frequencies, whereas Saterland Frisian and Low German vowels show small differences. These findings suggest that vowels of different languages are likely to share the same phonological space when the speech communities largely overlap, as is the case with Saterland Frisian and Low German, but may resist convergence if at least one language is shared with a larger, monolingual speech community, as is the case with High German. PMID- 28863566 TI - Propagation of coherent transverse waves: Influence of the translational and rotational subwavelength resonances. AB - The propagation of coherent transverse waves through a homogeneous elastic medium containing a set of spherical dense inclusions is an interesting topic. In such a material, in addition to the coherent longitudinal wave, two coherent transverse waves can propagate. The modeling used is based on the multiple scattering theory, which requires the scattering coefficients of the single scattering problem. These coefficients are calculated for moving rigid particles, leading to approximations of the two subwavelength dipolar resonances, one associated to a translational motion and the other to a rotational motion. Numerical simulations are carried out in order to compare the effective wavenumbers of the coherent elastic waves through the analysis of their phase velocity and attenuation. This comparison is performed for elastic and moving rigid spheres. It is shown that both dipolar resonances may have a great influence on the propagation of coherent transverse waves. PMID- 28863567 TI - Mixed modeling for irregularly sampled and correlated functional data: Speech science applications. AB - The speech sciences often employ complex experimental designs requiring models with multiple covariates and crossed random effects. For curve-like data such as time-varying signals, single-time-point feature extraction is commonly used as data reduction technique to make the data amenable to statistical hypothesis testing, thereby discarding a wealth of information. The present paper discusses the application of functional linear mixed models, a functional analogue to linear mixed models. This type of model allows for the holistic evaluation of curve dynamics for data with complex correlation structures due to repeated measures on subjects and stimulus items. The nonparametric, spline-based estimation technique allows for correlated functional data to be observed irregularly, or even sparsely. This means that information on variation in the temporal domain is preserved. Functional principal component analysis is used for parsimonious data representation and variance decomposition. The basic functionality and usage of the model is illustrated based on several case studies with different data types and experimental designs. The statistical method is broadly applicable to any types of data that consist of groups of curves, whether they are articulatory or acoustic time series data, or generally any types of data suitably modeled based on penalized splines. PMID- 28863568 TI - Investigation of the sound generation mechanisms for in-duct orifice plates. AB - Sound generation due to an orifice plate in a hard-walled flow duct which is commonly used in air distribution systems (ADS) and flow meters is investigated. The aim is to provide an understanding of this noise generation mechanism based on measurements of the source pressure distribution over the orifice plate. A simple model based on Curle's acoustic analogy is described that relates the broadband in-duct sound field to the surface pressure cross spectrum on both sides of the orifice plate. This work describes careful measurements of the surface pressure cross spectrum over the orifice plate from which the surface pressure distribution and correlation length is deduced. This information is then used to predict the radiated in-duct sound field. Agreement within 3 dB between the predicted and directly measured sound fields is obtained, providing direct confirmation that the surface pressure fluctuations acting over the orifice plates are the main noise sources. Based on the developed model, the contributions to the sound field from different radial locations of the orifice plate are calculated. The surface pressure is shown to follow a U3.9 velocity scaling law and the area over which the surface sources are correlated follows a U1.8 velocity scaling law. PMID- 28863569 TI - Application of maximum entropy to statistical inference for inversion of data from a single track segment. AB - In this paper an approach is presented to estimate the constraint required to apply maximum entropy (ME) for statistical inference with underwater acoustic data from a single track segment. Previous algorithms for estimating the ME constraint require multiple source track segments to determine the constraint. The approach is relevant for addressing model mismatch effects, i.e., inaccuracies in parameter values determined from inversions because the propagation model does not account for all acoustic processes that contribute to the measured data. One effect of model mismatch is that the lowest cost inversion solution may be well outside a relatively well-known parameter value's uncertainty interval (prior), e.g., source speed from track reconstruction or towed source levels. The approach requires, for some particular parameter value, the ME constraint to produce an inferred uncertainty interval that encompasses the prior. Motivating this approach is the hypothesis that the proposed constraint determination procedure would produce a posterior probability density that accounts for the effect of model mismatch on inferred values of other inversion parameters for which the priors might be quite broad. Applications to both measured and simulated data are presented for model mismatch that produces minimum cost solutions either inside or outside some priors. PMID- 28863570 TI - Calibration of focused ultrasonic transducers and absolute measurements of fluid nonlinearity with diffraction and attenuation corrections. AB - This paper presents analytical and experimental techniques for absolute determination of the acoustic nonlinearity parameter (beta) in fluids using focused transducers. When focused transducers are used for beta measurements, the geometrical and mechanical calibrations are generally required for accurate determination of the receiver transfer function from which the absolute pressure can be calculated. The fundamental and second harmonic wave amplitudes in harmonic generation measurements should be modified to account for beam diffraction and material absorption. All these issues are resolved in this study and the proposed technique is validated through the beta measurement in water. An experimental method is developed to determine the effective radius and focal length of focused transducers. A simplified self-reciprocity calibration procedure for a broadband focused receiver is described. The diffraction and attenuation corrections for the fundamental and second harmonic waves are explicitly derived using the multi-Gaussian beam model, and the effects on the beta determination are discussed. When the diffraction and attenuation corrections are all properly made, the measurement of beta over a large range of propagation distances is possible with errors less than 8%. PMID- 28863571 TI - Localization of weak objects in reverberant fields using waveform inversion. AB - This paper presents an application of the Waveform inversion approach to localization of objects in reverberant fields and with limited spatial measurements. Reverberant fields in enclosures can potentially carry useful information, however, in an incoherent way. Incoherency comes from the consecutive reflections of the wave energy several times in the domain. This, along with diffraction and dispersion effects, can ultimately lead to mixing of the wave energy in a seemingly random way. However, spreading of the wave energy can lead to multiple interrogations of each point in the enclosure. Hence, any substructural changes in the enclosure can be sensed with sufficient information carried by the wave energy flow. Furthermore, the temporal information buried in the data makes it feasible to conduct only a few spatial measurements. The authors present a localization scheme that benefits from the reverberant field and can reduce the required number of spatial measurements. PMID- 28863572 TI - On the underwater sound field from impact pile driving: Arrival structure, precursor arrivals, and energy streamlines. AB - Underwater noise from impact pile driving is studied through measurements using a vertical line array (VLA) placed at range 120 m from the pile source (water depth 7.5 m) over which bathymetry varied gradually increasing to depth 12.5 m at the VLA. The data were modeled assuming the pile impact produces a radial expansion that acts as sound source and propagates along the pile at supersonic speed. This leads to the conceptualization of the pile as a discrete, vertical line source for which frequency- and source-depth-dependent complex phasing is applied. Dominant features of the pressure time series versus measurement depth are reproduced in modeled counterparts that are linearly related. These observations include precursor arrivals for which arrival timing depends on hydrophone depth and influence of a sediment sound speed gradient on precursor amplitude. Spatial gradients of model results are taken to obtain estimates of acoustic particle velocity and vector intensity for which active intensity is studied in the time domain. Evaluation of energy streamlines based on time-integrated active intensity, and energy path lines based on instantaneous (or very-short-time integrated) active intensity reveal interesting structure in the acoustic field, including an inference as to the source depth of the precursor. PMID- 28863573 TI - Older and younger adults' identification of sentences filtered with amplitude and frequency modulations in quiet and noise. AB - Adding frequency modulations (FM) cues to vocoded (AM) speech aids speech recognition for younger listeners. However, this may not be true for older listeners since they have poorer FM detection thresholds. We measured FM detection thresholds of young and older adults; and in a sentence context examined whether adding FM cues to vocoded speech would assist older adults. Young and old participants were presented vocoded sentences in quiet and multitalker-babble with/without FM cues. Older adults had elevated FM detection thresholds but received the same-size FM benefit as younger adults, showing that they have the capacity to benefit from FM speech cues. PMID- 28863574 TI - Anomaly detection for a vibrating structure: A subspace identification/tracking approach. AB - Mechanical devices operating in noisy environments lead to low signal-to-noise ratios creating a challenging signal processing problem to monitor the vibrational signature of the device in real-time. To detect/classify a particular type of device from noisy vibration data, it is necessary to identify signatures that make it unique. Resonant (modal) frequencies emitted offer a signature characterizing its operation. The monitoring of structural modes to determine the condition of a device under investigation is essential, especially if it is a critical entity of an operational system. The development of a model-based scheme capable of the on-line tracking of structural modal frequencies by applying both system identification methods to extract a modal model and state estimation methods to track their evolution is discussed along with the development of an on line monitor capable of detecting anomalies in real-time. An application of this approach to an unknown structural device is discussed illustrating the approach and evaluating its performance. PMID- 28863575 TI - Effect of the three-dimensional microstructure on the sound absorption of foams: A parametric study. AB - The purpose of this work is to systematically study the effect of the throat and the pore sizes on the sound absorbing properties of open-cell foams. The three dimensional idealized unit cell used in this work enables to mimic the acoustical macro-behavior of a large class of cellular solid foams. This study is carried out for a normal incidence and also for a diffuse field excitation, with a relatively large range of sample thicknesses. The transport and sound absorbing properties are numerically studied as a function of the throat size, the pore size, and the sample thickness. The resulting diagrams show the ranges of the specific throat sizes and pore sizes where the sound absorption grading is maximized due to the pore morphology as a function of the sample thickness, and how it correlates with the corresponding transport parameters. These charts demonstrate, together with typical examples, how the morphological characteristics of foam could be modified in order to increase the visco-thermal dissipation effects. PMID- 28863576 TI - "Spot" call: A common sound from an unidentified great whale in Australian temperate waters. AB - Underwater passive acoustic recordings in the Southern and Indian Oceans off Australia from 2002 to 2016 have regularly captured a tonal signal of about 10 s duration at 22-28 Hz with a symmetrical bell-shaped envelope. The sound is often accompanied by short, higher frequency downsweeps and repeated at irregular intervals varying from 120 to 200 s. It is termed the "spot" call according to its appearance in spectrograms of long-time averaging. Although similar to the first part of an Antarctic blue whale Z-call, evidence suggests the call is produced by another great whale, with the source as yet not identified. PMID- 28863577 TI - Beamforming using subspace estimation from a diagonally averaged sample covariance. AB - The potential benefit of a large-aperture sonar array for high resolution target localization is often challenged by the lack of sufficient data required for adaptive beamforming. This paper introduces a Toeplitz-constrained estimator of the clairvoyant signal covariance matrix corresponding to multiple far-field targets embedded in background isotropic noise. The estimator is obtained by averaging along subdiagonals of the sample covariance matrix, followed by covariance extrapolation using the method of maximum entropy. The sample covariance is computed from limited data snapshots, a situation commonly encountered with large-aperture arrays in environments characterized by short periods of local stationarity. Eigenvectors computed from the Toeplitz constrained covariance are used to construct signal-subspace projector matrices, which are shown to reduce background noise and improve detection of closely spaced targets when applied to subspace beamforming. Monte Carlo simulations corresponding to increasing array aperture suggest convergence of the proposed projector to the clairvoyant signal projector, thereby outperforming the classic projector obtained from the sample eigenvectors. Beamforming performance of the proposed method is analyzed using simulated data, as well as experimental data from the Shallow Water Array Performance experiment. PMID- 28863578 TI - The echolocation transmission beam of free-ranging Indo-Pacific humpback dolphins (Sousa chinensis). AB - While the transmission beam of odontocetes has been described in a number of studies, the majority of them that have measured the transmission beam in two dimensions were focused on captive animals. Within the current study, a dedicated cross hydrophone array with nine elements was used to investigate the echolocation transmission beam of free-ranging Indo-Pacific humpback dolphins. A total of 265 on-axis clicks were analyzed, from which the apparent peak to peak source levels ranged between 168 to 207 dB (mean 184.5 dB +/- 6.6 dB). The 3-dB beam width along the horizontal and vertical plane was 9.6 degrees and 7.4 degrees , respectively. Measured separately, the directivity index of the horizontal and vertical plane was 12.6 and 13.5 dB, respectively, and the overall directivity index (both planes combined) was 29.5 dB. The beam shape was slightly asymmetrical along the horizontal and vertical axis. Compared to other species, the characteristics of the transmitting beam of Indo-Pacific humpback dolphins were relatively close to the bottlenose dolphin (Tursiops truncatus), likely due to the similarity in the peak frequency and waveform of echolocation clicks and comparable body sizes of the two species. PMID- 28863579 TI - Investigation of piezoelectric anisotropy of bovine cortical bone at an ultrasound frequency by coupling an experiment and a simulation. AB - An investigation of the piezoelectric anisotropy of bovine cortical bone at 1 MHz was attempted by coupling data obtained from an experiment and a simulation. In the experiment, a piezoelectric cell (PE-cell) was used as an ultrasound receiver. In the PE-cell, the cortical bone disk, which was cut in the direction perpendicular to the bone axis, was electrically shielded. The directivity of the PE-cell was measured at 0 degrees -22.5 degrees and was compared to four simulated results using the piezoelectric finite-difference time-domain method. It was shown that the piezoelectric signal in the bone could be generated by a transverse ultrasound wave. PMID- 28863581 TI - Hearing thresholds of a male and a female harbor porpoise (Phocoena phocoena). AB - To study intra-species variability in audiograms, the hearing sensitivity of a six-year-old female and a three-year-old male harbor porpoise was measured by using a standard psycho-acoustic technique under low ambient noise conditions. The porpoises' hearing thresholds for 13 narrow-band sweeps with center frequencies between 0.125 and 150 kHz were established. The resulting audiograms were U-shaped and similar. The main difference (25 dB) in mean thresholds between the two porpoises was at the high-frequency end of the hearing range (at 150 kHz). Maximum sensitivity (47 dB re 1 MUPa for the female and 44 dB re 1 MUPa for the male) occurred at 125 kHz. The range of most sensitive hearing (defined as within 10 dB of maximum sensitivity) was from 16 to ~140 kHz. Sensitivity declined sharply above 125 kHz. All five porpoises for which a valid behavioral audiogram now exists were rehabilitated stranded animals, all were tested with similar psycho-acoustic techniques, and all had similar audiograms. The present study provides further evidence to confirm that the hearing range and sensitivity of the first three harbor porpoises, which have been used in secondary research and on which policy decisions have been based, are representative of those of young harbor porpoises in general. PMID- 28863582 TI - Effect of gate choice on backscatter difference measurements of cancellous bone. AB - A variety of ultrasonic techniques have been developed to detect changes in bone caused by osteoporosis. One approach, called the backscatter difference technique, analyzes the power difference between two different portions of a backscatter signal. Analysis gates with a certain delay taud, width tauw, and separation taus are used to define portions of the backscatter signal for analysis. The goal of the present study was to investigate how different choices of taud, tauw, and taus affect four backscatter difference parameters: the normalized mean of the backscatter difference (nMBD), the normalized slope of the backscatter difference (nSBD), the normalized intercept of the backscatter difference (nIBD), and the normalized backscatter amplitude ratio (nBAR). Backscatter measurements were performed on 54 cube shaped specimens of human cancellous bone. nMBD, nSBD, nIBD, and nBAR were determined for 34 different combinations of taud, tauw, and taus for each specimen. nMBD and nBAR demonstrated the strongest correlations with apparent bone density (0.48 <= Rs <= 0.90). Generally, the correlations were found to improve as tauw + taus was increased and as taud was decreased. Among the four backscatter difference parameters, the measured values of nMBD were least sensitive to gate choice (<16%). PMID- 28863584 TI - Nonlinear wave propagation in porous materials based on the Biot theory. AB - Nonlinearity must be considered with some porous granular media because of the large deformation under seismic waves. In this study, the propagation of nonlinear waves in porous media is studied based on the Biot theory and the governing equations are obtained by the Lagrangian formulation. Three new nonlinear parameters are introduced to consider the coupled nonlinearity between the solid and fluid components in porous media. It is shown that an additional nonlinear wave with a double frequency is generated by the coupling effect of linear fast and slow waves. When only a shear wave is applied at the source, no double-frequency nonlinear wave is predicted and three nonlinear longitudinal waves are generated. On the basis of the practical case studies, the effect of strong nonlinearity is computed under the influence of a one-dimensional single longitudinal wave source and a single shear wave source. PMID- 28863583 TI - Speech rate, rate-matching, and intelligibility in early-implanted cochlear implant users. AB - An important speech-language outcome for deaf people with cochlear implants is speech intelligibility-how well their speech is understood by others, which also affects social functioning. Beyond simply uttering recognizable words, other speech-language skills may affect communicative competence, including rate matching or converging toward interlocutors' speech rates. This initial report examines speech rate-matching and its relations to intelligibility in 91 prelingually deaf cochlear implant users and 93 typically hearing peers age 3 to 27 years. Live-voice spoken sentences were repeated and later transcribed by multiple hearing listeners. Speech intelligibility was calculated as proportions of words correctly transcribed. For speech rate-matching measures, speech rates (syllables/s) were normalized as percentages faster or slower than examiners' speech rates. Cochlear implant users had slower speech rates, less accurate and less consistent rate-matching, and poorer speech intelligibility than hearing peers. Among cochlear implant users, speech rate and rate-matching were correlated with intelligibility: faster talkers and better rate-matchers were more intelligible. Rate-matching and intelligibility improved during preschool, with cochlear implant users delayed by about a year compared to hearing peers. By school-age, rate-matching and intelligibility were good overall, but delays persisted for many cochlear implant users. Interventions targeting rate-matching skills are therefore warranted in speech-language therapy for this population. PMID- 28863585 TI - Geographic variation in Risso's dolphin echolocation click spectra. AB - Discrimination of bioacoustic signals to the species or population level is critical for using passive acoustic monitoring to study cetacean ecology. Risso's dolphins off southern California have distinctive peaks and notches in their echolocation clicks, but it was unknown whether Risso's dolphins from other geographic areas have similarly distinctive click spectra and whether populations are acoustically distinct. This study investigates using clicks for species and population identification by characterizing the spectral structure of Risso's dolphin echolocation clicks recorded over wide-ranging geographic regions including the U.S. waters of the North Atlantic Ocean, Gulf of Mexico, and North Pacific Ocean; and international waters of the Eastern Tropical Pacific. All recordings with Risso's dolphin clicks exhibited the spectral peak and notch pattern described off southern California, indicating the presence of peak banding patterns is useful for species discrimination. Geographic regions were a significant explanatory factor for variability in the frequencies of click spectral peaks, with relatively higher frequency peaks and notches found off Hawaii compared to California waters and off the southeast U.S. compared to the Gulf of Mexico. In the North Atlantic Ocean, a latitudinal cline in frequencies was evident. Potential causes of acoustic variation within and among acoustic encounters are evaluated. PMID- 28863586 TI - The energy based characteristics of sperm whale clicks using the Hilbert Huang transform analysis method. AB - In this paper, a unique analysis method for sperm whale clicks based on Hilbert Huang transform (HHT) is proposed. Four sperm whale click samples with durations of 10 ms (defined as click I), and four sperm whale click samples with durations of 5 ms (defined as click II) were illustrated. These click samples were recorded in the Mediterranean Sea by Centro Interdisciplinare di Bioacusticae Ricerche Ambientali, Universita degli Studi di Pavia. The empirical mode decomposition method was used to decompose click I samples into seven intrinsic mode functions (IMFs) and one residue function (RF), and click II samples were decomposed into six IMFs and one RF. The average energy distributions of multiple IMFs and the single RF domain for click I and click II samples were explored using the HHT analysis method. The average energy-frequency representations were also investigated for the same click I and click II samples. The analysis results show that the energy-frequency characteristics of sperm whale clicks can be extracted and understood by applying several IMFs and one RF signal with a high-resolution analysis. PMID- 28863587 TI - Identification of categories of liquid sounds. AB - Sounds involving liquid sources are part of everyday life. They form a category of sounds easily identified by human listeners in different experimental studies. Unlike acoustic models that focus on bubble vibrations, real life instances of liquid sounds, such as sounds produced by liquids with or without other materials, are very diverse and include water drop sounds, noisy flows, and even solid vibrations. The process that allows listeners to group these different sounds in the same category remains unclear. This article presents a perceptual experiment based on a sorting task of liquid sounds from a household environment. It seeks to reveal the cognitive subcategories of this set of sounds. The clarification of this perceptive process led to the observation of similarities between the perception of liquid sounds and other categories of environmental sounds. Furthermore, the results provide a taxonomy of liquid sounds on which an acoustic analysis was performed that highlights the acoustical properties of the categories, including different rates of air bubble vibration. PMID- 28863588 TI - Two-dimensional grid-free compressive beamforming. AB - Compressive beamforming realizes the direction-of-arrival (DOA) estimation and strength quantification of acoustic sources by solving an underdetermined system of equations relating microphone pressures to a source distribution via compressive sensing. The conventional method assumes DOAs of sources to lie on a grid. Its performance degrades due to basis mismatch when the assumption is not satisfied. To overcome this limitation for the measurement with plane microphone arrays, a two-dimensional grid-free compressive beamforming is developed. First, a continuum based atomic norm minimization is defined to denoise the measured pressure and thus obtain the pressure from sources. Next, a positive semidefinite programming is formulated to approximate the atomic norm minimization. Subsequently, a reasonably fast algorithm based on alternating direction method of multipliers is presented to solve the positive semidefinite programming. Finally, the matrix enhancement and matrix pencil method is introduced to process the obtained pressure and reconstruct the source distribution. Both simulations and experiments demonstrate that under certain conditions, the grid-free compressive beamforming can provide high-resolution and low-contamination imaging, allowing accurate and fast estimation of two-dimensional DOAs and quantification of source strengths, even with non-uniform arrays and noisy measurements. PMID- 28863589 TI - Dynamic mass density of resonant metamaterials with homogeneous inclusions. AB - The occurrence of a negative dynamic mass density is a striking property of metamaterials. It appears when an inner local resonance is present. Results coming from an asymptotic theory are recalled briefly, showing the scaling of physical properties leading to inner resonance in elastic composites containing homogeneous soft inclusions, with negligible scattering of waves traveling through the matrix. This appears for a large contrast of elastic properties between matrix and inclusion. The frequency-dependent dynamic mass density depends on the resonance frequencies of the inner inclusions and on their related participation factors. Having solved the dynamic elasticity problem, these physical quantities are provided in the case of homogeneous cylindrical and spherical inclusions. It is shown that numerous resonance frequencies do not contribute to the dynamic mass density or have small participation factors, which simplifies significantly the physics involved in the concerned inner resonance phenomena. Finally, non-dimensional resonance frequencies and participation factors are given for both cases of inclusions as functions of the Poisson's ratio, defining completely the dynamic mass density. PMID- 28863590 TI - Evidence of a speech evoked electrophysiological release from masking in noise. AB - In this study, a release from masking (RFM) was sought with cortical auditory evoked potentials (CAEPs) elicited by speech (/da/) in competing continuous and interrupted noises. Two paradigms (i.e., fixed speech with varying signal-to noise ratios and fixed noise with varying speech levels) were employed. Shorter latencies and larger amplitudes were observed in interrupted versus continuous noise at equivalent signal-to-noise ratios. With fixed speech presentation, P1-N1 P2 latencies were prolonged and peak N1 and P2 amplitudes decreased and more so with continuous noise. CAEP thresholds were lower in interrupted noise. This is the first demonstration of RFM with CAEPs to speech. PMID- 28863591 TI - Bottlenose dolphin (Tursiops truncatus) auditory brainstem responses to frequency modulated "chirp" stimuli. AB - Previous studies have demonstrated that increasing-frequency chirp stimuli (up chirps) can enhance human auditory brainstem response (ABR) amplitudes by compensating for temporal dispersion occurring along the cochlear partition. In this study, ABRs were measured in two bottlenose dolphins (Tursiops truncatus) in response to spectrally white clicks, up-chirps, and decreasing-frequency chirps (down-chirps). Chirp durations varied from 125 to 2000 MUs. For all stimuli, frequency bandwidth was constant (10-180 kHz) and peak-equivalent sound pressure levels (peSPLs) were 115, 125, and 135 dB re 1 MUPa. Up-chirps with durations less than ~1000 MUs generally increased ABR peak amplitudes compared to clicks with the same peSPL or energy flux spectral density level, while down-chirps with durations from above ~250 to 500 MUs decreased ABR amplitudes relative to clicks. The findings generally mirror those from human studies and suggest that the use of chirp stimuli may be an effective way to enhance broadband ABR amplitudes in larger marine mammals. PMID- 28863592 TI - Numerical evaluation of the backward propagating acoustic field in healing long bones. AB - The propagation of ultrasound in healing long bones induces complex scattering phenomena due to the interaction of an ultrasonic wave with the composite nature of callus and osseous tissues. This work presents numerical simulations of ultrasonic propagation in healing long bones using the boundary element method aiming to provide insight into the complex scattering mechanisms and better comprehend the state of bone regeneration. Numerical models of healing long bones are established based on scanning acoustic microscopy images from successive postoperative weeks considering the effect of the nonhomogeneous callus structure. More specifically, the scattering amplitude and the acoustic pressure variation are calculated in the backward direction to investigate their potential to serve as quantitative and qualitative indicators for the monitoring of the bone healing process. The role of the excitation frequency is also examined considering frequencies in the range 0.2-1 MHz. The results indicate that the scattering amplitude decreases at later stages of healing compared to earlier stages of healing. Also, the acoustic pressure could provide supplementary qualitative information on the interaction of the scattered energy with bone and callus. PMID- 28863593 TI - Double-mode lateral-field-excitation bulk acoustic wave characteristics of Ca3TaGa3Si2O14 crystals. AB - The double-mode lateral-field-excitation (LFE) bulk acoustic wave characteristics of Ca3TaGa3Si2O14 (CTGS) crystals are investigated. It is found that LFE devices based on (yxl)-57 degrees CTGS crystals can work on both pure-LFE and pseudo-LFE modes when the driving electric field direction is normal to the crystallographic x axis of the piezoelectric substrate. Several double-mode LFE bulk acoustic wave devices based on CTGS crystals are designed and tested. The experimental results conform to the theoretical prediction well. Being able to operate in pure-LFE and pseudo-LFE modes, the double-mode LFE sensors show high sensitivity to both mechanical and electrical property changes of analytes. The results provide the crystal cut for double-mode LFE sensors, which is a critical basis of designing high-performance chemical and biological sensors by using double-mode LFE devices. PMID- 28863595 TI - Bottlenose dolphin (Tursiops truncatus) auditory brainstem responses recorded using conventional and randomized stimulation and averaging. AB - Auditory brainstem response (ABR) measurements using conventional averaging (i.e., constant interstimulus interval, ISI) are limited to stimulus rates low enough to prevent overlapping of the ABRs to successive stimuli. To overcome this limitation, stimuli may be presented at high rates using pseudorandom sequences (e.g., maximum length sequences) or quasi-periodic sequences; however, these methods restrict the available stimulus sequences and require deconvolution to recover the ABR from the overlapping responses. Randomized stimulation and averaging (RSA) is an alternate method where evoked responses at high rates are obtained by averaging responses to stimuli with ISIs drawn from a random distribution. The RSA method enables precise control over stimulus jitter, is flexible with respect to stimulus sequence parameters, and does not require deconvolution to extract the ABR waveform. In this study, ABRs were measured in three normal-hearing dolphins using conventional averaging and RSA. Results show the RSA method to be effective in dolphins if the ISI jitter >= ~1.5 ms and that the influence of stimulus artifacts in the averaged ABR can be substantially reduced by alternating stimulus polarity on successive presentations rather than employing digital blanking or iterative processes. PMID- 28863594 TI - Sound speed, attenuation, and reflection in gassy sediments. AB - A predictive model for acoustic dispersion and attenuation in gassy sediments is proposed. The model combines the linear solution for gas-bubble pulsations in a viscoelastic medium with corrected Biot equations involving gas-bubble pulsations. Numerical results for sound speed and attenuation are compared with predictions from Anderson and Hampton's model to demonstrate the advantages of the proposed model. The most important advantage of the current model is that it combines the dispersion regimes associated with gas-bubble pulsations and relative motion between the pore water and solid framework. The reflection coefficient at the water/gassy-sediment interface is derived based on the current model, and numerical results show that gas-bubble resonance can lead to the highest reflection. This model can also be used with a full acoustic inversion to estimate gas-bubble size distributions. PMID- 28863596 TI - Linguistic initiation signals increase auditory feedback error correction. AB - Previous research has shown that speakers can adapt their speech in a flexible manner as a function of a variety of contextual and task factors. While it is known that speech tasks may play a role in speech motor behavior, it remains to be explored if the manner in which the speaking action is initiated can modify low-level, automatic control of vocal motor action. In this study, the nature (linguistic vs non-linguistic) and modality (auditory vs visual) of the go signal (i.e., the prompts) was manipulated in an otherwise identical vocal production task. Participants were instructed to produce the word "head" when prompted, and the auditory feedback they were receiving was altered by systematically changing the first formants of the vowel /epsilon/ in real time using a custom signal processing system. Linguistic prompts induced greater corrective behaviors to the acoustic perturbations than non-linguistic prompts. This suggests that the accepted variance for the intended speech sound decreases when external linguistic templates are provided to the speaker. Overall, this result shows that the automatic correction of vocal errors is influenced by flexible, context dependant mechanisms. PMID- 28863598 TI - Effective wavenumbers for sound scattering by trunks, branches, and the canopy in a forest. AB - Sound propagation in a forest is often represented as propagation in free space with an effective complex wavenumber, which accounts for scattering and absorption. In this paper, the effective wavenumbers due to sound scattering by trunks, large branches, and the canopy are determined and analyzed based on three dimensional multiple scattering theory. Trunks and branches are modeled as vertical and slanted finite cylinders, while the canopy is modeled by diffuse scatterers. The results are compared with two-dimensional effective wavenumbers previously used in the literature, which were obtained by approximating the trunk layer as infinite vertical cylinders. PMID- 28863597 TI - Instantaneous Bayesian regularization applied to real-time near-field acoustic holography. AB - Real-time near-field acoustic holography (RT-NAH) is used to recover non stationary sound sources using a planar microphone array. Direct propagation is described by the convolution of the wavenumber spectrum of the source under study with a known impulse response. The deconvolution operation is achieved by a singular value decomposition of the propagator and Tikhonov regularization is performed to stabilize the solution. The inverse problem has an innate ill-posed characteristic, and the regularization process is the key factor in obtaining acceptable results. The purpose of this paper is to present the instantaneous regularization process applied to RT-NAH method. Bayesian estimation of the regularization parameter is introduced from prior knowledge of the problem. The computation of the regularization parameter is updated for each block of constant time interval allowing one to take into account the fluctuating properties of the sound field. The superiority of Bayesian regularization, compared to state-of-the art methods, is observed numerically and experimentally for reconstruction of non stationary sources. RT-NAH is also enhanced to allow the reconstruction of long signals. Updating the regularization parameter accordingly to the fluctuations of the SNR is revealed to be a necessary effort to reconstruct highly non-stationary sources. PMID- 28863599 TI - Acoustic correlates for perceived effort levels in male and female acted voices. AB - The best actors, particularly classic Shakespearian actors, are experts at vocal expression. With prosodic inflection, change of voice quality, and non-textual utterances, they communicate emotion, emphasize ideas, create drama, and form a complementary language which works with the text to tell the story in the script. To begin to study selected elements of vocal expression in acted speech, corpora were curated from male actors' Hamlet and female actresses' Lady Macbeth soliloquy performances. L1 speakers of American English on Mechanical Turk listened to excerpts from the corpora, and provided descriptions of the speaker's vocal expression. In this exploratory, open-ended, mixed-methods study, approximately 60% of all responses described emotion, and the remainder of responses split evenly between voice quality (including effort levels) and prosody. Also, significant differences were found in the kind and quantity of descriptors applied to male and female speech. Perception-grounded male and female acoustic feature sets which tracked the actors' expressive effort levels through the continuum of whispered, breathy, modal, and resonant speech are presented and validated via multiple models. The best results in applying these features to simple, un-optimized, four-way decision tree classifiers yielded 76% accuracy for male and 73% accuracy for female expressive, acted speech. PMID- 28863600 TI - Ultrasonic harmonic generation from materials with up to cubic nonlinearity. AB - This letter considers the combined effects of quadratic and cubic nonlinearity on plane wave propagation in generally anisotropic elastic solids. Displacement solutions are derived that represent the fundamental, second-, and third-harmonic waves. In arriving at the solutions, the quadratic and cubic nonlinearity parameters for generally anisotropic materials are defined. The effects of quadratic and cubic nonlinearity are shown to influence the amplitude and phase of the fundamental wave. In addition, the phase of the third-harmonic depends on a simple combination of the quadratic and cubic nonlinearity parameters. Nonlinearity parameters are given explicitly for materials having isotropic and cubic symmetry. Lastly, acoustic nonlinearity surfaces are introduced, which illustrate the nonlinearity parameters as a function of various propagation directions in anisotropic materials. PMID- 28863601 TI - ACOUSTICAL STANDARDS NEWS. AB - American National Standards (ANSI Standards) developed by Accredited Standards Committees S1, S2, S3, S3/SC 1, and S12 in the areas of acoustics, mechanical vibration and shock, bioacoustics, animal bioacoustics, and noise, respectively, are published by the Acoustical Society of America (ASA). In addition to these standards, ASA publishes a catalog of Acoustical American National Standards. To receive a copy of the latest Standards catalog, please contact Neil B. Stremmel.Comments are welcomed on all material in Acoustical Standards News.This Acoustical Standards News section in JASA, as well as the National Catalog of Acoustical Standards and other information on the Standards Program of the Acoustical Society of America, are available via the ASA home page: http://acousticalsociety.org. PMID- 28863602 TI - Clear speech and lexical competition in younger and older adult listeners. AB - This study investigated whether clear speech reduces the cognitive demands of lexical competition by crossing speaking style with lexical difficulty. Younger and older adults identified more words in clear versus conversational speech and more easy words than hard words. An initial analysis suggested that the effect of lexical difficulty was reduced in clear speech, but more detailed analyses within each age group showed this interaction was significant only for older adults. The results also showed that both groups improved over the course of the task and that clear speech was particularly helpful for individuals with poorer hearing: for younger adults, clear speech eliminated hearing-related differences that affected performance on conversational speech. For older adults, clear speech was generally more helpful to listeners with poorer hearing. These results suggest that clear speech affords perceptual benefits to all listeners and, for older adults, mitigates the cognitive challenge associated with identifying words with many phonological neighbors. PMID- 28863603 TI - Modeling of the acoustic radiation force in elastography. AB - Elastography is a non-invasive imaging technique that can assess in vivo tissue stiffness. In shear wave elastography imaging, the acoustic radiation force (ARF) produced by focused ultrasound generates a local force that produces shear waves. The authors compare three existing formulations for the ARF: its full expression in the second-order approximation and two simplified formulations using a quasi plane wave and an attenuated plane wave approximation. Analytical expressions for the ARF are derived for the special cases of a concave spherical source and a quasi-Gaussian beam. They provide expressions for the resulting ARF and show discrepancies between the different formulations. For strongly divergent or highly focused beams the ARF expressed by the second-order approximation significantly differs from both simplified formulations. However, despite those differences the second-order and quasi-plane wave approximations create identical shear displacements in tissue. To compute the ARF and the displacements produced by a conventional ultrasound probe, the three formulations were incorporated into the k-Wave simulation package. The second-order and quasi-plane wave approximations give different forces but nearly identical displacements while the plane wave approximation significantly differs. It is concluded that to properly take into account the ultrasound field structure, the second-order or quasi-plane wave approximations should be preferably used. PMID- 28863604 TI - Fitting pole-zero micromechanical models to cochlear response measurements. AB - An efficient way of describing the linear micromechanical response of the cochlea is in terms of its poles and zeros. Pole-zero models with local scaling symmetry are derived for both one and two degree-of-freedom micromechanical systems. These elements are then used in a model of the coupled cochlea, which is optimised to minimise the mean square difference between its frequency response and that measured on the basilar membrane inside the mouse cochlea by Lee, Raphael, Xia, Kim, Grillet, Applegate, Ellerbee Bowden, and Oghalai [(2016) J. Neurosci. 36, 8160-8173] and Oghalai Lab [(2015). https://oghalailab.stanford.edu], at different excitation levels. A model with two degree-of-freedom micromechanics generally fits the measurements better than a model with single degree-of-freedom micromechanics, particularly at low excitations where the cochlea is active, except post-mortem conditions, when the cochlea is passive. The model with the best overall fit to the data is found to be one with two degree-of-freedom micromechanics and 3D fluid coupling. Although a unique lumped parameter network cannot be inferred from such a pole-zero description, these fitted results help indicate what properties such a network should have. PMID- 28863605 TI - Just noticeable differences for pitch direction, height, and slope for Mandarin and English listeners. AB - Previous studies on tones suggest that Mandarin listeners are more sensitive to pitch direction and slope while English listeners primarily attend to pitch height. In this study, just noticeable differences were established for pitch discrimination using a three-interval, forced-choice procedure with a two-down, one-up staircase design. A high rising and a high falling Mandarin tone were manipulated in terms of pitch direction, height, and slope. Results indicate that, overall, Mandarin listeners are more sensitive to pitch slope and English listeners to pitch height. However, these effects are modulated by both the direction (falling/rising) and slope of the pitch contours. PMID- 28863606 TI - Erratum: The effect of cubic material nonlinearity on the propagation of torsional wave modes in a pipe [J. Acoust. Soc. Am. 140, 3874-3883 (2016)]. PMID- 28863607 TI - Effect of level difference between left and right vocal folds on phonation: Physical experiment and theoretical study. AB - As an alternative factor to produce asymmetry between left and right vocal folds, the present study focuses on level difference, which is defined as the distance between the upper surfaces of the bilateral vocal folds in the inferior-superior direction. Physical models of the vocal folds were utilized to study the effect of the level difference on the phonation threshold pressure. A vocal tract model was also attached to the vocal fold model. For two types of different models, experiments revealed that the phonation threshold pressure tended to increase as the level difference was extended. Based upon a small amplitude approximation of the vocal fold oscillations, a theoretical formula was derived for the phonation threshold pressure. This theory agrees with the experiments, especially when the phase difference between the left and right vocal folds is not extensive. Furthermore, an asymmetric two-mass model was simulated with a level difference to validate the experiments as well as the theory. The primary conclusion is that the level difference has a potential effect on voice production especially for patients with an extended level of vertical difference in the vocal folds, which might be taken into account for the diagnosis of voice disorders. PMID- 28863608 TI - Using multipath reflections to obtain dive depths of beaked whales from a towed hydrophone array. AB - Beaked whales are deep divers, emitting echolocation clicks while at depth. Little is known about the dive behavior of most species; however, passive acoustic data collected with towed hydrophone arrays can provide depth information using multipath reflections of clicks coupled with a two-dimensional localization of the individual. Data were collected during a shipboard survey in the western North Atlantic Ocean using a towed linear hydrophone array. Beaked whale tracks were classified as either Cuvier's (Ziphius cavirostris) or Gervais'/True's (Mesoplodon europaeus/Mesoplodon mirus). Weighted species average depths and weighted species standard deviations were 1158 m +/- 287 m for Cuvier's (n = 24), and 870 m +/- 151 m for Gervais'/True's (n = 15). Depth uncertainties ranged from 3% to 142% of the average depth. Slant ranges were corrected for depth to provide average horizontal perpendicular distance estimates. The average horizontal perpendicular distance distribution exhibited fewer detections in the first bin than the second. This is the first report of dive depths for Gervais'/True's beaked whales and use of this method to obtain depths for beaked whales using a towed linear array. PMID- 28863609 TI - Wave Field Synthesis of moving sources with arbitrary trajectory and velocity profile. AB - The sound field synthesis of moving sound sources is of great importance when dynamic virtual sound scenes are to be reconstructed. Previous solutions considered only virtual sources moving uniformly along a straight trajectory, synthesized employing a linear loudspeaker array. This article presents the synthesis of point sources following an arbitrary trajectory. Under high frequency assumptions 2.5D Wave Field Synthesis driving functions are derived for arbitrary shaped secondary source contours by adapting the stationary phase approximation to the dynamic description of sources in motion. It is explained how a referencing function should be chosen in order to optimize the amplitude of synthesis on an arbitrary receiver curve. Finally, a finite difference implementation scheme is considered, making the presented approach suitable for real-time applications. PMID- 28863610 TI - Acoustic and perceptual effects of amplitude and frequency compression on high frequency speech. AB - This study investigated how six different amplification methods influence acoustic properties, and subsequently perception, of high-frequency cues in fricatives that have been processed with conventional full bandwidth amplification or nonlinear frequency compression (NFC)-12 conditions total. Amplification methods included linear gain, fast/slow-acting wide dynamic range compression crossed with fixed/individualized compression parameters, and a method with adaptive time constants. Twenty-one hearing-impaired listeners identified seven fricatives in nonsense syllables produced by female talkers. For NFC stimuli, frequency-compressed filters that precisely aligned 1/3-octave bands between input and output were used to quantify effective compression ratio, audibility, and temporal envelope modulation relative to the input. Results indicated significant relationships between these acoustic properties, each of which contributed significantly to fricative recognition across the entire corpus of stimuli. Recognition was significantly better for NFC stimuli compared with full bandwidth stimuli, regardless of the amplification method, which had complementary effects on audibility and envelope modulation. Furthermore, while there were significant differences in recognition across the amplification methods, they were not consistent across phonemes. Therefore, neither recognition nor acoustic data overwhelmingly suggest that one amplification method should be used over another for transmission of high-frequency cues in isolated syllables. Longer duration stimuli and more realistic listening conditions should be examined. PMID- 28863611 TI - Phonetic enhancement of Mandarin vowels and tones: Infant-directed speech and Lombard speech. AB - Speech units are reported to be hyperarticulated in both infant-directed speech (IDS) and Lombard speech. Since these two registers have typically been studied separately, it is unclear if the same speech units are hyperarticulated in the same manner between these registers. The aim of the present study is to compare the effect of register on vowel and tone modification in the tonal language Mandarin Chinese. Vowel and tone productions were produced by 15 Mandarin speaking mothers during interactions with their 12-month-old infants during a play session (IDS), in conversation with a Mandarin-speaking adult in a 70 dBA eight-talker babble noise environment (Lombard speech), and in a quiet environment (adult-directed speech). Vowel space expansion was observed in IDS and Lombard speech, however, the patterns of vowel-shift were different between the two registers. IDS displayed tone space expansion only in the utterance-final position, whereas there was no tone space expansion in Lombard speech. The overall pitch increased for all tones in both registers. The tone-bearing vowel duration also increased in both registers, but only in utterance-final position. The difference in speech modifications between these two registers is discussed in light of speakers' different communicative needs. PMID- 28863612 TI - Further understanding of doorway states in elastic systems. AB - In a previous work an elastic bar with a groove or notch that presents a doorway state was studied when the system was excited with 20 cycles of harmonic signals. The strength function had a Lorentzian width Gammad = 1/pitaud, where taud is the decay time of the prompt response. In the present paper, the doorway-state phenomenon is analyzed again for the same harmonic signals but for a very large number of cycles. The strength-function phenomenon is once more obtained, but now with a Lorentzian width Gamma' which is larger than Gammad. A qualitative and numerical explanation of this fact is given, leading therefore to further understanding of doorway states in elastic systems. The numerical results show a very good agreement with the values measured in the laboratory. PMID- 28863613 TI - Reciprocity relationships in vector acoustics and their application to vector field calculations. AB - The reciprocity equation commonly stated in underwater acoustics relates pressure fields and monopole sources. It is often used to predict the pressure measured by a hydrophone for multiple source locations by placing a source at the hydrophone location and calculating the field everywhere for that source. A similar equation that governs the orthogonal components of the particle velocity field is needed to enable this computational method to be used for acoustic vector sensors. This paper derives a general reciprocity equation that accounts for both monopole and dipole sources. This vector-scalar reciprocity equation can be used to calculate individual components of the received vector field by altering the source type used in the propagation calculation. This enables a propagation model to calculate the received vector field components for an arbitrary number of source locations with a single model run for each vector field component instead of requiring one model run for each source location. Application of the vector scalar reciprocity principle is demonstrated with analytic solutions for a range independent environment and with numerical solutions for a range-dependent environment using a parabolic equation model. PMID- 28863615 TI - Speech produced in noise: Relationship between listening difficulty and acoustic and durational parameters. AB - Conversational speech produced in noise can be characterised by increases in intelligibility relative to such speech produced in quiet. Listening difficulty (LD) is a metric that can be used to evaluate speech transmission performance more sensitively than intelligibility scores in situations in which performance is likely to be high. The objectives of the present study were to evaluate the LD of speech produced in different noise and style conditions, to evaluate the spectral and durational speech modifications associated with these conditions, and to determine whether any of the spectral and durational parameters predicted LD. Nineteen subjects were instructed to speak at normal and loud volumes in the presence of background noise at 40.5 dB(A) and babble noise at 61 dB(A). The speech signals were amplitude-normalised, combined with pink noise to obtain a signal-to-noise ratio of -6 dB, and presented to twenty raters who judged their LD. Vowel duration, fundamental frequency and the proportion of the spectral energy in high vs low frequencies increased with the noise level within both styles. LD was lowest when the speech was produced in the presence of high level noise and at a loud volume, indicating improved intelligibility. Spectrum balance was observed to predict LD. PMID- 28863616 TI - The role of short-time intensity and envelope power for speech intelligibility and psychoacoustic masking. AB - The generalized power spectrum model [GPSM; Biberger and Ewert (2016). J. Acoust. Soc. Am. 140, 1023-1038], combining the "classical" concept of the power-spectrum model (PSM) and the envelope power spectrum-model (EPSM), was demonstrated to account for several psychoacoustic and speech intelligibility (SI) experiments. The PSM path of the model uses long-time power signal-to-noise ratios (SNRs), while the EPSM path uses short-time envelope power SNRs. A systematic comparison of existing SI models for several spectro-temporal manipulations of speech maskers and gender combinations of target and masker speakers [Schubotz et al. (2016). J. Acoust. Soc. Am. 140, 524-540] showed the importance of short-time power features. Conversely, Jorgensen et al. [(2013). J. Acoust. Soc. Am. 134, 436-446] demonstrated a higher predictive power of short-time envelope power SNRs than power SNRs using reverberation and spectral subtraction. Here the GPSM was extended to utilize short-time power SNRs and was shown to account for all psychoacoustic and SI data of the three mentioned studies. The best processing strategy was to exclusively use either power or envelope-power SNRs, depending on the experimental task. By analyzing both domains, the suggested model might provide a useful tool for clarifying the contribution of amplitude modulation masking and energetic masking. PMID- 28863614 TI - Towards a joint reflection-distortion otoacoustic emission profile: Results in normal and impaired ears. AB - Otoacoustic emissions (OAEs) provide salient information about cochlear function and dysfunction. Two broad classes of emissions, linear reflection and nonlinear distortion, arise via distinct cochlear processes and hence, appear to provide independent information about cochlear health and hearing. Considered in combination, these two OAE types may characterize sensory hearing loss most effectively. In this study, the level-dependent growth of stimulus-frequency OAEs (a reflection-type emission) and distortion-product OAEs (a distortion-type emission) were measured in ten normal-hearing ears and eight ears with slight-to moderate sensorineural hearing loss. Metrics of OAE strength and compression were derived from OAE input/output functions and then considered in a combined fashion. Results indicate that SFOAEs and DPOAEs differ significantly in their strength and compression features. When SFOAE and DPOAE metrics are displayed together on a two-dimensional plot, relatively well-defined data clusters describe their normative relationship. In hearing-impaired ears, this relationship is disrupted but not in a uniform way across ears; ears with similar audiograms showed differently altered joint-OAE profiles. Hearing loss sometimes affected only one OAE or one more than the other. Results suggest a joint-OAE profile is promising and warrants study in a large group of subjects with sensory hearing loss of varied etiologies. PMID- 28863617 TI - Time-of-flight dependency on transducer separation distance in a reflective-path guided-wave ultrasonic flow meter at zero flow conditions. AB - Transit-time flow meters based on guided ultrasonic wave propagation in the pipe spool have several advantages compared to traditional inline ultrasonic flow metering. The extended interrogation field, obtained by continuous leakage from guided waves traveling in the pipe wall, increases robustness toward entrained particles or gas in the flow. In reflective-path guided-wave ultrasonic flow meters (GW-UFMs), the flow equations are derived from signals propagating solely in the pipe wall and from signals passing twice through the fluid. In addition to the time-of-flight (TOF) through the fluid, the fluid path experiences an additional time delay upon reflection at the opposite pipe wall due to specular and non-specular reflections. The present work investigates the influence of these reflections on the TOF in a reflective-path GW-UFM as a function of transducer separation distance at zero flow conditions. Two models are used to describe the signal propagation through the system: (i) a transient full-wave finite element model, and (ii) a combined plane-wave and ray-tracing model. The study shows that a range-dependent time delay is associated with the reflection of the fluid path, introducing transmitter-receiver distance dependence. Based on these results, the applicability of the flow equations derived using model (ii) is discussed. PMID- 28863618 TI - An assessment of a spatial ear training program for perceived auditory source width. AB - The authors propose a training program for a listener to quantify the horizontal extension of an auditory image-auditory source width (ASW). The proposed program controls the ASW of a five-channel sound source by spreading it across five front loudspeakers, displays the corresponding change in visual width, and trains listeners to remember the spread angle through an isomorphic mapping to the corresponding visual cue. To evaluate the efficacy of the training, the authors conducted pre- and post-training tests. The results show that the width judgment error of the post-training test was significantly smaller than the pre-training test. PMID- 28863619 TI - Vowel recognition at fundamental frequencies up to 1 kHz reveals point vowels as acoustic landmarks. AB - The phonological function of vowels can be maintained at fundamental frequencies (fo) up to 880 Hz [Friedrichs, Maurer, and Dellwo (2015). J. Acoust. Soc. Am. 138, EL36-EL42]. Here, the influence of talker variability and multiple response options on vowel recognition at high fos is assessed. The stimuli (n = 264) consisted of eight isolated vowels (/i y e o epsilon a o u/) produced by three female native German talkers at 11 fos within a range of 220-1046 Hz. In a closed set identification task, 21 listeners were presented excised 700-ms vowel nuclei with quasi-flat fo contours and resonance trajectories. The results show that listeners can identify the point vowels /i a u/ at fos up to almost 1 kHz, with a significant decrease for the vowels /y epsilon/ and a drop to chance level for the vowels /e o o/ toward the upper fos. Auditory excitation patterns reveal highly differentiable representations for /i a u/ that can be used as landmarks for vowel category perception at high fos. These results suggest that theories of vowel perception based on overall spectral shape will provide a fuller account of vowel perception than those based solely on formant frequency patterns. PMID- 28863620 TI - A one-school year longitudinal study of secondary school teachers' voice parameters and the influence of classroom acoustics. AB - Recent literature reports that a large percentage of teachers complain that teaching has an adverse effect on their voice status. Thus, more needs to be done to study their vocal behavior. The objective of this longitudinal study was twofold: to determine changes in the voice use of teachers over a school year, and to study the relationships between voice use and classroom acoustic parameters. Thirty-one teachers from two secondary schools in Turin (Italy) were involved at the beginning of the 2014-2015 school year, and 22 of them also participated at the end of the same school year. The results show that teachers adjust their voices with noise and reverberation. A minimum value of the sound pressure level of voice (SPL) was found at a mid-frequency reverberation time of 0.8 s in both periods. Moreover, the teachers who worked in the worst classroom acoustic conditions showed an increase of 2.3 dB in the mean SPL and a decrease of 10% in the voicing time percentage at the end of the school year. A predictive model that can be used to estimate the mean SPL from the background noise level and the reverberation time, based on collected data, is here proposed. PMID- 28863621 TI - Rigid and elastic acoustic scattering signal separation for underwater target. AB - Underwater target elastic acoustic scattering and other acoustic scattering components are aliasing together in the time and frequency domains, and the existing signal processing methods cannot recognize the elastic scattering features under the aliasing condition because of the resolution limitation. To address this problem, this study, which is based on the target echo highlight model, analyzes the characteristics of target acoustic scattering components when the transmitted signal is a linear frequency modulation pulse. The target acoustic scattering structure in the fractional Fourier transform (FRFT) domain is deduced theoretically. Then, filtering is used in the FRFT domain to separate the target elastic acoustic scattering components. In addition, noise suppression performance and filter resolution are discussed. The target rigid and elastic acoustic scattering components are separated. Experimental results show that filtering in the FRFT domain can separate the elastic scattering components from the target echoes. Moreover, separated elastic acoustic scattering components have consistent theoretical features, which lay the foundation for studying the elastic scattering characteristics further. PMID- 28863622 TI - Masking release effects of a standard and a regional linguistic variety. AB - Previous research has shown that the more similar the target and the masker signal, the harder it is to segregate the two streams effectively [i.e., target masker linguistic similarity hypothesis, e.g., Brouwer, Van Engen, Calandruccio, and Bradlow (2012). J. Acoust. Soc. Am. 131(2), 1449-1464]. The present study examined whether this hypothesis holds when a standard variety of a language (Dutch) is paired with one of its regional varieties (Limburgian). Dutch and Limburgian listeners were tested on a speech-in-speech recognition task to investigate whether familiarity with the target and/or maskers influenced their performance. The findings provide support for the hypothesis and suggest an influence of Limburgians' bidialectal status. PMID- 28863623 TI - Space-time domain solutions of the wave equation by a non-singular boundary integral method and Fourier transform. AB - The general space-time evolution of the scattering of an incident acoustic plane wave pulse by an arbitrary configuration of targets is treated by employing a recently developed non-singular boundary integral method to solve the Helmholtz equation in the frequency domain from which the space-time solution of the wave equation is obtained using the fast Fourier transform. The non-singular boundary integral solution can enforce the radiation boundary condition at infinity exactly and can account for multiple scattering effects at all spacings between scatterers without adverse effects on the numerical precision. More generally, the absence of singular kernels in the non-singular integral equation confers high numerical stability and precision for smaller numbers of degrees of freedom. The use of fast Fourier transform to obtain the time dependence is not constrained to discrete time steps and is particularly efficient for studying the response to different incident pulses by the same configuration of scatterers. The precision that can be attained using a smaller number of Fourier components is also quantified. PMID- 28863624 TI - Development of beam emission spectroscopy diagnostic on EAST. AB - Beam Emission Spectroscopy (BES) diagnostic based on Neutron Beam Injection (NBI) on the Experimental Advanced Superconducting Tokamak has been developed. This system consists of 16 * 8 channels which can diagnose the density fluctuation in a rectangular area of about 20 * 10 cm2 in the cross section, whose radial position is adjustable from the core to edge just by means of changing the angle of the rotation mirror. The spatial resolution is about 1-3 cm according to the diagnosed radial position. The temporal resolution is 1 MUs. Space calibration of the diagnostic system is done based on the reversibility of the optical path. The NBI modulation experiment shows the success of BES development. PMID- 28863625 TI - A tunable single-monochromator Raman system based on the supercontinuum laser and tunable filters for resonant Raman profile measurements. AB - Resonant Raman spectroscopy requires that the wavelength of the laser used is close to that of an electronic transition. A tunable laser source and a triple spectrometer are usually necessary for resonant Raman profile measurements. However, such a system is complex with low signal throughput, which limits its wide application by scientific community. Here, a tunable micro-Raman spectroscopy system based on the supercontinuum laser, transmission grating, tunable filters, and single-stage spectrometer is introduced to measure the resonant Raman profile. The supercontinuum laser in combination with transmission grating makes a tunable excitation source with a bandwidth of sub-nanometer. Such a system exhibits continuous excitation tunability and high signal throughput. Its good performance and flexible tunability are verified by resonant Raman profile measurement of twisted bilayer graphene, which demonstrates its potential application prospect for resonant Raman spectroscopy. PMID- 28863626 TI - Determining the wedge angle and optical homogeneity of a glass plate by statistically analyzing the deformation in the wavefront surface. AB - By using a light-emitting diode as the probing light source and a Shack-Hartmann wavefront sensor as the recorder for the wavefront surface to execute a relative measurement, we present a useful method for determining the small wedge angle and optical homogeneity of a nominally planar glass plate from the wavefront measurements. The measured wavefront surface from the light source was first calibrated to be a horizontal plane before the plate under test was inserted. The wedge angle of the plate can be determined from the inclining angle of the regression plane of the measured wavefront surface after the plate was inserted between the light source and the wavefront sensor. Despite the annoying time dependent altitude fluctuation in measured wavefront topography, the optical homogeneity of the plate can be estimated from the increment on the average variance of the wavefront surface to its regression plane after the light passes through it by using the Bienayme formula. PMID- 28863627 TI - Gated ion spectrometer for spectroscopy of neutral particles. AB - A new design of an ion mass spectrometer for the laser-plasma particle diagnostic, which is capable to detect simultaneously also neutral particles, is described. The particles are detected with micro-channel-plate detector operating in a gated mode. This allows us to separate x-rays and energetic electrons from other stray plasma emissions, e.g., neutral particles, which hit the detector in the same place. The ion energies are measured with the spectrometer in energy intervals corresponding to their time-of-flight within the gating window. The latter also defines the energy interval of neutrals recorded with the same time of-flight. The spectrum of neutral particles can be reconstructed by subsequently collecting different parts of the spectrum while applying different delays on the gate pulse. That separation-in-time technique (time-of-flight mass spectrometry) in combination with the spatially separating mass analyzer (ion mass spectrometer) is used for the neutral particles spectroscopy. PMID- 28863628 TI - Enhanced fast digital integrator for magnetic measurements. AB - An enhanced Fast Digital Integrator (eFDI) was prototyped to satisfy the new requirements arising from current on-field exploitation of the previous Fast Digital Integrator in magnetic measurements for particle accelerators at CERN. In particular, the prototype achieves improved performance in terms of offset (5 ppm on 10 V fullscale), self-calibration accuracy (1 ppm of residual error), and data throughput (100 MB/s), by simultaneously preserving high-level signal-to-noise and distortion ratio (SINAD 105 dB at 10 Hz). In this paper, initially, the specifications, the design solutions, and the main features of the eFDI are illustrated. Then, the experimental results of the metrological characterization are compared with the CERN state-of-the-art integrator FDI performance in order to highlight the achieved improvements. PMID- 28863629 TI - Pulsed characterization of a UV LED for pulsed power applications on a silicon carbide photoconductive semiconductor switch. AB - The electrical and optical characteristics of a high-power UV light emitting diode (LED) (365 nm wavelength) were evaluated under pulsed operating conditions at current amplitudes several orders of magnitude beyond the LED's manufacturer specifications. Geared towards triggering of photoconductive semiconductor switches (PCSSs) for pulsed power applications, measurements were made over varying pulse widths (25 ns-100 MUs), current (0 A-250 A), and repetition rates (single shot-5 MHz). The LED forward voltage was observed to increase linearly with increasing current (~3.5 V-53 V) and decrease with increasing pulse widths. The peak optical power observed was >30 W, and a maximum system efficiency of 23% was achieved. The evaluated LED and auxiliary hardware were successfully used as the optical trigger source for a 4H-SiC PCSS. The lowest measured on-resistance of SiC was approximately 67 kOmega. PMID- 28863630 TI - Development of cold cathode arc discharge filament based multi-cusp H- ion source. AB - A cold cathode arc discharge filament based multicusp H- ion source (HNIS) has been developed using an innovative low power igniter system working in a glow discharge regime to achieve a longer lifetime of the filament. This HNIS is cesium-free and its experimental prototype generates a maximum H- ion beam (HNIB) current of 12 mA at 50 keV beam energy in pulse mode with a peak arc power of 27 kW using the triode extraction system. This article presents the results of initial commissioning of the HNIS and steering magnetic field used to separate out the co-extracted electrons from HNIB, verified through experiments and 3-D ion beam simulations. PMID- 28863631 TI - Cyclic flattened Brazilian disc tests for measuring the tensile fatigue properties of brittle rocks. AB - We propose a cyclic flattened Brazilian disc (FBD) testing method to measure the tensile fatigue properties of brittle rocks. Our method has obvious merits in its specimen preparation and experimental operation. Two parallel flattens are introduced in the disc specimen, which facilitate easily and uniformly loading the specimen without special loading devices required. Moreover, the contact regions between two flattens and loading planes barely change during the entire loading and unloading process, ensuring a consistent contact condition. With certain appropriate loading angles, this method guarantees that the very first breakage of the specimen occurs at the center of the disc, which is the prerequisite of the Brazilian-type indirect tensile tests. To demonstrate our new method, nine cyclic FBD tensile tests are conducted. The fatigue load-deformation characteristics of FBD specimens are revealed. The tensile fatigue lives of tested specimens are observed to increase with the increase in cyclic loading frequency. Our proposed method provides a convenient and reliable approach to indirectly measure the fatigue tensile properties of brittle rocks and other brittle solids subjected to cyclic tensile loadings. PMID- 28863632 TI - Direct loop gain and bandwidth measurement of phase-locked loop. AB - A simple and robust technique for directly measuring the loop gain and bandwidth of a phase-locked loop (PLL) is proposed. This technique can be used for the real time measurement of the real loop gain in a closed PLL without breaking its locking state. The agreement of the measured loop gain and theoretical calculations proves the validity of the proposed measurement technique. This technique with a simple configuration can be easily expanded to other phase locking systems whose loop gain and bandwidth should be measured precisely. PMID- 28863633 TI - Note: On the study of metal/oxide hybrid ferromagnets with magneto-optical techniques. AB - We analyze here the magneto-optical measurements of hybrid materials containing metallic and oxide ferromagnetic phases. We show that the magnetization curves obtained with this technique can be fairly different to those obtained with standard magnetometry techniques and cannot be representative of the contribution of each phase to the magnetization of the material, due to the very different optical properties of metals and oxides. However, a proper numerical analysis of the magneto-optical measurements allows estimating the fraction of each phase present in the material. PMID- 28863634 TI - Correlation electron cyclotron emission diagnostic in TCV. AB - The correlation electron cyclotron emission diagnostic of tokamak a configuration variable has recently been upgraded. It now has the choice of three lines of sight: two horizontal lines placed on the low field side of the vessel, perpendicular to the magnetic field, and a dual-axis steerable antenna. The polarization of the radiation collected by the latter can be rotated using a universal polarizer situated in the transmission line. This line is also shared with a reflectometry system, allowing simultaneous measurements of temperature and density fluctuations in the same plasma volumes. When using this line, it is possible to choose between two dedicated front ends characterized by different local oscillator frequencies, adding flexibility in the choice of the plasma region to be studied. The intermediate frequency section is now equipped with six frequency tunable YIG filters allowing the study of turbulence properties in a wide range of radial positions. When studying fluctuations over the whole video bandwidth, the minimum detectable fluctuation level is deltaTe/Te~0.5%. The new system has been used to measure electron temperature fluctuations over a large fraction of the plasma profiles in a series of plasmas with triangularity varying from 0.6 to -0.6 but comparable collisionality profiles. PMID- 28863635 TI - High-temperature high-pressure calorimeter for studying gram-scale heterogeneous chemical reactions. AB - We present an instrument for measuring pressure changes and heat flows of physical and chemical processes occurring in gram-scale solid samples under high pressures of reactive gases. Operation is demonstrated at 1232 degrees C under 33 bars of pure hydrogen. Calorimetric heat flow is inferred using a grey-box non linear lumped-element heat transfer model of the instrument. Using an electrical calibration heater to deliver 900 J/1 W pulses at the sample position, we demonstrate a dynamic calorimetric power resolution of 50 mW when an 80-s moving average is applied to the signal. Integration of the power signal showed that the 900 J pulse energy could be measured with an average accuracy of 6.35% or better over the temperature range 150-1100 degrees C. This instrument is appropriate for the study of high-temperature metal hydride materials for thermochemical energy storage. PMID- 28863636 TI - A flexible dual-mode proximity sensor based on cooperative sensing for robot skin applications. AB - A flexible dual-mode proximity sensor has been designed and implemented, which is capable of combining capacitive-resistive detection in this paper. The capacitive type proximity sensor detecting is defined as mode-C, and the resistive type proximity sensor detecting is defined as mode-R. The characteristics of the proximity sensor are as follows: (1) the theoretical mode is developed which indicates that this proximity sensor can reflect proximity information accurately; (2) both sensing modes are vertically integrated into a sandwich-like chip with an 8 mm * 12 mm unit area. The thickness of a mode-R sensing material (graphene nanoplatelets) and mode-C dielectric (the mixture of carbon black and silicone rubber) is 1 mm and 2.5 mm, respectively; (3) for mode-R, the linearity of temperature-resistance curve can achieve 0.998 in the temperature range from 25 degrees C to 65 degrees C. And for mode-C, various materials can be successfully detected with fast response and high reversibility. Meanwhile, the study compensated the influence of object temperature to ensure mode-C properly works. A cooperative sensing test shows that R-C dual modes sense effectively which can enlarge the sensing distance compared with the single mode proximity sensor. The fabrication of this sensor is convenient, and the integrity of a flexible sandwich-like structure based on dual modes is beneficial to form arrays, which is suitable to be used in skin-like sensing applications. PMID- 28863637 TI - aCORN: An experiment to measure the electron-antineutrino correlation coefficient in free neutron decay. AB - We describe an apparatus used to measure the electron-antineutrino angular correlation coefficient in free neutron decay. The apparatus employs a novel measurement technique in which the angular correlation is converted into a proton time-of-flight asymmetry that is counted directly, avoiding the need for proton spectroscopy. Details of the method, apparatus, detectors, data acquisition, and data reduction scheme are presented, along with a discussion of the important systematic effects. PMID- 28863638 TI - Note: Development of a cryocooler based high efficiency cryosorption pump. AB - In this communication, we report the development of a cryosorption pump, whose pumping speeds are higher at least by a factor of 1.5 compared to the commercial pumps in specific pressure ranges. This uses a material of high adsorbing capacity along with an adhesive of high thermal conductivity. The measured pumping speeds of these pumps for different gases such as nitrogen, argon, hydrogen, and helium are higher than the commercial cryopumps in the pressure range from 5 * 10-6 mbar to 5 * 10-5 mbar. The developed pump will be quite useful for fusion applications. PMID- 28863639 TI - In situ flow cell for combined X-ray absorption spectroscopy, X-ray diffraction, and mass spectrometry at high photon energies under solar thermochemical looping conditions. AB - An in situ/operando flow cell for transmission mode X-ray absorption spectroscopy (XAS), X-ray diffraction (XRD), and combined XAS/XRD measurements in a single experiment under the extreme conditions of two-step solar thermochemical looping for the dissociation of water and/or carbon dioxide was developed. The apparatus exposes materials to relevant conditions of both the auto-reduction and the oxidation sub-steps of the thermochemical cycle at ambient temperature up to 1773 K and enables determination of the composition of the effluent gases by online quadrupole mass spectrometry. The cell is based on a tube-in-tube design and is heated by means of a focusing infrared furnace. It was tested successfully for carbon dioxide splitting. In combined XAS/XRD experiments with an unfocused beam, XAS measurements were performed at the Ce K edge (40.4 keV) and XRD measurements at 64.8 keV and 55.9 keV. Furthermore, XRD measurements with a focused beam at 41.5 keV were carried out. Equimolar ceria-hafnia was auto-reduced in a flow of argon and chemically reduced in a flow of hydrogen/helium. Under reducing conditions, all cerium(iv) was converted to cerium(iii) and a cation-ordered pyrochlore-type structure was formed, which was not stable upon oxidation in a flow of carbon dioxide. PMID- 28863640 TI - Synchronous acquisition of multi-channel signals by single-channel ADC based on square wave modulation. AB - Synchronous acquisition of multi-channel biopotential signals, such as electrocardiograph (ECG) and electroencephalograph, has vital significance in health care and clinical diagnosis. In this paper, we proposed a new method which is using single channel ADC to acquire multi-channel biopotential signals modulated by square waves synchronously. In this method, a specific modulate and demodulate method has been investigated without complex signal processing schemes. For each channel, the sampling rate would not decline with the increase of the number of signal channels. More specifically, the signal-to-noise ratio of each channel is n times of the time-division method or an improvement of 3.01*log2n dB, where n represents the number of the signal channels. A numerical simulation shows the feasibility and validity of this method. Besides, a newly developed 8-lead ECG based on the new method has been introduced. These experiments illustrate that the method is practicable and thus is potential for low-cost medical monitors. PMID- 28863642 TI - Nanometer-resolution depth-resolved measurement of florescence-yield soft x-ray absorption spectroscopy for FeCo thin film. AB - We develop a fluorescence-yield depth-resolved soft x-ray absorption spectroscopy (XAS) technique, which is based on the principle that the probing depth is changed by the emission angle of the fluorescence soft x rays. Compared with the electron-yield depth-resolved XAS technique, which has been established in this decade, we can observe wider range in-depth XAS distribution up to several tens of nm. Applying this technique to a 30 ML (~4.3 nm) FeCo thin film, we observe Fe L-edge XAS spectra at the probing depth of 0.3-6 nm and find that the film has 22 ML (~3.1 nm) surface oxide layer while its inner layer shows metallic state. We thus successfully obtain nanometer-resolution depth-resolved XAS spectra and further expect that operando measurement under the electric and/or magnetic fields is possible. PMID- 28863641 TI - A high-resolution frequency variable experimental setup for studying ferrofluids used in magnetic hyperthermia. AB - A scanning system for specific absorption rate of ferrofluids with superparamagnetic nanoparticles is presented in this study. The system contains an induction heating device designed and built with a resonant inverter in order to generate magnetic field amplitudes up to 38 mT, over the frequency band 180 525 kHz. Its resonant circuit involves a variable capacitor with 1 nF of capacitance steps to easily select the desired frequency, reaching from 0.3 kHz/nF up to 5 kHz/nF of resolution. The device performance is characterized in order to compare with the theoretical predictions of frequency and amplitude, showing a good agreement with the resonant inverters theory. Additionally, the setup is tested using a synthetic iron oxide with 10 +/- 1 nm diameter suspended in liquid glycerol, with concentrations at 1%. Meanwhile, the temperature rise is measured to determine the specific absorption rate and calculate the dissipated power density for each f. This device is a suitable alternative to studying ferrofluids and analyzes the dependence of the power absorption density with the magnetic field intensity and frequency. PMID- 28863643 TI - Linearized spectrum correlation analysis for line emission measurements. AB - A new spectral analysis method, Linearized Spectrum Correlation Analysis (LSCA), for charge exchange and passive ion Doppler spectroscopy is introduced to provide a means of measuring fast spectral line shape changes associated with ion-scale micro-instabilities. This analysis method is designed to resolve the fluctuations in the emission line shape from a stationary ion-scale wave. The method linearizes the fluctuations around a time-averaged line shape (e.g., Gaussian) and subdivides the spectral output channels into two sets to reduce contributions from uncorrelated fluctuations without averaging over the fast time dynamics. In principle, small fluctuations in the parameters used for a line shape model can be measured by evaluating the cross spectrum between different channel groupings to isolate a particular fluctuating quantity. High-frequency ion velocity measurements (100-200 kHz) were made by using this method. We also conducted simulations to compare LSCA with a moment analysis technique under a low photon count condition. Both experimental and synthetic measurements demonstrate the effectiveness of LSCA. PMID- 28863644 TI - Note: Planetary gravities made simple: Sample test of a Mars rover wheel. AB - We introduce an instrument for a wide spectrum of experiments on gravities other than our planet's. It is based on a large Atwood machine where one of the loads is a bucket equipped with a single board computer and different sensors. The computer is able to detect the falling (or rising) and then the stabilization of the effective gravity and to trigger actuators depending on the experiment. Gravities within the range 0.4 g-1.2 g are easily achieved with acceleration noise of the order of 0.01 g. Under Martian gravity, we are able to perform experiments of approximately 1.5 s duration. The system includes features such as WiFi and a web interface with tools for the setup, monitoring, and data analysis of the experiment. We briefly show a case study in testing the performance of a model Mars rover wheel in low gravities. PMID- 28863646 TI - Development of a 10 kHz high harmonic source up to 140 eV photon energy for ultrafast time-, angle-, and phase-resolved photoelectron emission spectroscopy on solid targets. AB - We present a newly developed high harmonic beamline for time-, angle-, and carrier-envelope phase-resolved extreme ultraviolet photoemission spectroscopy on solid targets for the investigation of ultrafast band structure dynamics in the low-fs to sub-fs time regime. The source operates at a repetition rate of 10 kHz and is driven by 5 fs few-cycle near-infrared laser pulses generating high harmonic radiation with photon energies up to 120 eV at a feasible flux. The experimental end station consists of a complementary combination of photoelectron detectors which are able to spectroscopically address electron dynamics both in real and in k-space. The versatility of the source is completed by a phase-meter which allows for tracking the carrier-envelope phase for each pulse and which is synchronized to the photoelectron detectors, thus enabling phase sensitive measurements on the one hand and the selection of single attosecond pulses for ultimate time resolution in pump-probe experiments on the other hand. We demonstrate the applicability of the source by an angle- and carrier-envelope phase-resolved photoemission measurement on a tungsten (110) surface with 95 eV extreme ultraviolet radiation. PMID- 28863647 TI - Development of a real time magnetic island identification system for HL-2A tokamak. AB - A novel real time magnetic island identification system for HL-2A is introduced. The identification method is based on the measurement of Mirnov probes and the equilibrium flux constructed by the equilibrium fit (EFIT) code. The system consists of an analog front board and a digital processing board connected by a shield cable. Four octal-channel analog-to-digital convertors are utilized for 100 KHz simultaneous sampling of all the probes, and the applications of PCI extensions for Instrumentation platform and reflective memory allow the system to receive EFIT results simultaneously. A high performance field programmable gate array (FPGA) is used to realize the real time identification algorithm. Based on the parallel and pipeline processing of the FPGA, the magnetic island structure can be identified with a cycle time of 3 ms during experiments. PMID- 28863645 TI - Instrumentation for electrochemical performance characterization of neural electrodes. AB - In an effort to determine the chronic stability, sensitivity, and thus the potential viability of various neurochemical recording electrode designs and compositions, we have developed a custom device called the Voltammetry Instrument for Neurochemical Applications (VINA). Here, we describe the design of the VINA and initial testing of its functionality for prototype neurochemical sensing electrodes. The VINA consists of multiple electrode fixtures, a flowing electrolyte bath, associated reservoirs, peristaltic pump, voltage waveform generator, data acquisition hardware, and system software written in National Instrument's LabVIEW. The operation of VINA was demonstrated on a set of boron doped diamond neurochemical recording electrodes, which were subjected to an applied waveform for a period of eighteen days. Each electrode's cyclic voltammograms (CVs) were recorded, and sensitivity calibration to dopamine (DA) was performed. Results showed an initial decline with subsequent stabilization in the CV current measured during the voltammetric sweep, corresponding closely with changes in electrode sensitivity to DA. The VINA has demonstrated itself as a useful tool for the characterization of electrode stability and chronic electrochemical performance. PMID- 28863648 TI - Low-profile self-sealing sample transfer flexure box. AB - A flexural bearing mechanism has enabled the development of a self-sealing box for protecting air sensitive samples during transfer between glove boxes, micro machining equipment, and microscopy equipment. The simplicity and self-actuating feature of this design makes it applicable to many devices that operate under vacuum conditions. The models used to design the flexural mechanism are presented in detail. The device has been tested in a Zeiss Merlin GEMINI II scanning electron microscope with Li3PS4 samples, showing effective isolation from air and corrosion prevention. PMID- 28863649 TI - Phase-ambiguity-free and accurate permittivity determination from waveguide measurements. AB - A microwave method has been proposed for accurate and unique extraction of relative complex permittivity (epsilonr) of dielectric materials from 2pi phase ambiguity-free amplitude-only two-port and one-port scattering parameter measurements. Improved accuracy has been shown by the applied uncertainty analysis. For the validation of our method, epsilonr of low-loss and lossy samples was extracted. PMID- 28863650 TI - Note: A miniature oscillating microbalance for sampling ice and volcanic ash from a small airborne platform. AB - A lightweight and low power oscillating microbalance for in situ sampling of atmospheric ice and volcanic ash is described for airborne platforms. Using a freely exposed collecting wire fixed at only one end to a piezo transducer, the instrument collects airborne materials. Accumulated mass is determined from the change in natural frequency of the wire. The piezo transducer is used in a dual mode to both drive and detect the oscillation. Three independent frequency measurement techniques are implemented with an on-board microcontroller: a frequency sweep, a Fourier spectral method, and a phase-locked loop. These showed agreement to +/-0.3 Hz for a 0.5 mm diameter collecting wire of 120 mm long, flown to 19 km altitude on a weather balloon. The instrument is well suited to disposable use with meteorological radiosondes, to provide high resolution vertical profiles of mass concentration. PMID- 28863651 TI - Validation of reverse Hartmann test for mirror shape measurement of parabolic trough concentrator. AB - A method for the surface shape qualification of a parabolic trough solar concentrator, based on the reflection of sinusoidal fringes in the mirror surface and their distortions due to the surface deviations from ideal geometry, has been developed. Without complex calibration, accurate surface slope data were collected and reduced by using sixteen-step phase shifting methods. As the gradient data may not be ideally available for the entire surface, surface deviations and geometrical parameters were obtained through Zernike slope polynomials iterative fitting and the Southwell integration algorithm. Additionally, an absolute reference measurement for calibration of the measurement accuracy using three standard mirrors is presented. It is shown that the proposed method can easily test the surface shape and concentration efficiency of a solar concentrator with high slope measurement accuracy (less than 0.05 mrad in the x-direction) and high spatial resolution (more than 2.5 * 106 points per mirror facet). PMID- 28863652 TI - High-speed 100 MHz strain monitor using fiber Bragg grating and optical filter for magnetostriction measurements under ultrahigh magnetic fields. AB - A high-speed 100 MHz strain monitor using a fiber Bragg grating, an optical filter, and a mode-locked optical fiber laser has been devised, whose resolution is DeltaL/L~10-4. The strain monitor is sufficiently fast and robust for the magnetostriction measurements of materials under ultrahigh magnetic fields generated with destructive pulse magnets, where the sweep rate of the magnetic field is in the range of 10-100 T/MUs. As a working example, the magnetostriction of LaCoO3 was measured at room temperature, 115 K, and 7 ~ 4.2 K up to a maximum magnetic field of 150 T. The smooth dependence on the squared magnetic field and the first-order transition were observed at 115 K and 7 ~ 4.2 K, respectively, reflecting the field-induced spin state evolution. PMID- 28863653 TI - Sine wave gating silicon single-photon detectors for multiphoton entanglement experiments. AB - Silicon single-photon detectors (SPDs) are the key devices for detecting single photons in the visible wavelength range. Here we present high detection efficiency silicon SPDs dedicated to the generation of multiphoton entanglement based on the technique of high-frequency sine wave gating. The silicon single photon avalanche diode components are acquired by disassembling 6 commercial single-photon counting modules (SPCMs). Using the new quenching electronics, the average detection efficiency of SPDs is increased from 68.6% to 73.1% at a wavelength of 785 nm. These sine wave gating SPDs are then applied in a four photon entanglement experiment, and the four-fold coincidence count rate is increased by 30% without degrading its visibility compared with the original SPCMs. PMID- 28863654 TI - Note: Measurement of synchrotron radiation phase-space beam properties to verify astigmatism compensation in Fresnel zone plate focusing optics. AB - The intensity distribution in phase space of an X-ray synchrotron radiation beamline was measured using a pinhole camera method, in order to verify astigmatism compensation by a Fresnel zone plate focusing optical system. The beamline is equipped with a silicon double crystal monochromator. The beam size and divergence at an arbitrary distance were estimated. It was found that the virtual source point was largely different between the vertical and horizontal directions, which is probably caused by thermal distortion of the monochromator crystal. The result is consistent with our astigmatism compensation by inclining a Fresnel zone plate. PMID- 28863655 TI - Design and implementation of improved LsCpLp resonant circuit for power supply for high-power electromagnetic acoustic transducer excitation. AB - This paper investigates the design and implementation of an improved series parallel inductor-capacitor-inductor (LsCpLp) resonant circuit power supply for excitation of electromagnetic acoustic transducers (EMATs). The main advantage of the proposed resonant circuit is the absence of a high-permeability dynamic transformer. A high-frequency pulsating voltage gain can be achieved through a double resonance phenomenon. Both resonant tailing behavior and higher harmonics are suppressed by the improved resonant circuit, which also contributes to the generation of ultrasonic waves. Additionally, the proposed circuit can realize impedance matching and can also optimize the transduction efficiency. The complete design and implementation procedure for the power supply is described and has been validated by implementation of the proposed power supply to drive a portable EMAT. The circuit simulation results show close agreement with the experimental results and thus confirm the validity of the proposed topology. The proposed circuit is suitable for use as a portable EMAT excitation power supply that is fed by a low-voltage source. PMID- 28863656 TI - Source reconstruction for neutron coded-aperture imaging: A sparse method. AB - Neutron coded-aperture imaging has been developed as an important diagnostic for inertial fusion studies in recent decades. It is used to measure the distribution of neutrons produced in deuterium-tritium plasma. Source reconstruction is an essential part of the coded-aperture imaging. In this paper, we applied a sparse reconstruction method to neutron source reconstruction. This method takes advantage of the sparsity of the source image. Monte Carlo neutron transport simulations were performed to obtain the system response. An interpolation method was used while obtaining the spatially variant point spread functions on each point of the source in order to reduce the number of point spread functions that needs to be calculated by the Monte Carlo method. Source reconstructions from simulated images show that the sparse reconstruction method can result in higher signal-to-noise ratio and less distortion at a relatively high statistical noise level. PMID- 28863657 TI - Development of high sensitivity 4H-SiC detectors for fission neutron pulse shape measurements. AB - 4H-silicon carbide (4H-SiC) detectors are well suited for measurements of fission neutron pulse shape for their compact size, excellent radiation resistance, and hydrogen free composition. The aim of this study is to improve the 4H-SiC detector's sensitivity to fission neutron pulses. 4H-SiC detectors with varied epilayer thicknesses are fabricated and then tested in the pulsed neutron field of the Chinese Fast Burst Reactor II (CFBR II). The sensitivity of the 4H-SiC detector to the CFBR II neutron pulse is increased by 139.8%, with the enlargement of epilayer thickness from 20 MUm to 120 MUm. By employing the proton recoil method, the sensitivity of the 4H-SiC detector to the CFBR II neutron pulse is further increased by 11.6%. With enhanced sensitivity to fission neutron pulses, 4H-SiC detectors are promising devices for high intensity neutron pulse measurements. PMID- 28863658 TI - Influence of non-local thermodynamic equilibrium and Zeeman effects on magnetic equilibrium reconstruction using spectral motional Stark effect diagnostic. AB - The Motional Stark Effect (MSE) diagnostic is a well established technique to infer the local internal magnetic field in fusion plasmas. In this paper, the existing forward model which describes the MSE data is extended by the Zeeman effect, fine-structure, and relativistic corrections in the interpretation of the MSE spectra for different experimental conditions at the tokamak ASDEX Upgrade. The contribution of the non-Local Thermodynamic Equilibrium (non-LTE) populations among the magnetic sub-levels and the Zeeman effect on the derived plasma parameters is different. The obtained pitch angle is changed by 3 degrees ...4 degrees and by 0.5 degrees ...1 degrees including the non-LTE and the Zeeman effects into the standard statistical MSE model. The total correction is about 4 degrees . Moreover, the variation of the magnetic field strength is significantly changed by 2.2% due to the Zeeman effect only. While the data on the derived pitch angle still could not be tested against the other diagnostics, the results from an equilibrium reconstruction solver confirm the obtained values for magnetic field strength. PMID- 28863659 TI - Taylor-Couette flow with radial fluid injection. AB - Taylor-Couette cells have been shown to improve a number of industrial processes due to the wide variety of hydrodynamic flow states accessible. Traditional designs, however, limit the ability to introduce new fluids into the annulus during device operation due to geometric confinement and complexity. In this paper, a co- and counter-rotating Taylor-Couette cell with radial fluid injection has been constructed. The incorporation of 16 ports in the inner cylinder enables radial fluid injection during rotation of both cylinders. The design is also capable of continuous axial flow, enabling large injection volumes. The new inner cylinder design does not modify the critical Re for flow instabilities and can precisely inject a desired mass at a desired flow rate. A range of injection rates and masses were explored to quantify the effect of radial injection on the stability of the turbulent Taylor vortex structure. Only the highest injection rate and total mass studied (5.9 g/s, 100 g) modified the turbulent Taylor vortex structure after injection for a sustained period. The post-injection vortices remained larger than the pre-injection vortices, whereas at lower injection rates or masses, the vortex structure quickly returned to the pre-injection structure. This new system allows for in situ study of hydrodynamic effects on fluid-fluid (gas and liquid) mixing and multiphase complexation, growth, and structure. We demonstrated this new design's potential for studying the flocculation of bentonite using cationic polyacrylamide for enhancing water treatment operations. PMID- 28863661 TI - Fringe order correction for the absolute phase recovered by two selected spatial frequency fringe projections in fringe projection profilometry. AB - The performance of the two selected spatial frequency phase unwrapping methods is limited by a phase error bound beyond which errors will occur in the fringe order leading to a significant error in the recovered absolute phase map. In this paper, we propose a method to detect and correct the wrong fringe orders. Two constraints are introduced during the fringe order determination of two selected spatial frequency phase unwrapping methods. A strategy to detect and correct the wrong fringe orders is also described. Compared with the existing methods, we do not need to estimate the threshold associated with absolute phase values to determine the fringe order error, thus making it more reliable and avoiding the procedure of search in detecting and correcting successive fringe order errors. The effectiveness of the proposed method is validated by the experimental results. PMID- 28863660 TI - Calibration of the linear response range of x-ray imaging plates and their reader based on image grayscale values. AB - X-ray imaging plates are one of the most important X-ray imaging detectors and are widely used in inertial-confinement fusion experiments. However, their linear response range, which is the foundation of their quantitative data analysis, has not been sufficiently deeply investigated. In this work, we develop an X-ray fluorescer calibration system and carefully explore the linear response range of X-ray imaging plates. For the first time, nearly the entire grayscale range of the X-ray imaging plate linear response-7819-64 879 in the range of 0-65 535-has been observed. Further, we discuss the uncertainties involved in the calibration process. This work demonstrates the excellent linear response qualities of X-ray imaging plates and provides a significant foundation for expanding their quantitative applied range. PMID- 28863662 TI - Noninvasive hemoglobin measurement using dynamic spectrum. AB - Spectroscopy methods for noninvasive hemoglobin (Hgb) measurement are interfered by individual difference and particular weak signal. In order to address these problems, we have put forward a series of improvement methods based on dynamic spectrum (DS), including instrument design, spectrum extraction algorithm, and modeling approach. The instrument adopts light sources composed of eight laser diodes with the wavelength range from 600 nm to 1100 nm and records photoplethysmography signals at eight wavelengths synchronously. In order to simplify the optical design, we modulate the light sources with orthogonal square waves and design the corresponding demodulation algorithm, instead of adopting a beam-splitting system. A newly designed algorithm named difference accumulation has been proved to be effective in improving the accuracy of dynamic spectrum extraction. 220 subjects are involved in the clinical experiment. An extreme learning machine calibration model between the DS data and the Hgb levels is established. Correlation coefficient and root-mean-square error of prediction sets are 0.8645 and 8.48 g/l, respectively. The results indicate that the Hgb level can be derived by this approach noninvasively with acceptable precision and accuracy. It is expected to achieve a clinic application in the future. PMID- 28863663 TI - Note: Progress on the use of MgB2 superconducting joint technique for the development of MgB2 magnets for magnetic resonance imaging (MRI). AB - This note presents a superconducting joint technique for the development of MgB2 magnetic resonance imaging (MRI) magnets. The MgB2 superconducting joint was fabricated by a powder processing method using Mg and B powders to establish a wire-bulk-wire connection. The joint resistance measured using a field-decay method was <10-14 Omega, demonstrating that the proposed joint technique could be employed for developing "next-generation" MgB2 MRI magnets operating in the persistent current mode. PMID- 28863664 TI - High-throughput powder diffraction measurement system consisting of multiple MYTHEN detectors at beamline BL02B2 of SPring-8. AB - In this study, we developed a user-friendly automatic powder diffraction measurement system for Debye-Scherrer geometry using a capillary sample at beamline BL02B2 of SPring-8. The measurement system consists of six one dimensional solid-state (MYTHEN) detectors, a compact auto-sampler, wide-range temperature control systems, and a gas handling system. This system enables to do the automatic measurement of temperature dependence of the diffraction patterns for multiple samples. We introduced two measurement modes in the MYTHEN system and developed new attachments for the sample environment such as a gas handling system. The measurement modes and the attachments can offer in situ and/or time resolved measurements in an extended temperature range between 25 K and 1473 K and various gas atmospheres and pressures. The results of the commissioning and performance measurements using reference materials (NIST CeO2 674b and Si 640c), V2O3 and Ti2O3, and a nanoporous coordination polymer are presented. PMID- 28863665 TI - Real-time digital signal recovery for a multi-pole low-pass transfer function system. AB - In order to solve the problems of waveform distortion and signal delay by many physical and electrical systems with multi-pole linear low-pass transfer characteristics, a simple digital-signal-processing (DSP)-based method of real time recovery of the original source waveform from the distorted output waveform is proposed. A mathematical analysis on the convolution kernel representation of the single-pole low-pass transfer function shows that the original source waveform can be accurately recovered in real time using a particular moving average algorithm applied on the input stream of the distorted waveform, which can also significantly reduce the overall delay time constant. This method is generalized for multi-pole low-pass systems and has noise characteristics of the inverse of the low-pass filter characteristics. This method can be applied to most sensors and amplifiers operating close to their frequency response limits to improve the overall performance of data acquisition systems and digital feedback control systems. PMID- 28863666 TI - Practical methods for generating alternating magnetic fields for biomedical research. AB - Alternating magnetic fields (AMFs) cause magnetic nanoparticles (MNPs) to dissipate heat while leaving surrounding tissue unharmed, a mechanism that serves as the basis for a variety of emerging biomedical technologies. Unfortunately, the challenges and costs of developing experimental setups commonly used to produce AMFs with suitable field amplitudes and frequencies present a barrier to researchers. This paper first presents a simple, cost-effective, and robust alternative for small AMF working volumes that uses soft ferromagnetic cores to focus the flux into a gap. As the experimental length scale increases to accommodate animal models (working volumes of 100s of cm3 or greater), poor thermal conductivity and volumetrically scaled core losses render that strategy ineffective. Comparatively feasible strategies for these larger volumes instead use low loss resonant tank circuits to generate circulating currents of 1 kA or greater in order to produce the comparable field amplitudes. These principles can be extended to the problem of identifying practical routes for scaling AMF setups to humans, an infrequently acknowledged challenge that influences the extent to which many applications of MNPs may ever become clinically relevant. PMID- 28863667 TI - Probabilistic n/gamma discrimination with robustness against outliers for use in neutron profile monitors. AB - A method to stochastically discriminate neutron and gamma-ray signals measured with a stilbene organic scintillator is proposed. Each pulse signal was stochastically categorized into two groups: neutron and gamma-ray. In previous work, the Expectation Maximization (EM) algorithm was used with the assumption that the measured data followed a Gaussian mixture distribution. It was shown that probabilistic discrimination between these groups is possible. Moreover, by setting the initial parameters for the Gaussian mixture distribution with a k means algorithm, the possibility of automatic discrimination was demonstrated. In this study, the Student's t-mixture distribution was used as a probabilistic distribution with the EM algorithm to improve the robustness against the effect of outliers caused by pileup of the signals. To validate the proposed method, the figures of merit (FOMs) were compared for the EM algorithm assuming a t-mixture distribution and a Gaussian mixture distribution. The t-mixture distribution resulted in an improvement of the FOMs compared with the Gaussian mixture distribution. The proposed data processing technique is a promising tool not only for neutron and gamma-ray discrimination in fusion experiments but also in other fields, for example, homeland security, cancer therapy with high energy particles, nuclear reactor decommissioning, pattern recognition, and so on. PMID- 28863668 TI - Gain depletion of X-ray framing camera. AB - X-ray imaging is very useful to investigate imploded core plasma in inertial fusion experiments. We can obtain information from X-ray images, such as shape, density, and temperature. An X-ray framing camera (XFC) capable of taking two dimensional, time-resolved X-ray images is used to capture the images. In previous work, we developed a numerical model of an XFC to analyze its X-ray image. The calculated results agreed qualitatively with experimental results. However, it was not accurate enough to determine the absolute value of the signal. We thought this discrepancy was caused by gain depletion. In high energy laser experiments, high photon flux may cause gain depletion. This is a problem for accurate X-ray measurement. In this paper, we report our new model, including gain depletion. The new model is evaluated by tabletop laser experiments and high energy laser experiments. The results calculated using the new model agree quantitatively with our experimental results. Furthermore, we confirmed that gain depletion occurs in our high energy laser experiments. For quantitatively accurate X-ray intensity measurements, the XFC should be used with limited incident photon flux such that the gain linearity is guaranteed. PMID- 28863669 TI - Electrometer with sub-attoampere current load. AB - By cooling a conventional junction field-effect transistor below 150 K, a simple and versatile electrometer with extremely high impedance can be realized. At operating condition, the leakage current to the gate amounts to a few hundredths of an attoampere. The electrometer can be used from DC up to a frequency of 10 kHz. Without reduction of the bandwidth, a sensitivity of a few MUV is obtained. Working at low frequencies, currents as low as a few attoamperes can be detected. If the input voltage is out of the operational range, the forward current or the Zener current of the gate junction protects the transistor against destructive charging. PMID- 28863670 TI - Temperature-stabilized differential amplifier for low-noise DC measurements. AB - A tabletop low-noise differential amplifier with a bandwidth of 100 kHz is presented. Low voltage drifts of the order of 100 nV/day are reached by thermally stabilizing relevant amplifier components. The input leakage current is below 100 fA. Input-stage errors are reduced by extensive circuitry. Voltage noise, current noise, input capacitance, and input current are extraordinarily low. The input resistance is larger than 1 TOmega. The amplifiers were tested with and deployed for electrical transport measurements of quantum devices at cryogenic temperatures. PMID- 28863671 TI - Instrumentation for ice crystal characterization in laboratory using interferometric out-of-focus imaging. AB - Airborne characterization of ice crystals has important applications. The extreme difficulty of realizing in situ tests requires the development of a complete instrumentation in the laboratory. Such an installation should enable design, development, test, and calibration of instruments in conditions as close as possible to real ones. We present a set of numerical and experimental tools that have been developed to realize ice crystal sensors based on interferometric particle imaging. The set of tools covers the development of complementary simulators for crystal growth and interferometric particle imaging predictions, experimental generation of "programmable" ice crystals, and instrumentation of a freezing column where different techniques as in-focus imaging, out-of-focus imaging, and digital in-line holography can be combined simultaneously for test and calibration. PMID- 28863672 TI - A new high sensitivity far-infrared laser interferometer for the HL-2A tokamak. AB - A new four-chord Michelson-type formic acid (HCOOH, lambda = 432.5 MUm) laser interferometer has been successfully commissioned on the HL-2A tokamak to measure the electron density and density fluctuations. Due to the employment of the two laser heterodyne technique, the time resolution of the interferometer reached 1.0 microseconds (MUs). Four chords of line electron densities with a line-averaged density resolution 2 * 1016/m3 were obtained in a recent HL-2A experimental campaign, and detailed electron density fluctuations, caused by events such as edge localized mode, sawtooth precursor-oscillations, and energetic particle driven instabilities, were distinctly measured. In particular, the high-frequency electron density fluctuations (up to 500 kHz) caused by the reversed shear Alfvenic eigenmode were observed by the internal two interferometry channels, and their fluctuation location could be approximately identified from the spectra characteristics of multi-chord line electron densities. PMID- 28863673 TI - Development of cable fed flash X-ray (FXR) system. AB - Flash X-ray sources driven by pulsed power find applications in industrial radiography, and a portable X-ray source is ideal where the radiography needs to be taken at the test site. A compact and portable flash X-ray (FXR) system based on a Marx generator has been developed with the high voltage fed to the FXR tube via a cable feed-through arrangement. Hard bremsstrahlung X-rays of few tens of nanosecond duration are generated by impinging intense electron beams on an anode target of high Z material. An industrial X-ray source is developed with source size as low as 1 mm. The system can be operated from 150 kV to 450 kV peak voltages and a dose of 10 mR has been measured at 1 m distance from the source window. The modeling of the FXR source has been carried out using particle-in cell and Monte Carlo simulations for the electron beam dynamics and X-ray generation, respectively. The angular dose profile of X-ray has been measured and compared with the simulation. PMID- 28863674 TI - New laser power sensor using diamagnetic levitation. AB - This paper presents a preliminary study of an elementary device consisting of a small plate made from pyrolytic carbon levitated above a magnet array which is sensitive to any irradiating laser power. This device might provide an interesting alternative to power meters based on thermal measurement techniques via the Stefan-Boltzmann law or the photon-electron interaction. We show that the photo-response of a pyrolytic carbon plate in terms of levitation height versus irradiation power in the range of 20 mW to 1 W is sufficiently linear, sensitive, and reproducible to be used as a laser power sensor. The elevation height change as a function of irradiance time appears to be a suitable measurement parameter for establishing a relation with the irradiating laser power. The influence of some quantities affecting the measurement results has been highlighted. The study demonstrates that such a device should prove useful for applications in metrology, industry, or emerging technologies. PMID- 28863675 TI - Note: Modification of an FTIR spectrometer for optoelectronic characterizations. AB - We propose a very simple system to be adapted to a Fourier Transform Infra-Red (FTIR) spectrometer with which three different types of characterizations can be done: the Fourier transform photocurrent spectroscopy, the recording of reflection-transmission spectra of thin film semiconductors, and the acquisition of spectral responses of solar cells. In addition to gather three techniques into a single apparatus, this FTIR-based system also significantly reduces the recording time and largely improves the resolution of the measured spectra compared to standard equipments. PMID- 28863676 TI - A 5-MUm pitch charge-coupled device optimized for resonant inelastic soft X-ray scattering. AB - We have developed a charge-coupled device (CCD) with 5 MUm * 45 MUm pixels on high-resistivity silicon. The fully depleted 200 MUm-thick silicon detector is back-illuminated through a 10 nm-thick in situ doped polysilicon window and is thus highly efficient for soft through >8 keV hard X-rays. The device described here is a 1.5 megapixel CCD with 2496 * 620 pixels. The pixel and camera geometry was optimized for Resonant Inelastic X-ray Scattering (RIXS) and is particularly advantageous for spectrometers with limited arm lengths. In this article, we describe the device architecture, construction and operation, and its performance during tests at the Advance Light Source (ALS) 8.0.1 RIXS beamline. The improved spectroscopic performance, when compared with a current standard commercial camera, is demonstrated with a ~280 eV (CK) X-ray beam on a graphite sample. Readout noise is typically 3-6 electrons and the point spread function for soft CK X-rays in the 5 MUm direction is 4.0 MUm +/- 0.2 MUm. The measured quantum efficiency of the CCD is greater than 75% in the range from 200 eV to 1 keV. PMID- 28863677 TI - A gated Thomson parabola spectrometer for improved ion and neutral atom measurements in intense laser produced plasmas. AB - Ions of high energy and high charge are accelerated from compact intense laser produced plasmas and are routinely analysed either by time of flight or Thomson parabola spectrometry. At the highest intensities where ion energies can be substantially large, both these techniques have limitations. Strong electromagnetic pulse noise jeopardises the arrival time measurement, and a bright central spot in the Thomson parabola spectrometer affects the signal to noise ratio of ion traces that approach close to the central spot. We present a gated Thomson parabola spectrometer that addresses these issues and provides an elegant method to improvise ion spectrometry. In addition, we demonstrate that this method provides the ability to detect and measure high energy neutral atoms that are invariably present in most intense laser plasma acceleration experiments. PMID- 28863678 TI - Note: Guaranteed collocated multimode control of an atomic force microscope cantilever using on-chip piezoelectric actuation and sensing. AB - The quality (Q) factor is an important parameter of the resonance of the microcantilever as it determines both imaging bandwidth and force sensitivity. The ability to control the Q factor of multiple modes is believed to be of great benefit for atomic force microscopy techniques involving multiple eigenmodes. In this paper, we propose a novel cantilever design employing multiple piezoelectric transducers which are used for separated actuation and sensing, leading to guaranteed collocation of the first eight eigenmodes up to 3 MHz. The design minimizes the feedthrough usually observed with these systems by incorporating a guard trace on the cantilever chip. As a result, a multimode Q controller is demonstrated to be able to modify the quality factor of the first two eigenmodes over up to four orders of magnitude without sacrificing robust stability. PMID- 28863679 TI - Novel diamond cells for neutron diffraction using multi-carat CVD anvils. AB - Traditionally, neutron diffraction at high pressure has been severely limited in pressure because low neutron flux required large sample volumes and therefore large volume presses. At the high-flux Spallation Neutron Source at the Oak Ridge National Laboratory, we have developed new, large-volume diamond anvil cells for neutron diffraction. The main features of these cells are multi-carat, single crystal chemical vapor deposition diamonds, very large diffraction apertures, and gas membranes to accommodate pressure stability, especially upon cooling. A new cell has been tested for diffraction up to 40 GPa with an unprecedented sample volume of ~0.15 mm3. High quality spectra were obtained in 1 h for crystalline Ni and in ~8 h for disordered glassy carbon. These new techniques will open the way for routine megabar neutron diffraction experiments. PMID- 28863680 TI - An investigation of interface transferring mechanism of surface-bonded fiber Bragg grating sensors. AB - Surface-bonded fiber Bragg grating sensor has been widely used in measuring strain in materials. The existence of fiber Bragg grating sensor affects strain distribution of the host material, which may result in a decrease in strain measurement accuracy. To improve the measurement accuracy, a theoretical model of strain transfer from the host material to optical fiber was developed, incorporating the influence of the fiber Bragg grating sensor. Subsequently, theoretical predictions were validated by comparing with data from finite element analysis and the existing experiment [F. Ansari and Y. Libo, J. Eng. Mech. 124(4), 385-394 (1998)]. Finally, the effect of parameters of fiber Bragg grating sensors on the average strain transfer rate was discussed. PMID- 28863681 TI - Optical device for thermal diffusivity determination in liquids by reflection of a thermal wave. AB - In this work, we present a device for determination of the thermal diffusivity using the oblique reflection of a thermal wave within a solid slab that is in contact with the medium to be characterized. By using the reflection near a critical angle under the assumption that thermal waves obey Snell's law of refraction with the square root of the thermal diffusivities, the unknown thermal diffusivity is obtained by simple formulae. Experimentally, the sensor response is measured using the photothermal beam deflection technique within a slab that results in a compact device with no contact of the laser probing beam with the sample. We describe the theoretical basis and provide experimental results to validate the proposed method. We determine the thermal diffusivity of tridistilled water and glycerin solutions with an error of less than 0.5%. PMID- 28863682 TI - Determining the ion temperature and energy distribution in a lithium-plasma interaction test stand with a retarding field energy analyzer. AB - The ThermoElectric-driven Liquid-metal plasma-facing Structures (TELS) experiment at the University of Illinois is a gas-puff driven, theta-pinch plasma source that is used as a test stand for off-normal plasma events incident on materials in the edge and divertor regions of a tokamak. The ion temperatures and resulting energy distributions are crucial for understanding how well a TELS pulse can simulate an extreme event in a larger, magnetic confinement device. A retarding field energy analyzer (RFEA) has been constructed for use with such a transient plasma due to its inexpensive and robust nature. The innovation surrounding the use of a control analyzer in conjunction with an actively sampling analyzer is presented and the conditions of RFEA operation are discussed, with results presented demonstrating successful performance under extreme conditions. Such extreme conditions are defined by heat fluxes on the order of 0.8 GW m-2 and on time scales of nearly 200 MUs. Measurements from the RFEA indicate two primary features for a typical TELS discharge, following closely with the pre-ionizing coaxial gun discharge characteristics. For the case using the pre-ionization pulse (PiP) and the theta pinch, the measured ion signal showed an ion temperature of 23.3 +/- 6.6 eV for the first peak and 17.6 +/- 1.9 eV for the second peak. For the case using only the PiP, the measured signal showed an ion temperature of 7.9 +/- 1.1 eV for the first peak and 6.6 +/- 0.8 eV for the second peak. These differences illustrate the effectiveness of the theta pinch for imparting energy on the ions. This information also highlights the importance of TELS as being one of the few linear pulsed plasma sources whereby moderately energetic ions will strike targets without the need for sample biasing. PMID- 28863683 TI - Portable double-sided pulsed laser heating system for time-resolved geoscience and materials science applications. AB - A portable double-sided pulsed laser heating system for diamond anvil cells has been developed that is able to stably produce laser pulses as short as a few microseconds with repetition frequencies up to 100 kHz. In situ temperature determination is possible by collecting and fitting the thermal radiation spectrum for a specific wavelength range (particularly, between 650 nm and 850 nm) to the Planck radiation function. Surface temperature information can also be time-resolved by using a gated detector that is synchronized with the laser pulse modulation and space-resolved with the implementation of a multi-point thermal radiation collection technique. The system can be easily coupled with equipment at synchrotron facilities, particularly for nuclear resonance spectroscopy experiments. Examples of applications include investigations of high-pressure high-temperature behavior of iron oxides, both in house and at the European Synchrotron Radiation Facility using the synchrotron Mossbauer source and nuclear inelastic scattering. PMID- 28863684 TI - Note: Hybrid-pi model and parameter extraction method for electrode-electrolyte interface characterization with superbly accurate reactance. AB - This paper presents an equivalent circuit model for the electrode-electrolyte interface and aims at improving the modeling accuracy of the parasitic effects at frequencies up to 300 MHz. Different from the conventional model, the electrode inductances, body loss capacitances, and body loss resistances are all included in the proposed hybrid-pi model. In addition, the S-parameters obtained by a vector network analyzer are innovatively used to extract the parameters of the electrode-electrolyte interface model for a frequency range from 10 Hz to 300 MHz. Since reactance is proportional to frequency, the proposed technique can precisely calculate the parasitic effects at higher frequencies. Verified by experiments, the hybrid-pi model presents better accuracies when fitted to both the phases and magnitudes of S11 and S21. The superb modeling accuracy of this work is beneficial for biomedical applications that have an electrode-electrolyte interface. PMID- 28863685 TI - Note: Single ion imaging and fluorescence collection with a parabolic mirror trap. AB - Efficient fluorescence collection is the most challenging part in remote entangled ion qubit state generation. To address this issue, we developed an ion trap consisting of a reflective parabolic surface and a needle electrode. This parabolic trap design covers a solid angle of 2pi steradians and allows precise ion placement at the focal point of the parabola. We measured (39 +/- 3)% fluorescence collection from a single ion with this trap and analyzed the mirror optical performance. We observed single ion image spot size of 3.4 times diffraction limit, improved to 2.8 times diffraction limit with the help of an external deformable mirror. The micromotion of the ion is determined to be the limiting factor, and the result is consistent with theoretical calculation. PMID- 28863686 TI - Optimization of grating duty cycle in non-interferometric grating-based X-ray phase contrast imaging. AB - Grating-based X-ray phase contrast imaging technology is one of the most potential imaging methods in real applications. It can be classified into two categories: interferometry and non-interferometric imaging. The non interferometric grating-based X-ray phase contrast imaging (NIGPCI) instrument has a great advantage in the forthcoming commercial applications for the flexible system design and the use of large periodic gratings. The performance of the NIGPCI instrument depends on its angular sensitivity to a great extent. Therefore, good angular sensitivity is mandatory in order to obtain high quality phase-contrast images. Several parameters, such as the X-ray spectrum, the inter grating distances, and the parameters of the three gratings, influence the angular sensitivity of the imaging system. However, the quantitative relationship between the angular sensitivity and grating duty cycle is unclear. Therefore, this paper is devoted to revealing their internal relation by theoretical deduction and emulation of the imaging process with the theories of linear system and Fourier optics. Furthermore, a quantitative analysis method to optimize the duty cycles of gratings is proposed and its applicability to a general NIGPCI system is verified. PMID- 28863687 TI - Comment on "Plasma fireball: A unique tool to fabricate patterned nanodots" [Rev. Sci. Instrum. 88, 063507 (2017)]. AB - The article of Chauhan et al. ["Plasma fireball: A unique tool to fabricate patterned nanodots," Rev. Sci. Instrum. 88(6), 063507 (2017)] describes the very interesting idea of utilising the plasma phenomenon of fireballs for the creation of patterned nanodots on a GaSb substrate. For this purpose, the authors obtained a large plasma fireball in a magnetised background plasma and used it to accelerate ions in the sheath, which surrounds such a fireball. Chauhan et al. were able to demonstrate the production of large ion fluxes that can be extracted from the fireball and that the properties of these fluxes define the geometric structure of the nanodots on the substrate surface. Hence, the nanodot pattern can be easily controlled by the discharge parameters of the plasma fireball. This is clearly a novel method of fireball-induced surface modification. However, plasma fireballs themselves have been known for about hundred years, although as a very particular plasma phenomenon. Therefore, this letter aims at providing some additional background information and references on this topic for the interested reader. PMID- 28863688 TI - A high voltage pulse generator based on silicon-controlled rectifier for field reversed configuration experiment. AB - A high voltage pulse generator based on a silicon-controlled rectifier has been designed and implemented for a field reversed configuration experiment. A critical damping circuit is used in the generator to produce the desired pulse waveform. Depending on the load, the rise time of the output trigger signal can be less than 1 MUs, and the peak amplitudes of trigger voltage and current are up to 8 kV and 85 A in a single output. The output voltage can be easily adjusted by changing the voltage on a capacitor of the generator. In addition, the generator integrates an electrically floating heater circuit so it is capable of triggering either pseudosparks (TDI-type hydrogen thyratron) or ignitrons. Details of the circuits and their implementation are described in the paper. The trigger generator has successfully controlled the discharging sequence of the pulsed power supply for a field reversed configuration experiment. PMID- 28863689 TI - 32-channel time-correlated-single-photon-counting system for high-throughput lifetime imaging. AB - Time-Correlated Single Photon Counting (TCSPC) is a very efficient technique for measuring weak and fast optical signals, but it is mainly limited by the relatively "long" measurement time. Multichannel systems have been developed in recent years aiming to overcome this limitation by managing several detectors or TCSPC devices in parallel. Nevertheless, if we look at state-of-the-art systems, there is still a strong trade-off between the parallelism level and performance: the higher the number of channels, the poorer the performance. In 2013, we presented a complete and compact 32 * 1 TCSPC system, composed of an array of 32 single-photon avalanche diodes connected to 32 time-to-amplitude converters, which showed that it was possible to overcome the existing trade-off. In this paper, we present an evolution of the previous work that is conceived for high throughput fluorescence lifetime imaging microscopy. This application can be addressed by the new system thanks to a centralized logic, fast data management and an interface to a microscope. The new conceived hardware structure is presented, as well as the firmware developed to manage the operation of the module. Finally, preliminary results, obtained from the practical application of the technology, are shown to validate the developed system. PMID- 28863690 TI - Erratum: "A memory efficient implementation scheme of Gauss error function in a Laguerre-Volterra network for neuroprosthetic devices" [Rev. Sci. Instrum. 88, 044301 (2017)]. PMID- 28863691 TI - TinyLev: A multi-emitter single-axis acoustic levitator. AB - Acoustic levitation has the potential to enable novel studies due to its ability to hold a wide variety of substances against gravity under container-less conditions. It has found application in spectroscopy, chemistry, and the study of organisms in microgravity. Current levitators are constructed using Langevin horns that need to be manufactured to high tolerance with carefully matched resonant frequencies. This resonance condition is hard to maintain as their temperature changes due to transduction heating. In addition, Langevin horns are required to operate at high voltages (>100 V) which may cause problems in challenging experimental environments. Here, we design, build, and evaluate a single-axis levitator based on multiple, low-voltage (ca. 20 V), well-matched, and commercially available ultrasonic transducers. The levitator operates at 40 kHz in air and can trap objects above 2.2 g/cm3 density and 4 mm in diameter whilst consuming 10 W of input power. Levitation of water, fused-silica spheres, small insects, and electronic components is demonstrated. The device is constructed from low-cost off-the-shelf components and is easily assembled using 3D printed sections. Complete instructions and a part list are provided on how to assemble the levitator. PMID- 28863692 TI - A hyperspectral X-ray computed tomography system for enhanced material identification. AB - X-ray computed tomography (CT) can distinguish different materials according to their absorption characteristics. The hyperspectral X-ray CT (HXCT) system proposed in the present work reconstructs each voxel according to its X-ray absorption spectral characteristics. In contrast to a dual-energy or multi-energy CT system, HXCT employs cadmium telluride (CdTe) as the x-ray detector, which provides higher spectral resolution and separate spectral lines according to the material's photon-counter working principle. In this paper, a specimen containing ten different polymer materials randomly arranged was adopted for material identification by HXCT. The filtered back-projection algorithm was applied for image and spectral reconstruction. The first step was to sort the individual material components of the specimen according to their cross-sectional image intensity. The second step was to classify materials with similar intensities according to their reconstructed spectral characteristics. The results demonstrated the feasibility of the proposed material identification process and indicated that the proposed HXCT system has good prospects for a wide range of biomedical and industrial nondestructive testing applications. PMID- 28863693 TI - Kinetic energy offsets for multicharged ions from an electron beam ion source. AB - Using a retarding field analyzer, we have measured offsets between the nominal and measured kinetic energy of multicharged ions extracted from an electron beam ion source (EBIS). By varying source parameters, a shift in ion kinetic energy was attributed to the trapping potential produced by the space charge of the electron beam within the EBIS. The space charge of the electron beam depends on its charge density, which in turn depends on the amount of negative charge (electron beam current) and its velocity (electron beam energy). The electron beam current and electron beam energy were both varied to obtain electron beams of varying space charge and these were related to the observed kinetic energy offsets for Ar4+ and Ar8+ ion beams. Knowledge of these offsets is important for studies that seek to utilize slow, i.e., low kinetic energy, multicharged ions to exploit their high potential energies for processes such as surface modification. In addition, we show that these offsets can be utilized to estimate the effective radius of the electron beam inside the trap. PMID- 28863694 TI - Note: Iodine dissociation with a pulsed arc discharge. AB - A new method is presented to dissociate iodine molecules in gas discharge. A high repetition rate spark gap is designed and used to trigger the circuit. Absorption spectroscopy is applied to measure the dissociation fraction of iodine molecules. It is found that more than 35% of iodine molecules are dissociated. The effect of switching frequency on the dissociation coefficient is investigated by changing the frequency of the rotating spark gap. Pulsed and equivalent direct current circuits are compared, and it is found that in the constant current glow discharge the dissociation fraction is near to the zero and negligible. PMID- 28863695 TI - A multi-frequency electrical impedance tomography system for real-time 2D and 3D imaging. AB - This paper presents the design and evaluation of a configurable, fast multi frequency Electrical Impedance Tomography (mfEIT) system for real-time 2D and 3D imaging, particularly for biomedical imaging. The system integrates 32 electrode interfaces and the current frequency ranges from 10 kHz to 1 MHz. The system incorporates the following novel features. First, a fully adjustable multi frequency current source with current monitoring function is designed. Second, a flexible switching scheme is developed for arbitrary sensing configuration and a semi-parallel data acquisition architecture is implemented for high-frame-rate data acquisition. Furthermore, multi-frequency digital quadrature demodulation is accomplished in a high-capacity Field Programmable Gate Array. At last, a 3D imaging software, visual tomography, is developed for real-time 2D and 3D image reconstruction, data analysis, and visualization. The mfEIT system is systematically tested and evaluated from the aspects of signal to noise ratio (SNR), frame rate, and 2D and 3D multi-frequency phantom imaging. The highest SNR is 82.82 dB on a 16-electrode sensor. The frame rate is up to 546 fps at serial mode and 1014 fps at semi-parallel mode. The evaluation results indicate that the presented mfEIT system is a powerful tool for real-time 2D and 3D imaging. PMID- 28863696 TI - X-ray source development for EXAFS measurements on the National Ignition Facility. AB - Extended X-ray absorption Fine Structure (EXAFS) measurements require a bright, spectrally smooth, and broad-band x-ray source. In a laser facility, such an x ray source can be generated by a laser-driven capsule implosion. In order to optimize the x-ray emission, different capsule types and laser irradiations have been tested at the National Ignition Facility (NIF). A crystal spectrometer is used to disperse the x-rays and high efficiency image plate detectors are used to measure the absorption spectra in transmission geometry. EXAFS measurements at the K-edge of iron at ambient conditions have been obtained for the first time on the NIF laser, and the requirements for optimization have been established. PMID- 28863697 TI - High-bandwidth and flexible tracking control for precision motion with application to a piezo nanopositioner. AB - For precision motion, high-bandwidth and flexible tracking are the two important issues for significant performance improvement. Iterative learning control (ILC) is an effective feedforward control method only for systems that operate strictly repetitively. Although projection ILC can track varying references, the performance is still limited by the fixed-bandwidth Q-filter, especially for triangular waves tracking commonly used in a piezo nanopositioner. In this paper, a wavelet transform-based linear time-varying (LTV) Q-filter design for projection ILC is proposed to compensate high-frequency errors and improve the ability to tracking varying references simultaneously. The LVT Q-filter is designed based on the modulus maximum of wavelet detail coefficients calculated by wavelet transform to determine the high-frequency locations of each iteration with the advantages of avoiding cross-terms and segmenting manually. The proposed approach was verified on a piezo nanopositioner. Experimental results indicate that the proposed approach can locate the high-frequency regions accurately and achieve the best performance under varying references compared with traditional frequency-domain and projection ILC with a fixed-bandwidth Q-filter, which validates that through implementing the LTV filter on projection ILC, high bandwidth and flexible tracking can be achieved simultaneously by the proposed approach. PMID- 28863698 TI - Full-wave finite space model of open-ended coaxial line for dielectric spectroscopy of liquids. AB - The physical equipment was built according to the mathematical model and tested. The performance of equipment is demonstrated measuring two known liquids, methanol and isopropanol, up to 40 GHz. The accuracy and sensitivity, and the versatility and ease of manufacturing of the measurement cell are discussed. PMID- 28863699 TI - VUV spectroscopy in impurity injection experiments at KSTAR using prototype ITER VUV spectrometer. AB - The ITER vacuum ultra-violet (VUV) core survey spectrometer has been designed as a 5-channel spectral system so that the high spectral resolving power of 200-500 could be achieved in the wavelength range of 2.4-160 nm. To verify the design of the ITER VUV core survey spectrometer, a two-channel prototype spectrometer was developed. As a subsequent step of the prototype test, the prototype VUV spectrometer has been operated at KSTAR since the 2012 experimental campaign. From impurity injection experiments in the years 2015 and 2016, strong emission lines, such as Kr xxv 15.8 nm, Kr xxvi 17.9 nm, Ne vii 46.5 nm, Ne vi 40.2 nm, and an array of largely unresolved tungsten lines (14-32 nm) could be measured successfully, showing the typical photon number of 1013-1015 photons/cm2 s. PMID- 28863700 TI - Fourier transform spectral interferometry with non-phase stable setups by broadband single shot detection of fs and ps pulses. AB - In this paper, we present a novel approach to Fourier transform spectral interferometry based on single-shot detection of broadband pulses. It allows heterodyne detection with non-phase-stabilised setups, which use ps- and fs pulsed laser sources. This approach can tremendously simplify the implementation of complex techniques such as heterodyne Fourier transform four-wave mixing and pave the way to novel phase-sensitive diagnostics for lasers and optical setups. PMID- 28863702 TI - Development of a wavy Stark velocity filter for studying interstellar chemistry. AB - Cold polar molecules are key to both the understanding of fundamental physics and the characterization of the chemical evolution of interstellar clouds. To facilitate such studies over a wide range of temperatures, we developed a new type of Stark velocity filter for changing the translational and rotational temperatures of velocity-selected polar molecules without changing the output beam position. The translational temperature of guided polar molecules can be significantly varied by exchanging the wavy deflection section with one having a different radius of the curvature and a different deflection angle. Combining in addition a temperature variable gas cell with the wavy Stark velocity filter enables to observe the translational and rotational temperature dependence of the reaction-rate constants of cold ion-polar molecule reactions over the interesting temperature range of 10-100 K. PMID- 28863703 TI - The world's smallest capacitive dilatometer, for high-resolution thermal expansion and magnetostriction in high magnetic fields. AB - For the characterization of novel quantum phases of matter, it is often required to study materials under multi-extreme conditions, in particular down to very low temperatures and in very high magnetic fields. We developed the world's smallest high-resolution capacitive dilatometer suitable for temperatures down to 10 mK and usage in high magnetic fields up to 37.5 T. Despite the extreme miniaturization, the capacitive dilatometer can resolve length changes down to 0.01 A. This is an unprecedented resolution in a capacitive dilatometer of this compact size. Many cryogenic devices have limited space. Due to the extremely reduced cell size (3 cm3, 12 g), implementation or new applications in many of these sample space lacking devices are now possible. As an important example, the minute device can now be rotated in any standard cryostat, including dilution refrigerators or the commercial physical property measurement system. The present super compact design provides also for high resolution thermal expansion and magnetostriction measurements in a 15.2 mm diameter tube, enabling its use in the 32 mm bore, 37.5 T Bitter magnet at the High Field Magnet Laboratory in Nijmegen down to a temperature of 300 mK. PMID- 28863704 TI - Power measurements and coupler optimization in inductive discharges. AB - The power absorbed by the plasma is one of the key parameters which defines processes in any plasma source. This power, however, can be very different from the power at the rf power source output or the coupler terminals, which has been used in many publications to characterize the plasma. This article describes how to find the power absorbed by the plasma and the power lost in the coupler and matcher network for inductively coupled plasmas. In addition, several practical coupler configurations to reduce the coupler coil loss and minimize the rf plasma potential are discussed. We propose an effective and simple method to achieve that by the coupler coil splitting and insertion of the resonating capacitor in the middle of the coil. Our experimental data demonstrate this approach having superior coupler efficiency and substantially lower rf plasma potential. PMID- 28863705 TI - Real-time microwave sensor system for detection of polluting substances in pure water. AB - In the present work, a real-time coaxial sensor for detecting foreign substances in aqueous solutions was developed and tested. This tool, based on a coaxial propagation line for determining the electromagnetic parameters of materials, was updated into a liquid permittivity monitoring sensor of continuous flow. A few solutions of different nature were tested, and while adding a liquid or electrolyte substance, named "pollutant," variations in the base solution were documented. Ethanol and water mixtures were used as reference, while the ability of the system to detect emulsions (such as oil in water solutions) was also evaluated. The system shows great potential for the quantification and qualification of liquid mixtures, having a threshold of reduced volume/volume fractions of foreign substances or pollutants, a property which is shown to be extremely useful in an analogue of high glycaemia (diabetes disease)-thus, opening the possibilities of monitoring biological liquids. PMID- 28863706 TI - Multi-rate cubature Kalman filter based data fusion method with residual compensation to adapt to sampling rate discrepancy in attitude measurement system. AB - This paper investigates the multi-rate inertial and vision data fusion problem in nonlinear attitude measurement systems, where the sampling rate of the inertial sensor is much faster than that of the vision sensor. To fully exploit the high frequency inertial data and obtain favorable fusion results, a multi-rate CKF (Cubature Kalman Filter) algorithm with estimated residual compensation is proposed in order to adapt to the problem of sampling rate discrepancy. During inter-sampling of slow observation data, observation noise can be regarded as infinite. The Kalman gain is unknown and approaches zero. The residual is also unknown. Therefore, the filter estimated state cannot be compensated. To obtain compensation at these moments, state error and residual formulas are modified when compared with the observation data available moments. Self-propagation equation of the state error is established to propagate the quantity from the moments with observation to the moments without observation. Besides, a multiplicative adjustment factor is introduced as Kalman gain, which acts on the residual. Then the filter estimated state can be compensated even when there are no visual observation data. The proposed method is tested and verified in a practical setup. Compared with multi-rate CKF without residual compensation and single-rate CKF, a significant improvement is obtained on attitude measurement by using the proposed multi-rate CKF with inter-sampling residual compensation. The experiment results with superior precision and reliability show the effectiveness of the proposed method. PMID- 28863707 TI - Note: A two-dimensional position-sensitive micro-channel plate detector with a cross-connected-pixels resistive anode and integrated spectroscopy amplifiers. AB - Based on the charge-division method, a compact detector system for charged particles is constructed. The system consists of a pair of micro-channel plates, a novel two-dimensional position-sensitive cross-connected-pixels resistive anode, and specially designed front-end electronics that can directly drive analog-to-digital converters. The detector is tested with an 241Am alpha-source. A position resolution of better than 0.3 mm and a maximum distortion within 0.5 mm in the active dimensions of 100 mm diameter are achieved. PMID- 28863708 TI - False star detection and isolation during star tracking based on improved chi square tests. AB - The star sensor is a precise attitude measurement device for a spacecraft. Star tracking is the main and key working mode for a star sensor. However, during star tracking, false stars become an inevitable interference for star sensor applications, which may result in declined measurement accuracy. A false star detection and isolation algorithm in star tracking based on improved chi-square tests is proposed in this paper. Two estimations are established based on a Kalman filter and a priori information, respectively. The false star detection is operated through adopting the global state chi-square test in a Kalman filter. The false star isolation is achieved using a local state chi-square test. Semi physical experiments under different trajectories with various false stars are designed for verification. Experiment results show that various false stars can be detected and isolated from navigation stars during star tracking, and the attitude measurement accuracy is hardly influenced by false stars. The proposed algorithm is proved to have an excellent performance in terms of speed, stability, and robustness. PMID- 28863709 TI - A surface science compatible epifluorescence microscope for inspection of samples under ultra high vacuum and cryogenic conditions. AB - We modified an epi-illumination light microscope and mounted it on an ultra high vacuum chamber for investigating samples used in a surface science experiment. For easy access and bake out, all optical components are placed outside the vacuum and the sample is imaged through a glass window. The microscope can be operated in reflection brightfield or epifluorescence mode to image the sample surface or fluorescent dye molecules adsorbed on it. The homemade sample mounting was made compatible for the use under the microscope; sample temperatures as low as 6 K can be achieved. The performance of the microscope is demonstrated on two model samples: Brightfield-images of a well-prepared Ag(100) surface show a macroscopic corrugation of the surface, although low energy electron diffraction data indicate a highly ordered crystalline surface. The surface shows macroscopic protrusions with flat regions, about 20-200 MUm in diameter, in between. Fluorescence images of diluted 3,4,9,10-perylene tetracarboxylicacid dianhydride (PTCDA) molecules adsorbed on an ultrathin epitaxial KCl film on the Ag(100) surface show a shading effect at surface protrusions due to an inclined angle of incidence of the PTCDA beam during deposition. For some preparations, the distribution of the fluorescence intensity is inhomogeneous and shows a dense network of bright patches about 5 MUm in diameter related to the macroscopic corrugation of the surface. We propose that such a light microscope can aid many surface science experiments, especially those dealing with epitaxial growth or fluorescent materials. PMID- 28863710 TI - Radio frequency source of a weakly expanding wedge-shaped xenon ion beam for contactless removal of large-sized space debris objects. AB - A theoretical-experimental research has been carried out to determine the characteristics of a radio frequency (RF) ion source for the generation of a weakly expanding wedge-shaped xenon ion beam. Such ion beam geometry is of interest as a prototype of an on-board ion injector for contactless "ion shepherding" by service spacecraft to remove large space debris objects from geostationary orbits. The wedge shape of the ion beam increases its range. The device described herein comprises an inductive gas discharge chamber and a slit type three-electrode ion extraction grid (IEG) unit. Calculations of accelerating cell geometries and ion trajectories determined the dependence of beam expansion half-angle on normalized perveance based on the measurements of the spatial distributions of the xenon plasma parameters at the IEG entrance for a xenon flow rate q ~ 0.2 mg/s and an incident RF power Pin <= 250 W at a driving frequency f = 2 MHz. Experimental studies showed that the ion beam, circular at the IEG exit, accepted the elliptical form at the distance of 580 mm with half-angle of beam expansion across IEG slits about 2 degrees -3 degrees and close to 0 degrees along them. Thus, the obtained result proved the possibility of creating a new generation on-board ion injector that could be used in spacecrafts for removal of debris. PMID- 28863711 TI - Measurement of contact angles of microscopic droplets by focal length method. AB - We present a method to measure contact angles of microscopic droplets with a conventional microscope that possesses a precision focus adjustment stage. The droplets are modeled as spherical caps that act as lenses. Their focal length is determined by measuring the distance from the substrate surface to the level where a sharp image of the aperture stop is observed. The lens diameter is found by edge detection of a microscope image of the microdroplets. The spherical cap model relates the focal length and diameter of such lenses to the contact angle of the used liquid with known refractive index. The measurement procedure was applied to condensed water droplets on a silicon substrate covered by its native oxide layer. The results are found to be in good agreement with conventional, goniometric sessile drop measurements of the advancing contact angle. PMID- 28863712 TI - Micrometer-thickness liquid sheet jets flowing in vacuum. AB - Thin liquid sheet jet flows in vacuum provide a new platform for performing experiments in the liquid phase, for example X-ray spectroscopy. Micrometer thickness, high stability, and optical flatness are the key characteristics required for successful exploitation of these targets. A novel strategy for generating sheet jets in vacuum is presented in this article. Precision nozzles were designed and fabricated using high resolution (0.2 MUm) 2-photon 3D printing and generated 1.49 +/- 0.04 MUm thickness, stable, and =70 years who were initially nondisabled in eADL. Restricting back pain and disability were assessed during monthly interviews for up to 159 months. Associations between restricting back pain and subsequent eADL and iADL disability were evaluated using recurrent events Cox models, adjusted for fixed in-time and time-varying covariates. RESULTS: Strong associations were found between restricting back pain and eADL and iADL disability, with hazard ratios (95% confidence intervals) of 3.47 [3.01, 3.90] and 2.33 [2.08, 2.61], respectively. DISCUSSION: Restricting back pain was independently associated with subsequent disability in eADL and iADL. Interventions focused on decreasing restricting back pain in older adults may have the potential to reduce the subsequent burden of disability. PMID- 28863725 TI - Clinical Practice Recommendations Based on an Updated Review of Breast Cancer Risk Among Women Treated for Childhood Cancer. AB - Breast cancer is the most common secondary malignancy among women treated for childhood cancer. This review highlights interacting etiologies contributing to development of secondary breast cancer to complement guidelines for surveillance and survivorship care and make recommendations for clinical practice. Treatment exposures determine Children's Oncology Group breast cancer surveillance guidelines; those treated with cumulative doses >=20 Gy chest irradiation should undergo annual magnetic resonance imaging and mammography after age 25 years or 8 years after exposure, whichever comes last. Recent investigations suggest that those treated with cumulative doses >=10 Gy in fields affecting breast tissue, specifically whole lung, should be counseled for similar surveillance. Childhood sarcoma and leukemia survivors treated with anthracyclines and/or alkylating agents without radiation have increased risk for breast cancer and may require enhanced surveillance. Multigene testing and/or genomic evaluation for predisposition among certain childhood cancer subtypes may prove to be beneficial in identifying those at greatest risk. Pediatric oncology nurses who incorporate this information into survivorship care planning discussions/documents and clinical research endeavors may help reduce breast cancer-related morbidity/mortality for this at-risk population. PMID- 28863726 TI - "You Have to Approach Us Right": A Qualitative Framework Analysis for Recruiting African Americans Into mHealth Research. AB - BACKGROUND: Despite the high ownership of smartphones, African Americans (AAs) remain underrepresented in health research and specifically mobile health (mHealth) research. This may be due to ineffective recruitment efforts. PURPOSE: To explore strategies for recruiting AAs into mHealth research and examine how these strategies may vary by gender and age-group. METHOD: Twenty triad focus groups ( n = 60) were conducted with AA males ( n = 9 groups) and females ( n = 11 groups). The framework method was used to manage, organize, synthesize, and analyze data themes by gender and age-group (18-29, 30-50, 51+). RESULTS: Most participants owned smartphones (71%) and were willing to participate in mHealth research (62%). The participants' narrative revealed the tension between mistrust of researchers and the excitement of participating in technology-based research. Both genders and all age-groups can be reached via word-of-mouth because it is "the best advertisement." Personal contact must precede traditional and electronic recruitment strategies because "we have to know you." Churches are excellent places for recruitment because they are "trustworthy" and have a "repeat audience." Facebook may be effective for both genders and all age-groups because "everybody is on Facebook" and it can "reach more people than text and e mail." Beauty/barber shops may be limited in reaching both genders and age groups, but especially young women who style their own hair natural, and young men who wear braids and dreadlocks. Personal contact must precede traditional and electronic recruitment strategies because "we have to know you." CONCLUSION: A tailored, multipronged strategy that combines traditional recruitment methods with texting, e-mail, and social media may be effective in recruiting AA adults into mHealth research. PMID- 28863727 TI - Soluble Endoglin (CD105) Serum Level as a Potential Marker in the Management of Head and Neck Paragangliomas. AB - OBJECTIVES: To assess the expression of endoglin in head and neck paragangliomas and the soluble endoglin level in serum of paraganglioma patients. METHODS: Seven tumor samples of patients operated for cervical paraganglioma were assessed, as well as serum samples collected preoperatively, on days 4 and 28 postoperation. Serum level of endoglin in healthy controls was also determined. Tumor samples were subjected to immunofluorescent staining and examined with confocal microscope. The level of soluble endoglin in serum samples was examined using the immunoenzymatic assay (ELISA). RESULTS: Endoglin was highly expressed in all tumor samples. The level of soluble endoglin was significantly higher in paraganglioma patients compared to healthy controls and correlated with the tumor size. The serum level of s-endoglin was reduced after surgical excision of the tumor and remained stable after 4 weeks in all patients with complete resection of the tumor. CONCLUSION: Endoglin is an important factor in the pathophysiology of head and neck paragangliomas and may be a potential diagnostic and prognostic marker in these types of tumors. PMID- 28863728 TI - Venous Complications in One Versus Two Vein Anastomoses in Head and Neck Free Flaps. AB - OBJECTIVE: The purpose of this study was to compare rates of reexploration and flap failure in patients with 1- and 2-vein anastomoses in free flap reconstructions. METHODS: Retrospective chart review of 300 patients undergoing free flap reconstruction to head and neck defects from 2010 to 2014. RESULTS: One venous anastomosis was performed in 229 patients, and 2 venous anastomoses were performed in 71 patients. The 1-vein group had significantly more reexplorations in the operating room (36/229, 15.7%) compared with the 2-vein group (4/71, 5.6%; P = .028), even when controlling for flap type ( P = .022). This finding remained true among radial forearm flaps (17/81, 21% vs 3/53, 5.7%; P = .024). The number of venous anastomoses was not significantly associated with flap failure, though patients with flap failure did have a significantly greater proportion of venous issues ( P < .001). CONCLUSIONS: Two-vein anastomoses do not appear to reduce rates of flap failure or postoperative venous thrombosis but are associated with a lower number of reexplorations in the operating room even after accounting for differences in flap types and surgeons. PMID- 28863729 TI - Rate of Neurologic Injury Following Lateralizing Calcaneal Osteotomy Performed Through a Medial Approach. AB - BACKGROUND: Calcaneal osteotomies are commonly used to correct varus hindfoot alignment in patients with symptomatic cavovarus deformity. Translational, closing wedge, and Malerba-type osteotomies have been implicated in the development of tarsal tunnel syndrome and neurologic injury to branches of the tibial nerve. The authors hypothesized that there would be minimal clinically important injury to the tibial nerve by performing a translational calcaneal osteotomy from a medial approach. METHODS: All patients undergoing a cavovarus reconstruction by a single surgeon were identified. Patients were included if they underwent a lateralizing calcaneal osteotomy via medial approach. Demographics, operative reports, and clinic notes were reviewed to identify concomitant procedures performed, incidence of postoperative tarsal tunnel syndrome, complications, and preoperative and postoperative nerve examinations. Postoperative radiographs were reviewed for location of the osteotomy relative to the posterior tubercle. RESULTS: Twenty-four patients underwent lateralizing calcaneal osteotomy via a medial approach. Of the osteotomies, 83.3% (20/24) were in the middle third of the calcaneus, with a mean of 11.6-mm translation. No patients developed postoperative tarsal tunnel syndrome or tibial nerve palsy. CONCLUSION: Lateralizing calcaneal osteotomy performed via a medial approach had a clinically negligible incidence of neurologic injury. Adequate translation was achieved to obtain correction of varus hindfoot deformity. The authors believe that there is less direct and less percussive injury to branches of the tibial nerve when performing the osteotomy from medial to lateral. This technique may represent an operative strategy to minimize risk to the tibial nerve and reduce neurologic deficit following cavovarus reconstruction. LEVEL OF EVIDENCE: Level IV, case series. PMID- 28863731 TI - 6th International Congress of the Cell Transplant Society. PMID- 28863730 TI - The Challenges of Identifying and Classifying Child Sexual Abuse Material. AB - The aim of the present study was to (a) assess the reliability with which indecent images of children (IIOC) are classified as being of an indecent versus nonindecent nature, and (b) examine in detail the decision-making process engaged in by law enforcement personnel who undertake the difficult task of identifying and classifying IIOC as per the current legislative offense categories. One experienced researcher and four employees from a police force in the United Kingdom coded an extensive amount of IIOC ( n = 1,212-2,233) to determine if they (a) were deemed to be of an indecent nature, and (b) depicted a child. Interrater reliability analyses revealed both considerable agreement and disagreement across coders, which were followed up with two focus groups involving the four employees. The first entailed a general discussion of the aspects that made such material more or less difficult to identify; the second focused around images where there had been either agreement ( n = 20) or disagreement ( n = 36) across coders that the images were of an indecent nature. Using thematic analysis, a number of factors apparent within IIOC were revealed to make the determination of youthfulness and indecency significantly more challenging for coders, with most relating to the developmental stage of the victim and the ambiguity of the context of an image. Findings are discussed in light of their implications for the identification of victims of ongoing sexual exploitation/abuse, the assessment and treatment of individuals in possession of IIOC, as well as the practice of policing and sentencing this type of offending behavior. PMID- 28863735 TI - Regulation of Trophic Factor Expression by Innervating Target Regions in Intraocular Double Transplants. AB - Trophic factors have been found to play a significant role both in long-term survival processes and in more rapid and dynamic processes in the brain and spinal cord. However, little is known regarding the regulation of expression of growth factors, and how these proteins interact on a cell-to-cell basis. We have studied protein levels of one growth factor known to affect the noradrenergic innervation of the hippocampal formation, namely brain-derived neurotrophic factor (BDNF). The purpose of the present study was to determine if appropriate innervation or contact between the LC noradrenergic neurons and their target, the hippocampus, affects expression of this growth factor in either brain region. Fetal brain stem tissue, containing the LC, and hippocampal formation were dissected from embryonic day 17 rat fetuses and transplanted together or alone into the anterior chamber of the eye of adult Fisher 344 rats. The tissue was grown together for 6 weeks, after which the animals were sacrificed and ELISAs for BDNF were undertaken. Transplantation to the anterior chamber of the eye increased the expression of BDNF in the hippocampal but not the brain stem tissue, compared with levels observed in fetal and adult rats in vivo. In addition, double grafting with hippocampal tissue more than tripled BDNF levels in brain stem grafts and doubled BDNF levels in the hippocampal portion of double grafts compared with hippocampal single grafts. Triple grafts containing basal forebrain, hippocampus, and brain stem LC tissue increased brain stem and hippocampal BDNF levels even further. Colchicine treatment of LC-hippocampal double grafts gave rise to a significant decrease in hippocampal BDNF levels to levels seen in single hippocampal grafts, while only a partial reduction of BDNF levels was seen in the brain stem portion of the same double grafts treated with colchicine. The findings suggest that an appropriate hippocampal innervation or contact with its target tissues is essential for regulation of BDNF expression in the brain stem, and that retrograde transport of BDNF can occur between double grafted fetal tissues in oculo. PMID- 28863737 TI - Improvement of Pancreatic Islet Isolation Outcomes Using Glutamine Perfusion during Isolation Procedure. AB - During procurement, isolation, and transplantation, islets are exposed to high levels of oxidative stress triggering a variety of signaling pathways that can ultimately lead to cell death. Glutamine is an important cellular fuel and an essential precursor for the antioxidant glutathione. The aim of this study was to examine the role of intraductal glutamine administration in facilitating recovery of isolated rat islets from pancreases subjected to a clinically relevant period of warm ischemia. Islets were isolated in Sprague-Dawley (SD) rats (n= 18 per group). Pancreata in groups 1 and 2 were procured immediately while groups 3 and 4 were subjected to 30-min warm ischemia. Groups 2 and 4 were treated intraductally with 5 mM glutamine prior to pancreatectomy. Exposure to 30-min warm ischemia significantly reduced islet yield [groups 1 & 2 (nonischemia): 503 +/- 29 islets/rat vs. groups 3 & 4 (ischemia): 247 +/- 26 islets/rat; p < 0.05]. Intraductal glutamine treatment significantly improved islet yield when pancreata were subjected to 30-min warm ischemia [144 +/- 16 islets/rat without glutamine (group 3) vs. 343 +/- 36 islets/rat with glutamine (group 4), p < 0.05]. Glutamine also significantly improved islet viability (values were 50 +/- 4% in group 4 vs. 27 +/- 3% in group 3, p < 0.05). Similarly, glutathione (reduced) levels were significantly elevated in both glutamine-treated groups; however, this increase was greatest in tissues exposed to ischemia (2.76 +/- 0.04 nmol/mg protein in group 4 vs. 1.66 +/- 0.04 nmol/mg protein in group 3, p < 0.05). Intraductal glutamine administration considerably improves the islet yield, viability, and augments endogenous glutathione levels in pancreata procured after a clinically relevant period of ischemia. Intraductal administration of glutamine at the time of digestive enzyme delivery into the harvested pancreas may represent a simple yet effective tool to improve islet yields in clinical isolations. PMID- 28863738 TI - Insulin-Induced Normoglycemia Reduces Islet Number Needed to Achieve Normoglycemia after Allogeneic Islet Transplantation in Diabetic Mice. AB - The Edmonton protocol established that insulin independence could be reached with the transplantation of an appropriate number of islet cells. However, to effect a cure, islets from two or three pancreases are needed. The aim of this study was to examine whether normoglycemia, with insulin treatment before and after transplantation, reduces the islet number needed to achieve normoglycemia in allogeneic islet transplantation. Swiss mice were used as donors and recipients. Diabetes was induced by IP administration of streptozotocin (180 mg/kg BW). Diabetic mice were transplanted with 300 (n = 16), 400 (n = 16), or 500 (n = 16) islets under the left kidney capsule. For every group, half the animals were kept normoglycemic with insulin treatment from day 4 before transplantation to day 10 after transplantation. At the end of the study, all normoglycemic mice were given an IP glucose tolerance test (IPGTT). For statistical analysis, paired or unpaired Student's t-test or ANOVA was used. Only insulin-treated mice achieved normoglycemia by the end of the study (37.5% of animals transplanted with 400 islets and 50% transplanted with 300 or 500 islets). At the end of the study, normoglycemic mice transplanted with 300 allogeneic islets showed better glycosylated hemoglobin (HbA1C) than did normoglycemic mice transplanted with 500 islets (300 islets: 2.7 +/- 0.2%; 500 islets: 3.6 +/- 0.2%; p < 0.05). After the IPGTT, insulin-treated mice transplanted with 500 islets showed abnormal glucose tolerance; however, insulin-treated mice transplanted with 300 or 400 islets showed normal glucose tolerance. Insulin treatment reduced the islet number needed to achieve normoglycemia in allogeneic islet transplantation. The HbA1C and IPGTT results suggest that transplanting smaller numbers of allogeneic islets improves beta-cell function; some studies suggest that this may be due to lower immunogenicity, hypoxia, and inflammation. PMID- 28863739 TI - Response of Encapsulated Rat Pancreatic Islets to Hypoxia. AB - Hypoxia contributes to encapsulated pancreatic islet graft failure. To gain insight into the mechanisms that lead to hypoxia-induced graft failure, encapsulated islet function, vitality, and cell replication were assessed after 2 and 5 days of hypoxic (1% O2) and normoxic (20% O2) culture. The mRNA expression levels of Bcl-2, Bax, inducible nitric oxide synthase (iNOS), and monocyte chemoattractant protein 1 (MCP-1) were assessed, as well as the amount of nitrite and MCP-1 in the culture medium. Hypoxia was associated with loss of encapsulated islet function and vitality, but not with an increase in islet cell replication. Loss of vitality was due to necrosis, and only modestly due to apoptosis. Hypoxia was not associated with changes in the Bcl-2/Bax mRNA ratio, but it did increase the expression of iNOS and MCP-1 mRNA. The increased mRNA levels were, however, not associated with elevated concentrations of nitrite nor with elevated levels of MCP-1 protein. The increased iNOS mRNA levels imply a role for NO in the completion of cell death by hypoxia. The increased MCP-1 mRNA levels suggest that encapsulated islets in vivo contribute to their own graft failure by attracting cytokine-producing macrophages. The discrepancy between iNOS mRNA and nitrite is explained by the longer half-life of NO during hypoxia. MCP-1 protein levels are underestimated as a consequence of the lower number of vital cells in combination with a higher proteolytic activity due to necrosis. Thus, strategies to eliminate hypoxia may not only improve islet function and vitality, but may also reduce the attraction of macrophages by encapsulated islets. PMID- 28863740 TI - Article Commentary: Cell Transplantation: The Regenerative Medicine Journal. A Biennial Analysis of Publications. PMID- 28863741 TI - 9th International Conference on Neural Transplantation and Repair. PMID- 28863743 TI - Abstracts for the 15th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28863744 TI - Maintenance of Mouse, Rat, and Pig Pancreatic Islet Functions by Coculture with Human Islet-Derived Fibroblasts. AB - Development of an efficient preculture system of islets is ideal. Toward that goal, we constructed a human pancreatic islet-derived fibroblast cell line MNNK-1 for a source as a coculture system for freshly isolated islets to maintain islet functions. Human pancreatic islet cells were nucleofected with a plasmid vector pYK-1 expressing simian virus 40 large T antigen gene (SV40T) and hygromycin resistance gene (HygroR). One of the transduced cell lines, MNNK-1, was established and served as a feeder cell in the coculture for freshly isolated mouse, rat, and pig islets. Morphology, viability, and glucose-responding insulin secretion were analyzed in the coculture system. MNNK-1 cells were morphologically spindle shaped and were negative for pancreatic endocrine markers. MNNK-1 cells were positive for alpha-smooth muscle actin and collagen type I and produced fibroblast growth factor. Coculture of the mouse, rat, and pig islets with MNNK-1 cells maintained their viability and insulin secretion with glucose responsiveness. A human pancreatic islet-derived fibroblast cell line MNNK-1 was established. MNNK-1 cells were a useful means for maintaining morphology and insulin secretion of islets in the coculture system. PMID- 28863745 TI - Survival and Function of Transplanted Islet Cells on an in Vivo, Vascularized Tissue Engineering Platform in the Rat: A Pilot Study 1. AB - As in vivo tissue engineering of complex tissues and organs progresses, there is a need for an independently vascularized, alterable, and recoverable model. Current models of islet cell transplantation (release into the portal venous system, placement under the renal capsule, and microencapsulation) lack these qualities. We have developed a model of angiogenesis and spontaneous tissue generation in the rat that lends itself as a potential platform for tissue engineering. In this experiment, we examined the effectiveness of such a model in addressing some of the shortcomings of endocrine pancreatic transplantation. An arteriovenous loop was created in the groins of five adult inbred Sprague-Dawley rats, and placed within polycarbonate chambers. Isolated pancreatic islet cell clusters were placed within the chambers, suspended in a matrix of Matrigel(r). The chambers were recovered at 3 weeks, and the newly generated tissue was processed for histologic and immunohistochemical analysis. By 3 weeks, spontaneous generation of angiogenesis and collagen matrix and deposition of a collagen matrix was observed. Surviving islet cells were identified by histology and their viability was confirmed via immunohistochemistry for insulin and glucagon. This study demonstrates the ability to maintain viability and functionality of transplanted islet cells on a tissue-engineered platform with an independent vascular supply. The model provides the ability to alter the graft environment via matrix substitution, cellular coculture, and administration of growth factors. The transplanted tissues are recoverable without animal sacrifice and are microsurgically transferable. This model may provide an in vivo culture platform for the study of islet transplantation. PMID- 28863747 TI - Chemokines and Their Receptors in Islet Allograft Rejection and as Targets for Tolerance Induction. AB - Graft rejection is a major barrier to successful outcome of transplantation surgery. Islet transplantation introduces insulin secreting tissue into type 1 diabetes mellitus recipients, relieving patients from exogenous insulin injection. However, insulitis of grafted tissue and allograft rejection prevent long-term insulin independence. Leukocyte trafficking is necessary for the launch of successful immune responses to pathogen or allograft. Chemokines, small chemotactic cytokines, direct the migration of leukocytes through their interaction with chemokine receptors found on cell surfaces of immune cells. Unique receptor expression of leukocytes, and the specificity of chemokine secretion during various states of immune response, suggest that the extracellular chemokine milieu specifically homes certain leukocyte subsets. Thus, only those leukocytes required for the current immune task are attracted to the inflammatory site. Chemokine blockade, using antagonists and monoclonal antibodies directed against chemokine receptors, is an emerging and specific immunosuppressive strategy. Importantly, chemokine blockade may potentiate tolerance induction regimens to be used following transplantation surgery, and prevent the need for life-long immunosuppression of islet transplant recipients. Here, the role for chemokine blockade in islet transplant rejection and tolerance is reviewed. PMID- 28863748 TI - The Development and Characterization of an HEK293-Derived Cell Line for Use in an Intratumoral Cytokine Delivery System. AB - As part of ongoing work to develop a method of cytokine delivery for use as an intratumoral depot, we noted that HEK293 cells, encapsulated in alginate, died within 24-48 h after in vivo, intratumoral implantation. We hypothesized that the highly hypoxic and acidic conditions found inside the tumor was the cause of the cells' premature demise. Therefore, we set out to develop a cell line, derived from HEK293, that would survive these hostile conditions. The HEK293 line was selected in 0.3-0.5% oxygen conditions over several weeks, followed by a further 6-week period of culture in alternating hypoxic and normoxic conditions. The most rapidly growing clones were selected and grown in normoxic conditions for several weeks to ensure their stability. The clones were then compared to the original line in terms of cell proliferation in normoxia and hypoxia, colony-forming efficiency, and morphological characteristics. The resulting line was able to proliferate in the harshest of conditions and continues to release its biological payload after alginate microencapsulation. PMID- 28863749 TI - Establishment of Immortalized Human Hepatocytes by Introduction of HPV16 E6/E7 and hTERT as Cell Sources for Liver Cell-Based Therapy. AB - For future cell-based therapies for liver diseases, the shortage of cell sources must be resolved. Immortalized human hepatocytes are expected to be among the new sources. In addition to telomerase activation by the introduction of human telomerase reverse transcriptase (hTERT), inactivation of the p16/RB pathway and/or p53 by E6/E7 of human papillomavirus type 16 (HPV16) has been shown to be useful for efficient immortalization of several human cell types. Here we report the immortalization of human hepatocytes by the introduction of HPV16 E6/E7 and hTERT. Human adult hepatocytes were lentivirally transduced with HPV16 E6/E7 and hTERT. Two human immortalized hepatocyte cell lines were established and were named HHE6E7T-1 and HHE6E7T-2. Those cells proliferated in culture beyond 200 population doublings (PDs). Albumin synthesis and expression of liver-enriched genes were confirmed, but gradually decreased as passages progressed. Karyotype analysis showed that HHE6E7T-1 cells remained near diploid but that HHE6E7T-2 cells showed severe aneuploidy at 150 PDs. Subcutaneous injection of these cells into severe combined immunodeficiency (SCID) mice did not induce tumor development. Intrasplenic transplantation of dedifferentiated HHE6E7T-1 cells over 200 PDs significantly improved the survival of acetaminophen-induced acute liver failure SCID mice. In conclusion, we successfully established immortalized human hepatocytes that retain the characteristics of differentiated hepatocytes. We also showed the reduction of hepatocyte-specific functions in long-term culture. However, the results of intrasplenic transplantation to SCID mice with acetaminophen-induced acute liver failure showed the possibility of HHE6E7T-1 serving as a cell source for hepatocyte transplantation. PMID- 28863751 TI - The Choice of Anatomical Site for Islet Transplantation. AB - Islet transplantation into the portal vein is the current clinical practice. However, it has now been recognized that this implantation site has several characteristics that can hamper islet engraftment and survival, such as low oxygen tension, an active innate immune system, and the provocation of an inflammatory response (IBMIR). These factors result in the loss of many transplanted islets, mainly during the first hours or days after transplantation, which could in part explain the necessity for the transplantation of islets from multiple pancreas donors to cure type 1 diabetes. This increases the burden on the limited pool of donor organs. Therefore, an alternative anatomical site for islet transplantation that offers maximum engraftment, efficacious use of produced insulin, and maximum patient safety is urgently needed. In this review, the experience with alternative sites for islet implantation in clinical and experimental models is discussed. Subcutaneous transplantation guarantees maximum patient safety and has become clinically applicable. Future improvements could be achieved with innovative designs for devices to induce neovascularization and protect the islets from cellular rejection. However, other sites, such as the omentum, offer drainage of produced insulin into the portal vein for direct utilization in the liver. The use of pigs would not only overcome the shortage of transplantable islets, but genetic modification could result in the expression of human genes, such as complement regulatory or "anticoagulation" genes in the islets to overcome some site-specific disadvantages. Eventually, the liver will most likely be replaced by a site that allows long-term survival of islets from a single donor to reverse type 1 diabetes. PMID- 28863750 TI - Variation in the Incidence of Teratomas after the Transplantation of Nonhuman Primate ES Cells into Immunodeficient Mice. AB - Embryonic stem (ES) cells have the ability to generate teratomas when transplanted into immunodeficient mice, but conditions affecting the generation remain to be elucidated. Nonhuman primate cynomolgus ES cells were transplanted into immunodeficient mice under different conditions; the number of transplanted cells, physical state (clumps or single dissociated cells), transplant site, differentiation state, and immunological state of recipient mice were all varied. The tumorigenicity was then evaluated. When cynomolgus ES cells were transplanted as clumps into the lower limb muscle in either nonobese diabetic/severe combined immunodeficiency (NOD/SCID) or NOD/SCID/?cnull (NOG) mice, teratomas developed in all the animals transplanted with 1 * 105 or more cells, but were not observed in any mouse transplanted with 1 * 103 cells. However, when the cells were transplanted as dissociated cells, the number of cells necessary for teratomas to form in all mice increased to 5 * 105. When the clump cells were injected subcutaneously (instead of intramuscularly), the number also increased to 5 * 105. When cynomolgus ES cell-derived progenitor cells (1 * 106), which included residual pluripotent cells, were transplanted into the lower limb muscle of NOG or NOD/SCID mice, the incidence of teratomas differed between the strains; teratomas developed in five of five NOG mice but in only two of five NOD/SCID mice. The incidence of teratomas varied substantially depending on the transplanted cells and recipient mice. Thus, considerable care must be taken as to tumorigenicity. PMID- 28863752 TI - Divergent Preferences for HIV Prevention: A Discrete Choice Experiment for Multipurpose HIV Prevention Products in South Africa. AB - BACKGROUND: The development of antiretroviral (ARV)-based prevention products has the potential to substantially change the HIV prevention landscape; yet, little is known about how appealing these products will be outside of clinical trials, as compared with the existing options. METHODS: We conducted a discrete choice experiment (DCE) to measure preferences for 5 new products among 4 important populations in the HIV response: adult men and women in the general population (aged 18 to 49 y), adolescent girls (aged 16 to 17 y), and self-identifying female sex workers (aged 18 to 49 y). We interviewed 661 self-reported HIV negative participants in peri-urban South Africa, who were asked to choose between 3 unique, hypothetical products over 10 choice sets. Data were analyzed using multinomial, latent class and mixed multinomial logit models. RESULTS: HIV protection was the most important attribute to respondents; however, results indicate significant demand among all groups for multipurpose prevention products that offer protection from HIV infection, other STIs, and unwanted pregnancy. All groups demonstrated a strong preference for long-lasting injectable products. There was substantial heterogeneity in preferences within and across population groups. LIMITATIONS: Hypothetical DCE data may not mirror real-world choices, and products will have more attributes in reality than represented in choice tasks. Background data on participants, including sensitive areas of HIV status and condom use, was self-reported. CONCLUSIONS: These results suggest that stimulating demand for new HIV prevention products may require a more a nuanced approach than simply developing highly effective products. No single product is likely to be equally attractive or acceptable across different groups. This study strengthens the call for effective and attractive multipurpose prevention products to be deployed as part of a comprehensive combination prevention strategy. PMID- 28863753 TI - Article Commentary: Cell Transplantation: Stem Cells in the Spotlight. PMID- 28863773 TI - Down-regulation of miRNA-148a and miRNA-625-3p in colorectal cancer is associated with tumor budding. AB - BACKGROUND: MiRNAs are often deregulated in colorectal cancer and might function as tumor suppressors or as oncogenes. They participate in controlling key signaling pathways involved in proliferation, invasion and apoptosis and may serve as prognostic and predictive markers. In this study we aimed to evaluate the role of miRNA-148a and miRNA-625-3p in metastatic colorectal cancer. METHODS: Fifty-four patients with a first-time diagnosed CRC receiving FOLFOX +/- Bevacizumab were involved in the study. Tumor samples underwent routine pathology examination including evaluation for tumor budding and KRAS. MiRNA-148a and miRNA 625-3p expression analysis was done by RT-PCR. Associations between expression of both miRNAs and clinico-pathological factors, treatment outcomes and survival were analyzed. RESULTS: Both miRNA-148a and miRNA-625-3p were down-regulated in the tumors compared to normal colonic mucosa. Significantly lower expression of both miRNAs was noticed in tumors with budding phenomenon compared to tumors without it (median values of miRNA-148a were 0.314 and 0.753 respectively, p = 0.011, and 0.404 and 0.620 respectively for miRNA-625-3p, p = 0.036). Significantly lower expression of miRNA-625-3p was detected in rectal tumors, compared to tumors in the colon (median 0.390 and 0.665 respectively, p = 0.037). Progression free survival was significantly lower in patients with high miRNA 148a expression (6 and 9 months respectively, p = 0.033), but there were no significant differences in PFS for miRNA-625-3p and in overall survival for both miRNAs. CONCLUSIONS: There was a significant relationship between low miRNA-148a and miRNA-625-3p expression and tumor budding, which is thought to represent epithelial-mesenchymal transition. Both studied miRNAs may be associated with a more aggressive phenotype and could be the potential prognostic and predictive biomarkers in CRC. Further investigation is needed to confirm miRNAs involvement in EMT, and their prognostic and predictive value. PMID- 28863774 TI - Cost-effectiveness analysis of a multifactorial fall prevention intervention in older home care clients at risk for falling. AB - BACKGROUND: Falls among older adults can cause serious morbidity and pose economic burdens on society. Older age is a known risk factor for falls and age has been shown to influence the effectiveness of fall prevention programs. To our knowledge, no studies have explicitly investigated whether cost-effectiveness of a multifactorial fall prevention intervention (the intervention) is influenced by age. This economic evaluation explores: 1) the cost-effectiveness of a multifactorial fall prevention intervention compared to usual care for community dwelling adults >= 75 years at risk of falling in Canada; and 2) the influence of age on the cost-effectiveness of the intervention. METHODS: Net benefit regression was used to examine the cost-effectiveness of the intervention with willingness-to-pay values ranging from $0-$50,000. Effects were measured as change in the number of falls, from baseline to 6-month follow-up. Costs were measured using a societal perspective. The cost-effectiveness analysis was conducted for both the total sample and by age subgroups (75-84 and 85+ years). RESULTS: For the total sample, the intervention was not economically attractive. However, the intervention was cost-effective at higher willingness-to-pay (WTP) (>= $25,000) for adults 75-84 years and at lower WTP (< $5,000) for adults 85+ years. CONCLUSIONS: The cost-effectiveness of the intervention depends on age and decision makers' WTP to prevent falls. Understanding the influence of age on the cost-effectiveness of an intervention may help to target resources to those who benefit most. TRIAL REGISTRATION: Retrospectively registered. Clinicaltrials.gov identifier: NCT00463658 (18 April 2007). PMID- 28863775 TI - Self-medication among the elderly in Iran: a content analysis study. AB - BACKGROUND: Self-medication is described as the use of drugs without a physician's prescription to treat self-recognized illness or symptoms, and an important health issue among the elderly. Despite the wide range of different definitions, recognizing all forms of self-medication among older adults, particularly, in developing countries, help healthcare professionals and providers to reduce harmful effects of self-medication. The purpose of this study is to describe the practice of self-medication and its related factors among elderly people in Iran based on the experiences of people who are involved in this phenomenon. METHODS: This qualitative study was conducted using content analysis. Purposive sampling was used to select the participants and continued until saturation. The participants were the elderly, their care-givers, physicians, and pharmacists. Data was collected using semi-structured interviews, and analysis was done using an inductive approach. The theory of planned behavior was used as a framework to explain the role of the emerged factors in the occurrence of self-medication behavior. RESULTS: Based on the expressed experiences of the participants, factors related to the practice of self- medication among the elderly in Iran fit in these 5 categories: "patient's attitudes towards disease, treatment, and physicians", "living with disease", "unfriendly environments", "enabling health system", and "influential others". CONCLUSIONS: Based on the results of this study, self-medication of the elderly in Iran has commonalities with many countries in regard to over-the-counter medications and complementary and alternative medicine; however, self-medication is also seen with drugs that require a prescription but can easily be obtained from pharmacies. Contributing factors, apart from the elderly themselves, include their families, caregivers, and social circle, the physical environment where they live, and the health system from which they receive services. PMID- 28863776 TI - A change in the study evaluation paradigm reveals that larynx preservation compromises survival in T4 laryngeal cancer patients. AB - BACKGROUND: Larynx preservation (LP) is recommended for up to low-volume T4 laryngeal cancer as an evidence-based treatment option that does not compromise survival. However, a reevaluation of the current literature raises questions regarding whether there is indeed reliable evidence to support larynx preservation for T4 tumor patients. METHODS: In an observational cohort study of 810 laryngeal cancer patients, we evaluated the outcomes of all T4 tumor patients treated with primary chemo-radiotherapy (CRT) or primary radiotherapy alone (RT) compared with upfront total laryngectomy followed by adjuvant (chemo)radiotherapy (TL + a[C]RT). Additionally, we reevaluated the studies that form the evidence base for the recommendation of LP for patients with up to T4 tumors (Pfister et al., J Clin Oncol 24:3693-704, 2006). RESULTS: The evaluation of all 288 stage III and IV patients together did not show a significant difference in overall survival (OS) between CRT-LP and TL + a(C)RT (hazard ratio (HR) 1.23; 95% confidence interval (CI): 0.82-1.86; p = 0.31) using a multivariate proportional hazard model. However, a subgroup analysis of T4 tumor patients alone (N = 107; 13.9%) revealed significantly worse OS after CRT compared with TL + a(C)RT (HR 2.0; 95% CI: 1.04-3.7; p = 0.0369). A reevaluation of the subgroup of T4 patients in the 5 LP studies that led to the ASCO clinical practice guidelines revealed that only 21-45 T4 patients had differential data on survival outcome. These data, however, showed a markedly worse outcome for T4 patients after LP. CONCLUSIONS: T4 laryngeal cancer patients who reject TL as a treatment option should be informed that their chance of organ preservation with primary conservative treatment is likely to result in a significantly worse outcome in terms of OS. Significant loss of survival in T4 patients after LP is also confirmed in recent literature. PMID- 28863778 TI - Gene flow during glacial habitat shifts facilitates character displacement in a Neotropical flycatcher radiation. AB - BACKGROUND: Pleistocene climatic fluctuations are known to be an engine of biotic diversification at higher latitudes, but their impact on highly diverse tropical areas such as the Andes remains less well-documented. Specifically, while periods of global cooling may have led to fragmentation and differentiation at colder latitudes, they may - at the same time - have led to connectivity among insular patches of montane tropical habitat with unknown consequences on diversification. In the present study we utilized ~5.5 kb of DNA sequence data from eight nuclear loci and one mitochondrial gene alongside diagnostic morphological and bioacoustic markers to test the effects of Pleistocene climatic fluctuations on diversification in a complex of Andean tyrant-flycatchers of the genus Elaenia. RESULTS: Population genetic and phylogenetic approaches coupled with coalescent simulations demonstrated disparate levels of gene flow between the taxon chilensis and two parapatric Elaenia taxa predominantly during the last glacial period but not thereafter, possibly on account of downward shifts of montane forest habitat linking the populations of adjacent ridges. Additionally, morphological and bioacoustic analyses revealed a distinct pattern of character displacement in coloration and vocal traits between the two sympatric taxa albiceps and pallatangae, which were characterized by a lack of gene flow. CONCLUSION: Our study demonstrates that global periods of cooling are likely to have facilitated gene flow among Andean montane Elaenia flycatchers that are more isolated from one another during warm interglacial periods such as the present era. We also identify a hitherto overlooked case of plumage and vocal character displacement, underpinning the complexities of gene flow patterns caused by Pleistocene climate change across the Andes. PMID- 28863777 TI - Dosage-sensitive genes in evolution and disease. AB - For a subset of genes in our genome a change in gene dosage, by duplication or deletion, causes a phenotypic effect. These dosage-sensitive genes may confer an advantage upon copy number change, but more typically they are associated with disease, including heart disease, cancers and neuropsychiatric disorders. This gene copy number sensitivity creates characteristic evolutionary constraints that can serve as a diagnostic to identify dosage-sensitive genes. Though the link between copy number change and disease is well-established, the mechanism of pathogenicity is usually opaque. We propose that gene expression level may provide a common basis for the pathogenic effects of many copy number variants. PMID- 28863779 TI - Optimization of a metatranscriptomic approach to study the lignocellulolytic potential of the higher termite gut microbiome. AB - BACKGROUND: Thanks to specific adaptations developed over millions of years, the efficiency of lignin, cellulose and hemicellulose decomposition of higher termite symbiotic system exceeds that of many other lignocellulose utilizing environments. Especially, the examination of its symbiotic microbes should reveal interesting carbohydrate-active enzymes, which are of primary interest for the industry. Previous metatranscriptomic reports (high-throughput mRNA sequencing) highlight the high representation and overexpression of cellulose and hemicelluloses degrading genes in the termite hindgut digestomes, indicating the potential of this technology in search for new enzymes. Nevertheless, several factors associated with the material sampling and library preparation steps make the metatranscriptomic studies of termite gut prokaryotic symbionts challenging. METHODS: In this study, we first examined the influence of the sampling strategy, including the whole termite gut and luminal fluid, on the diversity and the metatranscriptomic profiles of the higher termite gut symbiotic bacteria. Secondly, we evaluated different commercially available kits combined in two library preparative pipelines for the best bacterial mRNA enrichment strategy. RESULTS: We showed that the sampling strategy did not significantly impact the generated results, both in terms of the representation of the microbes and their transcriptomic profiles. Nevertheless collecting luminal fluid reduces the co amplification of unwanted RNA species of host origin. Furthermore, for the four studied higher termite species, the library preparative pipeline employing Ribo Zero Gold rRNA Removal Kit "Epidemiology" in combination with Poly(A) Purist MAG kit resulted in a more efficient rRNA and poly-A-mRNAdepletion (up to 98.44% rRNA removed) than the pipeline utilizing MICROBExpress and MICROBEnrich kits. High correlation of both Ribo-Zero and MICROBExpresse depleted gene expression profiles with total non-depleted RNA-seq data has been shown for all studied samples, indicating no systematic skewing of the studied pipelines. CONCLUSIONS: We have extensively evaluated the impact of the sampling strategy and library preparation steps on the metatranscriptomic profiles of the higher termite gut symbiotic bacteria. The presented methodological approach has great potential to enhance metatranscriptomic studies of the higher termite intestinal flora and to unravel novel carbohydrate-active enzymes. PMID- 28863780 TI - Feature tracking CMR reveals abnormal strain in preclinical arrhythmogenic right ventricular dysplasia/ cardiomyopathy: a multisoftware feasibility and clinical implementation study. AB - BACKGROUND: Regional right ventricular (RV) dysfunction is the hallmark of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), but is currently only qualitatively evaluated in the clinical setting. Feature Tracking Cardiovascular Magnetic Resonance (FT-CMR) is a novel quantitative method that uses cine CMR to calculate strain values. However, most prior FT-CMR studies in ARVD/C have focused on global RV strain using different software methods, complicating implementation of FT-CMR in clinical practice. We aimed to assess the clinical value of global and regional strain using FT-CMR in ARVD/C and to determine differences between commercially available FT-CMR software packages. METHODS: We analyzed cine CMR images of 110 subjects (39 overt ARVD/C [mutation+/phenotype+], 40 preclinical ARVD/C [mutation+/phenotype-] and 31 control) for global and regional (subtricuspid, anterior, apical) RV strain in the horizontal longitudinal axis using four FT-CMR software methods (Multimodality Tissue Tracking, TomTec, Medis and Circle Cardiovascular Imaging). Intersoftware agreement was assessed using Bland Altman plots. RESULTS: For global strain, all methods showed reduced strain in overt ARVD/C patients compared to control subjects (p < 0.041), whereas none distinguished preclinical from control subjects (p > 0.275). For regional strain, overt ARVD/C patients showed reduced strain compared to control subjects in all segments which reached statistical significance in the subtricuspid region for all software methods (p < 0.037), in the anterior wall for two methods (p < 0.005) and in the apex for one method (p = 0.012). Preclinical subjects showed abnormal subtricuspid strain compared to control subjects using one of the software methods (p = 0.009). Agreement between software methods for absolute strain values was low (Intraclass Correlation Coefficient = 0.373). CONCLUSIONS: Despite large intersoftware variability of FT-CMR derived strain values, all four software methods distinguished overt ARVD/C patients from control subjects by both global and subtricuspid strain values. In the subtricuspid region, one software package distinguished preclinical from control subjects, suggesting the potential to identify early ARVD/C prior to overt disease expression. PMID- 28863781 TI - Downregulation of GPR155 as a prognostic factor after curative resection of hepatocellular carcinoma. AB - BACKGROUND: Molecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC). In this study, we focused on G protein-coupled receptor 155 (GPR155), a cell surface signaling protein, as a candidate biomarker. METHODS: We analyzed GPR155 expression, DNA methylation, and copy number in HCC cell lines. The clinical significance of GPR155 expression was evaluated using 144 pairs of surgically resected liver and normal tissues with subgroup analysis based on hepatitis virus infection. RESULTS: GPR155 mRNA expression levels were differential and were decreased in 89% of HCC cell lines. No DNA methylation was detected, whereas copy number alterations were present in five (56%) HCC cell lines. GPR155 mRNA expression level was independent of background liver status and significantly lower in HCC tissues than corresponding normal liver tissues. The expression patterns of GPR155 protein by immunohistochemical staining were significantly associated with those of GPR155 mRNA. Downregulation of GPR155 was significantly associated with more aggressive HCC phenotypes including high preoperative alpha-fetoprotein, poor differentiation, serosal infiltration, vascular invasion, and advanced disease stage. Patients with downregulation of GPR155 were more likely to have worse prognosis after curative resection irrespective of hepatitis virus infection. Patients who experienced extrahepatic (distant) recurrences had significantly lower GPR155 expression than those with intrahepatic (liver confined) recurrences. CONCLUSIONS: Downregulation of GPR155 may serve as a prognosticator that also predicts initial recurrence sites independent of hepatitis virus infection. PMID- 28863783 TI - Erratum to: Thermotherapy. An alternative for the treatment of American cutaneous leishmaniasis. PMID- 28863782 TI - Effectiveness of PIVKA-II in the detection of hepatocellular carcinoma based on real-world clinical data. AB - BACKGROUND: Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) is an efficient biomarker specific for hepatocellular carcinoma (HCC). Some researchers have proved that levels of PIVKA-II reflect HCC oncogenesis and progression. However, the effectiveness of PIVKA-II based on real-world clnical data has barely been studied. METHODS: A total of 14,861 samples were tested in Southwest Hospital in over 2 years' time. Among them, 4073 samples were PIVKA-II positive. Finally, a total of 2070 patients with at least two image examinations were enrolled in this study. Levels of AFP and PIVKA-II were measured by chemiluminescence enzyme immunoassay (CLEIA) and chemiluminescent microparticle Immunoassay (CMIA), respectively. RESULTS: A total of 1016 patients with HCC were detected by PIVKA-II in a real-world application. In all these cases, 88.7% cases primarily occurred and patients with advanced HCC covered 61.3%. Levels of PIVKA II were significantly higher in advanced group (4650.0 mAU/ml, 667.0-33,438.0 mAU/ml) than early-stage group (104.5 mAU/ml, 61.0-348.8 mAU/ml; P < 0.001). Levels of PIVKA-II elevated significantly in recurrence and residual group than recovery group (P < 0.001). A total of 1054 PIVKA-II positive patients were non HCC cases. Among them, cirrhosis took the largest part (46.3%), followed by hepatitis (20.6%) and benign nodules (15.3%). High-levels of PIVKA-II in at-risk patients is an indicator of HCC development in two-year time. CONCLUSIONS: Our data showed that PIVKA-II effectively increases the detection rate of HCC was a valid complement to AFP and image examination in HCC surveillance. PMID- 28863784 TI - Erratum to: Whole metagenome profiles of particulates collected from the International Space Station. PMID- 28863785 TI - Erratum to Development of a core outcome set for orthodontic trials using a mixed methods approach: protocol for a multicentre study. PMID- 28863786 TI - Prdm13 forms a feedback loop with Ptf1a and is required for glycinergic amacrine cell genesis in the Xenopus Retina. AB - BACKGROUND: Amacrine interneurons that modulate synaptic plasticity between bipolar and ganglion cells constitute the most diverse cell type in the retina. Most are inhibitory neurons using either GABA or glycine as neurotransmitters. Although several transcription factors involved in amacrine cell fate determination have been identified, mechanisms underlying amacrine cell subtype specification remain to be further understood. The Prdm13 histone methyltransferase encoding gene is a target of the transcription factor Ptf1a, an essential regulator of inhibitory neuron cell fate in the retina. Here, we have deepened our knowledge on its interaction with Ptf1a and investigated its role in amacrine cell subtype determination in the developing Xenopus retina. METHODS: We performed prdm13 gain and loss of function in Xenopus and assessed the impact on retinal cell fate determination using RT-qPCR, in situ hybridization and immunohistochemistry. RESULTS: We found that prdm13 in the amphibian Xenopus is expressed in few retinal progenitors and in about 40% of mature amacrine cells, predominantly in glycinergic ones. Clonal analysis in the retina reveals that prdm13 overexpression favours amacrine cell fate determination, with a bias towards glycinergic cells. Conversely, knockdown of prdm13 specifically inhibits glycinergic amacrine cell genesis. We also showed that, as in the neural tube, prdm13 is subjected to a negative autoregulation in the retina. Our data suggest that this is likely due to its ability to repress the expression of its inducer, ptf1a. CONCLUSIONS: Our results demonstrate that Prdm13, downstream of Ptf1a, acts as an important regulator of glycinergic amacrine subtype specification in the Xenopus retina. We also reveal that Prdm13 regulates ptf1a expression through a negative feedback loop. PMID- 28863788 TI - Role of the National Institute of Standards and Technology (NIST) in Support of the Vitamin D Initiative of the National Institutes of Health, Office of Dietary Supplements. AB - Since 2005, the National Institute of Standards and Technology (NIST) has collaborated with the National Institutes of Health (NIH), Office of Dietary Supplements (ODS) to improve the quality of measurements related to human nutritional markers of vitamin D status. In support of the NIH-ODS Vitamin D Initiative, including the Vitamin D Standardization Program (VDSP), NIST efforts have focused on (1) development of validated analytical methods, including reference measurement procedures (RMPs); (2) development of Standard Reference Materials (SRMs); (3) value assignment of critical study samples using NIST RMPs; and (4) development and coordination of laboratory measurement QA programs. As a result of this collaboration, NIST has developed RMPs for 25-hydroxyvitamin D2 [25(OH)D2], 25(OH)D3, and 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3]; disseminated serum-based SRMs with values assigned for 25(OH)D2, 25(OH)D3, 3-epi 25(OH)D3, and 24R,25(OH)2D3; assigned values for critical samples for VDSP studies, including an extensive interlaboratory comparison and reference material commutability study; provided an accuracy basis for the Vitamin D External Quality Assurance Scheme; coordinated the first accuracy-based measurement QA program for the determination of 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 in human serum/plasma; and developed methods and SRMs for the determination of vitamin D and 25(OH)D in food and supplement matrix SRMs. The details of these activities and their benefit and impact to the NIH-ODS Vitamin D Initiative are described. PMID- 28863789 TI - Introduction: Translational Immunology in Kidney Disease. PMID- 28863787 TI - Venous thromboembolism and hyperhomocysteinemia as first manifestation of pernicious anemia: a case series. AB - BACKGROUND: Hyperhomocysteinemia has been suspected of favoring thrombosis. Several case-control studies and even a meta-analysis have confirmed a link between venous thrombosis and hyperhomocysteinemia. Homocysteine is due to genetic and acquired factors (poor diet in folate and vitamin B12, older age, renal impairment, thyroid diseases, and malignancies) induced by the intake and the concentrations of vitamin B9 or B12 in the majority of cases. CASES PRESENTATION: We report the cases of four Moroccan patients who presented with acute vein thrombosis of different sites: a 34-year-old man, a 60-year-old man, a 58-year-old man, and a 47-year-old woman. All patients had a low level of cobalamin with marked hyperhomocysteinemia with normal serum and red cell folic acid. Venous thrombosis revealed pernicious anemia in all patients. Their low levels of cobalamin, atrophic gastritis, and positive results for gastric parietal cell antibodies confirmed the diagnosis of pernicious anemia. There was no evidence of immobilization, recent surgery, malignancy, antiphospholipid antibody, myeloproliferative disorder, or hormone replacement therapy. No deficiencies in protein C and protein S were detected; they had normal antithrombin III function and factor V Leiden; no prothrombin gene mutations were detected. Treatment included orally administered anticoagulation therapy and cobalamin supplementation. The outcome was favorable in all cases. CONCLUSIONS: These reports demonstrate that pernicious anemia, on its own, can lead to hyperhomocysteinemia that is significant enough to lead to thrombosis. Understanding the molecular pathogenesis of the development of thrombosis in patients with hyperhomocysteinemia related to Biermer disease would help us to identify patients at risk and to treat them accordingly. The literature concerning the relationship between homocysteine and venous thrombosis is briefly reviewed. PMID- 28863790 TI - ANCA-Associated Vasculitis: Pathogenesis, Models, and Preclinical Testing. AB - Our understanding of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has developed greatly since the discovery of ANCA, directed against neutrophil components, in 1982. Observations in human disease, and increasingly sophisticated studies in vitro and in rodent models in vivo, have allowed a nuanced understanding of many aspects of the immunopathogenesis of disease, including the significance of ANCA as a diagnostic and monitoring tool as well as a mediator of microvascular injury. The mechanisms of leukocyte recruitment and tissue injury, and the role of T cells increasingly are understood. Unexpected findings, such as the role of complement, also have been uncovered through experimental studies and human observations. This review focusses on the pathogenesis of ANCA-associated vasculitis, highlighting the challenges in finding new, less-toxic treatments and potential therapeutic targets in this disease. The current suite of rodent models is reviewed, and future directions in the study of this complex and fascinating disease are suggested. PMID- 28863791 TI - Translational Aspects of Primary Membranous Nephropathy. AB - Membranous nephropathy (MN) in an autoimmune disease caused by binding of circulating antibodies to podocytic antigens. The search for the responsible target antigens has extended for more than 50 years and led to the identification of the major pathomechanisms leading to MN. The combination of clinical and morphologic observations, experimental work, and technical advancements has enabled us deep insights in the pathophysiology of this disease, simultaneously improving treatment of patients. MN represents a perfect example of how patient care may profit from the convergence of scientific and clinical achievements and the benefits of translational approaches in medicine. PMID- 28863792 TI - Genetics of Immune-Mediated Glomerular Diseases: Focus on Complement. AB - The spectrum of immune-mediated glomerular diseases is wide, ranging from rare diseases with well-recognized genetic origins to more common and multifactorial diseases. Immune-mediated glomerular injury is complex and involves both the innate and the adaptive immune systems. In the past 20 years a huge effort has been undertaken to unravel the genetic basis of immune-mediated glomerular diseases. The discovery of abnormalities in genes encoding proteins of the alternative pathway of complement in more than 50% of patients with atypical hemolytic uremic syndrome (aHUS), and in approximately 20% of patients with membranoproliferative glomerulonephritis (MPGN), has highlighted the role of this complement pathway in the pathogenesis of immune-mediated glomerular diseases. aHUS-associated complement gene abnormalities mainly result in complement dysregulation restricted to the cell surface, whereas complement activation in the fluid phase prevails in most, but not all, genetic cases of MPGN. Results achieved in aHUS and MPGN have boosted interest in the impact of complement gene abnormalities and variations in the predisposition to more common, multifactorial kidney diseases, including IgA nephropathy and lupus nephritis. Emerging findings in these complex diseases have broadened our understanding of the fragile balance between the protective and harmful functions of the complement system. PMID- 28863793 TI - Immunosuppression in IgA Nephropathy: Guideline Medicine Versus Personalized Medicine. AB - The role of immunosuppression in IgAN remains controversial despite a growing evidence base of randomized controlled trials (RCTs). In IgAN with nephrotic syndrome the role for corticosteroids is limited to cases with minimal change on light microscopy. In crescentic IgAN, the use of immunosuppression is supported only by anecdotal data, and outcome may be poor especially when glomerular filtration rate is impaired severely at presentation or there are pathologic features of chronic injury. In slowly progressive IgAN, prediction of outcome now is based both on clinical and pathologic features. Most RCTs have studied patients with urine protein levels greater than 1 g/24 h and only a minority have enrolled patients with a glomerular filtration rate less than 60 mL/min. The Supportive versus immunosuppressive Therapy of Progressive IgA nephropathy (STOP) IgAN study emphasized the efficacy of supportive therapy (including blood pressure control and renin-angiotensin system blockade) in decreasing proteinuria to less than the usually accepted threshold for the use of corticosteroids. Earlier RCTs of corticosteroids usually did not deploy supportive therapy optimally. The recent Therapeutic Evaluation of STeroids in IgA Nephropathy Global (TESTING) study closed prematurely because of excess toxicity, but the high dose of corticosteroids seemed to provide benefit. Guidelines provide valuable information about the quality and limitations of available evidence that needs to be personalized in application to the individual patient's medical and nonmedical circumstances to ensure wise clinical decision making. PMID- 28863795 TI - Erratum. PMID- 28863794 TI - Immunoadsorption in Autoimmune Diseases Affecting the Kidney. AB - Autoantibodies play an important role in the pathophysiology of renal involvement in systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), systemic vasculitis, and anti-glomerular basement membrane disease (or Goodpasture syndrome). Direct removal of autoantibodies therefore has been tried in various ways, first by plasma exchange. Today, immunoadsorption is the extracorporeal method that most effectively removes (pathogenic) immune complexes and antibodies. Although past data have shown efficacy and biocompatibility of immunoadsorption in (renal) SLE, it is still an experimental and expensive procedure, and evidence from randomized controlled trials is needed. Nevertheless, immunoadsorption is being used as a rescue therapy in life threatening situations of SLE patients because of its fast mode of action and its acceptable safety profile. In granulomatosis with polyangiitis (GPA) (or Wegener's granulomatosis), microscopic polyangiitis (MPA), and anti-glomerular basement membrane disease, the current standard is plasma exchange. Immunoadsorption, which probably would reduce the autoantibody burden more effectively, might be an even better more effective option, but sufficient evidence is lacking. PMID- 28863796 TI - A promising new treatment horizon for haemophilia A. PMID- 28863797 TI - Predicting death in patients with acute graft-versus-host disease after reduced intensity conditioning. PMID- 28863798 TI - Peripheral intravenous catheter assessment: beyond phlebitis. PMID- 28863799 TI - IMiD-induced gene expression profiling predicts multiple myeloma prognosis. PMID- 28863800 TI - Conflicts of interest in Twitter. PMID- 28863801 TI - Research on Biosimilars: pivotal trials and principles. PMID- 28863802 TI - Reply to correspondence "Do big numbers assure high-quality of data?" PMID- 28863803 TI - XXVI Congress of the International Society on Thrombosis and Haemostasis. PMID- 28863804 TI - Investigation of a gene signature to predict response to immunomodulatory derivatives for patients with multiple myeloma: an exploratory, retrospective study using microarray datasets from prospective clinical trials. AB - BACKGROUND: Immunomodulatory derivatives (IMiDs), along with proteasome inhibitors, are key components of treatment regimens for multiple myeloma. Nonetheless, outcomes vary among treated individuals. Drug-specific gene expression profile (GEP) signatures that aid the prediction of favourable and unfavourable outcomes can provide patients with the most effective therapy for their individual disease. We aimed to develop and validate a gene expression signature to suggest which patients would benefit most from IMiD-based therapies. METHODS: For this exploratory retrospective study, we selected a cohort of patients with newly diagnosed or relapsed or refractory multiple myeloma who were treated in clinical trials with IMiD-containing regimens. Cohorts were eligible if they had publicly available GEP data from patients' bone marrow plasma cells, with long-term follow-up and clinicopathological data. In the development stage of the model, we identified 176 IMiD response genes that were differentially expressed before and after IMiD exposure using pharmacogenomic GEP data from patients who had bone marrow samples taken before and 48 h after a test dose exposure with thalidomide (n=42), lenalidomide (n=18), or pomalidomide (n=18). 14 of these genes had p values less than 0.05 for associations with progression-free survival in patients who received thalidomide in induction and maintenance therapy in the Total Therapy (TT) 2 trial (ie, the training cohort). We combined the 14 genes to create a continuous IMiD-14 score and an optimal cutoff. The subgroup with an IMiD-14 score higher than the cutoff was deemed to be IMiD resistant. We obtained validation cohorts from four studies of IMiD combination regimens: the TT3a trial (thalidomide in induction and maintenance), the TT3b trial (thalidomide in induction and lenalidomide in maintenance), the TT6 trial (thalidomide in induction and lenalidomide in maintenance), and the vincristine, doxorubicin, and dexamethasone (VAD) group of the HOVON65/GMMG-HD4 trial (thalidomide in maintenance). The primary endpoint was to show the prognostic value of the IMiD-14 gene signature for progression-free survival. FINDINGS: In the training cohort, progression-free survival was significantly shorter in the 83 patients with IMiD-14 high scores than in the 92 patients with IMiD-14 low scores; 3 year progression-free survival was 52% (95% CI 42-64) for the IMiD-14 high group versus 85% (78-92) for the IMiD-14 low group, with a hazard ratio (HR) of 2.51 (95% CI 1.72-3.66; p<0.0001). These findings were supported by the results in the validation cohorts, TT3a (115 patients with IMiD-14 high vs 160 patients with IMiD-14 low; 3 year progression-free survival 63% [95% CI 55-73] vs 87% [82-92]; HR 1.54 [1.11-2.15], p=0.010), TT3b (77 patients with IMiD-14 high vs 89 patients with IMiD-14 low; 62% [52-74] vs 80% [72-89]; HR 2.07 [1.28-3.34], p=0.0024), TT6 (20 patients with IMiD-14 high vs 36 patients with IMiD-14 low; 39% [22-68] vs 74% [61-90]; HR 2.40 [1.09-5.30], p=0.026), and the VAD group of HOVON65/GMMG-HD4 (65 patients with IMiD-14 high vs 77 patients with IMiD-14 low; 16% [9-28] vs 54% [44-67]; HR 2.29 [1.52-3.45], p<0.0001). INTERPRETATION: Our results suggest that the IMiD-14 model has prognostic value in patients with multiple myeloma who are treated with IMiDs. Some genes in the model could provide novel targets for IMiD resistance and therapeutic intervention. The IMiD 14 model warrants evaluation in prospective studies. FUNDING: Conquer Cancer Foundation ASCO Young Investigator Award and the Carolinas Myeloma Research Fund. PMID- 28863805 TI - [Topical issues in neonatology]. PMID- 28863806 TI - Corrigendum to "Early Prediction of Functional Outcome Using Dynamic Contrast Enhanced Magnetic Resonance Imaging in Experimental Stroke" [Magnetic Resonance Imaging 34 (2016) 1000-1007]. PMID- 28863807 TI - Destruction of Clostridium difficile spores colitis using acidic electrolyzed water. PMID- 28863809 TI - APIC education online: Are you ready? We are.... PMID- 28863808 TI - Erratum. PMID- 28863810 TI - Exploring inappropriate certified nursing assistant glove use in long-term care. AB - BACKGROUND: Certified Nursing Assistants (CNAs) frequently wear gloves when they care for patients in standard precautions. If CNAs use gloves inappropriately, they may spread pathogens to patients and the environment, potentially leading to health care-associated infections (HAIs). METHODS: Using a descriptive structured observational design, we examined the degree of inappropriate health care personnel glove use in a random sample of 74 CNAs performing toileting and perineal care at 1 long-term care facility. RESULTS: During the 74 patient care events, CNAs wore gloves for 80.2% (1,774/2,213) of the touch points, failing to change gloves at 66.4% (225/339) of glove change points. CNAs changed gloves a median of 2.0 times per patient care event. A median of 1.0 change occurred at a change point. CNAs failed to change their gloves at a glove change point a median of 2.5 times per patient care event. Most (61/74; 82.4%) patient care events had >1 contaminated touch point. Over 44% (782/1,774) of the gloved touch points were defined as contaminated for a median of 8.0 contaminated glove touch points per patient care event. All contaminated touches were with gloved hands (P <.001). CONCLUSIONS: Inappropriate glove use was frequently observed in this study. Contaminated gloves may be a significant cause of cross-contamination of pathogens in health care environments. Future research studies should evaluate strategies to improve glove use to reduce HAIs. PMID- 28863811 TI - Can improving patient hand hygiene impact Clostridium difficile infection events at an academic medical center? AB - BACKGROUND: Hand hygiene plays an important role in the prevention of Clostridium difficile (CD) infection (CDI). Patient hand hygiene (PHH) may be a potentially underused preventative measure for CDI. Patient mobility and acuity along with a lack of education present obstacles to PHH for the hospitalized patient. Surveys of patients at our institution showed a need for increased PHH opportunities. The objective of this study was to increase PHH and to examine if PHH affected CDI at our hospital. METHODS: A biphasic, quasi-experimental study was performed to increase PHH through education for staff and to provide education, assistance, and opportunities to the patient for hand cleaning. PHH practice was assessed by patient surveys and analyzed by chi2 test. PHH effect on CDI was determined by following health care facility-onset CD laboratory-identified events data analyzed by National Healthcare Safety Network standardized infection ratios (SIRs). RESULTS: PHH opportunities improved significantly (P < .0001) after staff and patient education. CD SIRs deceased significantly for 6 months (P <= .05) after the PHH intervention. CONCLUSIONS: PHH opportunities can be increased by providing education and opportunities for patients to clean their hands. PHH should be considered a relevant preventative measure for CDI in hospitalized patients. PMID- 28863812 TI - A young man with frequent episodes of palpitations. PMID- 28863813 TI - Corrigendum to "Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease" [Neurobiol. Aging 58 (2017) 1-13]. PMID- 28863814 TI - Multiple Mechanisms of Regulation of Transient Receptor Potential Ion Channels by Cholesterol. AB - The transient receptor potential (TRP) family of ion channels is constituted by several nonselective cation channels that are activated by diverse stimuli and that function as polymodal receptors. TRP ion channels are expressed in neural and nonneural tissues where they play important roles in cell physiology. The activation of these ion channels is achieved through changes in temperature, osmolarity, voltage, pH, pressure, and by some natural or synthetic chemical compounds that directly bind to these proteins to regulate their activity. Other compounds that regulate TRP ion channel function are some endogenously synthetized lipid compounds. One such example of a compound of lipidic nature, commonly found in cells, is cholesterol. Cholesterol has been shown to exert positive and negative roles on TRP ion channel activity, albeit through different mechanisms which include a direct interaction of this molecule with specific amino acids located in the sequence of these channels or through the recruitment of the channels into specialized membrane microdomains (lipid rafts or caveolae). In this chapter, we will discuss important aspects of cholesterol as a regulator of some members of the TRP family of ion channels, and we will highlight the role of cholesterol on thermo-, chemo-, and osmosensation through regulation of the activity of these proteins. PMID- 28863815 TI - Direct Interactions of Cholesterol With Pentameric Ligand-Gated Ion Channels: Testable Hypotheses From Computational Predictions. AB - Several essential ionotropic neurotransmitter receptors, including the nicotinic acetylcholine receptor (nAChR) and gamma-aminobutyric acid (GABA) type A receptor (GABAAr), belong to the family of pentameric ligand-gated ion channels (pLGICs). Function of these receptors is particularly sensitive to their lipid environment, including cholesterol and cholesterol-derived neurosteroids. Direct structural data investigating interactions between sterols and pLGICs, as well as their role in modulatory mechanisms, are largely unavailable. Physics-based computational approaches can serve a vital role in interpretation of more indirect data as well as hypothesis generation and experimental design. In this chapter, I report several examples in which computational approaches were used to predict direct binding interactions of steroids and pLGICs, evaluate the relative likelihood of possible interpretations of experimental data, and present rationally designed simple experiments. I conclude by offering several predictions that could be tested by future experiments. PMID- 28863816 TI - Insights Into the Molecular Requirements for Cholesterol Binding to Ion Channels. AB - The concept that cholesterol binds to proteins via specific binding motifs, and thereby modulates their function, has emerged two decades ago. When we recently embarked on studies to uncover the putative binding region(s) of cholesterol in the Kir2.1 channel, we carried out an unbiased approach that combines computational and experimental methods. This approach resulted in the identification of novel cholesterol-binding regions distinct from known cholesterol-binding motifs. In recent years, a plethora of structures of proteins complexed with cholesterol have been determined revealing variegated cholesterol binding regions that can provide invaluable insights into the prerequisites for cholesterol binding. Thus, using this database of structures, the goal of this chapter is to present a comprehensive analysis of representative cholesterol binding regions, and thereby determine the molecular requirements for cholesterol binding. The analysis demonstrates that the primary requirement for cholesterol binding is a highly hydrophobic environment, and that the interaction with the cholesterol molecule can be stabilized by stacking interactions between its ring structure and hydrophobic aromatic residues, and by hydrogen bonding between its hydroxyl group and a variety of protein residues. This general requirement suggests that the known cholesterol-binding motifs describe a subset of cholesterol-binding regions, and provides a framework for expanding the search for novel cholesterol-binding regions in ion channels. PMID- 28863817 TI - Regulation of P2X Purinergic Receptor Signaling by Cholesterol. AB - P2X receptors are cation-selective channels that are activated by the binding of extracellular ATP. They have a high permeability to Ca2+, Na+, and K+ and are expressed widely throughout the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, and endocrine systems. Seven mammalian subtypes of P2X receptor subunits have been identified, P2X1-7, and those that function as homotrimeric receptors (P2X1, 2, 3, 4, and 7) are targeted to lipid rafts, although they show limited resistance to solubilization by Triton X-100. Recent crystal structures of P2X3 and P2X4 receptors have provided considerable high resolution information about the architecture of this family of receptors and yet the molecular details of how they are regulated by cholesterol are unknown. Currents mediated by the P2X1-4 receptors are either inhibited or relatively insensitive to cholesterol depletion, but there is no clear evidence to support the direct binding of cholesterol to these receptors. In contrast, the activity of the low-affinity, proinflammatory P2X7 receptor is potentiated by cholesterol depletion and regions within the proximal C-terminus play an important role in coupling changes in cholesterol to the gating of the pore. Based upon our understanding of the lipid signaling events that are triggered downstream of P2X7 receptor activation, a change in the levels of cholesterol may contribute to the sensitization of receptor currents and the dilation of the pore that occurs following prolonged, high-level stimulation. This chapter focuses on the regulation of P2X7 receptor signaling by cholesterol and our current understanding of the mechanisms that underlie this. PMID- 28863818 TI - Depletion of Membrane Cholesterol Suppresses Drosophila Transient Receptor Potential-Like (TRPL) Channel Activity. AB - Cholesterol is an essential compound of higher eukaryotic cell membranes and a known modulator of ion channel activity. Changes in phospholipids and cholesterol composition of cell membranes are known to alter the activity of ion channels. However, there is little knowledge on the effects of cholesterol on transient receptor potential (TRP) channels. In this study, we explore the effects of cholesterol depletion on the Drosophila photoreceptor channel TRP-like (TRPL), when expressed in tissue culture cells. Depletion of membrane cholesterol with methyl-beta-cyclodextrin (MbetaCD) induced fast (<100s) suppression of spontaneous TRPL channel activity, a typical state of expressed TRPL channels in Drosophila S2 cells. An equally fast suppression of receptor-induced TRPL channel activity in HEK293 cells, downstream of phospholipase C (PLC) activation, was also induced by MbetaCD. Biochemical experiments showed binding of TRPL to immobilized cholesterol, suggesting direct binding of cholesterol to TRPL. Exploring the effects of several mutations in a putative cholesterol-binding site of TRPL was inconclusive as some did not render the channel insensitive to cholesterol depletion while others rendered the channel inactive. We conclude that (i) cholesterol is essential for TRPL channel activity, (ii) TRPL channels interact with cholesterol, and (iii) the binding site of cholesterol in TRPL differs from the putative binding site of TRPV1. Thus, the fast and strong effects of cholesterol depletion on the TRPL channel activity suggest that cholesterol is an important component of fly photoreceptor signaling membrane. PMID- 28863819 TI - Differential Effects of Sterols on Ion Channels: Stereospecific Binding vs Stereospecific Response. AB - Numerous ion channels have been shown to be regulated by the level of membrane cholesterol, but the mechanisms responsible for these effects are still not well understood. The key question in the field is how to discriminate between the contributions of the two central mechanisms that might be responsible for the sensitivity of ion channels to cholesterol: specific sterol-protein interactions or regulation of channels by the bilayer physical properties. Comparative analysis of cholesterol and its isomers on the function of an ion channel is a powerful tool to achieve this goal. An increasing number of studies show that cholesterol regulates several types of ion channels in a stereospecific manner, suggesting an involvement of specific sterol-protein interactions. However in this chapter, we present evidence that the stereospecificity of cholesterol-ion channel interactions may be mediated, not by a lack of binding, as has been generally assumed, but by the specificity of the interaction, which results in a functional effect, in the case of native cholesterol, and a lack of functional effect, in the case of a cholesterol isomer. In other words, accumulating evidence suggests that the structural requirements of ion channel cholesterol binding sites are lax, allowing chiral isomers of cholesterol to bind to the same site in a nonstereospecific way, but the ability of a sterol to confer a functional effect on the channel activity can still be stereospecific. This is an important distinction both conceptually and methodologically. Indeed, our analysis shows that the orientations of cholesterol and its chiral isomer ent cholesterol within a hydrophobic binding pocket of Kir2.2 are significantly different, and we propose that this difference may underlie distinct functional outcomes. PMID- 28863820 TI - Sterol Regulation of Voltage-Gated K+ Channels. AB - Cholesterol is an essential lipid building block of the cellular plasma membrane. In addition to its structural role, it regulates the fluidity and raft structure of the membrane and influences the course of numerous membrane-linked signaling pathways and the function of transmembrane proteins, including ion channels. This is supported by a vast body of scientific data, which demonstrates the modulation of ion channels with a great variety of ion selectivity, gating, and tissue distribution by changes in membrane cholesterol. Here, we review what is currently known about the modulation of voltage-gated K+ (Kv) channels by changes in membrane cholesterol content, considering raft association of the channels, the roles of cholesterol recognition sites, and those of adaptor proteins in cholesterol-Kv channel interactions. We specifically focus on Kv1.3, the dominant K+ channel of human T cells. Effects of cholesterol depletion and enrichment and 7-dehydrocholesterol enrichment on Kv1.3 gating are discussed in the context of the immunological synapse and the comparison of the in vitro effects of sterol modifications on Kv1.3 function with ex vivo effects on cells from hypercholesterolemic and Smith-Lemli-Opitz patients. PMID- 28863821 TI - Relevance of CARC and CRAC Cholesterol-Recognition Motifs in the Nicotinic Acetylcholine Receptor and Other Membrane-Bound Receptors. AB - Cholesterol is a ubiquitous neutral lipid, which finely tunes the activity of a wide range of membrane proteins, including neurotransmitter and hormone receptors and ion channels. Given the scarcity of available X-ray crystallographic structures and the even fewer in which cholesterol sites have been directly visualized, application of in silico computational methods remains a valid alternative for the detection and thermodynamic characterization of cholesterol specific sites in functionally important membrane proteins. The membrane-embedded segments of the paradigm neurotransmitter receptor for acetylcholine display a series of cholesterol consensus domains (which we have coined "CARC"). The CARC motif exhibits a preference for the outer membrane leaflet and its mirror motif, CRAC, for the inner one. Some membrane proteins possess the double CARC-CRAC sequences within the same transmembrane domain. In addition to in silico molecular modeling, the affinity, concentration dependence, and specificity of the cholesterol-recognition motif-protein interaction have recently found experimental validation in other biophysical approaches like monolayer techniques and nuclear magnetic resonance spectroscopy. From the combined studies, it becomes apparent that the CARC motif is now more firmly established as a high affinity cholesterol-binding domain for membrane-bound receptors and remarkably conserved along phylogenetic evolution. PMID- 28863822 TI - Regulation of Ca2+-Sensitive K+ Channels by Cholesterol and Bile Acids via Distinct Channel Subunits and Sites. AB - Cholesterol (CLR) conversion into bile acids (BAs) in the liver constitutes the major pathway for CLR elimination from the body. Moreover, these steroids regulate each other's metabolism. While the roles of CLR and BAs in regulating metabolism and tissue function are well known, research of the last two decades revealed the existence of specific protein receptors for CLR or BAs in tissues with minor contribution to lipid metabolism, raising the possibility that these lipids serve as signaling molecules throughout the body. Among other lipids, CLR and BAs regulate ionic current mediated by the activity of voltage- and Ca2+ gated, K+ channels of large conductance (BK channels) and, thus, modulate cell physiology and participate in tissue pathophysiology. Initial work attributed modification of BK channel function by CLR or BAs to the capability of these steroids to directly interact with bilayer lipids and thus alter the physicochemical properties of the bilayer with eventual modification of BK channel function. Based on our own work and that of others, we now review evidence that supports direct interactions between CLR or BA and specific BK protein subunits, and the consequence of such interactions on channel activity and organ function, with a particular emphasis on arterial smooth muscle. For each steroid type, we will also briefly discuss several mechanisms that may underlie modification of channel steady-state activity. Finally, we will present novel computational data that provide a chemical basis for differential recognition of CLR vs lithocholic acid by distinct BK channel subunits and recognition sites. PMID- 28863823 TI - The Role of Cholesterol in the Activation of Nicotinic Acetylcholine Receptors. AB - Cholesterol is a potent modulator of the nicotinic acetylcholine receptor (nAChR) from Torpedo. Here, we review current understanding of the mechanisms underlying cholesterol-nAChR interactions in the context of increasingly available high resolution structural and functional data. Cholesterol and other lipids influence function by conformational selection and kinetic mechanisms, stabilizing varying proportions of activatable vs nonactivatable conformations, as well as influencing the rates of transitions between conformational states. In the absence of cholesterol and anionic lipids, the nAChR adopts an uncoupled conformation that binds agonist but does not undergo agonist-induced conformational transitions-unless the nAChR is located in a relatively thick lipid bilayer, such as that found in cholesterol-rich lipid rafts. We highlight different sites of cholesterol action, including the lipid-exposed M4 transmembrane alpha-helix. Cholesterol and other lipids likely alter function by modulating interactions between M4 and the adjacent transmembrane alpha-helices, M1 and M3. These same interactions have been implicated in both the folding and trafficking of nAChRs to the cell surface. We evaluate the nature of cholesterol nAChR interactions, considering the evidence supporting the roles of both direct binding to allosteric sites and cholesterol-induced changes in bulk membrane physical properties. PMID- 28863824 TI - Preface. PMID- 28863827 TI - Endovascular treatment of arterial ischaemic stroke in paediatric patients: A case-report. PMID- 28863826 TI - Impact of anti-rheumatic treatment on cardiovascular risk in Asian patients with rheumatoid arthritis. AB - OBJECTIVES: To estimate the incidence of cardiovascular disease (CVD) in Asian patients with rheumatoid arthritis (RA) and to evaluate the impact of anti rheumatic treatment on the development of CVD. METHODS: A retrospective cohort of Asian patients with RA was established to identify the incidence rate (IR) of CVD in RA patients. The cohort was generated using the Korean National Healthcare claims database, which contained claims from Jan 2009 to Dec 2013. A total of 137,512 RA patients were identified; individuals with a history of CVD for 6 months or more before the index date were excluded. Nested case-control samples were drawn from the full study population with a case:control ratio of 1:4 (n = 7102 cases; n = 27,018 controls without CVD). A conditional multivariate regression model was used to evaluate the impact of anti-rheumatic treatment on the development of CVD in RA patients after matching for age, sex, RA index date, comorbidities, and drug use (e.g., antiplatelet agents and cholesterol-lowering agents). RESULTS: The IR for development of overall CVD in RA patients was 182.1 (95% CI: 178.4-185.9) per 10,000 person-years. In models adjusted for other CVD risk factors, disease-modifying anti-rheumatic drugs (DMARDs) (OR = 0.79) were protective against CVD, and biologic DMARDs were not significantly associated with CVD risk (OR = 0.85). Corticosteroids (OR = 1.26) and NSAIDs (nonselective NSAIDs: OR = 1.32, Cox-2 inhibitors: OR = 1.31) were risk factors for CVD in RA patients. CONCLUSIONS: The use of DMARDs is protective against CVD, while corticosteroids and NSAIDs increased the risk of CVD in RA patients. PMID- 28863828 TI - Quantitative and qualitative analysis of semantic verbal fluency in patients with temporal lobe epilepsy. AB - INTRODUCTION: Patients with temporal lobe epilepsy (TLE) perform poorly on semantic verbal fluency (SVF) tasks. Completing these tasks successfully involves multiple cognitive processes simultaneously. Therefore, quantitative analysis of SVF (number of correct words in one minute), conducted in most studies, has been found to be insufficient to identify cognitive dysfunction underlying SVF difficulties in TLE. OBJECTIVES: To determine whether a sample of patients with TLE had SVF difficulties compared with a control group (CG), and to identify the cognitive components associated with SVF difficulties using quantitative and qualitative analysis. METHODS: SVF was evaluated in 25 patients with TLE and 24 healthy controls; the semantic verbal fluency test included 5 semantic categories: animals, fruits, occupations, countries, and verbs. All 5 categories were analysed quantitatively (number of correct words per minute and interval of execution: 0-15, 16-30, 31-45, and 46-60seconds); the categories animals and fruits were also analysed qualitatively (clusters, cluster size, switches, perseverations, and intrusions). RESULTS: Patients generated fewer words for all categories and intervals and fewer clusters and switches for animals and fruits than the CG (P<.01). Differences between groups were not significant in terms of cluster size and number of intrusions and perseverations (P>.05). CONCLUSIONS: Our results suggest an association between SVF difficulties in TLE and difficulty activating semantic networks, impaired strategic search, and poor cognitive flexibility. Attention, inhibition, and working memory are preserved in these patients. PMID- 28863829 TI - Experimental models of demyelination and remyelination. AB - INTRODUCTION: Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no such specific model able to provide an overview of the disease; multiple models covering the different pathophysiological features of the disease are therefore necessary. DEVELOPMENT: We reviewed the different in vitro and in vivo experimental models used in multiple sclerosis research. Concerning in vitro models, we analysed cell cultures and slice models. As for in vivo models, we examined such models of autoimmunity and inflammation as experimental allergic encephalitis in different animals and virus-induced demyelinating diseases. Furthermore, we analysed models of demyelination and remyelination, including chemical lesions caused by cuprizone, lysolecithin, and ethidium bromide; zebrafish; and transgenic models. CONCLUSIONS: Experimental models provide a deeper understanding of the different pathogenic mechanisms involved in multiple sclerosis. Choosing one model or another depends on the specific aims of the study. PMID- 28863830 TI - The great imitator: Mesial temporal alterations in MRI in an atypical case of neurosyphilis. PMID- 28863831 TI - Progressive multifocal leukoencephalopathy in an immunocompetent patient. PMID- 28863832 TI - Twenty five years of Cytokine: on a forward path to exciting discoveries of pathological mechanisms and therapeutics. AB - Cytokines, chemokines, adipokines, myokines, and other hematopoietic growth factors constitute the largest network of intercellular signaling proteins that shape organismal development, survival, tissue repair and host defenses. Cytokine has been established for reporting the original research studies in these burgeoning areas. A special issue dedicated to celebrate the quarter century of Cytokine as a journal is here. This review summarizes the contents of several articles published in this special issue. PMID- 28863833 TI - Allergic diseases: From bench to clinic - Contribution of the discovery of interleukin-5. AB - T helper 2 cells produce a number of cytokines including inteleukin (IL)-5, IL-4 and IL-13. Group 2 innate lymphoid cells (ILC2s) also produce IL-5 under sterile conditions. IL-5 is interdigitating homodimeric glycoprotein and a member of the four alpha helical bundle motifs conserved among hematopoietic cytokines. IL-5 exerts its effects on target cells via IL-5 receptor (IL-5R), composed of an IL 5R alpha and betac subunit. The membrane proximal proline-rich motif of the cytoplasmic domain of both IL-5R alpha and betac subunits is essential for IL-5 signal transduction. Although IL-5 was initially identified by its ability to support the growth and terminal differentiation of mouse B cells into antibody secreting cells, recombinant IL-5 exerts pleiotropic activities on various target cells. For example, IL-5 is now recognized as the major maturation and differentiation factor for eosinophils in mice and humans. Overexpression of IL-5 in mouse significantly increases eosinophil numbers and antibody levels in vivo, while mice lacking a functional gene for IL-5 or IL-5R display developmental and functional impairments in B cell and eosinophil lineages. In mice, the role of the IL-5/IL-5R system in the production and secretion of Immunoglobulin (Ig) M and IgA in mucosal tissues has been reported. Although eosinophils protect against invading pathogens including virus, bacteria and helminthes, they are also involved in the pathogenesis of various diseases, such as food allergy, asthma, and inflammatory bowel diseases. The recent expansion in our understanding in the context of IL-5 and IL-5-producing ILC2s in eosinophil activation and the pathogenesis of eosinophil-dependent inflammatory diseases has led to advances in therapeutic options. A new therapy currently under invetigarion in clinical trials uses humanized monoclonal antibodies against IL-5 or the IL-5R. In this review, we summarize our current understanding of the functions of IL-5 and its receptor, the innate regulation of IL-5-producing cells, and therapeutic potential of anti-IL-5 and anti-eosinophil (IL-5R) antibodies. PMID- 28863835 TI - Title Page Of Identification of risk factors associated with onset andprogression of amyotrophic lateral sclerosis using systematic review and meta-analysis. PMID- 28863834 TI - Title Page Of Burden of Neurological conditions in Canada. PMID- 28863836 TI - Title Page Of Systematic reviews of factors associated with the onset and progression of neurological conditions in humans: a methodological overview. PMID- 28863837 TI - Title Page Of Onset and Progression Factors in Parkinson's Disease: A Systematic Review. PMID- 28863838 TI - Title Page Of Risk factors associated with the onset and progression of Alzheimer's disease: a systematic review of the evidence. PMID- 28863839 TI - Title Page Of Factors associated with onset, relapses or progression in multiple sclerosis: a systematic review. PMID- 28863840 TI - Title Page Of A Systematic Review of the Risks Factors Associated with the Onset and Natural Progression of Spina Bifida. PMID- 28863841 TI - Title Page Of A systematic review of the risk factors associated with the onset and progression of primary brain tumours. PMID- 28863842 TI - Title Page Of Factors Associated with the Onset and Progression of Neurotrauma: A Systematic Review of Systematic Reviews and Meta-Analyses. PMID- 28863843 TI - Title Page Of Genetic variation associated with the occurrence and progression of neurological disorders. PMID- 28863844 TI - Title Page Of Determinants of Neurological Disease: Synthesis of Systematic Reviews. PMID- 28863845 TI - Title Page Of A Systematic Review of the Risks Factors Associated with the Onset and Natural Progression of Hydrocephalus. PMID- 28863846 TI - Title Page Of Onset Factors in Cerebral Palsy: A Systematic Review. PMID- 28863847 TI - Title Page Of A Systematic Review of Risk Factors associated with Muscular Dystrophies. PMID- 28863849 TI - Title Page Of Risk Factors for the Onset and Progression of Huntington Disease. PMID- 28863848 TI - Title Page Of A Systematic Review of the Risks Factors Associated with the Onset and Natural Progression of Epilepsy. PMID- 28863850 TI - Preface by Kim Elmslie and Joyce Gordon. PMID- 28863851 TI - Names of the conditions systematically reviewed. PMID- 28863852 TI - Guest Editors Affiliation And Pictures. PMID- 28863853 TI - Foreword by Celina Caesar-Chavannes. PMID- 28863854 TI - Group pictures of the investigators. PMID- 28863855 TI - Implicit guidance of attention: The priority state space framework. AB - Visual selective attention is the process by which we tune ourselves to the world so that, of the millions of bits per second transmitted by the retina, the information that is most important to us reaches awareness and directs action. Recently, new areas of attention research have opened up as classic models dividing attention into top-down and bottom-up systems have been challenged. In this paper, we propose a theoretical framework, the priority state space (PSS) framework, integrating sources of salience that guide visual attention according to a nested hierarchy of goals. Using the PSS framework as a scaffold, we review evidence of selected sources of implicit attentional guidance, including recent research on statistical learning, semantic associations, and motivational and affective salience. We next summarize current understanding of the underlying neural circuitry facilitating guidance of attention by specific sources of salience, including key neuromodulator systems, with an emphasis on affective salience and the noradrenergic system. Finally, we discuss evidence for common mechanisms of prioritization, including integration of sources of salience via priority maps, and introduce the concept of the PSS as a model for mapping a complex dynamic attentional landscape. PMID- 28863856 TI - Weld inspection by focused adjoint method. AB - This paper reports a methodology for the non-destructive ultrasonic evaluation of welds, based on probing, residue back-focusing and topological energy calculation using an enhanced (focused) adjoint method. The proposed method combines the advantages of time reversal to compensate for the cumulative distorsions experienced by a wave propagating in a heterogeneous medium, and topological imaging to highlight the defect location. The synergistic effect of this combined approach makes it possible to detect anomalies in the most efficient way. The method paves the way towards a matched-insonification imaging of anomalies in anisotropic media. PMID- 28863858 TI - Invasion Science: Looking Forward Rather Than Revisiting Old Ground - A Reply to Zenni et al. PMID- 28863857 TI - Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies. AB - Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders. PMID- 28863859 TI - Grafting materials for alveolar cleft reconstruction: a systematic review and best-evidence synthesis. AB - The purpose of this study was to compare the efficacy of alveolar bone reconstruction for alveolar cleft patients performed with the traditional iliac graft or alternative/supplementary bone grafting materials. Electronic databases, relevant journals, and reference lists of the included studies were searched to the end of June 2016. A best-evidence synthesis was performed to draw conclusions. A total of 38 studies were included, which provided 25 pieces of evidence: seven of moderate evidence and 18 of insufficient evidence. The seven pieces of moderate evidence indicated that (1) bone morphogenetic protein 2 bound to absorbable collagen sponge shares similar cleft repair efficacy to the iliac graft; (2) covering the iliac graft with an acellular dermis matrix membrane may increase bone retention for unilateral cleft patients; (3) mixing iliac graft with platelet-rich plasma may increase bone retention for skeletally mature patients, but (4) does not achieve the same result for younger patients; and compared with the iliac graft, (5) the mandible graft is more effective, whereas (6) the cranium graft and (7) rib graft are less effective for alveolar cleft reconstruction. The efficacy of the remaining grafting materials was supported by insufficient evidence. More well-designed controlled studies are needed to ascertain the long-term clinical results of alveolar cleft reconstruction. PMID- 28863861 TI - Neuromyelitis optica, atypical hemophagocytic lymphohistiocytosis and heterozygous perforin A91V mutation. AB - Neuromyelitis optica is an autoimmune demyelinating inflammatory disease characterized by optic neuritis and myelitis with anti-aquaporin 4 antibodies. Hemophagocytic lymphohistiocytosis is a severe systemic inflammatory syndrome that can present in a genetic primary form or secondarily to infective, neoplastic or autoimmune diseases. Our case discusses the first reported case of atypical late-onset hemophagocytic lymphohistiocytosis in a patient with neuromyelitis optica, with multiple triggering factors and carrying the common A91V hypomorphic perforin mutation, that blurs the distinction between primary and secondary forms. PMID- 28863860 TI - Discoidin domain receptor inhibition reduces neuropathology and attenuates inflammation in neurodegeneration models. AB - The role of cell surface tyrosine kinase collagen-activated receptors known as discoidin domain receptors (DDRs) is unknown in neurodegenerative diseases. We detect up-regulation in DDRs level in post-mortem Alzheimer and Parkinson brains. Lentiviral shRNA knockdown of DDR1 and DDR2 reduces the levels of alpha synuclein, tau, and beta-amyloid and prevents cell loss in vivo and in vitro. DDR1 and DDR2 knockdown alters brain immunity and significantly reduces the level of triggering receptor expressed on myeloid cells (TREM)-2 and microglia. These studies suggest that DDR1 and DDR2 inhibition is a potential target to clear neurotoxic proteins and reduce inflammation in neurodegeneration. PMID- 28863862 TI - Imaging strategy and outcome following partial nephrectomy. AB - OBJECTIVES: The aim of this study was to analyze the outcomes of surveillance after partial nephrectomy (PN) in a single institution and the relevance of imaging studies in detecting recurrence. MATERIAL AND METHODS: Retrospective study of 830 patients who underwent PN for localized renal cell carcinoma between 2007 and 2015 at a single institution. We studied the characteristics of recurrence according to pathological and clinical features and elaborated risk groups. The type and the total number of imaging studies performed during surveillance or until recurrence were evaluated. Outcomes of surveillance were analyzed. RESULTS: There were 48 patients (5.8%) diagnosed with recurrence during median 36 [21-52] months follow-up, including local recurrence in 18 patients (37.5%) and metastasis in 30 patients (62.5%). Totally, 17/18 patients (94.4%) with local recurrence and 26/30 patients (86.6%) with metastasis were diagnosed within the first 36 months after PN. When studying the recurrence rate, and time to-recurrence, 2 risk groups emerged. Patients with pathological characteristics (tumors with pT1b or higher or high-grade tumor or positive surgical margin status) or patients with anatomical characteristics (high or moderate R.E.N.A.L. score) or both had high recurrence rate. Chest x-ray and abdominal ultrasound detected 7.7% and 3.4% of all recurrences, respectively, whereas computed tomography scan and magnetic resonance imaging scan detected the rest. Of the 48 patients diagnosed with recurrence, 44 (91.6%) were suitable for secondary active treatment (systemic, surgery, and radiotherapy) including 26 (54.2%) suitable for metastasectomy. The rate of relapse after secondary treatment was 43.5% (16.6% for the local recurrence group and 60.7% for metastasis group). CONCLUSION: Local recurrence emerges earlier than distant metastasis. Patients with any adverse pathological or anatomical features should be considered as high-risk group and followed closely in the first 36 months after PN with cross-sectional studies. Secondary active treatment is suitable for most patients, while surgical treatment fits fewer patients. Local recurrence is associated with increased rates of metastatic progression. PMID- 28863863 TI - Unitary Properties of AMPA Receptors with Reduced Desensitization. AB - Wild-type AMPA receptors display a characteristic rapidly desensitizing phenotype. Many studies point to the dimer interface between pairs of extracellular ligand binding domains as the key region controlling the rate at which the receptors desensitize. However, mutations at the extracellular end of the pore-forming regions (near the putative ion channel gate) have also been shown to alter desensitization. Here we report the behavior of single GluA4 receptors carrying one of two mutations that greatly reduce desensitization at the level of ensemble currents: the dimer interface mutation L484Y and the Lurcher mutation (A623T, GluA4-Lc) in the extracellular end of M3 (the second true transmembrane helix). Analysis of unitary currents in patches with just one active receptor showed that each mutation greatly prolongs bursts of openings without prolonging the apparent duration of individual openings. Each mutation decreases the frequency with which individual receptors visit desensitized states, but both mutant receptors still desensitize multiple times per second. Cyclothiazide (CTZ) reduced desensitization of wild-type receptors and both types of mutant receptor. Analysis of shut-time distributions revealed a form of short lived desensitization that was resistant to CTZ and was especially prominent for GluA4-Lc receptors. Despite reducing desensitization of GluA4 L484Y receptors, CTZ decreased the amplitude of ensemble currents through GluA2 and GluA4 LY receptor mutants. Single-channel analysis and comparison of the GluA2 L483Y ligand binding domain dimer in complex with glutamate with and without CTZ is consistent with the conclusion that CTZ binding to the dimer interface prevents effects of the LY mutation to modulate receptor activation, resulting in a reduction in the prevalence of large-conductance substates that accounts for the decrease in ensemble current amplitudes. Together, the results show that similar nondesensitizing AMPA-receptor phenotypes of population currents can arise from distinct underlying molecular mechanisms that produce different types of unitary activity. PMID- 28863865 TI - LC-MS/MS quantitation of antimalarial drug piperaquine and metabolites in human plasma. AB - PURPOSE: This study aimed to develop a sensitive, quantitative assay for the antimalarial piperaquine (PQ) and its metabolites M1 and M2 in human plasma. RESULTS: Analytes were gradiently separated on a C18 column and detected with a Sciex API 4000 MS/MS with an ESI source operated in the positive ion mode with deuterated PQ as internal standard. The response was linear in the range 3.9 2508nM with a runtime of 7.0min per sample. The method was applied to clinical samples from healthy volunteers. CONCLUSION: This LC-MS/MS method for the simultaneous quantitation of PQ and two of its metabolites in plasma may prove helpful for assessment of metabolite safety issues in vivo. PMID- 28863864 TI - Two Pools of Vesicles Associated with Synaptic Ribbons Are Molecularly Prepared for Release. AB - Neurons that form ribbon-style synapses are specialized for continuous exocytosis. To this end, their synaptic terminals contain numerous synaptic vesicles, some of which are ribbon associated, that have difference susceptibilities for undergoing Ca2+-dependent exocytosis. In this study, we probed the relationship between previously defined vesicle populations and determined their fusion competency with respect to SNARE complex formation. We found that both the rapidly releasing vesicle pool and the releasable vesicle pool of the retinal bipolar cell are situated at the ribbon-style active zones, where they functionally interact. A peptide inhibitor of SNARE complex formation failed to block exocytosis from either pool, suggesting that these two vesicle pools have formed the SNARE complexes necessary for fusion. By contrast, a third, slower component of exocytosis was blocked by the peptide, as was the functional replenishment of vesicle pools, indicating that few vesicles outside of the ribbon-style active zones were initially fusion competent. In cone photoreceptors, similar to bipolar cells, fusion of the initial ribbon-associated synaptic vesicle cohort was not blocked by the SNARE complex-inhibiting peptide, whereas a later phase of exocytosis, attributable to the recruitment and subsequent fusion of vesicles newly arrived at the synaptic ribbons, was blocked. Together, our results support a model in which stimulus-evoked exocytosis in retinal ribbon synapses is SNARE-dependent; where vesicles higher up on the synaptic ribbon replenish the rapidly releasing vesicle pool; and at any given time, there are sufficient SNARE complexes to support the fusion of the entire ribbon-associated cohort of vesicles. An important implication of these results is that ribbon-associated vesicles can form intervesicular SNARE complexes, providing mechanistic insight into compound fusion at ribbon-style synapses. PMID- 28863866 TI - Rethinking number-needed-to-vaccinate for pneumococcal conjugate vaccines in older adults: Current and future implications. AB - BACKGROUND: Number-needed-to-vaccinate (NNV) is increasingly used to inform decisions about vaccine use, but it is not calculated uniformly across studies. This study compared two methodologies for calculating NNV with 13-valent pneumococcal conjugate vaccine (PCV13) to prevent one case of community-acquired pneumonia (CAP) among US adults aged >=65years: (i) using one-year absolute rate differences as was originally performed by the Centers for Disease Control and Prevention (CDC) and (ii) using absolute risk reduction over 5years. METHODS: We constructed a hypothetical fixed cohort of 200,000 adults aged >=65years equally separated into PCV13-vaccinated and PCV13-unvaccinated groups. We incorporated the same conservative assumptions used by CDC in 2014 regarding annual incidence of hospitalized (1375 per 100,000) and outpatient (2010 per 100,000) CAP, the initial (2014) proportion of adult PCV13-type CAP (10%), and PCV13 efficacy against vaccine-type CAP (45%). To model PCV13 impact over time, we assumed annual mortality was 5% for both groups, the percentage of adult PCV13-type CAP declined annually due to pediatric herd effects, and PCV13 efficacy did not wane over 5years. RESULTS: Among adults aged >=65years, NNV with PCV13 to prevent one hospitalized and one outpatient case of CAP as originally calculated by CDC in 2014 were 1620 and 1110, respectively. Accounting for 5-year cumulative effects, NNV with PCV13 to prevent one hospitalized and one outpatient case of CAP over 5years were 576 and 394, respectively. These revised NNV estimates are roughly one third of initial estimates in which cumulative effects were ignored. NNV to prevent any CAP (inpatient or outpatient) over 5years with one PCV13 dose was 234. CONCLUSION: Accounting for cumulative preventive effects of PCV13 vaccination over time is critical. Failing to do so, even when using conservative disease burden parameters, can grossly underestimate the public health impact of adult PCV13 use. PMID- 28863867 TI - Results on exposure during pregnancy from a pregnancy registry for AS04-HPV-16/18 vaccine. AB - OBJECTIVE: To assess pregnancy outcomes after exposure to AS04-HPV-16/18 vaccine (Cervarix, GSK, Belgium) prior to, or during pregnancy, as reported to a pregnancy registry. METHODS: A pregnancy exposure registry was established to collect data in the United Kingdom and the United States. Exposure was defined as vaccination with AS04-HPV-16/18 within 60days before the estimated conception date and delivery. Reporting was voluntary. RESULTS: Between September 2007 and November 2015, 306 pregnancy exposure reports were received of which 181 were prospective, evaluable reports. From these 181 reports, 154 (85.1%) pregnancies resulted in a live birth, 14 (7.7%) in spontaneous abortion, one (0.5%) in stillbirth, and 12 (6.6%) were electively terminated. There was no clustering of outcomes with respect to the timing of exposure. There were 18 infants born with a congenital anomaly of which nine were minor structural defects, seven were major structural defects, one was a hereditary disorder and one was likely the result of a congenital infection. In three cases of structural defect (two minor and one major), there was a temporal association to vaccination during the critical developmental period of gestation. There was no cluster or constellation of congenital anomalies suggestive of possible teratogenesis. CONCLUSION: The pharmacovigilance plan to investigate the effects of inadvertent exposure to AS04 HPV-16/18 vaccine during pregnancy included assessment of pregnancy outcomes among women enrolled in clinical trials, evaluation of pregnancy exposure reports from all countries as part of routine passive safety surveillance, a large, well conducted post-authorization observational study, and the pregnancy registry. These registry data complement other data from clinical trials and post-marketing surveillance showing no evidence that vaccination with AS04-HPV-16/18 during the defined exposure period (within 60days before conception until delivery) increases the risk of teratogenicity. PMID- 28863868 TI - Prevention of treatable infectious diseases: A game-theoretic approach. AB - We model outcomes of voluntary prevention using an imperfect vaccine, which confers protection only to a fraction of vaccinees for a limited duration. Our mathematical model combines a single-player game for the individual-level decision to get vaccinated, and a compartmental model for the epidemic dynamics. Mathematical analysis yields a characterization for the effective vaccination coverage, as a function of the relative cost of prevention versus treatment; note that cost may involve monetary as well as non-monetary aspects. Three behaviors are possible. First, the relative cost may be too high, so individuals do not get vaccinated. Second, the relative cost may be moderate, such that some individuals get vaccinated and voluntary vaccination alleviates the epidemic. In this case, the vaccination coverage grows steadily with decreasing relative cost of vaccination versus treatment. Unlike previous studies, we find a third case where relative cost is sufficiently low so epidemics may be averted through the use of prevention, even for an imperfect vaccine. However, we also found that disease elimination is only temporary-as no equilibrium exists for the individual strategy in this third case-and, with increasing perceived cost of vaccination versus treatment, the situation may be reversed toward the epidemic edge, where the effective reproductive number is 1. Thus, maintaining relative cost sufficiently low will be the main challenge to maintain disease elimination. Furthermore, our model offers insight on vaccine parameters, which are otherwise difficult to estimate. We apply our findings to the epidemiology of measles. PMID- 28863869 TI - Intention to accept pertussis vaccine among pregnant women in Karachi, Pakistan. AB - BACKGROUND: Maternal immunization against pertussis is a potential strategy to protect young infants from severe disease. We assessed factors associated with intention to accept pertussis vaccination among pregnant women in Karachi, Pakistan. METHODS: We conducted a cross-sectional survey between May and August 2013 in pregnant women who visited healthcare centers in urban slums of Karachi city. Women completed a survey examining socio-demographic factors, vaccination history, knowledge on pertussis disease, perception of vaccine recommendation sources, and potential influences on vaccine decision-making. RESULTS: Of the 283 participants, 259 (92%) provided their intention to either accept or decline pertussis vaccination. Eighty-three percent women were willing to accept the pertussis vaccine if offered during pregnancy. About half (53%) of the participants had ever heard of pertussis disease. Perceptions of pertussis vaccine efficacy, safety, and disease susceptibility were strongly associated with intention to accept pertussis vaccine (p<0.01). Healthcare providers, Ministry of Health, and mass media were considered as highly reliable sources of vaccine recommendation and associated with intention to accept antenatal pertussis vaccination (p<0.001). Healthcare provider recommendation was a common reason cited by respondents for pregnant women to accept antenatal pertussis vaccination (p=0.0005). However, opinion of primary decision-makers in the family (husbands and in-laws) was a crucial reason cited by respondents for pregnant women to reject pertussis vaccination in pregnancy (p=0.003). CONCLUSION: Antenatal pertussis vaccination initiatives in South Asia should strongly consider inclusion of family members, healthcare providers, national health ministries, and mass media to help implement new vaccination programs. PMID- 28863870 TI - The role of self-efficacy, self-esteem and optimism for using routine health check-ups in a population-based sample. A longitudinal perspective. AB - While several cross-sectional studies have shown that self-efficacy, self-esteem and optimism are associated with the use of routine health check-ups, little is known about this relationship based on longitudinal studies. Consequently, the purpose of this study was to examine whether these factors are associated with routine health check-ups longitudinally. Data were retrieved from a population based longitudinal study of individuals (>=40years of age) residing in private households in Germany (two waves: 2008 and 2011). Widely established scales were used to quantify self-efficacy, self-esteem, and optimism. Respondents reported whether they used a health check-up in the last two years. Conditional fixed effects logistic regressions were used (n=1504), adjusting for socio-demographic, lifestyle and health-related variables. After adjusting for various potential confounders, regression analysis revealed that the use of routine health check ups increased with self-efficacy [OR: 1.71 (95%-CI: 1.14-2.55)], self-esteem [OR: 1.78 (1.16-2.73)], and optimism [OR: 1.37 (1.01-1.86)]. Furthermore, the use of routine health check-ups increased with changes from employment to retirement [OR: 2.60 (1.34-5.03)], whereas it was not associated with changes in age, marital status, smoking status, the number of physical illnesses, self-rated health and body-mass index. The current study stresses the importance of an association between screening behavior and self-efficacy, self-esteem and optimism longitudinally. Interventions aiming at modifying these psychological factors might help to increase the use of routine health check-ups. PMID- 28863871 TI - Neighborhood built environment and socio-economic status in relation to multiple health outcomes in adolescents. AB - The study aim was to examine associations of neighborhood built environment and neighborhood socio-economic status (SES) with multiple physical activity (PA) behaviors, sedentary time, and obesity indicators among adolescents. Cross sectional study of 325 adolescents aged 14-18years recruited from schools in Valencia, Spain. Participants' home neighborhoods were classified according to walkability and SES levels. Walkability was defined as an index of three built environment characteristics (i.e., residential density, land use mix, and street connectivity) based on geographic information system data. Moderate-vigorous PA (MVPA) and sedentary time were assessed using accelerometers. Active commuting to school, leisure-time PA, and time in specific sedentary activities were evaluated by questionnaire. Objectively measured weight and height were used to calculate body mass index, and percent body fat was analyzed by bioelectrical impedance. Data were collected in 2013-15. Mixed model regression analyses were performed. Analyses showed an SES-by-walkability interaction for MVPA on weekends. MVPA was highest in high-SES/high-walkable neighborhoods. Another SES-by-walkability interaction was found for sedentary minutes per weekend day. The lowest average sedentary minutes were found in high-SES/high-walkable areas. Neighborhood SES was positively related to participation in sports teams/PA classes and, negatively to time spent in sedentary behaviors. Adolescents living in lower-SES neighborhoods spent more time watching TV and had more obesity and body fat. Present findings strengthen the rationale for targeting neighborhood built and SES environments as health promotion interventions for adolescents. PMID- 28863872 TI - Decision-making in fecal occult blood test compliance: A quali-quantitative study investigating motivational processes. AB - The qualitative-quantitative study investigates the co-existence of barriers and levers to FOBT screening in 5894 individuals reluctant to be screened, identifying operational motivational patterns that may increase screening compliance. Co-occurrence analysis was performed according to three motivational conditions (barriers, levers, or both).Cluster analysis then identified motivational predictors of effective screening. One quarter of the individuals who had refused screening nevertheless expressed at least one motivation towards FOBT. As such, co-existence of barriers and levers within the same individual demonstrates ambivalence tendencies. Intrinsic motivations appear to be the most likely to increase FOBT compliance. This study finds that certain factors well known to improve CRC screening compliance generally, may not have much impact on reluctant individuals due to ambivalence and contextual nuances. Several practical recommendations to encourage screening participation are offered, such as focusing on levers rather barriers, providing tailored education to improve awareness and readiness, and fostering intrinsic motivation with relevant approaches. PMID- 28863873 TI - Evaluation of the associations between immunoglobulin E levels and the number of natural teeth. AB - BACKGROUND/PURPOSE: The purpose of the study was to evaluate the association between the number of natural teeth and the total serum immunoglobulin E (IgE), allergen-specific IgE against Dermatophagoides farina, allergen-specific IgE against cockroaches, or allergen-specific IgE against dogs with nationally representative data using the Korean National Health and Nutrition Examination Survey (KNHANES). METHODS: This study involved a cross-sectional analysis using KNHANES data from 2010. A total of 1916 participants were eligible for this study. Multiple regression analyses were used to evaluate the risk of tooth loss in relation to IgE levels. The model was adjusted for age, sex, body mass index, smoking habits, drinking habits, exercise habits, vitamin D levels, metabolic syndrome, allergic rhinitis, asthma, atopic dermatitis, and tooth-brushing frequency. RESULTS: The number of natural teeth of the first quartile to the fourth quartile of total serum IgE were 25.9 +/- 0.2, 25.9 +/- 0.2, 25.1 +/- 0.2, and 25.4 +/- 0.2, respectively, showing an inverse association (P < 0.05). The number of natural teeth of the first quartile to the fourth quartile of allergen specific IgE against Dermatophagoides farina and allergen-specific IgE against dogs farina both showed an inverse association with statistical significance (P < 0.05). CONCLUSION: This study clearly showed the inverse association between total serum IgE and number of natural teeth after adjustments, especially regarding participants without systemic diseases, including diabetes mellitus, hypertension, metabolic diseases, and obesity. PMID- 28863875 TI - [Hypothyroidism in adults in a basic health area]. AB - INTRODUCTION: The objective of the present study is to study the prevalence, as well as the clinical and epidemiological characteristics of hypothyroid disease in adults using the computerised clinical records. MATERIAL AND METHODS: Observational, descriptive and cross-sectional study. The target population was the patients of the health centres of Lucena I and II (Cordoba). INCLUSION CRITERIA: Patients 14 years or older, diagnosed with hypothyroidism, born and resident in Lucena. Two hundred and fourteen patients were recruited by random sampling, who then underwent a clinical interview using a questionnaire. RESULTS: The mean age of the patients was 49.71 years (SD 17.03; 95% CI 47.34-51.98), with 85.5% women. A diagnosis of sub-clinical hypothyroidism was found in 74.8%, compared to 18.7% of primary hypothyroidism, and 6.5% of secondary hypothyroidism. The 53.7% (95% CI 46.81-60.59) of patients diagnosed with hypothyroidism did not have thyroid antibodies results. However, 75.2% (95% CI 68.89-80.86) were being treated with levothyroxine. The prevalence of hypothyroidism was 5.7% (95% CI 5.46-5.96). CONCLUSIONS: Sub-clinical hypothyroidism is very common in Primary Care clinics. Many patients are not correctly diagnosed and many are over-medicated, suggesting a need to review the diagnosis. PMID- 28863876 TI - [Haemoptysis and a radiological image that appears and disappears]. PMID- 28863874 TI - A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins. AB - BACKGROUND: There is a residual risk of coronary heart disease (CHD) despite intensive statin therapy for secondary prevention. The aim of this study was to investigate whether coronary plaque regression and stabilization are reinforced by the addition of eicosapentaenoic acid (EPA) to high-dose pitavastatin (PTV). METHODS: We enrolled 193 CHD patients who underwent percutaneous coronary intervention (PCI) in six hospitals. Patients were randomly allocated to the PTV group (PTV 4mg/day, n=96) or PTV/EPA group (PTV 4mg/day and EPA 1800mg/day, n=97), and prospectively followed for 6-8 months. Coronary plaque volume and composition in nonstenting lesions were analyzed by integrated backscatter intravascular ultrasound (IB-IVUS). RESULTS: The PTV/EPA group showed a greater reduction in total atheroma volume compared to PTV group. IB-IVUS analyses revealed that lipid volume was significantly decreased during follow-up period in only PTV/EPA group. The efficacy of additional EPA therapy on lipid volume reduction was significantly higher in stable angina pectoris (SAP) patients compared to acute coronary syndrome patients. EPA/AA ratio was significantly improved in PTV/EPA group compared to PTV group. There was no significant difference in the incidence of major adverse cardiovascular events and side effects. CONCLUSIONS: Combination EPA/PTV therapy significantly reduced coronary plaque volume compared to PTV therapy alone. Plaque stabilization was also reinforced by EPA/PTV therapy in particular SAP patients. The addition of EPA is a promising option to reduce residual CHD risk under intensive statin therapy. PMID- 28863877 TI - Gout Mimicking Soft Tissue Tumor. PMID- 28863878 TI - Pulmonary sarcoidosis mimicking tuberculosis: Importance of the galaxy sign on thoracic computed tomography. AB - Sarcoidosis and tuberculosis are two common granulomatous conditions that may share clinical and radiological presentations. The galaxy sign (sarcoid galaxy sign) is a characteristic radiological sign of pulmonary sarcoidosis on thoracic computed tomography (CT). We present the case of a patient with sarcoidosis that was initially misdiagnosed as tuberculosis, in whom the galaxy sign on CT was useful as it suggested the correct diagnosis. PMID- 28863879 TI - Vitamin C in Clinical Therapeutics. PMID- 28863880 TI - Plasma Cell Granuloma of the Jaw and the Infratemporal Fossa: A Clinical Case. AB - Plasma cell granuloma or inflammatory pseudotumor (IPT) is diagnosed by a process of elimination. The precise etiology is unknown, although it can occur after a bout of periodontal infection. This report describes the various stages of progression for this ailment. A 49-year-old woman with no noteworthy medical history presented with a recurrent periodontal abscess accompanied by progressive and severe destruction of the right maxilla. There was invasion of the infratemporal fossa and very tight trismus. Histologic examination indicated a reactive plasma cell granuloma. IPT is an entity recognized by the World Health Organization. A triggering infectious or inflammatory factor is often present. In the maxilla, progression is very aggressive. Treatment relies on corticotherapy, with or without radiotherapy, and administration of cyclosporine. PMID- 28863881 TI - Does Guided Bone Regeneration Prevent Unfavorable Bone Shapes in Distraction Gap? AB - PURPOSE: Complications related to distraction osteogenesis can cause degradation of newly regenerated bone. Additionally, an unfavorable shape of the regenerated bone at the distraction gap can reduce the quantity of regenerated bone. The aim of the present study was to report on the prevention of unfavorable shapes of regenerated bone using guided bone regeneration during distraction. MATERIALS AND METHODS: Bilateral alveolar distraction was performed in 10 beagle dog mandibles. One side of the mandible formed the experimental group and the other side served as the control group. In the experimental group, guided bone regeneration was performed simultaneously with distraction osteogenesis. In the control group, only alveolar distraction was applied. At the end of a 1-week latent period, all mandibles were distracted 10 mm (1 mm/day). After the distraction period, 3 months were allowed for consolidation. After consolidation, all the dogs were euthanized, and the shape of the regenerated bone was determined to be either favorable or unfavorable. Densitometric evaluation and area measurements were performed using computed tomography scans. Statistical evaluation was performed using the independent t test, with a significance level of P < .05. RESULTS: In the experimental group, no unfavorable bone shape developed in the distraction gap, and the new bone had a surface and volume similar to those of the segments. In contrast, in the control group, 4 mandibles had an unfavorable bone shape in the distraction gap and 4 showed favorable bone healing with no defect. The surface area of the regenerating bone in the experimental group was significantly greater than that in the control group. Also, the surface area differed significantly between the experimental and control groups (P < .05). However, the densitometric values did not differ between the 2 groups (P < .05). CONCLUSIONS: Concomitant use of guided bone regeneration with distraction osteogenesis could be an optimal method for generating a favorable bone shape within the distraction gap. PMID- 28863882 TI - Evaluation of Mandibular Bone After Dental Extraction in Rats Treated With Antiresorptive Drugs. AB - PURPOSE: Zoledronic acid (ZOL) and denosumab (Dmab) are commonly used to treat bone pathologies. Because these drugs suppress bone metabolism, this study sought to compare their effect on bone repair after tooth extraction. MATERIALS AND METHODS: Four-week-old male Wistar rats were randomly assigned to 1 of 3 groups: ZOL 0.125 mg/kg, Dmab 0.25 mg/kg, or saline solution 10 mL/kg (control). After 1 week of treatment, the first left molar was extracted; the rats were euthanized at 28 days. The jaws were removed and photographed for macroscopic analysis of wound healing and then subjected to tomographic and histologic analyses. Immunohistochemistry was carried out against the receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG). RESULTS: No difference in wound healing, presence of inflammatory infiltrate and bone sequestration, or osteocyte expression of RANKL and OPG was found among groups. Tomographic analysis showed that the ZOL group had less alveolar resorption and more complete alveolar repair compared with the other groups. There was a statistically significant difference in the OPG marker in the control (P = .008) and ZOL (P = .05) groups when comparing the extracted and non-extracted sides. CONCLUSION: Systemic use of ZOL can improve alveolar bone healing; however, the potential risk for the development of osteonecrosis should be considered. Higher expression of OPG seems to be associated with the control of osteoclastogenesis during bone repair. PMID- 28863883 TI - Clinicopathologic and Surgical Study of Pleomorphic Adenoma of the Parotid Gland: Analysis of Risk Factors for Recurrence and Facial Nerve Dysfunction. AB - PURPOSE: To determine whether clinicopathologic or surgical features are risk factors for recurrence and facial nerve dysfunction in pleomorphic adenoma (PA) of the parotid gland. PATIENTS AND METHODS: The records of 198 patients surgically treated for a PA of the parotid gland from 1999 through 2013 were retrospectively reviewed to identify patients who developed a tumor recurrence. The Fisher exact test and Mann-Whitney U test were used to analyze patient characteristics between recurrent and non-recurrent PAs. Logistic regression was used to determine the risks of recurrence and facial nerve dysfunction. RESULTS: Twenty-three patients (11.6%) developed a recurrence. Patients with tumor recurrence were notably younger than patients without recurrence. Of the 14 patients who underwent enucleation, 11 (78.6%) developed residual disease, as did 10 of 165 patients (6%) managed by a superficial parotidectomy (P < .0005). Furthermore, the risk of residual disease was 9.3 to 21.6 times higher in patients who underwent enucleation than in those who underwent a total or superficial parotidectomy. For tumor histology, recurrence was observed in 3 (15.8%) of the 19 cellular types, 18 (11.5%) of 157 classic cases, and 1 (4.8%) of 21 myxoid cases (P = .5). The risk of recurrence with positive resection margins was 49 times higher than with negative margins (P = .001). CONCLUSION: Young age, enucleation, and positive margins are risk factors for residual pleomorphic adenoma, and surgical technique and histomorphologic features are associated with increased facial nerve dysfunction. PMID- 28863884 TI - How Accurate Are Implant Surgical Guides Produced With Desktop Stereolithographic 3-Dimentional Printers? AB - PURPOSE: The use of tooth-supported static stereolithographic guides has greatly improved the ability to ideally place implants. This study was designed to determine the accuracy of in office-printed implant surgical guides. MATERIALS AND METHODS: Using 3shape Implant Studio, a treatment plan for implant placement for tooth 8 was developed using a digital intraoral scan from a Trios scanner and cone-beam computed tomography. Ten stereolithographic guides were printed using a Form2 3-dimensional printer. Pre- and post-implant insertion digital scans were used to determine distance and angulation differences in the mesiodistal and faciolingual positions of the implants compared with the planned position. RESULTS: The mean difference in mesiodistal direction at the alveolar crest between planned implants and placed implants was 0.28 mm (range, 0.05 to 0.62 mm) and the difference in the faciolingual direction was 0.49 mm (range, 0.08 to 0.72 mm). The mean mesiodistal angulation deviation was 0.84 degrees (range, 0.08 degrees to 4.48 degrees ) and the mean faciolingual angulation deviation was 3.37 degrees (range, 1.12 degrees to 6.43 degrees ). CONCLUSIONS: In-office fabricated stereolithographic implant surgical guides show similar accuracy to laboratory- or manufacturer-prepared guides. This technique provides a convenient and cost-effective means of assuring proper implant placement. PMID- 28863885 TI - A New Indication for Barbed Threads: Static Reanimation of the Paralyzed Face. AB - PURPOSE: The objective of this study was to present the authors' experience in static facial reanimation using a straightforward incisionless procedure adapted from techniques commonly used for performing minimally invasive facelifts. MATERIALS AND METHODS: Seventeen patients were treated by static suspension using barbed sutures and all resulting changes were reviewed. The technique used for suture placement is described in detail, as are the author's tips for achieving the best esthetic and functional results. All patients had preoperative indication for physiotherapy and rehabilitation procedures (local massage and mirror therapy). Facial nerve function was evaluated using the Arianna Disease Scale. RESULTS: The cosmetic outcome improved in all cases, with marked amelioration of the preoperative facial asymmetry. Oral competence was enhanced by elevating the oral commissure and reinforcing the cheek, and amelioration of symptoms related to lagophthalmos was achieved through increased support and decreased pull on the inferior eyelid. The addition of physiotherapy with specific rehabilitation exercises before the surgical intervention increased the success rate. CONCLUSION: This technique proved to be a good alternative to other static reanimation procedures because of its straightforward technique, availability, good outcomes, low complication rate, and ability to perform minor adjustments and corrections at any time. PMID- 28863886 TI - Is Superselective Neck Dissection Safer Than Supraomohyoid Neck Dissection for Oral Carcinoma Patients With N0 Neck in Terms of Shoulder Morbidity and Recurrence Rate? AB - PURPOSE: To estimate the clinical and functional results of patients who underwent distinctive types of neck dissection, with particular emphasis on shoulder function, rate of recurrence, and quality of life in patients with N0 neck. MATERIALS AND METHODS: A randomized clinical trial was conducted from August 2014 to March 2017 in which 20 adult patients with T1 to T3 lesions of the oral cavity and N0 neck were included. Patients were randomly allocated to group I (n = 10; selective neck dissection) or group II (n = 10; superselective neck dissection). All patients were evaluated objectively for degree of arm abduction and subjectively for quality of life using a questionnaire completed pre- and postoperatively at 6 months. Also, locoregional recurrence was investigated for 2.5 years. Data were scrutinized by applying mean and standard deviation, unpaired t test, Mann-Whitney U test, and Kaplan-Meier test. RESULTS: Mean values of the Arm Abduction Test and quality-of-life scores were statistically significant (P < .05) for group II compared with group I at all intervals. Data analyzed for locoregional recurrence showed a statistically significant difference between groups (P < .05), with group II having the better outcome. CONCLUSION: The results showed less shoulder morbidity and improved quality of life for superselective neck dissection (group II) compared with selective neck dissection (group I). Furthermore, group II was better for locoregional recurrence, which determines the oncologic safety of the procedure. PMID- 28863887 TI - Development of monoclonal antibodies against the human 3beta-hydroxysteroid dehydrogenase/isomerase isozymes. AB - The human 3beta-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzymes catalyze the conversion of 3beta-hydroxy Delta5-6 steroids into 3-keto Delta4-5 steroids, which is required for the synthesis of the mature steroid hormones secreted by the adrenal and gonads. The human has 2 isozymes, the HSD3B1 that is traditionally located in placenta and extra-adrenal tissues and the HSD3B2 that is expressed in the adrenal and gonads. Mice with both cryptochrome 1 and 2 genes deletion were recently found to have salt-sensitive hypertension and hyperaldosteronism. These deletions were also associated with overexpression of the Hsd3b6 enzyme, the homolog of the human HSD3B1, in the zona glomerulosa which was believed to explain the hyperaldosteronism. A report using antibodies against human HSD3B1 suggested that it was expressed in the zona glomerulosa of normal human adrenals and in patients with idiopathic hyperaldosteronism and the HSD3B2 expressed in both the zona fasciculata and glomerulosa. We have developed specific monoclonal antibodies against the human HSD3B1 and HSD3B2 isozymes and found that the main enzyme expressed in the zona glomerulosa was the HSD3B2. Faint staining of the adrenal was also obtained using the anti-HSD3B1antibody only at high concentrations of antibody. This study fails to confirm that HSD3B1 expression in the human zona glomerulosa and double immunofluorescence clearly shows that the HSD3B2 is expressed in the zona glomerulosa and fasciculata and in the zona glomerulosa HSD3B2 is co-expressed with aldosterone synthase (CYP11B2). PMID- 28863888 TI - Marine yeast Yarrowia lipolytica improves the immune responses in Pacific red snapper (Lutjanus peru) leukocytes. AB - The climatic conditions in saltern saline environments allows the growth of microorganisms adapted to these peculiar ambient and could represent a promising source of new bioactive compounds that could have applications on as animal food supplements, including aquaculture. In this study, we evaluated the role of Yarrowia lipolytica N-6 isolate, from a hypersaline natural environment (Guerrero Negro, Baja California Sur, Mexico), as immunostimulant of the non-specific immune response of head-kidney and spleen Pacific red snapper (Lutjanus peru) leukocytes after challenge with Vibrio parahaemolyticus. In this study, the presence of Y. lipolytica reduced considerably the V. parahaemolyticus load in spleen leukocytes. In vitro assays using head-kidney and spleen leukocytes showed that the response to V. parahaemolyticus infection reveled that leukocyte pre incubated with Y. lipolytica N-6 significantly increased the non-specific immune response such as respiratory burst, phagocytic activity, NO and MPO activities follow by an increase in SOD and CAT activities, and at the same time inhibited leukocyte apoptosis caused by V. parahaemolyticus. Moreover, Y. lipolytica N-6 incubation also regulated the transcription of genes related to immunity (IL 1beta) or oxidative stress (MnSOD, icCu/ZnSOD or CAT) in leukocytes. These results strongly support the idea that the extreme yeast Y. lipolytica N-6 isolate can stimulate the non-specific immune parameters and the antioxidant immune mechanism in head-kidney and spleen Pacific red snapper leukocytes and could be used as potential immunostimulant. PMID- 28863889 TI - Transcriptome analysis of Mytilus coruscus hemocytes in response to Vibrio alginnolyficus infection. AB - As an economically important bivalve, the Mytilus coruscus is cultured widely in the eastern coast of China. In recent years, this bivalve has been seriously affected by the pathogenic infections. To elucidate the host defense mechanisms of M. coruscus against pathogenic challenge, the hemocyte transcriptomes of M. coruscus before and after Vibrio alginnolyficus infection were analyzed using the deep-sequencing platform Illumina/HiSeq-2500, meanwhile the differentially expressed genes (DEGs) were investigated. In total, 130,031,083 clean reads were obtained and then assembled into 63,942 unigenes with an average length of 810 bp and an N50 of 1056 bp. Unigenes were annotated by comparing against nr, Swiss Prot, KEGG, COG, KOG, GO, and Pfam databases, and 27,345 unigenes (42.77%) were annotated in at least one database. After bacterial challenge, 1270 and 265 genes were identified as remarkably up- or down-regulated, respectively, amongst 1154 were associated with 122 pathways, including classical immune-related pathways, such as 'Toll-like receptor signaling', 'the complement cascades', 'MAPK signaling pathway', 'Apoptosis' and 'Wnt signaling pathway'. Besides, nine genes which were differently-expressed immuno-related were confirmed by using quantitative real-time PCR. These findings would provide new insights on the M. coruscus innate immunity, based on which, some novel strategies for management of diseases and long-term sustainability of M. coruscus culture could be developed. PMID- 28863890 TI - Effects of Astragalus polysaccharides (APS) and chitooligosaccharides (COS) on growth, immune response and disease resistance of juvenile largemouth bass, Micropterus salmoides. AB - The effects of oral administration of Astragalus polysaccharides (APS) and chitooligosaccharides (COS), single or combined, on the growth performance, immunity and disease resistance of M. salmoides were investigated. Largemouth bass juvenile were divided into 4 groups and each group was fed with diets supplemented with or without immunostimulant for 8 weeks. After 8 weeks of feeding trial, five fish per tank were sampled for immunity determination, ten fish per tank were challenged by A. hydrophila. The results showed that the largemouth bass fed with two immunostimulants alone or in combination significantly enhanced the final weight and specific growth rate (SGR), decreased feed conversion ratio (FCR) (P < 0.05). However, there were no significant differences (P < 0.05) in specific growth rate (SGR) between dietary COS and dietary APS. In addition, both COS and APS upregulated respiratory burst activity (RBA), phagocytic activity (PA), lysozyme activity and superoxide dismutase (SOD) activity. Meanwhile, COS also exhibited a increase in total leukocyte count, nitric oxide (NO) content and inducible nitric oxide synthase (iNOS) activity compared to the control. When challenged with A. hydrophila, the mortality of groups fed with COS and/or APS was lower than the control (P < 0.05). Under the experimental conditions, dietary APS and COS had a synergistic effect on lysozme activity, iNOS activity, NO content and disease resistance of fish (P < 0.05). PMID- 28863891 TI - Black carp STING functions importantly in innate immune defense against RNA virus. AB - Stimulator of interferon genes (STING) is a central and multifaceted mediator in the innate immune response of higher vertebrates. To explore its role in teleost fish, the STING homolog of black carp (Mylopharyngodon piceus) (bcSTING) has been cloned and characterized in this paper. bcSTING transcription in Mylopharyngodon piceus fin (MPF) cells increased remarkably in response to GCRV and SVCV infection, or poly (I:C) stimulation. bcSTING migrated around 42 KDa in immunoblot assay and was identified as a cytosolic protein locating on ER majorly through immunofluorescence staining. Under condition of SVCV/GCRV infection or poly (I:C) stimulation, the subcellular distribution of bcSTING majorly displayed on mitochondria, which overlapped with that of bcMAVS. HA-bcSTING instead of bcSTING-HA presented strong IFN-inducing activity in reporter assay and antiviral ability against both SVCV and GCRV in plaque assay. Site mutation of serine (S) on C-terminus of bcSTING demonstrated that both S371 and S379 were crucial for its mediated signaling. Taken together, our study support the conclusion that bcSTING plays an important role in host innate immune defense against RNA virus such as SVCV and GCRV, in which its C-terminus functions crucially. PMID- 28863892 TI - Simultaneous detection and differentiation of human parvovirus B19 and human parvovirus 4 by an internally controlled multiplex quantitative real-time PCR. AB - Human parvovirus B19 (B19V) and human parvovirus 4 (PARV4) are two parvoviruses known to infect humans and transmit through blood and plasma derived medicinal products (PDMPs). Inactivation of the two parvoviruses has proven to be difficult and nucleic acid testing (NAT) would be an efficient means to exclude viruses. In this study, an internally controlled multiplex quantitative real-time PCR (qPCR) assay for B19V and PARV4 simultaneous detection and quantification was established and evaluated. The optimized multiplex qPCR assay allowed for simultaneous detection of all of the genotypes (1-3) of B19V and PARV4, with equal limit of quantification (LOQ) of 5 copies/MUL, rather than other blood borne viruses. It had a wide dynamic range of reliable amplification linearity of at least 8 orders of magnitude. Low standard deviations (SD) of quantification cycle (Cq) values and low coefficients of variation (CV) of copy numbers for both B19V and PARV4 suggested a high level of repeatability and reproducibility for the multiplex qPCR assay. This multiplex qPCR assay can be served as a readily applicable approach to screen plasma units intended for further manufacturing into PDMPs to reduce the risk of parvoviruses infection by such products and may also be useful for the detection of B19V/PARV4 co-infection or co-existence. PMID- 28863893 TI - Lactoferrin promotes MC3T3-E1 osteoblast cells proliferation via MAPK signaling pathways. AB - Lactoferrin has attracted great attention as a potential functional factor to prevent osteoporosis due to its various bioactivities. However, the molecular mechanism underlining the osteogenic activity of lactoferrin is unclear. In this study, effect of lactoferrin on MC3T3-E1 osteoblast cells proliferation was determined using MTT assay, while MAPK signaling pathways related to proliferation of MC3T3-E1 osteoblast cells were investigated based on mRNA and protein expressions. The distribution of cells at different cell cycle stages was evaluated by flow cytometry. Our findings indicated that lactoferrin enhanced MC3T3-E1 osteoblast cells proliferation in a dose-dependent manner; namely, it increased the proportion of cells in S and G2/M phases. Furthermore, we also found that lactoferrin could stimulate ERK, JNK and p38 MAPK. The mRNA expression of MAPK were significantly enhanced after treatment of lactoferrin. Lactoferrin significantly promoted the activation-associated phosphorylation of ERK and p38 MAPK and prevented the activation of JNK. Additionally, lactoferrin could enhance c-Fos and c-Jun expression by 3 times and 26 times, respectively. These results indicated that lactoferrin induced MC3T3-E1 osteoblast cells proliferation through c-Fos and c-Jun by stimulating ERK, JNK and p38, elucidating the molecular basis of the osteogenic activity of lactoferrin on MC3T3-E1 osteoblast cells. PMID- 28863894 TI - Characterization of a pectin from Lonicera japonica Thunb. and its inhibition effect on Abeta42 aggregation and promotion of neuritogenesis. AB - Pectin is a class of complex polysaccharides and recognized for its potential bioactivities. In this study, we showed that a pectic polysaccharide, LFA03-a, was extracted from Lonicera japonica Thunb. flowers and purified with DEAE cellulose and Sephacryl S-100HR. LFA03-a was composed of rhamnose, arabinose, galactose and galacturonic acid in the molar ratio of 18.1:25.3:36.8:19.5. Its structure was determined to possess a rhamnogalacturonan I (RG-I) backbone consisting of alpha-l-1,2-Rhap and alpha-d-1,4-GalAp disaccharide repeating unit, substituted at O-4 of l-rhamnose. The side chain was involved with beta-d-1,4 Galp, beta-d-1,3-Galp, beta-d-1,3,6-Galp and branched alpha-l-1,5-Araf. Fluorescence spectroscopic analysis with thioflavine T (ThT) and atomic force microscopy (AFM) results showed that LFA03-a inhibited Abeta42 aggregation in a dose dependent manner and impeded Abeta42 oligomerization and fibril formation. In addition, LFA03-a mildly induced the differentiation of PC12 cells and promoted neuritogenesis.The results suggested that pectin LFA03-a might be a potential targeted therapeutic drug for Alzheimer's disease. PMID- 28863895 TI - Polylactide/graphene oxide nanosheets/clove essential oil composite films for potential food packaging applications. AB - Antimicrobial nanopackaging films were developed by incorporating clove essential oil (CLO) (15-30% w/w) and graphene oxide (GO) nanosheets (1% w/w) into polylactide (PLA), suitable for use as food packaging, via solution casting. Addition of CLO into PLA matrix improved the flexibility of the composite films by lowering tensile stress, complex viscosity (eta*), and glass transition temperature (Tg). GO improved the Tg, eta* and lowered the oxygen permeability of the plasticized PLA matrix. Optical and anti-UV properties of the film were influenced by both GO and CLO incorporation. FTIR spectra exhibited a change in the molecular organization of the plasticized PLA film after incorporation with CLO. Microstructural studies revealed that the reinforcement of GO prevented porosity of plasticized PLA/CLO film surface. The developed composite film showed excellent antibacterial activity against Staphylococcus aureus and Escherichia coli and therefore, has a potential to be used as active packaging material for food safety and preservation. PMID- 28863896 TI - Evaluation of antibacterial properties on polysulfone composite membranes using synthesized biogenic silver nanoparticles with Ulva compressa (L.) Kutz. and Cladophora glomerata (L.) Kutz. extracts. AB - Polysulfone (PS) composite membrane using green synthesized biogenic silver nanoparticles (Ag-NPs) with Ulva compressa (L.) Kutz. and Cladophora glomerata (L.) Kutz. extract were prepared by spin coating technique and are tested for antimicrobial activity using a direct contact test for the first time. Initially green synthesis of Ag-NPs was accomplished utilizing green macro algae i.e. U. compressa (L.) Kutz. and C. glomerata (L.) Kutz. by the reduction of AgNO3. The Ag-NPs/PS composite membranes from both algae revealed outstanding antimicrobial activity against all bacteria i.e. K. pneumonia, P. aeruginasa, E. coli, E. faecium and S. aureus. Bacterial growth was monitored for 17h with a temperature controlled microplate spectrophotometer. The kinetics of the outgrowth in each well were recorded continuously at 630nm every 60min. Thus present work remarkably offers a feasible, cheap and efficient alternative for making Ag-NPs and their utilization as antimicrobial agent on the PS composite membrane. PMID- 28863897 TI - Lactoferrin functionalized PEG-PLGA nanoparticles of shikonin for brain targeting therapy of glioma. AB - Shikonin (SHK) is a highly liposoluble naphthoquinone pigment has recently been investigated as a potential antiglioma agent. However, shikonin shows several limitations like poor aqueous solubility, short half-life and non-selective biodistribution. Herein, we have developed a nanoparticles (NPs) prepared from PEG-PLGA using an emulsion solvent evaporation method. Nanoparticle surfaces were modified by coating with lactoferrin (Lf) to improve the crossing of the blood brain barrier and targeting of glioma cells via receptor-mediated path-ways. X ray powder diffraction and differential scanning calorimetry analysis revealed the amorphous nature of SHK encapsulated within the NPs. Moreover, the drug loaded NPs exhibit narrow size distribution and high encapsulation efficiency. The in vitro release experiments of the NPs exhibited sustained release for more than 72h. When compared to free SHK and SHK/NPs, in vivo study demonstrated higher brain concentration of SHK, indicating a significant effect of Lf coated NPs on brain targeting. Accordingly, these findings provide evidence for the potential of Lf-modified NPs as a targeted delivery system for brain glioblastomas treatment. PMID- 28863898 TI - The enhanced inhibition of water extract of black tea under baking treatment on alpha-amylase and alpha-glucosidase. AB - This paper studied the inhibition of water extract of natural or baked black tea on the activity of alpha-amylase and alpha- glucosidase. Baking treatment was found to be one effective way to enhance the inhibition of black tea on both alpha-amylase and alpha- glucosidase, and IC50 of water extract of baked black tea (BBTWE) were 1.213mg/mL and 4.190mg/mL, respectively, while IC50 of water extract of black tea (BTWE) were 1.723mg/mL and 6.056mg/mL, respectively. This study further studied the mechanism of the effect of water extract on alpha amylase and alpha- glucosidase using HPLC, circular dichroism, and synchronous fluorescence. HPLC analysis of tea polyphenols showed that the content of tea polyphenols with low polarity increased after baking. In addition, BBTWE had higer abilty on decreasing the hydrophobicity of tryptophan residues than BTWE for both alpha-amylase and alpha- glucosidase.The increase of alpha-helix proportion of alpha-amylase when treated with BBTWE was more obvious than that when treated with BTWE. In a word, thermal process of baked foods may be beneficial for tea polyphenols to reduce the rate of starch digestion. PMID- 28863899 TI - An orthodontic registry: Producing evidence from existing resources. PMID- 28863900 TI - Authors' response. PMID- 28863901 TI - Will similar force magnitude cause differential tooth movement? PMID- 28863902 TI - Mandibular molar mesialization. PMID- 28863903 TI - Authors' response. PMID- 28863904 TI - Authors' response. PMID- 28863905 TI - Midpalatal suture density ratio as a predictor of skeletal response to rapid maxillary expansion. PMID- 28863906 TI - Atomic force microscopy analysis of enamel nanotopography after interproximal reduction. PMID- 28863907 TI - Authors' response. PMID- 28863909 TI - The proof is in the pudding. PMID- 28863910 TI - Influence of cortical bone thickness on miniscrew microcrack formation. AB - INTRODUCTION: The aim of this in-vitro study was to investigate the influence of cortical bone thickness on the amount of surface microdamage produced after insertion of orthodontic miniscrews (OM) in porcine tibia bone. METHODS: Aarhus OMs (Medicon, Tuttlingen, Germany; diameter, 1.5 mm; length, 6 mm) were inserted into 1.0 mm (group A; n = 10), 1.5 mm (group B; n = 10), and 2.0 mm (group C; n = 10) of porcine cortical bone using a torque-limiting hand screwdriver set at 18 Ncm. A sequential staining technique was used to identify microdamage under laser confocal microscopy. Virtual slices were stitched together using ImageJ software (National Institutes of Health, Bethesda, Md) to form a compressed 2-dimensional composition of the microdamage. The ImageJ software was used to quantify the total damage area, diffuse damage area, maximum crack length, maximum damage radius, and maximum diffuse damage radius. Kruskal-Wallis tests and Wilcoxon rank sum tests were used to analyze the data. RESULTS: All OMs in group A (1.0 mm) were inserted completely; however, 2 OMs from group B (1.5 mm) and all OMs in group C (2.0 mm) failed to insert completely. The entry surface of group C (2.0 mm) exhibited significantly higher amounts of total damage, diffuse damage area, maximum crack length, and maximum crack damage radius compared with groups A (1.0 mm) and B (1.5 mm). The maximum crack length observed on the entry and exit surfaces ranged from 1.03 to 3.06 mm. CONCLUSIONS: In this study, we demonstrated a higher level of microdamage after the insertion of OMs into 2.0-mm thick cortical bone compared with 1.0-mm thick cortical bone. Therefore, clinicians need to consider the thickness of the cortical bone at the insertion site, because mechanisms to reduce cortical bone thickness would likely reduce the amount of microdamage formed. A safety zone of 3.5 mm from the OM is also recommended for OMs inserted into 1.0- and 1.5-mm cortical bone thicknesses to minimize any detrimental effects after targeted remodeling. PMID- 28863911 TI - Quantitative analysis of enamel on debonded orthodontic brackets. AB - INTRODUCTION: Iatrogenic damage to the tooth surface in the form of enamel tearouts can occur during removal of fixed orthodontic appliances. The aim of this study was to assess debonded metal and ceramic brackets attached with a variety of bonding materials to determine how frequently this type of damage occurs. METHODS: Eighty-one patients close to finishing fixed orthodontic treatment were recruited. They had metal brackets bonded with composite resin and a 2-step etch-and-bond technique or ceramic brackets bonded with composite resin and a 2-step etch-and- bond technique, and composite resin with a self-etching primer or resin-modified glass ionomer cement. Debonded brackets were examined by backscattered scanning electron microscopy with energy dispersive x-ray spectroscopy to determine the presence and area of enamel on the base pad. RESULTS: Of the 486 brackets collected, 26.1% exhibited enamel on the bonding material on the bracket base pad. The incidences of enamel tearouts for each group were metal brackets, 13.3%; ceramic brackets, 30.2%; composite resin with self-etching primer, 38.2%; and resin-modified glass ionomer cement, 21.2%. The percentage of the bracket base pad covered in enamel was highly variable, ranging from 0% to 46.1%. CONCLUSIONS: Enamel damage regularly occurred during the debonding process with the degree of damage being highly variable. Damage occurred more frequently when ceramic brackets were used (31.9%) compared with metal brackets (13.3%). Removal of ceramic brackets bonded with resin-modified glass ionomer cement resulted in less damage compared with the resin bonding systems. PMID- 28863912 TI - Prevalence of extraction space reopening in different orthodontic treatment protocols. AB - INTRODUCTION: In this study, we aimed to compare the amount and frequency of extraction space reopening after 2- and 4-premolar extraction treatments in Class II and 4-premolar extractions in Class I malocclusion patients. METHODS: The sample comprised 105 subjects with full-cusp Class II and Class I malocclusions, divided into 3 groups. Group 1 consisted of 33 full-cusp Class II malocclusion patients treated with a 2-premolar extraction protocol. Group 2 had 34 full-cusp Class II malocclusion patients treated with 4-premolar extractions, and group 3 included 38 Class I malocclusion patients treated with 4-premolar extractions. The Peer Assessment Rating index was used to assess initial malocclusion severity and quality of the occlusal outcome, measured on dental casts. The amounts of extraction spaces were measured with a digital caliper on the final and long-term posttreatment dental casts, after an average of 9.79 years posttreatment. Intergroup comparisons were performed by analysis of variance, followed by Tukey tests and chi-square tests. RESULTS: There were no significant differences regarding the amount and frequency of extraction space reopening among the groups. CONCLUSIONS: Two- and 4-premolar extractions in Class II and 4-premolar extraction treatment in Class I malocclusion patients show similar reopening of extraction spaces in the long term. PMID- 28863913 TI - Bone-anchored maxillary protraction therapy in patients with unilateral complete cleft lip and palate: 3-dimensional assessment of maxillary effects. AB - INTRODUCTION: The aim of this study was to 3-dimensionally assess the treatment outcomes of bone-anchored maxillary protraction (BAMP) in patients with unilateral cleft lip and palate. METHODS: The cleft group comprised 24 patients with unilateral cleft lip and palate and Class III malocclusion with mean initial and final ages of 11.8 and 13.2 years, respectively. The noncleft group comprised 24 noncleft patients with Class III malocclusion with mean initial and final ages of 11.9 and 12.9 years, respectively. Cone-beam computed tomography examinations were performed before and after BAMP therapy in both groups and superimposed at the cranial base. Three-dimensional displacements of maxillary landmarks were quantified and visualized with color-coded maps and semitransparent superimpositions. The t test corrected for multiple testing (Holm-Bonferroni method), and the paired t test was used for statistical comparison between groups and sides, respectively (P <0.05). RESULTS: BAMP produced anterior (1.66 mm) and inferior (1.21 mm) maxillary displacements in the cleft group with no significant differences compared with the noncleft group. The maxillary first molars of the cleft group showed significantly greater medial displacement than did those in the noncleft group. The zygoma showed significantly greater lateral displacement at the cleft side compared with the noncleft side. CONCLUSIONS: BAMP caused similar amounts of maxillary protraction in patients with and without unilateral cleft lip and palatem with discrete differences between the cleft side and the noncleft side. PMID- 28863914 TI - Three-dimensional assessment of soft tissue changes associated with bone-anchored maxillary protraction protocols. AB - INTRODUCTION: The aim of this study was to assess the 3-dimensional soft tissue changes in growing Class III patients with maxillary deficiency associated with 2 bone-anchored maxillary protraction protocols in relation to an untreated control group of Class III patients. METHODS: Growing skeletal Class III patients between the ages of 10 and 14 years participated in this study. In group 1 (n = 10), skeletally anchored facemasks were used with miniplates placed at the zygomatic buttress. In group 2 (n = 10), the patients were treated with Class III elastics extending from infrazygomatic miniplates in the maxilla to symphyseal miniplates in the mandible. Group 3 (n = 10) was an untreated control group. Three dimensional stereophotogrammetry images were acquired before and after treatment, and then superimposed and analyzed. In addition, lateral cephalometric radiographs were analyzed. RESULTS: The maxilla moved forward significantly in groups 1 and 2 compared with the untreated control group (group 1, 4.87 mm; group 2, 5.81 mm). The 3-dimensional soft tissue analysis showed significant treatment effects; the major changes were observed in the upper lips, cheeks, and middle of the face, which had a significant positive sagittal displacement in both treatment groups. The lower lip and chin area showed significant negative sagittal changes that indicated that the soft tissue growth in this area was restrained with backward displacement especially in group 1 more than in group 2. CONCLUSIONS: The 2 bone-anchored maxillary protraction protocols effectively improved the Class III concave soft tissue profile. PMID- 28863916 TI - A simple and accurate craniofacial midsagittal plane definition. AB - INTRODUCTION: In this article, we aimed to establish an ideal definition for the craniofacial midsagittal plane (MSP) by first finding an optimal "plane of best fit" and then deriving a simple approximation for clinical use that is highly accurate. METHODS: For 60 adolescent patients, 3-dimensional coordinates of 8 central landmarks and 6 pairs of lateral landmarks were collected. Across all patients, the coplanarity of the central landmarks was compared with that of the midpoints of the lateral landmarks. The MSP of best fit was then found by minimizing the mean square distance of the 8 central landmarks to a plane. Across all patients, each possible 3-point plane was compared with the MSP of best fit with respect to both orientation and proximity. RESULTS: The central landmarks were more coplanar and thus more accurate than the midpoints of the lateral pairs. The plane defined by nasion, basion, and incisive foramen was the closest to the MSP of best fit in both orientation and proximity. CONCLUSIONS: The nasion basion-incisive foramen plane should be used for skull orientation and 3 dimensional cephalometric analyses because it approximates the MSP of best fit with high accuracy, avoids the use of horizontal reference planes, avoids influence from upper and midface asymmetry, uses easily identifiable relevant landmarks, and is simple to define. PMID- 28863915 TI - Root resorptions associated with canine retraction treatment. AB - INTRODUCTION: The hypothesis of this study was that multiple factors are dominant in causing external apical root resorption (EARR). The objective of this investigation was to better understand the clinical factors that may lead to EARR. METHODS: Maxillary cone-beam computed tomography scans of 18 subjects who were treated with bilateral canine retractions during orthodontics were used to calculate EARR. The subjects were treated using well-calibrated segmental T-loops for delivering a 124-cN retraction force and the moment-to-force ratio suitable for moving the canine under either translation or controlled tipping. The subjects' age, sex, treatment duration, and genotype were collected. RESULTS: Six subjects of the 18 showed definite EARR, meaning that load was not the only causing factor. All 5 subjects with the genotype identified had GG genotype of IL 1beta rs11143634, indicating that people with this genotype may be at high risk. Longer treatment duration, female sex, and older age may also contribute to EARR, although the findings were not statistically significant. CONCLUSIONS: EARR appears to be related to multiple factors. The orthodontic load and the genotype should be the focuses for future studies. PMID- 28863917 TI - Assessment of upper airway size after orthopedic treatment for maxillary protrusion or mandibular retrusion. AB - INTRODUCTION: The aim of this retrospective study was to find out whether different Class II treatments would affect the airway sizes of patients having maxillary protrusion or mandibular retrusion. METHODS: The study sample comprised 57 Class II patients whose upper airway sizes were not significantly different at the start of treatment and whose sagittal skeletal jaw relationships showed that they had maxillary protrusion or mandibular retrusion. Twenty-two of them were treated with cervical headgear, 16 with activator, and 19 were selected as a control. Lateral cephalograms at the start of treatment and the end of orthopedic treatment were assessed. The intragroup comparisons were performed by using the paired-samples t test, and intergroup comparisons of the skeletal features and upper airways were performed with 1-way analysis of variance, with the Tukey test as a second step, at P < 0.05. RESULTS: The ANB angle decreased significantly in the treatment groups. The middle airway space and the SNB angle were significantly increased after the activator therapy (P < 0.05). The SNB angle increased and SN-1 decreased in the mandibular retrusion group when compared with both maxillary protrusion and control groups. No statistically significant difference between the maxillary protrusion and the mandibular retrusion groups was found regarding the upper airway sizes after cervical headgear or activator treatments, respectively (P > 0.05). The only significant differences observed in airway variables were at the middle airway space of the activator and control groups with an increase of 1.6 +/- 2.5 mm and a decrease of 1.5 +/- 2.3 mm, respectively. CONCLUSIONS: Orthopedic treatment with either cervical headgear or activator did not result in different upper airway changes, but activator treatment resulted in increased middle airway space with regard to the Class II control group. PMID- 28863918 TI - Three-dimensional evaluation of the airway spaces in patients with and without cleft lip and palate: A digital volume tomographic study. AB - INTRODUCTION: Patients with cleft lip and palate (CLP) suffer from several esthetic and functional challenges. Comprehensive treatment of these patients involves orthognathic surgery that may lead to velopharyngeal insufficiency or reduction in lower airway. Several cases of airway insufficiency, velopharyngeal incompetence, snoring, hypopnea, and obstructive sleep apnea have been reported in subjects with CLP. The aim of this study was to compare the anteroposterior dimensions of the oropharyngeal airway at 5 levels, the height of the oropharyngeal column, and the volume of the oropharyngeal airway in subjects with and without CLP. METHODS: The sample consisted of 62 patients with CLP and 42 subjects with Angle Class I malocclusion. Anteroposterior dimension, height, and volume of the oropharyngeal airway were measured using the midsagittal and axial slices obtained from 3-dimensional digital volume tomographic scans for both groups. RESULTS: The anteroposterior dimensions of the airway were significantly reduced in the study subjects compared with the control group at the level of the postnasal spine, the base of the tongue, and the epiglottis. The airway dimensions measured on the axial sections at the level of the palatal and epiglottic plane were also significantly lower in the study group. The height and volume of the oropharyngeal airway were also significantly smaller in patients with CLP compared with subjects without CLP. CONCLUSIONS: Patients with CLP showed reduced dimensions and volumes of the oropharyngeal airway in all 3 planes compared with the control group. PMID- 28863919 TI - Genome-wide association study for mandibular prognathism using microsatellite and pooled DNA method. AB - INTRODUCTION: The purpose of this study was to extend an association study from chromosome 1 to the whole genome (genome-wide association study) to find susceptibility loci of mandibular prognathism. METHODS: Two hundred forty patients diagnosed with mandibular prognathism and 360 healthy controls of Japanese descent were recruited. The typing of microsatellites covering the whole genome was conducted using a pooled DNA method. Upon completion of the first and second screenings with pooled DNA, the positive microsatellite markers from both the first and second typings were retyped using individual-subject DNA samples to confirm the significance of allele frequency. RESULTS: Six microsatellites (D1S0411i, D1S1358i, D3S0810i, D6S0827i, D7S0133i, and D15S0154i) showed differences between allele frequencies of the subjects and controls at P <0.001. D1S0411i, D1S1358i, D3S0810i, D6S0827i, D7S0133i, and D15S0154i were located on chromosomes 1p22.3, 1q32.2, 3q23, 6q23.2, 7q11.22, and 15q22.22, respectively. SSX2IP, PLXNA2, RASA2, TCF21, CALN1, and RORA were suggested as candidate genes. CONCLUSIONS: The genome-wide association study using microsatellites suggested that 6 loci (1p22.3, 1q32.2, 3q23, 6q23.2, 7q11.22, and 15q22.22) were susceptibility regions of mandibular prognathism. The locus 1p22.3 was supported by a previous linkage analysis, and the other 5 were novel loci. PMID- 28863920 TI - Combined orthodontic-orthopedic treatment of an adolescent Class II Division 2 patient with extreme deepbite using the Forsus Fatigue Resistant Device. AB - Class II Division 2 malocclusion is often characterized by severe, traumatic deepbite with lingually inclined and overerupted incisors. Combined orthodontic orthopedic treatment of this malocclusion is a challenging issue for orthodontists. This case report describes the combined orthodontic-orthopedic treatment of an adolescent Class II Division 2 patient with an extreme deepbite and a retrognathic mandible using the Forsus Fatigue Resistant Device. PMID- 28863921 TI - Fixed-functional appliance treatment combined with growth hormone therapy. AB - The purpose of this study was to illustrate the effects of growth hormone (GH) therapy and fixed functional appliance treatment in a 13-year-old Class II malocclusion patient without GH deficiency. GH has been shown to effectively increase endochondral growth and induce a more prognathic skeletal pattern. Although a major concern in Class II retrognathic patients is chin deficiency, long-term studies have shown that the mandibular growth enhancement effects of functional appliances are clinically insignificant. This case report demonstrates that the mandible grew significantly during fixed functional appliance treatment combined with GH therapy, with stable results during 2 years 11 months of retention. More studies are needed to evaluate GH therapy as a supplement in Class II treatment. PMID- 28863922 TI - Miniscrew biomechanics: Guidelines for the use of rigid indirect anchorage mechanics. AB - Indirect anchorage is an established form of anchorage provided by orthodontic miniscrews. Although there are different ways to set up the mechanics, rigid indirect anchorage offers the greatest biomechanical versatility but is more difficult to install than conventional, nonrigid indirect anchorage or direct anchorage. The purpose of this article was to introduce readers to the concept of rigid indirect anchorage and provide guidelines as to its use. PMID- 28863923 TI - Accuracy of 3-dimensional curvilinear measurements on digital models with intraoral scanners. AB - INTRODUCTION: Our objectives were to evaluate and compare the digital dental models generated from 2 commercial intraoral scanners with manual measurements when performing 3-dimensional surface measurements along a curved line (curvilinear). METHODS: Dry mandibles (n = 61) with intact dentition were used. The mandibles were digitized using 2 chair-side intraoral scanners: Cadent iTero (Align Technology, San Jose, Calif) and Lythos Digital Impression system (Ormco, Orange, Calif). Digitized 3-dimensional models were converted to individual stereolithography files and used with commercial software to obtain the curvilinear measurements. Manual measurements were carried out directly on the mandibular teeth. Measurements were made on different locations on the dental arch in various directions. One-sample t tests and linear regression analyses were performed. To further graphically examine the accuracy between the different methods, Bland-Altman plots were computed. The level of significance was set at P <0.05. RESULTS: There were no significant differences between any of the paired methods; this indicated a certain level of agreement between the methods tested (P >0.05). Bland-Altman analysis showed no fixed bias of 1 approach vs the other, and random errors were detected in all comparisons. Although the mean biases of the digital models obtained by the iTero and Lythos scanners, when compared with direct caliper measurements, were low, the comparison of the 2 intraoral scanners yielded the lowest mean bias. No comparison displayed statistical significance for the t scores; this indicated the absence of proportional bias in these comparisons. CONCLUSIONS: The intraoral scanners tested in this study produced digital dental models that were comparatively accurate when performing direct surface measurements along a curved line in 3 dimensions. PMID- 28863924 TI - Immunity from what? PMID- 28863925 TI - Survival analysis, part 1: Introduction. PMID- 28863926 TI - Association between maternal circulating IL-27 levels and preeclampsia. AB - In this study, we investigated the relationship between serum level of IL-27 with preeclampsia and its severity. Fifty-six preeclamptic, 21 health pregnant and 20 health nonpregnant women formed the study group. The levels of IL-27 in maternal circulation were determined by ELISA. IL-27 serum levels were found to be elevated in healthy pregnant and preeclamptic groups as compared to non-pregnant women, this increase was significant in preeclamptic cases (p=0.0004). Moreover, a significant difference of IL-27 serum level was observed between groups and the healthy pregnant controls, (p=0.0095). Notably, the level of IL-27 was considerably elevated in women with severe preeclampsia, but not with mild preeclampsia as compared with healthy pregnant women (p=0.0056, p=0.0964, respectively). Furthermore, IL-27 serum levels were significantly differences in early onset and late onset sever preeclampsia than in gestation matched healthy pregnancies (p=0.0376, p=0.0085, respectively). In conclusion, our results suggest IL-27 might be a useful biomarker for disease severity in preeclampsia. PMID- 28863928 TI - Potential relationships between chikungunya and depression: Solving the puzzle with key cytokines. PMID- 28863927 TI - The role of non-invasive modalities for assessing inflammation in patients with non-cystic fibrosis bronchiectasis. AB - INTRODUCTION: Bronchiectasis is a heterogeneous entity, taking into account clinical characteristics, inflammatory response, effectiveness of treatment and frequency of exacerbations. In stable state non-cystic fibrosis (non-CF) bronchiectasis, little is known about non-invasive techniques used for evaluating airway inflammation in obstructive airway diseases. OBJECTIVES: We sought to evaluate the associations between induced sputum and clinical/radiologic characteristics, and the differences between biomarkers expressing Th1 and Th2 response in patients with non-CF bronchiectasis and to compare our findings with a previously studied population of patients with asthma and COPD. METHODS: We evaluated prospectively collected data from subjects with bronchiectasis. Comparisons were made between clinical, radiographic and physiologic characteristics, as well as induced sputum markers using appropriate statistical tools. We compared the levels of sputum markers with those of a previously studied cohort of asthma and COPD patients. RESULTS: We enrolled 40 subjects (21men, mean age 63.5yrs) with bronchiectasis. Fifteen subjects (37.5%) had a neutrophilic phenotype, 7 (17.5%) had an eosinophilic phenotype, 3 (12.5%) had a mixed neutrophilic-eosinophilic phenotype and 15 (37.5%) had a paucigranulocytic phenotype. Subjects with sputum neutrophilia had more severe bronchiectasis in HRCT and higher levels of IL-8 in sputum, whereas subjects with eosinophilia had higher levels of FeNO, greater bronchodilator reversibility and higher sputum IL 13. Sputum IL-8 levels were higher in subjects exhibiting frequent exacerbations and correlated with neutrophils in sputum (r=0.799), the extent of bronchiectasis in HRCT (r=0.765) and post-bronchodilator FEV1 (r=-0.416). Sputum IL-13 levels correlated with sputum eosinophils (r=0.656) and bronchodilator reversibility (r=0.441). Neutrophilic bronchiectasis exhibited comparable IL-8 levels to COPD, whereas eosinophilic bronchiectasis showed significantly lower IL-13 levels compared to asthma. CONCLUSIONS: Sputum cell counts and IL-8 and IL-13 correlate with distinct clinical and functional measurements of disease severity and therefore may have a role for non-invasively assessing inflammation in non-cystic fibrosis bronchiectasis. PMID- 28863929 TI - Tracing the phylogeographic history of Southeast Asian long-tailed macaques through mitogenomes of museum specimens. AB - The biogeographical history of Southeast Asia is complicated due to the continuous emergences and disappearances of land bridges throughout the Pleistocene. Here, we use long-tailed macaques (Macaca fascicularis), which are widely distributed throughout the mainland and islands of Southeast Asia, asa model for better understanding the biogeographical patterns of diversification in this geographically complex region. A reliable intraspecific phylogeny including individuals from localities on oceanic islands, continental islands, and the mainland is needed to trace relatedness along with the pattern and timing of colonization in this region. We used high-throughput sequencing techniques to sequence mitochondrial genomes (mitogenomes) from 95 Southeast Asian M. fascicularis specimens housed at natural history museums around the world. To achieve a comprehensive picture, we more than tripled the mitogenome sample size for M. fascicularis from previous studies, and for the first time included documented samples from the Philippines and several small Indonesian islands. Confirming the result from a previous, recent intraspecific phylogeny for M. fascicularis, the newly reconstructed phylogeny of 135 specimens divides the samples into two major clades: Clade A includes haplotypes from the mainland and some from northern Sumatra, while Clade B includes all insular haplotypes along with lineages from southern Sumatra. This study resolves a previous disparity by revealing a disjunction in the origin of Sumatran macaques, with separate lineages originating within the two major clades, suggesting that at least two major migrations to Sumatra occurred. However, our dated phylogeny reveals that the two major clades split ~1.88Ma, which is earlier than in previously published phylogenies. Our new data reveal that most Philippine macaque lineages diverged from the Borneo stock within the last ~0.06-0.43Ma. Finally, our study provides insight into successful sequencing of DNA across museums and shotgun sequencing of DNA specimens asa method to sequence the mitogenome. PMID- 28863930 TI - The role of Eastern approaches in David Bohm's scientific-philosophical odysseia. PMID- 28863931 TI - Diabetes mellitus does not affect the neuromuscular blocking action of atracurium in dogs. AB - OBJECTIVE: To compare the duration of action of atracurium in diabetic and nondiabetic dogs. STUDY DESIGN: Prospective, blinded, clinical study. ANIMALS: A total of 26 diabetic and 29 nondiabetic dogs. METHODS: Following preanaesthetic medication and intravenous (IV) propofol induction, anaesthesia was maintained with isoflurane in oxygen. Atracurium 0.2 mg kg-1 IV was administered to provide neuromuscular blockade (NMB) and the responses (twitches; T) to train-of-four nerve stimulation were recorded by palpation and electromyography (EMG). Time to onset of NMB (from atracurium administration to loss of T4 by EMG), duration of NMB (to return of T1 by EMG) and also times to loss and return of T2-T4 were recorded. Heart rate (HR), mean arterial pressure, end-tidal isoflurane (Fe'Iso), end-tidal CO2 concentrations and oesophageal temperature were recorded at onset of NMB and when T1EMG returned. Groups were compared using t tests and Mann Whitney U tests (p<0.05). RESULTS: Diabetic dogs were older (9.9+/-0.3 compared with 6.8+/-0.7 years, p=0.0003). Group parameters were similar at onset and offset of NMB apart from HR at offset, which was higher for diabetics compared to nondiabetics (114+/-4 compared with 100+/-3 beats minute-1, respectively, p=0.004), Fe'Iso was higher in the diabetic group at onset (1.3+/-0.03% compared with 1.2+/-0.04%, p=0.026) and offset (1.4+/-0.03% compared with 1.3+/-0.03%, p=0.007), and temperature was higher for diabetics at onset (37.5+/-0.1 degrees C compared with 37.0+/-0.2 degrees C, p=0.012) and offset (37.5+/-0.1 degrees C compared with 36.9+/-0.2 degrees C, p=0.004). The duration of action of atracurium(tactile) and atracurium(EMG) were similar for both groups. CONCLUSIONS AND CLINICAL RELEVANCE: The duration of action of atracurium was similar in diabetic and nondiabetic dogs as indicated by tactile and EMG monitoring. PMID- 28863932 TI - Tissue iron quantification in chronic liver diseases using MRI shows a relationship between iron accumulation in liver, spleen, and bone marrow. AB - AIM: To investigate iron loading within the liver, pancreas, spleen, and bone marrow using magnetic resonance imaging (MRI) transverse relaxation rate (R2*), in patients with diffuse liver diseases; to evaluate the relationships between iron accumulation in these tissue compartments; and to assess the association between tissue iron overload and the pattern of hepatic cellular iron distribution (hepatocytes versus Kupffer cells). MATERIAL AND METHODS: Fifty-six patients with diffuse liver diseases had MRI-derived R2* values, using a multi echo chemical-shift encoded MRI sequence, of the liver, pancreas, spleen, and vertebral bone marrow. All patients had liver biopsy samples scored for hepatic iron grading (0-4) and iron cellular distribution (within hepatocytes only or within both hepatocytes and Kupffer cells). RESULTS: Liver R2* increased with histological iron grade (RS=0.58, p<0.001) and correlated with spleen (RS=0.71, p<0.001) and bone marrow R2* (RS=0.66, p<0.001), but not with pancreatic R2* (RS=0.22, p=0.096). Splenic and bone marrow R2* values were also correlated (RS=0.72, p<0.001). Patients with iron inside Kupffer cells had the highest R2* in liver, spleen and bone marrow. CONCLUSIONS: Patients with chronic diffuse liver diseases have concomitant hepatic, splenic, and bone marrow iron loading. The highest hepatic iron scores and iron inside Kupffer cells were associated with the highest splenic and bone marrow deposits, suggesting systemic iron accumulation in the mononuclear phagocytic system. PMID- 28863933 TI - Window of implantation transcriptomic stratification reveals different endometrial subsignatures associated with live birth and biochemical pregnancy. AB - OBJECTIVE: To refine the endometrial window of implantation (WOI) transcriptomic signature by defining new subsignatures associated to live birth and biochemical pregnancy. DESIGN: Retrospective cohort study. SETTING: University-affiliated in vitro fertilization clinic and reproductive genetics laboratory. PATIENT(S): Healthy fertile oocyte donors (n = 79) and patients with infertility diagnosed by Endometrial Receptivity Analysis (n = 771). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): WOI transcriptomic signatures associated with specific reproductive outcomes. RESULT(S): The retrospective cohort study was designed to perform a prediction model based on transcriptomic clusters for endometrial classification (training set, n = 529). The clinical follow-up set in the expected WOI (n = 321) was tested with the transcriptomic predictor to detect WOI variability and the pregnancy outcomes associated with these subsignatures (n = 228). The endometrial receptivity signature was redefined into four WOI transcriptomic profiles. This stratification identified an optimal endometrial receptivity (RR) signature resulting in an ongoing pregnancy rate (OPR) of 80% in terms of live birth, as well as a late receptive-stage (LR) signature with a potential high risk of 50% biochemical pregnancy. Abnormal down-regulation of the cell cycle was the main dysregulated function among the 22 genes associated with biochemical pregnancy. CONCLUSION(S): The major differences between the WOI transcriptomic stratification were in the OPR and biochemical pregnancy rate. The OPR ranged from 76.9% and 80% in the late prereceptive (LPR) and RR signatures, respectively, versus 33.3% in the LR. The biochemical pregnancy rate was 7.7% and 6.6% in LPR and RR, respectively, but 50% in LR, which highlights the relevance of endometrial status in the progression of embryonic implantation. PMID- 28863934 TI - Semen characteristics and pregnancy loss: an important step in addressing a complex problem. PMID- 28863935 TI - Preferential selection and transfer of euploid noncarrier embryos in preimplantation genetic diagnosis cycles for reciprocal translocations. AB - OBJECTIVE: To develop and validate a new strategy to distinguish between balanced/euploid carrier and noncarrier embryos in preimplantation genetic diagnosis (PGD) cycles for reciprocal translocations and to successfully achieve a live birth after selective transfer of a noncarrier embryo. DESIGN: Retrospective and prospective study. SETTING: In vitro fertilization (IVF) units. PATIENT(S): Eleven patients undergoing mate pair sequencing for identification of translocation breakpoints, followed by clinical PGD cycles. INTERVENTION(S): Embryo biopsy with 24-chromosome testing to determine carrier status of balanced/euploid embryos. MAIN OUTCOME MEASURE(S): Definition of translocation breakpoints and polymerase chain reaction (PCR) diagnostic primers, correct diagnosis of euploid embryos for carrier status, and a live birth with a normal karyotype after transfer of a noncarrier embryo. RESULT(S): In 9 of 11 patients (82%), translocation breakpoints were successfully identified. In four patients with a term PGD pregnancy established with a balanced/euploid embryo of unknown carrier status, the correct carrier status was retrospectively determined, matching with the cytogenetic karyotype of the resulting newborns. In a prospective PGD cycle undertaken by a patient with a 46,XY,t(7;14)(q22;q24.3) translocation, the four balanced/euploid embryos identified comprised three carriers and one noncarrier. Transfer of the noncarrier embryo resulted in birth of a healthy girl who was subsequently confirmed with a normal 46,XX karyotype. CONCLUSION(S): The combination of mate pair sequencing and PCR breakpoint analysis of balanced reciprocal translocation derivatives is a novel, reliable, and accurate strategy for distinguishing between carrier and noncarrier balanced/euploid embryos. The method has potential application in clinical PGD cycles for patients with reciprocal translocations or other structural rearrangements. PMID- 28863936 TI - Analysis of the morphological dynamics of blastocysts after vitrification/warming: defining new predictive variables of implantation. AB - OBJECTIVE: To describe the morphological dynamics of vitrified/warmed blastocysts and to identify quantitative morphological variables related to implantation. Subsequently, by using the most predictive parameters, to develop a hierarchical model by subdividing vitrified/warmed blastocysts into categories with different implantation potentials. DESIGN: Observational, retrospective, cohort study. SETTING: University-affiliated private IVF center. PATIENT(S): The study included 429 vitrified/warmed blastocysts with known implantation data, which were evaluated by time-lapse imaging. Blastocysts were routinely placed in EmbryoScope (Vitrolife) immediately after warming until transfer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Embryos were vitrified and warmed by the Cryotop method (KitazatoBiopharma). The studied variables included the initial and minimum thicknesses of zona pellucida (MUm), the initial and maximum areas (MUm2), the area of inner cell mass (MUm2), expansion (whether the embryo reexpands or not after warming), and collapsing or contraction after warming. After defining the optimal ranges according to the consecutive quartiles with the highest probability of implantation, a logistic regression analysis was performed by combining the former variables and the blastocyst morphological classification criteria defined by the Spanish Association of Embryologists into A, B, C, or D categories. RESULT(S): Reexpansion of vitrified/warmed blastocysts correlated strongly with implantation (44.6% for reexpanded vs. 6.5% for the blastocysts that did not reexpand after warming). Throughout the logistic regression analysis, the model identified the maximum blastocyst area, odds ratio (OR) = 0.41 (95% confidence interval [CI], 0.22-0.77), followed by the initial area, OR = 0.62 (95% CI, 0.35-1.08) as the most predictive variables related to implanting embryos. Blastocyst morphology was not considered relevant in our model. The hierarchical tree model subdivided embryos into four categories, A-D, with lowering expected implantation potentials (from 47.3% for A to 14.2% for D). CONCLUSION(S): The analysis of warmed blastocysts by time-lapse imaging may provide objective quantitative markers for the blastocyst implantation potential. We propose a hierarchical model to classify vitrified/warmed blastocysts according to their implantation probability. The observed correlations and the proposed algorithm should be validated in a prospective trial to evaluate its efficacy. PMID- 28863937 TI - Maternal endometriosis and genital malformations in boys: a Danish register-based study. AB - OBJECTIVE: To investigate the association between maternal endometriosis and occurrence of the genital anomalies cryptorchidism and hypospadias in sons. DESIGN: Population-based cohort study. SETTING: Not applicable. PATIENT(S): All live-born singleton boys born from 1978 to 2012. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cryptorchidism and hypospadias in boys based on information from the Danish National Patient Register. RESULT(S): The study included 1,073,026 live-born singleton boys. A total of 6,443 boys were sons of women diagnosed with endometriosis before pregnancy. Altogether, 27,342 boys were diagnosed with cryptorchidism, of whom 16,446 had corrective surgery. Hypospadias was diagnosed in 4,853 boys. As compared with unexposed boys, a tendency towards a slightly higher occurrence of cryptorchidism was observed among boys of women with endometriosis (adjusted hazard ratio [aHR] 1.18; 95% confidence interval [CI], 0.97, 1.44). When stratified by medically assisted reproduction (MAR) technologies, the association was slightly stronger among boys born to women with endometriosis who had conceived via MAR, yet it remained moderate and statistically insignificant (aHR 1.27; 95% CI, 0.86; 1.88). When women who conceived with MAR were excluded, the association between endometriosis and cryptorchidism disappeared. For hypospadias, we observed no association, either in the main analysis or the stratified analysis. CONCLUSION(S): The findings from this register-based study do not provide strong evidence for a higher occurrence of the studied genital anomalies among boys of women with endometriosis. PMID- 28863938 TI - Assisted hatching and live births in first-cycle frozen embryo transfers. AB - OBJECTIVE: To assess the effect of assisted hatching (AH) on live-birth rates in a retrospective cohort of patients undergoing first-cycle, autologous frozen embryo transfer (FET). DESIGN: Longitudinal cohort using cycles reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System between 2004 and 2013. SETTING: Not applicable. PATIENT(S): Women who underwent first-cycle, autologous FET with (n = 70,738) and without (n = 80,795) AH reported from 2004 to 2013. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live births. RESULT(S): Propensity matching was used to account for confounding covariates, and a logistic regression model was constructed to identify the predictors of live-birth rates in relationship to AH. In all first-cycle FETs, there was a slight but statistically significant decrease in the live-birth rate with AH compared with no AH (34.2% vs. 35.4%). In older patients and in the years 2012-2013 AH was associated with decreased live births. Live-birth rates and the number of AH cycles performed before FET vary by the geographic location of clinics. CONCLUSION(S): Assisted hatching slightly decreases the live-birth rate in first-cycle, autologous FET. Its use should be carefully considered, especially in patients 38 years old and older. Prospective, clinical studies are needed to improve our knowledge of the impact of AH. PMID- 28863939 TI - Semen quality and pregnancy loss in a contemporary cohort of couples recruited before conception: data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study. AB - OBJECTIVE: To study the relationship between semen quality and pregnancy loss in a cohort of couples attempting to conceive. DESIGN: Observational prospective cohort. SETTING: Not applicable. PATIENT(S): Three hundred and forty-four couples with a singleton pregnancy observed daily through 7 postconception weeks of gestation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Association between semen quality and pregnancy loss. RESULT(S): Ninety-eight (28%) of the couples experienced a pregnancy loss after singleton pregnancy. No differences were observed in semen volume, sperm concentration, total sperm count, sperm viability, or sperm morphology (World Health Organization [WHO] and strict criteria) by couple's pregnancy loss status irrespective of whether they were analyzed continuously or as dichotomous variables per the WHO 5th edition semen criteria. A dichotomous DNA fragmentation measure of >=30% was statistically significantly associated with pregnancy loss. No association was identified with other sperm morphometric or movement measures. Of the 70 couples who re-enrolled after a pregnancy loss, 14 experienced a second loss. Similar findings were identified when examining semen quality from couples with recurrent pregnancy loss. CONCLUSION(S): Although a few trends were identified (e.g., DNA fragmentation), general semen parameters seemed to have little relation with risk of pregnancy loss or recurrent pregnancy loss at the population level. However, given that 30% of pregnancies end in miscarriage and half the fetal genome is paternal in origin, the findings await corroboration. PMID- 28863940 TI - New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family. AB - OBJECTIVE: To identify the gene(s) involved in the etiology of premature ovarian insufficiency in a highly consanguineous Tunisian family. DESIGN: Genetic analysis of a large consanguineous family with several affected siblings. SETTING: University hospital-based cytogenetics and molecular genetics laboratories. PATIENT(S): A highly consanguineous Tunisian family with several affected siblings born to healthy second-degree cousins. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Targeted exome sequencing was performed by next generation sequencing for affected family members. Mutations were validated by Sanger sequencing. Functional experiments were performed to explore the deleterious effects of the identified mutation. DNA damage was induced by increasing mitomycin C (MMC) concentrations on cultured peripheral lymphocytes. RESULT(S): Analysis of the next-generation sequencing data revealed a new homozygous missense mutation in the minichromosome maintenance 8 gene (MCM8).This homozygous mutation (c. 482A>C; p.His161Pro) was predicted to be deleterious and segregated with the disease in the family. MCM8 participates in homologous recombination during meiosis and DNA double-stranded break repair by dimerizing with MCM9. Mcm8 knock out results in an early block in follicle development and small gonads. Given this, we tested the chromosomal breakage repair capacity of homozygous and heterozygous MCM8 p.His161Pro mutation on cultured peripheral lymphocytes exposed to increasing MMC concentrations. We found that chromosomal breakage after MMC exposure was significantly higher in cells from homozygously affected individuals than in those from a healthy control. CONCLUSION(S): Our findings provide additional support to the view that MCM8 mutations are involved in the primary ovarian insufficiency phenotype. PMID- 28863941 TI - Potential role of ferric hemoglobin in MS pathogenesis: Effects of oxidative stress and extracellular methemoglobin or its degradation products on myelin components. AB - There is a well-documented relationship between cerebral vasculature and multiple sclerosis (MS) lesions: abnormal accumulations of iron have been found in the walls of the dilated veins in cerebral MS plaques. The source of this iron is unknown, but could be related to the recognized phenomenon of capillary and venous hemorrhages leading to blood extravasation. In turn, hemorrhaging leading to hemolysis results in extracellular release of hemoglobin, a reactive molecule that could induce local oxidative stress, inflammation, and tissue damage. Our previous studies with a reduced form of hemoglobin (oxyHb) have demonstrated its ability to cause extensive lipid and protein oxidation in vitro, which would result in membrane destabilization. Here, we investigated in further detail the mechanism by which the more abundant oxidized form of extracellular hemoglobin (metHb), and dissociated hemin, cause direct oxidative damage to myelin components, specifically membrane-mimetic lipid vesicles and myelin basic protein (MBP), a highly-abundant protein in the CNS. Oxidation of lipids was assessed by the formation of conjugated diene/triene and malondialdehyde, and oxidation of MBP was demonstrated by the bityrosine formation and by the change in protein mass. Our results show that metHb causes oxidative damage to MBP and myelin lipids, partly by transferring its hemin moiety to protein and lipid, but mostly as an intact protein possibly via formation of a ferryl radical. These results elucidating the mechanism of extracellular hemoglobin-induced oxidative damage to myelin components support the need for further research into vascular pathology in MS pathogenesis, to gain insight into the role of iron deposits and/or in stimulation of different comorbidities associated with the disease. PMID- 28863943 TI - The Effect of Testing Reliability on Visual Field Sensitivity in Normal Eyes: The Singapore Chinese Eye Study. AB - PURPOSE: To quantitatively determine how the reliability indices in standard automated perimetry (SAP) affect the global indices of visual field (VF) results in nonglaucomatous eyes. DESIGN: Observational, cross-sectional study. PARTICIPANTS: A total of 830 adults aged 40 to 80 years, without visual impairment, glaucoma, significant cataract, and major eye diseases, were selected from the population-based Singapore Chinese Eye Study (SCES). METHODS: Study participants underwent a comprehensive and standardized ocular examination and VF assessment using a Humphrey Field Analyzer II (Carl Zeiss Meditec, Inc., Dublin, CA). The effects of the test reliability, as indicated by the false-negative (FN), false-positive (FP), and fixation loss (FL) rates, on global indices, as indicated by the mean deviation (MD) and pattern standard deviation (PSD), were analyzed with multivariable regression models. MAIN OUTCOME MEASURES: The MD and PSD. RESULTS: A total of 1828 VF results from 1235 normal eyes of 830 study subjects were included in the analyses. The multivariable regression analyses adjusted for age, gender, best-corrected visual acuity, and test duration showed that at lower frequencies of false answers (<15%), FNs decreased the MD (beta [change in decibels {dB} per 5% increment in false answers] = -0.71 dB; P < 0.001), whereas FPs increased the MD (beta = 0.65 dB; P < 0.001). At higher frequencies (>=15%), the false answers influenced the MD to a greater extent, where the beta for the associations with FN and FP rates was -1.15 and 1.26 dB, respectively (both P < 0.001). We also found that when FN rate was <15%, higher FN rate increased the PSD (beta = 0.51 dB; P < 0.001), and the effect was slightly larger when FN rate was >=15% (beta = 0.71 dB; P < 0.001). The effect of FPs on PSD was observed only when FP rate was <15% (beta = -0.22 dB; P < 0.001). The FL had no associations with the MD, and had minimal effects on the PSD. CONCLUSIONS: We quantified the effect of unreliable responses on the MD and PSD in SAP. Our study may allow clinicians to estimate how VF results are affected by varying degrees of unreliability, instead of relying on cutoff values for reliability indices. PMID- 28863942 TI - Mitochondrial dysfunction in the APP/PSEN1 mouse model of Alzheimer's disease and a novel protective role for ascorbate. AB - Mitochondrial dysfunction is elevated in very early stages of Alzheimer's disease and exacerbates oxidative stress, which contributes to disease pathology. Mitochondria were isolated from 4-month-old wild-type mice, transgenic mice carrying the APPSWE and PSEN1dE9 mutations, mice with decreased brain and mitochondrial ascorbate (vitamin C) via heterozygous knockout of the sodium dependent vitamin C transporter (SVCT2+/-) and transgenic APP/PSEN1 mice with heterozygous SVCT2 expression. Mitochondrial isolates from SVCT2+/- mice were observed to consume less oxygen using high-resolution respirometry, and also exhibited decreased mitochondrial membrane potential compared to wild type isolates. Conversely, isolates from young (4 months) APP/PSEN1 mice consumed more oxygen, and exhibited an increase in mitochondrial membrane potential, but had a significantly lower ATP/ADP ratio compared to wild type isolates. Greater levels of reactive oxygen species were also produced in mitochondria isolated from both APP/PSEN1 and SVCT2+/- mice compared to wild type isolates. Acute administration of ascorbate to mitochondria isolated from wild-type mice increased oxygen consumption compared with untreated mitochondria suggesting ascorbate may support energy production. This study suggests that both presence of amyloid and ascorbate deficiency can contribute to mitochondrial dysfunction, even at an early, prodromal stage of Alzheimer's disease, although occurring via different pathways. Ascorbate may, therefore, provide a useful preventative strategy against neurodegenerative disease, particularly in populations most at risk for Alzheimer's disease in which stores are often depleted through mitochondrial dysfunction and elevated oxidative stress. PMID- 28863944 TI - Cocaine Allergy in Drug-Dependent Patients and Allergic People. AB - BACKGROUND: Adverse reactions to local anesthetics (LAs), especially esters, are not uncommon, but true allergy is rarely diagnosed. To our knowledge, currently there is no reliable method of determining IgE-mediated hypersensitivity to LAs and cocaine. OBJECTIVE: To assess the clinical value of allergy tests (prick, IgE, challenges, and arrays) in people suffering hypersensitivity reactions (asthma and anaphylaxis) during local anesthesia with cocaine derivatives and drug abusers with allergic symptoms after cocaine inhalation. METHODS: We selected cocaine-dependent patients and allergic patients who suffered severe reactions during local anesthesia from a database of 23,873 patients. The diagnostic yield (sensitivity, specificity, and predictive value) of allergy tests using cocaine and coca leaf extracts in determining cocaine allergy was assessed, taking a positive challenge as the criterion standard. RESULTS: After prick tests, specific IgE, and challenge with cocaine extract, 41 of 211 patients (19.4%) were diagnosed as sensitized to cocaine. Prick tests and IgE to coca leaves (coca tea) had a good sensitivity (95.1% and 92.7%, respectively) and specificity (92.3 and 98.8%, respectively) for the diagnosis of cocaine allergy and LA-derived allergy. CONCLUSIONS: Cocaine may be an important allergen. Drug abusers and patients sensitized to local anesthesia and tobacco are at risk. Both prick tests and specific IgE against coca leaf extract detected sensitization to cocaine. The highest levels were related to severe clinical profiles. PMID- 28863945 TI - The renal artery is involved in Chinese Takayasu's arteritis patients. AB - Takayasu's arteritis is a rare systemic vasculitis mainly affecting the aorta and its major branches. Previous studies have suggested that almost half of the Asian Takayasu's patients have renal artery involvement. However, due to the rarity of the disease, little is known about renal artery involvement in Chinese Takayasu's arteritis patients. Here, we retrospectively reviewed and analyzed 411 patients diagnosed with Takayasu's arteritis in our center to explore the clinical features of renal artery involvement in this group of patients. Of these, 201 patients were diagnosed to have renal artery involvement, with stenosis (78.1%) the most common renal artery pattern. Compared to those without, patients with renal artery involvement were significantly younger at disease onset (23.5 vs 25.6 years) and more frequently had hypertension (74.6% vs 28.1%). Congestive heart failure (22.4% vs 7.6%) and pulmonary hypertension (19.9% vs 9.5%) were both significantly more prevalent among patients with than those without renal artery involvement. The estimated glomerular filtration rate (eGFR) significantly decreased as the severity of renal artery stenosis increased. Age at disease onset older than 24 years (odds ratio 6.06 [95% Confidence Interval 2.76-13.3]), disease duration longer than 19 months (3.35 [1.52-7.4]) and renal artery involvement (8.7 [3.8-20.1]) were independent risk factors for renal dysfunction (eGFR under 90 mL/min/1.73m2) among patients with Takayasu's arteritis. Thus, patients with renal artery involvement have more severe cardiac and renal dysfunction compared to those without. The eGFR is correlated negatively with the severity of renal artery stenosis. PMID- 28863946 TI - Regulatory elements driving the expression of skeletal lineage reporters differ during bone development and adulthood. AB - To improve bone healing or regeneration more insight in the fate and role of the different skeletal cell types is required. Mouse models for fate mapping and lineage tracing of skeletal cells, using stage-specific promoters, have advanced our understanding of bone development, a process that is largely recapitulated during bone repair. However, validation of these models is often only performed during development, whereas proof of the activity and specificity of the used promoters during the bone regenerative process is limited. Here, we show that the regulatory elements of the 6kb collagen type II promoter are not adequate to drive gene expression during bone repair. Similarly, the 2.3kb promoter of collagen type I lacks activity in adult mice, but the 3.2kb promoter is suitable. Furthermore, Cre-mediated fate mapping allows the visualization of progeny, but this label retention may hinder to distinguish these cells from ones with active expression of the marker at later time points. Together, our results show that the lineage-specific regulatory elements driving gene expression during bone development differ from those required later in life and during bone repair, and justify validation of lineage-specific cell tracing and gene silencing strategies during fracture healing and bone regenerative applications. PMID- 28863947 TI - The prenylflavonoid Icaritin enhances osteoblast proliferation and function by signal transducer and activator of transcription factor 3 (STAT-3) regulation of C-X-C chemokine receptor type 4 (CXCR4) expression. AB - In this study, we examined the effects of a natural prenylflavonoid Icaritin (ICT), on human osteoblast proliferation and osteogenic function. We observed that ICT dose-dependently enhanced osteoblast proliferation by ~15% over a 7day period. This increase in cell proliferation was associated with corresponding increases in osteoblast functions as measured by ALP secretion, intracellular calcium ions influx and calcium deposition. These anabolic effects were associated with a 4-fold increase in CXCR4 mRNA and protein expression. Silencing of CXCR4 protein expression using small interfering RNA reversed ICT-induced increase in cell proliferation, ALP activity and calcium deposition. Interestingly, we observed that ICT dose-dependently increased STAT-3 phosphorylation; and this resulted in increased binding of phosphorylated STAT-3 to the promoter region of the CXCR4 gene, to increase CXCR4 protein expression. Furthermore, we found that inhibition of STAT-3 phosphorylation resulted in a decrease in CXCR4 protein expression; whilst increasing phosphorylation of STAT-3 using a constitutive active STAT-3 vector significantly increased CXCR4 levels. Moreover, the chemical inhibition of STAT-3 phosphorylation annulled our previously observed ICT-induced increases of osteoblast proliferation and function. Finally, in a rat model of estrogen-deficient osteoporosis, ICT restored both osteoblasts numbers and CXCR4 expression. Taken together, both cellular and animal models support the novel findings that ICT; through the phosphorylation of STAT-3, up-regulated CXCR4, to increase osteoblast proliferation and function. PMID- 28863949 TI - Impact of rapid response car system on ECMO in out-of-hospital cardiac arrest: A retrospective cohort study. AB - INTRODUCTION: Extracorporeal life support (ECLS) has been reported to be more effective than conventional cardiopulmonary resuscitation (CPR). In ECLS, a shorter time from arrival to implantation of extracorporeal membrane oxygenation (ECMO; door-to-ECMO) time was predicted to be associated with better survival rates. This study aimed to examine the impact of the physician-based emergency medical services (P-EMS) using a rapid response car (RRC) on door-to-ECMO time in patients with out-of-hospital cardiac arrest (OHCA). METHODS: In this retrospective cohort study, adult patients with OHCA who were admitted to a Japanese tertiary care hospital from April 2012 to December 2016 and underwent venoarterial ECMO were included. Patients were either transferred by emergency medical service (EMS only group) or RRC (RRC group). Primary outcome was door-to ECMO time. Wilcoxon rank-sum test was used to compare the outcome between the two groups. RESULTS: A total of 34 patients were included in this study, and outcome data were available for all patients. The door-to-ECMO time was significantly shorter in the RRC group than in the EMS only group (median, 23min vs. 36min; P=0.006). Additionally, the RRC was also associated with earlier successful intubation and intravenous adrenaline administration. CONCLUSION: The physician based RRC system was associated with a shorter door-to-ECMO time and successful advanced procedures in prehospital settings. Combination of the RRC system with ECLS may lead to better outcomes in patients with OHCA. PMID- 28863948 TI - Fatty acid metabolism by the osteoblast. AB - The emergence of bone as an endocrine organ able to influence whole body metabolism, together with comorbid epidemics of obesity, diabetes, and osteoporosis, have prompted a renewed interest in the intermediary metabolism of the osteoblast. To date, most studies have focused on the utilization of glucose by this specialized cell, but the oxidation of fatty acids results in a larger energy yield. Osteoblasts express the requisite receptors and catabolic enzymes to take up and then metabolize fatty acids, which appears to be required during later stages of differentiation when the osteoblast is dedicated to matrix production and mineralization. In this article, we provide an overview of fatty acid beta-oxidation and highlight studies demonstrating that the skeleton plays a significant role in the clearance of circulating lipoproteins and non-esterified fatty acids. Additionally, we review the requirement for long-chain fatty acid metabolism during post-natal bone development and the effects of anabolic stimuli on fatty acid utilization by osteoblasts. These recent findings may help to explain the skeletal manifestations of human diseases associated with impaired lipid metabolism while also providing additional insights into the metabolic requirements of skeletal homeostasis. PMID- 28863950 TI - The state of T cells before cryopreservation: Effects on post-thaw proliferation and function. AB - AIM: We aim to assess the effect of the state of T cells before cryopreservation on the post-thaw proliferative capacity, phenotype and functional response. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from a hepatocellular carcinoma (HCC) patient, and the T cells were frozen during cell culture according to our experimental design. After a period of re-culture, the proliferative capacity of the cryopreserved cells, the expression of T cell surface markers and the secretion of IFN-gamma and IL-10 were assayed. RESULTS: There was >90% cell viability after thaw in every group. Lymphocytes cryopreserved at day 4, 8 or 12 during the cell culture were allowed to recover for 24 h, whereas lymphocytes cryopreserved while freshly isolated were allowed to recover for 72 h. After the period of re-culture, cryopreservation at day 4, 8 or 12 during T cell culture was not found to alter the T cell subpopulation. The proportions of NKT and Treg cells were unchanged when cells were cryopreserved at day 12 during T cell culture. IFN-gamma secretion was not impacted by cryopreservation, and IL-10 secretion was significantly decreased when cells were cryopreserved at day 8 or 12 during T cell culture. CONCLUSION: The state of T cells before cryopreservation has effects on the post-thaw proliferation capacity, the phenotype and the secretion of IFN-gamma and IL-10. Cryopreservation of lymphocytes at day 8 or 12 during the cell culture may be the best choice for T cell immunotherapy. PMID- 28863951 TI - Prevention of high-temperature-induced chromosome damage in mouse spermatozoa freeze-dried using Ca2+ chelator-containing buffer alkalinized with NaOH or KOH. AB - In order to protect sperm chromosomes against degradation when they are being stored for relatively high temperatures, we investigated the optimal pH of the freeze-drying solution, EGTA/Tris-HCl buffered solution alkalinized by NaOH (Na ETBS) or KOH (K-ETBS). Mouse spermatozoa suspended in Na-ETBS or K-ETBS were freeze-dried at pH 5.0-8.4 and stored at 4 degrees C or 50 degrees C for 3 days. Some freeze-dried samples were stored at 25 degrees C for 3 days or 1 month. After storage, samples injected into oocytes using intracytoplasmic sperm injection were assessed for chromosome damage in resulting zygotes. Irrespective of freeze-drying solutions and storage temperatures, almost all the zygotes (97 100%) produced using the spermatozoa freeze-dried at pH 5.0 had structural chromosome aberrations of sperm origin. When freeze-drying was conducted at pH 8.0-8.4 using Na-ETBS, the incidence of chromosome damage decreased to 14-17% in 4 degrees C storage and 24-26% in 50 degrees C storage. When freeze-dried in K ETBS, the lowest level of chromosome damage occurred at pH levels of 7.7-8.4 at 4 degrees C storage (13-15%) and at pH 7.7-8.0 at 50 degrees C storage (16-23%). Spermatozoa freeze-dried in Na-ETBS at pH 8.2 and K-ETBS at pH 7.7 showed no significant increase in chromosome damage during 25 degrees C storage from 3 days to 1 month (11%-20% in Na-ETBS; 13%-18% in K-ETBS). Thus, use of the solutions optimized for short-term storage at high temperature (50 degrees C, 3 days) permits prolonged storage (1 month) of freeze-dried spermatozoa at room temperature. PMID- 28863952 TI - Survival and risk factors for progression after resection of the dominant tumor in multifocal, lepidic-type pulmonary adenocarcinoma. AB - BACKGROUND: It remains unclear whether a dominant lung adenocarcinoma that presents with multifocal ground glass opacities (GGOs) should be treated by local therapy. We sought to address survival in this setting and to identify risk factors for progression of unresected GGOs. METHODS: Retrospective review of 70 patients who underwent resection of a pN0, lepidic adenocarcinoma, who harbored at least 1 additional GGO. Features associated with GGO progression were determined using logistic regression and survival was evaluated using the Kaplan Meier method. RESULTS: Subjects harbored 1 to 7 GGOs beyond their dominant tumor (DT). Mean follow-up was 4.1 +/- 2.8 years. At least 1 GGO progressed after DT resection in 21 patients (30%). In 11 patients (15.7%), this progression prompted resection (n = 5) or stereotactic radiotherapy (n = 6) at mean 2.8 +/- 2.3 years. Several measures of the overall tumor burden were associated with GGO progression (all P values < .03) and with progression prompting intervention (all P values < .01). In logistic regression, greater DT size (odds ratio, 1.07; 95% confidence interval, 1.01-1.14) and an initial GGO > 1 cm (odds ratio, 4.98; 95% confidence interval, 1.15-21.28) were the only factors independently associated with GGO progression. Survival was not negatively influenced by GGO progression (100% with vs 80.7% without; P = .1) or by progression-prompting intervention (P = .4). CONCLUSIONS: At 4.1-year mean follow-up, 15.7% of patients with unresected GGOs after resection of a pN0 DT underwent subsequent intervention for a progressing GGO. Some features correlated with GGO growth, but neither growth, nor need for an intervention, negatively influenced survival. Thus, even those at highest risk for GGO progression should not be denied resection of a DT. PMID- 28863953 TI - Endovascular repair of the aortic arch: To see the future, we need to look beyond. PMID- 28863954 TI - Extracorporeal membrane oxygenation support bridge to transplant: Avoiding a bridge to nowhere. PMID- 28863955 TI - An umbrella arrives toward the end of the storm: Patient-tailored aspirin dosing improves late perioperative thromboprophylaxis. PMID- 28863956 TI - Stent-graft balloon occlusion with selective cerebral perfusion for cardiac surgery after proximal aortic arch stent grafting: A case report. PMID- 28863957 TI - Do we see ourselves in the rat? PMID- 28863958 TI - The "Big Kowalski". PMID- 28863959 TI - Corrigendum to "Defluoridation of drinking water using a new flow column electrocoagulation reactor (FCER) - Experimental, statistical, and economic approach" [J. Environ. Manage. 197 (2017) 80-88]. PMID- 28863961 TI - Cerebellopathy secondary to anti-peroxidase antibody-mediated toxicity. A special case of Hashimoto encephalopathy. AB - OBJECTIVE: The aim of this case report is to highlight the importance of recognizing uncommon causes of cerebellar involvement. CASE PRESENTATION: A 45 year-old woman with no medical history who presented gait instability that appears suddenly and evolves rapidly in two weeks, causing frequent falls. Neurological examination revealed an inability to walk due to severe ataxia, accompanied by global hypotonia, appendicular dysmetria, opsoclonus and dysarthria. We studied this patient with cerebellar syndrome, obtaining as relevant findings global cerebellar atrophy in MRI (magnetic resonance imaging) and especially, considerably elevated levels of antibodies against thyroid peroxidase (TPO). The patient was treated with high doses of intravenous methylprednisolone for 5days. Six months after diagnosis and in treatment with low doses of prednisone, the patient is asymptomatic. CONCLUSION: We must considerer the cerebellar involvement secondary to steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) in a patient in whom other more frequent causes of isolated cerebellar disease have been ruled out. PMID- 28863962 TI - In vitro efficacy of essential oil mouthrinse versus dentifrices. AB - OBJECTIVES: To compare the antimicrobial efficacy and kill penetration of essential oils (EO) mouthrinse versus stannous fluoride, and triclosan dentifrice slurries on saliva-derived biofilms using confocal laser scanning microscopy (CLSM). METHODS: Saliva-derived biofilms were grown for 48h on hydroxyapatite discs using pooled, homogenized saliva from 8 healthy volunteers as the inoculum. The mean thickness of these biofilms was 84MUm (range, 23-241MUm). CLSM with viability mapping was used to visualize the antimicrobial kill penetration of each treatment regime within a biofilm. RESULTS: At 30s treatment durations, CLSM imaging revealed greater antimicrobial activity and kill penetration of EO mouthrinse compared to sodium fluoride-, stannous fluoride-, and triclosan containing dentifrice slurries. Quantification of biovolume revealed that EO mouthrinse treatment at 30s resulted in a greater non-viable biovolume proportion (84.6%+/-15.0%) than other treatment groups. Increasing the treatment duration of the triclosan dentifrice (to 60 and 120s) resulted in better penetration and an increased reduction of viable cells, comparable to EO mouthrinse treatment at 30s duration. Further, CLSM imaging showed that the combined treatment of a non antimicrobial dentifrice (45s) with EO mouthrinse (30s) showed superior antimicrobial activity (96.2%+/-3.7%) compared to the antimicrobial triclosan containing dentifrice used without a mouthrinse step (26.0%+/-32.0%). CONCLUSIONS: Within typical exposure times, the EO-containing mouthrinse can penetrate deep into the accumulating plaque biofilm compared to the chemotherapeutic dentifrice slurries, and may provide an efficacious alternative to triclosan, when used as an adjunct with a mechanical oral care regimen. CLINICAL SIGNIFICANCE: Using viability mapping and CLSM, this study demonstrated that EO-containing mouthrinse penetrates and kills microorganisms deeper and more effectively in plaque biofilm in typical exposure times when compared to dentifrice chemotherapeutic agents, providing an efficacious alternative to triclosan or stannous fluoride when used as an adjunct to mechanical oral care. PMID- 28863963 TI - A qualitative study of patients' views of techniques to reduce dental anxiety. AB - OBJECTIVES: To explore the fear/anxiety inducing triggers associated with dental treatment, and what dentally anxious adults would like from their dental encounter. METHODS: Two focus-groups and three interviews with fourteen dentally anxious people were conducted in this qualitative study. All discussions were tape-recorded and transcribed verbatim. Content was categorised by common characteristics to identify underlying themes using thematic analysis. RESULTS: Four themes were identified to bring general meaning within the content: 1. Preparedness, 2. Teamwork, 3. Reinforced trust, 4. Tailored treatment plan. CONCLUSIONS: Preparatory information may need to be tailored and comprehensive, yet dissociative and reassuring. Dentally-anxious people might want a sense of control and shared-decision making. They may not want dentists to understate the treatment procedures and risks to make them feel better temporarily. CLINICAL SIGNIFICANCE: Dental anxiety affects between 10 and 60% of the population. Participants in this study suggested different ways the dental team could help their anxiety. Therefore, it is key for whole dental team to find out what could be done to help dentally anxious patients. PMID- 28863960 TI - Memory responses of natural killer cells. AB - Natural killer (NK) cells have traditionally been classified as a cellular component of the innate immune system, given their ability to rapidly produce effector cytokines and kill infected or transformed cells without prior exposure. More recently, NK cells have been shown to possess features of adaptive immunity such as clonal expansion, longevity, and robust recall responses. NK cell memory can be broadly divided into two categories: antigen-specific and antigen independent. In the first case, exposure to certain viral or hapten stimuli endows NK cells with antigen-specific immunological memory, similar to T and B cells. In the second case, exposure of NK cells to specific cytokine milieus can imprint long-lasting changes on effector functions, resulting in antigen independent memory-like NK cells. In this review, we discuss the various conditions that promote generation of these two categories of memory NK cells, and the mechanistic requirements underlying these processes. PMID- 28863964 TI - Design and biological effects of a vaginally administered gel containing the GnRH agonist, triptorelin, for synchronizing ovulation in swine. AB - A novel gel formulation was selected for intravaginal delivery of the GnRH agonist (triptorelin) for synchronizing ovulation in pigs. Studies with gilt models were used to assess LH response profiles. The lowest dose of triptorelin that induced the most gilts to show an LH surge was 100 MUg in 1.2% methylcellulose gel. This formulation had a similar effect in weaned sows while also advancing ovulation. The timing of administration was evaluated in sows after weaning. Administration at 96 h induced more sows to ovulate (58%) by 48 h compared to treatment at estrus (45%) or for controls (34%), but the desired level of ovulation synchrony was not achieved. As a result, greater doses of triptorelin were tested and 200 MUg given at 96 h after weaning, induced 81% of sows to ovulate within 48 h after treatment. The best synchrony of ovulation occurred when given at 96 h after weaning compared to earlier or later intervals. The optimum time to give a single fixed time AI (SFT-AI) after administration of 200 MUg of triptorelin in 1.2% gel (OvuGel(r)) at 96 h after weaning was tested. A SFT-AI at 22 +/- 2 h after OvuGel achieved the highest fertility and was practical for staff during the normal work day. In field trials, a SFT-AI 22 +/- 2 h after all weaned sows were treated with OvuGel improved (P = 0.04) farrowing rate to 82.5% compared to control sows weaned (80.1%), with no effect on numbers of pigs born alive (12.1). Research continues for identifying the advantages for use of OvuGel in different production systems, and potential application for use in gilts. PMID- 28863965 TI - [Utility of normality low limit of spirometry in diagnosed COPD patients]. AB - AIM: To evaluate the differences in COPD patients below the lower limit of normal (LLN) of the fixed ratio FEV1/FVC < 0.70 and those above this limit. PATIENTS AND METHODS: Cross-sectional study. COPD patients between 40 and 85 years old included in primary care clinical record database were randomly selected. Baseline and postbronchodilator spirometries were performed. Two groups of patients were established: FEV1/FVC<0.70 and <=LIN (group1) and FEV/FVC<0.70 and >LIN (group 2). Sociodemographic, clinical, pulmonary obstruction, quality of life and attendance to health services variables were measured. The results of both groups were compared. RESULTS: 22.3% of the subjects were misdiagnosed FEV1/FVC < 0,70. Patients in group 2 (FEV1/FVC<0.70 y > LLN) are diagnosed at an older age, they have a lower exposure to tobacco and better pulmonary function (FEV1: 74.9% vs 54.6%). 35.5% of those patients belong to stage i of GOLD, vs 8.5%, this patients have an increased comorbidity. Patients in group 1 have more COPD exacerbations, worse quality of life, a higher BODEx index 2,3 (1.8) vs 1.1 (1.5); 55.1% of those patients were high risk patients (GoldC or Gold D). Diagnose before being 56 years old, an increased exposure to tobacco, the FEV>50%, and a lower comorbidity are associated with a greater chance of suffering COPD with LLN criteria. CONCLUSION: We obtain two groups of patients with differentiated clinical characteristics if we use LLN. Subjects with FEV1/FVC<0.7 and >LLN have less obstruction, less severity and more comorbidity, suggesting the possibility of overdiagnosis or misdiagnosis. On the other hand, younger age at the time of diagnosis, higher tobacco consumption and more severe obstruction are related with FEV1/FVC >0.70 andR+L) in males. Ten cases (45%) were lateral type, and 12 (55%) were supine type in females. There was no significant difference between males and females. Seventeen cases (56.6%) were right-dominant type (R-L>0), and 13 (43.3%) were left-dominant type (R-L<0) in males. Thirteen cases (59%) were right-dominant type, and 9 (41%) were left-dominant type in females. CONCLUSION: Body position and the number of position shifts during sleep differ substantially between individuals. There is no gender difference in the frequency of position shifts. Although the supine type is more common than the lateral type, there is no gender difference in sleep position. Therefore, the reason of higher incidence in women is not related to sleep. The right-dominant type occurs more than the left-dominant type in both genders. It is possible that this behavior is the reason for the predominant involvement of the right ear in BPPV. PMID- 28863982 TI - Non-invasive pre-lens tear film assessment with high-speed videokeratoscopy. AB - PURPOSE: To evaluate the effect of two types of daily contact lenses (delefilcon A and omafilcon A) on the tear film and establish whether it is dependent on pre corneal tear film characteristics using a new method to analyse high-speed videokeratoscopy recordings, as well as to determine the sensitivity of the method in differentiating between contact lens materials on eye. METHODS: High speed videokeratoscopy recordings were analysed using a custom made automated algorithm based on a fractal dimension approach that provides a set of parameters directly related to tear film stability. Fifty-four subjects participated in the study. Baseline measurements, in suppressed and natural blinking conditions, were taken before subjects were fitted with two different daily contact lenses and after four hours of contact lens wear. RESULTS: The method for analysing the stability of the tear film provides alternative parameters to the non-invasive break up time to assess the quality of the pre-corneal and pre-lens tear film. Both contact lenses significantly decreased the quality of the tear film in suppressed and natural blinking conditions (p<0.001). The utilised method was able to distinguish between contact lens materials on eye in suppressed blinking conditions. The pre-corneal tear film characteristics were not correlated with the decrease in pre-lens tear film quality. CONCLUSION: High-speed videokeratoscopy equipped with an automated method to analyse the dynamics of the tear film is able to distinguish between contact lens materials in vivo. Incorporating the assessment of pre-lens tear film to the clinical practice could aid improving contact lens fitting and understand contact lens comfort. PMID- 28863983 TI - The utility of measuring tear film break-up time for prescribing contact lenses. AB - PURPOSE: To evaluate the clinical value of non-invasive keratograph tear film breakup time (NIKBUT) in the assessment of pre-corneal and pre-lens tear film quality for prescribing contact lenses (CLs). METHODS: Forty-six subjects aged 25.5+/-4.3 (mean+/-standard deviation) years were recruited. Visual acuity (VA), anterior eye health checks and NIKBUT were evaluated. On the following day, subjects were fitted with a daily Silicon Hydrogel (SiHy) CL in one eye and a Hydrogel (Hy) CL in the other. After four hours one material for both eyes was chosen based on a qualitative analysis which included VA, CL fitting and comfort. Information about the first and the mean NIKBUT was then contrasted against the prescription decision. RESULTS: Thirty-four subjects were fitted with SiHy and twelve with Hy CL. No statistically significant differences were found for both NIKBUT parameters between left and right eye at baseline (p=0.38 and p=0.50, respectively) and post four hours of CL wear (p=0.61 and p=0.06). The chosen lens did not always correspond to longer NIKBUT. In 39.1% and 34.8% of cases (i.e., 18 and 16 out of 46), there was a match between prescription decision and the first and the mean NIKBUT results, respectively. CONCLUSIONS: Although there is no evidence whether tear film surface quality measurement has a superior diagnostic values compared to other traditional clinical measures used in practice, NIKBUT measurements have provided additional information that could be of interest during CL fit. PMID- 28863981 TI - Single cell analysis of normal and leukemic hematopoiesis. AB - The hematopoietic system is well established as a paradigm for the study of cellular hierarchies, their disruption in disease and therapeutic use in regenerative medicine. Traditional approaches to study hematopoiesis involve purification of cell populations based on a small number of surface markers. However, such population-based analysis obscures underlying heterogeneity contained within any phenotypically defined cell population. This heterogeneity can only be resolved through single cell analysis. Recent advances in single cell techniques allow analysis of the genome, transcriptome, epigenome and proteome in single cells at an unprecedented scale. The application of these new single cell methods to investigate the hematopoietic system has led to paradigm shifts in our understanding of cellular heterogeneity in hematopoiesis and how this is disrupted in disease. In this review, we summarize how single cell techniques have been applied to the analysis of hematopoietic stem/progenitor cells in normal and malignant hematopoiesis, with a particular focus on recent advances in single-cell genomics, including how these might be utilized for clinical application. PMID- 28863984 TI - Immunomodulatory Properties of Plants and Mushrooms. AB - Plants and mushrooms are used for medicinal purposes and the screening of molecules possessing biological activities. A single plant or mushroom may produce both stimulatory and inhibitory effects on immune cells, depending on experimental conditions, but the reason behind this dichotomy remains obscure. We present here a large body of experimental data showing that water extracts of plants and mushrooms usually activate immune cells, whereas ethanol extracts inhibit immune cells. The mode of extraction of plants and mushrooms may thus determine the effects produced on immune cells, possibly due to differential solubility and potency of stimulatory and inhibitory compounds. We also examine the possibility of using such plant and mushroom extracts to treat immune system disorders. PMID- 28863985 TI - Targeting 12-Lipoxygenase as a Potential Novel Antiplatelet Therapy. AB - Platelets are key contributors to the formation of occlusive thrombi; the major underlying cause of ischemic heart disease and stroke. Antiplatelet therapy has reduced the morbidity and mortality associated with thrombotic events; however, the utility of current antiplatelet therapies is limited by the concomitant risk of an adverse bleeding event. Novel antiplatelet therapies that are more efficacious at inhibiting thrombosis while minimally affecting hemostasis are required. Platelet-type 12-(S)-lipoxygenase (12-LOX), an oxygenase shown to potentiate platelet activation, represents a novel antiplatelet target. Recently, a selective 12-LOX inhibitor, ML355, was shown to decrease thrombosis without prolonging hemostasis. While published data suggests targeting 12-LOX is a viable approach, further work is required to determine the safety and effectiveness of 12-LOX inhibitors in humans. PMID- 28863987 TI - [Quality appraisal in systematic reviews of normative literature. A problem analysis]. AB - Systematic reviews aim at searching, selecting, analyzing and synthesizing scientific literature in a transparent and systematic way in order to inform decision-making in the health care system on the basis of the best available evidence. In recent years, such reviews have also gained importance also in bio-, public health- and research ethics, as well as in health technology assessment. Such reviews do not only analyze ethically relevant empirical literature (e.g. on risk and benefit), but normative literature as well, i.e. literature consisting of ethical arguments. As the appraisal of the literature that should be included is paramount for a systematic review, the problem of how to appraise the quality of normative literature arises. This problem has not yet been solved satisfactorily. After developing a pragmatic definition for "normative literature", a typology of different types of systematic reviews of normative literature is presented. Based on existing approaches for quality appraisal, this paper identifies three possible strategies for solving the problem of quality appraisal of normative literature, and discusses their respective strength and weaknesses relative to the different types of systematic reviews. It becomes apparent that none of the existing approaches is able to solve the problem of quality appraisal in a general and convincing way. The paper concludes with stating minimal conditions regarding the elaboration of future strategies, and outlines a promising strategy that is theoretically acceptable and practically feasible. PMID- 28863988 TI - Identifying the key factors that affect the formation of humic substance during different materials composting. AB - The aim of this work was to identify the factors which can affect humic substance (HS) formation. Composting periods, HS precursors, bacteria communities and environment factors were recognized as the key factors and few studies explored the potential relationships among them. During composting, HS precursors were mainly formed in the heating and thermophilic phases, but HS were polymerized in the cooling and mature phases. Moreover, bacterial species showed similar classification of community structure in the same composting period of different materials. Furthermore, structural equation model showed that NH4--N and NO3--N were the indirect environmental factors for regulating HS formation by the bacteria and precursors as the indirect and direct driver, respectively. Therefore, both environmental factors and HS precursors can be the regulating factors to promote HS formation. Given that, a new staging regulating method had been proposed to improve the amount of HS during different materials composting. PMID- 28863989 TI - Sorption of sulfamethazine to biochars as affected by dissolved organic matters of different origin. AB - Sorption characteristic of sulfamethazine (SMT) to straw biochars pyrolyzed at 300 degrees C (BC300) and 600 degrees C (BC600), and the effect of ubiquitous DOM were investigated. Results showed that physisorption (partition) and weak chemical binding (pi-pi EDA interaction) dominated the sorption of SMT to BC300 and BC600, respectively. Graphene sheets in biochar played important roles in the sorption of SMT, leading to higher sorption capacity (Kf) on BC600 (1.77mg1-nLng 1) than BC300 (0.11mg1-nLng-1). Sorption amount of SMT to BC300 was not affected by polysaccharide and malic acid, while it was slightly promoted by citric acid, but dramatically increased 1.25 times by methacrylic acid through decreasing solution pH and providing new sorption sites. Humic acid and bovine serum albumin restrained the sorption of SMT to BC600, but enhanced SMT- adsorption to BC300. The chemical nature of DOM, biochar properties and antibiotic species co determined the impact of DOM on antibiotics adsorption. PMID- 28863990 TI - Environmental application of biochar: Current status and perspectives. AB - In recent years, there has been a significant interest on biochar for various environmental applications, e.g., pollutants removal, carbon sequestration, and soil amelioration. Biochar has several unique properties, which makes it an efficient, cost-effective and environmentally-friendly material for diverse contaminants removal. The variability in physicochemical properties (e.g., surface area, microporosity, and pH) provides an avenue for biochar to maximize its efficacy to targeted applications. This review aims to highlight the vital role of surface architecture of biochar in different environmental applications. Particularly, it provides a critical review of current research updates related to the pollutants interaction with surface functional groups of biochars and the effect of the parameters variability on biochar attributes pertinent to specific pollutants removal, involved mechanisms, and competence for these removals. Moreover, future research directions of biochar research are also discussed. PMID- 28863991 TI - Enhanced methane production and wastewater sludge stabilization of a continuous full scale thermal pretreatment and thermophilic anaerobic digestion. AB - A continuous full scale thermophilic anaerobic digestion (AD) of wastewater sludge in conjunction with thermal pretreatment was developed for enhanced CH4 production as well as sludge stabilization and reduction. Continuous thermal sludge treatment obtained 45.5, 51.7, and 26.1% of hydrolysis based on TS, VS, and COD at 160 degrees C for 30min. After AD, TS, VS, and COD removal efficiencies reached 54.7, 60.4, and 59.2%, respectively, at 3.50kgVS/m3.d. Maximum CH4 yield (0.35m3 CH4/kg VSadd) was obtained at 2.49kgVS/m3.d and less, and the yield decreased with increasing sludge load while net available energy production increased. Continuous thermal sludge treatment and thermophilic AD enhanced CH4 production and solids reduction and showed stable performance for full scale application. PMID- 28863992 TI - Nutrient removal and energy recovery from high-rate activated sludge processes - Impact of sludge age. AB - This study evaluated high-rate activated sludge treatment across a broad range of short solids retention times (SRT)s (0.5-3d) and found a strong SRT-outcome dependence for performance and subsequent anaerobic degradability of the sludge. Up to 50% total nitrogen, and 35% ammonia removal was also achieved at the longer SRTs, via partitioning rather than reaction. The aerobic SRT significantly affected the anaerobic degradability of the sludge produced (p<0.001), with degradability increasing from 66% to over 80% while reducing the SRT from 3d to 0.5d. This is higher than predicted by conventional models, likely due to additional mechanisms such as adsorption and storage, not included in these. PMID- 28863993 TI - Impact of shear stress and impeller design on the production of biogas in anaerobic digesters. AB - Today, intensification of anaerobic digestion is still a scientific and technical challenge. The present study proposed combined experimental and computational fluid dynamics simulations to characterize the impact of shear stress and impeller design on the biogas production after sequential additions of substrate. Liquid phase (cattle manure digestate) rheological law was experimentally determined and input in numerical simulations. The results showed that the original use of a double helical ribbon in digester allowed a significantly faster dispersion of fresh substrate than the use of a classical Rushton turbine, leading to a 50% higher methane production rate. However, with both impellers, too high agitation rates entailed a clear slow-down of production rate and a decrease in CH4 content. To avoid this loss of productivity, it was shown that the maximal value of shear stress, determined by numerical simulations, was a consistent parameter to set the upper agitation conditions in digesters. PMID- 28863994 TI - High performance biological methanation in a thermophilic anaerobic trickle bed reactor. AB - In order to enhance energy efficiency of biological methanation of CO2 and H2, this study investigated the performance of a thermophilic (55 degrees C) anaerobic trickle bed reactor (ATBR) (58.1L) at ambient pressure. With a methane production rate of up to 15.4m3CH4/(m3trickle bed.d) at methane concentrations above 98%, the ATBR can easily compete with the performance of other mixed culture methanation reactors. Control of pH and nutrient supply turned out to be crucial for stable operation and was affected significantly by dilution due to metabolic water production, especially during demand-orientated operation. Considering practical applications, inoculation with digested sludge, containing a diverse biocenosis, showed high adaptive capacity due to intrinsic biological diversity. However, no macroscopic biofilm formation was observed at thermophilic conditions even after 313days of operation. The applied approach illustrates the high potential of thermophilic ATBRs as a very efficient energy conversion and storage technology. PMID- 28863995 TI - Bioelectrochemical enhancement of anaerobic digestion: Comparing single- and two chamber reactor configurations at thermophilic conditions. AB - Bioelectrochemical system (BES) can act as an auxiliary technology for improving organic waste treatment and biogas production in anaerobic digestion (AD). For the first time this study directly compared the performance of a single- and a cation-exchange membrane-equipped two-chamber BES-AD systems at thermophilic conditions. The results indicated that an active glucose-fed thermophilic anaerobic sludge could readily (<3days) increase biogas production in both reactor configurations by inserting a carbon electrode poised at -0.8V (vs. Ag/AgCl). However, after a 3-week operation, the biogas production rates from the single- and two-chamber BES reactor decreased due to volatile fatty acids accumulation. Only the two-chamber configuration could enable methane enrichment (98% CH4v/v) in biogas. Overall, this study suggests that integrating bioelectrodes in-situ could not sustainably improve biogas production in a thermophilic AD reactor, and future studies should be directed towards the use of bioelectrodes for improving biogas quality. PMID- 28863996 TI - Improvement of fermentation performance of Gluconobacter oxydans by combination of enhanced oxygen mass transfer in compressed-oxygen-supplied sealed system and cell-recycle technique. AB - Oxygen supply for microbial cultures is often identified as a limiting factor for aerobic fermentation. Through implementation of an integrated oxygen control strategy, the high oxygen mass transfer rate satisfied cellular metabolic demands. Gluconobacter oxydans NL71 fermentation of xylose to xylonic acid was improved remarkably. Finally, the productivity of xylonic acid from xylose by biooxidation was markedly increased to 32.5+/-3.1g/L/h compared to production levels using conventional laboratory-scale bioreactors. By improving microbial fermentative vitality, we successfully bio-converted 1800g xylose to 1813+/-36g xylonic acid by combination of a fed-batch addition of xylose substrate as well as a cell-recycling strategy. Bioconversion results demonstrated a highly efficient fermentation model that performs continuous bioreaction, assisting the effort to industrialize microbial xylonic acid production. PMID- 28863997 TI - Micronized progesterone pretreatment affects the inflammatory response of human gestational tissues and the cervix to lipopolysaccharide stimulation. AB - INTRODUCTION: Vaginal administration of micronized progesterone (utrogestan capsule, UG) reduces the risk of preterm birth (PTB) in asymptomatic women with a sonographic short cervix at mid-trimester or with a prior history of spontaneous PTB; however, its exact mechanisms remain unclear. We hypothesized that UG limits the inflammatory processes within the gestational tissues and the cervix. METHODS: Fetal membranes and villous tissues were obtained from normal term placentas from women with cesarean delivery before labor onset. Ectocervical tissues were obtained from premenopausal women undergoing hysterectomies for uterine fibroids. Explant tissue cultures were pretreated with UG for 24 h and then exposed to UG with or without lipopolysaccharide (LPS) for 48 h. Tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein-1, interleukin (IL)-1beta, IL-4, IL-6, IL-8, IL-10, IL-13, interferon-gamma, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 levels in tissue homogenates and culture medium were measured by enzyme-linked immunosorbent assays. Real-time quantitative PCR, Western blot, and gelatine zymography were used to measure matrix metalloproteinase (MMP)-9 and MMP-2 mRNA, protein, and activity levels, respectively. RESULTS: UG pretreatment did not cause a significant change in basal levels or in LPS-induced production and secretion of cytokines, chemokines, and TIMPs in the three tissues. However, UG pretreatment significantly reduced MMP-9 and MMP-2 expression and activity in fetal membranes stimulated with LPS but not in villous or cervical tissues. DISCUSSION: UG pretreatment significantly reduced MMP-9 and MMP-2 expression and activity in fetal membranes stimulated with LPS, suggesting a possible protective mechanism of micronized progesterone in preventing infection-associated PTB. PMID- 28863998 TI - Changes in mitochondrial respiration in the human placenta over gestation. AB - INTRODUCTION: Placental mitochondria are subjected to micro-environmental changes throughout gestation, in particular large variations in oxygen. How placental mitochondrial respiration adapts to changing oxygen concentrations remains unexplored. Additionally, placental tissue is often studied in culture; however, the effect of culture on placental mitochondria is unclear. MATERIAL AND METHODS: Placental tissue was obtained from first trimester and term (laboured and non laboured) pregnancies, and selectively permeabilized to access mitochondria. Respirometry was used to compare respiration states and substrate use in mitochondria. Additionally, explants of placental tissue were cultured for four, 12, 24, 48, or 96 h and respiration measured. RESULTS: Mitochondrial respiration decreased at 11 weeks compared to earlier gestations (p = 0.05-0.001), and mitochondrial content increased at 12-13 weeks compared to 7-10 weeks (p = 0.042). In term placentae, oxidative phosphorylation (OXPHOS) through mitochondrial complex IV (p < 0.001), the relative proportion of OXPHOS CI (p < 0.001), the total capacity of the respiratory system (p = 0.003), and mitochondrial content (p < 0.001) were higher compared to first trimester. Respiration was increased (p <= 0.006-0.001) in laboured compared to non-laboured placenta. After four hours of culture, respiration was depressed compared to fresh tissue from the same placenta and continued to decline with time in culture. Markers of apoptosis were increased, while markers of autophagy, mitochondrial biogenesis, and mitochondrial membrane potential were decreased after four hours of culture. DISCUSSION: Respiration and mitochondrial content alter over gestation/with labour. Decreased respiration at 11 weeks and increased mitochondrial content at 12-13 weeks may relate to onset of maternal blood flow, and increased respiration as a result of labour may be an adaptation to ischaemia reperfusion. At term, mitochondria were more susceptible to changes in respiratory function relative to first trimester when cultured in vitro, perhaps reflecting changes in metabolic demands as gestation progresses. Metabolic plasticity of placental mitochondria has relevance to placenta-mediated diseases. PMID- 28863999 TI - Isolation and characterization of the trophectoderm from the Arabian camel (Camelus dromedarius). AB - We isolated and characterized trophoblast from in vivo-derived camel embryos and compared with embryonic stem-like cells. Camel embryos were flushed on day 8 post insemination and used to derive trophectoderm and embryonic stem-like cells under feeder-free culture conditions using a basement membrane matrix. Embryos were evaluated for the expression of POU5F1, MYC, KLF4, SOX2, CDX2, and KRT8 mRNA transcripts by relative quantitative polymerase chain reaction. Camel embryos grew and expanded to ~4.5 mm and maintained their vesicular shape in vitro for 21 days post-insemination. Trophoblast and embryonic stem-like cell lines grew under feeder-free culture conditions and showed distinct morphological criteria and normal chromosomal counts. Embryonic stem-like cells showed positive staining in the alkaline phosphatase reaction. Trophoblast cells showed a significant increase in CDX2, KRT8, KLF4, and SOX2 expression compared with embryonic stem like cells and whole embryos. Embryonic stem-like cells showed a significant decrease in CDX2 expression and increase in SOX2 and KRT8 expression compared to embryonic expression. POU5F1 and MYC expression showed no difference between embryos and both cell lines. We characterized embryo survival in vitro, particularly the derivation of trophectoderm and embryonic stem-like cells, providing a foundation for further analysis of early embryonic development and placentation in camels. PMID- 28864000 TI - First-trimester placental thickness and the risk of preeclampsia or SGA. AB - INTRODUCTION: Placental thickness in the second trimester of pregnancy has been associated with risks of placenta-mediated complications of pregnancy. We aimed to estimate the association between first-trimester maximum placental thickness and the subsequent risk of preeclampsia and/or the delivery of small-for gestational-age (SGA) neonate. METHODS: Prospective cohort study of women recruited at 11-14 weeks gestation. Placental thickness was measured at its apparent center and reported in multiple of median (MoM) adjusted for gestational age. Participants were followed until delivery for pregnancy outcomes. Placental measurements of participants who developed preeclampsia and/or delivered SGA neonate (defined as birth weight below 10th percentile) were compared with those who did not using non-parametric statistical analyses. RESULTS: We recruited 991 participants at a mean gestational age of 12.7 +/- 0.7 weeks of gestation. SGA (n = 52) was associated with reduced 1st trimester placental thickness (median: 0.89 MoM; interquartile (IQ): 0.75-1.02 vs 0.98 MoM; IQ: 0.84-1.15; p < 0.01). Pregnancies that developed preeclampsia (n = 20) tended to have greater placental thickness (median: 1.10 MoM; IQ: 0.93-1.25 vs 0.97 MoM; IQ: 0.84-1.14; p = 0.06) with values > 1.2 MoM significantly increasing the risk for preeclampsia (relative risk: 3.6; 95%CI: 1.5-8.6, p < 0.01). Pregnancies complicated by both SGA and preeclampsia (n = 5) had similar placental thickness in the first trimester in comparison with uncomplicated pregnancies (median: 1.03 MoM; IQ: 0.89-1.42 vs 0.98 MoM; IQ: 0.84-1.14; p = 0.33). CONCLUSION: First-trimester placental thickness diverges in pregnancies at risk of preeclampsia (increased) or SGA (decreased), but remains within normal values in pregnancies at risk of both conditions, suggesting that the underlying pathologies have some opposing effects on early placental growth. The current findings should be validated in a larger cohort. PMID- 28864001 TI - Associations between the levels of soluble (pro)renin receptor in maternal and umbilical cord blood and hypertensive disorder of pregnancy. AB - INTRODUCTION: The prorenin (PR) receptor [(P)RR] contributes to the regulation of the tissue renin-angiotensin system (RAS) and Wnt signaling, which is involved in embryogenesis and the pathological progression of malignant tumors and diabetes mellitus. Placental (P)RR is significantly upregulated in placental tissues from preeclamptic women. However, because it cannot be examined during pregnancy, the chronological relationship between the acceleration of tissue RAS and the disease state of hypertensive disorder of pregnancy (HDP) has not been reported. In this study, we examined whether chronological changes in placental tissue RAS can be assessed by measuring soluble (P)RR [s(P)RR]. METHODS: We obtained maternal and umbilical cord blood samples from 517 pregnant women (441 singleton and 76 twin pregnancies). The concentrations of s(P)RR and prorenin (PR) were measured using enzyme-linked immunosorbent assays. RESULTS: Multivariate analysis showed that maternal serum s(P)RR levels were significantly higher in patients with HDP or fetal growth restriction (FGR) and were positively correlated with serum PR levels. Furthermore, the maternal s(P)RR level was significantly higher in HDP with severe hypertension and after the onset of HDP. However, maternal s(P)RR levels were not affected by the severity of proteinuria. Serum s(P)RR levels in umbilical cord blood of singleton pregnancies were significantly correlated with gestational week at delivery and PR level. DISCUSSION: Maternal serum s(P)RR concentrations may reflect acceleration of tissue RAS in the placenta and blood pressure severity; however, the umbilical serum s(P)RR concentration was not affected by maternal HDP. PMID- 28864002 TI - Interleukin-11 classic but not trans-signaling is essential for fertility in mice. AB - The cytokine interleukin (IL)-11 activates its target cells through binding to the membrane-bound IL-11 receptor (IL-11R). Female mice deficient in IL-11R (Il11ra-/-) are infertile due to a defect in decidualization when the blastocyst implants. We have recently shown that IL-11 can also signal via a soluble IL-11R (trans-signaling). Which IL-11 pathway is required for fertility in mice is unknown. We confirm that female Il11ra-/-mice, lacking both classic and trans signaling, are infertile. In contrast, the selective blockade of IL-11 trans signaling does not affect fertility in mice. These results show that classic, but not trans-signaling of IL-11, is essential for fertility in mice. PMID- 28864003 TI - Vesicular uptake of macromolecules by human placental amniotic epithelial cells. AB - INTRODUCTION: Studies in animal models have shown that unidirectional vesicular transport of amniotic fluid across the amnion plays a primary role in regulating amniotic fluid volume. Our objective was to explore vesicle type, vesicular uptake and intracellular distribution of vesicles in human amnion cells using high- and super-resolution fluorescence microscopy. METHODS: Placental amnion was obtained at cesarean section and amnion cells were prepared and cultured. At 20% 50% confluence, the cells were incubated with fluorophore conjugated macromolecules for 1-30 min at 22 degrees C or 37 degrees C. Fluorophore labeled macromolecules were selected as markers of receptor-mediated caveolar and clathrin-coated vesicular uptake as well as non-specific endocytosis. After fluorophore treatment, the cells were fixed, imaged and vesicles counted using Imaris(r) software. RESULTS: Vesicular uptake displayed first order saturation kinetics with half saturation times averaging 1.3 min at 37 degrees C compared to 4.9 min at 22 degrees C, with non-specific endocytotic uptake being more rapid at both temperatures. There was extensive cell-to-cell variability in uptake rate. Under super-resolution microscopy, the pattern of intracellular spatial distribution was distinct for each macromolecule. Co-localization of fluorescently labeled macromolecules was very low at vesicular dimensions. CONCLUSIONS: In human placental amnion cells, 1) vesicular uptake of macromolecules is rapid, consistent with the concept that vesicular transcytosis across the amnion plays a role in the regulation of amniotic fluid volume; 2) uptake is temperature dependent and variable among individual cells; 3) the unique intracellular distributions suggest distinct functions for each vesicle type; 4) non-receptor mediated vesicular uptake may be a primary vesicular uptake mechanism. PMID- 28864004 TI - Maternal BMI and gestational diabetes alter placental lipid transporters and fatty acid composition. AB - INTRODUCTION: Placental fatty acid (FA) uptake and metabolism depend on maternal supply which may be altered when women have a high pre-pregnancy body mass index (BMI) or develop gestational diabetes (GDM). Consequently, an impaired FA transport to the fetus may negatively affect fetal development. While placental adaptation of maternal-fetal glucose transfer in mild GDM has been described, knowledge on placental FA acid metabolism and possible adaptations in response to maternal obesity or GDM is lacking. We aimed to analyze the FA composition and the expression of key genes involved in FA uptake and metabolism in placentas from women with pre-pregnancy normal weight (18.5 <= BMI<25 kg/m2), overweight (25 <= BMI<30 kg/m2), obesity (BMI >= 30 kg/m2), and lean pregnant women with GDM. METHODS: Placental FA content was determined by gas liquid chromatography. Placental mRNA expression of FA transport proteins (FATP1, FATP4, FATP6), FA binding proteins (FABP3, FABP4, FABP7), FA translocase (FAT/CD36) and enzymes (Endothelial lipase (EL) and lipoprotein lipase (LPL)) were quantified by qRT PCR. RESULTS: High pre-pregnancy BMI and GDM were associated with decreased placental FATP1, FATP4, EL and increased FAT/CD36 and FATP6 expressions. LPL mRNA levels and placental total FA content were similar among groups. Specific FA, including some long-chain polyunsaturated FA, were altered. DISCUSSION: Our results demonstrate that high pre-pregnancy BMI or GDM independently alter mRNA expression levels of genes involved in FA uptake and metabolism and the placental FA profile, which could affect fetal development and long-term health. PMID- 28864005 TI - Sp1 transcription factor is a modulator of estradiol leptin induction in placental cells. AB - INTRODUCTION: Pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in the placenta, where it functions as an autocrine hormone. The synthesis of leptin in normal trophoblastic cells is regulated by different endogenous biochemical agents, but the regulation of placental leptin expression is still poorly understood. We have previously reported that 17beta estradiol up-regulates placental leptin expression through genomic and nongenomic mechanisms. METHODS: To improve the understanding of estrogen receptor mechanisms in regulating leptin gene expression, we examined Sp1 transcription factor effect on estradiol leptin induction in human BeWo cell line. RESULTS: We demonstrated that Sp1 induces leptin expression determined by qRT-PCR, Western blot and transient transfection experiments. We also found that estradiol induction effect on leptin expression is enhanced by the over expression of Sp1 factor. Moreover, estradiol effect was not evidenced when Sp1 binding site on leptin promoter is mutated, suggesting that estradiol action is dependent on Sp1. On the other hand we showed data that demonstrate that Sp1 induction of leptin expression is insensitive to the antiestrogen ICI 182 780. By over expression experiments, we have also found that Sp1 effect on leptin expression could be mediated by estrogen receptor alpha. Supporting this idea, the downregulation of estrogen receptor alpha level through a specific siRNA, abolished Sp1 effect on leptin expression. DISCUSSION: Taken together all these evidences suggest a cooperative behavior between estrogen receptor alpha and Sp1 transcription factors to induce leptin transcription. PMID- 28864006 TI - Endoplasmic reticulum stress responses in placentation - A true balancing act. AB - The unfolded protein response (UPR) is recognized as a key mechanism to promote protein folding and processing in eukaryotes when endoplasmic reticulum stress (ERS) occurs. Some conditions such as hypoxia or glucose deprivation are factors that may elicit ERS response. Recent literature collectively proposes that ERS response is crucial for mammalian reproduction by allowing decidualization and placentation to occur. However, prolonged ERS and activation of UPR pathways can lead to apoptosis and autophagy, which in turn could pose adverse effects on pregnancy outcomes and placentation. ERS associated pregnancy pathologies include intrauterine growth restriction and early-onset preeclampsia. Given these findings, evidence suggests that overactivation of UPR may lead to harmful reproductive circumstances, whereas physiological regulation of ERS response is essential for mammalian reproduction and placental function. In this review, we discuss the dual role of UPR activation with respect to its contribution to placental development as well as pathologies caused by pathway overactivation. In addition, we suggest potential protein markers associated with the UPR, as circulating C-terminal GRP78 or anti-GRP78 autoantibodies which may prove to be of clinical interest. PMID- 28864007 TI - Expression pattern and phosphorylation status of Smad2/3 in different subtypes of human first trimester trophoblast. AB - INTRODUCTION: TGF-beta superfamily members are thought to play a pivotal role in placental development and differentiation. However, their downstream effectors, the Smad transcription factors, have been poorly investigated in human trophoblasts. METHODS: Expression and localisation of the canonical TGF-beta targets Smad2/3 and their regulators (Smad4 and Smad7) were investigated in first trimester placenta and purified cytotrophoblast (CTB) subtypes using immunofluorescence, western blotting and qPCR. Canonical and non-canonical activation was analysed in nuclear/cytoplasmic extracts of trophoblast subtypes as well as in tissue sections using antibodies against Smad2/3, phosphorylated either at the C-terminus (pSmad2C/3C) or in their linker regions (pSmad2L/3L). Smad phosphorylation was also examined in differentiating extravillous trophoblasts (EVTs) in the absence or presence of decidual stromal cell (DSC) conditioned medium. RESULTS: Smad2, Smad4 and Smad7 protein were uniformly expressed between 6th and 12th week placentae and the different isolated CTB subtypes. Activated pSmad2L was mainly detected in nuclei and cytoplasm of villous CTBs, whereas pSmad2C was absent from these cells. In contrast, pSmad2C could be detected in the cytoplasm of cell column trophoblasts and in the cytoplasm/nuclei of EVTs. Smad3 and its phosphorylated forms pSmad3C and pSmad3L specifically localised to EVT nuclei. During EVT differentiation autocrine activation of pSmad2C/3C and pSmad3L was observed. DSC-conditioned medium further increased Smad2/3 phosphorylation in EVTs. DISCUSSION: The lack of pSmad2C in villous CTBs suggests that other mitogens than TGF-beta could promote Smad2 linker phosphorylation under homeostatic conditions. Whereas autocrine signalling activates Smad2/3 in differentiating EVTs, paracrine factors contribute to Smad phosphorylation in these cells. PMID- 28864008 TI - Temporal and spatial expression of glyceraldehyde 3-phosphate dehydrogenase (Gapdh) in the mouse placenta. AB - Glucose metabolism in trophoblast cells is essential to provide the required energy for the development and function of the placenta. Glyceraldehyde 3 phosphate dehydrogenase (Gapdh), a key enzyme in the glycolysis pathway has been considered ubiquitously expressed in cells. There is, however, a growing body of evidence suggesting that Gapdh has many functions in pathways unrelated to glucose metabolism. In the present study, we show that GAPDH expression and sub cellular localization changes through gestation in the mouse placenta. Our findings raise the possibility that GAPDH has multiple functions in trophoblast cells and the developing placenta, while also cautioning against its use as an endogenous reference or standard for gene expression in the placenta. PMID- 28864009 TI - Negative uterine asynchrony retards early equine conceptus development and upregulation of placental imprinted genes. AB - INTRODUCTION: Placental imprinted genes appear to be sensitive indicators of an inappropriate pre-implantation environment. This study examined the effects of negative uterine asynchrony after embryo transfer (ET) on early horse embryo development, and yolk-sac membrane expression of DNA methyltransferases (DNMTs) and equine specific placental imprinted genes. METHODS: Day 8 embryos were transferred to recipient mares on day 8 (synchronous) or day 3 (asynchronous) after ovulation, and conceptuses were recovered 6 or 11 days later (day 14 or 19 of development). RESULTS: Day 14 conceptuses recovered from an asynchronous uterus had a smaller embryonic disc, in which primitive streak development was visibly retarded compared to conceptuses from a synchronous uterus. Similarly, length, somite number and organogenesis were retarded in day 19 embryos after asynchronous ET. Maternal (GRB10, H19, IGF2R, PHLDA2) and paternal (IGF2, INSR, PEG3, PEG10, DIO3, NDN, SNRPN) imprinted genes and DNMTs (DNMT1, 3A and 3B) were all up-regulated between day 14 and 19 of pregnancy and, for most, mRNA expression was higher in synchronous than asynchronous day 19 yolk-sac membrane. Expression of the paternally imprinted gene HAT1 increased between day 14 and 19 of pregnancy, but was not affected by the asynchrony. DISCUSSION: Conceptus development and upregulation of DNMTs and imprinted genes were delayed rather than dysregulated after transfer into a negatively asynchronous uterus. We propose that this ability to 'reset' conceptus development to uterine stage is an adaptation that explains why horse embryos are unusually tolerant of asynchrony after ET. PMID- 28864010 TI - The association between placental histopathology and autism spectrum disorder. AB - INTRODUCTION: Research suggests that autism spectrum disorder (ASD) has its origins in utero. This study examines the association between evidence of placental histopathology and ASD. METHODS: Administrative claims data and medical records data were used to identify ASD cases (N = 55) and matched controls (N = 199) born at New York Methodist Hospital between 2007 and 2014 and subsequently seen in affiliated pediatrics clinics. Placentas from all births during this time period were reviewed as part of routine care. Data were analyzed using conditional logistic regression to account for the matched (gender, gestational age, and birth weight) design. RESULTS: Acute placental inflammation, regardless of type was associated with an increased risk of ASD (odds ratio [OR] = 3.14, 95% CI = 1.39, 6.95). Chronic uteroplacental vasculitis (OR = 7.13; 95% CI = 1.17, 43.38), the fetal inflammatory response in the chorionic plate vessels (OR = 5.12; 95% CI = 2.02, 12.96), and maternal vascular malperfusion pathology (OR = 12.29; 95% CI = 1.37, 110.69) were associated with an increased risk of ASD. Placental villous edema was associated with a decreased risk of ASD (OR = 0.05; 95% CI = 0.0005, 0.42). In subanalyses among male placentas acute inflammation overall, fetal inflammatory response in the chorionic plate vessels, and maternal vascular malperfusion pathology remained significantly associated with an increased risk of ASD whereas placental villous edema remained associated with a decreased risk of ASD. DISCUSSION: Histologic evidence of placental inflammation and maternal vascular malperfusion pathology are associated with ASD. PMID- 28864011 TI - Can color difference on the maternal side of the placenta distinguish between acute peripartum twin-twin transfusion syndrome and twin anemia-polycythemia sequence? AB - OBJECTIVE: To investigate the color difference between two placental shares in monochorionic placentas with acute peripartum twin-twin transfusion syndrome (TTTS) and twin anemia-polycythemia sequence (TAPS). METHODS: We evaluated all digital pictures of TAPS, acute peripartum TTTS and a control group of uncomplicated monochorionic placentas examined at our center. We determined the color intensity of the individual placental share on the maternal side of each monochorionic placenta using an image-processing program and calculated the color difference ratio (CDR). RESULTS: Digital pictures of 5 acute peripartum TTTS, 25 TAPS and 54 control group placentas were included in this study. The median CDR in acute peripartum TTTS was significantly lower compared to TAPS placentas, 1.20 (inter-quartile range (IQR) 1.05-1.20) and 2.50 (IQR 1.85-3.34), respectively (p < 0.01), and was comparable to the control group (CDR 1.11, IQR 1.05-1.22). CONCLUSION: TAPS placentas have a higher CDR compared to acute peripartum TTTS placentas. Examining color difference on the maternal side of the placenta might help distinguish between acute peripartum TTTS and TAPS. PMID- 28864012 TI - Maternal obesity and gestational weight gain are modestly associated with umbilical cord DNA methylation. AB - INTRODUCTION: Maternal obesity (OB) and excessive gestational weight gain (GWG) are strong independent contributors that augment obesity risk in offspring. However, direct evidence of epigenetic changes associated with maternal habitus remains sparse. METHODS: We utilized Bisulfite Amplicon Sequencing (BSAS) to conduct targeted DNA methylation association analysis of maternal obesity and excessive GWG with DNA methylation of select metabolism-related and imprinted genes. Umbilical cord (UC) tissue from infants born to normal weight and overweight/obese women from the Glowing study were utilized (n = 78). RESULTS: In multivariable linear regression adjusted for relevant confounders, Institute on Medicine (IOM) GWG category and infant sex were significantly associated with UC IGFBP1 methylation, while gestation length was significantly associated with UC PRKAA1 methylation. In addition, infant fat mass (%) at 2 weeks of age was significantly associated with umbilical cord methylation of RAPTOR. While regression tree analysis confirmed findings from multivariable models demonstrating that maternal early pregnancy BMI and IOM GWG category are associated with fetal UC DNA methylation patterns for select metabolic and imprinted genes, in general, effect sizes were quite small and statistical significance was not maintained when accounting for multiple testing. DISCUSSION: Our findings suggest that maternal obesity and excessive GWG are weakly correlated with offspring DNA methylation patterns at birth. PMID- 28864013 TI - The transformative potential of an integrative approach to pregnancy. AB - BACKGROUND: Complex traits typically involve diverse biological pathways and are shaped by numerous genetic and environmental factors. Pregnancy-associated traits and pathologies are further complicated by extensive communication across multiple tissues in two individuals, interactions between two genomes-maternal and fetal-that obscure causal variants and lead to genetic conflict, and rapid evolution of pregnancy-associated traits across mammals and in the human lineage. Given the multi-faceted complexity of human pregnancy, integrative approaches that synthesize diverse data types and analyses harbor tremendous promise to identify the genetic architecture and environmental influences underlying pregnancy-associated traits and pathologies. METHODS: We review current research that addresses the extreme complexities of traits and pathologies associated with human pregnancy. RESULTS: We find that successful efforts to address the many complexities of pregnancy-associated traits and pathologies often harness the power of many and diverse types of data, including genome-wide association studies, evolutionary analyses, multi-tissue transcriptomic profiles, and environmental conditions. CONCLUSION: We propose that understanding of pregnancy and its pathologies will be accelerated by computational platforms that provide easy access to integrated data and analyses. By simplifying the integration of diverse data, such platforms will provide a comprehensive synthesis that transcends many of the inherent challenges present in studies of pregnancy. PMID- 28864014 TI - Glycosylation and immunocytochemistry of binucleate cells in pronghorn (Antilocapra americana, Antilocapridae) show features of both Giraffidae and Bovidae. AB - Although the pronghorn (Antilocapra americana) resembles an antelope, its nearest relatives are the giraffe and okapi. In this study we have examined the placentae of 6 pronghorns using lectin- and immunocytochemistry to identify giraffid and bovid features. Binucleate cells (BNC) of the placenta exhibited features intermediate between those of the giraffe and bovine; Dolichos biflorus agglutinin binding - strong in the bovine BNC and absent in the giraffe - was evident in only a subpopulation of BNC while binding to blood vessels, as in the giraffe. Binding of Phytolacca americana agglutinin resembled that of the giraffe and okapi whereas many other glycans were found in all four clades. PAG antigens were similar to bovine and okapi but not giraffe. In summary, although the pronghorn outwardly resembles an antelope, placental BNC show giraffid features. Although each clade has its own individual characteristics, there are far more similarities than differences between them, emphasizing the common ancestry of all four clades. PMID- 28864015 TI - Availability of COLLECT, a database for pregnancy and placental research studies worldwide. AB - Cost and availability of a database often impede research while the lack of compatibility inhibits collaboration by making merging of databases difficult or impossible. The Global Pregnancy Collaboration (CoLab) has promoted harmonization of studies and standardized data collection to facilitate pregnancy and placental research. Its online database, COLLECT, allows collection of minimal and optimal clinical datasets to accompany basic and applied science studies and provides a placental sample inventory system. COLLECT is available free of charge in LMIC and for $100 per month in HIC. Data is the property of the investigator but with permission can be combined into larger studies across centers and countries. PMID- 28864017 TI - Maternal GRB10 microdeletion is a novel cause of cystic placenta: Spectrum of genomic changes in the etiology of enlarged cystic placenta. AB - INTRODUCTION: The genetics and pathology of diploid complete and triploid partial hydatidiform moles have been well established. Enlarged cystic placenta often indicates an underlying etiology and is frequently associated with adverse pregnancy outcome. Several imprinted genes are strongly expressed in placental tissues and essential for normal placental growth and development. Disruption of these imprinted genes can lead to abnormal placental pathology and placental stunting or overgrowth. We present the genetic etiologies of five unusual mosaic cases of enlarged cystic placentas and report a novel etiology, mosaicism for deletion of the maternal GRB10 gene. METHODS: Five mosaic placental mesenchymal dysplasia cases with discrete populations of "cystic" and "normal" villi and/or atypical p57KIP2 immunostaining were evaluated by genetic analysis; including G banded karyotyping, fluorescence in situ hybridization (FISH), whole genome CGH + SNP microarray, conventional Sanger sequencing, and STR microsatellite analysis. RESULTS: Genetic etiologies ranged from genome-wide changes, including mosaic androgenetic isodisomy and mosaic diandric triploidy, to a novel microdeletion of the maternally-expressed GRB10 gene. An abnormal mosaic population of cells was also detected in the fetus in two cases. DISCUSSION: Four cases were mosaic for either diandric triploidy or an androgenetic cell population, and the enlarged cystic placentas were likely due to an excess of paternally-expressed growth promoting genes and also the absence of maternally-expressed growth restricting genes. Also we identified mosaicism for a novel microdeletion of the maternal GRB10 allele, a potent growth inhibitor, which resulted in placental overgrowth in the cystic area of one placenta. We advocate the use of ancillary techniques to investigate complex mosaic cases of enlarged cystic placentas to discover atypical genetic etiologies and to increase our understanding of the placental genome. PMID- 28864016 TI - Effects of maternal diabetes and fetal sex on human placenta mitochondrial biogenesis. AB - Abnormal placental function in maternal diabetes affects fetal health and can predispose offspring to metabolic diseases in later life. There are fetal sex specific differences in placenta structure and gene expression, which may affect placental responses to maternal diabetes. The present study examined the effects of maternal diabetes on indices of mitochondrial biogenesis in placentae from male and female offspring. Mitochondrial DNA (mtDNA) copy number and expression of key regulators of mitochondrial biogenesis were assessed in placentae from 19 diabetic and 23 non-diabetic women. The abundance of peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha) and mitochondria transcription factor A (TFAM) were lower in female placentae compared to males, but not mtDNA content. In male offspring, maternal diabetes was associated with decreased placental PGC-1alpha and TFAM, and mitochondrial DNA (mtDNA) content. Male placental TFAM levels were highly correlated with PGC-1alpha and mtDNA content. However, despite decreased PGC-1alpha, concomitant changes in TFAM and mtDNA content by diabetes were not observed in females. In addition, TFAM abundance in female placentae was not correlated with PGC-1alpha or mtDNA content. In summary, placental PGC-1alpha/TFAM/mitochondrial biogenesis pathway is affected by maternal diabetes and offspring sex. Decreased PGC-1alpha in response to maternal diabetes plausibly contributes to impaired mitochondrial biogenesis in placentae of male offspring, which may affect long-term health and explain some of enhanced risk of future metabolic diseases in males. PMID- 28864018 TI - Bovine placentomal heparanase and syndecan expression is related to placental maturation. AB - INTRODUCTION: Impaired placental maturation has been associated with retention of fetal membranes, which is a major reproductive disease in cattle. This maturation includes alterations in all tissue compartments of the placenta, specifically of epithelial and stroma cells and extracellular matrix. It is believed to be controlled by hormones, adhesion molecules and proteolytic enzymes. To investigate if the proteolytic enzyme heparanase and its substrates, the syndecans (SDCs) could be involved in the release of fetal membranes, their expression in bovine placentomes was analyzed. METHODS: Placentomes were taken from gestational day 35 until term, directly after spontaneous parturition, after preterm caesarean section, and after chemically induced parturition. Heparanase and SDCs were localized by immunohistochemistry and the respective mRNAs were quantified by qRT-PCR. Heparanase expression was additionally quantified by Western blot. RESULTS: Heparanase, SDC1 and SDC4 displayed significant changes in expression and localization depending on gestational progress and mode of parturition. All three proteins showed an expression at the end of gestation, together with an altered, predominant localization in fetal and maternal epithelia. After physiological parturition, the placentomal tissue stained weaker for all syndecans. This change in staining pattern could not be observed after induced preterm parturition. SDC2 expression did not change during the course of gestation. DISCUSSION: The changing placental expression patterns of heparanase, SDC1 and SDC4 indicate that these molecules might be involved in fetomaternal communication and placental maturation in cattle. The matrix degrading properties of heparanase could assist in a timely reduction of fetomaternal adhesion and thus promote separation of the membranes after parturition. PMID- 28864019 TI - Glyburide treatment in gestational diabetes is associated with increased placental glucose transporter 1 expression and higher birth weight. AB - Use of glyburide in gestational diabetes (GDM) has raised concerns about fetal and neonatal side effects, including increased birth weight. Placental nutrient transport is a key determinant of fetal growth, however the effect of glyburide on placental nutrient transporters is largely unknown. We hypothesized that glyburide treatment in GDM pregnancies is associated with increased expression of nutrient transporters in the syncytiotrophoblast plasma membranes. We collected placentas from GDM pregnancies who delivered at term and were treated with either diet modification (n = 15) or glyburide (n = 8). Syncytiotrophoblast microvillous (MVM) and basal (BM) plasma membranes were isolated and expression of glucose (glucose transporter 1; GLUT1), amino acid (sodium-coupled neutral amino acid transporter 2; SNAT2 and L-type amino acid transporter 1; LAT1) and fatty acid (fatty acid translocase; FAT/CD36, fatty acid transporter 2 and 4; FATP2, FATP4) transporters was determined by Western blot. Additionally, we determined GLUT1 expression by confocal microscopy in cultured primary human trophoblasts (PHT) after exposure to glyburide. Birth weight was higher in the glyburide-treated group as compared to diet-treated GDM women (3764 +/- 126 g vs. 3386 +/- 75 g; p < 0.05). GLUT1 expression was increased in both MVM (+50%; p < 0.01) and BM (+75%; p < 0.01). In contrast, MVM FAT/CD36 (-65%; p = 0.01) and FATP2 (-65%; p = 0.02) protein expression was reduced in mothers treated with glyburide. Glyburide increased membrane expression of GLUT1 in a dose-dependent manner in cultured PHT. This data is the first to show that glyburide increases GLUT1 expression in syncytiotrophoblast MVM and BM in GDM pregnancies, and may promote transplacental glucose delivery contributing to fetal overgrowth. PMID- 28864020 TI - Pre-clinical evaluation of a nanoparticle-based blood-pool contrast agent for MR imaging of the placenta. AB - INTRODUCTION: Non-invasive 3D imaging that enables clear visualization of placental margins is of interest in the accurate diagnosis of placental pathologies. This study investigated if contrast-enhanced MRI performed using a liposomal gadolinium blood-pool contrast agent (liposomal-Gd) enables clear visualization of the placental margins and the placental-myometrial interface (retroplacental space). Non-contrast MRI and contrast-enhanced MRI using a clinically approved conventional contrast agent were used as comparators. MATERIALS AND METHODS: Studies were performed in pregnant rats under an approved protocol. MRI was performed at 1T using a permanent magnet small animal scanner. Pre-contrast and post-liposomal-Gd contrast images were acquired using T1 weighted and T2-weighted sequences. Dynamic Contrast enhanced MRI (DCE-MRI) was performed using gadoterate meglumine (Gd-DOTA, Dotarem(r)). Visualization of the retroplacental clear space, a marker of normal placentation, was judged by a trained radiologist. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated for both single and averaged acquisitions. Images were reviewed by a radiologist and scored for the visualization of placental features. Contrast enhanced CT (CE-CT) imaging using a liposomal CT agent was performed for confirmation of the MR findings. Transplacental transport of liposomal-Gd was evaluated by post-mortem elemental analysis of tissues. Ex-vivo studies in perfused human placentae from normal, GDM, and IUGR pregnancies evaluated the transport of liposomal agent across the human placental barrier. RESULTS: Post contrast T1w images acquired with liposomal-Gd demonstrated significantly higher SNR (p = 0.0002) in the placenta compared to pre-contrast images (28.0 +/- 4.7 vs. 6.9 +/- 1.8). No significant differences (p = 0.39) were noted between SNR in pre-contrast and post-contrast liposomal-Gd images of the amniotic fluid, indicating absence of transplacental passage of the agent. The placental margins were significantly (p < 0.001) better visualized on post-contrast liposomal-Gd images. DCE-MRI with the conventional Gd agent demonstrated retrograde opacification of the placenta from fetal edge to the myometrium, consistent with the anatomy of the rat placenta. However, no consistent and reproducible visualization of the retroplacental space was demonstrated on the conventional Gd enhanced images. The retroplacental space was only visualized on post-contrast T1w images acquired using the liposomal agent (SNR = 15.5 +/- 3.4) as a sharply defined, hypo-enhanced interface. The retroplacental space was also visible as a similar hypo-enhancing interface on CE-CT images acquired using a liposomal CT contrast agent. Tissue analysis demonstrated undetectably low transplacental permeation of liposomal-Gd, and was confirmed by lack of permeation through a perfused human placental model. CONCLUSIONS: Contrast-enhanced T1w-MRI performed using liposomal-Gd enabled clear visualization of placental margins and delineation of the retroplacental space from the rest of the placenta; the space is undetectable on non-contrast imaging and on post-contrast T1w images acquired using a conventional, clinically approved Gd chelate contrast agent. PMID- 28864022 TI - Child neurodevelopmental outcomes following preterm and term birth: What can the placenta tell us? AB - A significant proportion of children born preterm will experience some level of neurodevelopmental impairment. Changes in placental function have been observed with many antenatal conditions that are risk factors for preterm birth and/or poor neurodevelopment including fetal growth restriction and in-utero inflammation. This review will highlight placental factors that have been studied to understand the underlying mechanisms and identify biomarkers that lead to poor child neurodevelopmental outcomes. These include changes in gross morphological and histopathological structure and the placental inflammatory response to prenatal infection. Further, we will describe the placenta's role as both a barrier to maternally-derived bioactive substances critical for normal fetal brain development, such as cortisol, and a source of neuroactive steroids and neurotrophins known to have critical functions in neuronal proliferation, axonal growth, myelination and the regulation of apoptosis. Finally, emerging data supporting the potential utility of novel placental biomarkers in the early prediction of poor neurodevelopmental outcome in infants born both preterm and term will be discussed. These include the assessment of genetic variants (e.g. single nucleotide polymorphisms in placental tissue) and epigenetic biomarkers (e.g. placental microRNAs and placental DNA methylation). With the placenta the key tissue regulating the fetal environment, integration of observed changes in placental function with genetic and epigenetic variations may advance our ability to predict future infant health. Ultimately, this may facilitate targeted allocation of health resources with the aim of improving lifelong neurodevelopmental capability. PMID- 28864021 TI - The core transcriptome of mammalian placentas and the divergence of expression with placental shape. AB - INTRODUCTION: The placenta is arguably the most anatomically variable organ in mammals even though its primary function is conserved. METHOD: Using RNA-Seq, we measured the expression profiles of 55 term placentas of 14 species of mammals representing all major eutherian superordinal clades and marsupials, and compared the evolution of expression across clades. RESULTS: We identified a set of 115 core genes which is expressed (FPKM >=10) in all eutherian placentas, including genes with immune-modulating properties (ANXA2, ANXA1, S100A11, S100A10, and LGALS1), cell-cell interactions (LAMC1, LUM, and LGALS1), invasion (GRB2 and RALB) and syncytialization (ANXA5 and ANXA1). We also identified multiple pre eclampsia associated genes which are differentially expressed in Homo sapiens when compared to the other 13 species. Multiple genes are significantly associated with placenta morphology, including EREG and WNT5A which are both associated with placental shape. DISCUSSION: 115 genes are important for the core functions of the placenta in all eutherian species analyzed. The molecular functions and pathways enriched in the core placenta align with the evolutionarily conserved functionality of the placenta. PMID- 28864024 TI - Hemodynamic analysis of blood flow in umbilical artery using computational modeling. AB - The umbilical cord is the crucial pathway for blood flow between the fetus and the placenta. Umbilical coiling and length have been separately linked to adverse clinical outcomes; however, the effects of variations of these parameters on umbilical arterial blood flow are not well understood. Using 3D computational model, we studied the individual and combined effects of umbilical coiling index, cord length and arterial diameter on umbilical artery hemodynamics. We found that specific combinations of umbilical coiling index, cord length and arterial diameter yielded pressure and flow drops incompatible with fetal life. Such models are useful as hypothesis-developing tools. PMID- 28864023 TI - Clinicoplacental correlates of amniocyte vacuolization in association with gastroschisis. AB - INTRODUCTION/OBJECTIVES: Gastroschisis has been associated with a characteristic type of amniocyte vacuolization. In this study, we determined the frequency and clinicoplacental correlates of this apparently unique alteration of the amniotic epithelium. METHODS: We performed a retrospective clinicopathologic analysis of 74 consecutive cases of isolated gastroschisis. Placental membrane sections were reviewed for presence and extent of amniocyte vacuolization, and immunostained for adipophilin, a lipid droplet-associated protein. Controls included placentas from pregnancies complicated by omphalocele, meconium exposure or chorioamnionitis. RESULTS: A distinct type of diffuse, fine and homogeneous amniocyte vacuolization was present in 15/74 (20%), absent in 41/74 (55%), and equivocal in 18/74 (24%) gastroschisis cases. Similar amniocyte vacuolization was seen in only 1/30 meconium-stained controls, and in none of the other non gastroschisis controls. Adipophilin immunostaining enhanced the visualization of the cytoplasmic vacuoles and confirmed their lipid nature. Compared to gastroschisis cases without such vacuolization, cases with typical, extensive amniocyte vacuolization had a tendency to lower birth weight percentile (26% versus 40%; P < 0.08), a significantly lower fetal:placental weight ratio (4.72 versus 5.51; P < 0.01), and a significantly higher frequency of associated meconium exposure (14/15 versus 15/41, P < 0.001) and/or chorioamnionitis (8/15 versus 6/41; P < 0.01). The length of hospital stay was equivalent for infants with or without amniocyte vacuolization. CONCLUSION: Diffuse, fine and homogeneous lipid droplet accumulation in amniocytes is highly characteristic of gastroschisis, but only seen in about 20% of cases. The functional implications of excessive lipid accumulation, and the exact mechanisms underlying the strong association between amniocyte lipid accumulation and chorioamnionitis/meconium exposure in a subset of gastroschisis cases remain undetermined. PMID- 28864025 TI - Birth weight, umbilical and placental traits in relation to neonatal loss in cloned pigs. AB - Cloned piglets generated through somatic cell nuclear transfer (SCNT) have a high rate of neonatal death. Postnatal loss is associated with low birth weight, umbilical status and placental parameters in fertilisation-derived piglets. To investigate whether or not this relationship also exists in cloned piglets, birth weight, umbilical status, placental parameters, placental morphology and gene expression pattern were compared among four piglet groups, namely, SCNT-derived male piglets that died within 4 days (SCNT-DW4), SCNT-derived male piglets that survived over 4 days (SCNT-SO4), artificial insemination (AI)-generated male piglets that died within 4 days (AI-DW4) and AI-generated male piglets that survived over 4 days (AI-SO4). Results showed that the occurring frequency of abnormal umbilical cord in SCNT-DW4 piglets was significantly higher than that in AI-SO4 piglets but was similar to that in SCNT-SO4 and AI-DW4 piglets. The birth weight, placental surface area and placental weight of AI-SO4, AI-DW4 and SCNT SO4 groups were similar but were significantly higher than those in SCNT-DW4 group. SCNT-SO4 placentas exhibited mild but SCNT-DW4 placentas showed severe morphological abnormalities compared with AI-SO4 placentas. The expression profiles of imprinting, angiopoiesis, nutrient transport, apoptosis and oxidative stress-related genes in SCNT-DW4 placentas were erroneous compared with those in SCNT-SO4 and AI-SO4 placentas, which both had similar gene expression patterns. These results indicate that birth weight, umbilical status, placental parameters, placental morphology and gene expression were associated with neonatal death of cloned piglets. The high loss of cloned piglets during neonatal age may be caused by severe deficiency of extra-embryonic development during prenatal stage. PMID- 28864026 TI - Cardiac cycle-induced EPI time series fluctuations in the brain: Their temporal shifts, inflow effects and T2* fluctuations. AB - The cardiac-induced arterial pressure wave causes changes in cerebral blood flow velocities and volumes that affect the signals in echo-planar imaging (EPI). Using single-echo EPI time series data, acquired fast enough to unalias the cardiac frequency, we found that the cardiac cycle-induced signal fluctuations are delayed differentially in different brain regions. When referenced to the time series in larger arterial structures, the cortical voxels are only minimally shifted but significant shifts are observed in subcortical areas. Using double echo EPI data we mapped the voxels' "signal at zero echo time", S0, and apparent T2* over the cardiac cycle. S0 pulsatility was maximised for voxels with a cardiac cycle-induced timing that was close to the arterial structures and is likely explained by enhanced inflow effects in the cortical areas compared to subcortical areas. Interestingly a consistent T2* waveform over the cardiac cycle was observed in all voxels with average amplitude ranges between 0.3-0.55% in grey matter and 0.15-0.22% in white matter. The timing of the T2* waveforms suggests a partial volume fluctuation where arteriolar blood volume changes are counterbalanced by changes in CSF volumes. PMID- 28864028 TI - Convergence of carbapenem-resistance and hypervirulence in Klebsiella pneumoniae. PMID- 28864027 TI - Efficacy and safety of tribendimidine, tribendimidine plus ivermectin, tribendimidine plus oxantel pamoate, and albendazole plus oxantel pamoate against hookworm and concomitant soil-transmitted helminth infections in Tanzania and Cote d'Ivoire: a randomised, controlled, single-blinded, non-inferiority trial. AB - BACKGROUND: Preventive chemotherapy is the current strategy to control soil transmitted helminth infections (caused by Ascaris lumbricoides, hookworm, and Trichuris trichiura). But, to improve efficacy and avoid emerging resistance, new drugs are warranted. Tribendimidine has shown good anthelmintic efficacy and is therefore a frontrunner for monotherapy and combination chemotherapy. METHODS: We did a randomised, controlled, single-blinded, non-inferiority trial on Pemba Island, Tanzania, and in Cote d'Ivoire. We recruited adolescents aged 15-18 years from four primary schools on Pemba, and school attendees and non-schoolers from two districts in Cote d'Ivoire. Only hookworm-positive participants were randomly assigned (1:1:1:1) to single, oral doses of tribendimidine 400 mg plus placebo (tribendimidine monotherapy), tribendimidine 400 mg plus ivermectin 200 MUg/kg, tribendimidine 400 mg plus oxantel pamoate 25 mg/kg, or albendazole 400 mg plus oxantel pamoate 25 mg/kg. Randomisation was done via a computer-generated list in block sizes of four or eight. Participants were asked to provide two stool samples on 2 consecutive days at baseline and again 14-21 days at follow-up. The primary outcome was the difference in egg-reduction rates (ERRs; ie, the geometric mean reduction) in hookworm egg counts between treatment groups, measured by the Kato-Katz technique. Differences in coadministrated treatment groups were assessed for non-inferiority with a margin of -3% to albendazole plus oxantel pamoate based on the available-case population, analysed by intention to treat. Safety was assessed 3 h and 24 h after treatment. This study is registered with ISRCTN (number 14373201). FINDINGS: Between July 26, and Dec 23, 2016, we treated 636 hookworm-positive participants, and outcome data were available for 601 participants (151 assigned to tribendimidine monotherapy, 154 to tribendimidine plus ivermectin, 148 to tribendimidine plus oxantel pamoate, and 148 to albendazole plus oxantel pamoate). Tribendimidine plus ivermectin was non inferior to albendazole plus oxantel pamoate (ERRs 99.5% [95% CI 99.2-99.7] vs 96.0% [93.9-97.4]; difference 3.52 percentage points [2.05-5.65]). Likewise, tribendimidine plus oxantel pamoate was non-inferior to albendazole plus oxantel pamoate (ERRs 96.5% [95% CI 94.9 to 97.6] vs 96.0% [93.9 to 97.4]; difference 0.48 percentage points [-1.61 to 2.88]). 3 h after treatment, headache (n=50 [8%]) and vertigo (n=37 [6%]) were the most widely reported symptoms; 24 h after treatment, 50 (8%) patients reported vertigo and 41 (7%) reported headache. Mainly mild adverse events were reported with peak numbers (n=111 [18%]) at 24 h after treatment. Three participants had moderate adverse events 3 h after treatment: two (<1%) had vertigo and one (<1%) had headache, and two had moderate adverse events 24 h after treatment: one (<1%) had vomiting and one (<1%) had vomiting plus diarrhoea. INTERPRETATION: Tribendimidine in combination with either ivermectin or oxantel pamoate had a similar, non-inferior efficacy profile as albendazole plus oxantel pamoate, hence tribendimidine will be a useful addition to the depleted anthelmintic drug armamentarium. FUNDING: Swiss National Science Foundation. PMID- 28864029 TI - Global deworming: moving past albendazole and mebendazole. PMID- 28864030 TI - A fatal outbreak of ST11 carbapenem-resistant hypervirulent Klebsiella pneumoniae in a Chinese hospital: a molecular epidemiological study. AB - BACKGROUND: Hypervirulent Klebsiella pneumoniae strains often cause life threatening community-acquired infections in young and healthy hosts, but are usually sensitive to antibiotics. In this study, we investigated a fatal outbreak of ventilator-associated pneumonia caused by a new emerging hypervirulent K pneumoniae strain. METHODS: The outbreak occurred in the integrated intensive care unit of a new branch of the Second Affiliated Hospital of Zhejiang University (Hangzhou, China). We collected 21 carbapenem-resistant K pneumoniae strains from five patients and characterised these strains for their antimicrobial susceptibility, multilocus sequence types, and genetic relatedness using VITEK-2 compact system, multilocus sequence typing, and whole genome sequencing. We selected one representative isolate from each patient to establish the virulence potential using a human neutrophil assay and Galleria mellonella model and to establish the genetic basis of their hypervirulence phenotype. FINDINGS: All five patients had undergone surgery for multiple trauma and subsequently received mechanical ventilation. The patients were aged 53-73 years and were admitted to the intensive care unit between late February and April, 2016. They all had severe pneumonia, carbapenem-resistant K pneumoniae infections, and poor responses to antibiotic treatment and died due to severe lung infection, multiorgan failure, or septic shock. All five representative carbapenem-resistant K pneumoniae strains belonged to the ST11 type, which is the most prevalent carbapenem-resistant K pneumoniae type in China, and originated from the same clone. The strains were positive on the string test, had survival of about 80% after 1 h incubation in human neutrophils, and killed 100% of wax moth larvae (G mellonella) inoculated with 1 * 106 colony-forming units of the specimens within 24 h, suggesting that they were hypervirulent K pneumoniae. Genomic analyses showed that the emergence of these ST11 carbapenem-resistant hypervirulent K pneumoniae strains was due to the acquisition of a roughly 170 kbp pLVPK-like virulence plasmid by classic ST11 carbapenem-resistant K pneumoniae strains. We also detected these strains in specimens collected in other regions of China. INTERPRETATION: The ST11 carbapenem-resistant hypervirulent K pneumoniae strains pose a substantial threat to human health because they are simultaneously hypervirulent, multidrug resistant, and highly transmissible. Control measures should be implemented to prevent further dissemination of such organisms in the hospital setting and the community. FUNDING: Chinese National Key Basic Research and Development Program and Collaborative Research Fund of Hong Kong Research Grant Council. PMID- 28864031 TI - Comparison of Wound Complications and Deep Infections With Direct Anterior and Posterior Approaches in Obese Hip Arthroplasty Patients. AB - BACKGROUND: The purpose of this study was to compare the posterior approach (PA) with the direct anterior approach (DAA) among obese and nonobese total hip arthroplasty patients to determine if obese DAA patients have a higher risk of infection or wound complications compared with obese PA patients. METHODS: We retrospectively evaluated 4651 primary total hip cases performed via anterior approach or PA between 2009 and 2015. Patients were divided into 4 study groups based on approach and body mass index (BMI): (1) DAA <35 kg/m2, (2) DAA >=35 kg/m2, (3) PA <35 kg/m2, and (4) PA >=35 kg/m2. Infection rates and wound complications were compared. RESULTS: The rate of deep infection in groups 1 and 3 (nonobese anterior vs posterior) was 0.28% and 0.36%, respectively (P = .783); and in groups 2 and 4 (obese anterior vs posterior) was 2.35% and 2.7%, respectively (P = .80). The rate of wound complications between groups 1 and 3 (nonobese) was 1.0% and 0.3%, respectively (P = .005). Between groups 2 and 4 (obese), the rates of complications were 1.7% and 1.4%, respectively (P = 1.0). There was no difference in reoperation rates for wounds between groups 1 and 3 or between groups 2 and 4 (P = .217, P = .449). CONCLUSION: In the largest available series, there was no difference in deep infection rates between the 2 approaches. In the subset of obese patients with BMI >=35 kg/m2, there was no increased risk of deep infection or wound complications in DAA patients compared with PA patients. However, anterior hip cases experienced higher rates of superficial wound complications compared with posterior cases across all BMIs. PMID- 28864032 TI - In memory of Norman Bowery (1944-2016). AB - This article is in memory of Professor Norman Bowery (1944-2016). Norman was a pharmacologist who spent most of his career researching the pharmacology of gamma aminobutyric acid (GABA). He discovered a novel metabotropic receptor subtype, GABAB, that is pharmacologically, and structurally different from the original ionotropic receptor now designated as GABAA. In his research he also studied the neurotransmitters glutamate and substance P, two molecules whose release in parts of the spinal cord is inhibited by baclofen a GABAB receptor agonist. Norman was interested in the therapeutic potential of interacting with the GABAB receptor, in particular spasticity, pain and absence epilepsy. PMID- 28864034 TI - A Service Commitment to Fund Your Medical Education. PMID- 28864033 TI - Characterising the effect of antimalarial drugs on the maturation and clearance of murine blood-stage Plasmodium parasites in vivo. AB - The artemisinins are the first-line therapy for severe and uncomplicated malaria, since they cause rapid declines in parasitemia after treatment. Despite this, in vivo mechanisms underlying this rapid decline remain poorly characterised. The overall decline in parasitemia is the net effect of drug inhibition of parasites and host clearance, which competes against any ongoing parasite proliferation. Separating these mechanisms in vivo was not possible through measurements of total parasitemia alone. Therefore, we employed an adoptive transfer approach in which C57BL/6J mice were transfused with Plasmodium berghei ANKA strain-infected, fluorescent red blood cells, and subsequently drug-treated. This approach allowed us to distinguish between the initial drug-treated generation of parasites (Gen0), and their progeny (Gen1). Artesunate efficiently impaired maturation of Gen0 parasites, such that a sufficiently high dose completely arrested maturation after 6h of in vivo exposure. In addition, artesunate-affected parasites were cleared from circulation with a half-life of 6.7h. In vivo cell depletion studies using clodronate liposomes revealed an important role for host phagocytes in the removal of artesunate-affected parasites, particularly ring and trophozoite stages. Finally, we found that a second antimalarial drug, mefloquine, was less effective than artesunate at suppressing parasite maturation and driving host mediated parasite clearance. Thus, we propose that in vivo artesunate treatment causes rapid decline in parasitemia by arresting parasite maturation and encouraging phagocyte-mediated clearance of parasitised RBCs. PMID- 28864035 TI - The 2017 Match and the Future US Workforce. PMID- 28864036 TI - Aerobic Training Effect on Arterial Stiffness in Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome, physical inactivity, and central obesity contribute to early vascular aging, which leads to increased risk of cardiovascular disease. This study aimed to assess the effect of heart rate (HR) targeted aerobic exercise training on the indices of early vascular aging, in particular, arterial stiffness, and on anthropometric and clinical profile of metabolic syndrome subjects. METHODS: There were 126 metabolic syndrome subjects randomly selected. Anthropometric parameters, blood pressure (BP), blood sample, and arterial wall functional and structural parameters were obtained prior to and after the 8-week (84 patients) supervised training program. The age- and sex matched control group (42 patients) followed the same protocol, except for the HR targeted training program. RESULTS: In the study group, HR-targeted training was associated with decreased aortic pulse wave velocity (8.47 +/- 1.40 vs 8.01 +/- 1.06 m/s; P = .005), HR (P < .001), systolic (P < .015) and diastolic (P < .004) BP, waist circumference (P < .004), total and low-density-lipid cholesterol (respectively, 6.42 +/- 1.41 vs 5.89 +/- 1.32, P = .003 and 4.2 +/- 1.18 vs 3.8 +/- 1.21, P = .002), and an increase in aerobic capacity (P < .001). In the control group there were no statistically significant changes of arterial stiffness parameters. Multivariate analysis revealed that reduction of arterial stiffness was BP dependent. CONCLUSIONS: In subjects with metabolic syndrome, HR targeted exercise training is associated with BP-dependent decrease in aortic stiffness and improvement of metabolic and fitness parameters. PMID- 28864037 TI - Utility of T1- and T2-Weighted High-Resolution Vessel Wall Imaging for the Diagnosis and Follow Up of Isolated Posterior Inferior Cerebellar Artery Dissection with Ischemic Stroke: Report of 4 Cases and Review of the Literature. AB - BACKGROUND: An accurate diagnosis of isolated posterior inferior cerebellar artery dissection (iPICA-D) is difficult due to the limitation of spatial resolution on conventional magnetic resonance imaging (MRI) techniques to detect subtle vessel wall abnormalities. The recent development of MRI techniques, including high-resolution vessel wall imaging (HRVWI), has resulted in the improved diagnostic accuracy and efficiency of iPICA-D. In fact, T1-weighted HRVWI, which can reveal intramural hematomas in the posterior inferior cerebellar artery (PICA), is useful for the diagnosis of iPICA-D. However, the utility of T2 weighted HRVWI has not been previously reported. The aim of this study was to investigate the diagnostic utility of T1- and T2-weighted HRVWI for the diagnosis of iPICA-D. METHODS: We retrospectively evaluated MRI findings including intramural hematomas, dilations, and chronological changes in 4 patients with iPICA-D admitted to our hospital and related facility from January 2015 to August 2016. In addition to T1-weighted HRVWI, T2-weighted HRVWI was performed on isovoxel three-dimensional (3D) fast spin-echo or 3D sampling perfection with application-optimized contrast using different flip-angle evolution. We also reviewed cases of nonhemorrhagic iPICA-D with ischemic onset in which the MRI findings were described. RESULTS: In all 4 patients, in addition to the intramural hematomas on T1-weighted HRVWI, T2-weighted HRVWI clearly showed the fusiform dilation of the external diameter of the PICA. T2-weighted HRVWI was more useful than other techniques, including T1-weighted HRVWI, for the evaluation of arterial shape changes. CONCLUSIONS: Like T1-weighted HRVWI, T2 weighted HRVWI is useful for the diagnosis and assessment of chronological changes in vessel wall abnormalities during the follow-up period. PMID- 28864038 TI - Radiologically Isolated Cerebral Amyloid Angiopathy-Related Inflammation. AB - In amyloid beta-related angiitis of the central nervous system (also called cerebral amyloid angiopathy-related inflammation), cerebral amyloid angiopathy occurs in association with primary vasculitis of small- and medium-sized leptomeningeal and cortical arteries. To avoid brain biopsy, clinicoradiological criteria (including clinical features due to inflammation-related uni/multifocal white matter hyperintensities) for the diagnosis of cerebral amyloid angiopathy related inflammation have been validated recently. We report 3 cases with acute symptoms directly related to cerebral amyloid angiopathy in the presence of asymptomatic cerebral amyloid angiopathy-related inflammation hyperintensities on initial magnetic resonance imaging. Recognizing radiological features of cerebral amyloid angiopathy-related inflammation in patients with cerebral amyloid angiopathy is important because radiological isolated cerebral amyloid angiopathy related inflammation may become symptomatic and immunosuppressive treatment is often effective in cerebral amyloid angiopathy-related inflammation, although optimal treatment regimen is yet unknown. In contrast, apart from hypertension treatment, few therapeutic options exist in cerebral amyloid angiopathy. PMID- 28864039 TI - Conceiving of addicted pleasures: A 'modern' paradox. AB - Drawing on research with people who inject drugs in London, UK, this article will explore how participants conceived of pleasure, and try to understand some of the tensions that ensued. There is a strong sense in participants' accounts that drug use is at points pleasurable but it should not, or rather, could not be conceived of in this way. As such, the article will reflect on several situations in which pleasure came up during fieldwork but was quickly redirected towards addiction using terms such as 'denial'. Trying to make sense of this seemingly paradoxical dynamic, in which pleasure can be addictive, but addiction cannot be pleasurable, I turn to some of the practices that actively keep pleasure and addiction apart, indeed, in some areas of the addiction sciences, antithetical. That is, a singular account of pleasure is produced as freely chosen (of the 'free' subject) in opposition to the determined nature of addiction (of the automated brain or object). These realities materialise in participants' accounts, but due to their constructed nature they also collapse and multiply. This 'hybridisation' is what Bruno Latour refers to as the paradox of the Moderns. Considering pleasure, however, as both natural and cultural, it is better conceived of as always in tension, expressed by participants as 'mixed feelings', 'love/hate', 'sweet and sour', 'good things and bad things'. Against a backdrop of neglect, especially within the context of injecting drug use, such conceptualisation can help acknowledge pleasure where it is least conceivable and yet perhaps has the most to offer. PMID- 28864040 TI - Sundarbanxylogranins A-E, five new limonoids from the Sundarban Mangrove, Xylocarpus granatum. AB - Five new limonoids, named sundarbanxylogranins A-E (1-5), were isolated from the seeds of an Indian mangrove, Xylocarpus granatum, collected from mangrove swamps of the Sundarbans, India. The structures of these limonoids were established by HRESIMS and NMR spectroscopic data. Sundarbanxylogranin A (1) is a rare limonoid containing a bicyclo[5.2.1]dec-3-en-8-one scaffold as the ring A/B-fused core; whereas sundarbanxylogranin B (2) is a typical mexicanolide with an 8alpha, 30alpha-epoxy ring. Sundarbanxylogranins C-E (3-5), among which the former two possess a 29-OMe group with different orientation, belong to a small group of limonoids containing a C1-O-C29 oxygen bridge. Sundarbanxylogranin B exhibited moderate anti-HIV activity with an IC50 value of 23.14+/-1.29MUM and a CC50 value of 78.45+/-1.69MUM, respectively. PMID- 28864041 TI - Abietane diterpenoids from Sideritis montana L. and their antiproliferative activity. AB - The present study aimed at the phytochemical and pharmacological investigation of Sideritis montana L. (Lamiaceae). Two new abietane diterpenes [sideritins A (1) and B (2)] were isolated from the methanol extract of the plant. Six known compounds [pomiferin E (3), 9alpha,13alpha-epi-dioxyabiet-8(14)-en-18-ol (4), paulownin (5), 6-methoxysakuranetin (6), 3-oxo-alpha-ionol (7) and 4-allyl-2,6 dimethoxyphenol glucoside (8)] were also obtained from the plant. The structures were determined by means of HREIMS and NMR experiments. The antiproliferative effect of the isolated compounds was investigated on human cancer cell lines (HeLa, SiHa and C33A) at 10 and 30MUM concentrations, using the MTT assay. The results demonstrated that pomiferin E (3) and 6-methoxysakuranetin (6) displayed considerable activity [inhibition (%)+/-SEM: 46.93+/-2.35 on HeLa (pomiferin E), and 51.52+/-2.45 on C33A (6-methoxysakuranetin)] at 30MUM concentration. PMID- 28864042 TI - Colectomy in refractory Crohn's colitis improves nutrition and reduces steroid use. AB - BACKGROUND: Pediatric patients with severe refractory Crohn's colitis (CC) may require total colectomy (TC) or diverting loop ileostomy (DLI). Our understanding of outcomes (postoperative complications, nutrition and restoration of intestinal continuity) is currently limited. METHODS: Pediatric patients with severe CC who underwent TC or DLI were identified. Demographics, pre and postoperative anthropometric and biochemical data, surgical complications and medication requirements were recorded. RESULTS: Twenty-seven patients (TC=22, DLI=5) with a median age of 15.0years (range 3-18) were identified, 64% male with a median follow-up of 45months (range 3-120). Mean weight and BMI improved for TC patients by 1year postoperatively - weight z-score from -1.08 to -0.54 (p=0.02), BMI z score from -0.83 to -0.38 (p=0.04), with a non-significant height change from - 0.79 to -0.65 (p=0.07). Mean hemoglobin and albumin both also improved - 9.88g/dl to 11.76g/dl (p=0.003) and 3.44g/dl to 4.03g/dl (p=0.004) respectively. These measures did not significantly improve after DLI. Most TC patients (59%) had attempted restoration of intestinal continuity with 45% in continuity at end of follow-up. One DLI patient underwent ileostomy takedown but subsequently needed re-diversion. CONCLUSIONS: In severe CC, TC offers an opportunity to improve nutrition and growth, with a reasonable likelihood of restoring intestinal continuity. LEVEL OF EVIDENCE: Level IV - Case series. PMID- 28864043 TI - Development of an immunochromatographic strip for detection of antibodies against duck Tembusu virus. AB - Duck Tembusu virus (DTMUV), a novel flavivirus, causes severe disease in ducks. There is an urgent need for a rapid and effective diagnostic method to control the spread of DTMUV. We chose the envelope (E) protein from DTMUV as an antigen and combined it with colloidal gold particles as tracers to specifically detect anti-DTMUV antibodies. Based on the double-antigen sandwich format, an immunochromatographic strip (ICS) for the rapid detection of anti-DTMUV antibodies was developed. The ICS showed a high specificity and no cross reactivity with other sera. By detecting a serially diluted duck anti-DTMUV serum, the sensitivity of the ICS was 16-fold higher than that of the agar gel double diffusion test. Moreover, the ICS was both stable and reproducible, maintaining the same performance at 4 degrees C for at least 6 months. To evaluate the effectiveness of the ICS, 217 duck serum samples were tested with the ICS and an indirect enzyme-linked immunosorbent assay (iELISA). The consistency ratio of positive and negative results between the two methods was 97.87% and 97.06%, respectively. The agreement between the ICS and the ELISA was 97.24%. The ICS developed in this study offers a specific, sensitive, and rapid method to detect anti-DTMUV antibodies. PMID- 28864044 TI - Transvaginal Ultrasound for the Diagnosis of Adenomyosis: Systematic Review and Meta-Analysis. AB - Adenomyosis is characterized by the presence of ectopic foci of endometrial glandular tissue and/or stroma within the myometrium. The diagnosis of adenomyosis is traditionally made through histologic evaluation of the postsurgical specimen. More recently, imaging with transvaginal ultrasound (TVUS) has been used for the preoperative diagnosis of adenomyosis. As yet, there is no consensus regarding the best imaging feature or combination thereof for the nonsurgical diagnosis of adenomyosis. This study systematically evaluated the literature in the last 10 years to determine the accuracy of 2-dimensional (2D) TVUS, different imaging features, enhancing methods such as 3-dimensional (3D) TVUS, elastography and color Doppler in the nonsurgical diagnosis of adenomyosis. A total of 8 studies were included. Pooled sensitivity and specificity for 2D TVUS for the diagnosis of adenomyosis for all combined imaging characteristics was 83.8% and 63.9%, respectively. Pooled sensitivity for 355 total patients with use of imaging feature of heterogeneous myometrium with 2D TVUS was highest (86.0%), and pooled specificity for 283 total patients with use of globular uterus was highest (78.1%). After including the "question mark" sign with other TVUS features, higher sensitivity and specificity, of 92% and 88%, respectively, were noted. For 3D TVUS, pooled sensitivity and specificity for all combined imaging characteristics was 88.9% and 56.0%, respectively. Poor definition of junctional zone showed the highest pooled sensitivity (86%) and the highest pooled specificity (56.0%) for the diagnosis of adenomyosis with 3D TVUS. There was no improvement in overall accuracy in 3D TVUS compared with 2D TVUS. Preliminary results of TVUS with color Doppler showed a high sensitivity and specificity for the differentiation between adenomyosis and myomas (95.6% and 93.4%, respectively). Also, TVUS elastography in 1 study showed an improvement in specificity (82.9%) compared with 2D TVUS (63.9%), albeit with comparable sensitivity. Larger studies are needed to advance our understanding of the different types of adenomyosis and their clinical impact. PMID- 28864045 TI - Three-Dimensional Ultrasound Imaging of Deep Infiltrating Endometriotic Lesions of the Bowel. PMID- 28864046 TI - [Radiotherapy for head and neck squamous cell carcinoma: State of the art and future directions]. AB - Therapeutic principles of radiation therapy in head and neck carcinomas will be discussed in this review. Intensity-modulated radiotherapy with concomitant cisplatin should be standard. In case of contraindication to chemotherapy, cetuximab is an option, while hyperfractionation should be considered in patients unfit for concomitant treatment. Concomitant chemotherapy should be administered in the presence of extracapsular extensions and positive margins in the postoperative setting. Current research areas such as desescalation in human papillomavirus-positive tumours, adaptive radiotherapy, radiomics and immunotherapy will also be addressed. PMID- 28864048 TI - [Who can be dismissed in rectal cancer management?] AB - Dramatic progress has deeply moved rectal cancer management. Tailoring of treatment allow to select participants according to initial prognostic factors (radiotherapist) or tumoral response (surgeon). Today, this management must keep in mind tumoral initial staging, prognostic at the time of diagnosis, tumoral response and characteristic, and patient's motivation. The result of this patient care is more than oncologic, it is also functional. PMID- 28864047 TI - [Combination external beam radiation and brachytherapy boost for prostate cancer]. AB - Brachytherapy as sole treatment is standard of care for D'Amico classification low-risk prostate cancer. For intermediate and high-risk patients, brachytherapy can be associated to external beam radiation therapy to better take into account the risk of extracapsular effraction and/or seminal vesicle involvement. Three randomized studies have shown that this association increases freedom from relapse survival compared to exclusive external beam radiation therapy. This benefit is not shown for overall survival. The addition of a hormonal therapy to this association is most likely mandatory for high-risk patients, and needs to be confirmed for intermediate risk patients. Both high-dose rate and low-dose rate brachytherapy are suitable with similar biochemical disease free survival rates. High-dose rate brachytherapy seems to have a better genitourinary tolerance profile, while low-dose rate brachytherapy is an easier process and has a more widespread expertise. PMID- 28864049 TI - Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) or "Coats Plus": when peripheral retinal vasculature signals neurologic disease. AB - An 8-month-old girl presented with vitreous hemorrhage, peripheral retinal arteriovenous anastomosis, and hypoplasia of the thumb. Magnetic resonance imaging of the brain showed multiple hyperintensities, cysts, and calcifications in the white matter. DNA testing showed a mutation in one allele of the CTC gene, supporting the diagnosis of cerebroretinal microangiopathy with calcifications and cysts (CRMCC), or Coats plus disease, despite which designation this condition can present without subretinal exudate. In infants with peripheral retinal vascular disease, neuroimaging can identify the characteristic abnormalities of CRMCC. PMID- 28864050 TI - [Pap Smear after 65 years]. AB - The French recommendations (in favor of stopping cervical cancer screening by cervico-uterine smear from 65 years of age) are logical in the context of organized screening; however, it is not yet generalized in France. The proportion of invasive cervical cancer in the oldest patients is high and these cancers are more evolved and have a more pejorative prognosis. The prevalent infection with high-risk HPV virus remains important in elderly patients: if the HPV infection does not appear to be more risky in the elderly, HPV-induced lesions appear to be more evolving. Unfortunately, pap smear coverage rates are low in the most advanced age groups. Patients without adequate follow-up are exposed to invasive cancer after age 65: all studies insist on the protective effect of two or more normal pap smears between 50 and 65 years that would allow to stop screening. Recent publications in Europe insist, however, on the value of continuing screening beyond the age of 65 in populations that live longer. For the clinician, in France, patients who could benefit from systematic FCU after age 65 could be those: (1) who request it, (2) who have an HPV history, (3) who have not had more than 3 consecutive normal pap smears or (4) who have an associated pathogenic condition. The place of the HPV test deserves to be considered: because of its very high negative predictive value, it could be performed as an exit test or as an alternative test to the pap smear. PMID- 28864051 TI - [Bowel endometriosis and infertility: Do we need to operate?] AB - Endometriosis is a benign chronic inflammatory disease, whose pathogenesis is still unclear. Endometriosis is responsible for infertility and/or pelvic pain. One of the most important features of the disease is the heterogeneity (clinical and anatomical: superficial peritoneal, ovarian and/or deep infiltrating lesions). Bowel involvement constitutes one particularly severe form of the disease, affecting 8-12% of women with deep endometriosis. In case of associated infertility, bowel endometriosis constitutes a real therapeutic challenge for gynecologists. Indeed, while complete resection of the lesions alleviates pain and seems to improve spontaneous fertility, surgery remains technically challenging and may cause severe complications. Reverting to assisted Reproductive Technology (ART) is another valuable therapeutic option regarding pregnancy rates. Thus, the choice between surgical management or ART is still debated. Benefits and risks of these two options should be considered and discussed before planning treatment. In the present study, we aimed to answer the question: Bowel endometriosis and infertility: do we need to operate? PMID- 28864052 TI - The health literacy demands of electronic personal health records (e-PHRs): An integrative review to inform future inclusive research. AB - OBJECTIVE: To integrate the findings of research on electronic personal health records (e-PHRs) for an understanding of their health literacy demands on both patients and providers. METHODS: We sought peer-reviewed primary research in English addressing the health literacy demands of e-PHRs that are online and allow patients any degree of control or input to the record. A synthesis of three theoretical models was used to frame the analysis of 24 studies. RESULTS: e-PHRs pose a wide range of health literacy demands on both patients and health service providers. Patient participation in e-PHRs relies not only on their level of education and computer literacy, and attitudes to sharing health information, but also upon their executive function, verbal expression, and understanding of spoken and written language. CONCLUSION: The multiple health literacy demands of e-PHRs must be considered when implementing population-wide initiatives for storing and sharing health information using these systems. PRACTICE IMPLICATIONS: The health literacy demands of e-PHRs are high and could potentially exclude many patients unless strategies are adopted to support their use of these systems. Developing strategies for all patients to meet or reduce the high health literacy demands of e-PHRs will be important in population-wide implementation. PMID- 28864053 TI - Diaphragm and Lung Ultrasound to Predict Weaning Outcome: Systematic Review and Meta-Analysis. AB - BACKGROUND: Deciding the optimal timing for extubation in patients who are mechanically ventilated can be challenging, and traditional weaning predictor tools are not very accurate. The aim of this systematic review and meta-analysis was to assess the accuracy of lung and diaphragm ultrasound for predicting weaning outcomes in critically ill adults. METHODS: MEDLINE, the Cochrane Library, Web of Science, Scopus, LILACS, Teseo, Tesis Doctorales en Red, and OpenGrey were searched, and the bibliographies of relevant studies were reviewed. Two researchers independently selected studies that met the inclusion criteria and assessed study quality in accordance with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The summary receiver-operating characteristic curve and pooled diagnostic OR (DOR) were estimated by using a bivariate random effects analysis. Sources of heterogeneity were explored by using predefined subgroup analyses and bivariate meta-regression. RESULTS: Nineteen studies involving 1,071 people were included in the study. For diaphragm thickening fraction, the area under the summary receiver-operating characteristic curve was 0.87, and DOR was 21 (95% CI, 11-40). Regarding diaphragmatic excursion, pooled sensitivity was 75% (95% CI, 65-85); pooled specificity, 75% (95% CI, 60-85); and DOR, 10 (95% CI, 4-24). For lung ultrasound, the area under the summary receiver operating characteristic curve was 0.77, and DOR was 38 (95% CI, 7-198). Based on bivariate meta-regression analysis, a significantly higher specificity for diaphragm thickening fraction and higher sensitivity for diaphragmatic excursion was detected in studies with applicability concerns. CONCLUSIONS: Lung and diaphragm ultrasound can help predict weaning outcome, but its accuracy may vary depending on the patient subpopulation. PMID- 28864054 TI - Quality Gaps and Comparative Effectiveness of Management Strategies for Recurrent Malignant Pleural Effusions. AB - BACKGROUND: Guidelines for recurrent malignant pleural effusions (MPEs) recommend definitive procedures, such as indwelling pleural catheters (IPCs) or pleurodesis, over repeat thoracentesis. We hypothesized that many patients have multiple thoracenteses rather than definitive procedures and that this results in more procedures and complications. METHODS: Retrospective cohort study using SEER Medicare data from 2007 to 2011. Patients 66 to 90 years of age with an MPE were included. The primary outcome was whether patients with rapidly recurring MPE, defined as recurrence within 2 weeks of first thoracentesis, received guideline consistent care. Guideline consistent care was defined as a definitive second pleural procedure. RESULTS: Thoracentesis for MPE was performed in 23,431 patients. A second pleural procedure because of recurrence was required in 12,967 (55%). Recurrence was rapid in 7,565 (58%) of the 12,967 patients that had a recurrence. Of the 7,565 patients with rapid recurrence, 1,811 (24%) received guideline consistent care. Definitive pleural procedures compared with repeat thoracentesis resulted in fewer subsequent pleural procedures (0.62 vs 1.44 procedures per patient, respectively; P < .0001), fewer pneumothoraxes (< 0.0037 vs 0.009 pneumothoraxes per patient, respectively; P = .001), and fewer ED procedures (0.02 vs 0.04 ED procedures per patient, respectively; P < .001). Repeat thoracentesis and IPCs resulted in fewer inpatient days compared with chest tube or thoracoscopic pleurodesis (0.013 vs 0.013 vs 0.085 vs 0.097 inpatient days per day of life, respectively; P < .001). CONCLUSIONS: Guideline consistent care using definitive procedures compared with repeat thoracentesis was associated with fewer subsequent procedures and complications; however, pleurodesis resulted in more inpatient days. PMID- 28864055 TI - Tracheobronchopathy From Inhaled Corticosteroids. AB - Inhaled corticosteroids (ICSs) have become the mainstay of asthma control. They are also recommended as an add-on therapy to long-acting beta agonists and anticholinergics in moderate to severe COPD with recurrent exacerbations. Ultimately this clinical practice has led to the widespread use of ICSs, which are supported by a more favorable side effect profile than that of systemic steroids. PMID- 28864057 TI - The road to precision medicine in sepsis: blood transcriptome endotypes. PMID- 28864058 TI - Barriers to insulin initiation in elderly patients with type 2 diabetes mellitus in Brazil. AB - AIMS: We aimed to explore insulin initiation barriers in the Brazilian Type 2 Diabetes Mellitus (T2DM) elderly population, according to the physician's perspective, and suggest strategies to overcome them. METHODS: A 45-questions survey addressing issues as clinical characteristics, barriers to insulinization, and treatment strategies in elderly patients with T2DM, was sent to six endocrinologists from different Brazilian locations. Thereafter, all the respondents participated in a panel discussion to validate their responses and collect additional relevant data. RESULTS: Endocrinologists had at least 15 years of experience, with a mean of 63 elderly patients per month. Nearly 25% of the elderly patients were treated in the Brazilian public healthcare system (SUS, Unified Health System); only a quarter presented proper glycemic control. In contrast, 55% of the patients from private healthcare system presented adequate glycemic control. The main barriers for insulin initiation for patients, according to physicians' perspective, are side effects and negative perception over treatment (100%). For endocrinologists, main barriers were lack of time to guide patients and concern over side effects (83%). Therefore, specialists considered education for both healthcare professionals and patients as one of the most important strategies to circumvent the current scenario related insulin therapy among elderly patients in the country. CONCLUSION: Insulin therapy remains underused due to several barriers, such as concern over side effects and negative perception. Educational measures for patients and HCPs could improve the current scenario. PMID- 28864056 TI - Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. AB - BACKGROUND: Host responses during sepsis are highly heterogeneous, which hampers the identification of patients at high risk of mortality and their selection for targeted therapies. In this study, we aimed to identify biologically relevant molecular endotypes in patients with sepsis. METHODS: This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units (ICUs) in the Netherlands between Jan 1, 2011, and July 20, 2012 (discovery and first validation cohorts) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK (second validation cohort). We generated genome-wide blood gene expression profiles from admission samples and analysed them by unsupervised consensus clustering and machine learning. The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. We also established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice. FINDINGS: The discovery cohort had 306 patients, the first validation cohort had 216, and the second validation cohort had 265 patients. Four molecular endotypes for sepsis, designated Mars1-4, were identified in the discovery cohort, and were associated with 28-day mortality (log-rank p=0.022). In the discovery cohort, the worst outcome was found for patients classified as having a Mars1 endotype, and at 28 days, 35 (39%) of 90 people with a Mars1 endotype had died (hazard ratio [HR] vs all other endotypes 1.86 [95% CI 1.21-2.86]; p=0.0045), compared with 23 (22%) of 105 people with a Mars2 endotype (HR 0.64 [0.40-1.04]; p=0.061), 16 (23%) of 71 people with a Mars3 endotype (HR 0.71 [0.41 1.22]; p=0.19), and 13 (33%) of 40 patients with a Mars4 endotype (HR 1.13 [0.63 2.04]; p=0.69). Analysis of the net reclassification improvement using a combined clinical and endotype model significantly improved risk prediction to 0.33 (0.09 0.58; p=0.008). A 140-gene expression signature reliably stratified patients with sepsis to the four endotypes in both the first and second validation cohorts. Only Mars1 was consistently significantly associated with 28-day mortality across the cohorts. To facilitate possible clinical use, a biomarker was derived for each endotype; BPGM and TAP2 reliably identified patients with a Mars1 endotype. INTERPRETATION: This study provides a method for the molecular classification of patients with sepsis to four different endotypes upon ICU admission. Detection of sepsis endotypes might assist in providing personalised patient management and in selection for trials. FUNDING: Center for Translational Molecular Medicine, Netherlands. PMID- 28864060 TI - Corrigendum to "Intradiencephalon injection of histamine inhibited the recovery of locomotor function of spinal cord injured zebrafish" [Biochem. Biophys. Res. Comm. 489 (1) (2017) 275-280]. PMID- 28864059 TI - Role of omentin 1 and IL-6 in type 2 diabetes mellitus patients with diabetic nephropathy. AB - AIMS: Diabetic nephropathy (DN) is one of the major chronic vascular complication of T2DM and leading cause of end-stage renal disease. Inflammation is one of the proposed pathway which explains microvascular complications in T2DM but exact mechanism is still unclear. Omentin-1 is an anti-inflammatory adipokine which promotes insulin signaling. IL-6 is a multifunctional cytokine having role in immune and inflammatory responses. The present study was conducted to elucidate the role of omentin-1 and IL-6 in the pathogenesis of DN and its association with insulin resistance. We aimed to assess and compare the serum levels of omentin-1 and IL-6 in T2DM patients with and without DN. MATERIALS & METHODS: Our study comprised of 2 groups of 41 each. Group A (controls) included T2DM without nephropathy patients and group B (cases) included T2DM nephropathy patients. Parameters studied were serum omentin-1, insulin, IL-6, fasting blood glucose, urea, creatinine, lipid profile, HOMA-IR, eGFR and BMI. RESULTS & CONCLUSION: Omentin-1 (p=0.03) was significantly decreased; concomitantly, significant increase in levels of insulin (p=0.004), IL-6 (p=0.023) and HOMA-IR (p=0.0004) were found in cases compared to controls. Bivariate analysis showed eGFR correlating positively with omentin-1 and negatively with insulin in the study population. Our study results, based on serum omentin-1 and IL-6 data suggest important role played by inflammatory mechanism and insulin resistance in the pathogenesis of diabetic nephropathy in type 2 diabetes mellitus patients. PMID- 28864061 TI - Chlorhexidine with and without alcohol is effective in preventing biofilm formation in highly compliant patients, but chlorhexidine without alcohol has fewer adverse effects and better palatability. PMID- 28864062 TI - Cyanoacrylate and laser treatment result in small improvement in oral health related quality of life for patients with dentin hypersensitivity. PMID- 28864063 TI - Oral hygiene regimen that includes toothbrushing, tongue cleaning, and mouthrinsing is probably more effective in minimizing morning oral halitosis than toothbrushing alone. PMID- 28864064 TI - Moderate-quality evidence shows a strong association between inadequate oral hygiene and periodontitis. PMID- 28864065 TI - Insufficient evidence about the comparative effectiveness of 3 horizontal ridge augmentation techniques. PMID- 28864066 TI - Angulation, contact point, and cementoenamel junction distance of impacted mandibular third molars referred for extraction are probably associated with distal caries in the second molar. PMID- 28864067 TI - A novel chemoradiation targeting stem and nonstem pancreatic cancer cells by repurposing disulfiram. AB - Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of 8% and is projected to be the second leading cause of cancer death by 2030, underscoring the urgency to develop new strategies to improve current therapeutic modalities for PDAC. Targeting pancreatic cancer stem cells (PCSCs), which are resistant to radiation and chemotherapy, is a promising strategy. A novel approach which can be readily clinically translated is to repurpose disulfiram (DSF), a drug for treating alcoholism, to target PCSCs. Chemoradiation or the combination of chemotherapy agents FOLFIRINOX, currently standard care for PDAC, can increase stemness in some established or primary PDAC cell lines. However, DSF in the presence of exogenously or endogenously supplied copper (Cu), when combined with chemotherapy or chemoradiation, targets both PCSCs and nonstem PDAC cells. Previously, we demonstrated that DSF/Cu effectively targets breast cancer stem cells in the context of fractionated radiation (FIR) by inhibiting the NF kappaB-stemness gene pathway. Therefore, the hypothesis that PCSCs can be effectively targeted by incorporating DSF/Cu into the standard chemoradiation regimen consisting of 5-FU and FIR was investigated and found to be effective in vitro in targeting PCSCs, identified as either ALDHbright or CD24+/CD44+/ESA+ or sphere-forming cells, as well as nonstem PDAC cells. In vivo, the combination of IR+5-FU+DSF/Cu was more effective (72.46%) than either IR+5-FU (30.32%) or IR+FOLFIRINOX therapy (43.04%) in inhibiting growth of the mouse Panc02 tumor. These encouraging results provide a solid foundation for clinical trials to improve the outcomes of the current standard chemoradiation therapy regimen for PDAC. PMID- 28864068 TI - Y-linked iDmrt1 paralogue (iDMY) in the Eastern spiny lobster, Sagmariasus verreauxi: The first invertebrate sex-linked Dmrt. AB - Sex determination pathways are extensively diverse across species, with the master sex-determinants being the most variable element. Despite this, there is a family of DM-domain transcription factors (Dmrts), which hold a highly conserved function in sexual development. This work is the first to describe a heterogametic sex-linked Dmrt in an invertebrate species, the Eastern spiny lobster, Sagmariasus verreauxi. We have termed the Y-linked, truncated paralogue of the autosomal iDmrt1, Sv-iDMY. Considering the master sex-determining function of both DMY in medaka and DM-W in frog, we hypothesised a similar function of Sv iDMY. By conducting temporal expression analyses during embryogenesis we have identified a putative male sex-determining period during which iDMY>iDmrt1. Employing a GAL4-transactivation assay we then demonstrate the dominant negative suppression of iDMY over its autosomal iDmrt1 paralogue, suggesting the mechanism with which iDMY determines sex. Comparative analyses of Sv-iDMY, DM-W and medaka DMY, highlight the C'-mediated features of oligomerisation and transactivation as central to the mechanism that each exerts. Indeed, these features may underpin the plasticity facilitating the convergent emergence of these three sporadic sex linked master-Dmrts. PMID- 28864069 TI - PTHrP is essential for normal morphogenetic and functional development of the murine placenta. PMID- 28864070 TI - Pediatric Corneal Cross-linking: Comparison of Visual and Topographic Outcomes Between Conventional and Accelerated Treatment. AB - PURPOSE: To compare visual and topographic outcomes 1 year after conventional (C CXL) vs accelerated corneal cross-linking (A-CXL) in pediatric keratoconus (KC). DESIGN: Comparative, retrospective, consecutive case series. METHODS: Patients with topography-confirmed, progressive KC and a corneal thickness of >=400 MUm at the time of surgery were enrolled. Uncorrected (UCVA) and best phoropter corrected visual acuity (BCVA) and normal maximum keratometry reading (Kmax) were measured at study entry and at the 12-month follow-up. Treatment failure rate was defined as the percentage of eyes with an increase in Kmax of more than 1.0 diopter during follow-up. The adverse event rate was the percentage of eyes with a loss of >=2 Snellen lines of BCVA from baseline. This was a single-center analysis of 78 eyes of 58 patients that underwent C-CXL (39 eyes) and A-CXL (39 eyes). No eyes were lost to follow-up after 12 months. RESULTS: No significant difference between changes in 12 months after as compared to the time before CXL for UCVA (0.01 log MAR; 95% confidence interval -0.14 to 0.15, P = .944), BCVA (0.05 log MAR; 95% confidence interval -0.05 to 0.15, P = .310), and Kmax (-0.77 diopters; 95% confidence interval -2.20 to 0.65, P = .282) between the C-CXL and A-CXL group were observed. Treatment failure rate was observed in 9 of 39 eyes (23.1%) in C-CXL and in 6 of 39 eyes (15.4%) in A-CXL (P = .389). Adverse events were seen only in 1 eye in the C-CXL group. CONCLUSIONS: In this retrospective comparison, the accelerated approach was equally as effective as the conventional protocol to treat pediatric keratoconus. PMID- 28864071 TI - Forming and shaping the field of limb development: A tribute to Dr. John Saunders. PMID- 28864072 TI - Improvements in the quality of advanced life support and patient outcome after implementation of a standardized real-life post-resuscitation feedback system. AB - BACKGROUND: Educational aspects in the training of advanced life support (ALS) represent a key role in critical care management of patients with out-of-hospital cardiac arrest (OHCA) and received special attention in guidelines of various international societies. While a positive association of feedback on ALS performance in training conditions is well established, data on the impact of a real-life post-resuscitation feedback on both ALS quality and outcome remain scarce and inconclusive. We aimed to elucidate the impact of a standardized post resuscitation feedback on quality of ALS and improvements in patient outcome, in a real-life out-of-hospital setting. METHODS: We prospectively enrolled and analyzed 2209 patients presenting with OHCA receiving resuscitation attempts by the municipal emergency medical service (EMS) of Vienna over a two-year period. A standardized post-resuscitation feedback protocol was delivered to the respective EMS-team to elucidate its impact on the quality of ALS. RESULTS: We observed that both chest compression rates and ratios were in accordance to recommendations of recent guidelines. While interruptions of chest compressions longer than 30s declined during the observation period (-6.5%) rates of the recommended chest compressions during defibrillator-charging periods increased (+8.9%). Since the percentage of ROSC and 30-day survival remained balanced, the frequencies of both survival until hospital discharge (+6.3%) and favorable neurological outcome (+16%) in survivors significantly increased during the observation period. CONCLUSION: Improvements in the quality of advanced life support as well the patient outcome were observed after the implementation of a standardized post resuscitation feedback protocol. PMID- 28864075 TI - Large Scale Epitope Identification Screen and Its Potential Application to the Study of Alopecia Areata. PMID- 28864074 TI - Evaluation of antiviral effect of type I, II, and III interferons on direct acting antiviral-resistant hepatitis C virus. AB - Treatment of hepatitis C virus (HCV) infection has greatly improved in the last 5 years because of the identification of direct-acting antivirals (DAAs). However, concerns exist regarding the emergence of drug resistance-associated substitutions (RASs). In this study, we evaluated the in vivo antiviral effect of three classes of interferons (IFNs), namely, types I, II, and III IFNs, on DAA resistant HCVs. IFN-alpha2, IFN-gamma, and IFN-lambda1 were selected as typical types I, II, and III IFNs, respectively. Human hepatocyte-transplanted chimeric mice were infected with NS3-D168, NS5A-L31-, and NS5A-Y93-mutated HCVs, and the antiviral effect of IFN-alpha2, IFN-gamma, and IFN-lambda1 on these HCV RASs was examined. Chimeric mice infected with NS3- and NS5A-mutated HCVs were hydrodynamically injected with IFN-expressing plasmids to evaluate the antiviral effect of IFNs. Serum concentrations of IFNs were maintained for at least 42 days. We found that serum HCV level significantly decreased and serum and hepatic HCV levels reached below detection limit in 5/5 and 3/5 chimeric mice injected with IFN-gamma- and IFN-lambda1-expressing plasmids, respectively. The antiviral effect of IFN-alpha2 on DAA-resistant HCVs was weaker than that of IFN-gamma and IFN-lambda1. Serum ALT levels showed a small and transient increase in mice injected with the IFN-gamma-expressing plasmid but not in mice injected with the IFN-lambda1-expressing plasmid. However, no apparent histological damage was observed in the liver sections of mice injected with the IFN-gamma-expressing plasmid. These results indicate that IFN-gamma and IFN-lambda1 are an attractive therapeutic option for treating infection caused by NS3- and NS5A-mutated HCV. PMID- 28864073 TI - Treatment outcomes after reduction of the target volume of intensity-modulated radiotherapy following induction chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: A prospective, multi-center, randomized clinical trial. AB - PURPOSE: To investigate whether reducing the target volume of intensity-modulated radiotherapy (IMRT) after induction chemotherapy (IC) improves the quality of life (QOL) in locoregionally advanced nasopharyngeal carcinoma (NPC) without decreasing the local control and survival rate. PATIENTS AND METHODS: A total number of 212 NPC patients staged as III-IVb were randomly assigned to group A (n=97) or group B (n=115) in this prospective clinical trial. All patients received IC followed by cisplatin concurrent with IMRT. IMRT was planned using the images of pre-IC in group A and post-IC in group B. RESULTS: The dose received by normal tissues in group B was lower than that of group A (P<0.05). The recovery of the dry mouth symptoms in group B was significantly improved than group B. The quality of life (QOL) scores in group B were higher than group A. With a median follow-up of 35months, the 1-year estimated overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS) in group A versus group B were 97.9% vs 97.3%, 90.7% vs 92,2%, 99.0% vs 98.2%, 91.8% vs 94.8%. The 2-year OS, PFS, LRFFS, DMFS in group A versus group B were 93.7% vs 92.9%, 83.4% vs 84.3%, 96.8% vs 95.5%, 86.5% vs 89.5%. The 3-year OS, PFS, LRFFS, DMFS in group A versus group B were 82.3% vs 87%, 74.7% vs 83.4%, 91.8 vs 93.9%, 81.3% vs 88.6%, respectively. CONCLUSION: Reducing the IMRT target volume after IC did not reduce the local control and survival rate in locoregionally advanced NPC but the doses received by normal tissues were decreased, and the QOL scores were improved. PMID- 28864076 TI - The Role of Fibroblast Growth Factor-Binding Protein 1 in Skin Carcinogenesis and Inflammation. AB - Fibroblast growth factor-binding protein 1 (FGFBP1) is a secreted chaperone that mobilizes paracrine-acting FGFs, stored in the extracellular matrix, and presents them to their cognate receptors. FGFBP1 enhances FGF signaling including angiogenesis during cancer progression and is upregulated in various cancers. Here we evaluated the contribution of endogenous FGFBP1 to a wide range of organ functions as well as to skin pathologies using Fgfbp1-knockout mice. Relative to wild-type littermates, knockout mice showed no gross pathologies. Still, in knockout mice a significant thickening of the epidermis associated with a decreased transepidermal water loss and increased proinflammatory gene expression in the skin was detected. Also, skin carcinogen challenge by 7,12 dimethylbenz[a]anthracene/12-O-tetradecanoyl-phorbol-13-acetate resulted in delayed and reduced papillomatosis in knockout mice. This was paralleled by delayed healing of skin wounds and reduced angiogenic sprouting in subcutaneous matrigel plugs. Heterozygous green fluorescent protein (GFP)-knock-in mice revealed rapid induction of gene expression during papilloma induction and during wound healing. Examination of wild-type skin grafted onto Fgfbp1 GFP-knock-in reporter hosts and bone marrow transplants from the GFP-reporter model into wild type hosts revealed that circulating Fgfbp1-expressing cells migrate into healing wounds. We conclude that tissue-resident and circulating Fgfbp1-expressing cells modulate skin carcinogenesis and inflammation. PMID- 28864077 TI - Phenotype and Antimicrobial Activity of Th17 Cells Induced by Propionibacterium acnes Strains Associated with Healthy and Acne Skin. AB - Studies of the human skin microbiome suggest that Propionibacterium acnes strains may contribute differently to skin health and disease. However, the immune phenotype and functions of T helper type 17 (Th17) cells induced by healthy (PH) versus acne (PA) skin-associated P. acnes strains are currently unknown. We stimulated peripheral blood mononuclear cells from healthy donors and observed that PA strains induce higher IL-17 levels than PH strains. We next generated PH and PA strain-specific Th17 clones and show that P. acnes strains induce Th17 cells of varied phenotype and function that are stable in the presence of IL-2 and IL-23. Although PH- and PA-specific clones expressed similar levels of LL-37 and DEFB4, only PH-specific clones secreted molecules sufficient to kill P. acnes. Furthermore, electron microscopic studies showed that supernatants derived from activated PH and not PA-specific clones exhibited robust bactericidal activity against P. acnes, and complete breaches in the bacterial cell envelope were observed. This antimicrobial activity was independent of IL-26, because both natural IL-26 released by Th17 clones and rhIL-26 lacked antimicrobial potency against P. acnes. Overall, our data suggest that P. acnes strains may differentially modulate the CD4+ T-cell responses, leading to the generation of Th17 cells that may contribute to either homeostasis or acne pathogenesis. PMID- 28864078 TI - Re: Quantitative Evaluation of Biologic Therapy Options for Psoriasis: A Systematic Review and Network Meta-Analysis. PMID- 28864079 TI - Rubber Hand Illusion Increases Pain Caused by Electric Stimuli. AB - : The rubber hand illusion (RHI) has been shown to alter the experience of pain, although studies have yielded inconsistent results. In this experiment we tested the influence of the RHI on the intensity of pain caused by electric stimuli. Electric stimuli were delivered to participants' experimental and control hands before RHI induction (control condition) and afterward (experimental condition), in a procedure that was double-blind with respect to location and strength of noxious stimulation. All hands were covered during the stimulation to avoid the analgesic effect of seeing one's own body part. The perceived location of the hand and of pain were measured after each trial in the experimental condition. The results showed that noxious stimuli were experienced as more painful on the hand under the illusion. In addition, in the experimental condition the perceived location of noxious stimulation applied to the experimental hand drifted toward the rubber hand. Our data suggest that the link between bodily illusions and pain could be modulated by uncertainty about location of pain and the affected body part. Future studies should aim to determine which aspects of altered body awareness lead to pain sensitization. PERSPECTIVE: We show that the RHI can change the perceived location of pain and increase pain ratings caused by electric stimuli. Our data suggest that the link between bodily illusions and pain could be modulated by uncertainty about location of pain and the affected body part. PMID- 28864081 TI - Hypoxic acclimation leads to metabolic compensation after reoxygenation in Atlantic salmon yolk-sac alevins. AB - Hypoxia is common in aquatic environments and has substantial effects on development, metabolism and survival of aquatic organisms. To understand the physiological effects of hypoxia and its dependence on temperature, metabolic rate ( [Formula: see text] ) and cardiorespiratory function were studied in response to acute hypoxia (21->5kPa) at different measurement temperatures (Ta; 4, 8 and 12 degrees C) in Salmo salar alevins that were incubated under normoxic conditions (PO2=21kPa) or following hypoxic acclimation (PO2=10kPa) as well as two different temperatures (4 degrees C or 8 degrees C). Hypoxic acclimation lead to a developmental delay manifested through slower yolk absorption. The general response to acute hypoxia was metabolic depression (~60%). Hypoxia acclimated alevins had higher [Formula: see text] s when measured in normoxia than alevins acclimated to normoxia. [Formula: see text] s were elevated to the same degree (~30% per 4 degrees C change) irrespective of Ta. Under severe, acute hypoxia (~5kPa) and irrespective of Ta or acclimation, [Formula: see text] s were similar between most groups. This suggests that despite different acclimation regimes, O2 transport was limited to the same degree. While cardiorespiratory function (heart , ventilation rate) was unchanged in response to acute hypoxia after normoxic acclimation, hypoxic acclimation led to cardiorespiratory changes predominantly in severe hypoxia, indicating earlier onset and plasticity of cardiorespiratory control mechanisms. Although [Formula: see text] in normoxia was higher after hypoxic acclimation, at the respective acclimation PO2, [Formula: see text] was similar in normoxia and hypoxia acclimated alevins. This is indicative of metabolic compensation to an intrinsic [Formula: see text] at the acclimation condition in hypoxia-acclimated alevins after re-exposure to normoxia. PMID- 28864080 TI - Developing the Brain-Early Illustrations of Cerebral Cortex and Its Gyri. AB - BACKGROUND: Throughout the Middle Ages, most representations of the brain amounted to highly schematized ventricles housed within abstract squiggles of neural tissue. The works by the pre-eminent Flemish anatomist Andreas Vesalius in his De Humani Corporis Fabrica (1543) added considerably more accuracy and detail; still, his drawings of cerebral hemispheres do not exhibit the gyral sulcal pattern recognized today. Identifiable cortical landmarks would not be featured in print until Cerebri Anatome (1664) by the English physician Thomas Willis. METHODS: A review of primary and secondary sources on the subject. RESULTS: Medieval doctors understood neurophysiology according to the cell doctrine, whereby the first cell (modern-day lateral ventricles) was responsible for sensation, the second cell (third ventricle) for cognition, and the third cell (fourth ventricle) for memory. Vesalius challenged this ventricle-centric model and resolved to portray physical form only, without the influence of conceptual function. A century later, Willis and his illustrator, Christopher Wren, citing limited clinical evidence, proposed that the corpus striatum, the white matter, and the gray matter replace the three cells, finally allowing the cortex a physiological rather than a structurally supportive role. This relocation of executive function demanded the more meticulous rendering of the brain provided in the Cerebri Anatome. CONCLUSIONS: Thomas Willis produced anatomic drawings of the brain depicting previously ill-defined surface features, as in Fabrica by Vesalius, because of a paradigm shift in neurophysiology, emphasizing the cortex over the ventricles, not because of advances in techniques of dissection or illustration. Perhaps, as the study of the brain continues, another future revelation in neurophysiology will drive another unexpected, enduring change in the study of the structures of the nervous system. PMID- 28864083 TI - An operant-based detection method for inferring tinnitus in mice. AB - BACKGROUND: Subjective tinnitus is a hearing disorder in which a person perceives sound when no external sound is present. It can be acute or chronic. Because our current understanding of its pathology is incomplete, no effective cures have yet been established. Mouse models are useful for studying the pathophysiology of tinnitus as well as for developing therapeutic treatments. NEW METHOD: We have developed a new method for determining acute and chronic tinnitus in mice, called sound-based avoidance detection (SBAD). The SBAD method utilizes one paradigm to detect tinnitus and another paradigm to monitor possible confounding factors, such as motor impairment, loss of motivation, and deficits in learning and memory. RESULTS: The SBAD method has succeeded in monitoring both acute and chronic tinnitus in mice. Its detection ability is further validated by functional studies demonstrating an abnormal increase in neuronal activity in the inferior colliculus of mice that had previously been identified as having tinnitus by the SBAD method. COMPARISON WITH EXISTING METHODS: The SBAD method provides a new means by which investigators can detect tinnitus in a single mouse accurately and with more control over potential confounding factors than existing methods. CONCLUSION: This work establishes a new behavioral method for detecting tinnitus in mice. The detection outcome is consistent with functional validation. One key advantage of mouse models is they provide researchers the opportunity to utilize an extensive array of genetic tools. This new method could lead to a deeper understanding of the molecular pathways underlying tinnitus pathology. PMID- 28864082 TI - Effects of Aging on Vocal Fundamental Frequency and Vowel Formants in Men and Women. AB - PURPOSE: This study reports data on vocal fundamental frequency (fo) and the first four formant frequencies (F1, F2, F3, F4) for four vowels produced by speakers in three adult age cohorts, in a test of the null hypothesis that there are no age-related changes in these variables. Participants were 43 men and 53 women between the ages of 20 and 92 years. RESULTS: The most consistent age related effect was a decrease in fo for women. Significant differences in F1, F2, and F3 were vowel-specific for both sexes. No significant differences were observed for the highest formant F4. CONCLUSIONS: Women experience a significant decrease in fo, which is likely related to menopause. Formant frequencies of the corner vowels change little across several decades of adult life, either because physiological aging has small effects on these variables or because individuals compensate for age-related changes in anatomy and physiology. PMID- 28864084 TI - Emergency Nurse Implementation of the Brief Smoking-Cessation Intervention: Ask, Advise, and Refer. AB - PROBLEM: Smoking is the single most avoidable risk factor for many health problems such as cardiovascular disease and pulmonary dysfunction. Emergency departments provide care for many patients who smoke. Patients who smoke and are discharged to home from emergency departments do not customarily receive smoking cessation information. This project explored the feasibility and acceptability of a brief smoking-cessation intervention as part of emergency nursing practice. METHODS: This practice improvement project was conducted in a large midwestern emergency department. A review of data from 12 months before the project revealed a 17.6% prevalence of smoking among patients discharged from the emergency department with no patient having received smoking-cessation information, confirming the need for intervention. A survey of emergency nurse attitudes and learning needs indicated that nurses believed offering advice to quit was appropriate but that they had limited smoking-cessation training. A total of 83 nurses received training on an "Ask, Advise, Refer" protocol. RESULTS: Evaluation after training indicated that emergency nurses gained knowledge about brief smoking-cessation intervention methods, and 75.7% (n=74) felt adequately trained. During the 12-week intervention, data were collected on 7,465 emergency visits. Nurses advised all smokers to quit using the protocol, and 6.3% of patients accepted smoking-cessation referrals. IMPLICATIONS FOR PRACTICE: Emergency nurses felt comfortable performing the smoking-cessation intervention, suggesting that training was effective. Data indicated that patients were consistently advised to quit smoking. Results suggest that brief smoking-cessation interventions are feasible and acceptable in emergency settings. The training and protocol could be used in other emergency departments, and lessons learned can guide future efforts by emergency nurses to help patients quit smoking. PMID- 28864085 TI - Aseptic steatonecrosis in a patient with multiple sclerosis under treatment with interferon-beta 1b. PMID- 28864086 TI - Pulmonary toxicity by riluzole. PMID- 28864087 TI - Bone marrow trephine biopsy in Hodgkin's lymphoma. Comparison with PET-CT scan in 65 patients. AB - BACKGROUND AND OBJECTIVES: To compare bone marrow biopsy (BMB) and PET/CT in detecting bone marrow involvement in Hodgkin's lymphoma MATERIAL AND METHODS: Retrospective analysis of 65 patients with both tests in the initial staging or in relapse with special attention to the PET/CT uptake pattern. RESULTS: In 3 patients (4.6%), the BMB showed bone marrow involvement with the PET/CT being positive in them all: 2 with diffuse+multifocal pattern and one diffuse only. In 11 additional patients (total 14/65, 21%), bone marrow involvement was diagnosed by PET/CT because bone marrow uptake was above hepatic one. The pattern was focal only in 2 cases, multifocal in 5, diffuse in 3 and diffuse+multifocal in one. In these last 4 cases the BMB showed an unspecific myelopathy. CONCLUSIONS: PET/CT detects all cases with BMB affected and many that escape to biopsy, however when the uptake pattern is diffuse it could be by involvement or reactive hyperplasia and in those cases the BMB should be done. PMID- 28864088 TI - Stroke and arrhythmic storm: An atypical presentation of cardiac amyloidosis. PMID- 28864089 TI - Transient hyperandrogenism in 2 preterm twins with exposure to antiretrovirals. PMID- 28864091 TI - Consumption of teratogenic drugs in pregnant women in the primary care clinic. PMID- 28864090 TI - 2017, a key year on clinical trials transparency. PMID- 28864092 TI - Facts and controversies in mixed connective tissue disease. AB - Mixed connective tissue disease (MCTD) is a systemic autoimmune rheumatic disease (SARD) characterised by the combination of clinical manifestations of systemic lupus erythematosus (SLE), cutaneous systemic sclerosis (SSc) and polymyositis dermatomyositis, in the presence of elevated titers of anti-U1-RNP antibodies. Main symptoms of the disease are polyarthritis, hand oedema, Raynaud's phenomenon, sclerodactyly, myositis and oesophageal hypomobility. Although widely discussed, most authors today accept MCTD as an independent entity. Others, however, suggest that these patients may belong to subgroups or early stages of certain definite connective diseases, such as SLE or SSc, or are, in fact, SARD overlap syndromes. PMID- 28864093 TI - Biopsy-proven renal involvement and prognosis in 13 hispanic patients with primary Sjogren syndrome. AB - BACKGROUND: The aim of this study was to describe a case series of 13 Hispanic patients with primary Sjogren syndrome (pSS) and biopsy-proven renal involvement. METHODS: We describe the clinical, serological and histological characteristics as well as the prognosis in a group of patients with pSS and biopsy-proven renal involvement, treated in 2 referral nephrology units in Mexico City. RESULTS: Thirteen patients with pSS underwent kidney biopsy (KB) over a period of 27 years. The median duration from pSS diagnosis to KB was 13.9 months. Seven patients (54%) had glomerulonephritis and 6 patients (46%) had tubulointerstitial nephritis. All patients were treated with corticosteroids and/or immunosuppressants. Eight patients (62%) remained stable or their renal function improved after a median follow-up of 12 months. CONCLUSIONS: This case series reflects the broad spectrum of renal involvement in pSS. We observed that in our Hispanic population, glomerular involvement was the most frequent abnormality, mainly membranous glomerulopathy, followed by tubulointerstitial disease. Tubular atrophy and interstitial fibrosis were also common biopsy findings. Treatment with corticosteroids or other immunosuppressive agents appear to slow renal disease progression. PMID- 28864094 TI - Parathyroid crisis: Hypercalcemia as a medical emergency. PMID- 28864095 TI - Minimal residual disease in chronic lymphocytic leukaemia. AB - Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy. PMID- 28864096 TI - Hemichorea as first clinical manifestation of systemic lupus erythematosus. PMID- 28864098 TI - Childhood Stress and Adversity is Associated with Late-Life Dementia in Aboriginal Australians. PMID- 28864097 TI - Validating the 11-Item Revised University of California Los Angeles Scale to Assess Loneliness Among Older Adults: An Evaluation of Factor Structure and Other Measurement Properties. AB - OBJECTIVE: To examine the measurement properties and factor structure of the short version of the Revised University of California Los Angeles (R-UCLA) loneliness scale from the Health and Retirement Study (HRS). METHODS: Based on data from 3,706 HRS participants aged 65 + who completed the 2012 wave of the HRS and its Psychosocial Supplement, the measurement properties and factorability of the R-UCLA were examined by conducting an exploratory factor analysis (EFA) and the confirmatory factor analysis (CFA) on randomly split halves. RESULTS: The average score for the 11-item loneliness scale was 16.4 (standard deviation: 4.5). An evaluation of the internal consistency produced a Cronbach's alpha of 0.87. Results from the EFA showed that two- and three-factor models were appropriate. However, based on the results of the CFA, only a two-factor model was determined to be suitable because there was a very high correlation between two factors identified in the three-factor model, available social connections and sense of belonging. CONCLUSION: This study provides important data on the properties of the 11-item R-UCLA scale by identifying a two-factor model of loneliness: feeling isolated and available social connections. Our findings suggest the 11-item R-UCLA has good factorability and internal reliability. PMID- 28864099 TI - Dr Google: The readability and accuracy of patient education websites for Graves' disease treatment. AB - BACKGROUND: National guidelines emphasize the importance of incorporating patient preferences into the recommendations for the treatment of Graves' disease. Many patients use the Internet to obtain health information, and search results can affect their treatment decisions. This study compares the readability and accuracy of patient-oriented online resources for the treatment of Graves' disease by website affiliation and treatment modality. METHODS: A systematic Internet search was used to identify the top websites discussing the treatment of Graves' disease. Readability was measured using 5 standardized tests. Accuracy was assessed by a blinded, expert panel, which scored the accuracy of sites on a scale of 1 to 5. Mean readability and accuracy scores were compared among website affiliations and treatment modalities. RESULTS: We identified 13 unique websites, including 2 academic, 2 government, 5 nonprofit, and 4 private sites. There was a difference in both readability (mean 13.2, range 9.1-15.7, P = .003) and accuracy (mean 4.04, range 2.75-4.50, P = .019) based on website affiliation. Government sites (mean readability 11.1) were easier to read than academic (14.3, P < .01), nonprofit (13.9, P < .01), and private sites (13.5, P < .05). Academic sites (mean accuracy 4.50) were more accurate than private sites (3.56, P < .05). CONCLUSION: Online patient resources for the treatment of Graves' disease are written at an inappropriately high reading level. Academic sites contain both the most accurate and the most difficult to read information. Private sites represented the majority of our top results but contained the least accurate information. PMID- 28864100 TI - Optimal stump management in laparoscopic appendectomy: A network meta-analysis by the Minimally Invasive Surgery Synthesis of Interventions and Outcomes Network. AB - BACKGROUND: Laparoscopic appendectomy is the predominant method of treatment of acute appendicitis. There is insufficient evidence on the most effective management of the appendix stump. The aim of this study was to investigate the relative effectiveness and provide a treatment ranking of different options for securing the appendix stump. METHODS: Electronic databases were searched to identify randomized controlled trials comparing ligation methods of the appendix. The primary outcomes were organ/space infection and superficial operative site infection. We performed a network meta-analysis and estimated the pairwise relative treatment effects of the competing interventions using the odds ratio and its 95% confidence interval. We obtained a hierarchy of the competing interventions using rankograms and the surface under the cumulative ranking curve. RESULTS: Forty-three randomized controlled trials were eligible and provided data for >5,000 patients. Suture ligation seemed to be the most effective treatment strategy, in terms of both organ/space infection and superficial operative site infection. Statistical significance was reached for the comparisons of clip versus endoloop (odds ratio 0.56, 95% confidence interval, 0.32-0.96) for organ/space infection; and suture versus clip (odds ratio 0.20, 95% confidence interval 0.08-0.55) and clip versus endoloop (odds ratio 2.22, 95% confidence interval 1.56-3.13) for superficial operative site infection. The network was informed primarily by indirect treatment comparisons. CONCLUSION: The use of suture ligation of the appendix in laparoscopic appendectomy seems to be superior to other methods for the composite parameters of organ/space and superficial operative site infection. PMID- 28864101 TI - Brief surgical procedure code lists for outcomes measurement and quality improvement in resource-limited settings. AB - BACKGROUND: The lack of a classification system for surgical procedures in resource-limited settings hinders outcomes measurement and reporting. Existing procedure coding systems are prohibitively large and expensive to implement. We describe the creation and prospective validation of 3 brief procedure code lists applicable in low-resource settings, based on analysis of surgical procedures performed at Mbarara Regional Referral Hospital, Uganda's second largest public hospital. METHODS: We reviewed operating room logbooks to identify all surgical operations performed at Mbarara Regional Referral Hospital during 2014. Based on the documented indication for surgery and procedure(s) performed, we assigned each operation up to 4 procedure codes from the International Classification of Diseases, 9th Revision, Clinical Modification. Coding of procedures was performed by 2 investigators, and a random 20% of procedures were coded by both investigators. These codes were aggregated to generate procedure code lists. RESULTS: During 2014, 6,464 surgical procedures were performed at Mbarara Regional Referral Hospital, to which we assigned 435 unique procedure codes. Substantial inter-rater reliability was achieved (kappa = 0.7037). The 111 most common procedure codes accounted for 90% of all codes assigned, 180 accounted for 95%, and 278 accounted for 98%. We considered these sets of codes as 3 procedure code lists. In a prospective validation, we found that these lists described 83.2%, 89.2%, and 92.6% of surgical procedures performed at Mbarara Regional Referral Hospital during August to September of 2015, respectively. CONCLUSION: Empirically generated brief procedure code lists based on International Classification of Diseases, 9th Revision, Clinical Modification can be used to classify almost all surgical procedures performed at a Ugandan referral hospital. Such a standardized procedure coding system may enable better surgical data collection for administration, research, and quality improvement in resource limited settings. PMID- 28864102 TI - Presenting hypertension, burn injury, and mortality in combat casualties. AB - INTRODUCTION: The effect of presenting hypertension is poorly studied in combat casualties. We hypothesized that elevated mean arterial pressure (MAP) on presentation to combat hospitals would be associated with poor outcomes. METHODS: Data was obtained from the Department of Defense Trauma Registry and the Armed Forces Medical Examiner System. Variables analyzed included presenting vital signs to Role II-III military theater hospital, demographic variables, injury severity score (ISS), location and mechanism of injury, presence of traumatic brain injury (TBI), acute kidney injury (AKI), and mortality. Patients were stratified by decile of MAP and logistic regression analysis was employed to adjust for confounders. RESULTS: A total of 4072 subjects injured from February 2002 to February 2011 were identified. Compared to patients in the middle deciles of presenting MAP, patients in the highest and lowest MAP deciles were the only groups that demonstrated a higher mortality on univariate analysis (OR 2.06, 95% CI 1.16-2.31 and OR 2.86, 95% CI 1.76-4.67, respectively), and this relationship persisted after adjustment for ISS, HR, temperature, presence of burn injury, TBI, and AKI. Burn injury was associated with mortality in the full multivariate analysis. However, further analysis limited to patients without burn injury did not demonstrate an association between high MAP and mortality (OR 0.84, 95% CI 0.36-1.99; p=0.70). Conversely, when limited to patients with burn injury, high MAP was associated with mortality (OR 3.78, 95% CI 1.74-8.20; p=0.001). CONCLUSION: The relationship between mortality and presenting MAP appears to be U shaped, demonstrating increased mortality in the lowest and highest deciles. However, mortality in the highest MAP decile appears to be limited to casualties with associated burn injury, even after adjustment for TBI, AKI, and ISS, which takes into account the severity of the burn injury. Physicians should recognize that burn patients presenting with an elevated MAP are at an increased risk for poor outcomes. LEVEL OF EVIDENCE: III. PMID- 28864103 TI - An important caution to tissue expander manufacturing companies: Burned tissues because of their inherent weakness need more delicate expanders to reduce complications. PMID- 28864104 TI - Classifying patient portal messages using Convolutional Neural Networks. AB - OBJECTIVE: Patients communicate with healthcare providers via secure messaging in patient portals. As patient portal adoption increases, growing messaging volumes may overwhelm providers. Prior research has demonstrated promise in automating classification of patient portal messages into communication types to support message triage or answering. This paper examines if using semantic features and word context improves portal message classification. MATERIALS AND METHODS: Portal messages were classified into the following categories: informational, medical, social, and logistical. We constructed features from portal messages including bag of words, bag of phrases, graph representations, and word embeddings. We trained one-versus-all random forest and logistic regression classifiers, and convolutional neural network (CNN) with a softmax output. We evaluated each classifier's performance using Area Under the Curve (AUC). RESULTS: Representing the messages using bag of words, the random forest detected informational, medical, social, and logistical communications in patient portal messages with AUCs: 0.803, 0.884, 0.828, and 0.928, respectively. Graph representations of messages outperformed simpler features with AUCs: 0.837, 0.914, 0.846, 0.884 for informational, medical, social, and logistical communication, respectively. Representing words with Word2Vec embeddings, and mapping features using a CNN had the best performance with AUCs: 0.908 for informational, 0.917 for medical, 0.935 for social, and 0.943 for logistical categories. DISCUSSION AND CONCLUSION: Word2Vec and graph representations improved the accuracy of classifying portal messages compared to features that lacked semantic information such as bag of words, and bag of phrases. Furthermore, using Word2Vec along with a CNN model, which provide a higher order representation, improved the classification of portal messages. PMID- 28864105 TI - Morphine and metabolites plasma levels after administration of sustained release morphine in Roux-en-Y gastric bypass subjects versus matched control subjects. AB - BACKGROUND: Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB) is required for optimizing their use in this growing population. OBJECTIVE: The aim of this case-controlled pharmacokinetic (PK) study was to compare morphine and its glucuronidated metabolites (morphine-3-glucuronide and morphine-6-glucuronide) plasma PKs between patients with RYGB and their controls. SETTINGS: University hospital, Lariboisiere Hospital, Paris. METHODS: Thirty milligrams of morphine as a sustained-release formulation was orally administered in 12 women who had undergone RYGB for at least 2 years (RYGB group) and in their nonsurgical controls matched for sex, body mass index (+/-2 points), and age (+/ 5 yr). Morphine, morphine-3-glucuronide, and morphine-6-glucuronide plasma concentrations over a 12-hour period were determined by a validated method using liquid chromatography mass spectrometry in tandem. Drowsiness, respiratory rate, and oxygen saturation were monitored during the PK visit. RESULTS: Morphine oral area under the curve (for time 0-12 hr; 115.8 +/- 108.0 nmol.hr/L and 86.9 +/- 38.8 nmol.hr/L for RYGB group and control group, respectively, P = .71), morphine at maximal concentration, metabolites oral area under the curve (for time 0-12 hr), and other PK parameters were similar between groups. After drug administration, mean drowsiness was superior in RYGB group. Mean respiratory rate and oxygen saturation were similar in both groups. CONCLUSION: No dose adjustment seems to be needed for sustained release morphine when prescribed to RYGB patients. PMID- 28864106 TI - Gastric mesenchymal tumors as incidental findings during Roux-en-Y gastric bypass. AB - BACKGROUND: Occurrences of mesenchymal tumors have been more recognized in recent years, and the incidental diagnosis of these lesions during bariatric surgery has been previously reported. OBJECTIVE: To describe the cases of incidentally diagnosed mesenchymal tumors during consecutive bariatric surgeries. SETTING: Private health-providing service, Brazil. METHODS: A retrospective population based study, which enrolled individuals who consecutively underwent Roux-en-Y gastric bypass at a single center from January 2006 through July 2016. RESULTS: Of 1502 individuals, there were 16 cases (1.1%) of confirmed mesenchymal tumors. Of these 16 cases, 14 (87.5%) were gastrointestinal stromal tumors and 2 (12.5%) were leiomyomas. The affected individuals were significantly older (aged 46.2 +/- 6.3 versus 35.4 +/- 7.2 yr; P = .00031), presented a lower body mass index (38.2 +/- 5.1 versus 45.3 +/- 8.1 kg/m2; P<.00001), and had a lower weight (102.1 +/- 17.9 versus 121.1 +/- 7.4 kg; P = .00321). None of the individuals presented reported relapses of the mesenchymal tumors. CONCLUSION: The possibility of incidental gastric mesenchymal tumors during bariatric surgery should not be neglected; a careful inventory of the stomach at the beginning of the procedure and resection of lesions found are mandatory. (Surg Obes Relat Dis 2017;X:XXX XXX.) (c) 2017 American Society for Metabolic and Bariatric Surgery. All rights reserved. PMID- 28864107 TI - Application of dispersive solid phase extraction based on a surfactant-coated titanium-based nanomagnetic sorbent for preconcentration of bisphenol A in water samples. AB - Herein, a new extraction method employing a surfactant-coated titanium-based nanomagnetic sorbent for the effective extraction of bisphenol A (BPA) from various water samples was developed. Initially, the titanium-based nanomagnetic particles (Fe3O4/SiO2/TiO2 NPs) were successfully synthesized and subsequently characterized by Transmission Electron Microscopy and Fourier-transform infrared spectrometry. Two cationic surfactants were then incorporated into the particles to form a new sorbent for enhancing the extraction of BPA through micelle formation. Once the analyte was extracted, it was desorbed from the sorbent and quantified by high performance liquid chromatography with ultra violet detection (HPLC-UV). Various factors affecting the extraction and desorption of the analyte were investigated in detail and the optimum conditions established. Under these established conditions, the calibration curve was linear over the concentration range of 1-500ng/mL. The limit of detection was determined to be 0.5ng/mL based on a signal-to-noise ratio (S/N)=3. To test the extraction efficiency, the method was applied to various real water samples that were spiked. The average recoveries obtained from the spiked samples ranged between 92-105% with relative standard deviations of 3.2-7.8%. Finally, the approach was determined to be effective for BPA environmental analysis. PMID- 28864108 TI - Peak capacity and peak capacity per unit time in capillary and microchip zone electrophoresis. AB - The origins of the peak capacity concept are described and the important contributions to the development of that concept in chromatography and electrophoresis are reviewed. Whereas numerous quantitative expressions have been reported for one- and two-dimensional separations, most are focused on chromatographic separations and few, if any, quantitative unbiased expressions have been developed for capillary or microchip zone electrophoresis. Making the common assumption that longitudinal diffusion is the predominant source of zone broadening in capillary electrophoresis, analytical expressions for the peak capacity are derived, first in terms of migration time, diffusion coefficient, migration distance, and desired resolution, and then in terms of the remaining underlying fundamental parameters (electric field, electroosmotic and electrophoretic mobilities) that determine the migration time. The latter expressions clearly illustrate the direct square root dependence of peak capacity on electric field and migration distance and the inverse square root dependence on solute diffusion coefficient. Conditions that result in a high peak capacity will result in a low peak capacity per unit time and vice-versa. For a given symmetrical range of relative electrophoretic mobilities for co- and counter electroosmotic species (cations and anions), the peak capacity increases with the square root of the electric field even as the temporal window narrows considerably, resulting in a significant reduction in analysis time. Over a broad relative electrophoretic mobility interval [-0.9, 0.9], an approximately two-fold greater amount of peak capacity can be generated for counter-electroosmotic species although it takes about five-fold longer to do so, consistent with the well-known bias in migration time and resolving power for co- and counter electroosmotic species. The optimum lower bound of the relative electrophoretic mobility interval [MUr,Z, MUr,A] that provides the maximum peak capacity per unit time is a simple function of the upper bound, but its direct application is limited to samples with analytes whose electrophoretic mobilities can be varied independently of electroosmotic flow. For samples containing both co- and counter electroosmotic ions whose electrophoretic mobilities cannot be easily manipulated, comparable levels of peak capacity and peak capacity per unit time for all ions can be obtained by adjusting the EOF to devote the same amount of time to the separation of each class of ions; this corresponds to MUr,Z=-0.5. PMID- 28864109 TI - A modification on the vector cosine algorithm of Similarity Analysis for improved discriminative capacity and its application to the quality control of Magnoliae Flos. AB - Chromatographic fingerprint analysis has been widely used in quality control of herbal medicines, and Similarity Analysis (SA) as a well-established method has been applied in the quality control practice as well as publications related to the study of herbal medicines and preparations. However, in some cases the results of SA do not fit well with those of other chemometric approaches and quantitative analysis, and the problem remains unsolved. In this study, a modified SA algorithm has been proposed, with its advantages discussed in theory. The extract of dried flower bud of Magnolia biondii Pamp. obtained by pressurized solvent extraction was then selected as a case to verify the modified algorithm. After identification of the components, fingerprint analysis was performed using different chemometric methods including Hierarchical Cluster Analysis (HCA), Principal Component Analysis (PCA) as well as original and modified SA methods, and the improved discriminative capacity of modified SA algorithm was illustrated. Characteristic chemical markers were then identified using the modified SA approach and then confirmed using PCA method. The quantitative results were then utilized to confirm the advantage of modified SA approach over the original one. The study made a modification to the widely applied SA algorithm, which was possibly a beneficial improvement in fingerprint analysis and quality control practice of herbal medicines. PMID- 28864110 TI - Accurate prediction of retention in hydrophilic interaction chromatography by back calculation of high pressure liquid chromatography gradient profiles. AB - Gradient retention times are difficult to project from the underlying retention factor (k) vs. solvent composition (phi) relationships. A major reason for this difficulty is that gradients produced by HPLC pumps are imperfect - gradient delay, gradient dispersion, and solvent mis-proportioning are all difficult to account for in calculations. However, we recently showed that a gradient "back calculation" methodology can measure these imperfections and take them into account. In RPLC, when the back-calculation methodology was used, error in projected gradient retention times is as low as could be expected based on repeatability in the k vs. phi relationships. HILIC, however, presents a new challenge: the selectivity of HILIC columns drift strongly over time. Retention is repeatable in short time, but selectivity frequently drifts over the course of weeks. In this study, we set out to understand if the issue of selectivity drift can be avoid by doing our experiments quickly, and if there any other factors that make it difficult to predict gradient retention times from isocratic k vs. phi relationships when gradient imperfections are taken into account with the back-calculation methodology. While in past reports, the accuracy of retention projections was >5%, the back-calculation methodology brought our error down to ~1%. This result was 6-43 times more accurate than projections made using ideal gradients and 3-5 times more accurate than the same retention projections made using offset gradients (i.e., gradients that only took gradient delay into account). Still, the error remained higher in our HILIC projections than in RPLC. Based on the shape of the back-calculated gradients, we suspect the higher error is a result of prominent gradient distortion caused by strong, preferential water uptake from the mobile phase into the stationary phase during the gradient - a factor our model did not properly take into account. It appears that, at least with the stationary phase we used, column distortion is an important factor to take into account in retention projection in HILIC that is not usually important in RPLC. PMID- 28864111 TI - Investigation of the effect of column temperature and back-pressure in achiral supercritical fluid chromatography within the context of drug impurity profiling. AB - Twenty commercially available stationary phases were characterized in supercritical fluid chromatography (SFC) using a diverse set of pharmaceutical compounds. Six dissimilar phases were selected, and a benzodiazepine and a trimethoprim impurity mixture were screened on these phases. Two stationary phases were then selected for each mixture to study the effect of temperature and back-pressure on retention, separation and chromatographic efficiency using a response surface design approach. The maximal feasible domain for each phase was examined and column performance was monitored for stability during the duration of the study. Chromatographic responses of the individual mixture components, such as retention time, peak width and apparent plate count, were modelled as a function of temperature and back-pressure. The use of high temperatures led to improved separations and higher efficiencies while high back-pressures resulted in reduced retention. For the two mixtures, the response surface plots of the resolution of the worst-separated peak pair over the experimental domain allowed the identification of the temperature and back-pressure leading to the maximal resolution for the worst-separated peak pair. For the mixtures investigated, the use of high temperatures led to improved separations and high efficiencies, while high back-pressures resulted in reduced retention. These factors are fine-tuning parameters in SFC, and similarly to the modifier composition, they lead to local, rather than global selectivity differences. PMID- 28864112 TI - Solid phase microextraction and gas chromatography coupled to magnetic sector high resolution mass spectrometry for the ultra-trace determination of contaminants in surface water. AB - With the aim of monitoring water quality according to the regulations established by the European Union it would be necessary to implement analytical methodologies capable of simultaneously determining a broad range of organic pollutants at ultra-trace levels, allowing for increased sample throughput. In addition, the high number of samples to be analyzed requires a particular focus on setting up fully automated analytical methodologies. In view of that, this study is aimed at the development of a complete automated procedure for the ultra-trace determination of certain pesticides, polycyclic aromatic hydrocarbons (PAHs), brominated diphenyl ethers (BDEs) and polychlorinated biphenyls (PCBs) in surface waters. The proposed method is based on an on-line combination of solid phase microextraction (SPME) and gas chromatography coupled to double-focusing magnetic sector high resolution mass spectrometry (GC-HRMS). SPME as well as GC-HRMS conditions were optimized to achieve maximum extraction efficiency and sensitivity, which was reinforced by using multiple ion detection (MID) as acquisition mode. Using only 19mL of water and with minimum sample manipulation, the method allowed for the determination of 53 compounds exhibiting good linearity (R2>0.99), recoveries between 84 and 118% and relative standard deviation (RSD) values <20% for intra-day and inter-day precision. In addition, the method provides quantification limits (LOQs) between 0.1-50ngL-1, lower than the Environmental Quality Standards (EQS) fixed by Directive 2013/39/EC. Finally, the method was successfully applied to determine target contaminants in Almeria surface water compartments, detecting dioxin-like PCBs, BDEs and some pesticides. PMID- 28864113 TI - Identification of apoptosis-related genes Bcl2 and Bax from yellow catfish Pelteobagrus fulvidraco and their transcriptional responses to waterborne and dietborne zinc exposure. AB - Apoptosis plays a key role in the physiology of multicellular organisms, and has been well studied in mammals, but not in teleosts. Zinc (Zn) has been shown to be an important regulator of apoptosis and apoptosis involves in the regulation of lipid metabolism. Moreover, our recent study indicated that waterborne and dietborne Zn exposure differently influenced lipid metabolism in Pelteobagrus fulvidraco, but further mechanism remained unknown. The hypothesis of the present study is that apoptosis mediated the Zn-induced changes of lipid metabolism of P. fulvidraco subjected to different exposure pathways. To this end, we cloned full length cDNA sequences of Bcl2 and three Bax subtypes involved in apoptosis in P. fulvidraco, explored their mRNA expressions in responses to different Zn exposure pathways. Bcl2 and three Bax subtypes shared similar domain structure as typical pro- and anti-apoptotic Bcl2 family members. Their mRNAs were widely expressed among various tissues, but at variable levels. Waterborne Zn exposure down regulated mRNA levels of Baxg and ratios of Baxa/Bcl2, and Baxg/Bcl2, but showed no significant effects on mRNA abundances of Bcl2, Baxa and Baxb, and the ratio of Baxb/Bcl2. In contrast, dietborne Zn exposure up-regulated mRNA levels of Bcl2, Baxa, Baxb and Baxg, but reduced the ratios of Baxa/Bcl2, Baxb/Bcl2, and Baxg/Bcl2. Considering their important roles of these genes in apoptosis induced by Zn, apoptosis may mediate the Zn-induced changes of hepatic lipid metabolism of Pelteobagrus fulvidraco under different Zn exposure pathways. For the first time, we characterized the full-length cDNA sequences of Bcl2 and three Bax subtypes, determined their expression profiles and transcriptional responses to different Zn exposure pathways, which would contribute to our understanding of the molecular basis of apoptosis, and also provide new insights into physiological responses to different Zn exposure pathways. PMID- 28864114 TI - Leptin siRNA promotes ovarian granulosa cell apoptosis and affects steroidogenesis by increasing NPY2 receptor expression. AB - Leptin has been found to be involved in the ovarian granulosa cell apoptosis and steroidogenesis. Loss of neuropeptide Y (NPY) can correct the obesity syndrome of mutant mice lacking of leptin (ob/ob). However, the association of NPY and leptin in ovarian granulosa cells and ovarian steroidogenesis has not been investigated. Here, C57BL/6J ob/ob mice and C57BL/6J (control) mice were intraperitoneally injected with PBS, leptin (0.4MUg/g bodyweight) or BIIE0246 (NPY2 receptor [NPY2R] antagonist, 30MUg/kg bodyweight) every day for 15days. We found that NPY2R mRNA expression in mouse ovary was suppressed by leptin treatment, but increased by leptin deficiency. Leptin or BIIE0246 treatment significantly increased E2, but notably decreased progesterone in both mice. A lower level of E2 and a higher level of progesterone was observed in ob/ob mice than in control mice. Further, we then knocked down leptin expression in human ovarian granulosa cells by siRNA transfection and treated the cells with DMSO or BIIE0246. In vitro experiments confirmed the findings in mice. siLeptin treatment decreased the secretion of E2, anti-Mullerian hormone (AMH), insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-beta, and the cell proliferation, but increased the secretion of progesterone and cell apoptosis. Western blotting analysis of PCNA, Bcl-2 and Bax confirmed the results of cell proliferation and apoptosis. Activation of JAK2 and STAT3 was also suppressed by knocking down leptin. All the effects of siLeptin on ovarian granulosa cells were partially reversed by BIIE0246. In conclusion, knockdown of leptin significantly affected ovarian steroidogenesis and ovarian function through NPY. siLeptin transfection impaired the activation of JAK2/STAT3 and contributed to ovarian granulosa cell apoptosis partially through up-regulating NPY2R expression. PMID- 28864115 TI - RasGRP3 controls cell proliferation and migration in papillary thyroid cancer by regulating the Akt-MDM2 pathway. AB - Accumulating evidence has shown that Ras guanylnucleotide releasing peptide 3 (RasGRP3) is up-regulated in several distinct cancer types; however, its role in papillary thyroid cancer (PTC) remains unclear. In this study, we demonstrate that RasGRP3 was overexpressed in PTC tissues and cell lines. Downregulation of RasGRP3 using small interfering (si) RNA significantly inhibited PTC cell proliferation and migration in vitro, and tumor growth in vivo, reflecting an oncogenic role of RasGRP3 in PTC. We subsequently identified that the expression of mouse double minute 2 homolog (MDM2) and phosphorylated Akt (p-Akt) was significantly decreased in RasGRP3-downregulated PTC cells. Overexpression of MDM2 attenuated the function of si-RasGRP3. Taken together, our data show that RasGRP3 exerts its oncogenic effect in PTC through Akt-mediated MDM2 activation. RasGRP3 may serve as a potential new therapeutic target for PTC. PMID- 28864116 TI - The role of long non-coding RNA PCA3 in epithelial ovarian carcinoma tumorigenesis and progression. AB - OBJECTIVES: Ovarian carcinoma is one of the highest incidence of tumors in women, and the generation, development and prognosis of epithelial ovarian carcinoma (EOC) remains an open field of study. The role of long non-coding RNAs (lncRNAs) in epithelial ovarian carcinoma is an emerging area of research. MATERIALS AND METHODS: LncRNA PCA3 expression was determined in EOC and normal ovarian tissues by RT-PCR. Phenotypes indicative of tumor progression and aggressiveness, including cell proliferation, migration, invasion, and expression of related molecules, were analysed in EOC cell following knockdown of lncRNA PCA3 by transfection with small interfering RNA (siRNA). RESULTS: Expression of lncRNA PCA3 in epithelial ovarian cancer tissues was higher than in normal ovarian tissue. We discovered that knockdown of lncRNA PCA3 in EOC cells by siRNA transfection significantly suppressed cell proliferation, migration, and invasion. Bioinformatic predictions and dual-luciferase reporter assays indicate that the 3'UTR of PCA3 has potential binding sites for miR-106b-5p. Knockdown of the lncRNA PCA3 by siRNA resulted in up-regulated miR-106b expression. In addition, knockdown of PCA3 also reduced protein expression of Ras homolog gene family member C (RhoC), Bcl/xl, P70 ribosomal S6 kinase (P70S6K), and Matrix metallopeptidase 2 (MMP2), which are regulated by miR-106b. CONCLUSIONS: Research results show that lncRNA PCA3 may coordinate EOC tumorigenesis through disrupting miR-106b regulated gene expression. PCA3 may be a novel and important diagnostic biomarker and a valuable marker for prediction in the clinical care of epithelial ovarian carcinoma. PMID- 28864117 TI - MRC Centre Neuromuscular Biobank (Newcastle and London): Supporting and facilitating rare and neuromuscular disease research worldwide. AB - Neuromuscular diseases are both genetic and acquired conditions resulting in progressive muscle weakness and wasting which lead to disability and reduced survival. The availability of high-quality human biomaterial is crucial to support biomedical research with potential applications at all stages of development, from molecular pathophysiology to drug discovery, clinical trials and evaluation of biomarkers. Although significant progress has been made over the last few years in the diagnosis of these rare conditions, the genetic defect and underlying pathological abnormality remain unknown in approximately 1/3 of cases. Moreover, to date no definitive cure is available for most neuromuscular disorders, nor are there sufficiently reliable and specific biomarkers to monitor disease progression and response to treatment. This is in part due to the rarity and genetic heterogeneity of neuromuscular diseases and the lack of access to patient samples. The availability of the national MRC Centre Biobank for Neuromuscular Diseases in Newcastle and London has addressed this bottleneck and supported neuromuscular research. Nine years after the establishment of the MRC Centre Biobank, many high profile research publications have highlighted the positive impact of neuromuscular biobanking for translational research and proven this facility to be a unique repository source for diagnostics, basic science research, industry, drug development, and therapy. PMID- 28864118 TI - The impacts of institutional child sexual abuse: A rapid review of the evidence. AB - While awareness of institutional child sexual abuse has grown in recent years, there remains limited understanding of its occurrence and outcomes as a distinct form of abuse. Drawing on research commissioned by the Australian Royal Commission into Institutional Responses to Child Sexual Abuse, this article presents a rapid review of available evidence on the impacts of institutional abuse on victim/survivors. Literature searches identified 75 sources spanning international peer reviewed work and reports to Government that document or quantify the impacts of mostly historical child sexual abuse occurring in religious, educational, sporting and residential or out-of-home care settings. Consistent with child sexual abuse in other contexts, institutional child sexual abuse is found to be associated with numerous, pervasive and connected impacts upon the psychological, physical, social, educative and economic wellbeing of victims/survivors. Further, institutional child sexual abuse is associated with vicarious trauma at the individual, family and community level, and with impacts to the spiritual wellbeing of victims/survivors of abuse that occurs in religious settings. The identified literature suggests the trauma of institutional child sexual abuse may be exacerbated by the interplay of abuse dynamics in institutional settings, which may reduce or impede circumstances supporting disclosure, belief, support and protection from future harm. Acknowledging the limitations of the present study and the available evidence, this narrative synthesis provides insights into the complex impacts of institutional child sexual abuse. PMID- 28864120 TI - Attitudes towards disclosing a mental illness among German soldiers and their comrades. AB - Many soldiers with mental illness (SWMIs) struggle with the decision whether to disclose their condition in or outside the military. This study therefore explored views on (self-)labeling as 'mentally ill', experiences of discrimination and coping, risks and benefits of (non-)disclosure, service use, disclosure decisions and consequences of disclosing. Active-duty SWMIs as well as soldiers without mental illness (commanding officers; enlisted ranks) and military social workers participated in focus groups. Transcripts were analyzed using qualitative content analysis. SWMIs perceived negative stereotypes about their group (weakness, incompetence, blame, malingering) and saw stigma as a barrier to help-seeking. Being labeled 'mentally ill' was seen as harmful for one's career. Self-labeling led to poor self-esteem, greater need for help and feelings of weakness. Many SWMIs had experienced discrimination, such as gossip or inappropriate comments. Social isolation was a disadvantage of secrecy. Most SWMIs preferred selective disclosure and many did not disclose to their family. Military staff without mental illness expressed partly different views and described organizational challenges posed by SWMIs. Our findings suggest that disclosure decisions are personal and difficult and that stigma remains a barrier to re-integration and recovery of SWMIs in the military. Implications for interventions to support SWMIs are discussed. PMID- 28864119 TI - Value-based decision making under uncertainty in hoarding and obsessive- compulsive disorders. AB - Difficulties in decision making are a core impairment in a range of disease states. For instance, both obsessive- compulsive disorder (OCD) and hoarding disorder (HD) are associated with indecisiveness, inefficient planning, and enhanced uncertainty intolerance, even in contexts unrelated to their core symptomology. We examined decision-making patterns in 19 individuals with OCD, 19 individuals with HD, 19 individuals with comorbid OCD and HD, and 57 individuals from the general population, using a well-validated choice task grounded in behavioral economic theory. Our results suggest that difficulties in decision making in individuals with OCD (with or without comorbid HD) are linked to reduced fidelity of value-based decision making (i.e. increase in inconsistent choices). In contrast, we find that performance of individuals with HD on our laboratory task is largely intact. Overall, these results support our hypothesis that decision-making impairments in OCD and HD, which can appear quite similar clinically, have importantly different underpinnings. Systematic investigation of different aspects of decision making, under varying conditions, may shed new light on commonalities between and distinctions among clinical syndromes. PMID- 28864121 TI - Income disparity and mortality among patients with alcohol use disorder in South Korea. AB - Problems related to alcohol consumption, particularly alcohol disorders, occur frequently in South Korea and are gradually increasing due to the drinking culture and social atmosphere. We analyzed the relationship between mortality and income among patients with alcohol disorders. We used data from the National Sampling Claim Data 2003-2013, which included medical claims filed for 10,593 patients newly diagnosed with alcohol disorders. We performed survival analyses using a Cox proportional hazards model. 12.79% died during the study period. Patients with lower incomes were more positively associated with the risk of mortality than those with higher incomes (0-30 percentile: hazard ratio [HR] = 1.432, 95% confidence interval [CI] = 1.155-1.777; 31-60 percentile: HR = 1.318, 95% CI = 1.065-1.633; 61-90 percentile: HR = 1.352, 95% CI = 1.097-1.665; 91-100 percentile: ref). Such associations were significant in males, patients with mild conditions, or those who lived in metropolitan areas. In conclusion, we found that income disparity was related to mortality among patients diagnosed with disorders due to alcohol use. Thus, healthcare professionals need to provide active intervention in the early phase of alcohol disorders, and consider policy that would improve healthcare accessibility for low-income populations in order to reduce income disparity. PMID- 28864122 TI - Biological aspects and candidate biomarkers for rapid-cycling in bipolar disorder: A systematic review. AB - Rapid-cycling bipolar disorder represents a frequent severe subtype of illness which has been associated with poor response to pharmacological treatment. Aim of the present article is to provide an updated review of biological markers associated with rapid-cycling bipolar disorder. A research in the main database sources has been conducted to identify relevant papers about the topic. Rapid cycling bipolar disorder patients seem to have a more frequent family history for bipolar spectrum disorders (d range: 0.44-0.74) as well as an increased susceptibility to DNA damage or mRNA hypo-transcription (d range: 0.78-1.67) than non rapid-cycling ones. A susceptibility to hypothyroidism, which is exacerbated by treatment with lithium, is possible in rapid-cycling bipolar disorder, but further studies are needed to draw definitive conclusions. Rapid-cycling bipolar patients might have more insuline resistance as well as more severe brain changes in frontal areas (d range: 0.82-0.94) than non rapid-cycling ones. Many questions are still open about this topic. The first is whether the rapid-cycling is inheritable or is more generally the manifestation of a severe form of bipolar disorder. The second is whether some endocrine dysfunctions (diabetes and hypothyroidism) predispose to rapid-cycling or rapid-cycling is the consequence of drug treatment or medical comorbidities (e.g. obesity). PMID- 28864123 TI - Effects of glucose, lactate and basic FGF as limiting factors on the expansion of human induced pluripotent stem cells. AB - Pluripotent stem cells (PSCs) are one of the promising cell sources for tissue engineering and drug screening. However, mass production of induced pluripotent stem cells (iPSCs) is still developing. Especially, a huge amount of culture medium usage causes expensive cost in the mass production process. In this report, we reduced culture medium usage by extending interval of changing culture medium. In parallel, we also increased glucose concentration and supplied heparan sulfate to avoid depletion of glucose and bFGF, respectively. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses showed that reducing medium change frequency increased differentiation marker expressions but high glucose concentration downregulated these expressions. In contrast, heparan sulfate did not prevent differentiation marker expressions. According to analyses of growth rate, cell growth with extended medium change interval was decreased in later stage of log growth phase despite the existence of high glucose concentration and heparan sulfate. This result and culturing iPSCs with lactate showed that the accumulation of excreted lactate decreased the growth rate regardless of pH control. Conclusively, these experiments show that adding glucose and removing lactate are important to expand iPSCs with reduced culture medium usage. This knowledge should be useful to design economical iPSC mass production and differentiation system. PMID- 28864124 TI - Erratum. PMID- 28864125 TI - Erratum. PMID- 28864126 TI - Erratum. PMID- 28864127 TI - Graduated Driver Licensing for Older Novice Drivers: Critical Analysis of the Issues. PMID- 28864128 TI - Residential Green Space Quantity and Quality and Child Well-being: A Longitudinal Study. AB - INTRODUCTION: There are few studies on the potential benefits of green space quantity and quality for child well-being. The authors hypothesized that more and better quality residential green space would be favorable for well-being and that these associations could be subject to effect modification across childhood. METHOD: Multilevel linear regression adjusted for demographic and socioeconomic confounders was used to track change in well-being (Strengths and Difficulties Questionnaire Total Difficulties Score and "internalizing" and "externalizing" subscales) across five separate occasions among a cohort of 4,968 Australian children aged 4-5 years beginning in 2004. Well-being was assessed with respect to objectively measured green space quantity and parent-reported green space quality, with interaction terms fitted with age to assess for potential effect modification. Data were analyzed in 2015. RESULTS: Non-linear dose-response associations were observed for favorable well-being in relation to larger quantities of green space and also green space judged to be higher in quality. Favorable perceptions of green space quality were associated with larger quantities of green space regardless of neighborhood socioeconomic circumstances. Benefits for well-being appeared to top out at 21%-40% green space coverage and were reasonably consistent across childhood. Inequality in well-being (especially the internalizing subscale) emerged as children aged in relation to green space quality. CONCLUSIONS: Approximately 21%-40% of residential land-use allocated to green space may be an optimal amount for promoting child well-being, but the quality of this green space increases in importance as children age. PMID- 28864129 TI - The Potential for Federal Preemption of State and Local Sugar-Sweetened Beverage Taxes. PMID- 28864130 TI - Characteristics of Adults Who Switched From Cigarette Smoking to E-cigarettes. AB - INTRODUCTION: Because of the rapidly increasing use of electronic cigarettes (e cigarettes), this study aimed to investigate the individual characteristics and state-level prevalence of U.S. adults who have switched to e-cigarettes from traditional cigarettes. METHODS: Data from the 2012-2013 and 2013-2014 National Adult Tobacco Surveys were analyzed in 2016. Relative percent change in switching was estimated, and the state-specific prevalence of adults who switched to e cigarettes from traditional cigarettes was calculated and mapped. Multivariate logistic regression was conducted to examine how switching varied by sociodemographic subgroups and region. RESULTS: Overall, the number of individuals who switched from traditional cigarettes to e-cigarettes increased by approximately 100% over the 1-year interval. Significant increases were found among a number of sociodemographics and regions. Multivariate logistic regression analyses showed that young adults and those living in the South and West were more likely to switch to e-cigarettes, compared to former smokers who did not switch. Compared with current dual users, those with higher education and those who were not single were more likely to switch to e-cigarettes. The state with the highest prevalence of switching was New Mexico (7.3%), whereas Connecticut had the lowest prevalence (0.8 %) among former smokers. CONCLUSIONS: There is an increase in the progression from traditional cigarette use to e-cigarette use. Further research is warranted to determine whether this change continues and facilitates cigarette smoking cessation as a possible public health benefit and opportunity to save lives rather than constitutes a potential threat to public health. PMID- 28864131 TI - ZFP403, a novel tumor suppressor, inhibits the proliferation and metastasis in ovarian cancer. AB - OBJECTIVE: Zinc finger protein 403 (ZFP403) is located on human chromosome 17q12 21, the most common loss of heterozygosity regions for some oncogenes. However, the biological function of ZFP403 on tumor is controversial and its role in ovarian cancer remains unknown. This study aimed to investigate its biological function in ovarian cancer. METHODS: qRT-PCR and western blotting were first performed to detect the expression level of ZFP403 in ovarian cancer tissues and cells, respectively. The effect of ZFP403 on cell proliferation was determined by colony formation assays. Its effects on cell cycle were analyzed by flow cytometry and western blotting. Wound healing, Boyden chamber, western blotting and gelatin zymography assays were utilized to assess migration and invasion abilities of cells overexpressed with ZFP403. The xenograft model in nude mice was used to elucidate the role of ZFP403 on tumorigenesis in vivo. RESULTS: Compared with normal ovarian tissues and cells, significantly lower expression levels of ZFP403 were observed in ovarian cancer tissues and cells. Ectopic overexpression of ZFP403 in ovarian cancer cells dramatically suppressed cell proliferation by inducing cell cycle arrest at G2/M phase. Moreover, overexpression of ZFP403 in SK-OV3 cells inhibited cell migration and invasion. Xenograft study also demonstrated that overexpression of ZFP403 suppressed the tumor growth in vivo. CONCLUSION: The effects of ZFP403 on cell proliferation and metastasis suggest that it may serve as a tumor suppressor in ovarian cancer. PMID- 28864132 TI - Ghost ileostomy in advanced ovarian cancer. PMID- 28864133 TI - Association between use of pre-hospital ECG and 30-day mortality: A large cohort study of patients experiencing chest pain. AB - BACKGROUND: In the assessment of patients with chest pain, there is support for the use of pre-hospital ECG in the literature and in the care guidelines. Using propensity score methods, we aim to examine whether the mere acquisition of a pre hospital ECG among patients with chest pain affects the outcome (30-day mortality). METHODS: The association between pre-hospital ECG and 30-day mortality was studied in the overall cohort (n=13151), as well as in the one-to one matched cohort with 2524 patients not examined with pre-hospital ECG and 2524 patients examined with pre-hospital ECG. RESULTS: In the overall cohort, 21% (n=2809) did not undergo an ECG tracing in the pre-hospital setting. Among those who had pain during transport, 14% (n=1159) did not undergo a pre-hospital ECG while 32% (n=1135) of those who did not have pain underwent an ECG tracing. In the overall cohort, the OR for 30-day mortality in patients who had a pre hospital ECG, as compared with those who did not, was 0.63 (95% CI 0.05-0.79; p<0.001). In the matched cohort, the OR was 0.65 (95% CI 0.49-0.85; p<0.001). Using the propensity score, in the overall cohort, the corresponding HR was 0.65 (95% CI 0.58-0.74). CONCLUSION: Using propensity score methods, we provide real world data demonstrating that the adjusted risk of death was considerably lower among the cases in whoma pre-hospital ECG was used. The PH-ECG is underused among patients with chest discomfort and the mere acquisition of a pre-hospital ECG may reduce mortality. PMID- 28864134 TI - Rationale and design of a prospective study to assess the effect of left cardiac sympathetic denervation in chronic heart failure. AB - BACKGROUND: The main causes of mortality in patients with chronic heart failure include sudden cardiac death (SCD) and progressive heart failure. Autonomic dysfunction plays a detrimental role in the progression of chronic heart failure. Left cardiac sympathetic denervation (LCSD) is an inexpensive and safe procedure which modifies autonomic innervation of the heart and is associated with a significant antifibrillatory effect. Whether LCSD reduces the risk of SCD, delays progression of heart failure and improves quality of life in patients with heart failure with reduced ejection fraction (HFrEF) is not known. METHODS AND DESIGN: This is a 2-phased prospective, randomized trial to test the efficacy and safety of LCSD as an adjunct to guideline recommended medical therapy for patients with HFrEF. Once the safety and feasibility of conducting a large LCSD study have been demonstrated in the pilot phase, a phase III efficacy trial to assess the impact on ventricular arrhythmias, heart failure outcomes, and mortality will be completed. Outcome data from the pilot study will remain blinded and added to the results of phase III study for analysis. RESULTS: To date the study has received approval from local and national ethics and regulatory bodies and recruitment has commenced, and 4 patients have been randomized so far. CONCLUSION: If LCSD is proven to be safe, feasible and effective in this first ever study using this novel approach in patients with HFrEF it may be a cost-effective alternative to the implantable cardioverter defibrillator therapy especially in regions where ICDs and cardiac transplantation are unavailable. PMID- 28864135 TI - Reliability of right-to-left shunt screening in the prevention of scuba diving related-decompression sickness. AB - OBJECTIVES: The aim of this study was to investigate the relationship between right-to-left shunt (RLS) and the clinical features of decompression sickness (DCS) in scuba divers and to determine the potential benefit for screening this anatomical predisposition in primary prevention. METHODS: 634 injured divers treated in a single referral hyperbaric facility for different types of DCS were retrospectively compared to 259 healthy divers. All subjects had a RLS screening by contrast Transcranial Doppler (TCD) ultrasound according to a standardized method. The number of bubbles detected defined the degree of RLS (small if 5-20 bubbles, large if >20 bubbles). RESULTS: TCD detected 63% RLS in DCS group versus 32% in the control group (p<0.0001) The overall prevalence of RLS was higher in divers presenting a cerebral DCS (OR, 5.3 [95% CI, 3.2-8.9]; p<0.0001), a spinal cord DCS (OR, 2.1 [95% CI, 1.4-3.1]; p<0.0001), an inner ear DCS (OR, 11.8 [95% CI, 7.4-19]; p<0.0001) and a cutaneous DCS (OR, 17.3 [95% CI, 3.9-77]; p<0.0001) compared to the control group, but not in divers experiencing ambiguous symptoms or musculoskeletal DCS. There was in increased risk of DCS with the size of RLS. The determination of diagnostic accuracy of TCD testing through the estimation of likelihood ratios revealed that predetermination of RLS did not change significantly the prediction of developing or not a DCS event. CONCLUSION: The assessment of RLS remains indicated after an initial episode of spinal cord, cerebral, inner ear and cutaneous form of DCS but this approach is definitely not recommended in routine practice. PMID- 28864136 TI - Severe aortic stenosis patients with preserved ejection fraction according to flow and gradient classification: Prevalence and outcomes. AB - BACKGROUND: Clinicians often encounter patients with apparently discordant echocardiographic findings, severe aortic stenosis (SAS) defined by aortic valve area (AVA) despite a low mean gradient. A new classification according to flow state and pressure gradient has been proposed. We sought to assess the prevalence, characteristics and outcomes of patients with asymptomatic SAS with preserved left-ventricular ejection fraction (LVEF) according to flow and gradient. METHODS AND RESULTS: In total 442 patients with SAS (AVAi<0.6 cm2/m2) and LVEF >=50% (mean age 80+11years, 54,5% female) were included. Patients were classified according to flow state (>= or <35ml/m2) and mean pressure gradient (>= or <40mmHg): Low Flow/Low Gradient (LF/LG): 21.3%(n=94); Normal Flow/Low Gradient (NF/LG): 32.1%(n=142); Low Flow/High Gradient (LF/HG): 6.8%(n=30); Normal Flow/High Gradient (NF/HG): 39,8%(n=176). Mean follow-up time was 20.5months (SD=10.3). Primary combined endpoint was cardiovascular mortality and hospital admission for SAS related symptom, secondary endpoint was aortic valve replacement (AVR), comparing HG group to LF/LG group. During follow-up 17 (18%) of LF/LG patients and 21 (10.2%) of HG patients met the primary endpoint. A lower free of event survival (cardiovascular mortality and hospital admission) was observed in patients with LF/LG AS (Breslow, p=0.002). Significant differences were noted between groups with a lower AVR free survival in the LF/LG group compared to HG groups (Breslow, p=0.002). CONCLUSIONS: Our study confirms the high prevalence and worse prognosis of LF/LG SAS. Clinicians must be aware of this entity to ensure appropriate patient management. PMID- 28864137 TI - Adjuvant Peptide Pulsed Dendritic Cell Vaccination in Addition to T Cell Adoptive Immunotherapy for Cytomegalovirus Infection in Allogeneic Hematopoietic Stem Cell Transplantation Recipients. AB - Adoptive cellular immunotherapy has been shown to be effective in the management of cytomegalovirus (CMV) reactivation and disease. Whether adjuvant dendritic cell (DC) vaccination will provide additional benefit in prophylaxis or treatment of CMV in hematoietic cell transplantation (HSCT) recipients is unknown. In this study, we administered prophylactic CMV-peptide specific T cell infusions, followed by 2 doses of intradermal CMV peptide-pulsed DC vaccine, to 4 HSCT recipients. There were no immediate adverse events associated with T cell infusion or DC vaccinations. One of the 4 patients developed grade III acute gut graft-versus-host disease. Immune reconstitution against CMV was detected in all 4 patients. Patients receiving CMV peptide-specific T cells and DC vaccination had peak immune reconstitution at least 10 days after the second DC vaccination. In summary, combining DC vaccine with T cell infusion appears feasible, although further study is required to ascertain its safety and efficacy in augmenting the effects of infusing donor-derived CMV-specific T cells. PMID- 28864138 TI - Comparison of Different Rabbit Anti-Thymocyte Globulin Formulations in Allogeneic Stem Cell Transplantation: Systematic Literature Review and Network Meta Analysis. AB - Since 2000, various phase III randomized controlled trials (RCTs) have investigated the efficacy of rabbit antithymocyte globulin (ATG) in patients following allogeneic stem cell transplantation (allo-SCT). Comparisons of different ATG formulations are lacking, however. Our aim was to synthesize all published efficacy evidence to enable a comparison of all available formulations of rabbit ATG in the allo-SCT setting. We performed a systematic literature review to identify all available phase III RCT evidence. We searched the Cochrane Library, MEDLINE, MEDLINE In-Process, and the website www.ClinicalTrials.gov. In addition, a trial presented at the Annual Meeting of the American Society of Hematology 2016 was added to include the most recent evidence. We identified a total of 6 RCTs, including 2 formulations: anti-T lymphocyte globulin (ATLG; Grafalon, Neovii Biotech, Lexington, MA) and polyclonal globulin immunized with human thymocytes (Thymoglobulin [Thymo]; Genzyme-Sanofi, Cambridge, MA). The evidence was synthesized using a conventional network meta-analysis (NMA). The best treatment for preventing graft-versus-host disease (GVHD) was ATLG, which had a more favorable hazard ratio (HR) compared with standard treatment (chronic GVHD: HR, .42; 95% confidence interval [CI], .31 to .56; acute GVHD grade II-IV: HR, .54; 95% CI, .39 to .73; acute GVHD grade III-IV: HR, .50; 95% CI, .29 to .86), whereas both ATLG and Thymo were at least similarly effective in terms of transplantation-related mortality (TRM) (ATLG: HR, .90; 95% CI, .61 to 1.32; Thymo: HR, .90; 95% CI, .56 to 1.44). Thymo tended to be the better treatment option regarding overall survival (OS) (HR, .86; 95% CI, .59 to 1.26). Our NMA provides the first report of the relative efficacy of all available rabbit ATG formulations in patients undergoing allo-SCT. Until additional data from randomized head-to-head comparisons are available, based on the present analysis, ATLG seems to be the best option to prevent chronic and acute GVHD. Both formulations show similar efficacy in terms of TRM, whereas Thymo appears to be the better treatment option in terms of OS. PMID- 28864139 TI - Optimizing Antithymocyte Globulin Dosing for Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Based on Recipient Absolute Lymphocyte Count. AB - Antithymocyte globulin (ATG) is used as prophylaxis against graft-versus-host disease (GVHD). Current dosing regimens for ATG are empiric and weight-based, and do not account for patient-specific factors. Furthermore, the target of ATG, recipient T cells post-cytotoxic chemotherapy, is not a function of recipient weight. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration would interact with the dose of ATG administered to predict transplantation outcomes. We retrospectively analyzed 135 patients who received ATG for GVHD prophylaxis for unrelated allogeneic hematopoietic cell transplantation at 3 different doses: 10 mg/kg, 7.5 mg/kg, and 5 mg/kg. There was no difference in 2-year overall survival (OS) among ATG dosing groups; however, deaths from infectious complications were significantly higher with higher doses of ATG (3.7% versus 19% versus 26.7%; P = .02). Severity of chronic GVHD was lower with higher doses of ATG (28% versus 24% versus 4%; P = .03). In multivariate analysis, the median peripheral blood ALC on day of ATG administration and the total amount of ATG interacted to predict OS (hazard ratio, .09; P = .03). For low recipient ALC (10th percentile, or .56 * 102/uL), a higher total ATG dose was associated with a greater risk of death, whereas for high recipient ALC (90th percentile, or 24.96 * 102/uL), a higher ATG dose was associated with a lower risk of death. Our findings suggest that the interaction between ATG and its target, the recipient lymphocyte, could represent a new paradigm for ATG dosing. PMID- 28864140 TI - Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation: A Single-Center Analysis of 613 Adult Hematopoietic Cell Transplantation Recipients Using a Modified Composite Endpoint. AB - The composite endpoint graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) has recently been introduced as a tool to assess the success of allogeneic hematopoietic stem cell transplantation (HSCT) and has been incorporated into recent randomized trials of GVHD prophylaxis by the Blood and Marrow Transplant Clinical Trials Network. As developed, GRFS incorporates "chronic GVHD requiring systemic immunosuppression" as a measure of clinically significant chronic GVHD (cGVHD). However, the decision to start patients on immunosuppressive therapy for cGVHD is subjective and physician-dependent. We elected to assess a modification of the GRFS (m-GRFS) that uses a potentially more objective measure of cGVHD, specifically the development of National Institutes of Health grade moderate or severe cGVHD. A total of 613 patients who underwent a first allogeneic HSCT after an HLA-identical sibling (matched related donor [MRD]; n = 212), an 8/8 matched unrelated donor (MUD; n = 251) or T cell replete haploidentical donor (HID) transplant with post-transplantation cyclophosphamide (n = 150) were included in this analysis. In the HID group, 86 patients (54%) received peripheral blood stem cells as the graft source. The median duration of follow-up was 50.2 months. The unadjusted Kaplan-Meier estimates for 1- and 2-year m-GRFS were 36% (95% confidence interval [CI], 32% to 40%) and 28% (95% CI, 25% to 32%), respectively. The 2-year m-GRFS was 30% (95% CI, 24% to 36%) for MRD graft recipients, 24% (95% CI, 19% to 30%) for MUD graft recipients, and 33% (95% CI, 26% to 41%) for HID graft recipients. A multivariate Cox model for m-GRFS identified donor type, Disease Risk Index (DRI) risk, donor recipient sex mismatch, and year of transplantation as significant predictors of m-GRFS. Patients who received a MUD graft had worse m-GRFS compared to MRD graft recipients (hazard ratio [HR], 1.39; P = .003), whereas HID graft recipients had a similar m-GRFS as MRD graft recipients (HR, 1.10; P = .43). HID was associated with better m-GRFS compared with MUD (HR, .79; P = .046). These data show that m GRFS is significantly affected by several modifiable factors, including donor type, donor-recipient sex match, and DRI. Adjusting donor choice and earlier referral of patients for evaluation of transplantation to improve the DRI can potentially overcome the negative impact of these factors. PMID- 28864141 TI - Who Uses a Midwife for Prenatal Care and for Birth in the United States? A Secondary Analysis of Listening to Mothers III. AB - BACKGROUND: Although midwife care is slowly but consistently increasing in the United States, not much is known regarding women who use a midwife. Our objectives were to compare the sociodemographic and health history characteristics, and the quality of patient-provider communication, between women who used a midwife and those who used a physician for prenatal care and/or birth. METHODS: We performed a cross-sectional analysis of the nationally representative Listening to Mothers III survey. We report descriptive findings using weighted proportions and means with standard deviations. We used the two one-sided tests procedure to assess the equivalence of women who used midwives and those who used physicians. RESULTS: Nearly 13% of women used a midwife for prenatal care or as a birth attendant. Women who used a midwife for prenatal care were similar to women who used a physician in most sociodemographic and health history characteristics, as well as their patient-provider communication scores, with the exception of the percentage of White (61.7 +/- 5.0 [midwives], 54.3 +/- 1.5 [physicians]) and married women (68.7 +/- 4.9 [midwives], 60.6 +/- 1.5 [physicians]). Women who used a midwife as a birth attendant were similar to women who used a physician as a birth attendant in most characteristics, with the exception of age over 35 years (7.5 +/- 1.6 [midwives], 15.7 +/- 1.1 [physicians]) and Special Supplemental Nutrition Program for Women, Infants, and Children support (56.8 +/- 4.9 [midwives], 50.0 +/- 1.6 [physicians]). CONCLUSIONS: Women who use midwives are similar to those who use physicians and our findings do not confirm the common perception that midwife patients are a self-selected group of wealthier, more educated women. PMID- 28864142 TI - Optimistic value based optimal control for uncertain linear singular systems and application to a dynamic input-output model. AB - In this paper, optimal control problems for uncertain discrete-time singular systems and uncertain continuous-time singular systems are considered under optimistic value criterion. The above singular systems are assumed to be regular and impulse-free, and optimistic value method is employed to optimize uncertain objective functions. Firstly, based on Bellman's principle of optimality, a recurrence equation is presented for settling optimal control problems subject to uncertain discrete-time singular systems. Then, by applying the principle of optimality and uncertainty theory, an equation of optimality for an optimal control model subject to an uncertain continuous-time singular system is derived. The optimal control problem can be settled through solving the equation of optimality. Two numerical examples and a dynamic input-output model are given to show the effectiveness of the results obtained. PMID- 28864144 TI - Macronutrients and cardiovascular risk in a global context. PMID- 28864145 TI - IEF peptide fractionation method combined to shotgun proteomics enhances the exploration of rice milk proteome. AB - We conducted a proteomics study in order to detect the proteomic method which provides the most complete characterization of the proteins of rice milk. In particular, we compared the results obtained from LC-MS/MS after protein precipitation with acetone or TCA, as well as the results obtained from LC-MS/MS after protein prefractionation based on SDS-PAGE (GeLC-MS/MS) or ProteoMinerTM technology (ProteoMiner-LC-MS/MS), and after peptide prefractionation based on IEF (pIEF-LC-MS/MS). A total of 158 protein species have been detect in rice milk. The physical-chemical analysis and classification of the identified proteins were also reported. In particular, we showed that pIEF-LC-MS/MS method led to a significant increase in the proteome coverage, allowing the identification of a total of 96 proteins of milk rice. This study demonstrates the utility of a prefractionation step based on pIEF before the shotgun proteomic analysis and offers an in-depth insight into the rice milk proteome. PMID- 28864146 TI - Corrigendum to "New approach to improve the keratinised peri-implant soft tissues in patients with intraoral osteocutaneous reconstruction using a free flap" [Br J Oral Maxillofac Surg 55 (September (7)) (2017) 732-33]. PMID- 28864147 TI - Randomised controlled clinical trial of augmentation of the alveolar ridge using recombinant human bone morphogenetic protein 2 with hydroxyapatite and bovine derived xenografts: comparison of changes in volume. AB - The aim of this randomised controlled clinical trial was to assess the early efficacy of bone morphogenetic protein-2 with hydroxyapatite granules (BMP 2/hydroxyapatite) on augmentation of the alveolar ridge, by comparing changes in volume with those associated with the use of an inorganic bovine-derived xenograft (BDX). We studied 20 patients who were divided into two groups using a table of random numbers, and BMP-2/hydroxyapatite and BDX were applied accordingly. Computed tomographic (CT) images and panoramic radiographs were obtained immediately after operation and four months later. CT images were reconstructed in three dimensions to measure volumetric changes, and linear measurements were made on panoramic images. The mean (SD) absorption rates for BMP-2/hydroxyapatite and BDX were 13.2 (8.8)% and 13.8 (20.5)%, respectively. While the mean value did not differ significantly between the two materials, the SD was higher in the BDX group than in the BMP-2/hydroxyapatite group. No clinically important complications occurred in either group. We conclude that both BMP-2/hydroxyapatite and BDX were effective in augmenting the alveolar ridge, but BMP-2/hydroxyapatite seemed to be more useful in complicated bone defects. PMID- 28864148 TI - Sentinel lymph node biopsy for oral squamous cell carcinoma. Where are we now? AB - Recent data have confirmed that elective surgical management of the cN0 neck improves survival in patients with early (T1-T2) oral squamous cell carcinoma (SCC), and is better than watchful waiting. However, elective neck dissection (END) may not always be necessary. Sentinel node biopsy (SNB), which is a reliable staging test for patients with early disease and a radiologically N0 neck, can detect occult metastases with a sensitivity of 86%-94%. Patients with no sign of metastases on SNB could avoid neck dissection, and individual treatment should reduce both morbidity and cost. Currently, SNB for oral SCC is available at a limited number of centres in the UK, but this is likely to change as national guidelines have recommended that it is incorporated into the standard treatment pathway. It is therefore important to understand the current evidence that supports its use, its limitations and related controversies, and to plan for a validated training programme. PMID- 28864149 TI - Anticancer potential of aminomethylidene-diazinanes I. Synthesis of arylaminomethylidene of diazinetriones and its cytotoxic effects tested in glioblastoma cells. AB - Diazinane and aryl moieties with vinylamine linkers were synthesized to investigate the importance of their structural variations as potential anti glioblastoma agents. Structural variations incorporated on to the diazinane moiety included oxa and thio derivatives, each with a variety of nitrogen-bound substituents. The size and shape of the aromatic moiety was varied, with the final variation introducing two carbonyl groups, yielding a substituted anthraquinone. Readily available diazinanes and aryl amines were used asan advantageous foundation. Several parameters were calculated whilst engineering these compounds, including: ClogP, molecular polarizability, polar surface area, minimal molecular projected area, and pKa. In addition, a simple and efficient procedure was developed to synthesize these compounds. It was demonstrated that a vinylamine with 1,3-diazinane-2,4,6-trione and 1-anthraquinone moiety is the most promising drug candidate causing almost 70% of LN229 tumor cell death at 1ug/ml. In addition, its molecular polarizability, polar surface area and minimal molecular projected area indicate a possible potential of this molecule for crossing BBB. PMID- 28864150 TI - Standard and Strain Measurements by Echocardiography Detect Early Overloaded Right Ventricular Dysfunction: Validation against Hemodynamic and Myocyte Contractility Changes in a Large Animal Model. AB - BACKGROUND: Early detection of right ventricular (RV) failure is required to improve the management of patients with congenital heart diseases. The aim of this study was to validate echocardiography for the early detection of overloaded RV dysfunction, compared with hemodynamic and myocyte contractility assessment. METHODS: Using a porcine model reproducing repaired tetralogy of Fallot, RV function was evaluated over 4 months using standard echocardiography and speckle tracking compared with hemodynamic parameters (conductance catheter). Sarcomere shortening and calcium transients were recorded in RV isolated myocytes. Contractile reserve (DeltaEmax) was assessed by beta-adrenergic stimulation in vivo (dobutamine 5 MUg/kg) and ex vivo (isoproterenol 100 nM). RESULTS: Six operated animals were compared with four age- and sex-matched controls. In the operated group, hemodynamic RV efficient ejection fraction was significantly decreased (29.7% [26.2%-34%] vs 42.9% [40.7%-48.6%], P < .01), and inotropic responses to dobutamine were attenuated (DeltaEmax was 51% vs 193%, P < .05). Echocardiographic measurements of fraction of area change, tricuspid annular plane systolic excursion, tricuspid annular peak systolic velocity (S') and RV free wall longitudinal systolic strain and strain rate were significantly decreased. Strain rate, S', and tricuspid annular plane systolic excursion were correlated with DeltaEmax (r = 0.75, r = 0.78, and r = 0.65, respectively, P < .05). These alterations were associated in RV isolated myocytes with the decrease of sarcomere shortening in response to isoproterenol and perturbations of calcium homeostasis assessed by the increase of spontaneous calcium waves. CONCLUSIONS: In this porcine model, both standard and strain echocardiographic parameters detected early impairments of RV function and cardiac reserve, which were associated with cardiomyocyte excitation-contraction coupling alterations. PMID- 28864151 TI - Authors' Reply. PMID- 28864143 TI - Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study. AB - BACKGROUND: The relation between dietary nutrients and cardiovascular disease risk markers in many regions worldwide is unknown. In this study, we investigated the effect of dietary nutrients on blood lipids and blood pressure, two of the most important risk factors for cardiovascular disease, in low-income, middle income, and high-income countries. METHODS: We studied 125 287 participants from 18 countries in North America, South America, Europe, Africa, and Asia in the Prospective Urban Rural Epidemiology (PURE) study. Habitual food intake was measured with validated food frequency questionnaires. We assessed the associations between nutrients (total fats, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, carbohydrates, protein, and dietary cholesterol) and cardiovascular disease risk markers using multilevel modelling. The effect of isocaloric replacement of saturated fatty acids with other fats and carbohydrates was determined overall and by levels of intakes by use of nutrient density models. We did simulation modelling in which we assumed that the effects of saturated fatty acids on cardiovascular disease events was solely related to their association through an individual risk marker, and then compared these simulated risk marker-based estimates with directly observed associations of saturated fatty acids with cardiovascular disease events. FINDINGS: Participants were enrolled into the study from Jan 1, 2003, to March 31, 2013. Intake of total fat and each type of fat was associated with higher concentrations of total cholesterol and LDL cholesterol, but also with higher HDL cholesterol and apolipoprotein A1 (ApoA1), and lower triglycerides, ratio of total cholesterol to HDL cholesterol, ratio of triglycerides to HDL cholesterol, and ratio of apolipoprotein B (ApoB) to ApoA1 (all ptrend<0.0001). Higher carbohydrate intake was associated with lower total cholesterol, LDL cholesterol, and ApoB, but also with lower HDL cholesterol and ApoA1, and higher triglycerides, ratio of total cholesterol to HDL cholesterol, ratio of triglycerides to HDL cholesterol, and ApoB-to-ApoA1 ratio (all ptrend<0.0001, apart from ApoB [ptrend=0.0014]). Higher intakes of total fat, saturated fatty acids, and carbohydrates were associated with higher blood pressure, whereas higher protein intake was associated with lower blood pressure. Replacement of saturated fatty acids with carbohydrates was associated with the most adverse effects on lipids, whereas replacement of saturated fatty acids with unsaturated fats improved some risk markers (LDL cholesterol and blood pressure), but seemed to worsen others (HDL cholesterol and triglycerides). The observed associations between saturated fatty acids and cardiovascular disease events were approximated by the simulated associations mediated through the effects on the ApoB-to-ApoA1 ratio, but not with other lipid markers including LDL cholesterol. INTERPRETATION: Our data are at odds with current recommendations to reduce total fat and saturated fats. Reducing saturated fatty acid intake and replacing it with carbohydrate has an adverse effect on blood lipids. Substituting saturated fatty acids with unsaturated fats might improve some risk markers, but might worsen others. Simulations suggest that ApoB-to-ApoA1 ratio probably provides the best overall indication of the effect of saturated fatty acids on cardiovascular disease risk among the markers tested. Focusing on a single lipid marker such as LDL cholesterol alone does not capture the net clinical effects of nutrients on cardiovascular risk. FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments). PMID- 28864152 TI - Deformation Analysis of Myocardial Layers Detects Early Cardiac Dysfunction after Chemotherapy in Bone Marrow Transplantation Patients: A Continuous and Additive Cardiotoxicity Process. AB - BACKGROUND: Chemotherapy-induced cardiotoxicity has not been extensively validated in bone marrow transplantation (BMT) patients. Speckle-tracking echocardiography is a sensitive method for the detection of subclinical cardiac dysfunction. METHODS: Cardiac function was prospectively assessed in 80 patients (44 men; mean age, 45 +/- 11 years) after BMT for non-Hodgkin's lymphoma and acute or chronic myeloid leukemia by means of various echocardiographic techniques. Before chemotherapy for BMT, 89% of the patients had previously been treated with anthracyclines. Patients had normal left ventricular ejection fraction (LVEF). Left ventricular (LV) global longitudinal strain (GLS), subendocardial and subepicardial longitudinal strain, circumferential strain, LV twist, and right ventricular GLS were measured by speckle-tracking, and (2) three dimensionally derived LVEF and right ventricular ejection fraction were also assessed. Abnormal LVEF was defined as <53%. Studies were performed before (baseline) and 1, 3, 6, and 12 months after chemotherapy conditioning followed by BMT. RESULTS: Impaired LV GLS values were observed at 1 month after chemotherapy and at 3, 6, and 12 months compared with baseline (-20 +/- 2.2% at baseline, 18.4 +/- 2.1% at 1 month, -17.3 +/- 2.2% at 3 months, -17.1 +/- 2.1% at 6 months, and -17.1 +/- 2.2% at 12 months; P = .001). Early LV GLS changes were driven mostly by changes in subendocardial longitudinal strain (-22.5 +/- 2.4% at baseline, -20.5 +/- 2.3% at 1 month, -19.2 +/- 2.3% at 3 months, -19.2 +/- 2.4% at 6 months, and -19.1 +/- 2.4 at 12 months; P = .001), whereas significant subepicardial strain changes were observed at 3 months after BMT. Compared with baseline, right ventricular GLS was also impaired early after chemotherapy. Compared with baseline, LVEF was slightly reduced (P = .02) at the end of the follow-up. Among echocardiographic markers, LV GLS at 1 month had the strongest predictive value for abnormal LVEF (<53%) at 12 months (area under the curve 0.86; 95% CI, 0.76-0.96). A cutoff LV GLS value of -18.4% had sensitivity of 84.6% and specificity of 71.9% for the identification of abnormal LVEF at the end of follow-up. CONCLUSIONS: In BMT patients, myocardial deformation analysis detected early and progressive subclinical cardiac dysfunction. Impaired LV GLS had predictive value for the detection of abnormal LVEF at 12-month follow-up. Thus, myocardial deformation study should be applied early after BMT to prevent irreversible cardiac dysfunction by appropriate treatment. PMID- 28864153 TI - Inhibition coefficient and molecular diversity of multi stress tolerant Trichoderma as potential biocontrol agent against Sclerotium rolfsii Sacc. AB - Trichoderma is one of the most exploited biocontrol agent for the management of plant diseases. Twenty strains of Trichoderma (six of T. harzianum, four of T. viride, three of T. virens, three of T. koningii, each one of T. hamatum, T. reesei, T. parceramosum and Trichoderma spp.) subjected to in vitro antagonism up to 12days after inoculation against Sclerotium rolfsii Sacc. causing stem rot in groundnut. A new concept was developed to determine inhibition coefficient representing pathogen biology and biocontrol related biophysical variables. Results explained differential inhibition coefficient of test pathogen by Trichoderma antagonists. The inhibition coefficient of test pathogen was examined highest (91.13%) by T. virens NBAII Tvs12 followed by T. virens MTCC 794 (89.33%) and T. koningii MTCC 796 (62.39%). Microscopic study confirmed biocontrol mechanism as mycoparasitism for Tvs12 and antibiosis for T. koningii MTCC 796. The sclerotial biogenesis of test pathogen was elevated during weak antagonism and diminished in interactions with strong antagonists. The inhibition coefficient of S. rolfsii was significantly negatively correlated with sclerotia formation and lipid peroxidation during the antagonism. Trichoderma strains were screened for fungicides (carbendazim and tebuconazole, thiram and mancozeb) and abiotic stress (drought and salt) tolerance. Results indicated that T. koningii MTCC 796 efficiently grew better than the other strains with maximum radial growth under adverse conditions. The genetic variability among the Trichoderma was determined using 34 gene specific markers which amplified 146 alleles. The SSR similarities explained substantial diversity (15 to 87%) across Trichoderma strains and pathogen S. rolfsii. Principal coordinates analysis (PCA) were comparable to the cluster analysis and first three most informative PC components explained 64.45% of the total variation. In PCA, potent antagonists appear to be distinct from other strains. Five SSR markers T1F/T1R(311), TvCTT56f/TvCTT56r(387), TvGAT18f/TvGAT18r(364), TvCA39f/TvCA39r(196) and TvAG29f/TvAG29r(418) found to be unique to distinguish best antagonist strain Tvs12. However, MTCC 796 was examined most stress tolerant strain with better inhibition coefficient which might be useful to control the disease under adverse conditions or as a part of integrated pest management. PMID- 28864154 TI - Novel avian oropharyngeal trichomonads isolated from European turtle doves (Streptopelia turtur) and racing pigeons (Columba livia): genetic and morphometric characterisation of clonal cultures. AB - Extensive diversity has been described within the avian oropharyngeal trichomonad complex in recent years. In this study we developed clonal cultures from four isolates selected by their different ITS1/5.8S/ITS2 (ITS) genotype and their association with gross lesions of avian trichomonosis. Isolates were obtained from an adult racing pigeon and a nestling of Eurasian eagle owl with macroscopic lesions, and from a juvenile wood pigeon and an European turtle dove without clinical signs. Multi-locus sequence typing analysis of the ITS, small subunit of ribosomal rRNA (SSUrRNA) and Fe-hydrogenase (Fe-hyd) genes together with a morphological study by optical and scanning electron microscopy was performed. No significant differences in the structures were observed with scanning electron microscopy. However, the genetic characterisation revealed novel sequence types for the SSUrRNA region and Fe-hyd gene. Two clones were identified as Trichomonas gallinae in the MLST analysis, but the clones from the racing pigeon and European turtle dove showed higher similarity with Trichomonas tenax and Trichomonas canistomae than with T. gallinae at their ITS region, respectively. SSUrRNA sequences grouped all the clones in a clade that includes T. gallinae, T. tenax and T. canistomae. Further diversity was detected within the Fe-hyd locus, with a clear separation from T. gallinae of the clones obtained from the racing pigeon and the European turtle dove. In addition, morphometric comparison by optical microscopy with clonal cultures of T. gallinae revealed significant statistical differences on axostyle projection length in the clone from the European turtle dove. Morphometric and genetic data indicate that possible new species within the Trichomonas genus were detected. Taking in consideration the diversity in Trichomonas species present in the oral cavity of birds, a proper genetic analysis is highly recommended when outbreaks occur. PMID- 28864155 TI - Large-scale HFMD epidemics caused by Coxsackievirus A16 in Bangalore, India during 2013 and 2015. AB - Hand foot and mouth disease (HFMD) is a relatively unreported disease in India. This study was undertaken to characterize the enterovirus type/s associated with two unexpectedly-massive epidemics that occurred in Bangalore, India in 2013 and 2015. Stool samples of 229 children with HFMD living in Northern and Southern areas of Bangalore were tested by RT-PCR; 189 (82.5%) were enterovirus positive. The Indian CV-A16 strains exhibited 98-99% sequence identity with those reported in France and China in the 5' untranslated region. BLAST and phylogenetic analyses of complete genomes of representative Indian isolates revealed that the 2015 epidemic was predominated by an inter-species recombinant between CV-A16 and coxsackievirus B5. The 2013 epidemic was primarily caused by nonrecombinant strains. The CV-A16 strains circulated in India since 2007 and phylogeographic analyses indicated imported cases in France and China. In conclusion, CV-A16 associated HFMD epidemics should be recognized as an emerging public health problem in India. PMID- 28864156 TI - An evidence-based approach to the surgical interventions for severe pancreatic fistula after pancreatoduodenectomy. AB - BACKGROUND AND OBJECTIVE: To assess the safety and therapeutic outcome of different surgical interventions for severe pancreatic fistula after pancreatoduodenectomy. METHODS: A systematic literature search was performed in PubMed database for relevant articles published between 1990 and March 2017. Descriptive statistics were performed and data are expressed as mean. RESULTS: Twenty-four studies involving 370 patients undergoing surgical interventions for severe pancreatic fistula after pancreatoduodenectomy were included. Rates of further relaparotomy, in-hospital mortality, and long-term endocrine insufficiency were reported for completion pancreatectomy (31.8%, 42% and 100% respectively), disconnection of anastomosis with preservation of a pancreatic remnant (25%, 21.3% and 17.8% respectively), internal or external wirsungostomy (10.4%, 14.9%, and 12.3% respectively), salvage pancreaticogastrostomy (12.5%, 0% and 25%, respectively), and simple peripancreatic drainage (30%, 47.9% and 12.5%, respectively). CONCLUSIONS: The pancreas-preserving strategy of disconnection of anastomosis with preservation of a pancreatic remnant, internal or external wirsungostomy, and salvage pancreatogastrostomy seems to be the preferred option for the treatment of severe pancreatic fistula after pancreatoduodenectomy. As completion pancreatectomy is a very aggressive treatment, it should only be reserved for specific instances in which organ-preserving resection is technically unfeasible. PMID- 28864157 TI - Basal insulin for the management of diabetic ketoacidosis. AB - Due to its pharmacokinetic properties, it has been suggested that long-acting insulin analogues may have a role in facilitating the transition from continuous intravenous insulin infusion to subcutaneous maintenance therapy in patients with DKA for prevention of rebound hyperglycemia, particularly if there are high insulin requirements. Concomitant administration of basal insulin analogues with regular insulin infusion accelerates ketoacidosis resolution and prevents rebound hyperglycemia. Several studies have investigated the use of basal insulin in the management of DKA. Studies have been instituted on pediatric patients and adult patients. These studies reveal that co-administration of basal insulin in combination with an insulin infusion in the acute management of DKA is feasible. Basal insulin co-administration with regular insulin infusion was well tolerated, associated with faster resolution of acidosis without any adverse effects; patients required a shorter duration of intravenous insulin infusion and had a lower total dose of intravenous insulin and significantly decreased hyperglycemia after discontinuation of the intravenous insulin. This could potentially lead to a shorter ICU length of stay and reduced costs in the treatment of DKA. However, this approach may be associated with an increased risk of hypokalemia. The current literature on this management approach is incomplete, due to its many limitations (retrospective nature, small sample size, nonrandomized design). Additional prospective randomized studies are needed on this new therapeutic approach in the management patients with DKA. PMID- 28864158 TI - An unusual case of distal necrosis. Looking for the truth. PMID- 28864159 TI - Predictors of Prolonged Mechanical Ventilation in Adults After Acute Type-A Aortic Dissection Repair-Implications for the Future. PMID- 28864160 TI - Incidence and Outcomes of Heparin-Induced Thrombocytopenia in Patients Undergoing Vascular Surgery. AB - OBJECTIVE: The National Inpatient Sample (NIS) from years 2010 through 2012 was utilized to determine the incidence, predictive risk factors, and outcomes of heparin-induced thrombocytopenia (HIT) in patients undergoing vascular surgery. DESIGN: Retrospective population-based study. SETTING: Data from the National Inpatient Sample (NIS) (2011 through 2013) using specific International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) procedure codes corresponding with vascular surgery. PARTICIPANTS: 425,379 hospital admissions in patients which underwent vascular surgery. Among these, 1,290 (0.31%) were diagnosed with HIT, and 17,765 (4.18%) were diagnosed with secondary thrombocytopenia. MEASUREMENTS AND RESULTS: The incidence of HIT is 0.3% in the vascular surgery population. The highest incidence is observed in thoraco-subclavian and vein reconstruction procedures. This study indicated that liver disease, endocarditis, chronic renal failure, congestive heart failure, atrial fibrillation, obesity, and female sex are associated with a higher incidence of HIT in this population. In vascular surgery patients, HIT can increase mortality by 3-fold and lead to severe complications such as acute renal failure, venous embolism, pulmonary embolism, and respiratory failure. CONCLUSION: The incidence of HIT in the vascular surgery population is similar to previously reported incidence in cardiac surgery patients. In the vascular surgery population, mortality increases 3-fold in patients with HIT versus those without any thrombocytopenia. Understanding the associated risk factors and complications will allow clinicians to make informed decisions and anticipate HIT and associated complications in certain high-risk populations. PMID- 28864161 TI - Mecillinam - Reversion of Resistance and How to Test It. PMID- 28864163 TI - [Image-guided tumor ablation]. AB - INTRODUCTION: Ablatives techniques for destroying in situ a tumoral process aim tissular necrosis by the application of several physical principles. MATERIAL AND METHODS: We searched MEDLINE(r), Embase(r), using (MeSH) words; from January 2005 through May 2017, and we looked for all the studies. Investigators graded the strength of evidence in terms of methodology, language and relevance. RESULTS: Forty-seven articles were analyzed. We described ablative techniques and sorted them in thermal and non-thermal therapies according to the used physical principle and their frequency of use in the urological pathology. CONCLUSION: Percutaneous ablative therapies are mini-invasive techniques, which have an important role in tumors focal treatment. This article is a review of the ablative therapies and describes their physical principles, their equipment and their recent technological modifications, which have been developed to improve the clinical success of these techniques. PMID- 28864164 TI - Baumol's Disease. PMID- 28864162 TI - Treatment-Induced Viral Cure of Hepatitis C Virus-Infected Patients Involves a Dynamic Interplay among three Important Molecular Players in Lipid Homeostasis: Circulating microRNA (miR)-24, miR-223, and Proprotein Convertase Subtilisin/Kexin Type 9. AB - In patients with chronic hepatitis C virus (HCV) infection, viral hijacking of the host-cell biosynthetic pathways is associated with altered lipid metabolism, which contributes to disease progression and may influence antiviral response. We investigated the molecular interplay among four key regulators of lipid homeostasis [microRNA (miR)-122, miR-24, miR-223, and proprotein convertase subtilisin/kexin type 9 (PCSK9)] in HCV-infected patients (n=72) who achieved a treatment-based viral cure after interferon-based therapy with first-generation direct-acting antivirals. Real-time PCR was used to quantify microRNA plasma levels, and ELISA assays were used to determine plasma concentrations of PCSK9. We report that levels of miR-24 and miR-223 significantly increased in patients achieving sustained virologic response (SVR), whereas the levels of miR-122, a liver-specific cofactor for HCV infection, decreased in these patients. PCSK9 concentrations were significantly increased in SVRs, suggesting that PCSK9 may help impede viral infection. The modulatory effect of PCSK9 on HCV infection was also demonstrated in the context of HCV-infected Huh-7.5.1 cells employing recombinant human PCSK9 mutants. Together, these results provide insights into a novel coordinated interplay among three important molecular players in lipid homeostasis - circulating miR-24, miR-223 and PCSK9 - whose regulation is affected by HCV infection and treatment-based viral cure. PMID- 28864165 TI - Public Reporting of MRI of the Lumbar Spine for Low Back Pain and Changes in Clinical Documentation. AB - OBJECTIVE: OP-8 is the Medicare imaging efficiency metric for MRI of the lumbar spine for low back pain in the outpatient hospital. We studied trends in exclusion criteria coding over time by site of service after implementation of OP 8 to evaluate provider's response to public reporting. MATERIALS AND METHODS: We conducted a secondary data analysis using the Medicare Limited Data Set 5% sample for beneficiaries with MRI lumbar spine and lower back pain during 2009 to 2014. We evaluated the association between excluding condition prevalence and site by using generalized estimating equations regression. We produced model-based estimates of excluding condition prevalence by site and year. As a sensitivity analysis, we repeated the analysis while including additional conditions in the outcome measure. RESULTS: We included 285,911 MRIs of the lumbar spine for low back pain. Generalized estimating equations regression found that outpatient hospitals had a higher proportion of MRIs with at least one excluding condition documented compared with outpatient clinics (P < .05), but increases in excluding condition prevalence were similar across all sites during 2009 to 2014. Our results were not sensitive to the inclusion of additional conditions. CONCLUSION: Documentation of excluding conditions and other clinically reasonable exclusions for OP-8 increased over time for outpatient hospitals and clinics. Increases in documentation of comorbidities may not translate to actual improvement in imaging appropriateness for low back pain. When accounting for all relevant conditions, the proportion of patients with low back pain considered uncomplicated and being measured by OP-8 would be small, reflecting a small proportion of patients with low back pain. PMID- 28864166 TI - Artemisinin permeability via Caco-2 cells increases after simulated digestion of Artemisia annua leaves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia annua has been used for > 2000yrs to treat fever and is more recently known for producing the important antimalarial drug, artemisinin. AIM OF THE STUDY: Artemisinin combination therapies (ACTs) are effective for treating malaria, but are often unavailable to those in need. Dried leaves of A. annua (DLA) have recently been studied as a cost effective alternative to traditional ACTs. DLA was shown to dramatically increase oral bioavailability compared to pure artemisinin, so more investigation into the mechanisms causing this increased bioavailability is needed. MATERIALS AND METHODS: In this study, we used a simulated digestion system coupled with Caco-2 cell permeability assays to investigate the intestinal permeability of DLA compared to pure artemisinin. We also determined the effects of different phytochemicals (7 flavonoids, 3 monoterpenes, 2 phenolic acids, scopoletin and inulin) and the cytochrome P450 isoform CYP3A4 on artemisinin intestinal permeability. RESULTS: Artemisinin permeability, when delivered as digested DLA, significantly increased by 37% (Papp = 8.03 * 10-5cms-1) compared to pure artemisinin (Papp = 5.03 * 10-5cms-1). However, none of the phytochemicals tested or CYP3A4 had any significant effect on the intestinal permeability of artemisinin. We also showed that essential oil derived from A. annua negatively affected the intestinal permeability of artemisinin, but only after simulated digestion. Finally, we showed that A. annua essential oil reduced the transepithelial electrical resistance of Caco-2 monolayers, but only in the presence of bile. Although also reduced by essential oils, artemisinin Papp subsequently recovered in the presence of plant matrix. CONCLUSIONS: These results shed light on the mechanisms by which DLA enhances the oral bioavailability of artemisinin. PMID- 28864167 TI - A review of cinnabar (HgS) and/or realgar (As4S4)-containing traditional medicines. AB - ETHNOPHARMOCOLOGICAL RELEVANCE: Herbo-metallic preparations have a long history in the treatment of diseases, and are still used today for refractory diseases, as adjuncts to standard therapy, or for economic reasons in developing countries. AIM OF THE REVIEW: This review uses cinnabar (HgS) and realgar (As4S4) as mineral examples to discuss their occurrence, therapeutic use, pharmacology, toxicity in traditional medicine mixtures, and research perspectives. MATERIALS AND METHODS: A literature search on cinnabar and realgar from PubMed, Chinese pharmacopeia, Google and other sources was carried out. Traditional medicines containing both cinnabar and realgar (An-Gong-Niu-Huang Wan, Hua-Feng-Dan); mainly cinnabar (Zhu Sha-An-Shen Wan; Zuotai and Dangzuo), and mainly realgar (Huang-Dai Pian; Liu Shen Wan; Niu-Huang-Jie-Du) are discussed. RESULTS: Both cinnabar and realgar used in traditional medicines are subjected to special preparation procedures to remove impurities. Metals in these traditional medicines are in the sulfide forms which are different from environmental mercurials (HgCl2, MeHg) or arsenicals (NaAsO2, NaH2AsO4). Cinnabar and/or realgar are seldom used alone, but rather as mixtures with herbs and/or animal products in traditional medicines. Advanced technologies are now used to characterize these preparations. The bioaccessibility, absorption, distribution, metabolism and elimination of these herbo-metallic preparations are different from environmental metals. The rationale of including metals in traditional remedies and their interactions with drugs need to be justified. At higher therapeutic doses, balance of the benefits and risks is critical. Surveillance of patients using these herbo-metallic preparations is desired. CONCLUSION: Chemical forms of mercury and arsenic are a major determinant of their disposition, efficacy and toxicity, and the use of total Hg and As alone for risk assessment of metals in traditional medicines is insufficient. PMID- 28864168 TI - Liuweiwuling tablets attenuate BDL-induced hepatic fibrosis via modulation of TGF beta/Smad and NF-kappaB signaling pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Liuweiwuling (LWWL) tablets contain a six-herb Chinese formula and are commonly prescribed to facilitate nourishment of the liver and kidneys, clear away toxic materials and activate blood circulation. Administration of LWWL is well known for its protective effects on the liver and its capacity to confer long-term stability in patients exhibiting reduced transaminase levels. Clinical studies have reported that LWWL can also be used for the treatment of liver fibrosis with associated treatment regimens resulting in a concomitant reduction in transforming growth factor beta1 (TGF-beta1) levels in the serum of patients with hepatic fibrosis. TGF-beta1 plays a prominent role in stimulating liver fibrogenesis and this effect is mediated by myofibroblasts (MFB) derived from hepatic stellate cells (HSCs). It is likely that this phenomenon underpins the antifibrotic effects associated with LWWL. AIM: The purpose of this study was to investigate the antifibrotic effects and mechanisms pertaining to LWWL. METHODS: Hepatic fibrosis was induced in rats following bile duct ligation (BDL). Rats that underwent BDL received daily gavage administration of colchicine (0.2mg/kg per day), LWWL (0.4, 1.6, 6.4g/kg per day) or PBS (for the control group). Pathological changes in hepatic tissue were examined using hematoxylin and eosin (HE) and sirius red staining. Immunohistochemical analysis was performed to monitor alpha-SMA and type I collagen (Collagen I) protein expression. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot analyses were used to monitor the expression of genes and proteins in the TGF-beta/Smad signaling pathway, including TGF beta1, bone morphogenic protein and activin membrane-bound inhibitor (Bambi), Smad3, phosphorylated Smad3 (p-Smad3) and Smad7. We also monitored the expression of genes and proteins in the nuclear factor-kappaB (NF-kappaB) signaling pathway, including NF-kappaB p65, IkappaBalpha and phosphorylation of IkappaBalpha (p IkappaBalpha), tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and interleukin 1beta (IL-1beta). RESULTS: LWWL dose-dependently inhibited BDL induced liver injury and hepatic fibrosis in rats. Furthermore, LWWL reduced liver tissue collagen deposition, hydroxyproline content, liver dysfunction and alpha-SMA expression in BDL-induced hepatic fibrosis rats. Moreover, LWWL markedly prevented activation of the TGF-beta/Smad signaling pathway by inhibiting expression of Smad2/3 and phosphorylation of Smad3, and upregulating the expression of Bambi and Smad7. In addition, LWWL regulated the expression of the inflammatory cytokines IL-1beta, TNF-alpha and IL-6 by inhibiting the activation of NF-kappaB p65 and the phosphorylation of IkappaBalpha, and increasing the expression of IkappaBalpha. CONCLUSIONS: LWWL can attenuate BDL induced hepatic fibrosis in rats, and this effect may be due to modulation of the NF-kappaB-dependent inflammatory response and activation of HSC and TGF-beta/Smad mediated synthesis and degradation of Collagen I. PMID- 28864169 TI - Molecular understanding of Epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The compound epigallocatechin-3-gallate (EGCG), the major polyphenolic compound present in green tea [Camellia sinensis (Theaceae], has shown numerous cardiovascular health promoting activity through modulating various pathways. However, molecular understanding of the cardiovascular protective role of EGCG has not been reported. AIM OF THE REVIEW: This review aims to compile the preclinical and clinical studies that had been done on EGCG to investigate its protective effect on cardiovascular and metabolic diseases in order to provide a systematic guidance for future research. MATERIALS AND METHODS: Research papers related to EGCG were obtained from the major scientific databases, for example, Science direct, PubMed, NCBI, Springer and Google scholar, from 1995 to 2017. RESULTS: EGCG was found to exhibit a wide range of therapeutic properties including anti-atherosclerosis, anti-cardiac hypertrophy, anti-myocardial infarction, anti-diabetes, anti-inflammatory and antioxidant. These therapeutic effects are mainly associated with the inhibition of LDL cholesterol (anti-atherosclerosis), inhibition of NF-kappaB (anti-cardiac hypertrophy), inhibition of MPO activity (anti-myocardial infarction), reduction in plasma glucose and glycated haemoglobin level (anti-diabetes), reduction of inflammatory markers (anti-inflammatory) and the inhibition of ROS generation (antioxidant). CONCLUSION: EGCG shows different biological activities and in this review, a compilation of how this bioactive molecule plays its role in treating cardiovascular and metabolic diseases was discussed. PMID- 28864170 TI - FLAG-Ida Regimen as Bridge Therapy to Allotransplantation in Refractory/Relapsed Acute Myeloid Leukemia Patients. AB - BACKGROUND: Patients with primary refractory or first relapse acute myeloid leukemia (AML) are considered to have worse clinical outcomes after treatment. For these patients, the achievement of complete remission appears crucial for them to be able to undergo allotransplantation, which might be the only possible treatment. PATIENTS AND METHODS: We used the FLAG-Ida (fludarabine, cytarabine [cytosine arabinoside], granulocyte colony-stimulating factor, idarubicin) regimen in patients with primary refractory/first relapse AML as a bridge to transplantation. We studied its efficacy in terms of overall response and overall survival to assess which variables (age, lactate dehydrogenase, bone marrow blast count, peripheral blood blast count, platelet count, white blood cell count, de novo or secondary AML, molecular-cytogenetic risk, duration of response, and relapsed or refractory disease) might have an effect on outcome. RESULTS: We analyzed the data from 108 consecutive adult patients (52 males, 66 females; median age, 49 years; range, 17-72 years) with newly diagnosed AML refractory to standard induction regimens or relapse after first complete remission, who had received the FLAG-Ida protocol as salvage therapy from January 2005 to December 2015. An overall response was achieved in 48 patients (44%). On multivariate analysis, the variables with a positive effect on the response rate were molecular-cytogenetic risk (P = .009), duration of first response in relapsed AML (P = .003), AML status (relapsed or refractory; P = .047), and peripheral blood blast count (P = .016). On multivariate analysis, overall survival was significantly associated with FLAG-Ida response (hazard ratio, 0.343; P = .001) and receipt of allotransplantation (hazard ratio, 0.277; P < .001). CONCLUSION: Our data seem to confirm the value of FLAG-Ida in this setting and might suggest its best usage as bridge therapy for patients awaiting allotransplantation. PMID- 28864171 TI - Increased Mortality Among Patients With Acute Leukemia Admitted on Weekends Compared to Weekdays. AB - BACKGROUND: The association between weekend admission and patient outcomes has been reported in several acute illnesses but is unknown in acute leukemia. PATIENTS AND METHODS: We used the 2002 to 2014 Nationwide Inpatient Sample to identify patients admitted with a primary diagnosis of acute leukemia. Admissions were classified as weekend or weekday admissions for comparison. Hierarchical logistic regression models were used to analyze predictors of hospital mortality. RESULTS: There was a 22.3% decline in acute leukemia admissions in 2014 compared to 2002 and a 4% decline in in-hospital mortality (19.0%-14.9%; P < .001). A total of 82,833 admissions were included in the study, and 14,241 (17.19%) occurred over the weekend. Hospital mortality was higher for weekend than weekday admissions (18.8% vs. 16.1%; P < .001). Weekend admissions were less likely to undergo early bone marrow biopsy than their weekday counterparts (27.5% vs. 46.3%; P < .01). Bone marrow biopsy (adjusted odds ratio 0.36; 95% confidence interval [CI], 0.33-0.39; P < .001) and admission to a teaching hospital (adjusted odds ratio, 0.65; 95% CI, 0.56-0.75; P < .001) independently predicted lower hospital mortality. Weekend admission was associated with higher hospital mortality (adjusted odds ratio, 1.12; 95 CI, 1.02-1.23; P = .01) and more complications (50.6% vs. 47.8%; P < .001) than weekday admissions. CONCLUSION: There was significantly increased mortality among weekend admissions for acute leukemia. Mortality was reduced among patients admitted to teaching hospitals. PMID- 28864172 TI - Do Patients Understand the Role of Resident Physicians in the Operating Room? A Survey of Gynaecology Patients. AB - OBJECTIVE: Studies from disciplines outside gynaecology have found that most patients do not understand the clinical responsibilities allocated to physicians in-training. No research on this topic has been published in gynaecology, despite litigation against gynaecological surgeons regarding the role of residents in surgery. The goal of this research was to explore what gynaecological surgery patients understand about the role of resident doctors. METHODS: A questionnaire was distributed to female patients in gynaecological surgery pre-admission clinics in Edmonton, Alberta. Surveys included knowledge and opinion statements about residents' duties. Anonymous responses were entered into a secure database. Descriptive statistics were used to characterize the results. RESULTS: Of 108 participants, 83% understood that residents had a higher level of training than medical students, yet 40% were unsure whether residents were doctors. Almost one half (43%) of participants were uncertain whether residents required supervision, including while operating (20%). Most (92%) believed it was important to know their physician's level of training, yet only 63% reported knowing this information. Only 50% of participants would be comfortable with residents operating on them under supervision. A considerable number (56%) wanted to learn more about residents' roles. CONCLUSION: Patients do not fully understand the role of residents, and many are uncomfortable with trainees operating on them under supervision. Considering the significant role of residents in patient care, educating patients is essential to improve their comfort and the overall consent process. PMID- 28864173 TI - Stenose ureterale a la suite de l'excision de lesions d'endometriose profonde. PMID- 28864174 TI - Ureteric Stricture Following Excision of Deep Endometriosis. PMID- 28864175 TI - Non-Hodgkin Lymphomas in Mature Cystic Teratomas: A Case Report and Review of the Literature. AB - BACKGROUND: Mature teratomas, better known as dermoid cysts, are the most common ovarian neoplasms in women in the second and third decade of life. They are invariably benign, and most women are asymptomatic. Ovarian cystectomy is the preferred therapeutic option. CASE: A 24-year-old woman was planned for elective laparoscopic cystectomy for a suspected teratoma; operative findings led to a unilateral oophorectomy. Pathological analysis of the specimen revealed a focus of large cell lymphoma of unknown lineage arising in a mature cystic teratoma. A total body positron emission tomography (PET) scan revealed no other disease, and the patient was managed conservatively with regular follow-up. CONCLUSION: Lymphoma in a teratoma is an excessively rare finding with only five previously reported cases. A review of the literature revealed very different theories as to its pathogenesis and management. PMID- 28864176 TI - Riboflavin and ultraviolet A irradiation for the prevention of progressive myopia in a guinea pig model. AB - In this study, we evaluated the effect of oral administration of riboflavin combined with whole-body ultraviolet A (UVA) irradiation on the biochemical and biomechanical properties of sclera in a guinea pig model to control the progression of myopia. Experimental groups were administered 0.1% riboflavin solution with or without vitamin C by gavage from 3 days before myopic modeling and during the modeling process. Guinea pigs underwent 30 min of whole-body UVA irradiation after each gavage for 2 weeks. For control groups, guinea pigs were administered vitamin C and underwent either whole-body UVA irradiation without 0.1% riboflavin solution or whole-body fluorescent lamp irradiation with or without 0.1% riboflavin solution. Resultantly, myopia models were established with an increased axial length and myopic diopter. Compared with myopic eyes in the control groups, the net increase in axial length, diopter and strain assessment decreased significantly, and the net decrease in sclera thickness, ultimate load, and stress assessment decreased significantly in experimental groups. MMP-2 expression showed a lower net increase, while TIMP-2 expression showed a lower net decrease. In addition, hyperplasia of scleral fibroblasts was more active in myopic eyes of experimental groups. Overall, our results showed that oral administration of riboflavin with whole-body UVA irradiation could increase the strength and stiffness of sclera by altering the biochemical and biomechanical properties, and decreases in axial elongation and myopic diopter are greater in the guinea pig myopic model. PMID- 28864177 TI - Corneoscleral stiffening increases IOP spike magnitudes during rapid microvolumetric change in the eye. AB - Factors governing the steady-state IOP have been extensively studied; however, the dynamic aspects of IOP are less understood. Clinical studies have suggested that intraocular pressure (IOP) fluctuation may be associated with glaucoma risk. This study aims to investigate how stiffening of corneoscleral biomechanical properties affects IOP spikes induced by rapid microvolumetric change. Porcine eyes (n = 25 in total) were subjected to volumetric infusions before and after external treatment of a circular area (11 mm diameter) in either the central cornea or posterior sclera. The treated area in the control group was immersed in phosphate-buffered saline (PBS) for 40 min, while the treated area of the chemical crosslinking group was immersed in 4% glutaraldehyde/PBS for 40 min. A subset of the sham-treated eyes was also subjected to volumetric infusions at a raised steady-state IOP. The magnitude of IOP spikes increased after localized chemical crosslinking of either the cornea (27.5% increase, p < 0.001) or the sclera (14.3% increase, p < 0.001) with corneal crosslinking having a stronger effect than scleral crosslinking (p = 0.018). We also observed that raising the steady-state IOP from 15 to 25 mmHg resulted in marked increase in IOP spike magnitudes by 63.9% (p < 0.001). These results suggested that an increased corneoscleral stiffness could significantly increase IOP spike magnitudes at the same volumetric change. Corneal stiffness appeared to have a strong impact on the IOP spike magnitude and may play a major role in regulating rapid volume-pressure dynamics. An increase in steady-state IOP also resulted in larger IOP fluctuations due to the increased "apparent" stiffness of the ocular shell, suggesting a potential interaction between the magnitude of IOP and its fluctuations. Corneoscleral properties may represent additional pathways for understanding and managing glaucoma risk and warrant future investigation. PMID- 28864178 TI - Very early onset inflammatory bowel disease: Investigation of the IL-10 signaling pathway in Iranian children. AB - BACKGROUND & AIM: Comparing to adult inflammatory bowel disease (IBD), those with early onset manifestations have different features in terms of the underlying molecular pathology, the course of disease and the response to therapy. We investigated the IL-10 signaling pathway previously reported as an important cause of infantile (Very Early Onset) IBD to find any possible variants. METHOD: With the next generation sequencing technique we screened IL-10, IL-10RA and IL10RB genes of 15 children affected by very early onset-GI (gastrointestinal) disorders. Additionally, we analyzed them based on Thermo Fisher immune deficiency panel for genes either having a known role in IBD pathogenesis or cause the disorders with overlapping manifestations. We performed multiple functional analyses only for the cases showing variants in IL-10- related genes. RESULT: In 3 out of 15 patients we identified variants including a homozygous and heterozygote mutations in IL-10RA and a novel homozygous mutation in IL-12RB1. Our functional studies reveal that in contrast to the IL-10RA heterozygote mutation that does not have deleterious effects, the homozygous mutation abrogates the IL-10 signaling pathway. CONCLUSION: Our study suggests we need to modify the classical diagnostic approach from functional assays followed by candidate- gene or genes sequencing to the firstly parallel genomic screening followed by functional studies. PMID- 28864179 TI - Microfluidic device coupled with a microfabricated oxygen electrode for the measurement of bactericidal activity of neutrophil-like cells. AB - A microfluidic device coupled with a microfabricated Clark-type oxygen electrode was used to measure the bactericidal activity of neutrophil-like cells differentiated from HL-60 cells. The neutrophil-like cells and Escherichia coli (E. coli) cells were cultured in the same medium, which was introduced into the flow channel of the device. Changes in the respiratory activity of E. coli were measured as changes in the consumption of dissolved oxygen. As the activity of the neutrophil-like cells increased, the rate of elimination of E. coli increased. The accompanying decrease in the number of E. coli reduced the consumption of dissolved oxygen. The changes were actually observed as changes in generated current. A distinct difference in changes in dissolved oxygen concentrations was observed between E. coli cells co-incubated with IFN-gamma activated or non-activated neutrophil-like cells. The required sample volume was less than 10 MUL, and results could be obtained within 1-2 h. The device may be useful for the assessment of psychological stresses that affect the activity of neutrophils. PMID- 28864180 TI - Nitric oxide sensing by chlorophyll a. AB - Nitric oxide (NO) acts as a signalling molecule that has direct and indirect regulatory roles in various functional processes in biology, though in plant kingdom its role is relatively unexplored. One reason for this is the fact that sensing of NO is always challenging. There are very few probes that can classify the different NO species. The present paper proposes a simple but straightforward way for sensing different NO species using chlorophyll, the source of inspiration being hemoglobin that serves as NO sink in mammalian systems. The proposed method is able to classify NO from DETA-NONOate or (Z)-1-[N-(2-aminoethyl)-N-(2 ammonioethyl) amino] diazen-1-ium-1,2-diolate, nitrite, nitrate and S nitrosothiol or SNO. This discrimination is carried out by chlorophyll a (chl a) at nano molar (nM) order of sensitivity and at 293 K-310 K. Molecular docking reveals the differential binding effects of NO and SNO with chlorophyll, the predicted binding affinity matching with the experimental observation. Additional experiments with a diverse range of cyanobacteria reveal that apart from the spectroscopic approach the proposed sensing module can be used in microscopic inspection of NO species. Binding of NO is sensitive to temperature and static magnetic field. This provides additional support for the involvement of the porphyrin ring structures to the NO sensing process. This also, broadens the scope of the sensing methods as hinted in the text. PMID- 28864181 TI - Novel ionic liquid matrices for qualitative and quantitative detection of carbohydrates by matrix assisted laser desorption/ionization mass spectrometry. AB - Analysis of carbohydrates based on matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is still challenging and researchers have been devoting themselves to efficient matrices discovery. In the present study, the design, synthesis, qualitative and quantitative performance of non-derivative ionic liquid matrices (ILMs) were reported. DHB/N-methylaniline (N-MA) and DHB/N ethylaniline (N-EA), performing best for carbohydrate detection, have been screened out. The limit of detection for oligosaccharide provided by DHB/N-MA and DHB/N-EA were as low as 10 fmol. DHB/N-MA and DHB/N-EA showed significantly higher ion generation efficiency than DHB. The comparison of capacity to probe polysaccharide between these two ILMs and DHB also revealed their powerful potential. Their outstanding performance were probably due to lower proton affinities and stronger UV absorption at lambda = 355 nm. What is more, taking DHB/N-MA as an example, quantitative analysis of fructo-oligosaccharide mixtures extracted and identified from rice noodles has been accomplished sensitively using an internal standard method. Overall, DHB/N-MA and DHB/N-EA exhibited excellent performance and might be significant sources as the carbohydrate matrices. PMID- 28864182 TI - Integration of laminar flow extraction and capillary electrophoretic separation in one microfluidic chip for detection of plant alkaloids in blood samples. AB - The design, construction and testing for integration of liquid-liquid extraction (EX) and capillary electrophoretic (CE) separation on one glass microchip was reported. In this EX-CE chip, a 1.5 cm-long and 200 MUm-wide EX channel was used for extraction based on the two-phase laminar flow, followed by a single-cross CE unit for on-line analysis without any auxiliary devices. One side of the EX channel surface for the organic solvent phase was selectively modified to be hydrophobic while the surface of the other side for the aqueous phase remained hydrophilic, and the extraction product reservoir is also used as the sample reservoir for the subsequent chip separation in the CE channel. With the surface directed liquid flow behavior and liquid level adjustment in various reservoirs of the EX-CE chip, no disturbance occurred between the extraction (EX) and capillary electrophoretic (CE) units. A small heating block was placed under the chip to accelerate solvent evaporation after liquid-liquid extraction. Sanguinarine (SAN), a plant alkaloid, was used as a model analyte to evaluate the performance of the EX-CE chip. The influences of organic solvent type and liquid flow speed on the extraction efficiency were investigated. Rhodamine 123 (Rh123) was used as an internal standard for quantification of Sanguinarine (SAN) in a physiological buffer (e.g. PBS) or blood samples. A good linearity in the concentration range of 0.05 MUg mL-1 to 0.1 mg mL-1 for SAN in PBS was obtained, with the detection limit of 0.5 ng mL-1. Good repeatibilities for migration times (RSD of SAN is 0.63%, Rh123 is 0.91%, n = 5) and peak area ratio of SAN to Rh123 (RSD is 1.3%, n = 5) were obtained. For blood sample analysis, only 20 MUL of sample was needed, and the whole analysis was finished in 17 min. In addition to the advantages in fast analysis speed, minimum sample handling, potential automation, the reported method showed an on-line sample pre-concentration capability. PMID- 28864183 TI - Novel volumetric method for highly repeatable injection in microchip electrophoresis. AB - A novel injector for microchip electrophoresis (MCE) has been designed and evaluated that achieves very high repeatability of injection volume suitable for quantitative analysis. It eliminates the injection biases in electrokinetic injection and the dependence on pressure and sample properties in hydrodynamic injection. The microfluidic injector, made of poly(dimethylsiloxane) (PDMS), operates similarly to an HPLC injection valve. It contains a channel segment (chamber) with a well-defined volume that serves as an "injection loop". Using on chip microvalves, the chamber can be connected to the sample source during the "loading" step, and to the CE separation channel during the "injection" step. Once the valves are opened in the second state, electrophoretic potential is applied to separate the sample. For evaluation and demonstration purposes, the microinjector was connected to a 75 MUm ID capillary and UV absorbance detector. For single compounds, a relative standard deviation (RSD) of peak area as low as 1.04% (n = 11) was obtained, and for compound mixtures, RSD as low as 0.40% (n = 4) was observed. Using the same microchip, the performance of this new injection technique was compared to hydrodynamic injection and found to have improved repeatability and less dependence on sample viscosity. Furthermore, a non radioactive version of the positron-emission tomography (PET) imaging probe, FLT, was successfully separated from its known 3 structurally-similar byproducts with baseline resolution, demonstrating the potential for rapid, quantitative analysis of impurities to ensure the safety of batches of short-lived radiotracers. Both the separation efficiency and injection repeatability were found to be substantially higher when using the novel volumetric injection approach compared to electrokinetic injection (performed in the same chip). This novel microinjector provides a straightforward way to improve the performance of hydrodynamic injection and enables extremely repeatable sample volume injection in MCE. It could be used in any MCE application where volume repeatability is needed, including the quantitation of impurities in pharmaceutical or radiopharmaceutical samples. PMID- 28864184 TI - Reduced graphene oxide as a resonance light-scattering probe for thrombin detection using dual-aptamer-based dsDNA. AB - This paper describes a reduced graphene oxide (RGO)-based resonance light scattering (RLS) method for thrombin detection by using double strand DNA (dsDNA) as a binding element. dsDNA is obtained by hybridizing DNA1 and DNA2, which respectively consist of one aptamer of thrombin and the complementary strand of the other aptamer of thrombin. When thrombin is added, the specific binding of two aptamers to thrombin results in a complex (DNA1-thrombin-DNA2) and triggers the release of the complementary strand of two aptamers from dsDNA. The released ssDNA can be self-assembled on the surface of RGO to form a stable DNA1-thrombin DNA2-RGO complex, which increases RLS signals. This simple and rapid method has enabled the detection of thrombin in the picomolar level in buffer and human serum samples. This study is the first to use RGO as a platform in RLS sensor, which can extend the application of RGO. PMID- 28864185 TI - Sensitive amperometric detection of riboflavin with a whole-cell electrochemical sensor. AB - A novel whole-cell electrochemical sensor was developed and applied for sensitive amperometric detection of riboflavin. In this work, a whole-cell based riboflavin redox cycling system was characterized, in which electroactive bacteria Shewanella oneidensis MR-1 was employed as the biocatalyst to regenerate the reduced riboflavin after the electrode oxidation. This redox cycling system efficiently enhanced the electrochemical response of riboflavin and enabled a stable current output at poised electrode potential. Thus, a sensitive amperometric biosensing system for riboflavin detection was developed by integrating this whole-cell redox cycling system with the conventional riboflavin electrochemical sensor. Remarkably, this riboflavin biosensor exhibited high sensitivity (LOD = 0.85 +/- 0.09 nM, S/N = 3), excellent selectivity and stability. Additionally, reliable analysis of real samples (food and pharmaceutical samples) by this biosensor was achieved. This work provided sensitive and practical tool for riboflavin detection, and demonstrated that the integration of electroactive bacteria and using its outwards electron transfer for redox cycling would be a powerful and promising strategy to improve the performance of electrochemical sensing system. PMID- 28864186 TI - Facile synthesis of MnO2-embedded flower-like hierarchical porous carbon microspheres as an enhanced electrocatalyst for sensitive detection of caffeic acid. AB - Tailored designs/fabrications of hierarchical porous advanced electrode materials are of great importance for developing high-performance electrochemical sensors. Herein, we demonstrate a simple and low-cost in situ chemical approach for the facile synthesis of MnO2-embedded hierarchical porous carbon microspheres (MnO2/CM). By the characterizations of scanning electron microscopy, X-ray photoelectron spectroscopy, X-ray powder diffraction and energy dispersive spectroscopy, we evidenced that the synthesized product were flower-like carbon microspheres (CM) assembled by the bent flakes with thickness of about several nanometers and MnO2 nanorods were highly dispersed and successfully decorated on the CM layers, resulting in a rough surface and three-dimensional microstructure. The greatest benefit from the combined porous CM with MnO2 nanorods is that the MnO2/CM modified electrode has the synergetic catalysis effect on the electro oxidation of caffeic acid, leading to the remarkable increase in the electron transfer rate and significant decrease in the over-potential for the caffeic acid oxidation in contrast to the bare electrode and CM modified electrode. This implies that the prepared MnO2/CM can be employed as an enhanced electrocatalyst for the sensitive detection of caffeic acid. Under the optimum conditions, the anodic peak current of caffeic acid is linear with its concentration in the range of 0.01-15.00 MUmol L-1, and a detection limit of 2.7 nmol L-1 is achieved based on S/N = 3. The developed sensor shows good selectivity, sensitivity, reproducibility, and also excellent recovery in the detections of real samples, revealing the promising practicality of the sensor for the caffeic acid detection. PMID- 28864187 TI - Quantum-dot nanoprobes and AOTF based cross talk eliminated six color imaging of biomolecules in cellular system. AB - Primary cell cultures mimic the physiology and genetic makeup of in-vivo tissue of origin, nonetheless, a complication in the derivation and propagation of primary cell culture limits its use in biological research. However, in-vitro models using primary cells might be a complement model to mimic in vivo response. But, conventional techniques such as western blot and PCR employed to study the expression and activation of proteins requires a large number of cells, hence repeated establishment and maintenance of primary culture are unavoidable. Quantum dot (Q-dot) and acousto-optic tunable filters (AOTF) based multiplex imaging system is a viable alternative choice to evaluate multiple signaling molecules by using a small number of cells. Q-dots have broad excitation and narrow emission spectra, which allows to simultaneously excite multiple Q-dots by using single excitation wavelength. The use of AOTF in the fluorescence detection system enables to scan the fluorescence emission intensity of a Q-dot at their central wavelength, this phenomenon effectively avoids spectral overlap among the neighboring Q-dots. When Q-dots are conjugated with antibodies it acts as effective sensing probes. To validate this, the expression pattern of p-JNK-1, p GSK3beta, p-IRS1ser, p-IRS1tyr, p-FOXO1, and PPAR-gamma, involved in the insulin resistance were concurrently monitored in adipocyte and HepG2 co-cell culture model. The observed results clearly indicate that PPAR-gamma is the critical component in the development of insulin resistance. Moreover, the results proved that developed Q-dot based AOTF imaging methodology is a sensible choice to concurrently monitor multiple signaling molecules with limited cell population. PMID- 28864188 TI - Fluorescence sensor array based on amino acids-modulating quantum dots for the discrimination of metal ions. AB - We developed an easily extensible fluorescence sensor array based on amino acids modulating QDs for the discrimination of nine metal ions. Two amino acids (Glutamine and Arginine) were assembled with two quantum dots including 3 mercaptopropionic acid capped Mn-ZnS QDs (MPA-QDs) and alpha-thioglycerol capped Mn-ZnS QDs (TG-QDs), achieving six across-reactive sensing elements. Amino acids as the modulators imparted the diversity and differential detection of metal ions, because they could bind QDs and also form complexes with metal ions through their carboxyl, amino, and hydroxyl groups. Therefore, the fluorescence response signals for metal ions could be either enhanced or decreased. This sensing system allowed the accurate classification of nine metal ions in pure water at 0.5 MUM and tap water at 3.0 MUM. Moreover, two metal ions with different oxidation state Fe3+ and Fe2+, as well as their binary mixtures were well distinguished. Our sensor array was capable of the quantitative analysis of metal ions, showing a linear range from 0.5 MUM to 20 MUM for Co2+, Ni2+, Mn2+, and Fe2+. The results demonstrated that the number of sensing elements was easily extensible by using amino acids as QDs regulators. This strategy will provide a new direction to establish the sensitive array sensing systems. PMID- 28864189 TI - High-performance chiral stationary phases based on chitosan derivatives with a branched-chain alkyl urea. AB - In this study, two series of chitosan 3,6-bis(arylcarbamate)-2-(isobutylurea)s and corresponding coated-type chiral stationary phases (CSPs) were prepared from two kinds of chitosans with different molecular weights. Most of the prepared CSPs demonstrated better enantioseparation performance than the homemade CSP of cellulose tris(3,5-dimethylphenylcarbamate). The CSPs of chitosan 3,6-bis(4 methylphenylcarbamate)-2-(isobutylurea) with higher molecular weight and chitosan 3,6-bis(3-chloro-4-methylphenylcarbamate)-2-(isobutylurea) with lower molecular weight possessed outstanding chiral recognition abilities which were at least as good as that of the commercialized CSP of Chiralcel OD-H towards the tested chiral analytes. Except for the two CSPs derived from chitosan 3,6-bis(4 methylphenylcarbamate)-2-(isobutylurea)s, the CSPs (the first class) with the chiral selectors of lower molecular weight provided better enantioseparations than the ones (the second class) with the chiral selectors of higher molecular weight. On the other hand, the chiral selectors of the first class CSPs showed higher swelling capacities in organic solvents than the ones of the second class. All prepared CSPs could be analyzed with a wider range of mobile phases, in which some "unusual organic solvents" such as ethyl acetate, chloroform and THF etc. could be used as additives. According to separation performance and tolerance against organic solvents, we concluded that the chitosan derivatives with branched-chain alkyl urea at 2-C of glucosamine residue were preferable to be used as chiral selectors for enantiomeric separation. PMID- 28864190 TI - Core-shell silica microsphere-based trypsin nanoreactor for low molecular-weight proteome analysis. AB - Core-shell mesoporous silica (CSMS) microspheres with tunable mesopores in the shell are highly desired in various bioapplications. With novel CSMS microspheres that are synthesized using a convenient two-phase process, we report in this study the analysis of low molecular-weight (MW < 30 kDa) proteins by combining size-exclusion separation and enzyme immobilization. The obtained CSMS microspheres possess uniform diameter (1.3 MUm with a shell thickness of 57 nm), large and tunable perpendicular mesopores (7.9 nm), high surface area (55.5 m2/g), large pore volume (0.12 cm3/g) and excellent water dispersibility. The CSMS microsphere-based enzyme nanoreactors have been fabricated by immobilizing trypsin on the pore channels of the CSMS microspheres using either physical absorption or covalent binding via thiol or aldehyde group with a high loading capacity of 11.8-6.1 mg/g. Due to the unique fibrous pore structure, low MW proteins can enter the channels in the shell to interact with immobilized trypsin, followed by analysis of the digestion products using MALDI-TOF MS or electrophoresis (CE) techniques. The properties and analytical performance of different trypsin-immobilized CSMS microspheres has been systematically evaluated. The results show that the peptide-sequence coverage of the smaller protein is enhanced by using trypsin-CSMS microspheres, indicating the size dependent digestion which results from the size-exclusion interaction of the mesopores against the high-MW proteins. The present study would pave the way for further applications of mesoporous materials in proteome analysis. PMID- 28864191 TI - Focusing and non-focusing modulation strategies for the improvement of on-line two-dimensional hydrophilic interaction chromatography * reversed phase profiling of complex food samples. AB - Comprehensive two-dimensional liquid chromatography (LC * LC) is ever gaining interest in food analysis, as often, food-related samples are too complex to be analyzed through one-dimensional approaches. The use of hydrophilic interaction chromatography (HILIC) combined with reversed phase (RP) separations has already been demonstrated as a very orthogonal combination, which allows attaining increased resolving power. However, this coupling encompasses different analytical challenges, mainly related to the important solvent strength mismatch between the two dimensions, besides those common to every LC * LC method. In the present contribution, different strategies are proposed and compared to further increase HILIC * RP method performance for the analysis of complex food samples, using licorice as a model sample. The influence of different parameters in non focusing modulation methods based on sampling loops, as well as under focusing modulation, through the use of trapping columns in the interface and through active modulation procedures are studied in order to produce resolving power and sensitivity gains. Although the use of a dilution strategy using sampling loops as well as the highest possible first dimension sampling rate allowed significant improvements on resolution, focusing modulation produced significant gains also in peak capacity and sensitivity. Overall, the obtained results demonstrate the great applicability and potential that active modulation may have for the analysis of complex food samples, such as licorice, by HILIC * RP. PMID- 28864192 TI - Designed graphene-peptide nanocomposites for biosensor applications: A review. AB - The modification of graphene with biomacromolecules like DNA, protein, peptide, and others extends the potential applications of graphene materials in various fields. The bound biomacromolecules could improve the biocompatibility and bio recognition ability of graphene-based nanocomposites, therefore could greatly enhance their biosensing performances on both selectivity and sensitivity. In this review, we presented a comprehensive introduction and discussion on recent advance in the synthesis and biosensor applications of graphene-peptide nanocomposites. The biofunctionalization of graphene with specifically designed peptides, and the synthesis strategies of graphene-peptide (monomer, nanofibrils, and nanotubes) nanocomposites were demonstrated. On the other hand, the fabrication of graphene-peptide nanocomposite based biosensor architectures for electrochemical, fluorescent, electronic, and spectroscopic biosensing were further presented. This review includes nearly all the studies on the fabrication and applications of graphene-peptide based biosensors recently, which will promote the future developments of graphene-based biosensors in biomedical detection and environmental analysis. PMID- 28864193 TI - Process modeling and control applied to real-time monitoring of distillation processes by near-infrared spectroscopy. AB - A distillation device that acquires continuous and synchronized measurements of temperature, percentage of distilled fraction and NIR spectra has been designed for real-time monitoring of distillation processes. As a process model, synthetic commercial gasoline batches produced in Brazil, which contain mixtures of pure gasoline blended with ethanol have been analyzed. The information provided by this device, i.e., distillation curves and NIR spectra, has served as initial information for the proposal of new strategies of process modeling and multivariate statistical process control (MSPC). Process modeling based on PCA batch analysis provided global distillation trajectories, whereas multiset MCR ALS analysis is proposed to obtain a component-wise characterization of the distillation evolution and distilled fractions. Distillation curves, NIR spectra or compressed NIR information under the form of PCA scores and MCR-ALS concentration profiles were tested as the seed information to build MSPC models. New on-line PCA-based MSPC approaches, some inspired on local rank exploratory methods for process analysis, are proposed and work as follows: a) MSPC based on individual process observation models, where multiple local PCA models are built considering the sole information in each observation point; b) Fixed Size Moving Window - MSPC, in which local PCA models are built considering a moving window of the current and few past observation points; and c) Evolving MSPC, where local PCA models are built with an increasing window of observations covering all points since the beginning of the process until the current observation. Performance of different approaches has been assessed in terms of sensitivity to fault detection and number of false alarms. The outcome of this work will be of general use to define strategies for on-line process monitoring and control and, in a more specific way, to improve quality control of petroleum derived fuels and other substances submitted to automatic distillation processes monitored by NIRS. PMID- 28864194 TI - Cathodic electrogenerated chemiluminescence of aromatic Tb(III) chelates at polystyrene-graphite composite electrodes. AB - Tb(III) chelates exhibit intense hot electron-induced electrogenerated chemiluminescence during cathodic polarization of metal/polystyrene-graphite (M/PG) electrodes in fully aqueous solutions. The M/PG working electrode provides a sensitive means for the determination of aromatic Tb(III) chelates at nanomolar concentration levels with a linear log-log calibration curve spanning more than five orders of magnitude. The charge transport and other properties of these novel electrodes were studied by electrochemiluminescence measurements and cyclic voltammetry. The present composite electrodes can by utilized both under pulse polarization and DC polarization unlike oxide-coated metal electrodes which do not tolerate cathodic DC polarization. The present cost-effective electrodes could be utilized e.g. in immunoassays where polystyrene is extensively used as a solid phase for various bioaffinity assays by using electrochemiluminescent Tb(III) chelates or e.g. Ru(bpy)32+as labels. PMID- 28864195 TI - Flow injection amperometric sandwich-type aptasensor for the determination of human leukemic lymphoblast cancer cells using MWCNTs-Pdnano/PTCA/aptamer as labeled aptamer for the signal amplification. AB - In this research, we demonstrated a flow injection amperometric sandwich-type aptasensor for the determination of human leukemic lymphoblasts (CCRF-CEM) based on poly(3,4-ethylenedioxythiophene) decorated with gold nanoparticles (PEDOT Aunano) as a nano platform to immobilize thiolated sgc8c aptamer and multiwall carbon nanotubes decorated with palladium nanoparticles/3,4,9,10-perylene tetracarboxylic acid (MWCNTs-Pdnano/PTCA) to fabricate catalytic labeled aptamer. In the proposed sensing strategy, the CCRF-CEM cancer cells were sandwiched between immobilized sgc8c aptamer on PEDOT-Aunano modified surface electrode and catalytic labeled sgc8c aptamer (MWCNTs-Pdnano/PTCA/aptamer). After that, the concentration of CCRF-CEM cancer cells was determined in presence of 0.1 mM hydrogen peroxide (H2O2) as an electroactive component. The attached MWCNTs Pdnano nanocomposites to CCRF-CEM cancer cells amplified the electrocatalytic reduction of H2O2 and improved the sensitivity of the sensor to CCRF-CEM cancer cells. The MWCNT-Pdnano nanocomposite was characterized with transmission electron microscopy (TEM) and energy dispersive X-ray (EDX). The electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) were used to confirm the stepwise changes in the electrochemical surface properties of the electrode. The proposed sandwich-type electrochemical aptasensor exhibited an excellent analytical performance for the detection of CCRF-CEM cancer cells ranging from 1.0 * 101 to 5.0 * 105 cells mL-1. The limit of detection was 8 cells mL-1. The proposed aptasensor showed high selectivity toward CCRF-CEM cancer cells. The proposed aptasensor was also applied to the determination of CCRF-CEM cancer cells in human serum samples. PMID- 28864196 TI - A polypyrrole-chitosan cryogel stir-bead micro-solid phase extractor for the determination of phthalate esters in contact lenses storage solutions and in artificial saliva in contact with baby teethers. AB - Phthalate esters (PAEs), especially dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP) are widely used as plasticizers in plastics and polymers. They are not chemically bound and can easily migrate into food and human tissue that comes into contact with these materials. The method developed in this work was applied for the preconcentration and determination of these four phthalate esters that might leach from contact lenses and baby teethers. A novel stir-bead micro-solid phase extractor of chitosan cryogel composited with polypyrrole with a steel wire core was evaluated for the extraction of DMP, DEP, DBP and DEHP before analysis by high performance liquid chromatography (HPLC). Scanning electron micrographs of the polypyrrole chitosan cryogel beads revealed a high porosity with large surface area. Under the optimum conditions, the developed method provided a good linearity in a concentration range from 10 to 750 ng mL-1 for DMP and from 5.0 to 750 ng mL-1 for DEP, DBP and DEHP. The limits of detection (LOD) were 6.07 +/- 0.22 ng mL-1, 4.358 +/- 0.097 ng mL-1, 4.408 +/- 0.099 ng mL-1 and 3.916 +/- 0.053 ng mL-1 for DMP, DEP, DBP and DEHP, respectively, and the method reproducibility was good (n = 6, % RSD < 6.0). DBP and DEHP were detected in two original storage solutions of contact lenses from 13.2 +/- 1.1 ng mL-1 to 15.4 +/- 1.9 ng mL-1 and from 21.3 +/- 1.6 ng mL-1 to 23.5 +/- 1.5 ng mL-1, respectively. In the artificial saliva in contact with baby teether samples only DEHP was found, from 4.91 +/- 0.31 ng mL-1 to 6.78 +/- 0.23 ng mL-1, with good recoveries ranging from 81.3 +/- 8.4% to 106.3 +/- 5.2%. PMID- 28864197 TI - Electrophoretic separations on paper: Past, present, and future-A review. AB - Point-of-collection (POC) devices aim for a fast, on-site detection for medical and environmental purposes. In this area, microfluidic Paper-based Analytical Devices (MUPADs) have recently gained popularity because these are potentially cheap and environmentally friendly to produce, and easy to use. From an analytical perspective, paper is well known for its use as a substrate for chromatography, but less known for its use in electrophoretic separations. With the recent interest in MUPADs, most applications are based on rather simple assays with relatively few applications incorporating an analytical separation. The focus of this review is on paper-based electrophoresis, originating with the key developments in the 1940s and 1950s as well as the recent developments of electrophoretic MUPADs, and concluding with a critical discussion of the opportunities and challenges for electrophoretic MUPADS in the future. PMID- 28864198 TI - Comprehensive solid-phase extraction of multitudinous bioactive peptides from equine plasma and urine for doping detection. AB - The ability to analyze biological samples for multitudinous exogenous peptides with a single analytical method is desired for doping control in horse racing. The key to achieving this goal is the capability of extracting all target peptides from the sample matrix. In the present study, theory of mixed-mode solid phase extraction (SPE) of peptides from plasma is described, and a generic mixed mode SPE procedure has been developed for recovering multitudinous exogenous peptides with remarkable sequence diversity, from equine plasma and urine in a single procedure. Both the theory and the developed SPE procedure have led to the development of a novel analytical method for comprehensive detection of multitudinous bioactive peptides in equine plasma and urine using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). Thirty nine bioactive peptides were extracted with strong anion-exchange mixed-mode SPE sorbent, separated on a reversed-phase C18 column and detected by HRMS and data dependent tandem mass spectrometry. The limit of detection (LOD) was 10-50 pg mL 1 in plasma for most of the peptides and 100 pg mL-1 for the remaining. For urine, LOD was 20-400 pg mL-1 for most of the peptides and 1-4 ng mL-1 for the others. In vitro degradation of the peptides in equine plasma and urine was examined at ambient temperature; the peptides except those with a D-amino acid at position 2 were unstable not only in plasma but also in urine. The developed method was successful in analysis of plasma and urine samples from horses administered dermorphin. Additionally, dermorphin metabolites were identified in the absence of reference standards. The developed SPE procedure and LC-HRMS method can theoretically detect virtually all peptides present at a sufficient concentration in a sample. New peptides can be readily included in the method to be detected without method re-development. The developed method also generates such data that can be retrospectively analyzed for peptides unknown at the time of sample analysis. It is the first generic analytical method for comprehensive detection of multitudinous exogenous peptides in biological samples, to the authors' knowledge. PMID- 28864199 TI - Silica stationary phase functionalized by 4-carboxy-benzoboroxole with enhanced boronate affinity nature for selective capture and separation of cis-diol compounds. AB - 4-Carboxy-benzoboroxole was designed and synthesized. It was then combined with the modification effect of polyethyleneimine (PEI) for the preparation of boronate affinity silica stationary phase. The stationary phase showed improved binding strength with dissociation constant (Kd) towards xanthosine as low as 2.48 * 10-4 M. The column showed excellent selectivity, high binding capacities (88.3 MUmol adenosine g-1, pH 7.0) and the lowest binding pH (4.0 for cytidine and as low as 2.24 for xanthosine). These binding properties were superior to the existing boronate affinity materials, facilitating the selective extraction of trace cis-diol compounds in complex samples and greatly expanding the application scope of boronate affinity chromatography. In addition, the column showed secondary separation capability under acidic conditions and this secondary separation capability was investigated thoroughly. It was found that the separation was pH-dependent and mainly determined by binding strength with the possibility of involvement of other interaction, providing alternative strategy for the separation of cis-diol compounds. The feasibility and practicability were demonstrated through the selective enrichment of nucleosides in urine samples and the results indicated the excellent performance and great potential for the extraction of trace cis-diol compounds in complex samples. PMID- 28864200 TI - Vascular expression of angiopoietin1, alpha5beta1 integrin and tight junction proteins is tightly regulated during vascular remodeling in the post-ischemic brain. AB - The post-stroke angiogenic response is accompanied by changes of tight junctions (TJs) of the blood-brain barrier (BBB). However, the precise dynamic change of TJ proteins (TJPs) in the different stages of stroke-induced vascular remodeling and the molecules mediating these processes have yet to be fully defined. To investigate the temporal relationship between changes in TJPs, the pro-angiogenic factor alpha5beta1 integrin and the anti-permeability factor Ang1 in cerebral vessels following cerebral ischemic stroke, male C57Bl/6 mice were subject to 90min of ischemia by temporary occlusion of the middle cerebral artery followed by reperfusion and their brains analyzed 0, 1, 2, 4, 7 and 14days post-ischemia. Immunofluorescent studies demonstrated that in the ischemic penumbra, TJPs claudin-5 and ZO-1 levels decreased during the early stages of vascular remodeling, but then increased in the later stages. In contrast, within the ischemic core, TJPs levels decreased over the 14-day time-course, plateaued at day 4, and remained at low levels up to day 14. In the penumbra, Ang1 expression was induced, peaking at the same time point as alpha5beta1 expression. Consistent with these findings, oxygen glucose deprivation/reperfusion induced expression of alpha5beta1 and Ang1 on brain endothelial cell (BEC) in a similar manner in vitro, which correlated closely with BEC proliferation and increased expression of TJPs. Our results demonstrate that in the post-ischemic penumbra, a tight temporal correlation exists between the angiogenic markers alpha5beta1 and Ang1 and the TJPs, suggesting a potential role for Ang1 and alpha5beta1 in promoting BBB integrity following ischemic stroke. PMID- 28864202 TI - Pathogenesis of thromboangiitis obliterans: Gene polymorphism and immunoregulation of human vascular endothelial cells. AB - Thromboangiitis obliterans (TAO) is a nonatherosclerotic, segmental, inflammatory vasculitis, which commonly affects the small- and medium-sized arteries of the upper and lower extremities. Despite its discovery more than a century ago, little progress has been made in its treatment. Unless the pathogenesis is elucidated, therapeutic approaches will be limited. The purpose of this review article is to collate current knowledge of mechanisms for the pathogenesis of thromboangiitis obliterans and to propose potential mechanisms from a genetic and immunoreactive point of view for its inception. Therefore, we discuss the possibility that the pathogenesis of this disease is due to a type of gene polymorphism, which leads to an immunological inflammatory vasculitis associated with tobacco abuse, highly linked to T cells, human vascular endothelial cells (HVECs), and the TLR-MyD88-NFkappaB pathway, distinct from arteriosclerosis obliterans and other vasculitides. PMID- 28864201 TI - OPUS-DOSP: A Distance- and Orientation-Dependent All-Atom Potential Derived from Side-Chain Packing. AB - We report a new distance- and orientation-dependent, all-atom statistical potential derived from side-chain packing, named OPUS-DOSP, for protein structure modeling. The framework of OPUS-DOSP is based on OPUS-PSP, previously developed by us [JMB (2008), 376, 288-301], with refinement and new features. In particular, distance or orientation contribution is considered depending on the range of contact distance. A new auxiliary function in energy function is also introduced, in addition to the traditional Boltzmann term, in order to adjust the contributions of extreme cases. OPUS-DOSP was tested on 11 decoy sets commonly used for statistical potential benchmarking. Among 278 native structures, 239 and 249 native structures were recognized by OPUS-DOSP without and with the auxiliary function, respectively. The results show that OPUS-DOSP has an increased decoy recognition capability comparing with those of other relevant potentials to date. PMID- 28864203 TI - Vitamin A: An enhanced vision of the relationship between apolipoproteins and cardiovascular risk? PMID- 28864204 TI - Soluble form of receptor for advanced glycation end products and incidence of new cardiovascular events among patients with cardiovascular disease. AB - BACKGROUND AND AIMS: Soluble RAGE (sRAGE) serum level could be a biomarker for atherosclerosis and subsequent diseases such as cardiovascular disease (CVD). Therefore, we wanted to investigate whether peripheral sRAGE level is associated with new cardiovascular events among patients with CVD using the Cox's regression analysis. METHODS: In this three-year longitudinal cohort study, 1002 in-patients with angiographically proven CVD were included. In 933 patients, sRAGE levels were determined by a commercial available ELISA kit at the time of baseline examination. The combined endpoint was defined as myocardial infarction, stroke/TIA (non-fatal, fatal), and cardiovascular death. For risk analysis, sRAGE values were distributed in quartiles. For generation of adjusted hazard ratios (HR), other risk factors for CVD, such as age, gender, current smoking, body mass index, diabetes, hypertension, dyslipoproteinemia, family history of CVD, severe periodontitis, serum levels for C-reactive protein and interleukin-6, were recorded. RESULTS: 886 patients completed the 3-year follow-up. The overall incidence of the combined endpoint was 16%. Patients with sRAGE levels >838.19 pg/ml (fourth quartile) had the highest incidence of recurrent CVD events (24.9% versus 13.1%, p < 0.0001). In multivariate Cox regression with respect to further confounders for CVD, the association between sRAGE and new CVD events was confirmed (HR = 1.616, 95% CI 1.027-2.544, p = 0.038). CONCLUSIONS: Elevated sRAGE serum level is associated with further adverse events in patients with CVD. PMID- 28864205 TI - The delta opioid receptor agonist KNT-127 in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice. AB - We previously reported that systemic administration of the selective delta opioid receptor (DOP) agonist KNT-127 produces potent anxiolytic-like effects in rats. Although a higher distribution pattern of DOPs was reported in the prelimbic medial prefrontal cortex (PL-PFC) of rodents, the role of DOPs in PL-PFC and in anxiolytic-like effects have not been well examined. Recently, we demonstrated that activation of PL-PFC with the sodium channel activator veratrine increases glutamatergic neurotransmission and produces anxiety-like behaviors in mice. Therefore, we investigated the effects of co-perfusion with KNT-127 in PL-PFC on veratrine-induced anxiety-like behaviors in mice. We also simultaneously measured extracellular glutamate and GABA levels. In addition, we assessed the effect of KNT-127 on the expression of c-Fos in sub-regions of the amygdala. Extracellular glutamate levels were measured in seven-week-old male C57BL/6N mice using an in vivo microdialysis-HPLC/ECD system, and behaviors were assessed simultaneously in an open field test. Basal levels of glutamate were measured by collecting samples every 10min for 60min. The drug-containing medium was perfused for 30min, and the open field test was performed during the last 10min of drug perfusion. After drug treatments, the perfusion was switched from drug-containing medium to control medium without drugs and samples were collected for another 90min. KNT-127 co perfusion completely diminished veratrine-induced anxiety-like behaviors and attenuated the veratrine-induced increase in extracellular glutamate levels in PL PFC. Interestingly, KNT-127 perfusion alone in PL-PFC did not affect anxiety-like behaviors. Local perfusion of veratrine in PL-PFC induced c-Fos immunoreactivity in sub-regions of amygdala. Co-perfusion of KNT-127 diminished c-Fos expression. Here we demonstrate that the DOP agonist KNT-127 in PL-PFC attenuates veratrine induced anxiety-like behaviors in mice. These effects may be caused by the presynaptic suppression of activated glutamatergic transmission in PL-PFC, which projects to sub-regions of the amygdala. We propose that compounds like KNT-127, which inhibit glutamatergic transmission in PL-PFC, are candidates for novel anxiolytics. PMID- 28864206 TI - Mice lacking hippocampal left-right asymmetry show non-spatial learning deficits. AB - Left-right asymmetry is known to exist at several anatomical levels in the brain and recent studies have provided further evidence to show that it also exists at a molecular level in the hippocampal CA3-CA1 circuit. The distribution of N methyl-d-aspartate (NMDA) receptor NR2B subunits in the apical and basal synapses of CA1 pyramidal neurons is asymmetrical if the input arrives from the left or right CA3 pyramidal neurons. In the present study, we examined the role of hippocampal asymmetry in cognitive function using beta2-microglobulin knock-out (beta2m KO) mice, which lack hippocampal asymmetry. We tested beta2m KO mice in a series of spatial and non-spatial learning tasks and compared the performances of beta2m KO and C57BL6/J wild-type (WT) mice. The beta2m KO mice appeared normal in both spatial reference memory and spatial working memory tasks but they took more time than WT mice in learning the two non-spatial learning tasks (i.e., a differential reinforcement of lower rates of behavior (DRL) task and a straight runway task). The beta2m KO mice also showed less precision in their response timing in the DRL task and showed weaker spontaneous recovery during extinction in the straight runway task. These results indicate that hippocampal asymmetry is important for certain characteristics of non-spatial learning. PMID- 28864207 TI - Differential effects of relaxin-3 and a selective relaxin-3 receptor agonist on food and water intake and hypothalamic neuronal activity in rats. AB - The neuropeptide relaxin-3 (RLN3) binds with high affinity to its cognate receptor, relaxin-family peptide receptor 3 (RXFP3), and with lower affinity to RXFP1, the cognate receptor for relaxin. Intracerebroventricular (icv) administration of RLN3 in rats strongly increases food and water intake and alters the activity of the hypothalamic-pituitary-adrenal (HPA) and gonadal (HPG) axes, but the relative involvement of RXFP3 and RXFP1 in these effects is not known. Therefore, the effects of icv administration of equimolar (1.1 nmol) amounts of RLN3 and the RXFP3-selective agonist RXFP3-A2 on food and water intake, plasma levels of corticosterone, testosterone, and oxytocin and c-fos mRNA expression in key hypothalamic regions in male rats were compared. Food intake was increased by both RLN3 and RXFP3-A2, but the orexigenic effects of RXFP3-A2 were significantly stronger than RLN3, 30 and 60min after injection. Water intake and plasma corticosterone and testosterone levels were significantly increased by RLN3, but not by RXFP3-A2. Conversely, RXFP3-A2 but not RLN3 decreased oxytocin plasma levels. RLN3, but not RXFP3-A2, increased c-fos mRNA levels in the parvocellular (PVNp) and magnocellular (PVNm) paraventricular and supraoptic (SON) hypothalamic nuclei, in the ventral medial preoptic area (MPAv), and in the organum vasculosum of the lamina terminalis (OVLT). A significant increase in c-fos mRNA expression was induced in the perifornical lateral hypothalamic area (LHApf) by RLN3 and RXFP3-A2. These results suggest that RXFP1 is involved in the RLN3 stimulation of water intake and activation of the HPA and HPG axes. The reduced food intake stimulation by RLN3 compared to RXFP3-A2 may relate to activation of both orexigenic and anorexigenic circuits by RLN3. PMID- 28864208 TI - A new mechanism of inhibition of IL-1beta secretion by celastrol through the NLRP3 inflammasome pathway. AB - The NLRP3 (NOD-like receptor protein 3) inflammasome is a caspase-1-containing multiprotein complex that controls the release of IL-1beta and has been associated with the development of inflammatory diseases. Celastrol, a pharmacologically active ingredient extracted from Tripterygium wilfordii Hook, has anti-inflammatory activities based on its inhibition of IL-1beta secretion. The purpose of the present study was to investigate the possible modulation of NLRP3 inflammasome-mediated IL-1beta and IL-18 release from macrophages by celastrol. It was shown that celastrol significantly reduced the secretion of IL 1beta and IL-18 by inhibiting the expression of NLRP3 and the cleavage of caspase 1 in lipopolysaccharide (LPS)/ATP-induced macrophages. In addition, celastrol suppressed pyroptosis in macrophages, demonstrated by caspase-1 activation, LDH leakage and PI uptake assays. Furthermore, these inhibitory effects of celastrol were found to be at least partially achieved by decreasing the up-regulation of reactive oxygen species generation and NF-kappaB activation. Taken together, these findings suggested a new anti-inflammation mechanism of celastrol through inhibition of the NLRP3 inflammasome. PMID- 28864210 TI - Inhibition of the mevalonate pathway by simvastatin interferes with mast cell degranulation by disrupting the interaction between Rab27a and double C2 alpha proteins. AB - Statins are well-known inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase, which block the mevalonate pathway. The activity of statins not only decreases cholesterol levels but also ameliorates inflammation and modulates the immune system. In this study, we investigated the effects of simvastatin on histamine release using rat basophilic leukaemia (RBL-2H3) cells, and examined its interaction with proteins involved in the exocytosis process. Treatment with simvastatin for 24h inhibited histamine release in RBL-2H3 cells in a concentration-dependent manner after stimulation with dinitrophenylated bovine serum albumin (DNP-BSA, as an antigen), ionomycin (a calcium ion [Ca2+] ionophore), and thapsigargin (an inhibitor of Ca2+-ATPase in the endoplasmic reticulum). Simvastatin-induced inhibition was counteracted by co-administration of mevalonolactone or geranylgeraniol, but not farnesol. Indeed, several exocytotic proteins were post-translationally modified by isoprenylation, which is required for proper localization in the lipid membrane. RBL-2H3 cells express proteins involved in the fusion of granules and the plasma membrane, such as Ras like protein in the brain 27a (Rab27a), synaptosome-associated protein 23 (SNAP23), and vesicle-associated membrane protein 7 (VAMP7), as well as Ca2+ binding proteins, such as double C2 alpha (Doc2a), synaptotagmin2, and mammalian uncoordinated13-4 (munc13-4). The interaction of Rab27a and Doc2a proteins was detected using proximity ligation assays. Antigen stimulation caused these proteins to interact, and this interaction could be disrupted by co administration of simvastatin. In conclusion, simvastatin inhibited the mevalonate pathway, which suppressed the geranylgeranylation of Rab27a by depleting geranylgeranyl pyrophosphate and interfering with the Rab27a-Doc2a interaction. This activity resulted in the inhibition of exocytosis in RBL-2H3 cells. PMID- 28864209 TI - Danshensu accelerates angiogenesis after myocardial infarction in rats and promotes the functions of endothelial progenitor cells through SDF-1alpha/CXCR4 axis. AB - The present study was performed to investigate the potential role of Danshensu in therapeutic angiogenesis in ischemic myocardium and endothelial progenitor cells (EPCs) function. The rat model of myocardial infarction (MI) injury was induced by left anterior descending coronary artery ligation for 14 days. Danshensu significantly alleviated myocardial ischemia injury by ameliorating left ventricular function and reducing infarct size. Furthermore, Danshensu potentiated post-ischemia neovascularization as evidenced by increased microvessel density in infarction boundary zone, as well as the expression of marker proteins vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Moreover, Danshensu notably promoted stromal cell-derived factor-1alpha (SDF-1alpha) level in plasma and C-X-C chemokine receptor type 4 (CXCR4) expression in peri-infarction myocardium, and AMD3100 (CXCR4 antagonist) could reverse the angiogenic and cardioprotective effects of Danshensu. For in vitro study, EPCs were isolated from bone marrow of rats. On the one hand, Danshensu provided significant cytoprotection against hypoxia insult by boosting EPCs viability and inhibiting apoptosis, and upregulated Akt phosphorylation. On the other hand, Danshensu enhanced proangiogenic functions of EPCs on cell migration and tube formation, and increased SDF-1alpha and CXCR4 expression. Likewise, the cytoprotection and proangiogenic functions of Danshensu on EPCs were partly negated by LY294002 (PI3K antagonist) and CXCR4 siRNA, respectively. Taken together, our results suggested that the cardioprotection of Danshensu in MI rats may be related to promoting myocardial neovascularization. The possible mechanisms may involve improving EPCs survival in hypoxia condition through Akt phosphorylation, and accelerating EPCs proangiogenic functions through SDF 1alpha/CXCR4 axis. PMID- 28864211 TI - Effects of SPAK on vascular reactivity and nitric oxide production in endotoxemic mice. AB - Vasoplegia impedes therapeutic interventions to restore vascular tone, leading to severe hypotension, poor tissue perfusion, and multiple organ failure in septic shock. High levels of circulating nitric oxide (NO) play a crucial role in endotoxin-induced vascular hyporeactivity. Proinflammatory cytokines have been implicated in the induction of inducible NO synthase and overproduction of NO. Anti-inflammatory therapy can diminish NO formation and improve vascular hyporeactivity in septic shock. STE20/SPS1-realted proline/alanine-rich kinase (SPAK) has been reported to activate mitogen-activated protein kinase and contribute to intestinal inflammation. Thus, we evaluated the roles of SPAK in NO production and vascular hyporeactivity in endotoxemic animals. Male wild-type and SPAK deficiency mice were intraperitoneally administered vehicle or Escherichia coli lipopolysaccharide (LPS, 50mg/kg). The changes of systolic blood pressure and plasma nitrate and nitrite levels were measured during the experimental period. Thoracic aortas were exercised to assess vascular reactivity and SPAK expression. In the present study, mice in endotoxin model showed severe hypotension and hyporeactivity to serotonin, phenylephrine (PE), and acetylcholine in the aortic rings. Phosphorylated SPAK expression in the aorta and NO levels in the plasma were also increased in animals with endotoxic shock. However, deletion of SPAK not only reduced the elevation of NO levels but also improved vascular hyporeactivity to serotonin and PE in endotoxemic mice. Taken together, SPAK could be involved in the NO overproduction and vascular hyporesponsiveness to vasoconstrictors in endotoxic shock. Thus, inhibition of SPAK could be useful in the prevention of endotoxin-induced vascular hyporeactivity. PMID- 28864212 TI - 14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity. AB - 14-O-methyl (14-O-Me) group in morphine-6-O-sulfate (M6SU) or oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-O MeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal transit in in vivo. The potency and efficacy of test compound were measured by [35S]GTPgammaS binding, isolated mouse vas deferens (MVD) and rat vas deferens (RVD) assays. The affinity of 14-O-MeM for opioid receptors was assessed by radioligand binding and MVD assays. The antinociceptive and gastrointestinal effects of the novel compound were evaluated in the rat tail-flick test and charcoal meal test, respectively. Morphine, DAMGO, Ile5,6 deltorphin II, deltorphin II and U-69593 were used as reference compounds. 14-O-MeM showed higher efficacy (Emax) and potency (EC50) than morphine in MVD, RVD or [35S]GTPgammaS binding. In addition, 14-O-MeM compared to morphine showed higher affinity for MU-opioid receptor (MOR). In vivo, in rat tail-flick test 14-O-MeM proved to be stronger antinociceptive agent than morphine after peripheral or central administration. Additionally, both compounds inhibited the gastrointestinal peristalsis. However, when the antinociceptive and antitransit doses for each test compound are compared, 14-O-MeM proved to have slightly more favorable pharmacological profile. Our results affirm that 14-O-MeM, an opioid of high efficacy and affinity for MOR can be considered as a novel analgesic agent of potential clinical value. PMID- 28864213 TI - How pure is the honey? Distinguishing premature ventricular complex-induced from premature ventricular complex-worsened cardiomyopathy. PMID- 28864214 TI - MicroRNA-218 acts by repressing TNFR1-mediated activation of NF-kappaB, which is involved in MUC5AC hyper-production and inflammation in smoking-induced bronchiolitis of COPD. AB - Dysregulation of microRNAs (miRNAs) has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), which is largely attributable to cigarette smoke (CS). However, little is known about the effect of miRNAs on CS induced mucus hypersecretion and the inflammatory response in the airway epithelium, which are pathological characteristics of COPD-related chronic bronchiolitis. As determined in the present investigation, population-based data indicate that smokers with COPD had serious airflow obstruction and inflammation, whereas smokers without COPD had mild airflow obstruction and inflammation. Moreover, levels of serum miR-218 positively correlated with FEV1/FVC% and negatively correlated with levels of serum IL-6 and IL-8. In human bronchial epithelial (HBE) cells, cigarette smoke extract (CSE) decreased miR-218 levels and increased levels of MUC5AC, interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor receptor 1 (TNFR1), and p-p65. Enhancement of miR-218 levels by an miR-218 mimic blocked these CSE-induced changes. Moreover, luciferase reporter assays confirmed that miR-218 bound to the 3'UTR region of TNFR1 mRNA. Down regulation of TNFR1 blocked the CSE-induced increases of MUC5AC, IL-6, and IL-8 and the activation of NF-kappaB. Furthermore, over-expression of miR-218 attenuated the CSE-induced overproduction of MUC5AC, IL-6, and IL-8, effects that were reversed by elevated expression of TNFR1. In sum, our findings provide a mechanism by which miR-218 regulates CSE-induced MUC5AC hyper-production and inflammation by targeting TNFR1-mediated activation of NF-kappaB, indicating that overexpression of miR-218 may be a strategy against cigarette smoking-induced bronchiolitis in COPD. PMID- 28864215 TI - Experimental Sealers Containing Metal Methacrylates: Physical and Biological Properties. AB - INTRODUCTION: The aim of this study was to evaluate the physical properties, the antimicrobial effect, and the biocompatibility of dual polymerization experimental sealers after the incorporation of dibutyltin (ET) or calcium (EC) methacrylate at concentrations of 0.5%, 1%, 2%, and 5%. METHODS: RealSeal (RS; SybronEndo, Glendora, CA) was used as a commercial control. Materials were evaluated regarding film thickness, degree of conversion, radiopacity, antimicrobial effect against Enterococcus faecalis using the modified direct contact test, and cell viability. Data were analyzed using analysis of variance followed by the Tukey test or the Student-Newman-Keuls test in SigmaPlot 12.0 (Systat Software, Inc, Point Richmond, CA) (P = .05). RESULTS: The film thickness of the dibutyltin and calcium were greater than experimental sealers following the standards given by ISO 6876:2012. For degree of conversion, dual polymerization was not influenced by the addition of metal methacrylate. Regarding the modified direct contact test, calcium and dibutyltin at all concentrations showed antimicrobial activity when compared with the positive control after 48 hours of contact (P < .05). In cell viability, ET at all concentrations showed high cytotoxicity similar to RS, and EC at concentrations of 0.5%, 1%, and 2% showed moderate cytotoxicity that was less than 5% of calcium and RS. CONCLUSIONS: It was concluded that calcium and dibutyltin methacrylate incorporation in experimental sealers promoted the antimicrobial effect. The incorporation of calcium methacrylate at 0.5%, 1%, and 2% seemed to be a good treatment option to provide antimicrobial activity associated with moderate cytotoxicity and adequate physical properties. PMID- 28864216 TI - Langerhans Cell Histiocytosis Mimicking Periapical Pathology in a 39-year-old Man. AB - Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of Langerhans-type dendritic cells, with more than 50% of cases of LCH seen in children younger than 15 years of age. The most common clinical presentation of LCH is solitary or multiple bony lesions. The jaws are affected in approximately 10%-20% of cases, with a strong predilection for the mandible. The maxilla is involved in only 1% of head and neck cases. When the jaws are involved, lesions of LCH may mimic periapical pathology as seen in patients requiring endodontic therapy or bone loss as seen in periodontal disease. We report the case of a 39 year-old man with LCH involving the posterior maxilla. This is a rare presentation of LCH with respect to both location and patient age. Clinicians should consider LCH when developing a differential diagnosis of an apical radiolucency of vital teeth or teeth that fail to respond to endodontic therapy and be aware of its clinical and radiographic mimics. PMID- 28864217 TI - Tooth Discoloration Induced by Different Calcium Silicate-based Cements: A Systematic Review of In Vitro Studies. AB - INTRODUCTION: On the basis of many clinical observations, some calcium silicate based cements have a high potential for staining tooth tissue. This feature greatly limits the use of those cements, particularly for anterior teeth. This review aimed to provide a systematic evaluation of published in vitro studies to determine the effect of different calcium silicate-based cements on dental tissue discoloration. METHODS: This literature review was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The literature search was based on all publications without a year limit. The last search was performed on October 22, 2016. An electronic search was performed on MEDLINE (PubMed), Cochrane, and Scopus. The articles were selected to address the following research question: Which materials based on calcium silicate-based cements have hard tissue staining potential? The necessary information was extracted by 2 authors independently using a standardized form. RESULTS: The search resulted in 390 titles from all databases. Twenty-three studies met the inclusion criteria. Most of the studies exhibited a moderate risk of bias. The results indicated that some materials showed a strong potential for staining, including gray and white MTA Angelus (Londrina, PR, Brazil), gray and white ProRoot MTA (Dentsply, Tulsa, OK), and Ortho MTA (BioMTA, Seoul, Korea). Individual study results showed that Biodentine (Septodont, Saint Maur des Fosses, France), Retro MTA (BioMTA), Portland cement, EndoSequence Root Repair Material (Brasseler USA, Savannah, GA), Odontocem (Australian Dental Manufacturing, Brisbane, Australia), MM-MTA (Micro Mega, Besancon Cedex, France), and MTA Ledermix (Riemser Pharma GmbH, Greiswald-Insel Riems, Germany) were materials with the smallest staining potential. CONCLUSIONS: This review clearly showed that some calcium silicate-based cements have a high potential for staining hard tissue. On the other hand, some showed only a small change in color, which was nearly invisible to the human eye (DeltaE <3.3). However, more long-term clinical studies are needed. PMID- 28864218 TI - The Association between the Anatomic Landmarks of the Pulp Chamber Floor and the Prevalence of Middle Mesial Canals in Mandibular First Molars: An In Vivo Analysis. AB - INTRODUCTION: The present study aimed to determine the incidence and anatomic variation of the middle mesial (MM) canal in mandibular permanent first molars using cone-beam computed tomographic imaging and to evaluate the association between the presence of MM canals and anatomic landmarks of the pulp chamber floor in the mesial root. METHODS: In this in vivo cross-sectional study, 210 CBCT scans of mandibular fist molars from 210 patients were included. CBCT scans were evaluated in 3 sections, and the following data were collected for further analysis: identification of the MM canal, the distance between the mesiobuccal (MB) and mesiolingual (ML) orifices, the presence of any isthmus between the MB and ML orifices, and the MB and ML root canal system (RCS) configurations. Binary logistic regression was performed to assess the effect of pulp floor anatomic characteristics as an independent variable on the outcome variable (the presence of an MM canal). RESULTS: The overall prevalence of the identification of an MM canal regardless of age was 14.7%. Mandibular first molars with an isthmus between the MB and ML RCS configurations were almost 5 times more likely to show an MM canal (P < .05, odds ratio [OR] = 4.9). The MB-ML intraorifice distance was inversely associated with the presence of an MM canal (P < .05, OR = 0.73). Patients less than 42 years old were 4 times more likely to have an MM canal in their CBCT scans compared with patients older than 42 years old (P < .05, OR = 3.9). CONCLUSIONS: The suggested anatomic landmarks of the pulp chamber floor could act as a reliable predictive factor for the presence of an MM canal. This knowledge of anatomic clues may serve to better direct endodontists in locating an MM canal, which could prevent excessive removal of tooth structures. PMID- 28864219 TI - Regenerative Endodontics Versus Apexification in Immature Permanent Teeth with Apical Periodontitis: A Prospective Randomized Controlled Study. AB - INTRODUCTION: The aim of the study was to compare the outcomes of regenerative endodontic treatment (RET) and apexification on immature permanent teeth with pulp necrosis and apical periodontitis. METHODS: A total of 118 patients (118 teeth) were recruited and randomly assigned to either RET or apexification treatment. Each treatment group was divided into 2 subgroups according to the etiology: dens evaginatus or trauma. Clinical symptoms and complications were recorded, and cone-beam computed tomographic imaging with a limited field of view was used to measure the change of root length, root thickness, and apical foramen size at the 12-month follow-up. The t test/rank sum test and Fisher exact test were applied to compare the change of root morphology between RET and apexification. RESULTS: One hundred three of 118 cases were completed at the 12 month follow-up. The survival rate was 100% for both treatment groups. All cases were asymptomatic with apical healing. The RET group showed a significant increase in root length and root thickness compared with the apexification group (P < .05). In the RET group, the cases caused by dens evaginatus achieved increased root length and root thickness compared with those caused by trauma (P < .05). CONCLUSIONS: RET and apexification achieved a comparable outcome in regard to the resolution of symptoms and apical healing. RET showed a better outcome than apexification regarding increased root thickness and root length. The etiology had an impact on the outcome of RET. Dens evaginatus cases showed better prognoses than trauma cases after RET. PMID- 28864220 TI - Evaluation of Pulp Response to Novel Bioactive Glass Pulp Capping Materials. AB - INTRODUCTION: This study aimed to investigate dental pulp responses to novel bioactive glass (BG) pulp capping materials after direct pulp capping in vivo. METHODS: Novel BG pulp capping materials are composed of powder and fluid. The powder is BG (82.36% SiO2, 15.36% CaO, and 2.28% P2O5), and the fluid is provided in 2 kinds: (1) phosphate buffer solution (BG-PB) and (2) phosphate buffer solution with the addition of 1 wt% sodium alginate (BG-PB-SA). After mixing the powder and fluid, BG-PB and BG-PB-SA were prepared. Cavities with mechanical pulp exposure were prepared on maxillary first molars of Wistar rats. The exposures were randomly capped with BG-PB, BG-PB-SA, or mineral trioxide aggregate (MTA). After 1 (n = 6) and 4 weeks (n = 8), maxillary segments were obtained and prepared for histologic analysis with a scoring system. Statistical analysis was performed using the Kruskal-Wallis and Mann-Whitney U tests with the significance set at .05. RESULTS: After 1 week, few inflammatory cells were present in the BG PB, BG-PB-SA, and MTA groups. Moreover, a thin layer of newly generated matrix was observed in most specimens. After 4 weeks, all specimens from the 3 groups formed a heavy dentin bridge. BG-PB and BG-PB-SA groups exhibited no or slight inflammatory response, whereas the MTA group exhibited a slight to moderate inflammatory response. No significant difference was observed in pulp inflammation and dentin formation among the 3 groups at either time point (P > .05). CONCLUSIONS: When used as a pulp capping agent, BG-PB and BG-PB-SA had similar favorable cellular and inflammatory pulp responses to those of MTA. Therefore, BG is a promising pulp capping material. PMID- 28864222 TI - Upper Tract Urothelial Carcinomas: Prognostic Factors and Outcomes in Patients With Non-Lymph Node Distant Metastasis. AB - BACKGROUND: Upper tract urothelial carcinomas (UTUCs) are increasingly recognized as separate malignancies. Additional insight into clinical outcomes and key prognostic factors are needed. OBJECTIVES: To detail outcomes of patients with UTUCs recurring after radical nephroureterectomy (RNU) and to determine a risk score that predicts outcomes of patients with non-lymph node distant metastasis. DESIGN, SETTING, AND PARTICIPANTS: Chart review of all patients who had an extraurothelial recurrence after RNU for UTUC at Dana-Farber Cancer Institute between 2009 and 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Median overall survival defined as time from chemotherapy for distant relapse to death. Prognostic relevance of performance status, hemoglobin, and receipt of cisplatin were assessed by Cox regression model. RESULTS AND LIMITATIONS: A total of 102 patients were identified, 57 of whom had non-lymph node distant metastases at relapse; 45 received chemotherapy. Median follow-up was 29.8 months; median overall survival was 14.7 months. Objective response rate to any chemotherapy in the first-line setting was only 22%. Hemoglobin > 11 g/dL and receipt of cisplatin was associated with numerically longer median survival but did not reach statistical significance in univariate and multivariate analysis. Prognostic risk score scale including hemoglobin < 11 g/dL and receipt of cisplatin was inversely associated with survival, with scores of 0, 1, and 2 leading to median survival of 19.0, 14.9, and 7.2 months (P = .38), respectively. CONCLUSIONS: Advanced UTUC portends a poor prognosis, and most patients cannot receive cisplatin-based chemotherapy. A risk score that includes anemia and receipt of cisplatin helps stratify patients with distant metastasis for inclusion into eventual clinical trials. More studies are needed to validate these findings. PATIENT SUMMARY: Metastatic UTUC is an aggressive disease, where anemia and ineligibility to receive cisplatin are adverse features associated with shorter survival. PMID- 28864221 TI - A START-domain-containing protein is a novel marker of nervous system components of the sea cucumber Holothuria glaberrima. AB - One of the main challenges faced by investigators studying the nervous system of members of the phylum Echinodermata is the lack of markers to identify nerve cells and plexi. Previous studies have utilized an antibody, RN1, that labels most of the nervous system structures of the sea cucumber Holothuria glaberrima and other echinoderms. However, the antigen recognized by RN1 remained unknown. In the present work, the antigen has been characterized by immunoprecipitation, tandem mass spectrometry, and cDNA cloning. The RN1 antigen contains a START lipid-binding domain found in Steroidogenic Acute Regulatory (StAR) proteins and other lipid-binding proteins. Phylogenetic tree assembly showed that the START domain is highly conserved among echinoderms. We have named this antigen HgSTARD10 for its high sequence similarity to the vertebrate orthologs. Gene and protein expression analyses revealed an abundance of HgSTARD10 in most H. glaberrima tissues including radial nerve, intestine, muscle, esophagus, mesentery, hemal system, gonads and respiratory tree. Molecular cloning of HgSTARD10, consequent protein expression and polyclonal antibody production revealed the STARD10 ortholog as the antigen recognized by the RN1 antibody. Further characterization into this START domain-containing protein will provide important insights for the biochemistry, physiology and evolution of deuterostomes. PMID- 28864223 TI - Risk Factors for Disease Progression After Postprostatectomy Salvage Radiation: Long-term Results of a Single-institution Experience. AB - BACKGROUND: Salvage radiotherapy (SRT) has been successfully used for recurrent prostate cancer after radical prostatectomy; however, the optimal timing of SRT remains controversial. Our objective was to identify the risk factors for disease progression after SRT, with a focus on the pre-SRT prostate-specific antigen (PSA) levels in the modern era of PSA testing. PATIENTS AND METHODS: We performed a retrospective review of 551 consecutive patients who had undergone postradical prostatectomy SRT for recurrent prostate cancer from 2000 to 2013. The exclusion criteria were hormonal therapy before or concurrent with SRT, adjuvant RT, distant metastases, and missing data. Disease progression was defined as a repeat PSA level of >= 0.2 ng/mL greater than the post-SRT nadir, a continued increase in the PSA level despite SRT, initiation of systemic therapy, local recurrence, nodal failure, and/or distant metastases. Univariate and multivariable Cox regression analysis were performed to identify the predictors of disease progression. Secondarily, PSA kinetics were evaluated in the model and compared using the Akaike information criterion. RESULTS: Of the 551 patients, 307 underwent SRT, of whom 134 experienced subsequent disease progression. The median interval to recurrence was 6.03 years (95% confidence interval, 3.74-8.36 years). On multivariable analysis, Gleason score, T stage, positive surgical margins, and pre-SRT PSA level were associated with progression; PSA kinetics did not independently predict for progression. When the pre-SRT PSA level was stratified (<= 0.30, 0.31-0.50, 0.51-1.00, and > 1 ng/mL), incremental elevations were associated with an increased risk of disease progression. CONCLUSION: Multiple factors predict for progression after SRT. These risk factors could help identify those who would derive the greatest benefit from additional systemic treatment. The findings of the present study also support initiation of early SRT, irrespective of the PSA kinetics. PMID- 28864224 TI - Catheter-directed therapy as a treatment for submassive pulmonary embolism: A meta-analysis. AB - AIMS: Catheter-directed therapy (CDT) is included in the guidelines for diagnosing and treating massive pulmonary embolism. However, few studies have evaluated the efficacy of CDT as a treatment for submassive pulmonary embolism (SPE). Therefore, we used evidence-based medicine to evaluate the effectiveness and safety of CDT in treating SPE. METHODS: Search terms describing CDT in SPE and patients with intermediate pulmonary embolism were entered into the PubMed, Embase and Cochrane Library databases to identify relevant articles without language restrictions published between January 1990 and December 2016. A quality assessment and data extraction were performed by two investigators. The clinical efficacy of and major complications associated with treatment were analysed using a fixed effects model. KEY FINDINGS: A total of 552 patients in 16 studies were included in this meta-analysis. The clinical success rate in CDT was approximately 100% (95% confidence interval (CI): 99%, 100%), the primary bleeding rate was 0.02% (95% CI: 0%, 0.05%), and mortality during hospitalization was approximately 0% (95% CI: 0%, 0.01%). The mean decrease in pulmonary artery systolic pressure after treatment was -14.9% (95% CI: -19.25%, -10.55%), and the mean post-treatment change in the ratio of the right to the left ventricle (RV/LV) was -0.35% (95% CI: -0.48%, -0.22%). SIGNIFICANCE: CDT is effective and safe as a treatment for SPE and could be a first-line treatment for SPE under specific conditions. PMID- 28864226 TI - Magnesium co-administration decreases cisplatin-induced nephrotoxicity in the multiple cisplatin administration. AB - PURPOSE: Pretreatment with magnesium (Mg) has been reported to attenuate cisplatin (CDDP)-induced nephrotoxicity (CIN). This attenuation involves modulation of the expression of renal transporters, resulting in reduced renal platinum accumulation after a single round of CDDP treatment. In this study, we investigated whether Mg co-administration ameliorates CIN after multiple doses of CDDP as effectively as after a single dose. METHODS: Rats were divided into control, Mg alone, CDDP alone, and CDDP with Mg groups. Rats received CDDP (2.5mg/kg), MgSO4 (40mg/kg), or saline once per week for three weeks. Seven days after the third round of treatment, the kidneys were excised, and the expression of renal transporters and renal platinum accumulation were analyzed. RESULTS: CDDP significantly elevated serum creatinine levels, which were significantly reduced by Mg co-administration. Renal platinum accumulation was significantly lower in the CDDP-Mg group than in the CDDP group. Expression of renal organic cation transporter 2 (rOct2) and multidrug and toxin extrusion protein 1 (rMate1), which are involved in CDDP transport, did not differ between the groups. However, the expression of copper transporter 1 (rCtr1) was significantly downregulated after Mg co-administration. CONCLUSION: Mg co-administration significantly attenuated CIN by reducing renal platinum accumulation even after multiple rounds of treatment with CDDP as effectively as in a model of a single CDDP administration. However, the specific underlying mechanism was different between single and multiple administrations, further studies will be needed to identify what contributes to this difference and to elucidate how Mg regulates the expression of renal transporters. PMID- 28864227 TI - Azotobacter chroococcum as a potentially useful bacterial biofertilizer for cotton (Gossypium hirsutum): Effect in reducing N fertilization. AB - The aim of this research was to evaluate whether the application of two plant growth-promoting (rhizo)bacteria might reduce nitrogen fertilization doses in cotton. We used strains Azotobacter chroococcum AC1 and AC10 for their proven ability to promote seed germination and cotton growth. These microorganisms were characterized by their plant growth-promoting activities. Then, we conducted a glasshouse study to evaluate the plant growth promoting ability of these strains with reduced doses of urea fertilization in cotton. Results revealed that both strains are capable of fixing nitrogen, solubilizing phosphorus, synthesizing indole compounds and producing hydrolytic enzymes. After 12 weeks, the glasshouse experiment showed that cotton growth was positively influenced due to bacterial inoculation with respect to chemical fertilization. Notably, we observed that microbial inoculation further influenced plant biomass (p<0.05) than nitrogen content. Co-inoculation, interestingly, exhibited a greater beneficial effect on plant growth parameters compared to single inoculation. Moreover, similar results without significant statistical differences were observed among bacterial co inoculation plus 50% urea and 100% fertilization. These findings suggest that co inoculation of A. chroococcum strains allow to reduce nitrogen fertilization doses up to 50% on cotton growth. Our results showed that inoculation with AC1 and AC10 represents a viable alternative to improve cotton growth while decreasing the N fertilizer dose and allows to alleviate the environmental deterioration related to N pollution. PMID- 28864228 TI - Burkholderia species associated with legumes of Chiapas, Mexico, exhibit stress tolerance and growth in aromatic compounds. AB - Leguminous plants have received special interest for the diversity of beta proteobacteria in their nodules and are promising candidates for biotechnological applications. In this study, 15 bacterial strains were isolated from the nodules of the following legumes: Indigofera thibaudiana, Mimosa diplotricha, Mimosa albida, Mimosa pigra, and Mimosa pudica, collected in 9 areas of Chiapas, Mexico. The strains were grouped into four profiles of genomic fingerprints through BOX PCR and identified based on their morphology, API 20NE biochemical tests, sequencing of the 16S rRNA, nifH and nodC genes as bacteria of the Burkholderia genus, genetically related to Burkholderia phenoliruptrix, Burkholderia phymatum, Burkholderia sabiae, and Burkholderia tuberum. The Burkholderia strains were grown under stress conditions with 4% NaCl, 45 degrees C, and benzene presence at 0.1% as the sole carbon source. This is the first report on the isolation of these nodulating species of the Burkholderia genus in legumes in Mexico. PMID- 28864225 TI - RNA interference for glioblastoma therapy: Innovation ladder from the bench to clinical trials. AB - Glioblastoma multiforme (GBM) is the most common and deadliest type of primary brain tumor with a prognosis of 14months after diagnosis. Current treatment for GBM patients includes "total" tumor resection, temozolomide-based chemotherapy, radiotherapy or a combination of these options. Although, several targeted therapies, gene therapy, and immunotherapy are currently in the clinic and/or in clinical trials, the overall survival of GBM patients has hardly improved over the last two decades. Therefore, novel multitarget modalities are urgently needed. Recently, RNA interference (RNAi) has emerged as a novel strategy for the treatment of most cancers, including GBM. RNAi-based therapies consist of using small RNA oligonucleotides to regulate protein expression at the post transcriptional level. Despite the therapeutic potential of RNAi molecules, systemic limitations including short circulatory stability and low release into the tumor tissue have halted their progress to the clinic. The effective delivery of RNAi molecules through the blood-brain barrier (BBB) represents an additional challenge. This review focuses on connecting the translational process of RNAi based therapies from in vitro evidence to pre-clinical studies. We delineate the effect of RNAi in GBM cell lines, describe their effectiveness in glioma mouse models, and compare the proposed drug carriers for the effective transport of RNAi molecules through the BBB to reach the tumor in the brain. Furthermore, we summarize the most important obstacles to overcome before RNAi-based therapy becomes a reality for GBM treatment. PMID- 28864229 TI - Force-time characteristics during sustained maximal handgrip effort according to age and clinical condition. AB - BACKGROUND: Muscle fatigue, a prominent symptom in older patients, can be assessed by sustained maximal handgrip testing. The force decline during sustained maximal contraction is described for young adults, but data for elderly persons are scarce. The aim of this study was to investigate force-time characteristics during a sustained maximal handgrip effort according to age and clinical condition. METHODS AND MATERIALS: Force-time data were continuously recorded during sustained maximal grip effort in 91 elderly patients (aged 83+/ 5years), 100 elderly controls (aged 74+/-5years) and 100 young controls (aged 23+/-3years). The force-time curve was divided in 4 parts per 25% strength drop observed. Time (representing fatigue resistance (FR)) was measured during which grip strength (GS) dropped to 75% (FR75), 50% (FR50), 25% (FR25) of its maximum and to exhaustion (FRexhaustion). Grip work ((GW), the area under the force-time curve) was measured for the 4 parts as well as for the first 20 and 30s of the fatigue protocol test. Strength decay (GWdecay), defined as the difference between the area under the curve (% GW) and a theoretical maximal area under the curve (assuming there's no strength drop), was also studied. In the elderly participants, relationships (controlling for age and sex) of GS, FR and GW with circulating IL-6 and TNF-alpha were analyzed. RESULTS: FRexhaustion was similar for all groups, whereas the duration of each of the 4 parts was significantly different between the 3 groups. FR75 was shortest in old patients (p=0.004), FR75 50 was almost twice as long in old community-dwelling compared to old patients and young controls (p<0.001). This contrast was inverted for FR50-25 which was significantly shorter in old community-dwelling compared to the other groups (p=0.013). FR25-exhaustionwas significantly longer in young controls compared to the groups of older participants (p=0.017). Old patients showed lower GW for the first 2 parts compared to old community-dwelling and young controls. Also, GWdecay values during the first 20 and 30s were significantly higher in old patients compared to old community-dwelling and young controls (both p<0.001). IL 6 was significantly related to lower GSmax, FR75, FR50, FR25, FRexhaustion, GW75, GW50 and GW75-50. CONCLUSION: This is the first study reporting differences in strength decay during a sustained maximal handgrip effort according to age and clinical condition. Old patients showed a particularly rapid decline in GW during the first part of sustained handgrip. GW was also significantly related to circulating IL-6. Future studies should confirm whether a shorter FR test protocol (i.e. until FR75) but using a continuous registration of the strength decay could be more informative in a clinical setting compared to the classical FR test (measuring only FR50). PMID- 28864230 TI - There Is an Inclusion for That: Material Properties of Protein Granules Provide a Platform for Building Diverse Cellular Functions. AB - Proteins perform a staggering variety of functions in the cell. Traditionally, protein function was thought to be hard-wired into the folded structure and conformational dynamics of each protein molecule. Recent work describes a new mode of protein functionality driven by the collective behavior of many different proteins; most of which lack a defined structure. These proteins form clusters or granules in which unstructured polypeptides interact transiently. Nonspecific multivalent interactions drive the formation of phase-separated structures resembling aggregates. This type of functional aggregate granule can be thought of as a single supermolecular functional entity that derives function from its unique material properties. In this review we examine the emerging idea of protein granules as a new functional and structural unit of cellular organization. PMID- 28864232 TI - Development and validation of a liquid chromatography-tandem mass spectrometry assay for the simultaneous quantitation of 5 azole antifungals and 1 active metabolite. AB - BACKGROUND: Azole antifungal medications are often administered to prevent or treat invasive fungal infections. These infections are deadly in the immunocompromised population. Therapeutic drug monitoring of the azole antifungal medications may potentially decrease morbidity and mortality in patients undergoing azole treatment. METHODS: To assist with azole therapeutic drug monitoring, a liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for 6 azole analytes: fluconazole, voriconazole, posaconazole, isavuconazole, itraconazole, and its active metabolite hydroxyitraconazole. RESULTS: The validated method solely required a protein precipitation step before subsequent dilution and injection onto the LC-MS/MS system. Furthermore, the analysis time was <2min per sample. CONCLUSIONS: This method enables measurement of all 6 of these analytes into a single LC-MS/MS assay. PMID- 28864234 TI - Simultaneous measurement of salivary cortisol and alpha-amylase: Application and recommendations. AB - Salivary cortisol (sCort) and salivary alpha-amylase (sAA) constitute proxy measures of the two major stress response systems, i.e. the hypothalamic pituitary-adrenal axis and the autonomic nervous system, respectively. Potentially confounding determinants of sCort and sAA may limit a reliable concurrent measurement of both biomarkers, if not adequately considered. We reviewed the most important determinants of sCort and sAA and provide recommendations for handling these potential confounders. We focused on a selection of confounders, resulting in an in-depth consideration of age, sex steroid-related factors, somatic health, acute medication, smoking, consumption of food and drinks, alcohol consumption, physical activity/fitness, and sleep. Our review further highlights the importance of the consideration of potential confounders for a reliable and valid simultaneous measurement of sCort and sAA. We further provide recommendations about which and how to handle relevant confounders in the study design or data analysis. PMID- 28864231 TI - Improved sensitivity of serum/plasma 1alpha,25-dihydroxyvitamin D quantification by DAPTAD derivatization. AB - BACKGROUND: Although immunoassays have several limitations such as the cross reactivities of antibodies, such techniques are widely used for serum/plasma 1,25(OH)2D quantification. An accurate method is required for the determination of the 1,25(OH)2D status. METHODS: We designed a serum/plasma 1,25(OH)2D quantification method using LC-MS/MS. Immunoaffinity extraction (IE) and the recently developed Cookson-type reagent 4-(4'-dimethylaminophenyl)-1,2,4 triazoline-3,5-dione (DAPTAD) were used for sample preparation and derivatization, respectively. Analytical and pre-analytical validations were performed. Serum 1,25(OH)2D3 concentrations were determined in 232 healthy Japanese individuals. RESULTS: The intra- and inter-assay CVs for 1,25(OH)2D3 were 5.2% and 7.0%, respectively. The limit of quantification for 1,25(OH)2D3 was 7.1pg/ml. Rheumatoid factor (RF) at concentrations below 517IU/ml did not affect serum 1,25(OH)2D analysis. No significant differences were observed for various blood collection tubes, repeated freeze-thaw cycles, whole blood standing time, or serum storage time. A strong correlation between LC-MS/MS and radioimmunoassay (RIA) was observed (r=0.786), but serum 1,25(OH)2D concentrations obtained from RIA were 2-fold higher than those obtained from LC-MS/MS. Serum 1,25(OH)2D3 concentrations by LC-MS/MS were 18.7-53.9pg/ml. CONCLUSION: A highly sensitive and selective LC-MS/MS-based serum/plasma 1,25(OH)2D quantification method was developed using IE and DAPTAD derivatization. This method will enable the accurate determination of serum/plasma 1,25(OH)2D concentrations in the clinical setting. PMID- 28864233 TI - MicroRNA-10b and the clinical outcomes of various cancers: A systematic review and meta-analysis. AB - BACKGROUND: The impact of miR-10b expression on the survival outcome of patients with cancers is still controversial. METHOD AND MATERIALS: A systematic review and meta-analysis was performed to determine its implication on the survival of cancer patients. We carried out an electrical literature search to identify the eligible studies published in PubMed, Web of Science and Embase together with the Chinese databases. RESULT: In total, 28 studies of 23 articles enrolling 3134 patients were included for this meta-analysis, of which 25 studies reported overall survival (OS), 4 studies evaluated recurrence-free survival (RFS) and 3 studies were related to disease-free survival (DFS). As a result, this meta analysis revealed that up-regulation of miR-10b could confer an unfavorable factor for OS (HR=1.853, 95% CIs: 1.521-2.258, P<0.01) but not DFS (HR=1.309, 95% CIs: 0.699-2.453, P=0.4) or RFS (HR=2.692, 95% CIs: 0.877-8.265, P=0.084). Additionally, further analysis also suggested that overexpression of miR-10b predicted the shorter OS for the patient with different types of cancers, which contained lung cancer, breast cancer, glioma, colorectal cancer and gastric carcinoma. Subgroup analyses were also conducted according the region, sample size, system and miR-10b detection assay and statistical method. CONCLUSION: This study shows that augmented expression of miR-10b strongly predicts poor prognosis for patients with cancers. PMID- 28864235 TI - Alignment options for total knee arthroplasty: A systematic review. AB - In spite of improvements in implant designs and surgical precision, functional outcomes of mechanically aligned total knee arthroplasty (MA TKA) have plateaued. This suggests probable technical intrinsic limitations that few alternate more anatomical recently promoted surgical techniques are trying to solve. This review aims at (1) classifying the different options to frontally align TKA implants, (2) at comparing their safety and efficacy with the one from MA TKAs, therefore answering the following questions: does alternative techniques to position TKA improve functional outcomes of TKA (question 1)? Is there any pathoanatomy not suitable for kinematic implantation of a TKA (question 2)? A systematic review of the existing literature utilizing PubMed and Google Scholar search engines was performed in February 2017. Only studies published in peer-reviewed journals over the last ten years in either English or French were reviewed. We identified 569 reports, of which 13 met our eligibility criteria. Four alternative techniques to position a TKA are challenging the traditional MA technique: anatomic (AA), adjusted mechanical (aMA), kinematic (KA), and restricted kinematic (rKA) alignment techniques. Regarding osteoarthritic patients with slight to mid constitutional knee frontal deformity, the KA technique enables a faster recovery and generally generates higher functional TKA outcomes than the MA technique. Kinematic alignment for TKA is a new attractive technique for TKA at early to mid term, but need longer follow-up in order to assess its true value. It is probable that some forms of pathoanatomy might affect longer-term clinical outcomes of KA TKA and make the rKA technique or additional surgical corrections (realignment osteotomy, retinacular ligament reconstruction etc.) relevant for this sub-group of patients. Longer follow-up is needed to define the best indication of each alternative surgical technique for TKA. Level I for question 1 (systematic review of Level I studies), level 4 for question 2. PMID- 28864236 TI - Crossing the border - Solute entry into the chlamydial inclusion. AB - Chlamydiales comprise important human and animal pathogens as well as endosymbionts of amoebae. Generally, these obligate intracellular living bacteria are characterized by a biphasic developmental cycle, a reduced genome and a restricted metabolic capacity. Because of their metabolic impairment, Chlamydiales essentially rely on the uptake of diverse metabolites from their hosts. Chlamydiales thrive in a special compartment, the inclusion, and hence are surrounded by an additional membrane. Solutes might enter the inclusion through pores and open channels or by redirection of host vesicles, which fuse with the inclusion membrane and release their internal cargo. Recent investigations shed new light on the chlamydia-host interaction and identified an additional way for nutrient uptake into the inclusion. Proteome studies and targeting analyses identified chlamydial and host solute carriers in inclusions of Chlamydia trachomatis infected cells. These transporters are involved in the provision of UDP-glucose and biotin, and probably deliver further metabolites to the inclusion. By the controlled recruitment of specific solute carriers to the inclusion, the chlamydial resident thus can actively manipulate the metabolite availability and composition in the inclusion. This review summarizes recent findings and new ideas on carrier mediated solute uptake into the chlamydial inclusion in the context of the bacterial and host metabolism. PMID- 28864237 TI - [Comparison of the efficacy and safety of dronedarone and flecainide as maintenance antiarrhythmic therapy for sinus rhythm in atrial fibrillation]. AB - INTRODUCTION AND OBJECTIVES: Dronedarone and flecainide are the first pharmacological choice to reduce recurrence of atrial fibrillation (AF); however, there are no studies comparing them. A study was performed to compare the efficacy in terms of recurrence of AF and safety of both drugs. METHODS: A retrospective cohort study was conducted that included 123 consecutive patients treated with flecainide or dronedarone due to paroxysmal AF (76.4%) or persistent AF (23.6%), from October 2010 to February 2013. Electrical cardioversion was performed in 7.3% of patients and pharmacological cardioversion in 16.3%. The median (interquartile range) follow-up was 301days (92-474) with a mean of 2.8 reviews per patient. Time to first event analysis was performed using Kaplan Meier and Cox regression, adjusted for propensity score. RESULTS: Of the 123 consecutive patients with AF included, 71 were on dronedarone and 52 on flecainide. During the follow-up, there were 36 AF recurrences and 20 safety events. There were recurrences in 36.6% of patients treated with flecainide, compared with 21% of those receiving dronedarone (P=.073). Dronedarone showed to be at least as effective as flecainide in preventing recurrence of atrial fibrillation (HR: 0.53, 95% CI: 0.20-1.44, P=.221), and demonstrated an acceptable safety profile when compared with flecainide (HR: 0.68, 95% CI: 0.18 2.53, P=.566). CONCLUSIONS: In our experience, dronedarone has been at least as effective and safe as flecainide, despite it was most frequently prescribed in patients with worse baseline risk profile. PMID- 28864238 TI - [Sintrom-induced cutaneous necrosis; a little-known complication]. PMID- 28864239 TI - Network oscillatory activity driven by context memory processing is differently regulated by glutamatergic and cholinergic neurotransmission. AB - Memory retrieval requires coordinated intra- and inter-regional activity in networks of brain structures. Dysfunction of these networks and memory impairment are seen in many psychiatric disorders, but relatively little is known about how memory retrieval and memory failure are represented at the level of local and regional oscillatory activity. To address this question, we measured local field potentials (LFPs) from mice as they explored a novel context, retrieved memories for contextual fear conditioning, and after administration of two amnestic agents: the NMDA receptor antagonist MK-801 and muscarinic acetylcholine receptor antagonist scopolamine (SCOP). LFPs were simultaneously recorded from retrosplenial cortex (RSC), dorsal hippocampus (DH), and anterior cingulate cortex (ACC), which are involved in processing contextual memories, and analyzed for changes in intra-regional power and inter-regional peak coherence of oscillations across multiple frequency bands. Context encoding and memory retrieval sessions yielded similar patterns of changes across all three structures, including decreased delta power and increased theta peak coherence. Baseline effects of MK-801 and SCOP were primarily targeted to gamma oscillations, but in opposite directions. Both drugs also blocked memory retrieval, as indicated by reduced freezing when mice were returned to the conditioning context, but this common behavioral impairment was only associated with power and peak coherence disruptions after MK-801 treatment. These findings point to neural signatures for memory impairment, whose underlying mechanisms may serve as therapeutic targets for related psychiatric disorders. PMID- 28864240 TI - Global motion perception is associated with motor function in 2-year-old children. AB - The dorsal visual processing stream that includes V1, motion sensitive area V5 and the posterior parietal lobe, supports visually guided motor function. Two recent studies have reported associations between global motion perception, a behavioural measure of processing in V5, and motor function in pre-school and school aged children. This indicates a relationship between visual and motor development and also supports the use of global motion perception to assess overall dorsal stream function in studies of human neurodevelopment. We investigated whether associations between vision and motor function were present at 2 years of age, a substantially earlier stage of development. The Bayley III test of Infant and Toddler Development and measures of vision including visual acuity (Cardiff Acuity Cards), stereopsis (Lang stereotest) and global motion perception were attempted in 404 2-year-old children (+/-4 weeks). Global motion perception (quantified as a motion coherence threshold) was assessed by observing optokinetic nystagmus in response to random dot kinematograms of varying coherence. Linear regression revealed that global motion perception was modestly, but statistically significantly associated with Bayley III composite motor (r2=0.06, P<0.001, n=375) and gross motor scores (r2=0.06, p<0.001, n=375). The associations remained significant when language score was included in the regression model. In addition, when language score was included in the model, stereopsis was significantly associated with composite motor and fine motor scores, but unaided visual acuity was not statistically significantly associated with any of the motor scores. These results demonstrate that global motion perception and binocular vision are associated with motor function at an early stage of development. Global motion perception can be used as a partial measure of dorsal stream function from early childhood. PMID- 28864241 TI - Theacrine: A purine alkaloid from Camellia assamica var. kucha with a hypnotic property via the adenosine system. AB - Theacrine (l,3,7,9-tetramethyluric acid), a purine alkaloid from Camellia assamica var. kucha, has diverse pharmacological properties, including sedative and hypnotic activities, anti-inflammatory and analgesic activities, antidepressant effects, and a protective effect against stress-provoked liver damage. The present study aims to investigate the possible mechanism of the hypnotic activity of theacrine. The results revealed that theacrine significantly enhanced pentobarbital-induced sleep at a dose of 3.0mg/kg (i.g.) in mice. Sleep parameter analysis by EEG and EMG showed that theacrine obviously shortened wake time and increased NREM sleep time and that theacrine almost had no effect on REM sleep. Meanwhile, theacrine markedly attenuated caffeine (a nonselective antagonist of adenosine receptor)-induced insomnia. In pretreatment with the adenosine A1 receptor antagonist DPCPX and the A2A receptor antagonist SCH 58261, theacrine significantly reversed the decrease in sleeping time in pentobarbital treated mice. In addition, theacrine also markedly increased the adenosine content in the hippocampus of rats. These results suggested that theacrine might mediate the adenosine system to augment pentobarbital-induced sleep. PMID- 28864243 TI - Diagnostic value of conventional MRI combined with DTI for neonatal hyperbilirubinemia. AB - BACKGROUND: Neonatal hyperbilirubinemia (NHB) is a common clinical disease and can cause bilirubin encephalopathy in severe cases. It is now widely accepted that increased signal intensity in the globus pallidus on MR T1WI is an important sign of neonatal bilirubin encephalopathy. And brain diffusion tensor imaging (DTI) has not been used extensively to study hyperbilirubinemia (HB). So we compared newborns with different hyperbilirubinemia of different severities and healthy newborns in order to determine the relationships among MRI signal intensities, serum bilirubin levels, and the molecular changes in brain water diffusion in hyperbilirubinemia. METHODS: Seventy-three newborns with hyperbilirubinemia were grouped into three groups: the mild increase group (M, 27 cases), the moderate increase group (O, 28 cases), and the severe group (S, 18 cases). The groups were based on serum bilirubin levels. We performed cranial MRI in these newborns, as well as 29 healthy full-term infants (group N). We compared and analyzed the mean signal values for the globus pallidus and the relationship between the bilirubin level and the score on the neonatal behavioral neurological assessment. Fifteen, 10, and 10 patients in groups M, O + S, and N were successfully examined using diffusion tensor imaging (DTI). We assessed the relationships among the signal from the globus pallidus, fractional anisotropy (FA), and average diffusion coefficient (DCav) of the posterior limb of the internal capsule (PLIC). RESULTS: There were significant differences in the mean signal value of bilateral globus pallidus between group O/S and group N [p = 0.029 and 0.000 (left), 0.038 and 0.000 (right)]. There were no significant differences in bilateral FA or DCav values between the patient groups and group N. The bilateral PLIC-FA and DCav values were significantly different between the patient groups and group N (P = 0.014 and 0.047, respectively). CONCLUSIONS: Increased signal intensity in the globus pallidus on T1-weighted imaging can be used as an objective index to evaluate neonatal bilirubin encephalopathy. Globus pallidus and PLIC injuries are likely to occur when the total serum bilirubin level is >=20 mg/dl. PMID- 28864242 TI - Thymosin beta4 for the treatment of acute stroke in aged rats. AB - Thymosin beta4 (Tbeta4) is a 5K peptide which influences cellular migration by inhibiting organization of the actin-cytoskeleton. Tbeta4 has neurorestorative properties and is a potential candidate for the treatment of sub-acute stroke. Previous research demonstrated that Tbeta4 improved neurological outcome in a young (3 months) rat model of embolic stroke. We hypothesized that Tbeta4 would improve neurological outcome in an aged rat model of embolic stroke when administered 24h after embolic stroke. Aged Male Wistar rats (Charles River, France 18-21 months) were subjected to embolic middle cerebral artery occlusion (MCAo). Rats were randomized to receive Tbeta4 (12mg/kg, RegeneRx Biopharmaceuticals, Inc.) or control 24h after MCAo and then every 3days for 4 additional doses. The dose of 12mg/kg was the maximal dose of Tbeta4 that showed functional improvement in a young rat model of embolic stroke. Functional tests (adhesive-removal test (ART), foot fault test (FFT) and the modified Neurological Severity Score (mNSS)) were performed weekly. The rats were sacrificed 56days after MCAo and lesion volumes were measured. Immunohistochemical analysis for oligodendrogenesis, myelination and gliosis was also performed. Twenty-three rats were included in the study: control group (n=12) and Tbeta4 group (n=11). After randomization, there were three deaths in both the control and Tbeta4 groups. The Tbeta4 treatment reduced infarct volume by more than 50% (12.8%+/-9.3%, mean+/ SE, p<0.05) compared to the control group (26.0%+/-4.3%). However, Tbeta4 did not show improvement in functional outcome compared to control. There was no significant increase in oligodendrogenesis, myelination and gliosis between control and treatment with Tbeta4, however, we unexpectedly observed that overall (control and Tbeta4 groups) astrocytic gliosis as measured by GFAP immunoreactivity was significantly inversely correlated with neurological outcome measured using the modified Neurological Severity Score (mNSS) (p<0.01), suggesting that greater gliosis may be related to improvement of neurological outcome in aged rats. In summary, Tbeta4 treatment of stroke aged rats significantly reduces infarct volume compared to vehicle treated stroke, however, Tbeta4 treatment did not show improvement in functional outcome, myelination or gliosis when compared to control. GFAP staining was significantly inversely correlated to improvement in the mNSS, suggesting that gliosis in the aged rat may be of benefit in improvement of functional outcome. PMID- 28864244 TI - Performance on a Clinical Quadriceps Activation Battery Is Related to a Laboratory Measure of Activation and Recovery After Total Knee Arthroplasty. AB - OBJECTIVE: To determine the relation between performance on a clinical quadriceps activation battery with (1) activation measured by doublet interpolation and (2) recovery of quadriceps strength and functional performance after total knee arthroplasty (TKA). DESIGN: Planned secondary analysis of a randomized controlled trial. SETTING: University research laboratory. PARTICIPANTS: Patients (N=162; mean age, 63+/-7y; 89 women) undergoing TKA. MAIN OUTCOME MEASURES: Patients were classified as high (quadriceps activation battery >=4/6) or low (quadriceps activation battery <=3/6) based on performance on the quadriceps activation battery measured 4 days after TKA. Differences between groups in activation and recovery at 1, 2, 3, 6, and 12 months after TKA were compared using a repeated measures maximum likelihood model. RESULTS: The low quadriceps activation battery group demonstrated poorer quadriceps activation via doublet interpolation (P=.01), greater quadriceps strength loss (P=.01), and greater functional performance decline (all P<.001) at 1 month after TKA compared with the high quadriceps activation battery group. Differences between low and high quadriceps activation battery groups on all measures did not persist at 3 and 12 months (all P>.05). CONCLUSIONS: Poor performance on the quadriceps activation battery early after TKA is related to poor quadriceps activation and poor recovery in the early postoperative period. Patients in the low quadriceps activation battery group took 3 months to recover to the same level as the high quadriceps activation battery group. The quadriceps activation battery may be useful in identifying individuals who need specific interventions to target activation deficits or different care pathways in the early postoperative period to speed recovery after TKA. PMID- 28864245 TI - Musical training increases functional connectivity, but does not enhance mu suppression. AB - Musical training provides an ideal platform for investigating action representation for sound. Learning to play an instrument requires integration of sensory and motor perception-action processes. Functional neuroimaging studies have indicated that listening to trained music can result in the activity in premotor areas, even after a short period of training. These studies suggest that action representation systems are heavily dependent on specific sensorimotor experience. However, others suggest that because humans naturally move to music, sensorimotor training is not necessary and there is a more general action representation for music. We previously demonstrated that EEG mu suppression, commonly implemented to demonstrate mirror-neuron-like action representation while observing movements, can also index action representations for sounds in pianists. The current study extends these findings to a group of non-musicians who learned to play randomised sequences on a piano, in order to acquire specific sound-action mappings for the five fingers of their right hand. We investigated training-related changes in neural dynamics as indexed by mu suppression and task related coherence measures. To test the specificity of training effects, we included sounds similar to those encountered in the training and additionally rhythm sequences. We found no effect of training on mu suppression between pre- and post-training EEG recordings. However, task-related coherence indexing functional connectivity between electrodes over audiomotor areas increased after training. These results suggest that long-term training in musicians and short term training in novices may be associated with different stages of audiomotor integration that can be reflected in different EEG measures. Furthermore, the changes in functional connectivity were specifically found for piano tones, and were not apparent when participants listened to rhythms, indicating some degree of specificity related to training. PMID- 28864246 TI - Pathways for smiling, disgust and fear recognition in blindsight patients. AB - The aim of the present review is to discuss the localization of circuits that allow recognition of emotional facial expressions in blindsight patients. Because recognition of facial expressions is function of different centers, and their localization is not always clear, we decided to discuss here three emotional facial expression - smiling, disgust, and fear - whose anatomical localization in the pregenual sector of the anterior cingulate cortex (pACC), anterior insula (AI), and amygdala, respectively, is well established. We examined, then, the possible pathways that may convey affective visual information to these centers following lesions of V1. We concluded that the pathway leading to pACC, AI, and amygdala involves the deep layers of the superior colliculus, the medial pulvinar, and the superior temporal sulcus region. We suggest that this visual pathway provides an image of the observed affective faces, which, although deteriorated, is sufficient to determine some overt behavior, but not to provide conscious experience of the presented stimuli. PMID- 28864247 TI - Comparison of three methods for recovery of Brucella canis DNA from canine blood samples. AB - Brucella canis, a gram-negative, facultative intracellular and zoonotic bacterium causes canine brucellosis. Direct methods are the most appropriate for the detection of canine brucellosis and bacterial isolation from blood samples has been employed as gold-standard method. However, due to the delay in obtaining results and the biological risk of the bacterial culturing, the polymerase chain reaction (PCR) has been successfully used as an alternative method for the diagnosis of the infection. Sample preparation is a key step for successful PCR and protocols that provide high DNA yield and purity are recommended to ensure high diagnostic sensitivity. The objective of this study was to evaluate the performance of PCR for the diagnosis of B. canis infection in 36 dogs by testing DNA of whole blood obtained through different extraction and purification protocols. Methods 1 and 2 were based on a commercial kit, using protocols recommended for DNA purification of whole blood and tissue samples, respectively. Method 3 was an in-house method based on enzymatic lysis and purification using organic solvents. The results of the PCR on samples obtained through three different DNA extraction protocols were compared to the blood culture. Of the 36 dogs, 13 (36.1%) were positive by blood culturing, while nine (25.0%), 14 (38.8%), and 15 (41.6%) were positive by PCR after DNA extraction using methods 1, 2 and 3, respectively. PCR performed on DNA purified by Method 2 was as efficient as blood culturing and PCR performed on DNA purified with in-house method, but had the advantage of being less laborious and, therefore, a suitable alternative for the direct B. canis detection in dogs. PMID- 28864248 TI - Regulation of immune response by bioactive ions released from silicate bioceramics for bone regeneration. AB - : Silicate bioceramics have been considered to possess a wide prospect of clinical application for orthopedic tissue regeneration due to their excellent osteogenesis and angiogenesis. However, the mechanism for silicate bioceramics stimulating bone formation is not fully understood. The host immune defense to implants is proved to greatly influence the osteogenesis and new bone formation, but up to now, few studies are focused on the silicate bioceramics modulated host immune responses. In our present study, two representative silicate bioceramics, akermanite (AKT) and nagelschmidtite (NAGEL) were used as model materials to investigate the inflammation responses in vitro and in vivo, and beta-tricalcium phosphate (beta-TCP) bioceramics were used as a control. It was found that the mouse macrophage cell RAW264.7 that cultured on AKT and NAGEL bioceramics displayed not only less viability and proliferation, but also a significant less inflammatory cytokine secretion than those on beta-TCP in vitro. The formation of foreign body giant cells and fibrous capsules, the invasion of macrophages, as well as the detected inflammatory cytokines around the implanted materials were much lower in both AKT and NAGEL bioceramic groups as compared with those in the beta-TCP controls in vivo. Furthermore, it was found that not just the certain concentration of extracellular Si-containing ionic products released from the silicate bioceramics, but also the separate Si, Mg and Ca ions revealed the activity to inhibit the macrophage inflammatory responses by the way of suppressing the activated inflammatory MAPK and NF-kappaB signaling pathway and promoting the caspase-dependent apoptosis of macrophages. In general, our study suggests that the silicate bioceramics could regulate immune responses by altering the ionic microenvironment between the implants and hosts, which may offer new insight about the mechanism of the bioactivity of silicate bioceramics in bone regeneration and provide profitable guidance for designing new biomaterials for bone tissue engineering. STATEMENT OF SIGNIFICANCE: Silicate bioceramics have been widely used for orthopedic tissue regeneration because of their excellent characteristics in bone formation. However, there are few studies concerning their interrelationships with the host immune defense that has been proved to greatly influence osteogenesis. In our present study, the akermanite and nagelschmidtite were used as two representative silicate bioceramics to investigate the inflammation responses in vitro and in vivo; and for the first time, the bioactive ions released from the silicate bioceramics were discovered to regulate the macrophage immune responses through both inhibiting the inflammatory signaling and activating apoptosis of macrophages. Our findings in this study may not only increase the understanding in osteogenic activity of silicate bioceramics, but also provide profitable guidance for designing and manufacturing new biomaterials for bone tissue engineering. PMID- 28864249 TI - Hydrogel substrate stress-relaxation regulates the spreading and proliferation of mouse myoblasts. AB - : Mechanical properties of the extracellular microenvironment are known to alter cellular behavior, such as spreading, proliferation or differentiation. Previous studies have primarily focused on studying the effect of matrix stiffness on cells using hydrogel substrates that exhibit purely elastic behavior. However, these studies have neglected a key property exhibited by the extracellular matrix (ECM) and various tissues; viscoelasticity and subsequent stress-relaxation. As muscle exhibits viscoelasticity, stress-relaxation could regulate myoblast behavior such as spreading and proliferation, but this has not been previously studied. In order to test the impact of stress relaxation on myoblasts, we created a set of two-dimensional RGD-modified alginate hydrogel substrates with varying initial elastic moduli and rates of relaxation. The spreading of myoblasts cultured on soft stress-relaxing substrates was found to be greater than cells on purely elastic substrates of the same initial elastic modulus. Additionally, the proliferation of myoblasts was greater on hydrogels that exhibited stress-relaxation, as compared to cells on elastic hydrogels of the same modulus. These findings highlight stress-relaxation as an important mechanical property in the design of a biomaterial system for the culture of myoblasts. STATEMENT OF SIGNIFICANCE: This article investigates the effect of matrix stress-relaxation on spreading and proliferation of myoblasts by using tunable elastic and stress-relaxing alginate hydrogels substrates with different initial elastic moduli. Many past studies investigating the effect of mechanical properties on cell fate have neglected the viscoelastic behavior of extracellular matrices and various tissues and used hydrogels exhibiting purely elastic behavior. Muscle tissue is viscoelastic and exhibits stress-relaxation. Therefore, stress-relaxation could regulate myoblast behavior if it were to be incorporated into the design of hydrogel substrates. Altogether, we showed that stress-relaxation impacts myoblasts spreading and proliferation. These findings enable a better understanding of myoblast behavior on viscoelastic substrates and could lead to the design of more suitable substrates for myoblast expansion in vitro. PMID- 28864250 TI - A straightforward approach to enhance the textural, mechanical and biological properties of injectable calcium phosphate apatitic cements (CPCs): CPC/blood composites, a comprehensive study. AB - : Two commercial formulations of apatitic calcium phosphate cements (CPCs), Graftys(r) Quickset (QS) and Graftys(r) HBS (HBS), similar in composition but with different initial setting time (7 and 15min, respectively), were combined to ovine whole blood. Surprisingly, although a very cohesive paste was obtained after a few minutes, the setting time of the HBS/blood composite dramatically delayed when compared to its QS analogue and the two blood-free references. Using solid state NMR, scanning electron microscopy and high frequency impedance measurements, it was shown that, in the particular case of the HBS/blood composite, formation of a reticulated and porous organic network occurred in the intergranular space, prior to the precipitation of apatite crystals driven by the cement setting process. The resulting microstructure conferred unique biological properties to this material upon implantation in bone defects, since its degradation rate after 4 and 12weeks was more than twice that for the three other CPCs, with a significant replacement by newly formed bone. STATEMENT OF SIGNIFICANCE: A major challenge in the design of bone graft substitutes is the development of injectable, cohesive, resorbable and self-setting calcium phosphate cement (CPC) that enables rapid cell invasion with initial mechanical properties as close as bone ones. Thus, we describe specific conditions in CPC blood composites where the formation of a 3D clot-like network can interact with the precipitated apatite crystals formed during the cement setting process. The resulting microstructure appears more ductile at short-term and more sensitive to biological degradation which finally promotes new bone formation. This important and original paper reports the design and in-depth chemical and physical characterization of this groundbreaking technology. PMID- 28864252 TI - Design of protein delivery systems by mimicking extracellular mechanisms for protection of growth factors. AB - : Heparin sulfate proteoglycans (HSPGs) are responsible for the storage and stabilization of numerous growth factors in the extracellular matrix. In this complex native environment, the efficient binding of the growth factors is determined by multivalent, specific and reversible electrostatic interactions between the sulfate groups of HSPGs and the positively charged amino acids of the growth factor. Inspired by this naturally occurring stabilization process, we propose the use of diblock copolymers of heparin and polyethylene glycol (Hep-b PEG) for protection and delivery of FGF-2. We describe the encapsulation of FGF-2 into spontaneously assembling polyelectrolyte complexes (PECs) with Hep-b-PEG in which the Hep block ensures the formation of the PECs, while the PEG moiety confers stability of the generated complex by a stealth corona. Our results demonstrate that by this method we can generate homogeneous complexes (ca. 400nm diameter, PDI 0.29+/-0.07) with a very high encapsulation efficiency (about 99% encapsulated FGF-2). The release of the growth factor in response to different stimuli such as pH, ionic strength or presence of heparinase was also studied. We report a sustained release of up to 80% during 28days which is not influenced by the presence of heparinase - a result that clearly demonstrates the protective effect of the stealth corona. We also show that FGF-2 remains bioactive as it influences the morphology of bone marrow mesenchymal stem cells. STATEMENT OF SIGNIFICANCE: We describe a biopolymer that uses the way the cells shield a type of proteins (growth factors) to simultaneously assemble, slowly deliver and shield the protein in a "nanocarrier". Growth factors are essential for the regeneration of cartilage, bones by stem cell therapies but have a short life time as when added directly to tissues. Our design makes use of the heparin bioactivity towards such proteins in combination with a polyethylene glycol moiety (PEG) that makes a protecting shell. PEG, is biocompatible and used in approved medicines and countless cosmetic products. The highest novelty is the reaction (oxime click) used to bound these molecules that does not require modification of heparin and allows preservation of its bioactivity. PMID- 28864251 TI - Living nanofiber yarn-based woven biotextiles for tendon tissue engineering using cell tri-culture and mechanical stimulation. AB - : Non-woven nanofibrous scaffolds have been developed for tendon graft application by using electrospinning strategies. However, electrospun nanofibrous scaffolds face some obstacles and limitations, including suboptimal scaffold structure, weak tensile and suture-retention strengths, and compact structure for cell infiltration. In this work, a novel nanofibrous, woven biotextile, fabricated based on electrospun nanofiber yarns, was implemented as a tissue engineered tendon scaffold. Based on our modified electrospinning setup, polycaprolactone (PCL) nanofiber yarns were fabricated with reproducible quality, and were further processed into plain-weaving fabrics interlaced with polylactic acid (PLA) multifilaments. Nonwoven nanofibrous PCL meshes with random or aligned fiber structures were generated using typical electrospinning as comparative counterparts. The woven fabrics contained 3D aligned microstructures with significantly larger pore size and obviously enhanced tensile mechanical properties than their nonwoven counterparts. The biological results revealed that cell proliferation and infiltration, along with the expression of tendon-specific genes by human adipose derived mesenchymal stem cells (HADMSC) and human tenocytes (HT), were significantly enhanced on the woven fabrics compared with those on randomly-oriented or aligned nanofiber meshes. Co-cultures of HADMSC with HT or human umbilical vein endothelial cells (HUVEC) on woven fabrics significantly upregulated the functional expression of most tenogenic markers. HADMSC/HT/HUVEC tri-culture on woven fabrics showed the highest upregulation of most tendon-associated markers than all the other mono- and co-culture groups. Furthermore, we conditioned the tri-cultured constructs with dynamic conditioning and demonstrated that dynamic stretch promoted total collagen secretion and tenogenic differentiation. Our nanofiber yarn-based biotextiles have significant potential to be used as engineered scaffolds to synergize the multiple cell interaction and mechanical stimulation for promoting tendon regeneration. STATEMENT OF SIGNIFICANCE: Tendon grafts are essential for the treatment of various tendon-related conditions due to the inherently poor healing capacity of native tendon tissues. In this study, we combined electrospun nanofiber yarns with textile manufacturing strategies to fabricate nanofibrous woven biotextiles with hierarchical features, aligned fibrous topography, and sufficient mechanical properties as tendon tissue engineered scaffolds. Comparing to traditional electrospun random or aligned meshes, our novel nanofibrous woven fabrics possess strong tensile and suture-retention strengths and larger pore size. We also demonstrated that the incorporation of tendon cells and vascular cells promoted the tenogenic differentiation of the engineered tendon constructs, especially under dynamic stretch. This study not only presents a novel tissue engineered tendon scaffold fabrication technique but also provides a useful strategy to promote tendon differentiation and regeneration. PMID- 28864253 TI - Engineered Potato virus X nanoparticles support hydroxyapatite nucleation for improved bone tissue replacement. AB - : Bionanoparticles based on filamentous phages or flexuous viruses are interesting candidates for meeting the challenges of tailoring biomineralization in hydrogel-based bone tissue substitutes. We hypothesized that hydroxyapatite crystal nucleation and matrix mineralization can be significantly increased by mineralization-inducing (MIP) and integrin binding motif (RGD) peptides presented on biomimetic nanoparticles. In this study, Potato virus X (PVX), a flexible rod shaped plant virus was genetically engineered to present these functional peptides on its particle surface. Recombinant PVX-MIP/RGD particles were isolated from infected Nicotiana benthamiana plants and characterized by western blot, SEM, TEM, and TPLSM in MSC cultures. The presence of RGD was proven by cell attachment, spreading, and vinculin cluster analysis, and MIP by in vitro mineralization and osteogenic differentiation assays. Thus the tailored surface of genetically engineered PVX forms fibril-like nanostructures which enables enhanced focal adhesion-dependent cell adhesion, and matrix mineralization verified by Alizarin. Hydroxyapatite crystal nucleation is supported on recombinant PVX particles leading to a biomimetic network and bundle-like structures similar to mineralized collagen fibrils. In conclusion, the recombinant flexuous PVX nanoparticles exhibit properties with great potential for bone tissue substitutes. STATEMENT OF SIGNIFICANCE: A suitable biomaterial for tissue engineering should be able to mimic the endogenous extracellular matrix by presenting biochemical and biophysical cues. Novel hydrogel-based materials seek to meet the criteria of cytocompatibility, biodegradability, printability, and crosslinkability under mild conditions. However, a majority of existing hydrogels lack cell-interactive motifs, which are crucial to modulate cellular responses. The incorporation of the plant virus PVX to the hydrogel could improve functions like integrin-binding and mineralization due to peptide presentation on the particle surface. The tailored surface of genetically engineered PVX forms fibril-like nanostructures which enables enhanced focal adhesion-dependent cell adhesion and matrix mineralization and offers great potential for the development of new hydrogel compositions for bone tissue substitutes. PMID- 28864254 TI - Parental feeding behavior in relation to children's tasting behavior: An observational study. AB - Children's eating habits are shaped in part by parental feeding practices. While maladaptive practices have already received a lot of research attention, the effects of adaptive strategies, especially in elementary school aged children of different weight status, are less examined. This study examines how parents (1) model and (2) encourage their child to taste an unknown food. Thereby, attention is paid to the distinction between encouraging what (i.e. adaptive type of encouragement) and the amount (i.e. maladaptive type of encouragement) children eat/drink. Twenty-five families with a child with overweight and 30 families with a child of healthy weight (7-13 years) participated in a taste task. Both the child's tasting behavior and the parents' modelling and encouragement behavior were observed and related to the child's age and weight status. As 94.3% of the children tasted the unknown food, weight status differences between tasters and non-tasters could not be investigated. Only 26.9% of the parents used modelling to enhance tasting behavior; this was unrelated to age and weight status. 77.4% of the parents encouraged their children to taste (encouragement of what children eat/drink), and this was significantly more prevalent in parents of younger children and of healthy-weight children. 21.1% of the parents also encouraged their children to finish the juice (encouragement of amount children eat/drink) and this was also more prevalent in parents of the healthy-weight group. These results evidenced that parental modelling is not often used to enhance tasting behavior in children. In contrast, parental encouragement was frequently observed, especially in parents of younger children and of healthy-weight children. Encouragement, however, seems difficult to measure and more research on adaptive parental encouragement is needed. PMID- 28864255 TI - Salad bar selection patterns of elementary school children. AB - From the perspective of child-focused nutrition research, the analysis of the school cafeteria culture and environment is critical. Most children eat at least one meal at school per school day, thus elementary schools are a good setting for influencing the early development of healthy eating habits. The salad bar in particular has gained attention as a means of increasing fruit and vegetable consumption. The purpose of the present study was to provide insight about the types of items children choose or do not choose from the salad bar. Our aims were to document elementary school children's food selection patterns by examining photographs of 2903 cafeteria trays. Our results show students in this study took very few items - and a substantial number did not take any at all. We examined three factors, gender, grade, and item placement, in relation to food selection. Gender was the most significant factor, with girls being more likely to choose both fruits and vegetables. Students in lower grades were more likely to select vegetables and to choose more of them. Finally, item placement did not affect choice. Our findings lead us to suggest the importance of integrating information about fruits and vegetables into the school curriculum and that schools strongly consider which items to offer because our results indicate children consistently do not choose certain items and probably do not conceive of them in the context of the adult concept of a salad. Finally, because a child's choice of food is not always a simple act we suggest ethnographic research on how children perceive and use salad bars would provide important insight into the value of retaining or expanding salad bars in elementary schools. PMID- 28864256 TI - Pica is prevalent and strongly associated with iron deficiency among Hispanic pregnant women living in the United States. AB - INTRODUCTION: Anecdotal evidence suggests that pica occurs among Hispanic women in the United States, especially during pregnancy. However, the prevalence and socio-demographic and biological factors associated with pica in this population have not been adequately identified. METHODS: Trained, bilingual study personnel conducted structured interviews at public health clinics in Salinas Valley, California with 187 pregnant Hispanic women in their 2nd or 3rd trimesters of pregnancy. Hemoglobin was measured using Hemocue; concentrations of transferrin receptor (TfR) and alpha-1 acid glycoprotein (AGP) were measured in dried blood spots. Multivariable stepwise regression analyses were conducted with pica during pregnancy as the dependent variable and individual- and family-level factors as independent variables to identify significant associations. Additionally, multivariable models were built to explore the associations between pica and iron status (iron deficiency and anemia). RESULTS: Half of all participants (51.3%) had ever engaged in pica, and 37.6% had done so during the current pregnancy. Pica substances included large quantities of ice, frost, raw starches, and various earthen items. Pica during the current pregnancy was significantly associated with higher TfR concentrations [OR: 1.29; 95% CI: 1.11, 1.51] indicative of low iron stores and greater food insecurity [OR: 1.20, 95% CI: 1.03, 1.40]. Women who engaged in pica during the current pregnancy were more likely to be iron deficient [adjusted OR: 2.58; 95% CI: 1.19, 5.60], but not anemic [adjusted OR: 1.40; 0.60, 3.23]. CONCLUSIONS: Among pregnant Hispanic women, pica was prevalent and strongly associated with iron deficiency and food insecurity. Clinicians should screen for pica during pregnancy in Hispanic populations, and future studies should elucidate the underlying etiology and consequences of engaging in pica during pregnancy. PMID- 28864257 TI - Measurement invariance of the Feeding Practices and Structure Questionnaire-28 among a community of socioeconomically disadvantaged mothers and fathers. AB - OBJECTIVE: Determine whether feeding practices across mothers and fathers are interpreted and measured with equivalent accuracy (measurement invariance) using the Feeding Practices and Structure Questionnaire-28 (FPSQ-28). DESIGN: Cross sectional hard-copy and online survey design; Setting: Socioeconomically disadvantaged community in Queensland, Australia. PARTICIPANTS: Mothers (n = 279) and fathers (n = 225) of 2- to 5-year old children. VARIABLES MEASURED: Parental feeding practices were measured using the 7 multi-item factors from the FPSQ-28. ANALYSIS: Confirmatory factor analysis (CFA) was applied to evaluate the factor structure of the FPSQ-28 among mothers and fathers from a socioeconomically disadvantaged community. Measurement invariance between mothers and fathers was examined using hierarchical multi-group CFAs. RESULTS: The 7-factor FPSQ-28 model showed good fit and was invariant across parent gender. CONCLUSIONS AND IMPLICATIONS: The FPSQ-28 subscales appear to be interpreted equivalently, and thus to measure the same constructs, irrespective of the gender of the parents. The questionnaire can be used to measure or compare mothers' and fathers' self reported feeding practices and examine influence on child health outcomes. In the current sample of mothers and fathers recruited from a socioeconomically disadvantaged community, mothers used more 'covert restriction' than fathers. PMID- 28864258 TI - Emotion suppression and food intake in the context of a couple discussion: A dyadic analysis. AB - Using dyadic analysis, this study examined whether emotion suppression is a valid mediator in the relationship between mood change following a stressful couple discussion and subsequent food intake among cohabiting couples. In a laboratory setting, 80 heterosexual couples were presented with a bogus taste test immediately after discussing aspects that they would like each other to change. Mood change, emotion suppression and appetite perceptions were self-reported using visual analogue scales, and BMI was calculated based on objective measures. The moderated-mediation Actor-Partner Interdependence Model revealed a significant indirect conditional effect, showing that mood worsening was significantly associated with higher emotion suppression and that emotion suppression was significantly associated with more food intake among spouses with a high BMI. For spouses with a low BMI, the reverse effect was found, i.e., mood worsening was significantly associated with less food intake through the indirect effect of emotion suppression. Furthermore, an indirect partner effect was observed regardless of BMI, i.e., mood worsening was related to more food intake, which was mediated by the partner's emotion suppression. These results highlight the key role of emotion suppression in the relationship between mood change and food intake in the context of a stressful couple discussion. PMID- 28864259 TI - Perceived impact of smaller compared with larger-sized bottles of sugar-sweetened beverages on consumption: A qualitative analysis. AB - Sugar-sweetened beverage (SSB) consumption increases obesity risk and is linked to adverse health consequences. Large packages increase food consumption, but most evidence comes from studies comparing larger with standard packages, resulting in uncertainty regarding the impact of smaller packages. There is also little research on beverages. This qualitative study explores the experiences of consuming cola from smaller compared with larger bottles, to inform intervention strategies. Sixteen households in Cambridge, England, participating in a feasibility study assessing the impact of bottle size on in-home SSB consumption, received a set amount of cola each week for four weeks in one of four bottle sizes: 1500 ml, 1000 ml, 500 ml, or 250 ml, in random order. At the study end, household representatives were interviewed about their experiences of using each bottle, including perceptions of i) consumption level; ii) consumption-related behaviours; and iii) factors affecting consumption. Interviews were semi structured and data analysed using the Framework approach. The present analysis focuses specifically on experiences relating to use of the smaller bottles. The smallest bottles were described as increasing drinking occasion frequency and encouraging consumption of numerous bottles in succession. Factors described as facilitating their consumption were: i) convenience and portability; ii) greater numbers of bottles available, which hindered consumption monitoring and control; iii) perceived insufficient quantity per bottle; and iv) positive attitudes. In a minority of cases the smallest bottles were perceived to have reduced consumption, but this was related to practical issues with the bottles that resulted in dislike. The perception of greater consumption and qualitative reports of drinking habits associated with the smallest bottles raise the possibility that the 'portion size effect' has a lower threshold, beyond which smaller portions and packages may increase consumption. This reinforces the need for empirical evidence to assess the in-home impact of smaller bottles on SSB consumption. PMID- 28864260 TI - Interferon-gamma mediated signaling in the brain endothelium is critical for inflammation-induced aversion. AB - Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-gamma (IFN-gamma) in the aversive response to systemic inflammation induced by a low dose (10MUg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-gamma expression in the blood and deletion of IFN-gamma or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-gamma receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-gamma receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-gamma action. Collectively, these findings show that circulating IFN-gamma that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation induced aversion. PMID- 28864261 TI - The efficacy of (+)-Naltrexone on alcohol preference and seeking behaviour is dependent on light-cycle. AB - Circadian rhythm affects drug-induced reward behaviour and the innate immune system. Peaks in reward-associated behaviour and immune responses typically occur during the active (dark) phase of rodents. While the role of the immune system, specifically, Toll-like receptor 4 (TLR4, an innate immune receptor) in drug induced reward is becoming increasingly appreciated, it is unclear whether its effects vary according to light-cycle. Therefore, the aim of this study was to characterise the effects of the phase of the light-cycle and the state of the innate immune system on alcohol reward behaviour and subsequently determine whether the efficacy of targeting the immune component of drug reward depends upon the light-cycle. This study demonstrates that mice exhibit greater alcohol induced conditioned place preference and alcohol two-bottle choice preference during the dark cycle. This effect overlapped with elevations in reward-, thirst- and immune-related genes. Administration of (+)-Naltrexone, a TLR4 antagonist, reduced immune-related gene mRNA expression and alcohol preference with its effects most pronounced during the dark cycle. However, (+)-Naltrexone, like other TLR4 antagonists exhibited off-target side effects, with a significant reduction in overall saccharin intake - an effect likely attributable to a reduction in tyrosine hydroxylase (Th) mRNA expression levels. Collectively, the study highlights a link between a time-of-day dependent influence of TLR4 on natural and alcohol reward-like behaviour in mice. PMID- 28864262 TI - Balanced activation of IspG and IspH to eliminate MEP intermediate accumulation and improve isoprenoids production in Escherichia coli. AB - The MEP pathway genes were modulated to investigate whether there were new rate limiting steps and toxic intermediates in this pathway. Activating IspG led to significant decrease of cell growth and beta-carotene production. It was found that ispG overexpression led to accumulation of intermediate HMBPP, which seriously interfered with synthesis machinery of nucleotide and protein in Escherichia coli. Activation of the downstream enzyme IspH could solve HMBPP accumulation problem and eliminate the negative effects of ispG overexpression. In addition, intermediate MECPP accumulated in the starting strain, while balanced activation of IspG and IspH could push the carbon flux away from MECPP and led to 73% and 77% increase of beta-carotene and lycopene titer respectively. Our work for the first time identified HMBPP to be a cytotoxic intermediate in MEP pathway and demonstrated that balanced activation of IspG and IspH could eliminate accumulation of HMBPP and MECPP and improve isoprenoids production. PMID- 28864263 TI - Mechanism of chimeric vaccine stimulation of indoleamine 2,3-dioxygenase biosynthesis in human dendritic cells is independent of TGF-beta signaling. AB - Cholera toxin B subunit fusion to autoantigens such as proinsulin (CTB-INS) down regulate dendritic cell (DC) activation and stimulate synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased biosynthesis of indoleamine 2,3 dioxygenase (IDO1) may play an important role in CTB-INS vaccine suppression of DC activation. Studies in murine models suggest a role for transforming growth factor beta (TGF-beta) in the stimulation of IDO1 biosynthesis, for the induction of tolerance in DCs. Here, we investigated the contribution of TGF-beta superfamily proteins to CTB-INS induction of IDO1 biosynthesis in human monocyte derived DCs (moDCs). We show that CTB-INS upregulates the level of TGF-beta1, activin-A and the TGF-beta activator, integrin alphavbeta8 in human DCs. However, inhibition of endogenous TGF-beta, activin-A or addition of biologically active TGF-beta1, and activin-A, did not inhibit or stimulate IDO1 biosynthesis in human DCs treated with CTB-INS. While inhibition with the kinase inhibitor, RepSox, blocked SMAD2/3 phosphorylation and diminished IDO1 biosynthesis in a concentration dependent manner. Specific blocking of the TGF-beta type 1 kinase receptor with SB-431542 did not arrest IDO1 biosynthesis, suggesting the involvement of a different kinase pathway other than TGF-beta type 1 receptor kinase in CTB-INS induction of IDO1 in human moDCs. Together, our experimental findings identify additional immunoregulatory proteins induced by the CTB-INS fusion protein, suggesting CTB-INS may utilize multiple mechanisms in the induction of tolerance in human moDCs. PMID- 28864264 TI - A Self-Reported Needs Assessment Survey of Pediatric Orthopaedic Education in Haiti. AB - OBJECTIVE: The burden of musculoskeletal disease remains high in low-income countries, with a high rate of pediatric disease. Efforts continue for orthopedic education, but there is little guidance on local needs and desires. Our aim was to determine the specific content and modalities that would be most useful for pediatric orthopedic educational programs abroad, and we demonstrate a practical method of identifying country-specific educational deficits through a self reported needs survey in Haiti. DESIGN: A cross-sectional survey was administered using an automated response system. We obtained demographic information as well as training and practice patterns, comfort levels with pediatric diagnoses, and desired topics for education using a 5-point Likert Scale. SETTING: Haitian Annual Assembly for Orthopaedic Trauma (HAAOT), the only national, continuing medical education conference for orthopedic providers in Haiti. PARTICIPANTS: Of 60 eligible participants, 51 were included in the final analysis. RESULTS: Time spent on pediatric orthopedics varied widely, centered at 10% to 25%. Median comfort level with pediatric orthopedics was 3 of 5. Skills with lowest self reported competence included spica casting, clubfoot casting, and management of supracondylar humerus fractures. Skills with highest self-reported competence were long-leg casting and Salter-Harris classification. Modes of education highly requested included didactics/lectures, hands-on sessions, dedicated rotations, and exchanges with foreign peers/mentors. Diagnoses most encountered were osteomyelitis, trauma, and clubfoot; lowest comfort levels were in neuromuscular, spine, lower extremity deformity, congenital hip, and clubfoot; and most requested for future teaching were congenital hip, neuromuscular, and spine. CONCLUSIONS: Haitian orthopedic providers express a strong desire and need for ongoing pediatric orthopedic education. They describe a high prevalence of trauma and infection, but convey a requirement for more comprehensive, multimodal teaching that also includes congenital deformities/dysplasias, neuromuscular, and spine. Our results demonstrate the importance of assessing country-specific needs and involving local care providers in curriculum development. PMID- 28864265 TI - Effect of Continuous Motion Parameter Feedback on Laparoscopic Simulation Training: A Prospective Randomized Controlled Trial on Skill Acquisition and Retention. AB - OBJECTIVE: To investigate the effect of motion parameter feedback on laparoscopic basic skill acquisition and retention during a standardized box training curriculum. DESIGN: A Lap-X Hybrid laparoscopic simulator was designed to provide individual and continuous motion parameter feedback in a dry box trainer setting. In a prospective controlled trial, surgical novices were randomized into 2 groups (regular box group, n = 18, and Hybrid group, n = 18) to undergo an identical 5 day training program. In each group, 7 standardized tasks on laparoscopic basic skills were completed twice a day on 4 consecutive days in fixed pairs. Additionally, each participant performed a simulated standard laparoscopic cholecystectomy before (day 1) and after training (day 5) on a LAP Mentor II virtual reality (VR) trainer, allowing an independent control of skill progress in both groups. A follow-up assessment of skill retention was performed after 6 weeks with repetition of both the box tasks and VR cholecystectomy. SETTING: Muenster University Hospital Training Center, Muenster, Germany. PARTICIPANTS: Medical students without previous surgical experience. RESULTS: Laparoscopic skills in both groups improved significantly during the training period, measured by the overall task performance time. The 6 week follow-up showed comparable skill retention in both groups. Evaluation of the VR cholecystectomies demonstrated significant decrease of operation time (p < 0.01), path length of the left and right instrument, and the number of movements of the left and right instruments for the Hybrid group (all p < 0.001), compared to the box group. Similar results were found at the assessment of skill retention. CONCLUSION: Simulation training on both trainers enables reliable acquisition of laparoscopic basic skills. Furthermore, individual and continuous motion feedback improves laparoscopic skill enhancement significantly in several aspects. Thus, training systems with feedback of motion parameters should be considered to achieve long term improvement of motion economy among surgical trainees. PMID- 28864266 TI - The Colorado Humanitarian Surgical Skills Workshop: A Cadaver-Based Workshop to Prepare Residents for Surgery in Austere Settings. AB - OBJECTIVE: Interest in humanitarian surgery is high among surgical and obstetric residents. The Colorado Humanitarian Surgical Skills Workshop is an annual 2-day course exposing senior residents to surgical techniques essential in low- and middle-income countries but not traditionally taught in US residencies. We evaluated the course's ability to foster resident comfort, knowledge, and competence in these skills. DESIGN: The cohort of course participants was studied prospectively. Participants attended didactic sessions followed by skills sessions using cadavers. Sample areas of focus included general surgery (mesh free hernia repair), orthopedics (powerless external fixation), and neurosurgery (powerless craniotomy). Before and after the course, participants answered a questionnaire assessing confidence with taught skills; took a knowledge-based test composed of multiple choice and open-ended questions; and participated in a manual skills test of tibial external fixation. SETTING: The Center for Surgical Innovation, University of Colorado School of Medicine. PARTICIPANTS: A total of 12 residents (11 general surgical and 1 obstetric) from ten US institutions. RESULTS: After the course, participants perceived increased confidence in performing all 27 taught procedures and ability to practice in low- and middle income countries. In knowledge-based testing, 10 of 12 residents demonstrated improvement on multiple choice questioning and 9 of 12 residents demonstrated improvement on open-ended questioning with structured scoring. In manual skills testing, all external fixator constructs demonstrated objective improvement on structured scoring and subjective improvement on stability assessment. CONCLUSIONS: For senior residents interested in humanitarian surgery, a combination of skills-focused teaching and manual practice led to self-perceived and objective improvement in relevant surgical knowledge and skills. The Colorado Humanitarian Surgical Skills Workshop represents an effective model for transmitting essential surgical principles and techniques of value in low resource settings. PMID- 28864267 TI - Developing the Blueprint for a General Surgery Technical Skills Certification Examination: A Validation Study. AB - INTRODUCTION: There is a recognized need to develop high-stakes technical skills assessments for decisions of certification and resident promotion. High-stakes examinations requires a rigorous approach in accruing validity evidence throughout the developmental process. One of the first steps in development is the creation of a blueprint which outlines the potential content of examination. The purpose of this validation study was to develop an examination blueprint for a Canadian General Surgery assessment of technical skill certifying examination. METHODS: A Delphi methodology was used to gain consensus amongst Canadian General Surgery program directors as to the content (tasks or procedures) that could be included in a certifying Canadian General Surgery examination. Consensus was defined a priori as a Cronbach's alpha >= 0.70. All procedures or tasks reaching a positive consensus (defined as >=80% of program directors rated items as >=4 on the 5-point Likert scale) were then included in the final examination blueprint. RESULTS: Two Delphi rounds were needed to reach consensus. Of the 17 General Surgery Program directors across the country, 14 (82.4%) and 10 (58.8%) program directors responded to the first and second round, respectively. A total of 59 items and procedures reached positive consensus and were included in the final examination blueprint. CONCLUSIONS: The present study has outlined the development of an examination blueprint for a General Surgery certifying examination using a consensus-based methodology. This validation study will serve as the foundational work from which simulated model will be developed, pilot tested and evaluated. PMID- 28864268 TI - Baicalein induces cell death in murine T cell lymphoma via inhibition of thioredoxin system. AB - We have earlier demonstrated the radioprotective potential of baicalein using murine splenic lymphocytes. Here, we have studied the effect of baicalein on murine T cell lymphoma EL4 cells and investigated the underlying mechanism of action. We observed that baicalein induced a dose dependent cell death in EL4 cells in vitro and significantly reduced the frequency of cancer stem cells. Previously, we have reported that murine and human T cell lymphoma cells have increased oxidative stress tolerance capacity due to active thioredoxin system. Hence, we monitored the effect of baicalein on thioredoxin system in EL4 cells. Docking studies revealed that baicalein could bind to the active site of thioredoxin reductase. Baicalein treatment led to significant reduction in the activity of thioredoxin reductase and nuclear levels of thioredoxin-1 thereby increasing ASK1 levels and caspase-3 activity. Interestingly, CRISPR-Cas9 based knock-out of ASK1 or over-expression of thioredoxin-1 abolished anti-tumor effects of baicalein in EL4 cells. Further, baicalein administration significantly reduced intra-peritoneal tumor burden of EL4 cells in C57BL/6 mice. Thus, our study describes anti-tumor effects of baicalein in EL4 cells via inhibition of thioredoxin system. PMID- 28864269 TI - Uses of chitosan for treating different forms of serious obstetrics hemorrhages. AB - Postpartum hemorrhage is a major cause of maternal death worldwide. Many therapeutic strategies have been developed to reduce maternal morbidity and mortality like oxytocin, prostaglandin, and uterine balloons. A new member of the therapeutic arsenal has recently emerged, the chitosan (Celox(r)), used since several years by military doctors to stop bleeding of combat wounds. In 2012, a first study was reported with the successful use of chitosan-coated gauze to treat severe postpartum hemorrhage. We report here four cases of the use of chitosan to treat life-threatening obstetric bleeding. In the first case, a pelvic packing with chitosan gauze after hemostatic hysterectomy with persistent bleeding. In the second case, the use of chitosan powder in a case of severe bleeding from multiple vaginal tears. In the third case, the use of chitosan gauze in uterine packing for postpartum hemorrhage by atonia. In the fourth case, the use of chitosan powder for stop bleeding during a hemorrhagic cesarean section. Postpartum hemorrhage of uterine origin resistant to treatment with prostaglandins can be treated with chitosan-coated gauze. This treatment requires no training and its costs are one fifth those of a Bakri(r) intrauterine balloon. Using these two forms of chitosan, powder and gauze, we have a new therapeutic method at our disposal for dealing with the most serious cases of bleeding. PMID- 28864270 TI - Spontaneous Tear After Insufflation: A Unique Finding of Collagenous Colitis. PMID- 28864271 TI - Leukemic Infiltration of Colon in a Case of Diarrhea Post Hematopoietic Cell Transplantation (HCT). PMID- 28864272 TI - Reply. PMID- 28864273 TI - Transtympanic pseudoaneurysm of the internal carotid artery complicating a myringotomy in a four-year old child: Case report and literature review. AB - We report the first case of a transtympanic iatrogenic internal carotid artery (ICA) pseudoaneurysm diagnosed in a 4-year-old child following a myringotomy. An endovascular treatment with a covered-stent was decided; spontaneous thrombosis was found during the therapeutic arteriography, and the procedure was aborted. Otoscopy and computed tomography (CT) scan monitoring showed a prolonged thrombosis and the disappearance of the pseudoaneurysm 18months after the diagnostic arteriography. Based on literature review, endovascular techniques seem to be preferred to the surgical approach for treatment of intrapetrous ICA pseudoaneurysm, however clinical and CT scan monitoring may also be a valid option. PMID- 28864274 TI - Retraction notice to "Obesity-Induced Increase in Tumor Necrosis Factor-alpha Leads to Development of Colon Cancer in Mice" Gastroenterology 2012;143:741 753.e4. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and Deputy Editor-in-Chief following an investigation into the data that were presented in several figures within the article. A number of images used in this article are believed to be duplicated images. The authors stated that they inadvertently inserted images of the wrong blots in several of the figures, resulting in the duplications; however, they did not address all of the concerns raised. Because the editors were no longer confident in the conclusions of the article based on these incorrect data, a decision was made to retract the paper. All authors have been notified of this decision. The University of Campinas (UNICAMP) in Sao Paulo, Brazil was contacted regarding these concerns, but to date the journal has received no response. PMID- 28864275 TI - Racial disparity in infant mortality. AB - In the United States, African-American infants have significantly higher mortality than white infants. Previous work has identified associations between individual socioeconomic factors and select community-level factors. In this review, the authors look beyond traditional risk factors for infant mortality and examine the social context of race in this country, in an effort to understand African-American women's long-standing birth outcome disadvantage. In the process, recent insights are highlighted concerning neighborhood-level factors such as crime, segregation, built environment, and institutional racism, other likely causes for the poor outcomes of African-American infants in this country compared with infants in most other industrialized nations. PMID- 28864276 TI - Physiopathology of multiple organ dysfunctions in severely monocrotophos-poisoned rabbits. AB - OBJECTIVE: Acute organophosphorus pesticides poisoning has a serious threat on people's health. This study aimed to investigate the pathogenesis and molecular mechanism of multiple organ dysfunction syndrome (MODS) in severely monocrotophos poisoned rabbits. METHODS: Chinchilla rabbits were used to build the monocrotophos-poisoned animal model via subcutaneous abdominal injection. Acetylcholinesterase activity was determined using the dithiobisnitrobenzoic acid enzyme kinetics method, and the free organophosphorus (FOP) toxic substances content was analyzed using the enzyme inhibition method. The contents of tumor necrosis factor (TNF-alpha), interleukin 1-beta (IL-beta) and thromboxane B2 (TXB2) in the plasma and tissue homogenates were determined via radioimmunoassay. RESULTS: Twenty-four hours after exposure, in comparison to the plasma, blood cells and homogenates of various tissues, the bile had a significantly different FOP content (P < 0.05). In different phases, HE staining results confirmed that several degrees of pathological lesions (such as hemorrhage, edema, degeneration and necrosis) were detected in FOP poisoned rabbits. The TXB2 and TNF contents in plasma were significantly higher than those of the control (P < 0.05). Except for the intercostal muscle, all of the tissues had significantly higher TXB2 contents than the control. The TNF contents of the liver and lung and the IL-1beta contents of the liver and kidney were significantly higher than those of the control (P < 0.05). CONCLUSION: FOP stored in the gallbladder may play important role in enterohepatic circulation. In MODS rabbits, caused by OP poisoning, the TXB2 and TNF-alpha may play important role in inflammatory response and complement and coagulation systems respectively. PMID- 28864277 TI - Neolignans from leaves of Nectandra leucantha (Lauraceae) display in vitro antitrypanosomal activity via plasma membrane and mitochondrial damages. AB - Chagas disease is a neglected tropical disease, caused by the protozoan parasite Trypanosoma cruzi, which affects more than eight million people in Tropical and Subtropical countries especially in Latin America. Current treatment is limited to nifurtimox and benznidazole, both with reduced effectiveness and high toxicity. In this work, the n-hexane extract from leaves of Nectandra leucantha (Lauraceae) displayed in vitro antitrypanosomal activity against T. cruzi. Using several chromatographic steps, four related neolignans were isolated and chemically characterized as dehydrodieugenol B (1), 1-(8-propenyl)-3-[3'-methoxy 1'-(8-propenyl)-phenoxy]-4,5-dimethoxybenzene (2), 1-[(7S)-hydroxy-8-propenyl]-3 [3'-methoxy-1'-(8'-propenyl)-phenoxy]-4-hydroxy-5-methoxybenzene (3), and 1-[(7S) hydroxy-8-propenyl]-3-[3'-methoxy-1'-(8'-propenyl)-phenoxy]-4,5-dimethoxybenzene (4). These compounds were tested against intracellular amastigotes and extracellular trypomastigotes of T. cruzi and for mammalian cytotoxicity. Neolignan 4 showed the higher selectivity index (SI) against trypomastigotes (>5) and amastigotes (>13) of T. cruzi. The investigation of the mechanism of action demonstrated that neolignan 4 caused substantial alteration of the plasma membrane permeability, together with mitochondrial dysfunctions in trypomastigote forms. In silico studies of pharmacokinetics and toxicity (ADMET) properties predicted that all compounds were non-mutagenic, non-carcinogenic, non-genotoxic, weak hERG blockers, with acceptable volume of distribution (1.66-3.32 L/kg), and low rodent oral toxicity (LD50 810-2200 mg/kg). Considering some clinical events of cerebral Chagas disease, the compounds also demonstrated favorable properties, such as blood-brain barrier penetration. Unfavorable properties were also predicted as high promiscuity for P450 isoforms, high plasma protein binding affinity (>91%), and moderate-to-low oral bioavailability. Finally, none of the isolated neolignans was predicted as interference compounds (PAINS). Considering the promising chemical and biological properties of the isolated neolignans, these compounds could be used as starting points to develop new lead compounds for Chagas disease. PMID- 28864278 TI - Effects of sodium pyruvate on viability, synthesis of reactive oxygen species, lipid peroxidation and DNA integrity of cryopreserved bovine sperm. AB - The aim of this study was to examine effects of sodium pyruvate on viability as well as on synthesis of reactive oxygen species (ROS), lipid peroxidation and DNA integrity of cryopreserved bovine sperm. In each of 23 Simmental AI bulls three ejaculates were collected. In a split sample design ejaculates were diluted by using Triladyl(r) extender without and with the addition of 5mM sodium pyruvate. Both aliquots were equilibrated for 24h before freezing. Frozen sperm samples were thawed, and examined immediately after thawing (0h) as well as after 3, 6, 12, and 24h incubation at 37 degrees C. The percentages of rapidly motile sperm (RMS), plasma membrane and acrosome intact sperm (PMAI), sperm with a high mitochondrial membrane potential (HMMP), amounts of ROS synthesis (dichlorofluorescein-diacetate (DCFH), CellROX Deep Red Reagent(r) probe (CellROX)) and lipid peroxidation of sperm (LPO) and percentage of sperm with a high degree of DNA fragmentation (%DFI) were determined. Overall, sperm diluted with the extender containing sodium pyruvate showed higher levels of RMS, PMAI and HMMP, CellROX and lower %DFI values (P<0.001) compared to sperm frozen in the extender without sodium pyruvate. However, there was no effect (P>0.05) of sodium pyruvate on LPO and DCFH. The results of this study show that the addition of sodium pyruvate to the semen extender improved the viability as well as DNA integrity of cryopreserved sperm and did not affect their lipid peroxidation, although it increased the synthesis of some ROS. PMID- 28864279 TI - HBV recurrence after HCV clearance on DAAs: Sometimes they come back. PMID- 28864280 TI - Cultural factors in first episode psychosis treatment engagement. AB - Specialized First Episode Psychosis (FEP) services have been conceptualized in part around the issue of engagement. Creating treatment that is easier to access, with more frequent contacts, assertive outreach to clients between appointments, and an explicit youth-oriented culture could make services more attractive to those most in need of care. However, engagement has remained a mostly fuzzy, peripheral construct rather than the object of study in itself. As we recognize the importance of treatment engagement, we must prepare to address it more rigorously within psychosis and schizophrenia research. At the same time, factors enhancing or obstructing treatment engagement are inevitably local, rather than universal. The availability of care, its associated costs and stigmas, individuals' motivations for seeking treatment, and their beliefs and expectations about providers' roles are determined by local and cultural features. There can be no singular "best practice" for engagement - but curiosity about how culture and locale influence clients' willingness to participate in care, and creativity in how we account for and incorporate these variables into study designs, will help to shed light on the critical issue of engagement in FEP treatment. PMID- 28864281 TI - Interaction of Brain-Derived Neurotrophic Factor Val66Met genotype and history of stress in regulation of prepulse inhibition in mice. AB - The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism results in reduced activity-dependent BDNF release and has been implicated in schizophrenia. However, effects of the polymorphism on functional dopaminergic and N-methyl-d aspartate (NMDA) receptor-associated activity remain unclear. We used prepulse inhibition, a measure of sensorimotor gating which is disrupted in schizophrenia, and assessed the effects of acute treatment with the dopamine receptor agonist, apomorphine (APO), and the NMDA receptor antagonist, MK-801. We used adult humanized hBDNFVal66Met 'knockin' mice which express either the Val/Val, Val/Met or Met/Met genotype. An interaction of BDNF with stress was modelled by chronic young-adult treatment with corticosterone (CORT). At 1 or 3mg/kg, APO had no effect in Val/Val mice but significantly reduced PPI at the 100ms inter-stimulus interval (ISI) in Val/Met and Met/Met mice. However, after CORT pretreatment, APO significantly reduced PPI in all genotypes similarly. At 0.1 or 0.25mg/kg, MK-801 significantly disrupted PPI at the 100ms ISI independent of genotype or CORT pretreatment. There were differential effects of APO and MK-801 on PPI at the 30ms ISI and startle between the genotypes, irrespective of CORT pretreatment. These results show that the BDNF Val66Met Val/Met and Met/Met genotypes are more sensitive than the Val/Val genotype to the effect of APO on PPI. A history of stress, here modelled by chronic CORT administration, increases effects of APO in Val/Val mice. PMID- 28864282 TI - What do we know about insight into illness and its association with the underlying biology of schizophrenia? PMID- 28864283 TI - Covariation between motor signs and negative symptoms in drug-naive subjects with schizophrenia-spectrum disorders before and after antipsychotic treatment. AB - OBJECTIVE: To examine the covariation between negative symptoms and motor signs in a broad sample of drug-naive subjects with schizophrenia-spectrum psychoses before and after inception of antipsychotic medication. METHODS: One-hundred and eighty-nine antipsychotic-naive subjects with DSM-IV schizophrenia-spectrum psychoses were assessed for negative symptoms including affective flattening, alogia, avolition/apathy and anhedonia/associality, and motor signs including catatonia, parkinsonism and dyskinesia. We examined the association between negative and motor features at baseline, 4-weeks after inception of antipsychotic treatment and that of their mean change over the treatment period, such as their trajectories and treatment response pattern. RESULTS: At the drug-naive state, motor signs were strongly related to affective flattening and alogia (p<0.01); at 4-weeks, most negative and motor features were significantly interrelated (p<0.01); mean change of motor signs and negative symptoms tended to be unrelated. This association pattern was irrespective of levels of positive symptoms. Ratings of negative symptoms, excepting affective flattening, improved after treatment (p<0.001) while motor ratings showed divergent trajectories with catatonia improving (p<0.001), parkinsonism worsening (p<0.001) and dyskinesia remaining unchanged (p>0.01). Although to a different extent, motor and negative features showed drug-responsive, drug-worsening, of drug-unchanged patterns of response to antipsychotic medication. The main predictors of negative and motor features in treated subjects were their corresponding baseline ratings (p<0.001). CONCLUSIONS: Negative and motor features are differentiated, but to some extent, overlapping domains that are meaningfully influenced by antipsychotic medication. At the drug-naive state, motor signs and the diminished expression domain of negative symptoms may share underlying neurobiological mechanisms. PMID- 28864284 TI - Evaluation of caffeine versus codeine for pain and swelling management after implant surgeries: A triple blind clinical trial. AB - INTRODUCTION: There are controversies in recent studies over the application of NSAIDs for controlling pain and swelling after implant surgeries for osseointegration. The aim of this study was to compare caffeine-containing versus codeine-containing analgesics in relation to their anti-inflammatory and analgesic effects after dental implant surgeries. MATERIALS AND METHODS: 80 patients (40 in each group) were selected as the final sample size. Forty drug packs, which were formulated and made by the consultant pharmacist, each containing 10 capsules of acetaminophen caffeine (consisting of 300 mg of acetaminophen and 20 mg of caffeine), and another 40 packs, each containing 10 capsules of acetaminophen codeine (consisting of 300 mg acetaminophen and 20 mg codeine) were prepared. These drugs were administered randomly to patients 1 h before surgery and every 6 h afterward until 48 h, according to the protocol. The patients' pain severities were determined at 30-min, 3-h, 6-h, 12-h, 1-day, 2 day, and 1-week intervals. In addition, the swelling was evaluated after 1-day, 2 days, 3-days, and 1-week. Data were analyzed with Mann-Whitney, student's t, and chi-squared tests, using SPSS 11. RESULTS: A total of 76 patients, including 38 males and 38 females, with a mean age of 41.06 +/- 5 and an age range of 35-53 years, were studied. The pain severities in patients in the codeine group were significantly less than those in the caffeine group at 3-, 6-, and 12-h postoperative intervals (p = 0.001). However, the pain severities at the above intervals, even in caffeine group, were within the moderate pain severity range (VAS = 3-7). It is also interesting to note that the pain was at its maximum severity at the 6-h postoperative interval, and at its minimum at the 1-week interval. The severity of swelling was also evaluated in both groups, indicating that it was significantly less in the caffeine group at 1-, 2-, and 3-day postoperative intervals (p = 0.018). CONCLUSION: According to this study, the codeine-containing analgesics are significantly more effective than caffeine containing ones in reducing postoperative pain. It was also concluded that caffeine-containing analgesics are significantly more effective than codeine containing ones in reducing postoperative swelling, which was reported to be significantly less within the first 3-days in the caffeine group. As a result, caffeine-containing analgesics are effective and acceptable in reducing both postoperative pain and swelling. PMID- 28864285 TI - Impact of greenspaces in city on avian species richness and abundance in Northern Africa. AB - Increasing urbanization is a major challenge in the context of global changes, because this environment is known to negatively impact biodiversity. It is therefore important to identify factors maintaining biodiversity in such areas. Here, we tested in 650 sites whether the greenspaces in urbanized area of Annaba (Algeria) has positive effects on avian species richness and abundances. Our results show that species detection (n=26) is more important during the breeding season as compared to the winter season, and that avian species richness is positively affected by the greenspaces. For most species, greenspaces impact positively their presence and abundances. Only the feral pigeon was less detected in greenspaces as compared to built-up areas. Our study therefore confirmed, for the first time in a Northern African city, that greenspaces significantly increase the species richness and abundances of birds, and shows that the season can profoundly affect such indicators. PMID- 28864286 TI - Abnormalities of T-cell receptor repertoire in CD4+ regulatory and conventional T cells in patients with RAG mutations: Implications for autoimmunity. PMID- 28864288 TI - A novel hypothesis for the pathogenesis of glaucomatous disc hemorrhage. AB - Disc hemorrhage is known to be associated with glaucoma development and progression. Several hypotheses have been proposed to explain the pathogenesis of disc hemorrhage in glaucoma, including mechanical and ischemic theories. However, no theory has yet provided a clear explanation of cellular-level events and related histologic findings. Moreover, research has yet to elucidate why glaucomatous disc hemorrhage occurs around the optic disc and at the margin of the retinal nerve fiber layer defect. Understanding the pathogenic mechanism of disc hemorrhage will facilitate interpretation of its clinical importance, and provide better insight into clinical practice. In this review, we sought to provide a plausible hypothesis for the development of glaucomatous disc hemorrhage that could explain the aforementioned characteristic features. We suggest a new and detailed mechanism for disc hemorrhage. Critical microscopic events are also discussed in relation to reactive gliosis in glaucoma. With proliferative reactive gliosis, fibrous glial scar forms, and we suggest that the traction force induced by glial scar formation might disrupt capillary at the border between the healthy and damaged retinal nerve fiber layer, and develop splinter-shaped peripapillary hemorrhage. In addition to glial scar formation, remodeling and deformation of lamina cribrosa beams would insult the capillary surrounding the pore of the lamina cribrosa, and lead to development of round blotch-shaped cup hemorrhage. Histopathologic confirmation of these findings should be explored in future investigations. PMID- 28864289 TI - Phase 1 clinical trial of adoptive immunotherapy using "off-the-shelf" activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia. AB - BACKGROUND AIMS: Activated NK cells (aNK) generated by expansion of a human interleukin-2-dependent NK cell line (NK-92) were shown to mediate strong anti leukemia activity. This phase 1 study evaluated feasibility, safety, and activity of aNK cells adoptively transferred to patients with refractory/relapsed acute myeloid leukemia (AML). In addition, effects of these aNK cells on the patient's immune system were evaluated. METHODS: Two cell-dose levels (1 * 109 cells/m2 and 3 * 109 cells/m2) were used. One treatment course consisted of two infusions of the same cell dose, each cell infusion delivered 24 h apart. The aNK cells were administered in the outpatient setting. RESULTS: Seven patients with refractory/relapsed AML were treated with a total of 20 aNK cell infusions. None of the 7 patients experienced dose-limiting toxicities during the aNK cell administration or during 21 days of the post-infusion observation period. No grade 3-4 toxicities (probable or definite) related to aNK cell infusions occurred. Activity was transient in 3 of 7 patients. No significant changes in the patient's lymphocyte counts, subsets frequency, phenotype or activity were observed post-infusion. Cell dose-dependent effects in the plasma levels of several cytokines were observed. DISCUSSION: The trial demonstrated the safety and feasibility of adoptive cell therapy with "off-the-shelf" aNK cells in patients with refractory/relapsed AML. These data provide the foundation for future combination immunotherapy trials and for the optimization of aNK cell based therapies in patients with AML. PMID- 28864290 TI - Bone marrow-derived mesenchymal stromal cells regress aortic aneurysm via the NF kB, Smad3 and Akt signaling pathways. AB - BACKGROUND AIMS: We have confirmed that aortic aneurysm (AA) can be regressed by the administration of bone marrow-derived mesenchymal stromal cells (BM-MSCs). We investigated the kinetics of signaling pathways in AA following treatment with BM MSCs. METHODS: Angiotensin II-infused apolipoprotein E-deficient mice were treated by intravenous injection of 1 * 106 BM-MSCs in 0.2 mL saline (BM-MSCs group, n = 5) or 0.2 mL saline (saline group, n = 5). Mice were sacrificed 2 weeks after injection and subjected to measurements of the incidence of AA and levels of phosphorylated proteins. Levels of proteins in conditioned media of BM MSCs were also measured. RESULTS: The incidence of AA in the BM-MSCs group was reduced (BM-MSC 40% versus saline 100%, P <0.05). Levels of pNF-kB and pSTAT1 were reduced (pNF-kB: 0.28 versus 0.45 unit/mL, P <0.05, pSTAT1: 0.16 versus 0.34, P <0.05), whereas levels of pAkt and pSmad3 were elevated (pAkt: 0.13 versus 0.07, P <0.01, pSmad3: 1.07 versus 0.47, P <0.05) in the BM-MSCs group. The levels of pNF-kB, pAkt, and pSmad3 were correlated with aortic diameters. Trophic factors including IGFPB-3, NRF, Activin A and PDGF-AA were secreted from BM-MSCs (IGFBP-3: 35.2 pg/mL, NRF: 3.1 pg/mL, Activin A: 3.1 pg/mL, PDGF-AA: 0.45 pg/mL). CONCLUSIONS: Our findings suggested that the therapeutic mechanism of BM MSC-mediated AA regression could contribute to regulation of the NF-kB, Smad3 and Akt signaling pathways. In addition, paracrine actions by factors including NRF, IGFBP-3, Activin A and PDGF-AA might have affected these signaling pathways. PMID- 28864291 TI - Functional recovery upon human dental pulp stem cell transplantation in a diabetic neuropathy rat model. AB - Diabetic neuropathy (DN) is among the most debilitating complications of diabetes. Here, we investigated the effects of human dental pulp stem cell (DPSC) transplantation in Streptozotocin (STZ)-induced neuropathic rats. Six weeks after STZ injection, DPSCs were transplanted through two routes, intravenous (IV) or intramuscular (IM), in single or two repeat doses. Two weeks after transplantation, a significant improvement in hyperalgesia, grip-strength, motor coordination and nerve conduction velocity was observed in comparison with controls. A rapid improvement in neuropathic symptoms was observed for a single dose of DPSC IV; however, repeat dose of DPSC IV did not bring about added improvement. A single dose of DPSC IM showed steady improvement, and further recovery continued upon repeat IM administration. DPSC single dose IV showed greater improvement than DPSC single dose IM, but IM transplantation brought about better improvement in body weight. A marked reduction in tumor necrosis factor (TNF) alpha and C-reactive protein (CRP) levels was observed in the blood plasma for all treated groups, as compared with controls. With respect to inflammatory cytokines, repeat dose of DPSC IM showed further improvement, suggesting that a repeat dose is required to maintain the improved inflammatory state. Gene expression of inflammatory markers in liver confirmed amelioration in inflammation. Arachidonic acid level was unaffected by IV DPSC transplantation but showed noticeable increase through IM administration of a repeat dose. These results suggest that DPSC transplantation through both routes and dosage was beneficial for the retrieval of neuropathic parameters of DN; transplantation via the IM route with repeat dose was the most effective. PMID- 28864292 TI - The effect of bone mass and architecture on mandibular condyle after mandibular distraction. AB - OBJECTIVE: Mandibular distraction surgery is a critical treatment for jaw deformity. However, abnormal mandibular condylar bone resorption is often seen as complication after surgery. Our previous study using a rat mandibular distraction model suggested that overloading leads to mandibular condylar resorption. Host factors are also believed to influence the resorption. To understand the relationship between host factors and resorption, we investigated the effect of changing bone mass and architecture on the mandibular condyle using FK506. STUDY DESIGN: FK506, an immunosuppressant, was used to compromise bone mass and architecture in this study. Animals were divided into 4 groups: distraction surgery (Dist), FK506 administration (FK), distraction surgery with FK506 administration (FK + Dist), and no surgery or FK506 administration (Cont). RESULTS: The FK group showed reduced bone mass and impaired bone architecture. The Dist group exhibited abnormal bone resorption on the surface of the condyles, which was slightly exacerbated in the FK + Dist group. Bone defect length decreased over time as a result of bone apposition in the Dist group. However, in the FK + Dist group, the bone defect length remained the same. CONCLUSIONS: These results suggest that bone mass and architecture strongly affect the tolerance to the overloading and adaptation with bone apposition in condylar resorption site. PMID- 28864293 TI - DNA methylation profiles of 22 apoptosis-related genes in odontogenic keratocysts before and after marsupialization. AB - OBJECTIVE: Odontogenic keratocysts (OKCs) are cystic lesions of the jaw and tend to recur after treatment. Marsupialization is an effective preliminary treatment for large OKCs. This procedure induces epithelial lining changes in association with reduction of Bcl-2 protein expression, but the underlying mechanisms remain unknown. The purpose of our study was to compare the methylation profile of the apoptosis-related genes of OKCs before and after marsupialization. STUDY DESIGN: We assessed the methylation percentages of the promoter region of 22 apoptosis related genes in 13 OKCs, both marsupialized and nonmarsupialized lesions, by using methylation quantitative polymerase chain reaction array. We validated the expression of genes that showed the greatest differences in methylation percentages between the 2 groups. RESULTS: LTBR and BCLAF1 showed higher DNA methylation percentages in the marsupialized OKCs, but this difference did not affect gene expression (P > .05). The other 20 genes showed similar DNA methylation in both OKC groups. CONCLUSIONS: OKCs show a distinct methylation profile after marsupialization, but this is not followed by gene expression alterations. PMID- 28864294 TI - Preanalytical errors in transfusion medicine: Reply to "74-year-old female with new monoclonal protein on serum immunofixation electrophoresis". PMID- 28864295 TI - E-cigarettes emit very high formaldehyde levels only in conditions that are aversive to users: A replication study under verified realistic use conditions. AB - PURPOSE: In 2015, a study identified 5-15-fold higher levels of formaldehyde emissions from an old-generation e-cigarette tested at 5.0 V compared to tobacco cigarettes. We set to replicate this study using the same e-cigarette equipment and e-liquid, while checking for the generation of dry puffs. DESIGN: Experienced e-cigarette users (n = 26) took 4 s puffs at different voltage settings and were asked to report the generation of dry puffs. Formaldehyde emissions were measured at both realistic and dry puff conditions. RESULTS: Dry puffs were detected at <=4.2 V by 88% of participants; thus, 4.0 V was defined as the upper limit of realistic use. Levels ranged from 3.4 (SE = 2.2) MUg/10 puffs at 3.3 V to 718.2 (SE = 58.2) MUg/10 puffs at 5.0 V. The levels detected at 4.0 V were 19.8 (SE = 5.6) MUg/10 puffs. At 4.0 V, the daily exposure to formaldehyde from consuming 3 g of liquid with the device tested would be 32% lower compared to smoking 20 tobacco cigarettes. CONCLUSIONS: The high levels of formaldehyde emissions that were reported in a previous study were caused by unrealistic use conditions that create the unpleasant taste of dry puffs to e-cigarette users and are thus avoided. PMID- 28864287 TI - Age-related cataracts: Role of unfolded protein response, Ca2+ mobilization, epigenetic DNA modifications, and loss of Nrf2/Keap1 dependent cytoprotection. AB - Age-related cataracts are closely associated with lens chronological aging, oxidation, calcium imbalance, hydration and crystallin modifications. Accumulating evidence indicates that misfolded proteins are generated in the endoplasmic reticulum (ER) by most cataractogenic stresses. To eliminate misfolded proteins from cells before they can induce senescence, the cells activate a clean-up machinery called the ER stress/unfolded protein response (UPR). The UPR also activates the nuclear factor-erythroid-2-related factor 2 (Nrf2), a central transcriptional factor for cytoprotection against stress. Nrf2 activates nearly 600 cytoprotective target genes. However, if ER stress reaches critically high levels, the UPR activates destructive outputs to trigger programmed cell death. The UPR activates mobilization of ER-Ca2+ to the cytoplasm and results in activation of Ca2+-dependent proteases to cleave various enzymes and proteins which cause the loss of normal lens function. The UPR also enhances the overproduction of reactive oxygen species (ROS), which damage lens constituents and induce failure of the Nrf2 dependent cytoprotection. Kelch-like ECH-associated protein 1 (Keap1) is an oxygen sensor protein and regulates the levels of Nrf2 by the proteasomal degradation. A significant loss of DNA methylation in diabetic cataracts was found in the Keap1 promoter, which overexpresses the Keap1 protein. Overexpressed Keap1 significantly decreases the levels of Nrf2. Lower levels of Nrf2 induces loss of the redox balance toward to oxidative stress thereby leading to failure of lens cytoprotection. Here, this review summarizes the overall view of ER stress, increases in Ca2+ levels, protein cleavage, and loss of the well-established stress protection in somatic lens cells. PMID- 28864296 TI - RIFM fragrance ingredient safety assessment, 1-methyl-3-methoxy-4 isopropylbenzene, CAS Registry Number 1076-56-8. PMID- 28864297 TI - Structural analysis of phosphatidylinositol 4-kinase IIIbeta (PI4KB) - 14-3-3 protein complex reveals internal flexibility and explains 14-3-3 mediated protection from degradation in vitro. AB - Phosphatidylinositol 4-kinase IIIbeta (PI4KB) is responsible for the synthesis of the Golgi and trans-Golgi network (TGN) pool of phosphatidylinositol 4-phospahte (PI4P). PI4P is the defining lipid hallmark of Golgi and TGN and also serves as a signaling lipid and as a precursor for higher phosphoinositides. In addition, PI4KB is hijacked by many single stranded plus RNA (+RNA) viruses to generate PI4P-rich membranes that serve as viral replication organelles. Given the importance of this enzyme in cells, it has to be regulated. 14-3-3 proteins bind PI4KB upon its phosphorylation by protein kinase D, however, the structural basis of PI4KB recognition by 14-3-3 proteins is unknown. Here, we characterized the PI4KB:14-3-3 protein complex biophysically and structurally. We discovered that the PI4KB:14-3-3 protein complex is tight and is formed with 2:2 stoichiometry. Surprisingly, the enzymatic activity of PI4KB is not directly modulated by 14-3-3 proteins. However, 14-3-3 proteins protect PI4KB from proteolytic degradation in vitro. Our structural analysis revealed that the PI4KB:14-3-3 protein complex is flexible but mostly within the disordered regions connecting the 14-3-3 binding site of the PI4KB with the rest of the PI4KB enzyme. It also predicted no direct modulation of PI4KB enzymatic activity by 14-3-3 proteins and that 14-3-3 binding will not interfere with PI4KB recruitment to the membrane by the ACBD3 protein. In addition, the structural analysis explains the observed protection from degradation; it revealed that several disordered regions of PI4KB become protected from proteolytical degradation upon 14-3-3 binding. All the structural predictions were subsequently biochemically validated. PMID- 28864298 TI - Curvature of designed armadillo repeat proteins allows modular peptide binding. AB - Designed armadillo repeat proteins (dArmRPs) were developed to create a modular peptide binding technology where each of the structural repeats binds two residues of the target peptide. An essential prerequisite for such a technology is a dArmRP geometry that matches the peptide bond length. To this end, we determined a large set (n=27) of dArmRP X-ray structures, of which 12 were previously unpublished, to calculate curvature parameters that define their geometry. Our analysis shows that consensus dArmRPs exhibit curvatures close to the optimal range for modular peptide recognition. Binding of peptide ligands can induce a curvature within the desired range, as confirmed by single-molecule FRET experiments in solution. On the other hand, computationally designed ArmRPs, where side chains have been chosen with the intention to optimally fit into a geometrically optimized backbone, turned out to be more divergent in reality, and thus not suitable for continuous peptide binding. Furthermore, we show that the formation of a crystal lattice can induce small but significant deviations from the curvature adopted in solution, which can interfere with the evaluation of repeat protein scaffolds when high accuracy is required. This study corroborates the suitability of consensus dArmRPs as a scaffold for the development of modular peptide binders. PMID- 28864299 TI - The concerted movement of the switch region of Troponin I in cardiac muscle thin filaments as tracked by conventional and pulsed (DEER) EPR. AB - The absence of a crystal structure of the calcium free state of the cardiac isoform of the troponin complex has hindered our understanding of how the simple binding of Ca2+ triggers conformational changes in troponin which are then propagated to enable muscle contraction. Here we have used continuous wave (CW) and Double Electron-Electron Resonance (DEER) pulsed EPR spectroscopy to measure distances between TnI and TnC to track the movement of the functionally important regulatory 'switch' region of cardiac Tn. Spin labels were placed on the switch region of Troponin I and distances measured to Troponin C. Under conditions of high Ca2+, the interspin distances for one set (TnI151/TnC84) were 'short' (9 10A) with narrow distance distribution widths (3-8A) indicating the close interaction of the switch region with the N-lobe of TnC. Additional spin populations representative of longer interspin distances were detected by DEER. These longer distance populations, which were ~16-19A longer than the short distance populations, possessed notably broader distance distribution widths (14 29A). Upon Ca2+ removal, the interspin population shifted toward the longer distances, indicating the release of the switch region from TnC and an overall increase in disorder for this region. Together, our results suggest that under conditions of low Ca2+, the close proximity of the TnI switch region to TnC in the cardiac isoform is necessary for promoting the interaction between the regulatory switch helix with the N-lobe of cardiac Troponin C, which, unlike the skeletal isoform, is largely in a closed conformation. PMID- 28864300 TI - The pregenital abdomen of Enicocephalomorpha and morphological evidence for different modes of communication at the dawn of heteropteran evolution. AB - The internal and external anatomy of the posterior metathoracic region, pregenital abdomen, and associated nervous system of the heteropteran infraorder Enicocephalomorpha are thoroughly described, using an array of state-of-the art techniques. Based on morphology, it is hypothesised which modes of communication these insects use. This study is based primarily on an undescribed species of Cocles Bergroth, 1905 (Enicocephalidae) and another undescribed species of Lomagostus Villiers, 1958 (Aenictopecheidae), but additional representatives of the infraorder are also examined. Our results are compared with the literature on other Heteroptera. The metathoracic scent gland system of Enicocephalomorpha uses the same muscles as that of more derived Heteroptera, although the efferent system is different. The presence of a tergal plate and well-developed longitudinal musculature in the families Enicocephalidae and Aenictopecheidae, as well as a sexually dimorphic set of sclerites and membranes that allow an as yet undetermined type of motion, may indicate the presence of vibrational signaling in the infraorder, although experimental confirmation is required. Our findings raise new research questions regarding heteropteran functional morphology and communication. PMID- 28864301 TI - The scolopidial accessory organs and Nebenorgans in orthopteroid insects: Comparative neuroanatomy, mechanosensory function, and evolutionary origin. AB - Scolopidial sensilla in insects often form large sensory organs involved in proprioception or exteroception. Here the knowledge on Nebenorgans and accessory organs, two organs consisting of scolopidial sensory cells, is summarised. These organs are present in some insects which are model organisms for the physiology of mechanosensory systems (cockroaches and tettigoniids). Recent comparative studies documented the accessory organ in several taxa of Orthoptera (including tettigoniids, cave crickets, Jerusalem crickets) and the Nebenorgan in related insects (Mantophasmatodea). The accessory organ or Nebenorgan is usually a small organ of 8-15 sensilla located in the posterior leg tibia of all leg pairs. The physiological properties of the accessory organs and Nebenorgans are so far largely unknown. Taking together neuroanatomical and electrophysiological data from disparate taxa, there is considerable evidence that the accessory organ and Nebenorgan are vibrosensitive. They thus complement the larger vibrosensitive subgenual organ in the tibia. This review summarises the comparative studies of these sensory organs, in particular the arguments and criteria for the homology of the accessory organ and Nebenorgan among orthopteroid insects. Different scenarios of repeated evolutionary origins or losses of these sensory organs are discussed. Neuroanatomy allows to distinguish individual sensory organs for analysis of sensory physiology, and to infer scenarios of sensory evolution. PMID- 28864302 TI - The allometry of the central nervous system during the postembryonic development of the spider Eratigena atrica. AB - During ontogenesis, the size of a spider body, tissues and organs increases dramatically. The aim of the study was to estimate changes in the central nervous system of postembryonic stages of Eratigena atrica and compare them with the literature data on species differing in behavioural traits. Allometric analysis involved evaluation of histological slides embedded in paraffin and stained with hematoxylin and eosin. The reduced major axis regression (RMA) was applied to find allometric relationships between the volumes of the particular parts of the body. All the measured parts of the central nervous system (CNS) were negatively allometrically related to the volume of the prosoma, showing that the increment of the CNS was lower than that of the entire body. The growth of the brain was negatively allometrically related to the growth of the CNS but the increment of the subesophageal ganglion was greater than that of the CNS, exhibiting a positive allometry. Within both these structures, the increase in neuropil volume was greater than the growth of the cortex (cell body rind). Thus, in postembryonic development, the share of the subesophageal ganglion and neuropil in the total volume of the CNS increased, whereas that of the brain and cortex decreased. The mode of the CNS development in E. atrica is similar to that observed in other arthropods, including Argiope aurantia, a spider of different ecology and behaviour. PMID- 28864303 TI - Corrigendum to "Body weight loss, reduced urge for palatable food and increased release of GLP-1 through daily supplementation with green-plant membranes for three months in overweight women" [81 (1 October 2014) 295-304]. PMID- 28864304 TI - [Cancer diagnosis disclosure and supportive care seen from the patient side. A cross sectional multicentre survey]. AB - : The objective of this study was to describe patients' experience during cancer disclosure and initial carers' support phase, in three healthcare facilities in Haute-Savoie District, France. METHODOLOGY: We conducted a multicentric, cross sectional telephone survey. Patients registered on the multidisciplinary cancer consultation platform lists were randomised. Practitioners validated the inclusion criteria of their patients, i.e. age over 18, patient fully informed of his/her diagnosis and able to answer a telephone interview. RESULTS: Two hundred thirty-six patients have been included. Outcome indicators reported as satisfactory were: the general setting of the disclosure consultation, the patient-doctor relationship, the coordination between the different carers and the patient carer relationship. The overall duration of the medical disclosure consultation and the time dedicated to explain the treatment and its adverse effects have been considered as insufficient. DISCUSSION: The measured indicators, which were by essence subjective, convey useful information on the quality of care in cancer treatment in the initial disclosure phase, as experienced by patients. This study has in particular allowed carers to start exploring ways to improve the experience of care of their patients. PMID- 28864305 TI - Transport and retention of carbon dots (CDs) in saturated and unsaturated porous media: Role of ionic strength, pH, and collector grain size. AB - Carbon-based engineered nanoparticles (ENPs) are widely used in consumer products due to their small size and unique physicochemical properties. Therefore, their release and distribution into the surface and subsurface environment is a subject of concern. Several studies have evaluated the transport and retention of carbon nanotubes and fullerenes, but none investigated the transport and retention of carbon dots (CDs). The aim of this research is to fill this knowledge gap by evaluating the transport and retention of CDs in saturated and unsaturated porous medium. Here, we investigate the effects of solution ionic strength (IS, 1-700 mM NaCl) and pH (4-9), the initial concentration of CDs (50-200 mg L-1), and porous media grain size (0.20-0.50 mm, 0.50-1 mm, 1-1.5 mm and 1.5-2 mm grain diameters) on the transport and retention of CDs in saturated (upward flow) and unsaturated (downward flow) quartz porous media. A mathematical model based on the advection dispersion equation coupled with the second-order kinetics was used to fit the breakthrough curves and to calculate the attachment and straining rates under the different experimental conditions. These analyses were underpinned by characterization of CD surface functional groups, surface charge and aggregation under the different experimental conditions, calculation of CD-CD and CD-quartz sand interaction potential according to DLVO theory. Transport and retention of CDs in quartz porous media are consistent with those observed for other types of carbon-based ENPs such as fullerenes and carbon nanotubes. Mobility of CDs in both saturated and unsaturated porous media increases with the decrease in ionic strength, increase in pH, and increase in collector grain size. Retention of CDs increases with the increase in IS, decrease in pH and decrease in grain size. Generally, CDs mobility was higher under saturated than under unsaturated flow conditions, for the same experimental conditions. Overall, CDs tend to be highly mobile and could travel for long distances at a wide range of environmental conditions. PMID- 28864306 TI - A meta-analysis of nevus-associated melanoma: Prevalence and practical implications. AB - The reported prevalence of nevus-associated melanoma varies substantially. We performed a systematic review and meta-analysis to determine the incidence and prevalence of this disease; we also performed subanalyses considering age, tumor thickness, and nevus-type classification. In 38 observational cohort and case control studies, 29.1% of melanomas likely arose from a preexisting nevus and 70.9% de novo. Any given melanoma was 64% less likely to be nevus-associated than de novo (risk ratio 0.36, 95% confidence interval [CI] 0.29-0.44; P < .001; I2 = 99%); nevus-associated melanomas had a lower mean Breslow thickness than de novo melanomas (mean difference -0.39 mm; 95% CI -0.60 to -0.18; P = .0003; I2 = 66%). No significant differences were noted regarding the association of nevus associated melanomas with nondysplastic nevi or dysplastic nevi (risk ratio 0.77, 95% CI 0.49-1.20; P = .24; I2 = 98%). PMID- 28864307 TI - Identifying gaps in consumer knowledge about sunscreen. PMID- 28864308 TI - A neurosurgeon's view: Outcome after RF-ablation for mTLE. AB - We reviewed the current RF-ablation technique for mTLE and complications relating to the procedure. RF-ablation of the amygdalohippocampal complex (AHC) is a stereotactic technique, performed under local anesthesia, which achieved long term seizure-free clinical seizure outcomes in 71% of mTLE patients. Occipital access is used and thermolesions are made from a single trajectory in the long axis of the AHC. RF-ablation has shown a low complication rate and clinical seizure outcomes seem to be comparable with open surgical techniques. PMID- 28864309 TI - Combining contrast harmonic and elastography during EUS examination of pancreatic tumors increases diagnostic accuracy. PMID- 28864310 TI - Cost-effective treatment of swine wastes through recovery of energy and nutrients. AB - Wastes from concentrated animal feeding operations (CAFOs) are challenging to treat because they are high in organic matter and nutrients. Conventional swine waste treatment options in the U.S., such as uncovered anaerobic lagoons, result in poor effluent quality and greenhouse gas emissions, and implementation of advanced treatment introduces high costs. Therefore, the purpose of this paper is to evaluate the performance and life cycle costs of an alternative system for treating swine CAFO waste, which recovers valuable energy (as biogas) and nutrients (N, P, K+) as saleable fertilizers. The system uses in-vessel anaerobic digestion (AD) for methane production and solids stabilization, followed by struvite precipitation and ion exchange (IX) onto natural zeolites (chabazite or clinoptilolite) for nutrient recovery. An alternative approach that integrated struvite recovery and IX into a single reactor, termed STRIEX, was also investigated. Pilot- and bench-scale reactor experiments were used to evaluate the performance of each stage in the treatment train. Data from these studies were integrated into a life cycle cost analysis (LCCA) to assess the cost effectiveness of various process alternatives. Significant improvement in water quality, high methane production, and high nutrient recovery (generally over 90%) were observed with both the AD-struvite-IX process and the AD-STRIEX process. The LCCA showed that the STRIEX system can provide considerable financial savings compared to conventional systems. AD, however, incurs high capital costs compared to conventional anaerobic lagoons and may require larger scales to become financially attractive. PMID- 28864311 TI - Factors affecting the shear strength behavior of municipal solid wastes. AB - In this study, the shear strength behavior of European (E-1), Turkey (T-1), and United States of America (U-1) average synthetic municipal solid waste (MSW) compositions were investigated. The large-scale direct shear tests were conducted using fresh and aged MSW samples collected from the Manisa Landfill. The natural samples' test results were compared with synthetic samples. The affecting factors such as ageing, waste composition, and waste type (synthetic and natural) on the shear strength of MSWs were investigated. The effect of composition was evaluated using three main and six modified synthetic MSW compositions. In addition to the synthetic fresh MSW samples, synthetic aged samples were also used. Angle of shearing resistance decreased with increasing organic content whereas cohesion intercept increased with increasing organic content. The fresh and aged wastes with higher coarse fraction lead to a higher angle of shearing resistance. The synthetic aged samples had higher internal friction angles but lower cohesion values than the synthetic fresh samples. Waste with average European composition had the highest internal friction angle as it has the highest fibrous content. On the other hand, the highest cohesion belonged to the Turkey composition, which had the highest organic matter ratio. The main differences between E-1, T-1 and U 1 samples in terms of compositions were observed. The results of this study indicated that shear strength of waste significantly depends on composition and hence a site specific evaluation is recommended. PMID- 28864312 TI - Why Do the Children (Pretend) Play? AB - Pretend play appears to be an evolved behavior because it is universal and appears on a set schedule. However, no specific functions have been determined for pretend play and empirical tests for its functions in humans are elusive. Yet animal play fighting can serve as an analog, as both activities involve as-if, metacommunicative signaling and symbolism. In the rat and some other animals, adaptive functions of play fighting include assisting social behavior and emotion regulation. Research is presented suggesting that pretend play might serve similar functions for humans. PMID- 28864313 TI - Toe-to-finger combined with free flap transfer for primary one-stage post traumatic reconstruction of the complex fingerless hand. AB - Toe-to-finger transplantation is intimately related to the development of microsurgical free tissue transplantation, which is one of the most important advances in the history of reconstructive surgery. It is also generally acknowledged that a mangled hand with massive tissue loss and amputation of multiple digits presents a challenge for plastic and reconstructive surgeons. In this retrospective study we reviewed 11 cases of primary one-stage post-traumatic reconstruction of complex fingerless hands using a combination of toe-to-finger and free tissue transplantation performed in Shanghai Jiao Tong University affiliated Sixth People's Hospital and Shanghai Jiao Tong University School of Medicine affiliated Ninth People's Hospital from January 2001 to November 2014. Primary healing was achieved in 10 cases, while in the other case partial flap loss was documented and secondary healing was achieved by skin grafting. We concluded from this study that, by selecting suitable patients, use of a combination of toe-to-finger and free tissue transplantation may provide an alternative option for mangled hand salvage with satisfactory functional and esthetic results. PMID- 28864314 TI - Non-living microvascular training models: Face validity of liquid latex and the challenge of structural vs. "physiological" patency assessment. PMID- 28864315 TI - Preventing the complications of tissue expansion using fat grafting under expanded skin. PMID- 28864317 TI - Feasibility and Safety of Early Repeat Transradial Access Within 30 Days of Previous Coronary Angiography and Intervention. AB - Transradial approach (TRA) is the default access site for diagnostic angiography and intervention in many centers. Repeat ipsilateral radial artery access late after index procedure has been associated with failures. It is unknown whether early (<=30 days) and very early (<24 hours) repeat radial access is technically feasible and safe. Study population consisted of consecutive patients undergoing repeat (>=2) procedures within 30 days in a high-volume TRA center. Transradial access failure and resulting femoral approach was categorized as primary (no repeat attempt) or secondary (crossover). Timing of repeat access and reasons for failure were recorded. From November 2012 to December 2014, repeat catheterization by TRA was performed twice in 573 of 626 patients (92%) (median delay 4 [2 to 9] days), 3 times in 29 of 38 (76%) patients (median delay 15 [5 to 26] days), and 4 times in 1 patient within 21 days. When repeat catheterization occurred during the first 24 hours following the index procedure, 53% and 75% of patients had second and third procedures using the same ipsilateral radial artery, respectively. Primary radial failure occurred in 5.8% for second attempt and 13% for a third attempt, whereas crossovers were noted in 2.7% and 2.6%, respectively. Main reasons for failed re-access of ipsilateral radial artery were related either to operator's reluctance to repeat attempt (primary failure) or to issues with puncture site (crossover). In a high-volume TRA center, patients who required repeat catheterization within 24 hours and within the first 30 days had the same radial artery re-accessed in the majority of cases. PMID- 28864316 TI - Relation of Diastolic Blood Pressure and Coronary Artery Calcium to Coronary Events and Outcomes (From the Multi-Ethnic Study of Atherosclerosis). AB - Diastolic blood pressure has a J-curve relation with coronary heart disease and death. Because this association is thought to reflect reduced coronary perfusion at low diastolic blood pressure, we hypothesized that the J-curve would be most pronounced in persons with coronary artery calcium. In 6,811 participants from the Multi-Ethnic Study of Atherosclerosis, we used Cox models to examine if diastolic blood pressure category is associated with coronary heart disease events, stroke, and mortality. Analyses were conducted in the sample overall and after stratification by coronary artery calcium score. In multivariable-adjusted analyses, compared with diastolic blood pressure of 80 to 89 mm Hg (reference), persons with diastolic blood pressure <60 mm Hg had increased risk of coronary heart disease events (hazard ratio 1.69 [95% confidence interval 1.02 to 2.79]) and all-cause mortality (hazard ratio 1.48 [95% confidence interval 1.10 to 2.00]), but not stroke. After stratification, associations of diastolic blood pressure <60 mm Hg with events were present only in participants with coronary artery calcium >0. Diastolic blood pressure <60 mm Hg was not associated with events when coronary artery calcium was zero. However, the association between diastolic blood pressure and events did not demonstrate statistical interaction when stratified by presence or absence of coronary calcium. We also found no interaction in the association between low diastolic blood pressure and events based on race. In conclusion, diastolic blood pressure <60 mm Hg was associated with increased risk of coronary heart disease events and all-cause mortality in the sample overall, but this association appeared strongest in individuals with subclinical atherosclerosis. PMID- 28864318 TI - Comparison of the Effectiveness and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Newly Diagnosed Atrial Fibrillation. AB - No studies have performed direct pairwise comparisons of the effectiveness and safety of warfarin and the new oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban. Using 2013 to 2014 claims from a 5% random sample of Medicare beneficiaries, we identified patients newly diagnosed with atrial fibrillation who initiated apixaban, dabigatran, rivaroxaban, warfarin, or no oral anticoagulation therapy in 2013 to 2014. Outcomes included the composite of ischemic stroke, systemic embolism (SE) and death, any bleeding event, gastrointestinal bleeding, intracranial bleeding, and treatment persistence. We constructed Cox proportional hazard models to compare outcomes between each pair of treatment groups. The composite risk of ischemic stroke, SE, and death was lower for NOACs than for warfarin: hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76 to 0.98 for apixaban; 0.73, 95% CI 0.63 to 0.86 for dabigatran; and 0.82, 95% CI 0.75 to 0.89 for rivaroxaban, all compared with warfarin. There were no differences in effectiveness across NOACs. The risk of any bleeding was lower with apixaban than with warfarin, but higher with rivaroxaban than with warfarin. Apixaban (HR 0.69, 95% CI 0.60 to 0.79) and dabigatran (HR 0.79, 95% CI 0.69 to 0.92) were associated with lower bleeding risk than rivaroxaban. Treatment persistence was highest for apixaban (82%), and lowest for dabigatran and warfarin (64%) (p value <0.001). Compared with warfarin, NOACs are more effective in preventing stroke but their risk of bleeding varies, with rivaroxaban having higher risk than warfarin. Altogether, apixaban had the most favorable effectiveness, safety, and persistence profile. PMID- 28864319 TI - Evaluation of Imaging Strategy to Optimize and Improve Outcome of Transcatheter Aortic Valvular Implantation. AB - Cardiac computed tomography (CT) provides additional information with ultrasound in the transcatheter heart valve (THV) size selection. However, the influence of these incremental data on outcomes has not been evaluated in a randomized study. A single-center prospective, randomized, and open study was performed. Patients referred for transfemoral transcatheter aortic valve implantation with a balloon expandable endoprothesis were included. THV size selection was performed using either transthoracic and transesophageal echocardiography data (control group) or ultrasound and CT results (CT group). The primary composite end point included the occurrence of stroke, major vascular complications, and moderate or severe paravalvular aortic regurgitation (PAR) at 1 year. Fifty patients (n = 25 in the control and CT groups) were enrolled. The primary composite end point occurred in 40% and 8% of patients from the control and CT groups, respectively (p = 0.008). The Kaplan-Meier analysis revealed a pejorative association with not performing the CT (p = 0.007). A decrease in the occurrence of PAR was observed in the CT group compared with the control group (PAR 28% vs 4%, p = 0.04; major vascular complications 12% vs 4%, p = 0.6; all-cause death 16% vs. 4%, p = 0.34; no stroke). In conclusion, the use of cardiac CT in addition to ultrasound data in THV size selection reduced the long-term occurrence of cardiovascular events. PMID- 28864320 TI - Effect of Adjunctive Thrombus Aspiration on In-Hospital and 3-Year Outcomes in Patients With ST-Segment Elevation Myocardial Infarction and Large Native Coronary Artery Thrombus Burden. AB - Although the long-term clinical benefit of adjunctive thrombus aspiration (TA) during primary percutaneous coronary intervention (PPCI) remains controversial, the impact of TA in patients with large thrombus has not been evaluated. The aim of the present study was to investigate the effect of adjunctive TA during PPCI on clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and a large thrombus. We assessed the effect of adjunctive TA on in hospital and 3-year clinical outcomes in 627 patients with STEMI and a large thrombus in the native coronary artery. The cumulative 3-year incidence of all cause death was not significantly different between the 2 groups (91.5% vs 89.0%, log-rank test p = 0.347). After adjusting for confounders, the risk of all-cause death in the TA group was not significantly lower than that in the non-TA group (hazard ratio 1.11, 95% confidence interval 0.60 to 3.54, p = 0.674). The adjusted risks of target lesion revascularization, nonfatal acute myocardial infarction, and stent thrombosis were also not significantly different between the 2 groups. In conclusion, adjunctive TA during PPCI was not associated with better in-hospital and 3-year all-cause deaths in patients with STEMI and a large coronary artery thrombus. PMID- 28864321 TI - Frequency of Recovery from Complete Atrioventricular Block After Cardiac Surgery. AB - Best timing for permanent pacemaker implantation to treat complete atrioventricular block (AVB) after cardiac surgery is unclear, as late pacemaker dependency was found low in recent observational studies. This study aimed to identify factors associated with spontaneous recovery from AVB. In a prospective and observational cohort, all patients who underwent cardiothoracic surgery during a 14-month-period were included (n = 1,200). Risk factors of postoperative AVB were assessed by logistic regression. Among patients who developed AVB, variables associated with recovery from AVB were assessed by Cox and logistic regression. Overall incidence of postoperative AVB was 6.0%. Risk factors of AVB were age (OR 1.03 [1.00 to 1.06], p = 0.023); female gender (OR 2.06 [1.24 to 3.41], p = 0.005), active endocarditis (OR 3.31 [1.33 to 8.26], p = 0.01), and aortic valve replacement (OR 3.17 [1.92 to 5.25], p <0.001). Among aortic valve replacement, sutureless aortic valve replacement was associated with more AVB (26.7% vs 8.1%, p <0.01). Recovery from AVB occurred in 30 patients (41.7%) in a median period of 3 days [interquartile range = 1;5]. Among patients who would recover from AVB, 90% of patients did so before day 7. None of the studied variable was independently associated with recovery from AVB. In conclusion, identified risk factors of postoperative AVB after cardiac surgery were age, female gender, endocarditis, and aortic valve replacement. Because most patients who would recover did so before day 7, this study validates modern guidelines suggesting permanent pacemaker implantation on day 7. PMID- 28864322 TI - Impact of Body Mass Index on 5-Year Clinical Outcomes in Patients With ST-Segment Elevation Myocardial Infarction After Everolimus-Eluting or Bare-Metal Stent Implantation. AB - Patients with high body mass index (BMI) seem to have better outcomes after percutaneous coronary intervention than normal-weight patients. However, contrasting results have been reported on the "obesity paradox" in patients presenting with ST-elevation myocardial infarction (STEMI). The aim of our study was to investigate the impact of BMI on mortality in the population enrolled in the Evaluation of the Xience-V stent in Acute Myocardial INfArcTION (EXAMINATION) trial. The EXAMINATION trial randomized 1,498 patients with STEMI to a bare-metal stent or an everolimus-eluting stent. In this substudy patients were stratified into 3 groups according to BMI values: normal (BMI < 25 kg/m2), overweight (BMI = 25 to 29.9 kg/m2), and obese (BMI >= 30 kg/m2). The coprimary end points were the all-cause and cardiac deaths among the groups at the 5-year follow-up. BMI was available in 1,421 patients, divided in 401 (28.2%) normal, 702 (49.4%) overweight, and 318 (22.4%) obese. Obese patients were younger (p = 0.012) compared with the other groups, but with a worse cardiovascular risk profile. They were more frequently female (p <0.001) and with a higher rate of obesity related co-morbidity conditions such as diabetes mellitus (p = 0.005), arterial hypertension (p <0.001), and hyperlipidemia (p = 0.001) compared with the other groups. At the 5-year follow-up, all-cause and cardiac deaths were less frequent in obese patients than in the other groups (p = 0.003 and p = 0.030, respectively). After adjustment for confounding variables, BMI was an independent predictor of all-cause death (hazard ratio 0.765, 95% confidence interval 0.599 to 0.979, p = 0.033), but not of cardiac death, without any interaction with the stent type. In conclusion, in patients with STEMI who underwent primary PCI, the long-term all-cause death rate decreased as BMI increased, confirming the obesity paradox, irrespective of the stent type. PMID- 28864323 TI - Contemporary Determinants of Delayed Benchmark Timelines in Acute Myocardial Infarction in Men and Women. AB - Treatment delays in patients with acute myocardial infarction (AMI) are related to increased morbidity and mortality. Hence, identifying determinants of delay may help reduce time to treatment. Importantly, limited data suggest that there may be sex-related disparities in benchmark timelines. Although guidelines advocate the use of the first medical contact (FMC) rather than hospital admission as the moment from which delays to treatment should be monitored, the latter is still often used for quality purposes. We aimed to identify factors associated with treatment delays, with an emphasis on sex-related disparities. We reviewed data on 3,658 patients with AMI from 2 contemporary, consecutive multicenter surveys. Measured delays were FMC-to-electrocardiogram >10 minutes in ST-elevation MI (STEMI) and non-STEMI, FMC-to-primary percutaneous coronary intervention >90 minutes in STEMI, and invasive angiography >72 hours after admission in non-STEMI patients. Timely electrocardiogram was performed in 48% of patients with STEMI and in 39.8% of non-STEMI patients without significant sex related differences. Independent determinants of delay included atypical chest pain (CP) and presentation during daytime. In patients with STEMI, 37.5% had primary percutaneous coronary intervention in less than 90 minutes without significant sex-related disparities. Independent determinants of delay included atypical CP, night presentation, and diabetes. In non-STEMI patients, independent determinants of delayed invasive approach were female sex, age >75 years, atypical CP, and renal failure. In conclusion, significant treatment delays in patients with AMI are still frequent in contemporary practice, highlighting the need for improvement and guidelines implementation. Predictors of delay identified in our study may facilitate targeting of interventions to improve adherence to guidelines. PMID- 28864324 TI - Intracoronary Optical Coherence Tomography-Derived Virtual Fractional Flow Reserve for the Assessment of Coronary Artery Disease. AB - Fractional flow reserve (FFR) is widely used for the assessment of myocardial ischemia. Optical coherence tomography (OCT) provides accurate visualization of coronary artery morphology. The aim of this study was to investigate the relation between FFR and OCT-derived FFR. We retrospectively analyzed 31 lesions (25 left anterior descending arteries, 2 left circumflex arteries, and 4 right coronary arteries) in 31 patients with moderate-to-severe coronary stenosis, who underwent OCT and FFR measurements simultaneously. OCT-derived FFR was calculated by the original algorithm, which was calculated using the following equation based on fluid dynamics: DeltaP = FV + SV2, where V is the flow velocity, F is the coefficient of pressure loss because of viscous friction (Poiseuille resistance), and S is the coefficient of local pressure loss because of abrupt enhancement (flow separation). Mean values of % diameter stenosis by quantitative coronary angiography and FFR were 55.2 +/- 14.0% and 0.70 +/- 0.14, respectively. OCT derived FFR showed a stronger linear correlation with FFR measurements (r = 0.89, p <0.001; root mean square error = 0.062 FFR units) than quantitative coronary angiography % diameter stenosis (r = -0.65, p <0.001), OCT measurements of minimum lumen area (r = 0.68, p <0.001), and % area stenosis (r = -0.70, p <0.001). OCT-derived FFR has the potential to become an alternative method for the assessment of functional myocardial ischemia, and may elucidate the relation between coronary morphology and FFR. PMID- 28864325 TI - First genotyping of Blastocystis sp. in dairy, meat, and cashmere goats in northwestern China. AB - Blastocystis is one of the most common parasites inhabiting in small intestines of human and animals. Although its pathogenicity has been remaining controversial, the possibility of zoonotic transmission between human and animals was recognized. The goat was one of the most important economic animals supplying people with cashmere, meat, and dairy products. However, few studies were to investigate Blastocystis infection in goats. A total of 789 faecal specimens of goats (including 362 of dairy, 193 of meat and 234 of cashmere goats) were collected from multiple regions of Shaanxi province in northwestern China to investigate the colonization frequency and subtypes of Blastocystis, and to assess the zoonotic potential of these goats. The respective colonization frequencies of Blastocystis in dairy, meat and cashmere goats were 54.1% (196/362), 40.4% (78/193) and 78.6% (184/234). The prevalence of Blastocystis in pre-weaned (0-2-month) goats was significantly lower than that in goats of other age groups, and the highest colonization was observed in goats of 7-11-month age group. Sequence analysis of Blastocystis positive samples indicated the presence of seven subtypes in these goats, including six known subtypes (STs1, 3, 4, 5, 10, 14) and one possible novel subtype (isolate Sd26), with the subtype 10 as the predominant one. Additionally, zoonotic subtypes were found in dairy (ST1, ST3 and ST5) and cashmere (ST4 and ST5) goats, but not detected in meat goats. These results showed that Blastocystis is highly prevalent, widely distributed and genetically diverse in goats in Shaanxi province, northwestern China, and zoonotic potential of dairy and cashmere goats to transmit Blastocystis. PMID- 28864326 TI - Monocyte/high-density lipoprotein ratio predicts the mortality in ischemic stroke patients. AB - OBJECTIVE: The inflammatory process is a very important stage in the development and prognosis of acute ischemic stroke (AIS). The monocyte to high-density lipoprotein (HDL) ratio (MHR) is accepted as a novel marker for demonstrating inflammation. However, the role of MHR as a predictor of mortality in patients with AIS remains unclear. METHODS: We retrospectively enrolled 466 patients who were referred to our clinic within the first 24hours of symptom presentation and who were diagnosed with AIS between January 2008 and June 2016. Four hundred and eight controls of similar age and gender were also included. The patient group was classified into two groups according to 30-day mortality. The groups were compared in terms of monocyte counts, HDL, and MHR values. RESULTS: The patient group had significantly higher monocyte counts and lower HDL levels; therefore, this group had higher values of MHR compared to controls. Additionally, the monocyte count and MHR value were higher, and the HDL level was lower in non surviving patients (p<0.001). The MHR value was also observed as a significant independent variable of 30-day mortality in patients with AIS (p<0.001). The optimum cut-off value of MHR in predicting the 30-day mortality for patients with AIS was 17.52 (95% CI 0.95-0.98). CONCLUSION: Our study demonstrated that a high MHR value is an independent predictor of 30-day mortality in patients with AIS. PMID- 28864327 TI - Early endovascular stenting for extracranial carotid artery dissection with angiographic flow stasis: A series of four cases. AB - Extracranial carotid artery dissection is a major cause of ischemic stroke in young patients. Progressive stroke or recurrent ischemic symptoms may occur despite adequate medical treatment. Our treatment policy for these conditions is based on the fact that immediate vascular reconstruction is necessary in the cases with angiographic flow stasis in the true lumen beyond the dissection site. We report our experiences with four consecutive extracranial carotid artery dissections successfully treated with early endovascular stenting and discuss the indication of this treatment with a special emphasis on the angiographic findings. PMID- 28864328 TI - The patient with mild diencephalic-mesencephalic junction dysplasia - Case report and review of literature. AB - Diencephalic-mesencephalic junction dysplasia (DMJD) is very rare congenital brain malformation. We present a 66-years-old man with mild cognitive impairment, dysarthria, deafness, gait abnormality, and involuntary movements of the trunk. The first symptoms, psychomotor excitation and anxiety begun when he was over thirty years old however the symptoms gradually intensified and slowly progressed. The magnetic resonance imaging scans showed partial DMJD. According to recent date it represented type-B of the malformation with relatively mild phenotype in relation to the previously described in literature type-A. To the best of our knowledge this is the first description of an adult patient diagnosed with DMJD anomaly. PMID- 28864329 TI - Department of Error. PMID- 28864330 TI - PURE study challenges the definition of a healthy diet: but key questions remain. PMID- 28864334 TI - The benefits of avoiding cancer (or dying from cancer): Evidence from a four- country study. AB - We use stated-preference methods to estimate the cancer Value per Statistical Life (VSL) and Value per Statistical Case (VSCC) from a representative sample of 45-60-year olds in four countries in Europe. We ask respondents to report information about their willingness to pay for health risk reductions that are different from those used in earlier valuation work because they are comprised of two probabilities-that of getting cancer, and that of dying from it (conditional on getting it in the first place). The product of these two probabilities is the unconditional cancer mortality risk. Our hypothetical risk reductions also include two severity-related attributes-quality-of-life impacts and pain. The results show that respondents did appear to have an intuitive grasp of compound probabilities, and took into account each component of the unconditional cancer mortality risk when answering the valuation questions. We estimate the cancer VSL to be between approximately ? 2 and 5.950 million, depending on whether the (unconditional) mortality risk was reduced by lowering the chance of getting cancer, increasing the chance of surviving cancer, or both. The VSCC is estimated to be up to ? 0.578 million euro, and its magnitude depends on the initial (conditional) cancer mortality and on the improvement in survival. The survey responses show that our measures of cancer severity-impacts on daily activities and pain-have little or no effect on the WTP to reduce the adverse health risks. PMID- 28864333 TI - Fruits, vegetables, and legumes: sound prevention tools. PMID- 28864335 TI - The phagocyte respiratory burst: Historical perspectives and recent advances. AB - When exposed to certain stimuli, phagocytes (including neutrophils, macrophages and eosinophils) undergo marked changes in the way they handle oxygen. Firstly, their rate of oxygen uptake increases greatly. This is accompanied by (i) the production of large amounts of superoxide and hydrogen peroxide and (ii) the metabolism of large quantities of glucose through the hexose monophosphate shunt. We now know that the oxygen used is not for respiration but for the production of powerful microbiocidal agents downstream of the initial production of superoxide. Concomitantly, glucose is oxidised through the hexose monophosphate shunt to re generate the NADPH that has been consumed through the reduction of molecular oxygen to generate superoxide. This phagocyte respiratory burst is generated by an NADPH oxidase multi-protein complex that has a catalytic core consisting of membrane-bound gp91phox (CYBB) and p22phox (CYBA) sub-units and cytosolic components p47phox (NCF1), p67phox (NCF2) and p40phox (NCF4). Finally, another cytosolic component, the small G-protein Rac (Rac2 in neutrophils and Rac1 in macrophages) is also required for full activation. The importance of the complex in host defence is underlined by chronic granulomatous disease, a severe life limiting immunodeficiency caused by mutations in the genes encoding the individual subunits. In this review, I will discuss the experimental evidence that underlies our knowledge of the respiratory burst, outlining how elegant biochemical analysis, coupled with study of patients deficient in the various subunits has helped elucidate the function of this essential part of innate immunity. I will also discuss some exciting recent studies that shed new light on how the abundance of the various components is controlled. Finally, I will explore the emerging role of reactive oxygen species such as superoxide and hydrogen peroxide in the pathogenesis of major human diseases including auto inflammatory diseases. PMID- 28864337 TI - Complement genomics and antibody-mediated rejection in heart recipients. AB - In this issue of the Journal of Heart and Lung Transplantation, Marron-Linares et al report the results of an interesting study in which they evaluated 51 genes associated with the complement pathway in a small number of heart recipients to explore their relationship with antibody-mediated rejection (AMR). Next generation sequencing was used in 46 heart transplant recipients (23 with AMR and 23 without AMR). The authors identified a significant association of 2 single nucleotide polymorphisms with the absence or presence of AMR, respectively, p.Gly54Asp-MBL2 in the mannose-binding lectin (MBL) 2 gene and p.Asn428(p=)-CFP in the alternative complement factor properdin (CFP) gene. This article is a new contribution to the heart transplant literature. It suggests that complement single-nucleotide polymorphisms may influence circulating levels of selected proteins of both the lectin pathway and alternative complement pathways, thus potentially determining which patients will develop AMR. PMID- 28864336 TI - Analysis of Transfusion-Related Acute Lung Injury and Possible Transfusion Related Acute Lung Injury Reported to the French Hemovigilance Network From 2007 to 2013. AB - Using the French Hemovigilance Network database from 2007 to 2013, we provide information on demographics, incidence, and risk factors of reported transfusion related acute lung injury (TRALI) and possible TRALI, analyze TRALI mitigation efforts for fresh frozen plasma and platelet concentrates, and consider the impact of platelet additive solutions on TRALI incidence. We applied the Toronto consensus conference definitions for TRALI and possible TRALI. Two TRALI subgroups were considered: "antibody positive" when a donor has human leukocyte antigen (class I or II) and/or human neutrophil antigen antibodies and the recipient has cognate antigen, and "antibody negative" when immunological investigation is negative or not done. The analysis targeted 378 cases, divided into antibody-positive TRALI (n=75), antibody-negative TRALI (n=100), and possible TRALI (n=203). TRALI patients were younger and received more blood components than the general population of transfused patients. Moreover, we identified the following clinical conditions where patients seemed to be at higher risk to develop TRALI: postpartum hemorrhage, acute myeloid leukemia, liver transplantation, allogeneic and autologous hematopoietic stem cells transplantation, polytrauma, and thrombotic microangiopathy. Policy measures intended to reduce antibody-positive TRALI were found effective for apheresis platelet concentrates and fresh frozen plasma but not for whole blood-derived platelet concentrates. The use of platelet additive solutions was associated with a significant reduction in the incidence of TRALI following transfusion of buffy coat-derived platelet concentrates but not following transfusion of apheresis platelets. Our data reinforce the concept that possible TRALI and TRALI, as defined in the Canadian consensus conference, share many characteristics. No specific policy measures are currently directed at mitigation of possible TRALI despite its impact on transfusion safety. Despite TRALI mitigation measures, the overall incidence of TRALI cases reported to the French Hemovigilance system was not significantly reduced. Therefore, additional research is needed to reduce, if not eradicate, all TRALI categories. PMID- 28864338 TI - Low ejection fraction in donor hearts is not directly associated with increased recipient mortality. PMID- 28864339 TI - Preoperative Antibiotics Before Bladder Biopsy: Are They Necessary? AB - OBJECTIVE: To compare postoperative infectious outcomes of bladder biopsies performed in the office without antibiotic prophylaxis vs those done with preoperative antibiotic prophylaxis in the operating room (OR). MATERIALS AND METHODS: Our institutional review board-approved database was retrospectively reviewed for patients who underwent bladder biopsy in the office or in the OR between July 2014 and August 2015. All patients with bladder biopsies performed in the OR and none in the office received preoperative antibiotic prophylaxis. Patient characteristics and post-procedural outcomes including bacteriuria, urinary tract infection (UTI), and febrile UTI were recorded. The rates of these outcomes were compared between the 2 groups using the chi-square test. Patients were excluded from analysis if they experienced a UTI or were prescribed antibiotics within 30 days before their procedure. RESULTS: In all, 216 biopsies were identified (106 in the office and 110 in the OR). No difference was noted in the rate of UTI (0.94% vs 0.91%, P = .98), or febrile UTI (0% vs 0.91%, P = .33) between those undergoing bladder biopsy in the office and those in the OR. There was no difference in the incidence of new urinary symptoms (2.8% vs 5.5%, P = .33) or post-procedural bacteriuria (3.8% vs 3.6%, P = .96). CONCLUSION: Since the introduction of the mandated use of antibiotics for routine procedures such as bladder biopsy, antibiotic use has markedly increased. Our data suggest that the preoperative antibiotic prophylaxis that is recommended may not confer benefit to select patients. At a time when antibiotic stewardship is of utmost importance, guidelines regarding its use should be reconsidered. PMID- 28864340 TI - Clinical and Patient-reported Outcomes of 1-sided Anterior Urethroplasty for Long segment or Panurethral Strictures. AB - OBJECTIVE: To evaluate clinical and patient-reported urinary and sexual outcomes after a long-segment stricture repair using the 1-sided urethral dissection, penile invagination, and dorsal buccal mucosa graft onlay technique described by Kulkarni et al. METHODS: Patients from 4 institutions after single-stage repairs for long-segment urethral strictures (>8 cm) from January 2002 to April 2016 were reviewed. Technique described by Kulkarni et al was used in all cases. Clinical outcomes included uroflowmetry (Qmax) and post-void residuals. Patient-reported outcome measures included International Prostate Symptom Score survey, Sexual Health Inventory for Men, Male Sexual Health Questionnaire, and Global Response Assessment questionnaire to measure voiding, sexual, ejaculatory symptoms, and overall improvement, respectively. RESULTS: Seventy-three patients with a minimum of 12 months' follow-up were included. The mean age and stricture length were 56 (21-80) years and 13.6 (8-21) cm, respectively. At a mean follow-up of 44 (12 162) months, 9 of 73 (12%) strictures recurred. The mean baseline International Prostate Symptom Score of 23 (7-24) decreased to 10 (1-17) on follow-up (P <.001). Eight of 42 patients (21.4%) reported an increase, and 6 of 42 patients (14.3%) decreased in Sexual Health Inventory for Men following urethroplasty. Ejaculatory function on Male Sexual Health Questionnaire improved after urethroplasty from 8 preoperatively to 11 postoperatively (P <.004). All patients reported improvement after urethroplasty on Global Response Assessment questionnaire. Post-void dribbling and chordee occurred in 45% and 25% of patients, respectively. CONCLUSION: Durable patency in most patients is demonstrated in this study. PROMs indicate an improvement in urinary function and moderate effect on sexual function. Transient penile chordee was evident in 25% of patients. PMID- 28864331 TI - Fruit, vegetable, and legume intake, and cardiovascular disease and deaths in 18 countries (PURE): a prospective cohort study. AB - BACKGROUND: The association between intake of fruits, vegetables, and legumes with cardiovascular disease and deaths has been investigated extensively in Europe, the USA, Japan, and China, but little or no data are available from the Middle East, South America, Africa, or south Asia. METHODS: We did a prospective cohort study (Prospective Urban Rural Epidemiology [PURE] in 135 335 individuals aged 35 to 70 years without cardiovascular disease from 613 communities in 18 low income, middle-income, and high-income countries in seven geographical regions: North America and Europe, South America, the Middle East, south Asia, China, southeast Asia, and Africa. We documented their diet using country-specific food frequency questionnaires at baseline. Standardised questionnaires were used to collect information about demographic factors, socioeconomic status (education, income, and employment), lifestyle (smoking, physical activity, and alcohol intake), health history and medication use, and family history of cardiovascular disease. The follow-up period varied based on the date when recruitment began at each site or country. The main clinical outcomes were major cardiovascular disease (defined as death from cardiovascular causes and non-fatal myocardial infarction, stroke, and heart failure), fatal and non-fatal myocardial infarction, fatal and non-fatal strokes, cardiovascular mortality, non cardiovascular mortality, and total mortality. Cox frailty models with random effects were used to assess associations between fruit, vegetable, and legume consumption with risk of cardiovascular disease events and mortality. FINDINGS: Participants were enrolled into the study between Jan 1, 2003, and March 31, 2013. For the current analysis, we included all unrefuted outcome events in the PURE study database through March 31, 2017. Overall, combined mean fruit, vegetable and legume intake was 3.91 (SD 2.77) servings per day. During a median 7.4 years (5.5-9.3) of follow-up, 4784 major cardiovascular disease events, 1649 cardiovascular deaths, and 5796 total deaths were documented. Higher total fruit, vegetable, and legume intake was inversely associated with major cardiovascular disease, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, and total mortality in the models adjusted for age, sex, and centre (random effect). The estimates were substantially attenuated in the multivariable adjusted models for major cardiovascular disease (hazard ratio [HR] 0.90, 95% CI 0.74-1.10, ptrend=0.1301), myocardial infarction (0.99, 0.74-1.31; ptrend=0.2033), stroke (0.92, 0.67-1.25; ptrend=0.7092), cardiovascular mortality (0.73, 0.53-1.02; ptrend=0.0568), non-cardiovascular mortality (0.84, 0.68-1.04; ptrend =0.0038), and total mortality (0.81, 0.68-0.96; ptrend<0.0001). The HR for total mortality was lowest for three to four servings per day (0.78, 95% CI 0.69 0.88) compared with the reference group, with no further apparent decrease in HR with higher consumption. When examined separately, fruit intake was associated with lower risk of cardiovascular, non-cardiovascular, and total mortality, while legume intake was inversely associated with non-cardiovascular death and total mortality (in fully adjusted models). For vegetables, raw vegetable intake was strongly associated with a lower risk of total mortality, whereas cooked vegetable intake showed a modest benefit against mortality. INTERPRETATION: Higher fruit, vegetable, and legume consumption was associated with a lower risk of non-cardiovascular, and total mortality. Benefits appear to be maximum for both non-cardiovascular mortality and total mortality at three to four servings per day (equivalent to 375-500 g/day). FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments). PMID- 28864341 TI - Techniques Used to Create Continent Catheterizable Channels: A Comparison of Long term Results in Children. AB - OBJECTIVE: To compare long-term results of 3 different techniques used to create continent catheterizable channels (CCCs) in children in a single institution. PATIENTS AND METHODS: Data were retrospectively collected from 112 children who had a CCC (appendicovesicostomy [APV], tubularized bladder flap [TBF] or Monti) created between December 1995 and December 2013. Primary outcome was revision free survival. Secondary outcomes were channel stenosis, incontinence, and false channel requiring revision. Time-to-event survival was analyzed using a Kaplan Meier survival curve. RESULTS: A total of 117 CCCs were identified with median follow-up of 85 months. Surgical revision was required in 52%, with no significant difference between the different techniques. Major revision was required in 27% of the cases and significantly more often in Monti channels. Complete revision was required in 7%. Stenosis requiring revision was seen in 33%. A false channel was formed in 9% of the cases. Incontinence with a low leak point pressure was seen in 12%. A time-to-event analysis with a Kaplan-Meier curve showed no significant differences between the 3 techniques. CONCLUSION: Although CCC is an effective solution for children who cannot perform urethral catheterization, 52% requires surgical revision. Because no differences were found in outcome between APV, TBF, and Monti, we conclude that a TBF CCC is a good alternative for the APV. If the appendix is not available and bladder volume is sufficient, a TBF channel is preferred to a Monti channel. PMID- 28864342 TI - The logistics of afferent cortical specification in mice and men. AB - The mechanisms shaping areal specification in the neocortex have been the focus of a sustained interest over the past three decades. Studies in rodents have provided insight in the interplay between intrinsic genetic mechanisms and extrinsic inputs relayed to the cortex by thalamocortical axons. Here we focus on the exploration of the developing primate visual system which points to embryonic thalamic axons exerting a profound, early instructive role on arealisation in the primate cortex, via an influence on cortical progenitor cell-cycle and mode of division. PMID- 28864332 TI - Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. AB - BACKGROUND: The relationship between macronutrients and cardiovascular disease and mortality is controversial. Most available data are from European and North American populations where nutrition excess is more likely, so their applicability to other populations is unclear. METHODS: The Prospective Urban Rural Epidemiology (PURE) study is a large, epidemiological cohort study of individuals aged 35-70 years (enrolled between Jan 1, 2003, and March 31, 2013) in 18 countries with a median follow-up of 7.4 years (IQR 5.3-9.3). Dietary intake of 135 335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure). Secondary outcomes were all myocardial infarctions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality. Participants were categorised into quintiles of nutrient intake (carbohydrate, fats, and protein) based on percentage of energy provided by nutrients. We assessed the associations between consumption of carbohydrate, total fat, and each type of fat with cardiovascular disease and total mortality. We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random intercepts to account for centre clustering. FINDINGS: During follow-up, we documented 5796 deaths and 4784 major cardiovascular disease events. Higher carbohydrate intake was associated with an increased risk of total mortality (highest [quintile 5] vs lowest quintile [quintile 1] category, HR 1.28 [95% CI 1.12-1.46], ptrend=0.0001) but not with the risk of cardiovascular disease or cardiovascular disease mortality. Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs quintile 1, total fat: HR 0.77 [95% CI 0.67-0.87], ptrend<0.0001; saturated fat, HR 0.86 [0.76 0.99], ptrend=0.0088; monounsaturated fat: HR 0.81 [0.71-0.92], ptrend<0.0001; and polyunsaturated fat: HR 0.80 [0.71-0.89], ptrend<0.0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs quintile 1, HR 0.79 [95% CI 0.64-0.98], ptrend=0.0498). Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality. INTERPRETATION: High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings. FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments). PMID- 28864343 TI - Secondary growth as a determinant of plant shape and form. AB - Plants are the primary producers of biomass on earth. As an almost stereotypic feature, higher plants generate continuously growing bodies mediated by the activity of different groups of stem cells, the meristems. Shoot and root thickening is one of the fundamental growth processes determining form and function of these bodies. Mediated by a group of cylindrical meristems located below organ surfaces, vascular and protective tissues are continuously generated in a highly plastic manner, a competence essential for the survival in an ever changing environment. Acknowledging the fundamental role of this process, which is overall designated as secondary growth, we discuss in this review our current knowledge about the evolution and molecular regulation of the vascular cambium. The cambium is the meristem responsible for the formation of wood and bast, the two types of vascular tissues important for long-distance transport of water and assimilates, respectively. Although regulatory patterns are only beginning to emerge, we show that cambium activity represents a highly rewarding model for studying cell fate decisions, tissue patterning and differentiation, which has experienced an outstanding phylogenetic diversification. PMID- 28864344 TI - Understanding and engineering plant form. AB - A plant's form is an important determinant of its fitness and economic value. Here, we review strategies for producing plants with altered forms. Historically, the process of changing a plant's form has been slow in agriculture, requiring iterative rounds of growth and selection. We discuss modern techniques for identifying genes involved in the development of plant form and tools that will be needed to effectively design and engineer plants with altered forms. Synthetic genetic circuits are highlighted for their potential to generate novel plant forms. We emphasize understanding development as a prerequisite to engineering and discuss the potential role of computer models in translating knowledge about single genes or pathways into a more comprehensive understanding of development. PMID- 28864346 TI - Re"CYC"ling molecular regulators in the evolution and development of flower symmetry. AB - Flower forms are both highly diverse and multifaceted. As well as varying in colour, size, organ number, and much more, flowers show different types of symmetry. Floral symmetry can be grouped into three main categories: asymmetry, bilateral symmetry and radial symmetry, characterised by zero, one, and multiple planes of symmetry, respectively. This review will first explore floral symmetry from a classical morphological view, then from a modern molecular perspective. The recent molecular work on symmetry in monocots and eudicots will be discussed, followed by an in-depth discussion into the evolution of CYC genes, particularly in the capitulum of the sunflower family (Asteraceae). Whilst recent studies on non-model species are helping to bring new light to this field, more species coverage is required to understand how traits such as bilateral symmetry have evolved so many times, and whether the same molecular regulators were recruited for this function. PMID- 28864347 TI - Role of BAG3 in cancer progression: A therapeutic opportunity. AB - BAG3 is a multifunctional protein that can bind to heat shock proteins (Hsp) 70 through its BAG domain and to other partners through its WW domain, proline-rich (PXXP) repeat and IPV (Ile-Pro-Val) motifs. Its intracellular expression can be induced by stressful stimuli, while is constitutive in skeletal muscle, cardiac myocytes and several tumour types. BAG3 can modulate the levels, localisation or activity of its partner proteins, thereby regulating major cell pathways and functions, including apoptosis, autophagy, mechanotransduction, cytoskeleton organisation, motility. A secreted form of BAG3 has been identified in studies on pancreatic ductal adenocarcinoma (PDAC). Secreted BAG3 can bind to a specific receptor, IFITM2, expressed on macrophages, and induce the release of factors that sustain tumour growth and the metastatic process. BAG3 neutralisation therefore appears to constitute a novel potential strategy in the therapy of PDAC and, possibly, other tumours. PMID- 28864345 TI - Enhancing our brains: Genomic mechanisms underlying cortical evolution. AB - Our most distinguishing higher cognitive functions are controlled by the cerebral cortex. Comparative studies detail abundant anatomical and cellular features unique to the human developing and adult neocortex. Emerging genomic studies have further defined vast differences distinguishing developing human neocortices from related primates. These human-specific changes can affect gene function and/or expression, and result from structural variations such as chromosomal deletions and duplications, or from point mutations in coding and noncoding regulatory regions. Here, we review this rapidly growing field which aims to identify and characterize genetic loci unique to the human cerebral cortex. We catalog known human-specific genomic changes distinct from other primates, including those whose function has been interrogated in animal models. We also discuss how new model systems and technologies such as single cell RNA sequencing, primate iPSCs, and gene editing, are enabling the field to gain unprecedented resolution into function of these human-specific changes. Some neurological disorders are thought to uniquely present in humans, thus reinforcing the need to comprehensively understand human-specific gene expression in the developing brain. PMID- 28864348 TI - Acquisition of histologic diversity contributes to not only invasiveness but also lymph node metastasis in early gastric cancer. AB - BACKGROUND: As more endoscopic resections are performed in early gastric cancer, the pretreatment prediction of lymph node metastasis (LNM) becomes more important. Some tumor characteristics including histologic type, invasion depth, ulceration, size, and lymphovascular invasion have been used to determine the endoscopic resectability of early gastric cancer; however, a more detailed analysis between clinicopathologic factors and lymph node metastasis is needed. METHODS: We analyzed the correlation between the clinicopathological findings and LNM with 310 cases of early gastric cancer by dividing invasion depths in detail. RESULTS: LNM occurred in 3.2% and 16.2% of the T1a and T1b tumors, respectively. LNM was associated with invasion depth (p=0.002) and lymphatic (p<0.001) and perineural (p=0.013) invasion. Among them, lymphatic invasion was the most powerful factor associated with LNM and significantly constant in T1a and T1b. The rate of LNM increased gradually as the tumor invaded deeper, and invasion of the muscularis mucosae layer was associated with an increased mixed adenocarcinoma incidence, suggesting that histologic diversity was associated with tumor invasiveness. CONCLUSIONS: We demonstrated that lymphatic invasion was the most important and powerful parameter for LNM in early gastric cancers. In addition, tumor invasiveness into the muscularis mucosae was accompanied by tumor histologic diversity. PMID- 28864349 TI - Insulin-like growth factor binding protein-1 (IGFBP-1) upregulated by Helicobacter pylori and is associated with gastric cancer cells migration. AB - Insulin-like growth factor binding protein-1 (IGFBP-1), a secreted protein, implicated of various cells in mediating the proliferation, migration, invasion, adhesion, survival and so on. In this study, we assessed the expression and release of IGFBP-1 from gastric cancer cells with H. pylori 26695 infection and the biological functions of IGFBP-1 in gastric cancer cells. The results showed that the expression and release of IGFBP-1 were increased in gastric cancer cells (MGC-803, BGC-823, SGC-7901) infected with H. pylori 26695. In addition, the upregulation of IGFBP-1 was dose-dependent in BGC-823 cells infected with H. pylori 26695 but not time-dependent. The upregulation of IGFBP-1 got to peak at 12h after H. pylori 26695 infection and then decreased over time. Subsequently, we measured its functions by silencing and overexpressing IGFBP1 which suggested that overexpression of IGFBP-1 could inhibit the migration of BGC-823 and SGC 7901 cells. However, knocking down the IGFBP-1 could increase the migration of BGC-823 and SGC-7901 cells. Functional findings illustrated that IGFBP-1 was implicated in H. pylori 26695-induced MMP-9 expression in BGC-823 cells. In addition, overexpressing IGFBP1 reduce the promoting effect of MMP-9 on the BGC 823 cells migration. In summary, we demonstrated that IGFBP-1 suppress the migration of BGC-823 cells and play a protective role in the process of H. pylori induced gastric cancer. PMID- 28864350 TI - Immunohistochemical analysis of NKX2.2, ETV4, and BCOR in a large series of genetically confirmed Ewing sarcoma family of tumors. AB - Ewing sarcoma is an aggressive neoplasm of pediatric and adolescent patients. Immunohistochemistry (IHC) can be used to support the morphologic diagnosis of Ewing sarcoma family of tumors (ESFT) in a convincing clinical/radiological context. Although neither NKX2.2 nor CD99 alone are entirely specific, when combined, the diagnostic specificity is high. The aim of the present study was to investigate the IHC expression of NKX2.2, ETV4 and BCOR in a large series of genetically confirmed ESFT. The results for CD99 and CAV-1 immunoreactivity, and the histological and fusion gene subtypes were retrieved from our previous study. NKX2.2 demonstrated moderate or strong nuclear positivity in 91.2% of the tumors. The staining intensity was heterogeneous. Many of the ESFT with negative NKX2.2 immunoreactivity were in bone. Strong/moderate ETV4 nuclear expression was detected in two small round cell tumors, both were negative for NKX2.2. No relationships could be found between expression of NKX2.2 and the histological subgroups or ESFT gene fusion subtypes. BCOR was negative in all ESFT. In conclusion, NKX2.2, ETV4 and BCOR IHC may be helpful in daily practice for distinguishing ESFT from CIC or BCOR-associated sarcomas, especially in hospitals without access to molecular assays. In addition, the combination of strong CD99 membranous positivity and nuclear NKX2.2 positivity seems to be very reliable for ESFT diagnosis in an appropriate clinicoradiological setting. So far no antibody is entirely specific for ESFT diagnosis, and the IHC or molecular results in round cell tumors of bone may be strongly influenced by decalcification processes. PMID- 28864351 TI - Adaptation of a MR imaging protocol into a real-time clinical biometric ultrasound protocol for persons with spinal cord injury at risk for deep tissue injury: A reliability study. AB - BACKGROUND: High strain in soft tissues that overly bony prominences are considered a risk factor for pressure ulcers (PUs) following spinal cord impairment (SCI) and have been computed using Finite Element methods (FEM). The aim of this study was to translate a MRI protocol into ultrasound (US) and determine between-operator reliability of expert sonographers measuring diameter of the inferior curvature of the ischial tuberosity (IT) and the thickness of the overlying soft tissue layers on able-bodied (AB) and SCI using real-time ultrasound. MATERIAL AND METHODS: Part 1: Fourteen AB participants with a mean age of 36.7 +/- 12.09 years with 7 males and 7 females had their 3 soft tissue layers in loaded and unloaded sitting measured independently by 2 sonographers: tendon/muscle, skin/fat and total soft tissue and the diameter of the IT in its short and long axis. Part 2: Nineteen participants with SCI were screened, three were excluded due to abnormal skin signs, and eight participants (42%) were excluded for abnormal US signs with normal skin. Eight SCI participants with a mean age of 31.6 +/- 13.6 years and all male with 4 paraplegics and 4 tetraplegics were measured by the same sonographers for skin, fat, tendon, muscle and total. Skin/fat and tendon/muscle were computed. RESULTS: AB between-operator reliability was good (ICC = 0.81-0.90) for 3 soft tissues layers in unloaded and loaded sitting and poor for both IT short and long axis (ICC = -0.028 and -0.01). SCI between-operator reliability was good in unloaded and loaded for total, muscle, fat, skin/fat, tendon/muscle (ICC = 0.75-0.97) and poor for tendon (ICC = 0.26 unloaded and ICC = -0.71 loaded) and skin (ICC = 0.37 unloaded and ICC = 0.10). CONCLUSION: A MRI protocol was successfully adapted for a reliable 3 soft tissue layer model and could be used in a 2-D FEM model designed to estimate soft tissue strain as a novel risk factor for the development of a PU. PMID- 28864352 TI - An E-Pain intervention to spread modern pain education in Brazil. PMID- 28864354 TI - Methods of reactivation and reprogramming of neural stem cells for neural repair. AB - Research on the biology of adult neural stem cells (NSCs) and induced NSCs (iNSCs), as well as NSC-based therapies for diseases in central nervous system (CNS) has started to generate the expectation that these cells may be used for treatments in CNS injuries or disorders. Recent technological progresses in both NSCs themselves and their derivatives have brought us closer to therapeutic applications. Adult neurogenesis presents in particular regions in mammal brain, known as neurogenic niches such as the dental gyrus (DG) in hippocampus and the subventricular zone (SVZ), within which adult NSCs usually stay for long periods out of the cell cycle, in G0. The reactivation of quiescent adult NSCs needs orchestrated interactions between the extrinsic stimulis from niches and the intrinsic factors involving transcription factors (TFs), signaling pathway, epigenetics, and metabolism to start an intracellular regulatory program, which promotes the quiescent NSCs exit G0 and reenter cell cycle. Extrinsic and intrinsic mechanisms that regulate adult NSCs are interconnected and feedback on one another. Since endogenous neurogenesis only happens in restricted regions and steadily fails with disease advances, interest has evolved to apply the iNSCs converted from somatic cells to treat CNS disorders, as is also promising and preferable. To overcome the limitation of viral-based reprogramming of iNSCs, bioactive small molecules (SM) have been explored to enhance the efficiency of iNSC reprogramming or even replace TFs, making the iNSCs more amenable to clinical application. Despite intense research efforts to translate the studies of adult and induced NSCs from the bench to bedside, vital troubles remain at several steps in these processes. In this review, we examine the present status, advancement, pitfalls, and potential of the two types of NSC technologies, focusing on each aspects of reactivation of quiescent adult NSC and reprogramming of iNSC from somatic cells, as well as on progresses in cell-based regenerative strategies for neural repair and criteria for successful therapeutic applications. PMID- 28864353 TI - Manipulation of neural progenitor fate through the oxygen sensing pathway. AB - Neural progenitor cells hold significant promise in a variety of clinical settings. While both the brain and spinal cord harbor endogenous neural progenitor or stem cells, they typically are not capable of repopulating neural populations in case of injury or degenerative disease. In vitro systems for the culture of neural progenitors has come a long ways due to advances in the method development. Recently, many groups have shown that manipulation of the oxygen sensing pathway leading to activation of hypoxia inducible factors (HIFs) that can influence the proliferation, differentiation or maturation of neural progenitors. Moreover, different oxygen concentrations appear to affect lineage specification of neural progenitors upon their differentiation in vitro. Here we summarize some of these studies in an attempt to direct effort towards implementation of best methods to advance the use of neural progenitors from basic development towards clinical application. PMID- 28864356 TI - Lensless digital holographic microscopy and its applications in biomedicine and environmental monitoring. AB - Optical compound microscope has been a major tool in biomedical imaging for centuries. Its performance relies on relatively complicated, bulky and expensive lenses and alignment mechanics. In contrast, the lensless microscope digitally reconstructs microscopic images of specimens without using any lenses, as a result of which it can be made much smaller, lighter and lower-cost. Furthermore, the limited space-bandwidth product of objective lenses in a conventional microscope can be significantly surpassed by a lensless microscope. Such lensless imaging designs have enabled high-resolution and high-throughput imaging of specimens using compact, portable and cost-effective devices to potentially address various point-of-care, global-health and telemedicine related challenges. In this review, we discuss the operation principles and the methods behind lensless digital holographic on-chip microscopy. We also go over various applications that are enabled by cost-effective and compact implementations of lensless microscopy, including some recent work on air quality monitoring, which utilized machine learning for high-throughput and accurate quantification of particulate matter in air. Finally, we conclude with a brief future outlook of this computational imaging technology. PMID- 28864355 TI - Separation of neural stem cells by whole cell membrane capacitance using dielectrophoresis. AB - Whole cell membrane capacitance is an electrophysiological property of the plasma membrane that serves as a biomarker for stem cell fate potential. Neural stem and progenitor cells (NSPCs) that differ in ability to form neurons or astrocytes are distinguished by membrane capacitance measured by dielectrophoresis (DEP). Differences in membrane capacitance are sufficient to enable the enrichment of neuron- or astrocyte-forming cells by DEP, showing the separation of stem cells on the basis of fate potential by membrane capacitance. NSPCs sorted by DEP need not be labeled and do not experience toxic effects from the sorting procedure. Other stem cell populations also display shifts in membrane capacitance as cells differentiate to a particular fate, clarifying the value of sorting a variety of stem cell types by capacitance. Here, we describe methods developed by our lab for separating NSPCs on the basis of capacitance using several types of DEP microfluidic devices, providing basic information on the sorting procedure as well as specific advantages and disadvantages of each device. PMID- 28864357 TI - Biorelevant Drug Solubility Enhancement Modeled by a Linear Solvation Energy Relationship. AB - It is for the pharmaceutical sciences of vital importance to understand how drugs are solubilized in biorelevant media. However, the complexity of fasted state simulated intestinal fluid (FaSSIF) has so far hampered adequate solubility modeling. The present study focuses on apparently neutral compounds at physiological pH and a linear free energy relationship is introduced for biorelevant drug solubilization. Based on literature data of 40 compounds, the Abraham solvation descriptors were calculated from chemical structure to then predict the ratio of solubility enhancement log(SE) in FaSSIF compared to aqueous buffer solubility at pH 6.5. A suitable model was obtained with R2 of 0.810 and notable were especially the positive effect of McGowan's characteristic volume and the negative effect of drug basicity. A negative influence on log(SE) was further evidenced for dipolarity/polarizability and for the excess molar refraction descriptor. A positive solubilization effect was obtained for drug acidity and hence the tendency for proton donation, which was likely due to the different proton-accepting moieties of taurocholic acid and lecithin that are both present in the mixed colloids of FaSSIF. Overall, an improved understanding was achieved regarding the molecular features that are driving drug solubilization in biorelevant media. PMID- 28864358 TI - Granulomatous mastitis: We need a useful classification system. PMID- 28864359 TI - Hepatitis E in Italy: A silent presence. AB - Hepatitis E virus (HEV) was discovered in the 1980s and has been considered as being confined to developing countries. The purpose of this critical review was to determine the reported HEV seroprevalence rates in Italy, to identify predisposing factors and individuals at risk and to assess possible importation of HEV by immigrants. A critical review of 159 articles published in PubMed from 1994 to date was done. Only 27 original reports of 50 or more subjects, written in the English or Italian language, were included. Over three decades, the HEV seroprevalence varied from 0.12% to 49%, with the highest rates being reported from the central region of Italy. Risk factors included ingestion of raw pork or potentially contaminated food. The seroprevalence among immigrants ranged from 15.3% to 19.7% in Apulia. Italy has a population of 60656000; the total number of individuals surveyed was only 21.882 (0.036%). A national epidemiological survey program is needed to capture more comprehensive seroprevalence data. PMID- 28864360 TI - Current treatment options and the role of peptides as potential therapeutic components for Middle East Respiratory Syndrome (MERS): A review. AB - Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a highly pathogenic respiratory virus with mechanisms that may be driven by innate immune responses. Despite the effort of scientific studies related to this virus, Middle East Respiratory Syndrome (MERS) is still a public health concern. MERS-CoV infection has a high mortality rate, and to date, no therapeutic or vaccine has been discovered, that is effective in treating or preventing the disease. In this review, we summarize our understanding of the molecular and biological events of compounds acting as MERS-CoV inhibitors, the outcomes of existing therapeutic options and the various drugs undergoing clinical trials. Currently, several therapeutic options have been employed, such as convalescent plasma (CP), intravenous immunoglobulin (IVIG), monoclonal antibodies and repurposing of existing clinically approved drugs. However, these therapeutic options have drawbacks, thus the need for an alternative approach. The requirement for effective therapeutic treatment has brought the necessity for additional MERS treatments. We suggest that antimicrobial peptides (AMPs) may be used as alternative therapeutic agents against MERS-CoV infection. In addition, we propose the feasibility of developing effective agents by repurposing the existing and clinically approved anti-coronavirus and anti-viral peptide drugs. PMID- 28864362 TI - Benchmarking of antibiotic usage: An adjustment to reflect antibiotic stewardship program outcome in a hospital in Saudi Arabia. AB - Antimicrobial stewardship program aims to reduce antibiotic use. Periodic measurement and monitoring of antibiotic use and comparison within the institution as well as with other organizations are important indicators. We analyzed antibiotic usage in a general hospital in Saudi Arabia. Antibiotic data were collected retrospectively for 2011 and from 2013 to 2015, and only adult patients (>15year of age) were included in the study. Data were presented as days of therapy (DOT) and defined daily dose (DDD). DDD was adjusted per 100 bed-days and according to the case mix index (CMI). The total DDD was 37,557 in 2013, 36,550 in 2014 and 38,738 in 2015. The DDD per 100 patient-days was 90.7-94.5. There was a discordant findings of antibiotic measurements based on the DDD compared to DOT, and DDD/100 bed-days compared to DOT/100 bed-days. There was a negative correlation between CMI and DDD per 100 bed days (r -0.696), but a positive correlation of CMI with DOT (r +0.93). Adjusted DDD/100 bed-days showed decrease in the usage of antibiotics, reflecting activities of the antibiotic stewardship program. The increase in DOT/100 bed-days may indicate the favorable utilization of combination therapy. Antibiotic usage needs to be adjusted per 100 bed-days and correlated with CMI for better reflection of optimal antibiotic utilization, activities of the antibiotic stewardship program, and to allow benchmarking. PMID- 28864363 TI - Global research trends of yellow fever: A bibliometric overview. PMID- 28864361 TI - Healthcare associated infections in neonatal intensive care unit and its correlation with environmental surveillance. AB - Healthcare-associated infections (HAI) are frequent complications in neonatal intensive care units (NICU) with varying risk factors and bacteriological profile. There is paucity of literature comparing the bacteriological profile of organisms causing HAI with the environmental surveillance isolates. Therefore, this study aimed to evaluate demographic profile, risk factors and outcome of HAI in NICU and correlate with environmental surveillance. Three hundred newborns with signs and symptoms of sepsis were enrolled in the study group and their profile, risk factors and outcome were compared with the control group. Univariate analysis and multivariable logistic regression were performed. Environmental surveillance results were compared to the bacteriological profile of HAIs. We identified lower gestational age, male gender and apgar score less than 7 at 5min, use of peripheral vascular catheter & ventilator along with their duration as significant risk factors. Mortality rate was 29% in the study group (p<0.05). The HAI site distribution showed blood-stream infections (73%) to be the most common followed by pneumonia (12%) and meningitis (10%). Gram positive cocci were the most common isolates in HAI as well as environmental surveillance. The bacteriological profile of HAI correlates with the environmental surveillance report thus insisting for periodic surveillance and thereby avoiding irrational antibiotic usage. PMID- 28864364 TI - Role of astrocyte connexin hemichannels in cortical spreading depression. AB - Cortical spreading depression (CSD) is an intriguing phenomenon consisting of massive slow brain depolarizations that affects neurons and glial cells. It has been recognized since 1944, but its pathogenesis has only been uncovered during the last decade. Acute brain injuries can be further complicated by CSD in >50% of severe cases. This phenomenon is repetitive and produces a metabolic overload that increments secondary damage. Propagation of CSD is known to be linked to excitotoxicity, but the mechanisms associated with its initiation remain less understood. It has been shown that CSD can be initiated by increases in extracellular [K+] ([K+]e), and animal models use high [K+]e to promote CSD. Connexin hemichannel activity increases due to high [K+]e and low extracellular [Ca2+], conditions that occur after brain injury. Moreover, glial cell gap junction channels are fundamental in controlling extracellular medium composition, particularly in maintaining normal extracellular glutamate and K+ concentrations through "spatial buffering". However, the role of astrocytic gap junctions under tissue stress can change to damage spread in the acute damage zone whereas the reduced communication in adjacent zone would reduce cell dead propagation. Here, we review the main findings associated with CSD, and discuss the possible involvement of astrocytic connexin-based channels in secondary damage propagation. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. PMID- 28864365 TI - Diabetes-Related Dyslipidemia and Cardiovascular Events. PMID- 28864366 TI - Tuberculous Pleural Effusions: A New Look at an Old Problem. PMID- 28864367 TI - Thromboprophylaxis Failure in the Adult Medical Inpatient. AB - Venous thromboembolism (VTE), a leading cause of morbidity and mortality among hospitalized patients, is often due to prophylaxis failure rather than omission, but few studies have identified the risk factors for failure. Risk factors for thromboprophylaxis failure include personal or family history of VTE, use of vasopressors or inotropes, increased body mass index, cranial surgery, intensive care patient, leukocytosis, indwelling central venous catheter and admission from a long-term care facility. Identifying patients at risk for thromboprophylaxis failure should prompt close observation during hospitalization for signs of VTE, close observation after discharge and potentially more aggressive prophylaxis strategies, although no specific guidelines exist for medical patients at this time. PMID- 28864368 TI - Triglyceride to High-Density Lipoprotein Cholesterol Ratio and Cardiovascular Events in Diabetics With Coronary Artery Disease. AB - BACKGROUND: It has been demonstrated that an elevated ratio of triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) is a risk factor of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM) and is also found to be associated with cardiovascular events (CVEs) in the general population. However, its prognostic value in patients with T2DM along with CAD remains to be determined. MATERIALS AND METHODS: A total of 1,447 consecutive patients with T2DM with angiographic-proven stable CAD were enrolled in the present study and followed-up for an average of 20.3 months. The characteristics of all patients including fasting lipid profile were obtained at baseline and multivariate Cox proportional hazards models were constructed using log TG/HDL-C as a predictor variable. The relationships between CVEs and total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, TC/HDL-C, LDL-C/HDL C and apolipoprotein B/ apolipoprotein AI (apoB/apoAI) were also explored. RESULTS: Compared with patients without CVEs, the ones who experienced CVEs had a higher TG/HDL-C ratio. Univariable regression revealed a significant association of log TG/HDL-C with CVEs (hazard ratio = 2.5, P = 0.015). After adjusting for multiple traditional risk factors of cardiovascular disease, the association was still found (hazard ratio = 2.47, P = 0.047). Moreover, results suggested that the ratios of non-HDL-C, TC/HDL-C, LDL-C/HDL-C and apoB/apoAI were not predictors for CVEs in T2DM. CONCLUSIONS: In our primary study, data suggested that elevated TG/HDL-C value might be a useful predictor for future CVEs in Chinese patients with T2DM with stable CAD. Further study is needed to confirm our findings. PMID- 28864369 TI - Predictive Factors and Treatment Outcomes of Tuberculous Pleural Effusion in Patients With Cancer and Pleural Effusion. AB - BACKGROUND: Patients with cancer are at an increased risk of tuberculosis. As pleural effusion has great clinical significance in patients with cancer, the differential diagnosis between tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) is important. However, the predictive factors and treatment outcomes of TPE in patients with cancer have rarely been studied. MATERIALS AND METHODS: Confirmed TPE cases identified at cancer diagnosis and during anticancer management from 2008-2015 were retrospectively investigated. Patients in the study included coexisting TPE and cancer (n = 20), MPE (n = 40) and TPE without cancer (n = 40). Control groups were patients with MPE, and patients with TPE without cancer. Clinical, laboratory and pleural fluid characteristics were compared among groups. Treatment outcomes were compared between patients with TPE with and without cancer. RESULTS: In the final analysis, serum C-reactive protein (S-CRP) >=3.0mg/dL and pleural fluid adenosine deaminase (ADA) >=40U/L were independent predictors for identifying TPE in patients with cancer having pleural effusion. The combination of S-CRP with pleural fluid ADA using an "or" rule achieved a sensitivity of 100%, whereas both parameters combined in an "and" rule had a specificity of 98%. Treatment outcomes were not different between the TPE groups with and without cancer. CONCLUSIONS: S CRP and pleural fluid ADA levels may be helpful for predicting TPE in patients with cancer with pleural effusion. The combination of these biomarkers provides better information for distinguishing between TPE and MPE in these patients. Treatment outcomes of TPE in patients with cancer are comparable to those in patients without cancer. PMID- 28864370 TI - Pro-Brain Natriuretic Peptide and Troponin T-Hypersensitivity Levels Correlate With the Severity of Liver Dysfunction in Liver Cirrhosis. AB - BACKGROUND: Increased pro-brain natriuretic peptide (pro-BNP) or troponin T hypersensitivity (TnT-HSST) levels are common in liver cirrhosis. We conducted a retrospective observational study aimed to evaluate the correlation of pro-BNP and TnT-HSST levels with the clinical characteristics, laboratory data and in hospital outcomes of patients with liver cirrhosis. MATERIALS AND METHODS: We selected cirrhotic patients admitted to our hospital between January 2011 and June 2014. All eligible patients had pro-BNP or TnT-HSST data, or both. The pro BNP and TnT-HSST data were further divided according to the presence of cardiac diseases. RESULTS: The prevalence of pro-BNP level >900pg/mL was 41.72% (63 of 151 patients). The prevalence of TnT-HSST level >0.05ng/mL was 11.22% (45 of 401 patients). In the overall analysis, pro-BNP level significantly correlated with red blood cell (RBC), platelet, ascites, blood urea nitrogen (BUN), creatinine (Cr), Child-Pugh score, model for end-stage liver disease (MELD) score and in hospital death; TnT-HSST level significantly correlated with white blood cell, ascites, albumin (ALB), BUN, Cr, Child-Pugh score, MELD score and in-hospital death. In patients with cardiac diseases, pro-BNP level significantly correlated with RBC, ascites, BUN, Cr, Child-Pugh score and MELD score; TnT-HSST level significantly correlated with sex, ascites, white blood cell, ALB, BUN, Cr, Child Pugh score, MELD score and in-hospital death. In patients without cardiac diseases, pro-BNP level significantly correlated with ascites, RBC, platelet, BUN, Cr, MELD score and in-hospital death; TnT-HSST level significantly correlated with age, ascites, RBC, ALB, BUN, Cr, Child-Pugh score, MELD score and in-hospital death. CONCLUSIONS: Pro-BNP and TnT-HSST levels significantly correlated with the severity of liver dysfunction and in-hospital mortality in cirrhosis. PMID- 28864371 TI - Left Ventricular Noncompaction in Older Patients. AB - BACKGROUND: Information on left ventricular noncompaction (LVNC) in older people is sparse. This study aimed to investigate the clinical profile of LVNC in an older cohort. MATERIALS AND METHODS: Between August 2007 and September 2015, older patients (age >= 60 years) who were diagnosed with LVNC using cardiovascular magnetic resonance were prospectively enrolled at our hospital. RESULTS: A total of 35 patients (male, 80%; mean age, 65 +/- 5 years) were prospectively included in this study. LVNC was not detected in 18 patients (51%) at the initial echocardiographic evaluation. Of the 21 patients who received coronary imaging, 8 patients (38%) had coronary artery disease. Left ventricular (LV) dysfunction and dilation were detected in 31 patients (89%) and 30 patients (86%), respectively. Nine patients (26%) died during a follow-up period of 2.9 +/ 2.3 years. Cox analysis showed that patients with syncope (hazard ratio [HR] = 20.51; 95% CI: 1.70-246.60; P = 0.02), increased LV end-diastolic diameter (HR = 1.12; 95% CI: 1.01-1.24; P = 0.03), decreased LV ejection fraction (HR = 0.87; 95% CI: 0.77-0.98; P = 0.02) and the presence of late gadolinium enhancement on cardiovascular magnetic resonance (HR = 8.9; 95% CI: 1.07-74.08; P = 0.04) had a higher risk for death. CONCLUSIONS: The diagnosis of LVNC is easily missed at echocardiographic assessment in older patients. Coronary artery disease is a common concomitant disorder in these patients. Older patients with LVNC have a high risk for mortality. Syncope, LV dilation, systolic dysfunction and late gadolinium enhancement are related to adverse outcomes in older patients. PMID- 28864372 TI - Therapeutic Mechanism of Glucocorticoids on Cellular Crescent Formation in Patients With Antiglomerular Basement Membrane Disease. AB - BACKGROUND: This study aimed to explore the therapeutic mechanism of glucocorticoids (GCs) in antiglomerular basement membrane disease. MATERIALS AND METHODS: Thirty-four patients with biopsy-proven antiglomerular basement membrane nephritis were divided into the following 2 groups: group 1 (patients treated with GCs, n = 22) and group 2 (patients who were not treated with GCs, n = 12). The expression of parietal epithelial cells (PECs), activated PECs and glucocorticoid receptors (GRs) was examined quantitatively and compared between the 2 groups. Correlations between GR expression in glomeruli and patients' clinicopathological indices were also analyzed. RESULTS: Compared with patients in group 2, patients in group 1 showed lower levels of serum creatinine (SCr) (P = 0.03), average cellular crescent percentage (P = 0.005) and macrophages infiltrating in renal interstitium (P = 0.03). PECs (P = 0.007) and activated PECs (P = 0.03) were strongly detected in the cellular components of classic crescents, and both were significantly reduced in group 1 compared to group 2. GR expression either in glomeruli (P = 0.01) or interstitium (P = 0.009) was lower in group 1 after GCs treatment than in group 2. Additionally, GR expression in glomeruli was strongly correlated with renal function (SCr: r = 0.45, P = 0.009; eGFR: r = -0.35, P = 0.046), the proportion of cellular crescents (r = 0.67, P < 0.001), PECs (r = 0.64, P < 0.001) and activated PECs (r = 0.72, P < 0.001), and the degree of interstitial (r = 0.50, P = 0.004) and glomerular (r = 0.49, P = 0.007) macrophage infiltration. CONCLUSIONS: GCs might exert their therapeutic effects via inhibiting the activation and proliferation of PECs, as well as macrophage infiltration, which could contribute to crescent formation and determine renal survival. GRs are involved in this process as well. PMID- 28864373 TI - Significance of Hyperferritinemia in Hospitalized Adults. AB - BACKGROUND: Although high ferritin levels are associated with iron overload, it is known that ferritin is also an acute-phase reactant that may be elevated in conditions associated with acute and chronic inflammation. In addition, an elevated ferritin level is a criterion for the diagnosis of hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Therefore, the significance of elevated serum ferritin is often unclear. As HLH/MAS is a medical emergency, prompt diagnosis is important to guide appropriate treatment. MATERIALS AND METHODS: To study the spectrum of diagnoses associated with elevated serum ferritin, we did a retrospective review of adult patients admitted to our academic medical center from 2008-2012 with serum ferritin levels greater than 2,000ng/mL. The degree of hyperferritinemia was compared to different diagnoses and selected laboratory values. RESULTS: A total of 333 patients were identified with a serum ferritin level >2,000ng/mL. Hepatocellular injury was the most prevalent diagnosis with n = 126; infection was next with n = 96. Eleven patients were diagnosed with HLH/MAS. CONCLUSIONS: Elevated ferritin, as an isolated finding, was not a specific marker for the diagnosis of HLH/MAS. However, as a group, HLH/MAS patients had the highest mean and median ferritin values. PMID- 28864374 TI - Trends in the Incidence and In-Hospital Outcomes of Cardiogenic Shock Complicating Thyroid Storm. AB - BACKGROUND: Thyroid storm (TS) constitutes an endocrine emergency with an incidence of up to 10% of all admissions for thyrotoxicosis. Cardiogenic shock (CS) is a rare complication of TS and very limited data exists on its incidence and outcomes. We aimed to estimate the national trends in incidence and outcomes of CS among patients admitted to US hospitals with TS. MATERIALS AND METHODS: We queried the nationwide inpatient sample for patients with the discharge diagnosis of TS between the years of 2003 and 2011. RESULTS: Based on a weighted estimate, we identified 41,835 patients with a diagnosis of TS, of which 1% developed CS. Patients with CS were more likely to have history of atrial fibrillation, alcohol abuse, preexisting congestive heart failure, coagulopathy, drug use, liver disease, pulmonary circulation disorders, valvular disorders, weight loss, renal failure, fluid and electrolyte disorders as compared to those who did not develop CS (P < 0.001 for all). We observed an increase in incidence of CS from 0.5% in 2003 to 3% in 2011 and a decrease in mortality from 60.5% in 2003 to 20.9% in 2011 (Ptrend < 0.001 for both). CONCLUSIONS: We observed that CS is a rare complication of TS, which occurs more commonly in male patients with preexisting structural and atherosclerotic heart disease, and carries a very poor prognosis. Although incidence has increased over the years, mortality from CS has steadily declined. PMID- 28864375 TI - Metformin Use and Vitamin B12 Deficiency: Untangling the Association. AB - BACKGROUND: Current evidence linking vitamin B12 deficiency with metformin use is inconsistent. Hence, there is uncertainty regarding the diagnostic approach in this scenario. Furthermore, this possible association has not been studied in the complete spectrum of patients with diabetes. MATERIALS AND METHODS: We conducted a cross-sectional, controlled study with the objective of assessing differences in serum vitamin B12 levels among patients with and without diabetes with different metformin-treatment regimens. A total of 150 participants were recruited: patients with diabetes (group 1: metformin alone >=850mg/day, group 2: patients with type 2 diabetes naive to treatment and group 3: metformin >=850mg/day, in addition to any other oral glucose lowering agent or insulin, or both) and without diabetes (group 4: polycystic ovary syndrome or group 5: healthy individuals). Serum vitamin B12, folate levels and complete blood counts were obtained for the entire population. Methylmalonic acid and homocysteine were obtained for patients when vitamin B12 levels were found to be borderline or low. RESULTS: When patients with or without diabetes were compared, no significant difference was found in relation to their vitamin B12 levels (517.62 versus 433.83; P = 0.072). No difference in vitamin B12 levels was found among participants with metformin use and metformin naive participants (503.4 versus 462.3; P = 0.380). CONCLUSIONS: Irrespective of metformin use, no significant difference in the serum levels of vitamin B12 was observed, both in patients with and without diabetes. In the light of the body of evidence and the results of this study, a universal recommendation for vitamin B12 deficiency screening cannot be made. PMID- 28864376 TI - Methotrexate Hepatotoxicity and the Impact of Nonalcoholic Fatty Liver Disease. AB - Methotrexate (MTX) is commonly used to treat individuals with rheumatological and dermatologic disorders. Current American College of Rheumatology (ACR) and American Association of Dermatology (AAD) guidelines identify diabetes and obesity as risk factors for MTX-induced liver injury. Both diabetes and obesity are components of the metabolic syndrome, and are also risk factors for nonalcoholic fatty liver disease (NAFLD). NAFLD affects approximately 40% of the U.S. population, and those with more advanced NAFLD (i.e., nonalcoholic steatohepatitis with or without fibrosis) are likely to develop progressive liver disease. As such, individuals who are treated with MTX may need to be screened for advanced NAFLD, as this may put them at an increased risk of MTX-induced liver injury. In this mini-review, we review the current ACR and AAD guidelines on MTX hepatotoxicity, discuss the evidence (or lack thereof) of the impact of metabolic risk factors on MTX-induced liver injury and highlight the areas that need further research. PMID- 28864377 TI - Antiviral Drug Ribavirin Targets Thyroid Cancer Cells by Inhibiting the eIF4E beta-Catenin Axis. AB - BACKGROUND: Although eukaryotic translation initiation factor 4E (eIF4E) is important in cancer development and progression, its role in thyroid cancer is not well understood. Ribavirin, an anti-viral drug, has been identified as an eIF4E inhibitor. Herein, we investigated the effects of ribavirin on thyroid cancer and its molecular mechanisms of action. MATERIALS AND METHODS: The effects of ribavirin on thyroid cancer was investigated using in vitro cellular assays and in vivo xenograft mouse model. The mechanism of its action on eIF4E-beta catenin axis was examined using genetic and biochemical approaches. RESULTS: We show that ribavirin inhibited proliferation and induced apoptosis in the thyroid cancer cell lines 8505C and FTC-133. Ribavirin inhibited thyroid cancer growth in a xenograft mouse model. Ribavirin also sensitized thyroid cancer's response to paclitaxel. Mechanistically, ribavirin suppressed eIF4E phosphorylation and overexpression of its wildtype and phosphor-mimetic form (S209D) but not of the non-phosphorylatable form (S209A), which rescued the inhibitory effects of ribavirin in thyroid cancer cells. We further demonstrated that ribavirin suppressed phosphorylation and activities of beta-catenin and its subsequent gene transcriptional expression. beta-Catenin overexpression rescued the effects of ribavirin in thyroid cancer cells. Importantly, we show that eIF4E regulated beta catenin and that the regulation depended on phosphorylation at S209. The in vivo inhibitory effects of ribavirin on phosphorylation of eIF4E and beta-catenin were also observed in thyroid tumor. CONCLUSIONS: Our data clearly demonstrate that ribavirin acts on thyroid cancer cells by inhibiting eIF4E/beta-catenin signaling. Our findings suggest that ribavirin has the potential to be repurposed for thyroid cancer treatment and also highlight the therapeutic value of inhibiting eIF4E-beta-catenin in thyroid cancer. PMID- 28864378 TI - Potential Cardiovascular and Renal Protective Effects of Vitamin D and Coenzyme Q10 in l-NAME-Induced Hypertensive Rats. AB - BACKGROUND: Hypertension is one of the primary modifiable risk factors for cardiovascular disease. Adequate vitamin D (vit D) levels have been shown to reduce vascular smooth muscle contraction and to increase arterial compliance, which may be beneficial in hypertension. Further, coenzyme Q10 (COQ10) through its action to lower oxidative stress has been reported to have beneficial effects on hypertension and heart failure. This study examined the possible cardiac and renal protective effects of vit D and COQ10 both separately and in combination with an angiotensin II receptor blocker, valsartan (vals) in l-NAME hypertensive rats. MATERIALS AND METHODS: Hypertension was induced in rats by l-NAME administration. Following induction of hypertension, the rats were assigned into the following 6 subgroups: an l-NAME alone group and treated groups receiving the following drugs intraperitoneally for 6 weeks; vals, vit D, COQ10 and combination of vals with either vit D or COQ10. A group of normotensive rats were used as negative controls. At the end of the treatment period, blood pressure, serum creatinine, blood urea nitrogen, lipids and serum, cardiac and renal parameters of oxidative stress were measured. RESULTS: Compared to the l-NAME only group, all treatments lowered systolic, diastolic, mean arterial pressure, total cholesterol, low-density lipoprotein cholesterol, and creatinine levels as well as TNF-alpha and malondialdehyde. Further, the agents increased serum, cardiac and renal total antioxidant capacity. Interestingly, the combination of agents had further effects on all the parameters compared to treatment with each single agent. CONCLUSIONS: The study suggests that the additive protective effects of vit D and COQ10 when used alone or concurrent with vals treatment in hypertensive rats may be due to their effects as antioxidants, anticytokines and blood pressure conservers. PMID- 28864379 TI - Overexpression of Heparin-Binding Epidermal Growth Factor-Like Growth Factor Mediates Liver Fibrosis in Transgenic Mice. AB - BACKGROUND: The role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in liver fibrosis is not clear and is sometimes even contradictory. To clarify this role, a HB-EGF transgenic (Tg) mouse model was, for the first time, used to evaluate the functions of HB-EGF in liver fibrosis. MATERIALS AND METHODS: For the in vivo study, carbon tetrachloride injection and bile duct ligation treatment were used to induce liver fibrosis in HB-EGF Tg mice and wild-type (WT) mice, respectively. Primary hepatic satellite cells (HSCs) were isolated from HB-EGF Tg and WT mice for the in vitro study. RESULTS: Compared with the WT mice, HB-EGF Tg mice were shown to develop more severe liver fibrosis when treated with carbon tetrachloride or bile duct ligation, with increased matrix metalloproteinases 13 activity and enhanced expression of fibrogenic genes including alpha-smooth muscle actin and collagen I. HB-EGF gene transfer led to an increase in proliferation and a decrease in apoptosis in primary HSCs. The ERK signaling pathway was more highly activated in primary HSCs from HB-EGF Tg mice than in those from WT mice. CONCLUSIONS: Our investigation confirmed the profibrotic effect of HB-EGF on the liver using a Tg mouse model. This result may contribute to the elucidation of HB-EGF as a therapeutic target in liver fibrosis. PMID- 28864380 TI - Malakoplakia Presenting as an Endobronchial Lesion in a Human Immunodeficiency Virus-Positive Man. PMID- 28864381 TI - Cardiac Metastasis as Initial Site of Recurrence in Rectal Cancer. PMID- 28864382 TI - Occult Cardiac Angiosarcoma Presenting as Cardiac Tamponade. PMID- 28864383 TI - Retinal Metastases From Anaplastic Astrocytoma. PMID- 28864384 TI - Is it Your Disease or the Patient's? PMID- 28864385 TI - Pulmonary Mucormycosis in a Patient With Poorly Controlled Diabetes After a Liver Transplant. PMID- 28864386 TI - Coarctation of Aorta With Classical Imaging Findings. PMID- 28864387 TI - Tenosynovial Giant Cell Tumor in the Midfoot Treated With Femoral Head Allograft Reconstruction. AB - Tenosynovial giant cell tumor (also known as giant cell tumor of tendon sheath or pigmented villonodular synovitis) is a rare soft tissue tumor that arises from the tenosynovium of a tendon sheath or the synovium of a diarthrodial joint. This disease process occurs infrequently in the foot and ankle but can result in significant bone erosion and destructive changes of affected joints. These cases are challenging to treat, because the tumor most commonly presents in young, active patients and can be associated with extensive bone loss. We review a case of tenosynovial giant cell tumor of tendon sheath of the midfoot, which was treated with mass resection, structural femoral head allograft bone grafting, and internal fixation with dorsal plating. The patient had achieved successful bony fusion and acceptable functional outcomes at the final follow-up visit 40 months postoperatively. PMID- 28864388 TI - Validity and Reliability of Visual Analog Scale Foot and Ankle: The Turkish Version. AB - The present study tested the reliability and validity of the Turkish version of the visual analog scale foot and ankle (VAS-FA) among healthy subjects and patients with foot problems. A total of 128 participants, 65 healthy subjects and 63 patients with foot problems, were evaluated. The VAS-FA was translated into Turkish and administered to the 128 subjects on 2 separate occasions with a 5-day interval. The test-retest reliability and internal consistency were assessed with the intraclass correlation coefficient and Cronbach's alpha. The validity was assessed using the correlations with Turkish versions of the Foot Function Index, the Foot and Ankle Outcome Score, and the Short-Form 36-item Health Survey. A statistically significant difference was found between the healthy group and the patient group in the overall score and subscale scores of the VAS-FA (p < .001). The internal consistency of the VAS-FA was very good, and the test-retest reliability was excellent. Adequate to good correlations were found between the overall VAS-FA score and the Foot Function Index, Foot and Ankle Outcome Score, and Short-Form 36-item Health Survey scores in the healthy and patient groups both. The Turkish version of the VAS-FA is sensitive enough to distinguish foot and ankle-specific pathologic conditions from asymptomatic conditions. The Turkish version of the VAS-FA is a reliable and valid method and can be used for foot-related problems. PMID- 28864389 TI - Antibiotic incorporation in jet-sprayed nanofibrillar biodegradable scaffolds for wound healing. AB - In view of preparing antibiotic-loaded structures that can be used as dressing to prevent or contain wound infections, this study evaluates biodegradable nanofibrillar matrices obtained by jet-spraying and containing ciprofloxacin (CIF). The matrices were prepared from different blends of poly-(epsilon caprolactone) (PCL) and poly-d,l-(lactic acid) (PDLLA) in view of controlling mechanical properties, biodegradation and antibiotic release rate. The effect of CIF incorporation was assessed in regard of matrices fiber diameter, mechanical properties and degradation while antibiotic release from the polymer blends of different PCL/PDLLA ratios was measured in buffers of different pH to better mimic the wound context. Finally, antibiotic activity of the nanofibrillar matrices and their ability to be colonized by skin cells were evaluated. Non woven nanofibrillar matrices could be obtained from various polymer blends by jet spraying and CIF crystals incorporation was easily obtained. The crystals were dispersed in the fibers, without complete embedding. Antibiotic incorporation resulted in a slight increase of fiber diameter and did not modified the mechanical properties of the various matrices composed of different polymer blends. Unlike fiber diameter, degradation and mechanical properties of the fibrillar matrices, CIF release profiles were not controlled by the polymer blend ratios. However, sustained release was observed over more than 23days. Due to the antibiotic pH-dependent solubility, burst release was more prominent in acidic conditions, which mimic the pH of undamaged skin. Finally the incorporated antibiotic was efficient in inhibiting bacterial growth of E. coli and B. subtilis whereas human fibroblasts were able to colonize the CIF-loaded matrices. PMID- 28864390 TI - Protease-functionalized mucus penetrating microparticles: In-vivo evidence for their potential. AB - The focus of the current study was to explore whether immobilization of proteases to microparticles could result in their enhanced penetration into mucus. The proteases papain (PAP) and bromelain (BROM) were covalently attached to a polyacrylate (PAA; Carbopol 971P) via amide bond formation based on carbodiimide reaction. Microparticles containing these conjugates were generated via ionic gelation with calcium chloride and were characterized regarding size, surface charge, enzymatic activity and fluorescein diacetate (FDA) loading efficiency. Furthermore, mucus penetration potential of these microparticles was evaluated in vitro on freshly collected porcine intestinal mucus, on intact intestinal mucosa and in-vivo in Sprague-Dawley rats. Results showed mean diameter of microparticles ranging between 2-3MUm and surface charge between -8 to -18mV. The addition of PAA-microparticles to porcine intestinal mucus led to a 1.39-fold increase in dynamic viscosity whereas a 3.10- and 2.12-fold decrease was observed in case of PAA-PAP and PAA-BROM microparticles, respectively. Mucus penetration studies showed a 4.27- and 2.21- fold higher permeation of FDA loaded PAA-PAP and PAA-BROM microparticles as compared to PAA microparticles, respectively. Extent of mucus diffusion determined via silicon tube assay illustrated 3.96- fold higher penetration for PAA-PAP microparticles and 1.99- fold for PAA-BROM microparticles. An in-vitro analysis on porcine intestinal mucosa described up to 16- and 7.35-fold higher degree of retention and furthermore, during in-vivo evaluation in Sprague-Dawley rats a 3.35- and 2.07-fold higher penetration behavior was observed in small intestine for PAA-PAP and PAA-BROM microparticles as compared to PAA microparticles, respectively. According to these results, evidence for microparticles decorated with proteases in order to overcome the mucus barrier and to reach the absorption lining has been provided that offers wide ranging applications in mucosal drug delivery. PMID- 28864391 TI - Particle interactions of fluticasone propionate and salmeterol xinafoate detected with single particle aerosol mass spectrometry (SPAMS). AB - Particle co-associations between the active pharmaceutical ingredients fluticasone propionate and salmeterol xinafoate were examined in dry powder inhaled (DPI) and metered dose inhaled (MDI) combination products. Single Particle Aerosol Mass Spectrometry was used to investigate the particle interactions in Advair Diskus(r) (500/50 mcg) and Seretide(r) (125/25 mcg). A simple rules tree was used to identify each compound, either alone or co associated at the level of the individual particle, using unique marker peaks in the mass spectra for the identification of each drug. High levels of drug particle co-association (fluticasone-salmeterol) were observed in the aerosols emitted from Advair Diskus(r) and Seretide(r). The majority of the detected salmeterol particles were found to be in co-association with fluticasone in both tested devices. Another significant finding was that rather coarse fluticasone particles (in DPI) and fine salmeterol particles (both MDI and DPI) were forming the particle co-associations. PMID- 28864392 TI - Amphiphilic lipopeptide significantly enhances uptake of charge-neutral splice switching morpholino oligonucleotide in spinal muscular atrophy patient-derived fibroblasts. AB - Splice-switching antisense oligonucleotides (SSOs) are emerging therapeutics with two SSOs recently approved by the FDA for Duchenne muscular dystrophy and spinal muscular atrophy. SSOs are administered without any delivery vector and require large doses to achieve the therapeutic benefit, primarily due to their poor cellular uptake. Although cell-penetrating peptides (CPP) have shown great potential in delivering SSOs into cells, their capacity as delivery vector is limited. Here we have studied the effect of lipid conjugation on the cell permeability of a known CPP (ApoE). Myristic acid was coupled at the N-terminus of ApoE to a C-terminal cysteine residue. The myristoylated ApoE (Myr-ApoE) was conjugated to a maleimide functionalised phosphorodiamidate morpholino oligonucleotide (PMO). The Myr-ApoE-PMO conjugate showed no cytoxicity and had significantly higher efficiency in cell permeability with 30% higher splice switching activity compared to ApoE-PMO. The self-assembly properties of this amphiphilic lipopeptide-PMO conjugate was assessed. Transmission electron microscopy showed formation of nanoparticles with amphiphile behaviour and spherical structure. The self-assembly of Myr-ApoE-PMO into nanoparticles enabled it to better bind to cell membranes and to be more efficiently taken up by fibroblast cells. These results showed that modification of physico-chemical properties of peptides to produce peptide amphiphiles enhances cellular uptake and can be used as an efficient delivery vector for therapeutic SSOs. PMID- 28864393 TI - Biosorbents based on esterified starch carrying immobilized oil-degrading microorganisms. AB - The complex sorbents based on hydrophobized starch, which contain oil-degrading microorganisms, have been proposed for effective sorption and utilization of petroleum-related pollutants. The sorbents were made on the base of benzoic, lauric and stearic acid esters of starch with degrees of substitution of 0.4-1.1. The esterification of starch was carried out by the reaction with acyl chlorides of the corresponding acids in an aqueous-organic medium. The structure of the esters was studied by SEM, IR and NMR spectroscopy. As a result of porous hydrophobic structure, these sorbents are capable of binding and retention of petroleum products on the water surface, and keeping the flotation for at least 30days after the petroleum products sorption. The test of biodegradability of the obtained samples revealed that the modified starches can be degraded by microscopic fungi, therefore they do not cause secondary pollution. The cultures of yeast Rhodotorula glutinis VKM Y-2993D and bacteria Pseudomonas libanensis VKM B-3041D immobilized on the sorbent facilitate the rapid utilization of accumulated petroleum products. PMID- 28864394 TI - Trauma pneumonectomy: A narrative review. AB - PURPOSE: Thoracic injuries are common in both blunt and penetrating trauma. Most thoracic injuries are managed non-operatively, approximately 7-20% undergo thoracotomy. Of the injuries requiring thoracotomy, 1-6% ultimately require pulmonary resection. Wedge resection and lobectomies are well-studied in the literature; however, there is a paucity regarding reports on total pneumonectomy in the setting of trauma. Our objectives were to summarize the evidence supporting the role of trauma pneumonectomy (TP) in the current era and reiterate that despite the associated morbidity and mortality TP is justified in selective cases. METHODS: A review of the world's literature was conducted following standard guidelines. Inclusion criteria included those studies reviewing blunt and penetrating trauma to the lungs in adults (age greater than 15 year) that reported mortality rates and outcome measures. RESULTS: The PubMed search yielded 713 studies. Of these, 14 studies included pertinent information on TP. Studies included in this review were published from 1985 to 2017 and involved patient data that was collected from 1972 to 2014. Mortality ranged from 50% to 100% (median 63%; mean 68%). CONCLUSION: In the setting of severe thoracic trauma, pulmonary resection may be necessary. Less aggressive techniques are options in a stable patient; however, in the setting of ongoing hemorrhage, TP should be considered and expediently conducted. The role of damage control thoracic surgery and related techniques is vitally important in these patients to improve the significant mortality of trauma pneumonectomy. PMID- 28864395 TI - Bronchoscopic techniques in the management of patients with tuberculosis. AB - Tuberculosis (TB) is one of the leading causes of morbidity and mortality worldwide. Early diagnosis and treatment are key to prevent Mycobacterium tuberculosis transmission. Bronchoscopy can play a primary role in pulmonary TB diagnosis, particularly for suspected patients with scarce sputum or sputum smear negativity, and with endobronchial disease. Bronchoscopic needle aspiration techniques are accurate and safe means adopted to investigate hilar and mediastinal lymph nodes in cases of suspected TB lymphadenopathy. Tracheobronchial stenosis represents the worst complication of endobronchial tuberculosis. Bronchoscopic procedures are less invasive therapeutic strategies than conventional surgery to be adopted in the management of TB-related stenosis. We conducted a non-systematic review aimed at describing the scientific literature on the role of bronchoscopic techniques in the diagnosis and therapy of patients with TB. We focused on three main areas of interventions: bronchoscopic diagnosis of smear negative/sputum scarce TB patients, endobronchial TB diagnosis and treatment and needle aspiration techniques for intrathoracic TB lymphadenopathy. We described experiences on bronchoalveolar lavage, bronchial washing, and biopsy techniques for the diagnosis of patients with tracheobronchial and pulmonary TB; furthermore, we described the role played by conventional and ultrasound-guided transbronchial needle aspiration in the diagnosis of suspected hilar and mediastinal TB adenopathy. Finally, we assessed the role of the bronchoscopic therapy in the treatment of endobronchial TB and its complications, focusing on dilation techniques (such as balloon dilation and airway stenting) and ablative procedures (both heat and cold therapies). PMID- 28864396 TI - Environmental indicators of oyster norovirus outbreaks in coastal waters. AB - This paper presents an artificial intelligence-based approach to identifying environmental indicators of oyster norovirus outbreaks in coastal waters. It was found that oyster norovirus outbreaks are generally linked to the extreme combination of antecedent environmental conditions characterized by low water temperature, low solar radiation, low gage height, low salinity, strong wind, and heavy precipitation. Among the six environmental indicators, the most important three indicators, including water temperature, solar radiation and gage height, are capable of explaining 77.7% of model-predicted oyster norovirus outbreaks while the extremely low temperature alone may explain 37.2% of oyster norovirus outbreaks. It is, therefore, recommended that water temperature in oyster harvesting areas be monitored in the cold season and particularly the extremely low temperature during a low gage height be used as the primary indicator of oyster norovirus outbreaks. The findings are of profound significance to reducing the public health risk of norovirus outbreaks associated with consumption of oysters. PMID- 28864397 TI - Adrenocortical tumors associated with the TP53 p.R337H germline mutation can be identified during child-care consultations. AB - OBJECTIVE: To evaluate the clinical features associated with adrenocortical hormone overexpression and familial cancer profiling as potential markers for early detection of adrenocortical tumors in children from South and Southeast Brazil. METHODS: The clinical manifestations and anthropometric measurements of 103 children diagnosed with adrenocortical tumors were analyzed. RESULTS: Between 1982 and 2011, 69 girls and 34 boys diagnosed with adrenocortical tumors were followed-up for a median time of 9.0 years (0-34 years). Signs of androgen overproduction alone (n=75) or associated with cortisol (n=18) were present in 90.3%. TP53 p.R337H mutation was found in 90.5% of patients. Stages I, II, III, and IV were observed in 45.6%, 27.2%, 19.4%, and 7.8% of patients, respectively. At diagnosis, there were no significant differences in height (p=0.92) and weight (p=0.22) among children with adrenocortical tumors, but children with virilization alone had significantly higher height-for-age Z-scores (0.92+/-1.4) than children with hypercortisolism alone or combined (-0.32+/-1,8; p=0.03). The five-year overall survival was 76.7% (SD+/-4.2). Patients with advanced-stage disease had a significantly worse prognosis than those with limited disease (p<0.001). During follow-up, ten of 55 p.R337H carrier parents developed cancer, whereas none of the 55 non-carriers did. CONCLUSIONS: Signs of adrenocortical hormone overproduction appear early, even in cases with early-stage. These signs can be identified at the physical examination and anthropometric measurements. In southern Brazil, pediatric adrenocortical tumor is a sentinel cancer for detecting families with germline p.R337H mutation in TP53 gene. PMID- 28864398 TI - The role of asymptomatics and dogs on leishmaniasis propagation. AB - Leishmaniasis is a parasite disease transmitted by the bites of sandflies. Cutaneous leishmaniasis is the most common form of the disease and it is endemic in the Americas. Around 70 animal species, including humans, have been found as natural reservoir hosts of leishmania parasites. Among the reservoirs, dogs are the most important ones due to their proximity to the human habitat. Infection by leishmaniasis does not invariably cause illness in the host, and it also can remain asymptomatic for a long period, specially in dogs. In this work we formulate a model to study the transmission of the disease among the vector, humans and dogs. Our main objective is to asses the impact of dogs as a reservoir as well as the impact of asymptomatic humans and dogs on the spread of leishmaniasis. For this end we calculate the Basic Reproduction Number of the disease and we carry out sensitivity analysis of this parameter with respect to the epidemiological and demographic parameters. PMID- 28864399 TI - Multiple Symptoms in Family Caregivers of Intensive Care Unit Patients. AB - CONTEXT: Intensive care unit (ICU) patients experience physical and psychological challenges related to ICU admission in the acute and recovery phases after a critical illness. Involvement of family caregivers (FCs) is essential in the patients' struggle to survive critical illness. FCs report a high symptom burden related to ICU admission. Previous research has investigated mainly single symptoms. Little is known about multiple symptom burden related to FC experiences in an ICU. OBJECTIVE: This study aimed: 1) to describe the occurrence, severity, and distress related to multiple symptoms in FCs of ICU patients, and 2) to identify associations between the background characteristics and symptom burden of FCs. METHODS: This cross-sectional study investigated multiple symptoms in adult FCs of ICU patients. FCs completed a self-report symptom assessment questionnaire within 2 weeks after the patient's admission to the ICU. RESULTS: FCs (N=211) experienced a median of 9 (range 0-24) symptoms, among which, worrying (91%) was the most occurring. Severity and distress varied between symptoms. Younger age, being a spouse of an ICU patient, and having more comorbidities were significantly associated with the number of symptoms. CONCLUSIONS: FCs of ICU patients experience multiple symptoms, among which, psychological symptoms are most occurring. Age, relationship to the patient, and comorbidities were significantly associated with the number of symptoms reported by FCs. Comprehensive symptom assessment may identify FCs who are at risk of developing a high symptom burden when the patient is admitted to the ICU. PMID- 28864400 TI - Effects of Transcranial Direct-Current Stimulation on Neurosurgical Skill Acquisition: A Randomized Controlled Trial. AB - BACKGROUND: Recent changes in surgical training environments may have limited opportunities for trainees to gain proficiency in skill. Complex skills such as neurosurgery require extended periods of training. Methods to enhance surgical training are required to overcome duty-hour restrictions, to ensure the acquisition of skill proficiency. Transcranial direct-current stimulation (tDCS) can enhance motor skill learning, but is untested in surgical procedural training. We aimed to determine the effects of tDCS on simulation-based neurosurgical skill acquisition. METHODS: Medical students were trained to acquire tumor resection skills using a virtual reality neurosurgical simulator. The primary outcome of change in tumor resection was scored at baseline, over 8 repetitions, post-training, and again at 6 weeks. Participants received anodal tDCS or sham over the primary motor cortex. Secondary outcomes included changes in brain resected, resection effectiveness, duration of excessive forces (EF) applied, and resection efficiency. Additional outcomes included tDCS tolerability. RESULTS: Twenty-two students consented to participate, with no dropouts over the course of the trial. Participants receiving tDCS intervention increased the amount of tumor resected, increased the effectiveness of resection, reduced the duration of EF applied, and improved resection efficiency. Little or no decay was observed at 6 weeks in both groups. No adverse events were documented, and sensation severity did not differ between stimulation groups. CONCLUSIONS: The addition of tDCS to neurosurgical training may enhance skill acquisition in a simulation-based environment. Trials of additional skills in high-skill residents, and translation to nonsimulated performance are needed to determine the potential utility of tDCS in surgical training. PMID- 28864401 TI - Implementing Radiation Dose-Volume Liver Response in Biomechanical Deformable Image Registration. AB - PURPOSE: Understanding anatomic and functional changes in the liver resulting from radiation therapy is fundamental to the improvement of normal tissue complication probability models needed to advance personalized medicine. The ability to link pretreatment and posttreatment imaging is often compromised by significant dose-dependent volumetric changes within the liver that are currently not accounted for in deformable image registration (DIR) techniques. This study investigated using delivered dose, in combination with other patient factors, to biomechanically model longitudinal changes in liver anatomy for follow-up care and re-treatment planning. METHODS AND MATERIALS: Population models describing the relationship between dose and hepatic volume response were produced using retrospective data from 33 patients treated with focal radiation therapy. A DIR technique was improved by implementing additional boundary conditions associated with the dose-volume response in series with a previously developed biomechanical DIR algorithm. Evaluation of this DIR technique was performed on computed tomography imaging from 7 patients by comparing the model-predicted volumetric change within the liver with the observed change, tracking vessel bifurcations within the liver through the deformation process, and then determining target registration error between the predicted and identified posttreatment bifurcation points. RESULTS: Evaluation of the proposed DIR technique showed that all lobes were volumetrically deformed to within the respective contour variability of each lobe. The average target registration error achieved was 7.3 mm (2.8 mm left right and anterior-posterior and 5.1 mm superior-inferior), with the superior inferior component within the average limiting slice thickness (6.0 mm). This represented a significant improvement (P<.01, Wilcoxon test) over the application of the previously published biomechanical DIR algorithm (10.9 mm). CONCLUSIONS: This study demonstrates the feasibility of implementing dose-driven volumetric response in deformable registration, enabling improved accuracy of modeling liver anatomy changes, which could allow for improved dose accumulation, particularly for patients who require additional liver radiation therapy. PMID- 28864402 TI - Increased Number of Beam Angles Is Associated With Higher Cardiac Dose in Adjuvant Fixed Gantry Intensity Modulated Radiation Therapy of Left-Sided Breast Cancer. AB - PURPOSE: To analyze the relationship between angle number and mean heart dose (MHD) in adjuvant fixed gantry intensity modulated radiation therapy (FG-IMRT) treatment of left-sided breast cancer as is currently practiced in the community. METHODS AND MATERIALS: We performed a retrospective, multi-institutional review of women with left-sided breast cancer receiving adjuvant FG-IMRT between 2012 and 2014, encompassing 85 centers in 15 states. Bivariate and multivariate regression analyses were done to identify factors associated with MHD. Long-term cardiac risk was estimated according to a previously published model. RESULTS: Of the 538 women included, 284 had >2 gantry angle treatment plans (multi-angle), and 254 had 2 gantry angle (standard) plans. Median MHD was higher in patients with multi-angle plans compared with standard (median 475 vs 203 cGy). Number of gantry angles was significantly associated with MHD, with multi-angle plans independently increasing MHD by 229 cGy. Absolute risk of acute coronary events 20 years after treatment was estimated as 7 excess events per 1000 women for standard plans, compared with 12 excess events for multi-angle plans. CONCLUSIONS: Fixed gantry IMRT breast treatment plans with >2 gantry angles were associated with increased MHD, which translated to an increased cardiac risk. Clinicians should account for this potential drawback in treatment technique when assessing overall plan quality. PMID- 28864403 TI - Clinical Outcomes of Several IMRT Techniques for Patients With Head and Neck Cancer: A Propensity Score-Weighted Analysis. AB - PURPOSE: The Advanced Radiotherapy Oto-Rhino-Laryngologie (ART-ORL) study (NCT02024035) was performed to prospectively evaluate the clinical and economic aspects of helical TomoTherapy and volumetric modulated arc therapy (RapidArc, Varian Medical Systems, Palo Alto, CA) for patients with head and neck cancer. METHODS AND MATERIALS: Fourteen centers participated in this prospective comparative study. Randomization was not possible based on the availability of equipment. Patients with epidermoid or undifferentiated nasopharyngeal carcinoma or epidermoid carcinoma of the oropharynx and oral cavity (T1-T4, M0, N0-N3) were included between February 2010 and February 2012. Only the results of the clinical study are presented in this report, as the results of the economic assessment have been published previously. Inverse probability of treatment weighting using the propensity score analysis was undertaken in an effort to adjust for potential bias due to nonrandomization. Locoregional control, cancer specific survival, and overall survival assessed 18 months after treatment, as well as long-term toxicity and salivary function, were evaluated. RESULTS: The analysis included 166 patients. The following results are given after inverse probability of treatment weighting adjustment. The locoregional control rate at 18 months was significantly better in the TomoTherapy group: 83.3% (95% confidence interval [CI], 72.5%-90.2%) versus 72.7% (95% CI, 62.1%-80.8%) in the RapidArc group (P=.025). The cancer-specific survival rate was better in the TomoTherapy group: 97.2% (95% CI, 89.3%-99.3%) versus 85.5% (95% CI, 75.8%-91.5%) in the RapidArc group (P=.014). No significant difference was shown in progression-free or overall survival. TomoTherapy induced fewer acute salivary disorders (P=.012). Posttreatment salivary function degradation was worse in the RapidArc group (P=.012). CONCLUSIONS: TomoTherapy provided better locoregional control and cancer-specific survival than RapidArc treatment, with fewer salivary disorders. No significant difference was shown in progression-free and overall survival. These results should be explored in a randomized trial. PMID- 28864404 TI - Toxicity and Outcomes in Patients With and Without Esophageal Stents in Locally Advanced Esophageal Cancer. AB - PURPOSE: Esophageal stenting is often considered to relieve dysphagia in patients with locoregionally advanced esophageal cancer. We sought to determine the effects of stenting on the incidence of acute toxicity and oncologic outcomes in patients undergoing chemoradiation therapy (CRT). METHODS AND MATERIALS: The data from patients treated with curative intent CRT for locoregionally advanced esophageal cancer at the University of Utah were retrospectively analyzed. The chi2 or Fisher exact test was used to compare the demographic and tumor characteristics between patients with and without esophageal stenting before RT. Univariate and multivariate analyses using logistic regression modeling were used to identify the predictors of acute toxicities. A propensity score-matched analysis with shared frailty Cox hazard regression was performed according to stent status to identify the stent effect on survival. Acute toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4. RESULTS: From 2005 to 2013, 103 consecutive patients received CRT. Of the 103 patients, 28 had a stent in place during CRT. The median dose was 50.4 Gy for all patients. Grade >=3 acute toxicities were seen in 71% of the stent versus 27% of the no-stent patients (P<.01), including esophagitis (39% vs 20%; P=.05), dehydration (29% vs 13%; P=.07), and anorexia (14% vs 5%; P=.13). Of the 103 patients, 29% of the stent and 51% of the no-stent patients underwent esophagectomy (P=.05). The only significant predictor for acute toxicity on multivariate analysis was esophageal stenting (odds ratio 8.1; P<.01). After propensity score matching, the stent patients had a worse median overall survival compared with the no-stent patients (11.5 vs 22.0 months; hazard ratio 2.3; P=.016). CONCLUSIONS: In patients undergoing CRT with curative intent, esophageal stenting was associated with significantly increased grade >=3 acute toxicities, fewer patients proceeding to esophagectomy, and worse overall survival. PMID- 28864405 TI - Ischemic Cardiac Events Following Treatment of the Internal Mammary Nodal Region Using Contemporary Radiation Planning Techniques. AB - PURPOSE: Regional nodal irradiation, including radiation therapy (RT) to the internal mammary node (IMN) region, improves oncologic outcomes in patients with node-positive breast cancer. Concern remains, however, given the proximity of the IMNs to the heart and the association between cardiac RT exposure and toxicity. The objective of the study was to evaluate rates of ischemic cardiac events (ICEs) and associated risk with treatment of the IMN region. METHODS AND MATERIALS: The cardiac outcomes of 2126 patients treated with adjuvant breast RT or breast and nodal RT from 1984 to 2007 at a single institution were reviewed. The primary endpoint was an ICE following RT initiation. The association between IMN RT and ICEs was assessed using Cox proportional hazards models. Treatment with both IMN RT and 3-dimensional (3D) conformal radiation therapy (CRT) began in 1997; therefore, subset analyses of patients with only 3D CRT were performed to minimize bias associated with improved treatment technique. RESULTS: The median follow-up period was 9.3 years. An ICE occurred in 87 patients (4.1%). No increased 10-year rate of ICEs was observed with IMN RT compared with no IMN RT in the total cohort (3.2% [95% confidence interval (CI), 2.4%-4.3%] vs 3.4% [95% CI, 1.5%-7.5%]; hazard ratio [HR], 0.88; P=.73). Similarly, no statistically significant difference was noted in the 3D CRT-planned, left-sided disease subset (5.1% [95% CI, 1.8%-14.1%] vs 4.0% [95% CI, 2.0%-8.0%]; HR, 1.18, P=.76). On multivariate analysis, adjusting for cardiac risk factor imbalances, no significantly increased hazard was noted with IMN RT (HR, 1.84; P=.28) in the 3D CRT-planned, left-sided disease subset. CONCLUSIONS: No statistically significant association between IMN RT and ICEs was demonstrated in a review of patients treated at a single institution from 1984 to 2007. Given the long natural history and low overall rate of ICEs, continued follow-up of this study, as well as additional studies in the 3D CRT era, is warranted to confirm these results. Minimizing cardiac exposure, when treating a limited IMN field, is critical to limit excess risk of ICEs. PMID- 28864406 TI - Comparative study of perioperative complication rates of cervical laminoplasty performed by residents and teaching neurosurgeons. AB - Early surgical education is required for neurosurgical residents to learn many surgical procedures. However, the participation of less experienced residents may increase perioperative complication rates. Perioperative complication studies in the field of neurosurgery are being increasingly published; however, studies have not yet focused on cervical laminoplasty. The study population included 193 consecutive patients who underwent cervical laminoplasty in Tokyo Metropolitan Neurological Hospital between 2008 and 2014. Patient and surgeon background factors, as well as perioperative complication rates were retrospectively compared between resident and board-certified spine neurosurgeon groups. Deteriorated or newly developed neurological deficits and surgical site complications within 30days of cervical laminoplasty were defined as perioperative complications. Out of 193 patients, 123 (64%) were operated on by residents as the first operator and 70 (36%) by board-certified spine neurosurgeons. No significant differences were observed in patient and surgeon factors between the two groups, except for hyperlipidemia (13 vs 17, p=0.02). Furthermore, no significant differences were noted in perioperative complication rates between the two groups (7 [5.7%] vs 4 [5.7%], p=1). Cervical laminoplasty performed in a standardized manner by residents who received their surgical training in our hospital did not increase perioperative complication rates, and ensured the safety of patients. PMID- 28864407 TI - Military service and the risk of amyotrophic lateral sclerosis: A meta-analysis. AB - To explore the relationship between the risk of amyotrophic lateral sclerosis and exposure to overall military service, we conducted a search of articles relevant to military service and the risk of ALS that used human subjects and were published in English through 20 May 2016, using Ovid Medline and Embase databases. Studies specially investigating the risk of ALS for Gulf war veterans were excluded. Quality of the cohort and case-control studies was assessed according to the Newcastle-Ottawa Scale (NOS). Analysis of data and publication bias were performed with Review Manager 5.3. A total of 8 case-control studies and 3 cohort studies were included in the meta-analysis. Only two case-control studies were conducted in Japan, comparing to 9 studies conducted in Europe/USA. The NOS scores of all studies were >=6/9. The risk of ALS was significantly increased in military personnel compared to non-military personnel (pooled OR=1.29, 95% CI: 1.08-1.54, by random-effects model), with a moderate heterogeneity (P=0.01, I2=55%) due to some studies with lower quality, conformed by subgroup and sensitivity analysis. The present meta-analysis supports a positive association between overall military service and the risk of ALS. Additional studies are needed to find out related factors influencing the ALS risk of veterans, especially by gender and for specific geographic regions such as Asia. That would also do some favor to explore the etiology and mechanism of ALS. PMID- 28864408 TI - Spinal stereotactic body radiotherapy in the United States: A decade-long nationwide analysis of patient demographics, practice patterns, and trends over time. AB - Nationwide utilization of spinal stereotactic body radiotherapy (SBRT) is not known; to address this void, the National Cancer Data Base (NCDB) from 2004 to 2013 was used for analysis. Spinal SBRT was defined as 1-5 fractions (14-32Gy) delivered to the cervical, thoracic, lumbar or sacral spine. From 2004 to 2013, 1044 patients received spinal SBRT, most commonly in single-fraction (38%), three fraction (26%) and five-fractions (25%). Metastatic spinal disease most commonly originated from the lung (34%), kidney (14%), and blood (9%). The most common insurance status receiving spinal SBRT was private (44%) followed by Medicare (43%), with Medicaid (8%) a distant third. Fifty-six percent of patients were male, and 55% of patients were younger than age 65. 80% of patients were Caucasian, with 13% being African-American. The vast majority (74%) of patients had no Charlson/Deyo comorbidities. The incidence of spinal SBRT gradually increased over time, rising from 2% to 20% of cases from 2004 to 2013. Comprising only 1.4% of spinal metastases radiation in 2004, SBRT rose to a 5.8% share in 2013. In conclusion, SBRT for spine metastases in the United States has more than quadrupled in utilization over a recent ten-year span. Although the majority of spinal SBRT is multi-fraction, the most popular fractionation scheme was single fraction. It has been most commonly used for Caucasian men under age 65 with private/Medicare insurance and no comorbidities. By far the most common origin of spinal metastases treated by SBRT was the lung, followed by renal cancer. These results provide a baseline for further prospective investigation. PMID- 28864409 TI - Changes in brain amyloid-beta accumulation after donepezil administration. AB - Recent studies using the mouse model of Alzheimer's disease (AD) have shown that donepezil administration reduces brain amyloid-beta (Abeta) accumulation. This study investigated whether donepezil administration can reduce brain Abeta accumulation in human patients with AD. Ten patients with AD underwent two 11C Pittsburgh Compound B positron emission tomography sessions approximately one year apart to measure brain Abeta accumulation before and after donepezil treatment. Volumes-of-interest were placed on Abeta-preferred regions, and the standardized uptake value ratio (SUVR) was calculated considering the cerebellum as a reference region. Three and seven patients received 10mg and 5mg of donepezil, respectively. SUVR was significantly higher in the second than in the first session (P=0.026). This study showed that one year of donepezil administration does not reduce brain Abeta accumulation in human patients with AD. PMID- 28864410 TI - Aspiration thrombectomy with off-label distal access catheters in the distal intracranial vasculature. AB - BACKGROUND: As neurointerventionalists aim to treat occlusions in the ever more distal vasculature, off-label catheters (OLCs) have been adapted for aspiration thrombectomy. This may not be without its attendant risks. Recently issued, a letter from the FDA cautioned providers against using OLCs as substitutes for FDA cleared aspiration thrombectomy catheters, especially in the distal vasculature. In light of this, we evaluated the efficacy and safety of OLCs used for aspiration thrombectomy in the distal vasculature at our institution. METHODS: We retrospectively queried all patients who underwent thrombectomy at our institution between January 1, 2016 and March 1, 2017. Patients were screened for: (1) occlusion location in the distal vasculature (M2 or more distal) and (2) direct thrombus aspiration attempt with an OLC. Demographic, clinical, and procedural data were recorded. RESULTS: Eight patients were included for analysis (Table 1). The median admission NIHSS was 17 (IQR 13-23.3). Occlusion locations included left M2 (6/8), right M2 (1/8), and left M3 (1/8). The OLCs employed included the Stryker Catalyst 6 (5/8), Penumbra Velocity (2/8), and the MicroVention Sofia Plus (1/8). Direct thrombus aspiration was successful in 50% (4/8) of cases, though final TICI 2b-3 was achieved in all patients. There were no instances of symptomatic intracranial hemorrhage. Median NIHSS at discharge was 5 (IQR 0.8, 15). CONCLUSIONS: Aspiration thrombectomy with OLCs may be safe and effective in the distal vasculature. In light of the recent FDA warning regarding their use, further evaluation of OLCs in this capacity is warranted. PMID- 28864411 TI - "Revisions of the International Consensus Fukuoka Guidelines for the Management of IPMN of the Pancreas": Progress for twelve years. PMID- 28864412 TI - Role of the ribosomal quality control machinery in nucleocytoplasmic translocation of polyQ-expanded huntingtin exon-1. AB - The subcellular localization of polyQ-expanded huntingtin exon1 (Httex1) modulates polyQ toxicity in models of Huntington's disease. Using genome-wide screens in a yeast model system, we report that the ribosome quality control (RQC) machinery, recently implicated in neurodegeneration, is a key determinant for the nucleocytoplasmic distribution of Httex1-103Q. Deletion of the RQC genes, LTN1 or RQC1, caused the accumulation of Httex1-103Q in the nucleus through a process that required the CAT-tail tagging activity of Rqc2 and transport via the nuclear pore complex. We provide evidence that nuclear accumulation of Httex1 103Q enhances its cytotoxicity, suggesting that the RQC machinery plays an important role in protecting cells against the adverse effects of polyQ expansion proteins. PMID- 28864413 TI - Effect of sodium fluoride on the sperm mitochondrial DNA in mice. AB - Previous studies demonstrated that fluoride, as a widespread environmental pollutant, induced the reproductive toxicity at high dose. Besides the decrease of sperm characteristics like concentration, survival, and sperm motility, it was found that high fluoride induced the destructive mitochondrial ultrastructure and decreased ATP production from mitochondrial respiration. However, whether fluoride exposure can damage the mitochondrial DNA (mtDNA) of sperm is still unknown. In this study, 100 male mice were randomly divided into four groups 25 each, which were administrated with the distilled water containing 0, 25, 50 and 100 mg L-1 NaF, respectively for 60 days. After exposure, sperm mtDNA copy number was measured by real-time PCR, mtDNA integrity by acridine orange (AO) staining, and nuclear DNA (nDNA) integrity through long PCR amplification, as well as MTCYB and MTATP6 mutations by PCR and direct sequencing. The results showed that 100 mg L-1 NaF significantly increased sperm mtDNA copy number, and reduced nDNA integrity. There were no changes observed in mtDNA integrity, and mutations of MTCYB and MTATP6 between fluoride groups and the control group. These results indicated that along with low sperm quality, sperm mtDNA copy number is also a sensitive biomarker to reflect the sperm toxicity of fluoride. PMID- 28864414 TI - Structure of 4'-demethylepipodophyllotoxin in complex with tubulin provides a rationale for drug design. AB - Microtubules consists of alphabeta-tubulin heterodimers and are highly attractive targets for anti-cancer drugs. A broad range of agents have been identified to bind to tubulin and interfere with microtubule assembly, including colchicine binding site inhibitors (CBSIs). Podophyllotoxin is a CBSI that inhibits the assembly of microtubules. However, for a long time, the design and development of podophyllotoxin family drugs have been hindered by the lack of high-resolution structural information of the tubulin-agent complex. We report the first high resolution (2.8 A) structure of a podophyllotoxin family agent (4' demethylepipodophyllotoxin, DMEP) complexed with tubulin and revealed the detailed interactions between DMEP and tubulin. Comparison of this structure and other CBSIs explains previous results of the structure-activity-relationship (SAR) studies, and provides insights into the development of new podophyllotoxin derivatives targeting the colchicine site. PMID- 28864415 TI - Long pentraxin PTX3 mediates acute inflammatory responses against pneumococcal infection. AB - Streptococcus pneumoniae is an important human pathogen responsible for more than 2 million deaths annually worldwide. The airway epithelium acts as the first-line of defense against pneumococcal infections by regulating acute inflammation against invading pneumococcus. Despite the intact adaptive immunity, failure in early defense due to loss of pattern recognition receptors (PRRs) and/or acute phase proteins (APPs) results in detrimental damage and death. C-reactive protein (CRP), the first found APP, is a member of the pentraxin family of proteins and an important soluble PRR for pneumococcus. CRP and another short pentraxin, serum amyloid P, are critical for acute defense against pneumococcal infection. However, the role of the long pentraxin PTX3 in regulating pneumococcal infections is unknown. In this study, PTX3 expression was upregulated by pneumococcus in epithelial cells and in lungs of mice. In addition, PTX3 potentiated pneumococcal inflammation; overexpression of PTX3 enhanced pneumococcus-induced cytokine expression, whereas knock-down of PTX3 with siPTX3 inhibited the cytokine expression. Furthermore, PTX3 deficiency indeed ameliorated acute inflammation and protected mice against death following pneumococcal infection. Pneumococcal toxin pneumolysin was responsible for PTX3 expression and upregulated PTX3 expression via JNK MAPK signaling. These data implicate PTX3 as a novel therapeutic target for the control of acute inflammation by pneumococcus. PMID- 28864416 TI - Neuromedin U suppresses glucose-stimulated insulin secretion in pancreatic beta cells. AB - Neuromedin U (NMU), a highly conserved peptide in mammals, is implicated in energy homeostasis and glycemic control, and may also be involved in the regulation of adipoinsular axis function. However, the role of NMU in regulating insulin secretion has not been clearly established. In this study, we investigated the role of NMU in the regulation of insulin secretion both in vitro and in vivo. We found that NMU and NMU receptor (NMUR) 1 were expressed in mouse islets and beta cell-derived MIN6-K8 cells. In mice, NMU suppressed glucose stimulated insulin secretion (GSIS) both in vitro and in vivo. Additionally, an NMUR1 agonist inhibited GSIS in both MIN6-K8 cells and mice islets. Moreover, NMU attenuated intracellular Ca2+ influx in MIN6-K8 cells, potentially causing a decrease in insulin secretion. siNmu-transfected MIN6-K8 cells showed elevated GSIS. Treatment with anti-NMU IgG increased GSIS in isolated mouse pancreatic islets. These results suggested that NMU can act directly on beta cells through NMUR1 in an autocrine or paracrine fashion to suppress insulin secretion. Collectively, our results highlight the crucial role of NMU in suppressing pancreatic insulin secretion, and may improve our understanding of glucose homeostasis. PMID- 28864417 TI - TIF1beta is phosphorylated at serine 473 in colorectal tumor cells through p38 mitogen-activated protein kinase as an oxidative defense mechanism. AB - TIF1beta is a pleiotropic regulator of a diverse range of cellular processes such as DNA repair or gene repression in stem cells. This functional switch depends on phosphorylation at serine residue 473 and multiple pathways exist to accomplish this. However, the effects of exogenous reactive oxygen species (ROS) generated by bacterial flora and dietary metabolites in the colonic lumen or chemotherapy on TIF1beta have not been determined. We report here that exposure of colorectal cancer (CRC) cell lines DLD-1 and HCT116 to hydrogen peroxide specifically induces TIF1beta Ser473 phosphorylation. Hydrogen peroxide also induces primarily p38 MAPK and some p42/44 MAPK phosphorylation. Chemical inhibition of p38 MAPK and p42/44 MAPK reduced phosphorylation of TIF1beta serine 473 and increased CRC cell death upon peroxide exposure. Taken together, this suggests that it is primarily peroxide-induced p38 MAPK that mediates Ser473 phosphorylation and activation of TIF1beta to enable more efficient DNA repair to assist in tumor cell survival against exogenous ROS. PMID- 28864418 TI - The expression profiles of circRNAs in lung tissues from rats with lipopolysaccharide-induced acute respiratory distress syndrome: A microarray study. AB - The development of circular RNA (circRNA) microarray has facilitated the study of the role of circRNAs in regulating gene expression through a circRNA-miRNA-mRNA network. In our study, microarray was performed to detect the expression profiles of circRNAs during lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Twenty rats were randomly divided into 2 groups, the control group and the LPS group, 10 rats in each group. Three rats each from both groups were randomly selected. Using circRNA microarray data, we compared the circRNA expression profiles in lung tissues between these 6 rats. The most differentially expressed circRNA species from these profiles were validated and optimized as ARDS biomarkers and potential therapeutic targets. Overall, 395 and 562 circRNAs were significantly up- and down-regulated in LPS group vs. control group, respectively. Six up-regulated and 4 down-regulated circRNAs from the top 10 candidates were eventually selected to be validated. Among them, only 4 up regulated circRNAs (mmu_circRNA_19423, rno_circRNA_010489, rno_circRNA_011426, mmu_circRNA_30664) and 1 down-regulated circRNA (rno_circRNA_005564) exhibited significant validation. The 5 highest ranking target miRNAs of these 5 validated circRNAs were predicted according to the miRNA support vector regression method. This is the first study to investigate circRNA expression profile and a large number of aberrantly expressed circRNAs were revealed during ARDS. The significantly over- or under-expressed circRNA may represent a novel biomarker and be developed as a novel therapeutic target for the clinical management of ARDS. The results are preliminary and need to be confirmed in further well designed studies with larger sample size. PMID- 28864419 TI - Epiphycan is specifically expressed in cochlear supporting cells and is necessary for normal hearing. AB - The study of inner ear specific transcripts has revealed novel information about hereditary hearing loss and a mechanism of normal hearing. In this study, by analyzing a published cDNA library, we focused on Epiphycan (Epyc), a member of the small leucine-rich repeat proteoglycan family, whose transcript is enriched in the inner ear. Epyc mRNA was expressed abundantly and specifically in adult mice cochleae and was localized in supporting cells within the organ of Corti of both neonatal and adult mice. To examine the function of Epyc, we generated Epyc knockout (KO) mice using the CRISPR/Cas9 system. Epyc KO mice cochleae exhibited normal morphology. However, measurement of the auditory brain-stem response in Epyc KO mice revealed an elevated hearing threshold above 16 kHz frequency. This study suggests that Epyc is necessary for normal auditory function. PMID- 28864420 TI - Functional characterization of malaria parasites deficient in the K+ channel Kch2. AB - : K+ channels are integral membrane proteins, which contribute to maintain vital parameters such as the cellular membrane potential and cell volume. Malaria parasites encode two K+ channel homologues, Kch1 and Kch2, which are well conserved among members of the Plasmodium genus. In the rodent malaria parasite P. berghei, the functional significance of K+ channel homologue PbKch2 was studied using targeted gene knock-out. The knockout parasites were characterized in a mouse model in terms of growth-kinetics and infectivity in the mosquito vector. Furthermore, using a tracer-uptake technique with 86Rb+ as a K+ congener, the K+ transporting properties of the knockout parasites were assessed. RESULTS: Genetic disruption of Kch2 did not grossly affect the phenotype in terms of asexual replication and pathogenicity in a mouse model. In contrast to Kch1-null parasites, Kch2-null parasites were fully capable of forming oocysts in female Anopheles stephensi mosquitoes. 86Rb+ uptake in Kch2-deficient blood-stage P. berghei parasites (Kch2-null) did not differ from that of wild-type (WT) parasites. About two-thirds of the 86Rb+ uptake in WT and in Kch2-null parasites could be inhibited by K+ channel blockers and could be inferred to the presence of functional Kch1 in Kch2 knockout parasites. Kch2 is therefore not required for transport of K+ in P. berghei and is not essential to mosquito-stage sporogonic development of the parasite. PMID- 28864421 TI - Twinfilin 1 enhances milk bio-synthesis and proliferation of bovine mammary epithelial cells via the mTOR signaling pathway. AB - Twinfilin1 (TWF1) is an actin monomer-binding protein, which biological function has not yet been fully uncovered. In our previous study, we found by mass spectrometry analysis that TWF1 might be one of the major proteins responsible for milk bio-synthesis and proliferation of bovine mammary epithelial cells (BMECs). The purpose of this study was to explore the possible mechanism by which TWF1 regulates signaling pathways that enhance milk bio-synthesis and proliferation of BMECs. We first explored the effects of TWF1 on milk bio synthesis and cell proliferation, and analyzed the role of TWF1 on the protein levels of signaling molecules (mTOR, SREBP-1c and Cyclin D1) related to milk bio synthesis and cell proliferation. Then we determinate the impacts of amino acids (methionine and leucine) and hormones (estrogen and prolactin) on the expressions of TWF1. These results reveal that TWF1 is highly induced by the stimulation of amino acids and hormones and involved in regulation of milk bio-synthesis and cell proliferation via the mTOR pathway in BMECs. PMID- 28864422 TI - ALS-linked mutant SOD1 proteins promote Abeta aggregates in ALS through direct interaction with Abeta. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons. Aggregation of ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) is a hallmark of a subset of familial ALS (fALS). Recently, intracellular amyloid-beta (Abeta) is detected in motor neurons of both sporadic and familial ALS. We have previously shown that intracellular Abeta specifically interacts with G93A, an ALS-linked SOD1 mutant. However, little is known about the pathological and biological effect of this interaction in neurons. In this study, we have demonstrated that the Abeta-binding region is exposed on the SOD1 surface through the conformational changes due to misfolding of SOD1. Interestingly, we found that the intracellular aggregation of Abeta is enhanced through the direct interaction of Abeta with the Abeta-binding region exposed to misfolded SOD1. Ultimately, increased Abeta aggregation by this interaction promotes neuronal cell death. Consistent with this result, Abeta aggregates was three-fold higher in the brains of G93A transgenic mice than those of non Tg. Our study provides the first direct evidence that Abeta, an AD-linked factor, is associated to the pathogenesis of ALS and provides molecular clues to understand common aggregation mechanisms in the pathogenesis of neurodegenerative diseases. Furthermore, it will provide new insights into the development of therapeutic approaches for ALS. PMID- 28864423 TI - Alpha-mangostin inhibits both dengue virus production and cytokine/chemokine expression. AB - Since severe dengue virus (DENV) infection in humans associates with both high viral load and massive cytokine production - referred to as "cytokine storm", an ideal drug for treatment of DENV infection should efficiently inhibit both virus production and cytokine expression. In searching for such an ideal drug, we discovered that alpha-mangostin (alpha-MG), a major bioactive compound purified from the pericarp of the mangosteen fruit (Garcinia mangostana Linn), which has been used in traditional medicine for several conditions including trauma, diarrhea, wound infection, pain, fever, and convulsion, inhibits both DENV production in cultured hepatocellular carcinoma HepG2 and Huh-7 cells, and cytokine/chemokine expression in HepG2 cells. alpha-MG could also efficiently inhibit all four serotypes of DENV. Treatment of DENV-infected cells with alpha MG (20MUM) significantly reduced the infection rates of four DENV serotypes by 47 55%. alpha-MG completely inhibited production of DENV-1 and DENV-3, and markedly reduced production of DENV-2 and DENV-4 by 100 folds. Furthermore, it could markedly reduce cytokine (IL-6 and TNF-alpha) and chemokine (RANTES, MIP-1beta, and IP-10) transcription. These actions of alpha-MG are more potent than those of antiviral agent (ribavirin) and anti-inflammatory drug (dexamethasone). Thus, alpha-MG is potential to be further developed as therapeutic agent for DENV infection. PMID- 28864424 TI - Wheat streak mosaic virus coat protein is a host-specific long-distance transport determinant in oat. AB - Viral determinants involved in systemic infection of hosts by monocot-infecting plant viruses are poorly understood. Wheat streak mosaic virus (WSMV, genus Tritimovirus, family Potyviridae) exclusively infects monocotyledonous crops such as wheat, oat, barley, maize, triticale, and rye. Previously, we reported that WSMV CP amino acids 36-84 are expendable for systemic infection of wheat, maize, barley and rye. In this study, the role of coat protein (CP) in systemic infection of oat by WSMV was examined by using a series of viable deletion mutants. WSMV bearing deletions within or encompassing all of amino acids 36-57 efficiently infected oat, indicating that these amino acids are dispensable for systemic infection of oat. However, WSMV mutants lacking CP amino acids 58-84 or 85-100 failed to systemically infect oat. Furthermore, green fluorescent protein tagged WSMV mutants lacking CP amino acids 58-100 elicited local foci in oat but failed to enter the vasculature. These data suggest that CP amino acids 58-100 are required for systemic infection of oat by WSMV by specifically facilitating virus long-distance transport in oat. PMID- 28864425 TI - Functional RNA during Zika virus infection. AB - Zika virus (ZIKV; family Flaviviridae; genus Flavivirus) is a pathogenic mosquito borne RNA virus that currently threatens human health in the Americas, large parts of Asia and occasionally elsewhere in the world. ZIKV infection is often asymptomatic but can cause severe symptoms including congenital microcephaly and Guillain-Barre syndrome. The positive single-stranded RNA genome of the mosquito borne ZIKV requires effective replication in two evolutionary distinct hosts - mosquitoes and primates. In addition to some of the viral proteins, the ZIKV genomic RNA and functional RNAs produced thereof aid in the establishment of productive infection and the evasion of host cell antiviral responses. ZIKV has evolved to contain a nucleotide composition and RNA modifications, such as methylation and the formation of G-quadruplexes that allow effective replication in both hosts. Furthermore, a number of host factors interact with the viral genome to modulate RNA replication. Importantly, the ZIKV genome produces non coding subgenomic flavivirus RNA (sfRNA) due to stalling of host 5'- 3' ribonucleases on viral RNA structures in the 3' untranslated region (UTR). This sfRNA (sfRNA) exerts important proviral functions such as antagonizing the innate interferon response and RNA interference. Here, we discuss the ZIKV genomic RNA and functional RNAs thereof to assess their significance during ZIKV infection. Understanding the details of the ZIKV infection cycle will aid in the development of effective antiviral strategies and safe vaccines. PMID- 28864426 TI - IL-6-mediated signaling pathways limit Chlamydia muridarum infection and exacerbate its pathogenicity in the mouse genital tract. AB - Chlamydia muridarum induction of mouse hydrosalpinx, depending on both tubal infection and inflammation, has been used for investigating Chlamydia trachomatis pathogenesis. We now report that IL-6 both inhibits C. muridarum infection and exacerbates pathogenicity in the mouse genital tract. When intravaginally inoculated with a high dose of C. muridarum, IL-6-deficient mice developed more extensive genital tract infection with severe hydrosalpinx, suggesting that IL-6 is required for controlling the high dose infection but not essential for C. muridarum-induced pathology. However, at a low dose, IL-6-deficient mice still developed more extensive infection in the genital tract but no longer with significant pathology, suggesting that IL-6 is required for both controlling the low dose infection and exacerbating the low dose infection-induced pathology. The lack of hydrosalpinx in IL-6-deficient mice correlated with significantly reduced inflammatory infiltration in the oviduct tissue and decreased spleen CD4+ and CD8+ T cells that produce TNFalpha. Thus, IL-6-dependent pathways are important for both limiting chlamydial colonization in the genital tract mucosal tissues regardless of the infection doses and exacerbating chlamydial pathogenicity in the upper genital tract when IL-6-independent pathogenic mechanisms are not yet activated with a low infection dose. PMID- 28864428 TI - Legacy Effect of Delayed Blood Pressure-Lowering Pharmacotherapy in Middle-Aged Individuals Stratified by Absolute Cardiovascular Disease Risk: Protocol for a Systematic Review. AB - BACKGROUND: Many national and international guidelines recommend that the initiation of blood pressure (BP)-lowering drug treatment for the primary prevention of cardiovascular disease (CVD) should no longer be based on BP level alone, but on absolute cardiovascular risk. While BP-lowering drug treatment is beneficial in high-risk individuals at any level of elevated BP, clinicians are concerned about legacy effects on patients with low-to-moderate risk and mildly elevated BP who remain "untreated". OBJECTIVE: We aim to investigate the legacy effect of delayed BP-lowering pharmacotherapy in middle-aged individuals (45-65 years) with mildly elevated BP (systolic BP 140-159 mmHg and/or diastolic BP 90 99 mmHg) stratified by absolute risk for primary prevention of CVD, but particularly in the low-risk (<10% five-year absolute risk) group. METHODS: Randomized trials of BP-lowering therapy versus placebo or pretreated subjects in active comparator studies with posttrial follow-up will be identified using a 2 step process. First, randomized trials of BP-lowering therapy will be identified by (1) retrieving the references of trials included in published systematic reviews of BP-lowering therapy, (2) retrieving studies published by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), and (3) checking studies referenced in the 1993 World Health Organization/International Society of Hypertension meeting memorandum on BP management. Posttrial follow-up studies will then be identified by forward citation searching the randomized trials identified in step 1 through Web of Science. The search will include randomized controlled trials with at least 1-year in-trial period and a posttrial follow-up phase. Age is the major determinant of absolute cardiovascular risk, so the participants in our review will be restricted to middle-aged adults who are more likely to have a lower cardiovascular risk profile. The primary outcome will be all-cause mortality. Secondary outcomes will include cardiovascular mortality, fatal stroke, fatal myocardial infarction, and death due to heart failure. RESULTS: The searches for existing systematic reviews and BPLTTC studies were piloted and modified. The study is expected to be completed before June 2018. CONCLUSIONS: The findings of this study will contribute to the body of knowledge concerning the beneficial, neutral, or harmful effects of delayed BP-lowering drug treatment on the primary prevention of CVD in patients with mildly elevated BP and low-to-moderate CVD risk. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews: CRD42017058414; https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017058414 (Archived by WebCite(r) at http://www.webcitation.org/6t6sa8O2Q). PMID- 28864427 TI - Social Media for the Dissemination of Cochrane Child Health Evidence: Evaluation Study. AB - BACKGROUND: Health care providers value ready access to reliable synthesized information to support point-of-care decision making. Web-based communities, facilitated by the adoption of social media tools such as Facebook, Twitter, and YouTube, are increasingly being used for knowledge dissemination, bridging the gap between knowledge generation and synthesis and knowledge implementation. OBJECTIVE: Our objective was to implement and evaluate a structured social media strategy, using multiple platforms, to disseminate Cochrane Child Health evidence to health care providers caring for children. METHODS: Our social media strategy had three components: daily "tweets" using the Cochrane Child Health Twitter account, weekly WordPress blog posts, and a monthly journal club on Twitter ("tweet chat"). Each tweet, blog, and journal club shared Cochrane evidence on a child health topic. We evaluated the strategy through (1) Twitter and blog site analytics, (2) traceable link (Bitly) statistics, (3) Altmetric.com scores for promoted evidence, and (4) participant feedback. We also tracked the resources required to write the blog, tweet content, and manage the strategy. RESULTS: The 22-week social media strategy ran between November 2014 and April 2015. We created 25 blog posts, sent 585 tweets, and hosted 3 tweet chats. Monthly blog visits and views and Twitter account followers increased over time. During the study period, the blog received 2555 visitors and 3967 page views from a geographically diverse audience of health care providers, academics, and health care organizations. In total, 183 traceable Bitly links received 3463 clicks, and the Twitter account gained 469 new followers. The most visited and viewed blog posts included gastrointestinal topics (lactose avoidance), research on respiratory conditions (honey for cough and treatments for asthma), and maternal newborn care (skin-to-skin contact). On Twitter, popular topics were related to public health (vaccination) and pain management. We collected Altmetric.com scores for 61 studies promoted during the study period and recorded an average increase of 11 points. Research staff (n=3) contributed approximately 433 hours to promotion activities and planning (6.5 hours each per week) to implement the social media strategy, and study investigators reviewed all content (blog posts and tweets). CONCLUSIONS: This study provides empirical evidence on the use of a coordinated social media strategy for the dissemination of evidence to professionals providing health services to children and youth. The results and lessons learned from our study provide guidance for future knowledge dissemination activities using social media tools. PMID- 28864429 TI - Critical Care Is Guided by Why. PMID- 28864432 TI - Increasing Nurses' Palliative Care Communication Skills. PMID- 28864431 TI - Palliative Care Professional Development for Critical Care Nurses: A Multicenter Program. AB - BACKGROUND: Integrating palliative care into intensive care units (ICUs) requires involvement of bedside nurses, who report inadequate education in palliative care. OBJECTIVE: To implement and evaluate a palliative care professional development program for ICU bedside nurses. METHODS: From May 2013 to January 2015, palliative care advanced practice nurses and nurse educators in 5 academic medical centers completed a 3-day train-the-trainer program followed by 2 years of mentoring to implement the initiative. The program consisted of 8-hour communication workshops for bedside nurses and structured rounds in ICUs, where nurse leaders coached bedside nurses in identifying and addressing palliative care needs. Primary outcomes were nurses' ratings of their palliative care communication skills in surveys, and nurses' identification of palliative care needs during coaching rounds. RESULTS: Each center held at least 6 workshops, training 428 bedside nurses. Nurses rated their skill level higher after the workshop for 15 tasks (eg, responding to family distress, ensuring families understand information in family meetings, all P < .01 vs preworkshop). Coaching rounds in each ICU took a mean of 3 hours per month. For 82% of 1110 patients discussed in rounds, bedside nurses identified palliative care needs and created plans to address them. CONCLUSIONS: Communication skills training workshops increased nurses' ratings of their palliative care communication skills. Coaching rounds supported nurses in identifying and addressing palliative care needs. PMID- 28864433 TI - Determinants of Nurses' Use of Physical Restraints in Surgical Intensive Care Unit Patients. AB - BACKGROUND: Physical restraints are used in intensive care units, particularly among patients at risk for self-terminating necessary treatment interventions, including endotracheal tubes and invasive catheters. Assessments conducted by intensive care unit nurses often influence the collaborative decision to initiate and discontinue restraints in critical care patients. However, little is known about factors that influence the critical thought processes of intensive care unit nurses in determining use of restraints. OBJECTIVES: To describe nurses' determinants of initiation and discontinuation of restraints in surgical intensive care unit patients. METHODS: Semistructured interviews were conducted to identify and describe determinants of initiation and discontinuation of physical restraints. Demographic and employment data were collected via questionnaire. Interviews were recorded, transcribed, and analyzed by using conventional content analysis to establish categories and identify themes. RESULTS: A total of 13 nurses (mean age 43 [SD, 12] years, 92% female, mean of 18 [SD, 12] years of practice as a registered nurse, 69% bachelor of science in nursing) participated in the study. Content analysis revealed 3 general categories and 8 themes that indicated the thoughtful reflection processes nurses in a surgical intensive care unit use to determine use of restraints. CONCLUSIONS: Top priorities were ensuring patient safety and comfort. Nurses synthesized factors including practice experience, patient-specific behaviors and risk, and patients' need for devices in determining use of restraints. PMID- 28864434 TI - Psychotropic Drug Use in Physically Restrained, Critically Ill Adults Receiving Mechanical Ventilation. AB - BACKGROUND: Restraining therapies (physical or pharmacological) are used to promote the safety of both patients and health care workers. Some guidelines recommend nonpharmacological or pharmacological interventions be used before physical restraints in critically ill patients. OBJECTIVES: To characterize psychotropic drug interventions before and after use of physical restraints in critically ill adults receiving mechanical ventilation. METHODS: A single-center, prospective, observational study documenting psychotropic drug use and Sedation Agitation Scale (SAS) scores in the 2 hours before and the 6 hours after application of physical restraints. RESULTS: Ninety-three patients were restrained for a median of 21 hours (interquartile range, 9-70 hours). Thirty percent of patients did not receive a psychotropic drug or had a drug stopped or decreased before physical restraints were applied. More patients received a psychotropic drug intervention after use of physical restraints than before (86% vs 56%, P = .001). Administration of opioids was more common after the use of physical restraints (54% vs 20% of patients, P = .001) and accounted for more drug interventions (45% vs 29%, P = .001). Fifty patients had SAS scores from both time periods; 16% remained oversedated, 24% were appropriately sedated, and 16% remained agitated in both time periods. Patients became oversedated (20%), more agitated (10%), less agitated (8%), and less sedated (6%) after restraint use. CONCLUSIONS: Psychotropic drug interventions (mostly using opioids) were more common after use of physical restraints. Some patients may be physically restrained for anticipated treatment interference without consideration of pharmacological options and without documented agitation. PMID- 28864435 TI - Patterns of Instability Associated With Endotracheal Suctioning in Infants With Single-Ventricle Physiology. AB - BACKGROUND: In infants with single-ventricle physiology, endotracheal suctioning poses risks because of the instability between pulmonary and systemic blood flow. OBJECTIVE: To examine processes and adverse events associated with endotracheal suctioning in the first 48 hours after 3 surgical procedures: the Norwood or Norwood-Sano procedure, pulmonary artery banding, and the modified Blalock Taussig shunt. METHODS: Prospective observational study in a pediatric intensive care unit. RESULTS: Bedside nurses collected data from 211 episodes of endotracheal suctioning in 24 infants. Most (62%,130/211) suction episodes were unplanned; 38% (81/211) were planned. The most common reason for unplanned suctioning was arterial desaturation (48%, 62/130 episodes). The infants' oxygen saturation levels before suctioning ranged from 27% to 86%. Serious adverse events occurred in 9% (19/211) of suction episodes. In 8 (42%) of the episodes involving a serious adverse event, the patient received no additional intravenous bolus of analgesic or muscle relaxant before suctioning; in 8 episodes (42%), the patient received both an analgesic and a relaxant; in 3 episodes (16%), the patient received either an analgesic or a relaxant but not both. More adverse events occurred with open suctioning (68%, 13/19) than with closed suctioning (32%, 6/19). Most adverse events (68%, 13/19) occurred during the night shift. CONCLUSIONS: Significant hemodynamic instability and adverse events occur during routine suctioning in infants with single-ventricle physiology after surgical palliation. PMID- 28864436 TI - Enrollment Challenges in Critical Care Nursing Research. AB - BACKGROUND: Enrollment challenges for critical care research are common. Contributing factors include short enrollment windows, the crisis nature of critical illness, lack of research staff, unavailable legal proxy, family dynamics, and language barriers. OBJECTIVE: To describe enrollment statistics for an ongoing critical care nursing trial, barriers to recruitment, and strategies to enhance enrollment. METHODS: Two years' worth of recruitment and enrollment data from an oral care intervention trial in critically ill adults receiving mechanical ventilation at 1 hospital were analyzed. Recruitment logs include number of patients screened, eligible, enrolled, and declined and patients' sex, race, and ethnicity. RESULTS: Target enrollment (15.5 patients per month) was based on experience and historical data. Strategies implemented to promote enrollment included providing study personnel at least 18 hours per day for 7 days per week, regular rounds, communication with direct care staff, and Spanish consent processes. In 2 years, 6963 patients were screened; 1551 (22%) were eligible. Consent was sought from 366 (24% of eligible patients). Enrollment averaged 13.3 patients per month (86% of projected target). The main factor impeding enrollment was unavailability of a legal proxy to provide consent (88%). The refusal rates of white (11%), black (13%), and Hispanic (16%) patients did not differ significantly. However, those classified as Asian or as more than 1 race declined significantly more often (35%) than did white or black patients (P = .02). CONCLUSIONS: Unavailability of a legal proxy within a short enrollment window was the major challenge to enrollment. Various factors influenced consent decisions. Clinical study design requires more conservative estimates. PMID- 28864437 TI - Organizational Factors Associated With Perceived Quality of Patient Care in Closed Intensive Care Units. AB - BACKGROUND: Improving patient care quality in intensive care units is increasingly important as intensive care unit services account for a growing proportion of hospital services. Organizational factors associated with quality of patient care in such units have been identified; however, most were examined in isolation, making it difficult to assess the relative importance of each. Furthermore, though most intensive care units now use a closed model, little research has been done in this specific context. OBJECTIVES: To examine the relative importance of organizational factors associated with patient care quality in closed intensive care units. METHOD: In a national exploratory, cross sectional study focused on intensive care units at US Veterans Health Administration acute care hospitals, unit directors were surveyed about nurse and physician staffing, work resources and training, patient care coordination, rounding, and perceptions of patient care quality. Administrative records yielded data on patient volume and facility teaching status. Descriptive statistics, bivariate analyses, and regression modeling were used for data analysis. RESULTS: Sixty-nine completed surveys from directors of closed intensive care units were returned. Regression model results showed that better patient care coordination (beta = 0.43; P = .01) and having adequate work resources (beta = 0.26; P = .02) were significantly associated with higher levels of patient care quality in such units (R2 = 0.22). CONCLUSIONS: Augmenting work resources and/or focusing limited hospital resources on improving patient care coordination may be the most productive ways to improve patient care quality in closed intensive care units. PMID- 28864438 TI - Measuring Stroke Volume: Impedance Cardiography vs Phase-Contrast Magnetic Resonance Imaging. AB - BACKGROUND: Determination of cardiac output requires measurement of both heart rate and stroke volume. Techniques for measuring heart rate are widespread, and 1 technique for bedside monitoring of stroke volume is electrical impedance cardiography. OBJECTIVES: To determine the accuracy and precision of stroke volume measured via impedance cardiography and whether the technique can be used to detect trends. METHODS: Eleven healthy research participants (22-52 years old) were examined with simultaneous impedance cardiography and phase-contrast magnetic resonance imaging at rest and during exercise. Bland-Altman analysis with repeated-measures correction was used to compare stroke volumes determined with the 2 methods. The suitability of impedance cardiography for detecting trends in stroke volume was analyzed by using the Critchley radial limits of agreement method. RESULTS: Phase-contrast magnetic resonance imaging indicated a mean stroke volume of 87 (SD, 16) mL at rest; in 9 volunteers, it changed during exercise (P = .04 to P < .001); in 2 volunteers, it did not (P = .32, P = .06). For the range of stroke-volume measurements (60-122 mL), impedance cardiography yielded underestimates of stroke volumes at the low end (bias, -17 mL) and overestimates at the high end (bias, +17 mL; P < .001). Corresponding 95% limits of agreement were 64 mL, a 73% overestimate or underestimate of stroke volume at rest. Critchley radial limits of agreement indicated poor concordance of stroke volume trends. CONCLUSIONS: Impedance cardiography had low accuracy and precision in measuring absolute stroke volume and was a poor detector of stroke-volume trends. PMID- 28864439 TI - Post-Intensive Care Syndrome in Family Decision Makers of Long-term Acute Care Hospital Patients. AB - BACKGROUND: Family members of critically ill patients experience indications of post-intensive care syndrome, including anxiety, depression, and posttraumatic stress disorder. Despite increased use of long-term acute care hospitals for critically ill patients, little is known about the impact of long-term hospitalization on patients' family members. OBJECTIVES: To examine indications of post-intensive care syndrome, coping strategies, and health-related quality of life among family decision makers during and after patients' long-term hospitalization. METHODS: A single-center, prospective, longitudinal descriptive study was undertaken of family decision makers of adult patients admitted to long term acute care hospitals. Indications of post-intensive care syndrome and coping strategies were measured on the day of hospital admission and 30 and 60 days later. Health-related quality of life was measured by using the Short Form-36, version 2, at admission and 60 days later. RESULTS: The sample consisted of 30 family decision makers. On admission, 27% reported moderate to severe anxiety, and 20% reported moderate to severe depression. Among the decision makers, 10% met criteria for a provisional diagnosis of posttraumatic stress disorder. At admission, the mean physical summary score for quality of life was 47.8 (SD, 9.91) and the mean mental summary score was 48.00 (SD, 10.28). No significant changes occurred during the study period. Problem-focused coping was the most frequently used coping strategy at all time points. CONCLUSION: Family decision makers of patients in long-term acute care hospitals have a significant prevalence of indications of post-intensive care syndrome. PMID- 28864440 TI - Global ST-T Wave Changes: Ischemic vs Nonischemic. PMID- 28864441 TI - All GP referrals should be subject to clinical peer review, says NHS England. PMID- 28864442 TI - Integrated Noninvasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients With Stable Coronary Artery Disease. AB - BACKGROUND: It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. METHODS: MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF <1.8 mL.g-1.min-1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. RESULTS: A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38-2.31; P<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84-1.27; P=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9-3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3-2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6 1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3-0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. CONCLUSIONS: CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease. PMID- 28864443 TI - Conscious Sedation Versus General Anesthesia for Transcatheter Aortic Valve Replacement: Insights from the National Cardiovascular Data Registry Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. AB - BACKGROUND: Conscious sedation is used during transcatheter aortic valve replacement (TAVR) with limited evidence as to the safety and efficacy of this practice. METHODS: The National Cardiovascular Data Registry Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry was used to characterize the anesthesia choice and clinical outcomes of all US patients undergoing elective percutaneous transfemoral TAVR between April 1, 2014, and June 30, 2015. Raw and inverse probability of treatment-weighted analyses were performed to compare patients undergoing TAVR with general anesthesia with patients undergoing TAVR with conscious sedation on an intention to-treat basis for the primary outcome of in-hospital mortality, and secondary outcomes including 30-day mortality, in-hospital and 30-day death/stroke, procedural success, intensive care unit and hospital length-of-stay, and rates of discharge to home. Post hoc falsification end point analyses were performed to evaluate for residual confounding. RESULTS: Conscious sedation was used in 1737/10 997 (15.8%) cases with a significant trend of increasing usage over the time period studied (P for trend<0.001). In raw analyses, intraprocedural success with conscious sedation and general anesthesia was similar (98.2% versus 98.5%, P=0.31). The conscious sedation group was less likely to experience in-hospital (1.6% versus 2.5%, P=0.03) and 30-day death (2.9% versus 4.1%, P=0.03). Conversion from conscious sedation to general anesthesia was noted in 102 of 1737 (5.9%) of conscious sedation cases. After inverse probability of treatment weighted adjustment for 51 covariates, conscious sedation was associated with lower procedural success (97.9% versus 98.6%, P<0.001) and a reduced rate of mortality at the in-hospital (1.5% versus 2.4%, P<0.001) and 30-day (2.3% versus 4.0%, P<0.001) time points. Conscious sedation was associated with reductions in procedural inotrope requirement, intensive care unit and hospital length of stay (6.0 versus 6.5 days, P<0.001), and combined 30-day death/stroke rates (4.8% versus 6.4%, P<0.001). Falsification end point analyses of vascular complications, bleeding, and new pacemaker/defibrillator implantation demonstrated no significant differences between groups after adjustment. CONCLUSIONS: In US practice, conscious sedation is associated with briefer length of stay and lower in-hospital and 30-day mortality in comparison with TAVR with general anesthesia in both unadjusted and adjusted analyses. These results suggest the safety of conscious sedation in this population, although comparative effectiveness analyses using observational data cannot definitively establish the superiority of one technique over another. PMID- 28864444 TI - Hypoplastic Left Heart Syndrome With Intact or Restrictive Atrial Septum: A Report From the International Fetal Cardiac Intervention Registry. PMID- 28864445 TI - Dissection of the molecular circuitry controlling virulence in Francisella tularensis. AB - Francisella tularensis, the etiological agent of tularemia, is one of the most infectious bacteria known. Because of its extreme pathogenicity, F. tularensis is classified as a category A bioweapon by the US government. F. tularensis virulence stems from genes encoded on the Francisella pathogenicity island (FPI). An unusual set of Francisella regulators-the heteromeric macrophage growth locus protein A (MglA)-stringent starvation protein A (SspA) complex and the DNA binding protein pathogenicity island gene regulator (PigR)-activates FPI transcription and thus is essential for virulence. Intriguingly, the second messenger, guanosine-tetraphosphate (ppGpp), which is produced during infection, is also involved in coordinating Francisella virulence; however, its role has been unclear. Here we identify MglA-SspA as a novel ppGpp-binding complex and describe structures of apo- and ppGpp-bound MglA-SspA. We demonstrate that MglA SspA, which binds RNA polymerase (RNAP), also interacts with the C-terminal domain of PigR, thus anchoring the (MglA-SspA)-RNAP complex to the FPI promoter. Furthermore, we show that MglA-SspA must be bound to ppGpp to mediate high affinity interactions with PigR. Thus, these studies unveil a novel pathway different from those described previously for regulation of transcription by ppGpp. The data also indicate that F. tularensis pathogenesis is controlled by a highly interconnected molecular circuitry in which the virulence machinery directly senses infection via a small molecule stress signal. PMID- 28864446 TI - The potential of the microbiota to influence vaccine responses. AB - After clean water, vaccines are the primary public health intervention providing protection against serious infectious diseases. Antigen-specific antibody mediated responses play a critical role in the protection conferred by vaccination; however these responses are highly variable among individuals. In addition, vaccine immunogenicity is frequently impaired in developing world populations, for reasons that are poorly understood. Although the factors that are associated with interindividual variation in vaccine responses are likely manifold, emerging evidence from mouse models and studies in human populations now suggests that the gut microbiome plays a key role in shaping systemic immune responses to both orally and parenterally administered vaccines. Herein, we review the evidence to date that the microbiota can influence vaccine responses and discuss the potential mechanisms through which these effects may be mediated. In addition, we highlight the gaps in this evidence and suggest future directions for research. PMID- 28864447 TI - Use of parecoxib by continuous subcutaneous infusion for cancer pain in a hospice population. AB - OBJECTIVES: To characterise the use of the parenteral non-steroidal anti inflammatory drug parecoxib when given by continuous subcutaneous infusion (CSCI) in a hospice population. Clinical experience suggests parecoxib CSCI may be of benefit in this population, but empirical evidence in relation to its safety and efficacy is lacking. METHODS: Retrospective chart review of patients with a cancer diagnosis receiving parecoxib CSCI from 2008 to 2013 at the Marie Curie Hospice, Belfast. Data were collected on treatment regime, tolerability and, in patients receiving at least 7 days treatment, baseline opioid dose and changes in pain scores or opioid rescue medication requirements. RESULTS: Parecoxib CSCI was initiated in 80 patients with a mean administration of 17.9 days (median 11, range 1-94). When used for a period of 7 days, there was a statistically significant reduction in pain scores (p=0.002) and in the number of rescue opioid doses required (p=0.001), but no statistically significant opioid-sparing effect (p=0.222). It was generally well tolerated, although gastrointestinal, renal adverse effects and local site irritation were reported. CONCLUSIONS: Parecoxib may have a valuable place in the management of cancer pain, especially towards the end of life when oral administration is no longer possible and CSCI administration is relied on. Further studies into the efficacy and tolerability of parecoxib CSCI are merited. PMID- 28864448 TI - Discussion and documentation of future care: a before-and-after study examining the impact of an alternative approach to recording treatment decisions on advance care planning in an acute hospital. AB - OBJECTIVE: To determine whether discussion and documentation of decisions about future care was improved following the introduction of a new approach to recording treatment decisions: the Universal Form of Treatment Options (UFTO). METHODS: Retrospective review of the medical records of patients who died within 90 days of admission to oncology or respiratory medicine wards over two 3-month periods, preimplementation and postimplementation of the UFTO. A sample size of 70 per group was required to provide 80% power to observe a change from 15% to 35% in discussion or documentation of advance care planning (ACP), using a two sided test at the 5% significance level. RESULTS: On the oncology ward, introduction of the UFTO was associated with a statistically significant increase in cardiopulmonary resuscitation decisions documented for patients (pre-UFTO 52% to post-UFTO 77%, p=0.01) and an increase in discussions regarding ACP (pre-UFTO 27%, post-UFTO 49%, p=0.03). There were no demonstrable changes in practice on the respiratory ward. Only one patient came into hospital with a formal ACP document. CONCLUSIONS: Despite patients' proximity to the end-of-life, there was limited documentation of ACP and almost no evidence of formalised ACP. The introduction of the UFTO was associated with a change in practice on the oncology ward but this was not observed for respiratory patients. A new approach to recording treatment decisions may contribute to improving discussion and documentation about future care but further work is needed to ensure that all patients' preferences for treatment and care at the end-of-life are known. PMID- 28864449 TI - Feasibility and acceptability of a patient-reported outcome intervention in chronic heart failure. AB - : Patients with chronic heart failure (CHF) have symptoms and concerns which are inadequately addressed. Patient-reported outcome measures (PROMs) can potentially improve the identification and management of advanced symptoms and palliative concerns. However, these have not been used in CHF. OBJECTIVES: To examine the feasibility and acceptability of using a PROM-the Integrated Palliative care Outcome Scale (IPOS)-together with heart failure nurse education and training to improve the identification and management of symptoms and concerns among patients with CHF. METHODS: A parallel, mixed methods design with an embedded qualitative component was used to examine the feasibility of recruitment, retention, intervention adherence/compliance and follow-up assessment completion (symptom burden, quality of life, psychological well-being). Patient and nurse qualitative semistructured interviews explored intervention and study design feasibility and its acceptability. RESULTS: Conversion to consent was 46.9% (372 screened, 81 approached, 38 recruited). 66% of patient participants completed the IPOS; 6% of IPOS questionnaire items were missing (non-response). Over two-thirds (65.6%) of these missing items related to three patients. No item was consistently missing; appetite was the most frequent missing item (1.4%). 92% of participants who completed the IPOS completed all follow-up assessments (1-2 days, 1-2 weeks and 4 6 weeks post-IPOS completion) with no missing data. The a priori feasibility objectives were met. Patients and nurses reported the intervention and study design feasible and acceptable. CONCLUSIONS: A palliative-specific PROM-based intervention is feasible and acceptable to both patients with CHF and nurses in nurse-led disease management clinics for the purposes of both clinical care and research. PMID- 28864452 TI - Addressing Disparities: The 10th Anniversary of the AACR Cancer Health Disparities Conference. PMID- 28864453 TI - No Association of Vitamin D Pathway Genetic Variants with Cancer Risks in a Population-Based Cohort of German Older Adults. AB - Background: Several investigations assessed the association of vitamin D receptor (VDR) SNPs with cancer risk. Less is known about the implications of other vitamin D pathway SNPs on cancer risk.Methods: In a population-based cohort study of 9,949 German older adults, we used Cox regression to assess the association of 6 SNPs in the VDR, vitamin D-binding protein (GC), 7-dehydrocholesterol reductase (DHCR7), vitamin D 25-hydroxylase (CYP2R1), and vitamin D 24-hydroxylase (CYP24A1) genes with total and site-specific cancer incidence endpoints.Results: Overall, no association of SNPs with cancer incidence endpoints was observed, except for a genotype score based on SNPs associated with lower 25(OH)D, which was associated with higher lung cancer risk [HR, 1.20; 95% confidence intervals (CI), 1.03-1.39], although this was no longer significant after correcting for multiple testing.Conclusions: Our data provide little to no evidence of a major influence of vitamin D genetic predisposition on cancer risks.Impact: Large-scale genetic epidemiology consortia and meta-analysis of smaller published studies are needed to verify a potential modest influence of genetic variation in the association of vitamin D with the risk of cancer. Cancer Epidemiol Biomarkers Prev; 26(9); 1459-61. (c)2017 AACR. PMID- 28864454 TI - Genome-Wide Testing of Exonic Variants and Breast Cancer Risk in the California Teachers Study. AB - Background: Few studies have focused on the relationship of exonic variation with breast cancer and subtypes defined by tumor markers: estrogen receptor (ER), progesterone receptor (PR), and HER2.Methods: We genotyped 1,764 breast cancer patients and 1,400 controls from the California Teachers Study cohort using the Infinium HumanExome Beadchip. Individual variant and gene-based analyses were conducted for overall breast cancer and by individual tumor marker subtype.Results: No exonic variants or gene-based analyses were statistically significantly associated with breast cancer overall or by ER-, PR-, or HER2 defined subtype.Conclusions: We did not detect any novel statistically significant exonic variants with overall breast cancer risk or by subtype.Impact: Exonic variants in the exome chip may not be associated with overall breast cancer or subtype susceptibility. Cancer Epidemiol Biomarkers Prev; 26(9); 1462 5. (c)2017 AACR. PMID- 28864455 TI - Genetic Ancestry Is not Associated with Breast Cancer Recurrence or Survival in U.S. Latina Women Enrolled in the Kaiser Permanente Pathways Study. AB - Background: The U.S. Hispanic/Latino population is heterogeneous both socioculturally and by the proportion of European, Indigenous American, and African ancestry of the regions from which individuals originate. A previous study reported that genetic ancestry was associated with breast cancer survival among Latinas, independent of sociodemographic and tumor characteristics, suggesting that a genetic factor associated with ancestry may affect breast cancer survival.Methods: We evaluated the association of genetic ancestry with breast cancer outcomes among 506 Latina women with invasive breast cancer in the Pathways Study, a cohort study within Kaiser Permanente, an integrated health care delivery system. Proportional hazards models were used to assess the effect of ancestry on breast cancer recurrence (53 events), breast cancer-specific mortality (31 events) and all-cause mortality (54 events), with a mean follow-up time of 6 years.Results: Indigenous American ancestry was not associated with breast cancer recurrence [HR = 1.00 per 10% increase; 95% confidence interval (CI), 0.86-1.16], breast cancer mortality (HR = 0.95; 95% CI, 0.77-1.17), or all cause mortality (HR = 0.93; 95% CI, 0.80-1.08). Adjustment for sociodemographic variables, tumor characteristics, and treatment did not alter the associations.Conclusions: Our results suggest that previously reported differences in breast cancer survival by genetic ancestry may be overcome by improving health care access and/or quality.Impact: Improving health care access and quality may reduce breast cancer disparities among U.S. Latinas. Cancer Epidemiol Biomarkers Prev; 26(9); 1466-9. (c)2017 AACR. PMID- 28864457 TI - Gestational Diabetes Mellitus and Incident Invasive Breast Cancer-Letter. PMID- 28864456 TI - History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium. AB - Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients.Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes.Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced).Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival.Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470-3. (c)2017 AACR. PMID- 28864458 TI - Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation. AB - Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions (P < 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney U test, P < 1 * 10-16). We focus on the application to epilepsy genes; however, the framework is applicable to disease genes beyond epilepsy. PMID- 28864459 TI - RNA editing in bacteria recodes multiple proteins and regulates an evolutionarily conserved toxin-antitoxin system. AB - Adenosine (A) to inosine (I) RNA editing is widespread in eukaryotes. In prokaryotes, however, A-to-I RNA editing was only reported to occur in tRNAs but not in protein-coding genes. By comparing DNA and RNA sequences of Escherichia coli, we show for the first time that A-to-I editing occurs also in prokaryotic mRNAs and has the potential to affect the translated proteins and cell physiology. We found 15 novel A-to-I editing events, of which 12 occurred within known protein-coding genes where they always recode a tyrosine (TAC) into a cysteine (TGC) codon. Furthermore, we identified the tRNA-specific adenosine deaminase (tadA) as the editing enzyme of all these editing sites, thus making it the first identified RNA editing enzyme that modifies both tRNAs and mRNAs. Interestingly, several of the editing targets are self-killing toxins that belong to evolutionarily conserved toxin-antitoxin pairs. We focused on hokB, a toxin that confers antibiotic tolerance by growth inhibition, as it demonstrated the highest level of such mRNA editing. We identified a correlated mutation pattern between the edited and a DNA hard-coded Cys residue positions in the toxin and demonstrated that RNA editing occurs in hokB in two additional bacterial species. Thus, not only the toxin is evolutionarily conserved but also the editing itself within the toxin is. Finally, we found that RNA editing in hokB increases as a function of cell density and enhances its toxicity. Our work thus demonstrates the occurrence, regulation, and functional consequences of RNA editing in bacteria. PMID- 28864460 TI - A germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents. AB - Defects in genes involved in DNA damage repair (DDR) pathway are emerging as novel biomarkers and targets for new prostate cancer drug therapies. A previous report revealed an association between an exceptional response to cisplatin treatment and a somatic loss of heterozygosity (LOH) of FANCA in a patient with metastatic prostate cancer who also harbored a germline FANCA variant (S1088F). Although germline FANCA mutations are the most frequent alterations in patients with Fanconi anemia, germline alterations are less common in prostate cancer. We hypothesized that the germline S1088F FANCA variant in combination with FANCA LOH was deleterious for FANCA function and contributed to the patient's exceptional response to cisplatin. We show that although it properly localizes to the nucleus, the S1088F FANCA mutant protein disrupts the FANC protein complex resulting in increased sensitivity to DNA damaging agents. Because molecular stratification is emerging as a strategy for treating men with metastatic, castrate-resistant prostate cancer harboring specific DDR gene defects, our findings suggest that more biomarker studies are needed to better define clinically relevant germline and somatic alterations. PMID- 28864461 TI - Somatic uniparental disomy of Chromosome 16p in hemimegalencephaly. AB - Hemimegalencephaly (HME) is a heterogeneous cortical malformation characterized by enlargement of one cerebral hemisphere. Somatic variants in mammalian target of rapamycin (mTOR) regulatory genes have been implicated in some HME cases; however, ~70% have no identified genetic etiology. Here, we screened two HME patients to identify disease-causing somatic variants. DNA from leukocytes, buccal swabs, and surgically resected brain tissue from two HME patients were screened for somatic variants using genome-wide genotyping arrays or sequencing of the protein-coding regions of the genome. Functional studies were performed to evaluate the molecular consequences of candidate disease-causing variants. Both HME patients evaluated were found to have likely disease-causing variants in DNA extracted from brain tissue but not in buccal swab or leukocyte DNA, consistent with a somatic mutational mechanism. In the first case, a previously identified disease-causing somatic single nucleotide in MTOR was identified. In the second case, we detected an overrepresentation of the alleles inherited from the mother on Chromosome 16 in brain tissue DNA only, indicative of somatic uniparental disomy (UPD) of the p-arm of Chromosome 16. Using methylation analyses, an imprinted locus on 16p spanning ZNF597 was identified, which results in increased expression of ZNF597 mRNA and protein in the brain tissue of the second case. Enhanced mTOR signaling was observed in tissue specimens from both patients. We speculate that overexpression of maternally expressed ZNF597 led to aberrant hemispheric development in the patient with somatic UPD of Chromosome 16p possibly through modulation of mTOR signaling. PMID- 28864462 TI - Rapid whole-genome sequencing identifies a novel GABRA1 variant associated with West syndrome. AB - A 9-mo-old infant was admitted with infantile spasms that improved on administration of topiramate and steroids. He also had developmental delay, esotropia, and hypsarrhythmia on interictal electroencephalogram (EEG), and normal brain magnetic resonance imaging (MRI). West syndrome is the triad of infantile spasms, interictal hypsarrhythmia, and mental retardation. Rapid trio whole-genome sequencing (WGS) revealed a novel, likely pathogenic, de novo variant in the gene encoding gamma-aminobutyric acid (GABA) type A receptor, alpha1 polypeptide (GABRA1 c.789G>A, p.Met263Ile) in the proband. GABRA1 mutations have been associated with early infantile epileptic encephalopathy type 19 (EIEE19). We suggest that GABRA1 p.Met263Ile is associated with a distinct West syndrome phenotype. PMID- 28864463 TI - Screening for rheumatic heart disease: is a paradigm shift required? AB - This focused review presents a critical appraisal of the World Heart Federation criteria for the echocardiographic diagnosis of rheumatic heart disease (RHD) and its performance in African RHD screening programmes. It identifies various logistical and methodological problems that negatively influence the current guideline's performance. The authors explore novel RHD screening methodology that could address some of these shortcomings and if proven to be of merit, would require a paradigm shift in the approach to the echocardiographic diagnosis of subclinical RHD. PMID- 28864464 TI - Use of the CHA2DS2VASc score to reduce utilisation of transoesophageal echocardiography prior to ablation for atrial fibrillation. AB - Transoesophageal echocardiography (TOE) is frequently performed prior to atrial fibrillation (AF) ablation to exclude left atrial appendage (LAA) thrombus. However, patients undergoing AF ablation are usually anticoagulated, thus making the presence of thrombus unlikely in most cases. This study aimed to determine whether the CHA2DS2VASc scoring system can be used to identify patients that do not require TOE prior to AF ablation. In this single-centre retrospective study, local institutional and primary care databases and electronic patient records were searched to identify patients that had undergone TOE prior to AF ablation. Patient demographics, CHA2DS2VASc score, TOE findings and anticoagulation status were collected for analysis. Over a 7-year period (2008-2014), 332 patients (age 57 +/- 10 years; 74% male) underwent TOE prior to proposed AF ablation. CHA2DS2VASc scores of 0, 1, 2 and >2 were found in 39, 34, 15 and 12% of patients, respectively. The prevalence of LAA thrombus was 0.6% (2 patients) and these 2 patients had risk scores of 2 and 4. No patients with a score of 0 or 1 had LAA thrombus. Patients that are classed as low risk by the CHA2DS2VASc score do not require a pre-ablation TOE to screen for LAA thrombus provided they are adequately anticoagulated. This would lead to a significant reduction in health care expenditures by reducing unnecessary TOE requests and thereby improve patient experience. PMID- 28864467 TI - Upregulation of Epac-1 in Hepatic Stellate Cells by Prostaglandin E2 in Liver Fibrosis Is Associated with Reduced Fibrogenesis. AB - Exchange protein activated by cAMP (Epac-1) is an important signaling mechanism for cAMP-mediated effects, yet factors that change Epac-1 levels are unknown. Such factors are relevant because it has been postulated that Epac-1 directly affects fibrogenesis. Prostaglandin E2 (PGE2) is a well-known cAMP activator, and we therefore studied the effects of this cyclo-oxygenase product on Epac-1 expression and on fibrogenesis within the liver. Liver fibrosis was induced by 8 weeks carbon tetrachloride (CCL4) administration to mice. In the last 2 weeks, mice received vehicle, PGE2, the cyclo-oxygenase-2 inhibitor niflumic acid (NFA), or PGE2 coupled to cell-specific carriers to hepatocytes, Kupffer cells, or hepatic stellate cells (HSC). Results showed antifibrotic effects of PGE2 and profibrotic effects of NFA in CCL4 mice. Western blot analysis revealed reduced Epac-1 protein expression in fibrotic livers of mice and humans compared with healthy livers. PGE2 administration to fibrotic mice completely restored intrahepatic Epac-1 levels and also led to reduced Rho kinase activity, a downstream target of Epac-1. Cell-specific delivery of PGE2 to either hepatocytes, Kupffer cells, or HSC identified the latter cell as the key player in the observed effects on Epac-1 and Rho kinase. No significant alterations in protein kinase A expressions were found. In primary isolated HSC, PGE2 elicited Rap1 translocation reflecting Epac-1 activation, and Epac-1 agonists attenuated platelet-derived growth factor-induced proliferation and migration of these cells. These studies demonstrate that PGE2 enhances Epac-1 activity in HSC, which is associated with significant changes in (myo)fibroblast activities in vitro and in vivo. Therefore, Epac-1 is a potential target for antifibrotic drugs. PMID- 28864468 TI - A Model of the Block of Voltage-Gated Potassium Kv4.2 Ionic Currents by 4 Aminopyridine. AB - Voltage clamp recordings of macroscopic currents were made from rat potassium gated potassium 4.2(Kv4.2) channels expressed in human embryonic kidney (HEK293) cells with the main goals of quantifying the concentration, time, and voltage dependence of the block and to generate a state model that replicates the features of the block. When applied either externally or internally, the block of Kv4.2 currents by 4-aminopyridine (4AP) occurs at the holding potential (-80 mV), is affected by the stimulus frequency, and is relieved by membrane depolarization. The Kd for the tonic block at -80 mV was 0.9 +/- 0.07 mM and was consistent with 1:1 binding. Relief of block during a step to 50 mV was well fitted by a single exponential with a time constant of ~40 milliseconds. At -80 mV, the association rate constant was 0.08 mM-1 s-1, and the off-rate was 0.08 s 1 The state model replicates the features of the experimental data reasonably well by assuming that 4AP binds only to closed states, that 4AP binding and inactivation are mutually exclusive processes, and that the activation of closed bound channels is the same as for closed channels. Since the open channel has a very low or no affinity for 4AP, channel opening promotes the unbinding of 4AP, which accounts for the reverse use dependence of the block. PMID- 28864466 TI - The Evolving Complexity of the Podocyte Cytoskeleton. AB - Podocytes exhibit a unique cytoskeletal architecture that is fundamentally linked to their function in maintaining the kidney filtration barrier. The cytoskeleton regulates podocyte shape, structure, stability, slit diaphragm insertion, adhesion, plasticity, and dynamic response to environmental stimuli. Genetic mutations demonstrate that even slight impairment of the podocyte cytoskeletal apparatus results in proteinuria and glomerular disease. Moreover, mechanisms underpinning all acquired glomerular pathologies converge on disruption of the cytoskeleton, suggesting that this subcellular structure could be targeted for therapeutic purposes. This review summarizes our current understanding of the function of the cytoskeleton in podocytes and the associated implications for pathophysiology. PMID- 28864469 TI - Project Haiku. PMID- 28864470 TI - The G-Box Transcriptional Regulatory Code in Arabidopsis. AB - Plants have significantly more transcription factor (TF) families than animals and fungi, and plant TF families tend to contain more genes; these expansions are linked to adaptation to environmental stressors. Many TF family members bind to similar or identical sequence motifs, such as G-boxes (CACGTG), so it is difficult to predict regulatory relationships. We determined that the flanking sequences near G-boxes help determine in vitro specificity but that this is insufficient to predict the transcription pattern of genes near G-boxes. Therefore, we constructed a gene regulatory network that identifies the set of bZIPs and bHLHs that are most predictive of the expression of genes downstream of perfect G-boxes. This network accurately predicts transcriptional patterns and reconstructs known regulatory subnetworks. Finally, we present Ara-BOX-cis (araboxcis.org), a Web site that provides interactive visualizations of the G-box regulatory network, a useful resource for generating predictions for gene regulatory relations. PMID- 28864471 TI - Peripheral Deletion of CD8 T Cells Requires p38 MAPK in Cross-Presenting Dendritic Cells. AB - Peripheral tolerance mechanisms exist to prevent autoimmune destruction by self reactive T cells that escape thymic deletion. Dominant tolerance imposed by CD4+Foxp3+ T regulatory cells can actively control autoaggressive T cell responses. Tolerance mechanisms that act endogenous to the T cell also exist. These mechanisms include T cell inactivation (anergy) and deletion. A major difference between anergic T cells and T cells undergoing peripheral deletion is the capacity of the latter to still signal through MAPKs upon TCR stimulation, suggesting these signals may be required for T deletion. In this study, we used several different models of CD8 T cell deletion to investigate the contribution of MAPK activation. Using chemical inhibitors, we established that inhibition of p38, but not ERK or JNK, rescue T cells from undergoing peripheral deletion both in vitro and in vivo. Using T cell-specific murine lines genetically altered in expression of p38alpha, and mice in which p38alpha was deleted only in CD11c expressing cells, we surprisingly found that CD8 T cell-intrinsic p38alpha activation was not responsible for increased survival, but rather that inhibition of p38alpha in the Ag-presenting dendritic cells prevented CD8 T cell deletion. PMID- 28864472 TI - The Stimulation of Macrophages with TLR Ligands Supports Increased IL-19 Expression in Inflammatory Bowel Disease Patients and in Colitis Models. AB - IL-19, a member of the IL-10 cytokine family that signals through the IL-20 receptor type I (IL-20Ralpha:IL-20Rbeta), is a cytokine whose function is not completely known. In this article, we show that the expression of IL19 in biopsies of patients with active ulcerative colitis was increased compared with patients with quiescent ulcerative colitis and that colitis was attenuated in IL 19-deficient mice. The disruption of the epithelial barrier with dextran sodium sulfate leads to increased IL-19 expression. Attenuated colitis in IL-19 deficient animals was associated with reduced numbers of IL-6-producing macrophages in the inflamed colonic lamina propria. Microbial-driven expression of IL-19 by intestinal macrophages may contribute to the pathogenesis of inflammatory bowel disease. PMID- 28864473 TI - HVEM Imprints Memory Potential on Effector CD8 T Cells Required for Protective Mucosal Immunity. AB - Mucosal immunity to reinfection with a highly virulent virus requires the accumulation and persistence of memory CD8 T cells at the site of primary infection. These cells may derive from memory precursor effector cells (MPECs), which are distinct from short-lived effector cells that provide acute protection but are often destined to die. Using respiratory virus infection, we show that herpes virus entry mediator (HVEM; TNFRSF14), a member of the TNF receptor superfamily, provides key signals for MPEC persistence. HVEM-deficient CD8 T cells expanded normally but were skewed away from MPECs with resultant poor development of circulating and lung-resident memory cells. HVEM was selectively expressed on MPECs whereas MPECs deficient in HVEM failed to survive in adoptive transfer recipients. As a consequence, HVEM-deficient recipients failed to afford protection against respiratory reinfection with influenza virus. HVEM therefore represents a critical signal for MPECs and development of protective mucosal CD8 T cell memory. PMID- 28864475 TI - Monitoring C5aR2 Expression Using a Floxed tdTomato-C5aR2 Knock-In Mouse. AB - The biological significance of C5a receptor [(C5aR)2/C5L2], a seven-transmembrane receptor binding C5a and C5adesArg, remains ill-defined. Specific ligation of C5aR2 inhibits C5a-induced ERK1/2 activation, strengthening the view that C5aR2 regulates C5aR1-mediated effector functions. Although C5aR2 and C5aR1 are often coexpressed, a detailed picture of C5aR2 expression in murine cells and tissues is still lacking. To close this gap, we generated a floxed tandem dye (td)Tomato C5aR2 knock-in mouse that we used to track C5aR2 expression in tissue-residing and circulating immune cells. We found the strongest C5aR2 expression in the brain, bone marrow, and airways. All myeloid-derived cells expressed C5aR2, although with different intensities. C5aR2 expression in blood and tissue neutrophils was strong and homogeneous. Specific ligation of C5aR2 in neutrophils from tdTomato-C5aR2 mice blocked C5a-driven ERK1/2 phosphorylation, demonstrating functionality of C5aR2 in the reporter mice. In contrast to neutrophils, we found tissue-specific differences in C5aR2 expression in eosinophils, macrophages, and dendritic cell subsets. Naive and activated T cells stained negative for C5aR2, whereas B cells from different tissues homogeneously expressed C5aR2. Also, NK cell subsets in blood and spleen strongly expressed C5aR2. Activation of C5aR2 in NK cells suppressed IL-12/IL-18-induced IFN-gamma production. Intratracheal IL-33 challenge resulted in decreased C5aR2 expression in pulmonary eosinophils and monocyte-derived dendritic cells. In summary, we provide a detailed map of murine C5aR2 immune cell expression in different tissues under steady-state conditions and upon pulmonary inflammation. The C5aR2 knock-in mouse will help to reliably track and conditionally delete C5aR2 expression in experimental models of inflammation. PMID- 28864474 TI - The Scaffolding Protein IQGAP1 Interacts with NLRC3 and Inhibits Type I IFN Production. AB - Sensing of cytosolic nucleotides is a critical initial step in the elaboration of type I IFN. One of several upstream receptors, cyclic GMP-AMP synthase, binds to cytosolic DNA and generates dicyclic nucleotides that act as secondary messengers. These secondary messengers bind directly to stimulator of IFN genes (STING). STING recruits TNFR-associated NF-kappaB kinase-binding kinase 1 which acts as a critical node that allows for efficient activation of IFN regulatory factors to drive the antiviral transcriptome. NLRC3 is a recently characterized nucleotide-binding domain, leucine-rich repeat containing protein (NLR) that negatively regulates the type I IFN pathway by inhibiting subcellular redistribution and effective signaling of STING, thus blunting the transcription of type I IFNs. NLRC3 is predominantly expressed in lymphoid and myeloid cells. IQGAP1 was identified as a putative interacting partner of NLRC3 through yeast two-hybrid screening. In this article, we show that IQGAP1 associates with NLRC3 and can disrupt the NLRC3-STING interaction in the cytosol of human epithelial cells. Furthermore, knockdown of IQGAP1 in THP1 and HeLa cells causes significantly more IFN-beta production in response to cytosolic nucleic acids. This result phenocopies NLRC3-deficient macrophages and fibroblasts and short hairpin RNA knockdown of NLRC3 in THP1 cells. Our findings suggest that IQGAP1 is a novel regulator of type I IFN production, possibly via interacting with NLRC3 in human monocytic and epithelial cells. PMID- 28864481 TI - CDK4/6 Inhibitors Induce Antitumor Immunity. AB - CDK4/6 inhibitors not only induce cell-cycle arrest but also promote antitumor immunity by stimulating the production of type III interferons, which enhance tumor antigen presentation, and suppress regulatory T cells. The immune effects of these drugs provide a rationale for combining CDK4/6 inhibitors with checkpoint blockade agents. PMID- 28864476 TI - Recurrent Tumor Cell-Intrinsic and -Extrinsic Alterations during MAPKi-Induced Melanoma Regression and Early Adaptation. AB - Treatment of advanced BRAFV600-mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (MAPKi) therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell-intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or CD45-positive fractions, implying tumor cell-intrinsic or stromal/immune alterations, respectively). Tumor cell intrinsic reprogramming attenuated MAPK dependency, while enhancing mesenchymal, angiogenic, and IFN-inflammatory features and growth/survival dependence on multi RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.Significance: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylome-wide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell-inflamed, stromal adaptations, many of which are tumor cell-driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy. Cancer Discov; 7(11); 1248-65. (c)2017 AACR.See related commentary by Haq, p. 1216This article is highlighted in the In This Issue feature, p. 1201. PMID- 28864483 TI - Cadaveric study of movement in the unstable upper cervical spine during emergency management: tracheal intubation and cervical spine immobilisation-a study protocol for a prospective randomised crossover trial. AB - INTRODUCTION: Emergency management of upper cervical spine injuries often requires cervical spine immobilisation and some critical patients also require airway management. The movement of cervical spine created by tracheal intubation and cervical spine immobilisation can potentially exacerbate cervical spinal cord injury. However, the evidence that previous studies have provided remains unclear, due to lack of a direct measurement technique for dural sac's space during dynamic processes. Our study will use myelography method and a wireless human motion tracker to characterise and compare the change of dural sac's space during tracheal intubations and cervical spine immobilisation in the presence of unstable upper cervical spine injury such as atlanto-occipital dislocation or type II odontoid fracture. METHODS AND ANALYSIS: Perform laryngoscopy and intubation, video laryngoscope intubation, laryngeal tube insertion, fiberoptic intubation and cervical collar application on cadaveric models of unstable upper cervical spine injury such as atlanto-occipital dislocation or type II odontoid fracture. The change of dural sac's space and the motion of unstable cervical segment are recorded by video fluoroscopy with previously performing myelography, which enables us to directly measure dural sac's space. Simultaneously, the whole cervical spine motion is recorded at a wireless human motion tracker. The maximum dural sac compression and the maximum angulation and distraction of the injured segment are measured by reviewing fluoroscopic and myelography images. ETHICS AND DISSEMINATION: This study protocol has been approved by the Ethics Committee of the State Medical Association Rhineland-Palatinate, Mainz, Germany. The results will be published in relevant emergency journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: DRKS00010499. PMID- 28864484 TI - Lifetime risks of kidney donation: a medical decision analysis. AB - OBJECTIVE: This study estimated the potential loss of life and the lifetime cumulative risk of end-stage renal disease (ESRD) from live kidney donation. DESIGN: Markov medical decision analysis. SETTING: USA. PARTICIPANTS: 40-year-old live kidney donors of both sexes and black/white race. INTERVENTION: Live donor nephrectomy. MAIN OUTCOME AND MEASURES: Potential remaining life years lost, quality-adjusted life years (QALYs) lost and added lifetime cumulative risk of ESRD from donation. RESULTS: Overall 0.532-0.884 remaining life years were lost from donating a kidney. This was equivalent to 1.20%-2.34% of remaining life years (or 0.76%-1.51% remaining QALYs). The risk was higher in male and black individuals. The study showed that 1%-5% of average-age current live kidney donors might develop ESRD as a result of nephrectomy. The added risk of ESRD resulted in a loss of only 0.126-0.344 remaining life years. Most of the loss of life was predicted to be associated with chronic kidney disease (CKD) not ESRD. Most events occurred 25 or more years after donation. Reducing the increased risk of death associated with CKD had a modest overall effect on the per cent loss of remaining life years (0.72%-1.9%) and QALYs (0.58%-1.33%). Smoking and obesity reduced life expectancy and increased overall lifetime risks of ESRD in non donors. However the percentage loss of remaining life years from donation was not very different in those with or without these risk factors. CONCLUSION: Live kidney donation may reduce life expectancy by 0.5-1 year in most donors. The development of ESRD in donors may not be the only measure of risk as most of the predicted loss of life predates ESRD. The study identifies the potential importance of following donors and treating risk factors aggressively to prevent ESRD and to improve donor survival. PMID- 28864485 TI - The prevalence and correlates of elder abuse and neglect in a rural community of Negeri Sembilan state: baseline findings from The Malaysian Elder Mistreatment Project (MAESTRO), a population-based survey. AB - BACKGROUND: As Malaysia is fast becoming an ageing nation, the health, safety and welfare of elders are major societal concerns. Elder abuse is a phenomenon recognised abroad but less so locally. This paper presents the baseline findings from the Malaysian Elder Mistreatment Project (MAESTRO) study, the first community-based study on elder abuse in Malaysia. DESIGN: Cross-sectional study, analysing baseline findings of a cohort of older adults. SETTING: Kuala Pilah district, Negeri Sembilan state, Malaysia. OBJECTIVES: To determine the prevalence of elder abuse among community dwelling older adults and its associated factors. PARTICIPANTS: A total of 2112 community dwelling older adults aged 60 years and above were recruited employing a multistage sampling using the national census. PRIMARY AND SECONDARY OUTCOME MEASURES: Elder abuse, measured using a validated instrument derived from previous literature and the modified Conflict Tactic Scales, similar to the Irish national prevalence survey on elder abuse with modification to local context. Factors associated with abuse and profiles of respondents were also examined. RESULTS: The prevalence of overall abuse was reported to be 4.5% in the past 12 months. Psychological abuse was most common, followed by financial, physical, neglect and sexual abuse. Two or more occurrences of abusive acts were common, while clustering of various types of abuse was experienced by one-third of abused elders. Being male (adjusted OR (aOR) 2.15, 95% CI 1.23 to 3.78), being at risk of social isolation (aOR 1.96, 95% CI 1.07 to 3.58), a prior history of abuse (aOR 3.28, 95% CI 1.40 to 7.68) and depressive symptomatology (aOR 7.83, 95% CI 2.88 to 21.27) were independently associated with overall abuse. CONCLUSION: Elder abuse occurred among one in every 20 elders. The findings on elder abuse indicate the need to enhance elder protection in Malaysia, with both screening of and interventions for elder abuse. PMID- 28864486 TI - How can primary care enhance end-of-life care for liver disease? Qualitative study of general practitioners' perceptions and experiences. AB - BACKGROUND: Liver disease is the third most common cause of premature death in the UK. The symptoms of terminal liver disease are often difficult to treat, but very few patients see a palliative care specialist and a high proportion die in hospital. Primary care has been identified as a setting where knowledge and awareness of liver disease is poor. Little is known about general practitioners' (GPs) perceptions of their role in managing end-stage liver disease. OBJECTIVE: To explore GPs' experiences and perceptions of how primary care can enhance end of-life care for patients with liver disease. DESIGN: Qualitative interview study, thematic analysis. PARTICIPANTS: Purposive sample of 25 GPs from five regions of England. RESULTS: GPs expressed a desire to be more closely involved in end-of-life care for patients with liver disease but identified a number of factors that constrained their ability to contribute. These fell into three main areas; those relating directly to the condition, (symptom management and the need to combine a palliative care approach with ongoing medical interventions); issues arising from patients' social circumstances (stigma, social isolation and the social consequences of liver disease) and deficiencies in the organisation and delivery of services. Collaborative working with support from specialist hospital clinicians was regarded as essential, with GPs acknowledging their lack of experience and expertise in this area. CONCLUSIONS: End-of-life care for patients with liver disease merits attention from both primary and secondary care services. Development of care pathways and equitable access to symptom relief should be a priority. PMID- 28864487 TI - Self-administered versus provider-directed sampling in the Anishinaabek Cervical Cancer Screening Study (ACCSS): a qualitative investigation with Canadian First Nations women. AB - BACKGROUND: While (Pap)anicolaou screening has helped to decrease cervical cancer incidence in Canada, First Nations women continue to have a higher burden and mortality relative to mainstream populations. Many First Nations women may feel uncomfortable with the invasiveness of this test, contributing to this statistic. Implemented from 2009 to 2015 in 10 Northwest Ontario First Nations communities, the Anishinaabek Cervical Cancer Screening Study (ACCSS) uniquely addressed this Indigenous health inequity through a mixed methods approach. OBJECTIVE: Our goal was to offer an alternative test which the women could do themselves: human papillomavirus (HPV) testing based on self-sampling. We investigated whether First Nations women preferred HPV self-sampling over healthcare provider (HCP) administered Pap screening. METHODS: Participatory action researchinformed by the ethical space concept has guided all stages of the ACCSS. We conducted qualitative interviews with 16 HCPs and 8 focus group discussions with 69 female community members followed by a cluster-randomised controlled trial (RCT). Here, we draw on the qualitative field data and an end-of-study community update gathering to disseminate and contextualise research findings. Informant data were evaluated using thematic analysis. RESULTS: We discuss factors influencing participants' strong preference for HPV self-sampling over physician-conducted Pap screening. Key arguments included enhanced accessibility and more personal control, less physical and emotional discomfort and fewer concerns regarding privacy of test results. For future implementation of HPV self-sampling, study participants emphasised the need for more culturally sensitive education addressed to community members of all genders, starting at school, clarifying that HPV causes cervical cancer. Further, HPV infection should be de-stigmatised by accentuating that it affects men and women alike. CONCLUSION: Here we show that self-sampling in conjunction with community engagement and culturally sensitive education and could be a viable option for underscreened Canadian First Nations women. These informant data echo our previous RCT results. PMID- 28864489 TI - Correction: Protocol for a multicentre, prospective, observational cohort study of variation in practice in perioperative analgesic strategies in elective laparoscopic colorectal surgery: the LapCoGesic Study. PMID- 28864488 TI - How does preclinical laboratory training impact physical examination skills during the first clinical year? A retrospective analysis of routinely collected objective structured clinical examination scores among the first two matriculating classes of a reformed curriculum in one Polish medical school. AB - OBJECTIVE: As a result of a curriculum reform launched in 2012 at our institution, preclinical training was shortened to 2 years instead of the traditional 3 years, creating additional incentives to optimise teaching methods. In accordance with the new curriculum, a semester-long preclinical module of clinical skills (CS) laboratory training takes place in the second year of study, while an introductory clinical course (ie, brief introductory clerkships) is scheduled for the Fall semester of the third year. Objective structured clinical examinations (OSCEs) are carried out at the conclusion of both the preclinical module and the introductory clinical course. Our aim was to compare the scores at physical examination stations between the first and second matriculating classes of a newly reformed curriculum on preclinical second-year OSCEs and early clinical third-year OSCEs. DESIGN: Analysis of routinely collected data. SETTING: One Polish medical school. PARTICIPANTS: Complete OSCE records for 462 second year students and 445 third-year students. OUTCOME MEASURES: OSCE scores by matriculation year. RESULTS: In comparison to the first class of the newly reformed curriculum, significantly higher (ie, better) OSCE scores were observed for those students who matriculated in 2013, a year after implementing the reformed curriculum. This finding was consistent for both second-year and third year cohorts. Additionally, the magnitude of the improvement in median third-year OSCE scores was proportional to the corresponding advancement in preceding second year preclinical OSCE scores for each of two different sets of physical examination tasks. In contrast, no significant difference was noted between the academic years in the ability to interpret laboratory data or ECG - tasks which had not been included in the second-year preclinical training. CONCLUSION: Our results suggest the importance of preclinical training in a CS laboratory to improve students' competence in physical examination at the completion of introductory clinical clerkships during the first clinical year. PMID- 28864490 TI - Correction: Factors predicting self-reported medication low adherence in a large sample of adults in the US general population: a cross-sectional study. PMID- 28864491 TI - Correction: A randomised controlled trial to evaluate the impact of sexual health clinic based automated text message reminders on testing of HIV and other sexually transmitted infections in men who have sex with men in China: protocol for the T2T Study. PMID- 28864492 TI - Correction: Incidence and prevalence of diabetic ketoacidosis (DKA) among adults with type 1 diabetes mellitus (T1D): a systematic literature review. PMID- 28864493 TI - Correction: Protocol for a prospective longitudinal study of risk factors for hypertension incidence in a Mexico City population: the Tlalpan 2020 cohort. PMID- 28864495 TI - What to expect when you're expecting. AB - Applying systems immunology to study human pregnancy. PMID- 28864496 TI - A recycling program that keeps PD-L1 out of the cancer cell's junkyard. AB - CMTM6 limits antitumor immunity by ensuring efficient recycling of endocytosed PD L1 protein. PMID- 28864494 TI - An immune clock of human pregnancy. AB - The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2 dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies. PMID- 28864497 TI - A role for T helper cells in anti-CTLA-4 therapy. AB - Comparison of immune responses to CTLA4 and PD-1 blockade uncovers a role for helper T cells in anti-CTLA-4 therapy. PMID- 28864498 TI - New ultrasonographic screening method for oropharyngeal dysphagia: tissue Doppler imaging. AB - Ultrasound tissue Doppler imaging (US-TDI) has been used to diagnose regional wall motion (WM) abnormalities in coronary artery disease but has not been applied to oropharyngeal diseases. This study aimed first to validate an US-TDI method to assess cervical esophageal (CE) WM and secondly to use the method to evaluate CE WM in patients with oropharyngeal dysphagia (OD). First, we enrolled 22 healthy men (mean age: 59.7 yr) who all underwent both US-TDI and videofluoroscopy (VF) and then esophageal high-resolution manometry (HRM) in the same week. We evaluated the reproducibility of the US-TDI and the relationship between US-TDI and other modalities (VF and HRM). Second, we enrolled 56 mild OD patients (mean age: 58.0 yr) and age- and sex-matched healthy controls. Difference in CE WM between these groups was evaluated by US-TDI. All healthy subjects underwent US-TDI, VF, and HRM successfully, with a sufficiently high reproducibility coefficient for this method, and significant correlation between US-TDI and VF/HRM parameters. US-TDI showed mean time to open CE wall and mean velocity of CE wall opening significantly differed between patients and healthy controls ( P < 0.01). In conclusion, we have developed a US-TDI method for easily assessing CE WM in daily practice and also found significant differences in CE WM between mild OD patients and healthy controls. NEW & NOTEWORTHY A new ultrasonographic screening method using tissue Doppler imaging for oropharyngeal dysphagia was found to be a reliable, reproducible, and well-tolerated method. There is a significant correlation between this new method and conventional methods. This method revealed that patients having mild symptoms of oropharyngeal dysphagia had already significantly delayed cervical esophageal wall opening. PMID- 28864499 TI - Ethanol metabolism by alcohol dehydrogenase or cytochrome P450 2E1 differentially impairs hepatic protein trafficking and growth hormone signaling. AB - The liver metabolizes alcohol using alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1). Both enzymes metabolize ethanol into acetaldehyde, but CYP2E1 activity also results in the production of reactive oxygen species (ROS) that promote oxidative stress. We have previously shown that microtubules are hyperacetylated in ethanol-treated polarized, hepatic WIF-B cells and livers from ethanol-fed rats. We have also shown that enhanced protein acetylation correlates with impaired clathrin-mediated endocytosis, constitutive secretion, and nuclear translocation and that the defects are likely mediated by acetaldehyde. However, the roles of CYP2E1-generated metabolites and ROS in microtubule acetylation and these alcohol-induced impairments have not been examined. To determine if CYP2E1 mediated alcohol metabolism is required for enhanced acetylation and the trafficking defects, we coincubated cells with ethanol and diallyl sulfide (DAS; a CYP2E1 inhibitor) or N-acetyl cysteine (NAC; an antioxidant). Both agents failed to prevent microtubule hyperacetylation in ethanol-treated cells and also failed to prevent impaired secretion or clathrin-mediated endocytosis. Somewhat surprisingly, both DAS and NAC prevented impaired STAT5B nuclear translocation. Further examination of microtubule-independent steps of the pathway revealed that Jak2/STAT5B activation by growth hormone was prevented by DAS and NAC. These results were confirmed in ethanol-exposed HepG2 cells expressing only ADH or CYP2E1. Using quantitative RT-PCR, we further determined that ethanol exposure led to blunted growth hormone-mediated gene expression. In conclusion, we determined that alcohol-induced microtubule acetylation and associated defects in microtubule-dependent trafficking are mediated by ADH metabolism whereas impaired microtubule-independent Jak2/STAT5B activation is mediated by CYP2E1 activity.NEW & NOTEWORTHY Impaired growth hormone-mediated signaling is observed in ethanol exposed hepatocytes and is explained by differential effects of alcohol dehydrogenase (ADH)- and cytochrome P450 2E1 (CYP2E1)-mediated ethanol metabolism on the Jak2/STAT5B pathway. PMID- 28864501 TI - Zinc strengthens the jejunal barrier by reversibly tightening the paracellular route. AB - During the postweaning period, piglets are prone to gastrointestinal infections. The resulting impairment of intestinal barrier function may cause diarrhea associated with growth retardation or even death of piglets. Orally applied Zn is commonly used to prevent and treat diarrhea, but its mode of action still needs to be elucidated. To analyze the molecular mechanism whereby Zn acts on porcine intestinal barrier function, ex vivo studies on piglet jejunum and accompanying in vitro studies on a porcine jejunal epithelial cell line, IPEC-J2/PS, were performed with electrophysiological tools. Feeding pharmacological Zn doses exerted no significant electrophysiologically ascertainable short- and long-term effects on jejunal barrier function ex vivo. However, in IPEC-J2/PS, basolateral Zn was cytotoxic since its application caused a release of lactate dehydrogenase and an irreversible breakdown of the epithelial barrier. In contrast, apical Zn application caused an immediate increase in paracellular resistance and a decrease in permeability to the paracellular marker fluorescein, reflecting overall barrier strengthening in vitro. Apical effects were fully reversible upon washout. This indicates that Zn supplemented to feed was completely washed out during ex vivo jejunum preparation. We conclude that there is no evidence for long-term barrier effects through prophylactic Zn supplementation and that extracellular Zn acts acutely and reversibly from the apical side via tightening the paracellular route, thus counteracting leak-flux diarrhea.NEW & NOTEWORTHY Therapeutically administered Zn successfully treats diarrhea in veterinary and human medicine. Here we present data that Zn strengthens the porcine jejunal epithelial barrier by reversibly tightening the paracellular route for inorganic ions and small solutes. Acute or long-lasting Zn effects on transcellular transport (Cl- secretion) were not detected. We therefore conclude that Zn is useful for acutely treating leak-flux diarrhea rather than secretory diarrhea. Suitability as prophylactic feed supplement, however, is questionable. PMID- 28864500 TI - Kruppel-like factor 5 is essential for maintenance of barrier function in mouse colon. AB - Kruppel-like factor 5 (KLF5) is a member of the zinc finger family of transcription factors that regulates homeostasis of the intestinal epithelium. Previous studies suggested an indispensable role of KLF5 in maintaining intestinal barrier function. In the current study, we investigated the mechanisms by which KLF5 regulates colonic barrier function in vivo and in vitro. We used an inducible and a constitutive intestine-specific Klf5 knockout mouse models (Villin-CreERT2;Klf5fl/fl designated as Klf5DeltaIND and Villin-Cre;Klf5fl/fl as Klf5DeltaIS ) and studied an inducible KLF5 knockdown in Caco-2 BBe cells using a lentiviral Tet-on system (Caco-2 BBe KLF5DeltaIND). Specific knockout of Klf5 in colonic tissues, either inducible or constitutive, resulted in increased intestinal permeability. The phenotype was accompanied by a significant reduction in Dsg2, which encodes desmoglein-2, a desmosomal cadherin, at both mRNA and protein levels. Transmission electron microscopy showed alterations of desmosomal morphology in both KLF5 knockdown Caco-2 BBe cells and Klf5 knockout mouse colonic tissues. Inducible knockdown of KLF5 in Caco-2BBe cells grown on Transwell plates led to impaired barrier function as evidenced by decreased transepithelial electrical resistance and increased paracellular permeability to fluorescein isothiocyanate-4 kDa dextran. Furthermore, DSG2 was significantly decreased in KLF5 knockdown cells, and DSG2 overexpression partially rescued the impaired barrier function caused by KLF5 knockdown. Electron microscopy studies demonstrated altered desmosomal morphology after KLF5 knockdown. In combination with chromatin immunoprecipitation analysis and promoter study, our data show that KLF5 regulates intestinal barrier function by mediating the transcription of DSG2, a gene encoding a major component of desmosome structures.NEW & NOTEWORTHY The study is original research on the direct function of a Kruppel-like factor on intestinal barrier function, which is commonly exerted by cell junctions, including tight junctions, adherens junctions, and desmosomes. Numerous previous studies were focused on tight junctions and adherens junctions. However, this study provided a new perspective on how the intestinal barrier function is regulated by KLF5 through DSG2, a component of desmosome complexes. PMID- 28864504 TI - It's time to manage pain in calves. PMID- 28864502 TI - Pharmacologic Differences of Sulfonylureas and the Risk of Adverse Cardiovascular and Hypoglycemic Events. AB - OBJECTIVE: Sulfonylureas have been associated with an increased risk of cardiovascular adverse events and hypoglycemia, but it is unclear if these risks vary with different agents. We assessed whether the risks of acute myocardial infarction, ischemic stroke, cardiovascular death, all-cause mortality, and severe hypoglycemia differ between sulfonylureas grouped according to pancreas specificity and duration of action. RESEARCH DESIGN AND METHODS: Using the U.K. Clinical Practice Research Datalink, linked with the Hospital Episodes Statistics and the Office for National Statistics databases, we conducted a cohort study among patients with type 2 diabetes initiating monotherapy with sulfonylureas between 1998 and 2013. Adjusted hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, comparing use of pancreas-nonspecific, long-acting sulfonylureas (glyburide/glimepiride) to pancreas-specific, short acting sulfonylureas (gliclazide/glipizide/tolbutamide). RESULTS: The cohort included 17,604 sulfonylurea initiators (mean [SD] follow-up 1.2 [1.5] years). Compared with specific, short-acting sulfonylureas (15,741 initiators), nonspecific, long-acting sulfonylureas (1,863 initiators) were not associated with an increased risk of acute myocardial infarction (HR 0.86; CI 0.55-1.34), ischemic stroke (HR 0.92; CI 0.59-1.45), cardiovascular death (HR 1.01; CI 0.72 1.40), or all-cause mortality (HR 0.81; CI 0.66-1.003), but with an increased risk of severe hypoglycemia (HR 2.83; CI 1.64-4.88). CONCLUSIONS: The nonspecific, long-acting sulfonylureas glyburide and glimepiride do not have an increased risk of cardiovascular adverse events compared with the specific, short acting sulfonylureas gliclazide, glipizide, and tolbutamide. However, nonspecific, long-acting sulfonylureas glyburide and glimepiride have an increased risk of severe hypoglycemia. PMID- 28864505 TI - Scotland pushes for tougher action on cattle farmers to eradicate BVD. PMID- 28864506 TI - Vets 'extremely concerned' about reclassification of sheep anthelmintic. PMID- 28864508 TI - Medicines update. AB - The following information has been produced for Veterinary Record by the Veterinary Medicines Directorate (VMD) to provide an update for veterinary surgeons on recent changes to marketing authorisations for veterinary medicines in the UK. PMID- 28864509 TI - Small animal disease surveillance: GI disease and salmonellosis. AB - Presentation for gastrointestinal (GI) disease comprised 2.2 per cent of cat, 3.2 per cent of dog and 2.2 per cent of rabbit consultations between April 1, 2016 and March 31, 2017Diarrhoea and vomiting without blood were the most frequently reported GI disease clinical signs (34.4 and 38.9 per cent in cats and 42.8 and 37.3 per cent in dogs, respectively)The mean percentage of samples testing positive for Salmonella in dogs was double that in cats (0.82 per cent and 0.41 per cent, respectively) from January 1, 2011 to December 31, 2016In dogs, autumn was associated with a greater proportion of Salmonella-positive sample submissions; no clear suggestion of seasonal variation in cats was observedIn both cats and dogs, isolates belonging to Salmonella enterica group B serotypes were the most common (68.9 per cent in cats and 55.0 per cent in dogs). PMID- 28864510 TI - Clinical significance of equine cheek teeth infundibular caries. PMID- 28864511 TI - What does the futurologists' view hold for vets? PMID- 28864512 TI - Bovine TB controls in the UK. PMID- 28864513 TI - Need for clear product labelling. PMID- 28864514 TI - Preparing graduates for practice. PMID- 28864515 TI - The mosquito Aedes vexans in England. PMID- 28864516 TI - Bovine TB in the pilot badger cull zone in Gloucestershire. PMID- 28864517 TI - Death notice. PMID- 28864518 TI - John Alexander MacKenzie. AB - John MacKenzie was a well-liked veterinary officer with a wry sense of humour, who could always be relied on to solve problems. PMID- 28864519 TI - John Maelor Gittins. AB - John Gittins was a small animal vet who excelled at surgery. PMID- 28864520 TI - BVA offers support in practice veterinary ethics. AB - Sean Wensley, BVA Senior Vice President discusses how the growth of veterinary ethics has prompted the need for additional support and learning for veterinary teams. PMID- 28864521 TI - What should you look for in your first practice role? AB - Will Chandler reflects on his experience finding his first clinical job after qualifying, including his tips on what to look for in a potential employer. PMID- 28864523 TI - Make customer service a priority. AB - BVA has partnered with Moneypenny, one of the UK's leading outsourced communications providers, to provide members with an effective way to respond to client calls. Moneypenny talked to Pauline Sloan, receptionist at Village Vets in East Lothian, about her practice's experience of using their service. PMID- 28864522 TI - The privilege of connecting with your clients. AB - Nicky Mansell, one of the Young Vet Network representatives on BVA Council, reflects on the importance of keeping your clients in mind. PMID- 28864524 TI - Career advice and practice management support at the London Vet Show. AB - Zoe Davies, BVA Marketing Manager, outlines this year's programme for the BVA career stream and financial one-to-ones at London Vet Show. PMID- 28864525 TI - Making animal welfare education fun for children. AB - Girija Duggal, BVA Media Officer, explains how to make learning about animal welfare fun for all ages. PMID- 28864526 TI - Recent graduate places at Northern Ireland dinner. AB - Helena Cotton, BVA Public Affairs Manager, explains how recent graduates can get involved with BVA's annual dinners. PMID- 28864527 TI - Vet Virtual Congress 2018 launched. AB - The Webinar Vet has announced the line-up for next year's Virtual Congress, which takes place from 19 to 21 January. PMID- 28864528 TI - Parallel careers: a parasitologist and a vet. AB - Ian Wright heads the European Scientific Counsel Companion Animal Parasites (ESCCAP) UK and Ireland, which involves some international travel. He and his wife are also practice owners and they have two children. He admits that work life balance can be a challenge. PMID- 28864529 TI - Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation. AB - An effect of thyroid hormone (TH) on erythropoiesis has been known for more than a century but the molecular mechanism(s) by which TH affects red cell formation is still elusive. Here we demonstrate an essential role of TH during terminal human erythroid cell differentiation; specific depletion of TH from the culture medium completely blocked terminal erythroid differentiation and enucleation. Treatment with TRbeta agonists stimulated premature erythroblast differentiation in vivo and alleviated anemic symptoms in a chronic anemia mouse model by regulating erythroid gene expression. To identify factors that cooperate with TRbeta during human erythroid terminal differentiation, we conducted RNA-seq in human reticulocytes and identified nuclear receptor coactivator 4 (NCOA4) as a critical regulator of terminal differentiation. Furthermore, Ncoa4-/- mice are anemic in perinatal periods and fail to respond to TH by enhanced erythropoiesis. Genome-wide analysis suggests that TH promotes NCOA4 recruitment to chromatin regions that are in proximity to Pol II and are highly associated with transcripts abundant during terminal differentiation. Collectively, our results reveal the molecular mechanism by which TH functions during red blood cell formation, results that are potentially useful to treat certain anemias. PMID- 28864530 TI - Cbfbeta governs osteoblast-adipocyte lineage commitment through enhancing beta catenin signaling and suppressing adipogenesis gene expression. AB - The mechanism underlying how transcription factors regulate mesenchymal stem cell lineage commitment remains unclear. To determine the role of core-binding factor subunit beta (Cbfbeta) in osteoblast lineage commitment, we generated three mouse models by deleting Cbfbeta at different osteoblast lineage stages. We demonstrated that the Cbfbetaf/fPrx1-Cre, Cbfbetaf/fCol2alpha1-Cre, and Cbfbetaf/fOsx-Cre mice exhibited severe osteoporosis with substantial accumulation of marrow adipocytes resembling aged bone from enhanced adipogenesis, indicating that mesenchymal stem cells and osteoblasts can be programed and reprogramed, respectively, into adipocytes. Consistently, Cbfbeta deficient calvarial cells and bone marrow mesenchymal stem cells displayed strong adipogenic potential, with 5- to ~70-fold increased adipocyte gene expression, which can be rescued by Cbfbeta overexpression. Canonical Wnt signaling was impeded in the Cbfbeta-deficient cells, with ~80% decrease of Wnt10b expression. Accordingly, ChIP and luciferase assays demonstrated that Cbfbeta/RUNX2 binds to Wnt10b promoter driving Wnt10b expression. Furthermore, Wnt3a suppressed adipogenesis but did not rescue osteoblastogenesis in Cbfbeta-deficient cells. Notably, mixing culture of Cbfbeta-deficient with normal cells demonstrates that Cbfbeta functions not only through WNT paracrine pathway but also through endogenous signaling. Further analysis shows that Cbfbeta/RUNX2 inhibits c/ebpalpha expression at transcriptional level. Our results show that, besides its osteogenic role, Cbfbeta governs osteoblast-adipocyte lineage commitment both cell nonautonomously through enhancing beta-catenin signaling and cell autonomously through suppressing adipogenesis gene expression to maintain osteoblast lineage commitment, indicating Cbfbeta may be a therapeutic target for osteoporosis. PMID- 28864532 TI - Warmer climate squeezes aquatic predators out of their preferred habitat. PMID- 28864531 TI - Multiple proteolytic events in caspase-6 self-activation impact conformations of discrete structural regions. AB - Caspase-6 is critical to the neurodegenerative pathways of Alzheimer's, Huntington's, and Parkinson's diseases and has been identified as a potential molecular target for treatment of neurodegeneration. Thus, understanding the global and regional changes in dynamics and conformation provides insights into the unique properties of caspase-6 that may contribute to achieving control of its function. In this work, hydrogen/deuterium exchange MS (H/DX-MS) was used to map the local changes in the conformational flexibility of procaspase-6 at the discrete states that reflect the series of cleavage events that ultimately lead to the fully active, substrate-bound state. Intramolecular self-cleavage at Asp 193 evoked higher solvent exposure in the regions of the substrate-binding loops L1, L3, and L4 and in the 130s region, the intersubunit linker region, the 26-32 region as well as in the stabilized loop 2. Additional removal of the linker allowed caspase-6 to gain more flexibility in the 130s region and in the L2 region converting caspase-6 to a competent substrate-binding state. The prodomain region was found to be intrinsically disordered independent of the activation state of caspase-6; however, its complete removal resulted in the protection of the adjacent 26-32 region, suggesting that this region may play a regulatory role. The molecular details of caspase-6 dynamics in solution provide a comprehensive scaffold for strategic design of therapeutic approaches for neurodegenerative disorders. PMID- 28864534 TI - Letter to the editor: BET inhibitors might target innate inflammatory and profibrotic signaling networks in COPD. PMID- 28864533 TI - First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor. AB - The polycomb repressive complex 2 (PRC2) histone methyltransferase plays a central role in epigenetic regulation in development and in cancer, and hence to interrogate its role in a specific developmental transition, methods are needed for disrupting function of the complex with high temporal and spatial precision. The catalytic and substrate recognition functions of PRC2 are coupled by binding of the N-terminal helix of the Ezh2 methylase to an extended groove on the EED trimethyl lysine binding subunit. Disrupting PRC2 function can in principle be achieved by blocking this single interaction, but there are few approaches for blocking specific protein-protein interactions in living cells and organisms. Here, we describe the computational design of proteins that bind to the EZH2 interaction site on EED with subnanomolar affinity in vitro and form tight and specific complexes with EED in living cells. Induction of the EED binding proteins abolishes H3K27 methylation in human embryonic stem cells (hESCs) and at all but the earliest stage blocks self-renewal, pinpointing the first critical repressive H3K27me3 marks in development. PMID- 28864535 TI - Cardiovascular manifestations of primary hyperparathyroidism: a narrative review. AB - Data on cardiovascular disease in primary hyperparathyroidism (PHPT) are controversial; indeed, at present, cardiovascular involvement is not included among the criteria needed for parathyroidectomy. Aim of this narrative review is to analyze the available literature in an effort to better characterize cardiovascular involvement in PHPT. Due to physiological effects of both parathyroid hormone (PTH) and calcium on cardiomyocyte, cardiac conduction system, smooth vascular, endothelial and pancreatic beta cells, a number of data have been published regarding associations between symptomatic and mild PHPT with hypertension, arrhythmias, endothelial dysfunction (an early marker of atherosclerosis), glucose metabolism impairment and metabolic syndrome. However, the results, mainly derived from observational studies, are inconsistent. Furthermore, parathyroidectomy resulted in conflicting outcomes, which may be linked to several potential biases. In particular, differences in the methods utilized for excluding confounding co-existing cardiovascular risk factors together with differences in patient characteristics, with varying degrees of hypercalcemia, may have contributed to these discrepancies. The only meta analysis carried out in PHPT patients, revealed a positive effect of parathyroidectomy on left ventricular mass index (a predictor of cardiovascular mortality) and more importantly, that the highest pre-operative PTH levels were associated with the greatest improvements. In normocalcemic PHPT, it has been demonstrated that cardiovascular risk factors are almost similar compared to hypercalcemic PHPT, thus strengthening the role of PTH in the cardiovascular involvement. Long-term longitudinal randomized trials are needed to determine the impact of parathyroidectomy on cardiovascular diseases and mortality in PHPT. PMID- 28864538 TI - Hospital Costs and Charges of Discharge Delays in Children Hospitalized for Abuse and Neglect. AB - OBJECTIVES: Hospitalizations for child maltreatment cases are longer and costlier than hospitalizations for medically similar nonabuse cases. Some discharges are delayed despite medical clearance because of a lack of safe disposition, increasing the cost of hospitalization. We aim to quantify the additional charges and costs of these delays. METHODS: A retrospective chart review evaluated the dates of medical clearance and clinical characteristics of child protection team inpatient consults from 2012 to 2014 at a 595-bed quaternary-care urban hospital. Charges and costs were compared between those with no delay, those with any delay, and those with a delay >1 day. We excluded children who were not admitted, in whom no abuse was suspected, or in whom sexual abuse was suspected absent extragenital injury. RESULTS: Thirty-six percent (134 of 375) of children hospitalized for abuse remained hospitalized after medical clearance and 20.5% (77 of 375) of children were delayed >1 day. Among those who were delayed, the mean number of days delayed was 4.37 (SD +/-7.44). Mean charges after medical clearance were $13 647.53 (+/-$30 172.17), and mean costs after medical clearance were $6521.93 (+/-$13 975.34). Both charges and costs were markedly right-skewed. Median costs after medical clearance were $1553.64 (interquartile range, $26.10 $5244.20). Cumulatively, 586 total days of delay resulted in excess charges of $1.8 million. CONCLUSIONS: Continued hospitalization beyond medical clearance occurs often and represents a significant cost. Further study is needed to evaluate whether interventions can be targeted at children with characteristics correlated with prolonged discharge delays. PMID- 28864536 TI - Changes in the clinicopathological characteristics and genetic alterations of follicular thyroid cancer. AB - OBJECTIVE: Changes in the clinicopathological characteristics and genetic alterations of follicular thyroid cancer (FTC) over time have not been reported. Moreover, the prognostic effects of RAS and TERT promoter mutations in FTC have not been clearly elucidated. We investigated changes in the clinicopathological characteristics of patients with FTC over four decades, as well as the clinical significance of genetic mutations of FTC. DESIGN AND METHODS: This retrospective study included 690 patients with FTC who underwent thyroidectomy between 1973 and 2015 at the Seoul National University Hospital. In 134 samples, genetic tests for N/H/KRAS and TERT promoter mutations and PAX8/PPARgamma rearrangement were performed. RESULTS: The age at diagnosis has increased (P < 0.001) in recent decades and extrathyroidal extension of the tumor has become less common (P = 0.033). Other clinicopathological characteristics and prognosis of FTC have not significantly changed. The prevalence of RAS mutations decreased (P = 0.042) over time, whereas that of TERT promoter mutations remained stable. RAS mutations were associated with distant metastasis and persistent disease, and TERT promoter mutations were associated with distant metastasis, advanced TNM stage, recurrence and disease-specific mortality. FTC patients with coexistent RAS and TERT promoter mutations showed a higher recurrence risk than those with only one mutation. CONCLUSIONS: The age at diagnosis of FTC and the frequency of extrathyroidal extension have changed over four decades. Moreover, the prevalence of RAS mutations decreased. RAS and TERT promoter mutations may be associated with poor clinical outcomes in FTC, especially when the two mutations coexist. PMID- 28864540 TI - Vps13-Mcp1 interact at vacuole-mitochondria interfaces and bypass ER-mitochondria contact sites. AB - Membrane contact sites between endoplasmic reticulum (ER) and mitochondria, mediated by the ER-mitochondria encounter structure (ERMES) complex, are critical for mitochondrial homeostasis and cell growth. Defects in ERMES can, however, be bypassed by point mutations in the endosomal protein Vps13 or by overexpression of the mitochondrial protein Mcp1. How this bypass operates remains unclear. Here we show that the mitochondrial outer membrane protein Mcp1 functions in the same pathway as Vps13 by recruiting it to mitochondria and promoting its association to vacuole-mitochondria contacts. Our findings support a model in which Mcp1 and Vps13 work as functional effectors of vacuole-mitochondria contact sites, while tethering is mediated by other factors, including Vps39. Tethered and functionally active vacuole-mitochondria interfaces then compensate for the loss of ERMES-mediated ER-mitochondria contact sites. PMID- 28864539 TI - Signals from the Adipose Microenvironment and the Obesity-Cancer Link-A Systematic Review. AB - Obesity and its associated metabolic dysregulation are established risk factors for many cancers. However, the biologic mechanisms underlying this relationship remain incompletely understood. Given the rising rates of both obesity and cancer worldwide, and the challenges for many people to lose excess adipose tissue, a systematic approach to identify potential molecular and metabolic targets is needed to develop effective mechanism-based strategies for the prevention and control of obesity-driven cancer. Epidemiologic, clinical, and preclinical data suggest that within the growth-promoting, proinflammatory microenvironment accompanying obesity, crosstalk between adipose tissue (comprised of adipocytes, macrophages and other cells) and cancer-prone cells may occur via obesity associated hormones, cytokines, and other mediators that have been linked to increased cancer risk and/or progression. We report here a systematic review on the direct "crosstalk" between adipose tissue and carcinomas in humans. We identified 4,641 articles with n = 20 human clinical studies, which are summarized as: (i) breast (n = 7); (ii) colorectal (n = 4); (iii) esophageal (n = 2); (iv) esophageal/colorectal (n = 1); (v) endometrial (n = 1); (vi) prostate (n = 4); and (vii) ear-nose-throat (ENT) cancer (n = 1). Findings from these clinical studies reinforce preclinical data and suggest organ-dependent crosstalk between adipose tissue and carcinomas via VEGF, IL6, TNFalpha, and other mechanisms. Moreover, visceral white adipose tissue plays a more central role, as it is more bioenergetically active and is associated with a more procancer secretome than subcutaneous adipose tissue. Efforts to eavesdrop and ultimately interfere with this cancer-enhancing crosstalk may lead to new targets and strategies for decreasing the burden of obesity-related cancers. Cancer Prev Res; 10(9); 494-506. (c)2017 AACR. PMID- 28864541 TI - Karyopherins regulate nuclear pore complex barrier and transport function. AB - Nucleocytoplasmic transport is sustained by karyopherins (Kaps) and a Ran guanosine triphosphate (RanGTP) gradient that imports nuclear localization signal (NLS)-specific cargoes (NLS-cargoes) into the nucleus. However, how nuclear pore complex (NPC) barrier selectivity, Kap traffic, and NLS-cargo release are systematically linked and simultaneously regulated remains incoherent. In this study, we show that Kapalpha facilitates Kapbeta1 turnover and occupancy at the NPC in a RanGTP-dependent manner that is directly coupled to NLS-cargo release and NPC barrier function. This is underpinned by the binding affinity of Kapbeta1 to phenylalanine-glycine nucleoporins (FG Nups), which is comparable with RanGTP.Kapbeta1, but stronger for Kapalpha.Kapbeta1. On this basis, RanGTP is ineffective at releasing standalone Kapbeta1 from NPCs. Depleting Kapalpha.Kapbeta1 by RanGTP further abrogates NPC barrier function, whereas adding back Kapbeta1 rescues it while Kapbeta1 turnover softens it. Therefore, the FG Nups are necessary but insufficient for NPC barrier function. We conclude that Kaps constitute integral constituents of the NPC whose barrier, transport, and cargo release functionalities establish a continuum under a mechanism of Kap centric control. PMID- 28864544 TI - Share research profits with NHS trusts to encourage innovation, says NHS Confederation. PMID- 28864542 TI - Somatodendritic accumulation of Tau in Alzheimer's disease is promoted by Fyn mediated local protein translation. AB - The cause of protein accumulation in neurodegenerative disease is incompletely understood. In Alzheimer's disease (AD), the axonally enriched protein Tau forms hyperphosphorylated aggregates in the somatodendritic domain. Consequently, a process of subcellular relocalization driven by Tau phosphorylation and detachment from microtubules has been proposed. Here, we reveal an alternative mechanism of de novo protein synthesis of Tau and its hyperphosphorylation in the somatodendritic domain, induced by oligomeric amyloid-beta (Abeta) and mediated by the kinase Fyn that activates the ERK/S6 signaling pathway. Activation of this pathway is demonstrated in a range of cellular systems, and in vivo in brains from Abeta-depositing, Abeta-injected, and Fyn-overexpressing mice with Tau accumulation. Both pharmacological inhibition and genetic deletion of Fyn abolish the Abeta-induced Tau overexpression via ERK/S6 suppression. Together, these findings present a more cogent mechanism of Tau aggregation in disease. They identify a prominent role for neuronal Fyn in integrating signal transduction pathways that lead to the somatodendritic accumulation of Tau in AD. PMID- 28864543 TI - Structural basis for antibacterial peptide self-immunity by the bacterial ABC transporter McjD. AB - Certain pathogenic bacteria produce and release toxic peptides to ensure either nutrient availability or evasion from the immune system. These peptides are also toxic to the producing bacteria that utilize dedicated ABC transporters to provide self-immunity. The ABC transporter McjD exports the antibacterial peptide MccJ25 in Escherichia coli Our previously determined McjD structure provided some mechanistic insights into antibacterial peptide efflux. In this study, we have determined its structure in a novel conformation, apo inward-occluded and a new nucleotide-bound state, high-energy outward-occluded intermediate state, with a defined ligand binding cavity. Predictive cysteine cross-linking in E. coli membranes and PELDOR measurements along the transport cycle indicate that McjD does not undergo major conformational changes as previously proposed for multi drug ABC exporters. Combined with transport assays and molecular dynamics simulations, we propose a novel mechanism for toxic peptide ABC exporters that only requires the transient opening of the cavity for release of the peptide. We propose that shielding of the cavity ensures that the transporter is available to export the newly synthesized peptides, preventing toxic-level build-up. PMID- 28864549 TI - Atrial Natriuretic Peptide Affects Stimulus-Secretion Coupling of Pancreatic beta Cells. AB - Atrial natriuretic peptide (ANP) influences glucose homeostasis and possibly acts as a link between the cardiovascular system and metabolism, especially in metabolic disorders like diabetes. The current study evaluated effects of ANP on beta-cell function by the use of a beta-cell-specific knockout of the ANP receptor with guanylate cyclase activity (betaGC-A-KO). ANP augmented insulin secretion at the threshold glucose concentration of 6 mmol/L and decreased KATP single-channel activity in beta-cells of control mice but not of betaGC-A-KO mice. In wild-type beta-cells but not beta-cells lacking functional KATP channels (SUR1-KO), ANP increased electrical activity, suggesting no involvement of other ion channels. At 6 mmol/L glucose, ANP readily elicited Ca2+ influx in control beta-cells. This effect was blunted in beta-cells of betaGC-A-KO mice, and the maximal cytosolic Ca2+ concentration was lower. Experiments with inhibitors of protein kinase G (PKG), protein kinase A (PKA), phosphodiesterase 3B (PDE3B), and a membrane-permeable cyclic guanosine monophosphate (cGMP) analog on KATP channel activity and insulin secretion point to participation of the cGMP/PKG and cAMP/PKA/Epac (exchange protein directly activated by cAMP) directly activated by cAMP Epac pathways in the effects of ANP on beta-cell function; the latter seems to prevail. Moreover, ANP potentiated the effect of glucagon-like peptide 1 (GLP 1) on glucose-induced insulin secretion, which could be caused by a cGMP-mediated inhibition of PDE3B, which in turn reduces cAMP degradation. PMID- 28864550 TI - Corrigendum: Building a genomic framework for prospective MRSA surveillance in the United Kingdom and the Republic of Ireland. PMID- 28864551 TI - Corrigendum: The evolution of African great ape subtelomeric heterochromatin and the fusion of human chromosome 2. PMID- 28864552 TI - Corrigendum: Transcriptome analyses of rhesus monkey preimplantation embryos reveal a reduced capacity for DNA double-strand break repair in primate oocytes and early embryos. PMID- 28864553 TI - Language Matters: Identifying Medically Complex Children in Foster Care. PMID- 28864554 TI - Dietary Supplements, Isotretinoin, and Liver Toxicity in Adolescents: A Retrospective Case Series. AB - Isotretinoin is the most effective acne therapy available, but has the potential for a number of adverse side effects, including transaminitis. The iPLEDGE isotretinoin program recommends avoiding some herbals and supplements due to potential side effects. However, little is known about the effects of protein supplements on the liver, particularly in patients taking isotretinoin. We designed a retrospective chart review to evaluate the symptoms, diagnosis, treatment, and outcome of patients on or preparing to take isotretinoin therapy who were concurrently ingesting protein or herbal supplementation and who developed transaminitis. In 100% (8/8) of cases, dietary supplementation was determined to be at least a possible cause of elevated liver transaminases. In 75% (6/8) of cases, dietary supplement appears to be the most likely cause at some point in their evaluation. Most of our patients' elevations in aspartate aminotransferase and/or alanine aminotransferase were likely caused by supplementation with protein, creatine, or herbal extracts, rather than prescribed isotretinoin or tetracycline antibiotics for acne. Hence, dietary supplementation may cause liver function abnormalities. As supplement usage appears common in teenagers, clinicians should consider counseling their patients to avoid these products, particularly when prescribing known hepatotoxic drugs. PMID- 28864556 TI - Massive splenomegaly due to concurrent primary Epstein-Barr virus and cytomegalovirus infection in a patient on adalimumab. AB - A 32-year-old man who was receiving adalimumab for seronegative rheumatoid arthritis presented with a 4-week history of fever, night sweats, fatigue, myalgias and diarrhoea. On examination, he had obvious splenomegaly but no lymphadenopathy or pharyngitis. Full blood count revealed mild neutropenia and significant lymphocytosis, with a blood film showing atypical lymphocytes. Liver function tests were mildly deranged with a mixed hepatitic and obstructive pattern. Ultrasound confirmed massive splenomegaly with a span of 21 cm in the long axis. Serological tests confirmed the presence of both primary Epstein-Barr virus and cytomegalovirus infections. The patient had his adalimumab withheld, was treated with supportive measures and improved over a period of 8 weeks. He remained well 5 months after the onset of illness with complete normalisation of blood count and a resolution of the splenomegaly. PMID- 28864555 TI - Distinct Signaling Patterns of Allosteric Antagonism at the P2Y1 Receptor. AB - Traditionally, G protein-coupled receptor antagonists are classified as competitive or noncompetitive and surmountable or insurmountable based on functional antagonism. P2Y1 receptor (P2Y1R) structures showed two antagonists binding to two spatially distinct sites: nucleotide MRS2500 (orthosteric, contacting the helical bundle) and urea BPTU (allosteric, on the external receptor surface). However, the nature of their P2Y1R antagonism has not been characterized. Here we characterized BPTU antagonism at various signaling pathways activated by structurally diverse agonists. BPTU rightward shifted the concentration-response curves of both 2-methylthioadenosine 5'-diphosphate trisodium salt and MRS2365 (5'-diphosphates) in some signaling events, such as extracellular signal-regulated kinase 1/2 and label free, in a parallel manner without affecting the maximum agonist effect (Emax) but antagonized insurmountably (suppressed agonist Emax) in signaling events such as guanosine 5' 3-O-(thio)triphosphate binding and beta-arrestin2 recruitment. However, with dinucleotide Ap4A as an agonist, BPTU suppressed the Emax insurmountably in all signaling pathways. By comparison, MRS2500 behaved as surmountable antagonist rightward-shifting concentration-response curves of all three agonists in a parallel manner for all signaling pathways measured. Thus, we demonstrated a previously undocumented phenomenon that P2Y1R antagonism patterns could vary in different signaling pathways, which could be related to conformational selection, signaling amplification, and probe dependence. This phenomenon may apply generally to other receptors considering that antagonism by a specific ligand is often not compared at multiple signaling pathways. Thus, antagonism can be surmountable or insurmountable depending on the signaling pathways measured and the agonists used, which should be of broad relevance to drug discovery and disease treatment. PMID- 28864558 TI - Correction: Atypical presentation of false asystole detection in implantable loop recorder. PMID- 28864557 TI - Over-the-scope-clip system secured nasojejunal tube feeding in refractory hyperemesis gravidarum. AB - Hyperemesis gravidarum (HG) is a severe form of nausea and vomiting in pregnancy. It complicates up to 2% of all pregnancies and can be associated with adverse outcomes. Its management commonly involves a combination pharmacotherapy, however, the efficacy of such treatment is limited. Supplemental nutrition is often required in refractory cases. Enteral route is preferred over parenteral, given the high rate of intravenous catheter-related complications. Enteral feeding tube placement can be challenging and is commonly thwarted by dislodgement. We present a pharmacotherapy refractory HG case where the over-the scope-clip (OTSC) system was successfully used for durable mucosal fixation of the nasojejunal feeding tube. PMID- 28864559 TI - Cerebellar abscesses, infective endocarditis and bacteraemia due to a rare pathogen: Streptococcus constellatus. AB - Intracranial infections may result from contiguity, such as mastoiditis or acute otitis media, or from haematogenous dissemination from an infectious source. Streptococcus constellatus, a coccus from the normal genital, oral and gastrointestinal flora, has a tendency to form abscesses, but not to cause infective endocarditis (IE). Also, S. constellatus is an extremely rare causative agent of brain abscess. We report the case of a woman with a colorectal tumour who presented with IE and cerebellar abscesses due to a S. constellatus bacteraemia. PMID- 28864560 TI - Delayed diagnosis and management of second trimester abdominal pregnancy. AB - Second trimester abdominal ectopic pregnancies are rare and life threatening. Early diagnosis and treatment are paramount in reducing maternal morbidity and mortality. We describe an unusually late diagnosis of abdominal pregnancy despite multiple ultrasounds beginning in early pregnancy. A 28-year-old G2P1001 sought pregnancy termination at 22 weeks' gestation after fetal anomalies were noted on an 18-week ultrasound during evaluation for elevated maternal serum alfa fetoprotein. Due to abortion restrictions in her home state, she travelled over 500 miles for abortion care. During dilation and evacuation, suspected uterine perforation led to the finding of a previously undiagnosed abdominal pregnancy. At laparotomy, she underwent left salpingo-oophorectomy and removal of abdominal pregnancy and placenta. A multidisciplinary team approach was paramount in optimising the patient's outcome. Abortion restrictions requiring travel away from the patient's home community interrupted her continuity of care and created additional hardships, complicating management of an unexpected, rare and life threatening condition. PMID- 28864561 TI - Wet purpura: a sinister sign in thrombocytopenia. PMID- 28864562 TI - Waiting for the Sun: the circannual programme of reindeer is delayed by the recurrence of rhythmical melatonin secretion after the arctic night. AB - At temperate latitudes, the annual cycle of day length synchronizes circannual rhythms, and, in mammals, this is mediated via nocturnal production of the pineal hormone melatonin, proportional to the length of the night. Here, we studied circannual synchronization in an arctic species, the reindeer (Rangifer tarandus tarandus), which ceases to produce a rhythmic melatonin signal when it is exposed to extended periods of continuous midwinter darkness and continuous midsummer light. Using food intake, antler growth and moult as endpoints, we demonstrate that when animals living at 70 degrees N are transferred from natural photoperiods in late autumn to either continuous light or continuous darkness, they undergo a conspicuous acceleration of the circannual programme. We conclude that rhythmical melatonin secretion, recommencing when the Sun reappears late in January, is required for proper timing of spring physiological responses, through a delaying effect on the circannual programme set in motion during the preceding autumn. PMID- 28864563 TI - Induced parental care in a poison frog: a tadpole cross-fostering experiment. AB - Understanding the external stimuli and natural contexts that elicit complex behaviours, such as parental care, is key in linking behavioural mechanisms to their real-life function. Poison frogs provide obligate parental care by shuttling their tadpoles from terrestrial clutches to aquatic nurseries, but little is known about the proximate mechanisms that control these behaviours. In this study, we used Allobates femoralis, a poison frog with predominantly male parental care, to investigate whether tadpole transport can be induced in both sexes by transferring unrelated tadpoles to the backs of adults in the field. Specifically, we asked whether the presence of tadpoles on an adult's back can override the decision-making rules preceding tadpole pick-up and induce the recall of spatial memory necessary for finding tadpole deposition sites. We used telemetry to facilitate accurate tracking of individual frogs and spatial analysis to compare movement trajectories. All tested individuals transported their foster-tadpoles to water pools outside their home area. Contrary to our expectation, we found no sex difference in the likelihood to transport or in the spatial accuracy of finding tadpole deposition sites. We reveal that a stereotypical cascade of parental behaviours that naturally involves sex-specific offspring recognition strategies and the use of spatial memory can be manipulated by experimental placement of unrelated tadpoles on adult frogs. As individuals remained inside their home area when only the jelly from tadpole-containing clutches was brushed on the back, we speculate that tactile rather than chemical stimuli trigger these parental behaviours. PMID- 28864564 TI - Metabolite Extraction from Saccharomyces cerevisiae for Liquid Chromatography Mass Spectrometry. AB - Prior to mass spectrometric analysis, cellular small molecules must be extracted and separated from interfering components such as salts and culture medium. To ensure minimal perturbation of metabolism, yeast cells grown in liquid culture are rapidly harvested by filtration as described here. Simultaneous quenching of metabolism and extraction is afforded by immediate immersion in low-temperature organic solvent. Samples prepared using this method are suitable for a range of downstream liquid chromatography-mass spectrometry analyses and are stable in solvent for >1 yr at -80 degrees C. PMID- 28864565 TI - A High-Throughput Method for the Quantitative Determination of Free Amino Acids in Saccharomyces cerevisiae by Hydrophilic Interaction Chromatography-Tandem Mass Spectrometry. AB - Amino acids are the building blocks for protein synthesis and the precursors for many biomolecules, such as glutathione and S-adenosylmethionine. Their intracellular concentrations provide valuable information about the overall metabolic state of the cell, as they are closely connected to carbon and nitrogen metabolism and are tightly regulated to meet cellular demands in ever-changing environments. Here, we describe a fast and simple method enabling metabolic profiling for free amino acids for large numbers of yeast strains. Metabolites are extracted with boiling ethanol and, without further conditioning, analyzed by hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS). Several hundred samples can be prepared in a single day with an analytical runtime of 3.25 min. This method is valuable for functional characterization, identification of metabolic regulators and processes, or monitoring of biotechnological processes. PMID- 28864566 TI - Spectrophotometric Analysis of Ethanol and Glucose Concentrations in Yeast Culture Media. AB - Fermentative growth on glucose is one of the most widely studied conditions of yeast growth in the laboratory. The production of ethanol from sugars is relevant to the wine, beer, and bread industries and to production of biofuels. Assaying the levels of glucose and ethanol in yeast growth medium allows the experimenter to determine the consumption of the carbon source glucose and the production of ethanol. This protocol describes enzyme-coupled assays for determination of glucose and ethanol concentrations in a sample of cell-free culture medium. Enzymes convert glucose or ethanol into other compounds through chemical reactions that reduce NAD(P)+ to NAD(P)H, and the production of NAD(P)H is measured using a spectrophotometer. The methods presented are highly sensitive, with a detection limit of ~0.4 mg/L of glucose and 50 mg/L of ethanol, and also have the advantage of high specificity. For example, glucose and fructose have identical chemical formulas and thus cannot be distinguished by a mass spectrometer, but the enzyme assay presented here is specific for glucose. The glucose assay can be coupled to other assays to determine the quantity of additional carbohydrates such as fructose, trehalose, and glycogen. PMID- 28864567 TI - Preparation of Genomic DNA from Mouse Tails and Other Small Samples. AB - This protocol is used for extracting DNA from fragments of tissue for genotyping transgenic and knockout mice. Digestions of mouse tail fragments are performed overnight at 55 degrees C. Each tail snippet generates 50-100 ug of DNA that can be used in dot or slot blotting to detect a transgene of interest, in Southern hybridization to detect DNA fragments that are <20 kb in size, and, more expediently, as a template in polymerase chain reactions (PCRs). PMID- 28864568 TI - Using Phage Display to Create Recombinant Antibodies. AB - A variety of phage display technologies have been developed since the approach was first described for antibodies. The most widely used approaches incorporate antibody sequences into the minor coat protein pIII of the nonlytic filamentous phage fd or M13. Libraries of variable gene sequences, encoding either scFv or Fab fragments, are made by incorporating sequences into phagemid vectors. The phagemid is packaged into phage particles with the assistance of a helper phage to produce the antibody display phage. This protocol describes a method for creating a phagemid library. The multiple cloning site (MCS) of the pBluescript KS(-) phagemid vector is replaced by digestion with the restriction enzyme BssHII, followed by the insertion of four overlapping oligonucleotides to create a new MCS within the vector. Next, the 3' portion of gene III (from M13mp18) is amplified and combined with an antibody sequence using overlap extension PCR. This product is inserted into the phagemid vector to create pPDS. Two helper plasmids are also created from the modified pBluescript vector: pLINK provides the linker between the heavy and light chains, and pFABC provides the CH1 domain of the heavy chain. An antibody cDNA library is constructed from the RNA of interest and ligated into pPDS. The phagemid library is electroporated into Escherichia coli cells along with the VCS-M13 helper phage. PMID- 28864569 TI - Modification of Antibody Function by Mutagenesis. AB - The ability to "fine-tune" recombinant antibodies by mutagenesis separates recombinant antibodies from hybridoma-derived antibodies because the latter are locked with respect to their properties. Recombinant antibodies can be modified to suit the application: Changes in isotype, format (e.g., scFv, Fab, bispecific antibodies), and specificity can be made once the heavy- and light-chain sequences are available. After immunoglobulin heavy and light chains for a particular antibody have been cloned, the binding site-namely, the complementarity determining regions (CDR)-can be manipulated by mutagenesis to obtain antibody variants with improved properties. The method described here is relatively simple, uses commercially available reagents, and is effective. Using the pComb3H vector, a commercial mutagenesis kit, PfuTurbo polymerase (Agilent), and two mutagenic primers, a library of phage with mutagenized heavy and light CDR3 can be obtained. PMID- 28864570 TI - Isolation, Propagation, and Differentiation of Radial Glia-Like Neural Progenitor Cells in Adherent Cultures. AB - This protocol describes the isolation of radial glia-like neural progenitors (RGLs) from embryonic and adult mouse brain. Their propagation as an adherent monolayer is greatly supported by use of the AK-cyclo(RGDfC) adhesive peptide conjugate that allows the application of fully defined culture conditions in which epidermal growth factor (EGF) represents the only growth factor supplement. RGL cells maintained that way can be efficiently differentiated into the three major CNS cell types: neurons, astrocytes, and oligodendrocytes. PMID- 28864571 TI - Injecting Embryonic Stem Cells into Eight-Cell-Stage Mouse Embryos. AB - In this protocol, eight-cell-stage precompaction embryos from outbred mouse strains are used for the injection of hybrid or inbred embryonic stem (ES) cells. This process often leads to generation of fully ES cell-derived so-called F0 mice (VelociMice). Postinjection culture of embryos is necessary to achieve the highest ratio of fully ES cell-derived mice and high-degree chimeras. Typically, 50 embryos are injected per ES cell clone. PMID- 28864572 TI - Cell Proliferation Analysis during Xenopus Metamorphosis: Using 5-Ethynyl-2 Deoxyuridine (EdU) to Stain Proliferating Intestinal Cells. AB - Proper cell proliferation is important for organ homeostasis and normal tissue development. Aberrations in cell proliferation, however, can give rise to degenerative diseases and cancer. Therefore, accurate and simple methods to evaluate cell proliferation are important and necessary to understand the pathways regulating cell proliferation and mechanisms underlying normal development and pathogenesis. The thymidine analog 5-ethynyl-2'-deoxyuridine (EdU), which is incorporated into DNA during active DNA synthesis (e.g., during S phase of the cell cycle), allows easy visualization of proliferating cells. Incorporated EdU can be detected without harsh chemical or enzymatic treatments and is fully compatible with a number of other staining methods, such as immunohistochemistry and in situ hybridization. This protocol describes how to detect proliferating cells using EdU staining in the intestines of Xenopus tadpoles (stages 54-66). Although this method was developed for studying intestinal metamorphosis, it should be applicable to other tissues/organs and other developmental stages as well. PMID- 28864573 TI - Metabolomics in Yeast. AB - Budding yeast has from the beginning been a major eukaryotic model for the study of metabolic network structure and function. This is attributable to both its genetic and biochemical capacities and its role as a workhorse in food production and biotechnology. New inventions in analytical technologies allow accurate, simultaneous detection and quantification of metabolites, and a series of recent findings have placed the metabolic network at center stage in the physiology of the cell. For example, metabolism might have facilitated the origin of life, and in modern organisms it not only provides nutrients to the cell but also serves as a buffer to changes in the cellular environment, a regulator of cellular processes, and a requirement for cell growth. These findings have triggered a rapid and massive renaissance in this important field. Here, we provide an introduction to analysis of metabolomics in yeast. PMID- 28864574 TI - Genome-Wide RNA Interference: Functional Genomics in the Postgenomics Era. AB - This introduction briefly describes the types of RNAi libraries (both shRNA-based and double-stranded siRNA-based) that are available for understanding diverse biological questions and then discusses recent advances in RNAi screening methodologies in mouse, rat, humans, Drosophila, and worms. PMID- 28864575 TI - Substitution of whole grains for refined grains: a means to avoid excess B vitamin intake. PMID- 28864576 TI - Reply to S-S Zhou and Y Zhou. PMID- 28864577 TI - Moderate-to-vigorous physical activity, but not sedentary time, predicts changes in cardiometabolic risk factors in 10-y-old children: the Active Smarter Kids Study. PMID- 28864578 TI - Reply to A Lu and R Wang. PMID- 28864579 TI - The use of implausible data without caveats is misleading. PMID- 28864580 TI - Reply to E Archer. PMID- 28864581 TI - The NHANES dietary data are physiologically implausible and inadmissible as scientific evidence. PMID- 28864582 TI - Reply to E Archer. PMID- 28864583 TI - Mediterranean diet: omega-6 and omega-3 fatty acids and diabetes. PMID- 28864584 TI - Odd-chain fatty acids as dietary biomarkers for fiber and fish intake. PMID- 28864585 TI - Reply to TM Venalainen et al. PMID- 28864586 TI - Dietary whole grains and zinc nutriture. PMID- 28864587 TI - Reply to HH Sandstead and AS Prasad. PMID- 28864588 TI - Considerations in hypermetabolism, cachexia, and survival in cancer. PMID- 28864589 TI - Reply to N Dominguez and T Canada. PMID- 28864590 TI - Regarding "Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants". PMID- 28864591 TI - Reply to WG Thompson. PMID- 28864592 TI - Invitation for Nominations for 2018. PMID- 28864594 TI - Erratum for Pettit et al. Dietary methionine restriction regulates liver protein synthesis and gene expression independently of eukaryotic initiation factor 2 phosphorylation in mice. J Nutr 2017;147:1031-40. PMID- 28864596 TI - Doctors' use of Facebook, Twitter, and WhatsApp is the focus of 28 GMC investigations. PMID- 28864597 TI - Parvovirus B19 Infection in Children With Arterial Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Case-control studies suggest that acute infection transiently increases the risk of childhood arterial ischemic stroke. We hypothesized that an unbiased pathogen discovery approach utilizing MassTag polymerase chain reaction would identify pathogens in the blood of childhood arterial ischemic stroke cases. METHODS: The multicenter international VIPS study (Vascular Effects of Infection in Pediatric Stroke) enrolled arterial ischemic stroke cases, and stroke-free controls, aged 29 days through 18 years. Parental interview included questions on recent infections. In this pilot study, we used MassTag-polymerase chain reaction to test the plasma of the first 161 cases and 34 controls enrolled for a panel of 28 common bacterial and viral pathogens. RESULTS: Pathogen DNA was detected in no controls and 14 cases (8.7%): parvovirus B19 (n=10), herpesvirus 6 (n=2), adenovirus (n=1), and rhinovirus 6C (n=1). Parvovirus B19 infection was confirmed by serologies in all 10; infection was subclinical in 8. Four cases with parvovirus B19 had underlying congenital heart disease, whereas another 5 had a distinct arteriopathy involving a long-segment stenosis of the distal internal carotid and proximal middle cerebral arteries. CONCLUSIONS: Using MassTag-polymerase chain reaction, we detected parvovirus B19 a virus known to infect erythrocytes and endothelial cells-in some cases of childhood arterial ischemic stroke. This approach can generate new, testable hypotheses about childhood stroke pathogenesis. PMID- 28864598 TI - Relationship of Preexisting Cardiovascular Comorbidities to Newly Diagnosed Atrial Fibrillation After Ischemic Stroke. AB - BACKGROUND AND PURPOSE: There remains uncertainty as whether newly diagnosed atrial fibrillation (AF) after ischemic stroke reflects underlying heart disease and represents an increased risk of cardioembolic stroke, or whether it is triggered by neurogenic mechanisms. We aimed to determine whether cardiovascular comorbidities in patients with new AF after ischemic stroke differ from patients with previous known AF or without AF. METHODS: This French longitudinal cohort study was based on the database covering hospital care from 2009 to 2012 for the entire population. RESULTS: Of 336 291 patients with ischemic stroke, 240 459 (71.5%) had no AF and 95 832 (28.5%) had previously known AF at baseline. Patients without previous AF had a mean CHA2DS2-VASc score of 4.98+/-1.63 SD. During a mean follow-up of 7.9+/-11.5 months, 14 095 (5.9%) of these patients had incident AF, representing an annual incidence of AF after ischemic stroke of 8.9 per 100 person-years (95% confidence interval, 8.8-9.0). New AF patients had higher CHA2DS2-VASc score, more likely comorbidities, and more frequent history of previous transient ischemic attack than patients with previous known AF or without AF. CONCLUSIONS: Preexisting cardiovascular comorbidities underlie AF newly diagnosed after stroke. Consequently, these high-risk patients should be closely monitored for incident AF to facilitate an earlier diagnosis of AF and avoid stroke with appropriate thromboprophylaxis. PMID- 28864599 TI - Response by Brinjikji to Letter Regarding Article "Neurons Over Nephrons: Systematic Review and Meta-Analysis of Contrast-Induced Nephropathy in Patients With Acute Stroke". PMID- 28864600 TI - Letter by Malhotra et al Regarding Article, "Neurons Over Nephrons: Systematic Review and Meta-Analysis of Contrast-Induced Nephropathy in Patients With Acute Stroke". PMID- 28864602 TI - Intermediate Filaments and the Regulation of Cell Motility during Regeneration and Wound Healing. AB - SUMMARYIntermediate filaments (IFs) comprise a diverse group of flexible cytoskeletal structures, the assembly, dynamics, and functions of which are regulated by posttranslational modifications. Characteristically, the expression of IF proteins is specific for tissues, differentiation stages, cell types, and functional contexts. Recent research has rapidly expanded the knowledge of IF protein functions. From being regarded as primarily structural proteins, it is now well established that IFs act as powerful modulators of cell motility and migration, playing crucial roles in wound healing and tissue regeneration, as well as inflammatory and immune responses. Although many of these IF-associated functions are essential for tissue repair, the involvement of IF proteins has been established in many additional facets of tissue healing and regeneration. Here, we review the recent progress in understanding the multiple functions of cytoplasmic IFs that relate to cell motility in the context of wound healing, taking examples from studies on keratin, vimentin, and nestin. Wound healing and regeneration include orchestration of a broad range of cellular processes, including regulation of cell attachment and migration, proliferation, differentiation, immune responses, angiogenesis, and remodeling of the extracellular matrix. In this respect, IF proteins now emerge as multifactorial and tissue-specific integrators of tissue regeneration, thereby acting as essential guardian biopolymers at the interface between health and disease, the failing of which contributes to a diverse range of pathologies. PMID- 28864601 TI - Predictive Value of Computed Tomography Angiography-Determined Occlusion Type in Stent Retriever Thrombectomy. AB - BACKGROUND AND PURPOSE: We investigated whether occlusion type identified with computed tomography angiography (CTA-determined occlusion type) could predict endovascular treatment success using stent retriever (SR) thrombectomy. METHODS: Consecutive patients with stroke who underwent CTA and then endovascular treatment for intracranial large artery occlusion were retrospectively reviewed. CTA-determined occlusion type was classified into truncal-type occlusion or branching-site occlusion and compared with digital subtraction angiography determined occlusion type during endovascular treatment. Three rapidly- and readily-assessable pre-procedural findings (CTA-determined occlusion type, atrial fibrillation, and hyperdense artery sign), which may infer occlusion pathomechanism (embolic versus nonembolic) before endovascular treatment, were evaluated for association with SR success along with stroke risk factors and laboratory results. In addition, the predictive power of the 3 pre-procedural findings for SR success was compared with receiver operating characteristic curve analyses. RESULTS: A total of 238 patients (mean age, 70.0 years; male patients, 52.9%) were included in this study. CTA-determined occlusion type corresponded adequately with digital subtraction angiography-determined occlusion type (P=0.453). Atrial fibrillation (odds ratio, 2.66; 95% confidence interval, 1.25 5.66) and CTA-determined branching-site occlusion (odds ratio, 8.20; confidence interval, 3.45-19.5) were independent predictors for SR success. For predicting SR success, the area under the receiver operating characteristic curve value for CTA-determined branching-site occlusion (0.695) was significantly greater than atrial fibrillation (0.594; P=0.038) and hyperdense artery sign (0.603; P=0.023). CONCLUSIONS: CTA-determined branching-site occlusion was significantly associated with SR success. Furthermore, among the 3 rapidly- and readily-assessable pre procedural findings, CTA-determined branching-site occlusion had the greatest predictive power for SR success. PMID- 28864603 TI - Career Options for Scientists. AB - Most PhD students in the biological sciences will not go on to become academics. For these individuals, choosing the best career path can be difficult. Fortunately, there are many options that allow them to take advantage of skills they hone during graduate and postdoctoral work. PMID- 28864604 TI - Careers in Science Journalism and Writing. AB - Science journalists cover some of the most complex, exciting, and important issues of our day, ranging from the impacts of climate change to emerging infectious diseases. They use words, sounds, images, and graphics to create compelling stories about science that appear in newspapers and magazines, in print and online, on the radio and TV, and in podcasts and videos. The field is undergoing rapid change, which presents both challenges and opportunities. The migration of readers and advertising to the internet and digital platforms has led to declining sales of print publications. This means that jobs are now scarce in traditional print media, but that there are growing opportunities to produce digital content. PMID- 28864605 TI - Radioembolization of Colorectal Liver Metastases: Indications, Technique, and Outcomes. AB - Liver metastases are a major cause of death from colorectal cancer. Intraarterial therapy options for colorectal liver metastases include chemoinfusion via a hepatic arterial pump or port, irinotecan-loaded drug-eluting beads, and radioembolization using 90Y microspheres. Intraarterial therapy allows the delivery of a high dose of chemotherapy or radiation into liver tumors while minimizing the impact on liver parenchyma and avoiding systemic effects. Specificity in intraarterial therapy can be achieved both through preferential arterial flow to the tumor and through selective catheter positioning. In this review, we discuss indications, contraindications, preprocedure evaluation, activity prescription, follow-up, outcomes, and complications of radioembolization of colorectal liver metastases. Methods for preventing off target embolization, increasing the specificity of microsphere delivery, and reducing the lung-shunt fraction are discussed. There are 2 types of 90Y microspheres: resin and glass. Because glass microspheres have a higher activity per particle, they can deliver a particular radiation dose with fewer particles, likely reducing embolic effects. Glass microspheres thus may be more suitable when early stasis or reflux is a concern, in the setting of hepatocellular carcinoma with portal vein invasion, and for radiation segmentectomy. Because resin microspheres have a lower activity per particle, more particles are needed to deliver a particular radiation dose. Resin microspheres thus may be preferable for larger tumors and those with high arterial flow. In addition, resin microspheres have been approved by the U.S. Food and Drug Administration for colorectal liver metastases, whereas institutional review board approval is required before glass microspheres can be used under a compassionate-use or research protocol. Finally, radiation segmentectomy involves delivering a calculated lobar activity of 90Y microspheres selectively to treat a tumor involving 1 or 2 liver segments. This technique administers a very high radiation dose and effectively causes the ablation of tumors that are too large or are in a location considered unsafe for thermal ablation. The selective delivery spares surrounding normal liver, reducing the risk of liver failure. PMID- 28864606 TI - Approaches to Multireceptor Targeting: Hybrid Radioligands, Radioligand Cocktails, and Sequential Radioligand Applications. AB - Modern drug discovery highly depends on the identification and validation of the drug targets. Using the method of in vitro quantitative receptor autoradiography, we demonstrated that-for instance, in neuroendocrine tumors-up to 3 receptors can be coexpressed at a relatively high density. In addition, nonendocrine tumors such as breast, prostate, and brain tumors concomitantly express several G protein-coupled receptors at a high density. We propose 3 strategies for exploiting these findings for multireceptor targeting in vivo: use of heterobivalent or heteromultivalent ligands, which may bind simultaneously or monovalently to their different molecular targets; coinjection of a cocktail of radioligands; and sequential injection of different radioligands. Any of these strategies may help to remedy some of the major problems in cancer targeting: heterogeneity, change in phenotype during disease progression, and resistance. PMID- 28864607 TI - Glu-Ureido-Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers. AB - In recent years, several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of theranostic radiopharmaceuticals for the treatment of prostate cancer (PC). In the second decade of the 21st century, a new era in nuclear medicine was initiated by the clinical introduction of small-molecule PSMA inhibitor radioligands, 40 y after the clinical introduction of 18F-FDG. Because of the high incidence and mortality of PC, the new PSMA radioligands have already had a remarkable impact on the clinical management of PC. For the continuing clinical development and long-term success of theranostic agents, designing modern prospective clinical trials in theranostic nuclear medicine is essential. First-in-human studies with PSMA radioligands derived from small-molecule PSMA inhibitors showed highly sensitive imaging of PSMA-positive PC by means of PET and SPECT as well as a dramatic response of metastatic castration-resistant PC after PSMA radioligand therapy. This tremendous success logically led to the initiation of prospective clinical trials with several PSMA radioligands. Meanwhile, MIP-1404, PSMA-11, 2-(3-{1 carboxy-5-[(6-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL), PSMA-617, PSMA-1007, and others have entered or will enter prospective clinical trials soon in several countries. The significance becomes apparent by, for example, the considerable increase in the number of publications about PSMA-targeted PET imaging from 2013 to 2016 (e.g., a search of the Web of Science for "PSMA" AND "PET" found only 19 publications in 2013 but 218 in 2016). Closer examination of the initial success of PC treatment with PSMA inhibitor radiotracers leads to several questions from the basic research perspective as well as from the perspective of clinical demands: What lessons have been learned regarding the design of PSMA radioligands that have already been developed? Has an acceptable compromise between optimal PSMA radioligand design and a broad range of clinical demands been reached? Can the lessons learned from multiple successes within the PSMA experience be transferred to further theranostic approaches? PMID- 28864608 TI - Theranostic Concepts: More Than Just a Fashion Trend-Introduction and Overview. PMID- 28864609 TI - Identification of Ligands and Translation to Clinical Applications. AB - Technologic advances in molecular biology and biotechnology are increasingly being used for the development of new tumor-targeting tracers. In oncology, major progress has recently been achieved with peptidic and proteinaceous compounds. The development of new biocompatible molecules relies on the identification and validation of new target structures in close conjunction with the application of novel techniques. The identification of lead compounds by these techniques is followed by the screening of various derivatives of these molecules. Hence, high throughput methods that generate vast libraries of epitopes have been applied. These libraries are screened to identify the few variants that bind with a high affinity to the target structure. A key feature of this strategy is the large number of candidate molecules that can be identified. Further evaluation and optimization of these molecules requires characterization of structure-function relationships and subsequent improvement with respect to binding, internalization, and biodistribution through a rational design of corresponding analogs. PMID- 28864610 TI - Iodine Symporter Targeting with 124I/131I Theranostics. AB - Theranostics, a modern approach combining therapeutics and diagnostics, is among the most promising concepts in nuclear medicine for optimizing and individualizing treatments for many cancer entities. Theranostics has been used in clinical routines in nuclear medicine for more than 60 y-as 131I for diagnostic and therapeutic purposes in thyroid diseases. In this minireview, we provide a survey of the use of 2 different radioiodine isotopes for targeting the sodium-iodine symporter in thyroid cancer and nonthyroidal neoplasms as well as a brief summary of theranostics for neuroendocrine neoplasms and metastatic castration-refractory prostate cancer. In particular, we discuss the role of 124I based dosimetry in targeting of the sodium-iodine symporter and describe the clinical application of 124I dosimetry in a patient who had radioiodine refractory thyroid cancer and who underwent a redifferentiation treatment with the mitogen-activated extracellular signal-related kinase kinase inhibitor trametinib. PMID- 28864612 TI - Clinical History of the Theranostic Radionuclide Approach to Neuroendocrine Tumors and Other Types of Cancer: Historical Review Based on an Interview of Eric P. Krenning by Rachel Levine. AB - In nuclear medicine, the term theranostics describes the combination of therapy and diagnostic imaging. In practice, this concept dates back more than 50 years; however, among the most successful examples of theranostics are peptide receptor scintigraphy and peptide receptor radionuclide therapy of neuroendocrine tumors. The development of these modalities through the radiolabeling of somatostatin analogs with various radionuclides has led to a revolution in patient management and established a foundation for expansion of the theranostic principle into other oncology indications. This article provides a review of the evolution and development of the theranostic radionuclide approach to the management of neuroendocrine tumors, as described by the inventor of this technique, Eric P. Krenning, in an interview with Rachel Levine. PMID- 28864613 TI - Somatostatin Receptor 2-Targeting Compounds. AB - The molecular imaging and treatment of neuroendocrine tumors (NETs) with radiolabeled somatostatin analogs represent a milestone in the development of theranostic compounds. Whole-body scintigraphy with 111In-pentetreotide has revolutionized the diagnosis and staging of NETs and the evaluation of treatment outcomes. At present, diagnostic accuracy with positron-emitting radionuclides is greater than 90%. Peptide receptor radionuclide therapy (PRRT) has become a well accepted treatment for patients with well-differentiated inoperable or metastatic NETs and disease progression after first-line treatment. Disease control rates (complete or partial remission or stable disease in patients with formerly progressive disease) of up to 95%, with a low incidence of long-term hematologic and renal toxicity, have been reported. In a recently published randomized trial, compared with intensified treatment of midgut NETs with long-acting and repeatable octreotide, PRRT reduced the hazard of disease progression and death by 79%. Upcoming developments in PRRT include the use of somatostatin receptor antagonists and alpha-emitting radionuclides, which may further enhance treatment outcomes. PMID- 28864611 TI - Norepinephrine Transporter as a Target for Imaging and Therapy. AB - The norepinephrine transporter (NET) is essential for norepinephrine uptake at the synaptic terminals and adrenal chromaffin cells. In neuroendocrine tumors, NET can be targeted for imaging as well as therapy. One of the most widely used theranostic agents targeting NET is metaiodobenzylguanidine (MIBG), a guanethidine analog of norepinephrine. 123I/131I-MIBG theranostics have been applied in the clinical evaluation and management of neuroendocrine tumors, especially in neuroblastoma, paraganglioma, and pheochromocytoma. 123I-MIBG imaging is a mainstay in the evaluation of neuroblastoma, and 131I-MIBG has been used for the treatment of relapsed high-risk neuroblastoma for several years, however, the outcome remains suboptimal. 131I-MIBG has essentially been only palliative in paraganglioma/pheochromocytoma patients. Various techniques of improving therapeutic outcomes, such as dosimetric estimations, high-dose therapies, multiple fractionated administration and combination therapy with radiation sensitizers, chemotherapy, and other radionuclide therapies, are being evaluated. PET tracers targeting NET appear promising and may be more convenient options for the imaging and assessment after treatment. Here, we present an overview of NET as a target for theranostics; review its current role in some neuroendocrine tumors, such as neuroblastoma, paraganglioma/pheochromocytoma, and carcinoids; and discuss approaches to improving targeting and theranostic outcomes. PMID- 28864614 TI - Somatostatin Receptor Antagonists for Imaging and Therapy. AB - Somatostatin receptor (sstr) scintigraphy for imaging and sstr analogs for treatment have been used for more than 20 y. An important improvement in recent years was the introduction of peptide receptor radionuclide therapy with radiolabeled sstr agonists, such as [90Y-DOTA0,Tyr3]octreotide or [177Lu DOTA0,Tyr3]octreotide (90Y- or 177Lu-DOTATOC, respectively) and [177Lu DOTA0,Tyr3]octreotate (177Lu-DOTATATE). PET/CT with 68Ga-labeled sstr agonists, such as 68Ga-DOTATOC, 68Ga-DOTATATE, and [68Ga-DOTA,1-Nal3]octreotide (68Ga DOTANOC), plays an important role in staging and restaging neuroendocrine tumors. Most importantly, sstr scintigraphy and sstr PET/CT can distinguish patients who will qualify for and benefit from peptide receptor radionuclide therapy. This characteristic of sstr targeting is important because it allows a personalized treatment approach (theranostic approach). Until recently, it was thought that internalization of the radiolabeled agonist was mandatory for sstr-mediated imaging and therapy. It was Ginj et al. who proposed in 2006 the paradigm shift that radiolabeled sstr antagonists may perform better than agonists despite the lack of internalization. Despite the rather limited number of head-to-head comparisons of sstr antagonists and agonists, the superiority of sstr antagonists was demonstrated in several cases. From a small library of sstr antagonists, the analog JR11 (Cpa-c[d-Cys-Aph(Hor)-d-Aph(Cbm)-Lys-Thr-Cys]-d-Tyr-NH2), an antagonist with selectivity for sstr subtype 2, showed the best overall characteristics for sstr subtype 2 targeting and was therefore selected for clinical translation. JR11 is under clinical development as a PET imaging agent when labeled with 68Ga (68Ga-NODAGA-JR11 or 68Ga-OPS202) and as a therapeutic agent when labeled with 177Lu (177Lu-DOTA-JR11 or 177Lu-OPS201). In this article, we discuss the development and current status of radiolabeled sstr antagonists. Evidence based on preclinical work, on quantitative in vivo autoradiography of human tumor slices, and on human data now supports a shift to sstr antagonists. PMID- 28864615 TI - Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy. AB - The prostate-specific membrane antigen (PSMA) is highly expressed on most prostate cancer (PC) cells. Therefore, the targeting of PSMA has become increasingly important over the last decade. Glu-urea-based PSMA ligands used for both imaging and radioligand therapy are the mainstays of the current success. For PET imaging, both 68Ga- and 18F-labeled agents have been successfully translated to clinical applications. Mainly retrospective cohort studies have shown a high value in the setting of biochemical recurrence, with high detection rates even in the presence of low prostate-specific antigen levels. Preliminary data indicated that radioguided surgery with PSMA ligands may help to further improve patient outcomes because it facilitates the removal of small tumor deposits that are otherwise difficult to detect. For primary PC, PSMA ligand PET imaging has been shown to be superior to cross-sectional imaging for the detection of metastatic lymph nodes. In addition, it promises to also provide intraprostatic tumor localization, especially when used in combination with multiparametric MRI. Increasing numbers of studies have reported considerable changes in management resulting from PSMA ligand PET imaging for both biochemical recurrence and primary disease. The use of 177Lu-PSMA-based radioligand therapy has demonstrated a reasonable response, mainly as defined by a prostate-specific antigen response of more than 50%, comparable to other recently introduced agents. Especially given the high level of safety of 177Lu-PSMA radioligand therapy, with only minimal grade 3 and 4 toxicities reported so far, it has the potential to expand options for metastatic castration-resistant PC. This review is intended to provide a comprehensive overview of the current literature on low molecular-weight PSMA ligands for both PET imaging and therapeutic approaches, with a focus on agents that have been clinically adopted. PMID- 28864616 TI - CXCR4 Ligands: The Next Big Hit? AB - The G protein-coupled protein receptor C-X-C chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematologic cancers. Binding of its ligand, C-X-C chemokine ligand 12 (CXCL12), results in receptor internalization and activation of several signal transduction pathways, such as phosphoinositide 3-kinase/protein kinase B, which are critical in cell proliferation, angiogenesis, development of metastasis, and survival. Also, the CXCR4-CXCL12 axis is involved in the interaction between hematopoietic stem cells (as well as hematologic and solid tumor cells) and their protective microenvironment. This interaction can be disrupted by CXCR4 antagonists. This concept is being used clinically to harvest hematopoietic stem or progenitor cells from bone marrow and to sensitize cancer cells to conventional chemotherapy and radiotherapy, and the potential to overcome tumor microenvironment-driven immunosuppression is being explored. This review focuses on new strategies for improvement of cancer treatment by targeting of the CXCR4 CXCL12 interaction. Because of its critical role in cancer, many peptidic and nonpeptidic ligands with different modes of antagonistic activity against the CXCR4-CXCL12 axis have been developed, with some of them reaching clinical trials. Molecular imaging with recently developed radiolabeled CXCR4 ligands could facilitate the selection of patients who might benefit from directed targeted therapy, including CXCR4-directed endoradiotherapy. PMID- 28864618 TI - Theranostics Using Antibodies and Antibody-Related Therapeutics. AB - In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment. In addition, these drugs are relatively easy to radiolabel. Noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibody-related therapeutics. Molecular antibody imaging can potentially elucidate drug target expression, tracer uptake in the tumor, tumor saturation, and heterogeneity for these parameters within the tumor. These data can support drug development and may aid in patient stratification and monitoring of the treatment response. Selecting a radionuclide for theranostic purposes generally starts by matching the serum half-life of the mAb or antibody-related therapeutic and the physical half-life of the radionuclide. Furthermore, PET imaging allows better quantification than the SPECT technique. This information has increased interest in theranostics using PET radionuclides with a relatively long physical half-life, such as 89Zr. In this review, we provide an overview of ongoing research on mAbs and antibody-related theranostics in preclinical and clinical oncologic settings. We identified 24 antibodies or antibody-related therapeutics labeled with PET radionuclides for theranostic purposes in patients. For this approach to become integrated in standard care, further standardization with respect to the procedures involved is required. PMID- 28864619 TI - Therapeutic Radiometals Beyond 177Lu and 90Y: Production and Application of Promising alpha-Particle, beta--Particle, and Auger Electron Emitters. AB - In recent years, new alpha-particle-, beta--particle-, and Auger electron emitting radiometals-such as 67Cu, 47Sc, 166Ho, 161Tb, 149Tb, 212Pb/212Bi, 225Ac, and 213Bi-have been produced and evaluated (pre)clinically for therapeutic purposes. In this short review article, the most important routes of production of these radiometals are critically discussed, as are examples of their application in preclinical and clinical studies. PMID- 28864620 TI - Individualized Dosimetry for Theranostics: Necessary, Nice to Have, or Counterproductive? AB - In 2005, the term theragnostics (theranostics) was introduced for describing the use of imaging for therapy planning in radiation oncology. In nuclear medicine, this expression describes the use of tracers for predicting the absorbed doses in molecular radiotherapy and, thus, the safety and efficacy of a treatment. At present, the most successful groups of isotopes for this purpose are 123I/124I/131I, 68Ga/177Lu, and 111In/86Y/90Y. The purpose of this review is to summarize available data on the dosimetry and dose-response relationships of several theranostic compounds, with a special focus on radioiodine therapy for differentiated thyroid cancer and peptide receptor radionuclide therapy. These are treatment modalities for which dose-response relationships for healthy tissues and tumors have been demonstrated. In addition, available data demonstrate that posttherapeutic dosimetry after a first treatment cycle predicts the absorbed doses in further cycles. Both examples show the applicability of the concept of theranostics in molecular radiotherapies. Nevertheless, unanswered questions need to be addressed in clinical trials incorporating dosimetry-related concepts for determining the amount of therapeutic activity to be administered. PMID- 28864621 TI - Nuclear Medicine Career Portal for Young Physicians. PMID- 28864622 TI - Nominations Open for 2 SNMMI Awards. PMID- 28864623 TI - From the ABNM: Updates on MOC Part 3. PMID- 28864624 TI - SNMMI Leadership Update: Strategic Advocacy. PMID- 28864628 TI - All tests can sometimes cause more harm than good. PMID- 28864629 TI - Predictive Value of PET Response Combined with Baseline Metabolic Tumor Volume in Peripheral T-Cell Lymphoma Patients. AB - Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non Hodgkin lymphomas with poor outcomes on current therapy. We investigated whether response assessed with PET/CT combined with baseline total metabolic tumor volume (TMTV) could detect early relapse or refractory disease. Methods: From 7 European centers, 140 patients with nodal PTCL who underwent baseline PET/CT were selected. Forty-three had interim PET (iPET) performed after 2 cycles (iPET2), 95 had iPET performed after 3 or 4 cycles (iPET3/4), and 96 had end-of-treatment PET (eotPET). Baseline TMTV was computed with a 41% SUVmax threshold, and PET response was reported using the Deauville 5-point scale. Results: With a median of 43 mo of follow-up, the 2-y progression-free survival (PFS) and overall survival (OS) were 51% and 67%, respectively. iPET2-positive patients (Deauville score >= 4) had a significantly worse outcome than iPET2-negative patients (P < 0.0001, hazard ratio of 6.8 for PFS; P < 0.0001, hazard ratio of 6.6 for OS). The value of iPET3/4 was also confirmed for PFS (P < 0.0001) and OS (P < 0.0001). The 2-y PFS and OS for iPET3/4-positive (n = 28) and iPET3/4-negative (n = 67) patients were 16% and 32% versus 75% and 85%, respectively. The eotPET results also reflected patient outcome. A model combining TMTV and iPET3/4 stratified the population into distinct risk groups (TMTV <= 230 cm3 and iPET3/4-negative [2-y PFS/OS, 79%/85%]; TMTV > 230 cm3 and iPET3/4-negative [59%/84%]; TMTV <= 230 cm3 and iPET3/4-positive [42%/50%]; TMTV > 230 cm3 and iPET3/4-positive [0%/18%]). Conclusion: iPET response is predictive of outcome and allows early detection of high-risk PTCL patients. Combining iPET with TMTV improves risk stratification in individual patients. PMID- 28864630 TI - A PET/CT-Based Strategy Is a Stronger Predictor of Survival Than a Standard Imaging Strategy in Patients with Head and Neck Squamous Cell Carcinoma. AB - Our purpose was to examine whether staging of head and neck squamous cell carcinoma (HNSCC) by upfront 18F-FDG PET/CT (i.e., on the day of biopsy and before the biopsy) discriminates survival better than the traditional imaging strategies based on chest x-ray plus head and neck MRI (CXR/MRI) or chest CT plus head and neck MRI (CCT/MRI). Methods: We performed a masked prospective cohort study based on paired data. Consecutive patients with histologically verified primary HNSCC were recruited from Odense University Hospital from September 2013 to March 2016. All patients underwent CXR/MRI, CCT/MRI, and PET/CT on the same day. Tumors were categorized as localized (stages I and II), locally advanced (stages III and IVB), or metastatic (stage IVC). Discriminative ability for each imaging modality with respect to HNSCC staging were compared using Kaplan-Meier analysis, Cox proportional hazards regression with the Harrell C-index, and net reclassification improvement. Results: In total, 307 patients with histologically verified HNSCC were included. Use of PET/CT significantly altered the stratification of tumor stage when compared with either CXR/MRI or CCT/MRI (chi2, P < 0.001 for both). Cancer stages based on PET/CT, but not CXR/MRI or CCT/MRI, were associated with significant differences in mortality risk on Kaplan-Meier analyses (P <= 0.002 for all PET/CT-based comparisons). Furthermore, overall discriminative ability was significantly greater for PET/CT (C-index, 0.712) than for CXR/MRI (C-index, 0.675; P = 0.04) or CCT/MRI (C-index, 0.657; P = 0.02). Finally, PET/CT was significantly associated with a positive net reclassification improvement when compared with CXR/MRI (0.184, P = 0.03) but not CCT/MRI (0.094%, P = 0.31). Conclusion: Tumor stages determined by PET/CT were associated with more distinct prognostic properties in terms of survival than those determined by standard imaging strategies. PMID- 28864631 TI - Radionuclide Tumor Targeting Using ADAPT Scaffold Proteins: Aspects of Label Positioning and Residualizing Properties of the Label. AB - Visualization of cancer-associated alterations of molecular phenotype using radionuclide imaging is a noninvasive approach to stratifying patients for targeted therapies. The engineered albumin-binding domain-derived affinity protein (ADAPT) is a promising tracer for radionuclide molecular imaging because of its small size (6.5 kDa), which satisfies the precondition for efficient tumor penetration and rapid clearance. Previous studies demonstrated that the human epidermal growth factor receptor type 2 (HER2)-targeting ADAPT6 labeled with radiometals at the N terminus is able to image HER2 expression in xenografts a few hours after injection. The aim of this study was to evaluate whether the use of a nonresidualizing label or placement of the labels at the C terminus would further improve the targeting properties of ADAPT6. Methods: Two constructs, Cys2 ADAPT6 and Cys59-ADAPT6, having the (HE)3DANS sequence at the N terminus were produced and site-specifically labeled using 111In-DOTA or 125I-iodo-((4 hydroxyphenyl)ethyl) maleimide (HPEM). The conjugates were compared in vitro and in vivo. HER2-targeting properties and biodistribution were evaluated in BALB/C nu/nu mice bearing ovarian carcinoma cell (SKOV-3) xenografts. Results: Specific HER2 binding and high affinity were preserved after labeling. Both Cys2-ADAPT6 and Cys59-ADAPT6 were internalized slowly by HER2-expressing cancer cells. Depending on the label position, uptake at 4 h after injection varied from 10% to 22% of the injected dose per gram of tumor tissue. Regardless of terminus position, the 125I-HPEM label provided more than 140-fold lower renal uptake than the 111In-DOTA label at 4 after injection. The tumor-to-organ ratios were, in contrast, higher for both of the 111In-DOTA-labeled ADAPT variants in other organs. Tumor-to-blood ratios for 111In-labeled Cys2-ADAPT6 and Cys59-ADAPT6 did not differ significantly (250-280), but 111In-DOTA-Cys59-ADAPT6 provided significantly higher tumor-to-lung, tumor-to-liver, tumor-to-spleen, and tumor-to muscle ratios. Radioiodinated variants had similar tumor-to-organ ratios, but 125I-HPEM-Cys59-ADAPT6 had significantly higher tumor uptake and a higher tumor to-kidney ratio. Conclusion: Residualizing properties of the label strongly influence the targeting properties of ADAPT6. The position of the radiolabel influences targeting as well, although to a lesser extent. Placement of a label at the C terminus yields the best biodistribution features for both radiometal and radiohalogen labels. Low renal retention of the radioiodine label creates a precondition for radionuclide therapy using 131I-labeled HPEM-Cys59-ADAPT6. PMID- 28864632 TI - 223Ra Therapy of Advanced Metastatic Castration-Resistant Prostate Cancer: Quantitative Assessment of Skeletal Tumor Burden for Prognostication of Clinical Outcome and Hematologic Toxicity. AB - The aim of this study was to investigate the prognostic value of the quantitative assessment of skeletal tumor burden on bone scintigraphy (Bone Scan Index [BSI]) in patients who have advanced metastatic castration-resistant prostate cancer (mCRPC) and are receiving 223RaCl2 We hypothesized that the BSI can serve as a prognostic biomarker of overall survival (OS) and hematologic toxicity and as a tool for response assessment in patients with mCRPC treated with 223RaCl2Methods: This study was a retrospective investigation of a Danish cohort of mCRPC patients who received 223RaCl2 therapy between March 2014 and October 2015 and for whom baseline bone scintigraphy was available. Bone scintigraphy studies were reviewed and graded according to the extent of disease. Furthermore, an automated BSI (EXINI BoneBSI) was obtained for baseline scintigraphy studies and follow-up scans after 3 cycles as well as at the end of therapy. Clinical outcomes were OS and occurrence of hematologic toxicity of grades 2-5. Associations between the BSI and clinical outcomes were investigated in multivariate regression models including the visual assessment of bone scintigraphy and other relevant covariates. Results: A total of 88 patients were included. The median number of completed 223RaCl2 cycles was 4, and 27 patients (31%) completed 6 cycles. The BSI was significantly associated with OS in the multivariate analysis; the median OS for patients with a BSI of greater than 5 was 8.2 mo, and the median OS for patients with a BSI of less than or equal to 5 was 15.0 mo (hazard ratio, 2.65 [95% confidence interval, 1.5-4.71]; P = 0.001). Likewise, the baseline BSI was prognostic for the occurrence of hematologic toxicity; patients with a BSI of greater than 5 had an odds ratio of 3.02 (95% confidence interval, 1.2-7.8; P = 0.02) for toxicity. The BSI declined during therapy in 44% of the patients who completed 3 cycles of 223RaCl2 (n = 52) and in 84% of the patients after the end of therapy (n = 32). There was no significant association between a change in the BSI during therapy and OS. Conclusion: The BSI is a promising biomarker for prognostication of OS and hematologic toxicity in late-stage mCRPC patients receiving 223RaCl2 Further prospective studies are needed to evaluate the potential of the BSI for response assessment in 223RaCl2 therapy. PMID- 28864633 TI - Correlations of 18F-THK5351 PET with Postmortem Burden of Tau and Astrogliosis in Alzheimer Disease. AB - Clinical PET studies using 18F-THK5351 have demonstrated significant tracer retention in sites susceptible to tau burden in Alzheimer disease (AD). However, the in vivo PET signal to reflect tau aggregates remains controversial. Methods: We examined the spatial pattern of tracer binding, amyloid-beta, tau, and gliosis in an autopsy-confirmed AD patient who underwent 18F-THK5351 and 11C-Pittsburgh compound B PET before death. Results: Regional in vivo 18F-THK5351 retention was significantly correlated with the density of tau aggregates in the neocortex and monoamine oxidase-B in the whole brain, but not correlated with that of insoluble amyloid-beta. Furthermore, significant association was observed between the density of tau aggregates, monoamine oxidase-B, and glial fibrillary acidic protein, suggesting that neocortical tau would strongly influence the formation of reactive astrocytes. Conclusion:18F-THK5351 PET may have limited utility as a biomarker of tau pathology in AD; however, it could be used to monitor the neuroinflammatory processes in the living brain. PMID- 28864634 TI - Evaluation of the Lysophosphatidic Acid Receptor Type 1 Radioligand 11C-BMT 136088 for Lung Imaging in Rhesus Monkeys. AB - The lysophosphatidic acid receptor type 1 (LPA1) is 1 of 6 known receptors of the extracellular signaling molecule lysophosphatidic acid. It mediates effects such as cell proliferation, migration, and differentiation. In the lung, LPA1 is involved in pathways leading, after lung tissue injury, to pulmonary fibrosis instead of normal healing, by mediating fibroblast recruitment and vascular leakage. Thus, a LPA1 PET radiotracer may be useful for studying lung fibrosis or for developing LPA1-targeting drugs. We developed and evaluated the radiotracer 11C-BMT-136088 (1-(4'-(3-methyl-4-(((1(R)-(3-11C methylphenyl)ethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1'-biphenyl]-4 yl)cyclopropane-1-carboxylic acid) in rhesus monkeys to image LPA1 in the lung in vivo with PET. Methods: The study consisted of 3 parts: test-retest scans; self saturation to estimate the tracer's in vivo dissociation constant, nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND); and dosimetry. In the first 2 parts, the radiotracer was administered using a bolus-plus-infusion protocol, the arterial input function was measured, and the animals underwent 2 scans per day separated by about 4 h. Lung regions of interest were segmented, and the tissue density estimated, from CT images. A fixed blood volume correction was applied. The tracer volume of distribution (VT) was estimated using multilinear analysis 1 (MA1) or equilibrium analysis (EA). Results:11C-BMT-136088 baseline VT was 1.83 +/- 0.16 (MA1, n = 5) or 2.1 +/- 0.55 (EA, n = 7) mL of plasma per gram of tissue in the left and right lung regions of interest, with a test-retest variability of -6% (MA1, n = 1) or 1% +/- 14% (EA, n = 2). For the self-saturation study, 11C-BMT-136088 VND and BPND were estimated to be 0.9 +/- 0.08 mL of plasma per gram of tissue and 1.1 +/ 0.14, respectively. The unlabeled drug dose and plasma concentration leading to a 50% reduction of 11C-BMT-136088 specific binding were 73 +/- 30 nmol/kg and 28 +/- 12 nM, respectively. The average plasma free fraction was 0.2%; thus, the tracer's in vivo dissociation constant was estimated to be 55 pM. For the dosimetry study, the highest organ dose was in the liver (43.1 +/- 4.9 and 68.9 +/- 9.4 MUSv/MBq in reference human male and female phantoms, respectively), and the effective dose equivalent was 6.9 +/- 0.6 and 8.7 +/- 0.6 MUSv/MBq, respectively. Conclusion: Specific binding of 11C-BMT-136088 can be reliably measured to quantify LPA1 in the lungs of rhesus monkeys in vivo. PMID- 28864638 TI - Fast-TRKing Drug Development for Rare Molecular Targets. AB - Drug development for rare molecular targets in oncology presents unique challenges. In this issue of Cancer Discovery, Drilon and colleagues report the accelerated development and innovative initial clinical trial strategy of a next generation TRK inhibitor, LOXO-195, designed to overcome common secondary TRK resistance mutations. Cancer Discov; 7(9); 934-6. (c)2017 AACR.See related article by Drilon et al., p. 963. PMID- 28864639 TI - Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions. AB - Reversion mutations associated with PARP inhibitor resistance have been identified in tumors with RAD51C, RAD51D, and PALB2 as well as BRCA1 and BRCA2 mutations. Multiple different reversion mutations can occur in a single patient, and they can be detected by analysis of circulating cell-free DNA. Cancer Discov; 7(9); 937-9. (c)2017 AACRSee related article by Kondrashova et al., p. 984See related article by Quigley et al., p. 999See related article by Goodall et al., p. 1006. PMID- 28864640 TI - Spotlight on Ibrutinib in PCNSL: Adding Another Feather to Its Cap. AB - In this issue Grommes and colleagues elegantly show that the irreversible inhibitor of Bruton tyrosine kinase, ibrutinib, promotes a high proportion of durable responses in primary central nervous system lymphoma, a type of diffuse large B-cell lymphoma (DLBCL), and also in secondary DLBCL relapsing to the central nervous system. Mutations in the B-cell antigen receptor-associated protein CD79B with upregulation of the MTOR pathway were associated with diminished response, but preclinical combination of PIK3CA and PIK3CD inhibitors synergized with ibrutinib to overcome this resistance mechanism, providing opportunity for further targeted therapy of this difficult-to-treat disease. Cancer Discov; 7(9); 940-2. (c)2017 AACRSee related article by Grommes et al., p. 1018. PMID- 28864641 TI - Trends in Treatment, Outcomes, and Incidence of Orthopedic Surgery in Patients with Rheumatoid Arthritis: An Observational Cohort Study Using the Japanese National Database of Rheumatic Diseases. AB - OBJECTIVE: In this study, we investigated the changes in clinical outcome, treatment, and incidence of orthopedic surgery in patients with rheumatoid arthritis (RA) from 2004 to 2014. METHODS: Data were studied from the Japanese nationwide cohort database, NinJa (National Database of Rheumatic Diseases by iR net in Japan), from 2004 to 2014. The time trends in the incidence of orthopedic procedures were analyzed using linear regression analysis. The cross-sectional annual data were compared between 2004 and 2014 to analyze the changes in clinical outcome and treatment. RESULTS: The incidence of orthopedic surgeries in patients with RA consistently decreased from 72.2 procedures per 1000 patients in 2004 to 51.5 procedures per 1000 patients in 2014 (regression coefficient = 0.0028, 95% CI -0.0038 to -0.0019, p < 0.001). The greatest reduction was found in total knee arthroplasty and total hip arthroplasty. Disease activity and functional disability improved significantly over this decade. The proportions of patients receiving methotrexate and biologic disease-modifying antirheumatic drugs significantly increased from 39.6% and 1.7% in 2004 to 63.8% and 27.4% in 2014, respectively. CONCLUSION: The overall incidence of orthopedic surgeries in patients with RA significantly decreased, accompanied by improved clinical outcomes because of the expanded use of effective drugs; however, the declining trend differed between procedures or locations. The results from the present study suggest that there might be a change in supply and demand for orthopedic surgeries. PMID- 28864642 TI - Closing the Serological Gap in the Antiphospholipid Syndrome: The Value of "Non criteria" Antiphospholipid Antibodies. AB - OBJECTIVE: Most clinicians use the 2006 Sydney classification criteria to evaluate patients suspected of having antiphospholipid syndrome (APS). Although sensitive and specific for APS, many patients fulfilling clinical criteria for the syndrome are persistently negative for the specific serological tests ("laboratory criteria"). These "seronegative APS" (SN-APS) patients can go undiagnosed and untreated until they experience serious clinical events. This study's objective was to describe antibody profiles of SN-APS patients using non criteria markers, assess the clinical utility of these markers separately and in combination, and suggest incorporation into guidelines for patients suspected of APS. METHODS: We categorized 175 consecutive patients suspected of APS into 2 subgroups: 107 fulfilling Sydney APS classification for seropositive APS (SP-APS) and 68 with clinical manifestations suggestive of APS but having negative serology, on 2 occasions, for criteria markers (SN-APS). On study inclusion, samples were retested for criteria and 11 non-criteria markers, including antiphosphatidylserine/prothrombin antibodies. RESULTS: Using 4 of 11 non criteria tests, a cumulative 30.9% of SN-APS patients were detected. Combining results of all 11 non-criteria tests, 25 SN-APS (36.8%) and 89 SP-APS (83.2%) were positive for 1 or more non-criteria antibodies. CONCLUSION: Failure to diagnose APS can result in severe clinical consequences. Patients displaying clinical features of APS, but negative for conventional criteria markers, should undergo additional testing for non-criteria biomarkers. In our cohort, around one third of SN-APS patients showed reactivity to 1 or more non-criteria markers. An update to the current classification criteria incorporating new serological markers should be considered to identify and stratify patients with APS for more effective treatment and management. PMID- 28864643 TI - Performance of Screening Tests for Cognitive Impairment in Systemic Lupus Erythematosus. AB - OBJECTIVE: There is a need for a cognitive function screening test that can be administered to patients with systemic lupus erythematosus (SLE) in clinic. The objectives of this study were to determine (1) prevalence of cognitive impairment (CI) in SLE by the Montreal Cognitive Assessment (MoCA), Mini Mental State Examination (MMSE), in relation to the Hopkins Verbal Learning Test-Revised (HVLT R), and Perceived Deficits Questionnaire 5-Item (PDQ-5); and (2) associated factors with CI. METHODS: Consecutive patients followed at a single center were recruited. HVLT-R, MoCA, and MMSE were administered. Sensitivity/specificity, positive (PPV)/negative (NPV) predictive values, and positive likelihood ratio (LR+) of MoCA/MMSE were determined (compared to HVLT-R). A test on intellectual ability and questionnaires on anxiety, depression, and perceived cognitive deficits were completed. Regression analyses determined associations with CI. RESULTS: Of 98 patients, 48% had CI using MoCA and 31% using HVLT-R. Sensitivity was higher for MoCA (73%) compared to MMSE (27%), though MMSE was more specific (90%) than MoCA (63%). PPV and LR+ were similar in MoCA and MMSE (PPV: 47%, 53%; LR+: 2.0, 2.6, respectively), but NPV was higher in MoCA (84%) than MMSE (74%). PDQ-5 predicted objective CI (HVLT-R: sensitivity 100%, specificity 89%). Although CI was associated with depression in univariate analyses, it did not hold in the multivariate analysis, while longer SLE disease duration and more years of education remained significant. CONCLUSION: CI is highly prevalent and MoCA may be a useful tool to screen for CI in SLE. Patients with more years of education were less likely to have CI. PMID- 28864644 TI - Myositis-associated Interstitial Lung Disease: Predictors of Failure of Conventional Treatment and Response to Tacrolimus in a US Cohort. AB - OBJECTIVE: Patients with myositis-associated interstitial lung disease (MA-ILD) are often refractory to conventional treatment, and predicting their response to therapy is challenging. Recent case reports and small series suggest that tacrolimus may be useful in refractory cases. METHODS: A retrospective cohort study of patients with MA-ILD comparing clinical characteristics between those who responded to or failed conventional treatment. In those who failed conventional treatment and received adjunctive tacrolimus, response to tacrolimus was measured by the improvement in myositis, ILD, and change in the dose of glucocorticoids. RESULTS: Thirty-one of 54 patients (57%) responded to conventional treatment based on the predefined variables of improvement in myositis and/or ILD. Patients with polymyositis (PM)-ILD were more likely to respond to conventional treatment than those with dermatomyositis (DM)-ILD (67% vs 35%, p = 0.013). Twenty-three patients failed conventional treatment, 18 of whom subsequently received adjunctive tacrolimus. Ninety-four percent had improvements in ILD and 72% showed improvement in both myositis and ILD. The mean doses of prednisone decreased from baseline by 65% at 3-6 months (p = 0.002) and 81% at 1 year (p < 0.001). CONCLUSION: Patients with PM-ILD were more likely to respond to conventional treatment than patients with DM-ILD, but clinical characteristics and serology did not otherwise predict response to therapy. A majority of patients with MA-ILD refractory to conventional therapy improved while receiving tacrolimus and were able to decrease their dose of both glucocorticoids and other disease-modifying antirheumatic drugs. PMID- 28864645 TI - Risk of Retinal Toxicity in Longterm Users of Hydroxychloroquine. AB - OBJECTIVE: Several studies have reported risk factors for hydroxychloroquine (HCQ) retinal toxicity, but data are limited for patients of Asian ancestry. The aim of this study was to investigate the rate of and factors for HCQ retinal toxicity in the Korean population. METHODS: There were 123 patients enrolled in this study who were using or had used HCQ. Retinal toxicity was detected using spectral domain optical coherence tomography, fundus autofluorescence, multifocal electroretinography, and automated visual field testing. Binary logistic regression analysis was performed to identify factors associated with HCQ retinal toxicity. RESULTS: Mean duration of HCQ use and mean HCQ dose in study participants was 10.1 years and 6.4 mg/kg, respectively. We found 17 patients (13.8%) with HCQ retinal toxicity among 123 patients. Patients with retinal toxicity took HCQ ranging from 6.7-21.9 years and daily dosage ranging from 4.9 9.1 mg/kg. Only 1 patient had retinal toxicity among patients with daily dose < 5.0 mg/kg. These factors increased the risk of HCQ retinal toxicity: longer duration of HCQ use [adjusted OR (aOR) = 4.71, 95% CI 2.18-10.15 for duration of HCQ use in 5-yr increments], higher daily HCQ dose (aOR = 3.34, 95% CI 1.03-10.80 for daily HCQ dose in 100-mg increments), and the presence of kidney disease (aOR = 8.56, 95% CI 1.15-64.00). CONCLUSION: HCQ retinal toxicity is associated with duration of HCQ use, daily HCQ dose, and presence of kidney disease. Proper dosing of maximum 5 mg/kg and regular screening according to risk factors are important in HCQ use. PMID- 28864646 TI - Development of a Core Set of Outcome Measures for Large-vessel Vasculitis: Report from OMERACT 2016. AB - OBJECTIVE: Among the challenges in conducting clinical trials in large-vessel vasculitis (LVV), including both giant cell arteritis (GCA) and Takayasu arteritis (TA), is the lack of standardized and meaningful outcome measures. The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group initiated an international effort to develop and validate data-driven outcome tools for clinical investigation in LVV. METHODS: An international Delphi exercise was completed to gather opinions from clinical experts on LVV-related domains considered important to measure in trials. Patient interviews and focus groups were completed to identify outcomes of importance to patients. The results of these activities were presented and discussed in a "Virtual Special Interest Group" using telephone- and Internet-based conferences, discussions through electronic mail, and an in-person session at the 2016 OMERACT meeting. A preliminary core set of domains common for all forms of LVV with disease-specific elements was proposed. RESULTS: The majority of experts agree with using common outcome measures for GCA and TA, with the option of supplementation with disease specific items. Following interviews and focus groups, pain, fatigue, and emotional effect emerged as health-related quality of life domains important to patients. Current disease assessment tools, including the Birmingham Vasculitis Activity Score, were found to be inadequate to assess disease activity in GCA and standardized assessment of imaging tests were felt crucial to study LVV, especially TA. CONCLUSION: Initial data from a clinician Delphi exercise and structured patient interviews have provided themes toward an OMERACT-endorsed core set of domains and outcome measures. PMID- 28864647 TI - Isolated Arthritis of the Temporomandibular Joint as the Initial Manifestation of Juvenile Idiopathic Arthritis. AB - OBJECTIVE: To describe characteristics of patients with juvenile idiopathic arthritis (JIA) presenting with isolated arthritis of the temporomandibular joints (TMJ). METHODS: Patients with JIA with isolated TMJ arthritis from 4 large tertiary pediatric rheumatology centers were included. Demographic and clinical data were analyzed using descriptive statistics. RESULTS: Fifty-five patients were identified (65% bilateral presentation). Six patients developed arthritis in other joints (median time 6 mos); 4 patients developed uveitis, all prior to arthritis. At last followup, 9% were still taking antirheumatic medications. CONCLUSION: JIA TMJ arthritis can occur in isolation, and is probably underdiagnosed. Care providers including dentists and orthodontists should be aware of this presentation. PMID- 28864649 TI - Phenotypic Features and Longterm Outcomes of Pediatric Inflammatory Bowel Disease Patients with Arthritis and Arthralgia. AB - OBJECTIVE: The natural history of pediatric inflammatory bowel disease (IBD) patients with joint involvement has not been clearly described. Thus, we aimed to investigate phenotypic features and clinical outcomes of this distinct association. METHODS: The medical records of patients with pediatric IBD diagnosed from 2000 to 2016 were reviewed retrospectively. Main outcome measures included time to first flare, hospitalization, surgery, and biologic therapy. RESULTS: Of 301 patients with Crohn disease (median age 14.2 yrs), 37 (12.3%) had arthritis while 44 (14.6%) had arthralgia at diagnosis. Arthritis and arthralgia were more common in women (p = 0.028). Patients with arthritis and arthralgia demonstrated lower rates of perianal disease (2.7% and 4.5% vs 16.9%, p = 0.013), whereas patients with arthritis were more likely to be treated with biologic therapy (HR 2.05, 95% CI 1.27-3.33, p = 0.009). Of 129 patients with ulcerative colitis (UC; median age 13.7 yrs), 3 (2.3%) had arthritis and 16 (12.4%) had arthralgia at diagnosis. Patients with arthralgia were treated more often with corticosteroids (p = 0.03) or immunomodulator therapies (p = 0.003) compared with those without joint involvement. The likelihood to undergo colectomy was significantly higher in patients with arthralgia (HR 2.9, 95% CI 1.1-7.4, p = 0.04). During followup (median 9.0 yrs), 13 patients developed arthritis (3.3%). Arthralgia at diagnosis was a significant predictor for the development of arthritis during followup (HR 9.0, 95% CI 2.86-28.5, p < 0.001). CONCLUSION: Pediatric IBD patients with arthritis have distinct phenotypic features. Arthralgia at diagnosis is a predictor for colectomy in UC and a risk factor for the development of arthritis during followup. PMID- 28864648 TI - Assessment of Disease Activity in Large-vessel Vasculitis: Results of an International Delphi Exercise. AB - OBJECTIVE: To arrive at consensus for candidate outcomes for disease activity assessment in large-vessel vasculitis (LVV) in clinical trials. METHODS: A Delphi survey including 99 items was circulated among international experts for 3 rounds. RESULTS: Fifty-seven items were accepted for both giant cell arteritis and Takayasu arteritis. Sixty-seven percent of experts voted to have a common approach for both diseases with additional disease-specific items such as weight loss, scalp tenderness/necrosis, morning stiffness, dizziness, visual symptoms, and imaging. CONCLUSION: This study highlights similarities and differences in experts' perspectives for assessing clinical activity in LVV and may guide a consensus-driven core set of validated outcomes. PMID- 28864651 TI - Associations Between Knee Effusion-synovitis and Joint Structural Changes in Patients with Knee Osteoarthritis. AB - OBJECTIVE: To describe the associations between effusion-synovitis and joint structural abnormalities in patients with knee osteoarthritis (OA) over 24 months. METHODS: A posthoc analysis using data from a randomized controlled trial in 413 patients with symptomatic OA (aged 63 +/- 7 yrs, 208 women). Knee effusion synovitis volume and score, cartilage defects, cartilage volume, and bone marrow lesions (BML) were assessed using magnetic resonance imaging. Joint space narrowing (JSN) and osteophytes were assessed using radiograph. Least significant change criterion was used to define change in effusion-synovitis volume. Knee symptoms were assessed by Western Ontario and McMaster University OA Index. Multivariable linear/logistic regression and multilevel generalized mixed-effects models were used in longitudinal analyses. RESULTS: Total effusion-synovitis volume increased modestly from baseline (8.0 +/- 8.5 ml) to followup (9.0 +/- 10.5 ml). Baseline BML, cartilage defect, JSN, and osteophyte scores were positively associated with change in effusion-synovitis volume (p < 0.05). Baseline cartilage defects and JSN were also associated with change in effusion synovitis score (p < 0.05). However, neither baseline effusion-synovitis score nor volume consistently predicted change in the above structures except cartilage volume. In the mixed-effects models, knee effusion-synovitis was positively associated with BML (volume: beta = 1.19 ml/grade; score: OR = 1.75/grade) and cartilage defects (volume: beta = 1.87 ml/grade; score: OR = 2.22/grade), while negatively associated with cartilage volume loss. Change in effusion-synovitis volume was positively correlated with changes in knee pain and stiffness scores (p < 0.05). CONCLUSION: Knee cartilage and subchondral bone abnormalities predicted change in effusion-synovitis, but effusion-synovitis did not predict knee structural changes. These findings suggest that synovial inflammation is likely the result of joint structural abnormalities in established OA. ClinicalTrials.gov identifier: NCT01176344. Australian New Zealand Clinical Trials Registry: ACTRN12610000495022. PMID- 28864650 TI - OMERACT Endorsement of Patient-reported Outcome Instruments in Antineutrophil Cytoplasmic Antibody-associated Vasculitis. AB - OBJECTIVE: The antineutrophil cytoplasmic antibody-associated vasculitides (AAV) are multiorgan diseases. Patients with AAV report impairment in their health related quality of life (HRQOL) and have different priorities regarding disease assessment compared with physicians. The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group previously received endorsement for a core set of domains in AAV. Two approaches to measure patient-reported outcomes (PRO) were presented at OMERACT 2016. METHODS: A novel 5-step tool was used to facilitate assessment of the instruments by delegates: the OMERACT Filter 2.0 Instrument Selection Algorithm, with a red-amber-green checklist of questions, including (1) good match with domain (face and content validity), (2) feasibility, (3) do numeric scores make sense (construct validity)?, (4) overall ratings of discrimination, and (5) can individual thresholds of meaning be defined? Delegates gave an overall endorsement. Three generic Patient-Reported Outcomes Measurement Information System (PROMIS) instruments (fatigue, physical functioning, and pain interference) and a disease-specific PRO, the AAV-PRO (6 domains related to symptoms and HRQOL), were presented. RESULTS: OMERACT delegates endorsed the use of the PROMIS instruments for fatigue, physical functioning, and pain interference (87.6% overall endorsement) and the disease specific AAV-PRO instrument (89.4% overall endorsement). CONCLUSION: The OMERACT Vasculitis Working Group gained endorsement by OMERACT for use of the PROMIS and the AAV-PRO in clinical trials of vasculitis. These instruments are complementary to each other. The PROMIS and the AAV-PRO need further work to assess their utility in longitudinal settings, including their ability to discriminate between treatments of varying efficacy in the setting of a randomized controlled trial. PMID- 28864652 TI - CRISPR-Cas9D10A Nickase-Assisted Genome Editing in Lactobacillus casei. AB - Lactobacillus casei has drawn increasing attention as a health-promoting probiotic, while effective genetic manipulation tools are often not available, e.g., the single-gene knockout in L. casei still depends on the classic homologous recombination-dependent double-crossover strategy, which is quite labor-intensive and time-consuming. In the present study, a rapid and precise genome editing plasmid, pLCNICK, was established for L. casei genome engineering based on CRISPR-Cas9D10A In addition to the P23-Cas9D10A and Pldh-sgRNA (single guide RNA) expression cassettes, pLCNICK includes the homologous arms of the target gene as repair templates. The ability and efficiency of chromosomal engineering using pLCNICK were evaluated by in-frame deletions of four independent genes and chromosomal insertion of an enhanced green fluorescent protein (eGFP) expression cassette at the LC2W_1628 locus. The efficiencies associated with in-frame deletions and chromosomal insertion is 25 to 62%. pLCNICK has been proved to be an effective, rapid, and precise tool for genome editing in L. casei, and its potential application in other lactic acid bacteria (LAB) is also discussed in this study.IMPORTANCE The lack of efficient genetic tools has limited the investigation and biotechnological application of many LAB. The CRISPR-Cas9D10A nickase-based genome editing in Lactobacillus casei, an important food industrial microorganism, was demonstrated in this study. This genetic tool allows efficient single-gene deletion and insertion to be accomplished by one-step transformation, and the cycle time is reduced to 9 days. It facilitates a rapid and precise chromosomal manipulation in L. casei and overcomes some limitations of previous methods. This editing system can serve as a basic technological platform and offers the possibility to start a comprehensive investigation on L. casei As a broad-host-range plasmid, pLCNICK has the potential to be adapted to other Lactobacillus species for genome editing. PMID- 28864653 TI - Chemical Pretreatment-Independent Saccharifications of Xylan and Cellulose of Rice Straw by Bacterial Weak Lignin-Binding Xylanolytic and Cellulolytic Enzymes. AB - Complete utilization of carbohydrate fractions is one of the prerequisites for obtaining economically favorable lignocellulosic biomass conversion. This study shows that xylan in untreated rice straw was saccharified to xylose in one step without chemical pretreatment, yielding 58.2% of the theoretically maximum value by Paenibacillus curdlanolyticus B-6 PcAxy43A, a weak lignin-binding trifunctional xylanolytic enzyme, endoxylanase/beta-xylosidase/arabinoxylan arabinofuranohydrolase. Moreover, xylose yield from untreated rice straw was enhanced to 78.9% by adding endoxylanases PcXyn10C and PcXyn11A from the same bacterium, resulting in improvement of cellulose accessibility to cellulolytic enzyme. After autoclaving the xylanolytic enzyme-treated rice straw, it was subjected to subsequent saccharification by a combination of the Clostridium thermocellum endoglucanase CtCel9R and Thermoanaerobacter brockii beta glucosidase TbCglT, yielding 88.5% of the maximum glucose yield, which was higher than the glucose yield obtained from ammonia-treated rice straw saccharification (59.6%). Moreover, this work presents a new environment-friendly xylanolytic enzyme pretreatment for beneficial hydrolysis of xylan in various agricultural residues, such as rice straw and corn hull. It not only could improve cellulose saccharification but also produced xylose, leading to an improvement of the overall fermentable sugar yields without chemical pretreatment.IMPORTANCE Ongoing research is focused on improving "green" pretreatment technologies in order to reduce energy demands and environmental impact and to develop an economically feasible biorefinery. The present study showed that PcAxy43A, a weak lignin binding trifunctional xylanolytic enzyme, endoxylanase/beta xylosidase/arabinoxylan arabinofuranohydrolase from P. curdlanolyticus B-6, was capable of conversion of xylan in lignocellulosic biomass such as untreated rice straw to xylose in one step without chemical pretreatment. It demonstrates efficient synergism with endoxylanases PcXyn10C and PcXyn11A to depolymerize xylan in untreated rice straw and enhanced the xylose production and improved cellulose hydrolysis. Therefore, it can be considered an enzymatic pretreatment. Furthermore, the studies here show that glucose yield released from steam- and xylanolytic enzyme-treated rice straw by the combination of CtCel9R and TbCglT was higher than the glucose yield obtained from ammonia-treated rice straw saccharification. This work presents a novel environment-friendly xylanolytic enzyme pretreatment not only as a green pretreatment but also as an economically feasible biorefinery method. PMID- 28864654 TI - Exogenous Polyunsaturated Fatty Acids Impact Membrane Remodeling and Affect Virulence Phenotypes among Pathogenic Vibrio Species. AB - The pathogenic Vibrio species (V. cholerae, V. parahaemolyticus, and V. vulnificus) represent a constant threat to human health, causing foodborne and skin wound infections as a result of ingestion of or exposure to contaminated water and seafood. Recent studies have highlighted Vibrio's ability to acquire fatty acids from environmental sources and assimilate them into cell membranes. The possession and conservation of such machinery provokes consideration of fatty acids as important factors in the pathogenic lifestyle of Vibrio species. The findings here link exogenous fatty acid exposure to changes in bacterial membrane phospholipid structure, permeability, phenotypes associated with virulence, and consequent stress responses that may impact survival and persistence of pathogenic Vibrio species. Polyunsaturated fatty acids (PUFAs) (ranging in carbon length and unsaturation) supplied in growth medium were assimilated into bacterial phospholipids, as determined by thin-layer chromatography and liquid chromatography-mass spectrometry. The incorporation of fatty acids variably affected membrane permeability, as judged by uptake of the hydrophobic compound crystal violet. For each species, certain fatty acids were identified as affecting resistance to antimicrobial peptide treatment. Significant fluctuations were observed with regard to both motility and biofilm formation following growth in the presence of individual PUFAs. Our results illustrate the important and complex roles of exogenous fatty acids in the membrane physiology and virulence of a bacterial genus that inhabits aquatic and host environments containing an abundance of diverse fatty acids.IMPORTANCE Bacterial responses to fatty acids include, but are not limited to, degradation for metabolic gain, modification of membrane lipids, alteration of protein function, and regulation of gene expression. Vibrio species exhibit significant diversity with regard to the machinery known to participate in the uptake and incorporation of fatty acids into their membranes. Both aquatic and host niches occupied by Vibrio are rife with various free fatty acids and fatty acid-containing lipids. The roles of fatty acids in the environmental survival and pathogenesis of bacteria have begun to emerge and are expected to expand significantly. The current study demonstrates the responsiveness of V. cholerae, V. parahaemolyticus, and V. vulnificus to exogenous PUFAs. In addition to phospholipid remodeling, PUFA assimilation impacts membrane permeability, motility, biofilm formation, and resistance to polymyxin B. PMID- 28864655 TI - Cupriavidus necator H16 Uses Flavocytochrome c Sulfide Dehydrogenase To Oxidize Self-Produced and Added Sulfide. AB - Production of sulfide (H2S, HS-, and S2-) by heterotrophic bacteria during aerobic growth is a common phenomenon. Some bacteria with sulfide:quinone oxidoreductase (SQR) and persulfide dioxygenase (PDO) can oxidize self-produced sulfide to sulfite and thiosulfate, but other bacteria without these enzymes release sulfide into the medium, from which H2S can volatilize into the gas phase. Here, we report that Cupriavidus necator H16, with the fccA and fccB genes encoding flavocytochrome c sulfide dehydrogenases (FCSDs), also oxidized self produced H2S. A mutant in which fccA and fccB were deleted accumulated and released H2S. When fccA and fccB were expressed in Pseudomonas aeruginosa strain Pa3K with deletions of its sqr and pdo genes, the recombinant rapidly oxidized sulfide to sulfane sulfur. When PDO was also cloned into the recombinant, the recombinant with both FCSD and PDO oxidized sulfide to sulfite and thiosulfate. Thus, the proposed pathway is similar to the pathway catalyzed by SQR and PDO, in which FCSD oxidizes sulfide to polysulfide, polysulfide spontaneously reacts with reduced glutathione (GSH) to produce glutathione persulfide (GSSH), and PDO oxidizes GSSH to sulfite, which chemically reacts with polysulfide to produce thiosulfate. About 20.6% of sequenced bacterial genomes contain SQR, and only 3.9% contain FCSD. This is not a surprise, since SQR is more efficient in conserving energy because it passes electrons from sulfide oxidation into the electron transport chain at the quinone level, while FCSD passes electrons to cytochrome c The transport of electrons from the latter to O2 conserves less energy. FCSDs are grouped into three subgroups, well conserved at the taxonomic level. Thus, our data show the diversity in sulfide oxidation by heterotrophic bacteria.IMPORTANCE Heterotrophic bacteria with SQR and PDO can oxidize self produced sulfide and do not release H2S into the gas phase. C. necator H16 has FCSD but not SQR, and it does not release H2S. We confirmed that the bacterium used FCSD for the oxidation of self-produced sulfide. The bacterium also oxidized added sulfide. The common presence of SQRs, FCSDs, and PDOs in heterotrophic bacteria suggests the significant role of heterotrophic bacteria in sulfide oxidation, participating in sulfur biogeochemical cycling. Further, FCSDs have been identified in anaerobic photosynthetic bacteria and chemolithotrophic bacteria, but their physiological roles are unknown. We showed that heterotrophic bacteria use FCSDs to oxidize self-produced sulfide and extraneous sulfide, and they may be used for H2S bioremediation. PMID- 28864656 TI - Impacts of Repeated Glyphosate Use on Wheat-Associated Bacteria Are Small and Depend on Glyphosate Use History. AB - Glyphosate is the most widely used herbicide worldwide and a critical tool for weed control in no-till cropping systems. However, there are concerns about the nontarget impacts of long-term glyphosate use on soil microbial communities. We investigated the impacts of repeated glyphosate treatments on bacterial communities in the soil and rhizosphere of wheat in soils with and without long term history of glyphosate use. We cycled wheat in the greenhouse using soils from 4 paired fields under no-till (20+-year history of glyphosate) or no history of use. At each cycle, we terminated plants with glyphosate (2* the field rate) or by removing the crowns, and soil and rhizosphere bacterial communities were characterized. Location, cropping history, year, and proximity to the roots had much stronger effects on bacterial communities than did glyphosate, which only explained 2 to 5% of the variation. Less than 1% of all taxa were impacted by glyphosate, more in soils with a long history of use, and more increased than decreased in relative abundance. Glyphosate had minimal impacts on soil and rhizosphere bacteria of wheat, although dying roots after glyphosate application may provide a "greenbridge" favoring some copiotrophic taxa.IMPORTANCE Glyphosate (Roundup) is the most widely used herbicide in the world and the foundation of Roundup Ready soybeans, corn, and the no-till cropping system. However, there have been recent concerns about nontarget impacts of glyphosate on soil microbes. Using next-generation sequencing methods and glyphosate treatments of wheat plants, we described the bacterial communities in the soil and rhizosphere of wheat grown in Pacific Northwest soils across multiple years, different locations, and soils with different histories of glyphosate use. The effects of glyphosate were subtle and much less than those of drivers such as location and cropping systems. Only a small percentage of the bacterial groups were influenced by glyphosate, and most of those were stimulated, probably because of the dying roots. This study provides important information for the future of this important tool for no-till systems and the environmental benefits of reducing soil erosion and fossil fuel inputs. PMID- 28864657 TI - Recovery Optimization and Survival of the Human Norovirus Surrogates Feline Calicivirus and Murine Norovirus on Carpet. AB - Carpets have been implicated in prolonged and reoccurring outbreaks of human noroviruses (HuNoV), the leading cause of acute gastroenteritis worldwide. Viral recovery from environmental surfaces, such as carpet, remains undeveloped. Our aim was to determine survival of HuNoV surrogates on an understudied environmental surface, carpet. First, we measured the zeta potential and absorption capacity of wool and nylon carpet fibers, we then developed a minispin column elution (MSC) method, and lastly we characterized the survival of HuNoV surrogates, feline calicivirus (FCV) and murine norovirus (MNV), over 60 days under 30 and 70% relative humidity (RH) on two types of carpet and one glass surface. Carpet surface charge was negative between relevant pH values (i.e., pH 7 to 9). In addition, wool could absorb approximately two times more liquid than nylon. The percent recovery efficiency obtained by the MSC method ranged from 4.34 to 20.89% and from 30.71 to 54.14% for FCV and MNV on carpet fibers, respectively, after desiccation. Overall, elution buffer type did not significantly affect recovery. Infectious FCV or MNV survived between <1 and 15 or between 3 and 15 days, respectively. However, MNV survived longer under some conditions and at significantly (P < 0.05) higher titers compared to FCV. Albeit, surrogates followed similar survival trends, i.e., both survived longest on wool then nylon and glass, while 30% RH provided a more hospitable environment compared to 70% RH. Reverse transcription-quantitative PCR signals for both surrogates were detectable for the entire study, but FCV genomic copies experienced significantly higher reductions (<3.80 log10 copies) on all surfaces compared to MNV (<1.10 log10 copies).IMPORTANCE Human noroviruses (HuNoV) are the leading cause of acute gastroenteritis worldwide. Classical symptoms of illness include vomiting and diarrhea which could lead to severe dehydration and death. HuNoV are transmitted by the fecal-oral or vomitus-oral route via person-to person contact, food, water, and/or environmental surfaces. Published laboratory controlled studies have documented the environmental stability of HuNoV on hard surfaces, but there is limited laboratory-based evidence available about survival on soft surfaces, e.g., carpet and upholstered furniture. Several epidemiological reports have suggested soft surfaces may be HuNoV fomites illustrating the importance of conducting a survival study. The three objectives of our research were to demonstrate techniques to characterize soft surfaces, develop a viral elution method for carpet, and characterize the survival of HuNoV surrogates on carpet. These results can be used to improve microbial risk assessments, the development of much-needed soft surface disinfectant, and standardizing protocols for future soft surface studies. PMID- 28864658 TI - PLA2 and ENPP6 may act in concert to generate phosphocholine from the matrix vesicle membrane during skeletal mineralization. AB - Mineralization is a key process in the formation of bone and cartilage in vertebrates, involving the deposition of calcium- and phosphate-containing hydroxyapatite (HA) mineral within a collagenous matrix. Inorganic phosphate (Pi) accumulation within matrix vesicles (MVs) is a fundamental stage in the precipitation of HA, with PHOSPHO1 being identified as the principal enzyme acting to produce Pi PHOSPHO1 is a dual-specific phosphocholine/phosphoethanolamine phosphatase enriched in mineralizing cells and within MVs. However, the source and mechanism by which PHOSPHO1 substrates are formed before mineralization have not been determined. Here, we propose that 2 enzymes-phospholipase A2 (PLA2) and ectonucleotide pyrophophatase/phosphodiesterase 6 (ENPP6)-act in sequence upon phosphatidylcholine found in MV membranes to produce phosphocholine, which PHOSPHO1 can hydrolyze to liberate Pi This hypothesis is supported by evidence that both enzymes are expressed in mineralizing cells and data showing that phosphatidylcholine is broken down in MVs during mineralization. Therefore, PLA2 and ENPP6 activities may represent a key step in the mineralization process. Further functional studies are urgently required to examine their specific roles in the initiation of skeletal mineralization.-Stewart, A. J., Leong, D. T. K., Farquharson, C. PLA2 and ENPP6 may act in concert to generate phosphocholine from the matrix vesicle membrane during skeletal mineralization. PMID- 28864660 TI - De novo digenic mutations of telomere-associated proteins and inflammasomes initiate many chronic human diseases: a hypothesis. AB - Many age-related human diseases have inflammatory components of uncertain causes. It has been proposed that some may be initiated or sustained by doubly mutated immune cells that have both inappropriately activated inflammasomes and enhanced replicative potential. Genes of cells that express mutant TERT and NLRP3 proteins are presumed to be at increased risk for mutagenesis because they reside in subtelomeric regions of chromatin that are deficient in DNA repair mechanisms. Expanded clones of proinflammatory cells can occur throughout one's lifetime and could represent an alternative explanation for some forms of pathologic scarring that are now attributed to truncated telomeres.-Marchesi, V. T. De novo digenic mutations of telomere-associated proteins and inflammasomes initiate many chronic human diseases: a hypothesis. PMID- 28864662 TI - Spondyloarthritis: Harlequin or Chameleon? PMID- 28864659 TI - A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis. AB - Perilipin 2 (PLIN2) is a lipid-droplet protein that is up-regulated in alcoholic steatosis and associated with hepatic accumulation of ceramides, bioactive lipids implicated in alcoholic liver disease pathogenesis. The specific role of ceramide synthetic enzymes in the regulation of PLIN2 and promotion of hepatocellular lipid accumulation is not well understood. We examined the effects of pharmacologic ceramide synthesis inhibition on hepatic PLIN2 expression, steatosis, and glucose and lipid homeostasis in mice with alcoholic steatosis and in ethanol-incubated human hepatoma VL17A cells. In cells, pharmacologic inhibition of ceramide synthase reduced lipid accumulation by reducing PLIN2 RNA stability. The subtype ceramide synthase (CerS)6 was specifically up-regulated in experimental alcoholic steatosis in vivo and in vitro and was up-regulated in zone 3 hepatocytes in human alcoholic steatosis. In vivo ceramide reduction by inhibition of de novo ceramide synthesis reduced PLIN2 and hepatic steatosis in alcohol-fed mice, but only de novo synthesis inhibition, not sphingomyelin hydrolysis, improved glucose tolerance and dyslipidemia. These findings implicate CerS6 as a novel regulator of PLIN2 and suggest that ceramide synthetic enzymes may promote the earliest stage of alcoholic liver disease, alcoholic steatosis. Williams, B., Correnti, J., Oranu, A., Lin, A., Scott, V., Annoh, M., Beck, J., Furth, E., Mitchell, V., Senkal, C. E., Obeid, L., Carr, R. M. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis. PMID- 28864661 TI - Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition. PMID- 28864663 TI - Cardiovascular Morbidity in Psoriatic Arthritis: What Is the Effect of Inflammation? PMID- 28864664 TI - Psoriatic Disease 10 Years Later. PMID- 28864665 TI - The Clinical and Research Implications of Anti-carbamylated Protein Antibodies. PMID- 28864666 TI - Lytic Bone Lesions: Osteomyelitis or Intraosseous Gout? PMID- 28864667 TI - Tongue Involvement in Parry-Romberg Syndrome. PMID- 28864668 TI - Demographic and Clinical Characteristics Associated with Central Nervous System Hemorrhage in Patients with Eosinophilic Granulomatosis with Polyangiitis: A Case Report and Review of the Literature. PMID- 28864669 TI - Use of Belimumab throughout 2 Consecutive Pregnancies in a Patient with Systemic Lupus Erythematosus. PMID- 28864670 TI - Anti-HMGCR Autoantibodies in Juvenile Idiopathic Inflammatory Myopathies Identify a Rare but Clinically Important Subset of Patients. PMID- 28864671 TI - Expression of an RNA glycosidase inhibits HIV-1 transactivation of transcription. AB - HIV-1 (human immunodeficiency virus) transcription is primarily controlled by the virally encoded Tat (transactivator of transcription) protein and its interaction with the viral TAR (transcription response element) RNA element. Specifically, binding of a Tat-containing complex to TAR recruits cellular factors that promote elongation of the host RNA polymerase engaging the viral DNA template. Disruption of this interaction halts viral RNA transcription. In the present study, we investigated the effect of pokeweed antiviral protein (PAP), an RNA glycosidase (EC#: 3.2.2.22) synthesized by the pokeweed plant (Phytolacca americana), on transcription of HIV-1 mRNA. We show that co-expression of PAP with a proviral clone in culture cells resulted in a Tat-dependent decrease in viral mRNA levels. PAP reduced HIV-1 transcriptional activity by inhibiting Tat protein synthesis. The effects of PAP expression on host factors AP-1 (activator protein 1), NF kappaB (nuclear factor kappa-light-chain-enhancer of activated B-cells) and specificity protein 1, which modulate HIV-1 transcription by binding to the viral LTR (5'-long terminal repeat), were also investigated. Only AP-1 showed a modest JNK pathway-dependent increase in activity in the presence of PAP; however, this activation was not sufficient to significantly enhance transcription from a partial viral LTR containing AP-1 binding sites. Therefore, the primary effect of PAP on HIV-1 transcription is to reduce viral RNA synthesis by decreasing the abundance of Tat. These findings provide a mechanistic explanation for the observed decrease in viral RNAs in cells expressing PAP and contribute to our understanding of the antiviral effects of this plant protein. PMID- 28864672 TI - The coproporphyrin ferrochelatase of Staphylococcus aureus: mechanistic insights into a regulatory iron-binding site. AB - The majority of characterised ferrochelatase enzymes catalyse the final step of classical haem synthesis, inserting ferrous iron into protoporphyrin IX. However, for the recently discovered coproporphyrin-dependent pathway, ferrochelatase catalyses the penultimate reaction where ferrous iron is inserted into coproporphyrin III. Ferrochelatase enzymes from the bacterial phyla Firmicutes and Actinobacteria have previously been shown to insert iron into coproporphyrin, and those from Bacillus subtilis and Staphylococcus aureus are known to be inhibited by elevated iron concentrations. The work herein reports a Km (coproporphyrin III) for S. aureus ferrochelatase of 1.5 uM and it is shown that elevating the iron concentration increases the Km for coproporphyrin III, providing a potential explanation for the observed iron-mediated substrate inhibition. Together, structural modelling, site-directed mutagenesis, and kinetic analyses confirm residue Glu271 as being essential for the binding of iron to the inhibitory regulatory site on S. aureus ferrochelatase, providing a molecular explanation for the observed substrate inhibition patterns. This work therefore has implications for how haem biosynthesis in S. aureus is regulated by iron availability. PMID- 28864673 TI - Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy. PMID- 28864674 TI - Neurologic complications of sickle cell disease in Africa: A systematic review and meta-analysis. AB - OBJECTIVE: To summarize prevalence data on the neurologic complications of sickle cell disease (SCD) in Africa. METHODS: We searched EMBASE, PubMed, and African Index Medicus to identify all relevant articles published from inception to May 31, 2016. Each study was reviewed for methodologic quality. A random-effects model was used to estimate the prevalence of neurologic complications of SCD across studies. RESULTS: Thirty-one studies were included. Methodologic quality was high or moderate in 90% of studies. Stroke, conditional and abnormal cerebral blood flow, seizures, and headache were the complications most frequently reported, with overall prevalence rates of 4.2%, 10.6%, 6.1%, 4.4%, and 18.9%, respectively. Some complications, like silent brain infarcts, peripheral neuropathies, neurocognitive deficits, or moyamoya disease, have been rarely or not studied at all in the African setting. Incidence data were scarce and of poor quality. CONCLUSIONS: The burden of neurologic complications of SCD is important in Africa and most likely underestimated. A better evaluation of this burden requires larger prospective studies using standard up-to-date screening methods. Accessibility to diagnostic tools such as neuroimaging, transcranial Doppler, EEG, and neuropsychological evaluation, as well as to preventive and therapeutic interventions and trained health care providers, should be improved in routine clinical practice. PMID- 28864675 TI - Causal inference methods to study gastric tube use in amyotrophic lateral sclerosis. AB - OBJECTIVE: To estimate effects of gastric tube (G-tube) on survival and quality of life (QOL) in people with amyotrophic lateral sclerosis (ALS) correcting for confounding by indication inherent in nonrandomized observational data. METHODS: To complement a recent causal inference analysis, which concluded that G-tube placement increases the hazard of death, permanent assisted ventilation, or tracheostomy by 28%, we fit causal inference models on a different sample of 481 patients with ALS enrolled in a recent clinical trial of ceftriaxone. Forward selection identified predictors of G-tube placement. Effects of G-tube on survival and QOL were estimated using structural nested models and marginal structural models, accounting for predictors of G-tube treatment. RESULTS: Forced vital capacity and the total score and bulbar subscale of the revised ALS Functional Rating Scale best predicted G-tube placement. Correcting for these confounders, G-tube placement decreased survival time by 46% (p < 0.001) and had no effect on QOL (p = 0.078). Sensitivity survival analyses varied in significance, but none revealed a survival benefit. CONCLUSIONS: In the absence of randomization, causal inference methods are necessary to correct for time varying confounding. G-tube placement may have a negative effect on survival with no QOL-related benefit for people with ALS. A randomized controlled trial is warranted to further evaluate the efficacy of this widely used intervention. CLINICALTRIALSGOV IDENTIFIER: NCT00349622. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with ALS, G-tube placement decreases survival time and does not affect QOL. PMID- 28864676 TI - A predictive model to identify Parkinson disease from administrative claims data. AB - OBJECTIVE: To use administrative medical claims data to identify patients with incident Parkinson disease (PD) prior to diagnosis. METHODS: Using a population based case-control study of incident PD in 2009 among Medicare beneficiaries aged 66-90 years (89,790 cases, 118,095 controls) and the elastic net algorithm, we developed a cross-validated model for predicting PD using only demographic data and 2004-2009 Medicare claims data. We then compared this model to more basic models containing only demographic data and diagnosis codes for constipation, taste/smell disturbance, and REM sleep behavior disorder, using each model's receiver operator characteristic area under the curve (AUC). RESULTS: We observed all established associations between PD and age, sex, race/ethnicity, tobacco smoking, and the above medical conditions. A model with those predictors had an AUC of only 0.670 (95% confidence interval [CI] 0.668-0.673). In contrast, the AUC for a predictive model with 536 diagnosis and procedure codes was 0.857 (95% CI 0.855-0.859). At the optimal cut point, sensitivity was 73.5% and specificity was 83.2%. CONCLUSIONS: Using only demographic data and selected diagnosis and procedure codes readily available in administrative claims data, it is possible to identify individuals with a high probability of eventually being diagnosed with PD. PMID- 28864677 TI - Sickle cell disease and the unmet challenges of neurologic complications. PMID- 28864678 TI - The yin and yang of gastrostomy in the management of ALS: Friend or foe? PMID- 28864679 TI - Mitochondrial genome inheritance and replacement in the human germline. PMID- 28864680 TI - Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemotherapy- and radiotherapy-resistant tumors. The c-Met and Hedgehog (Hh) pathways have been shown previously by our group to be key regulatory pathways in the primary tumor growth and metastases formation. Targeting both the HGF/c-Met and Hh pathways has shown promising results in preclinical studies; however, the benefits were not readily translated into clinical trials with PDAC patients. In this study, utilizing mouse models of PDAC, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDAC tumors to gemcitabine, resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to these single inhibitors, likely because the single c-Met treatment leads to enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single-inhibitor treatment and led to a more potent antitumor effect in combination with the chemotherapy treatment. Mol Cancer Ther; 16(11); 2399-409. (c)2017 AACR. PMID- 28864681 TI - Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma. AB - The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated protumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP-competitive orally available small molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients. Mol Cancer Ther; 16(11); 2473-85. (c)2017 AACR. PMID- 28864682 TI - mTOR Kinase Inhibition Effectively Decreases Progression of a Subset of Neuroendocrine Tumors that Progress on Rapalog Therapy and Delays Cardiac Impairment. AB - Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNET) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi), such as CC-223, could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors that progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432-41. (c)2017 AACR. PMID- 28864683 TI - A CRISPR/Cas9-Based Screening for Non-Homologous End Joining Inhibitors Reveals Ouabain and Penfluridol as Radiosensitizers. AB - Non-homologous end joining (NHEJ) is the major pathway responsible for the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSB), and correspondingly regulates the cellular response to IR. Identification of NHEJ inhibitors could substantially enhance the tumor radiosensitivity and improve the therapeutic efficiency of radiotherapy. In this study, we demonstrated a screening for NHEJ inhibitors using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and high resolution melting (HRM) analysis. Because NHEJ is regarded as an error-prone mechanism, the NHEJ-mediated ligation of the site-specific DSB induced by Cas9 nuclease would eventually cause the mutation of the targeted sequence. Then, HRM analysis, a reliable and rapid assay for detecting sequence variation, was performed to evaluate the mutation efficiency of the targeted site. Validating analysis confirmed the NHEJ activities were positively correlated with the mutation frequencies. Next, an approved drug library containing 1,540 compounds was interrogated by using this screening strategy. Our results identified ouabain, a cardiotonic agent, and penfluridol, an antipsychotic agent, have the capacity to restrain NHEJ activity. Further experiments in vitro revealed the radiosensitizing effects of these compounds. Overall, we presented a cell-based screening for NHEJ inhibitors, which could promote the discovery of novel radiosensitizers. Mol Cancer Ther; 17(2); 419-31. (c)2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." PMID- 28864684 TI - Adverse childhood experiences (ACEs) and later-life depression: perceived social support as a potential protective factor. AB - OBJECTIVE: To investigate associations between adverse childhood experiences (ACEs) and later-life depressive symptoms; and to explore whether perceived social support (PSS) moderates these. METHOD: We analysed baseline data from the Mitchelstown (Ireland) 2010-2011 cohort of 2047 men and women aged 50-69 years. Self-reported measures included ACEs (Centre for Disease Control ACE questionnaire), PSS (Oslo Social Support Scale) and depressive symptoms (CES-D). The primary exposure was self-report of at least one ACE. We also investigated the effects of ACE exposure by ACE scores and ACE subtypes abuse, neglect and household dysfunction. Associations between each of these exposures and depressive symptoms were estimated using logistic regression, adjusted for socio demographic factors. We tested whether the estimated associations varied across levels of PSS (poor, moderate and strong). RESULTS: 23.7% of participants reported at least one ACE (95% CI 21.9% to 25.6%). ACE exposures (overall, subtype or ACE scores) were associated with a higher odds of depressive symptoms, but only among individuals with poor PSS. Exposure to any ACE (vs none) was associated with almost three times the odds of depressive symptoms (adjusted OR 2.85; 95% CI 1.64 to 4.95) among individuals reporting poor PSS, while among those reporting moderate and strong PSS, the adjusted ORs were 2.21 (95% CI 1.52 to 3.22) and 1.39 (95% CI 0.85 to 2.29), respectively. This pattern of results was similar when exposures were based on ACE subtype and ACE scores, though the interaction was clearly strongest among those reporting abuse. CONCLUSIONS: ACEs are common among older adults in Ireland and are associated with higher odds of later-life depressive symptoms, particularly among those with poor PSS. Interventions that enhance social support, or possibly perceptions of social support, may help reduce the burden of depression in older populations with ACE exposure, particularly in those reporting abuse. PMID- 28864685 TI - Suicide and all-cause mortality in Swedish deployed military veterans: a population-based matched cohort study. AB - OBJECTIVE: To investigate suicide and mortality risk in deployed military veterans versus non-deployed comparators who had gone through military conscription testing. DESIGN: Population-based matched cohort study. SETTING: Sweden. PARTICIPANTS: Participants were identified from the Military Service Conscription Register and deployment status from the Swedish Military Information Personnel Register. Of 1.9 million conscripts, 21 721 had deployed at some time between 1990 and 2013 (deployed military veterans). Non-deployed comparators were matched to deployed military veterans in two ways: (1) by cognitive ability, psychological assessment, mental health, body mass index, sex, birth-year and conscription-year (carefully matched), with further adjustment for exercise capacity and suicide attempt history; and (2) by sex, birth-year and conscription year (age- and sex-matched). MAIN OUTCOME: Suicide retrieved from the Swedish National Patient and Causes of Death Register until 31 December 2013. RESULTS: During a median follow-up of 12 years, 39 and 211 deaths by suicide occurred in deployed military veterans (n=21 627) and carefully matched non-deployed comparators (n=107 284), respectively (15 vs 16/100 000 person-years; adjusted HR (aHR) 1.07; 95% CI 0.75 to 1.52; p=0.72) and 329 in age- and sex-matched non deployed comparators (n=108 140; 25/100 000 person-years; aHR 0.59; 95% CI 0.42 to 0.82; p=0.002). There were 284 and 1444 deaths by suicide or attempted suicides in deployed military veterans and carefully matched non-deployed comparators, respectively (109 vs 112; aHR 0.99; 95% CI 0.88 to 1.13; p=0.93) and 2061 in age- and sex-matched non-deployed comparators (158; aHR 0.69; 95% CI 0.61 to 0.79; p<0.001). The corresponding figures for all-cause mortality for carefully matched non-deployed comparators were 159 and 820 (61 vs 63/100 000 person-years; aHR 0.97; 95% CI 0.82 to 1.15; p=0.71) and 1289 for age- and sex matched non-deployed comparators (98/100 000 person-years; aHR 0.62; 95% CI 0.52 to 0.73; p<0.001). CONCLUSION: Deployed military veterans had similar suicide and mortality risk as non-deployed comparators after accounting for psychological, psychiatric and physical factors. Studies of mental health in deployed veterans need to adjust for more factors than age and sex for comparisons to be meaningful. PMID- 28864686 TI - Epidemiology of competence: a scoping review to understand the risks and supports to competence of four health professions. AB - OBJECTIVES: This study examined the risks and supports to competence discussed in the literature related to occupational therapists, pharmacists, physical therapists and physicians, using epidemiology as a conceptual model. DESIGN: Articles from a scoping literature review, published from 1975 to 2014 inclusive, were included if they were about a risk or support to the professional or clinical competence of one of four health professions. Descriptive and regression analyses identified potential associations between risks and supports to competence and the location of study, type of health profession, competence life cycle and the domain(s) of competence (organised around the CanMEDS framework). RESULTS: A total of 3572 abstracts were reviewed and 943 articles analysed. Most focused on physicians (n=810, 86.0%) and 'practice' (n=642, 68.0%). Fewer articles discussed risks to competence (n=418, 44.3%) than supports (n=750, 79.5%). The top four risks, each discussed in over 15% of articles, were: transitions in practice, being an international graduate, lack of clinical exposure/experience (ie, insufficient volume of procedures or patients) and age. The top two supports (over 35%) were continuing education participation and educational information/programme features. About 60% of all the articles discussed medical expert and about 25% applied to all roles. Articles focusing on residents had a greater probability of reporting on risks. CONCLUSIONS: Articles about physicians were dominant. The majority of articles were written in the last decade and more discussed supports than risks to competence. An epidemiology based conceptual model offers a helpful organising framework for exploring and explaining the competence of health professions. PMID- 28864687 TI - Suicide and self-harm trends in recent immigrant youth in Ontario, 1996-2012: a population-based longitudinal cohort study. AB - OBJECTIVE: To describe the trends in suicide and emergency department (ED) visits for self-harm in youth by immigration status and immigrant characteristics. DESIGN: Population-based longitudinal cohort study from 1996 to 2012 using linked health and administrative datasets. SETTING: Ontario, Canada. PARTICIPANTS: Youth 10 to 24 years, living in Ontario, Canada. EXPOSURE: The main exposure was immigrant status (recent immigrant (RI) versus long-term residents (LTR)). Secondary exposures included region of birth, duration or residence, and refugee status. MAIN OUTCOME MEASURE: Trends over time in suicide and ED self-harm were modelled within consecutive 3-year time periods. Rate ratios were estimated using Poisson regression models. RESULTS: 2.5 to 2.9 million individuals were included per cohort period. LTR suicide rates ranged from 7.4 to 9.4/100 000 male person years versus 2.2-3.4/100 000 females. RI's suicide rates were 2.7-7.2/100,000 male versus 1.9-2.7/100 000 female person-years. Suicide rates were lower among RI compared with LTR (adjusted relative rate (aRR)=0.70, 95% CI=0.57 to 0.85) with different mechanisms of suicide. No significant time trend in suicide rates was observed (p=0.40). ED self-harm rates for LTR and RI were highest in females (2.6-3.4/1000 LTR females versus 1.1-1.5/1000 males, 1.2-1.8/1000 RI females versus 0.4-0.6/1000 males). RI had lower rates of self-harm compared with LTR (aRR=0.60, 95% CI=0.56 to 0.65). Stratum-specific rates showed a steeper decline per period in RI compared with LTR (RI: aRR=0.85, 95% CI=0.81 to 0.89; LTR: aRR=0.91, 95% CI=0.90 to 0.93). Observed trends were not universal across region of origin and by refugee status. INTERPRETATION: Suicide rates have been stable and ED self-harm rates are declining over time among RI youth. These trends by important subgroups should continue to be monitored to allow for early identification of subpopulations of immigrant youth in need of targeted and culturally appropriate public health interventions. PMID- 28864688 TI - Effect of propofol combined with opioids on cough reflex suppression in gastroscopy: study protocol for a double-blind randomized controlled trial. AB - INTRODUCTION: The best methods for inducing analgesia and sedation for gastroscopy are still debated but finding an adequate regimen of sedation/analgesia is important. Stimulation of the larynx under sedation can cause reflex responses. Propofol with opioids has been recommended for gastroscopy sedation but the effects on cough reflex suppression remain unclear. This trial will evaluate the effects of propofol combined with small doses of dezocine, oxycodone, sufentanil or fentanyl for gastroscopy. We hypothesise that better performance may be obtained with a combination of propofol and oxycodone. We will observe the incidence and degree of reflex coughing and gagging under sedation when using propofol combined with one of the above drugs or propofol alone. METHODS AND ANALYSIS: This will be a prospective, randomised, double blind, controlled trial. ASA I-II level patients aged 18-65 years and scheduled for gastroscopy will be included. It is planned that 500 subjects will be randomised to intravenously receive 2-2.2 mg/kg propofol plus 0.5-0.8 MUg/kg fentanyl (fentanyl group), 2-2.2 mg/kg propofol plus 0.05-0.08 MUg/kg sufentanil (sufentanil group), 2-2.2 mg/kg propofol plus 0.04-0.05 mg/kg dezocine (dezocine group), 2-2.2 mg/kg propofol plus 0.04-0.05 mg/kg oxycodone (oxycodone group), or 2.4-3 mg/kg propofol plus 2-2.5 mL saline (control group) for sedation. The primary endpoint is the incidence and degree of reflex coughing and gagging. The secondary endpoints include the occurrence of discomfort or side effects, the use of jaw thrust, assisted ventilation or additional propofol, recovery time, duration of procedure and Steward score. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Ethics Committee for Clinical Research of Zhongda Hospital, Affiliated to Southeast University (No. 2015ZDSYLL033.0). The results of the trial will be published in an international peer-reviewed journal. TRIAL REGISTRATION: This study has been registered with the Chinese Clinical Trial Register (No. ChiCTR-ICR-15006952). TRIAL STATUS: At the time of manuscript submission, the study was in the recruitment phase. PMID- 28864689 TI - Stepped-wedge cluster-randomised controlled trial to assess the cardiovascular health effects of a managed aquifer recharge initiative to reduce drinking water salinity in southwest coastal Bangladesh: study design and rationale. AB - INTRODUCTION: Saltwater intrusion and salinisation have contributed to drinking water scarcity in many coastal regions globally, leading to dependence on alternative sources for water supply. In southwest coastal Bangladesh, communities have few options but to drink brackish groundwater which has been associated with high blood pressure among the adult population, and pre-eclampsia and gestational hypertension among pregnant women. Managed aquifer recharge (MAR), the purposeful recharge of surface water or rainwater to aquifers to bring hydrological equilibrium, is a potential solution for salinity problem in southwest coastal Bangladesh by creating a freshwater lens within the brackish aquifer. Our study aims to evaluate whether consumption of MAR water improves human health, particularly by reducing blood pressure among communities in coastal Bangladesh. METHODS AND ANALYSIS: The study employs a stepped-wedge cluster-randomised controlled community trial design in 16 communities over five monthly visits. During each visit, we will collect data on participants' source of drinking and cooking water and measure the salinity level and electrical conductivity of household stored water. At each visit, we will also measure the blood pressure of participants >=20 years of age and pregnant women and collect urine samples for urinary sodium and protein measurements. We will use generalised linear mixed models to determine the association of access to MAR water on blood pressure of the participants. ETHICS AND DISSEMINATION: The study protocol has been reviewed and approved by the Institutional Review Boards of the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b). Informed written consent will be taken from all the participants. This study is funded by Wellcome Trust, UK. The study findings will be disseminated to the government partners, at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02746003; Pre-results. PMID- 28864690 TI - Interprofessional team assessments of the patient safety climate in Swedish operating rooms: a cross-sectional survey. AB - BACKGROUND: A positive patient safety climate within teams has been associated with higher safety performance. The aim of this study was to describe and compare attitudes to patient safety among the various professionals in surgical teams in Swedish operating room (OR) departments. A further aim was to study nurse managers in the OR and medical directors' estimations of their staffs' attitudes to patient safety. METHODS: A cross-sectional survey with the Safety Attitudes Questionnaire (SAQ) was used to elicit estimations from surgical teams. To evoke estimations from nurse managers and medical directors about staff attitudes to patient safety, a short questionnaire, based on SAQ, was used. Three OR departments at three different hospitals in Sweden participated. All licensed practical nurses (n=124), perioperative nurses (n=233), physicians (n=184) and their respective manager (n=22) were invited to participate. RESULTS: Mean percentage positive scores for the six SAQ factors and the three professional groups varied, and most factors (safety climate, teamwork climate, stress recognition, working conditions and perceptions of management), except job satisfaction, were below 60%. Significantly lower mean values were found for perioperative nurses compared with physicians for perceptions of management (56.4 vs 61.4, p=0.013) and working conditions (63.7 vs 69.8, p=0.007). Nurse managers and medical directors' estimations of their staffs' ratings of the safety climate cohered fairly well. CONCLUSIONS: This study shows variations and some weak areas for patient safety climate in the studied ORs as reported by front-line staff and acknowledged by nurse managers and medical directors. This finding is a concern because a weak patient safety climate has been associated with poor patient outcomes. To raise awareness, managers need to support patient safety work in the OR. PMID- 28864691 TI - Efficacy and safety of renal denervation for Chinese patients with resistant hypertension using a microirrigated catheter: study design and protocol for a prospective multicentre randomised controlled trial. AB - INTRODUCTION: Available data show that approximately 8%-18% of patients with primary hypertension will develop resistant hypertension. In recent years, catheter-based renal denervation (RDN) has emerged as a potential treatment option for resistant hypertension. A number of observational studies and randomised controlled trials among non-Chinese patients have demonstrated its potential safety and efficacy. METHODS AND ANALYSIS: This is a multicentre, randomised, open-label, parallel-group, active controlled trial that will investigate the efficacy and safety of a 5F saline-irrigated radiofrequency ablation (RFA) used for RDN in the treatment of Chinese patients with resistant hypertension. A total of 254 patients who have failed pharmacological therapy will be enrolled. Eligible subjects will be randomised in a 1:1 ratio to undergo RDN using the RFA plus antihypertensive medication or to receive treatment with antihypertensive medication alone. The primary outcome measure is the change in 24 hours average ambulatory systolic blood pressure from baseline to 3 months, comparing the RDN-plus-medication group with the medication-alone group. Important secondary endpoints include the change in office blood pressure from baseline to 6 months after randomisation. Safety endpoints such as changes in renal function will also be evaluated. The full analysis set, according to the intent-to-treat principle, will be established as the primary analysis population. ETHICS AND DISSEMINATION: All participants will provide informed consent; the study protocol has been approved by the Independent Ethics Committee for each site. This study is designed to investigate the efficacy and safety of RDN using a 5F saline microirrigated RFA. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of resistant hypertension in China. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02900729; pre-results. PMID- 28864692 TI - Common evidence gaps in point-of-care diagnostic test evaluation: a review of horizon scan reports. AB - OBJECTIVE: Since 2008, the Oxford Diagnostic Horizon Scan Programme has been identifying and summarising evidence on new and emerging diagnostic technologies relevant to primary care. We used these reports to determine the sequence and timing of evidence for new point-of-care diagnostic tests and to identify common evidence gaps in this process. DESIGN: Systematic overview of diagnostic horizon scan reports. PRIMARY OUTCOME MEASURES: We obtained the primary studies referenced in each horizon scan report (n=40) and extracted details of the study size, clinical setting and design characteristics. In particular, we assessed whether each study evaluated test accuracy, test impact or cost-effectiveness. The evidence for each point-of-care test was mapped against the Horvath framework for diagnostic test evaluation. RESULTS: We extracted data from 500 primary studies. Most diagnostic technologies underwent clinical performance (ie, ability to detect a clinical condition) assessment (71.2%), with very few progressing to comparative clinical effectiveness (10.0%) and a cost-effectiveness evaluation (8.6%), even in the more established and frequently reported clinical domains, such as cardiovascular disease. The median time to complete an evaluation cycle was 9 years (IQR 5.5-12.5 years). The sequence of evidence generation was typically haphazard and some diagnostic tests appear to be implemented in routine care without completing essential evaluation stages such as clinical effectiveness. CONCLUSIONS: Evidence generation for new point-of-care diagnostic tests is slow and tends to focus on accuracy, and overlooks other test attributes such as impact, implementation and cost-effectiveness. Evaluation of this dynamic cycle and feeding back data from clinical effectiveness to refine analytical and clinical performance are key to improve the efficiency of point-of-care diagnostic test development and impact on clinically relevant outcomes. While the 'road map' for the steps needed to generate evidence are reasonably well delineated, we provide evidence on the complexity, length and variability of the actual process that many diagnostic technologies undergo. PMID- 28864693 TI - Ablation with irreversible electroporation in patients with advanced perihilar cholangiocarcinoma (ALPACA): a multicentre phase I/II feasibility study protocol. AB - INTRODUCTION: The majority of patients with perihilar cholangiocarcinoma (PHC) has locally advanced disease or distant lymph node metastases on presentation or exploratory laparotomy, which makes them not eligible for resection. As the prognosis of patients with locally advanced PHC or lymph node metastases in the palliative setting is significantly better compared with patients with organ metastases, ablative therapies may be beneficial. Unfortunately, current ablative options are limited. Photodynamic therapy causes skin phototoxicity and thermal ablative methods, such as stereotactic body radiation therapy and radiofrequency ablation, which are affected by a heat/cold-sink effect when tumours are located close to vascular structures, such as the liver hilum. These limitations may be overcome by irreversible electroporation (IRE), a relatively new ablative method that is currently being studied in several other soft tissue tumours, such as hepatic and pancreatic tumours. METHODS AND ANALYSIS: In this multicentre phase I/II safety and feasibility study, 20 patients with unresectable PHC due to vascular or distant lymph node involvement will undergo IRE. Ten patients who present with unresectable PHC will undergo CT-guided percutaneous IRE, whereas ultrasound-guided IRE will be performed in 10 patients with unresectable tumours detected at exploratory laparotomy. The primary outcome is the total number of clinically relevant complications (Common Terminology Criteria for Adverse Events, score of>=3) within 90 days. Secondary outcomes include quality of life, tumour response, metal stent patency and survival. Follow-up will be 2 years. ETHICS AND DISSEMINATION: The protocol has been approved by the local ethics committees. Data and results will be submitted to a peer-reviewed journal. CONCLUSION: The Ablation with irreversible eLectroportation in Patients with Advanced perihilar CholangiocarcinomA (ALPACA) study is designed to assess the feasibility of IRE for advanced PHC. The main purpose is to inform whether a follow-up trial to evaluate safety and effectiveness in a larger cohort would be feasible. PMID- 28864694 TI - Labtracker+, a medical smartphone app for the interpretation of consecutive laboratory results: an external validation study. AB - OBJECTIVES: When monitoring patients over time, clinicians may struggle to distinguish 'real changes' in consecutive blood parameters from so-called natural fluctuations. In practice, they have to do so by relying on their clinical experience and intuition. We developed Labtracker+, a medical app that calculates the probability that an increase or decrease over time in a specific blood parameter is real, given the time between measurements. DESIGN: We presented patient cases to 135 participants to examine whether there is a difference between medical students, residents and experienced clinicians when it comes to interpreting changes between consecutive laboratory results. Participants were asked to interpret if changes in consecutive laboratory values were likely to be 'real' or rather due to natural fluctuations. The answers of the study participants were compared with the calculated probabilities by the app Labtracker+ and the concordance rates were assessed. SETTING AND PARTICIPANTS: Medical students (n=92), medical residents from the department of internal medicine (n=19) and internists (n=24) at a Dutch University Medical Centre. PRIMARY AND SECONDARY OUTCOME MEASURES: Concordance rates between the study participants and the calculated probabilities by the app Labtracker+ were compared. Besides, we tested whether physicians with clinical experience scored better concordance rates with the app Labtracker+ than inexperienced clinicians. RESULTS: Medical residents and internists showed significantly better concordance rates with the calculated probabilities by the app Labtracker+ than medical students, regarding their interpretation of differences between consecutive laboratory results (p=0.009 and p<0.001, respectively). CONCLUSION: The app Labtracker+ could serve as a clinical decision tool in the interpretation of consecutive laboratory test results and could contribute to rapid recognition of parameter changes by physicians. PMID- 28864695 TI - Pregnancy physiology pattern prediction study (4P study): protocol of an observational cohort study collecting vital sign information to inform the development of an accurate centile-based obstetric early warning score. AB - INTRODUCTION: Successive confidential enquiries into maternal deaths in the UK have identified an urgent need to develop a national early warning score (EWS) specifically for pregnant or recently pregnant women to aid more timely recognition, referral and treatment of women who are developing life-threatening complications in pregnancy or the puerperium. Although many local EWS are in use in obstetrics, most have been developed heuristically. No current obstetric EWS has defined the thresholds at which an alert should be triggered using evidence based normal ranges, nor do they reflect the changing physiology that occurs with gestation during pregnancy. METHODS AND ANALYSIS: An observational cohort study involving 1000 participants across three UK sites in Oxford, London and Newcastle. Pregnant women will be recruited at approximately 14 weeks' gestation and have their vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation and temperature) measured at 4 to 6-week intervals during pregnancy. Vital signs recorded during labour and delivery will be extracted from hospital records. After delivery, participants will measure and record their own vital signs daily for 2 weeks. During the antenatal and postnatal periods, vital signs will be recorded on an Android tablet computer through a custom software application and transferred via mobile internet connection to a secure database. The data collected will be used to define reference ranges of vital signs across normal pregnancy, labour and the immediate postnatal period. This will inform the design of an evidence-based obstetric EWS. ETHICS AND DISSEMINATION: The study has been approved by the NRES committee South East Coast-Brighton and Sussex (14/LO/1312) and is registered with the ISRCTN (10838017). All participants will provide written informed consent and can withdraw from the study at any point. All data collected will be managed anonymously. The findings will be disseminated in international peer-reviewed journals and through research conferences. PMID- 28864696 TI - Risk factors of diabetic retinopathy and sight-threatening diabetic retinopathy: a cross-sectional study of 13 473 patients with type 2 diabetes mellitus in mainland China. AB - OBJECTIVE: To explore the risk factors of diabetic retinopathy (DR) and sight threatening diabetic retinopathy (STDR) among Chinese patients with diabetes. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional investigation was performed in eight screening clinics in six provinces across mainland China. Information about the risk factors was recorded in screening clinics. Some risk factors (sex, age, diagnosis age, diabetes duration, systolic blood pressure (SBP), diastolic blood pressure, fasting blood glucose (FBG) and glycosylated haemoglobin (HbA1c)) were recorded in all eight clinics, while others were collected only in a subset of the clinics. The relationships between the risk factors and DR and between the risk factors and STDR were explored for the eight factors mentioned above and for all factors studied. MAIN OUTCOMES AND MEASURES: Risk factors of DR and STDR were assessed, and a nomogram of the results was produced. RESULTS: Younger age, longer diabetes duration, higher SBP, higher FBG and higher HbA1c were found to be independent risk factors for both DR and STDR in the eight-factor analyses. In the all-factor analysis, younger age, longer diabetes duration, higher SBP, oral medicine use and insulin use were independent risk factors for both DR and STDR; higher postprandial blood glucose (PBG), HbA1c, triglyceride andlow-density lipoprotein were independent risk factors for DR only, and higher FBG was a risk factor for STDR only. CONCLUSIONS: In this cross-sectional investigation, several risk factors were found for DR and STDR. Notably, FBG, PBG and HbA1c were all risk factors for DR or STDR, suggesting that stricter blood glucose control in clinical practice is required. PMID- 28864697 TI - Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. AB - OBJECTIVES: Heterozygous familial hypercholesterolaemia (FH) confers a significant risk for premature cardiovascular disease (CVD). However, the estimated prevalence of FH varies substantially among studies. We aimed to provide a summary estimate of FH prevalence in the general population and assess variations in frequency across different sociodemographic characteristics. SETTING, PARTICIPANTS AND OUTCOME MEASURES: We searched MEDLINE, EMBASE, Global Health, the Cochrane Library, PsycINFO and PubMed for peer-reviewed literature using validated strategies. Results were limited to studies published in English between January 1990 and January 2017. Studies were eligible if they determined FH prevalence using clinical criteria or DNA-based analyses. We determined a pooled point prevalence of FH in adults and children and assessed the variation of the pooled frequency by age, sex, geographical location, diagnostic method, study quality and year of publication. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were investigated through subgroups, meta-regression and sensitivity analyses. RESULTS: The pooled prevalence of FH from 19 studies including 2 458 456 unique individuals was 0.40% (95% CI 0.29% to 0.52%) which corresponds to a frequency of 1 in 250 individuals. FH prevalence was found to vary by age and geographical location but not by any other covariates. Results were consistent in sensitivity analyses. CONCLUSIONS: Our systematic review suggests that FH is a common disorder, affecting 1 in 250 individuals. These findings underscore the need for early detection and management to decrease CVD risk. PMID- 28864698 TI - Development and validation of the Fracture Risk Scale (FRS) that predicts fracture over a 1-year time period in institutionalised frail older people living in Canada: an electronic record-linked longitudinal cohort study. AB - OBJECTIVES: To develop and validate our Fracture Risk Scale (FRS) over a 1-year time period, using the long-term care (LTC) Resident Assessment Instrument Minimum Data Set Version 2.0 (RAI-MDS 2.0). DESIGN: A retrospective cohort study. SETTING: LTC homes in Ontario, Canada. PARTICIPANTS: Older adults who were admitted to LTC and received a RAI-MDS 2.0 admission assessment between 2006 and 2010. RESULTS: A total of 29 848 LTC residents were enrolled in the study. Of these 22 386 were included in the derivation dataset and 7462 individual were included in the validation dataset. Approximately 2/3 of the entire sample were women and 45% were 85 years of age or older. A total of 1553 (5.2%) fractures were reported over the 1-year time period. Of these, 959 (61.8%) were hip fractures. Following a hip fracture, 6.3% of individuals died in the emergency department or as an inpatient admission and did not return to their LTC home. Using decision tree analysis, our final outcome scale had eight risk levels of differentiation. The percentage of individuals with a hip fracture ranged from 0.6% (lowest risk level) to 12.6% (highest risk level). The area under the curve of the outcome scale was similar for the derivation (0.67) and validation (0.69) samples, and the scale exhibited a good level of consistency. CONCLUSIONS: Our FRS predicts hip fracture over a 1-year time period and should be used as an aid to support clinical decisions in the care planning of LTC residents. Future research should focus on the transformation of our scale to a Clinical Assessment Protocol and to assess the FRS in other healthcare settings. PMID- 28864699 TI - Uterine balloon tamponade as an adjunct to misoprostol for the treatment of uncontrolled postpartum haemorrhage: a randomised controlled trial in Benin and Mali. AB - OBJECTIVE: To assess the effectiveness of low-cost uterine tamponade as an adjunct to misoprostol for the treatment of uncontrolled postpartum haemorrhage (PPH) in low-resource settings. DESIGN: Randomised controlled trial. SETTING: Seven healthcare facilities in Cotonou, Benin and Bamako, Mali. POPULATION: Women delivering vaginally who had clinically diagnosed PPH that was suspected to be due to uterine atony, who were unresponsive to oxytocin and who needed additional uterotonics. METHODS: Women were randomly assigned to receive uterine balloon tamponade with a condom-catheter device or no tamponade; both groups were also given intrarectal or sublingual misoprostol. MAIN OUTCOME MEASURE: Proportion of women with invasive surgery or who died before hospital discharge. RESULTS: The proportion of primary composite outcome did not differ significantly between the tamponade arm (16%; 9/57) and the standard second line treatment arm (7%; 4/59): relative risk 2.33 (95% CI 0.76 to 7.14, p=0.238). A significantly increased proportion of women with tamponade and misoprostol versus misoprostol alone had total blood loss more than 1000 mL: relative risk 1.52 (95% CI 1.15 to 2.00, p=0.01). Case fatality rate was higher in the tamponade group (10%; 6/57) than in the control group (2%; 1/59) (p=0.059). TRIAL REGISTRATION NUMBER: ISRCT Registry Number 01202389; Post-results. PMID- 28864700 TI - Psychological distress and quality of life: rationale and protocol of a prospective cohort study in a rural district in Bangaladesh. AB - INTRODUCTION: A significant proportion of the global burden of disease has been attributed to mental and behavioural disorders. People with mental disorders (MDs) have lower levels of health-related quality of life than those without MDs. Several studies have shown that in low-resource countries, a range of social determinants including poor health literacy is critical in the epidemiological transition of disease outcome. There is a lack of evidence of MDs literacy, the prevalence and risk factors of common mental health conditions, or any validated instruments to measure psychological distress or evaluate the quality of life in rural areas of Bangladesh. AIMS: The aims of this study are: (1) report the awareness, knowledge, attitudes and practice (KAP) of MDs; (2) estimate the prevalence of and risk factors for psychological distress; (3) measure association of psychological distress and other socio-demographic factors with quality of life and (4) test the feasibility to use Kessler 10-item (K10) and WHO Quality Of Life-BREF (WHOQOL-BREF) questionnaires in rural Bangladesh for measuring psychological distress and quality of life. METHODS AND ANALYSIS: A sample of 1500 adults aged 18-59 years and 1200 older adults aged 60-90 years will be interviewed from a multistage cluster random sample. Each participant will go through a face-to-face interview to assess their awareness and KAP of MDs. Information about the participant's sociodemographic and socioeconomic status will be collected along with the psychological distress (K10) and quality of life (WHOQOL-BREF) questionnaires. Internal consistency, validity, reliability and item discrimination of K10 and WHOQOL-BREF instruments will be determined by using Rasch analysis and regression techniques. ETHICS AND DISSEMINATION: Human Ethics Approval was received from the Swinburne University of Technology Human Ethics Committee. Results of this research will be disseminated via scientific forums including peer-reviewed publications and presentations at national and international conferences. PMID- 28864701 TI - Is there evidence that the yearly numbers of children newly certified with sight impairment in England and Wales has increased between 1999/2000 and 2014/2015? A cross-sectional study. AB - OBJECTIVES: To use routine data capture from hospitals in England and Wales to identify whether there has been an increase in the annual numbers of children newly certified sight impaired in England and Wales between 1999/2000 and 2014/2015 and to examine causes of certifiable sight impairment in children certified in 2014/2015. DESIGN: A cross-sectional study including an analysis of all certificates of vision impairment completed in hospitals in England and Wales each year between 2007/2008 and 2014/2015 and all certificates completed in hospitals in England and Wales in 1999/2000. PARTICIPANTS: Certificates for all individuals aged 16 years or less at the time of certification in England and Wales for each financial year between 1 April 2007 and the 31 March 2015 and for individuals aged 15 years or less for the year ending 31 March 2000. We obtained information on the main cause of certifiable sight loss for all children certified in 2014/2015. We estimated crude and sex specific incidence estimates with 95% confidence intervals computed by Byars method. RESULTS: In 1999/2000, the estimated incidence (95 % CI) of certification was 8.2 (7.7 to 8.8) per 1 00 000. In 2007/2008, the estimated incidence was statistically significantly higher at 10.1 (9.5 to 10.7). Since then a trend of increasing incidence with time has been observed until 2014/2015 when an estimated incidence of 13.3 (12.6 to 14.0) was observed. Hereditary retinal dystrophies, cerebral visual impairment and nystagmus were the most common single causes of certifiable sight impairment in children in 2014/2015. CONCLUSION: Our findings show that in England and Wales there has been an increase in the number of children newly certified sight impaired by consultant ophthalmologists since 1999/2000. This mirrors our previous findings based on data originating within social service departments. PMID- 28864702 TI - Design and validation of a clinical scale for prehospital stroke recognition, severity grading and prediction of large vessel occlusion: the shortened NIH Stroke Scale for emergency medical services. AB - OBJECTIVE: To develop an NIH Stroke Scale (NIHSS)-compatible, all-in-one scale for rapid and comprehensive prehospital stroke assessment including stroke recognition, severity grading and progression monitoring as well as prediction of large vessel occlusion (LVO). METHODS: Emergency medical services (EMS) personnel and stroke physicians (n=326) rated each item of the NIHSS regarding suitability for prehospital use; best rated items were included. Stroke recognition was evaluated retrospectively in 689 consecutive patients with acute stroke or stroke mimics, prediction of LVO in 741 consecutive patients with ischaemic stroke with acute vessel imaging independent of admission NIHSS score. RESULTS: Nine of the NIHSS items were rated as 'suitable for prehospital use.' After excluding two items in order to increase specificity, the final scale (termed shortened NIHSS for EMS, sNIHSS-EMS) consists of 'level of consciousness', 'facial palsy', 'motor arm/leg', 'sensory', 'language' and 'dysarthria'. Sensitivity for stroke recognition of the sNIHSS-EMS is 91% (95% CI 86 to 94), specificity 52% (95% CI 47 to 56). Receiver operating curve analysis revealed an optimal cut-off point for LVO prediction of >=6 (sensitivity 70% (95% CI 65 to 76), specificity 81% (95% CI 76 to 84), positive predictive value 70 (95% CI 65 to 75), area under the curve 0.81 (95% CI 0.78 to 0.84)). Test characteristics were non-inferior to non comprehensive scales. CONCLUSIONS: The sNIHSS-EMS may overcome the sequential use of multiple emergency stroke scales by permitting parallel stroke recognition, severity grading and LVO prediction. Full NIHSS-item compatibility allows for evaluation of stroke progression starting at the prehospital phase. PMID- 28864703 TI - Admission to psychiatric hospital for mental illnesses 2 years prechildbirth and postchildbirth in Scotland: a health informatics approach to assessing mother and child outcomes. AB - OBJECTIVE: To identify factors associated with: admission to a specialist mother and baby unit (MBU) and the impact of perinatal mental illness on early childhood development using a data linkage approach in the 2 years prechildbirth and postchildbirth. METHODS: Scottish maternity records (SMR02) were linked to psychiatric hospital admissions (SMR04). 3290 pregnancy-related psychiatric admissions for 1730 women were assessed. To investigate factors associated with MBU admission, the group of mothers admitted to an MBU were compared with those admitted to general psychiatric wards. To assess the impact of perinatal mental illness on early child development, a pragmatic indicator for 'at potential risk of adversity', defined as a child who was recorded as requiring intensive treatment at any time under the health plan indicators (HPI) and/or who had no record of completing three doses of the 5-in-1 vaccine by 12 months was generated. Logistic regression models were used to describe the association between each variable and the risk of admission between those with a history of prior psychiatric admission and those without. RESULTS: Women admitted to an MBU were significantly more likely to be admitted with non-affective psychosis (OR=1.97, 95% CI 1.22 to 3.18), affective psychosis (OR=2.44, 95% CI 1.37 to 4.33) and non-psychotic depressive episodes (OR=1.93, 95% CI 1.42 to 2.63). They were less likely to come from deprived areas (OR=0.68 95% CI 0.49 to 0.93). Women with a previous history of psychiatric admission were significantly more likely to be located in the two most deprived quintiles. Almost one-third (29%) of children born to mothers with a pregnancy-related psychiatric admission were assessed as 'at potential risk of adversity.' CONCLUSIONS: A health informatics approach has potential for improving understanding of social and clinical factors, which contribute to the outcomes of perinatal mental illness, as well as potential adverse developmental outcomes for offspring. PMID- 28864704 TI - "It is merely a paper tiger." Battle for increased tobacco advertising regulation in Indonesia: content analysis of news articles. AB - OBJECTIVE: At the end of 2012, the Indonesian government enacted tobacco control regulation (PP 109/2012) that included stricter tobacco advertising, promotion and sponsorship (TAPS) controls. The PP did not ban all forms of TAPS and generated a great deal of media interest from both supporters and detractors. This study aims to analyse stakeholder arguments regarding the adoption and implementation of the regulation as presented through news media converge. DESIGN: Content analysis of 213 news articles reporting on TAPS and the PP that were available from the Factiva database and the Google News search engine. SETTING: Indonesia, 24 December 2012-29 February 2016. METHODS: Arguments presented in the news article about the adoption and implementation of the PP were coded into 10 supportive and 9 opposed categories. The news actors presenting the arguments were also recorded. Kappa statistic were calculated for intercoder reliability. RESULTS: Of the 213 relevant news articles, 202 included stakeholder arguments, with a total of 436 arguments coded across the articles. More than two-thirds, 69% (301) of arguments were in support of the regulation, and of those, 32.6% (98) agreed that the implementation should be enhanced. Of 135 opposed arguments, the three most common were the potential decrease in government revenue at 26.7% (36), disadvantage to the tobacco industry at 18.5% (25) and concern for tobacco farmers and workers welfare at 11.1% (15). The majority of the in support arguments were made by national government, tobacco control advocates and journalists, while the tobacco industry made most opposing arguments. CONCLUSIONS: Analysing the arguments and news actors provides a mapping of support and opposition to an essential tobacco control policy instrument. Advocates, especially in a fragmented and expansive geographic area like Indonesia, can use these findings to enhance local tobacco control efforts. PMID- 28864705 TI - A protocol for a randomised controlled trial of the bone response to impact loading or resistance training in young women with lower than average bone mass: the OPTIMA-Ex trial. AB - INTRODUCTION: The aim of the Osteoporosis Prevention Through Impact and Muscle loading Approaches to Exercise trial is to compare the bone response to two known osteogenic stimuli - impact loading exercise and resistance training. Specifically, we will examine the effect of a 10-month, twice-weekly, high intensity impact loading exercise intervention and a 10-month, twice-weekly, high intensity resistance training intervention on bone mass and strength at clinically important skeletal sites. The intervention groups will be compared against a home-based 'positive' control group. Safety and acceptability of each exercise modality will also be determined. METHODS AND ANALYSIS: Sedentary otherwise healthy young women aged 18-30 years with bone mineral density (BMD) T scores less than or equal to 0 at the hip and lumbar spine, screened for conditions and medications that influence bone and physical function, will be recruited. Eligible participants are randomised to 10-month, twice-weekly, either supervised high-intensity impact training, high-intensity resistance training or a home-based 'positive' control group. The primary outcome measure will be lumbar spine areal BMD, while secondary outcome measures will include: whole body, femoral neck and regional measures (upper and lower limb) of bone, muscle and fat; anthropometrics; muscle strength and power; quality of life and exercise safety, enjoyment and acceptability. All outcome measures will be conducted at baseline (T0) and 10 months (T10) and will be analysed according to the intention to-treat principle and per protocol. ETHICS AND DISSEMINATION: The study has been granted ethical approval from the Griffith University Human Research Ethics Committee (GU Ref: 2015/775). Standard scientific reporting practices will occur, including publication in peer-reviewed journals. Participant confidentiality will be maintained in all forms of reporting. TRIAL REGISTRATION NUMBER: ACTRN12616001444471. PMID- 28864706 TI - Contingency management for tobacco smoking during opioid addiction treatment: a randomised pilot study. AB - INTRODUCTION: Smoking rates among individuals in treatment for opioid addiction are close to five times that of the general public. Moreover, drug-addicted smokers have a premature mortality rate four times greater than drug-addicted non smokers. The aim of this pilot study was to investigate whether contingency management (CM) can be successfully added to evidence-based stop smoking treatment in individuals undergoing treatment for opioid addiction and assess preliminary evidence for its impact. PARTICIPANTS: Forty tobacco smokers currently undergoing treatment for opioid addiction. INTERVENTION: Escalating with reset CM as an adjunct to standard smoking cessation treatment. Financial incentives will be administered over a 5-week period for either biochemically verified abstinence from smoking or attendance at the clinic. Participants will be randomised to conditions stratified on current levels of smoking (high or low). OBJECTIVES AND ANALYSES: To assess whether a CM intervention can be successfully added to standard stop smoking services treatment, in patients undergoing outpatient treatment for opioid addiction. This will be measured as the number of people completing the 5 weeks of the intervention. ETHICS AND DISSEMINATION: Ethics approval for the study was granted on the 16 June 2016 by the London-city and east (reference 16/LO/0990) ethics committee. The pilot study was retrospectively registered on clincaltrials.gov in January 2017 (ID: NCT03015597). A SPIRIT checklist and figure are available for this protocol. It is planned that the results of this study will be published in an academic journal. PMID- 28864707 TI - Patients' and nurses' views on providing psychological support within cardiac rehabilitation programmes: a qualitative study. AB - OBJECTIVE: To explore patients' and nurses' views on the feasibility and acceptability of providing psychological care within cardiac rehabilitation services. DESIGN: In-depth interviews analysed thematically. PARTICIPANTS: 18 patients and 7 cardiac nurses taking part in a pilot trial (CADENCE) of an enhanced psychological care intervention delivered within cardiac rehabilitation programmes by nurses to patients with symptoms of depression. SETTING: Cardiac services based in the South West of England and the East Midlands, UK. RESULTS: Patients and nurses viewed psychological support as central to good cardiac rehabilitation. Patients' accounts highlighted the significant and immediate adverse effect a cardiac event can have on an individual's mental well-being. They also showed that patients valued nurses attending to both their mental and physical health, and felt this was essential to their overall recovery. Nurses were committed to providing psychological support, believed it benefited patients, and advocated for this support to be delivered within cardiac rehabilitation programmes rather than within a parallel healthcare service. However, nurses were time-constrained and found it challenging to provide psychological care within their existing workloads. CONCLUSIONS: Both patients and nurses highly value psychological support being delivered within cardiac rehabilitation programmes but resource constraints raise barriers to implementation. Consideration, therefore, should be given to alternative forms of delivery which do not rely solely on nurses to enable patients to receive psychological support during cardiac rehabilitation. TRIAL REGISTRATION NUMBER: ISCTRN34701576. PMID- 28864709 TI - Early interventions for the prevention of post-traumatic stress symptoms in survivors of critical illness: protocol for a systematic review. AB - INTRODUCTION: Post-traumatic stress disorder (PTSD) is being increasingly reported among survivors of critical illness and injury. Previous work has demonstrated that PTSD reduces patient quality of life and ability to return to work, as well as increases healthcare costs. As such, identifying interventions aimed at preventing the development of critical illness-related PTSD could have an important public health impact. The objective of this systematic review is to collate the world's literature on early interventions aimed at preventing PTSD among survivors of critical illness. METHODS AND ANALYSIS: We will perform a qualitative systematic review of human clinical trials of interventions aimed at preventing or reducing critical illness-related PTSD symptoms. We will methodically search CENTRAL, MEDLINE, Embase and CINAHL. We will also search websites containing details on clinical trials registration (National Library of Medicine's ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform), as well as screen reference lists of the articles we select for inclusion to identify additional studies for potential inclusion. Two authors will independently review all search results. After identification and inclusion of articles, we will use a standardised form for data extraction. We will use tables to describe the study type, populations, interventions tested and timing of interventions, outcome measures and effects of interventions on outcome measures compared with control groups. This review will be completed between 1 August 2017 and 31 August 2017. ETHICS AND DISSEMINATION: The proposed systematic review will not collect individual patient level data and does not require ethical approval. Results of this study will contribute to the understanding of critical illness-related PTSD and help prompt future research aimed at further developing interventions to prevent PTSD symptoms in survivors of critical illness. PROSPERO REGISTRATION NUMBER: This systematic review is registered in the PROSPERO international prospective register of systematic reviews (registration number CRD42017069672). PMID- 28864708 TI - Does supplementation with carnosine improve cardiometabolic health and cognitive function in patients with pre-diabetes and type 2 diabetes? study protocol for a randomised, double-blind, placebo-controlled trial. AB - INTRODUCTION: Carnosine, an over-the-counter food supplement, has a promising potential for the prevention and treatment of chronic diseases such as type 2 diabetes (T2DM), cardiovascular and neurodegenerative diseases through its anti inflammatory, antiglycation, antioxidative and chelating effects. We have previously shown that supplementation with carnosine preserves insulin sensitivity and secretion in non-diabetic overweight and obese individuals. The effect of carnosine on cardiometabolic risk and related cognitive outcomes in patients with pre-diabetes and T2DM has thus far not been studied. We therefore aim to investigate whether supplementation with carnosine improves cardiometabolic health and cognitive function in patients with pre-diabetes and T2DM. METHODS AND ANALYSIS: We will employ a parallel design randomised controlled trial. Fifty participants with pre-diabetes (impaired fasting glycaemia and impaired glucose tolerance) and T2DM (with HbA1c level < 8%) aged between 18 to 70 years will be randomly assigned to the intervention or control group. At baseline, participants will undergo a medical review and series of tests including anthropometric measurements (body mass index, a dual X-ray absorptiometry and peripheral quantitative computed tomography scan), an oral glucose tolerance test, cardiovascular measurements (central blood pressure, endothelial function and arterial stiffness), cognitive function, physical activity measurement, heart rate variability and liver fibroscan as well as questionnaires to assess dietary habits, sleep quality, depression and quality of life. The intervention group will receive 2 g of carnosine daily in two divided doses while the control group will receive identical placebo capsules for 14 weeks. All baseline measurements will be repeated at the end of the intervention. The change in glycaemic, cardiovascular and cognitive parameters as well as other measures will be compared between the groups. ETHICS AND DISSEMINATION: This study is approved by the Human Research Ethics Committee of Monash Health and Monash University, Australia. The findings will be disseminated via peer-reviewed publications and conference presentations. TRIAL REGISTRATION: NCT02917928; Pre results. PMID- 28864710 TI - Principles of Child Health Care Financing. AB - After passage of the Patient Protection and Affordable Care Act, more children and young adults have become insured and have benefited from health care coverage than at any time since the creation of the Medicaid program in 1965. From 2009 to 2015, the uninsurance rate for children younger than 19 years fell from 9.7% to 5.3%, whereas the uninsurance rate for young adults 19 to 25 years of age declined from 31.7% to 14.5%. Nonetheless, much work remains to be done. The American Academy of Pediatrics (AAP) believes that the United States can and should ensure that all children, adolescents, and young adults from birth through the age of 26 years who reside within its borders have affordable access to high quality and comprehensive health care, regardless of their or their families' incomes. Public and private health insurance should safeguard existing benefits for children and take further steps to cover the full array of essential health care services recommended by the AAP. Each family should be able to afford the premiums, deductibles, and other cost-sharing provisions of the plan. Health plans providing these benefits should ensure, insofar as possible, that families have a choice of professionals and facilities with expertise in the care of children within a reasonable distance of their residence. Traditional and innovative payment methodologies by public and private payers should be structured to guarantee the economic viability of the pediatric medical home and of other pediatric specialty and subspecialty practices to address developing shortages in the pediatric specialty and subspecialty workforce, to promote the use of health information technology, to improve population health and the experience of care, and to encourage the delivery of evidence-based and quality health care in the medical home, as well as in other outpatient, inpatient, and home settings. All current and future health care insurance plans should incorporate the principles for child health financing outlined in this statement. Espousing the core principle to do no harm, the AAP believes that the United States must not sacrifice any of the hard-won gains for our children. Medicaid, as the largest single payer of health care for children and young adults, should remain true to its origins as an entitlement program; in other words, future fiscal or regulatory reforms of Medicaid should not reduce the eligibility and scope of benefits for children and young adults below current levels nor jeopardize children's access to care. Proposed Medicaid funding "reforms" (eg, institution of block grant, capped allotment, or per-capita capitation payments to states) will achieve their goal of securing cost savings but will inevitably compel states to reduce enrollee eligibility, trim existing benefits (such as Early and Periodic Screening, Diagnostic, and Treatment), and/or compromise children's access to necessary and timely care through cuts in payments to providers and delivery systems. In fact, the AAP advocates for increased Medicaid funding to improve access to essential care for existing enrollees, fund care for eligible but uninsured children once they enroll, and accommodate enrollment growth that will occur in states that choose to expand Medicaid eligibility. The AAP also calls for Congress to extend funding for the Children's Health Insurance Program, a plan vital to the 8.9 million children it covered in fiscal year 2016, for a minimum of 5 years. PMID- 28864711 TI - Meningococcal B Vaccine Failure With a Penicillin-Resistant Strain in a Young Adult on Long-Term Eculizumab. AB - We describe a case of invasive meningococcal disease due to a vaccine-preventable and penicillin-resistant strain in a fully immunized young adult on long-term complement inhibitor therapy and daily penicillin chemoprophylaxis. Eculizumab is a humanized monoclonal antibody that binds human complement C5 protein and inhibits the terminal complement pathway. It is currently recommended for the treatment of complement-mediated thrombotic microangiopathies. An unwanted complication of inhibiting complement, however, is an increased risk of invasive meningococcal disease. Here, we report the first case of meningococcal group B vaccine failure in a young adult receiving eculizumab for atypical hemolytic uremic syndrome. She developed invasive meningococcal disease due to a vaccine preventable and penicillin-resistant meningococcal group B strain 4 months after receiving 2 doses of meningococcal group B vaccine while on oral penicillin prophylaxis against meningococcal infection. PMID- 28864712 TI - Age at Intervention for Permanent Hearing Loss and 5-Year Language Outcomes. AB - OBJECTIVES: Universal newborn hearing screening has been implemented to detect permanent childhood hearing loss (PCHL) early, with the ultimate goal of improving outcomes through early treatment. However, there is disagreement between studies on the size of this benefit and in some cases whether it is significantly different from 0. There have been no studies of sufficient size in which researchers have determined reliably whether the effect varies with degree of PCHL. We aimed to explore how intervention timing influences 5-year language in children with PCHL. METHODS: Via a prospective study of 350 children, we used standard multiple regression analyses to investigate the effect of age at intervention or hearing screening on language outcomes after allowing for the effects of nonverbal IQ, degree of PCHL, sex, birth weight, maternal education, additional disabilities, and communication mode. RESULTS: The benefit of early intervention for language development increased as hearing loss increased. Children whose amplification started at age 24 months had poorer language than those whose amplification started at 3 months. The difference was larger for 70 dB HL (-11.8 score points; 95% confidence interval [95% CI]: -18.7 to -4.8) than for 50-dB HL (-6.8; 95% CI: -10.8 to -2.8). Children who received cochlear implants at 24 months had poorer language than those implanted at 6 months ( 21.4; 95% CI: -33.8 to -9.0). There was no significant effect of screening on outcomes. CONCLUSIONS: Early intervention improves language outcomes, thereby lending support to streamlining clinical pathways to ensure early amplification and cochlear implantation after diagnosis. PMID- 28864713 TI - Is Shared Decision-making the Right Approach for Febrile Infants? PMID- 28864714 TI - A new modification for mammalian messenger RNA. AB - The discovery of multiple RNA modifications in the past few years has broadened our views of the structures and potential functions of RNA species, but deciphering which modifications are made where and how remains a challenge. A new study by Xu et al. applies a combination of mass spectrometry, biochemistry, genetics, and cellular biology tools to reveal the two mammalian methyltransferases that are responsible for m3C installation in tRNA and a third that mediates the previously unknown installation of m3C in mammalian mRNA. PMID- 28864715 TI - Opposites attract in bispecific antibody engineering. AB - Bispecific antibodies show great promise as intrinsic combination therapies, but often suffer from poor physiochemical properties, many times related to poor heterodimerization. De Nardis et al. identify specific electrostatic interactions that facilitate efficient heterodimerization, resulting in bispecific antibodies with physiochemical properties very similar to those of naturally occurring antibodies. This provides a new platform for the treatment of an array of diseases from cancer and autoimmune diseases to infectious diseases. PMID- 28864716 TI - Trajectories and characteristics of work disability before and after acute myocardial infarction. AB - OBJECTIVE: Scientific knowledge on work disability in terms of sickness absence and disability pension (SA/DP) among patients with acute myocardial infarction (AMI) is scarce. The study aimed to investigate trajectories of SA/DP among individuals with or without AMI and examined the associations between sociodemographic, morbidity and coronary revascularisation characteristics with such trajectories among patients with AMI. METHODS: This is a population-based cohort study of 10 255 individuals aged 30-60 years who had a first AMI during 2008-2010 and were alive 30 days after AMI. Each case was matched by sociodemographics to one control without AMI. Trajectories of annual SA/DP months over a 6-year period for cases and controls were analysed by group-based trajectory modelling. Associations of characteristics with trajectory groups were estimated by Chi2 test and multinomial logistic regression. RESULTS: The majority of patients (59%) had slightly increased annual levels of SA/DP (1 month) at the time of AMI, which returned to no SA/DP 2 years after the event. One group (4%) had increasing SA/DP months preceding and after AMI. Three groups showed constant SA/DP months on low (14%), medium (9%) and high (15%) levels. Sex, unemployment, education, musculoskeletal disorders and prescription of antidepressants were the strongest factors discriminating the SA/DP trajectories (R2difference=0.02-0.03, p<0.01). CONCLUSIONS: The majority of patients with AMI have a good outcome in terms of low levels of work disability within 2 years after AMI. Patterns of SA/DP before AMI, sex, socioeconomic status as well as comorbid musculoskeletal and mental disorders provide crucial clinical information on work disability after AMI. PMID- 28864717 TI - Impact of presynaptic sympathetic imbalance in long-QT syndrome by positron emission tomography. AB - OBJECTIVE: We investigated the impact of cardiac presynaptic norepinephrine recycling in patients with long-QT syndrome (LQTS) using positron emission tomography (PET) with 11C-meta-hydroxyephedrine ([11C]mHED-PET). METHODS: [11C]mHED-PET was performed in 25 patients with LQTS (LQT1: n=14; LQT2: n=11) and 20 healthy controls and correlated with clinical parameters. [11C]mHED-PET images were analysed for global and regional retention indices (RI) and washout rates (WO) reflecting dynamic parameters of the tracer activity. RESULTS: Global and regional RI values were similar between patients with LQTS and controls. Although the global WO rates were similar between these groups, regional WO rates were on average higher in the lateral left ventricle (LV) wall in patients with LQTS (dose, mean +/-SD; 0.08+/-0.14 vs 0.00%+/-0.09% min-1; p=0.033). In addition, patients with LQTS with a longer QTc interval showed a higher global WO rate. Clinical symptoms correlated with higher global WO rates. In the presence of normal global WO rates, asymptomatic LQTS patients showed higher global RI values. CONCLUSION: The increased regional WO rate of [11C]mHED in the lateral LV suggests an imbalance of presynaptic catecholamine reuptake and release, resulting in a higher synaptic catecholamine concentration, in particular in LQT1 patients. This might enhance beta-adrenoceptor signalling and thereby aggravate inherited ion channel dysfunction and may facilitate occurrence of ventricular tachyarrhythmias. Detection of regional differences in LV sympathetic nervous function may modify disease expression and potentially serve as a non-invasive risk marker in congenital LQTS. TRIAL REGISTRATION NUMBER: 2006-002767 41;Results. PMID- 28864718 TI - Assessment of the 2016 National Institute for Health and Care Excellence high sensitivity troponin rule-out strategy. AB - OBJECTIVE: We aimed to evaluate the limit of detection of high-sensitivity troponin (hs-cTn) and Thrombolysis In Myocardial Infarction (TIMI) score combination rule-out strategy suggested within the 2016 National Institute for Health and Care Excellence (NICE) Chest Pain of Recent Onset guidelines and establish the optimal TIMI score threshold for clinical use. METHODS: A pooled analysis of adult patients presenting to the emergency department with chest pain and a non-ischaemic ECG, recruited into six prospective studies, from Australia, New Zealand and the UK. We evaluated the sensitivity of TIMI score thresholds from 0 to 2 alongside hs-cTnT or hs-cTnI for the primary outcome of major adverse cardiac events within 30 days. RESULTS: Data were available for 3159 patients for hs-cTnT and 4532 for hs-cTnI, of these 376 (11.9%) and 445 (9.8%) had major adverse cardiac events, respectively. Using a TIMI score of 0, the sensitivity for the primary outcome was 99.5% (95% CI 98.1% to 99.9%) alongside hs-cTnT and 98.9% (97.4% to 99.6%)%) alongside hs-cTnI, identifying 17.9% and 21.0% of patients as low risk, respectively. For a TIMI score <=1 sensitivity was 98.9% (97.3% to 99.7%)%) alongside hs-cTnT and 98.4% (96.8% to 99.4%)%) alongside hs cTnI, identifying 28.1% and 35.7% as low risk, respectively. For TIMI<=2, meta sensitivity was <98% with either assay. CONCLUSIONS: Our findings support the rule-out strategy suggested by NICE. The TIMI score threshold suggested for clinical use is 0. The proportion of patients identified as low risk (18%-21%) and suitable for early discharge using this threshold may be sufficient to encourage change of practice. TRIAL REGISTRATION NUMBERS: ADAPT observational study/IMPACT intervention trial ACTRN12611001069943.ADAPT-ADP randomised controlled trial ACTRN12610000766011. EDACS-ADP randomised controlled trial ACTRN12613000745741. TRUST observational study ISRCTN no. 21109279. PMID- 28864719 TI - Anatomical and clinical predictors of valve dysfunction and aortic dilation in bicuspid aortic valve disease. AB - OBJECTIVE: Bicuspid aortic valve (BAV) is associated with early valvular dysfunction and proximal aorta dilation with high heterogeneity. This study aimed to assess the determinants of these complications. METHODS: Eight hundred and fifty-two consecutive adults diagnosed of BAV referred from cardiac outpatient clinics to eight echocardiographic laboratories of tertiary hospitals were prospectively recruited. Exclusion criteria were aortic coarctation, other congenital disorders or intervention. BAV morphotype, significant valve dysfunction and aorta dilation (>=2 Z-score) at sinuses and ascending aorta were established. RESULTS: Three BAV morphotypes were identified: right-left coronary cusp fusion (RL) in 72.9%, right-non-coronary (RN) in 24.1% and left-non-coronary (LN) in 3.0%. BAV without raphe was observed in 18.3%. Multivariate analysis showed aortic regurgitation (23%) to be related to male sex (OR: 2.80, p<0.0001) and valve prolapse (OR: 5.16, p<0.0001), and aortic stenosis (22%) to BAV-RN (OR: 2.09, p<0.001), the presence of raphe (OR: 2.75, p<0.001), age (OR: 1.03; p<0.001), dyslipidaemia (OR: 1.77, p<0.01) and smoking (OR: 1.63, p<0.05). Ascending aorta was dilated in 76% without differences among morphotypes and associated with significant valvular dysfunction. By contrast, aortic root was dilated in 34% and related to male sex and aortic regurgitation but was less frequent in aortic stenosis and BAV-RN. CONCLUSIONS: Normofunctional valves are more prevalent in BAV without raphe. Aortic stenosis is more frequent in BAV-RN and associated with some cardiovascular risk factors, whereas aortic regurgitation (AR) is associated with male sex and sigmoid prolapse. Although ascending aorta is the most commonly dilated segment, aortic root dilation is present in one-third of patients and associated with AR. Remarkably, BAV-RL increases the risk for dilation of the proximal aorta, whereas BAV-RN spares this area. PMID- 28864722 TI - Refining Immunotherapy Approvals. PMID- 28864720 TI - Overexpression of TrpC5 promotes tumor metastasis via the HIF-1alpha-Twist signaling pathway in colon cancer. AB - In cancer cells, intracellular Ca2+ homeostasis is altered, and this is involved in tumor initiation, progression, and metastasis. However, little is known about the underlying mechanisms. Here, we report that transient receptor potential channel 5 (TrpC5), a receptor-activated non-selective Ca2+ channel, is correlated with tumor metastasis in colon cancer patients. Moreover, in colon cancer cells, overexpression of TrpC5 caused a robust rise in the concentration of ([Ca2+]i), decreased E-cadherin, and increased mesenchymal biomarker expression, then promoted cell migration, invasion, and proliferation. Interestingly, we found that TrpC5 mediated hypoxia-inducible factor 1alpha (HIF-1alpha) expression, activating Twist to promote the epithelial-mesenchymal transition (EMT). Notably, patients with high expression of TrpC5 displayed poorer overall and metastasis free survival. Taken together, our findings demonstrate that TrpC5 induces the EMT through the HIF-1alpha-Twist signaling pathway to promote tumor metastasis in colon cancer. PMID- 28864723 TI - Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies. AB - Immunotherapy adds an exciting new dimension to the treatment of cancer, joining other approaches as a key pillar in the oncotherapeutics armamentarium. Immuno oncology agents harbor unique mechanisms of antitumor activity by leveraging the host immune system, which may result in response patterns, resistance kinetics, and toxicity profiles that differ from other systemic therapies. These features have led to many discussions on ways to optimally integrate immunotherapy into cancer clinical trials. This overview provides an introduction to the four CCR Focus articles that ensue, with special thoughts paid to clinical trial endpoints, biomarker development and validation, combination strategies, and limitations that arise with increasing use of these agents. In addition, this overview examines design concepts that may be applied to invigorate clinical trials and to maximize their impact in the immuno-oncology era. PMID- 28864724 TI - Immuno-oncology Trial Endpoints: Capturing Clinically Meaningful Activity. AB - Immuno-oncology (I-O) has required a shift in the established paradigm of toxicity and response assessment in clinical research. The design and interpretation of cancer clinical trials has been primarily driven by conventional toxicity and efficacy patterns observed with chemotherapy and targeted agents, which are insufficient to fully inform clinical trial design and guide therapeutic decisions in I-O. Responses to immune-targeted agents follow nonlinear dose-response and dose-toxicity kinetics mandating the development of novel response evaluation criteria. Biomarker-driven surrogate endpoints may better capture the mechanism of action and biological response to I-O agents and could be incorporated prospectively in early-phase I-O clinical trials. While overall survival remains the gold standard for evaluation of clinical efficacy of I-O agents in late-phase clinical trials, exploration of potential novel surrogate endpoints such as objective response rate and milestone survival is to be encouraged. Patient-reported outcomes should also be assessed to help redefine endpoints for I-O clinical trials and drive more efficient drug development. This paper discusses endpoints used in I-O trials to date and potential optimal endpoints for future early- and late-phase clinical development of I-O therapies. PMID- 28864725 TI - The Challenge for Development of Valuable Immuno-oncology Biomarkers. AB - The development of immunotherapy is an important breakthrough for the treatment of cancer, with antitumor efficacy observed in a wide variety of tumors. To optimize immunotherapy use, approaches must be developed to identify which patients are likely to achieve benefit. To minimize therapeutic toxicities and costs, understanding the ideal choice and sequencing of the numerous immuno oncology agents available for individual patients is thus critical, but fraught with challenges. The immune tumor microenvironment (TME) is a unique aspect of the response to immuno-oncology agents and measurement of single biomarkers does not adequately capture these complex interactions. Therefore, multiple potential biomarkers are likely needed. Current candidates in this area include PD-L1 expression, CD8+ tumor-infiltrating lymphocytes, tumor mutation load and neoantigen burden, immune-related gene signatures, and multiplex IHC assays that examine the pharmacodynamic and spatial interactions of the TME. The most fruitful investigations are likely to use several techniques to predict response and interrogate mechanisms of resistance. Immuno-oncology biomarker research must employ validated assays to ask focused research questions utilizing clinically annotated tissue collections and biomarker-focused clinical trial designs to investigate specific endpoints. Real-time input from patients and their advocates into biomarker discovery is necessary to ensure that the investigations pursued will improve both clinical outcomes and quality of life. We herein provide a framework of recommendations to guide the search for immuno-oncology biomarkers of value. PMID- 28864728 TI - mTOR Pathway Mutations and Response to Rapalogs in RCC-Letter. PMID- 28864726 TI - From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely. AB - Not until the turn of this century has immunotherapy become a fundamental component of cancer treatment. While monotherapy with immune modulators, such as immune checkpoint inhibitors, provides a subset of patients with durable clinical benefit and possible cure, combination therapy offers the potential for antitumor activity in a greater number of patients. The field of immunology has provided us with a plethora of potential molecules and pathways to target. This abundance makes it impractical to empirically test all possible combinations efficiently. We recommend that potential immunotherapy combinations be chosen based on sound rationale and available data to address the mechanisms of primary and acquired immune resistance. Novel trial designs may increase the proportion of patients receiving potentially efficacious treatments and, at the same time, better define the balance of clinical activity and safety. We believe that implementing a strategic approach in the early development of immunotherapy combinations will expedite the delivery of more effective therapies with improved safety and durable outcomes. PMID- 28864727 TI - Immuno-oncology Clinical Trial Design: Limitations, Challenges, and Opportunities. AB - Recent advances in immuno-oncology and regulatory approvals have been rapid and paradigm shifting in many difficult-to-treat malignancies. Despite immune checkpoint inhibitor therapy becoming the standard of care across multiple tumor types, there are many unanswered questions that need to be addressed before this therapeutic modality can be fully harnessed. Areas of limitations include treatment of patients not sufficiently represented in clinical trials, uncertainty of the optimal treatment dosing and duration, and lack of understanding regarding long-term immune related toxicities and atypical tumor responses. Patients such as those with autoimmune disease, chronic viral infections, limited performance status, and brain metastases were often excluded from initial trials due to concerns of safety. However, limited data suggest that some of these patients can benefit from therapy with manageable toxicities; thus, future studies should incorporate these patients to clearly define safety and efficacy. There are still controversies regarding the optimal dosing strategy that can vary from weight-based to flat dosing, with undefined treatment duration. Further elucidation of the optimal dosing approach and evaluation of predictive biomarkers should be incorporated in the design of future trials. Finally, there are long-term immune-mediated toxicities, atypical tumor responses such as pseudoprogression and endpoints unique to immuno-oncology that are not adequately captured by traditional trial designs; thus, novel study designs are needed. In this article, we discuss in detail the above challenges and propose needed areas of research for exploration and incorporation in the next generation of immuno-oncology clinical trials. PMID- 28864729 TI - Retraction: Polymorphisms of the CYP1B1 Gene as Risk Factors for Human Renal Cell Cancer. PMID- 28864731 TI - Management of Pediatric Community-acquired Bacterial Pneumonia. PMID- 28864732 TI - Pediatric Lymphoma. PMID- 28864733 TI - Approach to Hypertriglyceridemia in the Pediatric Population. AB - Hypertriglyceridemia is increasingly identified in children and adolescents, owing to improved screening and higher prevalence of childhood obesity. Hypertriglyceridemia can result from either increased triglyceride (TG) production or reduced TG clearance. The etiologic origin can be primary (genetic) or secondary, but it is often multifactorial. Management is challenging because of the interplay of genetic and secondary causes and lack of evidence-based guidelines. Lifestyle changes and dietary interventions are most important, especially in hypertriglyceridemia associated with obesity. Dietary restriction of fat remains the mainstay of management in primary hypertriglyceridemia. When fasting TG concentration is increased above 500 mg/dL (5.65 mmol/L), fibrates may be used to prevent pancreatitis. Omega-3 fatty acids are often used as an adjunctive therapy. When the fasting TG concentration is less than 500 mg/dL (5.65 mmol/L) and if the non-high-density lipoprotein cholesterol level is above 145 mg/dL (3.76 mmol/L), statin treatment can be considered. PMID- 28864734 TI - Case 1: Fever and Ataxia in a Toddler with Pica. PMID- 28864736 TI - Case 3: Abdominal Pain and Epididymitis in an 8-year-old Boy. PMID- 28864735 TI - Case 2: Sternal Mass in an 18-year-old Boy. PMID- 28864737 TI - Case 4: Suspected Sudden Visual Loss in a 2-year-old Girl. PMID- 28864738 TI - Case 5: Large Amounts of Urine Bilirubin on Urine Dipstick in a 14-year-old Girl. PMID- 28864739 TI - Case 6: Dehydration and Electrolyte Abnormalities in an 11-year-old Boy. PMID- 28864740 TI - CME Quiz Correction. PMID- 28864741 TI - Human Papillomavirus and HPV Vaccines. PMID- 28864742 TI - Retractions. PMID- 28864743 TI - Sun Exposure. PMID- 28864744 TI - Visual Diagnosis: Vesicular Rash in a Neonate. PMID- 28864746 TI - ERRATUM. PMID- 28864745 TI - Visual Diagnosis: A 3-week-old Girl with an Unusual Rash. PMID- 28864747 TI - ERRATUM. PMID- 28864749 TI - Wuzhi Tablet (Schisandra sphenanthera Extract) is a Promising Tacrolimus-Sparing Agent for Renal Transplant Recipients Who are CYP3A5 Expressers: a Two-Phase Prospective Study. AB - Tacrolimus is a potent but expensive first-line immunosuppressant, thus solutions to reduce tacrolimus consumption while maintain therapeutic level are in urgent need. A two-phase prospective study was conducted to assess the efficacy of an ethanolic extraction preparation of Schisandra sphenanthera (Wuzhi tablet) as a tacrolimus-sparing agent in renal transplant recipients who were high-dose tacrolimus consumers (CYP3A5*1 allele carriers, CYP3A5 expressers). A total of 12 patients were included in the Part I study. After co-administration of Wuzhi tablet, the average individual increment (%) in dose-adjusted C0, Cmax and AUC0 12 hour of tacrolimus were 198.8% (95% CI 149.2, 248.3), 111.0% (95% CI 63.4, 158.6) and 126.1% (95% CI 89.4, 162.8), respectively (P < 0.01), while the average individual reduction (%) in tacrolimus daily dose was 40.9% (95% CI 25.2, 56.6) (P < 0.01). Subsequently, 32 patients were enrolled in a prospective, randomized, controlled study and randomly assigned to receive tacrolimus by CYP3A5 genotype plus Wuzhi tablet co-administration guided dosing (study group) or standard dosing (control group). Besides less tacrolimus dose requirement (P < 0.01), a more accurate tacrolimus initial dose characterized by lower incidence of out-of-range C0 after initial dose (P < 0.01) and fewer dose changes (P < 0.01) was found in the study group. Moreover, no significant differences in acute rejection rate and serum creatinine levels were observed between two groups. Our results show that CYP3A5 genotype plus Wuzhi tablet co-administration guided tacrolimus dosing is a promising therapy for CYP3A5 expressers in the early post transplant stage, while further study with a larger sample size is required to prove these findings. PMID- 28864750 TI - Do antipsychotic drugs lose their efficacy for relapse prevention over time? AB - There is a debate about long-term treatment of schizophrenia with antipsychotic drugs, with some experts suggesting that these drugs should be discontinued. In this issue, Takeuchi et al demonstrated by a meta-analysis of 11 trials that antipsychotic drugs maintained their efficacy for relapse prevention for 1 year, whereas patients on placebo kept getting worse. We consider these findings in the light of the current discussion about possible dose-related brain volume loss, supersensitivity psychosis, the high variability of results in long-term follow up studies and recent approaches to discontinue antipsychotics in patients with a first-episode. The new findings speak in favour of continuing antipsychotics at the same dose, at least in patients whose condition is chronic, but the topic is complex. PMID- 28864751 TI - Up and Away by Isobell Prescott - psychiatry in pictures. PMID- 28864752 TI - Closing the mortality gap for severe mental illness: are we going in the right direction? AB - In this editorial, we discuss a UK-based cohort study examining the mortality gap for people with schizophrenia and bipolar disorder from 2000 to 2014. There have been concerted efforts to improve physical and mental healthcare for this population in recent decades. Have these initiatives reduced mortality and 'closed the gap'? PMID- 28864748 TI - Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers. AB - The gut microbiome is a novel frontier in xenobiotic metabolism. Polybrominated diphenyl ethers (PBDEs), especially BDE-47 (2, 2', 4, 4'-tetrabromodiphenyl ether) and BDE-99 (2, 2', 4, 4',5-pentabromodiphenyl ether), are among the most abundant and persistent environmental contaminants that produce a variety of toxicities. Little is known about how the gut microbiome affects the hepatic metabolism of PBDEs and the PBDE-mediated regulation of drug-processing genes (DPGs) in vivo. The goal of this study was to determine the role of gut microbiome in modulating the hepatic biotransformation of PBDEs. Nine-week-old male C57BL/6J conventional (CV) or germ-free (GF) mice were treated with vehicle, BDE-47 or BDE-99 (100 MUmol/kg) for 4 days. Following BDE-47 treatment, GF mice had higher levels of 5-OH-BDE-47 but lower levels of four other metabolites in liver than CV mice; whereas following BDE-99 treatment GF mice had lower levels of four minor metabolites in liver than CV mice. RNA sequencing demonstrated that the hepatic expression of DPGs was regulated by both PBDEs and enterotypes. Under basal conditions, the lack of gut microbiome upregulated the Cyp2c subfamily but downregulated the Cyp3a subfamily. Following PBDE exposure, certain DPGs were differentially regulated by PBDEs in a gut microbiome-dependent manner. Interestingly, the lack of gut microbiome augmented PBDE-mediated upregulation of many DPGs, such as Cyp1a2 and Cyp3a11 in mouse liver, which was further confirmed by targeted metabolomics. The lack of gut microbiome also augmented the Cyp3a enzyme activity in liver. In conclusion, our study has unveiled a novel interaction between gut microbiome and the hepatic biotransformation of PBDEs. PMID- 28864753 TI - Bipolar disorder and addictions: the elephant in the room. AB - Addictions are highly prevalent in bipolar disorder and greatly affect clinical outcomes. In this editorial, we review the evidence that addictions are a key challenge in bipolar disorder, examine putative neurobiological mechanisms, and reflect on the limited clinical trial evidence base with suggestions for treatment strategies and further developments. PMID- 28864754 TI - Doctor in court: what do lawyers really need from doctors, and what can doctors learn from lawyers? AB - Doctors and lawyers are usually well-educated, thoughtful people. Both groups have to assimilate large amounts of information and use it to make decisions. But the way that they do it is very different. Doctors have a better chance of helping courts to make good decisions if they understand exactly what courts need from them. PMID- 28864755 TI - The Gastroenterology ward at Delphi - poems by doctors. PMID- 28864756 TI - Public anti-stigma programmes might impove help-seeking. PMID- 28864757 TI - Authors' reply. PMID- 28864758 TI - Suicide risk assessment tools do not perform worse than clinical judgement. PMID- 28864759 TI - Authors' reply. PMID- 28864761 TI - Kaleidoscope. PMID- 28864760 TI - Correction. PMID- 28864762 TI - Life-course psychiatry: promoting healthy parenting, childhoods, treatment, and living space. PMID- 28864764 TI - Optogenetic interrogation of integrin alphaVbeta3 function in endothelial cells. AB - The integrin alphaVbeta3 is reported to promote angiogenesis in some model systems but not in others. Here, we used optogenetics to study the effects of alphaVbeta3 interaction with the intracellular adapter kindlin-2 (Fermt2) on endothelial cell functions potentially relevant to angiogenesis. Because interaction of kindlin-2 with alphaVbeta3 requires the C-terminal three residues of the beta3 cytoplasmic tail (Arg-Gly-Thr; RGT), optogenetic probes LOVpep and ePDZ1 were fused to beta3DeltaRGT-GFP and mCherry-kindlin-2, respectively, and expressed in beta3 integrin-null microvascular endothelial cells. Exposure of the cells to 450 nm (blue) light caused rapid and specific interaction of kindlin-2 with alphaVbeta3 as assessed by immunofluorescence and total internal reflection fluorescence (TIRF) microscopy, and it led to increased endothelial cell migration, podosome formation and angiogenic sprouting. Analyses of kindlin-2 mutants indicated that interaction of kindlin-2 with other kindlin-2 binding partners, including c-Src, actin, integrin-linked kinase and phosphoinositides, were also likely necessary for these endothelial cell responses. Thus, kindlin-2 promotes alphaVbeta3-dependent angiogenic functions of endothelial cells through its simultaneous interactions with beta3 integrin and several other binding partners. Optogenetic approaches should find further use in clarifying spatiotemporal aspects of vascular cell biology. PMID- 28864765 TI - Vinexin family (SORBS) proteins play different roles in stiffness-sensing and contractile force generation. AB - Vinexin, c-Cbl associated protein (CAP) and Arg-binding protein 2 (ArgBP2) constitute an adaptor protein family called the vinexin (SORBS) family that is targeted to focal adhesions (FAs). Although numerous studies have focused on each of the SORBS proteins and partially elucidated their involvement in mechanotransduction, a comparative analysis of their function has not been well addressed. Here, we established mouse embryonic fibroblasts that individually expressed SORBS proteins and analysed their functions in an identical cell context. Both vinexin-alpha and CAP co-localized with vinculin at FAs and promoted the appearance of vinculin-rich FAs, whereas ArgBP2 co-localized with alpha-actinin at the proximal end of FAs and punctate structures on actin stress fibers (SFs), and induced paxillin-rich FAs. Furthermore, both vinexin-alpha and CAP contributed to extracellular matrix stiffness-dependent vinculin behaviors, while ArgBP2 stabilized alpha-actinin on SFs and enhanced intracellular contractile forces. These results demonstrate the differential roles of SORBS proteins in mechanotransduction. PMID- 28864767 TI - Sequential activities of Dynein, Mud and Asp in centrosome-spindle coupling maintain centrosome number upon mitosis. AB - Centrosomes nucleate microtubules and are tightly coupled to the bipolar spindle to ensure genome integrity, cell division orientation and centrosome segregation. While the mechanisms of centrosome-dependent microtubule nucleation and bipolar spindle assembly have been the focus of numerous works, less is known about the mechanisms ensuring the centrosome-spindle coupling. The conserved NuMA protein (Mud in Drosophila) is best known for its role in spindle orientation. Here, we analyzed the role of Mud and two of its interactors, Asp and Dynein, in the regulation of centrosome numbers in Drosophila epithelial cells. We found that Dynein and Mud mainly initiate centrosome-spindle coupling prior to nuclear envelope breakdown (NEB) by promoting correct centrosome positioning or separation, while Asp acts largely independently of Dynein and Mud to maintain centrosome-spindle coupling. Failure in the centrosome-spindle coupling leads to mis-segregation of the two centrosomes into one daughter cell, resulting in cells with supernumerary centrosomes during subsequent divisions. Altogether, we propose that Dynein, Mud and Asp operate sequentially during the cell cycle to ensure efficient centrosome-spindle coupling in mitosis, thereby preventing centrosome mis-segregation to maintain centrosome number. PMID- 28864766 TI - Distinct intracellular sAC-cAMP domains regulate ER Ca2+ signaling and OXPHOS function. AB - cAMP regulates a wide variety of physiological functions in mammals. This single second messenger can regulate multiple, seemingly disparate functions within independently regulated cell compartments. We have previously identified one such compartment inside the matrix of the mitochondria, where soluble adenylyl cyclase (sAC) regulates oxidative phosphorylation (OXPHOS). We now show that sAC knockout fibroblasts have a defect in OXPHOS activity and attempt to compensate for this defect by increasing OXPHOS proteins. Importantly, sAC knockout cells also exhibit decreased probability of endoplasmic reticulum (ER) Ca2+ release associated with diminished phosphorylation of the inositol 3-phosphate receptor. Restoring sAC expression exclusively in the mitochondrial matrix rescues OXPHOS activity and reduces mitochondrial biogenesis, indicating that these phenotypes are regulated by intramitochondrial sAC. In contrast, Ca2+ release from the ER is only rescued when sAC expression is restored throughout the cell. Thus, we show that functionally distinct, sAC-defined, intracellular cAMP signaling domains regulate metabolism and Ca2+ signaling. PMID- 28864771 TI - Two independent but synchronized Gbetagamma subunit-controlled pathways are essential for trailing-edge retraction during macrophage migration. AB - Chemokine-induced directional cell migration is a universal cellular mechanism and plays crucial roles in numerous biological processes, including embryonic development, immune system function, and tissue remodeling and regeneration. During the migration of a stationary cell, the cell polarizes, forms lamellipodia at the leading edge (LE), and triggers the concurrent retraction of the trailing edge (TE). During cell migration governed by inhibitory G protein (Gi)-coupled receptors (GPCRs), G protein betagamma (Gbetagamma) subunits control the LE signaling. Interestingly, TE retraction has been linked to the activation of the small GTPase Ras homolog family member A (RhoA) by the Galpha12/13 pathway. However, it is not clear how the activation of Gi-coupled GPCRs at the LE orchestrates the TE retraction in RAW264.7 macrophages. Here, using an optogenetic approach involving an opsin to activate the Gi pathway in defined subcellular regions of RAW cells, we show that in addition to their LE activities, free Gbetagamma subunits also govern TE retraction by operating two independent, yet synchronized, pathways. The first pathway involves RhoA activation, which prevents dephosphorylation of the myosin light chain, allowing actomyosin contractility to proceed. The second pathway activates phospholipase Cbeta and induces myosin light chain phosphorylation to enhance actomyosin contractility through increasing cytosolic calcium. We further show that both of these pathways are essential, and inhibition of either one is sufficient to abolish the Gi-coupled GPCR-governed TE retraction and subsequent migration of RAW cells. PMID- 28864772 TI - Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b. AB - TRIP8b, an accessory subunit of hyperpolarization-activated cyclic nucleotide gated (HCN) ion channels, alters both the cell surface expression and cyclic nucleotide dependence of these channels. However, the mechanism by which TRIP8b exerts these dual effects is still poorly understood. In addition to binding to the carboxyl-terminal tripeptide of HCN channels, TRIP8b also binds directly to the cyclic nucleotide-binding domain (CNBD). That interaction, which requires a small central portion of TRIP8b termed TRIP8bcore, is both necessary and sufficient for reducing the cAMP-dependent regulation of HCN channels. Here, using fluorescence anisotropy, we report that TRIP8b binding to the CNBD of HCN2 channels decreases the apparent affinity of cAMP for the CNBD. We explored two possible mechanisms for this inhibition. A noncompetitive mechanism in which TRIP8b inhibits the conformational change of the CNBD associated with cAMP regulation and a competitive mechanism in which TRIP8b and cAMP compete for the same binding site. To test these two mechanisms, we used a combination of fluorescence anisotropy, biolayer interferometry, and double electron-electron resonance spectroscopy. Fitting these models to our fluorescence anisotropy binding data revealed that, surprisingly, the TRIP8b-dependent reduction of cAMP binding to the CNBD can largely be explained by partial competition between TRIP8b and cAMP. On the basis of these findings, we propose that TRIP8b competes with a portion of the cAMP-binding site or distorts the binding site by making interactions with the binding pocket, thus acting predominantly as a competitive antagonist that inhibits the cyclic-nucleotide dependence of HCN channels. PMID- 28864773 TI - The calcium-binding protein ALG-2 regulates protein secretion and trafficking via interactions with MISSL and MAP1B proteins. AB - Mobilization of intracellular calcium is essential for a wide range of cellular processes, including signal transduction, apoptosis, and vesicular trafficking. Several lines of evidence have suggested that apoptosis-linked gene 2 (ALG-2, also known as PDCD6), a calcium-binding protein, acts as a calcium sensor linking calcium levels with efficient vesicular trafficking, especially at the endoplasmic reticulum (ER)-to-Golgi transport step. However, how ALG-2 regulates these processes remains largely unclear. Here, we report that MAPK1-interacting and spindle-stabilizing (MISS)-like (MISSL), a previously uncharacterized protein, interacts with ALG-2 in a calcium-dependent manner. Live-cell imaging revealed that upon a rise in intracellular calcium levels, GFP-tagged MISSL (GFP MISSL) dynamically relocalizes in a punctate pattern and colocalizes with ALG-2. MISSL knockdown caused disorganization of the components of the ER exit site, the ER-Golgi intermediate compartment, and Golgi. Importantly, knockdown of either MISSL or ALG-2 attenuated the secretion of secreted alkaline phosphatase (SEAP), a model secreted cargo protein, with similar reductions in secretion by single- and double-protein knockdowns, suggesting that MISSL and ALG-2 act in the same pathway to regulate the secretion process. Furthermore, ALG-2 or MISSL knockdown delayed ER-to-Golgi transport of procollagen type I. We also found that ALG-2 and MISSL interact with microtubule-associated protein 1B (MAP1B) and that MAP1B knockdown reverts the reduced secretion of SEAP caused by MISSL or ALG-2 depletion. These results suggest that a change in the intracellular calcium level plays a role in regulation of the secretory pathway via interaction of ALG-2 with MISSL and MAP1B. PMID- 28864774 TI - Negatively charged residues in the first extracellular loop of the L-type CaV1.2 channel anchor the interaction with the CaValpha2delta1 auxiliary subunit. AB - Voltage-gated L-type CaV1.2 channels in cardiomyocytes exist as heteromeric complexes. Co-expression of CaValpha2delta1 with CaVbeta/CaValpha1 proteins reconstitutes the functional properties of native L-type currents, but the interacting domains at the CaV1.2/CaValpha2delta1 interface are unknown. Here, a homology-based model of CaV1.2 identified protein interfaces between the extracellular domain of CaValpha2delta1 and the extracellular loops of the CaValpha1 protein in repeats I (IS1S2 and IS5S6), II (IIS5S6), and III (IIIS5S6). Insertion of a 9-residue hemagglutinin epitope in IS1S2, but not in IS5S6 or in IIS5S6, prevented the co-immunoprecipitation of CaV1.2 with CaValpha2delta1. IS1S2 contains a cluster of three conserved negatively charged residues Glu-179, Asp-180, and Asp-181 that could contribute to non-bonded interactions with CaValpha2delta1. Substitutions of CaV1.2 Asp-181 impaired the co immunoprecipitation of CaVbeta/CaV1.2 with CaValpha2delta1 and the CaValpha2delta1-dependent shift in voltage-dependent activation gating. In contrast, single substitutions in CaV1.2 in neighboring positions in the same loop (179, 180, and 182-184) did not significantly alter the functional up regulation of CaV1.2 whole-cell currents. However, a negatively charged residue at position 180 was necessary to convey the CaValpha2delta1-mediated shift in the activation gating. We also found a more modest contribution from the positively charged Arg-1119 in the extracellular pore region in repeat III of CaV1.2. We conclude that CaV1.2 Asp-181 anchors the physical interaction that facilitates the CaValpha2delta1-mediated functional modulation of CaV1.2 currents. By stabilizing the first extracellular loop of CaV1.2, CaValpha2delta1 may up regulate currents by promoting conformations of the voltage sensor that are associated with the channel's open state. PMID- 28864775 TI - Proteolytic processing of lysyl oxidase-like-2 in the extracellular matrix is required for crosslinking of basement membrane collagen IV. AB - Lysyl oxidase-like-2 (LOXL2) is an enzyme secreted into the extracellular matrix that crosslinks collagens by mediating oxidative deamination of lysine residues. Our previous work demonstrated that this enzyme crosslinks the 7S domain, a structural domain that stabilizes collagen IV scaffolds in the basement membrane. Despite its relevant role in extracellular matrix biosynthesis, little is known about the structural requirements of LOXL2 that enable collagen IV crosslinking. In this study, we demonstrate that LOXL2 is processed extracellularly by serine proteases, generating a 65-kDa form lacking the first two scavenger receptor cysteine-rich domains. Site-specific mutagenesis to prevent proteolytic processing generated a full-length enzyme that is active in vitro toward a soluble substrate, but fails to crosslink insoluble collagen IV within the extracellular matrix. In contrast, the processed form of LOXL2 binds to collagen IV and crosslinks the 7S domain. Together, our data demonstrate that proteolytic processing is an important event that allows LOXL2-mediated crosslinking of basement membrane collagen IV. PMID- 28864777 TI - Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome. PMID- 28864776 TI - A histone-mimicking interdomain linker in a multidomain protein modulates multivalent histone binding. AB - N-terminal histone tails are subject to many posttranslational modifications that are recognized by and interact with designated reader domains in histone-binding proteins. BROMO domain adjacent to zinc finger 2B (BAZ2B) is a multidomain histone-binding protein that contains two histone reader modules, a plant homeodomain (PHD) and a bromodomain (BRD), linked by a largely disordered linker. Although previous studies have reported specificity of the PHD domain for the unmodified N terminus of histone H3 and of the BRD domain for H3 acetylated at Lys14 (H3K14ac), the exact mode of H3 binding by BAZ2B and its regulation are underexplored. Here, using isothermal titration calorimetry and NMR spectroscopy, we report that acidic residues in the BAZ2B PHD domain are essential for H3 binding and that BAZ2B PHD-BRD establishes a polyvalent interaction with H3K14ac. Furthermore, we provide evidence that the disordered interdomain linker modulates the histone-binding affinity by interacting with the PHD domain. In particular, lysine-rich stretches in the linker, which resemble the positively charged N terminus of histone H3, reduce the binding affinity of the PHD finger toward the histone substrate. Phosphorylation, acetylation, or poly(ADP-ribosyl)ation of the linker residues may therefore act as a cellular mechanism to transiently tune BAZ2B histone-binding affinity. Our findings further support the concept of interdomain linkers serving a dual role in substrate binding by appropriately positioning the adjacent domains and by electrostatically modulating substrate binding. Moreover, inhibition of histone binding by a histone-mimicking interdomain linker represents another example of regulation of protein-protein interactions by intramolecular mimicry. PMID- 28864778 TI - Quantitative Mass Spectrometry Reveals Food Intake-Induced Neuropeptide Level Changes in Rat Brain: Functional Assessment of Selected Neuropeptides as Feeding Regulators. AB - Endogenous neuropeptides are important signaling molecules that function as regulators of food intake and body weight. Previous work has shown that neuropeptide gene expression levels in a forebrain reward site, the nucleus accumbens (NAc), were changed by feeding. To directly monitor feeding-induced changes in neuropeptide expression levels within the NAc, we employed a combination of cryostat dissection, heat stabilization, neuropeptide extraction and label-free quantitative neuropeptidomics via a liquid chromatography-high resolution mass spectrometry platform. Using this methodology, we described the first neuropeptidome in NAc and discovered that feeding caused the expression level changes of multiple neuropeptides derived from different precursors, especially proSAAS-derived peptides such as Big LEN, PEN and little SAAS. We further investigated the regulatory functions of these neuropeptides derived from the ProSAAS family by performing an intra-NAc microinjection experiment using the identified ProSAAS neuropeptides, 'Big-LEN' and 'PEN'. Big LEN significantly increased rats' food and water intake, whereas both big LEN and PEN affected other behaviors including locomotion, drinking and grooming. In addition, we quantified the feeding-induced changes of peptides from hippocampus, hypothalamus and striatum to reveal the neuropeptide interplay among different anatomical regions. In summary, our study demonstrated neuropeptidomic changes in response to food intake in the rat NAc and other key brain regions. Importantly, the microinfusion of ProSAAS peptides into NAc revealed that they are behaviorally active in this brain site, suggesting the potential use of these peptides as therapeutics for eating disorders. PMID- 28864779 TI - RNAi-mediated TCF-3 gene silencing inhibits proliferation of Eca-109 esophageal cancer cells by inducing apoptosis. AB - Esophageal cancer (EC) remains an important health problem in China. In the present study, through the use of siRNA, specific gene knockdown of transcription factor 3 gene (TCF-3) was achieved in vitro and the effect of TCF-3 gene on human EC Eca-109 cell proliferation and apoptosis. Eca-109 cells were treated using negative control (NC) of siRNA against TCF-3 (siTCF-3) and siTCF-3 group. Colony formation assay was used to detect the colony formation ability in Eca-109 cells. MTT assay was used to measure the cell growth and viability, whereas BrDU assay was used to evaluate cell proliferation, and flow cytometry (FCM) to assess cell apoptosis. Reverse-transcription quantitative PCR (RT-qPCR) was applied to measure TCF-3 gene expression. Protein expressions of TCF-3, apoptosis-related proteins, Bcl-2, Bax, and caspase-3 were determined using Western blotting. Transfection of siTCF-3 successfully down-regulated TCF-3 gene expression. In addition, siTCF-3, reduced Eca-109 cell viability and proliferation, in a time dependent manner, and inhibited progression of cell cycle from G0/G1 to S-stage. When treated with siTCF-3, the Eca-109 cells exhibited increased apoptosis, with up-regulated cleaved caspase and Bax expressions, whereas Bcl-2 expression was down-regulated. The present study shows that TCF-3 gene silencing inhibits Eca 109 cell growth and proliferation, suppresses cell cycle progression, and promotes apoptosis, which might serve as a new objective for EC treatment. PMID- 28864780 TI - MicroRNA sequence analysis identifies microRNAs associated with peri-implantitis in dogs. AB - Peri-implantitis, which is characterized by dense inflammatory infiltrates and increased osteoclast activity, can lead to alveolar bone destruction and implantation failure. miRNAs participate in the regulation of various inflammatory diseases, such as periodontitis and osteoporosis. Therefore, the present study aimed to investigate the differential expression of miRNAs in canine peri-implantitis and to explore the functions of their target genes. An miRNA sequence analysis was used to identify differentially expressed miRNAs in peri-implantitis. Under the criteria of a fold-change >1.5 and P<0.01, 8 up regulated and 30 down-regulated miRNAs were selected for predictions of target genes and their biological functions. Based on the results of Gene Ontology (GO) and KEGG pathway analyses, these miRNAs may fine-tune the inflammatory process in peri-implantitis through an intricate mechanism. The results of quantitative real time PCR (qRT-PCR) revealed that let-7g, miR-27a, and miR-145 may play important roles in peri-implantitis and are worth further investigation. The results of the present study provide insights into the potential biological effects of the differentially expressed miRNAs, and specific enrichment of target genes involved in the mitogen-activated protein kinase (MAPK) signaling pathway was observed. These findings highlight the intricate and specific roles of miRNAs in inflammation and osteoclastogenesis, both of which are key aspects of peri implantitis, and thus may contribute to future investigations of the etiology, underlying mechanism, and treatment of peri-implantitis. PMID- 28864781 TI - Homocysteine inhibits angiogenesis through cytoskeleton remodeling. AB - Homocysteine (Hcy) is an intermediate non-diet amino acid connecting methionine and folate cycles. Elevated total Hcy level in blood, denoted as hyperhomocysteinemia, has emerged as a prevalent and strong risk factor for multiple diseases including atherosclerotic vascular disease in coronary, cerebral, and peripheral vessels. Its detrimental effect on vascular system implies the potential application as an inhibitor of angiogenesis. However, the detailed mechanism is unveiled. Inhibitory effect of Hcy was assessed on vascular endothelial growth factor (VEGF) induced cell proliferation and migration with endothelial cell (EC) culture system. Its effect on angiogenesis was further examined in vitro and in vivo After Hcy treatment, key angiogenic factors were measured by RT-qPCR. Cellular skeletal structure was also evaluated by actin stress fiber staining. VEGF-induced human umbilical vein EC (HUVEC) proliferation and migration were dramatically down-regulated by Hcy in a dose-responsive manner. Hcy treatment significantly inhibited the VEGF-induced angiogenesis in vitro by tube formation assay and chick chorioallantoic membrane (CAM) vessel formation in vivo Key angiogenic factors like VEGFR1/2 and angiopoietin (Ang)1/2 were substantially reduced by Hcy in HUVEC- and VEGF-induced actin stress fiber cytoskeletal structure was abolished. We demonstrated that Hcy could inhibit angiogenesis by targetting key angiogenic factor and disruption of actin cytoskeleton which is crucial for cell migration. PMID- 28864783 TI - Mesenchymal stromal cells can be applied to red blood cells storage as a kind of cellular additive. AB - During storage in blood banks, red blood cells (RBCs) undergo the mechanical and metabolic damage, which may lead to the diminished capacity to deliver oxygen. At high altitude regions, the above-mentioned damage may get worse. Thus, more attention should be paid to preserve RBCs when these components need transfer from plain to plateau regions. Recently, we found that mesenchymal stromal cells (MSCs) could rescue from anemia, and MSCs have been demonstrated in hematopoietic stem cells (HSCs) transplantation to reconstitute hematopoiesis in vivo by us. Considering the functions and advantages of MSCs mentioned above, we are trying to find out whether they are helpful to RBCs in storage duration at high altitudes. In the present study, we first found that mice MSCs could be preserved in citrate phosphate dextrose adenine-1 (CPDA-1) at 4 +/- 2 degrees C for 14 days, and still maintained great viability, even at plateau region. Thus, we attempted to use MSCs as an available supplement to decrease RBCs lesion during storage. We found that MSCs were helpful to support RBCs to maintain biochemical parameters and kept RBCs function well on relieving anemia in an acute hemolytic murine model. Therefore, our investigation developed a method to get a better storage of RBCs through adding MSCs, which may be applied in RBCs storage as a kind of cellular additive into preservation solution. PMID- 28864782 TI - Ozone oil promotes wound healing by increasing the migration of fibroblasts via PI3K/Akt/mTOR signaling pathway. AB - Skin injury affects millions of people via the uncontrolled inflammation and infection. Many cellular components including fibroblasts and signaling pathways such as transforming growth factor-beta (TGF-beta) were activated to facilitate the wound healing to repair injured tissues. C57BL/6 female mice were divided into control and ozone oil treated groups. Excisional wounds were made on the dorsal skin and the fibroblasts were isolated from granulation tissues. The skin injured mouse model revealed that ozone oil could significantly decrease the wound area and accelerate wound healing compared with control group. QPCR and Western blotting assays showed that ozone oil up-regulated collagen I, alpha-SMA, and TGF-beta1 mRNA and protein levels in fibroblasts. Wound healing assay demonstrated that ozone oil could increase the migration of fibroblasts. Western blotting assay demonstrated that ozone oil increased the epithelial-mesenchymal transition (EMT) process in fibroblasts via up-regulating fibronectin, vimentin, N-cadherin, MMP-2, MMP-9, insulin-like growth factor binding protein (IGFBP)-3, IGFBP5, and IGFBP6, and decreasing epithelial protein E-cadherin and cellular senescence marker p16 expression. Mechanistically, Western blotting assay revealed that ozone oil increased the phosphorylation of PI3K, Akt, and mTOR to regulate the EMT process, while inhibition of PI3K reversed this effect of ozone oil. At last, the results from Cytometric Bead Array (CBA) demonstrated ozone oil significantly decreased the inflammation in fibroblasts. Our results demonstrated that ozone oil facilitated the wound healing via increasing fibroblast migration and EMT process via PI3K/Akt/mTOR signaling pathway in vivo and in vitro The cellular and molecular mechanisms we found here may provide new therapeutic targets for the treatment of skin injury. PMID- 28864785 TI - Leveling the Three-Legged Stool. PMID- 28864784 TI - SH003 reverses drug resistance by blocking signal transducer and activator of transcription 3 (STAT3) signaling in breast cancer cells. AB - Overcoming drug resistance is an important task for investigators and clinician to achieve successful chemotherapy in cancer patients. Drug resistance is caused by various factors, including the overexpression of P-glycoprotein (P-gp, MDR1). The development of new, useful compounds that overcome drug resistance is urgent. SH003 is extracted from the mixture of three different herbs, and its anticancer effect has been revealed in different cancer cell types. In the present study, we investigated whether SH003 is able to reverse drug resistance using paclitaxel resistant breast cancer cells (MCF-7/PAC). In our experiments, SH003 significantly decreased cell growth and colony formation in MCF-7/PAC cells and parental MCF-7 cells. This growth inhibition was related to the accumulation of cells in the sub-G0/G1 apoptotic population and an increase in the number of apoptotic cells. SH003 reduced the mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated proteins (MRPs) in MCF-7/PAC cells. SH003 also down-regulated the expression of P-gp. SH003 reversed drug efflux from MCF-7/PAC cells, resulting in rhodamine123 (Rho123) accumulation. Inhibition of drug resistance by SH003 is related to the suppression of the signal transducer and activator of transcription 3 (STAT3) signaling pathway. SH003 decreased STAT3 activation (p-STAT3) and its nuclear translocation and inhibited the secretion of VEGF and MMP-2, which are STAT3 target genes. An STAT3 inhibitor, JAK inhibitor I and an HIF-1alpha inhibitor decreased cell growth in MCF-7 and MCF-7/PAC cells. Taken together, these results demonstrate that SH003 can overcome drug resistance, and SH003 might be helpful for chemotherapy in cancer patients. PMID- 28864786 TI - Enhancing Dental Students' Understanding of Poverty Through Simulation. AB - Dental students should develop an understanding of the barriers to and frustrations with accessing dental care and maintaining optimal oral health experienced by persons with limited resources rather than blaming the patient or caregiver. Developing this understanding may be aided by helping students learn about the lives of underserved and vulnerable patients they will encounter not only in extramural rotations, but throughout their careers. The aim of this study was to determine if dental students' understanding of daily challenges faced by families with low income changed as a result of a poverty simulation. In 2015 and 2016, an experiential poverty simulation was used to prepare third-year dental students at one U.S. dental school for their upcoming required community-based rotations. In 2015, United Way staff conducted the simulation using the Missouri Community Action Poverty Simulation (CAPS); in 2016, faculty members trained in CAPS conducted the simulation using a modified version of the tool. In the simulation, students were assigned to family units experiencing various types of hardship and were given specific identities for role-playing. A retrospective pretest and a posttest were used to assess change in levels of student understanding after the simulation. Students assessed their level of understanding in five domains: financial pressures, difficult choices, difficulties in improving one's situation, emotional stressors, and impact of community resources for those living in poverty. The survey response rates in 2015 and 2016 were 86% and 74%, respectively. For each of the five domains, students' understanding increased from 58% to 74% per domain. The majority reported that the exercise was very valuable or somewhat valuable (74% in 2015, 88% in 2016). This study found that a poverty simulation was effective in raising dental students' understanding of the challenges faced by low-income families. It also discovered that framing the issues in the context of accessing dental care was important. PMID- 28864787 TI - Screening for Diabetes in a Dental School Clinic to Assess Interprofessional Communication Between Physicians and Dental Students. AB - If a dental student diagnoses a patient in a dental school clinic as being at high risk of prediabetes or diabetes, the patient should be referred to his or her physician for further diagnostic evaluation, and the physician should send back the evaluation results so that the dental team can optimize treatment and health care choices if the diagnosis is confirmed. The primary aim of this study was to evaluate physicians' responses to written and oral requests for information regarding follow-up diabetes testing. A secondary aim was to evaluate patients' compliance with recommendations to seek medical care after being determined to be at high risk of prediabetes or diabetes in the dental clinic. Based on at least one positive risk factor for diabetes, 74 patients in one U.S. dental school's clinic were screened by third- and fourth-year dental students for prediabetes or diabetes and underwent point of care HbA1C (glycalated hemoglobin) blood tests between June 2014 and June 2015. Patients with an HbA1C value of 5.7% or above were referred to their physicians for follow-up testing. The physician was mailed the patient's HIPAA release and a request for updates to the student regarding the patient's diabetes status. If the physician did not provide the requested information, a dental student telephoned him or her to obtain the patient's diabetes status. Of the 74 patients, 34 (46%) tested positive with HbA1C tests and were referred to their physicians. Of those 34 referred patients, 20 (59%) saw their physicians for additional evaluations within six months of referral. None of the 20 physicians responded to the written requests for information on additional diabetes testing. After one or two telephone requests, all 20 physicians provided the test results. This study found that most of the patients (59%) followed their dental practitioner's advice to seek follow-up care with their physician, supporting the value of conducting these tests in a dental clinic. However, the results also suggested that a single written request may be insufficient to prompt physicians to return those results and that follow-up communication in a phone call may be more effective. PMID- 28864788 TI - Oral Health Education for Medical Students: Malaysian and Australian Students' Perceptions of Educational Experience and Needs. AB - Education in oral health is important to prepare future medical professionals for collaborative roles in maintaining patients' oral health, an important component of general health and well-being. The aims of this study were to determine the perceptions of medical students in Malaysia and Australia of the quality of their training in oral health care and their perceptions of their professional role in maintaining the oral health of their patients. A survey was administered in the classroom with final-year Malaysian (n=527; response rate=79.3%) and Australian (n=455; response rate: 60%) medical students at selected institutions in those countries. In the results, most of these medical students reported encountering patients with oral health conditions including ulcers, halitosis, and edentulism. A majority in both countries reported believing they should advise patients to obtain regular dental check-ups and eat a healthy diet, although they reported feeling less than comfortable in managing emergency dental cases. A high percentage reported they received a good education in smoking cessation but not in managing dental trauma, detecting cancerous lesions, or providing dietary advice in oral disease prevention. They expressed support for inclusion of oral health education in medical curricula. These students' experience with and perceptions of oral health care provide valuable information for medical curriculum development in these two countries as well as increasing understanding of this aspect of interprofessional education and practice now in development around the world. PMID- 28864789 TI - Improving Dental Students' Long-Term Retention of Pharmacy Knowledge with "Medication Minutes". AB - A major challenge in foundational science courses in dental curricula is the application of information from the classroom to a clinical setting. To bridge this gap, the aim of this study was to increase students' learning in a foundational pharmacology course through increasing clinical relevance and using formative assessment. Second-year dental students in an introductory pharmacology course were presented material in a traditional basic science lecture format and in brief examples of pharmacy-generated clinical content (Medication Minutes). Short-term retention was assessed with a series of five post-class session, non graded quizzes, each containing four questions: two knowledge-based (one from basic science material and one Medication Minute) and two application-based (one from basic science material and one Medication Minute). Ten knowledge-based (basic science material) questions and ten application-based (Medication Minutes) questions were included on exams throughout the semester. The primary outcome was to measure long-term retention using performance on these questions on an assessment the following semester. Additionally, the impact of student engagement on examination performance was evaluated based on the number of quizzes each student completed. Students who completed three or more quizzes (n=43, 53%) were designated as "highly engaged," while students who completed less than three quizzes (n=36, 44%) were defined as "less engaged." Two students (3%) were excluded for not completing the long-term assessment or not consenting to the study. On short-term retention measures, the students performed better on the Medication Minute (M=0.76) than basic science (M=0.58) (p<0.001) material; however, on the in-semester examinations, there was no difference in performance. On long-term retention measures, the students performed better on Medication Minute material (M=0.64) than basic science material (M=0.33) (p<0.001); this was true for both highly engaged and less-engaged students. These results suggest that teaching pharmacology in a clinical context yielded better long-term retention than teaching with a non-clinical focus. PMID- 28864790 TI - A Survey of Dental Implant Instruction in Predoctoral Dental Curricula in North America. AB - The aim of this study was to investigate the extent and forms of predoctoral implant dentistry instruction in North American dental schools and to identify future directions and challenges. The survey collected data on curriculum content, departmental oversight, techniques, and materials, as well as current problems to be solved. The 30-question survey was sent in 2012 to the dean or administrator in charge of the predoctoral curriculum of all 73 dental schools in the U.S. and Canada at the time; four reminders were sent. Forty-seven schools responded, for a response rate of 64%. Of the 47 responding schools, 46 (98%) offered didactic instruction (mean of 17 hours); 87% had a laboratory component (mean of 14.46 hours); and 57% had a clinical requirement. In the responding schools, students had an average of 1.85 implant restorative cases and 0.61 surgical cases. Forty-two of the schools (89%) had implemented observation of implant surgery and/or assisting with implant surgery in their curricula. Major challenges reported in implementing a comprehensive predoctoral implant curriculum included expense of implant systems to the schools and to patients, shortage of predoctoral cases, and lack of curriculum time and trained faculty. These results show that implant education for predoctoral dental students continues to expand, with a trend towards more preclinical exercises and clinical experiences and fewer didactic courses. PMID- 28864791 TI - Dental and Medical Students' Use and Perceptions of Learning Resources in a Human Physiology Course. AB - The aim of this study was to determine the use and perceived utility of various learning resources available during the first-year Integrated Human Physiology course at the dental and medical schools at Harvard University. Dental and medical students of the Class of 2018 were surveyed anonymously online in 2015 regarding their use of 29 learning resources in this combined course. The learning resources had been grouped into four categories to discern frequency of use and perceived usefulness among the categories. The survey was distributed to 169 students, and 73 responded for a response rate of 43.2%. There was no significant difference among the learning resource categories in frequency of use; however, there was a statistically significant difference among categories in students' perceptions of usefulness. No correlation was found between frequency of use and perceived usefulness of each category. Students seemingly were not choosing the most useful resources for them. These results suggest that, in the current educational environment, where new technologies and self-directed learning are highly sought after, there remains a need for instructor-guided learning. PMID- 28864792 TI - Color-Blind Racial Beliefs Among Dental Students and Faculty. AB - Providing culturally competent patient care requires an awareness of racial and cultural norms as well as a recognition of racism. Yet, there is a paucity of research devoted to this problem. In dental education, increased attention has focused on eliminating oral health care disparities due to ethnicity and race. Further investigation to determine the relationship between color-blind attitudes (failing to recognize the impact of race and racism on social justice) and dental educators' cultural competence is needed. The aim of this study was to determine dental faculty and student baseline color-blind racial attitudes scale scores, using the color-blind racial attitudes scale (CoBRAS). This 20-item instrument that measures three subscales of color-blind racial attitudes (Unawareness of Racial Privilege, Institutional Discrimination, and Blatant Racial Issues) was administered to student and faculty groups at one U.S. dental school. Out of a total 245 students in three class years, 235 responded to all items, for a response rate of 96%; out of a total 77 faculty members invited to participate, 71 responded to all items, for a response rate of 92%. Underrepresented minority (URM) faculty scored significantly higher on the Institutional Discrimination subscale and lower on Unawareness of Racial Privilege compared to non-URM students. Males scored significantly higher on Institutional Discrimination and Blatant Racial Issues compared to females. Compared to white students, URM students scored lower on all three subscales. The findings were consistent with previous studies indicating that female and URM students were more sensitive to racism compared to male and majority students. The findings that white faculty had higher awareness of racial privilege than white students and that URM faculty were less aware of institutional discrimination than URM students provided new information. These findings suggest that dental faculty members need professional development opportunities that promote becoming color-conscious and understanding privilege and biases, that model instruction on discussing race and racism, and that extend beyond a brief workshop. PMID- 28864793 TI - Impact of a Differential Learning Approach on Practical Exam Performance: A Controlled Study in a Preclinical Dental Course. AB - The aim of this study was to evaluate if differential learning in a preclinical dental course impacted the performance of dental students in a practical exam (preparation of a gold partial crown) immediately after the training session and 20 weeks later compared to conventional learning. This controlled study was performed in a preclinical course in operative dentistry at a dental school in Germany. Third-year students were trained in preparing gold partial crowns by using either the conventional learning (n=41) or the differential learning approach (n=32). The differential learning approach consisted of 20 movement exercises with a continuous change of movement execution during the learning session, while the conventional learning approach was mainly based on repetition, a methodological series of exercises, and correction of preparations during the training phase. Practical exams were performed immediately after the training session (T1) and 20 weeks later (T2, retention test). Preparations were rated by four independent and blinded examiners. At T1, no significant difference between the performance (exam passed) of the two groups was detected (conventional learning: 54.3%, differential learning: 68.0%). At T2, significantly more students passed the exam when trained by the differential learning approach (68.8%) than by the conventional learning approach (18.9%). Interrater reliability was moderate (Kappa: 0.57, T1) or substantial (Kappa: 0.67, T2), respectively. These results suggest that a differential learning approach can increase the manual skills of dental students. PMID- 28864794 TI - Developing Common Competencies for Southeast Asian General Dental Practitioners. AB - Current policy in Southeast Asian dental education focuses on high-quality dental services from new dental graduates and the free movement of dental practitioners across the region. The Southeast Asian Nations (ASEAN) Dental Councils have proposed the "Common Major Competencies for ASEAN General Dental Practitioners" to harmonize undergraduate dental education. This article discusses how the ASEAN competencies were developed and established to assist the development of general dental practitioners with comparable knowledge, skills, and attitudes across ASEAN. The competencies were developed through four processes: a questionnaire about current national oral health problems, a two-round Delphi process that sought agreement on competencies, a panel discussion by representatives from ASEAN Dental Councils, and data verification by the representatives after the meeting. Key themes of the ASEAN competencies were compared with the competencies from the U.S., Canada, Europe, Australia, and Japan. A total of 33 competency statements, consistent with other regions, were agreed upon and approved. Factors influencing the ASEAN competencies and their implementation include oral health problems in ASEAN, new knowledge and technology in dentistry, limited institutional resources, underregulated dental schools, and uneven distribution of dental practitioners. The ASEAN competencies will serve as the foundation for further developments in ASEAN dental education including policy development, curriculum revision, quality assurance, and staff development. Collaboration amongst stakeholders is essential for successful harmonization of ASEAN dental education. PMID- 28864795 TI - The Oral Health Care Delivery System in 2040: Executive Summary. AB - This executive summary for Section 4 of the "Advancing Dental Education in the 21st Century" project examines the projected oral health care delivery system in 2040 and the likely impact of system changes on dental education. Dental care is at an early stage of major changes with the decline in solo practice and increase in large group practices. These groups are not consolidated at the state level, but further consolidation is expected as they try to increase their negotiating leverage with dental insurers. At this time, there is limited integration of medical and dental care in terms of financing, regulation, education, and delivery. This pattern may change as health maintenance organizations and integrated medical systems begin to offer dental care to their members. By 2040, it is expected that many dentists will be employed in large group practices and working with allied dental staff with expanded duties and other health professionals, and more dental graduates will seek formal postdoctoral training to obtain better positions in group practices. PMID- 28864796 TI - The Allied Dental Professions: Executive Summary. AB - This executive summary for Section 5 of the "Advancing Dental Education in the 21st Century" project addresses the current and future educational systems for dental assisting, dental hygiene, dental therapy, and dental laboratory technology. Nineteen experts prepared six background articles on the educational changes necessary for future roles and practices. The key issues addressed relate to delivery system changes, educational curricula, scopes of practice, regulatory measures, and the public's oral health. The major finding is that substantial reforms will be needed to adequately prepare allied oral health professionals for the changes anticipated in 2040. A reconsideration of current accreditation guidelines, more flexibility with scopes of practice, and an adherence to rigorous academic programs are essential elements for the future of these professions. PMID- 28864797 TI - Oral Health Research and Scholarship in 2040: Executive Summary. AB - This executive summary for Section 6 of the "Advancing Dental Education in the 21st Century" project provides an overview of five background articles that address the role of research and scholarship in dental education in the year 2040. Beginning with a historical account of research and discovery science in dentistry's evolution as a profession, the article then reviews the role of early thought leaders and organized dentistry in establishing research as a cornerstone of dental education and dental practice. The dental research workforce faces an uncertain future fueled by a volatile funding environment and inadequate mentoring and training of research faculty. Dental schools must forge stronger academic and scientific ties to their university and academic health centers and will be challenged to develop sustainable research and patient care collaborations with other health professions. The changing health care environment will create new opportunities for oral health care providers to expand their scope of practice and focus on prevention and screening for non communicable chronic diseases. Dental practitioners in the future are likely to place greater emphasis on managing the overall health of their patients while promoting closer integration with other health professionals. All dental schools must develop a sustainable research mission if they hope to graduate dentists who function effectively in a collaborative health care environment. The changing scientific and health care landscape will dramatically alter dental education and dental practice. Dental schools need to reconsider their research and educational priorities and clinical practice objectives. Until dental schools and the practicing community come to grips with these challenges, a persistent attitude of complacency will likely be at the dental profession's peril. PMID- 28864798 TI - Future Organization of Oral Health Services Delivery: From 2012 to 2042. AB - The United States is currently experiencing a vortex of change in both general health and oral health care delivery, the ultimate outcome of which is still not well understood. The specific focus of this article is to examine the future organization of the oral health services delivery system (OHSDS) in the U.S., with special attention given to the role of large group dental practices (LGDPs) in that future. The article describes the various types of LGDPs and their ability to change the economic characteristics of the OHSDS. Large geographically distributed corporate group dental practices (LGDCGDPs) are the type that may expand their market share to the extent that they could change the economic characteristics of the OHSDS. A wide range of scenarios is used to project the expansion of LGDCGDPs into the future. The scenarios modeled are not intended as predictions but rather to present a range of possible OHSDS market structures that may emerge over the next 30 years. The implications of each scenario for the economic competition within the OHSDS are described. Possible implications of these trends for dental education are also discussed. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864799 TI - Expected Changes in Regulation and Licensure: Influence on Future Education of Dentists. AB - This article is based on the following assumptions about dental care in the United States: there is an access to oral health care problem; the number of individuals with dental insurance is increasing; the demographics of the dental profession does not mirror the overall demographics of the U.S. population; and emerging oral health workforce models may help improve access to care. Based on these assumptions, this article explores related licensure and regulatory factors that will influence the education and practice of dentists in the future. The issues discussed are licensure of emerging oral health practitioners, mobility of the dental health care workforce, corporate ownership of dental practices, ethical issues related to use of human subjects in dental licensure examinations, interprofessional education and practice, and health care reform. The licensure and regulatory bodies discussed are the Commission on Dental Accreditation (CODA), state legislatures and boards of dentistry, federal legislative activities, judicial activities, and the Federal Trade Commission. Recommendations based on this discussion are presented. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864800 TI - Integrated Medical-Dental Delivery Systems: Models in a Changing Environment and Their Implications for Dental Education. AB - Models and systems of the dental care delivery system are changing. Solo practice is no longer the only alternative for graduating dentists. Over half of recent graduates are employees, and more than ever before, dentists are practicing in groups. This trend is expected to increase over the next 25 years. This article examines various models of dental care delivery, explains why it is important to practice in integrated medical-dental teams, and defines person-centered care, contrasting it with patient-centered care. Systems of care in which teams are currently practicing integrated oral health care delivery are described, along with speculation on the future of person-centered care and the team approach. Critical steps in the education of dental and other health care professionals and the development of clinical models of care in moving forward are considered. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864801 TI - The Evolution of the Dental Assisting Profession. AB - The objectives of this article are to describe the dental assistant's role in the dental delivery system; assess the educational structure of the dental assisting profession; and project factors likely to impact the future role of the dental assistant. The article summarizes the current status and trends of the dental assisting profession including general responsibilities, credentialing, and regulation. An overview of the workforce and parameters of employment is provided with a description of the broad scope of practice, education, and licensure options, which vary by state. Existing academic models and enrollment trends in accredited dental programs are included, as are the strengths and weaknesses of the current educational system. Multiple factors may impact the future of this profession. To address the anticipated increase in the demand for and responsibilities of dental assistants, curricular revisions will be needed to prepare for implementation of interprofessional care models in which dental assistants will play a vital role. Well-educated dental assistants will be needed to support viable models of dental care and wellness in the U.S. Enhanced career opportunities and varied employment environments may increase job satisfaction and practice longevity. As protection of the public is of the utmost importance in the dental profession, this evolving dental clinician must be formally educated in all aspects of clinical practice and be permitted to perform delegated patient care, as legally allowed by their states. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864802 TI - Strengths and Weaknesses of the Current Dental Hygiene Educational System. AB - The state of the dental hygiene educational system in the United States is evolving. The numbers of programs, extent of curricula, and diversity of students, faculty, and practice settings vary significantly across the country. New trends in workforce utilization and delivery models are challenging current educational foundations and mandating an interprofessional approach to both the education and practice of dental hygienists. This article presents an overview of the current state of dental hygiene education to create a baseline for discussion of desired educational models for 2040. The strengths and weaknesses are defined to motivate change. Limitations of the current two-year associate degree are emphasized, along with the need to add expanded content and development of new skills. The developing non-traditional practice settings bring both a challenge to dental hygiene education and a promise of increasing potential in primary care interprofessional settings for the 21st century. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864803 TI - Preparing the Future Dental Hygiene Workforce: Knowledge, Skills, and Reform. AB - With the health care delivery system in transition, the way in which oral health care services are delivered in 2040 will inevitably change. To achieve the aims of reduced cost, improved access, and higher quality and to advance population wellness, oral health care will likely become a more integrated part of medical care. An integrated primary care system would better meet the needs of an increasingly diverse and aging U.S. population with uneven access to health care services. By 2040, trends suggest that a smaller proportion of dental hygienists will work in traditional solo dental offices; many more will practice with multidisciplinary health care teams in large-group dental and medical practices and in a variety of non-traditional community settings. This integration will require changes in how dental hygienists are educated. To shape the skill sets, clinical judgment, and knowledge of future practitioners, current dental hygiene curricula must be reexamined, redirected, and enhanced. This article examines some of the factors that are likely to shape the future of dental hygiene practice, considers the strengths and weaknesses of current curricula, and proposes educational changes to prepare dental hygienists for practice in 2040. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864804 TI - Exploring Current and Future Roles of Non-Dental Professionals: Implications for Dental Hygiene Education. AB - The health care system is undergoing transformation in which oral health is not only valued as an aspect of overall health, but health care delivery systems are aligning to better deliver total patient care. As a result of this transformation, education for many non-dental professionals incorporates oral health content to prepare them to practice in comprehensive delivery models. While some non-dental professionals already incorporate oral health care in their service, many opportunities exist for expansion of oral health care delivery by other non-dental professionals, including radiologic technicians, nursing staff, and human services professionals. As non-dental professionals take on expanded roles in oral health care, the dental hygiene workforce must be prepared to practice in settings with new types of professionals. Dental hygiene curricula should prioritize interprofessional education to best prepare these students for practice in evolved delivery models. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864805 TI - Transforming Dental Technology Education: Skills, Knowledge, and Curricular Reform. AB - Dental technology is one of the core allied dental health professions supporting the practice of dentistry. By definition, it is the art, science, and technologies that enable the design and fabrication of dental prostheses and/or corrective devices to restore natural teeth and supporting structures to fulfill a patient's physiological and esthetic needs. Dental technology educational programs are faced with serious challenges, including rapid changes in technology, inadequate funding for educational programs, and the need to develop curricula that reflect current industry needs. Better communications between dental technologists and practitioners are needed to gain greater recognition of the contribution that technologists make to patient health. Amid these challenges, the technology workforce is dedicated to providing patients with the best possible restorative dental prostheses. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864806 TI - Dental Therapists as New Oral Health Practitioners: Increasing Access for Underserved Populations. AB - The development of dental therapy in the U.S. grew from a desire to find a workforce solution for increasing access to oral health care. Worldwide, the research that supports the value of dental therapy is considerable. Introduction of educational programs in the U.S. drew on the experiences of programs in New Zealand, Australia, Canada, and the United Kingdom, with Alaska tribal communities introducing dental health aide therapists in 2003 and Minnesota authorizing dental therapy in 2009. Currently, two additional states have authorized dental therapy, and two additional tribal communities are pursuing the use of dental therapists. In all cases, the care provided by dental therapists is focused on communities and populations who experience oral health care disparities and have historically had difficulties in accessing care. This article examines the development and implementation of the dental therapy profession in the U.S. An in-depth look at dental therapy programs in Minnesota and the practice of dental therapy in Minnesota provides insight into the early implementation of this emerging profession. Initial results indicate that the addition of dental therapists to the oral health care team is increasing access to quality oral health care for underserved populations. As evidence of dental therapy's success continues to grow, mid-level dental workforce legislation is likely to be introduced by oral health advocates in other states. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864807 TI - How Research Training Will Shape the Future of Dental, Oral, and Craniofacial Research. AB - This is a critical time in the history of the dental profession for it to fully embrace the responsibility to safeguard its reputation as a learned profession. In this golden era of scientific and technological advances, opportunities abound to create new diagnostics, preventions, treatments, and cures to improve oral health. Dental schools are the largest national resource entrusted with the responsibility to educate, train, and retain oral health researchers who can leverage such technologies and research opportunities that will benefit the profession at large as well as patients. This article reemphasizes the theme that research training and scholarship must be inextricably woven into the environment and culture in dental schools to ensure the future standing of the profession. An overview of the history of support provided by the National Institutes of Health and National Institute of Dental and Craniofacial Research for the training and career development of dentist-scientists is presented. In addition, new data on the outcomes of such investments are presented along with a comparison with other health professions. This overview underscores the need to expand the capacity of a well-trained cadre of oral health researchers through the reengineering of training programs. Such strategies will best prepare future graduates for team science, clinical trials, and translational research as well as other emerging opportunities. The urgent need for national organizations like the American Dental Association, American Dental Education Association, and American Association for Dental Research to create new alliances and novel initiatives to assist dental schools and universities in fulfilling their research mission is emphasized. To ignore such calls for action is to disavow a valuable legacy inherited by the dental profession. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864808 TI - Oral Health Care in the Future: Expansion of the Scope of Dental Practice to Improve Health. AB - The health care environment in the U.S. is changing. The population is aging, the prevalence of non-communicable diseases (NCDs) is increasing, edentulism is decreasing, and periodontal infection/inflammation has been identified as a risk factor for NCDs. These trends offer an opportunity for oral health care providers to broaden the scope of traditional dental practice, specifically becoming more involved in the management of the general health of patients. This new practice paradigm will promote a closer integration with the larger health care system. This change is based on the realization that a healthy mouth is essential for a healthy life, including proper mastication, communication, esthetics, and comfort. Two types of primary care are proposed: screenings for medical conditions that are directly affected by oral disease (and may modify the provision of dental care), and a broader emphasis on prevention that focuses on lifestyle behaviors. Included in the former category are screenings for NCDs (e.g., the risk of cardiovascular disease and identification of patients with undiagnosed dysglycemia or poorly managed diabetes mellitus), as well as identification of infectious diseases, such as HIV or hepatitis C. Reducing the risk of disease can be accomplished by an emphasis on smoking cessation and dietary intake and the prevention of obesity. These activities will promote interprofessional health care education and practice. While change is always challenging, this new practice paradigm could improve both oral health and health outcomes of patients seen in the dental office. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864809 TI - The Future of Dental Schools in Research Universities and Academic Health Centers. AB - As a profession, dentistry is at a point of discernible challenge as well as incredible opportunity in a landscape of evolving changes to health care, higher education, and evidence-based decision making. Respecting the past yet driving forward, a well-mapped future course is critical. Orchestrating this course in a collaborative manner is essential for the visibility, well-being, and potentially the existence of the dental profession. The research performed in dental institutions needs to be contemporary, aligned with biomedical science in general, and united with other disciplines. Dentistry is at risk of attrition in the quality of its research and discovery mission if participation with bioscience colleagues in the collaborative generation of new knowledge is underoptimized. A fundamental opportunity dentistry has is to contribute via its position in academic health centers. Rigorous research as to the impact of interprofessional education and collaborative care on population health outcomes provides significant potential for the dental profession to participate and/or lead such evidence-centered efforts. It is imperative that academic dental institutions are part of interdisciplinary and transdisciplinary organizations that move health care into its new day. Strategizing diversity by bringing together people who have different ways of seeing problems to share perspectives, heuristics, interpretations, technologies, and predictive models across disciplines will lead to impactful progress. Academic dental institutions are a natural part of an emphasis on translational research and acceleration of implementing new scientific discoveries. Dentistry needs to remain an essential and integrated component of higher education in the health professions; doing so necessitates deliberate, respectful, and committed change. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864810 TI - Research and Discovery Science and the Future of Dental Education and Practice. AB - Dental graduates of 2040 will face new and complex challenges. If they are to meet these challenges, dental schools must develop a research and discovery mission that will equip graduates with the new knowledge required to function in a modern health care environment. The dental practitioner of 2040 will place greater emphasis on risk assessment, disease prevention, and health maintenance; and the emerging discipline of precision medicine and systems biology will revolutionize disease diagnosis and reveal new targeted therapies. The dental graduate of 2040 will be expected to function effectively in a collaborative, learning health care system and to understand the impact of health care policy on local, national, and global communities. Emerging scientific fields such as big data analytics, stem cell biology, tissue engineering, and advanced biomimetics will impact dental practice. Despite all the warning signs indicating how the changing scientific and heath care landscape will dramatically alter dental education and dental practice, dental schools have yet to reconsider their research and educational priorities and clinical practice objectives. Until dental schools and the practicing community come to grips with these challenges, this persistent attitude of complacency will likely be at the dental profession's peril. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864811 TI - The Impact of Research on the Future of Dental Education: How Research and Innovation Shape Dental Education and the Dental Profession. AB - Scientific inquiry and discovery are the fuel for education, research, technology, and health care in all the health professions: dentistry, medicine, nursing, pharmacy, and allied health sciences. The progression of discoveries from basic or fundamental to clinical research is followed by the progression from clinical to implementation and improved health outcomes and processes. Generally, implementation science is the scientific study of methods to promote the systematic uptake of research findings (e.g., basic, translational, behavioral, socioeconomic, and clinical) as well as other related evidence-based practices into standards of care, thereby improving the quality, effectiveness, and cost benefits of health care services. There is little doubt that science has and will continue to provide the essential fuel for innovations that lead to new and improved technologies for risk assessment, prevention, diagnosis, treatments and therapeutics, and implementation for addressing oral and craniofacial diseases and disorders. The history of the U.S. dental profession reviewed in this article gives testimony to the continued need for investments in scientific inquiry that accelerate progress in comprehensive health care for all people. This article was written as part of the project "Advancing Dental Education in the 21st Century." PMID- 28864812 TI - Yeast Prp2 liberates the 5' splice site and the branch site adenosine for catalysis of pre-mRNA splicing. AB - The RNA helicase Prp2 facilitates the remodeling of the spliceosomal Bact complex to the catalytically activated B* complex just before step one of splicing. As a high-resolution cryo-EM structure of the B* complex is currently lacking, the precise spliceosome remodeling events mediated by Prp2 remain poorly understood. To investigate the latter, we used chemical structure probing to compare the RNA structure of purified yeast Bact and B* complexes. Our studies reveal deviations from conventional RNA helices in the functionally important U6 snRNA internal stem-loop and U2/U6 helix Ib in the activated Bact complex, and to a lesser extent in B*. Interestingly, the N7 of U6-G60 of the catalytic triad becomes accessible to DMS modification in the B* complex, suggesting that the Hoogsteen interaction with U6-A52 is destabilized in B*. Our data show that Prp2 action does not unwind double-stranded RNA, but enhances the flexibility of the first step reactants, the pre-mRNA's 5' splice site and branch site adenosine. Prp2 therefore appears to act primarily as an RNPase to achieve catalytic activation by liberating the first step reactants in preparation for catalysis of the first step of splicing. PMID- 28864813 TI - The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes. AB - The expression of the key regulator of iron homeostasis hepcidin is activated by the BMP-SMAD pathway in response to iron and inflammation and among drugs, by rapamycin, which inhibits mTOR in complex with the immunophilin FKBP12. FKBP12 interacts with BMP type I receptors to avoid uncontrolled signaling. By pharmacologic and genetic studies, we identify FKBP12 as a novel hepcidin regulator. Sequestration of FKBP12 by rapamycin or tacrolimus activates hepcidin both in vitro and in murine hepatocytes. Acute tacrolimus treatment transiently increases hepcidin in wild-type mice. FKBP12 preferentially targets the BMP receptor ALK2. ALK2 mutants defective in binding FKBP12 increase hepcidin expression in a ligand-independent manner, through BMP-SMAD signaling. ALK2 free of FKBP12 becomes responsive to the noncanonical inflammatory ligand Activin A. Our results identify a novel hepcidin regulator and a potential therapeutic target to increase defective BMP signaling in disorders of low hepcidin. PMID- 28864814 TI - Rituximab-based first-line treatment of cGVHD after allogeneic SCT: results of a phase 2 study. AB - Chronic graft-versus-host disease (cGVHD) is the main cause of late nonrelapse mortality and morbidity after allogeneic stem cell transplantation (allo-SCT). To improve such patients' outcomes, we conducted a phase 2, prospective, multicenter trial to test the efficacy of the addition of rituximab to corticosteroids (CSs) and cyclosporine A (CsA) as first-line therapy for newly diagnosed cGVHD after allo-SCT. Twenty-four patients (median age, 47 years) with mild (n = 2), moderate (n = 7), or severe (n = 15) cGVHD were included. All patients received rituximab 375 mg/m2 weekly for 4 weeks, followed by a second course 1 month later for patients with partial response. Twenty of 24 patients (83%) were in response at 1 year. Furthermore, among 19 evaluable patients, 14 (74%) were off CSs. The estimated 1-year overall survival was 83%, and the 1-year cumulative incidence of nonrelapse mortality was 14%. One patient died of progressive multifocal leukoencephalopathy. Although PD-L1hi naive B cells were significantly decreased at diagnosis of cGVHD, they increased after anti-CD20 B-cell depletion. In contrast, activated ICOShi PD-1hi circulating T follicular helper (Tfh) cells decreased after rituximab treatment. Overall, the addition of rituximab to corticosteroid and CsA appeared to be safe and effective for first-line treatment of cGVHD. Furthermore, our data suggest that this efficacy may be in part related to an effect on PD-L1hi B cells and Tfh cells. This study was registered at www.clinicaltrials.gov as identifier NCT01135641. PMID- 28864815 TI - Eltrombopag: a powerful chelator of cellular or extracellular iron(III) alone or combined with a second chelator. AB - Eltrombopag (ELT) is a thrombopoietin receptor agonist reported to decrease labile iron in leukemia cells. Here we examine the previously undescribed iron(III)-coordinating and cellular iron-mobilizing properties of ELT. We find a high binding constant for iron(III) (log beta2=35). Clinically achievable concentrations (1 uM) progressively mobilized cellular iron from hepatocyte, cardiomyocyte, and pancreatic cell lines, rapidly decreasing intracellular reactive oxygen species (ROS) and also restoring insulin secretion in pancreatic cells. Decrements in cellular ferritin paralleled total cellular iron removal, particularly in hepatocytes. Iron mobilization from cardiomyocytes exceeded that obtained with deferiprone, desferrioxamine, or deferasirox at similar iron binding equivalents. When combined with these chelators, ELT enhanced cellular iron mobilization more than additive (synergistic) with deferasirox. Iron-binding speciation plots are consistent with ELT donating iron to deferasirox at clinically relevant concentrations. ELT scavenges iron citrate species faster than deferasirox, but rapidly donates the chelated iron to deferasirox, consistent with a shuttling mechanism. Shuttling is also suggested by enhanced cellular iron mobilization by ELT when combined with the otherwise ineffective extracellular hydroxypyridinone chelator, CP40. We conclude that ELT is a powerful iron chelator that decreases cellular iron and further enhances iron mobilization when combined with clinically available chelators. PMID- 28864816 TI - Swimming in a sea of drugs: Psychiatric drugs in the aquatic environment could have severe adverse effects on wildlife and ecosystems. PMID- 28864818 TI - The Italian Pharmacovigilance Program: An Observational Study of Adverse Effects of Natalizumab in Multiple Sclerosis Therapy. AB - BACKGROUND This study shows the results of a regional pharmacovigilance program on Natalizumab therapy in relapsing-remitting multiple sclerosis (RR-MS) patients after 3 years of experience. MATERIAL AND METHODS The primary objectives of this study were to estimate the incidence of expected and unexpected adverse effects correlated to Natalizumab therapy in a cohort of 88 RR-MS patients from Sicily, Italy, and to investigate the procedures adopted by the physicians to minimize the risk of developing severe adverse reactions correlated to Natalizumab therapy. Secondary objectives of this study were to evaluate the effectiveness of Natalizumab therapy for a careful examination of the risk/benefit ratio and to assess the actions undertaken in case of adverse reactions. RESULTS Among 88 RR MS patients, 55.68% did not report any type of adverse reaction, 35.22% showed expected adverse reactions (58.70% slight, 22.58% moderate, and 19.35% severe), and 9.10% showed unexpected adverse effects (62.50% slight, 25.00% moderate, and 12.50% severe). Approximately 4.54% of the patients treated with Natalizumab interrupted the therapy. Overall, among all patients, 56.62% showed ameliorated condition, 32.53% had stable disease condition, and 10.85% worsened. CONCLUSIONS We provide a short overview of evidence, which may be useful to better characterize the efficacy and potential adverse effects correlated to Natalizumab therapy. PMID- 28864819 TI - Direct imaging of delayed magneto-dynamic modes induced by surface acoustic waves. AB - The magnetoelastic effect-the change of magnetic properties caused by the elastic deformation of a magnetic material-has been proposed as an alternative approach to magnetic fields for the low-power control of magnetization states of nanoelements since it avoids charge currents, which entail ohmic losses. Here, we have studied the effect of dynamic strain accompanying a surface acoustic wave on magnetic nanostructures in thermal equilibrium. We have developed an experimental technique based on stroboscopic X-ray microscopy that provides a pathway to the quantitative study of strain waves and magnetization at the nanoscale. We have simultaneously imaged the evolution of both strain and magnetization dynamics of nanostructures at the picosecond time scale and found that magnetization modes have a delayed response to the strain modes, adjustable by the magnetic domain configuration. Our results provide fundamental insight into magnetoelastic coupling in nanostructures and have implications for the design of strain controlled magnetostrictive nano-devices.Understanding the effects of local dynamic strain on magnetization may help the development of magnetic devices. Foerster et al. demonstrate stroboscopic imaging that allows the observation of both strain and magnetization dynamics in nickel when surface acoustic waves are driven in the substrate. PMID- 28864820 TI - A prophage tail-like protein is deployed by Burkholderia bacteria to feed on fungi. AB - Some bacteria can feed on fungi, a phenomenon known as mycophagy. Here we show that a prophage tail-like protein (Bg_9562) is essential for mycophagy in Burkholderia gladioli strain NGJ1. The purified protein causes hyphal disintegration and inhibits growth of several fungal species. Disruption of the Bg_9562 gene abolishes mycophagy. Bg_9562 is a potential effector secreted by a type III secretion system (T3SS) and is translocated into fungal mycelia during confrontation. Heterologous expression of Bg_9562 in another bacterial species, Ralstonia solanacearum, confers mycophagous ability in a T3SS-dependent manner. We propose that the ability to feed on fungi conferred by Bg_9562 may help the bacteria to survive in certain ecological niches. Furthermore, considering its broad-spectrum antifungal activity, the protein may be potentially useful in biotechnological applications to control fungal diseases.Some bacteria can feed on live fungi through unclear mechanisms. Here, the authors show that a T3SS secreted protein, which is homologous to phage tail proteins, allows a Burkholderia gladioli strain to kill and feed on various fungal species. PMID- 28864821 TI - Timely regulated sorting from early to late endosomes is required to maintain cerebellar long-term depression. AB - An important feature of long-term synaptic plasticity is the prolonged maintenance of plastic changes in synaptic transmission. The trafficking of AMPA type glutamate receptors (AMPARs) is involved in the expression of many forms of synaptic plasticity, yet the subsequent events accomplishing the maintenance of plastic changes in synaptic AMPAR numbers are not fully understood. Here, we find that maintenance of cerebellar long-term depression results from a reduction in the number of AMPARs residing within endocytic recycling pathways. We then develop a genetically encoded, photosensitive inhibitor of late endosome sorting and use this to discover that initial maintenance of long-term depression relies on timely regulated late endosome sorting, which exhibits a threshold as well as switch-like behavior. Thus, our results indicate that recycling AMPAR numbers are reduced by a switching machinery of transient late endosome sorting, and that this process enables the transition from basal synaptic transmission to long-term depression maintenance.Long term depression (LTD) of the cerebellum is known to be mediated by postsynaptic trafficking of glutamate receptor AMPAR. Here, Kim and colleagues show that early- to late-endosomal sorting of AMPAR represents the switch from expression to maintenance phase of cerebellar LTD. PMID- 28864822 TI - Hepcidin is regulated by promoter-associated histone acetylation and HDAC3. AB - Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in iron deficiency and increased erythropoiesis but is pathologic in thalassemia and hemochromatosis. Here we show that epigenetic events govern hepcidin expression. Erythropoiesis and iron deficiency suppress hepcidin via erythroferrone-dependent and -independent mechanisms, respectively, in vivo, but both involve reversible loss of H3K9ac and H3K4me3 at the hepcidin locus. In vitro, pan-histone deacetylase inhibition elevates hepcidin expression, and in vivo maintains H3K9ac at hepcidin-associated chromatin and abrogates hepcidin suppression by erythropoietin, iron deficiency, thalassemia, and hemochromatosis. Histone deacetylase 3 and its cofactor NCOR1 regulate hepcidin; histone deacetylase 3 binds chromatin at the hepcidin locus, and histone deacetylase 3 knockdown counteracts hepcidin suppression induced either by erythroferrone or by inhibiting bone morphogenetic protein signaling. In iron deficient mice, the histone deacetylase 3 inhibitor RGFP966 increases hepcidin, and RNA sequencing confirms hepcidin is one of the genes most differentially regulated by this drug in vivo. We conclude that suppression of hepcidin expression involves epigenetic regulation by histone deacetylase 3.Hepcidin controls systemic iron levels by inhibiting intestinal iron absorption and iron recycling. Here, Pasricha et al. demonstrate that the hepcidin-chromatin locus displays HDAC3-mediated reversible epigenetic modifications during both erythropoiesis and iron deficiency. PMID- 28864823 TI - Rechargeable aqueous zinc-manganese dioxide batteries with high energy and power densities. AB - Although alkaline zinc-manganese dioxide batteries have dominated the primary battery applications, it is challenging to make them rechargeable. Here we report a high-performance rechargeable zinc-manganese dioxide system with an aqueous mild-acidic zinc triflate electrolyte. We demonstrate that the tunnel structured manganese dioxide polymorphs undergo a phase transition to layered zinc-buserite on first discharging, thus allowing subsequent intercalation of zinc cations in the latter structure. Based on this electrode mechanism, we formulate an aqueous zinc/manganese triflate electrolyte that enables the formation of a protective porous manganese oxide layer. The cathode exhibits a high reversible capacity of 225 mAh g-1 and long-term cyclability with 94% capacity retention over 2000 cycles. Remarkably, the pouch zinc-manganese dioxide battery delivers a total energy density of 75.2 Wh kg-1. As a result of the superior battery performance, the high safety of aqueous electrolyte, the facile cell assembly and the cost benefit of the source materials, this zinc-manganese dioxide system is believed to be promising for large-scale energy storage applications.The development of rechargeable aqueous zinc batteries are challenging but promising for energy storage applications. With a mild-acidic triflate electrolyte, here the authors show a high-performance Zn-MnO2 battery in which the MnO2 cathode undergoes Zn2+ (de)intercalation. PMID- 28864824 TI - Automatic Categorization and Scoring of Solid, Part-Solid and Non-Solid Pulmonary Nodules in CT Images with Convolutional Neural Network. AB - We present a computer-aided diagnosis system (CADx) for the automatic categorization of solid, part-solid and non-solid nodules in pulmonary computerized tomography images using a Convolutional Neural Network (CNN). Provided with only a two-dimensional region of interest (ROI) surrounding each nodule, our CNN automatically reasons from image context to discover informative computational features. As a result, no image segmentation processing is needed for further analysis of nodule attenuation, allowing our system to avoid potential errors caused by inaccurate image processing. We implemented two computerized texture analysis schemes, classification and regression, to automatically categorize solid, part-solid and non-solid nodules in CT scans, with hierarchical features in each case learned directly by the CNN model. To show the effectiveness of our CNN-based CADx, an established method based on histogram analysis (HIST) was implemented for comparison. The experimental results show significant performance improvement by the CNN model over HIST in both classification and regression tasks, yielding nodule classification and rating performance concordant with those of practicing radiologists. Adoption of CNN-based CADx systems may reduce the inter-observer variation among screening radiologists and provide a quantitative reference for further nodule analysis. PMID- 28864825 TI - Multiple periodicity in a nanoparticle-based single-electron transistor. AB - A single-electron transistor is a nano-device with large potential for low-power applications that can be used as logic elements in integrated circuits. In this device, the conductance oscillates with a well-defined period due to the Coulomb blockade effect. By using a unique technique, we explore single-electron transistors based on a single metallic nanoparticle with tunable coupling to electric leads. We demonstrate a unique regime in which the transistor is characterized by multi-periodic oscillations of the conductance with gate voltage where the additional periods are harmonics of the basic periodicity of the Coulomb blockade and their relative strength can be controllably tuned. These harmonics correspond to a charge change on the dot by a fraction of the electron charge. The presence of multiple harmonics makes these transistors potential elements in future miniaturization of nano-sized circuit elements.Single-electron transistors are elements for nanoscale electronics. Employing single-electron transistors based on gold nanoparticles, Bitton et al., report a fabrication technique that allows precise control over the coupling between a nanodot and leads, resulting in new transport characteristics. PMID- 28864827 TI - Ultrathin metal-organic framework membrane production by gel-vapour deposition. AB - Ultrathin, molecular sieving membranes composed of microporous materials offer great potential to realize high permeances and selectivities in separation applications, but strategies for their production have remained a challenge. Here we show a route for the scalable production of nanometre-thick metal-organic framework (MOF) molecular sieving membranes, specifically via gel-vapour deposition, which combines sol-gel coating with vapour deposition for solvent /modification-free and precursor-/time-saving synthesis. The uniform MOF membranes thus prepared have controllable thicknesses, down to ~17 nm, and show one to three orders of magnitude higher gas permeances than those of conventional membranes, up to 215.4 * 10-7 mol m-2 s-1 Pa-1 for H2, and H2/C3H8, CO2/C3H8 and C3H6/C3H8 selectivities of as high as 3,400, 1,030 and 70, respectively. We further demonstrate the in situ scale-up processing of a MOF membrane module (30 polymeric hollow fibres with membrane area of 340 cm2) without deterioration in selectivity.MOF-based membranes have shown great promise in separation applications, but producing thin membranes that allow for high fluxes remains challenging. Here, the authors use a gel-vapour deposition strategy to fabricate composite membranes with less than 20 nm thicknesses and high gas permeances and selectivities. PMID- 28864826 TI - IgSF21 promotes differentiation of inhibitory synapses via binding to neurexin2alpha. AB - Coordinated development of excitatory and inhibitory synapses is essential for higher brain function, and impairment in this development is associated with neuropsychiatric disorders. In contrast to the large body of accumulated evidence regarding excitatory synapse development, little is known about synaptic adhesion and organization mechanisms underlying inhibitory synapse development. Through unbiased expression screens and proteomics, we identified immunoglobulin superfamily member 21 (IgSF21) as a neurexin2alpha-interacting membrane protein that selectively induces inhibitory presynaptic differentiation. IgSF21 localizes postsynaptically and recruits axonal neurexin2alpha in a trans-interaction manner. Deleting IgSF21 in mice impairs inhibitory presynaptic organization, especially in the hippocampal CA1 stratum radiatum, and also diminishes GABA mediated synaptic transmission in hippocampal CA1 neurons without affecting their excitatory synapses. Finally, mice lacking IgSF21 show a sensorimotor gating deficit. These findings suggest that IgSF21 selectively regulates inhibitory presynaptic differentiation through interacting with presynaptic neurexin2alpha and plays a crucial role in synaptic inhibition in the brain.Molecular mechanisms regulating the development of inhibitory synapses are poorly understood. Here the authors show that IgSF21 interacts with neurexin2alpha to induce presynaptic differentiation of inhibitory synapses, and that mice lacking IgSF21 exhibit deficits in inhibitory synaptic transmission. PMID- 28864828 TI - [Severe atypical ketoacidosis due to SGLT2-inhibitor therapy : Two case reports]. AB - Two female patients were admitted due to ketoacidosis. Serum glucose was moderately elevated. The patients exhibited abdominal and neurologic symptoms. Treatment consisted of metformin, insulin glargin and empagliflozin, as well as glimepiride, insulin detemir and empagliflozin, respectively. Treatment with intravenous fluid replacement, insulin, glucose, potassium and buffer solution led to a normalisation of pH and serum glucose levels. Our report describes two cases of atypical ketoacidosis with moderately elevated serum glucose during sodium-glucose co-transporter-2 (SGLT2) inhibitor therapy. PMID- 28864829 TI - Physiologic and Genetic Factors Influencing the Zoonotic Cycle of Borrelia burgdorferi. AB - Borrelia burgdorferi is a symbiont of ticks of the Ixodes ricinus complex. These ticks serve as vectors to disseminate the spirochete to a variety of susceptible vertebrate hosts, which, in turn, act as reservoirs for naive ticks to become infected, perpetuating the infectious life cycle of B. burgdorferi. The pivotal role of ticks in this life cycle and tick-spirochete interactions are the focus of this chapter. Here, we describe the challenging physiological environment that spirochetes encounter within Ixodes ticks, and the genetic factors that B. burgdorferi uses to successfully infect, persist, and be transmitted from the vector. PMID- 28864830 TI - ER Stress and Neurodegenerative Disease: A Cause or Effect Relationship? AB - The accumulation of protein aggregates has a fundamental role in the patophysiology of distinct neurodegenerative diseases. This phenomenon may have a common origin, where disruption of intracellular mechanisms related to protein homeostasis (here termed proteostasis) control during aging may result in abnormal protein aggregation. The unfolded protein response (UPR) embodies a major element of the proteostasis network triggered by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as possible mechanism of neurodegenerative and synaptic dysfunction, and in addition contribute to the abnormal aggregation of key disease-related proteins. In this article we overview the most recent findings suggesting a causal role of ER stress in neurodegenerative diseases. PMID- 28864831 TI - Ultrastructural features of aberrant glial cells isolated from the spinal cord of paralytic rats expressing the amyotrophic lateral sclerosis-linked SOD1G93A mutation. AB - In the rat model of amyotrophic lateral sclerosis expressing the G93A superoxide dismutase-1 mutation, motor neuron death and rapid paralysis progression are associated with the emergence of a population of aberrant glial cells (AbAs) that proliferate in the degenerating spinal cord. Targeting of AbAs with anti neoplasic drugs reduced paralysis progression, suggesting a pathogenic potential contribution of these cells accelerating paralysis progression. In the present study, analyze the cellular and ultrastructural features of AbAs following their isolation and establishment in culture during several passages. We found that AbAs exhibit permanent loss of contact inhibition, absence of intermediate filaments and abundance of microtubules, together with an important production of extracellular matrix components. Remarkably, AbAs also exhibited exacerbated ER stress together with a significant abundance of lipid droplets, as well as autophagic and secretory vesicles, all characteristic features of cellular stress and inflammatory activation. Taken together, the present data show AbA cells as a unique aberrant phenotype for a glial cell that might explain their pathogenic and neurotoxic effects. PMID- 28864832 TI - MRI findings associated with microscopic residual tumor following unplanned excision of soft tissue sarcomas in the extremities. AB - INTRODUCTION: MRI is often used to determine the presence of residual disease following unplanned excisions (UPE) of soft tissue sarcomas (STS). We sought to identify MRI features associated with histologic evidence of residual disease after TBE. MATERIALS AND METHODS: This was an IRB-approved retrospective review of 27 patients with R1-type UPE of STS over a 32-month period, with subsequent MRI and TBE. MRI studies were retrospectively evaluated to determine depth of tissue involvement, presence of nodular enhancement, and maximum length of soft tissue edema normalized to extremity size. MRI findings were correlated with histology from unplanned excision and TBE. RESULTS: Among the 21 subjects, there were 13 males and 8 females, mean age 58. Eighteen of 21 STS were grade 2 or 3. Deep compartments were involved in 5/21 cases. Original margins were positive in 17/21 UPE, with inadequate margin assessment in the remaining 4 cases. Residual tumor was present at TBE in 11/21 cases; it was found in 4/6 cases with nodular enhancement and 7/15 cases without nodular enhancement (sensitivity = 0.36; specificity = 0.80; PPV = 0.67; NPV = 0.53). Increased extent of soft tissue edema increased the likelihood of residual tumor at TBE (OR = 35.0; 95% CI = 1.6 to 752.7; p = 0.023). CONCLUSION: Nodular enhancement is neither sensitive nor specific in predicting residual microscopic tumor in TBE following UPE. Extensive soft tissue edema on MRI after UPE increases the likelihood of finding a residual microscopic tumor, justifying ample margins at TBE and consideration of adjuvant therapy. PMID- 28864833 TI - Impact of multiple malignancies on surgical outcomes in patients with 1 cm or smaller non-small cell lung cancer. AB - BACKGROUND: Because most patients with small-sized non-small cell lung cancer (NSCLC) are asymptomatic, their lesions are detected by cancer screenings or routine checkups for other diseases. Incidences of multiple malignancies have been reported to be 27% in patients with stage I-III NSCLC. Some patients have treatment histories for other malignancies, and their small-sized NSCLC was incidentally detected during follow-up. There is no established report regarding the influence of multiple malignancies on small-sized NSCLC prognosis. Therefore, we investigated the correlation between multiple malignancies and surgical outcomes in patients with small-sized NSCLC. METHODS: In total, 44 patients underwent definitive pulmonary resection for NSCLC of 1 cm or smaller between January 2003 and December 2012. Tumor size was measured by macroscopic findings of the resected specimens, and we then retrospectively investigated their clinical courses. RESULTS: One patient had hemoptysis symptoms, whereas 43 patients were asymptomatic; among them, NSCLC was detected by examinations for other diseases in 31 patients and by cancer screening in 12 patients. In total, 20 patients (45%) had multiple malignancies. The median follow-up period was 68 months. One patient had a recurrence from current NSCLC. No patients died of current NSCLC. The overall 5-year survival rate was 90% for all patients. Patients with multiple malignancies had significantly poorer prognoses compared with those without multiple malignancies (P = 0.016). However, patients with treatment intervals of more than 5 years had prognoses equivalent to those of patients without multiple malignancies (P = 0.829). Only the presence of multiple malignancies was a significantly poor prognostic factor in univariate and multivariate analyses. CONCLUSION: NSCLC of 1 cm or smaller showed good prognoses. The presence of multiple malignancies was a significantly poor prognostic factor, and short treatment intervals also correlated with poor prognosis. PMID- 28864834 TI - Rapid and efficient CRISPR/Cas9 gene editing in Citrus using the YAO promoter. PMID- 28864835 TI - NEAT1 accelerates the progression of liver fibrosis via regulation of microRNA 122 and Kruppel-like factor 6. AB - : Long non-coding RNAs (lncRNAs) have been reported to be involved in many important biological processes including proliferation, apoptosis, differentiation, and survival. Recently, nuclear paraspeckle assembly transcript 1 (NEAT1), a novel lncRNA, serves as a crucial regulator in tumors. However, the biological role of NEAT1 in liver fibrosis is largely unknown. In this study, the role of NEAT1 was explored in primary mouse hepatic stellate cells (HSCs) and carbon tetrachloride (CCl4)-induced mouse liver fibrosis models. We found that NEAT1 expression was significantly increased in CCl4-induced mice and activated HSCs. Loss of NEAT1 suppressed liver fibrosis in vivo and in vitro. Conversely, NEAT1 overexpression accelerated HSC activation, including increased cell proliferation and collagen expression. Further studies indicated that the microRNA-122 (miR-122)-Kruppel-like factor 6 (KLF6) axis was involved in the effects of NEAT1 on HSC activation. The effects of NEAT1 on HSC activation were almost blocked down by miR-122 mimics or KLF6 knockdown. Interestingly, both NEAT1 and KLF6 are targets of miR-122. In addition, miR-122 led to a significant reduction in NEAT1 level while NEAT1 overexpression resulted in the suppression of miR-122 expression. Pull-down assay confirmed a direct interaction between miR 122 and NEAT1. NEAT1 contributes to HSC activation via the miR-122-KLF6 axis. In human fibrotic liver samples, increased NEAT1 levels positively correlated with liver fibrosis markers. In conclusion, we disclose a novel NEAT1-miR-122-KLF6 signaling cascade and its implication in liver fibrosis. KEY MESSAGES: NEAT1 was significantly increased in CCl4-induced mice and activated HSCs. Loss of NEAT1 suppressed liver fibrosis in vivo and in vitro. KLF6 and miR-122 were required for the effects of NEAT1 on HSC activation. NEAT1 contributes to HSC activation via competitively binding miR-122. We disclose a novel NEAT1-miR-122-KLF6 signaling cascade. PMID- 28864836 TI - Parental Perceptions and Child Emotional and Behavioral Problems in Autism. AB - Emotional and behavioral difficulties in children with autism often present problems for families seeking appropriate treatment interventions. Using data from the 2011 Survey of Pathways to Diagnosis and Services, ordinal logistic regression models were used to examine the association between parental perceptions about autism and their reports of child emotional and behavioral problems. Results showed that parents who attributed their child's autism to environmental factors, experienced emotional upset or confusion about autism, or perceived the condition to be pervasive or burdensome, were more likely to reported clinically significant emotional and behavioral difficulties. Findings suggest that support services must consider parent perceptions when developing interventions to assist with children's emotional and behavioral challenges. Implications for practice and research are discussed. PMID- 28864838 TI - An improved multi-objective optimization-based CICA method with data-driver temporal reference for group fMRI data analysis. AB - Group independent component analysis (GICA) has been successfully applied to study multi-subject functional magnetic resonance imaging (fMRI) data, and the group independent component (GIC) represents the commonality of all subjects in the group. However, some studies show that the performance of GICA can be improved by incorporating a priori information, which is not always considered when looking for GICs in existing GICA methods. In this paper, we propose an improved multi-objective optimization-based constrained independent component analysis (CICA) method to take advantage of the temporal a priori information extracted from all subjects in the group by incorporating it into the computational process of GICA for group fMRI data analysis. The experimental results of simulated and real data show that the activated regions and the time course detected by the improved CICA method are more accurate in some sense. Moreover, the GIC computed by the improved CICA method has a higher correlation with the corresponding independent component of each subject in the group, which means that the improved CICA method with the temporal a priori information extracted from the group can better reflect the commonality of the subjects. These results demonstrate that the improved CICA method has its own advantages in fMRI data analysis. PMID- 28864839 TI - Outcomes of treatment in men with prostate cancer at the cancer centre Bahamas. AB - PURPOSE: This is a first report from The Bahamas of management and long-term outcomes in men with non-metastatic prostate cancer treated with radiotherapy, with or without androgen deprivation therapy, from 2004 to 2016. METHODS: Patients were characterized by baseline factors, stratified by risk groups using tumor stage (clinical T-stage), prostate-specific antigen (PSA) test result and Gleason grade, and sorted by treatment combinations (by radiation volume and use of androgen deprivation). RESULTS: Overall, 205/216 men were Afro-Caribbean. Median age was 66. There were 18 low-, 77 intermediate-, and 121 high-risk patients, treated with prostate-only versus pelvis plus prostate radiotherapy, many receiving 2 years of androgen suppression. Time to commence radiation was about 6 months from initial diagnosis. In those not relapsing, global PSA nadir was reached in 4 years and was under 1.0, reduced from a mean at baseline of 31. At 10 years, disease-free experience (32 relapses) was 68% and overall survival was 87%, although only 2/12 deaths were related to prostate cancer. This experience compares favorably with recently published outcomes from other countries using very similar treatments. CONCLUSIONS: This study establishes benchmark statistics from diagnosis to long-term follow-up. Outcomes in Bahamian men are consistent with expectations from risk-stratified guidelines followed in developed countries. PMID- 28864837 TI - Near-infrared spectroscopy (NIRS) and vagus somatosensory evoked potentials (VSEP) in the early diagnosis of Alzheimer's disease: rationale, design, methods, and first baseline data of the Vogel study. AB - Functional near-infrared spectroscopy (fNIRS) and vagus somatosensory evoked potentials (VSEP) show deviant patterns in subjects with Alzheimer's disease (AD) compared to healthy controls. We now aimed at testing the predictive value of these methods in the early diagnosis of AD. The Vogel study is a prospective, observational, long-term follow-up study with three time points of investigation within 6 years. Residents of the city of Wurzburg born between 1936 and 1941 were recruited. Every participant underwent physical, psychiatric, and laboratory examinations, and performed an intense neuropsychological testing as well as VSEP and NIRS according to the published procedures. 604 subjects were included. Mean age of the participants was 73.9 +/- 1.55 years. The most frequent pathological physical and laboratory examination results were observed for blood pressure (62%), body weight (54%), HbA1c (16%), cholesterol (42%), and homocysteine (69%). Comprehensive analysis of cognitive testing showed mild cognitive impairment (MCI) in 12.3% of the patients. Concurrent major depression was found in 6.6% of the patients. We observed a high rate of MCI and somatic comorbidity in our cohort. The high rate of vascular risk factors and depressive symptoms, all of which are known risk factors of AD, is consistent with the notion that there are multiple options to prevent or postpone the onset of AD in a geriatric population like the one of the Vogel studies. PMID- 28864840 TI - Renal, auricular, and ocular outcomes of Alport syndrome and their current management. AB - Alport syndrome is a hereditary glomerular basement membrane disease caused by mutations in the COL4A3/4/5 genes encoding the type IV collagen alpha 3-5 chains. Most cases of Alport syndrome are inherited as X-linked dominant, and some as autosomal recessive or autosomal dominant. The primary manifestations are hematuria, proteinuria, and progressive renal failure, whereas some patients present with sensorineural hearing loss and ocular abnormalities. Renin angiotensin-aldosterone system blockade is proven to delay the onset of renal failure by reducing proteinuria. Renal transplantation is a curative treatment for patients who have progressed to end-stage renal disease. However, only supportive measures can be used to improve hearing loss and visual loss. Although both stem cell therapy and gene therapy aim to repair the basement membrane defects, technical difficulties require more research in Alport mice before clinical studies. Here, we review the renal, auricular, and ocular manifestations and outcomes of Alport syndrome and their current management. PMID- 28864842 TI - A semiparametric regression cure model for doubly censored data. AB - This paper discusses regression analysis of doubly censored failure time data when there may exist a cured subgroup. By doubly censored data, we mean that the failure time of interest denotes the elapsed time between two related events and the observations on both event times can suffer censoring (Sun in The statistical analysis of interval-censored failure time data. Springer, New York, 2006). One typical example of such data is given by an acquired immune deficiency syndrome cohort study. Although many methods have been developed for their analysis (De Gruttola and Lagakos in Biometrics 45:1-12, 1989; Sun et al. in Biometrics 55:909 914, 1999; 60:637-643, 2004; Pan in Biometrics 57:1245-1250, 2001), it does not seem to exist an established method for the situation with a cured subgroup. This paper discusses this later problem and presents a sieve approximation maximum likelihood approach. In addition, the asymptotic properties of the resulting estimators are established and an extensive simulation study indicates that the method seems to work well for practical situations. An application is also provided. PMID- 28864841 TI - Diabetic Neuropathy and Gait: A Review. AB - Diabetic peripheral neuropathy (DPN) is a major sequela of diabetes mellitus and may have a detrimental effect on the gait of people with this complication. DPN causes a disruption in the body's sensorimotor system and is believed to affect up to 50% of patients with diabetes mellitus, dependent on the duration of diabetes. It has a major effect on morbidity and mortality. The peripheral nervous system controls the complex series of events in gait through somatic and autonomic functions, careful balancing of eccentric and concentric muscle contractions and a reliance on the sensory information received from the plantar surface. In this literature review focussing on kinetics, kinematics and posture during gait in DPN patients, we have identified an intimate link between DPN and abnormalities in gait and demonstrated an increased risk in falls for older patients with diabetes. As such, we have identified a need for further research on the role of gait abnormalities in the development of diabetic foot ulceration and subsequent amputations. PMID- 28864843 TI - Pupillary autonomic dysfunction in patients with ANCA-associated vasculitis. AB - OBJECTIVE: To assess autonomic function by infrared dynamic pupillometry in patients with ANCA-vasculitis (AAV) in correlation to autonomic symptoms, disease specific clinical parameters and cardiovascular reflex tests. METHODS: Patients with AAV and healthy controls underwent pupillometry at rest and after sympathetic stimulation (cold pressor test). Three parasympathetic parameters (amplitude, relative amplitude, maximum constriction velocity) and one sympathetic parameter (late dilatation velocity) were assessed. Results were correlated with clinical parameters, symptoms of autonomic dysfunction (COMPASS31 questionnaire), heart rate variability during deep breathing test and blood pressure response to pain. RESULTS: 23 patients and 18 age-matched controls were enrolled. Patients had a smaller amplitude (1.44 vs. 1.70 mm; p = 0.009) and a slower constriction velocity (4.15 vs. 4.71 mm/s; p = 0.028) at baseline and after sympathetic stimulation (1.47 vs. 1.81 mm, p = 0.001; 4.38 vs. 5.19 mm/s, p = 0.006, respectively). Relative amplitude was significantly smaller in patients after sympathetic stimulation (28.6 vs. 32.5%; p = 0.043), but not at baseline. There was no difference in sympathetic pupillary response between the groups. In patients, parasympathetic pupil response was correlated negatively with age and positively with parasympathetic cardiac response. After adjusting for age, no significant correlation was observed with clinical parameters. However, there was a trend towards a negative correlation with disease duration, vasculitis damage index and CRP. CONCLUSION: Patients with AAV exhibit parasympathetic pupillary autonomic dysfunction. Although correlations were weak and not significant, pupillary autonomic dysfunction is rather linked to chronic damage than to active inflammation or symptoms of autonomic dysfunction. PMID- 28864844 TI - Checkpoint inhibitors: the new treatment paradigm for urothelial bladder cancer. AB - Bladder cancer is the most common malignancy involving the genitourinary system (Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). In the USA, it is the fifth most common cancer and approximately 79,000 new cases will be diagnosed in 2017 (Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). The mortality from bladder cancer is approximately 17,000 deaths each year (Siegel et al. in CA Cancer J Clin, 66:7-30, 2016). The incidence rate for bladder cancer is higher in men compared to women. Risk factors are predominantly related to tobacco smoking, although infection with Schistosoma haematobium is another risk factor in selected populations (Antoni et al. in Eur Urol, 71:96-108, 2017). Cisplatin based systemic chemotherapy regimens remain the standard of care in both the neoadjuvant and metastatic setting for muscle-invasive bladder cancer (Gupta et al. in Cancer, 9(15):1-14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602 4608, 2005; De Santis et al. in J Clin Oncol, 30:191-199, 2012; Bellmunt et al. in J Clin Oncol, 27: 4454-4461, 2009). There is an estimated overall survival of 9-15 months in metastatic bladder cancer in those who receive the standard of care platinum-based chemotherapy (Von der Maase et al. in J Clin Oncol, 23:4602 4608, 2005; De Santis et al. in J Clin Oncol, 30:191-199, 2012). The median survival, however, is significantly reduced after relapse in patient treated with platinum chemotherapy to less than 7 months (Bellmunt et al. in J Clin Oncol, 27: 4454-4461, 2009). Thus, this approach is preferred for patients who can tolerate this treatment as first-line chemotherapy (Gupta et al. in Cancer, 9(15):1-14, 2017). Until recently, there were few treatment options for those patients with poor performance status who are ineligible to receive cisplatin including renal insufficiency and multiple comorbidities or had disease progression after receiving platinum-based chemotherapy (Gupta et al. in Cancer, 9(15):1-14, 2017). With further understanding of tumor immune evasion, systemic immunotherapy which utilizes the patient's own immune system directly to eradicate and target neoplastic cells, has now been approved for urothelial bladder cancer. Monoclonal antibodies that target programmed cell death protein 1 (PD-1), including Nivolumab and Pembrolizumab, and its ligand, PD-L1, including Atezolizumab, Durvalumab, Avelumab, have all been investigated and approved in the setting of metastatic refractory urothelial cancer (Gupta et al. in Cancer, 9(15):1-14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602-4608, 2005; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ). Atezolizumab and Pembrolizumab have also been approved as first-line therapy in the setting of cisplatin-ineligible metastatic bladder cancer (Gupta et al. in Cancer, 9(15):1 14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ). Those that target cytotoxic T-lymphocyte-associated protein 4, including Ipilimumab and Tremelimumab, have also been investigated and further studies are being performed (Gupta et al. in Cancer, 9(15):1-14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174 ). This review outlines the systemic immunotherapies that have been approved or are currently being investigated. PMID- 28864845 TI - Delayed Diagnosis and Treatment Among Children with Autism Who Experience Adversity. AB - The effects of family adverse childhood experiences (ACEs) on timing of ASD diagnoses and receipt of therapies were measured using data from the 2011-2012 National Survey of Children's Health. Parametric accelerated failure time models estimated the relationship between family ACEs and both timing of ASD diagnosis and receipt of therapies among US children (age 2-17 years; N = 1624). Compared to children without family ACEs, the adjusted effects of 1-2 and >= 3 ACEs resulted in prolonged time of diagnoses with time ratios of 1.17 and 1.23. Report of 1-2 and >= 3 ACEs were associated with a 22 and 27% increase in the median age of entry into services. ACEs may pose significant barriers to diagnoses and treatment of children with ASD. PMID- 28864846 TI - The Use of Decision-Analytic Models in Atopic Eczema: A Systematic Review and Critical Appraisal. AB - OBJECTIVE: The objective of this systematic review was to identify and assess the quality of published economic decision-analytic models within atopic eczema against best practice guidelines, with the intention of informing future decision analytic models within this condition. METHODS: A systematic search of the following online databases was performed: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews, NHS Economic Evaluation Database, EconLit, Scopus, Health Technology Assessment, Cost-Effectiveness Analysis Registry and Web of Science. Papers were eligible for inclusion if they described a decision-analytic model evaluating both the costs and benefits associated with an intervention or prevention for atopic eczema. Data were extracted using a standardised form by two independent reviewers, whilst quality was assessed using the model-specific Philips criteria. RESULTS: Twenty-four models were identified, evaluating either preventions (n = 12) or interventions (n = 12): 14 reported using a Markov modelling approach, four utilised decision trees and one a discrete event simulation, whilst five did not specify the approach. The majority, 22 studies, reported that the intervention was dominant or cost effective, given the assumptions and analytical perspective taken. Notably, the models tended to be short-term (16 used a time horizon of <=1 year), often providing little justification for the limited time horizon chosen. The methodological and reporting quality of the studies was generally weak, with only seven studies fulfilling more than 50% of their applicable Philips criteria. CONCLUSIONS: This is the first systematic review of decision models in eczema. Whilst the majority of models reported favourable outcomes in terms of the cost effectiveness of the new intervention, the usefulness of these findings for decision-making is questionable. In particular, there is considerable scope for increasing the range of interventions evaluated, for improving modelling structures and reporting quality. PMID- 28864847 TI - A monocentric centerline extraction method for ring-like blood vessels. AB - Centerline is generally used to measure topological and morphological parameters of blood vessels, which is pivotal for the quantitative analysis of vascular diseases. However, previous centerline extraction methods have two drawbacks on complex blood vessels, represented as the failure on ring-like structures and the existing of multi-voxel width. In this paper, we propose a monocentric centerline extraction method for ring-like blood vessels, which consists of three components. First, multiple centerlines are generated from the seed points that are chosen by randomly sprinkling points on blood vessel data. Second, multi centerline fusion is used to repair the notches of centerlines on ring-like vessels, and the local maximum of distance from oundary is employed to remedy the missing centerline points. Finally, monocentric processing is devised to keep the vascular centerline with single voxel width. We compared the proposed method with Wan et al.'s method and topological thinning on five groups of data including synthesized vascular datasets and MR brain images. The result showed the proposed method performed better than the two contrast methods both by visual inspection and by quantitative assessment, which demonstrated the performance of the proposed method on ring-like blood vessels as well as the elimination of multi voxel width points. PMID- 28864848 TI - Lessons learned from 300 consecutive pancreaticoduodenectomies over a 25-year experience: the "safety net" improves the outcomes beyond surgeon skills. AB - Pancreaticoduodenectomy (PD) is associated with high postoperative morbidity. The management of postoperative complications is paramount for reducing the mortality rate. The aim of this study was to evaluate the importance of surgical and hospital experience on outcomes by comparing postoperative results in three different hospitals with increasing resources for supporting the same surgical team. Patients data and surgical outcome of 300 consecutive patients undergoing PD were collected prospectively in the department database and divided into three periods (A = 1990-2000, B = 2001-March 2007, C = April 2007-2015). Pancreatico jejunostomy was the procedure of choice between 1995 and 2004, and pancreatico gastrostomy was performed afterwards. In the periods A, B and C, a total of 78, 85 and 137 PD were performed, respectively, and the number of PDs per year increased from 5 to 25. Between the three periods, the death rate (10.4 vs. 6 vs. 1.6%, p = 0.01) and intraoperative RBC transfusion rate (84.9 vs. 42.4 vs. 6.5%, p = 0.01) decreased significantly, whereas the vascular resection rate increased significantly (1.2 vs. 7 vs. 14.5, p < 0.002). Morbidity and reoperation rates did not change significantly between the three periods as well as operative time and median length of stay. Infectious complications and sepsis represented the most frequent major complication. Massive bleeding associated with uncontrolled pancreatic leak represented the major cause of morbidity and reoperation in the three periods, however, the relative mortality rate decreased significantly with no deaths in the last period. PD remains a challenging procedure with high morbidity and mortality rate. A multidisciplinary pancreatic team represents the "safety net" of pancreatic surgeon because it improves the results beyond the surgeon skills and experience. PMID- 28864849 TI - Maximal exercise increases mucosal associated invariant T cell frequency and number in healthy young men. AB - PURPOSE: Mucosal associated invariant T (MAIT) cells have properties of the innate and acquired immune systems. While the response to vigorous exercise has been established for most leukocytes, MAIT cells have not been investigated. Therefore, the purpose was to determine if MAIT cell lymphocytosis occurs with acute maximal aerobic exercise and if this response is influenced by exercise duration, cardiovascular fitness, or body composition. METHODS: Twenty healthy young males with moderate fitness levels performed an extended graded exercise test until volitional fatigue. Peripheral blood mononuclear cells were isolated from venous blood obtained prior and immediately after exercise and were labeled to identify specific T cell populations using flow cytometry. RESULTS: The percentage of MAIT cells relative to total T cells significantly increased from 3.0 to 3.8% and absolute MAIT cell counts increased by 2.2-fold following maximal exercise. MAIT cell subpopulation proportions were unchanged with exercise. Within cytotoxic T lymphocytes (CTL), MAIT cells consisted of 8% of these cells and this remained constant after exercise. MAIT cell counts and changes with exercise were not affected by body composition, VO2peak, or exercise duration. CONCLUSIONS: Maximal exercise doubled MAIT cell numbers and showed preferential mobilization within total T cells but the response was not influenced by fitness levels, exercise duration, or body composition. These results suggest that acute exercise could be used to offset MAIT cell deficiencies observed with certain pathologies. MAIT cells also make up a substantial proportion of CTLs, which may have implications for cytotoxicity assays using these cells. PMID- 28864850 TI - Comment to: "Factors associated with hernia recurrence after laparoscopic total extraperitoneal repair for inguinal hernia: a 2-year prospective cohort study." By Schjoth-Iversen L. (Hernia. 2017 Jul 27. doi:10.1007/s10029-017-1634-7. [Epub ahead of print]). PMID- 28864851 TI - Dietary sugar/starches intake and Barrett's esophagus: a pooled analysis. AB - Barrett's esophagus (BE) is the key precursor lesion of esophageal adenocarcinoma, a lethal cancer that has increased rapidly in westernized countries over the past four decades. Dietary sugar intake has also been increasing over time, and may be associated with these tumors by promoting hyperinsulinemia. The study goal was to examine multiple measures of sugar/starches intake in association with BE. This pooled analysis included 472 BE cases and 492 controls from two similarly conducted case-control studies in the United States. Dietary intake data, collected by study-specific food frequency questionnaires, were harmonized across studies by linking with the University of Minnesota Nutrient Database, and pooled based on study-specific quartiles. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race, total energy intake, study indicator, body mass index, frequency of gastro-esophageal reflux, and fruit/vegetable intake. In both studies, intake of sucrose (cases vs. controls, g/day: 36.07 vs. 33.51; 36.80 vs. 35.06, respectively) and added sugar (46.15 vs. 41.01; 44.18 vs. 40.68, respectively) were higher in cases than controls. BE risk was increased 79% and 71%, respectively, for associations comparing the fourth to the first quartile of intake of sucrose (ORQ4vs.Q1 = 1.79, 95% CI = 1.07-3.02, P trend = 0.01) and added sugar (ORQ4vs.Q1 = 1.71, 95% CI = 1.05-2.80, P trend = 0.15). Intake of sweetened desserts/beverages was associated with 71% increase in BE risk (ORQ4vs.Q1 = 1.71, 95% CI = 1.07-2.73, P trend = 0.04). Limiting dietary intake of foods and beverages that are high in added sugar, especially refined table sugar, may reduce the risk of developing BE. PMID- 28864852 TI - Effect of influent C/N ratio on N2O emissions from anaerobic/anoxic/oxic biological nitrogen removal processes. AB - The problem of producing strong greenhouse gas of nitrous oxide (N2O) from biological nitrogen removal (BNR) process in wastewater treatment plants (WWTP) has elicited great concern from various sectors. In this study, three laboratory scale wastewater treatment systems, with influent C/N ratios of 3.4, 5.4, and 7.5, were set up to study the effect of influent C/N ratio on N2O generation in anaerobic/anoxic/oxic (A2O) process. Results showed, with the increased influent C/N ratio, N2O generation from both nitrification and denitrification process was decreased, and the N2O-N conversion ratio of the process was obviously reduced from 2.23 to 0.05%. Nitrification rate in oxic section was reduced, while denitrification rate in anaerobic and anoxic section was elevated and the removal efficiency of COD, NH4+-N, TN, and TP was enhanced in different extent. As the C/N ratio increased from 3.4 to 7.5, activities of three key denitrifying enzymes of nitrate reductase, nitrite reductase, and nitrous oxide reductase were increased. Moreover, microorganism analysis indicated that the relative abundance of ammonium-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) were positively correlated with N2O generation, which was reduced from (8.42 +/- 3.65) to (3.61 +/- 1.66)% and (10.38 +/- 4.12) to (4.67 +/- 1.62)%, respectively. NosZ gene copy numbers of the A2O system were increased from (1.19 +/- 0.49) * 107 to (2.84 +/- 0.54) * 108 copies/g MLSS with the influent C/N ratio elevated from 3.4 to 7.5. Hence, appropriate influent C/N condition of A2O process could optimize the microbial community structure that simultaneously improve treatment efficiency and decrease the N2O generation. PMID- 28864853 TI - [Cooperation between nursing homes and intellectual disability care services : State of affairs in Flanders]. AB - Considering the increasing life expectancy of people with intellectual disabilities (ID), the importance of cooperation between services for people with ID and elderly care services has been stressed in Flanders and the Netherlands, as well as internationally. However, the prevalence, intensity and content of such a cooperation are yet unknown. In order to gain information to address this issue, an online-survey was delivered to directors of all nursing homes in Flanders (n = 781). 229 surveys were completed.In more than 75% of the nursing homes, people with ID were among the residents over the past decade. However, at the same time a lack of expertise has been identified as a barrier to provide them optimal care and support. Hence, the respondents point out that a cooperation with ID care services could be beneficial. Nevertheless, those partnerships only arose in a quarter of the nursing homes so far, primarily for the purpose of exchange of expertise. Intersectoral multidisciplinary consultations and intersectoral care team consultations have been taking place as well, be it mainly in the context of a persons' transition from an ID care service to a nursing home. Until now, radical cooperations which involve an exchange of staff, seem to be rather rare. PMID- 28864854 TI - Time-resolved CT assessment of collaterals as imaging biomarkers to predict clinical outcomes in acute ischemic stroke. AB - PURPOSE: Collateral circulation plays a pivotal role in the pathophysiology of acute ischemic stroke and is increasingly recognized as a promising biomarker for predicting the clinical outcome. However, there is no single established grading system. We designed a novel machine-learning software that allows non-invasive, objective, and quantitative assessment of collaterals according to their vascular territories. Our goal is to investigate the prognostic and predictive value of this collateral score for the prediction of acute stroke outcome. METHODS: This is a retrospective study of 135 patients with anterior circulation stroke treated with IV TPA. An equation using this collateral score (adjusting for age, baseline NIHSS, and recanalization) was derived to predict the clinical outcome (90-day mRS). The primary analyses focused on determining the prognostic value of our newly developed collateral scores. Secondary analyses examined the interrelationships between the collateral score and other variables. RESULTS: The collateral score emerged as a statistically significant prognostic biomarker for good clinical outcome (p < 0.033) among recanalized patients, but not among non recanalized patients (p < 0.497). Our results also showed that collateral score was a predictive biomarker (p < 0.044). These results suggest that (1) patients with good collateral score derive more benefit from successful recanalization than patients with poor collateral score and (2) collateral status is inconsequential if recanalization is not achieved. CONCLUSION: Our data results reinforce the importance of careful patient selection for recanalization therapy to avoid futile recanalization. The paucity of collaterals predicts poor clinical outcome despite recanalization. On the other hand, robust collaterals warrant consideration for recanalization therapy given the better odds of good clinical outcome. PMID- 28864855 TI - Erratum to: The Economic Burden of Insulin-Related Hypoglycemia in Spain. PMID- 28864856 TI - Comparison of adverse events following injection of original or generic docetaxel for the treatment of breast cancer. AB - PURPOSE: The approval of injectable generic drugs does not require bioequivalence testing. However, although generic products contain the same level of the active compound, the levels and types of additives present can differ from those used in the original product. Since docetaxel is highly lipophilic, polysorbate 80 (PS80), polyethylene glycol (PEG), and ethyl alcohol are employed to solubilize this anticancer agent. This retrospective study compared the safety of five docetaxel products (Taxotere(r), Docetaxel Hospira, Docetaxel Sandoz, Docetaxel Sawai, and Docetaxel EE). METHODS: The incidence and severity of adverse events were analyzed using the medical records of operable breast cancer patients (n = 363) treated with docetaxel (75 mg/m2) in Showa University Hospital, Japan, from Jan 2013 to Mar 2016. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Significant product-related differences were observed in the following non-hematological adverse events: injection site reaction (P = 0.0012), hand-foot syndrome (>=grade 3) (P = 0.0003), and oral mucositis (>=grade 3) (P = 0.0080). Multivariate logistic regression analyses of the associations between these adverse events and the total additive administered (g/m2) identified significant negative effects of PS80 and ethyl alcohol. CONCLUSIONS: Injectable docetaxel products had different adverse event profiles, which showed negative associations with the amounts of PS80 and ethyl alcohol present. This finding indicated that there might be additive-related pharmacokinetic and physiochemical differences among these products, suggesting a need for further pre- or post-approval testing of injectable generic products containing noticeable different levels of additives. PMID- 28864857 TI - Guidance for establishing an integrative oncology service in the Australian healthcare setting-a discussion paper. AB - There is an obvious mismatch between the high reported rates of use of traditional and complementary medicines (T&CM) by Australian cancer patients and cancer survivors and the low numbers of Australian cancer services integrating T&CM. An estimated 65% of Australian cancer patients use at least one form of T&CM. Over half use T&CM in conjunction with conventional cancer therapy. Yet, less than 20% of Australian hospital cancer care facilities provide access to T&CM. This compares to around 70% of UK cancer care facilities offering at least one T&CM therapy. Barriers to developing integrative oncology services include determining an appropriate service model and revenue structure; concerns with ethical and legal issues such as regulations and credentialing; and inadequate high-quality scientific evidence demonstrating safety and effectiveness, including concerns about the possibility of adversely affecting chemotherapy or radiotherapy treatment. This paper aims to provide general guidance and practical strategies for those seeking to develop integrative oncology services in Australian cancer care facilities. PMID- 28864858 TI - Erratum to: An IGRT margin concept for pelvic lymph nodes in high-risk prostate cancer. PMID- 28864859 TI - Expression and purification of classical swine fever virus E2 protein from Sf9 cells using a modified vector. AB - OBJECTIVE: To develop a simple method for efficient expression of classical swine fever virus (CSFV) E2 protein. RESULTS: The pFastBac HT B vector (pFastHTB-M1) was modified by adding a melittin signal peptide sequence. The E2 gene fragment without the transmembrane region was cloned into pFastHTB-M1. The modified vector has clear advantage over the original one, as evidenced by the purified recombinant E2 protein that was detected significantly by SDS-PAGE. CONCLUSIONS: The modified vector has the potential for large-scale production and easy purification of the CSFV E2 protein or other proteins of interests. PMID- 28864860 TI - Overseas Hepatitis B Vaccinations Among Newly Arrived Cubans in Texas-2010-2015. AB - We assessed hepatitis B virus (HBV) serologic results among newly arrived Cubans with vaccination documentation. We matched the post-arrival health assessment HBV serologic results of Cubans who arrived during 2010-2015 in Texas with their overseas hepatitis B (HepB) vaccination records in the CDC's Electronic Disease Notification database and calculated the proportion of those immune due to HepB vaccinations. Among 2123 who had overseas HepB vaccination and serologic results, 1072 (50.5%) had three valid documented doses of HepB. Of these 1072, 441 (41.1%) were immune due to HepB vaccination, 24 (2.2%), immune due to natural infection, 599 (55.9%), susceptible to HBV, and 8 (0.7%), HBV infected. Stratified by age, 21 (87.5%) of 24 children <5 years of age showed protection, and the antibody to HepB surface antigen (anti-HBs) decreased as age increased. Our findings concurred with previous observations that anti-HBs serologic results wane over time. Many newly arrived Cubans with complete HepB vaccination records on the U.S. Department of State overseas vaccination forms might be immune despite <10 mIU/mL anti-HBs response levels. PMID- 28864861 TI - Clarification of a suspicious thyroid nodule by use of camSPECT/US fusion imaging. PMID- 28864862 TI - Is the novel olecranon tension plate a valid alternative to tension band wiring of olecranon fractures? A biomechanical study on cadaver bones. AB - INTRODUCTION: Tension band wiring (TBW) used for olecranon fractures is afflicted with a high rate of complications. The aim of this study was to compare the stability of the TBW versus an alternative, novel low-profile olecranon tension plate (OTP) with angular stable screws in a simulated complex fracture model. MATERIALS AND METHODS: Nine fresh-frozen pairs of cadaver proximal ulnae with an oblique osteotomy and an additional wedge fragment simulating an unstable fracture were tested. The TBW and OTP were implanted pairwise. The elbow motion was simulated in a single-muscle model and ranged from full extension to 90 degrees of flexion. The pulling force of the triceps tendon ranged from 50 to 200 N. The displacement of the fracture fragments was measured with a video motion analysis system over 304 cycles. Data were assessed statistically using the Wilcoxon signed-rank test. RESULTS: The cyclic loading tests showed mean loosening of the fracture fragments at the articular surface of 0.56 mm using TBW (SD 0.65) and 0.15 mm for OTP (SD 0.39). There was no statistical significance in loosening between the two constructs (p = 0.31). No plate breakage or screw loosening occurred. CONCLUSIONS: The low-profile OTP, using the principles of pre tensioning, lag, cortical, and angular stable screws together, demonstrated similar stability after olecranon fracture fixation when compared with the TBW technique and a lag screw in the olecranon fracture model with a third wedge fragment. PMID- 28864863 TI - Fampridine Prolonged Release: A Review in Multiple Sclerosis Patients with Walking Disability. AB - Oral fampridine prolonged release (PR) [Fampyra(r)] is a lipid-soluble selective potassium channel blocker that is approved in the EU for the improvement of walking in adult multiple sclerosis (MS) patients with walking disability (expanded disability status scale score of 4-7). In clinical trials (MS-F203 and MS-F204) using an objective measure of walking improvement [the timed 25-foot walk (T25FW)], more than one-third of patients receiving fampridine PR achieved a consistent on-treatment improvement in walking speed (i.e. became TW responders) over 9-14 weeks of treatment. Fampridine PR recipients who fulfilled the definition of TW responder had mean improvements of ~25% from baseline in T25FW walking speed. In a clinical trial (ENHANCE) that used a patient-rated measure of walking improvement [12-item MS walking scale (MSWS-12)], a significantly greater proportion of fampridine PR recipients than placebo recipients achieved a >=8 point improvement on the MSWS-12 with 24 weeks of treatment. Where reported, adverse events were mostly mild or moderate in severity, and generally consistent with the underlying disease or mechanism of action of fampridine PR. Fampridine PR is a useful treatment option to consider in adult MS patients with walking disability. PMID- 28864864 TI - The anticancer estrogen receptor antagonist tamoxifen impairs consolidation of inhibitory avoidance memory through estrogen receptor alpha. AB - Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor alpha agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation. PMID- 28864865 TI - The effect of single-dose methylphenidate on the rate of error-driven learning in healthy males: a randomized controlled trial. AB - RATIONALE AND OBJECTIVES: Norepinephrine mediates the adjustment of error-driven learning to match the rate of change of the environment, while phasic dopamine signals prediction errors. We tested the hypothesis that pharmacologic manipulation may modulate this process. METHODS: We administered a single dose of methylphenidate, a norepinephrine/dopamine reuptake inhibitor, or placebo in double-blind randomized fashion to 20 healthy human males, who then performed a probabilistic learning task. Each subject was tested in two sessions, receiving methylphenidate in one session and placebo in the other, in randomized order. Task performance was quantified by the percentage of trials on which subjects chose the most likely option, while learning rate was measured using a computational model-based parameter as well as with a behavioral analogue of this parameter. RESULTS: There was a substance-by-session interaction effect on behavioral learning rate and model-based learning rate, such that subjects receiving methylphenidate exhibited higher learning rates than those receiving placebo in session 1, with no difference observed in session 2, suggesting that subjects retained the increased learning rate across sessions. Higher behavioral learning rate was associated with both higher task performance and with the model based learning rate. Higher learning rates were advantageous given the high rate of change on the task. Subjects receiving methylphenidate and placebo began the task in session 1 with a similar behavioral learning rate, but those receiving methylphenidate rapidly increased learning rate toward the optimal value, suggesting that methylphenidate accelerated the adaptation of learning rate based on the environment. CONCLUSIONS: The results suggest that methylphenidate may improve disrupted probabilistic learning in disorders involving noradrenergic or dopaminergic dysfunction. PMID- 28864866 TI - Autoimmune progesterone dermatitis. AB - Autoimmune progesterone dermatitis (APD) is an exceptional condition affecting young women of childbearing age with a high prevalence during the third decade of life. The diagnosis should be confirmed using an intradermal skin test to progesterone, during the follicular phase of the menstrual cycle. APD represents an early manifestation of autoimmune disease. A case of APD is presented who after curative treatment did not develop other autoimmune diseases during a 6 year follow-up. Dermatologists, gynecologists and obstetricians should be aware of this rare but highly invalidating entity. PMID- 28864867 TI - Safety of the Solitaire 4 * 40 mm Stent Retriever in the Treatment of Ischemic Stroke. AB - PURPOSE: Stent retrievers apply mechanical force to the intracranial vasculature. Our aim was to evaluate the safety and efficacy of the long Solitaire 4 * 40 mm stent retriever for large vessel occlusion in stroke patients. METHODS: We conducted a retrospective analysis of all patients treated for acute ischemic large vessel occlusion stroke with the Solitaire 2 FR 4 * 40 device between May and October 2016 at our institution. Patient-specific data at baseline and at discharge were documented. Reperfusion was graded with the thrombolysis in cerebral infarction (TICI) classification. Postinterventional angiograms and follow-up cross-sectional imaging were used to evaluate complications. RESULTS: TICI 2b/3 recanalization was achieved in 20 of 23 patients (87.0%), in 17 patients with the first retriever pass. NIHSS improved from a mean score at presentation of 16 (range 4-36) to 11 (range 0-41) at discharge. Mean mRS score at discharge was 3 (range 0-6) and 3 (range 0-6) at 90 days post-treatment. No infarcts in other territories were observed. One patient showed a (reversible) vasospasm in the postinterventional angiogram and another a small contrast extravasation in follow-up imaging. CONCLUSION: The Solitaire 2 FR 4 * 40 stent retriever is a safe and efficient device for large vessel occlusion acute ischemic stroke with a high recanalization rate and a low peri- and postinterventional complication rate together with a good clinical outcome. Despite potentially higher friction and shearing forces, no increased incidence of visible damage to the vessel wall was observed. PMID- 28864868 TI - Meta-Analysis of Intelligence Quotient (IQ) in Obsessive-Compulsive Disorder. AB - Obsessive compulsive disorder (OCD) is associated with a moderate degree of underperformance on cognitive tests, including deficient processing speed. However, despite little research focusing on Intelligence Quotient (IQ) in OCD, it has long been speculated that the disorder is associated with elevated intellectual capacity. The present meta-analytic study was, therefore, conducted to quantitatively summarize the literature on IQ in OCD systematically. We identified 98 studies containing IQ data among individuals with OCD and non psychiatric comparison groups, and computed 108 effect sizes for Verbal IQ (VIQ, n = 55), Performance IQ (PIQ, n = 13), and Full Scale IQ (FSIQ, n = 40). Across studies, small effect sizes were found for FSIQ and VIQ, and a moderate effect size for PIQ, exemplifying reduced IQ in OCD. However, mean IQ scores across OCD samples were in the normative range. Moderator analyses revealed no significant moderating effect across clinical and demographic indices. We conclude that, although lower than controls, OCD is associated with normative FSIQ and VIQ, and relatively lowered PIQ. These results are discussed in light of neuropsychological research in OCD, and particularly the putative impact of reduced processing speed in this population. Recommendations for utilization of IQ tests in OCD, and directions for future studies are offered. PMID- 28864869 TI - Charlson Comorbidity Index, inappropriate medication use and cognitive impairment : Bermuda Triangle. AB - BACKGROUND: The aim is to evaluate the association between the Charlson Comorbidity Index (CCI), polypharmacy, inappropriate medication use and cognitive impairment in long-term care facility patients. METHODS: A cross-sectional study including 105 long-term care facility residents was performed. The Charlson Comorbidity Index (CCI) was used. Inappropriate drug use (IDU) was defined according to the STOPP (Screening Tool of Older People's Prescriptions) criteria. Univariate analysis to identify variables associated with patient outcome related with cognitive impairment was investigated with chi2, Pearson correlation, Fisher exact, and Mann-Whitney U test where appropriate. For the multivariate analysis, the possible factors identified with univariate analysis were further entered into logistic regression analysis. RESULTS: A significant difference was found between gender, CCI and cognitive impairment (p = 0.038, p = 0.01). While every one point increment in the CCI increases the risk of cognitive impairment 3.1 fold (95% CI = 1.8-5.4, p < 0.001), hypertension increases the risk 12 fold (95% CI = 2.5-67.8, p = 0.002). While the correlation between Mini-Mental Status Examination (MMSE) score and polypharmacy is significant (p = 0.015), the correlation between MMSE and IDU was insignificant (p = 0.739). The association of urogenital system drugs and dementia was significant (p = 0.044). CONCLUSIONS: Comorbidities, especially hypertension and old age, are risk factors for cognitive impairment. Polypharmacy correlates with MMSE and is considered a risk factor for cognitive impairment. Inappropriate medication use is high among long term care facility residents. More studies on large cohorts are needed regarding optimal drug prescription and detection of specific drugs that may have an impact on cognitive performance. PMID- 28864870 TI - 20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol negatively regulates activation of STAT3 and ERK pathways and exhibits anti-cancer effects in HepG2 cells. AB - The pro-inflammatory cytokine interleukin 6 (IL-6), via activating its downstream JAK/STAT3 and Ras/ERK signaling pathways, is involved in cell growth, proliferation and anti-apoptotic activities in various malignancies. To screen inhibitors of IL-6 signaling, we constructed a STAT3 and ERK dual-pathway responsive luciferase reporter vector (Co.RE). Among several candidates, the natural compound 20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol (25-OCH3 PPD, GS25) was identified to clearly inhibit the luciferase activity of Co.RE. GS25 was confirmed to indeed inhibit activation of both STAT3 and ERK pathways and expression of downstream target genes of IL-6, and to predominantly decrease the viability of HepG2 cells via induction of cell cycle arrest and apoptosis. Interestingly, GS25 showed preferential inhibition of HepG2 cell viability relative to normal liver L02 cells. Further investigation showed that GS25 could not induce apoptosis and block activation of STAT3 and ERK pathways in L02 cells as efficiently as in HepG2 cells, which may result in differential effects of GS25 on malignant and normal liver cells. In addition, GS25 was found to potently suppress the expression of endogenous STAT3 at a higher concentration and dramatically induce p38 phosphorylation in HepG2 cells, which could mediate its anti-cancer effects. Finally, we demonstrated that GS25 also inhibited tumor growth in HepG2 xenograft mice. Taken together, these findings indicate that GS25 elicits its anti-cancer effects on HepG2 cells through multiple mechanisms and has the potential to be used as an inhibitor of IL-6 signaling. Thus, GS25 may be developed as a treatment for hepatocarcinoma with low toxicity on normal liver tissues as well as other inflammation-associated diseases. PMID- 28864871 TI - Eltrombopag for thrombocytopenia in patients with advanced solid tumors receiving gemcitabine-based chemotherapy: a randomized, placebo-controlled phase 2 study. AB - In this phase 2 study, patients with solid tumors receiving gemcitabine monotherapy or gemcitabine plus cisplatin/carboplatin were randomized 2:1 to eltrombopag 100 mg (n = 52) or placebo (n = 23) for 5 days before and after chemotherapy was started. The primary endpoint was prechemotherapy (Day 1) platelet count across <=6 cycles. Prechemotherapy platelet counts were numerically higher with eltrombopag than placebo. Frequencies of grades 3/4 thrombocytopenia were lower with eltrombopag in both the combination therapy (77 vs. 100%) and monotherapy (36 vs. 42%) groups. Proportionately fewer eltrombopag treated patients had platelet counts <100 * 109/L at nadir. Among patients receiving combination chemotherapy, mean time to recovery from platelet nadir was 8 days with eltrombopag vs. 15 days with placebo. Eltrombopag-treated patients had fewer dose delays/reductions or missed doses due to thrombocytopenia in both the combination therapy (77 vs. 91%) and monotherapy (62 vs. 83%) groups. Adverse events and serious adverse events were less frequent with eltrombopag in both chemotherapy groups, with reduced rates of anemia, neutropenia, and thrombocytopenia in patients receiving combination chemotherapy. In conclusion, eltrombopag treatment shortened the time to recovery from platelet nadir in patients treated with gemcitabine-based chemotherapy and reduced dose delays/reductions due to thrombocytopenia. PMID- 28864872 TI - Pathobiology of myomatosis uteri: the underlying knowledge to support our clinical practice. AB - INTRODUCTION: Uterine myomatosis, a benign condition, is the most common indication for hysterectomies worldwide, affecting the reproductive goals and quality of health of women. However, gynecologists have been provided with interesting insights on its pathobiology, which are the basis for uterine preserving therapies. The aim of this paper is to discuss the latest evidence on these mechanisms and its importance in the clinical practice. METHOD: A comprehensive literature search was made in Pubmed, Medline, the Cochrane Library, Orbis plus and Google Scholar for articles related to the epidemiological, biological, and genetic bases. RESULTS: There is extensive evidence that genetic, epigenetic, hormonal, environmental, proinflamatory, angiogenetic, and growing factors are involved in the biology of myomatosis. Such factors are capable of activating and promoting inhibitory signaling pathways leading to initiation, development, and regression of myomata through changes in myometrial cells and myomata fibers, such as cellular proliferation, differentiation, apoptosis, angiogenesis, and changes in the surrounding environment. CONCLUSION: A good understanding of the pathobiologic mechanisms of myomatosis gives reasons to physicians to elect conservative or combined therapies, and allow affected women to receive an individualized management, according to age, reproduction desire, and clinical condition. PMID- 28864873 TI - Health Outcomes in Individuals with Problem and Pathological Gambling: An Analysis of the 2014 North Carolina Behavioral Risk Factor Survey System (BRFSS). AB - Problem and pathological gambling refers to subclinical and clinical levels of maladaptive gambling, respectively, and is associated with specific sociodemographic characteristics as well as a number of poor health outcomes. We examined such demographic, physical health, mental health, and health-related behaviors in a sample of 7045 low-risk gamblers and 244 problem/pathological gamblers. Participants completed the 2014 North Carolina Behavioral Risk Factor Surveillance System telephone survey. Using the National Opinion Research Center's Diagnostic Screen for Gambling Disorders-CLiP, participants were categorized as either "problem/pathological gamblers" or "low-risk gamblers." Problem/pathological gamblers were younger, more likely to be male, of ethnic minority status, unmarried, and of lower education than low-risk gamblers. No physical health variables differentiated the groups but problem/pathological gamblers reported experiencing significantly more adverse childhood experiences and engaging in significantly more tobacco and alcohol use compared to low-risk gamblers. Moreover, gender moderated relationships between gambling group and several of the alcohol use variables such that male problem/pathological gamblers exhibited greater alcohol use behavior than male low-risk gamblers but no such relationship was present in females. Overall, this study expands the current knowledgebase on disordered gambling and highlights the need to assess disordered gambling in public health samples. Clinical implications are discussed. PMID- 28864874 TI - Close interpersonal proximity modulates visuomotor processing of object affordances in shared, social space. AB - Research suggests that the human brain codes manipulable objects as possibilities for action, or affordances, particularly objects close to the body. Near-body space is not only a zone for body-environment interaction but also is socially relevant, as we are driven to preserve our near-body, personal space from others. The current, novel study investigated how close proximity of a stranger modulates visuomotor processing of object affordances in shared, social space. Participants performed a behavioural object recognition task both alone and with a human confederate. All object images were in participants' reachable space but appeared relatively closer to the participant or the confederate. Results revealed when participants were alone, objects in both locations produced an affordance congruency effect but when the confederate was present, only objects nearer the participant elicited the effect. Findings suggest space is divided between strangers to preserve independent near-body space boundaries, and in turn this process influences motor coding for stimuli within that social space. To demonstrate that this visuomotor modulation represents a social phenomenon, rather than a general, attentional effect, two subsequent experiments employed nonhuman joint conditions. Neither a small, Japanese, waving cat statue (Experiment 2) nor a metronome (Experiment 3) modulated the affordance effect as in Experiment 1. These findings suggest a truly social explanation of the key interaction from Experiment 1. This study represents an important step toward understanding object affordance processing in real-world, social contexts and has implications broadly across fields of social action and cognition, and body space representation. PMID- 28864876 TI - Molecular evolution and epidemiological links study of Newcastle disease virus isolates from 1995 to 2016 in Iran. AB - In the case of Newcastle disease virus, multiple factors such as host adaptation, immune response evasion, and selective pressures have been suggested to result in evolution of viruses and the emergence of genetic variants. Multiple studies on virus classification and global epidemiological links have yielded consistent data. Here, we have performed a molecular analysis study of circulating Newcastle disease viruses in Iran (1995-2016). According to evolutionary divergences, subgenotype VIg, VIj, VIIj, VIId, XIIIa and XIIId isolates have been circulating in the country during a 21-year period. Based on data analysis, VIg isolates shared highest sequence identity with Russian and Polish isolates of the VIg subgenotype, while VIj subgenotype isolates (2012) were most similar to a virus isolated in 2015 in India. Analysis of the evolutionary divergence of subgenotype VIIj suggests that Chinese and Ukrainian viruses may have played a crucial role in the emergence of VIIj isolates. Evolutionary difference studies also indicated that XIIIa isolates circulating in Iran may have caused the emergence of adapted variants of subgenotype XIIId. Therefore, we propose that the evolutionary and epidemiological study of virulent Newcastle disease viruses could help to provide accurate molecular data about variants circulating in the region, thus aiding in the design of more efficient recombinant vaccines. PMID- 28864875 TI - Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the "Scene of the Crime". AB - PURPOSE OF REVIEW: Autoimmune-mediated destruction of insulin-producing beta cells within the pancreas results in type 1 diabetes (T1D), which is not yet preventable or curable. Previously, our understanding of the beta-cell specific T cell repertoire was based on studies of autoreactive T cell responses in the peripheral blood of patients at risk for, or with, T1D; more recently, investigations have included immunohistochemical analysis of some T cell specificities in the pancreas from organ donors with T1D. Now, we are able to examine live, islet-infiltrating T cells from donors with T1D. RECENT FINDINGS: Analysis of the T cell repertoire isolated directly from the pancreatic islets of donors with T1D revealed pro-inflammatory T cells with targets of known autoantigens, including proinsulin and glutamic acid decarboxylase, as well as modified autoantigens. We have assayed the islet-infiltrating T cell repertoire for autoreactivity and function directly from the inflamed islets of T1D organ donors. Design of durable treatments for prevention of or therapy for T1D requires understanding this repertoire. PMID- 28864877 TI - Clinical Assessment and Management of Delirium in the Palliative Care Setting. AB - Delirium is a neurocognitive syndrome arising from acute global brain dysfunction, and is prevalent in up to 42% of patients admitted to palliative care inpatient units. The symptoms of delirium and its associated communicative impediment invariably generate high levels of patient and family distress. Furthermore, delirium is associated with significant patient morbidity and increased mortality in many patient populations, especially palliative care where refractory delirium is common in the dying phase. As the clinical diagnosis of delirium is frequently missed by the healthcare team, the case for regular screening is arguably very compelling. Depending on its precipitating factors, a delirium episode is often reversible, especially in the earlier stages of a life threatening illness. Until recently, antipsychotics have played a pivotal role in delirium management, but this role now requires critical re-evaluation in light of recent research that failed to demonstrate their efficacy in mild- to moderate severity delirium occurring in palliative care patients. Non-pharmacological strategies for the management of delirium play a fundamental role and should be optimized through the collective efforts of the whole interprofessional team. Refractory agitated delirium in the last days or weeks of life may require the use of pharmacological sedation to ameliorate the distress of patients, which is invariably juxtaposed with increasing distress of family members. Further evaluation of multicomponent strategies for delirium prevention and treatment in the palliative care patient population is urgently required. PMID- 28864879 TI - Engineering of Microbial Electrodes. AB - This chapter provides an overview of the current state-of-the-art in the engineering of microbial electrodes for application in microbial electrosynthesis. First, important functional aspects and requirements of basic materials for microbial electrodes are introduced, including the meaningful benchmarking of electrode performance, a comparison of electrode materials, and methods to improve microbe-electrode interaction. Suitable current collectors and composite materials that combine different functionalities are also discussed. Subsequently, the chapter focuses on the design of macroscopic electrode structures. Aspects such as mass transfer and electrode topology are touched upon, and a comparison of the performance of microbial electrodes relevant for practical application is provided. The chapter closes with an overall conclusion and outlook, highlighting the future prospects and challenges for the engineering of microbial electrodes toward practical application in the field of microbial electrosynthesis. Graphical Abstract. PMID- 28864878 TI - Self-rated health as a predictor of mid-term and long-term mortality in older Afro-Caribbeans hospitalised via the emergency department. AB - PURPOSE: To determine whether self-rated health (SRH) is an independent predictor for mortality in older Afro-Caribbean patients hospitalised for an acute condition. METHODS: Prospective cohort of patients recruited from the University Hospitals of Martinique Acute Care for Elders unit. Patients aged 75 or older and hospitalised for an acute condition were eligible. The outcome was time to death within the 36-week follow-up. SRH was the explanatory variable of interest. Cox's Proportional Hazards model was used to estimate the relationship between SRH and mortality. RESULTS: The 223 patients included in the study were aged 85.1 +/- 5.5 years. In total, 123 patients reported "very good to good" health, and 100 "medium to very poor" health. Crude mortality rates at six months, 1, 2, and 3 years were 30.5, 34.8, 48.4, and 57.0%, respectively. By multivariate analysis, SRH reached significant relationship for all mortality timepoints. The adjusted hazard ratios for subjects who perceived their health as medium, poor or very poor was 1.6-2.7 times greater than that of subjects who reported good or very good health. CONCLUSION: Assessment of SRH could have implications for clinical practice, particularly in helping practitioners to better estimate prognosis in the acute care settings. PMID- 28864880 TI - Cytotoxicity of novel fluorinated alternatives to long-chain perfluoroalkyl substances to human liver cell line and their binding capacity to human liver fatty acid binding protein. AB - Although shorter chain homologues and other types of fluorinated chemicals are currently used as alternatives to long-chain perfluoroalkyl substances (PFASs), their safety information remains unclear and urgently needed. Here, the cytotoxicity of several fluorinated alternatives (i.e., 6:2 fluorotelomer carboxylic acid (6:2 FTCA), 6:2 fluorotelomer sulfonic acid (6:2 FTSA), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), and hexafluoropropylene oxide (HFPO) homologues) to human liver HL-7702 cell line were measured and compared with perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Their binding mode and affinity to human liver fatty acid binding protein (hL-FABP) were also determined. Compared with PFOA and PFOS, 6:2 Cl-PFESA, HFPO trimer acid (HFPO-TA), HFPO tetramer acid (HFPO-TeA), and 6:2 FTSA showed greater toxic effects on cell viabilities. At low exposure doses, these alternatives induced cell proliferation with similar mechanism which was different from that of PFOA and PFOS. Furthermore, binding affinity to hL-FABP decreased in the order of 6:2 FTCA < 6:2 FTSA < HFPO dimer acid (HFPO-DA) < PFOA < PFOS/6:2 Cl-PFESA/HFPO-TA. Due to their distinctive structure, 6:2 Cl-PFESA and HFPO homologues were bound to the hL-FABP inner pocket with unique binding modes and higher binding energy compared with PFOA and PFOS. This research enhances our understanding of the toxicity of PFAS alternatives during usage and provides useful evidence for the development of new alternatives. PMID- 28864881 TI - Improving quality of life in patients with pancreatic neuroendocrine tumor following peptide receptor radionuclide therapy assessed by EORTC QLQ-C30. AB - INTRODUCTION: Neuroendocrine tumors (NETs) have proven to be appropriate neoplasms for peptide receptor radionuclide therapy (PRRT), as the majority of these slow-growing malignancies overexpress somatostatin receptors. The aim of this study was to evaluate changes in quality of life (QoL) of patients with P NET following PRRT. METHODS: Sixty-eight patients with P-NET (31 female, mean age 61.4 y) underwent PRRT: 12 with NET of grade 1, 40 of grade 2, 8 of grade 3 (grade non-available n = 8). Prior to treatment, 39 patients showed ECOG 0, 26 patients ECOG 1, and three patients ECOG 2. Clinical assessment included evaluation of QoL and symptom changes using a standardized questionnaire (EORTC QLQ-C30) and was performed at baseline and every three months following each therapy cycle up to 12 months. Primary analysis compared QoL at baseline and after the fourth treatment cycle (N = 53). RESULTS: Up to four treatment cycles PRRT were performed for each patient. The median cumulative administered activity was 28.2 GBq. Primary analysis revealed that compared to baseline QoL was significantly improved revealing increased global health status (p = 0.008) and social functioning (p = 0.049) at the end of the study. Furthermore, fatigue and appetite loss showed a significant improvement after the last PRRT cycle (fatigue: p = 0.029, appetite loss p = 0.015). Sub-analyses showed that QoL was improved revealing increased global health status (3 months after first, second, and third treatment cycle p = 0.048, p = 0.002, and p < 0.001, respectively), emotional functioning (3 months after first-third cycle p = 0.003, p = 0.049, and p = 0.001, respectively) and social functioning (3 months after the first and second p < 0.001, and after the third cycle p = 0.015, respectively). Furthermore, some symptoms were significantly alleviated compared with baseline: fatigue (after first-third cycle p = 0.026, p = 0.050, and p = 0.008, respectively), nausea and vomiting (after first and second cycle p = 0.006 and p = 0.001, respectively), dyspnea (after third cycle p = 0.025), appetite loss (after first-third cycle p = 0.010, p = 0.001, and p = 0.009, respectively), constipation (after first-third cycle p = 0.050, p = 0.003, and p = 0.060, respectively). CONCLUSION: PRRT is an effective treatment of P-NET improving QoL of patients in terms of increasing global health and mitigation of physical complaints. PMID- 28864882 TI - Identification of additional loci associated with antibody response to Mycobacterium avium ssp. Paratuberculosis in cattle by GSEA-SNP analysis. AB - Mycobacterium avium subsp. paratuberculosis: (MAP) causes a contagious chronic infection results in Johne's disease in a wide range of animal species, including cattle. Several genome-wide association studies (GWAS) have been carried out to identify loci putatively associated with MAP susceptibility by testing each marker separately and identifying SNPs that show a significant association with the phenotype, while SNP with modest effects are usually ignored. The objective of this study was to identify modest-effect genes associated with MAP susceptibility using a pathway-based approach. The Illumina BovineSNP50 BeadChip was used to genotype 966 Holstein cows, 483 positive and 483 negative for antibody response to MAP, data were then analyzed using novel SNP-based Gene Set Enrichment Analysis (GSEA-SNP) and validated with Adaptive Rank Truncated Product methodology. An allele-based test was carried out to estimate the statistical association for each marker with the phenotype, subsequently SNPs were mapped to the closest genes, considering for each gene the single variant with the highest value within a window of 50 kb, then pathway-statistics were tested using the GSEA-SNP method. The GO biological process "embryogenesis and morphogenesis" was most highly associated with antibody response to MAP. Within this pathway, five genes code for proteins which play a role in the immune defense relevant to response to bacterial infection. The immune response genes identified would not have been considered using a standard GWAS, thus demonstrating that the pathway approach can extend the interpretation of genome-wide association analyses and identify additional candidate genes for target traits. PMID- 28864883 TI - Transcriptional regulation of CRMP5 controls neurite outgrowth through Sox5. AB - Transcriptional regulation of proteins involved in neuronal polarity is a key process that underlies the ability of neurons to transfer information in the central nervous system. The Collapsin Response Mediator Protein (CRMP) family is best known for its role in neurite outgrowth regulation conducting to neuronal polarity and axonal guidance, including CRMP5 that drives dendrite differentiation. Although CRMP5 is able to control dendritic development, the regulation of its expression remains poorly understood. Here we identify a Sox5 consensus binding sequence in the putative promoter sequence upstream of the CRMP5 gene. By luciferase assays we show that Sox5 increases CRMP5 promoter activity, but not if the putative Sox5 binding site is mutated. We demonstrate that Sox5 can physically bind to the CRMP5 promoter DNA in gel mobility shift and chromatin immunoprecipitation assays. Using a combination of real-time RT-PCR and quantitative immunocytochemistry, we provide further evidence for a Sox5 dependent upregulation of CRMP5 transcription and protein expression in N1E115 cells: a commonly used cell line model for neuronal differentiation. Furthermore, we report that increasing Sox5 levels in this neuronal cell line inhibits neurite outgrowth. This inhibition requires CRMP5 because CRMP5 knockdown prevents the Sox5-dependent effect. We confirm the physiological relevance of the Sox5-CRMP5 pathway in the regulation of neurite outgrowth using mouse primary hippocampal neurons. These findings identify Sox5 as a critical modulator of neurite outgrowth through the selective activation of CRMP5 expression. PMID- 28864884 TI - Sensitive indicators of Stipa bungeana response to precipitation under ambient and elevated CO2 concentration. AB - Precipitation is a primary environmental factor in the semiarid grasslands of northern China. With increased concentrations of atmospheric greenhouse gases, precipitation regimes will change, and high-impact weather events may be more common. Currently, many ecophysiological indicators are known to reflect drought conditions, but these indicators vary greatly among species, and few studies focus on the applicability of these drought indicators under high CO2 conditions. In this study, five precipitation levels (- 30%, - 15%, control, + 15%, and + 30%) were used to simulate the effects of precipitation change on 18 ecophysiological characteristics in Stipa bungeana, including leaf area, plant height, leaf nitrogen (N), and chlorophyll content, among others. Two levels of CO2 concentration (ambient, 390 ppm; 550 ppm) were used to simulate the effects of elevated CO2 on these drought indicators. Using gray relational analysis and phenotypic plasticity analysis, we found that total leaf area or leaf number (morphology), leaf water potential or leaf water content (physiology), and aboveground biomass better reflected the water status of S. bungeana under ambient and elevated CO2 than the 13 other analyzed variables. The sensitivity of drought indicators changed under the elevated CO2 condition. By quantifying the relationship between precipitation and the five most sensitive indicators, we found that the thresholds of precipitation decreased under elevated CO2 concentration. These results will be useful for objective monitoring and assessment of the occurrence and development of drought events in S. bungeana grasslands. PMID- 28864885 TI - A systematic meta-analysis of the association of Neuregulin 1 (NRG1), D-amino acid oxidase (DAO), and DAO activator (DAOA)/G72 polymorphisms with schizophrenia. AB - The glutamate hypothesis of schizophrenia is related to the proposed dysregulation of D-amino acid oxidase (DAO), DAO activator (DAOA)/G72, and Neuregulin 1 (NRG1) genes. Genetic studies have shown significant associations between DAO, DAOA, NRG1 single-nucleotide polymorphisms (SNPs), and schizophrenia. The systematic literature search yielded 6, 5, and 18 new studies for DAO, DAOA, and NRG1 published after 2011 and not included in the previous SchizophreniaGene (SZGene) meta-analysis. We conducted meta-analyses of 20, 23, and 48 case-control studies, respectively, to comprehensively evaluate the association of 8 DAO, 12 DAOA, and 14 NRG1 SNPs with schizophrenia. The updated meta-analyses resulted in the following findings: the C-allele of DAO rs4623951 was associated with schizophrenia across all pooled studies [Odds ratio (OR) = 0.88, 95% confidence interval (CI) = 0.79-0.98, p = 0.02, N = 3143]; however, no new reports could be included. The G-allele of DAOA rs778293 was associated with schizophrenia in Asian patients (OR = 1.17, 95% CI = 1.08-1.27, p = 0.00008, N = 6117), and the T-allele of DAOA rs3916971 was associated with schizophrenia across all studies (OR = 0.84, 95% CI = 0.73-0.96, p = 0.01, N = 1765). Again, for both SNPs, no new eligible studies were available. After adding new reports, the T-allele of NRG1 SNP8NRG241930 (rs62510682) across all studies (OR = 0.95, 95% CI = 0.91-0.997, p = 0.04, N = 22,898) and in Caucasian samples (OR = 0.95, 95% CI = 0.90-0.99, p = 0.03, N = 16,014), and the C-allele of NRG1 rs10503929 across all studies (OR = 0.89, 95% CI = 0.81-0.97, p = 0.01, N = 6844) and in Caucasian samples (OR = 0.89, 95% CI = 0.81-0.98, p = 0.01, N = 6414) were protective against schizophrenia. Our systematic meta-analysis is the most updated one for the association of DAO, DAOA, and NRG1 SNPs with schizophrenia. PMID- 28864886 TI - Essential oils of aromatic Egyptian plants repel nymphs of the tick Ixodes ricinus (Acari: Ixodidae). AB - Due to the role of Ixodes ricinus (L.) (Acari: Ixodidae) in the transmission of many serious pathogens, personal protection against bites of this tick is essential. In the present study the essential oils from 11 aromatic Egyptian plants were isolated and their repellent activity against I. ricinus nymphs was evaluated Three oils (i.e. Conyza dioscoridis L., Artemisia herba-alba Asso and Calendula officinalis L.) elicited high repellent activity in vitro of 94, 84.2 and 82%, respectively. The most active essential oil (C. dioscoridis) was applied in the field at a concentration of 6.5 ug/cm2 and elicited a significant repellent activity against I. ricinus nymphs by 61.1%. The most repellent plants C. dioscoridis, C. officinalis and A. herba-alba yielded essential oils by 0.17, 0.11 and 0.14%, respectively. These oils were further investigated using gas chromatography-mass spectrometry analysis. alpha-Cadinol (10.7%) and hexadecanoic acid (10.5%) were the major components of C. dioscoridis whereas in C. officinalis, alpha-cadinol (21.2%) and carvone (18.2%) were major components. Artemisia herba-alba contained piperitone (26.5%), ethyl cinnamate (9.5%), camphor (7.7%) and hexadecanoic acid (6.9%). Essential oils of these three plants have a potential to be used for personal protection against tick bites. PMID- 28864887 TI - Patients' experience of breast reconstruction after mastectomy and its influence on postoperative satisfaction. AB - PURPOSE: Breast cancer patients have the option to choose a breast reconstruction after mastectomy. A range of studies have postulated that patients' individually appraised significance of their breast is an important factor in the decision for or against breast reconstruction. This study explored the individually perceived significance of the breast among patients with and without breast reconstruction and its correlation with postoperative satisfaction. METHODS: Ten patients without breast reconstruction, and ten patients with immediate breast reconstruction after mastectomy participated in the study. The perceived importance of the breast and the pre-and postoperative esthetic satisfaction of the patients were obtained using an 11-point Likert scale. Qualitative interviews explored patients' views on the meaning of their breast and their experience after surgery. RESULTS: Patients who had decided for breast reconstruction rated the importance of their breast for femininity (p = 0.004) and attractiveness (p = 0.037) significantly higher than patients without reconstruction. The qualitative data provide evidence that the breast of a woman fulfills a variety of intrapsychic and interactional functions. Difficulties in integrating the reconstructed breast into the body image were reported. A high importance of the breast correlated significantly with a decrease in satisfaction with the breast after reconstruction (rs = -0.652, p = 0.041). CONCLUSIONS: Patients who found their breast to be highly important were more likely to decide for a reconstruction. Mastectomy has an impact on various psychosocial variables but impairments may also occur after breast reconstruction. Patients reporting a high significance of their breast showed the greatest decrease in satisfaction with their breast after reconstruction. PMID- 28864890 TI - [Computer-based diagnosis of skin cancer using artificial intelligence]. PMID- 28864889 TI - Methylglyoxal-derived advanced glycation end products contribute to negative cardiac remodeling and dysfunction post-myocardial infarction. AB - Advanced glycation end-products (AGEs) have been associated with poorer outcomes after myocardial infarction (MI), and linked with heart failure. Methylglyoxal (MG) is considered the most important AGE precursor, but its role in MI is unknown. In this study, we investigated the involvement of MG-derived AGEs (MG AGEs) in MI using transgenic mice that over-express the MG-metabolizing enzyme glyoxalase-1 (GLO1). MI was induced in GLO1 mice and wild-type (WT) littermates. At 6 h post-MI, mass spectrometry revealed that MG-H1 (a principal MG-AGE) was increased in the hearts of WT mice, and immunohistochemistry demonstrated that this persisted for 4 weeks. GLO1 over-expression reduced MG-AGE levels at 6 h and 4 weeks, and GLO1 mice exhibited superior cardiac function at 4 weeks post-MI compared to WT mice. Immunohistochemistry revealed greater vascular density and reduced cardiomyocyte apoptosis in GLO1 vs. WT mice. The recruitment of c-kit+ cells and their incorporation into the vasculature (c-kit+CD31+ cells) was higher in the infarcted myocardium of GLO1 mice. MG-AGEs appeared to accumulate in type I collagen surrounding arterioles, prompting investigation in vitro. In culture, the interaction of angiogenic bone marrow cells with MG-modified collagen resulted in reduced cell adhesion, increased susceptibility to apoptosis, fewer progenitor cells, and reduced angiogenic potential. This study reveals that MG AGEs are produced post-MI and identifies a causative role for their accumulation in the cellular changes, adverse remodeling and functional loss of the heart after MI. MG may represent a novel target for preventing damage and improving function of the infarcted heart. PMID- 28864888 TI - Molecular cloning of a CC-NBS-LRR gene from Vitis quinquangularis and its expression pattern in response to downy mildew pathogen infection. AB - Downy mildew, caused by Plasmopara viticola, can result in a substantial decrease in grapevine productivity. Vitis vinifera is a widely cultivated grapevine species, which is susceptible to this disease. Repeated pesticide applications are harmful for both the environment and human health. Thus, it is essential to develop varieties/cultivars that are resistant to downy mildew and other diseases. In our previous studies, we investigated the natural resistance of the Chinese wild grapevine V. quinquangularis accession 'PS' against P. viticola and obtained several candidate resistance (R) genes that may play important roles in plant disease resistance. In the present study, we isolated a CC-NBS-LRR-type R gene from 'PS' and designated it VqCN. Its open reading frame is 2676 bp which encodes a protein of 891 amino acids with a predicted molecular mass of 102.12 kDa and predicted isoelectric point of 6.53. Multiple alignments with other disease resistant (R) proteins revealed a conserved phosphate-binding loop (P loop), resistance nucleotide binding site, a hydrophobic domain (GLPL) and methionine-histidine-aspartate (MHD) motifs, which are typical components of nucleotide-binding site leucine-rich repeat proteins, as well as a coiled-coil region in the N-terminus. Quantitative real-time polymerase chain reaction analysis showed that the transcript of VqCN was rapidly and highly induced after infection with P. viticola in 'PS'. Moreover, the leaves of susceptible 'Cabernet Sauvignon' transiently expressing VqCN manifested increased resistance to P. viticola. The results indicated that VqCN might play a positive role in protecting grapevine against infection with P. viticola. Cloning and functional analysis of a putative resistance gene provide a basis for disease-resistance breeding. PMID- 28864891 TI - Cytotoxicity of targeted HER2-specific phototoxins based on flavoprotein miniSOG is determined by the rate of their internalization. AB - The concept of targeted therapy implies the development of bifunctional agents complementing the therapeutic module with a targeting one. A promising target for the delivery of imaging and/or toxic modules is the HER2 (ErbB2) receptor. Earlier, we have functionally characterized the targeted photosensitizers 4D5scFv miniSOG and DARPin-miniSOG, causing the death of HER2-overexpressing cells when irradiated with blue light. However, the cytotoxicity of targeted toxins 4D5scFv miniSOG and DARPin-miniSOG (both having functionally active targeted and cytotoxic modules in recombinant proteins) against human breast adenocarcinoma cells differs 5 times. The study of the dynamics of internalization of 4D5scFv miniSOG and DARPin-miniSOG proteins in the complex with HER2 in this work showed that the rate of internalization contributes most significantly to the toxicity of these photosensitizers, because it determines the duration of the presence of the phototoxin in the lipid bilayer of the cell membrane, where its damaging effect is maximum. PMID- 28864892 TI - Influence of dicarbonyls on kinetic characteristics of glutathione peroxidase. AB - Se-containing glutathione peroxidase (GSH-Px) is one of the key enzymes of the body's antioxidant system. The kinetic characteristics of GSH-Px (substrate is tert-butyl hydroperoxide) after modification of the enzyme by various concentrations of natural dicarbonyls (glyoxal, methylglyoxal, malonic dialdehyde) were studied. It was shown that dicarbonyls affected both K m and V max for GSH-Px. It is suggested that the effect of various dicarbonyls on GSH-Px depends on the molecular mechanisms of their interaction with the amino acid residues of the enzyme. PMID- 28864893 TI - The metabolic changes in tumor-associated macrophages during cancer grow in mice with Ehrlich ascites carcinoma. AB - In this work, we investigated the activity of the key NAD(P)-dependent dehydrogenases associated with macrophage tumors in mice with Ehrlich ascites carcinoma. It was shown that cancer grow is associated with the development of conditions in macrophages leading to a decrease in the substrate flow intensity in the tricarboxylic acid cycle, deceleration of oxidative deamination of L glutamate, NADP regeneration, and a decrease in the antioxidant defense efficiency. There results are consistent with our recent concept on the nonspecific metabolic reaction of cells to extreme exposures. PMID- 28864895 TI - The role of production of adipsin and leptin in the development of insulin resistance in patients with abdominal obesity. AB - We investigated the tissue-specific features of the production of adipokines (leptin and adipsin) by adipose tissue in obese patients depending on the degree of obesity and the state of carbohydrate metabolism. An increase in the content of adipsin and leptin in the blood plasma was found. In patients with varying degrees of obesity with and without type 2 diabetes mellitus (DM 2), we determined the level of tissue-specific expression of LEP and CFD genes encoding leptin and adipsin, respectively. The contribution of different adipose tissue depots to the blood plasma level of adipsin and leptin in obese patients with and without DM 2 was established. The disturbance of reciprocal relationships between adipsin and leptin in obesity is associated with the development of insulin resistance. PMID- 28864894 TI - Evolution of catalytic centers of antibodies by virtual screening of broad repertoire of mutants using supercomputer. AB - It is proposed to perform quantum mechanical/molecular dynamics calculations of chemical reactions that are planned to be catalyzed by antibodies and then conduct a virtual screening of the library of potential antibody mutants to select an optimal biocatalyst. We tested the effectiveness of this approach by the example of hydrolysis of organophosphorus toxicant paraoxon using kinetic approaches and X-ray analysis of the antibody biocatalyst designed de novo. PMID- 28864896 TI - Dependence of expression of regulatory master genes of embryonic development in pancreatic cancer cells on the intracellular concentration of the master regulator PDX1. AB - Exogenous expression of the gene encoding the pancreatic master regulator PDX1 in cell lines with different degrees of differentiation of pancreatic cancer cells is accompanied by changes in the expression of known master genes involved in cancer progression. In BxPC3PDX+ cells, as compared to BxPC3PDX-, we detected an increased expression of the following genes: NKX6.1 (2 times), NR5A2 (2.5 times), KLF5 (1.8 times), ZEB1 (3 times), and ONECUT1 (1.3 times), as well as a decreased expression of MUC1 and SLUG genes (3 and 2 times, respectively). In PANC1PDX+ cells, as compared to the control PANC1PDX- cells, we detected a decreased expression of ISL1 (2 times) and an increased expressed of KRT8 (2 times) and MUC1 (by 30%). In the high-grade cell lines (including the BxPC3 line studied), the total content of sites containing the marks of active enhancers was higher than that in the low-grade cell lines (PANC1). PMID- 28864897 TI - New paradoxical three-finger toxin from the cobra Naja kaouthia venom: Isolation and characterization. AB - A new three-finger toxin nakoroxin was isolated from the cobra Naja kaouthia venom, and its complete amino acid sequence was established. Nakoroxin belongs to the group of "orphan" toxins, data on the biological activity of which are practically absent. Nakoroxin shows no cytotoxicity and does not inhibit the binding of alpha-bungarotoxin to nicotinic acetylcholine receptors of muscle and alpha7 types. However, it potentiates the binding of alpha-bungarotoxin to the acetylcholine-binding protein from Lymnaea stagnalis. This is the first toxin with such an unusual property. PMID- 28864898 TI - Antiglycation activity of melatonin. AB - For the first time, it was found that the hormone melatonin exhibited antiglycation activity in vitro. It was shown that melatonin significantly slowed down the accumulation of fluorescent Schiff adducts formed as a result of BSA modification in the presence of high concentration of fructose. It was noted that, unlike the fructosylation reaction, melatonin did not affect the process of modification of BSA by methylglyoxal. We assume that melatonin is able to inhibit the development of the Maillard reaction but does not affect the process of BSA modification by reactive carbonyls. PMID- 28864899 TI - Detection of human neuronal alpha7 nicotinic acetylcholine receptors by conjugates of snake alpha-neurotoxin with quantum dots. AB - Fluorescent derivatives are widely used to study the structure and functions of proteins. Quantum dots (QDs), fluorescent semiconductor nanocrystals, have a high quantum yield and are much more resistant to bleaching compared to organic dyes. Conjugates of alpha-neurotoxins with QDs were used for visualization of human alpha7 acetylcholine receptors heterologously expressed in GH4C1 pituitary adenoma cells. Specific staining of cells by the conjugated toxins was observed. PMID- 28864900 TI - Expression of master regulatory genes of embryonic development in pancreatic tumors. AB - The expression level of some important master regulators of embryonic development of the pancreas in the tumor samples of this human organ was determined. We found that the transcription of SOX9, GATA4, PDX1, PTF1a, and HNF1b genes in the tumor samples was reduced as compared to the samples of normal pancreatic tissues, and the KLF5 gene expression in the tumor cells was elevated. We assume that all the studied genes, except KLF5, form a single regulatory module that supports the identity of tumor progenitor cells. A simultaneous suppression of expression of these master factors may be critical for the neoplastic transformation of pancreatic cells. PMID- 28864901 TI - Expression of transcription factor genes in cell lines corresponding to different stages of pancreatic cancer progression. AB - The expression level of six transcription factor genes and the content of their protein products in five pancreatic cancer cell lines with parallel control of expression of three marker genes reflecting epithelial or mesenchymal state of cells was investigated. Cell lines MIA PaCa-2 and Capan-2 represented the best models of quasi-mesenchymal and epithelial, respectively, types of progression of the pancreatic ductal adenocarcinoma, according to the content of E-cadherin and vimentin and the expression of KLF5 and ZEB1 transcription factors. PMID- 28864902 TI - Fatty acid composition of odonate's eyes. AB - We have studied the fatty acid composition of eyes of amphibiotic insects, namely, the odonate Sympetrum flaveolum. The main polyunsaturated fatty acid of odonate's eyes has been found to be 20:5n-3 (eicosapentaenoic fatty acid, EPA) rather than 18:2n-6 and 18:3n-3, which usually dominate in eyes of terrestrial insects, or 22:6n-3, which dominates in eyes of vertebrates. The prevalence of EPA in odonate's eyes probably provides a more effective transmission of light signal in this animal compared to terrestrial insects. It is important for odonates because vision plays a decisive role in finding and catching prey. PMID- 28864903 TI - A pepper mottle virus-based vector enables systemic expression of endoglucanase D in non-transgenic plants. AB - Plant-virus-based expression vectors have been used as an alternative to the creation of transgenic plants. Using a virus-based vector, we investigated the feasibility of producing the endoglucanase D (EngD) from Clostridium cellulovorans in Nicotiana benthamiana. This protein has endoglucanase, xylanase, and exoglucanase activities and may be of value for cellulose digestion in the generation of biofuels from plant biomass. The EngD gene was cloned between the nuclear inclusion b (NIb)- and coat protein (CP)-encoding sequences of pSP6PepMoV Vb1. In vitro transcripts derived from the clone (pSP6PepMoV-Vb1/EngD) were infectious in N. benthamiana but caused milder symptoms than wild-type PepMoV Vb1. RT-PCR amplification of total RNA from non-inoculated upper leaves infected with PepMoV-Vb1/EngD produced the target band for the CP, partial NIb and EngD-CP regions of PepMoV-V1/EngD, in addition to nonspecific bands. Western blot analysis showed the CP target bands of PepMoV-Vb1/EngD as well as non-target bands. EngD enzymatic activity in infected plants was detected using a glucose assay. The plant leaves showed increased senescence compared with healthy and PepMoV-Vb1-infected plants. Our study suggests the feasibility of using a viral vector for systemic infection of plants for expression of heterologous engD for the purpose of digesting a cellulose substrate in plant cells for biomass production. PMID- 28864904 TI - Veno-veno-arterial extracorporeal membrane oxygenation for acute respiratory distress syndrome with septic-induced cardiomyopathy due to severe pulmonary tuberculosis. AB - We describe the rare experience of veno-veno-arterial (VVA) extracorporeal membrane oxygenation (ECMO) in a patient with acute respiratory distress syndrome and septic-induced cardiomyopathy due to pulmonary tuberculosis (TB). A 24-year old male patient who developed septic-induced cardiomyopathy secondary to pulmonary TB was administered veno-arterial (VA) ECMO for cardiac support. Six days later, the ECMO configuration mode was changed from VA to VVA to improve hypoxemia of the upper body and to prevent further lung injury. The patient was then successfully managed using an appropriate alternative ECMO strategy. PMID- 28864905 TI - Measurement of protein backbone 13CO and 15N relaxation dispersion at high resolution. AB - Peak overlap in crowded regions of two-dimensional spectra prevents characterization of dynamics for many sites of interest in globular and intrinsically disordered proteins. We present new three-dimensional pulse sequences for measurement of Carr-Purcell-Meiboom-Gill relaxation dispersions at backbone nitrogen and carbonyl positions. To alleviate increase in the measurement time associated with the additional spectral dimension, we use non uniform sampling in combination with two distinct methods of spectrum reconstruction: compressed sensing and co-processing with multi-dimensional decomposition. The new methodology was validated using disordered protein CD79A from B-cell receptor and an SH3 domain from Abp1p in exchange between its free form and bound to a peptide from the protein Ark1p. We show that, while providing much better resolution, the 3D NUS experiments give the similar accuracy and precision of the dynamic parameters to ones obtained using traditional 2D experiments. Furthermore, we show that jackknife resampling of the spectra yields robust estimates of peak intensities errors, eliminating the need for recording duplicate data points. PMID- 28864906 TI - Composite tumor with pheochromocytoma and immature neuroblastoma: report of two cases with cytogenetic analysis and discussion of current terminology. PMID- 28864907 TI - Alterations in the reduced pteridine contents in the cerebrospinal fluids of LRRK2 mutation carriers and patients with Parkinson's disease. AB - Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase that is essential for the biosynthesis of dopamine. Parkinson's disease (PD) is characterized by a progressive degeneration of nigrostriatal dopaminergic neurons, and biomarkers reflecting the degree of neurodegeneration are important not only for basic research but also for clinical diagnosis and the treatment of the disease. Although the total neopterin and biopterin levels in the cerebrospinal fluids (CSF) of the patients with PD were reported, alterations in the composition of reduced and oxidized forms of pteridine compounds have not been examined. In this study, we first examined the time-dependent alterations in BH4 and other reduced pteridine compounds in the CSF of an MPTP-treated monkey as a primate PD model. We found that the CSF levels of BH4 and dihydroneopterin, an intermittent metabolite of BH4-biosynthesis, altered inversely with progression of neurodegeneration, whereas those of dihydrobiopterin and neopterin were relatively low and constant. Next, we assayed the amounts of reduced pteridine compounds in the CSF of 36 pre-symptomatic LRRK2-mutation (N1437H or G2019S) carriers (LRRK2-carrier), 13 patients with PD symptoms (LRRK2-PD), 46 patients with sporadic PD (sPD), and 26 non-PD individuals. The BH4 levels were significantly lower in both the LRRK2-PD and sPD patients, and the LRRK2-carriers exhibited higher BH4 levels compared with the sPD patients. The total neopterin levels in the CSF of the LRRK2-PD were significantly higher than those in the sPD and non-PD individuals, which indicated greater inflammatory responses in the brains of LRRK2-PD patients. The present results suggest that detailed analyses of pteridine levels in the CSF might be useful for understanding the pathophysiology of familial PD and for monitoring PD progression. PMID- 28864908 TI - Antitumor activity and expression profiles of genes induced by sulforaphane in human melanoma cells. AB - PURPOSE: Human melanoma is a highly aggressive incurable cancer due to intrinsic cellular resistance to apoptosis, reprogramming, proliferation and survival during tumour progression. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, plays a role in carcinogenesis in many cancer types. However, the cytotoxic molecular mechanisms and gene expression profiles promoted by SFN in human melanoma remain unknown. METHODS: Three different cell lines were used: two human melanoma A375 and 501MEL and human epidermal melanocytes (HEMa). Cell viability and proliferation, cell cycle analysis, cell migration and invasion and protein expression and phosphorylation status of Akt and p53 upon SFN treatment were determined. RNA-seq of A375 was performed at different time points after SFN treatment. RESULTS: We demonstrated that SFN strongly decreased cell viability and proliferation, induced G2/M cell cycle arrest, promoted apoptosis through the activation of caspases 3, 8, 9 and hampered migration and invasion abilities in the melanoma cell lines. Remarkably, HEMa cells were not affected by SFN treatment. Transcriptomic analysis revealed regulation of genes involved in response to stress, apoptosis/cell death and metabolic processes. SFN upregulated the expression of pro-apoptotic genes, such as p53, BAX, PUMA, FAS and MDM2; promoted cell cycle inhibition and growth arrest by upregulating EGR1, GADD45B, ATF3 and CDKN1A; and simultaneously acted as a potent inhibitor of genotoxicity by launching the stress-inducible protein network (HMOX1, HSPA1A, HSPA6, SOD1). CONCLUSION: Overall, the data show that SFN cytotoxicity in melanoma derives from complex and concurrent mechanisms during carcinogenesis, which makes it a promising cancer prevention agent. PMID- 28864910 TI - Acute kidney injury and stroke: unresolved issues. PMID- 28864911 TI - The Effectiveness of Aquatic Group Therapy for Improving Water Safety and Social Interactions in Children with Autism Spectrum Disorder: A Pilot Program. AB - Drowning is the number one cause of accidental death in children with Autism Spectrum Disorder (ASD). Few studies have examined the effectiveness of swim instruction for improving water safety skills in children with moderate to severe ASD. This study examines the feasibility and effectiveness of an aquatic therapy program on water safety and social skills in children with mild to severe ASD (n = 7). Water safety skills were evaluated using the Aquatics Skills Checklist and social skills were measured using the Social Skills Improvement Scale. We provide preliminary evidence that children with ASD can improve water safety skills (p = 0.0002), which are important for drowning prevention after only 8 h of intervention. However, social skills did not respond to intervention (p = 0.6409). PMID- 28864909 TI - Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas. AB - Melatonin is an ancient antioxidant. After its initial development in bacteria, it has been retained throughout evolution such that it may be or may have been present in every species that have existed. Even though it has been maintained throughout evolution during the diversification of species, melatonin's chemical structure has never changed; thus, the melatonin present in currently living humans is identical to that present in cyanobacteria that have existed on Earth for billions of years. Melatonin in the systemic circulation of mammals quickly disappears from the blood presumably due to its uptake by cells, particularly when they are under high oxidative stress conditions. The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2. Thus, melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant. In addition to being taken up from the circulation, melatonin may be produced in the mitochondria as well. During evolution, mitochondria likely originated when melatonin-forming bacteria were engulfed as food by ancestral prokaryotes. Over time, engulfed bacteria evolved into mitochondria; this is known as the endosymbiotic theory of the origin of mitochondria. When they did so, the mitochondria retained the ability to synthesize melatonin. Thus, melatonin is not only taken up by mitochondria but these organelles, in addition to many other functions, also probably produce melatonin as well. Melatonin's high concentrations and multiple actions as an antioxidant provide potent antioxidant protection to these organelles which are exposed to abundant free radicals. PMID- 28864912 TI - Evaluation of port site hernias, chronic pain and recurrence rates after laparoscopic ventral hernia repair: a monocentric long-term study. AB - OBJECTIVE: The aim of this study was to evaluate hernia appearance at the trocar site after laparoscopic treatment of primary or incisional ventral hernias using an intraperitoneal prosthetic mesh. Chronic pain at the trocar site and primary hernia recurrence were also evaluated. PATIENTS AND METHODS: Two-hundred and twenty-six consecutive patients who underwent a standardized laparoscopic hernia repair for primary or incisional ventral hernia at our centre between January 2000 and December 2008 were included. All patients had clinical and radiological examinations. Primary end points were port site hernia and the occurrence of chronic trocar site pain. Secondary end point was primary hernia recurrence. RESULTS: Seventy-eight patients were excluded: 6 declined to participate, 48 were unreachable, and 24 did not meet the inclusion criteria (nine underwent a single site laparoscopic approach, ten died of unrelated disease, three were unable to visit the hospital and two had relocated). After exclusion, 148 remained in our study. Mean follow-up was 49 +/- 12.6 months. Mean age at the time of surgery was 60 years (range, 28-83) In total, 504 port sites were clinically and radiologically evaluated, and only one (0.02%) had secondary herniation. Three patients (2.0%) had a recurrent hernia, and 14 (9.5%) had developed chronic pain at time of assessment. Nine patients (6.1%) were re-operated for the recurrent hernia before the follow-up evaluation. The overall recurrence rate is, therefore, 8.1%. Only two minor complications and no major complications occurred after surgery. No mortality was observed. CONCLUSION: Laparoscopic repair for primary or incisional ventral hernias is a safe surgical approach, with low rates of hernia recurrence and a low morbidity rate. When fascial closure is maintained for 10 mm port sites, the incidence of port site hernias is very low. Five millimetre ports do not require closure. PMID- 28864914 TI - Nonketotic hyperglycinemia: spectrum of imaging findings with emphasis on diffusion-weighted imaging. AB - PURPOSE: The purpose of this study was to explore brain abnormalities in nonketotic hyperglycinemia (NKH) using diffusion-weighted imaging (DWI) and when feasible, diffusion tensor imaging (DTI) and tractography. METHODS: Seven patients with confirmed diagnosis of NKH (8 days-2 years) underwent brain MRI. Conventional T1 and T2WI were acquired in all patients, DWI in six and DTI and tractography in two (4 months and 2 years). Measurements of fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) and Trace from eight white matter regions were compared between the two patients and age-matched controls. Tractography of corpus callosum, superior longitudinal fasciculus and corticospinal tracts was performed with extraction of their FA and diffusivity indices. RESULTS: MRI showed nonspecific brain atrophy in three children. Corpus callosum atrophy was found as a part of these atrophic changes. Cerebellar vermian hypoplasia and supratentorial hydrocephalus were seen in one patient. The topographic distribution of diffusion restriction was different among patients. The affected white matter regions were not predominantly following the expected areas of myelination according to patients' age. Deep grey matter nuclei were affected in one patient. DTI revealed lower FA with higher RD in most of the measured white matter regions and tracts. These changes were more appreciated in the 2-year-old patient. However, Trace was higher in the 2-year-old patient and lower in the 4-month-old one. The extracted tracts were decreased in volume. CONCLUSION: DWI, DTI and tractography with FA and diffusivity measurements can give insights into white matter microstructural alterations that can occur in NKH. PMID- 28864913 TI - Pancreatic neuro-insular network in young mice revealed by 3D panoramic histology. AB - AIMS/HYPOTHESIS: It has been proposed that the neuro-insular network enables rapid, synchronised insulin secretion. However, to date, acquiring the pancreatic tissue map to study the neural network remains a challenging task as there is a lack of feasible approaches for large-scale tissue analysis at the organ level. Here, we have developed 3-dimensional (3D) panoramic histology to characterise the pancreatic neuro-insular network in young mice. METHODS: Pancreases harvested from young wild-type B6 mice (3 and 8 weeks old) and db/db mice (3 weeks old; db/db vs db/+) were used to develop 3D panoramic histology. Transparent pancreases were prepared by optical clearing to enable deep-tissue, tile-scanning microscopy for qualitative and quantitative analyses of islets and the pancreatic tissue network in space. RESULTS: 3D panoramic histology reveals the pancreatic neurovascular network and the coupling of ganglionic and islet populations via the network. This integration is identified in both 3- and 8-week-old mice, featuring the peri-arteriolar neuro-insular network and islet-ganglionic aggregation. In weaning hyperphagic db/db mice, the 3D image data identifies the associated increases in weight, adipose tissue attached to the pancreas, density of large islets (major axis > 150 MUm) and pancreatic sympathetic innervation compared with db/+ mice. CONCLUSIONS/INTERPRETATION: Our work provides insight into the neuro-insular integration at the organ level and demonstrates a new approach for investigating previously unknown details of the pancreatic tissue network in health and disease. PMID- 28864915 TI - A gene-based test of association through an orthogonal decomposition of genotype scores. AB - The burden test and the sequence kernel association test (SKAT) are two popular methods for detecting association with rare variants. Treated as two different sources of association information, they are adaptively combined to form an optimal SKAT (SKAT-O) method for optimal power. We show that the burden test is part of rather than independent of the SKAT. We introduce a new test statistic that is the sum of the burden statistic and a statistic asymptotically independent of the burden statistic. The performance of this new test statistic is demonstrated through extensive simulation studies and applications to a Genetic Analysis Workshop 17 data set and the Ocular Hypertension Treatment Study data. PMID- 28864917 TI - Formulation, physicochemical characterization and in vitro evaluation of human insulin-loaded microspheres as potential oral carrier. AB - The objective of the present investigation was to formulate and characterize the human insulin entrapped Eudragit S100 microspheres containing protease inhibitors and to develop an optimized formulation with desirable features. A w/o/w multiple emulsion solvent evaporation technique was employed to produce microspheres of human insulin using Eudragit S-100 as coating material and polyvinyl alcohol as a stabilizer. The resultant microspheres were evaluated for drug-excipient compatibility, encapsulation efficiency, particle size, surface morphology, micromeritic properties, enteric nature, and in vitro drug release studies. Micromeritic properties indicated good flow properties and compressibility. In present investigation formulation F6 with drug/polymer ratio (1:100) was found to be optimal in terms of evaluated parameters where it showed a significantly higher percentage of encapsulation efficiency (76.84%) with minimal drug release (3.25%) in an acidic environment. The optimized formulation (F6) also possessed good spherical shape and particle size (57.42 um) required to achieve the desired in vitro drug release profile at pH 7.4. The results confirmed that human insulin loaded Eudragit S-100 microspheres containing protease inhibitor possessed good encapsulation efficiency, pH dependant controlled release carrying encapsulated insulin to its optimum site of absorption. This ultimately resulted in enhanced insulin absorption and biological response. PMID- 28864916 TI - Effects of transcranial direct current stimulation on the auditory mismatch negativity response and working memory performance in schizophrenia: a pilot study. AB - Cognitive impairment has been proposed to be the core feature of schizophrenia (Sz). Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation which can improve cognitive function in healthy participants and in psychiatric patients with cognitive deficits. tDCS has been shown to improve cognition and hallucination symptoms in Sz, a disorder also associated with marked sensory processing deficits. Recent findings in healthy controls demonstrate that anodal tDCS increases auditory deviance detection, as measured by the brain-based event-related potential, mismatch negativity (MMN), which is a putative biomarker of Sz that has been proposed as a target for treatment of Sz cognition. This pilot study conducted a randomized, double-blind assessment of the effects of pre- and post-tDCS on MMN-indexed auditory discrimination in 12 Sz patients, moderated by auditory hallucination (AH) presence, as well as working memory performance. Assessments were conducted in three sessions involving temporal and frontal lobe anodal stimulation (to transiently excite local brain activity), and one control session involving 'sham' stimulation (meaning with the device turned off, i.e., no stimulation). Results demonstrated a trend for pitch MMN amplitude to increase with anodal temporal tDCS, which was significant in a subgroup of Sz individuals with AHs. Anodal frontal tDCS significantly increased WM performance on the 2-back task, which was found to positively correlate with MMN-tDCS effects. The findings contribute to our understanding of tDCS effects for sensory processing deficits and working memory performance in Sz and may have implications for psychiatric disorders with sensory deficits. PMID- 28864918 TI - Ingwenascaris n. g. (Nematoda: Ascaridida: Heterocheilidae) established for I. sprenti n. sp. and I. assymmetrica (Ortlepp, 1932) n. comb., parasites of African crocodiles, and an identification key to the genera of the Heterocheilidae. AB - Ingwenascaris n. g. (Nematoda: Heterocheilidae) is established to accommodate Ingwenascaris sprenti n. g., n. sp., described from the stomach of Crocodylus niloticus Laurenti (Reptilia: Crocodylidae) in South Africa, based on light and scanning electron microscopy studies of its morphology. The new genus can be distinguished from other heterocheilid genera through a combination of its characters, including the pronounced asymmetry of each subventral lip due to an alate ventral margin and a non-alate margin facing the dorsal lip, the presence of continuous ridges of triangular denticles along the free labial margins, the lack of interlocking processes or a rostral plate, interlabia being indistinct or represented by small lateral interlabia between the dorsal and ventral lips only, the absence of prominent interlabial longitudinal cuticular ridges, the presence of lateral alae that are fused with the subventral lips, the presence of lateral caudal alae in both sexes, spicules of males that are composed of handle and alate blade, the presence of a gubernaculum, the number and arrangement of male caudal papillae and the position of the vulva near the anterior and middle third of the body in females. Ingwenascaris sprenti n. g., n. sp. represents the sixth heterocheilid genus parasitising African crocodilians. Trispiculascaris assymmetrica (Ortlepp, 1932) (syn. Porrocaecum assymmetricum Ortlepp, 1932) from a Central African crocodile is transferred to the new genus as I. assymmetrica (Ortlepp, 1932) n. comb. The genus Trispiculascaris Skrjabin, 1916 is considered a genus incertae sedis. An identification key to the genera of the family Heterocheilidae is presented. PMID- 28864919 TI - Electrochemical treatment of penicillin, cephalosporin, and fluoroquinolone antibiotics via active chlorine: evaluation of antimicrobial activity, toxicity, matrix, and their correlation with the degradation pathways. AB - Antibiotics are pharmaceuticals widely consumed and frequently detected in environmental water, where they can induce toxic effects and development of resistant bacteria. Their structural variety makes the problem of antibiotics in natural water more complex. In this work, six highly used antibiotics (at 40 MUmol L-1) belonging to three different classes (penicillins, cephalosporins, and fluoroquinolones) were treated using an electrochemical system with a Ti/IrO2 anode and a Zr cathode in the presence of NaCl (0.05 MUmol L-1). The attack of electrogenerated active chlorine was found to be the main degradation route. After only 20 min of treatment, the process decreased more than 90% of the initial concentration of antibiotics, following the degradation order: fluoroquinolones > penicillins > cephalosporins. The primary interactions of the degrading agent with fluoroquinolones occurred at the cyclic amine (i.e., piperazyl ring) and the benzene ring. Meanwhile, the cephalosporins and penicillins were initially attacked on the beta-lactam and sulfide groups. However, the tested penicillins presented an additional reaction on the central amide. In all cases, the transformations of antibiotics led to the antimicrobial activity decreasing. On the contrary, the toxicity level showed diverse results: increasing, decreasing, and no change, depending on the antibiotic type. In fact, due to the conservation of quinolone nucleus in the fluoroquinolone by-products, the toxicity of the treated solutions remained unchanged. With penicillins, the production of chloro-phenyl-isoxazole fragments increased the toxicity level of the resultant solution. However, the opening of beta-lactam ring of cephalosporin antibiotics decreased the toxicity level of the treated solutions. Finally, the application of the treatment to synthetic hospital wastewater and seawater containing a representative antibiotic showed that the high amount of chloride ions in seawater accelerates the pollutant degradation. In contrast, the urea and ammonium presence in the hospital wastewater retarded the removal of this pharmaceutical. PMID- 28864920 TI - Discovery of mutations in homologous recombination genes in African-American women with breast cancer. AB - African-American women are more likely to develop aggressive breast cancer at younger ages and experience poorer cancer prognoses than non-Hispanic Caucasians. Deficiency in repair of DNA by homologous recombination (HR) is associated with cancer development, suggesting that mutations in genes that affect this process may cause breast cancer. Inherited pathogenic mutations have been identified in genes involved in repairing DNA damage, but few studies have focused on African Americans. We screened for germline mutations in seven HR repair pathway genes in DNA of 181 African-American women with breast cancer, evaluated the potential effects of identified missense variants using in silico prediction software, and functionally characterized a set of missense variants by yeast two-hybrid assays. We identified five likely-damaging variants, including two PALB2 truncating variants (Q151X and W1038X) and three novel missense variants (RAD51C C135R, and XRCC3 L297P and V337E) that abolish protein-protein interactions in yeast two hybrid assays. Our results add to evidence that HR gene mutations account for a proportion of the genetic risk for developing breast cancer in African-Americans. Identifying additional mutations that diminish HR may provide a tool for better assessing breast cancer risk and improving approaches for targeted treatment. PMID- 28864921 TI - Invasive Pulmonary Fungal Infections in Cystic Fibrosis. AB - Invasive pulmonary mycosis is after allergic bronchopulmonary aspergillosis (ABPA) a frequent and severe complication of CF lung disease. Among CF caregivers, there is an insecurity when and how to treat infections of the lung parenchyma caused by different fungi in patients with CF. This case series provides a multicenter experience on diagnostic, manifestation, and treatment of non-ABPA cases of pulmonary. Non-ABPA cases of pulmonary mycoses in patients with CF have been collected from the CF Centers in Berlin, Essen, Worms, Frankfurt (Germany), Leeds (UK), and Barcelona (Spain). Non-ABPA was defined as total serum IgE level <500 kU/L. Scedosporium and Lomentospora species seem to be more virulent in patients with CF and have been successfully treated with triple antifungal drug regimens in several cases. Rare fungi including yeasts can have pathogenic potential in CF. In this series, antibiotic treatment failure was the main indicator for the initiation of antifungal treatment. For an early and effective treatment of pulmonary mycoses in CF, the identification of biomarkers and of risk factors beyond antibiotic treatment failure is crucial and urgently needed. Furthermore, treatment efficacy studies are necessary for the different causative agents of these infections. PMID- 28864922 TI - A phase I, randomized, single-dose study evaluating the pharmacokinetic equivalence of biosimilar ABP 215 and bevacizumab in healthy adult men. AB - PURPOSE: This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 215 with bevacizumab in healthy males. METHODS: In this randomized, single-blind, single-dose, three-arm, parallel-group study, healthy subjects were randomized to receive ABP 215 (n = 68), bevacizumab (US) (n = 67), or bevacizumab (EU) (n = 67) 3 mg/kg intravenously. Primary endpoints were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (C max). Secondary endpoints included safety and immunogenicity. RESULTS: AUCinf and C max were similar across the three groups. Geometric means ratio (GMR) for C max and AUCinf, respectively, was 0.98 and 0.99 for ABP 215 versus bevacizumab (US); 1.03 and 0.96 for ABP 215 versus bevacizumab (EU); and 1.05 and 0.97 for bevacizumab (US) versus bevacizumab (EU). The 90% confidence intervals for the GMRs of AUCinf and C max were within the prespecified standard PK bioequivalence criteria of 0.80 to 1.25. The incidence of adverse events (AEs) was 47.1, 32.8, and 61.2% in the ABP 215, bevacizumab (US) and bevacizumab (EU) groups, respectively. When analyzed by investigational site, the incidence and severity of AEs were comparable in the ABP 215 and bevacizumab groups. There were no AEs leading to study discontinuation. No binding or neutralizing anti-drug anti-bodies was detected. CONCLUSIONS: This study demonstrated the PK similarity of ABP 215 to both bevacizumab (US) and bevacizumab (EU), and of bevacizumab (US) to bevacizumab (EU). Safety and tolerability were comparable between treatments and no subject developed binding or neutralizing anti-drug anti-bodies. PMID- 28864923 TI - Evaluation of carbon dioxide laser therapy for benign tumors of the eyelid margin. AB - Eyelid margin tumors require special attention based on both anatomical and histological perspectives. Our aim in this study was to evaluate carbon dioxide (CO2) laser therapy for the treatment of eyelid margin tumors. Fifty-two patients with 55 eyelid margin tumors were included in this study. All tumors were removed with a CO2 laser, and histopathological evaluation was obtained in 52 cases. All patients were followed up for a mean period of 8.5 months (range 6 to 14 months). There were no bleedings in the intra- and postoperative period; the wounds were dry and reepithelized after 10-14 days and no recurrence occurred during follow up period. Compared to the surrounding tissue, the treated area was hypopigmented and maximum five eyelashes (average 2.5) were wasted during the procedure. We achieved complete patient and surgeon satisfaction with cosmetic and therapeutic results. CO2 laser treatment of eyelid margin is a safe and effective procedure; its cosmetic result is beneficial as it does not cause malposition of the eyelid or damage to the lacrimal drainage system if the tumor is located in its proximity. PMID- 28864925 TI - Colored noise and a stochastic fractional model for correlated inputs and adaptation in neuronal firing. AB - High variability in the neuronal response to stimulations and the adaptation phenomenon cannot be explained by the standard stochastic leaky integrate-and fire model. The main reason is that the uncorrelated inputs involved in the model are not realistic. There exists some form of dependency between the inputs, and it can be interpreted as memory effects. In order to include these physiological features in the standard model, we reconsider it with time-dependent coefficients and correlated inputs. Due to its hard mathematical tractability, we perform simulations of it for a wide investigation of its output. A Gauss-Markov process is constructed for approximating its non-Markovian dynamics. The first passage time probability density of such a process can be numerically evaluated, and it can be used to fit the histograms of simulated firing times. Some estimates of the moments of firing times are also provided. The effect of the correlation time of the inputs on firing densities and on firing rates is shown. An exponential probability density of the first firing time is estimated for low values of input current and high values of correlation time. For comparison, a simulation-based investigation is also carried out for a fractional stochastic model that allows to preserve the memory of the time evolution of the neuronal membrane potential. In this case, the memory parameter that affects the firing activity is the fractional derivative order. In both models an adaptation level of spike frequency is attained, even if along different modalities. Comparisons and discussion of the obtained results are provided. PMID- 28864924 TI - Cardiovascular disease mortality among women with endometrial cancer in the Iowa Women's Health Study. AB - PURPOSE: Obesity is associated with endometrial cancer (EC) development and cardiovascular disease (CVD) mortality. As the number of obese EC survivors continues to increase, an examination of CVD mortality in this vulnerable population is warranted. METHODS: In the Iowa Women's Health Study (1986-2011), we examined CVD mortality among 552 women with EC compared with 2,352 age- and body mass index-matched women without EC (controls). Hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD mortality were estimated using multivariable adjusted Cox proportional hazards regression models stratified by an indicator for match set. RESULTS: Compared to controls, women with EC more often reported a history of diabetes, hypertension, and never smoking. Compared with controls, women with EC had lower CVD mortality (HR 0.75, 95% CI 0.56-0.99), and higher all cause mortality (HR 1.50, 95% CI 1.30-1.74). CONCLUSIONS: Although some CVD risk factors were more common in women with versus without EC, CVD mortality was lower among the former group. Additional well-adjusted analyses with larger study populations are needed to understand interactions between CVD risk factors with CVD mortality among EC survivors. The CVD risk factor profile of EC survivors warrants emphasis on cardiovascular health. PMID- 28864926 TI - In reply: Clinical supervision: what does it mean to be better? PMID- 28864927 TI - Cost analysis on the use of rituximab and calcineurin inhibitors in children and adolescents with steroid-dependent nephrotic syndrome. AB - BACKGROUND: Rituximab (RTX) is increasingly being used in place of calcineurin inhibitors (CNI) in pediatric patients with steroid-dependent nephrotic syndrome (SDNS). However, despite its favorable safety profile, its unit cost is prohibitive. We therefore compared the healthcare costs associated with the use of both agents in a retrospective cohort. METHODS: This study was a retrospective analysis of data retrieved from the medical charts and electronic databases of pediatric patients (age range 2-18 years) with SDNS who were treated with either CNI or RTX from January 2008 to December 2012 at Children's Hospital of New Orleans, Louisiana. The minimum follow-up period was 12 months. RESULTS: Of the 18 patients whose medical data were analyzed, ten received RTX and eight were treated with CNI. The annualized healthcare cost for the rituximab group was $197,031 versus $189,857 (all values in US dollars) for the CNI group (p > 0.05). At the 12-month follow-up, more patients in the RTX group were in remission (40 vs. 25%). Duration of freedom from steroid use was longer in the RTX group, while body mass index was higher in the CNI arm (p > 0.05). No significant adverse events occurred in either group. CONCLUSION: The expenditure for the RTX and CNI groups was comparable, but there were fewer clinical encounters in the former group, potentially reducing the burden of healthcare on the patient's family. PMID- 28864928 TI - Effects of cholesterol, C-reactive protein, and interleukin-6 on prostate cancer risk in a population of African ancestry. AB - PURPOSE: To investigate the association between serum cholesterol and prostate cancer and whether any effect may be mediated through inflammatory markers. METHODS: Data from a case-control study of 40-80 years old Jamaican male patients (229 cases; 252 controls) were used. Cases had incident histologically-confirmed prostate cancer and controls were men with normal digital rectal examination and prostate-specific antigen (PSA) < 4 MUg/L or free: total PSA > 0.15 obtained from the same clinic. Total and HDL cholesterol, interleukin-6 (IL-6), and C-reactive protein (CRP) were measured from a non-fasting sample. Multivariable logistic regression models were used to evaluate the associations between these factors and prostate cancer, adjusting for age, body mass index, waist circumference, family history of prostate cancer, diabetes, hypertension, use of cholesterol lowering drugs, and smoking. RESULTS: Total cholesterol [Mean (cases, 4.71 +/- 1.07; controls, 4.64 +/- 1.07 mmol/L)], CRP [median (cases, 2.11; controls, 2.09 ug/ml)], and IL-6: [median (cases, 3.34; controls, 3.24 pg/ml)] did not differ by PCA status. Higher total cholesterol was associated with an increased risk of low grade disease after adjusting for potential confounders [multivariable-adjusted OR (95% CI): tertile 2: 3.32(1.66, 6.45), tertile 3: 2.14(1.07, 4.32)]. Total cholesterol was unrelated to overall prostate cancer or high-grade disease. There was no significant association between HDL cholesterol or any of the inflammatory markers with prostate cancer. CONCLUSIONS: Increasing total cholesterol but not inflammatory markers were associated with low-grade prostate cancer in Caribbean men. PMID- 28864929 TI - Antibiotic resistance genes in an urban river as impacted by bacterial community and physicochemical parameters. AB - Antibiotic resistance genes (ARGs) in urban rivers are a serious public health concern in regions with poorly planned, rapid development. To gain insights into the predominant factors affecting the fate of ARGs in a highly polluted urban river in eastern China, a total of 285 ARGs, microbial communities, and 20 physicochemical parameters were analyzed for 17 sites. A total of 258 unique ARGs were detected using high-throughput qPCR, and the absolute abundance of total ARGs was positively correlated with total organic carbon and total dissolved nitrogen concentrations (P < 0.01). ARG abundance and diversity were greatly altered by microbial community structure. Variation partitioning analysis showed that the combined effects of multiple factors contributed to the profile and dissemination of ARGs, and variation of microbial communities was the major factor affecting the distribution of ARGs. The disparate distribution of some bacteria, including Bacteroides from mammalian gastrointestinal flora, Burkholderia from zoonotic infectious diseases, and Zoogloea from wastewater treatment, indicates that the urban river was strongly influenced by point-source pollution. Results imply that microbial community shifts caused by changes in water quality may lead to the spread of ARGs, and point-source pollution in urban rivers requires greater attention to control the transfer of ARGs between environmental bacteria and pathogens. PMID- 28864930 TI - Contemporary epidemiology and novel predictors of uterine rupture: a nationwide population-based study. AB - PURPOSE: In spite of several policies aiming to decrease cesarean rates and related complications such as uterine rupture, data show that uterine rupture and associated morbidity are increasing along the years. Whether previously unidentified risk factors are currently playing an important role on these trends is unknown. We analyze current risks of uterine rupture and main preceding factors from more recent years compared to former data. METHODS: All uterine rupture cases in the US from 2011-2012 were selected, with matched non-uterine rupture cases selected as controls. Variables considered for analysis included demographics, maternal morbidity, and obstetric complications. Likelihood forward selection was used to identify main risk factors of uterine rupture. Medians of main factors identified were used to simulate groups at risk and calculate odds ratios of uterine rupture. RESULTS: From ~8 million births, 1925 presented uterine rupture. In patients with no prior cesarean delivery, multiple gestation, chronic hypertension and chorioamnionitis presented the highest odds of uterine rupture, with the combination of these factors increasing the odds of rupture 59 times (~1%). In women with prior cesarean delivery, induction/augmentation and chorioamnionitis were the most significant predictors, with the combination increasing the odds 33 times (~3%). CONCLUSIONS: Despite policies implemented and changes in clinical practice, uterine rupture remains an important issue. Previously unidentified risk factors are playing now an important role, information that should be considered during patient counseling and clinical practice. Combinations of some of these factors may increase the risk of uterine rupture significantly enough to modify clinical care. PMID- 28864931 TI - Bone metastases from breast cancer: associations between morphologic CT patterns and glycolytic activity on PET and bone scintigraphy as well as explorative search for influential factors. AB - BACKGROUND: This study aimed to compare the detection of bone metastases from breast cancer on F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and bone scintigraphy (BS). An explorative search for factors influencing the sensitivity or uptake of BS and FDG-PET was also performed. METHODS: Eighty-eight patients with bone metastases from breast cancer were eligible for this study. Histological confirmation of bone metastases was obtained in 31 patients. The bone metastases were visually classified into four types based on their computed tomography (CT) appearance: osteoblastic, osteolytic, mixed, and negative. The sensitivity of BS and FDG-PET were obtained regarding CT type, adjuvant therapy, and the primary tumor characteristics. The FDG maximum standardized uptake value (SUVmax) was analyzed. RESULTS: The sensitivities of the three modalities (CT, BS, and FDG-PET) were 77, 89, and 94%, respectively. The sensitivity of FDG-PET for the osteoblastic type (69%) was significantly lower than that for the other types (P < 0.001), and the sensitivity of BS for the negative type (70%) was significantly lower than that for the others. Regarding tumor characteristics, the sensitivity of FDG-PET significantly differed between nuclear grade (NG)1 and NG2-3 (P = 0.032). The SUVmax of the osteoblastic type was significantly lower than that of the other types (P = 0.009). The SUVmax of NG1 was also significantly lower than that of NG2-3 (P = 0.011). No significant difference in FDG uptake (SUVmax) was detected between different histological types. CONCLUSION: Although FDG-PET is superior to BS for the detection of bone metastases from breast cancer, this technique has limitations in depicting osteoblastic bone metastases and NG1. PMID- 28864933 TI - Cigarette smoking in Austria - a call for action. PMID- 28864932 TI - Perceived Intensity of Emotional Point-Light Displays is Reduced in Subjects with ASD. AB - One major characteristic of autism spectrum disorder (ASD) is problems with social interaction and communication. The present study explored ASD-related alterations in perceiving emotions expressed via body movements. 16 participants with ASD and 16 healthy controls observed video scenes of human interactions conveyed by point-light displays. They rated the valence of the depicted emotions in terms of their intensity and judged their confidence in their ratings. Results showed that healthy participants rated emotional interactions displaying positive emotionality as being more intense and were more confident about their ratings than ASD subjects. Results support the idea that patients with ASD have an altered perception of emotions. This extends research on subjective features (intensity, confidence) of emotion perception to the domain of emotional body movements and kinematics. PMID- 28864935 TI - Program and Abstracts of the 14th Transgenic Technology Meeting (TT2017) : Snowbird Resort, Salt Lake City, Utah, USA, 1-4 October 2017. PMID- 28864936 TI - A Case of Cutaneous Mycosis Caused by Scedosporium dehoogii on an Immunocompromised Patient. AB - This report describes a 77-year-old man with cutaneous mycosis caused by Scedosporium dehoogii while taking oral betamethasone and tacrolimus for the treatment of rheumatoid arthritis. At examination in our clinic, the patient had multiple cystic lesions and nodules with slight tenderness, varying in size up to 4 cm, on his left knee and shin. He had not noticed any traumatic injury at the site of the lesions. Fungal cultures of samples taken from the abscesses, scales, and crusts of the lesions yielded white, later grayish brown, fluffy surfaced colonies. Partial sequencing of the beta-tubulin gene confirmed the species of the isolate. The patient was initially treated with oral voriconazole and local hyperthermia, but experienced hepatic injury 2 weeks later. His treatment was changed to itraconazole (ITC) and local hyperthermia, followed by a combination of ITC and terbinafine. The patient recovered completely during the 12-month course of treatment. PMID- 28864934 TI - Gene therapy for chondral and osteochondral regeneration: is the future now? AB - Gene therapy might represent a promising strategy for chondral and osteochondral defects repair by balancing the management of temporary joint mechanical incompetence with altered metabolic and inflammatory homeostasis. This review analysed preclinical and clinical studies on gene therapy for the repair of articular cartilage defects performed over the last 10 years, focussing on expression vectors (non-viral and viral), type of genes delivered and gene therapy procedures (direct or indirect). Plasmids (non-viral expression vectors) and adenovirus (viral vectors) were the most employed vectors in preclinical studies. Genes delivered encoded mainly for growth factors, followed by transcription factors, anti-inflammatory cytokines and, less frequently, by cell signalling proteins, matrix proteins and receptors. Direct injection of the expression vector was used less than indirect injection of cells, with or without scaffolds, transduced with genes of interest and then implanted into the lesion site. Clinical trials (phases I, II or III) on safety, biological activity, efficacy, toxicity or bio-distribution employed adenovirus viral vectors to deliver growth factors or anti-inflammatory cytokines, for the treatment of osteoarthritis or degenerative arthritis, and tumour necrosis factor receptor or interferon for the treatment of inflammatory arthritis. PMID- 28864937 TI - Meta-analysis of randomised trials comparing the use of prophylactic mesh to standard midline closure in the reduction of incisional herniae. AB - : Purpose Incisional hernia (IH) is common complication following laparotomy. Research suggests that the use of a prophylactic mesh can reduce the rate of IH. We performed an updated meta-analysis to better understand the evidence regarding prevention of IH using prophylactic mesh. METHODS: PubMed, clinictrials.gov.uk, and the Cochrane database were searched for randomised controlled trials comparing closure of the abdomen after laparotomy using a prophylactic mesh with suture closure. A meta-analysis was then performed. The primary outcome was the occurrence of IH. RESULTS: Eight studies were identified for inclusion in the meta-analysis with a total of 727 patients. PRIMARY OUTCOME: There was a significant reduction in the occurrence of IH in the mesh group vs. the suture repair group, OR 0.14 (95% CI 0.07-0.27). SECONDARY OUTCOMES: There was a significant increase in the number of seromas in the mesh group vs. the suture repair group, OR 1.73 (95% CI 1.04-2.87). There was also a significant increase in operative time in the mesh group vs. the suture repair group SMD 0.24 (95% CI 0.00-0.48). CONCLUSIONS: This meta-analysis found a reduction in the occurrence of IH after a laparotomy when a prophylactic mesh is used versus a suture repair. The majority of patients included in the studies were deemed to be at high risk of IH. There appears to be sufficient evidence to recommend the use of a prophylactic mesh during laparotomy in high-risk patients. PMID- 28864938 TI - Danish sperm donors and the ethics of donation and selection. AB - There has been a great deal of discussion about the ethical implications of donating sperm and of the ways in which donated tissue is presented, selected, and sold for use in assisted reproduction. Debates have emerged within the academic sphere, from donor offspring and recipients, and in broader popular culture, including questions about the commodification of human tissue and the eugenic potential of selecting donors from particular demographic categories. However, the voices of donors themselves on this subject have been largely silent. This paper draws on data from qualitative interviews with men who donated at a major Danish sperm bank between 2012 and 2013. It argues that many of them are indeed thinking through these complex issues. Donors' approaches to ethical issues fell into two broad 'types': a pragmatic, individualistic approach which focused on more immediate personal consequences, and an ethically-driven approach in which donors considered the impact of donation on offspring and on a wider societal level. PMID- 28864940 TI - Discussion of "Microsurgical Reconstruction Following Oncologic Resection in Pediatric Patients: A 15-Year Experience" by M. Starnes-Roubaud et al. PMID- 28864939 TI - Intravenous immunoglobulins for treatment of connective tissue diseases in dermatology. AB - BACKGROUND: Connective tissue diseases are a heterogeneous group of autoimmune disorders affecting not only skin, but also various organs and systems. First line treatment of connective tissue diseases is systemic steroids as monotherapy or combined with immunosuppressive drugs. Since intravenous immunoglobulins (IVIGs) have been found to be effective for various autoimmune dermatoses, their indications have expanded tremendously. OBJECTIVE: The aim this review article is to highlight the indications, effectiveness, and side effects of high doses immunoglobulins for treatment of patients with connective tissue diseases. METHODS: MEDLINE was searched for prospective clinical studies and case reports on IVIG treatment of lupus erythematosus, dermatomyositis, systemic sclerosis, and mixed connective tissue disease (MCTD). Included studies were analyzed and discussed in terms of the different disease entities. RESULTS AND CONCLUSION: IVIGs are a valuable alternative for treating therapy-resistant patients with lupus erythematosus, dermatomyositis, systemic sclerosis, or MCTD. However, more placebo-controlled clinical studies are needed to evaluate the exact indications and therapeutic regimens. PMID- 28864941 TI - Influence of diligent disintegration on anaerobic biomass and performance of microbial fuel cell. AB - OBJECTIVES: To enhance the performance of microbial fuel cells (MFC) by increasing the surface area of cathode and diligent mechanical disintegration of anaerobic biomass. RESULTS: Tannery effluent and anaerobic biomass were used. The increase in surface area of the cathode resulted in 78% COD removal, with the potential, current density, power density and coulombic efficiency of 675 mV, 147 mA m-2, 33 mW m-2 and 3.5%, respectively. The work coupled with increased surface area of the cathode with diligent mechanical disintegration of the biomass, led to a further increase in COD removal of 82% with the potential, current density, power density and coulombic efficiency of 748 mV, 229 mA m-2, 78 mW m-2 and 6% respectively. CONCLUSIONS: Mechanical disintegration of the biomass along with increased surface area of cathode enhances power generation in vertical MFC reactors using tannery effluent as fuel. PMID- 28864942 TI - A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects. AB - BACKGROUND: Mutations in the myosin heavy chain 7 (MYH7) gene commonly cause cardiomyopathy but are less frequently associated with congenital heart defects. METHODS: In this study, we describe a mutation in the MYH7 gene, c. 5754C > G; p. (Asn1918Lys), present in 15 probands and 65 family members. RESULTS: Of the 80 carriers (age range 0-88 years), 46 (57.5%) had cardiomyopathy (mainly dilated cardiomyopathy (DCM)) and seven (8.8%) had a congenital heart defect. Childhood onset of cardiomyopathy was present in almost 10% of carriers. However, in only a slight majority (53.7%) was the left ventricular ejection fraction reduced and almost no arrhythmias or conduction disorders were noted. Moreover, only one carrier required heart transplantation and nine (11.3%) an implantable cardioverter defibrillator. In addition, the standardised mortality ratio for MYH7 carriers was not significantly increased. Whole exome sequencing in several cases with paediatric onset of DCM and one with isolated congenital heart defects did not reveal additional known disease-causing variants. Haplotype analysis suggests that the MYH7 variant is a founder mutation, and is therefore the first Dutch founder mutation identified in the MYH7 gene. The mutation appears to have originated in the western region of the province of South Holland between 500 and 900 years ago. CONCLUSION: Clinically, the p. (Asn1918Lys) mutation is associated with congenital heart defects and/or cardiomyopathy at young age but with a relatively benign course. PMID- 28864943 TI - Two novel Alphaflexiviridae members revealed by deep sequencing of the Vanilla (Orchidaceae) virome. AB - The genomes of two novel viruses were assembled from 454 pyrosequencing data obtained from vanilla leaves from La Reunion. Based on genome organization and homologies, one agent was unambiguously classified as a member of the genus Potexvirus and named vanilla virus X (VVX). The second one, vanilla latent virus (VLV), is phylogenetically close to three unclassified members of the family Alphaflexiviridae with similarity to allexiviruses, and despite the presence of an additional 8-kDa open reading frame, we propose to include VLV as a new member of the genus Allexivirus. Both VVX and VLV were mechanically transmitted to vanilla plants, resulting in asymptomatic infections. PMID- 28864944 TI - Induction of antitumor response to fibrosarcoma by Newcastle disease virus infected tumor vaccine. AB - Fibrosarcoma is a locally aggressive malignant tumor with a high recurrence rate, so that wide excisional surgery is necessary for treatment. However, it is often difficult to resect with a sufficient margin of excision at the site of tumor infiltration. Recombinant tumor vaccine therapy is a useful method to induce specific immunity. In this study, we have shown its utility as a candidate for therapy by applying a recombinant Newcastle disease virus (rNDV) tumor vaccine (rNDV-TV). Although the therapeutic effect of similar viruses has been examined in several tumors, the vaccination efficacy against fibrosarcoma has not been demonstrated until now. In this study, we showed the induction of an antitumor response by rNDV-TV against murine fibrosarcoma and investigated the role of lymphocytes in tumor elimination. Intraperitoneal inoculation of murine fibrosarcoma (WEHI164) cells showed increased lethality in C.B.17scid/scid (scid) mice within 2 weeks of inoculation. The survival rate increased to 80% when the mice were transfused with CD3+ cells from BALB/c mice previously immunized with rNDV-TV. However, all mice died from tumor growth after inoculation with non immunized CD3+ cells. Although the survival rate was around 50% in mice receiving only immunized CD4+ and CD8+ cells, the survival rate was not decreased in mice receiving CD3+CD4-CD8- (natural killer T; NKT) cells together with immunized CD4+ and CD8+ cells. This study showed rNDV-TV induced an antitumor T cell response to WEHI164 cells, and major subsets of cells involved in tumor exclusion were CD4+ and CD8+ cells, together with NKT cells. PMID- 28864945 TI - Fecal microbiota of lambs fed purple prairie clover (Dalea purpurea Vent.) and alfalfa (Medicago sativa). AB - The present study assessed the effect of purple prairie clover (PPC) and PPC condensed tannins (CT) on the fecal microbiota of lambs using high-throughput 16S rRNA gene pyrosequencing. A total of 18 individual lambs were randomly divided into three groups and fed either green chop alfalfa (Alf), a 40:60 (DM basis; Mix) mixture of Alf and PPC, or Mix supplemented with polyethylene glycol (Mix-P) for 18 days. Fecal samples were collected on days 13 through 18 using digital rectal retrieval. The DNA of fecal samples was extracted and the microbial 16S rRNA gene amplicons were sequenced using 454 pyrosequencing. Regardless of diet, the bacterial community was dominated by Firmicutes and Bacteroidetes with many sequences unclassified at the genus level. Forage type and CT had no effect on the fecal microbial composition at the phylum level or on alpha-diversity. Compared to the Alf diet, the Mix diet reduced the relative abundance of Akkermansia (P = 0.03) and Asteroleplasma (P = 0.05). Fecal microbial populations in Alf and Mix-P clustered separately from each other when assessed using unweighted UniFrac (P < 0.05). These results indicate that PPC CT up to 36 g/kg DM in the diet had no major effect on fecal microbial flora at the phyla level and exerted only minor effects on the genera composition of fecal microbiota in lambs. PMID- 28864946 TI - TMDIM: an improved algorithm for the structure prediction of transmembrane domains of bitopic dimers. AB - [Formula: see text]-Helical transmembrane proteins are the most important drug targets in rational drug development. However, solving the experimental structures of these proteins remains difficult, therefore computational methods to accurately and efficiently predict the structures are in great demand. We present an improved structure prediction method TMDIM based on Park et al. (Proteins 57:577-585, 2004) for predicting bitopic transmembrane protein dimers. Three major algorithmic improvements are introduction of the packing type classification, the multiple-condition decoy filtering, and the cluster-based candidate selection. In a test of predicting nine known bitopic dimers, approximately 78% of our predictions achieved a successful fit (RMSD <2.0 A) and 78% of the cases are better predicted than the two other methods compared. Our method provides an alternative for modeling TM bitopic dimers of unknown structures for further computational studies. TMDIM is freely available on the web at https://cbbio.cis.umac.mo/TMDIM . Website is implemented in PHP, MySQL and Apache, with all major browsers supported. PMID- 28864947 TI - Immortal time bias in pharmacoepidemiological studies on cancer patient survival: empirical illustration for beta-blocker use in four cancers with different prognosis. AB - Immortal time bias (ITB) is still seen frequently in medical literature. However, not much is known about this bias in the field of cancer (pharmaco-)epidemiology. In context of a hypothetical beneficial beta-blocker use among cancer patients, we aimed to demonstrate the magnitude of ITB among 9876 prostate, colorectal, lung and pancreatic cancer patients diagnosed between 1998 and 2011, which were selected from a database linkage of the Netherlands Cancer Registry and the PHARMO Database Network. Hazard ratios (HR) and 95% confidence intervals from three ITB scenarios, defining exposure at a defined point after diagnosis (model 1), at any point after diagnosis (model 2) and as multiple exposures after diagnosis (model 3), were calculated to investigate the association between beta blockers and cancer prognosis using Cox proportional hazards regression. Results were compared to unbiased estimates derived from the Mantel-Byar model. Ignoring ITB led to substantial smaller HRs for beta-blocker use proposing a significant protective association in all cancer types [e.g. HR 0.18 (0.07-0.43) for pancreatic cancer in model 1], whereas estimates derived from the Mantel-Byar model were mainly suggesting no association [e.g. HR 1.10 (0.84-1.44)]. The magnitude of bias was consistently larger among cancer types with worse prognosis [overall median HR differences between all scenarios in model 1 and Mantel-Byar model of 0.56 (prostate), 0.72 (colorectal), 0.77 (lung) and 0.85 (pancreas)]. In conclusion, ITB led to spurious beneficial associations of beta-blocker use among cancer patients. The magnitude of ITB depends on the duration of excluded immortal time and the prognosis of each cancer. PMID- 28864948 TI - Building Community Partnerships: Using Social Network Analysis to Strengthen Service Networks Supporting a South Carolina Program for Pregnant and Parenting Teens. AB - In 2013, South Carolina implemented a multi-year program providing support services for pregnant and parenting teens. Local lead sites were responsible for coordinating service delivery in partnership with other multidisciplinary community-based organizations. We used social network theory and analyses (SNA) to examine changes in partnerships over time. Using two-stage purposeful sampling, we identified three lead sites and their self-reported community partners. We administered two web-based surveys grounded in social network theory that included questions about partnership relationships and organizational characteristics. We calculated selected whole-network measures (size, cohesion, equity, diversity). Following the Year 1 surveys, we reviewed our findings with the lead sites and suggested opportunities to strengthen their respective partnerships. Following the Year 3 surveys, we observed changes across the networks. Survey response rates were 91.5% (43/47) in Year 1 and 68.2% (45/66) in Year 3. By Year 3, the average network size increased from 15.6 to 20.3 organizations. By Year 3, one lead site doubled its measure of network cohesion (connectedness); another lead site doubled in size (capacity). A third lead site, highly dense in Year 1, increased in size but decreased in cohesion by Year 3. Innovative use of SNA findings can help community partnerships identify gaps in capacity or services and organizations needed to fulfill program aims. SNA findings can also improve partnership function by identifying opportunities to improve connectedness or reduce redundancies in program work. The ability of lead sites to strategically reconfigure partnerships can be important to program success and sustainability. PMID- 28864949 TI - Skeletal muscle mitochondrial mass is linked to lipid and metabolic profile in individuals with spinal cord injury. AB - PURPOSE: Changes in metabolism and body composition after spinal cord injury (SCI) predispose individuals to obesity, type II diabetes, and cardiovascular disease. A link between lean mass and skeletal muscle mitochondrial mass has been reported but it is unknown how skeletal muscle mitochondrial mass and activity impact metabolic health. This study examined the relationship between skeletal muscle mitochondrial mass, activity and metabolic profile in individuals with chronic SCI. METHODS: Twenty-two men with motor complete SCI participated in the study. Citrate synthase (CS) and complex III (CIII) activity was measured in vastus lateralis biopsies. Metabolic profile was assessed by intravenous glucose tolerance test, basal metabolic rate (BMR), maximum oxygen uptake (VO2 peak) and blood lipid profile. RESULTS: Skeletal muscle CS activity was negatively related to the cholesterol:high density lipoprotein cholesterol (HDL-C) ratio and triglycerides (r = -0.60, p = 0.009; r = -0.64, p = 0.004, respectively). CS activity was positively related to insulin sensitivity and BMR (r = 0.67, p = 0.006; r = 0.64, p = 0.005, respectively). Similar relationships were found for CIII and metabolic profile, but not CIII normalized to CS. Many of the relationships between CS and metabolism remained significant when age, level of injury, or time since injury were accounted for. They also remained significant when CS activity was normalized to total lean mass. CONCLUSIONS: These results suggest that an increase in skeletal muscle mitochondrial mass is associated with improved metabolic health independent of age, level of injury, or time since injury in individuals with chronic SCI. This highlights the importance of maintaining and improving mitochondrial health in individuals with SCI. PMID- 28864950 TI - Correlation of early PET findings with tumor response to molecular targeted agents in patients with advanced driver-mutated non-small cell lung cancer. AB - Recent advances in positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) have facilitated not only the diagnosis and staging of lung cancer, but also the prediction of treatment outcome. The present study was designed to assess the usefulness of early FDG-PET examination for predicting subsequent tumor size reduction in response to molecular targeted agents in metastatic non-small cell lung cancer (NSCLC) with sensitive gene anomalies. I. In 29 targeted lesions of 10 NSCLC patients, changes in FDG uptake before and on day 7 after the initiation of molecular targeted therapy (gefitinib, n = 7; crizotinib, n = 3) were compared with subsequent radiographic tumor size reduction by RECIST. FDG uptake was evaluated as the maximum standardized uptake value (SUVmax) of each targeted lesion. SUVmax decreased in all lesions after therapy (mean SUVmax 8.3 +/- 3.4 before to 3.7 +/- 1.8 after therapy, p < 0.05). The % decrease in SUVmax of each lesion was significantly correlated with the % tumor size reduction (r = 0.44). In addition, the reduction rate of SUVmax in metastatic bone lesions after initiation of molecular targeted therapy was significantly lower than that in targeted organs (27.1 +/- 27.5 vs. 51.2 +/- 21.3%, respectively, p < 0.05). Early reduction in FDG-PET uptake after initiation of molecular targeted agents was able to predict subsequent tumor reduction in patients harboring EGFR-mutated or ALK-positive NSCLC. In addition, nontargeted bone metastasis may have different glucose metabolism after TKI treatment compared with other involved organs. PMID- 28864952 TI - Transitions from Assertive Community Treatment Among Urban and Rural Teams: Identifying Barriers, Service Options, and Strategies. AB - An emerging focus of Assertive Community Treatment (ACT) teams is the transition of clients to less intensive services, which creates space for individuals in need of ACT and is consistent with a recovery orientation of treatment. However, there is limited research on team transition rates, post-ACT services, and strategies to overcome transition barriers. In addition, few studies have examined differences in these factors among urban and rural ACT teams. To address these knowledge gaps, we interviewed eight ACT teams in urban and rural areas of eastern Ontario regarding their transition rates, processes of transitioning ACT clients to less intensive services, transition barriers, and solutions to overcoming these barriers. On average, teams transitioned about 6% of their clients over our 3-year study period. Urban and rural teams described both similar and distinct clinical and systemic barriers, such as client reluctance to transition and finding psychiatric follow-up outside of ACT. Implications for ACT practice and policy are discussed. PMID- 28864951 TI - Time course of cellular HIV-DNA and low-level HIV viremia in HIV-HCV co-infected patients whose HCV infection had been successfully treated with directly acting antivirals. AB - This longitudinal study described cellular HIV-DNA changes and their correlation with HIV low-level plasma viremia (LLV) in HIV-HCV co-infected patients on successful antiretroviral and anti-HCV therapy by treatment with direct-acting antivirals (DAA). Thirty-nine patients were examined prior to the start of DAA (T0), after week 12 (T1) and 24 weeks (T2) of anti-HCV therapy. Cellular PBMC HIV DNA was analysed as an absolute value and as the percentage of increase or decrease from T0 to T2. Patients were classified as having undetectable plasma HIV viraemia (UV) or LLV in the year before the start of anti-HCV treatment and within the T0-T2 study period. Thirty-five patients (89.7%) of the 39 subjects enrolled had the same plasma HIV viraemia control in the year before HCV treatment and in the T0-T2 interval. The HIV-DNA value at T0 and at T2 was higher in patients with LLV than in subjects with UV (p = 0.015 and p = 0.014, respectively). A similar proportion of patients with LLV and UV experienced an increase or decrease of HIV-DNA from T0 to T2. The percentage increase in HIV-DNA value (262.8%) from T0 to T2 was higher compared to the decrease (43.5%) in patients with UV (p = 0.012), and it was higher compared to the percentage increase in HIV-DNA value reported in subjects with LLV (262.8 versus 49%, p = 0.026). HIV-HCV co-infected patients experienced a multifaceted perturbation of cellular HIV-DNA levels within a 24-week period during anti-HCV treatment; the extent of the phenomenon was greater in subjects with UV. Fast HCV-RNA clearance seemed to have a greater influence on the cellular reservoir than on plasma HIV RNA. PMID- 28864953 TI - Monitoring of genetically modified Escherichia coli in laboratory wastewater. AB - Containment of genetically modified (GM) microorganisms such as Escherichia coli is a legal requirement to protect the environment from an unintended release and to avoid horizontal gene transfer (HGT) of recombinant DNA to native bacteria. In this study, we sampled the laboratory wastewater (LWW) at a large Swiss university from three sources over 2 years and cultured ampicillin-resistant, presumptive GM E. coli. From a total of 285 samples, 127 contained presumptive GM E. coli (45%) at a mean concentration of 2.8 * 102 CFU/ml. Plasmid DNA of 11 unique clones was partially or entirely sequenced. All consisted of cloning vectors harboring research-specific inserts. To estimate the chance of HGT between GM E. coli and native bacteria in LWW, we identified taxa representative for the bacterial community in LWW using 16S rRNA amplicon sequencing and measured conjugation frequencies of E. coli with five LWW isolates. At optimal conjugation conditions, frequencies were between 3.4 * 10-3 and 2.4 * 10-5. Given the absence of transferable broad-host range plasmids and suboptimal conjugation conditions in the LWW system, we conclude that the chance of HGT is relatively low. Still, this study shows that the implementation of robust containment measures is key to avoid the escape of GM microorganisms. PMID- 28864954 TI - Comparison of the Trace Elements and Active Components of Lonicera japonica flos and Lonicera flos Using ICP-MS and HPLC-PDA. AB - Thirteen trace elements and active constituents of 40 batches of Lonicera japonica flos and Lonicera flos were comparatively studied using inductively coupled plasma mass-spectrometry (ICP-MS) and high-performance liquid chromatography-photodiode array (HPLC-PDA). The trace elements were 24Mg, 52Cr, 55Mn, 57Fe, 60Ni, 63Cu, 66Zn, 75As, 82Se, 98Mo, 114Cd, 202Hg, and 208Pb, and the active compounds were chlorogenic acid, 3,5-O-dicaffeoylquinc acid, 4,5-O dicaffeoylquinc acid, luteolin-7-O-glucoside, and 4-O-caffeoylquinic acid. The data of 18 variables were statistically processed using principal component analysis (PCA) and discriminate analysis (DA) to classify L. japonica flos and L. flos. The validated method was developed to divide the 40 samples into two groups based on the PCA in terms of 18 variables. Furthermore, the species of Lonicera was better discriminated by using DA with 12 variables. These results suggest that the method and statistical analysis of the contents of trace elements and chemical components can classify the L. japonica flos and L. flos using 12 variables, such as 3,5-O-dicaffeoylquincacid, luteolin-7-O-glucoside, Cd, Mn, Hg, Pb, Ni, 4-O-caffeoyl-quinic acid, 4,5-O-dicaffeoylquinc acid, Fe, Mg, and Cr. PMID- 28864956 TI - Overextended Personality Disorder is Epidemic in Academic Medical Centers: Proposed Criteria and Preliminary Treatment Suggestions. PMID- 28864955 TI - Laparoscopic extraperitoneal repair versus open inguinal hernia repair: 20-year follow-up of a randomized controlled trial. AB - PURPOSE: This study compared the long-term recurrence rates of laparoscopic totally extraperitoneal (TEP) and open inguinal hernia repair in patients from a randomised trial completed in 1994. Laparoscopic inguinal hernia surgery, especially TEP repair, has gained widespread acceptance in recent years. There is still paucity of data on long-term follow-up comparing recurrence rates for open and laparoscopic techniques. This is the first study providing direct long-term comparative data about these techniques. METHODS: A randomised controlled trial was conducted between 1992 and 1994 on patients undergoing a laparoscopic TEP or an open inguinal hernia (Shouldice) repair at our institution. Of the original 104 participants, contemporary follow-up data could be obtained for 98 patients with regards to long-term recurrence. These data were collected with the help of questionnaires, telephone calls and retrieval of case records. Medical records were reviewed for all patients. Data were analysed using a Cox proportional hazards model. RESULTS: There were 7/72 (9.7%) recurrences in the open group and 9/35 (25.7%) recurrences in the laparoscopic group. This difference in recurrence rates was statistically significant (HR = 2.94; 95% CI 1.05-8.25; p = 0.041.) CONCLUSION: Laparoscopic TEP inguinal hernia repair performed in 1992-1994 had a higher recurrence rate than open Shouldice inguinal hernia repair during the same period. The original study was undertaken in the inceptive days of laparoscopic surgery and results need to be interpreted considering the technology and expertise available at that time. PMID- 28864957 TI - Physical Activity and Nutrition INfluences In ageing (PANINI): consortium mission statement. PMID- 28864958 TI - Mathematical Modeling of Ischemia-Reperfusion Injury and Postconditioning Therapy. AB - Reperfusion (restoration of blood flow) after a period of ischemia (interruption of blood flow) can paradoxically place tissues at risk of further injury: so called ischemia-reperfusion injury or IR injury. Recent studies have shown that postconditioning (intermittent periods of further ischemia applied during reperfusion) can reduce IR injury. We develop a mathematical model to describe the reperfusion and postconditioning process following an ischemic insult, treating the blood vessel as a two-dimensional channel, lined with a monolayer of endothelial cells that interact (respiration and mechanotransduction) with the blood flow. We investigate how postconditioning affects the total cell density within the endothelial layer, by varying the frequency of the pulsatile flow and the oxygen concentration at the inflow boundary. We find that, in the scenarios we consider, the pulsatile flow should be of high frequency to minimize cellular damage, while oxygen concentration at the inflow boundary should be held constant, or subject to only low-frequency variations, to maximize cell proliferation. PMID- 28864959 TI - Transoral robotic-assisted surgery for the approach to anterior cervical spine lesions. AB - The Da Vinci robotic surgical system is increasingly being used by head and neck surgeons in transoral approaches for head and neck cancer. Our experience using the Da Vinci system for transoral robotic-assisted surgery (TORS) is presented. The feasibility of TORS for lesions involving the anterior portion of C1-C2 and the cranio-cervical junction has been evaluated from an anatomical viewpoint in a cadaveric laboratory. Two patients treated using the Da Vinci system to reach C1 C2 benign lesions are presented. The anatomical cadaveric study showed that this approach is safe and feasible. The first two cases which we describe confirmed the advantages of the Da Vinci system in the anterior approach to the cervical spine and allowed the limitations of this procedure to be assessed. TORS may be useful to reach anterior lesions of the cervical spine localized at the level of C1 and C2: first, for removal of small benign and well-delineated lesions; and second, for diagnostic purposes with biopsy of large lesions. Further studies and new instruments are needed to confirm the safety and results of this approach in terms of morbidity. PMID- 28864960 TI - Anoplodiscus Sonsino, 1890 (Monogenea: Anoplodiscidae): a new Australian species, and the first African record from South African hosts. AB - Species of Anoplodiscus Sonsino, 1890 were previously only known from host members of Sparidae. A new species, Anoplodiscus hutsonae n. sp. is proposed for museum specimens originally collected from species of Scolopsis Cuvier (Nemipteridae) off Heron Island and Lizard Island, Australia. Additionally, Anoplodiscus tai Ogawa, 1994 is synonymised with Anoplodiscus cirrusspiralis Roubal, Armitage & Rohde, 1983 due to a lack of support for differential characters, and Anoplodiscus richiardii is considered a species inquirenda. Anoplodiscus cirrusspiralis causes visible lesions on the skin and fins of its host, and may also contribute to poor food conversion rates in sparid aquaculture. Anoplodiscus cirrusspiralis has been recorded from cultured sparids in Australia, Japan, South Africa, and South Korea, and was implicated as a disease agent in fish from the former two countries. However, the discovery of A. cirrusspiralis on Chrysoblephus gibbiceps (Valenciennes), Ch. laticeps (Valenciennes) and Cymatoceps nasutus (Castelnau) in South Africa, ?Pagrus major (Temminck & Schlegel) in South Korea, and P. auratus (Forster) in Australia, New Zealand and Japan suggests that this species may have a wide distribution and low host-specificity within the Sparidae. In South Africa, A. cirrusspiralis was first encountered on a morbid C. nasutus and Ch. gibbiceps from two public aquaria in 2009 (Two Oceans Aquarium, Cape Town and uShaka Sea World, Durban, respectively). Additional material was collected from C. laticeps kept at an abalone farm in Hermanus that originated from Struisbaai on the South African south coast. Anoplodiscus cirrusspiralis is redescribed from the South African specimens. This is the first record of a member of Anoplodiscidae Tagliani, 1912 from Africa. PMID- 28864961 TI - The effect of smoking on surgical outcomes in ventral hernia repair: a propensity score matched analysis of the National Surgical Quality Improvement Program data. AB - PURPOSE: Although studies have implicated smoking as a positive predictor of post operative outcomes in inguinal hernia repair, its impact on ventral hernia repair (VHR) is not as clear. This study aims to fill this gap by investigating the impact of smoking on developing adverse 30-day post-operative outcomes in VHR. METHODS: Patients undergoing VHR between 2005 and 2014 were extracted from the American College of Surgeons National Surgical Quality Improvement Program database. Patients were stratified by smoking status and compared for significant differences in baseline characteristics. Logistic regression modeled the impact of smoking on the primary outcome variable of 30-day mortality and the secondary outcome variables of 30-day overall, cardiac, respiratory, or wound morbidity. To evaluate the influence of smoking in comparable groups undergoing VHR, a propensity score matched analysis was performed. RESULTS: Out of 169,458 patients identified, 32,973 (19.5%) were classified as current smokers. Smokers and non/ex smokers differed significantly in multiple pre-operative baseline characteristics. Unmatched univariate analyses revealed smoking status as a positive predictor of every post-operative outcome. These findings were validated with propensity score matching analyses, which found current smokers have an increased likelihood of 30-day mortality (OR 1.42), overall morbidity (OR 1.39), wound (OR 1.40), respiratory (OR 1.14), or cardiac morbidity (OR 1.88) compared to non/ex-smokers (p < 0.05 for all). CONCLUSIONS: Smoking is a modifiable risk factor with a detrimental impact on outcomes in patients undergoing ventral hernia repair. Delaying VHR and promoting smoking cessation prior to surgery may help reduce the odds of adverse 30-day post-operative outcomes. PMID- 28864962 TI - Heat stress mortality and desired adaptation responses of healthcare system in Poland. AB - Heat stress is one of the environmental factors influencing the health of individuals and the wider population. There is a large body of research to document significant increases in mortality and morbidity during heat waves all over the world. This paper presents key results of research dealing with heat related mortality (HRM) in various cities in Poland which cover about 25% of the country's population. Daily mortality and weather data reports for the years 1991 2000 were used. The intensity of heat stress was assessed by the universal thermal climate index (UTCI). The research considers also the projections of future bioclimate to the end of twenty-first century. Brain storming discussions were applied to find necessary adaptation strategies of healthcare system (HCS) in Poland, to minimise negative effects of heat stress. In general, in days with strong and very strong heat stress, ones must expect increase in mortality (in relation to no thermal stress days) of 12 and 47%, respectively. Because of projected rise in global temperature and heat stress frequency, we must expect significant increase in HRM to the end of twenty-first century of even 165% in comparison to present days. The results of research show necessity of urgent implementation of adaptation strategies to heat in HCS. PMID- 28864963 TI - A 46-year-old man with recurrent embolic events. PMID- 28864964 TI - Chronic kidney disease of unknown etiology and the effect of multiple-ion interactions. AB - High incidence of chronic kidney disease of unknown etiology (CKDU) prevalent in many countries (e.g., Sri Lanka, equatorial America) is reviewed in the context of recent experimental work and using our understanding of the hydration of ions and proteins. Qualitative considerations based on Hofmeister-type action of these ions, as well as quantitative electrochemical models for the Gibbs free energy change for ionpair formation, are used to explain why (1) fluoride and water hardness due to magnesium ions (but not due to calcium ions) and similarly (2) cadmium ions in the presence of suitable pairing ions can be expected to be more nephrotoxic, while arsenite in the presence of fluoride and hardness may be expected to be less nephrotoxic. No synergy of arsenic with calcium hardness is found. The analysis is applied to a variety of ionic species that may be found in typical water sources to predict their likely combined electrochemical action. These results clarify the origins of chronic kidney disease that has reached epidemic proportions in the North Central Province of Sri Lanka as being most likely due to the joint presence of fluoride and magnesium ions in drinking water. The conclusion is further strengthened by a study of the dietary load of Cd and other toxins in the affected regions and in the healthy regions where the dietary toxin loads and lifestyles are similar, and found to be safe especially when the mitigating effects of micronutrient ionic forms of Zn, Se, as well as corrections for bioavailability are taken into account. The resulting etiological picture is consistent with the views of most workers in the field who have suspected that fluoride and other ions found in the hard water stagnant in shallow household wells were the major causative factors of the disease. Similar incidence of CKDu found in other hot tropical climates is likely to have similar origins. PMID- 28864966 TI - Race, Remarital Status, and Infertility in 1910: More Evidence of Multiple Causes. AB - The dominant approach to studying historical race-related fertility differences has been to limit samples to first-married and younger women. We argue that studying historical race-related fertility differences in the context of remarriage is also important: remarriage and fertility patterns are both rooted in the biosocial conditions that produce racial disparities in health. We employ a multiple causes framework that attributes variation in fertility patterns to voluntary limitation and involuntary factors (infecundity/subfecundity). We use data from the 1910 Integrated Public Use Microdata Series and estimate zero inflated negative binomial models that simultaneously distinguish those who are infecund (vs. fecund) and estimate the number of remarital births among the fecund. Our approach allows us to evaluate historical remarital (in)fertility differences, accounting for marital, socioeconomic, and geographic influences on fecundity and fertility, while empirically accounting for the influence of children "missing" from the household due to mortality and fostering/aging out. Consistent with past studies that emphasized poorer African American health as a major influence on involuntary infertility, we find that African American women were more likely than white women to be in the always-zero (infecund) group and to have fewer remarital births. Supplemental analyses nuance these findings but indicate that these results are robust. Overall, we find support for a multiple causes perspective: while the findings are consistent with the adoption of deliberate fertility control among urban and higher-status women at higher parities, remarital fertility differences in 1910 also reflected greater infecundity/subfecundity among subgroups of women, especially African American women. PMID- 28864965 TI - Pharmacological Management of Gestational Diabetes Mellitus. AB - Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse pregnancy outcomes in the setting of poor glycemic control. The initial management for GDM includes intensive lifestyle modification, which often requires behavioral and nutritional changes to optimize glycemic control. Pharmacotherapy for GDM is initiated when glycemic targets are not met. The rapid acting bolus analogues aspart and lispro achieve postprandial targets with less hypoglycemia compared to regular insulin, with similar fetal outcomes. The long acting insulin analogues glargine and detemir appear safe with similar maternal/fetal outcomes compared to NPH. While insulin has been the mainstay therapy for women with GDM to improve glycemic control when lifestyle modifications are insufficient, certain oral antihyperglycemic drugs (OADs) can be considered as alternative treatment options for GDM but continue to be controversial for use as first-line treatment options compared to insulin by many professional bodies. Metformin has good efficacy and short-term safety data but it freely crosses the placenta and long-term safety data are lacking. Glyburide has good efficacy and short-term data but it also crosses the placenta and may be associated with increased rates of large-for-gestational-age (LGA) infants and neonatal hypoglycaemia when compared with insulin. This review aims to give an overview of the pharmacological treatment for women with GDM including some of the known safety profiles of current therapeutic options. PMID- 28864967 TI - Characterization and Cu sorption properties of humic acid from the decomposition of rice straw. AB - Humic acid (HA) derived from rice straw decomposed for 1 (HA-1), 3 (HA-3), 6 (HA 6) and 12 (HA-12) months was characterized by potentiometric titration and solid state cross-polarization magic-angle spinning 13C nuclear magnetic resonance spectroscopy (CPMAS 13C NMR). The sorption of Cu on examined HA was investigated using a combination of batch sorption, isothermal titration calorimetry (ITC) and sequential desorption. Results showed that the functional group content and the humification degree of HA tended to increase with increasing decomposition time especially in the latter stage of examined decomposition period. Cu sorption on HA was a rapid process that occurred within the first 1 h and the sorption capacity increased from 245.4 mmol kg-1 on HA-1 to 294.6 mmol kg-1 on HA-12. The sorption of Cu was endothermic, spontaneous and the randomness was increased during Cu sorption. Sorbed Cu on examined HA can be hardly released by NH4Ac but nearly fully released by EDTA. Forming inner-sphere complexes was the main mechanism of Cu sorption on examined HA. This study could provide valuable information for a better understanding on the environmental impacts of the decomposition of organic waste. PMID- 28864970 TI - ? PMID- 28864968 TI - Ethylene promotes pollen tube growth by affecting actin filament organization via the cGMP-dependent pathway in Arabidopsis thaliana. AB - Ethylene and cGMP are key regulators of plant developmental processes. In this study, we demonstrate that ethylene or cGMP promote pollen tube growth in a dose dependent manner. The etr1-1 mutant was found to be insensitive to ethylene with regard to pollen tube growth, while the growth-promoting effect of ethylene in etr2-2, ein4-4, or ein4-7 did not change, suggesting that ethylene signaling was mainly perceived by ETR1. However, the function of cGMP was not inhibited in etr1 1 and pollen tubes became insensitive to ethylene when the endogenous cGMP level was artificially decreased. This shows that cGMP is necessary for the control of pollen tube growth and that it might be a downstream component of ETR1 in the ethylene signaling pathway. Our study also found that ethylene or cGMP increase the actin bundles and elevated the percentage of relative amount of F-actin, while removal of cGMP decreased actin bundles abundance and altered the ratio of F-actin in the tip and base regions of pollen tubes. In conclusion, our data suggests that ethylene functions as the upstream signal of cGMP, and that both signals promote pollen germination and tube growth by regulating F-actin, which is essential for vesicular transport and cytoplasmic streaming. PMID- 28864969 TI - Auditory Event-Related Potentials in the Interictal Phase of Migraine Indicate Alterations in Automatic Attention. AB - Migraine has been characterized by interictal cortical hyperresponsivity. We compared event-related brain potentials (ERPs) to unattended tone pairs in migraineurs (interictal) versus non-headache controls, with particular interest in attention-related activity (i.e., the N1 component). Electroencephalograms were recorded from 11 interictal migraineurs and 14 headache-free controls while they watched a silent video. Pairs of 50-ms tones with 500-ms inter-tone intervals were presented with inter-pair intervals of 1 or 5 s. P1, N1, P2, and N2 components were analyzed. N1 peak amplitudes were larger in migraineurs than in controls, especially after the 5-s inter-pair interval. However, there was no difference between groups in the attenuation of the N1 (i.e., no interaction). P2 peak amplitudes were larger in migraineurs, but only after the first tone in the pair. The three migraineurs without aura had larger N1s than the eight with aura. Our findings are consistent with interictal hyperresponsivity of cortical generators of these ERPs in migraineurs. However, areas that inhibit the responses with stimulus repetition do not seem to be affected. PMID- 28864971 TI - Proteomics and 1H NMR-based metabolomics analysis of pathogenic Vibrio vulnificus aquacultures isolated from sewage drains. AB - Vibrio bacteria live in both marine and freshwater habitats and are associated with aquatic animals. Vibrio vulnificus is a pathogenic bacterium that infects people and livestock. It is usually found in offshore waters or within fish and shellfish. This study presents a comparative proteomic analysis of the outer membrane protein (OMP) changes in V. vulnificus proteins after stimulation with sewage from sewage drains. Using two-dimensional electrophoresis followed by MALDI-TOF MS/MS, 32 protein spots with significant differences in abundance were identified and characterized. These identified proteins were found to be involved in various functional categories, including catalysis, transport, membrane proteins progresses, receptor activity, energy metabolism, cytokine activity, and protein metabolism. The mRNA expression levels of 12 differential proteins were further assessed by qRT-PCR. Seven genes including carboxypeptidase, hemoglobin receptor, succinate dehydrogenase iron-sulfur subunit, ATP synthase subunit alpha, thioredoxin, succinyl-CoA synthetase subunit, and alanine dehydrogenase were downregulated upon stimulation, whereas the protein expression levels HupA receptor, type I secretion outer membrane protein, glutamine synthetase, superoxide dismutase, OmpU, and VuuA were upregulated. 1H NMR spectra showed 18 dysregulated metabolites from V. vulnificus after the sewage stimulation and the pathogenicity was enhanced after that. PMID- 28864973 TI - The Role of Oxytocin in Social Buffering: What Do Primate Studies Add? AB - The ability to maintain close social bonds impacts on reproductive success, longevity, stress and health in social mammals, including humans (Silk et al., Curr Biol 20(15):1359-1361, 2010; Crockford et al., Horm Behav 53(1):254-265, 2008; Wittig et al., Horm Behav 54(1):170-177, 2008; Archie et al., Proc R Soc B 281(1793):20141261, 2014; Cameron et al., Proc Natl Acad Sci U S A 106:13850 13853, 2009; Schulke et al., Curr Biol 20:2207-2210, 2010; Silk et al., Science 302:1231-1234, 2003; Holt-Lunstad et al., PLoS Med 7(7):e1000316, 2010). Close social bonds provide an important social support system, at least in part by acting as a buffer against the deleterious effects of chronic exposure to stressors (Young et al., Proc Natl Acad Sci U S A 51:18195-18200, 2014; Heinrichs et al., Biol Psychiatry 54:1389-1398, 2003). There is accumulating evidence that individuals that provide predictable affiliation or support to others (bond partners) may moderate the perception of the stressor as well as of the physiological stress response. The neuropeptide, oxytocin, may mediate social buffering by down-regulating HPA activity and thus reducing the stress response. However, much within this process remains unclear, such as whether oxytocin is always released when exposed to a stressor, whether more oxytocin is released if there is social support, what aspect of stress or social support triggers oxytocin release and whether social support in the absence of a stressor also impacts oxytocin release and HPA activity, during everyday life. We review the literature that addresses each of these questions in an attempt to clarify where future research effort will be helpful. A better understanding of these dynamics is likely to have implications for enhancing social and health gains from human social relationships. PMID- 28864972 TI - Oxytocin Modulation of Neural Circuits. AB - Oxytocin is a hypothalamic neuropeptide first recognized as a regulator of parturition and lactation which has recently gained attention for its ability to modulate social behaviors. In this chapter, we review several aspects of the oxytocinergic system, focusing on evidence for release of oxytocin and its receptor distribution in the cortex as the foundation for important networks that control social behavior. We examine the developmental timeline of the cortical oxytocin system as demonstrated by RNA, autoradiographic binding, and protein immunohistochemical studies, and describe how that might shape brain development and behavior. Many recent studies have implicated oxytocin in cognitive processes such as processing of sensory stimuli, social recognition, social memory, and fear. We review these studies and discuss the function of oxytocin in the young and adult cortex as a neuromodulator of central synaptic transmission and mediator of plasticity. PMID- 28864974 TI - Oxytocin and Schizophrenia Spectrum Disorders. AB - In this chapter, we present an overview of studies of oxytocin (OXT) in schizophrenia and the schizophrenia spectrum. We first outline the current state of pharmacological treatment of the symptoms of schizophrenia and point to unmet clinical needs. These relate particularly to the debilitating negative symptoms and social cognitive deficits that are frequently observed in patients suffering from schizophrenia. We argue that new treatments are needed to alleviate these impairments. As OXT has been proposed and investigated as a putative treatment, we will then summarise evidence from studies in patients with schizophrenia that have investigated the effects of OXT at several levels, i.e. at the levels of clinical symptoms, social cognitive function as assessed with experimental and neuropsychological tasks, and brain function as assessed using functional magnetic resonance imaging (fMRI). Finally, we will introduce the concept of the schizophrenia spectrum and highlight the importance of studying OXT effects in subclinical spectrum samples, such as in people with high levels of schizotypal personality. We conclude that the evidence of beneficial effects of OXT in schizophrenia is inconsistent, calling for further research in this field. PMID- 28864975 TI - Oxytocin and Aggression. AB - The neuropeptide oxytocin (OT) has a solid reputation as a facilitator of social interactions such as parental and pair bonding, trust, and empathy. The many results supporting a pro-social role of OT have generated the hypothesis that impairments in the endogenous OT system may lead to antisocial behavior, most notably social withdrawal or pathological aggression. If this is indeed the case, administration of exogenous OT could be the "serenic" treatment that psychiatrists have for decades been searching for.In the present review, we list and discuss the evidence for an endogenous "hypo-oxytocinergic state" underlying aggressive and antisocial behavior, derived from both animal and human studies. We furthermore examine the reported effects of synthetic OT administration on aggression in rodents and humans.Although the scientific findings listed in this review support, in broad lines, the link between a down-regulated or impaired OT system activity and increased aggression, the anti-aggressive effects of synthetic OT are less straightforward and require further research. The rather complex picture that emerges adds to the ongoing debate questioning the unidirectional pro-social role of OT, as well as the strength of the effects of intranasal OT administration in humans. PMID- 28864976 TI - Overview of Human Oxytocin Research. AB - Social dysfunction is a core symptom of many psychiatric disorders and current medications have little or no remedial effects on this. Following on from extensive studies on animal models demonstrating that the neuropeptide oxytocin plays an important role in social recognition and bonding, human-based research has explored its therapeutic potential for social dysfunction in psychiatric disorders. Here we outline the historical background of this human-based research and some of the current methodological challenges it is facing. To date, research has primarily attempted to establish functional effects through measuring altered endogenous concentrations, observing effects of exogenous administration and by investigating the effects of polymorphisms and epigenetic modifications of the oxytocin receptor gene. We summarize some of the key findings on behavioral and neural effects that have been reported in healthy subjects in the context of social cognition which have provided encouragement that oxytocin could represent a promising therapeutic target. At the same time, we have identified a number of key areas where we urgently need further information about optimal dosing strategies and interactions with other peptide and transmitter systems. Finally, we have summarized current translational findings, particularly in the context of therapeutic outcomes of intranasal oxytocin administration in autism and schizophrenia. These clinical findings while somewhat varied in outcome do offer increasing cause for optimism that targeting the oxytocin system may provide a successful therapeutic approach for social dysfunction. However, future research needs to focus on the most effective treatment strategy and which types of individuals are likely to benefit most. PMID- 28864977 TI - Oxytocin and Animal Models for Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions characterized by deficits in social communication and by repetitive and stereotypic patterns of behaviors, with no pharmacological treatments available to treat these core symptoms. Oxytocin is a neuropeptide that powerfully regulates mammalian social behavior and has been shown to exert pro social effects when administered intranasally to healthy human subjects. In the last decade, there has been a significant interest in using oxytocin to treat social behavior deficits in ASD. However, little attention has been paid to whether the oxytocin system is perturbed in subgroups of individuals with ASD and whether these individuals are likely to benefit more from an oxytocin treatment. This oversight may in part be due to the enormous heterogeneity of ASD and the lack of methods to carefully probe the OXT system in human subjects. Animal models for ASD are valuable tools to clarify the implication of the oxytocin system in ASD and can help determine whether perturbation in this system should be considered in future clinical studies as stratifying biomarkers to inform targeted treatments in subgroups of individuals with ASD. In this chapter, we review the literature on genetic- and environmental-based animal models for ASD, in which perturbations in the oxytocin system and/or the effect of oxytocin administration on the ASD-associated phenotype have been investigated. PMID- 28864979 TI - [Painless, soft, livid erythematous swelling on the neck and upper part of the back]. PMID- 28864978 TI - Phase II basket trial of perifosine monotherapy for recurrent gynecologic cancer with or without PIK3CA mutations. AB - Objective Perifosine exhibits anti-tumor activity by inhibiting AKT phosphorylation. The purpose of this phase II basket trial was to evaluate the efficacy and safety of perifosine monotherapy for ovarian, endometrial, and cervical cancers. Methods Recurrent or persistent ovarian, endometrial, or cervical cancer patients were assigned to PIK3CA wild-type or mutant groups. Each patient received 600 mg oral perifosine on day 1 followed by a maintenance dose of 100 mg daily. The primary endpoint was disease control rate; secondary endpoints included response rate, progression-free survival, overall survival, and safety. Immunohistochemical staining and targeted sequencing were used to explore new biomarkers in such patients. Results Sixteen and 5 ovarian, 17 and 7 endometrial, and 18 and 8 cervical cancer patients with PIK3CA wild-type and mutant, respectively, were enrolled. Disease control rates (wild-type/mutant) were 12.5/40.0%, 47.1/14.3%, and 11.1/25.0% in ovarian, endometrial, and cervical cancer, respectively. The most common grade 3/4 toxicities were anemia (22.5%) and anorexia (11.3%). Immunohistochemical staining revealed that the disease control rate in patients with negative phosphatase and tensin homolog (PTEN) expression was 50.0%, and the odds ratio of positive to negative patients was 0.24 in all patients. Conclusions Perifosine monotherapy showed good tolerability but expected efficacy was not achieved. Modest efficacy was demonstrated in ovarian cancer patients with PIK3CA mutations and endometrial cancer patients with PIK3CA wild-type; no difference was observed between PIK3CA wild-type and mutant in cervical cancer. Absence of PTEN expression may be predictive of clinical efficacy with perifosine monotherapy. PMID- 28864981 TI - Technical aspects of acquiring and measuring myocardial blood flow: Method, technique, and QA. AB - Measuring absolute myocardial blood flow (MBF) is becoming a common aid for diagnosing patients suspected to have coronary artery disease. An MBF study, however, requires a scanner with high count rate capability, is more susceptible to artifacts, and is much more technically involved than static imaging, which leads to a greater risk of artifactual results contaminating the final result. This technical note gives the reader an introductory understanding of the method for calculating MBF. It then describes the scanning protocol, potential pitfalls and how to recognize them, and quality control steps that should be taken to avoid basing a clinical decision on possibly inaccurate flow information. PMID- 28864980 TI - Activated carbon-plasticised agarose composite films for the adsorption of thiol as a model of wound malodour. AB - Conditions such as diabetes, cardiovascular disease and long-term immobilisation can precipitate the development of chronic dermal ulcers. Such wounds are associated with inflammation and bacterial contamination which in turn can lead to the liberation of offensive odours that cause patient embarrassment and, in some instances, social isolation. Activated carbon-containing dressings have been used to manage the odours from such wounds. However, these can be bulky and can become fouled by wound exudate. Agarose is a natural polysaccharide derived from seaweed that forms brittle free-standing films that can be made pliable by addition of a plasticiser. In this study, activated carbon-containing plasticised agarose films were evaluated for their ability to sequester thiol-containing molecules from solution and the gaseous phase. The water vapour transmission rate was also evaluated to determine the potential breathability of these films should they be considered for application to the skin. It was found that the adsorption of thiols was directly proportional to the activated carbon content of the films. Water vapour was found to pass relatively freely through the films indicating that sweat-induced tissue maceration would be unlikely to occur if applied clinically. In conclusion, activated carbon-containing plasticised agarose films have some potential in the sequestration of malodourous molecules such as those liberated from chronic dermal wounds. PMID- 28864982 TI - Introduction: A Brief Guide to the Periconception Environment. AB - Definition of the periconception period is not an exact science and is probably somewhat arbitrary. One can define it as spanning the period from the final stages of gamete maturation until formation of the embryo and the stages of embryonic development and implantation. Hence, the periconception period includes periods when spermatozoa are in the female reproductive tract, oocytes are matured and ovulated into the oviduct, fertilization occurs and the embryo undergoes development. By definition the implantation process and the early stages of placenta formation are also regarded as a part of the periconception period. In this article we highlight a few of the major advances which have transformed this topic over the last two decades. It is now clear that the fitness and wellbeing of developing mammalian embryos, including the human, are highly dependent on the health status, diet and habits of both parents especially in the months and weeks that precede the formation of oocytes and spermatozoa. PMID- 28864983 TI - Epigenetic Influences During the Periconception Period and Assisted Reproduction. AB - The periconception period starts 6 months before conception and lasts until the tenth week of gestation. In this chapter, we will focus on epigenetic modifications to DNA and gene expression within this period and during assisted reproduction. There are two critical times during the periconception window when significant epigenetic 'reprogramming' occur: one during gametogenesis and another during the pre-implantation embryonic stage. Furthermore, assisted conception treatments, laboratory protocols and culture media can affect the embryo development and birth weights in laboratory animals. There is, however, an ongoing debate as to whether epigenetic changes in humans, causing embryo mal development, placenta dysfunction and birth defects, result from assisted reproductive technologies or are consequences of pre-existing medical and/or genetic conditions in the parents. The periconception period starts from ovarian folliculogenesis, through resumption of oogenesis, fertilisation, peri implantation embryo development, embryogenesis until the end of organogenesis. In men, it is the period from spermatogenesis to epididymal sperm storage and fertilisation. Gametes and developing embryos are sensitive to environmental factors during this period, and epigenetic modifications can occur in response to adverse lifestyles and environmental factors. We now know that lifestyle factors such as advanced parentage age, obesity or undernutrition, smoking, excessive alcohol and caffeine intake and recreational drugs used during gamete production and embryogenesis could induce epigenetic alterations, which could impact adversely on pregnancy outcomes and health of the offspring. Furthermore, these can also result in a permanent and irreversible effect in a dose-dependent manner, which can be passed on to the future generations. PMID- 28864984 TI - The Importance of the Periconception Period: Immediate Effects in Cattle Breeding and in Assisted Reproduction Such as Artificial Insemination and Embryo Transfer. AB - In livestock breeding, the successful outcome is largely depending on the "periconception environment" which, in a narrow sense, refers to the genital tract, where gametogenesis and embryogenesis occur. During these early stages of development, gametes and embryos are known to be particularly sensitive to alterations in their microenvironment. However, as the microenvironment somehow reflects what is going on in the external world, we must widen our definition of "periconception environment" and refer to all events taking place around the time of conception, including metabolic state and health and nutrition of the dam. In modern dairy cows that have to manage an optimal reproductive performance with continued growth and high milk yield, the periconception period is particularly challenging. The metabolic priority for growth and lactation is known to generate adverse conditions hampering optimal ovarian function, oocyte maturation, and development of embryo/fetus. In addition, by using artificial reproductive technologies (ARTs), gametes and/or embryos of livestock are exposed to unnatural conditions outside the male and female genital tract. Artificial insemination, the most widely used technique, is currently yielding pregnancy rates similar to natural mating, and calves produced by AI are equally viable after natural mating. In contrast, other ART, such as multiple ovulation and embryo transfer, have been reported to induce changes in gene expression and DNA methylation patterns with potential consequences for development.Finally, the "periconceptional" environment has been shown to not only influence the successful establishment of pregnancy but also the long-term health and productivity of the offspring. Hence, the optimization of management around the time of conception might open doors to improve animal production and product quality. PMID- 28864985 TI - The Consequences of Maternal-Embryonic Cross Talk During the Periconception Period on Subsequent Embryonic Development. AB - The periconception period comprises the final maturation of sperm and the processes of fertilization and early embryonic development, which take place in the oviduct. The final goal of these important events is to lead to establishment of pregnancy leading to the birth of healthy offspring. Studies in rodents and domestic animals have demonstrated that environmental conditions experienced during early development affect critical aspects of future growth, metabolism, gene expression, and physiology. Similarly, in vitro culture of embryos can be associated with changes in fetal growth, gene expression and regulation, and postnatal behavior.In the oviduct, the cross talk between the mother and gametes/embryo begins after ovulation, between the oocyte and the female reproductive tract, and continues with the sperm and the early embryo after successful fertilization. These signals are mainly the result of direct interaction of gametes and embryos with oviductal and endometrial cells, influencing the microenvironment at the specific location. Identifying and understanding the mechanisms involved in this cross talk during the critical period of early reproductive events leading to pregnancy establishment could potentially lead to improvements in current in vitro embryo production systems in domestic mammals and humans. In this review, we discuss current knowledge of the short- and long-term consequences of in vitro embryo production on embryo development. PMID- 28864986 TI - The Role of Maternal Nutrition During the Periconceptional Period and Its Effect on Offspring Phenotype. AB - The early preimplantation embryo has been rigorously studied for decades to understand inherent reproductive and developmental mechanisms driving its morphogenesis from before fertilisation through to and beyond implantation. Recent research has demonstrated that this short developmental window is also critical for the embryo's interaction with external, maternal factors, particularly nutritional status. Here, maternal dietary quality has been shown to alter the pattern of development in an enduring way that can influence health throughout the lifetime. Thus, using mouse models, maternal protein restriction exclusively during the preimplantation period with normal nutrition thereafter is sufficient to cause adverse cardiometabolic and neurological outcomes in adult offspring. Evidence for similar effects whereby environmental factors during the periconceptional window can programme postnatal disease risk can be found in human and large animal models and also in response to in vitro conditions such as assisted conception and related infertility treatments. In this review, using mouse malnutrition models, we evaluate the step-by-step mechanisms that lead from maternal poor diet consumption though to offspring disease. We consider how adverse programming within the embryo may be induced, what nutrient factors and signalling pathways may be involved, and how these cues act to change the embryo in distinct ways across placental and foetal lineage paths, leading especially to changes in the growth trajectory which in turn associate with later disease risk. These mechanisms straddle epigenetic, molecular, cellular and physiological levels of biology and suggest, for health outcomes, preimplantation development to be the most important time in our lives. PMID- 28864987 TI - The Long-Term Effect of the Periconception Period on the Embryo's Epigenetic Profile and Phenotype: The Role of Maternal Disease Such as Diabetes and How the Effect Is Mediated (Example from a Rabbit Model). AB - Maternal metabolic diseases such as diabetes mellitus with diabetogenic hypoinsulinemia and hyperglycemia change periconceptional developmental conditions in utero. In preimplantation rabbit embryos, all major metabolic pathways are affected. Alterations in protein, lipid and glucose metabolism, adipokines, advanced glycation end products (AGEs) and reactive oxygen species (ROS) are described in this review. The embryonic metabolism is characterized by a high plasticity which enables survival of most preimplantation embryos under the non-physiological developmental conditions in diabetic mothers. Adiponectin, for example, compensates for the missing insulin-driven glucose supply and stimulates intracellular lipid accumulation in embryonic cells. AGEs and ROS are clear indicators of metabolic stress. The price paid for survival, however, needs to be taken into consideration. It is an increase in lipogenesis and proteinogenesis, leading to metabolic stress and with potentially negative long term health effects. PMID- 28864988 TI - Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated. AB - Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of stress mechanisms - particularly psychiatric disorders - represent a significant global health problem. While it has long been observed that levels of stress experienced in the periconception period may greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance is then extensively discussed, including the role of chromatin remodelling associated with specific HPA axis-related genes and the possible role of regulatory RNAs as messengers of environmental stress both in the intrauterine environment and across the germ line. Furthering our understanding of the role of stress on embryonic development is crucial if we are to increase our predictive power of disease risk and devise-effective treatments and intervention strategies. PMID- 28864989 TI - The Long-Term Effects of the Periconceptional Period on Embryo Epigenetic Profile and Phenotype; The Paternal Role and His Contribution, and How Males Can Affect Offspring's Phenotype/Epigenetic Profile. AB - The number of adults afflicted with heart disease, obesity and diabetes, central components of metabolic disorder, has grown rapidly in recent decades, affecting up to one quarter of the world's population. Typically, these diseases are attributed to lifestyle factors such as poor diet, lack of exercise and smoking. However, studies have now identified strong associations between patterns of growth during foetal and neonatal life and an increase predisposition towards developing heart disease, obesity and diabetes in adult life. While the connection between a mother's diet and the long-term health of her offspring has been studied in great detail, our understanding of whether offspring health might be affected by a father's diet remains limited. Greater insight into the impact that paternal nutrition has on sperm quality, epigenetic status and potential offspring programming mechanisms is needed to redress this parental-programming knowledge imbalance. Disturbances in paternal reproductive epigenetic status represents one key mechanism linking paternal diet with the programing of offspring development and adult health, as many enzymatic processes involved in epigenetic regulation use metabolic intermediates to modify DNA and histones. Here, poor paternal nutrition could result in perturbed sperm and testicular epigenetic status, impacting on post-fertilisation gene transcriptional regulation and protein expression in offspring tissues, resulting in increased incidences of metabolic disorder in adult life. PMID- 28864990 TI - Exploitation of Non-mammalian Model Organisms in Epigenetic Research. AB - Model organisms are widely used in research that is ultimately aimed at understanding the causes and consequences of human disease. It may seem counterintuitive to expect clinically useful information to be obtained from species as diverse as fishes and insects, but because fundamental biological mechanisms share evolutionary origins they transcend species barriers. Epigenetic mechanisms fulfil this expectation admirably as more and more is discovered about the basic operational rules of inheritance, which are much more elaborate than formerly thought. Only a few decades ago, although the complex interplay between genes, inheritance and the environment was recognized, it was difficult to explain. Recent discoveries about the controlling influences of gene silencing through DNA and histone methylation, the roles of so-called non-coding DNA and microRNA, and the way in which these factors respond to environmental conditions have started to shed light on these basic mechanisms. Diverse model species allow epigenetic mechanisms to be studied from different perspectives; for example, some are better suited to studies of sex determination while others may be more convenient for studying the earliest stages of organ development, growth and the influence of nutrition on future wellbeing. The rationale for including this chapter in a book that is focused on uncovering relationships between periconception nutrition in humans is to highlight the opportunities and insights that may be gained by focusing attention on studies in non-mammalian model species. PMID- 28864991 TI - Evaluating safety of thrombolysis in chronic kidney disease patients presenting with pulmonary embolism using propensity score matching. AB - To assess the safety of thrombolytic therapy in chronic kidney disease (CKD) patients who present with pulmonary embolism (PE). We used the Nationwide Inpatient Sample Database to identify patients who underwent thrombolysis for PE between 2010 and 2014. The patients were divided into two groups: (1) No CKD and (2) CKD. Patients with and without CKD were matched using 1:1 propensity score matching and a caliper width of 0.01. The primary outcomes were in-hospital mortality and hemorrhagic events. The secondary outcomes were blood transfusions, length of stay and total hospitalization charge. Two separate, multivariate analyses were also performed to determine the predictors for primary outcomes. The No CKD group had 16,238 and CKD group had 1341 patients prior to matching. Patients with CKD were older (Median age 67 vs. 57 years; p < 0.01), male (60.6 vs. 51.8%) and had a higher prevalence of coronary artery disease, congestive heart failure, diabetes, hyperlipidemia, hypertension, and prior stroke among other comorbidities. They also had significantly higher rate of in-hospital mortality (OR 1.66) and hemorrhagic events (OR 1.47) prior to matching. Post matching, there was no difference in hospital mortality (22.9 vs. 21.8%; p = 0.51) or hemorrhagic events (3.8 vs. 3.0%; p = 0.27) between CKD and No CKD groups. Patients with CKD had a longer length of stay, but no difference in proportion of patients receiving a blood transfusion and total hospitalization charges post-matching. Multivariate analysis showed that CKD did not predict mortality (OR 0.88, 0.75-1.02; p = 0.09) or hemorrhagic events (OR 0.89, 95% CI 0.76-1.04; 0.13). There was no increase in rate of hospital mortality or hemorrhagic events among CKD patients who underwent thrombolysis for PE. PMID- 28864992 TI - Optimization of blood loss during robotic IVC thrombectomy in a Jehovah's witness: a case report with 14-month follow up. PMID- 28864993 TI - What is This Image? 2017: Image 3. PMID- 28864995 TI - Reply to Drs. Karakonstantis and Kalemaki. PMID- 28864994 TI - A genetic variant in the placenta-derived MHC class I chain-related gene A increases the risk of preterm birth in a Chinese population. AB - Preterm birth (PTB) is a predominant contributor to neonatal mortality and morbidity worldwide. However, the pathophysiology of PTB is not well-understood. We tested the hypothesis that single-nucleotide polymorphisms (SNPs) in the placenta-derived MHC class I chain-related gene A (MICA) could disrupt placental development and hence result in PTB. Nineteen selected SNPs in MICA were genotyped in a case-control study of 127 premature infants and 634 term controls in a Chinese Han population. We found that significantly increased PTB risk was associated with homozygosity for the A variant of rs2256318 (adjusted odds ratio = 6.97 and 95% confidence interval = 2.34-20.74 for A/A, compared with G/G genotype, P = 0.001). In addition, the A/A genotype of rs2256318 was associated with decreased placental weight of neonates (beta = -25.331; P = 0.033). Furthermore, stratified analysis demonstrated that the A/A genotype of rs2256318 was associated with increased PTB risk in female group. In addition, we observed statistical interaction between the polymorphism rs2516448 and sex (P = 0.04). No significant differences in the distribution of haplotypes between cases and controls were detected. Our results indicate that the polymorphism of rs2256318 in MICA may contribute to the etiology of PTB through interfering with placental development. These findings need to be further validated in larger and multi ethnic populations. PMID- 28864996 TI - Immunomodulatory basis of antioxidant therapy and its future prospects: an appraisal. AB - Antioxidants are agents which can modulate oxidant-antioxidant profile of body system by neutralizing pro-oxidant molecules. The current scientific knowledge on mechanisms of antioxidant activity of biomolecules was critically reviewed with a special emphasis on immunomodulation. The immuno-oxidative wreckage of animals in various disease conditions and the role of biomodulators in curbing the oxidative stress through immune pathways were analyzed. The critical role of immunomodulatory mechanisms in controlling oxidative damage was identified. Selection of antioxidant therapy considering the immunopharmacology of the drug as well as immunological basis of disease may reduce treatment failure and adverse health effects. Hence, it is suggested that future studies on antioxidants may focus on the immuno-oxidative pathobiology to better understand its clinical effects and effective disease management. PMID- 28864997 TI - Rationale, Design, and Baseline Characteristics of the Utopia Trial for Preventing Diabetic Atherosclerosis Using an SGLT2 Inhibitor: A Prospective, Randomized, Open-Label, Parallel-Group Comparative Study. AB - INTRODUCTION: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are anti diabetic agents that improve glycemic control with a low risk of hypoglycemia and ameliorate a variety of cardiovascular risk factors. The aim of the ongoing study described herein is to investigate the preventive effects of tofogliflozin, a potent and selective SGLT2 inhibitor, on the progression of atherosclerosis in subjects with type 2 diabetes (T2DM) using carotid intima-media thickness (IMT), an established marker of cardiovascular disease (CVD), as a marker. METHODS: The Study of Using Tofogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, blinded-endpoint, multicenter, and parallel-group comparative study. The aim was to recruit a total of 340 subjects with T2DM but no history of apparent CVD at 24 clinical sites and randomly allocate these to a tofogliflozin treatment group or a conventional treatment group using drugs other than SGLT2 inhibitors. As primary outcomes, changes in mean and maximum IMT of the common carotid artery during a 104-week treatment period will be measured by carotid echography. Secondary outcomes include changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, the occurrence of CVD and adverse events, and biochemical measurements reflecting vascular function. CONCLUSION: This is the first study to address the effects of SGLT2 inhibitors on the progression of carotid IMT in subjects with T2DM without a history of CVD. The results will be available in the very near future, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent CVD. FUNDING: Kowa Co., Ltd. CLINICAL TRIAL REGISTRATION: UMIN000017607. PMID- 28864998 TI - Sequential use of extracorporeal devices to avoid mechanical ventilation in a patient with complicated pulmonary fibrosis. AB - Extracorporeal lung assist devices are widely used these days for a growing number of indications. We report the case of a patient managed with three different flow-range devices sequentially, enabling us to avoid mechanical ventilation. Handling and ethics of this approach are discussed. PMID- 28864999 TI - Early Depiction of a Parotid Tumour in the "School of Athens" (1509-1511) by Raphael (1483-1520). PMID- 28865000 TI - Assessment of DDT contamination in house rat as a possible bioindicator in DDT sprayed areas from Ethiopia and South Africa. AB - Ethiopia and South Africa are among the few countries to still implement indoor residual spraying with dichloro-diphenyl-trichloroethane (DDT) for malaria vector control. In this study, we investigated the levels and ecological risks of DDT and its metabolites in liver tissues of house rat, as a sentinel animal, for providing an early warning system for public health and wildlife intervention from Ethiopia and South Africa. The results showed that SigmaDDT concentration ranged from 127 to 9155 MUg/kg wet weight, and the distribution order of DDT and its metabolites in the analyzed liver samples was p,p'-DDD > p,p'-DDE >> p,p' DDT, o,p'-DDT, and o,p'-DDD. The risk assessment indicated a potential adverse impact on humans, especially for pregnant women and children, because they spend majority of their time in a DDT-sprayed house. The ecological assessment also showed a concern for birds of prey and amphibians like frogs. This study is the first report on DDT contamination in liver tissues of house rats from Ethiopia and South Africa, and henceforth, the data will serve as a reference data for future studies. PMID- 28865001 TI - The Social Networks of Children With and Without Disabilities in Early Childhood Special Education Classrooms. AB - Interaction with peers is an important contributor to young children's social and cognitive development. Yet, little is known about the nature of social networks within preschool inclusive classrooms. The current study applied a social network analysis to characterize children's peer interactions in inclusive classrooms and their relations with children's disability status. The participants were 485 preschoolers from 64 early childhood special education (ECSE) inclusive classrooms. Results from teachers' report of children's social networks showed that children with disabilities formed smaller play networks compared to their typically developing peers in the classroom, but no evidence indicated that children with disabilities engaged in more conflict networks than their counterparts. Children's play and conflict networks were segregated by children's disability status. PMID- 28865002 TI - Clinical supervision: what does it mean to be better? PMID- 28865003 TI - Influence of farmyard manure on some morphological and biochemical parameters of cowpea (Vigna unguiculata) seedling grown in cadmium-treated soil. AB - The present study aims to assess the effects of the two kinds of farmyard manure (poultry and pig manures) as amendments for soil on cadmium (Cd) toxicity in plants using cowpea seedlings as plant model. Cd toxicity was evaluated by assessing the effect of the metal on the growth rate and antioxidant status as well as the ability of the plant to metabolise xenobiotic. There was a significantly (p < 0.05) increased concentration of Cd in the root, stem and leaves of cowpea seedlings grown in all the treated soils relative to control. Addition of poultry manure to the soil significantly (p < 0.05) decreased the level of Cd in these component parts of the seedlings and their corresponding bioaccumulation factor in a dose-dependent manner as compared with treatments with Cd pollution without manure addition and Cd pollution with pig manure addition. There was restoration of Cd-induced effect on growth rate parameters to levels comparable to controls in cowpea seedlings grown in Cd-treated soil augmented with poultry manure but not in cowpea seedlings in cadmium-treated soil with pig manure amendments. Similarly, augmentation of Cd-treated soil with pig manure did not alter the Cd-induced effect on the levels of superoxide dismutase (SOD) and lipid peroxidation (LPO) in leaf, stem and roots, as SOD remained significantly (p < 0.05) decreased and LPO increased relative to control. On the other hand, the levels of SOD and LPO in these parts of cowpea seedlings grown in Cd-treated soils amended with poultry manure were restored to a level not significantly (p > 0.05) different from control. Like in the case of SOD, the Cd induced inhibition of the activity of xenobiotic metabolising enzymes, aldehyde oxidase and sulphite oxidase remained significantly (p < 0.05) decreased in the organs of seedling grown in Cd-treated soil amended with pig manure. Conversely, the Cd-induced effect on the activities of these enzymes was reversed in the organs of seedlings exposed to Cd and poultry manure as it was not significantly (p > 0.05) different from control. In conclusion, the findings of the study revealed that supplementation of Cd-treated soils with pig and poultry manures reversed effects of Cd on cowpea seedlings. However, poultry manure was more effective than pig manure in ameliorating the effects of Cd. PMID- 28865005 TI - A Laplacian characterization of phytoplankton shape. AB - Phytoplankton exhibit pronounced morphological diversity, impacting a range of processes. Because these impacts are challenging to quantify, however, phytoplankton are often approximated as spheres, and when effects of non sphericity are studied it is usually experimentally or via geometrical approximations. New methods for quantifying phytoplankton size and shape generally, so all phytoplankton are analyzable by the same procedure, can complement advances in microscopic imagery and automated classification to study the influence of shape in phytoplankton. Here we apply to phytoplankton a technique for defining the size of arbitrary shapes based on the Laplacian-the operator that governs processes, such as nutrient uptake and fluid flow, where phytoplankton shape is expected to have the greatest effect. Deviations from values given by spherical approximation are a measure of phytoplankton shape and indicate the fitness increases for phytoplankton conferred by their non-spherical shapes. Comparison with surface-to-volume quotients suggests the Laplacian-based metric is insensitive to small-scale features which can increase surface area without affecting key processes, but is otherwise closely related to surface-area to-volume, demonstrating this metric is a meaningful measure. While our analysis herein is limited to axisymmetric phytoplankton due to relative sparsity of 3D information about other phytoplankton shapes, the definition and method are directly generalizable to 3D shape data, which will in the near future be more readily available. PMID- 28865006 TI - Dexamethasone for chronic subdural haematoma: a systematic review and meta analysis. AB - BACKGROUND: Chronic subdural haematoma is a common but retractable neurological disease in the elderly with a high rate of recurrence. Dexamethasone (DX) either as monotherapy or adjuvant therapy has been applied clinically, but its effectiveness and feasibility remain controversial. We conducted this review to clarify this issue. METHODS: With a systematic review through multiple databases, we retrieved eligible English language publications and extracted relevant data to perform meta-analyses. The respective risk ratio (RR) and its 95% confidence interval (CI) were pooled to evaluate the overall effect. RESULTS: Our meta analysis showed overall that DX (alone or adjuvant) resulted in a lower recurrence rate when compared with non-DX therapy (RR, 0.54; 95% CI, 0.33-0.88; p = 0.01), but sensitivity analysis by excluding the most influential study achieved inconsistent results. The pooled effect revealed no statistical difference on recurrence rate between DX alone and non-DX therapy or surgical therapy (RR, 0.86; 95% CI, 0.43-1.71; p = 0.66) (RR, 0.89; 95% CI, 0.43-1.85; p = 0.76). Comparison between DX alone with the surgical therapy demonstrated no difference on the poor outcome (RR, 0.40; 95% CI, 0.15-1.04; p = 0.06). CONCLUSIONS: We had no enough evidence to support DX use as an effective alternation to surgical therapy. But adjuvant DX use may facilitate the surgical therapy by reducing recurrence. Further study focusing on adjuvant DX was required. PMID- 28865004 TI - Gold nanoparticles with patterned surface monolayers for nanomedicine: current perspectives. AB - Molecular self-assembly is a topic attracting intense scientific interest. Various strategies have been developed for construction of molecular aggregates with rationally designed properties, geometries, and dimensions that promise to provide solutions to both theoretical and practical problems in areas such as drug delivery, medical diagnostics, and biosensors, to name but a few. In this respect, gold nanoparticles covered with self-assembled monolayers presenting nanoscale surface patterns-typically patched, striped or Janus-like domains represent an emerging field. These systems are particularly intriguing for use in bio-nanotechnology applications, as presence of such monolayers with three dimensional (3D) morphology provides nanoparticles with surface-dependent properties that, in turn, affect their biological behavior. Comprehensive understanding of the physicochemical interactions occurring at the interface between these versatile nanomaterials and biological systems is therefore crucial to fully exploit their potential. This review aims to explore the current state of development of such patterned, self-assembled monolayer-protected gold nanoparticles, through step-by-step analysis of their conceptual design, synthetic procedures, predicted and determined surface characteristics, interactions with and performance in biological environments, and experimental and computational methods currently employed for their investigation. PMID- 28865008 TI - [Endocrine and diabetic emergencies]. PMID- 28865007 TI - Cryphonectria hypovirus 1-Induced Epigenetic Changes in Infected Phytopathogenic Fungus Cryphonectria parasitica. AB - Biotic stress caused by virus infections induces epigenetic changes in infected plants and animals, but this is the first report on methylation pattern changes in a fungus after mycovirus infection. As a model pathosystem for mycovirus-host interactions, we used Cryphonectria hypovirus 1 (CHV1) and its host fungus Cryphonectria parasitica, in which deregulation of methylation cycle enzymes upon virus infection was observed previously. Six CHV1 strains of different subtypes were transferred into three different C. parasitica isolates in order to assess the effect of different CHV1 strains and/or subtypes on global cytosine methylation level in infected fungus, using methylation-sensitive amplification polymorphism (MSAP). Infection with CHV1 affected the methylation pattern of the C. parasitica genome; it increased the number and diversity of methylated, hemi methylated, and total MSAP markers found in infected fungal isolates compared to virus-free controls. The increase in methylation levels correlated well with the CHV1-induced reduction of fungal growth in vitro, indicating that C. parasitica genome methylation upon CHV1 infection, rather than being the defensive mechanism of the fungus, is more likely to be the virulence determinant of the virus. Furthermore, the severity of CHV1 effect on methylation levels of infected C. parasitica isolates depended mostly on individual CHV1 strains and on the combination of host and virus genomes, rather than on the virus subtype. These novel findings broaden our knowledge about CHV1 strains which could potentially be used in human-aided biocontrol of chestnut blight, a disease caused by C. parasitica in chestnut forest ecosystems and orchards. PMID- 28865009 TI - Inverse relationship between Ki67 and survival in early luminal breast cancer: confirmation in a multivariate analysis. AB - INTRODUCTION: Ki67 is a prognostic marker in early breast cancer, but its real usefulness remains controversial. The standard cut-off values for Ki67 have not been universally accepted and different values may be used depending on the type of biopsy (fine needle biopsy versus surgical specimen biopsy). The objective of this study was to evaluate the prognostic significance of Ki67 and to determine the most accurate prognostic cut-off. MATERIALS AND METHODS: 495 tissue samples from patients with luminal tumours who underwent breast surgery between 2005 and 2011 were collected from the Department of Pathology at Hospital de la Santa Creu i Sant Pau, Barcelona. Patients with stage IV, HER2-positive tumours or triple negative breast carcinoma were excluded from the study. Pathology data including tumour grading and ki67 percentage were obtained retrospectively from clinical records. In all cases, the percentage of ki67 was evaluated in fine needle biopsies. RESULTS: In the multivariate analysis, Ki67 as a continuous variable was associated with poor overall survival (OS) and cancer-specific survival (CSS) (OS p = 0.0001, HR 1.037, CI 1.014-1.059; CSS p = 0.0001, HR 1.063, CI 1.031 1.096) (Cox regression model). CSS was poor when associated with a KI67 cut-off point >14% (p = 0.013, HR 14.85; CI 1.074-120.53) (Cox regression model). Disease free survival (DFS) was not associated with Ki67 CONCLUSIONS: Prognosis of luminal breast carcinoma can be predicted using Ki67 as a continuous variable and a standard cut-off value of 14%. Information about the specimen type used to determine ki67 should be recorded in the pathological report. PMID- 28865010 TI - Genome Characterization of Oleaginous Aspergillus oryzae BCC7051: A Potential Fungal-Based Platform for Lipid Production. AB - The selected robust fungus, Aspergillus oryzae strain BCC7051 is of interest for biotechnological production of lipid-derived products due to its capability to accumulate high amount of intracellular lipids using various sugars and agro industrial substrates. Here, we report the genome sequence of the oleaginous A. oryzae BCC7051. The obtained reads were de novo assembled into 25 scaffolds spanning of 38,550,958 bps with predicted 11,456 protein-coding genes. By synteny mapping, a large rearrangement was found in two scaffolds of A. oryzae BCC7051 as compared to the reference RIB40 strain. The genetic relationship between BCC7051 and other strains of A. oryzae in terms of aflatoxin production was investigated, indicating that the A. oryzae BCC7051 was categorized into group 2 nonaflatoxin producing strain. Moreover, a comparative analysis of the structural genes focusing on the involvement in lipid metabolism among oleaginous yeast and fungi revealed the presence of multiple isoforms of metabolic enzymes responsible for fatty acid synthesis in BCC7051. The alternative routes of acetyl-CoA generation as oleaginous features and malate/citrate/pyruvate shuttle were also identified in this A. oryzae strain. The genome sequence generated in this work is a dedicated resource for expanding genome-wide study of microbial lipids at systems level, and developing the fungal-based platform for production of diversified lipids with commercial relevance. PMID- 28865011 TI - General Introduction to Drebrin. AB - Drebrin was first discovered by our group as "developmentally regulated brain protein" from the chicken optic tectum. Drebrin is an actin-binding protein, which is classified into two major isoforms produced by alternative splicing from a single DBN1 gene. The isoform predominantly expressed in the adult brain (drebrin A) is neuron specific, containing a neuron-specific sequence (Ins2) in the middle of the molecule. Drebrin A is highly concentrated in dendritic spines, and its accumulation level is regulated by synaptic activity. In contrast, drebrin E, which lacks Ins2, is found in widespread but not ubiquitous cell types in various tissues. The isoform conversion from drebrin E to drebrin A occurs in parallel with synaptogenesis. Drebrin decorating F-actin is found at the recipient side of cell-cell communication systems, such as gap junctions, adherens junctions, immunological synapses, and neuronal synapses. In addition, it is involved in the cellular mechanisms of cell migration, cell process formation, cancer metastasis, and spermatogenesis. Lack of drebrin leads to the dysfunction of cell-cell communication, resulting in aberrant migration of metastatic cancer cells, aberrant synaptic function in dementia, and rupture of endothelial integrity. Because drebrin forms a unique F-actin with a longer helical crossover, drebrin may create an F-actin platform for molecular assembly and play a pivotal role in intercellular communication. PMID- 28865012 TI - Molecular Cloning of Drebrin: Progress and Perspectives. AB - Chicken drebrin isoforms were first identified in the optic tectum of developing brain. Although the time course of protein expression was different in each drebrin isoform, the similarity between their protein structures was suggested by biochemical analysis of purified protein. To determine their protein structures, the cloning of drebrin cDNAs was conducted. Comparison between the cDNA sequences shows that all drebrin cDNAs are identical except that the internal insertion sequences are present or absent in their sequences. Chicken drebrin are now classified into three isoforms, namely, drebrins E1, E2, and A. Genomic cloning demonstrated that the three isoforms are generated by an alternative splicing of individual exons encoding the insertion sequences from single drebrin gene. The mechanism should be precisely regulated in cell-type-specific and developmental stage-specific fashion. Drebrin protein, which is well conserved in various vertebrate species, although mammalian drebrin has only two isoforms, namely, drebrin E and drebrin A, is different from chicken drebrin that has three isoforms. Drebrin belongs to an actin-depolymerizing factor homology (ADF-H) domain protein family. Besides the ADF-H domain, drebrin has other domains, including the actin-binding domain and Homer-binding motifs. Diversity of protein isoform and multiple domains of drebrin could interact differentially with the actin cytoskeleton and other intracellular proteins and regulate diverse cellular processes. PMID- 28865013 TI - Biochemistry of Drebrin and Its Binding to Actin Filaments. AB - Drebrin is an actin-binding protein mainly expressed in developing neurons and dendritic spine in mature neurons. To understand the functions of drebrin in vivo, we must understand its molecular properties. In this chapter, I will focus on the purification and characterization of drebrin in vitro. Drebrin binds to F actin with a stoichiometry of 1:5~6 with a K d of 1~3 * 10-7 M and strongly inhibits the binding of other actin-binding proteins such as tropomyosin, caldesmon, fascin, alpha-actinin, and cofilin. It also inhibits the activities of myosin-II and myosin-V. These results are discussed in terms of the possible roles of drebrin in the stability, dynamics, and organizations of actin structures in neuronal cells. PMID- 28865014 TI - Phosphorylation of Drebrin and Its Role in Neuritogenesis. AB - Neuritogenesis is an early event in neuronal development in which newborn neurons first form growth cones, as a prerequisite for the formation of axons and dendrites. Growth cones emerge from segmented regions of the lamellipodium of embryonic neurons and grow away from the cell body leaving behind a neurite that will eventually polarise into an axon or dendrite. Growth cones also function to navigate precise routes through the embryo to locate an appropriate synaptic partner. Dynamic interactions between two components of the neuronal cytoskeleton, actin filaments and microtubules, are known to be essential for growth cone formation and hence neuritogenesis. The molecular mechanisms that coordinate interactions between actin filaments and dynamic microtubules during neuritogenesis are beginning to be understood. One candidate pathway coupling actin filaments to microtubules consists of the actin filament-binding protein drebrin and the microtubule-binding +TIP protein EB3. This pathway is regulated proximally by cyclin-dependent kinase 5 phosphorylation of drebrin but the upstream elements in the pathway have yet to be identified. PMID- 28865015 TI - Remodeling of Actin Filaments by Drebrin A and Its Implications. AB - Dendritic spines are small protrusions of dendrites that are critical for synaptic transmission. The plasticity and stability of dendritic spines is tightly linked to actin cytoskeleton. However, our understanding of specific properties and the fine-tuning of neuronal actin structures is incomplete. Drebrin A is highly enriched in dendritic spines, but its effects on actin morphology, dynamics, and interplay with other actin regulators are yet to be clarified. Here we review recent advances in understanding drebrin effects on actin morphology and dynamics. PMID- 28865016 TI - Cell Shape Change by Drebrin. AB - Drebrin is localized in actin-rich regions of neuronal and non-neuronal cells. In mature neurons, its localization is strictly restricted to the postsynaptic sites. In order to understand the function of drebrin in cells, many studies have been performed to examine the effect of overexpression or knocking down of drebrin in various cell types, including neurons, myoblasts, kidney cells, and intestinal epithelial cells. In most cases alteration of cell shape and impairment or facilitation of actin-based activities of these cells were observed. Interestingly, overexpression of drebrin in matured neurons results in the alteration in dendritic spine morphology. Further studies have shown alteration in the localization of postsynaptic receptors and even changes in synaptic transmission caused by drebrin overexpression or depletion in neurons. These drebrin's effects are thought to come from drebrin's actin-cross-linking activity or competitive binding to actin against tropomyosin, fascin, and alpha actinin. Furthermore, drebrin binds to various molecules, such as homer, EB3, and cell-cell junctional proteins, indicating that drebrin is a multifunctional cytoskeletal regulator. PMID- 28865017 TI - Localization of Drebrin: Light Microscopy Study. AB - Developmental changes in the expression and localization of drebrin has been mainly analyzed in chick embryo and young rat by various anti-drebrin polyclonal and monoclonal antibodies. Immunoblot analysis demonstrated that the adult drebrin isoform (drebrin A) is restricted to neural tissues, while the embryonic drebrin isoforms (drebrin E1 and E2 in chicken and drebrin E in mammals) are found in a wide variety of tissues. In the developing brain, drebrin E (including chicken drebrin E2) is expressed in newly generated neurons. During neuronal migration, drebrin E is distributed ubiquitously within the neurons. Once drebrin A is expressed in the developing neuron, drebrin E is no longer present within the cell soma and accumulates in the growth cone of growing processes, resulting in the cessation of neuronal migration. The limited subcellular localization of drebrin A, which is possibly regulated by a drebrin A-specific mechanism, is likely to affect the localization of drebrin E. In the adult brain, drebrin is mainly localized in dendritic spines, but in some nuclei, drebrin can be detected in neuronal somata as well as dendritic spines. The fact that the developmental changes in drebrin expression highly correlate in time with the sensitive period of visual cortical plasticity in kittens suggests that synaptic plasticity depends on drebrin. PMID- 28865019 TI - Drebrin in Neuronal Migration and Axonal Growth. AB - During development, production of neurons from neural stem cells, migration of neurons from their birthplace to their final location, and extension of neurites, axons, and dendrites are important for the formation of functional neuronal circuits. The actin cytoskeleton has major roles in the morphological development of neurons. In this chapter, we focused on the distribution and function of the actin-binding protein, drebrin, to elucidate the importance of drebrin-bound F actin in neurons during early developmental stages of neurons in embryonic, postnatal, and adult brains. There are three major isoforms of drebrin in the chicken brain (E1, E2, and A) and two major isoforms in the mammalian brain (E and A). Among these drebrin isoforms, drebrin E1 and E2 in chicken and drebrin E in the mammalian brain are involved in these neuronal stages. In migrating neurons of the developing and adult brain, drebrin is localized at the base of filopodia of leading processes, to regulate neuronal migration. In axonal growth cones, drebrin is localized in the transitional zone to regulate axonal growth by inhibiting actomyosin interactions and mediating the interactions between F-actin and microtubules. For axonal collateral branching, drebrin is localized at axonal actin patches and the base of filopodia, to accelerate the transition from actin patches to filopodia and stabilize the filopodia. PMID- 28865018 TI - Making of a Synapse: Recurrent Roles of Drebrin A at Excitatory Synapses Throughout Life. AB - Mature excitatory synapses are composed of more than 1500 proteins postsynaptically and hundreds more that operate presynaptically. Among them, drebrin is an F-actin-binding protein that increases noticeably during juvenile synaptogenesis. Electron microscopic analysis reveals that drebrin is highly enriched specifically on the postsynaptic side of excitatory synapses. Since dendritic spines are structures specialized for excitatory synaptic transmission, the function of drebrin was probed by analyzing the ultrastructural characteristics of dendritic spines of animals with genetic deletion of drebrin A (DAKO), the adult isoform of drebrin. Electron microscopic analyses revealed that these brains are surprisingly intact, in that axo-spinous synaptic junctions are well-formed and not significantly altered in number. This normal ultrastructure may be because drebrin E, the alternate embryonic isoform, compensates for the genetic deletion of drebrin A. However, DAKO results in the loss of homeostatic plasticity of N-methyl-D-aspartate receptors (NMDARs). The NMDAR activation dependent trafficking of the NR2A subunit-containing NMDARs from dendritic shafts into spine head cytoplasm is greatly diminished within brains of DAKO. Conversely, within brains of wild-type rodents, spines respond to NMDAR blockade with influx of F-actin, drebrin A, and NR2A subunits of NMDARs. These observations indicate that drebrin A facilitates the trafficking of NMDAR cargos in an F-actin-dependent manner to mediate homeostatic plasticity. Analysis of the brains of transgenic mice used as models of Alzheimer's disease (AD) reveals that the loss of drebrin from dendritic spines predates the emergence of synaptic dysfunction and cognitive impairment, suggesting that this form of homeostatic plasticity contributes toward cognition. Two studies suggest that the nature of drebrin's interaction with NMDARs is dependent on the receptor's subunit composition. Drebrin A can be found co-clustering with NR2B-containing NMDARs at the plasma membrane, while NR2A-containing NMDARs co-traffic into the spine cytoplasm but do not co-cluster at the plasma membrane. Most recently, we encountered a physiological condition that supports this idea. When adolescent female rats are reared under a condition of restricted food access and ad libitum wheel access, they paradoxically become excessive runners, choosing to run, even during the limited hours of food availability. This behavioral pattern is termed activity-based anorexia (ABA) and has served as an animal model for anorexia nervosa. Those animals that exhibit the greatest ABA vulnerability, in that they lose the most amount of body weight and run with greatest exuberance to the point of risking their lives, exhibit the highest levels of NR2B-NMDARs and drebrin at the postsynaptic membrane of hippocampal pyramidal neurons. Those animals that exhibit the greatest resilience to ABA, in that they run minimally under such condition, thereby losing minimal amount of weight, exhibit the highest level of NR2A-NMDARs in the spine cytoplasm and lowest levels of drebrin at the postsynaptic membrane. This pattern suggests that drebrin has dual roles: retention of NR2A-NMDARs in the reserve pool and trafficking of NR2B-NMDARs to the postsynaptic membrane, ultimately contributing to an individual's reactivity to stress. Altogether, these observations indicate that drebrin is a protein that is important for synaptic plasticity and deserves the attention of neuroscientists studying the neurobiological basis of cognition and stress reactivity. PMID- 28865020 TI - Drebrin and Spine Formation. AB - Dendritic spines are the postsynaptic receptive regions of most excitatory synapses in the central nervous system. Thus, spines are supposed to act as a fundamental unit for information processing of the brains. Previous studies have demonstrated the roles of drebrin in the formation of dendritic spines and in the recruitment of synaptic proteins to postsynaptic sites. Further, a live imaging study has revealed the unique dynamics of drebrin in dendritic spines, which help to understand how drebrin is involved in dendritic spine formation. This review will provide a basic knowledge about dendritic spine and overview recent progresses in understanding of the roles of drebrin in dendritic spine morphogenesis and synaptogenesis. PMID- 28865021 TI - Role of Drebrin in Synaptic Plasticity. AB - Synaptic plasticity underlies higher brain function such as learning and memory, and the actin cytoskeleton in dendritic spines composing excitatory postsynaptic sites plays a pivotal role in synaptic plasticity. In this chapter, we review the role of drebrin in the regulation of the actin cytoskeleton during synaptic plasticity, under long-term potentiation (LTP) and long-term depression (LTD). Dendritic spines have two F-actin pools, drebrin-decorated stable F-actin (DF actin) and drebrin-free dynamic F-actin (FF-actin). Resting dendritic spines change their shape, but are fairly constant over time at steady state because of the presence of DF-actin. Accumulation of DF-actin is inversely regulated by the intracellular Ca2+ concentration. However, LTP and LTD stimulation induce Ca2+ influx through N-methyl-D-aspartate (NMDA) receptors into the potentiated spines, resulting in drebrin exodus via myosin II ATPase activation. The potentiated spines change to excited state because of the decrease in DF-actin and thus change their shape robustly. In LTP, the Ca2+ increase via NMDA receptors soon returns to the basal level, and alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR) expression at the postsynaptic membrane is increased. The Ca2+ recovery and AMPAR increase coordinately induce the re accumulation of DF-actin and change the dendritic spines from the excited state to steady state during LTP maintenance. During LTD, the prolonged intracellular Ca2+ increase inhibits the re-accumulation of DF-actin, resulting in facilitation of AMPAR endocytosis. Because of the positive feedback loop of the AMPAR decrease and drebrin re-accumulation inhibition, the dendritic spines are instable during LTD maintenance. Taken together, we propose the presence of resilient spines at steady state and plastic spines at excited state and discuss the physiological and pathological relevance of the two-state model to synaptic plasticity. PMID- 28865022 TI - Drebrin in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder accompanied by severe progressive memory and cognitive impairment. The brain of AD patients has an abundance of two abnormal structures, amyloid plaques (senile plaques) and neurofibrillary tangles. In addition, drebrin loss is another hallmark of AD brains, which is a common feature in the brain of both AD patients and AD mouse models. Strong evidence from human genetics and transgenic mouse models has indicated that amyloid beta (Abeta) is part of the etiology and pathogenesis of AD. Recently, it has become clear that synaptic dysfunction, including reduced synaptic transmission and loss of dendritic spines, occurs prior to the formation of amyloid plaques and neuronal cell loss. Furthermore, immunohistochemistry using postmortem human brains and AD mouse models has shown that drebrin loss in postsynaptic sites occurs earlier than the presynaptic change in AD brains. In addition, dysregulation of glutamate receptor trafficking and the p21-activated kinase/LIM kinase pathway has been observed in AD brains. It is now believed that soluble Abeta oligomers, namely, Abeta-derived diffusible ligands (ADDLs), but not insoluble Abeta aggregation mediates Abeta toxicity. ADDLs bind to the postsynaptic site and induce the aberrant morphology and density of dendritic spines. Consistent with the AD mouse models, the surface expression of glutamate receptors decreases after ADDL exposure. Importantly, the ADDL-induced drebrin loss in dendritic spines occurs prior to aberrations in dendritic spine morphology and density. These observations indicate that drebrin loss in dendritic spines occurs at the prodromal stage of AD, before the density and morphology of dendritic spines change. Quantitation of drebrin may be a possible tool for diagnosing the prodromal stage of AD, before dementia development in AD. PMID- 28865023 TI - Drebrins and Connexins: A Biomedical Perspective. AB - In this chapter we summarize knowledge on the role of drebrin in cell-cell communications. Specifically, we follow drebrin-connexin-43 interactions and drebrin behavior at the cell-cell interface described earlier. Drebrin is a part of the actin cytoskeleton which is a target of numerous bacteria and viruses invading mammalian cells. Drebrin phosphorylation, self-inhibition and transition between filaments, particles, and podosomes underlie cellular mechanisms involved in diseases and cognitive disorders. Cytoskeletal rearrangements influence the state of gap junction contacts which regulate cell signaling and metabolic flow of information across cells in tissues. Taking into account that connexin-43 (Cx43) (together with Cx30) is heavily expressed in astrocytes and that drebrin supports cell-cell contacts, the understanding of details of how brain cells live and die reveals molecular pathology involved in neurodegeneration, Alzheimer's disease (AD), other cognitive disorders, and aging.Bidirectional connexin channels are permeable to Ca2+ ions, IP3, ATP, and cAMP. Connexin hemichannels are important for paracrine regulation and can release and exchange energy with other cells using ATP to transfer information and to support damaged cells. Connexin channels, hemichannels, and adhesion plaques are regulated by assembly and disassembly of the actin cytoskeleton. Drebrin degradation can alter gap junction communication, and drebrin level is decreased in the brain of AD patients. The diversity of drebrin functions in neurons, astrocytes, and non neuronal cells still remains to be revealed. We believe that the knowledge on drebrin summarized here will contribute to key questions, "covering the gap" between cell-cell communications and the submembrane cytoskeleton. PMID- 28865024 TI - Homer, Spikar, and Other Drebrin-Binding Proteins in the Brain. AB - Drebrin is a major F-actin-binding protein in the brain. In the past two decades, many drebrin-binding proteins in addition to F-actin have been identified in several research fields including neuroscience, oncology, and immunology. Among the drebrin-binding proteins, there are various kinds of proteins including scaffold proteins, nuclear proteins, phosphatases, microtubule-binding proteins, G-actin-binding proteins, gap junction proteins, chemokine receptors, and cell adhesion-related proteins. The interaction between drebrin and its binding partners seems to play important roles in higher brain functions, because drebrin is involved in the pathogenesis of some neurological diseases with cognitive defects. In this chapter, we will first review the interaction of Homer and spikar with drebrin, particularly focusing on spine morphogenesis and synaptic function. Homer contributes to spine morphogenesis by cooperating with shank and activated Cdc42 small GTPase, suggesting a novel signaling pathway comprising Homer, drebrin, shank, and Cdc42 for spine morphogenesis. Drebrin sequesters spikar in the cytoplasm and stabilizes it in dendritic spines, leading to spine formation. Finally, we will introduce some other drebrin-binding proteins including end-binding protein 3 (EB3), profilin, progranulin, and phosphatase and tensin homologue (PTEN). These proteins are involved in Alzheimer's disease and cancer. Therefore, further studies on drebrin and its binding proteins will be of great importance to elucidate the pathologies of various diseases and may contribute to their medical treatment and diagnostics development. PMID- 28865025 TI - Role of Drebrin at the Immunological Synapse. AB - Although drebrin was first described in neurons, it is also expressed in cells of the immune system, such as T lymphocytes and mast cells. Another member of the drebrin family of proteins, mammalian actin-binding protein 1 (mAbp-1) is more widely expressed and plays important roles in the function of macrophages, polymorphonuclear neutrophils, and B lymphocytes. We will briefly discuss on the function of mAbp-1 and drebrin in immune cells with emphasis on T cells. Specifically, drebrin enables the immune responses of CD4+ T lymphocytes. T cells are activated after the recognition of an antigen presented by antigen-presenting cells through cognate cell-cell contacts called immunological synapses (IS). In CD4+ T cells, drebrin associates with the chemokine receptor CXCR4, and both molecules redistribute to the IS displaying similar dynamics. Through its interaction with CXCR4 and the actin cytoskeleton, drebrin regulates T cell activation. CD4+ T cells are one of the main targets for the human immunodeficiency virus (HIV)-1. This virus utilizes the IS structure to be transmitted to uninfected cells, forming cell-cell contacts called virological synapses (VS). Interestingly, drebrin negatively regulates HIV-1 infection of CD4+ T lymphocytes, by regulating actin polymerization at the VS. PMID- 28865026 TI - Drebrin Regulation of Calcium Signaling in Immune Cells. AB - Store-operated Ca2+ channels are plasma membrane channels that are activated by depletion of intracellular Ca2+ stores, resulting in an increase in intracellular Ca2+; however, little is known about their regulation. Our work has shown that the immunosuppressant compound BTP2, which blocks Ca2+ influx into cells, interacts with the actin-reorganizing protein, drebrin. Here we review the role of drebrin in the regulation of calcium signaling, with a focus on immune cells. PMID- 28865028 TI - Drebrin at Junctional Plaques. AB - Adhesion, segregation, and cellular plasticity are regulated by actin filaments anchored at the plaques of adherens junctions, sites of mechanical stabilization, and interfaces of multiple signaling networks. Drebrins were originally identified in neuronal cells, but the isoform drebrin E was also detected at adherens junctions of a wide range of non-neuronal cells, including polarized epithelia, endothelia, and fibroblasts. Here the protein is enriched at actin filament bundles associated with junctional plaques. Polarized epithelial cells contain two types of actin-associated complexes, one comprising drebrin but not vinculin and the other involving vinculin, but not drebrin. At gap junctions drebrin interacts with connexin 43, stabilizes this protein at membranes, and links it to the actin cytoskeleton. In vivo drebrin is widespread in diverse non neuronal tissues of epithelial, endothelial, and smooth muscle origin, but not ubiquitous. In intestinal cells it is involved in cell compaction, linking of actin filaments to microtubules and formation and stabilization of the terminal web. Upregulation of drebrin was noted in several types of cancers, e.g., basal cell carcinomas for which it may serve as marker, liver metastases of colon carcinomas, and bladder cancer, suggesting that it is involved in regulating actin dynamics during tumor development, progression, and metastasis. PMID- 28865029 TI - Juxtanuclear Drebrin-Enriched Zone. AB - Drebrin E contributes to remodeling of the actin cytoskeleton and formation of cell processes. Therefore, its role in cell migration was studied in prototypes of motile cells with prominent lamellipodia such as murine B16F1 melanoma and Swiss 3T3 cells and in human SV80 fibroblasts. Confocal microscopy revealed absence of drebrin from the tips of lamellipodia but enrichment in the tail of the cells, in retraction zones and in a specific juxtanuclear actin filament compartment, named "drebrin-enriched zone." A similar subset of juxtanuclear actin filaments is characterized by the actin-binding protein SWAP-70, but drebrin and SWAP-70 localized to different compartments, suggesting the existence of novel distinct subdomains within the actin filament system. In cells overexpressing drebrin-EGFP, numerous long, branched cell processes were formed which slowly retracted and extended. However, in stable transfectants containing lower amounts of the fusion protein, drebrin-EGFP was recruited to the same sites as the endogenous protein during cell migration, i.e., to retracting membrane domains and into the juxtanuclear drebrin-enriched zone. In the leading edges of SV80 cells, characterized by pronounced actin microspikes, drebrin was concentrated along posterior portions of the microspikes, together with tropomyosin, with which it competes for actin binding. Drebrin knockdown by siRNA did not impact forward migration or ruffling. Taken together, these findings suggest that during cell migration drebrin is involved in retraction processes but not in lamellipodia formation. The novel, sizable juxtanuclear drebrin enriched zone remains to be characterized in detail with respect to its molecular assembly and functions. PMID- 28865030 TI - Drebrin in Renal Glomeruli. AB - The central function of renal glomeruli is plasma ultrafiltration for primary urine production. The glomerular filtration barrier consists of a fenestrated endothelium, the glomerular basement membrane and podocytes, mesenchymal-like cells with actin filament-rich protrusions, the "foot processes." Their architecture and function are maintained and regulated by actin and several actin binding proteins, mutations of which can be causative of glomerular diseases. Since initial immunostaining experiments had demonstrated intense drebrin reactions in renal glomeruli, the distribution of this protein was studied in detail in the kidneys of diverse mammalian species. Double-label confocal laser scanning microscopy revealed drebrin enrichment in mesangial cells of human, bovine, murine, and rat kidneys. In Thy-1.1 nephritic rat glomeruli, the protein was concentrated in mesangial cell processes and upregulated during their formation and remodeling. In adult human and bovine kidneys, drebrin was additionally accumulated in the foot processes of podocytes, a finding confirmed by immunoelectron microscopy. By contrast, podocytes of rodent glomeruli contained significant amounts of drebrin only during early developmental stages. In cultured murine podocytes induced to form cell processes, however, drebrin was concentrated in these protrusions, partly in colocalization with other actin binding proteins. Protein extracts from human and bovine kidneys comprised 20 S complexes of drebrin and actin, so-called drebrosomes. In summary, drebrin has to be added to the list of actin-binding proteins regulating actin dynamics of mesangial cell processes and foot processes of podocytes. It will be important to determine its role in hereditary and acquired glomerulopathies. PMID- 28865027 TI - Drebrin and Spermatogenesis. AB - Drebrin is a family of actin-binding proteins with two known members called drebrin A and E. Apart from the ability to stabilize F-actin microfilaments via their actin-binding domains near the N-terminus, drebrin also regulates multiple cellular functions due to its unique ability to recruit multiple binding partners to a specific cellular domain, such as the seminiferous epithelium during the epithelial cycle of spermatogenesis. Recent studies have illustrated the role of drebrin E in the testis during spermatogenesis in particular via its ability to recruit branched actin polymerization protein known as actin-related protein 3 (Arp3), illustrating its involvement in modifying the organization of actin microfilaments at the ectoplasmic specialization (ES) which includes the testis specific anchoring junction at the Sertoli-spermatid (apical ES) interface and at the Sertoli cell-cell (basal ES) interface. These data are carefully evaluated in light of other recent findings herein regarding the role of drebrin in actin filament organization at the ES. We also provide the hypothetical model regarding its involvement in germ cell transport during the epithelial cycle in the seminiferous epithelium to support spermatogenesis. PMID- 28865031 TI - Drebrin's Role in the Maintenance of Endothelial Integrity. AB - The human endothelium forms a permeable barrier between the blood stream and surrounding tissues, strictly governing the passage of immune cells, fluids and metabolites. The regulation of cell-cell contact dynamics between endothelial cells is essential for this function and thus for the maintenance of vascular integrity. Intercellular adhesion within the endothelium is mainly dependent on adherens junctions, composed of cell-cell adhesion proteins such as VE-cadherin and nectin, and their associated proteins. Recent research points to a critical role of the actin cytoskeleton in endothelial integrity, by providing anchorage of adhesion complexes to the cell cortex. We could show that the F-actin-binding protein drebrin is a critical regulator of endothelial integrity, by linking nectin to the cortical actin cytoskeleton. In particular, the knockdown of drebrin leads to functional impairment of endothelial cells, characterized by rupturing of endothelial monolayers cultured under conditions mimicking vascular flow. This weakening of cell-cell contacts upon drebrin depletion is based on the destabilization of nectin at adherens junctions, followed by internalization and degradation in lysosomes. Conducting interaction studies, we showed that drebrin binds to nectin's interaction partner afadin, thus linking the nectin/afadin system to the cortical F-actin network. Drebrin, containing binding sites for both afadin and F-actin, is thus uniquely equipped to stabilize nectin at adherens junctions, thereby preserving endothelial integrity. Collectively, these results contribute to the current understanding of cell-cell junction regulation, introducing a new function of drebrin as a stabilizer of endothelial integrity. PMID- 28865032 TI - Regulation of Skeletal Myoblast Differentiation by Drebrin. AB - Myoblast differentiation is a complex process. As myoblasts differentiate into myofibers, they acquire a cell type-specific transcriptional program, irreversibly exit the cell cycle, and dramatically change their morphology. The morphological changes include cell elongation, alignment, and fusion into syncytial myofibers. Several lines of evidence suggest that these events may be co-regulated. However, the mechanisms that coordinate major alterations in a cell's transcriptome and its shape are not well understood. Muscle-specific transcription is controlled by proteins of the MyoD family, transcription factors whose activity is regulated by specific signal transduction pathways, including the p38 MAP kinase pathway. In a search for genes that might play a role in linking myogenic signal transduction, cytoskeletal regulation, and myoblast differentiation, Dbn1 (encoding the actin regulator drebrin) was identified. Dbn1 expression is induced during myoblast differentiation, in a p38 MAP kinase- and MyoD- dependent manner. RNAi-mediated depletion of drebrin, or treatment with a chemical drebrin inhibitor, resulted in a similar phenotype in myoblasts: defective differentiation, with low levels of early and late differentiation markers and inefficient production of myofibers. Drebrin localizes at sites of cell-cell contact and cell extensions, locations that are also enriched for F actin. Drebrin may be important in linking transcriptional and morphological aspects of myoblast differentiation. PMID- 28865033 TI - The Role of Drebrin in Cancer Cell Invasion. AB - Cancer progression is characterized by the capacity of malignant cells to exploit an innate migratory ability in order to invade adjacent tissues, enter the vasculature and eventually metastasize to secondary organs. It is this spread of cancer cells that is the major cause of death in cancer patients. Understanding the basic biology of how cancer cells generate an invasive phenotype will be crucial to the identification of drug targets with the aim of impeding tumour dissemination. Ten years on from its initial description in neuronal cells, drebrin expression was found in a wide variety of non-neuronal cells that importantly included cancer cell lines. Since then mounting evidence suggests that drebrin may be a key player in the advancement of several diverse cancer types where its expression is frequently upregulated. Cancer cell motility and invasion are crucial elements in the metastatic cascade and involve dramatic changes in cellular morphology that are associated with dynamic remodelling of the cytoskeleton. Interestingly, it now appears that drebrin could deliver this role during cancer development. PMID- 28865034 TI - 'The Elephant on the Table': Religious and Ethnic Diversity in Home Health Services. AB - Healthcare services are increasingly being provided in the home. At the same time, these home contexts are changing as global migration has brought unprecedented diversity both in the recipients of care, and home health workers. In this paper, we present findings of a Canadian study that examined the negotiation of religious and ethnic plurality in home health. Qualitative analysis of the data from interviews and observations with 46 participants clients, administrators, home healthcare workers-revealed how religion is expressed and 'managed' in home health services. PMID- 28865036 TI - Giant Hepatic Adenoma in a 12-Year-Old Girl. PMID- 28865035 TI - Effect of zoledronic acid on lumbar spinal fusion in osteoporotic patients. AB - PURPOSE: To investigate the effect of zoledronic acid (ZA) on lumbar spinal fusion in patients with osteoporosis. METHODS: This retrospective study includes 94 osteoporotic patients suffering from lumbar degenerative diseases or lumbar fracture who underwent lumbar spinal fusion in our institution from January 2013 to August 2014. They were divided into ZA group and control group according to whether the patient received ZA infusion or not. The patients in ZA group were given 5 mg intravenous ZA at the 3rd-5th days after operation. All patients took daily oral supplement of 600 mg calcium carbonate and 800 IU vitamin D during the follow-up after operation. The Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Short Form 36 (SF-36) scores were recorded preoperatively and post-operatively to evaluate the clinic outcomes; the spinal fusion was assessed by X-ray or CT Scan. RESULTS: 64 patients finished the final follow-up, including 30 patients in ZA group and 34 patients in control group. No significant difference was observed in gender, age, and preoperative BMI VAS, ODI, and SF-36 scores between the two groups (P > 0.05). The post-operative VAS and ODI scores decreased rapidly at 3 and 6 months, but rose back slightly at 12 and 24 months in both groups. On the contrary, post-operative SF-36 scores increased rapidly at 3 and 6 months, while fell back slightly at 12 and 24 months, with a statistically significant difference between the two groups at 12 months, but not at 3 and 6 month post-operation. The spinal fusion rate in ZA group was 90% at 6 months, 92% at 12 months, while it was 75% at 6 months, 92.86% at 12 months in control group, significantly different between the two groups at 12 months, but not at 6 months. In the whole follow-up period, adjacent vertebral compressing fracture occurred in five patients in control group, none in ZA group. No pedicle screw loosening was observed in ZA group, with six in control group. CONCLUSIONS: Zoledronic acid accelerates spinal fusion, shortens the time of fusion without changing fusion rate, and also decreases the risk of adjacent vertebral compressing fracture and the rate of pedicle screw loosening, resulting in the improvement of clinical outcomes and quality of life. PMID- 28865037 TI - The presence of anaemia negatively influences survival in patients with POLG disease. AB - BACKGROUND: Mitochondria play an important role in iron metabolism and haematopoietic cell homeostasis. Recent studies in mice showed that a mutation in the catalytic subunit of polymerase gamma (POLG) was associated with haematopoietic dysfunction including anaemia. The aim of this study was to analyse the frequency of anaemia in a large cohort of patients with POLG related disease. METHODS: We conducted a multi-national, retrospective study of 61 patients with confirmed, pathogenic biallelic POLG mutations from six centres, four in Norway and two in the United Kingdom. Clinical, laboratory and genetic data were collected using a structured questionnaire. Anaemia was defined as an abnormally low haemoglobin value adjusted for age and sex. Univariate survival analysis was performed using log-rank test to compare differences in survival time between categories. RESULTS: Anaemia occurred in 67% (41/61) of patients and in 23% (14/61) it was already present at clinical presentation. The frequency of anaemia in patients with early onset disease including Alpers syndrome and myocerebrohepatopathy spectrum (MCHS) was high (72%) and 35% (8/23) of these had anaemia at presentation. Survival analysis showed that the presence of anaemia was associated with a significantly worse survival (P = 0.004). CONCLUSION: Our study reveals that anaemia can be a feature of POLG-related disease. Further, we show that its presence is associated with significantly worse prognosis either because anaemia itself is impacting survival or because it reflects the presence of more serious disease. In either case, our data suggests anaemia is a marker for negative prognosis. PMID- 28865039 TI - The Roles of Relative Linguistic Proficiency and Modality Switching in Language Switch Cost: Evidence from Chinese Visual Unimodal and Bimodal Bilinguals. AB - The current study investigated the mechanism of language switching in unbalanced visual unimodal bilinguals as well as balanced and unbalanced bimodal bilinguals during a picture naming task. All three groups exhibited significant switch costs across two languages, with symmetrical switch cost in balanced bimodal bilinguals and asymmetrical switch cost in unbalanced unimodal bilinguals and bimodal bilinguals. Moreover, the relative proficiency of the two languages but not their absolute proficiency had an effect on language switch cost. For the bimodal bilinguals the language switch cost also arose from modality switching. These findings suggest that the language switch cost might originate from multiple sources from both outside (e.g., modality switching) and inside (e.g., the relative proficiency of the two languages) the linguistic lexicon. PMID- 28865040 TI - The impact of peri-operative dexamethasone administration on the normal hypothalamic pituitary adrenal response to major surgical procedures. AB - BACKGROUND: Surgical procedures are associated with activation of the hypothalamic-pituitary-adrenal axis (HPA). Studies examining HPA dynamics peri operatively are limited and the modulating influence of peri-operatively administered glucocorticoids on that is not well established. This investigation examined alterations in HPA function and the impact of dexamethasone (DEX) administration during the peri-operative period. METHODS: We examined HPA function in 297 patients with normal function who had surgical procedures including pituitary mass resection (n = 191), craniotomy (n = 17) and other thoracic/ abdominal/ pelvic surgeries (n = 89). HPA function was assessed by frequent measurements of parameters defining adrenal function: ACTH, cortisol, DHEA and DHEA-S levels for 48 h. DEX was administered as a single dose (2-10 mg) to 30 and as multiple doses (12-36 mg) to 21 patients. The data of DEX-treated subjects within each group were similar and were combined together. RESULTS: Pre operative data were similar for patients having different surgical procedures. Without DEX exposure, ACTH increased to 225 +/- 100 ng/L at 2-4 h and gradually declined to baseline values by 36 h while cortisol levels peaked (39.2 +/- 13.2 ug/dL) at 6-8 h declining gradually thereafter. Cortisol rise was paralleled by an equimolar increase in DHEA and a subsequent increase in DHEA-S levels. Single doses of DEX did not influence ACTH or cortisol secretion but suppressed the expected rise in DHEA and DHEA-S levels. Multiple doses of DEX suppressed ACTH and cortisol after the 15th postoperative hour and completely blocked the expected rise in DHEA and DHEA-S levels. CONCLUSIONS: The data provide a detailed overview of HPA function in a large number of subjects who had major surgical procedures. Single and large doses of DEX did not suppress ACTH or cortisol secretion but suppressed adrenal androgen secretion. It took multiple doses of DEX to partially suppress ACTH and cortisol secretion in the peri-operative period. PMID- 28865041 TI - Bezlotoxumab: A Review in Preventing Clostridium difficile Infection Recurrence. AB - Bezlotoxumab (ZinplavaTM) is a fully human monoclonal antibody against Clostridium difficile toxin B indicated for the prevention of C. difficile infection (CDI) recurrence in patients with a high recurrence risk. It is the first agent approved for recurrence prevention and is administered as a single intravenous infusion in conjunction with standard-of-care (SoC) antibacterial treatment for CDI. In well-designed, placebo-controlled, phase 3 trials (MODIFY 1 and 2), a single infusion of bezlotoxumab, given in combination with SoC antibacterial therapy for CDI in adults, was effective in reducing CDI recurrence in the 12 weeks post-treatment, with this benefit being seen mainly in the patients at high recurrence risk. Bezlotoxumab did not impact the efficacy of the antibacterials being used to treat the CDI and, consistent with its benefits on CDI recurrence, appeared to reduce the need for subsequent antibacterials, thus minimizing further gut microbiota disruption. Longer term, there were no further CDI recurrences over 12 months' follow-up among patients who had received bezlotoxumab in MODIFY 2 and entered an extension substudy. Bezlotoxumab has low immunogenicity and is generally well tolerated, although the potential for heart failure in some patients requires consideration; cost-effectiveness data for bezlotoxumab are awaited with interest. Thus, a single intravenous infusion of bezlotoxumab during SoC antibacterial treatment for CDI is an emerging option for reducing CDI recurrence in adults at high risk of recurrence. PMID- 28865038 TI - Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research. AB - Various adverse events resulting from, or associated with, benzodiazepine and/or Z-drug use have been extensively reported on and discussed in great detail within the biomedical literature. It is widely accepted that motor vehicle accidents and falls leading to fractures in older adults are major adverse events that have been shown to occur more frequently in users of sedative-hypnotic medication, especially of the benzodiazepine and related Z-drug variety. However, the last few years have seen increasing reports in the literature raising the issue of benzodiazepine and Z-drug exposure in the development of other serious medical issues including dementia, infections, respiratory disease exacerbation, pancreatitis, and cancer. This article provides an overview and interpretation on the current state of evidence regarding each of these associations and proposes what gaps in the evidence for drug-exposure-harm associations need to be addressed in the future for the purpose of evaluating causality of harm as it relates to these drugs. PMID- 28865042 TI - Influence of undersized cementless hip stems on primary stability and strain distribution. AB - INTRODUCTION: Undersizing of cementless hip stems is a risk factor for aseptic loosening and early subsidence. The purpose of this study was to evaluate the effects of undersized stems and determine whether a biomechanical study can predict the clinical results. MATERIALS AND METHODS: Three consecutive sizes of a clinically proven stem (CLS Spotorno) were implanted into six composite femora (size large, Sawbones(r)), respectively. According to the Canal Fill Index (CFI), two stems (size 11.25 and 12.5) were undersized (CFI < 80%) and one stem (size 13.75) had an appropriate size (CFI > 80%). The primary stability was evaluated by measurement of 3-dimensional (3D)-micromotions under physiological adapted load and surface strains were recorded before and after implantation to detect stress-shielding processes. RESULTS: Both undersized stems revealed significantly higher micromotions in all regions compared to the appropriate stem. The highest micromotions were registered at the distal tip of the three stem sizes. The changes in surface strain did not show a significant difference between the three stem sizes, but the highest strain reduction was observed proximally indicating a tendency for stress shielding. CONCLUSIONS: This study confirms the clinical assumption that undersized stem result in a significantly reduced primary stability. Furthermore, in vitro studies allow to determine the effects of undersizing and stress shielding processes. PMID- 28865043 TI - Cerebrospinal fluid injection into adult zebrafish for disease research. AB - A modified method of cerebrospinal fluid injection was developed for the efficient and reliable administration of substances to the zebrafish central nervous system. The accuracy of this modified method was evaluated using Alexa Fluor dye injection. A high survival ratio was achieved due to the simplicity of the procedure and ice-tricaine combined anaesthesia. To validate this new method, we injected ammonium chloride, which successfully blocked lysosome function resulting in elevated LC3-II and the accumulation of ubiquitinated proteins. Injection of human alpha-synuclein fibrils initiated a prion-like propagation of alpha-synuclein pathology in zebrafish. This method can be used to investigate the effects of various substances and the propagation of alpha-synuclein in the central nervous system. PMID- 28865044 TI - The Implications of Genetics for Prevention and Intervention Programming. PMID- 28865045 TI - Best not to bet on the horserace: A comment on Forrin and MacLeod (2017) and a relevant stimulus-response compatibility view of colour-word contingency learning asymmetries. AB - One powerfully robust method for the study of human contingency learning is the colour-word contingency learning paradigm. In this task, participants respond to the print colour of neutral words, each of which is presented most often in one colour. The contingencies between words and colours are learned, as indicated by faster and more accurate responses when words are presented in their expected colour relative to an unexpected colour. In a recent report, Forrin and MacLeod (2017b, Memory & Cognition) asked to what extent this performance (i.e., response time) measure of learning might depend on the relative speed of processing of the word and the colour. With keypress responses, learning effects were comparable when responding to the word and to the colour (contrary to predictions). However, an asymmetry appeared in a second experiment with vocal responses, with a contingency effect only present for colour identification. In a third experiment, the colour was preexposed, and contingency effects were again roughly symmetrical. In their report, they suggested that a simple speed-of-processing (or "horserace") model might explain when contingency effects are observed in colour and word identification. In the present report, an alternative view is presented. In particular, it is argued that the results are best explained by appealing to the notion of relevant stimulus-response compatibility, which also resolves discrepancies between horserace model predictions and participant results. The article presents simulations with the Parallel Episodic Processing model to demonstrate this case. PMID- 28865046 TI - Prospective experience of percutaneous endoscopic gastrostomy tubes placed by otorhinolaryngologist-head and neck surgeons: safe and efficacious. AB - Percutaneous endoscopic gastrostomy (PEG) is often the treatment of choice in head and neck cancer (HNC) patients needing long-term nutritional support. Prospective studies on PEG tube placement in an otorhinolaryngologist service are lacking. At our hospital, otolaryngologist-head and neck (ORL-HN) surgeons-have performed PEG insertions for HNC patients since 2008. We prospectively analyzed 127 consecutive HNC patients who received their PEG tubes at the Department of Otorhinolaryngology-head and neck surgery, and evaluated the outcome of PEG tube insertions performed by ORL-HN surgeons. To compare time delays before and after, PEG placement service was transferred from gastrointestinal surgeons to ORL-HN surgeons, and we retrospectively analyzed a separate group of 110 HNC patients who had earlier received PEG tubes at the Department of Gastrointestinal Surgery. ORL-HN surgeons' success rate in PEG insertion was 97.6%, leading to a final prospective study group of 124 patients. Major complications occurred in four (3.2%): two buried bumper syndromes, one subcutaneous hemorrhage leading to an abscess in the abdominal wall, and one metastasis at the PEG site. The most common minor complication was peristomal granulomatous tissue affecting 23 (18.5%) patients. After the change in practice, median time delay before PEG insertion decreased from 13 to 10 days (P < 0.005). The proportion of early PEG placements within 0-3 days increased from 3.6 to 14.6% (P < 0.005). PEG tube insertion seems to be a safe procedure in the hands of an ORL-HN surgeon. Independence from gastrointestinal surgeons' services reduced the time delay and improved the availability of urgent PEG insertions. PMID- 28865047 TI - Facile synthesis of Gd-doped CdTe quantum dots with optimized properties for optical/MR multimodal imaging. AB - Each imaging modality has its own merits and intrinsic limitations; therefore, combining two or more complementary imaging modalities has become an interesting area of research. Recently, magnetic ion-doped quantum dots have become an increasingly promising class of optical/magnetic resonance multimodal imaging probes due to their excellent physical and chemical properties. In this work, Gd doped CdTe quantum dots (QDs) were successfully synthesized via a facile one-step refluxing route,and their optimal synthesis conditions were investigated. The prepared CdTe:Gd QDs were shown to exhibit good optical properties with high quantum yields up to 69%, high longitudinal relaxivity (r 1 = 3.8 mM-1 s-1), and good crystalline structures. In addition, after further QD surface modification with dextran amine (DA), the resulting DA-modified QDs (i.e. DA-CdTe:Gd QDs) showed strong magnetic resonance imaging contrast (r 1 = 3.5 mM-1 s-1) and improved biocompatibility when tested with cell cultures in vitro. Taken together, this new material demonstrated promising performances for both optical and magnetic resonance imaging modalities, suggesting its promising potential applications in non-invasive imaging, particularly in neuronal tracing. PMID- 28865048 TI - Assessing the combined toxicity of conventional and newer insecticides on the cotton mealybug Phenacoccus solenopsis. AB - Reduced susceptibility to insecticides often results in failure of insect pest control and repetitive use of broad-spectrum insecticides, which could have detrimental effects on beneficial arthropods and surrounding agro-ecosystems. The cotton mealybug, Phenacoccus solenopsis Tinsley is a pest of worldwide importance that can be effectively controlled using a number of insecticides. This insect has developed resistance due to injudicious use and repeated exposure to insecticides throughout the year. The aim of the present study was to investigate the toxicity of the insecticides chlorpyrifos, deltamethrin, spinosad, emamectin benzoate and indoxacarb tested either singly or in combination on laboratory susceptible (Lab-PK) and field population (Field Pop) of P. solenopsis. In the Field Pop, combination of chlorpyrifos with either spinosad or emamectin benzoate or indoxacarb showed a synergistic effect at 1:1, 1:10 and 1:20. The combination of deltamethrin with either emamectin benzoate or indoxacarb at all ratios showed synergistic effect, while the combination of deltamethrin with spinosad at 1:1 and 1:20 ratios showed antagonistic effects and that at 1:10 ratio showed synergistic effect against Field Pop. The results of synergism experiments using piperonyl butoxide (PBO) and S,S,S-tributylphosphorotrithioate (DEF) enzyme inhibitors, when combined with insecticides against the Field Pop, toxicities of all tested insecticides were significantly increased. The present study suggests that insecticide combinations and synergism could help achieve effective control of less susceptible populations of P. solenopsis. This would contribute to suitably managing resistance of this pest to insecticides with reduced negative impacts on the surrounding environment. PMID- 28865050 TI - Histogram Analysis of T1-Weighted, T2-Weighted, and Postcontrast T1-Weighted Images in Primary CNS Lymphoma: Correlations with Histopathological Findings-a Preliminary Study. AB - PURPOSE: Previously, some reports mentioned that magnetic resonance imaging (MRI) can predict histopathological features in primary CNS lymphoma (PCNSL). The reported data analyzed diffusion-weighted imaging findings. The aim of this study was to investigate possible associations between histopathological findings, such as tumor cellularity, nucleic areas and proliferation index Ki-67, and signal intensity on T1-weighted and T2-weighted images in PCNSL. PROCEDURES: For this study, 18 patients with PCNSL were retrospectively investigated by histogram analysis on precontrast and postcontrast T1-weighted and fluid-attenuated inversion recovery (FLAIR) images. For every patient, histopathology parameters, nucleic count, total nucleic area, and average nucleic area, as well as Ki-67 index, were estimated. RESULTS: Correlation analysis identified several statistically significant associations. Skewness derived from precontrast T1 weighted images correlated with Ki-67 index (p = - 0.55, P = 0.028). Furthermore, entropy derived from precontrast T1-weighted images correlated with average nucleic area (p = 0.53, P = 0.04). Several parameters from postcontrast T1 weighted images correlated with nucleic count: maximum signal intensity (p = 0.59, P = 0.017), P75 (p = 0.56, P = 0.02), and P90 (p = 0.52, P = 0.04) as well as SD (p = 0.58, P = 0.02). Maximum signal intensity derived from FLAIR sequence correlated with nucleic count (p = 0.50, P = 0.03). CONCLUSION: Histogram-derived parameters of conventional MRI sequences can reflect different histopathological features in PSNCL. PMID- 28865049 TI - Exercise therapy for treatment of supraspinatus tears does not alter glenohumeral kinematics during internal/external rotation with the arm at the side. AB - PURPOSE: Rotator cuff tears are a significant clinical problem, with exercise therapy being a common treatment option for patients. Failure rates of exercise therapy may be due to the failure to improve glenohumeral kinematics. Tears involving the supraspinatus may result in altered glenohumeral kinematics and joint instability for internal/external rotation with the arm at the side because not all muscles used to stabilize the glenohumeral joint are functioning normally. The objective of the study is to assess in vivo glenohumeral kinematic changes for internal/external rotation motions with the arm at the side of patients with a symptomatic full-thickness supraspinatus tear before and after a 12-week exercise therapy programme. METHODS: Five patients underwent dynamic stereoradiography analysis before and after a 12-week exercise therapy protocol to measure changes in glenohumeral kinematics during transverse plane internal/external rotation with the arm at the side. Patient-reported outcomes and shoulder strength were also evaluated. RESULTS: No patient sought surgery immediately following exercise therapy. Significant improvements in isometric shoulder strength and patient-reported outcomes were observed (p < 0.05). No significant changes in glenohumeral kinematics following physical therapy were found. CONCLUSION: Isolated supraspinatus tears resulted in increased joint translations compared to healthy controls from the previous literature for internal/external rotation with the arm at the side. Despite satisfactory clinical outcomes following exercise therapy, glenohumeral kinematics did not change. The lack of changes may be due to the motion studied or the focus of current exercise therapy protocols being increasing shoulder strength and restoring range of motion. Current exercise therapy protocols should be adapted to also focus on restoring glenohumeral kinematics to improve joint stability since exercise therapy may have different effects depending on the motions of daily living. LEVEL OF EVIDENCE: Prognostic study, Level II. PMID- 28865051 TI - Tree growth response of Fokienia hodginsii to recent climate warming and drought in southwest China. AB - To date, few attempts have been made to assess the influence of climate change on forest ecosystems and on the relationship between tree growth and climate in humid areas of low latitudes. In this paper, we studied the response of tree growth and forest ecosystem to climate change by using Fokienia hodginsii tree ring cores from the northern Yunnan-Guizhou Plateau, southwest of China. Tree growth correlates the highest (r = -0.64, p < 0.01) with mean temperature (July September), but the coefficients were changing with time as revealed by a moving correlation analysis. Tree growth is significantly (p < 0.05) and positively correlated with January-April mean temperature from AD 1961-1987, while correlations with precipitation are insignificant. In contrast, from 1988 to 2014, tree growth correlated negatively with mean temperature of previous summer and positively with precipitation of previous August-September. This indicated that the limiting factors for tree growth have changed under different climate conditions. The meteorological data suggested that from 1961 to 1987 it was cold and wet in the study area and radial growth is limited by winter and spring temperatures. This restriction is weaker if the climate is appropriate in general. However, from 1988 to 2014, the combined effects of recent warming and decreasing precipitation have led to an increasing response of tree-ring width to drought. In addition, a large proportion of mature F. hodginsii mortality occurred from 2007 to 2013, which corresponds with a drastic reduction of radial growth (narrowest in recent 100 years). The recent drought, induced by decreasing precipitation and increasing temperature, may have passed the threshold which F. hodginsii could tolerate, causing tree growth reduction, tree growth-climate relationship change, as well as catastrophic tree mortality. All these changes may lead to further responses of the local ecosystem to climate change which should be highly regarded. PMID- 28865052 TI - An improved method for identifying SUMOylation sites of viral proteins. AB - In this study, we improved the most commonly used methods for MS detection of SUMOylated sites and used an E. coli recombination SUMOylation system with SUMO-1 (T95R). This system provides fast enrichment of SUMOylated viral protein in less than 2 days, and shows advantage over the method of collecting modified protein from cells in convenience and sensitivity. Furthermore, this method provides an option for rapid and accurate identification of the potential viral protein SUMOylation sites. PMID- 28865053 TI - DC-SIGN promotes Japanese encephalitis virus transmission from dendritic cells to T cells via virological synapses. AB - Skin-resident dendritic cells (DCs) likely encounter incoming viruses in the first place, and their migration to lymph nodes following virus capture may promote viral replication. However, the molecular mechanisms underlying these processes remain unclear. In the present study, we found that compared to cell free viruses, DC-bound viruses showed enhanced capture of JEV by T cells. Additionally, JEV infection was increased by co-culturing DCs and T cells. Blocking the C-type lectin receptor DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) with neutralizing antibodies or antagonists blocked JEV transmission to T cells. Live-cell imaging revealed that DCs captured and transferred JEV viral particles to T cells via virological synapses formed at DC-T cell junctions. These findings indicate that DC-SIGN plays an important role in JEV transmission from DCs to T cells and provide insight into how JEV exploits the migratory and antigen-presenting capabilities of DCs to gain access to lymph nodes for dissemination and persistence in the host. PMID- 28865054 TI - The history of medicine : Challenges and successes. PMID- 28865055 TI - Polychlorinated biphenyl 19 blocks the most common form of store-operated Ca2+ entry through Orai. AB - PCB19, a 2,2',6-trichlorinated biphenyl, is one of many non-dioxin-like polychlorinated biphenyls (NDL-PCBs), which are ubiquitous pollutants. NDL-PCBs affect cytosolic Ca2+ signaling by promoting Ca2+ release from ryanodine receptor sensitive Ca2+ pools and inhibiting store-operated Ca2+ entry (SOCE) from the extracellular space. However, NDL-PCB-mediated SOCE inhibition has only been demonstrated in PC12 cells, in which SOCE is thought to be mainly mediated by TRPC family channels. Here, we investigated the effect of PCB19 on SOCE using human embryonic kidney 293 (HEK293) cells, human leukemia T cell line Jurkat-T cells and human promyelocytoma HL-60 cells which are the cell lines that are previously demonstrated to mediate the most common form of SOCE solely by the intrinsic Orai channels. PCB19 reduced thapsigargin-induced Ca2+ influx after Ca2+ pool depletion in HEK293 cells. SOCEs in HEK293, Jurkat T, HL-60 and PC12 cells showed distinct sensitivities to SOCE inhibitors such as Gd3+ and ML-9; however, PCB19 also showed a common effect of inhibiting SOCEs in all cell lines. PCB19-mediated SOCE inhibition was confirmed by demonstrating the ability of PCB19 to inhibit the SOCE current but not the TRPM7 current. These results imply that PCB19 inhibits not only TRPC-mediated SOCE as in PC12 cells but also Orai mediated SOCE as in many other cells including HEK293, Jurkat T and HL-60 cells. PMID- 28865056 TI - Blinded evaluation of farnesoid X receptor (FXR) ligands binding using molecular docking and free energy calculations. AB - Our participation to the D3R Grand Challenge 2 involved a protocol in two steps, with an initial analysis of the available structural data from the PDB allowing the selection of the most appropriate combination of docking software and scoring function. Subsequent docking calculations showed that the pose prediction can be carried out with a certain precision, but this is dependent on the specific nature of the ligands. The correct ranking of docking poses is still a problem and cannot be successful in the absence of good pose predictions. Our free energy calculations on two different subsets provided contrasted results, which might have the origin in non-optimal force field parameters associated with the sulfonamide chemical moiety. PMID- 28865058 TI - Combined metformin-associated lactic acidosis and euglycemic ketoacidosis. AB - BACKGROUND: In renal failure metformin can lead to lactic acidosis. Additional inhibition of hepatic gluconeogenesis by accumulation of the drug may aggravate fasting-induced ketoacidosis. We report the occurrence of metformin-associated lactic acidosis (MALA) with concurrent euglycemic ketoacidosis (MALKA) in three patients with renal failure. CASE PRESENTATIONS: Patient 1: a 78-year-old woman (pH = 6.89, lactic acid 22 mmol/l, serum ketoacids 7.4 mmol/l and blood glucose 63 mg/dl) on metformin and insulin treatment. Patient 2: a 79-year-old woman on metformin treatment (pH = 6.80, lactic acid 14.7 mmol/l, serum ketoacids 6.4 mmol/l and blood glucose 76 mg/dl). Patient 3: a 71-year-old man on metformin, canagliflozin and liraglutide treatment (pH = 7.21, lactic acid 5.9 mmol/l, serum ketoacids 16 mmol/l and blood glucose 150 mg/dl). In all patients, ketoacidosis receded on glucose infusion and renal replacement therapy. CONCLUSION: This case series highlights the parallel occurrence of MALA and euglycemic ketoacidosis, the latter exceeding ketosis due to starvation, suggesting a metformin-triggered inhibition of gluconeogenesis. Affected patients benefit from glucose infusion counteracting suppressed hepatic gluconeogenesis. PMID- 28865057 TI - Patient-Reported Outcome Measures 2 Years After Standard and Distal Gastric Bypass-a Double-Blind Randomized Controlled Trial. AB - BACKGROUND: The preferred surgical procedure for treating morbid obesity is debated. Patient-reported outcome measures (PROMs) are relevant for evaluation of the optimal bariatric procedure. METHODS: A total of 113 patients with BMI from 50 to 60 were randomly assigned to standard (n = 57) or distal (n = 56) Roux-en-Y gastric bypass (RYGB). Validated PROMS questionnaires were completed at baseline and 2 years after surgery. Data were analyzed using mixed models for repeated measures and the results are expressed as estimated means and mean changes. RESULTS: Obesity-related quality of life improved significantly after both procedures, without significant between-group differences (- 0.4 (95% CI = - 8.4, 7.2) points, p = 0.88, ES = 0.06). Both groups had significant reductions in the number of weight-related symptoms and symptom distress score, with a mean group difference (95% CI) of 1.4 (- 0.3, 3.3) symptoms and 5.0 (2.9. 12.8) symptom distress score points. There were no between-group differences for uncontrolled eating (22.0 (17.2-26.7) vs. 28.9 (23.3-34.5) points), cognitive restraint (57.4 (52.0-62.7) vs. 62.1 (57.9-66.2) points), and emotional eating (26.8 (20.5-33.1) vs. 32.6 (25.5-39.7) points). The prevalence of anxiety was 33% after standard and 25% after distal RYGB (p = 0.53), and for depression 12 and 9%, respectively (p = 0.76). CONCLUSIONS: There were no statistically significant differences between standard and distal RYGB 2 years post surgery regarding weight loss, obesity-related quality of life, weight-related symptoms, anxiety, depression, or eating behavior. TRIAL REGISTRATION: Clinical Trials.gov number NCT00821197. PMID- 28865059 TI - Sinus bradycardia induced by darunavir-ritonavir in a patient with acquired immunodeficiency syndrome. PMID- 28865060 TI - Gut contents, digestive half-lives and feeding state prediction in the soil predatory mite Pergamasus longicornis (Mesostigmata: Parasitidae). AB - Mid- and hind-gut lumenal changes are described in the free-living predatory soil mite Pergamasus longicornis (Berlese) from a time series of histological sections scored during and after feeding on fly larval prey. Three distinct types of tangible material are found in the lumen. Bayesian estimation of the change points in the states of the gut lumenal contents over time is made using a time homogenous first order Markov model. Exponential processes within the gut exhibit 'stiff' dynamics. A lumen is present throughout the midgut from 5 min after the start of feeding as the gut rapidly expands. It peaks at about 21.5 h-1.5 days and persists post-feeding (even when the gut is contracted) up until fasting/starvation commences 10 days post start of feeding. The disappearance of the lumen commences 144 h after the start of feeding. Complete disappearance of the gut lumen may take 5-9 weeks from feeding commencing. Clear watery prey material arrives up to 10 min from the start of feeding, driving gut lumen expansion. Intracellular digestion triggered by maximum gut expansion is indicated. Detectable granular prey material appears in the lumen during the concentrative phase of coxal droplet production and, despite a noticeable collapse around 12 h, lasts in part for 52.5 h. Posterior midgut regions differ slightly from anterior regions in their main prey food dynamics being somewhat faster in processing yet being slightly delayed. Posterior regions are confirmed as Last-In-Last-Out depots, anterior regions confirmed as First-In-First-Out conveyor belt processes. Evidence for differential lability of prey fractions is found. A scheme is presented of granular imbibed prey material being first initially rapidly absorbed ([Formula: see text] = 23 min), and also being quickly partly converted to globular material extra-corporeally/extracellularly ([Formula: see text] = 36 min)-which then rapidly disappears ([Formula: see text] = 1.1 h, from a peak around 4 h). This is then followed by slow intracellular digestion ([Formula: see text] = 6.9 h) of the resultant resistant prey residue matching the slow rate of appearance of opaque pre-excretory egestive refractive grains (overall [Formula: see text] = 4.5 days). The latter confirmed latent 'catabolic fraction' (along with Malpighian tubule produced guanine crystals) drives rectal vesicle expansion as 'faeces' during the later phases of gut emptying/contraction. Catabolic half-lives are of the order of 6.3-7.8 h. Membraneous material is only present in the lumen of the gut in starving mites. No obvious peritrophic membrane was observed. The total feeding cycle time may be slightly over 52.5 h. Full clearance in the gut system of a single meal including egestive and excretory products may take up to 3 weeks. Independent corroborative photographs are included and with posterior predictive densities confirm the physiological sequence of ingestion/digestion, egestion, excretion, defecation, together with their timings. Visually dark midguts almost certainly indicate egestive refractive grains (xanthine?) production. Nomograms to diagnose the feeding state of P. longicornis in field samples are presented and show that the timing of these four phases in the wild could be inferred by scoring 10-12 mites out of a sample of 20. Suggestions to critically confirm or refute the conclusions are included. PMID- 28865062 TI - The fever of Tommaso Campanella. PMID- 28865061 TI - Severe Enteropathy and Hypogammaglobulinemia Complicating Refractory Mycobacterium tuberculosis Complex Disseminated Disease in a Child with IL 12Rbeta1 Deficiency. AB - PURPOSE: Mendelian susceptibility to mycobacterial disease is a rare clinical condition characterized by a predisposition to infectious diseases caused by poorly virulent mycobacteria. Other infections such as salmonellosis and candidiasis are also reported. The purpose of this article is to describe a young boy affected with various infectious diseases caused by Mycobacterium tuberculosis complex, Salmonella sp, Klebsiella pneumonie, Citrobacter sp., and Candida sp, complicated with severe enteropathy and transient hypogammaglobulinemia. METHODS: We reviewed medical records and performed flow cytometry staining for lymphocyte populations, lymphocyte proliferation in response to PHA, and intracellular IFN-gamma production in T cell PHA blasts in the patient and a healthy control. Sanger sequencing was used to confirm the genetic variants in the patient and relatives. RESULTS: Genetic analysis revealed a bi-allelic mutation in IL12RB1 (C291Y) resulting in complete IL-12Rbeta1 deficiency. Functional analysis demonstrated the lack of intracellular production of IFN-gamma in CD3+ T lymphocytes from the patient in response to rhIL-12p70. CONCLUSIONS: To our knowledge, this is the third patient with MSMD due to IL 12Rbeta1 deficiency complicated with enteropathy and hypogammaglobulinemia and the first case of this disease to be described in Colombia. PMID- 28865063 TI - Potential Role of Thyroid Receptor beta Agonists in the Treatment of Hyperlipidemia. AB - Thyroid hormones have important effects on cellular development, growth, and metabolism and are necessary for the healthy function of almost all tissues. Hyperthyroid patients with excess thyroid hormone levels experience tachycardia, fatigue, muscle wasting, and osteoporosis. However, although high thyroid hormone levels have adverse effects, efforts have been made to harness the beneficial effects, such as reduced serum low-density lipoprotein (LDL) cholesterol levels, elevated basal metabolic rate, and weight loss. Thyroid hormones interact with nuclear thyroid hormone receptors (TRs), and cholesterol levels are reduced through TRbeta, whereas extrahepatic adverse actions are primarily connected to TRalpha. Thus, to develop a useful compound for clinical use, efforts have been focusing on developing compounds with isomer-specific functions based on the structure of thyroid hormones, i.e., thyromimetics that are liver and/or TRbeta specific. In this short review, we discuss the development of the early thyromimetics that enabled, through modern molecular techniques, the progress towards improved design of TRbeta-selective thyromimetics. We also address the early promise shown in human clinical trials and the current status of these drugs and other emerging compounds. PMID- 28865064 TI - Self-disorders in schizophrenia-spectrum disorders: a 5-year follow-up study. AB - Self-disorders have been hypothesized to be an underlying and trait-like core feature of schizophrenia-spectrum disorders and a certain degree of temporal stability of self-disorders would therefore be expected. The aim of the study was to examine the persistence of self-disorders measured by the Examination of Anomalous Self Experiences over a time span of 5 years. 48 patients with schizophrenia-spectrum disorders were thoroughly assessed for psychopathology at baseline and 5 years later. Self-disorders were assessed by the Examination of Anomalous Self Experiences. The level of self-disorders was same at the two occasions for the full Examination of Anomalous Self Disorders and for four out of the five domains. For one domain, the level of self-disorders increased slightly from baseline to follow-up. The correlations between baseline and follow up were moderate. 9 out of the 13 most-frequently rated items at baseline showed equal frequencies at follow-up. The baseline level of self-disorders predicted global symptomatic, but not functional outcome. Self-disorders measured by the Examination of Anomalous Self Experiences show a high level of temporal persistence over 5 years and predict symptomatic outcome. PMID- 28865065 TI - Fluoride in saliva and dental biofilm after 1500 and 5000 ppm fluoride exposure. AB - OBJECTIVES: The aim of this randomized, double-blind, crossover study was to measure fluoride in saliva and 7-day-old biofilm fluid and biofilm solids after rinsing three times per day for 3 weeks with 0, 1500, or 5000 ppm fluoride (NaF). MATERIALS AND METHODS: Following the 3-week wash-in/wash-out period, including 1 week of biofilm accumulation, saliva and biofilm samples were collected from 12 participants immediately before (background fluoride), and 10, 30, and 60 min after a single rinse. Biofilm samples were separated into fluid and solids, and samples were analyzed using a fluoride electrode (microanalysis). RESULTS: The background fluoride concentration was statistically significantly higher in the 5000 compared to the 1500 ppm F rinse group in all three compartments (22.3 and 8.1 MUM in saliva, 126.8 and 58.5 MUM in biofilm fluid, and 10,940 and 4837 MUmol/kg in biofilm solids). The 1-h fluoride accumulation for the 5000 ppm F rinse was higher than for the 1500 ppm F rinse in all three compartments, although not statistically significant for saliva and biofilm solids. CONCLUSION: Regular exposure to 5000 ppm fluoride elevates background fluoride concentrations in saliva, biofilm fluid, and biofilm solids compared to 1500 ppm fluoride. Increasing the fluoride concentration almost 3.5 times (from 1500 to 5000 ppm) only elevates the background fluoride concentrations in saliva, biofilm fluid, and biofilm solids twofold. CLINICAL RELEVANCE: Even though fluoride toothpaste may be diluted by saliva, the results of the present study indicate that use of 5000 ppm fluoride toothpaste might lead to improved caries control. PMID- 28865068 TI - Expert protocol teams enhance patient centered cardiac testing and care. PMID- 28865066 TI - Spatial distribution and human health risk assessment of mercury in street dust resulting from various land-use in Ahvaz, Iran. AB - Mercury as a toxic element and its associated health hazard has been an important topic of research for urban pollution for many years. In this paper, the spatial distribution, pollution assessment, and health risk associated with Hg in roadside dust 96 street dust samples, representing differing land-uses, have been investigated. Land-uses included residential areas (RA), industrial areas (IA), public gardens (PG), roadside areas (RS), and suburban areas (SA) in the city of Ahvaz, Iran were investigated. Compared with other cities, the concentration of Hg in Ahvaz was considerably higher with a mean value of 2.53 mg kg-1, ranging from 0.02 to 8.75 mg kg-1. Residential areas exhibited higher Hg in street dust than other areas, as demonstrated by spatial mapping illustrating hot spots associated with old urban areas with high residential density, high volume traffic of roadside areas, and industrial districts: including oil-drilling activities, steel smelting-related industries, and small industrial towns around Ahvaz. However, Hg concentrations in street dust near to the public gardens (PG) and suburban areas (SA) were not at elevated levels compared other land-uses investigated in this study. A health risk assessment model of non-carcinogenic effects was evaluated for both children and adults. The HQ values also revealed that the main exposures route for children and adults decreased as follows: vapour > ingestion > dermal contact > inhalation. The hazard index (HI) in each area is less than the safe level (HI <= 1) for children and adults, but higher for children. The HI value decreases as the following order: RS > IA > RA > SA > PG, which indicates potentially serious health hazards for children in the study areas. PMID- 28865067 TI - Predictors of CPAP compliance in different clinical settings: primary care versus sleep unit. AB - BACKGROUND: Good adherence to continuous positive airway pressure (CPAP) treatment improves the patient's quality of life and decreases the risk of cardiovascular disease. Previous studies that have analyzed the adherence to CPAP were performed in a sleep unit (SU) setting. The involvement of primary care (PC) in the management of obstructive sleep apnea (OSA) patients receiving CPAP treatment could introduce factors related to the adherence to treatment. OBJECTIVES: The objective was to compare the baseline predictors of CPAP compliance in SU and PC settings. METHODS: OSA patients treated with CPAP were followed for 6 months in SU or PC setting. We included baseline clinical and anthropometrical variables, the Epworth Sleep Scale (ESS) score, the quality of life index, and the Charlson index. A logistic regression was performed for each group to determine the CPAP compliance predictors. Discrimination and calibration were performed using the area under the curve and Hosmer-Lemeshow tests. RESULTS: We included 191 patients: 91 in the PC group and 100 in the SU group. In 74.9% of the patients, the compliance was >= 4 h per day, with 80% compliance in the SU setting and 69.2% compliance in the PC setting (p = 0.087). The predictors of CPAP compliance were different between SU and PC settings. Body mass index, ESS, and CPAP pressure were predictors in the SU setting, and ESS, gender, and waist circumference were predictors in the PC setting. CONCLUSIONS: The predictors of adequate CPAP compliance vary between SU and PC settings. Detecting compliance predictors could help in the planning of early interventions to improve CPAP adherence. PMID- 28865069 TI - Effect of dietary copper level on the gut microbiota and its correlation with serum inflammatory cytokines in Sprague-Dawley rats. AB - In China's swine industry, copper is generally supplemented above the National Research Council (NRC) requirement (2012) because of its antimicrobial properties and the potential for growth promotion. Yet few are concerned about whether this excess supplementation is necessary. In this study, the 16S rRNA pyrosequencing was designed and used to investigate the effect of dietary copper level on the diversity of the fecal microbial community and the correlation of copper level with the serum level of inflammatory cytokines in Sprague-Dawley rat models. The results showed that the diet containing a high level of Cu (120 and 240 mg/kg) changed the microbial richness and diversity of rat feces associated with the increased copper content in the rat ileac and colonic digesta. Furthermore, a Pearson's correlation analysis indicated that an accumulation of unabsorbed copper in the chyme was correlated with the microbial composition of the rat feces, which was linked with TNF-alpha in serum. The results suggest that dietary copper level may have a direct impact on circulating inflammatory cytokines in the serum, perhaps inducing an inflammatory response by altering the microbial composition of rat feces. Serum TNF-alpha could be the chief responder to excessive copper exposure. PMID- 28865070 TI - Variations in bacterial and fungal communities through soil depth profiles in a Betula albosinensis forest. AB - Microbial communities in subsurface soil are specialized for their environment, which is distinct from that of the surface communities. However, little is known about the microbial communities (bacteria and fungi) that exist in the deeper soil horizons. Vertical changes in microbial alpha-diversity (Chao1 and Shannon indices) and community composition were investigated at four soil depths (0-10, 10-20, 20-40, and 40-60 cm) in a natural secondary forest of Betula albosinensis by high-throughput sequencing of the 16S and internal transcribed spacer rDNA regions. The numbers of operational taxonomic units (OTUs), and the Chao1 and Shannon indices decreased in the deeper soil layers. Each soil layer contained both mutual and specific OTUs. In the 40-60 cm soil layer, 175 and 235 specific bacterial and fungal OTUs were identified, respectively. Acidobacteria was the most dominant bacterial group in all four soil layers, but reached its maximum at 40-60 cm (62.88%). In particular, the 40-60 cm soil layer typically showed the highest abundance of the fungal genus Inocybe (47.46%). The Chao1 and Shannon indices were significantly correlated with the soil organic carbon content. Redundancy analysis indicated that the bacterial communities were closely correlated with soil organic carbon content (P = 0.001). Collectively, these results indicate that soil nutrients alter the microbial diversity and relative abundance and affect the microbial composition. PMID- 28865071 TI - Promising cellulolytic fungi isolates for rice straw degradation. AB - The objective of this study was to evaluate the potential of eight fungal isolates obtained from soils in rice crops for straw degradation in situ. From the initial eight isolates, Pleurotus ostreatus T1.1 and Penicillium sp. HC1 were selected for further characterization based on qualitative cellulolytic enzyme production and capacity to use rice straw as a sole carbon source. Subsequently, cellulolytic, xylanolytic, and lignolytic (Pleurotus ostreatus) activity on carboxymethyl cellulose, oat xylan, and rice straw with different nitrogen sources was evaluated. From the results obtained it was concluded both isolates are capable to produce enzymes necessary for rice straw degradation. However, their production is dependent upon carbon and nitrogen source. Last, it was established that Pleurotus ostreatus T1.1 and Penicillium sp. HC1 capability to colonize and mineralize rice straw, in mono-and co-culture, without affecting nitrogen soil content. PMID- 28865072 TI - Gallibacterium elongation factor-Tu possesses amyloid-like protein characteristics, participates in cell adhesion, and is present in biofilms. AB - Gallibacterium, which is a bacterial pathogen in chickens, can form biofilms. Amyloid proteins present in biofilms bind Congo red dye. The aim of this study was to characterize the cell-surface amyloid-like protein expressed in biofilms formed by Gallibacterium strains and determine the relationship between this protein and curli, which is an amyloid protein that is commonly expressed by members of the Enterobacteriaceae family. The presence of amyloid-like proteins in outer membrane protein samples from three strains of G. anatis and one strain of Gallibacterium genomospecies 2 was evaluated. A protein identified as elongation factor-Tu (EF-Tu) by mass spectrometric analysis and in silico analysis was obtained from the G. anatis strain F149T. This protein bound Congo red dye, cross-reacted with anti-curli polyclonal serum, exhibited polymerizing properties and was present in biofilms. This protein also reacted with pooled serum from chickens that were experimentally infected with G. anatis, indicating the in vivo immunogenicity of this protein. The recombinant EF-Tu purified protein, which was prepared from G. anatis 12656-12, polymerizes under in vitro conditions, forms filaments and interacts with fibronectin and fibrinogen, all of which suggest that this protein functions as an adhesin. In summary, EF-Tu from G. anatis presents amyloid characteristics, is present in biofilms and could be relevant for the pathogenesis of G. anatis. PMID- 28865073 TI - Spirosoma daeguensis sp. nov., isolated from beach soil. AB - A Gram-stain-negative, non-motile, non-spore-forming, rod-shaped, aerobic bacterium, designated 15J9-6T, was isolated from beach soil on Jeju Island, South Korea. Strain 15J9-6T, grew at 10-30 degrees C (optimum growth at 25 degrees C) and pH 7-8 (optimum growth at pH 7) on R2A, NA, and TSA agar. Phylogenetically, the strain was closely related to members of the genus Spirosoma (92.3-90.1% 16S rRNA gene sequence similarities) and showed highest sequence similarity to Spirosoma panaciterrae DSM 21099T (92.3%). The G+C content of the genomic DNA of strain 15J9-6T was 45.7 mol%. The strain contained phosphatidylethanolamine, two unidentified aminophospholipids, an unidentified phospholipid, and an unidentified lipid as the major polar lipids; menaquinone MK-7 as the predominant respiratory quinone and summed feature 3 (C16:1 omega6c/C16:1 omega7c; 30.1%), C16:1 omega5c (23.1%), iso C15:0 (13.3%), and C16:0 (8.4%) as the major fatty acids which supported the affiliation of strain 15J9-6T to the genus Spirosoma. The results of physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain 15J9-6T from recognized Spirosoma species. On the basis of its phenotypic properties and phylogenetic distinctiveness, strain 15J9-6T represents a novel species of the genus Spirosoma, for which the name Spirosoma daeguensis sp. nov. is proposed. The type strain is 15J9-6T (=KCTC 52036T =JCM 31995T). PMID- 28865074 TI - Diversity of lactic acid bacteria from Miang, a traditional fermented tea leaf in northern Thailand and their tannin-tolerant ability in tea extract. AB - The microbiota of lactic acid bacteria (LAB) in thirty-five samples of Miang, a traditional fermented tea leaf product, collected from twenty-two different regions of eight provinces in upper northern Thailand was revealed through the culture-dependent technique. A total of 311 presumptive LAB strains were isolated and subjected to clustering analysis based on repetitive genomic element-PCR (rep PCR) fingerprinting profiles. The majority of the strains belonged to the Lactobacillus genera with an overwhelming predominance of the Lb. plantarum group. Further studies of species-specific PCR showed that 201 of 252 isolates in the Lb. plantarum group were Lb. plantarum which were thus considered as the predominant LAB in Miang, while the other 51 isolates belonged to Lb. pentosus. In contrast to Lb. plantarum, there is a lack of information on the tannase gene and the tea tannin-tolerant ability of Lb. pentosus. Of the 51 Lb. pentosus isolates, 33 were found to harbor the genes encoding tannase and shared 93-99% amino acid identity with tannase obtained from Lb. pentosus ATCC 8041T. Among 33 tannase gene-positive isolates, 23 isolates exhibited high tannin- tolerant capabilities when cultivated on de Man Rogosa and Sharpe agar-containing bromocresol purple (0.02 g/L, MRS-BCP) supplemented with 20% (v/v) crude tea extract, which corresponded to 2.5% (w/v) tannins. These Lb. pentosus isolates with high tannin-tolerant capacity are expected to be the high potential strains for functional tannase production involved in Miang fermentation as they will bring about certain benefits and could be used to improve the fermentation of tea products. PMID- 28865075 TI - Comparison of antibiotic resistance and copper tolerance of Enterococcus spp. and Lactobacillus spp. isolated from piglets before and after weaning. AB - In China, antimicrobials and copper are used extensively as growth-promoting agents for piglets. This study aimed to characterize the role of in-feed copper in the emergence of copper-tolerant and antibiotic-resistant Enterococcus and Lactobacillus isolates in Chinese pig farms. Feces of the same eight piglets from four litters at 7 and 55 days old and their mothers were traced in order to isolate Enterococcus spp. and Lactobacillus spp.. The minimum inhibitory concentrations of 10 antimicrobials and copper sulfate were determined using an agar dilution method. The feed levels of Cu2+ for lactating sows, suckling piglets, and weaned piglets were 6, 177, and 18 mg/kg, respectively. All the 136 Enterococcus isolates were sensitive to vancomycin; and the resistance rates to penicillin, enrofloxacin, and high level streptomycin resistance increased significantly after weaning. For the 155 Lactobacillus isolates, the resistance rates to ampicillin, chloramphenicol, tetracycline, and enrofloxacin were significantly higher in weaned piglets. The ratios of copper tolerant Enterococcus and Lactobacillus isolates both increased significantly after weaning (P < 0.05). A phenotypic correlation was observed after classifying the isolates into two groups (CuSO4 MIC50 < 16 or ?16 for enterococci; CuSO4 MIC50 < 12 or ?12 for lactobacilli) and comparing the antimicrobial-resistant percentage of two groups. On species level, a significant increase of E. faecalis to enrofloxacin was observed in line with the increase of copper MIC (P < 0.05). The findings revealed the changes of the antibiotic resistance and copper tolerance level of enterococci and lactobacilli between suckling and weaned piglets and demonstrated that there might be a strong association between in-feed copper and increased antibiotic resistance in enterococci and lactobacilli in Chinese intensive swine farms. PMID- 28865077 TI - Sunburn and ambient temperature. PMID- 28865076 TI - Loss of FrmB results in increased size of developmental structures during the multicellular development of Dictyostelium cells. AB - FERM domain-containing proteins are involved in diverse biological and pathological processes, including cell-substrate adhesion, cell-cell adhesion, multicellular development, and cancer metastasis. In this study, we determined the functions of FrmB, a FERM domain-containing protein, in the cell morphology, cell adhesion, and multicellular development of Dictyostelium cells. Our results show that FrmB appears to play an important role in regulating the size of developmental structures. frmB null cells showed prolonged aggregation during development, resulting in increased size of developmental structures, such as mounds and fruiting bodies, compared to those of wild-type cells, whereas FrmB overexpressing cells exhibited decreased size of developmental structures. These results suggest that FrmB may be necessary for limiting the sizes of developmental structures. Loss of FrmB also resulted in decreased cell-substrate adhesion and slightly increased cell area, suggesting that FrmB had important roles in the regulation of cell adhesion and cell morphology. These studies would contribute to our understanding of the intertwined and overlapped functions of FERM domain-containing proteins. PMID- 28865078 TI - Epidemiology and survival outcomes of sinonasal verrucous carcinoma in the United States. AB - INTRODUCTION: Verrucous carcinoma (VC) is a rare, variant of squamous cell carcinoma with benign cytohistopathologic features and a generally favorable prognosis. Epidemiologic and clinical outcomes data are lacking as a result of limited cases of sinonasal VC. OBJECTIVE: To describe the incidence and determinants of survival of patients with verrucous carcinoma of the sinonasal tract between the years of 1973 to 2014 using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The SEER registry was utilized to calculate survival trends for patients with verrucous carcinoma of the sinonasal tract between 1973 and 2014. Patient data then was analyzed with respect to age, sex, race, and treatment modalities (surgery and radiation therapy). Overall survival (OS) and disease-specific survival (DSS) were calculated. RESULTS: A total of 86 cases of VC of the sinonasal tract were identified. The cohort was comprised of 69.8% males. The mean age at diagnosis was 67.4 years. The nasal cavity was the most common primary site (51.2%), followed by the maxillary sinus (40.7%) and nasopharynx (5.8%). The median OS was 97.6 months. 89.5% of cases underwent surgery and 20.9% received both surgery and radiation therapy. Overall survival at 2, 5, and 10 years was 73%, 59%, and 36%, respectively. On multivariate analysis, advanced age (P < 0.05) and primary site (P < 0.05) were associated with worse OS and DSS, respectively. Primary nasopharyngeal tumor site was associated with reduced DSS (P < 0.05). Surgery improved OS (P < 0.001) and DSS (P < 0.001). CONCLUSION: Verrucous carcinoma of the sinonasal tract is associated with a generally favorable prognosis. Age, primary site, and surgical therapy are independent predictors of OS and DSS, respectively. We present the first population-based analysis of sinonasal VC, thus clarifying the prognosis and reinforcing the management of this malignancy. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:651-656, 2017. PMID- 28865079 TI - Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report. AB - Congenital erythropoietic porphyria is a rare autosomal recessive disease caused by a deficiency of uroporphyrinogen III synthase, owing to mutations in UROS in chromosome 10. Occasionally, patients show a mild, late-onset disease, without germline UROS mutations, associated with haematological malignancies. We report a 65-year-old patient with photosensitivity, overexcretion of porphyrins and thrombocytopenia. Bone marrow analysis gave a diagnosis of myelodysplastic syndrome (MDS) with the presence of a derivative chromosome 3, possibly due to an inversion including 3q21 and 3q26 break points. After allogeneic stem-cell transplantation, complete remission of MDS and uroporphyria was achieved. To our knowledge, this is the first reported case of acquired erythropoietic uroporphyria associated with MDS, with chromosome 3 alterations. PMID- 28865080 TI - Density functional study of porphyrin distortion effects on redox potential of heme. AB - Heme is involved in various biochemical roles in hemoproteins. In the present study, the effect of heme distortion on the redox potential was systematically investigated with density functional calculations. We focused on the ruffled and saddled distortions of heme, which correspond to the two lowest-frequency normal modes. Our computations demonstrated that the ruffled distortion tended to reduce the redox potential of heme and that the transition of the electronic configuration occurred from (dxz , dyz )3 (dxy )2 to (dxz , dyz )4 (dxy )1 . In contrast, the saddled distortion had a tendency toward an increase in the redox potential, and no transition of the electronic configuration occurred. In experiments, these tendencies were found in the relationship between with the heme distortions and the redox potentials in cytochrome c3 . (c) 2017 Wiley Periodicals, Inc. PMID- 28865081 TI - Chronic treatment with zoledronic acid increases inflammatory markers in periodontium of rats. AB - BACKGROUND: Bisphosphonates (BF) rise proinflammatory markers and irreversibly bind to bone. Chronically, BF can lead to an inflammatory status and can increase the local oxidative stress in periodontium. Therefore, the objective of this study was to evaluate whether the chronic infusion of Zoledronic Acid (ZA) increases inflammatory markers in periodontium of rats. METHODS AND RESULTS: Chronically, infusion therapy was performed with ZA (0.04, 0.2 or 1 mg/kg or saline) by four doses in over a 70-day period to analyze periodontium of the first right inferior molar using histologic, histochemical (toluidine blue), and immunohistochemical (CD68, tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-kB)) tests. The experiment was replicated (ZA 0.2 mg/kg versus saline) for myeloperoxidase (MPO) assay and dose TNF-alpha, IL-1beta, malondialdehyde (MDA) and glutathione (GSH) in gingiva of the same tooth. Despite there is no alteration in mast cells (P = .608) and CD68 mononuclear-positive cells (P = .351), in the periodontium of the ZA-treated group, was observed an increase in the presence of inflammatory cells (P = .001) and cytoplasmic immunostaining for TNF-alpha (P = .003), IL-1b (P = .004), iNOS (P = .008), and NF-kB (P = .025). Levels of MPO (P < .001), TNF-alpha (P = .002), IL-1beta (P < .001), and GSH (P = .005) were augmented in gingiva of ZA-treated group but MDA (P = .993) levels and NF-kB nuclear staining (P = .923) were not altered. CONCLUSIONS: Chronic treatment with ZA increase proinflammatory cytokines and the number of inflammatory cells in periodontium of rats and GSH are expressed probably in a compensatory manner. PMID- 28865082 TI - Highly Luminescent Pincer Gold(III) Aryl Emitters: Thermally Activated Delayed Fluorescence and Solution-Processed OLEDs. AB - Herein are described the synthesis, photophysical properties and applications of a series of luminescent cyclometalated AuIII complexes having an auxiliary aryl ligand. These complexes show photoluminescence with emission quantum yields of up to 0.79 in solution and 0.84 in thin films (4 wt % in PMMA) at room temperature, both of which are the highest reported values among AuIII complexes. Thermally activated delayed fluorescence (TADF) is the emission origin for some of these complexes. Solution-processed OLEDs made with these complexes showed sky-blue to green electroluminescence with external quantum efficiencies (EQEs) of up to 23.8 %, current efficiencies of up to 70.4 cd A-1 , and roll-off of down to 1 %, highlighting the bright prospect of AuIII -TADF emitters in OLEDs. PMID- 28865083 TI - Radiation-induced changes in the microstructure of epithelial cells of the oral mucosa: A comparative light and electron microscopic study. AB - OBJECTIVES: The microplicae is a typical structure of the epithelial cell surface of the oral mucosa. The cell surface is potentially of great significance, as it provides the underlying basis for the protective function of the salivary pellicle. The aim of this study was to investigate whether radiation therapy affects the surface morphology of the superficial cells of the human oral mucosa in patients who have received radiotherapy for oral cancer. MATERIAL AND METHODS: Oral mucosal tissue samples from 91 patients were collected during dental implant surgery or ablative surgery. Study group 1 consisted of 28 patients who underwent dental implant surgery after radiotherapy. Group 2 consisted of five patients who developed osteoradionecrosis. Group 3 consisted of eight oral cancer patients without radiotherapy. Group 4 consisted of 50 clinically healthy subjects as controls. The samples were studied with scanning electron microscopy and compared with both light and transmission electron micrographs. RESULTS: Radiation therapy (RT) induces breakage and destruction in the microplicae morphology and declines the density of the microplicae surface structures. In some of the irradiated cells, the microplicae were completely vanished, especially in patients who developed osteoradionecrosis. In non-irradiated tissue, the microplicae of the superficial epithelial cells were intact in all cases. CONCLUSION: Scanning electron microscopy, in contrast to light microscopy, appears to be a useful tool to reveal the condition of superficial oral mucosal cells. In respect of the possible pathogenesis of osteoradionecrosis, the radiation-induced damage of the microplicae and its influence on the mucosal salivary pellicle is discussed. PMID- 28865084 TI - Eosinophilic esophagitis in children under the age of 5 years: Clinical characteristics. AB - OBJECTIVES/HYPOTHESIS: To delineate clinical characteristics and treatment outcomes of eosinophilic esophagitis (EoE) in the youngest of children. STUDY DESIGN: Retrospective chart review. METHODS: A 7-year retrospective chart review of children with clinicopathologic diagnosis of EoE was performed with specific analysis of patients under 5 years old. EoE was defined as the presence of symptoms of esophageal dysfunction with pathologically proven eosinophilic inflammation (>=15 eosinophils per high-power field [EOS/HPF]) unresponsive to reflux therapy. Patient parameters and clinical results were systematically reviewed. RESULTS: Of 558 children diagnosed with EoE, 127 (22.8%) were younger than 5 years old (mean age 2.5 years). This subgroup presented with reflux symptoms (90.1%), vomiting (86.2%), diarrhea (55.3%), liquid dysphagia (52.0%), and constipation (50.0%), whereas food impaction (1.6%) was rare. Liquid dysphagia was present at all ages but significantly more common in younger children (P = .0101). The most common food and environmental allergens were egg whites (39.7%), cow's milk (36.5%), peanuts (34.9%), animal dander (15.1%), and weed pollen (11.1%). Patients were managed with antireflux medication (100%), elimination diet (83.5%), and steroid medication (68.5%). After treatment, 86% of parents reported symptom improvement. Mean reduction of EOS in pos-treatment biopsy was 33.5 EOS/HPF (P < .0001), and 67 patients showed histologic resolution of EoE (56.8%, P < .0001). CONCLUSIONS: Approximately one-quarter of children with EoE present under 5 years of age with multiple esophageal symptoms, comorbidities, and allergen-sensitization profiles. These patients demonstrate substantial clinicohistologic improvement following therapy. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:798-805, 2018. PMID- 28865085 TI - Commercial Programs' Online Weight-Loss Claims Compared to Results from Randomized Controlled Trials. AB - OBJECTIVE: To characterize weight-loss claims and disclaimers present on websites for commercial weight-loss programs and compare them with results from published randomized controlled trials (RCTs). METHODS: A content analysis of all home pages and testimonials available on the websites of 24 randomly selected programs was performed. Two team members independently reviewed each page and abstracted information from text and images to capture relevant content, including demographics, weight loss, and disclaimers. A systematic review was performed to evaluate the efficacy of these programs by searching MEDLINE and the Cochrane Database of Systematic Reviews, and the mean weight change from each RCT included was abstracted. RESULTS: Overall, the amount of weight loss portrayed in the testimonials was extreme across all programs examined (range median weight loss 10.7-49.5 kg). Only 10 out of the 24 programs had eligible RCTs. Median weight losses reported in testimonials exceeded that achieved by trial participants. Most programs with RCTs (78%) provided disclaimers stating that the testimonial's results were nontypical and/or gave a range of typical weight loss. CONCLUSIONS: Weight-loss claims within testimonials were higher than results from RCTs. Future studies should examine whether commercial programs' advertising practices influence patients' expectations or satisfaction with modest weight-loss results. PMID- 28865086 TI - Fragmentation of 2-aroylbenzofuran derivatives by electrospray ionization tandem mass spectrometry. AB - We investigated the gas-phase fragmentation reactions of a series of 2 aroylbenzofuran derivatives by electrospray ionization tandem mass spectrometry (ESI-MS/MS). The most intense fragment ions were the acylium ions m/z 105 and [M+H-C6 H6 ]+ , which originated directly from the precursor ion as a result of 2 competitive hydrogen rearrangements. Eliminations of CO and CO2 from [M+H-C6 H6 ]+ were also common fragmentation processes to all the analyzed compounds. In addition, eliminations of the radicals *Br and *Cl were diagnostic for halogen atoms at aromatic ring A, whereas eliminations of *CH3 and CH2 O were useful to identify the methoxyl group attached to this same ring. We used thermochemical data, obtained at the B3LYP/6-31+G(d) level of theory, to rationalize the fragmentation pathways and to elucidate the formation of E, which involved simultaneous elimination of 2 CO molecules from B. PMID- 28865088 TI - A co-culture system with three different primary human cell populations reveals that biomaterials and MSC modulate macrophage-driven fibroblast recruitment. AB - The biological response to implanted biomaterials is a complex and highly coordinated phenomenon involving many different cell types that interact within 3D microenvironments. Here, we increased the complexity of a 3D platform to include at least 3 cell types that play a role in the host response upon scaffold implantation. With this system, it was possible to address how immune responses triggered by 3D biomaterials mediate recruitment of stromal cells that promote tissue regeneration, mesenchymal stromal/stem cells (MSC), or a foreign body response, fibroblasts. Primary human macrophages yielded the highest fibroblast recruitment when interacting with chitosan scaffolds but not polylactic acid. Interestingly, when there were MSC and fibroblasts in the same environment, macrophages in chitosan scaffolds again promoted a significant increase on fibroblast recruitment, but not of MSC. However, macrophages that were firstly allowed to interact with MSC within the scaffolds were no longer able to recruit fibroblasts. This study illustrates the potential to use different scaffolds to regulate the dynamics of recruitment of proregenerative or fibrotic cell types through immunomodulation. Overall, this work strengths the idea that ex vivo predictive systems need to consider the different players involved in the biological response to biomaterials and that timing of arrival of specific cell types will affect the outcome. PMID- 28865087 TI - The Arabidopsis U-box E3 ubiquitin ligase PUB30 negatively regulates salt tolerance by facilitating BRI1 kinase inhibitor 1 (BKI1) degradation. AB - The Arabidopsis U-box E3 ubiquitin ligases play an important role in the ubiquitin/26S proteasome-mediated protein degradation pathway. Recently, PUB30 has been reported to participate in the salt stress response during seed germination stage in abscisic acid (ABA)-independent manner, but the molecular mechanism remains to be elucidated. Here, we displayed that the pub30 mutant was more tolerant to salt stress during seed germination, whereas the mutant of its closest homologue PUB31 showed mild sensitivity to salt stress. PUB30 exhibited E3 ubiquitin ligase activity in vitro. PUB30 specifically interacted with BRI1 kinase inhibitor 1 (BKI1), a regulator playing dual roles in brassinosteroids signaling, in vitro and in vivo. We found that BKI1 protein was ubiquitinated and degraded by the 26S proteasome. The degradation of BKI1 was slowed down in the pub30-1 mutant compared with that in the wild type. The bki1 mutant was sensitive to salt, whereas the transgenic plants overexpressing BKI1 showed salt tolerant phenotype. All these results indicate that PUB30 negatively regulates salt tolerance probably through regulating the degradation of BKI1 and brassinosteroids signaling in Arabidopsis. PMID- 28865089 TI - Impact of enzalutamide and its main metabolite N-desmethyl enzalutamide on pharmacokinetically important drug metabolizing enzymes and drug transporters. AB - Enzalutamide is a new drug against castration-resistant prostate cancer. Recent data indicate profound induction of drug metabolizing enzymes (e.g. cytochrome P450 isoenzyme (CYP) 3A4) but comprehensive in vitro data on other CYP enzymes, drug conjugating enzymes or drug transporters is scarce. Moreover, the mechanisms of induction are poorly investigated and the effects of the active metabolite N desmethyl enzalutamide are unknown. Using LS180 cells as an induction model and quantitative real-time reverse transcription polymerase chain reaction, our study demonstrated a concentration-dependent induction of CYP1A1, CYP1A2, CYP3A5, CYP3A4, UGT1A3, UGT1A9, ABCB1, ABCC2 and ABCG2 mRNA. Induction of CYP3A4 and ABCB1 was confirmed by Western blot analysis and is likely mediated by activation of the nuclear receptor pregnane x receptor, elucidated by a luciferase-based reporter gene assay. Enzalutamide's main active metabolite N-desmethyl enzalutamide exhibited only weak induction properties. mRNA expression of UGT2B7 was suppressed by enzalutamide and its metabolite. Both compounds are apparently not transported by P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). N-desmethyl enzalutamide more potently inhibited important drug transporters (P-gp, BCRP, OATPs) than enzalutamide. Taken together, the pharmacokinetics of concurrently administered drugs is likely altered during enzalutamide therapy. Levels of metabolically (mainly CYP3A4) eliminated drugs are expected to be decreased, whereas the abundance of compounds with solely transporter-determined pharmacokinetics (P-gp, OATPs) is likely enhanced. PMID- 28865090 TI - Sinonasal quality of life after endoscopic resection of malignant sinonasal and skull base tumors. AB - OBJECTIVES: Improvement in sinonasal quality of life (QoL) following sinus surgery has been well-documented across the literature. To our knowledge, only one series has evaluated long-term QoL in patients undergoing tumor resection, and that study demonstrated no improvement in rhinologic QoL following malignant tumor resection at 2-year follow-up. The objective of the present study was to evaluate QoL in the 2 years following endoscopic malignant tumor resection. METHODS: A prospective cohort study was performed, including patients with both malignant and benign sinonasal tumors in a tertiary academic medical center. Patients undergoing endoscopic tumor resection who had completed Sinonasal Outcome Test 22 (SNOT-22) questionnaires were included in the cohort. SNOT-22 questionnaires were administered preoperatively and over a 2-year follow-up period at clinic visits. Longitudinal linear mixed-effects regression was used to compare preoperative QoL to QoL over the 2 years following surgery. RESULTS: Among 145 patients included in this study, 64 had malignant tumors. There was a statistically significant improvement in SNOT-22 score from baseline to 2 years for patients with both malignant tumors (37.0, 95% confidence Interval [CI] 32.0 42.1 at baseline; 26.5 95% CI 20.8-32.2 at 2 years; P < 0.001) and benign tumors (26.5, 95% CI 21.4-30.4 at baseline; 12.9 95% CI 7.6-18.2 at 2 years; P < 0.001). CONCLUSION: In contrast to previously reported series, in this cohort endoscopic resection of sinonasal tumors appears to be followed by an improvement in QoL, which is sustained over a 2-year period. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:789-793, 2018. PMID- 28865091 TI - Biocompatibility of two model elastin-like recombinamer-based hydrogels formed through physical or chemical cross-linking for various applications in tissue engineering and regenerative medicine. AB - Biocompatibility studies, especially innate immunity induction, in vitro and in vivo cytotoxicity, and fibrosis, are often lacking for many novel biomaterials including recombinant protein-based ones, such as elastin-like recombinamers (ELRs), and has not been extensively explored in the scientific literature, in contrast to traditional biomaterials. Herein, we present the results from a set of experiments designed to elucidate the preliminary biocompatibility of 2 types of ELRs that are able to form extracellular matrix-like hydrogels through either physical or chemical cross-linking both of which are intended for different applications in tissue engineering and regenerative medicine. Initially, we present in vitro cytocompatibility results obtained upon culturing human umbilical vein endothelial cells on ELR substrates, showing optimal proliferation up to 9 days. Regarding in vivo cytocompatibility, luciferase-expressing hMSCs were viable for at least 4 weeks in terms of bioluminescence emission when embedded in ELR hydrogels and injected subcutaneously into immunosuppressed mice. Furthermore, both types of ELR-based hydrogels were injected subcutaneously in immunocompetent mice and serum TNFalpha, IL-1beta, IL-4, IL-6, and IL-10 concentrations were measured by enzyme-linked immunosorbent assay, confirming the lack of inflammatory response, as also observed upon macroscopic and histological evaluation. All these findings suggest that both types of ELRs possess broad biocompatibility, thus making them very promising for tissue engineering and regenerative medicine-related applications. PMID- 28865092 TI - Aqueous and Template-Free Synthesis of Meso-Macroporous Polymers for Highly Selective Capture and Conversion of Carbon Dioxide. AB - Meso-macroporous polymers possessing nitrogen functionality were innovatively synthesized through an aqueous and template-free route herein. Specifically, the polymerization of 1-(4-vinylbenzyl)-1,3,5,7-tetraazaadamantan-1-ium chloride in aqueous solution under high temperatures induces the decomposition of the hexamethylenetetramine unit into ammonia and formaldehyde molecules, followed by the cross-linking of benzene rings through "resol chemistry". During this process, extended meso-macroporous frameworks were constructed, and active nitrogen species were incorporated. Taking the advantage of the meso macroporosity and nitrogen functionality, the synthesized polymers offer competitive CO2 capacities (0.37-1.58 mmol g-1 at 0 degrees C and 0.15 bar) and outstanding CO2 /N2 selectivities (155-324 at 0 degrees C). Furthermore, after complexed with metal ions, the synthesized polymers show excellent activity for catalyzing the cycloaddition of propylene oxide with CO2 (yield>98.5 %, turnover frequency: 612.9-761.1 h-1 ). PMID- 28865093 TI - In reference to Does mutational analysis influence the management of differentiated thyroid cancers? PMID- 28865095 TI - Are donors or recipients a more important predictive factor for the development of non-alcoholic fatty liver disease after liver transplantation? PMID- 28865094 TI - Use of systemic corticosteroids for atopic dermatitis: International Eczema Council consensus statement. AB - BACKGROUND: Guidelines discourage the use of systemic corticosteroids for atopic dermatitis (AD), but their use remains widespread. OBJECTIVES: To reach consensus among an international group of AD experts on the use of systemic corticosteroids for AD. METHODS: A survey consisting of statements accompanied by visual analogue scales ranging from 'strongly disagree' to 'neutral' to 'strongly agree' was distributed to the International Eczema Council (IEC). Consensus was reached in agreement on a statement if < 30% of respondents marked to the left of 'neutral' towards 'strongly disagree'. RESULTS: Sixty of 77 (78%) IEC members participated. Consensus was reached on 12 statements, including that systemic corticosteroids should generally be avoided but can be used rarely for severe AD under certain circumstances, including a lack of other treatment options, as a bridge to other systemic therapies or phototherapy, during acute flares in need of immediate relief, in anticipation of a major life event or in the most severe cases. If used, treatment should be limited to the short term. Most respondents agreed that systemic corticosteroids should never be used in children, but consensus was not reached on that statement. The conclusions of our expert group are limited by a dearth of high-quality published evidence. If more stringent consensus criteria were applied (e.g. requiring < 20% of respondents marking towards 'strongly disagree'), consensus would have been reached on fewer statements. CONCLUSIONS: Based on expert opinion from the IEC, routine use of systemic corticosteroids for AD is generally discouraged and should be reserved for special circumstances. PMID- 28865096 TI - The predictive value of coronary artery calcium detected by computed tomography in a prospective study on cardiac allograft vasculopathy in heart transplant patients. AB - The predictive value of coronary artery calcium (CAC) in heart transplant (HTX) patients is not established. We explored if the absence of CAC on computed tomography (CT) could exclude moderate and severe cardiac allograft vasculopathy [CAV2-3 ; the International Society for Heart and Lung Transplantation (ISHLT) recommended nomenclature] and significant coronary artery stenosis (diameter reduction >=50%) and predict long-term clinical outcomes. HTX recipients (n = 133) were prospectively included and underwent CT for CAC scoring and invasive coronary angiography (ICA) 7.8 +/- 5.0 years after HTX. CAC was detected in 73 (55%) patients. The absence of CAC on CT had a negative predictive value of 97% for ISHLT CAV2-3 and 88% for significant stenosis on ICA. During 7.5 +/- 2.6 years of follow-up after CAC CT (n = 127), there were 57 (45%) nonfatal major adverse cardiac events and 23 (18%) deaths or graft losses registered as first events. Patients with CAC had significantly more events (P = 0.011). In an adjusted Cox regression analysis, the presence of CAC was significantly associated with a negative outcome (HR 1.8, 95% CI 1.1-3.0; P = 0.023). The absence of CAC predicted low prevalences of ISHLT CAV2-3 and significant coronary artery stenosis in HTX patients. The presence of CACS was significantly associated with a worse long-term outcome. PMID- 28865097 TI - Suspected Phenobarbital-Induced Pseudolymphoma in a Dog. AB - Pseudolymphoma is a drug reaction to anti-epileptics that is well recognized in humans; it has been reported in one cat but not dogs. In this report, lymphoma like clinical signs are suspected to be secondary to phenobarbital administration in a dog. A 2.5-year-old male, neutered Shepherd mix presented for a 3-day history of progressive ataxia, dazed mentation, pyrexia, and lethargy. While hospitalized, the dog developed generalized lymphadenopathy and sustained pyrexia. The dog was receiving levetiracetam and phenobarbital for epilepsy, and serum concentrations of both were within standard therapeutic ranges. Abdominal ultrasound revealed hepatomegaly, splenomegaly, and generalized lymphadenopathy. Cytology of the peripheral lymph nodes was consistent with reactive lymph nodes, and aspirates of the liver and spleen revealed histiocytic-neutrophilic inflammation. Phenobarbital was discontinued and replaced with zonisamide. Within 24 hours, the dog was normothermic, and other clinical signs resolved within a week. This case highlights a potentially serious yet reversible adverse reaction to phenobarbital in a dog. This idiosyncratic reaction could be mistaken for neoplasia and is an important differential for lymphoma-like signs in any dog administered phenobarbital. PMID- 28865099 TI - A computational study of samarium diiodide-induced cyclizations of N-oxoalkyl substituted methyl indole-3-carboxylates-A rationale of the diastereoselectivity. AB - A detailed model for the reaction mechanism of the samarium diiodide (SmI2 ) mediated reductive coupling of N-oxoalkyl-substituted methyl indole-3 carboxylates is developed in this study by determining the Gibbs energies for the intermediates of possible reaction pathways. The Gibbs energies at ambient temperature are calculated with dispersion corrected density functional theory in combination with implicit (D-COSMO-RS) and explicit solvent description. Temperature dependent ro-vibrational contributions are considered with the help of statistical thermodynamics. In contrast to previous proposals for the reaction mechanism, the high diastereoselectivity in the cyclization is found to be due to the formation of an energetically highly favorable chelate complex in which the final relative configuration is already preformed. After cyclization and a second electron transfer, alkylation of the resulting anion takes place under kinetic control from the more "open" face whereas protonation is under thermodynamic control. The calculations are in good agreement with these experimental findings. (c) 2017 Wiley Periodicals, Inc. PMID- 28865098 TI - Therapy of gastroesophageal reflux disease and functional dyspepsia overlaps with symptoms after usual-dose proton pump inhibitor: Acotiamide plus usual-dose proton pump inhibitor versus double-dose proton pump inhibitor. AB - BACKGROUND AND AIM: Gastroesophageal reflux disease (GERD) and functional dyspepsia (FD) often coexist or overlap. In this study, the efficacy of acotiamide in combination with a standard dose of rabeprazole for GERD and FD was compared with that of a double dose of rabeprazole. METHODS: Patients with overlap between GERD and FD experiencing heartburn and epigastric fullness symptoms after standard-dose proton pump inhibitor (PPI) for >= 8 weeks were randomized into two groups and received either acotiamide 300 mg/day + rabeprazole 10 mg/day or rabeprazole 20 mg/day for 4 weeks. Efficacy was assessed by reductions in symptom scores using the Izumo scale questionnaire and modified F-scale questionnaire. RESULTS: As the primary endpoint, three upper gastrointestinal symptoms (heartburn, epigastralgia, and epigastric fullness) were reduced by >= 50% in 40.8% and 46.9% of patients in the combination and PPI double-dose groups, respectively, with no significant difference between the two groups. Essentially similar results were obtained for the modified F-scale questionnaire. No serious adverse events were noted. CONCLUSIONS: Acotiamide 300 mg/day in combination with rabeprazole 10 mg/day or rabeprazole 20 mg/day relieved symptoms in patients with overlap between GERD and FD experiencing heartburn and epigastric fullness symptoms after standard-dose PPI for >= 8 weeks, and the efficacies did not differ between the two treatments. The combination therapy may be an alternative option for persistent symptoms in these patients. PMID- 28865100 TI - Untreated oral cavity cancer: Long-term survival and factors associated with treatment refusal. AB - OBJECTIVE: Oral cavity cancer is the most common malignant disease of the head and neck. The natural course of the disease is poorly characterized and unavailable for patient consideration during initial treatment planning. Our primary objective was to outline this natural history, with a secondary aim of identifying predictors of treatment refusal. STUDY DESIGN: Retrospective review of adult patients with oral cavity cancer who refused surgery that was recommended by their physician in the National Cancer Database. METHODS: Demographic, tumor, and survival variables were included in the analyses. Multivariate Cox regressions as well as univariate Kaplan-Meier analyses were conducted. RESULTS: Patients who were older, uninsured, had government insurance, or had more advanced disease were more likely to go untreated. Survival among untreated patients was poor, but there was a small proportion of patients surviving long term. Five-year survival rates ranged from 31.1% among early-stage patients to 12.6% among stage 4 patients. CONCLUSION: Although the natural course of oral cavity cancer carries a poor prognosis, there are a number of patients with longer-than-expected survival. The survival estimates may provide supplemental information for patients deciding whether to pursue treatment. In addition to age and extent of disease, system factors such as insurance status and facility case volume are associated with a patient's likelihood of refusing treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:664-669, 2018. PMID- 28865101 TI - Oral mucosa is a useful substrate for detecting autoantibodies of mucous membrane pemphigoid. PMID- 28865102 TI - Influence of UV filters on the texture profile and efficacy of a cosmetic formulation. AB - OBJECTIVE: Considering that many cosmetic products contain UV filters in their composition and that few studies have evaluated the role of UV filters in the physical properties and clinical efficacy of these products, the aim of this study was to assess the influence of UV filters on the properties and immediate effects of a cosmetic formulation. METHODS: Four cosmetic formulations, vehicle (V), vehicle containing UV filters (F), vehicle containing cassava polysaccharides and alfalfa (A) oligosaccharides and vehicle containing UV filters plus cassava polysaccharides and alfalfa oligosaccharides (multifunctional formulation, M) were developed. The texture profile of the formulations was analysed with a TA.XT plus Texturometer(r) . Twenty female volunteers aged 39-45 years were then selected for the assessment of immediate clinical efficacy of the formulations under study and of transepidermal water loss (TEWL), stratum corneum water content and microrelief of the skin obtained with their use. RESULTS: The presence of UV filters resulted in an improvement of the physical properties of the multifunctional cosmetic formulation (M) and of skin microrelief. However, the presence of UV filters also caused a significant decrease in hydration. CONCLUSION: The presence of sunscreens had a negative influence on immediate skin hydration and TEWL. On the other hand, it positively influenced parameters related to the physical properties of the multifunctional formulation and skin microrelief. Thus, we conclude that the influence of UV filters on the development of cosmetic formulations is an important factor to be considered because it can have either positive or negative effect on the efficacy of the product. PMID- 28865104 TI - Developing a quality-of-life questionnaire for oral submucous fibrosis patients. PMID- 28865103 TI - The worldwide diversity of scalp seborrhoea, as daily experienced by seven human ethnic groups. AB - OBJECTIVE: The re-greasing process and kinetics of the human scalp, post shampooing, have been previously documented, in vivo, on a few Caucasian subjects. The objective of the presented research was to extend such knowledge over seven different ethnic groups. METHODS: The post-shampooing re-greasing kinetics of the scalp was studied on 1325 subjects (women and men of two distinct age classes) from seven different ethnic groups in their residential and native country. Sebum amounts were determined onto small shaved scalp areas at various times post-shampooing, using the Sebumeter(r) technique. RESULTS: As previously published on Caucasian subjects, scalp re-greasing process follows a hyperbolic like kinetics over days. However, amounts of collected sebum highly vary with ethnicity. As recorded through the casual level (CL) at the equilibrium phase, 2 3 days post-shampooing, the highest amount of sebum was found in African American subjects, followed in descending order by Caucasian American, Japanese, Chinese, Thai, Caucasian European and Indian subjects, the latter showing very low values. Lower amounts of sebum were recorded in the older age class in all ethnics, as compared to the younger one, and male subjects were found higher sebum producers than women, irrespective of ethnicity. CONCLUSION: The kinetics and slopes of the re-greasing process of the human scalp appear similar in all ethnic groups studied. However, striking quantitative differences are found between the seven ethnic groups, resulting from different sebaceous production levels and scalp hygiene routines. PMID- 28865105 TI - Minimally invasive and targeted therapeutic cell delivery to the skin using microneedle devices. AB - BACKGROUND: Translation of cell therapies to the clinic is accompanied by numerous challenges, including controlled and targeted delivery of the cells to their site of action, without compromising cell viability and functionality. OBJECTIVES: To explore the use of hollow microneedle devices (to date only used for the delivery of drugs and vaccines into the skin and for the extraction of biological fluids) to deliver cells into skin in a minimally invasive, user friendly and targeted fashion. METHODS: Melanocyte, keratinocyte and mixed epidermal cell suspensions were passed through various types of microneedles and subsequently delivered into the skin. RESULTS: Cell viability and functionality are maintained after injection through hollow microneedles with a bore size >= 75 MUm. Healthy cells are delivered into the skin at clinically relevant depths. CONCLUSIONS: Hollow microneedles provide an innovative and minimally invasive method for delivering functional cells into the skin. Microneedle cell delivery represents a potential new treatment option for cell therapy approaches including skin repigmentation, wound repair, scar and burn remodelling, immune therapies and cancer vaccines. PMID- 28865106 TI - Neonatal Encephalopathy in Calves Presented to a University Hospital. AB - BACKGROUND: While studies have examined bovine dystocia in relation to calf survival, little has been published regarding perinatal morbidity and treatment of newborn calves beyond failure of transfer of passive immunity (FTPI). Neonatal encephalopathy (NE) is a clinical syndrome commonly diagnosed in infants and foals but is poorly described in calves. HYPOTHESIS/OBJECTIVES: To identify risk factors for development of NE in calves and factors predictive of survival. ANIMALS: Neonatal calves presented to a University hospital over a 10-year period. METHODS: Retrospective cohort study (2005-2015). Medical records of all neonatal calves presented to the hospital were examined, and cases of NE were identified. Data pertaining to demographics, dam parity, labor, treatment, and outcome were collected and analyzed with univariate and multivariate statistics. RESULTS: Of 200 calves in the final analysis, 58 (29%; 95% CI: 22.8-35.8%) were classified as NE and 142 calves as non-NE. In univariate analysis, factors significantly associated with diagnosis of NE included male sex, presence of dystocia, abnormal position in the birth canal, and prolonged labor. In the multivariate model, only orientation of the calf in the birth canal remained significant (OR 2.14; 95% CI: 1.02-4.49; P = 0.044). Overall survival of calves with NE was good (45/58; 77.6%; 95% CI: 64.7-87.5); dam parity and being a twin was significantly associated with nonsurvival. CONCLUSIONS: Calves born after dystocia, especially if malpresented, should be closely monitored for nursing behavior within the first 24 hours of life. Prognosis for survival is good, but supportive care might be required for several days. PMID- 28865108 TI - Glycerolipid analysis during desiccation and recovery of the resurrection plant Xerophyta humilis (Bak) Dur and Schinz. AB - Xerophyta humilis is a poikilochlorophyllous monocot resurrection plant used as a model to study vegetative desiccation tolerance. Dehydration imposes tension and ultimate loss of integrity of membranes in desiccation sensitive species. We investigated the predominant molecular species of glycerolipids present in root and leaf tissues, using multiple reaction monitoring mass spectrometry, and then analysed changes therein during dehydration and subsequent rehydration of whole plants. The presence of fatty acids with long carbon chains and with odd numbers of carbons were detected and confirmed by gas chromatography. Dehydration of both leaves and roots resulted in an increase in species containing polyunsaturated fatty acids and a decrease in disaturated species. Upon rehydration, lipid saturation was reversed, with this being initiated immediately upon watering in roots but only 12-24 hr later in leaves. Relative levels of species with short chained odd-numbered saturated fatty acids decreased during dehydration and increased during rehydration, whereas the reverse trend was observed for long chained fatty acids. X. humilis has a unique lipid composition, this report being one of the few to demonstrate the presence of odd-numbered fatty acids in plant phosphoglycerolipids. PMID- 28865107 TI - Effect of Body Position, Exercise, and Sedation on Estimation of Pulmonary Artery Pressure in Dogs with Degenerative Atrioventricular Valve Disease. AB - BACKGROUND: Severity of pulmonary hypertension (PH) in dogs is related to clinical signs and prognosis. HYPOTHESIS/OBJECTIVES: We hypothesized that Doppler echocardiographic (DE) indices of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) are influenced by independent factors that create clinically important variability of DE-based estimates of PH in dogs. ANIMALS: Thirty-eight client owned dogs with naturally acquired degenerative atrioventricular valve disease and tricuspid regurgitation (TR). METHODS: Dogs were prospectively enrolled, and target variables were acquired during 4 echocardiographic study periods (lateral recumbency, standing, lateral recumbency after a 6-minute walk test [6MWT], and lateral recumbency after sedation with butorphanol 0.25 mg/kg IM). Statistical methods included repeated measures ANOVA, mixed model analysis, and Chi-squared test of association. RESULTS: There was a significant increase in peak TR flow velocity (TRFV; P < 0.01) after sedation in 78% of dogs, with TRFV increasing by >0.4 m/s in 42% of dogs, independent of stroke volume. A significant effect of study period on DE-estimated PVR was not found (P = 0.15). There were negligible effects of sonographer, body position, and 6MWT on echocardiographic variables of PH. Clinically relevant cyclic variation of TRFV was found. There was an association between estimation of right atrial pressure based on subjective assessment and estimation based on cranial vena cava collapsibility (P = 0.03). CONCLUSIONS AND CLINICAL IMPORTANCE: The increase in TRFV observed with sedation could change assessment of PH severity and impact prognostication and interpretation of treatment response. Further studies with invasive validation are needed. PMID- 28865109 TI - Effects of Moxonidine and Low-Calorie Diet: Cardiometabolic Benefits from Combination of Both Therapies. AB - OBJECTIVE: Because sympathetic nervous system activity plays a detrimental role in metabolic and cardiovascular health, this study compared the effects of a centrally acting sympatholytic agent, the effects of a weight loss (WL) program using a low-calorie diet, and the effects of a combination of both. METHODS: Young (18-30 years) male subjects with overweight (BMI > 25 kg/m2 ) were allocated to a WL program (n = 10), a moxonidine treatment course (M; n = 10, 0.4 mg/d), a combination of both (WL + M; n = 11), or to a control (C) group (n = 6) for 6 months. Muscle sympathetic nerve activity (MSNA), endothelial function, renal function (Cockcroft-Gault formula), and the metabolic profile were assessed before and after intervention. RESULTS: WL occurred in the WL and WL + M groups ( 7.6 +/- 1.9 kg, P < 0.001 in both). MSNA and systolic blood pressure decreased similarly in the WL, M, and WL + M groups (by ~10 bursts/min, P < 0.001, and by ~9 mm Hg, P < 0.05). All other parameters for the WL, C, and M groups remained unchanged. In the WL + M group, decreased total cholesterol (-0.78 +/- 0.23 mmol/L, P < 0.001), decreased low-density lipoprotein cholesterol (-0.49 +/- 0.16 mmol/L, P < 0.01), decreased insulin (-6.5 +/- 2.8 mmol/L, P < 0.05), and attenuated glomerular hyperfiltration (-19 +/- 5 mL/min, P < 0.01) occurred. CONCLUSIONS: The combination of moxonidine with a WL program has beneficial effects on aspects of the metabolic profile and end organ damage in young males with overweight. PMID- 28865110 TI - The effect of photodamage on the female Caucasian facial stratum corneum corneome using mass spectrometry-based proteomics. AB - BACKGROUND: The effect of photodamage on facial stratum corneum (SC) is still poorly understood. OBJECTIVE: To describe the SC proteome from tape strippings of Caucasian SC from photoexposed cheek and photoprotected post-auricular (PA) site, a global analysis of photodamage on the skin will be developed leading to a better understanding of keratinocyte signalling pathways and identification of new molecular targets for the treatment of photoaged skin. METHODS: Female Caucasian subjects had nine consecutive tape strippings taken from their cheeks and PA site. Proteins were extracted and the trypsin-digested peptides were analysed by nanochromatography coupled to a high-resolution mass spectrometer. Data-dependent acquisition allowed protein identification that was processed by Paragon algorithm of Protein Pilot software. RESULTS: Changes in the levels of epidermal differentiation proteins were apparent indicating poor epidermal differentiation and SC maturation (keratins, cornified envelope (CE) proteins) on photoexposed cheeks. Differences in protease-anti-protease balance were observed for corneodesmolysis (favouring desquamation) and filaggrinolysis (favouring reduced filaggrin processing). 12R-LOX, a CE maturation enzyme, was reduced in photodamaged skin but not transglutaminases. Changes in signal keratinocyte transduction pathway markers were demonstrated especially by reduced levels of downstream signalling markers such as calreticulin (unfolded protein response; UPR) and increased level of stratifin (target of rapamycin; mTOR). Evidence for impaired proteostasis was apparent by reduced levels of a key proteasomal subunit (subunit beta type-6). Finally, key antioxidant proteins were upregulated except catalase. CONCLUSION: Clear examples of poor keratinocyte differentiation and associated metabolic and signalling pathways together with reduced SC maturation were identified in photodamaged facial SC. Corneocyte immaturity was evident with changes in CE proteins. Particularly, the reduction in 12R-LOX is a novel finding in photodamaged skin and supports the lack of SC maturation. Moreover, filaggrinolysis was reduced, whereas corneodesmolysis was enhanced. From our results, we propose that there is a poor cross-talk between the keratinocyte endoplasmic reticulum UPR, proteasome network and autophagy machinery that possibly leads to impaired keratinocyte proteostasis. Superimposed on these aberrations is an apparently enhanced mTOR pathway that also contributes to reduced SC formation and maturation. Our results clearly indicate a corneocyte scaffold disorder in photodamaged cheek SC. PMID- 28865111 TI - Neodymium-doped yttrium aluminium garnet laser to treat primary pilonidal cysts: an alternative treatment. PMID- 28865112 TI - On the Electronic Origin of Remarkable Ligand Effects on the Reactivities of [NiL]+ Complexes (L=C6 H5 , C5 H4 N, CN) towards Methane. AB - The gas-phase reactions of [NiL]+ (L=C6 H5 , C5 H4 N, CN) with methane have been explored by using electrospray-ionization mass spectrometry (ESI-MS) complemented by quantum chemical calculations. Though the phenyl Ni complex [Ni(C6 H5 )]+ exclusively abstracts one hydrogen atom from methane at ambient conditions, the cyano Ni complex [Ni(CN)]+ brings about both H-atom abstraction and ligand exchange to generate [Ni(CH3 )]+ . In contrast, the complex 2-pyridinyl Ni [Ni(C5 H4 N)]+ is inert towards this substrate. The presence of the empty 4s(Ni) orbital dominates the proton-coupled electron transfer (PCET) processes for the investigated systems. PMID- 28865113 TI - Investigation on the absolute and relative photoionization cross sections of 3 potential propargylic fuels. AB - Absolute photoionization cross sections for 2 potential propargylic fuels (propargylamine and dipropargyl ether) along with the partial ionization cross sections for their dissociative fragments are measured and presented for the first time via synchrotron photoionization mass spectrometry. The experimental setup consists of a multiplexed orthogonal time-of-flight mass spectrometer and is located at the Advanced Light Source facility of the Lawrence Berkeley National Laboratory in Berkeley, California. Data for a third propargylic compound (propargyl alcohol) were taken; however, because of its low signal, due to its weakly bound cation, only the dissociative ionization fragment from the H loss channel is observed and presented. Suggested pathways leading to formation of dissociative photoionization fragments along with CBS-QB3 calculated adiabatic ionization energies and appearance energies for the dissociative fragments are also presented. PMID- 28865115 TI - Paving the future of rhinosinusitis care. AB - Novel insights into the pathophysiology of chronic rhinosinsusitis (CRS) will lead to endo-type driven treatment and reduce oral corticosteroid treatment. PMID- 28865114 TI - Prenatal Alcohol Exposure Leads to Enhanced Serine 9 Phosphorylation of Glycogen Synthase Kinase-3beta (GSK-3beta) in the Hippocampal Dentate Gyrus of Adult Mouse. AB - BACKGROUND: The goal of this study was to evaluate the expression and serine 9 phosphorylation of glycogen synthase kinase (GSK-3beta) within the adult hippocampal dentate gyrus (DG) in a preclinical mouse model of fetal alcohol spectrum disorders. GSK-3beta is a multifunctional kinase that modulates many hippocampal processes affected by gestational alcohol, including synaptic plasticity and adult neurogenesis. GSK-3beta is a constitutively active kinase that is negatively regulated by phosphorylation at the serine 9 residue. METHODS: We utilized a well-characterized limited access "drinking-in-the-dark" paradigm of prenatal alcohol exposure (PAE) and measured p(Ser9)GSK-3beta and total GSK 3beta within adult DG by Western blot analysis. In addition, we evaluated the expression pattern of both p(Ser9)GSK-3beta and total GSK-3beta within the adult hippocampal dentate of PAE and control mice using high-resolution confocal microscopy. RESULTS: Our findings demonstrate a marked 2.0-fold elevation of p(Ser9)GSK-3beta in PAE mice, concomitant with a more moderate 36% increase in total GSK-3beta. This resulted in an approximate 63% increase in the p(Ser9)GSK 3beta/GSK-3beta ratio. Immunostaining revealed robust GSK-3beta expression within Cornu Ammonis (CA) pyramidal neurons, hilar mossy cells, and a subset of GABAergic interneurons, with low levels of expression within hippocampal progenitors and dentate granule cells. CONCLUSIONS: These findings suggest that PAE may lead to a long-term disruption of GSK-3beta signaling within the DG, and implicate mossy cells, GABAergic interneurons, and CA primary neurons as major targets of this dysregulation. PMID- 28865116 TI - Power input effects on degeneration in prolonged penicillin chemostat cultures: A systems analysis at flux, residual glucose, metabolite, and transcript levels. AB - In the present work, by performing chemostat experiments at 400 and 600 RPM, two typical power inputs representative of industrial penicillin fermentation (P/V, 1.00 kW/m3 in more remote zones and 3.83 kW/m3 in the vicinity of the impellers, respectively) were scaled-down to bench-scale bioreactors. It was found that at 400 RPM applied in prolonged glucose-limited chemostat cultures, the previously reported degeneration of penicillin production using an industrial Penicillium chrysogenum strain was virtually absent. To investigate this, the cellular response was studied at flux (stoichiometry), residual glucose, intracellular metabolite and transcript levels. At 600 RPM, 20% more cell lysis was observed and the increased degeneration of penicillin production was accompanied by a 22% larger ATP gap and an unexpected 20-fold decrease in the residual glucose concentration (Cs,out ). At the same time, the biomass specific glucose consumption rate (qs ) did not change but the intracellular glucose concentration was about sixfold higher, which indicates a change to a higher affinity glucose transporter at 600 RPM. In addition, power input differences cause differences in the diffusion rates of glucose and the calculated Batchelor diffusion length scale suggests the presence of a glucose diffusion layer at the glucose transporting parts of the hyphae, which was further substantiated by a simple proposed glucose diffusion-uptake model. By analysis of calculated mass action ratios (MARs) and energy consumption, it indicated that at 600 RPM glucose sensing and signal transduction in response to the low Cs,out appear to trigger a gluconeogenic type of metabolic flux rearrangement, a futile cycle through the pentose phosphate pathway (PPP) and a declining redox state of the cytosol. In support of the change in glucose transport and degeneration of penicillin production at 600 RPM, the transcript levels of the putative high-affinity glucose/hexose transporter genes Pc12g02880 and Pc06g01340 increased 3.5- and 3.3 fold, respectively, and those of the pcbC gene encoding isopenicillin N synthetase (IPNS) were more than twofold lower in the time range of 100-200 hr of the chemostat cultures. Summarizing, changes at power input have unexpected effects on degeneration and glucose transport, and result in significant metabolic rearrangements. These findings are relevant for the industrial production of penicillin, and other fermentations with filamentous microorganisms. PMID- 28865117 TI - Development of a general defined medium for Pichia pastoris. AB - Pichia pastoris is widely used as a host for recombinant protein production. More than 500 proteins have been expressed in the organism at a variety of cultivation scales, from small shake flasks to large bioreactors. Large-scale fermentation strategies typically employ chemically defined growth medium because of its greater batch-to-batch consistency and in many cases, lower costs compared to complex medium. For biopharmaceuticals, defined growth medium may also simplify downstream purification and regulatory documentation. Standard formulations of defined media for P. pastoris are minimal ones that lack the metabolic intermediates provided by complex components such as peptone and yeast extract. As a result, growth rates and per-cell productivities are significantly lower than in complex medium. We have designed a rich defined medium (RDM) for Pichia pastoris by systematically evaluating nutrients of increasing complexity and identifying those that are most critical for growth. We have also employed transcriptomics to gain deeper insights into the underlying metabolic processes and inform our media design. We have demonstrated that using RDM for expression of three heterologous proteins yields titers comparable to, or higher than, those in standard complex medium. RDM improves productivity of P. pastoris fermentations and its development demonstrates the usefulness of transcriptomics to accelerate process development for new molecules. PMID- 28865119 TI - We have to do more for former paediatric renal transplant recipients! PMID- 28865120 TI - Uptake of radiolabeled 3,3',4,4'-tetrachlorobiphenyl into Japanese quail egg compartments and embryo following air cell and albumen injection. AB - The avian embryo is an excellent model for testing adverse developmental effects of environmental chemicals as well as uptake and movement of xenobiotics within the egg compartments. Before incubation at embryonic day 0, 14 C 3,3',4,4' tetrachlorobiphenyl (14 C PCB 77) was injected into Japanese quail eggs either onto the air cell or into the albumen. All egg components were collected on embryonic day 1, 5, or 10, and concentrations of 14 C PCB 77 were measured in various egg components (shell, membrane, yolk, albumen, and embryo). The results showed measurable 14 C PCB 77 in all egg components, with changing concentrations in each egg component over the course of embryonic development. Specifically, concentrations in the shell content decreased between embryonic days 1 and 10, increased in albumen from embryonic days 1 to 5 and then decreased at embryonic day 10, and increased in both yolk and embryo from embryonic days 1 to 10. Vehicle and injection site both influenced 14 C PCB 77 allantoic fluid concentrations, with little effect on other egg components except for the inner shell membrane. The fatty acid vehicle injected into the albumen yielded the highest 14 C PCB 77 recovery. These findings demonstrate dynamic movement of toxicants throughout the egg components during avian embryonic development and a steady increase of relatively low levels of 14 C PCB 77 in the embryo compared with the yolk, albumen, and shell, suggesting that embryonic uptake (i.e., exposure) mirrors utilization of egg components for nutrition and growth during development. Environ Toxicol Chem 2018;37:126-135. (c) 2017 SETAC. PMID- 28865121 TI - HNF1A/CASC2 regulates pancreatic cancer cell proliferation through PTEN/Akt signaling. AB - Pancreatic cancer (PC) has a high mortality rate in all cancers worldwide. According to recent studies, long noncoding RNA-CASC2 is involved in the development and progression of many malignant tumors; in the present study, we demonstrated that lncRNA-CASC2 was specifically downregulated in PC tissues and cell lines, and a lower CASC2 expression in PC was related with a poorer prognosis. CASC2 suppressed PC cell proliferation. Hepatocyte nuclear factor 1 alpha (HNF1A) is a transcription factor known to regulate pancreatic differentiation and maintain the homeostasis of the endocrine pancreas. Recently, HNF1A is considered to be a possible tumor suppressor in PC. In the present study, we observed that HNF1A positively regulated CASC2 expression. Through luciferase assays, we demonstrated that CASC2 gene possessed an HNF1A-responsive element (CASC2-HNF1A RE); HNF1A could promote CASC2 expression through direct binding to CASC2-HNF1A RE. Further, PTEN/Akt signaling was involved in HNF1A regulation of CASC2. Finally, we evaluated the expression level of HNF1A in PC tissues; lower HNF1A expression was correlated with shorter overall survival in patients with PC. Taken together, these findings will shed light on the role and mechanism of HNF1A/CASC2 in regulating PC cells proliferation through PTEN/Akt signaling. CASC2 may serve as a potential therapeutic target in PC in the future. PMID- 28865118 TI - Glucose-stimulated insulin release: Parallel perifusion studies of free and hydrogel encapsulated human pancreatic islets. AB - To explore the effects immune-isolating encapsulation has on the insulin secretion of pancreatic islets and to improve our ability to quantitatively describe the glucose-stimulated insulin release (GSIR) of pancreatic islets, we conducted dynamic perifusion experiments with isolated human islets. Free (unencapsulated) and hydrogel encapsulated islets were perifused, in parallel, using an automated multi-channel system that allows sample collection with high temporal resolution. Results indicated that free human islets secrete less insulin per unit mass or islet equivalent (IEQ) than murine islets and with a less pronounced first-phase peak. While small microcapsules (d = 700 um) caused only a slightly delayed and blunted first-phase insulin response compared to unencapsulated islets, larger capsules (d = 1,800 um) completely blunted the first-phase peak and decreased the total amount of insulin released. Experimentally obtained insulin time-profiles were fitted with our complex insulin secretion computational model. This allowed further fine-tuning of the hormone-release parameters of this model, which was implemented in COMSOL Multiphysics to couple hormone secretion and nutrient consumption kinetics with diffusive and convective transport. The results of these GSIR experiments, which were also supported by computational modeling, indicate that larger capsules unavoidably lead to dampening of the first-phase insulin response and to a sustained-release type insulin secretion that can only slowly respond to changes in glucose concentration. Bioartificial pancreas type devices can provide long term and physiologically desirable solutions only if immunoisolation and biocompatibility considerations are integrated with optimized nutrient diffusion and insulin release characteristics by design. PMID- 28865122 TI - Investigation of challenging spin systems using Monte Carlo configuration interaction and the density matrix renormalization group. AB - We investigate if a range of challenging spin systems can be described sufficiently well using Monte Carlo configuration interaction (MCCI) and the density matrix renormalization group (DMRG) in a way that heads toward a more "black box" approach. Experimental results and other computational methods are used for comparison. The gap between the lowest doublet and quartet state of methylidyne (CH) is first considered. We then look at a range of first-row transition metal monocarbonyls: MCO when M is titanium, vanadium, chromium, or manganese. For these MCO systems we also employ partially spin restricted open shell coupled-cluster (RCCSD). We finally investigate the high-spin low-lying states of the iron dimer, its cation and its anion. The multireference character of these molecules is also considered. We find that these systems can be computationally challenging with close low-lying states and often multireference character. For this more straightforward application and for the basis sets considered, we generally find qualitative agreement between DMRG and MCCI. (c) 2017 Wiley Periodicals, Inc. PMID- 28865123 TI - Kaempferol increases apoptosis in human acute promyelocytic leukemia cells and inhibits multidrug resistance genes. AB - Acute promyelocytic leukemia (APL) is one of the most life-threatening hematological malignancies. Defects in the cell growth and apoptotic pathways are responsible for both disease pathogenesis and treatment resistance. Therefore, pro-apoptotic agents are potential candidates for APL treatment. Kaempferol is a flavonoid with antioxidant and anti-tumor properties. This study was designed to investigate the cytotoxic, pro-apoptotic, and differentiation-inducing effects of kaempferol on HL-60 and NB4 leukemia cells. Resazurin assay was used to determine cell viability following treatment with kaempferol (12.5-100 MUM) and all-trans retinoic acid (ATRA; 10 MUM; used as a positive control). Apoptosis and differentiation were also detected using propidium iodide and NBT staining techniques, respectively. Furthermore, the expression levels of genes involved in apoptosis (PI3 K, AKT, BCL2, BAX, p53, p21, PTEN, CASP3, CASP8, and CASP9), differentiation (PML-RAR and HDAC1), and multi-drug resistance (ABCB1 and ABCC1) were determined using quantitative real-time PCR. The protein expressions of Bax/Bcl2 and casp3 were confirmed using Western blot. The results showed that kaempferol decreased cell viability and increased subG1 population in the tested leukemic cells. This effect was associated with decreased expression of Akt, BCL2, ABCB1, and ABCC1 genes, while the expression of CASP3 and BAX/BCL-2 ratio were significantly increased at both gene and protein levels. Kaempferol promoted apoptosis and inhibited multidrug resistance in a concentration-dependent manner, without any differential effect on leukemic cells. In conclusion, this study suggested that kaempferol may be utilized as an appropriate alternative for ATRA in APL patients. PMID- 28865124 TI - Dry biorefining maximizes the potentials of simultaneous saccharification and co fermentation for cellulosic ethanol production. AB - Despite the well-recognized merits of simultaneous saccharification and co fermentation (SSCF) on relieving sugar product inhibition on cellulase activity, a practical concomitance difficulty of xylose with inhibitors in the pretreated lignocellulose feedstock prohibits the essential application of SSCF for cellulosic ethanol fermentation. To maximize the SSCF potentials for cellulosic ethanol production, a dry biorefining approach was proposed starting from dry acid pretreatment, disk milling, and biodetoxification of lignocellulose feedstock. The successful SSCF of the inhibitor free and xylose conserved lignocellulose feedstock after dry biorefining reached a record high ethanol titer at moderate cellulase usage and minimum wastewater generation. For wheat straw, 101.4 g/L of ethanol (equivalent to 12.8% in volumetric percentage) was produced with the overall yield of 74.8% from cellulose and xylose, in which the xylose conversion was 73.9%, at the moderate cellulase usage of 15 mg protein per gram cellulose. For corn stover, 85.1 g/L of ethanol (equivalent to 10.8% in volumetric percentage) is produced with the overall conversion of 84.7% from cellulose and xylose, in which the xylose conversion was 87.7%, at the minimum cellulase usage of 10 mg protein per gram cellulose. Most significantly, the SSCF operation achieved the high conversion efficiency by generating the minimum amount of wastewater. Both the fermentation efficiency and the wastewater generation in the current dry biorefining for cellulosic ethanol production are very close to that of corn ethanol production, indicating that the technical gap between cellulosic ethanol and corn ethanol has been gradually filled by the advancing biorefining technology. PMID- 28865125 TI - Countercurrent staged diafiltration for formulation of high value proteins. AB - A number of groups have studied the application of continuous bioreactors and continuous chromatographic systems as part of efforts to develop an integrated continuous biomanufacturing process. The objective of this study was to examine the feasibility of using a countercurrent staged diafiltration process for continuous protein formulation with reduced buffer requirements. Experiments were performed using a polyclonal immunoglobulin (IgG) with CadenceTM Inline Concentrators. Model equations were developed for the product yield, impurity removal, and buffer requirements as a function of the number of stages and the stage conversion (ratio of permeate to feed flow rate). Data from a countercurrent two-stage system were in excellent agreement with model calculations, demonstrating the potential of using countercurrent staged diafiltration for protein formulation. Model simulations demonstrated the importance of the countercurrent staging on both the extent of buffer exchange and the amount of buffer required per kg of formulated product. The staged diafiltration process not only provides for continuous buffer exchange, it could also provide significant reductions in the number of pump passes while providing opportunities for reduced buffer requirements. PMID- 28865126 TI - Circadian control of pain and neuroinflammation. AB - The importance of a neuroinflammatory response to the development and maintenance of inflammatory and neuropathic pain have been highlighted in recent years. Inflammatory cells contributing to this response include circulating immune cells such as monocytes, T and B lymphocytes, and neutrophils, as well as microglia in the central nervous system. Pain signals are transmitted via sensory neurons in the peripheral nervous system, which express various receptors and channels that respond to mediators secreted from these inflammatory cells. Chronobiological rhythms, which include the 24-hr circadian cycle, have recently been shown to regulate both nervous and immune cell activity and function. This review examines the current literature on chronobiological control of neuroinflammatory processes, with a focus on inflammatory and neuropathic pain states. While the majority of this work has stemmed from observational studies in humans, recent advances in using animal models have highlighted distinct mechanisms underlying these interactions. Better understanding interactions between the circadian and neuroimmune systems can help guide the development of new treatments and provide improved care for patients suffering from acute and chronic pain. PMID- 28865128 TI - Mechanisms underlying human genetic diversity: consequence for antigraft antibody responses. AB - This review focuses on the emerging concept of genomewide genetic variation as basis of an alloimmune response. Chronic antibody-mediated rejection is the major cause of long-term graft loss and growing evidence supports the clinical relevance of HLA but also non-HLA related alloimmune responses. Several polymorphic gene products have been identified as minor histocompatibility antigens. The formation of donor-specific alloantibodies is driven by indirect allorecognition of donor-derived peptides representing a form of conventional T cell response. With the availability of high-throughput sequencing and genotyping technologies, the identification of genomewide genetic variation and thus mismatches between organ donors and graft recipients has become feasible. First clinical data linking genetic polymorphism and clinical outcome have been published and larger studies are currently under way. Protein arrays have successfully been used to identify a large variety of non-HLA antibodies in kidney transplant recipients and the availability of customizable peptide arrays made screening for linear epitopes on an individual patient level feasible. This review provides a summary of the recent findings in histocompatibility matching in the field of solid organ transplantation and complements it with a clear workflow for assessing the impact of genetic differences in protein-coding genes in solid organ transplantation. PMID- 28865127 TI - Evaluation of an acute oral gavage method for assessment of pesticide toxicity in terrestrial amphibians. AB - Development of an acute oral toxicity test with a terrestrial-phase amphibian was considered necessary to remove the uncertainty within the field of agrochemical risk assessments. The bullfrog (Lithobates catesbeianus) was selected for use as it is a representative of the family Ranidae and historically this species has been used as an amphibian test model species. Prior to definitive study, oral gavage methods were developed with fenthion and tetraethyl pyrophosphate. Dimethoate and malathion were subsequently tested with both male and female juvenile bullfrogs in comprehensive acute oral median lethal dose (LD50) studies. Juvenile bullfrogs were administered a single dose of the test article via oral gavage of a single gelatin capsule of dimethoate technical (dimethoate) or neat liquid Fyfanon(r) Technical (synonym malathion), returned to their respective aquaria, and monitored for survival for 14 d. The primary endpoint was mortality, whereas behavioral responses, food consumption, body weight, and snout-vent length (SVL) were used to evaluate indications of sublethal toxicity (secondary endpoints). Acute oral LD50 values (95% fiducial interval) for dimethoate were 1459 (1176-1810, males) and 1528 (1275-1831, females), and for malathion they were 1829 (1480-2259, males) and 1672 (1280-2183, females) mg active substance/kg body weight, respectively. Based on the results of these studies, the methodology for the acute oral gavage administration of test items to terrestrial-phase amphibians was demonstrated as being a practical method of providing data for risk assessments. Environ Toxicol Chem 2018;37:436-450. (c) 2017 SETAC. PMID- 28865129 TI - Effects of long-term low oxygen tension in human chondrosarcoma cells. AB - The cell-based therapies could be potential methods to treat damaged cartilage tissues. Instead of native hyaline cartilage, the current therapies generate mainly weaker fibrocartilage-type of repair tissue. A correct microenvironment influences the cellular phenotype, and together with external factors it can be used, for example, to aid the differentiation of mesenchymal stem cells to defined types of differentiated adult cells. In this study, we investigated the effect of long-term exposure to 5% low oxygen atmosphere on human chondrosarcoma HCS-2/8 cells. This atmosphere is close to normal oxygen tension of cartilage tissue. The proteome was analyzed with label-free mass spectrometric method and further bioinformatic analysis. The qRT-PCR method was used to gene expression analysis, and ELISA and dimethylmethylene blue assays for type II collagen and sulfated glycosaminoglycan measurements. The 5% oxygen atmosphere did not influence cell proliferation, but enhanced slightly ACAN and COL2A1 gene expression. Proteomic screening revealed a number of low oxygen-induced protein level responses. Increased ones included NDUFA4L2, P4HA1, NDRG1, MIF, LDHA, PYGL, while TXNRD1, BAG2, TXN2, AQSTM1, TNFRSF1B, and EPHX1 decreased during the long term low oxygen atmosphere. Also a number of proteins previously not related to low oxygen tension changed during the treatment. Of those S100P, RPSS26, NDUFB11, CDV3, and TUBB8 had elevated levels, while ALCAM, HLA-B, EIF1, and ACOT9 were lower in the samples cultured at low oxygen tension. In conclusion, low oxygen condition causes changes in the cellular amounts of several proteins. PMID- 28865130 TI - Temperature-dependent dynamic control of the TCA cycle increases volumetric productivity of itaconic acid production by Escherichia coli. AB - Based on the recently constructed Escherichia coli itaconic acid production strain ita23, we aimed to improve the productivity by applying a two-stage process strategy with decoupled production of biomass and itaconic acid. We constructed a strain ita32 (MG1655 DeltaaceA Deltapta DeltapykF DeltapykA pCadCs), which, in contrast to ita23, has an active tricarboxylic acid (TCA) cycle and a fast growth rate of 0.52 hr-1 at 37 degrees C, thus representing an ideal phenotype for the first stage, the growth phase. Subsequently we implemented a synthetic genetic control allowing the downregulation of the TCA cycle and thus the switch from growth to itaconic acid production in the second stage. The promoter of the isocitrate dehydrogenase was replaced by the Lambda promoter (pR ) and its expression was controlled by the temperature-sensitive repressor CI857 which is active at lower temperatures (30 degrees C). With glucose as substrate, the respective strain ita36A grew with a fast growth rate at 37 degrees C and switched to production of itaconic acid at 28 degrees C. To study the impact of the process strategy on productivity, we performed one-stage and two-stage bioreactor cultivations. The two-stage process enabled fast formation of biomass resulting in improved peak productivity of 0.86 g/L/hr (+48%) and volumetric productivity of 0.39 g/L/hr (+22%) in comparison to the one stage process. With our dynamic production strain, we also resolved the glutamate auxotrophy of ita23 and increased the itaconic acid titer to 47 g/L. The temperature-dependent activation of gene expression by the Lambda promoters (pR /pL ) has been frequently used to improve protein or, in a few cases, metabolite production in two-stage processes. Here we demonstrate that the system can be as well used in the opposite direction to selectively knock-down an essential gene (icd) in E. coli to design a two-stage process for improved volumetric productivity. The control by temperature avoids expensive inducers and has the potential to be generally used to improve cell factory performance. PMID- 28865131 TI - Quercetin reduces neural tissue damage and promotes astrocyte activation after spinal cord injury in rats. AB - Spinal cord injury (SCI) is lead to locomotor impairment because of neurological damage after following trauma. Quercetin (Que) has been confirmed to have a neuro protective effect during nerve damage processes. The purpose of this study was to determine the roles of Que in functional recovery, cavity formation, astrocyte activation, and nerve regeneration following SCI. Sprague-Dawley rats were randomly divided into three groups: Sham group, SCI group, and Que + SCI group. A rat model of SCI was made at T10 using the modified Allen's method. In the Que + SCI group, animals underwent laminectomy and were then intraperitoneally injected with 20 mg/kg Que for 7 days. Locomotor function was determined with the Basso, Beattie, Bresnahan (BBB) scores at 1, 3, 5, and 7 days post-injury. At 7 days post-injury, somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were recorded. Hematoxylin-Eosin (HE) staining was used to investigate cavity formation. Astrocyte activation was assayed by immunohistochemistry staining with an antibody specific for glial fibrillary acidic protein (GFAP), as well as the expression of GFAP and S100beta. Axons were stained using an antibody specific for neurofilament 200 (NF200) and 5-hydroxytryptamine (5-HT). In addition, the protein level of BDNF, p-JNK2, and p-STAT3 was detected using Western blot. Que promoted locomotor function and electrophysiological recovery, reduced cavity formation, contributed to astrocyte activation and axonal regeneration after acute SCI. Moreover, Que up-regulated the expression of BDNF, but reduced p-JNK2 and p-STAT3 expression after acute SCI. Taken together, Que promoted locomotor and electrophysiological functional recovery, astrocyte activation and axonal regeneration after acute SCI, possibly through BDNF and JAK2/STAT3 signaling pathways. PMID- 28865132 TI - Growth Rate Changes in CHO Host Cells Are Associated with Karyotypic Heterogeneity. AB - Chinese hamster ovary (CHO) cell line instability and clonality issues can affect cell culture phenotypes such as cell growth, productivity, or product quality and remain challenges for biopharmaceutical manufacturing. While there have been efforts for characterizing cell line instability in CHO production cell lines, a pre-existing level of cell line instability in CHO host cells has not been determined. In this study, cell line instability and chromosomal heterogeneity of the host, CHO-DUK cell line, is reported by using a karyotyping approach. Long term cultures and karyotype analysis of CHO-DUK cells revealed that the growth rate was higher in later passage cultures, correlating with an increase in the population ratio containing the mar3 chromosome. To further investigate a correlation between growth rate and karyotype, CHO-DUK cells are subcloned by limiting dilution and the growth rate and karyotype of each subclone are determined. Subclones containing the mar3 chromosome exhibit higher cell growth rates than subclones without the mar3 chromosome. Finally, karyotype analysis indicate that CHO-DUK cells, as well as limiting-diluted subclones, exhibit a karyotypically heterogeneous population, suggesting that chromosomal rearrangements occur spontaneously and frequently even in non-engineered host cells. These results demonstrate CHO host cell line instability and suggest that chromosomal instability and karyotypic changes are associated with compromised clonality (heterogeneity), affecting cell line (in)stability in CHO host cells. PMID- 28865133 TI - Prosthodontic Rehabilitation of an Ectodermal Dysplasia Patient with Implant Telescopic Crown Attachments. AB - Telescopic crown attachments have been successfully used in completely and partially edentulous patients. This type of attachment provides retention, support, and stability with optimal hygiene for the removable dental prosthesis (RDP). With the emergence of CAD/CAM technology, telescopic crown attachments can be virtually designed and milled precisely to ensure a passive fit of the attachment parts and maximal functionality of the RDP. This article reviews both the clinical outcome and prosthodontic rehabilitation of telescopic crown attachments of an edentulous ectodermal dysplasia patient with solitary rigid conical telescopic crown attachments. PMID- 28865134 TI - Human Pulmonary 3D Models For Translational Research. AB - Lung diseases belong to the major causes of death worldwide. Recent innovative methodological developments now allow more and more for the use of primary human tissue and cells to model such diseases. In this regard, the review covers bronchial air-liquid interface cultures, precision cut lung slices as well as ex vivo cultures of explanted peripheral lung tissue and de-/re-cellularization models. Diseases such as asthma or infections are discussed and an outlook on further areas for development is given. Overall, the progress in ex vivo modeling by using primary human material could make translational research activities more efficient by simultaneously fostering the mechanistic understanding of human lung diseases while reducing animal usage in biomedical research. PMID- 28865135 TI - Designing Randomized DNA Sequences Free of Restriction Enzyme Recognition Sites. AB - DNA libraries containing random "barcodes" complicate synthetic biology workflows that utilize restriction enzymes since restriction sites can appear inside some barcodes. By removing bases at particular sites in the barcodes, it is possible to create semi-random pools of barcodes that do not contain any restriction sites. The challenge is to remove as few bases as possible to maximize the number of sequences in the pool while ensuring all sequences are free of restriction sites. The authors present CutFree, a computational approach to create pools of random DNA barcodes that lack a pre-defined set of restriction sites. The resulting pools can be inexpensively produced en masse with standard DNA synthesis techniques. CutFree is experimentally validated by blocking digestion of pools of barcodes designed to frequently contain restriction sites. Using CutFree, a pool of 1.3 billion barcodes that are free from recognition sites for 182 commercially available restriction enzymes is designed. CutFree is available as a software package and an online tool (http://jensenlab.net/tools). PMID- 28865136 TI - Covalent Binding of Bone Morphogenetic Protein-2 and Transforming Growth Factor beta3 to 3D Plotted Scaffolds for Osteochondral Tissue Regeneration. AB - Engineering the osteochondral tissue presents some challenges mainly relying in its function of transition from the subchondral bone to articular cartilage and the gradual variation in several biological, mechanical, and structural features. A possible solution for osteochondral regeneration might be the design and fabrication of scaffolds presenting a gradient able to mimic this transition. Covalent binding of biological factors proved to enhance cell adhesion and differentiation in two-dimensional culture substrates. Here, we used polymer brushes as selective linkers of bone morphogenetic protein-2 (BMP-2) and transforming growth factor-beta3 (TGF-beta3) on the surface of 3D scaffolds fabricated via additive manufacturing (AM) and subsequent controlled radical polymerization. These growth factors (GFs) are known to stimulate the differentiation of human mesenchymal stromal cells (hMSCs) toward the osteogenic and chondrogenic lineages, respectively. BMP-2 and TGF-beta3 were covalently bound both homogeneously within a poly(ethylene glycol) (PEG)-based brush functionalized scaffolds, and following a gradient composition by varying their concentration along the axial section of the 3D constructs. Following an approach previously developed by our group and proved to be successful to generate fibronectin gradients, opposite brush-supported gradients of BMP-2 and TGF-beta3 were finally generated and subsequently tested to differentiate cells in a gradient fashion. The brush-supported GFs significantly influenced hMSCs osteochondral differentiation when the scaffolds were homogenously modified, yet no effect was observed in the gradient scaffolds. Therefore, this technique seems promising to maintain the biological activity of growth factors covalently linked to 3D scaffolds, but needs to be further optimized in case biological gradients are desired. PMID- 28865137 TI - High-Performance CsPb1-x Snx Br3 Perovskite Quantum Dots for Light-Emitting Diodes. AB - All inorganic CsPbBr3 perovskite quantum dots (QDs) are potential emitters for electroluminescent displays. We have developed a facile hot-injection method to partially replace the toxic Pb2+ with highly stable Sn4+ . Meanwhile, the absolute photoluminescence quantum yield of CsPb1-x Snx Br3 increased from 45 % to 83 % with SnIV substitution. The transient absorption (TA) exciton dynamics in undoped CsPbBr3 and CsPb0.67 Sn0.33 Br3 QDs at various excitation fluences were determined by femtosecond transient absorption, time-resolved photoluminescence, and single-dot spectroscopy, providing clear evidence for the suppression of trion generation by Sn doping. These highly luminescent CsPb0.67 Sn0.33 Br3 QDs emit at 517 nm. A device based on these QDs exhibited a luminance of 12 500 cd m 2 , a current efficiency of 11.63 cd A-1 , an external quantum efficiency of 4.13 %, a power efficiency of 6.76 lm w-1 , and a low turn-on voltage of 3.6 V, which are the best values among reported tin-based perovskite quantum-dot LEDs. PMID- 28865138 TI - A Cost-Effective Culture System for the In Vitro Assembly, Maturation, and Stimulation of Advanced Multilayered Multiculture Tubular Tissue Models. AB - The development of tubular engineered tissues is a challenging research area aiming to provide tissue substitutes but also in vitro models to test drugs, medical devices, and even to study physiological and pathological processes. In this work, the design, fabrication, and validation of an original cost-effective tubular multilayered-tissue culture system (TMCS) are reported. By exploiting cellularized collagen gel as scaffold, a simple moulding technique and an endothelialization step on a rotating system, TMCS allowed to easily prepare in 48 h, trilayered arterial wall models with finely organized cellular composition and to mature them for 2 weeks without any need of manipulation. Multilayered constructs incorporating different combinations of vascular cells are compared in terms of cell organization and viscoelastic mechanical properties demonstrating that cells always progressively aligned parallel to the longitudinal direction. Also, fibroblast compacted less the collagen matrix and appeared crucial in term of maturation/deposition of elastic extracellular matrix. Preliminary studies under shear stress stimulation upon connection with a flow bioreactor are successfully conducted without damaging the endothelial monolayer. Altogether, the TMCS herein developed, thanks to its versatility and multiple functionalities, holds great promise for vascular tissue engineering applications, but also for other tubular tissues such as trachea or oesophagus. PMID- 28865139 TI - Expression of Synthetic Phytoene Synthase Gene to Enhance beta-Carotene Production in Scenedesmus sp. CPC2. AB - beta-carotene is a valuable pigment abundant in some microalgal species but the low beta-carotene productivity of microalgae has become the major obstacles against its commercialization. This work aims to improve the productivity of algae-based beta-carotene via genetic engineering approaches. First, a synthetic psy gene construct (891 bp) encoding 297 amino acids is expressed in Scenedesmus sp. CPC2 host to enhance the beta-carotene production. The synthetic psy gene is designed by considering the highest consensus of amino acids (i.e., 62% identity) from Chlamydomonas reinhardtii, Dunaliella salina, and Mariella zofingiensis. The original beta-carotene content in wild-type Scenedesmus sp. CPC2 is 10.8 mg g-1 cell when grown on BG11 medium under 2% CO2 aeration, 150 MUmol m-2 s-1 light intensity and 25 degrees C. After transformation of the psy gene into the microalgal host, the beta-carotene content of the best recombinant strain (i.e., transformant CPC2-4) significantly increased to over 30 mg g-1 -cell. The optimal production of beta-carotene with the CPC2-4 recombinant strain was achieved when the strain is grown on BG11 medium amended with 0.075 g of MgSO4 , giving approximately 3-fold higher beta-carotene content than that of the wild-type strain. The best cellular beta-carotene content obtained (i.e., 31.8 mg g-1 ) is superior to most algae-based beta-carotene production performance reported in the literature. PMID- 28865140 TI - The comparison of nasal surgery and CPAP on daytime sleepiness in patients with OSAS. AB - OBJECTIVE: Residual sleepiness after continuous positive airway pressure (CPAP) is a critical problem in some patients with obstructive sleep apnea syndrome (OSAS). However, nasal surgery is likely to reduce daytime sleepiness and feelings of unrefreshed sleep. The aim of this study is to clarify the effects of nasal surgery and CPAP on daytime sleepiness. METHODOLOGY: This is a retrospective and matched-case control study. The participants were consecutive 40 patients with OSAS who underwent nasal surgery (Surgery group) and 40 matched patients who were treated with CPAP (CPAP group). RESULTS: In the Surgery group, although the nasal surgery did not decrease either apnea or hypopnea, it improved oxygenation, the quality of sleep. In the CPAP Group, the CPAP treatment reduced apnea and hypopnea, and improved oxygenation, quality of sleep. The degree of relief from daytime sleepiness was different between the two groups. The improvement of Epworth Sleepiness Scale was more significant in the Surgery Group than those in the CPAP Group (Surgery from 11.0 to 5.1, CPAP from 10.0 to 6.2). DISCUSSION: These findings suggest that the results of the nasal surgery is more satisfactory for some patients with OSAS than CPAP on daytime sleepiness. PMID- 28865141 TI - Hen's egg allergen in house and bed dust is significantly increased after hen's egg consumption-A pilot study. AB - Environmental exposure to food allergens may be a risk factor for cutaneous sensitization. Previous studies could detect peanut allergen in house dust. In this pilot study, we wanted to investigate whether hen's egg allergen is detectable in house dust collected from different household areas and whether levels are increased after intentional hen's egg consumption. Hen's egg protein levels of dust samples were measured using ELISA. In 8 of 8 households, hen's egg was detectable in dust samples of eating area and bed. Forty-eight hours after intentional hen's egg consumption, hen's egg protein levels were significantly increased in both. Still, further research is necessary to investigate whether hen's egg allergen in house and bed dust plays a role in sensitization via skin. PMID- 28865142 TI - Learning curve for the single-incision suburethral sling procedure for female stress urinary incontinence. AB - OBJECTIVE: To evaluate the learning curve for the single-incision sling (SIS) procedure in a single-surgeon case series. METHODS: Data were retrospectively analyzed from women with non-recurrent symptomatic stress urinary incontinence confirmed by urodynamics and treated at San Gerardo Hospital, Monza, Italy, between October 2008 and November 2015. All women underwent the SIS procedure using a MiniArc sling fitted by the same urogynecologic surgeon. Blood loss, operative time, and complications were recorded. At follow-up visits, objective cure was assessed with a stress test and subjective outcome was determined by International Consultation on Incontinence Questionnaire-Short Form and Patient Global Impression of Improvement scores. Postoperative overactive bladder syndrome and voiding symptoms were recorded. RESULTS: In total, 192 patients underwent the SIS procedure. Estimated blood loss, operative time, and complication rate were not influenced by the number of procedures performed. Among 191 patients who completed 12 months of follow-up, neither objective nor subjective outcomes at longest follow-up available were influenced by surgeon's experience. Conversely, de novo overactive bladder syndrome (P<0.001) and voiding symptoms (P=0.029) decreased with increasing experience. CONCLUSION: SIS showed encouraging objective and subjective outcomes with a minimal complication rate even at the beginning of the learning curve. However, increasing experience reduced postoperative voiding symptoms and overactive bladder syndrome. PMID- 28865143 TI - Identifying Patients With High Data Completeness to Improve Validity of Comparative Effectiveness Research in Electronic Health Records Data. AB - Electronic health record (EHR)-discontinuity, i.e., having medical information recorded outside of the study EHR system, is associated with substantial information bias in EHR-based comparative effectiveness research (CER). We aimed to develop and validate a prediction model identifying patients with high EHR continuity to reduce this bias. Based on 183,739 patients aged >=65 in EHRs from two US provider networks linked with Medicare claims data from 2007-2014, we quantified EHR-continuity by mean proportion of encounters captured (MPEC) by the EHR system. We built a prediction model for MPEC using one EHR system as training and the other as the validation set. Patients with top 20% predicted EHR continuity had 3.5-5.8-fold smaller misclassification of 40 CER-relevant variables, compared to the remaining study population. The comorbidity profiles did not differ substantially by predicted EHR-continuity. These findings suggest that restriction of CER to patients with high predicted EHR-continuity may confer a favorable validity to generalizability trade-off. PMID- 28865144 TI - Intraoperative cervical treatment does not affect the prevalence of vaginal bleeding 1 year postoperatively after subtotal hysterectomy. A register study from the Swedish National Register for Gynecological Surgery. AB - INTRODUCTION: The objectives were to establish the prevalence of persistent vaginal bleeding following subtotal hysterectomy, to analyze the effect of intraoperative cervical treatment on the occurrence of persistent vaginal bleeding, and to evaluate the impact of persistent vaginal bleeding on the patient-reported opinion concerning result of surgery and medical condition. MATERIAL AND METHODS: Retrospective study with data from the Swedish National Register for Gynecological Surgery including 5240 women undergoing subtotal hysterectomy for benign conditions between January 2004 and June 2016. Demographic and clinical data were obtained from the pre- and perioperative forms. Data concerning occurrence of persistent vaginal bleeding, rating of medical condition and contentment with result of surgery were collected from the 1-year inquiry form. Statistical analyses were performed with multivariable logistic regression models. The results are presented as adjusted odd ratios and 95% confidence intervals. RESULTS: Persistent vaginal bleeding occurred in 18.6%. Intraoperative cervical treatment did not affect the frequency of persistent vaginal bleeding (adjusted odds ratio 1.48; 95% confidence interval 0.93-2.37). More than 90% were satisfied with the result of the hysterectomy, but women with persistent vaginal bleeding were less content compared with those without persistent vaginal bleeding (adjusted odds ratio 0.42; 95% confidence interval 0.26-0.67). The self-perception of the medical condition did not differ between the women with and without persistent vaginal bleeding (adjusted odds ratio 1.16; 95% confidence interval 0.33-4.12). CONCLUSIONS: Nearly two in ten women may expect persistent vaginal bleeding following subtotal hysterectomy, and cervical treatment intraoperatively did not affect this. More than 90% were satisfied with the result but women with persistent vaginal bleeding were less content. Preoperative information on this risk of persistent vaginal bleeding may be important when choosing hysterectomy technique. PMID- 28865145 TI - First record of resting cysts of the benthic dinoflagellate Prorocentrum leve in a natural reservoir in Gujan-Mestras, Gironde, France. AB - The resting cysts of the benthic dinoflagellate Prorocentrum leve from a natural reservoir in Gujan-Mestras (Gironde, France) were described in this study. The incubated urn-shaped cysts gave rise to cells of P. leve. Morphological observations through light microscopy and scanning electron microscopy, particularly of the periflagellar platelets, combined with large subunit ribosomal DNA sequences obtained through single-cell analysis confirm their affinity to the species P. leve. The cysts were characterized by a specific shape and the presence of an anterior plug. This is the first conclusive evidence for fossilizable resting stages within the Prorocentrales, one of the major orders within the Dinophyceae. Palynological treatments show that the cysts and endospores withstand hydrochloric and hydrofluoric acids. Micro-Fourier transform infrared analysis on single specimens suggests that the composition of the endospore is cellulosic and the cyst wall a more robust, noncellulosic beta glucan. The spectra overall are similar to other published spectra of resting cysts from autotrophic, planktonic dinoflagellates. PMID- 28865148 TI - Chronic elevation of plasma fibroblast growth factor 19 in long-term farnesoid X receptor agonist therapy, a happy marriage or cause for oncological concern? PMID- 28865146 TI - Cocoa agroforestry is less resilient to sub-optimal and extreme climate than cocoa in full sun. AB - Cocoa agroforestry is perceived as potential adaptation strategy to sub-optimal or adverse environmental conditions such as drought. We tested this strategy over wet, dry and extremely dry periods comparing cocoa in full sun with agroforestry systems: shaded by (i) a leguminous tree species, Albizia ferruginea and (ii) Antiaris toxicaria, the most common shade tree species in the region. We monitored micro-climate, sap flux density, throughfall, and soil water content from November 2014 to March 2016 at the forest-savannah transition zone of Ghana with climate and drought events during the study period serving as proxy for projected future climatic conditions in marginal cocoa cultivation areas of West Africa. Combined transpiration of cocoa and shade trees was significantly higher than cocoa in full sun during wet and dry periods. During wet period, transpiration rate of cocoa plants shaded by A. ferruginea was significantly lower than cocoa under A. toxicaria and full sun. During the extreme drought of 2015/16, all cocoa plants under A. ferruginea died. Cocoa plants under A. toxicaria suffered 77% mortality and massive stress with significantly reduced sap flux density of 115 g cm-2 day-1 , whereas cocoa in full sun maintained higher sap flux density of 170 g cm-2 day-1 . Moreover, cocoa sap flux recovery after the extreme drought was significantly higher in full sun (163 g cm-2 day-1 ) than under A. toxicaria (37 g cm-2 day-1 ). Soil water content in full sun was higher than in shaded systems suggesting that cocoa mortality in the shaded systems was linked to strong competition for soil water. The present results have major implications for cocoa cultivation under climate change. Promoting shade cocoa agroforestry as drought resilient system especially under climate change needs to be carefully reconsidered as shade tree species such as the recommended leguminous A. ferruginea constitute major risk to cocoa functioning under extended severe drought. PMID- 28865147 TI - Differential regulation of PD-1 and its ligands in allergic asthma. AB - BACKGROUND: Targeting PD-1/PD-1 ligand signalling is an established treatment option for cancer. The role of these molecules in allergic asthma has been investigated in several mouse studies yielding conflicting results. However, human studies investigating the expression and regulation of PD-1 and its ligands in allergic inflammation are lacking. OBJECTIVE: To analyse the expression and regulation of PD-1 and its ligands in human allergic asthma. METHODS: The well established human asthma model of segmental allergen challenge (SAC) was used to analyse the regulation of PD-1 and its ligands PD-L1 and PD-L2 on T lymphocytes and dendritic cells by flow cytometry. The impact of immunoglobulin E (IgE) mediated signalling on PD-L1 expression was analysed on isolated plasmacytoid dendritic cells (pDCs). RESULTS: PD-1 expression by blood CD4+ T cells was negatively associated with total and specific (against the allergen used for provocation) IgE serum concentrations. Twenty-four hours after SAC, a small decrease in endobronchial PD-1+ CD4+ T cells was accompanied by an increase in PD L1 expression on endobronchial myeloid dendritic cells (mDCs) and pDCs. The PD-L1 up-regulation on pDCs was not induced by IgE-mediated mechanisms. In contrast, PD L2 was only detected on endobronchial mDCs and was significantly down-regulated 24 hours after SAC. CONCLUSION AND CLINICAL RELEVANCE: This study shows, for the first time, an association of a low PD-1 expression by circulating CD4+ T cells with high total and specific (against the allergen used for provocation) IgE concentrations in allergic asthma. In addition, we demonstrate a differential regulation of PD-1 ligands on endobronchial DCs after allergen challenge which may favour Th2 inflammation. Therefore, modulating PD-1 ligand-mediated pathways might be a promising target in allergic asthma. PMID- 28865149 TI - Bordetella bronchiseptica bloodstream infection in a renal transplant patient. AB - Bordetella bronchiseptica is a gram-negative coccobacillus that infects animals, but rarely affects humans. B. bronchiseptica has been reported to cause disease in immunocompromised hosts. We present a case of a 61-year-old man with a renal transplant who developed B. bronchiseptica bacteremia likely as a result of close contact between dogs and his skin cancer biopsy sites. The patient was successfully treated with 2 weeks of oral levofloxacin. This case alerts physicians to B. bronchiseptica as a cause of bacteremia in solid organ transplant patients with exposure to animals. PMID- 28865150 TI - Comparative proteomic profiling of the choline transporter-like1 (CHER1) mutant provides insights into plasmodesmata composition of fully developed Arabidopsis thaliana leaves. AB - In plants, intercellular communication and exchange are highly dependent on cell wall bridging structures between adhering cells, so-called plasmodesmata (PD). In our previous genetic screen for PD-deficient Arabidopsis mutants, we described choline transporter-like 1 (CHER1) being important for PD genesis and maturation. Leaves of cher1 mutant plants have up to 10 times less PD, which do not develop to complex structures. Here we utilize the T-DNA insertion mutant cher1-4 and report a deep comparative proteomic workflow for the identification of cell-wall embedded PD-associated proteins. Analyzing triplicates of cell-wall-enriched fractions in depth by fractionation and quantitative high-resolution mass spectrometry, we compared > 5000 proteins obtained from fully developed leaves. Comparative data analysis and subsequent filtering generated a list of 61 proteins being significantly more abundant in Col-0. This list was enriched for previously described PD-associated proteins. To validate PD association of so far uncharacterized proteins, subcellular localization analyses were carried out by confocal laser-scanning microscopy. This study confirmed the association of PD for three out of four selected candidates, indicating that the comparative approach indeed allowed identification of so far undescribed PD-associated proteins. Performing comparative cell wall proteomics of Nicotiana benthamiana tissue, we observed an increase in abundance of these three selected candidates during sink to source transition. Taken together, our comparative proteomic approach revealed a valuable data set of potential PD-associated proteins, which can be used as a resource to unravel the molecular composition of complex PD and to investigate their function in cell-to-cell communication. PMID- 28865151 TI - Immune evasion mechanisms of human papillomavirus: An update. AB - Human papillomavirus (HPV) is the most frequently sexually transmitted agent in the world. It can cause cervical and other anogenital malignancies, and oropharyngeal cancer. HPV has the unique ability to persist in the host's epithelium for a long time-longer than most viruses do-which is necessary to complete its replication cycle. To this end, HPV has developed a variety of immune evasion mechanisms, which unfortunately also favor the progression of the disease from infection to chronic dysplasia and eventually to cancer. This article summarizes the current knowledge about HPV immune evasion strategies. A special emphasis lies in HPV-mediated changes of the antigen processing machinery, which is generating epitopes for T cells and contributes to the detectability of infected cells. PMID- 28865152 TI - Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection. AB - : Glecaprevir (nonstructural protein 3/4A protease inhibitor) and pibrentasvir (nonstructural protein 5A inhibitor) (G/P), a coformulated once-daily, all oral, ribavirin (RBV)-free, direct-acting antiviral regimen, was evaluated for safety and efficacy in hepatitis C virus genotype 2 (GT2)-infected Japanese patients, including those with compensated cirrhosis. CERTAIN-2 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in treatment-naive and interferon +/- RBV treatment-experienced Japanese patients without cirrhosis but with GT2 infection. Patients were randomized 2:1 to receive 8 weeks of G/P (arm A) or 12 weeks of sofosbuvir (400 mg once daily) + RBV (600-1000 mg weight-based, twice daily) (arm B). The primary endpoint was noninferiority of G/P compared to sofosbuvir + RBV by assessing sustained virologic response at posttreatment week 12 (SVR12) among patients in the intent to-treat population. SVR12 was also assessed in treatment-naive and interferon +/ RBV treatment-experienced patients with GT2 infection and compensated cirrhosis who received G/P for 12 weeks in the CERTAIN-1 study. A total of 136 patients were enrolled in CERTAIN-2. SVR12 was achieved by 88/90 (97.8%) patients in arm A and 43/46 (93.5%) patients in arm B. No patient in arm A experienced virologic failure, while 2 did in arm B. The primary endpoint was achieved. In CERTAIN-1, 100% (18/18) of GT2-infected patients with compensated cirrhosis achieved SVR12. Treatment-emergent serious adverse events were experienced by 2 patients without cirrhosis in each arm and no patient with cirrhosis. CONCLUSION: The results demonstrate high efficacy and favorable tolerability of G/P in GT2-infected Japanese patients. (Hepatology 2017). PMID- 28865153 TI - Evaluation of the pharmacokinetic drug interaction potential of tivantinib (ARQ 197) using cocktail probes in patients with advanced solid tumours. AB - AIMS: This phase 1, open-label, crossover study sought to evaluate drug-drug interactions between tivantinib and cytochrome P450 (CYP) substrates and tivantinib and P-glycoprotein. METHODS: The effect of tivantinib doses on the pharmacokinetics of the probe drugs for CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), and CYP3A4 (midazolam), and for P-glycoprotein (digoxin) was investigated in 28 patients with advanced cancer using a cocktail probe approach. Patients received single doses of probe drugs alone and, after 5 days of treatment, with tivantinib 360 mg twice daily. RESULTS: The ratios of geometric least squares mean (90% confidence interval) for the area under the concentration-time curve from time zero to the last quantifiable concentration in the presence/absence of tivantinib were 0.97 (0.89-1.05) for caffeine, 0.88 (0.76 1.02) for S-warfarin, 0.89 (0.60-1.31) for omeprazole, 0.83 (0.67-1.02) for midazolam, and 0.69 (0.51-0.94) for digoxin. Similar effects were observed for maximum plasma concentrations; the ratio for digoxin in the presence/absence of tivantinib was 0.75 (0.60-0.95). CONCLUSIONS: The data suggest that tivantinib 360 mg twice daily has either a minimal or no effect on the pharmacokinetics of probe drugs for CYP1A2, CYP2C9, CYP2C19 and CYP3A4 substrates, and decreases the systemic exposure of P-glycoprotein substrates when administered with tivantinib. PMID- 28865154 TI - Multimodular assessment of a calcified extraradicular deposit on the root surfaces of a mandibular molar. AB - AIM: To achieve a better understanding of a calcified extraradicular deposit on the apical root surfaces of a mandibular first molar associated with a radicular cyst and a sinus tract. A multimodular approach was applied using a combination of multiple investigation methods. SUMMARY: This case report presents a mandibular first molar with a calcified extraradicular deposit on the apical root surfaces of both roots. An apical periodontitis lesion was present and a sinus tract served as the only communication with the oral cavity. Diagnosis and treatment planning were based on clinical, radiographic (two- and three dimensional) and ultrasound examination. The tooth was further analysed after extraction using microscopic imaging, nano-computed tomography (nano-CT), hard- and soft tissue histology and electron probe microanalysis. This multimodular approach revealed the calculus-like appearance and mineral composition of the extraradicular deposit. Multiple hypotheses about its aetiology are discussed. KEY LEARNING POINTS: Calcified extraradicular deposits can develop on the apical root surfaces of teeth with apical periodontitis in association with a radicular cyst and sinus tract. A sinus tract can serve as the only communication between the apical lesion and the oral cavity whilst no periodontal defects are present. The interplay of intra-oral radiography, high resolution CBCT, nano-CT, hard tissue histology and EPMA can reveal the calculus-like appearance and composition of the extraradicular deposit. Calcified extraradicular deposits appear hyperechoic on ultrasound imaging and can lead to the occurrence of twinkling artefacts due to their rough mineralized surface. PMID- 28865155 TI - A distinct class of vesicles derived from the trans-Golgi mediates secretion of xylogalacturonan in the root border cell. AB - Root border cells lie on the surface of the root cap and secrete massive amounts of mucilage that contains polysaccharides and proteoglycans. Golgi stacks in the border cells have hypertrophied margins, reflecting elevated biosynthetic activity to produce the polysaccharide components of the mucilage. To investigate the three-dimensional structures and macromolecular compositions of these Golgi stacks, we examined high-pressure frozen/freeze-substituted alfalfa root cap cells with electron microscopy/tomography. Golgi stacks in border cells and peripheral cells, precursor cells of border cells, displayed similar morphological features, such as proliferation of trans cisternae and swelling of the trans cisternae and trans-Golgi network (TGN) compartments. These swollen margins give rise to two types of vesicles larger than other Golgi-associated vesicles. Margins of trans-Golgi cisternae accumulate the LM8 xylogalacturonan (XGA) epitope, and they become darkly stained large vesicles (LVs) after release from the Golgi. Epitopes for xyloglucan (XG), polygalacturonic acid/rhamnogalacturonan-I (PGA/RG-I) are detected in the trans-most cisternae and TGN compartments. LVs produced from TGN compartments (TGN-LVs) stained lighter than LVs and contained the cell wall polysaccharide epitopes seen in the TGN. LVs carrying the XGA epitope fuse with the plasma membrane only in border cells, whereas TGN-LVs containing the XG and PGA/RG-I epitopes fuse with the plasma membrane of both peripheral cells and border cells. Taken together, these results indicate that XGA is secreted by a novel type of secretory vesicles derived from trans-Golgi cisternae. Furthermore, we simulated the collapse in the central domain of the trans-cisternae accompanying polysaccharide synthesis with a mathematical model. PMID- 28865156 TI - Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies. AB - : Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC], and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of published data on gene variants, gene expression, and functional studies and applied network-based analytics in the search for shared molecular circuits. Mining the data platform with largest connected component and interactome analyses, we validated previously reported associations and identified essential and hub genes. In addition to disease specific modules, we found a substantial overlap of disease neighborhoods and uncovered a group of 34 core genes that are enriched for immune processes and abnormal intestine/hepatobiliary mouse phenotypes. Within this core, we identified a gene subcore containing signal transduction and activator of transcription 3, interleukin-6, tumor necrosis factor, and forkhead box P3 prominently placed in a regulatory connectome of genes related to cellular immunity and fibrosis. We also found substantial gene enrichment in the advanced glycation endproduct/receptor for advanced glycation endproducts (RAGE) pathway and showed that RAGE activation induced cholangiocyte proliferation. CONCLUSION: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC, and PSC. (Hepatology 2017). PMID- 28865157 TI - Acute simvastatin treatment restores cerebral functional capillary density and attenuates angiotensin II-induced microcirculatory changes in a model of primary hypertension. AB - OBJECTIVE: We investigated the acute effects of SIM on cerebral microvascular rarefaction and dysfunction in SHRs. METHODS: Male WKY and SHRs were divided into 4 groups of 8 animals each: WKY-CTL and SHR-CTL, treated with 0.9% saline; and WKY+SIM and SHR+SIM, treated with SIM (30 mg/kg/d) for 3 days by gavage. Cerebral FCD was assessed by intravital fluorescence videomicroscopy. mCBF before and after administration within the cranial window of angiotensin II (1 MUmol L-1 ) was investigated using laser speckle contrast imaging. RESULTS: Cerebral FCD was reduced in SHR-CTL compared to WKY-CTL (P < .05). SIM increased cerebral FCD in SHRs compared to SHR-CTL (P < .05). The mCBF was reduced in SHR-CTL compared to WKY-CTL (P < .05), and SIM increased mCBF compared with SHR-CTL (P < .05). Angiotensin II elicited a reduction of mCBF in SHR-CTL and increased mCBF in WKY CTL (SHR-CTL -13.53 +/- 2% vs WKY-CTL +13.74 +/- 4%; P < .001), which was attenuated in SHRs treated with SIM (SHR+SIM -6.7 +/- 1% vs SHR-CTL -13.53 +/- 2%; P < .01). CONCLUSIONS: The antihypertensive effect of SIM is associated with an improvement in cerebral microvascular perfusion and capillary density that may help to prevent hypertension-induced cerebrovascular damage independent of cholesterol-lowering. PMID- 28865158 TI - Assessing SSU rDNA Barcodes in Foraminifera: A Case Study using Bolivina quadrata. AB - The Small Subunit Ribosomal RNA gene (SSU rDNA) is a widely used tool to reconstruct phylogenetic relationships among foraminiferal species. Recently, the highly variable regions of this gene have been proposed as DNA barcodes to identify foraminiferal species. However, the resolution of these barcodes has not been well established, yet. In this study, we evaluate four SSU rDNA hypervariable regions (37/f, 41/f, 43/e, and 45/e) as DNA barcodes to distinguish among species of the genus Bolivina, with particular emphasis on Bolivina quadrata for which ten new sequences (KY468817-KY468826) were obtained during this study. Our analyses show that a single SSU rDNA hypervariable sequence is insufficient to resolve all Bolivina species and that some regions (37/f and 41/f) are more useful than others (43/e and 45/e) to distinguish among closely related species. In addition, polymorphism analyses reveal a high degree of variability. In the context of barcoding studies, these results emphasize the need to assess the range of intraspecific variability of DNA barcodes prior to their application to identify foraminiferal species in environmental samples; our results also highlight the possibility that a longer SSU rDNA region might be required to distinguish among species belonging to the same taxonomic group (i.e. genus). PMID- 28865159 TI - Ligation and interposition of a modified Martius graft for rectovaginal fistula repair after low anterior resection for rectal cancer - a video vignette. PMID- 28865161 TI - Methylene blue submucosal infiltration may facilitate transanal submucosal dissection. PMID- 28865162 TI - Three new cases of bullous pemphigoid during anti-PD-1 antibody therapy. PMID- 28865163 TI - Maternal health outcomes following the implementation of Janani Shishu Suraksha Yojana (JSSY) at a tertiary healthcare center in Rajasthan. AB - OBJECTIVES: To assess the impact of the Janani Shishu Suraksha Yojana (JSSY) initiative on maternal health in terms of the number of prenatal checkup registrations, institutional deliveries, and maternal deaths. The aim of JSSY was to reduce maternal and infant mortality by promoting institutional delivery. METHODOLOGY: The present retrospective descriptive study included data from all institutional deliveries that occurred at the Department of Obstetrics and Gynecology, Mahila Chikitsalaya, SMS Medical College Jaipur, India, both before (between January 1, 2008, and December 31, 2011) and after the implementation of JSSY (between January 1, 2012, and December 31, 2015). Numbers of prenatal outpatient department registrations, institutional deliveries, and maternal deaths per year were compared between the periods using the Mann-Whitney U test. RESULTS: Increases in the mean number of prenatal outpatient department registrations (P=0.021) and institutional deliveries (P=0.021) were recorded following the implementation of JSSY; a non-significant decrease in the maternal mortality ratio was also observed (P=0.248). CONCLUSION: JSSY appeared to be an effective program in improving maternal health; use of prenatal care and institutional deliveries increased following its implementation. PMID- 28865164 TI - Viral-specific T-cell response in hemorrhagic cystitis after haploidentical donor stem cell transplantation. AB - Viral hemorrhagic cystitis (HC) after hematopoietic stem cell transplantation (HSCT) can be devastating. Standard treatment modalities have not been well established, but immune reconstitution may be necessary for sustained viral clearance. We studied five pediatric patients who developed viral HC after haplo identical HSCT. All patients developed virus-specific CD4- and CD8-positive T cells, and the emergence of these viral-specific T cells was temporally associated with successful viral clearance. PMID- 28865165 TI - Spectroanalysis in native gels (SING): rapid spectral analysis of pigmented thylakoid membrane complexes separated by CN-PAGE. AB - Photosynthetic organisms rapidly adjust the capture, transfer and utilization of light energy to optimize the efficiency of photosynthesis and avoid photodamage. These adjustments involve fine-tuning of expression levels and mutual interactions among electron/proton transfer components and their associated light harvesting antenna. Detailed studies of these interactions and their dynamics have been hindered by the low throughput and resolution of currently available research tools, which involve laborious isolation, separation and characterization steps. To address these issues, we developed an approach that measured multiple spectroscopic properties of thylakoid preparations directly in native polyacrylamide gel electrophoresis gels, enabling unprecedented resolution of photosynthetic complexes, both in terms of the spectroscopic and functional details, as well as the ability to distinguish separate complexes and thus test their functional connections. As a demonstration, we explore the thylakoid membrane components of Chlamydomonas reinhardtii acclimated to high and low light, using a combination of room temperature absorption and 77K fluorescence emission to generate a multi-dimensional molecular and spectroscopic map of the photosynthetic apparatus. We show that low-light-acclimated cells accumulate a photosystem I-containing megacomplex that is absent in high-light-acclimated cells and contains distinct LhcII proteins that can be distinguished based on their spectral signatures. PMID- 28865166 TI - Asymmetries in leaf branch are associated with differential speeds along growth axes: A theoretical prediction. AB - BACKGROUND: Morphogenesis, when accompanied by continuous growth, requires stable positional information to create a balanced shape in an organism. Evenly spaced branches are examples of such morphogenesis. Previously, we created a model that showed when a one-dimensional (1D) ring (a boundary of a 2D field) was periodically deformed based on a stable, doubled iterative pattern during expansion; a nested, regularly spaced, symmetrically branched structure was generated. The characteristic divaricating pattern is common in the leaves of many plant species; however, the divarication symmetry was often broken. To evaluate this type of asymmetry, we investigated several species with dissected or compound leaves. RESULTS: Sometimes these leaves showed asymmetries in the number of lobes or segments positioned on either side of the secondary axes. The direction of the asymmetry, i.e., which side of a secondary axis has more axes, appeared to be species-specific. CONCLUSIONS: When different growth speeds along axes of a divaricating leaf were introduced into our previous model, robust and directed asymmetries were reproduced. The differences in growth speed could be predicted from the distributions of leaf segments in actual leaves. Developmental Dynamics 246:981-991, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28865167 TI - Colorectal surveillance after segmental resection for young-onset colorectal cancer: is there evidence for extended resection? AB - AIM: Although sporadic colorectal cancer (CRC) usually occurs in patients aged over 50, recent evidence suggests that the incidence is increasing in younger patients. Such patients are theoretically at high risk of metachronous neoplasia and may be candidates for extended prophylactic colectomy. This study aimed to define the risk of metachronous cancer/adenomas during follow-up of younger patients who underwent segmental colectomy for CRC. METHOD: A CRC database was used to identify patients aged under 50 who underwent surgery for CRC between 1994 and 2010. Patients diagnosed with hereditary cancer or inflammatory bowel disease were excluded. The primary end-points were frequency of extended resection and the rates of metachronous cancer and high-risk adenomas during follow-up. RESULTS: There were 284 young patients with a resectable primary tumour, of whom 280 (98.6%) underwent segmental resection, 3 (1%) extended resection and 1 (0.4%) local resection. Endoscopic follow-up was available for 150 of the patients who had segmental colectomy, with a mean age of 42.6 (+/-5.8) years at diagnosis and median follow-up time of 68 months (interquartile range 45 105). Out of these 150 patients, 4 (2.7%) developed metachronous colonic adenocarcinoma at 24, 71, 151 and 228 months after index surgery. Thirty additional patients had at least one adenoma identified during surveillance, and three had sessile serrated polyps. Out of the three patients undergoing extended resection, none had metachronous cancer or advanced adenomas at an average follow up of 17 years. CONCLUSION: A segmental colectomy or proctectomy is adequate treatment for patients presenting with CRC under the age of 50. PMID- 28865168 TI - On the Redox Reactivity of a Geometrically Constrained Phosphorus(III) Compound. AB - The reactivity of a geometrically constrained phosphorus(III) complex bearing the N,N-bis(3,5-di-tert-butyl-2-phenolate)amide pincer ligand (P(ONO); 1) towards oxidants and reductants is explored. This compound can be readily oxidized to the phosphorus(V) dihalo-derivatives P(ONO)X2 where X=Cl (2), Br (3) and I (4). Attempts at isolating the analogous difluoride through oxidation of 1 were unsuccessful yielding only the hydrofluoride P(ONO)(H)F (5), however P(ONO)F2 (6) can be accessed via a halide exchange reaction of 2 with KF. Compound 2 can be employed as a precursor to novel cationic species through chloride ion displacement using strong Lewis bases. Thus, reaction of 2 with two or three molar equivalents of dimethylaminopyridine (DMAP) affords [P(ONO)(Cl)(DMAP)2 ]+ (7) and [P(ONO)(DMAP)3 ]2+ (8). Reaction of 2 with the weaker bidentate base 2,2' bipyridine (bipy) affords [P(ONO)(Cl)(bipy)]+ (9), although this species was only accessible upon addition of a halide abstracting agent. The dicationic tris(pyridine) adduct [P(ONO)(py)3 ]2+ (10) is also accessible by reaction of 4 with pyridine. Oxidation of 1 using oxygen gas proceeds slowly and allows for the observation of two compounds, a mixed valence dimeric phosphorus(III)/phosphorus(V) compound [P(ONO)(MU2 -O)(MU2 :kappa1 ,kappa2 ONO)P] (11) and the fully oxidized species [P(ONO)(MU2 -O)(MU2 :kappa1 ,kappa2 ONO)P(O)] (12). Finally, reaction of 1 using KC8 results in the dimerization of the putative radical anion [P(ONO)].- through formation of a P-P bond to afford [P(ONO)]22- (13). Reactions with TEMPO result in the formation of the trigonal bipyramidal species P(ONO)(TEMPO)2 (14). PMID- 28865170 TI - A method for characterizing and matching CT image quality across CT scanners from different manufacturers. AB - PURPOSE: The purpose of this study was to quantitatively characterize the fundamental aspects of image quality (IQ) associated with different computed tomography (CT) reconstruction algorithms, the resolution, noise texture, noise magnitude per dose, and use those data to devise a methodology to match IQ between different CT systems. METHODS AND MATERIALS: This study entailed a 3-step methodology involving (a) characterizing the noise magnitude, texture, and resolution for a CT system-reconstruction using the relationship between noise magnitude and Computed Tomography Dose Index (CTDI), noise power spectrum (NPS), and modulation transfer function (MTF), (b) developing clinically relevant strategies of weighting the differences among system-reconstructions as a means to determine the best match (c) identifying for each target system reconstruction, system-reconstructions with matched in terms of that minimum IQ differences. Images of the ACR CT phantom were acquired at two dose levels on each of two CT scanners. Images were reconstructed using all available reconstruction kernels and multiple iterative reconstruction (IR) settings. Each reconstruction was characterized as described above. Percent changes for each IQ metric were calculated for every possible pair of system-reconstructions. Weighting functions, reflecting the human visual system's limit to discriminate between spatial frequencies with differences below 5%, were applied to the differences and the product of the weighted values was used to indicate the best match for each system-reconstruction. RESULTS: Noise texture and resolution are governed by choice of reconstruction kernel and IR strength, while noise magnitude is additionally dependent on dose. Harder kernels have better resolution, finer noise texture, and increase the required dose for a given noise magnitude, and vice versa. Increasing IR strength generally improves resolution, coarsens noise texture, and lowers the required dose. Seventy-one percent of Siemens matches for GE target reconstructions had percent changes in noise texture/resolution under 5%. Seventy-three percent of GE matches for Siemens target reconstructions had percent changes in noise texture/resolution under 5%. ACR phantom images for each matched reconstruction pair appeared similar in both noise magnitude and noise texture. CONCLUSION: Matching image appearance in terms of resolution, noise magnitude, and noise texture provides a quantitative and reproducible strategy to improve consistency in image quality among different CT scanners and reconstructions. PMID- 28865169 TI - A developmental-based motivational intervention to reduce alcohol and marijuana use among non-treatment-seeking young adults: a randomized controlled trial. AB - AIMS: To test the hypothesis that among non-treatment-seeking emerging adults (EA) who both use marijuana and have alcohol binges, a brief, longitudinally delivered, developmentally based motivational intervention would show greater reductions in the use of these two substances compared with a health education control condition. DESIGN: Parallel, two-group, randomized controlled trial with follow-up interventions conducted at 1, 3, 6 and 9 months and final assessments at 12 and 15 months. SETTING: Hospital-based research unit in the United States. PARTICIPANTS: Community-based 18-25-year-olds who reported at least monthly binge drinking and at least weekly marijuana use. INTERVENTION: Motivational intervention (EA-MI) focused primarily on themes of emerging adulthood (identity exploration, instability, self-focus, feeling in-between, a sense of possibilities) and the subjects' relationship to substance use (n = 110) compared with an attention-matched health education control condition (n = 116). MEASUREMENTS: The primary outcomes were days of binge alcohol, marijuana and dual use day as measured using the timeline follow-back method analysing the treatment by time interaction to determine relative differences in the rate of change between intervention arms. FINDINGS: At baseline, the mean rate (days/30) of binge drinking was 5.23 (+/- 4.31) of marijuana use was 19.4 (+/- 10.0) and of dual (same day) use was 4.11 (+/- 4.13). Relative to baseline, there were reductions in the rate of binge alcohol use, marijuana use and days of combined binge alcohol and marijuana use (P < 0.001) at all follow-up assessments. However, the treatment * time interaction was not statistically significant for alcohol (P = 0.37), for marijuana (P = 0.07) or for dual use (P = 0.55). Averaged over all follow-ups, mean reductions in binge, marijuana and dual use days were 1.16, 1.45 and 1.08, respectively, in the health education arm, and 1.06, 1.69 and 0.96 in EA-MI. Bayes factors were < 0.01 for frequency of binge alcohol use and frequency of dual binge alcohol and marijuana and 0.016 for marijuana use. CONCLUSIONS: A brief, longitudinally delivered, developmentally based motivational intervention for young adults did not produce reductions in binge alcohol, marijuana use or dual use days relative to a control condition. PMID- 28865173 TI - The extracts of bredigite bioceramics enhanced the pluripotency of human dental pulp cells. AB - Biomaterials have a profound effect on tissue engineering and regenerative medicine, but few studies have reported the role of extracts from bioceramics in the regulation of stem cell pluripotency. The present study investigated the effects of bioceramics extracts, including silicate bredigite (Ca7 MgSi4 O16 ) and conventional beta-tricalcium phosphate (beta-TCP), on the pluripotency and the multilineage differentiation potential of human dental pulp cells (hDPCs). Basic fibroblast growth factor (bFGF), which is a known regulator of hDPCs pluripotency, was used as a reference. Bredigite extracts significantly promoted cell growth, proliferation, TERT expression and maintained hDPCs in a presenescent state. The extracts of bredigite significantly up-regulated the expression of pluripotency-related genes such as Stro1, Oct4 and Sox2, and further promoted the multilineage differentiation of hDPCs after odontogenic/adipogenic induction. The stimulation of bredigite extracts on hDPCs pluripotency was comparable to that of bFGF, whereas beta-TCP extracts lacked these properties. Our results suggested for the first time that bredigite extracts enhance the pluripotency of dental-derived stem cells, paving the way for extended applications in regenerative medicine. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3465-3474, 2017. PMID- 28865172 TI - Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation. AB - The Retinoblastoma (RB) tumor suppressor regulates G1 /S transition during cell cycle progression by modulating the activity of E2F transcription factors. The RB pathway plays a central role in the suppression of most cancers, and RB mutation was initially discovered by virtue of its role in tumor initiation. However, as cancer genome sequencing has evolved to profile more advanced and treatment resistant cancers, it has become increasingly clear that, in the majority of cancers, somatic RB inactivation occurs during tumor progression. Furthermore, despite the presence of deregulation of cell cycle control due to an INK4A deletion, additional CCND amplification and/or other mutations in the RB pathway, mutation or deletion of the RB gene is often observed during cancer progression. Of note, RB inactivation during cancer progression not only facilitates G1 /S transition but also enhances some characteristics of malignancy, including altered drug sensitivity and a return to the undifferentiated state. Recently, we reported that RB inactivation enhances pro-inflammatory signaling through stimulation of the interleukin-6/STAT3 pathway, which directly promotes various malignant features of cancer cells. In this review, we highlight the consequences of RB inactivation during cancer progression, and discuss the biological and pathological significance of the interaction between RB and pro-inflammatory signaling. PMID- 28865174 TI - Considerations for reporting of stillbirths and fetal deaths. PMID- 28865175 TI - Control of cell growth on 3D-printed cell culture platforms for tissue engineering. AB - Biocompatible tissue growth has excellent prospects for tissue engineering. These tissues are built over scaffolds, which can influence aspects such as cell adhesion, proliferation rate, morphology, and differentiation. However, the ideal 3D biological structure has not been developed yet. Here, we applied the electro hydrodynamic jet (E-jet) 3D printing technology using poly-(lactic-co-glycolic acid, PLGA) solution to print varied culture platforms for engineered tissue structures. The effects of different parameters (electrical voltage, plotting speed, and needle sizes) on the outcome were investigated. We compared the biological compatibility of the 3D printed culture platforms with that of random fibers. Finally, we used the 3D-printed PLGA platforms to culture fibroblasts, the main cellular components of loose connective tissue. The results show that the E-jet printed platforms could guide and improve cell growth. These highly aligned fibers were able to support cellular alignment and proliferation. Cell angle was consistent with the direction of the fibers, and cells cultured on these fibers showed a much faster migration, potentially enhancing wound healing performance. Thus, the potential of this technology for 3D biological printing is large. This process can be used to grow biological scaffolds for the engineering of tissues. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3281-3292, 2017. PMID- 28865176 TI - Feasibility of dynamic risk prediction for hepatocellular carcinoma development in patients with chronic hepatitis B. AB - BACKGROUND & AIMS: Several risk prediction models for hepatocellular carcinoma (HCC) development are available. We explored whether the use of risk prediction models can dynamically predict HCC development at different time points in chronic hepatitis B (CHB) patients. METHODS: Between 2006 and 2014, 1397 CHB patients were recruited. All patients underwent serial transient elastography at intervals of >6 months. RESULTS: The median age of this study population (931 males and 466 females) was 49.0 years. The median CU-HCC, REACH-B, LSM-HCC and mREACH-B score at enrolment were 4.0, 9.0, 10.0 and 8.0 respectively. During the follow-up period (median, 68.0 months), 87 (6.2%) patients developed HCC. All risk prediction models were successful in predicting HCC development at both the first liver stiffness (LS) measurement (hazard ratio [HR] = 1.067-1.467 in the subgroup without antiviral therapy [AVT] and 1.096-1.458 in the subgroup with AVT) and second LS measurement (HR = 1.125-1.448 in the subgroup without AVT and 1.087-1.249 in the subgroup with AVT). In contrast, neither the absolute nor percentage change in the scores from the risk prediction models predicted HCC development (all P > .05). The mREACH-B score performed similarly or significantly better than did the other scores (AUROCs at 5 years, 0.694-0.862 vs 0.537-0.875). CONCLUSIONS: Dynamic prediction of HCC development at different time points was achieved using four risk prediction models, but not using the changes in the absolute and percentage values between two time points. The mREACH B score was the most appropriate prediction model of HCC development among four prediction models. PMID- 28865179 TI - Histopathological challenges in suspected drug-induced liver injury. AB - When a patient with suspected drug-induced liver injury (DILI) undergoes liver biopsy, the pathologist is confronted with two major challenges. The first and most important is to establish the pattern(s) of injury which are present. Patterns of injury represent stereotypical responses of an organ to injury and relate to specific aetiologies of liver damage. The pattern of injury and the histological details of that injury can then be analysed with respect to the patient's intercurrent diseases and medication history. The specific expertise of the pathologist can be used to weigh the prospect of DILI against the likelihood of other explanations of injury. The second challenge is to characterize specific types of injury and the severity of injury, both of which may have importance for clinical decision-making and prognosis. The pathologist's report should convey both an accurate description of the pathology as well its interpretation. PMID- 28865177 TI - Surface topography of silicon nitride affects antimicrobial and osseointegrative properties of tibial implants in a murine model. AB - While silicon nitride (Si3 N4 ) is an antimicrobial and osseointegrative orthopaedic biomaterial, the contribution of surface topography to these properties is unknown. Using a methicillin-resistant strain of Staphylococcus aureus (MRSA), this study evaluated Si3 N4 implants in vitro utilizing scanning electron microscopy (SEM) with colony forming unit (CFU) assays, and later in an established in vivo murine tibia model of implant-associated osteomyelitis. In vitro, the "as-fired" Si3 N4 implants displayed significant reductions in adherent bacteria versus machined Si3 N4 (2.6 * 104 vs. 8.7 * 104 CFU, respectively; p < 0.0002). Moreover, SEM imaging demonstrated that MRSA cannot directly adhere to native as-fired Si3 N4 . Subsequently, a cross-sectional study was completed in which sterile or MRSA contaminated as-fired and machined Si3 N4 implants were inserted into the tibiae of 8-week old female Balb/c mice, and harvested on day 1, 3, 5, 7, 10, or 14 post-operatively for SEM. The findings demonstrated that the antimicrobial activity of the as-fired implants resulted from macrophage clearance of the bacteria during biofilm formation on day 1, followed by osseointegration through the apparent recruitment of mesenchymal stem cells on days 3-5, which differentiated into osteoblasts on days 7-14. In contrast, the antimicrobial behavior of the machined Si3 N4 was due to repulsion of the bacteria, a phenomenon that also limited osteogenesis, as host cells were also unable to adhere to the machined surface. Taken together, these results suggest that the in vivo biological behavior of Si3 N4 orthopaedic implants is driven by critical features of their surface nanotopography. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3413-3421, 2017. PMID- 28865180 TI - Automated and simplified identification of normal and abnormal plasma cells in Multiple Myeloma by flow cytometry. AB - BACKGROUND: Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell (PC) proliferation within the bone marrow (BM). Next-generation flow cytometry has become the reference tool to follow minimal residual disease (MRD). We developed a new simpler and cheaper flow cytometry method to analyze bone marrow samples in patients with MM. METHODS: To identify and characterize abnormal PCs, we designed a simple panel composed of anti-CD38, antikappa, and antilambda light chain antibodies, combined with two antibody pools with the same fluorophore (anti-CD19 and anti-CD27 for the negative pool and anti-CD56, anti CD117, and anti-CD200 antibodies for the positive pool). We also developed dedicated software for the automated identification of malignant PCs and MRD assessment. We then compared PC identification with our simple antibody panel and with the larger antibody panel routinely used at Montpellier University Hospital Center in 52 patients with MM (M-CHU cohort). RESULTS: Results for total PC detection (r2 = 0.9965; P < 0.001; n = 52) and malignant PC detection (r2 = 0.9486; P < 0.001; n = 38) obtained with the two panels were significantly correlated. Moreover, comparison of the results obtained by automated detection with our software and by manual gating analysis in 80 BM samples (38 from the M CHU cohort and 42 patients from another MM cohort) showed strong correlation for both total and malignant PC selection (respectively, r2 = 0.936; P < 0.001 and r2 = 0.9505; P < 0.001). CONCLUSIONS: Our simple and automated strategy for MRD assessment in MM could help increasing reproducibility and productivity without compromising sensitivity and specificity, while decreasing the test cost. (c) 2017 International Clinical Cytometry Society. PMID- 28865178 TI - Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels. AB - To investigate whether IL-6 signaling affects the susceptibility of castration resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL-6 levels) were developed by lentiviral transduction. While observing no secreted IL-6 level in parental C4-2 and CWR22Rv1 cells, we found the IL-6 expression/secretion in these cells was induced after the transduction process and the IL-6 level difference in C4-2siIL 6/sc and CWR22siIL-6/sc cell CRPC cell sets could be detected. We then found that IL-6-knockdown cells were more susceptible to NK cell cytotoxicity than control cells due to lowered programmed death receptor ligand 1 (PD-L1) and increased NK group 2D (NKG2D) ligand levels. In animal studies, to concur with the in vitro results, we found that IL-6-expressing cell-derived tumors were more resistant to NK cell action than the tumors of IL-6-knockdown cells. Further, we discovered that JAK-Stat3 is the most critical IL-6 downstream signaling that modulates PD L1/NKG2D ligand levels in CRPC cells. Furthermore, inhibition of the JAK or Stat3 signaling effectively increased the susceptibility of C4-2sc and CWRsc cells to NK cell cytotoxicity. We observed the most effective cytotoxicity when the PD-L1 Ab and JAK inhibitor (or Stat 3 inhibitor) were used together. These results suggest that the strategy of targeting IL-6 signaling (or its downstream signaling) may enhance the NK cell-mediated immune action to CRPC tumors, thus yielding clinical implications in developing future immunotherapeutics of exploiting this strategy to treat patients with CRPC. PMID- 28865181 TI - Synthesis and Biological Evaluation of Novel 1-(4-(Hydroxy(1-oxo-1,3-dihydro-2H inden-2-ylidene)methyl)phenyl)-3-phenylurea Derivatives. AB - A series of novel phenylurea containing 2-benzoylindan-1-one derivatives 3a - 3j were synthesized from the reaction of phenylurea-substituted acetophenones 1a - 1j with phthalaldehyde 2 under mild reaction conditions in good yields. All synthesized compounds were characterized by spectroscopic methods. The obtained compounds (3a - 3j) were evaluated for anticancer activity against HeLa and C6 cell lines. Antiproliferative activity was determined by the BrdU proliferation ELISA assay, 3f and 3g were found to be most active compounds. The compounds were also screened for antimicrobial activity and all compounds showed remarkable activity against used microorganisms. PMID- 28865182 TI - Quercetin and alendronate multi-functionalized materials as tools to hinder oxidative stress damage. AB - In spite of its remarkable anti-oxidant, anti-inflammatory, anti-cancer properties and its possible inhibition activity towards bone resorption, quercetin therapeutic use is limited by its poor bioavailability. Herein we developed a new multifunctionalized system for the local administration of quercetin and alendronate, one of the most potent anti-osteoporotic drugs, with the aim to get a material with enhanced properties. To this purpose we loaded quercetin on hydroxyapatite functionalized with alendronate, as well as on hydroxyapatite. Characterization was performed by means of X-ray diffraction, FT IR and Raman spectroscopies, thermogravimetric and spectrophotometric analyses. Loading of quercetin from hydro-alcoholic solution increased with time and reached a constant value of about 5 weight% on both substrates, without causing significant structural and morphological modifications. Quercetin functionalized materials exhibit relevant anti-oxidant properties, in agreement with their high radical scavenging activity, and a quercetin sustained release in phosphate buffer. In vitro osteoblast and osteoclast co-culture in a microenvironment altered by oxidative stress shows that both alendronate and quercetin significantly reduce osteoclast viability, whereas they are able to counteract the negative effect of oxidative stress on osteoblast viability and differentiation, suggesting that their relative amount in the functionalized materials can be utilized to tailor bone cells response. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3293-3303, 2017. PMID- 28865183 TI - Comparison of Chemical Profile and Antioxidant Capacity of Seeds and Oils from Salvia sclarea and Salvia officinalis. AB - Composition of tocopherols, tocotrienols, carotenoids, fatty acids, as well as hydrophilic and lipophilic antioxidant activities, were determined in seeds of two Salvia species and oils obtained from them. Both seeds contained a large amount of oil (around 20%) rich in polyunsaturated fatty acids. While Salvia officinalis seed oil can be classified as oleic-linoleic oil, the predominant fatty acid in Salvia sclarea was alpha-linolenic acid (around 54%). Among tocols, the main isomers in both seeds and oils were gamma-tocopherol, followed by alpha tocopherol. Concerning carotenoids, their concentration was around 0.75 mg/100 g of seeds and 0.16 mg/100 g of oils, with a predominance of lutein. Oil and seeds of S. officinalis exhibited higher antioxidant potential compared to S. sclarea investigated samples which could be attributed to higher content of total vitamin E and carotenoids. This study provides results that enables use of two Salvia species as new alternative sources of vegetable oils. PMID- 28865184 TI - DNA barcoding of invasive plants in China: A resource for identifying invasive plants. AB - Invasive plants have aroused attention globally for causing ecological damage and having a negative impact on the economy and human health. However, it can be extremely challenging to rapidly and accurately identify invasive plants based on morphology because they are an assemblage of many different families and many plant materials lack sufficient diagnostic characteristics during border inspections. It is therefore urgent to evaluate candidate loci and build a reliable genetic library to prevent invasive plants from entering China. In this study, five common single markers (ITS, ITS2, matK, rbcL and trnH-psbA) were evaluated using 634 species (including 469 invasive plant species in China, 10 new records to China, 16 potentially invasive plant species around the world but not introduced into China yet and 139 plant species native to China) based on three different methods. Our results indicated that ITS2 displayed largest intra- and interspecific divergence (1.72% and 91.46%). Based on NJ tree method, ITS2, ITS, matK, rbcL and trnH-psbA provided 76.84%, 76.5%, 63.21%, 52.86% and 50.68% discrimination rates, respectively. The combination of ITS + matK performed best and provided 91.03% discriminatory power, followed by ITS2 + matK (85.78%). For identifying unknown individuals, ITS + matK had 100% correct identification rate based on our database, followed by ITS/ITS2 (both 93.33%) and ITS2 + matK (91.67%). Thus, we propose ITS/ITS2 + matK as the most suitable barcode for invasive plants in China. This study also demonstrated that DNA barcoding is an efficient tool for identifying invasive species. PMID- 28865185 TI - Developmental Morphology and Topography of the Components of the Cervical Sympathetic Trunk in Sheep (Ovis aries) During the Fetal Period. AB - The objective of this study was to clarify the typical architecture and morphological variations of cervical sympathetic trunk (CST) in sheep during fetal period. Components of CST were examined on both sides of 40 male and female sheep fetuses aged from 60 to 140 days under a stereomicroscope. Skeletotopy and frequency of presence of cranial cervical ganglion (CCG), syntopy of cervical ganglia, and composition and topography of vagosympathetic trunk were consistent among specimens whereas the shape of cervical ganglia, the skeletotopy and number of three middle cervical ganglia (MG), and the frequency of communicating branches of CCG to the first cervical spinal nerve exhibited differences during fetal period. A reduction in the number of MG and the caudal movement of main MG were noted by increasing fetal age. Based on these detailed findings, comparative and developmental anatomy and evolutionary changes are discussed and compared with previous studies. The number of MG, skeletotopy of CCG and main MG, the number and range of communicating branches of CCG to spinal nerves, and the association of vagus and sympathetic nerves in fetal sheep were fundamentally different from those of mostly reported species. These results suggest that data obtained from CST of fetal sheep are significantly different from those obtained from humans, and it is problematic to apply them to humans because of the more cranial position of CCG, very narrow contribution of CCG to spinal nerve, absence of the vertebral ganglion, existence of multiple MG, and no communicating branches from MG to spinal nerves. Anat Rec, 300:2250-2262, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28865186 TI - Hyaluronic acid-hydroxyapatite nanocomposite hydrogels for enhanced biophysical and biological performance in a dermal matrix. AB - A hyaluronic acid (HAc)-hydroxyapatite (HAp) nanocomposite (HAc-nanoHAp) hydrogel was fabricated through an in situ precipitation process for mechanical and biological enhancement as a soft tissue augmentation product. In this study, these composite hydrogel fillers were analyzed from three different perspectives and compared with pure HAc hydrogel for soft tissue augmentation application: (1) rheological behaviors, (2) in vivo lateral diffusion under mouse skin, and (3) wrinkle improvement in a photo-aged mouse model. HAc-nanoHAp provided great improvement to wrinkles because of its higher stiffness and gel cohesiveness in comparison with that of pure HAc. HAc-nanoHAp also presented great enhancement in strengthening the dermal matrix by stimulating the synthesis of collagen and elastin. Thus, HAc-nanoHAp filler has great potential as a soft tissue augmentation product, improving the biophysical and biological performance in skin tissue. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3315-3325, 2017. PMID- 28865187 TI - Sustained release of multicomponent platelet-rich plasma proteins from hydrolytically degradable PEG hydrogels. AB - Platelet-rich plasma (PRP), an autologous blood derived product is a concentrated mix of multiple growth factors and cytokines. Direct injections of PRP are clinically used for treatment of various musculoskeletal disorders and in wound healing. However, PRP therapy has met with limited clinical success possibly due to unpredictable and premature bolus delivery of PRP growth factors. The objective of this study was to predictably control the bioavailability of PRP growth factors using a hydrolytically degradable polyethylene glycol (PEG) hydrogel. We used a step-growth polymerization based on a Michael-type addition reaction between a 6-arm PEG-acrylate and a dithiol crosslinker, which led to the formation of a homogenous hydrogel network under mild, physiologically relevant conditions. Specifically, to model the release of multicomponent PRP through PEG hydrogels, we examined bulk diffusion of PRP as well as model proteins in a size range corresponding to that of growth factors found in PRP. Our results indicated that protein size and hydrogel degradation controlled diffusion of all proteins and that secondary structure of proteins encapsulated during gelation remained unaffected post-release. Analysis of specific PRP proteins released from the hydrogel showed sustained release until complete hydrogel degradation. PRP released from hydrogels promoted proliferation of human dermal fibroblast, indicating retained bioactivity upon encapsulation and release. The versatile hydrogel system holds clinical potential as a therapeutic drug delivery depot of multicomponent mixtures like PRP. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3304-3314, 2017. PMID- 28865194 TI - Poster session 3. Imaging and image processing III. PMID- 28865200 TI - Poster session 35: Radiation therapy VI. PMID- 28865202 TI - Poster session 15: Radiation therapy II. PMID- 28865188 TI - PhenoGraph and viSNE facilitate the identification of abnormal T-cell populations in routine clinical flow cytometric data. AB - BACKGROUND: Flow cytometric identification of neoplastic T-cell populations is complicated by the wide range of phenotypic abnormalities in T-cell neoplasia, and the diverse repertoire of reactive T-cell phenotypes. We evaluated whether a recently described clustering algorithm, PhenoGraph, and dimensionality-reduction algorithm, viSNE, might facilitate the identification of abnormal T-cell populations in routine clinical flow cytometric data. METHODS: We applied PhenoGraph and viSNE to peripheral blood mononuclear cells labeled with a single 8-color T/NK-cell antibody combination. Individual peripheral blood samples containing either a T-cell neoplasm or reactive lymphocytosis were analyzed together with a cohort of 10 normal samples, which established the location and identity of normal mononuclear-cell subsets in viSNE displays. RESULTS: PhenoGraph-derived subpopulations from the normal samples formed regions of phenotypic similarity in the viSNE display describing normal mononuclear-cell subsets, which correlated with those obtained by manual gating (r2 = 0.99, P < 0.0001). In 24 of 24 cases of T-cell neoplasia with an aberrant phenotype, compared with 4 of 17 cases of reactive lymphocytosis (P = 1.4 * 10-7 , Fisher Exact test), PhenoGraph-derived subpopulations originating exclusively from the abnormal sample formed one or more distinct phenotypic regions in the viSNE display, which represented the neoplastic T cells, and reactive T-cell subpopulations not present in the normal cohort, respectively. The numbers of neoplastic T cells identified using PhenoGraph/viSNE correlated with those obtained by manual gating (r2 = 0.99; P < 0.0001). CONCLUSIONS: PhenoGraph and viSNE may facilitate the identification of abnormal T-cell populations in routine clinical flow cytometric data. (c) 2017 Clinical Cytometry Society. PMID- 28865204 TI - Diagnosis of Caprine Arthritis Encephalitis Virus infection in dairy goats by ELISA, PCR and Viral Culture. AB - For preventive and control strategies of Caprine Arthritis Encephalitis Virus (CAEV) infection in dairy goats, performance of the available diagnostic tests was described as one of the most important and necessary aspects. The study aimed at evaluating the diagnostic test performance, including PCR, ELISA and viral culture, for CAEV infection in dairy goats in Thailand. Blood samples of 29 dairy goats from five low- to medium-prevalence herds and one very low-prevalence herd were collected for PCR and ELISA methods. The performance of these two diagnostic methods was evaluated by comparing with cytopathic effects (CPE) in the co cultivation of CAEV and primary synovial cells. Results indicated that sensitivity, specificity were, respectively, 69.6%, 100%, for PCR; and 95.7%, 83.3% for ELISA. The PCR assay tended to have lower sensitivity and higher specificity than ELISA. When multiple tests were applied, parallel testing provided sensitivity and specificity of 98.7% and 83.3%, while series testing showed sensitivity and specificity of 66.6% and 100% respectively. These results indicated that combination of ELISA and PCR provided some advantages and possibly offered optimal methods to detect CAEV-infected goats. Kappa value of the agreement between PCR and ELISA test was 0.34, indicating fair agreement. Regarding the possibility of antigenic variation between CAEV strains used in both PCR and ELISA assays, the actual circulating CAEV strain should be reviewed in order to develop and enhance the diagnostic tests using the CAE viral antigens derived from specific local strains of Thailand. PMID- 28865203 TI - Pharmacological and phytochemical screening of Palestinian traditional medicinal plants Erodium laciniatum and Lactuca orientalis. AB - BACKGROUND: Various epidemiological studies showed that herbal remedies containing polyphenols may protect against various diseases such as cancers, vascular diseases and inflammatory pathologies. Currently, such groups of bioactive compounds have become a subject of many antimicrobials and antioxidant investigations. Accordingly, the current study aimed to conduct biological and phytochemical screening for two Palestinian traditional medicinal plants, Erodium laciniatum and Lactuca orientalis. METHODS: Current plants phytoconstituents and their antioxidant activities were evaluated by using standard phytochemical methods; meanwhile, antimicrobial activities were estimated by using several types of American Type Culture Collection and multidrug resistant clinical isolates by using agar diffusion well-variant, agar diffusion disc-variant and broth microdilution methods. RESULTS: Phytochemical screenings showed that L. orientalis and E. laciniatum contain mixtures of secondary and primary metabolites Moreover, total flavonoid, tannins and phenols content in E. laciniatum extract were higher than the L. orientalis extracts with almost the same antioxidant potentials. Additionally, both plants organic and aqueous extracts showed various potentials of antimicrobial activity Conclusions: Overall, the studied species have a mixture of phytochemicals, flavonoids, phenols and tannins also have antioxidant and antimicrobial activities which approved their folk uses in treatments of infectious and Alzheimer diseases and simultaneously can be used as therapeutic agents in the pharmaceutical industries. PMID- 28865205 TI - Investigation of the bone metabolism in dogs with leishmaniasis. AB - The present study was aimed at determining bone metabolism related changes in dogs with visseral leishmaniasis such as vitamin D, calcium, phosphate and ALP levels as compared to healthy ones. A total of 40 serums of male dogs aged between 4 and 6 years that were sent to Adnan Menderes University, Faculty of Medicine, Parasitology Laboratory from Kusadasy and Bodrum districts between the years 2012 and 2013, suspected with leishmaniasis, by the veterinary physicians in accordance with the cold chain rules and 20 of which were evaluated as leishmania seropositive and 20 as leishmania seronegative by the IFA test, were included in this study. There was no any statistically significant difference between the serum 25-OH-D3 levels of Leishmania positive and negative dogs (p>0.05). There was a statistically significant difference between the serum ALP (p<0.05), and P levels were observed to be higher in the seropositive dogs than in the seronegative dogs, while Ca level was low (p<0.001). PMID- 28865206 TI - The animal-dependent risk factors in canine osteosarcomas. AB - Canine osteosarcoma (OSA) is a malignant neoplastic tumor, which develops from the primitive mesenchymal stem cell, that has or can acquire the capacity to produce neoplastic osteoid with possible neoplastic bone formation. Predisposition of some dog breeds to OSA indicates genetic background of oncogenesis. The aim of the study was to characterize animal-dependent risk factors for canine osteosarcoma development in Poland. The study was conducted on canine patients diagnosed cytologically or histopathologically as having OSA, and data on age, breed, sex, as well as tumor location and character were recorded. No sex predisposition to OSA was observed, mongrels were significantly underrepresented. Large and giant dogs accounted for 47% and 35% of all pedigree dogs, respectively, and both proved predisposed to OSA. A vast majority of OSA developed in the skeleton (appendicular skeleton was more commonly affected than axial skeleton), soft tissues were affected less often. Rottweiler dogs are strongly predisposed to OSA, suggesting that the genetic background is involved in the tumor development, and indicates that dogs of this breed are a promising object for further studies on OSA pathogenesis. PMID- 28865207 TI - Immunohistochemical characterization of the jugular (superior vagal) ganglion in the pig. AB - The study was carried out on three 4-month old female pigs. All the animals were deeply anesthetized and transcardially perfused with 4% buffered paraformaldehyde (pH 7.4). Left and right superior vagal ganglia (SVG) were collected and processed for immunofluorescence labeling method. The preparations were examined under a Zeiss LSM 710 confocal microscope equipped with adequate filter block. Neurons forming SVG were round or oval in shape with a round nucleus in the center. The majority of them (52%) were medium (M) (31-50 MUm in diameter) while 7% and 41% were small (S) (up to 30MUm in diameter) or large (L) (above 50 MUm in diameter) in size, respectively. Double-labeling immunofluorescence revealed that SVG neurons stained for CGRP (approx. 57%; among them 37%, 9% and 54% were M, S and L in size, respectively), SP (14.5%; 72.4% M, 3.4% S, 24.2% L), VACHT (26%; 63% M, 24% S and 13% L), GAL (14%; 57% M, 29% S, 14% L), NPY (12%; 53% M, 12% S, 35% L), Met-Enk (5%; 40% M, 6% S and 54% L), PACAP (15%; 52% M, 24% S and 24% L), VIP (6.3%; 67% M, 8% S and 25% L), and NOS-positive (6%; 31% M and 69% L). The most abundant populations of intraganglionic nerve fibers were those which stained for CGRP or GAL, whereas only single SP-, PACAP- or Met-ENK-positive nerve terminals were observed. PMID- 28865208 TI - Identification of Transmissible Viral Proventriculitis (TVP) in broiler chickens in Poland. AB - The aim of the study was to investigate the possibility of Transmissible Viral Proventriculitis (TVP) occurrence in broiler chickens in Poland. In march 2016 proventriculi samples were collected from broiler chickens showing poor uniformity and decreased body weight, accompanied by enlarged proventriculi. Histopathological examination of affected proventriculi revealed typical lesions associated with TVP (vacuolar degeneration and necrosis of glandular epithelium, replacement of glandular epithelium by hyperplastic ductal epithelium and moderate to severe lymphocytic infiltration). To our best knowledge, up to date there is no report indicating the presence of TVP in Poland nor in Central and Eastern Europe. PMID- 28865209 TI - Impact of production technology on morphological lesions in the gills of commercial rainbow trout (Oncorhynchus mykiss, Walbaum 1792). AB - The most popular rainbow trout (Oncorhynchus mykiss, Walbaum 1792) production technologies include both an extensive method with the flow through system (FTS) and an intensive method with the recirculating aquaculture system (RAS). Their impact on the fish was evaluated with a morphological assessment of the gills, as these are organs susceptible to environmental changes. Trout of 350 - 500 g body mass were caught for trial in spring and autumn, with 36 fish originating from 3 fish farms with the FTS system and an equal number from 3 RAS fish farms (n = 6). The fish were macroscopically examined and the gills were investigated microscopically (haematoxylin and eosin staining). Hypertrophy and hyperplasia were most commonly detected, amounting to 89% of all structural abnormalities. These lesions were slightly more common in the FTS, especially in autumn, whereas the changes to the blood vessels in the gills were observed more frequently in the rainbow trout from the RAS system than in the fish obtained from the FTS technology (the difference was statistically significant). The morphological lesions in the mucous cells of the gills were detected at a comparable severity regardless of the technology or production season. The predominantly low values of the histopathologic indices, which described the microscopic lesions in the gills of fish from the FTS and RAS systems, showed that the examined organ was most often free of lesions or demonstrated only minor morphological damage regardless of the production technology. PMID- 28865210 TI - Clinical efficacy of nutraceutical diet for cats with clinical signs of cutaneus adverse food reaction (CAFR). AB - Food allergies and food intolerances are clinically difficult to discriminate. Most often, along with cutaneous adverse food reactions or CAFR, they are classified as adverse food reactions, whose causes are numerous, including toxic compounds. Eighteen indoor-housed domestic cats with evident clinical symptoms related to CAFR (drooling, back and neck intense itching, neck eczema, chronic conjunctivitis and stomatitis) involving skin lesions were studied. Cytological evaluations of ear, skin and gingival swabs revealed an increased turnover of keratinocytes while the oxytetracycline ELISA determination showed an unexpected high amount of oxytetracycline in all cats at the first visit. All cats were then randomly assigned to receive a standard (SD group) or a nutraceutical diet (ND group) for 60 days. In the ND group a significant reduction of the mean serum concentration of oxytetracycline, pruritus intensity and skin lesion severity (**p<0.01, ***p<0.001, and ***p<0.001, respectively) was observed after 60 days, and associated with a significant improvement in the clinical picture. Although a direct correlation between oxytetracycline presence within cat sera and CAFR related symptoms has never been described, this study highlights the benefit of a specific nutraceutical diet supplementation in improving clinical symptoms and skin lesions in cats with CARF. PMID- 28865211 TI - Evaluation of in-feed larch sawdust anti-inflammatory effect in sows. AB - The study aimed to investigate the possible anti-inflammatory activity of larch sawdust as feed supplement in lactating sows' diet and its possible effect on the prevalence of Postpartum Dysgalactia Syndrome under field conditions. In a Greek farrow-to-finish pig farm, fifteen sows were randomly and equally allocated to a negative control group (NC group), a positive control group (PC group), and a treatment group (LT group). The animals of the first two groups received 99% basic diet and 1% corn starch, while LT group animals received 99% basic diet and 1% larch sawdust. The whole trial period lasted 35 days (7 days prior to farrow - day of weaning). At parturition day, animals of the PC group received 2 ml of an anti-inflammatory drug intramuscularly (meloxicam, Metacam(r), Boehringer Ingelheim Vetmedica), while the animals of both other groups, received 2 ml of normal saline. Results showed insignificant differences among experimental groups for parameters such as post-partum rectal temperature and piglets performance. On the contrary, a significant increase of mean milk lactation index was observed in LT and PC groups on the 4th day of lactation period, when compared with NC group (p=0.014). Additionally, mean IL-6 concentrations in blood in the LT group showed a tendency for reduction when compared with those found in NC, and insignificant difference (p>0.05) when compared with those observed in PC group 24 hours postpartum. Moreover, the respective TNFalpha mean level in the LT group at 24 and 72 hours after parturition was similar to that found in PC group, respectively) and significantly lower than that determined in the NC group (p=0.003, p=0.024. The results suggest a possible anti-inflammatory effect of larch sawdust in sows. PMID- 28865212 TI - Indirect enzyme-linked immunosorbent assay method based on Streptococcus agalactiae rSip-Pgk-FbsA fusion protein for detection of bovine mastitis. AB - OBJECTIVE: The aim of this study was to establish a rapid and accurate method for the detection of the Streptococcus agalactiae antibody (SA-Ab) to determine the presence of the bovine mastitis (BM)-causative pathogen. METHODS: The multi subunit fusion protein rSip-Pgk-FbsA was prokaryotically expressed and purified. The triple activities of the membrane surface-associated proteins Sip, phosphoglycerate kinase (Pgk), and fibronectin (FbsA) were used as the diagnostic antigens to establish an indirect enzyme-linked immunosorbent assay (ELISA) method for the detection of SA-Ab in BM. RESULTS: The optimal antigen coating concentration was 2 MUg/mL, the optimal serum dilution was 1:160, and the optimal dilution of the enzyme-labeled secondary antibody was 1:6000. The sensitivity, specificity, and repeatability tests showed that the method established in this study had no cross-reaction with antibodies to Streptococcus pyogenes, Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis in the sera. The results of the sensitivity test showed that a positive result could be obtained even if the serum dilution reached 1:12,800, indicating the high sensitivity and good repeatability of the method. The positive coincidence rate of this method was 98.6%, which is higher than that of previous tests established with the Sip or Pgk mono-antigen fusion protein, respectively, demonstrating the relatively higher sensitivity of this newly established method. The detection rate for 389 clinical samples was 46.53%. CONCLUSIONS: The indirect ELISA method established in this study could provide a more accurate and reliable serological method for the rapid detection of S. agalactiae in cases of BM. PMID- 28865213 TI - Injection in temporomandibular joint of rats. Description of technical protocol. AB - The development of animal models for research has been very diffused. Osteoarthritis is a joint degenerative pathology that induces cartilage erosion, chondrocyte proliferation and osteophyte formation. The aim of this paper is to present a technical procedure to perform the injection of monosodium iodine acetate in the temporomandibular joints of rats to generate osteoarthritis and to contribute to future research analysis related to pathology progression and proper treatment performance. The use of rat models may be a complex process because of their size, but they can be compared to the human temporomandibular joint due to the similar characteristics and the possibility of performing diagnosis and treatment protocols in order to detect this pathology. PMID- 28865214 TI - Serum amyloid A protein (SAA), haptoglobin (Hp) and selected hematological and biochemical parameters in wild mares before and after parturition. AB - The aim of the study was to evaluate physiological changes in hematological and biochemical parameters in mares in perinatal period. Blood samples were collected from 24 pregnant Polish Konik breed mares which were divided into two groups. The first group (Group - I, n=12) comprised mares living in the wild, in the reserve. The second group (Group - II, n=12) consisted of mares kept in stables. The blood was collected 2 weeks prior to the parturition, then 24 hours after the delivery, and then at the 7th and 21st day after foaling. When comparing the two groups before the parturition, no significant differences in terms of WBC, RBC, and Hb were found, however, there was a significant difference in MCV, MCH, LYM, NEU and SEG NEU (p<=0.05). In Group II, 24 hours after the parturition and at the 21st day after foaling, a significant raise in WBC, NEU and SEG NEU (p<=0.05) was detected. No significant differences in serum concentrations of proteins such as TP, Alb or Glb were observed. As to acute phase proteins, significant rise in SAA and Hp (p<=0.05) was found in the two examined groups 24 hours after the parturition. Yet, this rise remained within physiological range. The study revealed a certain degree of fluctuations in hematological parameters, in serum concentrations of acute-phase proteins and total proteins in the mares in the perinatal period. However, these changes remained still within physiological ranges and thus they do not indicate potential susceptibility to disorders of perinatal period. PMID- 28865215 TI - Survivin expression in correlation with apoptotic activity in canine lymphomas. AB - Survivin regulates cell cycle and mitosis and has antiapoptotic properties. Because of its dual function survivin has been the subject of much research focusing on its role in tumorigenesis and the relationship between survivin expression and apoptotic and/or proliferative activity in many types of human tumor including non-Hodgkin's Lymphomas. Such studies have not been conducted in canine lymphomas. The aim of this study was to evaluate the expression of survivin in canine lymphomas of low (5/25) and high (20/25) grades in relation to apoptotic markers (apoptotic index and index of caspase-3). Survivin was found in all examined lymphomas. Most tumors (18/25) showed survivin expression in 10%-25% of positive cells. Only in single cases was lower (0-10% positive cells, 1/25) or higher (25%-50% and >50% positive cells, 5/25 and 1/25, respectively) survivin expression. No significant differences between mean values of either index of survivin or apoptotic index was found between low and high grade lymphomas. However, such a difference among lymphoma grades was shown regarding the caspase 3 index. No correlation between the survivin index and either the apoptotic index or caspase-3 index was found, irrespective of the method of quantification: in whole specimens or in areas of low and high survivin expression. Positive correlation was consistently noted only between both apoptotic markers. The results indicate that survivin is commonly expressed in canine lymphomas. It seems that survivin does not exhibit anti-apoptotic activity in canine lymphomas. Lack of correlation between survivin expression and apoptotic markers could indicate its potential role in cell cycle activation in lymphoma cells. PMID- 28865216 TI - Coagulology, biochemical profile and muscle pathology in calves diagnosed with nutritional muscular dystrophy. AB - The aim of this study was to explain the correlations between selenium deficiency, hemostatic and biochemical disorders, and the progression of pathological changes in calves diagnosed with nutritional muscular dystrophy (NMD). The study was performed on 20 calves with supplementation of 8 ml selenium and vitamin E preparation and 20 calves with symptoms of NMD. Blood was sampled from calves aged 5, 12 and 19 days. On day 19, samples of the biceps femoris muscle were collected from 6 animals in each group for histopathological analysis. The following blood parameters were determined: PLT, PT, TT, APTT, fibrinogen and D-dimer concentrations, antithrombin III activity, glucose, selenium and vitamin E concentrations, activity of CK, LDH and GSH-Px. Muscle sections were stained with H&E and HBFP. Platelet counts were significantly lower in calves with symptoms of NMD. No significant differences in coagulation parameters were observed between the groups. Sick calves were diagnosed with hyperglycemia and elevation of CK and LDH activity. Selenium and vitamin E concentrations in the blood serum were significantly lower in the experimental group together with significant drop in GSH-Px activity. Changes characteristic of Zenker's necrosis were observed in a muscle of the sick animals. To our best knowledge this is the first study in which the attempt was made to explain the relationship between selenium deficiency and changes in the coagulation system in ruminants. PMID- 28865217 TI - Effects of the platelet-activating factor (PAF) supplementation on ATP content of cryopreserved bull spermatozoa (AI). AB - The aim of this study was to investigate the effect of PAF supplementation in semen extender on ATP content in cryopreserved bull spermatozoa used for artificial insemination at different time intervals. Cryopreserved semen was treated with different concentrations of PAF: 1*10-5M, 1*10-6M, 1*10-7M, 1*10-8M and 1*10-9M at 37 degrees C. In the present work we showed that content of ATP in cryopreserved semen supplemented with 1*10-9M PAF was statistically significantly higher at 90 and 120 minutes of incubation in comparison to the control group (p<=0.05). Present study indicates the potential influence of PAF on ATP content in male spermatozoa via it's protective role towards mitochondria metabolic activity. PMID- 28865218 TI - Determination of tigecycline in turkey plasma by LC-MS/MS: validation and application in a pharmacokinetic study. AB - Tigecycline (TIG), a novel glycylcycline antibiotic, plays an important role in the management of complicated skin and intra-abdominal infections. The available data lack any description of a method for determination of TIG in avian plasma. In our study, a selective, accurate and reversed-phase high performance liquid chromatography-tandem mass spectrometry method was developed for the determination of TIG in turkey plasma. Sample preparation was based on protein precipitation and liquid-liquid extraction using 1,2-dichloroethane. Chromatographic separation of TIG and minocycline (internal standard, IS) was achieved on an Atlantis T3 column (150 mm * 3.0 mm, 3.0 MUm) using gradient elution. The selected reaction monitoring transitions were performed at 293.60 m/z -> 257.10 m/z for TIG and 458.00 m/z -> 441.20 m/z for IS. The developed method was validated in terms of specificity, selectivity, linearity, lowest limit of quantification, limit of detection, precision, accuracy, matrix effect, carry-over effect, extraction recovery and stability. All parameters of the method submitted to validation met the acceptance criteria. The assay was linear over the concentration range of 0.01-100 MUg/ml. This validated method was successfully applied to a TIG pharmacokinetic study in turkey after intravenous and oral administration at a dose of 10 mg/kg at various time-points. PMID- 28865219 TI - Expression and immunological evaluation of elongation factor Tu of Streptococcus suis serotype 2. AB - Streptococcus suis serotype 2 (SS2) is considered as a major pathogen that causes sepsis and meningitis in piglets and humans, but knowledge of its antigenic proteins remains limited so far. The surface-related proteins of pathogens often play significant roles in bacterium-host interactions and infection. Here, we obtained the elongation factor Tu (EF-Tu) gene of Streptococcus suis and constructed the recombinant expression plasmid successfully. The target recombinant plasmid was then expressed in Escherichia coli and the immuno protection of the recombinant protein was subsequently evaluated as well. The EF Tu gene of Streptococcus suis is 1197 bp in length, encodes 398 amino acids. The target recombinant EF-Tu (rEF-Tu) protein can recognize the antiserum of Streptococcus suis and can provoke obvious humoral immune responses in rabbits and conferred protection to rabbits against Streptococcus suis ear-vein challenge, implying that the EF-Tu may be used as an attractive candidate antigen for a component of subunit vaccine. PMID- 28865221 TI - Effect of deoxynivalenol on the levels of toll-like receptors 2 and 9 and their mRNA expression in enterocytes in the porcine large intestine: a preliminary study. AB - Deoxynivalenol (DON), one of the most prevalent mycotoxins in the world, and is capable of inducing immune disorders in humans and animals. The aim of this study was to determine the effect of feed contaminated with DON on the number of TLR2- and TLR9-positive cells and their mRNA expression in the porcine large intestine. The experiment was conducted on two equal groups of pigs (n=4). The experimental group (E) was administered feed contaminated with DON (1008 MUg/kg of feed) for 6 weeks, and the control group (C) was administered non-contaminated feed over the same period of time. A decrease in the expression of TLR2 mRNA was noted in the cecum. The percentage of TLR9-positive enterocytes increased in the ascending colon and decreased in the cecum. The results of this study indicate that DON can modify the local immune response by changing the expression of TLRs. PMID- 28865220 TI - Frequency of iss and irp2 genes by PCR method in Escherichia coli isolated from poultry with colibacillosis in comparison with healthy chicken in poultry farms of Zabol, South East of Iran. AB - There is no special trait for differentiation of Avian Pathogenic Escherichia coli from Avian Fecal Escherichia coli. This investigation is aimed, as a case control study, to evaluate and compare the frequency of iss and irp2 in 43 AFEC strains and also 40 and 56 E. coli strains isolated from the liver and kidney of chickens with colibacillosis, respectively, farmed in Zabol, as a border region of Iran, by PCR. 86.9% and 37.2% of isolates collected from chickens with colibacillosis and feces samples obtained from healthy chickens were positive for iss gene, respectively (P<0.05). On average, 59.3% of E. coli strains isolated from colibacillosis have irp2 gene while 27.9% of isolates from the feces of healthy birds were positive (P<0.05). 52.15% of isolates from colibacillosis and 19.62% of isolates from healthy chicken feces were positive for both genes, with statistical significant difference (p<0.05). This marked difference in the distribution of iss and irp2 genes makes these two genes good markers to differentiate AFEC and APEC strains especially in Sistan region to improve colibacillosis control measurements. PMID- 28865222 TI - Evaluation of intra-testicular injections of calcium chloride and 4 vinylcyclohexene 1,2 monoepoxide for chemical sterilization in guinea pigs. AB - This study was aimed at investigating the use of intra-testicular calcium chloride (CaCl2) and 4-vinylcyclohexene 1,2-monoepoxide (VCM) injections as a side effect-free alternative method for the control of reproduction in guinea pigs. Fifty male guinea pigs were randomly assigned to five groups. In all groups, the chemical agents were injected into both testes in 1% lidocaine hydrochloride. While Groups I, II and III were administered with a single dose (0.25 mL) of sterile physiological saline, 15 mg/100 g CaCl2, and 240 mg/kg VCM, respectively, Group IV and V received a daily dose of 15 mg/100 g CaCl2, and 240 mg/kg VCM for 3 days, respectively. On day 90 post-administration, all animals were weighed and later decapitated under ether anaesthesia. Blood and tissue (testis, liver, hypophysis and adrenal gland) samples were taken. Sperm samples from the cauda epididymis were examined for spermatological parameters. Blood was used for hormone analyses and tissue samples were examined histopathologically (haematoxylin-eosin) and immunohistochemically (Tunel staining). The epididymal sperm count decreased in all treatment groups. Excluding 2 animals, Group V displayed azoospermia. When compared to the control group, Group V displayed the highest prolactin and lowest testosterone levels, and Group III showed the highest testosterone level. Histopathological examination revealed no intoxication finding. Chemical castration with VCM may be a good alternative to surgical castration as it enables mass sterilization without postoperative risks in guinea pig. PMID- 28865223 TI - Improvement of dairy cow embryo yield with low level laser irradiation. AB - The goal of this study is to estimate the effects of low-level laser irradiation (LLLI) on the superovulatory response according to the number of corpora lutea (CL), follicles (F) and the embryo yield. In recent years, while searching for new, more efficient and organic methods to improve superovulatory response and embryo yield with respect to the conventional methods, low-level laser irradiation (LLLI) is a more sensitive and less costly technology that can be used to improve animal reproduction, namely, artificial insemination and the embryo production system. The dairy-cow donors were treated for superovulation with Pluset(r), at any time during the oestrus cycle, and the total dose per donor was 700 IU. The first group of the donors (n=25), test group (TG), was irradiated on the sacroiliac area for 180 seconds per day, from the 1st to 11th superovulatory treatment (ST) days in a row, with LLLI in the 870-970-nm wavelength, 65.93 J/cm dose, frequencies in the 20-2000 Hz range and pulse durations commonly in the range of about 1 second. For the second control group (CG) (n=25), the ST was performed without LLLI. After the ST, The mean number of CL in the right side ovaries in the TG was 25.43% (p<0.05) greater than in those of the CG. The number of total recovered and transferable embryos was greater in the TG compared with the CG by 28.97% (p<0.05) and 15.8% (p>0.05), respectively. With respect to conventional methods, LLLI can be used to improve the superovulatory response and embryo yield as a supplementary environment and animal-friendly method of treatment. PMID- 28865224 TI - Direct effect of hypothalamic neuropeptides on the release of catecholamines by adrenal medulla in sheep - study ex vivo. AB - Stress causes the activation of both the hypothalamic-pituitary-adrenocortical axis and sympatho-adrenal system, thus leading to the release from the adrenal medulla of catecholamines: adrenaline and, to a lesser degree, noradrenaline. It has been established that in addition to catecholamines, the adrenomedullary cells produce a variety of neuropeptides, including corticoliberine (CRH), vasopressin (AVP), oxytocin (OXY) and proopiomelanocortine (POMC) - a precursor of the adrenocorticotropic hormone (ACTH). The aim of this study was to investigate adrenal medulla activity in vitro depending, on a dose of CRH, AVP and OXY on adrenaline and noradrenaline release. Pieces of sheep adrenal medulla tissue (about 50 mg) were put on 24-well plates and were incubated in 1 mL of Eagle medium without hormone (control) or supplemented only once with CRH, AVP and OXY in three doses (10-7, 10-8 and 10-9 M) in a volume of 10 MUL. The results showed that CRH stimulates adrenaline and noradrenaline release from the adrenal medulla tissue. The stimulating influence of AVP on adrenaline release was visible after the application of the two lower doses of this neuropeptide; however, AVP reduced noradrenaline release from the adrenal medulla tissue. A strong, inhibitory OXY effect on catecholamine release was observed, regardless of the dose of this hormone. Our results indicate the important role of OXY in the inhibition of adrenal gland activity and thus a better adaptation to stress on the adrenal gland level. PMID- 28865225 TI - Horizontal transfer and functional evaluation of high pathogenicity islands in Avian Escherichia coli. AB - High pathogenicity islands (HPIs) in Escherichia coli encode genes that are primarily involved in iron uptake and regulation, and confer virulence and pathogenicity. The aim of this study was to investigate the transfer of HPIs in avian E. coli and identify the function of HPI in the acceptor strain. The HPI transfer strain was obtained under conditions of low temperature and low iron abundance, and the donor and acceptor strains were confirmed. E. coli HPIs are transferred by horizontal gene transfer events, which are likely mediated primarily by homologous recombination in HPI-adjacent sequences. Assays for biological activity and pathogenicity changes in the acceptor strain indicated that HPIs might not be involved in pathogenesis in avian E. coli, and thus the main function of HPIs in this strain of bacteria may be to regulate iron nutrition. PMID- 28865226 TI - Evaluation of clinicopathological features in cats with chronic gastrointestinal signs. AB - Food-responsive enteropathy (FRE), idiopathic inflammatory bowel disease (IBD), and alimentary tract lymphoma (AL) are often the remaining differentials for cats presenting with chronic gastrointestinal (GI) signs. Differential diagnosis is further complicated by overlapping clinicopathological features and histopathological changes, however. In this study we describe the clinical presentation of cats with chronic GI signs secondary to FRE, IBD, and AL, and evaluate possible associations between clinical, clinicopathological, ultrasonographic findings and diagnosis. The medical records of client-owned cats with chronic GI signs secondary to FRE, IBD, and AL were reviewed. Univariate and multivariate logistic regression models and receiver-operating characteristic curve (ROC) analysis were used for testing the data. Of the 56 cats included in the study, 22 were diagnosed with FRE (mean age, 70 months +/- 49), 17 with IBD (mean age, 101 months +/- 40), and 17 with AL (mean age, 122 months +/- 45). Cats with FRE were younger and presented more often with diarrhea and less frequently with muscle wasting than cats with IBD or AL. In cats with AL, serum cobalamin levels were lower than in those with FRE or IBD (239 +/- 190 ng/L vs. 762 +/- 408 ng/L and 625 +/- 443 ng/L, respectively) and folate levels were higher than in cats with IBD (18.2 +/- 4.2 MUg/L vs. 9.1 +/- 4.7 MUg/L, respectively). Multivariate/ROC curve analysis showed increased values of BUN (sensitivity 100, specificity 29.4, criterion >37 mg/dl) and serum folate (sensitivity 80, specificity 100, criterion >15.6 MUg/L) and reduced values of cobalamin (sensitivity 100, specificity 62.5, criterion <=540 ng/L), which suggested a diagnosis of AL versus IBD. Some clinicopathological features evaluated at diagnosis might suggest AL; however, because differentiating AL from IBD is often difficult, definitive diagnosis should be based on invasive diagnostic workup. PMID- 28865227 TI - Pathological findings in low-field magnetic resonance imaging of the canine spine - a study of 112 patients. AB - Magnetic resonance imaging (MRI) is a method of choice in diagnosing nervous system disorders. This paper presents the results of a study where selected segments of the canine spine were examined by low-field MRI in 112 patients. Images of pathological changes were obtained in spin echo (SE), fast spin echo (FSE) and hybrid contrast enhancement (3D HYCE) sequences. The cervical region of the spinal cord (C1-C5) was examined in 32 patients, the cervicothoracic region (C6-Th2)- in 14 patients, the thoracolumbar region (Th3-L3) - in 23 patients, and the lumbosacral region (L4-S3) - in 43 patients. The results were used to determine the incidence of pathological changes in different sections of the canine spine, such as intervertebral disc disease (IDD), disc desiccation, syringomyelia and changes characterized by higher uptake of the contrast medium. Intervertebral disc disease was diagnosed in 52.7% of patients and it was the most common abnormality. Disc dehydratation without protrusion or extrusion was noted in 23.2% of animals. Pathological changes with increased uptake of the contrast medium and indicative of neoplastic growth were observed in 13.4% of patients and syringomyelia was diagnosed in 9.82% of the examined animals. The proposed sequences revealed the presence of above abnormalities. PMID- 28865228 TI - The diagnostic importance of coagulation parameters in cattle having natural theileriosis. AB - The purpose of this study was to determine the diagnostic importance of coagulation parameters in cattle with natural theileriosis. Nine Holstein cross breed cattle with theileriosis as infected group and 6 healthy Holstein cattle as control group were used in the present study. Mean fibrinogen level, thrombin time (TT), activated partial thromboplastin time (aPTT) and prothrombin time (PT) were not statistically different when control and infected groups compared, except for the D-dimer concentration. Quantitative D-dimer concentrations were determined by immune-turbidimetric assay. D-dimer values increased significantly (p<0.05) in infected group (631.55 +/- 74.41 MUg/L) compared to control group (370.00 +/- 59.94 MUg/L). D-dimer sensitivity and specificity were also determined at cut-off concentrations (372 MUg/L). Sensitivity and specificity of D-dimer values were determined to be 88.89% and 83.33%, respectively. D-dimer is thought to be important indicator in the evaluation of the prognosis in theileriosis cases. Analysis of D-dimer values before and after treatment in controlled case studies were suggested in future studies to enlighten the issue. PMID- 28865229 TI - Cytokine profiles of dendritic cells (DCs) during infection with bovine leukaemia virus (BLV). AB - BLV is an agent of enzootic bovine leukaemia (EBL), an infectious disease affecting cattle worldwide. BLV infection has been associated with immune system disorders and discrepancies in the cytokine network. The significance of dendritic cells in the pathogenesis of BLV infection is largely unknown, but considering their fundamental role in immune response it may be crucial. DCs precursors were isolated with the use of immunomagnetic beads from BLV-infected and BLV-free cows. From these precursors cultures of monocyte derived dendritic cells (MoDCs) were generated with the use of a cytokine cocktail (IL-4 and GM CSF). Additionally, parallel DCs from BLV-negative animals were infected in vitro. The level of cytokines: IL-6, IL-10, IL-12(p40), IL-12(p70) was determined in DC cultures: infected in vitro, originating from naturally infected cattle and BLV-free cattle. The investigation showed significant changes in almost all analyzed populations of BLV-infected DCs. Cytokine profiles of blood MoDCs indicated activation of these groups during infection. In the case of spleen MoDCs and lymph node MoDCs a decrease in production of IL-12(p40) and IL-12(p70) in favour of IL-6 and IL-10 was noted, suggesting promotion of BLV infection development. PMID- 28865230 TI - Withdrawal of cefoperazone with milk after intramammary administration in dairy cows - prospective and retrospective analysis. AB - The aim of the study was to carry out retrospective and prospective comparative analyses of the pharmacokinetics of CEF after single intramammary (IMM) administration in cows. The prospective study (study A) was conducted on 9 dairy cows of the Polish Black-White race with clinical mastitis during the lactation period. Milk samples were collected at 2, 4, 6, 8, 10, 24, 36, 48, 72 and 84 h after single IMM administration of 250 mg of CEF to one quarter. Drug concentrations in milk samples were determined by HPLC-MS/MS technique and the results of the pharmacokinetic analysis were compared to those obtained in previous studies based on the microbiological (study B) and HPLC-UV methods (study C and D). Pharmacokinetic parameters were calculated based on adapted two compartment model of drug distribution. One of the findings of the comparison of the analysed investigations is that the CEF kinetics determined with the microbiological method is consistent with the results obtained by the authors of this paper. Both studies yielded similar results of the key pharmacokinetic parameters related to the level of the drug distribution to tissues and elimination half-life. In the pharmacodynamic analysis, the observations in all four studies were entirely consistent and have shown lower values of T>MIC90 in healthy animals and significantly higher values in infected dairy cows. The comparison of studies A, B, C, and D revealed that the time of complete CEF wash out of 90.90% varied and amounted to 5.7, 8.0, 2.2, and 2.2 days after administration of the drug, respectively. It was confirmed that not only the type of the analytical method but also correct sampling have a significant impact on determination of the correct value of the drug half-life after IMM administration. The comparative analysis of studies in which the milk yield was high and low allows a conclusion that this parameter in the case of CEF has no significant effect on T>MIC90. PMID- 28865231 TI - Effect of feeding with bilberry fruit on the expression pattern of alphaCaMKII in hippocampal neurons in normal and diabetic rats. AB - alphaCaMKII, widely occurring in the central nervous system, plays a significant role in cognitive processes. It is well known that diabetes is a risk factor that may trigger brain atrophy, cognitive dysfunction and finally lead to memory loss. Antioxidants richly present in bilberry fruits are believed to have significant effects on diabetes-related brain dysfunctions mainly due to their abilities to modulate neurotransmitter release that lead to reduction of the negative impact of free radicals on cognitive processes. The aim of the present research was to immunohistochemically investigate the expression patterns of alphaCaMKII in hippocampal neurons from non-diabetic, diabetic and diabetic rats fed with an extract of bilberry fruit. The obtained results show that in comparison to the control group, in diabetic rats hippocampal neurons immunoreactive (ir) to alphaCaMKII were swollen and the lengths of the neuronal fibres were reduced. Further study shows that in diabetic rats fed with bilberry fruit, alphaCaMKII positive nerve fibres were significantly longer when compared to the groups of diabetic and control rats. Additionally, we observed statistically significant changes in the average larger diameter of alphaCaMKII-ir hippocampal neurons between groups of diabetic rats (with vs. without supplement of bilberry fruit). The results of the present work suggest that antioxidants present in bilberry fruits influence the morphology of and possibly exhibit beneficial and neuroprotective effects on hippocampal neurons during diabetes. It is likely that changes in the appearance of alphaCaMKII-expressed hippocampal neurons may reflect the diabetes-evoked rise in Ca2+ level in the cerebral nerve terminals. The present research extends our knowledge of preventive mechanisms for cognitive dysfunctions occurring in the brain during diabetes. PMID- 28865232 TI - Hyponatremia, bone mineral density and falls in the elderly; Results from AHAP study. AB - BACKGROUND: Hyponatremia (HN) can be associated with osteoporosis, falls and bone fractures in the elderly. Recent researches demonstrated different results about the correlation of HN with bone mineral density and bone fractures. METHODS: This analytic research came from the AHAP project in northern IRAN. All people aged 60 years and over were included in the study. Individuals with severe comorbidities and then who had concurrent conditions which could have impact on bone mineral densities (BMD) such as long-term use of steroids, calcium and/or vitamin D supplements, bisphosphonates, calcitonin, thiazides and hormonal medications were excluded. RESULTS: One thousand and one hundred and thirteen older persons entered in the study. More than 10 percent of the participants had HN (serum Na+ level <= 137mEq/L). No significant difference has been observed between hyponatremic and nonhyponatremic individuals about their balance abilities; bone mineral density; incidence of falls and/or bone fracture during the previous 6 months; dependency in activities of daily living; and osteoporosis. CONCLUSION: HN was not a prevalent problem in older adults who met the inclusion criteria of this research. No significant difference has been observed between HN and bone mineral density and falls in the elderly. PMID- 28865233 TI - First allergenic pollen monitoring in Bucharest and results of three years collaboration with European aerobiology specialists. AB - INTRODUCTION: Respiratory allergies induced by allergenic plants pollen represent an important public health problem with increasing prevalence and severity. Aerobiologic study of allergenic pollens is performed in many countries on regular basis and correlated with health data from allergists in the frame of national aerobiology networks. Romania has no aerobiology network and pollen measurements have been done between 1999-2012 in West region only. In the frame of COST Action called Sustainable management of Ambrosia artemisiifolia in Europe (SMARTER FA 1203), three years collaboration with Reseau National de Surveillance Aerobiologique (RNSA) from France and the first pollen monitoring center in Bucharest were established.The aim of this paper is to present results of first pollen monitoring in Bucharest, activities of Romanian SMARTER group and collaboration with European aerobiology specialists. MATERIAL AND METHOD: We used a Hirst-type pollen trap placed on the roof of the Research Center from "Colentina" Clinical Hospital and the pollen monitoring method based on European Aeroallergen Network (EAN) standardized requirements. Monthly results during the pollen seasons 2014-2016 were sent to RNSA and EAN and posted on the European pollen information site. RESULTS: We found high amounts of allergenic pollen, mainly grasses from May to September and Ambrosia artemisiifolia during September. Conlcusions. We concluded that SMARTER offered access to aerobiology training, improved multidisciplinary collaboration and perspectives to further develop national and international projects. More coordinated efforts to develop national aerobiology network and to recuperate the gap comparing to other European countries in the field of aerobiology and respiratory allergology are needed. PMID- 28865234 TI - Impact of Seminal Plasma Trace Elements on Human Sperm Motility Parameters. AB - INTRODUCTION: Human seminal plasma contains a variety of macro and trace elements including magnesium (Mg), copper (Cu), zinc (Zn), and iron (Fe) that have essential roles in normal functioning of semen and its quality. The imbalance of these elements has been reported in several pathologic and male infertility disorders. Therefore, this study aimed to determine the levels of these elements in seminal plasma samples, their relationships with each other and their impact on sperm motility. METHODS: Overall, 192 males (96 normospermic and 96 asthenospermic males) were enrolled in the study. Semen samples were collected by masturbation and computer-assisted/aided semen analysis of sperm motility was performed. The samples were centrifuged and seminal levels of Mg, Cu, Zn and Fe were measured using atomic absorption spectroscopy. RESULTS: The levels of Zn did not differ between the two groups, while the levels of Mg, Cu, and Fe were significantly higher in normospermic males. Fe showed a positive correlation with Mg and Cu in asthenospermic group. However, a negative relationship was found between Mg and Fe levels and between Mg and sperm concentration in the normospermic group. Fe levels were higher in the normospermic group compared to the asthenospermic group. Nevertheless, increased Fe levels caused a decrease in most of sperm motility fractions. CONCLUSION: Elements play major roles in male fertility and directly affect sperm quality. According to the results of this study, the levels of Zn do not affect the sperm quality and motility, while Fe, Cu and Mg are decreased in males with sperm motility problems. Nevertheless, Fe levels can adversely affect sperm motility in normospermic men. PMID- 28865235 TI - Effect of Electro-Acupuncture on Neuroplasticity of Spinal Cord-Transected Rats. AB - BACKGROUND This study aimed to evaluate the effects of electro-acupuncture (EA) on neuroplasticity associated with the expressions of neurotrophic factors (NTFs) and their receptors in rats subjected to spinal cord transection (SCT). MATERIAL AND METHODS A total of 144 rats were randomly divided into 3 groups (n=48 per group): sham-operated group, SCT group, and EA (electro-acupuncture) group. Rats in SCT and EA groups received spinal cord transection at T10-T11 vertebral levels. Then, EA group rats received EA treatment. Reverse transcription polymerase chain reaction was used to detect NTFs and receptors at the mRNA level. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to detect the expression of NTFs and their receptors. Basso, Beattie, Bresnahan (BBB) scores and cortical somato-sensory evoked potentials (CSEP) were evaluated to assess the recovery of motor and sensory functions. We also measured BDA (Biotinylated dextran amine) axonal tracing, CGRP (Calcitonin gene-related peptide), GAP-43 (Growth-associated protein), and synaptophysin immunohistochemistry (IHC). RESULTS EA treatment led to obvious improvement in hindlimb locomotor and sensory functions. CNTF, FGF-2, and TrkB mRNA were significantly upregulated, while NGF, PDGF, TGF-b1, IGF-1, TrkA, and TrkC mRNA were concomitantly downregulated in the caudal spinal segment (CSS) following EA. Immunohistochemistry demonstrated an increased number of CGRP fibers, GAP-43, and synaptophysin profiles in the CSS in the EA rats. CONCLUSIONS EA may promote the recovery of neuroplasticity in rats subjected to SCT. This could be attributed to the systematic regulation of NTFs and their receptors after EA. PMID- 28865236 TI - Horse hair follicles: A novel dermal stem cell source for equine regenerative medicine. AB - The easily accessible niche represented by skin and its appendages may serve as a promising source to complement modern regenerative medicine for horses. In humans and in animal models for human medicine, the hair follicle and its stem cell niches are well characterized. Since literature in this field of equine research is scarce, we sought to analyze cells of the dermal stem cell niche of the equine hair follicle morphologically and for a subset of markers useful for cell characterization via immunolabeling. We cultured equine forelock skin explants to obtain cultures with cells migrating from the hair follicles. Isolation of cells revealed typical fibroblast morphology with a strong tendency to aggregate and form spheroids. For immunofluorescent characterization of primary isolations, we tested an antibody panel consisting of lineage makers for the dermal compartment of the hair follicle, markers associated with an undifferentiated cell status and markers for epithelial cell types as negative controls. All antibodies used were also tested on equine skin sections. The isolated cells displayed clear profiles of dermal and undifferentiated cells. To substantiate our findings, we tested our primary isolations for established equine multipotent mesenchymal stromal cell antigen expression markers in flow cytometry experiments yielding strong convergence. The data presented here provide insights to a stem cell source in horses almost unnoticed to date. The basic investigations of the equine dermal hair follicle stem cell niche confirm the expression of standard markers used in other species and lay the foundation for future studies on this easily available adult stem cell source. (c) 2017 International Society for Advancement of Cytometry. PMID- 28865237 TI - Dose-dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor. AB - AIMS: LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile. METHODS: Healthy subjects were randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated. RESULTS: The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing. CONCLUSIONS: This study emphasized the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207. PMID- 28865238 TI - Association between insulin-induced weight change and CVD mortality: Evidence from a historic cohort study of 18,814 patients in UK primary care. AB - BACKGROUND: This study explores the association of insulin-induced weight (wt) gain on cardiovascular outcomes and mortality among patients with type 2 diabetes (T2D) following insulin initiation using real-world data. METHODS: A historical cohort study was performed in 18,814 adults with insulin-treated T2D derived from the UK The Health Improvement Network database. Based on the average weight change of 5 kg, 1 year postinsulin initiation, patients were grouped into 5 categories (>5 kg wt loss; 1.0-5.0 kg wt loss; no wt change; 1.0-5.0 kg wt gain; >5.0 kg wt gain) and followed-up for 5 years. Cox proportional hazard models and Kaplan-Meier estimators were fitted to estimate the hazards of a 3-point composite of nonfatal myocardial infarction, stroke, and all-cause mortality between categories. RESULTS: The median age was 62.8 (IQR: 52.3-71.8) years, HbA1c : 8.6% (IQR: 7.4-9.8) and mean BMI: 31.8 (6.5) kg/m2 . The 5 year probability of survival differed significantly within the wt-change categories (log-rank test P value = .0005). Only 1963 composite events occurred. Compared with the weight-neutral group, the risk of composite events was 31% greater in the >5 kg wt-loss group (aHR: 1.31; 95% CI: 1.02, 1.68), the same in the 1.0 to 5.0 kg wt-gain category, but nonsignificantly increased in the 1.0 to 5.0 kg wt loss (15%) and >5.0 kg wt gain (13%) categories, respectively. In the obese subgroup, this risk was 50% (aHR: 1.50, 95% CI: 1.08-2.08) more in the >5 kg weight-loss group compared with the weight-neutral group. CONCLUSION: Insulin induced weight gain did not translate to adverse cardiovascular outcomes and mortality in patients with T2D. These data provide reassurance on the cardiovascular safety of insulin patients with T2D. PMID- 28865240 TI - Electropermeabilization by uni- or bipolar nanosecond electric pulses: The impact of extracellular conductivity. AB - Cellular effects caused by nanosecond electric pulses (nsEP) can be reduced by an electric field reversal, a phenomenon known as bipolar cancellation. The reason for this cancellation effect remains unknown. We hypothesized that assisted membrane discharge is the mechanism for bipolar cancellation. CHO-K1 cells bathed in high (16.1mS/cm; HCS) or low (1.8mS/cm; LCS) conductivity solutions were exposed to either one unipolar (300-ns) or two opposite polarity (300+300-ns; bipolar) nsEP (4-40kV/cm) with increasing interpulse intervals (0.1-50MUs). Time lapse YO-PRO-1 (YP) uptake revealed enhanced membrane permeabilization in LCS compared to HCS at all tested voltages. The time-dependence of bipolar cancellation was similar in both solutions, using either identical (22kV/cm) or isoeffective nsEP treatments (12 and 32kV/cm for LCS and HCS, respectively). However, cancellation was significantly stronger in LCS when the bipolar nsEP had no, or very short (<1MUs), interpulse intervals. Finally, bipolar cancellation was still present with interpulse intervals as long as 50MUs, beyond the time expected for membrane discharge. Our findings do not support assisted membrane discharge as the mechanism for bipolar cancellation. Instead they exemplify the sustained action of nsEP that can be reversed long after the initial stimulus. PMID- 28865241 TI - Processing speed and the relationship between Trail Making Test-B performance, cortical thinning and white matter microstructure in older adults. AB - Part B of the Trail Making Test (TMT-B) is widely used as a quick and easy to administer measure of executive dysfunction. The current study investigated the relationships between TMT-B performance, brain volumes, cortical thickness and white matter water diffusion characteristics in a large sample of older participants, before and after controlling for processing speed. Four hundred and eleven healthy, community-dwelling older adults who were all born in 1936 were assessed on TMT-B, 5 tests of processing speed, and provided contemporaneous structural and diffusion MRI data. Significant relationships were found between slower TMT-B completion times and thinner cortex in the frontal, temporal and inferior parietal regions as well as the Sylvian fissure/insula. Slower TMT-B completion time was also significantly associated with poorer white matter microstructure of the left anterior thalamic radiation, and the right uncinate fasciculus. The majority of these associations were markedly attenuated when additionally controlling for processing speed. These data suggest that individual differences in processing speed contribute to the associations between TMT-B completion time and the grey and white matter structure of older adults. PMID- 28865242 TI - Novel graphene-based biosensor for early detection of Zika virus infection. AB - We have developed a cost-effective and portable graphene-enabled biosensor to detect Zika virus with a highly specific immobilized monoclonal antibody. Field Effect Biosensing (FEB) with monoclonal antibodies covalently linked to graphene enables real-time, quantitative detection of native Zika viral (ZIKV) antigens. The percent change in capacitance in response to doses of antigen (ZIKV NS1) coincides with levels of clinical significance with detection of antigen in buffer at concentrations as low as 450pM. Potential diagnostic applications were demonstrated by measuring Zika antigen in a simulated human serum. Selectivity was validated using Japanese Encephalitis NS1, a homologous and potentially cross reactive viral antigen. Further, the graphene platform can simultaneously provide the advanced quantitative data of nonclinical biophysical kinetics tools, making it adaptable to both clinical research and possible diagnostic applications. The speed, sensitivity, and selectivity of this first-of-its-kind graphene-enabled Zika biosensor make it an ideal candidate for development as a medical diagnostic test. PMID- 28865239 TI - Principles of pharmacology in the eye. AB - The eye is a highly specialized organ that is subject to a huge range of pathology. Both local and systemic disease may affect different anatomical regions of the eye. The least invasive routes for ocular drug administration are topical (e.g. eye drops) and systemic (e.g. tablets) formulations. Barriers that subserve as protection against pathogen entry also restrict drug permeation. Topically administered drugs often display limited bioavailability due to many physical and biochemical barriers including the pre-corneal tear film, the structure and biophysiological properties of the cornea, the limited volume that can be accommodated by the cul-de-sac, the lacrimal drainage system and reflex tearing. The tissue layers of the cornea and conjunctiva are further key factors that act to restrict drug delivery. Using carriers that enhance viscosity or bind to the ocular surface increases bioavailability. Matching the pH and polarity of drug molecules to the tissue layers allows greater penetration. Drug delivery to the posterior segment is a greater challenge and, currently, the standard route is via intravitreal injection, notwithstanding the risks of endophthalmitis and retinal detachment with frequent injections. Intraocular implants that allow sustained drug release are at different stages of development. Novel exciting therapeutic approaches include methods for promoting transscleral delivery, sustained release devices, nanotechnology and gene therapy. PMID- 28865244 TI - Pathways from anxiety to stressful events: An expansion of the stress generation hypothesis. PMID- 28865243 TI - Self-harm and suicide attempts in Schizophrenia. AB - BACKGROUND: The risk of suicide among persons with schizophrenia (SZ) is higher than in general population, with multiple contributory factors. We assessed the prevalence of risk of deliberate self-harm and suicide attempts, along with associated socio-demographic and clinical factors in a group of SZ outpatients (n=61) as part of a larger study on overall schizophrenia-associated risks. AIMS: To investigate factors associated with risk of deliberate self-harm and suicide among persons with schizophrenia. METHOD: Out of 270 SZ participants evaluated for various risks using Ram Manohar Lohia Risk Assessment Interview (RML-RAI), 61 reported risk of self-harm including suicide attempt/s. The factors associated with this risk were further evaluated on clinical details and Diagnostic Interview for Genetic Studies. RESULTS: Risk of reported self-harm was 22.59%. Among them, 10% had attempted suicide at least once. Current age and past month Global Assessment of Functioning score from DIGS (GAF) were significantly correlated with suicide attempt. Attempters had significantly lower current GAF score, indicating poorer functioning. Among 27 attempters, 9 attempted at the onset of illness while 6 others attempted suicide within one year. Most common method of attempt was ingestion of insecticides or overdose of medication, followed by hanging or jumping from height. CONCLUSION: In our hospital-based sample of suicide attempters, 10% had attempted suicide, among them over 55% within first year of illness. Attempters were significantly older than non attempters and suffered from significantly more severe illness than non attempters. Positive symptoms were significantly associated with attempt, irrespective of time at which suicide was attempted. PMID- 28865245 TI - The SH2B3 and KCNK5 loci may be implicated in regulation of platelet count, volume, and maturity. AB - INTRODUCTION: In recent genome-wide association studies, coronary artery disease (CAD) and myocardial infarction (MI) have been linked to a number of genetic variants, but their role in thrombopoiesis is largely unknown. AIM: We investigated the association between CAD and MI-associated genetic variants and five thrombopoiesis-related indices: platelet count (PC), mean platelet volume (MPV), immature platelet count (IPC), immature platelet fraction (IPF), and serum thrombopoietin (TPO). METHODS: We genotyped 45 genome-wide significant CAD/MI markers in 879 stable CAD patients. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. Platelet indices were analysed using the Sysmex XE-2100 haematology analyser. TPO was measured by ELISA. RESULTS: Two variants were nominally associated with several indices; for rs10947789 (KCNK5), the adjusted geometric mean was 2% higher for MPV (95% confidence interval: 1-2%, p=0.002), 6% for IPC (0-12%, p=0.033), and 9% for IPF (3-16%, p=0.004) per CAD risk allele. Moreover, an 11% lower TPO (3-19%, p=0.010) was observed. Rs3184504 (SH2B3) was associated with a higher adjusted geometric mean of 3% (1-6%, p=0.003) per CAD risk allele for PC, and an 11% (5-17%, p<0.001) lower TPO. Furthermore, the adjusted IPC was 5% (0-9%, p=0.037) lower per CAD risk allele for PC, whereas IPF levels did not vary across genotypes. CONCLUSION: As a novel finding, our study suggests a role for KCNK5 in the regulation of platelet size and maturity. Furthermore, our findings confirm an association between the SH2B3-locus and platelet count. PMID- 28865246 TI - Factor XIII levels and factor XIII B subunit polymorphisms in patients with venous thromboembolism. AB - BACKGROUND: The association of plasma factor XIII (FXIII) level with venous thromboembolism (VTE) is still controversial and the effect of sex and FXIII B subunit (FXIII-B) polymorphisms in this respect have not been explored. OBJECTIVES: 1/ To determine FXIII activity and antigen levels in patients with a history of VTE and how they are influenced by sex and FXIII-B polymorphisms. 2/ To explore the association of FXIII levels and FXIII-B polymorphisms with the risk of VTE. METHODS: 218 VTE patients and equal number of age and sex matched controls were enrolled in the study. FXIII activity was measured by ammonia release assay; FXIII-A2B2 and FXIII-B levels were determined by ELISAs. FXIII-B polymorphisms were identified by RT-PCR using melting point analysis. RESULTS: Adjusted FXIII activity and FXIII-A2B2 antigen levels were significantly higher in females with a history of VTE than in the respective controls. FXIII-B levels were significantly lower in male VTE patients than in controls. FXIII-A2B2 antigen levels in the upper tertile increased the risk of VTE in females (adjusted OR: 2.52; CI: 1.18-5.38). Elevated FXIII-B antigen level had a protective effect only in males (adjusted OR: 0.19; CI: 0.08-0.46). FXIII-B Intron K c.1952+144 C>G polymorphism significantly lowered FXIII activity, FXIII A2B2 and FXIII-B antigen levels in both groups. FXIII-B polymorphisms did not influence the risk of VTE. CONCLUSIONS: In VTE patients the changes of FXIII level and their effect on the risk of VTE show considerable sex-specific differences. Intron K polymorphism results in decreased FXIII levels, but does not influence the risk of VTE. PMID- 28865247 TI - Allostery in enzyme catalysis. AB - Modern interpretations of allostery typically rely on conformational ensembles to describe enzyme function. Conformational motions controlling these ensembles are often stimulated or quenched by allosteric effectors, and are critical to optimizing ligand binding pockets and enzyme architectures. Thus, enzymes rely on dynamic allosteric pathways that transmit long-range binding information to control catalysis. In this review, we provide a brief discussion of the ever expanding principles of allosteric regulation in enzyme catalysis and highlight in-depth studies of three enzymes that have contributed to the paradigms of dynamic allostery. PMID- 28865248 TI - Analysis of multiple tank car releases in train accidents. AB - There are annually over two million carloads of hazardous materials transported by rail in the United States. The American railroads use large blocks of tank cars to transport petroleum crude oil and other flammable liquids from production to consumption sites. Being different from roadway transport of hazardous materials, a train accident can potentially result in the derailment and release of multiple tank cars, which may result in significant consequences. The prior literature predominantly assumes that the occurrence of multiple tank car releases in a train accident is a series of independent Bernoulli processes, and thus uses the binomial distribution to estimate the total number of tank car releases given the number of tank cars derailing or damaged. This paper shows that the traditional binomial model can incorrectly estimate multiple tank car release probability by magnitudes in certain circumstances, thereby significantly affecting railroad safety and risk analysis. To bridge this knowledge gap, this paper proposes a novel, alternative Correlated Binomial (CB) model that accounts for the possible correlations of multiple tank car releases in the same train. We test three distinct correlation structures in the CB model, and find that they all outperform the conventional binomial model based on empirical tank car accident data. The analysis shows that considering tank car release correlations would result in a significantly improved fit of the empirical data than otherwise. Consequently, it is prudent to consider alternative modeling techniques when analyzing the probability of multiple tank car releases in railroad accidents. PMID- 28865249 TI - Effects of ultra-low-dose versus standard hormone therapy on fibrinolysis and thrombin generation in postmenopausal women. AB - OBJECTIVE: To assess the effects of different doses of oral hormone therapy (HT) on thrombin generation and fibrinolysis. STUDY DESIGN: One hundred fifty postmenopausal women were assigned in a randomized controlled study in which the effect of standard dose (1mg 17beta-estradiol/5mg dydrogesterone), ultra-low-dose HT (0.5mg 17beta-estradiol/2.5mg dydrogesterone) on fibrinolysis and coagulation was compared to controls. Factors measured included plasma clot lysis time (CLT), fibrinolysis activators and inhibitors, thrombin generation (prothrombin fragments 1+2 [F1+2], endogenous thrombin potential [ETP]), normalized activated protein C sensitivity ratio (nAPCsr), and factor (F)VIII activity and were determined before and after 24 weeks of HT. RESULTS: In ultra-low-dose group posttreatment CLT tended to be shorter when compared to standard HT (-7%) and control group (-4%) with reduced plasminogen activator inhibitor-1 (PAI-1) antigen (by -16% vs both groups). Higher mean changes from baseline between ultra low-HT group and standard group in CLT (-7.4 vs 3.05) and PAI-1 antigen concentration (-5.1 vs 0.9) were observed. Standard HT, compared with the ultra low-dose HT, led to higher F1+2 (+9%) and FVIII activity (+37%). CONCLUSIONS: In contrast to the standard HT, ultra-low-dose HT may enhance fibrinolysis through reduced PAI-1 levels. PMID- 28865250 TI - Delay in diagnosis of psychogenic nonepileptic seizures in adults: A post hoc study. AB - PURPOSE: The aim of the current post hoc study was to investigate factors associated with delay in diagnosis of adult patients with psychogenic nonepileptic seizures (PNES). METHODS: We retrospectively investigated all patients with PNES admitted to the epilepsy-monitoring unit at the Jefferson Comprehensive Epilepsy Center from 2012 through 2016. We identified the median time to diagnosis of PNES and divided the patients into two groups. We studied factors associated with delay in diagnosis of PNES. RESULTS: In all, 49 patients (39 women and 10 men) were studied. Mean age at the time of admission was 40+/ 16years and at the onset of the seizures was 34+/-16years. Disease duration was 5.6+/-8.2years. The median for time to diagnosis was 3years. Patients with early diagnosis (before 3years after seizure onset) (21 patients) and patients with late diagnosis (delay of 3years or more from onset) (28 patients) were compared. Only history of head trauma had significant association with the delay in diagnosis: 2 of 19 patients (7%) with an early diagnosis and 11 of 28 patients (39%) with a late diagnosis reported head trauma (P=0.02). CONCLUSION: Delay in diagnosis of PNES is common, and some factors (e.g., history of head trauma) may contribute to this delay. It is important that physicians involved in the management of seizures appreciate the importance of making an early and definitive diagnosis of PNES. PMID- 28865251 TI - "Stay cool, sell stuff cheap, and smile": Examining how reputational management of dental tourism reinforces structural oppression in Los Algodones, Mexico. AB - Los Algodones, Mexico is characteristic of other medical border towns whose proximity to the Mexico-United States border enables American and Canadian patients to take advantage of economic asymmetries on either side of the border to access desired health care. Los Algodones is unique, however, in its focus on the provision of dental care and claims by local residents that it has the highest concentration of dentists per capita in the world. In this paper, we present an analysis of interviews with employees working in Los Algodones' dental tourism industry to examine interviewees' participation in practices related to reputational management of the industry site. Drawing on our interview discussions, we argue that many of these reputational management practices reinforce structural injustices and raise concerns for structural exploitation in the industry. This analysis nuances ethical considerations for medical tourism by highlighting structural factors informing unjust practices within the industry, factors which might be relevant to other medical tourism contexts. PMID- 28865252 TI - Finding HOPE: Changes in depressive symptomology following relocation from distressed public housing. AB - Many public housing residents suffer from poor mental health and depression, which may be a function of both socioeconomic deprivation and residing in disorderly, unstable, and disadvantaged neighborhoods. While not explicitly targeting mental health, the HOPE VI program may improve public housing residents' mental health by relocating them from distressed developments and into less-disadvantaged and disorderly neighborhoods. This paper examines post relocation depressive symptomology among residents relocated from the Boulevard Homes public housing development in Charlotte, NC. Drawing on pre- and post relocation surveys, as well as interviews with staff and case managers, we examine whether depressive symptomology - measured by the CES-D-10 - is associated with whether tenants relocate to other public housing or to private market housing through the Housing Choice Voucher program. Further, we investigate whether social support, perceptions of safety, or objective neighborhood measures result in improvements in post-relocation depressive symptomology. We find that depressive symptomology substantially decreased following relocation, and those with higher CES-D-10 scores were more likely to move to other public housing rather than through the voucher program. Interviews with case managers suggest that some residents were fearful of leaving public housing and assuming the responsibilities of a private-market rental unit - e.g., basic maintenance and utility payments. Further, we find that reductions in post relocation depressive symptomology are associated with greater perceptions of safety, greater social support in their new neighborhoods, and length of tenure at Boulevard Homes. Policy recommendations include expanding community-based mental health services, conducting pre-relocation mental health screenings, and providing additional relocation counseling to those suffering from depression. PMID- 28865253 TI - Why did life expectancy decline in the United States in 2015? A gender-specific analysis. AB - In 2015, age-adjusted mortality rates increased for 8 of the 10 leading causes of death in the United States. As a result, life expectancy declined by 0.17 years for both women and men. The decline could be just an anomaly, or it could represent the start of a new trend of stagnation or decline in life expectancy, as some scholars have warned. The first step is to determine the sources of the decline. In this study we analyze the contribution of specific causes of death to the decline in men's versus women's life expectancy, as well as the mechanisms that generated the decline. With regard to mechanisms, we examine whether the decline in life expectancy resulted from reductions in the average age at death for most causes of death, or from a greater risk of dying of causes that disproportionately affect the young and middle-aged. Using CDC mortality data, we construct life tables for men and women separately, based on 20 different underlying causes of death. We find that men's reduction in life expectancy was attributable primarily to changes in midlife mortality, with a greater risk of dying of causes such as accidental poisoning or homicide. The reduction in women's life expectancy, on the other hand, was attributable primarily to changes in old-age mortality, where the mean age at death for most causes (such as heart disease and mental illnesses) was lower in 2015 than it was in 2014. These gender specific mechanisms that contributed to the decline in life expectancy are common to the major racial/ethnic groups, but the magnitude of the decline differs greatly across racial/ethnic groups. Future research can use the tools provided here to investigate in more detail how the gender-specific mechanisms of the 2015 decline differ by race. PMID- 28865254 TI - "The land of the sick and the land of the healthy": Disability, bureaucracy, and stigma among people living with poverty and chronic illness in the United States. AB - Disability benefits have become an increasingly prominent source of cash assistance for impoverished American citizens over the past two decades. This development coincided with cuts and market-oriented reforms to state and federal welfare programs, characteristic of the wider political-economic trends collectively referred to as neoliberalism. Recent research has argued that contemporary discourses on 'disability fraudsters' and 'malingerers' associated with this shift represent the latest manifestation of age-old stigmatization of the 'undeserving poor'. Few studies, however, have investigated how the system of disability benefits, as well as these stigmatizing discourses, shapes the lived experience of disabling physical illness in today's United States. Here we present qualitative data from 64 semi-structured interviews with low-income individuals living with HIV and/or type 2 diabetes mellitus to explore the experience of long-term, work-limiting disability in the San Francisco Bay Area. Interviews were conducted between April and December 2014. Participants explained how they had encountered what they perceived to be excessive, obstructive, and penalizing bureaucracy from social institutions, leading to destitution and poor mental health. They also described being stigmatized as disabled for living with chronic ill health, and simultaneously stigmatized as shirking and malingering for claiming disability benefits as a result. Notably, this latter form of stigma appeared to be exacerbated by the bureaucracy of the administrating institutions. Participants also described intersections of health-related stigma with stigmas of poverty, gender, sexual orientation, and race. The data reveal a complex picture of poverty and intersectional stigma in this population, potentiated by a convoluted and inflexible bureaucracy governing the system of disability benefits. We discuss how these findings reflect the historical context of neoliberal cuts and reforms to social institutions, and add to ongoing debate around the future of public social provision for impoverished and chronically ill citizens under neoliberalism. PMID- 28865255 TI - Parent use of cannabis for intractable pediatric epilepsy: Everyday empiricism and the boundaries of scientific medicine. AB - Cannabis is an increasingly sought-after remedy for US children with intractable (biomedically uncontrollable) epilepsy. However, like other complementary alternative medicine (CAM) modalities, and particularly as a federally illegal, stigmatized substance, it is unsanctioned by mainstream medicine. Parents are largely on their own when it comes to learning about, procuring, dispensing, and monitoring treatments. Exploring how they manage is crucial to better assist them. Moreover, it can illuminate how 'research' done on the ground by laypeople variously disrupts and reinforces lay-expert and science-non-science divides. To those ends, in 2016, 25 Southern California parents who used, had used, or sought to use cannabis pediatrically for epilepsy/seizures were interviewed regarding their evidentiary standards, research methods, and aims when trying the drug. Parents generally described their work as experimentation; they saw their efforts as adhering to authorized scientific practices and standards, and as contributing to the authorized medical cannabis knowledge base. Findings subverted assumptions, based on an outdated stereotype of CAM, that cannabis-using parents do not believe in biomedicine. Indeed, parents' desire for their children's biomedical demarginalization, combined with biomedical dependency and a high caregiver burden, fueled a collaborative stance. Implications for understanding the boundaries of science are explored, as are norms for parent agency as ill children's care managers, radicalization among people affected by contested illnesses, and the future of 'medical marijuana.' PMID- 28865256 TI - Identification and verification of hybridoma-derived monoclonal antibody variable region sequences using recombinant DNA technology and mass spectrometry. AB - Antibody engineering requires the identification of antigen binding domains or variable regions (VR) unique to each antibody. It is the VR that define the unique antigen binding properties and proper sequence identification is essential for functional evaluation and performance of recombinant antibodies (rAb). This determination can be achieved by sequence analysis of immunoglobulin (Ig) transcripts obtained from a monoclonal antibody (MAb) producing hybridoma and subsequent expression of a rAb. However the polyploidy nature of a hybridoma cell often results in the added expression of aberrant immunoglobulin-like transcripts or even production of anomalous antibodies which can confound production of rAb. An incorrect VR sequence will result in a non-functional rAb and de novo assembly of Ig primary structure without a sequence map is challenging. To address these problems, we have developed a methodology which combines: 1) selective PCR amplification of VR from both the heavy and light chain IgG from hybridoma, 2) molecular cloning and DNA sequence analysis and 3) tandem mass spectrometry (MS/MS) on enzyme digests obtained from the purified IgG. Peptide analysis proceeds by evaluating coverage of the predicted primary protein sequence provided by the initial DNA maps for the VR. This methodology serves to both identify and verify the primary structure of the MAb VR for production as rAb. PMID- 28865257 TI - Highly efficient extraction and selective separation of uranium (VI) from transition metals using new class of undiluted ionic liquids based on H phosphonate anions. AB - In this paper, we report the development of an environmental friendly process to decontaminate uranium-containing ores and nuclear wastes by using non-fluorinated ionic liquids (ILs). The main advantages of this extraction process are the absence of any organic diluent and extra extraction agents added to the organic phase. Moreover, the process is cost-effective and maybe applied as a sustainable hydrometallurgical method to recover uranium. The distribution ratio (DU) and the extraction efficiency (%E) of uranium(VI) (UO22+) were found to be dependent on the acidity of the aqueous phase, the extraction time, the alkyl chain length in the ILs, the concentration of the aqueous feed and molar quantity of ILs. The DU value is higher than 600 and the %E is equal to 98.6% when [HNO3]=7M. The extraction reactions follows a neutral partition or ionic exchange mechanism depending on nitric acid concentration. The nature of bonding in the extracted complexes was investigated by spectroscopic techniques. The potential use of Mor1 8-OP for the separation of UO22+ from a mixture containing transition metal ions Mn+ was also examined. The UO22+ ions were separated and extracted efficiently. These ILs are promising candidates for the recovery and separation of uranium. PMID- 28865258 TI - Effects of magnesium-based hydrogen storage materials on the thermal decomposition, burning rate, and explosive heat of ammonium perchlorate-based composite solid propellant. AB - MgH2, Mg2NiH4, and Mg2CuH3 were prepared, and their structure and hydrogen storage properties were determined through X-ray photoelectron spectroscopy and thermal analyzer. The effects of MgH2, Mg2NiH4, and Mg2CuH3 on the thermal decomposition, burning rate, and explosive heat of ammonium perchlorate-based composite solid propellant were subsequently studied. Results indicated that MgH2, Mg2NiH4, and Mg2CuH3 can decrease the thermal decomposition peak temperature and increase the total released heat of decomposition. These compounds can improve the effect of thermal decomposition of the propellant. The burning rates of the propellant increased using Mg-based hydrogen storage materials as promoter. The burning rates of the propellant also increased using MgH2 instead of Al in the propellant, but its explosive heat was not enlarged. Nonetheless, the combustion heat of MgH2 was higher than that of Al. A possible mechanism was thus proposed. PMID- 28865259 TI - Current margin practice and effect on re-excision rates following the publication of the SSO-ASTRO consensus and ABS consensus guidelines: a national prospective study of 2858 women undergoing breast-conserving therapy in the UK and Ireland. AB - INTRODUCTION: There is variation in margin policy for breast conserving therapy (BCT) in the UK and Ireland. In response to the Society of Surgical Oncology and American Society for Radiation Oncology (SSO-ASTRO) margin consensus ('no ink on tumour' for invasive and 2 mm for ductal carcinoma in situ [DCIS]) and the Association of Breast Surgery (ABS) consensus (1 mm for invasive and DCIS), we report on current margin practice and unit infrastructure in the UK and Ireland and describe how these factors impact on re-excision rates. METHODS: A trainee collaborative-led multicentre prospective study was conducted in the UK and Ireland between 1st February and 31st May 2016. Data were collected on consecutive BCT patients and on local infrastructure and policies. RESULTS: A total of 79 sites participated in the data collection (75% screening units; average 372 cancers annually, range 70-900). For DCIS, 53.2% of units accept 1 mm and 38% accept 2-mm margins. For invasive disease 77.2% accept 1 mm and 13.9% accept 'no ink on tumour'. A total of 2858 patients underwent BCT with a mean re excision rate of 17.2% across units (range 0-41%). The re-excision rate would be reduced to 15% if all units applied SSO-ASTRO guidelines and to 14.8% if all units followed ABS guidelines. Of those who required re-operation, 65% had disease present at margin. CONCLUSION: There continues to be large variation in margin policy and re-excision rates across units. Altering margin policies to follow either SSO-ASTRO or ABS guidelines would result in a modest reduction in the national re-excision rate. Most re-excisions are for involved margins rather than close margins. PMID- 28865262 TI - Perfluoroalkyl substances (PFASs) in breast milk from Korea: Time-course trends, influencing factors, and infant exposure. AB - Breastfeeding is an important exposure pathway to perfluoroalkyl substances (PFASs) for newborn infants. Nevertheless, reports are limited on the occurrence and time-course of PFASs in breast milk, and most studies have focused on the analysis of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). In this study, 16 PFASs were analyzed in breast milk samples (n=293) collected from 128 mothers in Korea during various lactation periods to assess maternal exposure levels, contamination profiles, time-course variations, and infant health risks. The total concentrations of PFASs (SigmaPFAS) ranged from 31.7 to 1004 (median: 188) ng/L, which was within the ranges recently reported for Asian and European populations. After a month of nursing, the concentrations of PFOS, PFOA, perfluorononanoic acid (PFNA), and SigmaPFAS significantly increased. This could be due to changes in the dietary and behavior patterns of the mothers after the first month of lactation. The concentrations of PFOS and PFOA were significantly correlated with maternal age, body mass index, and parity. Certain types of diet (e.g. consuming snacks and milk) and eating-out frequency were significantly associated with increasing levels of PFAS. Significant correlations and similar time-course trends were found between PFASs and PCBs/DDTs, implying similar exposure sources and biokinetics for these contaminants. The estimated daily intakes of PFOS and PFOA via the consumption of breast milk were below the tolerable daily intakes for infants suggested by the European Food Safety Authority (EFSA). PMID- 28865263 TI - Source apportionment of PM2.5 for 25 Chinese provincial capitals and municipalities using a source-oriented Community Multiscale Air Quality model. AB - Source contributions to fine airborne particulate matter with aerodynamic diameters <2.5MUm (PM2.5) during 2013 were determined for 25 Chinese provincial capitals and municipalities using a source-oriented version of the Community Multiscale Air Quality (CMAQ) model. Based on the hierarchical clustering analysis of the observed PM2.5 concentrations, the 25 cities were categorized into nine groups. Generally, annual PM2.5 concentrations were highest in the cities in the north (81-154MUgm-3) and lowest in the cities close to seas in the south and east (27-57MUgm-3). Seasonal PM2.5 observations in the cities were generally higher in winter than in the other seasons. Industrial or residential sources were predicted to be the largest contributor to PM2.5 for all the city groups, with annually fractional contributions of 25.0%-38.6% and 9.6%-27%, respectively. The annual contributions from power plants, agriculture NH3, windblown dust, and secondary organic aerosol (SOA) for the city groups were 8.7% 12.7%, 9.5%-12%, 6.1%-12.5%, and 5.4%-15.5%, respectively. Meanwhile, the annual contributions from transportation, sea salt, and open burning were relatively low (<8%, <2%, and <6%, respectively). Secondary PM2.5 accounted for 47%-63% of total annual PM2.5 concentrations in the cities and contributed to as much as 70% of daily PM2.5 concentrations on PM2.5 pollution days (daily concentrations>75MUgm 3). Industrial or residential sources were generally the largest contributor on PM2.5 pollution days for all the city groups in each season, except that open burning, SOA, and windblown dust could be more important on some days, particularly in spring. The results of this study would be helpful to develop measures to reduce annual PM2.5 concentrations and the number of PM2.5 pollution days for different regions of China. PMID- 28865260 TI - Societal challenges of precision medicine: Bringing order to chaos. AB - The increasing number of drugs targeting specific proteins implicated in tumourigenesis and the commercial promotion of relatively affordable genome-wide analyses has led to an increasing expectation among patients with cancer that they can now receive effective personalised treatment based on the often complex genomic signature of their tumour. For such approaches to work in routine practice, the development of correspondingly complex biomarker assays through an appropriate and rigorous regulatory framework will be required. It is becoming increasingly evident that a re-engineering of clinical research is necessary so that regulatory considerations and procedures facilitate the efficient translation of these required biomarker assays from the discovery setting through to clinical application. This article discusses the practical requirements and challenges of developing such new precision medicine strategies, based on leveraging complex genomic profiles, as discussed at the Innovation and Biomarkers in Cancer Drug Development meeting (8th-9th September 2016, Brussels, Belgium). PMID- 28865264 TI - The association between environmental lead exposure with aggressive behavior, and dimensionality of direct and indirect aggression during mid-adolescence: Birth to Twenty Plus cohort. AB - Chronic lead exposure is associated with neurological ill-health including anti social behavior such as aggressive behavior. The main aim of this study was to examine the association between lead exposure at 13years old and dimensions of aggressive behavior during mid-adolescence. The study sample included 508 males and 578 females in mid-adolescence (age 14 to 15years) from the Birth to Twenty Plus cohort in Johannesburg, South Africa. Blood samples collected at age 13years were used to measure blood lead levels. Seventeen items characterizing aggression from the Youth Self Report questionnaire were used to examine aggressive behavior. Principal Component Analysis was used to derive composite variables from the original data for aggressive behavior; and data were examined for an association between blood lead levels and dimensionality of direct and indirect aggression and disobedience during mid-adolescence. We also examined the dimensions of aggression during mid-adolescence in relation to gender and socio demographic factors. Blood lead levels ranged from 1 to 28.1MUg/dL. Seventy two percent of males and 47.7% of females in the study had blood lead levels >=5MUg/dL. There was a positive association between elevated blood lead levels and direct aggression (p<0.05). Being male was positively associated with direct aggression (p<0.001) but, negatively associated with indirect aggression (p<0.001). Maternal education and age at birth were negatively associated with direct aggression during mid-adolescence. The significant association between elevated blood lead levels and direct aggressive behavior observed in this study may shed light on a possible environmental toxicological contribution to aggressive behavior in South African youth; and most importantly the type of aggressive behavior associated to lead exposure. PMID- 28865265 TI - Nitrification inhibitors mitigated reactive gaseous nitrogen intensity in intensive vegetable soils from China. AB - Nitrification inhibitors, a promising tool for reducing nitrous oxide (N2O) losses and promoting nitrogen use efficiency by slowing nitrification, have gained extensive attention worldwide. However, there have been few attempts to explore the broad responses of multiple reactive gaseous nitrogen emissions of N2O, nitric oxide (NO) and ammonia (NH3) and vegetable yield to nitrification inhibitor applications across intensive vegetable soils in China. A greenhouse pot experiment with five consecutive vegetable crops was performed to assess the efficacies of two nitrification inhibitors, namely, nitrapyrin and dicyandiamide on reactive gaseous nitrogen emissions, vegetable yield and reactive gaseous nitrogen intensity in four typical vegetable soils representing the intensive vegetable cropping systems across mainland China: an Acrisol from Hunan Province, an Anthrosol from Shanxi Province, a Cambisol from Shandong Province and a Phaeozem from Heilongjiang Province. The results showed soil type had significant influences on reactive gaseous nitrogen intensity, with reactive gaseous nitrogen emissions and yield mainly driven by soil factors: pH, nitrate, C:N ratio, cation exchange capacity and microbial biomass carbon. The highest reactive gaseous nitrogen emissions and reactive gaseous nitrogen intensity were in Acrisol while the highest vegetable yield occurred in Phaeozem. Nitrification inhibitor applications decreased N2O and NO emissions by 1.8-61.0% and 0.8-79.5%, respectively, but promoted NH3 volatilization by 3.2-44.6% across all soils. Furthermore, significant positive correlations were observed between inhibited N2O+NO and stimulated NH3 emissions with nitrification inhibitor additions across all soils, indicating that reduced nitrification posed the threat of NH3 losses. Additionally, reactive gaseous nitrogen intensity was significantly reduced in the Anthrosol and Cambisol due to the reduced reactive gaseous nitrogen emissions and increased yield, respectively. Our findings highlight the benefits of nitrification inhibitors for integrating environment and agronomy in intensive vegetable ecosystems in China. PMID- 28865266 TI - Vehicle exhaust: An overstated cause of haze in China. AB - Overall, total exhaust emissions of NOX, VOC and particulate matter (PM) declined, though vehicles in use continued to increase in China. This suggested that contribution of motor vehicle exhaust to haze in China may be exaggerated. A higher frequency of haze episodes in China with lower total emissions fraction from vehicle exhaust compared with those in the USA confirmed that there exists no strict causality between vehicle and haze. No significant correlation (p<0.05) between haze days and the contribution of vehicles to airborne PM2.5 (particulates that are <2.5MUm in aerodynamic diameter) or car ownerships. All results revealed again that vehicle exhaust is an overstated cause for haze formation in China. PMID- 28865261 TI - Quality analysis of population-based information on cancer stage at diagnosis across Europe, with presentation of stage-specific cancer survival estimates: A EUROCARE-5 study. AB - BACKGROUND: Cancer registries (CRs) are fundamental for estimating cancer burden, evaluating screening and monitoring health service performance. Stage at diagnosis-an essential information item collected by CRs-has been made available, for the first time, by CRs participating in EUROCARE-5. We analysed the quality of this information and estimated stage-specific survival across Europe for CRs with good data quality. DATA AND METHODS: Sixty-two CRs sent stage (as TNM, condensed TNM or extent of disease) for 15 cancers diagnosed in 2000-2007. We assessed the quality, partly by comparing stage according to the three systems. We also developed procedures to reconstruct stage (categories: local, regional, metastatic and unknown) using information from all three systems, thus minimising the amount of missing information. RESULTS: Moderate-to-excellent stage concordance was found for practically all 24 CRs, for which it was possible to compare at least two staging systems. However, since stage was often incorrectly assigned, and information on the presence/absence of metastases was often lacking, data on only 7/15 cancers from 34/62 CRs (15 countries) were of sufficient quality for further analysis. Cases diagnosed >=70 years had more advanced (or lacking) stage- and worse stage-specific survival than those <70 years. CONCLUSIONS: Many European CRs collect and record reasonably accurate stage information. Others have difficulties. Both the completeness of primary data and the accuracy of stage coding need to be improved in order for CRs to fulfil their expanding roles in cancer control. We propose our stage reconstruction/checking procedures as a means of fully exploiting the stage information provided by EUROCARE CRs. More advanced (or lacking) stage at diagnosis plus poorer stage-specific survival in the elderly are worrying. PMID- 28865267 TI - Halogenated and organophosphorus flame retardants in European aquaculture samples. AB - This work monitors flame retardants in sediment, mussel and water samples from European fish farms. Polybrominated diphenyl ethers (PBDEs) were detected in 95% of the sediment and mussel samples with mean levels of 8.60+/-22.6ngg-1 dw in sediments and 0.07+/-0.18ngg-1 dw in mussels. BDE-209 was the main contributor for the sediments and BDE-47 was found in about 60% of the samples of both matrices. Pentabromoethylbenzene (PBEB) and hexabromobenzene (HBB) were detected in 42% of the sediments, but not in mussels. Decabromodiphenyl ethane (DBDPE) was found in about 55% of the samples of both matrices. The same happened for dechloranes in mussels, but they were detected in 92% of the sediments. Syn-DP and anti-DP were always the main contributors. Methoxylated PBDEs (MeO-PBDEs) were detected in all mussels and some sediments, mainly 6-MeO-BDE-47 and 2'-MeO BDE-68. Organophosphorus flame retardants (OPFRs) were found in all matrices with concentrations of 0.04-92.8ngg-1 dw in sediment, 0.50-102ngg-1 dw in mussel and 0.43-867ngl-1 in water. Only OPFRs were analysed in water samples as halogenated flame retardants and MeO-PBDEs are highly unlikely to be detected in water due to their physicochemical properties. Flame retardants have no application in fish farming so results should reflect the impact of human activity on the farm locations. A large majority of the most contaminated samples were collected from sampling spots that were at urban shores or in enclosed water bodies not completely open to the sea. PMID- 28865268 TI - Effects of resource availability and hydrological regime on autochthonous and allochthonous carbon in the food web of a large cross-border river (China). AB - Resource availability and flooding disturbance restrict the amount of energy available to the upper trophic level consumers and thus determine the trophic structure and energy mobilization in river food webs. In this study, we evaluated the availability of primary and secondary food resources, food web structure (determined by delta13C and delta15N) and relative contributions of autochthonous and allochthonous particulate carbon to aquatic consumers in the Irtysh River, which spans from northwest China to Kazakhstan and suffers from a long frozen period. Despite higher density and biomass, epilithic algae did not make large contributions to aquatic consumers due to the restriction of flow velocity, water depth and turbidity. Aquatic invertebrates specialized in utilization of terrestrial carbon sources, whereas fish varied from aquatic to riparian plants. Different resource use of aquatic consumers across the three reaches in the Irtysh River was ascribed to the spatial distribution of species and resource availability determined by flooding, flood scouring and dam construction. The trophic positions and food chain length at the upper reach were higher than those at the middle and lower reaches. These findings suggest that allochthonous carbon had an advantage over autochthonous carbon in supporting aquatic food webs of the Irtysh River. Higher availability of allochthonous particulate carbon might be relevant to intensive forest cover and high energy flood events in the Irtysh River. PMID- 28865269 TI - Climate and drought risk regionalisation in China based on probabilistic aridity and drought index. AB - The general approach to drought regionalisation regards the multi-year average values of drought indexes as regionalisation indicators, without taking long-term variability into account. This type of regionalisation is known as static regionalisation, or mean regionalisation, and does not consider possible variations over multiple years. In order to analyse the probability of climate aridity and drought, in this study, we firstly introduce the novel concept of a probabilistic aridity index for climate regionalisation and a drought index for drought risk regionalisation, as well as a methodology for estimating the frequency of the probabilistic aridity and drought index. Details of the approach used in the regionalisation of aridity and drought risk, and its associated characteristics, are then discussed. Finally, the value of our approach is demonstrated in China. The result shows that climate and drought risk regionalisation is able to provide enriched aridity and drought probability information compared with general climate and drought regionalisation, and can thus provide enhanced technical support for the rational allocation of water resources and the prevention and mitigation of drought disasters. PMID- 28865270 TI - Phosphorus activators contribute to legacy phosphorus availability in agricultural soils: A review. AB - Phosphorus (P) is one of the most limiting macronutrients for crop productivity and P deficiency is a common phenomenon in agricultural soils worldwide. Despite long-term application of phosphate fertilizers to increase crop yields, P availability is often low, due to the high affinity of phosphate for the soil solid phase. It has been suggested that the accumulated (surplus) P in agricultural soils is sufficient to sustain crop yields worldwide for about 100years. In this paper, we try to clear up the potential for making use of legacy P in soils for crop growth potentially alleviating the global P resource shortage. Specifically, we try to clear up the potential of soil "P activators" for releasing fixed P. P activators accelerate and strengthen process which transform P into bio-available forms via a range of chemical reactions and biological interactions. They include phosphate solubilizing microorganisms, phosphatase enzymes and enzyme activators, low molecular weight organic acids, humic acids, lignin, crop residues, biochar and zeolites. Although reported performance is variable, there is growing evidence that P activators can promote the release of phosphate from soil and, hence, have potential for mitigating the impending global P crisis. Further basic and applied research is required to better understand the mechanisms of interaction of P activators with natural soils and to maximize activator efficacy. PMID- 28865271 TI - The phenotypic variability in Rana temporaria decreases in response to drying habitats. AB - In this study, we evaluated the diversity of skin coloration as a proxy for phenotypic diversity. The European common frog (Rana temporaria) populations from the Southern slope of central Pyrenees lie at the limit of the species distribution in latitude and altitude. We analysed the relationship of skin color typology with different environmental variables and found a large decrease in skin type variety in frogs developing in temporary water bodies when compared to those developing in permanent water bodies. Our results show that our method can be used as a non-invasive way to study phenotypic diversity and suggest that adaptation to an early metamorphosis in a rapidly-drying habitat can have negative effects on adult phenotypic diversity. In light of these results, we argue that access to permanent water bodies is important to prevent loss of diversity in anuran populations and reduce their vulnerability to environmental impacts as well as pathogens. PMID- 28865272 TI - Rhizoremediation half-lives of PCBs: Role of congener composition, organic carbon forms, bioavailability, microbial activity, plant species and soil conditions, on the prediction of fate and persistence in soil. AB - Polychlorinated biphenyls (PCBs) are persistent organic pollutants widely produced and used in many countries until the increasing concern about their environmental risk lead to their ban in the 1980s. Although their emissions decreased, PCBs are nowadays still present in the environment and can be reemitted from reservoir compartments such as contaminated soils. In the last two decades, there has been a growing interest in bioremediation technologies that use plants and microorganisms (i.e. rhizoremediation) to degrade organic chemicals in contaminated sites. Different studies have been conducted to investigate the potential of plant-microbe interactions in the remediation of organic chemical contaminated soils. They range from short-term and laboratory/greenhouse experiments to long-term and field trials and, when correctly set up, they could provide useful data such as PCB rhizoremediation half-lives in soil. Such type of data are important input parameters for multimedia fate models that aim to estimate the time requested to achieve regulatory thresholds in a PCB contaminated site, allowing to draw up its remediation plan. This review focuses on the main factors influencing PCB fate, persistence and bioavailability in soil including PCB mixture congener composition, soil organic carbon forms, microorganism activity, plant species and soil conditions. Furthermore, it provides an estimate of rhizoremediation half lives of the ten PCB families starting from the results of literature rhizoremediation experiments. Finally, guidance to perform appropriate experiments to obtain comparable, accurate and useful data for fate estimation is proposed. PMID- 28865273 TI - Designer carbon nanotubes for contaminant removal in water and wastewater: A critical review. AB - The search for effective materials for environmental cleanup is a scientific and technological issue of paramount importance. Among various materials, carbon nanotubes (CNTs) possess unique physicochemical, electrical, and mechanical properties that make them suitable for potential applications as environmental adsorbents, sensors, membranes, and catalysts. Depending on the intended application and the chemical nature of the target contaminants, CNTs can be designed through specific functionalization or modification processes. Designer CNTs can remarkably enhance contaminant removal efficiency and facilitate nanomaterial recovery and regeneration. An increasing number of CNT-based materials have been used to treat diverse organic, inorganic, and biological contaminants. These success stories demonstrate their strong potential in practical applications, including wastewater purification and desalination. However, CNT-based technologies have not been broadly accepted for commercial use due to their prohibitive cost and the complex interactions of CNTs with other abiotic and biotic environmental components. This paper presents a critical review of the existing literature on the interaction of various contaminants with CNTs in water and soil environments. The preparation methods of various designer CNTs (surface functionalized and/or modified) and the functional relationships between their physicochemical characteristics and environmental uses are discussed. This review will also help to identify the research gaps that must be addressed for enhancing the commercial acceptance of CNTs in the environmental remediation industry. PMID- 28865274 TI - Thermal effects on arsenic emissions during coal combustion process. AB - In this study, the rate of emission of arsenic during the burning process of different kinds of coal is examined in order to study the volatile characteristics of arsenic during coal combustion which have negative effects on the ecological environment and human health. The results show that the emission rate of arsenic gradually increases with increased burning temperature, with a threshold of approximately 700 degrees C to 800 degrees C in the process of temperature increase. Then, the relationships among the arsenic emission rate and combustion environment, original arsenic content, combustion time, burning temperature, air flow and amount of arsenic fixing agent are discussed, and it is found that except for the original arsenic content, the rest of the factors have a nonlinear relationship with the emission rate of arsenic. That is, up to a certain level, they all contribute to the release of arsenic, and then their impact is minimal. The original arsenic content in coal is proportional to the arsenic emission rate. Therefore, taking into consideration the nonlinear relationships between factors that affect the arsenic emission rate can reduce contamination from arsenic. PMID- 28865275 TI - Multitemporal mapping of peri-urban carbon stocks and soil sealing from satellite data. AB - Peri-urbanisation is the expansion of compact urban areas towards low-density settlements. This phenomenon directly challenges the agricultural landscape multifunctionality, including its carbon (C) storage capacity. Using satellite data, we mapped peri-urban C stocks in soil and built-up surfaces over three areas from 1993 to 2014 in the Emilia-Romagna region, Italy: a thinly populated area around Piacenza, an intermediate-density area covering the Reggio Emilia Modena conurbation and a densely anthropized area developing along the coast of Rimini. Satellite-derived maps enabled the quantitative analysis of spatial and temporal features of urban growth and soil sealing, expressed as the ratio between C in built-up land and organic C in soils (Cc/Co). The three areas show substantial differences in C stock balance and soil sealing evolution. In Piacenza (Cc/Co=0.07 in 1993), although questioned by late industrial expansion and connected residential sprawl (Cc/Co growth by 38%), most of the new urbanisation spared the best rural soils. The Reggio Emilia-Modena conurbation, driven by the polycentricism of the area and the heterogeneity of economic sectors (Cc/Co rising from 0.08 to 0.14 from 1993 to 2014), balances sprawl and densification. Rimini, severely sealed since the 1960s (Cc/Co=0.23 in 1993), densifies its existing settlements and develops an industrial expansion of the hinterland, with Cc/Co growth accelerating from +15% before 2003 to +36% for the last decade. PMID- 28865276 TI - Design, synthesis and biological evaluation of new pyrrolidine carboxamide analogues as potential chemotherapeutic agents for hepatocellular carcinoma. AB - The successful targeting of different malignancies by OSU-2S, encouraged us to design and synthesize a novel series of pyrrolidine aryl carboxamide derivatives. In this context, we found that, the amide nature and tether length were found to be key determinant elements for the anticancer activity of these new and rigid analogues of OSU-2S. The most effective analogues induced apoptosis in cancer cells by a similar mechanism to that of OSU-2S, possibly via the activation of PKCdelta in addition to their ability to induce cell cycle arrest and inhibition of cancer cell migration. Compound 10m, possesses anticancer potency comparable to that of OSU-2S when tested against cancer cell lines under study, and was found to be safer on normal cells. Furthermore, compound 10m, was found to be about 2-folds more potent than the anticancer drug Sorafenib in hepatocellular carcinoma (HCC). The newly developed compounds represent a therapeutically promising approach for the treatment of HCC. PMID- 28865277 TI - Study on the design, synthesis and structure-activity relationships of new thiosemicarbazone compounds as tyrosinase inhibitors. AB - 52 Structure-based thiosemicarbazone compounds bearing various substituted lipophilic part, including substituted-benzaldehyde, substituted-phenylalkan-1 one and their biphenyl-type thiosemicarbazone analogs, were designed, synthesized and evaluated as new tyrosinase inhibitors. The results demonstrated that 22 compounds have potent inhibitory activities against tyrosinase with the IC50 value of lower than 1.0 MUM. On the basis of the obtained experimental data, the structure-activity relationships (SARs) were rationally derived. Besides, the inhibition mechanism and the inhibitory kinetics of selected compounds 3d and 6e were investigated, revealing that such type of compounds were belonged to the reversible and competitive tyrosinase inhibitors. To verify the safety of these developed thiosemicarbazone compounds, four randomly selected compounds 3d, 4e, 6a and 9a were also tested in 293T cell line for the evaluation of the cytotoxicity. Interestingly, all these compounds almost did not perform any toxicity to 293T cells even at a high concentration of 1000 MUmol/L. Taken together, these results suggested that such compounds could serve as the highly efficient and more safe candidates for the treatment of tyrosinase-related disorders. PMID- 28865278 TI - Studies on the cytotoxicity and anticancer performance of heterocyclic hypervalent organobismuth(III) compounds. AB - Novel organobismuth(III) complex of 5H-dibenzo[c,f][1,5]oxabismocin-12(7H)-yl nitrate (C2) was synthesized and characterized by spectral and elemental analysis. It was compared with other five C,E,C-chelating (E = N, O, S) organobismuth(III) complexes against human adenocarcinoma alveolar basal epithelial cells (A549), human liver cancer cell line (SMCC7721), human gastric cancer cell line (SGC-7901), human colon adenocarcinoma cell line (SW480) and healthy human bronchial cell line (16HBE14o-) in vitro. It was found that C2 exhibited the best anticancer activity. Further mechanistic investigation indicated that toxicological activity of C2 was ascribable to apoptosis rather than anti-proliferative activity. Apoptosis was induced through up-regulating the level of Bcl-2/Bax as well as the activation of caspase-3. The results demonstrate that heterocyclic organobismuth(III) complexes of this type have great potential in the treatment of cancer. PMID- 28865279 TI - Design, synthesis and biological evaluation of novel C-29 carbamate celastrol derivatives as potent and selective cytotoxic compounds. AB - Celastrol and its derivatives have been reported for their potent anticancer activity. Among other celastrol analogues, novel carbamate derivatives were designed and synthesised, and their biological activity on the viability of human cancer cell lines was evaluated. Additionally, a preliminary structure-activity relationship study was conducted. Derivative 18 showed the highest activity on cancer cell viability, combined with the best selectivity between malignant cells and non-malignant fibroblasts. Preliminary mechanistic studies of its anti-tumour action indicated that compound 18 has an antiproliferative effect on SKOV-3 human ovarian cancer cells (IC50 = 0.54 MUM). The results also suggested that its potent anticancer activity is mediated by apoptosis, and that this process was mainly the result of the activation of the extrinsic apoptotic pathway. Moreover, our results demonstrated the potential of derivative 18 as a new agent for combinatorial drug therapy for ovarian cancer. PMID- 28865281 TI - Design strategies in the prodrugs of HIV-1 protease inhibitors to improve the pharmaceutical properties. AB - Combination antiretroviral therapy (cART) is currently the most effective treatment for HIV-1 infection. HIV-1 protease inhibitors (PIs) are an important component of some regimens of cART. However, PIs are known for sub-optimal ADME properties, resulting in poor oral bioavailability. This often necessitates high drug doses, combination with pharmacokinetic enhancers and/or special formulations in order to effectively deliver PIs, which may lead to a high pill burden and reduced patient compliance. As a remedy, improving the ADME properties of existing drugs via prodrug and other approaches has been pursued in addition to the development of next generation PIs with improved pharmacokinetic, resistance and side effect profiles. Phosphate prodrugs have been explored to address the solubility-limiting absorption and high excipient load. Prodrug design to target carrier-mediated drug delivery has also been explored. Amino acid prodrugs have been shown to improve permeability by engaging active transport mechanisms, reduce efflux and mitigate first pass metabolism while acyl migration prodrugs have been shown to improve solubility. Prodrug design efforts have led to the identification of one marketed agent, fosamprenavir, and clinical studies with two other prodrugs. Several of the reported approaches lack detailed in vivo characterization and hence the potential preclinical or clinical benefits of these approaches are yet to be fully determined. PMID- 28865280 TI - Synthesis, in vitro beta-glucuronidase inhibitory potential and molecular docking studies of quinolines. AB - In this study synthesis and beta-glucuronidase inhibitory potential of 3/5/8 sulfonamide and 8-sulfonate derivatives of quinoline (1-40) are discussed. Studies reveal that all the synthetic compounds were found to have good inhibitory activity against beta-glucuronidase. Nonetheless, compounds 1, 2, 5, 13, and 22-24 having IC50 values in the range of 1.60-8.40 MUM showed superior activity than the standard saccharic acid 1,4-lactone (IC50 = 48.4 +/- 1.25 MUM). Moreover, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites. Structures of all the synthetic compounds were confirmed through 1H NMR, EI-MS and HREI-MS spectroscopic techniques. PMID- 28865282 TI - Social capital and antenatal depression among Chinese primiparas: A cross sectional survey. AB - The aim of this study is to investigate the associations between social capital and antenatal depression among Chinese primiparas. A cross-sectional design was used and a questionnaire survey was conducted with 1471 participants using the intercept method at the provincial hospital in Zhejiang in 2016. Antenatal depression was evaluated using the Edinburgh Postnatal Depression Scale (EPDS) and social capital was assessed by the Chinese version of Social Capital Assessment Questionnaire (C-SCAQ). The prevalence of antenatal depression was assessed among Chinese primiparas in their third trimesters. The antenatal depression prevalence among sub-groups with lower social trust (ST), social reciprocity (SR), social network (SN), and social participation (SP) were significantly higher than those among higher score sub-groups. In the fully adjusted model, primiparas' antenatal depression was significantly associated with ST, SR, SN, and SP. Compared to the structural social capital, the cognitive social capital was a more crucial dimension to the prevalence of antenatal depression. For future community pregnancy health care management programs in China, it might be beneficial to add more social capital related intervention. PMID- 28865283 TI - The supramarginal and angular gyri underlie orthographic competence in Spanish language. AB - Orthographic competence allows automatic word recognition and reading fluency. To elucidate how the orthographic competence in Spanish-speaking adults might affect the neurofunctional mechanisms of visual word recognition, 32 young adults equally divided in two groups (HSS: High Spelling Skills, and LSS: Low Spelling Skills) were evaluated using fMRI methods, while they performed an orthographic recognition task involving pseudohomophones. HSS achieved significantly more correct responses and lower reaction times than LSS. Interestingly, LSS showed greater activation in the left angular and supramarginal regions with increased bilateral activation pattern in the inferior frontal gyrus, and the anterior temporal and posterior parietal regions. In contrast, HSS showed a more left lateralized pattern over these regions along with higher activation of the anterior cingulated gyrus for misspelled words. Results suggest that the differences found in cortical activation patterns might be explained by the higher degree of specialization for word recognition in HSS, a group of participants that due to their greater orthographic skills require less engagement of processing resources to succeed in the task. PMID- 28865285 TI - Towards an integrative model of visual short-term memory maintenance: Evidence from the effects of attentional control, load, decay, and their interactions in childhood. AB - Over the past decades there has been a surge of research aiming to shed light on the nature of capacity limits to visual short-term memory (VSTM). However, an integrative account of this evidence is currently missing. We argue that investigating parameters constraining VSTM in childhood suggests a novel integrative model of VSTM maintenance, and that this in turn informs mechanisms of VSTM maintenance in adulthood. Over 3 experiments with 7-year-olds and young adults (total N=206), we provide evidence for multiple cognitive processes interacting to constrain VSTM performance. While age-related increases in storage capacity are undisputable, we replicate the finding that attentional processes control what information will be encoded and maintained in VSTM in the face of increased competition. Therefore, a central process to the current model is attentional refreshment, a mechanism that it is thought to reactivate and strengthen the signal of the visual representations. Critically, here we also show that attentional influences on VSTM are further constrained by additional factors, traditionally studied to the exclusion of each other, such as memory load and temporal decay. We propose that these processes work synergistically in an elegant manner to capture the adult-end state, whereas their less refined efficiency and modulations in childhood account for the smaller VSTM capacity that 7-year-olds demonstrate compared to older individuals. We conclude that going beyond the investigation of single cognitive mechanisms, to their interactions, holds the promise to understand both developing and fully developed maintenance in VSTM. PMID- 28865286 TI - The influence of time on task on mind wandering and visual working memory. AB - Working memory relies on executive resources for successful task performance, with higher demands necessitating greater resource engagement. In addition to mnemonic demands, prior studies suggest that internal sources of distraction, such as mind wandering (i.e., having off-task thoughts) and greater time on task, may tax executive resources. Herein, the consequences of mnemonic demand, mind wandering, and time on task were investigated during a visual working memory task. Participants (N=143) completed a delayed-recognition visual working memory task, with mnemonic load for visual objects manipulated across trials (1 item=low load; 2 items=high load) and subjective mind wandering assessed intermittently throughout the experiment using a self-report Likert-type scale (1=on-task, 6=off task). Task performance (correct/incorrect response) and self-reported mind wandering data were evaluated by hierarchical linear modeling to track trial-by trial fluctuations. Performance declined with greater time on task, and the rate of decline was steeper for high vs low load trials. Self-reported mind wandering increased over time, and significantly varied asa function of both load and time on task. Participants reported greater mind wandering at the beginning of the experiment for low vs. high load trials; however, with greater time on task, more mind wandering was reported during high vs. low load trials. These results suggest that the availability of executive resources in support of working memory maintenance processes fluctuates in a demand-sensitive manner with time on task, and may be commandeered by mind wandering. PMID- 28865284 TI - The relationship between consumer, clinician, and organizational characteristics and use of evidence-based and non-evidence-based therapy strategies in a public mental health system. AB - We investigated the relationship between consumer, clinician, and organizational factors and clinician use of therapy strategies within a system-wide effort to increase the use of cognitive-behavioral therapy. Data from 247 clinicians in 28 child-serving organizations were collected. Clinicians participating in evidence based practice training initiatives were more likely to report using cognitive behavioral therapy when they endorsed more clinical experience, being salaried clinicians, and more openness to evidence-based practice. Clinicians participating in evidence-based practice initiatives were more likely to use psychodynamic techniques when they had older clients, less knowledge about evidence-based practice, more divergent attitudes toward EBP, higher financial strain, and worked in larger organizations. In clinicians not participating in evidence-based training initiatives; depersonalization was associated with higher use of cognitive-behavioral; whereas clinicians with less knowledge of evidence based practices were more likely to use psychodynamic techniques. This study suggests that clinician characteristics are important when implementing evidence based practices; and that consumer, clinician, and organizational characteristics are important when de-implementing non evidence-based practices. This work posits potential characteristics at multiple levels to target with implementation and deimplementation strategies. PMID- 28865287 TI - Do silhouettes and photographs produce fundamentally different object-based correspondence effects? AB - When participants classify pictures of objects as upright or inverted with a left or right keypress, responses are faster if the response location (left/right) corresponds with the location of a handle (left/right) than if it does not. This result has typically been attributed to a grasping affordance (automatic activation of muscles associated with grasping the object with the ipsilateral hand), but several findings have indicated instead that the effect is a spatial correspondence effect, much like the Simon effect for object location. Pappas (2014) reported evidence he interpreted as showing that spatial coding predominates with silhouettes of objects, whereas photographs of objects yield affordance-based effects. We conducted two experiments similar to those of Pappas, using frying pans as stimuli, with our two experiments differing in whether the entire object was centered on the display screen or the base was centered. When the objects were centered, a positive correspondence effect relative to the handle was evident for the silhouettes but a negative correspondence effect for the photographs. When the base was centered, the handle was clearly located to the left or right side of the display, and both silhouettes and photographs produced correspondence effects of similar size relative to the handle location. Despite the main results being counter to the grasping affordance hypothesis, response-time distribution analyses suggest that, instead of activating automatically at fast responses, an effector-specific component of the hypothesized type may come into play for responses that are selected after the handle location has been identified. PMID- 28865288 TI - Why consistent completion criterion are required in childhood weight management programmes. AB - OBJECTIVES: Current research in the field of childhood weight management (WM) effectiveness is hampered by inconsistent terminology and criterion for WM programme completion, alongside other engagement-related concepts (e.g. adherence, dropout and attrition). Evidence reviews are not able to determine conclusive intervention effectiveness because of this issue. This study aims to quantify how various completion criterion impacts upon on: 1) the percentage of WM completers; 2) the standardised body mass index (BMI SDS) reduction; and 3) the predictors of WM completion. STUDY DESIGN: A methodological, sensitivity analysis to examine how differential completion criterion affect programme outcomes and predictors. METHODS: Secondary data of 2948 children were used. All children attended a MoreLife WM programme between 2009 and 2014. The completion criterion was incrementally adjusted by 10% (i.e. completer attends 10%, 20%, 30%... of sessions) for research aims 1-2, with the percentage of completers and change in BMI SDS calculated at each increment. For aim 3, the stability (strength, direction and significance) of the predictors were examined when using the completion criterion of four alternative studies against our previous study (completion >=70% attendance). RESULTS: The volume of programme completers decreased in a linear manner as the completion criterion became more stringent (i.e. 70-100% attendance). The change in BMI SDS conversely became incrementally greater. The strength, direction and significance of the predictors was highly dependent on the completion criterion; the odds ratio varied by 24.2% across a single predictor variable (delivery period). The degree of change is evidenced in the paper. CONCLUSIONS: Inconsistent completion criterion greatly limits the synthesis of programme effectiveness and explains some of the inconsistency in the predictors of engagement. Standardised criterion for engagement-related terminology are called for. PMID- 28865289 TI - DNA polymerase iota: The long and the short of it! AB - The cDNA encoding human DNA polymerase iota (POLI) was cloned in 1999. At that time, it was believed that the POLI gene encoded a protein of 715 amino acids. Advances in DNA sequencing technologies led to the realization that there is an upstream, in-frame initiation codon that would encode a DNA polymerase iota (poliota) protein of 740 amino acids. The extra 25 amino acid region is rich in acidic residues (11/25) and is reasonably conserved in eukaryotes ranging from fish to humans. As a consequence, the curated Reference Sequence (RefSeq) database identified poliota as a 740 amino acid protein. However, the existence of the 740 amino acid poliota has never been shown experimentally. Using highly specific antibodies to the 25 N-terminal amino acids of poliota, we were unable to detect the longer 740 amino acid (iota-long) isoform in western blots. However, trace amounts of the iota-long isoform were detected after enrichment by immunoprecipitation. One might argue that the longer isoform may have a distinct biological function, if it exhibits significant differences in its enzymatic properties from the shorter, well-characterized 715 amino acid poliota. We therefore purified and characterized recombinant full-length (740 amino acid) poliota-long and compared it to full-length (715 amino acid) poliota-short in vitro. The metal ion requirements for optimal catalytic activity differ slightly between iota-long and iota-short, but under optimal conditions, both isoforms exhibit indistinguishable enzymatic properties in vitro. We also report that like iota-short, the iota-long isoform can be monoubiquitinated and polyubiuquitinated in vivo, as well as form damage induced foci in vivo. We conclude that the predominant isoform of DNA poliota in human cells is the shorter 715 amino acid protein and that if, or when, expressed, the longer 740 amino acid isoform has identical properties to the considerably more abundant shorter isoform. PMID- 28865290 TI - Erythrocyte membrane-encapsulated celecoxib improves the cognitive decline of Alzheimer's disease by concurrently inducing neurogenesis and reducing apoptosis in APP/PS1 transgenic mice. AB - Alzheimer's disease (AD) is characterized by the loss of neurogenesis and excessive induction of apoptosis. The induction of neurogenesis and inhibition of apoptosis may be a promising therapeutic approach to combating the disease. Celecoxib (CB), a cyclooxygenase-2 specific inhibitor, could offer neuroprotection. Specifically, the CB-encapsulated erythrocyte membranes (CB RBCMs) sustained the release of CB over a period of 72 h in vitro and exhibited high brain biodistribution efficiency following intranasal administration, which resulted in the clearance of aggregated beta-amyloid proteins (Abeta) in neurons. The high accumulation of the CB-RBCMs in neurons resulted in a decrease in the neurotoxicity of CB and an increase in the migratory activity of neurons, and alleviated cognitive decline in APP/PS1 transgenic (Tg) mice. Indeed, COX-2 metabolic products including prostaglandin E2 (PGE2) and PGD2, PGE2 induced neurogenesis by enhancing the expression of SOD2 and 14-3-3zeta, and PGD2 stimulated apoptosis by increasing the expression of BIK and decreasing the expression of ARRB1. To this end, the CB-RBCMs achieved better effects on concurrently increasing neurogenesis and decreasing apoptosis than the phospholipid membrane-encapsulated CB liposomes (CB-PSPD-LPs), which are critical for the development and progression of AD. Therefore, CB-RBCMs provide a rational design to treat AD by promoting the self-repairing capacity of the brain. PMID- 28865291 TI - Advances in polymeric islet cell encapsulation technologies to limit the foreign body response and provide immunoisolation. AB - Islet transplantation for the treatment of type 1 diabetes (T1D) is hampered by the shortage of donor tissue and the need for life-long immunosuppression. The engineering of materials to limit host immune rejection opens the possibilities of utilising allogeneic and even xenogeneic cells without the need for systemic immunosuppression. Here we discuss the most recent developments in immunoisolation of transplanted cells using advanced polymeric biomaterials, utilising macroscale to nanoscale approaches, to limit aberrant immune responses. PMID- 28865292 TI - Pyrazole-hydrazone derivatives as anti-inflammatory agents: Design, synthesis, biological evaluation, COX-1,2/5-LOX inhibition and docking study. AB - A new series of pyrazole-hydrazone derivatives 4a-i were designed and synthesized, their chemical structures were confirmed by IR, 1H NMR, 13C NMR, MS spectral data and elemental analysis. IC50 values for all prepared compounds to inhibit COX-1, COX-2 and 5-LOX enzymes were determined in vitro. Compounds 4a (IC50=0.67MUM) and 4b (IC50=0.58MUM) showed better COX-2 inhibitory activity than celecoxib (IC50=0.87MUM) with selectivity index (SI=8.41, 10.55 in sequent) relative to celecoxib (SI=8.85). Also, compound 4a and 4b exhibited superior inhibitory activity against 5-LOX (IC50=1.92, 2.31MUM) higher than zileuton (IC50=2.43MUM). All target pyrazoles were screened for their ability to reduce nitric oxide production in LPS stimulated peritoneal macrophages. Compounds 4a, 4b, 4f and 4i displayed concentration dependent reduction and were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compound 4f showed the highest anti-inflammatory activity (% edema inhibition=15 20%) at all doses when compared to reference drug celecoxib (% edema inhibition=15.7-17.5%). Docking studies were carried out to investigate the interaction of target compounds with COX-2 enzyme active site. PMID- 28865293 TI - A new lignan and a new alkaloid, and alpha-glucosidase inhibitory compounds from the grains of Echinochloa utilis Ohwi & Yabuno. AB - A new lignan, utilisin (1), and a new alkaloid, echinoutilin (2), together with eleven known compounds 3-13 were isolated from the grains of Echinochloa utilis Ohwi & Yabuno. Their structures were identified through the analysis of spectroscopic data. The absolute configuration of 2 was determined by Mosher's method. These compounds were evaluated for alpha-glucosidase inhibitory activity. Among them, compounds 2, 3 and 6 exhibited considerable alpha-glucosidase inhibitory activity with IC50 values of 42.1+/-1.3, 58.9+/-3.7, and 40.9+/ 1.1MUM, respectively. The results indicate that the grains of E. utilis will be useful in the treatment of diabetes control agents. PMID- 28865294 TI - Thiazolo[4,5-d]pyridazine analogues as a new class of dihydrofolate reductase (DHFR) inhibitors: Synthesis, biological evaluation and molecular modeling study. AB - A new series of 1,3-thiazoles and thiazolo[4,5-d]pyridazine both bearing the 2 thioureido function were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activities. Compound 26 proved to be the most active DHFR inhibitor (IC50 of 0.06MUM). Compound 4, 20 and 21 showed in vitro antitumor activity against a collection of cancer cell lines. Compound 26 proved lethal to HS 578T breast cancer cell line with IC50 value of 0.8MUM, inducing cell cycle arrest and apoptosis. Molecular modeling studies concluded that recognition with key amino acids Phe 31 and Arg 22 is essential for DHFR binding. The obtained model could be useful for the development of new class of DHFR inhibitors. PMID- 28865296 TI - Peroxiredoxin 6 phospholipid hydroperoxidase activity in the repair of peroxidized cell membranes. AB - Although lipid peroxidation associated with oxidative stress can result in cellular death, sub-lethal lipid peroxidation can gradually resolve with return to the pre-exposure state. We have shown that resolution of lipid peroxidation is greatly delayed in lungs or cells that are null for peroxiredoxin 6 (Prdx6) and that both the phospholipase A2 and the GSH peroxidase activities of Prdx6 are required for a maximal rate of recovery. Like other peroxiredoxins, Prdx6 can reduce H2O2 and short chain hydroperoxides, but in addition can directly reduce phospholipid hydroperoxides. This study evaluated the relative role of these two different peroxidase activities of Prdx6 in the repair of peroxidized cell membranes. The His26 residue in Prdx6 is an important component of the binding site for phospholipids. Thus, we evaluated the lungs from H26A-Prdx6 expressing mice and generated H26A-Prdx6 expressing pulmonary microvascular endothelial cells (PMVEC) by lentiviral infection of Prdx6 null cells to compare with wild type in the repair of lipid peroxidation. Isolated lungs and PMVEC were exposed to tert-butyl hydroperoxide and mice were exposed to hyperoxia (> 95% O2). Assays for lipid peroxidation in wild type control and mutant lungs and cells showed ~4 fold increase at end-exposure. Control lungs and cells showed gradual resolution during a post-exposure recovery period. However, there was no recovery from lipid peroxidation by H26A-Prdx6 lungs or PMVEC. These studies confirm an important role for Prdx6 in recovery from membrane lipid peroxidation and indicate that reduction of H2O2 or short chain hydroperoxides does not play a role in the recovery process. PMID- 28865295 TI - Observation of directional storybook reading influences young children's counting direction. AB - Even before formal schooling, children map numbers onto space in a directional manner. The origin of this preliterate spatial-numerical association is still debated. We investigated the role of enculturation for shaping the directionality of the association between numbers and space, focusing on counting behavior in 3- to 5-year-old preliterate children. Two studies provide evidence that, after observing reading from storybooks (left-to-right or right-to-left reading) children change their counting direction in line with the direction of observed reading. Just observing visuospatial directional movements had no such effect on counting direction. Complementarily, we document that book illustrations, prevalent in children's cultures, exhibit directionality that conforms to the direction of a culture's written language. We propose that shared book reading activates spatiotemporal representations of order in young children, which in turn affect their spatial representation of numbers. PMID- 28865297 TI - Effects of hCG and salmon gonadoliberine analogue on spermiation in the Eurasian perch (Perca fluviatilis). AB - This study analysed (i) the effect of human chorionic gonadotropin (hCG) and salmon gonadoliberine analogue (sGnRHa) on the effectiveness of induction of spermiation and (ii) the effect of latency time following the application of those spawning agents on the quantity and quality of the sperm of Eurasian perch, Perca fluviatilis, obtained during out-of-season spawning. For this study, pond reared fish were used which had been acclimated to the controlled conditions. Three groups were distinguished which were treated with either saline (0.9% NaCl; control group), hCG (500 IU kg-1) or sGnRHa (100 MUg kg-1). The fish were kept in a recirculating system at 12 degrees C throughout the study, during which sperm was collected every two days between the 2nd and 10th day following hormonal treatment. During the study, quantitative (e.g. sperm volume, total sperm production) and qualitative (measured with a computer-assisted sperm analysis system - i.e. CASA) parameters were monitored. The results of the study indicate that the hormonal treatment had a highly beneficial effect on the spermiation rate (100% in experimental groups from day 6 following injection) as well as quantity, which increased 50% in experimental groups (over 2200 * 109 of spermatozoa per kg of body weight) by day 4 following injection. For the sperm quality, both spawning agents tested had a rather positive effect, although sperm motility rate (MOT) was seen to be significantly reduced on day 10 following the application of hCG (MOT = 72.8% +/- 8.1), which was not observed after the application of sGnRHa (minimum mean MOT 81.7% +/- 6.1). The results clearly indicate that hormonal treatment had a positive effect on spermiation in Eurasian perch, most apparent from day 6 following injection, regardless of the hormonal agent used. Though application of sGnRHa allowed a high volume of high quality sperm to be stripped for two days longer (up to day 10 post-injection) compared to the application of hCG. PMID- 28865298 TI - Cognitive ability across the life course and cortisol levels in older age. AB - Elevated cortisol levels have been hypothesized to contribute to cognitive aging, but study findings are inconsistent. In the present study, we examined the association between salivary cortisol in older age and cognitive ability across the life course. We used data from 370 members of the 36-Day Sample of the Scottish Mental Survey 1947, who underwent cognitive testing at age 11 years and were then followed up at around age 78 years, completing further cognitive tests and providing diurnal salivary cortisol samples. We hypothesized that higher cortisol levels would be associated with lower cognitive ability in older age and greater cognitive decline from childhood to older age but also lower childhood cognitive ability. Few of the tested associations were significant, and of those that were, most suggested a positive relationship between cortisol and cognitive ability. Only 1 cognitive measure showed any sign of cortisol-related impairment. However, after correcting for multiple comparisons, no results remained significant. These findings suggest that cortisol may not play an important role in cognitive aging across the life course. PMID- 28865299 TI - Airway management: Utilizing radiologist expertise and neuroimaging with head and neck masses. PMID- 28865300 TI - Technical feasibility of personalized articulating knee joint distraction for treatment of tibiofemoral osteoarthritis. AB - BACKGROUND: Knee osteoarthritis is a highly prevalent degenerative joint disorder characterized by joint tissue damage and pain. Knee joint distraction has been introduced as a joint preserving surgical procedure to postpone knee arthroplasty. An often used standard externally fixation device for distraction poses a burden to patients due to the absence of joint flexion during the 6weeks treatment. Therefore, a personalized articulating distraction device was developed. The aim of this study was to test technical feasibility of this device. METHODS: Based on an often applied rigid device, using equal bone pin positions and connectors, a hinge mechanism was developed consisting of a cam following system for reproducing the complex joint-specific knee kinematics. In support, a device was developed for capturing the joint-specific sagittal plane articulation. The obtained kinematic data were translated into joint-specific cam shapes that were installed bilaterally in the hinge mechanism of the distraction device, as such providing personalized knee motion. Distraction of 5mm was performed within a range of motion of 30deg. joint flexion. Pre-clinical evaluation of the working principle was performed on human cadaveric legs and system stiffness characteristics were biomechanically evaluated. FINDINGS: The desired range of motion was obtained and distraction was maintained under physiologically representative loading. Moreover, the joint-specific approach demonstrated tolerance of deviations from anatomical and alignment origin during initial placement of the developed distraction device. INTERPRETATION: Articulation during knee distraction is considered technically feasible and has potential to decrease burden and improve acceptance of distraction therapy. Testing of clinical feasibility is warranted. PMID- 28865301 TI - Misidentified Human Gene Functions with Mouse Models: The Case of the Retinoblastoma Gene Family in Senescence. AB - Although mice models rank among the most widely used tools for understanding human genetics, biology, and diseases, differences between orthologous genes among species as close as mammals are possible, particularly in orthologous gene pairs in which one or more paralogous (i.e., duplicated) genes appear in the genomes of the species. Duplicated genes can possess overlapping functions and compensate for each other. The retinoblastoma gene family demonstrates typical composite functionality in its three member genes (i.e., RB1, RB2/P130, and P107), all of which participate in controlling the cell cycle and associated phenomena, including proliferation, quiescence, apoptosis, senescence, and cell differentiation. We analyzed the role of the retinoblastoma gene family in regulating senescence in mice and humans. Silencing experiments with each member of the gene family in mesenchymal stromal cells (MSCs) and fibroblasts from mouse and human tissues demonstrated that RB1 may be indispensable for senescence in mouse cells, but not in human ones, as an example of species specificity. Furthermore, although RB2/P130 seems to be implicated in maintaining human cell senescence, the function of RB1 within any given species might differ by cell type, as an example of cell specificity. For instance, silencing RB1 in mouse fibroblasts induced a reduced senescence not observed in mouse MSCs. Our findings could be useful as a general paradigm of cautions to take when inferring the role of human genes analyzed in animal studies and when examining the role of the retinoblastoma gene family in detail. PMID- 28865302 TI - Coordination difficulties in preschool-aged children are associated with maternal parenting stress: A community-based cross-sectional study. AB - BACKGROUND: Although coordination difficulties are sometimes observed even in children in the general population, no empirical studies have examined the impact of these difficulties on parenting stress. AIMS: The aim of this study was to elucidate the relationship between coordination difficulties and parenting stress in a community-based sample of preschool-aged children and their mothers. METHODS: The study included 1691 families. Mothers with 4- or 5-year-old children completed questionnaires about parenting stress and children's coordination difficulties, as well as traits associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). RESULTS: The results of hierarchical multiple regression analyses showed that coordination difficulties, and ADHD and ASD traits were each independent predictors of parenting stress. Among the significant predictive factors, impaired general coordination, as well as hyperactivity-impulsivity, showed a strong impact on parenting stress. In addition, a gender difference was observed in the manner in which coordination difficulties influenced parenting stress. CONCLUSIONS: Coordination difficulties in preschool-aged children in the general population increased maternal parenting stress (as did ADHD and ASD traits). This highlights the need to provide support for mothers who have children with coordination difficulties, even when there is no clinical diagnosis. PMID- 28865304 TI - Hypocoagulability as assessed by thrombin generation test in newly-diagnosed patients with multiple myeloma. PMID- 28865305 TI - Leaving moss and litter layers undisturbed reduces the short-term environmental consequences of heathland managed burns. AB - Variation in the structure of ground fuels, i.e. the moss and litter (M/L) layer, may be an important control on fire severity in heather moorlands and thus influence vegetation regeneration and soil carbon dynamics. We completed experimental fires in a Calluna vulgaris-dominated heathland to study the role of the M/L layer in determining (i) fire-induced temperature pulses into the soil and (ii) post-fire soil thermal dynamics. Manually removing the M/L layer before burning increased fire-induced soil heating, both at the soil surface and 2 cm below. Burnt plots where the M/L layer was removed simulated the fuel structure after high severity fires where ground fuels are consumed but the soil does not ignite. Where the M/L layer was manually removed, either before or after the fire, post-fire soil thermal dynamics showed larger diurnal and seasonal variation, as well as similar patterns to those observed after wildfires, compared to burnt plots where the M/L layer was not manipulated. We used soil temperatures to explore potential changes in post-fire soil respiration. Simulated high fire severity (where the M/L layer was manually removed) increased estimates of soil respiration in warm months. With projected fire regimes shifting towards higher severity fires, our results can help land managers develop strategies to balance ecosystem services in Calluna-dominated habitats. PMID- 28865303 TI - Defects at the crossroads of GABAergic signaling in generalized genetic epilepsies. AB - Seizure disorders are very common and affect 3% of the general population. The recurrent unprovoked seizures that are also called epilepsies are highly diverse as to both underlying genetic basis and clinic presentations. Recent genetic advances and sequencing technologies indicate that many epilepsies previously thought to be without known causes, or idiopathic generalized epilepsies (IGEs), are virtually genetic epilepsy as they are caused by genetic variations. IGEs are estimated to account for ~15-20% of all epilepsies. Initially IGEs were primarily considered channelopathies, because the first genetic defects identified in IGEs involved ion channel genes. However, new findings indicate that mutations in many non ion channel genes are also involved in addition to those in ion channel genes. Interestingly, mutations in many genes associated with epilepsy affect GABAergic signaling, a major biological pathway in epilepsy. Additionally, many antiepileptic drugs work via enhancing GABAergic signaling. Hence, the review will focus on the mutations that impair GABAergic signaling and selectively discuss the newly identified STXBP1, PRRT2, and DNM1 in addition to those long established epilepsy ion channel genes that also impair GABAergic signaling like SCN1A and GABAA receptor subunit genes. GABAergic signaling includes the pre- and post- synaptic mechanisms. Some mutations, such as STXBP1, PRRT2, DNM1, and SCN1A, impair GABAergic signaling mainly via pre-synaptic mechanisms while those mutations in GABAA receptor subunit genes impair GABAergic signaling via post synaptic mechanisms. Nevertheless, these findings suggest impaired GABAergic signaling is a converging pathway of defects for many ion channel or non ion channel mutations associated with genetic epilepsies. PMID- 28865306 TI - Natural ecosystem mimicry in traditional dryland agroecosystems: Insights from an empirical and holistic approach. AB - While the aim of Ecological Intensification is to enable the design of more sustainable and productive agricultural systems, it is not suited to dryland agroecosystems that are driven by non-equilibrium dynamics and intrinsic variability. Instead, a model based on mobility and variability management has been proposed for these agroecosystems. However, this model remains under-applied in southern Morocco where there have been few studies on the functioning of traditional agroecosystems. This paper focuses on an agroecosystem in the Moroccan Saharan fringe zone that combines agriculture and pastoralism in an acacia parkland. A grounded theory approach was used over a three-year investigation period (i) to highlight how agro-pastoral activities interface with environmental variability, and (ii) to analyze the formal and informal institutions that support these activities. Results show that farmers interface with rainfall variability through (i) an opportunistic agricultural calendar, (ii) a variation of cultivated areas, and (iii) crop diversification. Herders combine macro-mobility (nomads move over long distances to track rainfall) and micro-mobility (nomadic and sedentary herds are driven on a daily basis around settlements) to optimize the exploitation of ecological heterogeneity. During droughts, they also resort to State-subsidized forage supplies. Both cultivation and pastoral activities tend to interface with ecological dynamics and to mimic nature, resulting in a human-modified parkland that could be considered as a 'green agroecosystem'. The sustainability of natural resource use relies on flexible property rights, backed up by a social and cultural norm-based regulation system, that allow crop-livestock integration and landscape collective management. Despite encouraging results, the agroecosystem appears to be threatened by current agricultural policies, rural exodus and the lack of social recognition of nomadism. Nevertheless, because ecosystem mimicry of nature is often considered as a sound agricultural model for drylands, this case study could provide a basis for local development policies, and thus merits further attention from local managers and researchers. PMID- 28865307 TI - Active MgO-SiO2 hybrid material for organic dye removal: A mechanism and interaction study of the adsorption of C.I. Acid Blue 29 and C.I. Basic Blue 9. AB - A comparative analysis was performed concerning the removal of two different organic dyes from model aqueous solution using an inorganic oxide adsorbent. The key element of the study concerns evaluation of the influence of the dyes' structure and their acid-base character on the efficiency of the adsorption process. The selection of sorbent material for this research - an MgO-SiO2 oxide system synthesized via a modified sol-gel route - is also not without significance. The relatively high porous structure parameters of this material (ABET = 642 m2/g, Vp = 1.11 mL and Sp = 9.8 nm) are a result of the proposed methodology for its synthesis. Both organic dyes (C.I. Acid Blue 29 and C.I. Basic Blue 9) were subjected to typical batch adsorption tests, including investigation of such process parameters as time, initial adsorbate concentration, adsorbent dose, pH and temperature. An attempt was also made to estimate the sorption capacity of the oxide material with respect to the analyzed organic dyes. To achieve the objectives of the research - determine the efficiency of adsorption - it was important to perform a thorough physicochemical analysis of the adsorbents (e.g. FTIR, elemental analysis and porous structure parameters). The results confirmed the significantly higher affinity of the basic dye to the oxide adsorbents compared with the acidic dye. The regeneration tests, which indirectly determine the nature of the adsorbent/adsorbate interactions, provide further evidence for this finding. On this basis, a probable mechanism of dyes adsorption on the MgO-SiO2 oxide adsorbent was proposed. PMID- 28865308 TI - Hydrogen sulfide emissions from a swine building affected by dietary crude protein. AB - Hydrogen sulfide (H2S) is a toxic air pollutant at animal facilities; but the understanding of its generation and emission processes has been limited. This paper studied H2S emissions during a complete cycle of wean-finish pigs from a research building, where 12 pig rooms were divided into three groups that were fed with standard feed (control), and 2.1-3.8% (T1) and 4.4-7.8% (T2) reduced dietary crude protein (CP) feed. The group cycle mean H2S emission rates were 4.0 +/- 2.9, 4.3 +/- 3.2, and 5.4 +/- 4.0 g d-1 AU-1 (Animal Unit = 500 kg live mass), respectively, for the control, T1, and T2 groups. Emissions of H2S were promoted by 10.0 and 36.7%, respectively, for the T1 and T2 groups (p < 0.001), although large variabilities existed in the emissions from different rooms within the same groups. The enhanced H2S emissions from the T1 and T2 groups were related to the reduced manure pH and were possibly affected through a number of pathways, which could involve volatile fatty acids and nitrogen concentrations, and microbial activities in manure. PMID- 28865309 TI - Electrocoagulation treatment of raw landfill leachate using iron-based electrodes: Effects of process parameters and optimization. AB - The main problem of landfill leachate is its diverse composition comprising many persistent organic pollutants which must be removed before being discharge into the environment. This study investigated the treatment of raw landfill leachate using electrocoagulation process. An electrocoagulation system was designed with iron as both the anode and cathode. The effects of inter-electrode distance, initial pH and electrolyte concentration on colour and COD removals were investigated. All these factors were found to have significant effects on the colour removal. On the other hand, electrolyte concentration was the most significant parameter affecting the COD removal. Numerical optimization was also conducted to obtain the optimum process performance. Under optimum conditions (initial pH: 7.73, inter-electrode distance: 1.16 cm, and electrolyte concentration (NaCl): 2.00 g/L), the process could remove up to 82.7% colour and 45.1% COD. The process can be applied as a pre-treatment for raw leachates before applying other appropriate treatment technologies. PMID- 28865310 TI - Dynamic range of frontoparietal functional modulation is associated with working memory capacity limitations in older adults. AB - Older adults tend to over-activate regions throughout frontoparietal cortices and exhibit a reduced range of functional modulation during WM task performance compared to younger adults. While recent evidence suggests that reduced functional modulation is associated with poorer task performance, it remains unclear whether reduced range of modulation is indicative of general WM capacity limitations. In the current study, we examined whether the range of functional modulation observed over multiple levels of WM task difficulty (N-Back) predicts in-scanner task performance and out-of-scanner psychometric estimates of WM capacity. Within our sample (60-77years of age), age was negatively associated with frontoparietal modulation range. Individuals with greater modulation range exhibited more accurate N-Back performance. In addition, despite a lack of significant relationships between N-Back and complex span task performance, range of frontoparietal modulation during the N-Back significantly predicted domain general estimates of WM capacity. Consistent with previous cross-sectional findings, older individuals with less modulation range exhibited greater activation at the lowest level of task difficulty but less activation at the highest levels of task difficulty. Our results are largely consistent with existing theories of neurocognitive aging (e.g. CRUNCH) but focus attention on dynamic range of functional modulation asa novel marker of WM capacity limitations in older adults. PMID- 28865311 TI - NLRC5 promotes cell proliferation via regulating the NF-kappaB signaling pathway in Rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease and the pathogenesis remains unclear. Previous studies suggested that fibroblast-like synoviocytes (FLSs) play an important role in RA pathogenesis, including the injury of cartilage, the hyperplasia of the synovium and the release of inflammatory cytokines. We used complete Freund's adjuvant (CFA) induced rats as animal models for studying the RA pathogenesis. NLRC5 as the largest member of the NLR family has been reported to play a critical role in regulating immune responses. Increasing evidence suggests that NLRC5 is an pivotal negative modulator of inflammatory pathways. We investigated the mechanisms and signaling pathways of NLRC5 in RA progression. Significantly increased expression of NLRC5 was found in AA rats synovial tissues and cells. And high expression of inflammatory cytokine and cell proliferation of FLSs accompanied with NLRC5 overexpression, but inhibited in cells with NLRC5 silencing treatment. Interestingly, we found that overexpression of NLRC5 also coordinated the activation of NF-kappaB signaling pathway. These results suggested that NLRC5 promotes RA progression via the NF-kappaB signaling pathway potentially. PMID- 28865312 TI - Postural stability in subjects with temporomandibular disorders and healthy controls: A comparative assessment. AB - PURPOSE OF THE STUDY: The influence of the stomatognathic apparatus on body posture is a continuously discussed topic with contrasting results. The aim of this study is to analyze differences in postural stability between subjects with and without myogenous TMD. METHODS: 25 subjects affected by myogenous TMD according with DC/TMD (6 males, 19 females; mean age 31.75+/-6.68years) and a healthy control group of 19 subjects (4 Males, 15 Females; mean age 27.26+/ 3.85years) were enrolled in the study. Both groups underwent a posturo stabilometric force platform exam under different mandibular and visual conditions. Sway area and sway velocity of the COP (Center Of foot Pressure) posturo-stabilometric parameters were evaluated and compared applying Mann-U Whitney statistical test. RESULTS: The sway area and sway velocity parameters resulted statistically significantly higher in the TMD group (sway area p<0.01; sway velocity p<0.05) in mandibular maximum intercuspation and rest positions with eyes open. CONCLUSIONS: This study demonstrates a significant difference in body postural stability between subjects with myogenous TMD and healthy controls. In particular, sway area and sway velocity postural parameters are increased in these subjects. PMID- 28865313 TI - Autonomy facilitates repeated maximum force productions. AB - Performer autonomy (or self-control) has consistently been shown to enhance motor learning, and it can also provide immediate benefits for motor performance. Autonomy is also a key variable in the OPTIMAL theory of motor learning (Wulf & Lewthwaite, 2016). It is assumed to contribute to enhanced expectancies and goal action coupling, affecting performance effectiveness and efficiency. The purpose of the present study was to examine whether providing autonomy support by giving performers choices would enhance their ability to maintain maximum force levels. Participants were asked to repeatedly produce maximum forces using a hand dynamometer. After 2 initial trials with the dominant and non-dominant hand, stratified randomization was used to assign participants with the same average maximum force to one of two groups, choice or yoked control groups. Choice group participants were able to choose the order of hands (dominant, non-dominant) on the remaining trials (3 per hand). For control group participants, hand order was determined by choice-group counterparts. Maximum forces decreased significantly across trials in the control group, whereas choice group participants were able to maintain the maximum forces produced on the first trial. We interpret these findings as evidence that performer autonomy promotes movement efficiency. The results are in line with the view that autonomy facilitates the coupling of goals and actions (Wulf & Lewthwaite, 2016). PMID- 28865314 TI - Safety analysis of urban arterials at the meso level. AB - Urban arterials form the main structure of street networks. They typically have multiple lanes, high traffic volume, and high crash frequency. Classical crash prediction models investigate the relationship between arterial characteristics and traffic safety by treating road segments and intersections as isolated units. This micro-level analysis does not work when examining urban arterial crashes because signal spacing is typically short for urban arterials, and there are interactions between intersections and road segments that classical models do not accommodate. Signal spacing also has safety effects on both intersections and road segments that classical models cannot fully account for because they allocate crashes separately to intersections and road segments. In addition, classical models do not consider the impact on arterial safety of the immediately surrounding street network pattern. This study proposes a new modeling methodology that will offer an integrated treatment of intersections and road segments by combining signalized intersections and their adjacent road segments into a single unit based on road geometric design characteristics and operational conditions. These are called meso-level units because they offer an analytical approach between micro and macro. The safety effects of signal spacing and street network pattern were estimated for this study based on 118 meso-level units obtained from 21 urban arterials in Shanghai, and were examined using CAR (conditional auto regressive) models that corrected for spatial correlation among the units within individual arterials. Results showed shorter arterial signal spacing was associated with higher total and PDO (property damage only) crashes, while arterials with a greater number of parallel roads were associated with lower total, PDO, and injury crashes. The findings from this study can be used in the traffic safety planning, design, and management of urban arterials. PMID- 28865315 TI - On the use of naturalistic methods to examine safety-relevant behaviours amongst children and evaluate a cycling education program. AB - School-based cycling education programs aim to improve cycling safety and participation amongst children. Available research suggests that typical programs, which focus on bicycle manoeuvring skills, have limited effects on behaviour observed on a track or planned route. The current study uses theoretically more valid, naturalistic cycling data, to evaluate Safe Cycle, a program that incorporates hazard and self-awareness training. Soon after Safe Cycle was delivered at treatment schools, research bicycles instrumented with a rearward- and a forward-facing camera were loaned to six children from treatment schools and six children from (waitlist) control schools. In each group half the children were in Year 6, and half were in Year 7/8. Each child was instructed to ride the research bicycle instead of their own bicycle for the 1-2 weeks that they had a research bicycle. Video data were reduced using a purpose-designed coding scheme that identified whether participants performed specific safety relevant behaviours in appropriate circumstances. While the participants controlled their bicycles well, gave way appropriately to traffic at intersections, and stopped at red lights, participants frequently removed one or both hands from the handlebars, and seldom signalled turns, conducted over shoulder-checks when changing lanes, or looked in multiple directions at intersections (except when crossing a road). While aspects of design and small sample sizes limited evaluation findings, this research demonstrated the feasibility and potential of naturalistic data to support cycling education program evaluation. Further, the study substantially extended available naturalistic study of children's cycling behaviour to highlight behaviours which might be targeted by cycling safety initiatives. PMID- 28865317 TI - Photoprotection against UV-induced damage by skin-derived precursors in hairless mice. AB - BACKGROUND: Skin photodamage is associated with UV-induced overproduction of reactive oxygen species (ROS) and the inactivation of NF-E2-related factor 2 (Nrf2). Skin-derived precursor cells (SKPs), a population of dermal stem cells, are considered to be involved in wound repair and skin regeneration through the activation of Nrf2. However, no reports concentrate on the treatment of skin photodamage with SKPs. OBJECTIVE: To investigate the photoprotective role of SKPs against UV-induced damage in mice. METHODS: Fifty Balb/c hairless mice were divided into five groups (n=10), namely, normal (no intervention), model, prevention, treatment, and control groups. The latter four groups were dorsally exposed to UVA+UVB irradiation over a 2-week period. Mice in the prevention group received weekly SKP injections for 2weeks the day before irradiation. Mice in the treatment and Hanks groups received a two-time injection of SKPs and Hanks, respectively, after irradiation. One week after final intervention, skin appearance, pathological alterations, and oxidative indicators were evaluated by enzyme-linked immunosorbent assay, immunohistochemical analysis, and western blotting. RESULTS: After irradiation, lesions were observed on the dorsal skin of mice, including erythema, edema, scales, and wrinkles; however, these were significantly ameliorated by subcutaneous SKP injection. Hyperkeratosis, acanthosis, and spongiosis in the epidermis, as well as dermal papillae edema and inflammatory cell infiltration, were observed in both model and control groups; however, these conditions resolved with either pretreatment or posttreatment with SKPs. In addition, SKPs increased Nrf2, heme oxygenase-1, glutathione peroxidase, superoxide dismutase, catalase, and gluthathione expression, while decreasing levels of ROS, MDA, and H2O2. CONCLUSIONS: These findings suggest that SKPs have a photoprotective role against UV-induced damage in mice, which may be associated with their ability to scavenge photo-oxidative insults and activate Nrf2. PMID- 28865316 TI - Oxidative species-induced excitonic transport in tubulin aromatic networks: Potential implications for neurodegenerative disease. AB - Oxidative stress is a pathological hallmark of neurodegenerative tauopathic disorders such as Alzheimer's disease and Parkinson's disease-related dementia, which are characterized by altered forms of the microtubule-associated protein (MAP) tau. MAP tau is a key protein in stabilizing the microtubule architecture that regulates neuron morphology and synaptic strength. When MAP tau is degraded in tauopathic disorders, neuron dysfunction results. The precise role of reactive oxygen species (ROS) in the tauopathic disease process, however, is poorly understood. Classically, mitochondrial dysfunction has been viewed as the major source of oxidative stress and has been shown to precede tau and amyloid pathology in various dementias, but the exact mechanisms are not clear. It is known that the production of ROS by mitochondria can result in ultraweak photon emission (UPE) within cells. While of low intensity, surrounding proteins within the cytosol can still absorb these energetic photons via aromatic amino acids (e.g., tryptophan and tyrosine). One likely absorber of these photons is the microtubule cytoskeleton, as it forms a vast network spanning neurons, is highly co-localized with mitochondria, and shows a high density of aromatic amino acids. Functional microtubule networks may traffic this ROS-generated endogenous photon energy for cellular signaling, or they may serve as dissipaters/conduits of such energy to protect the cell from potentially harmful effects. Experimentally, after in vitro exposure to exogenous photons, microtubules have been shown to reorient and reorganize in a dose-dependent manner with the greatest effect being observed around 280nm, in the tryptophan and tyrosine absorption range. In this paper, recent modeling efforts based on ambient temperature experiment are presented, showing that tubulin polymers can feasibly absorb and channel these photoexcitations via resonance energy transfer, on the order of dendritic length scales and neuronal fine structure. Since microtubule networks are compromised in tauopathic diseases such as Alzheimer's and Parkinson's dementias, patients with these illnesses would be unable to support effective channeling of these photons for signaling or dissipation. Consequent emission surplus due to increased UPE production or decreased ability to absorb and transfer may lead to increased cellular oxidative damage, thus hastening the neurodegenerative process. PMID- 28865318 TI - Preparation and characterization of Fe3O4-Ag2O quantum dots decorated cellulose nanofibers as a carrier of anticancer drugs for skin cancer. AB - The Best performance drug delivery systems designed with Fe3O4-Ag2O quantum dots decorated cellulose nanofibers which that grafted with Etoposide and Methotrexate. Morphology properties were characterized by Scanning and Transmittance electron microscopy. The crystalline structure of prepared sample was evaluated using by X-ray diffraction. The vibrating sample magnetometer analysis was used for magnetic behavior of samples. The size distributions of Fe3O4-Ag2O QDs/Cellulose fibers nanocomposites indicate that the average diameter was 62.5nm. The Saturation magnetization (Ms) indicates the Fe3O4-Ag2O QDs/Cellulose fibers nanocomposites have ferromagnetic properties in nature. For make carrier, the Iron and Silver should be binds to cellulose nanofibers and to drug molecules and observe in UV-vis spectroscopy. The drug release kinetics was studied in vitro as spectrophotometrically. The release of Etoposide and Methotrexate were carried out with a constant speed, and the equilibrium reached at 24 and 30h with a total amount 78.94% and 63.84%, respectively. The results demonstrated that the obtained Fe3O4-Ag2O quantum dots/cellulose fibers nanocomposites could be applied for drug delivery systems. Cytotoxicity and antioxidant study confirmed the activity of the drug incorporated in nanocomposites. In addition, the cytotoxicity of drug was increased when loaded on nanocomposites, compared to pure Fe3O4-Ag2O quantum dots/cellulose fibers nanocomposites. PMID- 28865319 TI - Comparative in vitro study of photodynamic activity of hypericin and hypericinates in MCF-7 cells. AB - In this work we present a comparative in vitro study of photodynamic activity between hypericin (HYP) and some hypericinates (hypericin ionic pair with lysine or N-methylglucamine) in human mammary adenocarcinoma cells (MCF-7). The toxicity and phototoxicity of hypericin and hypericinates were compared, as well as their cellular uptake and localization and mutagenic, genotoxic and clonogenic capacity. Our results demonstrate that different cationic moieties promote differences in the hypericinate solubility in a biological environment, and can influence the cellular localization and the phototoxicity of the photosensitizer. It was verified that hypericinates have better efficiency to generate singlet oxygen than HYP, and a lower aggregation in biological medium. In vitro assays have shown that HYP and the hypericinates are able to permeate the MCF-7 cell membrane and accumulated in organelles near the nucleus. The difference in location, however, was not determinant to the cell death mechanism, and a higher prevalence of apoptosis for all studied compounds occurred. The photodynamic studies indicated that hypericinates were more effective than HYP and were able to inhibit the formation of cellular colonies, suggesting a possible ability to prevent the recurrence of tumors. It also appears that all compounds have relative safety for mutagenicity and genotoxicity, which opens up a further safe route for application in in vivo studies. PMID- 28865320 TI - Antiproliferation and antibacterial effect of biosynthesized AgNps from leaves extract of Guiera senegalensis and its catalytic reduction on some persistent organic pollutants. AB - The study concentrate on the biosynthesis of silver nanoparticles (AgNps) from the leaves extract of Guiera senegalensis with focus on its; antiproliferation effect on prostate (PC3), breast (MCF7) and liver (HepG2) cancer cell lines, antibacterial effect on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) and the degradation on 4-nitrophenol (4-NP) and congo red dye (CR). The synthesized AgNps were characterized by FTIR, TEM, FESEM, XRD and EDX analysis. The EDS spectrum revealed that the synthesized nanoparticles (Nps) were composed of 55.45% Ag atoms of spherical shape with approximately 50nm size, identified from TEM and FESEM data. The antiproliferation effect of the AgNps varies with cell lines in a concentration dependent manner. The result showed that the AgNps were more effective on PC3 (IC50 23.48MUg/mL) than MCF7 (29.25MUg/mL) and HepG2 (33.25MUg/mL) by the virtue of their IC50 values. The AgNps were highly effective against E. coli and S. aureus by killing 99% colonies. The AgNps also shows a good catalytic reduction of the toxic organic pollutants in which only 3mg of the AgNps degraded 95% of both CR dye and 4-NP in 22 and 36min respectively. Therefore, the green synthesis of AgNps may have potential applications in pharmacology and industries for the treatment of cancers, bacterial infections and in degrading toxic organic pollutants in water. PMID- 28865321 TI - In silico identification of inhibitors of ribose 5-phosphate isomerase from Trypanosoma cruzi using ligand and structure based approaches. AB - Chagas disease, caused by the protozoan Trypanosoma cruzi, affects approximately seven million people, mainly in Latin America, and causes about 7000 deaths annually. The available treatments are unsatisfactory and search for more effective drugs against this pathogen is critical. In this context, the ribose 5 phosphate isomerase (Rpi) enzyme is a potential drug target mainly due to its function in the pentose phosphate pathway and its essentiality (previously shown in other trypanosomatids). In this study, we propose novel potential inhibitors for the Rpi of T. cruzi (TcRpi) based on a computer-aided approach, including structure-based and ligand-based pharmacophore modeling. Along with a substructural and similarity search, the selected pharmacophore hypotheses were used to screen the purchasable subset of the ZINC Database, yielding 20,183 candidate compounds. These compounds were submitted to molecular docking studies in the TcRpi and Human Rpi (HsRpi) active sites in order to identify potential selective inhibitors for the T. cruzi enzyme. After the molecular docking and ADME-T (absorption, distribution, metabolism, excretion and toxicity)/PAINS (pan assay interference compounds) screenings, 211 molecules were selected as potential TcRpi inhibitors. Out of these, three compounds - ZINC36975961, ZINC63480117, and ZINC43763931 - were submitted to molecular dynamics simulations and two of them - ZINC36975961 and ZINC43763931- had good performance and made interactions with important active site residues over all the simulation time. These compounds could be considered potential TcRpi inhibitors candidates and also may be used as leads for developing new TcRpi inhibitors. PMID- 28865322 TI - Microvascular decompression for trigeminal neuralgia in patients with failed gamma knife surgery: Analysis of efficacy and safety. AB - OBJECTIVE: Though it is usually successful, failure or delayed pain recurrence may occur after gamma knife surgery (GKS) in patients with trigeminal neuralgia (TN), and additional intervention may be required. This study aimed to investigate whether the safety and efficacy of microvascular decompression (MVD) were influenced by prior GKS. PATIENTS AND METHODS: The authors retrospectively evaluated 36 consecutive TN patients who underwent MVD after failed GKS from January 2012 to June 2013. The clinical features, operative findings and surgical outcomes were reviewed and statistically analyzed, and the operation results were further compared with a cohort of 60 patients with no prior GKS. RESULTS: At surgery, atrophy of the trigeminal nerve was observed in 13 patients (36.1%), arachnoid thickening in 6 patients (16.7%), adhesions between vessels and the trigeminal nerve in 8 patients (22.2%), and atherosclerotic plaque in the offending vessels in 3 patients (8.3%). The complete pain relief rates were 83.3% immediately after MVD and 72.2% at last follow-up, which showed no statistical difference when compared with patients without GKS. New or worsened facial numbness occurred in 7 patients (19.4%), which was significantly higher than those without GKS (p=0.02). Univariate analysis suggested that a positive pain response to the prior GKS correlated with better long-term outcome (p=0.015), and the existence of arachnoid adhesions correlated with higher risk of facial numbness (p=0.03). CONCLUSIONS: MVD remains an appropriate and effective alternative therapy for patients with failed GKS, with no added technical difficulty. However, the risk of facial numbness seems to be higher than those with MVD alone. PMID- 28865323 TI - Impact of antithrombotic treatment on clinical outcomes after craniotomy for unruptured intracranial aneurysm. AB - OBJECTIVE: Patients receiving antithrombotic treatment occasionally undergo craniotomy. We aimed to explore the impact of perioperative use of antithrombotic agents on the occurrence of surgical complications and clinical outcomes in patients with unruptured intracranial aneurysm (UIA). PATIENTS AND METHODS: We retrospectively analyzed 401 consecutive patients who had undergone craniotomy for UIA at our institution between January 2006 and December 2016. Patients were divided into two groups: those who received oral antiplatelet and/or anticoagulant agents during the perioperative period (antithrombotic treatment group, n=45); and those who did not (no antithrombotic treatment group, n=356). In the antithrombotic treatment group, 40 patients received antiplatelet alone, 2 received anticoagulant alone, and 3 received antiplatelet plus anticoagulant. RESULTS: The two groups showed no significant differences in mortality, morbidity, or occurrence of symptomatic brain infarction, but intracranial hemorrhage was more frequent in the antithrombotic treatment group than in the no antithrombotic treatment group (p=0.0187). Multivariate analysis revealed posterior location of the aneurysm (odds ratio (OR), 8.10; 95% confidence interval (CI), 2.77-23.68; p=0.0001) and surgical procedure (OR, 5.48; 95%CI, 1.68-17.86; p=0.0048) as significantly correlated with severe morbidity, and intracranial hemorrhage as correlated significantly with antithrombotic treatment (OR, 3.83; 95%CI, 1.36-10.76; p=0.0110). CONCLUSIONS: This study provides important information about the occurrence of intracranial hemorrhage and clinical outcomes in patients undergoing antithrombotic treatment during the perioperative period of craniotomy for UIA. PMID- 28865324 TI - The impact of APOA5, APOB, APOC3 and ABCA1 gene polymorphisms on ischemic stroke: Evidence from a meta-analysis. AB - BACKGROUND AND AIMS: Genetic studies have been reported on the association between APOA5, APOB, APOC3 and ABCA1 gene polymorphisms and ischemic stroke, but results remain controversial. Hence, this meta-analysis aimed to infer the causal relationships of APOA5 (rs662799, rs3135506), APOB (rs693, rs1042031, rs1801701), APOC3 (rs4520, rs5128, rs2854116, rs2854117) and ABCA1 rs2230806 with ischemic stroke risk. METHODS: A systematic review was performed for all the articles retrieved from multiple databases, up until March 2017. Data were extracted from all eligible studies, and meta-analysis was carried out using RevMan 5.3 and R package 3.2.1. The strength of association between each studied polymorphism and ischemic stroke risk was measured as odds ratios (ORs) and 95% confidence intervals (CIs), under fixed- and random-effect models. RESULTS: A total of 79 studies reporting on the association between the studied polymorphisms and ischemic stroke risk were identified. The pooled data indicated that all genetic models of APOA5 rs662799 (ORs = 1.23-1.43), allelic and over-dominant models of APOA5 rs3135506 (ORs = 1.77-1.97), APOB rs1801701 (ORs = 1.72-2.13) and APOB rs1042031 (ORs = 1.66-1.88) as well as dominant model of ABCA1 rs2230806 (OR = 1.31) were significantly associated with higher risk of ischemic stroke. However, no significant associations were observed between ischemic stroke and the other five polymorphisms, namely ApoB (rs693) and APOC3 (rs4520, rs5128, rs2854116 and rs2854117), under any genetic model. CONCLUSIONS: The present meta-analysis confirmed a significant association of APOA5 rs662799 CC, APOA5 rs3135506 CG, APOB rs1801701 GA, APOB rs1042031 GA and ABCA1 rs2230806 GG with increased risk of ischemic stroke. PMID- 28865325 TI - Impact of cystatin C and microalbuminuria on cognitive impairment in the population of community-dwelling Japanese. AB - BACKGROUND AND AIMS: Cognitive impairment is an important element affecting our well-being, and as such, early diagnosis is critical today. We investigated whether serum cystatin C and microalbuminuria are associated with cognitive impairment. METHODS: A total of 1943 subjects (774 males, 1169 females, mean age 65.8 years) took part in the investigation, and underwent a health examination in Tanushimaru, Japan, in 2009. The participants' cognitive function was evaluated using of mini-mental state examination (MMSE). We measured the levels of serum cystatin C using latex nephelometric immunoassay. Spot urine samples were used to measure microalbuminuria levels. Multivariate linear regression analyses were used to assess the relationship between MMSE scores and the level of cystatin C or microalbuminuria. All statistical analyses were performed using the SAS system. RESULTS: The mean values of log-transformed serum cystatin C levels and log-transformed microalbuminuria were 0.95 (range 0.41-7.11) mg/L and 10.7 (range 1.1-2600) mg/g.Cr, respectively. The means of MMSE score were 27.7 +/- 2.5. In the multivariate linear regression analyses adjusted for age and sex, MMSE was significantly associated with systolic blood pressure (p = 0.024, inversely), cystatin C (p = 0.046, inversely) and microalbuminuria (p = 0.019, inversely), whereas estimated glomerular filtration rate (eGFR) had an insignificant association (p = 0.197). In the multiple stepwise linear regression analysis, age, history of stroke, systolic blood pressure, serum cystatin C were independently associated with MMSE levels. CONCLUSIONS: We demonstrated for the first time that cognitive function was significantly and inversely associated with cystatin C and microalbuminuria, in the relatively younger general population. PMID- 28865326 TI - Hydrogen sulfide attenuates calcification of vascular smooth muscle cells via KEAP1/NRF2/NQO1 activation. AB - BACKGROUND AND AIMS: Vascular calcification is a common health problem related to oxidative stress, inflammation, and circulating calciprotein particles (CPP). Hydrogen sulfide is an endogenous signaling molecule with antioxidant properties and potential for drug development targeting redox signaling. Yet, its molecular mechanisms of action in vascular smooth muscle cell (VSMC) calcification have not been delineated. We therefore sought to identify key pathways involved in the calcification-inhibitory properties of sulfide employing our recently developed CPP-induced VSMC calcification model. METHODS: Using next-generation sequencing, we investigated the transcriptomic changes of sodium hydrosulfide-treated versus non-treated calcifying VSMCs. The potential role of candidate genes and/or regulatory pathways in prevention of calcification was investigated by small interfering RNA (siRNA). RESULTS: CPP led to a pronounced accumulation of cell associated calcium, which was decreased by sulfide in a concentration-dependent manner. Both, CPP-induced hydrogen peroxide production and enhanced pro inflammatory/oxidative stress-related gene expression signatures were attenuated by sulfide-treatment. Gene ontology enrichment and in silico pathway analysis of our transcriptome data suggested NAD(P)H dehydrogenase [quinone] 1 (NQO1) as potential mediator. Corroborating these findings, silencing of Kelch-like ECH associated protein 1 (KEAP1), an inhibitor of nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear activity, enhanced NQO1 expression, whereas NRF2 silencing reduced the expression of NQO1 and abrogated the calcification suppressing activity of sulfide. Moreover, immunofluorescence microscopy and Western blot analysis confirmed nuclear translocation of NRF2 by sulfide in VSMC. CONCLUSIONS: Sulfide attenuates CPP-induced VSMC calcification in vitro via the KEAP1-NRF2 redox sensing/stress response system by enhancing NQO1 expression. PMID- 28865327 TI - Increased diabetes risk and interaction with social and medical events in patients upon stroke: Two nationwide studies. AB - BACKGROUND & AIMS: The relationship between stroke and diabetes is not completely understood. This study evaluated diabetes risk and post-diabetes adverse events in patients with stroke. METHODS: We identified 10,255 adults, newly diagnosed with stroke from 2000 to 2005, using the Taiwan's National Health Insurance Research Database. A comparison cohort of 41,020 adults without stroke was randomly selected from the same dataset, frequency matched by age and sex. Diabetes events from 2000 to 2013 were ascertained from medical claims. Adjusted hazard ratios (HRs) and 95% CIs were calculated for diabetes associated with stroke. A nested cohort study of 33,437 patients with inpatient care for diabetes between 2008 and 2013 was conducted to calculate the adjusted odds ratios (ORs) and 95% CIs for adverse events after diabetes, in patients with and without stroke. RESULTS: During 489,561 person-years of follow-up, there were 10,742 newly diagnosed diabetes cases. The incidence of diabetes for people with and without stroke was 43.9 and 17.8 per 1000 person-years, respectively (p < 0.0001). Compared to that for people without stroke, the adjusted HR for diabetes was 2.69 (95% CI 2.56-2.82) for stroke patients. The ORs of post-diabetes pneumonia, urinary tract infection, and mortality associated with stroke were 1.35 (95% CI 1.17-1.55), 1.52 (95% CI 1.36-1.70), and 1.71 (95% CI 1.27-2.29), respectively. CONCLUSIONS: We provide evidence that the consequences of stroke are not limited to the neurological defect, but evoke diabetes and a plethora of associated medical, psychological and social impacts the physician must be strongly aware of if evaluating and treating stroke patients. PMID- 28865328 TI - Uptake of Plutonium-238 into Solanum tuberosum L. (potato plants) in presence of complexing agent EDTA. AB - Bioavailability and plant uptake of radionuclides depend on various factors. Transfer into different plant parts depends on chemical and physical processes, which need to be known for realistic ingestion dose modelling when these plants are used for food. Within the scope of the present work, the plutonium uptake by potato plants (Solanum tuberosum L.) was investigated in hydroponic solution of low concentration [Pu] = 10-9 mol L-1. Particular attention was paid to the speciation of radionuclides in the solution which was modelled by the speciation code PHREEQC. The speciation, the solubility and therefore the plant availability of radionuclides mainly depend on the pH value and the redox potential of the solution. During the contamination period, the redox potential did not change significantly. In contrast, the pH value showed characteristic changes depending on exudates excreted by the plants. Plant roots took up high amounts of plutonium (37%-50% of the added total amount). In addition to the uptake into the roots, the radionuclides can also adsorb to the exterior root surface. The solution-to plant transfer factor showed values between 0.03 and 0.80 (Bq kg-1/ Bq L-1) for the potato tubers. By addition of the complexing agent EDTA (10-4 mol L-1), the plutonium uptake from solution increased by 58% in tubers and by 155% in shoots/leaves. The results showed that excreted substances by plants affect bioavailability of radionuclides at low concentration, on the one hand. On the other hand, the uptake of plutonium by roots and the accumulation in different plant parts can lead to non-negligible ingestion doses, even at low concentration. We are aware of the limited transferability of data obtained in hydroponic solutions to plants growing in soil. However, the aim of this study is twofold: First we want to investigate the influence of Pu speciation on plant uptake in a rather well defined system which can be modelled using available thermodynamic data. Second, techniques developed here shall be applied to the investigation of plants growing in soil in the future. The present work contributes to the basic understanding how plant induced effects on nutrient solution influence bioavailability of radionuclides and fosters the need for more detailed investigations of the complex uptake and accumulation processes of radionuclides into plants. PMID- 28865329 TI - A retrospective clinicopathological study of lung adenocarcinoma: Total tumor size can predict subtypes and lymph node involvement. AB - PURPOSE: To analyze the predictive ability of total tumor size in lung adenocarcinoma subtype and lymph node involvement. MATERIALS AND METHODS: 1018 patients, <=3cm tumor, were enrolled. The maximum diameter and other variables of each tumor were measured. RESULTS: The optimal cut-off value for total tumor size in differentiating AIS and MIA from IAC was <1.15cm, in distinguishing lymph node involvement, it was 1.65cm. CONCLUSIONS: Total tumor size could be a reliable predictor of lung adenocarcinoma subtype and lymph node involvement irrespective of ground glass, part solid and solid characteristics. PMID- 28865330 TI - Online monitoring of astragaloside II metabolism using a homemade cultural device coupled with microdialysis and ultra-performance liquid chromatography-mass spectrometry. AB - A new system was described for the online monitoring of astragaloside II (AII) metabolism in intestinal microbial community. The system was based on a homemade cultural device coupled with microdialysis (MD) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Main improvements include a simplified anaerobic incubator enabling the experiment to be conducted in ambient atmosphere, continuous sampling, and decreased matrix effect. Importantly, our method distinctly decreases the interference of small molecules by adding 20mgml 1 of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) to the perfusion fluid. Using the developed method, the metabolism of AII in intestinal bacteria was successfully investigated. Results were then compared with those obtained by conventional incubation and sampling method. We found that the integrated experimental system maintained the proper fermentation environment for bacteria and enabled high chromatography performance. With the advantages of auto sampling, online detection, non-requirement of expensive fermenting equipment, and negligible matrix interference, the method can greatly contribute to the investigation of the dynamic biotransformation of astragalosides in complicated matrix-based biological samples. PMID- 28865331 TI - Preparative separation of the polar part from the rhizomes of Anemarrhena asphodeloides using a hydrophilic C18 stationary phase. AB - The goal of this study was to develop a method that utilized a hydrophilic C18 stationary phase in the preparative high performance liquid chromatography to isolate the polar part from the rhizomes of Anemarrhena asphodeloides. The results showed that an initial mobile phase of pure water for the separation could greatly increase the retention and solubility of the polar compounds at the preparative scale. Introducing polar groups on the surface of the hydrophilic C18 column together with the use of optimized mobile phase compositions improved the column separation selectivity for polar compounds. Eleven previously undescribed compounds in Anemarrhena asphodeloides were obtained, indicating that the method developed in this study would facilitate the purification and separation of the polar part of traditional Chinese medicines. PMID- 28865333 TI - Assessing mood symptoms through heartbeat dynamics: An HRV study on cardiosurgical patients. AB - BACKGROUND: Heart Rate Variability (HRV) is reduced both in depression and in coronary heart disease (CHD) suggesting common pathophysiological mechanisms for the two disorders. Within CHD, cardiac surgery patients (CSP) with postoperative depression are at greater risk of adverse cardiac events. Therefore, CSP would especially benefit from depression early diagnosis. Here we tested whether HRV multi-feature analysis discriminates CSP with or without depression and provides an effective estimation of symptoms severity. METHODS: Thirty-one patients admitted to cardiac rehabilitation after first-time cardiac surgery were recruited. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D). HRV features in time, frequency, and nonlinear domains were extracted from 5-min-ECG recordings at rest and used as predictors of "least absolute shrinkage and selection" (LASSO) operator regression model to estimate patients' CES-D score and to predict depressive state. RESULTS: The model significantly predicted the CES-D score in all subjects (the total explained variance of CES-D score was 89.93%). Also it discriminated depressed and non-depressed CSP with 86.75% accuracy. Seven of the ten most informative metrics belonged to non-linear-domain. LIMITATIONS: A higher number of patients evaluated also with a structured clinical interview would help to generalize the present findings. DISCUSSION: To our knowledge this is the first study using a multi-feature approach to evaluate depression in CSP. The high informative power of HRV-nonlinear metrics suggests their possible pathophysiological role both in depression and in CHD. The high-accuracy of the algorithm at single-subject level opens to its translational use as screening tool in clinical practice. PMID- 28865332 TI - Metabolomic study for monitoring of biomarkers in mouse plasma with asthma by gas chromatography-mass spectrometry. AB - Asthma is a multifaceted chronic disease caused by an alteration of various genetic and environmental factors that is increasing in incidence worldwide. However, the biochemical mechanisms regarding asthma are not completely understood. Thus, we performed of metabolomic study for understanding of the biochemical events by monitoring of altered metabolism and biomarkers in asthma. In mice plasma, 27 amino acids(AAs), 24 fatty acids(FAs) and 17 organic acids(OAs) were determined by ethoxycarbonyl(EOC)/methoxime(MO)/tert butyldimethylsilyl(TBDMS) derivatives with GC-MS. Their percentage composition normalized to the corresponding mean levels of control group. They then plotted as star symbol patterns for visual monitoring of altered metabolism, which were characteristic and readily distinguishable in control and asthma groups. The Mann Whitney test revealed 25 metabolites, including eight AAs, nine FAs and eight OAs, which were significantly different (p<0.05), and orthogonal partial least squares-discriminant analysis revealed a clear separation of the two groups. In classification analysis, palmitic acid and methionine were the main metabolites for discrimination between asthma and the control followed by pipecolic, lactic, alpha-ketoglutaric, and linoleic acids for high classification accuracy as potential biomarkers. These explain the metabolic disturbance in asthma for AAs and FAs including intermediate OAs related to the energy metabolism in the TCA cycle. PMID- 28865334 TI - Agent-based modeling as a tool for program design and evaluation. AB - Recently, systems thinking and systems science approaches have gained popularity in the field of evaluation; however, there has been relatively little exploration of how evaluators could use quantitative tools to assist in the implementation of systems approaches therein. The purpose of this paper is to explore potential uses of one such quantitative tool, agent-based modeling, in evaluation practice. To this end, we define agent-based modeling and offer potential uses for it in typical evaluation activities, including: engaging stakeholders, selecting an intervention, modeling program theory, setting performance targets, and interpreting evaluation results. We provide demonstrative examples from published agent-based modeling efforts both inside and outside the field of evaluation for each of the evaluative activities discussed. We further describe potential pitfalls of this tool and offer cautions for evaluators who may chose to implement it in their practice. Finally, the article concludes with a discussion of the future of agent-based modeling in evaluation practice and a call for more formal exploration of this tool as well as other approaches to simulation modeling in the field. PMID- 28865335 TI - The capability of radial basis function to forecast the volume fractions of the annular three-phase flow of gas-oil-water. AB - The problem of how to precisely measure the volume fractions of oil-gas-water mixtures in a pipeline remains as one of the main challenges in the petroleum industry. This paper reports the capability of Radial Basis Function (RBF) in forecasting the volume fractions in a gas-oil-water multiphase system. Indeed, in the present research, the volume fractions in the annular three-phase flow are measured based on a dual energy metering system including the 152Eu and 137Cs and one NaI detector, and then modeled by a RBF model. Since the summation of volume fractions are constant (equal to 100%), therefore it is enough for the RBF model to forecast only two volume fractions. In this investigation, three RBF models are employed. The first model is used to forecast the oil and water volume fractions. The next one is utilized to forecast the water and gas volume fractions, and the last one to forecast the gas and oil volume fractions. In the next stage, the numerical data obtained from MCNP-X code must be introduced to the RBF models. Then, the average errors of these three models are calculated and compared. The model which has the least error is picked up as the best predictive model. Based on the results, the best RBF model, forecasts the oil and water volume fractions with the mean relative error of less than 0.5%, which indicates that the RBF model introduced in this study ensures an effective enough mechanism to forecast the results. PMID- 28865336 TI - Isotope investigation on groundwater recharge and dynamics in shallow and deep alluvial aquifers of southwest Punjab. AB - Groundwater samples collected from the alluvial aquifers of southwest Punjab, both shallow and deep zones were measured for environmental tritium (3H) and stable isotopes (2H and 18O) to evaluate the source of recharge and aquifer dynamics. The shallow groundwater shows wide variation in isotopic signature (delta18O: -11.3 to -5.00/00) reflecting multiple sources of recharge. The average isotopic signature of shallow groundwaters (delta18O: -6.73 +/- 1.030/00) is similar to that of local precipitation (-6.98 +/- 1.660/00) indicating local precipitation contributes to a large extent compared to other sources. Other sources have isotopically distinct signatures due to either high altitude recharge (canal sources) or evaporative enrichment (irrigation return flow). Deep groundwater shows relatively depleted isotopic signature (delta18O: -8.60/00) and doesn't show any evaporation effect as compared to shallow zone indicating recharge from precipitation occurring at relatively higher altitudes. Environmental tritium indicates that both shallow (3H: 5 - 10 T.U.) and deeper zone (3H: 1.5 - 2.5 T.U.) groundwaters are modern. In general the inter-aquifer connections seem to be unlikely except a few places. Environmental isotope data suggests that shallow groundwater is dynamic, local and prone to changes in land use patterns while deep zone water is derived from distant sources, less dynamic and not impacted by surface manifestations. A conceptual groundwater flow diagram is presented. PMID- 28865337 TI - Spectrally resolved thermoluminescence of pure potassium chloride crystals. AB - Alkali halides are wide band gap dielectric materials, which are very important for luminescence dosimetry. Nevertheless, only some of them were studied comprehensively. Potassium chloride (KCl) is alkali halide material, which shows pronounced thermoluminescence (TL) and optically stimulated luminescence (OSL). The material occurs also in natural mineral form as sylvite (or sylvine). This paper presents results of spectrally resolved thermoluminescence (SR-TL) measurements of pure KCl crystals in temperature range 300-550K for various doses of beta irradiation. Four emission bands were found relating to different recombination centers in this material. TL curves relating to these centers have different shape. It indicates that recombination centers are not filled concurrently. PMID- 28865338 TI - Impact of restarting home neuropsychiatric medications on sedation outcomes in medical intensive care unit patients. AB - PURPOSE: This single-center, retrospective cohort study investigated the effects of timing of initiating home neuropsychiatric medications (NPMs) on sedation related outcomes. MATERIALS AND METHODS: Subjects included adult medical intensive care unit (MICU) patients who had an NPM on their admission medication list; intubated before or on arrival to the intensive care unit (ICU); and were on benzodiazepine-based sedation. The intervention assessed was the timing of the initiation of home NPMs: early (<=5days) vs. late (>5days) into the ICU stay. RESULTS: There were 56 and 53 patients in the early and late restart groups, respectively. Early cohort patients maintained a median daily RASS of -1.5, while late cohort patients had a median daily RASS of -2.0 (p=0.02). The effect was driven by the subgroup of patients on home anti-depressant therapy who were restarted early on these agents. The early restart group had a higher percentage of days with RASS scores within goal (p=0.01) and less delirium (p=0.02). Early restarting of home NPMs was associated with a non-significant decrease in ventilator days compared with late restarting (p=0.11). CONCLUSIONS: Restarting home NPMs was associated with lighter sedation levels and less delirium. PMID- 28865339 TI - Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study. AB - PURPOSE: We investigated whether early enteral nutrition alone may be sufficient prophylaxis against stress-related gastrointestinal (GI) bleeding in mechanically ventilated patients. MATERIALS AND METHODS: Prospective, double blind, randomized, placebo-controlled, exploratory study that included mechanically ventilated patients in medical ICUs of two academic hospitals. Intravenous pantoprazole and early enteral nutrition were compared to placebo and early enteral nutrition as stress-ulcer prophylaxis. The incidences of clinically significant and overt GI bleeding were compared in the two groups. RESULTS: 124 patients were enrolled in the study. After exclusion of 22 patients, 102 patients were included in analysis: 55 patients in the treatment group and 47 patients in the placebo group. Two patients (one from each group) showed signs of overt GI bleeding (overall incidence 1.96%), and both patients experienced a drop of >3 points in hematocrit in a 24-hour period indicating a clinically significant GI bleed. There was no statistical significant difference in the incidence of overt or significant GI bleeding between groups (p=0.99). CONCLUSION: We found no benefit when pantoprazole is added to early enteral nutrition in mechanically ventilated critically ill patients. The routine prescription of acid-suppressive therapy in critically ill patients who tolerate early enteral nutrition warrants further evaluation. PMID- 28865340 TI - Is patient length of stay associated with intensive care unit characteristics? AB - PURPOSE: We described the association between Intensive care units (ICU) characteristics and ICU Length of stay (LoS), after correcting for patient characteristics. We also compared the predictive performances of models including either patient and ICU characteristics or only patient characteristics. MATERIALS AND METHODS: We included all admissions of 38 ICUs participating in the Dutch National Intensive Care Evaluation registry (NICE) between 2014 and 2016. We performed mixed effect regression including, one ICU characteristic in each model and a random intercept per ICU. Furthermore, we developed a prediction model containing multiple ICU characteristics and patients characteristics. RESULTS: We found negative associations for the number of hospital beds; number of ICU beds; availability of fellows in training for intensivist; full-time equivalent ICU nurses; and discharged in a shift with 100% bed occupancy. Furthermore, we found a U-shaped association with the nurses to patient ratio as spline function. The performance based on R2 was between 0.30 and 0.32 for both the model containing only patient characteristics and the model also containing ICU characteristics. CONCLUSION: After correcting for patient characteristics, we found statistically significant associations between ICU LoS and six ICU characteristics, mainly describing staff availability. Furthermore, we conclude that including ICU characteristics did not significantly improve ICU LoS prediction. PMID- 28865341 TI - Small RNAs in major foodborne pathogens: from novel regulatory activities to future applications. AB - Small regulatory RNAs (sRNAs) are involved in post-transcriptional control of important cellular processes and contribute to the success of a pathogen. Here, we use studies primarily selected from Salmonella enterica and Listeria monocytogenes to illustrate the current status of sRNA biology in important foodborne pathogens. We discuss how the regulatory activities of sRNAs can be affected by base pairing RNAs known as 'sponge RNAs', or by RNA-binding proteins, such as the newly discovered sRNA chaperone ProQ. Furthermore, we highlight recent findings for sRNAs with regulatory roles during infection, some of which are present in multiple copies, designated 'sibling sRNAs'. Importantly, knowledge on sRNA-mediated regulation can be exploited for biotechnological applications, such as in generating gene knockdowns to promote desired traits. PMID- 28865342 TI - Inclusion of oligonucleotide antimicrobials in biocompatible cationic liposomes: A structural study. AB - HYPOTHESIS: Transcription factor decoys (TFD) are short oligonucleotides designed to block essential genetic pathways in bacteria and defeat resistant infections. TFD protection in biological fluids and their delivery to the site of infection require formulation in appropriate delivery systems. In this work, we build on a classical phosphatidylcholine/phosphatidylethanolamine (POPC/DOPE) scaffold to design TFD-loaded cationic liposomes by combining the DNA-complexing abilities of a bolaamphiphile, (1,1'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4 tetrahydroacridinium) chloride (12-bis-THA), with the biocompatible cationic lipid ethyl-phosphatidylcholine (DPePC). The goal is to perform a structural study to determine the impact of the bolaamphiphile and TFD incorporation on the liposome structure, the capacity for TFD encapsulation, and the colloidal stability in saline media and cell culture environments. EXPERIMENTS: The systems are characterized by means of dynamic light scattering, small-angle X-ray scattering, and zeta-potential measurements, to provide a clear picture of the liposome structure. Circular dichroism (CD) spectroscopy is used to assess the compaction of the oligonucleotide in a psi form, while steady-state fluorescence and fluorescence correlation spectroscopies give insight into the entrapment rate and distribution of the TFD in the liposomes. FINDINGS: We found that the combination of the two cationic species, 12-bis-THA and DPePC, allows encapsulation of 90% of the TFD. Results of CD experiments revealed that the TFD is condensed, therefore likely protected from the lytic action of serum nucleases. Finally, the systems showed colloidal stability in aqueous dispersion with ionic strength comparable to biologically relevant media. PMID- 28865343 TI - Formation of peptide layers and adsorption mechanisms on a negatively charged cation-exchange membrane. AB - Polypeptide/solid charged surface interactions are omnipresent in the biomedical and biochemical fields. The present study aimed to understand the adsorption mechanisms of a cation-exchange membrane (CEM) by a well-characterized peptide mixture at three different pH values. Results demonstrated that fouling was important at pH 6, twice lower at pH 2 and negligible at pH 10. At pH 6, ALPMHIR and TKIPAVFK sequences firstly established electrostatic interactions with the negative CEM charges (SO3-) through their positive K and R residues (NH3+) creating a first nanolayer. Secondly, peptide/peptide interactions occurred through their respective hydrophobic residues creating a second nanolayer. At pH 2, VLVLDTDYK and IDALNENK sequences interacted only electrostatically and that in a lower proportion since at acidic pH values, most of the CEM charges would be protonated and uncharged (HSO3) and then limit the potential electrostatic interactions. In addition, the sequences of peptides interacting at pH 2 and 6 were different. This was explained by their structure in terms of residue nature and position in the sequence. At pH 10, no fouling was observed due to the lack of positive peptide charges. To the best of our knowledge, it is the first in depth study concerning the fouling of CEMs by peptides from a complex mixture. PMID- 28865344 TI - Heartland virus infection in hamsters deficient in type I interferon signaling: Protracted disease course ameliorated by favipiravir. AB - Heartland virus (HRTV) is an emerging tick-borne virus (Bunyaviridae, Phlebovirus) that has caused sporadic cases of human disease in several central and mid-eastern states of America. Animal models of HRTV disease are needed to gain insights into viral pathogenesis and advancing antiviral drug development. Presence of clinical disease following HRTV challenge in hamsters deficient in STAT2 function underscores the important role played by type I interferon-induced antiviral responses. However, the recovery of most of the infected animals suggests that other mechanisms to control infection and limit disease offer substantial protection. The most prominent disease sign with HRTV infection in STAT2 knockout hamsters was dramatic weight loss with clinical laboratory and histopathology demonstrating acute inflammation in the spleen, lymph node, liver and lung. Finally, we show that HRTV disease in hamsters can be prevented by the use of favipiravir, a promising broad-spectrum antiviral in clinical development for the treatment of influenza. PMID- 28865346 TI - Prevalence of depressive symptoms and their association with brainstem raphe echogenicity in patients with Parkinson's disease and non-PD controls. AB - Despite advances in diagnostics and clinical recognition, depressive symptoms in Parkinson's disease (PD) exceeding normal limits remain effectively untreated. In this study, we report on the prevalence and severity of depressive symptoms as well as their association with brainstem raphe echogenicity in patients with PD and non-PD controls. The study included 266 Estonian PD patients and 168 age- and education-matched controls. Demographic and clinical data was documented. Brainstem raphe (BR) was visualized by transcranial sonography (TCS). The prevalence of depressive symptoms in the patient sample was found to be significantly higher than in controls. BR echogenicity in both patients and controls was directly related to their total BDI score, although we found a significantly greater reduction of BR echogenicity in patients with PD and depressive symptoms compared to depressed non-PD controls. The present results corroborate the hypothesis that morphological alteration of the BR is involved in the pathogenesis of depressive disorders. TCS of BR could be used as a non invasive biomarker to improve detection of depressive symptoms in early PD stages where clinicians may not recognize affective disturbances in the context of PD phenomena. PMID- 28865347 TI - Time-varying assessment of heart rate variability parameters using respiratory information. AB - Analysis of heart rate variability (HRV) is commonly used for characterization of autonomic nervous system. As high frequency (HF, known as the respiratory related) component of HR, overlaps with the typical low frequency (LF) band when the respiratory rate is low, a reference signal for HF variations would help in better discriminating the LF and HF components of HR. The present study proposes a model for time-varying separation of HRV components as well as estimation of HRV parameters using respiration information. An autoregressive moving average with exogenous input (ARMAX) model of HRV is considered with a parametrically modeled respiration signal as the input. The model parameters are estimated using smoothed extended Kalman filtering. Results for different synthetic data show that our proposed joint model outperforms the classical AR modeling in estimation of HRV parameters especially in the case of low respiration rate. In addition, the possibility of using pulse transit time (PTT) and the amplitude of photoplethysmogram (PPGamp) as surrogates of the input respiratory signal has been investigated. To this end, electrocardiogram (ECG), PPG and respiration have been recorded from 21 healthy subjects (10 males and 11 females, mean age 27.5 +/ 4.1) during normal and deep respiration. Results show that indeed PTT and PPGamp offer good potential to be used as references for respiratory-related variations of HR, thus avoiding additional devices for recording respiration. PMID- 28865348 TI - Prediction of muscle activation for an eye movement with finite element modeling. AB - In this paper, a 3D finite element (FE) modeling is employed in order to predict extraocular muscles' activation and investigate force coordination in various motions of the eye orbit. A continuum constitutive hyperelastic model is employed for material description in dynamic modeling of the extraocular muscles (EOMs). Two significant features of this model are accurate mass modeling with FE method and stimulating EOMs for motion through muscle activation parameter. In order to validate the eye model, a forward dynamics simulation of the eye motion is carried out by variation of the muscle activation. Furthermore, to realize muscle activation prediction in various eye motions, two different tracking-based inverse controllers are proposed. The performance of these two inverse controllers is investigated according to their resulted muscle force magnitude and muscle force coordination. The simulation results are compared with the available experimental data and the well-known existing neurological laws. The comparison authenticates both the validation and the prediction results. PMID- 28865345 TI - White matter microstructural deficits in 22q11.2 deletion syndrome. AB - Diffusion tensor imaging (DTI) studies in 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition associated with psychosis, report brain white matter (WM) microstructure aberrations. Several studies report that WM disruptions in 22q11DS are similar to deficits in idiopathic schizophrenia. Yet, DTI results in 22q11DS are inconsistent. We used DTI to compare WM structure in 22q11DS individuals to healthy controls (HC) and explored WM differences in 22q11DS with (+) and without (-) psychosis spectrum symptoms. We examined 39 22q11DS individuals and 39 age, sex and race equivalent HC. DTI was performed at 3T using a 64-direction protocol. Fractional anisotropy (FA) was lower, while radial diffusivity was higher in 22q11DS within the cingulum bundle. Mean diffusivity was lower in the inferior longitudinal fasciculus, while axial diffusivity (AD) was lower in the cingulum bundle, forceps major, and several posterior to anterior fasciculi. 22q11DS+ had lower FA in the cingulum bundle and lower AD in the uncinate fasciculus compared to 22q11DS-. Overall, we found aberrant WM microstructure in individuals with 22q11DS compared to age and sex matched HC and exploratory analysis indicated subtle WM deficits associated with psychosis. The findings highlight the dysfunction of WM microstructure in 22q11DS and its potential importance in elucidating WM abnormalities in psychosis. PMID- 28865349 TI - Adsorption characteristics of Copper (II), Zinc (II) and Mercury (II) by four kinds of immobilized fungi residues. AB - This study investigated the adsorption characteristics of Copper (II), Zinc (II) and Mercury (II) by immobilized Flammulina velutipes, Auricularia polytricha, Pleurotus eryngii and Pleurotus ostreatus residues. Lagergren model, elovich and intraparticle diffusion model were used to present the adsorption kinetics, and it was proved that Langmuir isotherm model and pseudo-second order kinetics are the best suitable model with high correlation coefficient to characterize the adsorption process of Copper (II), Zinc (II) and Mercury (II). The results showed that adsorption process finished in 120min at pH 6.0. The adsorption rate of Cu2+, Zn2+ and Hg2+ were reached to 53.8-84.1% of total in the initial 60min, and finished in 120min. Ion exchange and complexation of F. velutipes were the main mechanisms for adsorption of metal ions by characterizations of Scanning electron microscopy (SEM) and Fourier transform infrared (FTIR). In addition the functional group of cell walls such as hydroxyl, amide, carbonyl, phosphoric played a critical role in ions adsorption of edible mushroom residues. Cu2+, Zn2+ and Hg2+ in wastewater could be efficiently removed by F. velutipes residue with removal ratio of 73.11%, 66.67% and 69.35%, respectively. PMID- 28865350 TI - How do educational contexts contribute to the social class achievement gap: documenting symbolic violence from a social psychological point of view. AB - This article examines how the educational system participates in the reproduction of social inequality. After exposing the basics of the Social Reproduction Theory developed in sociology by Bourdieu and Passeron in 1977, we examine the research in social psychology that documents the reality of 'symbolic violence' that is the symbolic power that operates in the classroom and undermines the performance of students from underprivileged backgrounds. Three lines of research are examined: self-esteem, self-threat and research on the non-neutrality of educational settings. PMID- 28865352 TI - Is it really penetration? Locomotion of devitalized Enterococcus faecalis cells within dentinal tubules of bovine teeth. AB - OBJECTIVE: The aim of the present study was to evaluate the penetration characteristics of devitalized and vital E. faecalis cells into root dentinal tubules. DESIGN: Thirteen root canals were incubated with devitalized (4days, 7days, 14days, 28days) and vital (28days) E. faecalis strains (streptomycin resistant strains) after root canal enlargement (size 80, taper 0.02) with 3 % NaOCl solution. The smear layer was intentionally removed with 20 % EDTA before inoculation. Samples were processed for analysis by scanning electron microscopy (SEM) and DAPI (4',6-diamidino-2-phenylindole) staining. DAPI was conducted for fluorescence microscopic visualization of the bacterial penetration into dentinal tubules. The penetration depth was calculated with the measurement tool of the Axio Vision program (Zeiss, Jena, Germany). RESULTS: Devitalized E. faecalis strains were able to penetrate into dentinal tubules of the root canal. Apikal penetration depths of the devitalized cells were 100.67MUm+/-26.54MUm after 7days, 230.67MUm+/-111.5MUm after 14days and 266.5MUm+/-92.63MUm after 28days of incubation. The total number and penetration depth of E. faecalis cells was lower compared to a vital suspension of E. faecalis (1002.45MUm) after 28days. It was noted that bacterial penetration was not common to all of the dentinal tubules in the vital E. faecalis control and especially in the devitalized control. CONCLUSIONS: Increased exposure times of devitalized bacteria into root canals lead to an increased number of penetrated dentinal tubules as well as to a deeper penetration. PMID- 28865351 TI - Exogenous testosterone enhances cortisol and affective responses to social evaluative stress in dominant men. AB - Stress often precedes the onset of mental health disorders and is linked to negative impacts on physical health as well. Prior research indicates that testosterone levels are related to reduced stress reactivity in some cases but correlate with increased stress responses in other cases. To resolve these inconsistencies, we tested the causal influence of testosterone on stress reactivity to a social-evaluative stressor. Further, prior work has failed to consider status-relevant individual differences such as trait dominance that may modulate the influence of testosterone on responses to stressors. Participants (n=120 males) were randomly assigned to receive exogenous testosterone or placebo (n=60 testosterone treatment group) via topical gel prior to a well-validated social-evaluative stressor. Compared to placebo, testosterone significantly increased cortisol and negative affect in response to the stressor, especially for men high in trait dominance (95% confidence intervals did not contain zero). The findings suggest that the combination of high testosterone and exposure to status-relevant social stress may confer increased risk for stress-mediated disorders, particularly for individuals high in trait dominance. PMID- 28865354 TI - The discrimination of 72 nitrate, chlorate and perchlorate salts using IR and Raman spectroscopy. AB - Inorganic oxidizing energetic salts including nitrates, chlorates and perchlorates are widely used in the manufacture of not only licit pyrotechnic compositions, but also illicit homemade explosive mixtures. Their identification in forensic laboratories is usually accomplished by either capillary electrophoresis or ion chromatography, with the disadvantage of dissociating the salt into its ions. On the contrary, vibrational spectroscopy, including IR and Raman, enables the non-invasive identification of the salt, i.e. avoiding its dissociation. This study focuses on the discrimination of all nitrate, chlorate and perchlorate salts that are commercially available, using both Raman and IR spectroscopy, with the aim of testing whether every salt can be unequivocally identified. Besides the visual spectra comparison by assigning every band with the corresponding molecular vibrational mode, a statistical analysis based on Pearson correlation was performed to ensure an objective identification, either using Raman, IR or both. Positively, 25 salts (out of 72) were unequivocally identified using Raman, 30 salts when using IR and 44 when combining both techniques. Negatively, some salts were undistinguishable even using both techniques demonstrating there are some salts that provide very similar Raman and IR spectra. PMID- 28865353 TI - Mechanisms involved in facial heat hyperalgesia induced by endothelin-1 in female rats. AB - OBJECTIVE: Pronociceptive responses to endothelins in the trigeminal system seem to be mediated by ETA and ETB receptors, which have been shown to be expressed in neurons of the trigeminal ganglion of humans and rats. The present study aimed to evaluate the ability of endothelin-1 (ET-1) to induce facial heat hyperalgesia in female rats, the contribution of ETA and ETB receptors to this response, as well as the mechanisms underlying heat hyperalgesia induced by ET-1. DESIGN: ET-1 (100pmol/50MUL) was injected into the upper lip and heat hyperalgesia was evaluated for up to 6h. Facial heat hyperalgesia induced by ET-1 was assessed in rats pre-treated locally with BQ-123 or BQ-788 (selective ETA and ETB receptor antagonists, respectively, 30nmol/50MUL); BCTC (TRPV1 receptor antagonist; 300MUg/50MUL); anti-NGF (3MUg/50MUL); K252a (TrkA inhibitor, 1MUg/50MUL); or in rats that received intraganglionar resiniferatoxin injection (RTX, 200ng/10MUL) to promote C-fibers ablation. RESULTS: ET-1 induced facial heat hyperalgesia that persisted up to 6h and was prevented by BQ-123, BQ-788 or by intraganglionar RTX injection. Likewise, local pre-treatment with BCTC abolished ET-1 induced facial heat hyperalgesia up to 3h. Local pre-treatment with anti-NGF or K252a was effective to prevent ET-1 induced heat hyperalgesia. CONCLUSIONS: In conclusion, ET-1 is able to induce heat hyperagelsia in trigeminal primary afferents of female rats, which is mediated by ETA and ETB receptors. Activation of TRPV1 receptors and NGF-signaling pathways may contribute to heat hyperalgesia induced by ET-1. PMID- 28865355 TI - Multi-spectroscopic investigation on the complexation of tetracycline with dissolved organic matter derived from algae and macrophyte. AB - Interactions of antibiotics with algae-derived dissolved organic matter (ADOM) and macrophyte-derived dissolved organic matter (MDOM) are of vital importance to the transport and ecotoxicity of antibiotics in eutrophic freshwater lakes. Multi spectroscopic techniques were used to investigate the complexation of tetracycline (TTC) with ADOM and MDOM collected from Lake Taihu (China). The 3 fluorescent components, tyrosine-, tryptophan-, and humic-like component, were identified by excitation emission matrix spectra with parallel factor analysis. Their fluorescence was quenched at different degree by TTC titration through static quenching. The complexation of TTC induced conformational changes in DOM fractions. Synchronous fluorescence spectra combined with two dimensional correlation spectroscopy further suggested that the formation of TTC-DOM complexes occurred on the sequential order of tryptophan-like->tyrosine-like >humic-like component. The effective quenching constants of tryptophan- and tyrosine-like component were similar, higher than those of humic-like component. The strong binding ability and abundant content of protein-like substances indicated their prominent role in the TTC-DOM complexation. Fourier transform infrared spectroscopy further revealed that the heterogeneous functional groups, including amide I and II, aromatics, and aliphatics, were responsible for the complexation. These results highlight the significant impact of the overgrowth of algae and macrophyte on the environmental behavior of antibiotics in waters. PMID- 28865356 TI - Chemical composition of submicron and fine particulate matter collected in Krakow, Poland. Consequences for the APARIC project. AB - Submicron particulate matter containing particles with an aerodynamic diameter <=1 MUm (PM1) are not monitored continuously by Environmental Protection Agencies around the World and are seldom studied. Numerous studies have indicated that people exposed to ultrafine (<=100 nm), submicron and fine particulate matter containing particles with an aerodynamic diameter <=2.5 MUm (PM2.5), can suffer from respiratory track diseases, cardiovascular, immunological or heart diseases and others. Inorganic pollutants containing redox active transition metals and small gaseous molecules, are involved in the generation of reactive oxygen and reactive nitrogen species. Inhalation of this kind of particles can affect immune toxicity. Environmental pollution may aggravate the course of autoimmune diseases, in particular influence the mechanisms of the autoimmune system. Important factors that influence the toxicity of particulate matter, are particle size distribution, composition and concentration. This report deals with the composition of PM1 and PM2.5 fractions collected in Krakow, Poland. In spring 2015, the mean concentrations of PM1 and PM2.5 were 19 +/- 14 and 27 +/- 19 MUg/m3, respectively. The PM2.5 fraction contained approximately 70 +/- 17% of submicron particulate matter. In spring 2016, the mean concentrations of PM1 and PM2.5 were 12 +/- 5 and 22 +/- 12 MUg/m3, respectively. The PM2.5 fraction contained approximately 60 +/- 15% of submicron particulate matter. The concentrations of the elements Cl, K, Ca, Ti, Cr, Mn, Fe, Ni, Cu, Zn, Br, Rb, Sr and Pb in both fractions were determined by X-ray fluorescence spectrometry. Most of the analyzed metals had higher concentrations in the fine fraction than in the submicron one. Concentrations of V and As were below the detection limit in both fractions, whereas concentrations of Mn and Ca were below the detection limits in the PM1 fraction. The results are discussed in terms of the consequences they may have on the APARIC project presently underway in Krakow. PMID- 28865357 TI - Check point inhibitors as therapies for infectious diseases. AB - The recent successes of immune check point targeting therapies in treating cancer patients has driven a resurgence of interest in targeting these pathways in chronically infected patients. While still in early stages, basic and clinical data suggest that blockade of CTLA-4 and PD-1 can be beneficial in the treatment of chronic HIV, HBV, and HCV infection, as well as other chronic maladies. Furthermore, novel inhibitory receptors such as Tim-3, LAG-3, and TIGIT are the potential next wave of check points that can be manipulated for the treatment of chronic infection. Blockade of these pathways influences more than simply T cell responses, and may provide new therapeutic options for chronically infected patients. PMID- 28865358 TI - Fabrication of all-trans-retinoic acid-loaded biocompatible precirol: A strategy for escaping dose-dependent side effects of doxorubicin. AB - BACKGROUND: Drug delivery-based nanoparticles have been emerged to be an alternative and efficient approach to cancer therapy compared to conventional systems. Here, we investigated the role of all-trans retinoic acid (ATRA) formulated with precirol in increasing doxorubicin (Dox) induced apoptosis and cell cycle arrest in MDA-MB-231 breast cancer cells. METHODS: ATRA-loaded Nano structured lipid carriers (NLCs) were evaluated in terms of particle size, zeta potential, Fourier transforms infrared spectroscopy (FTIR), cell internalization, and scanning electron microscope (SEM). To understand molecular mechanism of apoptosis and cell cycle progression flow cytometric assay, MTT and DAPI staining was applied. Real time (RT)-PCR analysis was employed to investigate the expression of apoptosis related genes, including Survivin, Bcl-2 and Bax. RESULTS: The optimized ATRA formulation exhibited average particle size of 95+/ 5nm with nearly narrow size distribution. The IC50 values for ATRA and doxorubicin were 48+/-0.4MUM and 0.81+/-0.02MUM, respectively. ATRA-loaded NLCs decreased percentage of cell proliferation from 51+/-7.2% to 36+/-4.1% (p <0.05). Co-treatment of the MDA-MB-231 cells with ATRA formulation and doxorubicin caused two-fold increase in the percentage of apoptosis (p<0.05). The results from gene expression exhibited a significant decrease in survivin along with increase at Bax mRNA levels accompanied by a slight increase in Bax/Bcl-2 ratio. CONCLUSION: Our results propose that ATRA encapsulated in precirol as a biocompatible compound augments the efficacy of Dox in cancer therapy. PMID- 28865359 TI - Thermosensitive in situ nanocomposite of rivastigmine hydrogen tartrate as an intranasal delivery system: Development, characterization, ex vivo permeation and cellular studies. AB - Intranasal administration of pharmaceutical compounds is gaining considerable attention as an alternative route for localized/systemic drug delivery. However, insufficient therapeutic efficacy of drugs via this route seems to be a major challenge for development of de novo intranasal formulations. This shortcoming can be overcome by simultaneous utilization of a nanoparticulate delivery system with a polymeric gel network. Therefore, the main aim of the present study was to develop erodible in-situ gel forming systems of poloxamer 407(r) (P407) as a promising platform, capable of prolonging rivastigmine hydrogen tartrate (RHT) release from the embedded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). PLGA NPs containing RHT were formulated and characterized, then were embedded in P407 gel forming matrix and analyzed in terms of viscosity, stability, gelation temperature, loading efficiency and mucoahesive behavior. The cytotoxicity of NPs was evaluated on A549 cell line using MTT assay. Cellular uptake of the NPs was also measured by means of fluorescence microcopy and flow cytometry analyses. The formulations were finally evaluated for their permeability across sheep nasal mucosa. A linear dependence of sol-gel temperature (Tsol-gel) on the P407 concentration was observed, and a P407 content of 18% was selected. The loading efficiencies of formulations were found to be around 100.22-104.31%. The RHT-loaded NPs showed a suitable cytocompatibility on A549 cells with a time-dependent increase in cellular uptake. Besides, nanocomposites showed higher amounts of drug permeation through nasal sheep mucosa than plain drug gel. Taken all, it is concluded that the formulated nanocomposites may be considered as useful drug delivery systems for the nasal delivery of RHT with enhanced therapeutic efficacy. PMID- 28865360 TI - Quantification of cell-substratum interactions by atomic force microscopy. AB - Microorganisms adhere to surfaces and, subsequently, form biofilms. This process is of major interest in biotechnology, environmental sciences and medicine. It is crucial to understand the mechanisms of interactions between substratum and cells or biofilms. By combining force mapping-based atomic force microscopy (AFM) with pyrite-modified cantilevers we quantified the adhesion forces between undenatured planktonic or biofilm cells of Sulfobacillus thermosulfidooxidans and the substratum pyrite with values of 2.6+/-0.3nN and 77.3+/-7.1pN, respectively. This was achieved under natural conditions without any artefact resulting from the use of denaturing chemicals such as glutaraldehyde. This new technique is unique for quantifying the real interaction forces between cells or biofilms and their substrata. PMID- 28865361 TI - Recent advances in biocompatible semiconductor nanocrystals for immunobiological applications. AB - Quantum confinement in inorganic semiconductor nanocrystals produces brightly luminescent nanoparticles endowed with unique photo-physical properties, such as tunable optical properties. These have found widespread applications in nanotechnology. The ability to render such nanostructures biocompatible, while maintaining their tunable radiation in the visible range of the electromagnetic spectrum, renders them appropriate for bio-applications. Promising in vitro and in vivo diagnostic applications have been demonstrated, such as fluorescence based detection of biological interactions, single molecule tracking, multiplexing and immunoassaying. In particular, these fluorescent inorganic semiconductor nanocrystals, generally known as quantum dots, have the potential of remarkable immunobiological applications. This review focuses on the current status of biocompatible quantum dots and their applications in immunobiology - immunosensing, immunofluorescent imaging and immunotherapy. PMID- 28865362 TI - The association between multidimensional feminine norms, binge drinking and alcohol-related problems among young adult college women. AB - Alcohol consumption among women has steadily increased over the past 30years, and women's drinking behavior is now similar to that of men's. The escalation of alcohol use among women highlights the critical need to examine gender issues and motivational factors that contribute to binge drinking and related problems within this population. Feminine norms or the socially constructed beliefs, messages and attitudes about what it means to be a woman may contribute to within group differences in drinking patterns among women. The current study examined the relationship between multidimensional feminine norms and binge drinking and alcohol-related problems among 1910 college women. Participants completed a self report measure of binge drinking, alcohol-related problems, conformity to feminine norms, alcohol expectancies and descriptive norms. Controlling for the covariates descriptive norms, positive alcohol expectancies, and sorority membership, adherence to feminine norms related to sexual fidelity and belief that one needs to be sweet and nice were negatively associated to binge drinking, while adhering to investment in appearance was positively associated to binge drinking and alcohol-related problems. Distinct feminine norms also had a significant indirect effect on alcohol-related problems through binge drinking. This study significant contributes to the literature by elucidating the theoretically gender-relevant risk and protective aspects of feminine norms in relation to binge drinking and related problems, and provides important information that might be used in clinical and prevention efforts to reduce alcohol-related harm among a vulnerable group: college women. PMID- 28865363 TI - Postcessation weight gain concern as a barrier to smoking cessation: Assessment considerations and future directions. AB - PURPOSE: Concern about postcessation weight gain may be one potential barrier to quitting smoking. In this 'mini-review' of recent literature, we summarize findings on the relationship between postcessation weight gain concern and smoking cessation, and evaluate varied use of postcessation weight gain concern assessments and potential moderators of the postcessation weight gain concern cessation association. METHODS: We conducted a search using the terms "smoking" OR "smoking cessation" AND "weight concern" for articles published between January 1, 2011 and December 31, 2016. We identified 17 studies assessing postcessation weight gain concern, seven of which evaluated the postcessation weight gain concern-cessation association. RESULTS: The relationship between postcessation weight gain concern and smoking cessation was mixed. Recent studies varied in their assessments of postcessation weight gain concern, many of which were not validated and assessed correlates of this construct. Studies varied in their adjustment of demographic (e.g., sex), smoking-specific (e.g., smoking level), and weight-specific (e.g., body mass index) variables. CONCLUSIONS: The use of non-validated assessments and variability in testing covariates/moderators may contribute to conflicting results regarding the postcessation weight gain concern-cessation relationship. We recommend validating an assessment of postcessation weight gain concern, maintaining vigilance in testing and reporting covariates/moderators, and investigating trajectories of this construct over time and by smoking status to inform future assessment and intervention efforts. PMID- 28865364 TI - Antitumor activity of Lobaplatin against esophageal squamous cell carcinoma through caspase-dependent apoptosis and increasing the Bax/Bcl-2 ratio. AB - Esophageal cancer is one of the most aggressive malignancies with poor prognosis. The administration of the first- and second-generation platinum drugs is frequently accompanied by drug resistance and severe toxicity. The aim of present study is to investigate the anti-tumor activity of the third-generation platinum drug Lobaplatin against esophageal squamous cell carcinoma in vitro and in vivo, and clarify the underlying molecular mechanism. The cytotoxicity of Lobaplatin against esophageal squamous cell carcinoma cell lines was determined by the MTT and clonogenic assay. Cell apoptosis was assessed by Annexin V-FITC/PI apoptosis assay using flow cytometry. The expression of proteins was determined by western blot analysis. The in vivo anti-tumor activity was evaluated in nude mice xenograft. Lobaplatin significantly inhibited the growth of KYSE-410 and EC-109 cells in a dose- and time-dependent manner and induced cell apoptosis by increasing expressions of cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9 and Bax, decreasing expression of Bcl-2. In vivo study showed that Lobaplatin suppressed tumor growth of EC-109 xenograft. Lobaplatin significantly inhibited the growth of esophageal squamous cell carcinoma by inducing apoptosis through the caspase-dependent pathway. Lobaplatin is an effective anti-cancer agent against esophageal cancer. PMID- 28865365 TI - MiR125b-5p protects endothelial cells from apoptosis under oxidative stress. AB - Endothelial cell damage, such as apoptosis and necrosis, is involved in many cardiovascular diseases. In recent years, the crucial role of microRNAs in controlling tissue homeostasis and disease in the epithelium has become widely recognized. In the present study, human umbilical vein endothelial cells were transfected with a miRNA agomir and a SMAD4 expression vector. The expression of miR125b-5p was determined by using quantitative real-time polymerase chain reaction. Cell apoptosis and necrosis were measured with flow cytometry. The expression of SMAD4 was evaluated with Western blotting. Here, we demonstrated that the rates of apoptosis and necrosis were significantly decreased in the miR125b-5p agomir group of HUVECs under H2O2-induced oxidative stress compared with the miR125b-5p antagomir group. Further experiments revealed that the expression of SMAD4 is negatively regulated by miR125b-5p. Moreover, we identified that the rates of apoptosis and necrosis were increased when SMAD4 and miR125b-5p were both overexpressed compared with miR125b-5p overexpression alone. The present study demonstrates for the first time that the overexpression of miR125b-5p can reduce H2O2-induced oxidative damage via SMAD4, suggesting that miR125b-5p has therapeutic potential for preventing oxidative stress-related diseases. PMID- 28865366 TI - Buyanghuanwu Decoction alleviated pressure overload induced cardiac remodeling by suppressing Tgf-beta/Smads and MAPKs signaling activated fibrosis. AB - Buyanghuanwu Decoction (BHD), a traditional Chinese medicine recipe, is a representative prescription for the treatment of qi-deficiency and blood-stasis syndrome. In this study, the effect of BHD on pressure overload induced cardiac remodeling was investigated and possible mechanism underlying was explored. Rats were randomly divided into four groups: sham, transverse aorta constriction (TAC) with saline, TAC with telmisartan (TAC+Tel), and TAC with BHD (TAC+BHD) for 16 weeks (n=6~8 in each group). Cardiac morphological and functional changes were evaluated by echocardiography and histological methods, the molecular alterations were detected by western blotting. Our results revealed that pressure overload prominently induced cardiac dysfunction, dilated and atrophied left ventricle, decreased cardiomyocyte cross sectional area, and fibrosis. However, BHD, similar to Tel, greatly reversed cardiac dysfunction, left ventricular dilation, and fibrosis, together with increased left ventricular wall thickness and size of cardiomyocyte. Furthermore, activated classical pro-fibrotic signaling of Tgf beta/Smads and MAPKs after TAC was dramatically suppressed by BHD or Tel treatment. Taken together, it was demonstrated in this study that BHD exerted a cardioprotective effect against pressure overload induced cardiac remodeling via inactivation of Tgf-beta/Smads and MAPKs signaling triggered fibrosis. PMID- 28865367 TI - The role of radionuclide probes for monitoring anti-tumor drugs efficacy: A brief review. AB - Despite recent advances in the development of new therapeutic agents and diagnostic imaging modalities, cancer is still one of the main causes of death worldwide. A better understanding of the molecular signature of cancer has promoted the development of a new generation of anti-cancer drugs and diagnostic agents that specifically target molecular components such as genes, ligands, receptors and signaling pathways. However, intrinsic heterogeneity of tumors has hampered the overall success of target therapies even among patients with similar tumor types but unpredictable different responses to therapy. In this sense, post treatment response monitoring becomes indispensable and nuclear medicine imaging modalities could provide the tools for an early indication of therapeutic efficacy. Herein, we briefly discuss the current role of PET and SPECT imaging in monitoring cancer therapy together with an update on the current radiolabeled probes that are currently investigated for tumor therapy response assessment. PMID- 28865368 TI - Sweroside eradicated leukemia cells and attenuated pathogenic processes in mice by inducing apoptosis. AB - Acute myeloid leukemia (AML), characterized by extremely heterogeneous molecular and biologic abnormalities, is an aggressive hematologic malignancy, hampering the research and development of effective targeted treatment modalities. Sweroside (SWE), an iridoid glycoside, is isolated from Lonicera japonIca. It has diverse biological activities, but little is known in human leukemia. Here, our study showed the potential of sweroside as an effective agent against human leukemia using in vitro and in vivo approaches. Sweroside treatment obviously reduced the cell viability in human leukemia cell lines and primary human leukemia cells. S and G2/M cell-cycle arrest were induced by sweroside, associated with the down-regulation of Cyclin D1, cyclin-dependent kinase 4 (CDK4), CDC2 and CDC25 as well as the up-regulation of p53 and p21. In addition, apoptosis was highly induced by sweroside both in vitro and in vivo through enhancement of cleaved Caspase-3 and poly (ADP-ribosyl) transferase (PARP). Consistently, anti-apoptotic molecule of B cell CLL/lymphoma 2 (Bcl-2) was impeded by sweroside, while pro-apoptotic signal of Bcl-2-associated X protein (Bax) was elevated. In vivo, HL-60-bearing tumor growth was considerably inhibited by sweroside, which was related to proliferation suppression and apoptosis induction. Our study highlighted the therapeutic potential of sweroside, and provided new insights into the molecular mechanism of sweroside chemosensitization in human leukemia. PMID- 28865369 TI - Binge eating behaviours in bipolar disorders. AB - BACKGROUND: Recent research, especially from the USA, suggests that comorbid binge eating (BE) behaviour and BE disorder are frequent in individuals with Bipolar Disorder (BD). Although basic clinical associations between BD and BE have been investigated, less is known about psychological or temperamental dimensions and qualitative aspects of eating habits. In a French cohort of patients with BD, we investigated the prevalence of BE behaviour and any associations with illness characteristics, anxiety, impulsivity, emotional regulation and eating habits. METHODS: 145 outpatients with BD (I and II) were assessed for the presence of BE behaviour using the Binge Eating Scale (BES). Characteristics identified in univariate analyses as differentiating BD cases with and without BE behaviour were then included in a backward stepwise logistic regression (BSLR) model. RESULTS: In this sample, 18.6% of BD patients met criteria for BE behaviour. Multivariate analysis (BSLR) indicated that shorter duration of BD, and higher levels of anxiety and emotional reactivity were observed in BD with compared to BD without BE behaviour. LIMITATIONS: Relatively small sample referred to specialist BD clinics and cross-sectional evaluation meant that it was not possible to differentiate between state and trait levels of impulsivity, emotional instability and disinhibition. These dimensions may also overlap with mood symptoms. CONCLUSION: BE behaviour is common in females and males with BD. Emotional dysregulation and anxiety may represent important shared vulnerability factors for worse outcome of BD and increased likelihood of BE behaviour. PMID- 28865370 TI - The relative influence of individual risk factors for attempted suicide in patients with bipolar I versus bipolar II disorder. AB - OBJECTIVES: To compare the relative influence (RI) of individual predictors for lifetime attempted suicide between adults with bipolar I (BDBD-I) and bipolar II disorder (BDBD-II). METHODS: We conducted an analysis of data from 1465 enrollees in the Mayo Clinic Bipolar Disorder Biobank. Demographic and clinical variables and history of attempted suicide were ascertained using standardized questionnaires. Height and weight were assessed to determine body mass index (BMI); obesity was defined as BMI >=30kg/m2. The frequencies of these variables were compared between persons with and without self-reported lifetime suicide attempts both overall, and within BD-I and BD-II subgroups. Gradient boosting machine (GBM) models were used to quantify the RI of study variables on the risk of lifetime attempted suicide. RESULTS: Nearly one-third of patients reported having a lifetime suicide attempt. Attempted suicide rates were higher in patients with BD-I than BD-II, but absolute differences were small. Lifetime attempted suicide was associated with female sex, BD-I subtype, psychiatric and substance use comorbidities, binge eating behavior, lifetime history of rapid cycling, other indicators of adverse illness course, and early age of bipolar illness onset in the entire cohort. Differences in the rank-ordering of RI for predictors of attempted suicide between BD-I and BD-II patients were modest. Rapid cycling was a strong risk factor for attempted suicide, particularly in men with BD-I. LIMITATIONS: Actively psychotic or suicidal patients needing psychiatric hospitalization were initially excluded, but were approached after these acute psychiatric problems resolved. CONCLUSIONS: The prevalence of lifetime attempted suicide was significantly higher in BD-I than BD-II in this large, cross-sectional cohort. Predictors of attempted suicide were similar in BD I and BD-II subgroups. PMID- 28865371 TI - The relationship between cognitions and symptoms in obsessive-compulsive disorder. AB - BACKGROUND: The cognitive theory of obsessive-compulsive disorder (OCD) ascertains that catastrophic (mis)interpretations of normally occurring intrusive thoughts are related to the maintenance of OCD. Nonetheless, findings supporting the relationship between cognitive biases and OCD symptoms are largely inconsistent. In the present study we examined the relationship between OCD cognitions and symptoms among 382 OCD patients participating in the longitudinal Netherlands Obsessive Compulsive Disorder Association (NOCDA) study. METHODS: OCD cognitions and OC, anxiety and depressive symptoms were assessed using self report questionnaires at baseline and at two-year follow-up. Baseline multiple regression analyses assessed the specificity of OC cognitions to OCD symptoms. Cross-lagged analyses examined whether cognitions predict OCD symptoms at two year follow up. RESULTS: Baseline analyses demonstrated significant relationships between comorbid anxiety, depressive severity and OC cognitions, adjusted for OCD symptoms (beta = .283, p < .001 and beta = .246, p < .001, respectively). OCD severity adjusted for comorbid symptoms was unrelated to cognitions at baseline (beta = .040, p = n.s). Unique associations were found between cognitions and two OCD symptom subtypes (Impulses: beta = .215, p < .001; Rumination/doubting: beta = .205, p < .001). Longitudinal analyses yielded non-significant associations between OCD cognitions and symptom severity. Prospective analyses of cognitions and OCD symptom subtypes yielded significant effects for both bidirectional and unidirectional associations (beta = .11-.16, p < .05). LIMITATIONS: Given the naturalistic design of the study, we did not assess therapeutic interventions between baseline and follow-up. CONCLUSIONS: Results only partially concord with the predictions of the cognitive theory of OCD. Future studies should focus on mechanisms alternative to cognitions when investigating the course of OCD. PMID- 28865372 TI - Impact of inoculum sources on biotransformation of pharmaceuticals and personal care products. AB - Limited knowledge of optimal microbial community composition for PPCP biotreatment, and of the microbial phylotypes that drive biotransformation within mixed microbial communities, has hindered the rational design and operation of effective and reliable biological PPCP treatment technologies. Herein, bacterial community composition was investigated as an isolated variable within batch biofilm reactors via comparison of PPCP removals for three distinct inocula. Inocula pre-acclimated to model PPCPs were derived from activated sludge (AS), ditch sediment historically-impacted by wastewater treatment plant effluent (Sd), and material from laboratory-scale soil aquifer treatment (SAT) columns. PPCP removals were found to be substantially higher for AS- and Sd-derived inocula compared to the SAT-derived inocula despite comparable biomass. Removal patterns differed among the 6 model compounds examined (diclofenac, 5-fluorouracil, gabapentin, gemfibrozil, ibuprofen, and triclosan) indicating differences in biotransformation mechanisms. Sphingomonas, Beijerinckia, Methylophilus, and unknown Cytophagaceae were linked with successful PPCP biodegradation via next generation sequencing of 16S rRNA genes over time. Results indicate the criticality of applying engineering approaches to control bacterial community compositions in biotreatment systems. PMID- 28865373 TI - Evaluation of risk assessment of new industrial pollutant, ionic liquids on environmental living systems. AB - Ionic liquids (ILs) are much known for their promising alternative for volatile solvents in industries and gained popularity as a greener solvent, however industrial effluent discharge containing ILs are also increasing. There is a scarcity of information on the toxicity of ILs; the present study will explore different facts about their harmfulness. The toxic effects of five different ILs: [C4MIM]Br, [Hx3PC14]N(CN)2, [C10MIM]BF4, [BTDA]Cl and [C4MPY]Cl were analysed on bacteria, fungi, plant and animal cells. Both Gram positive and negative bacteria were found to be more susceptible to [C10MIM]BF4 and [BTDA]Cl than [C4MIM]Br, [Hx3PC14]N(CN)2 and [C4MPY]Cl, whereas fungi revealed quite a resistance to all ILs. All ILs were toxic towards Triticum aestivum affecting their roots and shoots, however [C10MIM]BF4 and [BTDA]Cl were more toxic amongst them. Studies on Allium cepa described their toxic behaviour at the genetic level by altering cell division and nuclear material. Furthermore, studies on human red blood cells described by % haemolysis in which [Hx3PC14]N(CN)2 and [BTDA]Cl exhibited higher toxicity at very lower concentrations. While the genotoxic effect on blood lymphocytes exerted by [Hx3PC14]N(CN)2, [C10MIM]BF4 and [BTDA]Cl confirmed their toxic effects on human cells. PMID- 28865374 TI - Microbial competition among anammox bacteria in nitrite-limited bioreactors. AB - Phylogenetically diverse anammox bacteria have been detected in most of anoxic natural and engineered ecosystems and thus regarded as key players in the global nitrogen cycle. However, ecological niche differentiation of anammox bacteria remains unresolved despite its ecological and practical importance. In this study, the microbial competitions for a common substrate (nitrite) among three anammox species (i.e. "Candidatus Brocadia sinica", "Candidatus Jettenia caeni" and "Candidatus Kuenenia stuttgartiensis") were systematically investigated in nitrite-limited gel-immobilized column reactors (GICR) and membrane bioreactors (MBRs) under different nitrogen loading rates (NLRs). 16 S rRNA gene-based population dynamics revealed that "Ca. J. caeni" could proliferate only at low NLRs, whereas "Ca. B. sinica" outcompeted other two species at higher NLRs in both types of reactors. Furthermore, FISH analysis revealed that "Ca. J. caeni" was mainly present as spherical microclusters at the inner part (low NO2- environment), whereas "Ca. B. sinica" was present throughout the gel beads and granules. This spatial distribution supports the outcomes of the competition experiments. However, the successful competition of "Ca. J. caeni" at low NLR could not be explained with the Monod model probably due to inaccuracy of kinetic parameters such as half saturation constant (Ks) for nitrite and a difference in the maintenance rate (m). In addition, the growth of "Ca. K. stuttgartiensis" could not be observed in any experimental conditions, suggesting possible unknown factor(s) is missing. Taken together, NLR was one of factors determining ecological niche differentiation of "Ca. B. sinica" and "Ca. J. caeni". PMID- 28865375 TI - Dramatic enhancement of organics degradation and electricity generation via strengthening superoxide radical by using a novel 3D AQS/PPy-GF cathode. AB - A dramatic enhancement of organics degradation and electricity generation has been achieved in a wastewater fuel cell (WFC) system via strengthening superoxide radical with radical chain reaction by using a novel 3D anthraquinone/polypyrrole modified graphite felt (AQS/PPy-GF) cathode. The AQS/PPy-GF was synthesized by one-pot electrochemical polymerization method and used to in-situ generate superoxide radical by reducing oxygen under self-imposed electric field. Results showed that methyl orange (MO) were effectively degraded in AQS/PPy-GF/Fe2+ system with a high apparent rate constant (0.0677 min-1), which was 3.9 times that (0.0174 min-1) in the Pt/Fe2+ system and even 9.4 times that (0.0072 min-1) in the traditional WFC system (without Fe2+). Meanwhile, it showed a superior performance for electricity generation and the maximum power density output (1.130 mW cm-2) was nearly 3.3 times and 5.0 times higher, respectively, when compared with the Pt/Fe2+ system and traditional WFC. This dramatic advance was attributed to 3D AQS/PPy-GF cathode which produces more O2- via one-electron reduction process. The presence of O2- cannot only directly contribute to MO degradation, but also promotes the final complete mineralization by turning itself to OH. Additionally, O2- accelerates the Fe2+/Fe3+ couple cycling, thus avoiding continuous addition of any external ferrous ions. Inhibition and probe studies were conducted to ascertain the role of several radicals (OH and O2-) on the MO degradation. Superoxide radicals were considered as the primary reactive oxidants, and the degradation mechanism of MO was proposed. The proposed WFC system provides a more economical and efficient way for energy recovery and wastewater treatment. PMID- 28865376 TI - Assessment of the microbial growth potential of slow sand filtrate with the biomass production potential test in comparison with the assimilable organic carbon method. AB - Slow sand filtration is the final treatment step at four surface-water supplies in the Netherlands. The microbial growth potential (MGP) of the finished water was measured with the assimilable organic carbon (AOC) method using pure cultures and the biomass production potential (BPP) test. In the BPP test, water samples were incubated untreated at 25 degrees C and the active-biomass concentration was measured by adenosine tri-phosphate (ATP) analysis. Addition of a river-water inoculum improved the test performance and characteristic growth and maintenance profiles of the water were obtained. The maximum ATP concentration attained within seven days and the cumulative biomass production after 14 days of incubation (BPC14, d ng ATP L-1) showed highly significant and strong linear relationships with the AOC in the slow sand filtrates. The lowest AOC and BPC14 levels were observed in the supplies applying dune filtration without ozonation in post treatment, with AOC/TOC = 1.7 +/- 0.3 MUg acetate-C equivalents mg-1 C and BPC14/TOC = 16.3 +/- 2.2 d ng ATP mg-1 C, corresponding with 1.2 +/- 0.19 ng ATP mg-1 C. These characteristics may represent the lowest specific MGP of natural organic matter achievable by biofiltration at temperatures <=20 degrees C. The AOC and BPC14 concentrations in the slow sand filtrate of the supply treating lake water by ozonation with granular-activated-carbon filtration and slow sand filtration as post treatment increased with decreasing temperature. The BPP test revealed that this slow sand filtrate sampled at 2 degrees C contained growth-promoting compounds that were not detected with the AOC test. These observations demonstrate the utility of the BPP test for assessing the MGP of drinking water and show the performance limits of biofiltration for MGP reduction. PMID- 28865377 TI - Assessing pain in patients with chronic disorders of consciousness: Are we heading in the right direction? AB - The deterioration of sensory-motor integration within the pain matrix in patients with chronic Disorders of Consciousness (DoC) is one of the principal mechanisms responsible for non-conscious pain perception. The present study aimed to assess whether the variability in the inter-peak interval (IPI) between the N2 and P2 components of laser evoked potentials (LEP) could represent an objective marker of the behavioral responsiveness to nociceptive stimulation, as measured by the Nociception Coma Scale-Revised (NCS-R), and regardless of the sensory part of pain processing. We found that only IPI variability showed a significant correlation with NCS-R score, independently of the stimulation intensity (that influences the sensory part of pain processing). It was thus concluded that IPI variability might represent an objective measure of pain processing, which may help clinicians in the development of effective pain management strategies. PMID- 28865379 TI - Quantitative sensory tests (QST) are promising tests for clinical relevance of anti-nociceptive effects of new analgesic treatments. PMID- 28865378 TI - High-throughput dietary exposure predictions for chemical migrants from food contact substances for use in chemical prioritization. AB - Under the ExpoCast program, United States Environmental Protection Agency (EPA) researchers have developed a high-throughput (HT) framework for estimating aggregate exposures to chemicals from multiple pathways to support rapid prioritization of chemicals. Here, we present methods to estimate HT exposures to chemicals migrating into food from food contact substances (FCS). These methods consisted of combining an empirical model of chemical migration with estimates of daily population food intakes derived from food diaries from the National Health and Nutrition Examination Survey (NHANES). A linear regression model for migration at equilibrium was developed by fitting available migration measurements as a function of temperature, food type (i.e., fatty, aqueous, acidic, alcoholic), initial chemical concentration in the FCS (C0) and chemical properties. The most predictive variables in the resulting model were C0, molecular weight, log Kow, and food type (R2=0.71, p<0.0001). Migration-based concentrations for 1009 chemicals identified via publicly-available data sources as being present in polymer FCSs were predicted for 12 food groups (combinations of 3 storage temperatures and food type). The model was parameterized with screening-level estimates of C0 based on the functional role of chemicals in FCS. By combining these concentrations with daily intakes for food groups derived from NHANES, population ingestion exposures of chemical in mg/kg-bodyweight/day (mg/kg BW/day) were estimated. Calibrated aggregate exposures were estimated for 1931 chemicals by fitting HT FCS and consumer product exposures to exposures inferred from NHANES biomonitoring (R2=0.61, p<0.001); both FCS and consumer product pathway exposures were significantly predictive of inferred exposures. Including the FCS pathway significantly impacted the ratio of predicted exposures to those estimated to produce steady-state blood concentrations equal to in-vitro bioactive concentrations. While these HT methods have large uncertainties (and thus may not be appropriate for assessments of single chemicals), they can provide critical refinement to aggregate exposure predictions used in risk-based chemical priority-setting. PMID- 28865380 TI - Exploration of biodegradation mechanisms of black carbon-bound nonylphenol in black carbon-amended sediment. AB - The present study aimed to investigate biodegradation mechanisms of black carbon (BC)-bound contaminants in BC-amended sediment when BC was applied to control organic pollution. The single-point Tenax desorption technique was applied to track the species changes of nonylphenol (NP) during biodegradation process in the rice straw carbon (RC)-amended sediment. And the correlation between the biodegradation and desorption of NP was analyzed. Results showed that microorganisms firstly degraded the rapid-desorbing NP (6 h Tenax desorption) in RC-amended sediment. The biodegradation facilitated the desorption of slow desorbing NP, which was subsequently degraded as well (192 h Tenax desorption). Notably, the final amount of NP degradation was greater than that of NP desorption, indicating that absorbed NP by RC amendment can be degraded by microorganisms. Finally, the residual NP amount in RC-amended sediment was decided by RC content and its physicochemical property. Moreover, the presence of the biofilm was observed by the confocal laser scanning microscope (CLSM) and scanning electron microscope (SEM) so that microorganisms were able to overcome the mass transfer resistance and directly utilized the absorbed NP. Therefore, single-point Tenax desorption alone may not be an adequate basis for the prediction of the bioaccessibility of contaminants to microorganisms or bioremediation potential in BC-amended sediment. PMID- 28865381 TI - Nonmalignant respiratory mortality and long-term exposure to PM10 and SO2: A 12 year cohort study in northern China. PMID- 28865382 TI - Air quality considerations for stormwater green street design. AB - Green streets are increasingly being used as a stormwater management strategy to mitigate stormwater runoff at its source while providing other environmental and societal benefits, including connecting pedestrians to the street. Simultaneously, human exposure to particulate matter from urban transportation is of major concern worldwide due to the proximity of pedestrians, drivers, and cyclists to the emission sources. Vegetation used for stormwater treatment can help designers limit the exposure of people to air pollutants. This goal can be achieved through the deliberate placement of green streets, along with strategic planting schemes that maximize pollutant dispersion. This communication presents general design considerations for green streets that combine stormwater management and air quality goals. There is currently limited guidance on designing green streets for air quality considerations; this is the first communication to offer suggestions and advice for the design of green stormwater streets in regards to their effects on air quality. Street characteristics including (1) the width to height ratio of the street to the buildings, (2) the type of trees and their location, and (3) any prevailing winds can have an impact on pollutant concentrations within the street and along sidewalks. Vegetation within stormwater control measures has the ability to reduce particulate matter concentrations; however, it must be carefully selected and placed within the green street to promote the dispersion of air flow. PMID- 28865383 TI - Fluoride concentrations in traditional and herbal teas: Health risk assessment. AB - Traditional tea (Camellia sinensis) and herbal tea are being consumed across the world. However, long term consumption of tea can increase the chances of fluorosis owing to the presence of fluoride (F) in teas. Therefore, it is imperative to assess the health risk associated with tea consumption. The main objectives of this study were to: 1) estimate total F in 47 popular teas, including traditional and herbal teas and F concentrations in 1% (w/v) infusion of 5 min, and 2) assess the exposure risks of F from tea consumption in children and adults. The data showed that total F was the least in herbal teas (33-102 mg/kg) and their infusions (0.06-0.69 mg/L) compared to traditional teas (296 1112 mg/kg) and their infusions (1.47-6.9 mg/L). During tea infusion, 6-96% and 18-99% of the F was released into the water from herbal and traditional teas, respectively. Ten samples of traditional teas, including five green teas had chronic daily intake (CDI) values of F > 0.05 mg/d/kg bw, the stipulated permissible limits of F intake from all sources. Although the F from teas posed no immediate health hazards with hazard quotient <1, some tea samples could potentially contribute >4 mg F/d, thereby adding to the overall F burden. Therefore, together with F from food and water sources, daily F consumptions from teas might increase its health risks to humans. So, caution should be excised when drinking teas containing high F. PMID- 28865384 TI - Widespread detection of a brominated flame retardant, hexabromocyclododecane, in expanded polystyrene marine debris and microplastics from South Korea and the Asia-Pacific coastal region. AB - The role of marine plastic debris and microplastics as a carrier of hazardous chemicals in the marine environment is an emerging issue. This study investigated expanded polystyrene (EPS, commonly known as styrofoam) debris, which is a common marine debris item worldwide, and its additive chemical, hexabromocyclododecane (HBCD). To obtain a better understanding of chemical dispersion via EPS pollution in the marine environment, intensive monitoring of HBCD levels in EPS debris and microplastics was conducted in South Korea, where EPS is the predominant marine debris originate mainly from fishing and aquaculture buoys. At the same time, EPS debris were collected from 12 other countries in the Asia-Pacific region, and HBCD concentrations were measured. HBCD was detected extensively in EPS buoy debris and EPS microplastics stranded along the Korean coasts, which might be related to the detection of a quantity of HBCD in non-flame-retardant EPS bead (raw material). The wide detection of the flame retardant in sea-floating buoys, and the recycling of high-HBCD-containing EPS waste inside large buoys highlight the need for proper guidelines for the production and use of EPS raw materials, and the recycling of EPS waste. HBCD was also abundantly detected in EPS debris collected from the Asia-Pacific coastal region, indicating that HBCD contamination via EPS debris is a common environmental issue worldwide. Suspected tsunami debris from Alaskan beaches indicated that EPS debris has the potential for long-range transport in the ocean, accompanying the movement of hazardous chemicals. The results of this study indicate that EPS debris can be a source of HBCD in marine environments and marine food web. PMID- 28865386 TI - Response of Rhizobium to Cd exposure: A volatile perspective. AB - The volatile metabolome of Rhizobium sp. strain E20-8 exposed to three concentrations of cadmium (2.5, 5.0 and 7.5 MUM) was screened using comprehensive two-dimensional gas chromatography coupled to time of flight mass spectrometry (GC * GC-ToFMS), combined with headspace solid phase microextraction (HS-SPME). Cd exposure induced a global increase in the concentration of volatile organic compounds (VOCs) both intra and extracellularly. Peak areas of several linear alkanes, ketones, aldehydes, alcohols, terpenic and volatile sulfur compounds, and one ester (ethyl acetate), were especially increased when compared with the control condition (no Cd). These compounds might originate from the metabolization of toxic membrane peroxidation products, the proteolysis of oxidized proteins or the alteration of metabolic pathways, resulting from the oxidative stress imposed by Cd. Several VOCs are related to oxidative damage, but the production of VOCs involved in antioxidant response (menthol, alpha-pinene, dimethyl sulfide, disulfide and trisulfide, 1-butanol and 2-butanone) and in cell aggregation (2,3-butanedione, 3-methyl-1-butanol and 2-butanone) is also observed. These results bring new information that highlights the role of VOCs on bacteria response to Cd stress, identify a novel set of biomarkers related with metal stress and provide information to be applied in biotechnological and remediation contexts. PMID- 28865385 TI - Intake, distribution, and metabolism of decabromodiphenyl ether and its main metabolites in chickens and implications for human dietary exposure. AB - Diet is considered as the most important human exposure pathway for polybrominated diphenyl ethers (PBDEs). Metabolism and accumulation patterns of PBDEs in different growth periods of chickens are helpful for evaluating human dietary exposure, but such information is scarce. In this study, female chickens were fed with food spiked with BDE-209 at 85 mg kg-1, and the intake, accumulation, and excretion of BDE-209 and its main metabolites in various tissues were examined. Concentrations of BDE-209 in chicken tissues increased over time in a tissue-specific manner; they were the greatest in liver and generally the lowest in breast meat during the entire exposure period. The kinetic patterns were dependent on both growth-dilution effects and accumulated concentrations of BDE-209. Tissue concentrations of ?8PBDE (sum of BDE-28, 47, 99, 100, 153, 154, 183, and 209) followed the sequence of liver > blood > skin > intestine > stomach > leg meat > breast meat. Different tissue partition coefficients and perfusion rates for blood may have resulted in different PBDE concentrations in tissues. The absorption efficiency of BDE-209 in chicken tissues followed the sequence of liver (0.15 +/- 0.032%) > skin (0.14 +/- 0.038%) > intestine (0.071 +/- 0.021%) > breast meat (0.062 +/- 0.020%) > leg meat (0.059 +/- 0.016%) > stomach (0.021 +/- 0.0095%), likely due in part to facilitated absorption of BDE-209 by transport proteins (P-glycoproteins). On average, 9.3 +/ 1.7% of BDE-209 was excreted in feces. Estimated human average dietary intake via the consumption of chicken tissues of ?8PBDE for adults and children was 319 and 1380 ng day-1 for liver, 211 and 632 ng day-1 for leg meat, and 104 and 311 ng day-1 for breast meat from the contaminated group. Liver clearly poses the highest exposure risk for human consumption, particularly if chickens are fed with contaminated feed. PMID- 28865387 TI - Exploring the relationship between stride, stature and hand size for forensic assessment. AB - Forensic evidence often relies on a combination of accurately recorded measurements, estimated measurements from landmark data such as a subject's stature given a known measurement within an image, and inferred data. In this study a novel dataset is used to explore linkages between hand measurements, stature, leg length and stride. These three measurements replicate the type of evidence found in surveillance videos with stride being extracted from an automated gait analysis system. Through correlations and regression modelling, it is possible to generate accurate predictions of stature from hand size, leg length and stride length (and vice versa), and to predict leg and stride length from hand size with, or without, stature as an intermediary variable. The study also shows improved accuracy when a subject's sex is known a-priori. Our method and models indicate the possibility of calculating or checking relationships between a suspect's physical measurements, particularly when only one component is captured as an accurately recorded measurement. PMID- 28865388 TI - Post-mortem findings in 22 fatal Taxus baccata intoxications and a possible solution to its detection. AB - BACKGROUND: The yew (Taxus baccata) is a common evergreen tree containing the toxin taxine B. Between 42 and 91 g of yew leaf is lethal to a 70-kg adult. The objective of this article is to present an overview of findings in fatal yew intoxications. METHODS: A search using MeSH terms was performed in PubMed for yew intoxications in the period between January 1960 and August of 2016. RESULTS: We describe a total of 22 cases. Fatal intoxications can be divided into intoxications by leaves, by pulp, by bark and by yew tea. Recognizing yew tea intoxication is difficult since tea no longer contains any botanically recognisable parts. In autopsy and external examination no characteristic findings are reported, regarding the presence of parts of plants. CONCLUSIONS: Indications for yew tree intoxications at a post-mortem examination and autopsy are limited to finding parts of yew tree. The absence of recognisable parts can result in yew intoxications being overlooked. Therefore toxicological screening is recommended in unexplained deaths. PMID- 28865389 TI - Self-assessed remission rates after electroconvulsive therapy of depressive disorders. AB - BACKGROUND: Electroconvulsive therapy (ECT) effectively treats severe depression, but not all patients remit. The aim of the study was to identify clinical factors that associate with ECT-induced remission in a community setting. METHODS: Depressed patients who underwent ECT in 2011-2014 were identified from the Swedish National Quality Register for ECT. Remission was defined as self-rated Montgomery-Asberg Depression Rating Scale scores of 0-10 after ECT. Other registers provided data on previous antidepressant use, comorbidities, and demographics. RESULTS: Of 1671 patients fulfilling the inclusion criteria, 42.8% achieved remission. Older age, education length over 9 years, psychotic symptoms, shorter duration of preceding antidepressant use, pulse width stimulus>=0.50ms, absence of substance use disorders, anxiety diagnosis, lamotrigine, and benzodiazepines, were associated with remission. CONCLUSIONS: This study shows that psychotic subtype of depression and older age are clinically relevant predictors of a beneficial ECT effect. Additionally, ECT outcomes can be further improved by optimizing the treatment technique and concomitant medication. PMID- 28865390 TI - Association between public injecting and drug-related harm among HIV-positive people who use injection drugs in a Canadian setting: A longitudinal analysis. AB - BACKGROUND: and Aims Injecting illicit drugs in public settings has been linked to a higher risk of a range of drug-related harms, including overdose and HIV infection. However, the factors associated with public injecting among HIV positive individuals have not been previously explored. We investigated the links between public drug injecting, drug-related harm, and HIV treatment measures among a cohort of HIV-positive persons who inject drugs (PWID) in a Canadian setting. METHODS: We used data from a prospective cohort of HIV-positive PWID recruited from community settings in Vancouver, Canada, linked to comprehensive clinical monitoring data in the context of an ongoing Treatment-as-Prevention (TasP) initiative to examine harms associated with public injecting. We used generalized linear mixed-effects analyses to identify longitudinal factors associated with self-reported public drug injection. RESULTS: Between 2005 and 2014, 626 HIV-seropositive PWID were recruited, of whom 213 (34%) reported public injection in the preceding 180days. In a longitudinal multivariable model, public injection was positively associated with daily heroin injection (Adjusted Odds Ratio [AOR]=2.63), incarceration (AOR=1.78), and detectable plasma HIV-1 RNA viral load (VL, AOR=1.42). CONCLUSIONS: Public injecting was linked to numerous drug-related harms among HIV-seropositive PWID in this setting. Given its link with detectable VL, an important marker of poor HIV treatment outcomes, our findings support prioritizing individuals engaged in public injecting with harm reduction strategies as well as clinical and social supports as a part of TasP based efforts to prevent HIV-related morbidity and mortality, and HIV transmission. PMID- 28865392 TI - Type III CRISPR-Cas systems: when DNA cleavage just isn't enough. AB - Type III CRISPR-Cas systems have a unique targeting mechanism that requires the transcription of the DNA target and results in the degradation of not only the genome of the invader but also its transcripts. Here we discuss the most recent studies describing dual DNA and RNA targeting by these systems, as well as the implications of this complex molecular mechanism for immunity in vivo. PMID- 28865391 TI - Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine. AB - Novel psychoactive substances have maintained a prominent role in the global drug culture, despite increased regulation by governing bodies. Novel compounds continue to become available on the market, often in "Ecstasy" or "Molly" formulations in lieu of MDMA, at a much faster rate than they can be properly characterized. The current study aimed to investigate the discriminative stimulus and locomotor effects of three putatively entactogenic compounds that have become increasingly prevalent on the drug market: 5-(2-aminopropyl)-benzofuran (5-APB), 6-(2-aminopropryl)-2,3-dihydrobenzofuran (6-APDB), and 4-fluoroamphetamine (4 FA). Locomotor stimulant effects were assessed in an open-field assay for locomotor activity using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine, methamphetamine, DOM, or MDMA from vehicle. The benzofuran compounds produced locomotor stimulation whereas 4-FA depressed locomotor activity. The benzofurans substituted for the discriminative stimulus effects of MDMA, but only partially or not at all for methamphetamine, cocaine, and DOM, whereas 4-FA fully substituted for MDMA, methamphetamine and cocaine, but not DOM. These results indicate an MDMA-like pattern of abuse might be expected for the benzofurans, whereas 4-FA may be substituted for psychostimulants and MDMA. PMID- 28865393 TI - Pediatric aortoiliac injury following blunt abdominal trauma: A case report. AB - INTRODUCTION: The most common mechanism of aortic injury involves motor vehicle collisions resulting in aortic disruptions, occurring almost exclusively in the chest. Injury to the abdominal aorta following blunt trauma is nearly twenty times less likely to occur than the thoracic aorta. Because of the low incidence, there are few reports regarding the presentation and repair of these particular injuries, especially in the pediatric population. PRESENTATION OF CASE: We present a case of a 7-year-old boy involved in a high speed motor vehicle accident with an abdominal aorta transection at the aortic bifurcation extending into the left iliac artery. The injury was repaired using bovine pericardium with the adventitia and intima of the vessel approximated over the bovine bridge. DISCUSSION: Primary repair of thoracic aortic injury has been thoroughly described in the literature with good outcomes yet, abdominal aortic repair remains ambiguous. Few techniques and materials have been described with even less data surrounding the long-term outcomes. CONCLUSION: Bovine pericardium is a strong and stable acellular collagenous material with the potential to accelerate endothelialization and tissue regeneration. This remains an interesting field of research as stenosis and pseudo-coarction data have yet to be determined. PMID- 28865394 TI - Clinical measures of balance in people with type two diabetes: A systematic literature review. AB - Approximately 422 million people have diabetes mellitus worldwide, with the majority diagnosed with type 2 diabetes mellitus (T2DM). The complications of diabetes mellitus include diabetic peripheral neuropathy (DPN) and retinopathy, both of which can lead to balance impairments. Balance assessment is therefore an integral component of the clinical assessment of a person with T2DM. Although there are a variety of balance measures available, it is uncertain which measures are the most appropriate for this population. Therefore, the aim of this study was to conduct a systematic review on clinical balance measures used with people with T2DM and DPN. Databases searched included: CINAHL plus, MEDLINE, SPORTDiscus, Dentistry and Oral Sciences source, and SCOPUS. Key terms, inclusion and exclusion criteria were used to identify appropriate studies. Identified studies were critiqued using the Downs and Black appraisal tool. Eight studies were included, these studies incorporated a total of ten different clinical balance measures. The balance measures identified included the Dynamic Balance Test, balance walk, tandem and unipedal stance, Functional Reach Test, Clinical Test of Sensory Interaction and Balance, Berg Balance Scale, Tinetti Performance Oriented Mobility Assessment, Activity-Specific Balance Confidence Scale, Timed Up and Go test, and the Dynamic Gait Index. Numerous clinical balance measures were used for people with T2DM. However, the identified balance measures did not assess all of the systems of balance, and most had not been validated in a T2DM population. Therefore, future research is needed to identify the validity of a balance measure that assesses these systems in people with T2DM. PMID- 28865395 TI - Factors influencing knee adduction moment measurement: A systematic review and meta-regression analysis. AB - The external knee adduction moment has been identified as a key biomarker in biomechanics research, with associations with this variable and degenerative diseases such as knee osteoarthritis. Heterogeneity in participant characteristics and the protocols used to measure this variable may however complicate its interpretation. Previous reviews have focused on interventions or did not control for potential moderator variables in their analysis. In this meta regression analysis, we aimed to determine the influence of factors including the cohort type, footwear, and walking speed on the measurement of knee adduction moment. We performed a systematic review of the literature, identifying articles that used the Plug-in-Gait inverse dynamics model to calculate the knee adduction moment during level walking, and used a mixed effect model to determine the effect of the previously described factors on the measurement. Results for 861 individuals were described in 19 articles. Walking speed had the largest influence on knee adduction moment (p<0.001), and participants with medial knee osteoarthritis had an increased knee adduction moment (p=0.008) compared to healthy subjects. Footwear was found to have a significant overall effect (p=0.024). Participants tested barefoot or wearing their own shoes had lower adduction moments than those tested in footwear provided by the researchers. Overall, the moderators accounted for 60% of the heterogeneity in the results. These results support the hypothesis that an increased knee adduction moment is associated with medial compartment knee osteoarthritis, and that footwear choice can influence the results. Gait speed has the largest effect on knee adduction moment measurement and should be carefully controlled for in studies investigating this variable. PMID- 28865396 TI - How does wearable robotic exoskeleton affect overground walking performance measured with the 10-m and six-minute walk tests after a basic locomotor training in healthy individuals? AB - It is still unknown to what extent overground walking with a WRE is equivalent to natural overground walking without a WRE. Hence, the interpretability of the 10-m (10MWT) and six-minute (6MWT) walk tests during overground walking with a WRE against reference values collected during natural overground walking without a WRE is challenging. This study aimed to 1) compare walking performance across three different overground walking conditions: natural walking without a WRE, walking with a WRE providing minimal assistance (active walking), and walking with a WRE proving complete assistance (passive walking) and 2) assess the association and the agreement between the 10MWT and the 6MWT during passive and active walking with a WRE. Seventeen healthy individuals who underwent basic locomotor training with a WRE performed the 10MWT (preferred and maximal speeds) and the 6MWT under the three conditions. For the 10MWT, the speed progressively and significantly decreased from natural walking without a WRE (preferred: 1.40+/ 0.18m/s; maximal: 2.16+/-0.19m/s), to active walking with a WRE (preferred: 0.48+/-0.10m/s; maximal: 0.61+/-0.14m/s), and to passive walking with a WRE (preferred: 0.38+/-0.09m/s; maximal: 0.42+/-0.10m/s). For the 6MWT, total distances decreased from walking without a WRE (609+/-53.9m), to active walking with a WRE (196.6+/-42.6m), and to passive walking with a WRE (144.3+/-33.3m). The 10MWT and 6MWT provide distinct information and can't be used interchangeably to document speed only during active walking with the WRE. Speed and distance drastically decrease during active and, even more so, passive walking with the WRE in comparison to walking without a WRE. Selection of walking tests should depend on the level of assistance provided by the WRE. PMID- 28865398 TI - Practitioner and communities' awareness of CALFB: Child abuse linked to faith or belief. AB - This paper reports the results of an online survey which aimed to explore practitioners' and faith community groups' awareness and understanding of child abuse linked to faith or belief (CALFB) and to identify their further training needs in this area. The survey was founded in the work of the National working group for CALFB; a multi-agency response group committed to raising knowledge and awareness of this form of child abuse. Despite the relatively small number of recorded cases, CALFB continues to be a matter of concern to professionals and faith communities in the UK and beyond. One thousand three hundred and sixty two respondents comprising of frontline practitioners, faith and community group members completed the survey. A mixed-method analysis of the survey data illustrates a wide-ranging understanding of the term CALFB and disagreement about whether this is a specific form of child abuse. The results also indicate a relationship between confidence levels in identifying and responding to CALFB and specific training in this area. There is a call for specialised training to be more readily available. Further work is needed to develop a toolkit, which identifies indicators of CALFB and effective response pathways together with research across communities. The current research is timely and important in providing a foundation on which to build more effective identification of cases, policy and intervention. PMID- 28865397 TI - The relationship between childhood adversity, attachment, and internalizing behaviors in a diversion program for child-to-mother violence. AB - Very little research has been conducted on the role of childhood adversity in child-to-parent violence. Childhood adversity places youth at risk for internalizing behaviors (i.e. anxiety and depression) and externalizing behaviors (i.e. aggression). The purpose of this study was to explore the relationships between childhood adversity, child-mother attachment, and internalizing behaviors among a sample of 80 youth who have been arrested for domestic battery against a mother. This study reported high prevalence rates of childhood adversity (mean score of 10 out of 17 events). Multiple regression analysis indicated that insecure attachment predicted depression among females (F(6, 73)=4.87, p<0.001), and previous experience with child maltreatment and/or witness to parental violence predicted anxiety among females (F(6, 73)=3.08, p<0.01). This study is the first study to explore childhood adversity among a sample of perpetrators of child-to-mother violence and notably adds to our understanding of the multiple pathways connecting childhood adversity, child-mother attachment, and depression and anxiety among a difficult to treat youth population. PMID- 28865399 TI - The Child Abuse Potential Inventory: Development of an Arabic version. AB - The Child Abuse Potential Inventory (CAPI) is a well-validated screening tool for assessing potential for child physical abuse, and has been translated into many different languages. To date the CAPI has not been translated into Arabic or used in any studies in Arabic-speaking populations. This study reports on the process of adapting the CAPI into Arabic Language which was undertaken following the International Society of Pharma-economics and Outcomes Research (ISPOR) guidelines. The translation/adaptation process was multi-stage, and involved the use of a Delphi process, cognitive debriefing, back translation, and a pilot testing of the Arabic CAPI at two primary health care centers with a population of pregnant women (n=60). Following "literal translation" 73 out of the 160 items needed re-phrasing to adapt the items to the Oman context. No differences were found when comparing results of the translated or back-translated versions to source; however, eight items needed further amendment following translated to back-translated comparison and feedback from the pilot. Iterations were resolved following in-depth interviews. Discrepancies were due to differences in culture, parenting practices, and religion. Piloting of the tool indicated mean score value of 155.8 (SD=59.4) and eleven women (18%) scored above the cut off value of 215. This Arabic translation of the CAPI was undertaken using rigorous methodology and sets the scene for further research on the Arabic CAPI within Arabic-speaking populations. PMID- 28865400 TI - Accounting for the increase of children in care in western Australia: What can a client information system tell us? AB - This paper analyses a fourteen-year period of Western Australian data from the client information system of the Department for Child Protection and Family Support. Western Australia saw a large increase in the number of children in state care similar to trends across Australia as a whole. The study shows the following trends: changes in response to 'referrals' with particular increases in the number of findings of neglect and increasing proportions of these followed swiftly by entry to care; changes in patterns of entry to care with more children under one-year-old entering; increased length of stay of children in care; and, the high incidence of Aboriginal children entering and remaining in care. The data demonstrate unequivocally that increased 'referrals' are not associated with increased substantiations of harm or 'acts of commission with dangerous intent', but that neglect assessed early in the lives of children was the major precipitant for entry to care and particularly so for Aboriginal infants. PMID- 28865401 TI - Spatial and temporal determinants of A-weighted and frequency specific sound levels-An elastic net approach. AB - BACKGROUND: Urban sound levels are a ubiquitous environmental stressor and have been shown to be associated with a wide variety of health outcomes. While much is known about the predictors of A-weighted sound pressure levels in the urban environment, far less is known about other frequencies. OBJECTIVE: To develop a series of spatial-temporal sound models to predict A-weighted sound pressure levels, low, mid, and high frequency sound for Boston, Massachusetts. METHODS: Short-term sound levels were gathered at n = 400 sites from February 2015 - February 2016. Spatial and meteorological attributes at or near the sound monitoring site were obtained using publicly available data and a portable weather station. An elastic net variable selection technique was used to select predictors of A-weighted, low, mid, and high frequency sound. RESULTS: The final models for low, mid, high, and A-weighted sound levels explained 59 - 69% of the variability in each measure. Similar to other A-weighted models, our sound models included transportation related variables such as length of roads and bus lines in the surrounding area; distance to road and rail lines; traffic volume, vehicle mix, residential and commercial land use. However, frequency specific models highlighted additional predictors not included in the A-weighted model including temperature, vegetation, impervious surfaces, vehicle mix, and density of entertainment establishments and restaurants. CONCLUSIONS: Building spatial temporal models to characterize sound levels across the frequency spectrum using an elastic net approach can be a promising tool for noise exposure assessments within the urban soundscape. Models of sound's character may give us additional important sound exposure metrics to be utilized in epidemiological studies. PMID- 28865402 TI - Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine. AB - OBJECTIVE: To investigate serum concentrations of second-generation antipsychotics in relation to age and gender in a population ranging from 18 to 100 years. METHOD: Results from a routine therapeutic drug monitoring database were retrieved, and 43 079 samples from 11 968 patients were included (17 249 samples for clozapine, 16 171 samples for olanzapine, 5343 samples for risperidone, and 4316 samples for quetiapine). The dose-adjusted concentration was used as the primary target variable. A linear mixed model was used to allow the inclusion of multiple samples from each patient. RESULTS: Age had a significant impact on the concentrations of all four drugs. At the age of 80, the dose-adjusted concentrations were up to twice those of the age of 40. At the age of 90, dose-adjusted concentrations were two- to three-fold higher. Age-related increases were largest for clozapine (+108% at 80 years; +197% at 90 years) and smallest for olanzapine (+28% at 80 years; +106% at 90 years). Females generally had dose-adjusted concentrations 20-30% higher than males. CONCLUSION: The effect of age on the serum concentrations of the antipsychotics studied becomes pronounced with advanced age. The patient population aged above 70 should be subdivided according to exact age, and considerable dose reductions are recommended. PMID- 28865403 TI - Cumulative incidence and risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B who achieved sustained disappearance of viremia by nucleos(t)ide analog treatment. AB - AIM: Nucleos(t)ide analog (NA) therapy has been reported to reduce the risk of hepatocellular carcinoma (HCC). However, some patients who achieve hepatitis B virus (HBV)-DNA disappearance from serum by NA develop HCC. In this study, we investigated the cumulative incidence and risk factors for HCC in patients with chronic hepatitis B (CHB) who achieved sustained disappearance of viremia by NA treatment. METHODS: A total of 133 CHB patients (median age, 51 years; 79 men [59%]; 28 with cirrhosis [21%]) who received NA therapy and achieved HBV-DNA disappearance from serum were analyzed retrospectively. We evaluated the cumulative incidence of HCC and risk factors associated with HCC based on data collected at the time of HBV-DNA disappearance. RESULTS: Thirteen patients developed HCC during the follow-up period. The 1-, 3-, and 5-year cumulative incidence of HCC was 0.0%, 7.8%, and 11.1%, respectively. In multivariate analysis, advanced age (hazard ratio [HR], 4.601; 95% confidence interval [CI], 1.220-17.351; P = 0.024), liver cirrhosis (HR, 5.563; 95% CI, 1.438-21.519; P = 0.013), and higher HBV core-related antigen (HBcrAg) levels (HR, 13.532; 95% CI, 1.683-108.815; P = 0.014) at the time of HBV-DNA disappearance were significantly associated with the development of HCC. CONCLUSION: Our findings indicate the importance of continuous HCC surveillance especially in patients with advanced age, cirrhosis, and/or higher serum levels of HBcrAg, even if they achieve HBV DNA disappearance. PMID- 28865404 TI - From depression to anxiety, and back. PMID- 28865405 TI - The role of stress-regulation genes in moderating the association of stress and daily-life psychotic experiences. AB - OBJECTIVE: The interaction of single nucleotide polymorphisms with both distal and proximal environmental factors across the extended psychosis phenotype is understudied. This study examined (i) the interaction of relevant SNPs with both early-life adversity and proximal (momentary) stress on psychotic experiences (PEs) in an extended psychosis sample; and (ii) differences between early psychosis and non-clinical groups for these interactions. METHODS: Two hundred and forty-two non-clinical and 96 early-psychosis participants were prompted randomly eight times daily for 1 week to complete assessments of current experiences, including PEs and stress. Participants also reported on childhood trauma and were genotyped for 10 SNPs on COMT, RGS4, BDNF, FKBP5, and OXTR genes. RESULTS: Unlike genetic variants, distal and proximal stressors were associated with PEs in both samples and were more strongly associated with PEs in the early psychosis than in the non-clinical group. The RGS4 TA and FKBP5 CATT haplotypes interacted with distal stress, whereas the A allele of OXTR (rs2254298) interacted with proximal stress, increasing momentary levels of PEs in the early psychosis group. No interactions emerged with COMT or BDNF variants. CONCLUSION: Individual differences in relevant stress-regulation systems interact with both distal and proximal psychosocial stressors in shaping the daily-life manifestation of PEs across the psychosis continuum. PMID- 28865407 TI - Immunoglobulin Free Light Chains in the Pathogenesis of Lung Disorders. AB - Inflammation is an important component of numerous cancers and chronic diseases and many inflammatory mediators have been shown to have potential prognostic roles. Tumor-infiltrating mast cells can promote tumor growth and angiogenesis, but the mechanism of mast cell activation is unclear. Early studies have shown that immunoglobulin free light chains (FLC) can trigger mast cell activation in an antigen-specific manner. Increased expression of FLC is observed within the stroma of many human cancers including those of breast, colon, lung, pancreas, kidney, and skin. These overexpressed FLCs are co-localized to areas of mast cell infiltration. Importantly, FLC expression is associated with basal-like cancers with an aggressive phenotype. Moreover, FLC is expressed in areas of inflammatory cell infiltration and its expression is significantly associated with poor clinical outcome. In addition, serum and bronchoalveolar fluid FLC concentrations are increased in patients with idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP) compared to control subjects. In this review, we provide an update on the role of FLC in the pathogenesis of several lung disorders and indicate how this may contribute to new therapeutic opportunities. PMID- 28865408 TI - Peptide-based Vaccines Derived from FcepsilonRI Beta Subunit Can Reduce Allergic Response in Mice Model. AB - Current therapeutic approaches in allergic diseases especially asthma generally focus on using immunological strategies. According to the importance of FceRI in controlling allergic response we used two extracellular regions of Fc epsilon receptor I (FceRI) beta subunit peptides to design two peptide-based vaccines. Probably these peptides vaccines by triggering the immune response to FceRI can reduce the allergic symptoms through blocking the IgE specific receptor. Two extracellular parts of FceRI beta subunit were made by peptide synthesizer and conjugated with keyhole limpet Hemocyanin. These conjugated peptides were used and evaluated as therapeutic vaccines in allergic airway inflammation mouse model. Total IgE and anti ovalbumin specific IgE were measured in mice serum and compared in vaccinated and unvaccinated allergic mice. Histamine, prostaglandin D2 (PGD2), IL-4 and IL-13 were measured in bronchoalveolar lavage (BAL) fluid of vaccinated allergic mice versus unvaccinated and histopathologic examination were performed in studied groups. After vaccination of mice with each of the peptide vaccines the specific antibodies titer increased significantly in vaccinated groups versus unvaccinated. In histopathologic study, lavage eosinophil percentage and peribronchial inflammation in lung sections of vaccinated groups was decreased (p<0.05). Also the allergic components including total IgE, anti ovalbumin specific IgE, histamine, PGD2, IL-4, and IL-13 showed substantial decline in vaccinated allergic mice. Thus targeting the extracellular regions of FceRI beta subunit by peptide-based vaccines and induction of specific antibodies against them can reduce allergic responses in allergic mice model. PMID- 28865406 TI - Resting state perfusion in the language network is linked to formal thought disorder and poor functional outcome in schizophrenia. AB - OBJECTIVE: Formal thought disorder (FTD) is a core symptom in schizophrenia. Here, we focus on resting state cerebral blood flow (rCBF) linked to dimensions of FTD. METHODS: We included 47 schizophrenia spectrum patients and 30 age- and gender-matched healthy controls. We assessed FTD with the assessment of thought, language, and communication (TLC) and imaging on a 3T MRI scanner. Within patients, we tested the association of FTD dimensions and in a subgroup (n = 27) the association of functional outcome after 6 months with whole brain rCBF. RESULTS: Negative FTD was most prominently associated with perfusion within the superior temporal gyrus, while positive FTD was associated with perfusion within the supplementary motor area, and inferior frontal gyrus. Perfusion within the left supramarginal gyrus was associated with social functioning after 6 months. CONCLUSIONS: Distinguishable associations of rCBF with FTD dimensions point to distinct underlying pathophysiology. The location of aberrant perfusion patterns suggests that negative FTD might reflect defective access to semantic memory while positive FTD likely reflects defective suppression of irrelevant information during increased speech production. Finally, the neural correlates of thought block were also predictive of poor functional outcome. Thus, functional outcome and distinct FTD dimensions may share some pathophysiology. PMID- 28865409 TI - Determination of the Most Common Indoor and Outdoor Allergens in 602 Patients with Allergic Symptoms Using Specific IgE Local Panel. AB - Aeroallergens play an important role in developing allergic diseases. The aim of this study was to determine the outdoor and indoor sensitization using a specific regional panel of aeroallergens in allergic patients. All patients with allergic symptoms referred to Immunology, Asthma and Allergy Research Institute (IAARI) in Tehran, Iran from December 2010 to July 2013 entered this cross sectional study. We evaluated serum samples for specific IgE against 20 selected aeroallergens provided by a specific panel (RIDA Allergy Screen test, IAARI panel). A p value less than 0.05 was considered as significant. The patients (n=602) were 49.8 % male and 50.2% female. The median age was 9 years. Positive specific IgE at least to one allergen was 53.2%. The percentages of patients with only outdoor or indoor sensitization were 37.5 and 19.7%, respectively. Moreover, 42.8% showed sensitization to both indoor and outdoor aeroallergens. The most common outdoor aeroallergens in decreasing order were plane tree (32.8%), Bermuda grass (32.2%), timothy grass (30.6%), saltwort (28.4%). The percentage of specific IgE to indoor allergens including mold and mite were 23.8 % and 22.2%, respectively. There was a statistically significant relationship between specific IgE to timothy grass and mold allergens between two genders (p=0.04 and p=0.02, respectively).The results of this study shows that outdoor aeroallergens can be considered as the most common causes of allergic symptoms in our allergic patients. PMID- 28865410 TI - Decreased Sensitization to Aeroallergens among Southwestern Iranian Male Farmers. AB - Farmers are usually exposed to various inhaled allergens like pollens, mites, molds, and animal dander in their working environment which may lead to allergic rhinitis, asthma and urticaria. The purpose of this study was to identify sensitization to various aeroallergens in farmers and their occupational allergy symptoms. This cross sectional study included 103 male farmers and 100 non-farmer healthy controls. The work-related symptoms of farmers were recorded with a questionnaire. Spirometry and skin prick tests with 15 commercial allergen extracts were performed in both farmers and controls. The rate of sensitization to at least one of the applied aeroallergens was 47.6% in farmers compared to 65% in the control group (OR=0.48; CI 95%, 1.08 to 2.07) according to skin prick tests, after adjusting for age. Occupational allergy symptoms were reported by 54.3% farmers. Mean FEV1/FVC was significantly lower in farmers than in controls (p<0.001). The results of this study showed that farmers had no increased risk of sensitization to aeroallergens. Sensitization to pollens was more prevalent than to mites among the farmers in our study and smoking was an important predisposing factor in farmers who suffered from occupational allergy symptoms. PMID- 28865411 TI - Frequency of HLA DQbeta1*0201 and DQbeta1*0301 Alleles and Total Serum IgE in Patients with Bronchial Asthma: A Pilot Study from Pakistan. AB - In Pakistan about 3.7% of the population is suffering from asthma, a chronic inflammatory disorder of airways. Asthma has wide spectrum of predisposing factors including environment and genetics. Many studies have been performed to determine association of asthma with serum IgE and major histocompatibility complex (MHC) alleles but conflicting results were reported. Therefore, present study was designed to determine frequency of HLA-DQbeta1*0201 and DQbeta1*0301 alleles in patients with bronchial asthma. This case control study included 85 asthmatic patients and 85 healthy controls. HLA-DQbeta1*0201 and DQbeta1*0301 alleles were detected by allele specific PCR and serum IgE was determined by ELISA. Median and inter-quartile range (IQR) of total IgE level were more increased in asthma patients (585.7 IU/mL and 247.2-848.1 IU/mL) compared to healthy controls (65.1 IU/mL and 28.1-181.3 IU/mL) (p<0.001). Frequency of HLA DQbeta1*0201 and -DQbeta1*0301 alleles was more in healthy controls (32% and 38%, p=0.616) as compared to bronchial asthma patients (28% and 26%, p= 0.09). There was a significant association of IgE levels and HLA-DQbeta1*0201 allele. Patients positive for HLA-DQbeta1*0201 allele had low level of serum IgE 357.2 IU/mL (153.9-634.3 IU/mL) compared to the patients negative for this HLA allele i.e. 642.9 IU/mL (289.8-1299.5IU/mL) (p=0.005), whereas, HLA-DQbeta1*0301 allele was not associated with total serum IgE level (p=0.865). Our findings show that HLA DQbeta1*0201 and -DQbeta1*0301 alleles were not associated with asthma; however, HLA-DQbeta1*0201 allele was associated with low levels of total serum IgE in the study population. PMID- 28865412 TI - Association between +4259 T>G and -574 G>T Polymorphisms of TIM-3 with Asthma in an Iranian Population. AB - T-cell immunoglobulin and mucin domain (TIM)-3 have been shown to negatively regulate Th1 cell-mediated immunity. Activation of TIM-3 by galectin-9 induces Th1 cell apoptosis, which may contribute to skewing of immune response towards Th2-dominant immunity. The aim of this study was to determine whether certain genetic variations of TIM-3 influence predisposition to asthma in a sample of Iranian population. This case-control study was conducted on 209 patients with asthma and 200 healthy controls. The +4259 T>G and -574 G>T polymorphisms were detected using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) and amplification refractory mutation system-PCR(ARMS PCR). Total serum IgE was further measured with ELISA. Notably, +4259T > G and 574G>T polymorphisms of TIM-3 were significantly associated with the susceptibility to asthma. In addition, the present study showed a significant difference between the distribution frequency of the GT + TT genotype and T allele on the +4259 T>G and -574 G>T locus between the groups.However, no correlation between the +4259 T > G and -574G > T polymorphisms and total serum IgE levels were observed. Together these results suggest that the TIM-3 +4259 T>G and -574 G>T polymorphisms are greatly associated with the susceptibility of Iranian population to asthma, which could open up new horizons for better understanding of the pathophysiology, diagnostic, prognostic and therapeutic approaches of asthma. PMID- 28865413 TI - Correlation of Serum Levels of IL-33, IL-37, Soluble Form of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), and Circulatory Frequency of VEGFR2-expressing Cells with Multiple Sclerosis Severity. AB - IL-33 and IL-37 (new cytokines of IL-1 family), soluble form of vascular endothelial growth factor receptor-2 (sVEGFR2) as well as membranous expression of VEGFR2 have some key roles in the pathogenesis of autoimmune and inflammatory diseases. The aim of this study was to correlate circulatory changes of these factors with the severity of multiple sclerosis (MS) as an autoimmune and inflammatory disease. Our case-control study was performed on 84 patients with MS and 75 healthy subjects. The serum levels of IL-33, IL-37 and sVEGFR2 in the peripheral blood samples of all participants were measured by enzyme-linked immune sorbent assay (ELISA). Flow cytometry was used to analyze the circulatory number of VEGFR2-expressing cells. The severity of MS was evaluated using the expanded disability status scale (EDSS). Finally, we evaluated the correlation between serum levels of those factors with disease severity. Our findings showed that the serum level of IL-33, IL-37, sVEGFR2 and the circulatory number of VEGFR2-expressing cells were increased in patients with MS compared to healthy subjects (p<0.0001). Also, there was a significant correlation between serum levels of these 3 factors with disease severity according to EDSS. Our study showed that the serum levels of IL-33, IL-37 and sVEGFR2 may be important prognostic biomarkers of MS. PMID- 28865414 TI - Interleukin 7 Receptor Alpha Gene Variants Are Correlated with Gene Expression in Patients with Relapsing-remitting Multiple Sclerosis. AB - The association of single nucleotide polymorphisms (SNPs) of the IL-7Ralpha gene with multiple sclerosis (MS) have been documented in various populations. This study aimed to evaluate the genotype distributions of two SNPs, rs6897932 and rs201084372, and the functional association of rs6897932 in relation to IL 7Ralpha gene expression in a group of Iranian relapsing-remitting MS (RRMS) patients. Genotyping for both SNPs in the IL7Ralpha gene and relative quantification of mRNA expression for both isoforms of IL-7Ralpha were performed in 100 RRMS patients and 100 ethnic-matched healthy controls. Higher significant frequencies of the T allele and TT genotype for rs6897932 (C/T) were observed in patients comparing to controls (p=0.006). Higher frequencies of the T allele and the TT and TG genotypes and lower frequencies of the G allele and GG genotypes for rs201084372 (G/A) were found in patients comparing to controls (p<0.0001). A decreased level of mRNA expression for the membrane-bound IL-7Ralpha (mbIL 7Ralpha) and an increased level of mRNA for the soluble IL-7Ralpha (sIL-7Ralpha) were observed in patients versus controls (p=0.005 and p=0.002 respectively). A significant decreased level of mRNA expression for mbIL-7Ralpha (p=0.01) and an increased level of mRNA for sIL-7Ralpha (p=0.008) were observed in RRMS patients compared to healthy controls carrying the TT+CT genotypes. The higher levels of mRNA expression for the sIL-7Ralpha isoform in MS patients carrying the IL7R*TT genotype is a new finding not previously reported in studies on the genotype induced effects of IL-7Ralpha expression in multiple sclerosis. PMID- 28865415 TI - Polarization of Helper T Lymphocytes Maybe Involved in the Pathogenesis of Lumbar Disc Herniation. AB - This study aimed to explore the expression of T helper type 1 (Th1)/T helper type 2 (Th2) in herniated nucleus pulposus (NP) and determine their association with sciatic pain. NP was collected from 12 patients with lumbar disc herniation (LDH) (extrusion group) and 6 patients with a vertebral fracture (control group). The expression of Th1/Th2 and related cytokines in the NP was examined by flow cytometry, Western blot, and immunofluorescent staining. Subsequently, an LDH model was established in male Sprague-Dawley rats, and behavioral testings were carried out. The expression of Th1/Th2 and related cytokines in rat NP and the expression of macrophages in the dorsal root ganglia (DRG) were also examined. The number of Th1 cells in rat NP dramatically increased on day 14 after the surgery, but significantly decreased on day 28. The number of Th2 cells increased on day 28. Chemokine ligand 3(CCL3) and CD86 proteins (M1-specific molecules) were expressed at a relatively low level in naive DRG, markedly increased on day 14 after the surgery, and decreased on day 28. Arg1 and CD206 protein (M2 specific molecules) were expressed at a relatively low level in naive DRG and markedly increased on day 28. The mechanical allodynia and heat hyperalgesia developed after NP application and finally partially alleviated. The results suggested that the polarization of Th cells might be involved in the pathogenesis of LDH, and this might be achieved via the phenotypic shift of macrophages. PMID- 28865416 TI - Immunological Mechanisms Implicated in the Pathogenesis of Chronic Urticaria and Hashimoto Thyroiditis. AB - Autoimmunity represents the attack of the immune system of an organism against its own cells and tissues. Autoimmune diseases may affect one organ (Hashimoto thyroiditis) or can be systemic (chronic urticaria). Many factors are implicated in the pathogenesis of autoimmunity (white cells, cytokines, chemokines). Hashimoto thyroiditis has been associated with chronic urticaria in the last 3 decades in a number of clinical studies. Anti-thyroid antibodies have been documented in a proportion ranging from 10% to 30% in chronic urticaria patients in different countries from 3 continents. Two of the factors involved in the mechanism of autoimmunity are present both in the pathophysiology of Hashimoto thyroiditis and chronic urticaria. According to recent studies, IL6 is implicated in the pathogenesis of both diseases. TregsCD4+CD25+Foxp3+ cells have also been implicated in the pathological mechanisms of these 2 entities. This review offers an explanation of the clinical and statistical association between these two diseases from the pathophysiological point of view. PMID- 28865417 TI - Association between FcepsilonRIB Polymorphisms and Asthma in Asian Population: A Meta-analysis. AB - None. PMID- 28865418 TI - ODF4, MAGEA3, and MAGEB4: Potential Biomarkers in Patients with Transitional Cell Carcinoma AB - Background: This study aimed to evaluate the diagnostic value of outer dense fiber 4 (ODF4), melanoma-associated antigen A3 (MAGEA3), and MAGEAB4 mRNAs in transitional cell carcinoma (TCC), using a small amount of cell reverse transcriptase-polymerase chain reaction (RT-PCR) on urinary exfoliated cells. Methods: We recruited a total of 105 suspected TCC patients and 54 sex- and age matched non-TCC controls. The candidates' genetic expression patterns were investigated with RT-PCR, while reverse transcription quantitative PCR was applied to quantify and compare each mRNA level between cases and control groups. Results: The sensitivity of ODF4, MAGEA3, and MAGEAB4 RT-PCR was 54.8%, 63%, and 53.4%, whereas the specificity was 73.7%, 86%, and 94.7%, respectively. Combining ODF4, MAGEA3, and MAGEAB4 RT-PCR offered a relatively higher sensitivity (83.6%). Conclusion: RT-PCR with ODF4, MAGEA3, and MAGEAB4 on urinary exfoliated cells could provide clinicians with a promising method to improve TCC diagnosis, especially in the case of gross hematuria and catheterization. The method used here is non-invasive, simple and convenient, and unlike cytology, it does not rely directly on expert professional opinions. These features can be of particular importance to the management of TCC patients in whom regular and lifelong surveillance is required. PMID- 28865419 TI - Effect of unaffordable medical need on distress level of family member: analyses of 1997-2013 United States National Health Interview Surveys. AB - BACKGROUND: Reduced funding to public health care systems during economic downturns is a common phenomenon around the world. The effect of health care cost on family members of the patients has not been established. This paper aims to explore the relationship between affordability of health care and vulnerability of family members to distress levels. METHODS: Data of a total of 262,843 participants were obtained from 17 waves (1997-2013) of the United States National Health Interview Survey. Multinomial logistic regression was used to investigate psychological distress level as a result of having family members who experienced unmet medical needs due to cost. RESULTS: Among participants without family members who experienced unmet needs for medical care due to cost, risks of having 'moderate' (score of 5-12) or 'serious' (score of 13 or above) level of psychological distress were 1.0% and 11.5%, respectively. Risks of having 'moderate' or 'serious' level of psychological distress were 3.1% and 23.4%, respectively among participants with family members who experienced unmet needs. The adjusted relative risk ratio of 'moderate' and 'serious', as compared to 'normal' level of psychological distress, were 1.58 (95% confidence interval: 1.47-1.69) and 2.09 (95% confidence interval: 1.78-2.45) if one's family members experienced unmet medical needs. CONCLUSIONS: Unmet medical needs due to cost increases risk of distress levels experienced by family members. Careful planning and adequate funding to public health care system could be implemented to prevent any unnecessary detrimental effect on mental health among family members of the unwell and any further increment of the prevalence of mental illnesses. This recommendation aligns with the World Health Organization Mental Health Action Plan 2013-2020. PMID- 28865420 TI - Risk factors for failure of revision total hip arthroplasty using a Kerboull-type acetabular reinforcement device. AB - BACKGROUND: The present study aimed to identify the risk factors associated with revision total hip arthroplasty (THA) failure using a Kerboull-type (KT) plate. METHODS: We analyzed 77 revision THAs using cemented acetabular components with a KT plate for aseptic loosening between May 2000 and March 2012. We examined the association of bone graft type, acetabular bone defects, age at the time of surgery, preoperative Japanese Orthopaedic Association (JOA) score, postoperative JOA hip score, and body mass index, with radiographic failure as the outcome. RESULTS: The 7.4-year radiographic failure survival rate was 81.6%. The survival rate was significantly different between the beta-tricalcium phosphate (beta-TCP) group and the bulk allograft group (p = 0.019). The survival curves were also significantly different between the beta-TCP group and bulk allograft group (p = 0.036). American Academy of Orthopaedic Surgeons type IV was significantly associated with radiographic failure (odds ratio [OR]: 15.5, 95% confidence interval [CI]: 1.4-175.4; p = 0.032). CONCLUSIONS: The midterm outcomes of revision THA indicate that type of bone graft and bone defect size may affect radiographic survival rate when using a KT plate. PMID- 28865421 TI - Trends in risk classification and primary therapy of Japanese patients with prostate cancer in Nara urological research and treatment group (NURTG) - comparison between 2004-2006, 2007-2009, and 2010-2012. AB - BACKGROUND: To assess the trends in risk classification and primary therapy of Japanese prostate cancer patients who were diagnosed between 2004 and 2012. METHODS: A total of 7768 patients who were newly diagnosed with prostate cancer at Nara Medical University and its 23 affiliated hospitals between 2004 and 2012 were enrolled. The trends in risk classification and primary therapy in 2004-2006 (prior period), 2007-2009 (middle period), and 2010-2012 (latter period) were compared. RESULTS: The proportion of high-risk and worse patients significantly decreased in the latter period compared to the prior period (p < 0.001), while that of intermediate-risk patients significantly increased over the years (p < 0.001). The proportion of primary androgen deprivation therapy (PADT) was 50% in the prior period, 40% in the middle period, and 30% in the latter period, respectively. The proportions of radiation therapy and active surveillance significantly increased. The proportion of radical prostatectomy remained similar over these periods (30%). The primary therapy was significantly different between the three periods (p < 0.001). CONCLUSIONS: High-risk patients significantly decreased in the latter period. The use of PADT also significantly decreased, while radiation therapy and active surveillance significantly increased over these periods. PMID- 28865422 TI - Updating vital status by tracking in the community among patients with epidemic Kaposi sarcoma who are lost to follow-up in sub-Saharan Africa. AB - BACKGROUND: Throughout most of sub-Saharan Africa (and, indeed, most resource limited areas), lack of death registries prohibits linkage of cancer diagnoses and precludes the most expeditious approach to determining cancer survival. Instead, estimation of cancer survival often uses clinical records, which have some mortality data but are replete with patients who are lost to follow-up (LTFU), some of which may be caused by undocumented death. The end result is that accurate estimation of cancer survival is rarely performed. A prominent example of a common cancer in Africa for which survival data are needed but for which frequent LTFU has precluded accurate estimation is Kaposi sarcoma (KS). METHODS: Using electronic records, we identified all newly diagnosed KS among HIV-infected adults at 33 primary care clinics in Kenya, Uganda, Nigeria, and Malawi from 2009 to 2012. We determined those patients who were apparently LTFU, defined as absent from clinic for >=90 days at database closure and unknown to be dead or transferred. Using standardized protocols which included manual chart review, telephone calls, and physical tracking in the community, we attempted to update vital status amongst patients who were LTFU. RESULTS: We identified 1222 patients with KS, of whom 440 were LTFU according to electronic records. Manual chart review revealed that 18 (4.1%) were classified as LFTU due to clerical error, leaving 422 as truly LTFU. Of these 422, we updated vital status in 78%; manual chart review was responsible for updating in 5.7%, telephone calls in 26%, and physical tracking in 46%. Among 378 patients who consented at clinic enrollment to be tracked if they became LTFU and who had sufficient geographic contact/locator information, we updated vital status in 88%. Duration of LTFU was not associated with success of tracking, but tracking success was better in Kenya than the other sites. CONCLUSION: It is feasible to update vital status in a large fraction of patients with HIV-associated KS in sub-Saharan Africa who have become LTFU from clinical care. This finding likely applies to other cancers as well. Updating vital status amongst lost patients paves the way towards accurate determination of cancer survival. PMID- 28865423 TI - Patient's perspective of sustained remission in rheumatoid arthritis. AB - BACKGROUND: During the course of rheumatoid arthritis (RA), patients have profound negative effects on their patient-reported-outcomes (PRO); in addition, the impact of sustained remission (SR) on PROs may differ for each particular outcome. The objectives of this study were to identify SR from an inception cohort of RA patients and to examine the impact of SR in an ample spectrum of PROs. METHODS: The study was developed in a well characterized and ongoing cohort of RA patients with recent onset disease recruited from 2004 onwards. In November 2016, the cohort included 187 patients, of whom 145 had at least 30 months of follow-up, with complete rheumatic assessments at regular intervals in addition to a pain visual analogue scale (PVAS), overall disease-VAS (OVAS), health assessment questionnaire (HAQ), Short-Form 36v2 Survey (SF-36) and fatigue assessment. First SR was defined according to the DAS28 cut-offs (DAS28-SR) and ACR/EULAR 2011 Boolean definition (B-SR), if maintained for at least 12 consecutive months. The dependent t test and Mc Nemar's tests were used for comparisons between related groups. Local IRB approval was obtained. RESULTS: More patients achieved DAS28-SR than B-SR: 78 vs. 63, respectively. Fifty patients met both SR definitions. Follow-up to DAS28-SR was shorter than to B-SR and the duration of DAS28-SR was longer, p <= 0.023 for all comparisons. At SR, patients had PRO proxy to normal values; the percentage of patients with normal PRO varied from 97% (95% CI: 91-99) for HAQ to 50% (95% CI: 39-61) for absence of fatigue. In DAS28-SR patients, acute reactant phases within the normal range were detected very early (after 1.5-2.9 months). HAQ, PVAS, OVAS and SF-36 were scored within the normal range after 6-7 months. The absence of fatigue was detected at 8.7 months of follow-up, which was similar to DAS28-SR. In the 63 patients with B SR, a similar pattern was observed. The follow-up to outcomes of the 50 patients who met both SR definitions was similar, but the absence of fatigue and physical component SF-36 normalization were achieved earlier in B-SR patients (p <= 0.02). CONCLUSIONS: The impact of SR on PRO differs accordingly to each particular outcome. PMID- 28865424 TI - Prevalence, pattern and risk factors of retinal vein occlusion in an elderly population in Nepal: the Bhaktapur retina study. AB - BACKGROUND: This study aims to explore the prevalence, pattern and risk factors of retinal vein occlusion (RVO) in an elderly population of Nepal. METHOD: One thousand eight hundred sixty subjects of age 60 years and above were enrolled in a population-based, cross-sectional study. Detailed history, visual acuity, anterior segment and posterior segment examinations were done. Blood pressure, non-fasting blood sugar, body mass index and abdominal girth were measured. Retinal vein occlusions were further divided into branch retinal (BRVO), hemi retinal and central retinal vein occlusion (CRVO). RESULT: Age ranged from 60 to 95 years with a mean of 69.64 +/- 7.31 years. Overall population prevalence for RVO was 2.95% (95% Confidence interval (CI): 2.23-3.83), BRVO 2.74% (95% CI: 2.05 3.58) and CRVO 0.21% (95% CI: 0.06-0.55). BRVO was seen in 51 subjects (92.73%) and CRVO in 4 (7.27%). Among the total RVO, unilateral and bilateral involvement was 85.45% and 14.55%, respectively. Among the subjects with BRVO and CRVO, 37.25% and 50% had low vision, respectively. The risk of RVO increased with ageing and was more among males. There was an increased risk of RVO among those with hypertension, and with diabetes and hypertension. There was also an increased risk of RVO among subjects with hypermetropia, those with pseudophakia and those who were smokers and consumed alcohol. CONCLUSION: Retinal vein occlusion is a common retinal vascular disorder in the elderly population of Nepal. The main risk factors for RVO were increasing age and hypertension. PMID- 28865425 TI - Silver-coated modular Megaendoprostheses in salvage revision arthroplasty after periimplant infection with extensive bone loss - a pilot study of 34 patients. AB - BACKGROUND: Hip and knee replacements in patients with bone defects after infection correlates with high rates of reinfection. In this vulnerable patient population, the prevention of reinfection is to be considered superordinate to the functionality and defect bridging. The use of silver coating of aseptic implants as an infection prophylaxis is already proven; however, the significance of these coatings in septic reimplantation of large implants is still not sufficiently investigated. METHODS: In a retrospective analysis, 34 patients who have been treated with a modular mega-endoprosthesis after a cured bone infection of the lower limb (femur or tibia) have been evaluated. One group with 14 patients (NSCG: non silver- coated group) was supplied with the non silver- coated implants: MML Munchen- LubeckTM modular endoprosthesis system (AQ Implants, Ahrensburg, Germany) or MUTARS(r) Modular Universal Tumor And Revision System (Implantcast GmbH, Buxtehude, Germany). The other group with 20 patients (SCG: silver- coated group) was supplied with the silver- coated system of MUTARS(r). In addition to the clinical findings and the patients' histories, specifically the reinfection rates, the patients' mobility was assessed using the New Mobility Score (NMS, by Parker and Palmer). RESULTS: The median follow-up period was 72 months, ranging from 6 to 267 months. The dropout rate was 5.8%. The reinfection rate after healed reinfection in SCG was 40% (8/20), in NSCG 57% (8/14), p = 0.34; alpha =0.05. The time for reinfection was, on average, 14 months (1-72 months) in SCG and 8 months (1-48 months) in the NSCG (p = 0.61; alpha =0.05). The two groups showed no differences in the NMS. CONCLUSION: With this retrospective analysis, it can be determined that the rate of reinfection of modular mega-endoprostheses on the hip and knee joint after healed periprosthetic joint infection (PJI) can be reduced by the use of silver coated implants. The time until reinfection can also be delayed by utilizing silver coated implants. Due to the low number of cases of this highly specific patient population, no statistical significance could be determined. A positive effect, however, can be assumed through the use of silver coatings in mega-endoprostheses after an infectious situation. PMID- 28865426 TI - Robust gene selection methods using weighting schemes for microarray data analysis. AB - BACKGROUND: A common task in microarray data analysis is to identify informative genes that are differentially expressed between two different states. Owing to the high-dimensional nature of microarray data, identification of significant genes has been essential in analyzing the data. However, the performances of many gene selection techniques are highly dependent on the experimental conditions, such as the presence of measurement error or a limited number of sample replicates. RESULTS: We have proposed new filter-based gene selection techniques, by applying a simple modification to significance analysis of microarrays (SAM). To prove the effectiveness of the proposed method, we considered a series of synthetic datasets with different noise levels and sample sizes along with two real datasets. The following findings were made. First, our proposed methods outperform conventional methods for all simulation set-ups. In particular, our methods are much better when the given data are noisy and sample size is small. They showed relatively robust performance regardless of noise level and sample size, whereas the performance of SAM became significantly worse as the noise level became high or sample size decreased. When sufficient sample replicates were available, SAM and our methods showed similar performance. Finally, our proposed methods are competitive with traditional methods in classification tasks for microarrays. CONCLUSIONS: The results of simulation study and real data analysis have demonstrated that our proposed methods are effective for detecting significant genes and classification tasks, especially when the given data are noisy or have few sample replicates. By employing weighting schemes, we can obtain robust and reliable results for microarray data analysis. PMID- 28865427 TI - A split ubiquitin system to reveal topology and released peptides of membrane proteins. AB - BACKGROUND: Membrane proteins define biological functions of membranes in cells. Extracellular peptides of transmembrane proteins receive signals from pathogens or environments, and are the major targets of drug developments. Despite of their essential roles, membrane proteins remain elusive in topological studies due to technique difficulties in their expressions and purifications. METHODS: First, the target gene is cloned into a destination vector to fuse with C terminal ubiquitin at the N or C terminus. Then, Cub vector with target gene and NubWT or NubG vectors are transformed into AP4 or AP5 yeast cells, respectively. After mating, the diploid cells are dipped onto selection medium to check the growth. Topology of the target protein is determined according to Table 1. RESULTS: We present a split ubiquitin topology (SUT) analysis system to study the topology and truncation peptide of membrane proteins in a simple yeast experiment. In the SUT system, transcription activator (TA) fused with a nucleo-cytoplasmic protein shows strong auto-activation with both positive and negative control vectors. TA fused with the cytoplasmic end of membrane proteins activates reporter genes only with positive control vector with a wild type N terminal ubiquitin (NubWT). However, TA fused with the extracellular termini of membrane proteins can't activate reporter genes even with NubWT. Interestingly,TA fused with the released peptide of a membrane protein shows autoactivation in the SUT system. CONCLUSION: The SUT system is a simple and fast experimental procedure complementary to computational predictions and large scale proteomic techniques. The preliminary data from SUT are valuable for pathogen recognitions and new drug developments. PMID- 28865428 TI - Psychosocial stressors contributing to emergency psychiatric service utilization in a sample of ethno-culturally diverse clients with psychosis in Toronto. AB - BACKGROUND: Understanding the psychosocial stressors of people with psychoses from minority ethnic groups may help in the development of culturally appropriate services. This study aimed to compare psychosocial factors associated with attendance at an emergency department (ED) for six ethnic groups. Preventing crises or supporting people better in the community may decrease hospitalization and improve outcomes. METHOD: A cohort was created by retrospective case note analysis of people of East-Asian, South-Asian, Black-African, Black-Caribbean, White-North American and White-European origin groups attending a specialized psychiatric ED in Toronto with a diagnosis of psychosis between 2009 and 2011. The psychological or social stressors which were linked to the presentation at the ED that were documented by the attending physicians were collected for this study. Logistic regression models were constructed to analyze the odds of presenting with specific stressors. RESULTS: Seven hundred sixty-five clients were included in this study. Forty-four percent of the sample did not have a psychiatrist, and 53% did not have a primary care provider. Social environmental stressors were the most frequent psychosocial stressor across all six groups, followed by issues in the primary support group, occupational and housing stressors. When compared to White-North American clients, East-Asian and White European origin clients were less likely to present with a housing stressor, while Black-African clients had decreased odds of presenting with primary support group stressor. Having a primary care provider or psychiatrist were predominantly protective factors. CONCLUSION: In Toronto, moving people with chronic mental health conditions out of poverty, increasing the social safety net and improving access to primary care and community based mental health services may decrease many of the stressors which contribute to ED attendance. PMID- 28865429 TI - A new and updated resource for codon usage tables. AB - BACKGROUND: Due to the degeneracy of the genetic code, most amino acids can be encoded by multiple synonymous codons. Synonymous codons naturally occur with different frequencies in different organisms. The choice of codons may affect protein expression, structure, and function. Recombinant gene technologies commonly take advantage of the former effect by implementing a technique termed codon optimization, in which codons are replaced with synonymous ones in order to increase protein expression. This technique relies on the accurate knowledge of codon usage frequencies. Accurately quantifying codon usage bias for different organisms is useful not only for codon optimization, but also for evolutionary and translation studies: phylogenetic relations of organisms, and host-pathogen co-evolution relationships, may be explored through their codon usage similarities. Furthermore, codon usage has been shown to affect protein structure and function through interfering with translation kinetics, and cotranslational protein folding. RESULTS: Despite the obvious need for accurate codon usage tables, currently available resources are either limited in scope, encompassing only organisms from specific domains of life, or greatly outdated. Taking advantage of the exponential growth of GenBank and the creation of NCBI's RefSeq database, we have developed a new database, the High-performance Integrated Virtual Environment-Codon Usage Tables (HIVE-CUTs), to present and analyse codon usage tables for every organism with publicly available sequencing data. Compared to existing databases, this new database is more comprehensive, addresses concerns that limited the accuracy of earlier databases, and provides several new functionalities, such as the ability to view and compare codon usage between individual organisms and across taxonomical clades, through graphical representation or through commonly used indices. In addition, it is being routinely updated to keep up with the continuous flow of new data in GenBank and RefSeq. CONCLUSION: Given the impact of codon usage bias on recombinant gene technologies, this database will facilitate effective development and review of recombinant drug products and will be instrumental in a wide area of biological research. The database is available at hive.biochemistry.gwu.edu/review/codon . PMID- 28865430 TI - Aerobic training for improved memory in patients with stress-related exhaustion: a randomized controlled trial. AB - BACKGROUND: Patients with stress-related exhaustion suffer from cognitive impairments, which often remain after psychological treatment or work place interventions. It is important to find effective treatments that can address this problem. Therefore, the aim of this study was to investigate the effects on cognitive performance and psychological variables of a 12-week aerobic training program performed at a moderate-vigorous intensity for patients with exhaustion disorder who participated in a multimodal rehabilitation program. METHODS: In this open-label, parallel, randomized and controlled trial, 88 patients diagnosed with exhaustion disorder participated in a 24-week multimodal rehabilitation program. After 12 weeks in the program the patients were randomized to either a 12-week aerobic training intervention or to a control group with no additional training. Primary outcome measure was cognitive function, and secondary outcome measures were psychological health variables and aerobic capacity. RESULTS: In total, 51% patients in the aerobic training group and 78% patients in the control group completed the intervention period. The aerobic training group significantly improved in maximal oxygen uptake and episodic memory performance. No additional improvement in burnout, depression or anxiety was observed in the aerobic group compared with controls. CONCLUSION: Aerobic training at a moderate-vigorous intensity within a multimodal rehabilitation program for patients with exhaustion disorder facilitated episodic memory. A future challenge would be the clinical implementation of aerobic training and methods to increase feasibility in this patient group. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03073772 . Retrospectively registered 21 February 2017. PMID- 28865431 TI - Uncommon presentation of a rare tumour - incidental finding in an asymptomatic patient: case report and comprehensive review of the literature on intrapericardial solitary fibrous tumours. AB - BACKGROUND: A solitary fibrous tumour is a rare, mainly benign spindle cell mesenchymal tumour most commonly originating from the pleura. An intrapericardial location of a solitary fibrous tumour is extremely unusual. We present a case of an asymptomatic patient with a slow-growing massive benign cardiac solitary fibrous tumour. CASE PRESENTATION: A 37-year-old asymptomatic female patient was referred to our hospital with an enlarged cardiac silhouette found on her screening chest X-ray. The echocardiographic examination revealed pericardial effusion and an inhomogeneous mobile mass located in the pericardial sac around the left ventricle. Cardiac magnetic resonance (MRI) examination showed an intrapericardial, semilunar-shaped mass attached to the pulmonary trunk with an intermediate signal intensity on proton density-weighted images and high signal intensity on T2-weighted spectral fat saturation inversion recovery images. First pass perfusion and early and late gadolinium-enhanced images showed a vascularized mass with septated, patchy, inhomogeneous late enhancement. Coronary computed tomography angiography revealed no invasion of the coronaries. Based on the retrospectively analysed screening chest X-rays, the mass had started to form at least 7 years earlier. Complete resection of the tumour with partial resection of the pulmonary trunk was performed. Histological evaluation of the septated, cystic mass revealed tumour cells forming an irregular patternless pattern; immunohistochemically, the cells tested positive for vimentin, CD34, CD99 and STAT6 but negative for keratin (AE1-AE3), CD31 and S100. Thus, the diagnosis of an intrapericardial solitary fibrous tumour was established. There has been no recurrence for 3 years based on the regular MRI follow-up. CONCLUSION: Intrapericardial SFTs, showing slow growth dynamics, can present with massive extent even in completely asymptomatic patients. MRI is exceedingly useful for characterizing intrapericardial masses, allowing precise surgical planning, and is reliable for long-term follow up. PMID- 28865432 TI - A mixed-methods investigation of incident Hemodialysis access in a safety-net population. AB - BACKGROUND: Despite improved health outcomes associated with arteriovenous fistulas, 80% of Americans initiate hemodialysis using a catheter, influenced by low socioeconomic status among other factors. Risk factors for incident catheter use in safety-net populations are unknown. Our objective was to identify factors associated with incident catheter use among hemodialysis patients at one safety net hospital, with a goal of informing fistula placement initiatives targeted at safety-net populations more generally. METHODS: We performed a retrospective review of all incident hemodialysis patients at a single urban safety-net hospital from January 1, 2010 - December 31, 2015 (n = 241), as well as semi structured interviews with a multi-lingual convenience sample of patients (n = 10) from this cohort. The primary outcome was incident vascular access modality. Multivariable logistic regression was used to identify factors associated with incident catheter use. Interview transcripts were coded using a directed content analysis framework based on a model describing barriers to healthcare access. RESULTS: Subjects were 61.8% male, racially/ethnically diverse (19.5% white, 29.5% black, 28.6% Hispanic, 17.4% Asian), with a mean age of 52.4 years. Eighty eight percent initiated hemodialysis using a catheter. In multivariable analysis, longer duration of nephrology care was associated with decreased catheter use (>12 months vs. 0-6 months: adjusted Odds Ratio [aOR] 0.07, 95% CI 0.02-0.23, p < 0.001), whereas uninsured status increased odds of catheter use (aOR 3.96, 1.23 12.76, p = 0.02). There was a decrease in catheter use after vascular surgery services became available in-hospital (OR 0.40, 95% CI 0.16-0.98, p = 0.04), however this association was not significant in multivariable analysis (aOR 0.48, 0.17-1.36, p = 0.17). During interviews, patients cited emotional responses to disease, lack of social and financial resources, and limited health knowledge as barriers to obtaining fistula surgery. CONCLUSIONS: The rate of catheter use in this urban safety-net population is above the national average. Access to health insurance, early referrals to nephrology, and provision of in-hospital vascular surgery should be prioritized in the safety-net. Additionally, services that support patients' emotional and learning needs may decrease delays in fistula placement. PMID- 28865433 TI - RRCRank: a fusion method using rank strategy for residue-residue contact prediction. AB - BACKGROUND: In structural biology area, protein residue-residue contacts play a crucial role in protein structure prediction. Some researchers have found that the predicted residue-residue contacts could effectively constrain the conformational search space, which is significant for de novo protein structure prediction. In the last few decades, related researchers have developed various methods to predict residue-residue contacts, especially, significant performance has been achieved by using fusion methods in recent years. In this work, a novel fusion method based on rank strategy has been proposed to predict contacts. Unlike the traditional regression or classification strategies, the contact prediction task is regarded as a ranking task. First, two kinds of features are extracted from correlated mutations methods and ensemble machine-learning classifiers, and then the proposed method uses the learning-to-rank algorithm to predict contact probability of each residue pair. RESULTS: First, we perform two benchmark tests for the proposed fusion method (RRCRank) on CASP11 dataset and CASP12 dataset respectively. The test results show that the RRCRank method outperforms other well-developed methods, especially for medium and short range contacts. Second, in order to verify the superiority of ranking strategy, we predict contacts by using the traditional regression and classification strategies based on the same features as ranking strategy. Compared with these two traditional strategies, the proposed ranking strategy shows better performance for three contact types, in particular for long range contacts. Third, the proposed RRCRank has been compared with several state-of-the-art methods in CASP11 and CASP12. The results show that the RRCRank could achieve comparable prediction precisions and is better than three methods in most assessment metrics. CONCLUSIONS: The learning-to-rank algorithm is introduced to develop a novel rank-based method for the residue-residue contact prediction of proteins, which achieves state-of-the-art performance based on the extensive assessment. PMID- 28865434 TI - Association between life-course socioeconomic position and inflammatory biomarkers in older age: a nationally representative cohort study in Taiwan. AB - BACKGROUND: Evidence of an association between low socioeconomic position (SEP) and inflammatory markers is scant. This study aimed to examine how life-course SEP predicted C-reactive protein (CRP) and interleukin (IL-6) in older age from a national cohort. METHODS: We collected data from 1036 participants in the Social Environment and Biomarkers of Aging Study in Taiwan. Four SEP time points, childhood, young adulthood, active professional life, and older age were measured retrospectively. A group-based trajectory analysis method was used to identify the distinct trajectories of life-course SEP, and trajectory group membership was used as the predictor of CRP and IL-6 levels in older age. RESULTS: Three trajectories of life-course SEP were identified within the total sample: Low-Low (36.5%), Low-High (26.8%), and High-High (36.7%). Participants in the High-High group had the lowest levels of CRP and IL-6. Compared with those in the Low-Low group, the participants in the Low-High group had a similar adjusted CRP [-0.032 ln mg/L; 95% confidence interval (CI) - 0.193, 0.128] and IL-6 (0.017 ln pg/mL; 95% CI -0.093, 0.128); the participants in the High-High group had a significantly lower level of adjusted CRP concentration (-0.279 ln mg/L; 95% CI: 0.434, -0.125) and similarly lower IL-6 concentration (-0.129 ln pg/mL; 95% CI 0.236, -0.023) . CONCLUSIONS: Life-course SEP is related to the level of CRP and IL-6 in older age. Our data support the notion that life-course SEP predicts inflammatory markers in older age. Low SEP in childhood is related to elevated inflammatory markers in older age. Even after the transition from low SEP in childhood to high SEP in older age, the risk remains. Further study on SEP and inflammation-related disease is warranted. PMID- 28865435 TI - Role of adjuvant chemotherapy in locally advanced rectal cancer with ypT0-3N0 after preoperative chemoradiation therapy and surgery. AB - BACKGROUND: We aimed to explore the clinical benefit of adjuvant chemotherapy (AC) with fluoropyrimidine in patients with ypT0-3N0 rectal cancer after preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME). METHODS: Patients with ypT0-3N0 rectal cancer after preoperative CRT and TME were included using prospectively collected tumor registry cohort between January 2001 and December 2013. Patients were categorized into two groups according to the receipt of AC. Disease-free survival (DFS) and overall survival (OS) were compared between the adjuvant and observation groups. To control for potential confounding factors, we also calculated propensity scores and performed propensity score-matched analysis for DFS and OS. RESULTS: Of the 339 evaluated patients, 87 patients (25.7%) did not receive AC. There were no differences in DFS (hazard ratio [HR], 0.921; 95% confidence interval [CI], 0.562-1.507; P = 0.742) and OS (HR, 0.835; 95% CI, 0.423-1.648; P = 0.603) between the adjuvant and observation groups. After propensity score matching, DFS (HR, 1.129; 95% CI, 0.626-2.035; P = 0.688) and OS (HR, 1.200; 95% CI, 0.539-2.669; P = 0.655) did not differ between the adjuvant and observation groups. Advanced T stage and positive resection margin were independently associated with inferior DFS and OS on multivariate analysis. CONCLUSIONS: AC did not improve DFS and OS for patients with ypT0-3N0 rectal cancer after preoperative CRT followed by TME in this cohort study. The confirmative role of AC in locally advanced rectal cancer should be evaluated in prospective randomized trials with a larger sample size. PMID- 28865436 TI - The mediating role of the home environment in relation to parental educational level and preschool children's screen time: a cross-sectional study. AB - BACKGROUND: Previous studies suggest that preschoolers from low socioeconomic backgrounds engage in more screen time. Still, the factors in the social and physical home environment driving these differences in preschool children's screen time are poorly understood. This study examines potential home environment mediators in the associations between parental educational level and preschoolers' screen time. METHODS: A total of 864 children aged 3-6 years and their parents participated in a cross-sectional DAGIS study in 2015-2016. Parents recorded their children's screen time in a diary (N = 823). For the analyses, the daily average screen time at home was calculated. Parental questionnaires (N = 808) assessed educational level and eight social and physical environment factors in the home (i.e., descriptive norm for children's screen time, parental screen use in front of children, parental importance for limiting children's screen time, parental attitude toward societal pressures for children's screen time, access to screens at home, parental self-efficacy for limiting children's screen time, satisfaction of children's screen time, and rules for limiting children's screen time). Parental education was grouped into low, middle, and high education. The associations were tested by conducting mediation analyses adjusted by season and children's sex and age. The significant mediators in the single mediator models were included in the final multiple-mediator models. RESULTS: Of the potential eight mediators, the following four had a significant indirect association: descriptive norm for children's screen time, parental screen use in front of children, parental importance for limiting children's screen time, and parental attitude toward societal pressures for children's screen time. Parents with high education had lower descriptive norm and used fewer screens in front of children compared to parents with middle or low education, and in turn, these factors were associated with less screen time among children from parents with a higher education level. Parents with high education placed greater importance on limiting children's screen time and felt less societal pressures about children's screen time compared to parents with low education, and in turn, these factors were associated with less screen time among children from parents with a higher education level. CONCLUSIONS: Our study recognized multiple modifiable mediators in the associations between parental education and preschool children's screen time. When aiming to diminish socioeconomic status differences in preschool children's screen time, the focus should be on parental role models, attitudes, and norm related to children's screen time. PMID- 28865438 TI - Adjuvant chemotherapy versus chemoradiotherapy for small cell lung cancer with lymph node metastasis: a retrospective observational study with use of a national database in Japan. AB - BACKGROUND: The optimal postoperative treatment strategy for small cell lung cancer (SCLC) remains unclear, especially in patients with lymph node metastasis. We aimed to compare the outcomes of patients with SCLC and lymph node metastasis treated with postoperative adjuvant chemotherapy or chemoradiotherapy. METHODS: We retrospectively collected data on patients with postoperative SCLC diagnosed with N1 and N2 lymph node metastasis from the Diagnosis Procedure Combination database in Japan, between July 2010 and March 2015. We extracted data on patient age, sex, comorbidities, and TNM classification at lung surgery; operative procedures, chemotherapy drugs, and radiotherapy during hospitalization; and discharge status. Recurrence-free survival was compared between the chemotherapy and chemoradiotherapy groups using multivariable Cox regression analysis. RESULTS: Median recurrence-free survival was 1146 days (95% confidence interval [CI], 885-1407) in the chemotherapy group (n = 489) and 873 days (95% CI, 464 1282) in the chemoradiotherapy group (n = 75). There was no significant difference between these after adjusting for patient backgrounds (hazard ratio, 1.29; 95% CI, 0.91-1.84). CONCLUSIONS: There was no significant difference in recurrence-free survival between patients with SCLC and N1-2 lymph node metastasis treated with postoperative adjuvant chemotherapy and chemoradiotherapy. Further randomized clinical trials are needed to address this issue. PMID- 28865437 TI - The top tertile of hematocrit change during hospitalization is associated with lower risk of mortality in acute heart failure patients. AB - BACKGROUND: Hemoconcentration has been proposed as surrogate for changes in volume status among patients hospitalized with acute heart failure (AHF) and is associated with a favorable outcome. However, there is a dearth of research assessing the clinical outcomes of hospitalized patients with hemoconcentration, hemodilution and unchanged volume status. METHODS: We enrolled 510 consecutive patients hospitalized for AHF from April 2011 to July 2015. Hematocrit (HCT) levels were measured at admission and either at discharge or on approximately the seventh day of admission. Patients were stratified by delta HCT tertitles into hemodilution (DeltaHCT <= - 1.6%), no change (NC, -1.6% < DeltaHCT <=1.5%) and hemoconcentration (DeltaHCT >1.5%) groups. The endpoint was all-cause death, with a median follow-up duration of 18.9 months. RESULTS: Hemoconcentration was associated with lower left ventricle ejection fraction, as compared with NC and hemodilution groups, while renal function at entry, New York Heart Association class IV, and in-hospital worsening renal function (WRF) were not significantly different across the three groups. After multivariable adjustment, hemoconcentration had a lower risk of mortality as compared with hemodilution [hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.24-0.63, P < 0.001], or NC (HR 0.54, 95% CI 0.33-0.88, P = 0.015], while hemodilution and NC did not have significantly differ in mortality (HR 0.72, 95% CI 0.48-1.10, P = 0.130). CONCLUSIONS: In patients hospitalized with AHF, an increased HCT during hospitalization is associated with a lower risk of all-cause mortality than a decreased or unchanged HCT. Furthermore, all-cause mortality does not differ significantly between patients with unchanged and decreased HCT values. PMID- 28865439 TI - Apln-CreERT:mT/mG reporter mice as a tool for sprouting angiogenesis study. AB - BACKGROUND: Angiogenesis is defined as a new blood vessel sprouting from pre existing vessels, and the sprouting angiogenesis is the start phase of angiogenesis, which is critical for both physiological and pathological processes, such as embryonic development, organ growth, wound healing, tumor growth, diabetic retinopathy and age-related macular degeneration. Better understanding of the mechanisms of sprout angiogenesis will provide a rationale for the treatments of these angiogenesis related diseases. METHODS: mT/mG tool mice are crossed with Apln-CreERT mice to generate Apln-CreERT: mT/mG mice, then we used neonatal retinal angiogenesis model to observe the angiogenic pattern of Apln-CreERT:mT/mG mice compared with Cdh5-CreERT:mT/mG mice. FACS analysis was used to sort eGFP and tdTomato endothelial cells (ECs) for measuring Apelin and Cdh5 expression. Retinal sprouting angiogenesis pattern was also observed at different neonatal time when induced by tamoxifen and at hypoxia condition, as well as in vivo tumor in real-time angiogenesis in a dorsal skinfold window chamber in Apln-CreERT:mT/mG mice. RESULTS: Apln-CreERT:mT/mG mice exhibited eGFP signal only in the sprouting angiogenesis, with less eGFP expression in the retinal "optic nerve" area than in that of Cdh5-CreERT: mT/mG mice, which might be due to relative mature vessels in the "optic nerve" area. The ECs sorted by FACS confirmed that the Apelin expression level was higher in eGFP ECs than tdTomato ECs of "optic nerve" area. Further we found that GFP-labeled sprouting angiogenesis decreased gradually following tamoxifen administration from P5-P7, but increased significantly during hypoxia in Apln-CreERT:mT/mG mice. At last, using Apln-CreERT:mT/mG mice we found tumor sprouting angiogenesis in dorsal skinfold, but not in the normal skinfold tissue. CONCLUSIONS: Apln-CreERT:mT/mG mouse line is a useful tool to differentiate sprouting angiogenesis from whole blood vessels in the investigation of retinal and tumor sprouting angiogenesis in vivo. PMID- 28865440 TI - Adherence and outcomes to direct oral anticoagulants among patients with atrial fibrillation: findings from the veterans health administration. AB - BACKGROUND: The direct oral anticoagulants (DOACs) reduce the risk of stroke in moderate to high-risk patients with non-valvular atrial fibrillation (AF). Yet, concerns remain regarding its routine use in real world practice. We sought to describe adherence patterns and the association between adherence and outcomes to the DOACs among outpatients with AF. METHODS: We performed a retrospective cohort study of patients in the VA Healthcare System who initiated pharmacotherapy with dabigatran, rivaroxaban, or apixaban between November 2010 and January 2015 for non-valvular AF with CHA2DS2-VASc score >= 2. Adherence was determined using pharmacy refill data and estimated by the proportion of days covered (PDC) over the first year of therapy. Clinical outcomes, including all-cause mortality and stroke, were measured at 6 months and used to assess measures of adherence for each DOAC. RESULTS: A total of 2882 patients were included. Most were prescribed dabigatran (72.7%), compared with rivaroxaban (19.8%) or apixaban (7.5%). The mean PDC was 0.84 +/- 0.20 for dabigatran, 0.86 +/- 0.18 for rivaroxaban, and 0.89 +/- 0.14 for apixaban (p < 0.01). The proportion of non-adherent patients, PDC <0.80, was 27.6% for all and varied according DOAC. Lower adherence to dabigatran was associated with higher risk of mortality and stroke (HR 1.07; 1.03 1.12 per 0.10 decline in PDC). CONCLUSIONS: In a real-world VA population being prescribed anticoagulation for AF, more than one quarter had sub-optimal adherence. Lower adherence was associated with a higher risk of mortality and stroke. Efforts identifying non-adherent patients, and targeted adherence interventions are needed to improve outcomes. PMID- 28865442 TI - Midwives' experiences of performing maternal observations and escalating concerns: a focus group study. AB - BACKGROUND: For the past decade, Maternal Mortality Reports, published in the United Kingdom every three years, have consistently raised concerns about maternal observations in maternity care. The reports identify that observations are not being done, not being completed fully, are not recorded on Early Warning Score systems, and/or are not escalated appropriately. This has resulted in delays in referral, intervention and increases the risk of maternal morbidity or mortality. However there has been little exploration of the possible reasons for non-completion of maternal observations. METHODS: The aim of this study was to explore midwives' experiences of performing maternal observations and escalating concerns in rural and urban maternity settings in the West Midlands of England. A qualitative design involving a series of six focus groups with midwives and Supervisors of Midwives was employed to investigate the facilitators of, and barriers to the completion of maternal observations. RESULTS: Eighteen Midwives and 8 Supervisors of Midwives participated in a total of 6 focus groups. Three key themes emerged from the data: (1) Organisation of Maternal Observations (including delegation of tasks to Midwifery Support Workers, variation in their training, the care model used e.g. one to one care, and staffing issues); (2) Prioritisation of Maternal Observations (including the role of professional judgement and concerns expressed by midwives that they did not feel equipped to care for women with complex clinical needs; and (3) Negotiated Escalation (including the inappropriate response from senior staff to use of Modified Early Warning Score systems, and the emotional impact of escalation). CONCLUSIONS: A number of organisational and cultural barriers exist to the completion of maternal observations and the escalation of concerns. In order to address these the following actions are recommended: standardised training for Midwifery Support Workers, review of training of midwives to ensure it addresses the increasing complexity of the maternal population, identification and agreement regarding the organisation of maternal observations among staff, an emphasis on increasing the priority placed on maternal observations in all clinical settings, and clarification and reinforcement of escalation procedures for both midwives and senior clinicians. PMID- 28865441 TI - Predicting outcome in frozen shoulder (shoulder capsulitis) in presence of comorbidity as measured with subjective health complaints and neuroticism. AB - BACKGROUND: There is a substantive lack of knowledge about comorbidity in patients with frozen shoulder. The aim of this study was to investigate whether subjective health complaints and Neuroticism would predict treatment outcome in patients diagnosed with frozen shoulder as measured by the Shoulder Pain and Disability Index (SPADI) and change in SPADI. METHODS: A total of 105 patients with frozen shoulder were recruited for a randomised controlled trial, where 69 were in the intervention group and received intraarticular corticosteroid injections and 36 patients served as control group. The SPADI was used as the outcome measure after 8 weeks, and change in SPADI from baseline to 8 weeks as a measure of rate of recovery. To examine comorbidities, all participants completed the Subjective Health Complaints (SHC) questionnaire with its five subscales, and the Neuroticism (N) component of the Eysenck Personality Questionnaire Revised. Multiple regression analysis was performed with the baseline comorbidity variables that correlated significantly with SPADI after 8 weeks, and with change in SPADI from baseline to 8 weeks, controlling for the variables intervention, age, gender and duration of pain. RESULTS: In this study, patients with frozen shoulder had little comorbidity as measured with SHC and scored normally with respect to Neuroticism. Only the Pseudoneurology subscale in SHC correlated significantly with SPADI and had significant predictive power (p < 0.001) for the outcome at 8 weeks. The intervention group exhibited significant statistical predictive power (p < 0.001) for the treatment outcome as measured by a change in SPADI from baseline to 8 weeks. Being female also had some predictive significance for change in SPADI (p < 0.005). CONCLUSION: Psychometric parameters as measured by the Pseudoneurology subscale in SHC questionnaire did predict the treatment outcome in frozen shoulder as measured by SPADI at 8 weeks, but not by change in SPADI from baseline to 8 weeks. One may conclude that psychometric parameters may affect symptoms, but do not predict the rate of recovery in frozen shoulder. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT01570985 . PMID- 28865443 TI - Investigating MicroRNA and transcription factor co-regulatory networks in colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide with poor prognosis. Studies have showed that abnormal microRNA (miRNA) expression can affect CRC pathogenesis and development through targeting critical genes in cellular system. However, it is unclear about which miRNAs play central roles in CRC's pathogenesis and how they interact with transcription factors (TFs) to regulate the cancer-related genes. RESULTS: To address this issue, we systematically explored the major regulation motifs, namely feed-forward loops (FFLs), that consist of miRNAs, TFs and CRC-related genes through the construction of a miRNA-TF regulatory network in CRC. First, we compiled CRC related miRNAs, CRC-related genes, and human TFs from multiple data sources. Second, we identified 13,123 3-node FFLs including 25 miRNA-FFLs, 13,005 TF-FFLs and 93 composite-FFLs, and merged the 3-node FFLs to construct a CRC-related regulatory network. The network consists of three types of regulatory subnetworks (SNWs): miRNA-SNW, TF-SNW, and composite-SNW. To enhance the accuracy of the network, the results were filtered by using The Cancer Genome Atlas (TCGA) expression data in CRC, whereby we generated a core regulatory network consisting of 58 significant FFLs. We then applied a hub identification strategy to the significant FFLs and found 5 significant components, including two miRNAs (hsa miR-25 and hsa-miR-31), two genes (ADAMTSL3 and AXIN1) and one TF (BRCA1). The follow up prognosis analysis indicated all of the 5 significant components having good prediction of overall survival of CRC patients. CONCLUSIONS: In summary, we generated a CRC-specific miRNA-TF regulatory network, which is helpful to understand the complex CRC regulatory mechanisms and guide clinical treatment. The discovered 5 regulators might have critical roles in CRC pathogenesis and warrant future investigation. PMID- 28865444 TI - Application of postoperative autotransfusion in total joint arthroplasty reduces allogeneic blood requirements: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Total joint arthroplasty is associated with significant blood loss and often requires blood transfusion. However, allogeneic blood transfusion (ABT) may lead to severe problems, such as immunoreaction and infection. Postoperative autotransfusion, an alternative to ABT, is controversial. We conducted a meta analysis to evaluate the ability of postoperative autotransfusion to reduce the need for ABT following total knee arthroplasty (TKA) and total hip arthroplasty (THA). METHODS: Systematic literature searches for randomized controlled trials were performed using PubMed, Embase, and the Cochrane Library until February 2016. Relative risks (RRs) and weighted mean differences with 95% confidence intervals (CIs) were calculated using fixed-effect or random-effect models; we also evaluated publication bias and heterogeneity. RESULTS: Seventeen trials with a total of 2314 patients were included in the meta-analysis. The pooled RRs of ABT rate between autotransfusion and the regular drainage/no drainage groups for TKA and THA were 0.446 (95% CI = 0.287, 0.693; p < 0.001) and 0.757 (95% CI = 0.599, 0.958; p = 0.020), respectively. In the subgroup analysis performed in TKA patients according to control interventions, the pooled RRs were 0.377 (95% CI = 0.224, 0.634; p < 0.001) (compared with regular drainage) and 0.804 (95% CI = 0.453, 1.426, p = 0.456) (compared with no drainage). In the subgroup analysis performed for THA, the pooled RRs were 0.536 (95% CI = 0.379, 0.757, p < 0.001) (compared with regular drainage) and 1.020 (95% CI = 0.740, 1.405, p = 0.904) (compared with no drainage). CONCLUSIONS: Compared to regular drainage, autotransfusion reduces the need for ABT following TKA and THA. This reduction is not present when comparing autotransfusion to no drainage. However, the reliability of the meta-analytic results concerning TKA was limited by significant heterogeneity in methods among the included studies. PMID- 28865445 TI - Distinctive subgroups derived by cluster analysis based on pain and psychological symptoms in Swedish older adults with chronic pain - a population study (PainS65+). AB - BACKGROUND: Improved knowledge based on clinical features of chronic pain in older adults would be valuable in terms of patient-orientated approaches and would provide support for health care systems in optimizing health care resources. This study identifies subgroups based on pain and psychological symptoms among Swedish older adults in the general population and compares derived subgroups with respect to socio-demographics, health aspects, and health care costs. METHODS: This cross-sectional study uses data collected from four registers and one survey. The total sample comprised 2415 individuals >=65 years old. A two-step cluster analysis was performed. Data on pain intensity, number of pain sites, anxiety, depression, and pain catastrophizing were used as classification variables. Differences in socio-demographics, quality of life, general health, insomnia, and health care costs among the clusters were investigated. Association of the clusters with the above parameters was further evaluated using multinomial logistic regression. RESULTS: Four major clusters were identified: Subgroup 1 (n = 325; 15%) - moderate pain and high psychological symptoms; Subgroup 2 (n = 516; 22%) - high pain and moderate psychological symptoms; Subgroup 3 (n = 686; 30%) - low pain and moderate psychological symptoms; and Subgroup 4 (n = 767; 33%) - low pain and low psychological symptoms. Significant differences were found between the four clusters with regard to age, sex, educational level, family status, quality of life, general health, insomnia, and health care costs. The multinomial logistic regression analysis revealed that Subgroups 1 and 2, compared to Subgroup 4, were significantly associated with decreased quality of life, decreased general health, and increased insomnia. Subgroup 3, compared to Subgroup 4, was associated with decreased general health and increased insomnia. In addition, compared to Subgroup 4, Subgroups 1 and 2 were significantly associated with higher health care costs. CONCLUSIONS: Two high risk clusters of older adults suffering from chronic pain; one mainly based on psychological symptoms and one mainly on pain intensity and pain spread, associated with decreased quality of life and health and increased health care costs were identified. Our findings indicate that subgroup-specific treatment will improve pain management and reduce health care costs. PMID- 28865446 TI - Computational discovery and functional validation of novel fluoroquinolone resistance genes in public metagenomic data sets. AB - BACKGROUND: Fluoroquinolones are broad-spectrum antibiotics used to prevent and treat a wide range of bacterial infections. Plasmid-mediated qnr genes provide resistance to fluoroquinolones in many bacterial species and are increasingly encountered in clinical settings. Over the last decade, several families of qnr genes have been discovered and characterized, but their true prevalence and diversity still remain unclear. In particular, environmental and host-associated bacterial communities have been hypothesized to maintain a large and unknown collection of qnr genes that could be mobilized into pathogens. RESULTS: In this study we used computational methods to screen genomes and metagenomes for novel qnr genes. In contrast to previous studies, we analyzed an almost 20-fold larger dataset comprising almost 13 terabases of sequence data. In total, 362,843 potential qnr gene fragments were identified, from which 611 putative qnr genes were reconstructed. These gene sequences included all previously described plasmid-mediated qnr gene families. Fifty-two of the 611 identified qnr genes were reconstructed from metagenomes, and 20 of these were previously undescribed. All of the novel qnr genes were assembled from metagenomes associated with aquatic environments. Nine of the novel genes were selected for validation, and six of the tested genes conferred consistently decreased susceptibility to ciprofloxacin when expressed in Escherichia coli. CONCLUSIONS: The results presented in this study provide additional evidence for the ubiquitous presence of qnr genes in environmental microbial communities, expand the number of known qnr gene variants and further elucidate the diversity of this class of resistance genes. This study also strengthens the hypothesis that environmental bacterial communities act as sources of previously uncharacterized qnr genes. PMID- 28865447 TI - Multicenter assessment of sedation and delirium practices in the intensive care units in Poland - is this common practice in Eastern Europe? AB - BACKGROUND: The majority of critically ill patients experience distress during their stay in the Intensive Care Unit (ICU), resulting from systemic illness, multiple interventions and environmental factors. Providing humane care should address concomitant treatment of pain, agitation and delirium. The use of sedation and approaches to ICU delirium should be monitored according to structured guidelines. However, it is unknown to what extent these concepts are followed in Eastern European countries like Poland. The aim of this study was to evaluate sedation and delirium practices in ICUs in Poland, as a representative of the Eastern European block, particularly the implementation of sedation and ICU delirium screening tools, availability of written sedation guidelines, choice of sedation and delirium treatment agents. METHODS: A national postal survey was conducted in all Polish ICUs in early 2016. RESULTS: A total of 165 responses out of 436 addressed units were received (37.8%). Out of responding ICUs delirium is monitored in only 11.9% of the units in Poland. Sedation monitoring tool is used in only 46.1% of units. Only 19.4% of ICUs have written protocols for sedation and 32.1% do not practice daily sedation interruption. The most frequently used agents for short-term sedation (<24 h) were propofol and fentanyl infusions and benzodiazepines (midazolam) and morphine for longer sedation (>24 h). The preferred agents for delirium treatment were haloperidol (77.6%), dexmedetomidine (43.6%) and quetiapine (19.4%). Close to one-third (32.7%) of respondents chose a benzodiazepine (diazepam) for ICU delirium treatment. Non-pharmacological treatment for ICU delirium was reported by only 45% of the respondents. CONCLUSIONS: A majority of Polish ICUs do not adhere to international guidelines regarding sedation and delirium practices. There continues to be inadequate use of sedation and delirium monitoring tools. High usage of benzodiazepines for sedation and ICU delirium treatment reveals persistence of non-evidence-based practice. This study should prompt further assessment of other Eastern Europe countries and help generate a collective response to update these aspects of patient safety and comfort. PMID- 28865448 TI - Pediatric supraglottic airway devices in clinical practice: A prospective observational study. AB - BACKGROUND: Supraglottic airway devices (SGA) are commonly used in pediatric anesthesia and serve as primary or back-up devices for difficult airway management. Most SGA are marketed without proper clinical evaluation. The purpose of this study was to evaluate the performance of the pediatric LMA SupremeTM, Air Q(r) and Ambu(r) Aura-iTM. METHODS: This prospective observational study was performed at Bern University Hospital, Switzerland. With ethics committee approval and a waiver for written informed consent 240 children undergoing elective surgery with an ASA class I-III and a weight of 5-30 kg were included. Three different pediatric supraglottic airway devices were assessed: The LMA SupremeTM, Air-Q(r) and Ambu(r) Aura-iTM. Primary outcome parameter was airway leak pressure. Secondary outcome parameters included first attempt and overall success rate, insertion time, fiberoptic view through the SGA, and adverse events. The primary hypothesis was that the mean airway leak pressure of each tested SGA was 20 cmH2O +/- 10%. RESULTS: None of the SGA showed a mean airway leak pressure of 20 cmH2O +/- 10%, but mean airway leak pressures differed significantly between devices [LMA SupremeTM 18.0 (3.4) cmH2O, Air-Q(r) 15.9 (3.2) cmH2O, Ambu(r) Aura-iTM 17.3 (3.7) cmH2O, p < 0.001]. First attempt success rates (LMA SupremeTM 100%, Air-Q(r) 90%, Ambu(r) Aura-iTM 91%, p = 0.02) and overall success rates (LMA SupremeTM 100%, Air-Q(r) 91%, Ambu(r) Aura-iTM 95%, p = 0.02) also differed significantly. Insertion times ranged from 20 (7) seconds (Air-Q(r)) to 24 (6) seconds (LMA SupremeTM,

= 160 IU/ml, anti-CCP >= 100 U/ml), and "middle-C" (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes. RESULTS: Baseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2-14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 MUg/ml), and that Disease Activity Score in 28 joints based on C reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment. CONCLUSIONS: RF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00691028 . Retrospectively registered on 3 June 2008. PMID- 28865496 TI - [Vitamin D in the Prevention of Chronic Diseases: An Evidence Based Analysis]. PMID- 28865495 TI - Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression (TRMD) Veteran patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Evaluation of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression (TRMD) in Veterans offers unique clinical trial challenges. Here we describe a randomized, double-blinded, intent-to-treat, two-arm, superiority parallel design, a multicenter study funded by the Cooperative Studies Program (CSP No. 556) of the US Department of Veterans Affairs. METHODS: We recruited medical providers with clinical expertise in treating TRMD at nine Veterans Affairs (VA) medical centers as the trial local investigators. We plan to enroll 360 Veterans diagnosed with TRMD at the nine VA medical centers over a 3-year period. We will randomize participants into a double-blinded clinical trial to left prefrontal rTMS treatment or to sham (control) rTMS treatment (180 participants each group) for up to 30 treatment sessions. All participants will meet Diagnostic and statistical manual of mental disorders, 4 th edition (DSM-IV) criteria for major depression and will have failed at least two prior pharmacological interventions. In contrast with other rTMS clinical trials, we will not exclude Veterans with posttraumatic stress disorder (PTSD) or history of substance abuse and we will obtain detailed history regarding these disorders. Furthermore, we will maintain participants on stable anti-depressant medication throughout the trial. We will evaluate all participants on a wide variety of potential predictors of treatment response including cognitive, psychological and functional parameters. DISCUSSION: The primary dependent measure will be remission rate (Hamilton Rating Scale for Depression (HRSD24) <= 10), and secondary analyses will be conducted on other indices. Comparisons between the rTMS and the sham groups will be made at the end of the acute treatment phase to test the primary hypothesis. The unique challenges to performing such a large technically challenging clinical trial with Veterans and potential avenues for improvement of the design in future trials will be described. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01191333 . Registered on 26 August 2010. This report is based on the protocol version 4.6 amended in February 2016. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A. PMID- 28865497 TI - Exercise as an Essential Therapeutic Tool in Mental Health: Closing the Gap From Research to Practice, A Portuguese Perspective. PMID- 28865498 TI - [Analysis of the Cochrane Review: Pharmacotherapy for Hyperuricemia in Hypertensive Patients. Cochrane Database Syst Rev. 2017;4:CD008652.] AB - Arterial hypertension is a public health problem that affects approximately 25% of the world's adult population. The association between hypertension and hyperuricemia has been shown on epidemiological and experimental studies. However, it is unclear whether lowering serum uric acid might lower blood pressure. This Cochrane systematic review - a revised edition of a previously published one - intended as primary objective to evaluate the effect of hypouricemic drugs in patients with primary hypertension or prehypertension. The secondary objectives were to evaluate the efficacy and safety of hypouricemic drugs. A systematic search until February 2016 on controlled, randomized or quasi randomized trials comparing the effect of hypouricemic drug versus placebo in hypertensive or prehypertensive patients was performed on the following databases: The Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, The World Health Organization International Clinical Trials Registry Platform, e ClinicalTrials.gov. LILACS database up to March 2016 was also searched and the authors of relevant studies were contacted. There were 349 identified papers, 21 were preselected and three randomized clinical trials (211 patients) were included in the qualitative analysis and in the meta-analysis. Two of the trials were conducted exclusively on adolescents. The authors conclude that hypouricemic drugs are not effective in lowering blood pressure in patients with hyperuricemia and primary prehypertension or hypertension. However, this strategy might be more effective in the specific population of adolescents with prehypertension or mild primary hypertension recently diagnosed. Hypouricemic drugs effectively reduce serum uric acid level and withdrawals of therapy due to adverse effects were not superior in the treated group, comparing to placebo; however, one patient withdrew due to a severe cutaneous reaction. PMID- 28865499 TI - Association Between Weekend and Holiday Admission with Pneumonia and Mortality in a Tertiary Center in Portugal: A Cross-Sectional Study. AB - INTRODUCTION: Acute bacterial pneumonia is a common and potentially fatal disease where early recognition and treatment are crucial. Increasing medical literature suggests worse outcomes in patients admitted for medical and surgical conditions during the weekend. Little is known about this effect in patients with acute bacterial pneumonia. Obective: The aim of this study was to evaluate the impact of weekend and holiday hospital admission on the outcomes of acute bacterial pneumonia. MATERIAL AND METHODS: Retrospective analysis of adult patients (> 18 years) with acute bacterial pneumonia collected from a tertiary referral center database. Length of stay, total cost, admission to intensive care unit, development of sepsis and organ failure, and mortality were compared between patients admitted on a weekday and patients admitted during a weekend or holiday. RESULTS: We analyzed 53 854 hospital admissions from 42 512 patients (median age 84.0 years, range 18 - 118 years), corresponding to 30 554 admissions during weekdays, 21 222 at weekends and 2078 during public holidays. Weekend and holiday admission was not associated with increased costs, length of stay, intensive care unit admission, development of sepsis, organ failure, and mortality. CONCLUSION: A weekend/holiday effect in acute bacterial pneumonia was not evident in our series. PMID- 28865500 TI - [Determinant Factors of Morbidity in Patients with Systemic Lupus Erythematosus]. AB - INTRODUCTION: Severity in systemic lupus erythematosus may vary from mild to even fatal consequences. There are no biomarkers to predict the disease's prognosis. The Systemic Lupus International Collaborating Clinics/ Systemic Damage Index defines systemic lupus erythematosus disease severity and is found to predict prognosis. OBJECTIVE: To test damage determinants in a single-centre systemic lupus erythematosus cohort. MATERIAL AND METHODS: Retrospectively followed systemic lupus erythematosus female patients (defined by the identification of at least four systemic lupus erythematosus American College of Rheumatology criteria - fulfillment 100%, n = 76) over the past five years. Age of onset, ethnicity, disease duration, number of American College of Rheumatology criteria at the end of follow-up, cumulative: renal, neuropsychiatric and articular phenotypes, hypertension, dyslipidaemia, smoking and Systemic Lupus Erythematosus Disease Activity Index 2K were correlated to the presence and degree of irreversible damage (Systemic Lupus International Collaborating Clinics Damage Index). Accumulation of American College of Rheumatology criteria was measured in a sub group of patients followed from disease onset (within a year of the first symptom ascribed to systemic lupus erythematosus) (n = 39 - 51%); Systemic Lupus Erythematosus Disease Activity Index and Systemic Lupus International Collaborating Clinics Damage Index were performed. Statistical analysis was performed using Chi-square, Wilcoxon Mann-Whitney tests and Spearman correlation rho (Sig. 2-tailed p < 0.05). RESULTS: Systemic Lupus International Collaborating Clinics/Systemic Damage Index > 0 was present in 56.6% and significantly associated to a longer duration, a higher number of American College of Rheumatology criteria and a neuropsychiatric phenotype when compared with those with no damage. The final number of American College of Rheumatology criteria accrued was positively correlated to a higher disease activity over the past five years of follow-up (Spearman's rho 0.02 and p < 0.05). There was no effect from other features. DISCUSSION AND CONCLUSION: Disease duration and number of American College of Rheumatology criteria predict Systemic Lupus International Collaborating Clinics/ Systemic Damage Index. neuropsychiatric disease has an impact on damage accrual. PMID- 28865501 TI - Female Psychological Adjustment Following an Acute Coronary Syndrome. AB - INTRODUCTION: The outcomes of cardiovascular disease are consistently worse among women, regardless of age or disease severity. Such trend might arise from psychosocial factors, which should be examined in this population. Obective: To evaluate the influence of type-D personality on anxiety and depression symptoms reported by female patients after a first acute coronary syndrome. MATERIAL AND METHODS: As part of a larger study, 34 female patients with a first acute coronary syndrome were compared with 43 controls on psychosocial measures (Hospital Anxiety and Depression Scale; type-D personality, DS - 14). RESULTS: Hypertension (p < 0.001), diabetes (p < 0.05), dyslipidemia (p < 0.05), type-D personality (p = 0.001) and anxiety (p < 0.001) were more prevalent among patients. Exercise (p < 0.05) and antidepressant use (p < 0.05) were more common among controls. Logistic regression analysis confirmed that higher prevalence of hypertension (p < 0.05), dyslipidemia (p < 0.05), type-D personality (p < 0.05), anxiety (p < 0.05) and less antidepressant use (p < 0.05), were independently associated with acute coronary syndrome. Type-D personality was associated with higher Hospital Anxiety and Depression Scale scores in controls (anxiety: p = 0.001; depression: p < 0.001) but not in patients. DISCUSSION: High anxiety after an acute coronary syndrome might reflect a short-term adaptive response, albeit worsening the disease long-term prognosis. The lack of differences in some group comparisons (patients versus controls for depression scores; type-D 'positive' versus type-D 'negative' for anxiety and depression scores within patients) is discussed. CONCLUSION: Type-D personality, high anxiety, hypertension and dyslipidemia seem to cluster among female acute coronary syndrome patients. Nevertheless, type-D personality itself was not associated with higher anxiety and depressive scores during the post-acute period. PMID- 28865502 TI - [Validation of the Otitis Media-6 Questionnaire for European Portuguese]. AB - INTRODUCTION: Otitis media is one of the most prevalent childhood diseases. The impact of otitis media on quality of life of Portuguese children is unknown, because of the unavailability of a tool validated in European Portuguese to assess this consequence of otitis media. The Otitis Media-6 questionnaire (Otitis Media-6) is the most frequently used tool to assess health-related quality of life in children with otitis media. This study aims to create a version in the Portuguese language and culturally adapted to Portugal of the otitis media-6 questionnaire. MATERIAL AND METHODS: The Otitis Media-6 questionnaire was translated and culturally adapted to the Portuguese language and population. Then, to assess the instrument psychometric properties, it was applied to a sample of Portuguese children with chronic otitis media with effusion or recurrent acute otitis media. RESULTS: The Portuguese version of Otitis Media-6 questionnaire demonstrated the following psychometric properties: construct validity for baseline (rs = 0.98) and change scores (rs = 0.97), internal consistency (alpha = 0.780), test-retest reliability (rs = 0.89) and responsiveness to clinical change (t(59) = 10.104). DISCUSSION: The simplicity and brevity of application of the instrument make it ideal for use in research and in clinical practice, enabling a more objective assessment of the extension of the otitis media impact in children quality of life and a more targeted therapeutic decision. CONCLUSION: The Portuguese version of the Otitis Media-6 questionnaire is a valid, reliable and sensitive instrument to evaluate the health-related quality of life in Portuguese children with otitis media. PMID- 28865503 TI - Virtual Reality Simulation as a Tool to Monitor Surgical Performance Indicators: VIRESI Observational Study. AB - INTRODUCTION: Virtual reality simulation is a topic of discussion as a complementary tool to traditional laparoscopic surgical training in the operating room. However, it is unclear whether virtual reality training can have an impact on the surgical performance of advanced laparoscopic procedures. Our objective was to assess the ability of the virtual reality simulator LAP Mentor to identify and quantify changes in surgical performance indicators, after LAP Mentor training for digestive anastomosis. MATERIAL AND METHODS: Twelve surgeons from Centro Hospitalar de Sao Joao in Porto (Portugal) performed two sessions of advanced task 5: anastomosis in LAP Mentor, before and after completing the tutorial, and were evaluated on 34 surgical performance indicators. RESULTS: The results show that six surgical performance indicators significantly changed after LAP Mentor training. The surgeons performed the task significantly faster as the median 'total time' significantly reduced (p < 0.05) from 759.5 to 523.5 seconds. Significant decreases (p < 0.05) were also found in median 'total needle loading time' (303.3 to 107.8 seconds), 'average needle loading time' (38.5 to 31.0 seconds), 'number of passages in which the needle passed precisely through the entrance dots' (2.5 to 1.0), 'time the needle was held outside the visible field' (20.9 to 2.4 seconds), and 'total time the needle-holders' ends are kept outside the predefined operative field' (88.2 to 49.6 seconds). DISCUSSION: This study raises the possibility of using virtual reality training simulation as a benchmark tool to assess the surgical performance of Portuguese surgeons. CONCLUSION: LAP Mentor is able to identify variations in surgical performance indicators of digestive anastomosis. PMID- 28865504 TI - Reliability and Validity of 39-Item Parkinson's Disease Questionnaire and Parkinson's Disease Quality of Life Questionnaire. AB - INTRODUCTION: Parkinson's disease has a significant impact in quality of life, which can be assessed with 39-item Parkinson's Disease Questionnaire and Parkinson's Disease Quality of Life Questionnaire. This study aimed to evaluate the reliability and validity of these scales in Portuguese patients. MATERIAL AND METHODS: Reliability was assessed through internal consistency (Cronbach's alpha) and reproducibility (intraclass correlation coefficient). Regarding construct validity, we performed one-way analysis of variance across different groups according to modified Hoehn and Yahr scale. For criterion validity, we compared both scales with each other and with the Short Form 36-item Health Survey. RESULTS: In a total of 100 patients with Parkinson's disease, Cronbach's alpha ranged for 39-item Parkinson's Disease Questionnaire between 0.66 - 0.98, and for Parkinson's Disease Quality of Life Questionnaire, between 0.78 - 0.98. Intraclass correlation coefficient for 39-item Parkinson's Disease Questionnaire ranged between 0.49 - 0.96, and for Parkinson's Disease Quality of Life Questionnaire, ranged between 0.65 - 0.96. Both scales showed, in general, capacity to discriminate differences among patients in the different stages of disease. The scales presented moderate to strong magnitude correlations with some Short Form 36-item Health Survey domains. DISCUSSION: Cronbach's alpha coefficients for most domains were satisfactory. Overall, it has been demonstrated good reproducibility, as well as construct and criterion validity. CONCLUSION: The Portuguese versions of both scales showed to be valid and reliable. PMID- 28865505 TI - [Prevalence of Dental Caries in Patients with Type 1 Diabetes Mellitus Treated with Multiple Insulin Injections and that of Individuals without Diabetes]. AB - INTRODUCTION: In addition to macro and microvascular complications that are associated with the disease, hyperglycaemia is also a risk factor for several oral complications. The aim of this study is to establish a relationship between dental caries in patients with type 1 diabetes mellitus treated with multiple insulin injections and that of individuals without diabetes. It is also an aim to characterize the oral hygiene habits of this population. MATERIAL AND METHODS: An observational clinical study of analytical and cross-sectional nature was conducted. Thirty patients with type 1 diabetes mellitus and 30 individuals without diabetes were observed and questioned about information regarding their medical history. Oral examination was conducted according to the standards of the World Health Organization and ICDAS was used for caries detection. Statistical analysis was performed and the significance level was set at 5%. RESULTS: Patients with diabetes mellitus showed similar caries levels to that of individuals without diabetes. Patients with diabetes mellitus had a higher dental plaque index. Only 10% of the patients having episodes of nocturnal hypoglycaemia brush their teeth after glucose intake. DISCUSSION: Although there's some controversy in the literature regarding the prevalence of caries in patients with diabetes mellitus, the results are in agreement with a great number of studies. However, patients with diabetes mellitus have a higher plaque index which can be associated with a higher risk for developing certain oral pathologies. CONCLUSION: No statistically significant association was found between type 1 diabetes mellitus and dental caries. PMID- 28865507 TI - [Gorlin-Goltz Syndrome: Diagnosis and Treatment Options]. AB - The Gorlin-Goltz syndrome is a rare autosomal dominant hereditary condition, with complete penetrance and variable expressivity. Characterized by the appearance of multiple basaliomas, and often the development of keratocyst, it can also express itself by the presence of palmar/plantar depressions, calcification of brain sickle, and skeletal birth defects, although less frequently. This article presents two cases involving direct relatives, referred after the identification of several basaliomas and jaw cysts. After establishing the diagnosis, given the identification of three major criteria, the treatment consisted in the excision of the lesions followed, in one case, with vismodegib treatment resulting in complete remission. Gorlin-Goltz syndrome is therefore a multidisciplinary challenge, whose variable morbidity and high risk of recurrence make treatment and surveillance critical. However, new molecular targeted therapies have brought a new hope in treating these patients. PMID- 28865506 TI - [Anaerobic Bacteria with Clinical Relevance: Morphologic and Taxonomic Classification, Distribution among Human Microbiota and Microbiologic Diagnosis]. AB - The wide burden of anaerobic bacteria colonizing human body comprises about 90% of its total biomass. The biotic relationship between humans and its microbiota sets reciprocal benefits, albeit with pathogenic potencial for the human being in particular dysbiosis situations. Infections adjacent to or originating from the skin or mucous membranes of the intestinal, genitourinary and upper respiratory tracts are often polymicrobial in nature, whereby should anaerobes be invariably included in the etiological differential diagnosis of these conditions. Gram negative bacilli such as Bacteroides fragilis group, Fusobacterium spp., Porphyromonas spp., Prevotella spp. and Gram positive cocci such as Peptostreptococcus spp. stand out for their high virulence and frequence of isolation in suppurative infections and abcesses with metastatic or contiguous relation to human microbiota. The fastidious nature of anaerobic bacteria, especially of less aerotolerant species, compels to particular techniques of sample collection, transport and cultural isolation that challenge clinicians and microbiologists for a full efficient practice. Such requirements bring on a poor identification of anaerobic bacteria in the clinical practice and undervaluation of its aetiopathogenic potential amongst common polymicrobial infections. An approach over microbial flora's composition in the different human anatomical sites is a primary goal of the present article. Clinicians are intended to recognize the variability and proportion of likely involved anaerobic microorganisms in certain infectious processes related to human microbiota, in order to optimize samples processing and the establishment of an appropriate empirical antibiotic therapy, mindful of anaerobic coverage and according to known susceptibility profiles. PMID- 28865508 TI - Carcinoid Syndrome and Carcinoid Heart Disease as Manifestations of Non Metastatic Ovarian Neuroendocrine Tumour. AB - The carcinoid syndrome is rare but it is associated with carcinoid heart disease in more than a half of the cases. Carcinoid heart disease is typically characterised by morphological and functional modifications of right-sided valves. Its aetiology is probable multifactorial but serotonin appears to play a key role in the development of this valvular disease. Unlike gastrointestinal neuroendocrine tumours, ovarian neuroendocrine tumours can present with carcinoid syndrome and carcinoid heart disease in the absence of liver metastases; such ovarian neuroendocrine tumours are a unique clinical entity. The additional burden of cardiac impairment in these patients represents a significant reduction in survival. Early recognition and surgical valve replacement before advanced heart failure is established may improve the clinical outcome. We report the case of a woman with an ovarian neuroendocrine tumour and highly symptomatic carcinoid heart disease who was submitted to tumour resection followed by valvuloplasty. She demonstrated an outstanding clinical improvement and has remained free of tumour and symptomatology. PMID- 28865509 TI - Acute Gastrointestinal Bleeding Caused by Dieulafoy Lesion of the Esophagus. PMID- 28865510 TI - A Case of Exuberant Elephantiasis Nostras Verrucosa. PMID- 28865511 TI - Introduction. PMID- 28865513 TI - Functional Assays for Individual Radiosensitivity: A Critical Review. AB - A complete understanding of the mechanisms of the response to radiation would help in a better evaluation of the radiation-induced risks. To this aim, individual radiosensitivity, that is, the proneness to radiation-induced tissue reactions attributable to cell death, has been documented since the beginning of the 20th century. For several decades, developing informative predictive assays has been one of the most important challenges of radiobiologists. This article is a critical review devoted to the major functional assays to predict radiosensitivity and their strengths and weaknesses, notably those based on the quantification of clonogenic cell survival, micronuclei, p21 expression, apoptosis, chromosome and DNA repair, and signaling. Genomic approaches of radiosensitivity are reviewed in another article of this issue. PMID- 28865515 TI - Imaging Radiation-Induced Normal Tissue Injury to Quantify Regional Dose Response. AB - Noninvasive imaging has and will continue to play a pivotal role in the assessment of radiation-induced normal tissue toxicity. In this review, we will examine key literature regarding the use of anatomic and physiological imaging in relation to radiation-induced normal tissue toxicity. Additionally, this review contains a novel methodology for potentially incorporating dose-response data into treatment planning and normal tissue toxicity modeling. PMID- 28865512 TI - Radiogenomics: Identification of Genomic Predictors for Radiation Toxicity. AB - The overall goal of radiogenomics is the identification of genomic markers that are predictive for the development of adverse effects resulting from cancer treatment with radiation. The principal rationale for a focus on toxicity in radiogenomics is that for many patients treated with radiation, especially individuals diagnosed with early-stage cancers, the survival rates are high, and therefore a substantial number of people will live for a significant period of time beyond treatment. However, many of these patients could suffer from debilitating complications resulting from radiotherapy. Work in radiogenomics has greatly benefited from creation of the Radiogenomics Consortium (RGC) that includes investigators at multiple institutions located in a variety of countries. The common goal of the RGC membership is to share biospecimens and data so as to achieve large-scale studies with increased statistical power to enable identification of relevant genomic markers. A major aim of research in radiogenomics is the development of a predictive instrument to enable identification of people who are at greatest risk for adverse effects resulting from cancer treatment using radiation. It is anticipated that creation of a predictive assay characterized by a high level of sensitivity and specificity will improve precision radiotherapy and assist patients and their physicians to select the optimal treatment for each individual. PMID- 28865517 TI - Management of Radiation Toxicity in Head and Neck Cancers. AB - Head and neck cancers account for approximately 3% of all cancers in the United States with 62,000 new cases diagnosed annually. The global incidence is approximately 700,000 new cases a year. There has also been a recent increase in human papilloma virus-related oropharyngeal cancers. External beam radiation therapy (RT) is commonly used as an effective therapy for head and neck (H&N) cancers. This is used as a definitive treatment (alone or in combination with chemotherapy) or as an adjuvant treatment after surgical resection of the tumors. Because of the complex anatomy of the H&N region, several critical structures in and around the area receive radiation treatment. This includes the neural structures (brainstem, spinal cord, and brachial plexus), salivary glands, mucosa, major blood vessels, and swallowing musculature. Careful RT planning is necessary to avoid or mitigate the side effects of treatment. This review discusses some of the major acute and late side effects of RT for H&N cancers and provides evidence-based guidelines for their management. Patient-reported outcomes and quality-of-life implications are also discussed. PMID- 28865516 TI - Radiation Toxicity in the Central Nervous System: Mechanisms and Strategies for Injury Reduction. AB - The potential for radiation-induced toxicities in the brain produces significant anxiety, both among patients receiving radiation therapy and those radiation oncologists providing treatment. These concerns often play a significant role in the medical decision-making process for most patients with diseases in which radiotherapy may be a treatment consideration. Although the precise mechanisms of neurotoxicity and neurodegeneration after ionizing radiation exposure continue to be poorly understood from a biological perspective, there is an increasing body of scientific and clinical literature that is producing a better understanding of how radiation causes brain injury; factors that determine whether toxicities occur; and potential preventative, treatment, and mitigation strategies for patients at high risk or with symptoms of injury. This review will focus primarily on injuries and biological processes described in mature brain. PMID- 28865514 TI - Mechanisms of Normal Tissue Injury From Irradiation. AB - Normal tissue injury from irradiation is an unfortunate consequence of radiotherapy. Technologic improvements have reduced the risk of normal tissue injury; however, toxicity causing treatment breaks or long-term side effects continues to occur in a subset of patients. The molecular events that lead to normal tissue injury are complex and span a variety of biologic processes, including oxidative stress, inflammation, depletion of injured cells, senescence, and elaboration of proinflammatory and profibrogenic cytokines. This article describes selected recent advances in normal tissue radiobiology. PMID- 28865518 TI - Radiation-Induced Liver Toxicity. AB - The advent of highly conformal radiation therapy (RT) has defined a new role for RT in the treatment of both primary and metastatic liver cancer. Despite major advances in how RT is delivered, radiation-induced liver disease (RILD) remains a concern. Classic RILD, characterized by anicteric ascites and hepatomegaly, is unlikely to occur if treating to doses of <=30Gy in 2Gy per fraction in patients with baseline Child-Pugh A liver function. On the other hand, nonclassic RILD is a spectrum of liver toxicity, including a general decline in liver function and elevation of liver enzymes. It is less well defined and less predictable, especially in patients with underlying liver disease. Scoring and quantifying RILD remains a challenge. The Child-Pugh score has been the most consistently used parameter. Other scoring systems such as the albumin-bilirubin score provide further discrimination in patients with hepatocellular carcinoma, although their value in patients treated with RT remains to be established. Many serum and imaging biomarkers of liver function are currently being investigated, and they will provide further useful information in the future for local and global liver function assessment, for planning optimization, and for treatment adaptation. To date, no pharmacological therapies have provided consistent results in mitigating RILD once it has manifested clinically. Numerous promising treatment strategies including TGFbeta inhibition, Hedgehog inhibition, CXCR4 inhibition, hepatocyte transplantation, and bone marrow-derived stromal cell therapy, have potential to be helpful in the treatment of RILD in the future. PMID- 28865519 TI - Pelvic Radiation and Normal Tissue Toxicity. AB - Radiation is a component of treatment for many pelvic malignancies, most often originating in the gynecologic, gastrointestinal, and genitourinary systems. Therefore, the management of acute and long-term side effects is an important part of practice as a radiation oncologist, and limiting morbidity is a primary goal. Toxicities vary and are dependent on treatment techniques. Advances in radiation delivery, imaging, and knowledge of underlying biologic determinants of radiation-induced normal tissue toxicity can guide treatment of acute and long term side effects from pelvic radiation. PMID- 28865520 TI - Thoracic Radiation Normal Tissue Injury. AB - Thoracic malignancies are often a difficult group of tumors to treat definitively as the radiation doses needed to achieve a high probability for tumor control are often associated with high rates of radiation-induced toxicities. The lungs are particularly radiosensitive and are susceptible to radiation pneumonitis in the acute and subacute settings and pulmonary fibrosis in the late setting. Acute esophagitis is common and affects patient quality of life. Beyond acute pericarditis, late cardiac toxicities are increasingly being recognized as clinically relevant when delivering thoracic radiotherapy and can affect overall survival. This review details the common and dose-limiting acute and late toxicities associated with thoracic radiation therapy. As radiation-induced toxicities are often amplified with concurrent chemotherapy, this article focuses on the toxicities associated with irradiation for lung cancer, the most common thoracic malignancy, which is often treated with multimodality therapy. The management of radiation-induced toxicities and the changing patterns of toxicities with advanced radiation delivery modalities are also described. PMID- 28865521 TI - Emphasis on Repair, Not Just Avoidance of Injury, Facilitates Prudent Stereotactic Ablative Radiotherapy. AB - Stereotactic ablative radiotherapy (SAbR) is a potent, hypofractionated treatment against cancer which puts adjacent normal tissue in potential peril. Accurate delineation of normal tissue injury risks from SAbR has been challenging, and lack of clear understanding of SAbR tolerance continues to limit its potential. In this review, we contend that SAbR effects on normal tissue could be akin to a surgical "wound," and that adequate wound repair of organs at risk is an essential component of effective SAbR therapy. To mitigate risks of clinical relevance from an SAbR wound, in addition to the traditional views on architectural organization and functional organization of an organ at risk, one should also consider the organ's predominant wound healing tendencies. We also propose that avoidance of SAbR injury to organs at risk must involve careful thought to minimize risk factors that could further impair wound healing. It is imperative that efforts aimed at determining appropriate dose constraints based on predicted SAbR wound injury repair mechanisms for a particular organ to be studied as a critically important step to furthering our understanding of SAbR related normal tissue tolerances. This can be best achieved through thoughtful design of prospective phase I dose-escalation studies. PMID- 28865522 TI - Letter From the Guest Editor: Seminars 2017. PMID- 28865523 TI - Imaging of Female Pelvic Emergencies. AB - Pelvic pain is a common complaint in female patients who present to the emergency department. Although encountered frequently, the path to a definitive diagnosis is not always a straightforward one, and imaging offers a valuable tool to aid in this diagnostic challenge. Radiologists must be familiar with the most common etiologies of female pelvic pain in the emergency setting, their imaging characteristics, and the best way to further evaluate challenging clinical presentations. This allows the radiologist to serve as a valuable asset to the treating physician, aiding in accurate diagnosis, and in guiding the course of treatment, all while ensuring the "Image Wisely" principle. A sonographic approach to female patients presenting to the emergency setting with pelvic pain has been presented in this article and some example entities along with their imaging findings have also been reviewed. PMID- 28865524 TI - Ultrasound Emergencies of the Male Pelvis. AB - Male pelvic emergencies are uncommon, and symptoms typically include scrotal pain, scrotal enlargement, or a palpable scrotal mass or all of these. Ultrasound is often the first-line modality for evaluation of male pelvic emergencies, which may be stratified into vascular, infectious, or traumatic causes. Entities such as testicular torsion, Fournier gangrene, and testicular dislocation are surgical emergencies and should not be missed or misdiagnosed, as this may cause a significant delay in urgently necessary treatment. Radiologists need to be familiar with the role of imaging as well as the key characteristic imaging findings of these injuries to direct the appropriate management. PMID- 28865525 TI - Computed Tomography Angiography in Head and Neck Emergencies. AB - Computed tomography angiography (CTA) offers a rapid means of evaluating the vasculature of the head and neck in patients presenting with acute onset of neurologic symptoms and blunt trauma to the head and neck. CTA is noninvasive, easy to acquire, and offers excellent detail in identifying site and nature of the lesion. The learning objectives of this article are to review normal anatomy and variants, recognize CTA appearance of vascular pathologies, describe typical parameters used for acquiring the study, and recognize common pitfalls. PMID- 28865526 TI - Computed Tomography Angiography of the Extremities in Emergencies. AB - Computed tomography angiography (CTA) of the extremities offers a noninvasive, rapid means of evaluation of the extremities in vascular emergencies. CTA is now the first-line investigation for this purpose, offering high sensitivity and specificity in diagnosis. The learning objectives of this review article include reviewing normal arterial anatomy and variants of the upper and lower extremity, illustrating CTA findings in traumatic vascular injuries, and exploring the range of vascular pathologies that may cause acute ischemic symptoms in the extremities. PMID- 28865527 TI - Emergency Computed Tomography Angiogram of the Chest, Abdomen, and Pelvis. AB - In the setting of blunt trauma, the rapid assessment of internal injuries is essential to prevent potentially fatal outcomes. Computed tomography is a useful diagnostic tool for both screening and diagnosis. In addition to trauma, acute chest syndromes often warrant emergent computed tomographic angiography, looking for etiologies such as aortic aneurysms or complications of aortic aneurysms, or both, pulmonary emboli, as well as other acute vascular process like aortic dissection and Takayasu aortitis. With continued improvements in diagnostic imaging, computed tomographic angiography of the chest, abdominal and pelvis proves to be an effective modality to image the aorta and other major vascular structures. PMID- 28865528 TI - Neurologic Emergencies on Computed Tomography of the Head. AB - The purpose of this article is to provide the reader, a seasoned radiologist, a budding resident, or a curious practitioner, the background necessary to accurately and swiftly interpret a head computed tomography in the emergency setting. At the very least, being able to generate a reasonable differential diagnosis is the aim and will be accomplished by describing not only features of classic neurologic emergencies but also the possible traps to which one may fall prey. Images will be used to illustrate cases, and the reader will be instructed when other imaging modalities may be required to clarify diagnoses. PMID- 28865529 TI - Acute Bowel Computed Tomography. AB - Acute abdominal pain is a common presenting complaint in the emergency department. Increasingly, computed tomography is utilized for evaluating these patients. Radiologists are therefore expected to be familiar with the pertinent clinical and radiologic information related to acute bowel pathology. This primer will review the need-to-know and latest updates related to computed tomography evaluation of acute bowel pathology. PMID- 28865530 TI - The 4 Quadrants: Acute Pathology in the Abdomen and Current Imaging Guidelines. AB - With several different imaging options available, it is not surprising that health care providers are unsure which imaging study is most appropriate for evaluating patients who present to the emergency department with abdominal pain. The American College of Radiology, currently, has appropriateness criteria for patients presenting with right upper, right lower, and left lower quadrant pain, and there are different variants for each of these quadrants. Clinicians should be aware of the American College of Radiology appropriateness criteria and, whenever possible, should be using criteria as guide to help them order the most appropriate imaging study. PMID- 28865531 TI - Recognition and Appropriate Use of Magnetic Resonance Imaging for Emergent Neuroradiology. AB - The use of magnetic resonance imaging (MRI) for the diagnosis of emergent life threatening neurologic conditions and what are considered "do not miss" pathologies has dramatically increased over the past 10 years due to its increasing importance in the emergency department. Although computed tomography is likely to remain the more significantly used imaging modality due to lower cost and faster speeds, continuing technological advances in MRI have made its use more mainstream. Knowledge of specific clinical signs and symptoms as well as the technical limitations of MRI should help to guide emergency department clinicians with both the recognition and the appropriate use of emergent MRI. PMID- 28865532 TI - Magnetic Resonance Imaging of Musculoskeletal Emergencies. AB - Musculoskeletal trauma and infections are commonly encountered in the emergency department. Magnetic resonance imaging (MRI) is rarely employed in true emergencies and most musculoskeletal studies can be deferred to the outpatient setting. This article seeks to address the urgent conditions in which MRI can play a role in diagnosis, management, and treatment. This article outlines MRI's role in the evaluation of posterolateral corner injuries and other soft-tissue pathologies such as rhabdomyolysis, diabetic myonecrosis, septic arthritis, cellulitis, necrotizing fasciitis, and compartment syndrome. PMID- 28865533 TI - Introduction: Varicoceles: a contemporary perspective. AB - In this Views and Reviews section, four groups of authors address the timely and highly relevant issue of varicoceles across the male life spectrum. Varicoceles are very prevalent among men presenting for an infertility workup. While reduction in bulk semen parameters (including sperm concentration, motility, and morphology) has long been recognized as a deficit caused by varicoceles, in recent years a number of investigators have shown that varicoceles can have broader, multi-faceted effects on male reproductive health. Sperm DNA integrity and other aspects of sperm function appear to be impacted by the presence of varicoceles, and varicocele correction can result in significant improvement in not only semen parameters, but also fertilization and pregnancy rates. PMID- 28865534 TI - Varicoceles: prevalence and pathogenesis in adult men. AB - Varicocele, or dilation of the pampiniform venous plexus, affects up to 15% of men. However, few of these men encounter problems with fertility. This discrepancy between men with varicocele and the number of adversely affected men has led to abundant research to identify the mechanisms for formation of varicocele as well as the pathologic mechanisms by which varicoceles affect fertility potential. In this review, we discuss the prevalence of varicocele in adults, the anatomic features of varicocele, the leading theories as to how varicocele can negatively affect fertility potential, and finally, the current literature on the impact of varicocele on testosterone production. PMID- 28865535 TI - Treatment of varicoceles: techniques and outcomes. AB - Varicoceles, a dilation of veins within the pampiniform plexus, are present in ~15% of the general male population. This paper reviews the indications for treatment of varicoceles, post-intervention outcomes following treatment, and the various techniques for treatment of varicoceles. The aim of this review is to describe and compare complications associated with each approach to varicocele treatment. PMID- 28865536 TI - Varicocelectomy before assisted reproductive technology: are outcomes improved? AB - Clinical varicoceles have been associated with impaired semen parameters and male factor infertility. Varicocele repair can improve live birth rates for men with clinical varicocele. Varicocelectomy is often combined with assisted reproductive techniques (ART) such as intrauterine insemination (IUI), in vitro fertilization (IVF), or intracytoplasmic sperm injection (ICSI). Here we review the literature examining varicocelectomy before ART to evaluate whether improved pregnancy outcomes are realized. Although insufficient evidence exists to determine if correcting a varicocele improves IUI outcomes, a clinical benefit is observed when correcting a clinical varicocele in oligospermic and nonobstructed azoospermic men before IVF/ICSI. In couples seeking fertility with the use of ART, varicocele repair may offer improvement in semen parameters and may decrease the level of ART needed to achieve successful pregnancy. PMID- 28865537 TI - Normal ranges: normal for whom? PMID- 28865538 TI - Removal of myomas in asymptomatic patients to improve fertility and/or reduce miscarriage rate: a guideline. AB - The purpose of this systematic review is to evaluate if uterine myomas impact the likelihood of pregnancy and pregnancy loss, and if myomectomy influences pregnancy outcomes in asymptomatic women. There is insufficient evidence to conclude that the presence of myomas reduces the likelihood of achieving pregnancy. However, there is fair evidence that myomectomy (open or laparoscopic) for cavity-distorting myomas (intramural or intramural with a submucosal component) improves pregnancy rates and reduces the risk of early pregnancy loss. There is fair evidence that hysteroscopic myomectomy for cavity-distorting myomas improves clinical pregnancy rates but insufficient evidence regarding the impact of this procedure on the likelihood of live birth or early pregnancy loss. In women with asymptomatic cavity-distorting myomas, myomectomy may be considered to optimize pregnancy outcomes. PMID- 28865540 TI - Testicular sperm retrieval for intracytoplasmic sperm injection in non azoospermic men: when should we pull the trigger? PMID- 28865539 TI - Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. AB - Metformin alone compared with placebo increases the ovulation rate in women with polycystic ovary syndrome (PCOS) but should not be used as first-line therapy for anovulation because oral ovulation induction agents such as clomiphene citrate or letrozole alone are much more effective in increasing ovulation, pregnancy, and live-birth rates in women with PCOS. There is fair evidence that metformin alone does not increase rates of miscarriage when stopped at the initiation of pregnancy and insufficient evidence that metformin in combination with other agents used to induce ovulation increases live-birth rates. PMID- 28865541 TI - What else can we do? The latest attempt to improve the sperm's path. PMID- 28865542 TI - The earth isn't flat? PMID- 28865543 TI - A high-tech closer look to evaluate the impact of oocyte vitrification on embryo quality. PMID- 28865544 TI - Effectiveness and safety of time-lapse imaging for embryo culture and selection: it is still too early for any conclusions? PMID- 28865545 TI - Value of versatility in fibroid surgery. PMID- 28865546 TI - Reproductive outcomes of testicular versus ejaculated sperm for intracytoplasmic sperm injection among men with high levels of DNA fragmentation in semen: systematic review and meta-analysis. AB - OBJECTIVE: To compare sperm DNA fragmentation (SDF) levels between testicular and ejaculated sperm and to evaluate outcomes of intracytoplasmic sperm injection (ICSI) with the use of testicular (Testi-ICSI) versus ejaculated (Ejac-ICSI) sperm in nonazoospermic men with high SDF. DESIGN: Systematic review and meta analysis. SETTING: Not applicable. PATIENT(S): Normo- and oligozoospermic men with high levels of SDF in semen subjected to Testi-ICSI or Ejac-ICSI. INTERVENTION(S): Summary mean difference (MD) and odds ratio (OR) were calculated with the use of an inverse variance model and fixed- or random-effects models, respectively. MAIN OUTCOME MEASURE(S): Primary outcomes were SDF levels, clinical pregnancy rates (CPRs), and live birth rates (LBRs). Secondary outcomes were fertilization and miscarriage rates. RESULT(S): Five studies involving 143 patients provided paired SDF rates for testicular and ejaculated sperm, revealing lower SDF in testicular sperm (MD -24.58%). Four studies involving 507 cycles and 3,840 oocytes reported clinical outcomes of Testi-ICSI and Ejac-ICSI. Fertilization rates were not different between sperm sources, but a trend to lower rates was observed with Testi-ICSI. CPRs were higher for Testi-ICSI than for Ejac-ICSI, as were LBRs, whereas miscarriage rates were reduced with Testi ICSI. CONCLUSION(S): Testicular sperm have lower levels of SDF than ejaculated sperm, with Testi-ICSI for high post-testicular SDF men improving reproductive outcomes compared with Ejac-ICSI. Infertile couples may benefit from Testi-ICSI if male partners have confirmed high SDF in the ejaculate. PMID- 28865547 TI - Does the use of calcium ionophore during artificial oocyte activation demonstrate an effect on pregnancy rate? A meta-analysis. AB - OBJECTIVE: To study the effect, if any, of calcium ionophore as a method of artificial oocyte activation (AOA) on pregnancy outcomes and fertilization rates. DESIGN: Meta-analysis of randomized controlled trials, prospective observational and retrospective trials, case reports, and a case-control trial. SETTING: University-affiliated teaching hospital. PATIENT(S): Infertile couples undergoing fertilization treatment. INTERVENTION(S): Use of calcium ionophore during AOA. MAIN OUTCOME MEASURE(S): Odds ratio (OR) as the summary statistic for binary variables was used. Both a fixed and random effects model were applied. Subgroup analysis using quantitative methodology (risk of bias, metaregression) and graphical comparison (funnel plot) assessed statistical heterogeneity. RESULT(S): Fourteen studies were selected. AOA with calcium ionophore increased the overall clinical pregnancy rate (per ET; OR = 3.48; 95% confidence interval [CI], 1.65 7.37) and the live birth rate (OR = 3.33; 95% CI, 1.50-7.39). This effect of adding calcium ionophore was further demonstrated with fertilization, cleavage, blastocyst, and implantation rates. Subgroup analysis further supported our findings (studies where n > 10 in both arms; random and fixed effects models). A metaregression (beta = -.145) found that as the quality of the study increases, the effect of calcium ionophore is significantly more pronounced with regards to overall pregnancy rate. CONCLUSION(S): AOA with calcium ionophore treatment after intracytoplasmic sperm injection (ICSI) results in a statistically significant improvement in fertilization, cleavage, blastulation, and implantation rates, as well as overall pregnancy and live-birth rates. The conclusion of this systematic review, demonstrating a strong effect of calcium ionophore use, is reassuring and promising, particularly for couples for whom ICSI alone yields poor fertilization rates. PMID- 28865548 TI - Effects of adenomyosis on in vitro fertilization treatment outcomes: a meta analysis. AB - OBJECTIVE: To systematically review and summarize the existing evidence related to the effect of adenomyosis on fertility and on in vitro fertilization (IVF) clinical outcomes, and to explore the effects of surgical or medical treatments. DESIGN: Meta-analysis. SETTING: Not applicable. PATIENT(S): An electronic-based search was performed with the use of the following databases: Pubmed, Embase, Ovid Medline, Cochrane Central Register of Controlled Trials, and Google Scholar, identifying all related articles up to November 2016. We included 11 comparative studies that evaluated the clinical outcomes of IVF treatments in women with (519 patients) and without (1,535 patients) adenomyosis diagnosed with the use of magnetic resonance imaging or transvaginal ultrasound. We also separately evaluated four articles comparing fertility outcomes in two groups of infertile adenomyotic patients untreated and treated surgically or medically with the use of GnRH agonist (GnRHa). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome: clinical pregnancy rate after IVF. SECONDARY OUTCOMES: rates of implantation, ongoing pregnancy, live birth, miscarriage, and ectopic pregnancy. The summary measures were expressed as odds ratio (OR) and 95% confidence interval (CI). RESULT(S): The rates of implantation, clinical pregnancy per cycle, clinical pregnancy per embryo transfer, ongoing pregnancy, and live birth among women with adenomyosis were significantly lower than in those without adenomyosis. The miscarriage rate in women with adenomyosis was higher than in those without adenomyosis. It appears that surgical treatment or treatment withf GnRHa increases the spontaneous pregnancy rate in women with adenomyosis. CONCLUSION(S): Adenomyosis has a detrimental effect on IVF clinical outcomes. Pretreatment with the use of long-term GnRHa or long protocol could be beneficial. PMID- 28865549 TI - Effect of oocyte vitrification on embryo quality: time-lapse analysis and morphokinetic evaluation. AB - OBJECTIVE: To analyze whether oocyte vitrification may affect subsequent embryo development from a morphokinetic standpoint by means of time-lapse imaging. DESIGN: Observational cohort study. SETTING: University-affiliated private IVF center. PATIENT(S): Ovum donation cycles conducted with the use of vitrified (n = 631 cycles; n = 3,794 embryos) or fresh oocytes (n = 1,359 cycles; n = 9,935 embryos) over 2 years. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): Embryo development was analyzed in a time-lapse imaging incubator. The studied variables included time to 2 cells (t2), 3 cells (t3), 4 cells (t4), 5 cells (t5), morula (tM), and cavitated, early, and hatching blastocyst (tB, tEB, tHB) as well as 2nd cell cycle duration (cc2 = t3 - t2). All of the embryos were classified according to the hierarchic tree model currently used for embryo selection. The analyzed variables were compared with the use of analysis of variance or chi-square and included 95% confidence intervals (CIs). RESULT(S): The embryos that originated from vitrified oocytes showed a delay of ~1 hour from the first division to 2 cells (t2) to the time of blastulation (tB). The embryos that originated from vitrified oocytes showed a delay of ~1 hour from the 1st division to 2 cells (t2) to the time of blastulation (tB) (P<.05). The proportions of embryos allocated to categories A-E in the hierarchical tree were similar between groups. No differences in implantation rates between the fresh (51.3% [95% CI 47.1%-55.7%]) and vitrified (46.4% [95% CI 38.4%-54.4%]) groups were found. CONCLUSION(S): The embryo quality of vitrified oocytes was not impaired: cc2, quality according to our hierarchic morphokinetic model, and implantation rates were similar between fresh and vitrified oocytes. However, morphokinetic differences were observed from t2 to tB. Our main study limitation was the retrospective nature of the analysis, although a large database was studied. PMID- 28865550 TI - Obstetric and perinatal outcomes of pregnancies conceived with embryos cultured in a time-lapse monitoring system. AB - OBJECTIVE: To compare obstetric and perinatal outcomes of singleton pregnancies resulting from embryos incubated in a time-lapse system (TLS) with those of embryos grown in standard IVF incubators (SI). DESIGN: Retrospective description of a cohort of patients who conceived during a randomized, controlled trial. SETTING: Private university-affiliated IVF center. PATIENT(S): Of 856 randomized patients, 378 gave birth to a live-born infant: 216 of the deliveries originated from embryos incubated in TLS, and 162 deliveries were from embryos cultured in SI. INTERVENTION(S): Embryo incubation and selection in TLS. MAIN OUTCOME MEASURE(S): Delivery and neonatal outcomes. RESULT(S): No significant differences were observed in the baseline characteristics of the study population. The delivery rate was 49.3% (TLS) vs. 40.0% (SI), and multiple deliveries were higher in the TLS group: 31.0% (67 of 216) vs. 24.7% (40 of 162) in the SI group. When singleton pregnancies were analyzed no differences were found between the two groups in the rate of obstetric problems with respect to weeks at delivery: 38.8 (95% confidence interval [CI] 38.4-39.1) (TLS) vs. 39.5 (95% CI 38.0-39.9) (SI); preterm births (<37 weeks): 10.7% (TLS) vs. 12.3% (SI); and very preterm births (<34 weeks): 2.9% (TLS) vs. 3.3% (SI). No statistical differences were found in neonatal outcomes such as birth weight: 3,163 g (95% CI 3,035-3,292 g) (TLS) vs. 3,074 (95% CI 2,913-3,236) (SI); low birth weight (<2,500 g): 12.8% (TLS) vs. 12.3% (SI); very low birth weight (<1,500 g): 2.0% (TLS) vs. 2.4% (SI); or height: 50.3 cm (95% CI 49.6-50.9 cm) (TLS) vs. 49.7 (95% CI 48.9-50.4 cm) (SI). No major malformations or perinatal mortality were found in either of the two groups. CONCLUSION(S): No detrimental effects were observed in obstetric and perinatal outcomes when a time-lapse incubator was used rather than a more widely used conventional incubator. As far as we know this is the first report from a randomized study of the neonatal outcomes of time-lapse monitoring. Our results suggest that this technology is an effective and safe alternative for embryo incubation, though trials of larger numbers of patients are required to further confirm our conclusions. CLINICAL TRIAL REGISTRATION NUMBER: NCT01549262. PMID- 28865551 TI - Serum antimullerian hormone levels are independently related to miscarriage rates after in vitro fertilization-embryo transfer. AB - OBJECTIVE: To investigate whether serum antimullerian hormone (AMH) levels are independently related to miscarriage rates after in vitro fertilization-embryo transfer (IVF-ET). DESIGN: Cohort study. SETTING: University-affiliated IVF-ET center. PATIENT(S): A total of 1,060 patients who attained a clinical pregnancy after IVF-ET. INTERVENTIONS(S): Centralized serum AMH measurements were performed within the 12 months before IVF-ET. Binary logistic regression was used to verify whether serum AMH levels were associated with the occurrence of a miscarriage independently from confounding factors, such as age and intensity of ovarian response to controlled ovarian stimulation assessed by the number of oocytes retrieved. MAIN OUTCOME MEASURE(S): Miscarriage rates. RESULT(S): In patients displaying reduced serum AMH levels, miscarriage rates were significantly increased independently from age and the number of oocytes retrieved. CONCLUSION(S): The present data indicate that serum AMH levels are independently associated with the occurrence of a miscarriage after IVF-ET. PMID- 28865552 TI - Gonadotropin-releasing hormone agonist trigger increases the number of oocytes and embryos available for cryopreservation in cancer patients undergoing ovarian stimulation for fertility preservation. AB - OBJECTIVE: To compare the oocyte and embryo yield associated with GnRH-agonist triggers vs. hCG triggers in cancer patients undergoing controlled ovarian stimulation (COS) for fertilization preservation. DESIGN: Retrospective cohort study. SETTING: Academic center. PATIENT(S): Cancer patients undergoing COS with letrozole and gonadotropins or gonadotropin-only protocols for oocyte or embryo cryopreservation. INTERVENTION(S): Gonadotropin-releasing hormone agonist or hCG trigger. MAIN OUTCOME MEASURE(S): Number of metaphase II (MII) oocytes or two pronuclei (2PN) embryos available for cryopreservation were primary outcomes. Separate multivariate linear regression models were used to assess the effect of trigger type on the primary outcomes, after controlling for confounders of interest. RESULT(S): A total of 341 patients were included, 99 (29.0%) in the GnRH-agonist group and 242 (71%) in the hCG group. There was no difference in the baseline demographics of patients receiving GnRH-agonist or hCG triggers. Within the letrozole and gonadotropins group (n = 269), the number (mean +/- SD, 11.8 +/ 5.8 vs. 9.9 +/- 6.0) and percentage of MII oocytes (89.6% vs. 73.0%) available for cryopreservation was higher with GnRH-agonist triggers compared with hCG triggers. Similar results were noted with GnRH-agonist triggers in the gonadotropin-only group (n = 72) (i.e., a higher number [13.3 +/- 7.9 vs. 9.3 +/- 6.0] and percentage of MII oocytes [85.7% vs. 72.8%] available for cryopreservation). Multivariate linear regression demonstrated approximately three more MII oocytes and 2PN embryos available for cryopreservation in the GnRH agonist trigger group, irrespective of cancer and COS protocol type. CONCLUSION(S): Utilization of a GnRH-agonist trigger increases the number of MII oocytes and 2PN embryos available for cryopreservation in cancer patients undergoing COS for fertility preservation. PMID- 28865553 TI - Motivations and attitudes of candidate sperm donors in Belgium. AB - OBJECTIVE: To study the motivation and attitudes of a candidate sperm donor population in Belgium. DESIGN: Anonymous survey. SETTING: Tertiary referral infertility center. PATIENT(S): One hundred candidate sperm donors applying to the center for a first semen analysis between April 2013 and March 2016. INTERVENTION(S): Invitation to complete an anonymous questionnaire. MAIN OUTCOME MEASURE(S): Demographic characteristics, recruitment methods, motivations and attitudes toward payment, donor anonymity, disclosure to offspring, donation to lesbian couples and single women, views on the donor children and social aspects of sperm donation. RESULT(S): The majority of our candidate donor population were older men with a partner who were donating sperm for altruistic reasons. The financial compensation was only an important motivational factor in 31% of the candidate sperm donors. Eighty-two percent of the men said they were willing to reveal nonidentifying information about themselves to donor offspring, but only 26% were willing to donate nonanonymously. The wish to receive certain information about the recipient family and the donor offspring was linked to men who had a partner and a child of their own. CONCLUSION(S): The wish to receive and donate information depends on the characteristics and beliefs of the candidate donors. Also, the donor's characteristics were linked to the acceptance of meeting the offspring in the future: the donors with a partner and donors who said they would donate without financial reimbursement were less willing to meet the donor offspring. PMID- 28865554 TI - Erratum. PMID- 28865555 TI - Versatility of the suprapubic port in robotic assisted laparoscopic myomectomy. AB - OBJECTIVE: To demonstrate the multiple advantages of the suprapubic port in robotic assisted laparoscopic myomectomy. DESIGN: Video demonstration of a robotic assisted laparoscopic myomectomy technique using a suprapubic incisional retractor (GelPOINT). SETTING: Hospital. PATIENT(S): A 32-year-old primigravid women with heavy menstrual bleeding and pelvic pain with a 12-cm leiomyoma (International Federation of Gynecology and Obstetrics type 5). INTERVENTION(S): Illustrate a surgical approach during robotic assisted laparoscopic myomectomy with the use of a 5-cm suprapubic incision, an incisional retractor (GelPOINT) for the enucleation, and extraction of a large leiomyoma. MAIN OUTCOME MEASURE(S): The effective enucleation and extraction of a leiomyoma specimen using an incisional retractor and GelPOINT. The steps of the technique and the role of GelPOINT are demonstrated. RESULT(S): The procedure was performed without incident, and the patient experienced pain relief and lighter menses postoperatively. This technique has been performed successfully since June 2014 on 22 women. CONCLUSION(S): During a robotic assisted laparoscopic myomectomy the suprapubic incision is both advantageous and practical. The small incision allows the surgery to remain minimally invasive; the primary umbilical trocar is inserted under direct visualization in an already insufflated abdomen; the location of the incision allows the surgical assistant easy access to the port; the passing of the needles occurs under direct visualization with minimal camera manipulation; and last, the extraction of large tissue can be performed within a specimen pouch through this same suprapubic incision in a short period. PMID- 28865556 TI - Normative Reference Values of Right Heart in Competitive Athletes: A Systematic Review and Meta-Analysis. AB - Training-induced right ventricular (RV) enlargement is frequent in athletes. Unfortunately, RV dilatation is also a common phenotypic expression and one of the diagnostic criteria of arrhythmogenic RV cardiomyopathy (ARVC). The current echocardiographic reference values derived from the general population can overestimate the presence of RV dilatation in athletes. We performed a meta analysis of the literature to derive the proper reference values for assessing RV enlargement in competitive athletes. We conducted systematic review of English language studies in the MEDLINE, Scopus, and Cochrane databases investigating RV size and function by echocardiography and by cardiac magnetic resonance (CMR) in competitive athletes. In total, 6,806 and 740 competitive athletes were included for the echocardiographic and CMR quantification of the RV, respectively. In this review, we present normal reference values for RV size and function to be applied in competitive athletes according to the disciplines practiced. The reference ranges reported in this review suggest that physicians should be aware that application of the current recommendations for normal population could be misleading when evaluating athletes. We suggest using these normative reference values, obtained in competitive athletes, to avoid the potential for mistakenly concluding, in this specific population, that RV size or function are abnormal. PMID- 28865557 TI - Multimodality Noninvasive Imaging in the Monitoring of Pediatric Heart Transplantation. AB - Orthotopic heart transplantation is a well-established and effective therapeutic option for children with end-stage heart failure. Multiple modalities, including noninvasive cardiac imaging, cardiac catheterization, angiography, and endomyocardial biopsy, are helpful to monitor these patients for graft dysfunction, rejection, and vasculopathy. Because of morbidities associated with invasive monitoring, noninvasive imaging plays a key role in the surveillance and evaluation of symptoms in pediatric transplant recipients. Echocardiography with or without stress augmentation may provide serial data on systolic and diastolic function, ventricular deformation, and tissue characteristics in children after transplantation. Although not perfectly sensitive or specific, advanced two- and three-dimensional echocardiographic detection of functional changes in cardiac grafts may allow early recognition of allograft rejection. Magnetic resonance imaging has shown promise for characterization of edema and scar and myocardial perfusion reserve, as well as potential application for the detection of microvasculopathic changes in the transplanted heart. Cardiac computed tomography is particularly well suited for the demonstration of coronary artery dimensions and anatomic residual lesions. In combination, these noninvasive imaging techniques help the transplantation cardiologist screen for graft dysfunction, detect critical graft events, and identify situations that require invasive testing of the transplanted heart. Advanced multimodality imaging techniques are likely to increasingly shape the monitoring practices for children following heart transplantation. PMID- 28865558 TI - Impact of Accreditation on Quality in Echocardiograms: A Quantitative Approach. AB - BACKGROUND: Accreditation through the Intersocietal Accreditation Commission (IAC) is believed but not proven to increase quality in imaging. The goal of this study was to use quality metrics to evaluate the impact of accreditation on quality in pediatric echocardiography. METHODS: This is a retrospective study comparing quality metrics in 236 pediatric transthoracic echocardiograms in patients with congenital heart disease from (1) California Pacific Medical Center (CPMC), a community hospital, before and after IAC accreditation, and (2) the IAC accredited Lucile Packard Children's Hospital (LPCH), an academic children's referral center, during equivalent eras. Consecutive patients who required cardiac intervention were matched between sites based on age, complexity, and time period. Two raters independently evaluated echocardiograms for image quality and study comprehensiveness. A third rater reviewed echocardiogram reports and medical charts for report completeness and diagnostic accuracy. Diagnostic error characterization was performed by consensus among the three raters. Report completeness was an IAC tool approved for maintenance of certification. The remaining quality metrics were developed by the American College of Cardiology Adult Congenital Pediatric Cardiology Quality Metrics Working Group initiative. RESULTS: At each site, 74 echocardiograms in the era before CPMC accreditation and 44 echocardiograms in the era after CPMC accreditation were included. There was no significant difference in image quality and diagnostic accuracy at CPMC before and after accreditation. Study comprehensiveness and report completeness improved at CPMC after accreditation (P < .001). CONCLUSIONS: Accreditation through the IAC leads to increased study comprehensiveness and report completeness. Image quality and diagnostic accuracy did not differ significantly before and after IAC accreditation. We recommend further studies to assess the effects of accreditation on quality in echocardiography and patient outcomes. PMID- 28865560 TI - Correction. PMID- 28865559 TI - Laboratory Accreditation: Why This Quality Matter Matters. PMID- 28865561 TI - Quality Matters. PMID- 28865562 TI - YOU Make the Future Brighter by Sharing Your Voice in ASE's Council on Cardiovascular Sonography. PMID- 28865563 TI - Getting Back to Basics: The "Primary" Outcome Measure Determines a Study's Conclusion. AB - In this month's issue, Hollman, Wolterbeek, Zijl, van Egeraat, and Wessel from Nieuwegein, The Netherlands, investigate an essential and most basic concern: how does an abduction brace compare to a simple sling after arthroscopic rotator cuff repair? A criticism of the study, well noted in Editorial Commentary by Kevin Plancher, is that Hollman et al. selected postoperative pain (rather than long term clinical outcome) as their "primary" outcome measure. The primary outcome measure determines the conclusion of a study. Accurate conclusions require adequate statistical power, particularly if potentially underpowered secondary outcome measures (in this case, long-term clinical outcome) show no difference between 2 treatment options. Research clinicians, patients, and payers comparing abduction brace versus sling after shoulder rotator cuff repair ultimately need to understand if there is a difference in long-term clinical outcomes between the treatment options. PMID- 28865564 TI - Arthroscopy Association of North America: Past, Present, and Future-2016 Presidential Address. PMID- 28865565 TI - Editorial Commentary: Better Care, Better Health, Better Cost: Is Scientific Evidence Negatively Impacting the Transformation of Health Care? AB - The selection of an immobilization device and arm positioning may play a role in postoperative pain and healing after arthroscopic rotator cuff repair. Although the current evidence is inconclusive, it is important that we aim as a profession to produce meaningful evidence that will advance the care of our patients while controlling health care costs. PMID- 28865566 TI - Decreased Shoulder External Rotation and Flexion Are Greater Predictors of Injury Than Internal Rotation Deficits: Analysis of 132 Pitcher-Seasons in Professional Baseball. AB - PURPOSE: The primary aims of this work were to (1) describe normal range of motion (ROM) profiles for elite pitchers, (2) describe the characteristics of shoulder and elbow injuries in professional pitchers over a 6-year period in one Major League Baseball organization, and (3) identify ROM measures that were independently associated with a future shoulder or elbow injury. METHODS: Over 6 seasons (2010-2015), a preseason assessment was performed on all pitchers invited to Major League Baseball Spring Training for a single organization. ROM measures included shoulder flexion, horizontal adduction, external rotation (ER), internal rotation, as well as elbow flexion and extension, were measured for both the dominant and nondominant arm, and total range of motion and deficits were calculated. All noncontact shoulder and elbow injuries were identified. Using multivariate binomial logistic regression analysis to control for age, height, weight, and all other ROM measures, the factors associated with an increased risk of subsequent shoulder or elbow injury were identified. RESULTS: A total of 53 shoulder (n = 25) and elbow (n = 28) injuries occurred during 132 pitcher seasons (n = 81 pitchers). The most significant categorical risk factor associated with increased elbow injury rates was the presence of a shoulder flexion deficit >5 degrees (odds ratio [OR] 2.83; P = .042). For continuous variables, the risk of elbow injury increased by 7% for each degree of increased shoulder ER deficit (OR 1.07; P = .030) and 9% for each degree of decreased shoulder flexion (OR 1.09; P = .017). None of the measures significantly correlated with shoulder injuries. CONCLUSIONS: Preseason shoulder ER and flexion deficits are independent risk factors for the development of elbow injuries during the upcoming season. Although prior work has supported the importance of reducing glenohumeral internal rotation deficits in pitchers, this study demonstrates that deficits in shoulder ER and flexion are more significant predictors of subsequent elbow injury. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28865567 TI - Editorial Commentary: Pitching a New Curve: Identifying the Etiology of Nontraumatic Throwing Injuries. AB - Loss of shoulder motion, especially to flexion and external rotation, may increase the risk of nontraumatic shoulder and elbow injuries in elite pitchers. However, the etiology of these injuries is likely mulitifactorial, and before we direct our therapists to abandon sleeper stretches in favor of flexion and external rotation exercises, further research is needed to keep pitchers off the disabled list and on the mound. PMID- 28865568 TI - Editorial Commentary: Irreparable Rotator Cuff Tears Might Be Surgically Treatable After All. AB - It appears that implantation of a biodegradable subacromial spacer improves the function for patients with massive irreparable rotator cuff tears. In this issue of Arthroscopy, an interesting article dealing with the treatment of massive irreparable rotator cuff tears is published. PMID- 28865569 TI - Editorial Commentary: Success of Rotator Cuff Healing-Do We Need to Improve on the Strength Anymore? AB - We have had significant progress in improving the biomechanical strength of arthroscopic rotator cuff repairs over the past 3 decades. The field has advanced from simple suture repairs to double-row, transosseous, massive cuff and rip-stop constructs. I do think our focus next should be on improving the biology of tendon healing to improve our clinical outcomes. PMID- 28865570 TI - Editorial Commentary: Whatever You Do: Anatomic Restoration of the Biconcave Glenoid Morphometry for Bone Defects in Patients With Anterior Shoulder Instability Is Nearly Impossible. AB - There are many bone block procedures described to treat glenoid bone defects in anterior shoulder instability and most of these techniques apparently result in anatomic reconstruction. However, anatomic restoration of the biconcave glenoid morphometry for bone defects in patients with anterior shoulder instability is nearly impossible. PMID- 28865571 TI - Editorial Commentary: Fixation of Soft-Tissue Anterior Cruciate Ligament Grafts in Osteoporotic Bone. AB - Tibial-side fixation of soft-tissue grafts in osteoporotic bone has become an important concern, as anterior cruciate ligament reconstruction indications push toward older patients. Although soft-tissue fixation with an interference screw and cortical button may be statistically stronger than graft fixation with a screw or button alone, this hybrid construct is probably not optimized from a clinical perspective. PMID- 28865573 TI - Editorial Commentary: The Ribbon Theory. Another Quantum Leap? The Anterior Cruciate Ligament Is Twisted and in Fact a Flat Structure. Or not? AB - Is the double bundle structure of the anterior cruciate ligament (ACL) a myth? Derotation untwists the ACL and results in a flat ribbon structure. However, other researchers dispute this theory and revealed 2 distinct bundles separated by a synovial septum. The answer is simple: we do not know and the evidence is conflicting. PMID- 28865572 TI - Torsional Appearance of the Anterior Cruciate Ligament Explaining "Ribbon" and Double-Bundle Concepts: A Cadaver-based Study. AB - PURPOSE: To investigate the effect of the anterior cruciate ligament (ACL) torsion in 90 degrees knee flexion on the morphological appearance of the ACL. METHODS: Sixty knees from fresh frozen anatomical specimens were dissected. Eighteen knees were excluded according to selection criteria (torn ACL, mucoid degeneration of the ACL, arthritic lesions of the notch, or knees harboring synovial inflammatory pathologies). After the removal of the synovial membrane, the morphology of the ligamentous fibers of the ACL and the twist were analyzed. Twisting of the ACL was measured using a goniometer in 90 degrees knee flexion and defined by the angle of external rotation of the femur on the axis of the tibia required to visualize a flat ACL. The orientation of tibial and femoral footprint was described in a coronal plane for the tibia and a sagittal plane for the femur. RESULTS: In the 42 knees that were finally included, the ACL was always displayed as a single ribbon-like structure. The torsion of the fibers was on average 83.6 degrees (+/- 9.4 degrees ) in 90 degrees knee flexion. The twisting could be explained by the different orientations of the femoral (vertical in a sagittal plane) and tibial (horizontal in a coronal plane) footprints. An intraligamentous proximal cleavage area was encountered in 11 cases (i.e., 26%). CONCLUSIONS: The ACL is a twisted structure with 83.6 degrees of external torsion of fibers in 90 degrees knee flexion. It is the torsion in the fibers, due to the relative position of bone insertions, which gives the ACL the appearance of being double bundle. CLINICAL RELEVANCE: The concept of the torsional flat structure of the native ACL may be of importance during ACL reconstruction, both in terms of graft choice (flat rather than cylindrical) and of technical positioning (torsion). PMID- 28865574 TI - Can Competitive Athletes Return to High-Level Play After Osteochondral Allograft Transplantation of the Knee? AB - PURPOSE: To investigate functional outcomes among competitive athletes undergoing osteochondral allograft (OCA) transplantation of the knee, including rates of return to play (RTP), and factors preventing RTP. METHODS: A retrospective review identified all competitive athletes (high school, intercollegiate, professional) undergoing isolated femoral condyle OCA from 2004 to 2013. Patient-reported outcome (PRO) questionnaires (Lysholm, International Knee Documentation Committee [IKDC], Knee Injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMasters Universities Arthritis Index [WOMAC], 12-Item Short Form Health Survey [SF-12], Tegner, and Marx) and custom RTP surveys were administered. All subsequent reoperations were documented. RESULTS: Thirteen athletes (4 intercollegiate, 9 high-school) were identified with an average follow-up of 5.9 +/- 2.5 years. Seven athletes (54%) returned to competitive sport at an average of 7.9 +/- 3.5 months, 5 of whom returned to preinjury functional levels. Of the 8 athletes who either did not return to competitive sport or failed to sustain their high level of play, the most common reasons cited were graduation from high school or college (4 patients, 50%) or fear of reinjury (3 patients, 38%). All 4 patients citing graduation as the primary factor preventing return to preinjury level of competitive sport resumed recreational sport without limitations, yielding an adjusted RTP rate of 10 patients (77%) who either returned to competitive play or believed they could return if they had not graduated. At final follow-up, athletes reported significant improvements in all PRO scores except for KOOS-Sport, WOMAC-Stiffness, and SF-12 Mental subscales. There were 3 reoperations at an average of 3.8 +/- 3.3 years after the index OCA. There were no instances of graft failure. CONCLUSIONS: OCAs provide an adjusted RTP rate of 77% for high-level adolescent athletes. Social factors may be more likely than persistent pain to prevent return to sport. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28865576 TI - Editorial Commentary: Retrograde Femoral Nail Malpositioning Can Destroy Knee Cartilage. AB - Retrograde femoral nail malpositioning can obviously destroy knee trochlear cartilage. A solution is osteochondral allograft transplantation surgery. Although case reports are rarely published in Arthroscopy, we make an exception and publish a report of 2 cases of this complication (and how to treat it) because exposure of complications that have not been previously well-reported could allow future surgeons, and their patients, to solve-and, preferably, proactively avoid-similar problems. PMID- 28865575 TI - Single-Step Arthroscopic Repair With Cell-Free Polymer-Based Scaffold in Osteochondral Lesions of the Talus: Clinical and Radiological Results. AB - PURPOSE: To report the clinical and radiological results of patients with talar osteochondral lesions who were treated by microfracture and cell-free scaffold implantation in a single-step arthroscopic surgery. METHODS: Forty patients, treated with a single-step arthroscopic surgery, were evaluated in this single center-based retrospective study. Patients with degenerative arthritis (n = 1), history of ankle fracture (n = 1), kissing lesions (n = 1), lower extremity deformity (n = 1), and lesions <1.5 cm2 (n = 4) were excluded. Oversized (>10 mm depth) bone cysts were additionally treated with bone graft. Patients were evaluated clinically, using the American Orthopedic Foot and Ankle Society (AOFAS) hindfoot score. Radiological assessment was performed with magnetic resonance imaging, using the magnetic resonance observation of cartilage repair tissue (MOCART) score. RESULTS: Thirty-two patients with a mean age of 38 +/- 12 years were evaluated. The mean defect size was 2.5 +/- 0.8 cm2 and the mean defect volume was 2.4 +/- 1.9 cm3. The mean preoperative AOFAS score was 52.8 +/- 13.9 and increased to 87.1 +/- 11.1 postoperatively at the mean follow-up of 33.8 +/- 14.0 months (P = .0001). A total of 84.4% of patients had good to excellent clinical scores. Clinical scores had no significant relation with age, lesion size, depth, or body mass index. The mean MOCART score was 64.2 +/- 12.0. There was no significant correlation between the total MOCART and AOFAS scores (P = .123). A significant relation was found between the defect filling (the subgroup of the MOCART score) and the clinical outcomes (P = .0001, rho = 0.731). CONCLUSIONS: The arthroscopic scaffold implantation technique is a single-step, safe, and effective method for the treatment of talar osteochondral lesions with satisfactory clinical and radiological outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28865577 TI - Saucerization Versus Complete Resection of a Symptomatic Discoid Lateral Meniscus at Short- and Long-term Follow-up: A Systematic Review. AB - PURPOSE: To evaluate the surgical outcomes of symptomatic discoid menisci after total meniscectomy, saucerization, and suture repair of tears of a discoid meniscus at short- and long-term follow-up. METHODS: A systematic review was conducted using the Pubmed and ScienceDirect databases in adherence with Preferred Reporting Items of Systematic Reviews and Meta-Analysis guidelines. Short- and long-term follow-up were defined as an average follow-up of <4 years and >4 years, respectively. Pooled quantitative synthesis was performed on studies that reported results of total meniscectomy and saucerization in the same study. A systematic review was performed on studies that reported data on saucerization, total meniscectomy, and/or repair. RESULTS: A total of 19 studies for the short term and 22 for the long term were identified that met inclusion criteria for qualitative review. Of these, 4 short-term and 5 long-term studies were included in the quantitative synthesis. No significant differences in Ikeuchi scores are seen in the short-term studies between saucerization and total meniscectomy; however, the long-term studies did find a statistical difference favoring saucerization (P < .001). The differences noted between the preoperative and postoperative Lysholm scores in the short term were 24.1 (95% conflict of interest: 10.25-37.95) in 3 studies and 22.38 (95% conflict of interest: 17.68 27.07) in the 4 long-term studies for saucerization. Suture repair with saucerization versus saucerization without suture repair revealed a statistical difference in only 1 of 5 studies. CONCLUSIONS: Long-term data demonstrate significantly improved patient reported outcomes in favor of saucerization over total meniscectomy. Suture repair of tears of a lateral discoid meniscus does not demonstrate improved outcomes over partial meniscectomy without repair. Considering the cost of repair and lack of demonstrated improvement, based on the limited available data, we do not recommend repair of the abnormal anatomy in a torn lateral discoid meniscus. LEVEL OF EVIDENCE: Level IV, systematic review. PMID- 28865578 TI - Proximal Tibiofibular Joint Instability and Treatment Approaches: A Systematic Review of the Literature. AB - PURPOSE: To evaluate the treatment options, outcomes, and complications associated with proximal tibiofibular joint (PTFJ) instability, which will aim to improve surgical treatment of PTFJ instability and aid surgeons in their decision making and treatment selection. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Inclusion criteria were as follows: PTFJ instability treatment techniques, PTFJ surgical outcomes, English language, and human studies. Exclusion criteria were cadaveric studies, animal studies, basic science articles, editorial articles, review articles, and surveys. Furthermore, we excluded studies that did not report patient follow-up time and studies without any patient-reported, clinical or radiographic outcomes at the final follow-up. RESULTS: The systematic review identified 44 studies (96 patients) after inclusion and exclusion criteria application. For the treatment of PTFJ instability, there were 18 studies (35 patients) describing nonoperative management, 3 studies (4 patients) reported on open reduction, 11 studies (25 patients) reported on fixation, 4 studies (10 patients) that described proximal fibula resection, 3 studies (11 patients) reported on adjustable cortical button repair, 2 studies (3 patients) reported on ligament reconstructions, and 5 (8 patients) studies reported on biceps femoris tendon rerouting. The most (77% to 90%) PTFJ dislocations and instability were anterolateral/unspecified anterior dislocation or instability. Improved outcomes after all forms of PTFJ instability treatment were reported; however, high complication rates were associated with both PTFJ fixation (28%) and fibular head resection (20%). CONCLUSIONS: Improved outcomes can be expected after surgical treatment of PTFJ instability. Proximal tibiofibular ligament reconstruction, specifically biceps rerouting and anatomic graft reconstruction, leads to improved outcomes with low complication rates. Nonoperative treatment is associated with persistent symptoms, whereas both fixation and fibular head resection are associated with high complication rates. LEVEL OF EVIDENCE: Level IV, systematic review of level IV studies. PMID- 28865579 TI - Acute syndesmotic instability in ankle fractures: A review. AB - Ankle fractures are among the most common fracture types, and 10% of all ankle fractures lead to accessory syndesmotic injury. An injury that is challenging in every respect is syndesmotic instability. Since the range of diagnostic techniques and the therapeutic options is extensive, it still is a controversial subject, despite the abundance of literature. This review aimed to summarize the current knowledge on syndesmotic instability in ankle fractures and to formulate some recommendations for clinical practice. Chronic instability and the operative osseous treatment of ankle fractures are not part of this review. PMID- 28865580 TI - Mid-term outcomes of first metatarsophalangeal arthroplasty using the Primus FGT double-stemmed silicone implants. AB - BACKGROUND: Silicone implants for first metatarsophalangeal (MTP-1) arthroplasty are regaining popularity, though most studies have long inclusion periods, or short follow-up. The authors aimed to report mid-term outcomes of a cohort that received a third-generation MTP-1 implant at minimum follow-up of 5 years. METHODS: The authors evaluated 70 MTP-1 arthroplasties performed in 64 patients using the PrimusTM Flexible Great Toe implant. The indications were hallux rigidus of grade II (10%) and grade III (87.1%) or revision surgery (2.9%). RESULTS: All patients completed clinical and radiographic assessments at 83.5 months (range, 62-114). There were no revisions or reoperations and the AOFAS-HMI score was 88.9+/-9.1 (median, 90; range, 67-100). Metatarsalgia was 'absent' in 47.1%, 'mild' in 41.1%, 'moderate' in 7.1% and 'severe' in 1.4%. CONCLUSION: This study reported excellent mid-term clinical outcomes and survival rates of a third generation MTP-1 arthroplasty design and confirmed findings of recent studies regarding efficacy of silicone double-stemmed implants. LEVEL OF EVIDENCE: Level IV case series. PMID- 28865581 TI - The RotoglideTM total replacement of the first metatarso-phalangeal joint. A prospective series with 7-15 years clinico-radiological follow-up with survival analysis. AB - BACKGROUND: The Rotoglide total replacement of the MTP-1 joint. 15 years survival analysis. The purpose of this prospective study was to evaluate the long-term performance clinico-radiographically of an uncemented three-component total replacement for the first metatarso-phalangeal joint (MTP-1) used for hallux rigidus (primary osteoarthritis grades 3 and 4). The follow-up was median 11.5 years (7-15). METHODS: The AOFAS forefoot score was used preoperatively and at follow-up. Radiographs were taken weight-bearing in the AP-projection and in tip toe standing in the lateral view. Arthrosis in the sesamoid junction, prosthetic loosening, subsidence (of prosthesis as well as sesamoids), and dorsiflexion were measured, recorded and subjected to multiple variance analysis. Survival analysis was performed for 15 years. MATERIAL: Ninety implants in 80 patients (53 women and 27 men); median age 58 (41-76) were evaluated. RESULTS: Six patients representing seven prostheses in situ had died from unrelated reason. The median preoperative AOFAS increased significantly from 40 to 95. The median gain was 45. Four replacements (4.4%) were extracted for other reasons than loosening. No aseptic loosenings were recorded. The survival rate at 15 years was 91.5% (83 100). Multiple variance analysis showed that arthrosis in the metatarso-sesamoid junction correlated with reduced AOFAS score. CONCLUSION: The prosthesis has stood the test of time; the results justify its further use. PMID- 28865582 TI - 1st metatarso-phalangeal joint arthroplasty with ROTO-glide implant. AB - BACKGROUND: Total joint replacement of the 1st metatarso-phalangeal Joint (MTPJ) has been controversial as arthrodesis remains a good option for patients with end stage 1st MTPJ arthritis. We present a multi centre service evaluation of the ROTO-glide device METHODS: 33 ROTO-glide procedures were carried out in 30 patients across 7 sites within the UK. Exclusion criteria - hallux valgus and arthritis, age below 45 years and over 80 years, inflammatory joint disease. Patient assessed pre and post operatively with AOFAS and Oxford forefoot (MOXFQ) scores and plain radiographs. All patients carried out the same post operative protocol RESULTS: Average age at patients was 58.6 years (45-77). Follow up average was 16.9 months (12-29). Pre-op AOFAS scores average 41.4 (17-67) and post op average 76 (29-100) and the MOXFQ summary index decreased from an average of 43 (20-64) pre op to an average of 17 (0-51) post op. Average total range of motion pre operatively was 32 degrees and post operatively was 61 degrees . There were 2 post operative complications but no revisions were necessary. CONCLUSIONS: The early results of this multi centre service evaluation of the ROTO-glide 1st MTPJ replacement support its continued use and evaluation of the prosthesis further. PMID- 28865583 TI - A prospective 24 months follow-up of a three component press-fit prosthesis for hallux rigidus. AB - BACKGROUND: The aim of this study was to evaluate the results following total first metatarsophalangeal (FMTP) joint replacement arthroplasty using a modular three component press fit prosthesis at two year follow up. METHODS: All patient data was collected in a prospective way in four study centres. Both preoperative and postoperative evaluation consisted of an assessment using the AOFAS-HMI score, visual analogue scale for pain, evaluation of the range of motion and patient satisfaction scores. Postoperative X-rays were reviewed for loosening and radiolucency up to two years. RESULTS: Fifty-five feet were available for analysis at 24 months. Two implants were removed during the study. Six more feet had additional surgery due to stiffness or malalignment. Postoperative AOFAS-HMI scores improved significantly by 32.4 points at two year follow-up (p<0.001). The visual analogue scale for pain improved significantly from 6.8 (std 1,6) preoperatively to 1.6 (std 1,9) postoperatively (p<0.0001). Mean dorsiflexion improved from 12.6 (std 10,1) degrees preoperatively to 31.2 (std 16,8) degrees postoperatively. Eighty-seven percent of patients were moderately to well satisfied with the end result. Eighteen prostheses showed radiolucency at 24 months. CONCLUSION: Implantation of a Metis(r) modular three component press fit prosthesis for the metatarsophalangeal joint in hallux rigidus shows significant improvement in AOFAS-HMI scores and a decrease in pain. Concerns remain with regard to early reoperation rate (14.5%) and long term survival of the implant. Future studies will have to address these aspects. PMID- 28865584 TI - Bone-block arthrodesis procedure in failures of first metatarsophalangeal joint replacement. AB - BACKGROUND: The treatment for the failure of a first metatarsophalangeal joint (MTP1) prosthesis can be complex. There is no consensus regarding the ideal treatment. One of the main issues is the available bone stock after prosthesis removal. The aim of the study was to report the clinical and radiographic results for MTP1 arthrodesis with autologous calcaneus bone graft (bone-block fusion) as a revision procedure of a previous MTP1 implant failure. METHODS: This study included 12 patients diagnosed with failure of a MTP1 prosthesis. All patients were treated with MTP1 arthrodesis using ipsilateral calcaneal bone graft. Patients were evaluated with the Foot Ankle Disability Index (FADI), the visual analogue pain scale (VAS) and AOFAS Hallux Metatarsophalangeal Interphalangeal scoring system (AOFAS-HMI), weight-bearing radiograph of the foot, and a computed tomography scan. The 1-2 intermetatarsal angle, hallux valgus angle, and first ray length were measured before surgery and at final follow-up. RESULTS: Complications included 3 cases of arthrodesis nonunion, (1 symptomatic, 2 asymptomatic) with 2 of the 3 patients experiencing hardware failure and 1 superficial wound infection. The average FADI improved from 41.8 preoperatively to 84.6 at final follow-up (p<0.05); the average VAS improved from 8.5 preoperatively to 2 at final follow-up (p<0,05); the average AOFAS-HMI significantly improved from 50.7 preoperatively to 73.8 at final follow-up (p<0.05). The average length of the bone-block used was 14.3mm (range 11-19mm). The 1-2 intermetatarsal angle decreased from 9.5 degrees preoperatively to 8.4 degrees at final follow-up (p<0.05); hallux valgus angle improved from 19.7 degrees preoperatively to 14.3 degrees at final follow-up (p<0.05). CONCLUSIONS: The management of a failed first metatarsophalangeal joint prosthesis remains controversial. Bone-block arthrodesis using ipsilateral calcaneal autograft appears to be a viable option restoring the bone loss, and avoiding hallux shortening. Nonunion is the most frequent complication with 25% of patients affected, but only 1/3 of patients with nonunion were symptomatic and required revision. PMID- 28865585 TI - Are current foot- and ankle outcome measures appropriate for the evaluation of treatment for osteoarthritis of the ankle?: Evaluation of ceiling effects in foot and ankle outcome measures. AB - BACKGROUND: Many PROMs used for evaluation of ankle osteoarthritis are not validated for this purpose. We hypothesize that frequently used PROMs have an early ceiling or floor effect. METHODS: We prospectively collected data from patients with ankle osteoarthritis between 2011 and 2013. At baseline visit patients completed the Foot and Ankle Outcome Score, the Ankle Osteoarthritis Score, the American Orthopaedic Foot and Ankle Society scale, a visual analogue scale for pain and quality of life. Outcomes were analyzed for floor or ceiling effects. RESULTS: 197 patients were included in the study. A floor effect was present for the AOFAS and VAS for pain in all groups. Floor and ceiling effect are absent for the FAOS outcome measure for all groups. CONCLUSIONS: Physicians should be aware of floor or ceiling effects when evaluating treatment using patient reported outcome measures. The FAOS outcome measure lacks early ceiling or floor effects. PMID- 28865586 TI - Comparison of two different vacuum-assisted closure (VAC) treatments of multiple chronic diabetic foot wounds in the same extremity. AB - BACKGROUND: The aim of the present study is to compare the clinical efficacy and safety of two different vacuum-assisted closure (VAC) applications in one center between two groups of patients with Wagner Grade 3-4 multiple chronic diabetic foot wounds. METHODS: The study was a randomized-controlled, prospective investigation between two groups of patients with Wagner Grade 3-4 multiple chronic diabetic foot wounds at single extremity. There were 10 patients in the first group receiving VAC treatment by means of Y-connector and 11 patients in the second group receiving bridge-VAC treatment. RESULTS: There were no significant difference in Revised Foot Function Index scores and total treatment costs between the both groups. The cost of the VAC dressing supplies in one session of the dressings was lower in the bridge-VAC group. CONCLUSIONS: In conclusion, although bridge-VAC treatment seems to be an alternative method to the VAC treatment by means of Y-connector, we found no superiority of one over the other VAC application for chronic diabetic foot wounds. PMID- 28865587 TI - Surgical repair of symptomatic chronic achilles tendon rupture using synthetic graft augmentation. AB - BACKGROUND: Surgical repair of symptomatic chronic Achilles tendon (TA) rupture is a challenging problem due to the presence of a large defect between tendon edges. We report the results of surgical repair of symptomatic chronic TA rupture by synthetic graft augmentation. METHODS: Seven consecutive patients with a symptomatic chronic TA rupture underwent surgical repair by VY plasty and augmentation with bio-absorbable synthetic graft (Artelon(r)). In all patients, the intraoperative tendon gap after debridement was more than 5cm (Myerson Grade 3). The total duration of plaster immobilization was 10 weeks. The complications were recorded prospectively and functional outcome was assessed by AOFAS score and Achilles tendon Total Rupture Score (ATRS). RESULTS: At a mean follow up of 29 months there was no re-rupture or deep infection. All patients reported good functional outcome as shown by AOFAS and ATRS scores. There were no graft related complications. At final follow up, six patients were able to do single stance heel raise however, calf wasting was noted in all patients. CONCLUSIONS: Tendon repair augmented by absorbable synthetic graft is an acceptable technique in Myerson Grade 3 chronic symptomatic TA ruptures. LEVEL OF EVIDENCE: Level IV, Case series. PMID- 28865588 TI - The effect of active toe movement (AToM) on calf pump function and deep vein thrombosis in patients with acute foot and ankle trauma treated with cast - A prospective randomized study. AB - BACKGROUND: Patients with foot and ankle trauma treated with cast are advised to perform toe movements to prevent venous thromboembolism (VTE). Our aim was to determine the effect of active toe movement on asymptomatic deep vein thrombosis (DVT) and venous calf pump function. METHODS: Patients aged 18-60 years with acute foot and ankle trauma requiring below knee non weight bearing cast were randomized to intervention (regular active toe movement) or control groups (n=100). Patients had bilateral lower limb venous ultrasound to assess for DVT on discharge from clinic. Patients requiring chemical thromboprophylaxis were excluded. RESULTS: 78 completed the study. 27% sustained asymptomatic DVT, with no statistically significant difference in calf pump function or DVT incidence between groups. All DVT's occurred in the injured lower limb. CONCLUSION: Active toe movement is not a viable strategy for thromboprophylaxis in patients with acute foot and ankle trauma treated with cast. PMID- 28865589 TI - Effect of joint pathology, surface preparation and fixation methods on union frequency after first metatarsophalangeal joint arthrodesis: A systematic review of the English literature. AB - BACKGROUND: The aim of this systematic review was to perform a qualitative synthesis of the current literature to determine the union frequencies for first metatarsophalangeal joint arthrodesis as well as the influence of pathology, joint preparation and fixation methods on union. METHODS: MEDLINE and EMBASE were searched to identify relevant studies reporting on first metatarsophalangeal joint union frequencies. RESULTS: 26 studies with 2059 feet met our inclusion criteria. The mean age was 60 years (range 18-84) and the mean follow-up was 32.6 months (range 1.5-156). The union frequency was 93.5% (1923/2059). The union frequencies were significantly higher when low velocity joint preparation methods were used (P<0.0001, Chi Square 22.5) and the pathology was hallux rigidus (P=0.002, Chi square 9.3). There were similarly high union frequencies with crossed screws, locking plate and non-locking plates. CONCLUSIONS: High union frequency can be expected following first metatarsophalangeal arthrodesis, especially when low velocity joint preparation methods are used in patients with hallux rigidus. PMID- 28865590 TI - Matrix-associated stem cell transplantation (MAST) in chondral defects of the 1st metatarsophalangeal joint is safe and effective-2-year-follow-up in 20 patients. AB - The aim of the study was to assess the 2-year-follow-up of matrix-associated stem cell transplantation (MAST) in chondral defects of the 1st metatarsophalangeal joint (MTPJ). In a prospective consecutive non-controlled clinical follow-up study, 20 patients with 25 chondral defect at the 1st MTPJ that were treated with MAST from October 1st, 2011 to March, 30th, 2013 were analysed. The size and location of the chondral defects range of motion (ROM), and the Visual-Analogue Scale Foot and Ankle (VAS FA) before treatment and at follow-up were registered. Stem cell-rich blood was harvested from the ipsilateral pelvic bone marrow and centrifuged (10min, 1500 RPM). The supernatant was used to impregnate a collagen I/III matrix (Chondro-Guide). The matrix was fixed into the chondral defect with fibrin glue. The age of the patients was 42 years on average (range, 35-62 years). The VAS FA before surgery was 50.5 (range, 18.3-78.4). The defects were located as follows, dorsal metatarsal head, n=12, plantar metatarsal head, n=5, dorsal & plantar, n=8 (two defects, n=5). The defect size was 0.7cm2 (range, .5 2.5cm2). ROM was 10.3/0/18.8 degrees (dorsal extension/plantar flexion). All patients completed 2-year-follow-up. VAS FA improved to 91.5 (range, 74.2-100; t test, p<.01). ROM improved to 34.5/0/25.5 (p=.05). The surgical treatment including MAST led to improved clinical scores and ROM. Even though a control group is missing, we conclude that MAST is a safe and effective method for the treatment of chondral defects of the 1st MTPJ. PMID- 28865591 TI - Diagnostics in tarsal fusion: The theory and practise in The Netherlands. AB - BACKGROUND: This study compares the preferences of Dutch orthopaedic surgeons for different diagnostic modalities in performing tarsal fusions versus consensus, evidence or expert opinion reported in the literature. METHODS: A literature search of Medline was performed to obtain evidence-based information on various diagnostic tools. In addition, 89 registered Dutch foot and ankle surgeons were sent a questionnaire concerning the diagnostic modalities use in tarsal fusion. RESULTS: Fifty-eight (65%) questionnaires were returned. The experienced surgeons measured outcomes significantly more often than other surgeons. Diagnostic injections were often used, although scant evidence exists in the literature. Postoperative diagnostics mainly consist of X-ray examination, although there is consensus in the literature that computed tomography is more accurate. CONCLUSIONS: The study revealed some surprising discrepancies concerning the use of diagnostic imaging in tarsal fusion. More clinical research is needed to identify the most effective diagnostic imaging modalities so as to encourage their wider adoption. PMID- 28865592 TI - Corrigendum to "Case series of 17 modified Weil's osteotomies for Freiberg's and Kohler's II AVN, with AOFAS scoring pre- and post-operatively" [Foot Ankle Surg 17 (1) (2011) 19-24]. PMID- 28865593 TI - Obtaining local bone graft for Evans calcaneal osteotomy in pes planovalgus deformity correction. AB - Lateral column lengthening osteotomy is very useful surgical technique in treating stage II of pes planovalgus deformity of the foot. Either autograft from the iliac crest or allograft can be used for this purpose. In our technique we describe a novel method of obtaining bone graft locally from the calcaneus and therefore avoiding complications and morbidity associated with iliac crest graft. PMID- 28865594 TI - Modified Chevron osteotomy for hallux valgus deformity in female athletes. A 2 year follow-up study. PMID- 28865595 TI - Modified Chevron osteotomy for hallux valgus deformity in female athletes. A 2 year follow-up study. PMID- 28865596 TI - Percutaneous foot surgery for the treatment of brachymetatarsia: A case report. AB - BACKGROUND: The term brachimetatarsia refers to an abnormal shortening of the metatarsal bones as a result of early closure of the growth plate. The deformity, which may be congenital, idiopathic or secondary to surgery or trauma, may result in functional as well as cosmetic alterations, which require correction by an orthopedic surgeon. The purpose of this report is to illustrate the possibility of treating this condition by means of a minimally invasive technique which affords results as satisfactory as those of conventional techniques but with fewer complications. We report on the case of a 35-year-old female with a diagnosis of congenital brachymetatarsia, with bilateral involvement of the fourth toe. METHODS: We present our experience of surgical correction of brachymetatarsia using percutaneous surgery. The surgical technique is illustrated by a case report with a follow-up of 2 years. RESULTS: Radiographic and cosmetic correction of the deformity were satisfactory after 9 weeks of treatment. No complications were observed during follow-up. CONCLUSIONS: Although minimally invasive surgery for treatment of brachymetatarsia is a relatively unknown or explored procedure, it provides good clinical and radiological results in experienced hands. In addition, it causes little trauma to the soft tissues, reduces operative time and allows patients a better and faster functional recovery, offering clear advantages over other techniques used for correcting this bone malformation. PMID- 28865597 TI - Nonsuicidal Self-Injury and Suicidality Among Sexual Minority Youth: Risk Factors and Protective Connectedness Factors. AB - OBJECTIVE: We investigated differences in prevalence of repetitive nonsuicidal self-injury (NSSI), suicidal ideation, and a suicide attempt among youth who identified as bisexual, gay/lesbian, and questioning. In addition, we examined which types of social connections were associated with reduced risk of repetitive NSSI and suicidality among youth who identified with a specific sexual minority group. METHODS: Data came from the 2013 Minnesota Student Survey. The analytic sample included 77,758 students in grades 9 and 11. Connectedness factors included parent connectedness, teacher caring, connectedness to other nonparental adults, school safety, and friend caring. Logistic regression analyses, stratified according to sexual minority group, determined social connectedness factors associated with repetitive NSSI, suicidal ideation, and a suicide attempt, as well as moderating effects of significant connectedness factors on different risk factors (depression, anxiety, bullying, and violence victimization). RESULTS: Approximately 3% identified as bisexual or questioning their sexual orientation, and <1% identified as gay/lesbian. Sexual minority youth, particularly bisexual youth, were significantly more likely than heterosexual youth to report repetitive NSSI and suicidality. Effects of connectedness varied across sexual minority groups and outcomes on the basis of types of connections. Parent connectedness emerged as a robust protective factor for all self-harm behaviors among bisexual and questioning youth. Feeling connected to nonparental adults and safe at school represented additional factors that reduced risk of repetitive NSSI and suicidality among certain groups. CONCLUSIONS: In addition to facilitating connections between youth and parents, clinicians might consider encouraging sexual minority youth to remain connected to trusted nonparental adults who could offer support and care. Schools might consider implementing sociocultural norms of acceptance, tolerance, and positive identity development to reduce risk of self-harm. PMID- 28865598 TI - My Approach to the patient with CAD and aspirin resistance. PMID- 28865599 TI - miR-206 enhances nasopharyngeal carcinoma radiosensitivity by targeting IGF1. AB - Radioresistance remains a major problem in nasopharyngeal carcinoma (NPC) treatment. However, the underlying molecular mechanisms of NPC radioresistance remain poorly understood. The present study aimed to investigate the potential role and mechanism of miR-206 in NPC radioresistance. We observed that miR-206 was down-regulated in radioresistant NPC cells. Furthermore, restoration of miR 206 in CNE2-IR cells suppressed enhanced radiosensitivity of NPC cells. In contrast, inhibition of miR-206 in CNE2 cells reduced the radiosensitivity. We also found that miR-206 directly targeted IGF1 and inhibited the PI3K/AKT pathway. Our data demonstrate that miR-206 sensitizes NPC cell to irradiation by targeting IGF1, highlighting the therapeutic potential of miR-206 in NPC radiosensitization. PMID- 28865600 TI - The association of genetic polymorphisms of hypoxia inducible factor-1 alpha and vascular endothelial growth factor with increased risk of chronic obstructive pulmonary disease: A case-control study. AB - Accumulated data over the years have suggested that hypoxia inducible factor-1 alpha (HIF-1alpha) and its downstream vascular endothelial growth factor (VEGF) gene may be linked with chronic obstructive pulmonary disease (COPD). This study aims to investigate the association of HIF-1alpha and VEGF genetic polymorphisms and their correlated risks with COPD. COPD patients (case group) and healthy individuals (control group) were recruited. DNA was extracted to detect HIF 1alpha and VEGF genetic polymorphisms. Basal lung volume and forced expiratory capacity in 1st second (FEV1)/forced vital capacity (FVC) and FEV1/predicted value (pred)% were calculated. Genotype and allele distributions in HIF-1alpha and VEGF genes were analyzed. Kaplan-Meier curves and logistic regression model were used for analysis of survival and COPD risk factors. Haplotypes for HIF 1alpha rs11549465 and rs11549467 were analyzed. FEV1/FVC and FEV1/pred% in the case group were lower than the control group. Frequencies of HIF-1alpha rs11549465 CT + TT genotype and T allele, and rs11549467 GA + AA genotype and A allele were higher in the case group than the control group. Patients with rs11549465 CT + TT had higher COPD risk than those with the CC genotype. Patients with rs11549467 GA + AA showed higher COPD risk and lower FEV1/FVC and FEV1/pred% than those with the GG genotype. Patients with HIF-1alpha TA haplotype showed higher COPD risk than those with the CG haplotype. Survival rate of patients with HIF-1alpha rs11549467 GG genotype was higher than those with the GA + AA genotype. HIF-1alpha rs11549467 polymorphism may be associated with COPD risk. PMID- 28865601 TI - Relationship of the MTHFD1 (rs2236225), eNOS (rs1799983), CBS (rs2850144) and ACE (rs4343) gene polymorphisms in a population of Iranian pediatric patients with congenital heart defects. AB - Congenital heart defects are structural cardiovascular malformations that arise from abnormal formation of the heart or major blood vessels during the fetal period. To investigate the association of 4 single nucleotide polymorphisms (SNPs) in the MTHFD1, eNOS, CBS and ACE genes, we evaluated their relationship with CHD in Iranian patients. In this case-control study, a total of 102 children with CHD and 98 control children were enrolled. Four SNPs including MTHFD1 G1958A, eNOS G894T, CBS C-4673G and ACE A2350G were genotyped by PCR-SSCP, Multiplex ARMS PCR and PCR-RFLP methods and confirmed by direct sequencing. We genotyped 102 patients and 98 controls for four polymorphisms by statistically analysis. There were three SNPs including MTHFD1 G1958A, eNOS G894T and ACE A2350G which might increase the risk of CHD, but CBS C-4673G was not significantly different between patients and controls. (P = 0.017, P = 0.048, P = 0.025 and P = 0.081 respectively). The allele frequencies of three SNPs for MTHFD1 G1958A, eNOS G894T and ACE A2350G in CHD are higher than that in control. Our results show that there is a significant relationship between MTHFD1 G1958A, eNOS G894T and ACE A2350G polymorphisms with CHD. Therefore, The AA and GA genotypes of MTHFD1 G1958A, TT and GT genotypes of eNOS G894T and the AA and GA genotypes of ACE A2350G are susceptible factors for CHD and may increase the risk of CHD. PMID- 28865602 TI - Placental apoptosis in recurrent miscarriage. AB - Apoptosis is an interactive and dynamic biological process involved in all phases of embryogenesis. We aimed to study the effect of placental apoptosis on recurrent miscarriage (RM). Placental tissue samples were collected from 40 women with RM (study group) and 30 women with sporadic spontaneous abortion (control group). Samples were prepared and stained immunohistochemically with markers for both the apoptotic protein (p53) and anti-apoptotic Bcl-2 antibodies. Our results showed that expression of the apoptotic (p53) protein was significantly increased in the placental tissues of the RM group (p = 0.003). By contrast, the expression of anti-apoptotic (Bcl-2) antibodies was significantly increased in the placental tissues of the control group (p = 0.025). We concluded that placental apoptosis plays a crucial role in pregnancy continuation. However, increased p53 expression in placental tissue in early pregnancy could negatively affect pregnancy continuation. PMID- 28865603 TI - Independent and additive interaction between polymorphisms of tumor necrosis factor alpha-308 and lymphotoxin alpha+252 on risk of hepatocellular carcinoma related to hepatitis B. AB - : This case-control study was aimed to assess the effect of genetic variants of tumor necrosis factor (TNF) alpha-308 and lymphotoxin (LT) alpha+252 on development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Their gene-gene interaction was also investigated. We enrolled 200 pairs of age- and sex-matched patients with cirrhotic HBV-HCC and unrelated patients with HBV cirrhosis alone. Polymorphisms of TNFalpha-308 and LTalpha+252 were genotyped. Synergy index was used to calculate interaction between the variant genotypes. The results indicated that the frequency distribution of the variant genotypes (TNFalpha-308 G/A and LTalpha+252 G/G) in patients with HCC were significantly higher than those in patients with cirrhosis alone. Multivariate analysis indicated that TNFalpha-308 G/A (odds ratio [OR], 2.34) and LTalpha+252 G/G (OR, 2.04) were independent risk factors for HCC. By the clinical characteristics of study population, multivariate analysis demonstrated that independent factors associated with harboring the variant genotypes included cirrhosis with Child Pugh C (OR = 6.47 in cases and OR = 11.56 in controls) and thrombocytopenia (OR = 8.86 in cases and OR = 7.74 in controls). Calculation of synergy index (SI) indicated that there are additive interaction between TNFalpha-308 G/A and LTalpha+252 G/G on risk of HCC (SI = 1.29). IN CONCLUSION: There are independent and additive interactions between TNFalpha-308 G/A and LTalpha+252 G/G on risk for HBV-HCC. They correlated with advanced hepatic fibrosis and severe liver damage, which might contribute to a higher risk for HCC. PMID- 28865604 TI - Efficacy of holmium laser enucleation of the prostate (HoLEP) in men with bladder outlet obstruction (BOO) and non-neurogenic bladder dysfunction. AB - We aimed to compare the short-term outcomes of men who had urodynamic evidence of detrusor underactivity (DU) or detrusor overactivity (DO) of a non-neurogenic etiology as well as bladder outlet obstruction (BOO) and who underwent Holmium Laser Enucleation of the prostate (HoLEP). A database of 322 patients who underwent HoLEP between 2010 and 2014 was analyzed. Patients were classified into three groups according to the results of a preoperative urodynamic study. Preoperative parameters such as International Prostate Symptom Score (IPSS), Quality of Life (QoL) index, IPSS grade, uroflowmetry were compared with postoperative parameters measured at 6 months. There were 138 patients with BOO only and 89 patients with BOO and detrusor dysfunction including 56 with DO and 33 with DU. The degree of improvement in IPSS-total (BOO: 10.7, DO: 8.3, DU: 7.0; p = 0.023) was greater in the BOO-only group than in the DU group. There were more patients whose IPSS grade improved in the BOO-only group (71%) than in the detrusor dysfunction group (DO: 53.6% and DU: 45.5%). Postoperative IPSS-voiding (4.5 vs 7.0), and Qmax (18 vs 13.7) in the BOO-only group were significantly better than those in the DU group. Additionally, postoperative IPSS-storage (4.7 vs 6.7), and IPSS-total (9.1 vs 12.3) in the BOO-only group were significantly better than in the DO group (all p < 0.05). In conclusion, early surgical management for men with severe LUTS and associated BPH before secondary degeneration occurs may be beneficial for preserving detrusor function and yield better treatment outcomes. PMID- 28865605 TI - Three dimensional versus standard miniplate fixation in the management of mandibular fractures: A meta-analysis of randomized controlled trials. AB - The aim of this meta-analysis is to evaluate the efficacy of the 3-dimensional miniplate system in comparison with the standard miniplate system for the treatment of mandibular fractures (MFs). A systematic review was conducted according to PRISMA guidelines, examining Medline-Ovid, Embase, and PubMed databases. The primary search objective was to identify all papers reporting the results of randomized control trials (RCTs) for the treatment of adults with mandibular fractures, with the aim of comparing the different techniques. The incidence of complications was evaluated; nine studies including 283 patients with different fracture sites were enrolled in the analysis. The results showed no significant differences in overall complications (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.552-1.542; P = 0.81), postoperative infections (OR, 0.99; 95% CI, 0.40-2.48; P = 0.89), wound dehiscence (OR, 0.96; 95% CI, 0.13 7.37; P = 0.96), paresthesia (OR, 0.47; 95% CI, 0.20-1.07; P = 0.11), or malocclusion (OR, 1.8; 95% CI, 0.39-8.32; P = 0.47) between standard miniplates and 3-dimensional miniplates for treating mandibular fractures. Mandibular fractures treated with 3-dimensional miniplates and standard miniplates presented similar short-term complication rates, and the low postoperative maxillomandibular fixation rate of using standard miniplates also indicated that the standard miniplate has a promising application in the treatment of mandibular fractures. PMID- 28865606 TI - Acupuncture-related penetrating eye injury. PMID- 28865607 TI - Observation of bifid mandibular canals on cone-beam computed tomography. PMID- 28865608 TI - Divergent paths to the end of AIDS. PMID- 28865609 TI - Optimism and concern at IAS 2017. PMID- 28865610 TI - Volatile compounds and odour characteristics of seven species of dehydrated edible seaweeds. AB - The volatile fraction of dehydrated edible seaweeds belonging to seven species (Himanthalia elongata, Laminaria ochroleuca, Palmaria palmata, Porphyra umbilicalis, Saccharina latissima, Ulva lactuca and Undaria pinnatifida) was analyzed by gas chromatography-mass spectrometry, after solid-phase microextraction of samples. Thirty-six hydrocarbons, 34 ketones, 28 aldehydes, 23 alcohols, 8 carboxylic acids, 6 halogenated compounds, 4 furans, 3 esters, 2 sulphur compounds, 2 pyrazines, 1 pyridine and 1 amine were detected among the 151 volatile compounds found in seaweeds. There were significant differences between seaweed species for all the volatile compounds. Hydrocarbons reached their highest levels in U. pinnatifida, ketones in P. umbilicalis, aldehydes in P. palmata and P. umbilicalis, alcohols in P. umbilicalis, carboxylic acids in S. latissima, and halogenated compounds in L. ochroleuca and S. latissima. Sensory analysis revealed that P. palmata, U. lactuca and H. elongata were the seaweeds showing the most potent seafood odour and seaweed odour characteristics. PMID- 28865611 TI - Polysaccharides from macroalgae: Recent advances, innovative technologies and challenges in extraction and purification. AB - Polysaccharides obtained from macroalgae have promising prospects and could contribute greatly to the future of a marine based bio-economy. Specifically, laminarin and fucoidan from brown macroalgae have a wide variety of potential industrial applications including functional foods and nutraceuticals, due to their broad range of biological activities. These beneficial biological activities are related to the chemical composition and structure of the macroalgal polysaccharides. The molecular weight, monosaccharide composition and sulphate content of these polysaccharides could be influenced by both macroalgal biology (i.e. variations in polysaccharide composition due to macroalgae species and their biological cycle) and different extraction/purification techniques employed to obtain polysaccharide enriched products (i.e. de-sulphation or fragmentation of sulphated polysaccharides). This review focuses on the extraction and purification methods for the macroalgal polysaccharides laminarin and fucoidan used in the recent literature. The application of innovative extraction technologies (such as ultrasound, microwave and enzyme-assisted extractions), as well as new purification techniques (i.e. membrane separation), are also discussed together with the challenges concerning molecule structure function relationship and macroalgal variability. PMID- 28865612 TI - Extraction and characterization of protein from Irish brown seaweed Ascophyllum nodosum. AB - This study investigates traditional and non-conventional methods of extraction of protein from Irish brown seaweed A. nodosum. Acid, alkali, combined acid-alkali with and without ultrasound pretreatment were investigated for extraction of protein from A. nodosum. Molecular weight of protein was determined using high performance size exclusion chromatography and amino acid profiling was carried out using an amino acid analyzer. Combination of first acid and then alkali extraction was found to be the most efficient method of extraction among all methods investigated (59% of recovery); followed by single step of alkali extraction assisted with ultrasound (68.4MUm) which was able to extract 57% of total protein. Alkaline extraction was shown to yield the best protein/algae liquefaction ratio (1.28). This can be attributed to the release of polysaccharide complexes first by acid and then solubilization of proteins by alkali solvent. The molecular weight of extracted protein was found to be relatively low, in the range of 2-4kDa average MW. The alkali method of extraction was found to be optimum for extraction of amino acids from A. nodosum. PMID- 28865613 TI - Protein and carbohydrate extraction from S. platensis biomass by ultrasound and mechanical agitation. AB - Spirulina platensis is considered an alternative and excellent source of protein [46-63% dry basis (DB)], having protein levels comparable to meat and soybeans. Thus, it can be considered an adequate ingredient to supply the necessity of this compound in the food industry. Its carbohydrates (8-14% DB) may also be a useful food ingredient or a potential source of bioenergy. Thus, extracting these compounds from the microalgae biomass will maximize its exploitation. Sonication can completely or partially degrade the microalgal cell wall, providing a useful technique to extract the protein and carbohydrate. This study used a sequential strategy of experimental design (fractional factorial design and central composite rotatable design) to evaluate the protein and carbohydrate extraction from S. platensis defatted biomass using ultrasonic waves and mechanical agitation, under alkaline conditions. The optimal conditions for protein and carbohydrate co-extraction were established by selecting and maximizing the variables that significantly influenced the extraction. The optimized percentages recovery from the extraction process yielded 75.76% protein and 41.52% carbohydrate at 33-40min sonication and 40-55min agitation. The protein fraction may be further concentrated and purified for use in food formulations, and the carbohydrates may be a useful feedstock for bioethanol production. PMID- 28865614 TI - Identification of chlorophyll molecules with peroxyl radical scavenger capacity in microalgae Phormidium autumnale using ultrasound-assisted extraction. AB - The identification of chlorophyll molecules with peroxyl radical scavenger capacity in microalgae Phormidium autumnale was determined. The ultrasound assisted extraction was utilized for obtaining the chlorophyll compounds from biomass. A total of eleven molecules were separated in microalgae chlorophyll extract, with pheophytin a' (371MUg.g-1) and chlorophyll a (159.3MUg.g-1) as the major ones. The chlorophyll extract was shown to be a potent scavenger of peroxyl radical, being almost 200 times more potent than alpha-tocopherol. These facts suggest the microalgae Phormidium autumnale as potential source of bioactive tetrapyrrole compounds. PMID- 28865615 TI - C-phycocyanin extraction assisted by pulsed electric field from Artrosphira platensis. AB - This paper assesses the application of pulsed electric fields (PEF) to the fresh biomass of Artrhospira platensis in order to enhance the extraction of C phycocyanin into aqueous media. Electroporation of A. platensis depended on both electric field strength and treatment duration. The minimum electric field intensity for detecting C-phycocyanin in the extraction medium was 15kV/cm after the application of a treatment time 150MUs (50 pulses of 3MUs). However higher electric field strength were required when shorter treatment times were applied. Response surface methodology was used in order to investigate the influence of electric field strength (15-25kV/cm), treatment time (60-150MUs), and temperature of application of PEF (10-40 degrees C) on C-phycocyanin extraction yield (PEY). The increment of the temperature PEF treatment reduced the electric field strength and the treatment time required to obtain a given PEY and, consequently decreased the total specific energy delivered by the treatment. For example, the increment of temperature from 10 degrees C to 40 degrees C permitted to reduce the electric field strength required to extract 100mg/g dw of C-phycocyanin from 25 to 18kV/cm, and the specific energy input from 106.7 to 67.5kJ/Kg. Results obtained in this investigation demonstrated PEF's potential for selectively extraction C-phycocyanin from fresh A. platensis biomass. The purity of the C phycocyanin extract obtained from the electroporated cells was higher than that obtained using other techniques based on the cell complete destruction. PMID- 28865616 TI - Pressurized liquid extraction of Neochloris oleoabundans for the recovery of bioactive carotenoids with anti-proliferative activity against human colon cancer cells. AB - In recent years, the green microalgae Neochloris oleoabundans have demonstrated to be an interesting natural source of carotenoids that could be used as potential food additive. In this work, different N. oleoabundans extracts obtained by pressurized liquid extraction (PLE) have been analyzed in depth to evaluate the influence of different culture conditions (effect of nitrogen, light intensity or carbon supplied) not only on the total carotenoid content but also on the carotenoid composition produced by these microalgae. Regardless of the cultivation conditions, lutein and carotenoid monoesters were the most abundant carotenoids representing more than 60% of the total content in all extracts. Afterwards, the effect of the different N. oleoabundans extracts and the dose effect of the most potent algae extracts (namely, N9, PS and CO2 (-)) on the proliferation of human colon cancer cells lines (HT-29 and SW480) and a cell line established from a primary colon cancer cell culture (HGUE-C-1) were evaluated by an MTT assay whereas a stepwise multiple regression analysis was performed to get additional evidences on the relationship between carotenoid content and the antiproliferative activity. Results revealed that, as a general trend, those extracts with high total carotenoid content showed comparably antiproliferative activity being possible to establish a high correlation between the cell proliferation values and the carotenoid constituents. Monoesters showed the highest contribution to cell proliferation inhibition whereas lutein and violaxanthin showed negative correlation and diesters and zeaxanthin showed a positive significant contribution to cell proliferation. PMID- 28865617 TI - Development of new green processes for the recovery of bioactives from Phaeodactylum tricornutum. AB - Two novel extraction techniques, pressurized liquid extraction (PLE) and microwave-assisted solvent extraction (MAE) have been evaluated for the recovery of bioactive compounds from Phaeodactylum tricornutum. Microalga P. tricornutum is rich in polyunsaturated fatty acids (PUFAs), such as EPA, and has a high content of the carotenoid fucoxanthin, which is a valuable pigment with several biological activities. Cells were disrupted at high pressure and then freeze dried as a previous step to extraction. Additionally, only green solvents as water and ethanol (EtOH) - and mixtures of them - were used. For comparison purposes, the same response variables were considered in both processes: extraction yield (% w/w), total phenolic content (Folin-Ciocalteu assay), total carotenoids and chlorophylls, and antioxidant activity (ABTS assay, expressed as TEAC value). Factorial experimental designs were employed for both PLE and MAE optimization, being %EtOH in water and temperature the common experimental factors. Extraction time was also a factor considered for optimization in MAE. A detailed chemical characterization of pigments was performed by HPLC-DAD-MS/MS (high performance liquid chromatography-diode array detector-mass spectrometry), being fucoxanthin the main compound extracted. Optimum extraction conditions were 50 degrees C, 100% EtOH, 20min for PLE, while optimum conditions for MAE were 30 degrees C, 100% EtOH and 2min. Both technologies extract fucoxanthin as a main compound but higher recoveries were achieved using PLE due to a higher extraction yield. In addition, both MAE and PLE extracts contained different lipid classes potentially enriched in EPA, given an added-value to the extracts. PMID- 28865618 TI - Application of seaweeds to develop new food products with enhanced shelf-life, quality and health-related beneficial properties. AB - Edible seaweeds are a good source of antioxidants, dietary fibers, essential amino acids, vitamins, phytochemicals, polyunsaturated fatty acids, and minerals. Many studies have evaluated the gelling, thickening and therapeutic properties of seaweeds when they are used individually. This review gives an overview on the nutritional, textural, sensorial, and health-related properties of food products enriched with seaweeds and seaweed extracts. The effect of seaweed incorporation on properties of meat, fish, bakery, and other food products were highlighted in depth. Moreover, the positive effects of foods enriched with seaweeds and seaweed extracts on different lifestyle diseases such as obesity, dyslipidemia, hypertension, and diabetes were also discussed. The results of the studies demonstrated that the addition of seaweeds, in powder or extract form, can improve the nutritional and textural properties of food products. Additionally, low-fat products with less calories and less saturated fatty acids can be prepared using seaweeds. Moreover, the addition of seaweeds also affected the health properties of food products. The results of these studies demonstrated that the health value, shelf-life and overall quality of foods can be improved through the addition of either seaweeds or seaweed extracts. PMID- 28865619 TI - A comprehensive approach to formulation of seaweed-enriched meat products: From technological development to assessment of healthy properties. AB - Meat consumption is influenced by various kinds of factors, among them health implications. Different strategies can be effective in developing meat-based functional foods. These basically entail reducing the presence of compounds with negative health implications and enhancing the presence of beneficial compounds. This article reviews a comprehensive model for the development of meat-based functional foods based on a presentation of the research achieved in terms of the design and development of qualitatively and quantitatively modified meat products (frankfurters, patties and restructured steaks). These were reformulated to incorporate nutrients associated with three different seaweeds (wakame-Undaria pinnatifida; nori-Porphyra umbilicalis; and sea spaghetti-Himanthalia elongata) as sources of bioactive substances, while simultaneously reducing sodium and fat and improving fatty acid profiles. Those seaweeds were chosen, because in terms of composition and health implications, abundance on Spanish coasts, relatively widespread consumption, and suitability in terms of flavour and colour they are better suited than others for use as ingredients in new products. It also discusses the consequences of the use of this type of meat-based functional foods (combination of pork meat and 5% of each seaweed with or without hypercholesterolaemic agent included in the diets) on growing animals (Wistar male rats), and their effects on different aspects of lipoprotein metabolism, oxidative stress and liver structure. This article, then, reports a comprehensive approach to the production of seaweed-enriched meat products, considering aspects of technological development aimed at achieving the functional effect. PMID- 28865620 TI - Assessment of the antioxidant activity of Bifurcaria bifurcata aqueous extract on canola oil. Effect of extract concentration on the oxidation stability and volatile compound generation during oil storage. AB - In this research the antioxidant activity of water extracts of Bifurcaria bifurcata (BBE) at different dose against butylated hydroxytoluene (BHT) was evaluated in canola oil. Water extracts were firstly characterized in terms of total solid and polyphenolic compound contents, and their antioxidant activity together with that of BHT was evaluated using several in vitro tests (DPPH, ABTS, ORAC and FRAP). Next, the progress of lipid oxidation was assessed in canola oil added with five BBE concentrations (200, 400, 600, 800 and 1000ppm) and two BHT concentrations (50 and 200ppm) using an accelerated oxidation test. The progress in lipid oxidation was monitored by assessing some chemical indices (peroxide value, p-anisidine value, and conjugated dienes) during oil storage and some volatile compounds at the end of the storage period. BBE showed a significant antioxidant effect, being this ability concentration-dependent. The extent of lipid oxidation was inversely related to BBE dose, specially with regard to primary oxidation products. At the highest level of BBE, significant decreases of primary and secondary oxidation products, with respect to the control, were obtained with reduction percentages of 71.53%, 72.78%, 68.17% and 71.3% for peroxides, conjugated dienes, p-anisidine and TOTOX values, respectively. A level of 600ppm or higher concentration of the extract inhibits the lipid oxidation in a similar way than BHT at 200ppm. Regarding the inhibition of the formation of volatile compounds, both BBE and BHT strongly inhibited the formation of volatiles during oil storage, being this inhibition similar for all the concentrations of BBE and BHT essayed. Overall, results indicated that BBE can be used as a potential natural additive for improving oxidative stability of canola oil. PMID- 28865621 TI - Natural fortification of trout with dietary macroalgae and selenised-yeast increases the nutritional contribution in iodine and selenium. AB - Fish and seafood consumption are increasing worldwide and the contribution of aquaculture products to consumers' diets is significant. External feeding in aquaculture unlocks the possibility of tailoring fish products with health beneficial compounds. A study was undertaken to evaluate the feed fortification with an iodine-rich macroalgae (Laminaria digitata) and selenised yeast, at its maximum permitted levels, on minerals and vitamins content in rainbow trout edible part. Dietary supplementation resulted in a six-fold increase for iodine and a 2.9-fold increase for selenium contents in trout fillets without altering sensorial traits. The fortified fish presented a nutritional contribution of 12.5% DRI for iodine and 78% DRI for selenium, but all produced fish could supply 80% DRI for vitamin D3. Overall, fish from this trial could be labelled as "high in selenium and high in vitamin D3" under the EFSA definition for a functional food. PMID- 28865622 TI - Microalgae and seaweeds for food applications: Challenges and perspectives. PMID- 28865623 TI - Assessment of the functional properties of protein extracted from the brown seaweed Himanthalia elongata (Linnaeus) S. F. Gray. AB - A protein extract from the brown seaweed Himanthalia elongata (Linnaeus) S. F. Gray was prepared and its functional properties, colour and amino acid composition were assessed for its potential future use by the food industry. The total content of amino acids was determined as 54.02+/-0.46gaminoacids/kg dry weight, with high levels of the essential amino acids lysine and methionine. SDS PAGE showed 5 protein bands with molecular weights of 71.6, 53.7, 43.3, 36.4 and 27.1kDa. The water holding capacity and oil holding capacity were determined as 10.27+/-0.09gH2O/g and 8.1+/-0.07goil/g respectively. Foaming activity and stability were higher at alkaline pH values. The emulsifying capacity and stability of the extract varied depending on the pH and oil used. These results demonstrate the potential use of Himanthalia elongata protein extract in the food industry. PMID- 28865624 TI - Phenolic compounds from three brown seaweed species using LC-DAD-ESI-MS/MS. AB - The phenolic compounds of extracts from Ascophyllum nodosum (ANE), Bifurcaria bifurcata (BBE) and Fucus vesiculosus (FVE) from Galicia (NW Spain) were analyzed by liquid chromatography-diode array detection coupled to negative electrospray ionization-tandem mass spectrometry (LC-DAD-ESI-MS/MS) with the interest to evaluate their potential application as functional ingredients. Phlorotannins were tentatively identified as the main phenolic compounds in the three extracts, followed by phenolic acids, and flavonoids. Fuhalols were present in ANE and BBE, while hydroxyfuhalols were identified in BBE and FVE. Eckol derivatives were present in the three extracts. Quinic acid derivatives were tentatively identified in the three seaweed species; in addition, ANE showed specifically hydroxybenzoic and rosmarinic acid derivatives, BBE showed rosmarinic acid, and FVE contained p-coumaric and ferulic acid derivatives. Regarding flavonoids, acacetin derivatives were tentatively identified in the three extracts, hispidulin and a gallocatechin derivative were specifically detected in ANE, and cypellocarpin C was present in BBE. In conclusion, all brown seaweed extracts studied could be exploited as sources of antioxidant phenolic compounds with potential applications in the food and health sectors. PMID- 28865625 TI - Proximate composition, phenolic content and in vitro antioxidant activity of aqueous extracts of the seaweeds Ascophyllum nodosum, Bifurcaria bifurcata and Fucus vesiculosus. Effect of addition of the extracts on the oxidative stability of canola oil under accelerated storage conditions. AB - Extracts from three macroalgae species (Ascophyllum nodosum (ANE), Bifurcaria bifurcata (BBE) and Fucus vesiculosus (FVE)) were tested for proximate composition (total solid, protein and total carbohydrate contents), total phenols content (TPC), and for their antioxidant activities in vitro in comparison to that of BHT compound by using four different assays (ABTS radical cation decolouration, DPPH free radical scavenging activity, ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC)). The inclusion of the extracts as oil stabilizers in canola oil in substitution of the synthetic antioxidant (BHT) was also evaluated by assessing lipid oxidation parameters (peroxide value (PV), p-anisidine value (AV), TBARS value, conjugated dienes (CD) and TOTOX index) under accelerated storage conditions (16days, 60 degrees C). There was an inverse relationship between total solid content and total polyphenols content in the seaweed extracts. FVE showed an intermediate TPC (1.15g PGE/100g extract), but it presented the highest in vitro antioxidant activity when measured using the ABTS, DPPH and FRAP tests. BBE, that displayed the highest TPC (1.99g PGE/100g extract), only showed the highest in vitro antioxidant activity when measured using the ORAC test. ANE showed the lowest TPC and the lowest antioxidant activity in all the tests performed. The seaweed extracts added in a 500ppm concentration significantly reduced the oxidation during canola oil storage at 60 degrees C, being this antioxidant effect significantly higher than that of BHT added at 50ppm. Results indicate that seaweed extracts can effectively inhibit the oxidation of canola oil and they can be a healthier alternative to the synthetic antioxidants in the oil industry. PMID- 28865627 TI - Embrace Action: Protect Your Colleagues and Family Members by Preparing for Emergencies. PMID- 28865626 TI - Characterization of dietary fucoxanthin from Himanthalia elongata brown seaweed. AB - This study explored Himanthalia elongata brown seaweed as a potential source of dietary fucoxanthin which is a promising medicinal and nutritional ingredient. The seaweed was extracted with low polarity solvents (n-hexane, diethyl ether, and chloroform) and the crude extract was purified with preparative thin layer chromatography (P-TLC). Identification, quantification and structure elucidation of purified compounds was performed by LC-DAD-ESI-MS and NMR (1H and 13C). P-TLC led purification yielded 18.6mg/g fucoxanthin with 97% of purity based on the calibration curve, in single-step purification. LC-ESI-MS (parent ion at m/z 641 [M+H-H2O]+) and NMR spectra confirmed that the purified band contained all-trans fucoxanthin as the major compound. Purified fucoxanthin exhibited statistically similar (p>0.05) DPPH scavenging capacity (EC50: 12.9MUg/mL) while the FRAP value (15.2MUg trolox equivalent) was recorded lower (p<0.05) than the commercial fucoxanthin. The promising results of fucoxanthin purity, recovery and activity suggested that H. elongata seaweed has potential to be exploited as an alternate source for commercial fucoxanthin production. PMID- 28865628 TI - Friendly Hostiles: An Important Link to Successful Publishing. PMID- 28865629 TI - The Effect of Offloading Heels on Sacral Pressure. AB - Offloading a patient's heels during supine surgical procedures is a common practice to prevent heel pressure injuries. This practice may increase sacral pressure and jeopardize sacral skin integrity, but prophylactic dressings may help protect sacral skin. The purpose of this study was to examine the effects of offloading the heels and of multilayered silicone foam dressings on sacral pressure. We measured the sacral pressure of 50 healthy volunteers using a pressure-mapping system under four conditions: heels not offloaded and sacral dressing applied, heels offloaded and dressing applied, heels not offloaded and no dressing, and heels offloaded and no dressing. We used linear mixed-effects modeling to compare the effects of these conditions on sacral pressure. Offloading the heels significantly increased sacral pressure (P < .001), whereas the dressing had no effect on sacral pressure (P = .49). Offloading a patient's heels may increase the risk of sacral pressure injuries. PMID- 28865630 TI - Professional and Regulatory Infection Control Guidelines: Collaboration to Promote Patient Safety. AB - Professional organizations and regulatory agencies collaborate on infection prevention and control guidelines to support preventing and controlling infection in the surgical setting. More specifically, regulatory and accrediting agencies, professional associations, and advisory committees create and promote the use of evidence-based recommendations for preventing surgical site infections. Many agencies perform accreditation surveys to ensure compliance with these standards and guidelines. Perioperative personnel can use these resources to implement and sustain essential processes for infection prevention and control and to facilitate staff member compliance with standards, regulations, and best practices. To guide perioperative practice, it is important for nurses to understand the role of these agencies and organizations and the resources each offers to help ensure the best patient outcomes. PMID- 28865631 TI - An Integrative Review of the Hands-Free Technique in the OR. AB - Sharps injury rates are proportionally higher in perioperative areas than in other practice settings. The hands-free technique (HFT) has been shown to decrease the hazards of sharps injuries when passing sharps during surgery. We reviewed and synthesized research studies regarding compliance with the HFT and factors facilitating its use using a key word search of online databases and a secondary search of references. We reviewed English language studies published since 2001 regarding HFT compliance rates or related factors using the Johns Hopkins Nursing Evidence-Based Practice Model and Guidelines. We found 14 articles reporting a wide range of HFT compliance rates (ie, 5% to 84%), which identified that a number of organizational factors and health care workers' perceptions of infection risks influenced the use of the HFT. PMID- 28865632 TI - Back to Basics: Pneumatic Tourniquet Use. AB - Pneumatic tourniquets are commonly used in surgeries involving the limbs to achieve a nearly bloodless surgery and an optimal operating field or when administering regional anesthesia during surgery on a limb. Complications can arise from the use of tourniquets, including nerve injuries, pain, compartment syndrome, pressure injuries, chemical burns, and tissue necrosis. More serious injuries-including deep vein thrombosis, thermal damage to tissues, severe ischemic injuries, and rhabdomyolysis-also can occur. Therefore, it is important for perioperative team members to understand how to use pneumatic tourniquets effectively and safely to provide the best possible care to patients. This article addresses the safety risks to patients when using pneumatic tourniquets and optimal safe use of these devices. PMID- 28865633 TI - Guideline Implementation: Positioning the Patient. AB - Every surgical procedure requires positioning the patient; however, all surgical positions are associated with the potential for the patient to experience a positioning injury. The locations and types of potential injuries (eg, stretching, compression, pressure injury) depend on the position. Factors that may increase the patient's risk for an injury are the length of the procedure and risk factors inherent to the patient (eg, weight, age, frailty). AORN's updated "Guideline for positioning the patient" provides guidance on injury prevention practices for all surgical positions including supine, Trendelenburg, reverse Trendelenburg, lateral, lithotomy, prone, and sitting positions and modifications of these positions. This article focuses on the key points of the guideline covering the use of prophylactic dressings, neurophysiological monitoring, and safely positioning the patient in the supine and prone positions. Perioperative RNs should review the complete guideline for additional information and for guidance when writing and updating policies and procedures. PMID- 28865634 TI - Guideline Summary: Positioning the Patient. PMID- 28865635 TI - Improving Efficiency and Patient Experiences: The Perioperative Surgical Home Model. PMID- 28865637 TI - Evidence appraisal of Ravikumar V, Ho AL, Pendhakar AV, Sussman ES, Chow KK, Li G. The use of vancomycin powder for surgical prophylaxis following craniotomy.: Neurosurgery. 2017;80(5):754-758. PMID- 28865636 TI - Clinical Issues-September 2017. AB - Performing Staphylococcus aureus decolonization for urgent procedures Key words: decolonization, Staphylococcus aureus, MRSA, MSSA, mupirocin. Hand hygiene before donning gloves Key words: hand hygiene, glove, personal protective equipment. Hand hygiene before skin prep Key words: hand hygiene, skin prep, sterile task, aseptic task. Scrubbing by stroke versus timed method Key words: surgical hand rub, surgical scrub, stroke method, timed method. PMID- 28865638 TI - Guideline at a Glance: Information Management. PMID- 28865639 TI - Picking up the Cause of the Stroke. PMID- 28865640 TI - Child Well-being and Adverse Childhood Experiences in the United States. PMID- 28865641 TI - Adverse Childhood Experiences and Resilience: Addressing the Unique Needs of Adolescents. AB - Adolescents exposed to adverse childhood experiences (ACEs) have unique developmental needs that must be addressed by the health, education, and social welfare systems that serve them. Nationwide, over half of adolescents have reportedly been exposed to ACEs. This exposure can have detrimental effects, including increased risk for learning and behavioral issues and suicidal ideation. In response, clinical and community systems need to carefully plan and coordinate services to support adolescents who have been exposed to ACEs, with a particular focus on special populations. We discuss how adolescents' needs can be met, including considering confidentiality concerns and emerging independence; tailoring and testing screening tools for specific use with adolescents; identifying effective multipronged and cross-system trauma-informed interventions; and advocating for improved policies. PMID- 28865642 TI - Adapting the Patient-Centered Medical Home to Address Psychosocial Adversity: Results of a Qualitative Study. AB - OBJECTIVE: The patient-centered medical home (PCMH) seeks to improve population health. However, PCMH models often focus on improving treatment of chronic diseases rather than on addressing psychosocial adversity. We sought to gather key stakeholder input about how PCMHs might feasibly and sustainably address psychosocial adversity within their patient populations. METHODS: We conducted 25 semistructured interviews with key stakeholders, such as physicians, nurses, medical assistants, and patients. The audiorecorded interviews focused on participants' perceptions of the best ways to modify the PCMH to address patients' psychosocial adversity. To facilitate information gathering, a fictional patient case was presented. Analyses were conducted using a 3-stage content-analysis process. RESULTS: Participants identified provider-related and systems-level changes necessary for addressing these psychosocial adversities effectively. On the provider level, participants thought that practitioners should foster trusting relationships with patients and should be emotionally present as patients describe their life experiences. Participants also emphasized that providers need to have sensitive conversations about adversity and resilience. On a systems level, participants discussed that documentation must balance privacy and include relevant information in the medical record. In addition, care should be delivered not by a single provider but by a team that has a longitudinal relationship with the patient; this care team should include behavioral health support. CONCLUSIONS: Participants provided practical strategies and highlighted provider and systems level changes to adequately address patients' prior psychosocial adversity. Future studies need to assess the degree to which such a trauma-informed approach improves patient access, outcomes, and care quality, and reduces cost. PMID- 28865643 TI - Reclaiming the Patient Encounter. PMID- 28865644 TI - ACE, Place, Race, and Poverty: Building Hope for Children. AB - Adverse childhood experiences research has focused attention on the importance of family safety, stability, and nurturing in ensuring healthy development. This safety, stability, and nurturing can be compromised by family poverty, discrimination and marginalization, and geographic location. Drawing upon census data, this report shows that place, race, and poverty are intertwined concepts with particular implications for young children. Examining census tracts according to their levels of poverty shows that the poorest census tracts also: 1) are the "richest" in the proportion of young children, 2) have the least realized social, physical, and educational, as well as economic capital, and 3) are highly racially segregated and separated from many sources of economic opportunity. The implications are that the country's poorest neighborhoods require substantially more supports for young children but currently have many fewer. This includes individual services to young children and their families but also publicly available services and voluntary supports, such as parks, playgrounds, and libraries. These data suggest that improving child health trajectories and reducing health disparities according to race and socioeconomic status therefore will require concerted individual service as well as community building efforts directed to poor and usually racially segregated neighborhoods and communities. PMID- 28865645 TI - Developing a Community-Wide Initiative to Address Childhood Adversity and Toxic Stress: A Case Study of The Philadelphia ACE Task Force. AB - The Philadelphia ACE Task Force is a community based collaborative of health care providers, researchers, community-based organizations, funders, and public sector representatives. The mission of the task force is to provide a venue to address childhood adversity and its consequences in the Philadelphia metropolitan region. In this article we describe the origins and metamorphosis of the Philadelphia ACE Task Force, which initially was narrowly focused on screening for adverse childhood experiences (ACEs) in health care settings but expanded its focus to better represent a true community-based approach to sharing experiences with addressing childhood adversity in multiple sectors of the city and region. The task force has been successful in developing a research agenda and conducting research on ACEs in the urban context, and has identified foci of local activity in the areas of professional training and workforce development, community education, and local practical interventions around adversity, trauma, and resiliency. In this article we also address the lessons learned over the first 5 years of the task force's existence and offers recommendations for future efforts to build a local community-based ACEs collaborative. PMID- 28865646 TI - Addressing Adverse Childhood Experiences Through the Affordable Care Act: Promising Advances and Missed Opportunities. AB - Adverse childhood experiences (ACEs) occur when children are exposed to trauma and/or toxic stress and may have a lifelong effect. Studies have shown that ACEs are linked with poor adult health outcomes and could eventually raise already high health care costs. National policy interest in ACEs has recently increased, as many key players are engaged in community-, state-, and hospital-based efforts to reduce factors that contribute to childhood trauma and/or toxic stress in children. The Affordable Care Act (ACA) has provided a promising foundation for advancing the prevention, diagnosis, and management of ACEs and their consequences. Although the ACA's future is unclear and it does not adequately address the needs of the pediatric population, many of the changes it spurred will continue regardless of legislative action (or inaction), and it therefore remains an important component of our health care system and national strategy to reduce ACEs. We review ways in which some of the current health care policy initiatives launched as part of the implementation of the ACA could accelerate progress in addressing ACEs by fully engaging and aligning various health care stakeholders while recognizing limitations in the law that may cause challenges in our attempts to improve child health and well-being. Specifically, we discuss coverage expansion, investments in the health workforce, a family-centered care approach, increased access to care, emphasis on preventive services, new population models, and improved provider payment models. PMID- 28865647 TI - Prevent, Screen, Heal: Collective Action to Fight the Toxic Effects of Early Life Adversity. PMID- 28865648 TI - Financing Mechanisms for Reducing Adversity and Enhancing Resilience Through Implementation of Primary Prevention. AB - The experience of adversity and toxic stress in childhood is associated with the development of chronic health and behavioral health problems. These problems contribute substantially to health care expenditures and the overall burden of disease. Although a strong scientific literature documents the effectiveness of primary prevention in reducing childhood adversity, promoting well-being and lessening the incidence of negative outcomes, funding for these interventions is highly fragmented across multiple government agencies as well as private and philanthropic sectors. It is becoming increasingly clear that improving population health will require a concentrated public health effort to improve access to and the accountability of these interventions as well as the development of novel financing schemes. In this perspective we review existing financing mechanisms for funding interventions known to reduce adverse childhood experiences and discuss innovative financing approaches that use insurance as well as pay-for-success funding mechanisms. The latter require that cost savings associated with primary prevention be quantified and that these savings be used to offset program costs, sometimes with a return on investment for private investors. We provide a series of recommendations regarding better coordination and strategic oversight of existing resources as well as the need to further develop and validate methodologies for estimating the societal costs and benefits associated with the varying social policies that are designed to ameliorate the effects of adversity and to build resilience. PMID- 28865649 TI - Evolving a More Nurturing Society to Prevent Adverse Childhood Experiences. AB - This article presents a framework for evolving a society that nurtures the health and well-being of its population. We review evidence that adverse social conditions, including poverty, conflict, discrimination, and other forms of social rejection, contribute immensely to our most ubiquitous psychological, behavioral, and health problems. We then enumerate the ways that effective family and school prevention programs could ameliorate much of the social adversity leading to these problems. The widespread and effective implementation of these programs-in primary care, social services, and education-must be a high priority. Beyond the implementation of specific programs, however, we must also make a more concerted effort to promote prosocial values that support nurturing families and schools. Our society's priorities must be to generate specific policies that reduce poverty and discrimination and, in so doing, reduce the risk for negative health-related outcomes. PMID- 28865650 TI - ACEs Implications for Nurses, Nursing Education, and Nursing Practice. PMID- 28865651 TI - Lessons From ACEs: Pay Now or Pay (More) Later. PMID- 28865652 TI - "Nothing About Us Without Us". PMID- 28865653 TI - Culture Matters: Direct Service Programs Cannot Solve Widespread, Complex, Intergenerational Social Problems. Culture Change Can. PMID- 28865654 TI - Translating Brain Science Research into Community-Level Change. PMID- 28865655 TI - How Social Journalism Accelerates the ACEs Movement. PMID- 28865656 TI - Mitigating Adverse Childhood Experiences Through Investments in Early Childhood Programs. PMID- 28865657 TI - ACEs and State Maternal Child Health Programs. PMID- 28865658 TI - ACEs in the Criminal Justice System. PMID- 28865659 TI - Prioritizing Possibilities for Child and Family Health: An Agenda to Address Adverse Childhood Experiences and Foster the Social and Emotional Roots of Well being in Pediatrics. AB - OBJECTIVE: A convergence of theoretical and empirical evidence across many scientific disciplines reveals unprecedented possibilities to advance much needed improvements in child and family well-being by addressing adverse childhood experiences (ACEs), promoting resilience, and fostering nurturance and the social and emotional roots of healthy child development and lifelong health. In this article we synthesize recommendations from a structured, multiyear field-building and research, policy, and practice agenda setting process to address these issues in children's health services. METHODS: Between Spring of 2013 and Winter of 2017, the field-building and agenda-setting process directly engaged more than 500 individuals and comprised 79 distinct agenda-setting and field-building activities and processes, including: 4 in-person meetings; 4 online crowdsourcing rounds across 10 stakeholder groups; literature and environmental scans, publications documenting ACEs, resilience, and protective factors among US children, and commissioning of this special issue of Academic Pediatrics; 8 in person listening forums and 31 educational sessions with stakeholders; and a range of action research efforts with emerging community efforts. Modified Delphi processes and grounded theory methods were used and iterative and structured synthesis of input was conducted to discern themes, priorities, and recommendations. RESULTS: Participants discerned that sufficient scientific findings support the formation of an applied child health services research and policy agenda. Four overarching priorities for the agenda emerged: 1) translate the science of ACEs, resilience, and nurturing relationships into children's health services; 2) cultivate the conditions for cross-sector collaboration to incentivize action and address structural inequalities; 3) restore and reward for promoting safe and nurturing relationships and full engagement of individuals, families, and communities to heal trauma, promote resilience, and prevent ACEs; and 4) fuel "launch and learn" research, innovation, and implementation efforts. Four research areas arose as central to advancing these priorities in the short term. These are related to: 1) family-centered clinical protocols, 2) assessing effects on outcomes and costs, 3) capacity-building and accountability, and 4) role of provider self-care to quality of care. Finally, we identified 16 short term actions to leverage existing policies, practices, and structures to advance agenda priorities and research priorities. CONCLUSIONS: Efforts to address the high prevalence and negative effects of ACEs on child health are needed, including widespread and concrete understanding and strategies to promote awareness, resilience, and safe, stable, nurturing relationships as foundational to healthy child development and sustainable well-being throughout life. A paradigm-shifting evolution in individual, organizational, and collective mindsets, policies, and practices is required. Shifts will emphasize the centrality of relationships and regulation of emotion and stress to brain development as well as overall health. They will elevate relationship-centered methods to engage individuals, families, and communities in self-care related to ACEs, stress, trauma, and building the resilience and nurturing relationships science has revealed to be at the root of well-being. Findings reflect a palpable hope for prevention, mitigation, and healing of individual, intergenerational, and community trauma associated with ACEs and provide a road map for doing so. PMID- 28865660 TI - Promoting Lifelong Health and Well-being: Staying the Course to Promote Health and Prevent the Effects of Adverse Childhood and Community Experiences. PMID- 28865662 TI - Aligning Community Capacity, Networks, and Solutions to Address Adverse Childhood Experiences and Increase Resilience. PMID- 28865661 TI - Methods to Assess Adverse Childhood Experiences of Children and Families: Toward Approaches to Promote Child Well-being in Policy and Practice. AB - BACKGROUND: Advances in human development sciences point to tremendous possibilities to promote healthy child development and well-being across life by proactively supporting safe, stable and nurturing family relationships (SSNRs), teaching resilience, and intervening early to promote healing the trauma and stress associated with disruptions in SSNRs. Assessing potential disruptions in SSNRs, such as adverse childhood experiences (ACEs), can contribute to assessing risk for trauma and chronic and toxic stress. Asking about ACEs can help with efforts to prevent and attenuate negative impacts on child development and both child and family well-being. Many methods to assess ACEs exist but have not been compared. The National Survey of Children's Health (NSCH) now measures ACEs for children, but requires further assessment and validation. METHODS: We identified and compared methods to assess ACEs among children and families, evaluated the acceptability and validity of the new NSCH-ACEs measure, and identified implications for assessing ACEs in research and practice. RESULTS: Of 14 ACEs assessment methods identified, 5 have been used in clinical settings (vs public health assessment or research) and all but 1 require self or parent report (3 allow child report). Across methods, 6 to 20 constructs are assessed, 4 of which are common to all: parental incarceration, domestic violence, household mental illness/suicide, household alcohol or substance abuse. Common additional content includes assessing exposure to neighborhood violence, bullying, discrimination, or parental death. All methods use a numeric, cumulative risk scoring methodology. The NSCH-ACEs measure was acceptable to respondents as evidenced by few missing values and no reduction in response rate attributable to asking about children's ACEs. The 9 ACEs assessed in the NSCH co-occur, with most children with 1 ACE having additional ACEs. This measure showed efficiency and confirmatory factor analysis as well as latent class analysis supported a cumulative risk scoring method. Formative as well as reflective measurement models further support cumulative risk scoring and provide evidence of predictive validity of the NSCH-ACEs. Common effects of ACEs across household income groups confirm information distinct from economic status is provided and suggest use of population-wide versus high-risk approaches to assessing ACEs. CONCLUSIONS: Although important variations exist, available ACEs measurement methods are similar and show consistent associations with poorer health outcomes in absence of protective factors and resilience. All methods reviewed appear to coincide with broader goals to facilitate health education, promote health and, where needed, to mitigate the trauma, chronic stress, and behavioral and emotional sequelae that can arise with exposure to ACEs. Assessing ACEs appears acceptable to individuals and families when conducted in population-based and clinical research contexts. Although research to date and neurobiological findings compel early identification and health education about ACEs in clinical settings, further research to guide use in pediatric practice is required, especially as it relates to distinguishing ACEs assessment from identifying current family psychosocial risks and child abuse. The reflective as well as formative psychometric analyses conducted in this study confirm use of cumulative risk scoring for the NSCH-ACEs measure. Even if children have not been exposed to ACEs, assessing ACEs has value as an educational tool for engaging and educating families and children about the importance of SSNRs and how to recognize and manage stress and learn resilience. PMID- 28865663 TI - Income Inequality and the Differential Effect of Adverse Childhood Experiences in US Children. AB - OBJECTIVE: Adverse childhood experiences (ACEs) can affect health and development across the life course. Despite a general understanding that adversity is associated with lower income, we know less about how ACEs manifest at different income levels and how these income-related patterns affect children's health and development. METHODS: Data from the 2011 to 2012 National Survey of Children's Health were used to examine the prevalence of 9 ACEs in US children, across 4 levels of household income, and in relationship to 5 parent-reported measures of child health. Bivariate analyses and multivariable logistic regression models were used to examine the associations between number of ACEs and children's health outcomes on the basis of the 4 income groups. RESULTS: When partitioned according to income strata, the proportion of children who experienced ACEs showed a steep income gradient, particularly for children who experienced >=4 ACEs. The linear gradient across income groups was less pronounced for each specific ACE, with several ACEs (experience of divorce, drug and alcohol exposure, parental mental illness) showing high reported prevalence in all but the highest income group. Multivariate analysis showed a consistent income related gradient for each of the health outcomes. However, higher income was not necessarily found to be a protective factor against ACEs. CONCLUSIONS: ACEs are distributed across the income ladder and not just concentrated below the poverty level. This suggests that a more comprehensive policy strategy that includes targeted as well as universal interventions is warranted. PMID- 28865664 TI - Responding to ACEs With HOPE: Health Outcomes From Positive Experiences. AB - This article introduces a framework called "HOPE: Health Outcomes From Positive Experiences." The HOPE framework focuses on the need to actively promote positive childhood experiences that contribute to healthy development and well-being, as well as prevent or mitigate the effect of adverse childhood experiences and other negative environmental influences. Key positive childhood experiences fall within 4 broad categories: being in nurturing, supportive relationships; living, developing, playing, and learning in safe, stable, protective, and equitable environments; having opportunities for constructive social engagement and connectedness; and learning social and emotional competencies. The HOPE framework grows out of and complements prior holistic approaches to child health care. PMID- 28865665 TI - A New Framework for Addressing Adverse Childhood and Community Experiences: The Building Community Resilience Model. AB - OBJECTIVE: We propose a transformative approach to foster collaboration across child health, public health, and community-based agencies to address the root causes of toxic stress and childhood adversity and to build community resilience. METHODS: Physicians, members of social service agencies, and experts in toxic stress and adverse childhood experiences (ACEs) were interviewed to inform development of the Building Community Resilience (BCR) model. Through a series of key informant interviews and focus groups, we sought to understand the role of BCR for child health systems and their partners to reduce toxic stress and build community resilience to improve child health outcomes. RESULTS: Key informants indicated the intentional approach to ACEs and toxic stress through continuous quality improvement (data-driven decisions and program development, partners testing and adapting to changes to their needs, and iterative development and testing) which provides a mechanism by which social determinants or a population health approach could be introduced to physicians and community partners as part of a larger effort to build community resilience. Structured interviews also reveal a need for a framework that provides guidance, structure, and support for child health systems and community partners to develop collective goals, shared work plans, and a means for data-sharing to reinforce the components that will contribute to community resilience. CONCLUSIONS: Key informant interviews and focus group dialogues revealed a deep understanding of the factors related to toxic stress and ACEs. Respondents endorsed the BCR approach as a means to explore capacity issues, reduce fragmented health care delivery, and facilitate integrated systems across partners in efforts to build community resilience. Current financing models are seen as a potential barrier, because they often do not support restructured roles, partnership development, and the work to sustain upstream efforts to address toxic stress and community resilience. PMID- 28865666 TI - The Community and Public Well-being Model: A New Framework and Graduate Curriculum for Addressing Adverse Childhood Experiences. PMID- 28865667 TI - Quality of life, functional status and adhesiolysis during elective abdominal surgery. AB - BACKGROUND: Adhesiolysis during abdominal surgery can cause iatrogenic organ injury, increased operative time and a more complicated convalescence. We assessed the impact of adhesiolysis and adhesiolysis-related complications on quality of life and functional status following elective abdominal surgery. METHODS: Prospective cohort study, comparing patients requiring and not requiring adhesiolysis during an elective laparotomy or laparoscopy using the SF-36 and DASI questionnaire scores. RESULTS: 518 patients were included. Pre- and postoperative quality of life did not significantly differ between both groups. Patients with adhesiolysis had a significantly lower pre- and postoperative functional status (p < 0.01). Higher age, concomitant pulmonary disease, postoperative complications, readmissions and chronic abdominal pain 6 months after surgery were all associated with a significant and independent decline in quality of life and functional status six months after surgery. CONCLUSION: Adhesiolysis in itself does not affect functional status and quality of life six months after surgery. Postoperative complications, readmissions and chronic abdominal pain are associated with a lower health status. PMID- 28865668 TI - Management of colonoscopic perforations: A systematic review. AB - BACKGROUND: Perforation during colonoscopy is a rare but well recognized complication with significant morbidity and mortality. We aim to systematically review the currently available literature concerning care and outcomes of colonic perforation. An algorithm is created to guide the practitioner in management of this challenging clinical scenario. DATA SOURCES: A systematic review of the literature based on PRISMA-P guidelines was performed. We evaluate 31 articles focusing on findings over the past 10 years. CONCLUSION: Colonoscopic perforation is a rare event and published management techniques are marked by their heterogeneity. Reliable conclusions are limited by the nature of the data available - mainly single institution, retrospective studies. Consensus conclusions include a higher rate of perforation from therapeutic colonoscopy when compared to diagnostic colonoscopy and the sigmoid as the most common site of perforation. Mortality appears driven by pre-existing conditions. Treatment must be tailored according to the patient's comorbidities and clinical status as well as the specific conditions during the colonoscopy that led to the perforation. PMID- 28865669 TI - Reply for comment on "Bioflocculation management through high-rate contact stabilization: A promising technology to recover organic carbon from low-strength wastewater by Rahman, A., Meerburg, F. A., Ravadagundhi, S., Wett, B., Jimenez, J., Bott, C., Al-Omari, A., Riffat, R., Murthy, S. and De Clippeleir, H. [Water Research 104 (2016) 485-496]". PMID- 28865670 TI - Estimation of optimal donor number in Bone Marrow Donor Registry: Hong Kong's experience. AB - Better outcome for hematopoietic stem cell transplantation (HSCT) requires optimal matching between donor and recipient at the HLA-A, -B, -C, and -DRB1 loci. This study estimates the likelihood of identifying HLA matched donors in Hong Kong. 7595 volunteer unrelated Chinese donors at the Hong Kong Bone Marrow Donor Registry were typed with HLA-A, -B, -C and -DRB1 genotypes. The matching probabilities for 8/8 and 7/8 HLA match via the matching models were determined. Based on current 100,000 donors in the HKBMDR, the matching probabilities are 45% at 8/8 HLA match and 65% at 7/8 match. By increasing the registry to 200,000, the likelihoods of match become 54% and 73% at 8/8 and 7/8 match stringencies respectively. Our findings may be helpful in planning future donor recruitment and HLA typing. A cost-effective Bone Marrow Donor Registry with a larger pool of donors could increase chance of matching and the success of HSCT. PMID- 28865672 TI - Coming of Age. PMID- 28865671 TI - Imaging of Ankle Impingement Syndromes. AB - Ankle impingement syndromes are a commonly encountered clinical entity seen in athletes, secondary to repetitive forceful microtrauma. Symptoms are related to impingement of osseous or soft tissue abnormalities in the ankle joint, in particular the tibiotalar joint, which may result in painful limitation of ankle movements. Imaging modalities, such as radiographs and magnetic resonance imaging, are very useful in diagnosing osseous and soft tissue abnormalities seen in different types of ankle impingement syndromes. This article reviews the classification of ankle impingement syndromes, their etiology, and clinical and radiological findings. PMID- 28865673 TI - Locked to a wrong body: Eating disorders as the outcome of a primary disturbance in multisensory body integration. AB - In his recent paper "Distorted body representations in anorexia nervosa" Gadsby (2017) discussed empirical evidence regarding anorexic patients' distorted body representations. In particular, he interpreted them using the O'Shaughnessy's long-term body image (LTB) hypothesis (O'Shaughnessy, 1998): individuals with anorexia nervosa (AN) have a distorted LTB that tracks changes in the spatial content of the body and supplies this distorted content to other body representations. Even if we agree on the involvement of body memory in the distorted body representation, an open issue not fully addressed in the paper is: why AN patients do not update their LTBs to reflect their true dimensions? Our correspondence tries to answer to this question using a new neuropsychological and neurobiological theory: the Allocentric Lock Theory - ALT. PMID- 28865674 TI - Tumor Regression Grade After Neoadjuvant Chemoradiation and Surgery for Low Rectal Cancer Evaluated by Multiple Correspondence Analysis: Ten Years as Minimum Follow-up. AB - BACKGROUND: The role of Mandard's tumor regression grade (TRG) classification is still controversial in defining the prognostic role of patients who have undergone neoadjuvant chemoradiation (CRT) and total mesorectal excision. The present study evaluated multiple correspondence analysis (MCA) as a tool to better cluster variables, including TRG, for a homogeneous prognosis. PATIENTS AND METHODS: A total of 174 patients with a minimum follow-up period of 10 years were stratified into 2 groups: group A (TRG 1-3) and group B (TRG 4-5) using Mandard's classification. Overall survival and disease-free survival were analyzed using univariate and multivariate analysis. Subsequently, MCA was used to analyze TRG plus the other prognostic variables. RESULTS: The overall response to CRT was 55.7%, including 13.2% with a pathologic complete response. TRG group A correlated strictly with pN status (P = .0001) and had better overall and disease-free survival than group B (85.1% and 75.6% vs. 71.1% and 67.3%; P = .06 and P = .04, respectively). The TRG 3 subset (about one third of our series) showed prognostically heterogeneous behavior. In addition to multivariate analysis, MCA separated TRG 1 and TRG 2 versus TRG 4 and TRG 5 well and also allocated TRG 3 patients close to the unfavorable prognostic variables. CONCLUSION: TRG classification should be used in all pathologic reports after neoadjuvant CRT and radical surgery to enrich the prognostic profile of patients with an intermediate risk of relapse and to identify patients eligible for more conservative treatment. Thus, MCA could provide added value. PMID- 28865676 TI - Determining the outcomes of interventions to prevent respiratory syncytial virus disease in children: what to measure? AB - Respiratory syncytial virus (RSV) is the most common cause of viral acute lower respiratory tract illness (LRTI) in young children, and a major cause of hospital admissions and health-care utilisation globally. Substantial efforts have been made to develop RSV vaccines and vaccine-like monoclonal antibodies to prevent acute RSV LRTI. Prevention of acute disease could improve long-term lung health, with potential effects on wheezing, asthma, and chronic lung disease. This Personal View describes assessments that should be initiated during clinical trials and continued after licensure to fully evaluate the effect of RSV preventive interventions. These assessments include recording the incidence of RSV-specific LRTI and all-cause LRTI through two RSV seasons, and assessment of the prevalence and severity of recurrent wheezing or asthma in children aged up to 6 years. Standardised assessments in diverse settings are needed to fully determine the effect of interventions for the prevention of RSV disease. PMID- 28865675 TI - Plasma galectin-3 levels are associated with the risk of incident chronic kidney disease. AB - Galectin-3 has been proposed as a novel biomarker of heart failure and cardiac fibrosis, and may also be associated with fibrosis of other organs such as the kidney. To determine this, we prospectively analyzed data from 9,148 Atherosclerosis Risk in Communities (ARIC) Study participants with measured plasma galectin-3 levels (baseline, visit 4, 1996-98) and without prevalent chronic kidney disease (CKD) or heart failure. We identified 1,983 incident CKD cases through December 31, 2013 over a median follow-up of 16 years. At baseline, galectin-3 was cross-sectionally associated with estimated glomerular filtration rate and urine albumin-to-creatinine ratio; both significant. The results were adjusted for age, sex, race-center, education, physical activity, smoking status, body mass index, systolic blood pressure, anti-hypertensive medication use, history of cardiovascular disease, diabetes, fasting blood glucose, and rs4644 (a single nucleotide polymorphism of galactin-3). There was a significant, graded, and positive association between galectin-3 and incident CKD (quartile 4 vs. 1 hazard ratio: 2.22 [95% confidence interval: 1.89, 2.60]). The association was attenuated but remained significant after adjustment for estimated glomerular filtration rate, urine albumin-to-creatinine ratio, troponin T, and N-terminal pro-brain natriuretic peptide (quartile 4 vs. 1 hazard ratio: 1.75 [95% confidence interval: 1.49, 2.06]), and was stronger among those with hypertension at baseline (significant interaction). Thus, in this community-based population, higher plasma galectin-3 levels were associated with an elevated risk of developing incident CKD, particularly among those with hypertension. PMID- 28865677 TI - Berkeleyacetal C, a meroterpenoid isolated from the fungus Penicillium purpurogenum MHZ 111, exerts anti-inflammatory effects via inhibiting NF-kappaB, ERK1/2 and IRF3 signaling pathways. AB - Berkeleyacetal C (BAC), a meroterpenoid compound, was isolated from the fungus Penicillium purpurogenum MHZ 111 and showed favorable activity of inhibiting nitrogen oxide (NO) production of macrophages stimulated by lipopolysaccharide (LPS) in our preliminary screening. In order to develop novel therapeutic drug for acute and chronic inflammatory diseases, the anti-inflammatory activity and underlying mechanisms of BAC were investigated in macrophages and neutrophils. The results showed that BAC significantly inhibited the expression of inducible nitric oxide synthase (iNOS) and the following NO production by macrophages. The expression and secretion of key pro-inflammatory factors and chemokines, including tumor necrosis factor-alpha (TNF-alpha),interleukin-6 (IL-6), interleukin-1beta (IL-1beta), macrophage inflammatory protein-1alpha (MIP 1alpha), and monocyte chemotactic protein-1 (MCP-1) were also intensively suppressed by BAC. Furthermore, BAC also markedly inhibited activation of neutrophils and reactive oxygen species production. In mechanism study, BAC selectively suppressed phosphorylation of nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and interferon regulatory transcription factor 3 (IRF3) during the activation of NF-kappaB, mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 1 and 3 (STAT1/3), and IRF3 signaling pathways induced by LPS. In summary, BAC exerts strong anti-inflammatory effects by inhibiting NF-kappaB, ERK1/2 and IRF3 signaling pathways and thereby shows great potential to be developed into therapeutic agent for inflammatory disorders. PMID- 28865678 TI - Gabapentin and its salicylaldehyde derivative alleviate allodynia and hypoalgesia in a cisplatin-induced neuropathic pain model. AB - Cisplatin is an effective chemotherapeutic agent indicated in cancer chemotherapy. However, its clinical use is associated with peripheral neuropathy that invariably impairs patient quality of life. Gabapentin (GBP) is an effective analgesic for neuropathic pain conditions but its clinical efficacy in cisplatin induced neuropathic pain (CINP) is limited, in addition to generating unwanted side-effects. In this study, a gabapentin-salicylaldehyde derivative [gabapentsal (GPS)] was synthesized and evaluated to explore any potential benefit in comparison with GBP in a rat model of CIPN. Administration of cisplatin (3.0mg/kg/week, i.p.) for five consecutive weeks generated reproducible mechanical-allodynia (decreased paw withdrawal threshold to von Frey filament application; PWT, g) and thermal hypoalgesia (increased nociceptive reaction latency in the hot plate paradigm; s). Treatment with GBP or its derivative on the 37th day of the experimental protocol, dose dependently attenuated cisplatin induced nocifensive behaviors. Accordingly, doses of GBP (50-100mg/kg, i.p.) and GPS (25-100mg/kg, i.p.) suppressed the expression of CINP by normalizing the PWT and hot plate response latency 1h and 3h post administration. In the rotarod paradigm, GBP at all doses markedly impaired motor performance, whilst GPS was devoid of motor incoordination except at the highest dose, when a mild impairment occurred. Salicylaldehyde alone had no effect on CINP or rotarod performance and neither was there any synergism when coadministered with GBP. These findings suggest that both GBP and GPS have beneficial effects in the neuropathic pain model though GPS may be potentially more useful in the management of CINP. PMID- 28865680 TI - Year Two: The Effort Expands! PMID- 28865681 TI - Lifelong Learning through Research Techniques Made Simple. PMID- 28865679 TI - Quantification of myocardial perfusion reserve using dynamic SPECT images of patients with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disorders. The aim of this study was to examine whether the quantitatively measured myocardial blood flow (MBF) or myocardial perfusion reserve (MPR), calculated by dynamic single photon emission computed tomography (SPECT) analysis using a cardiac cadmium zinc telluride (CZT) gamma camera, was related to renal dysfunction in patients with normal myocardial perfusion imaging (MPI) findings. METHODS: The study population consisted of 46 patients with CKD and 46 individuals without CKD (controls). Their MPR index was quantitatively measured using adenosine MPI with a cardiac CZT gamma camera. All assessments were with a single tissue compartment kinetic model. The K1 value was calculated on stress and at-rest images. To obtain the MPR index we divided K1 stress-by K1 at-rest values. RESULTS: The at-rest K1 value was significantly higher and the MPR index was significantly lower in patients with CKD than those without CKD [CKD vs. CONTROLS: at-rest K1 value, 0.21 (0.17-0.25) vs. 0.19 (0.16-0.22), p=0.040; MPR index, 1.86 (1.69-2.22) vs. 2.19 (1.93-2.41), p<0.001]. The stress K1 values were not significantly different. CONCLUSION: The MPR index is significantly lower in CKD patients; this is considered as being mainly due to an increase in the at-rest K1 value. PMID- 28865682 TI - Purification of Trypanosoma cruzi metacyclic trypomastigotes by ion exchange chromatography in sepharose-DEAE, a novel methodology for host-pathogen interaction studies. AB - Metacyclic trypomastigotes are essential for the understanding of the biology of Trypanosoma cruzi, the agent of Chagas disease. However, obtaining these biological stages in axenic medium is difficult. Techniques based on charge and density of the parasite during different stages have been implemented, without showing a high efficiency in the purification of metacyclic trypomastigotes. So far, there is no protocol implemented where sepharose-DEAE is used as a resin. Therefore, herein we tested its ability to purify metacyclic trypomastigotes in Liver Infusion Triptose (LIT) medium cultures. A simple, easy-to-execute and effective protocol based on ion exchange chromatography on Sepharose-DEAE resin for the purification of T. cruzi trypomastigotes is described. T. cruzi strains from the Discrete Typing Units (DTUs) I and II were used. The strains were harvested in LIT medium at a concentration of 1*107epimastigotes/mL. We calculated the time of trypomastigotes increment (TTI). Based on the data obtained, Ion exchange chromatography was performed with DEAE-sepharose resin. To verify the purity and viability of the trypomastigotes, a culture was carried out in LIT medium with subsequent verification with giemsa staining. To evaluate if the technique affected the infectivity of trypomastigotes, in vitro assays were performed in Vero cells and in vivo in ICR-CD1 mice. The technique allowed the purification of metacyclic trypomastigotes of other stages of T. cruzi in a percentage of 100%, a greater recovery was observed in cultures of 12days. There were differences regarding the recovery of metacyclic trypomastigotes for both DTUs, being DTU TcI the one that recovered a greater amount of these forms. The technique did not affect parasite infectivity in vitro or/and in vivo. PMID- 28865683 TI - Evaluation of near-miss and adverse events in radiation oncology using a comprehensive causal factor taxonomy. AB - PURPOSE: Incident learning systems (ILSs) are a popular strategy for improving safety in radiation oncology (RO) clinics, but few reports focus on the causes of errors in RO. The goal of this study was to test a causal factor taxonomy developed in 2012 by the American Association of Physicists in Medicine and adopted for use in the RO: Incident Learning System (RO-ILS). METHODS AND MATERIALS: Three hundred event reports were randomly selected from an institutional ILS database and Safety in Radiation Oncology (SAFRON), an international ILS. The reports were split into 3 groups of 100 events each: low risk institutional, high-risk institutional, and SAFRON. Three raters retrospectively analyzed each event for contributing factors using the American Association of Physicists in Medicine taxonomy. RESULTS: No events were described by a single causal factor (median, 7). The causal factor taxonomy was found to be applicable for all events, but 4 causal factors were not described in the taxonomy: linear accelerator failure (n = 3), hardware/equipment failure (n = 2), failure to follow through with a quality improvement intervention (n = 1), and workflow documentation was misleading (n = 1). The most common causal factor categories contributing to events were similar in all event types. The most common specific causal factor to contribute to events was a "slip causing physical error." Poor human factors engineering was the only causal factor found to contribute more frequently to high-risk institutional versus low-risk institutional events. CONCLUSIONS: The taxonomy in the study was found to be applicable for all events and may be useful in root cause analyses and future studies. Communication and human behaviors were the most common errors affecting all types of events. Poor human factors engineering was found to specifically contribute to high-risk more than low-risk institutional events, and may represent a strategy for reducing errors in all types of events. PMID- 28865684 TI - Causal factors for error in radiation oncology. PMID- 28865685 TI - Association Between Compliance with Triage Directions from an Organized State Trauma System and Trauma Outcomes. AB - BACKGROUND: The Louisiana Emergency Response Network (LERN), a statewide trauma system, has a single communication center with real-time data on hospital capacity across the state. With these data, scene information, and a standardized triage protocol, prehospital providers are directed to the most appropriate hospital. The purpose of our study was to compare outcomes between those patients who complied with the LERN communication center direction and those who did not. STUDY DESIGN: Trauma patients directed by LERN from the field in 2014 were included. Patients who followed the LERN communication center direction were considered the compliant group. Patients brought to a hospital inconsistent with the LERN direction were considered the noncompliant group. Chi-square analysis was used to compare differences between groups and a p value of <0.05 was considered statistically significant. RESULTS: During the study period, LERN directed 14,071 patients to a destination hospital. Prehospital providers were compliant with the LERN direction in 13,037 (92.7%) patients and noncompliant in 1,034 (7.3%) patients. There were fewer patients in the compliant group (570 of 13,037 [4.3%]) requiring transfer to a second hospital than in the noncompliant group (312 of 1,034 [30.2%]) (p < 0.01). The mortality rate was lower in the compliant group (81 of 13,037 [0.6%]) than in the noncompliant group (21 of 1,034 [2.03%]) (p < 0.01). CONCLUSIONS: Following direction from a central communication center with real-time hospital capacity data yielded a 6-fold decrease in secondary transfer and a 3-fold decrease in mortality. These data emphasize the value of an organized statewide trauma network that routes patients to the appropriate facilities. PMID- 28865687 TI - Electrohydrodynamic methods for the development of pulmonary drug delivery systems. AB - Electrospinning and electrospraying are two highly versatile and scalable electrohydrodynamic methods, which have attracted considerable attention during the last years towards the fabrication of polymer-based drug delivery systems. The latter may be obtained in the form of nano- or microfibers (via electrospinning) or as drug-loaded nano- and microparticles (via electrospraying). This review article begins with an introduction on the basic principles and the important influencing parameters governing the electrospinning/electrospraying processes, followed by an overview on their use for the development of nano/microfibers and nano/microparticles destined for use in pharmaceutical applications. Focus is given on research efforts targeting in the formulation of drug delivery systems and devices designed for pulmonary drug delivery applications thus emphasizing on the potential use of electrospinning and electrospraying in the area of inhaled medicines. PMID- 28865686 TI - Use of the hyphenated LC-MS/MS technique and NMR/IR spectroscopy for the identification of exemestane stress degradation products during the drug development. AB - Exemestane (6-Methyleneandrosta-1,4-diene-3,17-dione) active pharmaceutical ingredient (EE-3) was subjected to thermal, photolytic, oxidative, acidic and base stress conditions prescribed by the ICH (International Conference on Harmonization) guideline Q1A(R2). EE-3 was found to degrade in base, acidic and oxidative conditions. Eleven new degradation products of EE-3 were characterized by the LC-MS/MS technique. One of these impurities was isolated and identified by the LC-MS/MS, NMR and IR techniques. The LC-MS/MS studies were carried out to establish fragmentation pathways of EE-3 and its new impurity. Based on the results obtained from different spectroscopic studies, this impurity was characterized as 3-hydroxy-1,6-dimethyl-oestratetraen-(1, 3, 5(10), 6)-17-one (EE 3Z). The degradation pathway of EE-3 leading to the generation of eleven products was proposed and this has not been reported so far. The separation of EE-3 from its impurities (process-related and degradants) was achieved using a Gemini C18 column (150mm*4.6mm*3MUm) with gradient elution. The degradation products were well resolved from the main peak and its impurities, thus proving the method's stability and indicating power of the method. The method was validated according to the ICH guidelines for parameters such as specificity, limit of detection, limit of quantitation, precision, linearity, accuracy, robustness and system suitability. PMID- 28865688 TI - ? PMID- 28865689 TI - ? PMID- 28865690 TI - [Cardiovascular disease in women in 2017]. AB - From an anatomical, physiological and clinical point of view, cardiovascular diseases in women are specific. Long considered as being less exposed to these risks, women are nevertheless victims of coronary disease, which remains, in developed countries, the leading cause of death in women. The situation is all the more concerning given that the number of young women presenting risk factors is constantly rising. Encouraging female patients to become players in their health care with regard to this pathology is especially important given that effective treatments exist which can improve the prognosis. PMID- 28865691 TI - [Emergency treatment of myocardial infarction in women]. AB - Acute myocardial infarction (MI) affects mainly men. In women, chest pain is less typical, delaying the diagnosis and increasing the time before treatment is delivered. Morbidity-mortality is greater notably due to a modification of the myocardial reperfusion strategy. The acute care of MI is almost identical for men and women. Knowing more about the epidemiology of women with MI enables prevention strategies to be targeted. PMID- 28865692 TI - [Raising women's awareness of cardiovascular risks]. AB - Professor Claire Mounier-Vehier, a cardiologist and vascular specialist at Lille university regional hospital, is a leading spokesperson for women in the field of the prevention of cardiovascular diseases. One of her many roles is head of the 'heart, arteries and women health care pathway' set up in 2013 at Lille university hospital. She discusses the importance of this specific and multidisciplinary care pathway at a time when epidemiological data show that the management of women's cardiovascular health has become a public health priority. PMID- 28865693 TI - [Therapeutic education program on stroke for prevention of the vascular risk in women]. AB - Stroke is a disease whose frequency is increasing especially in women and in the elderly, and that is associated with major functional impairment with adverse consequences in terms of quality of life. Implementation of a therapeutic education program is helpful for patients and their relatives so as to acquire skills to manage their own health, with the goal of reducing recurrences and improving personal experience of the disease. PMID- 28865694 TI - [Cardiorespiratory arrest at the age of 30]. AB - The cardiovascular risk of women is specific and polymorphous. Delays in treatment in women are evident and caused by multiple social and anthropological factors as well as changes to lifestyle habits which are becoming similar to those of men. Young women thereby have a higher risk of sudden death than the rest of the female and general population. A nurse who experienced cardiorespiratory arrest at the age of 30 shares her story. PMID- 28865695 TI - [Innovating to support the development of outpatient surgery]. AB - Le Confluent private hospital in Nantes has opened a unit devoted to outpatient surgery. Its architecture, organisation, facilities and services have all been designed to treat patients in as short a timeframe as possible. PMID- 28865696 TI - [Nursing perspective on the care of people with leprosy in Ivory Coast]. AB - Lucien Gbadie is a nurse at the Raoul-Follereau Institute in Adzope, Ivory Coast. In this article, he describes how people with leprosy or Buruli ulcer are treated and supported. PMID- 28865698 TI - [The TPE nurse improving the patient's quality of life]. AB - The impact of interventions by therapeutic education nurses on compliance and the quality of life of patients with chronic diseases has been proven. These different perspectives of caregivers and patients highlight the specific case of the treatment of HIV. PMID- 28865697 TI - [Cancer and elderly people, what palliative care?] AB - Epidemiological data relating to cancer and the ageing of the population highlight the need for oncology, geriatrics and palliative care to work more closely together. Geriatric and palliative care assessments in oncology are complex procedures and result in the modification of the oncological therapeutic choices. They have a significant impact on the methods of treatment of the patients concerned. PMID- 28865699 TI - [Infections of implantable ports in haematology patients]. AB - From 2010 to 2015, a study analysed the infections of implantable ports in haematology patients. Communication, collaboration and diligence were some of the main issues raised. PMID- 28865700 TI - ? PMID- 28865701 TI - Working in a Refugee Camp in Greece. AB - Sophie and Pierre have joined an international team of workers in a humanitarian organisation at a makeshift refugee camp in Greece, near the border to Macedonia. PMID- 28865702 TI - ? PMID- 28865703 TI - ? PMID- 28865704 TI - ? PMID- 28865705 TI - Corrigendum to "Phosphorus saturation and mobilization in two typical Chinese greenhouse vegetable soils" [Chemosphere 172 (2017) 316-324]. PMID- 28865706 TI - Quantification and visualization of coordination during non-cyclic upper extremity motion. AB - There are many design challenges in creating at-home tele-monitoring systems that enable quantification and visualization of complex biomechanical behavior. One such challenge is robustly quantifying joint coordination in a way that is intuitive and supports clinical decision-making. This work defines a new measure of coordination called the relative coordination metric (RCM) and its accompanying normalization schemes. RCM enables quantification of coordination during non-constrained discrete motions. Here RCM is applied to a grasping task. Fifteen healthy participants performed a reach, grasp, transport, and release task with a cup and a pen. The measured joint angles were then time-normalized and the RCM time-series were calculated between the shoulder-elbow, shoulder wrist, and elbow-wrist. RCM was normalized using four differing criteria: the selected joint degree of freedom, angular velocity, angular magnitude, and range of motion. Percent time spent in specified RCM ranges was used asa composite metric and was evaluated for each trial. RCM was found to vary based on: (1) chosen normalization scheme, (2) the stage within the task, (3) the object grasped, and (4) the trajectory of the motion. The RCM addresses some of the limitations of current measures of coordination because it is applicable to discrete motions, does not rely on cyclic repetition, and uses velocity-based measures. Future work will explore clinically relevant differences in the RCM as it is expanded to evaluate different tasks and patient populations. PMID- 28865707 TI - Effect of airway surface liquid on the forces on the pharyngeal wall: Experimental fluid-structure interaction study. AB - Obstructive sleep apnoea syndrome (OSAS) is a breathing disorder with a multifactorial etiology. The respiratory epithelium is lined with a thin layer of airway surface liquid preventing interactions between the airflow and epithelium. The effect of the liquid lining in OSAS pathogenesis remains poorly understood despite clinical research. Previous studies have shown that the physical properties of the airway surface liquid or altered stimulation of the airway mechanoreceptors could alleviate or intensify OSAS; however, these studies do not provide a clear physical interpretation. To study the forces transmitted from the airflow to the liquid-lined compliant wall and to discuss the effects of the airway surface liquid properties on the stimulation of the mechanoreceptors, a novel and simplified experimental system mimicking the upper airway fundamental characteristics (i.e., liquid-lined compliant wall and complex unsteady airflow features) was constructed. The fluctuating force on the compliant wall was reduced through a damping mechanism when the liquid film thickness and/or the viscosity were increased. Conversely, the liquid film damping was reduced when the surface tension decreased. Based on the experimental data, empirical correlations were developed to predict the damping potential of the liquid film. In the future, this will enable us to extend the existing computational fluid structure interaction simulations of airflow in the human upper airway by incorporating the airway surface liquid effect without adopting two-phase flow interface tracking methods. Furthermore, the experimental system developed in this study could be used to investigate the fundamental principles of the complex once/twice-coupled physical phenomena. PMID- 28865708 TI - Computational stability of human knee joint at early stance in Gait: Effects of muscle coactivity and anterior cruciate ligament deficiency. AB - As one of the most complex and vulnerable structures of body, the human knee joint should maintain dynamic equilibrium and stability in occupational and recreational activities. The evaluation of its stability and factors affecting it is vital in performance evaluation/enhancement, injury prevention and treatment managements. Knee stability often manifests itself by pain, hypermobility and giving-way sensations and is usually assessed by the passive joint laxity tests. Mechanical stability of both the human knee joint and the lower extremity at early stance periods of gait (0% and 5%) were quantified here for the first time using a hybrid musculoskeletal model of the lower extremity. The roles of muscle coactivity, simulated by setting minimum muscle activation at 0-10% levels and ACL deficiency, simulated by reducing ACL resistance by up to 85%, on the stability margin as well as joint biomechanics (contact/muscle/ligament forces) were investigated. Dynamic stability was analyzed using both linear buckling and perturbation approaches at the final deformed configurations in gait. The knee joint was much more stable at 0% stance than at 5% due to smaller ground reaction and contact forces. Muscle coactivity, when at lower intensities (<3% of its maximum active force), increased dynamic stability margin. Greater minimum activation levels, however, acted asan ineffective strategy to enhance stability. Coactivation also substantially increased muscle forces, joint loads and ACL force and hence the risk of further injury and degeneration. A deficiency in ACL decreases total ACL force (by 31% at 85% reduced stiffness) and the stability margin of the knee joint at the heel strike. It also markedly diminishes forces in lateral hamstrings (by up to 39%) and contact forces on the lateral plateau (by up to 17%). Current work emphasizes the need for quantification of the lower extremity stability margin in gait. PMID- 28865709 TI - Minilaparoscopy in urology: Systematic review. AB - CONTEXT: There has been a boom in recent years in urological procedures using minilaparoscopy (ML). OBJECTIVE: To conduct a systematic review of the published evidence on ML and its current role in urology. ACQUISITION OF EVIDENCE: We performed a search on MedLine spanning October 1983 to December 2016 according to PRISMA criteria. A total of 6 comparative articles and 13 series were selected for this manuscript. SUMMARY OF THE EVIDENCE: Only 1 study was randomised, 4 studies were prospective and comparative, and most were case series in which the operations were performed with 3-mm instruments. The most common procedures were adrenalectomy, followed by nephrectomy, living donor and pyeloplasty. Other minor conditions were also operated on, including cyst decortications, pyelolithotomies, lymphadenectomies, varicocelectomies and orchiectomies. DISCUSSION: There have been significant technical improvements in recent years in the materials of ML. Most procedures were for reconstructive surgery and by transperitoneal approach, with a gradually increasing number of cases of oncologic surgery. Only 36.8% of the series assessed the cosmetic results with validated questionnaires, and 68.4% of the studies used the visual analogue scale to measure pain during the postoperative period. CONCLUSIONS: The level of evidence of most published studies is low. ML is a reproducible technique for urological surgery and is safe even for operations on large surgical masses. The procedure's cosmetic and pain results after surgery are superior to those of conventional laparoscopy, although these conclusions should be taken with caution given the limitations of the current studies. PMID- 28865711 TI - Response to a letter to the editor. PMID- 28865712 TI - MicroRNA-31 promotes adverse cardiac remodeling and dysfunction in ischemic heart disease. AB - RATIONALE: Myocardial infarction (MI) triggers a dynamic microRNA response with the potential of yielding therapeutic targets. OBJECTIVE: We aimed to identify novel aberrantly expressed cardiac microRNAs post-MI with potential roles in adverse remodeling in a rat model, and to provide post-ischemic therapeutic inhibition of a candidate pathological microRNA in vivo. METHODS AND RESULTS: Following microRNA array profiling in rat hearts 2 and 14days post-MI, we identified a time-dependent up-regulation of miR-31 compared to sham-operated rats. A progressive increase of miR-31 (up to 91.4+/-11.3 fold) was detected in the infarcted myocardium by quantitative real-time PCR. Following target prediction analysis, reporter gene assays confirmed that miR-31 targets the 3'UTR of cardiac troponin-T (Tnnt2), E2F transcription factor 6 (E2f6), mineralocorticoid receptor (Nr3c2) and metalloproteinase inhibitor 4 (Timp4) mRNAs. In vitro, hypoxia and oxidative stress up-regulated miR-31 and suppressed target genes in cardiac cell cultures, whereas LNA-based oligonucleotide inhibition of miR-31 (miR-31i) reversed its repressive effect on target mRNAs. Therapeutic post-ischemic administration of miR-31i in rats silenced cardiac miR 31 and enhanced expression of target genes, while preserving cardiac structure and function at 2 and 4weeks post-MI. Left ventricular ejection fraction (EF) improved by 10% (from day 2 to 30 post-MI) in miR-31i-treated rats, whereas controls receiving scrambled LNA inhibitor or placebo incurred a 17% deterioration in EF. miR-31i decreased end-diastolic pressure and infarct size; attenuated interstitial fibrosis in the remote myocardium and enhanced cardiac output. CONCLUSION: miR-31 induction after MI is deleterious to cardiac function while its therapeutic inhibition in vivo ameliorates cardiac dysfunction and prevents the development of post-ischemic adverse remodeling. PMID- 28865714 TI - REMOVED: False aneurysm of the facial artery as complication of sagittal split osteotomy, [Journal of Cranio-Maxillofacial Surgery. Volume 36, Issue 3, April 2008, Pages 180-182]. PMID- 28865713 TI - Reduction of depressive symptoms predicts improved glycaemic control: Secondary results from the DIAMOS study. AB - AIMS: Evidence from randomised trials analysing effects of depression treatment on glycaemic control in group comparisons is inconsistent. The aim of this study was to test if the reduction of depressive symptoms would explain improved glycaemic control irrespective of treatment groups. METHODS: The DIAMOS study tested effects of cognitive-behavioural therapy (CBT) versus usual care on depressive symptoms in a 12-month prospective trial; HbA1c was a secondary outcome. Since the results suggested superiority of CBT for improving depressive symptoms, but not HbA1c, we conducted this secondary analysis to test if reduction of depressive symptoms could explain improved glycaemic control when assessed irrespective of treatment group affiliation. Reduction of depressive symptoms was assessed using baseline-to-follow-up changes in the Center for Epidemiologic Studies Depression Scale (CES-D). We used multiple regression analyses, adjusting for baseline HbA1c and depression, group affiliation and covariates, to assess associations between reduction of depressive symptoms and follow-up HbA1c. RESULTS: 181 participants provided eligible data. Depressive symptoms decreased between baseline and follow-up by averagely -5.1+/-11.8 CES-D points. Greater reduction of depressive symptoms predicted greater improvement of HbA1c at follow-up, while adjusting for baseline HbA1c and covariates (Beta= 0.24, P=0.004). Additionally, patients with greater reduction of depressive symptoms were more likely to reach in-target HbA1c (<7.5%) at follow-up (adjusted OR=1.04, 95% CI 1.01-1.08, P=0.023). CONCLUSIONS: The findings suggest that reduction of depressive symptoms can explain improved glycaemic control. Behavioural treatments might aim to improve both affective and glycaemic outcomes. PMID- 28865715 TI - Plasma oxytocin levels in major depressive and bipolar II disorders. AB - Oxytocin may play a role in mood regulation. Research has shown the plasma oxytocin level of patients with bipolar I disorder (BD I) during a manic episode was significantly higher than that of BD I patients of other statuses, and also that of healthy subjects. However, whether or not a difference in the level of oxytocin exists between patients with major depressive disorder (MDD) and those with BD II is unclear. This study aimed to investigate the plasma oxytocin levels in MDD and BD II patients in a depressive episode. 119 healthy controls, 135 BD II patients, and 97 MDD patients were enrolled. All of the BD II and MDD patients were drug-naive, with baseline depressive status 17-item Hamilton Depression Rating Scale scores >15. The plasma oxytocin level of the BD II patients was significantly higher than that of the MDD patients and controls at baseline. After treatment, the plasma oxytocin level of the BD II patients increased significantly; however, in the MDD group, the oxytocin level decreased slightly after treatment. Our findings suggested more significant plasma oxytocin dysregulation in the patients in the BD II group than in the MDD patients and controls, both before and after treatment. PMID- 28865716 TI - Symptomatic remission in schizophrenia: Results from a risperidone maintenance treatment study. AB - This study aimed to investigate remission following the treatment of schizophrenia patients with risperidone. Clinically stabilized patients with schizophrenia (n = 374) were randomly assigned to 4-week, 26-week, or no-dose reduction groups, in which the baseline risperidone dose was continued for 4, 26, or all weeks during 1-year period. The 'Positive and Negative Syndrome Scale' (PANNS) was assessed at baseline and monthly for six months, followed by every two months until the last recruited patient completed 1-year follow-up. Symptomatic remission was defined according to criteria established by the Schizophrenia Working Group. A Generalized Linear Mixed Model indicated significant variation in remission over time, which increased after baseline in the entire group (F = 49.32, df = 1, 3114, P < 0.001). The overall length of risperidone treatment (F = 4.34, df = 1, 416, P = 0.038) and the duration of illness (F = 8.51, df = 1, 359, P = 0.004) had significantly negative effects upon remission. Baseline remission patients were associated with a significantly increased time to relapse compared with the baseline of non-remission patients over a one year follow up period (F = 5.74, df = 1, 367, P = 0.017). One-year risperidone maintenance treatment increased remission rates in schizophrenia. A shorter illness duration, risperidone treatment length, and a lower total PANSS score were clinically useful predictors of remission. Achieving remission may postpone relapse. PMID- 28865717 TI - Measuring learning potential in people with schizophrenia: A comparison of two tasks. AB - Learning potential measures utilize dynamic assessment methods to capture performance changes following training on a cognitive task. Learning potential has been explored in schizophrenia research as a predictor of functional outcome and there have been calls for psychometric development in this area. Because the majority of learning potential studies have utilized the Wisconsin Card Sorting Test (WCST), we extended this work using a novel measure, the Rey Osterrieth Complex Figure Test (ROCFT). This study had the following aims: 1) to examine relationships among different learning potential indices for two dynamic assessment tasks, 2) to examine the association between WCST and ROCFT learning potential measures, and 3) to address concurrent validity with a performance based measure of functioning (Test of Grocery Shopping Skills; TOGSS). Eighty-one adults with schizophrenia or schizoaffective disorder completed WCST and ROCFT learning measures and the TOGSS. Results indicated the various learning potential computational indices are intercorrelated and, similar to other studies, we found support for regression residuals and post-test scores as optimal indices. Further, we found modest relationships between the two learning potential measures and the TOGSS. These findings suggest learning potential includes both general and task-specific constructs but future research is needed to further explore this question. PMID- 28865718 TI - Regional supply of outreach service and length of stay in psychiatric hospital among patients with schizophrenia: National case mix data analysis in Japan. AB - Several clinical trials have demonstrated that linkage to an outreach service can prevent prolonged length of stay of patients at psychiatric hospitals. However, there has been no investigation of the association between length of stay in psychiatric hospital and regional supply of outreach services using national case mix data. The aim of this study was to clarify the relationship between length of stay in psychiatric hospital and regional supply of outreach services. We used data from the National Patient Survey in Japan, a nationally representative cross sectional survey of inpatient care conducted every three years from 1996 to 2014. Data from 42,268 patients with schizophrenia who had been admitted to psychiatric hospitals were analyzed. After controlling for patient and regional characteristics, patients in regions with fewer number of visits for psychiatric nursing care at home had significantly longer length of stay in psychiatric hospitals. This finding implies that enhancement of the regional supply of outreach services would prevent prolonged length of stay in psychiatric hospitals. PMID- 28865719 TI - The construct and measurement of suicide-related coping. AB - Enhancing the ability to cope with suicidal thoughts, urges, and crises is a key component of therapeutic work with suicidal patients. Suicide-related coping can serve as a treatment target, can provide an additional component in the evaluation of suicidal patients, and can serve as an outcome in randomized controlled trials for the prevention of suicide. However, to date, psychometrically sound measures to assess suicide-related coping are lacking. The aim of this study was to examine the psychometric properties of a new measure, the Suicide-Related Coping Scale (SRCS). Adult patients who were either admitted to a psychiatric inpatient unit (n = 97) or an Emergency Department (n = 232) for suicide-related concerns were enrolled in this study. All were administered the SRCS at baseline and at one month. Factor analyses and internal consistency analyses were conducted. Additional measures were administered to assess convergent and divergent validity. Factor analysis of the SRCS revealed two factors, internal and external coping strategies. The SRCS had high internal consistency, good convergent validity and was sensitive to change. Suicide related coping is a promising construct as measured by the SRCS to assess suicide related coping in both clinical practice and trials. PMID- 28865720 TI - Predictors of short-term repetition of self-harm among patients admitted to an emergency room following self-harm: A retrospective one-year cohort study. AB - We conducted a retrospective chart-review study, examining predictors of the repetition of short-term self-harm (<1 month and <6 months) among the patients who were admitted to an emergency department in Japan following self-harm. A total of 405 patients were enrolled and were followed-up for a subsequent one year. The incidence of repeated self-harm within one- and six- months were 6.4% and 13.1%, respectively. Cox's proportional hazards model analyses demonstrated that history of self-harm and comorbid physical illness were associated with repeated self-harm within one month. The patients who lived alone and who were directly discharged from the emergency room after referral to a psychiatrist were at higher risk for repeated self-harm within both one and six months. Living on public assistance and having been discharged from psychiatric wards within the past 12 months were associated with repetition within six months. These risk factors should be incorporated into routine assessment at an emergency room, and elaborate follow-up plan should be provided to the patients with these risk factors upon discharge from the emergency room. Further prospective studies are warranted, addressing more comprehensive factors that are associated with short term risk for self-harm and suicide. PMID- 28865721 TI - To see in a mirror dimly. The looking glass self is self-shaming in borderline personality disorder. AB - Symptoms of borderline personality disorder (BPD) can be conceptualized as the expression of and defenses against or response to the painful emotion of chronic shame, which may relate to early maladaptive schemas (EMS). The goal of this research is to examine levels of early maladaptive schemas, self-reported shame, and anxious or angry reactions to social put-downs as well as their associations. We also looked to assess the association of shame with BPD symptoms. Fifty-six patients with BPD completed self-report measures of EMSs, chronic shame, and reactions to put-downs. Comparison groups consisted of 24 patients without personality disorder (non-PD) and 80 healthy controls (HC). Those with BPD reported higher levels of EMSs, characterological, behavioral and bodily shame, and were more prone to react with anxiety and anger than non-PD patients and HC subjects. EMSs domains had specific associations with chronic shame and reaction types to social put-downs. Identity disturbances were associated with characterological, behavioral and bodily shame. Stormy relationships were associated with bodily shame. Chronic shame and anxious and angry reactions to social put-downs are prominent in patients with borderline personality disorder and are associated with specific EMS domains and with the symptoms of identity disturbance and stormy relationships. PMID- 28865722 TI - Prevalence of depression, anxiety, and adjustment disorders in women with spontaneous abortion in Germany - A retrospective cohort study. AB - The aim of this study was to analyze the prevalence of depression, anxiety, and adjustment disorders in women within the year following miscarriage in Germany. This study included women between the ages of 16 and 45 with a first pregnancy terminated by spontaneous abortion between January 2007 and December 2015 (index date). These women were followed in 262 gynecological practices. Women with a spontaneous abortion were matched (1:1) with pregnant women without spontaneous abortion by age, index year, diagnosis of female infertility prior to the index date, procreative management prior to the index date, and physician. This retrospective cohort study included 12,158 women with a spontaneous abortion and 12,158 pregnant women without a spontaneous abortion. The mean age was 31.6 (SD: 5.5).years. One year after the index date, 8.9% of women with spontaneous abortion and 5.7% of controls were diagnosed with depression, anxiety, or adjustment disorder. Individuals who had previously undergone a spontaneous abortion were more likely to have one of these three psychiatric disorders compared to controls (OR = 1.53). Similar results were found in the age groups 21 30 and 31-40. Spontaneous abortion is associated with an increased prevalence of developing psychiatric diseases within the first year. PMID- 28865723 TI - Radiation Oncology Resident Mentorship: Results of a Resident-Coordinated Mentorship Program. PMID- 28865724 TI - The crystal structures of a copper-bound metallochaperone from Saccharomyces cerevisiae. AB - Atx1 is a metallochaperone protein from the yeast Saccharomyces cerevisiae (yAtx1) that plays a major role in copper homeostasis in this organism. yAtx1 functions as a copper transfer protein by shuttling copper to the secretory pathway to control intracellular copper levels. Here we describe the first crystal structures of yAtx1 that have been determined in the presence of Cu(I). The structures from two different crystal forms have been solved and refined to resolutions of 1.65 and 1.93A. In contrast to the previous metallated crystal structure of yAtx1 where a single Hg(II) atom was coordinated by one yAtx1 molecule, the Cu(I)-yAtx1 was crystallised as a dimer in both crystal forms, sharing one Cu(I) atom between two yAtx1 molecules. This is consistent with the crystal structure of the human homologue Cu(I)-hAtox1. Overall the structures in the two different crystal forms of Cu(I)-yAtx1 are remarkably similar to that of Cu(I)-hAtox1. However, subtle structural differences between Cu(I)-yCtr1 and Cu(I)-hAtox1 are observed in copper coordination geometries and in the conformations of Loop 2, with the latter potentially contributing to differential interactions and copper transfer mechanisms with membrane transport copper uptake systems. PMID- 28865725 TI - Aluminum exposure for 60days at an equivalent human dietary level promotes peripheral dysfunction in rats. AB - Aluminum (Al) is a neurotoxic associated with a number of chronic human diseases. We investigated the effects of Al exposure at doses similar to human dietary levels and at a high level exposure to Al on the peripheral nervous system. Wistar male rats were divided into two major groups and received orally: 1) First group - Low level - rats were subdivided and treated for 60days: a) Control - received ultrapure water; b) AlCl3 - received Al at 8.3mg/kg body weight (bw) for 60days; and 2) Second group - High level - rats were subdivided and treated for 42days: C) Control - received ultrapure water through oral gavage; d) AlCl3 - received Al at 100mg/kg bw for 42days. Von Frey hair test, plantar test, the presence of catalepsy and the spontaneous motor activity were investigated. Reactive oxygen species, lipid peroxidation and total antioxidant capacity, immunohistochemistry to investigate the nerve inflammation and, the specific presence of Al in the sciatic nerve fibers were investigated. Al exposure at a representative human dietary level promotes the development of mechanical allodynia, catalepsy, increased inflammation in the sciatic nerve, systemic oxidative stress and, is able to be retained in the sciatic nerve. The effects of low-dose Al were similar to those found in rats exposed to Al at a dose much higher (100mg/kg). Our findings suggest that Al may be considered toxic for the peripheral nervous system, thus inducing peripheral dysfunction. PMID- 28865726 TI - B-lines with Lung Ultrasound: The Optimal Scan Technique at Rest and During Stress. AB - Various lung ultrasound (LUS) scanning modalities have been proposed for the detection of B-lines, also referred to as ultrasound lung comets, which are an important indication of extravascular lung water at rest and after exercise stress echo (ESE). The aim of our study was to assess the lung water spatial distribution (comet map) at rest and after ESE. We performed LUS at rest and immediately after semi-supine ESE in 135 patients (45 women, 90 men; age 62 +/- 12 y, resting left ventricular ejection fraction = 41 +/- 13%) with known or suspected heart failure or coronary artery disease. B-lines were measured by scanning 28 intercostal spaces (ISs) on the antero-lateral chest, 2nd-5th IS, along with the midaxillary (MA), anterior axillary (AA), mid-clavicular (MC) and parasternal (PS) lines. Complete 28-region, 16-region (3rd and 4th IS), 8-region (3rd IS), 4-region (3rd IS, only AA and MA) and 1-region (left 3rd IS, MA) scans were analyzed. In each space, the B-lines were counted from 0 = black lung to 10 = white lung. Interpretable images were obtained in all spaces (feasibility = 100 %). B-lines (>0 in at least 1 space) were present at ESE in 93 patients (69%) and absent in 42. More B-lines were found in the 3rd IS and along AA and MA lines. The B-line cumulative distribution was symmetric at rest (right/left = 1.10) and asymmetric with left lung predominance during stress (right/left = 0.67). The correlation of per-patient B-line number between 28-S and 16-S (R2 = 0.9478), 8-S (R2 = 0.9478) and 4-S scan (R2 = 0.9146) was excellent, but only good with 1-S (R2 = 0.8101). The average imaging and online analysis time were 5 s per space. In conclusion, during ESE, the comet map of lung water accumulation follows a predictable spatial pattern with wet spots preferentially aligned with the third IS and along the AA and MA lines. The time-saving 4-region scan is especially convenient during stress, simply dismissing dry regions and focusing on wet regions alone. PMID- 28865727 TI - Altered mitochondrial epigenetics associated with subchronic doxorubicin cardiotoxicity. AB - Doxorubicin (DOX), a potent and broad-spectrum antineoplastic agent, causes an irreversible, cumulative and dose-dependent cardiomyopathy that ultimately leads to congestive heart failure. The mechanisms responsible for DOX cardiotoxicity remain poorly understood, but seem to involve mitochondrial dysfunction on several levels. Epigenetics may explain a portion of this effect. Since mitochondrial dysfunction may affect the epigenetic landscape, we hypothesize that this cardiac toxicity may result from epigenetic changes related to disruption of mitochondrial function. To test this hypothesis, eight-week-old male Wistar rats (n=6/group) were administered 7 weekly injections with DOX (2mgkg-1) or saline, and sacrificed two weeks after the last injection. We assessed gene expression patterns by qPCR, global DNA methylation by ELISA, and proteome lysine acetylation status by Western blot in cardiac tissue from saline and DOX-treated rats. We show for the first time that DOX treatment decreases global DNA methylation in heart but not in liver. These differences were accompanied by alterations in mRNA expression of multiple functional gene groups. DOX disrupted cardiac mitochondrial biogenesis, as demonstrated by decreased mtDNA levels and altered transcript levels for multiple mitochondrial genes encoded by both nuclear and mitochondrial genomes. Transcription of genes involved in lipid metabolism and epigenetic modulation were also affected. Western blotting analyses indicated a differential protein acetylation pattern in cardiac mitochondrial fractions of DOX-treated rats compared to controls. Additionally, DOX treatment increased the activity of histone deacetylases. These results suggest an interplay between mitochondrial dysfunction and epigenetic alterations, which may be a primary determinant of DOX-induced cardiotoxicity. PMID- 28865728 TI - Gender-specific association of exposure to non-dioxin-like polychlorinated biphenyls during pregnancy with methylation levels of H19 and long interspersed nuclear element-1 in cord blood in the Hokkaido study. AB - BACKGROUND: Associations between prenatal exposure to polychlorinated biphenyls (PCBs) and reduced birth-size, and between DNA methylation of insulin-like growth factor-2 (IGF-2), H19 locus, and long interspersed nuclear element-1 (LINE-1) and reduced birth-size are well established. To date, however, studies on the associations between prenatal exposure to PCBs and alterations in methylation of IGF-2, H19, and LINE-1 are lacking. Thus, in this study, we examined these associations with infant-gender stratification. METHODS: We performed a prospective birth cohort study using the Sapporo cohort from the previously described Hokkaido Birth Cohort Study on Environment and Children's Health conducted between 2002 and 2005 in Japan. In the final 169 study participants included in this study, we measured the concentrations of various non-dioxin-like PCBs in maternal blood during pregnancy using high-resolution gas chromatography/high-resolution mass spectrometry. IGF-2, H19 and LINE-1 methylation levels in cord blood were measured using the bisulfite pyrosequencing methods Finally, we assessed the associations between prenatal exposure to various PCBs and the gene methylation levels using multiple regression models stratified by infant gender. RESULTS: We observed a 0.017 (95% confidence interval [CI]: 0.003-0.031) increase in the log10-transformed H19 methylation levels (%) in cord blood for each ten-fold increase in the levels of decachlorinated biphenyls (decaCBs) in maternal blood among all infants. Similarly, a 0.005 (95% CI: 0.000-0.010) increase in the log10-transformed LINE-1 methylation levels (%) in cord blood was associated with each ten-fold increase in heptachlorinated biphenyls (heptaCBs) in maternal blood among all infants. In particular, we observed a dose-dependent association of the decaCB levels in maternal blood with the H19 methylation levels among female infants (P value for trend=0.040); likewise a dose-dependent association of heptaCB levels was observed with LINE-1 methylation levels among female infants (P value for trend=0.015). Moreover, these associations were only observed among infants of primiparous women. CONCLUSION: Our results suggest that the dose-dependent association between prenatal exposure to specific non-dioxin-like PCBs and increases in the H19 and LINE-1 methylation levels in cord blood might be more predominant in females than in males. PMID- 28865729 TI - Dysphagia: Multiple Pathologies, One Cause. PMID- 28865730 TI - Dysphagia After Neck Surgery. PMID- 28865731 TI - An Unusual Cause of Halitosis. PMID- 28865732 TI - An Unusual Cause of Abdominal Pain and Biliary Obstruction in a Patient With Hepatocellular Carcinoma. PMID- 28865733 TI - Anesthesia Assistance in Outpatient Colonoscopy and Risk of Aspiration Pneumonia, Bowel Perforation, and Splenic Injury. AB - BACKGROUND & AIMS: The increase in use of anesthesia assistance (AA) to achieve deep sedation with propofol during colonoscopy has significantly increased colonoscopy costs without evidence for increased quality and with possible harm. We investigated the effects of AA on colonoscopy complications, specifically bowel perforation, aspiration pneumonia, and splenic injury. METHODS: In a population-based cohort study using administrative databases, we studied adults in Ontario, Canada undergoing outpatient colonoscopy from 2005 through 2012. Patient, endoscopist, institution, and procedure factors were derived. The primary outcome was bowel perforation, defined using a validated algorithm. Secondary outcomes were splenic injury and aspiration pneumonia. Using a matched propensity score approach, we matched persons who had colonoscopy with AA (1:1) with those who did not. We used logistic regression models under a generalized estimating equations approach to explore the relationship between AA and outcomes. RESULTS: Data from 3,059,045 outpatient colonoscopies were analyzed; 862,817 of these included AA. After propensity matching, a cohort of 793,073 patients who had AA and 793,073 without AA was retained for analysis (51% female; 78% were age 50 years or older). Use of AA did not significantly increase risk of perforation (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.84-1.16) or splenic injury (OR, 1.09; 95% CI, 0.62-1.90]. Use of AA was associated with an increased risk of aspiration pneumonia (OR, 1.63; 95% CI, 1.11-2.37). CONCLUSIONS: In a population-based cohort study, AA for outpatient colonoscopy was associated with a significantly increased risk of aspiration pneumonia, but not bowel perforation or splenic injury. Endoscopists should warn patients, especially those with respiratory compromise, of this risk. PMID- 28865734 TI - Paneth Cell Defects Induce Microbiota Dysbiosis in Mice and Promote Visceral Hypersensitivity. AB - BACKGROUND & AIMS: Separation of newborn rats from their mothers induces visceral hypersensitivity and impaired epithelial secretory cell lineages when they are adults. Little is known about the mechanisms by which maternal separation causes visceral hypersensitivity or its relationship with defects in epithelial secretory cell lineages. METHODS: We performed studies with C3H/HeN mice separated from their mothers as newborns and mice genetically engineered (Sox9flox/flox-vil-cre on C57BL/6 background) to have deficiencies in Paneth cells. Paneth cell deficiency was assessed by lysozyme staining of ileum tissues and lysozyme activity in fecal samples. When mice were 50 days old, their abdominal response to colorectal distension was assessed by electromyography. Fecal samples were collected and microbiota were analyzed using Gut Low-Density Array quantitative polymerase chain reaction. RESULTS: Mice with maternal separation developed visceral hypersensitivity and defects in Paneth cells, as reported from rats, compared with mice without maternal separation. Sox9flox/flox vil-Cre mice also had increased visceral hypersensitivity compared with control littermate Sox9flox/flox mice. Fecal samples from mice with maternal separation and from Sox9flox/flox-vil-cre mice had evidence for intestinal dysbiosis of the microbiota, characterized by expansion of Escherichia coli. Daily gavage of conventional C3H/HeN adult mice with 109 commensal E coli induced visceral hypersensitivity. Conversely, daily oral administration of lysozyme prevented expansion of E coli during maternal separation and visceral hypersensitivity. CONCLUSIONS: Mice with defects in Paneth cells (induced by maternal separation or genetically engineered) have intestinal expansion of E coli leading to visceral hypersensitivity. These findings provide evidence that Paneth cell function and intestinal dysbiosis are involved in visceral sensitivity. PMID- 28865735 TI - A Rare Cause of Diarrhea and Polyposis. PMID- 28865737 TI - Vascular Trauma Revisited. PMID- 28865738 TI - Yeasticidal activity of chemical disinfectants and antiseptics against Candida auris. AB - Candida auris appears to be transmitted readily between patients, yet information regarding the efficacy of environmental disinfection and skin decolonization is lacking. A quantitative suspension test (EN 13624:2013) was used to evaluate the yeasticidal activity of different chemical disinfectants and antiseptics against C. auris and Candida albicans. When tested in suspension, both a chlorine-based disinfectant and iodine-based skin antiseptic were effective against C. auris, suggesting that their use could reduce environmental contamination and skin colonization, respectively, if applied appropriately. Chlorhexidine-based products may also be effective. However, in this study, activity depended on formulation, specifically the presence of isopropyl alcohol. PMID- 28865739 TI - The economics of recovery after pancreatic surgery: detailed cost minimization analysis of an enhanced recovery program. AB - BACKGROUND: Clinical pathways (CPW) are considered safe and effective at decreasing postoperative length of stay (LoS), but the effect on economic costs is uncertain. This study sought to elucidate the effect of a CPW on direct hospitalization costs for patients undergoing pancreaticoduodenectomy (PD). METHODS: A CPW for PD patients at a single Canadian institution was implemented. Outcomes included LoS, 30-day readmissions, and direct costs of hospital care. A retrospective cost minimization analysis compared patients undergoing PD prior to and following CPW implementation, using a bootstrapped t test and deviation-based cost modeling. RESULTS: 121 patients undergoing PD after CPW implementation were compared to 74 controls. Index LoS was decreased following CPW implementation (9 vs. 11 days, p = 0.005), as was total LoS (10 vs. 11 days, p = 0.003). The mean total cost of postoperative hospitalization per patient decreased in the CPW group ($15,678.45 CAD vs. $25,732.85 CAD, p = 0.024), as was the mean 30-day cost including readmissions ($16,627.15 CAD vs. $29,872.72 CAD, p = 0.016). Areas of significant cost savings included laboratory tests and imaging investigations. CONCLUSIONS: CPWs may generate cost savings by reducing unnecessary investigations, and improve quality of care through process standardization and decreasing practice variation. PMID- 28865740 TI - Repetitive 18F-FDG-PET/CT in patients with large-vessel giant-cell arteritis and controlled disease. AB - OBJECTIVE: 18F-FDG PET/CT can detect large-vessel involvement in giant-cell arteritis (GCA) with a good sensitivity. In patients with clinically and biologically controlled disease, we aimed to assess how vascular uptakes evolve on repetitive FDG-PET/CT. PATIENTS AND METHODS: All included patients had to satisfy the 4 following criteria: 1) diagnosis of GCA was retained according to the criteria of the American College of Rheumatology or based on the satisfaction of 2 criteria associated with the demonstration of large-vessel involvement on FDG-PET/CT; 2) all patients had a positive PET/CT that was performed at diagnosis before treatment or within the first 10days of treatment; 3) another FDG-PET/CT was performed after at least 3months of controlled disease without any relapse; 4) patients were followed-up at least for 12months. RESULTS: Twenty-five patients (17 [68%] women, median age: 69 [65-78]) with large-vessel inflammation on a baseline FDG-PET/CT and with repetitive imaging during the period with controlled disease were included and followed-up for 62 [25-95] months. Four repeated procedures revealed total extinction of vascular uptakes at 11.5 [8-12] months after the first FDG-PET/CT. Eight PET/CT revealed decreased numbers of vascular uptakes, and 10 procedures revealed no changes. The 3 remaining procedures indicated worsening of the numbers of vascular uptakes in the absence of relapse. CONCLUSIONS: Our study revealed long-term persistent vascular uptake on repeated FDG-PET/CT in >80% of our GCA patients with large-vessel inflammation and clinical-biological controlled disease. Prospective studies are required to confirm these findings. PMID- 28865736 TI - Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor. AB - BACKGROUND & AIMS: Dietary patterns affect systemic and local intestinal inflammation, which have been linked to colorectal carcinogenesis. Chronic inflammation can interfere with the adaptive immune response. We investigated whether the association of a diet that promotes intestinal inflammation with risk of colorectal carcinoma was stronger for tumors with lower lymphocytic reactions than tumors with higher lymphocytic reactions. METHODS: We collected data from the molecular pathological epidemiology databases of 2 prospective cohort studies: the Nurses' Health Study (since 1976) and the Health Professionals Follow-Up Study (since 1986). We used duplication-method time-varying Cox proportional cause-specific hazards regression to assess the association of empirical dietary inflammatory pattern (EDIP) score (derived from food frequency questionnaire data) with colorectal carcinoma subtype. Foods that contribute to high EDIP scores include red and processed meats, refined grains, carbonated beverages, and some vegetables; foods that contribute to low EDIP scores include beer, wine, coffee, tea, yellow and leafy vegetables, and fruit juice. Colorectal tissue samples were analyzed histologically for patterns of lymphocytic reactions (Crohn's-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, and tumor-infiltrating lymphocytes). RESULTS: During follow-up of 124,433 participants, we documented 1311 incident colon and rectal cancer cases with available tissue data. The association between the EDIP and colorectal cancer risk was significant (Ptrend = .02), and varied with degree of peritumoral lymphocytic reaction (Pheterogeneity < .001). Higher EDIP scores were associated with increased risk of colorectal cancer with an absent or low peritumoral lymphocytic reaction (highest vs lowest EDIP score quintile hazard ratio, 2.60; 95% confidence interval, 1.60-4.23; Ptrend < .001), but not risk of tumors with intermediate or high peritumoral lymphocytic reaction (Ptrend > .80). CONCLUSIONS: In 2 prospective cohort studies, we associated inflammatory diets with a higher risk of colorectal cancer subtype that contains little or no peritumoral lymphocytic reaction. These findings suggest that diet-related inflammation might contribute to development of colorectal cancer, by suppressing the adaptive anti-tumor immune response. PMID- 28865741 TI - Long-term outcomes of inappropriate antibiotic therapy for upper urinary tract infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae: a retrospective cohort study. AB - BACKGROUND: To evaluate the short- and long-term outcomes of different antimicrobial treatment options for upper urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. METHODS: We retrospectively analyzed patients with a first episode of febrile UTI and positive urine culture with ESBL-producing E. coli or K. pneumoniae during 2012 2015. We compared outcomes among patients who received: (1) definitive treatment with a carbapenem (CP), (2) a microbiologically appropriate intravenous non carbapenem agent (NCA), (3) a non-appropriate antimicrobial (NAA), and (4) an intravenous NAA followed by an oral NCA (NAA-PO). RESULTS: The majority of patients received empirical therapy with NAA (165/178, 93%), and definitive treatment with NCA (n=43), NAA (n=50), and NAA-PO (n=59). The NCA group had significantly higher SIRS score than the NAA-PO group (2.18 versus 1.76, P=0.018), but no differences were found between the NCA and NAA groups (2.18 and 1.92, P=0.15). Clinical cure at discharge from the index hospitalization was high (97-100%) in all 3 groups. The NCA group had longer length of stay as compared with the NAA-PO and NAA groups (8.7days versus 5.39 and 5.24days, P<0.0001) and a lower rate of early (48-72h) improvement (79% versus 96-100%, P=0.0002). Among re admitted patients, re-admission with ESBL-related bloodstream infection was significantly higher in the NAA group as compared to the NAA-PO and NCA groups (33% versus 4% and 0%, respectively, P=0.02). Death rate within 60days was also higher in the NAA and NCA groups as compared with the NAA-PO group (P=0.048). CONCLUSIONS: Inappropriate antimicrobial therapy for febrile non-bacteremic UTI with ESBL-producing enterobacteriaceae is associated with favorable short-term outcomes, but also with a long-term risk of relapsed bacteremic UTI. Definitive treatment with appropriate carbapenem-sparing antimicrobial agents effectively prevents late relapses. PMID- 28865742 TI - Review: Molecular detection of extended spectrum-beta-lactamase- and carbapenemase-producing Enterobacteriaceae in a clinical setting. AB - Enterobacteriaceae are a common source of both community- and hospital-acquired infections. The resistance of Enterobacteriaceae to beta-lactam antibiotics is a major public health problem and rapid detection is essential for the proper management of infections. Not only for the initiation of the proper antimicrobial regimen but also to stop the spread of multi-resistant bacteria. In this review, molecular methods that detect extended-spectrum-beta-lactamase-harboring and carbapenem-resistant Enterobacteriaceae were discussed. More specifically the performances of assays that were tested in a clinical situation were explored. When compared with conventional phenotypical methods (the gold standard) all molecular methods generated results faster and showed a higher sensitivity. Because molecular methods only detect selected genes, it is important to have good knowledge on the local gene pool. Furthermore, result need to be interpreted within a defined epidemiological context. Therefore, at this moment molecular methods should be seen as an important tool to complement rather than replace conventional methods. PMID- 28865743 TI - Molecular identification of cestodes and nematodes by cox1 gene real-time PCR and sequencing. AB - Unlike bacteria and fungi, identification of helminths by gene sequencing is not well-standardized. No "pan-cestode" or "pan-nematode" PCR primers are available. In this study, we designed 2 pairs of PCR primers for amplifying the cox1 genes of cestodes and nematodes respectively and validated their usefulness for real time PCR and sequencing identification using clinical samples with cestodes and nematodes collected from a variety of animals and human in 7 countries in Asia, Europe and Africa. The detection limits of the cox1 real-time PCR assays for cestodes and nematodes were 10 copies/reaction of extracted DNA, corresponding to CT values of 33 and 31 respectively. Real-time PCR using the 2 pairs of primers and probes showed positive results for all 20 clinical samples of cestodes and nematodes. Using phenotypic identification results as the reference standard, DNA sequencing successfully identified all the 5 cestodes and 7 nematodes with cox1 gene sequences available in GenBank, with all these names appearing as the best match of the cox1 gene sequences of the corresponding clinical samples. The percentage nucleotide identities between the cox1 gene sequences of the samples and those of the corresponding best match sequences in GenBank were 98-100%. For the remaining 5 cestodes and 3 nematodes, the corresponding cox1 gene sequences were not available in GenBank. cox1 gene sequencing is discriminative enough for accurately identifying most of the cestodes and nematodes in the present study. Further expansion of the cox1 gene sequence database will enable accurate identification of more cestodes and nematodes. PMID- 28865744 TI - Selective Ru(II)/lawsone complexes inhibiting tumor cell growth by apoptosis. AB - New Ru(II) complexes with lawsone (law) characterized as trans-[Ru(law)(PPh3)2(N N)]PF6, where PPh3 means triphenylphosphine and N-N is 2,2'-bipyridine (1), 4,4' dimethyl-2,2'-bipyridine (2), 4,4'-dimethoxy-2,2'-bipyridine (3), 1,10 phenanthroline (4) or 4,7-diphenyl-1,10-phenanthroline (5), induce apoptosis in tumor cells. Cytotoxicity of the complexes against the tumor cell lines DU-145 (prostate cancer cells), MCF-7 (breast cancer cells), A549 (lung cancer cells) and lung non-tumor cell line MRC-5 demonstrated promising IC50 values, lower than those found for the cisplatin, a drug used as a reference. Due to the high cytotoxic activity and selectivity against A549 cells line, complex (5) was selected for detailed assays. The complex (5) inhibits cells migration in concentrations in a nanomolar range, inducing tumor cell death by apoptosis, as confirmed by flow cytometry experiments. Furthermore, the antiproliferative activity of complex (5) on A549 tumor cells is attributed to a cell cycle arrest at the Sub G1 phase, followed by a decrease in the number of cells at the S phase. In addition, the interaction of the complexes (1-5) with CT-DNA was evaluated by circular dichroism, in which no changes in the secondary structure of DNA were observed, suggesting a weak interaction of the complexes with the biomolecule. On the other hand, complexes (1-5) showed a higher interaction with human serum albumin (HSA) by non-covalent van der Waals forces and hydrogen bonding, resulting in static quenching. PMID- 28865745 TI - Influence of ancillary ligands on preferential geometry and biomimetic catalytic activity in manganese(III)-catecholate systems: A combined experimental and theoretical study. AB - The present report describes the synthesis and structural characterizations of six new manganese(III) complexes with redox-active tetrachlorocatecholate ligand in the presence of different ancillary ligands (pyridines and imidazole). X-ray crystal structure analysis reveals that the geometry of manganese(III) centres in 1 and 2 is essentially square pyramidal, while it is discrete octahedron in compounds 3-6. These preferential structural diversities in these systems have been critically analysed by theoretical calculations. Remarkably, the characterization of both pi?pi stacking interactions and MnMn bonds in the supramolecular dimeric aggregates in the solid state in 1 and 2 by means of the Bader's theory of "atoms in molecules" (AIM) is quite interesting as that nicely corroborates the experimental fact. All the complexes are active toward the phenoxazinone synthase like activity and the detailed kinetic analysis was performed to get better insight into their catalytic efficiency. Electrochemical property of these complexes as well as different donor property of the ancillary ligands clearly establish that the ease of reduction of the metal centre i.e., the catalytic ability is favoured when the metal centre is bonded to the electron deficient pyridyl systems. EPR spectroscopy and theoretical study are further helpful to get insight into origin of the catalytic activity in these compounds. The present report overall highlights that tuning of the geometry and catalytic activity of manganese(III) complexes with tetrachlorocatecholate ligand can be attained by the introduction of different substitutions in ancillary pyridine ligands. PMID- 28865747 TI - Thalidomide as a Potential HIV Latency Reversal Agent: Is It the Right Time to Forget the Ancestral Sins? PMID- 28865748 TI - Circulating PCSK9 levels in acute coronary syndrome: Results from the PC-SCA-9 prospective study. AB - BACKGROUND: Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations have been shown to be positively associated with LDL cholesterol (LDL-C), but the relationship between PCSK9 and coronary atherosclerosis lesions remains unclear. OBJECTIVE: This study aims to investigate the correlation between serum PCSK9 levels and coronary damage severity in patients hospitalized for acute coronary syndrome (ACS). METHODS: In this prospective proof-of-concept study, coronary lesions were assessed using SYNTAX scores. Serum PCSK9 concentrations were measured on admission (Day 0) for ACS by Elisa, and on every day of hospitalization. Spearman's correlations were used to determine the association between PCSK9 levels, SYNTAX score and metabolic parameters. RESULTS: A total of 174 patients (mean age: 59+/-14 years, 79% male) with ACS (on Day 0, 119 patients were not taking statins, but 55 were) were included. After initiation of high-intensity statin therapy, serum PCSK9 concentrations increased significantly, reaching maximum levels on Day 2 (+31% vs. Day 0), and remained stable up to Day 4 (P<0.001, by mixed model). Serum PCSK9 on Day 0 was associated with LDL-C (rho=0.226, P=0.017) and apolipoprotein B (rho=0.282, P=0.005) in the statin-naive group only, and with triglycerides and non-HDL-C in all groups. More important, PCSK9 levels on Day 0 were positively associated with SYNTAX scores in the statin-naive group (rho=0.239, P=0.009), but not in the statin-treated group (P=NS). This association was maintained after adjusting for LDL-C (P=0.014) and major CV risk factors (P=0.008). CONCLUSION: Serum PCSK9 levels are positively associated with severity of coronary artery lesions independently of LDL-C concentrations in patients hospitalized for ACS. This reinforces the potential importance of PCSK9 inhibition in the management of ACS. PMID- 28865746 TI - Rapid Targeted Next-Generation Sequencing Platform for Molecular Screening and Clinical Genotyping in Subjects with Hemoglobinopathies. AB - Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 beta-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies. PMID- 28865749 TI - Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease. AB - Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Abeta) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Abeta pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest. PMID- 28865750 TI - Evaluation of Kunapa jala and Pancha gavya on plant quality, physiology, biochemistry, yield and growth attributes - A case study of Withania somnifera Dun. AB - BACKGROUND: 'Vrikshayurveda', an ancient science of plant life described by Surapala, has clearly outlined a systematized agricultural practice that insisted on the use of Kunapa jala (KJ) and Pancha gavya (PG) to enhance the yield and quality of plants. OBJECTIVE: An experiment was conducted to evaluate the effect of KJ and PG on growth, physiological, biochemical, quality attributes and yield of Withania somnifera Dun. MATERIALS AND METHODS: The effect of KJ and PG was evaluated in comparison with control, organic (farmyard manure and humic acid) and inorganic (NPK) fertilizer at 60, 90, 120 and 150 days after sowing (DAS). The study was conducted in randomized complete block design method. RESULTS: KJ group were higher in, total leaf area (1707.89 cm2) at 120 DAS, leaf area index (3.795) at 120 DAS, crop growth rate (0.256 g m-2 day-1) at 60-90 DAS, leaf area duration (101.909) at 120-150 DAS, relative growth rate (0.0170 g g-1 day-1) at 60-90 DAS, net assimilation rate (0.0537 g m-2 day-1) at 60-90 DAS. Leaf area ratio was higher in PG group (37.937 m2 g-1) at 60 DAS. The higher levels of chlorophyll a, b and carotenoids were in KJ group (1.877, 0.745 and 1318.14 mg g 1 respectively) at 90 DAS. Yield and quality attributes at harvest (150 DAS) indicated, higher dry root yield (5.93 quintal hectare-1), root length (15.66 cm) were higher in KJ group and root diameter was higher in PG group (1.36 cm). CONCLUSION: Vrikshayurveda practices viz. Kunapa jala and Pancha gavya were effective on studied parameters of W. somnifera. Economical and eco-friendly Vrikhayurveda practices can be initiated for sustainable agriculture. PMID- 28865752 TI - Preface 16th European Meeting of Complement in Human Disease, Copenhagen, Denmark, September 8th-12th 2017. PMID- 28865751 TI - RhoA activation and nuclearization marks loss of chondrocyte phenotype in crosstalk with Wnt pathway. AB - De-differentiation comprises a major drawback for the use of autologous chondrocytes in cartilage repair. Here, we investigate the role of RhoA and canonical Wnt signaling in chondrocyte phenotype. Chondrocyte de-differentiation is accompanied by an upregulation and nuclear localization of RhoA. Effectors of canonical Wnt signaling including beta-catenin and YAP/TAZ are upregulated in de differentiating chondrocytes in a Rho-dependent manner. Inhibition of Rho activation with C3 transferase inhibits nuclear localization of RhoA, induces expression of chondrogenic markers on 2D and enhances the chondrogenic effect of 3D culturing. Upregulation of chondrogenic markers by Rho inhibition is accompanied by loss of canonical Wnt signaling markers in 3D or on 2D whereas treatment of chondrocytes with Wnt-3a abrogates this effect. However, induction of canonical Wnt signaling inhibits chondrogenic markers on 2D but enhances chondrogenic re-differentiation on 2D with C3 transferase or in 3D. These data provide insights on the context-dependent role of RhoA and Wnt signaling in de differentiation and on mechanisms to induce chondrogenic markers for therapeutic approaches. PMID- 28865753 TI - Developing an emergency department crowding dashboard: A design science approach. AB - BACKGROUND: As an emergency department (ED) is a complex adaptive system, the analysis of continuously gathered data is valuable to gain insight in the real time patient flow. To support the analysis and management of ED operations, relevant data should be provided in an intuitive way. AIM: Within this context, this paper outlines the development of a dashboard which provides real-time information regarding ED crowding. METHODS: The research project underlying this paper follows the principles of design science research, which involves the development and study of artifacts which aim to solve a generic problem. To determine the crowding indicators that are desired in the dashboard, a modified Delphi study is used. The dashboard is implemented using the open source Shinydashboard package in R. RESULTS: A dashboard is developed containing the desired crowding indicators, together with general patient flow characteristics. It is demonstrated using a dataset of a Flemish ED and fulfills the requirements which are defined a priori. CONCLUSIONS: The developed dashboard provides real time information on ED crowding. This information enables ED staff to judge whether corrective actions are required in an effort to avoid the adverse effects of ED crowding. PMID- 28865754 TI - Prolonged sleep deprivation decreases cell proliferation and immature newborn neurons in both dorsal and ventral hippocampus of male rats. AB - Previous studies have indicated that sleep deprivation negatively affects hippocampal neurogenesis, which may explain the reason for the relation between sleep loss and depression. Increasing evidence indicates that the hippocampus is anatomically and functionally segregated along a dorsolateral (cognitive function)/ventromedial (control for mood and stress response) axis. Thus, the present study was conducted to elucidate regional differences in the adverse effects of sleep deprivation on hippocampal neurogenesis. Male Sprague-Dawley rats were subjected to sleep deprivation using the "platform on the water" method for 24- or 72-h. Quantification of hippocampal cell proliferation and immature newborn neurons was stereologically estimated using immunostaining with Ki-67 and doublecortin (DCX), respectively, by optical fractionator method. A consecutive three days of sleep deprivation significantly reduced the density of Ki-67- and DCX-immunopositive cells both in the dorsal and ventral hippocampal subgranular zone and the decrease in DCX-labeled cells was more pronounced in the ventral hippocampus than in dorsal region. Our results indicate that prolonged sleep deprivation decreases hippocampal cell proliferation and neurogenesis in both the dorsal and ventral dentate gyrus. Future studies will be needed to clarify the impact of sleep deprivation-induced decreases in hippocampal neurogenesis on the development of depression. PMID- 28865755 TI - The relationship between the superior frontal cortex and alpha oscillation in a flanker task: Simultaneous recording of electroencephalogram (EEG) and near infrared spectroscopy (NIRS). AB - Activity in the alpha band of the electroencephalogram (EEG) reflects functional inhibition of the cerebral cortex. The superior frontal cortex (SFC) is known to control alpha activity. Based on this relationship between SFC and alpha, we hypothesized that SFC controlled alpha mediates proactive control over interference. In this study, we examined the relationship between SFC and alpha in the flanker task by simultaneously recording EEG and near infrared spectroscopy (NIRS). Forty participants performed a flanker task with occasional (compatible 75%, incompatible 25%) and successive (incompatible 100%) conditions. In the occasional condition, larger SFC activity was related to pre-stimulus alpha enhancement under occipital electrodes. This is consistent with a model in which SFC enhances pre-stimulus alpha activity, leading to proactive control over interference. However, we could not detect a correlation between SFC activity and alpha activity in the successive condition. Active inhibition may have been reduced by a need to continuously inhibit brain regions associated with the irrelevant information. This may have reduced the role of the SFC in controlling alpha activity. Based on these findings, we postulate that there are two cerebral mechanisms of proactive control over interference. PMID- 28865756 TI - Curvilinear relationship between age and assisted reproduction technique success: retrospective analyses of US National ART Surveillance System data from 2010 2014. AB - In assisted reproduction technique cycles using fresh autologous embryos, the pattern by which outcomes per started cycle (live birth and clinical pregnancy) and per clinical pregnancy (live birth and miscarriage) change with age was determined. A dataset was created with 488,351 cycles. Success rates changed with age following well-fitted, ?-shaped curvilinear (quadratic, cubic, quartic) regressions. These rates increased steadily from age <24-28 years (P = 0.001; P = 0.02; P = 0.04; respectively) with positive slopes (P <= 0.03); live birth and pregnancy rates per cycle were lower in women aged <25 years versus women aged 25 28 years (P = 0.0002; P = 0.01, respectively), and declined steadily thereafter with negative slopes (P < 0.0001). The initial increase occurred at decreasing rates; subsequent decline occurred at increasing rates. Women aged <29 years with successful outcomes were older than those who were unsuccessful (P = 0.001; P = 0.04; P = 0.001; respectively); those with successful outcomes were younger in other age groups (P < 0.0001). Miscarriage followed similar but reverse ?-shaped curvilinear regressions. Age-driven decline in success rates begins <30 years and occurs at increasing rates, suggesting that women >30 years old with infertility should not delay assisted reproduction, if it is their only option. PMID- 28865758 TI - High doses of systemic corticosteroids in patients hospitalised for exacerbation of chronic obstructive pulmonary disease. A cohort study. AB - OBJECTIVES: To assess the effect of high doses of corticosteroids in patients hospitalised for exacerbation of chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: A prospective cohort study was conducted on patients hospitalized with COPD between January and March 2015, grouped according to the glucocorticoid dosage administered (cutoff, 40mg of prednisone/day). We compared the results of hospital stay, readmission and mortality at 3 months of discharge. RESULTS: We analysed 87 patients. The median daily dose was 60mg of prednisone (interquartile range, 46.67-82.33mg/day), and the administration route was intravenous in 96.6% of the cases. We established a relative risk (RR) for hospital stays longer than 8 days of 1.095 (95% CI 0.597-2.007; P=.765) when steroid dosages greater than 40mg/day were employed. In these patients, the hazard ratio (HR) for readmission in the 3 months after discharge was 0.903 (95% CI 0.392-2.082; P=.811), and the mortality was 1.832 (95% CI 0.229-16.645; P=.568). Neither the RR nor the HR varied in a statistically significant manner after adjusting for confounding factors. CONCLUSIONS: A daily dose greater than 40mg of prednisone in patients hospitalised for COPD exacerbation was not associated with a shorter hospital stay or a reduction in readmissions or mortality at 3 months. PMID- 28865757 TI - A cell impedance-based real-time in vitro assay to assess the toxicity of amphotericin B formulations. AB - Aerosolized liposomal amphotericin B (L-AmB) has been investigated as prophylaxis against invasive aspergillosis. However, the clinical results are controversial and some trials suggest that toxicity could be a limitation for wider use. Our aim was to assess the dynamics of cell toxicity induced in a human alveolar epithelial cell line (A549) after exposure to L-AmB (50 to 400MUg/ml) or amphotericin B deoxycholate (D-AmB; 50 to 200MUg/ml) by monitoring real-time A549 cell viability using an impedance-based technology. Results were expressed as cell index values integrating cell adhesion, proliferation, and survival. In parallel, the gene expression of proinflammatory cytokines was quantified at 6 and 24h after drug addition by real-time RT-PCR on cell lysates. No sustained reduction of cell indexes was observed with L-AmB or empty liposomes, even at 400MUg/ml. Only the highest concentration tested of L-AmB (400MUg/ml) yielded transient significant 6-fold and 4-fold induction of TNF-alpha and IL-8 mRNAs, respectively. In contrast, D-AmB induced a decrease in cell indexes and only the 50MUg/ml concentration of D-AmB was followed by cell recovery, higher concentrations leading to cell death. Significant 4-fold, 7-fold and 3-fold inductions of TNF-alpha, IL-8 and IL-33 mRNAs were also observed at 6h with 50MUg/ml of D-AmB. In conclusion, continuous cell impedance measurement showed no toxicity on overall cellular behavior although a slight proinflammatory cytokine expression is possible after L-AmB challenge. Real-time kinetics of cell impedance is an interesting tool for initial screening of cell toxicity. PMID- 28865759 TI - Enhanced transmucosal delivery of itraconazole by thiolated d-alpha-tocopheryl poly(ethylene glycol) 1000 succinate micelles for the treatment of Candida albicans. AB - This study aimed to investigate the transmucosal delivery of itraconazole (ITZ) by thiolated d-alpha-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS-Cys) micelles. TPGS-Cys polymer was successfully synthesized by the simple coupling between carboxyl-activated TPGS and Cys as confirmed by NMR and FTIR techniques. Afterwards, the TPGS/TPGS-Cys micelles were prepared using the blend of TPGS and TPGS-Cys at 10:0, 7:3, 5:5, 3:7 and 0:10mass ratios. All micelles had the size ranged from 8 to 10nm with narrow size distribution and showed spherical in shape. The surface of the 10:0 TPGS micelles exhibited negatively charge while, the TPGS-Cys micelles demonstrated the slightly positive surface charge. The critical micelle concentration, loading capacity and release profiles of TPGS/TPGS-Cys micelles were comparable to the TPGS micelles. The release of ITZ from all micelles was biphasic and sustained in simulated saliva fluid over 48h. The 3:7 and 0:10 TPGS/TPGS-Cys micelles had a good mucoadhesive property. Meanwhile, only 0:10 TPGS/TPGS-Cys micelles enhanced the permeability through buccal mucosa and potentiated the antifungal activity of ITZ against Candida albicans by at least 1.35 folds as compared to ITZ alone. Therefore, this formulation can be further developed for the transmucosal delivery of ITZ for the treatment of C. albicans. PMID- 28865762 TI - Uncoiling the Coil: Coil Extrusion After Coil Assisted Retrograde Transvenous Obliteration for Gastric Variceal Bleeding. PMID- 28865761 TI - Predicting severe hematologic toxicity from extended-field chemoradiation of para aortic nodal metastases from cervical cancer. AB - PURPOSE: The purpose of this study was to determine factors predictive for severe hematologic toxicity (HT) in cervical cancer patients with para-aortic lymph node metastasis treated with concurrent cisplatin chemoradiation to an extended field (EFCRT). METHODS AND MATERIALS: Thirty-eight patients with cervical cancer and para-aortic lymph node metastasis who underwent EFCRT were analyzed. Active bone marrow was defined as the region within irradiated total bone marrow (BMTOT) with a standard uptake value on 18F-fluorodeoxyglucose positron emission tomography/computed tomography greater than the mean standard uptake value for BMTOT. Serial weekly blood counts from the beginning to the end of radiation treatment were evaluated for HT using Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Nineteen patients had grade 3 or higher hematologic toxicity (HT3+), not including lymphocyte toxicity. Obese patients (n = 12) were less likely to get HT3+ (P = .03) despite getting equivalent doses of chemotherapy. Volumes of BMTOT and active bone marrow receiving doses of 20, 30, and 45 Gy and body mass index significantly predicted HT3+. Patients who had HT3+ had prolonged treatment time (62 vs 53 days, P < .001). CONCLUSIONS: For patients receiving EFCRT, bone marrow irradiation parameters and patient body mass index were associated with HT3+. A simplified nomogram has been created to predict HT3+ in these patients, allowing the potential to explore bone marrow-sparing delivery techniques. PMID- 28865760 TI - Inhibition of lysozyme amyloidogenesis by phospholipids. Focus on long-chain dimyristoylphosphocholine. AB - BACKGROUND: Protein amyloid aggregation is an important pathological feature of a group of different degenerative human diseases called amyloidosis. We tested effect of two phospholipids, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) on amyloid aggregation of hen egg white (HEW) lysozyme in vitro. METHODS: Effect of phospholipids was investigated using spectroscopic techniques (fluorescence and CD spectroscopy), atomic force microscopy and image analysis. RESULTS: Phospholipids DMPC and DHPC are able dose-dependently inhibit lysozyme fibril formation. The length of the phospholipid tails and different structural arrangement of the phospholipid molecules affect inhibitory activity; long-chain DMPC inhibits fibrillization more efficiently. Interestingly, interference of DMPC with lysozyme amyloid fibrils has no effect on their morphology or amount. CONCLUSIONS: Phospholipid molecules have significant effect on lysozyme amyloid fibrillization. We suggest that inhibitory activity is due to the interference of phospholipids with lysozyme leading to the blocking of the intermolecular protein interactions important for formation of the cross-beta structure within the core of the fibrils. The higher inhibitory activity of DMPC is probably due to adsorption of protein molecules on the liposome surfaces which caused decrease of species needed for fibrillization. Interaction of the phospholipids with formed fibrils is not sufficient enough to interrupt the bonds in beta-sheets which are required for destroying of amyloid fibrils. GENERAL SIGNIFICANCE: The obtained results contribute to a better understanding of the effect of phospholipids on amyloid fibrillization of the lysozyme. The data suggest that DMPC and DHPC phospholipids represent agents able to modulate lysozyme amyloid aggregation. PMID- 28865763 TI - Ascariasis Diagnosed by Wireless Capsule Endoscopy. PMID- 28865764 TI - The Combination Use of an Acetic Acid Indigo Carmine Mixture and Linked-Color Imaging to Detect Early Gastric Cancer. PMID- 28865765 TI - Two Colonic Masses: Twice the Enigma. PMID- 28865766 TI - Efficacy of a Surveillance Endoscopy After an Ileorectal Anastomosis in Patients With Ulcerative Colitis. PMID- 28865767 TI - Management of Acute Variceal Hemorrhage as a Model of Individualized Care for Patients With Cirrhosis. PMID- 28865768 TI - A first step to STOP cystic fibrosis exacerbations. PMID- 28865769 TI - Take it to the Bank. PMID- 28865770 TI - Immuno-engineering: The Next Frontier in Therapeutics Delivery. PMID- 28865771 TI - Can skull form predict the shape of the temporomandibular joint? A study using geometric morphometrics on the skulls of wolves and domestic dogs. AB - The temporomandibular joint (TMJ) conducts and restrains masticatory movements between the mammalian cranium and the mandible. Through this functional integration, TMJ morphology in wild mammals is strongly correlated with diet, resulting in a wide range of TMJ variations. However, in artificially selected and closely related domestic dogs, dietary specialisations between breeds can be ruled out as a diversifying factor although they display an enormous variation in TMJ morphology. This raises the question of the origin of this variation. Here we hypothesise that, even in the face of reduced functional demands, TMJ shape in dogs can be predicted by skull form; i.e. that the TMJ is still highly integrated in the dog skull. If true, TMJ variation in the dog would be a plain by-product of the enormous cranial variation in dogs and its genetic causes. We addressed this hypothesis using geometric morphometry on a data set of 214 dog and 60 wolf skulls. We digitized 53 three-dimensional landmarks of the skull and the TMJ on CT-based segmentations and compared (1) the variation between domestic dog and wolf TMJs (via principal component analysis) and (2) the pattern of covariation of skull size, flexion and rostrum length with TMJ shape (via regression of centroid size on shape and partial least squares analyses). We show that the TMJ in domestic dogs is significantly more diverse than in wolves: its shape covaries significantly with skull size, flexion and rostrum proportions in patterns which resemble those observed in primates. Similar patterns in canids, which are carnivorous, and primates, which are mostly frugivorous imply the existence of basic TMJ integration patterns which are independent of dietary adaptations. However, only limited amounts of TMJ variation in dogs can be explained by simple covariation with overall skull geometry. This implies that the final TMJ shape is gained partially independently of the rest of the skull. PMID- 28865772 TI - Expression of myosin heavy chain isoforms mRNA transcripts in the temporalis muscle of common chimpanzees (Pan troglodytes). AB - PURPOSE: The common chimpanzee (Pan troglodytes) is the primate that is phylogenetically most closely related to humans (Homo sapiens). In order to shed light on the anatomy and function of the temporalis muscle in the chimpanzee, we have analyzed the expression patterns of the mRNA transcripts of the myosin heavy chain (MyHC) isoforms in different parts of the muscle. BASIC PROCEDURES: We dissected the superficial, deep and sphenomandibularis portions of the temporalis muscle in five adult P. troglodytes and quantified the expression of the mRNA transcripts of the MyHC isoforms in each portion using real-time quantitative polymerase chain reaction. MAIN FINDINGS: We observed significant differences in the patterns of expression of the mRNA transcripts of the MyHC-IIM isoform between the sphenomandibularis portion and the anterior superficial temporalis (33.6% vs 47.0%; P=0.032) and between the sphenomandibularis portion and the anterior deep temporalis (33.6% vs 43.0; P=0.016). We also observed non significant differences between the patterns of expression in the anterior and posterior superficial temporalis. PRINCIPAL CONCLUSIONS: The differential expression patterns of the mRNA transcripts of the MyHC isoforms in the temporalis muscle in P. troglodytes may be related to the functional differences that have been observed in electromyographic studies in other species of primates. Our findings can be applicable to the fields of comparative anatomy, evolutionary anatomy, and anthropology. PMID- 28865773 TI - In vivo characterization of the murine venous system before and during dobutamine stimulation: implications for preclinical models of venous disease. AB - Although widely used as a preclinical model for studying venous diseases, there is a scarcity of in vivo characterizations of the naive murine venous system. Additionally, previous studies on naive veins (ex vivo) have not included the influence of surrounding structures and biomechanical forces. Using MRI, we noninvasively quantified the cross-sectional area, cyclic strain, and circularity of the venous system in young and old, male and female C57BL/6 mice. We investigated the most common venous locations used to perform venous disease research: the common jugular vein, suprarenal inferior vena cava (IVC), infrarenal IVC, common iliac vein, and common femoral vein. Our results elucidate age-dependent changes in venous cross-sectional area, which varied by location. Maximum cyclic strain, a parameter of lumen expansion, showed 10% change across the cardiac cycle, approximately half the magnitude of arteries. Veins demonstrated noncircular shapes, particularly in the core vasculature. The cardiovascular stressor dobutamine had only a small impact on the venous system. Also, our data demonstrate that the peripheral veins tend to decrease in cross sectional area and circularity with age. Conversely, the IVC tends to increase in size and circularity with age, with males exhibiting larger variability in response to dobutamine compared to females. This work provides a foundation for drawing age and sex comparisons in disease models, and represents the first in vivo characterization of the murine venous system at rest and during the application of a pharmacological exercise surrogate. PMID- 28865774 TI - Clock Genes, Metabolism, and Cardiovascular Risk. AB - The molecular clockwork drives rhythmic oscillations of signaling pathways managing intermediate metabolism; the circadian timing system synchronizes behavioral cycles and anabolic/catabolic processes with environmental cues, mainly represented by light/darkness alternation. Metabolic pathways, bile acid synthesis, and autophagic and immune/inflammatory processes are driven by the biological clock. Proper timing of hormone secretion, metabolism, bile acid turnover, autophagy, and inflammation with behavioral cycles is necessary to avoid dysmetabolism. Disruption of the biological clock and mistiming of body rhythmicity with respect to environmental cues provoke loss of internal synchronization and metabolic derangements, causing liver steatosis, obesity, metabolic syndrome, and diabetes mellitus. PMID- 28865775 TI - Cardiac Clocks and Preclinical Translation. AB - Circadian rhythms are fundamentally important for cardiovascular health, including heart rate, blood pressure, and molecular gene and protein responses. Rhythms also play a direct role in the pathophysiology of heart disease, such as in the timing of onset and severity of myocardial infarction, sudden cardiac death, ventricular arrhythmias, and stroke. Importantly, a flurry of new studies reveals translational applications for circadian biology to clinical medicine, and especially cardiology. Circadian medicine is a promising new approach that targets the heart's daily physiologic and molecular rhythms to benefit the treatment of patients with cardiovascular disease. PMID- 28865776 TI - Circadian Periodicity of Ischemic Heart Disease: A Systematic Review of the Literature. AB - The authors performed a MEDLINE search to identify reports, published during the last 20 years, focused on circadian variation of acute myocardial infarction (AMI), and prevalence and the ratios between the number of events per hour during the morning and the other hours of the day were calculated. Despite the optimization of interventional and medical therapy of AMI since the first reports of circadian patterns in AMI occurrence, it was found that such a pattern still exists and that AMI happens most frequently in the morning hours. PMID- 28865777 TI - Seasonal Periodicity of Ischemic Heart Disease and Heart Failure. AB - Seasonal variation for ischemic heart disease and heart failure is known. The interplay of environmental, biological, and physiologic changes is fascinating. This article highlights the seasonal periodicity of ischemic heart disease and heart failure and examines some of the potential reasons for these unique observations. PMID- 28865778 TI - Chronobiologic Aspects of Venous Thromboembolism. AB - In recent years, several studies have consistently described the chronobiologic aspects of many cardiovascular diseases. Several studies have also assessed the circadian and circannual patterns of occurrence and mortality of deep vein thrombosis and pulmonary embolism, but the results have been less univocal. Different mechanisms have been proposed to explain these possible patterns, including oscillation of coagulation proteins, the role of meteorologic parameters, and air pollution. This article summarizes the available evidence on chronobiologic aspects of venous thromboembolism and discusses the casual mechanism. PMID- 28865779 TI - Chronobiology of Acute Aortic Syndromes. AB - Acute aortic syndromes are highly morbid conditions that require prompt diagnosis and management. Aortic dissections have rhythmic patterns, with notable peaks at certain points in every 24 hours as well as weekly and seasonal variations. Several retrospective studies have assessed the chronobiology of acute aortic dissections and there seems to be a winter seasonal peak and morning daily peak in incidence. Although the pathophysiology of this chronobiology is unclear, there are several environmental and physiologic possibilities. This article reviews the major studies examining the chronobiology of acute aortic dissection, and summarizes some theories on the pathophysiology of this phenomenon. PMID- 28865780 TI - Circaseptan Periodicity of Cardiovascular Diseases. AB - The occurrence of cardiovascular events shows a different distribution during the week, with many studies reporting a Monday peak, possibly related to the role of stress associated with commencing weekly activities. Furthermore, a higher mortality has been observed among patients hospitalized for cardiovascular and other disorders on weekends, a phenomenon known as "weekend effect." Such effect may be explained by a higher level of disease severity among patients admitted over the weekend, and/or by a poorer quality of care associated with shortage of staff, lower experience of personnel, and limited availability of therapeutic and diagnostic procedures. PMID- 28865781 TI - Sex and Circadian Periodicity of Cardiovascular Diseases: Are Women Sufficiently Represented in Chronobiological Studies? AB - Women are often excluded/underrepresented in clinical trials; sometimes, the number of men/women participants or separate analysis by sex are not reported. A robust body of evidence demonstrated that several life-threatening acute cardiovascular diseases, for example, acute myocardial infarction, sudden cardiac death, cardiac arrest, rupture or dissection of aortic aneurysms, and stroke, exhibit a circadian periodicity with a morning peak. An analysis of 20 years of chronobiologic studies (44% of them, accounting for 85% of total cases, with separate analysis by sex) confirmed that morning hours are a critical time of onset of acute cardiovascular diseases in men and women. PMID- 28865782 TI - Signal Transduction and Chronopharmacology of Regulation of Circadian Cardiovascular Rhythms in Animal Models of Human Hypertension. AB - Inbred strains of rats can be used as models of human hypertension to evaluate mechanisms of regulation of the circadian rhythms underlying hypertension. Blood pressure and heart rate rhythms in rodents are endogenous (circadian). Studies have been performed in rats on the turnover of norepinephrine, on processes of signal transduction in the beta-adrenoceptor-adenylate cyclase-cyclic AMP phosphodiesterase system and in the renin-angiotensin-aldosterone system, and on circadian rhythms in blood pressure and heart rate using radiotelemetry. The findings allowed a better understanding of the circadian phase-dependent kinetics and effects of cardiovascular active drugs (chronopharmacology) used in humans. PMID- 28865783 TI - Bedtime Blood Pressure Chronotherapy Significantly Improves Hypertension Management. AB - Consistent evidence of numerous studies substantiates the asleep blood pressure (BP) mean derived from ambulatory BP monitoring (ABPM) is both an independent and a stronger predictor of cardiovascular disease (CVD) risk than are daytime clinic BP measurements or the ABPM-determined awake or 24-hour BP means. Hence, cost effective adequate control of sleep-time BP is of marked clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of 6 different classes and their combinations significantly improves BP control, particularly sleep-time BP, and reduces adverse effects. PMID- 28865784 TI - Bedtime Chronotherapy with Conventional Hypertension Medications to Target Increased Asleep Blood Pressure Results in Markedly Better Chronoprevention of Cardiovascular and Other Risks than Customary On-awakening Therapy. AB - The bases for bedtime hypertension chronotherapy (BHCT) as superior chronoprevention against cardiovascular disease (CVD) are: (1) correlation between blood pressure (BP) and various risks is greater for ambulatory BP monitoring (ABPM) than office BP measurements (OBPM); (2) asleep BP mean is a better predictor of CVD risk than ABPM awake and 24-hour means and OBPM; and (3) targeting of asleep BP by BHCT with one or more conventional medications versus usual on-awakening therapy better reduces major and total CVD events. BHCT offers the most cost-effective chronoprevention against adverse CVD outcomes in regular and vulnerable renal, diabetic, and resistant hypertensive patients. PMID- 28865785 TI - Erratum. PMID- 28865786 TI - A Journey into the Science of Cardiovascular Chronobiology. PMID- 28865787 TI - Sex-dependent effects of subacute mercuric chloride exposure on histology, antioxidant status and immune-related gene expression in the liver of adult zebrafish (Danio rerio). AB - Mercury (Hg) is a global pollutant that causes negative health effects. In order to assess Hg-induced hepatotoxicity in fish and examine whether gender differences existed in response to Hg exposure, adult zebrafish were exposed to 0, 15 and 30 MUg L-1 Hg2+ for 30 days, and histology, antioxidant status and the transcription levels of several immune-related genes were examined in the liver. Hg2+ exposure caused a dose-dependent increase in histopathological lesions of the liver, including vacuolization, parenchyma disorganization and pyknotic nucleus, and these lesions were more severe in males than in females. In females, Hg2+ exposure decreased CAT activity and its mRNA levels, while increased GSH content and the expressions of sod1, gpx1a, gstr and keap1. In males, the decrease in cat1 expression and the increase in GST activity, GSH and MDA contents as well as gpx1a, gstr, nrf2 and keap1 mRNA levels were observed in Hg2+ exposed groups, but the activities of CAT, SOD and GPX were only stimulated in the 15 MUg L-1 Hg2+ group. Moreover, both in females and males, Hg2+ exposure down-regulated il-8 expression while up-regulated il-10 and lyz mRNAs. However, the down-regulation of il-1beta and tnfalpha was detected only in males under Hg2+ treatments. Thus, our results indicated that HgCl2 exposure induced histopathological damage, oxidative stress and immunotoxicity in the liver of zebrafish. Different response patterns of histology, antioxidant status and immune defenses to Hg2+ between females and males suggested sex-dependent effects of Hg, and males showed more vulnerable to Hg2+ exposure than females. PMID- 28865788 TI - Bacterial community and molecular ecological network in response to Cr2O3 nanoparticles in activated sludge system. AB - The potential environmental risks of chromium oxide nanoparticles (Cr2O3 NPs) have caused great concerns. However, their possible impacts on activated sludge process are very limited. In this study, we carried out long-term exposure experiments to evaluate the influence of Cr2O3 NPs on wastewater nutrient removal, bacterial community and molecular ecological network (MEN) in the sequencing batch reactor (SBR). It was found that 1 mg/L Cr2O3 NPs increased the effluent concentrations of NO3--N and TP from 6.5 to 15.4 mg/L, and 0.6-2.7 mg/L, indicating the serious deterioration of denitrification and phosphorus removal. Cr2O3 NPs significantly decreased the bacterial richness in terms of the number of different OTUs (626 OTUs in Cr2O3 samples and 728 OTUs in controls). Detrended correspondence analysis (DCA) showed that the overall taxonomic structure of bacterial community was altered at Cr2O3 NPs in activated sludge systems. Further analysis revealed that three genera related to denitrification (Desulfovibrio, Pseudomonas and Hyphomicrobium) and two genera related to phosphorus removal (Accumulibacter and Rhodobacter) decreased significantly, which was consistent with the observed influences of Cr2O3 NPs on denitrification and phosphorus removal. MEN analysis showed that the overall architecture of the network under Cr2O3 NPs was substantially alerted. beta-Proteobacteria, playing an important role in nutrients removal, had less complex interactions in the presence of Cr2O3 NPs, which may be associated with the deterioration of denitrification and phosphorus removal. This study provides insights into our understanding of shifts in the bacteria community and their MEN under Cr2O3 NPs in activated sludge systems. PMID- 28865789 TI - Historical record of trace elements (1983-2007) in scales from Atlantic salmon (Salmo salar): Study of past metal contamination from a copper mine (Ulla River, NW Iberian Peninsula). AB - The chemical composition of fish scales has been reported to reflect the composition of the waters in which fish have been resident, therefore having the potential for the assessment of temporal trends in watershed water quality. Here we studied the historical (1983-2007) metal contamination in the Ulla river (NW Iberian Peninsula) watershed - impacted by a Cu mine that was in operation from 1973 until 1988 - by means of the analysis of major and trace elements in salmon scales. Results indicate the presence of a significant contamination for several metals (especially Cu, Au, Ag, Sb, Zn) during the 1980's. Concentrations of Cu in salmon scales during the influence of the mine (1983-1990) were 20 +/- 5 MUg/g, exceeding the values for the recent years (1995-2007): 1.8 +/- 0.4 MUg/g. Concentrations for Au in these two periods were 31 +/- 12 and 2.1 +/- 1.2 ng/g; for Ag: 21 +/- 4 and 4 +/- 2 ng/g; for Sb: 48 +/- 21 and 15 +/- 4 ng/g; and for Zn: 133 +/- 16 and 93 +/- 10 MUg/g. The estimated concentrations of dissolved copper during the operation of the mine indicate a scenario of toxic effects due to sensory impairments in the salmon, and a reduction in scales calcification. The results presented here demonstrate that the analysis of trace elements in archived fish scales is a suitable tool for the reconstruction of the past contamination in aquatic systems, and it can be also used as a non-lethal approach for biomonitoring purposes. PMID- 28865790 TI - Wastewater treatment plant effluents as source of cosmetic polyethylene microbeads to freshwater. AB - Microplastics in the environment are either a product of the fractionation of larger plastic items or a consequence of the release of microbeads, which are ingredients of cosmetics, through wastewater treatment plant (WWTP) effluents. The aim of this study was to estimate the amount of microbeads that may be released by the latter pathways to surface waters using Ljubljana, Slovenia as a case study. For this purpose, microbeads contained in cosmetics were in a first step characterized for their physical properties and particle size distribution. Subsequently, daily emission of microbeads from consumers to the sewerage system, their fate in biological WWTPs and finally their release into surface waters were estimated for Ljubljana. Most of the particles found in cosmetic products were <100 MUm. After application, microbeads are released into sewerage system at an average rate of 15.2 mg per person per day. Experiments using a lab-scale sequencing batch biological WWTP confirmed that on average 52% of microbeads are captured in activated sludge. Particle size analyses of the influent and effluent confirmed that smaller particles (up to 60-70 MUm) are captured within activated sludge while bigger particles were detected in the effluent. Applying these data to the situation in Ljubljana indicates that about 112,500,000 particles may daily be released into the receiving river, resulting in a microbeads concentration of 21 particles/m3. Since polyethylene particles cannot be degraded and thus likely accumulate, the data raise concerns about potential effects in aquatic ecosystems in future. PMID- 28865792 TI - Delayed fluorescence as an indicator of the influence of the herbicides Irgarol 1051 and Diuron on hard coral Acropora digitifera. AB - We examined the effect of two herbicides (Irgarol 1051 and Diuron) on symbiotic dinoflagellates in the hard coral Acropora digitifera using delayed fluorescence (DF), specifically assessing changes in molecular membrane transport, i.e. inflow and outflow rates, and the binding of the herbicides to target proteins in photosystem II. The DF approach is rapid (e.g. measurement time, 60 s) and non invasive, and can provide data on the extent of a photosynthetic system and the activity of its electron carriers. The DF of A. digitifera is inhibited 2 h after exposure to 1 MUg/L of either Irgarol or Diuron. Analysis of DF inhibition over time by a compartment model suggests that Irgarol exposure results in a relatively higher inflow rate and lower outflow rate than does Diuron exposure. This suggests that Irgarol exposure more strongly inhibits photosynthesis and that the coral symbiotic dinoflagellates recover less from inhibition. PMID- 28865791 TI - Cell death pathways of particulate matter toxicity. AB - Humans are exposed to various complex mixtures of particulate matter (PM) from different sources. Long-term exposure to high levels of these particulates has been linked to a diverse range of respiratory and cardiovascular diseases that have resulted in hospital admission. The evaluation of the effects of PM exposure on the mechanisms related to cell death has been a challenge for many researchers. Therefore, in this review, we have discussed the effects of airborne PM exposure on mechanisms related to cell death. For this purpose, we have compiled literature data on PM sources, the effects of exposure, and the assays and models used for evaluation, in order to establish comparisons between various studies. The analysis of this collected data suggested divergent responses to PM exposure that resulted in different cell death types (apoptosis, autophagy, and necrosis). In addition, PM induced oxidative stress within cells, which appeared to be an important factor in the determination of cell fate. When the levels of reactive oxygen species were overpowering, the cellular fate was directed toward cell death. This may be the underlying mechanism of the development or exacerbation of respiratory diseases, such as emphysema and chronic obstructive pulmonary diseases. In addition, PM was shown to cause DNA damage and the resulting mutations increased the risk of cancer. Furthermore, several conditions should be considered in the assessment of cell death in PM-exposed models, including the cell culture line, PM composition, and the interaction of the different cells types in in vivo models. PMID- 28865793 TI - Tracing the sources of lead (Pb) in Brunei Bay, Borneo by using integrated spectrometry ICP-MS and chemometric techniques. AB - The present study aims to define the possible sources that contribute to the level of Pb into the Brunei Bay, Borneo. The cluster analysis has classified the bay into the northern part with heavy and agriculture-related industries; the southern area with a moderate rural human settlement as well as the southwestern area with a more pristine environment and a low level of human settlement. The score plot of spatial discriminant analysis verified a significant influence of the river system toward the estuary, whereas the temporal discriminant analysis has discriminated the seasonal changes. In comparison to elsewhere, the stable Pb isotopic ratios in Brunei Bay showed a fingerprint similar to coal-related sources and of aerosol input. Briefly, even though Pb in the Brunei Bay ecosystem proved to be at a low level, the stable Pb isotopic ratios showed that human and industrial activities are slowly contributing Pb into the bay ecosystem. PMID- 28865795 TI - Insights into the molecular basis for substrate binding and specificity of the fungal cystine transporter CgCYN1. AB - Cystine transporters are a clinically important class of transporters found in bacteria, pathogenic fungi and mammalian cells. Despite their significance, very little is known about the mechanism of substrate recognition and transport. We have carried out studies on the plasma membrane Candida glabrata cystine transporter, CgCYN1 a member of the amino acid-polyamine-organocation (APC) transporter superfamily. A homology model of CgCYN1 was generated by using crystal structures of three known bacterial APC transporters followed by further refinement using molecular dynamics simulations. This revealed a possible translocation channel lined by TMD1, TMD3, TMD6, TMD8 and TMD10 helices. In silico docking studies with cystine along with comparison with other known cystine permeases and closely related lysine permeases allowed prediction of amino acid residues specifically involved in cystine binding. To validate this model a total of 19 predicted residues were subjected to site directed mutagenesis and functionally evaluated by growth on cystine and the analogues cystathionine and seleno-dl-cystine. Biochemical evaluation by radioactive uptake assays confirmed that these mutants showed reduced cystine uptake. Detailed kinetic analysis studies for the transport defective mutants revealed the involvement of residue G255 from the conserved FAYGGTE motif of TMD 6, and T339, S340 and H347 (all from TMD 8) in cystine binding. The implications of these findings on the homologous mammalian cystine transporter, XcT are also discussed. PMID- 28865794 TI - Changes in glucosylceramide structure affect virulence and membrane biophysical properties of Cryptococcus neoformans. AB - Fungal glucosylceramide (GlcCer) is a plasma membrane sphingolipid in which the sphingosine backbone is unsaturated in carbon position 8 (C8) and methylated in carbon position 9 (C9). Studies in the fungal pathogen, Cryptococcus neoformans, have shown that loss of GlcCer synthase activity results in complete loss of virulence in the mouse model. However, whether the loss of virulence is due to the lack of the enzyme or to the loss of the sphingolipid is not known. In this study, we used genetic engineering to alter the chemical structure of fungal GlcCer and studied its effect on fungal growth and pathogenicity. Here we show that unsaturation in C8 and methylation in C9 is required for virulence in the mouse model without affecting fungal growth in vitro or common virulence factors. However, changes in GlcCer structure led to a dramatic susceptibility to membrane stressors resulting in increased cell membrane permeability and rendering the fungal mutant unable to grow within host macrophages. Biophysical studies using synthetic vesicles containing GlcCer revealed that the saturated and unmethylated sphingolipid formed vesicles with higher lipid order that were more likely to phase separate into ordered domains. Taken together, these studies show for the first time that a specific structure of GlcCer is a major regulator of membrane permeability required for fungal pathogenicity. PMID- 28865796 TI - pH regulates pore formation of a protease activated Vip3Aa from Bacillus thuringiensis. AB - Vip3Aa insecticidal protein is produced from Bacillus thuringiensis and exerts a broad spectrum of toxicity against lepidopteran insect species. Although Vip3Aa has been effectively used as part of integrated pest management strategies, the mechanism of the toxin remains unclear. Here, we investigated the effect of pH in a range from 5.0 to 10.0 on the pore-forming activity of the trypsin activated Vip3Aa (actVip3Aa) by in vitro pore-forming assays. Based on calcein release assay, actVip3Aa could permeabilize the artificial neutral liposomes under all the pH tested, except pH10.0. The maximum membrane permeability of actVip3Aa was detected at pH8.0 and the permeability decreased and abolished when exposing to acidic and alkaline conditions, respectively. The planar lipid bilayer experiment revealed that actVip3Aa formed ion channels at pH5.0-8.0 but no current signals were detected at pH10.0, consistent with the observation from calcein release assay. The toxin formed ion channels with a diameter of 1.4nm at pH8.0 and pore size was gradually decreased when reducing the pH. This study provided a view of the molecular mechanism of Vip3Aa by which the pore-forming activity is regulated by pH. PMID- 28865797 TI - Structure and function of membrane proteins encapsulated in a polymer-bound lipid bilayer. AB - New technologies for the purification of stable membrane proteins have emerged in recent years, in particular methods that allow the preparation of membrane proteins with their native lipid environment. Here, we look at the progress achieved with the use of styrene-maleic acid copolymers (SMA) which are able to insert into biological membranes forming nanoparticles containing membrane proteins and lipids. This technology can be applied to membrane proteins from any host source, and, uniquely, allows purification without the protein ever being removed from a lipid bilayer. Not only do these SMA lipid particles (SMALPs) stabilise membrane proteins, allowing structural and functional studies, but they also offer opportunities to understand the local lipid environment of the host membrane. With any new or different method, questions inevitably arise about the integrity of the protein purified: does it retain its activity; its native structure; and ability to perform its function? How do membrane proteins within SMALPS perform in existing assays and lend themselves to analysis by established methods? We outline here recent work on the structure and function of membrane proteins that have been encapsulated like this in a polymer-bound lipid bilayer, and the potential for the future with this approach. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain. PMID- 28865798 TI - MPP1 directly interacts with flotillins in erythrocyte membrane - Possible mechanism of raft domain formation. AB - Flotillins are prominent, oligomeric protein components of erythrocyte (RBC) membrane raft domains and are considered to play an important structural role in lateral organization of the plasma membrane. In our previous work on erythroid membranes and giant plasma membrane vesicles (GPMVs) derived from them we have shown that formation of functional domains (resting state rafts) depends on the presence of membrane palmitoylated protein 1 (MPP1/p55), pointing to its new physiological role. Exploration of the molecular mechanism of MPP1 function in organizing membrane domains described here, through searching for its molecular partners in RBC membrane by using different methods, led to the identification of the raft-marker proteins, flotillin 1 and flotillin 2, as hitherto unreported direct MPP1 binding-partners in the RBC membrane. These proteins are found in high molecular-weight complexes in native RBC membrane and, significantly, their presence was shown to be separate from the well-known protein 4.1-dependent interactions of MPP1 with membrane proteins. Furthermore, FLIM analysis revealed that loss of the endogenous MPP1-flotillins interactions resulted in significant changes in RBC membrane-fluidity, emphasizing the physiological importance of such interactions in vivo. Therefore, our data establish a new perspective on the role of MPP1 in erythroid cells and suggests that direct MPP1-flotillins interactions could be the major driving-force behind the formation of raft domains in RBC. PMID- 28865799 TI - Pharmacokinetics, Safety, and Tolerability of Tedizolid Phosphate After Single dose Administration in Healthy Korean Male Subjects. AB - PURPOSE: Tedizolid phosphate is a next-generation oxazolidinone prodrug that is transformed into the active moiety tedizolid. Its indication is acute bacterial skin and skin structure infections caused by gram-positive species, including methicillin-resistant Staphylococcus aureus. Although tedizolid phosphate has been marketed in Korea, no data on the pharmacokinetic (PK) properties or tolerability of tedizolid phosphate in Korean subjects are available. This study was designed to evaluate the PK properties, oral bioavailability, and tolerability with a single-dose oral and intravenous administration of tedizolid phosphate in healthy Korean male subjects. METHODS: A block-randomized, double blind, placebo-controlled, single-dose study was conducted in 3 groups (200, 400, and 600 mg; 10 subjects in each group). In the second part of the study, subjects from the 200-mg group received administration orally and intravenously (1-hour infusion) via 2-way crossover for the evaluation of absolute bioavailability. There was a 7-day washout period between treatments in the absolute bioavailability part of the study. Serial blood samples for PK analysis were collected for up to 72 hours. Tolerability was assessed by analysis of adverse events. FINDINGS: Thirty healthy Korean subjects completed the study and were included in the PK and tolerability analyses. Tedizolid phosphate was rapidly converted into tedizolid. After a single oral dose, the Tmax of tedizolid was observed to be 1.5 to 2.5 hours, and the plasma concentration-time curve of tedizolid showed a 2-phase elimination pattern, with a half-life of ~11 hours. Dose-dependent increases were observed in the AUClast value (29,441-78,062 MUg . h/L) and in the Cmax value (2679-6980 MUg/L) with the administration of tedizolid phosphate 200 to 600 mg PO. The absolute bioavailability of tedizolid was 95.2% (90% CI, 92.7%-97.8%) in the 200-mg administration group. There were no serious adverse events or clinically significant changes in the tolerability assessment. IMPLICATIONS: Tedizolid phosphate at doses of up to 600 mg was well-tolerated in these healthy Korean male subjects. Tedizolid shows dose linearity with oral administration, and no dose adjustment of tedizolid phosphate 200 mg would be needed when switching administration routes. ClinicalTrials.gov identifier: NCT02097043. PMID- 28865800 TI - The Role of Continuing Medical Education in Increasing Enrollment in Prescription Drug Monitoring Programs. AB - PURPOSE: Opioid diversion, misuse, and abuse are rapidly growing problems in the United States; >60% of all drug overdose deaths involve an opioid. At least 49 states now have fully operational prescription drug monitoring programs (PDMPs) to support legitimate medical use of controlled substances; however, there is considerable underutilization of such programs. METHODS: To increase awareness of PDMPs and their use, a continuing medical education program including 2 webcasts and a series of newsletters was offered to health care providers. FINDINGS: Four hundred and sixty-five clinicians participated in 1 of 2 webcasts. Of those, 207 clinicians responded to a pre-survey and 64 responded to a post-survey. Slightly more than half of clinicians were registered for their state's PDMP program before the educational intervention, and although significantly more clinicians reported increased likelihood to access their state PDMP after participation, the number that actually registered only trended toward a statistically significant increase to 74% after the education (P = 0.06). Immediate post-activity evaluation also indicated that the education significantly improved clinician knowledge of the characteristics of addiction, findings in a PDMP that would suggest diversion or abuse, and strategies to complement the use of a PDMP (P < 0.001). IMPLICATIONS: Continuing medical education is effective for improving clinician knowledge and confidence related to opioid misuse, abuse, and diversion and effective use of a PDMP; however, the education did not result in a significant increase in enrollment in state PDMPs. PMID- 28865801 TI - Approach to Acute Heart Failure in the Emergency Department. AB - Acute heart failure (AHF) patients rarely present complaining of 'acute heart failure.' Rather, they initially present to the emergency department (ED) with a myriad of chief complaints, symptoms, and physical exam findings. Such heterogeneity prompts an initially broad differential diagnosis; securing the correct diagnosis can be challenging. Although AHF may be the ultimate diagnosis, the precipitant of decompensation must also be sought and addressed. For those AHF patients who present in respiratory or circulatory failure requiring immediate stabilization, treatment begins even while the diagnosis is uncertain. The initial diagnostic workup consists of a thorough history and exam (with a particular focus on the cause of decompensation), an EKG, chest X-ray, laboratory testing, and point-of-care ultrasonography performed by a qualified clinician or technologist. We recommend initial treatment be guided by presenting phenotype. Hypertensive patients, particularly those in severe distress and markedly elevated blood pressure, should be treated aggressively with vasodilators, most commonly nitroglycerin. Normotensive patients generally require significant diuresis with intravenous loop diuretics. A small minority of patients present with hypotension or circulatory collapse. These patients are the most difficult to manage and require careful assessment of intra- and extra-vascular volume status. After stabilization, diagnosis, and management, most ED patients with AHF in the United States (US) are admitted. While this is understandable, it may be unnecessary. Ongoing research to improve diagnosis, initial treatment, risk stratification, and disposition may help ease the tremendous public health burden of AHF. PMID- 28865802 TI - "A light heart lives long": A new avenue of secondary prevention we must explore. PMID- 28865803 TI - Microbial Identification Using Electrochemical Detection of Metabolites. AB - Curbing antibiotic use requires the development of simple diagnostic tests that provide caregivers with reliable, immediately actionable information to identify whether there is a need to prescribe a specific antibiotic. This Forum article highlights advances in infection screening approaches that use electrochemistry to detect molecular biomarkers for distinct pathogenic infections. PMID- 28865804 TI - Flashing LEDs for Microalgal Production. AB - Flashing lights are next-generation tools to mitigate light attenuation and increase the photosynthetic efficiency of microalgal cultivation systems illuminated by light-emitting diodes (LEDs). Optimal flashing light conditions depend on the reaction kinetics and properties of the linear electron transfer chain, energy dissipation, and storage mechanisms of a phototroph. In particular, extremely short and intense light flashes potentially mitigate light attenuation in photobioreactors without impairing photosynthesis. Intelligently controlling flashing light units and selecting electronic components can maximize light emission and energy efficiency. We discuss the biological, physical, and technical properties of flashing lights for algal production. We combine recent findings about photosynthetic pathways, self-shading in photobioreactors, and developments in solid-state technology towards the biotechnological application of LEDs to microalgal production. PMID- 28865805 TI - De novo root regeneration from leaf explants: wounding, auxin, and cell fate transition. AB - Root organogenesis after tissue damage is a type of plant regeneration known as de novo root regeneration (DNRR). The DNRR process is widely exploited in agricultural technologies, such as cuttings for vegetative propagation. This review summarizes recent advances in our understanding of the cellular and molecular framework of DNRR, mainly focusing on rooting from Arabidopsis thaliana leaf explants. The framework comprises three successive phases, that is, early signaling, auxin accumulation, and cell fate transition, and involves two types of cells with different functions: the converter cell that converts the early signals as the input into auxin flux as the output; and the regeneration competent cell that undergoes fate transition guided by auxin. PMID- 28865806 TI - Resveratrol promotes human embryonic stem cells self-renewal by targeting SIRT1 ERK signaling pathway. AB - Resveratrol (RSV), a natural polyphenol component, has diverse biological properties. It has been shown that RSV regulated the self-renewal and differentiation of several types of stem cells, but the precise role of this compound on regulation of human embryonic stem cells (hESCs) self- renewal remained to be elucidated. Here we have shown that RSV promoted hESCs proliferation through cell cycle modulation and up-regulation of anti-apoptotic markers, without affecting pluripotency. Furthermore, inhibition of SIRT1 by EX 527 resulted in suppression of RSV-induced enhancement of hESCs self-renewal. RSV exerted its beneficial effects by activation of MEK/ERK signaling pathway as verified by application of specific MEK inhibitor, PD0325901. In conclusion, RSV elevated self-renewal of hESCs at least partly via "SIRT1-MEK/ERK" axis. These findings provide a novel application of RSV for developing a defined medium for hESCs culture which could help to better understanding of the signaling events that govern self-renewal of hESCs. PMID- 28865807 TI - Intracrine androgen biosynthesis, metabolism and action revisited. AB - Androgens play an important role in metabolic homeostasis and reproductive health in both men and women. Androgen signalling is dependent on androgen receptor activation, mostly by testosterone and 5alpha-dihydrotestosterone. However, the intracellular or intracrine activation of C19 androgen precursors to active androgens in peripheral target tissues of androgen action is of equal importance. Intracrine androgen synthesis is often not reflected by circulating androgens but rather by androgen metabolites and conjugates. In this review we provide an overview of human C19 steroid biosynthesis including the production of 11 oxygenated androgens, their transport in circulation and uptake into peripheral tissues. We conceptualise the mechanisms of intracrinology and review the intracrine pathways of activation and inactivation in selected human tissues. The contribution of liver and kidney as organs driving androgen inactivation and renal excretion are also highlighted. Finally, the importance of quantifying androgen metabolites and conjugates to assess intracrine androgen production is discussed. PMID- 28865808 TI - Monitoring the evolution and migration of a methane gas plume in an unconfined sandy aquifer using time-lapse GPR and ERT. AB - Fugitive methane (CH4) leakage associated with conventional and unconventional petroleum development (e.g., shale gas) may pose significant risks to shallow groundwater. While the potential threat of stray (CH4) gas in aquifers has been acknowledged, few studies have examined the nature of its migration and fate in a shallow groundwater flow system. This study examines the geophysical responses observed from surface during a 72day field-scale simulated CH4 leak in an unconfined sandy aquifer at Canadian Forces Base Borden, Canada, to better understand the transient behaviour of fugitive CH4 gas in the subsurface. Time lapse ground-penetrating radar (GPR) and electrical resistivity tomography (ERT) were used to monitor the distribution and migration of the gas-phase and assess any impacts to groundwater hydrochemistry. Geophysical measurements captured the transient formation of a CH4 gas plume emanating from the injector, which was accompanied by an increase in total dissolved gas pressure (PTDG). Subsequent reductions in PTDG were accompanied by reduced bulk resistivity around the injector along with an increase in the GPR reflectivity along horizontal bedding reflectors farther downgradient. Repeat temporal GPR reflection profiling identified three events with major peaks in reflectivity, interpreted to represent episodic lateral CH4 gas release events into the aquifer. Here, a gradual increase in PTDG near the injector caused a sudden lateral breakthrough of gas in the direction of groundwater flow, causing free-phase CH4 to migrate much farther than anticipated based on groundwater advection. CH4 accumulated along subtle permeability boundaries demarcated by grain-scale bedding within the aquifer characteristic of numerous Borden-aquifer multi-phase flow experiments. Diminishing reflectivity over a period of days to weeks suggests buoyancy-driven migration to the vadose zone and/or CH4 dissolution into groundwater. Lateral and vertical CH4 migration was primarily governed by subtle, yet measurable heterogeneity and anisotropy in the aquifer. PMID- 28865809 TI - Lifestyle weight management programmes for children: A systematic review using Qualitative Comparative Analysis to identify critical pathways to effectiveness. AB - This study aimed to identify critical features of successful lifestyle weight management interventions for overweight children (0-11years). Eleven qualitative UK-based studies examining children's, parents' and providers' perspectives and experiences of programmes were synthesised to identify components felt to be critical. Studies for this views synthesis were identified from existing reviews and an update of one review's search, which was run in December 2015. The identified components were then explored in a synthesis of intervention evaluations (five 'most effective' and 15 'least effective') conducted in western Europe, North America, Australia or New Zealand. The intervention evaluations were identified from existing reviews and an update of one review's search, which was run in March 2016. This evaluation synthesis was carried out using Qualitative Comparative Analysis. Three important mechanisms were present in all the most effective interventions but absent in all the least effective: 1/ showing families how to change: a) providing child physical activity sessions, b) delivering practical behaviour change strategy sessions, c) providing calorie intake advice; 2/ ensuring all the family are on board: a) delivering discussion/education sessions for both children and parents, b) delivering child friendly sessions, c) aiming to change behaviours across the whole family; 3/ enabling social support for both parents and children by delivering both child group sessions and parent group sessions. To conclude, programmes should ensure the whole family is on board the programme, that parents and children can receive social support and are not just told what to change, but shown how. PMID- 28865810 TI - Consolidated state political party control and the enactment of obesity-related policies in the United States. AB - States play a key role in addressing obesity and its risk factors through policymaking, but there is variation in state activity nationally. The goal of this study was to examine whether the presence of a consolidated Democratic or Republican "trifecta" - when a state's governorship and both houses of the legislature are dominated by the same political party - or divided government (i.e., without a trifecta) is associated with obesity-related policy content and enactment. In 2016 and 2017, we gathered state bills and laws utilizing the CDC Chronic Disease State Policy Tracking System, and examined the association between state-level political party control and the enactment of state-level obesity-related policies in all states during 2009-2015. The three areas of interest included: policies specifically addressing obesity, nutrition, or physical activity in communities, schools, or workplaces using a public health framework; neutral policies, such as creating government task forces; and policies that employed a business-interest framework (e.g., Commonsense Consumption Acts that prohibit consumer lawsuits against restaurant establishments). Using divided governments as the reference group, we found that states with Democratic trifectas enacted significantly more laws, and more laws with a public health framework. Republican trifecta states enacted more laws related to physical activity, and in some states like Texas, Republican trifectas were exceptionally active in passing policies with a public health framework. States with Republican trifectas enacted a statistically similar amount of laws as states with divided governments. These findings suggest promise across states for obesity-related public health policymaking under a variety of political regimes. PMID- 28865811 TI - In Defense of Flossing: Part II-Can We Agree It's Premature to Claim Flossing Is Ineffective to Help Prevent Periodontal Diseases? AB - Periodontal diseases are complex, multifactorial disorders. Effective daily plaque control promotes gingival/periodontal health. Recent meta-analyses and other reviews have found inconclusive evidence to support that tooth flossing promotes gingival/periodontal health. Ideally, the claim should have been that, "at present, we do not have high-quality evidence from well-designed randomized clinical trials to determine whether flossing lowers the risk for periodontal diseases." Rather than "not proven to be effective," the lay public may now think that flossing is "almost entirely unhelpful and/or unnecessary." How does the dental community communicate the nuances of this topic? Herein, we examine the key structural issues underlying this area of research. We assert that effective flossing between specific teeth can promote gingival/periodontal health. Furthermore, we explore the nuances for whom this may be true and untrue, why our evidence is lacking, and what can be done to clarify the effectiveness of flossing on clinical outcomes. PMID- 28865812 TI - Efficacy of Rapid Maxillary Expansion in the Treatment of Obstructive Sleep Apnea Syndrome: A Systematic Review With Meta-analysis. AB - OBJECTIVE: The objective of this study was to assess the efficacy of rapid maxillary expansion (RME) in the treatment of OSAS in children and adolescents. METHODS: Five electronic databases were searched systematically: PubMed, Web of Science, LILACS, Embase and Cochrane Library. SELECTION CRITERIA: Randomized controlled trials, nonrandomized controlled trials, cohort studies, and systematic reviews published in English, Spanish, or Portuguese between January 2000 and December 2016, performed on children and adolescents younger than 18 years with OSAS who underwent RME, and assessing RME efficacy as measured by the Apnea-Hypopnea Index (AHI) normalization were included. Qualitative assessment of the selected studies was performed using Critical Appraisal Skills Programme checklists. Statistical evaluation included 2 meta-analyses and was based on a random-effects model and Cochran's Q test and I2 statistics to assess heterogeneity across the publications. Electronic searches identified 84 publications. Five publications were considered valid and included in this systematic review. RESULTS: Results from the meta-analysis show an overall reduction in AHI after RME therapy. CONCLUSIONS: Increasingly the evidence indicates that RME devices reduce AHI in children with OSAS, making RME therapy an appropriate alternative treatment option for these patients. PMID- 28865813 TI - Concordance Between Clinical Practice and Published Evidence: Findings From Virginia Commonwealth University School of Dentistry. AB - OBJECTIVES: To evaluate the concordance between clinical practice and published evidence by dental faculty and graduating students of the Virginia Commonwealth University School of Dentistry. METHODS: A questionnaire previously developed by the National Dental Practice-Based Research Network with 12 clinical scenarios was administered to VCU faculty and graduating students. Responses were scored as either consistent or inconsistent with published evidence and then analyzed for differences between dental faculty, graduating students, and the national results. RESULTS: There were 43 dental faculty members with at least half-time student contact who responded to the survey. Faculty concordance ranged from 33% to 100%, and general practice faculty had the highest concordance (82%). Eighty five of the graduating class of 98 responded to the survey, and student concordance ranged from 18% to 92% and averaged 67%. General practice faculty had higher concordance with published evidence than recently graduated dental students. CONCLUSIONS: Graduating students and dental faculty demonstrated higher concordance with evidence-based practice than practitioners in the National Dental Practice-Based Research Network. General practice dental faculty demonstrated adequate concordance, but students demonstrated only a medium-level concordance. Practitioners involved in teaching dental students are better able to keep up with evolving evidence and are better able to demonstrate evidence based practice. PMID- 28865814 TI - Patients' Values in Clinical Decision-Making. AB - OBJECTIVE: Shared decision-making involves the participation of patient and dental practitioner. Well-informed decision-making requires that both parties understand important concepts that may influence the decision. This fourth article in a series of 4 aims to discuss the importance of patients' values when a clinical decision is made. METHODS: We report on how to incorporate important concepts for well-informed, shared decision-making. Here, we present patient values as an important issue, in addition to previously established topics such as the risk of bias of a study, cost-effectiveness of treatment approaches, and a comparison of therapeutic benefit with potential side effects. RESULTS: We provide 2 clinical examples and suggestions for a decision tree, based on the available evidence. CONCLUSION: The information reported in this article may improve the relationship between patient and dental practitioner, resulting in more well-informed clinical decisions. PMID- 28865815 TI - Evaluation of the Need for Antibiotic Prophylaxis During Routine Intra-alveolar Dental Extractions in Healthy Patients: A Randomized Double-Blind Controlled Trial. AB - OBJECTIVE: The aim of this randomized double-blind controlled trial was to evaluate the role of antibiotics in the perioperative period of dental extractions in healthy patients. METHODS: The study population included patients visiting the outpatient department of our institute. Four hundred patients were selected and randomly divided into 4 groups and underwent routine dental extraction. In group A, patients were prescribed only anti-inflammatory drugs in the postoperative period. In group B, patients were prescribed antibiotics for 3 days and concomitant anti-inflammatory drugs in the postoperative period only. In group C, patients were prescribed a single dose of antibiotic 1 hour before the extraction procedure with no postoperative antibiotics, and only anti inflammatory drugs were prescribed in the postoperative period. In group D, patients were prescribed mouthwash starting 15 minutes before the procedure and continuing twice daily for a period of 7 days along with anti-inflammatory drugs in the postoperative period. Patients were asked to follow up on the seventh postoperative day for suture removal and were evaluated for pain, swelling, dry socket, and local signs of infection. The study was approved by the Internal Ethics Review Committee of the institute. RESULTS: No significant differences were seen among the groups with respect to pain (chi2 [1, N = 171] = 4.939, P = .552), swelling (chi2 [1, N = 171] = 10.048, P = .347), or postextraction complications. CONCLUSIONS: Prophylactic antibiotics are not required during routine dental extractions in healthy patients. The use of antibiotic therapy without appropriate indications can result in the development of resistant organisms. However, a clear trend is seen in which practitioners overprescribe antibiotics as well as medications in general. The current evidence questions the benefits of prophylactic antibiotic therapy for patients undergoing dental extractions. In our opinion, there is no justification for routine antibiotic prophylaxis for dental extractions in healthy patients. PMID- 28865816 TI - Bacteremia Associated With Oral Surgery: A Review. AB - OBJECTIVES: Bacterial (infective) endocarditis, a microbial infection of the endocardium surfaces after bacteremia, causes significant morbidity and mortality. Recent epidemiologic studies have reported a prevalence of 2-8 cases per 100,000 individuals per year, with the highest incidence in those aged 70-80 years and those living in developed countries. We systematically reviewed the literature on several critical aspects regarding the development of bacteremia after oral surgery. The purpose of this work is to assess the controversy regarding antibiotic prophylaxis before oral surgery. MATERIALS AND METHODS: Publications between 1976 and 2015 were included. Clinical studies focusing on oral surgery as the underlying cause were included. RESULTS: Among the 32 clinical studies reviewed, 3564 cases, accounting for 12,839 blood cultures, were evaluated. In 10 of these studies, amoxicillin usefulness was studied. Antimicrobial prophylaxis before an invasive dental procedure does not prevent bacteremia, although it can decrease both its magnitude and its persistence. CONCLUSIONS: The highly conflicting data and conclusions of the analyzed work highlight the need for new approaches to the study of bacteremia that would provide reliable evidence and thus appropriate prophylactic and therapeutic standards. Many reports have explored the occurrence of bacteremia after dental procedures, but the results have been conflicting. PMID- 28865818 TI - Single vs 2 Implants on Peri-implant Marginal Bone Level and Implant Failures in Mandibular Implant Overdentures: A Systematic Review With Meta-analysis. AB - BACKGROUND: As a consensus, the 2-implant supported overdentures (ODs) are considered as the first choice of treatment for the edentulous mandible. In the same context, there is increased evidence supporting the use of single-implant OD. The aim of any design is to preserve the remaining structures and allow the longevity of the treatment. OBJECTIVES: To evaluate the impact of single implant vs 2 implants on the peri-implant marginal bone loss (MBL) and number of implant failures in mandibular implant overdentures. METHODS: A literature search of electronic databases (PubMed and Cochrane) was performed up to March 2016 and complemented by hand search. Randomized clinical trials (RCTs) that evaluated MBL and number of implant failures relative to single-implant mandibular overdenture (MOD) were selected. The review and meta-analysis were performed using meta analytic statistical package and in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. FINDINGS: Five RCTs met the inclusion criteria for systematic review and qualitative synthesis. The observation period ranged from 12 months to 5 years in the selected RCTs. The comparison included in the meta-analysis is single- vs 2-implant MODs. Pooled data revealed that single-implant MODs significantly decreased the MBL (mean difference: 0.27, 95% confidence interval: 0.20-0.34, P < .0001, I2 = 0%) and number of implant failures (risk ratio: 3.26, 95% confidence interval: 1.18 8.97), P = .02; I2 = 0%). CONCLUSIONS: Single-implant MOD was found to be better than 2-implant MOD in terms of MBL and number of implant failures. However, this result should be interpreted with caution due to limited number of analyzed studies with different loading protocols and short follow-up period. PMID- 28865817 TI - Uncertain Decision-Making in Primary Root Canal Treatment. AB - OBJECTIVES: A systematic review of literature was conducted to compare the success and survivability of primary root canal interventions. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta Analyses protocol was adopted in this study to systematically assess and report systematic reviews related to success or survival or failure rates of primary root canal interventions. MEDLINE and Cochrane Oral Health Library were both searched by using specific search terms to identify relevant literature, until June 2016. The search was augmented by handsearching. Then, the quality of the included systematic reviews was assessed by using the Revised Assessment of Multiple Systematic Reviews (RAMSTAR) protocol. RESULTS: Only 9 systematic reviews were identified. The RAMSTAR scores of the included reviews ranged from 43/44 to 29/44. Nevertheless, the later reviews did not provide sufficient evidence or statistically significant evidence to support any of the interventions used during primary root canal treatment. In addition, a number of key steps during primary root canal treatment, such as types of dental files, root canal instrumentation techniques, orthograde obturation materials, and techniques, were not assessed by systematic reviews. CONCLUSION: The current status of evidence related to the success and survivability of primary root canal interventions is lacking. This puts dentists under marked degrees of uncertainty. Consequently, patients are potentially exposed to health care risks. It is then essential to develop tailored methods and tools for decision-making under uncertainty to aid both dentists and patients engaged in primary root canal treatment. PMID- 28865819 TI - Does Evidence Support a Combined Restorative Surgical Approach for the Treatment of Gingival Recessions Associated With Noncarious Cervical Lesions? AB - OBJECTIVES: Gingival recessions are frequently associated with noncarious cervical lesions. Combined restorative surgical approaches have been suggested for the management of these combined defects. The aim of this review was to analyze the current evidence on the effectiveness of these combined restorative surgical approaches. METHODS: A systematic review of randomized controlled studies published from January 2006 to June 2016 was performed. RESULTS: Ten articles comparing combined restorative surgical approaches to surgery alone were included. Both the procedures showed similar outcomes in term of root coverage but the combined restorative surgical approach achieved better result in the reduction of dentin hypersensitivity. In combined restorative surgical treatments, resin-modified glass ionomers showed better antimicrobial properties but poorer esthetic outcome than resin composites. CONCLUSION: Data to support or refute definitely the interest of combined approaches for the treatment of gingival recessions associated with noncarious cervical lesions are limited. PMID- 28865820 TI - Methodological Quality Assessment of Systematic Reviews on Autologous Platelet Concentrates for the Treatment of Periodontal Defects. AB - OBJECTIVES: Evaluation of the methodological quality of systematic reviews (SRs) on the effectiveness of autologous platelet concentrates as an adjunct to regenerative procedures for the treatment of periodontal defects. MATERIAL AND METHODS: After a literature screening, eligible SRs were qualitatively assessed using 2 validated instruments: A Measurement Tool to Assess systematic Reviews checklist and Overview Quality Assessment Questionnaire. The characteristics and findings of SRs were also reported. RESULTS: Ten SRs fulfilled the inclusion criteria and were evaluated. With A MeaSurement Tool to Assess systematic Reviews tool, SRs displayed a generally satisfying quality. Six SRs satisfied >=8 items of 11 (high-quality score), and 4 were classified of medium quality (score 4-7). Using Overview Quality Assessment Questionnaire instrument, more than half SRs (N = 6) satisfied >=7 items of 9, resulting to be of high quality; 3 were classified as medium quality (4-6 criteria met); and only 1 of low quality (3 items satisfied). A significant correlation between the results of the 2 questionnaires was found (Spearman's r = 0.915, P = .0005). CONCLUSIONS: SRs considered had an overall high methodological quality. However, some areas were not systematically addressed, like a thorough research strategy or publication bias assessment. Standard guidelines for designing, performing, and reporting SRs should always be followed. The use of platelet concentrates as an adjunct to periodontal surgery procedures may have beneficial effects for the treatment of periodontal defects. PMID- 28865821 TI - As an Adjunct to Mechanical Oral Hygiene, Essential Oil-containing Mouthwash, Compared to Floss, Cetylpryidinium Chloride, or Placebo may be more Effective in Reduction of Plaque and Gingitivitis. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Essential oils-containing mouthwashes for gingivitis and plaque: Meta-analysis and meta-regression. Haas AN, Wagner TP, Muniz FWMG, Fiorini T, Cavagni J, Celeste, RK. J Dent 2016;55:7 15. SOURCE OF FUNDING: No specific funding for this systematic review TYPE OF STUDY/DESIGN: Meta-analysis and meta-regression. PMID- 28865822 TI - Botulinum Toxin A Might Be an Alternative or Adjunct Therapy for the Treatment of Trigeminal and Postherpetic Neuralgia. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: The efficacy of botulinum toxin for the treatment of trigeminal and postherpetic neuralgia: A systematic review with meta-analyses. Shackleton T, Ram S, Black M, Ryder J, Clark GT, Enciso R. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122(1):61-71. SOURCE OF FUNDING: Information not available TYPE OF STUDY/DESIGN: Systematic review and meta analysis. PMID- 28865823 TI - Insufficient Evidence Supports the Use of Low-Level Laser Therapy to Accelerate Tooth Movement, Prevent Orthodontic Relapse, and Modulate Acute Pain During Orthodontic Treatment. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Efficacy of low-level laser therapy in accelerating tooth movement, preventing relapse and managing acute pain during orthodontic treatment in humans: A systematic review. Sonesson M, De Geer E, Subraian J, Petren S. BMC Oral Health 2017;17:11. SOURCE OF FUNDING: No funding was obtained for this study TYPE OF STUDY/DESIGN: Systematic review. PMID- 28865824 TI - Limited Evidence Links Silver Diamine Fluoride and Caries Arrest in Children. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Clinical trials of silver diamine fluoride in arresting caries among children: A systematic review. Gao SS, Zhao IS, Hiraishi N, Duangthi D, Mei ML, Lo ECM, Chu CH. JDR-CTR 2016;1:201-10. SOURCE OF FUNDING: Academic research funding from the General Research Fund of the Research Grants Council of Hong Kong TYPE OF STUDY/DESIGN: Systematic review and meta-analysis. PMID- 28865825 TI - Long-term Use of the Sialogogue Medications Pilocarpine and Cevimeline Can Reduce Xerostomia Symptoms and Increase Salivary Flow in Head and Neck Cancer Survivors After Radiotherapy. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Interventions for the management of radiotherapy-induced xerostomia and hyposalivation: A systematic review and meta analysis. Mercadante V, Hamad AA, Lodi G, Porter S, Fedele S. Oral Oncol 2017;66:64-74. SOURCE OF FUNDING: The authors reported that no external funding sources directly supported this study TYPE OF STUDY/DESIGN: Systematic review and meta-analysis. PMID- 28865826 TI - A Self-Report to 2-Domain Questions May Accurately Screen for Periodontitis. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: A two-domain self-report measure of periodontal disease has good accuracy for periodontitis screening in dental school outpatients. Chatzopoulos GS, Tsalikis L, Konstantinidis A, Kotsakis GA. J Periodontol 2016;87:1165-73. SOURCE OF FUNDING: Information not available TYPE OF STUDY/DESIGN: Cohort study. PMID- 28865827 TI - Measures of Dynamic Chewing Function, Rather than the Number of Teeth, are a Better Predictors of the Elderly's Ability to Intake Food and Nutrients. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Dietary intake is associated with occlusal force rather than number of teeth in 80-y-old Japanese. Inomata C, Ikebe K, Okubo H et al. J Dent Res 2016;2(2):187-97. SOURCE OF FUNDING: The study was supported by a Grant-in-Aid for Scientific Research (Nos. 23390440 and 25293394) from the Japan Society for the Promotion of Science TYPE OF STUDY/DESIGN: Cross sectional study. PMID- 28865828 TI - The Invisalign Appliance Could Be an Effective Modality for Treating Overbite Malocclusions Within a Mild to Moderate Range. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Management of overbite with the Invisalign appliance. Khosravi R, Cohanim B, Hujoel P, Daher S, Neal M, Liu W, Huang G. Am J Orthod Dentofacial Orthop 2017;151:691-9. SOURCE OF FUNDING: This study was supported by the University of Washington Orthodontic Alumni Association TYPE OF STUDY/DESIGN: A retrospective study. PMID- 28865829 TI - Limited Evidence Suggests That Symptomatic Cracked Teeth Share Characteristics Such as Clenching, Grinding, and Molars With Distal Cracks. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Correlation between symptoms and external characteristics of cracked teeth. Hilton TJ, Funkhouser E, Ferracane JL, Gilbert GH, Baltuck C, Benjamin P, Louis D, Mungia R, Meyerowitz. JADA 2017; 148(4):246-56.e1. SOURCE OF FUNDING: National Institutes of Health grant U19-DE 22516 TYPE OF STUDY/DESIGN: Cross-sectional study. PMID- 28865830 TI - Daily Intake of Probiotic Lactobacilli May Reduce Caries Risk in Young Children. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Probiotic compared with standard milk for high-caries children: A cluster randomized trial. Rodriguez G, Ruiz B, Faleiros S, Vistoso A, Marro ML, Sanchez J, Urzua I, Cabello R. J Dent Res 2016;95(4):402-7. SOURCE OF FUNDING: Chilean Government (CONICYT FONIS SA11I2035) TYPE OF STUDY/DESIGN: Cluster randomized controlled trial. PMID- 28865831 TI - Some Malocclusion Traits Significantly Reduce Quality of Life Among Adults. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Malocclusion traits and oral health related quality of life in Finnish adults. Masood M, Suominen AL, Pietila T, Lahti S. Community Dent Oral Epidemiol 2017;45:178-88. SOURCE OF FUNDING: Finnish Dental Society Apollonia and the Finnish Dental Association TYPE OF STUDY/DESIGN: Cross-sectional study. PMID- 28865832 TI - Although Limited Evidence Suggests Patient Perceptions and Expectations for Dental Implants Are Realistic, Many Misconceptions Remain. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: What do patients expect from treatment with Dental Implants? Perceptions, expectations and misconceptions: A multicenter study. Yao J, Li M, Tang H, Want P-L, Zhao Y-X, McGrath C, Mattheos N. Clin Oral Implants Res 28(3):261-71. SOURCE OF FUNDING: Information not available TYPE OF STUDY/DESIGN: Cross-sectional study (survey). PMID- 28865833 TI - Teeth With Mild and Moderate Enamel Fluorosis Demonstrate Increased Caries Susceptibility In Vitro. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Higher fluorosis severity makes enamel less resistant to demineralization. Marin LM, Cury JA, Tenuta LMA, Castellanos JE, Martignon S. Caries Res 2016; 50:407-13. SOURCE OF FUNDING: Government: COLCIENCIAS (grant No. 2012-442) and foundations: FUNCAMP (Conv 4252) TYPE OF STUDY/DESIGN: In vitro study. PMID- 28865834 TI - Knowledge Gaps Exist Among Dentists Regarding Curing Lights and Personal Protection. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Light curing procedures - performance, knowledge level and safety awareness among dentists. Kopperud SE, Rukke HV, Kopperud HM, Bruzell EM. J Dent 2017;58:67-73. SOURCE OF FUNDING: Information not available TYPE OF STUDY/DESIGN: Cross-sectional study. PMID- 28865835 TI - Low Bone Mineral Density Based on Metacarpal Cortical Bone Area May Predict Tooth Loss in Older Men. AB - ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Metacarpal cortical bone area predicts tooth loss in men. Kaye EK, Vokonas P, Garcia RI. JDR Clinical & Translational Research Online 2016;20(10):1-8. SOURCE OF FUNDING: US Department of Veterans Affairs Cooperative Studies Program TYPE OF STUDY/DESIGN: Cohort study. PMID- 28865836 TI - Reconstruction of neck and face scar contractures using occipito-cervico-dorsal supercharged "super-thin flaps": A retrospective analysis of 82 cases in Vietnam. AB - BACKGROUND: The concept of the "super-thin flap" (also known as the subdermal vascular network flap) was introduced in Japan in 1994. Its distinctive characteristic is its extreme thinness: it is thinned to the point that the subdermal vascular network (subdermal plexus) can be seen through the minimal fat layer. Since 2006 in Vietnam, we have used circumflex scapular artery supercharged occipito-cervico-dorsal (OCD) super-thin flaps to reconstruct cases of neck and face scar contracture. MATERIALS AND METHODS: This case series comprised all 82 patients with neck and face scar contracture who underwent reconstruction with an OCD supercharged super-thin flap from 2006-2015 at the Vietnam National Institute of Burns. The flap was thinned and anastomosed at the distal area after elevation. All patients received one flap. RESULTS: Of the 82 flaps, 77 survived completely. The remaining five developed distal superficial necrosis (n=3) and interruption of the sutures due to infection; these required resuturing (n=2). In two of the three necrosis cases, the necrotic area affected 50% of the flap. Eighty of the eighty-two patients were satisfied with both the functional and aesthetic results. CONCLUSIONS: The OCD super-thin flap has clear benefits, and although it is thin, its vasculature is reliable. Thus, it may be one of the best choices for reconstruction of neck and face scar contractures. PMID- 28865837 TI - Evaluation of scar quality after treatment of superficial burns of the hands and face with Dressilk or Biobrane-An intra-individual comparison. AB - INTRODUCTION: The aesthetic outcome after burn of exposed areas such as the hand and face is of high importance. A number of wound dressings used for the treatment of superficial and partial thickness burns promise rapid wound healing and reduced scarring. Previously, wound healing of hands and faces with superficial burns treated with Dressilk(r) compared to Biobrane(r) was evaluated intra-individually with similar results. Nevertheless, up to date objective information regarding the scarring after superficial burns treated with Dressilk(r) does not exist. METHODS: Therefore, 30 patients with superficial burns of the hand and face that were treated with Dressilk(r) and Biobrane(r) simultaneously were included in the study. An objective scar evaluation was performed analyzing melanin and erythema levels, skin elasticity, trans-epidermal water loss and scar perfusion three and six and 12 months after injury. Furthermore, a subjective scar evaluation was performed with the patient and observer scar assessment scale (POSAS) and the Vancouver scar scale (VSS). RESULTS: Dressilk(r) and Biobrane(r) both lead to an aesthetic pleasing outcome after superficial burns of the hands and faces. Regarding the objective scar evaluation only trans-epidermal water loss of burned hands after 6 months showed significant differences between the two dressings. However, these differences were not detected in the 12-month follow up examination. In the subjective scar evaluation no statistical differences could be found between the dressings. All patients stated high satisfaction of scar quality. CONCLUSION: Dressilk(r) is an interesting alternative to Biobrane(r) for the treatment of superficial burns of aesthetic and functional important areas. PMID- 28865838 TI - Placement of a cervical collar increases the optic nerve sheath diameter in healthy adults. AB - INTRODUCTION: Blunt head trauma is a common cause of increased intracranial pressure (ICP). Ultrasound measurement of the optic nerve sheath diameter (OSND) is an accurate and non-invasive way to detect increased ICP. Blunt trauma patients are often immobilized in a rigid cervical spine collar. Our objective was to describe the changes in ONSD following the placement of a c-collar and determine if any changes were time-dependent. METHODS: We performed a prospective cohort study measuring the ONSD of healthy volunteers before and after placement of a c-collar. Two physicians obtained the measurements. Each eye was scanned twice using a standardized technique. This was done before c-collar placement, 5min after placement and 20min after placement. A mean of both eyes was calculated and analyzed using descriptive statistics. An intraclass correlation coefficient (ICC) was used to assess inter-rater reliability. RESULTS: Twenty study participants with a mean age of 37.1years old were enrolled. The mean baseline ONSD was 3.77mm (95% CI 3.48-4.07). The mean ONSD 5 min after the c collar was placed was 4.47 (95% CI 4.17-4.78). The mean ONSD at 20min after c collar placement was 4.53 (95% CI 4.13-4.92). These changes were statistically significant (p=0.003 and <0.001). Reliability was relatively strong overall (ICC=0.74; 95% CI: 0.65, 0.81). CONCLUSION: The placement of a cervical collar increased the ONSD at 5min and this change remained increased at 20min. Future study should assess whether similar results are found in patients with blunt head trauma. PMID- 28865839 TI - oVEMP as an objective indicator of successful repositioning maneuver. AB - BACKGROUND AND OBJECTIVE: Benign paroxysmal positioning vertigo (BPPV) is the most common peripheral vestibular disorder. Canalolithiasis in the posterior semi circular canal is the most common underlying pathology that can be treated effectively by repositioning maneuvers. Our hypothesis suggested that successful maneuvers can lead to repositioning of dislodged otoconia to the utricle. MATERIALS AND METHODS: Air conducted oVEMP, which is thought to originate from the contra-lateral utricular organ was measured in twenty patients with unilateral BPPV and we compared n1-p1 peak to peak amplitude of the affected ears in 3 separate intervals: on pre-treatment when typical nystagmus was confirmed, immediately after, and 1 week after repositioning maneuvers to assess change, if any, in amplitude. RESULTS: This study showed significant increase of oVEMP amplitude in the affected ears after successful repositioning maneuver that was more significant after 1 week. CONCLUSIONS: oVEMP can be used as a reliable objective test for ensuring a successful maneuver rather than subjective dependence on the patient's symptoms, which may be misleading due to a remission. PMID- 28865840 TI - Efficacy of the myofascial pectoralis major flap in the reduction of salivary fistulas after salvage total laryngectomy. AB - INTRODUCTION: Pharyngocutaneous fistula is the most frequent complication after total laryngectomy. Its incidence varies between 9%-25% in post primary total laryngectomy patients, to 14%-57% in salvage laryngectomy post radiotherapy or post chemotherapy + radiotherapy. The pectoralis major myofascial flap (PMMF)is postulated as a useful tool to decrease the incidence of this complication. MATERIALS AND METHOD: Retrospective analysis of a group of patients treated by salvage laryngectomy, associated or not with pharyngeal closure reinforcement with PMMF. RESULTS: Twenty patients were included, 18 males (90%) and 2 females (10%), in 10 of whom the PMMF was used. The average age was 66.65 years. Seventeen (85%) had a laryngeal tumour and 3 (15%) had a hypopharyngeal tumour. Eight (80%) patients in the non-PMMF group had postoperative fistula, whereas only 2 (20%) patients in the PMMF group had a fistula during the postoperative period (P=.005). The mean time for fistula closure was significantly shorter in the cases where PMMF flap was used (16+/-11 days vs. 76.8+/-67 days, P=.001), as was hospital stay (19. 6+/-18 days vs. 83.9+/-77 days, P=.001). CONCLUSION: The use of PMMF in our series is associated with a lower rate of post salvage laryngectomy fistulas in patients treated primarily by organ preservation protocol for laryngeal/hypopharyngeal cancer. In turn, it promotes local healing by decreasing the mean duration of fistula closure and the mean hospital stay. PMID- 28865841 TI - Assessment selection in human-automation interaction studies: The Failure-GAM2E and review of assessment methods for highly automated driving. AB - Highly automated driving will change driver's behavioural patterns. Traditional methods used for assessing manual driving will only be applicable for the parts of human-automation interaction where the driver intervenes such as in hand-over and take-over situations. Therefore, driver behaviour assessment will need to adapt to the new driving scenarios. This paper aims at simplifying the process of selecting appropriate assessment methods. Thirty-five papers were reviewed to examine potential and relevant methods. The review showed that many studies still relies on traditional driving assessment methods. A new method, the Failure-GAM2E model, with purpose to aid assessment selection when planning a study, is proposed and exemplified in the paper. Failure-GAM2E includes a systematic step by-step procedure defining the situation, failures (Failure), goals (G), actions (A), subjective methods (M), objective methods (M) and equipment (E). The use of Failure-GAM2E in a study example resulted in a well-reasoned assessment plan, a new way of measuring trust through feet movements and a proposed Optimal Risk Management Model. Failure-GAM2E and the Optimal Risk Management Model are believed to support the planning process for research studies in the field of human-automation interaction. PMID- 28865842 TI - Lung fibrosis-associated soluble mediators and bronchoalveolar lavage from idiopathic pulmonary fibrosis patients promote the expression of fibrogenic factors in subepithelial lung myofibroblasts. AB - Idiopathic pulmonary fibrosis (IPF) is characterized by infiltration of inflammatory cells, excessive collagen production and accumulation of myofibroblasts. We explored the possible role of subepithelial lung myofibroblasts (SELMs) in the development of fibrosis in IPF. SELMs, isolated from surgical specimens of healthy lung tissue, were cultured with pro inflammatory factors or bronchoalveolar lavage fluid (BALF) from patients with IPF or idiopathic non-specific interstitial pneumonia (iNSIP) and their fibrotic activity was assessed. Stimulation of SELMs with pro-inflammatory factors induced a significant increase of Tissue Factor (TF) and Tumor necrosis factor-Like cytokine 1 A (TL1A) expression and collagen production in culture supernatants. Stimulation with BALF from IPF patients with mild to moderate, but not severe disease, and from iNSIP patients induced a significant increase of TF expression. BALF from all IPF patients induced a significant increase of TL1A expression and collagen production, while BALF from iNSIP patients induced a significant increase of TL1A, but not of collagen production. Interestingly, TGF-beta1 and BALF from all IPF, but not iNSIP patients, induced a significant increase in SELMs migration. In conclusion, BALF from IPF patients induces fibrotic activity in lung myofibroblasts, similar to mediators associated with lung fibrosis, indicating a key role of SELMs in IPF. PMID- 28865843 TI - Activation and inflammation of the venous endothelium in vein graft disease. AB - The long saphenous vein is the most commonly used conduit in coronary artery bypass graft (CABG) surgery when bypassing multiple diseased arteries; however, its use is complicated by the development of vascular inflammation, intimal hyperplasia and accelerated atherosclerosis leading to compromised graft efficacy. Despite refinement of surgical techniques to improve graft patency, late vein graft failure remains a significant problem. Moreover, there is a lack of pharmacological interventions proven to be effective in the treatment of late vein graft failure. A greater understanding of the molecular nature of the disease and the interactions between endothelial and smooth muscle cells as a result of alterations in local haemodynamics may assist with designing future beneficial pharmacological interventions. Venous endothelial cells (ECs) are physiologically adapted to chronic low shear stress; however, once the graft is implanted into the arterial circulation, they become suddenly exposed to acute high levels of shear stress. A small number of in vitro and ex vivo studies have demonstrated that acute high shear stress is associated with the activation of a pro-inflammatory profile in saphenous vein ECs, which may be mediated by mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signalling pathways. The impact of acute changes in shear stress on venous ECs and the role of ECs in the development of intimal hyperplasia remains incomplete and is the subject of this review. PMID- 28865844 TI - Factors affecting lifespan following below-knee amputation in diabetic patients. AB - INTRODUCTION: Untreatable foot problems in diabetics may require lower extremity amputation, which has a high level of patient mortality. This high mortality rate is worse than most malignancies. The present study aimed to identify parameters that can be used to estimate survival in DM patients undergoing below-knee amputations for diabetic foot problems. MATERIALS AND METHODS: A total of 470 patients (299 males, 171 females) with a mean age of 64.32 years who underwent below-knee amputation for diabetic foot problems between 2004 and 2014 were enrolled in the study. The length of time from the operation to time of death was recorded in days. Patient details were obtained, including age during surgery, BMI, oral antidiabetic and insulin usage, dialysis therapy history, lower extremity endovascular intervention, previous amputation at the same extremity, the need for stump revision surgery during follow-up, and above-knee amputation at the same site. Biochemical test results of pre-operative HbA1c, ESR, and levels of CRP, BUN, and creatinine were also obtained. RESULTS: A total of 333 patients (70.9%) died and 137 (29.1%) survived post-surgery. Survival rates were 90% in the first 7 days, 84% in the first 30 days, and 64% after the first year. Patient median life expectancy post-surgery was 930 +/- 106 days. Hemodialysis treatment (p = 0.001), endovascular intervention (p = 0.04), sex (p = 0.004), age (p = 0.001), BUN level (p = 0.001), and duration of insulin use (p = 0.003) were shown to be effective predictors of mortality. CONCLUSIONS: Life expectancy is low (<3 years) in DM patients requiring below-knee amputations for untreatable foot problems. Survival could be predicted by duration of insulin use, age, sex, and renal insufficiency. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 28865845 TI - Treatment preferences and help-seeking behaviors for sleep problems among psychiatric outpatients. AB - OBJECTIVE: To understand treatment preferences and help-seeking behaviors among psychiatric patients for their sleep problems, and to examine determinants of problem recognition and help-seeking among patients with sleep difficulties. METHOD: A cross-sectional survey was conducted among psychiatric outpatients in Singapore (n=400). Participants completed questionnaires that assessed their sleep quality, daytime fatigue, help-seeking behavior, treatment preferences for sleep problems, and sociodemographic information. Multiple logistic regressions were used to identify correlates of patients who recognized their sleep difficulties and of those who had sought help. RESULTS: Mental health professionals were the most preferred choice (60.8%) for consultation on sleep problems. Among patients with poor sleep quality (n=275), 28.4% denied having any problems and 38.9% had not sought help. Patients with chronic physical comorbidity were less likely to recognize their sleep problems (OR=0.432, p value=0.009), while those with psychiatric comorbidity were twice as likely to perceive the problems (OR=2.094, p-value=0.021) and to seek help (OR=1.957, p value=0.022). Daytime fatigue was associated with higher odds of problem recognition (OR=1.106, p-value=0.001) and help-seeking (OR=1.064, p-value=0.016). CONCLUSION: A considerable number of patients did not perceive their poor sleep as an issue and had not sought help for it. General sleep hygiene education is needed for psychiatric patients. PMID- 28865846 TI - Application of a newly designed mandibular distraction device for navigation surgery in goats. AB - PURPOSE: This animal study is to investigate the accuracy of navigation-guided mandibular distraction osteogenesis with a special designed distraction device by TBNavis-CMFS navigation system. MATERIALS AND METHODS: Four goats were included in this study. The 3D simulation unilateral mandibular distraction osteogenesis was simulated for 14 mm lengthening in TBNavis-CMFS navigation system. A new designed mandibular distraction device with the detachable adapter for navigation surgery in combination with the specific mandibular dynamic reference frame was applied. Navigation guided distraction osteogenesis was performed on goats and mandible was gradually distracted according to the simulation. Postsurgical 3-D skeletal measurements of presurgical simulations and postsurgical outcomes were compared statistically. RESULTS: Navigation assisted distraction osteogenesis was successfully performed and the new designed distraction devices worked uneventful. The accuracy of intra-operative registration was within 1 mm. The mandible was lengthened for 14.25 mm in average (13.87-14.36 mm). There were no significant differences between simulation distraction and post-operative 3-D measurements (p > 0.05). CONCLUSIONS: A new designed distraction device could be used in navigation guided mandibular distraction osteogenesis on goats with high accuracy by using the TBNavis-CMFS navigation system. PMID- 28865847 TI - Time to acknowledge the obvious. PMID- 28865848 TI - Grain challenge affects systemic and hepatic molecular biomarkers of inflammation, stress, and metabolic responses to a greater extent in Holstein than Jersey cows. AB - Long-term feeding of high-grain diets to dairy cows often results in systemic inflammation characterized by alterations in acute-phase proteins and other biomarkers, both in plasma and immune-responsive tissues like the liver. The molecular and systemic changes that characterize an acute grain feeding challenge remain unclear. The current study involved 6 Holstein and 6 Jersey cows in a replicated 2 * 2 Latin square. Periods (10 d) were divided into 4 stages (S): S1, d 1 to 3, served as baseline with total mixed ration (TMR) ad libitum; S2, d 4, served as restricted feeding, with cows offered 50% of the average daily intake observed in S1; S3, d 5, a grain challenge was performed, in which cows were fed a TMR ad libitum without (CON) or with an additional pellet wheat-barley (1:1; HIG) at 20% of dry matter intake top-dressed onto the TMR; S4, d 6 to 10, served as recovery during which cows were allowed ad libitum access to the TMR. Among the 28 biomarkers analyzed in blood 12 h after grain challenge on d 5, the concentrations of fatty acids and bilirubin increased in HIG Holstein but not Jersey cows. In Holsteins, feeding HIG also increased total protein and albumin while decreasing ceruloplasmin, myeloperoxidase, and alkaline phosphatase concentrations. At the molecular level, hepatic genes associated with inflammation (IL1B, IL6, TNF, TLR4, MYD88, and NFKB1) were upregulated in Holstein cows fed HIG versus CON. Despite such response, expression of the acute phase proteins SAA and HP in Holsteins fed HIG compared with CON was markedly downregulated. In Holsteins fed HIG versus CON, the marked downregulation of SCD, ELOVL6, and MTTP along with upregulated CPT1A, ACOX1, and APOA5 indicated alterations in fatty acid and lipoprotein metabolism during grain challenge. Genes related to ketogenesis (HMGCS2 and ACAT1) were upregulated in Jerseys, and gluconeogenic genes (PDK4 and PCK1) were upregulated in Holstein cows fed HIG, suggesting alterations in ketone body and glucose production. Expression of phosphorylated p70S6K1, RPS6, and 4EBP1 proteins, as well as total mechanistic target of rapamycin (mTOR) protein, decreased in Holsteins fed HIG, whereas phosphorylated mTOR and 4EBP1 proteins increased in Jerseys fed HIG. From a metabolic and inflammatory biomarker standpoint, data indicate that Jersey cows better tolerated the acute grain challenge. Alterations in mTOR signaling proteins in both Jerseys and Holsteins fed HIG suggest a potential role for exogenous AA in the hepatic adaptations to grain challenge. It remains to be determined if these acute responses to a grain challenge can elicit long-term liver dysfunction, which could negatively affect welfare of the cow. PMID- 28865849 TI - Longitudinal assessment of dairy farm management practices associated with the presence of psychrotolerant Bacillales spores in bulk tank milk on 10 New York State dairy farms. AB - The ability of certain spore-forming bacteria in the order Bacillales (e.g., Bacillus spp., Paenibacillus spp.) to survive pasteurization in spore form and grow at refrigeration temperatures results in product spoilage and limits the shelf life of high temperature, short time (HTST)-pasteurized fluid milk. To facilitate development of strategies to minimize contamination of raw milk with psychrotolerant Bacillales spores, we conducted a longitudinal study of 10 New York State dairy farms, which included yearlong monthly assessments of the frequency and levels of bulk tank raw milk psychrotolerant spore contamination, along with administration of questionnaires to identify farm management practices associated with psychrotolerant spore presence over time. Milk samples were first spore pasteurized (80 degrees C for 12 min) and then analyzed for sporeformer counts on the initial day of spore pasteurization (SP), and after refrigerated storage (6 degrees C) for 7, 14, and 21 d after SP. Overall, 41% of samples showed sporeformer counts of >20,000 cfu/mL at d 21, with Bacillus and Paenibacillus spp. being predominant causes of high sporeformer counts. Statistical analyses identified 3 management factors (more frequent cleaning of the bulk tank area, the use of a skid steer to scrape the housing area, and segregating problem cows during milking) that were all associated with lower probabilities of d-21 Bacillales spore detection in SP-treated bulk tank raw milk. Our data emphasize that appropriate on-farm measures to improve overall cleanliness and cow hygiene will reduce the probability of psychrotolerant Bacillales spore contamination of bulk tank raw milk, allowing for consistent production of raw milk with reduced psychrotolerant spore counts, which will facilitate production of HTST-pasteurized milk with extended refrigerated shelf life. PMID- 28865850 TI - Validation of genomic predictions for wellness traits in US Holstein cows. AB - The objective of this study was to evaluate the efficacy of wellness trait genetic predictions in commercial herds of US Holstein cows from herds that do not contribute phenotypic information to the evaluation. Tissue samples for DNA extraction were collected from more than 3,400 randomly selected pregnant Holstein females in 11 herds and 2 age groups (69% nulliparous, 31% primiparous) approximately 30 to 60 d before their expected calving date. Lactation records from cows that calved between September 1, 2015, and December 31, 2015, were included in the analysis. Genomically enhanced predicted transmitting abilities for the wellness traits of retained placenta, metritis, ketosis, displaced abomasum, mastitis, and lameness were estimated by the Zoetis genetic evaluation and converted into standardized transmitting abilities. Mean reliabilities of the animals in the study ranged between 45 and 47% for each of the 6 traits. Animals were ranked by their standardized transmitting abilities within herd and age group then assigned to 1 of 4 groups of percentile-based genetic groups of equal size. Adverse health events, including retained placenta, metritis, ketosis, displaced abomasum, mastitis, and lameness, were collected from on-farm herd management software, and animal phenotype was coded as either healthy (0), diseased (1), or excluded for each of the 6 outcomes of interest. Statistical analysis was performed using a generalized linear mixed model with genetic group, age group, and lactation as fixed effects, whereas herd and animal nested within herd were set as random effects. Results of the analysis indicated that the wellness trait predictions were associated with differences in phenotypic disease incidence between the worst and best genetic groups. The difference between the worst and best genetic groups in recorded disease incidence was 2.9% for retained placenta, 10.8% for metritis, 1.1% for displaced abomasum, 1.7% for ketosis, 7.4% for mastitis, and 3.9% for lameness. Odds ratio estimates between the highest and lowest genetic groups ranged from 1.6 (lameness) to 17.1 (displaced abomasum) for the 6 traits analyzed. These results indicate that wellness trait information of young calves and heifers can be used to effectively predict meaningful differences in future health performance. Improving wellness traits through direct genetic selection presents a compelling opportunity for dairy producers to help reduce disease incidence and improve profitability when coupled with sound management practices. PMID- 28865852 TI - Prevalence of digital dermatitis in young stock in Alberta, Canada, using pen walks. AB - Digital dermatitis (DD), an infectious bacterial foot lesion prevalent in dairy cattle worldwide, reduces both animal welfare and production. This disease was recently identified in replacement dairy heifers, with implications including increased risk of DD and decreased milk production in first lactation, poor reproductive performance, and altered hoof conformation. Therefore, a simple and effective method is needed to identify DD in young stock and to determine risk factors for DD in this group so that effective control strategies can be implemented. The objectives of this study were to (1) determine prevalence of DD in young stock (based on pen walks); and (2) identify potential risk factors for DD in young stock. A cross-sectional study was conducted on 28 dairy farms in Alberta, Canada; pen walks were used to identify DD (present/absent) on the hind feet of group-housed, young dairy stock. A subset of 583 young stock on 5 farms were selected for chute inspection of feet to determine the accuracy of pen walks for DD detection. Pen walks as a means of identifying DD lesions on the hind feet in young stock had sensitivity and specificity at the animal level of 65 and 98%, with positive and negative predictive values of 94 and 83%, respectively, at a prevalence of 37%. At the foot level, pen walks had sensitivity and specificity of 62 and 98%, respectively, with positive and negative predictive values of 92 and 88%, respectively, at a prevalence of 26%. Pen walks identified DD in 79 [2.9%; 95% confidence interval (95% CI): 2.3-3.6%] of 2,815 young stock on 11 (39%; 95% CI: 22-59%) of 28 farms, with all 79 DD-positive young stock >=309 d of age. Apparent within-herd prevalence estimates ranged from 0 to 9.3%, with a mean of 1.4%. True within-herd prevalence of DD in young stock, calculated using the sensitivity and specificity of the pen walks, ranged from 0 to 12.6%, with a mean of 1.4%. On the 11 DD-positive farms, the proportion of young stock >12 mo of age with DD lesions was 9.9% (95% CI: 7.8-12.0%). Multilevel logistic regression was used to assess associations with potential risk factors for DD lesions, including age, leg cleanliness, and lactating herd DD prevalence. Presence of DD in young stock increased as their age increased and was associated with increased prevalence of DD in the lactating herd. Pen walks can be used to identify specific young stock with DD or groups where management practices can be implemented to prevent disease proliferation and transmission. PMID- 28865851 TI - Prevalence, antimicrobial susceptibility, and molecular characterization of Staphylococcus aureus isolated from dairy herds in northern China. AB - Staphylococcus aureus is one of the main pathogens involved in dairy cow mastitis. Monitoring of antibiotic use would prove useful to assess the risk of Staph. aureus in raw milk. The objective of this work was to investigate the prevalence of Staph. aureus strais isolated from raw milk in northern China, and to characterize antimicrobial susceptibility of these strains and their key virulence genes. In total, 195 raw milk samples were collected from 195 dairy farms located in 4 cities of northern China from May to September 2015. Out of 195 samples, 54 (27.7%) were positive for Staph. aureus. Among these 54 samples, 54 strains of Staph. aureus were isolated, and 16 strains were identified as methicillin-resistant Staph. aureus. The strains exhibited high percentages of resistance to penicillin G (85.2%), ampicillin (79.6%), and erythromycin (46.3%). Moreover, 72% of the strains showed resistance to more than one antimicrobial agent. Overall, 63% of penicillin-resistant strains possessed the blaZ gene, and 60% of the erythromycin-resistant strains possessed erm(A), erm(B), erm(C), msr(A), or msr(B) genes with 8 different gene patterns. All isolates resistant to gentamicin, kanamycin, and oxacillin carried the aac6'-aph2", ant(4')-Ia, and mecA genes, respectively. Two tet(M)-positive isolates carried specific genes of the Tn916-Tn1545 transposon. The most predominant virulence genes were sec, sea, and pvl, which encode staphylococcal enterotoxins (sec and sea) and Panton Valentine leukocidin, respectively. Thirty-two isolates (59.2%) harbored one or more virulence genes. The majority of Staph. aureus strains were multidrug resistant and carried multiple virulence genes, which may pose a risk to public health. Our data indicated that antimicrobial resistance of Staph. aureus was prevalent in dairy herds in northern China, and that antibiotics, especially penicillin G and ampicillin, to treat mastitis caused by Staph. aureus should be used with caution in northern China. PMID- 28865853 TI - Fine-mapping of BTA17 using imputed sequences for associations with de novo synthesized fatty acids in bovine milk. AB - The aim of this study was to fine-map a genomic region associated with milk fatty acids (FA) on Bos taurus autosome (BTA) 17. This genomic region has been discovered with 50,000 (50k) single nucleotide polymorphisms (SNP) imputed to 777,000 (777k) SNP. In this study, high-density genotypes were imputed to whole genome sequences level to identify candidate gene(s) associated with milk FA composition on BTA17. Phenotypes and genotypes were available for 1,640 cows sampled in winter, and for 1,581 cows sampled in summer. Phenotypes consisted of gas chromatography measurements in winter and in summer milk samples of 6 individual FA and the indicator of de novo synthesis, C6:0-C14:0. Genotypes consisted of imputed 777k SNP, and 89 sequenced ancestors of the population of genotyped cows. In addition, 450 whole-genome sequences from the 1,000 Bull Genome Consortium were available. Using 495 Holstein-Friesian sequences as a reference population, the 777k SNP genotypes of the cows were imputed to sequence level. We then applied single-variant analyses with an animal model, and identified thousands of significant associations with C6:0, C8:0, C10:0, C12:0, C14:0, and C6:0-C14:0. For C8:0 in summer milk samples, the genomic region located between 29 and 34 Mbp on BTA17 revealed a total of 646 significant associations. The most significant associations [-log10(P-value) = 7.82] were 8 SNP in perfect linkage disequilibrium. After fitting one of these 8 SNP as a fixed effect in the model, and re-running the single-variant analyses, no further significant associations were found for any of the 6 FA or C6:0-C14:0. These findings suggest that one polymorphism underlying this QTL on BTA17 influences multiple de novo synthesized milk FA. Thirteen genes in the QTL region were identified and analyzed carefully. Six out of the 8 SNP that showed the strongest associations were located in the La ribonucleoprotein domain family, member 1B (LARP1B) gene, and we suggest LARP1B as a primary candidate gene. Another gene of interest for this QTL region might be PKL4. None of these suggested candidate genes have previously been associated with milk fat synthesis or milk FA composition. PMID- 28865854 TI - Urinary purine derivatives as a tool to estimate dry matter intake in cattle: A meta-analysis. AB - The objectives of this study were to investigate the relationship between dry matter intake (DMI) and urinary purine derivative (PD) excretion, to develop equations to predict DMI and to determine the endogenous excretion of PD for beef and dairy cattle using a meta-analytical approach. To develop the models, 62 published studies for both dairy (45 studies) and beef cattle (17 studies) were compiled. Twenty models were tested using DMI (kg/d) and digestible DMI (dDMI, kg/d) as response variables and PD:creatinine (linear term: PD:C, and quadratic term: PD:C2), allantoin:creatinine (linear term: ALLA:C, and quadratic term: ALLA:C2), metabolic body weight (BW0.75, kg), milk yield (MY, kg/d), and their combination as explanatory variables for dairy and beef (except for MY) cattle. The models developed to predict DMI for dairy cattle were validated using an independent data set from 2 research trials carried out at the University of Wisconsin (trial 1: n = 45; trial 2: n = 50). A second set of models was developed to estimate the endogenous PD excretion. In all evaluated models, the effect of PD (either as PD:C or ALLA:C) was significant, supporting our hypothesis that PD are in fact correlated with DMI. Despite the BW-independent relationship between PD and DMI, the inclusion of BW0.75 in the models with PD:C and ALLA:C as predictors slightly decreased the values of root mean square error (RMSE) and Akaike information criterion for the models of DMI. Our models suggest that both DMI and dDMI can be equally well predicted by PD-related variables; however, predicting DMI seems more useful from a practical and experimental standpoint. The inclusion of MY into the dairy models substantially decreased RMSE and Akaike information criterion values, and further increased the precision of the equations. The model including PD:C, BW0.75, and MY presented greater concordance correlation coefficient (0.93 and 0.63 for trials 1 and 2, respectively) and lower RMSE of prediction (1.90 and 3.35 kg/d for trials 1 and 2, respectively) when tested in the validation data set, emerging as a potentially useful estimator of nutrient intake in dairy cows. Endogenous PD excretion was estimated by the intercept of the linear regression between DMI (g/kg of BW0.75) and PD excretion (mmol/kg of BW0.75) for beef (0.404 mmol/kg of BW0.75) and dairy cattle (0.651 mmol/kg of BW0.75). Based on the very close agreement between our results for beef cattle and the literature, the linear regression appears to be an adequate method to estimate endogenous PD excretion. PMID- 28865855 TI - Could predicting fatty acid profile by mid-infrared reflectance spectroscopy be used as a method to increase the value added by milk production chains? AB - The aims of this work were (1) to develop prediction equations from mid-infrared spectroscopy (MIRS) to establish a detailed fatty acid (FA) composition of milk; (2) to propose a milk FA index, utilizing MIRS-developed equations, in which the precision of the FA-prediction equations is taken into account to increase the value of milk; and (3) to show application examples. A total of 651 bulk cow milk samples were collected from 245 commercial farms in northwest Italy. The results of the 651 gas chromatography analyses were used to establish (421 samples) and to validate (230 samples) the outcomes of the FA composition prediction that had been obtained by MIRS. A class-based approach, in which the obtained MIRS equations were used, was proposed to define a milk classification. The method provides a numerical index [milk FA index (MFAI)] that allows a premium price to be quantified to increase the value of a favorable FA profile of milk. Ten FA were selected to calculate MFAI, according to their relevance for human health and potential cheese sensory properties, and animal welfare and environmental sustainability were also considered. These factors were selected as dimensions of MFAI. A statistical analysis and expert judgment aggregation were performed on the selected FA by weighting the FA and normalizing the dimensions to reduce redundancy. A class approach was applied, using the precision of the MIRS equations to establish the classes. The median FA concentration of the data set was set as a reference value of class 0. The width, number, and limits of classes above and below the median were calculated using the 95% confidence level of the standard error of prediction, corrected with the bias of each FA. A progressive number and a positive or negative sign were assigned to each FA class above or below the median according to their role in the above mentioned dimensions. The sum of the numbers of each class, associated with its sign for each FA, was used to generate MFAI. The MFAI was applied to dairy farms characterized by different feeding strategies, all of which deliver milk to a commercial dairy plant. The MFAI values ranged from 0.7 to 4.2, and large variations, which depended on the cows' diet and forage quality, were observed for each feeding system. The proposed method has been found to be flexible and adaptable to several contexts on both intensive and extensive dairy farms. PMID- 28865856 TI - Effect of exosomes from plasma of dairy cows with or without an infected uterus on prostaglandin production by endometrial cell lines. AB - A contributing factor to declining fertility in dairy cows is an activated inflammatory system associated with uterine infection. Detecting uterine disease using biomarkers may allow earlier diagnosis and intervention with resultant improvements in fertility. Exosomes are known to participate in intercellular communication, paracrine, and endocrine signaling. Exosomes carry a cargo of proteins, lipids, and nucleic acids that represent specific cellular sources. Prostaglandins are lipids that are critical determinants of bovine fertility. In this study exosomes were isolated from the plasma of cows before (d 0) and during (d 10) the study in healthy animals or those with an induced uterine infection in a 2 * 2 factorial design. Exosomes were characterized for size and number (nanoparticle tracking analysis), exosomal marker expression (Western blot), and morphology (transmission electron microscopy). No significant differences were observed in exosome size or number. The abundance of exosome-enriched markers was confirmed in noninfected and infected animals. Transmission electron microscopy confirmed the morphology of the exosomes. These exosomes were co-incubated with bovine endometrial epithelial and stromal cells. Exosomes from d-10-infected animal plasma decreased PGF2alpha production in endometrial epithelial but not stromal cells. For future research, the identification of effectors in the cargo may provide a useful basis for early diagnosis of uterine infection using an exosomal characterization approach. PMID- 28865857 TI - Accuracies of breeding values for dry matter intake using nongenotyped animals and predictor traits in different lactations. AB - Given the interest of including dry matter intake (DMI) in the breeding goal, accurate estimated breeding values (EBV) for DMI are needed, preferably for separate lactations. Due to the limited amount of records available on DMI, 2 main approaches have been suggested to compute those EBV: (1) the inclusion of predictor traits, such as fat- and protein-corrected milk (FPCM) and live weight (LW), and (2) the addition of genomic information of animals using what is called genomic prediction. Recently, several methodologies to estimate EBV utilizing genomic information (EBV) have become available. In this study, a new method known as single-step ridge-regression BLUP (SSRR-BLUP) is suggested. The SSRR BLUP method does not have an imposed limit on the number of genotyped animals, as the commonly used methods do. The objective of this study was to estimate genetic parameters using a relatively large data set with DMI records, as well as compare the accuracies of the EBV for DMI. These accuracies were obtained using 4 different methods: BLUP (using pedigree for all animals with phenotypes), genomic BLUP (GBLUP; only for genotyped animals), single-step GBLUP (SS-GBLUP), and SSRR BLUP (for genotyped and nongenotyped animals). Records from different lactations, with or without predictor traits (FPCM and LW), were used in the model. Accuracies of EBV for DMI (defined as the correlation between the EBV and pre adjusted DMI phenotypes divided by the average accuracy of those phenotypes) ranged between 0.21 and 0.38 across methods and scenarios. Accuracies of EBV for DMI using BLUP were the lowest accuracies obtained across methods. Meanwhile, accuracies of EBV for DMI were similar in SS-GBLUP and SSRR-BLUP, and lower for the GBLUP method. Hence, SSRR-BLUP could be used when the number of genotyped animals is large, avoiding the construction of the inverse genomic relationship matrix. Adding information on DMI from different lactations in the reference population gave higher accuracies in comparison when only lactation 1 was included. Finally, no benefit was obtained by adding information on predictor traits to the reference population when DMI was already included. However, in the absence of DMI records, having records on FPCM and LW from different lactations is a good way to obtain EBV with a relatively good accuracy. PMID- 28865858 TI - Farm business and operator variables associated with bulk tank somatic cell count from dairy herds in the southeastern United States. AB - Mastitis is a worldwide problem in dairy cows and results in reduced milk production, the culling of cows, and other economic losses. Bulk tank somatic cell count (BTSCC) over 200,000 cells/mL often indicates underlying subclinical mastitis in dairy herds. Several preventative measures that can be implemented to help improve the incidence of mastitis exist, but surveys find these practices not fully adopted by producers. The goal of this research was to analyze the farm and operator characteristics associated with BTSCC in dairy herds by analyzing a survey of dairy producers in the southeastern United States. We examined this region because it has experienced a decline in the number of dairy farms, dairy cows, and milk production over the past 2 decades. The southeast region is also associated with higher BTSCC levels than the national average. Dairy farms in Georgia, Mississippi, Kentucky, North Carolina, South Carolina, Tennessee, and Virginia were surveyed. Producers were asked questions about the BTSCC at which they take action to address BTSCC, the information sources they use to learn about and manage BTSCC, farm structure and management characteristics, and attitudinal variables associated with profitability, managerial control, and planning horizon. Least squares regression was used to determine how these factors were associated with BTSCC levels across the 7-state region. Concern over mastitis, financial consequences of mastitis, and increased previous-year BTSCC were associated with higher current BTSCC levels. Obtaining information about mastitis from veterinarians and extension personnel, taking action against mastitis at a BTSCC less than 300,000 cells/mL, and perceived ability to control processes and mastitis incidence were associated with reduced BTSCC. We found average BTSCC was lower in North Carolina and Virginia. These results suggest that proactive producers (i.e., those that perceive they can control BTSCC and seek information from reliable sources), were more likely to report lower BTSCC. As a result, it may be possible to achieve improved milk quality, evident from lowered BTSCC, across the region. PMID- 28865859 TI - Hypocalcemia-Cow-level prevalence and preventive strategies in German dairy herds. AB - Hypocalcemia around calving is considered a gateway disease that can lead to health disorders and decreased milk production. The objective of this cross sectional study was to evaluate the prevalence of clinical and subclinical hypocalcemia 0 to 48 h after calving. Blood samples were drawn from 12 animals of each dairy farm (n = 115) and analyzed for serum calcium, magnesium, and phosphorus concentration. Cows not affected clinically but with a serum calcium concentration below 2.0 mmol/L were characterized as subclinical hypocalcemic animals. Recumbent cows with a serum calcium concentration below 2.0 mmol/L were defined as cows suffering from clinical milk fever. Herds were classified into negative (0 to 2/12), borderline (3 to 5/12), and positive (>=6/12) according to the number of animals with hypocalcemia. Strategies to control hypocalcemia were documented. Prevalence of clinical milk fever was 1.4, 5.7, and 16.1% for second, third, and >=fourth parity cows, respectively. None of the cows in first lactation were suffering from clinical milk fever. Based on the threshold of 2.0 mmol/L, 5.7, 29.0, 49.4, and 60.4% of cows in first, second, third, and >=fourth lactation were suffering from subclinical hypocalcemia, respectively. Fourteen, 51, and 50 herds were classified as negative, borderline, and positive, respectively. A positive association was observed between serum calcium and serum phosphorus concentration. Serum calcium and magnesium concentration were negatively associated. Only 50 of 115 farms had a control strategy implemented to avoid hypocalcemia. Most common was the use of oral calcium products (40/115 herds), followed by feeding of anionic salts in the close-up diet (10/115 herds). These results indicate that the prevalence of clinical and subclinical hypocalcemia in German dairy herds was high and that an active control strategy was not implemented on all farms. The negative association between calcium and magnesium warrants further research regarding the physiological regulation of these 2 minerals around parturition. PMID- 28865860 TI - Consistency over time of animal-based welfare indicators as a further step for developing a welfare assessment monitoring scheme: The case of the Animal Welfare Indicators protocol for dairy goats. AB - Consistency over time (COT) of animal-based indicators is key to a reliable and feasible welfare protocol, indicating that results are representative over long term situations. High levels of consistency ensure fairness for the farmer and credibility of the system. In addition, indicator COT reduces recording costs, as having indicators that do not change over a long period of time will require less farm visits to achieve reliable estimates. To date, COT of animal-based indicators included in the welfare assessment of dairy goats has never been tested. Therefore, our aim was to investigate COT of animal-based indicators included in the Animal Welfare Indicators (AWIN) welfare assessment prototype protocol for dairy goats. To meet this goal, a study was designed where an average of 3 mo elapsed between 2 sets of visits to the same 20 dairy goat farms (10 in Portugal and 10 in Italy), with no major changes in management routines or housing conditions occurring during this period. Initially, we performed a Wilcoxon signed rank test to investigate whether the results obtained during the 2 visits were significantly different. After this preliminary screening, the indicators presenting nonsignificant differences between visits were submitted to a second step analysis, where discriminative and evaluative analyses were conducted to reach a final indicator lineup. The discriminative approach helped distinguishing among farms, whereas the agreement analysis showed us the range of differences between repeated assessments. Some particular conclusions could be drawn from this combined analysis, helping to the development of the final AWIN welfare assessment protocol for dairy goats and as a further step to develop a welfare assessment monitoring scheme for this and other species. In this sense, the AWIN welfare assessment protocol allows for the quick differentiation between farms based on the identification of persistent welfare problems, by recording highly consistent and feasible indicators. In a second step, a more comprehensive protocol, consisting of indicators more likely to be subject to variations along time, was applied. Repeated assessments and long-term studies of indicator consistency are needed to help determine the frequency of visits required to obtain a consistent and feasible welfare assessment scheme. This paper adds to the literature by providing guidance on the variability of animal-based indicators over time. PMID- 28865861 TI - Liver transcriptome analysis reveals important factors involved in the metabolic adaptation of the transition cow. AB - During early lactation, dairy cows experience a severe metabolic load often resulting in the development of various diseases. The inevitable deficiency in nutrients and energy at the onset of lactation requires an optimal adaptation of the hepatic metabolism to overcome metabolic stress. We conducted a whole-liver transcriptome analysis for the transition cow to identify novel factors crucial for metabolic adaptation. Liver samples were obtained from 6 Red Holstein dairy cows (parity 2 to 7, mean +/- standard deviation: 3.7 +/- 2.3) at 3 time points: T1 = 22 +/- 4 d antepartum, T2 = 10 +/- 2 d postpartum, and T3 = 17 +/- 2 d postpartum. Using RNA sequencing (RNA-seq), we studied the transcriptomic profile of the transition cow before and after parturition. We performed a differential gene expression analysis (DGEA) and gene-set enrichment analysis (GSEA) for biological processes (gene ontology, GO) and pathways (Kyoto Encyclopedia of Genes and Genomes, KEGG). Among the 10,186 expressed genes, we discovered 1,063 differentially expressed genes (false discovery rate = 5%). The GSEA revealed 16 biological processes and 7 pathways significantly (false discovery rate = 5%) associated with the hepatic changes of the transition cow. Our results confirm that major hepatic changes are related to energy mobilization after parturition; in particular, they are related to fatty acid oxidation/metabolism, cholesterol metabolism, and gluconeogenesis. Using the STRING database (https://string db.org/), we investigated interactions between significant genes and identified 9 key genes (CYP7A1, APOA1, CREM, LOC522146, CYP2C87, HMGCR, FDFT1, SGLE, and CYP26A1) through which the different processes involved in the metabolic adaptation interact. Comparing our main results with the literature, we could identify further genes that have not yet been associated with the transition period (e.g., CPT1B, ADIPOR2, LEPR, CREB3L3, and CCND1) and that are mainly involved in processes controlled by AMP-activated protein kinase, an important regulator of energy homeostasis. PMID- 28865862 TI - Rapid and simultaneous quantification of viable Escherichia coli O157:H7 and Salmonella spp. in milk through multiplex real-time PCR. AB - Escherichia coli O157:H7 and Salmonella spp. in milk are 2 common pathogens that cause foodborne diseases. An accurate, rapid, specific method has been developed for the simultaneous detection of viable E. coli O157:H7 and Salmonella spp. in milk. Two specific genes, namely, fliC from E. coli O157:H7 and invA from Salmonella spp., were selected to design primers and probes. A combined treatment containing sodium deoxycholate (SDO) and propidium monoazide (PMA) was applied to detect viable E. coli O157:H7 and Salmonella spp. only. Traditional culture methods and SDO-PMA-multiplex real-time (mRT) PCR assay were applied to determine the number of viable E. coli O157:H7 and Salmonella spp. in cell suspensions with different proportions of dead cells. These methods revealed consistent findings regarding the detected viable cells. The detection limit of the SDO-PMA-mRT-PCR assay reached 102 cfu/mL for Salmonella spp. and 102 cfu/mL for E. coli O157:H7 in milk. The detection limit of SDO-PMA-mRT-PCR for E. coli O157:H7 and Salmonella spp. in milk was significantly similar even in the presence of 106 cfu/mL of 2 nontarget bacteria. The proposed SDO-PMA-mRT-PCR assay is a potential approach for the accurate and sensitive detection of viable E. coli O157:H7 and Salmonella spp. in milk. PMID- 28865863 TI - Differential enumeration of subpopulations in concentrated frozen and lyophilized cultures of Lactobacillus delbrueckii ssp. bulgaricus. AB - Differential enumeration of subpopulations in concentrated frozen and lyophilized cultures of Lactobacillus delbrueckii ssp. bulgaricus ND02 derived from 2 propagation procedures was determined. The subpopulations consisted of 3 categories (physiological states): viable cells capable of forming colonies on agar plates (VC+), viable cells incapable of forming colonies on agar plates (VC ), widely referred to as viable but nonculturable (VBNC) cells, and nonviable or dead cells (NVC). Counts of VC+ were recorded using a conventional plate count procedure. A fluorescent vital staining procedure that discriminates between viable (VC+ and VC-) and NVC cells was used to determine the number of viable and nonviable cells. Both propagation procedures had 2 variables: in procedure (P)1, the propagation medium was rich in yeast extract (4.0%) and the pH was maintained at 5.7; in P2, the medium was devoid of yeast extract and the pH was maintained at 5.1. The results showed that post-propagation operations-concentration of cells by centrifugation and subsequent freezing or lyophilization of cell concentrate-induced different degrees of transience from VC+ to VC- states in cells derived from P1 and P2. Compared with cells derived from P2, cells from P1 were more labile to stress associated with centrifugation, freezing, and lyophilization, as revealed by differential counting. PMID- 28865864 TI - Clinicopathologic and immunophenotypic features of eosinophilic fasciitis and morphea profunda: A comparative study of 27 cases. AB - BACKGROUND: Eosinophilic fasciitis (EF) and morphea profunda (MP) are inflammatory and sclerosing disorders of the subcutis that can exhibit clinical and pathologic presentations that overlap. OBJECTIVE: To identify clinicopathologic features that can be used to distinguish EF from MP. METHODS: We performed a retrospective review of 16 patients with EF and 11 patients with MP. Hematoxylin-eosin, CD123, CD34, and Verhoeff-Van Gieson stains were evaluated on skin biopsies that included the fascia. RESULTS: EF patients were more likely than MP patients to be men (P = .047), have forearm involvement (P = .003), and have peripheral eosinophilia (P < .01). Compared with MP patients, patients with EF were more likely to have fascia that contained eosinophils (P = .003), although eosinophils were absent in 3 (19%) patients with EF. Focal absence of CD34 staining was more prominent in the fascia of EF patients (P = .04). The extent of Verhoeff-Van Gieson staining did not differ between the 2 groups. Dermal sclerosis was not detected in many cases of EF and MP (56% and 36%, respectively). LIMITATIONS: This was a retrospective study at a single institution. CONCLUSION: Although EF and MP share clinical and pathologic features, our results indicate that the presence of eosinophils in the blood and fascia and focal loss of CD34 staining might be more suggestive of EF than MP. PMID- 28865865 TI - Managing sharps injuries and other occupational exposures to HIV, HBV, and HCV in the dermatology office. AB - Dermatologists and their staff are at risk for needlestick injuries and exposures to body fluids. Despite the availability of treatment to reduce the risk of blood borne infection, many exposures go unreported. This paper identifies current recommendations and the specific details for response to occupational exposures to HIV, hepatitis B virus, and hepatitis C virus in the dermatology office. Issues surrounding each virus are discussed individually, and a summary step-by step algorithm of how to proceed in the event of an occupational exposure is presented. In addition, a focused Practice Improvement Activity that is based on this paper and provides Maintenance of Certification credit has been developed. To view and participate, visit https://secure.dataharborsolutions.com/abdermorg/. PMID- 28865866 TI - Postexercise hypotension during different water-based concurrent training intrasession sequences in young women. AB - The purpose of the study was to compare the acute effects of water-based resistance-aerobic (RA) and aerobic-resistance (AR) sequences on systolic blood pressure, diastolic blood pressure (DBP), and mean blood pressure (MBP) in young women. Thirteen active women participated in four sessions: (1) exercises familiarization, (2) aquatic maximal test to determine the heart rate (HR) corresponding to the anaerobic threshold (HRAT), (3) concurrent protocol RA, and (4) concurrent protocol AR. Both protocols were initiated with the blood pressure measurements at rest in supine position. After that, either RA or AR concurrent protocol was performed. At the end of both protocols, blood pressure was measured throughout 60 minutes (every 10 minutes). The water-based resistance protocol was made up by exercises at maximal velocity, and the water-based aerobic protocol was performed at +/-5 bpm of HRAT continuously. Two-way analysis of variance with repeated measures was used to analyze the data (alpha = 0.05). There was no hypotensive effect on systolic blood pressure among the time points (P = .235) in both water-based intrasession exercise sequences (P = .423). Regarding the DBP and MBP, both intrasession exercise sequences presented similar (DBP: P = .980; MBP: P = .796) hypotensive effects in the first 10 minutes (DBP: P = .003; MBP: P = .008) at the end of RA and AR sessions (DBP: -4 vs. -13 mm Hg; MBP: -3 vs. -10 mm Hg). It was concluded that both RA and AR water-based concurrent training sessions resulted in postexercise hypotension (DBP and MBP) in normotensive young women. PMID- 28865867 TI - A Longitudinal Study of PROMIS Pediatric Symptom Clusters in Children Undergoing Chemotherapy. AB - CONTEXT: Children in treatment for cancer experience multiple, troubling, and interrelated symptoms. Analyzing the interrelatedness of symptoms and how that changes during treatment could yield clinically relevant patient profiles to guide patient care. OBJECTIVES: The aims were to identify pediatric profiles with respect to Patient-Reported Outcomes Measurement Information System(r) (PROMIS(r); U.S. Department of Health and Human Services, National Institutes of Health) symptom measures, changes in profile status throughout a chemotherapy cycle, and if a baseline single-item fatigue measure could significantly predict symptom profile status and its changes. METHODS: In a longitudinal, single-site, three data point (T1, T2, and T3) design, children between 8 and 18 years completed the PROMIS Pediatric short form measures for fatigue, depression, anxiety, and pain and one fatigue item from the Symptom Distress Scale. Latent profile analysis and latent transition analysis were conducted. RESULTS: About 96 children participated; 58.3% were between 13 and 18 years, and 54.2% were males. Two latent profiles (less severe symptoms and severe symptoms) were identified. The prevalence of the severe symptom profile remained relatively unchanged from T1 to T2 but significantly declined at T3. The baseline single-item fatigue score significantly predicted the child's profile membership and its changes. CONCLUSION: Children experiencing troubling symptoms during cancer treatment are heterogeneous. With respect to the PROMIS symptom measures, two a priori unknown distinct latent profiles of patients were identified in a course of chemotherapy, and the transitions in the profile status were significantly predicted by a baseline single-item fatigue measure. PMID- 28865868 TI - Translation and Psychometric Testing of the Persian Version of the Spiritual Needs Questionnaire Among Elders With Chronic Diseases. AB - CONTEXT: Spirituality plays an important role in coping with chronic diseases for patients and they often report unmet spiritual and existential needs, which should be considered for a holistic view of their health. Studying spiritual needs in this generation requires culturally appropriate and valid instruments. The aim of this study was to determine the psychometric properties, such as validity, reliability, and factor structure of the Persian version of Spiritual Needs Questionnaire (SpNQ). OBJECTIVES: The aim of this study was to determine the psychometric properties, such as validity, reliability, and factor structure of the Persian version of Spiritual Needs Questionnaire (SpNQ). METHODS: The "forward-backward" procedure was applied to translate the SpNQ from English into Persian. The SpNQ-Persian Version (SpNQ-PV) was checked in terms of validity and reliability with a convenience sample of 100 elders with chronic diseases who were recruited from the inpatient wards at two university hospitals in Qom, Iran. The validity was assessed using content, face, and construct validity. The Cronbach alpha and test-retest were used to assess the reliability of the questionnaire. RESULTS: The results of the exploratory factor analysis indicated a five-factor solution for the questionnaire, which included religious needs, existential needs, forgiveness/generativity needs, need for inner peace, and emotional needs. These accounted for 60.1% of the total observed variance. One item was removed (factor loading <0.4). Convergent validity was supported mostly by the pattern of association between SpNQ-PV and the Spiritual Well-being Scale. Cronbach alpha of the subscales ranged from 0.56 to 0.78 and the test-retest reliability ranged from 0.72 to 0.91, which indicated an acceptable range of reliability. CONCLUSION: The SpNQ-PV showed a minor difference in structuring and indicated good psychometric properties, which can be used to assess the spiritual needs of Iranian elders suffering from chronic diseases. PMID- 28865869 TI - Homing in on the Social: System-Level Influences on Overly Aggressive Treatments at the End of Life. AB - CONTEXT: The American Medical System is programmed to a default setting of aggressive care for the terminally ill. Institutional norms of decision making have been shown to promote high-intensity care, regardless of consistency with patient preferences. There are myriad factors at a system, clinician, surrogate, and patient level that drive the culture of overly aggressive treatments in American hospitals. OBJECTIVE: The objective of this study was to understand physician perspective of the ways systems-level factors influence patient, physician, and surrogate perceptions and consequent behavior. METHODS: Semi structured in-depth qualitative interviews with 42 internal medicine physicians across three American academic medical centers were conducted. This qualitative study was exploratory in nature, intended to enhance conceptual understanding of underlying phenomena that drive physician attitudes and behavior. RESULTS: The interviews revealed many factors that contributed to overly aggressive treatments at the end of life. Systemic factors, which describe underlying cultures (including institutional, professional, or community-based cultures), typical practices of care, or systemic defaults that drive patterns of care, manifested its influence both directly and through its impact on patient, surrogate, and physician behaviors and attitudes. CONCLUSION: Institutional cultures, social norms, and systemic defaults influence both normative beliefs regarding standards of care and treatments plans that may not benefit seriously ill patients. PMID- 28865871 TI - Variations in Denominators and Cut-off Points of Pain Intensity in the Pain Management Index: A Methodological Systematic Review. PMID- 28865870 TI - Outcomes That Define Successful Advance Care Planning: A Delphi Panel Consensus. AB - CONTEXT: Standardized outcomes that define successful advance care planning (ACP) are lacking. OBJECTIVE: The objective of this study was to create an Organizing Framework of ACP outcome constructs and rate the importance of these outcomes. METHODS: This study convened a Delphi panel consisting of 52 multidisciplinary, international ACP experts including clinicians, researchers, and policy leaders from four countries. We conducted literature reviews and solicited attendee input from five international ACP conferences to identify initial ACP outcome constructs. In five Delphi rounds, we asked panelists to rate patient-centered outcomes on a seven-point "not-at-all" to "extremely important" scale. We calculated means and analyzed panelists' input to finalize an Organizing Framework and outcome rankings. RESULTS: Organizing Framework outcome domains included process (e.g., attitudes), actions (e.g., discussions), quality of care (e.g., satisfaction), and health care (e.g., utilization). The top five outcomes included 1) care consistent with goals, mean 6.71 (+/-SD 0.04); 2) surrogate designation, 6.55 (0.45); 3) surrogate documentation, 6.50 (0.11); 4) discussions with surrogates, 6.40 (0.19); and 5) documents and recorded wishes are accessible when needed 6.27 (0.11). Advance directive documentation was ranked 10th, 6.01 (0.21). Panelists raised caution about whether "care consistent with goals" can be reliably measured. CONCLUSION: A large, multidisciplinary Delphi panel developed an Organizing Framework and rated the importance of ACP outcome constructs. Top rated outcomes should be used to evaluate the success of ACP initiatives. More research is needed to create reliable and valid measurement tools for the highest rated outcomes, particularly "care consistent with goals." PMID- 28865872 TI - Reliability and Validity of the Korean Memorial Symptom Assessment Scale-Short Form in Gynecological Cancer Patients. AB - CONTEXT: Symptoms of patients with cancer need to be evaluated with a standard instrument. The Memorial Symptom Assessment Scale-Short Form (MSAS-SF) is a symptom assessment tool that has been validated in many languages. OBJECTIVES: The aim of the present study was to validate the Korean-version Memorial Symptom Assessment Scale-Short Form (MSAS-SF) in patients with gynecologic cancer. METHODS: We translated the MSAS-SF into Korean, and 175 gynecologic cancer inpatients completed the MSAS-SF, Functional Assessment Cancer Therapy-General (FACT-G), and gathered demographic and clinical data and Karnofsky Performance Status (KPS). Reliability was assessed for internal consistency with Cronbach's alpha coefficient. Pearson's correlation coefficient was calculated between the MSAS-SF and FACT-G subscales for convergent validity. T-test analysis was used to compare differences in MSAS-SF subscales by cancer stage and KPS for discriminant validity. RESULTS: The Cronbach's alpha coefficients for the MSAS-SF subscales ranged from 0.80 to 0.91. The Korean-version MSAS-SF subscales showed convergent validity with FACT-G subscales. The correlation coefficients were -0.640 (P < 0.001) and -0.628 (P < 0.001) for global distress index and total MSAS score with FACT-G total score. The scores of MSAS-SF subscales showed appropriate differences by cancer stage and KPS. CONCLUSION: The Korean-version MSAS-SF is a valid tool for the reliable assessment of patients with gynecologic cancer in Korea. PMID- 28865874 TI - Predictors of falls in recreational snowboard jumping: An observational study. AB - PURPOSE: Jumping is popular in the sport of snowboarding. Epidemiological research has shown an increased risk of injury associated with this activity. Falls are common when jumping and although there is a logical connection between falling and injury occurrence, thus far little attention has been given to factors involved in the jumping-fall relationship. The current study aimed to add to the current knowledge base by identifying predictors of falling during intentional snowboard jumping within terrain park facilities. METHODS: Seven hundred and four jumps were video recorded and qualitatively coded using a custom template of predetermined parameters related to manoeuvre choice, landing technique and jump success. RESULTS: Falling was common within the sample population at a rate of one fall for every five jump attempts. Landings made on the flat or knuckle of the snow jump as well as incorrect board positioning at landing were found to be significant predictors of falling. Additionally the choice of manoeuvre was found to influence the risk of falls, with spinning jumps associated with a greater fall risk when compared to non spinning jumps. No clear relationship was identified between jump length measures and falling risk. CONCLUSION: It is likely that jumping will remain popular in snowboarding and thus research efforts should focus on minimising the risk of injury associated with this skill. Reducing the overall incidence of falling, identified in the current study to be high, is a potential area for improvement. The potential for fall risk reduction through technique and decision making changes provides justification for further research in this area. PMID- 28865873 TI - Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle. AB - Statins constitute the most commonly prescribed drugs to decrease cholesterol (CLR). CLR is an important modulator of alcohol-induced cerebral artery constriction (AICAC). Using rats on a high CLR diet (2% CLR) we set to determine whether atorvastatin administration (10mg/kg daily for 18-23weeks) modified AICAC. Middle cerebral arteries were pressurized in vitro at 60mmHg and AICAC was evoked by 50mM ethanol, that is within the range of blood alcohol detected in humans following moderate-to-heavy drinking. AICAC was evident in high CLR+atorvastatin group but not in high CLR diet+placebo. Statin exacerbation of AICAC persisted in de-endothelialized arteries, and was blunted by CLR enrichment in vitro. Fluorescence imaging of filipin-stained arteries showed that atorvastatin decreased vascular smooth muscle (VSM) CLR when compared to placebo, this difference being reduced by CLR enrichment in vitro. Voltage- and calcium gated potassium channels of large conductance (BK) are known VSM targets of ethanol, with their beta1 subunit being necessary for ethanol-induced channel inhibition and resulting AICAC. Ethanol-induced BK inhibition in excised membrane patches from freshly isolated myocytes was exacerbated in the high CLR diet+atorvastatin group when compared to high CLR diet+placebo. Unexpectedly, atorvastatin decreased the amount and function of BK beta1 subunit as documented by immunofluorescence imaging and functional patch-clamp studies. Atorvastatin exacerbation of ethanol-induced BK inhibition disappeared upon artery CLR enrichment in vitro. Our study demonstrates for the first time statin's ability to exacerbate the vascular effect of a widely consumed drug of abuse, this exacerbation being driven by statin modulation of ethanol-induced BK channel inhibition in the VSM via CLR-mediated mechanism. PMID- 28865875 TI - Photochemical internalization (PCI) of bleomycin is equally effective in two dissimilar leiomyosarcoma xenografts in athymic mice. AB - BACKGROUND: Photochemical internalization (PCI) is a novel technique for delivery of active macromolecules into cancerous cells, via light activation of a specific photosensitizer and a low dose systemic drug. Numerous pre-clinical studies and one clinical trial have confirmed the treatment potential in carcinomas. Soft tissue sarcomas are rare and generally resistant to radio- and chemotherapy. Due to treatment resistance and surgical morbidity in sarcoma care, we seek to increase knowledge on PCI effects in sarcomas by studying two different, but closely related leiomyosarcomas. METHODS: MES-SA and SK-LMS-1 tumours were established in the leg muscles of athymic mice. Treatment effects after AlPcS2a PCI of bleomycin, PCI with no drug (photodynamic therapy, PDT) and control groups were evaluated by: 1) assessment of tumour growth, 2) uptake of contrast agent during MRI and 3) histopathology. RESULTS: PCI of bleomycin induced a similar and significant increase in time to reach the end point in both tumour models, while neither responded to AlPcS2a-PDT. In the MES-SA tumours PCI reduced the growth rate, while in the SK-LMS-1 tumours the growth was blocked for 12days followed by exponential growth close to that of untreated tumours. SK-LMS-1 tumours were more homogenously and better vascularized than MES-SA. After PCI the vascular shutdown was more complete in the SK-LMS-1 tumours than in the MES-SA tumours. CONCLUSIONS: AlPcS2a-based PCI, but not PDT, induced significant tumour growth delay in the evaluated sarcomas. Cellular responsiveness to bleomycin and tumour vascularity are identified as predictive markers for PCI treatment effects. PMID- 28865876 TI - Resistance and tolerance defenses in cancer: Lessons from infectious diseases. AB - Infectious disease and cancer are two maladies with multiple similarities. Both types of disease induce activation of the host immune response and induce pathologies that compromise host heath and survival. In infection biology, defense against pathogens can be broken down into two distinct components called resistance and tolerance. Resistance protects the host by killing pathogens. Tolerance protects the host by alleviating the pathology caused by the infection. The conceptual framework of resistance and tolerance, concepts explored during infectious disease, is applicable to cancer, a condition for which patient survival is dependent on tumor eradication (resistance) and the mitigation of pathologies that occur during disease (tolerance). Here, we propose that integration of the concept of disease tolerance into cancer studies will result in new therapies to complement current resistance-based treatment strategies to increase the likelihood of patient survival and to improve quality of life. Furthermore, by drawing parallels between infectious disease and cancer, we propose that host interactions with microbes could provide therapeutic insight for promoting tolerance defense and focus our discussion on cachexia, a pathology resulting in significant morbidity in cancer patients. PMID- 28865878 TI - Will Perimetry Be Performed to Monitor Glaucoma in 2025? AB - Visual field testing has played an essential role in the diagnosis and management of glaucoma for more than a century. Methods to examine the visual field have been refined from early kinetic perimetry to current standard automated perimetry (SAP). Clinicians now use SAP for the diagnosis and management of glaucoma throughout the world. Various testing paradigms and analytic methods have been developed to simplify the diagnosis of glaucoma and the interpretation of progression. Moreover, strategies have been implemented to improve patient experience with visual field testing and to increase reliability. Objective functional tests, such as electroretinography, provide an alternative to subjective visual field testing but are not yet ready for widespread adoption. Standard automated perimetry is being adapted and improved constantly. New devices may allow patients to complete visual field tests at home, which could relieve patients and clinicians from in-office testing and allow for more frequent examinations. Glaucoma detection and progression analysis also are incorporating progressively more information and will be improved as deep learning strategies are applied. Finally, perimetric and structural testing likely will become more closely intertwined as testing platforms and progression analysis incorporate both of these measures. Visual field testing will continue to have an important role in the diagnosis and management of glaucoma. PMID- 28865879 TI - Epilogue. PMID- 28865880 TI - The Chalfont Centre, Bucks, United Kingdom. PMID- 28865877 TI - Oral immunotherapy for food allergy. AB - Food allergy is a pathological, potentially deadly cascade of immune responses to molecules or molecular fragments that are normally innocuous when encountered in foods, such as milk, egg, or peanut. As the incidence and prevalence of food allergy rise, the standard of care is poised to advance beyond food allergen avoidance coupled with injectable epinephrine treatment of allergen-induced systemic reactions. Recent studies provide evidence that oral immunotherapy may effectively redirect the atopic immune responses of food allergy patients as they ingest small but gradually increasing allergen doses over many months, eliciting safer immune responses to these antigens. Research into the molecular and cellular bases of pathological and therapeutic immune responses, and into the possibilities for their safe and effective modulation, is generating tremendous interest in basic and clinical immunology. We synthesize developments, innovations, and key challenges in our understanding of the immune mechanisms associated with atopy and oral immunotherapy for food allergy. PMID- 28865881 TI - National Center for Epilepsy, Oslo, Norway. PMID- 28865882 TI - Kempenhaeghe academic center for epileptology and residential epilepsy care, Heeze, The Netherlands. PMID- 28865883 TI - Semiology of psychogenic nonepileptic seizures: An international cross-cultural study. AB - PURPOSE: We compared the semiology of psychogenic nonepileptic seizures (PNES) between patients from the USA and Brazil. This international cross-cultural comparative study may expand understanding of PNES across the borders. METHODS: We retrospectively investigated all patients with PNES admitted to one epilepsy center in the USA and one in Brazil. We classified their seizures into four classes: generalized motor, akinetic, focal motor, and subjective symptoms. All patients were interviewed by an epileptologist in both countries and were administered psychological assessment measures, including questions about PNES risk factors. For the statistical analyses, we compared patients from the two nations. RESULTS: Eighty-nine patients (49 from the USA and 40 from Brazil) were studied. Patients from the two countries were not significantly different with regard to sex and age, but patients from Brazil had earlier age at onset (26years vs. 34years; P=0.004) and a significantly greater delay in diagnosis (9.9years vs. 5.6years; P=0.001). Some characteristics of PNES were different between the two groups; patients from the USA had generally more seizure types and more often reported subjective seizures (55% in the USA vs. 10% in Brazil; P=0.0001). Clinical and historical characteristics of the patients were not significantly different. CONCLUSION: Delay in diagnosis of PNES may represent a major factor in resource-limited countries. Large multicenter cross-cultural studies may reveal subtle but significant cross-cultural differences with respect to the semiological, clinical, and historical aspects of PNES; however, patients with PNES share more similarities than differences. PMID- 28865884 TI - The William Quarrier Scottish Epilepsy Centre, Glasgow, Scotland. PMID- 28865886 TI - Posterior hypospadias: Evaluation of a paradigm shift from single to staged repair. AB - INTRODUCTION: Repair of posterior hypospadias is a current dilemma. Single versus staged repair is the main question to answer. The answer is not easily reached due to lack of comparative studies. Hence such studies are not available, the reports of a change from one approach to the other one are important to point out the results of each procedure in the same hands and in the same center. Herein, we report our results of the repair of posterior hypospadias shifting from single stage to staged repair. PATIENTS AND METHODS: 65 children were operated in a single Centre in the period from 2011-2016 using single stage repair by dorsal island flap in the first 40 children and then a shift to staged repair involved 25 children repaired using Bracka procedure, children are evaluated for the outcome and for the development of complications during the period of follow up. RESULTS: The mean age of children operated using single stage technique was 2.8 years (0.83-12.0), Onlay repair was performed in 29 cases (72.5%), while a tube was performed in 11 cases (27.5%). The success rate was 55% with 45% complication rate, in the form of infection in (2.5%), partial dehiscence in (10%), urethrocutaneous fistula in (15%), meatal stenosis in (12.5%), urethral diverticulum in (5%). 25 children were operated using staged repair according to Bracka using inner preputial graft in fresh cases and buccal graft in redo cases. Mean age of 4.5 years (7 months-18 years), 15 primary cases and 10 redo cases, 12 penoscrotal, 11 scrotal and 2 perineal cases, preputial graft in 17, buccal graft in 8, 25 children completed their second stage, tunica vaginalis cover was used in 23 children, localized penile skin dartos was used in 2 children, the overall success after second stage was 80%, complications were in the form of 4 fistulas (16%), hematoma and complete disruption in a redo case (4%). There is a significant statistical difference in the incidence of complications between both groups in favor of lower complication rate (20%) in the staged group versus the single stage group (45%) with a P = 0.0419. CONCLUSION: Staged repair considerably improves complication rate of posterior hypospadias reconstruction compared to single stage repair using pedicled island flap. More follow up and continuous reporting of honest complication rate is needed to improve the outcome of a complex pathology and to help the choice of the best procedure. PMID- 28865885 TI - Stone growth patterns and risk for surgery among children presenting with hypercalciuria, hypocitraturia and cystinuria as underlying metabolic causes of urolithiasis. AB - INTRODUCTION: Hypercalciuria, hypocitraturia and cystinuria are the most common underlying metabolic stone abnormalities in children. The present study compared stone growth patterns, stone burden, and the risk of stone-related surgery among these underlying metabolic conditions. METHODS: A retrospective cohort of 356 children with renal stones, followed from 2000 to 2015, was studied. Differences among metabolic groups were determined using Kruskal-Wallis test; the Scheffe test was used for multiple comparisons to determine differences among single groups. Independent sample t-test was used when adequate, given the sample size, and Chi-squared test was used for categorical variables. Stone growth rates were calculated as differences in diameter divided by time elapsed between U/Ss (mm/year). Logistic regression was performed to assess the effect of initial stone size on the likelihood of surgery. RESULTS: Median stone size at presentation was significantly different among groups, with cystinuria being the group with the largest proportion of stones >10 mm, while patients with stones <5 mm were likely to have a normal metabolic workup (P < 0.05). Stones with a higher growth rate were found in the operative group, while slower growing stones were mostly managed conservatively (3.4 mm/year vs 0.8 mm/year, respectively; P = 0.014). However, stone growth rates were not significantly different among metabolic groups. On the other hand, the rate of new stone formation in cystinuric patients at their first follow-up was 30.4%, which was significantly higher than in patients with hypercalciuria (16.3%) or with a normal metabolic workup (17.2%; P < 0.05). Compared with stones <5 mm, stones measuring 5-10 mm were more than four times more likely to result in surgery, whereas the likelihood of surgery for 10-20 mm or >20 mm stones was almost 16 or 34 times, respectively (P < 0.001). CONCLUSIONS: It is believed that this is the first study to evaluate stone growth patterns, stone burden and surgical risk among children with hypercalciuria, hypocitraturia and cystinuria. Cystinuric patients presented with larger stones at the time of diagnosis, higher new stone formation rates, and were at higher risk of surgery. While no significant difference of growth rate was found among metabolic groups, stones with a higher growth rate were significantly more likely to result in surgical treatment than slower growing stones. Initial stone size, location of largest stone, previous urinary tract infection, and patient's metabolic type significantly influenced the likelihood of a surgical intervention. Better understanding of the natural history ultimately helps surgeons and clinicians defining prognosis, treatment, and prevention plans for pediatric urolithiasis. PMID- 28865887 TI - Flow characteristics of urethral catheters of the same caliber vary between manufacturers. AB - BACKGROUND: Clean intermittent catheterization (CIC) is frequently prescribed for bladder dysfunction, either per urethra or via a continent catheterizable channel. Small catheters may be required for infants or continent channels. Success with CIC is highly dependent upon patient and family compliance. The urinary flow rate through the catheter is an important factor, which can decrease CIC time and improve quality of life. There is little objective information regarding flow rate through urinary catheters to guide catheter recommendation or prescription. Clinically, we noted that there was a difference in flow among catheter brands, and we questioned if catheters of the same-labeled diameter exhibit the same flow characteristics, which could have implications for catheter selection. METHODS: Twenty-one commercially available male pediatric urinary catheters from nine brands were tested (11 straight tip, 10 coude tip). Nine of the 21 tested catheters had a hydrophilic coating. All tested catheters shared a 10F outer diameter. For each, microscopic imaging and a precision caliper were used to measure the inner diameter and tip inlet area. A hydraulic system modified from ASTM standard testing specifications was used to simulate bladder catheterization. Measurement of each catheter was repeated five times using three different static hydraulic pressures (20, 40 and 50 cmH2O). Catheter flow rate and structural measurements were identified and the fastest and slowest of the catheters are presented in the table. The variable flow rates between brands were due to the differences in catheter structural characteristics such as the inner diameter (ID) and the tip inlet area to inner lumen area ratio (AR). The maximum variation of flow rate of all tested 10F catheters was 48%, ID varied up to 22%, from 1.71 to 2.11 mm or 5.13-6.33F. AR varied up to 166%. The table delineates the fastest and slowest rates at three measured pressures. The outer diameter labeled 10F on packaging was true to size. CONCLUSIONS: Based on packaging information, providers, and patients are unable to predict urinary flow through a catheter and thus use information regarding flow rate to guide catheter selection. This information cannot be calculated based on ideal flow calculations and could be listed on packaging to assist physicians and families in selecting the optimal urinary catheter for CIC. PMID- 28865888 TI - Evolution after switching to biosimilar infliximab in inflammatory bowel disease patients in clinical remission. AB - BACKGROUND AND AIM: The biosimilar of infliximab (CT-P13) has been approved for the same indications held by the infliximab reference product (Remicade(r)); however, there are few clinical data on switching in inflammatory bowel disease (IBD). The aim of this study was to assess the efficacy, safety, bioavailability profile and factors associated with relapse after switching to biosimilar infliximab in IBD patients in clinical remission. MATERIAL AND METHOD: Observational study with IBD patients treated with Remicade(r) for at least 6 months and in clinical remission for at least 3 months who switched to infliximab biosimilar. The incidence of relapse, adverse effects and possible changes in drug bioavailability (trough level and antidrug antibodies) were evaluated. RESULTS: Thirty six patients were included (63.9% CD) with a mean follow-up of 8.4 months (SD+/-3.5). The 13.9% had clinical relapse. The longer clinical remission time before switching (HR=0.54, 95% CI=0.29-0.98, P=.04) and detectable infliximab levels at the time of switching (HR=0.03, 95% CI=0.001-0.89, P=.04) were associated with a lower risk of relapse. No differences were found between infliximab levels at the time of switching and at weeks 8 and 16 (P=.94); 8.3% of the patients had some adverse event, requiring the suspension of biosimilar in one patient for severe pneumonia. CONCLUSION: Switching to biosimilar infliximab in a real-life cohort of IBD patients in clinical remission did not have a significant impact on short-term clinical outcomes. The factors associated with relapse were similar to those expected in patients continuing with Remicade(r). PMID- 28865889 TI - Regional Variation in Utilization, In-hospital Mortality, and Health-Care Resource Use of Transcatheter Aortic Valve Implantation in the United States. AB - We queried the National Inpatient Sample database from 2012 to 2014 to identify all patients aged >=18 years undergoing transcatheter aortic valve implantation (TAVI) in the United States. Regional differences in TAVI utilization, in hospital mortality, and health-care resource use were analyzed. Of 41,025 TAVI procedures in the United States between 2012 and 2014, 10,390 were performed in the Northeast, 9,090 in the Midwest, 14,095 in the South, and 7,450 in the West. Overall, the number of TAVI implants per million adults increased from 24.8 in 2012 to 63.2 in 2014. The utilization of TAVI increased during the study period in all 4 geographic regions, with the number of implants per million adults being highest in the Northeast, followed by the Midwest, South, and West, respectively. Overall in-hospital mortality was 4.2%. Compared with the Northeast, risk adjusted in-hospital mortality was higher in the Midwest (adjusted odds ratio [aOR] 1.26 [1.07 to 1.48]) and the South (aOR 1.61 [1.40 to 1.85]) and similar in the West (aOR 1.00 [0.84 to 1.18]). Average length of stay was shorter in all other regions compared with the Northeast. Among patients surviving to discharge, disposition to a skilled nursing facility or home health care was most common in the Northeast, whereas home discharge was most common in the West. Average hospital costs were highest in the West. In conclusion, we observed significant regional differences in TAVI utilization, in-hospital mortality, and health-care resource use in the United States. The findings of our study may have important policy implications and should provide an impetus to understand the source of this regional variation. PMID- 28865890 TI - Natriuretic Propeptides as Markers of Atrial Fibrillation Burden and Recurrence (from the AMIO-CAT Trial). AB - Natriuretic peptides are established plasma markers of systolic heart failure, but their usefulness for the evaluation of atrial fibrillation (AF) is unknown. We examined mid-regional pro-atrial natriuretic peptide (MR-proANP) and N terminal pro-brain natriuretic peptide (NT-proBNP) in patients undergoing ablation for AF. A subpopulation of 102 patients (median age 60 [52;65], 82% male) from the AMIO-CAT trial (Recurrence of arrhythmia following short-term oral AMIOdarone after CATheter ablation for atrial fibrillation: a double-blind, randomized, placebo-controlled study) undergoing ablation for paroxysmal (n = 55) or persistent (n = 47) AF was studied. MR-proANP and NT-proBNP were measured before ablation and at 1, 3, and 6 months' follow-up. Three-day Holter monitoring was performed before ablation, and 6 to 8 weeks and 6 months after ablation. Plasma MR-proANP and NT-proBNP concentrations were higher during AF than during sinus rhythm before ablation (188 pmol/L [131;260] vs 94 pmol/L [64;125], p <0.001; 78 pmol/L [43;121] vs 10.3 pmol/L [5.9;121], p <0.001) and at 1, 3, and 6 months' follow-up. Categories of AF burden on 3-day Holter monitoring (0%, 0% to 99%, and 99% to 100%) were associated with plasma concentrations of both MR proANP (94 pmol/L [55;127] vs 117 pmol/L [88;185] vs 192 pmol/L [127;261], p <0.001) and NT-proBNP (10 pmol/L [5.9;22] vs 22 pmol/L [8.9;53] vs 81 pmol/L [45;116], p <0.001). In a multivariate regression analysis, however, there was no significant association between baseline propeptide concentrations and recurrence of AF at 6 months' follow-up. In conclusion, AF was associated with higher plasma concentrations of MR-proANP and NT-proBNP than sinus rhythm. Moreover, AF burden was associated with subsequent concentrations of both MR-proANP and NT-proBNP. The results suggest that natriuretic propeptide measurement reflects functional cardiac dysfunction during AF, and that AF burden should be included in biochemical assessment of left ventricular dysfunction. PMID- 28865891 TI - Serum Ferritin Levels in Blacks Without Known Cardiovascular Disease (from the Jackson Heart Study). AB - There has been conflicting results regarding the role of ferritin, a nonspecific marker of systemic inflammation, in the development of coronary heart disease (CHD). We aimed to evaluate the association of serum ferritin with incident CHD, incident stroke, and subclinical measurements of atherosclerosis among blacks. For our prospective study, we utilized data from the Jackson Heart Study. Eligible participants (n = 4,659) who were free from CHD were enrolled in 2000 to 2004. The participants' baseline serum ferritin levels were obtained, and they were followed up for an average of 8 years to identify incident CHD events and incident stroke. We used multivariate linear regression and Cox proportional hazard models to evaluate the association of serum ferritin with incident CHD events and incident stroke. The age-adjusted correlations between ferritin and specific study covariates, including carotid intima-media thickness, coronary artery calcium, and abdominal aortic calcium, were obtained. During an average of 8 years of follow-up, 161 incident CHD events and 117 incident stroke events were documented. There was no significant association between ferritin levels and incident CHD events (p = 0.54 in men and p = 0.31 in women) and incident stroke (p = 0.17 in men and p = 0.56 in women), or both considered together (p = 0.70 in men and p = 0.69 in women). Ferritin was significantly correlated with abdominal aortic calcium (r = 0.09, p <0.01) in women but not in men. In conclusion, a higher serum ferritin level was not associated with an increased risk of incident CHD events or incident stroke, and may not be an independent predictor of incident CHD or stroke in blacks. PMID- 28865892 TI - Comparison of Readmission Rates After Acute Myocardial Infarction in 3 Patient Age Groups (18 to 44, 45 to 64, and >=65 Years) in the United States. AB - Postacute myocardial infarction (AMI) readmissions are common among Medicare beneficiaries (>=65 years) and are associated with significant resource utilization. However, patterns of AMI readmissions for younger age groups in the United States are not known. In the Nationwide Readmissions Database, a nationally representative all-payer database of inpatient hospitalizations, we identified 212,171 index AMI hospitalizations in January to November 2013, weighted to represent 478,247 hospitalizations nationally (mean age 66.9 years, 38% women, 29% low income). This included 26,516 cases in the 18 to 44 age group, 183,703 in the 45 to 64 age group, and 268,027 in the >=65 age group. The overall 30-day readmission rate was 14.5% and varied across age groups (9.7% [18 to 44], 11.2% [45 to 64], and 17.3% [>=65]). The cumulative cost of 30-day readmissions was $1.1 billion, of which $365 million was spent on those <65 years of age. In multivariable hierarchical models, the risk of readmission was higher in women and in low-income patients, but the effect varied by age (p value for age-gender and age-income interactions <0.05) and was more prominent in the younger age groups. Further, patients in all age groups continue to have a high hospitalization burden beyond the typical 30-day readmission period, with an overall 24% post-AMI 90-day readmission rate. In conclusion, readmissions in young and middle-aged AMI survivors pose a substantial burden on patients and on U.S. health-care resources. Women and low-income patients with AMI, particularly those in younger age groups, are more frequently readmitted, and readmissions continue to burden the health-care system beyond the typical 30-day window. Future investigations would need to be targeted toward a better understanding and improvement of the rehospitalization burden for vulnerable patient groups. PMID- 28865893 TI - Prognostic Impact of in-Hospital-Bleeding in Patients With ST-Elevation Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention. AB - Several studies established a link between bleeding and mortality in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI); however, it is unclear whether bleeding has a direct role in worsening the prognosis or if it is simply a marker of patient frailty. We investigated whether bleeding is an independent predictor of mortality in patients with STEMI treated with pPCI. The relationship between the presence of heart failure on presentation (Killip classification), bleeding occurrence, and outcome was also assessed. Bleeding was defined as the combination of Thrombolysis in Myocardial Infarction major and minor bleeding. Short- and long-term mortalities were estimated using the Kaplan-Meyer analysis. Multivariable analysis was performed by the Cox regression model. As an alternative method to address the potential confounding factors, we performed a propensity-matched analysis adjusted for all variables included in the CRUSADE score. In the 1,911 consecutive patients with STEMI considered, bleeding (observed in 11.4% of patients) was an independent predictor of 30-day (hazard ratio 2.61, 95% confidence interval 1.30 to 5.25, p = 0.007) and 1-year mortality (hazard ratio 1.98, 95% confidence interval 1.13 to 3.47, p = 0.017) but not in a landmark analysis starting from 30 days to 1 year. Bleeding was significantly associated with higher 30-day and 1-year mortality in patients with Killip class >=II, but not in patients with Killip class I. In conclusion, in-hospital bleeding is independently associated with increased mortality in the early period after STEMI, also after adjusting for variables associated with the risk of bleeding. Bleeding was associated with increased mortality in patients with signs of heart failure at admission, whereas it had no effects in patients with Killip class I. PMID- 28865894 TI - Temporal Associations Between Smoking and Cardiovascular Disease, 1971 to 2006 (from the Framingham Heart Study). AB - Smoking has consistently been related to cardiovascular risk. Public health efforts have yielded reduced smoking prevalence and gains in cardiovascular disease (CVD) prevention. We hypothesized that the contribution of tobacco to CVD risk would be attenuated over prospective decades (1971 to 2006) in a community based cohort. We evaluated 5,041 Framingham Heart Study Offspring Cohort participants (mean age 36.1 years, 52% women) without prevalent CVD. We collected prospective data on smoking status, relevant CVD risk factors, and incident CVD events across prospective decades. We used multivariable-adjusted, Cox proportional hazard models to measure the effect of smoking on incident CVD over 3 prospective 12-year follow-up periods. Our results demonstrated a consistent twofold increased risk of CVD in men who smoke compared with nonsmokers for each 12-year time period spanning from 1971 to 2006. Women who smoked had a 1.5-fold increased CVD risk. Smoking remains an important risk factor despite substantial improvements in the prevention and treatment of CVD. Significant, contemporary improvements in CVD prevention-such as gains in hypertension and cholesterol treatment-have not attenuated the strong and persistent associations between smoking and CVD observed here. In conclusion, our results highlight the importance of continued public health efforts to address smoking as a modifiable exposure that strongly contributes toward CVD risk. PMID- 28865895 TI - Usefulness of Balloon Aortic Valvuloplasty in the Management of Patients With Aortic Stenosis. AB - We aim to evaluate the contemporary role and outcomes of balloon aortic valvuloplasty (BAV), based on physician intent, for the management of severe aortic stenosis. This is a prospective, 2-center study of 100 consecutive high risk patients with severe aortic stenosis who underwent BAV. Before BAV, physicians assigned intent as (1) bridge to decision (BTD); (2) therapeutic bridge to planned therapy; or (3) palliation. Patients in the BTD arm underwent clinical assessment at 30 days to determine eligibility for definitive valve therapy. All patients were followed up to 1 year, with outcomes measured including procedural complications, Kansas City Cardiomyopathy Questionnaires scores, 30-day and 1-year mortality, and definitive valve therapy. Enrolled patients had a mean age of 80.6 (+/-9.6) years, Society of Thoracic Surgeons predicted risk of mortality of 11.4% (+/-7.1%), and 91 (91.0%) patients had class III or IV New York Heart Association congestive heart failure. Intent in the 100 study patients was 76 BTD; 20 therapeutic bridge to planned therapy; and 4 palliation. Thirty-day mortality for all patients was 6 of 100 (6.0%), and 1-year mortality for all patients who received definitive valve therapy was 6 of 54 (11.1%). For patients surviving to 30 days, adjusted (by Society of Thoracic Surgeons predicted risk of mortality) Kansas City Cardiomyopathy Questionnaires scores were significantly improved from baseline for all patients and BTD patients. In conclusion, as a bridge to decision and treatment tool, BAV appears to have a valuable role in properly selecting and improving patients to undergo definitive valve replacement. PMID- 28865896 TI - Comparison of Electrocardiographic Characteristics in Men Versus Women <= 55 Years With Acute Myocardial Infarction (a Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients Substudy). AB - Young women with acute myocardial infarction (AMI) have a worse prognosis than their male counterparts. We searched for differences in the electrocardiographic presentation of men and women in a large, contemporary registry of young adults with AMI that could help explain gender differences in outcomes. The qualifying electrocardiogram was blindly assessed by a central core lab in 3,354 patients (67% women) aged 18 to 55 years included in the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients study. Compared with men, women did not have a different frequency of sinus rhythm, and they had shorter PR and QRS intervals and longer QTc intervals. Intraventricular conduction disturbances were not different among genders. Notably, women were more likely than men to have abnormal Q waves in anterior leads and a lower frequency of Q waves in other territories. ST-segment elevation myocardial infarction (STEMI) diagnosis was less frequent in women than in men (44.6% vs 55.1%, p < 0.001). Among patients with STEMI, women had less magnitude and extent of ST-segment elevation than men. In patients with non-STEMI, the frequency, magnitude, and extent of ST-segment depression were not different among genders, but women had anterior ST-segment depression less frequently and anterior negative T waves more frequently compared with men. These differences remained statistically significant after adjusting for baseline characteristics. In conclusion, there are significant gender differences in the electrocardiographic presentation of AMI among young patients. Further studies are warranted to evaluate their impact on gender-related differences in the management and outcomes of AMI. PMID- 28865897 TI - Bare metal versus drug eluting stents for ST-segment elevation myocardial infarction in the TOTAL trial. AB - BACKGROUND: The safety and efficacy of drug eluting stents (DES) in the setting of ST elevation myocardial infarction (STEMI) is not well established. METHODS: In the TOTAL trial, patients presenting with STEMI were randomized to routine thrombectomy versus PCI alone. In this post-hoc analysis, propensity matching was used to assess relative safety and efficacy according to type of stent used. RESULTS: Each propensity-matched cohort included 2313 patients. The composite primary outcome of cardiovascular death, recurrent MI, cardiogenic shock or class IV heart failure within one year was lower in the DES group (HR 0.67; 95% CI 0.54 to 0.84, p=0.0004). Cardiovascular death (HR 0.61; 95% CI 0.43 to 0.86, p=0.005), recurrent MI (HR 0.51; 95% CI 0.35 to 0.75, p=0.0005), target vessel revascularization (HR 0.47; 95% CI 0.36 to 0.62, p<0.0001) and stent thrombosis (HR 0.60; 95% CI 0.40 to 0.89, p=0.01) were lower in the DES group. There was no difference in major bleeding between groups. CONCLUSIONS: In this observational analysis, the use of DES was associated with improvement in cardiovascular outcomes compared to the use of BMS. These results support the use of DES during primary PCI for STEMI. PMID- 28865898 TI - Presence of a predator image in potential breeding sites and oviposition responses of a dengue vector. AB - In dengue vector control, attempts to minimize or replace the use of pesticides have mostly involved use of predators, but success has been severely impeded by difficulties associated with financial and environmental costs, predator mass production, and persistence in target habitats. Visual deterrents have been used successfully to control animal pests, in some cases in an effort to replace pesticide use. Despite evidence that visual signals are crucial in site choice for egg deposition by dengue vectors, and that female mosquitoes respond to artificial predation, the role of predator intimidation as it affects the oviposition behavior of dengue vectors remains largely unexplored. Here, we examined the oviposition responses of Aedes aegypti exposed to various mosquito predator pictures. Gravid females were presented with equal opportunities to oviposit in two cups with predator images [Toxorhynchites splendens-TXI, Goldfish (Carassius auratus)-small (SFI) and large (LFI) and Tx. splendens+Goldfish-TXFI] and two others without pictures. Differences in egg deposition were examined between sites with and without these images. When given a chance to oviposit in cups with and without TXI, Ae. aegypti females were similarly attracted to both sites. When provided an opportunity to oviposit in cups displaying pictures of fish (SFI or LFI) and blank cups, egg deposition rates were much lower in the fish picture sites. Females showed a preference for blank cups over TXFI for egg deposition. They also equally avoided cups with pictures of fish, regardless of the size of the picture. Our results indicate that the presence of images of goldfish and their association with Tx. larvae significantly reduced egg deposition by Ae. aegypti, and this was not the case with the predatory larvae alone. The observations that the images of natural predators can repel gravid females of a dengue vector provide novel possibilities to develop effective and inexpensive alternative tools to harmful insecticides. PMID- 28865899 TI - Amblyomma ticks and future climate: Range contraction due to climate warming. AB - Ticks of the Amblyomma cajennense species complex are important vectors of spotted fever in Latin America. Environmental conditions determine the geographic distribution of ticks, such that climate change could influence the distribution of tick-borne diseases. This study aimed to analyze the potential geographic distribution of A. cajennense complex ticks in a Brazil region under present-day and future climate models, assuming dispersal limitations and non-evolutionary adaptation of these tick populations to climate warming. Records of A. cajennense sensu stricto (s.s.) and Amblyomma sculptum were analyzed. Niche models were calibrated using Maxent considering climate variables for 1950-2000 and projecting models to conditions anticipated for 2050 and 2070 under two models of future climate (CCSM4 and HadGEM2-AO). Broad suitable areas for A. cajennense s.s. and A. sculptum were found in present-day climate models, but suitability was reduced when models were projected to future conditions. Our exploration of future climates showed that broad areas had novel climates not existing currently in the study region, including novel extremely high temperatures. Indeed, predicted suitability in these novel conditions would lead to biologically unrealistic results and therefore incorrect forecasts of future tick distribution. Previous studies anticipating expansions of vectors populations due to climate change should be considered with caution as they assume that model extrapolation anticipates that species would evolve rapidly for adaptation to novel climatic conditions. PMID- 28865900 TI - A benzimidazole derivative (RCB15) in vitro induces the alternative energetic metabolism and glycolysis in Taenia crassiceps cysticerci. AB - The emergence of resistance to albendazole has encouraged the search for effective alternatives for cysticercosis and other parasitosis treatment. RCB15 is a benzimidazole derivative that may be used against such diseases. The aim of this study was to determine the in vitro effect of RCB15 on the alternative energetic pathways of Taenia crassiceps cysticerci. The cysticerci were in vitro exposed to albendazole sulphoxide (ABZSO) or RCB15 at different concentrations during 24h. The cysticerci extract and the culture medium were analyzed through spectrophotometry and high performance liquid chromatography as to detect glucose, urea, creatinine and organic acids of the energetic metabolism. The drugs did not influence the protein catabolism. Fatty acids oxidation was enhanced through significantly higher acetate concentrations in the groups treated with RCB15 and ABZSO. Beta-hydroxybutyrate concentrations were decreased which indicates the use of fatty acids towards acetyl-CoA synthesis. There was a decrease in glucose uptake and pyruvate concentrations. The absence of lactate indicates the use of pyruvate in gluconeogenesis. Therefore it is possible to conclude that RCB15 enhanced the alternative energetic pathways of cysticerci in vitro exposed to different concentration, with emphasis on the fatty acids catabolism. PMID- 28865901 TI - Neuroimaging of Female Sexual Desire and Hypoactive Sexual Desire Disorder. AB - INTRODUCTION: Recent advances in neuroimaging offer an unprecedented window into the female sexual brain. The small samples and poor statistical power of individual functional magnetic resonance imaging studies have limited what can be gleaned about the systematic brain network that is involved in female sexual desire and female sexual dysfunction (eg, hypoactive sexual desire disorder [HSDD]). AIM: To quantitatively determine the brain network involved in HSDD. METHODS: Systematic retrospective review and statistical meta-analysis of pertinent neuroimaging literature. MAIN OUTCOME MEASURES: Review of published literature on functional magnetic resonance imaging studies illustrating brain regions associated with female sexual desire and female HSDD. RESULTS: HSDD is associated with a specific fronto-limbic-parietal dysfunction characterized by (i) lower blood oxygen level-dependent responses in the sexual desire brain network and (ii) higher blood oxygen level-dependent responses in the self referential brain network. CONCLUSION: The meta-analytic results are in line with a top-down neurofunctional model of HSDD in which inspecting, monitoring, and evaluating oneself (rather than sensory experience) before or during sexual activities interfere with sexual desire. These results raise new questions regarding the necessity and sufficiency of dysfunctional activation in the sexual desire and self-referential brain networks, whose answers bear on the development and evaluation of personalized treatments for HSDD. Cacioppo S. Neuroimaging of Female Sexual Desire and Hypoactive Sexual Desire Disorder. Sex Med Rev 2017;5:434-444. PMID- 28865902 TI - Immediate Auditory Feedback is Superior to Other Types of Feedback for Basic Surgical Skills Acquisition. AB - OBJECTIVE: We examined the effect of timing and type of feedback on medical students' knot-tying performance using visual versus auditory and immediate versus delayed feedback. We hypothesized that participants who received immediate auditory feedback would outperform those who received delayed and visual feedback. METHODS: Sixty-nine first- and second-year medical students were taught to tie 2-handed knots. All participants completed 3 pretest knot-tying trials without feedback. Participants were instructed to tie a knot sufficiently tight to stop the "blood" flow while minimizing the amount of force applied to the vessel. Task completion time was not a criterion. Participants were stratified and randomly assigned to 5 experimental groups based on type (auditory versus visual) and timing (immediate versus delayed) of feedback. The control group did not receive feedback. All groups trained to proficiency. Participants completed 3 posttest trials without feedback. RESULTS: There were fewer trials with leak (p < 0.01) and less force applied (p < 0.01) on the posttest compared to the pretest, regardless of study group. The immediate auditory feedback group required fewer trials to achieve proficiency than each of the other groups (p < 0.01) and had fewer leaks than the control, delayed auditory, and delayed visual groups (p < 0.02). CONCLUSIONS: In a surgical force feedback simulation model, immediate auditory feedback resulted in fewer training trials to reach proficiency and fewer leaks compared to visual and delayed forms of feedback. PMID- 28865903 TI - The Perfect Storm Is on the Horizon! AB - PURPOSE: Provide analysis of data identifying the impending mass turnover of Directors and Coordinators of General Surgery residency programs and the potential effect on successful continuing accreditation including the ACGME Next Accreditation System (NAS) and associated self study. METHODS: The Association of Residency Coordinators in Surgery, Executive Committee (ARCS EC) anonymously surveyed 254 general surgery Program Coordinators in September/October 2016. This represents 60'% of all the members within the Association of Residency Coordinators in Surgery. Survey was accomplished using SurveyMonkey. Questions included demographics and experience of the Director and Coordinator, accreditation status, significant job stressors, and potential retirements or position changes planned or possible. RESULTS: 153 (60%) respondents completed the survey. Data from the survey indicates that 67% of Program Directors have been in their position less than six (6) years. 34% of Program Coordinators have been in their position less than five (5) years. 56% of coordinators have been on the job less than ten (10) years. Coordinators in 76% of programs reported significant levels of burnout. 59% have considered resigning from their position in the past year. Participants consistently reported increasing responsibilities and expectations combined with declining or inadequate levels of support as sources of job stress. Other contributors to Coordinator burnout were identified as related to the additional ACGME accreditation requirements and salaries not commensurate with workload. CONCLUSION: This survey represents a sentinel preliminary look at the possible impending manning crisis in general surgery residency program leadership. A Program Director is supported by a Program Coordinators who are burned out and considering a job change. The resultant potential turnover in personnel and loss of collective program knowledge may have devastating ramifications to program accreditation. Subsequent survey of the workforce will evaluate proposed solutions and interventions to prevent this outcome and secure the future success of general surgery programs. PMID- 28865904 TI - Crude ethanolic extract from spent coffee grounds: Volatile and functional properties. AB - Espresso capsule consumption and spent coffee ground (SCG) generation have increased, and the present study was undertaken to evaluate the volatile profile (VP), the antioxidant activity (AA) and the sun protection factor (SPF) of the Crude ethanolic extract obtained from the SCG in capsules. The extract yield was superior to the ether yield because a higher unsaponifiable matter (U.M.) amount was recovered by ethanol. The obtained VP (70 compounds) was typical of roasted coffee oil. Furthermore, chemometric analysis using principal components (PCA) discriminated the extracts and grouped the replicates for each sample, which showed the repeatability of the extraction process. The AA ranged from 18.4 to 23.6 (mg extract mg DPPH-1) and the SPF from 2.27 to 2.76. The combination of the coffee VP, AA and SPF gave the espresso SCG's crude ethanolicextract, desirable properties that can be used in cosmetic and food industries. PMID- 28865905 TI - Analysis on carbon dioxide emission reduction during the anaerobic synergetic digestion technology of sludge and kitchen waste: Taking kitchen waste synergetic digestion project in Zhenjiang as an example. AB - With the popularization of municipal sewage treatment facilities, the improvement of sewage treatment efficiency and the deepening degree of sewage treatment, the sludge production of sewage plant has been sharply increased. Carbon emission during the process of municipal sewage treatment and disposal has become one of the important sources of greenhouse gases that cause greenhouse effect. How to reduce carbon dioxide emissions during sewage treatment and disposal process is of great significance for reducing air pollution. Kitchen waste and excess sludge, as two important organic wastes, once uses anaerobic synergetic digestion technology in the treatment process can on the one hand, avoid instability of sludge individual anaerobic digestion, improve sludge degradation rate and marsh gas production rate, and on the other hand, help increase the reduction of carbon dioxide emissions to a great extent. The paper uses material balance method, analyzes and calculates the carbon dioxide emissions from kitchen waste and sludge disposed by the anaerobic synergetic digestion technology, compares the anaerobic synergetic digestion technology with traditional sludge sanitary landfill technology and works out the carbon dioxide emission reductions after synergetic digestion. It takes the kitchen waste and sludge synergetic digestion engineering project of Zhenjiang city in Jiangsu province as an example, makes material balance analysis using concrete data and works out the carbon dioxide daily emission reductions. The paper analyzes the actual situation of emission reduction by comparing the data, and found that the synergetic digestion of kitchen waste and sludge can effectively reduce the carbon dioxide emission, and the reduction is obvious especially compared with that of sludge sanitary landfill, which has a certain effect on whether to promote the use of the technology. PMID- 28865906 TI - Effect of iron sulphate on the phosphorus speciation from agro-industrial sludge based and sewage sludge based compost. AB - Composting is considered a suitable process for organic waste management, providing stable products that can be safely utilized as fertilizers, but little is still known about the variation of phosphorous (P) extractability during the stabilization process. In this work, sequential chemical extraction (SCE) with increasing strength extractants (H2O; 0.5M NaHCO3 pH 8.5; 0.1M NaOH, 1M HCl) was applied for P speciation over 56days of composting of either agro-industrial or urban wastewater sludge with green waste treated (AICFe+; SSCFe+) or not (AICFe-; SSCFe-) with FeSO4 (2%v/v). Composting strongly reduced the H2O-P, promoting the organic-P (Po) mineralization from the labile fraction (H2O+NaHCO3 40%), in addition to the increases of NaHCO3- and HCl-extractable inorganic-P (Pi) in both AICFe- and SSCFe- (+20% on average). The FeSO4 treatment did not negatively affect the process, reducing the Po mineralization during composting by increasing the NaOH-P, also protecting this fraction from fixation in the sparingly soluble fraction. The final P fractionation (%) was in AICFe-: NaOH (41)=NaHCO3 (38)>HCl (18)>H2O (3); in AICFe+: NaOH (53)>NaHCO3 (24)=HCl (22)>H2O (2); in SSCFe-: NaOH (46)>NaHCO3 (29)>HCl (21)>H2O (4) and in SSCFe+: NaOH (66)>NaHCO3 (13)>HCl (20)>H2O (1). Composting reduced the more easily leachable fraction (labile-Po), reducing the risk of P loss by increasing the long-term available P fraction (NaOH-P). This was enhanced by the FeSO4 addition. Further investigation into soil behaviour and plant availability of P from this source is needed. PMID- 28865907 TI - Environmental comparison of alternative treatments for sewage sludge: An Italian case study. AB - A Life Cycle Assessment (LCA) was applied to compare different alternatives for sewage sludge treatment: such as land spreading, composting, incineration, landfill and wet oxidation. The LCA system boundaries include mechanical dewatering, the alternative treatment, transport, and final disposal/recovery of residues. Cases of recovered materials produced as outputs from the systems, were resolved by expanding the system boundaries to include avoided primary productions. The impact assessment was calculated using the CML-IA baseline method. Results showed that the incineration of sewage sludge with electricity production and solid residues recovery collects the lowest impact indicator values in the categories human toxicity, fresh water aquatic ecotoxicity, acidification and eutrophication, while it has the highest values for the categories global warming and ozone layer depletion. Land spreading has the lowest values for the categories abiotic depletion, fossil fuel depletion, global warming, ozone layer depletion and photochemical oxidation, while it collects the highest values for terrestrial ecotoxicity and eutrophication. Wet oxidation has just one of the best indicators (terrestrial ecotoxicity) and three of the worst ones (abiotic depletion, human toxicity and fresh water aquatic ecotoxicity). Composting process shows intermediate results. Landfill has the worst performances in global warming, photochemical oxidation and acidification. Results indicate that if the aim is to reduce the effect of the common practice of sludge land spreading on human and ecosystem toxicity, on acidification and on eutrophication, incineration with energy recovery would clearly improve the environmental performance of those indicators, but an increase in resource depletion and global warming is unavoidable. However, these conclusions are strictly linked to the effective recovery of solid residues from incineration, as the results are shown to be very sensitive with respect to this assumption. Similarly, the quality of the wet oxidation process residues plays an important role in defining the impact of this treatment. PMID- 28865908 TI - Review on landfill leachate treatment by electrochemical oxidation: Drawbacks, challenges and future scope. AB - Various studies on landfill leachate treatment by electrochemical oxidation have indicated that this process can effectively reduce two major pollutants present in landfill leachate; organic matter and ammonium nitrogen. In addition, the process is able to enhance the biodegradability index (BOD/COD) of landfill leachate, which make mature or stabilized landfill leachate suitable for biological treatment. The elevated concentration of ammonium nitrogen especially observed in bioreactor landfill leachate can also be reduced by electrochemical oxidation. The pollutant removal efficiency of the system depends upon the mechanism of oxidation (direct or indirect oxidation) which depends upon the property of anode material. Applied current density, pH, type and concentration of electrolyte, inter-electrode gap, mass transfer mode, total anode area to volume of effluent to be treated ratio, temperature, flow rate or flow velocity, reactor geometry, cathode material and lamp power during photoelectrochemical oxidation may also influence the system performance. In this review paper, past and present scenarios of landfill leachate treatment efficiencies and costs of various lab scale, pilot scale electrochemical oxidation studies asa standalone system or integrated with biological and physicochemical processes have been reviewed with the conclusion that electrochemical oxidation can be employed asa complementary treatment system with biological process for conventional landfill leachate treatment as well asa standalone system for ammonium nitrogen removal from bioreactor landfill leachate. Furthermore, present drawbacks of electrochemical oxidation process asa landfill leachate treatment system and relevance of incorporating life cycle assessment into the decision-making process besides process efficiency and cost, have been discussed. PMID- 28865909 TI - Research and demonstration results for a new "Double-Solution" technology for municipal solid waste treatment. AB - In this paper, the pyrolysis characteristics of six typical components in municipal solid waste (MSW) were investigated through a TG-FTIR combined technique and it was concluded that the main pyrolysis process of the biomass components (including food residues, sawdust and paper) occurred at 150-600 degrees C. The main volatiles were multi-component gas including H2O, CO2, and CO. The main pyrolysis temperatures of three artificial products (PP, PVC and leather) was ranged from 200to 500 degrees C. The wavelength of small molecule gases (CH4, CO2 and CO) and the the chemical bonds (CO and CC) were observed in the infrared spectrum Based on the pyrolysis temperature interval and volatile constituent, a new "double-solution" process of pyrolysis and oxygen-enrichment decomposition MSW was designed. To achieve this process, a double-solution project was built for the direct treatment of MSW (10t/d). The complete setup of equipment and analysis of the byproducts has been reported in this paper to indicate the performance of this process. Energy balance and economic benefits were analysed for the process supporting. It was successfully demonstrated that the double-solution process was the environmentally friendly alternative method for MSW treatment in Chinese rural areas. PMID- 28865910 TI - Methods to estimate the transfer of contaminants into recycling products - A case study from Austria. AB - Recycling of waste materials is desirable to reduce the consumption of limited primary resources, but also includes the risk of recycling unwanted, hazardous substances. In Austria, the legal framework demands secondary products must not present a higher risk than comparable products derived from primary resources. However, the act provides no definition on how to assess this risk potential. This paper describes the development of different quantitative and qualitative methods to estimate the transfer of contaminants in recycling processes. The quantitative methods comprise the comparison of concentrations of harmful substances in recycling products to corresponding primary products and to existing limit values. The developed evaluation matrix, which considers further aspects, allows for the assessment of the qualitative risk potential. The results show that, depending on the assessed waste fraction, particular contaminants can be critical. Their concentrations were higher than in comparable primary materials and did not comply with existing limit values. On the other hand, the results show that a long-term, well-established quality control system can assure compliance with the limit values. The results of the qualitative assessment obtained with the evaluation matrix support the results of the quantitative assessment. Therefore, the evaluation matrix can be suitable to quickly screen waste streams used for recycling to estimate their potential environmental and health risks. To prevent the transfer of contaminants into product cycles, improved data of relevant substances in secondary resources are necessary. In addition, regulations for material recycling are required to assure adequate quality control measures, including limit values. PMID- 28865911 TI - Trauma management therapy with virtual-reality augmented exposure therapy for combat-related PTSD: A randomized controlled trial. AB - Virtual reality exposure therapy (VRET) realistically incorporates traumatic cues into exposure therapy and holds promise in the treatment of combat-related posttraumatic stress disorder (PTSD). In a randomized controlled trial of 92 Iraq and Afghanistan veterans and active duty military personnel with combat-related PTSD, we compared the efficacy of Trauma Management Therapy (TMT; VRET plus a group treatment for anger, depression, and social isolation) to VRET plus a psychoeducation control condition. Efficacy was evaluated at mid- and post treatment, and at 3- and 6-month follow-up. Consistent with our hypothesis, VRET resulted in significant decreases on the Clinician Administered PTSD Scale and the PTSD Checklist-Military version for both groups. Also consistent with our hypothesis, significant decreases in social isolation occurred only for those participants who received the TMT group component. There were significant decreases for depression and anger for both groups, although these occurred after VRET and before group treatment. All treatment gains were maintained six-months later. Although not part of the original hypotheses, sleep was not improved by either intervention and remained problematic. The results support the use of VRET as an efficacious treatment for combat-related PTSD, but suggest that VRET alone does not result in optimal treatment outcomes across domains associated with PTSD. PMID- 28865913 TI - Developing a military nurse scientist program of research: A military women's health exemplar. AB - Developing a feasible, fundable, and sustainable program of research (POR) is an essential career goal in research. Nurse scientists can lay the foundation for a salient POR as early as during their doctoral studies. The ensuing years of postdoctoral experiences are informative as they expand their research skills and knowledge around their research area of interest. Following graduation from a doctoral research program, novice military nurse scientists (MNS) are placed in positions that are conducive to fostering a POR. Military organizational support and the rich experiences of peers and mentors facilitate early career development of MNS. The purpose of this article is to present a conceptual framework for research career development of the novice MNS. Using an exemplar POR in military women's health, the concepts are operationalized to illustrate how the military environment enhances the development of a successful POR. PMID- 28865914 TI - Quality of life of burn survivors treated in the military burn center. AB - BACKGROUND: Limited research explains the quality of life (QOL) among burn survivors during post-hospitalization rehabilitation. PURPOSE: To determine the QOL of military and civilian burn survivors treated in the military burn center. METHODS: In this longitudinal study, QOL was examined in 131 burn survivors (88 civilians; 43 military). Participants completed the Abbreviated Burn Specific Health Scale (BSHS-A) and the Satisfaction with Life Scale (SWLS) over 5 time points post-discharge. DISCUSSION: Civilian and military participants reported improved QOL over time on most BSHS-A subscales. Military participants had higher global BSHS-A scores at discharge, but at 6 months plateaued while civilians improved and had higher global BSHS-A scores at 18 months. Scores on the SWLS were consistently higher for military participants than for civilians. CONCLUSION: Military versus civilian patients may have different expectations about their ability to rehabilitate. The post-hospitalization period needs to be better understood to develop appropriate QOL interventions. PMID- 28865912 TI - Inhibition of AMPA receptor and CaMKII activity in the lateral habenula reduces depressive-like behavior and alcohol intake in rats. AB - Depression is a well-known risk factor for developing relapse drinking, but the neuronal mechanisms underlying the interactions between depression and alcohol use disorders remain elusive. Accumulating evidence has associated depression with hyperactivity of the lateral habenula (LHb), an epithalamic structure in the brain that encodes aversive signals. Glutamate receptors contribute substantially to the excitability of LHb neurons. Glutamatergic synapses in LHb neurons largely express GluA1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) that can be modulated by Ca2+/calmodulin-dependent protein II (CaMKII). In the current study, we tested the hypothesis that withdrawal from repeated cycles of ethanol drinking triggers an increase in LHb AMPAR and CaMKII activity concomitant with depression-like symptoms, and their inhibitions bring a reduction in depressive-like behaviors and alcohol consumption. Western blotting revealed a higher level of phosphorylated AMPAR GluA1 subunit at a CaMKII locus (GluA1-Ser831) in the LHb of ethanol-withdrawn rats than that of age-matched naive counterparts. In ethanol-withdrawn rats, pharmacological inhibition of LHb AMPAR activity significantly mitigated the depressive-like behavior and ethanol drinking and seeking behaviors, but affected neither sucrose intake nor locomotor activity; and inhibition of LHb CaMKII activity, or chemogenetic inhibition of LHb activity produced similar effects. Conversely, activation of LHb AMPARs induced depressive-like behaviors in ethanol-naive rats. These results demonstrate that CaMKII-AMPAR signaling in the LHb exemplifies a molecular basis for depressive-like symptoms during ethanol withdrawal and that inhibition of this signaling pathway may offer a new therapeutic approach to address the comorbidity of alcohol abuse and depression. PMID- 28865916 TI - Antipneumococcal vaccination in patients with chronic obstructive pulmonar disease: A matter of improvement. PMID- 28865915 TI - Anaesthetic depth control using closed loop anaesthesia delivery system vs. target controlled infusion in patients with moderate to severe left ventricular systolic dysfunction. AB - OBJECTIVES: To compare the efficacy of anaesthetic depth control using Closed Loop Anaesthesia Delivery System (CLADS) and Target Controlled Infusion (TCI) in patients with moderate to severe left ventricular dysfunction (LVSD). DESIGN: Randomized control trial. PATIENTS: Forty ASA III/IV adult patients with moderate to severe LVSD scheduled for open heart surgery. INTERVENTIONS: Propofol was administered using CLADS or TCI for maintaining BIS of 50. Induction and maintenance doses were controlled automatically in CLADS. Dixon's up and down method was used to estimate the plasma concentration needed for induction in TCI. MEASUREMENT: Percentage of total anaesthesia time ("valid CLADS time") for which BIS remained within +/-10 of target (BIS=50). MAIN RESULTS: BIS remained within +/-10 of the target for a significantly longer duration of time in CLADS group (p=0.001). Performance parameters like Median Performance Error (MDPE), p=0.024; Median Absolute Performance Error (MDAPE), p=0.0212; and global score p=0.017 were significantly better in CLADS group. Total propofol consumption was significantly less in CLADS group (p=0.014). Mean value (95% CI) of EC50 and EC95 for target plasma propofol concentration for induction was 1.62 (1.45-1.79) MUgml 1 and 1.87 (1.73-2.96) MUgml-1 respectively using probit analysis. CONCLUSIONS: Closed loop delivery of propofol using CLADS performed significantly better than TCI in this subset of patients. CLINICAL TRIALS REGISTRATION NO.: www.ClinicalTrials.gov-NCT02645994. PMID- 28865917 TI - Open innovation challenge as a strategy for developing new mobile health solutions. PMID- 28865919 TI - Syphilis. Status of a current epidemic. PMID- 28865918 TI - Extraparotidal low grade follicular lymphoma associated with primary Sjogren's syndrome. PMID- 28865920 TI - Lactic acidosis associated (or induced by) metformin. PMID- 28865921 TI - In vivo assessment of tumor heterogeneity in WHO 2016 glioma grades using diffusion kurtosis imaging: Diagnostic performance and improvement of feasibility in routine clinical practice. AB - PURPOSE: To assess the diagnostic performance of normalized and non-normalized diffusion kurtosis imaging (DKI) metrics extracted from different tumor volume data for grading glioma according to the integrated approach of the revised 2016 WHO classification. MATERIALS AND METHODS: Sixty patients with histopathologically confirmed glioma, who provided written informed consent, were retrospectively assessed between 01/2013 and 08/2016 from a prospective trial approved by the local institutional review board. Mean kurtosis (MK) and mean diffusivity (MD) metrics from DKI were assessed by two blinded physicians from four different volumes of interest (VOI): whole solid tumor including (VOItu-ed) and excluding perifocal edema (VOItu), infiltrative zone (VOIed), and single slice of solid tumor core (VOIslice). Intra-class correlation coefficient (ICC) was calculated to assess inter-rater agreement. One-way ANOVA was used to compare MK between 2016 CNS WHO tumor grades. Friedman's test compared MK and MD of each VOI. Spearman's correlation coefficient was used to correlate MK with 2016 CNS WHO tumor grades. ROC analysis was performed on MK for significant results. RESULTS: The MK assessment showed excellent inter-rater agreement for each VOI (ICC, 0.906-0.955). MK was significantly lower in IDHmutant astrocytoma (0.40+/ 0.07), than in 1p/19q-confirmed oligodendroglioma (0.54+/-0.10, P=0.001) or IDHwild-type glioblastoma (0.68+/-0.13, P<0.001). MK and 2016 WHO tumor grades were strongly and positively correlated (VOItu-ed, r=0.684; VOItu, r=0.734; VOIed, r=0.625; VOIslice, r=0.698; P<0.001). CONCLUSIONS: Non-normalized MK values obtained from VOItu and VOIslice showed the best reproducibility and highest diagnostic performance for stratifying glioma according to the integrated approach of the recent 2016 WHO classification. PMID- 28865922 TI - Prediction of hemorrhagic transformation after acute thrombolysis following major artery occlusion using relative ADC ratio: A retrospective study. AB - BACKGROUND: The relative apparent diffusion coefficient (ADC) ratio can be used to evaluate the extent of ischemia. We investigated the risk factors for, and correlation between, relative ADC ratio and hemorrhagic transformation (HT) after thrombolysis. METHODS: This single-center, retrospective study involved 105 patients with acute occlusion of the anterior circulation. Relative ADC ratio was calculated as the ratio of ADC pixel values, within the affected territory to ADC pixel values in the contralateral normal region. HT was determined by computed tomography and T2* weighted magnetic resonance imaging after endovascular revascularization. RESULTS: Data for 80 of the 105 patients were analyzed. Comparing the number of patients between the HT group (n=25) and the non-HT group (n=55), a significant difference was noted in tissue plasminogen activator (tPA) use (P=0.028), time from onset to reperfusion >=380min (P<0.001), fluid attenuated inversion recovery (FLAIR) hyperintensity (P=0.009), and relative ADC ratio<0.650 (P<0.001). Multivariable logistic regression analysis identified relative ADC ratio<0.650 as the only independent predictor of HT (odds ratio 7.79; 95% confidence interval 2.22-27.3; P=0.001). Twenty-nine patients (including 20 in the HT group) had a relative ADC ratio<0.650. Multivariable logistic regression analysis identified use of tPA as the only independent predictor of HT (odds ratio 13.8; 95% confidence interval 1.35-125.5; P=0.010). CONCLUSIONS: Relative ADC ratio<0.650 with use of tPA may be important for predicting HT. PMID- 28865923 TI - Rapid and label-free electrochemical DNA biosensor for detecting hepatitis A virus. AB - Diagnostic systems that can deliver highly specific and sensitive detection of hepatitis A virus (HAV) in food and water are of particular interest in many fields including food safety, biosecurity and control of outbreaks. Our aim was the development of an electrochemical method based on DNA hybridization to detect HAV. A ssDNA probe specific for HAV (capture probe) was designed and tested on DNAs from various viral and bacterial samples using Nested-Reverse Transcription Polymerase Chain Reaction (nRT-PCR). To develop the electrochemical device, a disposable gold electrode was functionalized with the specific capture probe and tested on complementary ssDNA and on HAV cDNA. The DNA hybridization on the electrode was measured through the monitoring of the oxidative peak potential of the indicator tripropylamine by cyclic voltammetry. To prevent non-specific binding the gold surface was treated with 3% BSA before detection. High resolution atomic force microscopy (AFM) confirmed the efficiency of electrode functionalization and on-electrode hybridization. The proposed device showed a limit of detection of 0.65pM for the complementary ssDNA and 6.94fg/uL for viral cDNA. For a comparison, nRT-PCR quantified the target HAV cDNA with a limit of detection of 6.4fg/uL. The DNA-sensor developed can be adapted to a portable format to be adopted as an easy-to- use and low cost method for screening HAV in contaminated food and water. In addition, it can be useful for rapid control of HAV infections as it takes only a few minutes to provide the results. PMID- 28865924 TI - Prospective, Randomized Study of Radiation Dose Escalation With Combined Proton Photon Therapy for Benign Meningiomas. AB - PURPOSE: To assess the outcomes of benign meningiomas (BM) treated to two radiation dose levels. METHODS AND MATERIALS: We randomly assigned patients (1:1) with incompletely resected or recurrent BM to 2 radiation doses: 55.8 Gy(relative biological effectiveness [RBE]) and 63.0 Gy(RBE) of fractionated combined proton photon radiation therapy. The primary endpoint was local control with hypothesis of improved tumor control with higher dose. Secondary endpoints included progression-free survival, overall survival, and rates of treatment-related toxicities. RESULTS: Between 1991 and 2000, 47 patients were randomized. Three patients were excluded for nonbenign histology; therefore, 44 patients were analyzed: 22 who received 55.8 Gy(RBE) and 22 who received 63.0 Gy(RBE). The median follow-up was 17.1 years. Local control for the entire cohort was 98% at 10 years and 90% at 15 years. Of the 5 patients with local recurrence, 4 occurred after 10 years of follow-up, and 3 were in the lower dose group (P=.322). In the modified intention to treat analysis, there was no difference in progression-free survival (P=.234) and overall survival (P=.271) between arms. A total of 26 patients (59%) experienced a grade 2 or higher late toxicity, including 9 patients (20%) incurring a cerebrovascular accident (CVA), 7 of which were deemed at least possibly attributable to irradiation. The median time between completion of radiation therapy and CVA was 5.6 years (range, 1.4-14.0 years). CONCLUSIONS: Fractionated combined proton-photon radiation therapy is effective for BM, with no apparent benefit in dose escalation. Further investigation is needed to better define the risk of late toxicities, including CVA after cranial radiation therapy. PMID- 28865925 TI - Refining Patient Selection for Reirradiation of Head and Neck Squamous Carcinoma in the IMRT Era: A Multi-institution Cohort Study by the MIRI Collaborative. AB - PURPOSE: The therapeutic ratio of reirradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck may be improved in the intensity modulated radiation therapy (IMRT) era. However, patient selection for reirradiation remains challenging. We performed a multi-institution cohort study to investigate modern outcomes after IMRT-based reirradiation and to identify prognostic subgroups. PATIENTS AND METHODS: Patients with RSP squamous carcinoma originating in a previously irradiated field (>=40 Gy) who underwent reirradiation with IMRT (>=40 Gy re-IMRT) were included. Locoregional failure and late toxicity were calculated using the Gray competing risk method. Cox proportional hazards regression was used to identify factors associated with overall survival (OS). Factors associated with OS were entered into a recursive partitioning analysis (RPA) for OS. RESULTS: From 7 institutions, 412 patients were included. The median dose of re-IMRT was 60 Gy, and the median time between RT courses was 2.4 years. Chemotherapy was used in 76% of patients. The rates of grade >=3, grade >=4, and grade 5 acute toxicities were 19%, 4.4%, and 1.2%, respectively. The 2-year cumulative incidence of grade >=3 late toxicity adjusted for the competing risks of recurrence or death was 14.2%. RPA identified 3 prognostic subgroups with distinct and homogenous OS (P<.001): class I included patients >2 years from their initial course of RT with resected tumors (2-year OS, 61.9%); class II included patients >2 years with unresected tumors or those <=2 years and without feeding tube or tracheostomy dependence (2-year OS, 40.0%), and the remaining patients formed class III (2-year OS, 16.8%). Fifty-nine percent of class III patients underwent postoperative re-irradiation. CONCLUSIONS: This study informs outcomes and expectations with IMRT-based reirradiation. The RPA classification identifies 3 distinct subgroups, which can guide patient selection for therapy and clinical trial design. RPA class III patients are not ideal candidates for protracted chemoradiation regardless of resection status. PMID- 28865926 TI - Hazard perception training in young bicyclists improves early detection of risk: A cluster-randomized controlled trial. AB - INTRODUCTION: Since child bicyclists are more likely to get involved in a traffic crash, there is a stringent need to provide child bicyclists with tailored interventions in order to enhance their capabilities to deal with the complexity of traffic situations. The current study therefore aimed to test the effectiveness of a hazard anticipation training in young bicyclists by means of eye tracking technology. METHODS: A cluster-randomized controlled design was used in which participating schools were randomly assigned to the intervention or the control group. At first, a baseline hazard anticipation test was carried out in the intervention group (78 children; 9.56+/-0.38years of age) and the control group (46 children; 9.58+/-0.41years of age). Child bicyclists who participated in the intervention followed the training that consisted of two classroom sessions. In each session children were presented with video clips from the perspective of a bicyclist encountering various (potentially) dangerous traffic situations. Following the intervention, a post-test directly after the training and a retention test three weeks later were completed. The control group received the intervention after the retention test. RESULTS: Trained child bicyclists were found to detect more hazards and reacted quicker compared to the control group that did not receive the training. However, the training did not result in improvements in anticipatory visual search behaviour. CONCLUSION: Trained child bicyclists seemed to have developed a better processing regarding potential dangerous situations but were not able to 'see' the hazard sooner. The potential of a brief hazard anticipation training is discussed. PMID- 28865927 TI - Construction accident narrative classification: An evaluation of text mining techniques. AB - Learning from past accidents is fundamental to accident prevention. Thus, accident and near miss reporting are encouraged by organizations and regulators. However, for organizations managing large safety databases, the time taken to accurately classify accident and near miss narratives will be very significant. This study aims to evaluate the utility of various text mining classification techniques in classifying 1000 publicly available construction accident narratives obtained from the US OSHA website. The study evaluated six machine learning algorithms, including support vector machine (SVM), linear regression (LR), random forest (RF), k-nearest neighbor (KNN), decision tree (DT) and Naive Bayes (NB), and found that SVM produced the best performance in classifying the test set of 251 cases. Further experimentation with tokenization of the processed text and non-linear SVM were also conducted. In addition, a grid search was conducted on the hyperparameters of the SVM models. It was found that the best performing classifiers were linear SVM with unigram tokenization and radial basis function (RBF) SVM with uni-gram tokenization. In view of its relative simplicity, the linear SVM is recommended. Across the 11 labels of accident causes or types, the precision of the linear SVM ranged from 0.5 to 1, recall ranged from 0.36 to 0.9 and F1 score was between 0.45 and 0.92. The reasons for misclassification were discussed and suggestions on ways to improve the performance were provided. PMID- 28865929 TI - Non-natural lipids: Synthesis and characterization of esters from meta-carborane 1-carboxylic acid. AB - Lipids are defined as apolar molecules comprising as major classes fatty acids and fatty acid esters of normally natural origin. Non-natural components, such as dicarba-closo-dodecaboranes (in short carboranes) can also form acids and esters, which reveal lipid-like properties. Carboranes are synthetic boron clusters featuring ten BH and two CH vertices, organized in icosahedral shape. The highly hydrophobic clusters are organic-inorganic hybrid constructs and can be modified at both the cluster boron and the cluster carbon atoms via adjusted organic reactions. Here, we report the synthesis and characterization of lipid esters from meta-carborane-1-carboxylic acid using a new coupling reagent strategy. Carboranyl esters from long-chain alcohols revealed wax-like properties. PMID- 28865928 TI - The use of a driving simulator to determine how time pressures impact driver aggressiveness. AB - Speeding greatly attributes to traffic safety with approximately a third of fatal crashes in the United States being speeding-related. Previous research has identified being late as a primary cause of speeding. In this driving simulator study, a virtual drive was constructed to evaluate how time pressures, or hurried driving, affected driver speed choice and driver behavior. In particular, acceleration profiles, gap acceptance, willingness to pass, and dilemma zone behavior were used, in addition to speed, as measures to evaluate whether being late increased risky and aggressive driving behaviors. Thirty-six drivers were recruited with an equal male/female split and a broad distribution of ages. Financial incentives and completion time goals calibrated from a control group were used to generate a Hurried and Very Hurried experimental group. As compared to the control group, Very Hurried drivers selected higher speeds, accelerated faster after red lights, accepted smaller gaps on left turns, were more likely to pass a slow vehicle, and were more likely to run a yellow light in a dilemma zone situation. These trends were statistically significant and were also evident with the Hurried group but a larger sample would be needed to show statistical significance. The findings from this study provide evidence that hurried drivers select higher speeds and exhibit riskier driving behaviors. These conclusive results have possible implications in areas such as transportation funding and commercial motor vehicle safety. PMID- 28865930 TI - Osteoporosis following heart transplantation and immunosuppressive therapy. AB - Heart transplantation (HT) remains the ultimate final therapy for patients with end-stage heart failure, who despite optimal medical and surgical treatments exhibit severe symptoms. To prevent rejection of the transplanted organ, HT patients require life-long immunosuppressive therapy. The goal of the immunosuppression is to minimise the risk of immune-mediated graft rejection, while avoiding clinical side-effects. Current immunosuppressive agents have yielded good survival outcome, however, complications of the immunosuppressive therapy, such as impaired bone strength and increased fracture risk, are common among HT patients rendering increased morbidity and mortality rates. The main aim of the present review was to summarise current knowledge on bone strength impairment after HT and concomitant immunosuppressive therapy. PMID- 28865932 TI - The role of nitric oxide in diabetic skin (patho)physiology. AB - The role of nitric oxide (NO) in cutaneous physiology/pathology became a growing research field since the discovery that almost all types of skin cells can synthetize this redox signaling molecule about 20 years ago. Now, it is evident that NO is an important player in skin physiological processes and in responses of cutaneous cells to external insults, while the impaired NO signaling has an important consequence in skin pathology. Skin disorders are common complications in diabetic conditions. Various metabolic/biochemical and immunological dysregulations in diabetic skin are tightly coupled with the disturbances in the redox state, primarily the ratio between NO and superoxide (O2-). This review describes possible therapeutic significance of different redox state modulators in the treatment of diabetic skin disorders. The focus is on those modulators that tightly control NO/O2- ratio through the complex mechanisms affecting endogenous NO and O2- producing and removing systems. The fact that classic antioxidants failed to show significant benefits in diabetes, emphasizes the importance of such redox mechanism-based and targeted approaches. PMID- 28865931 TI - Age-associated alterations in the levels of cytotoxic lipid molecular species and oxidative stress in the murine thymus are reduced by growth hormone treatment. AB - During age-associated thymic involution, thymocytes decrease and lipid-laden cells accumulate. However, if and how aging affects the thymic lipid profile is not well understood, nor is it known if the hormonal milieu modifies this process. Here we demonstrate a correlation between reduced thymocyte numbers and markers of inflammation and oxidative stress with age. Evaluating the lipidomics profile of the whole thymus, between the ages of 4 (young) and 18 months (old), we found increased amounts of triacylglycerides, free cholesterol, cholesterol ester and 4-hydroxynonenal (4-HNE) with age. Moreover, levels of C24:0 and C24:1 sphingomyelins and ceramide C16:0 were elevated in 12-14 month-old (middle-aged) mice while the levels of sulfatide ceramide and ganglioside GD1a increased in the old thymus. Evaluating isolated thymocytes, we found increased levels of cholesterol ester and 4-HNE adducts, as compared to young mice. Next, we treated middle-aged mice with growth hormone (GH), which has been considered a potent immunomodulator. GH reduced thymic levels of TNF-alpha and 4-HNE and increased the number of thymocytes as well as the thymic levels of dihydroceramide, a ceramide precursor and autophagic stimuli for cell survival. In conclusion, GH treatment attenuated inflammation and age-related increases in oxidative stress and lipotoxicity in the thymus. PMID- 28865933 TI - A positive touch: C-tactile afferent targeted skin stimulation carries an appetitive motivational value. AB - The rewarding sensation of touch in affiliative interactions is hypothesised to be underpinned by an unmyelinated system of nerve fibres called C-tactile afferents (CTs). CTs are velocity tuned, responding optimally to slow, gentle touch, typical of a caress. Here we used evaluative conditioning to examine whether CT activation carries a positive affective value. A set of neutral faces were paired with robotically delivered touch to the forearm. With half the faces touch was delivered at a CT optimal velocity of 3cm/s (CT touch) and with the other half at a faster, non-CT optimal velocity of 30cm/s (Control touch). Heart rate and skin conductance responses (SCRs) were recorded throughout. Whilst rated equally approachable pre-conditioning, post-conditioning faces paired with CT touch were judged significantly more approachable than those paired with Control touch. CT touch also elicited significantly greater heart-rate deceleration and lower amplitude SCRs than Control touch. The results indicate CT touch carries a positive affective value, which can be acquired by socially relevant stimuli it is associated with. PMID- 28865934 TI - Rule-based generalisation in single-cue and differential fear conditioning in humans. AB - Fear generalisation refers to the spread of conditioned fear to stimuli similar but distinct from the original conditioned stimulus. In this study, participants were presented with repeated pairings of a conditioned stimulus with a shock, in either a single-cue or differential conditioning paradigm. Generalisation of fear was then tested by presenting stimuli that were novel, but similar to the conditioned stimulus along a spatial stimulus dimension. Dependent measures were online shock expectancy ratings and skin conductance level. A diverse range of generalisation gradients was observed, and the shape of the gradients for both expectancy ratings and skin conductance responses corresponded with participants' verbally reported rules. The findings point to an important role for cognitively controlled processes in human fear generalisation, and provide support for a single-system learning model. They also highlight the potential importance of cognitive reappraisal in clinical treatments for over-generalised fear. PMID- 28865936 TI - Effectiveness of a shielded ultraviolet C air disinfection system in an inpatient pharmacy of a tertiary care children's hospital. AB - Viable air particles pose a risk in areas where sterile preparations are compounded. This study investigated the efficacy of an innovative air purification technology that uses a shielded ultraviolet C light lamp to continuously purify the air in an inpatient pharmacy. Mean airborne fungal and bacterial colony forming units were obtained preinstallation and again in 6 months. A statistically significant decrease of 78% and 62% was observed for fungal and bacterial particles, respectively. This study demonstrates a potential role for this novel technology in decreasing the spread of airborne pathogens. PMID- 28865935 TI - Expectancy effects in feedback processing are explained primarily by time frequency delta not theta. AB - The roles of outcome valence and expectancy in feedback processing have been investigated as important factors modulating event-related potential (ERP) measures including the feedback negativity (FN) and P300, but results have been inconsistent. Recent work from our group has shown that processes underlying the FN and P300 are better represented as separable processes in the theta (3-7Hz) and delta (0-3Hz) ranges using time-frequency analysis. The current study evaluated the modulation of time-domain FN and P300 and time-frequency theta and delta to outcome valence and expectancy in a gambling feedback task paradigm. Results revealed that the FN was sensitive to valence but not expectancy, and that valence effects were driven by loss-sensitive theta and gain-sensitive delta. Alternatively, the P300 was sensitive to the expectedness of outcomes but only for gain trials, and these expectancy differences were explained by time frequency delta not theta. These results add to a growing body of research showing that time-frequency measures reflect separable processes underlying time domain components, where theta is more sensitive to primary task features and less sensitive to secondary features while delta is sensitive to primary and more complex, secondary task features. PMID- 28865937 TI - Impact of respiratory virus molecular testing on antibiotic utilization in community-acquired pneumonia. AB - We compared the clinical characteristics and antibiotic therapy of community acquired pneumonia patients who were positive on a respiratory virus molecular test (polymerase chain reaction) with those who were negative. We found that respiratory virus molecular polymerase chain reaction testing has a minimal impact on reducing antibiotic utilization among viral pneumonia patients. PMID- 28865939 TI - [Prevalence of exfoliation syndrome and cardiovascular diseases in patients scheduled for cataract surgery]. AB - PURPOSE: To study the prevalence of exfoliation syndrome (XFS) and its association with cardiovascular disease in patients scheduled for cataract surgery. MATERIAL AND METHODS: This is a retrospective, single center, descriptive study of 260 patients admitted to a tertiary teaching hospital in Rabat, Morocco, between January 2015 and March 2016 and scheduled for cataract surgery. All patients had a preoperative cardiovascular exam, an electrocardiogram and, if needed, echocardiography. Statistical analysis was performed using SPSS software. Results with a P-value<0.05 were considered statistically significant. RESULTS: This study included 246 patients: 146 women (59.3 %) and 100 men (40.7 %). The mean age (years) was 67.6+/-10.1. The percentage of XFS increased with age (P=0.02). Sixty-two percent of patients with cardiovascular disease also had exfoliation syndrome (P<0.001). Patients with XFS had hypertension in 46.5 % of cases. 14 subjects (19.7 %) had ischemic heart disease and XFS. Using multivariate logistic regression and after adjusting for age, diabetes mellitus, hypertension, ischemic heart disease and arrhythmias, smoking was the only factor associated with exfoliation syndrome (P=0.01, odds ratio=5.2, confidence interval 95 %=1.35-20.15). CONCLUSION: Exfoliation syndrome is a common condition in the aging cataract population. Ischemic heart disease and hypertension are frequently associated with XFS. Smoking could be another factor associated with this syndrome. PMID- 28865940 TI - Oxytocin improves facial emotion recognition in young adults with antisocial personality disorder. AB - Deficient facial emotion recognition has been suggested to underlie aggression in individuals with antisocial personality disorder (ASPD). As the neuropeptide oxytocin (OT) has been shown to improve facial emotion recognition, it might also exert beneficial effects in individuals providing so much harm to the society. In a double-blind, randomized, placebo-controlled crossover trial, 22 individuals with ASPD and 29 healthy control (HC) subjects (matched for age, sex, intelligence, and education) were intranasally administered either OT (24 IU) or a placebo 45min before participating in an emotion classification paradigm with fearful, angry, and happy faces. We assessed the number of correct classifications and reaction times as indicators of emotion recognition ability. Significant group*substance*emotion interactions were found in correct classifications and reaction times. Compared to HC, individuals with ASPD showed deficits in recognizing fearful and happy faces; these group differences were no longer observable under OT. Additionally, reaction times for angry faces differed significantly between the ASPD and HC group in the placebo condition. This effect was mainly driven by longer reaction times in HC subjects after placebo administration compared to OT administration while individuals with ASPD revealed descriptively the contrary response pattern. Our data indicate an improvement of the recognition of fearful and happy facial expressions by OT in young adults with ASPD. Particularly the increased recognition of facial fear is of high importance since the correct perception of distress signals in others is thought to inhibit aggression. Beneficial effects of OT might be further mediated by improved recognition of facial happiness probably reflecting increased social reward responsiveness. PMID- 28865938 TI - [A "fast track" to improve management of neovascular age related macular degeneration]. AB - OBJECTIVE: To evaluate the role of a fast track for management of patients with neovascular age- related macular degeneration (nARMD) treated by intravitreal injection of anti-VEGF. PATIENTS: The records of 100 patients in the chronic maintenance phase of intravitreal anti-VEGF followed in the fast track and 63 patients followed in the standard protocol for at least 12 months were retrospectively analyzed. METHOD: Patients in the fast track underwent visual acuity (VA) testing by ETDRS, optical coherence tomography (OCT) and a physician assessment. The injection was performed the same day whenever possible. The primary endpoint to evaluate patient adherence was the time between the ideal date of visit or injection prescribed by the physician and the actual date of administration. RESULTS: The mean time between the ideal date of visit or injection prescribed by the physician and the actual date of administration was 4.1+/-7.5 days for the patients followed in the fast track and 5.6+/-18.7 days for the patients followed in the standard protocol. Mean VA remained stable for the patients followed in the fast track: 20/50 (20/800 to 20/20) at baseline vs. 20/50 (20/800 to 20/16) at the conclusion of follow-up. It dropped from 40/50 at baseline to 20/63 at the conclusion of follow-up for the patients followed in the standard protocol. CONCLUSION: In the context of a fast track, it was possible to improve the adherence of nARMD patients and maintain their VA gain or stabilization achieved after the induction phase. PMID- 28865941 TI - A field study of the association between CD38 gene and altruistic behavior: Empathic response as a mediator. AB - Inspired by the enhancement effects of oxytocin on empathic responses and altruistic behaviors, we conducted a field study with a real fundraising event and investigated to what extent oxytocin pathway genes (CD38 and OXTR) modulate individual differences in charitable donation. Participants were informed that a teacher in their university was diagnosed with uremia and could not afford the cost of medication. They were given the opportunity to donate any amount of money and report their empathic responses to the misfortune of the teacher. We found a significant association between CD38 rs3796863 and the amount of donation both before and after controlling for gender, age, subjective socioeconomic status, religious belief, and social desirability. Individuals with the genotypes (AA/AC) leading to higher oxytocin levels reported stronger empathic responses and donated more money than individuals with the CC genotype. Moreover, empathic response mediated the gene-altruism association. However, we observed no significant associations between the three polymorphisms of OXTR (rs53576, rs2254298, and rs1042778) and the amount of donation. This study demonstrates the importance of CD38 as a source of individual differences in altruistic behavior and highlights the role of empathic response in bridging the link between the oxytocin pathway gene and altruism. PMID- 28865942 TI - Left atrial appendage closure in patients with intracranial haemorrhage and atrial fibrillation. AB - INTRODUCTION: The use of oral anticoagulants in patients with a history of atrial fibrillation (AF) and intracranial haemorrhage (ICH) is controversial on account of the risk of haemorrhagic stroke recurrence. This study presents our experience regarding the safety and efficacy of percutaneous left atrial appendage closure (LAAC), an alternative to anticoagulation in these patients. METHODS: We conducted a retrospective, single-centre, observational study. LAAC was performed in patients with a history of ICH and non-valvular AF. Risk of ischaemic and haemorrhagic events was estimated using the CHA2DS2-VASc and HAS-BLED scales. We recorded periprocedural complications, IHC recurrence, cerebral/systemic embolism, mortality and use of antithrombotic drugs following the procedure. RESULTS: LAAC was performed in 9 patients (7 men, 2 women) using the AMPLATZER Amulet device in 7 cases and the AMPLATZER Cardiac Plug device in 2. Mean age was 72.7+/-8.2 years. Time between ICH and LAAC was less than one month in 5 patients and more than one month in 4 patients. Median CHA2DS2-VASc score was 4 (interquartile range of 2.5). Median HAS-BLED score was 3 (interquartile range of 0). No periprocedural complications were recorded. All patients received single anti-platelet therapy (clopidogrel in 5 patients, aspirin in 4) after the procedure; 5 patients received this treatment for 6 months and 4 received it indefinitely. No ischaemic or haemorrhagic events were recorded during follow-up (mean duration of 15 months). CONCLUSIONS: In our series, LAAC was found to be safe and effective in patients with a history of ICH who required anticoagulation due to AF. PMID- 28865943 TI - Argentinian/Chilean validation of the Spanish-language version of Addenbrooke's Cognitive Examination III for diagnosing dementia. AB - BACKGROUND: The Addenbrooke's Cognitive Examination III (ACE-III), an adaptation of the ACE cognitive screening test, has been demonstrated to have high sensitivity and specificity in detecting cognitive impairment in patients with dementia and other neurological and psychiatric disorders. Although the Spanish language version of the ACE-III has already been validated in Spain, it is yet to be validated in Latin America. The aim of this study was to validate the ACE-III test in an Argentinean and Chilean population. METHODS: ACE-III was administered to 70 patients with Alzheimer disease, 31 patients with behavioural variant frontotemporal dementia, and a control group of 139 healthy volunteers. Participants were recruited at centres in both countries. RESULTS: The Spanish language version of ACE-III was found to have good internal consistency (Cronbach's alpha=0.87). We found significant differences in total ACE-III scores between patients with Alzheimer disease and controls (p< .05) and between patients with Alzheimer disease and bvFTD (p< .05). With a cut-off point of 86, 98.6% of AD patients, 83.9% of behavioural variant frontotemporal dementia patients, and 84.2% of controls were correctly classified. CONCLUSIONS: This study shows that the Spanish-language version of ACE-III continues to be an effective tool for detecting cognitive dysfunction in patients with dementia. PMID- 28865944 TI - False ischaemic penumbras in CT perfusion in patients with carotid artery stenosis and changes following angioplasty and stenting. AB - INTRODUCTION: Carotid artery stenosis influences CT perfusion (CTP) studies, sometimes manifesting as a false ischaemic penumbra (FIP). This study aims to estimate the incidence of FIP in patients with carotid artery stenosis, establish their relationship with the degree of stenosis, and measure quantitative and qualitative changes in CTP after carotid angioplasty and stenting (CAS). METHODS: Between October 2013 and June 2015, we prospectively selected 26 patients with carotid stenosis who underwent CAS, with CTP being performed 2-10 days before and after CAS. RESULTS: Sixteen patients had unilateral stenosis (11 in the subgroup displaying < 90% stenosis and 5 in the subgroup with >= 90% stenosis) and 10 patients had bilateral stenosis. The incidence of FIP in patients with carotid artery stenosis was 38.5%. Risk of FIP increased in direct relation to degree of stenosis, with a relative risk of 11 in the subgroup with >= 90% stenosis with respect to the subgroup displaying < 90% stenosis (95% CI, 1.7-71.3; P=.0005). There were statistically significant changes in the parameters CBF, TTP, MTT, and Tmax CTP, which reverted after angioplasty. No significant changes were found in CBV. CONCLUSIONS: Carotid artery stenosis involves changes in CTP parameters. Patients with >= 90% stenosis carry a high risk of FIP; CTP studies may therefore be misinterpreted in these cases. Changes in CTP parameters are reverted after CAS. PMID- 28865945 TI - Relationship between Virchow-Robin spaces and Alzheimer disease: A case report. PMID- 28865946 TI - Immunosuppressive therapy in opsoclonus-myoclonus ataxia syndrome associated with paravertebral neuroblastoma. PMID- 28865947 TI - New variant associated with Niemann-Pick disease type C: Neurological manifestations and biochemical, molecular, and cellular characterisation. PMID- 28865948 TI - A new topical hemostatic agent TT-173 reduces blood loss in a sheep model of total knee arthroplasty. AB - BACKGROUND: Total knee arthroplasty is associated with blood loss during the intervention and may require allogenic blood transfusion. Treatments such as tranexamic acid and fibrin sealants improved the bleeding control in several clinical trials, but the hemorrhage associated with the intervention is still significant. Thus far, very few studies have evaluated hemostatic treatments in animal models of total knee arthroplasty. This work describes a sheep model of bleeding associated with total knee arthroplasty and investigates a new class of hemostatic treatment based on recombinant tissue factor. METHODS: Sheep were treated with the anticoagulant heparin, and the joint was accessed by a paramedial incision. Ligaments and menisci were eliminated and femoral condyles and tibia plateau were sectioned exposing the trabecular bone. An intra-articular drain was used to recover and quantify the blood loss during the 90-min period after treatment. The efficacy of one milligram and three milligrams of TT-173 was evaluated and compared with tranexamic acid. The occurrence of analytical alterations and systemic absorption was also investigated. RESULTS: Treatment with TT-173 reduced the blood loss in comparison with control or tranexamic acid. No significant differences were observed between the two doses evaluated. Moreover, a dose of six milligrams of TT-173 did not induce any clinical or analytical alteration, and significant systemic absorption was not observed. CONCLUSION: Data obtained strongly suggest that TT-173 could be useful in reducing the blood loss associated with total knee arthroplasty and without safety concerns derived from the systemic absorption of the product. PMID- 28865949 TI - Valproic acid increases NF-kappaB transcriptional activation despite decreasing DNA binding ability in P19 cells, which may play a role in VPA-initiated teratogenesis. AB - The nuclear factor-kappa B (NF-kappaB) family of transcription factors regulate gene expression in response to diverse stimuli. We previously demonstrated that valproic acid (VPA) exposure in utero decreases total cellular protein expression of the NF-kappaB subunit p65 in CD-1 mouse embryos with a neural tube defect but not in phenotypically normal littermates. This study evaluated p65 mRNA and protein expression in P19 cells and determined the impact on DNA binding ability and activity. Exposure to 5mM VPA decreased p65 mRNA and total cellular protein expression however, nuclear p65 protein expression was unchanged. VPA reduced NF kappaB DNA binding and nuclear protein of the p65 DNA-binding partner, p50. NF kappaB transcriptional activity was increased with VPA alone, despite decreased phosphorylation of p65 at Ser276, and when combined with tissue necrosis factor alpha. These results demonstrate that VPA increases NF-kappaB transcriptional activity despite decreasing DNA binding, which may play a role in VPA-initiated teratogenesis. PMID- 28865950 TI - Individual and combined toxicological effects of deoxynivalenol and zearalenone on human hepatocytes in in vitro chronic exposure conditions. AB - While numerous surveys highlighted the natural co-occurrence of mycotoxins in food, data about their toxicological combined effects is still limited. This is especially the case for chronic exposure conditions, although the latter are more representative of the mycotoxin risk associated with food consumption than acute exposure. In the present study, cell viability and gene expression levels of relevant hepatocyte-specific functions were evaluated for the HepaRG human liver cell line exposed to deoxynivalenol (DON) and/or zearalenone (ZEA) during 14, 28 and 42days at three subtoxic concentrations corresponding to i) the determined average exposure dose of French adult population, ii) the tolerable daily intake established by the Joint FAO/WHO Expert Committee and iii) the maximum level permitted by the European regulation in cereals intended for direct human consumption. For the latter, DON and DON+ZEA induced 90% cell mortality after 14days. In addition, depending on the considered toxin or mixture, doses and exposure periods, important variations of gene expression levels were observed. Despite the fact that in vitro conditions differ from the in vivo situation, the obtained results clearly highlighted that long-term toxicological effects of chronic exposure to mycotoxin combinations should be further investigated and, if necessary, taken into consideration at the regulatory level. PMID- 28865951 TI - Are person-related and socio-structural factors associated with nurses' self management support behavior? A correlational study. AB - OBJECTIVE: To explore nurses' self-perceived behavior of supporting patients' self-management, and its association with person-related and socio-structural factors. METHODS: Correlational study in a sample of nurses from nine general hospitals, three community healthcare organizations, and six private community practices. Nurses with >50% of their patients living with a chronic condition were eligible to participate. Data were collected at two time-points. Self management support behavior was measured by the SEPSS-36 instrument. The person related and socio-structural associated factors were derived from behavioral theories and measured by validated questionnaires. RESULTS: Nurses (N=477) scored overall low on self-management support behavior. Nurses lacked mainly competencies in collaborative goalsetting, shared decision making and organizing follow-up. Factors predicting nurses' behavior in supporting patients' self management were self-efficacy, priority, perceived supervisor support and training in self-management support. This model explained 51.7% of the variance in nurses' behavior. CONCLUSION: To date, nurses do not optimally fulfil their role in supporting patients' self-management. Self-management support is practiced from a narrow medical point of view and primarily consists of informing patients, which is the lowest level of patient participation. PRACTICE IMPLICATIONS: It is essential to better prepare and support nurses - and by extend all healthcare professionals - for the challenges of supporting patients' self-management. PMID- 28865952 TI - Sedative and physiological effects of brimonidine tartrate ophthalmic solution in healthy cats. AB - OBJECTIVE: To determine the effects of brimonidine tartrate ophthalmic solution on sedation, heart rate (HR), respiratory frequency (fR), rectal temperature (RT) and noninvasive mean arterial pressure (MAP) in healthy cats. STUDY DESIGN: Randomized, blinded crossover study, with 1 week washout between treatments. ANIMALS: Six healthy purpose-bred cats. METHODS: Brimonidine tartrate ophthalmic solution 0.1% (one or two drops; 58.6 +/- 3.3 MUg per drop) or a control solution (artificial tear solution) was administered to six healthy cats. Behavioural observations and measurements of HR, fR, RT and MAP were recorded before and at 30, 60, 90, 120, 180, 240, 300 and 360 minutes after topical administration. Behavioural scores were analysed using Friedman's test for repeated measures to evaluate the time effect in each treatment and treatment effect at each time point. Physiological variables (HR, fR, RT and MAP) were analysed using two-way analysis of variance for repeated measures to evaluate the time and treatment effects. The level of significance was set at p < 0.05. RESULTS: Dose-dependent behavioural and physiological responses were noted. A dose of two drops of brimonidine resulted in sedation in the cats and decreased HR and MAP. Significant sedative effects occurred between 30 and 120 minutes and for physiological responses up to 360 minutes. The most frequent adverse reaction was vomiting, occurring within 40 minutes in all six cats administered two drops and five of the six cats administered one drop of brimonidine. CONCLUSIONS AND CLINICAL RELEVANCE: The results demonstrated that ocular administration of brimonidine 0.1% ophthalmic solution induced sedation in cats and some cardiovascular effects usually associated with alpha2-adrenoceptor agonists. Further studies should be performed to determine clinical applications for this agent in cats. PMID- 28865953 TI - Ventilatory incidents monitored by electrical impedance tomography in an anaesthetized orangutan (Pongo abelii). PMID- 28865954 TI - Comparative expression profiling of AtRAD5B and AtNDL1: Hints towards a role in G protein mediated signaling. AB - Arabidopsis AtRAD5B encodes for a putative helicase of the class SWItch/Sucrose Non-Fermentable (SWI/SNF) ATPases. We identified AtRAD5B as an interactor of N MYC DOWNREGULATED-LIKE1 (AtNDL1) in a yeast two-hybrid screen. AtNDL1 is a G protein signaling component which regulates auxin transport and gradients together with GTP binding protein beta 1 (AGB1). Auxin gradients are known to recruit SWI/SNF remodeling complexes to the chromatin and regulate expression of genes involved in flower and leaf formation. In current study, a comparative spatial and temporal co-expression/localization analysis of AtNDL1, AGB1 with AtRAD5B was carried out in order to explore the possibility of their coexistence in a common signaling network. Translational fusion (GUS) of AtNDL1 and AtRAD5B in seedlings and reproductive organs revealed that both shared similar expression patterns with the highest expression observed in male reproductive organs. Moreover, they shared similar domains of localization in roots, suggesting their potential functioning together in reproductive and root development processes. This study predicts the existence of a signaling network involving AtNDL1, AGB1 with AtRAD5B. PMID- 28865955 TI - Nanoparticles as effective acaricides against ticks-A review. AB - Ticks serve as vectors of a wide range of infectious agents deleterious to humans and animals. Tick bite prevention is based to a large extent on the use of chemical repellents and acaricides. However, development of resistance in targeted ticks, environmental pollution, and contamination of livestock meat and milk are major concerns. Recently, metal, metal oxide and carbon nanoparticles, particularly those obtained through green fabrication routes, were found to be highly effective against a wide array of arthropod pests and vectors. We summarize current knowledge on the toxicity of nanoparticles against tick vectors of medical and veterinary importance. We also discuss the toxicity of products from botanical- and bacterial-based as well as classic chemical nanosynthesis routes, showing differences in bioactivity against ticks based on the products used for the fabrication of nanoparticles. Further research is needed, to validate the efficacy of nanoparticle-based acaricides in the field and clarify mechanisms of action of nanoparticles against ticks. From a technical point of view, the literature analyzed here showed little standardization of size and weight of tested ticks, a lack of uniform methods to assess toxicity and concerns related to data analysis. Finally, an important challenge for future research is the need for ecotoxicology studies to evaluate potential negative effects on non target organisms and site contamination arising from nanoparticle-based treatments in close proximity of livestock and farmers. PMID- 28865956 TI - Developmentally regulated GTP-binding protein 2 is required for stabilization of Rac1-positive membrane tubules. AB - Previously we have reported that developmentally regulated GTP-binding protein 2 (DRG2) localizes on Rab5 endosomes and plays an important role in transferrin (Tfn) recycling. We here identified DRG2 as a key regulator of membrane tubule stability. At 30 min after Tfn treatment, DRG2 localized to membrane tubules which were enriched with phosphatidylinositol 4-monophosphate [PI(4)P] and did not contain Rab5. DRG2 interacted with Rac1 more strongly with GTP-bound Rac1 and tubular localization of DRG2 depended on Rac1 activity. DRG2 depletion led to destabilization of membrane tubules, while ectopic expression of DRG2 rescued the stability of the membrane tubules in DRG2-depleted cells. Our results reveal a novel mechanism for regulation of membrane tubule stability mediated by DRG2. PMID- 28865957 TI - Zinc binds non-cooperatively to human liver metallothionein 2a at physiological pH. AB - Maintenance of the homeostasis of zinc is very important in regulating bodily functions. There are over 300 Zn-dependent enzymes identified where Zn(II) plays a structural or catalytic role. However, an excess of Zn(II) in a cell is toxic and free Zn(II) is tightly controlled. Metallothioneins (MTs) are small cysteine rich proteins that can bind up to seven Zn(II) and act as a Zn(II) reservoir. The MT2a isoform is predominantly found in the liver. This study focused on designing an MT2a construct of recombinant human MT2a to determine the Zn(II) binding profile of MT2a in vitro. We analyzed the pH dependence of Zn-MT2a speciation from electrospray ionization mass spectral data. At physiological pH, Zn(II) is terminally bound to the cysteine thiols of MT2a, making bead-like structures (non cooperative metal binding), while at low pH, Zn(II) formed Zn4S11-MT2a clusters involving bridged cysteinyl thiols to the Zn(II) (cooperative metal binding). The Zn(II) binding profile of MT2a was compared to Zn(II) binding profile of human kidney MT1a, which was reported in literature, and found that the Zn(II) binding profile of MT2a is similar to that of MT1a. The facility of forming bead-like structures at physiological pH for Zn5-MT2a means that Zn7-MT2a can donate up to two Zn(II) to Zn-dependent enzymes. PMID- 28865958 TI - Crystal structure of glucose isomerase in complex with xylitol inhibitor in one metal binding mode. AB - Glucose isomerase (GI) is an intramolecular oxidoreductase that interconverts aldoses and ketoses. These characteristics are widely used in the food, detergent, and pharmaceutical industries. In order to obtain an efficient GI, identification of novel GI genes and substrate binding/inhibition have been studied. Xylitol is a well-known inhibitor of GI. In Streptomyces rubiginosus, two crystal structures have been reported for GI in complex with xylitol inhibitor. However, a structural comparison showed that xylitol can have variable conformation at the substrate binding site, e.g., a nonspecific binding mode. In this study, we report the crystal structure of S. rubiginosus GI in a complex with xylitol and glycerol. Our crystal structure showed one metal binding mode in GI, which we presumed to represent the inactive form of the GI. The metal ion was found only at the M1 site, which was involved in substrate binding, and was not present at the M2 site, which was involved in catalytic function. The O2 and O4 atoms of xylitol molecules contributed to the stable octahedral coordination of the metal in M1. Although there was no metal at the M2 site, no large conformational change was observed for the conserved residues coordinating M2. Our structural analysis showed that the metal at the M2 site was not important when a xylitol inhibitor was bound to the M1 site in GI. Thus, these findings provided important information for elucidation or engineering of GI functions. PMID- 28865959 TI - Amyloid fibril aggregation: An insight into the underwater adhesion of barnacle cement. AB - Barnacles robustly adhere themselves to diverse submarine substrates through a proteinaceous complex termed the "barnacle cement". Previous studies have indicated that certain peptides derived from some barnacle cement proteins can self-assemble into amyloid fibrils. In this study, we assessed the self-assembly behavior of a full-length 19 kDa cement protein from Balanus albicostatus (Balcp19k) in different buffers. Results of Thioflavin T binding assay, transmission electron microscopy, and Fourier transform infrared spectroscopy suggested that the bacterial recombinant Balcp19k was able to aggregate into typical amyloid fibrils. The time required for the self-assembly process was close to that required for the complete curing of barnacle cement complex. Moreover, the solubility of Balcp19k amyloid deposits in guanidine hydrochloride and urea was same as that of the cured cement. These results indicated the inherent self-assembling nature of Balcp19k, implying that the amyloid fibril formation plays a critical role in barnacle cement curing procedure and its insolubility. Our results should be conducive to understanding barnacle underwater adhesion mechanisms and have implications in the development of new generation antifouling techniques and in the designing of novel wet adhesives for biomedical and technical applications. PMID- 28865960 TI - Cavin-2 is a specific marker for detection of well-differentiated liposarcoma. AB - Caveolae are cholesterol enriched invaginations of the plasma membrane involved in a variety of processes, including glucose and fatty acids absorption, cell transduction and mechanoprotection. The biogenesis and function of caveolae depend on the activity of Caveolin (Cav-1, -2 and -3) and Cavin (Cavin-1, -2, -3 and -4) protein families. Since the membrane Cavin-2 protein was reported to play a key role in caveolae formation of adipocytes, in this work we have used a multidisciplinary approach to investigate its expression in liposarcoma (LPS), an adipocytic soft tissue sarcoma affecting adults. Data obtained through an in silico and immunohistochemical analysis suggest that Cavin-2, along with Cavin-1, Cav-1 and Cav-2, is mostly expressed in the least aggressive LPS subtype, namely well-differentiated LPS, while is almost undetectable in the more aggressive myxoid, pleomorphic and dedifferentiated LPS tumors. Accordingly, in vitro analysis confirmed that Cavin-2 expression increases in LPS tumor cell lines during differentiation as compared to proliferation, as detected by immunoblotting and immunofluorescence analysis. Overall, these data suggest that Cavin-2 represents a useful marker for discriminating the degree of differentiation in LPS tumors. PMID- 28865961 TI - Effect of high-fat diet on cognitive impairment in triple-transgenic mice model of Alzheimer's disease. AB - High-fat diet (HFD)-induced obesity is a risk factor for cognitive impairment in Alzheimer's disease (AD). It has been reported that two typical neuropathological markers of AD, beta-amyloid (Abeta) peptide and hyperphosphorylated protein tau can cause neuronal apoptosis via oxidative stress, which ultimately leads to cognitive dysfunction. In this study, we tried to explore the molecular pathway underlying memory impairment in young AD transgenic mice model in response to HFD. We maintained non-transgenic control mice (non-Tg) and triple transgenic AD (3xTg-AD) mice aged 8 weeks on either normal diet (ND) containing 10% fat or HFD (60% fat) for 16 weeks. Cognitive functions were evaluated by Morris water maze and Y-maze tests. Behavioral tests showed a significant memory impairment in 3xTg AD mice fed with HFD. HFD did not alter the levels of Abeta and phospho-tau protein in the cortical region regardless of groups. However, 3xTg-AD mice fed with HFD exhibited increased neuronal oxidative stress and apoptosis as assessed by augmentation of lipid peroxidation, activation of caspase-3 and elevated ratio of Bax/Bcl-2. Furthermore, HFD markedly reduced the activation of redox-sensitive transcription factor NF-E2-related factor 2 (Nrf2) by suppressing its up-stream regulatory protein kinase B/Akt as well as down-stream targets such as heme oxygenase-1 and manganese superoxide dismutase in these mice. Our findings suggest that HFD may accelerate cognitive impairment by enhancing oxidative stress and aggravating neuronal apoptosis via inactivation of Nrf2 signaling pathway. PMID- 28865962 TI - Maternal trans-general analysis of the human mitochondrial DNA pattern. AB - There is an intimate connection between mitochondrial DNA (mtDNA) methylation and some diseases, such as cancer. MtDNA is almost strictly maternally inherited. However, whether the aberrant mtDNA methylation involved in breast cancer progression and whether mtDNA methylation can be transmitted through maternal line are poorly understood. Here we applied bisulfite sequencing to global mitochondrial DNA and whole genomic DNA methylation array from fifteen members of five three-female-generation families with one breast cancer patient in each family. We found that mtDNA methylation was maternally inherited in D-loop region and eight aberrant mtDNA methylation sites were correlated with breast cancer. Furthermore, conjoint analysis showed that mtDNA methylation sites could be potential biomarkers combined with nuclear DNA methylation sites for breast cancer risk prediction. PMID- 28865963 TI - Can shoulder range of movement be measured accurately using the Microsoft Kinect sensor plus Medical Interactive Recovery Assistant (MIRA) software? AB - BACKGROUND: This study compared the accuracy of measuring shoulder range of movement (ROM) with a simple laptop-sensor combination vs. trained observers (shoulder physiotherapists and shoulder surgeons) using motion capture (MoCap) laboratory equipment as the gold standard. METHODS: The Microsoft Kinect sensor (Microsoft Corp., Redmond, WA, USA) tracks 3-dimensional human motion. Ordinarily used with an Xbox (Microsoft Corp.) video game console, Medical Interactive Recovery Assistant (MIRA) software (MIRA Rehab Ltd., London, UK) allows this small sensor to measure shoulder movement with a standard computer. Shoulder movements of 49 healthy volunteers were simultaneously measured by trained observers, MoCap, and the MIRA device. Internal rotation was assessed with the shoulder abducted 90 degrees and external rotation with the shoulder adducted. Visual estimation and MIRA measurements were compared with gold standard MoCap measurements for agreement using Bland-Altman methods. RESULTS: There were 1670 measurements analyzed. The MIRA evaluations of all 4 cardinal shoulder movements were significantly more precise, with narrower limits of agreement, than the measurements of trained observers. MIRA achieved +/-11 degrees (95% confidence interval [CI], 8.7 degrees -12.6 degrees ) for forward flexion vs. +/-16 degrees (95% CI, 14.6 degrees -17.6 degrees ) by trained observers. For abduction, MIRA showed +/-11 degrees (95% CI, 8.7 degrees -12.8 degrees ) against +/-15 degrees (95% CI, 13.4 degrees -16.2 degrees ) for trained observers. MIRA attained +/-10 degrees (95% CI, 8.1 degrees -11.9 degrees ) during external rotation measurement, whereas trained observers only reached +/-21 degrees (95% CI, 18.7 degrees -22.6 degrees ). For internal rotation, MIRA achieved +/-9 degrees (95% CI, 7.2 degrees -10.4 degrees ), which was again better than TOs at +/-18 degrees (95% CI, 16.0 degrees -19.3 degrees ). CONCLUSIONS: A laptop combined with a Microsoft Kinect sensor and the MIRA software can measure shoulder movements with acceptable levels of accuracy. This technology, which can be easily set up, may also allow precise shoulder ROM measurement outside the clinic setting. PMID- 28865964 TI - Routine cultures for seemingly aseptic revision shoulder arthroplasty: are they necessary? AB - Propionibacterium acnes has recently gained attention as the leading cause of periprosthetic joint infections (PJIs) after shoulder arthroplasty. Unlike PJIs in the lower extremity, PJIs after shoulder arthroplasty usually have an indolent course and are notoriously difficult to diagnose. Most of the time, the diagnosis is made after positive intraoperative cultures are taken at the time of revision surgery. Adding even more complexity to the diagnosis is the high rate of P acnes positive cultures taken at the time of primary shoulder surgery. In many cases the preoperative workup yields no suspicion for infection; however, intraoperative cultures are taken to completely eliminate the potential of an ongoing indolent infection. Concerns over how to interpret positive P acnes culture results and the high rate of culture positivity in primary shoulder arthroplasty, as well as the potentially high rate of contamination, have led surgeons to wonder about the utility of obtaining intraoperative cultures at the time of revision shoulder arthroplasty. We present evidence for and against the practice of obtaining routine intraoperative cultures at the time of seemingly aseptic revision shoulder arthroplasty. PMID- 28865965 TI - Proximal stress shielding is decreased with a short stem compared with a traditional-length stem in total shoulder arthroplasty. AB - BACKGROUND: This study compared the outcome and radiographic humeral adaptations after placement of a traditional-length (TL) or short-stem (SS) humeral component during total shoulder arthroplasty (TSA). The hypothesis was there would be no difference in outcome or radiographic adaptations. METHODS: A multicenter retrospective review was performed of primary TSAs performed with a TL or SS press-fit humeral component. The stems were identical in geometry and coating, with the only variable being stem length. Functional outcome and radiographs were reviewed at a minimum of 2 years postoperatively in 58 TL stems and 56 SSs. RESULTS: There were significant improvements in all range of motion and functional outcome from baseline (P < .001) but no difference between the groups (P > .05). TL stems were placed in anatomic alignment 98% of the time compared with 86% of the SS cases (P = .015), but alignment did not influence outcome. Cortical thinning was more common in the medial metaphysis with the TL stem (74%) than with the SS (50%; P = .008). Partial calcar osteolysis was seen in 31% of TL stems and in 23% of SSs (P = .348). There was no difference in loosening or shift between the 2 groups. CONCLUSION: There is no difference in functional outcome at short-term follow-up between a TL stem and a SS in TSA. The pattern of radiographic adaptations may differ based on stem length. Further study is needed to evaluate the mid- to long-term differences, particularly with regard to calcar osteolysis. PMID- 28865966 TI - Characterizing the macro and micro mechanical properties of scaffolds for rotator cuff repair. AB - BACKGROUND: Retearing after rotator cuff surgery is a major clinical problem. Numerous scaffolds are being used to try to reduce retear rates. However, few have demonstrated clinical efficacy. We hypothesize that this lack of efficacy is due to insufficient mechanical properties. Therefore, we compared the macro and nano/micro mechanical properties of 7 commercially available scaffolds to those of the human supraspinatus tendons, whose function they seek to restore. METHODS: The clinically approved scaffolds tested were X-Repair, LARS ligament, Poly-Tape, BioFiber, GraftJacket, Permacol, and Conexa. Fresh frozen cadaveric human supraspinatus tendon samples were used. Macro mechanical properties were determined through tensile testing and rheometry. Scanning probe microscopy and scanning electron microscopy were performed to assess properties of materials at the nano/microscale (morphology, Young modulus, loss tangent). RESULTS: None of the scaffolds tested adequately approximated both the macro and micro mechanical properties of human supraspinatus tendon. Macroscale mechanical properties were insufficient to restore load-bearing function. The best-performing scaffolds on the macroscale (X-Repair, LARS ligament) had poor nano/microscale properties. Scaffolds approximating tendon properties on the nano/microscale (BioFiber, biologic scaffolds) had poor macroscale properties. CONCLUSION: Existing scaffolds failed to adequately approximate the mechanical properties of human supraspinatus tendons. Combining the macroscopic mechanical properties of a synthetic scaffold with the micro mechanical properties of biologic scaffold could better achieve this goal. Future work should focus on advancing techniques to create new scaffolds with more desirable mechanical properties. This may help improve outcomes for rotator cuff surgery patients. PMID- 28865967 TI - Bugging allergy; role of pre-, pro- and synbiotics in allergy prevention. AB - Large-scale biodiversity loss and complex changes in social behaviors are altering human microbial ecology. This is increasingly implicated in the global rise in inflammatory diseases, most notably the "allergy epidemic" in very early life. Colonization of human ecological niches, particularly the gastrointestinal tract, is critical for normal local and systemic immune development and regulation. Disturbances in composition, diversity and timing of microbial colonization have been associated with increased allergy risk, indicating the importance of strategies to restore a dysbiotic gut microbiota in the primary prevention of allergic diseases, including the administration of probiotics, prebiotics and synbiotics. Here, we summarize and discuss findings of randomized clinical trials that have examined the effects of these microbiome-related strategies on short and long-term allergy preventative effects - including new guidelines from the World Allergy Organization which now recommend probiotics and prebiotics for allergy prevention under certain conditions. The relatively low quality evidence, limited comparative studies and large heterogeneity between studies, have collectively hampered recommendations on specific probiotic strains, specific timing and specific conditions for the most effective preventive management. At the same time the risk of using available products is low. While further research is needed before specific practice guidelines on supplement probiotics and prebiotics, it is equally important that the underlying dietary and lifestyle factors of dysbiosis are addressed at both the individual and societal levels. PMID- 28865968 TI - [Computational medical imaging (radiomics) and potential for immuno-oncology]. AB - The arrival of immunotherapy has profoundly changed the management of multiple cancers, obtaining unexpected tumour responses. However, until now, the majority of patients do not respond to these new treatments. The identification of biomarkers to determine precociously responding patients is a major challenge. Computational medical imaging (also known as radiomics) is a promising and rapidly growing discipline. This new approach consists in the analysis of high dimensional data extracted from medical imaging, to further describe tumour phenotypes. This approach has the advantages of being non-invasive, capable of evaluating the tumour and its microenvironment in their entirety, thus characterising spatial heterogeneity, and being easily repeatable over time. The end goal of radiomics is to determine imaging biomarkers as decision support tools for clinical practice and to facilitate better understanding of cancer biology, allowing the assessment of the changes throughout the evolution of the disease and the therapeutic sequence. This review will develop the process of computational imaging analysis and present its potential in immuno-oncology. PMID- 28865969 TI - [Role and interest of induction chemotherapy for head and neck cancers]. AB - Induction chemotherapy must be integrated in a global approach for locally advanced head and neck cancer. Its use has theoretical advantages but should not compromise locoregional radiotherapy. Induction chemotherapy is a standard for organ preservation with the use of the TPF scheme to avoid total laryngectomy without compromising survival data. It is more controversial in other locally advanced head and neck cancer because concurrent chemoradiotherapy is the standard of care. It may be an option for patients with significant lymph node invasion to reduce the occurrence of distant metastasis. PMID- 28865970 TI - [Description of the GORTEC 2017-03 study: Postoperative stereotactic radiotherapy for early stage oropharyngeal and oral cavity cancer with high risk margin (PHRC K-16-164)]. AB - The GORTEC 2017-03-Stereo-postop study is a phase 2, multicentric, nationwide study, funded by the hospital clinical research program (PHRC). The sponsor is Centre Jean-Perrin in Clermont-Ferrand, in partnership with the GORTEC. The principal investigators are Dr J Biau and Dr M Lapeyre. The main objective is to study severe late toxicity of postoperative stereotactic radiotherapy (6*6Gy) for early stage oropharyngeal and oral cavity cancer with high risk margins. The secondary objectives include acute toxicity, efficacy, nutritional impact and quality of life. The population is adult patients, with pT1 or pT2 squamous cell carcinoma of the oropharynx or oral cavity (except lips), without indication of neck irradiation or concomitant chemotherapy, with at risk margin (R1, less than 5mm or uncertain). Ninety patients will be included over a 2-year period; this was calculated to limit the rate of 2-year severe toxicity at 5 to 15%, with a 2 year local control of at least 80 to 90%. If this study is considered as positive, stereotactic radiotherapy (6*6Gy) could become the third therapeutic option, with brachytherapy and normofractionated intensity-modulated radiotherapy (IMRT), for postoperative irradiation of oropharyngeal and oral cavity cancer with high risk margins. PMID- 28865971 TI - Haploidentical Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome. AB - This study aimed to validate the capability of the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic scoring system to predict outcomes of patients with myelodysplastic syndromes (MDS) who had undergone HLA haploidentical related donor hematopoietic stem cell transplantation (haplo HSCT). We also propose and validate a more suitable prognostic scoring system. A total of 157 patients with MDS who underwent haplo-HSCT were enrolled. The CIBMTR prognostic scoring system could predict the 2-year clinical outcomes, but failed to predict the 100-day clinical outcomes after haplo-HSCT. Our multivariable model identified 2 independent predictors of overall survival: age and monosomal karyotype (MK). Weighted scores of 5, 3, and 2 were assigned to age >=50 years, age 30 to 49 years, and MK, respectively, and a 2-category system was created: low (score <=3) and high (score >3). Our refined prognostic scoring system can predict both the 100-day and 2-year clinical outcomes after haplo-HSCT. Our findings indicate that the CIBMTR prognostic scoring system is predictive of the outcomes of patients with MDS following haplo-HSCT, and that older patients with MDS and/or patients with MK should be closely monitored after haplo-HSCT. PMID- 28865972 TI - High-Dose Melphalan and Stem Cell Transplantation in Patients on Dialysis Due to Immunoglobulin Light-Chain Amyloidosis and Monoclonal Immunoglobulin Deposition Disease. AB - The kidney is the most common organ affected by immunoglobulin light-chain (AL) amyloidosis and monoclonal immunoglobulin deposition disease (MIDD), often leading to end-stage renal disease (ESRD). High-dose melphalan and stem cell transplantation (HDM/SCT) is effective for selected patients with AL amyloidosis, with high rates of complete hematologic response and potential for improved organ dysfunction. Data on tolerability and response to HDM/SCT in patients with ESRD due to AL amyloidosis and MIDD are limited. We analyzed data on toxicity, efficacy, and hematologic and renal response of HDM/SCT in 32 patients with AL amyloidosis and 4 patients with MIDD who were dialysis-dependent for ESRD treated at Boston Medical Center between 1994 and 2016. The most common grade 3/4 nonhematologic toxicities were infections (75%), metabolic abnormalities (56%), mucositis (42%), constitutional symptoms (39%), pulmonary complications (39%), and diarrhea (28%). Treatment related mortality (defined as death within 100 days of SCT) occurred in 8% (3 of 36). A complete hematologic response was achieved in 70% of evaluable patients (19 of 27) at 1 year after HDM/SCT. In the entire cohort, median overall survival (OS) after HDM/SCT was 5.8 years; median OS was 1 year for those who did not achieve a complete hematologic response and 8 years for those who did achieve a complete hematologic response. Twelve patients (33%) underwent kidney transplantation after successful treatment with HDM/SCT at a median of 2.4 years after SCT. HDM/SCT is safe and effective in inducing hematologic complete responses and prolonging survival in patients with ESRD from AL amyloidosis and MIDD. Achievement of a durable hematologic response can make these patients possible candidates for renal transplantation. PMID- 28865974 TI - Vacuolar trafficking and biogenesis: a maturation in the field. AB - The vacuole is a prominent organelle that is essential for plant viability. The vacuole size, and its role in ion homeostasis, protein degradation and storage, place significant demands for trafficking of vacuolar cargo along the endomembrane system. Recent studies indicate that sorting of vacuolar cargo initiates at the ER and Golgi, but not the trans-Golgi network/early endosome, as previously thought. Furthermore, maturation of the trans-Golgi network into pre vacuolar compartments seems to contribute to a major route for plant vacuolar traffic that works by bulk flow and ends with membrane fusion between the pre vacuolar compartment and the tonoplast. Here we summarize recent evidence that indicates conserved and plant-specific mechanisms involved in sorting and trafficking of proteins to this major organelle. PMID- 28865973 TI - Recovery of Pulmonary Function after Allogeneic Hematopoietic Cell Transplantation in Children is Associated with Improved Survival. AB - Abnormal pulmonary function is prevalent in survivors of allogeneic hematopoietic cell transplantation (HCT). Post-transplantation recovery of pulmonary function, and its effect on survival, in children are not known. This retrospective cohort study of 308 children followed for 10 years after HCT at a single institution included 2 groups of patients. Group 1 comprised 188 patients with 3 or more pulmonary function test (PFT) results, of which at least 1 was abnormal, and group 2 comprised 120 patients with 3 or more PFTs, all of which were normal. Pulmonary function normalized post-transplantation in 51 patients (27%) in group 1. Obstructive lung disease, restrictive lung disease, mixed lung disease, and normal pattern were seen in 43%, 25%, 5%, and 27% of patients, respectively, at a median of 5 years (range, 0.5 to 11.9 years) post-transplantation. Lung volumes recovered better than spirometric indices. Pulmonary complications were seen in 80 patients (43%) in group 1. Patients who recovered pulmonary function had better overall survival (P = .006), which did not differ significantly from that in patients in group 2 with normal lung function post-transplantation (P = .80). After adjusting for duration of follow-up, pulmonary complications (P = .01), and lower pretransplantation forced vital capacity z-scores (P = .01) were associated with poor recovery. T cell depletion (P < .001), lower pretransplantation forced expired volume in 1 second z-scores (P = .006), and chronic graft-versus-host disease (P < .001) increased the risk for pulmonary complications. Nonrecovery of lung function with pulmonary complications (P = .03), acute graft-versus-host disease (P = .004), and mechanical ventilation (P < .001) were risk factors for nonrelapse mortality. Normalization of pulmonary function is possible in long term survivors of allogeneic HCT. Strategies to decrease the risk of pulmonary complications may improve outcomes. PMID- 28865975 TI - Membrane nanodomains and microdomains in plant-microbe interactions. AB - During plant-microbe interactions, host cells need to keep stringent control over the approaching pathogens and symbionts. This requires specific spatio-temporal assemblies of pattern recognition receptors and other complex constituents and a strict physical separation of genetically overlapping pathways. Increasing evidence suggests that this is, at least partially, achieved by the formation of nanometer scale membrane platforms that might act as signaling hubs. These and other larger-scale sub-compartments have been termed 'membrane rafts', 'nanodomains' and 'microdomains'. This review focuses on recent advances in understanding these nano-scale signaling platforms during plant-microbe interactions and proposes a common definition meant to facilitate the precise discrimination between different types of membrane domains in the future. PMID- 28865976 TI - From shaping organelles to signalling platforms: the emerging functions of plant ER-PM contact sites. AB - The plant endoplasmic reticulum (ER) defines the biosynthetic site of lipids and proteins destined for secretion, but also contains important signal transduction and homeostasis components that regulate multiple hormonal and developmental responses. To achieve its various functions, the ER has a unique architecture, both reticulated and highly plastic, that facilitates the spatial-temporal segregation of biochemical reactions and the establishment of inter-organelle communication networks. At the cell cortex, the cortical ER (cER) anchors to and functionally couples with the PM through largely static structures known as ER-PM contact sites (EPCS). These spatially confined microdomains are emerging as critical regulators of the geometry of the cER network, and as highly specialized signalling hubs. In this review, we share recent insights into how EPCS regulate cER remodelling, and discuss the proposed roles for plant EPCS components in the integration of environmental and developmental signals at the cER-PM interface. PMID- 28865977 TI - Safety and efficacy of polyurethane vascular grafts for early hemodialysis access. AB - BACKGROUND: Arteriovenous grafts made of polyurethane (PU) have the advantage of early cannulation obviating the placement of a central vein catheter in patients with an acute need for long-term hemodialysis. The aim of the present study was to evaluate the safety, efficacy and complication rate of PU vascular grafts for dialysis access in patients in whom early cannulation was performed. METHODS: Between January 2007 and December 2015, 125 straight brachial-axillary grafts were placed in patients with an acute thrombosis of a previous arteriovenous access. Sixty-four were PU and 61 were polytetrafluoroethylene (PTFE) grafts. Patency and complications rates were compared between the two groups. RESULTS: The median interval from implantation to cannulation was 1 day in the PU group vs 28 days in the PTFE group. Cumulative infection rate at 5 years was 13% and 8% in the PU and the PTFE groups, respectively (P = .6). None of the patients in the PU group developed a pseudoaneurysm necessitating intervention, compared with one patient in the PTFE group. Primary and secondary patency rates did not differ significantly between the two groups. The cumulative median primary patency was 23 months in the PU group vs 26 months in the PTFE group. Median secondary patency was 42 vs 33 months, respectively. Diabetes mellitus was the only factor adversely affecting graft patency in both groups. CONCLUSIONS: PU grafts offer the advantage of early cannulation with infection, pseudoaneurysm formation and patency rates similar to those of the PTFE grafts. PMID- 28865978 TI - A systematic review and meta-analysis of variations in branching patterns of the adult aortic arch. AB - OBJECTIVE: The aortic arch (AA) is the main conduit of the left side of the heart, providing a blood supply to the head, neck, and upper limbs. As it travels through the thorax, the pattern in which it gives off the branches to supply these structures can vary. Variations of these branching patterns have been studied; however, a study providing a comprehensive incidence of these variations has not yet been conducted. The objective of this study was to perform a meta analysis of all the studies that report prevalence data on AA variants and to provide incidence data on the most common variants. METHODS: A systematic search of online databases including PubMed, Embase, Scopus, ScienceDirect, Web of Science, SciELO, BIOSIS, and CNKI was performed for literature describing incidence of AA variations in adults. Studies including prevalence data on adult patients or cadavers were collected and their data analyzed. RESULTS: A total of 51 articles were included (N = 23,882 arches). Seven of the most common variants were analyzed. The most common variants found included the classic branching pattern, defined as a brachiocephalic trunk, a left common carotid, and a left subclavian artery (80.9%); the bovine arch variant (13.6%); and the left vertebral artery variant (2.8%). Compared by geographic data, bovine arch variants were noted to have a prevalence as high as 26.8% in African populations. CONCLUSIONS: Although patients who have an AA variant are often asymptomatic, they compose a significant portion of the population of patients and pose a greater risk of hemorrhage and ischemia during surgery in the thorax. Because of the possibility of encountering such variants, it is prudent for surgeons to consider potential variations in planning procedures, especially of an endovascular nature, in the thorax. PMID- 28865979 TI - Comparison of 30-day readmission rates and risk factors between carotid artery stenting and endarterectomy. AB - OBJECTIVE: The aim of this study was to analyze the rates, reasons, and risk factors of 30-day readmission, both planned and unplanned, after carotid revascularization as well as to evaluate major outcomes associated with those readmissions. METHODS: Using the Premier Healthcare database, we retrospectively identified patients undergoing carotid endarterectomy (CEA) and carotid artery stenting (CAS) between 2009 and 2015. The primary outcome was 30-day all-cause readmission. Secondary outcomes included mortality and overall cost associated with readmissions. Univariate and multivariate analyses were used and further validated using coarsened exact matching on baseline differences between CEA and CAS patients. RESULTS: A total of 95,687 patients underwent carotid revascularization, 13.5% of whom underwent CAS. Crude 30-day readmission rates were 6.5% after CEA vs 6.1% after CAS (P = .10). Stroke, bleeding, pneumonia, and respiratory failure were the most common reasons for readmission after both CEA and CAS (6.7% vs 8.3%, 6.9% vs 5.3%, 3.4% vs 2.4%, and 4.4% vs 3.9%; all P > .05). Myocardial infarction and wound complications were more likely to be an indication for readmission after CEA (4.1% vs 2.5% and 4.1% vs 1.5%, respectively; P < .05). On the other hand, readmissions due to vascular or stent related complications were more likely after CAS compared with CEA (5.8% vs 3.8%; P = .003). On multivariate analysis, CEA was found to be associated with 41% higher odds of readmission than CAS (adjusted odds ratio, 1.41; 95% confidence interval, 1.29-1.54; P < .001). Age, female gender, emergency/urgent procedures, concomitant cardiac procedures, rural hospitals, and Midwest region were significantly associated with 30-day readmission. Other risk factors included major preoperative comorbidities (diabetes, congestive heart failure, renal disease, chronic obstructive pulmonary disease, peripheral vascular disease, and history of cancer) as well as the occurrence of postoperative stroke and renal complications during the index admission and nonhome discharge. Coarsened exact matching between CEA and CAS patients also yielded higher adjusted rates of readmission after CEA (6.2% vs 4.9%; P < .001). On the other hand, patients readmitted after CAS had a longer length of hospital stay (5 days vs 4 days; P = .001), increased readmission mortality (6.2% vs 2.8%; P < .001), and higher rehospitalization costs ($8903 vs $7629; P = .01) compared with those readmitted after CEA. CONCLUSIONS: Our results show that CAS is associated with lower 30-day readmission rates compared with CEA. However, CAS readmissions are more complex and are associated with higher mortality and costs. We have also identified patients who are at high risk of readmissions, which can help focus attention on interventions that can improve the management of these patients and reduce readmission rates. PMID- 28865980 TI - Aneurysm sac expansion is independently associated with late mortality in patients treated with endovascular aneurysm repair. AB - BACKGROUND: Patients undergoing endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms can exhibit variations in sac behavior ranging from complete regression to expansion. We evaluated the impact of sac behavior at 1-year follow up on late survival. METHODS: We used the Vascular Study Group of New England (VSGNE) registry from 2003 to 2011 to identify EVAR patients with 1-year computed tomography follow-up. Aneurysm sac enlargement >=5 mm (sac expansion) and decrease >=5 mm (sac regression) were defined per Society for Vascular Surgery guidelines. Predictors of change in sac diameter and impact of sac behavior on long-term mortality were assessed by multivariable methods. RESULTS: Of 2437 patients who underwent EVAR, 1802 (74%) had complete 1-year follow-up data and were included in the study. At 1 year, 162 (9%) experienced sac expansion, 709 (39%) had a stable sac, and 931 (52%) experienced sac regression. Sac expansion was associated with preoperative renal insufficiency (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.5-8.0; P < .01), urgent repair (OR, 2.7; 95% CI, 1.4 5.1; P < .01), hypogastric coverage (OR, 1.7; 95% CI, 1.1-2.7; P = .02), and type I/III (OR, 16.8; 95% CI, 7.3-39.0; P < .001) or type II (OR, 2.9; 95% CI, 2.0 4.3; P < .001) endoleak at follow-up, and sac expansion was inversely associated with smoking (OR, 0.6; 95% CI, 0.4-0.96; P = .03) and baseline aneurysm diameter (OR, 0.7; 95% CI, 0.6-0.9; P < .001). Sac regression (vs expansion or stable sac) was associated with female gender (OR, 1.8; 95% CI, 1.4-2.4; P < .001) and larger baseline aneurysm diameter (OR, 1.4; 95% CI, 1.2-1.5; P < .001) and inversely associated with type I/III (OR, 0.2; 95% CI, 0.1-0.5; P < .01) or type II endoleak at follow-up (OR, 0.2; 95% CI, 0.2-0.3; P < .001). After risk-adjusted Cox regression, sac expansion was independently associated with late mortality (hazard ratio, 1.5; 95% CI, 1.1-2.0; P = .01), even with adjustment for reinterventions and endoleak during follow-up. Sac regression was associated with lower late mortality (hazard ratio, 0.6; 95% CI, 0.5-0.7; P < .001). Long-term survival was lower (log-rank, P < .001) in patients with sac expansion (98% 1 year and 68% 5-year survival) compared with all others (99% 1-year and 83% 5-year survival). CONCLUSIONS: These data suggest that an abdominal aortic aneurysm sac diameter increase of at least 5 mm at 1 year, although infrequent, is independently associated with late mortality regardless of the presence or absence of endoleak and warrants close observation and perhaps early intervention. PMID- 28865981 TI - Randomized clinical trial of negative pressure wound therapy for high-risk groin wounds in lower extremity revascularization. AB - OBJECTIVE: The surgical site infection (SSI) rate in vascular surgery after groin incision for lower extremity revascularization can lead to significant morbidity and mortality. This trial was designed to study the effect of negative pressure wound therapy (NPWT) on SSI in closed groin wounds after lower extremity revascularization in patients at high risk for SSI. METHODS: A single-center, randomized, controlled trial was performed at an academic tertiary medical center. Patients with previous femoral artery surgical exposure, body mass index of >30 kg/m2 or the presence of ischemic tissue loss were classified as a high risk patient for SSI. All wounds were closed primarily and patients were randomized to either NPWT or standard dressing. The primary outcome of the trial was postoperative 30-day SSI in the groin wound. The secondary outcomes included 90-day SSI, hospital duration of stay, readmissions or reoperations for SSI, and mortality. RESULTS: A total of 102 patients were randomized between August 2014 and December 2015. Patients were classified as at high risk owing to the presence of previous femoral artery cut down (29%), body mass index of >30 kg/m2 (39%) or presence of ischemic tissue loss (32%). Revascularization procedures performed included femoral to distal artery bypass (57%), femoral endarterectomy (18%), femoral to femoral artery crossover (17%), and other procedures (8%). The primary outcome of 30-day SSI was 11% in NPWT group versus 19% in standard dressing group (P = .24). There was a statistically significant shorter mean duration of hospital stay in the NPWT group (6.4 days) compared with the standard group (8.9 days; P = .01). There was no difference in readmission or reoperation for SSI or mortality between the two groups. CONCLUSIONS: This study demonstrated a nonsignificant lower rate of groin SSI in high-risk revascularization patients with NPWT compared with standard dressing. Owing to a lower than expected infection rate, the study was underpowered to detect a difference at the prespecified level. The NPWT group did show significantly shorter mean hospital duration of stay compared with the standard dressing group. PMID- 28865982 TI - Epidemiology of preterm birth. AB - Preterm birth is a worldwide epidemic with a global incidence of 15 million per year. Though rates of preterm birth in the United States have declined over the last decade, nearly 1 in 10 babies is still born preterm. The incidence, gestational age, and underlying etiology of preterm birth is highly variable across different racial and ethnic groups and geographic boundaries. In this article, we review the epidemiology of preterm birth in the United States and globally, with a focus on temporal trends and racial, ethnic, and geographic disparities. PMID- 28865983 TI - Distal radioulnar joint instability. AB - Distal radioulnar joint (DRUJ) instability is a rare but disabling problem. Surgical treatment remains a challenge. The advent of arthroscopic techniques has helped to rebuild the triangular fibrocartilaginous complex (TFCC), especially its deep part. However, isolated TFCC damage is not responsible for instability. Its repair is sometimes not sufficient to restore DRUJ stability, or the chronicity of the injury prevents its direct repair. Open surgical procedures still have a role in these cases. They require a detailed knowledge of the various stabilizers of the DRUJ. Passive and active stabilizers other than the TFCC include the bones, joint capsule, oblique distal bundle of the interosseous membrane and the extensor carpi ulnaris. The objective of this review was to analyze current anatomical and biomechanical data on DRUJ stability. Different arthroscopic and open repair techniques for these structures will be reviewed. Lastly, a decision tree will be presented that can be used to better plan the management of this complex entity, because most of these injuries often occur in combination in RUD instability cases. PMID- 28865984 TI - Impact of surgical intensive care unit interdisciplinary rounds on interprofessional collaboration and quality of care: Mixed qualitative quantitative study. AB - BACKGROUND: Interprofessional collaboration is a key requirement for safe and effective care delivery in the critical care setting. To promote collaboration between care providers, intensive care unit interdisciplinary rounds have been introduced by multiple institutions and subsequent subjective improvements in interprofessional collaboration have been reported. However, only limited data are currently available regarding the impact of these rounds on objective patient care outcomes. OBJECTIVES: The study had two main goals: (i) to evaluate the impact of introducing an interdisciplinary rounding format that formalised the participation of nurses in rounds on the effectiveness of interprofessional collaboration, specifically between nurses and physicians; and (ii) to evaluate a possible impact of adopting these rounds on measurable patient care outcomes. METHODS: General surgery rounds were introduced in our 32-bed medical-surgical intensive care unit. The impact of the rounds on the quality of collaboration was measured using anonymous web-based surveys of nurses and surgeons. Rates of falls and self-extubations (adverse events) were compared during five month pre- and post-intervention periods (August 2014-Jun 2015). RESULTS: Both nurses and physicians reported subjective improvement in collaboration following the introduction of interdisciplinary rounds. Additionally, a decline in both rates of falls and self-extubations was observed in the post-intervention period; however, due to the rarity of these events, neither trend reached statistical significance. CONCLUSIONS: Interdisciplinary rounds provide an attractive model for improving interprofessional collaboration in critical care. Our findings add support to the growing evidence that interdisciplinary rounds improve collaboration and have a positive impact on the quality of patient care delivery. PMID- 28865985 TI - Extended, continuous measures of functional status in community dwelling persons with Alzheimer's and related dementia: Infrastructure, performance, tradeoffs, preliminary data, and promise. AB - BACKGROUND: The past decades have seen phenomenal growth in the availability of inexpensive and powerful personal computing devices. Efforts to leverage these devices to improve health care outcomes promise to remake many aspects of healthcare delivery, but remain in their infancy. NEW METHOD: We describe the development of a mobile health platform designed for daily measures of functional status in ambulatory, community dwelling subjects, including those who have Alzheimer's disease or related neurodegenerative disorders. Using Smartwatches and Smartphones we measure subject overall activity and outdoor location (to derive their lifespace). These clinically-relevant measures allow us to track a subject's functional status in their natural environment over prolonged periods of time without repeated visits to healthcare providers. Functional status metrics are integrated with medical information and caregiver reports, which are used by a caregiving team to guide referrals for physician/APRN/NP care. COMPARISON: with Existing Methods We describe the design tradeoffs involved in all aspects of our current system architecture, focusing on decisions with significant impact on system cost, performance, scalability, and user-adherence. RESULTS: We provide real-world data from current subject enrollees demonstrating system accuracy and reliability. CONCLUSIONS: We document real-world feasibility in a group of men and women with dementia that Smartwatches/Smartphones can provide long-term, relevant clinical data regarding individual functional status. We describe the underlying considerations of this system so that interested organizations can adapt and scale our approach to their needs. Finally, we provide a potential agenda to guide development of future systems. PMID- 28865986 TI - Validation of salivary oxytocin and vasopressin as biomarkers in domestic dogs. AB - BACKGROUND: Oxytocin (OT) and Vasopressin (AVP) are phylogenetically conserved neuropeptides with effects on social behavior, cognition and stress responses. Although OT and AVP are most commonly measured in blood, urine and cerebrospinal fluid (CSF), these approaches present an array of challenges including concerns related to the invasiveness of sample collection, the potential for matrix interference in immunoassays, and whether samples can be collected at precise time points to assess event-linked endocrine responses. NEW METHOD: We validated enzyme-linked immunosorbent assays (ELISAs) for the measurement of salivary OT and AVP in domestic dogs. RESULTS: Both OT and AVP were present in dog saliva and detectable by ELISA and high performance liquid chromatography - mass spectrometry (HPLC-MS). OT concentrations in dog saliva were much higher than those typically detected in humans. OT concentrations in the same samples analyzed with and without sample extraction were highly correlated, but this was not true for AVP. ELISA validation studies revealed good accuracy and parallelism, both with and without solid phase extraction. Collection of salivary samples with different synthetic swabs, or following salivary stimulation or the consumption of food led to variance in results. However, samples collected from the same dogs using different techniques tended to be positively correlated. We detected concurrent elevations in salivary and plasma OT during nursing. COMPARISON WITH EXISTING METHODS: There are currently no other validated methods for measuring OT/AVP in dog saliva. CONCLUSIONS: OT and AVP are present in dog saliva, and ELISAs for their detection are methodologically valid. PMID- 28865987 TI - [The German Statutory Accident Insurance: A successful example of a value-based healthcare structure]. AB - In the mid-1920s Porter and others developed a reform approach for existing health care systems, aiming at a patient-focused, value-based orientation. Improving patient outcomes by attaining, preserving and restoring good health is inherently less costly than dealing with poor health. The authors of the present article will outline that the German statutory accident insurance system, which was already introduced in1884 and is of an evolving nature, reflects key elements of Porter's efficient value-based health care system. The German accident insurance system with its statutory mandate limited to the prevention and rehabilitation of work-related damage to one's health can also serve as a model for other larger health care insurance systems. Prevention and rehabilitation is pursued using all appropriate means to achieve the set goals of protecting and restoring individual health. In line with these objectives, the statutory health insurance controls the process in terms of the required care quality. The components of a complex health care system, usually managed by a variety of different institutions, are consolidated. Thus it can be ensured that in both prevention and rehabilitation all services that are necessary to keep focussing the value "individual health" rather than indemnities are applied. PMID- 28865988 TI - Sentinel lymph node biopsy for thin melanomas under the American Joint Committee on Cancer 8th edition cancer staging system. PMID- 28865989 TI - Risk of major limb amputation in diabetic foot ulcer and accompanying disease: A meta-analysis. AB - BACKGROUND: Limb amputation in diabetic patients raises important issues regarding low quality of life and survival rates. This meta-analysis aimed to identify predictive factors accompanying diseases with high major amputation rates in diabetic patients. METHODS: A systematic literature review and meta analysis were performed using MEDLINE, EMBASE and Cochrane databases. Eight variables were extracted from the included studies and evaluated according to major amputation rates. The Newcastle-Ottawa scale (NOS) was utilized to assess the quality of the studies. RESULTS: The search strategy identified 101 publications. After screening, 10 articles were selected for review. Hypertension, ischemic heart disease, cerebrovascular disease, and peripheral vascular disease were identified as predictive variables of higher major amputation rates. CONCLUSIONS: Although further investigation of long-term and prospective studies is needed, we identified four variables as predisposing factors for higher major amputation in diabetic patients through meta-analysis. PMID- 28865992 TI - Looking forward to safer HGVs: The impact of mirrors on driver reaction times. AB - Heavy Goods Vehicle (HGV) collisions are responsible for a disproportionate number of urban vulnerable road user casualties (VRU - cyclists and pedestrians). Blind-spots to the front and side of HGVs can make it difficult (sometimes impossible) to detect close proximity VRUs and may be the cause of some collisions. The current solution to this problem is to provide additional mirrors that can allow the driver to see into the blind-spots. However, keeping track of many mirrors requires frequent off-road glances which can be difficult to execute during demanding driving situations. One suggestion is that driving safety could be improved by redesigning cabs in order to reduce/remove blind-spot regions, with the aim of reducing the need for mirrors, and increasing detection rates (and thereby reducing collisions). To examine whether mirrors delay driver responses we created a series of simulated driving tasks and tested regular car drivers and expert HGV drivers. First we measured baseline reaction times to objects appearing when not driving ('Parked'). Participants then repeated the task whilst driving through a simulated town (primary driving tasks were steering, braking, and following directional signs): driving slowed reaction times to objects visible in mirrors but not to objects visible through the front windscreen. In a second experiment cognitive load was increased, this slowed RTs overall but did not alter the pattern of responses across windows and mirrors. Crucially, we demonstrate that the distribution of mirror RTs can be captured simply by the mirror's spatial position (eccentricity). These findings provide robust evidence that drivers are slower reacting to objects only visible in eccentric mirrors compared to direct viewing through the front windscreen. PMID- 28865991 TI - Highly porous scaffolds of PEDOT:PSS for bone tissue engineering. AB - : Conjugated polymers have been increasingly considered for the design of conductive materials in the field of regenerative medicine. However, optimal scaffold properties addressing the complexity of the desired tissue still need to be developed. The focus of this study lies in the development and evaluation of a conductive scaffold for bone tissue engineering. In this study PEDOT:PSS scaffolds were designed and evaluated in vitro using MC3T3-E1 osteogenic precursor cells, and the cells were assessed for distinct differentiation stages and the expression of an osteogenic phenotype. Ice-templated PEDOT:PSS scaffolds presented high pore interconnectivity with a median pore diameter of 53.6+/-5.9um and a total pore surface area of 7.72+/-1.7m2.g-1. The electrical conductivity, based on I-V curves, was measured to be 140uS.cm-1 with a reduced, but stable conductivity of 6.1uS.cm-1 after 28days in cell culture media. MC3T3-E1 gene expression levels of ALPL, COL1A1 and RUNX2 were significantly enhanced after 4weeks, in line with increased extracellular matrix mineralisation, and osteocalcin deposition. These results demonstrate that a porous material, based purely on PEDOT:PSS, is suitable as a scaffold for bone tissue engineering and thus represents a promising candidate for regenerative medicine. STATEMENT OF SIGNIFICANCE: Tissue engineering approaches have been increasingly considered for the repair of non-union fractions, craniofacial reconstruction or large bone defect replacements. The design of complex biomaterials and successful engineering of 3-dimensional tissue constructs is of paramount importance to meet this clinical need. Conductive scaffolds, based on conjugated polymers, present interesting candidates to address the piezoelectric properties of bone tissue and to induce enhanced osteogenesis upon implantation. However, conductive scaffolds have not been investigated in vitro in great measure. To this end, we have developed a highly porous, electrically conductive scaffold based on PEDOT:PSS, and provide evidence that this purely synthetic material is a promising candidate for bone tissue engineering. PMID- 28865990 TI - ECM turnover-stimulated gene delivery through collagen-mimetic peptide-plasmid integration in collagen. AB - : Gene therapies have great potential in regenerative medicine; however, clinical translation has been inhibited by low stability and limited transfection efficiencies. Herein, we incorporate collagen-mimetic peptide (CMP)-linked polyplexes in collagen scaffolds to increase DNA stability by up to 400% and enable tailorable in vivo transgene expression at 100-fold higher levels and 10 fold longer time periods. These improvements were directly linked to a sustained interaction between collagen and polyplexes that persisted during cellular remodeling, polyplex uptake, and intracellular trafficking. Specifically, incorporation of CMPs into polyethylenimine (PEI) polyplexes preserved serum exposed polyplex-collagen activity over a period of 14days, with 4 orders-of magnitude more intact DNA present in CMP-modified polyplex-collagen relative to unmodified polyplex-collagen after a 10day incubation under cell culture conditions. CMP-modification also altered endocytic uptake, as indicated by gene silencing studies showing a nearly 50% decrease in transgene expression in response to caveolin-1 silencing in modified samples versus only 30% in unmodified samples. Furthermore, cellular internalization studies demonstrated that polyplex-collagen association persisted within cells in CMP polyplexes, but not in unmodified polyplexes, suggesting that CMP linkage to collagen regulates intracellular transport. Moreover, experiments in an in vivo repair model showed that CMP modification enabled tailoring of transgene expression from 4 to 25days over a range of concentrations. Overall, these findings demonstrate that CMP decoration provides substantial improvements in gene retention, altered release kinetics, improved serum-stability, and improved gene activity in vivo. This versatile technique has great potential for multiple applications in regenerative medicine. STATEMENT OF SIGNIFICANCE: In this work, we demonstrate a novel approach for stably integrating DNA into collagen scaffolds to exploit the natural process of collagen remodelling for high efficiency non-viral gene delivery. The incorporation of CMPs into DNA polyplexes, coupled with the innate affinity between CMPs and collagen, not only permitted improved control over polyplex retention and release, but also provided a series of substantial and highly unique benefits via the stable and persistent linkage between CMP polyplexes and collagen fragments. Specifically, CMP-modification of polyplexes was demonstrated to (i) control release for nearly a month, (ii) improve vector stability under physiological-like conditions, and (iii) provide ligands able to efficiently transfer genes via endocytic collagen pathways. These unique properties overcome key barriers inhibiting non-viral gene therapy. PMID- 28865994 TI - Resting-state functional connectivity: An emerging method for the study of language networks in post-stroke aphasia. AB - Aphasia results both from direct effects of focal damage to eloquent cortical areas as well as dysfunction of interconnected remote areas within the language network. Resting-state functional MRI (rsfMRI) can be used to examine functional connectivity (FC) within these networks. Herein we review publications, which applied rsfMRI to understand network pathology in post stroke aphasia. A common finding in this research is an acute disruption of connectivity within the language network, which is correlated with loss of language function and tends to resolve with recovery from aphasia. All studies are limited by small sample sizes, heterogeneous patient characteristics and a wide range of analytical approaches, which further hinder deduction of common patterns across studies. One recent large-scale study examining FC and behavior across various cognitive domains, however, has made substantial progress with the description of a "network phenotype of stroke injury", which consists of a disruption of interhemispheric connectivity and reduced segregation of intrahemispheric networks. Unlike in other domains, language functions showed substantial dependence on intact left intrahemispheric connectivity (Siegel, Ramsey et al., 2016). In the future, such analyses of network pathology might support prognosis and development of effective treatment strategies in individual patients with aphasia. PMID- 28865993 TI - Genetic neutrophil deficiency ameliorates cerebral ischemia-reperfusion injury. AB - Neutrophils respond rapidly to cerebral ischemia and are thought to contribute to inflammation-mediated injury during stroke. Using myeloid Mcl1 knockout mice as a model of genetic neutrophil deficiency, we investigated the contribution of neutrophils to stroke pathophysiology. Myeloid Mcl1 knockout mice were subjected to transient middle cerebral artery occlusion and infarct size was assessed by MRI after 24h reperfusion. Immune cell mobilization and infiltration was assessed by flow cytometry. We found that myeloid Mcl1 knockout mice had significantly reduced infarct size when compared to heterozygous and wild type control mice (MyMcl1+/+: 78.0mm3; MyMcl1+/-: 83.4mm3; MyMcl1-/-: 55.1mm3). This was accompanied by a nearly complete absence of neutrophils in the ischemic hemisphere of myeloid Mcl1 knockout mice. Although myeloid Mcl1 knockout mice were protected from cerebral infarction, no significant differences in neurological deficit or the mRNA expression of inflammatory genes (TNFalpha, IL 1beta, and MCP1) were detected. Inhibition of neutrophil chemotaxis using CXCR2 pepducin treatment partially reduced neutrophil mobilization and recruitment to the brain after stroke, but did not reduce infarct size 24h after transient MCA occlusion. These data confirm that neutrophils have an important role in infarct development during stroke pathophysiology, and suggest that complete deficiency, but not partial inhibition, is necessary to prevent neutrophil-mediated injury during stroke. PMID- 28865995 TI - Formation of the Legionella-containing vacuole: phosphoinositide conversion, GTPase modulation and ER dynamics. AB - The environmental bacterium Legionella pneumophila replicates in free-living amoeba as well as in alveolar macrophages upon inhalation of bacteria-laden aerosols. Resistance of the opportunistic pathogen to macrophages is a prerequisite to cause a severe pneumonia called Legionnaires' disease. L. pneumophila grows intracellularly in a unique, ER-associated compartment, the Legionella-containing vacuole (LCV). The bacterial Icm/Dot type IV secretion system represents an essential virulence factor, which translocates approximately 300 "effector proteins" into protozoan or mammalian host cells. Some of these effectors contribute to the formation of the LCV by targeting conserved host factors implicated in membrane dynamics, such as phosphoinositide lipids and small GTPases. Here we review recent findings on the role of phosphoinositides, small and large GTPases as well as ER dynamics for pathogen vacuole formation and intracellular replication of L. pneumophila. PMID- 28865996 TI - Comparative Perioperative Outcomes in Septuagenarians and Octogenarians Undergoing Radical Cystectomy for Bladder Cancer-Do Outcomes Differ? AB - BACKGROUND: Treatment choice for muscle invasive bladder cancer continues to be radical cystectomy. However, radical cystectomy carries a relatively high risk of morbidity and mortality compared with other urological procedures. OBJECTIVE: To compare surgical complications following radical cystectomy in septuagenarians and octogenarians. DESIGN, SETTING, AND PARTICIPANTS: The National Surgical Quality Improvement Program database (2009-2013) was used to identify patients who were 70 yr and older and underwent radical cystectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The data were analyzed for demographics and comorbidities, and compared for complications, including pulmonary, thromboembolic, wound, and cardiac complications. Patients who were 70-79 yr of age were compared with those 80 yr and older. Univariate and multivariate analyses were completed. RESULTS AND LIMITATIONS: A total of 1710 patients aged >=70 yr met our inclusion criteria. Of them, 28.8% (n=493) were 80 yr and older, while 71.2% (n=1217) were between 70 and 79 yr old. Operative time (338.4 vs 307.2min, p=0.0001) and the length of stay (11.9 vs 10.4 d, p=0.0016) were higher in the octogenarian group. The intra- and postoperative transfusion rates, reoperative rates, wound dehiscence rates, and pneumonia, sepsis, and myocardial infarction rates were similar between the two groups. The wound infection rate (7.3% vs 4.1%, p=0.01) was higher in the septuagenarians and mortality rate (4.3% vs 2.3%, p=0.04) was higher in the octogenarian group. CONCLUSIONS: Radical cystectomy can safely be performed in octogenarians without increased cardiac, pulmonary, and thromboembolic complications when compared with septuagenarians. These patients need to be counseled that the mortality rate is slightly higher compared with that in septuagenarians. Chronological age alone should not be used to decide on offering radical cystectomy. PATIENT SUMMARY: We looked at complications following radical cystectomy in patients aged 80 yr and older. We found that there was no significant difference for wound, cardiac, or pulmonary complications, but there was an increased risk of mortality in this age group. PMID- 28865997 TI - Functional characterisation of the methionine sulfoxide reductase repertoire in Trypanosoma brucei. AB - To combat the deleterious effects that oxidation of the sulfur atom in methionine to sulfoxide may bring, aerobic cells express repair pathways involving methionine sulfoxide reductases (MSRs) to reverse the above reaction. Here, we show that Trypanosoma brucei, the causative agent of African trypanosomiasis, expresses two distinct trypanothione-dependent MSRs that can be distinguished from each other based on sequence, sub-cellular localisation and substrate preference. One enzyme found in the parasite's cytosol, shows homology to the MSRA family of repair proteins and preferentially metabolises the S epimer of methionine sulfoxide. The second, which contains sequence motifs present in MSRBs, is restricted to the mitochondrion and can only catalyse reduction of the R form of peptide-bound methionine sulfoxide. The importance of these proteins to the parasite was demonstrated using functional genomic-based approaches to produce cells with reduced or elevated expression levels of MSRA, which exhibited altered susceptibility to exogenous H2O2. These findings identify new reparative pathways that function to fix oxidatively damaged methionine within this medically important parasite. PMID- 28865998 TI - Quantitative Antisense Screening and Optimization for Exon 51 Skipping in Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder, is caused by mutations in the dystrophin (DMD) gene. Exon skipping is a therapeutic approach that uses antisense oligonucleotides (AOs) to modulate splicing and restore the reading frame, leading to truncated, yet functional protein expression. In 2016, the US Food and Drug Administration (FDA) conditionally approved the first phosphorodiamidate morpholino oligomer (morpholino)-based AO drug, eteplirsen, developed for DMD exon 51 skipping. Eteplirsen remains controversial with insufficient evidence of its therapeutic effect in patients. We recently developed an in silico tool to design antisense morpholino sequences for exon skipping. Here, we designed morpholino AOs targeting DMD exon 51 using the in silico tool and quantitatively evaluated the effects in immortalized DMD muscle cells in vitro. To our surprise, most of the newly designed morpholinos induced exon 51 skipping more efficiently compared with the eteplirsen sequence. The efficacy of exon 51 skipping and rescue of dystrophin protein expression were increased by up to more than 12-fold and 7-fold, respectively, compared with the eteplirsen sequence. Significant in vivo efficacy of the most effective morpholino, determined in vitro, was confirmed in mice carrying the human DMD gene. These findings underscore the importance of AO sequence optimization for exon skipping. PMID- 28866000 TI - Maternal Characteristics Associated With Social Support in At-Risk Mothers of Premature Infants. AB - OBJECTIVE: To identify maternal characteristics associated with social support among new mothers of premature infants who are at social-environmental risk. DESIGN: Cross-sectional analysis of intake interview data from a larger randomized controlled trial of a mother-premature infant developmentally based intervention. SETTING: Two urban community-based hospitals. PARTICIPANTS: One hundred ninety-four women (50% Black, 50% Hispanic) who recently gave birth to otherwise healthy, premature (29-34 weeks gestational age) infants. Participants had at least 2 of 10 social-environmental risks (e.g., poverty). METHODS: In hospital interviews were conducted to obtain data on sociodemographic characteristics, prior mental health problems, and social support through the use of the Personal Resources Questionnaire 2000. Bivariate and multivariable linear regression analyses were performed to identify factors associated with social support. RESULTS: Mean Personal Resources Questionnaire 2000 scores were significantly lower for Hispanic than Black participants (92.0 vs. 96.0, respectively), those interviewed in Spanish versus English (89.8 vs. 96.1), those with low versus age-appropriate education levels (89.7 vs. 95.3), multiparous versus primiparous women (92.7 vs. 96.0), and those reporting versus not reporting histories of mental health problems (84.7 vs. 94.8). After multivariable adjustment, only younger age, Spanish language preference, multiparity, and a history of mental health problems were associated with significantly lower levels of social support (R2 = 0.18). CONCLUSION: More programs should be made available to provide social support to at-risk mothers, especially younger mothers, and those with limited English ability, other children at home, or histories of mental health problems. Nurses should target these mothers for additional support during their premature infants' NICU stay. PMID- 28866001 TI - On "Empowering the Girl Child, Improving Global Health". PMID- 28866002 TI - Reply. PMID- 28865999 TI - A Novel Vaccine Targeting Glypican-3 as a Treatment for Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) has a high morbidity and mortality rate worldwide, with limited treatment options. Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored glycoprotein that is overexpressed in most HCC tissues but not in normal tissues. GPC3-targeting antibody therapy shows limited response in a clinical trial due to the lack of a tumor-specific cytotoxic T lymphocyte (CTL) response. Here, in C57/B6 mice, we demonstrated that intravenous infusion of GPC3-coupled lymphocytes (LC/GPC3+) elicited robust GPC3 specific antibody and CTL responses, which effectively restricted proliferation and lysed cultured-HCC cells. Treatment with LC/GPC3+ induced durable tumor regression in HCC-bearing C57/B6 mice. Administration of LC/GPC3+ induced elevated levels of the cytotoxic T cell bioactive factors tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), granzyme B, and perforin, and substantially increased the number of infiltrating CD8+ T cells in tumor tissues. Moreover, immune responses elicited by LC/GPC3+ selectively suppressed GPC3+ tumors, but didn't affect the GPC3- tumors in BALB/c mice. Our findings provide the first preclinical evidence that intravenous infusion of the LC/GPC3+ complex can induce a strong anti-HCC effect through regulating systemic and local immune responses. These results indicate that the LC/GPC3+ complex could be developed as precision therapeutics for HCC patients in the future. PMID- 28866003 TI - Anterior Chamber Angle and Anterior Segment Structure of Eyes in Children With Early Stages of Retinopathy of Prematurity. PMID- 28866004 TI - Neurodevelopmental outcomes of infants with very low birth weights are associated with the severity of their extra-uterine growth retardation. AB - BACKGROUND: For infants with very low birth weights (VLBW), their neurodevelopmental outcomes are thought to be associated with extra-uterine growth retardation (EUGR). In this study, based on a single institute, we analyzed the association between different levels or severity of EUGR of VLBW infants and their neurodevelopmental outcomes later at a corrected age of 24 months. METHODS: This is a hospital-based retrospective cohort study. The severity of EUGR was classified into three categories according to the z-score of discharge weight: z < -2.0, <-2.5, and <-3.0. The outcomes were assessed using the Bayley Scales of Infant Development-II (BSID-II) at a corrected age of 24 months. We then estimated the association of EUGR with low mental developmental index (MDI) or low psychomotor developmental index (PDI). Multiple logistic regression and stratified analyses were used to adjust for the possible confounding factors. RESULTS: In total, 224 VLBW infants were enrolled in this study from 1997 to 2006. In the univariate analysis, EUGR for weight at discharge from hospital was associated with MDI <85 at the corrected age of 24 months, and this association was related to the severity of EUGR (z < -2.5, OR: 1.92 (1.04 3.53); z < -3.0, OR: 2.83 (1.26-6.36)). In addition, the relationship was not confounded by gender nor small for gestational age. The stratified analysis against hemodynamic significant patent ductus arteriosus also revealed that EUGR was an independent predictor for neurodevelopmental outcomes. CONCLUSION: In VLBW preterm infants, EUGR was significantly associated with low MDI scores assessed at a corrected age of 24 months. Early evaluation and recognition of EUGR should be emphasized when caring for preterm infants. PMID- 28866005 TI - Discrete memory impairments in largely pure chronic users of MDMA. AB - Chronic use of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") has repeatedly been associated with deficits in working memory, declarative memory, and executive functions. However, previous findings regarding working memory and executive function are inconclusive yet, as in most studies concomitant stimulant use, which is known to affect these functions, was not adequately controlled for. Therefore, we compared the cognitive performance of 26 stimulant-free and largely pure (primary) MDMA users, 25 stimulant-using polydrug MDMA users, and 56 MDMA/stimulant-naive controls by applying a comprehensive neuropsychological test battery. Neuropsychological tests were grouped into four cognitive domains. Recent drug use was objectively quantified by 6-month hair analyses on 17 substances and metabolites. Considerably lower mean hair concentrations of stimulants (amphetamine, methamphetamine, methylphenidate, cocaine), opioids (morphine, methadone, codeine), and hallucinogens (ketamine, 2C-B) were detected in primary compared to polydrug users, while both user groups did not differ in their MDMA hair concentration. Cohen's d effect sizes for both comparisons, i.e., primary MDMA users vs. controls and polydrug MDMA users vs. controls, were highest for declarative memory (dprimary=.90, dpolydrug=1.21), followed by working memory (dprimary=.52, dpolydrug=.96), executive functions (dprimary=.46, dpolydrug=.86), and attention (dprimary=.23, dpolydrug=.70). Thus, primary MDMA users showed strong and relatively discrete declarative memory impairments, whereas MDMA polydrug users displayed broad and unspecific cognitive impairments. Consequently, even largely pure chronic MDMA use is associated with decreased performance in declarative memory, while additional deficits in working memory and executive functions displayed by polydrug MDMA users are likely driven by stimulant co-use. PMID- 28866006 TI - The natural selection of metabolism and mass selects allometric transitions from prokaryotes to mammals. AB - The exponents of inter-specific allometries for several life history (metabolism, lifespan, reproductive rate, survival) and ecological (population density, home range) traits may evolve from the spatial dimensionality (d) of the intra specific interactive competition that selects net assimilated energy into mass, with 1/4 exponents being the two-dimensional (2D) case of the more general 1/2d (Witting, 1995). While the exponents for mass-specific metabolism cluster around the predicted -1/4 and -1/6 in terrestrial and pelagic vertebrates, the allometries of mobile organisms are more diverse than the prediction. An exponent around zero has been reported for protists and protozoa (Makarieva et al., 2005, 2008), and the exponent appears to be strongly positive in prokaryotes with a value of about 5/6 (DeLong et al., 2010). I show that the natural selection of metabolism and mass is sufficient to explain exponents for mass-specific metabolism that decline from 5/6 over zero to -1/6 in 3D, and from 3/4 over zero to -1/4 in 2D. These results suggest that mass-specific metabolism is selected as the pace of the resource handling that generates net energy for self-replication and the selection of mass, with the decline in the metabolic exponent following from a decline in the importance of mass-specific metabolism for the selection of mass. The body mass variation in prokaryotes is found to be selected from primary variation in mass-specific metabolism, while the variation in multicellular animals is selected from primary variation in the handling and/or densities of the underlying resources, with protists and protozoa being selected as an intermediate lifeform. PMID- 28866007 TI - Forward and backward evolutionary processes and allele frequency spectrum in a cancer cell population. AB - A cancer grows from a single cell, thereby constituting a large cell population. In this work, we are interested in how mutations accumulate in a cancer cell population. We provide a theoretical framework of the stochastic process in a cancer cell population and obtain near exact expressions of allele frequency spectrum or AFS (only continuous approximation is involved) from both forward and backward treatments under a simple setting; all cells undergo cell divisions and die at constant rates, b and d, respectively, such that the entire population grows exponentially. This setting means that once a parental cancer cell is established, in the following growth phase, all mutations are assumed to have no effect on b or d (i.e., neutral or passengers). Our theoretical results show that the difference from organismal population genetics is mainly in the coalescent time scale, and the mutation rate is defined per cell division, not per time unit (e.g., generation). Except for these two factors, the basic logic is very similar between organismal and cancer population genetics, indicating that a number of well established theories of organismal population genetics could be translated to cancer population genetics with simple modifications. PMID- 28866008 TI - Evolutionary rescue of a parasite population by mutation rate evolution. AB - The risk of antibiotic resistance evolution in parasites is a major problem for public health. Identifying factors which promote antibiotic resistance evolution is thus a priority in evolutionary medicine. The rate at which new mutations enter the parasite population is one important predictor; however, mutation rate is not necessarily a fixed quantity, as is often assumed, but can itself evolve. Here we explore the possible impacts of mutation rate evolution on the fate of a disease circulating in a host population, which is being treated with drugs, the use of which varies over time. Using an evolutionary rescue framework, we find that mutation rate evolution provides a dramatic increase in the probability that a parasite population survives treatment in only a limited region, while providing little or no advantage in other regions. Both epidemiological features, such as the virulence of infection, and population genetic parameters, such as recombination rate, play important roles in determining the probability of evolutionary rescue and whether mutation rate evolution enhances the probability of evolutionary rescue or not. While efforts to curtail mutation rate evolution in parasites may be worthwhile under some circumstances, our results suggest that this need not always be the case. PMID- 28866009 TI - Long-Term Functional Outcomes in Military Service Members and Veterans After Traumatic Brain Injury/Polytrauma Inpatient Rehabilitation. AB - OBJECTIVE: To determine the effect of the established polytrauma/traumatic brain injury (TBI) infrastructure on immediate posttreatment functional gains, the long term sustainability of any gains, and participation-related community reintegration outcomes in a baseline cohort of patients 8 years postadmission. DESIGN: Retrospective review and prospective repeated measures of an inception cohort. SETTING: Polytrauma rehabilitation center (PRC). PARTICIPANTS: Patients consecutively admitted to the PRC inpatient rehabilitation unit during its first full fiscal year, 2006 (N=44). INTERVENTIONS: The PRC infrastructure and formalized rehabilitation for polytrauma/TBI. MAIN OUTCOME MEASURES: FIM scores at admission, discharge, 3 months, and 8 years postdischarge; participation related socioeconomic factors reflecting community reintegration 8 years after admission. RESULTS: Functional gains were statistically significantly increased from admission to discharge. Improvements were maintained at both 3 months postdischarge and 8 years postdischarge. The socioeconomic data collected at 8 year follow-up showed >50% either competitively employed or continuing their education and 100% living in a noninstitutionalized setting. CONCLUSIONS: This study addresses a concern regarding the long-term functional outcomes of rehabilitation patients treated by the established infrastructure of the Polytrauma System of Care inpatient rehabilitation centers. The results suggest that polytrauma/TBI rehabilitation care using a comprehensive, integrated approach is effective and durable in achieving functional gains and successful community reintegration within our initial PRC cohort. Follow-up of subsequent fiscal year cohorts would add to the validity of these outcome findings. PMID- 28866010 TI - Contextual Facilitators and Barriers of Community Reintegration Among Injured Female Military Veterans: A Qualitative Study. AB - OBJECTIVE: To understand the facilitators and barriers to community reintegration (CR) among injured female veterans. DESIGN: Phenomenologic qualitative design. SETTING: Community. PARTICIPANTS: Community-dwelling female veterans with physical and/or psychological injury (N=13). INTERVENTIONS: None. MAIN OUTCOME MEASURES: None. RESULTS: Conventional content analysis revealed 3 types of facilitators, including (1) strong social support, (2) impactful programs, and (3) protective personal beliefs. Six types of barriers included (1) inadequate services, (2) lack of access to services, (3) poor social support, (4) difficulty trusting others, (5) nonsupportive personal beliefs, and (6) injury factors. Multiple environmental and personal factors acted as facilitators and barriers to CR. Findings are relatively consistent with previous veteran and civilian community reintegration research that indicates the importance of health-related services, attitudes of others, and social support. However, women in this study reported being effected by many of these facilitators and barriers because of their sex. CONCLUSIONS: This study supports the need to foster social support among injured female veterans throughout the rehabilitation process to promote CR. Long-term social support can be gained by incorporating services (eg, adjunctive therapies, recreation, other social programming) into the rehabilitation repertoire to help with CR for all veterans, particularly women. PMID- 28866011 TI - Development of a Computerized Adaptive Test of Children's Gross Motor Skills. AB - OBJECTIVES: To (1) develop a computerized adaptive test for gross motor skills (GM-CAT) as a diagnostic test and an outcome measure, using the gross motor skills subscale of the Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT-GM) as the candidate item bank; and (2) examine the psychometric properties and the efficiency of the GM-CAT. DESIGN: Retrospective study. SETTING: A developmental center of a medical center. PARTICIPANTS: Children with and without developmental delay (N=1738). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The CDIIT-GM contains 56 universal items on gross motor skills assessing children's antigravity control, locomotion, and body movement coordination. RESULTS: The item bank of the GM-CAT had 44 items that met the dichotomous Rasch model's assumptions. High Rasch person reliabilities were found for each estimated gross motor skill for the GM-CAT (Rasch person reliabilities =.940-.995, SE=.68-2.43). For children aged 6 to 71 months, the GM-CAT had good concurrent validity (r values =.97-.98), adequate to excellent diagnostic accuracy (area under receiver operating characteristics curve =.80-.98), and moderate to large responsiveness (effect size =.65-5.82). The averages of items administered for the GM-CAT were 7 to 11, depending on the age group. CONCLUSIONS: The results of this study support the use of the GM-CAT as a diagnostic and outcome measure to estimate children's gross motor skills in both research and clinical settings. PMID- 28866012 TI - What Is the Longitudinal Profile of Impairments and Can We Predict Difficulty Caring for the Profoundly Affected Arm in the First Year Poststroke? AB - OBJECTIVES: To establish the longitudinal profile of impairments of body functions and activity limitations of the arm, and to evaluate potential predictors of difficulty caring for the profoundly affected arm poststroke. DESIGN: Prospective cohort study. SETTING: Stroke services. PARTICIPANTS: People unlikely to regain functional use of the arm (N=155) were recruited at 2 to 4 weeks poststroke, and followed up at 3, 6, and 12 months. Potential predictors at baseline were hypertonicity, pain, motor control, mood, sensation/perception, age, and stroke severity. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Difficulty caring for the arm (Leeds Arm Spasticity Impact Scale), pain, hypertonicity, range of movement, arm function, and skin integrity. Multivariable linear regression identified the best fitting model for predicting Leeds Arm Spasticity Impact Scale score at 12 months. RESULTS: There were 110 participants (71%) reviewed at 1 year. There was a large variation in the profile of arm functions and activity limitations. Inability or severe difficulty caring for the arm affected 29% of participants. Hypertonicity developed in 77%, with severe hypertonicity present in 25%. Pain was reported by 65%, 94% developed shoulder contracture, and 6% had macerated skin. Difficulty caring for the arm increased with age, greater level of hypertonicity, and stroke classification; collectively, these factors accounted for 33% of the variance in Leeds Arm Spasticity Impact Scale scores. CONCLUSIONS: At 1 year poststroke, there was a high incidence of impairments of body functions and activity limitations in people with a profoundly affected arm. Individual profiles were very variable and although some predisposing factors have been identified, it remains difficult to predict who is at greatest risk. PMID- 28866013 TI - Contrasting cellular damage after Blue-IRIS and Femto-LASIK in cat cornea. AB - Blue-intra-tissue refractive index shaping (Blue-IRIS) is a new approach to laser refractive correction of optical aberrations in the eye, which alters the refractive index of the cornea rather than changing its shape. Before it can be implemented in humans, it is critical to establish whether and to what extent, Blue-IRIS damages the cornea. Here, we contrasted the impact of -1.5 D cylinder refractive corrections inscribed using either Blue-IRIS or femtosecond laser in situ keratomileusis (femto-LASIK) on corneal cell viability. Blue-IRIS was used to write a -1.5 D cylinder gradient index (GRIN) lens over a 2.5 mm by 2.5 mm area into the mid-stromal region of the cornea in six freshly-enucleated feline eyes. The same correction (-1.5 D cylinder) was inscribed into another four cat eyes using femto-LASIK. Six hours later, all corneas were processed for histology and stained for terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) and p-gamma-H2AX to label damaged cells. In Blue-IRIS treated corneas, no tissue was removed and TUNEL-stained cells were confined to the laser focal zone in the stroma. In femto-LASIK, photoablation removed 14 MUm of anterior stroma, but in addition, TUNEL-positive cells clustered across the femto-flap, the epithelium at the flap edges and the stroma below the ablation zone. Keratocytes positive for p-gamma-H2AX were seen adjacent to all Blue-IRIS focal zones, but were completely absent from femto-LASIK-treated corneas. Unlike femto-LASIK, Blue-IRIS attains refractive correction in the cornea without tissue removal and only causes minimal, localized keratocyte death within the laser focal zones. In addition, Blue-IRIS induced DNA modifications associated with phosphorylation of gamma-H2AX in keratocytes adjacent to the laser focal zones. We posit that this p-gamma-H2AX response is related to alterations in chromatin structure caused by localized changes in osmolarity, a possible mechanism for the induced refractive index changes. PMID- 28866014 TI - Characterization of a novel polysaccharide isolated from Rosa roxburghii Tratt fruit and assessment of its antioxidant in vitro and in vivo. AB - In this study, a novel water-soluble polysaccharide (RRTP1-1) was obtained from Rosa roxburghii Tratt fruit through the ultrasonic-assisted extraction followed by anion-exchange and size-exclusion chromatography purification. The primary structure of RRTP1-1 was investigated by UV, FT-IR, HPLC, GC-MS, 1H and 13C NMR spectroscopy. Chemical composition analysis revealed that RRTP1-1 had an average molecular weight of 97.58kDa and consisted of Man, Rha, GlcA, GalA, Glc, Gal, Ara and Xyl in a molar ratio of 2.88:1.39:2.83:1.00:69.11:3.04:2.52:3.41. This polysaccharide was proven to be a kind of glucan, owning a backbone structure of >6)-alpha-d-Glcp-(1->6)-alpha-d-Glcp-(1->. Congo red test indicated that RRTP1-1 had no triple helix structure. Antioxidation tests performed in vitro revealed that RRTP1-1 possessed obviously DPPH, hydroxyl and superoxide radicals scavenging activities. Furthermore, antioxidant assays in vivo showed that RRTP1 1 at 200 or 400mg/kg dose could significantly enhance the activities of antioxidant enzymes (CAT, SOD, and GSH-Px), increase TAOC values, and decrease the LPO and MDA levels in different degrees in the serum of D-Gal aging-induced mice. The present results suggested that RRTP1-1 could be a new source of natural antioxidants for applications in functional foods and dietary supplemental products. PMID- 28866015 TI - Chitosan as biomaterial in drug delivery and tissue engineering. AB - Chitin is one of the most abundant polysaccharide found on earth. The deacetylated form of chitin viz. chitosan has been reported for its various important pharmacological properties and its role in tissue engineering and regenerative medicine is also well documented. Chitosan based bone graft substitutes are biocompatible, biodegradable, osteoconductive, osteoinductive and structurally similar to bone, with excellent mechanical strength and cost effectiveness. Chitosan based hydrogels and wound healing bandages have also found a great market in the field of medicine. More recently, chitosan has gained popularity for its use as a matrix molecule for drug delivery and also finds an upcoming utility in the area of dentistry. The present article has tried to review the latest research on chitosan based tissue engineering constructs, drug delivery vehicles as well as dental care products. An attempt has also been made to discuss the various modifications of chitosan that enhance its use for a given set of applications which would pave a way for future applied research in the field of biomedical innovation and regenerative medicine. PMID- 28866016 TI - Disintegration of collagen fibrils by Glucono-delta-lactone: An implied lead for disintegration of fibrosis. AB - Excess accumulation of collagen (fibrosis) undergoes self-aggregation, which leads to fibrillar collagen, on the extracellular matrix is the hallmark of a number of diseases such as keloids, hypertrophic scars, and systemic scleroderma. Direct inhibition or disintegration of collagen fibrils by small molecules offer a therapeutic approach to prevent or treat the diseases related to fibrosis. Herein, the anti-fibrotic property of Glucono-delta-lactone (GdL), known as acidifier, on the fibrillation and its disintegration of collagen was investigated. As collagen fibrillation is pH dependent, the pH modulation property of GdL is attractive to inhibit self-association of collagen. Optical density and microscopic data indicate that GdL elicits concentration-dependent fibril inhibition and also disintegrates pre-formed collagen fibrils. The simultaneous pH analysis showed that the modulation(lowering) of pH by GdL is the primary cause for its anti-fibrotic activity. The intact triple helical structure of collagen upon treatment of GdL suggests that collagen fibril disintegration can be achieved without affecting the native structure of collagen which is essential for any anti-fibrotic agents. Saturation transfer difference (STD) NMR result reveals that GdL is in proximity to collagen. The present results thus suggest that GdL provides a lead to design novel anti-fibrotic agents for the pathologies related to collagen deposition. PMID- 28866017 TI - Diatomite as a novel composite ingredient for chitosan film with enhanced physicochemical properties. AB - Practical applications of biopolymers in different industries are gaining considerable increase day by day. But still, these biopolymers lack important properties in order to meet the industrial demands. In the same regard, in the current study, chitosan composite films are produced by incorporating diatomite soil at two different concentrations. In order to obtain a homogeneous film, glutaraldehyde was supplemented to chitosan solution as a cross-linker. Compositing diatomaceous earth to chitosan film resulted in improvement of various important physicochemical properties compared to control such as; enhanced film wettability, increase elongation at break and improved thermal stability (264-277 degrees C). The microstructure of the film was observed to haveconsisted of homogeneously distributed blister-shaped structures arised due to the incorporation of diatomite. The incorporation of diatomite did not influence the overall antioxidant activity of the composite films, which can be ascribe to the difficulty radicals formation. Chitosan film incorporated with increasing fraction of diatomite revealed a notable enhancement in the antimicrobial activity. Additionally with the present study, for the first time possible interactions between chitosan/diatomite were determined via quantum chemical calculations. Current study will be helpful in giving a new biotechnological perspective to diatom in terms of its successful application in hydrophobic composite film production. PMID- 28866018 TI - Molecular level insight into the effect of triethyloctylammonium bromide on the structure, thermal stability, and activity of Bovine serum albumin. AB - Understanding the interactions between protein and ionic liquids (IL) is vital in order to avail the ILs in biological applications. In this study, we have investigated the influence of triethyloctylammonium bromide on the structure, stability, and activity of Bovine Serum Albumin (BSA) using different spectroscopic methods Fluorescence and circular dichroism measurements revealed that BSA appears to be in a non-native compact structure in the presence of IL (up to concentration 0.02M). But beyond that limit (0.02M), the protein was found to be in an unfolded state. The results are supported by dynamic light scattering (DLS) measurements and also esterase-like activity test proves non-native or unfolded form of protein at a higher concentration of IL. In addition, molecular docking study is carried out to find the possible binding sites of IL with BSA. PMID- 28866019 TI - Comparative mitochondrial genome analysis of Spilarctia subcarnea and other noctuid insects. AB - This study was performed to better understand the phylogenetic relationships within the lepidopteran superfamily Noctuoidea. The mitochondrial genome (mitogenome) has been extensively used for studying phylogenetic relationships at different taxonomic levels. In this study, the complete mitogenome of Spilarctia subcarnea (Noctuoidea: Erebidae) was sequenced and annotated. The mitogenome is 15,441bp in length, containing 13 typical protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs) and a noncoding control region (CR). The order and orientation of genes of S. subcarnea mitogenome with the order trnM-trnI-trnQ-nad2 is different from the ancestral insects in which trnM is located between trnQ and nad2 (trnI-trnQ-trnM-nad2). The phylogenetic relationships based on mitochondrial sequences using Bayesian inference and Maximum likelihood methods showed that S. subcarnea was closely related to Lemyra melli, supporting that S. subcarnea belongs to Erebidae. These analyses confirm that Lymantriidae should be included as subfamilies within Erebidae. The Erebidae was sister to (Nolidae+(Euteliidae+Noctuidae)); Notodontidae is sister to the other families of Noctuoidea in our study. PMID- 28866020 TI - Sleep quality during pregnancy: A meta-analysis. AB - Women's sleep quality has been reported to change during pregnancy; prevalence estimates of poor sleep quality during pregnancy vary widely. To further understand the observed variation of findings, we conducted a meta-analysis to quantify the prevalence of poor sleep quality during pregnancy. Articles (N = 24) that reported prevalence of poor sleep quality as captured by the Pittsburgh sleep quality index (PSQI) >= 5 were included, with a total of 11,002 participants contributing data. PubMed, PsycINFO, and Web of Science databases were systematically searched. Results indicated that the average PSQI score during pregnancy was 6.07, 95% confidence interval (CI) [5.30, 6.85], and 45.7%, 95% CI [36.5%, 55.2%], of pregnant women experienced poor sleep quality. Longitudinal studies indicated that sleep quality decreased from second (M = 5.31, SE = 0.40) to third trimester (M = 7.03, SE = 0.85) by 1.68 points, 95% CI [0.42, 2.94]. Gestational age moderated the average PSQI scores and prevalence of PSQI scores >=5; older samples reported higher mean PSQI scores and higher prevalence of poor sleep quality. Clinicians should be aware that some reduction in sleep quality is expected during pregnancy, but complaints of very poor sleep quality could require intervention. Future research should examine various factors underlying poor sleep quality during pregnancy. PMID- 28866021 TI - Low-frequency oscillations in default mode subnetworks are associated with episodic memory impairments in Alzheimer's disease. AB - Disruptions to functional connectivity in subsystems of the default mode network are evident in Alzheimer's disease (AD). Functional connectivity estimates correlations in the time course of low-frequency activity. Much less is known about other potential perturbations to this activity, such as changes in the amplitude of oscillations and how this relates to cognition. We examined the amplitude of low-frequency fluctuations in 44 AD patients and 128 cognitively normal participants and related this to episodic memory, the core deficit in AD. We show higher amplitudes of low-frequency oscillations in AD patients. Rather than being compensatory, this appears to be maladaptive, with greater amplitude in the ventral default mode subnetwork associated with poorer episodic memory. Perturbations to default mode subnetworks in AD are evident in the amplitude of low-frequency oscillations in the resting brain. These disruptions are associated with episodic memory demonstrating their behavioral and clinical relevance in AD. PMID- 28866022 TI - Eradication of HT-29 colorectal adenocarcinoma cells by controlled photorelease of CO from a CO-releasing polymer (photoCORP-1) triggered by visible light through an optical fiber-based device. AB - The gaseous signaling molecule carbon monoxide (CO) has recently been recognized for its wide range of physiological activity as well as its antineoplastic properties. However, site-specific delivery of this noxious gas presents a major challenge in hospital settings. In this work, a visible light-sensitive CO releasing molecule (photoCORM) derived from manganese(I) and 2 (quinolyl)benzothiazole (qbt) namely, [Mn(CO)3(qbt)(4-vpy)](CF3SO3) (1), has been co-polymerized within a gas-permeable HEMA/EGDMA hydrogel. The resulting photoactive CO-releasing polymer (photoCORP-1) incorporates 1 such that neither the carbonyl complex nor its photoproduct(s) exits the polymer at any time. The material can be triggered to photorelease CO remotely by low-power broadband visible light (<1mWcm-2) with the aid of fiber optics technology. The CO photorelease rates of photoCORP-1 (determined by spectrophotometry) can be modulated by both the concentration of 1 in the hydrogel and the intensity of the light. A CO-delivery device has been assembled to deliver CO to a suspension of human colorectal adenocarcinoma cells (HT-29) under the control of visible light and the extent of CO-induced apoptotic death of the cancer cells has been determined via Annexin V/Propidium iodide stain and flow cytometry. This photoactive CO-releasing polymer could find use in delivering controlled doses of CO to cellular targets such as malignant tissues in remote parts of the body. PMID- 28866023 TI - Where Do Transrectal Ultrasound- and Magnetic Resonance Imaging-guided Biopsies Miss Significant Prostate Cancer? AB - OBJECTIVE: To identify the location of missed significant prostate cancer (sPCa) lesions by transrectal ultrasound-guided biopsy (TRUSbx) and multiparametric magnetic resonance imaging-guided biopsy (mpMRIbx) in men undergoing repeat biopsies. MATERIALS AND METHODS: A total of 289 men with prior negative TRUSbx underwent multiparametric magnetic resonance imaging. The location of any suspicious lesion was registered and scored using Prostate Imaging Reporting and Data System version 1 classification according to the likelihood of being sPCa. All patients underwent repeat transrectal ultrasound-guided biopsy (reTRUSbx) and targeted mpMRIbx (image fusion) of any suspicious lesion. Biopsy results were compared and the locations of missed sPCa lesions were registered. Cancer significance was defined as (1) any core with a Gleason score of >6, (2) cancer core involvement of >=50% and for reTRUSbx on patient level, and (3) the presence of >=3 positive cores. RESULTS: Of the 289 patients, prostate cancer was detected in 128 (44%) with 88 (30%) having sPCa. Overall, 165 separate prostate cancer lesions were detected with 100 being sPCa. Of these, mpMRIbx and reTRUSbx detected 90% (90/100) and 68% (68/100), respectively. The majority of sPCa lesions (78%) missed by primary TRUSbx were located either anteriorly or in the apical region. Missed sPCa lesions at repeat biopsy were primarily located anteriorly (84%) for reTRUSbx (n = 27/32) and posterolateral midprostatic (60%) for mpMRIbx (n = 6/10). CONCLUSION: Both TRUSbx and mpMRIbx missed sPCa lesions in specific segments of the prostate. Missed sPCa lesions at repeat biopsy were primarily located anteriorly for TRUSbx and posterolateral midprostatic for mpMRIbx. Localization of these segments may improve biopsy techniques in men undergoing repeat biopsies. PMID- 28866024 TI - CON4EI: CONsortium for in vitro Eye Irritation testing strategy - EpiOcularTM time-to-toxicity (EpiOcular ET-50) protocols for hazard identification and labelling of eye irritating chemicals. AB - Assessment of acute eye irritation potential is part of the international regulatory requirements for testing of chemicals. The objective of the CON4EI (CONsortium for in vitro Eye Irritation testing strategy) project was to develop tiered testing strategies for eye irritation assessment for all drivers of classification. A set of 80 reference chemicals (38 liquids and 42 solids) was tested with eight different alternative methods. Here, the results obtained with reconstructed human cornea-like epithelium (RhCE) EpiOcularTM in the EpiOcular time-to-toxicity Tests (Neat and Dilution ET-50 protocols) are presented. The primary aim of this study was to evaluate whether test methods can discriminate chemicals not requiring classification for serious eye damage/eye irritancy (No Category) from chemicals requiring classification and labelling for Category 1 and Category 2. In addition, the predictive capacity in terms of in vivo drivers of classification was investigated. The chemicals were tested in two independent runs by MatTek In Vitro Life Science Laboratories. Results of this study demonstrate very high specificity of both test protocols. With the existing prediction models described in the SOPs, the specificity of the Neat and Dilution method was 87% and 100%, respectively. The Dilution method was able to correctly predicting 66% of GHS Cat 2 chemicals, however, prediction of GHS Cat 1 chemicals was only 47%-55% using the current protocols. In order to achieve optimal prediction for all three classes, a testing strategy was developed which combines the most predictive time-points of both protocols and for tests liquids and solids separately. Using this new testing strategy, the sensitivity for predicting GHS Cat 1 and GHS Cat 2 chemicals was 73% and 64%, respectively and the very high specificity of 97% was maintained. None of the Cat 1 chemicals was underpredicted as GHS No Category. Further combination of the EpiOcular time-to toxicity protocols with other validated in vitro systems evaluated in this project, should enable significant reduction and even possible replacement of the animal tests for the final assessment of the irritation potential in all of the GHS classes. PMID- 28866026 TI - The peroxisome proliferator-activated receptor pan-agonist bezafibrate suppresses microvascular inflammatory responses of retinal endothelial cells and vascular endothelial growth factor production in retinal pigmented epithelial cells. AB - A randomized clinical trial showed the beneficial effects of the selective peroxisome proliferator-activated receptor (PPAR)-alpha agonist, fenofibrate, in reducing the progression of diabetic retinopathy independent of serum lipid levels. All subtypes of PPAR (PPAR-alpha, PPAR-gamma, and PPAR-beta/delta) have been reported to play a key role in microvascular inflammation and angiogenesis. Therefore, the agonistic function of fenofibrate against the PPAR-alpha has been suggested to contribute to its medicinal effect. Furthermore, bezafibrate is a fibrate drug commonly used as a lipid-lowering agent to treat hyperlipidemia and acts as a pan-agonist of all PPARs subtypes. However, the effects of bezafibrate in diabetic retinopathy remain unclear. Therefore, the purpose of this study was to investigate the effects of bezafibrate on retinal microvascular inflammation. Bezafibrate was not cytotoxic against human retinal microvascular endothelial cells (HRMECs) and human retinal pigment epithelial cells (ARPE-19 cells) treated with <100 and 200MUM bezafibrate, respectively. In HRMECs, the expression levels of tumor necrosis factor (TNF)-alpha-induced monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 were significantly suppressed by bezafibrate in a dose dependent manner. TNF-alpha-induced nuclear translocation of nuclear factor (NF) kappaB p65 and cell migration were also significantly inhibited in bezafibrate treated HRMECs. Furthermore, bezafibrate treatment significantly suppressed interleukin (IL)-1beta-induced vascular endothelial growth factor (VEGF) production in ARPE-19 cells. These results suggest that bezafibrate has beneficial effects on retinal microvascular inflammation. Our study demonstrates the therapeutic potential of bezafibrate for managing diabetic retinopathy. PMID- 28866027 TI - Cortisol treatment affects locomotor activity and swimming behaviour of male smallmouth bass engaged in paternal care: A field study using acceleration biologgers. AB - Paternal care, where the male provides sole care for the developing brood, is a common form of reproductive investment among teleost fish and ubiquitous in the Centrarchidae family. Throughout the parental care period, nesting males expend energy in a variety of swimming behaviours, including routine and burst swimming, vigilantly monitoring the nest area and protecting the brood from predators. Parental care is an energetically demanding period, which is presumably made even more difficult if fish are exposed to additional challenges such as those arising from human disturbance, resulting in activation of the hypothalamic-pituitary interrenal axis (i.e., elevation of cortisol). To study this situation, we examined the effects of experimental manipulation of the stress hormone cortisol on locomotor activity and behaviour of nest guarding male smallmouth bass (Micropterus dolomieu). We exogenously elevated circulating cortisol levels (via intracoelomic implants) and attached tri-axial accelerometers to wild smallmouth bass for three days. During the recovery period (i.e., <=4h post-release), cortisol-treated fish exhibited significantly reduced locomotor activity and performed significantly less burst and routine swimming relative to control fish, indicating cortisol uptake was rapid, as were the associated behavioural responses. Post-recovery (i.e., >4h post-release), fish with high cortisol exhibited lower locomotor activity and reduced routine swimming relative to controls. Fish were less active and reduced routine and burst swimming at night compared to daylight hours, an effect independent of cortisol treatment. Collectively, our results suggest that cortisol treatment (as a proxy for anthropogenic disturbance and stress) contributed to altered behaviour, and consequently cortisol-treated males decreased parental investment in their brood, which could have potential fitness implications. PMID- 28866025 TI - Muller cells and diabetic retinopathy. AB - Muller cells are one of the primary glial cell types found in the retina and play a significant role in maintaining retinal function and health. Since Muller cells are the only cell type to span the entire width of the retina and have contact to almost every cell type in the retina they are uniquely positioned to perform a wide variety of functions necessary to maintaining retinal homeostasis. In the healthy retina, Muller cells recycle neurotransmitters, prevent glutamate toxicity, redistribute ions by spatial buffering, participate in the retinoid cycle, and regulate nutrient supplies by multiple mechanisms. Any disturbance to the retinal environment is going to influence proper Muller cell function and well being which in turn will affect the entire retina. This is evident in a disease like diabetic retinopathy where Muller cells contribute to neuronal dysfunction, the production of pro-angiogenic factors leading to neovascularization, the set up of a chronic inflammatory retinal environment, and eventual cell death. In this review, we highlight the importance of Muller cells in maintaining a healthy and functioning retina and discuss various pathological events of diabetic retinopathy in which Muller cells seem to play a crucial role. The beneficial and detrimental effects of cytokine and growth factor production by Muller cells on the microvasculature and retinal neuronal tissue will be outlined. Understanding Muller cell functions within the retina and restoring such function in diabetic retinopathy should become a cornerstone for developing effective therapies to treat diabetic retinopathy. PMID- 28866028 TI - Long term impairment of cognitive functions and alterations of NMDAR subunits after continuous microwave exposure. AB - OBJECTIVE: The long term effects of continuous microwave exposure cannot be ignored for the simulation of the real environment and increasing concerns about the negative cognitive effects of microwave exposure. METHODS: In this study, 220 male Wistar rats were exposed by a 2.856GHz radiation source with the average power density of 0, 2.5, 5 and 10mW/cm2 for 6min/day, 5days/week and up to 6weeks. The MWM task, the EEG analysis, the hippocampus structure observation and the western blot were applied until the 12months after microwave exposure to detect the spatial learning and memory abilities, the cortical electrical activity, changes of hippocampal structure and the NMDAR subunits expressions. RESULTS: Results found that the rats in the 10mW/cm2 group showed the decline of spatial learning and memory abilities and EEG disorders (the decrease of EEG frequencies, and increase of EEG amplitudes and delta wave powers). Moreover, changes of basic structure and ultrastructure of hippocampus also found in the 10 and 5mW/cm2 groups. The decrease of NR 2A, 2B and p-NR2B might contribute to the impairment of cognitive functions. CONCLUSIONS: Our findings suggested that the continuous microwave exposure could cause the dose-dependent long term impairment of spatial learning and memory, the abnormalities of EEG and the hippocampal structure injuries. The decrease of NMDAR key subunits and phosphorylation of NR 2B might contribute to the cognitive impairment. PMID- 28866029 TI - Similarities in smell and taste preferences in couples increase with relationship duration. AB - Numerous studies point to partners' congruence in various domains and note an increase in their compatibility over time. However, none have explored a shift in chemosensory perception related to relationship duration. Here, we examined the relationship between the time heterosexual couples have spent together and the degree to which they share their gustatory and olfactory preferences. Additionally, we investigated whether these preferences are associated with relationship satisfaction. One-hundred couples aged from 18 to 68 years being together for a period between 3 and 540 months rated the pleasantness of a wide variety of olfactory and gustatory stimuli. We showed that both taste and smell preferences are more similar the longer couples have been in a relationship. We also observed a very interesting trend in terms of smell preferences, with relationship satisfaction being negatively related to congruence in smell preferences between partners. We discuss these results from the perspective of evolutionary psychology. PMID- 28866030 TI - Dietitians' perceptions of the healthiness of packaged food. AB - The aim of this cross-sectional study was to determine the factors that influence Australian dietitians' perceptions of the healthiness of a sample of packaged foods. Participant dietitians (n = 120) rated the healthiness (1, less healthy to 10, more healthy), of seven packaged foods (bread, confectionary, breakfast cereal, flavoured yoghurt, curry, spread and crumble) based on information obtained from an ingredient list and nutrient information panel (NIP). Influences on each food's rating were explored via Likert-scale and open-response questions. There was variation in the healthiness rating of all foods, however, least so for confectionary and crumble. Bread (M = 7.39 +/- 1.44) and confectionary (M = 1.33 +/- 0.69) were rated the most and least healthy foods respectively. Crumble was rated significantly (p = 0.03) healthier by those with more experience (>=6 vs. <=5 years). No other differences were detected. Highly reported influences on healthiness were sugar, total fat, sodium and saturated fat values and the ingredient list. Content analysis identified 13 categories of information not provided on the NIP that influenced participants' ratings. References to the Australian Guide to Healthy Eating food groups, micronutrients not listed as ingredients, comparisons to other foods, and fibre were most common among the sample. These results have implications for research or public health policy where expert opinion of the healthiness of food is used as a reference measure. PMID- 28866031 TI - Emotional eating is related with temperament but not with stress biomarkers in preschool children. AB - Emotional eating (EE) corresponds to a change in eating behavior in response to distress and results in an increase of food intake (overeating (EOE)) or in food avoidance (undereating (EUE)). EE has been related to temperament (i.e. negative emotionality) and dysregulated stress biomarkers in school-aged children; parenting has been understood to influence this relationship in older children. The aim of the study was to investigate to which extent stress biomarkers and negative emotionality are related to EE and to understand the role of parenting in this relationship. The sample consisted of 271 children aged 2-6 years of the Swiss cohort study SPLASHY. We assessed the child's EE, negative emotionality and parenting by parent based reports. Salivary samples were collected over two days to analyze cortisol and salivary alpha-amylase levels. From the whole sample of children, 1.1% showed EOE and 32.9% EUE. Negative emotionality was related to EOE and EUE (0.13 (CI 0.06, 021), p < 0.001; 0.25 (CI 0.14, 0.35), p < 0.001). There was no relationship between stress biomarkers and EE and parenting had any moderating role (all p > 0.05). Similar to a Danish study, parents reported more often EUE than EOE of their child. Both are related to the temperament. Even though the course of EE has not yet been well documented, we conclude that a certain subgroup of children with difficult temperament could be at-risk for eat and weight regulation problems in later childhood. PMID- 28866032 TI - Intracardiac Echocardiography for Endovascular Left Atrial Appendage Closure: Is it Ready for Primetime? PMID- 28866033 TI - Very Late Restenosis Following Bioresorbable Scaffold Implantation. PMID- 28866034 TI - Bioabsorbable Stents: A Solution in Search of a Problem? PMID- 28866035 TI - Neoatherosclerosis as the Cause of Late Failure of a Bioresorbable Vascular Scaffold at 8 Months. PMID- 28866037 TI - Very Late Restenosis of a BVS Implanted in a Degenerated Saphenous Vein Graft. PMID- 28866038 TI - Native Aortic Valve Thrombosis Leading to ST-Segment Elevation Myocardial Infarction. PMID- 28866036 TI - Bioresorbable Vascular Scaffolds for Patients With In-Stent Restenosis: The RIBS VI Study. AB - OBJECTIVES: This study sought to assess the value of bioresorbable vascular scaffolds (BVS) in patients with in-stent restenosis (ISR). BACKGROUND: Currently both drug-eluting stents (DES) and drug-eluting balloons (DEB) are recommended in patients with ISR. However, the value of BVS in this setting remains unclear. METHODS: RIBS VI (Restenosis Intra-stent: drug-eluting Balloon vs everolimus eluting Stent) was a prospective multicenter study (19 Spanish sites) that included 141 patients treated with BVS for either bare-metal stent (BMS) ISR or DES-ISR. Late angiography was scheduled at 6 to 9 months. Inclusion/exclusion criteria were similar to those used in the RIBS IV (patients with DES-ISR) and RIBS V (patients with BMS-ISR) trials, where DEB (n = 249) was compared with everolimus (EES)-DES (n = 249). Results of BVS in RIBS VI were compared with those obtained with DEB and EES in the RIBS IV and V trials. RESULTS: On late angiography (n = 134; 95% of eligible) the in-segment minimal lumen diameter (primary endpoint) was 1.87 +/- 0.5 mm, late lumen loss was 0.23 +/- 0.4 mm, and restenosis rate was 11%. At 1-year follow-up (100% of patients) no patient died, 4 (2.8%) experienced a myocardial infarction, and 16 (11.3%) required target lesion revascularization. One patient (0.7%) who discontinued antiplatelet therapy experienced definitive BVS thrombosis. Freedom from cardiac death, myocardial infarction, and target lesion revascularization was 86%. The minimal lumen diameter at follow-up after BVS was similar to that obtained with DEB (1.88 +/- 0.6 mm; p = NS) but smaller than that achieved after EES (2.16 +/- 0.7 mm; p < 0.001). Likewise, target lesion revascularization rates after BVS were similar to those seen with DEB (10.4%) but higher than with EES (3.2%; p < 0.001). Results remained unchanged after adjusting for potential confounders in baseline characteristics. CONCLUSIONS: This study suggests the safety and efficacy of BVS in patients with ISR. In this challenging anatomic scenario BVS obtained late angiographic and clinical results similar to DEB but inferior to EES. (Restenosis Intrastent: Bioresorbable Vascular Scaffolds Treatment [RIBS VI]; NCT02672878). PMID- 28866039 TI - Asymptomatic Large Thrombus Formation in Drug-Eluting Stent 2 Days After Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction Patient. PMID- 28866040 TI - Percutaneous Treatment of a Giant Infected Femoral Artery Pseudoaneurysm. PMID- 28866041 TI - Transcatheter Closure of Aortic Anastomosis Leak Resulting in Patent Cabrol Shunt After Aortic Replacement. PMID- 28866042 TI - Intracardiac Echocardiography From the Left Atrium for Procedural Guidance of Transcatheter Left Atrial Appendage Occlusion. AB - OBJECTIVES: The aim of this study was to compare the efficacy and safety of intracardiac echocardiography (ICE) from the left atrium (LA) with transesophageal echocardiography (TEE) for procedural guidance of transcatheter left atrial appendage occlusion (LAAO). BACKGROUND: TEE with general anesthesia is the current gold standard to guide LAAO. By the use of ICE from the LA, LAAO can be performed in local anesthesia and may potentially have advantages over TEE. METHODS: A single-center, cohort study of patients undergoing LAAO with the Amplatzer Cardiac Plug or Amulet (St. Jude Medical, St. Paul, Minnesota). Procedures were guided by ICE from the LA with local anesthesia (n = 109) or TEE using general anesthesia (n = 107). All patients had pre-procedural cardiac computed tomography. Efficacy outcomes were technical success, procedural success, and peridevice leakage at TEE 8 weeks after LAAO. Safety outcome was a composite of periprocedural complications. RESULTS: Technical success was achieved in 99% of both the TEE and ICE group. Procedural success was similar between groups: 94.4% success rate in the TEE-guided group, and 94.5% in the ICE guided group. Major periprocedural complications occurred in 4.7% of the TEE group and 1.8% of the ICE group. Rate and degree of peridevice leak did not differ between groups at follow-up. Turnover time in the catheter laboratory, and contrast use were reduced with ICE. CONCLUSIONS: LA ICE to guide LAAO as compared with TEE appears to be effective and safe, without increased procedure-related complications. The rate of peridevice leak is low and similar to TEE-guided procedures. Time spent in the catheterization room may decrease substantially. PMID- 28866043 TI - Clinical Factors Predicting Detection of T790M Mutation in Rebiopsy for EGFR Mutant Non-small-cell Lung Cancer. AB - BACKGROUND: T790M, a secondary epidermal growth factor receptor (EGFR) mutation, accounts for approximately 50% of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs). To facilitate the use of third-generation EGFR-TKIs to potentially overcome T790M-mediated resistance, we evaluated the clinical factors influencing the incidence of T790M mutation. PATIENTS AND METHODS: We retrospectively screened patients with non-small-cell lung cancer harboring EGFR mutations with progressive disease who were rebiopsied between January 2013 and December 2016. Factors influencing T790M status were evaluated by univariate and multivariate analysis. RESULTS: Among 131 rebiopsied patients for whom EGFR mutation status was available, 58 (44%) had T790M mutations. Patient characteristics at rebiopsy were not significantly different between T790M positive and -negative groups, except for surgical history (postsurgery recurrence). Total duration of EGFR-TKI treatment before rebiopsy, TKI-free interval, EGFR-TKI treatment history immediately before rebiopsy, continuation of initial EGFR-TKI beyond progressive disease, progression-free survival after initial TKI treatment, and rebiopsy site (other than fluid samples) significantly influenced T790M status. The incidence of T790M mutation was shown by multivariate analysis to be significantly higher in patients with postsurgery recurrence and total duration of EGFR-TKI treatment >= 1 year before rebiopsy (odds ratio, 4.2; 95% confidence interval, 1.3-15.7 and odds ratio, 4.4; 95% confidence interval, 1.1-19.8, respectively). CONCLUSION: Postsurgery recurrence and longer total duration of EGFR-TKI treatment before rebiopsy may represent useful predictive markers for T790M detection. In patients with these clinical factors, rebiopsies are more recommended to detect T790M mutation. PMID- 28866044 TI - Investigation of the preventive effect of Sijunzi decoction on mitomycin C induced immunotoxicity in rats by 1H NMR and MS-based untargeted metabolomic analysis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sijunzi decoction (SJZD) is a well known traditional Chinese prescription used for the treatment of gastrointestinal disorders and immunity enhancement. It has been found to indeed improve life quality of chemotherapy patients and extensive used in clinical conbined with chemotherapeutics for the treatment of cancer. AIM OF THE STUDY: The aim of this study was to investigate the preventive effect of the immunotoxicity of SJZD on mitomycin C (MMC) and the metabolic mechanism of action. MATERIALS AND METHODS: NMR and MS-based metabolomics approaches were combined for monitoring MMC-induced immunotoxicity and the protective effect of SJZD. Body weight change and mortality, histopathological observations and relative viscera weight determinations of spleen and thymus, sternum micronucleus assay and hematological analysis were used to confirm the immunotoxicity and attenuation effects. An OPLS DA approach was used to screen potential biomarkers of immunotoxicity and the MetaboAnalyst and KEGG PATHWAY Database were used to investigate the metabolic pathways. RESULTS: 8 biomarkers in plasma samples, 19 in urine samples and 10 in spleen samples were identified as being primarily involved in amino acid metabolism, carbohydrate metabolism and lipid metabolism. The most critical pathway was alanine, aspartate and glutamate metabolism. CONCLUSIONS: The variations in biomarkers revealed the preventive effect of the immunotoxicity of SJZD on MMC and significant for speculating the possible metabolic mechanism. PMID- 28866045 TI - Corticosteroid inhibits chemokines production in systemic sclerosis patients. AB - In this study, we evaluated glucocorticoids (GC) effects on cytokine/chemokine levels in serum samples and peripheral blood mononuclear cell (PBMC) production from systemic sclerosis (SSc) patients. We evaluated cytokine and chemokine levels in serum samples from SSc patients taking or not taking systemic glucocorticoids. PBMCs response to methylprednisolone (MP) was examined from 15 SSc patients and 8 healthy control subjects following PBMC stimulation with anti CD3/CD28. Cytokine (IFN-gamma, TNF, IL-2, IL-4, IL-6, IL-10, and IL-17A) and chemokine (CXCL8/IL-8, CCL5/RANTES, CXCL9/MIG, CCL2/MCP-1, and CXCL10/IP-10) levels were quantified in serum and in PBMC culture supernatants by CBA or ELISA. Compared with patients not taking corticosteroids, we did not observe any significant differences in cytokines/chemokines serum levels in patients using systemic corticosteroids. After stimulation with anti-CD3/CD28, PBMCs treated with MP (100MUM), showed a significant reduction of CCL2/MCP-1 (p=0.001), CCL5/RANTES (p=0.04), and CXCL8/IL-8 (p=0.003) levels in SSc patients. In PBMC from healthy controls, we observed decreased IFN-gamma, TNF, IL-2, and IL-10 levels after MP treatment, compared with stimulated condition (p<0.01 for all). However in SSc patients, we did not find any significant reduction in these cytokine levels after MP treatment. In conclusion, CCL2/MCP-1, CCL5/RANTES, and CXCL8/IL-8 are chemokines that are potentially modulated by corticosteroids in vitro in SSc patients, but no effect was observed on IL-2, IL-4, IL-6, IL-10, IL 17A, TFN, and IFN-gamma secretion. These results suggest a potential effect of GCs on SSc treatment and may reflect the benefit of their use in some patients. PMID- 28866046 TI - Formaldehyde alters triglyceride synthesis and very low-density lipoprotein secretion in a time-dependent manner. AB - Formaldehyde is a common indoor air pollutant that is toxic to the liver. This study aimed to investigate the effects of formaldehyde on triglyceride metabolism in human hepatocellular carcinoma cells (HepG2). Cell viability was detected using a MTT (3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide) assay. Following treatment with different concentrations of formaldehyde for 24 and 48h, the intra and extra-hepatocellular triglyceride (TG) content was determined using a chemical-enzymatic method; Western blotting was used to detect the levels of fatty acid synthesis and VLDL-related proteins. Our results showed that cell viability significantly decreased after formaldehyde treatment (0.5-12.5mM, 24/48h). Extracellular TG levels in the hepatocytes increased after formaldehyde treatment at 0.004mM-0.1mM for 24h. SREBP-1c, ACC, FASN, and MTP, CES3 and DGAT1 proteins increased significantly after 24h of formaldehyde treatment. Intracellular TG levels decreased for 48h treatment of formaldehyde. AMPKalpha increased significantly in all tested groups and p-AMPK increased significantly after 0.1mM formaldehyde treatment for 48h. Our results indicated that short-term formaldehyde exposure balances triglyceride metabolism by promoting hepatocellular TG synthesis and VLDL secretion; Long-term formaldehyde disturbs the TG metabolism balance in the hepatocytes. PMID- 28866047 TI - Mathematical models in cancer therapy. AB - In this article, deterministic mathematical models are derived from biochemical models within a human cell in two distinct cases, for comparison: healthy cell and cancerous cell. The former model is based in the cell cycle model by Novak and Tyson and its adaptation by Conradie, and makes use of the MAPK cascade pathway and the PI3K/AKT pathway for signalling transduction, to create a wider updated model for the regulation of a healthy cell. The latter model, for the cancer cell, is derived from the healthy cell model by altering specific pathways and interpreting the outcome in the light of literature in cancer. This last study is done in two approaches: simulation of common deregulations and specific cancer simulation, colon cancer. After studying both models, we propose targeting therapies and simulate their consequences. We thus explore mathematical modelling efficacy and usefulness in providing enough information from which to derive ideas for therapies. The purpose is to validate mathematics, once again, as a powerful tool with which one can model the underlying nature of chaotic systems and extract useful conclusions to real-life problems. PMID- 28866048 TI - Subcutaneous Lipoatrophy and Skin Depigmentation Secondary to TMJ Intra-Articular Corticosteroid Injection. AB - Chronic orofacial pain is a complex multidimensional experience that produces disability and impairment of normal mandibular function. Overall estimations of chronic orofacial pain prevalence are 7 to 11% of the general population. Temporomandibular disorders (TMDs) are one of the most prevalent chronic orofacial pain conditions, with temporomandibular joint (TMJ) arthralgia accounting for 30.1% of TMD patients. Interventional procedures are often used in pain and palliative medicine to achieve reasonable and cost-effective pain relief. The use of intra-articular corticosteroids in relieving arthralgia and improving joint function has been well documented. We present the clinical case of an 84-year-old female patient who presented to the Hospital del Salvador orofacial pain service with preauricular pain, limited range of motion, provoked pain at palpation, and decreased function in the preauricular region. In accordance with the DC/TMD criteria, left TMJ arthralgia and degenerative joint disease was diagnosed and was later corroborated by cone beam computed tomography. An intra-articular injection of 10 mg of methylprednisolone was prescribed, and the patient underwent the procedure in accordance with Hospital del Salvador's intra-articular injection protocol. The patient underwent the intervention without any inconvenience. At the 3-week follow-up visit, the patient presented with a depigmented depression zone adjacent to the site of injection. After echotomography, we concluded that the patient had developed skin depigmentation and subcutaneous lipoatrophy related to the intra-articular injection of methylprednisolone. To the best of our knowledge, this is the first report of this complication secondary to an interventional procedure in the TMJ. Clinicians should be aware of, and patients must be advised of, this rare complication before an intra-articular intervention. PMID- 28866049 TI - Overexpression of Mitogen-activated protein kinase phosphatase-3 (MKP-3) reduces FoxO1 phosphorylation in mice hypothalamus. AB - The mitogen-activated kinase phosphatase-3 (MKP-3) has gained great importance in the scientific community by acting as a regulator of the cell cycle through dephosphorylation of FoxO1, an important transcription factor involved in the insulin intracellular signaling cascade. When dephosphorylated and translocated to the nuclei, FoxO1 can promote the transcription of orexigenic neuropeptides (NPY/AgRP) in the hypothalamus, whereas insulin signaling is responsible for the disruption of this process. However, it is not understood if the hypothalamic activation of MKP-3 affects FoxO1 phosphorylation, and we hypothesized that MKP-3 overexpression reduces the capacity of the insulin signal to phosphorylate FoxO1. In the present study, we overexpressed the DUSP6 gene through an injection of adenovirus directly into the hypothalamic third ventricle of Swiss mice. The colocalization of the adenovirus was confirmed by the immunofluorescence assay. Then, MKP-3 overexpression resulted in a significant reduction of hypothalamic FoxO1 phosphorylation after insulin stimulation. This effect was independent of changes in Akt phosphorylation. Thus, the role of MKP-3 in the hypothalamus is closely associated with FoxO1 dephosphorylation and may provide a potential therapeutic target against hypothalamic disorders related to obesity and unbalanced food intake control. PMID- 28866050 TI - Orexin receptors mediate long-term depression of excitatory synaptic transmission in the spinal cord dorsal horn. AB - Neuropeptides orexin-A and -B are related to the regulation of sleep/wakefulness and feeding behaviors. Recently, the peptides have also been shown to yield antinociceptive effects in various pain models. However, it is not clear whether orexins are involved in forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), the increase and the decrease of synaptic efficacy, respectively. In the present study, we examined whether orexin receptor type 1 (OX1) and 2 (OX2) are involved in the induction or maintenance of LTD of excitatory synaptic transmission using transverse spinal cord slices of young rats. Repetitive electrical stimulation of Lissauer's tract zone at 2Hz for 5min (600 pulses), combined with a holding potential of -30mV, induced LTD of the amplitude of excitatory postsynaptic currents (EPSCs) which are evoked by the activation of primary afferent fibers. The maintenance of LTD was significantly prevented by bath application of SB674042 (1MUM), an OX1 antagonist, or EMPA (1MUM), an OX2 antagonist. In addition, LTD was dependent on the NMDA receptor, as the NMDA receptor antagonist D-AP5 blocked the maintenance of LTD. Our study suggests that orexins, via activation of both OX1 and OX2, play a significant role in the expression of NMDA-dependent LTD, thereby contributing to the spinal modulation of pain transmission. PMID- 28866051 TI - The effects of cognitive versus motor demands on postural performance and weight bearing asymmetry in patients with stroke. AB - While several studies have investigated the interaction between postural control and secondary cognitive tasks in stroke patients, little is known about the influence of secondary motor task on postural control in these patients. The current research was designed to further examine dual-task performance by comparing the effects of cognitive versus motor dual-tasks on postural performance and weight bearing asymmetry (WBA) in stroke patients (n=23) relative to healthy, matched controls (n=22). All participants stood on dual-force plate under 5 conditions: (1) free standing; (2) simple cognitive task (easy Stroop) while standing; (3) difficult cognitive task (difficult Stroop) while standing; (4) simple motor task (holding a tray while a cylinder lying on its flat side) while standing; and (5) difficult motor task (holding a tray while a cylinder lying on its round side) while standing. The center of pressure (COP) measures was greater in stroke patients than healthy controls. Also, the WBA of the patients was greater than the controls. The COP measures increased when moving from single-task to cognitive dual-task conditions. No significant effect of motor dual-tasking was seen when moving from single-task to motor dual-task conditions. However, in contrast to cognitive dual-tasking, stroke patients and healthy controls employed different strategies during simultaneous performance of postural and motor tasks. It can be suggested that performing a motor task while standing requires greater attentional resources compared to performing a cognitive task while standing and this resulted in greater dual-task interference on motor performance in the stroke patients. PMID- 28866052 TI - Sleep-inducing effect of substance P-cholera toxin A subunit in mice. AB - Evidence indicates that the neuropeptide substance P (SP) can act through neurokinin receptors to alter sleep and/or non-rapid eye movement (NREM) sleep slow-wave activity. Consequently, drugs acting on SP receptors could potentially be used as a novel treatment for sleep-related disorders. In the present study, we used SP conjugated with cholera toxin A subunit (SP-CTA), which enhances its duration of activity on SP receptor-expressing cells, to determine the effects of selectively activating SP receptor-expressing brain cells on sleep regulation in mice. Herein, we found that intracerebroventricular administration of SP-CTA enhanced amounts of NREM sleep which was highly fragmented. This result suggests that the activation of SP receptor-expressing cells in the brain can produce not only arousal effects as shown in previous studies but also sleep-inducing effects. PMID- 28866053 TI - Anti-oxidative effects of safranal on immobilization-induced oxidative damage in rat brain. AB - Safranal, a major constituent of saffron, possesses antioxidant and anti apoptotic properties showing considerable neuroprotective effects. The present study was designed to investigate the effects of safranal against restraint stress induced oxidative damage in the rat brain. For inducing the chronic restraint stress, rats were kept in the restrainers for 1h every day, for 21 consecutive days, then, the animals received systemic administrations of vehicle (0.1% DMSO) acted as the control group or safranal daily for 21days. Results indicated that the rats submitted to restraint stress showed an increase in the immobility time versus the non-stress rats. In addition, stress decreased number of crossing in the rats submitted to restraint stress versus the non-stress animals. Treatment with safranal (0.75mg/kg) showed a significant reduction in the immobility time compared to the non-treated stress group, while, the treatment improved the number of crossing in rats submitted to restraint stress versus the vehicle-treated stress rats. In the stressed animals that received vehicle, the MDA level was significantly higher and the levels of GSH and antioxidant enzymes were significantly lower than the non-stressed rats. Safranal ameliorated the changes in the stressed animals as compared with the control groups. The present findings indicate that safranal might be effective against depressant-like effects induced by chronic stress via modulating brain oxidative response. PMID- 28866054 TI - Substitutions in the cardenolide binding site and interaction of subunits affect kinetics besides cardenolide sensitivity of insect Na,K-ATPase. AB - Substitutions within the cardenolide target site of several insects' Na,K-ATPase alpha-subunits may confer resistance against toxic cardenolides. However, to which extent these substitutions alter the Na,K-ATPase's kinetic properties and how they interact with different beta-subunits is not clear. The cardenolide adapted milkweed bug Oncopeltus fasciatus possesses three paralogs of the alpha subunit (A, B, and C) that differ in number and identity of resistance-conferring substitutions. We introduced these substitutions into the alpha-subunit of Drosophila melanogaster and combined them with the beta-subunits Nrv2.2 and Nrv3. The substitutions Q111T-N122H-F786N-T797A (A-copy mimic) and Q111T-N122H-F786N (B copy mimic) mediated high insensitivity to ouabain, yet they drastically lowered ATPase activity. Remarkably, the identity of the beta-subunit was decisive and all alpha-subunits were less active when combined with Nrv3 than when combined with Nrv2.2. Both the substitutions and the co-expressed beta-subunit strongly affected the enyzme's affinity for Na+ and K+. Na+ affinity was considerably higher for all enzymes expressed with nrv3 while expression with nrv2.2 mostly increased K+ affinity. Our results provide the first evidence that resistance against cardenolides comes at the cost of significantly altered kinetic properties of the Na,K-ATPase. The beta-subunit can strongly modulate these properties but cannot fully compensate for the effect of the substitutions. PMID- 28866055 TI - A novel culture method reveals unique neural stem/progenitors in mature porcine iris tissues that differentiate into neuronal and rod photoreceptor-like cells. AB - Iris neural stem/progenitor cells from mature porcine eyes were investigated using a new protocol for tissue culture, which consists of dispase treatment and Matrigel embedding. We used a number of culture conditions and found an intense differentiation of neuronal cells from both the iris pigmented epithelial (IPE) cells and the stroma tissue cells. Rod photoreceptor-like cells were also observed but mostly in a later stage of culture. Neuronal differentiation does not require any additives such as fetal bovine serum or FGF2, although FGF2 and IGF2 appeared to promote neural differentiation in the IPE cultures. Furthermore, the stroma-derived cells were able to be maintained in vitro indefinitely. The evolutionary similarity between humans and domestic pigs highlight the potential for this methodology in the modeling of human diseases and characterizing human ocular stem cells. PMID- 28866056 TI - Mitochondrial dynamics, transport, and quality control: A bottleneck for retinal ganglion cell viability in optic neuropathies. AB - Retinal ganglion cells, the neurons that selectively die in glaucoma and other optic neuropathies, are endowed with an exceedingly active metabolism and display a particular vulnerability to mitochondrial dysfunction. Mitochondria are exquisitely dynamic organelles that are continually responding to endogenous and environmental cues to readily meet the energy demand of neuronal networks. The highly orchestrated regulation of mitochondrial biogenesis, fusion, fission, transport and degradation is paramount for the maintenance of energy-expensive synapses at RGC dendrites and axon terminals geared for optimal neurotransmission. The present review focuses on the progress made to date on understanding the biology of mitochondrial dynamics and quality control and how dysregulation of these processes can profoundly affect retinal ganglion cell viability and function in optic nerve diseases. PMID- 28866057 TI - Mitochondrial disruption in peroxisome deficient cells is hepatocyte selective but is not mediated by common hepatic peroxisomal metabolites. AB - The structural disruption of the mitochondrial inner membrane in hepatocytes lacking functional peroxisomes along with selective impairment of respiratory complexes and depletion of mitochondrial DNA was previously reported. In search for the molecular origin of these mitochondrial alterations, we here show that these are tissue selective as they do neither occur in peroxisome deficient brain nor in peroxisome deficient striated muscle. Given the hepatocyte selectivity, we investigated the potential involvement of metabolites that are primarily handled by hepatic peroxisomes. Levels of these metabolites were manipulated in L-Pex5 knockout mice and/or compared with levels in different mouse models with a peroxisomal beta-oxidation deficiency. We show that neither the deficiency of docosahexaenoic acid nor the accumulation of branched chain fatty acids, dicarboxylic acids or C27 bile acid intermediates are solely responsible for the mitochondrial anomalies. In conclusion, we demonstrate that peroxisomal inactivity differentially impacts mitochondria depending on the cell type but the cause of the mitochondrial destruction needs to be further explored. PMID- 28866058 TI - Surgical "Fat Patch" Improves Secondary Intracranial Hypotension Orthostatic Headache Associated with Lumbosacral Dural Ectasia. AB - BACKGROUND: Secondary intracranial hypotension is a clinical syndrome associated with reduction of cerebrospinal fluid volume and dural continuity violation. The main symptoms are orthostatic headache associated with nausea, vomiting, diplopia, dizziness, and tinnitus. The treatment is usually nonspecific. CASE DESCRIPTION: A 37-year-old woman developed secondary intracranial hypotension caused by lumbosacral iatrogenic dural ectasia following detethering surgery. An orthostatic headache was the mainstay of her clinical picture, and it was confirmed by intracranial pressure monitoring. Conservative treatment including spinal blood patch improved symptoms for a limited amount of time (<1 month). Altered compliance of the dural spinal sac was suspected. Therefore thecal sac remodeling by placing autologous fat at the level of the dural ectasia was performed, improving the symptoms for 2 years. CONCLUSION: Volumetric reduction of the epidural space may be considered as a valuable therapeutic option in case of intracranial hypotension that is unresponsive to medical treatments and spinal blood patch, as well as when an altered compliance of the dural sac is hypothesized. PMID- 28866059 TI - Revascularization Operation for Moyamoya Disease with Concurrent von Willebrand Disease. AB - BACKGROUND: Although extracranial-intracranial (EC-IC) bypass is an effective treatment strategy for symptomatic moyamoya disease, surgeons need to be cautious regarding the possibility of postoperative hemorrhagic complications in patients with a concurrent coagulation disorder. Here, we describe a case of EC-IC bypass for moyamoya disease concurrent with von Willebrand disease type 1. CASE DESCRIPTION: Following perioperative replacement of the von Willebrand factor, the patient showed an uneventful and uncomplicated clinical course. CONCLUSION: This is the first reported case of EC-IC bypass being performed for moyamoya disease in a patient with concurrent von Willebrand disease. We emphasize the importance of appropriate management with replacement of the von Willebrand factor during the perioperative period to avoid hemorrhagic complications. PMID- 28866060 TI - Fluorescence Behavior and Dural Infiltration of Meningioma Analyzed by 5 Aminolevulinic Acid-Based Fluorescence: Operating Microscope Versus Mini Spectrometer. AB - OBJECTIVE: To compare fluorescence intensity of tumor specimens, as measured by a fluorescence-guided surgery microscope and a spectrometer, to evaluate tumor infiltration of dura mater around meningiomas with help of these 2 different 5 aminolevulinic acid (5-ALA)-based fluorescence tools, and to correlate fluorescence intensity with histopathologic data. MATERIAL AND METHODS: In a clinical series, meningiomas were resected by 5-ALA fluorescence-guided surgery. Fluorescence intensity was semiquantitatively rated by the surgeon at predefined points. Biopsies were harvested and fluorescence intensity measured by a spectrometer and histopathologically analyzed. Sampling was realized at the level of the dura in a centrifugal direction. RESULTS: A total of 104 biopsies (n = 13 tumors) were analyzed. Specificity and sensitivity of the microscope were 0.96 and 0.53 and of the spectrometer 0.95 and 0.93, respectively. Fluorescence intensity as measured by the spectrometer was correlated to histologically confirmed tumor burden. In a centrifugal direction, tumor burden and fluorescence intensity continuously decreased (along the dural tail). Below a threshold value of 639 arbitrary units no tumor was histologically detectable. CONCLUSIONS: At the level of the dura the spectrometer was highly sensitive for detection of meningioma cells. The surgical microscope showed false negative results and missed residual tumor cells in more than one half of the cases. The complementary use of both fluorescence tools may improve resection quality. PMID- 28866061 TI - Staged Trapping of Traumatic Basilar Trunk Pseudoaneurysm: Case Report and Review of Literature. AB - BACKGROUND: Traumatic intracranial aneurysms (TICAs) of the posterior circulation in the pediatric populations are rare. Only a few reports in the literature document basilar artery TICA in the pediatric population. These cases were typically associated with a clival fracture and commonly diagnosed weeks to months after trauma. We present a case of a patient with a basilar TICA diagnosed after a motor vehicle collision treated with staged trapping and review of the literature. CASE DESCRIPTION: We present a case of a 14-year-old boy who sustained a high-speed motor vehicle collision and developed a basilar trunk TICA identified on admission. Initially, the patient underwent craniotomy for proximal sacrifice of the basilar artery in hope for spontaneous thrombosis of the aneurysm through flow reversal. Endovascular options were reviewed and felt to be less feasible than surgical trapping. Due to continued filling through the right posterior communicating artery, the second surgery was performed to distally trap the aneurysm. The aneurysm was opened, showing some thrombosis and the absence of flow. Repeat magnetic resonance imaging did not reveal any new infarction, and the patient was discharged with neurologic improvement over time. At 1 year, he was able to ambulate unassisted and had a modified Rankin Scale score of 3. CONCLUSION: Development of a TICA may be more acute than literature previously suggested. Treatment consists of a wide range of options and should be considered, especially in the pediatric population, to prevent rupture. Trapping can be performed safely if adequate collateral flow is present in the setting of a large basilar artery aneurysm. PMID- 28866062 TI - Presurgical Administration of mTOR Inhibitors in Patients with Large Subependymal Giant Cell Astrocytoma Associated with Tuberous Sclerosis Complex. AB - BACKGROUND: Direct surgical resection remains the standard treatment for patients with tuberous sclerosis complex (TSC) with a large subependymal giant cell astrocytoma (SEGA). Rapamycin or everolimus is seldom used in these patients because of the risk of increased intracranial pressure and possibility of sudden death. CASE DESCRIPTIONS: Three patients with TSC and a large intracranial SEGA received oral rapamycin (0.5 mg/day) or everolimus (2.5 mg/day) before surgery for tumor resection. After mTOR inhibitor therapy, computed tomography scans and magnetic resonance imaging revealed tumor reduction. Tumor bleeding was easy to control during surgery, and the border between tumor and surrounding brain tissue was clearly differentiated. Analysis of postsurgical tumor specimens showed low blood density and focal necrosis. CONCLUSIONS: Preoperative mTOR inhibitors could be a potentially novel treatment modality in large TSC-SEGA with hydrocephalus. In this series, mTOR inhibitors were not only safe and well tolerated, but also beneficial for tumor resection. PMID- 28866064 TI - Surgical Outcomes of Posterolateral Sulcus Approach for Spinal Intramedullary Tumors: Tumor Resection and Functional Preservation. AB - BACKGROUND: Selection of the access myelotomy is a key issue in surgery for spinal intramedullary tumors. This study focused on surgical outcomes with the posterolateral sulcus (PLS) approach, equivalent to dorsal root entry zone myelotomy. METHODS: This retrospective study of the 10-year period from 2007 to 2016 included 90 cases of spinal intramedullary lesions (99 operations). A PLS approach was indicated for intramedullary lesions situated laterally in the spinal cord showing no contact with the spinal cord surface. Neurological conditions before and after surgery were carefully assessed objectively. RESULTS: A PLS approach was applied in 34 of the 99 operations (34.3%). Among 70 cases involving astrocytic tumor, ependymal tumor, cavernous malformation or hemangioblastoma, 23 cases (32.9%) were operated on using a PLS approach. Microscopically gross total or subtotal removal of the tumor was achieved in 18 of 23 cases (78.3%). These 18 cases demonstrated mild deterioration of motor function on the approach side early after surgery, but usually resolving within several months postoperatively. Average grade of the modified McCormick functional schema before surgery was maintained 6 months postoperatively. Average grade of the sensory pain scale before surgery was significantly improved by 6 months postoperatively. Segmental dysesthesia on the approach side unexpectedly remained in 2 of 18 cases (11.1%) even late after surgery. CONCLUSIONS: These findings suggest that the PLS approach can provide direct access to tumors with minimal tissue damage, when applied appropriately after careful case selection. PMID- 28866063 TI - Spinal Cord Astrocytoma with Isocitrate Dehydrogenase 1 Gene Mutation. AB - BACKGROUND: In 2016, the World Health Organization updated its classification of tumors, adding genetic profiles to the conventional histopathologic typing. CASE DESCRIPTION: The authors present herein the first case of a 44-year-old female with isocitrate dehydrogenase-mutant World Health Organization grade II diffuse spinal astrocytoma diagnosed on the basis of both histopathologic and genetic findings. CONCLUSIONS: The present case underscores the significant role of a molecular genetic analysis in the differential diagnosis of intramedullary spinal gliomas. PMID- 28866065 TI - Intradural Chordoma of Cerebellopontine Angle: Case Report and Review. AB - BACKGROUND: Chordomas are rare, notochord-derived neoplasms. Of these tumors, intradural chordomas are exceedingly rare. Most occur within the prepontine, parasellar, or other midline intradural locations. An intradural chordoma arising from the cerebellopontine angle has not been described previously. CASE REPORT: We describe the first case of an intradural chordoma originating from the left cerebellopontine angle resected over the course of 2 operations. CONCLUSIONS: Intradural chordomas are rare and can arise anywhere in the posterior fossa. Lack of bony involvement on computed tomography and magnetic resonance imaging are indicative of this pathology when there is also a lack of markers indicating the presence of more common cerebellopontine angle tumors. Treatment goals should include gross total resection and possible radiation therapy. PMID- 28866067 TI - Fostering Student Interest in Neurologic Surgery: The University of Pittsburgh Experience. AB - INTRODUCTION: Early involvement and research in neurosurgery can increase chances for medical students to matriculate successfully into residency. This study reports the creation of a Neurological Surgery Interest Group (NSIG) at the University of Pittsburgh School of Medicine and shares its activities over 2 academic years. METHODS: In October 2014, the University of Pittsburgh School of Medicine's NSIG was created to augment medical student interest in neurosurgery. The group consisted of 4 appointed officers for a membership base of 100 students. In June 2015, a neurosurgery resident and faculty member joined as mentors. A research committee of 14 medical students was created to conduct collaborative research projects with the department. In August of 2015 and 2016, surveys were sent out to the research committee regarding research productivity. RESULTS: The NSIG hosted 17 medical student-oriented events over 2 years, including didactic and suturing workshops, senior faculty panels, postmatch talks, and a neurosurgery networking dinner. A survey of students about scholarly achievement in neurosurgery reported 17 accepted publications in peer-reviewed journals with a mean impact factor of 3.5 +/- 2.5. Ten abstracts were submitted to the 2015 and 2016 American Association of Neurological Surgeons Scientific Meetings, with a 100% acceptance rate. An increase in the number of students matching from our institution into neurosurgery residencies was observed following the group's inception. CONCLUSIONS: An NSIG can be mutually beneficial to both medical students and an institution's neurosurgical department. This study's findings may be applied to numerous specialties and across various academic institutions. PMID- 28866066 TI - The Quantitative and Functional Changes of Postoperative Peripheral Blood Immune Cell Subsets Relate to Prognosis of Patients with Subarachnoid Hemorrhage: A Preliminary Study. AB - OBJECTIVE: It has been suggested that the preoperative (PRE) and postoperative (POST) immune system alteration triggered by aneurysmal subarachnoid hemorrhage (SAH) and surgical treatment itself may affect patients' prognosis and contribute to POST complications. The mechanisms may be attributed to immune suppression triggered infection or immune overreaction-triggered aseptic inflammation. In this study, we investigated the dynamic changes in peripheral immune cell subsets as well as the alterations of inflammatory cytokines in patients with aneurysmal SAH who received craniotomy and clipping surgery. In addition, we studied the association of those changes with POST complications and clinical prognosis. METHODS: We investigated 27 patients who received craniotomy and clipping surgery for aneurysmal SAH. The operations were all performed within 24 hours after the occurrence of aneurysm rupture. Detailed immune monitoring (peripheral blood leukocytes and lymphocyte subsets and inflammatory cytokines) was performed on PRE (on admission), day 1, day 3, and day 6 after operation. RESULTS: Our data showed that the percentage of CD3+, CD8+, natural killer T (NKT), CD4+, and regulatory T (Treg) cells significantly decreased and the level of interleukin 4 (IL-4), interferon gamma, and IL-2 significantly increased 1 day after surgery compared with the data in PRE. On the contrary, natural killer (NK), NK group 2 (NKG2D), and B cells increased and the level of IL-10 in plasma decreased. In study of the relationship between POST fever and the change in immune cell subgroups, the fever group had a lower percentage of CD3+, CD4+, NKT, Tregs, and B cells on day 1, day 3, and day 6 after surgery compared with the patients who did not have fever, whereas the CD8+, NK, and NKG2D subsets showed the opposite trend. Furthermore, we analyzed the association between immune profile changes and the prognosis of those patients. The patients were divided into those with an unfavorable prognosis (n = 6) and those with a favorable prognosis (n = 21) according to Glasgow Outcome Scale score and postoperation (POST) coma. Our results showed that except for B cells, patients with a favorable prognosis had a relatively higher percentage of CD3+, CD4+, CD8+, NK, NKT, NKG2D, and Treg cells compared with the unfavorable prognosis group from PRE to day 6 POST. CONCLUSIONS: Our results indicated that patients with aneurysmal SAH undergoing craniotomy and clipping surgery had a profound transient deterioration in immune function. In addition, the changes in immune cell subgroups had a strong association with POST fever. The changes in immune cell subgroups were also directly associated with clinical prognosis of the patients. These association findings might be attributable to a better biomarker to predict patient diagnosis. PMID- 28866068 TI - Treating Cerebrospinal Fluid Rhinorrhea without Dura Repair: A Case Report of Posterior Fossa Choroid Plexus Papilloma and Review of the Literature. AB - BACKGROUND: Choroid plexus papilloma revealed by nontraumatic cerebrospinal fluid (CSF) rhinorrhea has only been described 5 times, to our knowledge, in the literature. The challenges in this situation are to recognize CSF leak, to rapidly understand the pathophysiology of the leak, and to choose the best treatment strategy in emergency. We report an original case of posterior fossa choroid plexus papilloma revealed by CSF leak. We then discuss the surgical strategy and the pathophysiology of CSF leak, which is explained, in this case, by both hyperproduction of CSF and local skull base erosion. CASE DESCRIPTION: We report the case of a 47-year-old man who has developed spontaneous rhinorrhea, right hearing loss, and confusion. A choroid plexus papilloma of the right cerebellomedullary cistern was diagnosed. Hydrocephalus and pneumocephalus were associated with an erosion of the homolateral skull base. The patient underwent surgical total tumor removal by a median suboccipital approach after implantation of a temporary external ventricular drainage. The patient recovered completely without any recurrence of CSF rhinorrhea. The 5-month postoperative images show total bone re-growth and resolution of hydrocephalus. CONCLUSIONS: Our case shows that 1) causal reasoning is of major importance when dealing with CSF rhinorrhea and that 2) dura repair can be avoided when treating CSF leak secondary to posterior fossa choroid plexus papilloma. PMID- 28866069 TI - Revesz syndrome masquerading as traumatic retinal detachment. AB - A 13-month-old boy with mild hemophilia A presented for strabismus evaluation and was found to have retinal hemorrhages in the right eye, left exotropia, and left total retinal detachment. These findings were attributed to trauma and hemophilia A. Routine blood work for hemophilia A subsequently showed pancytopenia. A bone marrow aspirate showed marked hypocellularity consistent with severe aplastic anemia, and telomere testing revealed very short telomeres. The patient was found to have a TINF2 mutation consistent with a diagnosis of Revesz syndrome, a variant of dyskeratosis congenita. He underwent successful bone marrow transplantation, and on subsequent evaluation was found to have retinal hemorrhages, vessel sclerosis, and cotton wool spots in the right eye associated with peripheral retinal nonperfusion. He underwent retinal laser treatment to the areas of retinal nonperfusion which resulted in stable visual function. PMID- 28866070 TI - Next-Generation Sequencing: A Novel Approach to Distinguish Multifocal Primary Lung Adenocarcinomas from Intrapulmonary Metastases. AB - Distinguishing between multiple lung primary tumors and intrapulmonary metastases is imperative for accurate staging. The American Joint Committee on Cancer (AJCC) criteria are routinely used for this purpose but can yield equivocal conclusions. This study evaluated whether next-generation sequencing (NGS) using the 50-gene AmpliSeq Cancer Hotspot Panel version 2 can help facilitate this distinction. NGS was performed on known primary-metastatic pairs (8 patients) and multiple lung adenocarcinomas (11 patients). Primary-metastatic pairs had high mutational concordance. Seven pairs shared mutations, and 1 was concordant for having no mutations. Driver mutations in KRAS (n = 4), EGFR (n = 2), and BRAF (n = 1) were always concordant. Multiple lung tumors from 3 patients were completely concordant and predicted by NGS to be intrapulmonary metastases, whereas 8 had completely discordant mutations and were predicted to be independent primary tumors. The NGS prediction correlated with the AJCC (eighth edition) prediction in all patients for whom the latter was unequivocal (8 of 11). Furthermore, it separated patients by overall survival. Patients with predicted multiple independent primary tumors by NGS had better survival than those with distant metastases (P = 0.016, log-rank test), whereas those with predicted intrapulmonary metastases had no difference (P = 0.527). With further validation, the 50-gene panel has the potential to serve as an adjunct to the AJCC criteria. PMID- 28866071 TI - Neuropathological and behavioral sequelae in IL-1R1 and IL-1Ra gene knockout mice after soman (GD) exposure. AB - Soman (GD) exposure results in status epilepticus (SE) that leads to neurodegeneration, neuroinflammation, and behavioral consequences including learning and memory deficits. The neuroinflammatory response is characterized by the upregulation of the pro-inflammatory cytokine, interleukin-1 (IL-1), which mediates the expression of other neurotoxic cytokines induced after GD exposure. However, the specific role of IL-1 signaling has not been defined in terms of the consequences of GD-induced SE. Therefore, the purpose of this study was to regulate IL-1 signaling and study the behavioral deficits and neurodegeneration that occur after convulsion onset. Wild type (WT), IL-1 receptor (IL-1R1) knockout (KO), and IL-1 receptor antagonist (IL-1Ra) KO mice were exposed to a convulsive dose of GD, and behavior was evaluated up to 18days later. Activity was studied using the Open Field, anxiety was assessed in the Zero Maze, and spatial learning and memory were evaluated with the Barnes Maze. The animals were euthanized at 24hours and 18days to determine neuropathology in the piriform cortex, amygdala, thalamus, and CA1, CA2/3, and CA4 regions of the hippocampus. Unlike the IL-1Ra KO, the IL-1R1 KO showed less neuropathology compared to WT at 24hours, but moderate to severe injury was found in all strains at 18days. Compared to their saline controls, the exposed WT mice were significantly more active in the Open Field, and the IL-1R1 KO strain showed reduced anxiety in the Zero Maze Test. Compared to WT mice, IL-1R1 and IL-1Ra KO mice had spatial learning and memory impairments in the Barnes Maze. Therefore, the IL-1 signaling pathway affects neurodegeneration and behavior after GD-induced convulsions. PMID- 28866072 TI - Changes in the cannabinoids receptors in rats following treatment with antidepressants. AB - The endocannabinoid (eCB) system plays a significant role in the pathophysiology of depression. The potential participation of this system in the mechanism of action of antidepressants has been highlighted in recent years. The aim of this study was to investigate the expression of cannabinoid (CB) receptors using Western blot and CB1 receptor density using autoradiography after acute or chronic administration of antidepressant drugs [imipramine (IMI, 15mg/kg), escitalopram (ESC, 10mg/kg) and tianeptine (TIA, 10mg/kg)]. Antidepressants given chronically elevated CB1 receptor density in the cortical structures and hippocampal areas, while a decrease of CB1 receptor density was observed in the striatum after IMI and ESC treatment. The CB1 receptor expression decreases in the dorsal striatum after chronic administration of IMI and ESC or the receptor rise in the hippocampus after chronic ESC and TIA treatment were confirmed using Western blot analyses. An increase in the CB2 receptor expression was observed in the cortical structures and hippocampus after chronic administration of ESC and TIA, while a decrease in this expression was noted in the striatum and cerebellum after chronic IMI treatment. Our results provide clear evidence that the antidepressant exposures provoke some modulations within the eCB system through CB receptors. PMID- 28866073 TI - National trends in radiotherapy for brain metastases at time of diagnosis of non small cell lung cancer. AB - BACKGROUND: To analyze the national trends of patients treated radiotherapy for brain metastases from non-small cell lung cancer (NSCLC) that were found at diagnosis. METHODS: The National Cancer Database was queried for patients with NSCLC diagnosed from 2004 to 2013 that received brain irradiation for metastases and patients grouped into having had received fractionated brain radiotherapy (5 15 fractions with or without radiosurgery) or intracranial radiosurgery alone (1 5 fractions). Univariable and multivariable (MVA) analyses were performed to investigate factors associated with the receipt of SRS alone, and temporal/regional trends. RESULTS: 47,746 patients met inclusion criteria, of which 42,148 received fractionated brain irradiation (88%) and 5,598 received radiosurgery (12%). 345 patients received fractioned brain irradiation with a radiosurgical boost (0.8%). The utilization of radiosurgery-alone increased over time owing to increases in each radiosurgery modality. On MVA, several factors were associated with increased odds of receiving intracranial radiosurgery-alone over fractionated brain radiotherapy including more recent year of diagnosis, increased median income, eastern U.S. regions, further distance to the hospital, and the receipt of chemotherapy (each p<0.001). Patients of Asian descent were less likely to receive radiosurgery alone (p=0.044). CONCLUSIONS: In the management of brain metastases from NSCLC, overall utilization of an intracranial radiosurgery alone treatment strategy has increased over the past decade. Despite this, there appear to be significant geographic variations and disparities remain based on patient income level and race. Further study is needed to define the reasons for these disparities and appropriate actions to mitigate them. PMID- 28866074 TI - Anatomical connections between the buccinator and the tendons of the temporalis. AB - The aim of this study was to clarify the anatomical relationship between the buccinator and the temporalis in order to improve understanding of the precise and coordinated movements of the mouth and the mandible. The buccinator and the temporalis were investigated in 72 hemifaces from Korean cadavers. Removing the buccal fat pad from the buccinator revealed that the fascia encircled the space between the superficial and deep tendons of the temporalis laterally, and the external surface of the buccinator medially in all specimens (100%). The fascia was located between the buccinator and the tendons of the temporalis, thereby connecting these two muscles. The fascial space was filled with connective tissue, and the buccal nerve and artery passed through this space. The inferior fibers of the buccinator arose from the anterior portion of the deep tendon of the temporalis in all specimens (100%). The anterior portion of the deep tendon of the temporalis extended forward obliquely between the ramus and body of the mandible. Thus, both the anterior portion of the deep tendon of the temporalis and its attaching inferior muscle fibers of the buccinator coursed obliquely. The above observations indicate that the connecting fascia between the buccinator and tendons of the temporalis and the inferior fibers of the buccinator that were attached to the deep tendon of the temporalis could assist in coordinatation of the movements of the mandibular region and the mouth angle in the timing and strength of contraction of the muscles during mastication, facial expression, and speech. PMID- 28866075 TI - Between Disease-Causing and an Innocent Bystander: The Role of Titin as a Modifier in Hypertrophic Cardiomyopathy. PMID- 28866077 TI - Importance of Optimization of Cardiovascular Risk Factors and Lifestyle Behaviours. PMID- 28866076 TI - Score of Adherence to 2016 European Cardiovascular Prevention Guidelines Predicts Cardiovascular and All-Cause Mortality in the General Population. AB - BACKGROUND: Guidelines on cardiovascular (CV) disease prevention promote healthy lifestyle behaviours and CV risk factor control to reduce CV risk. The effect of adherence to these guidelines on CV and all-cause mortality is not well known. METHODS: We assessed the effect of baseline adherence to "2016 European Guidelines on CV Disease Prevention in Clinical Practice" on long-term CV and all cause mortality in a sample recruited from the French general population. Analysis was on the basis of the Third French Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) population-based survey (recruitment period: 1994-1997). We built an adherence score to European guidelines, considering adherence to recommendations for smoking, drinking, physical activity, body mass index, blood pressure, low-density and high-density lipoprotein cholesterol, fasting blood glucose, and diet at baseline. Vital status was obtained 18 years after inclusion. Statistical analysis was on the basis of multivariate Cox modelling. RESULTS: Adherence score was assessed in 1311 apparently healthy participants aged 35-64 years (73% men). During the follow-up, 186 deaths occurred (41 were due to a CV cause). Considering CV mortality, the adjusted hazard ratio for subjects in the fourth quartile of the adherence score (worse adherence) was 3.12 (95% confidence interval [CI], 1.62 6.01; P = 0.001), compared with subjects in the first, second, or third quartile (best adherence). Considering all-cause mortality, the adjusted hazard ratio for subjects in the fourth quartile of the adherence score was 2.27 (95% CI, 1.68 3.06; P < 0.001). CONCLUSIONS: Better baseline adherence to European guidelines on CV disease prevention was associated with a significantly reduced long-term CV and all-cause mortality in a sample from the French general population. PMID- 28866078 TI - Utility of Unfractionated Heparin in Transradial Cardiac Catheterization: A Systematic Review and Meta-analysis. AB - BACKGROUND: Unfractionated heparin (UFH) is purported to reduce the risk of radial artery occlusion (RAO) after transradial cardiac catheterization. However, the efficacy and optimal dose remain unclear. This meta-analysis evaluates the safety and efficacy of UFH in this context. METHODS: MEDLINE, EMBASE, ISI Web of Science, and the Cochrane Registry were searched from 1948-May 2017. Studies investigating UFH for reducing RAO in transradial coronary catheterization were included. Data were combined using a random-effects model. RESULTS: Of 220 citations, 8 studies (6 randomized, 2 nonrandomized; 2937 patients) were included. Two studies comparing UFH and no UFH (n = 778) found no significant benefit of UFH in reducing RAO (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.01-4.67; P = 0.34; I2 = 97%). Studies comparing higher-dose (5000 IU) and lower-dose (2,000-3,000 IU) UFH (n = 2475) found a reduction in RAO with higher dose UFH but significant heterogeneity was demonstrated (OR, 0.28; 95% CI, 0.12 0.64; P = 0.003; I2 = 82%). These studies were stratified by study method: for nonrandomized studies (n = 411), a lower rate of RAO was observed with no heterogeneity (OR, 0.14; 95% CI, 0.07-0.28; P < 0.001; I2 = 0%); for randomized studies (n = 2064), a borderline significant reduction was also noted, but significant heterogeneity was demonstrated (OR, 0.37; 95% CI, 0.14-0.99; P = 0.05; I2 = 84%). There was a trend toward more bleeding events with high-dose UFH (OR, 1.75; 95% CI, 0.93-3.29; P = 0.08; I2, 0%). CONCLUSIONS: Observational studies suggest a benefit of higher-dose vs lower-dose UFH in reducing RAO. However, this is less clear in randomized trials. Adequately powered randomized studies are required to determine the role of UFH in preventing RAO in transradial cardiac catheterization. PMID- 28866079 TI - Alternate synthesis to d-glycero-beta-d-manno-heptose 1,7-biphosphate. AB - d-glycero-beta-d-manno-heptose 1,7-biphosphate (HBP) is an enzymatic intermediate in the biosynthesis of the heptose component of lipopolysaccharide (LPS), and was recently revealed to be a pathogen-associated molecular pattern (PAMP) that allows detection of Gram-negative bacteria by the mammalian immune system. Cellular detection of HBP depends upon its stimulation of a cascade that leads to the phosphorylation and assembly of the TRAF-interacting with forkhead-associated domain protein A (TIFA), which activates the transcription factor NF-kappaB. In this note, an alternate chemical synthesis of HBP is described and its biological activity is established, providing pure material for further assessing and exploiting the biological activity of this compound. PMID- 28866080 TI - The Tartary Buckwheat Genome Provides Insights into Rutin Biosynthesis and Abiotic Stress Tolerance. AB - Tartary buckwheat (Fagopyrum tataricum) is an important pseudocereal crop that is strongly adapted to growth in adverse environments. Its gluten-free grain contains complete proteins with a well-balanced composition of essential amino acids and is a rich source of beneficial phytochemicals that provide significant health benefits. Here, we report a high-quality, chromosome-scale Tartary buckwheat genome sequence of 489.3 Mb that is assembled by combining whole-genome shotgun sequencing of both Illumina short reads and single-molecule real-time long reads, sequence tags of a large DNA insert fosmid library, Hi-C sequencing data, and BioNano genome maps. We annotated 33 366 high-confidence protein-coding genes based on expression evidence. Comparisons of the intra-genome with the sugar beet genome revealed an independent whole-genome duplication that occurred in the buckwheat lineage after they diverged from the common ancestor, which was not shared with rosids or asterids. The reference genome facilitated the identification of many new genes predicted to be involved in rutin biosynthesis and regulation, aluminum stress resistance, and in drought and cold stress responses. Our data suggest that Tartary buckwheat's ability to tolerate high levels of abiotic stress is attributed to the expansion of several gene families involved in signal transduction, gene regulation, and membrane transport. The availability of these genomic resources will facilitate the discovery of agronomically and nutritionally important genes and genetic improvement of Tartary buckwheat. PMID- 28866081 TI - Mapping the Arabidopsis Metabolic Landscape by Untargeted Metabolomics at Different Environmental Conditions. AB - Metabolic genome-wide association studies (mGWAS), whereupon metabolite levels are regarded as traits, can help unravel the genetic basis of metabolic networks. A total of 309 Arabidopsis accessions were grown under two independent environmental conditions (control and stress) and subjected to untargeted LC-MS based metabolomic profiling; levels of the obtained hydrophilic metabolites were used in GWAS. Our two-condition-based GWAS for more than 3000 semi-polar metabolites resulted in the detection of 123 highly resolved metabolite quantitative trait loci (p <= 1.0E-08), 24.39% of which were environment specific. Interestingly, differently from natural variation in Arabidopsis primary metabolites, which tends to be controlled by a large number of small effect loci, we found several major large-effect loci alongside a vast number of small-effect loci controlling variation of secondary metabolites. The two condition-based GWAS was followed by integration with network-derived metabolite transcript correlations using a time-course stress experiment. Through this integrative approach, we selected 70 key candidate associations between structural genes and metabolites, and experimentally validated eight novel associations, two of them showing differential genetic regulation in the two environments studied. We demonstrate the power of combining large-scale untargeted metabolomics-based GWAS with time-course-derived networks both performed under different abiotic environments for identifying metabolite-gene associations, providing novel global insights into the metabolic landscape of Arabidopsis. PMID- 28866082 TI - The in situ morphology of microglia is highly sensitive to the mode of tissue fixation. AB - Microglia are known as the most motile cells in the central nervous system (CNS). It was shown in vivo that they permanently scan their direct microenvironment and react to pathological conditions within minutes. Many studies of brain pathologies use fixed brain tissue to investigate cellular changes. Unfortunately, due to technical reasons, the time span between the induction of the fixation procedure (start of the perfusion) and the finally-fixed tissue lasts several minutes, giving time to microglia to start reacting to the ischemic conditions due to perfusion start. Here, we investigated the microglial changes generated by the fixation itself in TgH(CX3CR1-EGFP) mice with fluorescent labelled microglia using confocal laser scanning microscopy (CLSM) of fixed brain tissue as well as two-photon laser scanning microscopy (2P-LSM) during the perfusion of a living animal. We revealed the impact of fixation and buffer parameters on cell morphology. The largest morphological differences compared to physiological in vivo branch arborization were observed when the directly dissected brain was immersed in paraformaldehyde fixation solution overnight, without prior fixative perfusion of the animal. But even perfusion with a fixative, followed by post-fixation leads to small changes in microglial process length and number and could not be prevented when compared to physiological in vivo microglia morphology acquired using in vivo 2P-LSM. Interestingly, perfusion with different buffers either oxygenated artificial cerebrospinal fluid or phosphate buffered saline prior to perfusion-fixation showed minor microglia changes in arborization and/or number of processes. Fixation methods influence microglia morphology. Therefore, to define microglia activation states immunohistochemical stainings or genetic labelling of the cells have to be included in addition to morphological analysis. PMID- 28866083 TI - The developmental transcriptome landscape of receptive endometrium during embryo implantation in dairy goats. AB - Under natural conditions, some embryos cannot implant successfully because of the dysfunction of receptive endometrium (RE). Thus, it is imperative for us to study the molecular mechanisms involved in the formation of the RE from pre-receptive endometrium (PE). In this study, the endometrium from gestational day 5 (D5, PE) and gestational day 15 (D15, RE) dairy goats were selected to systematically analyze the transcriptome using strand-specific Ribo-Zero RNA-Seq, >120 million high-quality paired-end reads were generated and 47,616 transcripts were identified in the endometrium of dairy goats. A total of 810 mRNAs were differentially expressed genes (DEGs) between the RE and PE meeting the criteria of P-values<0.05. Bioinformatics analysis of the DEGs revealed that a number of biological processes and pathways were potentially involved in the establishment of the RE, notably energy metabolism and amino acid metabolism. Furthermore, we speculated that CXCL14, IGFBP3, and LGALS15 potentially participated in the development of endometrium. What's more, putative SNPs, InDels and AS events were identified and analyzed in the endometrium. In a word, this resulting view of the transcriptome greatly enhances the comprehensive transcript catalog and uncovers the global trends in gene expression during the formation of receptive endometrium in dairy goats. PMID- 28866084 TI - A homozygous CEP135 mutation is associated with multiple morphological abnormalities of the sperm flagella (MMAF). AB - Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare disease associated with primary infertility; however, ~50% of the genetic alterations associated with MMAF remain unclear. Here, we reported the case of a 30-year-old infertile male from a consanguineous family. Whole-exome sequencing identified a homozygous mutation in the CEP135 gene (c.A1364T:p.D455V), with CEP135 previously reported to play a role in centriole biogenesis and specifically central pair assembly. D455V-mutated proteins formed protein aggregates in the centrosome and the flagella, which might potentially affect the function of centriole assembly. Moreover, intracytoplasmic sperm injection was performed using sperm from this patient; however, pregnancy failed following embryo transfer. This represents the first report of a homozygous mutation of CEP135 associated with MMAF. These results provide researchers and clinicians with a deeper understanding of the gene involved with MMAF and will help predict and assess pregnancy outcomes associated with in vitro fertilization. PMID- 28866085 TI - Comparative profiling of microRNAs and their association with sexual dimorphism in the fig wasp Ceratosolen solmsi. AB - microRNAs (miRNAs) are small noncoding RNAs that regulate various biological processes, including insect metamorphosis and sexual dimorphism. The fig pollinating wasp, Ceratosolen solmsi, is a member of the super family Chalcidoidea, which have mutualistic relationships with their fig tree hosts. C. solmsi exhibits extreme sexual dimorphism, which corresponds to the distinct lifestyles of both sexes. Our previous studies showed that these dimorphic characteristics are associated with a dimorphic gene expression pattern. In this study, we constructed six small RNA libraries from female and male wasps in three different developmental stages, i.e., larvae, early pupae, and late pupae. We detected known miRNAs and predicted novel miRNAs, and compared their expression patterns in both sexes and among different developmental stages. We focused mainly on the miRNAs with significantly different expression patterns between sexes and among different life stages, as well as their putative associations with metamorphosis and the formation of sexual dimorphism. PMID- 28866086 TI - Evaluation of the relationship between CD36 and MARCO single-nucleotide polymorphisms and susceptibility to carotid atherosclerosis in a Chinese Han population. AB - OBJECTIVE: This study analyzed the genetic association between two scavenger receptors single nucleotide polymorphisms (CD36 rs1761667, MARCO rs12998782) and carotid atherosclerosis in a Chinese Han population. METHODS: Samples of genomic DNA collected from patients (n=215) and healthy control subjects (n=252) were analyzed by the polymerase chain reaction with high-resolution melting analysis. Odds ratios and 95% confidence intervals were used to evaluate the association between the two SNPs and carotid atherosclerosis. RESULTS: There was no difference between the SNPs regarding their association with the frequency of carotid atherosclerosis in the case and control groups or in the male case group and control group. Female patients of genotype GA for CD36 rs1761667 and CT for MARCO rs12998782 were at an increased risk for carotid atherosclerosis. The presence of rs1761667 GA and rs12998782 CT may increase the risk for carotid atherosclerosis among postmenopausal females. CONCLUSIONS: CD36 and MARCO are associated with the susceptibility of Chinese Han females to carotid atherosclerosis. Menopausal status may affect the association between gene polymorphisms and carotid atherosclerosis in the female Chinese Han population. PMID- 28866087 TI - Identification, structural characterization and expression analysis of a novel carbonic anhydrase from freshwater mussel Hyriopsis cumingii. AB - In this study, an alpha-carbonic anhydrase (alpha-CA), HcCA3, from Hyriopsis cumingii was characterized. The full-length cDNA of HcCA3 was 1628bp, including a CA domain and an ORF of 1053bp which encoded 350 amino acids. Its predicted molecular weight was 39.69kDa and the pI was 5.92. qRT-PCR was used to determine the expression of the gene in various tissues at 0h, 3h, 6h, 12h, 24h, 48h, 96h, 7d, 14d, 21d, 28d and 35d after inserting the pearl nucleus. The results showed that the HcCA3 was highly expressed in the mantle, whereas its expression was low in other tissues. Expression in the posterior mantle pallial (pMP) was significantly higher than that in the anterior mantle pallial (aMP) and mantle center (MC). Expression in the aMP, pMP and MC was significantly higher in purple mussels compared with that in white mussels. At the same time, during the formation of pearls, expression in the aMP, pMP and pearl sac (PS) decreased and then increased; whereas expression in the MC increased and then decreased. In situ hybridization showed that the HcCA3 was expressed in both inside and outside epidermal cells. In protein level, Western blot showed that HcCA3 was mainly expressed in the aMP, pMP and MC. Our results suggest that HcCA3 play a role in the formation of shell and pearl sac formation. PMID- 28866088 TI - Statin use and virus-related cirrhosis: A systemic review and meta-analysis. AB - BACKGROUND/OBJECTIVES: Liver cirrhosis and its complications are important factors contributing to mortality worldwide. Statin use is probably associated with lower risk of hepatic decompensation and mortality, but not with cirrhosis or fibrosis progression according to a recent systematic review. We aimed to evaluate the definite effects of statins on the risk of virus-related cirrhosis. METHODS: We systematically searched four databases up to May 7, 2017, without language restriction. Studies were included if they evaluated and clearly defined exposure to statins, reported fibrosis progression, risk of cirrhosis in patients with chronic viral hepatitis or decompensation in cirrhotic patients, and reported relative risks (RRs) or odds ratios (ORs), or provided data for their estimation. Pooled RRs (or ORs) with 95% confidence intervals were calculated using the random-effects models irrespective of statistical heterogeneity assessed with the Cochran's Q statistic and I2 statistic. RESULTS: Ten observational studies involving 12,3445 patients (8 cohort studies, n=12,1823; 1 nested case-control, n=1350; and 1 abstract, n=272) were included. Statin use was associated with a statistically significant 51% reduction in the risk of virus related cirrhosis (pooled RRs, 0.49; 95% CI, 0.30-0.80; P=0.004), with substantial heterogeneity (I2=98.3%; P<0.001). Statin use was also associated with a 51% reduction in the risk of decompensation (pooled RRs, 0.49; 95% CI, 0.41-0.59; P<0.001), which was statistically significant, with no heterogeneity (I2=33.8%; P=0.210). CONCLUSIONS: The meta-analysis showed that statin use was associated with a significantly reduced risk of virus-related cirrhosis and decompensation. However, these results should be interpreted with caution given the possibility of residual confounding. Large randomized controlled trials are warranted in future studies. PMID- 28866089 TI - The association between non-alcoholic fatty liver disease and atrial fibrillation: A meta-analysis. AB - BACKGROUND/OBJECTIVES: The association between non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) has been suggested by recent epidemiological studies although the results were inconsistent. This meta-analysis was conducted to summarize all available data. METHODS: A comprehensive literature review was conducted using MEDLINE and EMBASE database through May 2017 to identify all studies that reported the risk of AF among patients with NAFLD versus those without NAFLD. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Of 1009 studies, 5 studies (two cross-sectional studies and three cohort studies) with 238,129 participants met the eligibility criteria and were included in the meta-analysis. The risk of AF in patients with NAFLD was significantly higher than subjects without NAFLD with the pooled risks ratio of 2.06 (95% confidence interval, 1.10-3.85). The statistical heterogeneity was high with an I2 of 78%, which was the major limitation of this meta-analysis. CONCLUSIONS: A significantly increased risk of AF among patients with NAFLD was demonstrated in this study. PMID- 28866090 TI - Is within-normal range liver enzymes associated with metabolic syndrome in adults? AB - BACKGROUND: Considering the clear association between metabolic syndrome and future cardiovascular disease, early detection of metabolic syndrome is important. This study was conducted to assess the correlation between metabolic syndrome components and within-normal-range of liver enzymes in Iranian adults. METHODS: This cross-sectional study was comprised of 700 Iranian adults in the districts of East Azerbaijan-Iran in 2015. The levels of lipid profile and glucose were measured by enzymatic colorimetric methods. Weight, height, waist circumferences were measured with standard protocols. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) were assessed using the ultraviolet method. The Pearson correlation and Logistic regression were used to for statistical analysis. RESULTS: With increasing the number of metabolic abnormalities, the mean ALT level was increased significantly (Ptrend=0.04). In women, the increase in AST and ALT with increasing the number of metabolic abnormalities was statistically significant (PAST=0.01; PALT<0.001). In men, ALT level had significantly positive correlation with waist circumference (r=0.14, P<0.05), serum TG (r=0.16, P<0.05) and fasting plasma glucose (r=0.17, P<0.01). In women, there was a significant correlation between AST level and serum TG (r=0.15, P<0.05). A significant positive and negative correlation were found respectively between serum ALT and AST/ALT ratio and waist circumference, serum TG and fasting blood glucose. Women in the 4th quartile of ALT were 4.43 fold at an increased risk for metabolic syndrome outcome when compared to those in the first quartile [OR (95% CI): 4.43 (1.69, 11.63)]. In women, with increasing the quartiles of ALT within normal limits, the percent of participants with metabolic syndrome also increased significantly (Ptrend=0.04). CONCLUSIONS: Based on the results, the use of ALT and AST:ALT ratio as continuous biomarkers for early signaling of dysmetabolism especially in women could be encouraged. PMID- 28866091 TI - Variation in Sodium Intake and Intra-individual Change in Blood Pressure in Chronic Kidney Disease. AB - OBJECTIVE: In the kidney disease clinic setting, higher-than-usual blood pressure is often ascribed to recent dietary sodium indiscretion. While clinical trials demonstrate a clear relationship between salt intake and blood pressure on the population level, it is uncertain whether real-world variation in sodium intake within individual chronic kidney disease (CKD) patients is associated with fluctuations in blood pressure. METHODS: We analyzed data from the Phosphorus Normalization Trial, in which participants with CKD eating their usual diets completed at least three 24-hour urine collections over 9 months, from which we measured sodium. Blood pressure was measured at the time of 24-hour urine collections. For each individual participant, we assessed the slope of the relationship between sodium intake and mean arterial blood pressure (MAP). RESULTS: Among 119 participants (mean age 67 years and mean estimated glomerular filtration rate 31 mL/minute/1.73 m2), there was substantial variation in sodium intake as measured by 24-hour urine collections (mean intake 3,903 mg/day, standard deviation 1037 mg/day). Individual participants had highly variable associations between their sodium intake and their MAP; 47% (n = 56) had inverse associations between sodium and MAP, whereas the remainder had positive (salt sensitive) associations. CONCLUSIONS: Among CKD patients, there is substantial variation in sodium intake but no predictable relationship between dietary sodium and blood pressure in individuals. The frequent dismissal of elevated blood pressure readings as related to recent sodium intake in clinic may be a misapplication of large-scale population data to explain individual variability and may contribute to clinical inertia regarding high blood pressure treatment. PMID- 28866093 TI - MiR-127 and miR-376a act as tumor suppressors by in vivo targeting of COA1 and PDIA6 in giant cell tumor of bone. AB - Giant cell tumors of bone (GCTB) are generally benign bone tumors associated with expansive osteolytic defects, a high rate of recurrence and potential malignant transformation. We recently observed silencing of miR-127-3p and miR-376a-3p in GCTB and identified COA1 and PDIA6 as their target genes. Here, we investigate the impact of these microRNAs and their target genes on tumor engraftment and progression of giant cell tumor stromal cells (GCTSC) in vivo by xenotransplantation on the chorioallantoic membrane of chicken eggs. Prior to transplantation, the neoplastic GCTSCs were transfected with miRNA mimics or siRNAs directed against their target genes. Restoration of miR-127-3p and miR 376a-3p reduced the tumor take rate to 17% and 47% compared to 95% in the controls. The tumor volumes were significantly reduced to 29% by both miRNAs. Silencing of COA1 and PDIA6 significantly decreased the tumor volumes to 37.7% and 42.7%, while the tumor take rates remained stable. Our results indicate that re-expression of miR-127-3p and miR-376a-3p induces a strong tumor suppressor effect in GCTSC, which is partially mediated via COA1 and PDIA6. PMID- 28866094 TI - Palbociclib, a selective CDK4/6 inhibitor, enhances the effect of selumetinib in RAS-driven non-small cell lung cancer. AB - KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). Resistance to MEK inhibitor monotherapy develops through a variety of mechanisms. CDK4 was reported to have a synthetic lethal interaction with KRAS. In this study, we demonstrated the combination effects of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib in RAS-driven NSCLC. In vitro, cell lines with CDKN2A mutations were insensitive to selumetinib. We used siRNA and pharmacologic inhibition of CDK4 and found that the combination of selumetinib and palbociclib synergistically inhibited RAS-driven NSCLC cases with CDKN2A mutations but not those with wild type CDKN2A. The combination treatment potentiated growth inhibition and increased the population of cells in G1 phase. Selumetinib completely inhibited p-ERK but not p-RB. The addition of palbociclib markedly inhibited p-RB and downregulated survivin expression. In vivo, the combination treatment inhibited the growth of NSCLC xenografts, which correlated with decreased levels of p-RB, downregulated survivin and decreased Ki-67 staining. These data suggest that the combination treatment of palbociclib and selumetinib is effective in preclinical models of RAS-driven NSCLC with CDKN2A mutations. PMID- 28866092 TI - Metabolic reprogramming and apoptosis sensitivity: Defining the contours of a T cell response. AB - An effective adaptive immune response hinges on the rapid clonal expansion of T cells in response to antigen. The sensitivity of these T cells to programmed cell death (i.e. apoptosis) is carefully calibrated at various stages to ensure a robust yet measured reaction that resolves without inflicting unintended damage to host tissues. To meet bioenergetic demands associated with vigorous proliferation, acquisition of effector functions, and memory formation, T cells also undergo dynamic changes in their metabolism at every stage of this response. In this review, we focus on relatively recent studies that illuminate intimate links between metabolic programs and apoptosis sensitivity in T cells. We then examine how these connections ultimately influence T cell survival and function within the metabolically taxing environs of the tumor microenvironment. PMID- 28866095 TI - Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2 rearranged acute lymphoblastic leukemia patients with distinct secondary lesions. AB - CRLF2-rearrangements (CRLF2-r) occur frequently in Ph-like B-ALL, a high-risk ALL sub-type characterized by a signaling profile similar to Ph + ALL, however accumulating evidence indicates genetic heterogeneity within CRLF2-r ALL. We performed thorough genomic characterization of 35 CRLF2-r cases (P2RY8-CRLF2 n = 18; IGH-CRLF2 n = 17). Activating JAK2 mutations were present in 34% of patients, and a CRLF2-F232C mutation was identified in an additional 17%. IKZF1 deletions were detected in 63% of cases. The majority of patients (26/35) classified as Ph like, and these were characterized by significantly higher levels of MUC4, GPR110 and IL2RA/CD25. In addition, Ph-like CRLF2-r samples were significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased expression of JAK/STAT target genes (CISH, SOCS1), suggesting that mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is known about the genomics of CRLF2-r cases lacking JAK2-pathway mutations, but KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work highlights the heterogeneity of secondary lesions which may arise and influence intracellular-pathway activation in CRLF2-r patients, and importantly presents distinct therapeutic targets within a group of patients harboring identical primary translocations, for whom efficient directed therapies are currently lacking. PMID- 28866096 TI - Regulation and evolution of the interaction of the seed B3 transcription factors with NF-Y subunits. AB - The LAFL genes (LEC2, ABI3, FUS3, LEC1) encode transcription factors that regulate different aspects of seed development, from early to late embryogenesis and accumulation of storage compounds. These transcription factors form a complex network, with members able to interact with various other players to control the switch between embryo development and seed maturation and, at a later stage in the plant life cycle, between the mature seed and germination. In this review, we first summarize our current understanding of the role of each member in the network in the light of recent advances regarding their regulation and structure/function relationships. In a second part, we discuss new insights concerning the evolution of the LAFL genes to address the more specific question of the conservation of LEAFY COTYLEDONS 2 in both dicots and monocots and the putative origin of the network. Last we examine the current major limitations to current knowledge and future prospects to improve our understanding of this regulatory network. PMID- 28866097 TI - Preoperative Imaging is a Critical Component in the Workup of Deeply Infiltrating Endometriosis. PMID- 28866098 TI - Tissue Extraction Techniques During Laparoscopic Uterine Surgery. AB - Morcellation allows minimally invasive approaches to surgery even in the presence of large uteri or myomas. Recent restrictions in the use of power morcellation, as well as concerns regarding the potential for morcellation to disseminate malignant tissue, have initiated investigation and innovation to find safer methods. This review examines current techniques for tissue extraction during uterine surgery, with a focus on contained power morcellation and contained manual morcellation via mini-laparotomy or colpotomy. Videos are included to demonstrate these methods. PMID- 28866099 TI - Nicotine transport in lung and non-lung epithelial cells. AB - AIMS: Nicotine is rapidly absorbed from the lung alveoli into systemic circulation during cigarette smoking. However, mechanism underlying nicotine transport in alveolar epithelial cells is not well understood to date. In the present study, we characterized nicotine uptake in lung epithelial cell lines A549 and NCI-H441 and in non-lung epithelial cell lines HepG2 and MCF-7. MATERIALS AND METHODS: Characteristics of [3H]nicotine uptake was studied using these cell lines. KEY FINDINGS: Nicotine uptake in A549 cells occurred in a time- and temperature-dependent manner and showed saturation kinetics, with a Km value of 0.31mM. Treatment with some organic cations such as diphenhydramine and pyrilamine inhibited nicotine uptake, whereas treatment with organic cations such as carnitine and tetraethylammonium did not affect nicotine uptake. Extracellular pH markedly affected nicotine uptake, with high nicotine uptake being observed at high pH up to 11.0. Modulation of intracellular pH with ammonium chloride also affected nicotine uptake. Treatment with valinomycin, a potassium ionophore, did not significantly affect nicotine uptake, indicating that nicotine uptake is an electroneutral process. For comparison, we assessed the characteristics of nicotine uptake in another lung epithelial cell line NCI-H441 and in non-lung epithelial cell lines HepG2 and MCF-7. Interestingly, these cell lines showed similar characteristics of nicotine uptake with respect to pH dependency and inhibition by various organic cations. SIGNIFICANCE: The present findings suggest that a similar or the same pH-dependent transport system is involved in nicotine uptake in these cell lines. A novel molecular mechanism of nicotine transport is proposed. PMID- 28866100 TI - Autophagy: The spotlight for cellular stress responses. AB - Autophagy is an essential cellular mechanism which plays "housekeeping" role in normal physiological processes including removing of long lived, aggregated and misfolded proteins, clearing damaged organelles, growth regulation and aging. Autophagy is also involved in a variety of biological functions like development, cellular differentiation, defense against pathogens and nutritional starvation. The integration of autophagy into these biological functions and other stress responses is determined by the transcriptional factors that undertake the regulatory mechanism. This review discusses the machinery of autophagy, the molecular web that connects autophagy to various stress responses like inflammation, hypoxia, ER stress, and various other pathologic conditions. Defects in autophagy regulation play a central role in number of diseases, including neurodegenerative diseases, cancer, pathogen infection and metabolic diseases. Similarly, inhibiting autophagy would contribute in the treatment of cancer. However, understanding the biology of autophagy regulation requires pharmacologically active compounds which modulate the autophagy process. Inducers of autophagy are currently receiving considerable attention as autophagy upregulation may be a therapeutic benefit for certain neurodegenerative diseases (via removal of protein aggregates) while the inhibitors are being investigated for the treatment of cancers. Both induction and inhibition of autophagy have been proven to be beneficial in the treatment of cancer. This dual role of autophagy in cancers is now getting uncovered by the advancement in the research findings and development of effective autophagy modulators. PMID- 28866101 TI - MiR-542-3p exerts tumor suppressive functions in non-small cell lung cancer cells by upregulating FTSJ2. AB - AIMS: Up-regulation or down-regulation of microRNAs (miRNAs) has been found in non-small cell lung cancer (NSCLC). However, the role and mechanism of regulation of miR-542-3p in NSCLC is still unclear. This study aimed at investigating the primary biological function of miR-542-3p and FTSJ2 in NSCLC tumorigenesis and the correlation of miR-542-3p and FTSJ2 in NSCLC. MAIN METHODS: Our present results showed that miR-542-3p was down-regulated in NSCLC tissues and cancer cells. Overexpression of miR-542-3p inhibited cell proliferation, cell migration, cell cycle, EMT process and tumor growth in vitro, and induced cell apoptosis by MTT assay, colony formation assay, transwell migration assay, flow cytometry assay, RT-qPCR assay, western blot experiment and vivo model assay; miR-542-3p directly bound to the 3'UTR of FTSJ2 and upregulated FTSJ2 both mRNA and protein level by EGFP reporter assay, RT-qPCR and western blot analysis in NSCLC cells. FTSJ2 also reduced the aggressiveness of NSCLC cells. KEY FINDINGS: In short, miR 542-3p functions as a suppressor gene by targeting and upregulating FTSJ2, thus inhibiting the malignancy of NSCLC cells. SIGNIFICANCE: According to the results, miRNA-542-3p and its targeted FTSJ2 may be indispensable as a predictive biomarker of the response to the treatment in patients with NSCLC. PMID- 28866102 TI - Liver steatosis in hypothalamic obese rats improves after duodeno-jejunal bypass by reduction in de novo lipogenesis pathway. AB - AIMS: Hypothalamic obesity is a severe condition without any effective therapy. Bariatric operations appear as an alternative treatment, but the effects of this procedure are controversial. We, herein, investigated the effects of duodeno jejunal bypass (DJB) surgery upon the lipid profile and expression of genes and proteins, involved in the regulation of hepatic lipid metabolism, in hypothalamic obese (HyO) rats. METHODS: During the first 5days of life, male newborn Wistar rats received subcutaneous injections of monosodium glutamate [4g/kg body weight, HyO group] or saline (control, CTL group). At 90days of life, HyO rats were randomly submitted to DJB (HyO DJB) or Sham-operations (HyO Sham group). Six months after DJB, adiposity, hepatic steatosis and lipid metabolism were verified. KEY FINDINGS: HyO Sham rats were obese, hyperinsulinemic, insulin resistant and dyslipidemic. These rats had higher liver contents of trygliceride (TG) and presented disorganization of the hepatocyte structures, in association with higher hepatic contents of acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 mRNAs and protein. DJB surgery normalized insulinemia, insulin resistance, and dyslipidemia in HyO rats. TG content in the liver and the hepatic microscopic structures were also normalized in HyO DJB rats, while the expressions of ACC and FASN proteins were decreased in the liver of these rodents. SIGNIFICANCE: The DJB-induced amelioration in hepatic steatosis manifested as a late effect in HyO rats, and was partly associated with a downregulation in hepatic de novo lipogenesis processes, indicating that DJB protects against liver steatosis in hypothalamic obesity. PMID- 28866103 TI - Research progress on the roles of microRNAs in governing synaptic plasticity, learning and memory. AB - The importance of non-coding RNA involved in biological processes has become apparent in recent years and the mechanism of transcriptional regulation has also been identified. MicroRNAs (miRNAs) represent a class of small regulatory non coding RNAs of 22bp in length that mediate gene silencing by identifying specific sequences in the target messenger RNAs (mRNAs). Many miRNAs are highly expressed in the central nervous system in a spatially and temporally controlled manner in normal physiology, as well as in certain pathological conditions. There is growing evidence that a considerable number of specific miRNAs play important roles in synaptic plasticity, learning and memory function. In addition, the dysfunction of these molecules may also contribute to the etiology of several neurodegenerative diseases. Here we provide an overview of the current literatures, which support non-coding RNA-mediated gene function regulation represents an important but underappreciated, layer of epigenetic control that facilitates learning and memory functions. PMID- 28866104 TI - The impact of nonpolar lipids on the regulation of the steryl ester hydrolases Tgl1p and Yeh1p in the yeast Saccharomyces cerevisiae. AB - In the yeast Saccharomyces cerevisiae degradation of steryl esters is catalyzed by the steryl ester hydrolases Tgl1p, Yeh1p and Yeh2p. The two steryl ester hydrolases Tgl1p and Yeh1p localize to lipid droplets, a cell compartment storing steryl esters and triacylglycerols. In the present study we investigated regulatory aspects of these two hydrolytic enzymes, namely the gene expression level, protein amount, stability and enzyme activity of Tgl1p and Yeh1p in strains lacking both or only one of the two major nonpolar lipids, steryl esters and triacylglycerols. In a strain lacking both nonpolar lipids and consequently lipid droplets, Tgl1p as well as Yeh1p were present at low amount, became highly unstable compared to wild-type cells, and lost their enzymatic activity. Under these conditions both steryl ester hydrolases were retained in the endoplasmic reticulum. The lack of steryl esters alone was not sufficient to cause an altered intracellular localization of Tgl1p and Yeh1p. Surprisingly, the stability of Tgl1p and Yeh1p was markedly reduced in a strain lacking triacylglycerols, but their capacity to mobilize steryl esters remained unaffected. We also tested a possible cross-regulation of Tgl1p and Yeh1p by analyzing the behavior of each hydrolase in the absence of its counterpart steryl ester hydrolases. In summary, this study demonstrates a strong regulation of the two lipid droplet associated steryl ester hydrolases Tgl1p and Yeh1p due to the presence/absence of their host organelle. PMID- 28866106 TI - Elevated baseline D-dimer plasma levels are associated with a prompt response to omalizumab in patients with severe CSU. PMID- 28866105 TI - Dietary phlorizin enhances osteoblastogenic bone formation through enhancing beta catenin activity via GSK-3beta inhibition in a model of senile osteoporosis. AB - Osteoporosis is one of the most prevalent forms of age-related bone diseases. Increased bone loss with advancing age has become a grave public health concern. This study examined whether phlorizin and phloretin, dihydrochalcones in apple peels, inhibited senile osteoporosis through enhancing osteoblastogenic bone formation in cell-based and aged mouse models. Submicromolar phloretin and phlorizin markedly stimulated osteoblast differentiation of MC3T3-E1 cells with increased transcription of Runx2 and osteocalcin. Senescence-accelerated resistant mouse strain prone-6 (SAMP6) mice were orally supplemented with 10 mg/kg phlorizin and phloretin daily for 12 weeks. Male senescence-accelerated resistant mouse strain R1 mice were employed as a nonosteoporotic age-matched control. Oral administration of ploretin and phorizin boosted bone mineralization in all the bones of femur, tibia and vertebra of SAMP6. In particular, phlorizin reduced serum RANKL/OPG ratio and diminished TRAP-positive osteoclasts in trabecular bones of SAMP6. Additionally, treating phlorizin to SAMP6 inhibited the osteoporotic resorption in distal femoral bones through up-regulating expression of BMP-2 and collagen-1 and decreasing production of matrix-degrading cathepsin K and MMP-9. Finally, phlorizin and phloretin antagonized GSK-3beta induction and beta-catenin phosphorylation in osteoblasts and aged mouse bones. Therefore, phlorizin and phloretin were potential therapeutic agents encumbering senile osteoporosis through promoting bone-forming osteoblastogenesis via modulation of GSK-3beta/beta-catenin-dependent signaling. PMID- 28866108 TI - Characteristics and outcome of patients with hypothermic out-of-hospital cardiac arrest: Experience from a European trauma center. AB - BACKGROUND: Aim of the study was to investigate patient characteristics, survival rates and neurological outcome among hypothermic patients with out-of-hospital cardiac arrest (OHCA) admitted to a trauma center. METHODS: A review of patients with OHCA and a core temperature <=32 degrees C admitted to a trauma center between 2004 and 2016. RESULTS: Ninety-six patients (mean temperature 25.8 degrees C+/-3.9 degrees C) were entered in the study, 37 (39%) of them after avalanche burial. 47% showed return of spontaneous circulation (ROSC) prior to hospital admission. Survival with Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale 1 or 2 was achieved in 25% of all patients and was higher in non-avalanche than in avalanche cases (35.6% vs 8.1%, p=0.002). Witnessed cardiac arrest was the most powerful predictor of favourable neurological outcome (RR: 10.8; 95% Confidence Interval: 3.2-37.1; Wald: 14.3; p<0.001), whereas ROSC prior to admission and body core temperature were not associated with survival with favourable neurological outcome. Cerebral CT scan pathology within 12h of admission increased the risk for unfavourable neurological outcome 11.7 fold (RR: 11.7; 95% CI: 3.1-47.5; p<0.001). Favourable neurological outcome was associated lower S 100-binding protein (0.69+/-0.5MUg/l vs 5.8+/-4.9MUg/l, p 0.002) and neuron-specific enolase (34.7+/-14.2MUg/l vs 88.4+/-42.7MUg/l, p 0.004) concentrations on intensive care unit (ICU) admission. CONCLUSIONS: Survival with favourable neurological outcome was found in about a third of all hypothermic non avalanche patients with OHCA admitted to a trauma center. PMID- 28866107 TI - Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age. AB - BACKGROUND: The effect of age on asthma severity is poorly understood. OBJECTIVES: The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features. METHODS: SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity. RESULTS: Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma. CONCLUSIONS: The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age. PMID- 28866109 TI - A three-year epidemiological prospective cohort study of rugby league match injuries from the European Super League. AB - OBJECTIVES: Conduct a comprehensive epidemiological study of match injury characteristics (incidence, severity, causes, diagnostics, and temporal trends) in professional rugby league. DESIGN: Prospective cohort design. METHODS: Data was captured over the 2013, '14, and '15 seasons, collected via an online reporting survey tool, and underpinned by nominal group technique-agreed definitions. Injury details were provided by club medical staff in accordance to the survey fields from all European Super League teams (e.g. injury occurrence/return dates, diagnosis, mechanism, recurrence). All time-loss injuries have been reported. RESULTS: Injury incidence of 57 injuries/1000h has been observed over the three-year period, with an average of 34days missed per injury. The final 20-min period was the most significant period for injury occurrence, and higher incidence of injury/1000h played was during the start of the season in February, although an absolute injury risk for injury frequency was shown in April due to the greatest playing time. Forward positions reported the highest injury incidence whilst tackle activities were the most frequent mechanism of injury. Concussions and hamstring strains (5 injuries/1000h) were the most commonly diagnosed injuries, although the knee joint region (10 injuries/1000h) was the most frequently injured area. CONCLUSIONS: In light of the most common injury diagnoses, mechanisms, identified seasonal risk, and time of match, the data should look to inform player preparation in terms of physical conditioning and tackle technique in order to optimise player welfare and availability for participation. PMID- 28866110 TI - Effect of a 16-week Bikram yoga program on perceived stress, self-efficacy and health-related quality of life in stressed and sedentary adults: A randomised controlled trial. AB - OBJECTIVES: The purpose of this study was to investigate the effect of 16 weeks of Bikram yoga on perceived stress, self-efficacy and health related quality of life (HRQoL) in sedentary, stressed adults. DESIGN: 16 week, parallel-arm, randomised controlled trial with flexible dosing. METHODS: Physically inactive, stressed adults (37.2+/-10.8 years) were randomised to Bikram yoga (three to five classes per week) or control (no treatment) group for 16 weeks. Outcome measures, collected via self-report, included perceived stress, general self-efficacy, and HRQoL. Outcomes were assessed at baseline, midpoint and completion. RESULTS: Individuals were randomised to the experimental (n=29) or control group (n=34). Average attendance in the experimental group was 27+/-18 classes. Repeated measure analyses of variance (intention-to-treat) demonstrated significantly improved perceived stress (p=0.003, partial eta2=0.109), general self-efficacy (p=0.034, partial eta2=0.056), and the general health (p=0.034, partial eta2=0.058) and energy/fatigue (p=0.019, partial eta2=0.066) domains of HRQoL in the experimental group versus the control group. Attendance was significantly associated with reductions in perceived stress, and an increase in several domains of HRQoL. CONCLUSIONS: 16 weeks of Bikram yoga significantly improved perceived stress, general self-efficacy and HRQoL in sedentary, stressed adults. Future research should consider ways to optimise adherence, and should investigate effects of Bikram yoga intervention in other populations at risk for stress-related illness. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12616000867493. Registered 04 July 2016. URL: http://www.anzctr.org.au/ACTRN12616000867493.aspx. PMID- 28866111 TI - Does player unavailability affect football teams' match physical outputs? A two season study of the UEFA champions league. AB - OBJECTIVES: Player unavailability negatively affects team performance in elite football. However, whether player unavailability and its concomitant performance decrement is mediated by any changes in teams' match physical outputs is unknown. We examined whether the number of players injured (i.e. unavailable for match selection) was associated with any changes in teams' physical outputs. DESIGN: Prospective cohort study. METHODS: Between-team variation was calculated by correlating average team availability with average physical outputs. Within-team variation was quantified using linear mixed modelling, using physical outputs - total distance, sprint count (efforts over 20km/h), and percent of distance covered at high speeds (>14km/h) - as outcome variables, and player unavailability as the independent variable of interest. To control for other factors that may influence match physical outputs, stage (group stage/knockout), venue (home/away), score differential, ball possession (%), team ranking (UEFA Club Coefficient), and average team age were all included as covariates. RESULTS: Teams' average player unavailability was positively associated with the average number of sprints they performed in matches across two seasons. Multilevel models similarly demonstrated that having 4 unavailable players was associated with 20.8 more sprints during matches in 2015/2016, and with an estimated 0.60-0.77% increase in the proportion of total distance run above 14km/h in both seasons. Player unavailability had a possibly positive and likely positive association with total match distances in the two respective seasons. CONCLUSIONS: Having more players injured and unavailable for match selection was associated with an increase in teams' match physical outputs. PMID- 28866112 TI - Hemodynamic Assessment of Patients With Septic Shock Using Transpulmonary Thermodilution and Critical Care Echocardiography: A Comparative Study. AB - BACKGROUND: To assess the agreement between transpulmonary thermodilution (TPT) and critical care echocardiography (CCE) in ventilated patients with septic shock. METHODS: Ventilated patients in sinus rhythm requiring advanced hemodynamic assessment for septic shock were included in this prospective multicenter descriptive study. Patients were assessed successively using TPT and CCE in random order. Data were interpreted independently at bedside by two investigators who proposed therapeutic changes on the basis of predefined algorithms. TPT and CCE hemodynamic assessments were reviewed offline by two independent experts who identified potential sources of discrepant results by consensus. Lactate clearance and outcome were studied. RESULTS: A total of 137 patients were studied (71 men; age, 61 +/- 15 years; Simplified Acute Physiologic Score, 58 +/- 18; Sequential Organ Failure Assessment, 10 +/- 3). TPT and CCE interpretations at bedside were concordant in 87/132 patients (66%) without acute cor pulmonale (ACP), resulting in a moderate agreement (kappa, 0.48; 95% CI, 0.37 0.60). Experts' adjudications were concordant in 100/129 patients without ACP (77.5%), resulting in a good intertechnique agreement (kappa, 0.66; 95% CI, 0.55 0.77). In addition to ACP (n = 8), CCE depicted a potential source of TPT inaccuracy in 8/29 patients (28%). Lactate clearance at H6 was similar irrespective of the concordance of online interpretations of TPT and CCE (55/84 [65%] vs 32/45 [71%], P = .55). ICU and day 28 mortality rates were similar between patients with concordant and discordant interpretations (29/87 [36%] vs 13/45 [29%], P = .60; and 31/87 [36%] vs 16/45 [36%], P = .99, respectively). CONCLUSIONS: Agreement between TPT and CCE was moderate when interpreted at bedside and good when adjudicated offline by experts, but without impact on lactate clearance and mortality. PMID- 28866113 TI - Infected breast cyst due to Prevotella buccae resistant to metronidazole. AB - Prevotella buccae is a Gram-negative anaerobic rod involved in some human infections. We report the first case of an infected breast cyst in a non puerperal women due to this pathogen. A 53-year-old woman presented with pain and a cystic lesion in the right breast. Culture of abscess drainage resulted in isolation of P. buccae. High level of resistance to metronidazole was documented. Treatment with drainage and amoxicillin-clavulanate was established, and improvement of this infection was observed. PMID- 28866114 TI - Traditional approaches versus mass spectrometry in bacterial identification and typing. AB - Biochemical methods such as metabolite testing and serotyping are traditionally used in clinical microbiology laboratories to identify and categorize microorganisms. Due to the large variety of bacteria, identifying representative metabolites is tedious, while raising high-quality antisera or antibodies unique to specific biomarkers used in serotyping is very challenging, sometimes even impossible. Although serotyping is a certified approach for differentiating bacteria such as E. coli and Salmonella at the subspecies level, the method is tedious, laborious, and not practical during an infectious disease outbreak. Mass spectrometry (MS) platforms, especially matrix assisted laser desorption and ionization-time of flight mass spectrometry (MALDI-TOF-MS), have recently become popular in the field of bacterial identification due to their fast speed and low cost. In the past few years, we have used liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based approaches to solve various problems hindering serotyping and have overcome some insufficiencies of the MALDI-TOF-MS platform. The current article aims to review the characteristics, advantages, and disadvantages of MS-based platforms over traditional approaches in bacterial identification and categorization. PMID- 28866115 TI - Association between promoter polymorphism (-108C>T) of paraoxonase1 gene and it's paraoxonase activity in patients with Type2 diabetes in northern Iran. AB - Type 2 diabetes mellitus (T2DM) is one of the diseases which depend on the obesity associated with insulin resistance. Various factors, such as a reduction in the activity of paraoxonase-1 enzyme (PON1), could affect T2DM. PON1 is a multifunctional enzyme with paraoxonase and arylesterase activities. The Activity of PON1 is influenced by various SNPs. The aim of presence study is to investigate the association between promoter polymorphism (-108C>T) of PON1 gene and its paraoxonase activity in patients suffering from Type 2 diabetes in Golestan Province, north of Iran. To this end, genomic DNA was extracted from whole blood then genotyping was carried out using PCR-RFLP and enzymatic activity of paraoxonase was measured in the serum of 90 healthy subjects and 90 diabetic patients. Data was analyzed using SPSS version 16. The relationship between the level of paraoxonase activity with polymorphisms of CC, CT, and TT was statistically significant in patients with T2DM. There was a significant association between polymorphism C-108>T of PON1 and type2 diabetes mellitus, with 24.4% of control group subjects and 15.5% of patients having CC genotype; p<0.05. The ratio for CT genotype in target and control groups was 51.1% and 61.1% respectively; p<0.05. TT genotype was 33.3% in patients and 14.4% in the control group; p<0.05. In the present study, the highest frequency belonged to CT genotype in both the control and the target groups, followed by CC genotype in control group and TT genotype in target group. Our findings revealed that paraoxonase activity of PON1 in the control group was significantly higher in comparison with diabetic patients. PMID- 28866116 TI - lncRNA PVT1 in cancer: A review and meta-analysis. AB - OBJECTIVES: Plasmacytoma variant translocation 1 (PVT1) is a newly discovered long non-coding RNA that functions as an oncogenic molecule in different cancers. We conducted a systematic review and meta-analysis to determine its prognostic potential for malignant tumors. MATERIALS AND METHODS: A literature survey was conducted by searching the PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure and Wanfang electronic databases for articles published as of June 1, 2017. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to demonstrate the relationship between PVT1 expression and overall survival (OS) and disease-free survival (DFS) using RevMan 5.2 and Stata 12.0 software. A quality assessment of the included studies was performed according to the Newcastle-Ottawa scale. RESULTS: A total of 1443 patients from 15 studies were included in this meta-analysis. Elevated PVT1 expression was significantly correlated with poor overall survival (HR=2.03, 95% CI: 1.69-2.43) and disease-free survival (HR=1.55, 95% CI: 1.29-1.87). Statistical significance was also observed in a subgroup meta-analysis that was stratified by variance analysis, cancer type, sample size and PVT1 cut-off value. Additionally, increased PVT1 expression was significantly associated with positive lymph node metastasis (odds ratio (OR)=1.94, 95% CI: 1.03-3.68), positive distant metastasis (OR=3.85, 95% CI: 2.14-6.93), advanced tumor-node-metastasis stage (OR=3.19, 95% CI: 2.45-4.15) and poor differentiation grade (OR=1.57, 95% CI: 1.15-2.16), but not tumor size (P>0.05). CONCLUSION: Elevated PVT1 expression was related to poor prognosis and might be a potential biomarkerof clinicopathological characteristics in different cancer types. More studies need to be conducted to verify the clinical value of PVT1 in human cancers. PMID- 28866117 TI - Association of post-procedural early (within 24h) increases in serum creatinine with all-cause mortality after coronary angiography. AB - BACKGROUND: The majority of patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) are discharged early, with only early (within 24h) serum creatinine (SCr) data available without evidence of clinical prognosis. We aimed to systemically evaluate the association between post procedural early increase in SCr and all-cause mortality following CAG. METHODS: We performed a retrospective sub-study analysis within a prospective observational study including 3091 consecutive patients with baseline and post procedural early (within 24h) SCr data. The degree (mild, moderate, or large) of absolute and relative increases in SCr from baseline. The mean follow-up time was 2.49years. RESULT: Moderate or large early increases in SCr were relatively rare (large increase: >1.0mg/dl [0.5%], >100% [0.4%]), whereas mild absolute and relative increases in SCr were more common (mild increase: 0.25 to 0.50mg/dl [4.5%], 25% to 50% [5.9%]). During the follow-up period, there were 136 post procedural deaths (5.6%). After adjustment for confounders, mild absolute and relative increases in SCr were associated with increased mortality (hazard ratio [HR]: 1.9 and 1.8, respectively, both P<0.05). Moderate or large increases in SCr were associated with higher mortality, even higher than with pre-existing renal dysfunction (HR: 5.36 and 4.12 for moderate increase [0.5 to 1.0mg/dl] and estimated glomerular filtration rate<60ml/min). CONCLUSION: Post-procedural mild, moderate, or large early increase in SCr, is associated with significantly increased long-term mortality. Although moderate or large increase in SCr following CAG was relatively rare, the prognosis is more serious, and is worse than that of pre-existing renal dysfunction. CLINICAL TRIAL REGISTRATION: Predictive Value of Contrast Volume to Creatinine Clearance Ratio (PRECOMIN, ClinicalTrials.govNCT01400295). PMID- 28866118 TI - Elevation of plateletcrit increasing the risk of non-alcoholic fatty liver disease development in female adults: A large population-based study. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the one of the most common form of chronic liver disease in China, so it is important to apply bio marker in predict the development of NAFLD. AIMS: This study aims to evaluate association between plateletcrit (PCT) and non-alcoholic fatty liver disease (NAFLD) in Chinese female adults. METHODS: NAFLD was defined as per ultrasound in this study and 9737 NAFLD-free female subjects from Wenzhou People's Hospital were followed for five years in average in the study. The determination of NAFLD PCT quartiles (Q1 to Q4) were defined: 0-0.16, 0.17-0.18, 0.19-0.21, >=0.22. With Q1 used as reference, 95% confidence intervals (CIs) and hazard ratios (HRs) in different models were computed across each quartile. RESULTS: From Q1 to Q4, the incidence ratios (95% CIs) were 8.30 (7.14-9.47), 11.51 (10.12-12.89), 12.68 (11.47-13.89) and 16.46 (15.03-17.88). Simply considering PCT, in the longitudinal population, values in Q2, Q3 and Q4 had HRs (95% CIs) are 1.51 (1.25 1.84), 1.72 (1.44-2.06) and 2.34 (1.96-2.79) versus Q1. After adjusting for all known confounding variables, values in Q2, Q3 and Q4 had HRs (95% CIs) of 1.31 (1.08-1.60), 1.30 (1.09-1.56) and 1.54 (1.29-1.84) in females compared with Q1. CONCLUSIONS: We reported that elevated serum PCT levels are considered as an independently significant predictor for NAFLD development in females. The high PCT level contributes to the development of NAFLD. PMID- 28866119 TI - What constitutes back pain flare? A cross sectional survey of individuals with low back pain. AB - BACKGROUND AND PURPOSE: Low back pain (LBP) is a lifelong problem for many. In acute episodes, or as a persistent condition, LBP is fluctuating in nature, with pain and other features of the condition varying in intensity and duration over time. Symptom flares (also known as flare ups) contribute to this variation and can have a great impact on the lives of those who have LBP. An important goal of treatments for, and research on, LBP is arguably to decrease symptom flare in both frequency and severity. However, this goal is problematic with little research, and no consensus, on how to define LBP flare. In particular, patients' understandings of LBP flare have received limited attention in the literature. To appropriately address this issue, we sought to understand how flares are conceptualized by individuals with LBP. METHODS: We used an inductive, predominantly qualitative methodology, conducting an online survey with 130 individuals who self-reported experiencing LBP. The survey investigated participants' views on LBP flare including its meaning, features and symptoms, and whether 'flare' and 'pain increase' were synonymous. Qualitative analysis of responses involved thematic and content analysis with descriptive statistics used for the quantitative component. RESULTS: Our data analysis found that participants identified many aspects of a flare to be important. Qualitative analyses highlighted a number of themes including that LBP flare was conceptualized as: (1) an increase in pain and other uncomfortable sensations such as paraesthesia or muscle tension, (2) an increase in the area, quality and/or duration of symptoms, (3) a reduction in physical, cognitive and/or social functioning, and (4) negative psychological and/or emotional factors. Flare was also discussed as a change that was difficult to settle. When participants considered whether 'flare' and 'pain increase' were synonymous, responses were evenly divided between 'no' (47%) and 'yes' (46%) with remaining participants 'unsure'. CONCLUSIONS: The key finding was that many people with LBP do not consider their condition to be flared simply on the basis of a pain increase. In general, other features were required to also change. Results highlighted that a narrow focus on pain is unlikely to differentiate minor pain events from a flare. These findings are important as they contrast with most commonly used definitions of a flare that focus predominantly on pain increase. IMPLICATIONS: Our findings have implications for understanding the trajectory of LBP over time. Understandings derived from perspectives of individuals with LBP highlight that defining flare in LBP is complex. In order to provide person-centred care, individual context and experiences should be taken into account. Therefore, understandings of LBP flare require consideration of factors beyond simply an increase in pain. A comprehensive, person-centred understanding of flare that includes a number of features beyond simply an increase in pain intensity is likely to be useful to better identify flares in research settings, assisting endeavours to understand and reduce LBP. Similarly, in clinical settings a nuanced conceptualisation of flare is likely to help health professionals communicate understandings of flare when working with individuals to manage their LBP. PMID- 28866120 TI - Identification of a novel single chain fragment variable antibody targeting CD24 expressing cancer cells. AB - CD24 is a heavy glycosylated protein that is overexpressed in numerous cancer and cancer stem cells. It is involved in the development, invasion, and metastasis of the cancer cells. CD24 can be considered in targeted cancer therapy as a new target. Here, phage display technology was used for the identification of novel scFv antibodies against CD24. To do so, the CD24 protein was expressed and purified from a stable transgenic CHO cell line. The cells were developed by using a CD24 encoding construct, which targets the 18S rRNA gene. The recombinant CD24 was used in the biopanning process. Four rounds of biopanning were performed with the Tomlinson J library. The polyclonal phage ELISA and DNA sequencing of the selected colonies confirmed that specific binders have been enriched during the biopanning process. Based on the DNA sequencing results, three phage displaying scFv were obtained and their specificity to CD24 was verified in the monoclonal phage ELISA. The results showed that clone 3 (called Jd3) has the highest affinity to CD24 and also is the most abundant clone (80%) among the three clones. Therefore, Jd3 was selected for further analyses. In order to produce soluble Jd3-scFv, the phage was transfected to E. coli BL21 pLysS. Soluble Jd3 scFv was expressed and purified successfully. The soluble Jd3 scFv showed appropriate affinity to recombinant CD24 in the ELISA analysis. Also, the immunocytochemistry experiment showed that the purified Jd3 scFv can bind to the CD24 expressing A549 cells. So, the scFv may be useful in the targeted delivery of drugs or diagnostic nanoparticles to the CD24 expressing cancer cells. To the best of our knowledge, this study is the first report to identify an scFv antibody against CD24, using the phage display method. PMID- 28866121 TI - Focus on uterine fibroids: evolving options to optimize care. PMID- 28866122 TI - Trends in contraceptive use according to HIV status among privately insured women in the United States. AB - BACKGROUND: There is limited information on the patterns and trends of contraceptive use among women living with HIV, compared with noninfected women in the United States. Further, little is known about whether antiretroviral therapy correlates with contraceptive use. Such information is needed to help identify potential gaps in care and to enhance unintended pregnancy prevention efforts. OBJECTIVE: We sought to compare contraceptive method use among HIV-infected and noninfected privately insured women in the United States, and to evaluate the association between antiretroviral therapy use and contraceptive method use. STUDY DESIGN: We used a large US nationwide health care claims database to identify girls and women ages 15-44 years with prescription drug coverage. We used diagnosis, procedure, and National Drug Codes to assess female sterilization and reversible prescription contraception use in 2008 and 2014 among women continuously enrolled in the database during 2003 through 2008 or 2009 through 2014, respectively. Women with no codes were classified as using no method; these may have included women using nonprescription methods, such as condoms. We calculated prevalence of contraceptive use by HIV infection status, and by use of antiretroviral therapy among those with HIV. We used multivariable polytomous logistic regression to calculate unadjusted and adjusted odds ratios and 95% confidence intervals for female sterilization, long-acting reversible contraception, and short-acting hormonal contraception compared to no method. RESULTS: While contraceptive use increased among HIV-infected and noninfected women from 2008 through 2014, in both years, a lower proportion of HIV-infected women used prescription contraceptive methods (2008: 17.5%; 2014: 28.9%, compared with noninfected women (2008: 28.8%; 2014: 39.8%, P < .001 for both). Controlling for demographics, chronic medical conditions, pregnancy history, and cohort year, HIV-infected women compared to HIV-noninfected women had lower odds of using long acting reversible contraception (adjusted odds ratio, 0.67; 95% confidence interval, 0.52-0.86 compared to no method) or short-acting hormonal contraception method (adjusted odds ratio, 0.59; 95% confidence interval, 0.50-0.70 compared to no method). In 2014, HIV-infected women using antiretroviral therapy were significantly more likely to use no method (76.8% vs 64.1%), and significantly less likely to use short-acting hormonal contraception (11.0% vs 22.7%) compared to HIV-infected women not using antiretroviral therapy. Those receiving antiretroviral therapy had lower odds of using short-acting hormonal contraception compared to no method (adjusted odds ratio, 0.45; 95% confidence interval, 0.32-0.63). There was no significant difference in female sterilization by HIV status or antiretroviral therapy use. CONCLUSION: Despite the safety of reversible contraceptives for women with HIV, use of prescription contraception continues to be lower among privately insured HIV-infected women compared to noninfected women, particularly among those receiving antiretroviral therapy. PMID- 28866123 TI - A systematic review finds underreporting of ethics approval, informed consent, and incentives in clinical trials. AB - OBJECTIVES: In this study, we aim to review researchers' reporting practices of the ethics statement, financial incentives, and local ethical committees' profile in their clinical trials. STUDY DESIGN AND SETTING: A systematic search was done through top-ranked 50 medical journals (Scimago Ranking) to retrieve 2,000 latest publications. Only primary clinical trials were included with no restriction to language or participants. RESULTS: Among the 927 included trials, 14 trials (1.5%) did not report an ethical statement and two-third (63%) did not completely report the investigated components (Institutional Review eBoard approval, Helsinki Declaration, and informed consent). Moreover, 21 trials (2.26%) reported motivational incentives with the method and amount of payment for participants. Of them, 15 trials offered monetary incentives to participants in different forms. In the remaining six trials, the incentives were mainly medical benefits. Only one trial reported the profile or quality of local Institutional Review Board. CONCLUSION: A potential gap in the reporting practices of ethics statement and financial incentives was addressed in this review. Authors are urged to fully report all ethical components related to their study, including incentives and compensations plan. Medical journals are also recommended to implement further publication requirements concerning ethics reporting. PMID- 28866124 TI - Modeling the peak of emergence in systems: Design and katachi. AB - It is difficult to model emergence in biological systems using reductionist paradigms. A requirement for computational modeling is that individual entities can be recorded parametrically and related logically, but their transformation into whole systems cannot be captured this way. The problem stems from an inability to formally represent the implicit influences that inform emergent organization, such as context, shifts in causal agency or scale, and self reference. This lack hampers biological systems modeling and its computational counterpart, indicating a need for new fundamental abstraction frameworks that support system-level characteristics. We develop an approach that formally captures these characteristics, focusing on the way they come together to enable transformation at the 'peak' of the emergent process. An example from virology is presented, in which two seemingly antagonistic systems - the herpes cold sore virus and its host - are capable of altering their basic biological objectives to achieve a new equilibrium. The usual barriers to modeling this process are overcome by incorporating mechanisms from practices centered on its emergent peak: design and katachi. In the Japanese science of form, katachi refers to the emergence of intrinsic structure from real situations, where an optimal balance between implicit influences is achieved. Design indicates how such optimization is guided by principles of flow. These practices leverage qualities of situated abstraction, which we understand through the intuitive method of physicist Kodi Husimi. Early results indicate that this approach can capture the functional transformations of biological emergence, whilst being reasonably computable. Due to its geometric foundations and narrative-based extension to logic, the method will also generate speculative predictions. This research forms the foundations of a new biomedical modeling platform, which is discussed. PMID- 28866125 TI - The impact of using electrical impedance spectroscopy (ZedScan) on the performance of colposcopy in diagnosing high grade squamous lesions of the cervix. AB - OBJECTIVES: To determine the efficacy of colposcopy plus ZedScan, which measures changes in tissue electrical impedance, for detecting intraepithelial high-grade lesions compared to colposcopy alone. METHODS: A prospective study conducted at a university hospital colposcopy clinic. Patients referred following abnormal cervical cytology or colposcopic follow up were examined by colposcopy plus ZedScan to assess the cervix. The results of ZedScan directed and colposcopically directed biopsies were compared. RESULTS: Ninety-one patients were included in this study. The median age was 33 years. Eighty (88%) were referred with abnormal cytology; LSIL 45%, ASCUS 27%, ACS-H 8%, HSIL 7%, AGC 1% and 12% follow-up postconisation or colposcopic follow up. Colposcopy alone detected 18 high-grade lesions with 64 women undergoing biopsy with a total of 115 biopsies being taken with a sensitivity of 60% and NPV estimated at 81.7%. ZedScan with colposcopy increased the detection of high-grade lesions by 47.3%, identifying 27 high-grade lesions and one case of invasive cancer. Sensitivity was 93.1% and NPV estimated at 91.3%. A combination of normal colposcopy practice and ZedScan had a sensitivity and NPV of 100%. CONCLUSION: ZedScan used in conjunction with the colposcopy improves sensitivity in detecting high-grade lesions at the expense of a moderate increase in the number of biopsies. PMID- 28866126 TI - Female pelvic anatomy: Are we there yet? Assessment of the knowledge of residents. AB - BACKGROUND: Anatomy is considered a keystone in medical education and pelvic anatomy comprehension is the groundwork of the understanding of birthing process and pelvic surgery. The objectives of this study were to assess the state of the knowledge in anatomy of ob/gyn residents. MATERIEL AND METHODS: The assessment of pelvic anatomy knowledge of 52 ob/gyn residents was performed in a cross sectional analysis in Lille University Hospital in 2015. A survey was designed with educational and clinical objectives on pelvic anatomy to assess the resident's real level of knowledge. RESULTS: Ob/gyn residents were not satisfied with the learning of anatomy at the medical school with a global rate of 92% of unhappy residents. The global score in anatomy for the overall population was 6.67+/-0.46 (on 20 points). The eldest residents had a significant better global score than the youngest, 9.24+/-0.76 vs. 5.53+/-0.46 (P<0.0001). CONCLUSIONS: Ob/gyn residents should be educated to a specific teaching in anatomy throughout their residency program. Some strategies could improve the level of ob/gyn residents in anatomy and the survey showed the attractiveness of residents to modern medias, such as anatomy videos, compared to current historical anatomy lectures human cadaveric dissections or books. PMID- 28866127 TI - Is anagrelide safe during pregnancy? PMID- 28866128 TI - Melatonin prevents memory impairment induced by high-fat diet: Role of oxidative stress. AB - Consumption of high-fat diet (HFD) induces oxidative stress in the hippocampus that leads to memory impairment. Melatonin has antioxidant and neuroprotective effects. In this study, we hypothesized that chronic administration of melatonin can prevent memory impairment induced by consumption of HFD. Melatonin was administered to rats via oral gavage (100mg/kg/day) for 4 weeks. HFD was also instituted for the same duration. Behavioral studies were conducted to test spatial memory using the radial arm water maze. Additionally, oxidative stress biomarkers were assessed in the hippocampus. Results showed that HFD impaired both short- and long- term memory (P<0.05), while melatonin treatment prevented such effects. Furthermore, melatonin prevented HFD-induced reduction in levels of GSH, and ratio of GSH/GSSG, and increase in GSSG in the hippocampus. Melatonin also prevented reduction in the catalase activity in hippocampus of animals on HFD. In conclusion, HFD induced memory impairment and melatonin prevented this impairment probably by preventing alteration of oxidative stress in the hippocampus. PMID- 28866129 TI - Inhibition of GABA A receptor improved special memory impairment in the local model of demyelination in rat hippocampus. AB - Cognitive impairment and memory deficit are common features in multiple Sclerosis patients. The mechanism of memory impairment in MS is unknown, but neuroimaging studies suggest that hippocampal demyelination is involved. Here, we investigate the role of GABA A receptor on spatial memory in the local model of hippocampal demyelination. Demyelination was induced in male Wistar rats by bilaterally injection of lysophosphatidylcholine (LPC) 1% into the CA1 region of the hippocampus. The treatment groups were received daily intraventricular injection of bicuculline (0.025, 0.05MUg/2MUl/animal) or muscimol (0.1, 0.2MUg/2MUl/animal) 5days after LPC injection. Morris Water Maze was used to evaluate learning and memory in rats. We used Luxol fast blue staining and qPCR to assess demyelination extention and MBP expression level respectively. Immunohistochemistry (IHC) for CD45 and H&E staining were performed to assess inflammatory cells infiltration. Behavioral study revealed that LPC injection in the hippocampus impaired learning and memory function. Animals treated with both doses of bicuculline improved spatial learning and memory function; however, muscimol treatment had no effect. Histological and MBP expression studies confirmed that demylination in LPC group was maximal. Bicuculline treatment significantly reduced demyelination extension and increased the level of MBP expression. H&E and IHC results showed that bicuculline reduced inflammatory cell infiltration in the lesion site. Bicuculline improved learning and memory and decreased demyelination extention in the LPC-induced hippocampal demyelination model. We conclude that disruption of GABAergic homeostasis in hippocampal demyelination context may be involved in memory impairment with the implications for both pathophysiology and therapy. PMID- 28866130 TI - Differential effects of imipramine and CORT118335 (Glucocorticoid receptor modulator/mineralocorticoid receptor antagonist) on brain-endocrine stress responses and depression-like behavior in female rats. AB - Depression is commonly associated with hypothalamic-pituitary adrenal (HPA) axis dysfunction that primarily manifests as aberrant glucocorticoid secretion. Glucocorticoids act on Type I mineralocorticoid (MR) and Type II glucocorticoid receptors (GR) to modulate mood and endocrine responses. Successful antidepressant treatment normalizes HPA axis function, in part due to modulatory effects on MR and GR in cortico-limbic structures. Although women are twice as likely to suffer from depression, little is known about how antidepressants modulate brain, endocrine, and behavioral stress responses in females. Here, we assessed the impact of CORT118335 (GR modulator/MR antagonist) and imipramine (tricyclic antidepressant) on neuroendocrine and behavioral responses to restraint or forced swim stress (FST) in female rats (n=10-12/group). Increased immobility CORT118335 in the FST is purported to reflect passive coping or depression-like behavior. CORT118335 dampened adrenocorticotropic hormone (ACTH) and corticosterone responses to the FST, but did not affect immobility. Imipramine suppressed ACTH, but had minimal effects on corticosterone responses to FST. Despite these marginal effects, imipramine decreased immobility, suggesting antidepressant efficacy. In an effort to link brain-endocrine responses with behavior, c-Fos was assessed in HPA axis and mood modulatory regions in response to the FST. CORT118335 upregulated c-Fos expression in the paraventricular nucleus of the hypothalamus. Imipramine decreased c-Fos in the basolateral amygdala and hippocampus (CA1 and CA3), but increased c-Fos in the central amygdala. These data suggest the antidepressant-like (e.g., active coping) properties of imipramine may be due to widespread effects on cortico limbic circuits that regulate emotional and cognitive processes. PMID- 28866131 TI - Increased emotional reactivity to affective pictures in patients with skin picking disorder: Evidence from functional magnetic resonance imaging. AB - The predominant symptom of skin-picking disorder (SPD) is the recurrent picking of one's own skin, leading to tissue damage and discomfort. Psychological disorder models suggest an enhanced emotional reactivity in patients with SPD, which contributes to the maintenance of symptoms. This functional magnetic resonance imaging (fMRI) experiment analyzed both subjective and neuronal responses to affective pictures (categories: fear, disgust, happiness, neutral) in 19 women with SPD and 16 healthy controls. Also, affective traits (disgust, anxiety, depression) were assessed. Those with SPD scored higher on trait anxiety/depression, and reported higher intensities of negative emotions experienced during the picture viewing. On the neuronal level, the clinical group showed enhanced localized brain activation to fear, disgust and happiness in the amygdala, the insula and the orbitofrontal cortex. These regions are part of a brain circuit mediating affective responses and affective awareness. The current fMRI study provides first data on the neuronal basis of elevated emotional reactivity to affective pictures in SPD. PMID- 28866132 TI - Combining R-DOTAP and a particulate antigen delivery platform to trigger dendritic cell activation: Formulation development and in-vitro interaction studies. AB - The utilization of the cationic lipid R-DOTAP as immune cell stimulant (e.g. its stimulating effects on immature dendritic cells) and correspondingly as possible adjuvant for vaccination is well known. Likewise, it is described in literature that solid polymer particles loaded with antigens can be size-tailored in a manner to be suitable for phagocytosis by antigen presenting cells. The effects of DOTAP-microparticle combinations, however, are not well understood. This study aimed therefore to explore the potential of R-DOTAP stabilized microparticles (MP) to act as a carrier platform for antigens e.g. for cancer vaccination. It was investigated whether or not a combination of R-DOTAP and PLGA leads to a boosted adjuvant effect in dendritic cell maturation. For proper comparison, neutral and negatively charged MPs of comparable sizes were developed. Toxicity, uptake, routing and maturation of the MP platform was assessed in-vitro on human immature dendritic cells (iDCs). Interestingly, none of the tested placebo formulations (without antigen) was capable to induce DC maturation when compared to LPS as positive control. This is in contrast to experiments previously reported in literature, where R-DOTAP (e.g. in liposomal form) triggered iDC maturation even without antigen. Possible reasons and further approaches are discussed in the paper. PMID- 28866133 TI - MDA-MB-231 breast cancer cells fuel osteoclast metabolism and activity: A new rationale for the pathogenesis of osteolytic bone metastases. AB - Recent progress in dissecting the molecular paracrine circuits of cancer and stromal cells in bone metastases (BM) are offering new options to improve current merely palliative approach. The study of tumor-stroma metabolic interplay may further ameliorate this scenario. In this context, we demonstrated that highly glycolytic MDA-MB-231 cancer cells, that form osteolytic BM in vivo, release a large amount of lactate at a significantly higher level than MCF7 cells. Thus, we speculated that lactate released from carcinoma cells is uptaken and metabolically used by osteoclasts, the key players of osteolysis associated with BM. First, we demonstrated that the release of lactate at the bone site is mediated by monocarboxylate transporter 4 (MCT4), as revealed by immunostaining and MCT4 localization at the plasma membrane of tumor cells in mouse model of BM and in human tissue sections of BM. Then, we showed that in vitro lactate is uptaken by osteoclasts to be used as a fuel for the oxidative metabolism of osteoclasts, ultimately enhancing Type I collagen resorption. The passive transport of lactate into osteoclasts was mediated by MCT1: MCT1 expression is significantly upregulated during osteoclast differentiation and Type I collagen resorption is significantly impaired when osteoclasts are treated with 7-(N benzyl-N-methylamino)-2-oxo-2H-chromene-3-carboxylic acid, an MCT-1 inhibitor. Together, these data demonstrate that lactate released by glycolytic breast carcinoma cells in the bone microenvironment promotes the formation of osteolytic lesions, and provide the rationale for further studies on the use of MCT1 targeting as a novel therapeutic approach in advanced cancer patients with BM. PMID- 28866134 TI - Wnt/beta-catenin signaling links embryonic lung development and asthmatic airway remodeling. AB - Embryonic lung development requires reciprocal endodermal-mesodermal interactions; mediated by various signaling proteins. Wnt/beta-catenin is a signaling protein that exhibits the pivotal role in lung development, injury and repair while aberrant expression of Wnt/beta-catenin signaling leads to asthmatic airway remodeling: characterized by hyperplasia and hypertrophy of airway smooth muscle cells, alveolar and vascular damage goblet cells metaplasia, and deposition of extracellular matrix; resulting in decreased lung compliance and increased airway resistance. The substantial evidence suggests that Wnt/beta catenin signaling links embryonic lung development and asthmatic airway remodeling. Here, we summarized the recent advances related to the mechanistic role of Wnt/beta-catenin signaling in lung development, consequences of aberrant expression or deletion of Wnt/beta-catenin signaling in expansion and progression of asthmatic airway remodeling, and linking early-impaired pulmonary development and airway remodeling later in life. Finally, we emphasized all possible recent potential therapeutic significance and future prospectives, that are adaptable for therapeutic intervention to treat asthmatic airway remodeling. PMID- 28866135 TI - Congenital Zika syndrome with prolonged detection of Zika virus RNA. PMID- 28866136 TI - Major globally disseminated clonal complexes of antimicrobial resistant enterococci associated with infections in cancer patients in Brazil. AB - Cancer and hematological malignancies constitute major comorbidities in enterococcal infections, but little is known about the characteristics of enterococci affecting cancer patients. The aim of this study was to characterize 132 enterococcal clinical isolates obtained from cancer patients attending a Cancer Reference Center in Brazil between April 2013 and March 2014. Susceptibility to 17 antimicrobial agents was assessed by disk diffusion method. Resistance and virulence genes were investigated by PCR. Multilocus sequence typing (MLST) was performed for selected Enterococcus faecalis and Enterococcus faecium isolates. The predominant species was E. faecalis (108 isolates), followed by E. faecium (18), Enterococcus gallinarum (3), Enterococcus avium (2) and Enterococcus durans (1). Multidrug-resistant (MDR) isolates made up 44.7%, but all isolates were susceptible to fosfomycin, linezolid and glycopeptides. The most prevalent genes associated with erythromycin- and tetracycline-non susceptible isolates were erm(B) (47/71; 66.2%) and tet(M) (24/68; 35.3%), respectively. High-level resistance (HLR) to gentamicin was found in 22 (16.7%) isolates and 13 (59.1%) of them carried the aac(6')-Ie-aph(2")-Ia gene. HLR to streptomycin was detected in 34 (25.8%) isolates, of which 15 (44.1%) isolates had the ant(6')-Ia gene. The most common virulence genes were gelE (48.9%), esp (30.5%) and asa1 (29.8%). MLST performed for 26 E. faecalis isolates revealed 18 different sequence-types (STs), with seven corresponding to novel STs (625, 626, 627, 628, 629, 630, and 635). On the other hand, nine of 10 E. faecium isolates analyzed by MLST belonged to a single clonal complex, comprised of mostly ST412, which emerged worldwide after mid-2000s, but also two novel STs (963 and 964). We detected major globally disseminated E. faecalis and E. faecium clonal complexes along with novel closely related STs, indicating the fitness and continuous evolution of these hospital-adapted lineages. PMID- 28866137 TI - Aedes Aegypti saliva enhances chikungunya virus replication in human skin fibroblasts via inhibition of the type I interferon signaling pathway. AB - Chikungunya virus (CHIKV) transmission occurs through the bite of an infected Aedes mosquito which injects virus-containing saliva into the skin of the human host during blood feeding. In the present study, we have determined the effect of Aedes aegypti saliva on CHIKV replication in human skin fibroblasts, a major cell type for viral entry, which mimics the events that occur during natural transmission. A significant increase in the expression of viral transcripts and infectious viral particles was observed in fibroblasts infected with CHIKV in the presence of saliva, as compared with those infected with virus alone. CHIKV infected human fibroblasts were found to express significantly increased levels of various type I IFN-responsive genes, as demonstrated by specific PCR array analysis. In contrast, the expression of these genes was markedly decreased in cells infected with CHIKV in the presence of mosquito saliva. Moreover, Western blotting analysis revealed that STAT2 and its phosphorylated form were down regulated in the presence of mosquito saliva. Our data demonstrate for the first time the significance of Aedes aegypti saliva in promoting CHIKV infection via down-regulation of several type I IFN-responsive genes in infected human skin fibroblasts via the JAK-STAT signaling pathway. PMID- 28866138 TI - Identification of two novel Rotavirus A genotypes, G35 and P[50], from Peruvian alpaca faeces. AB - Rotavirus A (RVA) Alp11B was detected from a neonatal Peruvian alpaca presenting with diarrhea, and the Alp11B VP7, VP4, VP6, NSP4, and NSP5 genes were sequenced. The partial genotype constellation of this strain, RVA/Alpaca-wt/PER/Alp11B/2010, was determined to be G35-P[50]-I13-E16-H6. PMID- 28866139 TI - Impact of caloric intake in critically ill patients with, and without, refeeding syndrome: A retrospective study. AB - BACKGROUND & AIMS: Refeeding syndrome comprises metabolic disturbances that occur after the reintroduction of feeding after prolonged fasting. Standard care consists of correcting fluid and electrolytes imbalances. Energy intake during refeeding syndrome is heavily debated. This study addresses the effect of caloric intake on outcome during the management of refeeding syndrome. METHODS: A retrospective study among critically ill invasive mechanically ventilated patients admitted for >7 days to a medical-surgical ICU. Refeeding syndrome was diagnosed by the occurrence of new onset hypophosphatemia (<0.65 mmol/l) within 72 h of the start of nutritional support. Primary outcome was 6-month mortality. Secondary outcomes were 3-month mortality, ICU and hospital length of stay and duration of mechanical ventilation. Outcomes of patients with and without refeeding syndrome were compared and subgroup analysis on energy intake within the refeeding population was performed for the duration of survival. RESULTS: Of 337 enrolled patients, 124 (36.8%) developed refeeding syndrome and 213 patients (63.2%) maintained normal serum phosphate levels. Between the two groups, no statistical significant differences in clinical outcomes were observed. Within the refeeding syndrome group, a reduced 6-month mortality risk for low caloric intake (<50% of target) was seen compared with normal intake, adjusted Hazard Ratio 0.39, (95% CI 0.16-0.95, p = 0.037). In this group, low caloric intake was associated with an increased overall survival time at day 180 (153.0 (SE 10.1) vs 119.1 (SE 8.0) days, log-rank p = 0.018). CONCLUSIONS: Refeeding syndrome is common among prolonged mechanically ventilated critically ill patients, however not predictable by baseline characteristics. Among patients that develop refeeding syndrome low caloric intake was associated with a reduction in 6-month mortality risk. This effect was not seen in patients without refeeding syndrome. Findings support caloric restriction in refeeding syndrome during critical illness. PMID- 28866140 TI - Perioperative supplementation with a fruit and vegetable juice powder concentrate and postsurgical morbidity: A double-blind, randomised, placebo-controlled clinical trial. AB - BACKGROUND & AIMS: Surgical trauma leads to an inflammatory response that causes surgical morbidity. Reduced antioxidant micronutrient (AM)a levels and/or excessive levels of Reactive Oxygen Species (ROS)b have previously been linked to delayed wound healing and presence of chronic wounds. We aimed to evaluate the effect of pre-operative supplementation with encapsulated fruit and vegetable juice powder concentrate (JuicePlus+(r)) on postoperative morbidity and Quality of Life (QoL)c. METHODS: We conducted a randomised, double-blind, placebo controlled two-arm parallel clinical trial evaluating postoperative morbidity following lower third molar surgery. Patients aged between 18 and 65 years were randomised to take verum or placebo for 10 weeks prior to surgery and during the first postoperative week. The primary endpoint was the between-group difference in QoL over the first postoperative week, with secondary endpoints being related to other measures of postoperative morbidity (pain and trismus). RESULTS: One hundred and eighty-three out of 238 randomised patients received surgery (Intention-To-Treat population). Postoperative QoL tended to be higher in the active compared to the placebo group. Furthermore, reduction in mouth opening 2 days after surgery was 3.1 mm smaller (95% CI 0.1, 6.1), the mean pain score over the postoperative week was 8.5 mm lower (95% CI 1.8, 15.2) and patients were less likely to experience moderate to severe pain on postoperative day 2 (RR 0.58, 95% CI 0.35, 0.95), comparing verum to placebo groups. CONCLUSION: Pre-operative supplementation with a fruit and vegetable supplement rich in AM may improve postoperative QoL and reduce surgical morbidity and post-operative complications after surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01145820; Registered June 16, 2010. PMID- 28866141 TI - Clinical nutrition education in medical schools: Results of an ESPEN survey. PMID- 28866142 TI - In vitro and in vivo degradation of rapamycin-eluting Mg-Nd-Zn-Zr alloy stents in porcine coronary arteries. AB - In this work, rapamycin-eluting poly (d, l-lactic acid) coating (PDLLA/RAPA) was prepared on biodegradable Mg-Nd-Zn-Zr alloy (JDBM) for both in vitro and in vivo investigation of the degradation behaviors of the magnesium alloy stent platform. Electrochemical tests and hydrogen evolution test demonstrated significant in vitro protection of the polymeric coating against magnesium degradation both in short and long term. The 3-month in vivo study on the RAPA-eluting JDBM stent implanted into porcine coronary arteries confirmed its favorable safety, and in the meanwhile revealed similar neointima proliferation compared to the second generation DES Firebird 2 with no occurrence of adverse complications. Moreover, Micro-CT examination combined with IVUS and OCT detection indicated a remarkably lower degradation rate and prolonged radial supporting duration of the drug eluting JDBM stent as compared to the bare, attributable to the protection of the coating in vivo. Hence, rapamycin-eluting JDBM stents exhibit great potential for clinical application. PMID- 28866143 TI - Construction of ICG encapsulated W18O49@MSN as a fluorescence carrier for real time tracked photothermal therapy. AB - Photothermal therapy (PTT) has drawn tremendous attention because of its high therapeutic efficiency in targeting cells while minimizing the damage to normal tissues and organs. Tungsten oxide (W18O49, WO) plays a pivotal role in PTT development and its use in PTT systems has been extensively studied. However, it is difficult to control morphology of WO through conventional hydrothermal method. Which make its related researches have been limited up to now. In this study, we describe the construction and effects on tumor of a novel nanoplatform based on WO and indocyanine green (ICG) loaded in mesoporous silica nanoparticles (MSN) for dual-modal PTT and near-infrared imaging. (WO+ICG)@MSN could efficiently control WO shape without the need of surface modification due to its water-soluble of MSN. (WO+ICG)@MSN produced a PTT synergistic effect under irradiation of a single 808nm near-infrared (NIR) laser. Notably, an enhanced lethal effect of the 808nm laser triggering dual-modal therapy on B16 tumor cells was observed. The in vivo animal experiments showed that (WO+ICG)@MSN induced an effective solid tumor reduction under 808nm NIR light irradiation, revealing the potential of these nanocomposites as a NIR-mediated dual-modal therapeutic platform for cancer treatment. PMID- 28866144 TI - Solvothermal synthesis of Sm3+-doped Fe3O4 nanoparticles. AB - Magnetic iron oxide nanoparticles doped with samarium were prepared by solvothermal polyol method. An introduction of 2,2'-bipyridine during the synthesis reduces the particle diameter to about 9nm in average. The difference in physical and magnetic properties of the samples prepared with and without capping agent was outlined on the basis of complex characterization by a number of experimental techniques. The characteristics of resulted product make it suitable for biomedical applications, for instance, as a contrast agent for MRI. PMID- 28866145 TI - Bactericidal performance of nanostructured surfaces by fluorocarbon plasma. AB - This study presents the characterization and antibacterial activity of nanostructured Si by plasma treatment method using a tetrafluoromethane (CF4) and hydrogen (H2) mixture. Nanostructured-Si is a synthetic nanomaterial that contains high aspect ratio nanoprotrusions on its surface, produced through a reactive-ion etching process. We have shown that the nanoprotrusions on the surfaces produce a mechanical bactericidal effect. Nanostructured-Si exhibited notable activity against three different microorganisms: Gram-negative (Escherichia coli), Gram-positive (Staphylococcus aureus) and spore-forming bacteria (Bacillus cereus) producing a > 5 log10 reduction after 24h of incubation. Scanning electron microscopy was used to analysis the structure and morphology character of different surfaces evidencing the physical bactericidal activity of the Nanostructured-Si. These results provide excellent prospects for the development of a new generation of antibacterial surfaces. PMID- 28866147 TI - Nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/collagen/graphene oxide scaffolds for wound coverage. AB - The purpose of wound management is to prevent wound from infection, increase the fibroblast cell growth, and preserve cellular function. The polymeric electrospun nanofiber scaffold made up of natural and/or synthetic polymer provides an extracellular matrix for support and initiates the growth, proliferation and differentiation of fibroblast cells. The present study deals with the development of poly3-hydroxybutyric acid-co-3-hydroxyvaleric acid (PHBV) nanofibrous scaffold imbedded with graphene oxide (GO), and collagen. Nanofibrous PHBV offers advantages like structural resemblance to native extracellular matrix, high porosity and surface area to volume ratio. The nanofibrous mats were morphologically and chemically characterized by Field Emission Scanning Electron Microscopy (FESEM) and Fourier Transform Infrared (FTIR) Spectroscopy. FESEM images showed the nanofiber diameter was decreased and porosity increased by adding GO and collagen into the matrix without any chemical interaction among them. Incorporation of GO into the matrix increases mechanical strength of scaffold in addition to antibacterial activity against E. coli and S. aureus with decrease in pore size and hydrophilicity. In contrast, collagen addition into the nanofibers enhanced hydrophilicity without affecting mechanical strength and porosity significantly. Moreover, collagen enhanced cell proliferation capacity of nanofibers in comparison to the samples of PHBV+GO and virgin PHBV. The combination of collagen and GO with PHBV has balanced properties which can be utilised for the application. PMID- 28866146 TI - Rehabilitation of the atrophic mandible with short implants in different positions: A finite elements study. AB - OBJECTIVE: The aim of this study was to analyze whether the use of inclined short implants without lower transcortical involvement (test model - SI), thus preserving the mandibular lower cortical bone, could optimize stress distribution. MATERIALS AND METHODS: Six identical atrophic mandible models were created featuring 8mm of height at the symphysis. Two study factors were evaluated: implant length and angulation. Implant length was represented either by short implants (7mm) with preservation of the mandibular lower cortical bone or standard implants (9mm) with a bicortical approach and 3 possible implant positioning configurations: 4 distally-inclined implants at 45 degrees (experimental model), all-on-four, 4 vertical implants. All tridimensional (3D) models were analyzed using the Finite Element Method (FEM) and the Ansys Workbench software. RESULTS: The maximum stress on the bone at the cervical region of the implants in the experimental model was 132MPa and transcortical involvement with implant inclination yielded higher values (171MPa). Regarding von Mises stress on the retaining screw of the prosthesis, 61MPa was recorded for the experimental model while upright implants had the highest values (223MPa). At the acrylic base, 4MPa was recorded for the experimental model whereas models with upright implants showed the highest stress values (11MPa). CONCLUSION: Rehabilitation of severely resorbed mandibles with 4 short implants placed distally at 45 degrees , without lower transcortical involvement, were biomechanically more favorable, generating lower stress peaks, than the models with short implants on an all-on-four, or on an upright configuration, with or without lower transcortical involvement. PMID- 28866148 TI - Investigation on direct electrochemical and electrocatalytic behavior of hemoglobin on palladium-graphene modified electrode. AB - Palladium-graphene (Pd-GR) nanocomposite was acted as modifier for construction of the modified electrode with direct electrochemistry of hemoglobin (Hb) realized. By using Nafion as the immobilization film, Hb was fixed tightly on Pd GR nanocomposite modified carbon ionic liquid electrode. Electrochemical behaviors of Hb modified electrode were checked by cyclic voltammetry and a pair of redox peaks originated from direct electron transfer of Hb was appeared. The Hb modified electrode had excellent electrocatalytic activity to the reduction of trichloroacetic acid and sodium nitrite in the concentration range from 0.6 to 13.0mmol.L-1 and from 0.04 to 0.5 mmol.L-1. Therefore Pd-GR nanocomposite was proven to be a good candidate for the fabrication of third-generation electrochemical biosensor. PMID- 28866149 TI - Three-dimensional finite element analysis of occlusal splint and implant connection on stress distribution in implant-supported fixed dental prosthesis and peri-implantal bone. AB - The aim of this study was to investigate the influence of occlusal splint therapy on the stress distribution of implant-supported fixed dental prosthesis (FDP) and peri-implantal bone structures using three-dimensional (3D) finite element analysis (FEA). The system consisted of two implants (positioned on region of second premolar and second molar) as retainers of fixed porcelain-fused-to-metal 3-unit FDP (first molar as pontic element). Two implant connections systems (external and internal hexagon) were tested. Static axial loads simulating functional (100N) and overloaded (300N) chewing were applied on the occlusal surface of the FDP covered or not with the occlusal splint. Maximum von Mises stress and bioperformance were accessed for the implants and bone tissues (cortical and cancellous) models. Analytic results indicated that independently of the load condition, implant region, and connection type, the presence of the occlusal splint decreased the stress developed in the implants. Both bone tissues showed increased levels of von Mises stress, and the bioperformance index was far from their maximum yield strength. The internal hexagon implants presented lower stress on premolar and molar regions than external hexagon implants under functional load and overload. The presence of the occlusal splint device over implant-supported FDP may be clinically useful for forwarding stresses towards the bone structure to maintain implants for long term. PMID- 28866150 TI - Synthesis and study of thermal, mechanical and biodegradation properties of chitosan-g-PMMA with chicken egg shell (nano-CaO) as a novel bio-filler. AB - The important objective of this study is to evaluate the effect of chicken eggshell (nano-Cao) as a functionalized bio-filler on the mechanical strength and thermal stability of acrylic based bionanocomposite of chitosan grafted with poly(methyl methacrylate)(PMMA). The chitosan grafted PMMA adsorbed with functionalized biofiller was prepared via emulsion polymerisation technique and physicochemically characterized as bone graft substitute. The so prepared grafted bioactive bone cement (BBC) bionanocomposite (BNC), chitosan-g-PMMA/nano-CaO was characterized by FTIR, XRD, FESEM and TGA. The water uptake, retention ability, their biodegradability and the nanosize particle arrangement in the polymeric BBC BNCs were undertaken. These preliminary investigations of the BNCs will open the door for their use in bioadhesive bone cement implants in future. PMID- 28866151 TI - Liposomes coated with thiolated chitosan as drug carriers of curcumin. AB - Liposome is one of a promising delivery system to improve water solubility, stability, and bioavailability of curcumin. But its instability is not favorable for long-circulating treatment, controlled release or conservation. To overcome the disadvantages, thiol derivatised chitosan (CSSH) were synthesized and utilized to coat liposomes. The CSSH coated curcumin liposomes (Cur-Lip-CSSH) had an encapsulation efficiency (EE) of 93.95%, a drug loading (DL) of 7.95%, an average particle size of 406.0nm, and a positive zeta-potential of 36.6mV, which were all higher than that of Cur-Lip. Cur-Lip-CSSH showed slower in vitro release than Cur-Lip at pH5.5 and pH7.4, and the higher retention of curcumin would be remained for the following uptake of cells. The stability of the both liposomes at 4 degrees C was almost the same, but Cur-Lip-CSSH displayed a higher stability at room temperature and higher temperature by DSC characterization. Curcumin can inhibit the growth of cancer cells under certain conditions. MCF-7 cell line was used to study its inhibition and proliferation after treating with curcumin and Cur-Lip-CSSH. Treatment of MCF-7 with curcumin and Cur-Lip-CSSH showed dose and time dependent cytotoxicity, with growth suppression at 200MUM, 72h, obviously. These results indicate that the proper coating of liposomes is able to improve the stability of liposomes and the Lip-CSSH can function as potential drug delivery system. PMID- 28866152 TI - Glycerol-plasticised silk membranes made using formic acid are ductile, transparent and degradation-resistant. AB - Regenerated silk fibroin membranes tend to be brittle when dry. The use of plasticisers such as glycerol improve membrane ductility, but, when combined with aqueous processing, can lead to a higher degradation rate than solvent-annealed membranes. This study investigated the use of formic acid as the solvent with glycerol to make deformable yet degradation-resistant silk membranes. Here we show that membranes cast using formic acid had low light scattering, with a diffuse transmittance of less than 5% over the visible wavelengths, significantly lower than the 20% transmittance of aqueous derived silk/glycerol membranes. They had 64% beta-sheet content and lost just 30% of the initial silk weight over 6h when tested with an accelerated enzymatic degradation assay, in comparison the aqueous membranes completely degraded within this timeframe. The addition of glycerol also improved the maximum elongation of formic acid derived membranes from under 3% to over 100%. They also showed good cytocompatibility and supported the adhesion and migration of human tympanic membrane keratinocytes. Formic acid based, silk/glycerol membranes may be of great use in medical applications such as repair of tympanic membrane perforation or ocular applications where transparency and resistance to enzymatic degradation are important. PMID- 28866153 TI - Nonenzymatic glucose sensor based on Ag&Pt hollow nanoparticles supported on TiO2 nanotubes. AB - This study was dedicated to develop a nonenzymatic glucose sensor based on Ag&Pt hollow nanoparticles supported on TiO2 nanotubes. The Ag&Pt-TiO2/(500 degrees C) was synthesized by a simple reduction and galvanic replacement method in an aqueous solution. The surface morphology and structure of Ag&Pt-TiO2/(500 degrees C) could be examined by transmission electron microscopy, scanning electron microscopy and energy dispersive spectrometer. The mechanical behavior was measured by nanoindentation test and the hydropathy property was measured by contact angle test. It can be observed that Ag&Pt hollow structures with a particle size of 100nm and a wall thickness of 27nm were deposited on TiO2 nanotubes. The electrochemical properties were investigated by Electrochemical Workstation with three-electrode system. Ag&Pt(6h)-TiO2/(500 degrees C) electrode exhibited excellent catalytic ability from cyclic voltammetry and fast electron transfer rate according to the electron transfer resistance of 330Omega from impedance spectroscopy. Differential pulse voltammetry results showed the sensitivity to glucose was 3.99MUA*cm-2*mM-1, the linearity increased to 180mM and the detection limit was 22.6MUM. The prepared nonenzyme glucose sensor with good analytical performance and simple preparation method looks promising in accurate glucose detection applications. PMID- 28866154 TI - siRNA delivery using polyelectrolyte-gold nanoassemblies in neuronal cells for BACE1 gene silencing. AB - Small interfering RNA (siRNA) mediated RNA interference is a versatile therapeutic tool for many intractable genetic disorders. Various nanoassemblies specifically designed to deliver the siRNAs could be utilized for efficient siRNA delivery which is one of the major concern for the success of this therapeutic. Thus, in the present study, polyelectrolyte-gold nanoassemblies (PE-Gold NAs) were selected for siRNA delivery of an in vitro verified siRNA. Three different polyelectrolytes (polyethyleneimine, citraconic anhydride modified poly (allylamine) hydrochloride and poly l-arginine) were used to formulate the PE Gold NAs using the layer-by-layer technique. Successful physico-chemical characterizations of these PE-Gold NAs were performed using UV-Visible, FTIR, 1H NMR spectroscopies, XRD, TEM, DLS and Zeta potential measurements. In vitro studies for the cytotoxicity, the uptake of these nanoassemblies and the gene silencing were carried out using these PE-Gold NAs in N2a and NB4 1A3 (murine neuronal) cell lines. The three selected PE-Gold NAs showed significant BACE1 (beta-site APP cleaving enzyme 1) gene silencing (50-60%). This work demonstrates the potential of PE-Gold NAs to deliver siRNA targeting BACE1 in neuronal cells. Finally, it was concluded that different polyelectrolytes used in the PE-Gold NAs achieve different gene silencing due to the variation in their delivery efficiencies. PMID- 28866155 TI - A novel sensor made of Antimony Doped Tin Oxide-silica composite sol on a glassy carbon electrode modified by single-walled carbon nanotubes for detection of norepinephrine. AB - In this study, we designed a novel molecularly imprinted polymer (MIP), Antimony Doped Tin Oxide (ATO)-silica composite sol, which was made using a sol-gel method. Then a sensitive and selective imprinted electrochemical sensor was constructed with the ATO-silica composite sol on a glassy carbon electrode modified by single-walled carbon nanotubes (SWNTs). The introduction of SWNTs increased the sensitivity of the MIP sensor. The surface morphology of the MIP and MIP/SWNTs were characterized by scanning electron microscopy (SEM), and the optimal conditions for detection were determined. The oxidative peak current increased linearly with the concentration of norepinephrine in the range of 9.99*10-8M to 1.50*10-5M, as detected by cyclic voltammetry (CV), the detection limit was 3.33*10-8M (S/N=3). In addition, the proposed electrochemical sensors were successfully applied to detect the norepinephrine concentration in human blood serum samples. The recoveries of the sensors varied from 99.67% to 104.17%, indicating that the sensor has potential for the determination of norepinephrine in clinical tests. Moreover, the imprinted electrochemical sensor was used to selectively detect norepinephrine. The analytical application was conducted successfully and yielded accurate and precise results. PMID- 28866156 TI - Polymer microneedles fabricated from alginate and hyaluronate for transdermal delivery of insulin. AB - To reduce the inconvenient and painful of subcutaneous needle injection, the polymer microneedle patches that fabricated from modified alginate and hyaluronate were prepared for transdermal delivery of insulin. The as-prepared microneedles (MNs) exhibited excellent mechanical strength to penetrate the skin and good degradability to release loaded insulin. In vitro skin insertion capability was determined by staining with tissue-marking dye after insertion, and the real-time penetration depth was monitored using optical coherence tomography. Confocal microscopy images revealed that the rhodamine B and fluorescein isothiocyanate-labeled insulin (FITC-insulin) can gradually diffuse from the puncture sites to deeper tissue. In vivo and pharmacodynamic studies were then conducted to estimate the feasibility of the administration of insulin loaded microneedle patches on diabetic mice for glucose regulation. The relative pharmacologic availability (RPA) and relative bioavailability (RBA) of insulin from microneedle patches were 90.5+/-6.8% and 92.9+/-7%, respectively. These results suggests the MNs developed in this study have a promising application in diabetes treatment via transdermal delivery. PMID- 28866157 TI - Low modulus and bioactive Ti/alpha-TCP/Ti-mesh composite prepared by spark plasma sintering. AB - A titanium mesh scaffold composite filled with Ti/alpha-TCP particles was prepared by spark plasma sintering (SPS). The microstructures and interfacial reactions of the composites were investigated by scanning electron microscopy (SEM), Energy Dispersive Spectroscopy (EDS) and X-ray diffraction (XRD) analyses. The compressive strength and elastic modulus were also measured. In vitro bioactivity and biocompatibility was evaluated by using simulated body fluid and cells culture, respectively. After high temperature sintering, Ti oxides, TixPy and CaTiO3 were formed. The formation of Ti oxides and TixPy were resulted from the diffusion of O and P elements from alpha-TCP to Ti. CaTiO3 was the reaction product of Ti and alpha-TCP. The composite of 70Ti/alpha-TCP incorporated with Ti mesh showed a high compressive strength of 589MPa and a low compressive modulus of 30GPa. The bioactivity test showed the formation of a thick apatite layer on the composite and well-spread cells attachment. A good combination of mechanical properties and bioactivity indicated a high potential application of Ti/alpha TCP/Ti-mesh composite for orthopedic implants. PMID- 28866158 TI - Use of a fluorescent probe to monitor the enhanced affinity of rh-BMP-2 to silicated-calcium phosphate synthetic bone graft substitutes under competitive conditions. AB - A comparative investigation was undertaken on 1-2mm sized granules of two forms of synthetic bone graft substitute (SBG) with identical pore structure but varied bulk chemistry, stoichiometric hydroxyapatite (HA) and silicate substituted (0.8wt% Si) hydroxyapatite (SA), to assess the influence of SBG chemistry on the relative affinity of an osteogenic growth factor (GF), recombinant human bone morphogenetic protein-2 (rhBMP-2). A previously described novel fluorescent probe, fluoresceinthioureidoaminocaproic acid (FTCA), was covalently attached to rhBMP-2 to give FTCA-rhBMP-2 and facilitate the quantitative monitoring of GF uptake and release from the two chemistries of SBG. The relative affinity of rhBMP-2 for the HA and SA granules was assessed at a physiologically relevant concentration of 300ngmL-1 from three (increasingly complex) environments; phosphate buffered saline (PBS), minimum Eagles' medium (MEM) and serum supplemented MEM (SCEM) in order to closely mimic clinical bone repair procedures. The results demonstrated that rhBMP-2 affinity to SBGs was highly sensitive to both SBG chemistry and the composition of the local environment. Under the most physiologically relevant competitive conditions of SCEM, rhBMP-2 showed greater affinity to SA (P<0.05) such that 50% of the rhBMP-2 in solution was adsorbed to the SA granules after only 15min, as compared to 30% adsorbed to the HA granules. Subsequent investigation of the desorption of adsorbed GF from the SBGs demonstrated that a significantly higher percentage of the adsorbed rhBMP-2 was desorbed from HA as compared to SA granules. Together, these observations suggested that at physiologically relevant concentrations and conditions, rhBMP-2 has a greater affinity to silicate-substituted hydroxyapatite as compared to stoichiometric hydroxyapatite, which may in part explain the enhanced osteoconductivity and reported osteoinductivity for silicate-substituted hydroxyapatite based SBGs. PMID- 28866159 TI - Biomimetic modification of polyurethane-based nanofibrous vascular grafts: A promising approach towards stable endothelial lining. AB - The emerging demand for small caliber vascular grafts to replace damaged vessels has attracted research attention. However, there is no perfect replacement in clinical use yet, mainly due to low patency rate of synthetic small caliber grafts. The main pathology behind low patency rate include thrombosis and graft/vessel hemodynamic mismatch, leading to intimal hyperplasia. Rapid in-situ endothelialization of vascular grafts is considered as one of the best strategies to overcome these complications. In the present study, Heparin and VEGF were immobilized via self-polymerization and deposition of polydopamine (PDA) on polyurethane (PU) nanofibrous scaffolds to improve endothelialization. Polyurethane nanofibrous scaffold (PUNF) that mimics vascular extracellular matrix (ECM) was chosen owing to its biocompatibility, biodegradability. Scanning electron microscopy (SEM), water contact angle (CA) measurement and Raman spectroscopy were used to characterize the surface, and tensile test was used to analyze mechanical properties before and after surface modification of the scaffolds. It was found that tensile strength and young's modulus were significantly increased after PDA coating on PUNF membranes. The hemocompatibility tests revealed that surface heparinization significantly inhibited the adhesion of platelet on the scaffolds. Immobilization of VEGF on the scaffolds significantly enhanced the proliferation of human umbilical vein endothelial cells (HUVECs) through enhanced cells adhesion and improved cell scaffold interactions. The results suggest that dual-factor immobilization resulted in not only confluent monolayer of endothelial cells but also conferred excellent antithrombotic properties to the surface. This method of surface modification (immobilization of Heparin, VEGF by PDA layer) is suggested as a promising modification technique to increase hemocompatibility of small-diameter vascular grafts. PMID- 28866160 TI - Diatomite reinforced chitosan composite membrane as potential scaffold for guided bone regeneration. AB - In this study, natural silica source, diatomite, incorporated novel chitosan based composite membranes were fabricated and characterized for bone tissue engineering applications as possible bone regeneration membrane. The effect of diatomite loading on the mechanical, morphological, chemical, thermal and surface properties, wettability and in vitro cytotoxicity and cell proliferation on of composite membranes were investigated and observed by tensile test, atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), protein adsorption assay, air/water contact angle analysis and WST-1 respectively. Swelling studies were also performed by water absorption capacity determination. Results showed that incorporation of diatomite to the chitosan matrix increased the surface roughness, swelling capacity and tensile modulus of membranes. An increase of about 52% in Young's modulus was achieved for 10wt% diatomite composite membranes compared with chitosan membranes. High cell viability results were obtained with indirect extraction method. Besides, in vitro cell proliferation and ALP activity results showed that diatom incorporation significantly increased the ALP activity of Saos-2 cells cultured on chitosan membranes. The novel composite membranes prepared in the present study with tunable properties can be considered as a potential candidate as a scaffold in view of its enhanced physical & chemical properties as well as biological activities for bone tissue engineering applications. PMID- 28866161 TI - A graded graphene oxide-hydroxyapatite/silk fibroin biomimetic scaffold for bone tissue engineering. AB - To better mimic natural bone, a graphene oxide-hydroxyapatite/silk fibroin (cGO HA/SF) scaffold was fabricated by biomineralizing carboxylated GO sheets, blending with SF, and freeze-drying. The material has increasing porosity and decreasing density from outside to inside. Analysis of GO mineralization in simulated body fluid indicated that carboxylation and Chitosan may synergistically regulate HA growth along the c-axis of weakly crystalline, rod like GO-HA particles. Compared with HA/SF gradient composites, a cGO-HA gradient scaffold with cGO:HA mass ratio 1:4 has 5-fold and 2.5-fold higher compressive strength and compressive modulus, respectively. Additionally, the cGO-HA/SF composite stimulated mouse mesenchymal stem cell adhesion and proliferation, alkaline phosphatase secretion, and mineral deposition more strongly than HA/SF and pure HA scaffolds. Hence, the material may prove to be an excellent and versatile scaffold for bone tissue engineering. PMID- 28866162 TI - Synthesis and characterization of pectin-6-aminohexanoic acid-magnetite nanoparticles for drug delivery. AB - In this study, we have synthesized magnetic nanocomposites of magnetite nanoparticles coated with 6-aminohexanoic acid and pectin (MAP). The size of the aqueous dispersion of the nanocomposites was 147nm with a Polydispersity index (PDI) of 0.32, and the nanocomposites were stable in NaCl up to a concentration of 0.45% (w/v) after which they aggregated. The dispersion of the nanocomposites was stable in Dulbecco's Modified Eagle's medium (DMEM) in the presence of 5 and 10% fetal bovine serum (FBS). Curcumin was used as a model drug to evaluate the potential of the nanocomposites for drug delivery applications. The release behavior of curcumin from the nanocomposites showed a biphasic pattern with initial burst release followed by a slow release, and the size of the aqueous dispersion of curcumin loaded nanocomposites was 159nm with a PDI of 0.34. PMID- 28866163 TI - Synergistic effects of Woodfordia fruticosa gold nanoparticles in preventing microbial adhesion and accelerating wound healing in Wistar albino rats in vivo. AB - Therapeutic effectiveness of biogenically synthesized Woodfordia fruticosa nano gold particles (WfAuNPs) has been claimed in this study which prevents microbial adhesion and enhanced wound healing potential on Wistar albino rats. The synthesized WfAuNPs were characterized using several biophysical techniques such as UV-Visible Spectroscopy (UV-vis), X-Ray Diffraction (XRD), Dynamic Light Scattering (DLS), Zeta Potential, Fourier Transform Infrared Spectroscopy (FTIR), Field Emission Scanning Electron Microscopy (FE-SEM), Atomic Force Microscopy (AFM) and High Resolution Transmission Electron Microscopy (HR-TEM) analysis. The synthesized WfAuNPs in the size range of 10-20nm were used to develop 1% Carbopol(r) 934 based nano gold formulation (WfAuNPs-Carbopol(r) 934). The WfAuNPs-Carbopol(r) 934 nanoformulation was evaluated using viscosity and spreadability measurements. The wound healing potential of WfAuNPs-Carbopol(r) 934 monitored up to 12days was confirmed by performing wound contraction (%), epithelialization, and histopathological studies done in vivo on Wistar albino rats. The hydroxyproline content was also measured in the re-epithelized skin for quantification of collagen content. The effects of WfAuNPs on microbial adhesion leading to biofilm formation were evaluated against Candida albicans and Cryptococcus neoformans fungal strains. The respective Minimum Inhibitory Concentration (MIC80), Biofilm Inhibitory Concentration (BIC80) and Biofilm Eradication Concentration (BEC80) values of C. albicans was found to be 16, 32, 256MUg/ml respectively while for C. neoformans it was recorded to be 32, 64, 256MUg/ml respectively. Data obtained, confirmed the effectiveness in preventing microbial adhesion and wound healing potential of the WfAuNPs as compared to current marketed formulations. PMID- 28866164 TI - Comparison of glutaraldehyde and procyanidin cross-linked scaffolds for soft tissue engineering. AB - Soft tissue injuries are among the most difficult orthopaedic conditions to treat, and regenerative medicine holds the promise of better treatments of these injuries. There is therefore a requirement for substrates and porous scaffolds which provide an appropriate chemical and mechanical environment for cell attachment, growth, proliferation and differentiation. In this study, cross linked porous gelatin-chitosan (Gel/Chi) scaffolds with high porosity (>90%) were fabricated and their internal morphology, pore sizes and porosities were characterized using scanning electron microscopy (SEM), micro computed tomography (micro-CT) and mercury intrusion porosimetry. The cross-linking agents chosen for this study were Procyanidin (PA), chosen for its biocompatibility, and glutaraldehyde (GA), chosen for comparison as a highly effective cross-linker. Concentrations of these cross-linkers varied from 0.1% to 1% (w/v) and controls had the same gelatin-chitosan blend but were untreated. It was found that the water absorption of cross-linked scaffolds decreased as the cross-linker concentration increased and in vitro collagenase degradation test showed both cross-linkers increased the biostability of the scaffolds. Scaffolds were also tested under compressive load to investigate their resistance to deformation. The results indicated that both cross-linkers increase the stiffness of the scaffolds both initially and at higher strains, but GA cross-linked scaffolds had a higher compressive stiffness than scaffolds cross-linked with PA for a given concentration. Results from cyclic compression and stress relaxation tests showed that PA cross-linked scaffolds recover more rapidly after deformation. 3T3 fibroblasts were cultured on the scaffolds to assess cytotoxicity and biocompatibility. The results indicated that PA was non-cytotoxic and promoted the attachment and proliferation of the seeded cells, while fewer cells were seen on GA cross-linked scaffolds, indicating that the GA had conferred some cytotoxicity. PA cross-linked Gel/Chi porous scaffolds show promise as three dimentional porous scaffolds in tissue engineering, as porous substrates for biomimetic culture environments, and for regenerative medicine applications, due to their excellent biocompatibility and easily adaptable mechanical properties, as well as their lower cost compared to collagen and fibrin based substrates. PMID- 28866165 TI - Multifunctional gold coated iron oxide core-shell nanoparticles stabilized using thiolated sodium alginate for biomedical applications. AB - In this paper we report synthesis of aqueous based gold coated iron oxide nanoparticles to integrate the localized surface plasma resonance (SPR) properties of gold and magnetic properties of iron oxide in a single system. Iron oxide-gold core shell nanoparticles were stabilized by attachment of thiolated sodium alginate to the surface of nanoparticles. Transmission electron microscope (TEM) micrograph presents an average elementary particle size of 8.1+/-2.1nm. High resolution TEM (HR-TEM) and X-ray photon spectroscopy further confirms the presence of gold shell around iron oxide core. Gold coating is responsible for reducing saturation magnetization (Ms) value from ~41emu/g to ~24emu/g - in thiolated sodium alginate stabilized gold coated iron oxide core-shell nanoparticles. The drug (curcumin) loading efficiency for the prepared nanocomposites was estimated to be around 7.2wt% (72MUgdrug/mg nanoparticles) with encapsulation efficiency of 72.8%. Gold-coated iron oxide core-shell nanoparticles could be of immense importance in the field of targeted drug delivery along with capability to be used as contrast agent for MRI & CT. PMID- 28866166 TI - Polymer brush hexadecyltrimethylammonium bromide (CTAB) modified poly (propylene g-styrene sulphonic acid) fiber (ZB-1): CTAB/ZB-1 as a promising strategy for improving the dissolution and physical stability of poorly water-soluble drugs. AB - The feasibility of polymer brush as drug delivery vehicle was demonstrated with the goal of improving the dissolution and physical stability of poorly water soluble drugs. Polymer brush CTAB/ZB-1 was synthesized by electrostatic interaction using a physical modification method with anionic poly (propylene-g styrene sulphonic acid) fiber (ZB-1) as the substrate and cationic hexadecyltrimethylammonium bromide (CTAB) as the modifier. The polymer brush structure of CTAB/ZB-1 was validated by atomic force microscopy (AFM) and the channels of brush provided the drug loading sites. Flurbiprofen (FP), a BCS class II representative drug, was selected as the model poorly water-soluble drug to be loaded into this polymer brush. Then the drug loading and release were systematically investigated. Besides, the transformation from crystalline FP to amorphous state was observed by differential scanning calorimeter (DSC). In vitro dissolution in pure water and pH1.2 HCl media with/without 0.1% sodium dodecyl sulfate (SDS) was tested. Moreover, the optimal formulations (namely carrier/drug ratios) were determined. The results demonstrated prominent improvement of dissolution when FP was released from CTAB/ZB-1. After a long time storage, FP remained amorphous in CTAB/ZB-1 according to DSC determinations and performed an approximately equivalent dissolution compared with fresh samples, suggesting the advantage of CTAB/ZB-1 as carrier in enhancing the physical stability of drugs. The study introduced the versatile easily formulated polymer brush CTAB/ZB-1 and demonstrated the potential of polymer brush as an alternative approach for improving the dissolution and physical stability of poorly water-soluble drugs. PMID- 28866167 TI - Design of multi-functional cotton gauze with antimicrobial and drug delivery properties. AB - The ideal biomedical fiber/fabric materials can both promote the drug delivery properties and prevent microbial infection. Herein we present an innovation-based strategy for fabrication of biomedical cotton gauze which concomitantly displays antimicrobial and drug delivery performance properties. The innovative strategy involved three distinct steps: (1) Cationization of cotton gauze by reacting it with 3-chloro-2-hydroxypropyl trimethyl ammonium chloride [Quat-188] or anionization of cotton gauze through partial carboxymethylation. (2) Thus modified samples of cotton gauze along with unmodified blank samples were submitted to in situ formation of silver nanoparticles (AgNPs) using trisodium citrate (TSC) which has three-fold functions: (a) reducing agent for conversion of Ag+ to Ago (atom), (b) stabilizing agent to prevent aggregation of AgNPs and, (c) linker for fixation of AgNPs on the surfaces of the cotton gauze. (3) All the modified and unmodified cotton gauze samples were loaded with oxytetracyline hydrochloride drug. To this end, characterization of the modified and unmodified cotton samples before and after being loaded with drug using state-of-the-art facilities was undertaken. These facilities comprised UV-vis spectroscopy, energy dispersive X-ray, scanning electron microscope and Infrared Spectroscopy by Attenuated total Reflectance (ATR/IR). Evaluation of the antimicrobial and drug release properties of the cotton gauze samples in question was conducting. Results obtained signified that the modified cotton gauze can be used in the area of biomedical textiles particularly as antimicrobial and drug delivery. Also reported were mechanisms entailed in chemical modifications of cotton gauze and interactions of this modified cotton gauze with antimicrobial as well as with drugs. PMID- 28866168 TI - Osteogenic differentiation of mesenchymal stem cells (MSCs) induced by three calcium phosphate ceramic (CaP) powders: A comparative study. AB - Calcium phosphate ceramics (CaPs) appear to be suitable alternatives for bone grafts because of their similarity to bone. Tricalcium phosphate (TCP), hydroxyapatite (HA) and biphasic calcium phosphates (BCP) are most commonly used CaPs. In this study, we studied and compared the osteoinductive ability of the powders of the three CaPs including HA, TCP and BCP (HA/beta-TCP weight ratio of 60/40) by using bone marrow derived mesenchymal stem cells (MSCs). Osteoblastic formation, mineralization and gene expression of osteogenesis markers were measured in MSCs after 7, 14, 21days of culture. Results showed a positive osteogenic differentiation effect of CaPs powders on MSCs as evidenced by an increased alkaline phosphatase (ALP) activity, positive ALP and Alizarin Red S staining, and upregulated osteoblastic gene expression compared with control. For the three CaPs, BCP powders showed the most prominent effect on osteoinduction. Next to BCP is TCP. Thus, this study supported that BCP may have better application prospects for repairing of bone defects in clinic. PMID- 28866170 TI - Printability study of hydrogel solution extrusion in nanoclay yield-stress bath during printing-then-gelation biofabrication. AB - Yield-stress support bath-enabled extrusion printing is emerging as a promising filament-based direct-write strategy for different applications in tissue engineering and regenerative medicine. Central to the printing quality of complex three-dimensional structures fabricated by the support bath-enabled fabrication approach is the formation of a continuous filament with well-defined geometry. The objective of this research is to study the printability of hydrogel precursor solutions in a Laponite nanoclay yield-stress bath during extrusion printing where the printed hydrogel precursor solutions remain liquid. The printability herein is mainly evaluated based on the morphology and dimensions of printed liquid filaments. Seven filament types are observed during extrusion in the nanoclay bath: three types of well-defined filaments (swelling, equivalent diameter, and stretched) and four types of irregular filaments (rough surface, over-deposited, compressed, and discontinuous). When the alginate concentration increases, the diameter of filaments made of alginate-gelatin blends decreases. The nanoclay concentration significantly affects the morphology of deposited filaments: low concentration Laponite bath (such as 0.5% (w/v)) may lead to the formation of irregular filaments such as rough surface and over-deposited filaments while high concentration bath (such as 8.0% (w/v)) may result in the formation of compressed filaments. Operating conditions affect the filament diameter and morphology similar to those as observed during conventional extrusion printing. The printability knowledge enables the successful fabrication of cellular vascular constructs in the Laponite nanoclay bath. PMID- 28866169 TI - Peptide functionalized poly ethylene glycol-poly caprolactone nanomicelles for specific cabazitaxel delivery to metastatic breast cancer cells. AB - Metastatic cancer is responsible for 90% of deaths in world. Usage of nano carriers improve the delivery and efficacy of chemotherapeutic agents. Recent studies suggest that decoration of the surface of nano-carriers with various targeting agents may further improve their overall therapeutic efficacy. Using specified peptides in targeted drug delivery is a key point in recent researches. In this study, tumor metastasis targeting (TMT) homing peptide was applied as a targeting group to improve specific drug delivery to tumor cells. TMT peptide is conjugated to poly ethylene glycol-poly caprolactone (PEG-PCL) micellar nanoparticles as carriers for targeted delivery of cabazitaxel to metastatic breast cancer cells. Synthesis of PEG-PCL copolymer was performed by amidation reaction between carboxylic acid group of PEG and amine group of PCL. Nanomicelles were prepared via solvent evaporation method. TMT peptide was covalently conjugated onto nanomicelles through the amine group of PEG. TMT-PEG PCL nanoparticles were analyzed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), dynamic light scattering (DLS), gel permeation chromatography (GPC) and nuclear magnetic resonance (NMR). Toxicity and cellular uptake of nanomicelles were investigated by in vitro cytotoxicity assays and confocal scanning microscopy in MCF-7 (non-metastatic breast cancer cells) and MDA-MB-231 (metastatic breast cancer cells). The final nanomicelles had about 110nm mean size and encapsulation efficiency of 82.5%. Treatment of metastatic breast cancer cells with targeted nanomicelles significantly increased the necrosis rate to 65%, compared to 33% in non-targeted nanomicelles and 8% in control group. The MDA-MB-231 cells treated with targeted nanomicelles exhibited a strong increase in the fluorescence intensity of coumarin in comparison to the cells treated with non-targeted nanomicelles (p<0.001). It could be concluded that the present carrier has the potential to be considered in treatment of metastatic breast cancer cells. PMID- 28866171 TI - An injectable hydroxyapatite/poly(lactide-co-glycolide) composite reinforced by micro/nano-hybrid poly(glycolide) fibers for bone repair. AB - Porous nanocomposite of hydroxyapatite/poly(lactide-co-glycolide) (HA/PLGA) is conventionally used in bone tissue engineering but seldom in load-bearing orthopedic applications due to poor mechanical property. This study aimed to fabricate an injectable ternary composite by incorporating different contents of poly(glycolide) (PGA) fibers (0, 30, 50 and 70wt%) into the nanocomposite HA/PLGA matrix as reinforcing fillers for bone tissue repair. The fibers were obtained from melt-spinning and fiber diameter ranged from 70nm to 191MUm. The injectability, mechanical strength, solidification rate and cytotoxicity of injectable composites were characterized. All composites achieved the acceptable injectability under an injection force of 100N. The mechanical properties of composites were gradually enhanced by increasing PGA fiber contents. The compression strength of composite with 70wt% content of PGA fibers was up to 31.1MPa, which was four times stronger than that of composite without PGA fibers. In the solidification rate analysis, the compression strength of composites with 50 or 70wt% PGA fibers in immersion time of only 45min was similar to that of composite without fibers in immersion time of 4-5h. The MTT test showed that exceeding 70% cells could survive in the fourfold dilution of extract, and its cytotoxicity focused on the first 4h after immersing. This study have revealed that the PGA fiber-reinforced HA/PLGA composite is a promising candidate for orthopedic applications. PMID- 28866172 TI - Influence of bovine serum albumin in Hanks' solution on the corrosion and stress corrosion cracking of a magnesium alloy. AB - It is essential for any temporary implant to possess adequate strength to maintain their mechanical integrity under the synergistic effects of mechanical loading characteristics of human body and the corrosive physiological environment. Such synergistic effects can cause stress corrosion cracking (SCC). The aim of the present study is to investigate the effect of the addition of bovine serum albumin (BSA) to Hanks' solution in corrosion and SCC susceptibility of AZ91D magnesium alloy. The electrochemical impedance spectroscopy (EIS) results indicated that the addition of BSA increased corrosion resistance of the alloy during the first 48h of immersion and then decreased it rapidly. The energy dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) analyses indicated adsorption of BSA on the alloy surface during initial hours of immersion. However, with the increasing immersion time, BSA chelated with the corrosion products causing disruption of the protective film; thus, it accelerated the corrosion of the alloy. Both the mechanical data and fractographic evidence have confirmed susceptibility of the alloy to SCC. However, in the presence of BSA, the alloy suffered greater SCC which was attributed to its increased susceptibility towards localized corrosion. PMID- 28866173 TI - A novel fish collagen scaffold as dural substitute. AB - The novel fish collagen scaffolds were prepared by lyophilization. The collagen sponges and chitosan were chemically cross-linked with the 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDC) as a cross-linking agent by pressing in one special mould. The collagen scaffolds were analyzed by scanning electron microscopy (SEM) and mechanical property, and the in vitro collagenase degradation was tested. The results revealed that the scaffold has a suitable porosity, elasticity and prevent fluid leakage, suggesting potential applications in the tissue-engineered. In vitro collagenase degradation demonstrated that the collagen cross-linking with EDC by pressing played an important role in their resistance to biodegradation. Moreover, the scaffold proved excellent biocompatibility for the activity and proliferation of mouse embryonic fibroblasts cells (MEFs) in vitro. The rabbit dural defect model demonstrated that the scaffolds could prevent brain tissue adhesion, which reduce the opportunity of inflammation, facilitate the growth of fibroblasts and enhance the tissue regeneration and healing. The novel fish collagen scaffold as dural substitute, demonstrate a capability for using in the field of tissue engineering. PMID- 28866174 TI - Modification of calcium phosphate cement with poly (gamma-glutamic acid) and its strontium salt for kyphoplasty application. AB - To meet the requirements of minimally invasive surgical treatments for osteoporotic vertebral compression fracture, various strategies have been proposed to enhance the properties of calcium phosphate cement (CPC). Here, a new strategy was developed by incorporating poly (gamma-glutamic acid) (gamma-PGA) and its strontium salt into the formulation of alpha tricalcium phosphate (alpha TCP)-based CPC. Effects of gamma-PGA on the injectability, cohesion, setting times, mechanical compressive strengths and cytocompatibility were systematically studied. Results showed that the injectability, cohesion and setting times were considerably improved by introducing gamma-PGA into the CPC. Moreover, after setting for 7days, the compressive strengths increased from 14.6+/-1.4MPa for pure CPC to 35.3+/-1.7MPa for CPC with 8.9wt% gamma-PGA and further to 61.2+/ 5.4MPa for CPC with 8.9wt% gamma-PGA combined with its strontium salt. In vitro osteoblast proliferation tests showed that the group of CPC modified by gamma-PGA and its strontium salt had better cytocompatibility than the pure CPC group. All results suggest that optimal properties were obtained for the cement with 8.9wt% gamma-PGA added to its solid phases and using strontium salt as the reactive liquid phase, making it as a promising candidate for application in kyphoplasty. PMID- 28866175 TI - Near infrared radiated stimulus-responsive liposomes based on photothermal conversion as drug carriers for co-delivery of CJM126 and cisplatin. AB - Synergistic therapy has caused increasing interest in recent treatment of cancer owing to its preferable therapeutic efficiency to most single antineoplastic protocol. Herein, we design a co-delivery two drugs nanosystem based on biodegradable liposomes, loading cisplatin, Indocyanine green (ICG), and CJM126 coupled with cholesterol derivative (CJM-Chol) for the purpose of synergistic therapy. The obtained nanoparticles showed a uniform diameter of 103.8nm and a favorable morphology. The investigation on near infrared radiated (NIR) responsive release showed that NIR mediated photothermal conversion induced a controllable drug release from liposomes. Furthermore, the designed liposomes (only 50MUg/mL) displayed an inspiring photothermal conversion efficiency and received a high temperature (65.6 degrees C, Tm=42 degrees C) when exposed to an 808nm near infrared laser (1.54W, 5min). Besides, it turned out that the delivery system could be efficiently endocytosed by tumor cells, which attributed to its admirable biocompatibility and the targeting role of folate. The prepared nanoparticles showed significantly excellent inhibitory effect (3.05% cell viability in 24h) on MDA-MB-231 cells when added irradiation as compared with free cisplatin (28.41%) or treatment without NIR (11.24%) in our study. Our research highlights the present nanoparticles provide a promising strategy for targeted delivery and photothermal treatment. PMID- 28866176 TI - Electrospinning of gelatin with tunable fiber morphology from round to flat/ribbon. AB - The electrospinning of gelatin with tunable fiber morphology from round to flat/ribbon was shown, and the detailed studies were conducted to correlate the fiber morphology with electrospinning process parameters and gelatin concentration in electrospinning solution. Particularly, variations in the applied voltage and the concentration of gelatin led to the transition of fiber shape from round to flat/ribbon. The formation of flat-shaped fibers was attributed to rapid evaporation of the solvent (formic acid) from the fiber matrix with increasing the applied voltage and gelatin concentration. On the other hand, round fibers were due to the steady evaporation of formic acid throughout the cross-section of fibers. WAXS analysis revealed that the loss of triple-helical crystalline structure in gelatin after the electrospinning process. The gelatin fibers were cross-linked through treatment with toluene 2,4 diisocyanate (TDI) in a mixed solution of acetone and pyridine, and XPS confirmed the cross-linking of the fibers over an increased carbon content on the elemental composition of the fiber surface due to the incorporated TDI moieties. Overall, this study focuses on morphological tuning of gelatin electrospun fibers towards a flat/ribbon-like structure by variation of electrospinning parameters and polymer concentration, and thus, the proposed concept can be adapted towards flattened/ribbon-like fibers of other protein-based systems by electrospinning. PMID- 28866177 TI - Biomimetics in thin film design: Niche-like wrinkles designed for i-cell progenitor cell differentiation. AB - The future and development of science are in interdisciplinary areas, such as biomedical engineering. Self-assembled structures, similar to stem cell niches, inhibit rapid cellular division processes and enable the capture of stem cells from blood flow. By modifying the surface topography and stiffness properties, progenitor cells were differentiated towards the formation of endothelial cell monolayers to effectively inhibit the coagulation cascade. Wrinkled material layers in the form of thin polymeric coatings were prepared. An optimized surface topography led to proper cell differentiation and influenced the appropriate formation of endothelial cell monolayers. Blood activation was decelerated by the formed endothelium. PMID- 28866178 TI - Cissus quadrangularis mediated ecofriendly synthesis of copper oxide nanoparticles and its antifungal studies against Aspergillus niger, Aspergillus flavus. AB - Recently, non-toxic source mediated synthesis of metal and a metal oxide nanoparticle attains more attention due to key applicational responsibilities. This present report stated that the eco-friendly synthesis of copper oxide nanoparticles (CuO NPs) using Cissus quadrangularis (C. quadrangularis) plant extract. Further the eco-friendly synthesized CuO NPs were characterized using a number of analytical techniques. The observed results stated that the synthesized CuO NPs were spherical in shape with 30+/-2nm. Then the eco-friendly synthesized CuO NPs were subjected for anti-fungal against two strains namely Aspergillus niger (A. niger) resulted in 83% at 500ppm, 86% of inhibition at 1000ppm and Aspergillus flavus (A. flavus) resulted in 81% at 500ppm, 85% of inhibition at 1000ppm respectively. Despite the fact that compared to standard Carbendazim, eco friendly synthesized CuO NPs exhibits better results were discussed in this manuscript. PMID- 28866179 TI - Fabrication and in vivo evaluation of hydroxyapatite/carbon nanotube electrospun fibers for biomedical/dental application. AB - The aim was to synthesize bioactive electrospun fibers for biomedical and dental application with improved biocompatibility. In situ precipitation of nano hydroxyapatite (nHA) was performed with various concentrations (0.5%, 1%, 2%, 3%, and 5% wt/wt) of functionalized multi-walled-carbon nanotubes (MWCNTs) by using microwave irradiation technique. The obtained composites were characterized by Fourier Transform Infrared (FTIR), X-ray Diffraction (XRD), Thermogravimetric Analysis/Differential Scanning Calorimetry (TGA/DSC), and the cylindrical discs were made for mechanical testing. The failure behavior was analyzed by Scanning Electron Microscope (SEM). CNT and HA/CNT were silanized with gamma methacryloxypropyl-trimethoxysilane (MPTS) and mixed with polyvinyl alcohol (10% wt./vol.) and electrospun to fabricate fibers. The biocompatibility of both fibers was accessed by their effects on angiogenesis in a chick chorioallantoic membrane (CAM) assay. The electrospun fibers were analyzed by SEM. FTIR confirmed the structural behavior of pre and post-silanized HA/CNT. XRD showed the phase purity and crystallinity before and after heat treatment. Mechanical properties showed that 3% loaded HA/CNT has higher compressive strength (100.5+/-5.9MPa) compared to others and the failure behavior exhibited dispersion of CNT in HA matrix. The HA/CNT electrospun fibers showed significantly more blood vessels formation compared to CNT fibers. These HA/CNT electrospun fibers showed promising results in terms of biocompatibility and with improved mechanical properties of CNT reinforced composites, they can be used in load bearing clinical applications. PMID- 28866180 TI - Fabrication of high-performance poly(l-lactic acid)/lignin-graft-poly(d-lactic acid) stereocomplex films. AB - The need for green renewable alternatives such as lignin to traditional fillers has driven recent interest in polylactic acid blend materials. Herein, lignin graft-polylactic acid copolymers (LG-g-PDLA, LG-g-PDLLA, and LG-g-PLLA) have been synthesized via ring-opening polymerization of d-, dl-, and l-lactic acid. Then poly(l-lactic acid)/lignin-graft-polylactic acid (PLLA/LG-g-PDLA, /LG-g-PDLLA, and /LG-g-PLLA) complex films have been prepared. The results showed that, compared with LG-g-PDLA and LG-g-PLLA, a small amount of LG-g-PDLA addition could improve the crystallization rate, reduce the glass transition temperature and cold crystallization temperature of PLLA due to the stereocomplex crystallites. The thermal stability, tensile strength and strain of the stereocomplex films were also enhanced. Moreover, the PLLA/LG-g-PDLA films have good ultraviolet resistance and excellent biocompatibility. This study provides a green approach to design advanced polylactic acid-based blends with renewable natural resources. PMID- 28866181 TI - Biomimetic PEGylation of carbon nanotubes through surface-initiated RAFT polymerization. AB - Carbon nanotubes (CNTs) are a type of one-dimensional carbon nanomaterials that possess excellent physicochemical properties and have been potentially utilized for a variety of applications. Surface modification of CNTs with polymers is a general route to expand and improve the performance of CNTs and has attracted great research interest over the past few decades. Although many methods have been developed previously, most of these methods still showed some disadvantages, such as low efficiency, complex experimental procedure and harsh reaction conditions etc. In this work, we reported a practical and novel way to fabricate CNTs based polymer composites via the combination of mussel inspired chemistry and reversible addition fragmentation chain transfer (RAFT) polymerization. First, the amino group was introduced onto the surface of CNTs via self polymerization of dopamine. Then, chain transfer agent can be immobilized on the amino groups functionalized CNTs to obtain CNT-PDA-CTA, which can be utilized for surface-initiated RAFT polymerization. A water soluble and biocompatible monomer poly(ethylene glycol) monomethyl ether methacrylate (PEGMA) was adopted to fabricate pPEGMA functionalized CNTs through RAFT polymerization. The successful preparation of CNTs based polymer composites (CNT-pPEGMA) was confirmed by transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis and X-ray photoelectron spectroscopy in details. The CNT-pPEGMA showed good dispersibility and desirable biocompatibility, making them highly potential for biomedical applications. More importantly, a large number of CNTs based polymer composites could also be fabricated through the same strategy when different monomers were used due to the good monomer adaptability of RAFT polymerization. Therefore, this strategy should be a general method for preparation of various multifunctional CNTs based polymer composites. PMID- 28866182 TI - Preparation of AIE-active fluorescent polymeric nanoparticles through a catalyst free thiol-yne click reaction for bioimaging applications. AB - Fluorescent polymeric nanoparticles (FPNs) with aggregation-induced emission (AIE) characteristics have attracted much attention for biomedical applications due to their remarkable AIE feature, high water dispersity and desirable biocompatibility. The development of facile and effective strategies for fabrication of these AIE-active FPNs therefore should be of great importance for their biomedical applications. In this work, we reported that a catalyst-free thiol-yne click reaction can be utilized for fabrication of AIE-active FPNs in short reaction time and even without protection of inert gas. The results indicated that the obtained AIE-active amphiphilic copolymers (PEGMA-PhE) can readily self-assemble into luminescent nanoparticles (PEGMA-PhE FPNs) with high water dispersity, uniform size and morphology, red fluorescence. Cell viability examination and cell uptake behavior of PEGMA-PhE FPNs confirmed that these AIE active FPNs possess low toxicity towards cells and can be easily internalized by cells through non-specific route. Therefore the remarkable properties of PEGMA PhE FPNs such as high water dispersity, AIE-active fluorescence and nanoscale size as well as excellent biocompatibility make them promising for biomedical applications. PMID- 28866183 TI - Application of Gemini quaternary ammonium with ester groups in cationic P(St-co BA) nanolatex and study on its antibacterial properties. AB - Novel Gemini quaternary ammonium salts (GQASs) with ester groups were synthesized. Cationic poly(styrene-co-butyl acrylate) (P(St-co-BA)) nanolatex was synthesized in the presence of GQASs as emulsifier. The structures of GQASs were characterized with Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy; the property of P(St-co-BA) nanolatex was characterized with dynamic light scattering. The results indicated that GQASs and P(St-co-BA) nanolatex with GQASs were successfully synthesized. GQASs, nanolatex, and the polymer films exhibited excellent antibacterial activities against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. The GQASs performed even better than the corresponding single-stranded quaternary ammoniums. The antibacterial mechanism was also preliminarily studied, and longer, softer hydrophobic chains of GQAS had stronger antibacterial activity. The work provided a novel, simple approach for developing high-efficiency antibacterial polymer material with a low cost, which has broad biomaterial applications. PMID- 28866184 TI - A strategy to promote the electroactive platform adopting poly(o-anisidine) silver nanocomposites probed for the voltammetric detection of NADH and dopamine. AB - A study on the voltammetric detection of NADH (beta-nicotinamide adenine dinucleotide), Dopamine (DA) and their simultaneous determination is presented in this work. The electrochemical sensor was fabricated with the hybrid nanocomposites of poly(o-anisidine) and silver nanoparticles prepared by simple and cost-effective insitu chemical oxidative polymerization technique. The nanocomposites were synthesized with different (w/w) ratios of o-anisidine and silver by increasing the amount of o-anisidine in each, by keeping silver at a fixed quantity. The XRD patterns revealed the semi-crystalline nature of poly(o anisidine) and the face centered cubic structure of silver. The presence of silver in its metallic state and the formation of nanocomposite were established by XPS analysis. Raman studies suggested the presence of site-selective interaction between poly(o-anisidine) and silver. HRTEM studies revealed the formation of polymer matrix type nanocomposite with the embedment of silver nanoparticles. The sensing performance of the materials were studied via cyclic voltammetry, differential pulse voltammetry and chronoamperometry techniques. Fabricated sensor with 3:1 (w/w) ratio of poly(o-anisidine) and silver exhibited good catalytic activity towards the detection of NADH and DA in terms of potential and current response, when compared to others. Several important electrochemical parameters regulating the performance of the sensor have been evaluated. Under the optimum condition, differential pulse voltammetry method exhibited the linear response in the range of 0.03 to 900MUM and 5 to 270MUM with a low detection limit of 0.006MUM and 0.052MUM for NADH and DA, respectively. The modified electrodes exhibited good sensitivity, stability, reproducibility and selectivity with well-separated oxidation peaks for NADH and DA in the simultaneous determination of their binary mixture. The analytical performance of the nanocomposite as an electrochemical sensor was also established for the determination of NADH in human urine and water samples and DA in pharmaceutical dopamine injections with satisfactory coverage. PMID- 28866185 TI - Monitoring structural features, biocompatibility and biological efficacy of gamma irradiated methotrexate-loaded spray-dried microparticles. AB - In this study, biodegradable and biocompatible gamma irradiated poly-(dl-lactide co-glycolide) (PLGA) spray-dried microparticles were prepared aiming to improve the efficacy of methotrexate (MTX). The experimental design included three formulations of microparticles containing distinct drug amount (9%, 18%, and 27% w/w) and three distinct gamma irradiation dose (15kGy, 25kGy, and 30kGy). The physicochemical and drug release properties of the microparticles supported their biocompatibility and biological efficacy studies in different cell lines. The irradiation induced slight changes in the spherical shape of the microparticles and the formation of free radicals was dependent on the drug loading. However, the amorphous character, particle size, drug loading, and drug release rate of the microparticles were preserved. The drug release data from all microparticles formulation were evaluated by using four drug kinetic models and by comparison of their similarity factor (f2). The gamma irradiation did not induce changes in the biocompatibility of PLGA microparticles and in the biological activity of the MTX loaded microparticles. Finally, the spray-dried MTX-loaded PLGA microparticles enhanced the efficacy of the drug in the human cervical cancer cells (SiHa cell line). This study demonstrated the feasibility of the gamma irradiated spray dried PLGA microparticles for prolonged release of MTX, supporting a promising antitumor-drug delivery system for parenteral (subcutaneous) or pulmonary use. PMID- 28866186 TI - PLLA scaffolds produced by thermally induced phase separation (TIPS) allow human chondrocyte growth and extracellular matrix formation dependent on pore size. AB - Damage of hyaline cartilage species such as nasoseptal or joint cartilage requires proper reconstruction, which remains challenging due to the low intrinsic repair capacity of this tissue. Implantation of autologous chondrocytes in combination with a biomimetic biomaterial represents a promising strategy to support cartilage repair. The aim of this work was to assess the viability, attachment, morphology, extracellular matrix (ECM) production of human articular and nasoseptal chondrocytes cultured in vitro in porous poly(l-lactic) (PLLA) scaffolds of two selected pore sizes (100 and 200MUm). The PLLA scaffolds with 100 and 200MUm pore sizes were prepared via ternary thermally induced phase separation (TIPS) technique and analyzed using scanning electron microscopy (SEM). Articular and nasoseptal chondrocytes were seeded on the scaffold and cultures maintained for 7 and 14days. Live/dead staining, (immuno-)histology and gene expression analysis of type II, type I collagen, aggrecan and SOX9 were performed to assess scaffold cytocompatibility and chondrocyte phenotype. The majority of both chondrocyte types survived on both scaffolds for the whole culture period. Hematoxylin-eosin (HE), alcian blue (visualizing glycosaminoglycans) stainings, immunoreactivity and gene expression of ECM proteins and cartilage marker (type II, I collagen, aggrecan, SOX9) of the chondrocyte scaffold constructs indicated that the smaller pore dimensions promoted the differentiation of the chondrocytes compared with the larger pore size. The present work revealed that the scaffold pore size is an important factor influencing chondrocyte differentiation and indicated that the scaffolds with 100MUm pores serve as a cytocompatible basis for further future modifications. PMID- 28866187 TI - Interconnected porosity analysis by 3D X-ray microtomography and mechanical behavior of biomimetic organic-inorganic composite materials. AB - Hydroxyapatite-based materials have been used for dental and biomedical applications. They are commonly studied due to their favorable response presented when used for replacement of bone tissue. Those materials should be porous enough to allow cell penetration, internal tissue growth, vascular incursion and nutrient supply. Furthermore, their morphology should be designed to guide the growth of new bone tissue in anatomically applicable ways. In this work, the mechanical performance and 3D X-ray microtomography (X-ray MUCT) study of a biomimetic, organic-inorganic composite material, based on hydroxyapatite, with physicochemical, structural, morphological and mechanical properties very similar to those of natural bone tissue is reported. Ceramic pieces in different shapes and several porous sizes were produced using a Modified Gel Casting Method. Pieces with a controlled and 3D hierarchical interconnected porous structure were molded by adding polymethylmethacrylate microspheres. Subsequently, they were subject to a thermal treatment to remove polymers and to promote a sinterization of the ceramic particles, obtaining a HAp scaffold with controlled porosity. Then, two different organic phases were used to generate an organic-inorganic composite material, so gelatin and collagen, which was extracted from bovine tail, were used. The biomimetic organic-inorganic composite material was characterized by Scanning Electron Microscopy, Energy Dispersive X-ray Spectroscopy, X-ray Diffraction, Fourier Transform Infrared Spectroscopy and 3D X ray microtomography techniques. Mechanical properties were characterized in compression tests, obtaining a dramatic and synergic increment in the mechanical properties due to the chemical and physical interactions between the two phases and to the open-cell cellular behavior of the final composite material; the maximum compressive strength obtained corresponds to about 3 times higher than that reported for natural cancellous bone. The pore size distribution obtained could be capable to allow cell penetration, internal tissue in-growth, vascular incursion and nutrient supply and this material has tremendous potential for use as a replacement of bone tissue or in the manufacture and molding of prosthesis with desired shapes. PMID- 28866188 TI - Interpenetrating network hydrogels with high strength and transparency for potential use as external dressings. AB - Interpenetrating polymer network (IPN) hydrogels composed of gelatin and hydroxypropyl cellulose (HPC) were prepared by successive enzymatic and chemical crosslinking approaches. The hydrogels displayed porous structure and the pore size decreased with the increase of HPC content. Due to the entanglement and interpenetrating between the two crosslinked networks, the IPN hydrogels exhibited excellent mechanical strength and light transmittance. The maximum tensile and tear strengths of the IPN hydrogels reached 3.1 and 5.2MPa, respectively. The water vapor permeability of the IPN hydrogels was within the acceptable range to maintain appropriate moisture for wound healing. The cytotoxicity evaluation indicated that the IPN hydrogels exhibited no toxicity to fibroblast cells. In addition, the hydrogels were loaded with chloramphenicol by pre-soaking in drug solutions to evaluate drug-loading capacity and in vitro release behavior. It was found that the drug loaded hydrogels could act as drug delivery devices to create microbe free microenvironment, which was advantageous for wound healing. PMID- 28866189 TI - Comparison of thermal properties of fish collagen and bovine collagen in the temperature range 298-670K. AB - The increased interest in fish collagen is a consequence of the risk of exposure to Creutzfeld-Jacob disease (CJD) and the bovine spongiform encephalopathy (BSE), whose occurrence is associated with prions carried by bovine collagen. Collagen is the main biopolymer in living organisms and the main component of the skin and bones. Until the discovery of the BSE, bovine collagen had been widely used. The BSE epidemic increased the interest in new sources of collagen such as fish skin collagen (FSC) and its properties. Although the thermal properties of collagen originating from mammals have been well described, less attention has been paid to the thermal properties of FSC. Denaturation temperature is a particularly important parameter, depending on the collagen origin and hydration level. In the reported experiment, the free water and bound water release processes along with thermal denaturation process were studied by means of the differential scanning calorimetry (DSC). Measurements were carried out using a DSC 7 instrument (Elmer Perkin), in the temperature range 298-670K. The study material was FSC derived by acidic hydration method. The bovine Achilles tendon (BAT) collagen type I was used as the control material. The thermograms recorded revealed both, exothermic and endothermic peaks. For both materials, the peaks in the temperature range of 330-360K were assigned to the release of free water and bound water. The denaturation temperatures of FSC and BAT collagen were determined as 420K and 493K, respectively. Thermal decomposition process was observed at about 500K for FSC and at about 510K for BAT collagen. These results show that FSC is less resistant to high temperature than BAT collagen. PMID- 28866190 TI - Enhanced cell affinity of PHBHHx composite scaffold with polylactide-graft hydroxyapatite as compatibilizer. AB - Poor interfacial bonding and liability to aggregation were the major obstacles for designing of composite scaffolds. Herein, hydroxyapatite (HA) surface-grafted with poly (l-lactide) via ring-opening polymerization was prepared and introduced into PHBHHx-based complex scaffold serving as oligomer compatibilizer. The physicochemical properties, including superficial roughness and wettability, mechanical strength, as well as in vitro bioactivity were systematically investigated. Improved cellular response was acquired owing to the favourable uniformity and interfacial compatibility, as well as the decreased contact angle and elevated roughness, through surface-modification strategy. Moreover, some of the osteogenic marker genes (COL I, Runx2, OCN and OPN) were up-regulated, thus made for the osteogenic differentiation. Our study extrapolated that the PHBHHx based composite scaffold combined with surface-graft HA compatibilizer might be a potential candidate for bone repairing. PMID- 28866191 TI - Nanosized CaP-silk fibroin-PCL-PEG-PCL/PCL based bilayer membranes for guided bone regeneration. AB - Guided bone regeneration (GBR) concept has been developed to prevent the formation of non-functional scar tissue layer on defect site by undertaking barrier role. In this study, a new bilayer membrane which consisted of one layer of electrospun silk fibroin/PCL-PEG-PCL incorporating nanocalcium phosphate (SPCA)1 and one layer of PCL membrane was developed for GBR. To improve the osteoconductivity of membranes, nanosized calcium phosphate particles synthesized by Flame Spray Pyrolysis method were incorporated into membranes at 10% (wt) (SPCA10) and 20% (wt) (SPCA20) of the polymer content. The structural and chemical analyses revealed the well-integrated two layers of membranes with a total thickness of ca 100MUm. In the regenerative layer, the highly porous mesh structure had a thickness of 12.6MUm with randomly oriented fibers having diameters around 760nm, and nanoparticles dispersed homogenously. The mechanical test results showed remarkable improvement on the tensile strength of membranes with incorporation of nanoparticles. Higher water affinity of nanoCaP included membranes was proved by lower contact angle values and higher percent water uptake capacity. Biomineralization assay revealed that nucleation and growth of apatites around fibers of SPCA10 and SPCA20 were apparent while on SPCA0 apatite minerals were barely detected after 10days. Human dental pulp stem cells (DPSC) were seeded on electrospun layer of the bilayer membranes for biocompatibility and osteo-compatibility study. Increasing nanoCaP amount resulted in higher cell adhesion, proliferation, ALP activity and calcium deposition on membranes. These overall results confirmed the biocompatibility and potential applicability of proposed membranes for GBR treatments. PMID- 28866192 TI - Fabrication of biosensor based on Chitosan-ZnO/Polypyrrole nanocomposite modified carbon paste electrode for electroanalytical application. AB - A sensitive conductive nanocomposite sensor consisting of chitosan, zinc oxide nanoparticles, and polypyrrole was developed. The sensor was prepared by oxidative polymerization of pyrrole using (NH4)2S2O8 as the oxidant followed by mixing a Chitosan-Zinc oxide composite with a different content of Chitosan. The morphology and surface area of the nanocomposites were changed by changing the percentage of chitosan. The newly developed nanocomposites also showed a significant improvement in electrical conductivity as mentioned from the cyclic voltammetry measurements of the K3[Fe(CN)6] sample. A square-wave adsorptive anodic stripping voltammetry method successfully measured Isoxsuprine hydrochloride using different types of nanocomposite modified CPEs and showed a large enhancement of stripping peak current compared to bare CPE. Consequently, the proposed sensors proved to have a promissing feature for applications in biosensors. PMID- 28866193 TI - Injectable natural polymer compound for tissue engineering of intervertebral disc: In vitro study. AB - Intervertebral disc degeneration is recognized to be the leading cause for chronic low-back pain. Injectable hydrogel is one of the great interests for tissue engineering and cell encapsulation specially for intervertebral (IVD) affecting rate of regeneration success, in this study we assessed viscoelastic properties of a Chitosan-beta glycerophosphate-hyaluronic acid, Chondroitin-6 sulfate, type 2 of Collagen, gelatin, fibroin silk (Ch-beta-GP-HA-CS-Col-Ge-FS) hydrogel which was named as NP hydrogel that is natural extracellular matrix of IVD. Chitosan-based hydrogel was made in the ratio of 1.5%: 7%: 1%:1%:1%-1.5%-1% (Ch: beta-GP: HA-CS-Col-Ge-FS). Gelation time and other rheological properties were studied using amplitude sweep and frequency sweep tests. Also, the cytotoxicity of the hydrogel invitro assessed by MTT and trypan blue tests. Morphology of the hydrogel and attachment of NP cells were evaluated by SEM. Our result showed that NP hydrogel in 4 degrees C is an injectable transparent solution. It started gelation in 37 degrees C after about 30min. Gelation temperature of NP hydrogel was 37 degrees C. Storage modulus (G') of this hydrogel at 37 degrees C was almost constant over a wide range of strain. MTT and trypan blue tests showed hydrogel was cytocompatible. The obtained results suggest that this hydrogel would be a natural and cytocompatible choice as an injectable scaffold for using in vivo study of IVD regeneration. PMID- 28866194 TI - In situ green synthesis and characterization of sericin-silver nanoparticle composite with effective antibacterial activity and good biocompatibility. AB - Silver nanoparticle has been widely applied to a variety of fields for its outstanding antimicrobial activity. However, the stability of silver nanoparticle limits its application under certain conditions. Thus, improving the stability of silver nanoparticle via biosynthesis is a promising shortcut to expand its application. Sericin from silkworm cocoon has good hydrophilicity, reaction activity, biocompatibility and biodegradability. In this study, we developed a novel, simple, one-step biosynthesis method to prepare sericin-silver nanoparticle composite in situ in solution. Sericin served as the reductant of silver ion, the dispersant and stabilizer of the prepared sericin-silver nanoparticle composite. Natural light was the only power source used to catalyze the synthesis of silver nanoparticle in situ in solution. The novel sericin silver nanoparticle composite was characterized by ultraviolet-visible and fluorescence spectroscopy, X-ray diffraction, transmission electron microscopy and fourier transform infrared spectroscopy. The results showed silver nanoparticle could be synthesized through the reduction of AgNO3 by the phenolic hydroxyl group of tyrosine residues of sericin under the catalysis of natural light. The synthesized silver nanoparticle had good crystalline, size distribution and long-term stability at room temperature. Light irradiation was essential for the preparation of sericin-silver nanoparticle composite. The antibacterial activity assay showed 25mg/L and 100mg/L were the minimum concentrations of sericin-silver nanoparticle composite required to inhibit the growth of Staphylococcus aureus and kill this bacterium, respectively. The cytotoxicity assay showed cell viability and cell growth were almost not affected by sericin-silver nanoparticle composite under the concentration of 25mg/L. Our study suggested the preparation of sericin-silver nanoparticle composite was environmentally friendly and energy conservation, and the prepared sericin-silver nanoparticle composite had long-term stability, effective antibacterial activity and good biocompatibility. This novel sericin-silver nanoparticle composite has shown great potentials for biomedical application such as antibacterial agent and wound care. PMID- 28866195 TI - Polyglycerol mediated covalent construction of magnetic mesoporous silica nanohybrid with aqueous dispersibility for drug delivery. AB - Construction of nanohybrids with chemical and colloidal stability is of great importance for the exploration of their potential applications in biomedical field. In this work, a versatile strategy based on polyglycerol (PG) mediated covalent linkage is developed to fabricate a core-satellite nanohybrid, termed MMSN, consisting of a mesoporous silica nanoparticle (MSN) as a core and many superparamagnetic iron oxide nanoparticles (SPION) on the outer surface. In this synthetic strategy, the PG grafted SPION is derivatized to convert partial periphery hydroxyl groups to carboxyl moieties, followed by attachment to aminated MSN through amide bonds. The PG layer accounting for ~17wt% of MMSN not only serves as a tether to connect the two nanoparticles but also greatly enhances the colloidal stability of the nanohybrid, resulting in no significant change in hydrodynamic diameter and zeta potential during four months. Taking advantage of the combined porosity and magnetic property of the nanohybrid, a photosensitizer chlorin e6 (Ce6) is loaded on MMSN and efficiently delivered into target cells under magnetic guidance, leading to an enhanced efficacy of photodynamic therapy (PDT). The versatile strategy presented here opens up a new route to rational design and fabrication of multifunctional nanohybrids for various biomedical purposes. PMID- 28866196 TI - Respiring cellular nano-magnets. AB - Magnetotactic bacteria provide an interesting example for the biosynthesis of magnetic (Fe3O4 or Fe3S4) nanoparticles, synthesized through a process known as biologically controlled mineralization, resulting in complex monodispersed, and nanostructures with unique magnetic properties. In this work, we report a novel aerobic bacterial strain isolated from sludge of an oil refinery. Microscopic and staining analysis revealed that it was a gram positive rod with the capability to thrive in a medium (9K) supplemented, with Fe2+ ions at an acidic pH (~3.2). The magnetic behaviour of these cells was tested by their alignment towards a permanent magnet, and later on confirmed by magnetometry analysis. The X-ray diffraction studies proved the cellular biosynthesis of magnetite nanoparticles inside the bacteria. This novel, bio-nano-magnet, could pave the way for green synthesis of magnetic nanoparticles to be used in industrial and medical applications such as MRI, magnetic hyperthermia and ferrofluids. PMID- 28866197 TI - Fabrication and characterization of hydrothermal cross-linked chitosan porous scaffolds for cartilage tissue engineering applications. AB - The use of various chemical cross-linking agents for the improvement of scaffolds physical and mechanical properties is a common practical method, which is limited by cytotoxicity effects. Due to exerting contract type forces, chondrocytes are known to implement shrinkage on the tissue engineered constructs, which can be avoided by the scaffold cross-linking. In the this research, chitosan scaffolds are cross-linked with hydrothermal treatment with autoclave sterilization time of 0, 10, 20 and 30min, to avoid the application of the traditional chemical toxic materials. The optimization studies with gel content and crosslink density measurements indicate that for 20min sterilization time, the gel content approaches to ~80%. The scaffolds are fully characterized by the conventional techniques such as SEM, porosity and permeability, XRD, compression, thermal analysis and dynamic mechanical thermal analysis (DMTA). FT-IR studies shows that autoclave inter-chain cross-linking reduces the amine group absorption at 1560cm 1 and increase the absorption of N-acetylated groups at 1629cm-1. It is anticipated, that this observation evidenced by chitosan scaffold browning upon autoclave cross-linking is an indication of the familiar maillard reaction between amine moieties and carbonyl groups. The biodegradation rate analysis shows that chitosan scaffolds with lower concentrations, possess suitable degradation rate for cartilage tissue engineering applications. In addition, cytotoxicity analysis shows that fabricated scaffolds are biocompatible. The human articular chondrocytes seeding into 3D cross-linked scaffolds shows a higher viability and proliferation in comparison with the uncross-linked samples and 2D controls. Investigation of cell morphology on the scaffolds by SEM, shows a more spherical morphology of chondrocytes on the cross-linked scaffolds for 21days of in vitro culture. PMID- 28866198 TI - Bacterial biofilm elimination using gold nanorod localised surface plasmon resonance generated heat. AB - Antimicrobial resistance is an increasing global health concern and the world is facing a major challenge to develop novel ways of replacing antibiotics. Gold nanorods exhibit localised surface plasmon resonance upon optical irradiation. During relaxation, absorbed energy is dissipated as heat, which has been utilized to kill bacteria. In this study, 10*45nm gold nanorods were attached to glass surfaces using silanisation. Then biofilms were cultured on the surfaces and studied using microscopy. On average, 71% of the early biofilm bacteria were eliminated after 5min of near infrared radiation (LED emission peak at 850nm) of the gold nanorod coated surfaces, showing the potential of this novel antibiofilm technique. Most notably, the best individual result showed 97% biofilm elimination. This study demonstrates that nanoplasmonic generated heat offers a novel way of eliminating bacterial biofilms. In future applications, this method may be used to eliminate bacterial contamination during implant surgery. PMID- 28866199 TI - The one-step acetalization reaction for construction of hyperbranched and biodegradable luminescent polymeric nanoparticles with aggregation-induced emission feature. AB - The development of luminescent bioprobes based on organic dyes with aggregation induced emission (AIE) characteristic has attracted great attention in recent years. In this work, we reported for the first time that AIE-active luminescent polymeric nanoparticles (LPNs) can be facilely prepared via a one-step acetalization reaction, which can be used to conjugate the aldehyde group containing AIE dye (PTH-CHO) and methoxypolyethylene glycols (mPEG-CHO) with a commercially available dendritic polyester (H40) using p-toluenesulfonic acid (TsOH) as the catalyst. As-prepared star-shaped hyperbranched luminescent polymers (named as H40-mPEG-mPTH) were prone to self-assemble into core-shell nanoparticles in aqueous solution because of their amphiphilic structure, in which hydrophobic components (such as PTH-CHO and H40) were encapsulated in the core while the hydrophilic components (mPEG-CHO) were acted as the shell. The final AIE-active H40-mPEG-mPTH LPNs displayed uniform spherical structure, strong fluorescence, excellent photostability and high water dispersity. Furthermore, biological evaluation results demonstrated that H40-mPEG-mPTH LPNs possess low toxicity and excellent biocompatibility, indicating their great potential for biomedical applications. Taken together, we reported a novel strategy for the construction of hyperbranched and biodegradable LPNs with AIE feature through a one-step acetalization reaction, which can be also utilized for construction of many other AIE-active LPNs with a variety structure and properties. PMID- 28866200 TI - Effect of pH on polyethylene glycol (PEG)-induced silk microsphere formation for drug delivery. AB - The effects of changing solution pH in the range of 3.6-10.0 during a one-step silk microsphere preparation process, by mixing silk and polyethylene glycol (PEG), was assessed. The microspheres prepared at low pH (3.6) showed a more homogeneous size (1-3MUm) and less porous texture than those prepared at neutral pH. High pH (10.0) inhibited microsphere formation, yielding small and inhomogeneous microspheres. Compared to neutral pH, low pH also increased the content of silk crystalline beta-sheet structure from approx. 30% to above 40%. As a result, the microspheres produced at low pH were more thermally stable as well as resistant to chemical (8M urea) and enzymatic (protease XIV) degradation when compared to microspheres prepared at neutral pH. Doxorubicin hydrochloride (DOX) and curcumin (CUR) were successfully loaded in silk microspheres via control of solution pH. The loading efficiency of DOX was approx. 95% at pH7.0 and approx. 60% for CUR at pH3.6, attributed to charge-charge interactions and hydrophobic interactions between the silk and drug molecules, respectively. When PBS, pH7.4, was used as a medium for release studies, the pH3.6 microspheres released both drugs more slowly than the pH7.0 microspheres, likely due to the high content of crystalline beta-sheet structure that enhanced drug-silk interactions as well as restricted drug molecule diffusion. PMID- 28866201 TI - High-performance peroxidase mimics for rapid colorimetric detection of H2O2 and glucose derived from perylene diimides functionalized Co3O4 nanoparticles. AB - N,N'-di-caboxy methyl perylene diimides (PDI), as one of the most promising functional materials in optional chemosensing, was first used to combine with Co3O4 nanoparticles through a facile two-step hydrothermal method and obtain the PDI functionalized Co3O4 nanocomposites (PDI-Co3O4 NCs). PDI-Co3O4 NCs were characterized by a series of technical analysis including transmission electron microscope (TEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR), respectively. The experimental results indicated that the as-prepared PDI-Co3O4 NCs possessed the higher peroxidase-like activity than that of Co3O4 nanoparticles without PDI, and could rapidly catalyze oxidation reaction of the chromogenic substrate TMB in the presence of H2O2 to a blue product (oxTMB) observed by the naked eye. The improved catalytic activity of PDI-Co3O4 NCs for colorimetric reactions could be attributed to the synergistic effects of PDI and Co3O4 nanoparticles. On the basis of these experimental results, a convenient colorimetric system based on PDI-Co3O4 as enzyme mimic that is highly sensitive and selective was developed for glucose detection. Meanwhile, the electron transfer between H2O2 and TMB was responsible for the oxidation of TMB. The present work demonstrates a general strategy for the design of organic molecules functionalized oxide for different applications, such as nanocatalysts, biosensors and nanomedicine. PMID- 28866202 TI - Mussel-inspired superhydrophobic surfaces with enhanced corrosion resistance and dual-action antibacterial properties. AB - In this study, a multilayer antibacterial film was assembled onto 316L stainless steel via mussel-inspired depositions of polydopamine (PDA) and silver (Ag) nanoparticles followed by post-modification with 1H, 1H, 2H, 2H perfluorodecanethiol. The resulting surface exhibited excellent superhydrophobicity with hierarchical micro/nanostructures that were constructed by both PDA and Ag nanoparticles. The crystal structure and chemical composition of these surfaces were investigated using X-ray photoelectron spectroscopy (XPS) analysis. Potentiodynamic polarization measurements revealed that the corrosion resistance of the as-prepared surfaces were sequentially increased after each step of the fabrication process. Compared with the surface covered with only Ag nanoparticles, the superhydrophobic surfaces exhibited substantially enhanced antibacterial activity against the Gram-negative Escherichia coli and Gram positive Staphylococcus aureus, resulting from the synergistic antibacterial actions of the superhydrophobic surface and Ag nanoparticles. The superhydrophobic surface exhibited lower cytotoxicity, compared to the surface covered with Ag nanoparticles. PMID- 28866203 TI - Microwave-assisted multicomponent reactions for rapid synthesis of AIE-active fluorescent polymeric nanoparticles by post-polymerization method. AB - The development of simple and effective methods for synthesis of fluorescent polymeric nanoparticles (FPNs) with aggregation-induced emission (AIE) plays an important role for the biomedical applications of AIE-active FPNs. In present work, we developed a facile strategy for the fabrication of AIE-active FPNs by a post-polymerization method based on the microwave-assisted Kabachnik-Fields (KF) reaction, which can conjugate with poly(PEGMA-NH2), AIE-active dye (TPE-CHO) and diethyl phosphate (DP) under microwave irradiation within 5min. The characterization results confirm that PEGMA-TPE FPNs are successfully prepared through the microwave-assisted KF reaction. The resultant AIE-active FPNs show high water dispersity, intensive fluorescence and low cytotoxicity. These features make these AIE-active FPNs great potential for biomedical applications. Moreover, the microwave-assisted KF reaction is simple, fast, atom economy that should be a general strategy for the fabrication of various multifunctional AIE active FPNs. We believe this work will open up a new avenue for the preparation of AIE-active functional materials with great potential for different applications. PMID- 28866204 TI - A facile novel fluorocarbon copolymer solution coating process for improving platelet compatibility of titanium. AB - Titanium (Ti) and its alloys possess mechanical properties that are desirable in many biomedical applications compared to other metals. Furthermore, the native metal oxide layer that prevents further oxidation is also known to be biocompatible. However, clinical findings have shown that titanium and its alloys are prone to adverse bioreactions such as platelet adhesion and activation which could lead to thrombogenic complications. It has been found that surfaces modified with fluorocarbons could reduce the degree of both platelet adhesion and activation. Nevertheless, direct fluorocarbon deposition onto titanium substrates would require significant technical efforts. Instead, this research utilized a facile coating process with novel copolymers containing 2,2,2-trifluoroethyl methacrylate (TFEMA) and vinylphosphonic acid (VPA) to modify the titanium surface, giving the surface lower surface energy and higher hydrophobicity, significantly reducing the thrombus formation while exhibiting good cytocompatibility. The anchorage group, phosphonic acid provided by VPA, can be covalently bound to the oxide surface of titanium metal. Via free radical polymerization, VPA and TFEMA formed copolymers with different hydrophobicity were then used to modify titanium substrates, on which a series of surface characterization, in vitro platelet adhesion tests, and cytotoxicity assays were performed. Nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) confirmed the synthesis of the copolymers and the modification of Ti substrates. The platelet adhesion tests showed significantly reduced amount of adherent platelets on certain copolymer-modified Ti substrates with low degrees of activation. The in vitro cytotoxicity assays further highlighted that the modifications conducted on Ti does not induce cytotoxicity. PMID- 28866205 TI - Biocompatible curcumin loaded PMMA-PEG/ZnO nanocomposite induce apoptosis and cytotoxicity in human gastric cancer cells. AB - Although curcumin is efficient in killing cancer cells, its poor water solubility and assocaited inadequate bioavailability remain major limitations to its therapeutic application. The formulation of curcumin micellar nanoparticles (NPs) encapsulated with a biodegradable polymer promises to significantly improve curcumin's solubility, stability, and bioavailability. The past decade has witnessed the development of nanoscale curcumin delivery systems: curcumin-loaded liposomes or nanoparticles, self-microemulsifying drug delivery systems (SMEDDS), cyclodextrin inclusions, solid dispersions, nanodisks, and nanotubes. The intention of the present investigation was to enhance the bioavailability and ultimately the efficacy of curcumin by developing a curcumin loaded PMMA-PEG/ZnO bionanocomposite utilizing insoluble curcumin and poorly soluble ZnO nanoparticles. Here, the drug (curcumin) may be carry and deliver the biomolecule(s) by polymer-encapsulated ZnO NPs. Physical characteristics of these novel nanomaterials have been studied with transmission electron microscopy (TEM) and powder X-ray diffraction (XRD) in conjunction with spectral techniques. Aqueous solubility of curcumin was augmented upon conjugation with the polymer stabilized ZnO NPs. A narrow nanocomposite particle size distribution with an average value of 40 to 90nm was found via TEM. Most importantly, the pH responsive release of curcumin from the nano-vehicle ensures safer, more controlled delivery of the drug at physiological pH. Cytotoxic potential and cellular uptake of curcumin loaded ZnO NPs were assessed by) cell viability assay, cell cycle assays along with the cell imaging studies have been done in addition to MTT using AGS cancer cells. Hence, these studies demonstrate that the clinical potential of the Curcumin Loaded PMMA-PEG/ZnO can induce the apoptosis of cancer cells through a cell cycle mediated apoptosis corridor, which raises its probability to cure gastric cancer cells. PMID- 28866206 TI - Differentiation of dental pulp stem cells into chondrocytes upon culture on porous chitosan-xanthan scaffolds in the presence of kartogenin. AB - Adhesion, proliferation and differentiation of dental pulp stem cells (DPSCs) into chondrocytes were investigated in this work with the purpose of broadening the array of cell alternatives to the therapy of cartilage lesions related to tissue engineering approaches. A porous chitosan-xanthan (C-X) matrix was used as scaffold and kartogenin was used as a selective chondrogenic differentiation promoter. The scaffold was characterized regarding aspect and surface morphology, absorption and stability in culture medium, thickness, porosity, thermogravimetric behavior, X-ray diffraction, mechanical properties and indirect cytocompatibility. The behavior of DPSCs cultured on the scaffold was evaluated by scanning electron microscopy and cell differentiation, by histological analysis. A sufficiently stable amorphous scaffold with mean thickness of 0.89+/ 0.01mm and high culture medium absorption capacity (13.20+/-1.88g/g) was obtained, and kartogenin concentrations as low as 100nmol/L were sufficient to efficiently induce DPSCs differentiation into chondrocytes, showing that the strategy proposed may be a straightforward and effective approach for tissue engineering aiming at the therapy of cartilage lesions. PMID- 28866207 TI - ZnO@Gd2O3 core/shell nanoparticles for biomedical applications: Physicochemical, in vitro and in vivo characterization. AB - The chemical composition of nanoparticles (NPs) may be so designed as to provide measurability for numerous imaging techniques in order to achieve synergistic advantages. Innovative and unique structure of the core/shell ZnO@Gd2O3 NPs possesses luminescent and magnetic properties, and is expected that they will become a new generation of contrast agents for Magnetic Resonance Imaging (MRI) and nanocarriers for theranostics. Thus, by surface biofunctionalization, it is possible to indicate particular nanoparticle compositions which provide efficient imaging, targeted drug delivery, and biocompatibility. Novel ZnO@Gd2O3 NPs were synthesized and biofunctionalized by folic acid (FA) and doxorubicin (Doxo) to provide target and anticancer functions. Physicochemical analyses of the nanoparticles were performed. The biological study included a cytotoxicity in vitro, cellular distribution evaluation, as well as toxicity analyses, performed for the first time, on the in vivo zebrafish (Danio rerio) model. Nanoparticles were found to be effective double-function biomarkers (MRI T2 contrast agents, fluorescent imaging). The biological study showed that ZnO@Gd2O3 and ZnO@Gd2O3@OA polySi@FA NPs are biocompatible in a particular concentration ranges. Conjugation with folic acid and/or doxorubicin resulted in effective drug delivery targeting. The in vivo results described the toxicology profile toward the zebrafish embryo/larvae, including new data concerning the survival, hatching ratio, and developmental malformations. PMID- 28866208 TI - Microwave assisted synthesis of luminescent carbonaceous nanoparticles from silk fibroin for bioimaging. AB - Bombyx mori silk as a natural protein based biopolymer with high nitrogen content, is abundant and sustainable because of its mass product all over the world per year. In this study, we developed a facile and fast microwave-assisted synthesis of luminescent carbonaceous nanoparticles using Bombyx mori silk fibroin and silk solution as the precursors. As a result, the obtained carbonaceous nanoparticles exhibit a photoluminescence quantum yield of ~20%, high stability, low cytotoxicity, high biocompatibility. Most importantly, we successfully demonstrated bioimaging using these luminescent carbonaceous nanoparticles with excitation dependent luminescence. In addition, the microwave assisted hydrothermal method can be extended to convert other biomass into functional nanomaterials. PMID- 28866209 TI - The application of silver nano-particles on developing potential treatment for chronic rhinosinusitis: Antibacterial action and cytotoxicity effect on human nasal epithelial cell model. AB - Chronic rhinosinusitis (CRS) has raised attentions both in many countries due to its high relapsing rate and the resistance of certain treatments especially antibiotics application on both acute and chronic bacterial rhinosinusitis. The aim of this research is stressing on developing an effective alternative treatment for treating CRS and reducing the use of antibiotics to avoid further resistance forming. The antibacterial functions of silver nano-particles (AgNPs) are well known according to previous reports and studies. However, for developing a suitable treatment for further clinical application, a variety of AgNPs cell cytotoxicity experiments and AgNPs antibacterial properties experiments were examined in vitro in this study. For imitating the clinical condition of CRS, the human nasal epithelial cell line (RPMI2650) has chosen as experimental model. Moreover, Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) were selected for antibacterial function experiments. The analytical results demonstrated that 5ppm of AgNPs not only maintains >80% of cell activity to RPMI2650, but also possesses >80% of antibacterial function to S. aureus and 100% of antibacterial function to E. coli. Therefore, 5ppm of AgNPs might be considered as a promising antibacterial agent for treating CRS. PMID- 28866211 TI - Preparation of an antibacterial, hydrophilic and photocatalytically active polyacrylic coating using TiO2 nanoparticles sensitized by graphene oxide. AB - In recent years more attentions have been paid for preparation of coatings with self-cleaning and antibacterial properties. These properties allow the surface to maintain clean and health over long times without any need to cleaning or disinfection. Acrylic coatings are widely used on various surfaces such as automotive, structural and furniture which their self-cleaning and antibacterial ability is very important. The aim of this work is the preparation of a polyacrylic based self-cleaning and antibacterial coating by the modification of TiO2 as a coating additive. TiO2 nanoparticles were sensitized to the visible light irradiation using graphene oxide through the preparation of TiO2/graphene oxide nanocomposite. Graphene oxide was prepared via a modified Hummers method. TiO2/graphene oxide nanocomposite was used as additive in a polyacrylic coating formulation. Hydrophilicity, photocatalytic and antibacterial activities as well as coating stability were evaluated for TiO2/graphene oxide modified polyacrylic coating and compared with that of pristine TiO2 modified and unmodified polyacrylic coatings. TiO2/graphene oxide nanocomposite and polyacrylic coating modified by TiO2/graphene oxide additive were characterized using FT-IR, UV-Vis, XRD, and FESEM techniques. The effect of TiO2/graphene oxide composition and its percent in the coating formulation was evaluated on the polyacrylic coating properties. Results showed that polyacrylic coating having 3% W TiO2/graphene oxide nanocomposite additive with TiO2 to graphene oxide ratio of 100:20 is the best coating considering most of beneficial features such as high photodecolorization efficiency of organic dye contaminants, high hydrophilicity, and stability in water. According to the results, TiO2 is effectively sensitized by graphene oxide and the polyacrylic coating modified by TiO2/graphene oxide nanocomposite shows good photocatalytic activity under visible light irradiation. PMID- 28866210 TI - Synergic effect of chitosan and dicalcium phosphate on tricalcium silicate-based nanocomposite for root-end dental application. AB - In recent years, cement composites based on calcium silicate have been more generally considered for medical applications. Calcium silicate Cement are among the categories that are used in dental root canal treatment. The aim of this study is to make new calcium silicate cement with dicalcium phosphate and chitosan additives to preserve and strengthen desirable properties of this type of cements. In this study, composite dental cement based on calcium silicate was prepared. Then effect of adding biodegradable and biocompatible polymer such as chitosan on setting properties and its structure were studied. In this study, a combination of calcium silicate, dicalcium phosphate (DCP) and bismuth oxide (Bi2O3) as powder phase and 2% solution of the chitosan dissolved in 1% acetic acid solution as liquid phase, was used. As well as control sample was obtained by mixing the powder with distilled water as the liquid phase. Based on the obtained results, setting time of composite cement was changed from 51 to 67 minutes by adding chitosan polymer. Presence of chitosan also reduced the compressive strength a little. The bioactivity of the cement were studied in a solution of simulated body fluid (SBF) for 14 days. The samples were analyzed by SEM to identify the microstructure and by XRD to determine crystal structure. The composition of cement before incubation in SBF was included early phases (phase calcium silicate and calcium phosphate) that after 14 days of immersion in SBF, they were converted to layer-shaped hydroxy apatite and the presence of chitosan had not any influence on the final phase of hydroxy apatite. PMID- 28866212 TI - Growth of a TiNb adhesion interlayer for bioactive coatings. AB - Surface bioactivity has been under intensive study with reference to its use in medical implants. Our study is focused on coatings prepared from an electroactive material which can support bone cell adhesion. Until now, hydroxyapatite films have usually been utilized as a chemically-active surface agent. However, electrically-active films could set a new direction in hard tissue replacement. As a base for these films, it is necessary to prepare an intermediate film, which can serve as a suitable barrier against the possible diffusion of some allergens and toxic elements from the substrate. The intermediate film also improves the adaptation of the mechanical properties of the basic material to an electroactive film. The aim of our work was to select an implantable and biocompatible material for this intermediate film that is suitable for coating several widely-used materials, to check the possibility of preparing an electroactive film for use on a material of this type, and to characterize the structure and several mechanical properties of this intermediate film. TiNb was selected as the material for the intermediate film, because of its excellent chemical and mechanical properties. TiNb coatings were deposited by magnetron sputtering on various substrates, namely Ti, Ti6Al4V, stainless steel, and bulk TiNb (as standard), and important properties of the layers, e.g. surface morphology and surface roughness, crystalline structure, etc., were characterized by several methods (SEM, EBSD, X ray diffraction, nanoindentation and roughness measurement). It was found that the structure and the mechanical properties of the TiNb layer depended significantly on the type of substrate. TiNb was then used as a substrate for depositing a ferroelectrically active material, e.g., BaTiO3, and the adhesion, viability and proliferation of human osteoblast-like Saos-2 cells on this system were studied. We found that the electroactive BaTiO3 film was not only non cytotoxic (i.e. it did not affect the cell viability). It also enhanced the growth of Saos-2 cells in comparison with pure TiNb and with standard tissue culture polystyrene wells, and also in comparison with BaTiO3 films deposited on Ti, i.e. a material clinically used for implantation into the bone. PMID- 28866213 TI - Multifunctional biosynthesized silver nanoparticles exhibiting excellent antimicrobial potential against multi-drug resistant microbes along with remarkable anticancerous properties. AB - This study demonstrates the therapeutic potential of silver nanoparticles (AgNPs), which were biosynthesized using the extracts of Citrus maxima plant. Characterization through UV-Vis spectrophotometry, Dynamic Light Scattering (DLS), Fourier Transform Infrared spectroscopy (FTIR), X-ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) confirmed the formation of AgNps in nano-size range. These nanoparticles exhibited enhanced antioxidative activity and showed commendable antimicrobial activity against wide range of microbes including multi-drug resistant bacteria that were later confirmed by TEM. These particles exhibited minimal toxicity when cytotoxicity study was performed on normal human lung fibroblast cell line as well as human red blood cells. It was quite noteworthy that these particles showed remarkable cytotoxicity on human fibrosarcoma and mouse melanoma cell line (B16-F10). Additionally, the apoptotic topographies of B16-F10 cells treated with AgNps were confirmed by using acridine orange and ethidium bromide dual dye staining, caspase-3 assay, DNA fragmentation assay followed by cell cycle analysis using fluorescence-activated cell sorting. Taken together, these results advocate promising potential of the biosynthesized AgNps for their use in therapeutic applications. PMID- 28866214 TI - Facile fabrication of nickel immobilized on magnetic nanoparticles as an efficient affinity adsorbent for purification of his-tagged protein. AB - In the present research, an efficient, convenient, and inexpensive method for the one-pot synthesis of Fe3O4@Histidine is developed. Histidine is readily loaded on magnetic nanoparticles by one step and simple method without any supplemental linkers. In the structure of Fe3O4@Histidine, histidine covalently immobilized on the surface of Fe3O4, magnetic nanoparticles are able to trap Ni2+ ions through a strong interaction between nickel and histidines in protein tag. Two coordination sites of nickel are occupied with ligand on the surface of magnetic nanoparticles and four coordination sites have been remained that these sites will be occupied with histidine tag of recombinant protein A. The functionalized nanoparticles were spherical and well separated with an average diameter around 30nm. The obtained magnetic nanoparticles have a saturation magnetization of about 54emu/g. Fe3O4@Histidine-Ni was used to enrich and purify 6*histidine-tagged recombinant protein-A directly from the mixture of lysed cells. It has been found that Ni(II) immobilized Fe3O4@Histidine magnetic nanoparticles present negligible nonspecific protein adsorption and high His-tag protein binding capacity The average binding capacity (MW 42k Da), is 700+/-25MUg.mg-1 (protein/Fe3O4@Histidine-Ni). PMID- 28866215 TI - Enhanced antiadhesive properties of chitosan/hyaluronic acid polyelectrolyte multilayers driven by thermal annealing: Low adherence for mammalian cells and selective decrease in adhesion for Gram-positive bacteria. AB - The development of antifouling coatings with restricted cell and bacteria adherence is fundamental for many biomedical applications. A strategy for the fabrication of antifouling coatings based on the layer-by-layer assembly and thermal annealing is presented. Polyelectrolyte multilayers (PEMs) assembled from chitosan and hyaluronic acid were thermally annealed in an oven at 37 degrees C for 72h. The effect of annealing on the PEM properties and topography was studied by atomic force microscopy, zeta-potential, circular dichroism and contact angle measurements. Cell adherence on PEMs before and after annealing was evaluated by measuring the cell spreading area and aspect ratio for the A549 epithelial, BHK kidney fibroblast, C2C12 myoblast and MC-3T3-E1 osteoblast cell lines. Chitosan/hyaluronic acid PEMs show a low cell adherence that decreases with the thermal annealing, as observed from the reduction in the average cell spreading area and more rounded cell morphology. The adhesion of S. aureus (Gram-positive) and E. coli (Gram-negative) bacteria strains was quantified by optical microscopy, counting the number of colony-forming units and measuring the light scattering of bacteria suspension after detachment from the PEM surface. A 20% decrease in bacteria adhesion was selectively observed in the S. aureus strain after annealing. The changes in mammalian cell and bacteria adhesion correlate with the changes in topography of the chitosan/hyaluronic PEMs from a rough fibrillar 3D structure to a smoother and planar surface after thermal annealing. PMID- 28866216 TI - Ultrasonically assisted preparation of poly(acrylic acid)/calcium phosphate hybrid nanogels as pH-responsive drug carriers. AB - Biocompatible, biodegradable and stimuli-responsive nanomaterials can be used as drug carriers and to achieve controlled drug delivery, which is crucial for treating tumors and lowering drug side effects. Calcium phosphate (CaP) nanoparticles and poly(acrylic acid) (PAA) hydrogels can be used as biocompatible and pH-responsive drug carriers. In this study, based on the ultrasound effect, PAA/CaP hybrid nanogels (approximately 100nm, PDI<0.2) are obtained via the cross linking of CaP nanoparticles and PAA molecules between the Ca2+ ions and -COOH groups. The PAA/CaP hybrid nanogels show good stability in biological media as well as no hemolysis and no cytotoxicity to L02 cells. Moreover, the PAA/CaP hybrid nanogels display an enhanced loading capacity (approximately 32%) for doxorubicin hydrochloride (DOX) compared to pure CaP nanoparticles (approximately 7.5%) and a pH-controlled drug release due to their dissolution in acidic environment. DOX can be delivered into cancer cells by the PAA/CaP hybrid nanogels, which show an inhibitory effect comparable to that of free DOX, although the inhibitory effect is delayed due to the slow release of DOX from the carriers. In vivo, the PAA/CaP hybrid nanogels cannot avoid the capture by the reticuloendothelial system; however, they show passive tumor targeting ability. In brief, the biocompatible, biodegradable and pH-responsive PAA/CaP hybrid nanogels have the potential to act as drug carriers for controlled drug release. PMID- 28866217 TI - Zirconium amine tris(phenolate): A more effective initiator for biomedical lactide. AB - Here a zirconium amine tris(phenolate) is used as the initiator for the production of polylactide for biomedical applications, as a replacement for a tin initiator (usually tin octanoate). The ring opening polymerization (ROP) was carried out in the melt at 130 degrees C. The zirconium-catalyzed PLA (PLA-Zr) required 30min, resulting in a polydispersity index (PDI) of 1.17, compared to 1h and PDI=1.77 for tin-catalyzed PLA (PLA-Sn). PLA-Zr and PLA-Sn supported osteosarcoma cell (MG63) culture to the same extent (cell number, morphology, extracellular matrix production and osteogenic function) until day 14 when the PLA-Zr showed increased cell number, overall extracellular matrix production and osteogenic function. To conclude, the reduction in reaction time, controllable microstructure and biologically benign nature of the zirconium amine tris(phenolate) initiator shows that it is a more effective initiator for ROP of polylactide for biomedical applications. PMID- 28866218 TI - Preparation of spherical metal-organic frameworks encapsulating ag nanoparticles and study on its antibacterial activity. AB - A metal-organic frameworks (CuTCPP MOFs) were synthesized with Cu(NO3)2.3H2O and 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) by the solvothermal method. The structure and morphology of the CuTCPP MOFs were characterized by UV-vis absorption spectra, X-ray diffraction (PXRD), energy dispersive spectra, scanning electron microscopy (EDS-SEM) and transmission electron microscopy (TEM). The structure of the as-synthesized MOF includes copper ions and copper metalloporphyrin (Cu-TCPP) by UV-vis absorption spectra and PXRD. The SEM and TEM images of the as-synthesized MOF showed the morphology of the CuTCPP MOFs were spherical. The as-synthesized spherical MOFs as the carriers were used to encapsulate the Ag nanoparticles and prepared Ag-CuTCPP MOFs. The Ag-CuTCPP MOFs was also characterized by UV-vis, PXRD, SEM and TEM. The Ag nanoparticles were completely encapsulated into the CuTCPP MOFs and no surface absorption, which have been confirmed by comparing TEM and SEM-EDS of Ag-CuTCPP MOFs before crushing with that of Ag-CuTCPP MOFs after crushing. In addition, the release of Ag ions from Ag-CuTCPP MOFs was also investigated by Inductively Coupled Plasma Optical Emission Spectrometer (ICP-OES). Furthermore, the antimicrobial activities and cytotoxicity of Ag-CuTCPP MOFs were performed by in vitro and in vivo experiment. In vitro, the antibacterial effect of Ag-CuTCPP MOFs was even better than that of the penicillin as the positive control and the cytotoxicity of Ag-CuTCPP MOFs was significantly lower than that of naked Ag nanoparticles and Ag ions; in vivo, Ag-CuTCPP MOFs not only exhibited the excellently antibacterial effect and extremely low cytotoxicity but also effectively promoted the wound healing. PMID- 28866219 TI - Effect of low-intensity pulsed ultrasound on the biological behavior of osteoblasts on porous titanium alloy scaffolds: An in vitro and in vivo study. AB - Low-intensity pulsed ultrasound (LIPUS) has been used in patients with fresh fractures, delayed union and non-union to enhance bone healing and improve functional outcome. However, there were few studies concerning the effects of LIPUS on the biological behavior of osteoblasts on porous scaffolds. This study aimed to evaluate the effects of LIPUS on the biological behavior of osteoblasts on porous titanium-6aluminum-4vanadium (Ti6Al4V) alloy scaffolds in vitro and in vivo. Scaffolds were randomly divided into an ultrasound group and a control group. Mouse pre-osteoblast cells were cultured with porous Ti6Al4V scaffolds in vitro. The effects of LIPUS on the biological behavior of osteoblasts were evaluated by observing the adhesion, proliferation, differentiation and ingrowth depth on porous Ti6Al4V scaffolds. In addition, scaffolds were implanted into rabbit mandibular defects in vivo. The effects of LIPUS on bone regeneration were evaluated via micro-CT, fluorescent staining and toluidine blue staining. The results revealed that osteoblast adhered well to the scaffolds, and there was no significant difference in the methyl thiazolyl tetrazolium value between the ultrasound group and the control group (p>0.05). Compared with the control group, ultrasound promoted the alkaline phosphatase activity, osteocalcin levels and ingrowth depth of the cells on the scaffolds (p<0.05). In addition, micro-CT and histomorphological analysis showed that the volume and amount of new bone formation were increased and that bone maturity was improved in the ultrasound group compared to the control group. These results indicate that LIPUS promotes osteoblast differentiation as well as enhances bone ingrowth in porous Ti6Al4V scaffolds, and promotes bone formation and maturity in porous Ti6Al4V scaffolds. PMID- 28866220 TI - Facile fabrication of luminescent polymeric nanoparticles containing dynamic linkages via a one-pot multicomponent reaction: Synthesis, aggregation-induced emission and biological imaging. AB - Luminescent polymeric nanoparticles (LPNs) with aggregation-induced emission (AIE) feature have emerged as the most promising candidates for biological imaging owing to their unique AIE feature, great water dispersity, strong fluorescence, low cytotoxicity and biocompatibility. Although numerous successful strategies for construction of AIE-active LPNs have been developed, the preparation of dynamic linkages containing AIE-active LPNs based on multicomponent reactions has been rarely reported. In this work, we report a facile method for the formation of AIE-active LPNs via a one-pot conjugation of PEG-B(OH)2, 1-thioglycerol and AIE-active dye PhE-alc in short time under rather mild reaction conditions (e.g. ambient temperature, air atmosphere, absent of metal catalysts and in the present of water). The successful formation of AIE active mPEG-PhE LPNs was confirmed by different characterization techniques in details. The great optical and biological properties certified their applicable for biological imaging application. More importantly, the novel method for the formation of AIE-active LPNs is rather simple, high efficiency and atom economy, which greatly enriched their practical biomedical applications. PMID- 28866221 TI - Microstructural effects in drug release by solid and cellular polymeric dosage forms: A comparative study. AB - In recent studies, we have introduced melt-processed polymeric cellular dosage forms to achieve both immediate drug release and predictable manufacture. Dosage forms ranging from minimally-porous solids to highly porous, open-cell and thin walled structures were prepared, and the drug release characteristics investigated as the volume fraction of cells and the excipient molecular weight were varied. In the present study, both minimally-porous solid and cellular dosage forms consisting of various weight fractions of Acetaminophen drug and polyethylene glycol (PEG) excipient are prepared and analyzed. Microstructures of the solid forms and the cell walls range from single-phase solid solutions of the excipient and a small amount of drug molecules to two-phase composites of the excipient and tightly packed drug particles. Results of dissolution experiments show that the minimally-porous solid forms disintegrate and release drug by slow surface erosion. The erosion rate decreases as the drug weight fraction is increased. By contrast, the open-cell structures disintegrate rapidly by viscous exfoliation, and the disintegration time is independent of drug weight fraction. Drug release models suggest that the solid forms erode by convective mass transfer of the faster-eroding excipient if the drug volume fraction is small. At larger drug volume fractions, however, the slower-eroding drug particles hinder access of the free-flowing fluid to the excipient, thus slowing down erosion of the composite. Conversely, the disintegration rate of the cellular forms is limited by diffusion of the dissolution fluid into the excipient phase of the thin cell walls. Because the wall thickness is of the order of the drug particle size, and the particles are enveloped by the excipient during melt-processing, the drug particles cannot hinder diffusion through the excipient across the walls. Thus the disintegration time of the cellular forms is mostly unaffected by the volume fraction of drug in the walls. PMID- 28866222 TI - Detection of alprazolam with a lab on paper economical device integrated with urchin like Ag@ Pd shell nano-hybrids. AB - We present results of the studies relating to fabrication of a microfluidic biosensor chip based on urchin like Ag@ Pd shell nano-hybrids that is capable of sensing alprazolam through electrochemical detection. Using this chip we demonstrate, with high reliability and in a time efficient manner, the detection of alprazolam present in buffer solutions at clinically relevant concentrations. Methylene blue (MB) was also doped as redox transition substance for sensing alprazolam. Nano-hybrids modified EMUPAD showed wide linear range 1-300ng/ml and low detection limit of 0.025ng/l. Low detection limit can further enhance its suitability for forensic application. Nano-hybrids modified EMUPAD was also employed for determination of drug in real samples such as human urine. Reported facile lab paper approach integrated with urchin like Ag@ Pd shell nano-hybrids could be well applied for the determination of serum metabolites. PMID- 28866223 TI - Development of polyurethanes for bone repair. AB - The purpose of this paper is to review recent developments on polyurethanes aimed at the design, synthesis, modifications, and biological properties in the field of bone tissue engineering. Different polyurethane systems are presented and discussed in terms of biodegradation, biocompatibility and bioactivity. A comprehensive discussion is provided of the influence of hard to soft segments ratio, catalysts, stiffness and hydrophilicity of polyurethanes. Interaction with various cells, behavior in vivo and current strategies in enhancing bioactivity of polyurethanes are described. The discussion on the incorporation of biomolecules and growth factors, surface modifications, and obtaining polyurethane-ceramics composites strategies is held. The main emphasis is placed on the progress of polyurethane applications in bone regeneration, including bone void fillers, shape memory scaffolds, and drug carrier. PMID- 28866224 TI - Highlights in nanocarriers for the treatment against cervical cancer. AB - Cervical cancer is the second most common malignant tumor in women worldwide and has a high mortality rate, especially when it is associated with human papillomavirus (HPV). In US, an estimated 12,820 cases of invasive cervical cancer and an estimated 4210 deaths from this cancer will occur in 2017. With rare and very aggressive conventional treatments, one sees in the real need of new alternatives of therapy as the delivery of chemotherapeutic agents by nanocarriers using nanotechnology. This review covers different drug delivery systems applied in the treatment of cervical cancer, such as solid lipid nanoparticles (SNLs), liposomes, nanoemulsions and polymeric nanoparticles (PNPs). The main advantages of drug delivery thus improving pharmacological activity, improving solubility, bioavailability to bioavailability reducing toxicity in the target tissue by targeting of ligands, thus facilitating new innovative therapeutic technologies in a too much needed area. Among the main disadvantage is the still high cost of production of these nanocarriers. Therefore, the aim this paper is review the nanotechnology based drug delivery systems in the treatment of cervical cancer. PMID- 28866225 TI - Fabrication and characterization of two-layered nanofibrous membrane for guided bone and tissue regeneration application. AB - Membranes used in dentistry act as a barrier to prevent invasion of intruder cells to defected area and obtains spaces that are to be subsequently filled with new bone and provide required bone volume for implant therapy when there is insufficient volume of healthy bone at implant site. In this study a two-layered bioactive membrane were fabricated by electrospinning whereas one layer provides guided bone regeneration (GBR) and fabricated using poly glycerol sebacate (PGS)/polycaprolactone (PCL) and Beta tri-calcium phosphate (beta-TCP) (5, 10 and 15%) and another one containing PCL/PGS and chitosan acts as guided tissue regeneration (GTR). The morphology, chemical, physical and mechanical characterizations of the membranes were studied using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), tensile testing, then biodegradability and bioactivity properties were evaluated. In vitro cell culture study was also carried out to investigate proliferation and mineralization of cells on different membranes. Transmission electron microscope (TEM) and SEM results indicated agglomeration of beta-TCP nanoparticles in the structure of nanofibers containing 15% beta-TCP. Moreover by addition of beta-TCP from 5% to 15%, contact angle decreased due to hydrophilicity of nanoparticles and bioactivity was found to increase. Mechanical properties of the membrane increased by incorporation of 5% and 10% of beta-TCP in the structure of nanofibers, while addition of 15% of beta-TCP was found to deteriorate mechanical properties of nanofibers. Although the presence of 5% and 10% of nanoparticles in the nanofibers increased proliferation of cells on GBR layer, cell proliferation was observed to decrease by addition of 15% beta-TCP in the structure of nanofibers which is likely due to agglomeration of nanoparticles in the nanofiber structure. Our overall results revealed PCL/PGS containing 10% beta-TCP could be selected as the optimum GBR membrane in view point of physical and mechanical properties along with cell behavior. PCL/PGS nanofibers containing 10% beta-TCP were electrospun on the GTR layer for fabrication of final membrane. Addition of chitosan in the structure of PCL/PGS nanofibers was found to decrease fiber diameter, contact angle and porosity which are favorable for GTR layer. Two layered dental membrane fabricated in this study can serve as a suitable substrate for application in dentistry as it provides appropriate osteoconductivity and flexibility along with barrier properties. PMID- 28866226 TI - Networks based on biodegradable polyesters: An overview of the chemical ways of crosslinking. AB - Biodegradable polymers have gained more importance due to growing concern of our society for the ecology and sustainable development. Among them, aliphatic polyesters, poly(epsilon-caprolactone) PCL, poly(lactic acid) PLA and poly(3 hydroxyalkanoate)s PHAs present the advantage to be both biodegradable and biocompatible. Nevertheless, their thermal and mechanical properties represent a major drawback limiting some engineering applications. As a result the design of novel structures such as networks based on polyesters is revealing as a great challenge for enhancing their mechanical and thermal properties. The networks can be obtained throughout several approaches. This review focuses on the different chemical methods of crosslinking by using radical mechanisms, condensation reactions of polyesters or functionalized oligoesters. Preparation of hybrid, interpenetrated or reversible networks are described. This review highlights the relations structure-properties of the resulted materials and their potential applications. PMID- 28866228 TI - Corrigendum to "Cytoprotective effect of the enzyme-mediated polygallic acid on fibroblast cells under exposure of UV-irradiation" [Mater. Sci. Eng. C 76C (2017) 417-424]. PMID- 28866227 TI - Polymeric nanoparticles: A study on the preparation variables and characterization methods. AB - Since the emergence of Nanotechnology in the past decades, the development and design of nanomaterials has become an important field of research. An emerging component in this field is nanomedicine, wherein nanoscale materials are being developed for use as imaging agents or for drug delivery applications. Much work is currently focused in the preparation of well-defined nanomaterials in terms of size and shape. These factors play a significantly role in the nanomaterial behavior in vivo. In this context, this review focuses on the toolbox of available methods for the preparation of polymeric nanoparticles. We highlight some recent examples from the literature that demonstrate the influence of the preparation method on the physicochemical characteristics of the nanoparticles. Additionally, in the second part, the characterization methods for this type of nanoparticles are discussed. PMID- 28866229 TI - Photo-controlled aptamers delivery by dual surface gold-magnetic nanoparticles for targeted cancer therapy. AB - Dual surfaced dumbbell-like gold magnetic nanoparticles (Au-Fe3O4) were synthesized for targeted aptamers delivery. Their unique biological properties were characterized as a smart photo-controlled drug carrier. DNA aptamers targeting vascular endothelial growth factor (VEGF) were assembled onto the surface of Au-Fe3O4 by electrostatic absorption. The binding capacity of the nanoparticles with VEGF aptamers was confirmed by gel electrophoresis. The targeted recognization of ovarian cancer cells by the aptamers-functionalized Au Fe3O4 nanoparticles (Apt-Au-Fe3O4 NPs) was observed by confocal microscopy. Apt Au-Fe3O4 was found to bind with SKOV-3 ovarian cancer cells specifically, leading to marked intracellular release of aptamers upon plasmon-resonant light (605nm) radiation, and to enhance the in vitro inhibition against tumor cell proliferation. The results show high potential of Apt-Au-Fe3O4as a targeted cancer hyperthermia carrier by remote control with high spatial/temporal resolution. PMID- 28866230 TI - Strontium doped injectable bone cement for potential drug delivery applications. AB - Microwave assisted wet precipitation method was used to synthesize calcium deficient strontium doped beta-tricalcium phosphate (Sr-betaTCP) with a chemical formula of Ca2.96-xSrx(PO4)2. Sr-betaTCP was reacted with monocalcium phosphate monohydrate [Ca(H2PO4)2.H2O, MCPM] in presence of water to furnish corresponding Sr containing brushite cement (Sr-Brc). The samples were characterized by using X ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR) and field emission scanning electron microscopy (FESEM). Strontium content in the prepared samples was determined by using inductively coupled plasma optical emission spectrometry (ICP-OES). The effect of Sr2+ ions on the structural, mechanical, setting properties and drug release of the cement is reported. Incorporation of Sr2+ ions improved the injectability, setting time and mechanical properties of the Brc. The release profiles of antibiotics incorporated in Brc and Sr-Brc confirmed that the Sr incorporation into the Brc results in the efficient release of the antibiotics from the cement. PMID- 28866232 TI - Aortic Reconstruction in an Infected Field. Commentary on "Self-made Xeno pericardial Aortic Tubes to Treat Native and Aortic Graft Infections". PMID- 28866231 TI - Gardasil Vaccination for Recurrent Laryngeal Papillomatosis in Adult Men Second Report: Negative Conversion of HPV in Laryngeal Secretions. AB - BACKGROUND: In our first report on antibody levels in middle-aged and older men with recurrent laryngeal papillomatosis (RLP), we reported increases in human papillomavirus (HPV) antibody levels similar to those seen in adult women and young men. We posited that HPV antibodies produced in laryngeal mucus by Gardasil would prevent postoperative reinfection in patients with RLP. STUDY DESIGN: This is a case series study. PURPOSE: The purpose of this study was to examine whether Gardasil injection effectively inhibits recurrence of RLP. Specifically, in this second report, whether HPV antibodies produced in laryngeal secretions by Gardasil are capable of causing negative conversion of HPV-DNA (deoxyribonucleic acid) in laryngeal mucosa was investigated. METHODS: A total of 11 patients for whom antibodies were measured in the first report were studied. Before vaccination and after 1 year Post-vaccination, HPV screening tests were performed on laryngeal secretions, and whether HPV-DNA negative conversion had occurred was evaluated. At the time of collection of laryngeal secretions, the presence or absence of laryngeal papillomas was examined. RESULTS: Before vaccination, all patients were HPV low-risk positive on laryngeal secretion screening tests. After vaccination, three patients were positive. Laryngeal papillomas remained in five patients. CONCLUSIONS: The HPV-DNA test showed negative conversion in eight of 11 (72.7%) patients after vaccination. Residual laryngeal papillomas were found in five of 11 (45.5%) patients. The serum HPV antibody titer did not differ significantly between the group in which laryngeal secretions showed HPV negative conversion and the group in which conversion did not occur. The serum antibody titer did not differ significantly as a function of whether there were residual tumors. PMID- 28866233 TI - Cyanobacteria growing on tree barks possess high amount of sunscreen compound mycosporine-like amino acids (MAAs). AB - The present study describes cyanobacterial species composition and their dominance in biological crusts from barks of different trees, roof top of building and soil of agricultural field. An attempt was also made to explore the presence of photoprotective compounds such as mycosporine-like amino acids (MAAs) in the crust samples. Microscopic examination and growth studies revealed the presence of Oscillatoria species in all the crust samples excluding the crust of roof top of a building. Study on the abundance of dominant genera showed marked differences among various crust samples but Hapalosiphon, Lyngbya, Oscillatoria and Scytonema sp. were the most dominant genera, Oscillatoria being dominant in three crust samples. Screening for the presence of photoprotective compounds showed the presence of major peaks in the range of 308-334 nm thereby pointing to the presence of MAAs in all the crust samples. The highest amount of MAAs was found in the crust of Borassus flabellifer (15,729 nmol g dry wt-1 of bark) followed by crust of roof top (14,543 nmol g dry wt-1 of crust). MAAs were separated and partially purified employing HPLC, the most common MAA present in all the crusts was identified as mycosporine-glycine. Presence of mycosporine glycine (M-Gly) was further confirmed by FTIR and NMR. Test of in vitro colonization on the bark of Mangifera indica and Azadirachta indica by three isolates namely Hapalosiphon, Oscillatoria and Scytonema sp. showed sign of active colonization. It is felt that identification of all the MAAs other than M Gly may prove useful in future studies especially for assessing their significance in the protection mechanism of cyanobacteria/algae against various types of abiotic stresses. PMID- 28866234 TI - Relative contribution of Na+/K+ homeostasis, photochemical efficiency and antioxidant defense system to differential salt tolerance in cotton (Gossypium hirsutum L.) cultivars. AB - In this study, the role of specific components of different coping strategies to salt load were identified. A pot experiment was conducted with four cotton (Gossypium hirsutum L.) cultivars (differing in salt-sensitivity) under salinity stress. Based on observed responses in growth performance and physiological characteristics, CZ91 was the most tolerant of the four cultivars, followed by cultivars CCRI44 and CCRI49, with Z571 being much more sensitive to salt stress. To perform this tolerant response, they implement different adaptative mechanisms to cope with salt-stress. The superior salt tolerance of CZ91 was conferred by at least three complementary physiological mechanisms: its ability to regulate K+ and Na+ transport more effectively, its higher photochemical efficiency and better antioxidant defense capacity. However, only one or a few specific components of these defense systems play crucial roles in moderately salt tolerant CCRI44 and CCRI49. Lower ROS load in CCRI44 may be attributed to simultaneous induction of antioxidant defenses by maintaining an unusually high level of SOD, and higher activities of CAT, APX, and POD during salt stress. CCRI49 could reduce the excess generation of ROS not only by maintaining a higher selective absorption of K+ over Na+ in roots across the membranes through SOS1, AKT1, and HAK5, but also by displaying higher excess-energy dissipation (e.g., higher ETR, PR and qN) during salt stress. Overall, our data provide a mechanistic explanation for differential salt stress tolerance among these cultivars and shed light on the different strategies employed by cotton cultivars to minimize the ill effects of stress. PMID- 28866235 TI - Genome-wide analysis of the YABBY family in soybean and functional identification of GmYABBY10 involvement in high salt and drought stresses. AB - YABBY family is a plant specific transcription factor family, with the typical N terminal C2C2 type zinc finger domain and the C-terminal YABBY conservative structure domain, which plays important biological roles in plant growth, development and morphogenesis. In this study, a total of 17 YABBY genes were identified in the soybean genome. The results of this research showed that 17 soybean YABBY genes were located on 11 chromosomes. Analysis of putative cis acting elements showed that soybean YABBY genes contained lots of MYB and MYC elements. Quantitative Real-time PCR (qRT-PCR) showed that the expressions of GmYABBY3, GmYABBY10 and GmYABBY16 were more highly sensitive in drought, NaCl and ABA stresses. And the transient expression in Arabidopsis protoplasts showed that GmYABBY3 protein distributed uniformly the whole cells, while GmYABBY10 protein was mainly localized in the membranes and cytoplasm and GmYABBY16 protein was localized the nucleus and membranes. To further identify the function of GmYABBY10, we obtained the transgenic Arabidopsis overexpression GmYABBY10. Based on germination and seedling root arrays in transgenic Arabidopsis, we found that the rates of wild type seeds was a litter higher than that of GmYABBY10 transgenic seeds under both PEG and NaCl treatment. While the root length and root surface of wild type seedlings were bigger than those of GmYABBY10 transgenic seedlings. When seedlings were grown in soil, the survival rates of wild type were higher than those of transgenic plants under both PEG and NaCl treatment, which indicated that GmYABBY10 may be a negatively regulator in plant resistances to drought and salt stresses. This study provided valuable information regarding the classification and functions of YABBY genes in soybean. PMID- 28866236 TI - Differential accumulation of flavonoids and phytohormones resulting from the canopy/rootstock interaction of citrus plants subjected to dehydration/rehydration. AB - Water scarcity can elicit drastic changes in plant metabolic and hormonal regulation, which may be of fundamental importance to stress tolerance. The study of plant the metabolic alterations in response to water deficit, especially the effects of the rootstocks level, is important to elucidate the mechanisms associated to drought tolerance. To verify the influence of rootstock and grafting on the tolerance to drought in citrus plants, we analyzed the growth, phytohormone levels and flavonoid profiles in grafted and ungrafted citrus plants subjected to different soil water regimes on plant status (well-watered, moderate drought and severe drought and rehydrated) under field conditions. The experiments were conducted under field conditions in the Brazilian Agricultural Research Corporation (EMBRAPA), Cruz das Almas, BA, Brazil. Water deficit reduced the total leaf area per plant in all canopy/rootstock combinations. Self-grafting reduce root volume, area and length when compared to ungrafted plants. Drought induced increases in salicylic acid and abscisic acid associated with concomitant reductions in indoleacetic acid were observed in most canopy/rootstock combinations. However, plants with 'Sunki Maravilha' rootstocks exhibited the most pronounced changes in hormonal levels upon drought stress. Associated to these hormonal changes, drought also significantly affected flavonoid content and profile in both leaves and roots of the distinct citrus combinations. Glycosylated (GFs) and polimethoxylated flavonoids were predominantly found in leaves, whereas prenylated coumarins were found in the roots. Leaf levels of GFs (vicenin, F11, rutin and rhoifolin) were particularly modulated by drought in plants with 'Rangpur Santa Cruz' lime rootstock, whereas root levels of prenylated coumarins were most regulated by drought in plants with the 'Sunki Maravilha' root system. Taken together, these data indicate that the impacts of water deficit restriction on growth, hormonal balance and flavonoid profiles significantly varies depending on the canopy/rootstock combinations. PMID- 28866237 TI - Effects of simultaneously elevated temperature and CO2 levels on Nicotiana benthamiana and its infection by different positive-sense RNA viruses are cumulative and virus type-specific. AB - We have studied how simultaneously elevated temperature and CO2 levels [climate change-related conditions (CCC) of 30 degrees C, 970 parts-per-million (ppm) of CO2 vs. standard conditions (SC) of 25 degrees C, ~ 405ppm CO2] affect physiochemical properties of Nicotiana benthamiana leaves, and also its infection by several positive-sense RNA viruses. In previous works we had studied effects of elevated temperature, CO2 levels separately. Under CCC, leaves of healthy plants almost doubled their area relative to SC but contained less protein/unit of-area, similarly to what we had found under conditions of elevated CO2 alone. CCC also affected the sizes/numbers of different foliar cell types differently. Under CCC, infection outcomes in titers and symptoms were virus type-specific, broadly similar to those observed under elevated temperature alone. Under either condition, infections did not significantly alter the protein content of leaf discs. Therefore, effects of elevated temperature and CO2 combined on properties of the pathosystems studied were overall cumulative. PMID- 28866238 TI - Genetic variation and co-evolutionary relationship of RNA polymerase complex segments in influenza A viruses. AB - The RNA polymerase complex (RNApc) in influenza A viruses (IVs) is composed of the PB2, PB1 and PA subunits, which are encoded by the three longest genome segments (Seg1-3) and are responsible for the replication of vRNAs and transcription of viral mRNAs. However, the co-evolutionary relationships of the three segments from the known 126 subtypes IVs are unclear. In this study, we performed a detailed analysis based on a total number of 121,191 nucleotide sequences. Three segment sequences were aligned before the repeated, incomplete and mixed sequences were removed for homologous and phylogenetic analyses. Subsequently, the estimated substitution rates and TMRCAs (Times for Most Recent Common Ancestor) were calculated by 175 representative IVs. Tracing the cladistic distribution of three segments from these IVs, co-evolutionary patterns and trajectories could be inferred. The further correlation analysis of six internal protein coding segments reflect the RNApc segments have the closer correlation than others during continuous reassortments. This global approach facilitates the establishment of a fast antiviral strategy and monitoring of viral variation. PMID- 28866239 TI - An evaluation of soil chemistry in human cadaver decomposition islands: Potential for estimating postmortem interval (PMI). AB - Soil samples from the Forensic Anthropology Research Facility (FARF) at Texas State University, San Marcos, TX, were analyzed for multiple soil characteristics from cadaver decomposition islands to a depth of 5centimeters (cm) from 63 human decomposition sites, as well as depths up to 15cm in a subset of 11 of the cadaver decomposition islands plus control soils. Postmortem interval (PMI) of the cadaver decomposition islands ranged from 6 to 1752 days. Some soil chemistry, including nitrate-N (NO3-N), ammonium-N (NH4-N), and dissolved inorganic carbon (DIC), peaked at early PMI values and their concentrations at 0 5cm returned to near control values over time likely due to translocation down the soil profile. Other soil chemistry, including dissolved organic carbon (DOC), dissolved organic nitrogen (DON), orthophosphate-P (PO4-P), sodium (Na+), and potassium (K+), remained higher than the control soil up to a PMI of 1752days postmortem. The body mass index (BMI) of the cadaver appeared to have some effect on the cadaver decomposition island chemistry. To estimate PMI using soil chemistry, backward, stepwise multiple regression analysis was used with PMI as the dependent variable and soil chemistry, body mass index (BMI) and physical soil characteristics such as saturated hydraulic conductivity as independent variables. Measures of soil parameters derived from predator and microbial mediated decomposition of human remains shows promise in estimating PMI to within 365days for a period up to nearly five years. This persistent change in soil chemistry extends the ability to estimate PMI beyond the traditionally utilized methods of entomology and taphonomy in support of medical-legal investigations, humanitarian recovery efforts, and criminal and civil cases. PMID- 28866240 TI - An investigation into artefacts formed during gas chromatography/mass spectrometry analysis of firearms propellant that contains diphenylamine as the stabiliser. AB - In the course of providing assistance to legal counsel in a matter that involved the analysis of firearms propellant by gas chromatography/mass spectrometry it was noticed that phenoxazine was reported as a component of 0.22 calibre propellant that contained diphenylamine as the stabiliser. The research was conducted to find how phenoxazine was formed. The results showed that the compound was not phenoxazine but a diphenylamine derivative 4-(phenylimino) cyclohexa-2,5-dien-1-one that formed in the injection port of the gas chromatograph. In addition a second artefact was found to form in the ion source of the mass spectrometer. While the presence of the artefacts does not affect the ability to identify particles as propellant they may impact on comparison with source ammunition. PMID- 28866241 TI - Acylpeptide hydrolase is a component of the cellular response to DNA damage. AB - Acylpeptide hydrolase (APEH) deacetylates N-alpha-acetylated peptides and selectively degrades oxidised proteins, but the biochemical pathways that are regulated by this protease are unknown. Here, we identify APEH as a component of the cellular response to DNA damage. Although APEH is primarily localised in the cytoplasm, we show that a sub-fraction of this enzyme is sequestered at sites of nuclear damage following UVA irradiation or following oxidative stress. We show that localization of APEH at sites of nuclear damage is mediated by direct interaction with XRCC1, a scaffold protein that accelerates the repair of DNA single-strand breaks. We show that APEH interacts with the amino-terminal domain of XRCC1, and that APEH facilitates both single-strand break repair and cell survival following exposure to H2O2 in human cells. These data identify APEH as a novel proteolytic component of the DNA damage response. PMID- 28866242 TI - To engraft or not to engraft: an ecological framework for gut microbiome modulation with live microbes. AB - Strategies aimed at modulating the gut microbiota by using live microbes range from single strains (probiotics or live biotherapeutics) to whole non-defined fecal transplants. Although often clinically efficacious, our understanding on how microbial-based strategies modulate gut microbiome composition and function is vastly incomplete. In this review, we present a framework based on ecological theory that provides mechanistic explanations for the findings obtained in studies that attempted to modulate the gut microbiota of humans and animals using live microbes. We argue that an ecological perspective grounded in theory is necessary to interpret and predict the impact of microbiome-modulating strategies and thus advance our ability to develop improved and targeted approaches with enhanced therapeutic efficiency. PMID- 28866244 TI - National Trends and Predictors of Locally Advanced Penile Cancer in the United States (1998-2012). AB - BACKGROUND: We analyzed the trends in presentation of squamous cell carcinoma (SCC) of the penis and determined the socioeconomic predictors for locally advanced (cT3-cT4) disease in the United States. PATIENT AND METHODS: The National Cancer Database was queried for patients with clinically nonmetastatic penile SCC and staging available from 1998 to 2012. Temporal trends per tumor stage were evaluated, and a multivariable logistic regression model was used to identify predictors for advanced presentation during the study period. RESULTS: A total of 5767 patients with stage <= T1-T2 (n = 5423) and T3-T4 (n = 344) disease were identified. Increasing trends were noted in all stages of penile SCC with a greater proportion of advanced cases over time (P = .001). Significant predictors of advanced presentation were age > 55 years, the presence of comorbidities, and Medicaid or no insurance (P < .05 for all). CONCLUSION: More penile SCC is being detected in the United States. Our results have demonstrated older age, presence of comorbidities, and Medicaid or no insurance as potential barriers to early access of care in the male population. Understanding the current socioeconomic gaps could help guide targeted interventions in vulnerable populations. PMID- 28866243 TI - Intestinal Lactobacillus in health and disease, a driver or just along for the ride? AB - Metagenomics and related methods have led to significant advances in our understanding of the human microbiome. Members of the genus Lactobacillus, although best understood for essential roles in food fermentations and applications as probiotics, have also come to the fore in a number of untargeted gut microbiome studies in humans and animals. Even though Lactobacillus is only a minor member of the human colonic microbiota, the proportions of those bacteria are frequently either positively or negatively correlated with human disease and chronic conditions. Recent findings on Lactobacillus species in human and animal microbiome research, together with the increased knowledge on probiotic and other ingested lactobacilli, have resulted in new perspectives on the importance of this genus to human health. PMID- 28866245 TI - Incidence and Effect of Thromboembolic Events in Radical Cystectomy Patients Undergoing Preoperative Chemotherapy for Muscle-invasive Bladder Cancer. AB - BACKGROUND: We evaluated the incidence and effect of thromboembolic events (TEEs) in patients with muscle-invasive bladder cancer treated with preoperative chemotherapy (POC) and radical cystectomy (RC) with pelvic lymph node dissection (PLND). PATIENTS AND METHODS: We performed a retrospective review of all patients who had undergone POC followed by RC plus PLND for muscle-invasive bladder cancer from June 2000 to January 2013 (n = 357). The chemotherapy type (neoadjuvant vs. induction), incidence and timing of TEE diagnosis (preoperatively vs. <= 90 days postoperatively), and effect of TEEs on clinical outcomes were recorded. RESULTS: Overall, 79 patients (22%; 95% confidence interval [CI], 18%-27%) experienced a TEE: 57 (16%) occurred during POC and 22 (6.2%) were diagnosed postoperatively. Forty patients (11%; 95% CI, 8.1%-15%) required an inferior vena cava filter. We found no significant differences in neoadjuvant versus induction chemotherapy and the risk of TEEs (difference, 3.3%; 95% CI, -5% to 12%; P = .5). No significant difference were found in the rates of POC completion according to the presence of a TEE (difference, 1.0%; 95% CI, -11% to 13%; P = .9). The occurrence of TEE did not significantly affect other perioperative outcomes. The risk of recurrence and overall survival were not associated with TEE on multivariable analysis. CONCLUSION: We found a high incidence of TEEs (22%) in patients undergoing POC before RC plus PLND, with a 16% incidence in the preoperative period. TEEs in the POC setting leads to invasive procedures; however, we did not find a significant effect on POC completion or postoperative complication risk. Further research is required to determine whether preventative TEE measures during POC can improve clinical outcomes. PMID- 28866246 TI - Radiofrequency Ablation for Renal Cancer in Von Hippel-Lindau Syndrome Patients: A Prospective Cohort Analysis. AB - INTRODUCTION: Management of renal-cell carcinoma (RCC) in patients with Von Hippel-Lindau syndrome (VHL) represents a clinical dilemma: the oncologic outcomes must be weighed against preservation of renal function. Radiofrequency ablation (RFA) is currently used in selected cases for treatment of small-size RCC. The aim of this study was to evaluate the safety, complications, and functional and oncologic outcomes of RFA in the treatment of RCC in VHL patients. PATIENTS AND METHODS: RCCs were treated with ultrasound-guided RFA or with laparoscopic RFA. Clinical and radiologic response, disease recurrence, and survival outcomes were evaluated during follow-up. Early and late complications were recorded and graded. RESULTS: Nine RCC patients underwent RFA. The median number of RCCs per patient was 3 (interquartile range, 2-4). Among these 9 patients, a total of 20 RCCs were treated by RFA (19 ultrasound-guided RFA and 1 laparoscopic procedure). Median RCC size was 2.5 cm (interquartile range, 2.0 3.0). RFA did not impair renal function (P = .35). In 2 cases disease persisted, and in 1 case disease recurred after 18 months. These patients were retreated with ultrasound-guided RFA with complete response and no renal function impairment. RFA treatment was overall well tolerated and safe. No complications were recorded. Postoperative stay was no longer than 1 day. CONCLUSION: RCC occurred in about two-thirds of VHL patients, who had young age at presentation; it was frequently multifocal and recurrent. The use of RFA, with extended indications, could represent a tailored treatment for VHL patients, reducing the risk of renal failure and resulting in satisfying oncologic results. PMID- 28866247 TI - Using personal construct methodology to explore relationships with adolescents with Autism Spectrum Disorder. AB - BACKGROUND: Research shows that adolescents with Autism Spectrum Disorder (ASD) experience difficulties developing friendships, and that loneliness is a significant factor contributing to higher incidence of anxiety and depression within this population. AIMS: This study aimed to provide an in-depth analysis of relationships as described by adolescents with ASD, and, from these descriptions, to explore what can be inferred about the development of successful interpersonal relationships for these individuals. METHODS AND PROCEDURE: Eight adolescents with ASD participated in semi-structured interviews using established personal construct theory (PCT) techniques. OUTCOMES AND RESULTS: PCT was found to be a helpful approach to elicit rich, qualitative data. A thematic analysis identified four themes: relationships as a source of support, perceptions of similarity and difference, valued qualities in self and others, and the development and maintenance of relationships. CONCLUSIONS AND IMPLICATIONS: Whilst this exploratory study highlighted some commonality in terms of perceptions of family support and friendships as protective and desirable, participants differed in their ability to establish and maintain peer relationships. Participants valued personal qualities such as intelligence, humour and trust within relationships, and recognised the important role of peers and siblings in the development of social skills, a finding which has implications for the delivery of social skills training and other interventions. The study provides empirical support for the application of personal construct methodologies in ASD research and offers a potentially useful approach to therapeutic intervention. PMID- 28866249 TI - The synthesis of novel sulfamides derived from beta-benzylphenethylamines as acetylcholinesterase, butyrylcholinesterase and carbonic anhydrase enzymes inhibitors. AB - In this study, a series of novel beta-benzylphenethylamines and their sulfamide derivatives were synthesized starting from (Z)-2,3-diphenylacrylonitriles. Pd-C catalysed hydrogenation of diphenylacrylonitriles, reduction of propanenitriles with LiAlH4 in the presence of AlCl3 followed by addition of conc. HCl afforded beta-benzylphenethylamine hydrochloride salts. The reactions of these amine hydrochloride salts with chlorosulfonyl isocyanate (CSI) in the presence of tert BuOH and excess Et3N gave sulfamoylcarbamates. Removing of Boc group from the synthesized sulfamoylcarbamates with trifluoroacetic acid (TFA) yielded novel sulfamides in good yields. These novel sulfamides derived from beta benzylphenethylamines were effective inhibitors of the cytosolic carbonic anhydrase I and II isoenzymes (hCA I and II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with Ki values in the range of 0.278-2.260nM for hCA I, 0.187-1.478nM for hCA II, 0.127-2.452nM for AChE and 0.494-1.790nM for BChE. The inhibitory effects of the synthesized novel sulfamides derived from beta benzylphenethylamines were compared to those of acetazolamide and dorzolamide as clinical hCA I and II isoenzymes inhibitors and tacrine as a clinical AChE and BChE enzymes inhibitors. In addition to in vitro tests, molecular modeling approaches are implemented not only for prediction of the binding affinities of the compounds but also to study their inhibition mechanisms in atomic level at the catalytic domains. PMID- 28866250 TI - Flow optimization in one-dimensional and comprehensive two-dimensional gas chromatography. AB - Theoretical considerations of optimal flow in a GC column under different conditions are outlined from a single perspective, and numerical recommendations are provided. The optimal flow rate in a temperature programmed column is about 30% lower than its isothermal counterpart in the same column with the same carrier gas. A simplified calculation of recommended optimal or near optimal flow rate in a single column under different conditions is summarized in a single equation. In GC * GC, the primary column operates under temperature-programmed conditions while each secondary run is essentially isothermal. As a result, their flow optimization requirements are different. The complementary IDs (internal diameters) corresponding to equal optimal flow rates in both GC * GC columns should relate as 2d = 0.7 .1d. Typical complementary ID pairs are tabulated. If choosing the complementary IDs is not an option, several ways to reconcile the difference in their optimal flow rates are considered. The most typical cases of the column mismatch are identified and their boundary conditions are formulated. The effect of the flow reconciliation in these column pairs on the performance of GC * GC analysis is evaluated. PMID- 28866248 TI - Short overview on metabolomics approach to study pathophysiology of oxidative stress in cancer. AB - Association of oxidative stress with carcinogenesis is well known, but not understood well, as is pathophysiology of oxidative stress generated during different types of anti-cancer treatments. Moreover, recent findings indicate that cancer associated lipid peroxidation might eventually help defending adjacent nonmalignant cells from cancer invasion. Therefore, untargeted metabolomics studies designed for advanced translational and clinical studies are needed to understand the existing paradoxes in oncology, including those related to controversial usage of antioxidants aiming to prevent or treat cancer. In this short review we have tried to put emphasis on the importance of pathophysiology of oxidative stress and lipid peroxidation in cancer development in relation to metabolic adaptation of particular types of cancer allowing us to conclude that adaptation to oxidative stress is one of the main driving forces of cancer pathophysiology. With the help of metabolomics many novel findings are being achieved thus encouraging further scientific breakthroughs. Combined with targeted qualitative and quantitative methods, especially immunochemistry, further research might reveal bio-signatures of individual patients and respective malignant diseases, leading to individualized treatment approach, according to the concepts of modern integrative medicine. PMID- 28866251 TI - Comprehensive two-dimensional gas chromatography coupled to high resolution time of-flight mass spectrometry for screening of organohalogenated compounds in cat hair. AB - The coupling of comprehensive two-dimensional gas chromatography with high resolution time-of-flight mass spectrometry offers the best separation efficiency combined with accurate mass measurements over a wide mass range. The tremendous power of this screening tool is illustrated by trace qualitative screening analysis of organohalogenated compounds (OHCs) in pet cat hair. Tentative identification was supported by mass spectral database searches and elemental formula prediction from the experimentally determined accurate mass data. This screening approach resulted in the first tentative identification of pentabromoethylbenzene, decabromodiphenyl ethane, hexabromocyclododecane, trisbromoneopentyl alcohol, tris(2-chloroethyl) phosphate and tris(2 chloroisopropyl)phosphate in the South African indoor environment. A total of seventy-two OHCs were identified in the samples and include known flame retardants, such as polybrominated diphenyl ethers, and legacy contaminants such as polychlorinated biphenyls and organochlorine, organophosphorous and pyrethroid pesticides. The results obtained from cat hair indicate that these pets are exposed to complex mixtures of OHCs and the detection of these compounds suggests that non-invasive cat hair samples can be used to model indoor exposure with reference to external deposition of OHCs present in the air and dust surrounding people. Toddlers share the same environment as pet cats and therefore also the same health risks. PMID- 28866252 TI - Comprehensive determination of flavouring additives and nicotine in e-cigarette refill solutions. Part I: Liquid chromatography-tandem mass spectrometry analysis. AB - Liquid chromatography-tandem mass spectrometry with electrospray ionization (HPLC ESI-MS/MS) methods were developed for the simultaneous determination of 42 flavouring compounds and nicotine in liquids for e-cigarettes. The chromatographic separation was performed using an Ace(r) UltracoreTM SuperC18TM (100*2.1mm, 2.5MUm) column in both acidic and alkaline pH conditions to separate all the compounds. A simple "dilute & shoot" approach was used for the sample preparation. The method validation was performed by evaluating key analytical parameters such as linearity, accuracy, selectivity, precision, limit of detection (LOD) and limit of quantification (LOQ). The calibration curves showed good linearity within the specific ranges for the investigated compounds with correlation coefficients greater than 0.990 in each case. The recovery for all the investigated compounds varied from 89% to 110%. The intra- and inter-day precision were within the acceptable limits (+/-15%) at all tested concentrations. The applicability of the methods was examined by analysing 25 liquid samples from e-cigarettes commercially available on the Polish market. PMID- 28866253 TI - Human odor and forensics. Optimization of a comprehensive two-dimensional gas chromatography method based on orthogonality: How not to choose between criteria. AB - The use of comprehensive two-dimensional gas chromatography coupled with mass spectrometry would be a real asset for the forensic profiling of human hand odor. This paper focuses on the optimization of a comprehensive gas chromatography method using a synthetic mixture of 80 compounds representative of human hand odor composition. In order to rank the candidate column sets, instead of using a unique criterion, we used a chemometric tool called desirability which is based on Derringer functions and enables to consider several criteria simultaneously and hence to get the best compromise. Nine criteria including six orthogonality criteria were used to evaluate the quality and the efficiency of the separation. The desirability analysis lead to a straightforward ranking and an accurate overview of the results in two situations, with an objective of routine analysis and without. In both cases, the DB-1MS*DB-1701 set was found to be best suited for the separation of the considered mixture, however with different gradients. PMID- 28866254 TI - The effects of nursing education on professional values: A longitudinal study. AB - BACKGROUND: It is considered to be extremely important to ensure that nurses adopt professional values during their education in order to improve nursing practices and develop a professional identity. OBJECTIVES: The aim of this study is to investigate the effects of nursing education on development of professional values. DESIGN: This study was designed as a longitudinal study. SETTINGS: The study was conducted in a nursing department at a nursing school in the western Turkey. PARTICIPANTS: The population of the study consisted of nursing students who were enrolled in the nursing department in academic year of 2011-2012. The data of the study were collected from 59 first-year students in 2011 and 83 fourth-year students in 2015. METHODS: The data of the study were collected using Personal Information Form and Nursing Professional Values Scale-NPVS. The participants responded to the same questionnaire in their first and fourth years in the department. RESULTS: The scale mean score of the students in their first year was 3.44+/-0.635. The highest scores were obtained from the subscales of responsibility, security, and autonomy. Their scale mean score in their fourth year was 3.93+/-0.727. The highest scores were obtained from the subscales of dignity and autonomy. The difference between the mean scores was statistically significant (p=0.001). CONCLUSIONS: It was concluded that nursing education had a significant effect on development of professional values. PMID- 28866255 TI - Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. AB - BACKGROUND: Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. OBJECTIVE: To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification. DESIGN, SETTING, AND PARTICIPANTS: We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR (AR-FL) and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated clinical correlates of AR-FL/AR-V7 measurements, including association with prostate-specific antigen progression-free survival (PSA-PFS) and clinical and radiographic progression-free survival (PFS), in a subset of patients starting treatment with abiraterone or enzalutamide following biopsy. RESULTS AND LIMITATIONS: Quantitative AR-FL/AR-V7 data were generated from 56 of the 63 (88.9%) biopsy specimens examined, of which 44 were mCRPC biopsies. Positive AR V7 signals were detected in 34.1% (15/44) mCRPC specimens, all of which also co expressed AR-FL. The median AR-V7/AR-FL ratio was 11.9% (range 2.7-30.3%). Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. Among the 25 CRPC biopsies collected before treatment with abiraterone or enzalutamide, positive AR-V7 detection, but not higher AR-FL, was significantly associated with shorter PSA-PFS (hazard ratio 2.789, 95% confidence interval 1.12-6.95; p=0.0081). CONCLUSIONS: We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance. PATIENT SUMMARY: Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to abiraterone or enzalutamide in prostate cancer. PMID- 28866256 TI - Evaluation of ecdysteroid antisera for a competitive enzyme immunoassay and extraction procedures for the measurement of mosquito ecdysteroids. AB - Ecdysteroid hormones regulate several aspects of insect development and reproduction. The predominant ecdysteroids produced by insects including mosquitoes are ecdysone (E) and 20-hydroxyecdysone (20E). The ability to measure E and 20E titers is essential for many studies, but few sensitive, low cost options are currently available for doing so. To address this deficiency, we developed a new enzyme-linked immunoassay (EIA). In the first part of the study, we compared the affinity of two new antisera named EAB25 and EAB27 to other available ecdysteroid antisera. EAB25 had a 27-fold higher affinity for 20E than E, while EAB27 had a four-fold higher affinity for 20E. In the second part of the study, EIA protocols were developed for analyzing E and 20E produced by the mosquito Aedes aegypti. Results indicated that pelts from fourth instar larvae and ovaries from blood-fed, adult females produced E and 20E. Methanol extraction in the presence of magnesium from whole body samples altered antibody recognition of E and 20E by EIA. However, extraction with 1-butanol and two organic/water phase separations eliminated this problem and improved assay performance. We conclude the new antisera used in the EIA provide a low-cost, flexible, and sensitive method for measuring E and 20E in insects. PMID- 28866257 TI - Hyphenated 3D-QSAR statistical model-scaffold hopping analysis for the identification of potentially potent and selective sigma-2 receptor ligands. AB - A 3D quantitative structure-activity relationship (3D-QSAR) model for predicting the sigma2 receptor affinity has been constructed with the aim of providing a useful tool for the identification, design, and optimization of novel sigma2 receptor ligands. The model has been built using a set of 500 selective sigma2 receptor ligands recovered from the sigma-2 receptor selective ligand database (S2RSLDB) and developed with the software Forge. The present model showed high statistical quality as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn up 3D map allows for a prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying sigma2 receptor ligands interaction. A theoretic approach for the generation of new lead compounds with optimized sigma2 receptor affinity has been performed by means of scaffold hopping analysis. Obtained results further confirmed the validity of our model being some of the identified moieties have already been successfully employed in the development of potent sigma2 receptor ligands. For the first time is herein reported a 3D-QSAR model which includes a number of chemically diverse sigma2 receptor ligands and well accounts for the individual ligands affinities. These features will ensure prospectively advantageous applications to speed up the identification of new potent and selective sigma2 receptor ligands. PMID- 28866258 TI - [Change of care model in natural childbirth: Implementation in La Ribera delivery room]. AB - OBJECTIVE: To assess knowledge, wish for inclusion and implementation of normal childbirth care protocols at La Ribera University Hospital, the reason why they are not applied, and to assess the attendance at antepartum training activities. MATERIAL AND METHOD: Cross-sectional descriptive study. They were carried out 186 surveys by convenience sampling to pregnant women attending fetal well-being control at hospital between 2014 and 2015. They were collected data about knowledge, wish for inclusion, compliance of protocols and reasons for non compliance, and attendance at antepartum training activities. Percentages and confidence intervals were calculated. Chi-square test was used to compare categorical variables. RESULTS: They were collected percentages of knowledge (77%, CI95%: 75,5-78,5) and wish for inclusion (84,6%, CI95%: 82,5-86,7). Protocol compliance ranged from 6% (nitrous oxide administration) to 91% (skin-to skin contact). The main reasons for non-compliance were due to circumstances of childbirth process (56,3%, CI95%: 51,1-61,5). Attendance at maternal education classes was 62%, mainly primiparous women (p=0,0001) with medium or high education level (p=0,001). CONCLUSIONS: Pregnant women have a high knowledge and wish for inclusion of normal childbirth care protocols. Attendance at antepartum training activities could by improved and the main reason for non-attendance is lack of information. Compliance is good enough in most protocols; when they are not applied is due to childbirth circumstances. Remaining tasks include the introduction of additional protocols and to involve pregnant women in decision making. PMID- 28866259 TI - Intravoxel Incoherent Motion Diffusion-weighted Imaging: Evaluation of the Differentiation of Solid Hepatic Lesions. AB - PURPOSE: To evaluate whether intravoxel incoherent motion (IVIM)-related parameters could be used to differentiate malignant from benign focal liver lesions (FLLs) and to improve diagnostic efficiency. METHODS: Seventy-four patients with 75 lesions, including 51 malignant FLLs and 24 benign FLLs, underwent liver 3.0-T magnetic resonance imaging for routine examination sequences. IVIM diffusion-weighted imaging (DWI) with 11 b values (0-800s/mm2) was also acquired concurrently. Apparent diffusion coefficient (ADCtotal) and IVIM-derived parameters, such as the pure diffusion coefficient (D), the pseudodiffusion coefficient (D*), and the perfusion fraction (f), were calculated and compared between the two groups. A receiver operating characteristic curve analysis was performed to assess their diagnostic value. RESULTS: ADCtotal, D, and f were significantly lower in the malignant group than in the benign group, whereas D* did not show a statistical difference. D had a larger area under the curve value (0.968) and higher sensitivity (92.30%) for differentiation. CONCLUSION: IVIM is a useful method to differentiate malignant and benign FLLs. The D value showed higher efficacy to detect hepatic solid lesions. PMID- 28866260 TI - Spatiotemporal Optoacoustic Mapping of Tumor Hemodynamics in a Clinically Relevant Orthotopic Rabbit Model of Head and Neck Cancer. AB - The purpose of this study was to investigate the usefulness of photoacoustic imaging (PAI) for spatiotemporal mapping of tumor hemodynamics in a rabbit model of head and neck carcinoma. Shope cottontail rabbit papilloma virus associated VX2 carcinomas were established in adult male New Zealand White rabbits (n = 9) by surgical transplantation of tumor tissue in the neck. Noninvasive PAI with co registered ultrasound (US) was performed to longitudinally monitor tumor growth, oxygen saturation (%sO2), and hemoglobin concentration (HbT). PAI findings were validated with Doppler sonography measures of percent vascularity (PV). Differences in tumor volumes, %sO2, HbT, and PV values over time were analyzed using repeated-measures analysis of variance with multiple comparisons. Two tailed Spearman correlation analysis was performed to determine the correlation coefficient (r) for comparisons between %sO2, HbT, and tumor volume. US revealed a significant (P < .0001) increase in tumor volume over the 3-week period from 549 +/- 260 mm3 on day 7 to 5055 +/- 438 mm3 at 21 days postimplantation. Consistent with this aggressive tumor growth, PAI revealed a significant (P < .05) and progressive reduction in %sO2 from day 7 (37.6 +/- 7.4%) to day 21 (9.5 +/- 2.1%). Corresponding Doppler images also showed a decrease in PV over time. PAI revealed considerable intratumoral spatial heterogeneity with the tumor rim showing two- to three-fold higher %sO2 values compared to the core. Noninvasive PAI based on endogenous contrast provides a label-free method for longitudinal monitoring of temporal changes and spatial heterogeneity in thick head and neck tumors. PMID- 28866261 TI - No Fukushima Dai-ichi derived plutonium signal in marine sediments collected 1.5 57km from the reactors. AB - Based on AMS analysis, it is shown that no Pu signals from the Fukushima accident could be discerned in marine sediments collected 1.5-57km away from the Fukushima Da-ichi power plant (FDNPP), which were clearly influenced by accident-derived radiocesium. The 240Pu/239Pu atom ratios (0.21-0.28) were significantly higher than terrestrial global fallout (0.182 +/- 0.005), but still in agreement with pre-FDNPP accident baseline data for Pu in near coastal seawaters influenced by global fallout and long-range transport of Pu from the Pacific Proving Grounds. PMID- 28866262 TI - Groin pain associated with sacroiliac joint dysfunction and lumbar disorders. AB - OBJECTIVE: We investigated the prevalence of groin pain in patients with sacroiliac joint (SIJ) dysfunction, lumbar spinal canal stenosis (LSS), and lumbar disc herniation (LDH) who did not have hip disorders, and evaluated the clinical features that distinguished SIJ dysfunction from LSS and LDH. PATIENT AND METHODS: We evaluated 127 patients (57 men, 70 women, average age 55 years) with SIJ dysfunction, 146 (98 men, 48 women, average age 71 years) with LSS, and 124 (83 men, 41 women, average age 50 years) with LDH. The following data were retrospectively collected from the patients' medical charts: (1) the prevalence of groin pain for each pathology; (2) corresponding spinal level of LSS and LDH in the patients with groin pain; (3) the pain areas in the buttocks and back; pain increase while in positions such as sitting, lying supine, and side-lying; an SIJ shear test; and four tender points composed of the posterior superior iliac spine (PSIS), long posterior sacroiliac ligament (LPSL), sacrotuberous ligament (STL), and iliac muscle. RESULTS: Fifty-nine (46.5%) patients with SIJ dysfunction, 10 (6.8%) with LSS, and 10 (8.1%) with LDH reported groin pain. Of the 10 patients with LSS, five presented with cauda equina symptoms, two had stenosis of L2-L3, and three had stenosis below L3-L4. The other five presented with radiculopathy: the corresponding nerve root was L2, L3, and L4 in one patient each, and L5 in two. Of the 10 patients with LDH, eight presented with radiculopathy: the corresponding nerve root was L2 and L4 in three patients each, and L5 in two. Two patients presented with L4-L5 discogenic pain without radiculopathy. In patients with groin pain, pain provoked by the SIJ shear test and the tenderness of the PSIS and LPSL were significant physical signs that differentiated SIJ dysfunction from LSS and LDH. (Fisher's exact test, P<0.05) CONCLUSION: The prevalence of groin pain in patients with SIJ dysfunction was higher than in those with LSS or LDH. When patients who do not have hip disorders complain of groin and lumbogluteal pain, not only lumbar disorders but also SIJ dysfunction should be considered. PMID- 28866263 TI - Use of multiplex PCR based molecular diagnostics in diagnosis of suspected CNS infections in tertiary care setting-A retrospective study. AB - OBJECTIVES: CNS infections like meningitis and encephalitis pose enormous healthcare challenges due to mortality, sequelae and socioeconomic burden. In tertiary setting, clinical, microbiological, cytological and radiological investigations are not distinctive enough for diagnosing microbial etiology. Molecular diagnostics is filling this gap. We evaluated the clinical impact of a commercially available multiplex molecular diagnostic system - SES for diagnosing suspected CNS infections. PATIENTS AND METHODS: This study was conducted in our tertiary level Neurology ICU. 110 patients admitted during Nov-2010 to April-2014 were included. CSF samples of patients clinically suspected of having CNS infections were subjected to routine investigation in our laboratory and SES test at XCyton Diagnostics. We studied the impact of SES in diagnosis of CNS infections and its efficacy in helping therapeutic management. RESULTS: SES showed detection rate of 42.18% and clinical specificity of 100%. It had 10 times higher detection rate than conventional tests. Streptococcus pneumoniae and Mycobacterium tuberculosis were two top bacterial pathogens. VZV was most detected viral pathogen. SES results elicited changes in therapy in both positive and negative cases. We observed superior patient outcomes as measured by GCS scale. 75% and 82.14% of the patients positive and negative on SES respectively, recovered fully. CONCLUSION: Detecting causative organism and ruling out infectious etiology remain the most critical aspect for management and prognosis of patients with suspected CNS infections. In this study, we observed higher detection rate of pathogens, target specific escalation and evidence based de escalation of antimicrobials using SES. Institution of appropriate therapy helped reduce unnecessary use of antimicrobials. PMID- 28866264 TI - A randomized controlled study of intravenous fluid in acute ischemic stroke. AB - OBJECTIVE: To compare the outcome of patients with acute ischemic stroke who received or did not receive intravenous fluid. PATIENTS AND METHODS: This study was a prospective, multicenter, randomized, open-label trial with blinded outcome assessment. We enrolled acute ischemic stroke patients without dehydration aged between 18 and 85 years with NIH Stroke Scale score (NIHSS) score from 1 to 18 who presented within 72h after onset. Patients were randomly assigned to receive 0.9% NaCl solution 100ml/h for 3days or no intravenous fluid. RESULTS: On the interim unblinded analysis of the safety data, significant excess early neurological deterioration was observed among patients in the non-intravenous fluid group. Therefore, the study was prematurely discontinued after enrollment of 120 patients, mean age 60 years, 56.6% male. Early neurological deterioration (increased NIHSS >=3 over 72h) not of metabolic or hemorrhagic origin was observed in 15% of the non-IV fluid group and 3.3% of the IV fluid group (p=0.02). Predictors of neurological deterioration were higher NIHSS score, higher plasma glucose, and increased pulse rate. There was no difference in the primary efficacy outcome, NIHSS<=4 at day 7, 83.3% vs 86.7%, p=0.61 or secondary efficacy outcomes. CONCLUSION: Administration of 0.9% NaCl 100ml/h for 72h in patients with acute ischemic stroke is safe and may be associated with a reduced risk of neurological deterioration. These study findings support the use of intravenous fluid in acute ischemic stroke patients with NIHSS less than 18 who have no contraindications. PMID- 28866265 TI - Chemical-induced asthma and the role of clinical, toxicological, exposure and epidemiological research in regulatory and hazard characterization approaches. AB - Uncertainties in understanding all potential modes-of-action for asthma induction and elicitation hinders design of hazard characterization and risk assessment methods that adequately screen and protect against hazardous chemical exposures. To address this challenge and identify current research needs, the University of Cincinnati and the American Cleaning Institute hosted a webinar series to discuss the current state-of-science regarding chemical-induced asthma. The general consensus is that the available database, comprised of data collected from routine clinical and validated toxicological tests, is inadequate for predicting or determining causal relationships between exposures and asthma induction for most allergens. More research is needed to understand the mechanism of asthma induction and elicitation in the context of specific chemical exposures and exposure patterns, and the impact of population variability and patient phenotypes. Validated tools to predict respiratory sensitization and to translate irritancy assays to asthma potency are needed, in addition to diagnostic biomarkers that assess and differentiate allergy versus irritant-based asthmatic responses. Diagnostic methods that encompass the diverse etiologies of asthmatic responses and incorporate robust exposure measurements capable of capturing different temporal patterns of complex chemical mixtures are needed. In the absence of ideal tools, risk assessors apply hazard-based safety assessment methods, in conjunction with active risk management, to limit potential asthma concerns, proactively identify new concerns, and ensure deployment of approaches to mitigate asthma-related risks. PMID- 28866266 TI - Subchronic toxicity study of yttrium nitrate by 90-day repeated oral exposure in rats. AB - Concerns regarding the adverse effects of long-term exposure to low levels of rare earth elements (REEs) from foods on human health have arisen in recent years. Nevertheless, no official acceptable daily intake (ADI) has yet been proposed for either total REEs or individual REE. In accordance with the Organization for Economic Co-operation and Development (OECD) testing guideline, the present study was undertaken to evaluate the subchronic toxicity of yttrium, a representative heavy REE with higher contaminated level in foods in China, to achieve a no observed adverse effect level (NOAEL) which is a critical basis for the establishment of an ADI. Yttrium nitrate was orally administered to rats at doses of 0, 10, 30 and 90 mg/kg/day for 90 days followed by a recovery period of 4 weeks. The following toxicity indices were measured: mortality, clinical signs, daily food consumption and weekly body weight; urinalysis, hematology, blood coagulation, clinical biochemistry and histopathology at the end of administration and recovery periods. No toxicologically significant changes were found in any yttrium-treated group as compared to the concurrent control group. Under the present experimental condition, the NOAEL in rats was thus set at 90 mg/kg for yttrium nitrate, i.e. 29.1 mg/kg for yttrium. PMID- 28866267 TI - How well can carcinogenicity be predicted by high throughput "characteristics of carcinogens" mechanistic data? AB - IARC has begun using ToxCast/Tox21 data in efforts to represent key characteristics of carcinogens to organize and weigh mechanistic evidence in cancer hazard determinations and this implicit inference approach also is being considered by USEPA. To determine how well ToxCast/Tox21 data can explicitly predict cancer hazard, this approach was evaluated with statistical analyses and machine learning prediction algorithms. Substances USEPA previously classified as having cancer hazard potential were designated as positives and substances not posing a carcinogenic hazard were designated as negatives. Then ToxCast/Tox21 data were analyzed both with and without adjusting for the cytotoxicity burst effect commonly observed in such assays. Using the same assignments as IARC of ToxCast/Tox21 assays to the seven key characteristics of carcinogens, the ability to predict cancer hazard for each key characteristic, alone or in combination, was found to be no better than chance. Hence, we have little scientific confidence in IARC's inference models derived from current ToxCast/Tox21 assays for key characteristics to predict cancer. This finding supports the need for a more rigorous mode-of-action pathway-based framework to organize, evaluate, and integrate mechanistic evidence with animal toxicity, epidemiological investigations, and knowledge of exposure and dosimetry to evaluate potential carcinogenic hazards and risks to humans. PMID- 28866268 TI - Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications. AB - Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over the last several decades, especially in conjunction with emerging alternative methods to animal testing, such as in vitro studies and data-driven in silico quantitative-structure-activity-relationship (QSAR) predictions. Experimental information derived from these new approach methods can be used as input for model parameters and allows for increased confidence in models for chemicals that did not have in vivo data for model calibration. Despite significant advancements in good modelling practice (GMP) for model development and evaluation, there remains some reluctance among regulatory agencies to use such models during the risk assessment process. Here, the results of a survey disseminated to the modelling community are presented in order to inform the frequency of use and applications of PBK models in science and regulatory submission. Additionally, the survey was designed to identify a network of investigators involved in PBK modelling and knowledgeable of GMP so that they might be contacted in the future for peer review of PBK models, especially in regards to vetting the models to such a degree as to gain a greater acceptance for regulatory purposes. PMID- 28866270 TI - Small molecule inhibitors of bacterial transcription complex formation. AB - Knoevenagel condensation was employed to generate a set of molecules potentially capable of inhibiting the RNA polymerase-sigma70/sigmaA interaction in bacteria. Synthesis was achieved via reactions between a variety of indole-7-carbaldehydes and rhodanine, N-allylrhodanine, barbituric acid or thiobarbituric acid. A library of structurally diverse compounds was examined by enzyme-linked immunosorbent assay (ELISA) to assess the inhibition of the targeted protein protein interaction. Inhibition of bacterial growth was also evaluated using Bacillus subtilis and Escherichia coli cultures. The structure-activity relationship studies demonstrated the significance of particular structural features of the synthesized molecules for RNA polymerase-sigma70/sigmaA interaction inhibition and antibacterial activity. Docking was investigated as an in silico method for the further development of the compounds. PMID- 28866269 TI - Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4 (piperidin-1-yl)quinoline-3-carbonitrile core. AB - This Letter details the discovery and subsequent optimization of a novel M4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M4 PAM chemotypes. Optimized compounds in this series demonstrated improved M4 PAM potency on both human and rat M4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma Kp=5.3, Kp,uu=2.4; MDCK-MDR1 (P-gp) ER=1.1). PMID- 28866272 TI - Editorial overview: Cell signaling and gene regulation: nutrient sensing, signaling, and transport. PMID- 28866271 TI - Novel alpha,beta-unsaturated amide derivatives bearing alpha-amino phosphonate moiety as potential antiviral agents. AB - Based on flexible construction and broad bioactivity of ferulic acid, a series of novel alpha,beta-unsaturated amide derivatives bearing alpha-aminophosphonate moiety were designed, synthesized and systematically evaluated for their antiviral activity. Bioassay results indicated that some compounds exhibited good antiviral activities against cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV) in vivo. Especially, compound g18 showed excellent curative and protective activities against CMV, with half-maximal effective concentration (EC50) values of 284.67MUg/mL and 216.30MUg/mL, which were obviously superior to that of Ningnanmycin (352.08MUg/mL and 262.53MUg/mL). Preliminary structure-activity relationships (SARs) analysis revealed that the introduction of electron withdrawing group at the 2-position or 4-position of the aromatic ring is favorable for antiviral activity. Present work provides a promising template for development of potential inhibitor of plant virus. PMID- 28866273 TI - Exploring gene expression changes in the amphioxus gill after poly(I:C) challenge using digital expression profiling. AB - Amphioxus, a cephalochordate, is a key model animal for studying the evolution of vertebrate immunity. Recently, studies have revealed that microRNA (miRNA) expression profiles change significantly in the amphioxus gill after immune stimulation, but it remains largely unknown how gene expression responds to immune stress. Elucidating gene expression changes in the amphioxus gill will provide a deeper understanding of the evolution of gill immunity in vertebrates. Here, we used high-throughput RNA sequencing technology (RNA-seq) to conduct tag based digital gene expression profiling (DGE) analyses of the gills of control Branchiostoma belcheri and of those exposed to the viral mimic, poly(I:C) (pIC). Six libraries were created for the control and treatment groups including three biological replicates per group. A total of 1999 differently expressed genes (DEGs) were obtained, with 571 and 1428 DEGs showing up- or down-regulation, respectively, in the treatment group. Enrichment analysis of gene ontology (GO) terms and pathways revealed that the DEGs were primarily related to immune and defense response, apoptosis, human disease, cancer, protein metabolism, enzyme activity, and regulatory processes. In addition, eight DEGs were randomly selected to validate the RNA-seq data using real-time quantitative PCR (qRT-PCR), and the results confirmed the accuracy of the RNA-seq approach. Next, we screened eight key responding genes to examine the dynamic changes in expression levels at different time points in more detail. The results indicated that expressions of TRADD, MARCH, RNF31, NF-kappab, CYP450, TNFRSF6B, IFI and LECT1 were induced to participate in the antiviral response against pIC. This study provides a valuable resource for understanding the role of the amphioxus gill in antiviral immunity and the evolution of gill immunity in vertebrates. PMID- 28866274 TI - Biological parameters, immune enzymes, and histological alterations in the livers of grass carp infected with Aeromonas hydrophila. AB - Aeromonas hydrophila is the causative agent of bacterial septicemia that is frequently observed in grass carp, Ctenopharyngodon idellus. In this study, we evaluated the biological parameters and immune enzymes in the liver of grass carp following A. hydrophila infection and quantified the alterations in liver histology using a semi-quantitative system. For the biological parameters, we found that the liver somatic index (LSI) was more sensitive than Fulton's condition factor (CF) and was significantly decreased at three days post injection (DPI). At the immune enzyme level, the level of peroxidase (POD) in the liver significantly increased at 1 and 3 DPI. The activity of alkaline phosphatase (ALP) significantly increased at 3 DPI. Similarly, acid phosphatase (ACP) activity significantly increased at 1, 3, and 5 DPI. Histologically, the results indicated that the liver index at 3, 5, and 7 DPI was significantly higher than that of control groups. The regressive alterations as the highly variable reactions patterns and its index at 5 DPI was significantly higher than that of 1, 21 DPI, and the control groups. Based on our results, we suggest that grass carp resist A. hydrophila infection via an innate immune mechanism in the liver. The findings of this study will help elucidate the underlying mechanisms of resistance to A. hydrophila infection. PMID- 28866275 TI - MHC class II alpha, beta and MHC class II-associated invariant chains from Chinese sturgeon (Acipenser sinensis) and their response to immune stimulation. AB - The major histocompatibility complex class II (MHC II) molecules play a vital role in adaptive immune response through presenting antigenic peptides to CD4+ T lymphocytes. To accomplish this physiologic function, the MHC class II-associated invariant chain interacts with the MHC II alpha/beta subunits and promotes their correct assembly and efficient traffic. Here, we isolated the cDNAs of MHC II alpha, beta and MHC II-associated invariant chains (designated as CsMHC II alpha, CsMHC II beta, and CsMHC II gamma) from Chinese sturgeon (Acipenser sinensis). The CsMHC II alpha, beta, and gamma mRNAs were widely expressed in Chinese sturgeon, and the highest expression was found in spleen for CsMHC II alpha and beta chains, while in head kidney for CsMHC II gamma chain. Stimulation to Chinese sturgeon with inactivated trivalent bacterial vaccine or polyinosinic polycytidylic acid (poly(I:C)) up-regulated the expressions of CsMHC II alpha, and beta mRNAs, and their transcripts were overall more quickly up-regulated by poly(I:C) than by bacterial vaccine. Poly(I:C) induced higher CsMHC II gamma expression than bacterial vaccine in intestine and spleen, while lower than bacterial vaccine in head kidney and liver. When co-expressed in mouse dendritic cells, the CsMHC II gamma chain bound to both the MHC II alpha and beta chains. Furthermore, the over-expressed CsMHC II gamma chain, not CsMHC II alpha or CsMHC II beta chain, activated NF-kappaB and STAT3 in mouse dendritic cells, and induced TNF-alpha and IL-6 expressions as well. This activity was nearly abolished by mutation of the Ser29/Ser34 to Ala29/Ala34 in CsMHC II gamma. These results suggested that CsMHC II alpha, beta, and gamma chains might play important role in immune response to pathogen microbial infection of Chinese sturgeon possibly via a conserved functional mechanism throughout vertebrate evolution, which might contribute to our understanding the immune biology of sturgeons. PMID- 28866276 TI - Deciphering transcriptome profile of the yellow catfish (Pelteobagrus fulvidraco) in response to Edwardsiella ictaluri. AB - Edwardsiella ictaluri is one of the most important pathogens posing a serious threat for yellow catfish (Pelteobagrus fulvidraco), a highly valuable fish species of increasing commercial interest in China. Here, a transcriptomic strategy was undertaken to investigate the yellow catfish gene expression profile against infection by the bacterial pathogen E. ictaluri. Comparison of the transcriptome profiles between the infected and uninfected samples showed that a massive gene expression change occurred in yellow catfish following bacterial exposure. A total of 5527 differentially expressed genes (DEGs) were detected, of which 2265 showed up-regulation and 3262 down-regulation. Gene set enrichment analysis revealed the presence of canonical pathways directly linked to innate and adaptive immune response, such as pattern recognition receptor (PRR) signaling pathways, complement and coagulation cascades, as well as T-cell receptor (TCR) and B-cell receptor (BCR) signaling pathways. Additionally, 47,526 putative EST-liked simple sequence repeats (SSRs) markers were retrieved for use in genetic studies. This study establishes the first molecular clues to understand the potential mechanisms of yellow catfish resistance to E. ictaluri, thus enabling future efforts on disease control programs in this valuable aquaculture species. PMID- 28866277 TI - Evaluation of antibody response to an adjuvanted hapten-protein vaccine as a potential inhibitor of sexual maturation for farmed Atlantic salmon. AB - An experimental contraceptive vaccine was evaluated in Atlantic salmon (Salmo salar). A peptide derived from the beta subunit of luteinizing hormone (LH) was conjugated to two different carrier proteins, bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH), and formulated with one of four immunostimulants in a water-in-oil emulsion. Specific antibody responses to the peptide and each carrier protein were evaluated. While the antibody response to KLH was stronger than the response to BSA, both carrier proteins stimulated comparable antibody responses to the LH peptide. The immunostimulant proved to be more important for enhancing the LH peptide antibody response than the carrier protein selection; vaccines containing a combination of Aeromonas salmonicida and Vibrio anguillarum stimulated significantly greater LH peptide antibody production than any of the other three immunostimulants evaluated at 12 weeks post-vaccination. This study provides proof-of-concept for specific antibody production against a hapten carrier protein antigen in Atlantic salmon and reinforces the importance of vaccine immunostimulant selection. PMID- 28866278 TI - Precise immune tolerance for hPSC derivatives in clinical application. AB - Human pluripotent stem cells (hPSCs) promise a foreseeing future for regeneration medicine and cell replacement therapy with their abilities to produce almost any types of somatic cells of the body. The complicated immunogenicity of hPSC derivatives and context dependent responses in variable transplantations greatly hurdle the practical application of hPSCs in clinic. Especially for applications of hPSCs, induction of immune tolerance at the same time increases the risks of tumorigenesis. Over the past few years, thanks to the progress in immunology and practices in organ transplantation, endeavors on exploring strategies to induce long term protection of allogeneic transplants have shed light on overcoming this barrier. Novel genetic engineering techniques also allow to precisely cradle the immune response of transplantation. Here we reviewed the current understanding on immunogenicity, and efforts have been attempted on inducing immune tolerance for hPSC derivatives, with extra focus on modifying the graft cells. We also glimpse on employing cutting-edge genome editing technologies for this purpose, which will potentially endow hPSC derivatives with the nature of wide spectrum drugs for therapy. PMID- 28866279 TI - Simulation of the behavior of a refuse landfill on a laboratory scale. AB - The characteristics and properties of waste in a landfill, and its evolution over time, are difficult to estimate because of the heterogeneity of materials, biomass degradation, density, cover material, and infiltration of water. In this work, a lysimeter was used to simulate how refuse from mechanical-biological treatment (MBT) plants evolved in a landfill over a 45-day period. Water was added as a way to imitate the effects produced during rainy seasons. Field capacity and changes in the physical and chemical properties (volatile solids, biomass, and heating value) were analyzed. The results of this research show that the percentage of biomass lowers, and the heating value increases, after bringing about infiltration and percolation of water in the waste mass. Therefore in order to stabilize waste in a landfill, employing irrigation or leachate recirculation could be advisable. As the heating value increases after percolation, it could also be a good idea to recover the fuel material after stabilization. PMID- 28866280 TI - Estrogen alters gonadal soma-derived factor (Gsdf)/Foxl2 expression levels in the testes associated with testis-ova differentiation in adult medaka, Oryzias latipes. AB - Testis-ova differentiation in sexually mature male medaka (Oryzias latipes) is easily induced by estrogenic chemicals, indicating that spermatogonia persist in sexual bipotentiality, even in mature testes in medaka. By contrast, the effects of estrogen on testicular somatic cells associated with testis-ova differentiation in medaka remain unclear. In this study, we focused on the dynamics of sex-related genes (Gsdf, Dmrt1, and Foxl2) expressed in Sertoli cells in the mature testes of adult medaka during estrogen-induced testis-ova differentiation. When mature male medaka were exposed to estradiol benzoate (EB; 800ng/L), testis-ova first appeared after EB treatment for 14days (observed as the first oocytes of the leptotene-zygotene stage). However, the testis remained structurally unchanged, even after EB treatment for 28days. Although Foxl2 is a female-specific sex gene, EB treatment for 7days induced Foxl2/FOXL2 expression in all Sertoli cell-enclosed spermatogonia before testis-ova first appeared; however, Foxl2 was not detected in somatic cells in control testes. Conversely, Sertoli-cell-specific Gsdf mRNA expression levels significantly decreased after EB treatment for 14days, and no changes were observed in DMRT1 localization following EB treatment, whereas Dmrt1 mRNA levels increased significantly. Furthermore, after EB exposure, FOXl2 and DMRT1 were co-localized in Sertoli cells during testis-ova differentiation, although FOXL2 localization was undetectable in Sertoli-cell-enclosed apoptotic testis-ova, whereas DMRT1 remained localized in Sertoli cells. These results indicated for the first time that based on the expression of female-specific sex genes, feminization of Sertoli cells precedes testis-ova differentiation induced by estrogen in mature testes in medaka; however, complete feminization of Sertoli cells was not induced in this study. Additionally, it is suggested strongly that Foxl2 and Gsdf expression constitute potential molecular markers for evaluating the effects of estrogenic chemicals on testicular somatic cells associated with estrogen-induced testis-ova differentiation in mature male medaka. PMID- 28866281 TI - Integrated assessment of toxic effects of maghemite (gamma-Fe2O3) nanoparticles in zebrafish. AB - The increasing use of nanotechnology in the last decade has raised concerns about the impact of nanoparticles in the environment. In particular, the potential harmful effects of iron oxide nanoparticles (IONPs) in aquatic organisms have been poorly addressed. We analyze here the toxic effects induced by IONPs in zebrafish using a combination of classical (genotoxicity, oxidative stress) and molecular (transcriptomic) methodologies. Adult animals were exposed for 96h to five sub-lethal IONP concentrations, ranging from 4.7 to 74.4mg/L. Comet and micronucleus assays revealed a significant number of DNA lesions induced by IONPs at all concentrations tested. Conversely, the thiobarbituric acid reactive substances (TBARS) test detected only a mild oxidative damage in liver cells (~1.5-fold increase of malondialdehyde concentrations) and only at the two higher IONP concentrations tested. Microarray analysis of liver samples identified 953 transcripts (927 unique genes) differentially expressed between controls and IONP exposed samples. Subsequent functional analysis identified genes related to cation/metal ion binding, membrane formation, and morphogenesis among the transcripts overrepresented upon IONP treatments, whereas mRNAs encompassing genes associated with RNA biogenesis, translation, ribosomes, and several metabolic processes became underrepresented in treated samples. Taken together, these results indicate considerable genotoxic effects of IONPs combined with general negative effect on cell growth and on the ability of the cell produce new proteins. On the contrary, IONPs showed only a limited capacity to induce oxidative stress. To our knowledge, this is the first study on IONPs toxicity using such an integrative approach in an aquatic organism. PMID- 28866282 TI - Calcium channel blockers and breast cancer incidence: An updated systematic review and meta-analysis of the evidence. AB - Controversy exists regarding the potential association between taking calcium channel blockers (CCBs) and the development of breast cancer. As a positive association would have important public health implications due to the widespread use of CCBs, this study aimed to incorporate new evidence to determine whether an association is likely to exist. We searched MEDLINE, EMBASE and the Cochrane Library to 28 June 2016 for relevant literature. References and citing articles were checked and authors contacted as necessary. Two authors independently selected articles and extracted data. Twenty-nine studies were reviewed; 26 were non-randomised studies (NRS). Meta-analysis of study data where adjustment for 'confounding by indication' was judged to be present suggests that an association, if any, is likely to be modest in magnitude (pooled odds/risk ratio 1.09 (95% confidence interval (CI) 1.03-1.15, I2=0%, 8 sub-studies; pooled hazard ratio 0.99 (95% CI 0.94-1.03, I2=35%, 9 sub-studies)). There are credible study data showing an increased relative risk with long-term use of CCBs, but the results of our meta-analysis and of meta-regression of log relative risk against minimum follow-up time are mixed. The current summative evidence does not support a clear association between taking CCBs and developing breast cancer. However, uncertainty remains, especially for long-term use and any association might not be uniform between different populations and/or breast cancer sub-types. We thus recommend further NRS in settings where CCB use is highly prevalent and population-based cancer, prescription and health-registries exist, to resolve this continuing uncertainty. PROSPERO, CRD42015026712. PMID- 28866283 TI - Traumatic brain injury: Comparison between autopsy and ante-mortem CT. AB - PURPOSE: The aim of this study was to compare pathological findings after traumatic brain injury between autopsy and ante-mortem computed tomography (CT). A second aim was to identify changes in these findings between the primary posttraumatic CT and the last follow-up CT before death. METHODS: Through the collaboration between clinical radiology and forensic medicine, 45 patients with traumatic brain injury were investigated. These patients had undergone ante mortem CT as well as autopsy. During autopsy, the brain was cut in fronto parallel slices directly after removal without additional fixation or subsequent histology. Typical findings of traumatic brain injury were compared between autopsy and radiology. Additionally, these findings were compared between the primary CT and the last follow-up CT before death. RESULTS: The comparison between autopsy and radiology revealed a high specificity (>=80%) in most of the findings. Sensitivity and positive predictive value were high (>=80%) in almost half of the findings. Sixteen patients had undergone craniotomy with subsequent follow-up CT. Thirteen conservatively treated patients had undergone a follow-up CT. Comparison between the primary CT and the last ante-mortem CT revealed marked changes in the presence and absence of findings, especially in patients with severe traumatic brain injury requiring decompression craniotomy. CONCLUSION: The main pathological findings of traumatic brain injury were comparable between clinical ante-mortem CT examinations and autopsy. Comparison between the primary CT after trauma and the last ante-mortem CT revealed marked changes in the findings, especially in patients with severe traumatic brain injury. Hence, clinically routine ante-mortem CT should be included in the process of autopsy interpretation. PMID- 28866284 TI - Intracardiac electrocardiographic assessment of precordial TASER shocks in human subjects: A pilot study. AB - BACKGROUND: Case reports of cardiac arrest in temporal proximity to Conducted Electrical Weapon(CEW) exposure raise legitimate concerns about this as a rare possibility. In this pilot study, we respectfully navigate the oversight and regulatory hurdles and demonstrate the intra-shock electrocardiographic effects of an intentional transcardiac CEW discharge using subcutaneous probes placed directly across the precordium of patients with a previously implanted intracardiac EKG sensing lead. METHODS: Adults scheduled to undergo diagnostic EP studies or replacement of an implanted cardiac device were enrolled. Sterile subcutaneous electrodes were placed at the right sternoclavicular junction and the left lower costal margin at the midclavicular line. A standard police issue TASER Model X26 CEW was attached to the subcutaneous electrodes and a 5 s discharge was delivered. Continuous surface and intracardiac EKG monitoring was performed. RESULTS: A total of 157 subjects were reviewed for possible inclusion and 21 were interviewed. Among these, 4 subjects agreed and completed the study protocol. All subjects tolerated the 5 s CEW discharge without clinical complications. There were no significant changes in mean heart rate or blood pressure. Interrogation of the devices after CEW discharge revealed no ventricular pacing, dysrhythmias, damage or interference with the implanted devices. CONCLUSIONS: In this pilot study, we have successfully navigated the regulatory hurdles and demonstrated the feasibility of performing intracardiac EKG recording during intentional precordial CEW discharges in humans. While no CEW-associated dysrhythmias were noted, the size of this preliminary dataset precludes making conclusions about the risk of such events. Larger studies are warranted and should consider exploring variations of the CEW electrode position in relation to the cardiac silhouette. PMID- 28866285 TI - Sex determination from the femur in Portuguese populations with classical and machine-learning classifiers. AB - The assessment of sex is of paramount importance in the establishment of the biological profile of a skeletal individual. Femoral relevance for sex estimation is indisputable, particularly when other exceedingly dimorphic skeletal regions are missing. As such, this study intended to generate population-specific osteometric models for the estimation of sex with the femur and to compare the accuracy of the models obtained through classical and machine-learning classifiers. A set of 15 standard femoral measurements was acquired in a training sample (100 females; 100 males) from the Coimbra Identified Skeletal Collection (University of Coimbra, Portugal) and models for sex classification were produced with logistic regression (LR), linear discriminant analysis (LDA), support vector machines (SVM), and reduce error pruning trees (REPTree). Under cross-validation, univariable sectioning points generated with REPTree correctly estimated sex in 60.0-87.5% of cases (systematic error ranging from 0.0 to 37.0%), while multivariable models correctly classified sex in 84.0-92.5% of cases (bias from 0.0 to 7.0%). All models were assessed in a holdout sample (24 females; 34 males) from the 21st Century Identified Skeletal Collection (University of Coimbra, Portugal), with an allocation accuracy ranging from 56.9 to 86.2% (bias from 4.4 to 67.0%) in the univariable models, and from 84.5 to 89.7% (bias from 3.7 to 23.3%) in the multivariable models. This study makes available a detailed description of sexual dimorphism in femoral linear dimensions in two Portuguese identified skeletal samples, emphasizing the relevance of the femur for the estimation of sex in skeletal remains in diverse conditions of completeness and preservation. PMID- 28866286 TI - Infant massage improves attitudes toward childbearing, maternal satisfaction and pleasure in parenting. AB - The first year of motherhood is a period of growth and adaptation in women's lives with several challenges such as identifying the baby's needs and giving appropriate answers, so that mother and baby get to know each other and form a strong bond. Infant massage is one of the approaches that make an important contribution to the psychological and physiological wellbeing of both baby and mother, helping to form a harmonious relationship. This longitudinal study assessed the benefits of infant massage in the relationship between mother and baby, from birth to 12 months old. Comprising 194 dyads of mothers and their babies the subjects were divided into two groups of 97 dyads each. The Experimental group (EG) comprised mothers who undertook infant massage in a postnatal program with a physical therapist once a week. The Control group (CG) comprised mothers who did not attend any postnatal program and did not perform infant massage. Self-reported measures of attitudes concerning motherhood (CAQ P), experience associated to motherhood (WBPB), parental satisfaction (PSS) and maternal separation anxiety (MSAS) were evaluated. Results showed that mothers in the experimental group were better adapted to motherhood, had greater confidence in their abilities and received more support from their mothers and husbands than mothers in the control group and were therefore more confident in their abilities. The EG group experienced a stronger relationship with their babies and described it as more positive than mothers in the control group. This longitudinal study suggests that mothers who learned how to perform infant massage had more positive attitudes towards the experience of motherhood in helping to increase the level of knowledge, regulation and proximity in the dyad. These findings can in turn help mothers to develop strategies that enable them to better cope with motherhood. PMID- 28866287 TI - Dangerous arachnids-Fake news or reality? AB - The public perception of spiders and scorpions is skewed towards the potential harm they can inflict in humans, despite recent scientific evidence that arachnid venom components might be useful as bioinsecticides or even human therapeutics. Nevertheless, arachnids are becoming more popular as pets in Europe, America and Asia, raising the question for regulatory agencies in these regions as to whether they need to take measurements to protect their citizens. In order to decide upon the necessary regulatory steps, they first need to determine which arachnids are actually dangerous to humans. This review therefore provides an overview of the current literature on verified bites and stings from spiders and scorpions with the aim of assessing their potential danger for human health. As a guideline, we also provide a list of those arachnid genera that we consider as potentially dangerous, which includes 10 spider and 11 scorpion genera. The arachnid genera classified as dangerous comprise less than a quarter of all extant scorpion species and only 0.5% of all spiders species, with the actual number most likely being much lower than that, as not all species in those genera might turn out to pose an actual threat for humans. In conclusion, we found that only a small percentage of scorpions and a minute percentage of all spiders can be considered as potentially dangerous to humans. While in some countries of origin the high incidence of envenomations by dangerous arachnids can result in a serious problem to the health system, we assessed the risk that the same species pose when kept as pets under controlled maintenance conditions as significantly lower. PMID- 28866288 TI - Confronting reality: A case study of a group of student nurses undertaking a management of aggression training (MOAT) program. PMID- 28866290 TI - Immunogenicity, safety and reactogenicity of the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in 2-17-year-old children with asplenia or splenic dysfunction: A phase 3 study. AB - BACKGROUND: Immunization with pneumococcal vaccines is an important prophylactic strategy for children with asplenia or splenic dysfunction, who are at high risk of bacterial infections (including S. pneumoniae). This study aimed to assess immunogenicity and safety of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, GSK) in this at-risk population. METHODS: This phase III, multi-centre, open-label, controlled study, in which at-risk children with asplenia or splenic dysfunction were enrolled (age strata: 2-4, 5 10 and 11-17years), was conducted in Poland and the Russian Federation. For the 2 4years at-risk group, healthy age-matched children were enrolled as control. Unprimed children (not previously vaccinated with any pneumococcal vaccine) received 2 PHiD-CV doses (>=2months apart) and pneumococcal vaccine-primed children received 1 dose. Immune responses were assessed pre-vaccination and one month post-each dose. Solicited and unsolicited adverse events (AEs) were recorded for 4 and 31days post-vaccination, respectively, and serious AEs (SAEs) throughout the study. RESULTS: Of 52 vaccinated children (18 at-risk primed, 28 at-risk unprimed and 6 control unprimed), 45 (18, 23 and 4, respectively) were included in the according-to-protocol cohort for immunogenicity. Post-vaccination (post-dose 1 in primed and post-dose 2 in unprimed children), for each vaccine pneumococcal serotype and vaccine-related serotype 6A all at-risk children had antibody concentrations >=0.2ug/mL, and for vaccine-related serotype 19A at least 94.4%. Increases in antibody geometric mean concentrations were observed. For most serotypes, all at-risk children had post-vaccination opsonophagocytic activity (OPA) titers >=8 and increases in OPA geometric mean titers were observed. No safety concerns were raised. One non-fatal SAE (respiratory tract infection, considered not vaccine-related) was reported by one at-risk unprimed child. CONCLUSION: PHiD-CV was immunogenic and well tolerated in 2-17-year-old children with asplenia or splenic dysfunction. Clinical Trial Registry: www.clinicaltrials.gov, NCT01746108. PMID- 28866291 TI - A single dose and long lasting vaccine against pandemic influenza through the controlled release of a heterospecies tandem M2 sequence embedded within detoxified bacterial outer membrane vesicles. AB - The influenza A virus undergoes genetic drift and shift, leaving the general population susceptible to emerging pandemic strains, despite seasonal flu vaccination. Here we describe a single dose influenza vaccine derived from recombinant outer membrane vesicles (rOMVs) that display an antigen-mapped heterospecies tandem sequence of the M2 protein from the influenza A virus, released over 30days from poly(lactic-co-glycolide) (PLGA) microparticles. Four weeks post vaccination, BALB/c mice developed high anti-M2e IgG titers that were equivalent to those generated at 8weeks in a typical prime/boost vaccine regimen. Challenge of mice with a lethal dose of mouse adapted influenza virus PR8 (H1N1) 10weeks post vaccination resulted in 100% survival for both rOMV single-dose microparticle and prime/boost vaccinated mice. Anti-M2e IgG1 and IgG2a antibody titers were weighted toward IgG1, but splenocytes isolated from rOMV single-dose microparticle vaccinated mice produced high levels of IFNgamma relative to IL-4 in response to stimulation with M2e peptides, supporting a more Th1 biased immune response. The protective immune response was long lasting, eliciting sustained antibody titers and 100% survival of mice challenged with a lethal dose of PR8 six months post initial vaccination. Together, these data support the potential of controlled release rOMVs as an effective single dose, long lasting and rapidly effective vaccine to protect against influenza. PMID- 28866292 TI - The road to a more effective influenza vaccine: Up to date studies and future prospects. AB - Influenza virus causes an acute respiratory infection in humans. Frequent point mutations in the influenza genome and occasional exchange of genetic segments between virus strains help the virus evade the pre-existing immunity, resulting in epidemics and pandemics. Although vaccination is the most effective intervention, mismatches between circulating viruses and vaccine strains reduce vaccine efficacy. Furthermore, current injectable vaccines induce IgG antibodies in serum (which limit progression of influenza symptoms) but not secretory IgA antibodies in the respiratory mucosa (which prevent virus infection efficiently). Therefore, numerous studies have attempted to improve influenza vaccines. The discovery of broadly neutralizing antibodies has progressed research into antigen design. Studies designed to improve vaccine efficacy by changing the vaccine administration route have also been conducted. A thorough understanding of the mechanisms underlying the action of various vaccines is essential if we are to develop a universal influenza vaccine. Therefore, evaluating the quality and quantity of antibodies induced by vaccines, which determine vaccine efficacy, is critical. However, at present vaccine evaluation relies on hemagglutination inhibition tests, which only measure the quantity of antibody produced. Antibody repertoires comprise a set of antibodies with specific genetic or molecular features that correspond to their functions. Genetically and functionally similar antibodies may be produced by multiple individuals exposed to an identical stimulus. Therefore, it may be possible to evaluate and compare multiple vaccine strategies in terms of the quality and quantity of an antibody response induced by a vaccine by examining antibody repertoires. Recent studies have used single cell expression and high-throughput immunoglobulin sequencing to provide a detailed picture of antibody responses. These novel methods may be critical for detailed characterization of antibody repertoires induced by various vaccination strategies. PMID- 28866293 TI - Attenuation of pCREB and Egr1 expression in the insular and anterior cingulate cortices associated with enhancement of CFA-evoked mechanical hypersensitivity after repeated forced swim stress. AB - The perception and response to pain are severely impacted by exposure to stressors. In some animal models, stress increases pain sensitivity, which is termed stress-induced hyperalgesia (SIH). The insular cortex (IC) and anterior cingulate cortex (ACC), which are typically activated by noxious stimuli, affect pain perception through the descending pain modulatory system. In the present study, we examined the expression of phospho-cAMP response element-binding protein (pCREB) and early growth response 1 (Egr1) in the IC and ACC at 3h (the acute phase of peripheral tissue inflammation) after complete Freund's adjuvant (CFA) injection in naive rats and rats preconditioned with forced swim stress (FS) to clarify the effect of FS, a stressor, on cortical cell activities in the rats showing SIH induced by FS. The CFA injection into the hindpaw induced mechanical hypersensitivity and increased the expression of the pCREB and Egr1 in the IC and ACC at 3h after the injection. FS (day 1, 10min; days 2-3, 20min) prior to the CFA injection enhanced the CFA-induced mechanical hypersensitivity and attenuated the increase in the expression of pCREB and Egr1 in the IC and ACC. These findings suggested that FS modulates the CFA injection-induced neuroplasticity in the IC and ACC to enhance the mechanical hypersensitivity. These findings are thought to signify stressor-induced dysfunction of the descending pain modulatory system. PMID- 28866294 TI - Impact of adaptation algorithm, timing, and stopping boundaries on the performance of Bayesian response adaptive randomization in confirmative trials with a binary endpoint. AB - Despite the concerns of time trend in subject profiles, the use of Bayesian response adaptive randomization (BRAR) in large multicenter phase 3 confirmative trials has been reported in recent years, motivated by the potential benefits in subject ethics and/or trial efficiency. However three issues remain unclear to investigators: 1) among several BRAR algorithms, how to choose one for the specific trial setting; 2) when to start and how frequently to update the allocation ratio; and 3) how to choose the interim analyses stopping boundaries to preserve the type 1 error. In this paper, three commonly used BRAR algorithms are evaluated based on type 1 error, power, sample size, the proportion of subjects assigned to the better performing arm, and the total number of failures, under two specific trial settings and different allocation ratio update timing and frequencies. Simulation studies show that for two-arm superiority trials, none of the three BRAR algorithms has predominant benefits in both patient ethics and trial efficiency when compared to fixed equal allocation design. For a specific trial aiming to identify the best or the worst among three treatments, a properly selected BRAR algorithm and its implementation parameters are able to gain ethical and efficiency benefits simultaneously. Although the simulation results come from a specific trial setting, the methods described in this paper are generally applicable to other trials. PMID- 28866295 TI - The psychometric properties of depression screening tools in primary healthcare settings: A systematic review. AB - BACKGROUND: Consensus on a tool for depression screening among adults in primary healthcare (PHC) settings is lacking. This systematic review aimed to explore the psychometric properties of depression screening tools. METHODS: A systematic literature search composed of four terms (screening AND psychometric AND depression AND primary healthcare) was conducted in PubMed, EMBASE, PsycINFO and MEDLINE, between January 1995 through October 2015. Studies that aimed to psychometrically test a depression screening tool among the general adult population in a PHC setting were included. Studies exploring the diagnostic properties of depression screening tools among specific populations were excluded. RESULTS: Sixty publications, evaluating the psychometric properties of 55 tools or adaptations, were included. Studies were conducted in 24 countries and 18 languages on 48234 adults. The Patient Health Questionnaire-9 was the most evaluated tool with 14 studies evaluating its psychometric properties. Fifty-four studies reported on at least one measure of receiver operating characteristics. Sensitivity and specificity values ranged from 28% to 100% and 43% to 100%, respectively. Cronbach alpha values ranged from 0.56 to 0.94. Other forms of reliability and validity testing were less consistently and commonly reported. LIMITATIONS: The inclusion of studies regardless of methodological quality or design may have limited generalizability, but allowed for a comprehensive and detailed overview of the current literature. CONCLUSIONS: Depression screening tools vary in their psychometric properties. The PHQ-9 was the most extensively psychometrically tested tool. This systematic review may aid PHC professionals in choosing a depression screening tool for universal use as it provides a comprehensive overview of their psychometric properties. PMID- 28866297 TI - The impact of personality disorder pathology on the effectiveness of Cognitive Therapy and Interpersonal Psychotherapy for Major Depressive Disorder. AB - BACKGROUND: Despite extensive research, there is no consensus how Personality Disorders (PD) and PD features affect outcome for Major Depressive Disorder (MDD). The present study evaluated the effects of PD (features) on treatment continuation and effectiveness in Cognitive Therapy (CT) and Interpersonal Psychotherapy (IPT) for MDD. METHODS: Depressed outpatients were randomized to CT (n=72) and IPT (n=74). Primary outcome was depression severity measured repeatedly with the Beck Depression Inventory-II (BDI-II) at baseline, three months, at the start of each therapy session, at post-treatment and monthly during five months follow-up. RESULTS: Comorbid PD and PD features did not affect dropout. Multilevel and Cox regression models indicated no negative effect of PD on BDI-II change and remission rates during treatment and follow-up, irrespective of the treatment received. For both therapies, higher dependent PD features predicted overall lower BDI-II scores during treatment, however this effect did not sustain through follow-up. Cluster A PD features moderated treatment outcome during treatment and follow-up: individuals with high cluster A PD features had greater BDI-II reductions over time in CT as compared to IPT. LIMITATIONS: Not all therapists and participants were blind to the assessment of PD (features), and assessments were performed by one rater. Further research must investigate the state and trait dependent changes of PD and MDD over time. CONCLUSIONS: We found no negative impact of PD on the effectiveness and treatment retention of CT and IPT for MDD during treatment and follow-up. If replicated, cluster A PD features can be used to optimize treatment selection. PMID- 28866296 TI - Relation of plasma tryptophan concentrations during pregnancy to maternal sleep and mental well-being: The GUSTO cohort. AB - BACKGROUND: Evidence suggests a relation between plasma tryptophan concentrations and sleep and mental well-being. As no studies have been performed in pregnant women, we studied the relation of plasma tryptophan concentrations during pregnancy with sleep quality, and mood during and after pregnancy. METHODS: Pregnant women (n = 572) from the Growing Up in Singapore Towards healthy Outcomes study completed the Pittsburgh Sleep Quality Index (PSQI), the Edinburgh Postnatal Depression Scale (EPDS) and the State-Trait Anxiety Inventory (STAI) at 26-28 weeks gestation and three months post-delivery. Plasma tryptophan concentrations were measured at 26-28 weeks gestation. Poisson regressions estimated prevalence ratios (PR) for the association between tryptophan and poor sleep quality (PSQI global score > 5), probable antenatal depression (EPDS >= 15) and probable anxiety (STAI-state >= 41) were calculated adjusting for covariates. RESULTS: Mean plasma tryptophan concentrations was 48.0umol/L (SD: 8.09). Higher plasma tryptophan concentrations were associated with a lower prevalence of antenatal poor sleep quality adjusting for covariates [PR: 0.88 (95% CI 0.80, 0.97) per 10umol/L], especially in those participants who also suffered from anxiety symptoms [PR: 0.80 (95% CI 0.67, 0.95)]. No associations were observed between tryptophan concentrations during pregnancy and postnatal sleep quality or mental well-being. LIMITATION: Subjective measures were used to assess sleep and mental well-being. CONCLUSIONS: We observed that higher plasma tryptophan concentrations were associated with a 12% lower prevalence of poor sleep quality during pregnancy, in particular among those with anxiety symptoms. These findings suggest the importance of having adequate tryptophan concentrations during pregnancy. PMID- 28866299 TI - Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype. AB - OBJECTIVES: Fear of Harm (FOH) is a pediatric onset phenotype of bipolar disorder (BD) characterized by BD plus treatment resistance, separation anxiety, aggressive obsessions, parasomnias, and thermal dysregulation. Intranasal ketamine (InK) in 12 youths with BD-FOH produced marked improvement during a two week trial. Here we report on the open effectiveness and safety of InK in maintenance treatment of BD-FOH from the private practice of one author. METHODS: As part of a chart review, patients 18 years or older and parents of younger children responded to a clinical effectiveness and safety survey. Effectiveness was assessed from analysis of responses to 49 questions on symptomatology plus qualitative content analyses of written reports and chart review. Adverse events (AEs) were analyzed by frequency, duration and severity. Peak InK doses ranged from 20 to 360mg per administration. RESULTS: Surveys were completed on 45 patients treated with InK for 3 months to 6.5 years. Almost all patients were "much" to "very much" improved clinically and in ratings of social function and academic performance. Significant reductions were reported in all symptom categories. There were 13 reports of persistent AEs, none of which resulted in discontinuation. Acute emergence reactions were sporadically observed in up to 75%, but were mild and of brief duration. LIMITATIONS: Retrospective review from a single practice without placebo control with potential for response and recall bias. CONCLUSIONS: InK every 3-4 days at sub-anesthetic doses appeared to be a beneficial and well-tolerated treatment. Use of InK may be considered as a tertiary alternative in treatment refractory cases. Randomized control trials are warranted. PMID- 28866298 TI - Disrupted topology of hippocampal connectivity is associated with short-term antidepressant response in major depressive disorder. AB - BACKGROUND: Graph theoretical analyses have identified disrupted functional topological organization across the brain in patients with major depressive disorder (MDD). However, the relationship between brain topology and short-term treatment responses in patients with MDD remains unknown. METHODS: Sixty-eight patients with MDD and 63 cognitively normal (CN) subjects were recruited at baseline and underwent resting-state functional magnetic resonance imaging scans. Graph theory analysis was used to examine group differences in the whole-brain functional topological properties. The association between altered brain topology and the early antidepressant response was examined. RESULTS: Patients with MDD showed lower normalized clustering coefficients, lower small-worldness scalars and increased nodal efficiencies in the default mode network and decreased nodal efficiencies in basal ganglia and hippocampal networks. In addition, the decreased nodal efficiency in left hippocampus was negatively correlated with depressive severity at baseline and positively correlated with changes in the depressive scores after two weeks of antidepressant treatment. LIMITATIONS: The patients in the present study received different medications. CONCLUSION: These findings indicated that the altered brain functional topological organization in patients with MDD is associated with the treatment response in the early phase of medication. Therefore, brain topology assessments might be considered a useful and convenient predictor of short-term antidepressant responses. PMID- 28866300 TI - Action observation effects reflect the modular organization of the human motor system. AB - Action observation, similarly to action execution, facilitates the observer's motor system and Transcranial Magnetic Stimulation (TMS) has been instrumental in exploring the nature of these motor activities. However, contradictory findings question some of the fundamental assumptions regarding the neural computations run by the Action Observation Network (AON). To better understand this issue, we delivered TMS over the observers' motor cortex at two timings of two reaching grasping actions (precision vs power grip) and we recorded Motor-Evoked Potentials (4 hand/arm muscles; MEPs). At the same time, we also recorded whole hand TMS Evoked Kinematics (8 hand elevation angles; MEKs) that capture the global functional motor output, as opposed to the limited view offered by recording few muscles. By repeating the same protocol twice, and a third time after continuous theta burst stimulation (cTBS) over the motor cortex, we observe significant time-dependent grip-specific MEPs and MEKs modulations, that disappeared after cTBS. MEKs, differently from MEPs, exhibit a consistent significant modulation across pre-cTBS sessions. Beside clear methodological implications, the multidimensionality of MEKs opens a window on muscle synergies needed to overcome system redundancy. By providing better access to the AON computations, our results strengthen the idea that action observation shares key organizational similarities with action execution. PMID- 28866302 TI - Hemophagocytic syndrome: primary forms and predisposing conditions. AB - Hemophagocytic lymphohistiocytosis (HLH, also referred to a hemophagocytic syndrome) is a life-threatening condition in which uncontrolled activation of lymphocytes and macrophages, and thus the secretion of large amounts of inflammatory cytokines, leads to a severe hyperinflammatory state. Over the last few decades, researchers have characterized primary forms of HLH caused by genetic defects that impair lymphocytes' cytotoxic machinery. Other genetic causes of HLH not related to impaired cytotoxicity have also recently been identified. Furthermore, the so-called 'acquired' forms of HLH are encountered in the context of severe infections, autoimmune and autoinflammatory diseases, malignancy, and metabolic disorders, and may also be associated with primary immunodeficiencies. This implies that a variety of disease mechanisms can lead to HLH. Today's research seeks to gain a better understanding of the various pathogenetic and environmental factors that converge to induce HLH. PMID- 28866301 TI - Investigating the origin of nonfluency in aphasia: A path modeling approach to neuropsychology. AB - A major challenge in understanding the origin of clinical symptoms in neuropsychological impairments is capturing the complexity of the underlying cognitive structure. This paper presents a practical guide to path modeling, a statistical approach that is well-suited for modeling multivariate outcomes with a multi-factorial origin. We discuss a step-by-step application of such a model to the problem of nonfluency in aphasia. Individuals with aphasia are often classified into fluent and nonfluent groups for both clinical and research purposes, but despite a large body of research on the topic, the origin of nonfluency remains obscure. We propose a model of nonfluency inspired by the psycholinguistic approach to sentence production, review several bodies of work that have independently suggested a relationship between fluency and various elements in this model, and implement it using path modeling on data from 112 individuals with aphasia from the AphasiaBank. The results show that word production, comprehension, and working memory deficits all contribute to nonfluency, in addition to syntactic impairment which has a strong and direct impact on fluency. More generally, we demonstrate that a path model is an excellent tool for exploring complex neuropsychological symptoms such as nonfluency. PMID- 28866303 TI - Fuzzy inference model evaluating turn for Parkinson's disease patients. AB - Parkinson's disease is a chronic illness that affects motor skills. The Unified Parkinson's Disease Rating Scale sponsored by the Movement Disorder Society (MDS UPDRS) quantifies the current state of the disease based on clinician's observations. In this scale, turning is part of the gait assessment, yet specific guidelines on which features to observe and rate are still unclear. What is more, only visual impairment detection is used as the main subjective rating tool. In this respect, four biomechanical features are extracted from sensors worn on the lower limbs in this work. Afterwards, a turning assessment score is computed by means of a fuzzy inference model constructed based on the examiners knowledge. Overall, 46 patients with varying motor impairment severity underwent a full MDS UPDRS motor examination and were monitored using a measurement system that includes inertial sensors on each ankle. Turning rating scores computed are reasonably consistent with examiners opinions. Nevertheless, the model proposed herein will always output the same score given the same inputs; whereas the subjective nature of examiners observations translates into uncertainty and variability in the rating scores. Furthermore, the continuous scale implemented in this work prevents the floor/ceiling effect inherent of discrete scales. PMID- 28866304 TI - Clinical and biological response to rituximab treatment in 3 patients with acquired C1-inhibitor deficiency. PMID- 28866305 TI - Parental perception of anxiety in children with eosinophilic esophagitis in a tertiary care center. PMID- 28866306 TI - Eosinophil-derived neurotoxin as a biomarker for disease severity and relapse in recalcitrant atopic dermatitis. AB - BACKGROUND: Eosinophils are encountered in many skin diseases, but the role of eosinophils in atopic dermatitis (AD) remains uncertain. OBJECTIVE: To examine the role of serum eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and total IgE as a biomarker of disease severity and relapse in severe recalcitrant AD. METHODS: We enrolled 99 patients with AD: 37 with severe recalcitrant AD, 20 with severe AD, and 42 with mild to moderate AD. We examined the difference in serum level of total IgE, ECP, and EDN between the groups and whether any correlation existed between disease severity and ECP or EDN. Lastly, difference in levels of ECP or EDN between those who experienced relapse was examined in the severe recalcitrant group. RESULTS: Serum levels of total IgE, ECP, and EDN were significantly higher in the severe recalcitrant AD group and severe AD group compared with the mild to moderate AD group. No significant difference was found in serum levels of total IgE, ECP, and EDN between the severe recalcitrant group and severe group. EDN had a significant positive correlation with the SCORing Atopic Dermatitis. No significant correlation was found between EDN and ECP. In the severe recalcitrant group, 29.7% of patients experienced relapse, and EDN was significantly higher in those who experienced relapse. The cutoff value of EDN for predicting relapse was 64.5. CONCLUSION: EDN correlated with the disease severity of AD. EDN may predict relapse in severe recalcitrant AD. The EDN serum level could be considered a candidate molecule as a clinical biomarker for evaluating AD disease activity and a predictor of relapse. PMID- 28866307 TI - Evaluation of periprocedural hypersensitivity reactions. AB - BACKGROUND: Identifying the cause of periprocedural hypersensitivity reactions (HSRs) remains challenging because of the multitude of medications involved. Antibiotics are the most common cause in the United States, whereas neuromuscular blocking agents are most common in Europe. OBJECTIVE: To identify causative agents for periprocedural HSRs. METHODS: This study was a 7-year retrospective medical record review of patients evaluated between December 2009 and January 2017 at a drug allergy center in Bronx, New York for periprocedural HSRs, defined as occurring soon before, during, or soon after a medical procedure or operation with or without general anesthesia. Demographics, description of historical HSRs, results of testing to potential causative medications, and tolerance of subsequent anesthesia were reviewed. RESULTS: Thirty-four patients completed a comprehensive evaluation. Skin testing identified an IgE-mediated cause in 22 patients (64.7%). The most common causative class of medications was induction agents (n = 9 [36%]), with midazolam being the most frequently implicated (n = 6 [3 positive skin test results, 3 equivocal skin test results]). Cefazolin was the most common agent identified (n = 8 [32%]) followed by ondansetron (n = 3 [12%]). Sixteen of 22 contacted patients were exposed to subsequent anesthesia, including 3 patients with negative evaluations. One patient experienced a mild urticarial HSR. CONCLUSION: Induction agents were the most common causative agents in our patients, which differs from other studies. Given the variability in evaluations of periprocedural HSRs across the United States with data published on small sample sizes, there is a need to establish national guidelines to standardize evaluations and to create a national registry to allow for data sharing. PMID- 28866308 TI - Unique heterozygous presentation in an infant with DNA ligase IV syndrome. PMID- 28866309 TI - Management around invasive procedures in mastocytosis: An update. AB - OBJECTIVE: Mastocytosis is a chronic hematologic disorder that is characterized by the accumulation of aberrant mast cells and typically involves the skin and/or bone marrow. Patients with mastocytosis are at increased risk of anaphylaxis. Based on theoretical assumptions, medical procedures requiring general anesthesia or radiocontrast media are deemed hazardous for patients with mastocytosis. The objective of this article is to provide a comprehensive overview of the actual risk of iatrogenic anaphylaxis and provide recommendations for daily practice. DATA SOURCES: Various scientific search engines were used (eg, PubMed and Medline). STUDY SELECTIONS: Because of the paucity of high-level studies on this topic, all available evidence was considered, including case reports. RESULTS: Reliable data on the incidence of iatrogenic anaphylaxis in mastocytosis are lacking. However, although the incidence as reported in (retrospective) cohort studies is higher than in the general population, it is still lower than commonly anticipated, with an incidence of 5.4% in 1 study. Adequate premedication and avoidance of certain physical stimuli can further decrease this risk by 10-fold. The role of drugs as elicitors of anaphylaxis is perhaps overestimated, and physical stimuli are at least as important in inducing release of mast cell mediators. CONCLUSION: This article provides practical recommendations for the management of invasive procedures in patients with mastocytosis based on current knowledge of this topic. PMID- 28866310 TI - Identification and validation of asthma phenotypes in Chinese population using cluster analysis. AB - BACKGROUND: Asthma is a heterogeneous airway disease, so it is crucial to clearly identify clinical phenotypes to achieve better asthma management. OBJECTIVE: To identify and prospectively validate asthma clusters in a Chinese population. METHODS: Two hundred eighty-four patients were consecutively recruited and 18 sociodemographic and clinical variables were collected. Hierarchical cluster analysis was performed by the Ward method followed by k-means cluster analysis. Then, a prospective 12-month cohort study was used to validate the identified clusters. RESULTS: Five clusters were successfully identified. Clusters 1 (n = 71) and 3 (n = 81) were mild asthma phenotypes with slight airway obstruction and low exacerbation risk, but with a sex differential. Cluster 2 (n = 65) described an "allergic" phenotype, cluster 4 (n = 33) featured a "fixed airflow limitation" phenotype with smoking, and cluster 5 (n = 34) was a "low socioeconomic status" phenotype. Patients in clusters 2, 4, and 5 had distinctly lower socioeconomic status and more psychological symptoms. Cluster 2 had a significantly increased risk of exacerbations (risk ratio [RR] 1.13, 95% confidence interval [CI] 1.03 1.25), unplanned visits for asthma (RR 1.98, 95% CI 1.07-3.66), and emergency visits for asthma (RR 7.17, 95% CI 1.26-40.80). Cluster 4 had an increased risk of unplanned visits (RR 2.22, 95% CI 1.02-4.81), and cluster 5 had increased emergency visits (RR 12.72, 95% CI 1.95-69.78). Kaplan-Meier analysis confirmed that cluster grouping was predictive of time to the first asthma exacerbation, unplanned visit, emergency visit, and hospital admission (P < .0001 for all comparisons). CONCLUSION: We identified 3 clinical clusters as "allergic asthma," "fixed airflow limitation," and "low socioeconomic status" phenotypes that are at high risk of severe asthma exacerbations and that have management implications for clinical practice in developing countries. PMID- 28866311 TI - Filaggrin mutations and Molluscum contagiosum skin infection in patients with atopic dermatitis. AB - BACKGROUND: Although mutations in the filaggrin (FLG) gene have been reported to predispose patients with atopic dermatitis (AD) skin infection susceptibility, to date, the data reported in the literature are still controversial. OBJECTIVE: To evaluate the role of FLG polymorphisms expression and risk of developing a concomitant Molluscum contagiosum sustained skin infection in the pediatric population with AD. METHODS: A total of 100 children with AD and 97 healthy children were enrolled. AD was diagnosed and assessed according to the validated European Task Force on Atopic Dermatitis. DNA samples of patients were analyzed for allelic variants in the promoter and coding exon of FLG. Genotyping was performed with polymerase chain reaction amplification and direct sequencing. RESULTS: Sixteen FLG variants have been detected in 29% of patients with AD: 2 synonymous (rs79808464 and rs116222149), 12 missense (rs11584340, rs113136594, rs145828067, rs374910442, rs747005144, rs145627745, rs144209313, rs74129443, rs192455877, rs150957860, rs138055273, rs147472105), 1 stop gained (rs183942200), and 1 frameshift (rs 558269137). In contrast, only 13% of the control group reported FLG mutations (22 heterozygous variants). In addition, the age at disease onset correlated significantly with FLG variants (P < .001). In addition, the AD with FLG gene variants (rs145627745, rs79808464, rs150957860, rs145828067, rs747005144, rs374910442, rs138055273, rs183942200, rs11584340, and rs113136594) reported moderate to severe Scoring Atopic Dermatitis scores. Finally, the AD group and the AD plus M contagiosum skin infection group had a significant association with FLG mutations when compared with the control group (P < .01). CONCLUSION: FLG mutations are associated with early onset of AD, more severe clinical course of disease, and a significantly increased risk of M contagiosum sustained skin infection. PMID- 28866312 TI - Orthotopic liver transplantation provides a survival advantage compared with resection in patients with hepatocellular carcinoma and preserved liver function. AB - BACKGROUND: Prior studies comparing the efficacy of orthotopic liver transplantation to resection in patients with hepatocellular carcinoma have not controlled for underlying severity of liver disease. METHODS: Patients with stage I to III hepatocellular carcinoma and preserved liver function (model for end stage liver disease <12) who underwent resection or orthotopic liver transplantation between 2010 and 2013 were identified from the National Cancer Database. Short-term (30- and 90-day) and overall survival were assessed from 1:1 propensity score-matched cohorts based on patient and tumor characteristics. RESULTS: During the period studied, 689 (28%) underwent orthotopic liver transplantation, and 1,774 (72%) patients underwent resection. Propensity score matching yielded 374 undergoing orthotopic liver transplantation matched to 374 patients undergoing resection. Rates of 30-day mortality (01.9% vs 0.8%, respectively; P = .34) and 90-day mortality (3.5% vs 2.1%, P = .38) were not different between matched cohorts. Orthotopic liver transplantation did, however, result in a greater overall survival compared with resection (median overall survival not reached versus 4.5 years; P = .01). On multivariable Cox regression, resection was associated with a 67% greater likelihood of overall mortality compared with orthotopic liver transplantation (hazard ratio 1.67; 95% confidence interval, 1.15-2.43). CONCLUSION: For patients diagnosed with hepatocellular carcinoma in the context of preserved liver function, orthotopic liver transplantation was associated with a significant improvement in overall survival relative to resection. PMID- 28866313 TI - Impact of super obesity on perioperative outcomes after hepatectomy: The weight of the risk. AB - BACKGROUND: We evaluated perioperative outcomes in super obese patients (body mass index >50 kg/m2) undergoing liver resection using the American College of Surgeons National Surgical Quality Improvement Program. METHODS: Patients undergoing hepatectomy recorded in the American College of Surgeons National Surgical Quality Improvement Program dataset from 2005 to 2015 were analyzed. Out of 21,228 hepatectomies in the National Surgical Quality Improvement Program dataset, 146 were performed on super obese patients. RESULTS: Seventy-two percent of the super obese patients were female with a median age of 50.6 years, and 10% were classified as American College of Surgeons Class >=III. In this group, 69.2% were hypertensive, 38.4% were diabetics, and 17.8% had dyspnea. The median operation time was 248 minutes in the super obese group, greater than any other body mass index class. Twenty-two percent of these patients required perioperative transfusion, although 74% underwent partial hepatectomies. Body mass index >50 kg/m2 significantly increased morbidity in patients undergoing hepatectomies, almost 2-fold. Infectious complications increased by 86%, and the risk of developing critical care complications increased by 63%. CONCLUSION: Our data show that super obesity (body mass index >50 kg/m2) is the strongest independent predictor of perioperative morbidity. These patients also are at much greater risk of infectious complications and critical care complications. Future studies should be conducted using weight loss strategies in extreme obese patients to reduce their risk of life-threatening complications after hepatectomy. PMID- 28866314 TI - Preoperative risk factors for conversion and learning curve of minimally invasive distal pancreatectomy. AB - BACKGROUND: Although laparoscopic distal pancreatectomy is considered a standard approach, 10% to 40% of these are converted. The preoperative risk factors for conversion are not well described. The aim of this study was to identify risk factors associated with conversion. METHODS: Clinicopathological variables of 211 consecutive patients who underwent laparoscopic distal pancreatectomy between January 2007 and December 2015 at Johns Hopkins were analyzed to identify factors associated with conversion. Furthermore, the learning curve for laparoscopic distal pancreatectomy was studied. RESULTS: On univariate analysis of diabetes mellitus, preoperative diagnosis of malignant disease, multiorgan resection, surgeons' years and case experience were significantly associated with conversion (all P < .05). Risk factors independently associated with conversion included diagnosis of malignant disease (odds ratio = 5.40; 95% confidence interval, 1.93 15.12, P = .001), multiorgan resection (odds ratio = 7.10; 95% confidence interval, 1.60-31.53, P = .01), and surgeons' case experience (odds ratio = 0.32; 95% confidence interval, 0.12-0.85, P = .023). Intraoperative reasons for conversion included presence of excessive intraabdominal and retroperitoneal fat (N = 10, 32.3%), adhesions (N = 10, 32.3%), extent of tumor invasion (N = 8, 25.8%), anatomy of vessels (N = 6, 19.4%), and intraoperative bleeding (N = 2, 6.5%). CONCLUSION: Patients undergoing laparoscopic distal pancreatectomy with a preoperative diagnosis of malignant disease or possible multiorgan resection are at a higher risk of conversion. Surgeon experience of performing >15 procedures significantly reduces the risk of conversion. PMID- 28866315 TI - Nursing home staff perspectives on adoption of an innovation in goals of care communication. AB - Nursing homes (NH) are important settings for end-of-life care, but limited implementation may impede goals of care discussions. The purpose of this study was to understand NH staff perceptions of adoption and sustainability of the Goals of Care video decision aid for families of residents with advanced dementia. Study design was a cross-sectional survey of staff at 11 NHs in North Carolina who participated in the Goals of Care (GOC) cluster randomized clinical trial. Staff perceived the GOC decision aid intervention as a positive innovation; it was perceived as more compatible with current practices by male staff, nurses, and more experienced NH staff. Perceptions were correlated with experience, implying that experience with an innovative approach may help to promote improved GOC communication in nursing homes. Nurses and social work staff could be effective champions for implementing a communication technique, like the GOC intervention. PMID- 28866316 TI - The impact of mobility limitations on health outcomes among older adults. AB - The purpose of this study was to stratify an older adult population for subsequent interventions based on functional ability, and to estimate prevalence, characteristics and impact of mobility limitations on health outcomes. In 2016, surveys were sent to a stratified random sample of AARP(r) Medicare Supplement insureds; mobility limitations were defined using two screening questions. Responses were stratified to three mobility limitation levels. Multivariate regression models determined characteristics and impact on health outcomes. Among weighted survey respondents (N = 15,989), severe, moderate and no limitation levels were 21.4%, 18.4% and 60.3%, respectively. The strongest predictors of increased limitations included pain and poor health. Individuals with more severe limitations had increased falls, decreased preventive services compliance and increased healthcare utilization and expenditures. Utilizing two screening questions stratified this population to three meaningful mobility limitation levels. Higher levels of mobility limitations were strongly associated with negative health outcomes. Mobility-enhancing interventions could promote successful aging. PMID- 28866317 TI - Resilience and psychopathology among victimized youth in residential care. AB - This study examines the role of several resilience resources in the relationship between lifetime victimization and mental health problems among adolescents in care. The sample comprised 127 adolescents (53.% females, aged 12-17 years) from residential care facilities in Catalonia, Spain. The Juvenile Victimization Questionnaire, the Youth Self-Report, and the Adolescent Resilience Questionnaire were used to assess victimization, psychological symptoms, and resilience respectively. Results indicated that poly-victimization was associated with fewer resources, and with an increased risk of mental health problems. Self-resources mediated the relationship between victimization and internalizing and externalizing symptoms; community support mediated the relationship between victimization and internalizing symptoms. Self, school and peer support moderated the relationship between victimization and externalizing symptoms. Adolescents with fewer self-resources and less school support reported more externalizing symptoms, as did those with more peer support. However, poly-victimized youths reported symptoms within the clinical range, regardless of their level of resources. The findings stress the importance of preventing poly-victimization and of empowering poly-victimized adolescents, who appear to present low levels of resources. Researchers and clinicians should continue to study the poly victimization/psychopathology relationship, and also design interventions and prevention programs which incorporate the most relevant resilience resources. PMID- 28866318 TI - High vagally mediated resting-state heart rate variability is associated with superior action cascading. AB - The neurovisceral integration model suggests that individual differences in heart rate variability (HRV), an index of vagal tone, may relate to prefrontal cortical activity and predict performance on cognitive control tasks. The aim of this study was to further verify this model by investigating the relationship between vagally-mediated resting-state HRV and action cascading, a crucial cognitive control function which refers to the ability to cope with multiple response options when confronted with various task goals. Resting-state HRV and performance on the stop-change paradigm, which provides a relatively well established diagnostic measure of action cascading and response inhibition, was assessed in 88 healthy volunteers (age range 18-33). Compared to individuals with low resting-state HRV, participants with high resting-state HRV showed enhanced action cascading performance, both when a disruption (stopping) and change towards an alternative response were required simultaneously, and when requirements were cascaded (i.e. when the stopping process had already finished at the time the change was required). Our findings represent an important step towards extending our understanding of the neurovisceral integration model in cognitive control. PMID- 28866319 TI - The effect of blast overpressure on the mechanical properties of a chinchilla tympanic membrane. AB - The rupture of tympanic membrane (TM) has long been viewed as an indicator of blast injury, especially for hearing loss. However, little is known about damage to the TM caused by blast with pressure lower than the rupture threshold. In this paper, we present our study on the effect of blast overpressure on the static mechanical properties of TM. Chinchilla was used as the animal model and exposed to multiple blasts with pressures lower than the rupture threshold of the TM. Using a micro-fringe projection method, we observed the alteration of the static mechanical properties of post-blast chinchilla's TMs as compared to those of control TMs. Specifically, after exposing to multiple blasts, the Young's modulus of chinchilla TM decreased by ~53% while the ultimate failure pressure decreased by ~33%. Scanning Electron Microscope (SEM) images show the damage formation in the post-blast TM as compared with its control counterpart. PMID- 28866320 TI - Differences in perioperative femoral and radial arterial blood pressure in neonates and infants undergoing cardiac surgery requiring cardiopulmonary bypass. AB - OBJECTIVE: Several reports claim that blood pressure (BP) in the radial artery may underestimate the accurate BP in critically ill patients. Here, the authors evaluated differences in mean blood pressure (MBP) between the radial and femoral artery during pediatric cardiac surgery to determine the effectiveness of femoral arterial BP monitoring. METHOD: The medical records of children under 1 year of age who underwent open-heart surgery between 2007 and 2013 were retrospectively reviewed. Radial and femoral BP were measured simultaneously, and the differences between these values were analyzed at various times: after catheter insertion, after the initiation of cardiopulmonary bypass (CPB-on), after aortic cross clamping (ACC), after the release of ACC, after weaning from CPB, at arrival in the intensive care unit (ICU), and every 6h during the first day in the ICU. RESULTS: A total of 121 patients who underwent open-heart surgery met the inclusion criteria. During the intraoperative period, from the beginning to the end of CPB, radial MBPs were significantly lower than femoral MBPs at each time point measured (p<0.05). Multivariate analysis showed that longer CPB time (>60min, odds ratio: 7.47) was a risk factor for lower radial pressure. However, discrepancies between these two values disappeared after arrival in the ICU. There was no incidence of ischemic complications associated with the catheterization of both arteries. CONCLUSION: The authors suggest that femoral arterial pressure monitoring can be safely performed, even in neonates, and provides more accurate BP values during CPB-on periods, and immediately after weaning from CPB, especially when CPB time was greater than 60min. PMID- 28866321 TI - Cerebrospinal fluid lactate: a differential biomarker for bacterial and viral meningitis in children. AB - OBJECTIVE: To assess the performance of cerebrospinal fluid (CSF) lactate as a biomarker to differentiate bacterial meningitis from viral meningitis in children, and to define an optimal CSF lactate concentration that can be called significant for the differentiation. METHODS: Children with clinical findings compatible with meningitis were studied. CSF lactate and other conventional CSF parameters were recorded. RESULTS: At a cut-off value of 3mmol/L, CSF lactate had a sensitivity of 0.90, specificity of 1.0, positive predictive value of 1.0, and negative predictive value of 0.963, with an accuracy of 0.972. The positive and negative likelihood ratios were 23.6 and 0.1, respectively. When comparing between bacterial and viral meningitis, the area under the curve for CSF lactate was 0.979. CONCLUSIONS: The authors concluded that CSF lactate has high sensitivity and specificity in differentiating bacterial from viral meningitis. While at a cut-off value of 3mmol/L, CSF lactate has high diagnostic accuracy for bacterial meningitis, mean levels in viral meningitis remain essentially below 2mmol/L. PMID- 28866322 TI - Advanced bone age as an indicator facilitates the diagnosis of precocious puberty. AB - OBJECTIVE: Diagnosis of central precocious puberty has always been challenging in clinical practice. As an important method in the diagnosis of central precocious puberty, luteinizing hormone-releasing hormone stimulation test is complex and time-consuming. In many cases, clinical traits are inconsistent with luteinizing hormone-releasing hormone stimulation test results, therefore not reliable for diagnosis. In this study, the authors intended to find an indicator that predicts the results of the luteinizing hormone-releasing hormone stimulation test among subjects with early pubertal signs. METHODS: Cases of 382 girls with early breast development before 8 years old and luteinizing hormone-releasing hormone stimulation test before 9 years old were included and underwent follow-up tests. Patients with peak luteinizing hormone level >=5IU/L were considered positive in the luteinizing hormone-releasing hormone stimulation test. Anthropometric data, body mass index, bone age evaluation, blood hormones levels of luteinizing hormone, estradiol, follicle-stimulating hormone, and uterine and ovarian volumes were analyzed. RESULTS: Subjects with positive results in the initial test demonstrated early bone maturation, accelerated growth, and elevated basal blood luteinizing hormone, estradiol, and follicle-stimulating hormone levels, when compared with subjects with negative results in the initial test. Subjects with positive results in the follow-up test presented a more advanced bone age and more accelerated linear growth, when compared with subjects with negative results in the follow-up test. CONCLUSIONS: According to the statistical analysis, advanced bone age is the most effective predictor of the result of luteinizing hormone-releasing hormone stimulation test. PMID- 28866323 TI - Risk factors for central venous catheter-related infections in a neonatal population - systematic review. AB - OBJECTIVE: This was a systematic review of the incidence density and risk factors for central venous catheter-related infections in a neonatal population. DATA SOURCE: The MEDLINE, Embase, Cochrane, BDENF, SciELO, and LILACS databases were used without date or language restriction. Studies that analyzed risk factors for bloodstream infections in newborns were identified. DATA SYNTHESIS: A total of 134 articles were found that met the eligibility criteria. Of these articles, 14 were selected that addressed risk factors for central venous catheter-related infection in neonates. Catheter-related bloodstream infections remain an important complication, as shown by the incidence rates reported in the studies included in this review. The observed risk factors indicate that low birth weight, prematurity, and longer catheter permanence are related to a higher incidence of bloodstream infections. It has been observed that low rates of catheter-related infections, i.e., close to zero, are already a reality in health institutions in developed countries, since they use infection surveillance and control programs. CONCLUSION: Catheter-related bloodstream infections still show high incidence density rates in developing countries. The authors emphasize the need for further longitudinal studies and the need for better strategies to prevent risk factors, aiming at the reduction of catheter-related infections. PMID- 28866324 TI - Effects of in vivo deletion of GATA2 in bone marrow stromal cells. AB - The bone marrow (BM) microenvironment comprises multiple stem cell niches derived from BM mesenchymal stem cells (MSCs). Previous in vitro analyses have suggested that transcription factor GATA2 plays an important role in adipocyte differentiation of BM-MSCs and in hematopoietic support, but the role of GATA2 in vivo remains unknown. We evaluated GATA2 effects in BM-MSCs in vivo. Expression profiling analysis of Gata2-knockout Ter119-CD45- mesenchymal stromal cells obtained from compact bone from tamoxifen-treated Gata2 conditional knockout mice (Gata2f/f/ER-Cre mice) revealed upregulation of 110 genes and downregulation of 141 genes by a factor of 2. Moreover, gene ontology analysis revealed significant enrichment of genes involved in cell adhesion and chemotaxis. We did not find any phenotypic changes when Gata2 was deleted with BM-MSC-related gene promoters, such as Nestin, Prx1, and Lepr, except for a significant decrease in the colony number of Gata2f/f/Prx1-Cre mice. There was a significant decrease in the percentage of the common myeloid progenitor fraction when Gata2 was deleted in all BM cells, except hematopoietic cells after normal BM cells were transplanted into irradiated Gata2f/f/ER-Cre mice with Gata2 subsequently knocked out by tamoxifen administration. In conclusion, GATA2 could affect the function of BM MSCs in vivo, presumably by regulating the expression of extracellular signals. PMID- 28866325 TI - Phosphoinositide 3-kinase participates in l-methionine sulfoximine-induced cell death via salicylic acid mediated signaling in Nicotiana benthamiana. AB - Pseudomonas syringae pv. tabaci causes wildfire disease by the action of tabtoxinine-beta-lactam (TbetaL), a non-specific bacterial toxin. To better understand the molecular mechanisms of wildfire disease and its development, we focused on the phosphoinositide 3-kinase in Nicotiana benthamiana (NbPI3K) and its potential role in the disease outbreak, using l-methionine sulfoximine (MSX) as an easily accessible mimic of the TbetaL action. The NbPI3K-silenced plants showed accelerated induction of cell death and necrotic lesion formation by MSX, and the expression of hin1, marker gene for the programmed cell death, was strongly induced in the plants. However, the accumulation of ammonium ions, caused by MSX inhibition of glutamine sythetase activity, was not affected by the NbPI3K-silencing. Interestingly, the expression of PR-1a, a marker gene for salicylic acid (SA) innate immunity signaling, and accumulation of SA were both enhanced in the NbPI3K-silenced plants. Accordingly, the acceleration of MSX induced cell death by NbPI3K-silencing was reduced in NahG plants, and by double silencing of NbPI3K together with the NbICS1 encoding a SA-biosynthetic enzyme. As silencing of NbPI3K accelerated the TbetaL-induced necrotic lesions, and lesions of wildfire disease caused by P. syringae pv. tabaci, these results suggest that the NbPI3K-related pathway might act as a negative regulator of cell death during development of wildfire disease that involves SA-dependent signaling pathway downstream of TbetaL action in N. benthamiana. PMID- 28866326 TI - Progesterone improves neurocognitive outcomes following therapeutic cranial irradiation in mice. AB - Despite improved therapeutic methods, CNS toxicity resulting from cancer treatment remains a major cause of post-treatment morbidity. More than half of adult patients with cranial irradiation for brain cancer develop neurobehavioral/cognitive deficits that severely impact quality of life. We examined the neuroprotective effects of the neurosteroid progesterone (PROG) against ionizing radiation (IR)-induced neurobehavioral/cognitive deficits in mice. Male C57/BL mice were exposed to one of two fractionated dose regimens of IR (3Gy*3 or 3Gy*5). PROG (16mg/kg; 0.16mg/g) was given as a pre-, concurrent or post-IR treatment for 14days. Mice were tested for short- and long-term effects of IR and PROG on neurobehavioral/cognitive function on days 10 and 30 after IR treatment. We evaluated both hippocampus-dependent and -independent memory functions. Locomotor activity, elevated plus maze, novel object recognition and Morris water maze tests revealed behavioral deficits following IR. PROG treatment produced improvement in behavioral performance at both time points in the mice given IR. Western blot analysis of hippocampal and cortical tissue showed that IR at both doses induced astrocytic activation (glial fibrillary acidic protein), reactive macrophages/microglia (CD68) and apoptosis (cleaved caspase-3) and PROG treatment inhibited these markers of brain injury. There was no significant difference in the degree of deficit in any test between the two dose regimens of IR at either time point. These findings could be important in the context of patients with brain tumors who may undergo radiotherapy and eventually develop cognitive deficits. PMID- 28866327 TI - Beyond quality control: The role of nonsense-mediated mRNA decay (NMD) in regulating gene expression. AB - Nonsense-mediated mRNA decay (NMD) has traditionally been described as a quality control system that rids cells of aberrant mRNAs with crippled protein coding potential. However, transcriptome-wide profiling of NMD deficient cells identified a plethora of seemingly intact mRNAs coding for functional proteins as NMD targets. This led to the view that NMD constitutes an additional post transcriptional layer of gene expression control involved in the regulation of many different biological pathways. Here, we review our current knowledge about the role of NMD in embryonic development and tissue-specific cell differentiation. We further summarize how NMD contributes to balancing of the integrated stress response and to cellular homeostasis of splicing regulators and NMD factors through auto-regulatory feedback loops. In addition, we discuss recent evidence that suggests a role for NMD as an innate immune response against several viruses. Altogether, NMD appears to play an important role in a broad spectrum of biological pathways, many of which still remain to be discovered. PMID- 28866328 TI - Splicing dysfunction and disease: The case of granulopoiesis. AB - Splicing is a ubiquitous process in eukaryotic cells, long recognised as contributing to diversity of the transcriptome. More specifically, splicing fine tunes the transcriptome output for highly individual outcomes at different stages of cell development, in specific timeframes, which when perturbed result in significant human diseases. Granulopoiesis provides a particularly well studied example of how splicing can be a highly flexible but tightly regulated process. Focusing on the specific case of granulopoiesis, this review surveys the contribution of cis-splicing variations in individual genes and the trans regulation of global splicing outcomes during the normal development of neutrophils. Further, the contribution of splicing dysfunction to the pathogenesis of diseases of neutrophil number, function and maturation including hereditary neutropenia, myelodysplasia, and acute myeloid leukaemia is explored. PMID- 28866329 TI - Nuclear export of RNA: Different sizes, shapes and functions. AB - Export of protein-coding and non-coding RNA molecules from the nucleus to the cytoplasm is critical for gene expression. This necessitates the continuous transport of RNA species of different size, shape and function through nuclear pore complexes via export receptors and adaptor proteins. Here, we provide an overview of the major RNA export pathways in humans, highlighting the similarities and differences between each. Its importance is underscored by the growing appreciation that deregulation of RNA export pathways is associated with human diseases like cancer. PMID- 28866330 TI - Aggression and violence in psychiatric hospitals with and without open door policies: A 15-year naturalistic observational study. AB - Aggressive behavior and violence in psychiatric patients have often been quoted to justify more restrictive settings in psychiatric facilities. However, the effects of open vs. locked door policies on aggressive incidents remain unclear. This study had a naturalistic observational design and analyzed the occurrence of aggressive behavior as well as the use of seclusion or restraint in 21 German hospitals. The analysis included data from 1998 to 2012 and contained a total of n = 314,330 cases, either treated in one of 17 hospitals with (n = 68,135) or in one of 4 hospitals without an open door policy (n = 246,195). We also analyzed the data according to participants' stay on open, partially open, or locked wards. To compare hospital and ward types, we used generalized linear mixed effects models on a propensity score matched subset (n = 126,268) and on the total dataset. The effect of open vs. locked door policy was non-significant in all analyses of aggressive behavior during treatment. Restraint or seclusion during treatment was less likely in hospitals with an open door policy. On open wards, any aggressive behavior and restraint or seclusion were less likely, whereas bodily harm was more likely than on closed wards. Hospitals with open door policies did not differ from hospitals with locked wards regarding different forms of aggression. Other restrictive interventions used to control aggression were significantly reduced in open settings. Open wards seem to have a positive effect on reducing aggression. Future research should focus on mental health care policies targeted at empowering treatment approaches, respecting the patient's autonomy and promoting reductions of institutional coercion. PMID- 28866331 TI - Microcystin-LR exposure induces oxidative damage in Caenorhabditis elegans: Protective effect of lutein extracted from marigold flowers. AB - Microcystin-LR (MIC-LR) is a hepatotoxin, with toxicity mechanisms linked to oxidative stress. Besides, neurotoxic effects of MIC-LR have recently been described. Herein, we evaluated the effects of environmentally important concentrations of MIC-LR (1, 10, 100, 250, and 500 MUg/L) on oxidative stress markers and the survival rate of the nematode Caenorhabditis elegans (C. elegans). In addition, a possible protective effect of the carotenoid lutein (LUT) extracted from marigold flowers against MIC-LR toxicity was investigated. Higher concentrations (250 and 500 MUg/L) of MIC-LR induced the generation of reactive oxygen species (ROS) and resulted in a survival loss in C elegans. Meanwhile, all MIC-LR concentrations caused an increase in the superoxide dismutase (SOD) expression, while catalase (CAT) expression was only affected at 500 MUg/L. The carotenoid LUT prevented the ROS generation, impairment in the CAT expression, and the survival loss induced by MIC-LR in C. elegans. Our results confirm the toxicity of MIC-LR even in a liver-lacking invertebrate and the involvement of oxidative events in this response. Additionally, LUT appears to be able to mitigate the MIC-LR toxic effects. PMID- 28866332 TI - Permethrin decreased insulin-stimulated AKT phosphorylation dependent on extracellular signal-regulated kinase-1 (ERK), but not AMP-activated protein kinase alpha (AMPKalpha), in C2C12 myotubes. AB - Previously 10 MUM permethrin (38.7% cis and 59.4% trans isomers), a pyrethroid insecticide widely used in agriculture and household products for pest control, was reported to reduce insulin-stimulated glucose uptake and phosphorylation of protein kinase B (p-AKT) in C2C12 mouse myotubes. The underlying mechanisms on how permethrin decreases insulin-stimulated AKT phosphorylation, however, are unknown. Thus, the goal of this study was to determine the possible mechanism(s) through which permethrin reduced insulin-stimulated AKT phosphorylation in C2C12 myotubes. Permethrin treatment, at 10 MUM, decreased insulin-stimulated membrane glucose transporter type 4 (GLUT4) and AKT phosphorylation, and increased insulin receptor substrate 1 (IRS1) Ser307 phosphorylation in the presence of insulin. The inactivation of AKT by permethrin was independent of AMPKalpha. ERK inactivation by U0126, however, restored insulin-stimulated AKT phosphorylation, which was decreased by permethrin treatment. These results suggest that permethrin decreased insulin-stimulated AKT phosphorylation via ERK activation, but not by AMPKalpha inactivation. PMID- 28866333 TI - Epilepsy may cause increased pain sensitivity: Evidence from absence epileptic WAG/Rij rats. AB - OBJECTIVE: The comorbidity of epilepsy and pain disorders as well as effectiveness of certain therapeutic approaches in both conditions attracted attention to epilepsy-pain interactions. This lead to the discovery of significantly shared pathophysiological mechanisms although many aspects remain largely unknown. To test the hypothesis that epilepsy may be associated with altered pain sensitivity, we analyzed interictal pain sensitivity using epilepsy prone WAG/Rij rats, a genetic model exhibiting age-related-onset absence epilepsy. METHODS: Two series of experiments were conducted. In experiment I, pain sensitivity of symptomatic WAG/Rij rats were compared with age-matched control Wistar rats. In experiment II, pain sensitivity of WAG/Rij rats were monitored longitudinally when they were presymptomatic (at 2months) and symptomatic (after maturation, at 8months), and compared with age-matched control Wistar rats. Pain sensitivity was assessed by applying heat stimuli to hind paws and measuring the paw-withdrawal latency using thermal plantar analgesia meter in awake and freely moving animals. All pain measurements were made during the interictal period, confirmed by simultaneous electroencephalography through intracranially implanted electrodes. RESULTS: In experiment I, the interictal pain withdrawal latency of symptomatic WAG/Rij rats was significantly shorter than control Wistar rats (P<0.01). In experiment II, WAG/Rij rats had significantly shorter latency of withdrawal response than control Wistar rats, both at presymptomatic (P<0.05) and symptomatic stage (P<0.0001). Matured (8months old) control Wistar rats demonstrated significantly increased withdrawal latency compared to the 2months animals (P<0.01), but the WAG/Rij rats did not (P>0.5). CONCLUSION: Epileptic WAG/Rij rats present significantly increased pain sensitivity when compared to control Wistar rats, suggesting comorbidity of epilepsy and pain. PMID- 28866334 TI - Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study. AB - OBJECTIVE: The objective of the study was to assess common practice in pediatric epilepsy surgery in Italy between 2008 and 2014. METHODS: A survey was conducted among nine Italian epilepsy surgery centers to collect information on presurgical and postsurgical evaluation protocols, volumes and types of surgical interventions, and etiologies and seizure outcomes in pediatric epilepsy surgery between 2008 and 2014. RESULTS: Retrospective data on 527 surgical procedures were collected. The most frequent surgical approaches were temporal lobe resections and disconnections (133, 25.2%) and extratemporal lesionectomies (128, 24.3%); the most frequent etiologies were FCD II (107, 20.3%) and glioneuronal tumors (105, 19.9%). Volumes of surgeries increased over time independently from the age at surgery and the epilepsy surgery center. Engel class I was achieved in 73.6% of patients (range: 54.8 to 91.7%), with no significant changes between 2008 and 2014. Univariate analyses showed a decrease in the proportion of temporal resections and tumors and an increase in the proportion of FCDII, while multivariate analyses revealed an increase in the proportion of extratemporal surgeries over time. A higher proportion of temporal surgeries and tumors and a lower proportion of extratemporal and multilobar surgeries and of FCD were observed in low (<50surgeries/year) versus high-volume centers. There was a high variability across centers concerning pre- and postsurgical evaluation protocols, depending on local expertise and facilities. SIGNIFICANCE: This survey reveals an increase in volume and complexity of pediatric epilepsy surgery in Italy between 2008 and 2014, associated with a stable seizure outcome. PMID- 28866335 TI - Predictors of outcomes and refractoriness in status epilepticus: A prospective study. AB - OBJECTIVE: The objective of this study was to determine the predictors of outcomes and refractoriness in status epilepticus (SE). METHODS: This is a prospective study of 59 adult patients with SE who were admitted to the Emergency Department between February 2012 and December 2013. The effects of clinical, demographic, and electrophysiologic features of patients with SE were evaluated. To evaluate outcome in SE, STESS, mSTESS, and EMSE scales were used. RESULTS: Logistic regression analysis showed that being aged >=65years (p=0.02, OR: 17.68, 95% CI: [1.6-198.4]) for the short term and having potentially fatal etiology (p=0.027, OR: 11.7, 95% CI: [1.3-103]) for the long term were the only independent predictors of poor outcomes; whereas, the presence of periodic epileptiform discharges (PEDs) in EEG was the only independent predictor of refractoriness (p=0.032, OR: 13.7, 95% CI: [1.3-148.5]). The patients with >=3 Status Epilepticus Severity Score (STESS) did not have poorer outcomes in the short- (p=0.157) and long term (p=0.065). There was no difference between patients with 0-2, 3-4, and >=4 mSTESS in the short- and long term in terms of outcome (p=0.28 and 0.063, respectively). Also, there was no difference between subgroups (convulsive SE [CSE], nonconvulsive SE [NCSE], and epilepsia partialis continua [EPC]) in terms of STESS and mSTESS. When patients with EPC were excluded, both STESS and mSTESS scores of the patients correlated with poorer long-term outcomes (p=0.025 and 0.017, respectively). The patients with >=64 points in the Epidemiology-based Mortality in SE-Etiology, age, comorbidity, EEG (EMSE-EACE) score and those with >=27 points in EMSE-Etiology, age, comorbidity (EMSE-EAC) score did not have poorer outcomes in the short term (p=0.06 and 0.274, respectively) while they had significantly poorer outcome in the long term (p<0.001 and 0.002, respectively). In subgroup analysis, patients with CSE with >=64 points in EMSE-EACE had significantly poorer outcome in the both short- and long term (p=0.014 and 0.012, respectively), and patients with CSE with >=27 points in EMSE-EAC had significantly poorer outcome in the long term (p=0.03) but not in the short term (p=0.186). Outcomes did not correlate with EMSE scores in patients with NCSE and EPC. Status epilepticus was terminated with intravenous (IV) levetiracetam (LEV) in 68.75% of patients and with IV phenytoin (PHT) in 83.3% of patients. No statistically significant difference was found between the two groups in terms of efficacy (p=0.334). CONCLUSION: Being aged >=65years predicts poor short-term outcomes, and having potentially fatal etiology predicts poor long-term outcomes, which highlight the importance of SE treatment management in the elderly. Both STESS and mSTESS are not predictive for poor outcomes in EPC. Excluding patients with EPC, STESS, and mSTESS could predict poor long-term outcomes but not in the short term in SE. Epidemiology-based Mortality in Status Epilepticus score could predict poor outcome in the long term better than STESS and mSTESS. Specifically, EMSE scores correlated with poor outcome in patients with CSE but not with NCSE and EPC. New scales are needed to predict outcome especially in patients with NCSE and EPC. The presence of PEDs in EEG is a predictor of RSE, and EMSE score can also be used to predict RSE. There was no difference in the efficacy of IV LEV and IV PHT in SE. This study is significant for having one of the longest follow-up periods in the literature. PMID- 28866336 TI - "Atypical forms" of benign epilepsy with centrotemporal spikes (BECTS): How to diagnose and guide these children. A practical/scientific approach. AB - Benign epilepsy with centrotemporal spikes (BECTS) epilepsy, also known as rolandic epilepsy, is the most common childhood type of epilepsy. There is debate on its "benign" definition given the numerous literature data on its correlation to cognitive morbidity. Although its prognosis is often favorable, BECTS can present or evolve however to an atypical form, characterized by a worse prognosis and negative impact on cognitive development. It is possible that abnormal electrical activity, marker of neurological dysfunction, has the potential to disrupt neural network function and development. Numerous studies tried to identify clinical or electroencephalographic criteria for atypical forms and atypical evolution of BECTS in order to guide follow-up and treatment of patients and to predict their outcome. This review provides a compact summery of literature data with a focus on predictive features of future cognitive decline. PMID- 28866337 TI - The possibility of adverse effect of Kv7-channel opener retigabine on memory processes in rats. AB - OBJECTIVE: Retigabine is a novel antiepileptic drug with a unique and complex mechanism of action which allows its use in many diseases associated with impaired neuronal activity. This study sought to examine the impact of retigabine on two types of memory in rats. METHODS: Adult male Wistar rats were used to assess the effect of retigabine, administered p.o. as single (10mg/kg or 20mg/kg) or repeated doses, on spatial memory with the Morris water maze test (MWM) and emotional memory, associated with fear, with the passive avoidance test (PA). RESULTS: Retigabine administered at a high single dose transiently impairs learning processes in rats. In the MWM, these changes were delayed in time and of a lesser degree when retigabine was given at low single dose. Additionally, the drug administered repeatedly for 2weeks slowed learning processes in the MWM, but this effect occurred only after 1week of administration in the PA. CONCLUSION: These findings indicate that retigabine may affect memory and learning processes, especially in the first phase of administration. PMID- 28866338 TI - Wake up to sleep: The effects of lacosamide on daytime sleepiness in adults with epilepsy. AB - OBJECTIVE: The objective of the study was to investigate the effects of lacosamide (LCM) on daytime sleepiness ascertained by the Epworth Sleepiness Scale (ESS) in adults with focal epilepsy in a randomized, controlled design. METHODS: Subjects taking <=2 AEDs for >=4weeks underwent polysomnography with EEG followed by the maintenance of wakefulness test (MWT) and completed the ESS and other patient-reported outcomes (PROs) at baseline, LCM 200mg/day, and LCM 400mg/day (Visit 4; V4). Primary endpoint was ESS change (V4 to baseline) between LCM and placebo. Noninferiority test on ESS used a one-sided t-test based on a hypothesized difference of 4-point change between groups. Superiority test used a two-sided t-test to investigate the difference in change in PROs and MWT mean sleep latency (MSL) between groups. Fifty-five subjects provided 80% power to show noninferiority of LCM assuming 10% dropout. RESULTS: Fifty-two subjects (mean age: 43.5+/-13.2years, 69% female, median monthly seizure frequency: 1 [0, 4.0]) participated. Baseline group characteristics including age, sex, ethnicity, standardized AED dose, seizure frequency, and ESS were similar. Abnormal baseline ESS scores were found in 35% of subjects. Noninferiority test found a <=4-point increase in ESS (mean [95% CI]) in LCM subjects vs. placebo (-1.2 [-2.9, 0.53] vs. -1.1 [-5.2, 3.0], p=0.027) at V4. No significant difference in change in PROs, MSL, seizure frequency, or AED standardized dose was observed between groups. SIGNIFICANCE: Our interventional trial found that LCM is not a major contributor to daytime sleepiness based on subjective and objective measures. Inclusion of sleepiness measures in AED trials is warranted given the high prevalence of sleep-wake complaints in people with epilepsy. PMID- 28866339 TI - Arthroscopic Partial Repair of Irreparable Rotator Cuff Tears: Factors Related to Greater Degree of Clinical Improvement at 2 Years of Follow-Up. AB - PURPOSE: This study aimed to evaluate the clinical outcomes of irreparable rotator cuff tears (RCT) treated with an arthroscopic partial repair, as well as the preoperative factors that may be related to greater improvement of clinical outcomes at short-term follow-up. METHODS: We retrospectively reviewed patients with irreparable RCT who underwent arthroscopic partial rotator cuff repair between January 2011 and April 2014. Minimal follow-up of 24 months was required. Partial repair was defined as repairing the less retracted posterosuperior rotator cuff with a residual defect of the tendon-footprint junction. Tearing involving the subscapularis tendon was excluded. Factors collected included age, sex, diabetes, smoking, night pain, duration of symptoms, pain visual analog scale (VAS) score, acromiohumeral distance (AHD), and American Shoulder and Elbow Surgeons (ASES) score. Magnetic resonance images without intra-articular contrast were assessed for healing 6 months after surgery for all patients. Functional outcome was evaluated with ASES score. Degree of functional improvement was defined as the difference of ASES scores pre- and postoperatively (d-ASES). Paired t-test and simple linear analysis were used for statistical analysis. RESULTS: Thirty-seven patients were included with a mean follow-up period of 29.6 +/- 6.6 months. VAS score improved from 5.22 to 1.51 (P < .001). ASES score improved from 46.0 to 78.6 (P < .001). The incidence of night pain improved from 70.3% to 8.1% (P < .001). Only a preoperative lower ASES score, higher VAS score, and night pain were related to the higher d-ASES score (P < .001, P = .005, P = .017, respectively). The rate of repair failure was 41.6% at a mean follow-up of 6.4 months. CONCLUSIONS: Arthroscopic partial repair of irreparable RCTs is an effective treatment to improve the shoulder function and decrease the pain, despite the high repair failure rate of 41.6%. Patients with preoperative lower functional score, higher VAS score, or night pain experienced a greater degree of functional improvement from the surgery. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28866340 TI - Single-Bundle and Double-Bundle Posterior Cruciate Ligament Reconstructions: A Systematic Review and Meta-analysis of 441 Patients at a Minimum 2 Years' Follow up. AB - PURPOSE: To perform a systematic review on the techniques and a meta-analysis on the functional and objective outcomes after single-bundle (SB) versus double bundle (DB) posterior cruciate ligament (PCL) reconstructions. METHODS: A systematic review of the techniques, as well as functional and objective outcomes of clinical studies comparing SB versus DB PCL reconstruction with a mean follow up of at least 24 months and minimum level of evidence of III were performed. After review of the literature, a quality analysis of the studies (Detsky score) and a meta-analysis comparing raw mean differences in data between SB and DB PCL groups were performed. Clinical outcome measures included in the meta-analysis were functional outcomes (Lysholm, Tegner, and objective International Knee Documentation Committee [IKDC] scores) and objective measurements (arthrometer and stress radiographs). RESULTS: The systematic search identified 11 studies (441 patients). Three studies were prospective randomized controlled trials and the other 8 studies were case-control studies. Two hundred thirty-two patients were treated with SB PCL reconstruction, whereas 209 were treated with DB PCL reconstruction. Only 4 studies satisfied the threshold for a satisfactory level of methodologic quality (>75%). There were no significant differences between SB and DB PCL reconstructions in postoperative Lysholm (P = .6, 95% confidence interval [CI], -0.98, 2.18) or Tegner scores (P = .37, 95% CI, -0.19, 0.92). DB PCL reconstruction provided significantly better objective posterior tibial translation stability than the SB technique using the Telos technique at 90 degrees (P = -.58, 95% CI, -1.06, -0.10). CONCLUSIONS: Improved patient-reported outcomes and knee stability were achieved with both SB and DB PCL reconstruction surgery. DB PCL reconstruction provided significantly improved objective posterior tibial stability and objective IKDC scores when compared with SB PCL reconstruction in randomized clinical trials. No significant difference was found for the other patient-reported outcomes. LEVEL OF EVIDENCE: Level III, systematic review and meta-analysis of Level II and III studies. PMID- 28866341 TI - Similar 30-Day Complications for Septic Knee Arthritis Treated With Arthrotomy or Arthroscopy: An American College of Surgeons National Surgical Quality Improvement Program Analysis. AB - PURPOSE: The purpose of the current study was to use the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) to determine whether there were differences in 30-day perioperative complications between open arthrotomy and arthroscopy for the treatment of septic knees in a large national sample. METHODS: Patients who were diagnosed with a septic knee and underwent open arthrotomy or arthroscopy were identified in the 2005-2014 NSQIP data sets. Patient demographics and perioperative complications were characterized and compared between the 2 procedures. RESULTS: In total, 168 patients undergoing knee arthrotomy and 216 patients undergoing knee arthroscopy for septic knee were identified. There were no statistically significant differences in demographic variables between the 2 groups. On univariate analysis, the rate of minor adverse events (MAEs; 15.48% vs 8.80%, P = .043) was higher in the open arthrotomy treatment group, while the rate of serious adverse events (SAEs; 37.50% vs 26.19%, P = .019) was higher in the arthroscopic surgery treatment group. On multivariate analysis, which controlled for patient characteristics/comorbidities and used the Bonferroni correction for multiple comparisons, there were no statistically significant differences in risk of any adverse events (relative risk [RR] = 0.851; 99% confidence interval [CI], 0.598-1.211; P = .240), MAE (RR = 1.653; 99% CI, 0.818-3.341; P = .066), SAE (RR = 0.706; 99% CI, 0.471-1.058; P = .027), return to the operating room (RR = 0.810; 99% CI, 0.433-1.516; P = .387), or readmission (RR = 1.022; 99% CI, 0.456-2.294; P = .944) between open compared with arthroscopic surgery. CONCLUSIONS: Univariate analysis revealed a lower rate of MAE but a higher rate of SAE in the arthroscopic surgery treatment group. However, on multivariate analysis, similar perioperative complications, rate of return to the operating room, and rate of readmission were found after open and arthroscopic debridement for septic knees. Based on the lack of demonstrated superiority of either of these 2 treatment modalities for this given diagnosis, and the expectation that most differences in perioperative complications for this diagnosis would have declared themselves within the first 30 days, deciding between the studied treatment modalities may be based more on other factors not included in this study. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 28866342 TI - Recurrent Instability After Arthroscopic Bankart Reconstruction: A Systematic Review of Surgical Technical Factors. AB - PURPOSE: Recurrent instability remains of concern after arthroscopic Bankart reconstruction. We evaluated various technical factors including anchor design, anchor material, number of anchors used, and interval closure on risk of recurrent instability after arthroscopic Bankart reconstruction. METHODS: A systematic review of MEDLINE and Cochrane databases was conducted, following PRISMA guidelines. Extracted data were recorded on a standardized form. Methodological index for non-randomized studies (MINORS) and Newcastle-Ottawa Scale (NOS) were used to assess study quality and risk bias. Because of study heterogeneity and low levels of evidence, meta-analysis was not possible. Pooled weighted means were calculated and individual study evaluation and comparisons (qualitative analysis) were performed for systematic review. RESULTS: Of 2097 studies identified, 26 met criteria for systematic review. Pooled weighted means revealed 11.4% versus 15% recurrent instability with 3 or more suture anchors versus fewer than 3 anchors, 10.1% versus 7.8% with absorbable versus nonabsorbable suture anchors, respectively, and 8.0% versus 9.4% with knotless versus standard anchors, respectively. Interval closure did not qualitatively decrease recurrent instability or decrease range of motion. CONCLUSIONS: Our systematic review reveals that despite individual study, and previous systematic reviews pointing to the contrary, the composite contemporary published literature would support no difference in the risk of recurrent instability after arthroscopic Bankart reconstruction with rotator interval closure, differing numbers of anchors used for the repair, use of knotless versus standard anchors, or use of bioabsorbable versus nonabsorbable anchors. We recommend surgeons focus on factors that have been shown to modify the risk factors after arthroscopic Bankart reconstruction, such as patient selection. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies. PMID- 28866343 TI - Clinical Outcome of Arthroscopic Treatment for Posteromedial Elbow Impingement in Adolescent Baseball Players. AB - PURPOSE: To evaluate the clinical outcomes of arthroscopic treatment in adolescent baseball players with posteromedial elbow impingement. METHODS: This retrospective study evaluated the clinical outcome of arthroscopic treatment for posteromedial elbow impingement in adolescent baseball players. Patients were eligible for participation if they had undergone surgery at least 2 years earlier and excluded if they had arthritis, loose bodies, osteochondritis dissecans, ulnar collateral ligament tear, flexor/pronator injuries or medial epicondylitis, or nerve problems. Patients were also excluded if they had undergone prior elbow surgery, were younger than 13 years, or were older than 19 years. Arthroscopic treatment included debridement of posteromedial synovitis, fragment removal, and olecranon spur excision. At a mean follow-up of 26.7 (range 24-42) months, patients were evaluated based on a questionnaire, examination, and the previously reported elbow outcome score. RESULTS: This retrospective study involved 15 male patients, comprising 6 pitchers, 3 catchers, and 6 fielders, of mean age 15.7 (range 14-17) years. Mean time from onset of symptoms to surgery was 4.9 (range 3 18) months. Intraoperative findings included posteromedial synovitis and olecranon spurs in all patients and fragments in 10. The elbow outcome score was considered excellent in 11 patients and good in 2, with a mean score of 92 points (maximum 100 points). The mean postoperative range of motion at the elbow was 5 degrees to 139.7 degrees of flexion. All patients were able to return to their previous level of play after an average of 3.4 (range 2.5-4.5) months. No patient developed medial instability that later required reconstructive surgery. CONCLUSIONS: Arthroscopic debridement, excision of the olecranon spur, and removal of fragments yield reliable subjective and objective results and allow a return to baseball in adolescent patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28866344 TI - Clinical Outcomes in Revision Anterior Cruciate Ligament Reconstruction: A Meta analysis. AB - PURPOSE: The purpose of this meta-analysis was to determine overall objective graft failure rate, failure rate by graft type (allograft vs autograft reconstruction), instrumented laxity, and patient outcome scores following revision anterior cruciate ligament (ACL) reconstruction. Outcomes of interest were collected for all studies meeting the study inclusion criteria, but lower level studies (level III/IV) were not pooled for quantitative synthesis due to high levels of heterogeneity in these study populations. METHODS: A comprehensive search strategy was performed to identify studies reporting outcomes of revision ACL reconstruction. The primary outcome reported was graft failure. A meta analysis comparing rate of failure by graft type was conducted using a random effects model. Studies also reported patient clinical outcome scores, including International Knee Documentation Committee (IKDC), Lysholm, and knee injury and osteoarthritis outcome scores (KOOS) and graft laxity. RESULTS: Eight studies with 3,021 patients (56% male, 44% female) with an average age of 30 +/- 4 years and mean follow-up time of 57 months were included. The overall objective failure rate was 6% (95% confidence interval [CI], 1.8%-12.3%). Mean instrumented laxity as side-to-side difference was 2.5 mm (95% CI, 1.9-3.1 mm). Mean IKDC subjective score was 76.99 (95% CI, 76.64-77.34), mean KOOS symptoms score was 76.73 (95% CI, 75.85-77.61), and mean Lysholm score was 86.18 (95% CI, 79.08-93.28). The proportion of patients with IKDC grade A or B was 85% (95% CI, 77%-91%). When the available data for failure rate were analyzed by graft type, autograft reconstruction had a failure rate of 4.1% (95% CI, 2.0%-6.9%), similar to allograft reconstruction at 3.6% (95% CI, 1.4%-6.7%). CONCLUSIONS: In this meta analysis, revision ACL reconstruction had failure rates similar to autograft or allograft reconstruction. Overall outcome scores for revision reconstruction have improved but appear modest when compared with primary ACL reconstruction surgery. LEVEL OF EVIDENCE: Meta-analysis of Level II studies, Level II. PMID- 28866345 TI - Should the Capsule Be Repaired or Plicated After Hip Arthroscopy for Labral Tears Associated With Femoroacetabular Impingement or Instability? A Systematic Review. AB - PURPOSE: To critically evaluate the existing literature on hip capsule biomechanics, clinical evidence of instability, and outcomes of capsular management to answer the following question: Should the capsule be repaired or plicated after hip arthroscopy for labral tears associated with femoroacetabular impingement or instability? METHODS: We used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines to find articles using PubMed and Embase. Included studies were Level I through V studies and focused on hip capsule biomechanics, postarthroscopic instability, and clinical outcomes. Articles were excluded if they discussed treatment of the hip capsule during arthroplasty, dislocations without a history of arthroscopy, and pre-existing conditions. The Methodological Index for Non-randomized Studies (MINORS) was used for quality assessment of clinical outcome studies. RESULTS: A total of 34 articles were included: 15 biomechanical studies, 9 instability case reports, and 10 outcome studies. There is consensus from biomechanical studies that the capsule is an important stabilizer of the hip and repairing it provides better stability than when unrepaired. Case reports of instability have raised concerns about capsular management during the index procedure to decrease the complications associated with this problem. Furthermore, outcome studies suggest that there may be an advantage of capsular closure versus capsulotomy during hip arthroscopy for nonarthritic patients. CONCLUSIONS: Short-term outcome studies suggest that capsular closure is safe and effective in nonarthritic patients undergoing hip arthroscopic procedures and may yield superior outcomes compared with unrepaired capsulotomy. Moreover, biomechanical evidence strongly supports the role of capsular repair in maintaining stability of the hip. In patients with stiffness or inflammatory hip disorders, a release may be appropriate. In patients who have signs and symptoms of instability, there is existing evidence that capsular plication may be associated with significant improvement in patient reported outcomes. Although the multiple procedures performed in combination with capsular treatment present confounding variables, current evidence appears to support routine capsular closure in most cases and to support capsular plication in cases of instability or borderline dysplasia. LEVEL OF EVIDENCE: Level IV, systematic review of Level II through IV studies. PMID- 28866346 TI - Surgical Management of Deep Gluteal Syndrome Causing Sciatic Nerve Entrapment: A Systematic Review. AB - PURPOSE: To assess the causes, surgical indications, patient-reported clinical outcomes, and complications in patients with deep gluteal syndrome causing sciatic nerve entrapment. METHODS: Three databases (PubMed, Ovid [MEDLINE], and Embase) were searched by 2 reviewers independently from database inception until September 7, 2016. The inclusion criteria were studies reporting on both arthroscopic and open surgery and those with Level I to IV evidence. Systematic reviews, conference abstracts, book chapters, and technical reports with no outcome data were excluded. The methodologic quality of the studies was assessed with the MINORS (Methodological Index for Non-randomized Studies) tool. RESULTS: The search identified 1,539 studies, of which 28 (481 patients; mean age, 48 years) were included for assessment. Of the studies, 24 were graded as Level IV, 3 as Level III, and 1 as Level II. The most commonly identified causes were iatrogenic (30%), piriformis syndrome (26%), trauma (15%), and non-piriformis (hamstring, obturator internus) muscle pathology (14%). The decision to pursue surgical management was made based on clinical findings and diagnostic investigations alone in 50% of studies, whereas surgical release was attempted only after failed conservative management in the other 50%. Outcomes were positive, with an improvement in pain at final follow-up (mean, 23 months) reported in all 28 studies. The incidence of complications from these procedures was low: Fewer than 1% and 8% of open surgical procedures and 0% and fewer than 1% of endoscopic procedures resulted in major (deep wound infection) and minor complications, respectively. CONCLUSIONS: Although most of the studies identified were case series and reports, the results consistently showed improvement in pain and a low incidence of complications, particularly for endoscopic procedures. These findings lend credence to surgical management as a viable option for buttock pain caused by deep gluteal syndrome and warrant further investigation. LEVEL OF EVIDENCE: Level IV, systematic review of Level II through IV studies. PMID- 28866347 TI - Wearable Inertial Sensors Allow for Quantitative Assessment of Shoulder and Elbow Kinematics in a Cadaveric Knee Arthroscopy Model. AB - PURPOSE: To develop a model using wearable inertial sensors to assess the performance of orthopaedic residents while performing a diagnostic knee arthroscopy. METHODS: Fourteen subjects performed a diagnostic arthroscopy on a cadaveric right knee. Participants were divided into novices (5 postgraduate year 3 residents), intermediates (5 postgraduate year 4 residents), and experts (4 faculty) based on experience. Arm movement data were collected by inertial measurement units (Opal sensors) by securing 2 sensors to each upper extremity (dorsal forearm and lateral arm) and 2 sensors to the trunk (sternum and lumbar spine). Kinematics of the elbow and shoulder joints were calculated from the inertial data by biomechanical modeling based on a sequence of links connected by joints. Range of motion required to complete the procedure was calculated for each group. Histograms were used to compare the distribution of joint positions for an expert, intermediate, and novice. RESULTS: For both the right and left upper extremities, skill level corresponded well with shoulder abduction adduction and elbow prono-supination. Novices required on average 17.2 degrees more motion in the right shoulder abduction-adduction plane than experts to complete the diagnostic arthroscopy (P = .03). For right elbow prono-supination (probe hand), novices required on average 23.7 degrees more motion than experts to complete the procedure (P = .03). Histogram data showed novices had markedly more variability in shoulder abduction-adduction and elbow prono-supination compared with the other groups. CONCLUSIONS: Our data show wearable inertial sensors can measure joint kinematics during diagnostic knee arthroscopy. Range-of motion data in the shoulder and elbow correlated inversely with arthroscopic experience. Motion pattern-based analysis shows promise as a metric of resident skill acquisition and development in arthroscopy. CLINICAL RELEVANCE: Wearable inertial sensors show promise as metrics of arthroscopic skill acquisition among residents. PMID- 28866348 TI - The Effect of Intra-articular Cocktail Versus Femoral Nerve Block for Patients Undergoing Hip Arthroscopy. AB - PURPOSE: To compare clinical efficacy and complication rate as measured by postoperative falls and development of peripheral neuritis between intra articular blockade and femoral nerve block in patients undergoing arthroscopic hip surgery. METHODS: An institutional review board approved retrospective review was conducted on a consecutive series of patients who underwent elective arthroscopic hip surgery by a single surgeon, between November 2013 and April 2015. Subjects were stratified into 2 groups: patients who received a preoperative femoral nerve block for perioperative pain control, and patients who received an intra-articular "cocktail" injection postoperatively. Demographic data, perioperative pain scores, narcotic consumption, incidence of falls, and iatrogenic peripheral neuritis were collected for analysis. Postoperative data were then collected at routine clinical visits. RESULTS: A total of 193 patients were included in this study (65 males, 125 females). Of them, 105 patients received preoperative femoral nerve blocks and 88 patients received an intraoperative intra-articular "cocktail." There were no significant differences in patient demographics, history of chronic pain (P = .35), worker's compensation (P = .24), preoperative pain scores (P = .69), or intraoperative doses of narcotics (P = .40). Patients who received preoperative femoral nerve blocks reported decreased pain during their time in PACU (P = .0001) and on hospital discharge (P = .28); however, there were no statistically significant differences in patient-reported pain scores at postoperative weeks 1 (P = .34), 3 (P = .64), and 6 (P = .70). Administration of an intra-articular block was associated with a significant reduction in the rate of postoperative falls (P = .009) and iatrogenic peripheral neuritis (P = .0001). CONCLUSIONS: Preoperative femoral nerve blocks are associated with decreased immediate postoperative pain, whereas intraoperative intra-articular anesthetic injections provide effective postoperative pain control in patients undergoing arthroscopic hip surgery and result in a significant reduction in the rate of postoperative falls and iatrogenic peripheral neuritis. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28866350 TI - Critical thinking evaluation in reflective writing: Development and testing of Carter Assessment of Critical Thinking in Midwifery (Reflection). AB - OBJECTIVE: develop and test a tool designed for use by academics to evaluate pre registration midwifery students' critical thinking skills in reflective writing. DESIGN: a descriptive cohort design was used. SAMPLE: a random sample (n = 100) of archived student reflective writings based on a clinical event or experience during 2014 and 2015. METHODS: a staged model for tool development was used to develop a fifteen item scale involving item generation; mapping of draft items to critical thinking concepts and expert review to test content validity; inter rater reliability testing; pilot testing of the tool on 100 reflective writings; and psychometric testing. Item scores were analysed for mean, range and standard deviation. Internal reliability, content and construct validity were assessed. FINDINGS: expert review of the tool revealed a high content validity index score of 0.98. Using two independent raters to establish inter-rater reliability, good absolute agreement of 72% was achieved with a Kappa coefficient K = 0.43 (p<0.0001). Construct validity via exploratory factor analysis revealed three factors: analyses context, reasoned inquiry, and self-evaluation. The mean total score for the tool was 50.48 (SD = 12.86). Total and subscale scores correlated significantly. The scale achieved good internal reliability with a Cronbach's alpha coefficient of .93. CONCLUSION: this study establishedthe reliability and validity of the CACTiM (reflection) for use by academics to evaluate midwifery students' critical thinking in reflective writing. Validation with large diverse samples is warranted. IMPLICATIONS FOR PRACTICE: reflective practice is a key learning and teaching strategy in undergraduate Bachelor of Midwifery programmes and essential for safe, competent practice. There is the potential to enhance critical thinking development by assessingreflective writing with the CACTiM (reflection) tool to provide formative and summative feedback to students and inform teaching strategies. PMID- 28866352 TI - Drug Use and Mortality in Parkinson Disease. PMID- 28866351 TI - Human T-cell leukemia virus type I Tax genotype analysis in Okinawa, the southernmost and remotest islands of Japan: Different distributions compared with mainland Japan and the potential value for the prognosis of aggressive adult T cell leukemia/lymphoma. AB - Okinawa, comprising remote islands off the mainland of Japan, is an endemic area of human T-cell leukemia virus type I (HTLV-1), the causative virus of adult T cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). We investigated the tax genotype of HTLV-1 among 29 HTLV-1 carriers, 74 ATL patients, and 33 HAM patients in Okinawa. The genotype distribution-60 (44%) taxA cases and 76 (56%) taxB cases-differed from that of a previous report from Kagoshima Prefecture in mainland Japan (taxA, 10%; taxB, 90%). A comparison of the clinical outcomes of 45 patients (taxA, 14; taxB, 31) with aggressive ATL revealed that the overall response and 1-year overall survival rates for taxA (50% and 35%, respectively) were lower than those for taxB (71% and 49%, respectively). In a multivariate analysis of two prognostic indices for aggressive ATL, Japan Clinical Oncology Group-Prognostic Index and Prognostic Index for acute and lymphoma ATL, with respect to age, performance status, corrected calcium, soluble interleukin-2 receptor, and tax genotype, the estimated hazard ratio of taxA compared with taxB was 2.68 (95% confidence interval, 0.87-8.25; P=0.086). Our results suggest that the tax genotype has clinical value as a prognostic factor for aggressive ATL. PMID- 28866349 TI - Individual differences in regional cortical volumes across the life span are associated with regional optical measures of arterial elasticity. AB - Aging is often accompanied by changes in brain anatomy and cerebrovascular health. However, the specific relationship between declines in regional cortical volumes and loss of cerebral arterial elasticity is less clear, as only global or very localized estimates of cerebrovascular health have been available. Here we employed a novel tomographic optical method (pulse-DOT) to derive local estimates of cerebral arterial elasticity and compared regional volumetric estimates (obtained with FreeSurfer) with optical arterial elasticity estimates from the same regions in 47 healthy adults (aged 18-75). Between-subject analyses revealed a global correlation between cortical volume and cortical arterial elasticity, which was a significant mediator of the association between age and cortical volume. Crucially, a novel within-subject analysis highlighted the spatial association between regional variability in cortical volumes and arterial elasticity in the same regions. This association strengthened with age. Gains in the predictability of cortical volumes from arterial elasticity data were obtained by sharpening the resolution up to individual cortical regions. These results indicate that some of the variance of sub-clinical age-related brain atrophy is associated with differences in the status of cerebral arteries, and can help explain the unique patterns of brain atrophy found within each individual. PMID- 28866354 TI - Beyond the Neuropsychiatric Horizon: Assessing the Risk of Sudden Unexpected Death in Parkinson Disease. PMID- 28866353 TI - FRAIL Questionnaire Screening Tool and Short-Term Outcomes in Geriatric Fracture Patients. AB - OBJECTIVES: There are limited screening tools to predict adverse postoperative outcomes for the geriatric surgical fracture population. Frailty is increasingly recognized as a risk assessment to capture complexity. The goal of this study was to use a short screening tool, the FRAIL scale, to categorize the level of frailty of older adults admitted with a fracture to determine the association of each frailty category with postoperative and 30-day outcomes. DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PARTICIPANTS: A total of 175 consecutive patients over age 70 years admitted to co-managed orthopedic trauma and geriatrics services. MEASUREMENTS: The FRAIL scale (short 5-question assessment of fatigue, resistance, aerobic capacity, illnesses, and loss of weight) classified the patients into 3 categories: robust (score = 0), prefrail (score = 1-2), and frail (score = 3-5). Postoperative outcome variables collected were postoperative complications, unplanned intensive care unit admission, length of stay (LOS), discharge disposition, and orthopedic follow-up after surgery. Thirty-day outcomes measured were 30-day readmission and 30-day mortality. Analysis of variance (1-way) and Kruskal-Wallis tests were used to compare continuous variables across the 3 FRAIL categories. Fisher exact tests were used to compare categorical variables. Multiple regression analysis, adjusted by age, sex, and Charlson index, was conducted to study the association between frailty category and outcomes. RESULTS: FRAIL scale categorized the patients into 3 groups: robust (n = 29), prefrail (n = 73), and frail (n = 73). There were statistically significant differences between groups in terms of age, comorbidity, dementia, functional dependency, polypharmacy, and rate of institutionalization, being higher in the frailest patients. Hip fracture was the most frequent fracture, and it was more frequent as the frailty of the patient increased (48%, 61%, and 75% in robust, prefrail, and frail groups, respectively). The American Society of Anesthesiologists preoperative risk significantly correlated with the frailty of the patient (American Society of Anesthesiologists score 3-4: 41%, 82% and 86%, in robust, prefrail, and frail groups, P < .001). After adjustment by age, sex, and comorbidity, there was a statistically significant association between frailty and both LOS and the development of any complication after surgery (LOS: 4.2, 5.0, and 7.1 days, P = .002; any complication: 3.4%, 26%, and 39.7%, P = .03; in robust, prefrail, and frail groups). There were also significant differences in discharge disposition (31% of robust vs 4.1% frail, P = .008) and follow-up completion (97% of robust vs 69% of the frail ones). Differences in time to surgery, unplanned intensive care unit admission, and 30-day readmission and mortality, although showing a trend, did not reach statistical significance. CONCLUSIONS: Frailty, measured by the FRAIL scale, was associated with increase LOS, complications after surgery, and discharge to rehabilitation facility in geriatric fracture patients. The FRAIL scale is a promising short screen to stratify and help operationalize the perioperative care of older surgical patients. PMID- 28866355 TI - Use of the Spanish Version of the Rapid Geriatric Assessment in Mexican Patients in Long-Term Care. AB - We report our experience with the use of a Spanish version of the rapid geriatric assessment of 30 patients in 2 long-term care institutions in Mexico City by a group of healthcare students without prior experience in geriatric medicine. The Spanish version of the rapid geriatric assessment is a very easy tool to administer that can provide overall good results for identifying frailty, sarcopenia, anorexia, weight loss, and cognitive impairment. PMID- 28866356 TI - Associations of Neuropsychiatric Symptoms and Antidepressant Prescription with Survival in Alzheimer's Disease. AB - OBJECTIVE: Depression is associated with increased mortality in community samples. The use of antidepressant medication may also increase mortality, however, it is still unclear whether taking antidepressants before or after a diagnosis of dementia influences survival. DESIGN: Retrospective. SETTING: A cohort with a diagnosis of Alzheimer disease (AD) from a large mental health and dementia care database in South London, linked to hospitalization and mortality data. PARTICIPANTS: Mild dementia (Mini-Mental State Examination >=18/30) at the point of diagnosis. MEASUREMENTS: We ascertained antidepressant prescription, either in the 6 months before or after dementia diagnosis, and used the HoNOS65+, a standard clinician-rated measure of patient well-being, to determine depression severity and other neuropsychiatric, physical health, and functional difficulties. We conducted a survival analysis, adjusted for potential confounders and addressed possible confounding by indication through adjusting for a propensity score. RESULTS: Of 5473 patients with AD, 22.8% were prescribed an antidepressant in a 1-year window around dementia diagnosis. Of these, 2415 (44.1%) died in the follow-up period [mean (standard deviation) 3.5 (2.4) years]. Prescription of an antidepressant, both before and after dementia diagnosis, was significantly associated with higher mortality after adjusting for a broad range of potential confounders including symptom severity, functional status, and physical illness (hazard ratio 1.22; 95% confidence interval 1.08-1.37 for prescription prior to dementia diagnosis; 95% confidence interval 1.04-1.45 for prescription post dementia diagnosis). In stratified analyses, risks remained significant in those without neuropsychiatric symptoms. CONCLUSIONS: The prescription of antidepressants around the time of dementia diagnosis may be a risk factor for mortality. PMID- 28866357 TI - Basis for Sarcopenia Screening With the SARC-CalF in Nursing Homes. AB - BACKGROUND: Sarcopenia is a major health problem of the older population. The European Working Group on Sarcopenia in Older People (EWGSOP) developed diagnostic criteria for diagnosis of sarcopenia that require assessing muscle mass and strength or physical performance. Recently, however, a rapid screening method SARC-CalF was developed. OBJECTIVE: The aim of the present study was to validate the SARC-CalF test using EWGSOP sarcopenia diagnostic criteria in a sample of nursing home residents. METHODS: Cross-sectional study. A sample of 80 nursing home residents [30% of men; mean age 84.3 (7.9) years]. Sarcopenia was determined as proposed by the EWGSOP diagnostic criteria, whereby muscle mass was measured by bioelectrical impedance, muscle strength by handgrip strength, and physical performance by usual gait speed and a Short Physical Performance Battery score. Sarcopenia was also assessed by the SARC-CalF screening test. RESULTS: A total of 38.7% of sarcopenia was evaluated using EWGSOP diagnostic criteria and 36.2% using the SARC-CalF test. The SARC-CalF demonstrated a sensitivity level of 77.4% and specificity of 89.8%. The area under the receiver operating characteristic curves of SARC-CalF test was 0.84 (95% confidence interval 0.74, 0.94). CONCLUSIONS: SARC-CalF could be a useful screening test for sarcopenia in nursing home residents. The incorporation of the test as a basis for sarcopenia screening will provide additional value to current nursing home preventive measures. PMID- 28866358 TI - LC-MS/MS based method development for the analysis of florfenicol and its application to estimate relative distribution in various tissues of broiler chicken. AB - Florfenicol, a broad spectrum bacteriostatic antibiotic belonging to amphenicol class, is widely used in poultry and livestock for the treatment of various infections. The major metabolite of florfenicol in different animal species is florfenicol amine which is exploited as the marker residue for the determination of florfenicol. Analysis of florfenicol merely by solvent extraction cannot determine the accurate amount of the drug present in incurred tissues (muscle, liver and kidney) of treated birds, as indicated by this study. Thus the methods solely based on solvent extraction may lead to false negative results. A reliable LC-MS/MS based confirmatory method for the analysis of florfenicol and its metabolites in chicken muscle was developed and validated according to the European Union Commission Decision 2002/657/EC. The method was based on acid hydrolysis to liberate non-extractable residues having presumably been covalently bound to tissues, and to convert all the florfenicol residues as well as its metabolites into florfenicol amine. The amine was subsequently recovered with ethyl acetate at pH 10.5, defatted and further cleaned up with dispersive solid phase extraction (dSPE). The LC separation was achieved on reverse phase C-18 column with isocratic elution using acetonitrile/water mobile phase and the analysis was performed on linear ion trap mass spectrometer. Calibration curve was obtained over a concentration range of 25-600MUg/kg for chicken muscles. The accuracy values ranged from 84 to 101.4% and the precision values for within day and between days ranged from 1.2-11.7%, respectively. Limit of detection (LOD), limit of quantification (LOD), CCalpha and CCbeta values were 0.98, 3.2, 113 and 126MUg/kg, respectively. The developed method was highly robust and was further applied to estimate the relative distribution of solvent-extractable against solvent-non-extractable florfenicol drug residues in muscle, liver and kidney samples of broiler chicken after 5days of oral dosing. PMID- 28866359 TI - Micro-matrix solid-phase dispersion coupled with MEEKC for quantitative analysis of lignans in Schisandrae Chinensis Fructus using molecular sieve TS-1 as a sorbent. AB - A simple and effective method was developed for determining lignans in Schisandrae Chinensis Fructus by using a micro-matrix solid phase dispersion (MSPD) technique coupled with microemulsion electrokinetic chromatography (MEEKC). Molecular sieve, TS-1, was applied as a solid supporting material in micro MSPD extraction for the first time. Parameters that affect extraction efficiency, such as type of dispersant, mass ratio of the sample to the dispersant, grinding time, elution solvent and volume were optimized. The optimal extraction conditions involve dispersing 25mg of powdered Schisandrae samples with 50mg of TS-1 by a mortar and pestle. A grinding time of 150s was adopted. The blend was then transferred to a solid-phase extraction cartridge and the target analytes were eluted with 500MUL of methanol. Moreover, several parameters affecting MEEKC separation were studied, including the type of oil, SDS concentration, type and concentration of cosurfactant, and concentration of organic modifier. A satisfactory linearity (R>0.9998) was obtained, and the calculated limits of quantitation were less than 2.77MUg/mL. Finally, the micro MSPD-MEEKC method was successfully applied to the analysis of lignans in complex Schisandrae fructus samples. PMID- 28866360 TI - Quantitative assessment of mandibular canal compression assessed by cone beam computed tomography. AB - OBJECTIVE: The aim of this study was to objectively quantify the topographic relation of the mandibular canals, impacted third molars, and cortical plates using cone beam computed tomography (CBCT). STUDY DESIGN: A retrospective chart review was conducted using the database of a university-based imaging service. Two calibrated reviewers examined the CBCT images of 100 cases scheduled for mandibular third molar removal. They characterized the position and condition of the mandibular canal and measured its dimensions at 3 different points relative to the third molars. RESULTS: The mandibular canal is more often located buccal to the third molars but is more likely to be compressed when in a lingual position. The vertical (cephalocaudal) dimensions of the mandibular canal change significantly as the canal progresses toward the ramus. The horizontal (buccolingual) dimensions of the mandibular canal fluctuate very little but significantly narrow in proximity to the third molars. Thinning of the lingual cortical plate is common, whereas grooving of molar roots is uncommon. CONCLUSIONS: Minor variations in the horizontal dimensions of the mandibular canal close to the third molars signify an effect on the canal. This effect may indicate an increased risk of neurovascular injury. The mandibular canal can have a direct or indirect effect on the cortical plates. PMID- 28866361 TI - Targeted next-generation sequencing of glandular odontogenic cyst: a preliminary study. AB - OBJECTIVE: Glandular odontogenic cyst (GOC) is an uncommon developmental cyst. Its molecular pathogenesis is unclear, and deep sequencing may help identify causative low-frequency variants in tumors. We investigated in GOC mutations in 50 genes commonly altered in human cancers. STUDY DESIGN: Targeted next generation sequencing was used to interrogate a panel of approximately 2800 mutations in GOC. RESULTS: Six missense single nucleotide variations (SNVs) were reported. Three SNVs (TP53 rs1042522, KDR rs1870377, and KIT rs3822214) are listed as "common single-nucleotide polymorphisms" at the UCSC Genome Browser. The other SNVs (PIK3CA p.Glu689Lys, PIK3CA p.Ala708Thr, and TP53 p.Leu289Phe) are predicted to have deleterious or damaging effects on proteins, but they showed very low frequency in our samples and could not be further validated by orthogonal methods. CONCLUSIONS: No pathogenic SNV was detected in this cohort of GOCs. Further studies with larger gene panels or whole exome sequencing are needed to find the genetic basis of GOC. PMID- 28866364 TI - Development of rapid and highly sensitive detection of Bean common mosaic necrosis virus in leguminous crops using loop-mediated isothermal amplification assay. AB - Bean common mosaic necrosis virus (BCMNV) is a plant pathogenic virus that can infect leguminous crops such as kidney beans, sunn hemp, red beans, and mung beans. BCMNV has not been reported in Korea and is classified as a quarantine plant virus. Currently, the standard diagnostic method for diagnosis of BCMNV is reverse transcription (RT)-nested PCR system. However a more rapid monitoring system is needed to enable the testing of more samples. The use of highly efficient loop-mediated isothermal amplification (LAMP) assay for its detection has not yet been reported, and development of LAMP for detecting BCMNV in this study. In addition, confirmation of LAMP amplification can be achieved using restriction enzyme Mse I (T/TAA). The developed technique could be used for more rapid, specific and sensitive monitoring of BCMNV in leguminous crops than conventional nested RT-PCR. PMID- 28866363 TI - Effects of apolipoprotein M in uremic atherosclerosis. AB - BACKGROUND AND AIMS: Chronic kidney disease is characterized by uremia and causes premature death, partly due to accelerated atherosclerosis. Apolipoprotein (apo) M is a plasma carrier protein for the lipid sphingosine-1-phosphate (S1P). The Apom-S1P complex associates with HDL, and may contribute to its anti atherosclerotic effects. The role of Apom/S1P in atherosclerosis is presently controversial and has not been explored in a uremic setting. We aimed to explore whether plasma concentrations of Apom/S1P are altered by uremia and whether Apom overexpression or deficiency affects classical and uremic atherosclerosis. METHODS: Mild to moderate uremia was induced by subtotal nephrectomy (NX) in 86 92 Apoe-deficient mice that were either Apom-wild type, Apom-deficient, or overexpressed Apom (~10 fold). The effects of uremia on plasma Apom/S1P and atherosclerosis were evaluated and compared to non-nephrectomized controls. RESULTS: Uremia increased plasma Apom by ~25%, but not S1P. Plasma S1P was elevated by ~300% in mice overexpressing Apom, and decreased by ~25% in Apom deficient mice. Apom overexpression augmented aortic root atherosclerosis and plasma cholesterol. In contrast, aortic arch atherosclerosis was unaffected by the Apom genotype. There was no effect of Apom-deficiency or Apom overexpression on uremic atherosclerosis. CONCLUSIONS: This study highlights the complexity of Apom/S1P in atherosclerosis and challenges the notion that the Apom/S1P complex is anti-atherogenic, at least in Apoe-deficient mice. PMID- 28866362 TI - Gene, cell, and organ multiplication drives inner ear evolution. AB - We review the development and evolution of the ear neurosensory cells, the aggregation of neurosensory cells into an otic placode, the evolution of novel neurosensory structures dedicated to hearing and the evolution of novel nuclei in the brain and their input dedicated to processing those novel auditory stimuli. The evolution of the apparently novel auditory system lies in duplication and diversification of cell fate transcription regulation that allows variation at the cellular level [transforming a single neurosensory cell into a sensory cell connected to its targets by a sensory neuron as well as diversifying hair cells], organ level [duplication of organ development followed by diversification and novel stimulus acquisition] and brain nuclear level [multiplication of transcription factors to regulate various neuron and neuron aggregate fate to transform the spinal cord into the unique hindbrain organization]. Tying cell fate changes driven by bHLH and other transcription factors into cell and organ changes is at the moment tentative as not all relevant factors are known and their gene regulatory network is only rudimentary understood. Future research can use the blueprint proposed here to provide both the deeper molecular evolutionary understanding as well as a more detailed appreciation of developmental networks. This understanding can reveal how an auditory system evolved through transformation of existing cell fate determining networks and thus how neurosensory evolution occurred through molecular changes affecting cell fate decision processes. Appreciating the evolutionary cascade of developmental program changes could allow identifying essential steps needed to restore cells and organs in the future. PMID- 28866365 TI - Store-operated calcium entry is dispensable for the activation of ERK1/2 pathway in prostate cancer cells. AB - STIM1, the endoplasmic reticulum Ca2+ sensor that modulates the activity of plasma membrane Ca2+ channels, becomes phosphorylated at ERK1/2 target sites during Ca2+ store depletion triggered by thapsigargin or epidermal growth factor (EGF). This ERK1/2-dependent phosphorylation regulates STIM1 localization and dissociation from microtubules, and it is known that enhances the binding to ORAI1, a store-operated Ca2+ entry (SOCE) channel, leading to the activation of this Ca2+ influx pathway. However, there remained some evidence of a role for SOCE in the activation of ERK1/2, and here we assessed the contribution of SOCE to ERK1/2 activation by generating a STIM1-deficient cell line by CRISPR/Cas9 genome editing of the STIM1 locus in prostate cancer PC3 cells. The genomic modification consisted of a 16 base-pair insertion in exon 5 of both alleles, therefore abrogating STIM1 synthesis. STIM1-KO cells did show a striking decrease in Ca2+ influx in response to thapsigargin or EGF, a result that demonstrates that SOCE mediates Ca2+ entry in PC3 cells during stimulation with EGF. Moreover, identical levels of total ERK1/2 were found in STIM1-KO cells and the parental cell line, and ERK1/2 activation was fully activated in KO cells, both in the presence and in the absence of extracellular Ca2+, a result that supports that STIM1 and SOCE are not required for ERK1/2 activation. This activation was sensitive to Src kinase inhibition, but not to CAMKII nor PKC inhibition, a result that sets STIM1 and SOCE as downstream targets of the axis Src-Raf-MEK ERK, rather than upstream regulators. PMID- 28866366 TI - Interleukin-8 in cancer pathogenesis, treatment and follow-up. AB - Interleukin-8 (CXCL8) was originally described asa chemokine whose main function is the attraction of a polymorphonuclear inflammatory leukocyte infiltrate acting on CXCR1/2. Recently, it has been found that tumors very frequently coopt the production of this chemokine, which in this malignant context exerts different pro-tumoral functions. Reportedly, these include angiogenesis, survival signaling for cancer stem cells and attraction of myeloid cells endowed with the ability to immunosuppress and locally provide growth factors. Given the fact that in cancer patients IL-8 is mainly produced by tumor cells themselves, its serum concentration has been shown to correlate with tumor burden. Thus, IL-8 serum concentrations have been shown to be useful asa pharmacodynamic biomarker to early detect response to immunotherapy. Finally, because of the roles that IL-8 plays in favoring tumor progression, several therapeutic strategies are being developed to interfere with its functions. Such interventions hold promise, especially for therapeutic combinations in the field of cancer immunotherapy. PMID- 28866367 TI - The FOP Connection Registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva. AB - The Fibrodysplasia Ossificans Progressiva (FOP) Connection Registry is an international, voluntary, observational study that directly captures demographic and disease information initially from patients with FOP (the patient portal) and in the near future from treating physicians (the physician portal) via a secure web-based tool. It was launched by the International FOP Association (IFOPA) with a guiding vision to develop and manage one unified, global, and coordinated Registry allowing the assembly of the most comprehensive data on FOP. This will ultimately facilitate greater access and sharing of patient data and enable better and faster development of therapies and tracking their long-term treatment effectiveness and safety. This report outlines the FOP Connection Registry's design and procedures for data collection and reporting, as well as the long-term sustainability of Registry. Patient-reported, aggregate data are summarized for the first 196 enrolled patients, representing participation from 42 countries and approximately 25% of the world's known FOP population. Fifty-seven percent of the current Registry participants are female with a mean age of 23.8years (median=21years, range=1, 76years). Among the Registry participants who provided their FOP type, 51% reported FOP Classic (R206H), 41% reported FOP Type Unknown, and 8% reported FOP Variant. Patients reported 5.4years (median=3.0years, range=0, 45.8years) as the mean age at which they noticed their first FOP symptoms and a mean age at final FOP diagnosis of 7.5years (median=5.0years, range=0.1, 48.4years). Information on the patients' diagnostic journeys in arriving at a correct diagnosis of FOP is also presented. These early patient reported data suggest that the IFOPA's vision of one, unified, global, and coordinated approach to the FOP Connection Registry is well underway to being realized. In addition, the positive response from the FOP patient community to the initial launch of the Registry's patient portal has created a solid foundation upon which to build the largest international registry for monitoring the clinical progression of FOP among patients. PMID- 28866369 TI - Interpreting quantitative urine buprenorphine and norbuprenorphine levels in office-based clinical practice. AB - BACKGROUND: Quantitative urine buprenorphine testing is used to monitor patients receiving buprenorphine for the treatment of opioid use disorder (OUD), however the interpretation of urine buprenorphine testing is complex. Currently, interpretation of quantitative buprenorphine testing is guided by data from drug assay development studies and forensic labs rather than clinical treatment cohorts. METHODS: In this retrospective study, we describe the patterns of urine buprenorphine and norbuprenorphine levels in patients prescribed sublingual buprenorphine for OUD in an office-based addiction treatment clinic. Urine buprenorphine and norbuprenorphine levels were analyzed in patients who reported having adulterated their urine, patients clinically suspected of adulterating their urine, and patients without concern for urine adulteration. Finally, we tested the accuracy of urine buprenorphine, norbuprenorphine, and norbuprenorphine: buprenorphine ratio (Norbup:Bup) to identify adulterated urine samples. RESULTS: Patients without suspicion for urine adulteration rarely provided specimens with buprenorphine >=1000ng/ml (4.4%), while the proportion provided by those who endorsed or were suspected of urine adulteration was higher (42.9%, 40.6%, respectively). Compared to patients without reported urine adulteration, specimens from patients who reported or were suspected of urine adulteration had significantly higher buprenorphine (p=0.0001) and lower norbuprenorphine (<0.0001) levels, and significantly lower Norbup:Bup ratios (p=0.04). Buprenorphine >=700ng/ml offered the best accuracy for discriminating between adulterated and non-adulterated specimens. CONCLUSION: This study describes the patterns of urine buprenorphine and norbuprenorphine levels from patients with OUD receiving buprenorphine treatment in an office-based addiction treatment clinic. Parameters for identifying urine adulterated by submerging buprenorphine medication in the urine specimen are discussed. PMID- 28866370 TI - Acute effects of direct inhibitory pressure over the biceps brachii myotendinous junction on skeletal muscle activation and force output. AB - Force (F) reduction is reported with myotendinous junction (MTJ) manipulation. Autogenic inhibition reflex (AIR) activation is supposed to be the main mechanism. Still, its role remains unclear. The study aimed at assessing the effects of MTJ direct inhibitory pressure (DIP) on neuromuscular activation and F in the elbow flexor (agonist) and extensor (antagonist) muscles. After maximum voluntary contraction (MVC) assessment, thirty-five participants randomly performed submaximal contractions at 20, 40, 60, and 80% MVC. Electromyographic (EMG), mechanomyographic (MMG), and F signals were recorded. Protocol was repeated under (i) DIP (10-s pressure on the biceps brachii MTJ) with the elbow at 120 degrees (DIP120), (ii) DIP with the elbow at 180 degrees (DIP180), and (iii) without DIP (Ctrl). Electromechanical delay (EMD) components, EMG and MMG root mean square (RMS), and rate of force development (RFD) were calculated. Independently from the angle, DIP induced decrements in MVC, RFD, and RMS of EMG and MMG signals and lengthened the EMD components in agonist muscles (P<0.05). The DIP-induced decrease in F output of the agonist muscles seems to be possibly due to a concomitant impairment of the neuromuscular activation and a transient decrease in stiffness. After DIP, the antagonist muscle displayed no changes; therefore, the intervention of AIR remains questionable. PMID- 28866368 TI - Overlapping functions of bone sialoprotein and pyrophosphate regulators in directing cementogenesis. AB - Although acellular cementum is essential for tooth attachment, factors directing its development and regeneration remain poorly understood. Inorganic pyrophosphate (PPi), a mineralization inhibitor, is a key regulator of cementum formation: tissue-nonspecific alkaline phosphatase (Alpl/TNAP) null mice (increased PPi) feature deficient cementum, while progressive ankylosis protein (Ank/ANK) null mice (decreased PPi) feature increased cementum. Bone sialoprotein (Bsp/BSP) and osteopontin (Spp1/OPN) are multifunctional extracellular matrix components of cementum proposed to have direct and indirect effects on cell activities and mineralization. Studies on dentoalveolar development of Bsp knockout (Bsp-/-) mice revealed severely reduced acellular cementum, however underlying mechanisms remain unclear. The similarity in defective cementum phenotypes between Bsp-/- mice and Alpl-/- mice (the latter featuring elevated PPi and OPN), prompted us to examine whether BSP is operating by modulating PPi associated genes. Genetic ablation of Bsp caused a 2-fold increase in circulating PPi, altered mRNA expression of Alpl, Spp1, and Ank, and increased OPN protein in the periodontia. Generation of a Bsp knock-out (KO) cementoblast cell line revealed significantly decreased mineralization capacity, 50% increased PPi in culture media, and increased Spp1 and Ank mRNA expression. While addition of 2MUg/ml recombinant BSP altered Spp1, Ank, and Enpp1 expression in cementoblasts, changes resulting from this dose were not dependent on the integrin-binding RGD motif or MAPK/ERK signaling pathway. Decreasing PPi by genetic ablation of Ank on the Bsp-/- mouse background reestablished cementum formation, allowing >3-fold increased acellular cementum volume compared to wild-type (WT). However, deleting Ank did not fully compensate for the absence of BSP. Bsp-/-; Ank-/- double deficient mice exhibited mean 20-27% reduced cementum thickness and volume compared to Ank-/- mice. From these data, we conclude that the perturbations in PPi metabolism are not solely driving the cementum pathology in Bsp-/- mice, and that PPi is more potent than BSP as a cementum regulator, as shown by the ability to override loss of BSP by lowering PPi. We propose that BSP and PPi work in concert to direct mineralization in cementum and likely other mineralized tissues. PMID- 28866371 TI - No longer any role for routine follow-up chest x-rays in men with stage I germ cell cancer. AB - Following radical orchidectomy for testicular cancer, most patients undergo protocolled surveillance to detect tumour recurrences rather than receive adjuvant chemotherapy. Current United Kingdom national and most international guidelines recommend that patients require a chest x-ray (CXR) and serum tumour markers at each follow-up visit as well as regular CT scans; there is however, variation among cancer centres with follow-up protocols. Seminomas often do not cause tumour marker elevation; therefore, CT scans are the main diagnostic tool for detecting relapse. For non-seminomatous tumours, serum beta-HCG (HCG) and AFP levels are a very sensitive harbinger of relapse, but this only occurs in 50% of patients [1], and therefore, imaging remains as important. CXRs are meant to aid in the detection of lung recurrences and before the introduction of modern cross sectional imaging in the early 1980s, CXRs would have been the only method of identifying lung metastasis. We examined the Thames Valley and Mount Vernon Cancer Centre databases to evaluate the role of CXRs in the 21st century for the follow-up of men with stage I testicular cancer between 2003 and 2015 to assess its value in diagnosing relapsed germ cell tumours. From a total of 1447 patients, we identified 159 relapses. All relapses were detected either by rising tumour markers or planned follow-up CT scans. Not a single relapse was identified on CXR. We conclude that with timely and appropriate modern cross-sectional imaging and tumour marker assays, the CXR no longer has any value in the routine surveillance of stage I testicular cancer and should be removed from follow-up guidelines and clinical practice. Omitting routine CXR from follow-up schedules will reduce anxiety as well as time that patients spend at hospitals and result in significant cost savings. PMID- 28866372 TI - Sutureless enterostomy for extremely low birth weight infants. AB - OBJECTIVE: In recent years, improved survival rates of extremely low birth weight infants (ELBWIs) have led to an increasing number of enterostomy performed for those with meconium obstruction of prematurity (MOP)1,2, spontaneous intestinal perforation (SIP)3,4. To prevent serious stoma-related complications such as stoma side perforation, prolapse, fall and surgical site infection, we introduce our new "sutureless enterostomy" technique. METHODS: We present the procedures in detail. We reviewed the medical records of twelve patients who underwent "sutureless enterostomy" in our neonatal intensive care unit from 2007 to 2013. Patient attributes, surgery-related items, stoma-related complications and outcomes were investigated. RESULTS: Mean birth weight was 671+/-158g (mean+/ S.D.). Six cases of MOP, three cases of SIP and three cases of NEC were diagnosed. Mean operative time was 75+/-35min (mean+/-S.D.) None of them presented any of early stoma-related complications (necrosis, fall, and surgical site infection). However the parastomal hernia occurred in one patient as late complication. Three deaths occurred postoperatively as a result of exacerbations of their conditions. CONCLUSIONS: Based on our preliminary observations, our new "sutureless enterostomy" was done safely and reduced the risk of stoma-related complications. It may be an ideal procedure for the ELBWI with MOP or SIP. PMID- 28866373 TI - ROS activates autophagy in follicular granulosa cells via mTOR pathway to regulate broodiness in goose. AB - Broodiness causes reduced reproductive ability in poultry, but its regulatory mechanism remains poorly understood. ROS (reactive oxygen species) and autophagy are important for follicular development, and the interaction between the two may play a role in regulating broodiness. We examined goose follicles for ROS and oxidation scavenger activities during the egg-laying and broody stages. The follicular granulosa cells were exposed to media containing H2O2, and the interactions between ROS and autophagy in follicular granulosa cells in vitro were analyzed using a Western blot method. We found that the activities of superoxide dismutase (SOD) and lactate dehydrogenase (LDH) were enhanced and the amount of malondialdehyde (MDA) decreased in broody goose follicles. H2O2 inhibited the cell viability and induced autophagy. Furthermore, it was also found that H2O2 regulated autophagy by reducing mTOR and increasing p53; however, H2O2 had no impact on Beclin1 or ATG12. It was also shown that the enhanced autophagy lessened ROS-induced damages. We conclude that ROS and autophagy both played important roles in regulating follicular development to control broodiness in geese, and ROS activated autophagy in follicular granulosa cells via the mTOR pathway. PMID- 28866374 TI - 1-Phenyl-1H-indole derivatives as a new class of Bcl-2/Mcl-1 dual inhibitors: Design, synthesis, and preliminary biological evaluation. AB - Bcl-2 proteins, such as B-cell lymphoma (Bcl-2) protein, myeloid cell leukemia sequence 1 (Mcl-1) protein, has been implicated in the progression and survival of multiple tumor types and become a validated and attractive target for cancer therapy. In this work, a series of 1-phenyl-1H-indole derivatives has been designed and synthesized. The preliminary biological studies (binding assay for Bcl-2 proteins and MTT assay) suggested that some active compounds showed potent inhibitory activities on Bcl-2/Mcl-1 without binding on Bcl-XL. Furthermore, Compound 9c and 9h showed better anti-proliferative activity than WL-276. PMID- 28866375 TI - Design and optimization of N-acylhydrazone pyrimidine derivatives as E. coli PDHc E1 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study. AB - By targeting the thiamin diphosphate (ThDP) binding site of Escherichia coli (E. coli) pyruvate dehydrogenase multienzyme complex E1 (PDHc E1), a series of novel 'open-chain' classes of ThDP analogs A, B, and C with N-acylhydrazone moieties was designed and synthesized to explore their activities against E. coli PHDc E1 in vitro and their inhibitory activity against microbial diseases were further evaluated in vivo. As a result, A1-23 exhibited moderate to potent inhibitory activities against E. coli PDHc E1 (IC50=0.15-23.55MUM). The potent inhibitors A13, A14, A15, C2, had strong inhibitory activities with IC50 values of 0.60, 0.15, 0.39 and 0.34MUM against E. coli PDHc E1 and with good enzyme-selective inhibition between microorganisms and mammals. Especially, the most powerful inhibitor A14 could 99.37% control Xanthimonas oryzae pv. Oryzae. Furthermore, the binding features of compound A14 within E. coli PDHc E1 were investigated to provide useful insights for the further construction of new inhibitor by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that A14 had most powerful inhibition against E. coli PDHc E1 due to the establishment of stronger interaction with Glu571, Met194, Glu522, Leu264 and Phe602 at active site of E.coli PDHc E1. It could be used as a lead compound for further optimization, and may have potential as a new microbicide. PMID- 28866377 TI - A prospective study of short-term functional outcome after dysvascular major lower limb amputation. AB - : This study investigates functional status on Day 21 after dysvascular major lower limb amputation compared with one month pre-amputation and evaluates factors potentially influencing outcome. METHODS: A prospective cohort study design was used. Data were collected via in-person interviews using structured instruments and covered functional level (Barthel index 100) one month pre amputation and on Day 21. Out of a consecutive sample of patients having major lower limb amputation (tibia, knee or femoral) (n = 105), 51 participated on Day 21 follow-up. Clinical, demographic, body function and environmental data were analysed as factors potentially influencing outcome. RESULTS: From pre-amputation to Day 21, participants' functional level decreased significantly in all ten activities of daily living activities as measured by the Barthel Index. Almost 60% of participants were independent in bed-chair transfer on Day 21. Being independent in transfer on Day 21 was positively associated with younger age and attending physiotherapy after discharge. CONCLUSIONS: The findings indicate that short-term functional outcome is modifiable by quality of the postoperative care provided and thus highlights the need for increased focus on postoperative care to maintain basic function as well as establish and provide everyday rehabilitation in the general population of patients who have dysvascular lower limb amputations. PMID- 28866376 TI - Synthesis of amide isosteres of schweinfurthin-based stilbenes. AB - The schweinfurthins are plant-derived stilbenes with an intriguing profile of anti-cancer activity. To obtain analogues of the schweinfurthins that might preserve the biological activity but have greater water solubility, a formal replacement of the central olefin with an amide has been explored. Two pairs of amides have been prepared, each containing the same hexahydroxanthene "left half" joined through an amide linkage to two different "right halves." In each series, the amide has been inserted in both possible orientations, placing the carbonyl group on the tricyclic ABC ring system and the amine on the D-ring, or placing the amine on the hexahydroxanthene and the carbonyl group on the D-ring. The four new schweinfurthin analogues have been tested in the NCI 60 cell line screen, and in both cases the more active isomer carried the carbonyl group on the C-ring. PMID- 28866378 TI - Association of impaired renal function with venous thrombosis: A genetic risk score approach. AB - OBJECTIVE: The association between impaired kidney function and venous thrombosis has been previously reported but supportive data are still sparse. We here wish to strengthen this association by investigating, by use of a genetic risk score approach, whether single nucleotide polymorphisms (SNPs) known to decrease the estimated glomerular filtration rate (eGFR), a surrogate marker for renal dysfunction, are associated with increased risk of venous thrombosis. APPROACH AND RESULTS: Fifty-one polymorphisms selected from the literature to robustly associate with eGFR were first tested for association with venous thrombosis in a French case-control collection of 1953 patients and 2338 healthy individuals. This led to the identification of a genetic risk score based on 9 polymorphisms that strongly associated with increased risk (odds ratio (OR)=1.09 [1.06-1.15], p=1.44.10-7). This genetic score association replicated (OR=1.18 [1.11-1.26], p=8.86.10-8) in an independent sample of 1289 patients and 1049 healthy controls part of the Dutch MEGA study. We then categorized the genetic score distribution observed in the combined samples into quintiles. Compared with the lowest quintile, the OR for increased risk of disease associated with the second, third, fourth and fifth quintiles were 1.13 [0.94-1.16], 1.47 [1.22-1.77], 1.52 [1.26 1.82] and 1.70 [1.41-2.05], respectively. CONCLUSIONS: Using a genetic risk score analysis, our study provides new elements supporting the association between impaired renal function and the risk of venous thrombosis. PMID- 28866379 TI - Compounding variants rescue the effect of a deleterious ADAMTS13 mutation in a child with severe congenital heart disease. PMID- 28866380 TI - Mitochondrial transition ROS spike (mTRS) results from coordinated activities of complex I and nicotinamide nucleotide transhydrogenase. AB - Mitochondria exhibit suppressed ATP production, membrane potential (?Psimt) polarization and reactive oxygen species (ROS) bursts during some cellular metabolic transitions. Although mitochondrial ROS release is influenced by ?Psimt and respiratory state, the relationship between these properties remains controversial primarily because they have not been measured simultaneously. We developed a multiparametric method for probing mitochondrial function that allowed precise characterization of the temporal relationship between ROS, ?Psimt and respiration. We uncovered a previously unknown spontaneous ROS spike - termed mitochondrial transition ROS spike (mTRS) - associated with re-polarization of ?Psimt that occurs at the transition between mitochondrial energy states. Pharmacological inhibition of complex CI (CI), nicotinamide nucleotide transhydrogenase (NNT) and antioxidant system significantly decreased the ability of mitochondria to exhibit mTRS. NADH levels followed a similar trend to that of ROS during the mTRS, providing a link between CI and NNT in mTRS regulation. We show that (i) mTRS is enhanced by simultaneous activation of CI and complex II (CII); (ii) CI is the principal origin of mTRS; (iii) NNT regulates mTRS via NADH and ?Psimt-dependent mechanisms; (iv) mTRS is not a pH spike; and (v), mTRS changes in amplitude under stress conditions and its occurrence can be a signature of mitochondrial health. Collectively, we uncovered and characterized the biophysical properties and mechanisms of mTRS, and propose it as a potential diagnostic tool for CI-related dysfunctions, and as a biomarker of mitochondrial functional integrity. PMID- 28866381 TI - Cytochrome c oxidase inhibition by calcium at physiological ionic composition of the medium: Implications for physiological significance of the effect. AB - Cytochrome c oxidase (CcO) from mammalian mitochondria binds Ca2+ and Na+ in a special cation binding site. Binding of Ca2+ brings about partial inhibition of the enzyme while Na+ competes with Ca2+ for the binding site and protects the enzyme from the inhibition [Vygodina, T., Kirichenko, A. and Konstantinov, A.A. (2013). Direct Regulation of Cytochrome c oxidase by Calcium Ions. PLoS One 8(9): e74436]. In the original studies, the inhibition was found to depend significantly on the ionic composition of the buffer. Here we describe inhibition of CcO by Ca2+ in media containing the main ionic components of cytoplasm (150mM KCl, 12mM NaCl and 1mM MgCl2). Under these conditions, Ca2+ inhibits CcO with effective Ki of 20-26MUM, that is an order of magnitude higher than determined earlier in the absence of Na+. At physiological value of ionic strength, the inhibition can be observed at any turnover number of CcO, rather than only at low TN (<10s-1) as found previously. The inhibition requires partially oxidized state of cytochrome c and is favored by high ionic strength with a sharp transition at 0.1-0.2M. The high Ki=20-26MUM found for CcO inhibition by calcium matches closely the known value of "Km" for Ca2+-induced activation of the mitochondrial calcium uniporter. The inhibition of CcO by Ca2+ is proposed to modulate mitochondrial Ca2+-uptake via the mitochondrial calcium uniporter, promote permeability transition pore opening and induce reduction of Mia40 in the mitochondrial intermembrane space. PMID- 28866382 TI - Robustness of intra urban land-use regression models for ultrafine particles and black carbon based on mobile monitoring. AB - Land-use regression (LUR) models for ultrafine particles (UFP) and Black Carbon (BC) in urban areas have been developed using short-term stationary monitoring or mobile platforms in order to capture the high variability of these pollutants. However, little is known about the comparability of predictions of mobile and short-term stationary models and especially the validity of these models for assessing residential exposures and the robustness of model predictions developed in different campaigns. We used an electric car to collect mobile measurements (n = 5236 unique road segments) and short-term stationary measurements (3 * 30min, n = 240) of UFP and BC in three Dutch cities (Amsterdam, Utrecht, Maastricht) in 2014-2015. Predictions of LUR models based on mobile measurements were compared to (i) measured concentrations at the short-term stationary sites, (ii) LUR model predictions based on short-term stationary measurements at 1500 random addresses in the three cities, (iii) externally obtained home outdoor measurements (3 * 24h samples; n = 42) and (iv) predictions of a LUR model developed based upon a 2013 mobile campaign in two cities (Amsterdam, Rotterdam). Despite the poor model R2 of 15%, the ability of mobile UFP models to predict measurements with longer averaging time increased substantially from 36% for short-term stationary measurements to 57% for home outdoor measurements. In contrast, the mobile BC model only predicted 14% of the variation in the short-term stationary sites and also 14% of the home outdoor sites. Models based upon mobile and short-term stationary monitoring provided fairly high correlated predictions of UFP concentrations at 1500 randomly selected addresses in the three Dutch cities (R2 = 0.64). We found higher UFP predictions (of about 30%) based on mobile models opposed to short-term model predictions and home outdoor measurements with no clear geospatial patterns. The mobile model for UFP was stable over different settings as the model predicted concentration levels highly correlated to predictions made by a previously developed LUR model with another spatial extent and in a different year at the 1500 random addresses (R2 = 0.80). In conclusion, mobile monitoring provided robust LUR models for UFP, valid to use in epidemiological studies. PMID- 28866383 TI - Renal glucose metabolism in normal physiological conditions and in diabetes. AB - The kidney plays an important role in glucose homeostasis via gluconeogenesis, glucose utilization, and glucose reabsorption from the renal glomerular filtrate. After an overnight fast, 20-25% of glucose released into the circulation originates from the kidneys through gluconeogenesis. In this post-absorptive state, the kidneys utilize about 10% of all glucose utilized by the body. After glucose ingestion, renal gluconeogenesis increases and accounts for approximately 60% of endogenous glucose release in the postprandial period. Each day, the kidneys filter approximately 180g of glucose and virtually all of this is reabsorbed into the circulation. Hormones (most importantly insulin and catecholamines), substrates, enzymes, and glucose transporters are some of the various factors influencing the kidney's role. Patients with type 2 diabetes have an increased renal glucose uptake and release in the fasting and the post prandial states. Additionally, glucosuria in these patients does not occur at plasma glucose levels that would normally produce glucosuria in healthy individuals. The major abnormality of renal glucose metabolism in type 1 diabetes appears to be impaired renal glucose release during hypoglycemia. PMID- 28866384 TI - Intestinal microbiota in infants at high risk for allergy: Effects of prebiotics and role in eczema development. AB - BACKGROUND: Development of the gut microbiota in infancy is important in maturation of the immune system. Deviations in colonization patterns have been associated with allergic manifestations such as eczema, but exact microbiome dysfunctions underlying allergies remain unclear. We studied the gut microbiota of 138 infants at increased risk of allergy, participating in a clinical trial investigating the effectiveness of a partially hydrolyzed protein formula supplemented with nondigestible oligosaccharides on the prevention of eczema. OBJECTIVE: The effects of interventions and breast-feeding on fecal microbiota were investigated. Additionally, we aimed to identify microbial patterns associated with the onset of eczema. METHODS: Bacterial taxonomic compositions in the first 26 weeks of life were analyzed by using 16S rRNA gene sequencing. Additionally, fecal pH and microbial metabolite levels were measured. RESULTS: Fecal microbial composition, metabolites, and pH of infants receiving partially hydrolyzed protein formula supplemented with nondigestible oligosaccharides was closer to that of breast-fed infants than that of infants receiving standard cow's milk formula. Infants with eczema by 18 months showed discordant development of bacterial genera of Enterobacteriaceae and Parabacteroides species in the first 26 weeks, as well as decreased acquisition of lactate-utilizing bacteria producing butyrate, namely Eubacterium and Anaerostipes species, supported by increased lactate and decreased butyrate levels. CONCLUSIONS: We showed that a partially hydrolyzed protein infant formula with specific prebiotics modulated the gut microbiota closer to that of breast-fed infants. Additionally, we identified a potential link between microbial activity and onset of eczema, which might reflect a suboptimal implementation of gut microbiota at specific developmental stages in infants at high risk for allergy. PMID- 28866385 TI - T-cell receptor sequencing reveals decreased diversity 18 years after early thymectomy. PMID- 28866386 TI - Effects of orally self-administered bath salt constituent 3,4 methylenedioxypyrovalerone (MDPV) in mice. AB - Synthetic cathinones in bath salts products are psychostimulant drugs of abuse, and 3,4-methylenedioxypyrovalerone (MDPV) is a common constituent of these products. Oral MDPV has been show to stimulate locomotor activity but reinforcing, locomotor and appetitive stimulus effects of oral MDPV are unknown. Choice procedures evaluated preference for 0.03, 0.10, 0.30, and 1.00mg/mL MDPV solutions versus 0.10mg/mL quinine solution or water. To verify that oral MDPV produced pharmacological effects, locomotor activity was monitored during and after consumption of water, quinine, or MDPV solutions. Conditioned place preference (CPP) tested the apparent appetitive effects of a preferred concentration of oral MDPV with locomotor stimulant effects (0.30mg/mL), using water as a control, and compared with results from intraperitoneally-administered MDPV. Consumption of MDPV solutions (0.03-1.00mg/mL) was low when the alternative fluid was water, but a history of MDPV consumption increased MDPV choice. When paired with a quinine control solution, MDPV solutions (0.03-0.30mg/mL) were almost exclusively preferred, and treatment with the catecholamine synthesis inhibitor alphaMPT decreased MDPV choice. Consumption of MDPV concentrations (0.1 1.0mg/mL) stimulated locomotor activity. Chronic (10day) access to 0.30mg/mL MDPV resulted in escalated consumption, but locomotor effects did not systematically change across the access period. Finally, consumption of 0.30mg/mL MDPV elicited CPP with a magnitude similar to the preference observed following intraperitoneal administration of MDPV. Consistent with human abuse patterns, oral MDPV has reinforcing effects in the mouse which are most likely related to its psychostimulant-like pharmacological profile. PMID- 28866387 TI - Static and dynamic liver stiffness: An ex vivo porcine liver study using MR elastography. AB - Magnetic resonance elastography (MRE) is an MRI-based noninvasive technique for quantitatively assessing tissue stiffness. The hypothesis of this study is that stiffness increases with portal pressure. We further hypothesized that the rate of stiffness change with pressure would be larger in liver tissue treated to simulate the stiffening effects of fibrosis. In agreement with our hypothesis, the formalin-treated livers were stiffer than the untreated livers, and in both groups the liver stiffness increased with portal venous pressure. The rate of stiffness change with portal pressure was significantly greater after formalin treatment. In this study, we have developed an ex vivo liver model incorporating portal venous pressure variations and observed significant changes in liver stiffness due to portal pressure. This model could be useful for understanding and investigating the changes in the static and dynamic components of liver stiffness. PMID- 28866388 TI - Structural properties of the intrinsically disordered, multiple calcium ion binding otolith matrix macromolecule-64 (OMM-64). AB - Fish otoliths are calcium carbonate biominerals that are involved in hearing and balance sensing. An organic matrix plays a crucial role in their formation. Otolith matrix macromolecule-64 (OMM-64) is a highly acidic, calcium-binding protein (CBP) found in rainbow trout otoliths. It is a component of high molecular-weight aggregates, which influence the size, shape and polymorph of calcium carbonate in vitro. In this study, a protocol for the efficient expression and purification of OMM-64 was developed. For the first time, the complete structural characteristics of OMM-64 were described. Various biophysical methods were combined to show that OMM-64 occurs as an intrinsically disordered monomer. Under denaturing conditions (pH, temperature) OMM-64 exhibits folding propensity. It was determined that OMM-64 binds approximately 61 calcium ions with millimolar affinity. The folding-unfolding experiments showed that calcium ions induced the collapse of OMM-64. The effect of other counter ions present in trout endolymph on OMM-64 conformational changes was studied. The significance of disordered properties of OMM-64 and the possible function of this protein is discussed. PMID- 28866389 TI - Environmental sustainability of the solar photo-Fenton process for wastewater treatment and pharmaceuticals mineralization at semi-industrial scale. AB - The environmental sustainability of a semi-industrial solar photo-Fenton reactor, treating real effluents emanating from a pharmaceutical laboratory, is assessed herein. The life cycle assessment/analysis (LCA) methodology was employed and real life cycle inventory (LCI) data was collected from a ferrioxalate-assisted homogeneous solar photo-Fenton wastewater treatment plant (WWTP), at Ciudad Real, Spain. Electricity was provided by photovoltaic (PV) panels in tandem with a battery bank, making the plant autonomous from the local grid. The effective treatment of 1m3 of secondary-treated pharmaceutical wastewater, containing antipyrine, was used as a functional unit. The main environmental hotspot was identified to be the chemical reagents used to enhance treatment efficiency, mainly hydrogen peroxide (H2O2) and to a smaller degree oxalic acid. On the other hand, land use, PV panels, battery units, compound parabolic collectors (CPC), tanks, pipes and pumps, as materials, had a low contribution, ranging from as little as 0.06% up to about 2% on the total CO2eq emissions. Overall, the solar photo-Fenton process was found to be a sustainable technology for treating wastewater containing micropollutants at semi-industrial level, since the total environmental footprint was found to be 2.71kgCO2m-3 or 272mPtm-3, using IPCC 2013 and ReCiPe impact assessment methods, respectively. A sensitivity analysis revealed that if the excess of solar power is fed back into the grid then the total environmental footprint is reduced. Depending on the amount of solar power fed back into the grid the process could have a near zero total environmental footprint. PMID- 28866390 TI - Fully integrated modelling for sustainability assessment of resource recovery from waste. AB - This paper presents an integrated modelling approach for value assessments, focusing on resource recovery from waste. The method tracks and forecasts a range of values across environmental, social, economic and technical domains by attaching these to material-flows, thus building upon and integrating unidimensional models such as material flow analysis (MFA) and lifecycle assessment (LCA). We argue that the usual classification of metrics into these separate domains is useful for interpreting the outputs of multidimensional assessments, but unnecessary for modelling. We thus suggest that multidimensional assessments can be better performed by integrating the calculation methods of unidimensional models rather than their outputs. To achieve this, we propose a new metric typology that forms the foundation of a multidimensional model. This enables dynamic simulations to be performed with material-flows (or values in any domain) driven by changes in value in other domains. We then apply the model in an illustrative case highlighting links between the UK coal-based electricity production and concrete/cement industries, investigating potential impacts that may follow the increased use of low-carbon fuels (biomass and solid recovered fuels; SRF) in the former. We explore synergies and trade-offs in value across domains and regions, e.g. how changes in carbon emissions in one part of the system may affect mortality elsewhere. This highlights the advantages of recognising complex system dynamics and making high-level inferences of their effects, even when rigorous analysis is not possible. We also indicate how changes in social, environmental and economic 'values' can be understood as being driven by changes in the technical value of resources. Our work thus emphasises the advantages of building fully integrated models to inform conventional sustainability assessments, rather than applying hybrid approaches that integrate outputs from parallel models. The approach we present demonstrates that this is feasible and lays the foundations for such an integrated model. PMID- 28866391 TI - Identifying socio-ecological networks in rural-urban gradients: Diagnosis of a changing cultural landscape. AB - Socio-ecological systems maintain reciprocal interactions between biophysical and socioeconomic structures. As a result of these interactions key essential services for society emerge. Urban expansion is a direct driver of land change and cause serious shifts in socio-ecological relationships and the associated lifestyles. The framework of rural-urban gradients has proved to be a powerful tool for ecological research about urban influences on ecosystems and on sociological issues related to social welfare. However, to date there has not been an attempt to achieve a classification of municipalities in rural-urban gradients based on socio-ecological interactions. In this paper, we developed a methodological approach that allows identifying and classifying a set of socio ecological network configurations in the Region of Madrid, a highly dynamic cultural landscape considered one of the European hotspots in urban development. According to their socio-ecological links, the integrated model detects four groups of municipalities, ordered along a rural-urban gradient, characterized by their degree of biophysical and socioeconomic coupling and different indicators of landscape structure and social welfare. We propose the developed model as a useful tool to improve environmental management schemes and land planning from a socio-ecological perspective, especially in territories subject to intense urban transformations and loss of rurality. PMID- 28866392 TI - Chemical composition and speciation of particulate organic matter from modern residential small-scale wood combustion appliances. AB - Combustion technologies of small-scale wood combustion appliances are continuously developed decrease emissions of various pollutants and increase energy conversion. One strategy to reduce emissions is the implementation of air staging technology in secondary air supply, which became an established technique for modern wood combustion appliances. On that account, emissions from a modern masonry heater fuelled with three types of common logwood (beech, birch and spruce) and a modern pellet boiler fuelled with commercial softwood pellets were investigated, which refer to representative combustion appliances in northern Europe In particular, emphasis was put on the organic constituents of PM2.5, including polycyclic aromatic hydrocarbons (PAHs), oxygenated PAHs (OPAHs) and phenolic species, by targeted and non-targeted mass spectrometric analysis techniques. Compared to conventional wood stoves and pellet boilers, organic emissions from the modern appliances were reduced by at least one order of magnitude, but to a different extent for single species. Hence, characteristic ratios of emission constituents and emission profiles for wood combustion identification and speciation do not hold for this type of advanced combustion technology. Additionally, an overall substantial reduction of typical wood combustion markers, such as phenolic species and anhydrous sugars, were observed. Finally, it was found that slow ignition of log woods changes the distribution of characteristic resin acids and phytosterols as well as their thermal alteration products, which are used as markers for specific wood types. Our results should be considered for wood combustion identification in positive matrix factorisation or chemical mass balance in northern Europe. PMID- 28866393 TI - Occurrence, distribution and environmental risk of pharmaceutically active compounds (PhACs) in coastal and ocean waters from the Gulf of Cadiz (SW Spain). AB - In this study, we have evaluated the occurrence and distribution of 78 pharmaceuticals in different aquatic marine environments from the Gulf of Cadiz (SW Spain) for the first time. The obtained results revealed that pharmaceuticals were present in seawater at total concentrations ranging 61-2133 and 16-189ngL-1 in coastal and oceanic transects, respectively. Potential marine pollution hotspots were observed in enclosed or semi-enclosed water bodies (Cadiz Bay), showing concentrations that were one or two orders of magnitude higher than in the open ocean. The presence of these chemicals in local sewage treatment plants (STPs), one of the main contamination sources, was also assessed, revealing total concentrations of up to 23MUgL-1 in effluents. PhACs with the highest detection frequencies and concentrations in the sampling region were analgesics and anti inflammatories followed by antibiotics in the case of samples from Cadiz Bay or caffeine in oceanic seawater samples. Risk quotients, expressed as ratios between the measured environmental concentration (MEC) and the predicted no-effect concentrations (PNEC) were higher than 1 for two compounds (gemfibrozil and ofloxacin) in effluent of Jerez de la Frontera sewage treatment plant (STP). No high environmental risk was detected in both coastal and oceanic sampling areas, although the information available about the effects of these chemicals on marine biota is still very limited and negative effects on non-target species cannot be discarded. PMID- 28866394 TI - Direct and indirect effects of multiple stressors on stream invertebrates across watershed, reach and site scales: A structural equation modelling better informing on hydromorphological impacts. AB - The purpose of our approach was to take into account the nested spatial scales driving stream functioning in the description of pressures/ecological status links by analysing the results of a hierarchical model. The development of this model has allowed us to answer the following questions: Does the consideration of the indirect links between anthropogenic pressures and stream ecological status modify the hierarchy of pressure types impacting benthic invertebrates? Do the different nested scales play different roles in the anthropogenic pressures/ecological status relationship? Does this model lead to better understanding of the specific role of hydromorphology in the evaluation of stream ecological status? To achieve that goal, we used the Partial Least Square (PLS) path modelling method to develop a structural model linking variables describing (i) land use and hydromorphological alterations at the watershed scale, (ii) hydromorphological alterations at the reach scale, (iii) nutrients-organic matter contamination levels at the site scale, and (iv) substrate characteristics at the sampling site scale, to explain variation in values of a macroinvertebrate-based multimetric index: the French I2M2. We have highlighted the importance of land use effects exerted on both hydromorphological and chemical characteristics of streams observed at finer scales and their subsequent indirect impact on stream ecological status. Hydromorphological alterations have an effect on the substrate mosaic structure and on the concentrations of nutrients and organic matter at site scale. This result implies that stream hydromorphology can have a major indirect effect on macroinvertebrate assemblages and that the hierarchy of impacts of anthropogenic pressures on stream ecological status generally described in the literature - often determining strategic restoration priorities has to be re-examined. Finally, the effects of nutrients and organic matter on macroinvertebrate assemblages are lower than expected when all the indirect effects of land use and hydromorphological alterations are taken into account. PMID- 28866395 TI - Tritium in river waters from French Mediterranean catchments: Background levels and variability. AB - Tritium background levels in various environmental compartments are deeply needed in particular to assess radiological impact, especially in river systems where most of releases from nuclear facilities are performed. The present study aims to identify the main environmental factors that influence tritium background levels in rivers at the regional scale. 41 samples were collected from 2014 to 2016 along 17 small rivers in the south of France. All were located out of the influence of direct releases from nuclear facilities. Tritiated water (HTO) concentrations measured in water samples ranged from 0.12+/-0.11 to 0.86+/ 0.15BqL-1 and HTO concentrations in rains were modelled between 2015 and 2016 over the study period referring to time series acquired from 1963 to 2014 at Thonon-les-Bains monitoring station. The results of tritium concentrations in rivers studied present a significant variability and are more than twice lower than forecasted values in rain. Multiple linear regressions allowed identifying that HTO concentration in rains, watershed area and altitude were the main tested parameters that are linked to the variability of HTO concentrations in the studied rivers. Finally, HTO fluxes delivered to the Mediterranean Sea by French coastal rivers out of influence of nuclear releases were estimated. The results highlight that those account for around 1% of HTO exported while 99% are transferred by the nuclearized Rhone River. PMID- 28866396 TI - Estimating premature mortality attributable to PM2.5 exposure and benefit of air pollution control policies in China for 2020. AB - In past decade of rapid industrial development and urbanization, China has witnessed increasingly persistent severe haze and smog episodes, posing serious health hazards to the Chinese population, especially in densely populated cities. Quantification of health impacts attributable to PM2.5 (particulates with aerodynamic diameter<=2.5MUm) has important policy implications to tackle air pollution. The Chinese national monitoring network has recently included direct measurements of ground level PM2.5, providing a potentially more reliable source for exposure assessment. This study reports PM2.5-related long-term mortality of year 2015 in 161 cities of nine regions across China using integrated exposure risk (IER) model for PM2.5 exposure-response functions (ERF). It further provides an estimate of the potential health benefits by year 2020 with a realization of the goals of Air Pollution Prevention and Control Action Plan (APPCAP) and the three interim targets (ITs) and Air Quality Guidelines (AQG) for PM2.5 by the World Health Organization (WHO). PM2.5-related premature mortality in 161 cities was 652 thousand, about 6.92% of total deaths in China during year 2015. Among all premature deaths, contributions of cerebrovascular disease (stroke), ischemic heart disease (IHD), chronic obstructive pulmonary disease (COPD), lung cancer (LC) and acute lower respiratory infections (ALRIs) were 51.70, 26.26, 11.77, 9.45 and 0.82%, respectively. The premature mortality in densely populated cities is very high, such as Tianjin (12,533/year), Beijing (18,817/year), Baoding (10,932/year), Shanghai (18,679/year), Chongqing (23,561/year), Chengdu (11,809/year), Harbin (9037/year) and Linyi (9141/year). The potential health benefits will be 4.4, 16.2, 34.5, 63.6 and 81.5% of the total present premature mortality when PM2.5 concentrations in China meet the APPCAP, WHO IT-1, IT-2, IT 3 and AQG respectively, by the year 2020. In the current situation, by the end of year 2030, even if Chines government fulfills its own target to meet national ambient air quality standard of PM2.5 (35MUg/m3), total premature mortality attributable to PM2.5 will be 574 thousand across 161 cities. The present methodology will greatly help policy makers and pollution control authorities to further analyze cost and benefits of air pollution management programs in China. PMID- 28866397 TI - A mobile pool of contaminated sediment in the Penobscot Estuary, Maine, USA. AB - The natural recovery of estuaries from contamination is largely determined by the timescale over which contaminated sediment is exported or buried and replaced by cleaner sediment that enters from the watershed or the ocean. That timescale depends on the size of the "pool" of contaminated sediment that resides in the estuary. The larger the pool, the longer the recovery timescale for a given rate of sediment input. A field study was undertaken as part of a study of mercury contamination in the Penobscot estuary to assess the mechanisms affecting the transport and fate of contaminated sediment. Based on measurements of water properties, currents and sediment transport and seabed samples analyzed for sediment properties and contaminant concentrations, a "mobile pool" of contaminated sediment with relatively uniform geochemical characteristics along a 20-km reach of the estuary was identified. This pool of sediment is mobilized seasonally by resuspension and trapping processes associated with salinity fronts that vary in location with discharge conditions. Sediment is transported down estuary during high discharge and up-estuary during low discharge, with seasonal, bi-directional transport of sediment in the estuary significantly exceeding the annual input of new sediment from the watershed. This continual, bi-directional transport leads to homogenization of the chemical properties of the mobile sediment, including contaminant concentrations. The large mass of mobile sediment relative to the input of sediment from the watershed helps explain the long recovery timescale of contaminants in the Penobscot estuary. PMID- 28866398 TI - Holistic assessment of occurrence and fate of metolachlor within environmental compartments of agricultural watersheds. AB - BACKGROUND: Metolachlor [(RS)-2-Chloro-N-(2-ethyl-6-methyl-phenyl)-N-(1 methoxypropan-2-yl)acetamide] and two degradates (metolachlor ethane-sulfonic acid and metolachlor oxanilic acid) are commonly observed in surface and groundwater. The behavior and fate of these compounds were examined over a 12 year period in seven agricultural watersheds in the United States. They were quantified in air, rain, streams, overland flow, groundwater, soil water, subsurface drain water, and water at the stream/groundwater interface. The compounds were frequently detected in surface and groundwater associated with agricultural areas. A mass budget approach, based on all available data from the study and literature, was used to determine a percentage-wise generalized distribution and fate of applied parent metolachlor in typical agricultural environments. RESULTS: In these watersheds, about 90% of applied metolachlor was taken up by plants or degraded, 10% volatilized, and 0.3% returned as rainfall. One percent was transported to surface water, while an equal amount infiltrated into the unsaturated zone soil water. <0.02% reached the groundwater. Subsurface flow paths resulted in greater degradation of metolachlor because degradation reactions had more time to proceed. CONCLUSIONS: An understanding of the residence times of water in the different environmental compartments, and the important processes affecting metolachlor as it is transported along flowpaths among the environmental compartments allows for a degree of predictability of metolachlor's fate. Degradates with long half-lives can be used (in a limited capacity) as tracers of metolachlor, because of their persistence and widespread occurrence in the environment. PMID- 28866399 TI - Temporal variations in a phytoplankton community in a subtropical reservoir: An interplay of extrinsic and intrinsic community effects. AB - The phytoplankton community structure is potentially influenced by both extrinsic effects originating from the surrounding environment and intrinsic effects relying on interspecific interactions between two species. However, few studies have simultaneously considered both types of effects and assessed the relative importance of these factors. In this study, we used data collected over nine months (August 2012-May 2013) from a typical subtropical reservoir in southeast China to analyze the temporal variation of its phytoplankton community structure and develop a quantitative understanding of the extrinsic and intrinsic effects on phytoplankton community dynamics. Significant temporal variations were observed in environmental variables as well as the phytoplankton and zooplankton communities, whereas their variational trajectories and directions were entirely different. Variance partitioning analysis showed that extrinsic factors significantly explained only 31% of the variation in the phytoplankton community, thus suggesting that these factors were incomplete predictors of the community structure. Random forest-based models showed that 48% of qualified responsible phytoplankton species were more accurately predicted by phytoplankton-only models, which revealed clear effects of interspecific species-to-species interactions. Furthermore, we used association networks to model the interactions among phytoplankton, zooplankton and the environment. Network comparisons indicated that interspecific interactions were widely present in the phytoplankton community and dominated the network rather than those between phytoplankton and extrinsic factors. These findings expand the current understanding of the underlying mechanisms that govern phytoplankton community dynamics. PMID- 28866400 TI - Valorisation of N and P from waste water by using natural reactive hybrid sorbents: Nutrients (N,P,K) release evaluation in amended soils by dynamic experiments. AB - The removal of nutrients (nitrogen (N), phosphorous (P)) from waste water has become a resource recovery option in recent regulations worldwide, as observed in the European Union. Although both of these nutrients could be recovered from the sludge line, >70-75% of the N and P is discharged into the water line. Efforts to improve the nutrient recovery ratios have focused on developing low-cost technologies that use sorption processes. In this study, a natural zeolite (clinoptilolite type) in its potassium (K) form was impregnated with hydrated metal oxides and used to prepare natural hybrid reactive sorbents (HRS) for the simultaneous recovery of ammonium (NH4+) and phosphate (PO43-) from treated urban waste water. Three unfertile soils (e.g., one acidic and two basic) amended with N-P-K charged HRS were leached with deionized water (e.g. to simulate infiltration in the field) at two- and three-day time intervals over 15 different leaching cycles (equivalent to 15 bed volumes). The N-P-K leaching profiles for the three charged hybrid sorbents exhibited continuous nutrient release, with their values dependent on the composition of minerals in the soils. In the basic soil that is rich in illite and calcite, the release of potassium (K+) and ammonium (NH4+) is favoured by-ion exchange with calcium (Ca2+) and accordingly diminishes the release of phosphate (PO43-) due to its limited solubility in saturated calcite solutions (pH8 to 9). The opposite is true for sandy soils that are rich in albite (both acidic and basic), whereas the release of NH4+ and K+ was limited and the values of both ions measured in the leaching solutions were below 1mg/L. Their leaching solutions were poor in Ca2+, and the release of PO43- was higher (up to 12mgP-PO43-/L). The nutrient releases necessary for plant growth were provided continuously and were controlled primarily by the soil mineral dissolution rates fixing the soil aqueous solution composition (e.g. pH and ionic composition; in particular, the presence of calcite is a determinant for nutrient release, especially in alkaline soils). The N-P-K charged HRS sorbents that were used for soil amendment may be an alternative for avoiding nutrient leaching and reaching the goals of soil sustainability in agriculture and reducing the nutrient overloading of surface waters. PMID- 28866401 TI - Nitrous oxide emission and denitrifier communities in drip-irrigated calcareous soil as affected by chemical and organic fertilizers. AB - The effects of consecutive application of chemical fertilizer with or without organic fertilizer on soil N2O emissions and denitrifying community structure in a drip-irrigated field were determined. The four fertilizer treatments were (i) unfertilized, (ii) chemical fertilizer, (iii) 60% chemical fertilizer plus cattle manure, and (iv) 60% chemical fertilizer plus biofertilizer. The treatments with organic amendments (i.e. cattle manure and biofertilizer) reduced cumulative N2O emissions by 4.9-9.9%, reduced the N2O emission factor by 1.3-42%, and increased denitrifying enzyme activities by 14.3-56.2%. The nirK gene copy numbers were greatest in soil which received only chemical fertilizer. In contrast, nirS- and nosZ-copy numbers were greatest in soil amended with chemical fertilizer plus biofertilizer. Chemical fertilizer application with or without organic fertilizer significantly changed the community structure of nirK-type denitrifiers relative to the unfertilized soil. In comparison, the nirS- and nosZ-type denitrifier genotypes varied in treatments receiving organic fertilizer but not chemical fertilizer alone. The changes in the denitrifier communities were closely associated with soil organic carbon (SOC), NO3-, NH4+, water holding capacity, and soil pH. Modeling indicated that N2O emissions in this soil were primarily associated with the abundance of nirS type denitrifying bacteria, SOC, and NO3-. Overall, our findings indicate that (i) the organic fertilizers increased denitrifying enzyme activity, increased denitrifying-bacteria gene copy numbers, but reduced N2O emissions, and (ii) nirS- and nosZ-type denitrifiers were more sensitive than nirK-type denitrifiers to the organic fertilizers. PMID- 28866402 TI - Human health risks of polycyclic aromatic hydrocarbons in the urban soils of Nanjing, China. AB - Polycyclic aromatic hydrocarbons (PAHs) are a major group of toxic pollutants in urban areas. We calculated the critical concentrations of PAHs in the urban soils of Nanjing, China based on a human health risk assessment. In the study area, the risk was divided into four levels and toxic equivalent values of benzo[a]pyrene (BaPeq) corresponded to <70ngg-1, 70-700ngg-1, 700-7000ngg-1, and >7000ngg-1. By this standard, most urban areas in Nanjing fall under level II (potentially low risk), while older urban districts, commercial centers, and transportation centers exceed the critical concentration (level III) at present. Additionally, the correlations between PAH concentrations, factors associated with urbanization, and soil properties were analyzed. Population density and black carbon content were determined to be the key factors involved. Multiple linear regression models and the scenario simulation method were used to predict PAH levels in urban soils through 2030. The results indicated that the future distribution characteristics of soil BaPeq under various scenarios were different than at present, but PAH concentrations remained stable only under the low-carbon scenario. Therefore, the consumption of traditional fossil fuels should be controlled and replaced with alternative energy sources. In addition, the growth of traffic land use should be controlled in the southern and southwestern parts of the urban area. PMID- 28866403 TI - Operation setup of a nanofiltration membrane unit for purification of two-phase olives and olive oil washing wastewaters. AB - In this research work, the purification of olives and olive oil washing wastewaters from two-phase extraction mills by a novel polymeric NF membrane is addressed. The effluent was previously subjected to a physicochemical secondary tertiary treatment previously optimized at pilot and industrial scales. Within the adequate operating conditions, suspended solids could be completely removed, and the EC was considerable lowered down to good quality values acceptable for irrigation purposes (1.9-2.0mScm-1), whereas the chemical oxygen demand was reduced below 31.9mgL-1. The standards for discharging in public waterways or reusing the final treated effluent for irrigation with acceptable quality were therefore accomplished. Moreover, the performance of the NF membrane ranged between 2.82 and 6.96Lh-1m-2bar-1, that is, a flux of up to 160Lh-1m-2 at 25bar. Furthermore, the 15-minute acid cleaning plus 15-minute alkaline/detergent cleaning could recover satisfactorily the permeability of the membrane. The necessary overdesign of the membrane operation was estimated as 9.42-17.53%, which meant a maximum required membrane area of 61.82m2. Hence, just 2 membrane modules should be implemented in a medium-sized mill to engineer the operation, boosting the economic feasibility of the proposed process both from operational and capital costs point of views. PMID- 28866404 TI - Fresh water, marine and terrestrial cyanobacteria display distinct allergen characteristics. AB - During the last decades, global cyanobacteria biomass increased due to climate change as well as industrial usage for production of biofuels and food supplements. Thus, there is a need for thorough characterization of their potential health risks, including allergenicity. We therefore aimed to identify and characterize similarities in allergenic potential of cyanobacteria originating from the major ecological environments. Different cyanobacterial taxa were tested for immunoreactivity with IgE from allergic donors and non-allergic controls using immunoblot and ELISA. Moreover, mediator release from human FcepsilonR1-transfected rat basophilic leukemia (RBL) cells was measured, allowing in situ examination of the allergenic reaction. Phycocyanin content and IgE-binding potential were determined and inhibition assays performed to evaluate similarities in IgE-binding epitopes. Mass spectrometry analysis identified IgE reactive bands ranging between 10 and 160kDa as phycobiliprotein compounds. Levels of cyanobacterial antigen-specific IgE in plasma of allergic donors and mediator release from sensitized RBL cells were significantly higher compared to non-allergic controls (p<0.01). Inhibition studies indicated cross-reactivity between IgE-binding proteins from fresh water cyanobacteria and phycocyanin standard. We further addressed IgE-binding characteristics of marine water and soil-originated cyanobacteria. Altogether, our data suggest that the intensive use and the strong increase in cyanobacterial abundance due to climate change call for increasing awareness and further monitoring of their potential health hazards. PMID- 28866405 TI - Impacts of future climate and land cover changes on threatened mammals in the semi-arid Chinese Altai Mountains. AB - Dryland biodiversity plays important roles in the fight against desertification and poverty, but is highly vulnerable to the impacts of environmental change. However, little research has been conducted on dual pressure from climate and land cover changes on biodiversity in arid and semi-arid environments. Concequntly, it is crutial to understand the potential impacts of future climate and land cover changes on dryland biodiversity. Here, using the Chinese Altai Mountains as a case study area, we predicted the future spatial distributions and local assemblages of nine threatened mammal species under projected climate and land cover change scenarios for the period 2010-2050. The results show that remarkable declines in mammal species richness as well as high rates of species turnover are seen to occur across large areas in the Chinese Altai Mountains, highlighting an urgent need for developing protection strategies for areas outside of current nature reserve network. The selected mammals are predicted to lose more than 50% of their current ranges on average, which is much higher than species' range gains (around 15%) under future climate and land cover changes. Most of the species are predicted to contract their ranges while moving eastwards and to higher altitudes, raising the need for establishing cross-border migration pathways for species. Furthermore, the inclusion of land cover changes had notable effects on projected range shifts of individual species under climate changes, demonstrating that land cover changes should be incorporated into the assessment of future climate impacts to facilitate biodiversity conservation in arid and semi-arid environments. PMID- 28866406 TI - Rapid startup of thermophilic anaerobic digester to remove tetracycline and sulfonamides resistance genes from sewage sludge. AB - Spread of antibiotic resistance genes (ARGs) originating from sewage sludge is highlighted as an eminent health threat. This study established a thermophilic anaerobic digester using one-step startup strategy to quickly remove tetracycline and sulfonamides resistance genes from sewage sludge. At least 20days were saved in the startup period from mesophilic to thermophilic condition. Based on the results of 16S rDNA amplicons sequencing and predicted metagenomic method, the successful startup largely relied on the fast colonization of core thermophilic microbial population (e.g. Firmicutes, Proteobacteria, Actinobacteria). Microbial metabolic gene pathways for substrate degradation and methane production was also increased by one-step mode. In addition, real-time quantitative PCR approach revealed that most targeted tetracycline and sulfonamides resistance genes ARGs (sulI, tetA, tetO, tetX) were substantially removed during thermophilic digestion (removal efficiency>80%). Network analysis showed that the elimination of ARGs was attributed to the decline of their horizontal (intI1 item) and vertical (potential hosts) transfer-related elements under high-temperature. This research demonstrated that rapid startup thermophilic anaerobic digestion of wastewater solids would be a suitable technology for reducing quantities of various ARGs. PMID- 28866408 TI - Spectroscopic investigations on the interaction of thioacetamide with ZnO quantum dots and application for its fluorescence sensing. AB - The purpose of the present work was to develop a method for the sensing of thioacetamide by using spectroscopic techniques. Thioacetamide is a carcinogen and it is important to detect its presence in food-stuffs. Semiconductor quantum dots are frequently employed as sensing probes since their absorption and fluorescence properties are highly sensitive to the interaction with substrates present in the solution. In the present work, the interaction between thioacetamide and ZnO quantum dots has been investigated by using UV-visible, fluorescence and infrared spectroscopy. Besides, dynamic light scattering (DLS) has also been utilized for the interaction studies. UV-visible absorption studies indicated the bonding of the lone pair of sulphur atom of thioacetamide with the surface of the semiconductor. The fluorescence band of the ZnO quantum dots was found to be quenched in the presence of micromolar concentrations of thioacetamide. The quenching was found to follow the Stern-Volmer relationship. The Stern-Volmer constant was evaluated to be 1.20*105M-1. Infrared spectroscopic measurements indicated the participation of the NH2 group and the sulphur atom of thioacetamide in bonding with the surface of the ZnO quantum dots. DLS measurements indicated that the surface charge of the semiconductor was shielded by the thioacetamide molecules. PMID- 28866407 TI - Removal of emerging organic contaminants in a poplar vegetation filter. AB - Vegetation filters (VFs), a type of land application system, are a robust technology based on natural treatment mechanisms for the removal of wastewater contaminants. Their capacity to attenuate emerging organic contaminants (EOCs) has not yet been evaluated. The present study reports the results of a 2-year EOC monitoring carried out using a poplar VF receiving wastewater primarily treated by an Imhoff tank. The compounds selected included analgesics, a beta-adrenergic blocker, stimulants, an anticonvulsant, an anti-depressant, an anti-inflammatory, an antibiotic and analgesic and stimulant metabolites. EOCs were analysed in the Imhoff tank effluent, in the infiltrated water at a depth of 90cm and in the groundwater at a depth of 10m. The results demonstrated that EOC attenuation was more significant in the first 90cm than in the rest of the soil profile. The removal efficiency for all of the selected EOCs was higher than 90% with the exception of ketoprofen, which may pose a higher threat of groundwater contamination. The observed attenuation correlated with the hydrophobicity and charge state of the EOCs. The higher persistence of the metabolites 4-AAA and 4 FAA shows that progression in the degradation pathway does not always imply a mitigation of contamination. PMID- 28866409 TI - Intermolecular vibrational modes and H-bond interactions in crystalline urea investigated by terahertz spectroscopy and theoretical calculation. AB - The characteristic absorption spectra of crystalline urea in 0.6-1.8 THz region have been measured by terahertz time-domain spectroscopy at room temperature experimentally. Five broad absorption peaks were observed at 0.69, 1.08, 1.27, 1.47 and 1.64 THz respectively. Moreover, density functional theory (DFT) calculation has been performed for the isolated urea molecule, and there is no infrared intensity in the region below 1.8 THz. This means that single molecule calculations are failure to predict the experimental spectra of urea crystals. To simulate these spectra, calculations on a cluster of seven urea molecules using M06-2X and B3LYP-D3 are performed, and we found that M06-2X perform better. The observed THz vibrational modes are assigned to bending and torsional modes related to the intermolecular H-bond interactions with the help of potential energy distribution (PED) method. Using the reduced-density-gradient (RDG) analysis, the positions and types of intermolecular H-bond interactions in urea crystals are visualized. Therefore, we can confirm that terahertz spectroscopy can be used as an effective means to detect intermolecular H-bond interactions in molecular crystals. PMID- 28866410 TI - Additive-induced aggregate changes of two structurally similar dyes in aqueous solutions: A comparative photophysical study. AB - Absorption and emission spectral characteristics of the two structurally similar phenothiazine dyes, azure B and toluidine blue, in aqueous solutions of the two sets of molecular additives (ureas and monosaccharides) were studied as a function of the dye and additive concentrations. The absorption spectra of the dyes were also studied in pure tetramethylurea with an aprotic nature. The spectral data were analyzed using DECOM Program. The dimer structure of the interacting molecules in these dyes was discussed using the exciton model. The urea class of additives was found to act as water structure-breakers over the range of studied concentration. The carbohydrate additives were found to act as water structure-breakers at low concentrations. However, the water structure breaking process may be disfavored by the additive-additive interactions at higher concentrations. It can be concluded that at low additive concentrations, the main driving force for breaking the dye association is water-additive interaction, which disrupts the water hydrogen bonds induced by the additives. However, at the high additive concentrations, the different phenomena including additive-additive and additive-dye interactions can change the structure, strength, and aggregative properties of the dyes. Finally, the urea in water induces noticeably fluorescence quenching in emission spectra of both the dyes. PMID- 28866411 TI - Colorimetric and fluorimetric detection of Hg2+ and Cr3+ by boronic acid conjugated rhodamine derivatives: Mechanistic aspects and their bio-imaging application in bacterial cells. AB - Colorimetric and fluorimetric detection of toxic metal ions such as Hg2+ and Cr3+ has gained tremendous popularity over the conventional methods due to their operational simplicity, high selectivity, and speediness. Although numerous colorimetric and fluorescent receptors for Hg2+ or Cr3+ were reported in the literature, boronic acid-based receptors for these metal ions are rather scarce in the literature. Hence, in the present study dual function boronic acid conjugated rhodamine derivatives were developed, and their toxic metal ion detection abilities were studied by absorption, emission and visual detection methods. Absorption and emission spectral studies revealed that these derivatives displayed selectivity towards Hg2+, Cr3+ and Fe3+ among the other metal ions studied by forming new absorption band. Both the derivatives exhibited colorimetric response towards Hg2+ and Cr3+ by the change in color of the solution to pink and reddish pink with Fe3+. The detailed mechanism involved in the detection of Hg2+ was deduced by 1H NMR and ESI-MS studies. Further, these derivatives were used for fluorescence imaging of Hg2+ and Cr3+ in S. aureus bacterial cells. Thus the present manuscript demonstrated the use of boronic acid conjugated rhodamine derivatives as a dual function (colorimetric and fluorescent) probes and as imaging agents for Hg2+ and Cr3+, which are known for their toxic influence on bacterial cells. PMID- 28866412 TI - Boron difluoride dibenzoylmethane derivatives: Electronic structure and luminescence. AB - Electronic structure and optical properties of boron difluoride dibenzoylmethanate and four of its derivatives have been studied by X-ray photoelectron spectroscopy, absorption and luminescence spectroscopy and quantum chemistry (DFT, TDDFT). The relative quantum luminescence yields have been revealed to correlate with charge transfers of HOMO-LUMO transitions, energy barriers of aromatic substituents rotation and the lifetime of excited states in the investigated complexes. The bathochromic shift of intensive bands in the optical spectra has been observed to occur when the functional groups are introduced into p-positions of phenyl cycles due to destabilizing HOMO levels. Calculated energy intervals between electronic levels correlate well with XPS spectra structure of valence and core electrons. PMID- 28866413 TI - Nano-structural comparison of 2-methacryloyloxyethyl phosphorylcholine- and ethylene glycol-based surface modification for preventing protein and cell adhesion. AB - Polymer brush, owing to its precisely controllable nanostructure, has great potential for surface modification in the biomedical field. In this study, we evaluated the bio-inertness of polymer brush, monomer monolayers, and polymer coated surfaces based on their structures, to identify the most effective bio inert modification. We focused on two well-known bio-inert materials, 2 methacryloyloxyethyl phosphorylcholine (MPC) and ethylene glycol (EG). The amount of adsorbed proteins on the surface was found to be dependent on the monomer unit density in the case of MPC, whereas this correlation was not observed in the case of EG. Cell adhesion was suppressed on the brush structure of both MPC and EG units, regardless of their density. The brush structure of MPC and EG units showed better anti-protein- and anti-cell-adhesion than monolayers and polymer coated surfaces. Thus, the steric repulsion was not only important in EG units based surface, but also in MPC-based surface. In addition, multiple polymer layers formed by MPC-based polymer coating also displayed similar properties. PMID- 28866414 TI - Bioactive carbon dots lights up microtubules and destabilises cell cytoskeletal framework - A robust imaging agent with therapeutic activity. AB - A class of bioactive, microtubule specific, self-targeted carbon dots (CDs) has been synthesised by simple one-step hydrothermal treatment with Catharanthus roseus as the precursor. Apart from excitation dependent multicolour fluorescence of as-prepared CDs, they were also attributed with an inherent affinity for microtubules of cell cytoskeletal framework. As prepared CDs in-vitro bio labelling and live cell imaging studies in NIH 3T3 cells illustrates their tubulin specific bio-labelling potential which lights up the cell microtubule framework prominently under all filters. The ability of as-prepared CDs to simultaneously label tubulin and effectuate microtubule depolymerisation and fragmentation enables us to track its therapeutic potential on a real time basis. The cascade of events starting from cellular uptake, microtubule labelling and subsequent cytoskeletal changes (microtubule fragmentation, depolymerisation and cytoplasmic constriction) have been investigated comprehensively in this work by flow cytometer, confocal microscope, AFM microscopy (Peak Force QNM) and FE-SEM analysis. In summary, this work outlines the synthesis, characterization and application of a new class of highly fluorescent self-targeted microtubule specific CDs as a potent bioactive imaging nanotags. PMID- 28866415 TI - Psychological sequelae of myocardial infarction. AB - Patient with myocardial infarction (MI) are often affected by psychological disorders such as depression, anxiety, and post-traumatic stress disorder. Psychological disorders are disabling and have a negative influence on recovery, reduce the quality of life and causes high mortality rate in MI patients. Despite tremendous advancement in technologies, screening scales, and treatment strategies, psychological sequelae of MI are currently understudied, underestimated, underdiagnosed, and undertreated. Depression is highly prevalent in MI patients followed by anxiety and post-traumatic stress disorder. Pathophysiological factors involved in psychopathologies observed in patients with MI are sympathetic over-activity, hypothalamic-pituitary-adrenal axis dysfunction, and inflammation. Numerous preclinical and clinical studies evidenced a positive association between MI and psychopathologies with a common molecular pathophysiology. This review provides an update on diagnostic feature, prevalence, pathophysiology, clinical outcomes, and management strategies of psychopathologies associated with MI. Moreover, preclinical research findings on molecular mechanisms involved in post-MI psychopathologies and future therapeutic strategies have been outlined in the review. PMID- 28866416 TI - Upregulation of miR-3607 promotes lung adenocarcinoma proliferation by suppressing APC expression. AB - Lung cancer is the leading cause of worldwide cancer-related deaths, although many drugs and new therapeutic approaches have been used, the 5-years survival rate is still low for lung cancer patients. microRNAs have been shown to regulate lung cancer initiation and development, here we studied the role of miR-3607 in lung cancer cell proliferation. We found miR-3607 was upregulated in lung cancer tissues and cells, miR-3607 overexpression promoted lung cancer cell A549 proliferation determined by MTT assay, colony formation assay, anchorage independent growth ability assay and bromodeoxyuridine incorporation assay, while the opposite phenotypes were shown when miR-3607 was knocked down. Predicted analysis suggested a Wnt signaling pathway regulator adenomatous polyposis coli (APC) was the target of miR-3607, miR-3607 could directly bind to the 3'UTR of APC, and promoted Cyclin D1 and c-Myc expression which can be suppressed by APC. Double knockdown of miR-3607 and APC copied the phenotypes of miR-3607 overexpression, suggesting miR-3607 promoted lung cancer cell A549 proliferation by targeting APC. In conclusion, our study suggested miR-3607 contributes to lung cancer cell proliferation by inhibiting APC. PMID- 28866417 TI - Effects of Ganoderma lucidum polysaccharides against doxorubicin-induced cardiotoxicity. AB - Doxorubicin (DOX) is a widely used anthracycline derivative anticancer drug, but the use of DOX in clinical applications is limited by its cardiotoxicity. In the current research, we were aiming to assess the effects of Ganoderma lucidum polysaccharides (GLPS) on DOX-induced cardiotoxicity and to illustrate the associated mechanisms. H9c2 rat cardiomyocytes were treated with DOX in the absence or presence of GLPS, and we found GLPS treatment ameliorated DOX-induced H9c2 cell death. Moreover, results of in vivo studies indicated that GLPS significantly decreased the serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and aspartate aminotransferase (AST) and attenuated DOX-induced histological changes of the heart tissues. In addition, we found DOX administration promoted myocardial apoptosis, potentiated oxidative stress, decreased the activities of antioxidant enzymes and increased the production of pro-inflammatory cytokines. However, GLPS pretreatment markedly attenuated all these untoward effects of DOX. Furthermore, GLPS pretreatment was found to inhibit Cul3-mediated K48-linked polyubiquitination of Nrf2 through suppressing Cul3 expression, thereby stabilizing Nrf2 expression in H9c2 cells after DOX treatment, leading to the decreased expression of P53 and p-P65 and increased levels of MDM2 and HO-1, resulted in the attenuated apoptosis, oxidative stress and inflammation induced by DOX. PMID- 28866418 TI - PEG modification of Amorfrutin B from Amorpha fructicosa increases gastric absorption, circulation half-life and glucose uptake by T3T-L1 adipocytes. AB - Through a simple PEG-conjugation of the natural product Amorfrutin B, we enhanced its pharmacokinetic profile. The PEGylated molecule displayed significantly improved gastrointestinal absorption (p<0.05) and had a longer systemic circulation life (p<0.05). Oral glucose tolerance study showed PEGylated Amorfrutin B displayed longer protection against oral glucose load compared to Amorfrutin B (p<0.05). It also showed significant improvement in glucose uptake in-vitro by T3T-L1 adipocytes (p<0.05). The PEGylated molecule also showed reduced propensity of crossing the blood brain barrier and accumulating in the brain (p<0.05). It also showed reduced accumulation in the adipose tissue. Preliminary liver and kidney toxicity screening showed no significant alteration in liver or kidney function of Amorfrutin B or its PEGylated form. In conclusion, PEG modification can be an attractive strategy to reduce lipophilicity and enhance pharmacokinetic properties of natural products, derived from traditional medicine. PMID- 28866419 TI - Erhuang Formula ameliorates renal damage in adenine-induced chronic renal failure rats via inhibiting inflammatory and fibrotic responses. AB - AIMS: The present study aimed to evaluate the protective effects of Erhuang Formula (EHF) and explore its pharmacological mechanisms on adenine-induced chronic renal failure (CRF). MATERIALS AND METHODS: The compounds in EHF were analyzed by HPLC/MS. Adenine-induced CRF rats were administrated by EHF. The effects were evaluated by renal function examination and histology staining. Immunostaining of some proteins related cell adhesion was performedin renal tissues, including E-cadherin, beta-catenin, fibronectin and laminin. The qRT-PCR was carried out determination of gene expression related inflammation and fibrosis including NF-kappaB, TNF-alpha, TGF-beta1, alpha-SMA and osteopontin (OPN). RESULTS: Ten compounds in EHF were identified including liquiritigenin, farnesene, vaccarin, pachymic acid, cycloastragenol, astilbin, 3,5,6,7,8,3',4' heptemthoxyflavone, physcion, emodin and curzerene. Abnormal renal function and histology had significant improvements by EHF treatment. The protein expression of beta-catenin, fibronectin and laminin were significantly increased and the protein expression of E-cadherin significantly decreased in CRF groups. However, these protein expressions were restored to normal levels in EHF group. Furthermore, low expression of PPARgamma and high expression of NF-kappaB, TNF alpha, TGF-beta1, alpha-SMA and OPN were substantially restored by EHF treatment in a dose-dependent manner. CONCLUSIONS: EHF ameliorated renal damage in adenine induced CRF rats, and the mechanisms might involve in the inhibition of inflammatory and fibrotic responses and the regulation of PPARgamma, NF-kappaB and TGF-beta signaling pathways. PMID- 28866420 TI - Protective effects of phloridzin against methotrexate-induced liver toxicity in rats. AB - BACKGROUND: Liver is the largest internal organ concerning with metabolism, hormonal balance and clarifying of the toxins. One of the main complications of methotrexate (MTX) therapy was the hepatic injury. OBJECTIVE: This study was conducted to elucidate the possible protective effects of phloridzin (PHL) against MTX-induced hepatotoxicity as compared to standard agent N-acetylcysteine (NAC). MATERIALS AND METHODS: Rats were randomly divided into a normal control group, a respective group (PHL 40mg/kg/day orally (p.o.) for 10 consecutive days), a hepatotoxicity control group (MTX 20mg/kg, i.p., once), and three treated groups received NAC (150mg/kg/day; a reference standard), PHL (40mg/kg/day) and PHL (80mg/kg/day) p.o. for 10 consecutive days, at the end of the day 3 of the experiment rats were administered MTX. Assessed biomarkers included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) as liver function parameters, serum tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-II (COX-II), as inflammatory biomarkers, hepatic total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), nitrite (NO2-), catalase (CAT), glutathione-S-transferase (GST) and superoxide dismutase (SOD) as oxidative stress biomarkers. Furthermore, hepatic caspase-3 expression was assessed. Biochemical and molecular estimations reinforced by histopathological findings. RESULTS: Rats pre-treated with PHL significantly reduced hepatic injury, evidenced by significant reductions in ALT, AST and LDH, TNF-alpha and COX-II levels, significant reductions in hepatic NO2- and TBARS levels, and significant elevations in hepatic TAC, GSH, GST, CAT and SOD levels. Additionally, downregulation of hepatic caspase-3 expression. Finally, histopathological results consistent with our previous findings. CONCLUSION: PHL protects against hepatic injury in rats mainly through mitigation of oxidative stress, inflammation and apoptosis in hepatic tissues and may be promising to alleviate and early treatment of MTX-induced hepatoxicity in man. PMID- 28866423 TI - Modelling heavy metals build-up on urban road surfaces for effective stormwater reuse strategy implementation. AB - Urban road stormwater is an alternative water resource to mitigate water shortage issues in the worldwide. Heavy metals deposited (build-up) on urban road surface can enter road stormwater runoff, undermining stormwater reuse safety. As heavy metal build-up loads perform high variabilities in terms of spatial distribution and is strongly influenced by surrounding land uses, it is essential to develop an approach to identify hot-spots where stormwater runoff could include high heavy metal concentrations and hence cannot be reused if it is not properly treated. This study developed a robust modelling approach to estimating heavy metal build-up loads on urban roads using land use fractions (representing percentages of land uses within a given area) by an artificial neural network (ANN) model technique. Based on the modelling results, a series of heavy metal load spatial distribution maps and a comprehensive ecological risk map were generated. These maps provided a visualization platform to identify priority areas where the stormwater can be safely reused. Additionally, these maps can be utilized as an urban land use planning tool in the context of effective stormwater reuse strategy implementation. PMID- 28866421 TI - In vivo antileishmanial activity and histopathological evaluation in Leishmania infantum infected hamsters after treatment with a furoxan derivative. AB - N-oxide derivatives compounds such as furoxan and benzofuroxan are promising scaffolds for designing of new antileishmanial drugs. A series of furoxan (1,2,5 oxadiazole 2-N-oxide) (compounds 4a-b, and 14a-f) and benzofuroxan (benzo[c][1,2,5]oxadiazole1-N-oxide) (compounds 8a-c) derivatives were evaluated against in vitro cultured L. infantum promastigotes and amastigotes. The compounds exhibited activity against promastigote and intracellular amastigote forms with EC50 values ranging from 2.9 to 71.2MUM and 2.1 to 18.2MUM, respectively. The most promising compound, 14e, showed good antileishmanial activity (EC50=3.1MUM) against intracellular amastigote forms of L. infantum with a selectivity index, based on murine macrophages (SI=66.4), almost 3-times superior to that presented by the standard drug amphotericin B (AmpB). The efficacy of 14e to eliminate the parasites in vivo was also demonstrated. Treatment of L. infantum-infected hamsters with compound 14e at 3.0mg/Kg/day led to a meaningful reduction of parasite load in spleen (49.9%) and liver (54.2%), respectively; these data were corroborated by histopathological analysis, which also revealed reduction in the number of inflammatory cells in the liver of the treated animals. Moreover, histological analysis of the spleen and kidney of treated animals did not reveal alterations suggestive of toxic effects. The parasite load reduction might be related to NO production, since this molecule is a NO-donor. We observed neither side effects nor elevation of hepatic/renal biomarker levels in the plasma. The data herein presented suggest that the compound should be considered in the development of new drugs for treatment of visceral leishmaniasis. PMID- 28866422 TI - Alterations in cardiovascular function by particulate matter in rats using a crossover design. AB - The objective of this study was to investigate associations between cardiovascular effects and urban ambient particle constituents using an in vivo crossover experimental design. Ambient particles were introduced to an exposure chamber for whole-body exposure of WKY rats, where the particulate matter with an aerodynamic diameter of <2.5 MUm (PM2.5) mass concentration, particle number concentration, and black carbon (BC) were monitored. Organic carbon (OC), elemental carbon (EC), and soluble ions of PM2.5 were determined. In a crossover design, rats were exposed to ambient particles or high-efficiency particle arrestance (HEPA)-filtered control air for 7 days following a 7-day washout interval. The crossover exposure between particles and HEPA-filtered air was repeated 4 times. Radiotelemetric data on blood pressure (BP) [systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP)], heart rate (HR), and heart rate viability (HRV) were subsequently obtained during the entire study. Exposure to the PM2.5 mass concentration was associated with decreases in the SBP, DBP, MAP, and HR (p < 0.05), whereas no significant changes in the BP or HR occurred with the particle number or black carbon. For HRV, the ln 5-min standard deviation of the normal-to-normal (NN) interval (LnSDNN) and the ln root mean square of successive differences in adjacent NN intervals (LnRMSSD) were positively associated with the PM2.5 mass concentration (p < 0.05). There were no significant effects of the particle number concentration or BC on HRV. Alterations in the HR were associated with OC, EC, Na+, Cl-, and NO3-. Cl- was associated with the DBP, MAP, HR, SDNN, and RMSSD. NO3- was correlated with the SBP, MAP, HR, SDNN, and RMSSD. In conclusion, we observed cardiovascular responses to ambient particles in vivo using a crossover design which can reduce animal use in future environmental studies. PMID- 28866424 TI - Transfer of antibiotics from wastewater or animal manure to soil and edible crops. AB - Antibiotics are added to agricultural fields worldwide through wastewater irrigation or manure application, resulting in antibiotic contamination and elevated environmental risks to terrestrial environments and humans. Most studies focused on antibiotic detection in different matrices or were conducted in a hydroponic environment. Little is known about the transfer of antibiotics from antibiotic-contaminated irrigation wastewater and animal manure to agricultural soil and edible crops. In this study, we evaluated the transfer of five different antibiotics (tetracycline, sulfamethazine, norfloxacin, erythromycin, and chloramphenicol) to different crops under two levels of antibiotic-contaminated wastewater irrigation and animal manure fertilization. The final distribution of tetracycline (TC), norfloxacin (NOR) and chloramphenicol (CAP) in the crop tissues under these four treatments were as follows: fruit > leaf/shoot > root, while an opposite order was found for sulfamethazine (SMZ) and erythromycin (ERY): root > leaf/shoot > fruit. The growth of crops could accelerate the dissipation of antibiotics by absorption from contaminated soil. A higher accumulation of antibiotics was observed in crop tissues under the wastewater treatment than under manure treatment, which was due to the continual irrigation that increased adsorption in soil and uptake by crops. The translocation of antibiotics in crops mainly depended on their physicochemical properties (e.g. log Kow), crop species, and the concentrations of antibiotics applied to the soil. The levels of antibiotics ingested through the consumption of edible crops under the different treatments were much lower than the acceptable daily intake (ADI) levels. PMID- 28866425 TI - Impact of commuting exposure to traffic-related air pollution on cognitive development in children walking to school. AB - A few studies have found associations between the exposure to traffic-related air pollution at school and/or home and cognitive development. The impact on cognitive development of the exposure to air pollutants during commuting has not been explored. We aimed to assess the role of the exposure to traffic-related air pollutants during walking commute to school on cognitive development of children. We performed a longitudinal study of children (n = 1,234, aged 7-10 y) from 39 schools in Barcelona (Catalonia, Spain) who commuted by foot to school. Children were tested four times during a 12-month follow-up to characterize their developmental trajectories of working memory (d' of the three-back numbers test) and inattentiveness (hit reaction time standard error of the Attention Network Test). Average particulate matter <=2.5 MUm (PM2.5), Black Carbon (BC) and NO2 concentrations were estimated using Land Use Regression for the shortest walking route to school. Differences in cognitive growth were evaluated by linear mixed effects models with age-by-pollutant interaction terms. Exposure to PM2.5 and BC from the commutes by foot was associated with a reduction in the growth of working memory (an interquartile range increase in PM2.5 and BC concentrations decreased the annual growth of working memory by 5.4 (95% CI [-10.2, -0.6]) and 4.6 (95% CI [-9.0, -0.1]) points, respectively). The findings for NO2 were not conclusive and none of the pollutants were associated with inattentiveness. Efforts should be made to implement pedestrian school pathways through low traffic streets in order to increase security and minimize children's exposure to air pollutants. PMID- 28866426 TI - Biophysics of Biochemical Signaling in Dendritic Spines: Implications in Synaptic Plasticity. AB - Dendritic spines are mushroom-shaped postsynaptic compartments that host biochemical signal cascades important for synaptic plasticity and, ultimately, learning and memory. Signaling events in spines involve a signaling network composed of hundreds of signaling proteins interacting with each other extensively. Synaptic plasticity is typically induced by Ca2+ elevation in spines, which activates a variety of signaling pathways. This leads to changes in the actin cytoskeleton and membrane dynamics, which in turn causes structural and functional changes of the spine. Recent studies have demonstrated that the activities of these proteins have a variety of spatiotemporal patterns, which orchestrate signaling activity in different subcellular compartments at different timescales. The diffusion and the decay kinetics of signaling molecules play important roles in determining the degree of their spatial spreading, and thereby the degree of the spine specificity of the signaling pathway. PMID- 28866427 TI - Influence of neck torsion on near point convergence in subjects with idiopathic neck pain. AB - BACKGROUND: People with neck pain (NP) experience sensorimotor and oculomotor deficits thought to be due to abnormal cervical afferent input. Convergence insufficiency (CI) measured by near point convergence (NPC) may be a feature in NP and neck torsion might help to differentiate a cervical cause. OBJECTIVES: This study aimed to investigate repeatability and reliability of NPC in neutral and torsion and compare between idiopathic NP and controls along with correlation to the Convergence Insufficiency Symptom Survey (CISS). DESIGN: Comparative cross sectional observational study. METHOD: A Royal Airforce (RAF) Rule measured NPC with the neck in neutral and in 45 degrees torsion to the left and right in 42 subjects. A revised 15 item CISS was also completed. The average of 3 trials in each position and torsion difference were calculated. Within one week, NPC inter rater and test-retest reliability was evaluated in 10 subjects. RESULTS: A significant NPC torsion difference was demonstrated in participants with NP compared to controls (P = 0.01). No significant differences were seen for NPC values in neutral (P = 0.73). High inter-rater reliability (ICC = 0.95) and repeatability (ICC = 0.84) was obtained. No correlations were present between the CISS and NPC measures (r <= 0.18). CONCLUSIONS: NPC is impaired in neck torsion compared to neutral in NP supporting a cervical afferent cause. NPC, measured using the RAF Rule, is a reliable and repeatable measure and can be used to assess NPC and CI in those with NP. Objective rather than self-reported measures should be used to examine CI in NP. PMID- 28866429 TI - Demystifying Medical Science: We're Here to Help. PMID- 28866428 TI - Ultrasound imaging transducer motion during standing postural tasks with and without using transducer fixator. AB - BACKGROUND: Changes in the orientation of ultrasound (US) transducer relative to the body surface during dynamic standing tests can affect US measurements. OBJECTIVE: The purpose of the study was to evaluate ultrasound imaging transducer motion while measuring the lateral abdominal muscle thickness during standing tasks with and without using transducer fixator (TF). DESIGN: Cross-sectional experimental study. METHODS: A digital optical motion analysis system was used to assess the motions of US transducer during double-leg stance in different levels of platform stability of Biodex Balance System (BBS) (static, levels 6 and 3) with and without using TF in 45 healthy individuals. In addition, lateral abdominal muscle thickness was evaluated by US imaging. RESULTS: The results indicated that the amount of angular and linear transducer motions during static and dynamic standing tasks significantly decreased by the use of TF as compared to the conditions without TF (P < 0.001, effect size> 0.84). CONCLUSION: TF can significantly control US transducer motions within acceptable threshold limits during standing postural task. This may improve the clinical application of US imaging. PMID- 28866431 TI - Outcomes of stage II endometrial cancer: The UPMC Hillman Cancer Center experience. AB - PURPOSE: Previous studies of stage II endometrial cancer have included cancers with cervical glandular involvement, a factor no longer associated with risk of recurrence. In order to better assess relapse patterns and the impact of adjuvant therapy, a retrospective analysis was conducted for patients with modern stage II endometrial cancer, defined as cervical stromal invasion. MATERIALS AND METHODS: Patients diagnosed with surgically staged FIGO stage II endometrial cancer at the UPMC Hillman Cancer Center from 1990-2013 were reviewed. Factors associated with rates of locoregional control (LRC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) were analyzed using the log rank test. RESULTS: 110 patients with FIGO stage II disease were identified. Most (84.5%) received EBRT+/-BT, with 13.6% receiving BT alone. With a median follow-up of 64.6months, the 5-year actuarial rates of LRC, DM, DFS, and OS were 94.9%, 85.1%, 67.9%, and 75.0%, respectively. With 5 locoregional failures, the only factor predictive of LRC was pelvic lymph node dissection. Characteristics associated with DM included age, LVSI, depth of myometrial invasion, and receipt of chemotherapy. Factors predictive of both DFS and OS were age, grade, adverse histology, LVSI, depth of myometrial invasion, and receipt of chemotherapy. CONCLUSIONS: This represents the largest single-institution study for modern stage II endometrial cancer, confirming high rates of pelvic disease control after surgery and adjuvant therapy. With most patients receiving adjuvant radiotherapy, the predominant mode of failure, albeit low in absolute number, remains distant metastases. PMID- 28866432 TI - [Statins in primary prevention of cardiovascular disease]. AB - Cardiovascular events are the second leading cause of death in France. The assessment of overall cardiovascular risk using a personalized assessment with weighting risk factors can predict the risk of cardiovascular events in ten years. The validated treatments to reduce cardiovascular mortality in primary prevention are few. The use of statins in primary prevention is discussed. We report in this review the updated conclusions from clinical trials regarding the treatment with statins in primary prevention. PMID- 28866430 TI - The role of MicroRNA molecules and MicroRNA-regulating machinery in the pathogenesis and progression of epithelial ovarian cancer. AB - MicroRNA molecules are small, single-stranded RNA molecules that function to regulate networks of genes. They play important roles in normal female reproductive tract biology, as well as in the pathogenesis and progression of epithelial ovarian cancer. DROSHA, DICER, and Argonaute proteins are components of the microRNA-regulatory machinery and mediate microRNA production and function. This review discusses aberrant expression of microRNA molecules and microRNA-regulating machinery associated with clinical features of epithelial ovarian cancer. Understanding the regulation of microRNA molecule production and function may facilitate the development of novel diagnostic and therapeutic strategies to improve the prognosis of women with epithelial ovarian cancer. Additionally, understanding microRNA molecules and microRNA-regulatory machinery associations with clinical features may influence prevention and early detection efforts. PMID- 28866433 TI - Multivariate brain network graph identification in functional MRI. AB - Motivated by recent interest in identification of functional brain networks, we develop a new multivariate approach for functional brain network identification and name it as Multivariate Vector Regression-based Connectivity (MVRC). The proposed MVRC method regresses time series of all regions to those of other regions simultaneously and estimates pairwise association between two regions with consideration of influence of other regions and builds the adjacency matrix. Next, modularity method is applied on the adjacency matrix to detect communities or functional brain networks. We compare the proposed MVRC method with existing methods ranging from simple Pearson correlation to advanced Multivariate Adaptive Sparse Representation (ASR) methods. Experimental results on simulated and real fMRI dataset demonstrate that MVRC is able to extract functional brain networks that are consistent with the literature. Also, the proposed MVRC method is 650 750 times faster compared to the existing ASR method on 90 node network. PMID- 28866434 TI - Gender, social class, and women's employment. AB - People in low-power positions, whether due to gender or class, tend to exhibit other-oriented rather than self-oriented behavior. Women's experiences at work and at home are shaped by social class, heightening identification with gender for relatively upper class women and identification with class for relatively lower class women, potentially mitigating, or even reversing, class-based differences documented in past research. Gender-class differences are reflected in women's employment beliefs and behaviors. Research integrating social class with gendered experiences in homes and workplaces deepens our understanding of the complex interplay between sources of power and status in society. PMID- 28866435 TI - A contextual model of self-regulation change mechanisms among individuals with addictive disorders. AB - Numerous behavioral treatments for addictive disorders include components explicitly aimed at targeting self-regulation (e.g., coping and emotion regulation). We first provide a summary of key findings to date among studies that have examined self-regulation as a mechanism of behavior change (MOBC) in behavioral treatments for addictive disorders. Based on our review, we conclude that the role of self-regulation as a MOBC across behavioral treatments for addictive disorders is not well-characterized and findings are inconsistent across studies. For example, our review indicates that there is still inconsistent evidence that coping is a unique MOBC in cognitive-behavioral approaches for addictive behaviors. We propose that there has been slow progress in understanding self-regulation as a MOBC in addiction treatment because of a lack of attention to contextual factors. Accordingly, in the second half of this paper, we propose a contextual model of self-regulation change mechanisms, which emphasizes that the role of various facets of self-regulation as MOBC may depend on contextual factors in the immediate situational context (e.g., fluctuating internal and external cues) and in the broader context in which an individual is embedded (e.g., major life stressors, environmental conditions, dispositions). Additionally, we provide specific recommendations to guide future research for understanding both between-person and within-person self-regulation MOBC in addiction treatment. In particular, we provide key recommendations for how to capitalize on intensive longitudinal measurement methods (e.g., ecological momentary assessment) when bringing a contextual perspective to the study of self regulation as MOBC in various addiction treatments. PMID- 28866436 TI - Exploration of Parent-Provider Communication During Clinic Visits for Children With Chronic Conditions. AB - INTRODUCTION: The purpose of this study was to explore the communication behaviors demonstrated by parents of children with chronic conditions and provider team members when communicating about the child's care in outpatient clinics using concepts from the Theory of Shared Communication (TSC). METHODS: This was a secondary data analysis of 30 previously recorded pediatric clinic visits. Communication among parents and provider team members was analyzed using a researcher-developed coding scheme based on the TSC. RESULTS: Provider team members dominated communication during clinic visits, showing more frequent use of asking, explaining, advocating, and negotiating behaviors than parents. Parents were engaged in communication with frequent asking, explaining, and advocating behaviors. DISCUSSION: Parents of children with chronic conditions and multidisciplinary providers demonstrated the communication behaviors of the TSC in an outpatient clinic setting. Provider dominance of communication in the clinic setting may disempower parents and impair relationships. PMID- 28866437 TI - Adiponectin prevents orthodontic tooth movement in rats. AB - OBJECTIVE: The objective was to examine the effects of repetitive local administration of adiponectin on experimental tooth movement in rats. MATERIALS AND METHODS: The maxillary right first molar of male Wistar rats (n=24) was moved mesially for 14days, with local adiponectin injections (0.2 or 2MUg) every third day. Micro-computed tomography was performed at days 0, 6 and 14 and molar movement, bone density and bone volume fraction were calculated from the scans. Changes in extracellular matrix collagen and cell numbers in the periodontal ligament were analyzed histologically, and levels of circulating cytokines were measured by Luminex and ELISA. RESULTS: Adiponectin injections induced a reduction in tooth movement after 12 and 14days compared to controls. No tooth movement was observed between days 3 and 14 in the group receiving the highest dosage (2MUg) of adiponectin. Differences in bone density and bone volume fractions between treatment and control groups were not identified. Relative size and morphology of collagen fibrils, and cell number in the periodontal region after adiponectin injections were unchanged compared to controls. Levels of circulating adiponectin or other selected factors in plasma were not influenced by the adiponectin injections. CONCLUSIONS: Submucosal injections of adiponectin prevented experimental tooth movement in rats. The effect was dosage-dependent and local. Adiponectin injections caused no detectable changes in bone density, periodontal cell number or collagen content. PMID- 28866438 TI - Observations on fluid flow from exposed dentine in primary teeth: An in vitro study. AB - OBJECTIVE: To investigate fluid flow through dentine in primary teeth in vitro using the replica technique, and to compare the results with those obtained from permanent dentine. DESIGN: The experiments were carried out on 22 extracted, mandibular, primary, incisor teeth. The incisal edge was removed to 1mm below the dentino-enamel junction and half the exposed surface etched with phosphoric acid. The exposed dentine was blotted dry and the pressure in the pulp cavity held at 0, 15, 30 or 45cm H2O above atmospheric for 30s. Fluid that accumulated on the dentine surface was recorded with impression material and a replica made with epoxy resin which was examined in a scanning electron microscope. RESULTS: Structures resembling fluid droplets were present in the replicas of unetched dentine in all 22 teeth, and at all the pulpal pressures tested. The droplets formed at 45cm H2O were significantly larger (median diam., 5.14mm; interquartile range, 3.26mm; Friedman repeated measures analysis of variance on ranks (RMAVR) and Tukey test) than those formed at other pressures. There was no evidence of droplets in the replicas of etched dentine with any of the pulpal pressures. CONCLUSIONS: These results demonstrate that fluid will tend to flow from dentine in deciduous teeth when it is exposed. They are similar to those obtained in a previous study in this laboratory on permanent teeth. The fact that fluid droplets were absent from etched dentine suggests that, after being blotted, the etched dentine matrix absorbed fluid that tended to flow out through the dentinal tubules. PMID- 28866439 TI - Ultrasound guided continuous transmuscular quadratus lumborum analgesia for open renal surgery: A case series. PMID- 28866440 TI - Neurofibromatosis type 1 and right mandibular hypoplasia: unusual diagnosis of occlusion of the left common carotid artery. PMID- 28866441 TI - Cardiac Magnetic Resonance Evaluation of Left Ventricular Myocardial Strain in Pulmonary Hypertension. AB - RATIONALE AND OBJECTIVES: We investigated the feasibility of detecting left ventricular (LV) cardiac magnetic resonance (CMR) strain abnormalities using feature-tracking in patients with pulmonary hypertension (PH). MATERIALS AND METHODS: CMR was performed in 16 patients with all groups of PH and in 13 controls. Global and regional peak circumferential strains (%) (which have been shown to be robust by CMR), peak diastolic strain rate (%/s), and dyssynchrony index (ms) were quantified with feature-tracking software. Ventricular function and volumes were calculated from CMR, and right heart pressures were measured with catheterization. RESULTS: Left ventricular ejection fraction (LVEF) was similar in patients (60.2% +/- 11.0%) and controls (61.9% +/- 4.5%), P = .150. Global LV peak circumferential strain was significantly different in patients compared to controls, -16.7 +/- 2.8% vs -19.9 +/- 1.8%, respectively (P = .001). The greatest difference in strain was seen in the LV septum, -11.6 +/- 4.3% in patients vs -16.7 +/- 4.0% in controls (P < .001). There was a significant association between septal strain and right ventricular end-diastolic volume index (P = .047) in patients with PH; however, there were no associations with pulmonary artery pressures or right ventricular ejection fraction. CONCLUSIONS: Feature-tracking CMR can detect LV strain abnormalities in patients with PH and preserved or mildly depressed LVEF, with greatest abnormality in the septum. The association between septal strain and right ventricular end-diastolic volume index suggests that ventricular interdependence may be a mechanism of LV dysfunction in PH. Feature-tracking CMR may be useful for identification of LV dysfunction before LVEF significantly declines in patients with PH. The feasibility of detecting LV strain abnormalities in patients with PH shown by this study paves the way for a variety of future investigations into the applications of LV strain in this patient population. PMID- 28866443 TI - Subminimal inhibitory concentration (sub-MIC) of antibiotic induces electroactive biofilm formation in bioelectrochemical systems. AB - Electroactive biofilms (EABs) generated from mixed inocula are attractive due to their unique direct extracellular electron transfer abilities and potential use in water pollution control. In this study, for the first time, we identified a chemical that can be used for EAB regulation (both inhibition and promotion). We confirmed that tobramycin, an antibiotic previously demonstrated to inhibit the activity of EABs, is an agonist of EAB formation at subminimal inhibitory concentrations (sub-MICs). Compared to the control, at tobramycin concentrations of 0.05 (1/80 MIC) and 0.1 mg/L (1/40 MIC), the time required to reach 3 A/m2 was shorter, and the limiting current densities increased by 17%. The enhanced EAB activity was primarily attributed to the 50% increase in biomass density from 289 +/- 21 to 434 +/- 12 MUg protein/cm2 and the increased biofilm thickness from 28 +/- 1 to 37 +/- 0.5 MUm. Geobacter species in the microbial communities were selectively increased from 76% to 82%, and their abundance was estimated to increase by 1.63-fold. The accelerated growth was further confirmed using the model strain G. sulfurreducens PCA. Transcriptomic analysis revealed that 0.05 mg/L of tobramycin led to a significant upregulation of genes related to cytochromes and the type IV pilus, suggesting a possible mechanism for the observed current enhancement. These findings extend our knowledge of the regulation of EAB formation by antibiotics and the selective enrichment of Geobacter from a mixed culture, with broader implications on the potential impact of trace antibiotics on the dissimilatory metal reduction process in water environment. PMID- 28866442 TI - Passive material properties of stroke-impaired plantarflexor and dorsiflexor muscles. AB - BACKGROUND: Following a stroke, intrinsic muscle properties such as stiffness may be altered, which is accompanied by increased spasticity and contractures. Previously, quantification of muscle stiffness has been based off of indirect measurements. Using shear wave ultrasound elastography, direct measurements of muscle material properties can be made. METHODS: Our aim was to evaluate material properties, specifically passive stiffness, using shear wave ultrasound elastography across a range of muscle lengths, in the medial gastrocnemius and the tibialis anterior in chronic stroke survivors. FINDINGS: Our main results show significant increases of 27.7% and 26.9% in shear wave velocity of stroke impaired medial gastrocnemius compared to the unimpaired contralateral side at 90 degrees ankle angle (P=0.033) and 15 degrees plantarflexion (P=0.001), respectively. However, no significant difference was found in the tibialis anterior between the two sides. Relatively weak correlations were found between SW velocity in the medial gastrocnemius and joint stiffness for both the non paretic (rho=0.384, P=0.001), and paretic side (rho=0.363, P=0.002). Additionally, muscle stiffness estimates of stroke-impaired tibialis anterior from joint torque and angle measurements were significantly greater by 23.1% (P=0.033) than the unimpaired contralateral side. However, no significant difference was found in the medial gastrocnemius. INTERPRETATION: These results indicate that there are non-uniform changes in passive stiffness of stroke impaired muscle. Therefore, muscles need to be evaluated individually to assess alterations. Additionally, interpretation of joint-based calculations of muscle stiffness should be made cautiously. Having the ability to non-invasively assess muscle stiffness adaptations in vivo would aid in prognosis, evaluation, and treatment following a stroke. PMID- 28866444 TI - Palladized cells as suspension catalyst and electrochemical catalyst for reductively degrading aromatics contaminants: Roles of Pd size and distribution. AB - The palladized cell (Pd-cell) could be used as an efficient catalyst in catalyzing the degradations of a wide variety of environmental contaminants. Nevertheless, when the Pd NPs associate with the bacteria, the catalytic activity likely significantly affected by the biomass. Quantitative indicators that characterize of Pd-cell are necessary and little attention has been paid to investigate how the catalytic efficiency of Pd-cell is affected by the size and distribution of Pd NPs. To fill this gap, we explored the roles of the above mentioned key factors on the performance of Pd-cell in catalyzing the degradations of two aromatic contaminants (nitrobenzene and p-chlorophenol) in two commonly used scenarios: (1) using Pd-cell as suspended catalyst in solution and (2) using Pd-cell as electrocatalyst directly coated on electrode. In scenario (1), the relationship of exposing area to Pd particle size and distribution factors was established. Based on theoretical estimation and catalytic performance analysis, the results indicated that adjusting the exposing area to a large value (9.3 +/- 0.1 * 105 nm2 mg-1 Pd) was extremely effective for improving the catalytic activity of Pd-cell used as a suspension catalyst. In scenario (2), our results showed that the best electrocatalytic performances were achieved on the electrode decorated with Pd-cells with the largest NP size (54.3 +/- 16.4 nm), which exerted maximum electrochemical active surface area (10.6 m2 g-1) as well as favorable conductivity. The coverage of deposited Pd NPs (>95%) on the cell surface played a crucial role in boosting the conductivity of biocatalyst, thus determining the possibility of Pd-cell as an efficient electrocatalyst. The findings of this study provide a guidance for the synthesis and application of Pd-cell, which enables the design of Pd-cell to be suitable for different catalysis systems with high catalytic performance. PMID- 28866445 TI - Mainstream upflow nitritation-anammox system with hybrid anaerobic pretreatment: Long-term performance and microbial community dynamics. AB - Mainstream nitritation-anammox is of strong interest to energy- and resource efficient domestic wastewater treatment. However, there lack in-depth studies of pretreatment, tests of actual wastewater, and examination of long-term performance. Herein, an upflow nitritation-anammox granular reactor has been investigated to treat primary effluent with a hybrid anaerobic reactor (HAR) as pretreatment for more than 300 days. This system achieved 92% of COD removal, 75% of which was accomplished by the HAR, and had an average final effluent COD concentration of 22 mg L-1. More than 90% of ammonium was removed in the nitritation-anammox reactor, achieving a nitrogen removal rate of 81.0 g N m-3 d 1 in the last stage. The accumulation of sulfate-reducing bacteria in the HAR evidenced the effect of sulfate on COD removal and subsequent nitrogen removal. Anammox bacteria (predominantly Ca. Jettenia asiatica) accounted for up to 40.2% of total granular communities, but their abundance decreased over time in the suspended communities. The dynamics of major metabolisms and functional genes involved in nitrogen conversion were predicted by PICRUSt based on the taxonomic data, providing more insights into the functions of the microbial communities. These results have demonstrated the effectiveness and importance of anaerobic pretreatment to successful mainstream nitritation-anammox. PMID- 28866446 TI - Augmentation of acyl homoserine lactones-producing and -quenching bacterium into activated sludge for its granulation. AB - Quorum sensing (QS), especially acyl homoserine lactone (AHL)-mediated QS, in activated sludge arouses great interests because of its vital role in the formation of biofilm and aerobic granules (AG). Although QS is reported to be largely related to the properties of activated sludge, it is not economically feasible to tune QS in an activated sludge reactor through dosing pure AHL or AHL hydrolase. A more reasonable way to tune QS is to augment reactors with AHL producing or -quenching bacteria. In this work, the impacts of continuous dose of AHL-producing or -quenching strains on the activated sludge during its granulation process were explored. Augmentation of AHL-producing or -quenching strains resulted in up- or down-regulation of the AHL concentration in the reactors. Granulation of activated sludge was also accomplished in all reactors, but the granules showed negligible or slight differences in the physicochemical properties of sludge, such as nutrients removal, biomass concentration, extracellular polymeric substances, and zeta potential. Interestingly, a smaller granule size was observed for both the reactor augmented with either an AHL quenching strain or an AHL-producing strain, suggesting that the AHL augmentation suppressed the biofilm development. Pyrosequencing analysis reveals that the granules cultured in the reactors varied widely in bacterial community structure, indicating that the AHL augmentation had a greater impact on the bacterial community structure, rather than on the physicochemical properties of activated sludge. These results demonstrate that the role of QS in the biofilm formation in complex wastewater treatment bioreactors should be re-evaluated. PMID- 28866447 TI - Efficacy of fronto-temporal transcranial direct current stimulation for refractory auditory verbal hallucinations in schizophrenia: A randomized, double blind, sham-controlled study. AB - Persistent auditory verbal hallucinations (AVH) that are refractory to antipsychotic medications are reported in about 20-30% of schizophrenia patients. Transcranial Direct Current Stimulation (tDCS), a non-invasive and safe neuromodulatory technique, has attracted significant interest as an add-on treatment for refractory AVH in schizophrenia. Studies examining the efficacy of tDCS for refractory AVH in schizophrenia have reported inconsistent findings. In this study, using a randomized, double-blind, sham-controlled design (RCT), we sought to examine the effect of add-on tDCS [anode corresponding to left dorsolateral prefrontal cortex and cathode to left temporo-parietal junction; 2 mA, twice-daily sessions for 5-days] to treat refractory AVH in schizophrenia patients (N=25); following this RCT phase, patients that had <30% reduction in AVH severity were offered an open-label extension (OLE) active stimulation to evaluate the effect of cross-over to verum tDCS. In the RCT phase, repeated measures ANOVA with tDCS type [verum (N=12) vs. sham (N=13)] as between subjects factor demonstrated a significant tDCS-type X time-point interaction [F=21.5, p<0.001, partial-eta2=0.48] with significantly greater reduction of AVH score in verum tDCS group as compared to sham group. In the OLE phase, sham-to-verum crossed over patients (N=13) showed significantly greater reduction in AVH severity than their corresponding change during RCT phase (t=2.9; p=0.01). Together, these observations add further support to the beneficial effects of add on tDCS to treat refractory AVH schizophrenia. PMID- 28866448 TI - Paradoxical elevation of systemic inflammatory markers and physical activity in patients with schizophrenia. PMID- 28866449 TI - Fractional flow reserve in below the knee arteries with critical limb ischemia and validation against gold-standard morphologic, functional measures and long term clinical outcomes. AB - INTRODUCTION: The aim of this study was to assess the applicability of fractional flow reserve measurement (FFR) in below-the-knee (BTK) arteries and to evaluate its correlation with non-invasive functional parameters before and after angioplasty. METHODS: We enrolled 39 patients with severe BTK arterial lesions. Inclusion criteria were critical limb ischemia (Rutherford 4-6) and angiographically proven arterial stenosis of the distal lower limb (percent diameter stenosis >=70%). Exclusion criteria were chronic total occlusion, diabetic foot syndrome and non-viable distal lower limb. The transstenotic distal/proximal pressure ratio was measured under resting (Pd/Pa) and hyperemic (FFR) conditions induced by 40mg intra-arterial Papaverin and was compared with quantitative angiography-, laser Doppler- and duplex ultrasound-derived measurements before and after percutaneous angioplasty (PTA). RESULTS: Comparing measurements before and after PTA, we found significant improvements in the resting Pd/Pa values (0.79 [0.67-0.90] vs 0.90 [0.85-0.97]; p<0.001) and FFR values (0.60+/-0.19 vs 0.76+/-0.15; p<0.001), respectively. At baseline, Pd/Pa ratio and FFR were significantly albeit weakly correlated with % area stenosis (r:-0.31, p=0.05 and r:-0.31, p=0.05, respectively). After PTA, neither Pd/Pa nor FFR remained correlated with % area stenosis. Similarly, prior PTA, Pd/Pa ratio and FFR were significantly correlated with TcO2% and perfusion unit change (r:0.48, p<0.01 and r:0.34, p<0.05, respectively), but after intervention, these significant correlations vanished. Pd/Pa and FFR values did not show correlation with duplex ultrasound-derived measurements. At 1year, major adverse events (MAEs) and major adverse cardiovascular and cerebrovascular (MACCEs) were observed in 7 (17.9%) and in 9 (23.1%) patients, respectively. CONCLUSION: CLI due to severe BTK arterial disease was associated with several impediments of baseline pressure measurements which were significantly improved after successful PTA and stenting. Significant relationships between pressure data and functional and imaging parameters existed prior intervention but vanished after. Further studies are required to determine the clinical value of pre- and post-PTA pressure measurements in BTK arterial disease. PMID- 28866450 TI - CFTR structure. AB - Structural studies of the cystic fibrosis transmembrane conductance regulator (CFTR) protein are critical to understand molecular mechanisms involved in gating of the apical anion channel as well as the way in which the gating is regulated, especially by the regulatory region (R region). They are also instrumental for understanding the root cause of cystic fibrosis (CF) and supporting the development of therapeutic strategies. In this short review, we summarize recent progress in the knowledge of the CFTR 3D structure and briefly discuss implications for CF drug development. PMID- 28866451 TI - Sexual and reproductive health care utilization and preferences reported by young women with cystic fibrosis. AB - BACKGROUND: This study aimed to describe and compare the sexual and reproductive health (SRH) care utilization among young women with cystic fibrosis (CF) with the general United States (U.S.) population. METHODS: Women with CF ages 15 24years from five geographically diverse U.S. CF centers participated in a survey investigating SRH. Results were summarized and compared to a nationally representative sample of young women aged 15-24 who participated in the U.S. National Survey of Family Growth (NSFG) using logistic regression to adjust for confounders. RESULTS: A total of 188 women with CF (19.7+/-2.7years) completed the survey; data were compared to 1997 NSFG respondents (19.6+/-0.10years). Women with CF had lower lifetime rates of ever obtaining a Pap smear or pelvic exam (26% vs. 57%; p<0.001) and similar rates of HPV vaccination (44% vs. 43%; p=0.64) compared to NSFG respondents. Thirty-seven percent of women with CF reported seeking contraception and <10% reported contraceptive counseling, STI testing/counseling, or pregnancy testing in their lifetime. In the prior 12months, 41% of NSFG respondents reported seeking contraception, 24% received contraceptive counseling, 22% STI testing/counseling, and 23% pregnancy testing. A minority of women with CF received or discussed SRH care in the CF setting, although 66% wanted to discuss SRH with their CF team. CONCLUSIONS: Young women with CF report low rates of SRH care utilization and desire SRH discussions in the CF setting. Interventions should target improved SRH care delivery and encourage patient-provider communication around SRH in the CF care setting. PMID- 28866452 TI - Circulating interleukin-6 levels and cardiovascular and all-cause mortality in the elderly population: A meta-analysis. AB - OBJECTIVE: Inflammatory markers may be associated with mortality in the elderly population. We conducted this meta-analysis to evaluate the association of elevated circulating interleukin-6 levels with cardiovascular or all-cause mortality in the general elderly population. METHODS: A comprehensive literature search was conducted through the Pubmed and Embase databases until April 2016. Prospective observational studies that investigated the association of circulating interleukin-6 levels with cardiovascular or all-cause mortality in the elderly general population (aged 60 years or more) were included. Pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated by the highest vs. the lowest interleukin-6 levels. RESULTS: Nine prospective studies involving 9087 participants were identified. When comparing the highest with the lowest interleukin-6 levels, the pooled RR of all-cause mortality and cardiovascular mortality were 1.49 (95% CI 1.33-1.67) and 1.69 (95% CI 1.27-2.25), respectively. Subgroup analysis indicated the effects of interleukin-6 on all-cause mortality were consistently observed in sample sizes, region, durations of follow-up, interleukin-6 cutoff value and number of adjusted for covariates subgroups. CONCLUSIONS: This meta-analysis indicates that elevated circulating interleukin-6 levels are independently associated with greater risk of cardiovascular and all cause mortality in the general elderly population. PMID- 28866453 TI - Ponseti method is superior to surgical treatment in clubfoot - Long-term, randomized, prospective trial. AB - Treatment of idiopathic clubfoot has shifted from extensive surgical release to conservative Ponseti method; however, randomized prospective trials to compare both methods are lacking. The goal of this study was to compare the long-term results of Ponseti method with those of surgery in terms of morphology, function, X-rays, overall health and gait. In 2001, a single center, prospective, randomized, and controlled trial with a parallel design was started. Twenty-four feet of 15 patients were randomly assigned to two groups: 12 feet each to a Ponseti and surgical group. Mean follow-up was 10 years. International Clubfoot Study Group score (ICFSG), the Pediatric Outcomes Data Collection Instrument (PODCI) and the Functional Rating System (FRS) were used to compare morphology, functional, radiological and subjective outcomes, and the Oxford Foot Model (OFM) was used to evaluate foot kinematics. No significant difference was seen between groups in the initial Pirani scores (p=0.618). Ponseti group had more favorable long-term outcomes according to the FRS (p=0.005), higher ICFSG, scores for morphology (p=0.021), function (p=0.005) and X-rays (p=0.02), and better parent reported functional status according to the PODCI (p=0.018). Surgically treated clubfeet were stiffer - ankle dynamic range of motion (p=0.015) and the maximal hindfoot dorsiflexion during gait were limited as measured by OFM (p=0.039). This was compensated by an increase in motion between the hindfoot and forefoot. Furthermore, these children had more difficulty playing sports and experienced more pain, which might have led to inferior results in the happiness domain of the PODCI. These results suggest that the Ponseti method provides superior long term outcomes for idiopathic clubfoot deformity. PMID- 28866454 TI - Gait abnormalities of COPD are not directly related to respiratory function. AB - STUDY OBJECTIVE: To assess whether gait abnormalities in COPD depend on mere impairment of respiratory function. METHODS: In 40 patients with COPD at different GOLD stages and 28 controls, we evaluated: forced expiratory volume in 1s (FEV1); partial pressure of oxygen; Mini-Mental State Examination (MMSE); dynamic balance through the Mini-BESTest (MBT); Timed Up and Go (TUG) test without and with dual task counting aloud back by three; 6-min walk test (6MWT); body sway during quiet stance (stabilometry); spatial-temporal variables of gait by a 4-m long sensorized walkway (baropodometry). Lower-limb muscle strength, tendon reflexes, and sensation were also clinically evaluated. RESULTS: Muscle strength of proximal but not distal muscles was slightly reduced in patients, whereas reflexes and sensation were unaffected. FEV1, partial pressure of oxygen, MMSE, MBT, stabilometry, as well as baropodometry, were abnormal and unrelated to muscle weakness. The time taken to perform the TUG test was increased, and to a larger extent with than without dual task. At baropodometry, variability of step length was increased; abnormalities of gait variables were associated with larger body sway but not with FEV1 or hypoxemia. Gait speed at 6MWT was correlated with MBT score and with FEV1 as well as hypoxemia. CONCLUSIONS: 6MWT findings give a measure of gait disability linked to endurance-related respiratory failure. Gait at baropodometry is associated with impairment of balance, cognitive status and abnormal dual task performance. We suggest that central nervous lesions, presumably of vascular origin, are detrimental to balance and gait in COPD. PMID- 28866455 TI - Gait deviations in transverse plane after SCFE in dependence on the femoral offset. AB - Residual deformity of the femoral head after slipped capital femoral epiphysis (SCFE) may be accompanied by a loss of femoral offset and lead to femoro acetabular impingement (FAI), especially during hip flexion. It is hypothesized that during phases of the gait cycle, when the hip is flexed, the offset-loss is compensated by an increased external rotation. The gait pattern of 36 patients suffering from SCFE, who were treated by pinning-in-situ, were compared to a control group of 40 healthy adults by an instrumented 3D-gait analysis. Total patient group was subdivided into 3 subgroups in dependence on the offset (offset groups (OG)) quantified by the angle alpha according to Notzli: OG1: alpha-angle <55 degrees , OG2: alpha-angle between 55 and 75 degrees , OG3: alpha-angle >75 degrees . Comparisons were made at 3 instants: initial foot contact (0% gait cycle (GC)), 40-60% GC and 90-100% GC. Patients showed an increased external hip rotation during all 3 periods of the GC with a tendency of increasing external rotation in association with offset-loss. Only during hip extension (40-60% GC) there was a weak correlation between angle alpha and hip rotation (r=-0.375, p=0.024). In conclusion, the offset-loss does not lead to a functional relevant impingement during walking which needs compensation strategies like increasing external rotation during periods of hip flexion. PMID- 28866456 TI - Physician characteristics associated with higher adenoma detection rate. AB - BACKGROUND AND AIMS: Patients who receive a colonoscopy from a physician with a low adenoma detection rate (ADR) are at higher risk of subsequent colorectal cancer. It is unclear what drives the variation across physicians in ADR. We describe physician characteristics associated with higher ADR. METHODS: In this retrospective cohort study a natural language processing system was used to analyze all outpatient colonoscopy examinations and their associated pathology reports from October 2013 to September 2015 for adults age 40 years and older across physicians from 4 diverse health systems. Physician performance on ADR was risk adjusted for differences in patient population and procedure indication. Our sample included 201 physicians performing at least 30 colonoscopy examinations during the study period, totaling 104,618 colonoscopy examinations. RESULTS: The mean ADR was 33.2% (range, 6.3%-58.7%). Higher ADR was seen among female physicians (4.2 percentage points higher than men, P = .020), gastroenterologists (9.4 percentage points higher than nongastroenterologists, P < .001), and physicians with <=9 years since their residency completion (6.0 percentage points higher than physicians who have had 27-51 years of practice, P = .004). CONCLUSIONS: Gastroenterologists, female physicians, and more recently trained physicians had higher performance in adenoma detection. PMID- 28866458 TI - TiO2 nanoparticles supported on PMMA nanofibers for photocatalytic degradation of methyl orange. AB - In this paper, a photocatalyst composed of TiO2 nanoparticles supported on the nanofibers of poly(methyl methacrylate) (PMMA) was successfully prepared by hydrothermally treating the electrospun PMMA nanofibers containing titanium n butoxide precursor at 135 degrees C for 8h. As-prepared composite was characterized by field-emission scanning electron microscopy, X-ray diffraction pattern, thermal gravimetric analysis and Brunauer-Emmett-Teller (BET) surface area measurements. It is revealed that high content (42%) of tetragonal anatase TiO2 nanoparticles are uniformly loaded on the PMMA nanofibers to constitute the composite (TiO2@PMMA) photocatalyst with BET surface area of 21.4m2g-1. The photocatalytic activity of TiO2@PMMA towards the degradation of methyl orange (MO), a model pollutant, has been investigated. It is observed that 0.1g of the composite could degrade 100mL of MO (10mg/L) completely within 50min under UV illumination, exhibiting a high catalytic activity. Moreover, the composite could be easily separated from the reaction system by filtration, and maintain high photocatalytic activity in five consecutive cycles of the degradation of MO, suggesting its potentials in recycling use. The work provides a new approach for the development of novel supported photocatalysts with high catalytic activity and good reusability. PMID- 28866457 TI - Randomized trial of cholangioscopy-guided laser lithotripsy versus conventional therapy for large bile duct stones (with videos). AB - BACKGROUND AND AIMS: Bile duct stones >1 cm have a decreased incidence of successful endoscopic extraction and often require lithotripsy. Although previous guidelines suggested mechanical lithotripsy for large common bile duct stones, current guidelines suggest cholangioscopy-guided lithotripsy as an adjunct with or without balloon dilation or mechanical lithotripsy. However, no randomized trials have assessed the usefulness of this practice. METHODS: Patients with bile duct stones >1 cm in diameter were randomized in a 2:1 ratio to cholangioscopy guided laser lithotripsy versus conventional therapy only. Conventional therapies such as mechanical lithotripsy or balloon dilation were also allowed in the laser lithotripsy group. Randomization was stratified by history of ERCP in the past 3 months. The primary outcome was endoscopic clearance of the bile duct stones. RESULTS: Endoscopic clearance was achieved in 39 (93%) of 42 patients treated with cholangioscopy-guided laser lithotripsy and 12 (67%) of 18 treated with conventional therapy only (P = .009). The 9 patients in whom ERCP was unsuccessful underwent surgical common duct exploration with stone removal. Mean procedure time was 120.7 +/- 40.2 minutes for the cholangioscopy-guided laser lithotripsy group compared with 81.2 +/- 49.3 minutes for the conventional therapy group (P = .0008). There was no significant difference in fluoroscopy time, number of procedures, or adverse events (cholangitis) (cholangioscopy, 2; conventional, 1) and post-ERCP pancreatitis (cholangioscopy, 2; conventional, 1). CONCLUSION: Cholangioscopy-guided laser lithotripsy increases the incidence of endoscopic clearance of large bile duct stones and decreases the need for surgery compared with conventional therapy alone. However, it is associated with longer procedure times. (Clinical trial registration number: NCT0175997.). PMID- 28866459 TI - Functional modification of breathable polyacrylonitrile/polyurethane/TiO2 nanofibrous membranes with robust ultraviolet resistant and waterproof performance. AB - Exploiting high-added-value textiles equipped with multiple functionalities like ultraviolet (UV) resistance, waterproofness, and thermal-moisture comfort is facing tremendous demand by a more discerning consumer market. However, the major challenge is to realize the equilibrium among the multifunction. Herein, a new attempt of fabricating superhydrophobic electrospun polyacrylonitrile (PAN)/polyurethane (PU)/titanium dioxide (TiO2) nanofibrous membranes has been tried, and the membranes exhibited multifunction of UV resistance, waterproofness and breathability by coating modification with 2-hydroxy-4-n-octoxybenzophenone (UV531) and fluorinated acrylic copolymer (FAC). TiO2 NPs as inorganic blocker and UV531 as organic absorber were utilized to impart the excellent double UV resistant function for the modified nanofibrous membranes. The hydrophobic coating with FAC endowed the pristine membranes with enhanced superhydrophobic wettability and the advancing contact angle was 152.1 degrees . Regulating the addition amount of TiO2 NPs, the UV531 and FAC concentration, the multiple functionalities of the modified PAN/PU/TiO2 were systemically optimized: robust tensile strength (14.6MPa), good ultraviolet protection factor of 1485, modest waterproofness (62kPa), and moisture breathability (12.9kgm-2 d-1). The equilibrium among the multifunction of the as-prepared membranes indicated their diverse possibilities can be used in various applications, including high altitude garments, protective clothing, covering materials, self-cleaning materials, and other medical products. PMID- 28866460 TI - Nitric oxide-sensing actuators for modulating structure in lipid-based liquid crystalline drug delivery systems. AB - Herein we report on the development of a nitric oxide-sensing lipid-based liquid crystalline (LLC) system specifically designed to release encapsulated drugs on exposure to NO through a stimulated phase change. A series of nitric oxide (NO) sensing lipids compatible with phytantriol and GMO cubic phases were designed and synthesized, and utilized in enabling nitric oxide-sensing LLC systems. The nitric oxide (NO)-sensing lipids react with nitric oxide, resulting in hydrolysis of these lipids and phase transition of the LLC system. Specifically, the N-3 aminopyridinyl myristylamine (NAPyM)+phytantriol mixture formed a lamellar phase in excess aqueous environment. The NAPyM+phytantriol LLC responded to the nitric oxide gas as a chemical stimulus which triggers a phase transition from lamellar phase to inverse cubic and hexagonal phase. The nitric oxide-triggered phase transition of the LLC accelerated the release of encapsulated model drug from the LLC bulk phase, resulting in a 15-fold increase in the diffusion coefficient compared to the starting lamellar structure. The nitric oxide-sensing LLC system has potential application in the development of smart medicines to treat nitric oxide implicated diseases. PMID- 28866461 TI - A novel electrochemical sensor based on calixarene functionalized reduced graphene oxide: Application to simultaneous determination of Fe(III), Cd(II) and Pb(II) ions. AB - A glassy carbon electrode (GCE) modified by calixarene functionalized reduced graphene oxide (CA/RGO) has been fabricated and utilized in this study for simultaneous voltammetric detection of several metal ions, Fe(II), Cd(II) and Pb(II), in aqueous solution. The CA/RGO nanocomposite was characterized in surface and electrochemical properties using scanning electron microscopy (SEM), infrared spectroscopy (IR), X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), Raman spectroscopy and electrochemical impedance spectroscopy (EIS). The CA/RGO coating significantly improves the sensitivity of electrochemical responses and separation of heavy metals. The electrochemical oxidation of Fe(III), Cd(II), and Pb(II) was performed by square wave voltammetry (SWV). The metal ions, Fe(III), Cd(II), and Pb(II), gave a linear relationship with their concentrations at 1.0*10-10-1.0*10-8M on the CA/RGO/GCE. The detection limits of the metal ions were found to be similar at 2.0*10-11M. A good recovery was also obtained for practical use of the CA/RGO/GCE in pharmaceutical formulation. PMID- 28866462 TI - A spectroscopic sensing platform for MARCKS protein monolayers. AB - We developed a highly sensitive silicon platform, suitable to assess the molecular organization of protein samples. Prototype platforms were obtained using different electrochemical protocols for the electrodeposition of Ag nanoparticles onto the hydrogenated silicon surface. A platform with high Surface Enhanced Raman Scattering efficiency was selected based on the surface coverage and the number density of particles size distribution. The performance of the platform was determined by studying the interaction of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) protein with the substrate according to its molecular organization. The chemical and structural characteristics of MARCKS molecules were examined under two configurations: i) a disordered distribution given by a MARCKS solution drop deposited onto the platform and, ii) a compact monolayer transferred to the platform by the Langmuir-Blodgett method. Raman spectra show vibrational bands of Phenylalanine and Lysine residues specific for the protein effector domain, and evidence the presence of alpha helix structure in both configurations. Moreover, we distinguished the supramolecular order between the compact monolayer and random molecular distribution. The platforms containing Ag nanoparticles are suitable for studies of protein structure and interactions, advancing a methodological strategy for our long term goal, which is to explore the interaction of proteins with model membranes. PMID- 28866463 TI - One-pot controlled synthesis of AuPd@Pd core-shell nanocrystals with enhanced electrocatalytic performances for formic acid oxidation and glycerol oxidation. AB - In this work, AuPd@Pd core-shell nanocrystals (AuPd@Pd NCs) were fabricated by a one-pot co-reduction approach, where theophylline-7-acetic acid (TAA) acted asa new structure-directing agent. The crystal structure and composition were mainly characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), X-ray diffraction (XRD), together with X-ray photoelectron spectroscopy (XPS). The growth mechanism of AuPd@Pd NCs was investigated in detail. The obtained AuPd@Pd NCs exhibited superior catalytic characters for formic acid oxidation reaction (FAOR) and glycerol oxidation reaction (GOR) in contrast with commercial Pd black in alkaline media. PMID- 28866464 TI - Do Transurethral Treatments Increase the Complexity of Urethral Strictures? AB - PURPOSE: We examined the impact on urethral stricture complexity at urethroplasty of previous transurethral treatments such as dilation, urethrotomy and stenting, which are most commonly performed when treating male urethral stricture. MATERIALS AND METHODS: We retrospectively reviewed the records of 45 males who had undergone transurethral treatments before urethroplasty. We compared urethrography findings at initial diagnosis with those at urethroplasty. Males with failed hypospadias repair, lichen sclerosis or a history of prior urethroplasty were excluded from analysis. We considered stricture complexity increased if the number and/or length of strictures on urethrography at urethroplasty was greater than that at initial diagnosis or false passage was newly identified. RESULTS: Of the patients 39 (87%), 32 (71%) and 13 (29%) had undergone urethral dilation, urethrotomy and urethral stenting, respectively, and 39 (87%) had undergone repeat or multiple kinds of transurethral treatments. Stricture complexity was increased in 22 men (49%) while 7 (16%) required urethroplasty more complex than that anticipated from urethrography findings at initial diagnosis. Increased stricture complexity was significantly associated with a history of urethrotomy (p = 0.03), urethral stenting (p = 0.0002) and repeat transurethral treatments (p = 0.01). Multivariate analysis revealed that urethral stenting (p = 0.01) and repeat transurethral treatments (p = 0.01) were independent predictors of increased stricture complexity. CONCLUSIONS: Repeat transurethral treatments increase stricture complexity and are potentially counterproductive. Even a single application of temporary urethral stenting carries a high risk of complicating the stricture and requiring complex urethroplasty. PMID- 28866465 TI - Three-Dimensional Computerized Model Based on the Sonourethrogram: A Novel Technique to Evaluate Anterior Urethral Stricture. AB - PURPOSE: The sonourethrogram is a useful alternative to the traditional retrograde urethrogram to evaluate anterior urethral strictures. With the development of 3-dimensional reconstructive techniques 3-dimensional urethral imaging can provide more accurate and useful information to enable the surgeon to make the best surgical decisions. We evaluated the accuracy and efficacy of a 3 dimensional reconstructed digital model of the urethra based on the sonourethrogram to assess anterior urethral disease. MATERIALS AND METHODS: A total of 50 patients with an anterior urethral stricture and 10 healthy volunteers were enrolled in this study from April 2014 to January 2017. All patients and volunteers underwent sonourethrogram and retrograde urethrogram. Three-dimensional urethral models were reconstructed based on the sonourethrogram. Stricture length and location on retrograde urethrogram or sonourethrogram based images were compared with those found at operation. RESULTS: The 3-dimensional digital model revealed the entire anterior urethra, including the navicular fossa, and the penile and bulbar parts. The semitransparent model clearly demonstrated the structure of the corpus spongiosum and inside the urethral lumen. Further information on spongiofibrosis could also be seen in the 3-dimensional digital model. There was no significant difference in stricture length or location in the 3-dimensional model compared with retrograde urethrogram imaging and actual surgical findings. However, the latest technique could only reconstruct the short segment of the anterior urethra due to the probe width limitation. CONCLUSIONS: The 3-dimensional computerized model based on the sonourethrogram is a novel and effective technique of evaluating anterior urethral strictures. PMID- 28866466 TI - Impact of Clinical Guidelines on Voiding Cystourethrogram Use and Vesicoureteral Reflux Incidence. AB - PURPOSE: To prevent over diagnosis and overtreatment of vesicoureteral reflux the 2007 NICE (National Institute for Health and Care Excellence) and 2011 AAP (American Academy of Pediatrics) guidelines recommended against routine voiding cystourethrograms in children presenting with first febrile urinary tract infections. The impact of these guidelines on clinical practice is unknown. MATERIALS AND METHODS: Using an administrative claims database (ClinformaticsTM Data Mart) children who underwent voiding cystourethrogram studies or had a diagnosis of vesicoureteral reflux between 2001 and 2015 were identified. The cohort was divided into children age 0 to 2 and 3 to 10 years. Single and multiple group interrupted time series analyses (difference-in-difference) were performed with the guidelines as intervention points. The incidence of vesicoureteral reflux was compared across each period. RESULTS: Of the 51,649 children who underwent voiding cystourethrograms 19,422 (38%) were diagnosed with vesicoureteral reflux. In children 0 to 2 years old voiding cystourethrogram use did not decrease after the 2007 NICE guidelines were announced (-0.37, 95% CI 1.50 to 0.77, p = 0.52) but did decrease significantly after the 2011 AAP guidelines were announced (-2.00, 95% CI -3.35 to -0.65, p = 0.004). Among children 3 to 10 years old voiding cystourethrogram use decreased during the entire study period. There was a decrease in the incidence of vesicoureteral reflux in both groups that mirrored patterns of voiding cystourethrogram use. CONCLUSIONS: The 2011 AAP guidelines led to a concurrent decrease in voiding cystourethrogram use and incidence of vesicoureteral reflux among children 0 to 2 years old. Further studies are needed to assess the risks and benefits of reducing the diagnosis of vesicoureteral reflux in young children. PMID- 28866467 TI - CTA1: Purified and display onto gram-positive enhancer matrix (GEM) particles as mucosal adjuvant. AB - The A1 subunit of cholera toxin (CTA1) retains the adjuvant function of CT, without its toxic side effects, making the molecule a promising mucosal adjuvant. However, the methods required to obtain a pure product are both complicated and expensive, constricting its potential commercial applicability. Here, we fused the peptidoglycan binding domain (PA) to the C-terminus of CTA1, which enabled the fusion protein to be expressed by Bacillus subtilis, and secreted into the culture medium. CTA1 was then purified and displayed on GEM particles using a one step process, which resulted in the formation of CTA1-GEM complexes. Next, the CTA1-GEM complexes were used as an adjuvant to enhance the immune responses of mice to the influenza subunit vaccine. It was observed that the CTA1-GEM complexes enhanced specific systemic (IgG) and mucosal (IgA) immune responses against antigen, and induced cellular immune responses as well. The data presented here suggests that CTA1-GEM complexes can serve as a viable mucosal adjuvant. PMID- 28866468 TI - Topical silver diamine fluoride for dental caries arrest in preschool children: A randomized controlled trial and microbiological analysis of caries associated microbes and resistance gene expression. AB - OBJECTIVES: The Stopping Cavities Trial investigated effectiveness and safety of 38% silver diamine fluoride in arresting caries lesions. MATERIALS AND METHODS: The study was a double-blind randomized placebo-controlled superiority trial with 2 parallel groups. The sites were Oregon preschools. Sixty-six preschool children with >=1 lesion were enrolled. Silver diamine fluoride (38%) or placebo (blue tinted water), applied topically to the lesion. The primary endpoint was caries arrest (lesion inactivity, Nyvad criteria) 14-21days post intervention. Dental plaque was collected from all children, and microbial composition was assessed by RNA sequencing from 2 lesions and 1 unaffected surface before treatment and at follow-up for 3 children from each group. RESULTS AND CONCLUSION: Average proportion of arrested caries lesions in the silver diamine fluoride group was higher (0.72; 95% CI; 0.55, 0.84) than in the placebo group (0.05; 95% CI; 0.00, 0.16). Confirmatory analysis using generalized estimating equation log-linear regression, based on the number of arrested lesions and accounting for the number of treated surfaces and length of follow-up, indicates the risk of arrested caries was significantly higher in the treatment group (relative risk, 17.3; 95% CI: 4.3 to 69.4). No harms were observed. RNA sequencing analysis identified no consistent changes in relative abundance of caries-associated microbes, nor emergence of antibiotic or metal resistance gene expression. Topical 38% silver diamine fluoride is effective and safe in arresting cavities in preschool children. CLINICAL SIGNIFICANCE: The treatment is applicable to primary care practice and may reduce the burden of untreated tooth decay in the population. PMID- 28866469 TI - L-type VDCCs participate in behavioral-LTP and memory retention. AB - Although L-type voltage-dependent calcium channels (VDCCs) have been reported to display different even contrary actions on cognitive functions and long-term potentiation (LTP) formation, there is little information regarding the role of L type VDCCs in behavioral LTP, a learning-induced LTP model, in the intact brain of freely behaving animals. Here we investigated the effects of verapamil, a non selective blocker of L-type VDCCs, on behavioral LTP and cognitive functions. Population spikes (PS) were recorded by using electrophysiological methods to examine the role of verapamil in behavioral LTP in the hippocampal dentate gyrus (DG) region. Y-maze assay was used to evaluate the effects of verapamil on learning and memory. Electron microscope was used to observe the changes on synaptic ultrastructural morphology in hippocampal DG area. We found that intrahippocampal verapamil treatments had no significant changes on the PS amplitude during a 90min recordings period. However, intrahippocampal applications of verapamil, including pre- or post-training, reduced behavioral LTP magnitude and memory retention but did not prevent the induction of behavioral LTP and the acquisition of learning. The saline group with behaving trainings showed obvious increases in the number of smile synapses, the length of active zones and the thickness of postsynaptic density as compared to the baseline group, but verapamil with pre-training treatment almost returned these changes to the baseline levels except for the synaptic interface curvature. In conclusion, our results suggest that L-type VDCCs may only contribute to the magnitude of behavioral LTP and the memory maintenance with an activity independent relationship. L-type VDCCs may be critical to new information long term storage rather than acquisition in hippocampus. PMID- 28866470 TI - Photosensitized enzyme deactivation and protein oxidation by axial-substituted phosphorus(V) tetraphenylporphyrins. AB - The activity for photodynamic therapy of water-soluble cationic porphyrins, tetraphenylporphyrin P(V) complexes, was investigated. Bis(cyclohexylmethoxy)P(V)tetraphenylporphyrin (DCHMP(V)TPP), dichloroP(V)tetraphenylporphyrin (Cl2P(V)TPP), and dimethoxyP(V)tetraphenylporphyrin (DMP(V)TPP) could cause the photosensitized deactivation of tyrosinase. The tryptophan residue of human serum albumin (HSA) and several kinds of amino acids could be damaged by these P(V)porphyrins under visible light irradiation. The photosensitized damage of these biomolecules was inhibited by sodium azide, a singlet oxygen (1O2) quencher, and enhanced in deuterium oxide, suggesting the contribution of 1O2. However, an excess amount of sodium azide did not completely inhibit the photosensitized damage. In addition, the redox potential measurements demonstrated the possibility of electron transfer from tryptophan and tyrosine to photoexcited P(V)porphyrins. These results suggest that electron transfer-mediated oxidation of amino acids contributes to the photosensitized protein and amino acid damage by these P(V)porphyrins. Specifically, Cl2P(V)TPP showed the highest photodamaging activity in the P(V)porphyrins used in this study. Oxidized products of amino acids by photoexcited P(V)porphyrins were analyzed with a liquid chromatography mass spectrometer. Because of the hypoxic condition of a tumor, photodynamic therapy through a 1O2-mediated mechanism should be restricted, and the electron transfer-mediated mechanism may improve the photodynamic effect. In the cases of these P(V)porphyrins, redox potential is the most important factor for photosensitized protein and amino acid oxidation through photoinduced electron transfer. PMID- 28866471 TI - Feature selection before EEG classification supports the diagnosis of Alzheimer's disease. AB - OBJECTIVE: In many decision support systems, some input features can be marginal or irrelevant to the diagnosis, while others can be redundant among each other. Thus, feature selection (FS) algorithms are often considered to find relevant/non redundant features. This study aimed to evaluate the relevance of FS approaches applied to Alzheimer's Disease (AD) EEG-based diagnosis and compare the selected features with previous clinical findings. METHODS: Eight different FS algorithms were applied to EEG spectral measures from 22 AD patients and 12 healthy age matched controls. The FS contribution was evaluated by considering the leave-one subject-out accuracy of Support Vector Machine classifiers built in the datasets described by the selected features. RESULTS: The Filtered Subset Evaluator technique achieved the best performance improvement both on a per-patient basis (91.18% of accuracy) and on a per-epoch basis (85.29+/-21.62%), after removing 88.76+/-1.12% of the original features. All algorithms found out that alpha and beta bands are relevant features, which is in agreement with previous findings from the literature. CONCLUSION: Biologically plausible EEG datasets could achieve improved accuracies with pre-processing FS steps. SIGNIFICANCE: The results suggest that the FS and classification techniques are an attractive complementary tool in order to reveal potential biomarkers aiding the AD clinical diagnosis. PMID- 28866472 TI - Second harmonic generation microscopy as a tool for the early detection of crystallization in spray dried dispersions. AB - Various techniques have been used to detect crystallization in amorphous solid dispersions (ASD). However, most of these techniques do not enable the detection of very low levels of crystallinity (<1%). The aim of the current study was to compare the sensitivity of second harmonic generation (SHG) microscopy with powder X-ray diffraction (XRPD) in detecting the presence of crystals in low drug loading amorphous solid dispersions. Amorphous solid dispersions of the poorly water soluble compounds, flutamide (FTM, 15wt.% drug loading) and ezetimibe (EZT, 30wt.% drug loading) with hydroxypropyl methylcellulose acetate succinate (HPMCAS) were prepared by spray drying. To induce crystallization, samples were subsequently stored at 75% or 82% relative humidity (RH) and 40 degrees C. Crystallization was monitored by XRPD and by SHG microscopy. Solid state nuclear magnetic resonance spectroscopy (ssNMR) was used to further investigate crystallinity in selected samples. For flutamide, crystals were detected by SHG microscopy after 8days of storage at 40 degrees C/82% RH, whereas no evidence of crystallinity could be observed by XRPD until 26days. Correspondingly, for FTM samples stored at 40 degrees C/75% RH, crystals were detected after 11days by SHG microscopy and after 53days by XRPD. The evolution of crystals, that is an increase in the number and size of crystalline regions, with time could be readily monitored from the SHG images, and revealed the formation of needle shaped crystals. Further investigation with scanning electron microscopy indicated an unexpected mechanism of crystallization, whereby flutamide crystals grew as needle-shaped projections from the surface of the spray dried particles. Similarly, EZT crystals could be detected at earlier time points (15days) with SHG microscopy relative to with XRPD (60days). Thus, SHG microscopy was found to be a highly sensitive method for detecting and monitoring the evolution of crystals formed from spray dried particles, providing much earlier detection of crystallinity than XRPD under comparable run times. PMID- 28866473 TI - The perception of fairness in infant care and mothers' postpartum depression. AB - This study investigates a potential causal effect of mothers' perceptions of the fairness of infant care on their postpartum depression. Based on the tenets of equity theory, it is hypothesized that, net of controls, mothers who see infant care as fairly apportioned between themselves and their husbands will be less depressed than others. We utilize data from a longitudinal study of a nonrandom sample of 178 heterosexual couples experiencing the birth of their first child together. The primary focus variable is the mothers' perception in the first couple of months postpartum that infant care is fair to them. Statistical analysis involved the careful chronological sequencing of response variable and controls, along with regression modeling using propensity scores. We find that a perception of fairness is associated with about a quarter of a standard deviation lower depressive symptomatology, controlling for key covariates. Depressive symptomatology is additionally elevated for mothers experiencing more pre-partum depression, and for those who more generally felt, before the birth, that they were overbenefiting in the marriage. This paper contributes to both equity theory and research on postpartum depression. In a scenario in which it is not practical or ethical to randomly assign people to fairness-in-infant-care conditions, we are able to utilize longitudinal data and a natural "experiment," along with propensity-score modeling to attempt to assess the causal impact of fairness in infant care on postpartum depression. The finding that fairness in this arena appears to reduce postpartum depression emphasizes the importance of encouraging father participation in this critical stage of parenting. Limitations of the study with respect to causal inference are also discussed. PMID- 28866474 TI - Access to occupational networks and ethnic variation of depressive symptoms in young adults in Sweden. AB - Social capital research has recognized the relevance of occupational network contacts for individuals' life chances and status attainment, and found distinct associations dependent on ethnic background. A still fairly unexplored area is the health implications of occupational networks. The current approach thus seeks to study the relationship between access to occupational social capital and depressive symptoms in early adulthood, and to examine whether the associations differ between persons with native Swedish parents and those with parents born in Iran and the former Yugoslavia. The two-wave panel comprised 19- and 23-year-old Swedish citizens whose parents were born in either Sweden, Iran or the former Yugoslavia. The composition of respondents' occupational networks contacts was measured with a so-called position generator. Depressive symptoms were assessed with a two-item depression screener. A population-averaged model was used to estimate the associations between depressive symptoms and access to occupational contact networks. Similar levels of depressive symptoms in respondents with parents born in Sweden and Yugoslavia were contrasted by a notably higher prevalence of these conditions in those with an Iranian background. After socioeconomic conditions were adjusted for, regression analysis showed that the propensity for depressive symptoms in women with an Iranian background increased with a higher number of manual class contacts, and decreased for men and women with Iranian parents with a higher number of prestigious occupational connections. The respective associations in persons with native Swedish parents and parents from the former Yugoslavia are partly reversed. Access to occupational contact networks, but also perceived ethnic identity, explained a large portion of the ethnic variation in depression. Mainly the group with an Iranian background seems to benefit from prestigious occupational contacts. Among those with an Iranian background, social status concerns and expected marginalization in manual class occupations may have contributed to their propensity for depressive symptoms. PMID- 28866475 TI - The spatial politics of place and health policy: Exploring Sustainability and Transformation Plans in the English NHS. AB - This paper explores how 'place' is conceptualised and mobilized in health policy and considers the implications of this. Using the on-going spatial reorganizing of the English NHS as an exemplar, we draw upon relational geographies of place for illumination. We focus on the introduction of 'Sustainability and Transformation Plans' (STPs): positioned to support improvements in care and relieve financial pressures within the health and social care system. STP implementation requires collaboration between organizations within 44 bounded territories that must reach 'local' consensus about service redesign under conditions of unprecedented financial constraint. Emphasising the continued influence of previous reorganizations, we argue that such spatialized practices elude neat containment within coherent territorial geographies. Rather than a technical process financially and spatially 'fixing' health and care systems, STPs exemplify post-politics-closing down the political dimensions of policy making by associating 'place' with 'local' empowerment to undertake highly resource-constrained management of health systems, distancing responsibility from national political processes. Relational understandings of place thus provide value in understanding health policies and systems, and help to identify where and how STPs might experience difficulties. PMID- 28866476 TI - Regulation of ERVs in pluripotent stem cells and reprogramming. AB - Recent advances in our understanding of endogenous retroviruses (ERVs) regulation and its functional aspects have provided us with vast power to unravel its role in the host's genome. Co-evolutionary model of ERVs and Kruppel associated box Zinc Finger Proteins (KRAB-ZFPs) provides a deeper knowledge of how the genome is shaped during the course of evolution. However, the role of ERVs in normal cellular function still remains an enigma. Here we review studies in recent years with a focus on the role of ERVs in maintaining stemness and cell fate reprogramming, along with the recent discoveries of novel regulatory factors which have been shown to mediate ERV expression in both canonical and non canonical pathways. PMID- 28866478 TI - Correction to "Automatic Quality Assessment of Echocardiograms Using Convolutional Neural Networks: Feasibility on the Apical Four-Chamber View". AB - In the above paper [1], the first footnote should have indicated the following information: A. H. Abdi and C. Luong are joint first authors. PMID- 28866477 TI - Amphiphilic semiconducting polymer as multifunctional nanocarrier for fluorescence/photoacoustic imaging guided chemo-photothermal therapy. AB - Chemo-photothermal nanotheranostics has the advantage of synergistic therapeutic effect, providing opportunities for optimized cancer therapy. However, current chemo-photothermal nanotheranostic systems generally comprise more than three components, encountering the potential issues of unstable nanostructures and unexpected conflicts in optical and biophysical properties among different components. We herein synthesize an amphiphilic semiconducting polymer (PEG-PCB) and utilize it as a multifunctional nanocarrier to simplify chemo-photothermal nanotheranostics. PEG-PCB has a semiconducting backbone that not only serves as the diagnostic component for near-infrared (NIR) fluorescence and photoacoustic (PA) imaging, but also acts as the therapeutic agent for photothermal therapy. In addition, the hydrophobic backbone of PEG-PCB provides strong hydrophobic and pi pi interactions with the aromatic anticancer drug such as doxorubicin for drug encapsulation and delivery. Such a trifunctionality of PEG-PCB eventually results in a greatly simplified nanotheranostic system with only two components but multimodal imaging and therapeutic capacities, permitting effective NIR fluorescence/PA imaging guided chemo-photothermal therapy of cancer in living mice. Our study thus provides a molecular engineering approach to integrate essential properties into one polymer for multimodal nanotheranostics. PMID- 28866479 TI - Type-1 Diabetes Patient Decision Simulator for In Silico Testing Safety and Effectiveness of Insulin Treatments. AB - OBJECTIVE: Type-1 diabetes (T1D) treatment requires exogenous insulin administrations finely tuned based on glucose monitoring to avoid hyper/hypoglycemia. The safety and effectiveness of insulin treatments is commonly assessed in clinical trials, which are time demanding and expensive. These limitations can be overtaken by in silico clinical trials (ISCT) that require realistic patient and treatment models. The aim is to develop a T1D patient decision simulator usable to perform reliable ISCT. METHODS: The T1D patient decision simulator was developed by connecting the UVA/Padova T1D model, which describes glucose, insulin, and glucagon kinetics, with modules describing glucose monitoring devices, like self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM), the patient's behavior in making treatment decisions, and insulin administration. The reliability of the simulator was assessed by comparing its predictions with data collected in 44 T1D subjects using the Dexcom G5 Mobile CGM sensor as an adjunct to the Bayer Contour Next USB SMBG device. RESULTS: Metrics like time spent in eu/hypo/hyperglycemia of simulated data well match those observed in subjects. In particular, mean time in euglycemia, mean time in hyperglycemia, and median time in hypoglycemia are 61.75% versus 63.60% (p-value = 0.4825), 33.38% versus 33.40% (p -value = 0.9950), and 3.17% versus 2.14% (p-value = 0.1134), respectively, in real versus simulated data. CONCLUSION: The proposed simulator can be used to perform credible ISCT in realistic insulin treatment scenarios. SIGNIFICANCE: The T1D patient decision simulator can be used to reliably assess novel insulin treatments, e.g., based on use of CGM only, in a realistic multiple-day scenario. PMID- 28866480 TI - Lung Ultrasound Surface Wave Elastography: A Pilot Clinical Study. AB - A lung ultrasound surface wave elastography (LUSWE) technique is developed to measure superficial lung tissue elastic properties. The purpose of this paper was to translate LUSWE into clinical studies for assessing patients with interstitial lung disease (ILD) and present the pilot data from lung measurements on 10 healthy subjects and 10 patients with ILD. ILD includes multiple lung disorders in which the lung tissue is distorted and stiffened by tissue fibrosis. Chest radiography and computed tomography are the most commonly used techniques for assessing lung disease, but they are associated with radiation and cannot directly measure lung elastic properties. LUSWE provides a noninvasive and nonionizing technique to measure the elastic properties of superficial lung tissue. LUSWE was used to measure regions of both lungs through six intercostal spaces for patients and healthy subjects. The data are presented as wave speed at 100, 150, and 200 Hz at the six intercostal spaces. As an example, the surface wave speeds are, respectively, 1.88 +/- 0.11 m/s at 100 Hz, 2.74 +/- 0.26 m/s at 150 Hz, and 3.62 +/- 0.13 m/s at 200 Hz for a healthy subject in the upper right lung; this is in comparison to measurements from an ILD patient of 3.3 +/- 0.37 m/s at 100 Hz, 4.38 +/- 0.33 m/s at 150 Hz, and 5.24 +/- 0.44 m/s at 200 Hz in the same lung space. Significant differences in wave speed between healthy subjects and ILD patients were found. LUSWE is a safe and noninvasive technique which may be useful for assessing ILD. PMID- 28866481 TI - Probabilistic Framework for the Characterization of Surfaces and Edges in Range Images, with Application to Edge Detection. AB - We develop a powerful probabilistic framework for the local characterization of surfaces and edges in range images. We use the geometrical nature of the data to derive an analytic expression for the joint probability density function (pdf) for the random variables used to model the ranges of a set of pixels in a local neighborhood of an image. We decompose this joint pdf by considering independently the cases where two real world points corresponding to two neighboring pixels are locally on the same real world surface or not. In particular, we show that this joint pdf is linked to the Voigt pdf and not to the Gaussian pdf as it is assumed in some applications. We apply our framework to edge detection and develop a locally adaptive algorithm that is based on a probabilistic decision rule. We show in an objective evaluation that this new edge detector performs better than prior art edge detectors. This proves the benefits of the probabilistic characterization of the local neighborhood as a tool to improve applications that involve range images. PMID- 28866482 TI - Robust Light Field Depth Estimation Using Occlusion-Noise Aware Data Costs. AB - Depth estimation is essential in many light field applications. Numerous algorithms have been developed using a range of light field properties. However, conventional data costs fail when handling noisy scenes in which occlusion is present. To address this problem, we introduce a light field depth estimation method that is more robust against occlusion and less sensitive to noise. Two novel data costs are proposed, which are measured using the angular patch and refocus image, respectively. The constrained angular entropy cost (CAE) reduces the effects of the dominant occluder and noise in the angular patch, resulting in a low cost. The constrained adaptive defocus cost (CAD) provides a low cost in the occlusion region, while also maintaining robustness against noise. Integrating the two data costs is shown to significantly improve the occlusion and noise invariant capability. Cost volume filtering and graph cut optimization are applied to improve the accuracy of the depth map. Our experimental results confirm the robustness of the proposed method and demonstrate its ability to produce high-quality depth maps from a range of scenes. The proposed method outperforms other state-of-the-art light field depth estimation methods in both qualitative and quantitative evaluations. PMID- 28866483 TI - A Multi-Modal, Discriminative and Spatially Invariant CNN for RGB-D Object Labeling. AB - While deep convolutional neural networks have shown a remarkable success in image classification, the problems of inter-class similarities, intra-class variances, the effective combination of multi-modal data, and the spatial variability in images of objects remain to be major challenges. To address these problems, this paper proposes a novel framework to learn a discriminative and spatially invariant classification model for object and indoor scene recognition using multi-modal RGB-D imagery. This is achieved through three postulates: 1) spatial invariance $-$ this is achieved by combining a spatial transformer network with a deep convolutional neural network to learn features which are invariant to spatial translations, rotations, and scale changes, 2) high discriminative capability $-$ this is achieved by introducing Fisher encoding within the CNN architecture to learn features which have small inter-class similarities and large intra-class compactness, and 3) multi-modal hierarchical fusion$-$ this is achieved through the regularization of semantic segmentation to a multi-modal CNN architecture, where class probabilities are estimated at different hierarchical levels (i.e., image- and pixel-levels), and fused into a Conditional Random Field (CRF)-based inference hypothesis, the optimization of which produces consistent class labels in RGB-D images. Extensive experimental evaluations on RGB-D object and scene datasets, and live video streams (acquired from Kinect) show that our framework produces superior object and scene classification results compared to the state-of-the-art methods. PMID- 28866484 TI - Image Visual Realism: From Human Perception to Machine Computation. AB - Visual realism is defined as the extent to which an image appears to people as a photo rather than computer generated. Assessing visual realism is important in applications like computer graphics rendering and photo retouching. However, current realism evaluation approaches use either labor-intensive human judgments or automated algorithms largely dependent on comparing renderings to reference images. We develop a reference-free computational framework for visual realism prediction to overcome these constraints. First, we construct a benchmark dataset of 2,520 images with comprehensive human annotated attributes. From statistical modeling on this data, we identify image attributes most relevant for visual realism. We propose both empirically-based (guided by our statistical modeling of human data) and deep convolutional neural network models to predict visual realism of images. Our framework has the following advantages: (1) it creates an interpretable and concise empirical model that characterizes human perception of visual realism; (2) it links computational features to latent factors of human image perception. PMID- 28866485 TI - Learning Joint-Sparse Codes for Calibration-Free Parallel MR Imaging. AB - The integration of compressed sensing and parallel imaging (CS-PI) has shown an increased popularity in recent years to accelerate magnetic resonance (MR) imaging. Among them, calibration-free techniques have presented encouraging performances due to its capability in robustly handling the sensitivity information. Unfortunately, existing calibration-free methods have only explored joint-sparsity with direct analysis transform projections. To further exploit joint-sparsity and improve reconstruction accuracy, this paper proposes to Learn joINt-sparse coDes for caliBration-free parallEl mR imaGing (LINDBERG) by modeling the parallel MR imaging problem as an - - minimization objective with an norm constraining data fidelity, Frobenius norm enforcing sparse representation error and the mixed norm triggering joint sparsity across multichannels. A corresponding algorithm has been developed to alternatively update the sparse representation, sensitivity encoded images and K-space data. Then, the final image is produced as the square root of sum of squares of all channel images. Experimental results on both physical phantom and in vivo data sets show that the proposed method is comparable and even superior to state-of-the-art CS-PI reconstruction approaches. Specifically, LINDBERG has presented strong capability in suppressing noise and artifacts while reconstructing MR images from highly undersampled multichannel measurements. PMID- 28866486 TI - Estimation of Basis Line-Integrals in a Spectral Distortion-Modeled Photon Counting Detector Using Low-Rank Approximation-Based X-Ray Transmittance Modeling: K-Edge Imaging Application. AB - Photon counting detectors (PCDs) provide multiple energy-dependent measurements for estimating basis line-integrals. However, the measured spectrum is distorted from the spectral response effect (SRE) via charge sharing, K-fluorescence emission, and so on. Thus, in order to avoid bias and artifacts in images, the SRE needs to be compensated. For this purpose, we recently developed a computationally efficient three-step algorithm for PCD-CT without contrast agents by approximating smooth X-ray transmittance using low-order polynomial bases. It compensated the SRE by incorporating the SRE model in a linearized estimation process and achieved nearly the minimum variance and unbiased (MVU) estimator. In this paper, we extend the three-step algorithm to K-edge imaging applications by designing optimal bases using a low-rank approximation to model X-ray transmittances with arbitrary shapes (i.e., smooth without the K-edge or discontinuous with the K-edge). The bases can be used to approximate the X-ray transmittance and to linearize the PCD measurement modeling and then the three step estimator can be derived as in the previous approach: estimating the x-ray transmittance in the first step, estimating basis line-integrals including that of the contrast agent in the second step, and correcting for a bias in the third step. We demonstrate that the proposed method is more accurate and stable than the low-order polynomial-based approaches with extensive simulation studies using gadolinium for the K-edge imaging application. We also demonstrate that the proposed method achieves nearly MVU estimator, and is more stable than the conventional maximum likelihood estimator in high attenuation cases with fewer photon counts. PMID- 28866487 TI - Motion Tracking of the Carotid Artery Wall From Ultrasound Image Sequences: a Nonlinear State-Space Approach. AB - The motion of the common carotid artery (CCA) wall has been established to be useful in early diagnosis of atherosclerotic disease. However, tracking the CCA wall motion from ultrasound images remains a challenging task. In this paper, a nonlinear state-space approach has been developed to track CCA wall motion from ultrasound sequences. In this approach, a nonlinear state-space equation with a time-variant control signal was constructed from a mathematical model of the dynamics of the CCA wall. Then, the unscented Kalman filter (UKF) was adopted to solve the nonlinear state transfer function in order to evolve the state of the target tissue, which involves estimation of the motion trajectory of the CCA wall from noisy ultrasound images. The performance of this approach has been validated on 30 simulated ultrasound sequences and a real ultrasound dataset of 103 subjects by comparing the motion tracking results obtained in this study to those of three state-of-the-art methods and of the manual tracing method performed by two experienced ultrasound physicians. The experimental results demonstrated that the proposed approach is highly correlated with (intra-class correlation coefficient >= 0.9948 for the longitudinal motion and >= 0.9966 for the radial motion) and well agrees (the 95% confidence interval width is 0.8871 mm for the longitudinal motion and 0.4159 mm for the radial motion) with the manual tracing method on real data and also exhibits high accuracy on simulated data (0.1161 ~ 0.1260 mm). These results appear to demonstrate the effectiveness of the proposed approach for motion tracking of the CCA wall. PMID- 28866488 TI - Radiation Dose Reduction in CT Myocardial Perfusion Imaging Using SMART-RECON. AB - In this paper, a newly developed statistical model-based image reconstruction [referred to as Simultaneous Multiple Artifacts Reduction in Tomographic RECONstruction (SMART-RECON)] is applied to low dose computer tomography (CT) myocardial perfusion imaging (CT-MPI). This method uses the nuclear norm of the spatial-temporal image matrix of the CT-MPI images as a regularizer, rather than a conventional spatial regularizer that incorporates image smoothness, edge preservation, or spatial sparsity into the reconstruction. In addition to providing the needed noise reduction for low-dose CT-MPI, SMART-RECON provides images with spatial resolution and noise power spectrum (NPS) properties, which are independent of contrast and dose levels. Both numerical simulations and in vivo animal studies were performed to validate the proposed method. In these studies, it was found that: 1) quantitative accuracy of perfusion maps in CT-MPI was well maintained for radiation dose level as low as 10 mAs per image frame, compared with the reference standard of 200 mAs for conventional filtered backprojection; 2) flow-occluded myocardium in the porcine heart was well delineated by SMART-RECON at 10 mAs per frame when compared with model-based image reconstruction using spatial total variation (TV) as the regularizer (referred to as TV-SIR) or spatial-temporal TV (ST-TV-SIR); the CT-MPI results were confirmed with positron-emission tomography imaging; 3) image sharpness in SMART-RECON images was nearly independent of image contrast level and radiation dose level, in stark contrast to TV-SIR and ST-TV-SIR, which displayed a strong dependence on both image contrast and radiation dose levels; and 4) the structure of the dose-normalized NPS for the SMART-RECON method did not depend on dose, while the TV-SIR and ST-TV-SIR NPS structure was dose-dependent. PMID- 28866489 TI - Simultaneous Ultrasonic Measurement of Thickness and Speed of Sound in Elastic Plates Using Coded Excitation Signals. AB - Layer thickness and the speed of sound are important parameters for nondestructive testing applications. If one of the parameters is known, the other one can be determined by simple time-of-flight (TOF) measurement of ultrasound. However, often these parameters are both unknown. In this contribution, we examine and adapt ultrasonic imaging techniques using coded excitation signals to simultaneously measure the thickness and the speed of sound of homogeneous elastic plates of unknown material. Good axial resolution is required to measure thin samples. We present a new approach for transmission signal conditioning to improve axial resolution. This conditioning consists of enhancing spectral components that are damped by the transducer prior to transmit. Due to the long duration of coded excitation signals, pulse compression techniques are required for TOF measurements. Common pulse compression filters are discussed, and appropriate filtering of the compression waveform is designed to keep the sidelobe level (SLL) acceptably low. An experimental assessment of the presented measurement techniques reveals that the signal conditioning substantially increases the axial resolution. However, a tapered Wiener filter should be used for the best tradeoff between SLL and axial resolution. We used the proposed method to measure different plates of steel, aluminum, and polymethylmethacrylate of various thicknesses, and the results show very good agreement with the reference values, which we obtained with a micrometer screw and by standard TOF measurement, respectively. The relative error for the plate thickness is smaller than 2.2% and that for the speed of sound is smaller than 3%. It is remarkable that plate thickness could be measured down to 60% of the wavelength. PMID- 28866490 TI - Hadamard-Encoded Multipulses for Contrast-Enhanced Ultrasound Imaging. AB - The development of contrast-enhanced ultrasound (CEUS) imaging offers great opportunities for new ultrasound clinical applications such as myocardial perfusion imaging and abdominal lesion characterization. In CEUS imaging, the contrast agents (i.e., microbubbles) are utilized to improve the contrast between blood and tissue based on their high nonlinearity under low ultrasound pressure. In this paper, we propose a new CEUS pulse sequence by combining Hadamard-encoded multipulses (HEM) with fundamental frequency bandpass filter (i.e., filter centered on transmit frequency). HEM consecutively emits multipulses encoded by a second-order Hadamard matrix in each of the two transmission events (i.e., pulse echo events), as opposed to conventional CEUS methods which emit individual pulses in two separate transmission events (i.e., pulse inversion (PI), amplitude modulation (AM), and PIAM). In HEM imaging, the microbubble responses can be improved by the longer transmit pulse, and the tissue harmonics can be suppressed by the fundamental frequency filter, leading to significantly improved contrast to-tissue ratio (CTR) and signal-to-noise ratio (SNR). In addition, the fast polarity change between consecutive coded pulse emissions excites strong nonlinear microbubble echoes, further enhancing the CEUS image quality. The spatial resolution of HEM image is compromised as compared to other microbubble imaging methods due to the longer transmit pulses and the lower imaging frequency (i.e., fundamental frequency). However, the resolution loss was shown to be negligible and could be offset by the significantly enhanced CTR, SNR, and penetration depth. These properties of HEM can potentially facilitate robust CEUS imaging for many clinical applications, especially for deep abdominal organs and heart. PMID- 28866491 TI - Fusion of Deep Learning and Compressed Domain Features for Content-Based Image Retrieval. AB - This paper presents an effective image retrieval method by combining high-level features from convolutional neural network (CNN) model and low-level features from dot-diffused block truncation coding (DDBTC). The low-level features, e.g., texture and color, are constructed by vector quantization -indexed histogram from DDBTC bitmap, maximum, and minimum quantizers. Conversely, high-level features from CNN can effectively capture human perception. With the fusion of the DDBTC and CNN features, the extended deep learning two-layer codebook features is generated using the proposed two-layer codebook, dimension reduction, and similarity reweighting to improve the overall retrieval rate. Two metrics, average precision rate and average recall rate (ARR), are employed to examine various data sets. As documented in the experimental results, the proposed schemes can achieve superior performance compared with the state-of-the-art methods with either low-or high-level features in terms of the retrieval rate. Thus, it can be a strong candidate for various image retrieval related applications. PMID- 28866492 TI - Recovery of Lost Color and Depth Frames in Multiview Videos. AB - In this paper, we consider an integrated error concealment system for lost color frames and lost depth frames in multiview videos with depths. We first proposed a pixel-based color error-concealment method with the use of depth information. Instead of assuming that the same moving object in consecutive frames has minimal depth difference, as is done in a state-of-the-art method, a more realistic situation in which the same moving object in consecutive frames can be in different depths is considered. In the derived motion vector candidate set, we consider all the candidate motion vectors in the set, and weight the reference pixels by the depth differences to obtain the final recovered pixel. Compared with the two state-of-the-art methods, the proposed method has average peak signal-to-noise ratio gains of up to 8.73 and 3.98 dB, respectively. Second, we proposed an iterative depth frame error-concealment method. The initial recovered depth frame is obtained by depth-image-based rendering from another available view. The holes in the recovered depth frame are then filled in the proposed priority order. Preprocessing methods (depth difference compensation and inconsistent pixel removal) are performed to improve the performance. Compared with a method that uses the available motion vector in a color frame to recover the lost depth pixels, the hybrid motion vector extrapolation method, the inpainting method and the proposed method have gains of up to 4.31, 10.29, and 6.04 dB, respectively. Finally, for the situation in which the color and the depth frames are lost at the same time, our two methods jointly perform better with a gain of up to 7.79 dB. PMID- 28866493 TI - Objective Quality Assessment of Image Retargeting by Incorporating Fidelity Measures and Inconsistency Detection. AB - The tremendous growth in mobile devices has resulted in huge generation and usage of digital images. Image quality assessment is thus an important issue for mobile media applications. In this paper, we focus on the quality evaluation of images generated by content-aware image retargeting, in which the reference and the distorted images are of different sizes. Through retargeting, many types of deformation inconsistency lead to shape distortion, deformation artifacts, and content information loss, worsening its perceptual quality. The deformation inconsistency occurs on different levels of the retargeted images. Limited by the accuracy of the alignment between the original and retargeted images, previous methods only focus on pixel-level and patch-level fidelity analyses and fail to detect deformation inconsistency. In this paper, we improve the alignment algorithm and propose a three-level representation of the retargeting process. Based on the analysis of this three-level representation, both fidelity measures and inconsistency detection are combined to determine the final retargeting quality. The proposed algorithm is validated on the public data sets RetargetMe and CUHK. Experimental results demonstrate that inconsistency detection contributes to accurately assessing the image retargeting perceptual quality. This inspires us to investigate more about deformation inconsistency to formulate the objective quality of image retargeting. PMID- 28866494 TI - Unifying the Video and Question Attentions for Open-Ended Video Question Answering. AB - Video question answering is an important task toward scene understanding and visual data retrieval. However, current visual question answering works mainly focus on a single static image, which is distinct from the dynamic and sequential visual data in the real world. Their approaches cannot utilize the temporal information in videos. In this paper, we introduce the task of free-form open ended video question answering. The open-ended answers enable wider applications compared with the common multiple-choice tasks in Visual-QA. We first propose a data set for open-ended Video-QA with the automatic question generation approaches. Then, we propose our sequential video attention and temporal question attention models. These two models apply the attention mechanism on videos and questions, while preserving the sequential and temporal structures of the guides. The two models are integrated into the model of unified attention. After the video and the question are encoded, the answers are generated wordwisely from our models by a decoder. In the end, we evaluate our models on the proposed data set. The experimental results demonstrate the effectiveness of our proposed model. PMID- 28866495 TI - Background-Foreground Modeling Based on Spatiotemporal Sparse Subspace Clustering. AB - Background estimation and foreground segmentation are important steps in many high-level vision tasks. Many existing methods estimate background as a low-rank component and foreground as a sparse matrix without incorporating the structural information. Therefore, these algorithms exhibit degraded performance in the presence of dynamic backgrounds, photometric variations, jitter, shadows, and large occlusions. We observe that these backgrounds often span multiple manifolds. Therefore, constraints that ensure continuity on those manifolds will result in better background estimation. Hence, we propose to incorporate the spatial and temporal sparse subspace clustering into the robust principal component analysis (RPCA) framework. To that end, we compute a spatial and temporal graph for a given sequence using motion-aware correlation coefficient. The information captured by both graphs is utilized by estimating the proximity matrices using both the normalized Euclidean and geodesic distances. The low-rank component must be able to efficiently partition the spatiotemporal graphs using these Laplacian matrices. Embedded with the RPCA objective function, these Laplacian matrices constrain the background model to be spatially and temporally consistent, both on linear and nonlinear manifolds. The solution of the proposed objective function is computed by using the linearized alternating direction method with adaptive penalty optimization scheme. Experiments are performed on challenging sequences from five publicly available datasets and are compared with the 23 existing state-of-the-art methods. The results demonstrate excellent performance of the proposed algorithm for both the background estimation and foreground segmentation. PMID- 28866496 TI - Convex Multiview Semi-Supervised Classification. AB - In many practical applications, there are a great number of unlabeled samples available, while labeling them is a costly and tedious process. Therefore, how to utilize unlabeled samples to assist digging out potential information about the problem is very important. In this paper, we study a multiclass semi-supervised classification task in the context of multiview data. First, an optimization method named Parametric multiview semi-supervised classification (PMSSC) is proposed, where the built classifier for each individual view is explicitly combined with a weight factor. By analyzing the weakness of it, a new adapted weight learning strategy is further formulated, and we come to the convex multiview semi-supervised classification (CMSSC) method. Comparing with the PMSSC, this method has two significant properties. First, without too much loss in performance, the newly used weight learning technique achieves eliminating a hyperparameter, and thus it becomes more compact in form and practical to use. Second, as its name implies, the CMSSC models a convex problem, which avoids the local-minimum problem. Experimental results on several multiview data sets demonstrate that the proposed methods achieve better performances than recent representative methods and the CMSSC is preferred due to its good traits. PMID- 28866497 TI - Discriminant Analysis on Riemannian Manifold of Gaussian Distributions for Face Recognition With Image Sets. AB - To address the problem of face recognition with image sets, we aim to capture the underlying data distribution in each set and thus facilitate more robust classification. To this end, we represent image set as the Gaussian mixture model (GMM) comprising a number of Gaussian components with prior probabilities and seek to discriminate Gaussian components from different classes. Since in the light of information geometry, the Gaussians lie on a specific Riemannian manifold, this paper presents a method named discriminant analysis on Riemannian manifold of Gaussian distributions (DARG). We investigate several distance metrics between Gaussians and accordingly two discriminative learning frameworks are presented to meet the geometric and statistical characteristics of the specific manifold. The first framework derives a series of provably positive definite probabilistic kernels to embed the manifold to a high-dimensional Hilbert space, where conventional discriminant analysis methods developed in Euclidean space can be applied, and a weighted Kernel discriminant analysis is devised which learns discriminative representation of the Gaussian components in GMMs with their prior probabilities as sample weights. Alternatively, the other framework extends the classical graph embedding method to the manifold by utilizing the distance metrics between Gaussians to construct the adjacency graph, and hence the original manifold is embedded to a lower-dimensional and discriminative target manifold with the geometric structure preserved and the interclass separability maximized. The proposed method is evaluated by face identification and verification tasks on four most challenging and largest databases, YouTube Celebrities, COX, YouTube Face DB, and Point-and-Shoot Challenge, to demonstrate its superiority over the state-of-the-art.To address the problem of face recognition with image sets, we aim to capture the underlying data distribution in each set and thus facilitate more robust classification. To this end, we represent image set as the Gaussian mixture model (GMM) comprising a number of Gaussian components with prior probabilities and seek to discriminate Gaussian components from different classes. Since in the light of information geometry, the Gaussians lie on a specific Riemannian manifold, this paper presents a method named discriminant analysis on Riemannian manifold of Gaussian distributions (DARG). We investigate several distance metrics between Gaussians and accordingly two discriminative learning frameworks are presented to meet the geometric and statistical characteristics of the specific manifold. The first framework derives a series of provably positive definite probabilistic kernels to embed the manifold to a high-dimensional Hilbert space, where conventional discriminant analysis methods developed in Euclidean space can be applied, and a weighted Kernel discriminant analysis is devised which learns discriminative representation of the Gaussian components in GMMs with their prior probabilities as sample weights. Alternatively, the other framework extends the classical graph embedding method to the manifold by utilizing the distance metrics between Gaussians to construct the adjacency graph, and hence the original manifold is embedded to a lower-dimensional and discriminative target manifold with the geometric structure preserved and the interclass separability maximized. The proposed method is evaluated by face identification and verification tasks on four most challenging and largest databases, YouTube Celebrities, COX, YouTube Face DB, and Point-and-Shoot Challenge, to demonstrate its superiority over the state-of-the-art. PMID- 28866498 TI - Random Walks for Synthetic Aperture Radar Image Fusion in Framelet Domain. AB - A new framelet-based random walks (RWs) method is presented for synthetic aperture radar (SAR) image fusion, including SAR-visible images, SAR-infrared images, and Multi-band SAR images. In this method, we build a novel RWs model based on the statistical characteristics of framelet coefficients to fuse the high-frequency and low-frequency coefficients. This model converts the fusion problem to estimate the probability of each framelet coefficient being assigned each input image. Experimental results show that the proposed approach improves the contrast while preserves the edges simultaneously, and outperforms many traditional and state-of-the-art fusion techniques in both qualitative and quantitative analysis. PMID- 28866499 TI - What Would a Graph Look Like in this Layout? A Machine Learning Approach to Large Graph Visualization. AB - Using different methods for laying out a graph can lead to very different visual appearances, with which the viewer perceives different information. Selecting a "good" layout method is thus important for visualizing a graph. The selection can be highly subjective and dependent on the given task. A common approach to selecting a good layout is to use aesthetic criteria and visual inspection. However, fully calculating various layouts and their associated aesthetic metrics is computationally expensive. In this paper, we present a machine learning approach to large graph visualization based on computing the topological similarity of graphs using graph kernels. For a given graph, our approach can show what the graph would look like in different layouts and estimate their corresponding aesthetic metrics. An important contribution of our work is the development of a new framework to design graph kernels. Our experimental study shows that our estimation calculation is considerably faster than computing the actual layouts and their aesthetic metrics. Also, our graph kernels outperform the state-of-the-art ones in both time and accuracy. In addition, we conducted a user study to demonstrate that the topological similarity computed with our graph kernel matches perceptual similarity assessed by human users. PMID- 28866500 TI - MyBrush: Brushing and Linking with Personal Agency. AB - We extend the popular brushing and linking technique by incorporating personal agency in the interaction. We map existing research related to brushing and linking into a design space that deconstructs the interaction technique into three components: source (what is being brushed), link (the expression of relationship between source and target), and target (what is revealed as related to the source). Using this design space, we created MyBrush, a unified interface that offers personal agency over brushing and linking by giving people the flexibility to configure the source, link, and target of multiple brushes. The results of three focus groups demonstrate that people with different backgrounds leveraged personal agency in different ways, including performing complex tasks and showing links explicitly. We reflect on these results, paving the way for future research on the role of personal agency in information visualization. PMID- 28866501 TI - Imagining Replications: Graphical Prediction & Discrete Visualizations Improve Recall & Estimation of Effect Uncertainty. AB - People often have erroneous intuitions about the results of uncertain processes, such as scientific experiments. Many uncertainty visualizations assume considerable statistical knowledge, but have been shown to prompt erroneous conclusions even when users possess this knowledge. Active learning approaches been shown to improve statistical reasoning, but are rarely applied in visualizing uncertainty in scientific reports. We present a controlled study to evaluate the impact of an interactive, graphical uncertainty prediction technique for communicating uncertainty in experiment results. Using our technique, users sketch their prediction of the uncertainty in experimental effects prior to viewing the true sampling distribution from an experiment. We find that having a user graphically predict the possible effects from experiment replications is an effective way to improve one's ability to make predictions about replications of new experiments. Additionally, visualizing uncertainty as a set of discrete outcomes, as opposed to a continuous probability distribution, can improve recall of a sampling distribution from a single experiment. Our work has implications for various applications where it is important to elicit peoples' estimates of probability distributions and to communicate uncertainty effectively. PMID- 28866502 TI - Assessing the Graphical Perception of Time and Speed on 2D+Time Trajectories. AB - We empirically evaluate the extent to which people perceive non-constant time and speed encoded on 2D paths. In our graphical perception study, we evaluate nine encodings from the literature for both straight and curved paths. Visualizing time and speed information is a challenge when the x and y axes already encode other data dimensions, for example when plotting a trip on a map. This is particularly true in disciplines such as time-geography and movement analytics that often require visualizing spatio-temporal trajectories. A common approach is to use 2D+time trajectories, which are 2D paths for which time is an additional dimension. However, there are currently no guidelines regarding how to represent time and speed on such paths. Our study results provide InfoVis designers with clear guidance regarding which encodings to use and which ones to avoid; in particular, we suggest using color value to encode speed and segment length to encode time whenever possible. PMID- 28866503 TI - The Topology ToolKit. AB - This system paper presents the Topology ToolKit (TTK), a software platform designed for the topological analysis of scalar data in scientific visualization. While topological data analysis has gained in popularity over the last two decades, it has not yet been widely adopted as a standard data analysis tool for end users or developers. TTK aims at addressing this problem by providing a unified, generic, efficient, and robust implementation of key algorithms for the topological analysis of scalar data, including: critical points, integral lines, persistence diagrams, persistence curves, merge trees, contour trees, Morse-Smale complexes, fiber surfaces, continuous scatterplots, Jacobi sets, Reeb spaces, and more. TTK is easily accessible to end users due to a tight integration with ParaView. It is also easily accessible to developers through a variety of bindings (Python, VTK/C++) for fast prototyping or through direct, dependency free, C++, to ease integration into pre-existing complex systems. While developing TTK, we faced several algorithmic and software engineering challenges, which we document in this paper. In particular, we present an algorithm for the construction of a discrete gradient that complies to the critical points extracted in the piecewise-linear setting. This algorithm guarantees a combinatorial consistency across the topological abstractions supported by TTK, and importantly, a unified implementation of topological data simplification for multi-scale exploration and analysis. We also present a cached triangulation data structure, that supports time efficient and generic traversals, which self adjusts its memory usage on demand for input simplicial meshes and which implicitly emulates a triangulation for regular grids with no memory overhead. Finally, we describe an original software architecture, which guarantees memory efficient and direct accesses to TTK features, while still allowing for researchers powerful and easy bindings and extensions. TTK is open source (BSD license) and its code, online documentation and video tutorials are available on TTK's website [108]. PMID- 28866504 TI - Data Visualization Saliency Model: A Tool for Evaluating Abstract Data Visualizations. AB - Evaluating the effectiveness of data visualizations is a challenging undertaking and often relies on one-off studies that test a visualization in the context of one specific task. Researchers across the fields of data science, visualization, and human-computer interaction are calling for foundational tools and principles that could be applied to assessing the effectiveness of data visualizations in a more rapid and generalizable manner. One possibility for such a tool is a model of visual saliency for data visualizations. Visual saliency models are typically based on the properties of the human visual cortex and predict which areas of a scene have visual features (e.g. color, luminance, edges) that are likely to draw a viewer's attention. While these models can accurately predict where viewers will look in a natural scene, they typically do not perform well for abstract data visualizations. In this paper, we discuss the reasons for the poor performance of existing saliency models when applied to data visualizations. We introduce the Data Visualization Saliency (DVS) model, a saliency model tailored to address some of these weaknesses, and we test the performance of the DVS model and existing saliency models by comparing the saliency maps produced by the models to eye tracking data obtained from human viewers. Finally, we describe how modified saliency models could be used as general tools for assessing the effectiveness of visualizations, including the strengths and weaknesses of this approach. PMID- 28866505 TI - Globe Browsing: Contextualized Spatio-Temporal Planetary Surface Visualization. AB - Results of planetary mapping are often shared openly for use in scientific research and mission planning. In its raw format, however, the data is not accessible to non-experts due to the difficulty in grasping the context and the intricate acquisition process. We present work on tailoring and integration of multiple data processing and visualization methods to interactively contextualize geospatial surface data of celestial bodies for use in science communication. As our approach handles dynamic data sources, streamed from online repositories, we are significantly shortening the time between discovery and dissemination of data and results. We describe the image acquisition pipeline, the pre-processing steps to derive a 2.5D terrain, and a chunked level-of-detail, out-of-core rendering approach to enable interactive exploration of global maps and high-resolution digital terrain models. The results are demonstrated for three different celestial bodies. The first case addresses high-resolution map data on the surface of Mars. A second case is showing dynamic processes, such as concurrent weather conditions on Earth that require temporal datasets. As a final example we use data from the New Horizons spacecraft which acquired images during a single flyby of Pluto. We visualize the acquisition process as well as the resulting surface data. Our work has been implemented in the OpenSpace software [8], which enables interactive presentations in a range of environments such as immersive dome theaters, interactive touch tables, and virtual reality headsets. PMID- 28866506 TI - Bubble Treemaps for Uncertainty Visualization. AB - We present a novel type of circular treemap, where we intentionally allocate extra space for additional visual variables. With this extended visual design space, we encode hierarchically structured data along with their uncertainties in a combined diagram. We introduce a hierarchical and force-based circle-packing algorithm to compute Bubble Treemaps, where each node is visualized using nested contour arcs. Bubble Treemaps do not require any color or shading, which offers additional design choices. We explore uncertainty visualization as an application of our treemaps using standard error and Monte Carlo-based statistical models. To this end, we discuss how uncertainty propagates within hierarchies. Furthermore, we show the effectiveness of our visualization using three different examples: the package structure of Flare, the S&P 500 index, and the US consumer expenditure survey. PMID- 28866507 TI - The Good, the Bad, and the Ugly: A Theoretical Framework for the Assessment of Continuous Colormaps. AB - A myriad of design rules for what constitutes a "good" colormap can be found in the literature. Some common rules include order, uniformity, and high discriminative power. However, the meaning of many of these terms is often ambiguous or open to interpretation. At times, different authors may use the same term to describe different concepts or the same rule is described by varying nomenclature. These ambiguities stand in the way of collaborative work, the design of experiments to assess the characteristics of colormaps, and automated colormap generation. In this paper, we review current and historical guidelines for colormap design. We propose a specified taxonomy and provide unambiguous mathematical definitions for the most common design rules. PMID- 28866508 TI - Screen-Space Normal Distribution Function Caching for Consistent Multi-Resolution Rendering of Large Particle Data. AB - Molecular dynamics (MD) simulations are crucial to investigating important processes in physics and thermodynamics. The simulated atoms are usually visualized as hard spheres with Phong shading, where individual particles and their local density can be perceived well in close-up views. However, for large scale simulations with 10 million particles or more, the visualization of large fields-of-view usually suffers from strong aliasing artifacts, because the mismatch between data size and output resolution leads to severe under-sampling of the geometry. Excessive super-sampling can alleviate this problem, but is prohibitively expensive. This paper presents a novel visualization method for large-scale particle data that addresses aliasing while enabling interactive high quality rendering. We introduce the novel concept of screen-space normal distribution functions (S-NDFs) for particle data. S-NDFs represent the distribution of surface normals that map to a given pixel in screen space, which enables high-quality re-lighting without re-rendering particles. In order to facilitate interactive zooming, we cache S-NDFs in a screen-space mipmap (S-MIP). Together, these two concepts enable interactive, scale-consistent re-lighting and shading changes, as well as zooming, without having to re-sample the particle data. We show how our method facilitates the interactive exploration of real world large-scale MD simulation data in different scenarios. PMID- 28866509 TI - TopoAngler: Interactive Topology-Based Extraction of Fishes. AB - We present TopoAngler, a visualization framework that enables an interactive user guided segmentation of fishes contained in a micro-CT scan. The inherent noise in the CT scan coupled with the often disconnected (and sometimes broken) skeletal structure of fishes makes an automatic segmentation of the volume impractical. To overcome this, our framework combines techniques from computational topology with an interactive visual interface, enabling the human-in-the-Ioop to effectively extract fishes from the volume. In the first step, the join tree of the input is used to create a hierarchical segmentation of the volume. Through the use of linked views, the visual interface then allows users to interactively explore this hierarchy, and gather parts of individual fishes into a coherent sub-volume, thus reconstructing entire fishes. Our framework was primarily developed for its application to CT scans of fishes, generated as part of the ScanAllFish project, through close collaboration with their lead scientist. However, we expect it to also be applicable in other biological applications where a single dataset contains multiple specimen; a common routine that is now widely followed in laboratories to increase throughput of expensive CT scanners. PMID- 28866510 TI - Multiscale Visualization and Scale-Adaptive Modification of DNA Nanostructures. AB - We present an approach to represent DNA nanostructures in varying forms of semantic abstraction, describe ways to smoothly transition between them, and thus create a continuous multiscale visualization and interaction space for applications in DNA nanotechnology. This new way of observing, interacting with, and creating DNA nanostructures enables domain experts to approach their work in any of the semantic abstraction levels, supporting both low-level manipulations and high-level visualization and modifications. Our approach allows them to deal with the increasingly complex DNA objects that they are designing, to improve their features, and to add novel functions in a way that no existing single-scale approach offers today. For this purpose we collaborated with DNA nanotechnology experts to design a set of ten semantic scales. These scales take the DNA's chemical and structural behavior into account and depict it from atoms to the targeted architecture with increasing levels of abstraction. To create coherence between the discrete scales, we seamlessly transition between them in a well defined manner. We use special encodings to allow experts to estimate the nanoscale object's stability. We also add scale-adaptive interactions that facilitate the intuitive modification of complex structures at multiple scales. We demonstrate the applicability of our approach on an experimental use case. Moreover, feedback from our collaborating domain experts confirmed an increased time efficiency and certainty for analysis and modification tasks on complex DNA structures. Our method thus offers exciting new opportunities with promising applications in medicine and biotechnology. PMID- 28866511 TI - Robust Detection and Visualization of Jet-Stream Core Lines in Atmospheric Flow. AB - Jet-streams, their core lines and their role in atmospheric dynamics have been subject to considerable meteorological research since the first half of the twentieth century. Yet, until today no consistent automated feature detection approach has been proposed to identify jet-stream core lines from 3D wind fields. Such 3D core lines can facilitate meteorological analyses previously not possible. Although jet-stream cores can be manually analyzed by meteorologists in 2D as height ridges in the wind speed field, to the best of our knowledge no automated ridge detection approach has been applied to jet-stream core detection. In this work, we -a team of visualization scientists and meteorologists-propose a method that exploits directional information in the wind field to extract core lines in a robust and numerically less involved manner than traditional 3D ridge detection. For the first time, we apply the extracted 3D core lines to meteorological analysis, considering real-world case studies and demonstrating our method's benefits for weather forecasting and meteorological research. PMID- 28866512 TI - The Interactive Visualization Gap in Initial Exploratory Data Analysis. AB - Data scientists and other analytic professionals often use interactive visualization in the dissemination phase at the end of a workflow during which findings are communicated to a wider audience. Visualization scientists, however, hold that interactive representation of data can also be used during exploratory analysis itself. Since the use of interactive visualization is optional rather than mandatory, this leaves a "visualization gap" during initial exploratory analysis that is the onus of visualization researchers to fill. In this paper, we explore areas where visualization would be beneficial in applied research by conducting a design study using a novel variation on contextual inquiry conducted with professional data analysts. Based on these interviews and experiments, we propose a set of interactive initial exploratory visualization guidelines which we believe will promote adoption by this type of user. PMID- 28866513 TI - Structuring Visualization Mock-Ups at the Graphical Level by Dividing the Display Space. AB - Mock-ups are rapid, low fidelity prototypes, that are used in many design-related fields to generate and share ideas. While their creation is supported by many mature methods and tools, surprisingly few are suited for the needs of information visualization. In this article, we introduce a novel approach to creating visualizations mock-ups, based on a dialogue between graphic design and parametric toolkit explorations. Our approach consists in iteratively subdividing the display space, while progressively informing each division with realistic data. We show that a wealth of mock-ups can easily be created using only temporary data attributes, as we wait for more realistic data to become available. We describe the implementation of this approach in a D3-based toolkit, which we use to highlight its generative power, and we discuss the potential for transitioning towards higher fidelity prototypes. PMID- 28866514 TI - Nonlinear Dot Plots. AB - Conventional dot plots use a constant dot size and are typically applied to show the frequency distribution of small data sets. Unfortunately, they are not designed for a high dynamic range of frequencies. We address this problem by introducing nonlinear dot plots. Adopting the idea of nonlinear scaling from logarithmic bar charts, our plots allow for dots of varying size so that columns with a large number of samples are reduced in height. For the construction of these diagrams, we introduce an efficient two-way sweep algorithm that leads to a dense and symmetrical layout. We compensate aliasing artifacts at high dot densities by a specifically designed low-pass filtering method. Examples of nonlinear dot plots are compared to conventional dot plots as well as linear and logarithmic histograms. Finally, we include feedback from an expert review. PMID- 28866515 TI - VISTILES: Coordinating and Combining Co-located Mobile Devices for Visual Data Exploration. AB - We present VISTILES, a conceptual framework that uses a set of mobile devices to distribute and coordinate visualization views for the exploration of multivariate data. In contrast to desktop-based interfaces for information visualization, mobile devices offer the potential to provide a dynamic and user-defined interface supporting co-located collaborative data exploration with different individual workflows. As part of our framework, we contribute concepts that enable users to interact with coordinated & multiple views (CMV) that are distributed across several mobile devices. The major components of the framework are: (i) dynamic and flexible layouts for CMV focusing on the distribution of views and (ii) an interaction concept for smart adaptations and combinations of visualizations utilizing explicit side-by-side arrangements of devices. As a result, users can benefit from the possibility to combine devices and organize them in meaningful spatial layouts. Furthermore, we present a web-based prototype implementation as a specific instance of our concepts. This implementation provides a practical application case enabling users to explore a multivariate data collection. We also illustrate the design process including feedback from a preliminary user study, which informed the design of both the concepts and the final prototype. PMID- 28866516 TI - Interactive Design and Visualization of Branched Covering Spaces. AB - Branched covering spaces are a mathematical concept which originates from complex analysis and topology and has applications in tensor field topology and geometry remeshing. Given a manifold surface and an -way rotational symmetry field, a branched covering space is a manifold surface that has an -to-1 map to the original surface except at the ramification points, which correspond to the singularities in the rotational symmetry field. Understanding the notion and mathematical properties of branched covering spaces is important to researchers in tensor field visualization and geometry processing, and their application areas. In this paper, we provide a framework to interactively design and visualize the branched covering space (BCS) of an input mesh surface and a rotational symmetry field defined on it. In our framework, the user can visualize not only the BCSs but also their construction process. In addition, our system allows the user to design the geometric realization of the BCS using mesh deformation techniques as well as connecting tubes. This enables the user to verify important facts about BCSs such as that they are manifold surfaces around singularities, as well as the Riemann-Hurwitz formula which relates the Euler characteristic of the BCS to that of the original mesh. Our system is evaluated by student researchers in scientific visualization and geometry processing as well as faculty members in mathematics at our university who teach topology. We include their evaluations and feedback in the paper. PMID- 28866517 TI - On the Treatment of Field Quantities and Elemental Continuity in FEM Solutions. AB - As the finite element method (FEM) and the finite volume method (FVM), both traditional and high-order variants, continue their proliferation into various applied engineering disciplines, it is important that the visualization techniques and corresponding data analysis tools that act on the results produced by these methods faithfully represent the underlying data. To state this in another way: the interpretation of data generated by simulation needs to be consistent with the numerical schemes that underpin the specific solver technology. As the verifiable visualization literature has demonstrated: visual artifacts produced by the introduction of either explicit or implicit data transformations, such as data resampling, can sometimes distort or even obfuscate key scientific features in the data. In this paper, we focus on the handling of elemental continuity, which is often only continuous or piecewise discontinuous, when visualizing primary or derived fields from FEM or FVM simulations. We demonstrate that traditional data handling and visualization of these fields introduce visual errors. In addition, we show how the use of the recently proposed line-SIAC filter provides a way of handling elemental continuity issues in an accuracy-conserving manner with the added benefit of casting the data in a smooth context even if the representation is element discontinuous. PMID- 28866518 TI - Dynamic Load Balancing Based on Constrained K-D Tree Decomposition for Parallel Particle Tracing. AB - We propose a dynamically load-balanced algorithm for parallel particle tracing, which periodically attempts to evenly redistribute particles across processes based on k-d tree decomposition. Each process is assigned with (1) a statically partitioned, axis-aligned data block that partially overlaps with neighboring blocks in other processes and (2) a dynamically determined k-d tree leaf node that bounds the active particles for computation; the bounds of the k-d tree nodes are constrained by the geometries of data blocks. Given a certain degree of overlap between blocks, our method can balance the number of particles as much as possible. Compared with other load-balancing algorithms for parallel particle tracing, the proposed method does not require any preanalysis, does not use any heuristics based on flow features, does not make any assumptions about seed distribution, does not move any data blocks during the run, and does not need any master process for work redistribution. Based on a comprehensive performance study up to 8K processes on a Blue Gene/Q system, the proposed algorithm outperforms baseline approaches in both load balance and scalability on various flow visualization and analysis problems. PMID- 28866519 TI - An Intelligent System Approach for Probabilistic Volume Rendering Using Hierarchical 3D Convolutional Sparse Coding. AB - In this paper, we propose a novel machine learning-based voxel classification method for highly-accurate volume rendering. Unlike conventional voxel classification methods that incorporate intensity-based features, the proposed method employs dictionary based features learned directly from the input data using hierarchical multi-scale 3D convolutional sparse coding, a novel extension of the state-of-the-art learning-based sparse feature representation method. The proposed approach automatically generates high-dimensional feature vectors in up to 75 dimensions, which are then fed into an intelligent system built on a random forest classifier for accurately classifying voxels from only a handful of selection scribbles made directly on the input data by the user. We apply the probabilistic transfer function to further customize and refine the rendered result. The proposed method is more intuitive to use and more robust to noise in comparison with conventional intensity-based classification methods. We evaluate the proposed method using several synthetic and real-world volume datasets, and demonstrate the methods usability through a user study. PMID- 28866520 TI - A Virtual Reality Visualization Tool for Neuron Tracing. AB - Tracing neurons in large-scale microscopy data is crucial to establishing a wiring diagram of the brain, which is needed to understand how neural circuits in the brain process information and generate behavior. Automatic techniques often fail for large and complex datasets, and connectomics researchers may spend weeks or months manually tracing neurons using 2D image stacks. We present a design study of a new virtual reality (VR) system, developed in collaboration with trained neuroanatomists, to trace neurons in microscope scans of the visual cortex of primates. We hypothesize that using consumer-grade VR technology to interact with neurons directly in 3D will help neuroscientists better resolve complex cases and enable them to trace neurons faster and with less physical and mental strain. We discuss both the design process and technical challenges in developing an interactive system to navigate and manipulate terabyte-sized image volumes in VR. Using a number of different datasets, we demonstrate that, compared to widely used commercial software, consumer-grade VR presents a promising alternative for scientists. PMID- 28866521 TI - How Do Ancestral Traits Shape Family Trees Over Generations? AB - Whether and how does the structure of family trees differ by ancestral traits over generations? This is a fundamental question regarding the structural heterogeneity of family trees for the multi-generational transmission research. However, previous work mostly focuses on parent-child scenarios due to the lack of proper tools to handle the complexity of extending the research to multi generational processes. Through an iterative design study with social scientists and historians, we develop TreeEvo that assists users to generate and test empirical hypotheses for multi-generational research. TreeEvo summarizes and organizes family trees by structural features in a dynamic manner based on a traditional Sankey diagram. A pixel-based technique is further proposed to compactly encode trees with complex structures in each Sankey Node. Detailed information of trees is accessible through a space-efficient visualization with semantic zooming. Moreover, TreeEvo embeds Multinomial Logit Model (MLM) to examine statistical associations between tree structure and ancestral traits. We demonstrate the effectiveness and usefulness of TreeEvo through an in-depth case study with domain experts using a real-world dataset (containing 54,128 family trees of 126,196 individuals). PMID- 28866522 TI - LDSScanner: Exploratory Analysis of Low-Dimensional Structures in High Dimensional Datasets. AB - Many approaches for analyzing a high-dimensional dataset assume that the dataset contains specific structures, e.g., clusters in linear subspaces or non-linear manifolds. This yields a trial-and-error process to verify the appropriate model and parameters. This paper contributes an exploratory interface that supports visual identification of low-dimensional structures in a high-dimensional dataset, and facilitates the optimized selection of data models and configurations. Our key idea is to abstract a set of global and local feature descriptors from the neighborhood graph-based representation of the latent low dimensional structure, such as pairwise geodesic distance (GD) among points and pairwise local tangent space divergence (LTSD) among pointwise local tangent spaces (LTS). We propose a new LTSD-GD view, which is constructed by mapping LTSD and GD to the axis and axis using 1D multidimensional scaling, respectively. Unlike traditional dimensionality reduction methods that preserve various kinds of distances among points, the LTSD-GD view presents the distribution of pointwise LTS ( axis) and the variation of LTS in structures (the combination of axis and axis). We design and implement a suite of visual tools for navigating and reasoning about intrinsic structures of a high-dimensional dataset. Three case studies verify the effectiveness of our approach. PMID- 28866523 TI - Uncertainty Visualization Using Copula-Based Analysis in Mixed Distribution Models. AB - Distributions are often used to model uncertainty in many scientific datasets. To preserve the correlation among the spatially sampled grid locations in the dataset, various standard multivariate distribution models have been proposed in visualization literature. These models treat each grid location as a univariate random variable which models the uncertainty at that location. Standard multivariate distributions (both parametric and nonparametric) assume that all the univariate marginals are of the same type/family of distribution. But in reality, different grid locations show different statistical behavior which may not be modeled best by the same type of distribution. In this paper, we propose a new multivariate uncertainty modeling strategy to address the needs of uncertainty modeling in scientific datasets. Our proposed method is based on a statistically sound multivariate technique called Copula, which makes it possible to separate the process of estimating the univariate marginals and the process of modeling dependency, unlike the standard multivariate distributions. The modeling flexibility offered by our proposed method makes it possible to design distribution fields which can have different types of distribution (Gaussian, Histogram, KDE etc.) at the grid locations, while maintaining the correlation structure at the same time. Depending on the results of various standard statistical tests, we can choose an optimal distribution representation at each location, resulting in a more cost efficient modeling without significantly sacrificing on the analysis quality. To demonstrate the efficacy of our proposed modeling strategy, we extract and visualize uncertain features like isocontours and vortices in various real world datasets. We also study various modeling criterion to help users in the task of univariate model selection. PMID- 28866524 TI - Visualizing Nonlinear Narratives with Story Curves. AB - In this paper, we present story curves, a visualization technique for exploring and communicating nonlinear narratives in movies. A nonlinear narrative is a storytelling device that portrays events of a story out of chronological order, e.g., in reverse order or going back and forth between past and future events. Many acclaimed movies employ unique narrative patterns which in turn have inspired other movies and contributed to the broader analysis of narrative patterns in movies. However, understanding and communicating nonlinear narratives is a difficult task due to complex temporal disruptions in the order of events as well as no explicit records specifying the actual temporal order of the underlying story. Story curves visualize the nonlinear narrative of a movie by showing the order in which events are told in the movie and comparing them to their actual chronological order, resulting in possibly meandering visual patterns in the curve. We also present Story Explorer, an interactive tool that visualizes a story curve together with complementary information such as characters and settings. Story Explorer further provides a script curation interface that allows users to specify the chronological order of events in movies. We used Story Explorer to analyze 10 popular nonlinear movies and describe the spectrum of narrative patterns that we discovered, including some novel patterns not previously described in the literature. Feedback from experts highlights potential use cases in screenplay writing and analysis, education and film production. A controlled user study shows that users with no expertise are able to understand visual patterns of nonlinear narratives using story curves. PMID- 28866525 TI - Priming and Anchoring Effects in Visualization. AB - We investigate priming and anchoring effects on perceptual tasks in visualization. Priming or anchoring effects depict the phenomena that a stimulus might influence subsequent human judgments on a perceptual level, or on a cognitive level by providing a frame of reference. Using visual class separability in scatterplots as an example task, we performed a set of five studies to investigate the potential existence of priming and anchoring effects. Our findings show that-under certain circumstances-such effects indeed exist. In other words, humans judge class separability of the same scatterplot differently depending on the scatterplot(s) they have seen before. These findings inform future work on better understanding and more accurately modeling human perception of visual patterns. PMID- 28866526 TI - LSTMVis: A Tool for Visual Analysis of Hidden State Dynamics in Recurrent Neural Networks. AB - Recurrent neural networks, and in particular long short-term memory (LSTM) networks, are a remarkably effective tool for sequence modeling that learn a dense black-box hidden representation of their sequential input. Researchers interested in better understanding these models have studied the changes in hidden state representations over time and noticed some interpretable patterns but also significant noise. In this work, we present LSTMVis, a visual analysis tool for recurrent neural networks with a focus on understanding these hidden state dynamics. The tool allows users to select a hypothesis input range to focus on local state changes, to match these states changes to similar patterns in a large data set, and to align these results with structural annotations from their domain. We show several use cases of the tool for analyzing specific hidden state properties on dataset containing nesting, phrase structure, and chord progressions, and demonstrate how the tool can be used to isolate patterns for further statistical analysis. We characterize the domain, the different stakeholders, and their goals and tasks. Long-term usage data after putting the tool online revealed great interest in the machine learning community. PMID- 28866527 TI - StreetVizor: Visual Exploration of Human-Scale Urban Forms Based on Street Views. AB - Urban forms at human-scale, i.e., urban environments that individuals can sense (e.g., sight, smell, and touch) in their daily lives, can provide unprecedented insights on a variety of applications, such as urban planning and environment auditing. The analysis of urban forms can help planners develop high-quality urban spaces through evidence-based design. However, such analysis is complex because of the involvement of spatial, multi-scale (i.e., city, region, and street), and multivariate (e.g., greenery and sky ratios) natures of urban forms. In addition, current methods either lack quantitative measurements or are limited to a small area. The primary contribution of this work is the design of StreetVizor, an interactive visual analytics system that helps planners leverage their domain knowledge in exploring human-scale urban forms based on street view images. Our system presents two-stage visual exploration: 1) an AOI Explorer for the visual comparison of spatial distributions and quantitative measurements in two areas-of-interest (AOIs) at city- and region-scales; 2) and a Street Explorer with a novel parallel coordinate plot for the exploration of the fine-grained details of the urban forms at the street-scale. We integrate visualization techniques with machine learning models to facilitate the detection of street view patterns. We illustrate the applicability of our approach with case studies on the real-world datasets of four cities, i.e., Hong Kong, Singapore, Greater London and New York City. Interviews with domain experts demonstrate the effectiveness of our system in facilitating various analytical tasks. PMID- 28866528 TI - Scatterplots: Tasks, Data, and Designs. AB - Traditional scatterplots fail to scale as the complexity and amount of data increases. In response, there exist many design options that modify or expand the traditional scatterplot design to meet these larger scales. This breadth of design options creates challenges for designers and practitioners who must select appropriate designs for particular analysis goals. In this paper, we help designers in making design choices for scatterplot visualizations. We survey the literature to catalog scatterplot-specific analysis tasks. We look at how data characteristics influence design decisions. We then survey scatterplot-like designs to understand the range of design options. Building upon these three organizations, we connect data characteristics, analysis tasks, and design choices in order to generate challenges, open questions, and example best practices for the effective design of scatterplots. PMID- 28866529 TI - Keeping Multiple Views Consistent: Constraints, Validations, and Exceptions in Visualization Authoring. AB - Visualizations often appear in multiples, either in a single display (e.g., small multiples, dashboard) or across time or space (e.g., slideshow, set of dashboards). However, existing visualization design guidelines typically focus on single rather than multiple views. Solely following these guidelines can lead to effective yet inconsistent views (e.g., the same field has different axes domains across charts), making interpretation slow and error-prone. Moreover, little is known how consistency balances with other design considerations, making it difficult to incorporate consistency mechanisms in visualization authoring software. We present a wizard-of-oz study in which we observed how Tableau users achieve and sacrifice consistency in an exploration-to-presentation visualization design scenario. We extend (from our prior work) a set of encoding-specific constraints defining consistency across multiple views. Using the constraints as a checklist in our study, we observed cases where participants spontaneously maintained consistent encodings and warned cases where consistency was overlooked. In response to the warnings, participants either revised views for consistency or stated why they thought consistency should be overwritten. We categorize participants' actions and responses as constraint validations and exceptions, depicting the relative importance of consistency and other design considerations under various circumstances (e.g., data cardinality, available encoding resources, chart layout). We discuss automatic consistency checking as a constraint-satisfaction problem and provide design implications for communicating inconsistencies to users. PMID- 28866530 TI - Considerations for Visualizing Comparison. AB - Supporting comparison is a common and diverse challenge in visualization. Such support is difficult to design because solutions must address both the specifics of their scenario as well as the general issues of comparison. This paper aids designers by providing a strategy for considering those general issues. It presents four considerations that abstract comparison. These considerations identify issues and categorize solutions in a domain independent manner. The first considers how the common elements of comparison-a target set of items that are related and an action the user wants to perform on that relationship-are present in an analysis problem. The second considers why these elements lead to challenges because of their scale, in number of items, complexity of items, or complexity of relationship. The third considers what strategies address the identified scaling challenges, grouping solutions into three broad categories. The fourth considers which visual designs map to these strategies to provide solutions for a comparison analysis problem. In sequence, these considerations provide a process for developers to consider support for comparison in the design of visualization tools. Case studies show how these considerations can help in the design and evaluation of visualization solutions for comparison problems. PMID- 28866531 TI - iTTVis: Interactive Visualization of Table Tennis Data. AB - The rapid development of information technology paved the way for the recording of fine-grained data, such as stroke techniques and stroke placements, during a table tennis match. This data recording creates opportunities to analyze and evaluate matches from new perspectives. Nevertheless, the increasingly complex data poses a significant challenge to make sense of and gain insights into. Analysts usually employ tedious and cumbersome methods which are limited to watching videos and reading statistical tables. However, existing sports visualization methods cannot be applied to visualizing table tennis competitions due to different competition rules and particular data attributes. In this work, we collaborate with data analysts to understand and characterize the sophisticated domain problem of analysis of table tennis data. We propose iTTVis, a novel interactive table tennis visualization system, which to our knowledge, is the first visual analysis system for analyzing and exploring table tennis data. iTTVis provides a holistic visualization of an entire match from three main perspectives, namely, time-oriented, statistical, and tactical analyses. The proposed system with several well-coordinated views not only supports correlation identification through statistics and pattern detection of tactics with a score timeline but also allows cross analysis to gain insights. Data analysts have obtained several new insights by using iTTVis. The effectiveness and usability of the proposed system are demonstrated with four case studies. PMID- 28866532 TI - SparseLeap: Efficient Empty Space Skipping for Large-Scale Volume Rendering. AB - Recent advances in data acquisition produce volume data of very high resolution and large size, such as terabyte-sized microscopy volumes. These data often contain many fine and intricate structures, which pose huge challenges for volume rendering, and make it particularly important to efficiently skip empty space. This paper addresses two major challenges: (1) The complexity of large volumes containing fine structures often leads to highly fragmented space subdivisions that make empty regions hard to skip efficiently. (2) The classification of space into empty and non-empty regions changes frequently, because the user or the evaluation of an interactive query activate a different set of objects, which makes it unfeasible to pre-compute a well-adapted space subdivision. We describe the novel SparseLeap method for efficient empty space skipping in very large volumes, even around fine structures. The main performance characteristic of SparseLeap is that it moves the major cost of empty space skipping out of the ray casting stage. We achieve this via a hybrid strategy that balances the computational load between determining empty ray segments in a rasterization (object-order) stage, and sampling non-empty volume data in the ray-casting (image-order) stage. Before ray-casting, we exploit the fast hardware rasterization of GPUs to create a ray segment list for each pixel, which identifies non-empty regions along the ray. The ray-casting stage then leaps over empty space without hierarchy traversal. Ray segment lists are created by rasterizing a set of fine-grained, view-independent bounding boxes. Frame coherence is exploited by re-using the same bounding boxes unless the set of active objects changes. We show that SparseLeap scales better to large, sparse data than standard octree empty space skipping. PMID- 28866533 TI - Instant Construction and Visualization of Crowded Biological Environments. AB - We present the first approach to integrative structural modeling of the biological mesoscale within an interactive visual environment. These complex models can comprise up to millions of molecules with defined atomic structures, locations, and interactions. Their construction has previously been attempted only within a non-visual and non-interactive environment. Our solution unites the modeling and visualization aspect, enabling interactive construction of atomic resolution mesoscale models of large portions of a cell. We present a novel set of GPU algorithms that build the basis for the rapid construction of complex biological structures. These structures consist of multiple membrane-enclosed compartments including both soluble molecules and fibrous structures. The compartments are defined using volume voxelization of triangulated meshes. For membranes, we present an extension of the Wang Tile concept that populates the bilayer with individual lipids. Soluble molecules are populated within compartments distributed according to a Halton sequence. Fibrous structures, such as RNA or actin filaments, are created by self-avoiding random walks. Resulting overlaps of molecules are resolved by a forced-based system. Our approach opens new possibilities to the world of interactive construction of cellular compartments. We demonstrate its effectiveness by showcasing scenes of different scale and complexity that comprise blood plasma, mycoplasma, and HIV. PMID- 28866534 TI - Abstractocyte: A Visual Tool for Exploring Nanoscale Astroglial Cells. AB - This paper presents Abstractocyte, a system for the visual analysis of astrocytes and their relation to neurons, in nanoscale volumes of brain tissue. Astrocytes are glial cells, i.e., non-neuronal cells that support neurons and the nervous system. The study of astrocytes has immense potential for understanding brain function. However, their complex and widely-branching structure requires high resolution electron microscopy imaging and makes visualization and analysis challenging. Furthermore, the structure and function of astrocytes is very different from neurons, and therefore requires the development of new visualization and analysis tools. With Abstractocyte, biologists can explore the morphology of astrocytes using various visual abstraction levels, while simultaneously analyzing neighboring neurons and their connectivity. We define a novel, conceptual 2D abstraction space for jointly visualizing astrocytes and neurons. Neuroscientists can choose a specific joint visualization as a point in this space. Interactively moving this point allows them to smoothly transition between different abstraction levels in an intuitive manner. In contrast to simply switching between different visualizations, this preserves the visual context and correlations throughout the transition. Users can smoothly navigate from concrete, highly-detailed 3D views to simplified and abstracted 2D views. In addition to investigating astrocytes, neurons, and their relationships, we enable the interactive analysis of the distribution of glycogen, which is of high importance to neuroscientists. We describe the design of Abstractocyte, and present three case studies in which neuroscientists have successfully used our system to assess astrocytic coverage of synapses, glycogen distribution in relation to synapses, and astrocytic-mitochondria coverage. PMID- 28866535 TI - Blinded with Science or Informed by Charts? A Replication Study. AB - We provide a reappraisal of Tal and Wansink's study "Blinded with Science", where seemingly trivial charts were shown to increase belief in drug efficacy, presumably because charts are associated with science. Through a series of four replications conducted on two crowdsourcing platforms, we investigate an alternative explanation, namely, that the charts allowed participants to better assess the drug's efficacy. Considered together, our experiments suggest that the chart seems to have indeed promoted understanding, although the effect is likely very small. Meanwhile, we were unable to replicate the original study's findings, as text with chart appeared to be no more persuasive - and sometimes less persuasive - than text alone. This suggests that the effect may not be as robust as claimed and may need specific conditions to be reproduced. Regardless, within our experimental settings and considering our study as a whole (), the chart's contribution to understanding was clearly larger than its contribution to persuasion. PMID- 28866536 TI - Decision Graph Embedding for High-Resolution Manometry Diagnosis. AB - High-resolution manometry is an imaging modality which enables the categorization of esophageal motility disorders. Spatio-temporal pressure data along the esophagus is acquired using a tubular device and multiple test swallows are performed by the patient. Current approaches visualize these swallows as individual instances, despite the fact that aggregated metrics are relevant in the diagnostic process. Based on the current Chicago Classification, which serves as the gold standard in this area, we introduce a visualization supporting an efficient and correct diagnosis. To reach this goal, we propose a novel decision graph representing the Chicago Classification with workflow optimization in mind. Based on this graph, we are further able to prioritize the different metrics used during diagnosis and can exploit this prioritization in the actual data visualization. Thus, different disorders and their related parameters are directly represented and intuitively influence the appearance of our visualization. Within this paper, we introduce our novel visualization, justify the design decisions, and provide the results of a user study we performed with medical students as well as a domain expert. On top of the presented visualization, we further discuss how to derive a visual signature for individual patients that allows us for the first time to perform an intuitive comparison between subjects, in the form of small multiples. PMID- 28866537 TI - CyteGuide: Visual Guidance for Hierarchical Single-Cell Analysis. AB - Single-cell analysis through mass cytometry has become an increasingly important tool for immunologists to study the immune system in health and disease. Mass cytometry creates a high-dimensional description vector for single cells by time of-flight measurement. Recently, t-Distributed Stochastic Neighborhood Embedding (t-SNE) has emerged as one of the state-of-the-art techniques for the visualization and exploration of single-cell data. Ever increasing amounts of data lead to the adoption of Hierarchical Stochastic Neighborhood Embedding (HSNE), enabling the hierarchical representation of the data. Here, the hierarchy is explored selectively by the analyst, who can request more and more detail in areas of interest. Such hierarchies are usually explored by visualizing disconnected plots of selections in different levels of the hierarchy. This poses problems for navigation, by imposing a high cognitive load on the analyst. In this work, we present an interactive summary-visualization to tackle this problem. CyteGuide guides the analyst through the exploration of hierarchically represented single-cell data, and provides a complete overview of the current state of the analysis. We conducted a two-phase user study with domain experts that use HSNE for data exploration. We first studied their problems with their current workflow using HSNE and the requirements to ease this workflow in a field study. These requirements have been the basis for our visual design. In the second phase, we verified our proposed solution in a user evaluation. PMID- 28866538 TI - Extracting and Retargeting Color Mappings from Bitmap Images of Visualizations. AB - Visualization designers regularly use color to encode quantitative or categorical data. However, visualizations "in the wild" often violate perceptual color design principles and may only be available as bitmap images. In this work, we contribute a method to semi-automatically extract color encodings from a bitmap visualization image. Given an image and a legend location, we classify the legend as describing either a discrete or continuous color encoding, identify the colors used, and extract legend text using OCR methods. We then combine this information to recover the specific color mapping. Users can also correct interpretation errors using an annotation interface. We evaluate our techniques using a corpus of images extracted from scientific papers and demonstrate accurate automatic inference of color mappings across a variety of chart types. In addition, we present two applications of our method: automatic recoloring to improve perceptual effectiveness, and interactive overlays to enable improved reading of static visualizations. PMID- 28866539 TI - Clique Community Persistence: A Topological Visual Analysis Approach for Complex Networks. AB - Complex networks require effective tools and visualizations for their analysis and comparison. Clique communities have been recognized as a powerful concept for describing cohesive structures in networks. We propose an approach that extends the computation of clique communities by considering persistent homology, a topological paradigm originally introduced to characterize and compare the global structure of shapes. Our persistence-based algorithm is able to detect clique communities and to keep track of their evolution according to different edge weight thresholds. We use this information to define comparison metrics and a new centrality measure, both reflecting the relevance of the clique communities inherent to the network. Moreover, we propose an interactive visualization tool based on nested graphs that is capable of compactly representing the evolving relationships between communities for different thresholds and clique degrees. We demonstrate the effectiveness of our approach on various network types. PMID- 28866540 TI - Clustering Trajectories by Relevant Parts for Air Traffic Analysis. AB - Clustering of trajectories of moving objects by similarity is an important technique in movement analysis. Existing distance functions assess the similarity between trajectories based on properties of the trajectory points or segments. The properties may include the spatial positions, times, and thematic attributes. There may be a need to focus the analysis on certain parts of trajectories, i.e., points and segments that have particular properties. According to the analysis focus, the analyst may need to cluster trajectories by similarity of their relevant parts only. Throughout the analysis process, the focus may change, and different parts of trajectories may become relevant. We propose an analytical workflow in which interactive filtering tools are used to attach relevance flags to elements of trajectories, clustering is done using a distance function that ignores irrelevant elements, and the resulting clusters are summarized for further analysis. We demonstrate how this workflow can be useful for different analysis tasks in three case studies with real data from the domain of air traffic. We propose a suite of generic techniques and visualization guidelines to support movement data analysis by means of relevance-aware trajectory clustering. PMID- 28866541 TI - Functional Decomposition for Bundled Simplification of Trail Sets. AB - Bundling visually aggregates curves to reduce clutter and help finding important patterns in trail-sets or graph drawings. We propose a new approach to bundling based on functional decomposition of the underling dataset. We recover the functional nature of the curves by representing them as linear combinations of piecewise-polynomial basis functions with associated expansion coefficients. Next, we express all curves in a given cluster in terms of a centroid curve and a complementary term, via a set of so-called principal component functions. Based on the above, we propose a two-fold contribution: First, we use cluster centroids to design a new bundling method for 2D and 3D curve-sets. Secondly, we deform the cluster centroids and generate new curves along them, which enables us to modify the underlying data in a statistically-controlled way via its simplified (bundled) view. We demonstrate our method by applications on real-world 2D and 3D datasets for graph bundling, trajectory analysis, and vector field and tensor field visualization. PMID- 28866542 TI - Skeleton-Based Scagnostics. AB - Scatterplot matrices (SPLOMs) are widely used for exploring multidimensional data. Scatterplot diagnostics (scagnostics) approaches measure characteristics of scatterplots to automatically find potentially interesting plots, thereby making SPLOMs more scalable with the dimension count. While statistical measures such as regression lines can capture orientation, and graph-theoretic scagnostics measures can capture shape, there is no scatterplot characterization measure that uses both descriptors. Based on well-known results in shape analysis, we propose a scagnostics approach that captures both scatterplot shape and orientation using skeletons (or medial axes). Our representation can handle complex spatial distributions, helps discovery of principal trends in a multiscale way, scales visually well with the number of samples, is robust to noise, and is automatic and fast to compute. We define skeleton-based similarity metrics for the visual exploration and analysis of SPLOMs. We perform a user study to measure the human perception of scatterplot similarity and compare the outcome to our results as well as to graph-based scagnostics and other visual quality metrics. Our skeleton based metrics outperform previously defined measures both in terms of closeness to perceptually-based similarity and computation time efficiency. PMID- 28866543 TI - DeepEyes: Progressive Visual Analytics for Designing Deep Neural Networks. AB - Deep neural networks are now rivaling human accuracy in several pattern recognition problems. Compared to traditional classifiers, where features are handcrafted, neural networks learn increasingly complex features directly from the data. Instead of handcrafting the features, it is now the network architecture that is manually engineered. The network architecture parameters such as the number of layers or the number of filters per layer and their interconnections are essential for good performance. Even though basic design guidelines exist, designing a neural network is an iterative trial-and-error process that takes days or even weeks to perform due to the large datasets used for training. In this paper, we present DeepEyes, a Progressive Visual Analytics system that supports the design of neural networks during training. We present novel visualizations, supporting the identification of layers that learned a stable set of patterns and, therefore, are of interest for a detailed analysis. The system facilitates the identification of problems, such as superfluous filters or layers, and information that is not being captured by the network. We demonstrate the effectiveness of our system through multiple use cases, showing how a trained network can be compressed, reshaped and adapted to different problems. PMID- 28866544 TI - Modeling Color Difference for Visualization Design. AB - Color is frequently used to encode values in visualizations. For color encodings to be effective, the mapping between colors and values must preserve important differences in the data. However, most guidelines for effective color choice in visualization are based on either color perceptions measured using large, uniform fields in optimal viewing environments or on qualitative intuitions. These limitations may cause data misinterpretation in visualizations, which frequently use small, elongated marks. Our goal is to develop quantitative metrics to help people use color more effectively in visualizations. We present a series of crowdsourced studies measuring color difference perceptions for three common mark types: points, bars, and lines. Our results indicate that peoples' abilities to perceive color differences varies significantly across mark types. Probabilistic models constructed from the resulting data can provide objective guidance for designers, allowing them to anticipate viewer perceptions in order to inform effective encoding design. PMID- 28866545 TI - Visual Diagnosis of Tree Boosting Methods. AB - Tree boosting, which combines weak learners (typically decision trees) to generate a strong learner, is a highly effective and widely used machine learning method. However, the development of a high performance tree boosting model is a time-consuming process that requires numerous trial-and-error experiments. To tackle this issue, we have developed a visual diagnosis tool, BOOSTVis, to help experts quickly analyze and diagnose the training process of tree boosting. In particular, we have designed a temporal confusion matrix visualization, and combined it with a t-SNE projection and a tree visualization. These visualization components work together to provide a comprehensive overview of a tree boosting model, and enable an effective diagnosis of an unsatisfactory training process. Two case studies that were conducted on the Otto Group Product Classification Challenge dataset demonstrate that BOOSTVis can provide informative feedback and guidance to improve understanding and diagnosis of tree boosting algorithms. PMID- 28866546 TI - Understanding the Relationship Between Interactive Optimisation and Visual Analytics in the Context of Prostate Brachytherapy. AB - The fields of operations research and computer science have long sought to find automatic solver techniques that can find high-quality solutions to difficult real-world optimisation problems. The traditional workflow is to exactly model the problem and then enter this model into a general-purpose "black-box" solver. In practice, however, many problems cannot be solved completely automatically, but require a "human-in-the-loop" to iteratively refine the model and give hints to the solver. In this paper, we explore the parallels between this interactive optimisation workflow and the visual analytics sense-making loop. We assert that interactive optimisation is essentially a visual analytics task and propose a problem-solving loop analogous to the sense-making loop. We explore these ideas through an in-depth analysis of a use-case in prostate brachytherapy, an application where interactive optimisation may be able to provide significant assistance to practitioners in creating prostate cancer treatment plans customised to each patient's tumour characteristics. However, current brachytherapy treatment planning is usually a careful, mostly manual process involving multiple professionals. We developed a prototype interactive optimisation tool for brachytherapy that goes beyond current practice in supporting focal therapy - targeting tumour cells directly rather than simply seeking coverage of the whole prostate gland. We conducted semi-structured interviews, in two stages, with seven radiation oncology professionals in order to establish whether they would prefer to use interactive optimisation for treatment planning and whether such a tool could improve their trust in the novel focal therapy approach and in machine generated solutions to the problem. PMID- 28866547 TI - Voila: Visual Anomaly Detection and Monitoring with Streaming Spatiotemporal Data. AB - The increasing availability of spatiotemporal data continuously collected from various sources provides new opportunities for a timely understanding of the data in their spatial and temporal context. Finding abnormal patterns in such data poses significant challenges. Given that there is often no clear boundary between normal and abnormal patterns, existing solutions are limited in their capacity of identifying anomalies in large, dynamic and heterogeneous data, interpreting anomalies in their multifaceted, spatiotemporal context, and allowing users to provide feedback in the analysis loop. In this work, we introduce a unified visual interactive system and framework, Voila, for interactively detecting anomalies in spatiotemporal data collected from a streaming data source. The system is designed to meet two requirements in real-world applications, i.e., online monitoring and interactivity. We propose a novel tensor-based anomaly analysis algorithm with visualization and interaction design that dynamically produces contextualized, interpretable data summaries and allows for interactively ranking anomalous patterns based on user input. Using the "smart city" as an example scenario, we demonstrate the effectiveness of the proposed framework through quantitative evaluation and qualitative case studies. PMID- 28866548 TI - Interactive Dynamic Volume Illumination with Refraction and Caustics. AB - In recent years, significant progress has been made in developing high-quality interactive methods for realistic volume illumination. However, refraction - despite being an important aspect of light propagation in participating media - has so far only received little attention. In this paper, we present a novel approach for refractive volume illumination including caustics capable of interactive frame rates. By interleaving light and viewing ray propagation, our technique avoids memory-intensive storage of illumination information and does not require any precomputation. It is fully dynamic and all parameters such as light position and transfer function can be modified interactively without a performance penalty. PMID- 28866549 TI - BiDots: Visual Exploration of Weighted Biclusters. AB - Discovering and analyzing biclusters, i.e., two sets of related entities with close relationships, is a critical task in many real-world applications, such as exploring entity co-occurrences in intelligence analysis, and studying gene expression in bio-informatics. While the output of biclustering techniques can offer some initial low-level insights, visual approaches are required on top of that due to the algorithmic output complexity. This paper proposes a visualization technique, called BiDots, that allows analysts to interactively explore biclusters over multiple domains. BiDots overcomes several limitations of existing bicluster visualizations by encoding biclusters in a more compact and cluster-driven manner. A set of handy interactions is incorporated to support flexible analysis of biclustering results. More importantly, BiDots addresses the cases of weighted biclusters, which has been underexploited in the literature. The design of BiDots is grounded by a set of analytical tasks derived from previous work. We demonstrate its usefulness and effectiveness for exploring computed biclusters with an investigative document analysis task, in which suspicious people and activities are identified from a text corpus. PMID- 28866550 TI - Activity-Centered Domain Characterization for Problem-Driven Scientific Visualization. AB - Although visualization design models exist in the literature in the form of higher-level methodological frameworks, these models do not present a clear methodological prescription for the domain characterization step. This work presents a framework and end-to-end model for requirements engineering in problem driven visualization application design. The framework and model are based on the activity-centered design paradigm, which is an enhancement of human-centered design. The proposed activity-centered approach focuses on user tasks and activities, and allows an explicit link between the requirements engineering process with the abstraction stage-and its evaluation-of existing, higher-level visualization design models. In a departure from existing visualization design models, the resulting model: assigns value to a visualization based on user activities; ranks user tasks before the user data; partitions requirements in activity-related capabilities and nonfunctional characteristics and constraints; and explicitly incorporates the user workflows into the requirements process. A further merit of this model is its explicit integration of functional specifications, a concept this work adapts from the software engineering literature, into the visualization design nested model. A quantitative evaluation using two sets of interdisciplinary projects supports the merits of the activity centered model. The result is a practical roadmap to the domain characterization step of visualization design for problem-driven data visualization. Following this domain characterization model can help remove a number of pitfalls that have been identified multiple times in the visualization design literature. PMID- 28866551 TI - BASTet: Shareable and Reproducible Analysis and Visualization of Mass Spectrometry Imaging Data via OpenMSI. AB - Mass spectrometry imaging (MSI) is a transformative imaging method that supports the untargeted, quantitative measurement of the chemical composition and spatial heterogeneity of complex samples with broad applications in life sciences, bioenergy, and health. While MSI data can be routinely collected, its broad application is currently limited by the lack of easily accessible analysis methods that can process data of the size, volume, diversity, and complexity generated by MSI experiments. The development and application of cutting-edge analytical methods is a core driver in MSI research for new scientific discoveries, medical diagnostics, and commercial-innovation. However, the lack of means to share, apply, and reproduce analyses hinders the broad application, validation, and use of novel MSI analysis methods. To address this central challenge, we introduce the Berkeley Analysis and Storage Toolkit (BASTet), a novel framework for shareable and reproducible data analysis that supports standardized data and analysis interfaces, integrated data storage, data provenance, workflow management, and a broad set of integrated tools. Based on BASTet, we describe the extension of the OpenMSI mass spectrometry imaging science gateway to enable web-based sharing, reuse, analysis, and visualization of data analyses and derived data products. We demonstrate the application of BASTet and OpenMSI in practice to identify and compare characteristic substructures in the mouse brain based on their chemical composition measured via MSI. PMID- 28866552 TI - Visualization Multi-Pipeline for Communicating Biology. AB - We propose a system to facilitate biology communication by developing a pipeline to support the instructional visualization of heterogeneous biological data on heterogeneous user-devices. Discoveries and concepts in biology are typically summarized with illustrations assembled manually from the interpretation and application of heterogenous data. The creation of such illustrations is time consuming, which makes it incompatible with frequent updates to the measured data as new discoveries are made. Illustrations are typically non-interactive, and when an illustration is updated, it still has to reach the user. Our system is designed to overcome these three obstacles. It supports the integration of heterogeneous datasets, reflecting the knowledge that is gained from different data sources in biology. After pre-processing the datasets, the system transforms them into visual representations as inspired by scientific illustrations. As opposed to traditional scientific illustration these representations are generated in real-time - they are interactive. The code generating the visualizations can be embedded in various software environments. To demonstrate this, we implemented both a desktop application and a remote-rendering server in which the pipeline is embedded. The remote-rendering server supports multi threaded rendering and it is able to handle multiple users simultaneously. This scalability to different hardware environments, including multi-GPU setups, makes our system useful for efficient public dissemination of biological discoveries. PMID- 28866553 TI - Do Convolutional Neural Networks Learn Class Hierarchy? AB - Convolutional Neural Networks (CNNs) currently achieve state-of-the-art accuracy in image classification. With a growing number of classes, the accuracy usually drops as the possibilities of confusion increase. Interestingly, the class confusion patterns follow a hierarchical structure over the classes. We present visual-analytics methods to reveal and analyze this hierarchy of similar classes in relation with CNN-internal data. We found that this hierarchy not only dictates the confusion patterns between the classes, it furthermore dictates the learning behavior of CNNs. In particular, the early layers in these networks develop feature detectors that can separate high-level groups of classes quite well, even after a few training epochs. In contrast, the latter layers require substantially more epochs to develop specialized feature detectors that can separate individual classes. We demonstrate how these insights are key to significant improvement in accuracy by designing hierarchy-aware CNNs that accelerate model convergence and alleviate overfitting. We further demonstrate how our methods help in identifying various quality issues in the training data. PMID- 28866554 TI - Applying Pragmatics Principles for Interaction with Visual Analytics. AB - Interactive visual data analysis is most productive when users can focus on answering the questions they have about their data, rather than focusing on how to operate the interface to the analysis tool. One viable approach to engaging users in interactive conversations with their data is a natural language interface to visualizations. These interfaces have the potential to be both more expressive and more accessible than other interaction paradigms. We explore how principles from language pragmatics can be applied to the flow of visual analytical conversations, using natural language as an input modality. We evaluate the effectiveness of pragmatics support in our system Evizeon, and present design considerations for conversation interfaces to visual analytics tools. PMID- 28866555 TI - Visualizing Big Data Outliers through Distributed Aggregation. AB - Visualizing outliers in massive datasets requires statistical pre-processing in order to reduce the scale of the problem to a size amenable to rendering systems like D3, Plotly or analytic systems like R or SAS. This paper presents a new algorithm, called hdoutliers, for detecting multidimensional outliers. It is unique for a) dealing with a mixture of categorical and continuous variables, b) dealing with big-p (many columns of data), c) dealing with big-n (many rows of data), d) dealing with outliers that mask other outliers, and e) dealing consistently with unidimensional and multidimensional datasets. Unlike ad hoc methods found in many machine learning papers, hdoutliers is based on a distributional model that allows outliers to be tagged with a probability. This critical feature reduces the likelihood of false discoveries. PMID- 28866556 TI - Understanding a Sequence of Sequences: Visual Exploration of Categorical States in Lake Sediment Cores. AB - This design study focuses on the analysis of a time sequence of categorical sequences. Such data is relevant for the geoscientific research field of landscape and climate development. It results from microscopic analysis of lake sediment cores. The goal is to gain hypotheses about landscape evolution and climate conditions in the past. To this end, geoscientists identify which categorical sequences are similar in the sense that they indicate similar conditions. Categorical sequences are similar if they have similar meaning (semantic similarity) and appear in similar time periods (temporal similarity). For data sets with many different categorical sequences, the task to identify similar sequences becomes a challenge. Our contribution is a tailored visual analysis concept that effectively supports the analytical process. Our visual interface comprises coupled visualizations of semantics and temporal context for the exploration and assessment of the similarity of categorical sequences. Integrated automatic methods reduce the analytical effort substantially. They (1) extract unique sequences in the data and (2) rank sequences by a similarity measure during the search for similar sequences. We evaluated our concept by demonstrations of our prototype to a larger audience and hands-on analysis sessions for two different lakes. According to geoscientists, our approach fills an important methodological gap in the application domain. PMID- 28866557 TI - ACTIVIS: Visual Exploration of Industry-Scale Deep Neural Network Models. AB - While deep learning models have achieved state-of-the-art accuracies for many prediction tasks, understanding these models remains a challenge. Despite the recent interest in developing visual tools to help users interpret deep learning models, the complexity and wide variety of models deployed in industry, and the large-scale datasets that they used, pose unique design challenges that are inadequately addressed by existing work. Through participatory design sessions with over 15 researchers and engineers at Facebook, we have developed, deployed, and iteratively improved ACTIVIS, an interactive visualization system for interpreting large-scale deep learning models and results. By tightly integrating multiple coordinated views, such as a computation graph overview of the model architecture, and a neuron activation view for pattern discovery and comparison, users can explore complex deep neural network models at both the instance- and subset-level. ACTIVIS has been deployed on Facebook's machine learning platform. We present case studies with Facebook researchers and engineers, and usage scenarios of how ACTIVIS may work with different models. PMID- 28866558 TI - SkyLens: Visual Analysis of Skyline on Multi-Dimensional Data. AB - Skyline queries have wide-ranging applications in fields that involve multi criteria decision making, including tourism, retail industry, and human resources. By automatically removing incompetent candidates, skyline queries allow users to focus on a subset of superior data items (i.e., the skyline), thus reducing the decision-making overhead. However, users are still required to interpret and compare these superior items manually before making a successful choice. This task is challenging because of two issues. First, people usually have fuzzy, unstable, and inconsistent preferences when presented with multiple candidates. Second, skyline queries do not reveal the reasons for the superiority of certain skyline points in a multi-dimensional space. To address these issues, we propose SkyLens, a visual analytic system aiming at revealing the superiority of skyline points from different perspectives and at different scales to aid users in their decision making. Two scenarios demonstrate the usefulness of SkyLens on two datasets with a dozen of attributes. A qualitative study is also conducted to show that users can efficiently accomplish skyline understanding and comparison tasks with SkyLens. PMID- 28866559 TI - SOMFlow: Guided Exploratory Cluster Analysis with Self-Organizing Maps and Analytic Provenance. AB - Clustering is a core building block for data analysis, aiming to extract otherwise hidden structures and relations from raw datasets, such as particular groups that can be effectively related, compared, and interpreted. A plethora of visual-interactive cluster analysis techniques has been proposed to date, however, arriving at useful clusterings often requires several rounds of user interactions to fine-tune the data preprocessing and algorithms. We present a multi-stage Visual Analytics (VA) approach for iterative cluster refinement together with an implementation (SOMFlow) that uses Self-Organizing Maps (SOM) to analyze time series data. It supports exploration by offering the analyst a visual platform to analyze intermediate results, adapt the underlying computations, iteratively partition the data, and to reflect previous analytical activities. The history of previous decisions is explicitly visualized within a flow graph, allowing to compare earlier cluster refinements and to explore relations. We further leverage quality and interestingness measures to guide the analyst in the discovery of useful patterns, relations, and data partitions. We conducted two pair analytics experiments together with a subject matter expert in speech intonation research to demonstrate that the approach is effective for interactive data analysis, supporting enhanced understanding of clustering results as well as the interactive process itself. PMID- 28866560 TI - Comparing Visual-Interactive Labeling with Active Learning: An Experimental Study. AB - Labeling data instances is an important task in machine learning and visual analytics. Both fields provide a broad set of labeling strategies, whereby machine learning (and in particular active learning) follows a rather model centered approach and visual analytics employs rather user-centered approaches (visual-interactive labeling). Both approaches have individual strengths and weaknesses. In this work, we conduct an experiment with three parts to assess and compare the performance of these different labeling strategies. In our study, we (1) identify different visual labeling strategies for user-centered labeling, (2) investigate strengths and weaknesses of labeling strategies for different labeling tasks and task complexities, and (3) shed light on the effect of using different visual encodings to guide the visual-interactive labeling process. We further compare labeling of single versus multiple instances at a time, and quantify the impact on efficiency. We systematically compare the performance of visual interactive labeling with that of active learning. Our main findings are that visual-interactive labeling can outperform active learning, given the condition that dimension reduction separates well the class distributions. Moreover, using dimension reduction in combination with additional visual encodings that expose the internal state of the learning model turns out to improve the performance of visual-interactive labeling. PMID- 28866561 TI - Graphiti: Interactive Specification of Attribute-Based Edges for Network Modeling and Visualization. AB - Network visualizations, often in the form of node-link diagrams, are an effective means to understand relationships between entities, discover entities with interesting characteristics, and to identify clusters. While several existing tools allow users to visualize pre-defined networks, creating these networks from raw data remains a challenging task, often requiring users to program custom scripts or write complex SQL commands. Some existing tools also allow users to both visualize and model networks. Interaction techniques adopted by these tools often assume users know the exact conditions for defining edges in the resulting networks. This assumption may not always hold true, however. In cases where users do not know much about attributes in the dataset or when there are several attributes to choose from, users may not know which attributes they could use to formulate linking conditions. We propose an alternate interaction technique to model networks that allows users to demonstrate to the system a subset of nodes and links they wish to see in the resulting network. The system, in response, recommends conditions that can be used to model networks based on the specified nodes and links. In this paper, we show how such a demonstration-based interaction technique can be used to model networks by employing it in a prototype tool, Graphiti. Through multiple usage scenarios, we show how Graphiti not only allows users to model networks from a tabular dataset but also facilitates updating a pre-defined network with additional edge types. PMID- 28866562 TI - Visualizing Dataflow Graphs of Deep Learning Models in TensorFlow. AB - We present a design study of the TensorFlow Graph Visualizer, part of the TensorFlow machine intelligence platform. This tool helps users understand complex machine learning architectures by visualizing their underlying dataflow graphs. The tool works by applying a series of graph transformations that enable standard layout techniques to produce a legible interactive diagram. To declutter the graph, we decouple non-critical nodes from the layout. To provide an overview, we build a clustered graph using the hierarchical structure annotated in the source code. To support exploration of nested structure on demand, we perform edge bundling to enable stable and responsive cluster expansion. Finally, we detect and highlight repeated structures to emphasize a model's modular composition. To demonstrate the utility of the visualizer, we describe example usage scenarios and report user feedback. Overall, users find the visualizer useful for understanding, debugging, and sharing the structures of their models. PMID- 28866563 TI - VIGOR: Interactive Visual Exploration of Graph Query Results. AB - Finding patterns in graphs has become a vital challenge in many domains from biological systems, network security, to finance (e.g., finding money laundering rings of bankers and business owners). While there is significant interest in graph databases and querying techniques, less research has focused on helping analysts make sense of underlying patterns within a group of subgraph results. Visualizing graph query results is challenging, requiring effective summarization of a large number of subgraphs, each having potentially shared node-values, rich node features, and flexible structure across queries. We present VIGOR, a novel interactive visual analytics system, for exploring and making sense of query results. VIGOR uses multiple coordinated views, leveraging different data representations and organizations to streamline analysts sensemaking process. VIGOR contributes: (1) an exemplar-based interaction technique, where an analyst starts with a specific result and relaxes constraints to find other similar results or starts with only the structure (i.e., without node value constraints), and adds constraints to narrow in on specific results; and (2) a novel feature aware subgraph result summarization. Through a collaboration with Symantec, we demonstrate how VIGOR helps tackle real-world problems through the discovery of security blindspots in a cybersecurity dataset with over 11,000 incidents. We also evaluate VIGOR with a within-subjects study, demonstrating VIGOR's ease of use over a leading graph database management system, and its ability to help analysts understand their results at higher speed and make fewer errors. PMID- 28866564 TI - Analyzing the Training Processes of Deep Generative Models. AB - Among the many types of deep models, deep generative models (DGMs) provide a solution to the important problem of unsupervised and semi-supervised learning. However, training DGMs requires more skill, experience, and know-how because their training is more complex than other types of deep models such as convolutional neural networks (CNNs). We develop a visual analytics approach for better understanding and diagnosing the training process of a DGM. To help experts understand the overall training process, we first extract a large amount of time series data that represents training dynamics (e.g., activation changes over time). A blue-noise polyline sampling scheme is then introduced to select time series samples, which can both preserve outliers and reduce visual clutter. To further investigate the root cause of a failed training process, we propose a credit assignment algorithm that indicates how other neurons contribute to the output of the neuron causing the training failure. Two case studies are conducted with machine learning experts to demonstrate how our approach helps understand and diagnose the training processes of DGMs. We also show how our approach can be directly used to analyze other types of deep models, such as CNNs. PMID- 28866565 TI - Podium: Ranking Data Using Mixed-Initiative Visual Analytics. AB - People often rank and order data points as a vital part of making decisions. Multi-attribute ranking systems are a common tool used to make these data-driven decisions. Such systems often take the form of a table-based visualization in which users assign weights to the attributes representing the quantifiable importance of each attribute to a decision, which the system then uses to compute a ranking of the data. However, these systems assume that users are able to quantify their conceptual understanding of how important particular attributes are to a decision. This is not always easy or even possible for users to do. Rather, people often have a more holistic understanding of the data. They form opinions that data point A is better than data point B but do not necessarily know which attributes are important. To address these challenges, we present a visual analytic application to help people rank multi-variate data points. We developed a prototype system, Podium, that allows users to drag rows in the table to rank order data points based on their perception of the relative value of the data. Podium then infers a weighting model using Ranking SVM that satisfies the user's data preferences as closely as possible. Whereas past systems help users understand the relationships between data points based on changes to attribute weights, our approach helps users to understand the attributes that might inform their understanding of the data. We present two usage scenarios to describe some of the potential uses of our proposed technique: (1) understanding which attributes contribute to a user's subjective preferences for data, and (2) deconstructing attributes of importance for existing rankings. Our proposed approach makes powerful machine learning techniques more usable to those who may not have expertise in these areas. PMID- 28866566 TI - Progressive Learning of Topic Modeling Parameters: A Visual Analytics Framework. AB - Topic modeling algorithms are widely used to analyze the thematic composition of text corpora but remain difficult to interpret and adjust. Addressing these limitations, we present a modular visual analytics framework, tackling the understandability and adaptability of topic models through a user-driven reinforcement learning process which does not require a deep understanding of the underlying topic modeling algorithms. Given a document corpus, our approach initializes two algorithm configurations based on a parameter space analysis that enhances document separability. We abstract the model complexity in an interactive visual workspace for exploring the automatic matching results of two models, investigating topic summaries, analyzing parameter distributions, and reviewing documents. The main contribution of our work is an iterative decision making technique in which users provide a document-based relevance feedback that allows the framework to converge to a user-endorsed topic distribution. We also report feedback from a two-stage study which shows that our technique results in topic model quality improvements on two independent measures. PMID- 28866567 TI - Clustervision: Visual Supervision of Unsupervised Clustering. AB - Clustering, the process of grouping together similar items into distinct partitions, is a common type of unsupervised machine learning that can be useful for summarizing and aggregating complex multi-dimensional data. However, data can be clustered in many ways, and there exist a large body of algorithms designed to reveal different patterns. While having access to a wide variety of algorithms is helpful, in practice, it is quite difficult for data scientists to choose and parameterize algorithms to get the clustering results relevant for their dataset and analytical tasks. To alleviate this problem, we built Clustervision, a visual analytics tool that helps ensure data scientists find the right clustering among the large amount of techniques and parameters available. Our system clusters data using a variety of clustering techniques and parameters and then ranks clustering results utilizing five quality metrics. In addition, users can guide the system to produce more relevant results by providing task-relevant constraints on the data. Our visual user interface allows users to find high quality clustering results, explore the clusters using several coordinated visualization techniques, and select the cluster result that best suits their task. We demonstrate this novel approach using a case study with a team of researchers in the medical domain and showcase that our system empowers users to choose an effective representation of their complex data. PMID- 28866568 TI - Open vs. Closed Shapes: New Perceptual Categories? AB - Effective communication using visualization relies in part on the use of viable encoding strategies. For example, a viewer's ability to rapidly and accurately discern between two or more categorical variables in a chart or figure is contingent upon the distinctiveness of the encodings applied to each variable. Research in perception suggests that color is a more salient visual feature when compared to shape and although that finding is supported by visualization studies, characteristics of shape also yield meaningful differences in distinctiveness. We propose that open or closed shapes (that is, whether shapes are composed of line segments that are bounded across a region of space or not) represent a salient characteristic that influences perceptual processing. Three experiments were performed to test the reliability of the open/closed category; the first two from the perspective of attentional allocation, and the third experiment in the context of multi-class scatterplot displays. In the first, a flanker paradigm was used to test whether perceptual load and open/closed feature category would modulate the effect of the flanker on target processing. Results showed an influence of both variables. The second experiment used a Same/Different reaction time task to replicate and extend those findings. Results from both show that responses are faster and more accurate when closed rather than open shapes are processed as targets, and there is more processing interference when two competing shapes come from the same rather than different open or closed feature categories. The third experiment employed three commonly used visual analytic tasks - perception of average value, numerosity, and linear relationships with both single and dual displays of open and closed symbols. Our findings show that for numerosity and trend judgments, in particular, that different symbols from the same open or closed feature category cause more perceptual interference when they are presented together in a plot than symbols from different categories. Moreover, the extent of the interference appears to depend upon whether the participant is focused on processing open or closed symbols. PMID- 28866569 TI - CasCADe: A Novel 4D Visualization System for Virtual Construction Planning. AB - Building Information Modeling (BIM) provides an integrated 3D environment to manage large-scale engineering projects. The Architecture, Engineering and Construction (AEC) industry explores 4D visualizations over these datasets for virtual construction planning. However, existing solutions lack adequate visual mechanisms to inspect the underlying schedule and make inconsistencies readily apparent. The goal of this paper is to apply best practices of information visualization to improve 4D analysis of construction plans. We first present a review of previous work that identifies common use cases and limitations. We then consulted with AEC professionals to specify the main design requirements for such applications. These guided the development of CasCADe, a novel 4D visualization system where task sequencing and spatio-temporal simultaneity are immediately apparent. This unique framework enables the combination of diverse analytical features to create an information-rich analysis environment. We also describe how engineering collaborators used CasCADe to review the real-world construction plans of an Oil & Gas process plant. The system made evident schedule uncertainties, identified work-space conflicts and helped analyze other constructability issues. The results and contributions of this paper suggest new avenues for future research in information visualization for the AEC industry. PMID- 28866570 TI - PhenoLines: Phenotype Comparison Visualizations for Disease Subtyping via Topic Models. AB - PhenoLines is a visual analysis tool for the interpretation of disease subtypes, derived from the application of topic models to clinical data. Topic models enable one to mine cross-sectional patient comorbidity data (e.g., electronic health records) and construct disease subtypes-each with its own temporally evolving prevalence and co-occurrence of phenotypes-without requiring aligned longitudinal phenotype data for all patients. However, the dimensionality of topic models makes interpretation challenging, and de facto analyses provide little intuition regarding phenotype relevance or phenotype interrelationships. PhenoLines enables one to compare phenotype prevalence within and across disease subtype topics, thus supporting subtype characterization, a task that involves identifying a proposed subtype's dominant phenotypes, ages of effect, and clinical validity. We contribute a data transformation workflow that employs the Human Phenotype Ontology to hierarchically organize phenotypes and aggregate the evolving probabilities produced by topic models. We introduce a novel measure of phenotype relevance that can be used to simplify the resulting topology. The design of PhenoLines was motivated by formative interviews with machine learning and clinical experts. We describe the collaborative design process, distill high level tasks, and report on initial evaluations with machine learning experts and a medical domain expert. These results suggest that PhenoLines demonstrates promising approaches to support the characterization and optimization of topic models. PMID- 28866571 TI - Conceptual and Methodological Issues in Evaluating Multidimensional Visualizations for Decision Support. AB - We explore how to rigorously evaluate multidimensional visualizations for their ability to support decision making. We first define multi-attribute choice tasks, a type of decision task commonly performed with such visualizations. We then identify which of the existing multidimensional visualizations are compatible with such tasks, and set out to evaluate three elementary visualizations: parallel coordinates, scatterplot matrices and tabular visualizations. Our method consists in first giving participants low-level analytic tasks, in order to ensure that they properly understood the visualizations and their interactions. Participants are then given multi-attribute choice tasks consisting of choosing holiday packages. We assess decision support through multiple objective and subjective metrics, including a decision accuracy metric based on the consistency between the choice made and self-reported preferences for attributes. We found the three visualizations to be comparable on most metrics, with a slight advantage for tabular visualizations. In particular, tabular visualizations allow participants to reach decisions faster. Thus, although decision time is typically not central in assessing decision support, it can be used as a tie-breaker when visualizations achieve similar decision accuracy. Our results also suggest that indirect methods for assessing choice confidence may allow to better distinguish between visualizations than direct ones. We finally discuss the limitations of our methods and directions for future work, such as the need for more sensitive metrics of decision support. PMID- 28866572 TI - A Utility-Aware Visual Approach for Anonymizing Multi-Attribute Tabular Data. AB - Sharing data for public usage requires sanitization to prevent sensitive information from leaking. Previous studies have presented methods for creating privacy preserving visualizations. However, few of them provide sufficient feedback to users on how much utility is reduced (or preserved) during such a process. To address this, we design a visual interface along with a data manipulation pipeline that allows users to gauge utility loss while interactively and iteratively handling privacy issues in their data. Widely known and discussed types of privacy models, i.e., syntactic anonymity and differential privacy, are integrated and compared under different use case scenarios. Case study results on a variety of examples demonstrate the effectiveness of our approach. PMID- 28866573 TI - Stable Treemaps via Local Moves. AB - Treemaps are a popular tool to visualize hierarchical data: items are represented by nested rectangles and the area of each rectangle corresponds to the data being visualized for this item. The visual quality of a treemap is commonly measured via the aspect ratio of the rectangles. If the data changes, then a second important quality criterion is the stability of the treemap: how much does the treemap change as the data changes. We present a novel stable treemapping algorithm that has very high visual quality. Whereas existing treemapping algorithms generally recompute the treemap every time the input changes, our algorithm changes the layout of the treemap using only local modifications. This approach not only gives us direct control over stability, but it also allows us to use a larger set of possible layouts, thus provably resulting in treemaps of higher visual quality compared to existing algorithms. We further prove that we can reach all possible treemap layouts using only our local modifications. Furthermore, we introduce a new measure for stability that better captures the relative positions of rectangles. We finally show via experiments on real-world data that our algorithm outperforms existing treemapping algorithms also in practice on either visual quality and/or stability. Our algorithm scores high on stability regardless of whether we use an existing stability measure or our new measure. PMID- 28866575 TI - TreePOD: Sensitivity-Aware Selection of Pareto-Optimal Decision Trees. AB - Balancing accuracy gains with other objectives such as interpretability is a key challenge when building decision trees. However, this process is difficult to automate because it involves know-how about the domain as well as the purpose of the model. This paper presents TreePOD, a new approach for sensitivity-aware model selection along trade-offs. TreePOD is based on exploring a large set of candidate trees generated by sampling the parameters of tree construction algorithms. Based on this set, visualizations of quantitative and qualitative tree aspects provide a comprehensive overview of possible tree characteristics. Along trade-offs between two objectives, TreePOD provides efficient selection guidance by focusing on Pareto-optimal tree candidates. TreePOD also conveys the sensitivities of tree characteristics on variations of selected parameters by extending the tree generation process with a full-factorial sampling. We demonstrate how TreePOD supports a variety of tasks involved in decision tree selection and describe its integration in a holistic workflow for building and selecting decision trees. For evaluation, we illustrate a case study for predicting critical power grid states, and we report qualitative feedback from domain experts in the energy sector. This feedback suggests that TreePOD enables users with and without statistical background a confident and efficient identification of suitable decision trees. PMID- 28866574 TI - Visual Exploration of Semantic Relationships in Neural Word Embeddings. AB - Constructing distributed representations for words through neural language models and using the resulting vector spaces for analysis has become a crucial component of natural language processing (NLP). However, despite their widespread application, little is known about the structure and properties of these spaces. To gain insights into the relationship between words, the NLP community has begun to adapt high-dimensional visualization techniques. In particular, researchers commonly use t-distributed stochastic neighbor embeddings (t-SNE) and principal component analysis (PCA) to create two-dimensional embeddings for assessing the overall structure and exploring linear relationships (e.g., word analogies), respectively. Unfortunately, these techniques often produce mediocre or even misleading results and cannot address domain-specific visualization challenges that are crucial for understanding semantic relationships in word embeddings. Here, we introduce new embedding techniques for visualizing semantic and syntactic analogies, and the corresponding tests to determine whether the resulting views capture salient structures. Additionally, we introduce two novel views for a comprehensive study of analogy relationships. Finally, we augment t SNE embeddings to convey uncertainty information in order to allow a reliable interpretation. Combined, the different views address a number of domain-specific tasks difficult to solve with existing tools. PMID- 28866576 TI - Visualizing Confidence in Cluster-Based Ensemble Weather Forecast Analyses. AB - In meteorology, cluster analysis is frequently used to determine representative trends in ensemble weather predictions in a selected spatio-temporal region, e.g., to reduce a set of ensemble members to simplify and improve their analysis. Identified clusters (i.e., groups of similar members), however, can be very sensitive to small changes of the selected region, so that clustering results can be misleading and bias subsequent analyses. In this article, we - a team of visualization scientists and meteorologists-deliver visual analytics solutions to analyze the sensitivity of clustering results with respect to changes of a selected region. We propose an interactive visual interface that enables simultaneous visualization of a) the variation in composition of identified clusters (i.e., their robustness), b) the variability in cluster membership for individual ensemble members, and c) the uncertainty in the spatial locations of identified trends. We demonstrate that our solution shows meteorologists how representative a clustering result is, and with respect to which changes in the selected region it becomes unstable. Furthermore, our solution helps to identify those ensemble members which stably belong to a given cluster and can thus be considered similar. In a real-world application case we show how our approach is used to analyze the clustering behavior of different regions in a forecast of "Tropical Cyclone Karl", guiding the user towards the cluster robustness information required for subsequent ensemble analysis. PMID- 28866577 TI - Beyond Tasks: An Activity Typology for Visual Analytics. AB - As Visual Analytics (VA) research grows and diversifies to encompass new systems, techniques, and use contexts, gaining a holistic view of analytic practices is becoming ever more challenging. However, such a view is essential for researchers and practitioners seeking to develop systems for broad audiences that span multiple domains. In this paper, we interpret VA research through the lens of Activity Theory (AT)-a framework for modelling human activities that has been influential in the field of Human-Computer Interaction. We first provide an overview of Activity Theory, showing its potential for thinking beyond tasks, representations, and interactions to the broader systems of activity in which interactive tools are embedded and used. Next, we describe how Activity Theory can be used as an organizing framework in the construction of activity typologies, building and expanding upon the tradition of abstract task taxonomies in the field of Information Visualization. We then apply the resulting process to create an activity typology for Visual Analytics, synthesizing a wide range of systems and activity concepts from the literature. Finally, we use this typology as the foundation of an activity-centered design process, highlighting both tensions and opportunities in the design space of VA systems. PMID- 28866578 TI - Bring It to the Pitch: Combining Video and Movement Data to Enhance Team Sport Analysis. AB - Analysts in professional team sport regularly perform analysis to gain strategic and tactical insights into player and team behavior. Goals of team sport analysis regularly include identification of weaknesses of opposing teams, or assessing performance and improvement potential of a coached team. Current analysis workflows are typically based on the analysis of team videos. Also, analysts can rely on techniques from Information Visualization, to depict e.g., player or ball trajectories. However, video analysis is typically a time-consuming process, where the analyst needs to memorize and annotate scenes. In contrast, visualization typically relies on an abstract data model, often using abstract visual mappings, and is not directly linked to the observed movement context anymore. We propose a visual analytics system that tightly integrates team sport video recordings with abstract visualization of underlying trajectory data. We apply appropriate computer vision techniques to extract trajectory data from video input. Furthermore, we apply advanced trajectory and movement analysis techniques to derive relevant team sport analytic measures for region, event and player analysis in the case of soccer analysis. Our system seamlessly integrates video and visualization modalities, enabling analysts to draw on the advantages of both analysis forms. Several expert studies conducted with team sport analysts indicate the effectiveness of our integrated approach. PMID- 28866579 TI - Orko: Facilitating Multimodal Interaction for Visual Exploration and Analysis of Networks. AB - Data visualization systems have predominantly been developed for WIMP-based direct manipulation interfaces. Only recently have other forms of interaction begun to appear, such as natural language or touch-based interaction, though usually operating only independently. Prior evaluations of natural language interfaces for visualization have indicated potential value in combining direct manipulation and natural language as complementary interaction techniques. We hypothesize that truly multimodal interfaces for visualization, those providing users with freedom of expression via both natural language and touch-based direct manipulation input, may provide an effective and engaging user experience. Unfortunately, however, little work has been done in exploring such multimodal visualization interfaces. To address this gap, we have created an architecture and a prototype visualization system called Orko that facilitates both natural language and direct manipulation input. Specifically, Orko focuses on the domain of network visualization, one that has largely relied on WIMP-based interfaces and direct manipulation interaction, and has little or no prior research exploring natural language interaction. We report results from an initial evaluation study of Orko, and use our observations to discuss opportunities and challenges for future work in multimodal network visualization interfaces. PMID- 28866580 TI - Data Through Others' Eyes: The Impact of Visualizing Others' Expectations on Visualization Interpretation. AB - In addition to visualizing input data, interactive visualizations have the potential to be social artifacts that reveal other people's perspectives on the data. However, how such social information embedded in a visualization impacts a viewer's interpretation of the data remains unknown. Inspired by recent interactive visualizations that display people's expectations of data against the data, we conducted a controlled experiment to evaluate the effect of showing social information in the form of other people's expectations on people's ability to recall the data, the degree to which they adjust their expectations to align with the data, and their trust in the accuracy of the data. We found that social information that exhibits a high degree of consensus lead participants to recall the data more accurately relative to participants who were exposed to the data alone. Additionally, participants trusted the accuracy of the data less and were more likely to maintain their initial expectations when other people's expectations aligned with their own initial expectations but not with the data. We conclude by characterizing the design space for visualizing others' expectations alongside data. PMID- 28866581 TI - Towards a Systematic Combination of Dimension Reduction and Clustering in Visual Analytics. AB - Dimension reduction algorithms and clustering algorithms are both frequently used techniques in visual analytics. Both families of algorithms assist analysts in performing related tasks regarding the similarity of observations and finding groups in datasets. Though initially used independently, recent works have incorporated algorithms from each family into the same visualization systems. However, these algorithmic combinations are often ad hoc or disconnected, working independently and in parallel rather than integrating some degree of interdependence. A number of design decisions must be addressed when employing dimension reduction and clustering algorithms concurrently in a visualization system, including the selection of each algorithm, the order in which they are processed, and how to present and interact with the resulting projection. This paper contributes an overview of combining dimension reduction and clustering into a visualization system, discussing the challenges inherent in developing a visualization system that makes use of both families of algorithms. PMID- 28866582 TI - Exploring Multivariate Event Sequences Using Rules, Aggregations, and Selections. AB - Multivariate event sequences are ubiquitous: travel history, telecommunication conversations, and server logs are some examples. Besides standard properties such as type and timestamp, events often have other associated multivariate data. Current exploration and analysis methods either focus on the temporal analysis of a single attribute or the structural analysis of the multivariate data only. We present an approach where users can explore event sequences at multivariate and sequential level simultaneously by interactively defining a set of rewrite rules using multivariate regular expressions. Users can store resulting patterns as new types of events or attributes to interactively enrich or simplify event sequences for further investigation. In Eventpad we provide a bottom-up glyph-oriented approach for multivariate event sequence analysis by searching, clustering, and aligning them according to newly defined domain specific properties. We illustrate the effectiveness of our approach with real-world data sets including telecommunication traffic and hospital treatments. PMID- 28866583 TI - Supporting Handoff in Asynchronous Collaborative Sensemaking Using Knowledge Transfer Graphs. AB - During asynchronous collaborative analysis, handoff of partial findings is challenging because externalizations produced by analysts may not adequately communicate their investigative process. To address this challenge, we developed techniques to automatically capture and help encode tacit aspects of the investigative process based on an analyst's interactions, and streamline explicit authoring of handoff annotations. We designed our techniques to mediate awareness of analysis coverage, support explicit communication of progress and uncertainty with annotation, and implicit communication through playback of investigation histories. To evaluate our techniques, we developed an interactive visual analysis system, KTGraph, that supports an asynchronous investigative document analysis task. We conducted a two-phase user study to characterize a set of handoff strategies and to compare investigative performance with and without our techniques. The results suggest that our techniques promote the use of more effective handoff strategies, help increase an awareness of prior investigative process and insights, as well as improve final investigative outcomes. PMID- 28866584 TI - Dynamic Influence Networks for Rule-Based Models. AB - We introduce the Dynamic Influence Network (DIN), a novel visual analytics technique for representing and analyzing rule-based models of protein-protein interaction networks. Rule-based modeling has proved instrumental in developing biological models that are concise, comprehensible, easily extensible, and that mitigate the combinatorial complexity of multi-state and multi-component biological molecules. Our technique visualizes the dynamics of these rules as they evolve over time. Using the data produced by KaSim, an open source stochastic simulator of rule-based models written in the Kappa language, DINs provide a node-link diagram that represents the influence that each rule has on the other rules. That is, rather than representing individual biological components or types, we instead represent the rules about them (as nodes) and the current influence of these rules (as links). Using our interactive DIN-Viz software tool, researchers are able to query this dynamic network to find meaningful patterns about biological processes, and to identify salient aspects of complex rule-based models. To evaluate the effectiveness of our approach, we investigate a simulation of a circadian clock model that illustrates the oscillatory behavior of the KaiC protein phosphorylation cycle. PMID- 28866585 TI - TACO: Visualizing Changes in Tables Over Time. AB - Multivariate, tabular data is one of the most common data structures used in many different domains. Over time, tables can undergo changes in both structure and content, which results in multiple versions of the same table. A challenging task when working with such derived tables is to understand what exactly has changed between versions in terms of additions/deletions, reorder, merge/split, and content changes. For textual data, a variety of commonplace "diff" tools exist that support the task of investigating changes between revisions of a text. Although there are some comparison tools which assist users in inspecting differences between multiple table instances, the resulting visualizations are often difficult to interpret or do not scale to large tables with thousands of rows and columns. To address these challenges, we developed TACO, an interactive comparison tool that visualizes the differences between multiple tables at various levels of detail. With TACO we show (1) the aggregated differences between multiple table versions over time, (2) the aggregated changes between two selected table versions, and (3) detailed changes between the selected tables. To demonstrate the effectiveness of our approach, we show its application by means of two usage scenarios. PMID- 28866586 TI - EventThread: Visual Summarization and Stage Analysis of Event Sequence Data. AB - Event sequence data such as electronic health records, a person's academic records, or car service records, are ordered series of events which have occurred over a period of time. Analyzing collections of event sequences can reveal common or semantically important sequential patterns. For example, event sequence analysis might reveal frequently used care plans for treating a disease, typical publishing patterns of professors, and the patterns of service that result in a well-maintained car. It is challenging, however, to visually explore large numbers of event sequences, or sequences with large numbers of event types. Existing methods focus on extracting explicitly matching patterns of events using statistical analysis to create stages of event progression over time. However, these methods fail to capture latent clusters of similar but not identical evolutions of event sequences. In this paper, we introduce a novel visualization system named EventThread which clusters event sequences into threads based on tensor analysis and visualizes the latent stage categories and evolution patterns by interactively grouping the threads by similarity into time-specific clusters. We demonstrate the effectiveness of EventThread through usage scenarios in three different application domains and via interviews with an expert user. PMID- 28866587 TI - EdWordle: Consistency-Preserving Word Cloud Editing. AB - We present EdWordle, a method for consistently editing word clouds. At its heart, EdWordle allows users to move and edit words while preserving the neighborhoods of other words. To do so, we combine a constrained rigid body simulation with a neighborhood-aware local Wordle algorithm to update the cloud and to create very compact layouts. The consistent and stable behavior of EdWordle enables users to create new forms of word clouds such as storytelling clouds in which the position of words is carefully edited. We compare our approach with state-of-the-art methods and show that we can improve user performance, user satisfaction, as well as the layout itself. PMID- 28866588 TI - The Explanatory Visualization Framework: An Active Learning Framework for Teaching Creative Computing Using Explanatory Visualizations. AB - Visualizations are nowadays appearing in popular media and are used everyday in the workplace. This democratisation of visualization challenges educators to develop effective learning strategies, in order to train the next generation of creative visualization specialists. There is high demand for skilled individuals who can analyse a problem, consider alternative designs, develop new visualizations, and be creative and innovative. Our three-stage framework, leads the learner through a series of tasks, each designed to develop different skills necessary for coming up with creative, innovative, effective, and purposeful visualizations. For that, we get the learners to create an explanatory visualization of an algorithm of their choice. By making an algorithm choice, and by following an active-learning and project-based strategy, the learners take ownership of a particular visualization challenge. They become enthusiastic to develop good results and learn different creative skills on their learning journey. PMID- 28866589 TI - Revisiting Stress Majorization as a Unified Framework for Interactive Constrained Graph Visualization. AB - We present an improved stress majorization method that incorporates various constraints, including directional constraints without the necessity of solving a constraint optimization problem. This is achieved by reformulating the stress function to impose constraints on both the edge vectors and lengths instead of just on the edge lengths (node distances). This is a unified framework for both constrained and unconstrained graph visualizations, where we can model most existing layout constraints, as well as develop new ones such as the star shapes and cluster separation constraints within stress majorization. This improvement also allows us to parallelize computation with an efficient GPU conjugant gradient solver, which yields fast and stable solutions, even for large graphs. As a result, we allow the constraint-based exploration of large graphs with 10K nodes - an approach which previous methods cannot support. PMID- 28866590 TI - The Hologram in My Hand: How Effective is Interactive Exploration of 3D Visualizations in Immersive Tangible Augmented Reality? AB - We report on a controlled user study comparing three visualization environments for common 3D exploration. Our environments differ in how they exploit natural human perception and interaction capabilities. We compare an augmented-reality head-mounted display (Microsoft HoloLens), a handheld tablet, and a desktop setup. The novel head-mounted HoloLens display projects stereoscopic images of virtual content into a user's real world and allows for interaction in-situ at the spatial position of the 3D hologram. The tablet is able to interact with 3D content through touch, spatial positioning, and tangible markers, however, 3D content is still presented on a 2D surface. Our hypothesis is that visualization environments that match human perceptual and interaction capabilities better to the task at hand improve understanding of 3D visualizations. To better understand the space of display and interaction modalities in visualization environments, we first propose a classification based on three dimensions: perception, interaction, and the spatial and cognitive proximity of the two. Each technique in our study is located at a different position along these three dimensions. We asked 15 participants to perform four tasks, each task having different levels of difficulty for both spatial perception and degrees of freedom for interaction. Our results show that each of the tested environments is more effective for certain tasks, but that generally the desktop environment is still fastest and most precise in almost all cases. PMID- 28866591 TI - Active Reading of Visualizations. AB - We investigate whether the notion of active reading for text might be usefully applied to visualizations. Through a qualitative study we explored whether people apply observable active reading techniques when reading paper-based node-link visualizations. Participants used a range of physical actions while reading, and from these we synthesized an initial set of active reading techniques for visualizations. To learn more about the potential impact such techniques may have on visualization reading, we implemented support for one type of physical action from our observations (making freeform marks) in an interactive node-link visualization. Results from our quantitative study of this implementation show that interactive support for active reading techniques can improve the accuracy of performing low-level visualization tasks. Together, our studies suggest that the active reading space is ripe for research exploration within visualization and can lead to new interactions that make for a more flexible and effective visualization reading experience. PMID- 28866593 TI - Taking Word Clouds Apart: An Empirical Investigation of the Design Space for Keyword Summaries. AB - In this paper we present a set of four user studies aimed at exploring the visual design space of what we call keyword summaries: lists of words with associated quantitative values used to help people derive an intuition of what information a given document collection (or part of it) may contain. We seek to systematically study how different visual representations may affect people's performance in extracting information out of keyword summaries. To this purpose, we first create a design space of possible visual representations and compare the possible solutions in this design space through a variety of representative tasks and performance metrics. Other researchers have, in the past, studied some aspects of effectiveness with word clouds, however, the existing literature is somewhat scattered and do not seem to address the problem in a sufficiently systematic and holistic manner. The results of our studies showed a strong dependency on the tasks users are performing. In this paper we present details of our methodology, the results, as well as, guidelines on how to design effective keyword summaries based in our discoveries. PMID- 28866592 TI - HiPiler: Visual Exploration of Large Genome Interaction Matrices with Interactive Small Multiples. AB - This paper presents an interactive visualization interface-HiPiler-for the exploration and visualization of regions-of-interest in large genome interaction matrices. Genome interaction matrices approximate the physical distance of pairs of regions on the genome to each other and can contain up to 3 million rows and columns with many sparse regions. Regions of interest (ROIs) can be defined, e.g., by sets of adjacent rows and columns, or by specific visual patterns in the matrix. However, traditional matrix aggregation or pan-and-zoom interfaces fail in supporting search, inspection, and comparison of ROIs in such large matrices. In HiPiler, ROIs are first-class objects, represented as thumbnail-like "snippets". Snippets can be interactively explored and grouped or laid out automatically in scatterplots, or through dimension reduction methods. Snippets are linked to the entire navigable genome interaction matrix through brushing and linking. The design of HiPiler is based on a series of semi-structured interviews with 10 domain experts involved in the analysis and interpretation of genome interaction matrices. We describe six exploration tasks that are crucial for analysis of interaction matrices and demonstrate how HiPiler supports these tasks. We report on a user study with a series of data exploration sessions with domain experts to assess the usability of HiPiler as well as to demonstrate respective findings in the data. PMID- 28866594 TI - Wavelet-Based Visual Analysis of Dynamic Networks. AB - Dynamic networks naturally appear in a multitude of applications from different fields. Analyzing and exploring dynamic networks in order to understand and detect patterns and phenomena is challenging, fostering the development of new methodologies, particularly in the field of visual analytics. In this work, we propose a novel visual analytics methodology for dynamic networks, which relies on the spectral graph wavelet theory. We enable the automatic analysis of a signal defined on the nodes of the network, making viable the robust detection of network properties. Specifically, we use a fast approximation of a graph wavelet transform to derive a set of wavelet coefficients, which are then used to identify activity patterns on large networks, including their temporal recurrence. The coefficients naturally encode the spatial and temporal variations of the signal, leading to an efficient and meaningful representation. This methodology allows for the exploration of the structural evolution of the network and their patterns over time. The effectiveness of our approach is demonstrated using usage scenarios and comparisons involving real dynamic networks. PMID- 28866595 TI - A Possible Explanation of How High-Frequency Deep Brain Stimulation Suppresses Low-Frequency Tremors in Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder of the central nervous system and one of its key symptoms is rest tremor. Deep brain stimulation (DBS) effectively suppresses rest tremor in Parkinson's disease. Despite being a successful treatment option, its underlying principle and the mechanism by which it attenuates tremors is not yet fully understood. Since existing methods for tuning DBS parameters are largely trial and error, understanding how DBS works can help to reduce time and costs, and could also ultimately lead to better treatment strategies for PD. In this paper, we set out to analyze how a high frequency stimulation applied through DBS can help reduce the low-frequency rest tremors observed in PD patients. We identify key elements in the sensorimotor loop (the feedback loop consisting of sensory feedbacks and motor responses) that play a role in the interaction of high-frequency DBS signal and the low-frequency tremor. Based on the analysis of these elements, we draw insights about the working of DBS and the role of frequency and the nature of stimulation. We verify these observations with numerical examples and a bench top experimental example. PMID- 28866596 TI - A 410-nW Efficient QRS Processor for Mobile ECG Monitoring in 0.18-MUm CMOS. AB - This paper proposes a low power and efficient QRS processor for real-time and continuous mobile ECG monitoring. The QRS detector contains the wavelet transform (WT), the modulus maxima pair identification (MMPI), and the R position modification (RPM). In order to reduce power consumption, we choose the Haar function as the mother wavelet of WT. It is implemented by an optimized FIR filter structure where none of the multiplier is used. The MMPI processes the wavelet coefficients at scale 24 and provides candidate R peak positions for the RPM. To improve the accuracy and robust performance, a number of modules have been designed in MMPI, including the preprocessing unit, the automatic threshold updating, and the decision state machine. The RPM is designed to eliminate digital time delay in wavelet transform and locate the R peak position precisely. Raw ECG signals and QRS detection results are output simultaneously. Fabricated in 0.18-MUm N-well CMOS 1P6M technology, the power consumption of this chip is only about 410 nW in 1 V voltage supply. Validated by all 48 sets of data in the MIT-BIH arrhythmia database, the sensitive and the positive prediction are 99.60% and 99.77% respectively. PMID- 28866597 TI - A Surface Acoustic Wave Pumped Lensless Microfluidic Imaging System for Flowing Cell Detection and Counting. AB - The future point-of-care diagnostics requires miniaturizing the existing bulky and expensive bioanalysis instruments, where lab-on-CMOS-chip-based technology can provide a promising solution. In this paper, we presented a surface acoustic wave (SAW) pumped lensless microfluidic imaging system for flowing cell detection and counting. Different from the previous lensless systems, which employ external bulky syringe pump for cell driven, the developed system directly integrates the SAW pump on the CMOS image sensor chip to drive the cell-containing microfluid. Moreover, an efficient temporal-differencing-based motion detection algorithm is proposed for continuous flowing cell detection and counting. Experimental results show that the SAW pump can drive the cells to flow at different driven powers, and also can keep the channel temperature below 40 degrees C so as not to harm the cells. The human bone marrow stromal cells flowing in the microfluidic channel can be automatically detected and counted with a low statistical error rate of -6.53%. The developed system thereby is competitive for point-of-care cell detection and counting application. PMID- 28866598 TI - A Magnetic Plethysmograph Probe for Local Pulse Wave Velocity Measurement. AB - OBJECTIVE: We present the design and experimental validation of an arterial compliance probe with dual magnetic plethysmograph (MPG) transducers for local pulse wave velocity (PWV) measurement. The MPG transducers (positioned at 23 mm distance apart) utilizes Hall-effect sensors and permanent magnets for arterial blood pulse detection. METHODS: The MPG probe was initially validated on an arterial flow phantom using a reference method. Further, 20 normotensive subjects (14 males, age = 24 +/- 3.5 years) were studied under two different physical conditions: 1) Physically relaxed condition, 2) Postexercise condition. Local PWV was measured from the left carotid artery using the MPG probe. Brachial blood pressure (BP) was measured to investigate the correlation of BP with local PWV. RESULTS: The proposed MPG arterial compliance probe was capable of detecting high fidelity blood pulse waveforms. Reliable local pulse transit time estimates were assessed by the developed measurement system. Beat-by-beat local PWV was measured from multiple subjects under different physical conditions. A profound increment was observed in the carotid local PWV for all subjects after exercise (average increment = 0.42 +/- 0.22 m/s). Local PWV values and brachial BP parameters were significantly correlated (r >= 0.72), except for pulse pressure (r = 0.42). CONCLUSION: MPG arterial compliance probe for local PWV measurement was validated. Carotid local PWV measurement, its variations due to physical exercise and correlation with BP levels were examined during the in vivo study. SIGNIFICANCE: A novel dual MPG probe for local PWV measurement and potential use in cuffless BP measurement. PMID- 28866599 TI - High-Throughput Separation of White Blood Cells From Whole Blood Using Inertial Microfluidics. AB - White blood cells (WBCs) constitute only about 0.1% of human blood cells, yet contain rich information about the immune status of the body; thus, separation of WBCs from the whole blood is an indispensable and critical sample preparation step in many scientific, clinical, and diagnostic applications. In this paper, we developed a continuous and high-throughput microfluidic WBC separation platform utilizing the differential inertial focusing of particles in serpentine microchannels. First, separation performance of the proposed method is characterized and evaluated using polystyrene beads in the serpentine channel. The purity of 10-MUm polystyrene beads is increased from 0.1% to 80.3% after two cascaded processes, with an average enrichment ratio of 28 times. Next, we investigated focusing and separation properties of Jurkat cells spiked in the blood to mimic the presence of WBCs in whole blood. Finally, separation of WBCs from human whole blood was conducted and separation purity of WBCs was measured by the flow cytometry. The results show that the purity of WBCs can be increased to 48% after two consecutive processes, with an average enrichment ratio of ten times. Meanwhile, a parallelized inertial microfluidic device was designed to provide a high processing flow rate of 288 ml/h for the diluted (*1/20) whole blood. The proposed microfluidic device can potentially work as an upstream component for blood sample preparation and analysis in the integrated microfluidic systems. PMID- 28866600 TI - A Review in Detection and Monitoring Gait Disorders Using In-Shoe Plantar Measurement Systems. AB - Gait is an important part of our life, as it affects many daily activities. Special footwear is fundamental to obtain an ergonomic gait and to extract data for analysis. The plantar foot pressure can be employed to detect many kinds of disorders, suggest improvements in treatments, rehabilitation tasks, patient monitoring, development of orthopedic devices, and other applications. In recent years, attention to this topic has grown and is reflected in many works issued in both commercial and academic groups, and has focused on the development of devices for foot plantar pressure measurement with applications in medicine, sports, and research. First works on this subject appeared around 1963 and have continuously evolved with emerging technologies. This paper reviews the reported developments in the field of footwear-embedded sensors for gait measurement, monitoring, diagnosis, and analysis in rehabilitation. Future work is proposed to improve the field of measurement of the footprint with electronic devices. PMID- 28866601 TI - Adaptive Neural Output-Feedback Control for a Class of Nonlower Triangular Nonlinear Systems With Unmodeled Dynamics. AB - This paper presents the development of an adaptive neural controller for a class of nonlinear systems with unmodeled dynamics and immeasurable states. An observer is designed to estimate system states. The structure consistency of virtual control signals and the variable partition technique are combined to overcome the difficulties appearing in a nonlower triangular form. An adaptive neural output feedback controller is developed based on the backstepping technique and the universal approximation property of the radial basis function (RBF) neural networks. By using the Lyapunov stability analysis, the semiglobally and uniformly ultimate boundedness of all signals within the closed-loop system is guaranteed. The simulation results show that the controlled system converges quickly, and all the signals are bounded. This paper is novel at least in the two aspects: 1) an output-feedback control strategy is developed for a class of nonlower triangular nonlinear systems with unmodeled dynamics and 2) the nonlinear disturbances and their bounds are the functions of all states, which is in a more general form than existing results. PMID- 28866602 TI - Deterministic Convergence for Learning Control Systems Over Iteration-Dependent Tracking Intervals. AB - This brief addresses the iterative learning control (ILC) problems for discrete time systems subject to iteration-dependent tracking time intervals. A modified class of P-type ILC algorithms is proposed by properly defining an available modified output, for which robust convergence analysis is performed with an inductive approach. It is shown that if a persistent full-learning property is ensured, then a necessary and sufficient convergence condition of ILC can be derived to reach the perfect output tracking objective though the tracking time interval is iteration-dependent. That is, the tracking of ILC for iteration dependent time intervals can be guaranteed in the same deterministic (not stochastic) convergence way as that of traditional ILC over a fixed time interval. Furthermore, the developed tracking results can be extended to admit iteration-dependent uncertainties in initial state and external disturbances. Simulation tests are also included to demonstrate the effectiveness of the modified P-type ILC. PMID- 28866603 TI - Boundary Control of 2-D Burgers' PDE: An Adaptive Dynamic Programming Approach. AB - In this paper, an adaptive dynamic programming-based near optimal boundary controller is developed for partial differential equations (PDEs) modeled by the uncertain Burgers' equation under Neumann boundary condition in 2-D. Initially, Hamilton-Jacobi-Bellman equation is derived in infinite-dimensional space. Subsequently, a novel neural network (NN) identifier is introduced to approximate the nonlinear dynamics in the 2-D PDE. The optimal control input is derived by online estimation of the value function through an additional NN-based forward-in time estimation and approximated dynamic model. Novel update laws are developed for estimation of the identifier and value function online. The designed control policy can be applied using a finite number of actuators at the boundaries. Local ultimate boundedness of the closed-loop system is studied in detail using Lyapunov theory. Simulation results confirm the optimizing performance of the proposed controller on an unstable 2-D Burgers' equation. PMID- 28866604 TI - Scaled Group Consensus in Multiagent Systems With First/Second-Order Continuous Dynamics. AB - We investigate scaled group consensus problems of multiagent systems with first/second-order linear continuous dynamics. For a complex network consisting of two subnetworks with different physical quantities or task distributions, it is concerned with this case that the agents' states in one subnetwork converge to a consistent value asymptotically, while the states in the other subnetwork approach another value with a ratio of the former. For the case of the information exchange being directed, novel consensus protocols are designed for both first-order and second-order dynamics to solve the scaled group consensus problems. By utilizing algebra theory, graph theory, and Lyapunov stability theory, several necessary and sufficient conditions are established to guarantee the agents' states reaching the scaled group consensus asymptotically. Finally, several simulation results are presented to demonstrate the effectiveness of the theoretical results. PMID- 28866605 TI - Robust Distributed Predictive Control of Waterborne AGVs-A Cooperative and Cost Effective Approach. AB - Waterborne autonomous guided vessels (waterborne AGVs) moving over open waters experience environmental uncertainties. This paper proposes a novel cost effective robust distributed control approach for waterborne AGVs. The overall system is uncertain and has independent subsystem dynamics but coupling objectives and state constraints. Waterborne AGVs determine their actions in a parallel way, while still minimizing an overall cost function and respecting coupling constraints robustly by communicating within a neighborhood. Our first contribution is the proposal of the system robustness level for the cost effective robust distributed model predictive control (RDMPC) for waterborne AGVs. Cost-effective RDMPC models the price of robustness by explicitly considering uncertainty and system characteristics in a tube-based robust control framework. The second contribution is an efficient integrated branch & bound (B&B) and the alternating direction method of multipliers (ADMMs) algorithm for solving the cost-effective RDMPC problem. The algorithm exploits special ordered variable sets and combining branching criteria with intermediate ADMM results conducting smart search in B&B. Simulation results demonstrate the effectiveness of the proposed approach for cooperative distributed waterborne AGVs with cost effective robustness. PMID- 28866606 TI - Quantizer-Based Triggered Control for Chaotic Synchronization With Information Constraints. AB - This paper mainly focuses on synchronization of controlled drive-response systems under Lurie form through a limited channel. The main contribution of this paper is the quantizer-based triggered methodology proposed based on three coders. By exploring coder structure information and fusing quantization and trigger errors together, this strategy can reduce transmission burden while increase synchronization speed concurrently. And the final synchronization error can be bounded within a predetermined fixed value. According to the initial output of drive system, different coders are purposely designed. With the proposed trigger schemes, traditional binary coder with memory cannot achieve desired performance. Meanwhile, it is found that the static coder leads to satisfactory performance when initial drive system output is within limited region. Combining the advantages of the above two coders, a mixed coder is designed to overcome the shortcomings. Moreover, synchronization error and transmission bit rate are thoroughly discussed and Zeno behavior is radically prevented. Finally, simulations for two Chua's circuits are given to illustrate the validity of the proposed method. PMID- 28866607 TI - Formative student-authored question bank: perceptions, question quality and association with summative performance. AB - PURPOSE OF THE STUDY: There are few studies on the value of authoring questions as a study method, the quality of the questions produced by students and student perceptions of student-authored question banks. Here we evaluate PeerWise, a widely used and free online resource that allows students to author, answer and discuss multiple-choice questions. STUDY DESIGN: We introduced two undergraduate medical student cohorts to PeerWise (n=603). We looked at their patterns of PeerWise usage; identified associations between student engagement and summative exam performance; and used focus groups to assess student perceptions of the value of PeerWise for learning. We undertook item analysis to assess question difficulty and quality. RESULTS: Over two academic years, the two cohorts wrote 4671 questions, answered questions 606 658 times and posted 7735 comments. Question writing frequency correlated most strongly with summative performance (Spearman's rank: 0.24, p=<0.001). Student focus groups found that: (1) students valued curriculum specificity; and (2) students were concerned about student authored question quality. Only two questions of the 300 'most-answered' questions analysed had an unacceptable discriminatory value (point-biserial correlation <0.2). CONCLUSIONS: Item analysis suggested acceptable question quality despite student concerns. Quantitative and qualitative methods indicated that PeerWise is a valuable study tool. PMID- 28866608 TI - Medical research and audit skills training for undergraduates: an international analysis and student-focused needs assessment. AB - INTRODUCTION: Interpreting, performing and applying research is a key part of evidence-based medical practice, however, incorporating these within curricula is challenging. This study aimed to explore current provision of research skills training within medical school curricula, provide a student-focused needs assessment and prioritise research competencies. METHODS: A international, cross sectional survey of final year UK and Irish medical students was disseminated at each participating university. The questionnaire investigated research experience, and confidence in the Medical Education in Europe (MEDINE) 2 consensus survey research competencies. RESULTS: Fully completed responses were received from 521 final year medical students from 32 medical schools (43.4% male, mean age 24.3 years). Of these, 55.3% had an additional academic qualification (49.5% Bachelor's degree), and 38.8% had been a named author on an academic publication. Considering audit and research opportunities and teaching experience, 47.2% reported no formal audit training compared with 27.1% who reported no formal research training. As part of their medical school course, 53.4% had not performed an audit, compared with 29.9% who had not participated in any clinical or basic science research. Nearly a quarter of those who had participated in research reported doing so outside of their medical degree course. Low confidence areas included selecting and performing the appropriate statistical test, selecting the appropriate research method, and critical appraisal. Following adjustment, several factors were associated with increased confidence including previous clinical research experience (OR 4.21, 2.66 to 6.81, P<0.001), additional degrees (OR 2.34, 1.47 to 3.75, P<0.001), and male gender (OR 1.90, 1.25 to 2.09, P=0.003). Factors associated with an increase in perceived opportunities included formal research training in the curriculum (OR 1.66, 1.12 to 2.46, P=0.012), audit skills training in the curriculum (OR 1.52, 1.03 to 2.26, P= 0.036) and research methods taught in a student selected component (OR 1.75, 1.21 to 2.54, P=0.003). DISCUSSION: Nearly one-third of students lacked formal training on undertaking research, and half of students lacked formal audit training and opportunities to undertake audit as part of their medical school course. The presence of research training in the cirriculum was associated with an increase in perceived opportunities to participate in MEDINE2 research competencies. Female gender and a lack of previous research experience were significant factors influencing confidence and participation in research. PMID- 28866609 TI - Estimation of the global burden of mesothelioma deaths from incomplete national mortality data. AB - BACKGROUND: Mesothelioma is increasingly recognised as a global health issue and the assessment of its global burden is warranted. OBJECTIVES: To descriptively analyse national mortality data and to use reported and estimated data to calculate the global burden of mesothelioma deaths. METHODS: For the study period of 1994 to 2014, we grouped 230 countries into 59 countries with quality mesothelioma mortality data suitable to be used for reference rates, 45 countries with poor quality data and 126 countries with no data, based on the availability of data in the WHO Mortality Database. To estimate global deaths, we extrapolated the gender-specific and age-specific mortality rates of the countries with quality data to all other countries. RESULTS: The global numbers and rates of mesothelioma deaths have increased over time. The 59 countries with quality data recorded 15 011 mesothelioma deaths per year over the 3 most recent years with available data (equivalent to 9.9 deaths per million per year). From these reference data, we extrapolated the global mesothelioma deaths to be 38 400 per year, based on extrapolations for asbestos use. CONCLUSIONS: Although the validity of our extrapolation method depends on the adequate identification of quality mesothelioma data and appropriate adjustment for other variables, our estimates can be updated, refined and verified because they are based on commonly accessible data and are derived using a straightforward algorithm. Our estimates are within the range of previously reported values but higher than the most recently reported values. PMID- 28866610 TI - Seasonality in oestrus and litter size in an assistance dog breeding colony in the United Kingdom. AB - Evidence of seasonality in oestrus in bitches within specialist breeding programmes, such as those for assistance dogs, may support colony management through tailoring the distribution of resources required for breeding throughout the year. However, at present there are conflicting data regarding seasonality in oestrus (and litter size) in domestic dogs. The primary objective of this study was to investigate seasonal variations in oestrus and litter size in a large assistance dog breeding colony in the UK in order to optimise colony management. The authors analysed the annual distribution of 3624 observations of oestrus collected from 568 brood bitches from January 2005 to June 2014. The authors also evaluated the relationship between month and litter size for 1609 litters observed during the same period. There was no evidence of regular seasonal variations in oestrus or litter size by meteorological season or month. The lack of seasonality in oestrus may be a function of dogs in the UK, particularly valuable breeding bitches, being exposed to fairly constant environmental conditions throughout the year as a consequence of artificial light and heating during the winter months. The authors' findings suggest that special consideration of the annual distribution of oestrus and litter size is unnecessary for the management of assistance dog breeding colonies similar to those in the UK. PMID- 28866612 TI - DNA repair-related functional assays for the classification of BRCA1 and BRCA2 variants: a critical review and needs assessment. AB - Mutation of BRCA1 and BRCA2 is the most common cause of inherited breast and ovarian cancer. Genetic screens to detect carriers of variants can aid in cancer prevention by identifying individuals with a greater cancer risk and can potentially be used to predict the responsiveness of tumours to therapy. Frequently, classification cannot be performed based on traditional approaches such as segregation analyses, including for many missense variants, which are therefore referred to as variants of uncertain significance (VUS). Functional assays provide an important alternative for classification of BRCA1 and BRCA2 VUS. As reviewed here, both of these tumour suppressors promote the maintenance of genome stability via homologous recombination. Thus, related assays may be particularly relevant to cancer risk. Progress in implementing functional assays to assess missense variants of BRCA1 and BRCA2 is considered here, along with current limitations and the path to more impactful assay systems. While functional assays have been developed to independently evaluate BRCA1 and BRCA2 VUS, high-throughput assays with sufficient sensitivity to characterise the large number of identified variants are lacking. Additionally, because of relatively low conservation of certain domains of BRCA1, and of BRCA2, between humans and rodents, heterologous expression in rodent cells may have limited reliability or capacity to assess variants present throughout either protein. Moving forward, it will be important to perform assays in human cell lines with relevance to particular tumour types, and to strengthen risk predictions based on multifactorial statistical analyses that also include available data on cosegregation and tumour pathology. PMID- 28866613 TI - Uses and abuses of snack foods in child health. AB - Snack foods, though regarded as unhealthy, are widely eaten by children, particularly those with eating and feeding difficulties. This article outlines the ways in which paediatricians have traditionally made use of snack foods as incentives and then reviews the key nutritional and practical characteristics of commonly eaten snack foods, to allow practitioners to evaluate their role in the child's diet. Generally savoury snacks are preferable to sweet, while dry foods are preferable to drinks or semiliquid desserts. Many ostensibly healthy snacks are also rich in sugar or fat. Eaten in addition to other meals, snack foods may lead to obesity or else displace family foods, but the instant appeal of snack foods can be exploited to introduce young children to otherwise aversive sensations and tastes and can prove a useful path towards a more diverse future diet. If a reasonable variety of snack foods are taken, this will still form a fairly balanced, if non-ideal, diet. PMID- 28866611 TI - Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability. AB - BACKGROUND: The list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism. OBJECTIVES: To explore whether variants in CHD1 are associated with a human phenotype. METHODS: We used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts. RESULTS: Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1. CONCLUSIONS: Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease. PMID- 28866614 TI - Use of Hirudo medicinalis in paediatric reconstructive surgery. PMID- 28866615 TI - Child maltreatment is associated with poor socioeconomic outcomes at 50 years of age. PMID- 28866616 TI - Antenatal betamethasone prevented respiratory distress syndrome in late preterm infants. PMID- 28866617 TI - Initial use of high-flow oxygen did not reduce duration of oxygen therapy in infants with bronchiolitis. PMID- 28866618 TI - Unusual cause of dyspnoea. AB - A 4-year-old boy was admitted to our department with fever, cough and dyspnoea, unresponsive to salbutamol and antibiotic therapy. He had previously contracted bronchiolitis at 20 days of life, followed by intermittent episodes of wheeze that never required hospitalisation and responded to short inhaled corticosteroid cycles. He had an atopic family history. On examination, he had dyspnoea, persistent cough with bronchospasm but normal oxygen saturations. Bloods showed elevated eosinophils (2004 uL), a slightly elevated C-reactive protein (1.5 mg/dL) and total IgE (326 kU/L), and specific IgE was raised for various inhalant allergens (box). A chest X-ray was performed (figure 1).BoxPositive inhalant allergens Anthoxanthum odoratum Cynodon dactylon Dactylis glomerata Dermatophagoides farinae Dermatophagoides pteronissimus Holcus lanatus Poa pratensis Phleum pratense edpract;103/6/300/F1F1F1Figure 1Chest X-ray of the patient. QUESTIONS: 1. What does the chest X-ray in figure 1 show? interstitial pneumoniapneumothoraxlung atelectasis with mild mediastinal shiftdiffuse air trappingenlargement of right hilar lymph nodes 2. Given the clinical picture and the chest X-ray, what would your differential diagnosis include from the following? plastic bronchitis (PB)mycoplasma infectiontuberculosisforeign body aspirationlung perforation 3. Are any of these conditions not associated with a specific type of cast/PB? Fontan procedurehaemophilialymphatic abnormalitiesasthma and other allergic disorderssickle cell disease. PMID- 28866619 TI - Vaccine uptake in under 19s: NICE Quality Standard (QS 145) 2017. PMID- 28866621 TI - Randomised controlled trial to assess the effect of a Just-in-Time training on procedural performance: a proof-of-concept study to address procedural skill decay. AB - BACKGROUND: A subset of high-risk procedures present significant safety threats due to their (1) infrequent occurrence, (2) execution under time constraints and (3) immediate necessity for patient survival. A Just-in-Time (JIT) intervention could provide real-time bedside guidance to improve high-risk procedural performance and address procedural deficits associated with skill decay. OBJECTIVE: To evaluate the impact of a novel JIT intervention on transvenous pacemaker (TVP) placement during a simulated patient event. METHODS: This was a prospective, randomised controlled study to determine the effect of a JIT intervention on performance of TVP placement. Subjects included board-certified emergency medicine physicians from two hospitals. The JIT intervention consisted of a portable, bedside computer-based procedural adjunct. The primary outcome was performance during a simulated patient encounter requiring TVP placement, as assessed by trained raters using a technical skills checklist. Secondary outcomes included global performance ratings, time to TVP placement, number of critical omissions and System Usability Scale scores (intervention only). RESULTS: Groups were similar at baseline across all outcomes. Compared with the control group, the intervention group demonstrated statistically significant improvement in the technical checklist score (11.45 vs 23.44, p<0.001, Cohen's d effect size 4.64), the global rating scale (2.27 vs 4.54, p<0.001, Cohen's d effect size 3.76), and a statistically significant reduction in critical omissions (2.23 vs 0.68, p<0.001, Cohen's d effect size -1.86). The difference in time to procedural completion was not statistically significant between conditions (11.15 min vs 12.80 min, p=0.12, Cohen's d effect size 0.65). System Usability Scale scores demonstrated excellent usability. CONCLUSION: A JIT intervention improved procedure perfromance, suggesting a role for JIT interventions in rarely performed procedures. PMID- 28866622 TI - Neurodevelopmental follow-up for high-risk neonates: current practice in Great Britain. PMID- 28866620 TI - Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. AB - OBJECTIVE: Hippo signalling is a recently identified major oncosuppressive pathway that plays critical roles in inhibiting hepatocyte proliferation, survival and hepatocellular carcinoma (HCC) formation. Hippo kinase (Mst1 and Mst2) inhibits HCC proliferation by suppressing Yap/Taz transcription activities. As human HCC is mainly driven by chronic liver inflammation, it is not clear whether Hippo signalling inhibits HCC by shaping its inflammatory microenvironment. DESIGN: We have established a genetic HCC model by deleting Mst1 and Mst2 in hepatocytes. Functions of inflammatory responses in this model were characterised by molecular, cellular and FACS analysis, immunohistochemistry and genetic deletion of monocyte chemoattractant protein-1 (Mcp1) or Yap. Human HCC databases and human HCC samples were analysed by immunohistochemistry. RESULTS: Genetic deletion of Mst1 and Mst2 in hepatocytes (DKO) led to HCC development, highly upregulated Mcp1 expression and massive infiltration of macrophages with mixed M1 and M2 phenotypes. Macrophage ablation or deletion of Mcp1 in DKO mice markedly reduced hepatic inflammation and HCC development. Moreover, Yap removal abolished induction of Mcp1 expression and restored normal liver growth in the Mst1/Mst2 DKO mice. Finally, we showed that MCP1 is a direct transcription target of YAP in hepatocytes and identified a strong gene expression correlation between YAP targets and MCP-1 in human HCCs. CONCLUSIONS: Hippo signalling in hepatocytes maintains normal liver growth by suppressing macrophage infiltration during protumoural microenvironment formation through the inhibition of Yap-dependent Mcp1 expression, providing new targets and strategies to treat HCCs. PMID- 28866623 TI - Epidemiology, management and outcome of ultrashort bowel syndrome in infancy. AB - Ultrashort bowel syndrome (USBS) is a group of heterogeneous disorders where the length of small bowel is less than 10 cm or 10% of expected for the age. It is caused by massive loss of the gut which in the neonatal period can be a result of vanishing gastroschisis or surgical resection following mid-gut volvulus, jejunoileal atresia and/or extensive necrotising enterocolitis. The exact prevalence of USBS is not known although there is a clear trend towards increasing numbers because of increased incidence and improved survival. Long term parenteral nutrition (PN) is the mainstay of treatment and is best delivered by a multidisciplinary intestinal rehabilitation team. Promoting adaptation is vital to improving long-term survival and can be achieved by optimising feeds, reducing intestinal failure liver disease and catheter-related bloodstream infections. Surgical techniques that can promote enteral tolerance and hence improve outcome include establishing intestinal continuity and bowel lengthening procedures. The outcome for USBS is similar to patients with intestinal failure due to other causes and only a small proportion of children who develop irreversible complications of PN and will need intestinal transplantation. In this review, we will summarise the available evidence focusing particularly on the epidemiology, management strategies and outcome. PMID- 28866624 TI - Severe acquired subglottic stenosis in neonatal intensive care graduates: a case control study. AB - OBJECTIVE: To analyse current incidence and risk factors associated with severe acquired subglottic stenosis (SASGS) requiring surgical intervention in neonates. DESIGN: Retrospective case-control study. SETTING: Sole tertiary children's hospital. PARTICIPANTS: Patients who underwent surgical intervention for SASGS from January 2006 to December 2014. For each neonatal intensive care unit (NICU) graduate with acquired SASGS, two controls were selected (matched for gestation and year of birth). MAIN OUTCOMES AND MEASURES: Incidences were calculated and cases and controls compared using conditional logistic regression analysis to identify risk factors for SASGS. RESULTS: Thirty-seven NICU graduates required surgical intervention for SASGS of whom 35 were <30-week gestation at birth. The incidence of SASGS in surviving children who had required ventilation in the neonatal period was 27/2913 (0.93%). Incidence was higher in infants <28-week gestation (24/623=3.8%) compared with infants >=28-week gestation (3/2290=0.13%; p=0.0001). On univariate analysis, risk factors for SASGS were: higher number of intubations (4 vs 2; p<0.001); longer duration ventilation (16 vs 9.5 days; p<0.001); unplanned extubation (45.7% vs 20.0%; p=0.007); traumatic intubation (34.3% vs 7.1%; p=0.003) and oversized endotracheal tubes (ETTs) (74.3% vs 42.9%; p=0.001). On multivariate analysis, risk factors for SASGS were: Sherman ratio >0.1 (adjusted OR (aOR) 6.40; 95% CI 1.65 to 24.77); more than five previous intubations (aOR 3.74; 95% CI 1.15 to 12.19); traumatic intubation (aOR 3.37; 95% CI 1.01 to 11.26). CONCLUSIONS: SASGS is a serious consequence of intubation for mechanical ventilation in NICU graduates, especially in preterm infants. Minimising trauma during intubations, avoiding recurrent extubation/reintubations and using appropriate sized ETTs may help prevent this serious complication. PMID- 28866626 TI - Sleep patterns in Parkinson's disease: direct recordings from the subthalamic nucleus. AB - Sleep is a fundamental homeostatic process, and disorders of sleep can greatly affect quality of life. Parkinson's disease (PD) is highly comorbid for a spectrum of sleep disorders and deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been reported to improve sleep architecture in PD. We studied local field potential (LFP) recordings in PD subjects undergoing STN-DBS over the course of a full-night's sleep. We examined the changes in oscillatory activity recorded from STN between ultradian sleep states to determine whether sleep-stage dependent spectral patterns might reflect underlying dysfunction. For this study, PD (n=10) subjects were assessed with concurrent polysomnography and LFP recordings from the DBS electrodes, for an average of 7.5 hours in 'off' dopaminergic medication state. Across subjects, we found conserved spectral patterns among the canonical frequency bands (delta 0-3 Hz, theta 3-7 Hz, alpha 7 13 Hz, beta 13-30 Hz, gamma 30-90 Hz and high frequency 90-350 Hz) that were associated with specific sleep cycles: delta (0-3 Hz) activity during non-rapid eye movement (NREM) associated stages was greater than during Awake, whereas beta (13-30 Hz) activity during NREM states was lower than Awake and rapid eye movement (REM). In addition, all frequency bands were significantly different between NREM states and REM. However, each individual subject exhibited a unique mosaic of spectral interrelationships between frequency bands. Our work suggests that LFP recordings from human STN differentiate between sleep cycle states, and sleep-state specific spectral mosaics may provide insight into mechanisms underlying sleep pathophysiology. PMID- 28866627 TI - Autophagy and mitophagy elements are increased in body fluids of multiple sclerosis-affected individuals. PMID- 28866628 TI - Identifying paediatric sepsis: the difficulties in following recommended practice and the creation of our own pathway. PMID- 28866625 TI - Autologous haematopoietic stem cell transplantation for neurological diseases. AB - Neuroinflammatory diseases such as multiple sclerosis, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis are leading causes of physical disability in people of working age. In the last decades significant therapeutic advances have been made that can ameliorate the disease course. Nevertheless, many affected will continue to deteriorate despite treatment, and the costs associated with disease-modifying drugs constitute a significant fiscal burden on healthcare in developed countries. Autologous haematopoietic stem cell transplantation is a treatment approach that aims to ameliorate and to terminate disease activity. The erroneous immune system is eradicated using cytotoxic drugs, and with the aid of haematopoietic stem cells a new immune system is rebuilt. As of today, more than 1000 patients with multiple sclerosis have been treated with this procedure. Available data suggest that autologous haematopoietic stem cell transplantation is superior to conventional treatment in terms of efficacy with an acceptable safety profile. A smaller number of patients with other neuroinflammatory conditions have been treated with promising results. Herein, current data on clinical effect and safety of autologous haematopoietic stem cell transplantation for neurological disease are reviewed. PMID- 28866629 TI - Strategies to reduce line infections in a small child with homozygous familial hypercholesterolaemia who cannot yet receive LDL apheresis. AB - Patients with homozygous familial hypercholesterolaemia are optimally treated with low-density lipoprotein apheresis. Young patients who do not meet a weight threshold (25 kg) receive regular plasmapheresis. This approach may remove excessive immunoglobulins and vascular access set-up can be challenging. We report the case of a 4 year-old child who exhibited repeated septic infections (5 in 6 months) and had recurrent access issues before two interventions were implemented: (1) the percutaneous central venous line was modified to two implanted paediatric ports, and (2) the patient started receiving two bags of Octaplasma at the end of each plasmapheresis treatment to account for the excessive loss of immunoglobulins. For the paediatric plasmapheresis access port, a 19-gauge Huber needle had to be used for the arterial port to prevent the collapse of the extension. These two simple changes have left the patient infection-free for 9 months. PMID- 28866630 TI - Primary osteoporosis in children. AB - Osteoporosis in childhood is uncommon, and it may be secondary to a spectrum of diverse conditions. Idiopathic juvenile osteoporosis is a primary osteoporosis of unknown aetiology present in previously well children and is a diagnosis of exclusion. We describe a 10-year-old prepubertal boy who presented with back pain of 1-week duration. His spinal X-ray showed generalised loss of vertebral body heights in keeping with osteoporosis. Endocrine and haematological work-up were normal. He was treated with vitamin D supplement and intravenous pamidronate. This case illustrates the general work-up and causes for paediatric osteoporosis, and the management for idiopathic juvenile osteoporosis. PMID- 28866631 TI - Association of gender-specific risk factors in metabolic and cardiovascular diseases: an NHANES-based cross-sectional study. AB - In the present cross-sectional study, based on National Health and Nutrition Examination Survey (NHANES, 2007-2010) cohorts, various risk factors for metabolic syndrome (MetS) and cardiovascular diseases (CVDs) were analyzed (n=12,153). The variables analyzed include, demographics, comorbidities associated with MetS or CVD, behavioral and dietary factors, while the primary endpoints were the prevalence of MetS and CVD. The prevalence of MetS and CVD was slightly higher in males as compared with females (42.50% and 7.65% vs 41.29% and 4.13%, respectively). After controlling for confounding factors, advanced age, family history of diabetes mellitus (DM), overweight, and obesity were significantly associated with the likelihood of MetS, irrespective of gender differences. In males, the diagnosis of prostate cancer and regular smoking were additional risk factors of MetS, whereas, advanced age, family history of heart attack or angina, health insurance coverage, diagnosis of rheumatoid arthritis or depression, obesity and low calorie intake were identified as risk factors for CVD. In addition to the above risk factors, higher physical activity and vitamin D insufficiency were also found to increase the risk of CVD in females. Furthermore, obesity was a higher risk factor for MetS than CVD. Emerging risk factors for CVD identified in this study has major clinical implications. Of interest is the correlation of higher physical activity and the risk of CVD in women and the role of depression and lower calorie intake in general population. PMID- 28866632 TI - Evaluation and characterization of monoclonal gammopathies using serum protein electrophoresis in a major urban population: one institution's experience. PMID- 28866633 TI - An ultrasound automated method for non-invasive assessment of carotid artery pulse wave velocity. AB - To validate the clinical applicability and feasibility of an automated ultrasound (US) method in measuring the arterial stiffness of patients with chronic inflammatory rheumatic diseases, comparing automated measurements performed by a rheumatologist without experience in vascular sonography with those obtained by a sonographer experienced in vascular US, using a standardized manual method. Twenty subjects affected by different chronic inflammatory rheumatic disorders were consecutively recruited. For each patient, the arterial stiffness of both common carotids was manually calculated. Subsequently, the measure of the pulse wave velocity (PWV) was obtained using an US device called Radio Frequency - Quality Arterial Stiffness (RF-QAS), provided by the same US system (ie, My Lab 70 XVG, Esaote SpA, Genoa, Italy) equipped with a 4-13 MHz linear probe. The reliability comparison between the two US methods was calculated using the intraclass correlation coefficient (ICC). ICC between the values obtained with the two methods for calculating the arterial stiffness resulted 0.789. A significant positive correlation between the two methods was also established with Pearson's (r=0.62, p<0.0001) and Spearman's analysis (r=0.66, p=0.001). A significant performance comparison was seen using Bland-Altman plot. The acquisition of the arterial stiffness parameter with the automated method required about 2 min for each patient. Clinical applicability of this US automated method to assess PWV at common carotid level by a rheumatologist is reliable and feasible in comparison with a conventional manual method. PMID- 28866634 TI - Quality of reporting of harms in randomised controlled trials of pharmacological interventions for rheumatoid arthritis: a systematic review. AB - BACKGROUND: The quality of reporting of harms data in randomised controlled trials (RCTs) has been reported to be suboptimal. Rheumatoid arthritis (RA) has seen a massive growth in novel pharmacotherapies in the last decade. OBJECTIVE: The aim of this study was to assess the quality of reporting of harms-related data in RCTs evaluating pharmacological interventions for RA according to the CONSORT (Consolidated Standards of Reporting Trials) statement on harms reporting extension. STUDY SELECTION: RCTs published between January 2011 and August 2016 in the five highest impact factor journals in general medicine and two in rheumatology subject categories as per 2015 Journal Citation Reports were included. Reports of secondary, supplementary or exploratory analyses of RCTs and non-inferiority trials were excluded. Two reviewers independently extracted data using a structured, pilot-tested, 18-item questionnaire developed based on CONSORT harms extension recommendations. FINDINGS: 68 RCTs were included in the review. Out of a maximum harms reporting score of 18, the mean (SD) score was 8.51 (3.5) (range=0-15). More than half (56.5%) of the RCTs reported <=50% of items and only three (4.3%) RCTs reported more than 70% (score >=14) of the items. Multilinear regression analyses found that region of trial origin (p=0.01), sample size (p=0.001) and whether the study was a long-term extension of a trial or not (p=0.04) were independent predictors associated with higher total harms reporting score. CONCLUSIONS: The adherence to CONSORT harms extension was poor in recently published RCTs of pharmacological interventions for RA. There is a need to improve quality of harms reporting in RCTs to allow transparent and balanced assessment of the benefit-risk ratio in clinical decision making. PMID- 28866636 TI - Transient aortitis documented by positron emission tomography in a case series of men and transgender women infected with syphilis. AB - OBJECTIVES: Syphilis infection persists globally contributing to preventable and treatable morbidity and mortality. How extensive early syphilis disseminates is unknown. To better understand the relationship between early syphilis infection and inflammation over time, our study enrolled six individuals recently infected with syphilis for sequential positron emission tomography (PET) scans. METHODS: We evaluated a case series of six individuals with high syphilis titres (two secondary, two early latent and two latent, unknown duration, but with high titre) who received sequential PET scans to assess inflammation over time and its response to treatment. RESULTS: At time of PET scan, four of the six individuals were co-infected with HIV. One of the four was not on antiretroviral therapy and three of the four were not virally suppressed (viral load of >400 copies/mL). Baseline rapid plasma reagin (RPR) titres ranged from 1:64 to 1:256 (four of the six participants had prior non-reactive RPR results). Five of the six participants had mild to intense hypermetabolic PET scan activity consistent with cervical (n=5), axillary (n=4), inguinal (n=5) and retroperitoneal (n=1) adenopathy. Mild hypermetabolic activity in the thoracic aortic wall, suggesting aortitis, was present among the same five participants and resolved within 30 days for four of the five participants and 60 days for the other participant. However, widespread lymphadenopathy remained present in PET scans up to 3 months following treatment in two participants. We did not find any abnormal PET scan activity of the central nervous system. CONCLUSION: We found abnormal aortic wall PET scan activity suggesting aortitis to be common in a case series of patients with early syphilis. In research settings, PET scans may be a sensitive tool to monitor inflammation associated with syphilis. PMID- 28866635 TI - Acceptability and ease of use of mailed HPV self-collection among infrequently screened women in North Carolina. AB - OBJECTIVES: Self-collection of cervico-vaginal samples for human papillomavirus (HPV) testing has the potential to make cervical cancer screening more accessible to underscreened women. We evaluated the acceptability and ease of use of home based HPV self-collection within a diverse population of low-income, infrequently screened women. METHODS: Participants were low-income women from North Carolina who had not received Pap testing in 4 or more years. Eligible women received a self-collection kit containing instructions and a brush for home-based sample collection. A total of 227 women returned a self-collected sample by mail and completed a questionnaire to assess their experiences with HPV self-collection. We described acceptability measures and used logistic regression to identify predictors of overall positive thoughts about the self-collection experience. RESULTS: Nearly all women were willing to perform HPV self-collection again (98%) and were comfortable receiving the self-collection kit in the mail (99%). Overall, 81% of participants reported positive thoughts about home-based self collection. Women with at least some college education and those who were divorced, separated or widowed were more likely to report overall positive thoughts. Aspects of self-collection that participants most commonly reported liking included convenience (53%), ease of use (32%) and privacy (23%). The most frequently reported difficulties included uncertainty that the self-collection was done correctly (16%) and difficulty inserting the self-collection brush (16%). CONCLUSIONS: Home-based self-collection for HPV was a highly acceptable screening method among low-income, underscreened women and holds the promise to increase access to cervical cancer screening in this high-risk population. PMID- 28866637 TI - Detection of human papillomavirus in urine among heterosexual men in relation to location of genital warts and circumcision status. AB - OBJECTIVE: Human papillomavirus (HPV) surveillance is important to monitor the effectiveness of national HPV vaccination programmes. Positivity of HPV in urine in men varies with different sampling methods. We aimed to determine the positivity for detection of HPV-6/11 in urine samples among men in relation to the position of genital warts and circumcision status. METHOD: We analysed stored chlamydia-positive urine specimens in young heterosexual men aged less than 25 years attending Melbourne Sexual Health Centre, Australia, between 2004 and 2015, for HPV genotypes. Positivity of HPV-6/11 and high-risk genotypes were stratified according to the position of genital warts and circumcision status. Positivity of HPV-6/11 was calculated using diagnosis of warts as the gold standard. Warts were classified as proximal penile warts from suprapubic area to midshaft of penis, and distal penile warts from distal shaft of penis to meatus. RESULTS: Of the 934 specimens, 253 (27.1%) men were positive for any HPV and 82 men (8.8%) had genital warts. The ORs of HPV-6/11 detection in urine were 4.63 (95% CI: 1.68 to 12.78) and 40.20 (95% CI: 19.78 to 81.70) times higher among men who had proximal penile warts and distal penile warts, respectively, compared with men who did not have genital warts. Circumcised men were less likely to have high-risk HPV (OR 0.31; 95% CI: 0.14 to 0.65) than uncircumcised men. Uncircumcised men were more likely to have distal penile warts than circumcised men (OR 8.22; 95% CI: 1.34 to 337.46). CONCLUSION: Positivity of HPV-6/11 in urine increases greatly in men with distal penile warts. Circumcised men are less likely to have distal penile warts, any HPV or high-risk HPV detected. Urine is likely to be an alternative sampling method for HPV-6/11 surveillance programme in men in countries with low circumcision rates. PMID- 28866638 TI - Prediction of hyperperfusion phenomenon after carotid artery stenting and carotid angioplasty using quantitative DSA with cerebral circulation time imaging. AB - BACKGROUND: Hyperperfusion syndrome after carotid interventions has a low incidence but it can lead to morbidity and mortality. OBJECTIVE: To evaluate the usefulness of quantitative DSA for predicting hyperperfusion phenomenon (HPP) after carotid artery stenting and angioplasty. METHODS: Thirty-three consecutive patients with carotid stenosis treated with carotid artery stenting or angioplasty between February 2014 and August 2016 were included. Color-coded digital subtraction angiograms showing the time to maximum contrast intensity of each image pixel were obtained from conventional DSA before and after procedures. The cerebral circulation time (CCT) was defined as the difference in the relative time to maximum intensity between arterial and venous regions of interest set on the angiograms. HPP was diagnosed straight after the procedure with qualitative 123I-IMP single-photon emission CT (SPECT). Cut-off points for detecting HPP for preprocedural CCT and periprocedural change of CCT were assessed by receiver operating characteristic analysis using 123I-IMP SPECT as reference standard. RESULTS: 123I-IMP SPECT showed HPP in 4 of 33 patients. In these 4 patients, preprocedural prolongation of CCT (13.0+/-6.1 vs 7.2+/-1.3 s; p<0.001) was seen compared with patients without HPP as well as larger periprocedural changes of CCT (5.9+/-5.7 vs 0.5+/-1.3 s; p<0.001). The optimal cut-off points of preprocedural CCT and change of CCT for predicting HPP were 8.0 s (100% sensitivity, 69% specificity) and 3.2 s (75% sensitivity, 100% specificity), respectively. CONCLUSIONS: Preprocedural prolongation and greater periprocedural change of CCT are associated with the occurrence of HPP. Periprocedural evaluation of CCT may be useful for predicting HPP. PMID- 28866639 TI - Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T in Drosophila melanogaster Indirect Flight Muscles. AB - MicroRNAs (miRNAs) are small noncoding endogenous RNAs, typically 21-23 nucleotides long, that regulate gene expression, usually post-transcriptionally, by binding to the 3'-UTR of target mRNA, thus blocking translation. The expression of several miRNAs is significantly altered during cardiac hypertrophy, myocardial ischemia, fibrosis, heart failure, and other cardiac myopathies. Recent studies have implicated miRNA-9 (miR-9) in myocardial hypertrophy. However, a detailed mechanism remains obscure. In this study, we have addressed the roles of miR-9 in muscle development and function using a genetically tractable model system, the indirect flight muscles (IFMs) of Drosophila melanogaster Bioinformatics analysis identified 135 potential miR-9a targets, of which 27 genes were associated with Drosophila muscle development. Troponin-T (TnT) was identified as major structural gene target of miR-9a. We show that flies overexpressing miR-9a in the IFMs have abnormal wing position and are flightless. These flies also exhibit a loss of muscle integrity and sarcomeric organization causing an abnormal muscle condition known as "hypercontraction." Additionally, miR-9a overexpression resulted in the reduction of TnT protein levels while transcript levels were unaffected. Furthermore, muscle abnormalities associated with miR-9a overexpression were completely rescued by overexpression of TnT transgenes which lacked the miR-9a binding site. These findings indicate that miR-9a interacts with the 3'-UTR of the TnT mRNA and downregulates the TnT protein levels by translational repression. The reduction in TnT levels leads to a cooperative downregulation of other thin filament structural proteins. Our findings have implications for understanding the cellular pathophysiology of cardiomyopathies associated with miR-9 overexpression. PMID- 28866640 TI - KinFin: Software for Taxon-Aware Analysis of Clustered Protein Sequences. AB - The field of comparative genomics is concerned with the study of similarities and differences between the information encoded in the genomes of organisms. A common approach is to define gene families by clustering protein sequences based on sequence similarity, and analyze protein cluster presence and absence in different species groups as a guide to biology. Due to the high dimensionality of these data, downstream analysis of protein clusters inferred from large numbers of species, or species with many genes, is nontrivial, and few solutions exist for transparent, reproducible, and customizable analyses. We present KinFin, a streamlined software solution capable of integrating data from common file formats and delivering aggregative annotation of protein clusters. KinFin delivers analyses based on systematic taxonomy of the species analyzed, or on user-defined, groupings of taxa, for example, sets based on attributes such as life history traits, organismal phenotypes, or competing phylogenetic hypotheses. Results are reported through graphical and detailed text output files. We illustrate the utility of the KinFin pipeline by addressing questions regarding the biology of filarial nematodes, which include parasites of veterinary and medical importance. We resolve the phylogenetic relationships between the species and explore functional annotation of proteins in clusters in key lineages and between custom taxon sets, identifying gene families of interest. KinFin can easily be integrated into existing comparative genomic workflows, and promotes transparent and reproducible analysis of clustered protein data. PMID- 28866641 TI - Extrathoracic hyperinflation. PMID- 28866642 TI - The quantitative link of lung clearance index to bronchial segments affected by bronchiectasis. AB - In adult patients with cystic fibrosis (CF), the lung clearance index (LCI) derived from the multiple breath washout relates to both acinar and conductive ventilation heterogeneity. The latter component predicts an association between LCI and the number of bronchial segments affected by bronchiectasis. Here, we experimentally demonstrated this association in patients with CF, and also examined an ancillary group of patients with non-CF bronchiectasis. We conclude that lung disease severity in terms of number of bronchial segments results in an associated LCI increase, likely constituting a portion of LCI that cannot be reversed by treatment in patients with CF lung disease. PMID- 28866643 TI - Influence of muscle mass in the assessment of lower limb strength in COPD: validation of the prediction equation. AB - Absence of established reference values limits application of quadriceps maximal voluntary contraction (QMVC) measurement. The impact of muscle mass inclusion in predictions is unclear. Prediction equations encompassing gender, age and size with (FFM+) and without (FFM-), derived in healthy adults (n=175), are presented and compared in two COPD cohorts recruited from primary care (COPD-PC, n=112) and a complex care COPD clinic (COPD-CC, n=189). Explained variance was comparable between the prediction models (R2: FFM+: 0.59, FFM-: 0.60) as were per cent predictions in COPD-PC (88.8%, 88.3%). However, fat-free mass inclusion reduced the prevalence of weakness in COPD, particularly in COPD-CC where 11.9% fewer were deemed weak. PMID- 28866644 TI - Functional phenotypes determined by fluctuation-based clustering of lung function measurements in healthy and asthmatic cohort participants. AB - RATIONALE: Asthma is characterised by inflammation and reversible airway obstruction. However, these features are not always closely related. Fluctuations of daily lung function contain information on asthma phenotypes, exacerbation risk and response to long-acting beta-agonists. OBJECTIVES: In search of subgroups of asthmatic participants with specific lung functional features, we developed and validated a novel clustering approach to asthma phenotyping, which exploits the information contained within the fluctuating behaviour of twice daily lung function measurements. METHODS: Forced expiratory volume during the first second (FEV1) and peak expiratory flow (PEF) were prospectively measured over 4 weeks in 696 healthy and asthmatic school children (Protection Against Allergy - Study in Rural Environments (PASTURE)/EFRAIM cohort), and over 1 year in 138 asthmatic adults with mild-to-moderate or severe asthma (Pan-European Longitudinal Assessment of Clinical Course and BIOmarkers in Severe Chronic AIRway Disease (BIOAIR) cohort). Using enrichment analysis, we explored whether the method identifies clinically meaningful, distinct clusters of participants with different lung functional fluctuation patterns. MEASUREMENTS AND MAIN RESULTS: In the PASTURE/EFRAIM dataset, we found four distinct clusters. Two clusters were enriched in children with well-known clinical characteristics of asthma. In cluster 3, children from a farming environment predominated, whereas cluster 4 mainly consisted of healthy controls. About 79% of cluster 3 carried the asthma-risk allele rs7216389 of the 17q21 locus. In the BIOAIR dataset, we found two distinct clusters clearly discriminating between individuals with mild to-moderate and severe asthma. CONCLUSIONS: Our method identified dynamic functional asthma and healthy phenotypes, partly independent of atopy and inflammation but related to genetic markers on the 17q21 locus. The method can be used for disease phenotyping and possibly endotyping. It may identify participants with specific functional abnormalities, potentially needing a different therapeutic approach. PMID- 28866646 TI - High-dose ustekinumab for severe childhood deficiency of interleukin-36 receptor antagonist (DITRA). PMID- 28866645 TI - Optimal methotrexate dose is associated with better clinical outcomes than non optimal dose in daily practice: results from the ESPOIR early arthritis cohort. AB - BACKGROUND: Although methotrexate (MTX) is the consensual first-line disease modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA), substantial heterogeneity remains with its prescription and dosage, which are often not optimal. OBJECTIVE: To evaluate the symptomatic and structural impact of optimal MTX dose in patients with early RA in daily clinical practice over 2 years. METHODS: Patients included in the early arthritis ESPOIR cohort who fulfilled the ACR-EULAR (American College of Rheumatology/European League against Rheumatism) criteria for RA and received MTX as a first DMARD were assessed. Optimal MTX dose was defined as >=10 mg/week during the first 3 months, with escalation to >=20 mg/week or 0.3 mg/kg/week at 6 months without Disease Activity Score in 28 joints remission. Symptomatic and structural efficacy with and without optimal MTX dose was assessed by generalised logistic regression with adjustment for appropriate variables. RESULTS: Within the first year of follow-up, 314 patients (53%) with RA received MTX as a first DMARD (mean dose 12.2+/-3.8 mg/week). Only 26.4% (n=76) had optimal MTX dose. After adjustment, optimal versus non-optimal MTX dose was more efficient in achieving ACR-EULAR remission at 1 year (OR 4.28 (95% CI 1.86 to 9.86)) and normal functioning (Health Assessment Questionnaire <=0.5; OR at 1 year 4.36 (95% CI 2.03 to 9.39)), with no effect on radiological progression. Results were similar during the second year. CONCLUSION: Optimal MTX dose is more efficacious than non-optimal dose for remission and function in early arthritis in daily practice, with no impact on radiological progression over 2 years. PMID- 28866648 TI - Consensus-based recommendations for the use of biosimilars to treat rheumatological diseases. AB - The study aimed to develop evidence-based recommendations regarding the evaluation and use of biosimilars to treat rheumatological diseases. The task force comprised an expert group of specialists in rheumatology, dermatology and gastroenterology, and pharmacologists, patients and a regulator from ten countries. Four key topics regarding biosimilars were identified through a process of discussion and consensus. Using a Delphi process, specific questions were then formulated to guide a systematic literature review. Relevant English language publications through November 2016 were searched systematically for each topic using Medline; selected papers and pertinent reviews were examined for additional relevant references; and abstracts presented at the 2015 and 2016 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) annual scientific meetings were searched for those about biosimilars. The experts used evidence obtained from these studies to develop a set of overarching principles and consensus recommendations. The level of evidence and grade of recommendation were determined for each. By the search strategy, 490 references were identified. Of these, 29 full-text papers were included in the systematic review. Additionally, 20 abstracts were retrieved from the ACR and EULAR conference abstract databases. Five overarching principles and eight consensus recommendations were generated, encompassing considerations regarding clinical trials, immunogenicity, extrapolation of indications, switching between bio originators and biosimilars and among biosimilars, and cost. The level of evidence and grade of recommendation for each varied according to available published evidence. Five overarching principles and eight consensus recommendations regarding the evaluation and use of biosimilars to treat rheumatological diseases were developed using research-based evidence and expert opinion. PMID- 28866647 TI - Chemotaxis of Vdelta2 T cells to the joints contributes to the pathogenesis of rheumatoid arthritis. AB - OBJECTIVES: To explore the role of Vdelta2 T cells in the pathogenesis of rheumatoid arthritis (RA). METHODS: Sixty-eight patients with RA, 21 patients with osteoarthritis and 21 healthy controls were enrolled in the study. All patients with RA fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA. Peripheral Vdelta2T population, chemokine receptor expression and proinflammatory cytokine secretion were quantified by flow cytometry. The infiltration of Vdelta2 T cells within the synovium was examined by immunohistochemistry and flow cytometry. The effect of tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 on Vdelta2 T migration was determined by flow cytometry and transwell migration assay. RESULTS: Peripheral Vdelta2T cells, but not Vdelta1 T cells, were significantly lower in patients with RA, which was negatively correlated with disease activity gauged by Disease Activity Score in 28 joints. Vdelta2 T cells from RA accumulated in the synovium and produced high levels of proinflammatory cytokines including interferon-gamma and IL-17. Phenotypically, Vdelta2 T cells from RA showed elevated chemotaxis potential and expressed high levels of chemokine receptors CCR5 and CXCR3, which was driven by increased serum TNF-alpha through nuclear factor kappa B signalling. In vivo, TNF-alpha neutralising therapy dramatically downregulated CCR5 and CXCR3 on Vdelta2 T cells and repopulated the peripheral Vdelta2 T cells in patients with RA. CONCLUSIONS: High levels of TNF-alpha promoted CCR5 and CXCR3 expression in Vdelta2 T cells from RA, which potentially infiltrated into the synovium and played crucial roles in the pathogenesis of RA. Targeting Vdelta2 T cells might be a potential approach for RA. PMID- 28866650 TI - Patient self-testing and self-management of anticoagulation is safe and patients are satisfied with these programmes. PMID- 28866649 TI - Weight loss for overweight and obese individuals with gout: a systematic review of longitudinal studies. AB - OBJECTIVES: Weight loss is commonly recommended for gout, but the magnitude of the effect has not been evaluated in a systematic review. The aim of this systematic review was to determine benefits and harms associated with weight loss in overweight and obese patients with gout. METHODS: We searched six databases for longitudinal studies, reporting the effect of weight loss in overweight/obese gout patients. Risk of bias was assessed using the tool Risk of Bias in Non Randomised Studies of Interventions. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation. RESULTS: From 3991 potentially eligible studies, 10 were included (including one randomised trial). Interventions included diet with/without physical activity, bariatric surgery, diuretics, metformin or no intervention. Mean weight losses ranged from 3 kg to 34 kg. Clinical heterogeneity in study characteristics precluded meta-analysis. The effect on serum uric acid (sUA) ranged from -168 to 30 MUmol/L, and 0%-60% patients achieving sUA target (<360 MUmol/L). Six out of eight studies (75%) showed beneficial effects on gout attacks. Two studies indicated dose-response relationship for sUA, achieving sUA target and gout attacks. At short term, temporary increased sUA and gout attacks tended to occur after bariatric surgery. CONCLUSIONS: The available evidence is in favour of weight loss for overweight/obese gout patients, with low, moderate and low quality of evidence for effects on sUA, achieving sUA target and gout attacks, respectively. At short term, unfavourable effects may occur. Since the current evidence consists of a few studies (mostly observational) of low methodological quality, there is an urgent need to initiate rigorous prospective studies (preferably randomised controlled trials). SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42016037937. PMID- 28866651 TI - Back pain in pregnancy among office workers: risk factors and its impact on quality of life. AB - Background Back pain is a common presenting complaint during pregnancy and it is often being considered as part of the pregnancy process. The purpose of the study is to investigate the prevalence of back pain in pregnancy, risk factors and its impact on the quality of life in pregnant women. Materials and methods Three hundred and fifty-eight pregnant women who attended the antenatal clinic in Universiti Kebangsaan Malaysia (UKM) Medical Centre were recruited in this cross sectional study from October 2011 until April 2012. The back pain was further classified into lumbar pain and posterior pelvic pain. The severity of back pain was assessed using visual analoque scale (VAS) and the functional limitation was assessed using the Oswestry Disability Questionnaire (ODQ). Result The prevalence of back pain in pregnancy was 84.6%. Occupation and previous history of back pain were associated with back pain in pregnancy. In terms of functional limitation disability, total ODQ score was statistically significant correlate with severity of pain (VAS score). Personal care, sitting, standing, sex life and social life were significantly affected. Conclusion The risk factors for back pain in pregnancy were type of occupation and history of back pain. The higher VAS score, the more ODQ will be affected. Personal care, sitting, standing, sex life and social life were significantly affected. PMID- 28866652 TI - The effects of high and low doses of folic acid on oxidation of protein levels during pregnancy: a randomized double-blind clinical trial. AB - Objective Oxidants include important active molecules which are created in the body and attack biological molecules especially lipids, carbohydrates, nucleic acids and proteins, and cause oxidation and various diseases in the body. Antioxidants existing in the body help to avoid the incidence of these injuries. Pregnant women are among those where oxidation of biological molecules may do irreparable damage to them and their embryos. So, the purpose of this study was to review the effect of folic acid with both high (5 mg/day) and low (0.5 mg/day) doses on the changes of oxidative protein in reducing plasma homocystein concentration during pregnancy. Materials and methods Forty-five pregnant women participated in this study. They were divided into two groups: group 1 included 23 women who received 5 mg/day folic acid and group 2 included 23 women who took 0.5 mg/day folic acid before pregnancy till the 36th week pregnancy. We measured the biochemical variables in the serum of pregnant women at the beginning and at the end of the study. Results Folic acid reduced plasma homocytein in both low and high dose groups (p = 0.035, p = 0.012, respectively). Also, the results showed that folic acid prescription led to reduce plasma level of carbonyl groups in both low and high dose groups (p = 0.01, p = 0.03, respectively). Furthermore, the results showed that there is no significant difference between two groups and folic acid affects both groups equally. Conclusion It is possible that folic acid administration can reduce plasma homocysteine and carbonyl levels during pregnancy in dose independent manner. PMID- 28866653 TI - Strategies for the construction of insect P450 fusion enzymes. AB - Cytochrome P450 monooxygenases (P450s) are ubiquitous enzymes with a broad substrate spectrum. Insect P450s are known to catalyze reactions such as the detoxification of insecticides and the synthesis of hydrocarbons, which makes them useful for many industrial processes. Unfortunately, it is difficult to utilize P450s effectively because they must be paired with cytochrome P450 reductases (CPRs) to facilitate electron transfer from reduced nicotinamide adenine dinucleotide phosphate (NADPH). Furthermore, eukaryotic P450s and CPRs are membrane-anchored proteins, which means they are insoluble and therefore difficult to purify when expressed in their native state. Both challenges can be addressed by creating fusion proteins that combine the P450 and CPR functions while eliminating membrane anchors, allowing the production and purification of soluble multifunctional polypeptides suitable for industrial applications. Here we discuss several strategies for the construction of fusion enzymes combining insect P450 with CPRs. PMID- 28866654 TI - Hydroxylation and sulfation of sex steroid hormones in inflammatory liver. AB - Sex steroids, also known as gonadal steroids, are oxidized with hydroxylation by cytochrome P450, glucuronidation by UDP-glucuronosyltransferase, sulfation by sulfotransferase, andO-methylation by catechol O-methyltransferase. Thus, it is important to determine the process by which inflammation influences metabolism of gonadal hormones. Therefore, we investigated the mechanism of metabolic enzymes against high physiologic inflammatory responsein vivo to study their biochemical properties in liver diseases. In this study, C57BL/6N mice were induced with hepatic inflammation by diethylnitrosamine (DEN) exposure. We observed upregulation of Cyp19a1, Hsd17b1, Cyp1a1, Sult1e1 in the DEN-treated livers compared to the control-treated livers using real time PCR. Moreover, the increased Cyp19a1 and Hsd17b1 levels support the possibility that estrogen biosynthesis from androgens are accumulated during inflammatory liver diseases. Furthermore, the increased levels of Cyp1a1 and Cyp1b1 in the hydroxylation of estrogen facilitated the conversion of estrogen to 2- or 4-hydroxyestrogen, respectively. In addition, the substantial increase in the Sult1e1 enzyme levels could lead to sulfate conjugation of hydroxyestrogen. The present information supports the concept that inflammatory response can sequester sulfate conjugates from the endogenous steroid hormones and may suppress binding of sex steroid hormones to their receptors in the whole body. PMID- 28866655 TI - Multifunctional quantum dots and liposome complexes in drug delivery. AB - Incorporating both diagnostic and therapeutic functions into a single nanoscale system is an effective modern drug delivery strategy. Combining liposomes with semiconductor quantum dots (QDs) has great potential to achieve such dual functions, referred to in this review as a liposomal QD hybrid system (L-QD). Here we review the recent literature dealing with the design and application of L QD for advances in bio-imaging and drug delivery. After a summary of L-QD synthesis processes and evaluation of their properties, we will focus on their multifunctional applications, ranging from in vitro cell imaging to theranostic drug delivery approaches. PMID- 28866657 TI - A novel entry point for pedicle screw placement in the thoracic spine. AB - This study was aimed to introduce a novel entry point for pedicle screw fixation in the thoracic spine and compare it with the traditional entry point. A novel entry point was found with the aim of improving accuracy, safety and stability of pedicle screw technique based on anatomical structures of the spine. A total of 76 pieces of normal thoracic CT images at the transverse plane and the thoracic pedicle anatomy of 6 cadaveric specimens were recruited. Transverse pedicle angle (TPA), screw length, screw placement accuracy rate and axial pullout strength of the two different entry point groups were compared. There were significant differences in the TPA, screw length, and the screw placement accuracy rate between the two groups (P<0.05). The maximum axial pullout strength of the novel entry point group was slightly larger than that of the traditional group. However, the difference was not significant (P>0.05). The novel entry point significantly improved the accuracy, stability and safety of pedicle screw placement. With reference to the advantages above, the new entry point can be used for spinal internal fixations in the thoracic spine. PMID- 28866656 TI - Immune checkpoint inhibitors in cancer therapy. AB - In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1 (CD80) and B7-2 (CD86), plays a pivotal role in attenuating the activation of naive and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses. PMID- 28866658 TI - Proteomic analysis of the dorsal spinal cord in the mouse model of spared nerve injury-induced neuropathic pain. AB - Peripheral nerve injury often causes neuropathic pain and is associated with changes in the expression of numerous proteins in the dorsal horn of the spinal cord. To date, proteomic analysis method has been used to simultaneously analyze hundreds or thousands of proteins differentially expressed in the dorsal horn of the spinal cord in rats or dorsal root ganglion of rats with certain type of peripheral nerve injury. However, a proteomic study using a mouse model of neuropathic pain could be attempted because of abundant protein database and the availability of transgenic mice. In this study, whole proteins were extracted from the ipsilateral dorsal half of the 4th-6th lumbar spinal cord in a mouse model of spared nerve injury (SNI)-induced neuropathic pain. In-gel digests of the proteins size-separated on a polyacrylamide gel were subjected to reverse phase liquid-chromatography coupled with electrospray ionization ion trap tandem mass spectrometry (MS/MS). After identifying proteins, the data were analyzed with subtractive proteomics using ProtAn, an in-house analytic program. Consequently, 15 downregulated and 35 upregulated proteins were identified in SNI mice. The identified proteins may contribute to the maintenance of neuropathic pain, and may provide new or valuable information in the discovery of new therapeutic targets for neuropathic pain. PMID- 28866659 TI - Profiles of metabolic gene expression in the white adipose tissue, liver and hypothalamus in leptin knockout (LepDeltaI14/DeltaI14 ) rats. AB - Leptin deficiency is principally linked to metabolic disorders. Leptin knockout (LepDeltaI14/DeltaI14) Sprague Dawley rats created by CRISPR/Cas9 is a new model to study metabolic disorders. We used a whole rat genome oligonucleotide microarray to obtain tissue-specific gene expression profiles of the white adipose tissue, liver and hypothalamus in LepDeltaI14/DeltaI14 and wild-type (WT) rats. We found 1,651 differentially expressed (enriched) genes in white adipose tissue, 916 in the liver, and 306 in the hypothalamus in the LepDeltaI14/DeltaI14 rats compared to WT. Gene ontology category and KEGG pathway analysis of the relationships among differentially expressed genes showed that these genes were represented in a variety of functional categories, including fatty acid metabolism, molecular transducers and cellular processes. The reliability of the data obtained from microarray was verified by quantitative real-time PCR on 14 representative genes. These data will contribute to a greater understanding of different metabolic disorders, such as obesity and diabetes. PMID- 28866660 TI - Generation of tryptophan hydroxylase 2 gene knockout pigs by CRISPR/Cas9-mediated gene targeting. AB - Unbalanced brain serotonin (5-HT) levels have implications in various behavioral abnormalities and neuropsychiatric disorders. The biosynthesis of neuronal 5-HT is regulated by the rate-limiting enzyme, tryptophan hydroxylase-2 (TPH2). In the present study, the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system was used to target theTph2 gene in Bama mini pig fetal fibroblasts. It was found that CRISPR/Cas9 targeting efficiency could be as high as 61.5%, and the biallelic mutation efficiency reached at 38.5%. The biallelic modified colonies were used as donors for somatic cell nuclear transfer (SCNT) and 10Tph2 targeted piglets were successfully generated. These Tph2 KO piglets were viable and appeared normal at the birth. However, their central 5-HT levels were dramatically reduced, and their survival and growth rates were impaired before weaning. TheseTph2 KO pigs are valuable large animal models for studies of 5-HT deficiency induced behavior abnomality. PMID- 28866661 TI - Observational Study of Perspectives of Inflammatory Bowel Disease Patients Concerning the Use of Corticosteroids. AB - AIM: We aimed to investigate the factors that make inflammatory bowel disease (IBD) patients more or less likely to be willing to take corticosteroids. METHODS: Respondents completed a questionnaire. The primary outcome was whether the respondents would or would not use corticosteroids again to treat their IBD. Three separate univariate and multivariate analyses were performed to examine which variables predicted willingness to take steroids, including specific side effects. RESULTS: Four hundred fifty three respondents (321 with Crohn's disease, 115 with ulcerative colitis; mean age 40 years, 297 [66%] female) completed the questionnaire. Corticosteroid efficacy (OR 6.83, 95% CI 3.67-12.7), lack of previous negative side effects (OR 0.11, 95% CI 0.04-0.32), and positive side effects (OR 2.96, 95% CI 1.63-5.40) were associated with a willingness to use corticosteroids in the future. In multivariate analysis, weight gain (OR 0.53, 95% CI 0.29-0.98) and hallucinations (OR 0.28, CI 0.09-0.89) were associated with an unwillingness to use corticosteroids again, whereas increased energy (OR 2.30, 95% CI 1.20-4.42) was the only significant positive side effect in a multivariate model. CONCLUSIONS: Past experiences with corticosteroids influence whether patients will take corticosteroids again. Clinicians should enquire about side effects and positive psychological symptoms associated with corticosteroid use. PMID- 28866663 TI - Infections of Intrathecal Baclofen Delivery Systems and Ventriculoperitoneal Shunting Systems: Clinical Series Discussion. AB - BACKGROUND/AIMS: The physiological interaction between the intrathecal baclofen (ITB) delivery system and the ventriculoperitoneal (VP) shunting system in a patient who had both systems implanted has not been reported previously. The aim of our report is to evaluate the effect that one system's infection might have on the other. METHODS: Records of children who were followed at our institution between 2004 and 2015 for management of their ITB systems were reviewed. In this group, children who had VP shunts were identified, and those who had any of their ITB or VP systems infected were included. RESULTS: Out of 313 children managed with ITB therapy at our institution, 31 (24%) children had VP shunts. Two patients had infection in both systems, and 3 patients had infection in 1 system. CONCLUSION: This report suggests that if aspiration from both systems showed positive cultures, the treatment would be removal of both systems. If the primarily not infected system does not show positive cultures, it does not need to be removed. Close follow-up is recommended, and any sign of infection or malfunction of the primarily not infected device should be approached with a high level of suspicion. PMID- 28866662 TI - Serum CA19-9 Response Is an Early Predictive Marker of Efficacy of Regorafenib in Refractory Metastatic Colorectal Cancer. AB - PURPOSE: Regorafenib improves survival in chemorefractory metastatic colorectal cancer (mCRC) patients. However, regorafenib induces various adverse events (AEs) that often impair patients' quality of life. Identification of early predictive markers of the efficacy is warranted. METHODS: We retrospectively examined 146 consecutive mCRC patients who received regorafenib. Clinical parameters, including patient background, AEs, and changes in biochemical parameters until day 28, were evaluated to identify efficacy predictors. RESULTS: Median progression-free survival (PFS) was 2.1 months, and median overall survival was 6.6 months. Major AEs in all cycles were hand-foot skin reaction, hypertension, and increased aspartate transaminase. We extracted 121 patients for prognostic analysis. In univariate analysis, decreased carcinoembryonic antigen (HR: 0.570, p = 0.012) and decreased carbohydrate antigen 19-9 (CA19-9) (HR: 0.422, p = 0.0012) were identified as prognostic markers of PFS. Patients in whom serum CA19 9 decreased after regorafenib exhibited significantly better PFS (median 3.7 vs. 2.0 months, p = 0.004) than those in whom serum CA19-9 did not decrease. Multivariate analysis revealed early CA19-9 decrease as an independent predictive factor (HR: 0.415, 95% CI: 0.210-0.818, p = 0.011). CONCLUSION: Early response of CA19-9 may predict the efficacy of regorafenib. Additional studies are needed for external validation. PMID- 28866665 TI - The Look of the Devil: Multiple Cranial Neuropathies. AB - The sculpture of the devil on a portal of the Lichtenthal Abbey School in Baden Baden, Germany displays neurological pathology, possibly consistent with multiple cranial neuropathy. One of the main abnormalities is an exotropia strabismus, a feature rarely depicted in works of art portraying the devil. PMID- 28866664 TI - Smoking Trajectories during the Perinatal Period and Their Risk Factors: The Nationally Representative French ELFE (Etude Longitudinale Francaise Depuis l'Enfance) Birth Cohort Study. AB - BACKGROUND: In France, rates of perinatal smoking are among the highest worldwide; however, perinatal smoking trajectories and associated factors have still not been adequately researched. METHODS: Among women participating in the French nationally representative etude longitudinale francaise depuis l'enfance birth cohort (n = 15,540), perinatal smoking trajectories were estimated using group-based modelling. Associated characteristics were studied using multinomial logistic regression. RESULTS: Four trajectories were identified: non-smokers (59%), quitters (20%), persistent moderate (12%) and persistent heavy (9%) smokers. Older age, being native French, low socioeconomic position, persistent psychological difficulties and alcohol use in pregnancy, lack of social support, partner's smoking, mistimed pregnancy, and child formula feeding at birth were associated with persistent heavy smoking. Most of these factors were also associated, but to a lesser extent, with persistent moderate smoking, except for age and migrant status, which had opposite effects. Women who successfully lost weight prior to pregnancy had higher levels of quitting smoking. CONCLUSION: Women's long-term smoking trajectories vary in terms of initial tobacco consumption level but also in relation to socio-demographic, psychological, behavioral and partner characteristics. Health professionals in contact with pregnant smokers should address perceived risks and benefits of smoking, including partner's smoking and weight-gain concerns. PMID- 28866666 TI - The Cumulative Effects of the MYH7-V878A and CACNA1C-A1594V Mutations in a Chinese Family with Hypertrophic Cardiomyopathy. AB - AIMS: We investigated the pathogenesis of MYH7-V878A and CACNA1C-A1594V mutations in a Chinese family with hypertrophic cardiomyopathy. METHODS: Clinical, electrocardiographic (ECG), echocardiographic, and cardiac magnetic resonance (CMR) examinations of members of a Chinese family were followed by exon and boarding intron analyses of 96 genes in the proband using second-generation sequencing. We confirmed the mutations by bidirectional Sanger sequencing in the members and in 300 healthy controls. RESULTS: We detected MYH7-V878A and CACNA1C A1594V mutations in this family. The members with both mutations showed inverted T-waves and ST-segment depression in ECG recordings, severe left ventricular (LV) hypertrophy in echocardiography, and myocardial fibrosis in CMR; subject II-11 did not show late gadolinium enhancement. Among those with only the MYH7-V878A mutation, subject III-7 showed abnormal ECG recordings, asymmetric septal hypertrophy, and myocardial fibrosis, and subjects II-13 and III-15 showed some abnormal repolarization, borderline LV wall thickness, and normal CMR findings. Those with only the CACNA1C-A1594V mutation showed nearly normal readings in all examinations. The members with both mutations displayed more severe LV hypertrophy and elevated LV filling pressure than those with 1 or no mutation (p < 0.05). CONCLUSION: Our results suggest that the pathogenesis of MYH7-V878A and CACNA1C-A1594V mutations may have a cumulative effect. PMID- 28866667 TI - A Modified Technique for the Transconjunctival and Sutureless External Drainage of Subretinal Fluid in Bullous Exudative Retinal Detachment Using a 24-G i.v. Catheter. AB - PURPOSE: To present the use of a 24-G Optiva(r) i.v. catheter for external drainage of subretinal fluid (SRF) in bullous exudative retinal detachment (RD). METHODS: Thirteen eyes with bullous exudative RD were included in our study. SRF drainage was accomplished via a transconjunctival scleral incision with a 24-G catheter followed by laser treatment, vitrectomy, or anti-VEGF treatment, as needed. Data on age, indications, visual acuities, the number of drainage times, drainage duration, complications, and fundoscopy were collected. RESULTS: Two females and 11 males, with a mean age of 4.2 +/- 2.7 years, were included. Surgical indications included exudative RD caused by Coats disease (12 eyes) and Sturge- Weber syndrome (1 eye). Successful drainage was achieved in all cases. The mean duration of the SRF drainage procedure was 63.5 +/- 16.9 s. Except for 1 case of localized subretinal haemorrhage, no complications were noted. CONCLUSIONS: External drainage of SRF using a 24-G Optiva(r) i.v. catheter is safe, efficient, and useful. PMID- 28866668 TI - Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing. AB - The emergence of kisspeptin as a crucial regulator of the hypothalamo-pituitary gonadal (HPG) axis over the last 14 years has answered many questions as to the control of reproductive hormone secretion from the hypothalamus. More recently, the role of kisspeptin outside the HPG axis has received increasing attention in the hope of delineating the pathways linking various sensory and social behaviours to reproduction. These studies, in a range of species from zebrafish to humans, have identified a role for kisspeptin in behavioural networks related to reproduction including olfaction, audition, fear, anxiety, mood, and sexual arousal. The available evidence suggests that extrahypothalamic kisspeptin signalling encourages positive aspects of emotional and sexual brain processing in a presumed drive towards reproduction and ultimately maintenance of the species at a population level. In this review, we examine these studies, which collectively propose that kisspeptin may integrate sexual and emotional brain processing with the control of the HPG axis. PMID- 28866669 TI - Observational Monitoring of Patients with Aplastic Anemia and Low/Intermediate-1 Risk of Myelodysplastic Syndromes Complicated with Iron Overload. AB - BACKGROUND: This study focuses on the iron overload (IOL) of patients with transfused aplastic anemia (AA) or a low/intermediate-1 risk of myelodysplastic syndrome (MDS). METHODS: Ninety-two AA or MDS patients with IOL were prospectively recruited. Clinical data were collected every 6 months, and organ magnetic resonance imaging T2* values were collected annually. Patients with IOL were chelated. RESULTS: Serum ferritin was correlated with liver T2* and pancreatic T2* in the AA and MDS groups. Transfusion amounts were correlated with serum ferritin values, liver T2*, and pancreatic T2* in the AA group. At the 6 month and 1-year evaluations, patients with sufficient chelation experienced significant decreases in serum ferritin, and those with decreased serum ferritin experienced an obvious increase in hemoglobin. At their 1-year-follow-up, patients with adequate chelation showed significant increases in hepatic T2*, cardiac T2*, and left ventricular ejection fraction (LVEF). Patients with decreased serum ferritin (including those without chelation) experienced an increase in hemoglobin, hepatic T2*, cardiac T2*, and LVEF. CONCLUSION: The transfusion amount was more reliable at predicting IOL in patients with AA than in those with MDS. Adequate iron chelation can decrease serum ferritin levels and may improve hepatic T2*, cardiac T2*, and LVEF levels. A decrease in serum ferritin, even in the absence of chelation, may also benefit patients. PMID- 28866670 TI - Clinical Outcome for Congenital Diaphragmatic Hernia at the Age of 1 Year in the Era of Fetal Intervention. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is an abnormal development of the diaphragm leading to high neonatal mortality and morbidity. Beyond the neonatal period, prospective data on overall long-term outcome in CDH survivors is scarce. In particular, for those treated with fetoscopic endoluminal tracheal occlusion (FETO), a promising new technique to increase survival chances for severe cases, the outcomes are even less documented. AIM: To prospectively document the clinical outcome of CDH at 1 year including FETO-treated infants in relation to ante- and postnatal variables. METHODS: A single-centre prospective clinical follow-up at 1 year of age included a standardised respiratory questionnaire. RESULTS: Thirty-four CDH survivors were included, 10 of which were FETO-treated infants. At 1 year, the median weight z score was -1.50 (interquartile range [IQR]: -2.45 to -0.88) and 10/34 were "failure to thrive" (FTT) cases. Gastro-intestinal (GI) problems at 1 year were mainly related to gastro-oesophageal reflux (16/34) with a high need for tube feeding in the first year (9/34). Tachypnoea was present in 10/29 (34%) and 8/34 (24%) were on chronic inhaled medication. The median total respiratory symptom score was 20 (IQR: 13 32) and correlated with the number of neonatal ventilation days (p = 0.048). Hospital re-admission occurred in 19/34 infants (56%), and was for respiratory problems in almost half of them (8/19). CONCLUSION: In this CDH cohort, morbidity at 1 year was determined more by GI problems and FTT than respiratory morbidity. The respiratory questionnaire may, however, have underestimated the respiratory morbidity since respondents had a 1-in-4 chance to have persistent tachypnoea and be on chronic inhalation therapy. PMID- 28866671 TI - Autoimmune Myelofibrosis: Clinical Features, Course, and Outcome. AB - BACKGROUND: Autoimmune myelofibrosis (AIMF) is an underrecognized cause of nonmalignant bone marrow fibrosis which occurs in the presence or absence of a defined systemic autoimmune disease. Patients with AIMF present with cytopenias and autoantibodies, and have a distinctive nonclonal myelofibrosis on bone marrow examination. AIMF is distinguished from primary myelofibrosis by the absence of splenomegaly, eosinophilia, or basophilia, and the absence of abnormal myeloid, erythroid, or megakaryocytic morphology. OBJECTIVES: The objective of the study was to describe the clinical presentation and outcomes of patients with AIMF. METHODS: We conducted a single-institution, retrospective chart review of patients diagnosed with AIMF to investigate clinical presentations, therapies, and outcomes. RESULTS: Twelve patients with AIMF were identified with a mean follow-up of 5.8 years. All patients had detectable autoantibodies and the majority had concomitant autoimmune disorders. Four patients experienced a complete response of cytopenias and 3 patients experienced a partial response (PR) of cytopenias with immunosuppressive therapy. One patient achieved a PR following splenectomy. No patients were diagnosed with myeloproliferative neoplasms during the follow-up period. CONCLUSIONS: AIMF contributes to cytopenias in the subset of patients with various autoimmune disorders. The majority of patients with AIMF experience an improvement in cytopenias with immunosuppressive therapy. PMID- 28866673 TI - Does Remifentanil Have a Place for Sedation in the Case of Endotracheal Intubation or Minimally Invasive Surfactant Therapy in Neonates? PMID- 28866672 TI - Increased Mobilization of CD45+CD34+VLA-4+ Cells in Acute Viral Myocarditis Induced by Coxsackievirus B3. AB - OBJECTIVES: Bone marrow-derived cells (BMCs) have recently been identified to play a vital role in repairing damaged myocardium; however, it is not known whether or not mobilization of BMCs is involved in the pathogenesis of acute viral myocarditis (VMC). Thus, we analyzed the expression of CD45+CD34+VLA-4+ cells and vascular cell adhesion protein-1 (VCAM-1) in a murine model of acute VMC. METHODS: Male BALB/c mice were intraperitoneally infected with coxsackievirus B3 to establish acute VMC. The frequency of CD45+CD34+VLA-4+ cells in the heart, peripheral blood, and bone marrow was examined by flow cytometry 3, 7, 14, and 28 days after injection. Cardiac VCAM-1 and pathology scores were determined by immunohistochemistry, and myocardial VCAM-1, IL-1beta, and TNF alpha were analyzed by RT-PCR and Western blot. RESULTS: In mice with acute VMC, the CD45+CD34+VLA-4+ cell population in the heart was significantly increased by day 7 and then decreased; in contrast, the CD45+CD34+VLA-4+ cell population decreased in the bone marrow and peripheral blood by day 3 and then increased. High expression of VCAM-1 was detected in the heart in parallel with CD45+CD34+VLA-4+ cell expression. CONCLUSIONS: In mice with acute VMC, VCAM-1 induced CD45+CD34+VLA-4+ cell mobilization into the injured heart is involved in the repair of injured myocardium. PMID- 28866674 TI - Association of Serum Potassium with All-Cause Mortality in Patients with and without Heart Failure, Chronic Kidney Disease, and/or Diabetes. AB - BACKGROUND: The relationship between serum potassium, mortality, and conditions commonly associated with dyskalemias, such as heart failure (HF), chronic kidney disease (CKD), and/or diabetes mellitus (DM) is largely unknown. METHODS: We reviewed electronic medical record data from a geographically diverse population (n = 911,698) receiving medical care, determined the distribution of serum potassium, and the relationship between an index potassium value and mortality over an 18-month period in those with and without HF, CKD, and/or DM. We examined the association between all-cause mortality and potassium using a cubic spline regression analysis in the total population, a control group, and in HF, CKD, DM, and a combined cohort. RESULTS: 27.6% had a potassium <4.0 mEq/L, and 5.7% had a value >=5.0 mEq/L. A U-shaped association was noted between serum potassium and mortality in all groups, with lowest all-cause mortality in controls with potassium values between 4.0 and <5.0 mEq/L. All-cause mortality rates per index potassium between 2.5 and 8.0 mEq/L were consistently greater with HF 22%, CKD 16.6%, and DM 6.6% vs. controls 1.2%, and highest in the combined cohort 29.7%. Higher mortality rates were noted in those aged >=65 vs. 50-64 years. In an adjusted model, all-cause mortality was significantly elevated for every 0.1 mEq/L change in potassium <4.0 mEq/L and >=5.0 mEq/L. Diuretics and renin angiotensin-aldosterone system inhibitors were related to hypokalemia and hyperkalemia respectively. CONCLUSION: Mortality risk progressively increased with dyskalemia and was differentially greater in those with HF, CKD, or DM. PMID- 28866676 TI - The Hippocampus: Questions of Homology. PMID- 28866677 TI - Of Horse-Caterpillars and Homologies: Evolution of the Hippocampus and Its Name. AB - The hippocampus was first named in mammals based on the appearance of its gross morphological features, one end of it being fancied to resemble the head of a horse and the rest of it a silkworm, or caterpillar. A hippocampus, occupying the most medial part of the telencephalic pallium, has subsequently been identified in diverse nonmammalian taxa, but in which the "horse-caterpillar" morphology is lacking. While some strikingly similar functional similarities have been identified, questions of its homology ("sameness") across these taxa and about the very fundamental relationship of structure to function in central nervous system structures remain open. The hippocampal formation of amniotes participates in allocentric (external landmark) spatial navigation, memory, and attention to novel stimuli, and these functions generally are shared across amniotes despite variation in its morphological features. Substantially greater deviation in its morphology occurs in anamniotes, including amphibians and ray-finned fishes (actinopterygians), but its functions of allocentric spatial navigation and/or memory have been found to be preserved by studies in these taxa. Its shared functional roles cannot be used as evidence of structural homology, but given that other criteria indicate homology of the medial pallial derivative across these clades, the similar functions themselves may be regarded as homologous functions if they are based on the same cellular mechanisms and connections. The question arises as to whether the similar functions are performed by as yet undiscovered, shared morphological features or by different features that accomplish the same results via different mechanisms of neural function. PMID- 28866675 TI - SAVE-AMD: Safety of VEGF Inhibitors in Age-Related Macular Degeneration. AB - OBJECTIVE: To determine whether intraocular treatment with vascular endothelial growth factor (VEGF) inhibitors change systemic endothelial function (EF) in patients with neovascular age-related macular degeneration (AMD). METHODS: In this prospective, randomized, 2-center, double-masked controlled interventional trial, patients with neovascular and dry AMD were enrolled. Eligible neovascular AMD patients received 2 intravitreal loading doses of either ranibizumab 0.5 mg or bevacizumab 1.25 mg at 4-week intervals and were subsequently followed every 4 weeks and treated according to a pro re nata regime for up to 1 year. Patients with dry AMD served as controls. The primary endpoint was the change in EF assessed by flow-mediated dilatation (FMD) after 2 months of treatment with VEGF inhibitors in patients with AMD compared to patients with dry AMD. FMD was assessed with B-mode high-resolution ultrasonography of the left brachial artery. RESULTS: 24 patients with neovascular AMD and 26 patients with dry ADM were included in the trial. Treatment with VEGF inhibitors did not significantly change FMD (from 4.7 +/- 2.4 to 3.9 +/- 1.9% after 8 weeks, p = 0.07, and to 5.1 +/- 2.0% after 1 year; p = 0.93 vs. baseline, respectively). CONCLUSIONS: EF did not significantly differ between patients with neovascular AMD treated with intravitreal VEGF inhibition and patients with dry AMD. PMID- 28866678 TI - Comparative Contemplations on the Hippocampus. AB - The hippocampus in mammals is a morphologically well-defined structure, and so are its main subdivisions. To define the homologous structure in other vertebrate clades, using these morphological criteria has been difficult, if not impossible, since the typical mammalian morphology is absent. Although there seems to be consensus that the most medial part of the pallium represents the hippocampus in all vertebrates, there is no consensus on whether all mammalian hippocampal subdivisions are present in the derivatives of the medial pallium in all vertebrate groups. The aim of this paper is to explore the potential relevance of connections to define the hippocampus across vertebrates, with a focus on mammals, reptiles, and birds. PMID- 28866679 TI - Contribution of Genoarchitecture to Understanding Hippocampal Evolution and Development. AB - The hippocampal formation is a highly conserved structure of the medial pallium that works in association with the entorhinal cortex, playing a key role in memory formation and spatial navigation. Although it has been described in several vertebrates, the presence of comparable subdivisions across species remained unclear. This panorama has started to change in recent years thanks to the identification of some of the genes that regulate the development of the hippocampal formation in the mouse and help to delineate its subdivisions based on molecular features. Some of these genes have been used to try to identify subdivisions in chicken and lizards comparable to those of the mammalian hippocampal formation and the entorhinal cortex. Here, we review some of these data, which suggest the existence of fields comparable to the dentate gyrus, CA3, CA1, subiculum, as well as medial and lateral parts of the entorhinal cortex in all amniotes. We also analyze available data suggesting the existence of serial connections between these fields, speculate on the possible existence of auto associative loops in CA3, and discuss general principles governing the formation of the connections. PMID- 28866680 TI - On the Value of Reptilian Brains to Map the Evolution of the Hippocampal Formation. AB - Our ability to navigate through the world depends on the function of the hippocampus. This old cortical structure plays a critical role in spatial navigation in mammals and in a variety of processes, including declarative and episodic memory and social behavior. Intense research has revealed much about hippocampal anatomy, physiology, and computation; yet, even intensely studied phenomena such as the shaping of place cell activity or the function of hippocampal firing patterns during sleep remain incompletely understood. Interestingly, while the hippocampus may be a 'higher order' area linked to a complex cortical hierarchy in mammals, it is an old cortical structure in evolutionary terms. The reptilian cortex, structurally much simpler than the mammalian cortex and hippocampus, therefore presents a good alternative model for exploring hippocampal function. Here, we trace common patterns in the evolution of the hippocampus of reptiles and mammals and ask which parts can be profitably compared to understand functional principles. In addition, we describe a selection of the highly diverse repertoire of reptilian behaviors to illustrate the value of a comparative approach towards understanding hippocampal function. PMID- 28866681 TI - Reflections on the Structural-Functional Evolution of the Hippocampus: What Is the Big Deal about a Dentate Gyrus? AB - The vertebrate hippocampal formation has been central in discussions of comparative cognition, nurturing an interest in understanding the evolution of variation in hippocampal organization among vertebrate taxa and the functional consequences of that variation. Assuming some similarity between the medial pallium of extant amphibians and the hippocampus of stem tetrapods, we propose the hypothesis that the hippocampus of modern amniotes began with a medial pallium characterized by a relatively undifferentiated cytoarchitecture, more direct thalamic and olfactory sensory inputs, and a broad role in associative learning and memory processes that nonetheless included the map-like representation of space. From this modest beginning evolved the cognitively more specialized hippocampal formation of birds and the hippocampus of mammals with its confounding dentate gyrus. Much has been made of trying to identify a dentate homologue in birds, but there are compelling reasons to believe no such structural homologue/functional equivalent exists. The uniqueness of the mammalian dentate then raises the question of what might be the functional consequences of a hippocampus with a dentate compared to one without. One might be tempted to speculate that the presence of a dentate gyrus facilitates so called pattern separation, but birds with their suspected dentate-less hippocampus display excellent hippocampal-dependent pattern separation relying on space. Perhaps one consequence of a dentate is a hippocampus better designed to process a broader array of stimuli beyond space to more robustly support episodic memory. What is clear is that any meaningful reconstruction of hippocampal evolution and the eventual identification of any subdivisional homologies will require more data on the neurobiological and functional properties of the nonmammalian hippocampus, particularly those of amphibians and reptiles. PMID- 28866682 TI - Are There Place Cells in the Avian Hippocampus? AB - Birds possess a hippocampus that serves many of the same spatial and mnemonic functions as the mammalian hippocampus but achieves these outcomes with a dramatically different neuroanatomical organization. The properties of spatially responsive neurons in birds and mammals are also different. Much of the contemporary interest in the role of the mammalian hippocampus in spatial representation dates to the discovery of place cells in the rat hippocampus. Since that time, cells that respond to head direction and cells that encode a grid-like representation of space have been described in the rat brain. Research with homing pigeons has discovered hippocampal cells, including location cells, path cells, and pattern cells, that share some but not all properties of spatially responsive neurons in the rodent brain. We have recently used patterns of immediate-early gene expression, visualized by the catFISH method, to investigate how neurons in the hippocampus of brood-parasitic brown-headed cowbirds respond to spatial context. We have found cells that discriminate between different spatial environments and are re-activated when the same spatial environment is re-experienced. Given the differences in habitat and behaviour between birds and rodents, it is not surprising that spatially responsive cells in their hippocampus and other brain regions differ. The enormous diversity of avian habitats and behaviour offers the potential for understanding the general principles of neuronal representation of space. PMID- 28866683 TI - The Avian Hippocampal Formation and the Stress Response. AB - Though widely studied for its function in memory and navigation, the hippocampal formation (HF) in mammals also plays an important role in regulating the stress response. If this is an ancestral feature of the hippocampus, then it is likely that the avian HF plays a similar role. Indeed, the avian HF strongly expresses both mineralocorticoid and glucocorticoid receptors, and has indirect projections to the paraventricular nucleus of the hypothalamus, which controls the hypothalamic-pituitary-adrenal (HPA) axis. Hippocampal lesions increase HPA activity, while electrical stimulation suppresses it. In addition, adult hippocampal neurogenesis in birds is reduced in response to different acute and chronic stressors, as it is in mammals. Because the mammalian hippocampus is functionally specialized along its septotemporal axis, with the temporal pole playing a more important role in the stress response, the hypothesis is put forward that a similar functional specialization exists in birds along the rostrocaudal hippocampal axis. Some, though not all, of the evidence supports a rostrocaudal functional gradient. The evidence for whether this is equivalent to the mammalian septotemporal organization is currently ambiguous at best and needs to be more extensively investigated. PMID- 28866684 TI - Functional Connectivity Pattern of the Internal Hippocampal Network in Awake Pigeons: A Resting-State fMRI Study. AB - In the last two decades, the avian hippocampus has been repeatedly studied with respect to its architecture, neurochemistry, and connectivity pattern. We review these insights and conclude that we unfortunately still lack proper knowledge on the interaction between the different hippocampal subregions. To fill this gap, we need information on the functional connectivity pattern of the hippocampal network. These data could complement our structural connectivity knowledge. To this end, we conducted a resting-state fMRI experiment in awake pigeons in a 7-T MR scanner. A voxel-wise regression analysis of blood oxygenation level-dependent (BOLD) fluctuations was performed in 6 distinct areas, dorsomedial (DM), dorsolateral (DL), triangular shaped (Tr), dorsolateral corticoid (CDL), temporo parieto-occipital (TPO), and lateral septum regions (SL), to establish a functional connectivity map of the avian hippocampal network. Our study reveals that the system of connectivities between CDL, DL, DM, and Tr is the functional backbone of the pigeon hippocampal system. Within this network, DM is the central hub and is strongly associated with DL and CDL BOLD signal fluctuations. DM is also the only hippocampal region to which large Tr areas are functionally connected. In contrast to published tracing data, TPO and SL are only weakly integrated in this network. In summary, our findings uncovered a structurally otherwise invisible architecture of the avian hippocampal formation by revealing the dynamic blueprints of this network. PMID- 28866686 TI - Meetings and Conferences. PMID- 28866685 TI - Relationship between Contrast-Enhanced CT and Clinicopathological Characteristics and Prognosis of Non-Small Cell Lung Cancer. AB - BACKGROUND: This study investigated the relationship between contrast-enhanced computed tomography (CECT) and clinicopathological characteristics and prognosis of non-small cell lung cancer (NSCLC). METHODS: A total of 198 NSCLC patients admitted to Enze Hospital from February 2009 to July 2012 underwent pre-surgical CECT to investigate parameters such as tumor size, CECT enhancement, lymph node enlargement, and lymph node size. Chi-square and log-rank tests were used to analyze associations between CECT parameters and pathological features as well as correlations of CECT parameters with prognosis. A Cox proportional hazard model and logistic regression analysis were applied to identify independent risk factors for prognosis. RESULTS: Tumor size, CECT enhancement, and lymph node enlargement and size were related to degree of differentiation, TNM stage, and lymph node metastasis. Tumor size, lymph node enlargement and metastasis, lymph node size, and CECT enhancement were independent risk factors for NSCLC prognosis. Large tumors and lymph nodes, tumor enhancement, and enlarged and metastatic lymph nodes indicated a poor prognosis. CONCLUSION: Our study indicates that CECT features can be associated with clinicopathological characteristics and can predict the prognosis of patients with NSCLC. PMID- 28866687 TI - Editorial Board / Contents / Imprint. PMID- 28866688 TI - Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection. AB - Intraneuronal accumulation of misfolded alpha-synuclein in the central and peripheral nervous systems is strongly linked to Parkinson disease (PD) and other related synucleinopathies. In rare inherited forms of PD, point mutations or gene multiplications mediate the formation of alpha-synuclein protein aggregates. However, in most PD cases it is presumed that the combined effects of ageing and environmental factors drive the formation of alpha-synuclein aggregates. Despite advances regarding alpha-synuclein pathobiology, the normal functions of this protein and factors that regulate its expression are not well understood. We discuss a recent study reporting that viral infection induces alpha-synuclein expression in neurons of the gastrointestinal tract. Alpha-synuclein levels increased during norovirus infection in the duodenum of children. In an in vitro paradigm, monomeric and oligomeric alpha-synuclein acted as chemoattractants for neutrophils and monocytes, and promoted the maturation of dendritic cells. This suggests that alpha-synuclein facilitates immune responses to infection. We explore the possibility that intestinal infections, and associated inflammation, place individuals at increased risk of PD by increasing alpha-synuclein levels and promoting the formation of alpha-synuclein aggregates that propagate in a prion-like fashion via the vagal nerve to the brainstem. PMID- 28866689 TI - Reply to the Letter to the Editor "Does Remifentanil Have a Place for Sedation in the Case of Endotracheal Intubation or Minimally Invasive Surfactant Therapy in Neonates?" PMID- 28866690 TI - Molecular analysis of fragile X syndrome (FXS) among Malaysian patients with developmental disability. AB - Fragile X syndrome (FXS) is a neurodevelopmental disorder commonly found worldwide, caused by the silencing of fragile X mental retardation 1 (FMR1) gene on the X-chromosome. Most of the patients lost FMR1 function due to an expansion of cytosine-guanine-guanine (CGG) repeat at the 5' untranslated region (5'UTR) of the gene. The purpose of this study is to identify the prevalence of FXS and characterize the FMR1 gene CGG repeats distribution among children with developmental disability in Malaysia. Genomic DNA of 2201 samples from different ethnicities (Malays, Chinese, Indian and others) of both genders were PCR amplified from peripheral blood leukocytes based on specific primers at 5'UTR of FMR1 gene. Full mutations and mosaics were successfully identified by triple methylation specific PCR (ms-PCR) and subsequently verified with FragilEase kit. The findings revealed for the first time the prevalence of FXS full mutation in children with developmental disability in Malaysia was 3.5%, a slightly higher figure as compared to other countries. Molecular investigation also identified 0.2% and 0.4% probands have permutation and intermediate alleles, respectively. The CGG repeats length observation showed 95% of patients had normal alleles within 11 to 44 CGG repeats; with 29 repeats found most common among Malays and Indians while 28 repeats were most common among Chinese. In conclusion, this is the first report of prevalence and characterisation of CGG repeats that reflects genetic variability among Malaysian ethnic grouping. PMID- 28866691 TI - Primary imatinib resistance in chronic myeloid leukemia patients in a developing country: BCR-ABL kinase domain mutations or BCR-ABL independent mechanisms? AB - Clinical resistance to imatinib (IM) in chronic myeloid leukemia (CML) carries adverse consequences. We investigated 22 CML patients who developed IM-resistance for BCR-ABL kinase domain (KD) mutations. The median follow-up for this study was 101.9 months (range: 22.2 to 176.5 months) and the estimated mean overall survival was 150.87 months (95% CI: 130.0 to 171.0). Five out of 22 patients tested positive for BCR-ABL KD mutations: 2 had T315I, 2 had E255K and 1 had V289F mutations. Of the remaining 17 patients who did not harbor BCR-ABL KD mutations, 11 patients received nilotinib while the rest continued on IM. All 17 achieved haematological remission but only 5 patients achieved complete cytogenetic remission, 4 of whom did so after switching to nilotinib. Our study shows that most of our IM-resistant patients do not test positive for BCR-ABL KD mutations by available testing methods and the role of second generation tyrosine kinase inhibitors remains undetermined. A critical analysis of the BCR-ABL KD mutations and the underlying mechanisms/ pathways of BCR-ABL independent IM resistance along with potential treatments in the horizon will be discussed. PMID- 28866692 TI - Frequency and molecular epidemiology of Panton-Valentine leukocidin gene in Staphylococcus aureus colonising HIV-infected patients. AB - BACKGROUND: HIV-infected patients pose a high risk of contracting skin and soft tissue infections caused by Staphylococcus aureus. Those who are colonized with methicillin-resistant S. aureus (MRSA) that carry Panton-Valentine leukocidin (PVL) are predisposed to severe infections that could lead to necrotic skin infections. However the association of S. aureus specifically methicillin sensitive S. aureus carrying PVL gene in HIV patients has not been widely reported. Here, we study the prevalence and the molecular epidemiology of PVL producing S. aureus in HIV-infected patients. METHODS: Swabs from four body sites of 129 HIV-infected patients were cultured for S. aureus and identified by standard microbiological procedures. The isolates were subjected to antimicrobial susceptibility testing by disk diffusion against penicillin, erythromycin, clindamycin, and cotrimoxazole. PCR was used to detect the PVL gene and genetic relationship between the isolates was determined by using pulse field gel electrophoresis. RESULTS: A total of 51 isolates of S. aureus were obtained from 40 (31%) of the patients. The majority (43.1%) of the isolates were obtained from the anterior nares. Thirteen (25.5%) of all the isolates were resistant to more than one category of antibiotics, with one isolate identified as MRSA. Thirty eight (74.5%) isolates (including the MRSA isolate) carried PVL gene where the majority (44.7%) of these isolates were from the anterior nares. A dendogram revealed that the isolates were genetically diverse with 37 distinct pulsotypes clustered in 11 groups. CONCLUSION: S. aureus obtained from multiple sites of the HIV patients were genetically diverse without any clonality observed. PMID- 28866693 TI - A 15-year single centre retrospective study of antiphospholipid syndrome patients from Northern Malaysia. AB - BACKGROUND: Antiphospholipid syndrome (APS) is an autoimmune disorder characterised by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPLs) based on the Sydney criteria. We aimed to explore the clinico-laboratory features and treatment strategies of APS patients retrospectively. METHODOLOGY: The medical records of APS patients registered under Hospital Universiti Sains Malaysia (Kelantan state) between 2000 and 2015 were reviewed. RESULTS: A total of 17 APS subjects (age 40.7 +/- 12.8 years) including 11 primary (64.7%) and six secondary APS (35.3%) patients were identified. The follow-up period was 9.5 +/- 6.7 years with male:female ratio of 1.0:4.7. Pregnancy morbidity was the most common clinical manifestation (11/14; 78.6%) followed by recurrent venous thrombosis (10/17; 58.8%). For other clinical features, menorrhagia was the most frequently observed manifestation (4/14; 28.6%) followed by aPLs-associated thrombocytopenia (4/17; 23.5%) and ovarian cyst (3/14; 21.4%). LA and aCL were positive in 94.1% (16/17) and 81.8% (9/11) of the patients, respectively. APTT value (76.7 +/- 17.0 sec) was significantly high (p < 0.05). Low intensity warfarin alone was successful to maintain target INR (2.0 - 3.0) and prevent recurrence of thrombosis. CONCLUSION: The tendency of pregnancy morbidity in this cohort of Malaysian Kelantanese APS patients was high compared to other previously reported APS cohorts. Low intensity warfarin was successful in preventing recurrence of thrombosis, however, APS women receiving long-term anticoagulants should be monitored for possible occurrence of menorrhagia and ovarian cysts. PMID- 28866694 TI - Determination of the 99th percentile upper reference limit for high-sensitivity cardiac troponin I in Malaysian population. AB - Introduction of high-sensitivity cardiac troponin I (hscTn I) assays for routine clinical use in Malaysia requires determination of the 99th percentile upper reference limit (URL) for each assay to suit local context. Hence, this study aimed to determine the 99th percentile URL for hscTn I in the Malaysian population. A total of 250 (120 males and 130 females) healthy Malaysian blood donors aged 18 to 60 years old were recruited. Blood samples for hscTn I were measured using Abbott Diagnostics hscTn I assay on Architect i2000sr analyser. The 99th percentile was calculated using a non-parametric method and gender specific results were compared. The 99th percentile URL for hscTn I for the overall population was 23.7 ng/L, with gender specific values being 29.9 ng/L and 18.6 ng/L for male and female, respectively. Females had significantly lower hscTn I compared to males. This study confirms the use of gender specific 99th percentile URL for hscTn I for clinical use in a multi-ethnic Malaysian population. PMID- 28866696 TI - Multiplex real-time RT-PCR assay for transfusion transmitted viruses in sero negative allogeneic blood donors: an experience from Southern Pakistan. AB - BACKGROUND: Blood transfusion safety commences with healthy donor recruitment. The threat of transfusion transmitted infections is greatly minimized by serological tools but not entirely eliminated. Recently, nucleic-acid testing for blood donor screening has virtually eliminated this jeopardy. METHODS: This prospective study was conducted from February 2015 to February 2016. Samples from seronegative donors were run on multiplex assay (Cobas, S-201 system platform, Roche) in a batch of six [MP-NAT]. In case of reactive pool, tests were run on every individual sample [IDNAT]. RESULTS: Of 16957 donors, 16836 (99.2%) were replacement donors and the remaining 121 (0.7%) were voluntary donors, with a mean age of 29.09 +/- 7.04 years. After serologic screening of all 16957 donors, 955 (5.6%) were found to be reactive; 291(1.71%) were reactive for hepatitis-B surface antigen, 361 (2.12%) for antibody to hepatitis C virus (anti-HCV), 14 (0.08%) for antibody to human immunodeficiency virus, 287 (1.69%) for syphilis and 2 (0.01%) for malaria. 14 (0.08%) NAT reactive donors were identified after testing the 16002 seronegative donors, with an overall NAT yield of one reactivity out of 1143 blood donations; 10 donors for HBV-DNA (HBV NAT yield 1:1600) and remaining 4 for HCV-RNA (HCV-NAT yield-1:4000). None were HIV positive. CONCLUSION: NAT has improved the safety attributes in blood products. Although the positivity rate for NAT testing is low but in view of the high prevalence of transfusion transmitted infections in our country, we recommend the parallel use of both serology and NAT screening of all donated blood. PMID- 28866695 TI - The value of Nottingham grade in breast cancer re-visited in the Sri Lankan setting. AB - OBJECTIVE: We aimed to assess the impact of Nottingham grade (NG) on breast cancer specific survival (BCSS) and recurrence free survival (RFS) of operable breast cancer (BC) patients presenting at different TNM stages in view of assessing the value of NG in prognostication of breast cancer in the Sri Lankan setting. METHOD: This retro-prospective study included a consecutive series of TNM stage I to III BC patients presented to our unit from 2006 to 2012. Data were collected through follow up visits, clinic and laboratory records. Grading and scoring of oestrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor 2 (Her2) expressions were done by a single investigator. Kaplan-Meier and Cox-regression models were used in the survival analysis. RESULTS: A total of 742 (NG1-12%; NG2-45%; NG3-43%) patients with a median follow up of 39.5 (range: 12 - 138) months were included. Five-year BCSS was 94%-NG1, 80%-NG2 and 72%-NG3 (p < 0.001). Five-year RFS was 86%-NG1, 75%-NG2 and 67%-NG3 (p = 0.001). Only the lymph-node status (LNS) (p = 0.001) had an independent effect on the BCSS and RFS of NG3 patients. LNS (p = 0.001), PR (p = 0.004) and Her2 (p < 0.001) independently affected the BCSS of NG2 patients. None of the factors considered had an effect on the BCSS/RFS of NG1 patients. A significant decrease in BCSS and RFS was seen with an increase in NG in the sub group of TNM stage III (p = 0.01 and 0.011). CONCLUSION: NG categorizes BC patients into prognostic groups with distinctly different survival outcomes. Sub categorization of TNM stage III by NG is suggested. PMID- 28866697 TI - Haematological parameters and screening tests of haemostasis in children with sepsis: results from a tertiary care centre in India. AB - Sepsis is a common cause of death in infants and children. Haemostatic abnormalities have been reported in such patients. There is scant information on the nature and frequency of these abnormalities in children especially from India. Our aim was to evaluate the nature and frequency of haematological and haemostatic abnormalities in children with sepsis. Fifty children between 1-10 years of age admitted with sepsis and 50 age-matched, healthy controls were included in the study. Complete blood counts, examination of stained peripheral blood film, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen, C-reactive protein, liver function tests and serum creatinine were done in all patients and controls. Prolonged PT and APTT were seen in 9 (18%) and 24 (48%) patients respectively. Plasma fibrinogen was decreased in 6% and increased in 8% patients. One or more haemostatic parameter was abnormal in 35 (70%) patients and in all patients who died. PMID- 28866698 TI - Isolation by culture and PCR identification of LipL32 gene of pathogenic Leptospira spp. in wild rats of Kuala Lumpur. AB - BACKGROUND: A study was conducted to confirm the status of rats as the carrier of pathogenic leptospira in Kuala Lumpur, Malaysia. METHOD: A total of 140 urine samples were collected from trapped rats. These samples were cultured in EMJH enriched media and 18 of these samples (12.9%) were found to be positive when observed under x40 by dark field microscope. Genomic DNA was extracted from all the 18 native isolates for PCR. RESULT: All the 18 isolates generated the expected 786 base pair band when the set of primers known to amplify LipL32 gene were utilized. These results showed that the primers were suitable to be used for the identification of pathogenic leptospira from the 18 rat samples. CONCLUSION: The sequencing of the PCR products and BLAST analysis performed on each representative isolates confirmed the pathogenic status of all these native isolates as the LipL32 gene was detected in all the Leptospira isolates. This indicates that the rats are carriers of the pathogenic leptospira in the study area, and therefore are of public health importance. PMID- 28866699 TI - A sudden paediatric death due to hand, foot and mouth disease: the importance of vigilance. AB - BACKGROUND: Hand, foot and mouth disease (HFMD) is caused by enteroviruses such as Coxsackie virus A16 (CVA16) and Enterovirus 71 (EV71). The diagnostic hallmarks are oral ulcers and maculo-papular or vesicular rash on the hands and feet. Severe form of this disease can lead to death due to neurological and cardiopulmonary complications. This case report aims to describe a fatal case of HFMD with minimal oral and skin manifestations. CASE REPORT: A four-year-old girl was brought to a hospital after suddenly becoming unresponsive at home. She had a history of fever and lethargy for three days prior to her demise. The patient, and f ive other children in her neighbourhood had been diagnosed to have HFMD at a local health clinic; the other children had recovered without complications. RESULTS: Autopsy revealed a few punctate, sub-epidermal vesicles measuring 1 to 2 mm on the palm of her right hand and sole of the right foot, visible only with a magnifying glass. Internal examination revealed prominent nodularity at the oro- and hypopharynxes. The lungs were markedly congested and oedematous. Histopathology of the lung showed marked oedema and haemorrhage with mild pneumonic changes. Oedema with increase in macroglia and astrocytic proliferation were seen in the cerebral tissue, but no lymphocytic infiltration was evident. Enterovirus EV71 was detected by polymerase chain reaction in samples from the lung, cerebrospinal fluid and serum. The cause of death was given as HFMD complicated by pneumonia. CONCLUSION: Fatal HFMD may have minimal signs. A complete history, careful physical examination and relevant investigations lead to a diagnosis at post mortem examination. Awareness of the subtle signs and rapid deterioration associated with a fatal case of HFMD is a challenge to clinicians who encounter these cases. PMID- 28866700 TI - Synchronous papillary thyroid carcinoma and medullary thyroid carcinoma - a pitfall waiting to happen. AB - Papillary thyroid carcinoma (PTC) is the most common thyroid carcinoma and is derived from thyroid follicular cells. In contrast, medullary thyroid carcinoma (MTC) is rare and originates from the parafollicular C-cells. Synchronous occurrence of these two carcinomas is uncommon and occurs as either discrete lesions or as a mixed lesion. The current case report describes a 50-year-old woman with synchronous multiple discrete MTC and PTC with lymph nodes metastasis. Pathologists and treating physicians should be aware of the synchronous coexistence of these entities to avoid possible misdiagnosis. PMID- 28866702 TI - A fatal gastric perforation secondary to ulcerated metastasis in undiagnosed breast cancer: pathological aspects and review of literature. AB - The authors describe a fatal case of gastric perforation secondary to an ulcerated metastasis in a woman with undiagnosed breast cancer. The 48-year-old woman, with no significant medical history, presented with weight loss, persistent dyspepsia and pain in the epigastric and mesogastric region. She was treated by her primary care physician with proton-pump inhibitors and antispasmodics. The following day she was found dead at her home. External examination showed a tumefaction in the lateral region of her left breast, near the axilla. Autopsy revealed 1000 ml of turbid, light-brown peritoneal fluid in the abdominal cavity and a perforated gastric wall. Histological examination of the breast mass showed an infiltrating, poorly-differentiated breast carcinoma. Microscopical analysis of the stomach wall revealed a perforated metastatic gastric ulcer. Immunohistochemistry was required to confirm the neoplastic involvement of the stomach due to metastatic breast cancer. PMID- 28866701 TI - p40 in metastatic pulmonary trophoblastic tumour: potential diagnostic pitfall on histopathology. AB - p40, one of the two isomers of p63, is nowadays widely used for diagnosis of squamous cell carcinoma, especially in subtyping non-small cell carcinoma on lung biopsies. We describe a case in which lung tumour was misdiagnosed as squamous cell carcinoma due to p40 immunopositivity. A 36-year-old lady presented with cough and left sided chest pain of 2 months duration. Chest imaging revealed a lesion in left lower lobe of the lung and biopsy was suggestive of squamous cell carcinoma. However, past history revealed amputation of great toe for non-healing discharging ulcer which on histopathology was diagnosed as choriocarcinoma. She also had a history of hysterectomy five years ago, details of which were not available. Post-amputation beta-hCG levels were high and she had been treated with multimodality chemotherapy for choriocarcinoma. She had good response to chemotherapy initially, however became resistant later on. Review of the lung biopsy in the light of the past history along with extensive literature review led to the final diagnosis of metastatic trophoblastic tumour to lung. Hence, awareness that p40 immunopositivity can be seen in trophoblastic tumours is essential to avoid misdiagnosis, especially in sites like the lung where squamous cell carcinoma is common. PMID- 28866703 TI - Clinical judgement perplexed by initially undisclosed use of herbal medicine and unexpected cross-reactivity of immunoassay. AB - We report a case of symptomatic bradycardia caused by consumption of a Chinese herbal medicine which was initially undisclosed to the attending emergency physician. The scientific name of the herb is Panax japonicus. Electrocardiogram revealed sinus bradycardia. Laboratory tests were normal except for the detection of a high serum digoxin level. Further interrogation of the patient eventually disclosed ingestion of the herb which, however, did not contain any digoxin. Other active ingredients in the herb include various types of ginsenoside. These are digoxin-like substances that had caused the observed false-positive detection of digoxin by fluorescence polarization immunoassay due to cross-reactivity. Our case-report provides an important insight about a blind-spot in the field of laboratory medicine (clinical pathology), namely, the false positive detection of digoxin due to crossreactivity in the immunoassay when we come across digoxin like substances in clinical scenarios, which has barely received attention in the medical literature. It also conveys a clear educational message that with full understanding of the laboratory methodology and its mechanistic rationale there are actually some tricks-of-the-trade that allow us to optimize the specificity of the biochemical tests and the treatment of digoxin-like substances overdose. PMID- 28866704 TI - Unexpected infant death secondary to a pulmonary infiltration due to acute myelocytic leukaemia. AB - Acute myeloid leukaemia (AML) often presents with non-specific symptoms such as fatigue, anaemia or infection. Pulmonary involvement is uncommon in AML during the course of the disease and is usually caused by infection, haemorrhage, leukaemic pulmonary infiltrates and leukostasis. Lung localization of AML is very uncommon and potentially life threatening if not diagnosed and treated rapidly. The authors describe the sudden death of an asymptomatic five-month-infant because of a misdiagnosed lung localization of AML. Autopsy examination followed by histopathological studies showed an extensive leukostasis and extramedullary leukaemic infiltrating the lungs. Special stains and immunohistochemical studies revealed findings consistent with acute myelogenous leukaemia. This case suggests that underlying acute leukaemia should be considered as a cause of flu-like symptoms in infants. Medical personnel are urged to be alert to fever, sore throat, weakness and dyspnea that may be characteristic of serious systemic diseases. PMID- 28866705 TI - Familial antithrombin III deficiency in a Malay patient with massive thrombosis. AB - Patients with low antithrombin III (AT III) has increased risk for arteriovenous thromboembolic (TE) disease. We report a 28-year-old Malay lady who presented with spontaneous right calf pain and swelling of one week duration. She was on oral contraceptive pills and had a history of travelling for a long distance prior to the presentation. Her brother who was diagnosed with AT III deficiency had arterial thrombosis at a young age. She was diagnosed as having right popliteal vein thrombosis by ultrasound and treated with subcutaneous fondaparinux. While on treatment, she developed massive bilateral pulmonary embolism (PE). Thrombophilia study showed reduced AT III activity (38MUl/dl) and normal results for protein C, protein S, activated protein C resistance and lupus anticoagulant assays. This patient has heterozygous AT III deficiency added with significant acquired factors responsible for the TE events. Those with AT III deficiency may have resistance to heparin therapy and require higher doses of heparin. PMID- 28866706 TI - Extensive left ventricular, pulmonary artery, and pericardial metastasis from myxoid liposarcoma 16 years after the initial detection of the primary tumour: a case report and review of the literature. AB - Liposarcoma is regarded as the second most common soft tissue malignant tumour. Metastasis of liposarcoma to the heart is very rare, and to date, less than 40 cases have been reported in the literature. We report a 46 year-old male with myxoid liposarcoma of the lower extremity who developed extensive metastasis to the left ventricle, pulmonary artery, and pericardium. The patient presented with acute symptoms of dyspnea 16 years after surgical resection of the primary tumour, and his dyspnea progressed to cardio-respiratory arrest within the first few days of hospital admission. PMID- 28866707 TI - A linking bridge between histopathological analysis and molecular assay in microbiology. AB - No abstract available. PMID- 28866708 TI - Quantitative Visualization of Dynamic Tracer Transportation in the Extracellular Space of Deep Brain Regions Using Tracer-Based Magnetic Resonance Imaging. AB - BACKGROUND This study assessed an innovative tracer-based magnetic resonance imaging (MRI) system to visualize the dynamic transportation of tracers in regions of deep brain extracellular space (ECS) and to measure transportation ability and ECS structure. MATERIAL AND METHODS Gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) was the chosen tracer and was injected into the caudate nucleus and thalamus. Real-time dynamic transportation of Gd-DTPA in ECS was observed and the results were verified by laser scanning confocal microscopy. Using Transwell assay across the blood-brain barrier, a modified diffusion equation was further simplified. Effective diffusion coefficient D* and tortuosity lambda were calculated. Immunohistochemical staining and Western blot analysis were used to investigate the extracellular matrix contributing to ECS structure. RESULTS Tracers injected into the caudate nucleus were transported to the ipsilateral frontal and temporal cortices away from the injection points, while both of them injected into the thalamus were only distributed on site. Although the caudate nucleus was closely adjacent to the thalamus, tracer transportation between partitions was not observed. In addition, D* and the lambda showed statistically significant differences between partitions. ECS was shown to be a physiologically partitioned system, and its division is characterized by the unique distribution territory and transportation ability of substances located in it. Versican and Tenascin R are possible contributors to the tortuosity of ECS. CONCLUSIONS Tracer-based MRI will improve our understanding of the brain microenvironment, improve the techniques for local delivery of drugs, and highlight brain tissue engineering fields in the future. PMID- 28866709 TI - Artemether Regulates Chemosensitivity to Doxorubicin via Regulation of B7-H3 in Human Neuroblastoma Cells. AB - BACKGROUND Artemether, originally used for malaria, exhibits potential therapeutic efficacy against several types of cancer, including gastric cancer, hepatocellular carcinoma, and gliomas. In this study, we investigated the role and mechanism of artemether on drug resistance of neuroblastoma cells. MATERIAL AND METHODS Cell viability and proliferation were determined by CCK-8 and EdU incorporation assay, respectively. Gene expression was measured by real-time PCR and Western blot analysis. RESULTS Our results revealed that artemether treatment remarkably inhibited the proliferation of neuroblastoma cell lines SH-SY5Y, SK-N SH, and SK-N-BE2. In addition, co-treatment of tumor cells with artemether and doxorubicin significantly reduced cell viability and DNA synthesis compared with doxorubicin-treated cells. On the molecular level, we found that combined treatment with artemether and doxorubicin suppressed the expression of B7-H3 both at the mRNA and protein levels. In addition, artemether failed to sensitize tumor cells to doxorubicin in SH-SY5Y cells overexpressing B7-H3. CONCLUSIONS Artemether-mediated inhibition of B7-H3 may contribute to doxorubicin sensitivity in neuroblastoma cells, suggesting that artemether could serve as a potential therapeutic option for neuroblastoma. PMID- 28866710 TI - Editorial. AB - no summary. PMID- 28866711 TI - ICD-11 - Draft diagnostic guidelines for mental disorders: A report for WPA Membership. AB - The 11th edition of the International Classification of Diseases (ICD-11) is scheduled for approval by the World Health Assembly in May 2018. The chapter on mental disorders is currently under development. A draft of the clinical descriptions and diagnostic guidelines for all the disorders has been produced by the relevant Working Groups. A simplified version of the diagnostic guidelines for some disorders (i.e., schizophrenia and other primary psychotic disorders, mood disorders, anxiety disorders, disorders specifically associated with stress, and feeding and eating disorders) has been made available for use in the field studies of the classification. For all the other sections of the chapter on mental disorders, a brief general definition and sometimes a description of some of the included disorders can be found on the ICD-11 beta platform. In the present article, we summarize the content of the various sections of the classification on the basis of the available documents, with the warning that some of the elements of these sections may still be subject to revision. PMID- 28866712 TI - A proposed new definition of mental health. AB - The authors propose a new approach to the definition of mental health, different than the definition proposed by the World Health Organization, which is established around issues of person's well-being and productivity. It is supposed to reflect the complexity of human life experience. PMID- 28866713 TI - Elevated hydroxylactam of hemopyrrole level in urine in perpetrators of extremely violent acts diagnosed with psychosis. AB - OBJECTIVES: Hydroxylactam of hemopyrrole (HPL) is an abnormal side product of porphyrin biosynthetic pathway, which may have a devastating impact on the behavior. The link between an aggressive behavior and an increased HPL level was postulated in the 1960s. Further researches concerning HPL brought contrary results and did not clarify its function and possible role in the pathogenesis of aggression. In our research we hypothesize that a heightened level of HPL may correspond to an extreme aggressive behavior in subjects diagnosed with psychosis. METHODS: We performed an analysis of HPL level in urine samples, collected from 36 male subjects diagnosed with a mental illness who presented an extreme aggressive behavior. The control group included 22 male subjects, matched with age. RESULTS: The variable HPL/creatinine quotient differs significantly between the study group and the control group. CONCLUSIONS: We used successfully proprietary method for marking HPL level in urine, developed for the purposes of the project. The results of our study indicate that in a group of subjects with a history of an extreme aggressive behavior a corrected level of HPL may be elevated, compared to subject without history of extreme aggressive behavior. Further studies are needed to evaluate the reasons of HPL elevation and its clinical implications in this group of patients. PMID- 28866714 TI - Significance of personality disorders in the face of drop-outs from psychiatric hospitalizations. The case of selected psychiatric units. AB - OBJECTIVES: The World Health Organization's estimations indicate that about 50% of patients in well-developed countries may not adhere to long-term therapies. In the field of psychiatry, drop-outs from psychiatric treatment are particularly important. Personality disorders are a significant part of this sphere. The aim of this research was to empirically verify the hypothesis regarding the relation between comorbid personality disorders and drop-outs from treatment among patients of psychiatric wards. METHODS: This study was a prospective cohort study. 110 patients, hospitalized in 3 different psychiatric wards, were included. Personality disorders were assessed with the Structured Clinical Interview For DSM-IV Personality Disorders (SCID-II). The research was financed by the Polish National Science Center (DEC-2011/01/N/NZ5/05364). RESULTS: The response rate was 89.1%. 72.56% of patients suffered from personality disorders (SCID-II) (among them the most prevalent were: personality disorder - not otherwise specified - 40.7% and borderline personality disorder - 12.38%; 22.95% of patients dropped out from treatment). However, occurrence of personality disorders was not relevant for those drop-outs. On the other hand, relationships at the level of certain criteria of borderline personality disorders and passive aggressive personality have been revealed. These relationships became stronger when considered from the perspective of differences in the organization of treatment at individual wards. CONCLUSIONS: Some personality disorders may play an important role in drop-outs from psychiatric treatment. Presented results require further research. PMID- 28866715 TI - The effect of vitamin D3 deficiency on the severity of depressive symptoms. Overview of current research. AB - Traditional methods of depression treatment with the use of pharmacotherapy with antidepressants have limited effectiveness. Biological, psychological and environmental causes of depressive disorders are known, but pathophysiology of depression has not been fully explained. Many factors and mechanisms play role in the pathophysiology of depression, one of which may be vitamin D3 deficiency. Deficiency or border level of vitamin D3 is fairly common in the general population and may occur even in one billion people globally. Epidemiological studies show that vitamin D3 or its metabolites do not reach an optimal level in most adults. Even lower than the optimal level may cause clinical symptoms and be one of the risk factors for depression. In the population of patients suffering from depressive disorders deficiency or insufficiency of vitamin D3 occur more frequently than in the general population. The use of vitamin D3in patients with depression may have antidepressant effect. Continuous supplementation may also reduce the risk of recurrence. This article is a review of literature on the possible impact of vitamin D3 deficiency on the prevalence of depression and antidepressant effect of the supplementation. Selection of articles was made by searching the Medline and PubMed databases using specific keywords: depression, vitamin D3 deficiency. Previous studies on the use of vitamin D3 and its role in prevention and treatment of depressive disorders included too small number of people to clearly assess the effectiveness and safety of supplementation used as adjunctive therapy to antidepressants, as well as and dose range which should be used. PMID- 28866716 TI - Blood serum concentrations of kynurenic acid in patients diagnosed with recurrent depressive disorder, depression in bipolar disorder, and schizoaffective disorder treated with electroconvulsive therapy. AB - OBJECTIVES: The aim of the present study was to compare blood serum kynurenic acid (KYNA) concentrations measured before ECT and after 1, 6 and 12 electroconvulsive treatment (ECT) sessions in patients with diagnoses of recurrent depressive disorder (RDD), depression in bipolar disorder (DBD) and schizoaffective disorder (SAD). METHODS: The study group comprised of 50 patients with ICD-10 diagnoses of RDD, DBD and SAD. Blood serum KYNA concentrations were determined and clinical assessment was performed using the MADRS and the GAF scale. RESULTS: Significant differences were found in blood serum KYNA levels between RDD, DBD and SAD patients treated with electroconvulsive therapy and healthy controls: 1) KYNA concentrations in DBD patients measured before ECT and after 12 ECT sessions were significantly lower than in the control group; 2) KYNA concentrations in the serum of RDD patients measured before ECT and after one and 12 ECT sessions were significantly lower than in the control group, while those measured after 6 ECT session did not differ significantly from KYNA concentrations in healthy controls; 3) higher pre-treatment blood serum concentrations of KYNA in DBD patients correlated with a higher number of illness phases and poorer general functioning before treatment; 4) significant relationships were found between higher blood serum concentrations of KYNA in RDD patients after 1 ECT session and male gender, and between higher KYNA concentrations after 6 ECT sessions and increased depression and poorer functioning before treatment in those patients. CONCLUSIONS: Results show that KYNA concentrations in all diagnostic groups were lower before ECT (not statistically significant for the SAD group) and that there were no significant changes in those concentrations (compared with the baseline) during ECT. PMID- 28866717 TI - The serum concentration of copper in bipolar disorder. AB - OBJECTIVES: Some scientific reports indicate the changes in the concentration of serum copper in patients with bipolar disorder (BD), however the data are inconclusive. The aim of this study was to assess the concentration of copper in the blood serum of patients in various phases of BD compared to healthy volunteers, taking into consideration the specific clinical features, and the stage of illness. METHODS: The study enrolled 133 patients with a diagnosis of BD (type I, II and NOS), including 61 people in depressive episode, 23 in mania or hypomania and 49 in remission. The control group consisted of 50 people. Atomic absorption spectrometry was used to measure the concentration of copper. RESULTS: There were no statistically significant differences in the serum copper concentration between patients in various phases of BD (mania/hypomania, depression, remission), sub-types (Type I, Type II + NOS) or stages and healthy volunteers. However, serum copper concentrations in patients in stage 1 was significantly higher than in advanced stages (2+3+4), (beta = 0.22; p = 0.02). Serum copper concentration was also the higher, the later the age of onset was (beta = 0.33; p < 0.001), and the lower, the greater the number of illness episodes (beta = - 0.23; p = 0.02) (multiple regression model, adj R2 = 0.19, p = 0.0001). CONCLUSIONS: The dependencies demonstrated above may reflect pathophysiological processes that occur in the course of BD (e.g., inflammatory response and oxidative stress) with a different intensity depending on its stage. PMID- 28866718 TI - Hypersomnia and cognitive impairment in a patient with bipolar disorder - a case report. AB - OBJECTIVES: Obstructive sleep apnea (OSA) is a common clinical problem that can have serious health consequences and complicate the course of mental disorders. It is estimated that the prevalence of sleep apnea in patients with bipolar disorder can be 21-47.5%. Some symptoms of OSA are the same as the symptoms of depression: daytime drowsiness, cognitive dysfunction, decreased drive, apathy, depressed mood, anhedonia. METHODS: We present a case of a patient whose depressive symptoms persisted despite repeated changes of pharmacological treatment and were exacerbated by severe sleep disorder. OSA was also the cause of serious respiratory complications and prolonged disorders of consciousness that occurred during ECT treatment. RESULTS: Based on test results of WatchPAT200 and polysomnography, the diagnosis of severe sleep apnea was established and Continuous Positive Airway Pressure (CPAP) treatment was introduced. Severe OSA led in this patient to almost total absence of REM sleep, a significant reduction of deep sleep as well as the reduction of total sleep time. CONCLUSIONS: The presence of daytime sleepiness, unremitting despite the modification of treatment, indicates the need for diagnostic screening for OSA, which can mimic some of the symptoms of depression, increase the risk of complications during anesthesia, and can be one of the causes of drug resistance. In addition to the negative impact of obstructive sleep apnea on the course of bipolar disorder, OSA also causes significant cognitive impairment in terms of attention and vigilance, long-term semantic and visual memory as well as visual-spatial and executive functions. PMID- 28866719 TI - Medical students and stigma of depression. Part I. Stigmatization of patients. AB - The stigmatization of the mentally ill is called the first barrier hampering their treatment and recovery: it leads to the rejection of such individuals, their discrimination and exclusion from participation in various areas of social life. It becomes particularly significant if the patients encounter this attitude among doctors, nurses and others healthcare professionals. The literature describes stigmatizing attitudes towards the mentally ill and it transpires that stigmatization and a negative approach can be found even among medical students, despite the fact that in the course of their studies they receive information on psychiatric disorders and their treatment. The attitude stigmatizing mental illnesses as presented by medical students may be related to their subsequent similar views as physicians, thus adversely affecting the quality of care offered to patients and cause self-stigmatization and its consequences. The paper presents a review of the literature on the stigmatization of patients suffering from depression by medical students and a review of the interventions proposed to date, as well as a discussion of their effectiveness. PMID- 28866720 TI - Medical students and stigma of depression. Part 2. Self-stigma. AB - Up to 30% of medical students suffer from depression. They have better access to healthcare, but still receive appropriate treatment less frequently than people with depression in the general population. Most of them do not seek medical help as depression is perceived as a stigmatizing disorder, which leads to self-stigma and hampers early diagnosis and treatment. Thus, self-stigma means less effective therapy, unfavorable prognosis and relapses. According to the literature, self stigma results in lowered self-esteem and is a major obstacle in the performance of social roles at work and in personal life. Stigmatization and self-stigma of depression among medical students are also associated with effects in their later professional life: they can lead to long-term consequences in the process of treating their patients in the future. Currently there are no unequivocal research results indicating the most effective ways of reducing stigmatization and self-stigma. It is necessary to educate about the symptoms and treatment of depression and to implement diverse intervention techniques to change behaviors and attitudes as early as possible. PMID- 28866721 TI - Progression of suicidal ideation to suicidal behavior from a perspective of selected suicidological models. AB - In clinical practice suicidal ideation (SI) is one of the most commonly encountered symptoms in patients with mental disorders. Such encounter calls for diligent evaluation of suicidal risk. Although the risk factors are widely known, accurate estimation of suicidal risk remains one of the most difficult and most important tasks that clinicians face - especially considering recently collected data showing increase in suicide prevalence in Poland. More thorough estimation of suicidal risk in patients with SI requires taking under consideration not only suicidal risk factors but also factors that are more specific for progression of SI to suicidal behaviors (SB). The review presented in this paper consists of a range of suicidological theories that allow to select a number of groups of factors and mechanisms that are most specific for progression of SI to SB. These groups include: (1) transgression of fear of causing harm and pain to oneself, as well as disintegration of other protective barriers such as (2) decline of social integration with others, feeling of being alienated or abandoned, decline of sense of belongingness, lack of social support, (3) resignation from family and social obligations, (4) dismissing cultural or religious norms, (5) rejection of life goals, values and aspirations that were appreciated earlier, (6) narrowing down in perceived alternatives for suicide, i.e., "tunnel vision", feelings of helplessness and powerlessness, (7) devising in details and accepting simple suicidal plan, especially when such plan is being consolidated through rehearsals and as if "automatized", (8) impulsiveness, (9) accumulation of aggression that may be vented out as suicide, and finally (10) accessibility of means to commit suicide. PMID- 28866722 TI - Changes in intensity of neurotic symptoms associated with reduction of suicidal ideation in patients who underwent psychotherapy in the day hospital for the treatment of neurotic and behavioral disorders. AB - OBJECTIVES: Analysis of associations between changes in the intensity of neurotic symptoms and reduction of suicidal ideation (SI) or lack of SI reduction, in patients who underwent a course of intensive psychotherapy conducted in integrative approach with predominance of psychodynamic approach in a day hospital. METHODS: Symptom Checklist KO"O" and Life Inventory completed by 461 women and 219 men treated in the psychotherapeutic day hospital due to neurotic, behavioral or personality disorders between 2005-2013. During the qualification for the therapy 134 women and 80 men reported SI, of whom 84.3% and 77.5% respectively improved. RESULTS: The reduction of neurotic symptoms intensity was greater in patients of both genders who improved in terms of SI than in those who did not. This referred to global intensity of neurotic symptoms (OWK coefficient) in both genders (p<0.001), as well as to the majority of the neurotic symptoms subtypes in both genders (p<0.05): Phobic disorders, Other anxiety disorders, Obsessive-compulsive disorders, Conversions and dissociations, Autonomic disorders, Somatization disorders, Neurasthenia, Avoidance and dependence, Sexual dysfunctions, Dysthymia; and in case of women (p<0.05): Hypochondriasis, Depersonalization and derealization, Impulsiveness and histrionism and Non organic sleep disorders. CONCLUSIONS: The results show effectiveness and comprehensiveness of intensive psychotherapy as a treatment method that leads to improvement in terms of both SI and neurotic symptoms. This suggests that the applied therapy may be effective in preventing suicidality in this group of patients. The observed associations also point in favor of hypothesis on similarities in etiopathogenesis of and partly identical personality-related factors predisposing to SI and neurotic disorders. PMID- 28866723 TI - Resilience as a predicator of mental health of incarcerated women. AB - OBJECTIVES: Serving a prison sentence is an experience that bears the hallmarks of a trauma. Scientific findings on how people handle traumatic The aim of the following research was to analyze the way in which psychological resilience differentiates mental states of incarcerated women and to identify the predicator of mental well-being in this group.experiences show that there are numerous personal and social resources that allow for better adaptation. One of the concepts used to describe the process reflecting relatively good adaptation is psychological resilience. METHODS: The study included women incarcerated in the External Department of Czersk Penitentiary for juvenile female offenders who serve a prison sentence for the first time and penitentiary recidivists. The following scales were used in the research: the Resilience Measurement Scale - RMS-25 and the HADS-M scale, which allows to conduct a test for symptoms of depression. RESULTS: The results revealed crucial statistical correlations between the results of the resilience scale and results of the HADS-M. It was also found that the predicators of anxiety and depression in the study group are the level of personal coping skills and tolerance of negative emotions (RMS-25). Additionally, a crucial factor in predicting the state of anxiety is the number of years of imprisonment. The conducted regression analysis also showed that the level of personal coping skills and tolerance of negative emotions (RMS-25) as well as openness to new experiences and sense of humor (RMS-25) are essential predicators of the level of aggression. CONCLUSIONS: The concept of psychological resilience is significant in analyzing the differences in mental health of incarcerated women and may help to create conditions that are conducive to reducing negative effects of prisoners staying in conditions of institutional constraint. PMID- 28866724 TI - Dr. Karol de Beaurain - a psychiatrist's profile. Part 1. AB - The paper sets out to recall the profile of Karol de Beaurain, a psychiatrist who belonged to the circle of first Poles who used psychoanalysis in treatment. So far, dr Beaurain has been known from brief references in publications relating to the life and works of Stanislaw Ignacy Witkiewicz (Witkacy) whose psychoanalytic sessions he conducted between 1912 and 1913. De Beaurain was born in 1867 and studied medicine at Swiss universities (Zurich, Berne, Geneva) where he defended his doctoral thesis as well. He was prepared for the career of a health resort physician and when he returned to Poland, he settled down in Poronin where except for working as a district physician, he also engaged in social and cultural activities. Around 1910 his professional interest shifted towards psychiatry and psychotherapy. In the final months of 1911 he relocated to Zakopane where he opened a private practice for "neu-rotic diseases". At the same time he started treating patients with the use of psychoanalytic methods. The first part of the paper concerns the life of doctor de Beaurain from birth and the period of studies and preparation for his professional career until the time when he started his psychoanalytic work. PMID- 28866725 TI - Dr. Karol de Beaurain - a psychiatrist's profile. Part 2. AB - The paper sets out to recall the profile of Karol de Beaurain, a psychiatrist, who was one of first Poles to use the psychoanalytic method in treatment. So far, he has been mostly known as the one who was Witkacy's psychoanalyst. Stanislaw Ignacy Witkiewicz and Eugenia Dunin-Borkowska are the first patients who are known by their names and who received psychoanalytic treatment in the history of the Polish medicine. Stanislaw Ignacy Witkiewicz's letters and drawings originating from the psychoanalysis period served as a source of information about Witkacy's psychoanalysis. The paper illustrates dr Beaurain's fate during World War I when he was first a military doctor in Skoczow and then an assistant in prof. Piltz's Neurological-Psychiatric Clinic in Krakow where he actively participated in the creation of a multidimensional programme of war neurosis treatment. After the war finished, initially Beaurain stayed at his assistant post at the Psychiatric Clinic in Krakow but then in 1921 he relocated to the National Psychiatric Hospital in Dziekanka near Poznan. With his professional expertise he contributed to the strengthening of the Great Poland region psychiatry that had experienced qualified personnel shortages after the German qualified staff left. The growing numbers of patients and the overload of professional duties were probably the factors that led to dr. Beaurain's premature death while he was holding the position of the head physician at the National Psychiatric Hospital in Owinska in February 1927. PMID- 28866726 TI - Application of white blood cell SPECT/CT to predict remission after a 6 or 12 week course of antibiotic treatment for diabetic foot osteomyelitis. AB - AIMS/HYPOTHESIS: Diabetic foot osteomyelitis is a major risk factor for amputation. Medical treatment allows remission in 53-82% of cases. However, the optimal duration of antibiotic therapy remains controversial as a validated marker of osteomyelitis remission is lacking. The aim of this cohort study was to assess prospectively the remission rate of diabetic foot osteomyelitis medically treated using white blood cell (WBC)-single-photon emission computed tomography (SPECT)/computed tomography (CT) as a predictive marker of remission. METHODS: Individuals with diabetic foot osteomyelitis that was non-surgically treated between April 2014 and December 2015 were included. All participants were treated with antibiotics alone. WBC-SPECT/CT was performed at 6 weeks and antibiotic treatment discontinued if the clinical signs of soft-tissue infection had resolved and there was no abnormal uptake of labelled WBCs. Treatment was otherwise continued for a total of 12 weeks and then discontinued. For these individuals, another WBC-SPECT/CT was performed at 12 weeks. Remission was defined as the absence of recurrence of osteomyelitis at the same location at 1 year. RESULTS: Forty-five individuals were included; overall remission rate was 84% at 1 year. A 6 week course of antibiotics was used in 23 participants, 22 of whom were in remission at 1 year (96%); a 12 week course was used for 22 participants, 16 of whom were in remission at 1 year (73%). Sensitivity of WBC SPECT/CT at 12 weeks was 100%, specificity 56%, positive predictive value 46% and negative predictive value 100%. CONCLUSIONS/INTERPRETATION: The study suggests that WBC-SPECT/CT could predict remission at the end of antibiotic treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02927678. PMID- 28866727 TI - Long-term reliability of fractioned CO2 laser as a treatment for vulvovaginal atrophy (VVA) symptoms. AB - PURPOSE: The aim of this study was to evaluate long-term effects of the fractional CO2 laser for the treatment of vulvovaginal atrophy (VVA) symptoms. METHODS: Women presenting with VVA symptoms and meeting inclusion criterion were enrolled to fractioned CO2 laser therapy. Patient's satisfaction was measured on five-point Likert scale at 4 weeks and 6, 12, 18, 24 months after treatment by interview and clinical examination for vaginal livability. RESULTS: 184 patients constituted the final study group: 128 women were spontaneous menopause and 56 were oncological menopause. 117 women were nulliparous and 36 had previous hysterectomy. 95.4% (172/184) of the patients declared that they were satisfied or very satisfied with the procedure at 4 weeks after treatment. At 6 months 92% (170/184) patients were satisfied; at 12 months 72% (118/162) were satisfied; at 18 months 63% (60/94) were satisfied; at 24 months 25% (4/16) of patients answered they were still satisfied. We observed a decline in patient's satisfaction between 18 and 24 months after laser therapy. Data showed that the time interval from onset of menopause was a statistically significant factor (p < 0.05) for treatment satisfaction in oncological group. CONCLUSION: Long-term data showed that the improvement of vaginal health may continue up to 24 months after fractional CO2 laser treatment although between 18 and 24 months benefits decline, and approximately 80% of women decide to start a new treatment cycle of laser applications. PMID- 28866728 TI - Electrochemical measurement of quantal exocytosis using microchips. AB - Carbon-fiber electrodes (CFEs) are the gold standard for quantifying the release of oxidizable neurotransmitters from single vesicles and single cells. Over the last 15 years, microfabricated devices have emerged as alternatives to CFEs that offer the possibility of higher throughput, subcellular spatial resolution of exocytosis, and integration with other techniques for probing exocytosis including microfluidic cell handling and solution exchange, optical imaging and stimulation, and electrophysiological recording and stimulation. Here we review progress in developing electrochemical electrode devices capable of resolving quantal exocytosis that are fabricated using photolithography. PMID- 28866729 TI - Experimental investigation on the vascular thermal response to near-infrared laser pulses. AB - Port wine stains (PWS) are congenital vascular malformations that progressively darken and thicken with age. To improve the effect of laser therapy in clinical practice, thermal response of blood vessel to a 1064 nm Nd:YAG laser with controlled energy doses and pulse durations was evaluated using the dorsal skin chamber model. A total of 137 vessels with 30-300 MUm diameters were selected from the dorsal skin of the mouse to match those capillaries in port wine stains. Experimental results showed that the thermal response of blood vessels to 1064 nm laser irradiation can be classified as follows: vessel dilation, coagulation, constriction with decreased diameter, complete constriction, hemorrhage, and collagen damage with increasing laser radiant exposure. In most cases, that is, 83 of 137 blood vessels (60.6%), Nd:YAG laser irradiation was characterized by complete constriction (immediate blood vessel disappearance). To reveal the possible damage mechanisms and evaluate blood vessel photocoagulation patterns, theoretical investigation using bioheat transfer equation was conducted in mouse skin with a depth of 1000 MUm. Complete constriction as the dominant thermal response as evidenced by uniform blood heating within the vessel lumen was noted in both experimental observation and theoretical investigation. To achieve the ideal clinical effect using the Nd:YAG laser treatment, the radiant exposure should not only be high enough to induce complete constriction of the blood vessels but also controlled carefully to avoid surrounding collagen damage. The short pulse duration of 1-3 ms is better than long pulse durations because hemorrhaging of small capillaries is occasionally observed postirradiation with pulse durations longer than 10 ms. PMID- 28866731 TI - Classification of Focal and Non Focal Epileptic Seizures Using Multi-Features and SVM Classifier. AB - Identifying epileptogenic zones prior to surgery is an essential and crucial step in treating patients having pharmacoresistant focal epilepsy. Electroencephalogram (EEG) is a significant measurement benchmark to assess patients suffering from epilepsy. This paper investigates the application of multi-features derived from different domains to recognize the focal and non focal epileptic seizures obtained from pharmacoresistant focal epilepsy patients from Bern Barcelona database. From the dataset, five different classification tasks were formed. Total 26 features were extracted from focal and non focal EEG. Significant features were selected using Wilcoxon rank sum test by setting p value (p < 0.05) and z-score (-1.96 > z > 1.96) at 95% significance interval. Hypothesis was made that the effect of removing outliers improves the classification accuracy. Turkey's range test was adopted for pruning outliers from feature set. Finally, 21 features were classified using optimized support vector machine (SVM) classifier with 10-fold cross validation. Bayesian optimization technique was adopted to minimize the cross-validation loss. From the simulation results, it was inferred that the highest sensitivity, specificity, and classification accuracy of 94.56%, 89.74%, and 92.15% achieved respectively and found to be better than the state-of-the-art approaches. Further, it was observed that the classification accuracy improved from 80.2% with outliers to 92.15% without outliers. The classifier performance metrics ensures the suitability of the proposed multi-features with optimized SVM classifier. It can be concluded that the proposed approach can be applied for recognition of focal EEG signals to localize epileptogenic zones. PMID- 28866730 TI - EGFR-targeted therapies in the post-genomic era. AB - Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is a Food and Drug Administration (FDA)-approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast, and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example, cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1E322K mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR. PMID- 28866732 TI - Gene Delivery in Neuro-Oncology. AB - PURPOSE OF REVIEW: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults with a dismal prognosis despite aggressive multimodal management thus novel treatments are urgently needed. Gene therapy is a versatile treatment strategy being investigated in multiple cancers including GBM. In gene therapy, a variety of vectors or "carriers" are used to deliver genes designed for different anti-tumoral effects. Gene delivery vehicles and approaches to treatment will be addressed in this review. RECENT FINDINGS: The most commonly studied vectors are viral based, however, driven by advances in biomedical engineering, mesenchymal and neural stem cells, as well as multiple different types of nanoparticles have been developed to improve tumor tropism and also increase gene transfer into tumor cells. Different genes have been studied including suicide genes, which convert non-toxic prodrug into cytotoxic drug; immunomodulatory genes, which stimulate the immune system; and tumor suppressor genes which repair the defect that allow cells to divide unchecked. Gene therapy may be a promising treatment strategy in neuro-oncology as it is versatile and flexible due to the ability to tailor vectors and genes for specific therapeutic activity. Pre-clinical studies and clinical trials have demonstrated feasibility and safety of gene therapy; however, further studies are required to determine efficacy. PMID- 28866733 TI - Single-Base Resolution Mapping of 5-Hydroxymethylcytosine Modifications in Hippocampus of Alzheimer's Disease Subjects. AB - Epigenetic modifications to cytosine have been shown to regulate transcription in cancer, embryonic development, and recently neurodegeneration. While cytosine methylation studies are now common in neurodegenerative research, hydroxymethylation studies are rare, particularly genome-wide mapping studies. As an initial study to analyze 5-hydroxymethylcytosine (5-hmC) in the Alzheimer's disease (AD) genome, reduced representation hydroxymethylation profiling (RRHP) was used to analyze more than 2 million sites of possible modification in hippocampal DNA of sporadic AD and normal control subjects. Genes with differentially hydroxymethylated regions were filtered based on previously published microarray data for altered gene expression in hippocampal DNA of AD subjects. Our data show significant pathways for altered levels of 5-hmC in the hippocampus of AD subjects compared to age-matched normal controls involved in signaling, energy metabolism, cell function, gene expression, protein degradation, and cell structure and stabilization. Overall, our data suggest a possible role for the dysregulation of epigenetic modifications to cytosine in late stage AD. PMID- 28866734 TI - The Retina of Osteopontin deficient Mice in Aging. AB - Osteopontin (OPN) is a secreted glycosylated phosphoprotein that influences cell survival, inflammation, migration, and homeostasis after injury. As the role of OPN in the retina remains unclear, this study issue was addressed by aiming to study how the absence of OPN in knock-out mice affects the retina and the influence of age on these effects. The study focused on retinal ganglion cells (RGCs) and glial cells (astrocytes, Muller cells, and resident microglia) in 3- and 20-month-old mice. The number of RGCs in the retina was quantified and the area occupied by astrocytes was measured. In addition, the morphology of Muller cells and microglia was examined in retinal sections. The deficiency in OPN reduces RGC density by 25.09% at 3 months of age and by 60.37% at 20 months of age. The astrocyte area was also reduced by 51.01% in 3-month-old mice and by 57.84% at 20 months of age, although Muller glia and microglia did not seem to be affected by the lack of OPN. This study demonstrates the influence of OPN on astrocytes and RGCs, whereby the absence of OPN in the retina diminishes the area occupied by astrocytes and produces a secondary reduction in the number of RGCs. Accordingly, OPN could be a target to develop therapies to combat neurodegenerative diseases and astrocytes may represent a key mediator of such effects. PMID- 28866735 TI - Implementation of Environmental Flows for Intermittent River Systems: Adaptive Management and Stakeholder Participation Facilitate Implementation. AB - Anthropogenic pressure on freshwater ecosystems is increasing, and often leading to unacceptable social-ecological outcomes. This is even more prevalent in intermittent river systems where many are already heavily modified, or human encroachment is increasing. Although adaptive management approaches have the potential to aid in providing the framework to consider the complexities of intermittent river systems and improve utility within the management of these systems, success has been variable. This paper looks at the application of an adaptive management pilot project within an environmental flows program in an intermittent stream (Tuppal Creek) in the Murray Darling Basin, Australia. The program focused on stakeholder involvement, participatory decision-making, and simple monitoring as the basis of an adaptive management approach. The approach found that by building trust and ownership through concentrating on inclusiveness and transparency, partnerships between government agencies and landholders were developed. This facilitated a willingness to accept greater risks and unintended consequences allowing implementation to occur. PMID- 28866736 TI - Peroxynitrite scavenging by Campylobacter jejuni truncated hemoglobin P. AB - Truncated hemoglobins (trHb) are present in protozoa, cyanobacteria, nemertean, bacteria, algae, and plants. They are characterized by the 2-on-2 topology and are ordered in four phylogenetic groups (I or N, II or O, III or P, and IV or Q). Several functions have been attributed to trHbs including the inactivation of reactive nitrogen and oxygen species, permitting the survival of microorganisms in the host. Here, the kinetics of peroxynitrite scavenging by ferric Campylobacter jejuni truncated hemoglobin P [i.e., Cj-trHbP(III)] in the absence and presence of CO2, between pH 6.3 and 7.9, and 25.0 degrees C, is reported. Mixing the Cj-trHbP(III) solution with peroxynitrite solution brings about absorption spectral changes at 302 nm reflecting the disappearance of this endogenous toxicant and cytotoxic effector against pathogens. CO2 affects only the rate of spontaneous decay of peroxynitrite without affecting the scavenging activity of Cj-trHbP(III). Moreover, the Cj-trHbP(III)-mediated isomerization of peroxynitrite is facilitated at low pH, indicating that peroxynitrous acid is the reactive species. The high reactivity of Cj-trHbP(III) towards peroxynitrite has been ascribed to the peroxidase-like geometry of the metal center. To investigate the protective role of Cj-trHbP(III) against peroxynitrite-mediated nitration, the relative yield of nitro-L-tyrosine formed by the reaction of peroxynitrite with free L-tyrosine was determined. According to fast kinetics of peroxynitrite isomerization by Cj-trHbP(III), this 2-on-2 globin impairs L-tyrosine nitrosylation. Present data suggest that Cj-trHbP could help the survival of C. jejuni. PMID- 28866737 TI - A frailty index from common clinical and laboratory tests predicts increased risk of death across the life course. AB - A frailty index (FI) based entirely on common clinical and laboratory tests might offer scientific advantages in understanding ageing and pragmatic advantages in screening. Our main objective was to compare an FI based on common laboratory tests with an FI based on self-reported data; we additionally investigated if the combination of subclinical deficits with clinical ones increased the ability of the FI to predict mortality. In this secondary analysis of the 2003-2004 and 2005 2006 National Health and Nutrition Examination Survey data, 8888 individuals aged 20+ were evaluated. Three FIs were constructed: a 36-item FI using self-reported questionnaire data (FI-Self-report); a 32-item FI using data from laboratory test values plus pulse and blood pressure measures (FI-Lab); and a 68-item FI that combined all items from each index (FI-Combined). The mean FI-Lab score was 0.15 +/- 0.09, the FI-Self-report was 0.11 +/- 0.11 and FI-Combined was 0.13 +/- 0.08. Each index showed some typical FI characteristics (skewed distribution with long right tail, non-linear increase with age). Even so, there were fewer people with low frailty levels and a slower increase with age for the FI-Lab compared to the FI-Self-report. Higher frailty level was associated with higher risk of death, although it was strongest at older ages. Both FI-Lab and FI-Self-report remained significant in a combined model predicting death. The FI-Lab was feasible and valid, demonstrating that even subclinical deficit accumulation increased mortality risk. This suggests that deficit accumulation, from the subcellular to the clinically visible is a useful construct that may advance our understanding of the ageing process. PMID- 28866738 TI - Preparation and Photocatalytic Performance of Hollow Structure LiNb3O8 Photocatalysts. AB - Hollow structure LiNb3O8 photocatalysts were prepared by a hydrothermal method assisting sintering process. The particles' aggregation to form hollow structures with obvious cavities can be attributed to the Li element volatilization during calcination process. All the LiNb3O8 powders show high photocatalytic efficiency of degradation of methylene blue (MB), especially for the sample calcined at 700 degrees C (LNO700), with only 3 h to completely decompose MB. The photo degradation of MB follows the pseudo-first-order kinetics, and the obtained first order rate is 0.97/h. The larger degradation rate of LNO700 can be attributed to its hollow structure which provides a larger specific surface area and more active sites to degrade the MB molecules. The cycling test of photo-degradation and adsorption of MB over LNO700 powder indicates that the hollow structure of the LiNb3O8 photocatalyst is stable and the LiNb3O8 photocatalyst is an efficient photocatalyst with good reusability, confirmed by the XRD and X-ray photoelectron spectroscopy tests before and after photo-degradation of MB. PMID- 28866739 TI - Effect of Sodium Chloride on Surface-Associated Motility of Acinetobacter baumannii and the Role of AdeRS Two-Component System. AB - Acinetobacter baumannii is an important bacterial pathogen whose resistance to antibiotics is a growing concern worldwide. Among a wide array of resistance mechanisms displayed by A. baumannii, energy-dependent efflux of antibiotics by proteins belonging the resistance-nodulation-division family serves as an important one. AdeABC pump has been shown to be active in various clinical isolates. Regulation of this pump is controlled by the AdeRS two-component system. In this study, we show that the AdeRS system, in addition to modulating A. baumannii's antibiotic susceptibility, also plays a role in biofilm formation as well as surface-associated motility. We also show that AdeRS deletion mutant is more sensitive to saline stress. In particular, motility of A. baumannii ATCC17978 on agar surface is severely hampered at higher salt concentrations when AdeRS system is absent. Therefore, our study shows that AdeRS could be part of the A. baumannii adaptation strategy to salinity stress. PMID- 28866740 TI - Factor analysis of the SRS-22 outcome assessment instrument in patients with adult spinal deformity. AB - PURPOSE: Designed for patients with adolescent idiopathic scoliosis, the SRS-22 is now widely used as an outcome instrument in patients with adult spinal deformity (ASD). No studies have confirmed the four-factor structure (pain, function, self-image, mental health) of the SRS-22 in ASD and under different contexts. Factorial invariance of an instrument over time and in different languages is essential to allow for precise interpretations of treatment success and comparisons across studies. This study sought to evaluate the invariance of the SRS-22 structure across different languages and sub-groups of ASD patients. METHODS: Confirmatory factor analysis was performed on the 20 non-management items of the SRS-22 with data from 245 American English-, 428 Spanish-, 229 Turkish-, 95 French-, and 195 German-speaking patients. Item loading invariance was compared across languages, age groups, etiologies, treatment groups, and assessment times. A separate sample of SRS-22 data from 772 American surgical patients with ASD was used for cross-validation. RESULTS: The factor structure fitted significantly better to the proposed four-factor solution than to a unifactorial solution. However, items 14 (personal relationships), 15 (financial difficulties), and 17 (days off work) consistently showed weak item loading within their factors across all language versions and in both baseline and follow up datasets. A trimmed SRS (16 non-management items) that used the four least problematic items in each of the four domains yielded better-fitting models across all languages, but equivalence was still not reached. With this shorter version there was equivalence of item loading with respect to treatment (surgery vs conservative), time of assessment (baseline vs 12 months follow-up), and etiology (degenerative vs idiopathic), but not age (< vs >=50 years). All findings were confirmed in the cross-validation sample. CONCLUSION: We recommend removal of the worst-fitting items from each of the four domains of the SRS instrument (items 3, 14, 15, 17), together with adaptation and standardization of other items across language versions, to provide an improved version of the instrument with just 16 non-management items. PMID- 28866741 TI - Remediation mechanisms of mercapto-grafted palygorskite for cadmium pollutant in paddy soil. AB - The immobilization agent was the key factor that determined the success of remediation of heavy metal polluted soil. In this study, mercapto-grafted palygorskite (MP) as a novel and efficient immobilization agent was utilized for the remediation of Cd-polluted paddy soil in pot trials, and the remediation mechanisms were investigated in the aspect of soil chemistry and plant physiology with different rice cultivars as model plants. Mercapto-grafted palygorskite at applied doses of 0.1-0.3% could reduce Cd contents of brown rice and straws of different cultivars significantly. Both reduced DTPA-extractable Cd contents in rhizosphere and non-rhizosphere soil and decreasing Cd contents in iron plaques on rice root surfaces confirmed that MP was an efficient immobilization agent for Cd pollutant in paddy soil. In the aspect of soil chemistry, the pH values of rhizosphere and non-rhizosphere soils had no statistical changes in the MP treatment groups, but their zeta potentials decreased obviously, indicating that MP could enhance the fixation or sorption of Cd on soil compositions. In the aspect of antioxidant system, MP could increase POD activity of rice roots significantly to alleviate the stress of Cd to roots, and resulted in the decrease of T-AOC, SOD, and CAT activities of rice roots of the selected cultivars. MP had no inhabitation or enhancement effects on TSH of rice roots but enhance the contents of MTs and NPT to binding Cd to complete detoxification process. MP as a novel and efficient immobilization agent could complete the remediation effects through soil chemistry and plant physiological mechanisms. PMID- 28866742 TI - CdS Nanoparticle-Modified alpha-Fe2O3/TiO2 Nanorod Array Photoanode for Efficient Photoelectrochemical Water Oxidation. AB - In this work, we demonstrate a facile successive ionic layer adsorption and reaction process accompanied by hydrothermal method to synthesize CdS nanoparticle-modified alpha-Fe2O3/TiO2 nanorod array for efficient photoelectrochemical (PEC) water oxidation. By integrating CdS/alpha-Fe2O3/TiO2 ternary system, light absorption ability of the photoanode can be effectively improved with an obviously broadened optical-response to visible light region, greatly facilitates the separation of photogenerated carriers, giving rise to the enhancement of PEC water oxidation performance. Importantly, for the designed abnormal type-II heterostructure between Fe2O3/TiO2, the conduction band position of Fe2O3 is higher than that of TiO2, the photogenerated electrons from Fe2O3 will rapidly recombine with the photogenerated holes from TiO2, thus leads to an efficient separation of photogenerated electrons from Fe2O3/holes from TiO2 at the Fe2O3/TiO2 interface, greatly improving the separation efficiency of photogenerated holes within Fe2O3 and enhances the photogenerated electron injection efficiency in TiO2. Working as the photoanodes of PEC water oxidation, CdS/alpha-Fe2O3/TiO2 heterostucture electrode exhibits improved photocurrent density of 0.62 mA cm- 2 at 1.23 V vs. reversible hydrogen electrode (RHE) in alkaline electrolyte, with an obviously negatively shifted onset potential of 80 mV. This work provides promising methods to enhance the PEC water oxidation performance of the TiO2-based heterostructure photoanodes. PMID- 28866744 TI - Basidiospores attach to the seed of Shorea leprosula in lowland tropical dipterocarp forest and form functional ectomycorrhiza on seed germination. AB - This research aimed to study the ectomycorrhiza formed by basidiospores attached to the outer surface of Shorea leprosula (Dipterocarpaceae) seed collected from a lowland tropical dipterocarp forest. Two groups of seeds were collected: control seeds collected from plastic net hanging 2 m above the ground and forest floor seeds collected on the forest floor. Before planting, 15 seeds from each group were observed for basidiospores attached to the seed. Ten of the 3-week-old S. leprosula seedlings of each group were individually grown in 1.5 kg of sterile zeolite for 8 months in a greenhouse. Pots were fertilized with MMN solution containing half the strength of phosphate. Fungal identity, ectomycorrhizal root tip colonization and anatomy, plant growth, and phosphate uptake were measured. The control seeds did not have basidiospores attached, whereas the forest floor seeds had 2 * 105 basidiospores of Tomentella. Bioassay test results indicate that the seedlings from the control seeds did not form ectomycorrhiza, whereas those seedlings from the forest floor seeds formed 3 morphotypes of ectomycorrhizae. Based on ITS1, 5.8S, and ITS2 rDNA region analyses, the 3 morphotypes belonged to Tomentella sp. HBT2, Tomentella sp. HBT4, and Scleroderma sp. HBS3. Root colonization percentage was above 70% for all three morphotypes. Root colonization in general increased plant growth and phosphate uptake. This is the first report of Tomentella basidiospores attached on the seed surface as a functional inoculum and of Tomentella ectomycorrhiza from dipterocarps lowland tropical forest. PMID- 28866743 TI - Effects of oral Delta9-tetrahydrocannabinol on the cerebral processing of olfactory input in healthy non-addicted subjects. AB - BACKGROUND: Considering the increasing acknowledgment of the human sense of smell as a significant component of the quality of life, olfactory drug effects gain potential clinical importance. A recent observation in a human experimental context indicated that Delta9-tetrahydrocannabinol (THC) impaired the subject's performance in olfactory tests. To further analyze the role of THC in human olfaction, the present report addresses its effects on the central processing of olfactory stimuli. METHODS: Employing a placebo-controlled randomized crossover design, an oral dose of 20 mg THC was administered in 15 healthy volunteers. The central processing of olfactory input, consisting of short pulses of gaseous vanillin or hydrogen sulfide, and for comparison, of non-odorous but painful carbon dioxide, were investigated before and after administration of THC or placebo in a pharmacological functional magnet resonance imaging study. RESULTS: Following THC administration, the vanillin stimuli lost their pleasantness and became hedonically inert. This observation had its functional correlate in reduced stimulus-associated brain activations located in the left amygdala, the hippocampus and superior temporal pole (peak MNI coordinates x = - 27, y = - 1, z = - 26 mm p = 0.039). Differences in amygdala activations were significantly correlated with the corresponding differences in vanillin pleasantness (p = 0.025). By contrast, no effects were observed on the perception of processing of H2S stimuli. CONCLUSIONS: The results support that THC induced a modulation of the central processing of olfactory input. The THC-induced reduction in the pleasantness of a pleasurable odor was accompanied by reduced activations in the limbic system. Results agree with previous observation of negative effects of cannabinoids on the human sense of smell and strengthen the evidence that THC based medications will be among drugs with olfactory side effects. PMID- 28866745 TI - Mortality and prognostic factors in idiopathic inflammatory myositis: a retrospective analysis of a large multicenter cohort of Spain. AB - The present study was undertaken to assess mortality, causes of death, and associated prognostic factors in a large cohort of patients diagnosed with idiopathic inflammatory myositis (IIM) from Spain. A retrospective longitudinal study was carried out in 467 consecutive patients with IIM, identified from 12 medical centers. Patients were classified as primary polymyositis, primary dermatomyositis (DM), overlap myositis, cancer-associated myositis (CAM), and juvenile idiopathic inflammatory myopathies. A total of 113 deaths occurred (24%) after a median follow-up time of 9.7 years. In the overall cohort, the 2-, 5-, and 10-year survival probabilities were 91.9, 86.7, and 77%, respectively. Main causes of death were infections and cancer (24% each). Multivariate model revealed that CAM (HR = 24.06), OM (HR = 12.00), DM (HR = 7.26), higher age at diagnosis (HR = 1.02), severe infections (HR = 3.66), interstitial lung disease (HR = 1.61), and baseline elevation of acute phase reactants (HR = 3.03) were associated with a worse prognosis, while edema of the hands (HR = 0.39), female gender (HR = 0.39), and longer disease duration (HR = 0.73) were associated with a better prognosis. The standardized mortality ratio was 1.56 (95% CI 1.28-1.87) compared to the Spanish general population. Our findings indicate that IIM has a high long-term mortality, with an excess of mortality compared to the Spanish population. A more aggressive therapy may be required in IIM patients presenting with poor predictive factors. PMID- 28866746 TI - Composting plant leachate treatment by a pilot-scale, three-stage, horizontal flow constructed wetland in central Iran. AB - Handling and treatment of composting leachate is difficult and poses major burdens on composting facilities. The main goal of this study was to evaluate usage of a three-stage, constructed wetland to treat leachate produced in Isfahan composting facility. A pilot-scale, three-stage, subsurface, horizontal flow constructed wetland, planted with vetiver with a flow rate of 24 L/day and a 15 day hydraulic retention time, was used. Removal of organic matter, ammonia, nitrate, total nitrogen, suspended solids, and several heavy metals from Isfahan composting facility leachate was monitored over a 3-month period. Constructed wetland system was capable of efficiently removing BOD5 (87.3%), COD (74.5%), ammonia (91.5%), nitrate (87.9%), total nitrogen (87.8%), total suspended solids (85.5%), and heavy metals (ranging from 70 to 90%) from the composting leachate. High contaminant removal efficiencies were achieved, but effluent still failed to meet Iranian standards for treated wastewater. This study shows that although a three-stage horizontal flow constructed wetland planted with vetiver cannot be used alone to treat Isfahan composting facility leachate, but it has the potential to be used as a leachate pre-treatment step, along with another complementary method. PMID- 28866747 TI - Prognostic implication of NOTCH1 in early stage oral squamous cell cancer with occult metastases. AB - OBJECTIVE: The objective of this study was to explore the prognostic value of cancer stem cell markers, namely CD133, NANOG, and NOTCH1, in early stage oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: One hundred forty-four patients with early stage (cT1T2N0) OSCC were identified from a pre-existing database of patients with oral cancer. We examined the impact of the immunohistochemical expression of CD133, NANOG, and NOTCH1 in OSCC. Overall survival (OS) curves were calculated using the Kaplan-Meier method. Predictors of outcome were identified using multivariate analysis. RESULTS: We found that CD133, NANOG, and NOTCH1 were significantly associated with lymph node metastasis, and NOTCH1 was also significantly associated with depth of invasion and locoregional recurrence. CONCLUSIONS: NOTCH1 was identified as an independent prognostic factor for OS. CLINICAL RELEVANCE: NOTCH1 might prove to be a useful indicator for high-risk patients with occult metastases from early stage OSCC. PMID- 28866748 TI - Early response of glutathione- and thioredoxin-dependent antioxidant defense systems to Tl(I)- and Tl(III)-mediated oxidative stress in adherent pheochromocytoma (PC12adh) cells. AB - Thallium (Tl) is a toxic heavy metal that causes oxidative stress both in vitro and in vivo. In this work, we evaluated the production of oxygen (ROS)- and nitrogen (RNS)-reactive species in adherent PC12 (PC12adh) cells exposed for 0.5 6 h to Tl(I) or Tl(III) (10-100 uM). In this system, Tl(I) induced mostly H2O2 generation while Tl(III) induced H2O2 and ONOO.- generation. Both cations enhanced iNOS expression and activity, and decreased CuZnSOD expression but without affecting its activity. Tl(I) increased MnSOD expression and activity but Tl(III) decreased them. NADPH oxidase (NOX) activity remained unaffected throughout the period assessed. Oxidant levels returned to baseline values after 6 h of incubation, suggesting a response of the antioxidant defense system to the oxidative insult imposed by the cations. Tl also affected the glutathione dependent system: while Tl(III) increased glutathione peroxidase (GPx) expression and activity, Tl(I) and Tl(III) decreased glutathione reductase (GR) expression. However, GR activity was mildly enhanced by Tl(III). Finally, thioredoxin dependent system was evaluated. Only Tl(I) increased 2-Cys peroxiredoxins (2-Cys Prx) expression, although both cations increased their activity. Tl(I) increased cytosolic thioredoxin reductase (TrxR1) and decreased mitochondrial (TrxR2) expression. Tl(III) had a biphasic effect on TrxR1 expression and slightly increased TrxR2 expression. Despite of this, both cations increased total TrxR activity. Obtained results suggest that in Tl(I)-exposed PC12adh cells, there is an early response to oxidative stress mainly by GSH-dependent system while in Tl(III)-treated cells both GSH- and Trx-dependent systems are involved. PMID- 28866749 TI - The radiographically diagnosed adrenal myelolipoma: what do we really know? AB - PURPOSE: Adrenal myelolipomas are uncommon, benign tumors of the adrenal glands that are not routinely evaluated for autonomous hormone secretion or followed by repeat imaging, but may lead to retroperitoneal hemorrhage. Little is known about the natural history these tumors with the majority of previous publications being confined to case reports and small case series. METHODS: We reviewed the computed tomography (CT) reports of 62,279 patients evaluated at a tertiary referral center between 2002 and 2015 for the presence of an adrenal myelolipoma >1 cm in size. We then reviewed the CT imaging and patient charts to determine tumor size, growth, evidence of retroperitoneal hemorrhage, and endocrine dysfunction. RESULTS: We identified 150 (0.24%) patients with 155 radiographically diagnosed adrenal myelolipomas found on a CT scan during our study period. The median tumor size at discovery was 2.1 cm. Twelve (7.7%) tumors were >6 cm. Sixty-nine (46%) patients had a follow-up CT with a mean time interval between scans of 3.9 years. Eleven tumors (16%) grew over our follow-up period with a median growth rate of 0.16 cm/year. No patient developed a retroperitoneal hemorrhage. Twenty (13%) patients underwent an evaluation for endocrine dysfunction. Three patients had evidence of hypercortisolism and one patient had primary aldosteronism. CONCLUSION: The majority of radiographically diagnosed adrenal myelolipomas found on abdominal CT imaging are small and slow growing. Retroperitoneal hemorrhage is uncommon, but the rate of associated endocrine dysfunction may be underestimated. PMID- 28866750 TI - Relationship Between Laryngeal Sensory Deficits, Aspiration, and Pneumonia in Patients with Dysphagia. AB - The laryngeal adductor reflex (LAR) is an airway protective reflex that manifests as a brief vocal fold closure in response to laryngeal stimulation. This study examined if the absence of the LAR in response to touch delivered by a laryngoscope is associated with penetration/aspiration or pneumonia in patients with dysphagia. Inpatients at a teaching hospital with clinical symptoms of dysphagia were recruited upon referral to the otolaryngology clinic for a swallowing evaluation. Otolaryngologists observed the status of secretions and touched each arytenoid with the tip of the laryngoscope. The patients were then asked to swallow 3-5 mL grape gelatin and 3-5 mL colored water. All procedures were video-recorded. Two independent raters noted absence/presence of the LAR and penetration/aspiration of pharyngeal secretions, gelatin, and water on the recorded videos. A diagnosis of pneumonia during the patient's entire hospital stay was determined by a review of the hospital's medical records. Statistical analyses were performed using Fisher's exact test. Sixty-one patients were included. Twenty-one patients (34.5%) did not exhibit the LAR. No association was found between the absent LAR and penetration or aspiration. There was, however, a significant association between an absence of the LAR and pneumonia development. Patients with an absent LAR had 6.8 times the odds of developing pneumonia as compared to those with a present LAR (OR 6.75; 95% CI 1.76-25.96; p < 0.01). Using the LAR as a marker of laryngeal sensory function appears to be valuable for identifying patients at high risk of pneumonia. PMID- 28866751 TI - Ultrasound variants of autoimmune thyroiditis in children and adolescents and their clinical implication in relation to papillary thyroid carcinoma development. AB - BACKGROUND: The prevalence of autoimmune thyroiditis (AIT) and papillary thyroid carcinoma (PTC) is rising in children and adolescents, and the coincidence of AIT and PTC is as high as 6.3-43%. OBJECTIVE: To investigate the ultrasound manifestation of AIT in relation to PTC development in paediatric patients. PATIENTS: 179 paediatric patients (133 females), mean (SD) age: 13.9 (3.03) years diagnosed with AIT and referred for ultrasound evaluation. Eight patients were diagnosed with PTC (6 females). METHODS: Retrospective analysis of thyroid ultrasound scans of patients diagnosed with AIT. Thyroid and autoimmune status was assessed based on TSH, fT4, fT3 and increased aTPO and/or aTG and/or TRAB levels. In patients with PTC, total thyroidectomy was performed. RESULTS: Analysis of thyroid US scans revealed that the following five ultrasound variants of AIT were observed in 179 patients: the most common in 35.2%-diffuse thyroiditis with hypoechogenic background and normoechogenic parenchyma, in 30.2% diffuse thyroiditis with irregular background, in 18.9% nodular variant with normoechogenic background, in 11.7%-micronodulations and in 3.9%-diffuse hypoechogenic background. Eight cases of PTC were diagnosed in nodular variant of AIT with normoechogenic irregular background. CONCLUSION: Patients with AIT and nodular variant with normoechogenic irregular background of the thyroid gland on US scans are in the risk group of developing PTC and should be followed up with regular neck US assessment. PMID- 28866752 TI - Altered Associations between Pain Symptoms and Brain Morphometry in the Pain Matrix of HIV-Seropositive Individuals. AB - Pain remains highly prevalent in HIV-seropositive (HIV+) patients despite their well-suppressed viremia with combined antiretroviral therapy. Investigating brain abnormalities within the pain matrix, and in relation to pain symptoms, in HIV+ participants may provide objective biomarkers and insights regarding their pain symptoms. We used Patient-Reported Outcome Measurement Information System (PROMIS(r)) pain questionnaire to evaluate pain symptoms (pain intensity, pain interference and pain behavior), and structural MRI to assess brain morphometry using FreeSurfer (cortical area, cortical thickness and subcortical volumes were evaluated in 12 regions within the pain matrix). Compared to seronegative (SN) controls, HIV+ participants had smaller surface areas in prefrontal pars triangularis (right: p = 0.04, left: p = 0.007) and right anterior cingulate cortex (p = 0.03) and smaller subcortical regions (thalamus: p <= 0.003 bilaterally; right putamen: p = 0.01), as well as higher pain scores (pain intensity-p = 0.005; pain interference-p = 0.008; pain-behavior-p = 0.04). Furthermore, higher pain scores were associated with larger cortical areas, thinner cortices and larger subcortical volumes in HIV+ participants; but smaller cortical areas, thicker cortices and smaller subcortical volumes in SN controls (interaction-p = 0.009 to p = 0.04). These group differences in the pain associated brain abnormalities suggest that HIV+ individuals have abnormal pain responses. Since these abnormal pain-associated brain regions belong to the affective component of the pain matrix, affective symptoms may influence pain perception in HIV+ patients and should be treated along with their physical pain symptoms. Lastly, associations of lower pain scores with better physical or mental health scores, regardless of HIV-serostatus (p < 0.001), suggest adequate pain treatment would lead to better quality of life in all participants. PMID- 28866753 TI - Two new and one known species of Tergestia Stossich, 1899 (Trematoda: Fellodistomidae) with novel molecular characterisation for the genus. AB - Combined morphological and molecular analyses are employed to characterise three species of Tergestia Stossich, 1899 (Digenea: Fellodistomidae) from fishes of Moreton Bay, Queensland, Australia. Tergestia clonacantha Manter, 1963 is reported here for the first time from the halfbeak (Beloniformes: Hemiramphidae) species Arrhamphus sclerolepis krefftii (Steindachner), Hyporhamphus australis (Steindachner), H. quoyi (Valenciennes) and H. regularis ardelio (Whitley). Two new species, both infecting trevally (Perciformes: Carangidae) species, are described: T. maryae n. sp. from Alepes apercna Grant and T. henryi n. sp. from Pantolabus radiatus (MacLeay). Complete ITS2 and partial 28S ribosomal DNA data were generated for each of the new taxa. The three species differ from each other by 47-58 base pairs (bp) in the ITS2 rDNA region. Phylogenetic analysis of 28S rDNA supports Tergestia as a reliable generic concept, with our analyses showing that some species of the genus form a well-supported clade to the exclusion of all other fellodistomids for which sequence data are available. PMID- 28866754 TI - Opioid-associated iatrogenic withdrawal in critically ill adult patients: a multicenter prospective observational study. AB - BACKGROUND: Opioids and benzodiazepines are frequently used in the intensive care unit (ICU). Regular use and prolonged exposure to opioids in ICU patients followed by abrupt tapering or cessation may lead to iatrogenic withdrawal syndrome (IWS). IWS is well described in pediatrics, but no prospective study has evaluated this syndrome in adult ICU patients. The objective of this study was to determine the incidence of IWS caused by opioids in a critically ill adult population. This multicenter prospective cohort study was conducted at two level 1 trauma ICUs between February 2015 and September 2015 and included 54 critically ill patients. Participants were eligible if they were 18 years and older, mechanically ventilated and had received more than 72 h of regular intermittent or continuous intravenous infusion of opioids. For each enrolled patient and per each opioid weaning episode, presence of IWS was assessed by a qualified ICU physician or senior resident according to the 5th edition of Diagnostic and Statistical Manual of Mental Disorders criteria for opioid withdrawal. RESULTS: The population consisted mostly of males (74.1%) with a median age of 50 years (25th-75th percentile 38.2-64.5). The median ICU admission APACHE II score was 22 (25th-75th percentile 12.0-28.2). The overall incidence of IWS was 16.7% (95% CI 6-27). The median cumulative opioid dose prior to weaning was higher in patients with IWS (245.7 vs. 169.4 mcg/kg, fentanyl equivalent). Patients with IWS were also exposed to opioids for a longer period of time as compared to patients without IWS (median 151 vs. 125 h). However, these results were not statistically significant. CONCLUSIONS: IWS was occasionally observed in this very specific population of mechanically ventilated, critically ill ICU patients. Further studies are needed to confirm these preliminary results and identify risk factors. PMID- 28866755 TI - Effect of Microcystins on Proto- and Metazooplankton Is More Evident in Artificial Than in Natural Waterbodies. AB - The increasing proliferation of cyanobacterial blooms prolongs the impact of cyanobacteria on aquatic fauna, potentially altering trophic relationships. We hypothesized that any effect of dissolved microcystins (toxins produced by cyanobacteria) on plankton assemblages would be more evident in artificial reservoirs and ponds than in natural ones. The concentrations of dissolved microcystins in the waters we studied ranged widely from 0.07 to 0.81 MUg/L. We showed that the artificial ponds were subjected to more frequent and longer lasting harmful algal blooms. The plankton occurring in them were exposed to significantly higher concentrations of dissolved microcystins than those in natural oxbow lakes. Using a general linear model (GLM) regression, our study identified a significant relationship between dissolved microcystins and both the density and biomass of particular zooplankton groups (ciliates, rotifers, cladocerans, copepods). The density, biomass, and richness of the animal plankton were significantly lower in the artificial ponds than in the natural oxbow lakes. The impact of microcystins and the length of time that they remained in the water caused structural homogenization of the plankton. PMID- 28866757 TI - Levels of amyloid-beta-42 and CSF pressure are directly related in patients with Alzheimer's disease. AB - Experimental data suggest that the cerebrospinal fluid (CSF) dynamic is involved in the clearance of beta-amyloid, a key event in the pathogenesis of Alzheimer's disease (AD). At this regard no evidence still exists in vivo. In this study we explored the relationships between CSF pressure and AD pathology, as measured with CSF core biomarkers. We enrolled 16 patients with probable AD and 21 controls, collecting demographics, clinical data, CSF opening pressure and CSF levels of beta-amyloid-42 fragment (Abeta42), total-tau (t-tau), phosphorylated tau-181 (p-tau), albumin and albumin ratio. Differences between the groups were calculated with non-parametric tests, while correlations among all parameters were separately calculated with Spearman's test in each group. The groups significantly differed in biomarkers' concentration with lower Abeta42, and higher t-tau and p-tau in AD patients. Moreover, CSF pressure was significantly lower in AD group (11.0 +/- 2.8 vs. 13.3 +/- 3.0 mmHg, p < 0.05) and directly correlated with Abeta42 levels (R = 0.512; p < 0.05), but not with other biomarkers or parameters. No significant correlations emerged for biomarkers in control group. AD patients exhibit low CSF pressure whose values are directly and selectively related to CSF Abeta42 levels. This interesting correlation may confirm in vivo the association between CSF dynamic and beta-amyloid metabolism occurring in AD. PMID- 28866756 TI - Unmet Needs in Systemic Sclerosis Understanding and Treatment: the Knowledge Gaps from a Scientist's, Clinician's, and Patient's Perspective. AB - Systemic sclerosis (SSc) is a highly heterogeneous disease caused by a complex molecular circuitry. For decades, clinical and molecular research focused on understanding the primary process of fibrosis. More recently, the inflammatory, immunological and vascular components that precede the actual onset of fibrosis, have become a matter of increasing scientific scrutiny. As a consequence, the field has started to realize that the early identification of this syndrome is crucial for optimal clinical care as well as for understanding its pathology. The cause of SSc cannot be appointed to a single molecular pathway but to a multitude of molecular aberrances in a spatial and temporal matter and on the backbone of the patient's genetic predisposition. These alterations underlie the plethora of signs and symptoms which patients experience and clinicians look for, ultimately culminating in fibrotic features. To solve this complexity, a close interaction among the patient throughout its "journey," the clinician through its clinical assessments and the researcher with its experimental design, seems to be required. In this review, we aimed to highlight the features of SSc through the eyes of these three professionals, all with their own expertise and opinions. With this unique setup, we underscore the importance of investigating the role of environmental factors in the onset and perpetuation of SSc, of focusing on the earliest signs and symptoms preceding fibrosis and on the application of holistic research approaches that include a multitude of potential molecular alterations in time in an unbiased fashion, in the search for a patient-tailored cure. PMID- 28866758 TI - Modelling the Survival Outcomes of Immuno-Oncology Drugs in Economic Evaluations: A Systematic Approach to Data Analysis and Extrapolation. AB - BACKGROUND: New immuno-oncology (I-O) therapies that harness the immune system to fight cancer call for a re-examination of the traditional parametric techniques used to model survival from clinical trial data. More flexible approaches are needed to capture the characteristic I-O pattern of delayed treatment effects and, for a subset of patients, the plateau of long-term survival. OBJECTIVES: Using a systematic approach to data management and analysis, the study assessed the applicability of traditional and flexible approaches and, as a test case of flexible methods, investigated the suitability of restricted cubic splines (RCS) to model progression-free survival (PFS) in I-O therapy. METHODS: The goodness of fit of each survival function was tested on data from the CheckMate 067 trial of monotherapy versus combination therapy (nivolumab/ipilimumab) in metastatic melanoma using visual inspection and statistical tests. Extrapolations were validated using long-term data for ipilimumab. RESULTS: Modelled PFS estimates using traditional methods did not provide a good fit to the Kaplan-Meier (K-M) curve. RCS estimates fit the K-M curves well, particularly for the plateau phase. RCS with six knots provided the best overall fit, but RCS with one knot performed best at the plateau phase and was preferred on the grounds of parsimony. CONCLUSIONS: RCS models represent a valuable addition to the range of flexible approaches available to model survival when assessing the effectiveness and cost effectiveness of I-O therapy. A systematic approach to data analysis is recommended to compare the suitability of different approaches for different diseases and treatment regimens. PMID- 28866759 TI - Essential oils from Algerian species of Mentha as new bio-control agents against phytopathogen strains. AB - Chemical composition and antifungal activity of essential oils of Algerian Mentha species were studied. Chemical compositions of different Mentha species oils (Mentha rotundifolia, M. spicata, M. pulegium, and M. piperita) were investigated by capillary GC and GC/MS, and their antifungal activities were evaluated by means of paper disc diffusion method and minimum inhibitory concentration (MIC) assays. In total, 98 components from all Mentha species were identified. All oils were rich in monoterpene-oxygenated components. In addition, we reported fumigant antifungal activity of Algerian Mentha essential oils against four fungi: Botrytis cinerea, Penicillium expansum, Monilinia laxa, and M. fructigena. All oils demonstrated very good inhibition especially against B. cinerea, M. laxa, and M. fructigena. Both Monilinia fungi were extremely sensitive to all Algerian Mentha oils, which suggests that Mentha essential oils have the potential to be used as bio-pesticides to protect fruit trees, such as apple and pear trees, and provides an alternative to chemical pesticides. PMID- 28866760 TI - Experimental Study on the Flow and Heat Transfer Characteristics of TiO2-Water Nanofluids in a Spirally Fluted Tube. AB - The flow and heat transfer characteristics of TiO2-water nanofluids with different nanoparticle mass fractions in a spirally fluted tube and a smooth tube are experimentally investigated at different Reynolds numbers. The effects of pH values and doses of dispersant agent on the stability of TiO2-water nanofluids are discussed. The effects of nanoparticle mass fractions and Reynolds numbers on Nusselt numbers and frictional resistance coefficients in the spirally fluted tube and the smooth tube are also investigated. It is found that TiO2-water nanofluids in the spirally fluted tube have a larger enhancement than that in the smooth tube. The heat transfer enhancement and the increase in frictional resistance coefficients of TiO2-water nanofluids in the spirally fluted tube and the smooth tube for laminar flow and turbulent flow are compared. It is found that there are a larger increase in heat transfer and a smaller increase in frictional resistance coefficients for turbulent flow than that for laminar flow of TiO2-water nanofluids in the spirally fluted tube. The comprehensive evaluations for the thermo-hydraulic performance of TiO2-water nanofluids in the smooth tube and spirally fluted tube are also discussed. PMID- 28866761 TI - T-protein is present in large excess over the other proteins of the glycine cleavage system in leaves of Arabidopsis. AB - MAIN CONCLUSION: T-protein is present in large excess over the other proteins of the glycine cleavage system in leaves of Arabidopsis and therefore, exerts little control over the photorespiratory pathway. T-protein is the aminomethyltransferase of the glycine cleavage multienzyme system (GCS), also known as the glycine decarboxylase complex, and essential for photorespiration and one-carbon metabolism. Here, we studied what effects varying levels of the GCS T-protein would have on GCS activity, the operation of the photorespiratory pathway, photosynthesis, and plant growth. To this end, we examined Arabidopsis thaliana T-protein overexpression lines with up to threefold higher amounts of leaf T-protein as well as one knockdown mutant with about 5% residual leaf T protein and one knockout mutant. Overexpression did not alter photosynthetic CO2 uptake and plant growth, and the knockout mutation was lethal even in the non photorespiratory environment of air enriched to 1% CO2. Unexpectedly in light of this very low T-protein content, however, the knockdown mutant was able to grow and propagate in normal air and displayed only some minor changes, such as a moderate glycine accumulation in combination with somewhat delayed growth. Neither overexpression nor the knockdown of T-protein altered the amounts of the other three GCS proteins, suggesting that the biosynthesis of the GCS proteins is not synchronized at this level. We also observed that the knockdown causes less T protein mostly in leaf mesophyll cells, but not so much in the vasculature, and discuss this phenomenon in light of the dual involvement of the GCS and hence T protein in plant metabolism. Collectively, this work shows that T-protein is present in large excess over the other proteins of the glycine cleavage system in leaves of Arabidopsis and therefore exerts little control over the photorespiratory pathway. PMID- 28866762 TI - Risk Factors for and Consequences of Substance Use in Post-Conflict Liberia: A Qualitative Study. AB - Substance use has a significant impact on post-conflict populations; however, little is known about this critical issue in Liberia. This study examined the current risk factors for and consequences of substance use in Monrovia, Liberia. In-depth interviews were conducted with 20 substance users and 21 key informants. Findings support that Liberia's civil war played a role in increasing substance use, but also that additional risk factors continue to generate substance use today. This study provides insights into the roles of civil war and additional risk factors for substance use in Liberia. Recommendations for substance use related policies and programs are provided. PMID- 28866763 TI - Bone Health is Maintained, While Fat Mass is Reduced in Pre-pubertal Children with Obesity Participating in a 1-Year Family-Centered Lifestyle Intervention. AB - Diet and physical activity (PA) influence bone health in children. This study tested whether increasing milk and milk products and weight-bearing types of PA favorably changed bone outcomes assessed by dual-energy X-ray absorptiometry (DXA) and bone biomarkers in children with obesity participating in a 1-year family-centered lifestyle intervention. Children were randomized to one of three groups: Control (Ctrl; no intervention), Standard treatment (StnTx: two servings milk and milk products/day; meet PA guidelines plus weight-bearing PA three times/week), or Modified treatment (ModTx: four servings milk and milk products/day; meet PA guidelines plus daily weight-bearing PA). Baseline and 12 month measurements included DXA scans for whole body (WB), lumbar spine (LS), lumbar lateral spine (LLS), and ultra-distal (UD) ulna + radius for bone mineral content (BMC), areal bone mineral density (aBMD) and BMD z-scores. Fat mass index (FMI), fat-free mass index (FFMI), and biomarkers of bone metabolism were assessed. Seventy-eight children 6-8 years old were recruited (mean body mass index for-age z-score: 3.3 +/- 1.2). Compared to baseline, all groups increased BMC of WB, LS, and LLS (p < 0.001), whereas only StnTx increased UD ulna + radius BMC at 12 months (p < 0.05). At 12 months, WB-BMD z-scores were significantly lower in Ctrl (p < 0.05), whereas WB and LLS aBMD increased in StnTx and ModTx (p < 0.001) but not in Ctrl. All groups increased FFMI (p < 0.001), while only Ctrl increased FMI (p < 0.001). Bone biomarkers did not change over time. Participating in a family-centered lifestyle intervention based on Canadian diet and PA guidelines maintained bone health in obese children. PMID- 28866764 TI - L-type calcium channels in exocytosis and endocytosis of chromaffin cells. AB - The coexistence of different subtypes of voltage-dependent calcium channels (VDCC) within the same chromaffin cell (CC) and the marked interspecies variability in the proportion of VDCC subtypes that are present in the plasmalemma of the CCs raises the question on their roles in controlling different physiological functions. Particularly relevant seems to be the role of VDCCs in the regulation of the exocytotic neurotransmitter release process, and its tightly coupled membrane retrieval (endocytosis) process since both are Ca2+ dependent processes. This review is focused on the role of Ca2+ influx through L type VDCC in the regulation of these two processes. It is currently accepted that the different VDCC subtypes (i.e., T, L, N, P/Q, R) contribute to exocytosis proportionally to their density of expression and gating properties. However, the pattern of stimulation defines a preferential role of the different subtypes of VDCC on exocytosis and endocytosis. Thus, L-type channels seem to control catecholamine release induced by prolonged stimuli while fast exocytosis in response to short square depolarizing pulses or action potentials is mediated by Ca2+ entering CCs through P/Q channels. The pattern of stimulation also influences the endocytotic process, and thus, electrophysiological data suggest the sustained Ca2+ entry through slow-inactivating L-type channels could be responsible for the activation of fast endocytosis. PMID- 28866765 TI - The implementation of web-based cognitive rehabilitation in adult cancer survivors: examining participant engagement, attrition and treatment fidelity. AB - PURPOSE: Low engagement and high attrition are common challenges in web-based interventions. Typical measures of engagement reported in the literature are not meaningful for describing participant activity within the intervention and can be misleading. This research aimed to develop a more meaningful method of measuring engagement in an online cognitive rehabilitation program whilst monitoring treatment fidelity. METHODS: A pilot study and randomised controlled trial (RCT) were conducted. Data from 60 participants were analysed from three intervention groups: pilot cancer group, pilot non-cancer group and RCT cancer group. Groups completed the 4-week eReCog program comprised of four online modules. Engagement scores were calculated based on activities completed in each module. Attrition, interaction with the program facilitator and correlations with outcome measures were analysed. RESULTS: Overall engagement in the intervention was high. The non cancer group participated significantly less than the cancer groups (p = < 0.001), whereby the percentage of activity items completed was 92, 87 and 78% in the pilot cancer, RCT cancer and pilot non-cancer groups, respectively. Attrition was higher in the pilot non-cancer group (24%) compared to the pilot cancer group (8%) and the RCT cancer group (16%). Total engagement was correlated with fewer prospective memory problems on instrumental activities of daily living (p = 0.018). CONCLUSIONS: Measuring completed activities in online interventions appears a more meaningful measure of engagement than other conventional methods described in the literature and has the potential to increase treatment fidelity in web-based research. PMID- 28866766 TI - An Human-Computer Interactive Augmented Reality System for Coronary Artery Diagnosis Planning and Training. AB - In order to let the doctor carry on the coronary artery diagnosis and preoperative planning in a more intuitive and more natural way, and to improve the training effect for interns, an augmented reality system for coronary artery diagnosis planning and training (ARS-CADPT) is designed and realized in this paper. At first, a 3D reconstruction algorithm based on computed tomographic (CT) images is proposed to model the coronary artery vessels (CAV). Secondly, the algorithms of static gesture recognition and dynamic gesture spotting and recognition are presented to realize the real-time and friendly human-computer interaction (HCI), which is the characteristic of ARS-CADPT. Thirdly, a Sort First parallel rendering and splicing display subsystem is developed, which greatly expands the capacity of student users. The experimental results show that, with the use of ARS-CADPT, the reconstruction accuracy of CAV model is high, the HCI is natural and fluent, and the visual effect is good. In a word, the system fully meets the application requirement. PMID- 28866767 TI - The PARTHENON Clinical Development Program: the Role of Ticagrelor in Patients with Atherothrombotic Disease. AB - Although the rate of cardiovascular disease (CVD)-related mortality has declined over the last decade, it is still the leading cause of mortality in the USA, accounting for over 1.4 million deaths annually. In addition, total direct (primarily hospital admissions) and indirect costs of CVD in the US is over $316 billion annually and is expected to grow to over $918 billion by 2030. Much of the etiology of CVD is due to atherosclerosis and its thrombotic complications, and central to this is the role of platelets. Atherosclerosis is a systemic disease, with meaningful morbidity and mortality when present in the coronary, cerebral, or major peripheral arteries. The recommended antiplatelet therapy differs based on the vascular bed impacted, with the optimal antiplatelet therapy yet to be defined. The PARTHENON program is a series of completed and ongoing phase III clinical trials investigating the efficacy and safety of ticagrelor in atherosclerotic CVD in comparison with established antiplatelet therapy or placebo. The overall aim of the program is to determine if more potent antiplatelet therapy, with different pharmacology, may reduce cardiovascular events in patients with atherosclerotic disease. PMID- 28866768 TI - Providers' Response to Clinical Decision Support for QT Prolonging Drugs. AB - Commonly used drugs in hospital setting can cause QT prolongation and trigger life-threatening arrhythmias. We evaluate changes in prescribing behavior after the implementation of a clinical decision support system to prevent the use of QT prolonging medications in the hospital setting. We conducted a quasi-experimental study, before and after the implementation of a clinical decision support system integrated in the electronic medical record (QT-alert system). This system detects patients at risk of significant QT prolongation (QTc>500ms) and alerts providers ordering QT prolonging drugs. We reviewed the electronic health record to assess the provider's responses which were classified as "action taken" (QT drug avoided, QT drug changed, other QT drug(s) avoided, ECG monitoring, electrolytes monitoring, QT issue acknowledged, other actions) or "no action taken". Approximately, 15.5% (95/612) of the alerts were followed by a provider's action in the pre-intervention phase compared with 21% (228/1085) in the post intervention phase (p=0.006). The most common type of actions taken during pre intervention phase compared to post-intervention phase were ECG monitoring (8% vs. 13%, p=0.002) and QT issue acknowledgment (2.1% vs. 4.1%, p=0.03). Notably, there was no significant difference for other actions including QT drug avoided (p=0.8), QT drug changed (p=0.06) and other QT drug(s) avoided (p=0.3). Our study demonstrated that the QT alert system prompted a higher proportion of providers to take action on patients at risk of complications. However, the overall impact was modest underscoring the need for educating providers and optimizing clinical decision support to further reduce drug-induced QT prolongation. PMID- 28866769 TI - An Efficient and Reliable Assay for Investigating the Effects of Hypoxia/Anoxia on Drosophila. AB - Stroke is a leading cause of death worldwide. Up to one thousand potential drugs or interventions have been developed to treat stroke, out of which ~160 have gone on to clinical trials. However, none of them has been successful. New insights into the molecular and cellular mechanisms of ischemia-induced injury are needed for discovering new therapeutic targets. Recently, Drosophila has been used to uncover new hypoxia-related genes. In this study, we describe an efficient and reliable assay with a sophisticated apparatus for studying the effects of oxygen deprivation on flies. Using this assay, wild-type flies were exposed to an anoxic environment for varying lengths of time, then the cumulative death rate and mobility recovery were systematically analyzed. We found that anoxia for over one hour caused lethality. The cumulative death rate on day 5 after anoxia was linearly and positively correlated with the duration of anoxia, and reached 50% when the duration was 2.5 h-3 h. We also found that the mobility recovery in normoxia was slow, as the climbing ability remained largely unchanged 4 h-6 h after 2.5-h of anoxia. We suggest that 2.5 h-3 h of anoxia and 4 h-6 h of recovery before mobility analysis are appropriate for future use of the anoxia assay. PMID- 28866770 TI - Anti-coagulant activity of plants: mini review. AB - Medicinal plants have been used for treatment of human ailments since ancient times. Objective of this study is to document the effect of herbal drugs on anticoagulant therapy. The material for this review was taken mostly from PubMed and the Cochrane database of systematic reviews. Some other relevant references were collected from personal database of papers on anti-coagulant properties of plants. Literature review shows that many plants such as Thymus vulgaris, Cyamopsis tetragonoloba taub, Pulmonaria officinalis and Cinnamomum cassia etc have anti-coagulant activity. This review shows that medicinal plants should be prescribed with care to patients on anticoagulant therapy. PMID- 28866771 TI - Atomic force microscopy analysis of extracellular vesicles. AB - Extracellular vesicles (EVs) are small vesicles ensuring transport of molecules between cells and throughout the body. EVs contain cell type-specific signatures and have been proposed as biomarkers in a variety of diseases. Their small size (<1 MUm) and biological and physical functions make them obvious candidates for therapeutic agents in immune therapy, vaccination, regenerative medicine and drug delivery. However, due to the complexity and heterogeneity of their origin and composition, the actual mechanism through which these vesicles exert their functions is still unknown and represents a great biomedical challenge. Moreover, because of their small dimensions, the quantification, size distribution and biophysical characterization of these particles are challenging and still subject to controversy. Here, we address the advantage of atomic force microscopy (AFM), for the characterization of isolated EVs. We review AFM imaging of EVs immobilized on different substrates (mica, glass) to identify the influence of isolation and deposition methods on the size distribution, morphology and mechanical properties of EVs. PMID- 28866773 TI - Chronic Testicular and Groin Pain: Pathway to Relief. AB - The management of patients suffering with chronic testicular and groin pain is very challenging. With increased awareness of men's health, more patients and clinicians are open to talk about this complex problem that affects over 100,000 men/year. The pathogenesis of chronic orchialgia is still not clear, but there are several postulated theories. Treatment options include conservative medical therapy with NSAIDs, antidepressants, anticonvulsants, and narcotics. Surgical options such as targeted microsurgical denervation and microcryoablation can provide permanent durable pain relief. The goal of this article is to review and discuss the management of patients with chronic orchialgia using currently available literature. PMID- 28866772 TI - The gymnastics of epigenomics in rice. AB - Epigenomics is represented by the high-throughput investigations of genome-wide epigenetic alterations, which ultimately dictate genomic, transcriptomic, proteomic and metabolomic dynamism. Rice has been accepted as the global staple crop. As a result, this model crop deserves significant importance in the rapidly emerging field of plant epigenomics. A large number of recently available data reveal the immense flexibility and potential of variable epigenomic landscapes. Such epigenomic impacts and variability are determined by a number of epigenetic regulators and several crucial inheritable epialleles, respectively. This article highlights the correlation of the epigenomic landscape with growth, flowering, reproduction, non-coding RNA-mediated post-transcriptional regulation, transposon mobility and even heterosis in rice. We have also discussed the drastic epigenetic alterations which are reported in rice plants grown from seeds exposed to the extraterrestrial environment. Such abiotic conditions impose stress on the plants leading to epigenomic modifications in a genotype-specific manner. Some significant bioinformatic databases and in silico approaches have also been explained in this article. These softwares provide important interfaces for comparative epigenomics. The discussion concludes with a unified goal of developing epigenome editing to promote biological hacking of the rice epigenome. Such a cutting-edge technology if properly standardized, can integrate genomics and epigenomics together with the generation of high-yielding trait in several cultivars of rice. PMID- 28866774 TI - Purine Biosynthesis Enzymes in Hippocampal Neurons. AB - Despite reports implicating disrupted purine metabolism in causing a wide spectrum of neurological defects, the mechanistic details of purine biosynthesis in neurons are largely unknown. As an initial step in filling that gap, we examined the expression and subcellular distribution of three purine biosynthesis enzymes (PFAS, PAICS and ATIC) in rat hippocampal neurons. Using immunoblotting and high-resolution light and electron microscopic analysis, we find that all three enzymes are broadly distributed in hippocampal neurons with pools of these enzymes associated with mitochondria. These findings suggest a potential link between purine metabolism and mitochondrial function in neurons and provide an impetus for further studies. PMID- 28866776 TI - 1H, 15N, 13C backbone resonance assignments of human phosphoglycerate kinase in a transition state analogue complex with ADP, 3-phosphoglycerate and magnesium trifluoride. AB - Human phosphoglycerate kinase (PGK) is an energy generating glycolytic enzyme that catalyses the transfer of a phosphoryl group from 1,3-bisphosphoglycerate (BPG) to ADP producing 3-phosphoglycerate (3PG) and ATP. PGK is composed of two alpha/beta Rossmann-fold domains linked by a central alpha-helix and the active site is located in the cleft formed between the N-domain which binds BPG or 3PG, and the C-domain which binds the nucleotides ADP or ATP. Domain closure is required to bring the two substrates into close proximity for phosphoryl transfer to occur, however previous structural studies involving a range of native substrates and substrate analogues only yielded open or partly closed PGK complexes. X-ray crystallography using magnesium trifluoride (MgF3-) as a isoelectronic and near-isosteric mimic of the transferring phosphoryl group (PO3 ), together with 3PG and ADP has been successful in trapping human PGK in a fully closed transition state analogue (TSA) complex. In this work we report the 1H, 15N and 13C backbone resonance assignments of human PGK in the solution conformation of the fully closed PGK:3PG:MgF3:ADP TSA complex. Assignments were obtained by heteronuclear multidimensional NMR spectroscopy. In total, 97% of all backbone resonances were assigned in the complex, with 385 out of a possible 399 residues assigned in the 1H-15N TROSY spectrum. Prediction of solution secondary structure from a chemical shift analysis using the TALOS-N webserver is in good agreement with the published X-ray crystal structure of this complex. PMID- 28866777 TI - Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor. AB - A series of tetrahydroisoquinolines functionalized with carbamates is reported here as highly selective ligands on the dopamine D2 receptor. These compounds were selected by means of a molecular modeling study. The studies were carried out in three stages: first an exploratory study was carried out using combined docking techniques and molecular dynamics simulations. According to these results, the bioassays were performed; these experimental studies corroborated the results obtained by molecular modeling. In the last stage of our study, a QTAIM analysis was performed in order to determine the main molecular interactions that stabilize the different ligand-receptor complexes. Our results show that the adequate use of combined simple techniques is a very useful tool to predict the potential affinity of new ligands at dopamine D1 and D2 receptors. In turn the QTAIM studies show that they are very useful to evaluate in detail the molecular interactions that stabilize the different ligand-receptor complexes; such information is crucial for the design of new ligands. PMID- 28866778 TI - Systematic Review of the Costs and Benefits of Prescribed Cannabis-Based Medicines for the Management of Chronic Illness: Lessons from Multiple Sclerosis. AB - INTRODUCTION: Cannabis-based medicines (CBMs) may offer relief from symptoms of disease; however, their additional cost needs to be considered alongside their effectiveness. We sought to review the economic costs and benefits of prescribed CBMs in any chronic illness, and the frameworks used for their economic evaluation. METHODS: A systematic review of eight medical and economic databases, from inception to mid-December 2016, was undertaken. MeSH headings and text words relating to economic costs and benefits, and CBMs were combined. Study quality was assessed using relevant checklists and results were synthesised in narrative form. RESULTS: Of 2514 identified records, ten studies met the eligibility criteria, all for the management of multiple sclerosis (MS). Six contained economic evaluations, four studies reported utility-based quality of life, and one was a willingness-to-pay study. Four of five industry-sponsored cost-utility analyses for MS spasticity reported nabiximols as being cost-effective from a European health system perspective. Incremental cost-effectiveness ratios per quality-adjusted life-year (QALY) gained for these five studies were L49,257 (UK); L10,891 (Wales); ?11,214 (Germany); ?4968 (Italy); and dominant (Spain). Nabiximols for the management of MS spasticity was not associated with statistically significant improvements in EQ-5D scores compared with standard care. Study quality was moderate overall, with limited inclusion of both relevant societal costs and discussions of potential bias. CONCLUSIONS: Prescribed CBMs are a potentially cost-effective add-on treatment for MS spasticity; however, this evidence is uncertain. Further investment in randomised trials with in-built economic evaluations is warranted for a wider range of clinical indications. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Registration Number: CRD42014006370. PMID- 28866775 TI - A comparative review of viral entry and attachment during large and giant dsDNA virus infections. AB - Viruses enter host cells via several mechanisms, including endocytosis, macropinocytosis, and phagocytosis. They can also fuse at the plasma membrane and can spread within the host via cell-to-cell fusion or syncytia. The mechanism used by a given viral strain depends on its external topology and proteome and the type of cell being entered. This comparative review discusses the cellular attachment receptors and entry pathways of dsDNA viruses belonging to the families Adenoviridae, Baculoviridae, Herpesviridae and nucleocytoplasmic large DNA viruses (NCLDVs) belonging to the families Ascoviridae, Asfarviridae, Iridoviridae, Phycodnaviridae, and Poxviridae, and giant viruses belonging to the families Mimiviridae and Marseilleviridae as well as the proposed families Pandoraviridae and Pithoviridae. Although these viruses have several common features (e.g., topology, replication and protein sequence similarities) they utilize different entry pathways to infect wide-range of hosts, including humans, other mammals, invertebrates, fish, protozoa and algae. Similarities and differences between the entry methods used by these virus families are highlighted, with particular emphasis on viral topology and proteins that mediate viral attachment and entry. Cell types that are frequently used to study viral entry are also reviewed, along with other factors that affect virus-host cell interactions. PMID- 28866779 TI - Live attenuated enterovirus vaccine (OPV) is not associated with islet autoimmunity in children with genetic susceptibility to type 1 diabetes: prospective cohort study. AB - AIMS/HYPOTHESIS: Animal and human studies have implied that enterovirus infections may modulate the risk of islet autoimmunity and type 1 diabetes. We set out to assess whether serial administration of live oral poliovirus vaccine (OPV) in early life can influence the initiation of islet autoimmunity in a cohort of genetically predisposed children. METHODS: OPV was administered to 64 children and a further 251 children received inactivated poliovirus vaccine (IPV). The emergence of type 1 diabetes-associated autoantibodies in serum (autoantibodies to GAD, insulinoma-associated protein 2, insulin and islet cells) was monitored during prospective follow-up. Stool and serum samples were collected for enterovirus detection by RT-PCR. RESULTS: Administration of OPV increased enterovirus detected in stool samples from 11.3% to 38.9% (p < 0.001) during the first year of life. During the follow-up (median 11.0 years), at least one autoantibody was detected in 17.2% of children vaccinated with OPV and 19.1% with IPV (p = 0.723). At least two autoantibodies were observed in 3.1% and 6.8% of children, respectively (p = 0.384). CONCLUSIONS/INTERPRETATION: Replication of attenuated poliovirus strains in gut mucosa is not associated with an increased risk of islet autoimmunity. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02961595. PMID- 28866780 TI - Effects of modified biochar on rhizosphere microecology of rice (Oryza sativa L.) grown in As-contaminated soil. AB - Biochar was carbon-rich and generated by high-temperature pyrolysis of biomass under oxygen-limited conditions. Due to the limitations of surface functional groups and the weakness of surface activity in the field of environmental remediation, the raw biochar frequently was chemically modified to improve its properties with a new performance. In this study, a kind of high-efficiency and low-cost amino biochar modified by nano zero-valent iron (ABC/NZVI) was synthesized and applied to paddy soil contaminated with arsenic (As). Dynamic changes of soil properties, arsenic speciations and rhizosphere microbial communities have been investigated over the whole growth period of rice plants. Pot experiments revealed that the ABC/NZVI could decrease the arsenic concentration in rice straw by 47.9% and increase the content of nitrogen in rice straw by 47.2%. Proportion of Geobacter in soil with ABC/NZVI treatment increased by 175% in tillering period; while Nitrososphaera decreased by 61 and 20% in tillering and maturity, respectively, compared to that of control. ABC/NZVI promotes arsenic immobilization in rhizosphere soil and precipitation on root surface and reduces arsenic accumulation in rice. At the same time, ABC/NZVI would inhibit Nitrososphaera which is related to ammonia oxidation process, and it would have a promising potential as soil amendment to reduce nitrogen loss probably. PMID- 28866781 TI - Dispositional use of emotion regulation strategies and resting-state cortico limbic functional connectivity. AB - Neuroimaging functional connectivity (FC) analyses have shown that the negative coupling between the amygdala and cortical regions is linked to better emotion regulation in experimental settings. Nevertheless, no studies have examined the association between resting-state cortico-amygdalar FC and the dispositional use of emotion regulation strategies. We aim at assessing the relationship between the resting-state FC patterns of two different amygdala territories, with different functions in the emotion response process, and trait-like measures of cognitive reappraisal and expressive suppression. Forty-eight healthy controls completed the Emotion Regulation Questionnaire (ERQ) and underwent a resting state functional magnetic resonance imaging acquisition. FC maps of basolateral and centromedial amygdala (BLA/CMA) with different cortical areas were estimated with a seed-based approach, and were then correlated with reappraisal and suppression scores from the ERQ. FC between left BLA and left insula and right BLA and the supplementary motor area (SMA) correlated inversely with reappraisal scores. Conversely, FC between left BLA and the dorsal anterior cingulate cortex correlated directly with suppression scores. Finally, FC between left CMA and the SMA was inversely correlated with suppression. Top-down regulation from the SMA seems to account for the dispositional use of both reappraisal and suppression depending on the specific amygdala nucleus being modulated. In addition, modulation of amygdala activity from cingulate and insular cortices seem to also account for the habitual use of the different emotion regulation strategies. PMID- 28866782 TI - Can adnexal torsion be predicted by measuring plasma heat shock protein 70 level? An experimental study. AB - OBJECTIVE: To investigate the effect of adnexal torsion on the plasma heat shock protein 70 level and to determine whether plasma heat shock protein 70 can be used in the adnexal torsion diagnosis. MATERIALS AND METHODS: Twenty-one nulligravid 3-month-old female Wistar albino rats were randomly and equally allocated into three groups: study group (ovarian torsion) (n = 7), laparotomy group (sham operation) (n = 7) and control group (received no special treatment) (n = 7). Ovarian torsion model was created by twisting the right adnexa two times around its pedicle and fixing over the lateral pelvis with 6.0 polyglactin absorbable surgical suture. Blood was sampled before and 12 h after operation to assess plasma heat shock protein 70 level. RESULTS: In the study group, the mean plasma heat shock protein 70 level was significantly higher than that in the laparotomy and control groups (1.75 +/- 0.25), (1.16 +/- 0.99), (1.19 +/- 0.11) ng/ml, respectively, P = 0.001), following 12 h of ovarian torsion. CONCLUSION: A significant increase in plasma heat shock protein 70 level in the study group indicates that plasma heat shock protein 70 level could be used as a serum marker in the early detection of adnexal torsion. However, further clinical and experimental studies of a larger size are required. PMID- 28866783 TI - What is the impact of stromal microinvasion on oncologic outcomes in borderline ovarian tumors? A multicenter case-control study. AB - PURPOSE: To investigate clinicopathological characteristics and oncological outcome of women with microinvasive BOTs. METHODS: A retrospective multicenter case-control study was conducted on 902 patients with BOT, who underwent surgery from January 2002 to December 2015 at six participating gynecologic oncology centers from Turkey. Among 902 patients, 69 had microinvasive BOT. For every patient with microinvasive BOT, two controls were randomly selected from another database based on decade of age and stage of disease at diagnosis. The clinical pathological characteristics and oncological outcomes were compared between BOT patients with and without stromal microinvasion. Risk factors for poor oncological outcomes were investigated in a multivariate analysis model. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan Meier method. RESULTS: Patients with microinvasive BOT had a significantly higher rate of recurrence than patients without microinvasive BOT (17.4 vs 7.8%, OR 3.55, %95 CI 1.091-11.59, p = 0.03). Stage at diagnosis (stage I versus II/III) and type of surgery (cystectomy versus others) were found as other significant prognostic factors for recurrence in multivariate analysis (OR 8.63, %95 CI 2.48 29.9, p = 0.001 and OR 19.4, %95 CI 3.59-105.6, p = 0.001, respectively). Stromal microinvasion was found as a prognostic factor for significantly shorter DFS (26.7 vs 11.9 months, p = 0.031, log rank). However, there was no significant difference in OS between two groups (p = 0.99, log rank). CONCLUSION: Stromal microinvasion is significantly associated with decreased DFS. In addition, our study confirms that the risk of recurrence is higher in patients with microinvasive BOT. PMID- 28866784 TI - An outbreak in intravenous drug users due to USA300 Latin-American variant community-acquired methicillin-resistant Staphylococcus aureus in France as early as 2007. AB - Intravenous drug users are at increased risk of Staphylococcus aureus infections. Most cases are related to clones prevalent in the community. We report an outbreak of community-acquired methicillin-resistant Staphylococcus aureus infections that occurred from 2007 to 2009 in intravenous drug users and their close contacts in Northwestern France. Clinical and molecular investigations suggested that the clones were more similar than those usually isolated in the American continent although none of the patients traveled abroad or had contact with individuals who had traveled to the Americas. Then, a retrospective whole genome sequencing and phylogenetic analyses demonstrated that the strains isolated from the first case belong to the USA300 Latin-American variant clone, based on the absence of arginine catabolic mobile element (ACME), and the presence of copper and mercury resistance mobile element (COMER), a distinctive feature of the South American variant. Our study shows genetic evidence for introduction of this clone as early as 2007 in France. This report also illustrates the importance of genome sequencing to finely characterize and monitor the emergence of unexpected S. aureus clones among high-risk populations, especially when living in promiscuity. PMID- 28866785 TI - Preparation of PPy-Coated MnO2 Hybrid Micromaterials and Their Improved Cyclic Performance as Anode for Lithium-Ion Batteries. AB - MnO2@PPy core-shell micromaterials are prepared by chemical polymerization of pyrrole on the MnO2 surface. The polypyrrole (PPy) is formed as a homogeneous organic shell on the MnO2 surface. The thickness of PPy shell can be adjusted by the usage of pyrrole. The analysis of SEM, FT-IR, X-ray photoelectron spectroscopy (XPS), thermo-gravimetric analysis (TGA), and XRD are used to confirm the formation of PPy shell. Galvanostatic cell cycling and electrochemical impedance spectroscopy (EIS) are used to evaluate the electrochemical performance as anode for lithium-ion batteries. The results show that after formation of MnO2@PPy core-shell micromaterials, the cyclic performance as anode for lithium-ion batteries is improved. Fifty microliters of PPy-coated caddice-clew-like MnO2 has the best cyclic performances as has 620 mAh g-1 discharge specific capacities after 300 cycles. As a comparison, the discharge specific capacity of bare MnO2 materials falls to below 200 mAh g-1 after 10 cycles. The improved lithium-storage cyclic stability of the MnO2@PPy samples attributes to the core-shell hybrid structure which can buffer the structural expansion and contraction of MnO2 caused by the repeated embedding and disengagement of Li ions and can prevent the pulverization of MnO2. This experiment provides an effective way to mitigate the problem of capacity fading of the transition metal oxide materials as anode materials for (lithium-ion batteries) LIBs. PMID- 28866786 TI - A pitfall of thoracoscopic thymectomy: a case with intraoperative and postoperative complications. AB - We have reported the usefulness of the subxiphoid approach in thymectomy. However, such a new operation method may have unknown complications that rarely occur. Surgeons cannot completely avoid intraoperative and postoperative complications. We report a case of intraoperative injury of the orifice of the left internal thoracic vein flowing to the left brachiocephalic vein and postoperative pericarditis following video-assisted thoracic surgery (VATS) thymectomy. The innominate vein has been considered to be the vessel that is most frequently injured especially at the orifice of the thymic veins. We also suggest that the orifice of the left internal thoracic vein is the second dangerous location that requires special care. In addition, postoperative pericarditis occurred in this patient. Pericardial drainage was necessary. No additional complications have been found in the 9 months since the operation. Though VATS thymectomy using the subxiphoid approach is a safe and less-invasive operation, intraoperative and postoperative complications were possible to be occurred. PMID- 28866787 TI - Iron metabolism and its detection through MRI in parkinsonian disorders: a systematic review. AB - Iron deposition in the brain normally increase with age, but its accumulation in certain regions is observed in a number of neurodegenerative diseases including Parkinson's disease (PD) and other parkinsonisms. Whether iron overload leads to dopaminergic neuronal death in the SN of PD patients or is instead simply a by product of the neurodegenerative progression is still yet to be ascertained. Magnetic resonance imaging (MRI) is a non-invasive method to assess brain iron content in PD patients. In PD, accurate radiologic visualization of basal ganglia is required. Deep gray matter nuclei are well presented in T2- and T2*-weighted images. T2*-weighted gradient-echo (GRE) is widely used to assess calcifications and also for iron detection. On the other hand, new methods specifically designed for detecting iron-induced susceptibility differences can be further improved by sequences like susceptibility-weighted imaging (SWI). In the present review, we aim to summarize the available data on brain iron deposition in PD. PMID- 28866788 TI - Enrichment of putatively damaging rare variants in the DYX2 locus and the reading related genes CCDC136 and FLNC. AB - Eleven loci with prior evidence for association with reading and language phenotypes were sequenced in 96 unrelated subjects with significant impairment in reading performance drawn from the Colorado Learning Disability Research Center collection. Out of 148 total individual missense variants identified, the chromosome 7 genes CCDC136 and FLNC contained 19. In addition, a region corresponding to the well-known DYX2 locus for RD contained 74 missense variants. Both allele sets were filtered for a minor allele frequency <=0.01 and high Polyphen-2 scores. To determine if observations of these alleles are occurring more frequently in our cases than expected by chance in aggregate, counts from our sample were compared to the number of observations in the European subset of the 1000 Genomes Project using Fisher's exact test. Significant P values were achieved for both CCDC136/FLNC (P = 0.0098) and the DYX2 locus (P = 0.012). Taken together, this evidence further supports the influence of these regions on reading performance. These results also support the influence of rare variants in reading disability. PMID- 28866789 TI - Population data and forensic efficiency of 21 autosomal STR loci included in AGCU EX22 amplification system in the Wanzhou Han population. AB - Autosomal short tandem repeats (STRs), widely distributed in the whole human genome, play an important role in personal identification and parentage testing. In this study, the allele frequencies and forensic efficiency parameters of 21 autosomal STR loci included in the AGCU EX22 kit were obtained from 433 Chinese Han individuals residing in the Wanzhou District in the north of Chongqing Municipality, Southwest China. No deviation from Hardy-Weinberg equilibrium was observed in all of the 21 STR loci. A total of 241 alleles were observed with allele frequencies ranging from 0.0011 to 0.5418. The cumulative power of discrimination and the cumulative probability of exclusion were 0.9999999999999999999999999 and 0.999999996, respectively. The results of genetic distance, neighbor-joining tree, principal component plots, and multidimensional scaling analysis revealed that the Wanzhou Han had more genetic differences when compared with Kazakh and Uyghur populations from Xinjiang than other included reference populations. In summary, the results in forensic characteristic analyses indicated that the 21 STRs are highly polymorphic and can be served as a useful tool in forensic routine practices. The population comparison indicated that close geographic or ethnic origin groups had a strong genetic affinity with each other. PMID- 28866790 TI - Weekend surgical handover enhances early management of acute clinical changes using a red flag system. AB - INTRODUCTION: Recent implementation of the European Working Time Directive in Ireland has resulted in a change from thetraditional model of patient care to a system characterised by shift work among clinicians. Effective handover ofpatient information is essential for transfer of responsibility between clinicians and maintaining continuity of care. The weekend has been identified as a particularly vulnerable transition of patient care. AIMS AND METHODS: Our study aims to determine if implementing a formal face-to-face handover accompanied by an electronictemplate in our surgical department can improve the number of adverse events reported back to the primary teamafter a weekend on call. Data was collected over 12 weekends between February and May 2016. A list of adverseevents was established, and during an initial observation period of 6 weeks, we documented the number of adverseevents that were informally handed over. A 6-week intervention was then performed, involving a formal face-to-facehandover on Monday morning supported by an electronic patient census using a red-flag system to highlightpatients who experienced an adverse event over the weekend. RESULTS: Our results showed the mean number of adverse events recorded pre-intervention was 3.17 +/- 0.6 over the 6-week period. Following the introduction of weekend face-to-face handover, there was 147% increase in the number of adverse events recorded with a mean of 7.83 +/- 1.2. CONCLUSION: The introduction of a formal face-to-face weekend handover with a red-flag system resulted in increased reporting of patient adverse events, allowing earlier recognition and management. PMID- 28866792 TI - Principles of Need and the Aggregation Thesis. AB - Principles of need are constantly referred to in health care priority setting. The common denominator for any principle of need is that it will ascribe some kind of special normative weight to people being worse off. However, this common ground does not answer the question how a plausible principle of need should relate to the aggregation of benefits across individuals. Principles of need are sometimes stated as being incompatible with aggregation and sometimes characterized as accepting aggregation in much the same way as utilitarians do. In this paper we argue that if one wants to take principles of need seriously both of these positions have unreasonable implications. We then characterize and defend a principle of need consisting of sufficientarian elements as well as prioritarian which avoids these unreasonable implications. PMID- 28866791 TI - Comparing perceived effectiveness of FDA-proposed cigarette packaging graphic health warnings between sexual and gender minorities and heterosexual adults. AB - BACKGROUND: In 2012, the U.S. Food and Drug Administration proposed nine graphic health warnings (GHWs) on cigarette packaging that were rated equally effective across racial/ethnic, education, or income groups of adult smokers. However, data on GHW effectiveness among sexual and gender minority (SGM) adults, who have higher smoking prevalence, are currently lacking. This study analyzed whether perceived effectiveness of GHWs differed by gender and sexual orientation. METHODS: Data came from a randomized experiment among 1,200 adults with an oversample from low socioeconomic status groups, conducted between 2013 and 2014 in three Massachusetts communities. Participants viewed and rated the effectiveness of nine GHWs. Mixed effects regression models predicted perceived effectiveness with gender and sexual orientation, adjusting for repeated measurements, GHWs viewed, age, race, ethnicity, smoking status, and health status. RESULTS: Female heterosexuals rated GHWs as more effective than male heterosexual, lesbian, and transgender and other gender respondents. There was no significant difference between female and male heterosexuals versus gay, male bisexual, or female bisexual respondents. Differences by gender and sexual orientation were consistent across all nine GHWs. Significant correlates of higher perceived effectiveness included certain GHWs, older age, being African American (vs white), being Hispanic (vs non-Hispanic), having less than high school education (vs associate degree or higher), and being current smokers (vs non-smokers). CONCLUSIONS: Perceived effectiveness of GHWs was lower in certain SGM groups. We recommend further studies to understand the underlying mechanisms for these findings and investments in research and policy to communicate anti smoking messages more effectively to SGM populations. PMID- 28866793 TI - Accuracy of preoperative MRI to assess lateral neck metastases in papillary thyroid carcinoma. AB - Primary treatment of papillary thyroid carcinoma (PTC) with lateral lymph node metastasis is surgery, but the extent of lateral neck dissection remains undefined. Preoperative imaging is used to guide the extent of surgery, although its sensitivity and specificity for defining the number and level of affected lymph nodes on the lateral neck is relatively modest. Our aim was to assess the role of preoperative magnetic resonance imaging (MRI) in predicting the requisite levels of neck dissection in patients with regionally metastatic PTC, with a focus on Levels II and V. All patients with PTC and lateral neck metastasis who had undergone neck dissection at the Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland from 2013 to 2016 and had a preoperative MRI available were retrospectively reviewed. A head and neck radiologist re-evaluated all MRIs, and the imaging findings were compared with histopathology after neck dissection. In the cohort of 39 patients, preoperative MRI showed concordance with histopathology for Levels II and V as follows: sensitivity of 94 and 67%, specificity of 20 and 91%, positive predictive value of 56 and 75%, and negative predictive value of 75 and 87%, respectively. In PTC, MRI demonstrated fairly high specificity and negative predictive value for Level V metastasis, and future studies are needed to verify our results to omit prophylactic dissection of this level. Routine dissection of Level II in patients with regionally metastatic PTC needs to be considered, as MRI showed low specificity. PMID- 28866794 TI - Predictors for hilar/intrapulmonary lymph node metastasis in discrete type of clinical N1 non-small cell lung cancer. AB - OBJECTIVE: Accurate preoperative evaluation of lymph nodes can provide optimal treatment for patients. However, in patients with clinical N1 disease (cN1) non small cell lung cancer (NSCLC), no suitable predictor has been identified for hilar/intrapulmonary lymph node metastasis (pathological N1 disease; pN1). The purpose of this study was to identify pN1 in cN1 NSCLC patients. METHODS: We retrospectively reviewed the clinicoradiological features of 109 patients with a discrete type of cN1 NSCLC who had undergone complete resection at our institution from 2004 to 2015. The association between clinicoradiological variables and nodal status was analyzed to identify predictors for pN1. RESULTS: The cohort consisted of 77 males and 32 females, ranging in age from 39 to 84 years. The breakdown by pathological N category was 40 (37%) pN0, 41 (38%) pN1, and 28 (25%) pN2 patients. Maximum lymph node diameter was identified as a significant predictor for pN1, with an odds ratio of 1.25 (P = 0.010). When limited to 63 patients who underwent positron emission tomography (FDG-PET) at our institution, the maximum standardized uptake value (SUVmax) of the lymph node was an independent predictor, with an odds ratio of 1.91 with logistic regression analysis (P = 0.004). The size of lymph node and the SUVmax were significant factors for pN1, with optimal cut-off values of 13 mm and 4.28, respectively. CONCLUSIONS: Among the patients with cN1, maximum lymph node size and SUVmax of the FDG-PET were significant predictors for pN1. PMID- 28866795 TI - On the Processes Underlying the Relationship Between Alexithymia and Gambling Severity. AB - A great number of individuals with persistent problematic gambling behavior exhibit alexithymic tendencies, greater impulsivity, impaired working memory and poor mood. However, the relationship between these cognitive, affective and personality factors in problem gambling remains poorly understood. Our aim was to investigate multiple pathways of the alexithymia and problem gambling relationship. One hundred and six male subjects with different levels of gambling problem severity were recruited. Alexithymia, impulsivity and verbal working memory were evaluated, and their relationships to disordered gambling was examined by means of a path analysis. Results indicate that alexithymia is related to an increase in the severity of gambling indirectly, i.e., through distress severity. In addition, a rise of alexithymic tendencies was also associated with problem gambling severity through enhanced impulsivity that directly increased distress. Working memory capacity failed to significantly impact our path model. Overall, our findings contribute a new finding to the literature by highlighting the importance of alexithymia, in addition to impulsivity, in the understanding of gambling problem severity and its clinical course. PMID- 28866796 TI - The Role of Family for Youth Friendships: Examining a Social Anxiety Mechanism. AB - The quality of family relationships and youth friendships are intricately linked. Previous studies have examined different mechanisms of family-peer linkage, but few have examined social anxiety. The present study examined whether parental rejection and family climate predicted changes in youth social anxiety, which in turn predicted changes in friendship quality and loneliness. Possible bidirectional associations also were examined. Data for mothers, fathers, and youth (M age at Time 1 = 11.27; 52.3% were female) from 687 two-parent households over three time points are presented. Results from autoregressive, cross-lagged analyses revealed that father rejection (not mother rejection or family climate) at Time 1 (Fall of 6th Grade) predicted increased youth social anxiety at Time 2 (Spring of 7th Grade), which in turn, predicted increased loneliness at Time 3 (Spring of 8th Grade). The indirect effect of father rejection on loneliness was statistically significant. Mother rejection, father rejection, and a poor family climate were associated with decreased friendship quality and increased loneliness over time. Finally, there was some evidence of transactional associations between father rejection and youth social anxiety as well as between social anxiety and loneliness. This study's findings underscore the important role of fathers in youth social anxiety and subsequent social adjustment. PMID- 28866798 TI - Development of an Amperometric Biosensor Platform for the Combined Determination of L-Malic, Fumaric, and L-Aspartic Acid. AB - Three amperometric biosensors have been developed for the detection of L-malic acid, fumaric acid, and L -aspartic acid, all based on the combination of a malate-specific dehydrogenase (MDH, EC 1.1.1.37) and diaphorase (DIA, EC 1.8.1.4). The stepwise expansion of the malate platform with the enzymes fumarate hydratase (FH, EC 4.2.1.2) and aspartate ammonia-lyase (ASPA, EC 4.3.1.1) resulted in multi-enzyme reaction cascades and, thus, augmentation of the substrate spectrum of the sensors. Electrochemical measurements were carried out in presence of the cofactor beta-nicotinamide adenine dinucleotide (NAD+) and the redox mediator hexacyanoferrate (III) (HCFIII). The amperometric detection is mediated by oxidation of hexacyanoferrate (II) (HCFII) at an applied potential of + 0.3 V vs. Ag/AgCl. For each biosensor, optimum working conditions were defined by adjustment of cofactor concentrations, buffer pH, and immobilization procedure. Under these improved conditions, amperometric responses were linear up to 3.0 mM for L-malate and fumarate, respectively, with a corresponding sensitivity of 0.7 MUA mM-1 (L-malate biosensor) and 0.4 MUA mM-1 (fumarate biosensor). The L-aspartate detection system displayed a linear range of 1.0-10.0 mM with a sensitivity of 0.09 MUA mM-1. The sensor characteristics suggest that the developed platform provides a promising method for the detection and differentiation of the three substrates. PMID- 28866797 TI - Susceptibility of Euseius concordis (Mesostigmata: Phytoseiidae) to pesticides used in citrus production systems. AB - Euseius concordis (Chant) is an important predatory mite found in citrus orchards. The toxicity of 19 pesticides used in citrus orchards on biological and population parameters of this mite was assessed. Our results indicated that formetanate hydrochloride, dimethoate and phosmet were highly harmful (100% mortality) to E. concordis. Carbosulfan, diflubenzuron, fenpropathrin, gamma cyhalothrin, imidacloprid, lambda-cyhalothrin, lambda-cyhalothrin + thiamethoxam, mineral and vegetable oils, spinosad and thiamethoxam reduced the female's survival and/or fecundity, and were moderately harmful to E. concordis. Besides the acute toxicity, carbosulfan and formetanate hydrochloride were highly persistent [>30 days after spraying (DAS)]; dimethoate was moderately persistent (16-30 DAS); spinosad, gamma-cyhalothrin, lambda-cyhalothrin and lambda cyhalothrin + thiamethoxam were slightly persistent (5-15 DAS); and the other pesticides were considered to be short-lived (<5 DAS). All compounds except lambda-cyhalothrin and thiamethoxam increased the pre-oviposition period in the female offspring. Carbosulfan, deltamethrin, diflubenzuron, etofenprox, fenpropathrin, gamma-cyhalothrin, mineral and vegetable oils, pyriproxyfen and tebufenozide reduced offspring fecundity, whereas thiamethoxam increased the fecundity. Mineral and vegetable oils reduced female longevity of the predator mite. Regarding population effects, imidacloprid, lambda-cyhalothrin, lambda cyhalothrin + thiamethoxam and thiamethoxam led to an increase in net reproductive rate (R o ), intrinsic rate of increase (r), and finite rate of increase (lambda) of E. concordis. Diflubenzuron, etofenprox, and mineral and vegetable oils reduced R o , r and lambda. All pesticides except beta cypermethrin, fenpropathrin and imidacloprid reduced the mean generation time (T) of the predator. Therefore, semi-field and field studies are needed to assess the compatibility of these compounds with E. concordis before adoption in IPM programs. PMID- 28866799 TI - Intranasal Administration of TAT-Conjugated Lipid Nanocarriers Loading GDNF for Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder (ND), characterized by the loss of dopaminergic neurons, microglial activation, and neuroinflammation. Current available treatments in clinical practice cannot halt the progression of the disease. During the last few years, growth factors (GFs) have been raised as a promising therapeutic approach to address the underlying neurodegenerative process. Among others, glial cell-derived neurotrophic factor (GDNF) is a widely studied GF for PD. However, its clinical use is limited due to its short half life, rapid degradation rate, and difficulties in crossing the blood-brain barrier (BBB). Lately, intranasal administration has appeared as an alternative non-invasive way to bypass the BBB and target drugs directly to the central nervous system (CNS). Thus, the aim of this work was to develop a novel nanoformulation to enhance brain targeting in PD through nasal administration. For that purpose, GDNF was encapsulated into chitosan (CS)-coated nanostructured lipid carriers, with the surface modified with transactivator of transcription (TAT) peptide (CS-nanostructured lipid carrier (NLC)-TAT-GDNF). After the physiochemical characterization of nanoparticles, the in vivo study was performed by intranasal administration to a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The CS-NLC TAT-GDNF-treated group revealed motor recovery which was confirmed with immunohistochemistry studies, showing the highest number of tyrosine hydroxylase (TH+) fibers in the striatum and TH+ neuron levels in the substantia nigra. Moreover, ionizing calcium-binding adaptor molecule 1 immunohistochemistry was performed, revealing that CS-NLC-TAT-GDNF acts as a modulator on microglia activation, obtaining values similar to control. Therefore, it may be concluded that the intranasal administration of CS-NLC-TAT-GDNF may represent a promising therapy for PD treatment. PMID- 28866800 TI - Chronologic Age at Hospitalization for Respiratory Syncytial Virus Among Preterm and Term Infants in the United States. AB - INTRODUCTION: Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States, and the risk for RSV hospitalizations is greater for infants born preterm. Recent studies in preterm and term infants have shown that RSV hospitalization rates vary considerably depending on infant chronologic age. This study sought to aggregate the data available from published literature and from nationally representative databases of US infant hospitalizations to generate a composite description of the effect of young chronologic age on RSV hospitalizations among US preterm and term infants by individual month of age. METHODS: Data describing the relative incidence of RSV hospitalizations by individual month of chronologic age during the first year of life were obtained from recently published studies, the 2006 2011 National Inpatient Sample databases, and the 2006 and 2009 Kids Inpatient Databases. RESULTS: All data sources showed that >=20% of infant RSV hospitalizations occurred in the second month of life and >50% and >75% of RSV hospitalizations were observed during the first 3 and 6 months of life, respectively. These findings were consistent for both preterm and term infants. CONCLUSION: Data from multiple sources demonstrate that the greatest risk of RSV hospitalization occurs during the first 6 months of life among US preterm and term infants. Strategies to prevent infant RSV hospitalizations should be targeted to infants during the first months of life. FUNDING: AstraZeneca. PMID- 28866801 TI - Recent advances in assays for the fragile X-related disorders. AB - The fragile X-related disorders are a group of three clinical conditions resulting from the instability of a CGG-repeat tract at the 5' end of the FMR1 transcript. Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X associated primary ovarian insufficiency (FXPOI) are disorders seen in carriers of FMR1 alleles with 55-200 repeats. Female carriers of these premutation (PM) alleles are also at risk of having a child who has an FMR1 allele with >200 repeats. Most of these full mutation (FM) alleles are epigenetically silenced resulting in a deficit of the FMR1 gene product, FMRP. This results in fragile X Syndrome (FXS), the most common heritable cause of intellectual disability and autism. The diagnosis and study of these disorders is challenging, in part because the detection of alleles with large repeat numbers has, until recently, been either time-consuming or unreliable. This problem is compounded by the mosaicism for repeat length and/or DNA methylation that is frequently seen in PM and FM carriers. Furthermore, since AGG interruptions in the repeat tract affect the risk that a FM allele will be maternally transmitted, the ability to accurately detect these interruptions in female PM carriers is an additional challenge that must be met. This review will discuss some of the pros and cons of some recently described assays for these disorders, including those that detect FMRP levels directly, as well as emerging technologies that promise to improve the diagnosis of these conditions and to be useful in both basic and translational research settings. PMID- 28866802 TI - Effects of a High-Fat Diet on Adipose Tissue CD8+ T Cells in Young vs. Adult Mice. AB - T cells are involved in chronic inflammation of adipose tissue in obese conditions. However, the impact of age on the adipose T cells remains unknown. In this study, we investigated T cells in the white adipose tissue of young and adult mice. Obesity was induced in the mice using a high-fat diet (HFD) for 14 weeks. The young mice were fed an HFD at 3 weeks old, and adult mice were fed the HFD at 12 weeks old. Relative to adult mice, the young mice gained less fat and exhibited better glucose tolerance. Their adipose tissue contained more CD8+ T cells and higher levels of pro-inflammatory cytokines. Young mice showed a larger increase in CD4+ T cells. The young and adult mice showed similar insulin tolerance. HFD reduced the colon muscle layer, which was more obvious in the young mice. These data suggested that young and adult mice exhibit different responses to an HFD in terms of adipose tissue, glucose tolerance, and the colon muscle layer. The increase in CD8+ T cells and CD4+ T cells, together with higher levels of pro-inflammatory cytokines, suggested elevated inflammation in the presence of less fat gain in the young mice, which was unexpected. The significance of this inflammation remains unknown. We propose that inflammation might inhibit energy storage in the adipose tissue to provide more energy to the lean body mass in favor of growth in the young mice. The present study provides another example of the beneficial effect of inflammation in physiological conditions. PMID- 28866804 TI - Medical epistemology. PMID- 28866803 TI - Personalized ex vivo multiple peptide enrichment and detection of T cells reactive to multiple tumor-associated antigens in prostate cancer patients. AB - Personalized peptide vaccination is a promising immunotherapeutic approach in prostate cancer (PCa). We therefore examined whether an approach, utilizing personalized multiple peptide-mediated ex vivo enrichment with effector T cells reactive to multiple tumor-associated antigens (TAAs), could be employed as a basis for the development of T cell immunotherapy of PCa. In this study, we used the non-adherent fraction (lymphocytes) of cryopreserved peripheral blood mononuclear cells from a leukapheretic product of biochemically recurrent (BR, n = 14) and metastatic hormone-refractory (HR, n = 12) PCa patients. The lymphocytes were primed with a pool of mixed overlapping peptides derived from 6 PCa TAAs-PSA, PAP, NY-ESO-1, MAGE-A1, MAGE-A3 and MAGE-A4. After 2 weeks of culture, the cells were stimulated with the peptides and T cell reactivity determined by externalization of CD107a. No TAAs-reactive effector T cells were detected in the patient's lymphocytes after their reconstitution. However, following their priming with the TAAs-derived peptides and 2-week culturing, the lymphocytes became enriched with polyclonal TAAs-reactive effector CD8+ T cells in 8 out of 14 BR and 5 out of 12 HR patients. No such reactive CD8+ T cells were detected in cultured lymphocytes without the peptide priming. Stimulation of the responding cultures with peptides derived from individual TAAs revealed a unique repertoire of the reactive CD8+ T cells. Our strategy revealed that the personalized multiple peptide-mediated ex vivo enrichment with multiple TAAs reactive T cells in the PCa patient's lymphocytes is a viable approach for development of T cell immunotherapy of PCa. PMID- 28866805 TI - Development of a tool to aid the radiologic technologist using augmented reality and computer vision. AB - This technical innovation describes the development of a novel device to aid technologists in reducing exposure variation and repeat imaging in computed and digital radiography. The device consists of a color video and depth camera in combination with proprietary software and user interface. A monitor in the x-ray control room displays the position of the patient in real time with respect to automatic exposure control chambers and image receptor area. The thickness of the body part of interest is automatically displayed along with a motion indicator for the examined body part. The aim is to provide an automatic measurement of patient thickness to set the x-ray technique and to assist the technologist in detecting errors in positioning and motion before the patient is exposed. The device has the potential to reduce the incidence of repeat imaging by addressing problems technologists encounter daily during the acquisition of radiographs. PMID- 28866806 TI - Potential of Mangrove-Associated Endophytic Fungi for Production of Carbohydrolases with High Saccharification Efficiency. AB - The endophytic fungi represent a potential source of microorganisms for enzyme production. However, there have been only few studies exploiting their potential for the production of enzymes of industrial interest, such as the (hemi)cellulolytic enzymatic cocktail required in the hydrolysis of lignocellulosic biomass. Here, a collection of endophytic fungi isolated from mangrove tropical forests was evaluated for the production of carbohydrolases and performance on the hydrolysis of cellulose. For that, 41 endophytic strains were initially screened using a plate assay containing crystalline cellulose as the sole carbon source and the selected strains were cultivated under solid-state fermentation for endoglucanase, beta-glucosidase, and xylanase enzyme quantification. The hydrolysis of a cellulosic material with the enzymes from endophytic strains of the Aspergillus genus resulted in glucose and conversion values more than twofold higher than the reference strains (Aspergillus niger F12 and Trichoderma reesei Rut-C30). Particularly, the enzymes from strains A. niger 56 (3) and A. awamori 82 (4) showed a distinguished saccharification performance, reaching cellulose conversion values of about 35% after 24 h. Linking hydrolysis performance to the screening steps played an important role towards finding potential fungal strains for producing enzymatic cocktails with high saccharification efficiency. These results indicate the potential of mangrove associated endophytic fungi for production of carbohydrolases with efficient performance in the hydrolysis of biomass, thus contributing to the implementation of future biorefineries. PMID- 28866807 TI - Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin. AB - AIMS: Inverse relationships have been described between the largely genetically determined levels of serum/plasma lipoprotein(a) [Lp(a)], type 2 diabetes (T2D) and fasting insulin. Here, we aimed to evaluate the nature of these relationships with respect to causality. METHODS: We tested whether we could replicate the recent negative findings on causality between Lp(a) and T2D by employing the Mendelian randomization (MR) approach using cross-sectional data from three independent cohorts, Berlin Aging Study II (BASE-II; n = 2012), LIFE-Adult (n = 3281) and LIFE-Heart (n = 2816). Next, we explored another frequently discussed hypothesis in this context: Increasing insulin levels during the course of T2D disease development inhibits hepatic Lp(a) synthesis and thereby might explain the inverse Lp(a)-T2D association. We used two fasting insulin-associated variants, rs780094 and rs10195252, as instrumental variables in MR analysis of n = 4937 individuals from BASE-II and LIFE-Adult. We further investigated causality of the association between fasting insulin and Lp(a) by combined MR analysis of 12 additional SNPs in LIFE-Adult. RESULTS: While an Lp(a)-T2D association was observed in the combined analysis (meta-effect of OR [95% CI] = 0.91 [0.87-0.96] per quintile, p = 1.3x10-4), we found no evidence of causality in the Lp(a)-T2D association (p = 0.29, fixed effect model) when using the variant rs10455872 as the instrumental variable in the MR analyses. Likewise, no evidence of a causal effect of insulin on Lp(a) levels was found. CONCLUSIONS: While these results await confirmation in larger cohorts, the nature of the inverse Lp(a)-T2D association remains to be elucidated. PMID- 28866808 TI - Chylomicrons stimulate incretin secretion in mouse and human cells. AB - AIMS/HYPOTHESIS: Lipids are a potent stimulus for the secretion of glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). Traditionally, this effect was thought to involve the sensing of lipid digestion products by free fatty acid receptor 1 (FFA1) and G-protein coupled receptor 119 (GPR119) on the apical surface of enteroendocrine cells. However, recent evidence suggests that lipids may in fact be sensed basolaterally, and that fatty acid absorption and chylomicron synthesis may be a prerequisite for their stimulatory effect on gut peptide release. Therefore, we investigated the effect of chylomicrons on GLP-1 and GIP secretion in vitro. METHODS: The effect of chylomicrons on incretin secretion was investigated using GLUTag cells and duodenal cultures of both murine and human origin. The role of lipoprotein lipase (LPL) and FFA1 in GLUTag cells was assessed by pharmacological inhibition and small (short) interfering RNA (siRNA)-mediated knockdown. The effect of chylomicrons on intracellular calcium concentration ([Ca2+]i) was determined by imaging GLUTag cells loaded with Fura-2. In the primary setting, the contributions of FFA1 and GPR119 were investigated using L cell-specific Gpr119 knockout cultures treated with the FFA1 antagonist GW1100. RESULTS: Chylomicrons stimulated GLP-1 release from GLUTag cells, and both GLP-1 and GIP secretion from human and murine duodenal cultures. Chylomicron-triggered GLP-1 secretion from GLUTag cells was largely abolished following lipase inhibition with orlistat or siRNA-mediated knockdown of Lpl. In GLUTag cells, both GW1100 and siRNA-mediated Ffar1 knockdown reduced GLP-1 secretion in response to chylomicrons, and, consistent with FFA1 Gq-coupling, chylomicrons triggered an increase in [Ca2+]i. However, LPL and FFA1 inhibition had no significant effect on chylomicron mediated incretin secretion in murine cultures. Furthermore, the loss of GPR119 had no impact on GLP-1 secretion in response to chylomicrons, even in the presence of GW1100. CONCLUSIONS/INTERPRETATION: Chylomicrons stimulate incretin hormone secretion from GLUTag cells as well as from human and murine duodenal cultures. In GLUTag cells, the molecular pathway was found to involve LPL mediated lipolysis, leading to the release of lipid species that activated FFA1 and elevated intracellular calcium. PMID- 28866809 TI - How radiation influences atherosclerotic plaque development: a biophysical approach in ApoE-/- mice. AB - Atherosclerosis is the development of lipid-laden plaques in arteries and is nowadays considered as an inflammatory disease. It has been shown that high doses of ionizing radiation, as used in radiotherapy, can increase the risk of development or progression of atherosclerosis. To elucidate the effects of radiation on atherosclerosis, we propose a mathematical model to describe radiation-promoted plaque development. This model distinguishes itself from other models by combining plaque initiation and plaque growth, and by incorporating information from biological experiments. It is based on two consecutive processes: a probabilistic dose-dependent plaque initiation process, followed by deterministic plaque growth. As a proof of principle, experimental plaque size data from carotid arteries from irradiated ApoE[Formula: see text] mice was used to illustrate how this model can provide insight into the underlying biological processes. This analysis supports the promoting role for radiation in plaque initiation, but the model can easily be extended to include dose-related effects on plaque growth if available experimental data would point in that direction. Moreover, the model could assist in designing future biological experiments on this research topic. Additional biological data such as plaque size data from chronically-irradiated mice or experimental data sets with a larger variety in biological parameters can help to further unravel the influence of radiation on plaque development. To the authors' knowledge, this is the first biophysical model that combines probabilistic and mechanistic modeling which uses experimental data to investigate the influence of radiation on plaque development. PMID- 28866810 TI - Reply to the letter "Nasal nitric oxide as biomarker in the evaluation and management of chronic rhino-sinusitis with nasal polyposis". PMID- 28866811 TI - Release of phosphorus from sewage sludge during ozonation and removal by magnesium ammonium phosphate. AB - The release rule of phosphorus from sewage sludge during ozonation and removal by the magnesium ammonium phosphate (MAP) method were investigated. The results showed that the concentrations of total phosphorus in aqueous phase (TP(A)) and orthophosphate (PO43--P) in ozonized sludge supernatant rose obviously with increasing ozone dose when ozone dose was below 61.2 mg O3/gSS then almost kept constant. The TP(A) and PO43--P contents in the ozonized sludge supernatant were 70.9 and 63.3 mg/L when ozone dose was 61.2 mg O3/gSS, respectively. Total phosphorus in the sludge solid (TP(S)) was mostly distributed in inorganic phosphorus (IP) (more than 81.5% of TP(S)), and non-apatite inorganic phosphorus (NAIP) was the major component of IP in the sludge (more than 78.7% of IP) during ozonation. The release contribution (RC) of IP to TP(A) accounted for over 73.9%. The optimized conditions for the removal of phosphorus from ozonized sludge supernatant were set at an initial Mg2+/PO43--P molar ratio of 1.8, pH 9.5, and reaction time of 5 min, under which the removal efficiencies of TP(A) and PO43--P were 43.1 and 52.2%, respectively. PMID- 28866812 TI - The pyramidalis-anterior pubic ligament-adductor longus complex (PLAC) and its role with adductor injuries: a new anatomical concept. AB - PURPOSE: Adductor longus injuries are complex. The conflict between views in the recent literature and various nineteenth-century anatomy books regarding symphyseal and perisymphyseal anatomy can lead to difficulties in MRI interpretation and treatment decisions. The aim of the study is to systematically investigate the pyramidalis muscle and its anatomical connections with adductor longus and rectus abdominis, to elucidate injury patterns occurring with adductor avulsions. METHODS: A layered dissection of the soft tissues of the anterior symphyseal area was performed on seven fresh-frozen male cadavers. The dimensions of the pyramidalis muscle were measured and anatomical connections with adductor longus, rectus abdominis and aponeuroses examined. RESULTS: The pyramidalis is the only abdominal muscle anterior to the pubic bone and was found bilaterally in all specimens. It arises from the pubic crest and anterior pubic ligament and attaches to the linea alba on the medial border. The proximal adductor longus attaches to the pubic crest and anterior pubic ligament. The anterior pubic ligament is also a fascial anchor point connecting the lower anterior abdominal aponeurosis and fascia lata. The rectus abdominis, however, is not attached to the adductor longus; its lateral tendon attaches to the cranial border of the pubis; and its slender internal tendon attaches inferiorly to the symphysis with fascia lata and gracilis. CONCLUSION: The study demonstrates a strong direct connection between the pyramidalis muscle and adductor longus tendon via the anterior pubic ligament, and it introduces the new anatomical concept of the pyramidalis-anterior pubic ligament-adductor longus complex (PLAC). Knowledge of these anatomical relationships should be employed to aid in image interpretation and treatment planning with proximal adductor avulsions. In particular, MRI imaging should be employed for all proximal adductor longus avulsions to assess the integrity of the PLAC. PMID- 28866813 TI - Psychophysiological Reactivity in Couples During a Marital Interaction Task. AB - The ability to regulate our own physiological arousal when dealing with the emotional expression of our partner is crucial for satisfactory and stable intimate relationships. In previous physiological studies of marital interactions, researchers have found greater levels of psychophysiological arousal for members of the couple in conflictual interactions in comparison with positive interactions. Past researchers have established that intense and prolonged autonomic and neuroendocrine arousal during marital conflict can have negative consequences for mental and physical health. In this study we examined the physiological reactivity, as measured by skin conductance level, heart rate and cortisol levels, from both partners during a couple's interaction task consisting of a structured conversation about positive and negative aspects of their relationship. Participants were thirty-two heterosexual couples (N = 64) in a committed monogamous relationship with a minimum duration of one year. We found higher heart rate and cortisol levels during negative interaction condition when compared with the positive condition. Skin conductance was higher in the positive interaction condition, when compared with the negative interaction condition. In addition, we found a significant negative association between heart rate variability and autonomic arousal evoked by the interaction task. The implications of these findings for the effects of marital strain on health as well as for the design of risk-reducing interventions, namely biofeedback are discussed. PMID- 28866814 TI - From mechanisms to therapy: RNA processing's impact on human genetics. PMID- 28866815 TI - Low Power Consumption Substrate-Emitting DFB Quantum Cascade Lasers. AB - In the present work, an ultra-low power consumption substrate-emitting distributed feedback (DFB) quantum cascade laser (QCL) was developed. The continuous-wave (CW) threshold power dissipation is reduced to 0.43 W at 25 degrees C by shortening the cavity length to 0.5 mm and depositing high reflectivity (HR) coating on both facets. As far as we know, this is the recorded threshold power dissipation of QCLs in the same conditions. Single-mode emission was achieved by employing a buried second-order grating. Mode-hop free emission can be observed within a wide temperature range from 15 to 105 degrees C in CW mode. The divergence angles are 22.5o and 1.94o in the ridge-width direction and cavity-length direction, respectively. The maximum optical power in CW operation was 2.4 mW at 25 degrees C, which is sufficient to spectroscopy applications. PMID- 28866816 TI - Distinctively Expressed Cytokines by Three Different Inflammation Cells and Their Interaction with Keratinocytes in Wound Healing. AB - Inflammatory cells exert crucial influence on wound healing, while exploration is still desired to get further insight into the key factors that promote the process. In the present study, we performed comparative microarray data analysis of the three types of inflammatory cells isolated from skin wounds and focused on differentially expressed secreted factors. Gene Ontology enrichment and receptor analysis indicated that 11 genes of secreted factors in Ly6C+ inflammatory macrophages and 27 genes of secreted factors in neutrophils exhibited higher (>= 5-fold) expression, and all these factors were considered as candidates with potentially important role in keratinocyte activation. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that TNF and IL17 signaling pathways were activated by Ly6C+ inflammatory macrophages secreted cytokines, while TGF-beta, HIF-1, NF-kappaB, and Rap 1 signaling pathways and pathways regulating pluripotency of stem cells were highly involved with neutrophils secreted cytokines. Taking TNF as an example, the source of the cytokine and its impact on keratinocytes were verified by immunofluorescence, gene knockout mice, and quantitative phosphoproteomics. Collectively, this study has indicated distinctively expressed cytokines in three inflammatory cells, which is helpful in identifying key factors in inducing keratinocyte signaling and in wound healing. PMID- 28866817 TI - A Review on Current Status and Future Prospects of Winged Bean (Psophocarpus tetragonolobus) in Tropical Agriculture. AB - Winged bean, Psophocarpus tetragonolobus (L.) DC., is analogous to soybean in yield and nutritional quality, proving a valuable alternative to soybean in tropical regions of the world. The presence of anti-nutritional factors and high costs associated with indeterminate plant habit have been major concerns in this crop. But occurrence of good genetic variability in germplasm collections offers precious resources for winged bean breeding. However, lack of germplasm characterization is hindering such efforts. From a genomic standpoint, winged bean has been little studied despite rapid advancement in legume genomics in the last decade. Exploiting modern genomics/breeding approaches for genetic resource characterization and the breeding of early maturing, high yielding, determinate varieties which are disease resistant and free of anti-nutritional factors along with developing consumer friendly value-added products of local significance are great challenges and opportunities in the future that would boost cultivation of winged bean in the tropics. We review past efforts and future prospects towards winged bean improvement. PMID- 28866818 TI - Examining colorectal cancer survivors' surveillance patterns and experiences of care: a SEER-CAHPS study. AB - PURPOSE: We examined associations between experiences of care and adherence to surveillance guidelines among Medicare Fee-For-Service beneficiaries with colorectal cancer (CRC). METHODS: Using linked data from the National Cancer Institute's Surveillance, Epidemiology, and End results (SEER) cancer registry program and the Medicare Consumer Assessment of Healthcare Providers and Systems (CAHPS(r)) patient experience surveys (SEER-CAHPS), we identified local/regional CRC survivors diagnosed in 1999-2009 aged 65+, who underwent surgical resection and completed a CAHPS survey <36 months of diagnosis. Adherence for a 3-year observation period was defined as receiving a colonoscopy; >=2 carcinoembryonic antigen (CEA) tests; and each year had >=2 office visits and >=1 computerized tomography test. RESULTS: Many of the 314 participants reported ratings of a 9 or 10 out of 10 for overall care (55.4%), personal doctor (58.6%), health plan (59.6%), and specialist doctor (47.0%). Adherence to post-resection surveillance was 76.1% for office visits, 36.9% for CEA testing, 48.1% for colonoscopy, and 10.3% for CT Imaging. Overall, 37.9% of the sample were categorized as non adherent (adhering to <=1 surveillance guideline). In multivariable models, ratings of personal doctor and specialist doctor were positively associated with adherence to office visits, and ratings of personal doctor were associated with adherence overall. CONCLUSIONS: Findings point to the potentially important role of patient-provider relationships in adherence to office visits for CRC surveillance. As adherence may increase survival among CRC survivors, further investigation is needed to identify specific components of this relationship that impact office visit adherence, and other potentially modifiable drivers of surveillance guidelines. PMID- 28866819 TI - Fluorescence in situ hybridization as prognostic predictor of tumor recurrence during treatment with Bacillus Calmette-Guerin therapy for intermediate- and high risk non-muscle-invasive bladder cancer. AB - A significant number of patients with intermediate- or high-risk bladder cancer treated with intravesical Bacillus Calmette-Guerin (BCG) immunotherapy are non responders to this treatment. Since we cannot predict in which patients BCG therapy will fail, markers for responders are needed. UroVysion(r) is a multitarget fluorescence in situ hybridization (FISH) test for bladder cancer detection. The aim of this study was to evaluate whether FISH can be used to early identify recurrence during treatment with BCG. In a multicenter, prospective study, three bladder washouts at different time points during treatment (t 0 = week 0, pre-BCG, t 1 = 6 weeks following TURB, t 2 = 3 months following TURB) were collected for FISH from patients with bladder cancer treated with BCG between 2008 and 2013. Data on bladder cancer recurrence and duration of BCG maintenance therapy were recorded. Thirty-six (31.6%) out of 114 patients developed a recurrence after a median of 6 months (range 2-32). No significant association was found between a positive FISH test at t 0 or t 1 and risk of recurrence (p = 0.79 and p = 0.29). A positive t 2 FISH test was associated with a higher risk of recurrence (p = 0.001). Patients with a positive FISH test 3 months following TURB had a 4.0-4.6 times greater risk of developing a recurrence compared to patients with a negative FISH. Patients with a positive FISH test 3 months following TURB and induction BCG therapy have a higher risk of developing tumor recurrence. FISH can therefore be a useful additional tool for physicians when determining a treatment strategy. PMID- 28866820 TI - Copper, Manganese, Zinc, and Cadmium in Tea Leaves of Different Types and Origin. AB - Concentrations of selected metals (Cu, Mn, Zn, Cd) in tea leaves were investigated. Samples included black, green, and other (red, white, yellow, and oolong) teas. They were purchased on a local market but they covered different countries of origin. Beverages like yerba mate, rooibos, and fruit teas were also included in the discussion. Metal determinations were performed using atomic absorption spectrometry. In black teas, Mn/Cd ratio was found to be significantly higher (48,091 +/- 35,436) vs. green (21,319 +/- 16,396) or other teas (15,692 +/ 8393), while Cd concentration was lower (31.4 +/- 18.3 MUg/kg) vs. other teas 67.0 (67.0 +/- 24.4). Moreover, Zn/Cu and Cu/Cd ratios were, respectively, lower (1.1 +/- 0.2 vs. 2.2 +/- 0.5) and higher (1086 +/- 978 vs. 261 +/- 128) when comparing black teas with other teas. Intake of each metal from drinking tea was estimated based on the extraction levels reported by other authors. Contributions to recommended daily intake for Cu, Mn, and Zn were estimated based on the recommendations of international authorities. Except for manganese, tea is not a major dietary source of the studied elements. From the total number of 27 samples, three have shown exceeded cadmium level, according to local regulations. PMID- 28866821 TI - Evaluating lipopolysaccharide-induced oxidative stress in bovine granulosa cells. AB - PURPOSE: The purpose of this study was to evaluate the capacity of bovine granulosa cells to generate reactive oxygen intermediates in response to lipopolysaccharide. We hypothesized that granulosa cells increase reactive oxygen intermediates in response to Gram-negative lipopolysaccharide in a similar manner to immune cells. METHODS: Bovine peripheral blood mononuclear cells and granulosa cells were cultured in the presence of lipopolysaccharide. Oxidative stress was evaluated using the fluorescent marker dye CellROX, and oxidative stress-related genes were measured using real-time RT-PCR. RESULTS: As expected, peripheral blood mononuclear cells increased oxidative stress in response to lipopolysaccharide as measured by accumulation of the fluorescent marker dye CellROX. While granulosa cells demonstrate the capacity to increase accumulation of CellROX dye in response to a positive control menadione, lipopolysaccharide had no effect on accumulation of CellROX dye. The expression of GSR, SOD1, and SOD2 were variable in peripheral blood mononuclear cells treated with lipopolysaccharide but were consistently upregulated when co-incubated with the antioxidant, N-acetyl cysteine. The expression of oxidative stress-related genes was not altered in granulosa cells, with the exception of elevated SOD1 following lipopolysaccharide exposure in the absence of antioxidant. CONCLUSIONS: Combined, these data suggest that while reactive stress is important in pathogen killing and inflammation in immune cells, granulosa cells do not increase oxidative stress in response to lipopolysaccharide. PMID- 28866822 TI - Dutch Economic Value of Radium-223 in Metastatic Castration-Resistant Prostate Cancer. AB - BACKGROUND: The treatment of metastatic castration-resistant prostate cancer has changed with the introduction of radium-223, cabazitaxel, abiraterone and enzalutamide. To assess value for money, their cost effectiveness in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective was investigated. METHODS: A cost effectiveness analysis was conducted using efficacy, symptomatic skeletal-related event and safety data obtained from indirect treatment comparisons. Missing skeletal-related event data for cabazitaxel were conservatively assumed to be identical to radium-223. A Markov model combined these clinical inputs with Dutch specific resource use and costs for metastatic castration-resistant prostate cancer treatment from a societal perspective. Total quality-adjusted life-years and costs in 2017 euros were calculated over a 5-year (lifetime) time horizon. RESULTS: Radium-223 resulted in ?6092 and ?4465 lower costs and 0.02 and 0.01 higher quality-adjusted life-years compared with abiraterone and cabazitaxel, respectively, demonstrating dominance of radium-223. Sensitivity analyses reveal a 64% (54%) chance of radium-223 being cost effective compared with abiraterone (cabazitaxel) at the informal ?80,000 willingness-to-pay threshold. Compared with enzalutamide, radium-223 resulted in slightly lower quality-adjusted life-years ( 0.06) and ?7390 lower costs, revealing a 61% chance of radium-223 being cost effective compared with enzalutamide. The lower costs of radium-223 compared with abiraterone and enzalutamide are driven by lower drug costs and prevention of expensive skeletal-related events. Compared with cabazitaxel, the lower costs of radium-223 are driven by lower costs of the drug, administration and adverse events. CONCLUSION: Radium-223 may be a less costly treatment strategy offering similar gains in health benefits compared with abiraterone, cabazitaxel and enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective. PMID- 28866823 TI - Neuroprotective Effects of Baicalein on Acrolein-induced Neurotoxicity in the Nigrostriatal Dopaminergic System of Rat Brain. AB - Elevated levels of acrolein, an alpha,beta-unsaturated aldehyde are detected in the brain of patients with Parkinson's disease (PD). In the present study, the neuroprotective effect of baicalein (a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi) on acrolein-induced neurodegeneration of nigrostriatal dopaminergic system was investigated using local infusion of acrolein in the substantia nigra (SN) of rat brain. Systemic administration of baicalein (30 mg/kg, i.p.) significantly attenuated acrolein-induced elevations in 4-hydroxy-2-noneal (a product of lipid peroxidation), N-(3-formyl-3,4 dehydropiperidino)lysine (a biomarker of acrolein-conjugated proteins), and heme oxygenase-1 levels (a redox-regulated protein) in the infused SN, indicating that baicalein inhibited acrolein-induced oxidative stress and protein conjugation. Furthermore, baicalein reduced acrolein-induced elevations in glial fibrillary acidic protein (a biomarker of activated astrocytes), ED-1 (a biomarker of activated microglia), and mature cathepsin B levels (a cysteine lysosomal protease), suggesting that baicalein attenuated acrolein-induced neuroinflammation. Moreover, baicalein attenuated acrolein-induced caspase 1 activation (a pro-inflammatory caspase) and interleukin-1beta levels, indicating that baicalein prevented acrolein-induced inflammasome activation. In addition, baicalein significantly attenuated acrolein-induced caspase 3 activation (a biomarker of apoptosis) as well as acrolein-induced elevation in receptor interacting protein kinase (RIPK) 3 levels (an initiator of necroptosis), indicating that baicalein attenuated apoptosis and necroptosis. At the same time, baicalein mitigated acrolein-induced reduction in dopamine levels in the striatum ipsilateral to acrolein-infused SN. In conclusion, our data suggest that baicalein is neuroprotective via inhibiting oxidative stress, protein conjugation, and inflammation. Furthermore, baicalein prevents acrolein-induced program cell deaths, suggesting that baicalein is therapeutically useful for slowing PD progression. PMID- 28866825 TI - Platelet to lymphocyte ratio and red cell distribution width as prognostic factors for survival and recurrence in patients with oral cancer. AB - Although platelet to lymphocyte ratio (PLR) and red cell distribution width (RDW) have been reported as good predictors for survival outcomes in various cancers, there is limited data supporting these as reliable predictors in oral cancer. This study thus aimed to assess the prognostic value of PLR and RDW markers in predicting survival and recurrence rates in patients with oral cancer. The records of 374 oral cancer patients treated with curative intent over a 7-year period (2009-2015) were reviewed. Survival and recurrence outcomes were compared between those with low and high PLR (<=135 vs. >135) and those with low and high RDW (<=14.05 vs. >14.05) using hazard ratios (HR). The 5-year disease-specific survival was significantly higher and recurrence rate significantly lower among the low PLR group compared to the high PLR group (65.7 vs. 37.6%; p < 0.001 and 34.4 and 57.5%; p < 0.001), respectively. There were no significant differences between the low and high RDW groups for disease-specific survival (53.6 vs. 54.7%, p = 0.408) and recurrence (40.0% vs. 53.8%, p = 0.079). Multivariate analysis showed that PLR was associated with disease-specific survival (HR = 2.05, p < 0.001) and recurrence (HR = 1.69, p < 0.005) after adjusting for other factors, but not RDW. High PLR shows promise as a prognostic predictor for poor survival and recurrence in patients with oral cancer, but further studies are required. RDW has no prognostic value on any outcome. PMID- 28866826 TI - Impact of pioglitazone regulatory withdrawal on antidiabetic drug use and health in diabetic patients. AB - PURPOSE: In 2011, pioglitazone was withdrawn from the French market owing to a potential risk of bladder cancer. This study aimed at assessing the impact of this pioglitazone withdrawal (PW) considering (i) trends in antidiabetic uses and (ii) changes in hospitalization/death rates in diabetic patients following PW. METHODS: We first considered the general population of the Echantillon Generaliste des Beneficiaires (EGB), a 1/97th representative sample of the French healthcare insurance system beneficiaries, for the 2010-2014 period. In this, for each non-insulinic antidiabetic drug class, changes within the numbers of monthly supplied drug units for 1000 subjects were studied through times series and Unobserved Component Models. Second, we identified from the EGB a cohort of patients who were delivered a non-insulinic antidiabetic between 01 April 2011 and 01 August 2011 (date of PW). In this, post-withdrawal incidences of all-cause hospitalization and death were compared amongst pioglitazone users and non-users using proportional subdistribution hazards models. RESULTS: PW was accompanied by an increase in metformin (+ 11.7; 95% CI 1.1-22.3) and glinide (+ 11.0; 95% CI 1.2-20.8) numbers of monthly supplied units for 1000 subjects. No significant change was found for GLP-1 agonists, DPP-4 inhibitors, sulphonylureas or alpha glucosidase inhibitors. In the cohort of non-insulinic antidiabetic users at the time of PW (1093 pioglitazone users, 17,900 non-users), being a pioglitazone user at PW was not associated with a subsequently higher rate of hospitalization. CONCLUSIONS: If PW was accompanied with significant changes in the use of some antidiabetics, no adverse impact of PW on hospitalization or death rates of diabetic type 2 patients was found. PMID- 28866824 TI - Oil body biogenesis and biotechnology in legume seeds. AB - The seeds of many legume species including soybean, Pongamia pinnata and the model legume Medicago truncatula store considerable oil, apart from protein, in their cotyledons. However, as a group, legume storage strategies are quite variable and provide opportunities for better understanding of carbon partitioning into different storage products. Legumes with their ability to fix nitrogen can also increase the sustainability of agricultural systems. This review integrates the cell biology, biochemistry and molecular biology of oil body biogenesis before considering biotechnology strategies to enhance oil body biosynthesis. Cellular aspects of packaging triacylglycerol (TAG) into oil bodies are emphasized. Enhancing seed oil content has successfully focused on the up regulation of the TAG biosynthesis pathways using overexpression of enzymes such as diacylglycerol acyltransferase1 and transcription factors such as WRINKLE1 and LEAFY COTYLEDON1. While these strategies are central, decreasing carbon flow into other storage products and maximizing the packaging of oil bodies into the cytoplasm are other strategies that need further examination. Overall there is much potential for integrating carbon partitioning, up-regulation of fatty acid and TAG synthesis and oil body packaging, for enhancing oil levels. In addition to the potential for integrated strategies to improving oil yields, the capacity to modify fatty acid composition and use of oil bodies as platforms for the production of recombinant proteins in seed of transgenic legumes provide other opportunities for legume biotechnology. PMID- 28866827 TI - Fistula Following Laparoscopic Sleeve Gastrectomy: a Proposed Classification and Algorithm for Optimal Management. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is an accepted restrictive procedure with a hormonal component. There is no definitive course of treatment for post-LSG fistula; it remains a feared complication. We aimed to classify post LSG fistulas and propose an algorithm to optimize their treatment. METHODS: Following primary and revisional LSG in obese patients, a retrospective observational study of fistulas was undertaken. Radiological studies were performed to identify anatomically distinct types of fistulas. An algorithm was elaborated for the classification and evolving treatment of each type of fistula. RESULTS: Twenty post-LSG fistulas were studied (13 [2.5%] from our center, 7 referred) with a mean body mass index of 43.1 +/- 10.2 kg/m2 (32.0-76.0) and mean age of 33.1 +/- 11.4 years (20.0-56.0). In all cases, the clinically suspected diagnosis was radiologically confirmed by water-soluble upper gastrointestinal series and double-contrast abdomino-pelvic CT scan. Three anatomical fistula types were characterized: type I, a small leak with no collection; type II, a leak with associated intra-abdominal abscess; and type III, a leak with multiple internal or external abscesses, a complex fistula. In accord with our algorithm, patients without sepsis received conservative treatment initially; this was sufficient for type I leaks. Type II abscesses received internal or external percutaneous drainage, and in some cases, stenting or endoprosthesis. Surgery was reserved for failure of conservative options and type III fistula. In cases of sepsis, surgery was mandatory. CONCLUSION: A radiologically defined, anatomically based classification system and treatment algorithm proved effective in clinical management of post-LSG fistula. PMID- 28866828 TI - Association of the severity of diabetes-related complications with stage of breast cancer at diagnosis among elderly women with pre-existing diabetes. AB - PURPOSE: This study assessed the association between the severity of diabetes complications using diabetes complications severity index (DCSI) and stage of breast cancer (BC) at diagnosis among elderly women with pre-existing diabetes and incident BC. METHODS: Using Surveillance, Epidemiology and End Results Medicare data, we identified women with incident BC during 2004-2011 and pre existing diabetes (N = 7729). Chi-square tests were used to test for group differences in stage of BC at diagnosis. Multinomial logistic regression was used to examine the associations between the severity of diabetes complications and stage of BC at diagnosis. RESULTS: Overall, women with a DCSI = 2 and a DCSI >= 3 were more likely to be diagnosed at advanced stages as compared to those with no diabetes complications. In full adjusted association (after adding BC screening to the analysis model), the severity of diabetes complications was no longer an independent predictor of advanced stages at diagnosis. However, women with a DCSI = 2 were 26% more likely to be diagnosed at stage I (versus stage 0) of BC at diagnosis as compared to those without diabetes complications (OR 1.26, 95% CI 1.03-1.53). CONCLUSION: The increased likelihood of having advanced-stage BC at diagnosis associated with severity of diabetes-related complications appears to be mediated by lower rates of breast cancer screening among elderly women with pre-existing diabetes complications. Therefore, reducing disparity in receiving breast cancer screening among elderly women with diabetes may reduce the risk of advanced-stage breast cancer diagnosis. PMID- 28866829 TI - An investigation of the prevalence of swallowing difficulties and impact on quality of life in patients with advanced lung cancer. AB - BACKGROUND: Dysphagia can occur in advanced lung cancer due to direct tumour invasion or nerve compression. Anti-cancer treatments and co-morbid conditions may also cause or compound dysphagic symptoms. Speech and language therapy (SLT), medical and surgical interventions are available to address dysphagic symptoms in patients with lung cancer, however, management options are not described in national guidelines. Given the potentially short prognoses for patients with lung cancer, the aim of care should be to reduce symptom burden and maximise quality of life (QOL). Central to that aim is the identification and treatment of swallowing difficulties. PURPOSE: This study sought to identify the prevalence and impact of dysphagia on QOL in patients with advanced lung cancer. METHODS: A single-site, prospective, exploratory study was undertaken. Previously validated patient-reported outcome measures of swallowing were used to identify the presence and impact of dysphagia on QOL: EAT-10 assessment and the SWAL-QOL assessment. RESULTS: Seventy-two participants were recruited with 18.1% identified as having dysphagia on completion of the EAT-10 assessment. On further evaluation using the SWAL-QOL, compromised quality of life was noted with increased fatigue and meal time duration, difficulties with food selection and reduced eating desire. Frequent throat clearing, coughing and perceived pharyngeal stasis were reported. CONCLUSIONS: Dysphagia is a potential symptom in advanced lung cancer which may impact QOL. Patients, carers and healthcare professionals should be aware of this so that early referral to SLT can be expedited. More robust prevalence and interventional studies are required to inform optimal management of this distressing condition. PMID- 28866830 TI - A transportation network for human ovarian tissue is indispensable to success for fertility preservation. AB - PURPOSE: The purpose of this study was to examine the efficacy of an ovarian tissue transportation network for fertility preservation (FP) for cancer patients in Japan. METHODS: PubMed was searched for papers on transportation of human ovarian tissue for FP. We analyzed population, area, number of cancer patients for ovarian tissue cryopreservation (OTC), quality control/assessment and safety, cost of a cryopreservation center for the building for 30 years, and medical fees of cancer patients (operation, cryopreservation, and storage of ovarian tissue). RESULTS: More than twenty babies have been born in Denmark and Germany through a transportation system. Up to 400 new patients a year need OTC. The fees for removal, cryopreservation, and storage for 5 years, and transplantation of ovarian tissue are around ?5,000, ?4,000, and ?5,000, respectively. It costs more than ?5 million to establish and maintain one cryopreservation center for 30 years. If we have a few cryopreservation centers in Japan, we can cryopreserve 400 patients' ovarian tissue per year by safer slow freezing and maintain quality control/assessment. We need to lighten the patients' burden for easy to use FP by a government subsidy and medical insurance coverage. CONCLUSIONS: This model has been termed the Danish model ("the woman stays - the tissue moves"). This is truly patient-centered medicine. We can have maximum effects with the minimum burden. A transportation network like those of Denmark and Germany is the best strategy for FP in Japan. It may be the best system for cancer patients, medical staff, and the Ministry of Health, Labor, and Welfare. PMID- 28866831 TI - Detection of a new species of torque teno mini virus from the gingival epithelium of patients with periodontitis. AB - We describe a novel species of torque teno mini virus called TTMV-204, which was isolated from the gingival epithelium of patients with periodontitis and characterized using viral metagenomics. The sequence of the full genome is 2824 nt in length. Phylogenetic analysis and genetic analyses show classic Betatorquevirus species organization with less than 40% amino acid similarity in ORF1. The prevalence of TTMV-204 in the periodontitis patient population was 18.75% (15/80), which was higher than in periodontally healthy individuals (10.00%, 10/80). However, the difference of the TTMV-204 prevalence between two groups was not statistically significant (p = 0.115). Further investigation is required to determine whether this new virus is associated with inflammation. PMID- 28866832 TI - Increased Levels of Brain Adrenomedullin in the Neuropathology of Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized by the loss of synaptic contacts caused in part by cytoskeleton disruption. Adrenomedullin (AM) is involved in physiological functions such as vasodilation, hormone secretion, antimicrobial activity, cellular growth, and angiogenesis. In neurons, AM and related peptides are associated with some structural and functional cytoskeletal proteins, causing microtubule destabilization. Here, we describe the relationships between AM and other signs of AD in clinical specimens. Frontal cortex from AD patients and controls were studied for AM, acetylated tubulin, NCAM, Ox-42, and neurotransmitters. AM was increased in AD compared with controls, while levels of acetylated tubulin, NCAM, and neurotransmitters were decreased. Interestingly, increases in AM statistically correlated with the decrease in these markers. Furthermore, Ox42 overexpression in AD correlated with levels of AM. It is proposed that AD patients may have neural cytoskeleton failure associated with increase of AM levels, resulting in axon transport collapse and synaptic loss. These observations suggest that reducing AM expression may constitute a new avenue to prevent/treat AD. PMID- 28866833 TI - Voriconazole-induced periostitis deformans: serial imaging in a patient with ANCA vasculitis. AB - OBJECTIVES: A 61-year-old with acute granulomatosis and polyangiitis developed Aspergillus fumigatus pneumonia after admission to the intensive care unit with a small bowel perforation. This occurred after immunosuppression (intravenous methylprednisolone, intravenous cyclophosphamide, and plasmapheresis) for his initial presentation with stage 3 acute kidney injury. MATERIALS AND METHODS: The mycologist recommended long-term treatment with voriconazole after initial recovery. RESULTS: After 7 months of treatment, the patient complained of joint pain and swelling in his hands. Radiographs, computed tomography, and single photon emission computed tomography appearances were consistent with periostitis. A diagnosis of Voriconazole-induced periostitis deformans was made and the voriconazole was stopped. Plasma fluoride level was 278 MUg/L (normal range < 50 MUg/L). Discontinuation of voriconazole led to clinical improvement. CONCLUSIONS: Periostitis deformans due to fluorosis is a rare complication of voriconazole treatment. The imaging in our case is unusually dramatic. We were able to track the evolution of periosteal reactions over serial imaging. PMID- 28866835 TI - Comprehensive characterization of a major capsid protein derived from a documented GII.6 norovirus strain. AB - In this study, we successfully produced VLPs derived from full-length or chimeric VP1 of a documented GII.6 strain. Trypsin digestion of purified VLPs led to total cleavage of VP1, while the integrity of assembled VLPs was not affected. In vitro VLP-histo-blood group antigen (HBGA) binding and binding blockade assays indicated that trypsin digestion enhanced the binding of GII.6 VLPs to salivary HBGAs and that this binding could only be blocked by serum produced against a homologous strain. The data regarding the assembly, morphology and binding patterns of GII.6 NoV VLPs presented here might be useful for further study of GII.6 NoVs. PMID- 28866834 TI - Insulin and osteocalcin: further evidence for a mutual cross-talk. AB - PURPOSE: In the last few years, bone has been recognized as an endocrine organ that modulates glucose metabolism by secretion of osteocalcin, an osteoblast specific hormone, that influences fat deposition and blood sugar levels. To date, however, very few in vitro models have been developed to investigate, at the molecular levels, the relationship between glucose, insulin and osteocalcin. This study aims at covering this gap. METHODS: We studied osteogenic differentiation, osteocalcin gene expression, and osteblast-mediated insulin secretion, using cultured MG-63 human osteoblast-like cells that underwent glucotoxicity and insulin resistance. In addition, we investigated whether a correlation existed between hyperglycemia and/or insulin resistance and total osteocalcin serum concentrations in patients. RESULTS: While insulin and low glucose increased osteocalcin gene expression, disruption of insulin signaling in MG-63 osteoblasts and high glucose concentration in cell culture medium decreased osteocalcin gene transcription and reduced osteogenic differentiation. Concomitantly, insulin secretion was significantly impaired in rat INS-1 beta-cells treated with conditioned medium from insulin resistant MG-63 cells or cells exposed to high glucose concentrations. Also, chronic hyperglycemia, but not insulin resistance, inversely correlated with circulating osteocalcin levels in patients. CONCLUSION: Our results further support the existence of an endocrine axis between bone, where osteocalcin is produced, and pancreatic beta-cells, and add new insights into the molecular details of this relationship. These findings may contribute to the understanding of osteocalcin regulation and its role in metabolism. PMID- 28866836 TI - Colistin nephrotoxicity in the ICU: Is it different in the geriatric patients? AB - OBJECTIVE: Most significant side effect of colistin therapy which is used for the treatment of multi-drug resistant Gram-negative infections is nephrotoxicity. Our aim was to investigate the differences of colistin nephrotoxicity between the geriatric age group (>=65 years) and the younger age group (<65 years) in critically ill medical intensive care unit (ICU) patients. MATERIAL AND METHOD: The medical records of the 76 patients who were taken colistin therapy due to multi-resistant Gram-negative infections between January 2010 and June 2014 in the our medical ICU were retrospectively investigated. Demographic characteristics, reasons for colistin use, daily colistin dose, duration of colistin use were recorded. Colistin-dependent renal dysfunction was evaluated according to the risk, injury, failure, loss and end-stage renal failure (RIFLE) criterias. RESULTS: The median age of the patients was 65 (65.8% male). Nephrotoxicity was developed in 36 (47.4%) patients. Thirty-nine (51.3%) patients were in geriatric age group, 37 (48.7%) were in younger age group. In geriatric age group, the rates of male gender (53.8 vs 78.4%, p = 0.031), pulmonary (48.7 vs 16.2%, p = 0.003) and cardiac diseases (71.8 vs 29.7%, p < 0.001), post nephrotoxicity BUN levels (p = 0.023) and urine output during nephrotoxicity (p = 0.016) were higher than younger age group. Nephrotoxicity was developed in 22 (56.4%) patients of geriatric age group, and in 14 (37.8%) patients in younger age group (p = 0.115). The presence of cardiac disease, renal pathology and high creatinin value on admission, daily amount of colistin per body mass, total amount of colistin, use of colistin for pulmonary infection, use of amphotericin and vasopressor on admission were found as risk factors for colistin nephrotoxicity development in all study group; the daily amount of colistin per body mass (risk ratio:0.41; 95% CI 0.19-0.89) and vasopressor use during hospitalization were found independent risk factors (risk ratio:13.54; 95% CI 2.21-83.09). CONCLUSION: In our study, in geriatric patient group colistin nephrotoxicity was not different from the younger age group. In the ICU, the age for nephrotoxicity does not appear to be a point to be considered for the initiation of colistin. PMID- 28866837 TI - Oxidative environment causes molecular remodeling in embryonic heart-a metabolomic and lipidomic fingerprinting analysis. AB - Environmental factors including pollution affect human health, and the unifying factor in determining toxicity and pathogenesis for a wide array of environmental factors is oxidative stress. Here, we created the oxidative environment with 2,2 azobis (2-amidinopropane) dihydrochloride (AAPH) and consequent cardiac remodeling in chick embryos. The metabolite fingerprint of heart tissue was obtained from Fourier transform infrared (FTIR) spectroscopic analysis. The global lipidomic analysis was done using electrospray ionization coupled with tandem mass spectrometry (ESI-MS/MS) by precursor ion scanning and neutral loss scanning methods. Further, the fatty acid levels were quantified in AAPH-treated H9c2 cardiomyoblasts with gas chromatography-mass spectrometry (GC-MS). Lipidomic fingerprinting study indicated that majority of differentially expressed phospholipids species in heart tissue belonged to ether phosphatidylcholine (ePC) species, and we conclude that excess oxidative environment may alter the phospholipid metabolism at earlier stages of cardiac remodeling. PMID- 28866838 TI - The path to colour discrimination is S-shaped: behaviour determines the interpretation of colour models. AB - Most of our current understanding on colour discrimination by animal observers is built on models. These typically set strict limits on the capacity of an animal to discriminate between colour stimuli imposed by physiological characteristics of the visual system and different assumptions about the underlying mechanisms of colour processing by the brain. Such physiologically driven models were not designed to accommodate sigmoidal-type discrimination functions as those observed in recent behavioural experiments. Unfortunately, many of the fundamental assumptions on which commonly used colour models are based have been tested against empirical data for very few species and many colour vision studies solely rely on physiological measurements of these species for predicting colour discrimination processes. Here, we test the assumption of a universal principle of colour discrimination only mediated by physiological parameters using behavioural data from four closely related hymenopteran species, considering two frequently used models. Results indicate that there is not a unique function describing colour discrimination by closely related bee species, and that this process is independent of specific model assumptions; in fact, different models produce comparable results for specific test species if calibrated against behavioural data. PMID- 28866839 TI - Image-guided ablations in patients with thyroid tumors. PMID- 28866840 TI - Topography of the human acoustic radiation as revealed by ex vivo fibers micro dissection and in vivo diffusion-based tractography. AB - The acoustic radiation is a compact bundle of fibers conveying auditory information from the medial geniculate nucleus of the thalamus to the auditory cortex. Topographical knowledge of this bundle in primates is scarce and in vivo diffusion-based tractography reconstructions in humans remains challenging, especially with the most widely used MRI acquisition protocols. Therefore, the AR represents a notable anatomical omission in the neurobiological investigation of acoustic and linguistic functional mechanisms in humans. In this study, we combine blunt micro-dissections and advanced diffusion tractography methods to provide novel insights into the topographical anatomy of this bundle in humans. Evidences from ex vivo blunt micro-dissection in three human (two right) hemispheres are compared to the 3D profile of this bundle as reconstructed by tractography techniques in four healthy adult data sets provided by the Human Connectome Project. Both techniques show the unique trajectory of the AR, a transversal course from the midline to the lateral convexity of the posterior temporal lobe. Blunt dissections demonstrated three portions of this bundle that we defined as the genu, stem, and fan, revealing the intimate relationships that each of these components has with neighboring association and projection pathways. Probabilistic tractography and ultra-high b values provided results comparable to blunt micro-dissections and highlighted the main limitations in tracking the AR. This is, to our knowledge, the first ex vivo/in vivo integrated study providing novel and reliable information about the precise anatomy of the AR, which will be important for future investigations in the neuroscientific, clinical, and surgical field. PMID- 28866841 TI - In vivo uptake of iodine from a Fucus serratus Linnaeus seaweed bath: does volatile iodine contribute? AB - Seaweed baths containing Fucus serratus Linnaeus are a rich source of iodine which has the potential to increase the urinary iodide concentration (UIC) of the bather. In this study, the range of total iodine concentration in seawater (22 105 ug L-1) and seaweed baths (808-13,734 ug L-1) was measured over 1 year. The seasonal trend shows minimum levels in summer (May-July) and maximum in winter (November-January). The bathwater pH was found to be acidic, average pH 5.9 +/- 0.3. An in vivo study with 30 volunteers was undertaken to measure the UIC of 15 bathers immersed in the bath and 15 non-bathers sitting adjacent to the bath. Their UIC was analysed pre- and post-seaweed bath and corrected for creatinine concentration. The corrected UIC of the population shows an increase following the seaweed bath from a pre-treatment median of 76 ug L-1 to a post-treatment median of 95 ug L-1. The pre-treatment UIC for both groups did not indicate significant difference (p = 0.479); however, the post-treatment UIC for both did (p = 0.015) where the median bather test UIC was 86 ug L-1 and the non-bather UIC test was 105 ug L-1. Results indicate the bath has the potential to increase the UIC by a significant amount and that inhalation of volatile iodine is a more significant contributor to UIC than previously documented. PMID- 28866842 TI - One-Pot Synthesis of Hierarchical Flower-Like Pd-Cu Alloy Support on Graphene Towards Ethanol Oxidation. AB - The synergetic effect of alloy and morphology of nanocatalysts play critical roles towards ethanol electrooxidation. In this work, we developed a novel electrocatalyst fabricated by one-pot synthesis of hierarchical flower-like palladium (Pd)-copper (Cu) alloy nanocatalysts supported on reduced graphene oxide (Pd-Cu(F)/RGO) for direct ethanol fuel cells. The structures of the catalysts were characterized by using scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), and X-ray photoelectron spectrometer (XPS). The as-synthesized Pd-Cu(F)/RGO nanocatalyst was found to exhibit higher electrocatalytic performances towards ethanol electrooxidation reaction in alkaline medium in contrast with RGO-supported Pd nanocatalyst and commercial Pd black catalyst in alkaline electrolyte, which could be attributed to the formation of alloy and the morphology of nanoparticles. The high performance of nanocatalyst reveals the great potential of the structure design of the supporting materials for the future fabrication of nanocatalysts. PMID- 28866843 TI - A Culturally Sensitive Approach to Large-Scale Prevention Studies: A Case Study of a Randomized Controlled Trial With Low-Income Latino Communities. AB - In response to U.S. federal mandates to increase the presence of underrepresented populations in prevention research, investigators have increasingly focused on using culturally sensitive research practices. However, scholars have rarely discussed these practices in terms of a larger culturally sensitive framework. Further, while the literature has explored how culturally sensitive approaches can be employed in a variety of methods, there has been little examination of how to incorporate such approaches into experimental designs. In this paper, we explain how we incorporated a culturally sensitive framework in a cluster randomized field trial with over 3000 predominantly low-income Latino families, utilizing an intervention designed to improve social relations and enhance family functioning. We offer conceptual and practical examples to guide other researchers who want to adopt a similar approach in their research designs. In addition, we discuss the benefits of forging local partnerships throughout the research process to ensure respect for racial and ethnic minorities participating in social and behavioral experimental studies. We conclude with practical considerations for utilizing a culturally sensitive framework to advance prevention programs, policies, and practices among underrepresented groups in order to achieve the ultimate goal of addressing the traditional underrepresentation of racial and ethnic minorities in research. PMID- 28866845 TI - CORR Insights(r): What Should Define Preoperative Anemia in Primary THA? PMID- 28866844 TI - Generation and characterization of transgenic mouse mesenchymal stem cell lines expressing hIGF-1 or hG-CSF. AB - Mesenchymal stem cells (MSC) are promising tools in the fields of cell therapy and regenerative medicine. In addition to their differentiation potential, MSC have the ability to secrete bioactive molecules that stimulate tissue regeneration. Thus, the overexpression of cytokines and growth factors may enhance the therapeutic effects of MSC. Here we generated and characterized mouse bone marrow MSC lines overexpressing hG-CSF or hIGF-1. MSC lines overexpressing hG-CSF or hIGF-1 were generated through lentiviral vector mediated gene transfer. The expression of hG-CSF or hIGF-1 genes in the clones produced was quantified by qRT-PCR, and the proteins were detected in the cell supernatants by ELISA. The cell lines displayed cell surface markers and differentiation potential into adipocytes, osteocytes and chondrocytes similar to the control MSC cell lines, indicating the conservation of their phenotype even after genetic modification. IGF-1 and G-CSF transgenic cells maintained immunosuppressive activity. Finally, we performed a comparative gene expression analysis by qRT-PCR array in the cell lines expressing hIGF-1 and hG-CSF when compared to the control cells. Our results demonstrate that the cell lines generated may be useful tools for cell therapy and are suitable for testing in disease models. PMID- 28866846 TI - MyHealthRecord in Australian Primary Health Care: An Attitudinal Evaluation Study. AB - Australia's investment in the national MyHealthRecord has not been successfully communicated to the myriad of stakeholder groups, resulting in negative perceptions about the system and serious consequences for the uptake of the MyHealthRecord. Local stakeholder attitudes and perceptions will be crucial in setting the scene for success or failure with MyHealthRecord. A survey was undertaken to identify primary healthcare provider perceptions of the MyHealthRecord system, and capture the perceived enablers and barriers for use of the MyHealthRecord system. Almost all (89%) of the twenty-seven (27) respondents had previously heard of the MyHealthRecord system prior to completing the survey. Enablers included a decrease in duplication of effort and an increase in continuity of care. However, concerns about the perceived impact on healthcare provider time, privacy, access controls, and the need for full participation will need to be managed if MyHealthRecord is to be successfully implemented. The MyHealthRecord system will only be perceived as trustworthy when there is full participation by healthcare organisations, providers, and consumers. If Australian consumers become participants in an opt-out approach, it will be a catalyst for participation by healthcare organisations and providers. Incentives to encourage MyHealthRecord participation need to be extended to all healthcare providers as healthcare provider attitudes are influential with consumers. Therefore MyHealthRecord training and education needs to be targeted towards healthcare providers. Research into the attitudes of the local healthcare provider cohort is valuable in creating a change management strategy for maximising local success. PMID- 28866848 TI - CORR Insights(r): Does Postoperative Glenoid Retroversion Affect the 2-Year Clinical and Radiographic Outcomes for Total Shoulder Arthroplasty? PMID- 28866847 TI - Successful conservative management of an anastomotic airway dehiscence at the left main bronchus following bilateral cadaveric lung transplantation. AB - There is a dearth of data on management of anastomotic airway dehiscence following lung transplantation. Herein we report a case of successful conservative management of an anastomotic airway dehiscence after cadaveric donor lung transplantation. A 41-year-old woman with primary ciliary dyskinesia underwent cadaveric bilateral lung transplantation without cardiopulmonary bypass. On the postoperative day 25, left pneumothorax developed and bronchoscopy demonstrated a localized anastomotic dehiscence at the left main bronchus. The dehiscence was managed with 2 weeks of pleural drainage and was completely covered with regenerated bronchial epithelium at 4 months after transplantation. There is no finding suggestive of significant stenosis at 4 years of follow-up. Our case suggested asymptomatic and localized anastomotic dehiscence does not always require endobronchial stent placement or re-operation. Multiple factors that may contribute to the successful conservative management were discussed in this article. PMID- 28866849 TI - Association of MSI2 Gene Polymorphism with Age-at-Onset of Schizophrenia in a Chinese Population. PMID- 28866850 TI - Can Biomarkers Help the Early Diagnosis of Parkinson's Disease? AB - Parkinson's disease (PD) is a complex neurodegenerative disease with progressive loss of dopamine neurons. PD patients usually manifest a series of motor and non motor symptoms. In order to provide better early diagnosis and subsequent disease modifying therapies for PD patients, there is an urgent need to identify sensitive and specific biomarkers. Biomarkers can be divided into four categories: clinical, imaging, biochemical, and genetic. Ideal biomarkers not only improve our understanding of PD pathogenesis and progression, but also provide benefits for early risk evaluation and clinical diagnosis of PD. Although many efforts have been made and several biomarkers have been extensively investigated, few if any have been found useful for early diagnosis. Here, we summarize recent developments in the discovered biomarkers of PD and discuss their merits and limitations for the early diagnosis of PD. PMID- 28866852 TI - Clinical and biochemical response to neridronate treatment in a patient with osteoporosis-pseudoglioma syndrome (OPPG). AB - Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive syndrome characterized by juvenile-onset osteoporosis and ocular abnormalities due to a low-density lipoprotein receptor-related protein 5 (LRP5) gene mutation. Treatment with bisphosphonates, particularly with pamidronate and risedronate, has been reported to be of some efficacy in this condition. We report on a patient with OPPG due to an LRP5 gene mutation, who showed an encouraging response after a 36-month period of neridronate therapy. We report a case of a patient treated with bisphosphonates. Bisphosphonates should be administered in OPPG patients as a first-line therapy during early childhood. PMID- 28866853 TI - Changes of soil thermal and hydraulic regimes in the Heihe River Basin. AB - Soil thermal and hydraulic regimes are critical factors influencing terrestrial processes in cold regions. Collection of field data from frozen ground has occurred at point scales, but limited data exist that characterize changes of soil thermal and hydraulic regimes at the scale of the whole Heihe River Basin. This study uses a long-term regional climate model coupled with land surface model to investigate the soil thermal and hydraulic regime changes at a large spatial scale. It also explores potential factors, including the climate and non climate factors. Results show that there is significant variability in mean annual air temperature (MAAT) of about 0.47 degrees C/decade during 1980-2013. A time series of area-averaged mean annual soil temperature (MAST) over the whole Heihe River Basin shows a significant increase between 0.25 and 0.36 degrees C/decade during 1984-2013, with a net change of 0.9 degrees C. A trend of increasing wetness is found in soil moisture. Frozen days (FD) decreased significantly both in seasonally frozen ground (SFG) regions and permafrost regions, with a net change between 7 and 13 days during 1984-2013. Freezing index (FI) had a positive effect on FD, while thawing index (TI), MAAT, precipitation, and normalized difference vegetation index (NDVI) had a negative effect. These results are important to understand dynamic mechanisms of soil freeze/thaw cycles. PMID- 28866851 TI - Systematic transcriptome-wide analysis of mRNA-miRNA interactions reveals the involvement of miR-142-5p and its target (FOXO3) in skeletal muscle growth in chickens. AB - The goal of this study was to perform a systematic transcriptome-wide analysis of mRNA-miRNA interactions and to identify candidates involved in the interplay between miRNAs and mRNAs that regulate chicken muscle growth. We used our previously published mRNA (GSE72424) and miRNA (GSE62971) deep sequencing data from two-tailed samples [i.e., the highest (h) and lowest (l) body weights] of Recessive White Rock (WRR) and Xinghua (XH) chickens to conduct integrative analyses of the miRNA-mRNA interactions involved in chicken skeletal muscle growth. A total of 162, 15, 173, and 27 miRNA-mRNA pairs with negatively correlated expression patterns were identified in miRNA-mRNA networks constructed on the basis of the WRRh vs. XHh, WRRh vs. WRRl, WRRl vs. XHl, and XHh vs. XHl comparisons, respectively. Ingenuity Pathway Analysis revealed that gene networks identified for the WRRh vs. XHh contrast were associated with developmental disorders. Importantly, the WRRh vs. XHh contrast miRNA-mRNA network was enriched in IGF-1 signaling pathway genes, including FOXO3. A dual-luciferase reporter assay showed that FOXO3 was a target of miR-142-5p. Furthermore, miR-142-5p overexpression significantly decreased FOXO3 mRNA levels and promoted the expression of growth-related genes. These data demonstrated that miR-142-5p targets FOXO3 and promotes growth-related gene expression and regulates skeletal muscle growth in chicken. Comprehensive analysis facilitated the identification of miRNAs and target genes that might contribute to the regulation of skeletal muscle development. Our results provide new clues for understanding the molecular basis of chicken growth. PMID- 28866854 TI - Health-Related Quality of Life and Oropharyngeal Dysphagia: A Systematic Review. AB - The negative impact of increased bolus modification on health-related quality of life (HRQoL) in persons with oropharyngeal dysphagia (OD) has been described in previous literature; however, findings may have been influenced by the severity of OD and underlying etiology. The current systematic review therefore aims to investigate the relationships between HRQoL and OD and to report on changes in HRQoL and OD following intervention. This review was conducted in accordance with the PRISMA statement. A systematic search of the literature was performed using PubMed and Embase. All available English publications up to February 2016 that reported on OD and HRQoL were included. Articles that studied OD arising from esophageal dysfunction or included less than 15 participants with OD, were excluded. Thirty-five studies met the inclusion criteria. Inverse bidirectional relationships were found between decreased HRQoL and increased OD severity. Following intervention, changes were evident through improved HRQoL with decreased OD severity. The findings of this paper highlight the importance of targeting HRQoL in patients with OD. However, because of the heterogeneity in methodology, terminology, and assessment procedures used in the retrieved articles, the generalization of study results is limited. More research investigating the relationships between HRQoL and OD is needed. Future studies should implement study designs that lead to stronger levels of evidence, quantify the severity of OD and underlying diseases, use validated measures and less ambiguous terminology. PMID- 28866856 TI - Accuracy of Modified Checklist for Autism in Toddlers (M-CHAT) in Detecting Autism and Other Developmental Disorders in Community Clinics. AB - This study determined the accuracy of Modified Checklist for Autism in Toddlers (M-CHAT) in detecting toddlers with autism spectrum disorder (ASD) and other developmental disorders (DD) in community mother and child health clinics. We analysed 19,297 eligible toddlers (15-36 months) who had M-CHAT performed in 2006 2011. Overall sensitivities for detecting ASD and all DD were poor but better in the 21 to <27 months and 27-36-month age cohorts (54.5-64.3%). Although positive predictive value (PPV) was poor for ASD, especially the younger cohort, positive M-CHAT helped in detecting all DD (PPV = 81.6%). This suggested M-CHAT for screening ASD was accurate for older cohorts (>21 months) and a useful screening tool for all DD. PMID- 28866855 TI - Associations between Prosocial and Problem Behavior from Early to Late Adolescence. AB - Though recent research has highlighted prosocial behavior as negatively associated with problem behavior during adolescence, we know little about how these variables might be associated longitudinally, whether there are bidirectional effects, and whether there might be different patterns of co occurrence of behaviors for different individuals. Thus, the current study examined relations between prosocial and problem behaviors in three different ways in an attempt to better understand these associations. Participants included 500 adolescents recruited from a Northwestern state in the USA who took part in the study every year from age 12 to 18 (50% female, 67% European American). Growth curve analyses suggested that change in prosocial behavior was negatively associated with change in aggression and delinquency over time. A longitudinal panel model suggested that prosocial behavior and aggression were negatively associated bidirectionally, and that prosocial behavior was negatively associated with delinquency over time. Finally, mixture modeling conducted at ages 12, 15, and 18 revealed heterogeneity in the ways in which prosocial and problem behaviors co-occur. The discussion focuses on the complexity of interrelations between prosocial behavior and problem behavior across adolescence. PMID- 28866857 TI - Malachite Green and Crystal Violet Decolorization by Ganoderma lucidum and Pleurotus ostreatus Supernatant and by rGlLCC1 and rPOXA 1B Concentrates: Molecular Docking Analysis. AB - Laccases catalyze the oxidation of various aromatic organic compounds concomitantly with molecular oxygen reduction to water. Triphenylmethane dyes are synthetic compounds widely used in diverse industries. Their removal from effluents is difficult, due to their high degree of structural complexity; hence, their high concentration in effluents cause a negative impact on the environment. In the present work, molecular docking was used to evaluate interactions between rGlLCC1 or rPOXA 1B enzymes with Crystal Violet (CV) or Malachite Green (MG) dyes. In addition, removal tests of the two dyes were performed. Van der Waals interactions were obtained for only the CV dye for both GlLCC1 and POXA 1B enzymes. Nevertheless, in the GlLCC1 model, two pi-pi interactions were observed. For the MG dye only, Van der Waals interactions were obtained. Moreover, amino acid composition interacting in each model with each dye was similar. It is important to highlight that by molecular docking, none of the estimated ligand configurations generated hydrogen bonds. Thus, explaining the difficulty to degrade CV and MG. Regarding CV, maximum decolorization percentage was 23.6 +/- 1.0% using Ganoderma lucidum supernatant and 5.0 +/- 0.5% with Pleurotus ostreatus supernatant. When using recombinant laccase enzyme concentrates, decolorization percentages were 9.9 +/- 0.1 and 7.5 +/- 1.0% for rGlLCC1 and rPOXA 1B, respectively. On the other hand, for the MG dye, maximum decolorization percentages were 52.1 +/- 5.1 and 2.3 +/- 0.2% using G. lucidum and P. ostreatus concentrates, respectively. Whereas with recombinant laccase enzymatic concentrates, values of 9.4 +/- 0.8% were obtained, with rGlLCC1, and 2.1 +/- 0.1% when using rPOXA 1B. These findings represent an important step in bioremediation processes improvement and efficiency of industry-generated products, using environmentally friendly alternatives. PMID- 28866858 TI - Sensory, Physico-Chemical and Water Sorption Properties of Corn Extrudates Enriched with Spirulina. AB - This study compares the quality of extrudates made from corn grits with the addition of up to 8% of spirulina powder. The sensory properties (shape, color, aroma, taste and crispness), chemicals (content of water, protein, fat, ash, fiber, carbohydrates, carotenoids, chlorophyll and phycocyanin) and physical properties (color, water absorption index, expansion indices, texture and water sorption properties) were determined. It has been found that spirulina-enriched extrudates had slightly lower sensory scores, but the addition of spirulina improved their nutritional value. The contents of protein, ash, fiber and beta carotene increased in extrudates with 8% of spirulina by 34, 36, 140 and 1,260%, respectively. The increasing addition of spirulina caused a decrease in extrudates lightness, an increase in their greenness and yellowness accompanied by a decrease of expansion indices and an increase of softness. Only small differences were found in water sorption properties, suggesting a similar behavior of spirulina-enriched extrudates during storage. PMID- 28866859 TI - Toxin Gene Contents and Activity of Bacillus thuringiensis Strains Against Two Sugarcane Borer Species, Diatraea saccharalis (F.) and D. flavipennella (Box). AB - Bacillus thuringiensis (Berliner) bears essential characteristics in the control of insect pests, such as its unique mode of action, which confers specificity and selectivity. This study assessed cry gene contents from Bt strains and their entomotoxicity against Diatraea saccharalis (F.) and Diatraea flavipennella (Box) (Lepidoptera: Crambidae). Bioassays with Bt strains were performed against neonates to evaluate their lethal and sublethal activities and were further analyzed by PCR, using primers to identify toxin genes. For D. saccharalis and D. flavipennella, 16 and 18 strains showed over 30% larval mortality in the 7th day, respectively. The LC50 values of strains for D. saccharalis varied from 0.08 * 105 (LIIT-0105) to 4104 * 105 (LIIT-2707) spores + crystals mL-1. For D. flavipennella, the LC50 values of strains varied from 0.40 * 105 (LIIT-2707) to 542 * 105 (LIIT-2109) spores + crystals mL-1. For the LIIT-0105 strain, which was the most toxic to D. saccharalis, the genes cry1Aa, cry1Ab, cry1Ac, cry1B, cry1C, cry1D, cry1F, cry1I, cry2Aa, cry2Ab, cry8, and cry9C were detected, whereas for the strain LIIT-2707, which was the most toxic to D. flavipennella, detected genes were cry1Aa, cry1Ab, cry1Ac, cry1B, cry1D, cry1F, cry1I, cry2Aa, cry2Ab, and cry9. The toxicity data and toxin gene content in these strains of Bt suggest a great variability of activity with potential to be used in the development of novel biopesticides or as source of resistance genes that can be expressed in plants to control pests. PMID- 28866860 TI - Protective Effects of Dietary Garlic Powder Against Cadmium-induced Toxicity in Sea Bass Liver: a Chemical, Biochemical, and Transcriptomic Approach. AB - To investigate the protective effect of garlic powder on cadmium-induced toxicity sea bass liver, juvenile fishes where maintained under three food diets (diet 1: normal without garlic supply, diet 2: 2% garlic powder; diet 3: 6% garlic powder). After 30 days of specific diets, each group was injected with 500 MUg kg 1of Cd. The control group was the one fed with normal diet and not injected with Cd. Liver Cd, Zn, and Se loads was assessed after 1 and 3 days of Cd injections. Moreover, antioxidant enzymes activities termed as catalase, superoxide dismutase, and glutathione peroxydase as well as their gene expression levels were monitored. Finally, metallothionein protein accumulation and its gene expression regulation (MTa) were determined. In fish fed with 2 and 6% garlic powder, the amounts of Cd, Zn, and Se significantly increase in liver tissues. Two percent garlic powder specific diet reversed the Cd-induced inhibition of catalase (CAT), superoxide dismutase (SOD), and gluthathione peroxydase (GPx) and restored the Cd-induced lipid peroxidation (MDA). The increase of liver metallothionein proteins as well as the MTa gene expression level under Cd influence was more pronounced in animals maintained for 30 days under garlic power 2% diet. Our data must be carefully considered in view of the garlic powder introduction in sea bass food composition at 2% since it is an efficient prevention against Cd-induced alterations. PMID- 28866861 TI - Effects of the Proton Pump Inhibitors Omeprazole and Pantoprazole on the Cytochrome P450-Mediated Metabolism of Venlafaxine. AB - : BACKGROUND AND OBJECTIVE: An increasing trend in prescribing proton pump inhibitors (PPIs) inevitably increases the risk of unwanted drug-drug interactions (DDIs). The aim of this study was to uncover pharmacokinetic interactions between two PPIs-omeprazole and pantoprazole-and venlafaxine. METHODS: A therapeutic drug monitoring database contained plasma concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine. We considered three groups: a group of patients who received venlafaxine without confounding medications (non-PPI group, n = 906); a group of patients who were comedicated with omeprazole (n = 40); and a group of patients comedicated with pantoprazole (n = 40). Plasma concentrations of venlafaxine, O-desmethylvenlafaxine and active moiety (venlafaxine + O-desmethylvenlafaxine), as well as dose-adjusted plasma concentrations, were compared using non-parametrical tests. RESULTS: Daily doses of venlafaxine did not differ between groups (p = 0.949). The Mann-Whitney U test showed significantly higher plasma concentrations of active moiety, as well as venlafaxine and O-desmethylvenlafaxine, in both PPI groups [p = 0.023, p = 0.011, p = 0.026, +29% active moiety, +27% venlafaxine, +36% O-desmethylvenlafaxine (pantoprazole); p = 0.003, p = 0.039 and p < 0.001, +36% active moiety, +27% venlafaxine, +55% O-desmethylvenlafaxine (omeprazole)]. Significantly higher concentration-by-dose (C/D) values for venlafaxine and active moiety were detected in the pantoprazole group (p = 0.013, p = 0.006, respectively), while in the omeprazole group, C/D ratios for all three parameters-venlafaxine, O desmethylvenlafaxine and active moiety-were significantly higher (p = 0.021, p < 0.001 and p < 0.001, respectively). CONCLUSIONS: Significantly higher plasma concentrations for all parameters (venlafaxine, O-desmethylvenlafaxine, active moiety) suggest clinically relevant inhibitory effects of both PPIs, most likely on the cytochrome P450 (CYP) 2C19-mediated metabolism of venlafaxine. The findings might be the result of different degrees of CYP2C19 involvement, therefore the inhibition of CYP2C19 by both PPIs may lead to an increased metabolism via CYP2D6 to O-desmethylvenlafaxine. PMID- 28866862 TI - Acetylshikonin is a novel non-selective cytochrome P450 inhibitor. AB - Acetylshikonin is a biologically active compound with anti-cancer and anti inflammatory activity, which is isolated from the roots of Lithospermum erythrorhizoma. An inhibitory effect of acetylshikonin against CYP2J2 activity was discovered recently. Based on this result, this study was expanded to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed a strong inhibitory effect against all P450s tested with IC50 values of 1.4-4.0 MU m. Pre-incubation of acetylshikonin with HLMs and NADPH did not alter the inhibition potency, indicating that acetylshikonin is not a mechanism-based inhibitor. SKF-525A, a widely used non-specific P450 inhibitor, had no inhibitory activity against CYP1A2, 2A6, 2E1 and 2J2, while it showed an inhibitory effect against CYP2B6, CYP2C19 and 2D6 with IC50 values of 2.5, 3.6 and 0.5 MU m, respectively. Our findings indicate that acetylshikonin may be a novel general P450 inhibitor, which could replace SKF-525A. PMID- 28866863 TI - From transcriptional complexity to cellular phenotypes: Lessons from yeast. AB - Pervasive transcription has been reported in many eukaryotic organisms, revealing a highly interleaved transcriptome organization that involves thousands of coding and non-coding RNAs. However, to date, the biological impact of transcriptome complexity is still poorly understood. Here I will review how subtle variations of the transcriptome can lead to divergent cellular phenotypes by fine-tuning both its coding potential and regulation. I will discuss strategies that can be used to link molecular variations with divergent biological outcomes. Finally, I will explore the implication of transcriptional complexity for our understanding of gene expression in the context of cell-to-cell phenotypic variability. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28866865 TI - Increased levels of mitochondrial DNA copy number in patients with vitiligo. AB - BACKGROUND: Oxidative stress is known to be involved in the pathogenesis of autoimmune diseases such as vitiligo. Evidence suggests that the human mitochondrial DNA copy number (mtDNAcn) is vulnerable to damage mediated by oxidative stress. The purpose of this study was to examine and compare peripheral blood mtDNAcn and oxidative DNA damage byproducts (8-hydroxy-2-deoxyguanosine; 8 OHdG) in patients with vitiligo and healthy controls (HCs). METHODS: The relative mtDNAcn and the oxidative damage (formation of 8-OHdG in mtDNA) of each sample were determined by real-time quantitative PCR. Blood samples were obtained from 56 patients with vitiligo and 46 HCs. RESULTS: The mean mtDNAcn and the degree of mtDNA damage were higher in patients with vitiligo than in HCs. CONCLUSION: These data suggest that increase in mtDNAcn and oxidative DNA damage may be involved in the pathogenesis of vitiligo. PMID- 28866864 TI - The association between insulin resistance and atrial fibrillation: A cross sectional analysis from SPRINT (Systolic Blood Pressure Intervention Trial). AB - It is unclear whether metabolic syndrome (MetS) is associated with atrial fibrillation (AF) in an older population with greater cardiovascular risk, including those with chronic kidney disease. The authors investigated the association between MetS and AF in participants in SPRINT (Systolic Blood Pressure Intervention Trial). MetS was defined based on the Modified Third National Cholesterol Education Program. The baseline prevalence rate for MetS was 55%, while 8.2% of the participants had AF. In multivariate regression analyses, AF was not associated with presence of MetS in either chronic kidney disease or non-chronic kidney disease subgroups. Age, race, history of cardiovascular diseases, decreased triglycerides, decreased pulse pressure, and albuminuria remained significantly associated with AF risk. In contrast to the general population, MetS was not associated with AF in the older population with increased cardiovascular risk studied in SPRINT. PMID- 28866867 TI - Morphoea after using a cardiac loop monitor. PMID- 28866866 TI - Hospital and out-of-hospital mortality in 670 hypertensive emergencies and urgencies. AB - Long-term mortality in patients with acute severe hypertension is unclear. The authors aimed to compare short-term (hospital) and long-term (12 months) mortality in these patients. A total of 670 adults presenting for acute severe hypertension between January 1, 2015, and December 31, 2015, were included. A total of 57.5% were hypertensive emergencies and 66.1% were hospitalized: 98% and 23.2% of those with hypertensive emergencies and urgencies, respectively (P = .001). Hospital mortality was 7.9% and was significantly higher for hypertensive emergencies (12.5% vs 1.8%, P = .001). At 12 months, 106 patients died (29.4%), mainly from hypertensive emergencies (38.9% vs 8.9%, P = .001). Median survival was 14 days for neurovascular emergencies and 50 days for cardiovascular emergencies. Patients with hypertensive emergencies or urgencies had bad long term prognosis. Short-term mortality is mainly caused by neurovascular emergencies, but cardiovascular emergencies are severe, with high mortality at 12 months. These results justify better follow-up and treatment for these patients. PMID- 28866869 TI - Total anomalous pulmonary venous connection (TAPVC): A familial cluster of 3 siblings. AB - Total anomalous pulmonary venous connection (TAPVC) is a rare form of cyanotic congenital heart disease (CHD) that occurs when the pulmonary veins drain into a site other than the morphologic left atrium. As with other forms of CHD, TAPVC has been shown to cluster in families and is known to have genetic association. We report on a case series of familial TAPVC in three consecutive siblings. A combination of fetal echocardiography, transthoracic echocardiography, as well as cross-sectional imaging was utilized in the diagnosis as well as management of each sibling. The third sibling was subsequently found to have a partial deletion in chromosome 15q13.3, which has been rarely associated with other forms of congenital heart disease. PMID- 28866868 TI - The lncRNA HNF1A-AS1 is a negative prognostic factor and promotes tumorigenesis in osteosarcoma. AB - Recent studies have revealed that long noncoding RNA HNF1A-antisense 1 (HNF1A AS1) plays an important role in the development of several human malignancy entities. However, the expression and function of HNF1A-AS1 in the carcinogenesis and development of osteosarcoma remains unknown. In this study, we detected the HNF1A-AS1 levels in human osteosarcoma tissues and cell lines by quantitative real-time polymerase chain reaction (qRT-PCR), and investigated its role in osteosarcoma by using in vitro assays. Our study showed that HNF1A-AS1 expression was significantly up-regulated in human osteosarcoma tissues and cell lines compared with their normal counterparts, and its expression level was positively correlated with the distance metastasis (P = 0.009) and tumour stage (P = 0.019). Moreover, Kaplan-Meier curves with the log-rank test showed that higher expression of HNF1A-AS1 conferred a significantly poorer survival and multivariate Cox proportional hazards analysis revealed that HNF1A-AS1 was an independent risk factor of overall survival. In addition, the expression of HNF1A AS1 in serum is correlated with patients' status and receiver operating characteristic (ROC) curve analysis demonstrated that HNF1A-AS1 could distinguish patients with osteosarcoma from healthy individuals (the area under curve 0.849, P < 0.001). Furthermore, in vitro knockdown of HNF1A-AS1 by siRNA significantly inhibited cell proliferation and G1 /S transition, and suppressed migration and invasion by reducing the epithelial-mesenchymal transition (EMT) program in osteosarcoma cells. Taken together, our data suggested that HNF1A-AS1 is a novel molecule involved in osteosarcoma progression, which may provide as a potential diagnostic, prognostic biomarker and therapeutic target. PMID- 28866870 TI - Secondary syphilis infection under treatment with ustekinumab. PMID- 28866872 TI - Abstracts from the Sixth Chinese Congress on Gerontology and Health Industry. PMID- 28866871 TI - Introduction of Abstracts to be Presented at the Sixth Chinese Congress on Gerontology and Health Industry. PMID- 28866873 TI - Carbon isotope fractionation by anoxygenic phototrophic bacteria in euxinic Lake Cadagno. AB - Anoxygenic phototrophic bacteria utilize ancient metabolic pathways to link sulfur and iron metabolism to the reduction of CO2 . In meromictic Lake Cadagno, Switzerland, both purple sulfur (PSB) and green sulfur anoxygenic phototrophic bacteria (GSB) dominate the chemocline community and drive the sulfur cycle. PSB and GSB fix carbon utilizing different enzymatic pathways and these fractionate C isotopes to different extents. Here, these differences in C-isotope fractionation are used to constrain the relative input of various anoxygenic phototrophs to the bulk community C-isotope signal in the chemocline. We sought to determine whether a distinct isotopic signature of GSB and PSB in the chemocline persists in the settling fraction and in the sediment. To answer these questions, we also sought investigated C-isotope fractionation in the water column, settling material, and sediment of Lake Cadagno, compared these values to C-isotope fractionation of isolated anoxygenic phototroph cultures, and took a mass balance approach to investigate relative contributions to the bulk fractionation signature. We found a large C-isotope fractionation between dissolved inorganic carbon (DIC) and particulate organic carbon (POC) in the Lake Cadagno chemocline. This large fractionation between the DIC and POC was also found in culture experiments carried out with anoxygenic phototrophic bacteria isolated from the lake. In the Lake Cadagno chemocline, anoxygenic phototrophic bacteria controlled the bulk C isotope fractionation, but the influence of GSB and PSB differed with season. Furthermore, the contribution of PSB and GSB to bulk C-isotope fractionation in the chemocline could be traced in the settling fraction and in the sediment. Taken together with other studies, such as lipid biomarker analyzes and investigations of other stratified lakes, these results offer a firmer understanding of diagenetic influences on bacterial biomass. PMID- 28866874 TI - Two-site evaluation of the diagnostic performance of the Sysmex XN Body Fluid (BF) module for cell count and differential in Cerebrospinal Fluid. AB - INTRODUCTION: Cellular analysis in cerebrospinal fluid (CSF) provides important diagnostic information in many pathological settings. The aim of this two-site study was to evaluate the Sysmex XN Body Fluid mode (XN-BF) for cell analysis of CSF compared to light microscopy (LM). METHODS: Two hundred and seven consecutive CSF samples were analyzed in parallel with XN-BF and LM. The study also included the estimation of the limit of blank (LoB), limit of detection (LoD), limit of quantitation (LoQ), carry-over and linearity of XN-BF module. RESULTS: LoQ of white blood cells (WBC) was 3*106 cells/L; linearity was good and carry-over negligible. XN-BF parameters were compared to LM for the following cell classes: total cells, WBC, polymorphonuclear (PMN), and mononuclear (MN) cells. The bias ranged from 1.3 to 15.2*106 cells/L. The receiver operating characteristics curve analysis for WBC showed an area under the curve of 0.98, and the global diagnostic agreement was 95% at a cutoff of 5*106 cells/L. CONCLUSIONS: XN-BF provides rapid and accurate counts in clinically relevant ranges of CSF values, thus providing a valuable alternative to conventional LM analysis. However, microscopic review remains advisable in samples with abnormal cell counts or high fluorescent (HF-BF) cell parameter exceeding 5*106 cells/L. PMID- 28866875 TI - Substance P and Calcitonin Gene-Related Peptide in the Glands of External Auditory Canal Skin. AB - OBJECTIVES: The earwax (cerumen) that covers external auditory canal (EAC) skin contains a mixture of ceruminous and sebaceous gland substances, such as lipids, peptides, and proteins. The components secreted from the ceruminous gland that is a modified sweat gland form cerumen and contain several antimicrobial factors. Since substance P (SP) and calcitonin gene-related peptide (CGRP), known as a secretagogue, have been found in sweat glands, our purpose was to determine the expression of SP and CGRP in the glands of EAC skin. METHODS: Sections of normal human EAC skins were immunostained for the presence of SP and CGRP using polyclonal antibodies. Immunoreactivity was detected using an avidin-biotin peroxidase complex method. RESULTS: SP staining was found in ceruminous gland acini and myoepithelial cells. But the SP staining was not found in the sebaceous glands and epidermal region. CGRP was strongly stained in the ceruminous gland and weakly in the sebaceous gland cells. Interestingly, most prominent staining of SP and CGRP was noted in the myoepithelial cells of the ceruminous gland. CONCLUSION: The findings in this study suggest that SP and CGRP are expressed in the glands of the EAC skin and secreted in the process of ceruminous gland secretion. PMID- 28866876 TI - Understanding the Chicago Classification: From Tracings to Patients. AB - Current parameters of the Chicago classification include assessment of the esophageal body (contraction vigour and peristalsis), lower esophageal sphincter relaxation pressure, and intra-bolus pressure pattern. Esophageal disorders include achalasia, esophagogastric junction outflow obstruction, major disorders of peristalsis, and minor disorders of peristalsis. Sub-classification of achalasia in types I, II, and III seems to be useful to predict outcomes and choose the optimal treatment approach. The real clinical significance of other new parameters and disorders is still under investigation. PMID- 28866877 TI - Occurrence and Source Effect of Novel Brominated Flame Retardants (NBFRs) in Soils from Five Asian Countries and Their Relationship with PBDEs. AB - This paper presents the first comprehensive survey of 19 novel brominated flame retardants (NBFRs) in soil samples collected among five Asian countries. High variability in concentrations of all NBFRs was found in soils with the geometric mean (GM) values ranging from 0.50 ng/g dry weight (dw) in Vietnam to 540 ng/g dw in the vicinity of a BFR manufacturer in China. In urban, rural, and background locations, the GM concentrations of ?19NBFRs decreased in the order of Japan > South Korea > China > India > Vietnam. Correlations among different NBFR compounds were positive and statistically significant (p < 0.05), suggesting that they originate from similar sources. Evidence for simultaneous application between polybrominated diphenyl ethers (PBDEs) and NBFRs were also noted. Principal component analysis of NBFR concentrations revealed specific pollution sources for different NBFRs coming from urban, BFR-related industrial, and e waste sites. For the first time, this study demonstrates a "point source fractionation effect" for NBFRs and PBDEs. The concentrations of all NBFRs and PBDEs were negatively and significantly correlated with the distance from BFR related industrial and e-waste regions. Positive and significant correlation between population density and NBFR concentrations in soils was identified. Our study revealed that the primary sources effects were stronger than the secondary sources effects in controlling the levels and distribution of NBFRs and PBDEs in soils in these five Asian countries. PMID- 28866878 TI - Design of Multifunctional Nanostructure for Ultrafast Extraction and Purification of Aflatoxins in Foodstuffs. AB - Aflatoxins (AFs) are a class of carcinogens, associated with liver cancers, that exist in foodstuffs. There are extremely low maximum limits of AFs in foodstuffs (0.025-20 MUg.kg-1). Quick and sensitive detection of such low concentration of AFs in foodstuffs is dominated by the efficiency and selectivity of the AF enrichment process, which is extremely challenging although substantial efforts have been made in recent decades. Here we design and synthesize a multilayer nanoarchitecture composed of a broad-spectrum aflatoxin monoclonal antibody shell, chitosan middle layer, and magnetic bead core (denoted AF-mAb/CTS/Fe3O4). The efficiency of AF-mAb/CTS/Fe3O4 in extracting AFs has been found to be more than 60 times higher than both conventional immunoaffinity chromatography and solid-phase extraction. Furthermore, the nanocomposite displays excellent selectivity and good reusability as well as outstanding efficiency. When coupled to ultraperformance liquid chromatography-tandem quadrupole mass spectrometry, this new nanoarchitecture enables us to probe six AFs at concentrations as low as 0.003 MUg.kg-1 in foodstuffs with free matrix effects, which is nearly 10 times smaller than the regulated maximum tolerated does. It is believed that the new nanoarchitecture will provide an efficient and fast pathway to detect AFs in foodstuffs to protect human being from some critical liver cancers. PMID- 28866879 TI - Versatility of Prolyl Oligopeptidase B in Peptide Macrocyclization. AB - Cyclic peptides are promising compounds for new chemical biological tools and therapeutics due to their structural diversity, resistance to proteases, and membrane permeability. Amatoxins, the toxic principles of poisonous mushrooms, are biosynthesized on ribosomes as 35mer precursor peptides, which are ultimately converted to hydroxylated bicyclic octapeptides. The initial cyclization steps, catalyzed by a dedicated prolyl oligopeptidase (POPB), involves removal of the 10 amino acid leader sequence from the precursor peptide and transpeptidation to produce a monocyclic octapeptide intermediate. The utility of POPB as a general catalyst for peptide cyclization was systematically characterized using a range of precursor peptide substrates produced either in E. coli or chemically. Substrates produced in E. coli were expressed either individually or in mixtures produced by codon mutagenesis. A total of 127 novel peptide substrates were tested, of which POPB could cyclize 100. Peptides of 7-16 residues were cyclized at least partially. Synthetic 25mer precursor peptide substrates containing modified amino acids including d-Ala, beta-Ala, N-methyl-Ala, and 4-hydroxy-Pro were also successfully cyclized. Although a phalloidin heptapeptide with all L amino acids was not cyclized, partial cyclization was seen when l-Thr at position #5 was replaced with the naturally occurring D amino acid. POPB should have broad applicability as a general catalyst for macrocyclization of peptides containing 7 to at least 16 amino acids, with an optimum of 8-9 residues. PMID- 28866880 TI - A Multiaxial Molecular Ferroelectric with Highest Curie Temperature and Fastest Polarization Switching. AB - The classical organic ferroelectric, poly(vinylidene fluoride) (PVDF), has attracted much attention as a promising candidate for data storage applications compatible with all-organic electronics. However, it is the low crystallinity, the large coercive field, and the limited thermal stability of remanent polarization that severely hinder large-scale integration. In light of that, we show a molecular ferroelectric thin film of [Hdabco][ReO4] (dabco = 1,4 diazabicyclo[2.2.2]octane) (1), belonging to another class of typical organic ferroelectrics. Remarkably, it displays not only the highest Curie temperature of 499.6 K but also the fastest polarization switching of 100k Hz among all reported molecular ferroelectrics. Combined with the large remanent polarization values (~9 MUC/cm2), the low coercive voltages (~10 V), and the unique multiaxial ferroelectric nature, 1 becomes a promising and viable alternative to PVDF for data storage applications in next-generation flexible devices, wearable devices, and bionics. PMID- 28866881 TI - Ascaroside Profiling of Caenorhabditis elegans Using Gas Chromatography-Electron Ionization Mass Spectrometry. AB - Nematodes such as the model organism Caenorhabditis elegans produce various homologous series of l-ascarylose-derived glycolipids called ascarosides, which include several highly potent signals in intra and interspecies communication as well as cross-kingdom interactions. Given their low concentrations and large number of structurally similar components, mass spectrometric screens based on high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) are commonly employed for ascaroside detection and quantification. Here, we describe a complementary gas chromatography-electron ionization mass spectrometry (GC-EIMS) screen that utilizes an ascarylose-derived K1-fragment ion signal at m/z 130.1 [C6H14OSi]+? to highlight known as well as yet unidentified ascaroside components in TMS-derivatized crude nematode exometabolome extracts. GC-EIMS-based ascaroside profiling of wild-type and mutant C. elegans facilitates the analysis of all basic ascarosides using the same ionization technique while providing excellent resolution for the complete homologous series with side chains ranging from 3 to 33 carbons. Combined screening for m/z 130.1 along with side chain-specific J1 [M - 173]+ and J2 [M - 291]+ fragment ions, as well as additional characteristic marker ions from alpha cleavage, enables convenient structure assignment of ca. 200 components from wild type and peroxisomal beta-oxidation mutants including (omega - 1)-linked acyl, enoyl, beta-hydroxyacyl, and 2-ketoalkyl ascarosides along with their (omega) linked or alpha-methyl isomers and ethanolamide derivatives, as well as 2 hydroxyalkyl ascarosides. Given the widespread availability of GC-MS and its increasing popularity in metabolomics, this method will promote the identification of ascarosides in C. elegans and other nematodes. PMID- 28866882 TI - Organophosphorus Flame Retardants and Plasticizers in Building and Decoration Materials and Their Potential Burdens in Newly Decorated Houses in China. AB - Organophosphorus flame retardants (OPFRs) have been increasingly used in various building and decoration materials to fulfill fire safety standards since the phasing out of polybrominated diphenyl ethers. We determined OPFR concentrations in the most commonly used building and decoration materials available in local markets and online in China. The OPFR concentrations varied significantly, from 14.78 ng/g (putty powder) to 9649000 ng/g (expanded polystyrene panel (EPS)). Relatively high concentrations of OPFRs were found in foam samples, followed by nonwoven and polyvinyl chloride (PVC) wallpaper, PVC pipes, sealing materials, boards, and paints. Low concentrations were found mostly in wall decoration powders, suggesting that no OPFRs had been added to these powders. Tris(1-chloro 2-propyl) phosphate and tris(1,3-dichloro-2-propyl) phosphate were the most detected halogenated OPFRs, while tri-n-butyl phosphate and tris(2-butoxyethyl) phosphate were the dominant nonhalogenated OPFRs, implying that they are commonly used in building and decoration materials. The estimated OPFR burden in interior decoration using nonwoven wallpaper was 330- and 2110-fold higher than that using latex paint and diatomite, respectively. The emission periods of OPFRs from nonwoven and PVC wallpaper may be greater than 13 years. We estimated that the total burden of OPFRs for decoration using wallpaper in newly decorated houses in China is ~63 t/y. Significantly higher concentrations of OPFRs in interior decoration materials, especially nonwoven wallpaper, pose potential health risks to the people using the buildings. PMID- 28866883 TI - Determination of Residual Concentration of Ionic Liquids with Different Anions and Alkyl-Chain Lengths in Water and Soil Samples. AB - Considering the wide synthesis and application of ionic liquids (ILs), the toxicity of ILs has recently gained growing attention. However, few studies focused on IL determination methods in environmental samples. In the present study, we implemented the determination methods for the 12 ILs with different chemical structures using high-performance liquid chromatography (HPLC) and ultraviolet (UV) spectrophotometry. The optimum conditions for extraction of ILs from soil samples were also obtained by single-factor experiments and response surface methodology (RSM). The instrument detection limits (IDLs) reached 10-10 g. Compared to the use of UV, HPLC had the standard curve with stronger correlation (R2 >= 0.999) and lower detection limit. We therefore used HPLC to detect the contents of ILs in water and soil samples. A standard adding method was used for the reliability test of the above methods. The average recovery in water samples was 90.46%-108.83%, and the coefficient of variation (CV) was 0.51% 9.07%. The method detection limits (MDLs) were below 0.1 mg/L. The optimized IL extraction conditions in soil samples were as follows: The ratio of methanol and saturated ammonium chloride was 90:10, the ultrasonic time was 50 min, and the power was 350 W. The average recovery in soil samples was 70.39%-85.30%, and the CV was 0.50%-9.99%. The MDLs were below 1 mg/kg. These results using the aforementioned methods met the standards of residue analysis. The present study can provide scientific analysis methods and a basis for evaluation of the study of IL residues in environmental samples. PMID- 28866884 TI - Discerning Inter- and Intramolecular Vibrations of Sulfur Polyaromatic Compounds. AB - Thiophenes are an important class of molecules in fields as diverse as petrochemistry, molecular electronics, and optoelectronics. Thiophenic submolecular motifs are thought to play a role in molecular association and nanoaggregation phenomena in both pure materials and natural and synthetic mixtures. Vibrational (infrared and Raman) spectroscopy provides the means to characterize these species. In this work far-infrared photoacoustic and low frequency Raman spectra of a series of polycyclic aromatic hydrocarbons containing sulfur have been measured and interpreted using DFT calculations based on a perturbational-variational method coupled with potential truncation. The approach and outcomes illustrate how inter- and intramolecular vibrations for thiophenic systems in single and multicomponent mixtures can be discriminated. This work offers the perspective to search the inter- and intramolecular signatures of the main submolecular motifs and heteroelements postulated as being present in the asphaltenes. PMID- 28866885 TI - Targeted Proteomic Analyses of Histone H4 Acetylation Changes Associated with Homologous-Recombination-Deficient High-Grade Serous Ovarian Carcinomas. AB - Approximately 20% of high-grade serous ovarian cancers are homologous recombination (HR)-deficient due to genetic and epigenetic mutations of HR pathway genes including the tumor suppressor genes BRCA1 and 2. HR deficiency (HRD) compromises cells' ability to efficiently repair DNA damage, but it also increases sensitivity to chemotherapeutic treatment strategies; however, not all ovarian cancer patients with HRD tumors exhibit positive responses to chemotherapy. Our previous iTRAQ-based comprehensive proteomic characterization of high-grade serous ovarian carcinomas found that lower levels of histone H4 acetylation at Lys12 and Lys16 (H4-K12acK16ac) were associated with HRD tumors compared with non-HRD tumors. In the current study, we developed and validated an H4-K12acK16ac parallel-reaction-monitoring (PRM)-targeted mass-spectrometry-based assay to analyze acetylation changes of histone H4 and to determine the association of these changes with total H4, histone acetyltransferase, and histone deacetylase (HDAC) levels. Whereas the levels of H4 and histone acetyltransferases were stable irrespective of HRD status, the levels of histone H4 acetylation and one HDAC, HDAC6, were elevated in the HRD tumors. Relative H4 acetylation levels were also analyzed by an antibody-based approach in additional ovarian tumors. It is possible that specific H4 acetylation at Lys12 and Lys16 associated with HRD could inform chemotherapeutic treatment modalities to improve ovarian cancer patients' treatment response. PMID- 28866886 TI - Efficient Expression of Glutathione Peroxidase with Chimeric tRNA in Amber-less Escherichia coli. AB - The active center of selenium-containing glutathione peroxidase (GPx) is selenocysteine (Sec), which is is biosynthesized on its tRNA in organisms. The decoding of Sec depends on a specific elongation factor and a Sec Insertion Sequence (SECIS) to suppress the UGA codon. The expression of mammalian GPx is extremely difficult with traditional recombinant DNA technology. Recently, a chimeric tRNA (tRNAUTu) that is compatible with elongation factor Tu (EF-Tu) has made selenoprotein expression easier. In this study, human glutathione peroxidase (hGPx) was expressed in amber-less Escherichia coli C321.DeltaA.exp using tRNAUTu and seven chimeric tRNAs that were constructed on the basis of tRNAUTu. We found that chimeric tRNAUTu2, which substitutes the acceptor stem and T-stem of tRNAUTu with those from tRNASec, enabled the expression of reactive hGPx with high yields. We also found that chimeric tRNAUTuT6, which has a single base change (A59C) compared to tRNAUTu, mediated the highest reactive expression of hGPx1. The hGPx1 expressed exists as a tetramer and reacts with positive cooperativity. The SDS-PAGE analysis of hGPx2 produced by tRNAUTuT6 with or without sodium selenite supplementation showed that the incorporation of Sec is nearly 90%. Our approach enables efficient selenoprotein expression in amber-less Escherichia coli and should enable further characterization of selenoproteins in vitro. PMID- 28866887 TI - Triplet Excited State of BODIPY Accessed by Charge Recombination and Its Application in Triplet-Triplet Annihilation Upconversion. AB - The triplet excited state properties of two BODIPY phenothiazine dyads (BDP-1 and BDP-2) with different lengths of linker and orientations of the components were studied. The triplet state formation of BODIPY chromophore was achieved via photoinduced electron transfer (PET) and charge recombination (CR). BDP-1 has a longer linker between the phenothiazine and the BODIPY chromophore than BDP-2. Moreover, the two chromophores in BDP-2 assume a more orthogonal geometry both at the ground and in the first excited state (87 degrees ) than that of BDP-1 (34-40 degrees ). The fluorescence of the BODIPY moiety was significantly quenched in the dyads. The charge separation (CS) and CR dynamics of the dyads were studied with femtosecond transient absorption spectroscopy (kCS = 2.2 * 1011 s-1 and 2 * 1012 s-1 for BDP-1 and BDP-2, respectively; kCR = 4.5 * 1010 and 1.5 * 1011 s-1 for BDP-1 and BDP-2, respectively; in acetonitrile). Formation of the triplet excited state of the BODIPY moiety was observed for both dyads upon photoexcitation, and the triplet state quantum yield depends on both the linker length and the orientation of the chromophores. Triplet state quantum yields are 13.4 and 97.5% and lifetimes are 13 and 116 MUs for BDP-1 and BDP-2, respectively. The spin-orbit charge transfer (SO-CT) mechanism is proposed to be responsible for the efficient triplet state formation. The dyads were used for triplet-triplet annihilation (TTA) upconversion, showing an upconversion quantum yield up to 3.2%. PMID- 28866888 TI - Additive Capacity of [6]-Shogaol and Epicatechin To Trap Methylglyoxal. AB - Methylglyoxal (MGO), a reactive dicarbonyl species, is thought to contribute to the development of long-term pathological diabetes as a direct toxin or as an active precursor of advanced glycation end products (AGEs). Trapping MGO by dietary phenols to inhibit the MGO induced AGE formation is an approach for alleviating diabetic complications. The present study investigated whether dietary compounds with different structures and active sites have the additive capacity to trap MGO. Ginger phenolic constituent [6]-shogaol and tea flavonoid ( )-epicatechin were selected and tested under simulated physiological conditions, showing that they additively trapped about 41% MGO at a concentration of 10 MUM within 24 h. Furthermore, whether [6]-shogaol and epicatechin can retain their MGO trapping efficacy in vivo or a biotransformation limits their MGO trapping capacity remain virtually unknown. An acute mouse study was carried out by giving a single dose of [6]-shogaol, epicatechin, and the combination of both ([6] shogaol + epicatechin) through oral gavage. A mono-MGO adduct of [6]-shogaol was identified from [6]-shogaol and [6]-shogaol + epicatechin treated mice, and mono- and di-MGO adducts of epicatechin and its metabolite, 3'-O-methyl epicatichin, were detected in urine samples collected from epicatechin and [6]-shogaol + epicatechin treated mice. To our knowledge, this is the first study demonstrating the additive MGO trapping efficacy of [6]-shogaol and epicatechin and that [6] shogaol and epicatechin retained their MGO trapping capacity in mice. PMID- 28866891 TI - Integration of hypnosis into pediatric palliative care. AB - At least 8 million children would need specialized pediatric palliative care (PPC) services annually worldwide, and of the more than 42,000 children and teenagers dying annually in the United States, at least 15,000 children would require PPC. Unfortunately, even in resource-rich countries the majority of children dying from serious advanced illnesses are suffering from unrelieved, distressing symptoms such as pain, dyspnea, nausea, vomiting, and anxiety. State of the art treatment and prevention of those symptoms requires employing multi modal therapies, commonly including pharmacology, rehabilitation, procedural intervention, psychology, and integrative modalities. This article describes the current practice of integrating hypnosis into advanced pain and symptom management of children with serious illness. Three case reports of children living with a life-limiting condition exemplify the effective use of this clinical modality to decrease distressing symptoms and suffering. Hypnosis for pediatric patients experiencing a life-limiting disease not only provides an integral part of advanced symptom management, but also supports children dealing with loss and anticipatory loss, sustains and enhances hope and helps children and adolescents live fully, making every moment count, until death. PMID- 28866892 TI - Plasma L-carnitine levels in terminally ill cancer patients receiving only palliative care. AB - BACKGROUND: Several studies indicated that plasma L-carnitine (LC) levels are significantly decreased during chemotherapy or chemoradiation and that LC supplementation can improve the fatigue score in some cancer patients. However, the LC levels in end-stage cancer patients treated only with palliative care remained unclear. The present study was performed to examine the plasma LC levels of terminally ill and hospitalized patients. METHODS: Twenty-one terminally ill cancer patients in our hospital, with expected survival of several months, were enrolled in the present study. Blood samples were taken for measurement of total, free, and acyl-LC. These values were compared with those in 22 chemo-naive cancer patients scheduled to receive cisplatin-containing chemotherapy as first-line therapy. We examined the relationships with body mass index, albumin and CRP levels, the presence of general fatigue, and body weight loss. RESULTS: Median survival in terminally ill cancer patients after enrollment was 38.5 days. Plasma concentrations of total, free, and acyl-LC in terminally ill cancer patients were 59.5+/-16.0, 46.1+/-14.2, and 13.4+/-5.9 umol/L, respectively. These values were not significantly different from those in chemo-naive patients (58.3+/-18.1, 48.7+/-16.3, and 9.6+/-3.3 umol/L, respectively). In addition, plasma LC levels in terminally ill patients showed no correlations with albumin or CRP values nor with other clinical parameters, such as fatigue or body weight loss. CONCLUSIONS: The present study suggested that plasma LC levels remain normal and its deficiency is not always common even in terminally ill and hospitalized palliative cancer patients. PMID- 28866893 TI - Why it's not OK for doctors to participate in executions. PMID- 28866894 TI - More chemo or home hospice? Narrative results from an N-of-1 trial. AB - Words matter. They have tremendous power to heal or hurt. And although the patients we care for in oncology and palliative medicine often die from, or despite, their neoplastic illness; caregivers and loved ones often hold onto the words that clinicians share with them during their times of struggle and grief. In this narrative, the author (as first person) reflects on some systemic challenges he faced in dealing with illness and loss when his father battled two distinct neoplastic processes. He explores the commonalities and differences that he experienced as a palliative care physician, and how that has guided his medical practice moving forward. Moreover, he shares his observations regarding breaking bad news, code status discussions, and transitioning to hospice-as a cautionary tale to all clinical providers that what we say to patients and families matters. He encourages clinicians to avoid losing sight of the power and responsibility we all have to provide optimal, patient-centered care. PMID- 28866895 TI - Attendance of older patients with bone metastases at a multidisciplinary bone metastases clinic: an 8-year experience. AB - BACKGROUND: Bone metastases clinic (BMC) is a multidisciplinary clinic where patients with bony metastases are assessed in conjunction by orthopedic surgery, radiation oncology, interventional radiology, and palliative medicine teams. The objective of the study was to determine the number of older adult (OA) referrals made to BMC and to examine their case dispositions. METHODS: Patients who were referred to the BMC from 2007 to 2015 were included in the study. Demographic information including gender, age, Karnofsky Performance Status (KPS), primary cancer site and reason for referral, as well as case dispositions were recorded for each patient. The proportion of OA attendance was calculated for each year from the total number of patient visits. OA attendance was defined as individuals >=65 years of age who attended the BMC, and non-OA patients were those <65 years of age. Descriptive statistics were employed. RESULTS: A total of 551 patients were included with a median age of 64 years. The median KPS was 70 for OA and 80 for non-OA patients. OA attendance ranged per year from 42.5% to 58.7%. 14.1% of non-OA and 10.9% of OA patients were offered surgery. 62 patients in both cohorts (22.6% of OA and 22.4% of non-OA patients) were offered palliative radiation. CONCLUSIONS: From 2007 to 2015, OA patients comprised a significant proportion of referrals to the BMC. Younger patients were offered surgery slightly more often when compared to OA patients. Age did not appear to be a precluding factor for BMC referral or a deterrent in treatments offered. PMID- 28866896 TI - Hospitalizations in elderly glioblastoma patients. AB - BACKGROUND: Elderly glioblastoma (GB) patients are at risk of hospitalizations due to the morbidity of the disease and possible treatment toxicity. METHODS: In this observational cohort study, 255 newly diagnosed GB patients age 65 years and older were included. Survival, emergency room visits and admissions to an acute care hospital were determined. Mean and median total health care costs were calculated. Risk factors for Emergency room visits and acute care hospital admissions were determined. RESULTS: Median overall survival was 6 months. The majority of patients (68%) had at least one visit to the emergency department and 77% had at least one admission to acute care. The mean and median total costs (hospital, ambulatory, physician billing, other health care costs) per patient were $162,479.78 (CAN) and $125,511.00 (CAN), respectively. Treatment with radiation or treatment with radio-chemotherapy was associated with a relative risk (RR) of 2.31 (95% CI: 1.44-3.7; P=0.0005) and 2.19 (95% CI: 1.28-3.74; P=0.004), respectively for emergency department visits as compared to patients who were managed with comfort measures only. Patients with a baseline ECOG 0 had a RR of 1.71 (95% CI: 1.06-2.77; P=0.0289) and patients with baseline ECOG 1 had a RR of 1.49 (0.98-2.26; P=0.0623) for hospital admission as compared to patients with ECOG 4. CONCLUSIONS: A large proportion of elderly GB patients (particularly those with good baseline performance status who underwent active treatment) presented to the emergency department and had at least one admission to acute care. PMID- 28866898 TI - Olanzapine induced delirium-a "probable" adverse drug reaction. AB - Olanzapine is an atypical antipsychotic indicated for the treatment of schizophrenia and known to be effective in the management of delirium. In addition to its use for these indications olanzapine has also been used in the management of chemotherapy induced nausea and vomiting and otherwise difficult to control nausea and vomiting in palliative care settings. Although considered to be well tolerated with a lower incidence of extrapyramidal effects than first generation antipsychotics there are a small number of reports of olanzapine inducing delirium. Reported here are two cases of "probable" acute cognitive impairment following treatment of nausea with olanzapine. The cognitive impairment associated with olanzapine is probably mediated through its activity at cholinergic receptors a known risk factor for delirium particularly in the elderly. PMID- 28866897 TI - Superior target delineation for stereotactic body radiotherapy of bone metastases from renal cell carcinoma on MRI compared to CT. AB - BACKGROUND: In metastatic renal cell carcinoma (mRCC) there has been a treatment shift towards targeted therapy, which has resulted in improved overall survival. Therefore, there is a need for better local control of the tumor and its metastases. Image-guided stereotactic body radiotherapy (SBRT) in bone metastases provides improved symptom palliation and local control. With the use of SBRT there is a need for accurate target delineation. The hypothesis is that MRI allows for better visualization of the extend of bone metastases in mRCC and will optimize the accuracy of tumor delineation for stereotactic radiotherapy purposes, compared with CT only. METHODS: From 2013 to 2016, patients who underwent SBRT for RCC bone metastases were included. A planning CT and MRI were performed in radiotherapy treatment position. Gross tumor volumes (GTV) in both CT and MRI were delineated. Contouring was performed by a radiation oncologist specialized in bone metastases and verified by a radiologist, based on local consensus contouring guidelines. In both CT and MRI, the GTV volumes, conformity index (CI) and distance between the centers of mass (dCOM) were compared. RESULTS: Nine patients with 11 RCC bone metastases were included. The GTV volume as defined on MRI was in all cases larger or at least as large as the GTV volume on CT. The median GTV volume on MRI was 33.4 mL (range 0.2-247.6 mL), compared to 18.1 mL on CT (range 0.1-195.9) (P=0.013). CONCLUSIONS: Contouring of RCC bone metastases on MRI resulted in clinically relevant and statistically significant larger lesions (mean increase 41%) compared with CT. MRI seems to represent the extend of the GTV in RCC bone metastases more accurately. Contouring based on CT only could result in an underestimation of the actual tumor volume, which may cause underdosage of the GTV in SBRT treatment plans. PMID- 28866899 TI - Covered biliary stents with proximal bare stent extension for the palliation of malignant biliary disease: can we reduce tumour overgrowth rate? AB - BACKGROUND: Covered biliary stents have shown significant effectiveness in the palliative management of patients with malignant biliary disease due to prevention of tumour ingrowth. However, stent dysfunction may still occur due to growth of tumour at the borders of the covered stent (tumour overgrowth). The aim of this study is to assess the effectiveness of a bare extension in the prevention of tumour overgrowth when covered stents are used in the palliative treatment of malignant biliary strictures. METHODS: This is a prospective, single arm, cohort study. Twenty-two patients with inoperable malignant biliary strictures in the distal common bile duct (Bismuth I-II) and life expectancy more than 6 months were included in the study. The combination of a fully covered biliary stent and a bare proximal and distal extension was used in all cases. All patients were followed-up until death. Primary patency, survival, complication rates and dysfunction cause were assessed. RESULTS: Mean survival was 263.7 days (median 255, SD: 77.6). Mean patency was 240 days (median: 237, SD: 87). The primary patency rate at 3, 6 and 12 months was 90%, 86% and 86% respectively. Tumour inor overgrowth did not occur in any of the patients. Dysfunction due to sludge formation occurred in three cases; all three were treated with bilioplasty. CONCLUSIONS: The combined use of a covered biliary stent and a bare extension appears to be a very effective tool in the palliation of malignant biliary disease, offering long-term patency for patients with inoperable malignant distal common bile duct strictures and increasing the quality of life of such patients. PMID- 28866900 TI - Patient preference for stereotactic radiosurgery plus or minus whole brain radiotherapy for the treatment of brain metastases. AB - BACKGROUND: Optimal management for limited, non-resectable brain metastases is an evolving area in radiation oncology. Previous data show no difference in survival between stereotactic radiosurgery (SRS) and SRS plus whole-brain radiotherapy (WBRT). Neurocognitive toxicities, treatment duration and tumor recurrence differ and therefore patient values play an important role in decision making. We aim to elicit patient preferences and understand factors important in deciding which treatment to pursue. METHODS: Patients were recruited from 2 centers in North America. Eligibility criteria included <=4 intracranial lesions and physician judgment that either treatment was appropriate. Those with prior treatment for brain metastases were excluded. A decision board presented the treatments and summarized evidence regarding disease control and toxicity. An option to either take an active or passive role was offered. If taking a passive role, treatment was left to the clinician. If an active role was taken, patients made a decision about whether to receive SRS alone, or in combination with WBRT. A debriefing questionnaire to rank important factors in decision making was then completed. Descriptive statistics summarized findings. RESULTS: A total of 23 patients were enrolled. The majority of patients were male (15/23; 65.2%), had primary lung cancer (15/23; 65.2%) and the mean age was 65.5 years. All patients took an active role in deciding their treatment. The majority of patients (21/23) chose to receive SRS alone. The highest ranked factors were quality of life (9.4/10), ability to maintain functional independence (9.3/10) and influence of treatment on survival (9.2/10). The least important factor was number of trips required to the cancer center (5.0/10). CONCLUSIONS: A patient centered approach to decision making in brain metastases is feasible. Most patients will take an active role in management if relevant information is presented in a clear, understandable manner. When informed, most patients prefer SRS alone rather than SRS + WBRT and identify quality of life, ability to maintain functional independence and influence of treatment on survival as highly important factors in making their decision. PMID- 28866901 TI - Anxiety and psychosomatic symptoms in palliative care: from neuro psychobiological response to stress, to symptoms' management with clinical hypnosis and meditative states. AB - Psychosomatic disorder is a condition in which psychological stresses adversely affect physiological (somatic) functioning to the point of distress. It is a condition of dysfunction or structural damage in physical organs through inappropriate activation of the involuntary nervous system and the biochemical response. In this framework, this review will consider anxiety disorders, from the perspective of the psychobiological mechanisms of vulnerability to extreme stress in severe chronic illnesses. Psychosomatic medicine is a field of behavioral medicine and a part of the practice of consultation-liaison psychiatry. Psychosomatic medicine in palliative care, integrates interdisciplinary evaluation and management involving diverse clinical specialties including psychiatry, psychology, neurology, internal medicine, allergy, dermatology, psychoneuroimmunology, psychosocial oncology and spiritual care. Clinical conditions where psychological processes act as a major factor affecting medical outcomes are areas where psychosomatic medicine has competence. Thus, the psychosomatic symptom develops as a physiological connected of an emotional state. In a state of rage or fear, for example, the stressed person's blood pressure is likely to be elevated and his pulse and respiratory rate to be increased. When the fear passes, the heightened physiologic processes usually subside. If the person has a persistent fear (chronic anxiety), however, which he is unable to express overtly, the emotional state remains unchanged, though unexpressed in the overt behavior, and the physiological symptoms associated with the anxiety state persist. This paper wants highlight how clinical hypnosis and meditative states can be important psychosocial and spiritual care, for the symptom management on neuro-psychobiological response to stress. PMID- 28866902 TI - Suicide in palliative care setting. PMID- 28866903 TI - Embracing the setting sun: provision of palliative care via a collaborative model between hospital and community for patients with intellectual disabilities. PMID- 28866904 TI - A selective review of medical cannabis in cancer pain management. AB - Insufficient management of cancer-associated chronic and neuropathic pain adversely affects patient quality of life. Patients who do not respond well to opioid analgesics, or have severe side effects from the use of traditional analgesics are in need of alternative therapeutic op-tions. Anecdotal evidence suggests that medical cannabis has potential to effectively manage pain in this patient population. This review presents a selection of representative clinical studies, from small pilot studies conducted in 1975, to double-blind placebo controlled trials conducted in 2014 that evaluated the efficacy of cannabinoid based therapies containing tetrahydrocannabinol (THC) and cannabidiol (CBD) for reducing cancer-associated pain. A review of literature published on Medline between 1975 and 2017 identified five clinical studies that evaluated the effect of THC or CBD on controlling cancer pain, which have been reviewed and summarised. Five studies that evaluated THC oil capsules, THC:CBD oromucosal spray (nabiximols), or THC oromucosal sprays found some evidence of cancer pain reduction associated with these therapies. A variety of doses ranging from 2.7 43.2 mg/day THC and 0-40 mg/day CBD were administered. Higher doses of THC were correlated with increased pain relief in some studies. One study found that significant pain relief was achieved in doses as low as 2.7-10.8 mg THC in combination with 2.5-10.0 mg CBD, but there was conflicting evidence on whether higher doses provide superior pain relief. Some reported side effects include drowsiness, hypotension, mental clouding, and nausea and vomiting. There is evidence suggesting that medical cannabis reduces chronic or neu-ropathic pain in advanced cancer patients. However, the results of many studies lacked statistical power, in some cases due to limited number of study subjects. Therefore, there is a need for the conduct of further double-blind, placebo-controlled clinical trials with large sample sizes in order to establish the optimal dosage and efficacy of different cannabis-based therapies. PMID- 28866905 TI - Where is the value in care? PMID- 28866906 TI - End-of-life care for advanced dementia patients in residential care home-a Hong Kong perspective. AB - Dementia will become more common as the population ages. Advanced dementia should be considered as a terminal illnesses and end-of-life (EOL) care is very much needed for this disease group. Currently, the EOL services provided to this vulnerable group in Hong Kong, especially those living in residential care homes, is limited. The usual practice of residential care homes is to send older residents with advanced dementia to acute hospitals when they are sick, irrespective of their wish, premorbid status, diagnoses and prognosis. This may not accord with what the patients perceive to be a "good death". There are many barriers for older people to die in place, both at home and at the residential care home. In the community, to enhance EOL care to residential care home for the elderly (RCHE) residents, pilot EOL program had been carried out by some Community Geriatric Assessment Teams. Since 2015, the Hospital Authority funded program "Enhance Community Geriatric Assessment Team Support to End-of-life Patients in Residential Care Homes for the Elderly" has been started. In the program, advance care planning (ACP), Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) (non-hospitalized) order will be established and the program will be expected to cover all clusters in Hong Kong by 2018/2019. In hospital setting, EOL clinical plan and EOL ward in geriatric step-down hospitals may be able to improve the quality of death of older patients. In Sep 2015, the Hospital Authority Guidelines on Life-Sustaining Treatment in the Terminally Ill was updated. Amongst other key EOL issues, careful (comfort) hand feeding was mentioned in the guideline. Other new developments include the possible establishment of enduring power of attorney for health care decision and enhancement of careful hand feeding amongst advanced dementia patients in RCHEs. PMID- 28866907 TI - Palliative radiotherapy, bone metastases, and global assessments in palliative care. PMID- 28866908 TI - High burden of coronary atherosclerosis in patients with a new diagnosis of type 2 diabetes. AB - PURPOSE: The purposes of this study were to compare the presence, extent and composition of coronary plaques in asymptomatic patients with newly diagnosed type 2 diabetes to age- and sex-matched controls. METHODS: Patients with newly diagnosed (<1 year) type 2 diabetes ( n = 44) and controls ( n = 44) underwent contrast-enhanced coronary computed tomography angiography. Advanced plaque analysis including total plaque volume and volumes of plaque components (calcified plaque and non-calcified plaque, including low-attenuation [low density non-calcified plaque]) was performed using validated semi-automated software. RESULTS: Coronary artery calcification was more often seen in patients with type 2 diabetes (66%) versus controls (48%), p < 0.05. Both the absolute volume (median; interquartile range) of low-density non-calcified plaque (7.9 mm3; 0-50.5 mm3 vs 0; 0-34.3 mm3, p < 0.05) and the increase in low-density non calcified plaque ratio in relation to total plaque volume ( tau = 0.5, p < 0.001) were significantly higher in patients with type 2 diabetes. More patients with type 2 diabetes had spotty calcification (31% vs 0%, p < 0.05). By multivariate analysis, the presence of any low-density non-calcified plaque was higher in males (odds ratio: 4.06, p < 0.05), who also demonstrated a larger low-density non-calcified plaque volume ( p < 0.001). The presence and extent of low-density non-calcified plaque increased with age, smoking, hypertension and hyperglycaemia, all p < 0.05. CONCLUSION: Asymptomatic patients with newly diagnosed type 2 diabetes had plaque features associated with increased vulnerability as compared with age- and sex-matched controls. PMID- 28866909 TI - The relationship between work, mental health, physical health, and fatigue in patients with rheumatoid arthritis: A cross-sectional study. AB - To evaluate the relationship between work, mental health, physical health, and fatigue in patients with rheumatoid arthritis, the data of 282 participants were drawn from baseline. The results of structural equation modeling showed that among rheumatoid arthritis patients, those who were engaged in occupational activity had lower levels of fatigue compared to those who did not work and that this relationship was mediated by better mental health, not by physical health. PMID- 28866910 TI - Factors associated with living situation among Alzheimer's caregivers in the south of Spain that affect the election of external support services. AB - Alzheimer's is a syndrome mainly suffered by women and the care they need is also mainly provided by other women. The aim of this paper is to describe the profile of users of professional support services and to find out if some socio demographic factors are linked with those elections. The study was conducted from January to June 2012 thanks to the cooperation of over 41 Alzheimer's Associations in Andalusia, in the south of Spain. A person trained by the main researcher (a social worker or a psychologist) completed the questionnaire during an interview with the caregiver. Seven hundred and seventy-eight questionnaires were analysed. Contrary to previous findings, the use of external services is not infrequent. The most commonly used services are Day Care Centres (22.4%) and Cognitive Workshops (19.2%), but Home Assistance Services are the most frequently used either alone or in combination with the other two (27.5%). A higher level of education increases the probability of choosing a nursing home. The two main factors for looking for external support are non-cohabitation and working outside the home. Among caregivers under 40 years old this is the main profile. Using no services or in low and medium intensity in service hours leads to informal caregivers being the main caregivers. The potential labour market for professional caring is reduced by a crowding-out effect. Employment reduces the chance of being a caregiver. PMID- 28866911 TI - Cognitive-Behavioral Therapy for Adult ADHD: A Randomized Clinical Trial in China. AB - OBJECTIVE: Cognitive-behavioral therapy (CBT) is effective for adult ADHD, and booster sessions may improve long-term outcome. This study was designed to investigate the effects of group CBT and its booster sessions for Chinese adult patients with ADHD. METHOD: There were CBT only group ( n = 43), CBT +booster group ( n = 43), and control group with patients on the waiting list ( n = 22). The primary outcome was the score of the ADHD-Rating Scale (ADHD-RS). Secondary outcomes included emotion, executive function (EF), impulsivity, self-esteem, and life quality at 12th and 24th week. RESULTS: At 12th week, the score of ADHD-RS, EF, and impulsivity showed significant improvement in CBT +booster group comparing with control group. At 24th week, differences between CBT only group and CBT +booster group were not significant. CONCLUSION: CBT was effective for Chinese adult patients with ADHD. Booster sessions do not appear to provide additional benefits. PMID- 28866912 TI - Additional Abstracts for the 17th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28866913 TI - Article Commentary: Cell Transplantation for Parkinson's Disease. AB - Hype slang. n. 1. Excessive publicity and the ensuing commotion. 2. Exaggerated or extravagant claims made especially in advertising or promotional material. (Source: The American Heritage Dictionary of the English Language, third edition). PMID- 28866918 TI - Article Retraction. PMID- 28866919 TI - Transplants of Encapsulated Rat Choroid Plexus Cells Exert Neuroprotection in a Rodent Model of Huntington's Disease. AB - Choroid plexus (CP) epithelial cells secrete several neurotrophic factors and have been used in transplantation studies designed to impart neuroprotection against central nervous system (CNS) trauma. In the present study, CP was isolated from adult rats, encapsulated within alginate microcapsules, and transplanted unilaterally into the rat striatum. Three days later, unilateral injections of quinolinic acid (QA; 225 nmol) were made into the ipsilateral striatum to mimic the pathology observed in Huntington's disease (HD). After surgery, animals were tested for motor function using the placement test. Rats receiving CP transplants were significantly less impaired on this test. Nissl stained sections demonstrated that CP transplants significantly reduced the volume of the striatal lesion produced by QA. Quantitative analysis of striatal neurons further demonstrated that choline acetyltransferase-immunoreactive, but not diaphorase-positive, neurons were protected by CP transplants. These data demonstrate that transplanted CP cells can be used to protect striatal neurons from excitotoxic damage and that the pattern of neuroprotection varies across specific neuronal populations. PMID- 28866920 TI - Multifunctional Pancreatic Islet Encapsulation Barriers Achieved via Multilayer PEG Hydrogels. AB - The diverse requirements for a successful islet encapsulation barrier suggest the benefit of a barrier system that presents differing functionalities to encapsulated cells and host cells. Initially, multifunctional hydrogels were synthesized via the sequential photopolymerization of PEG hydrogel layers, each with different isolated functionalities. The ability to achieve localized biological functionalities was confirmed by immunostaining of different entrapped antibodies within each hydrogel layer. Survival of murine islets macroencapsulated within the interior gel of two-layer hydrogel constructs was then assessed. Maintenance of encapsulated islet survival and function was observed within multilayer hydrogels over 28 days in culture. Additionally, the functionalization of the islet-containing interior PEG gel layer with cell-matrix moieties, with either 100 MUg/ml laminin or 5 mM of the adhesive peptide IKVAV found in laminin, resulted in increased insulin secretion from encapsulated islets similar to that in gels without an exterior hydrogel layer. Finally, through cell seeding experiments, the ability of an unmodified, exterior PEG layer to prevent interactions, and thus attachment, between nonencapsulated fibroblasts and entrapped ECM components within the interior PEG layer was demonstrated. Together the presented results support the potential of multilayer hydrogels for use as multifunctional islet encapsulation barriers that provide a localized biologically active islet microenvironment, while presenting an inert, immunoprotective exterior surface to the host environment, to minimize graft-host interactions. PMID- 28866921 TI - In Vivo Tracking of Human Mesenchymal Stem Cells in Experimental Stroke. AB - To understand the fates of human mesenchymal stem cells (hMSCs) following transplantation into a rodent model of middle cerebral artery occlusion (MCAo), magnetic resonance imaging (MRI) techniques were employed. hMSCs were labeled with ferumoxides (Feridex(r))-protamine sulfate complexes, which were visualized and examined by MRI up to 10 weeks following transplantation. Migration of the transplanted cells to the infarcted area was further confirmed by histological methods. We found that the hMSCs transplanted in MCAo models possess the capacity to migrate to the infarcted area extensively in both ipsilateral and contralateral injections, exhibiting a pathotropism. We also analyzed the detailed migration patterns of transplanted hMSCs. We speculate that the extensive migratory ability of hMSCs may represent a therapeutic potential for developing efficient cell transplantation strategies in stroke. PMID- 28866922 TI - Serum-Free Medium Provides a Clinically Relevant Method to Increase Olfactory Ensheathing Cell Numbers in Olfactory Mucosa Cell Culture. AB - There is much evidence to suggest that transplanted olfactory ensheathing cells may ameliorate the functional deficits associated with injuries to the nervous system, especially the spinal cord. For clinical implementation of this strategy it will be necessary to derive large numbers of these cells from an accessible and, preferably, autologous source, implying that olfactory mucosa would be ideal. Although olfactory ensheathing cells can be derived from olfactory mucosa, in routine culture conditions the proportion of these cells is unacceptably low for clinical purposes. This study compared the effect of culturing dissociated olfactory bulb and olfactory mucosa in two different media: one containing serum and one serum free. The results indicate that olfactory ensheathing cell proportion, and absolute cell numbers, is greatly increased in serum-free conditions. Further analysis suggests that serum-free medium has a differential effect on contaminating fibronectin-positive and p75-positive cells from olfactory bulb and olfactory mucosa. This study demonstrates that serum-free culture conditions provide a simple and useful means of deriving a sufficient number of olfactory ensheathing cells for transplantation and reveals a difference in biological behavior of the cells contained within olfactory bulb and olfactory mucosa. PMID- 28866923 TI - Recombinant AAV Viral Vectors Serotype 1, 2, and 5 Mediate Differential Gene Transfer Efficiency in Rat Striatal Fetal Grafts. AB - Intrastriatal grafts of fetal ganglionic eminences (GE) can reverse symptoms of striatal lesions in animal models of Huntington's disease. On the other hand, neurotrophic factors have been shown to protect host striatal neurons from ongoing degeneration. Neurotrophic gene transfer into GE prior to grafting could combine the benefits of striatal neuron replacement and in situ delivery of neurotrophic factors. Here we evaluate the potency of recombinant adeno associated viruses (rAAV) as vectors for gene delivery into rat embryonic (E15) GE using the eGFP reporter gene under the control of the strong cytomegalovirus (CMV) promoter. We observed a very efficient expression of the eGFP reporter gene in organotypic cultures of GE infected with rAAV serotype 1 from 4 days until at least 4 weeks postinfection. In contrast, transduction was low and absent when using serotype 2 and serotype 5 rAAV, respectively. Two months after transplantation of rAAV2/1-infected embryonic GE in adult rat striatum, more than 20% of grafted cells expressed eGFP. The majority of transduced cells in the graft were neurons as indicated by colabeling of GFP-immunoreactive cells with the NeuN marker. Our study suggests that GE transduced by rAAV-serotype 1 vectors could be an interesting tool to mediate efficient expression of a gene coding a neurotrophic factor in Huntington's disease. PMID- 28866924 TI - Automated, High-Throughput Assays for Evaluation of Human Pancreatic Islet Function. AB - An important challenge in pancreatic islet transplantation in association with type 1 diabetes is to define automatic high-throughput assays for evaluation of human islet function. The physiological techniques presently used are amenable to small-scale experimental samples and produce descriptive results. The postgenomic era provides an opportunity to analyze biological processes on a larger scale, but the transition to high-throughput technologies is still a challenge. As a first step to implement high-throughput assays for the study of human islet function, we have developed two methodologies: multiple automated perifusion to determine islet hormone secretion and high-throughput kinetic imaging to examine islet cellular responses. Both technologies use fully automated devices that allow performing simultaneous experiments on multiple islet preparations. Our results illustrate that these technologies can be applied to study the functional status and explore the pharmacological profiles of islet cells. These methodologies will enable functional characterization of human islet preparations before transplantation and thereby provide the basis for the establishment of predictive tests for beta-cell potency. PMID- 28866925 TI - Concentration of Bone Marrow Total Nucleated Cells by a Point-of-Care Device Provides a High Yield and Preserves Their Functional Activity. AB - Stem and progenitor cell therapy is a novel strategy to enhance cardiovascular regeneration. Cell isolation procedures are crucial for the functional activity of the administered cellular product. Therefore, new isolation techniques have to be evaluated in comparison to the Ficoll isolation procedure as the current gold standard. Here we prospectively evaluated a novel point-of-care device (Harvest BMAC System) for the concentration of bone marrow total nucleated cells (TNC) in comparison to the Ficoll isolation procedure for bone marrow mononucleated cells (MNC). The yield in total numbers of TNC was 2.4-fold higher for Harvest compared to Ficoll. Despite significant differences in their cellular compositions, the colony-forming capacity was similar for both products. Intriguingly, the migratory capacity was significantly higher for the Harvest TNC (164 +/- 66%; p = 0.007). In a mouse model of hind limb ischemia, the increase in blood flow recovery was similar between Harvest BM-TNC and Ficoll BM-MNC (0.53 +/- 0.20 vs. 0.46 +/- 0.15; p = 0.88). However, adjustment of the injected cell number based on the higher yield of Harvest TNC resulted in a significant better recovery (0.64 +/- 0.16 vs. 0.46 +/- 0.15; p = 0.003). Cells concentrated by the Harvest point-of-care device show similar or greater functional activity compared to Ficoll isolation. However, the greater yield of cells and the wider range of cell types for the Harvest device may translate into an even greater therapeutic effect. PMID- 28866926 TI - Comparison of Successful and Unsuccessful Islet/Sertoli Cell Cotransplant Grafts in Streptozotocin-Induced Diabetic Mice. AB - Sertoli cells (SC) protect islet allografts from immune destruction in diabetic rodents. In this study, we examined the difference between successful and rejected islet/SC cografts in order to further improve this procedure for optimal extension of islet allograft survival. We cotransplanted 500 BALB/c islets with 1 8 million BALB/c SC under the kidney capsule of diabetic BALB/c, C3H-HeJ, and C57BL/6 mice. Cotransplantation of islets with up to 8 million SC was not detrimental to long-term islet graft function in syngeneic mice. However, large numbers of SC were detrimental to islet graft survival in allogeneic mice with the optimal dose for cotransplantation of 4 or 1 million SC in C3H-HeJ or C57BL/6 mice, respectively. Examination of successful grafts, from euglycemic recipients, revealed the presence of SC arranged in tubule structures with islets surrounding these tubules. Cellular infiltrate in successful grafts revealed CD4 T cells and macrophages along the periphery and within the grafts, and very few CD8 T cells. Conversely, examination of unsuccessful grafts, harvested from hyperglycemic recipients at the time of rejection, revealed the presence of SC arranged randomly with islets adjacent to the Sertoli cells, when present, and massive CD4 and CD8 T cell as well as macrophage cell infiltration. Prolongation of islet allograft survival appeared to be a function of SC transplant mass and recipient genetic background. A consequence of long-term graft acceptance is the formation of SC tubule structures, which may be an additional requirement for optimal protection of islet allografts. PMID- 28866927 TI - The TIM Family of Cosignaling Receptors: Emerging Targets for the Regulation of Autoimmune Disease and Transplantation Tolerance. AB - Currently, lifelong immune suppression regimens are required for solid organ and cellular transplantation and carry significant increased risk of infection, malignancy, and toxicity. For non-life-saving procedures such as islet transplantation, the risk/benefit ratio of lifelong immunosuppression versus benefit from transplantation requires even more careful balance. The search for specific agents to modulate the immune system without chronic immunosuppression is important for the broad application of islet transplantation. The T-cell immunoglobulin mucin (TIM) family is a distinct group of coreceptors that are differentially expressed on TH1 and TH2 cells, and have the potential to regulate both cytotoxic and humoral immune responses. Completed murine studies demonstrate Tim pathways may be important in the regulation of tolerance to self (auto), harmless (allergic), and transplant (allo) antigen; however, the potential impact of targeting Tim coreceptors has yet to be fully explored in transplantation tolerance induction or autoimmune disease. The current review examines the impact of Tim coreceptor targeting as an emerging therapeutic option for regulating autoimmune diseases and prevention of allograft rejection. PMID- 28866929 TI - Cell Therapy 2001: Introduction. PMID- 28866928 TI - Intravenously Administered Bone Marrow Cells Migrate to Damaged Brain Tissue and Improve Neural Function in Ischemic Rats. AB - Accumulated evidence suggests that bone marrow stromal cells (BMSCs) are capable of regenerating damaged tissue. This study evaluated whether intravenously (noninvasively) administered, GFP-labeled BMSCs would migrate into damaged brain tissue and improve neurological function after a stroke. Wistar rats were subjected to middle cerebral artery occlusion and reperfusion. Twenty-four hours after injury, the rats received an IV injection of culture medium or BMSCs isolated from adult Wistar rats expressing green fluorescent protein (GFP). Two hours after injury and 1, 3, and 7 days after cell transplantation, neurological function was evaluated using a neurological severity scale. On day 7, the brain scar size was determined using tetrazolium chloride staining, and the implanted cells were identified using confocal microscopy. Immunohistochemistry was used to evaluate apoptosis and angiogenesis in the ischemic region, as well as the spatial distribution of the implanted BMSCs relative to the native neural cells. Implanted BMSCs migrated throughout the territory of the middle cerebral artery by 7 days after transplantation. Most implanted cells were located in the scar area and border zone of the ischemic region, and some expressed the neuronal marker NeuN. Rats receiving BMSC transplantation exhibited reduced scar size, limited apoptosis, and enhanced angiogenic factor expression and vascular density in the ischemic region relative to the control group, as well as significant improvements in the neurological severity scores. Intravenously administrated BMSCs facilitated the structural and functional recovery of neural tissue following ischemic injury, perhaps mediated by enhanced angiogenesis. PMID- 28866930 TI - Engineering of Human Hepatocyte Lines for Cell Therapies in Humans: Prospects and Remaining Hurdles. AB - Hepatocyte-based biological therapies are increasingly envisioned for temporary support in acute liver failure and provision of specific-liver functions in liver based metabolic deficiency. One of the hurdles to develop such therapies is severe shortage of human livers for hepatocyte isolation. To address the issue, we have focused on reversible immortalization of human hepatocytes. Such technology can allow rapid preparation of functional and uniform human hepatocytes. Here we present our strategy to construct transplantable human hepatocyte cell lines. PMID- 28866941 TI - Poly-L-Lysine Induces Fibrosis on Alginate Microcapsules via the Induction of Cytokines. AB - Alginate - poly-l-lysine (PLL) microcapsules can be used for transplantation of insulin-producing cells for treatment of type I diabetes. In this work we wanted to study the inflammatory reactions against implanted microcapsules due to PLL. We have seen that by reducing the PLL layer, less overgrowth of the capsule is obtained. By incubating different cell types with PLL and afterwards measuring cell viability with MTT, we found massive cell death at concentrations of PLL higher than 10 MUg/ml. Staining with annexin V and propidium iodide showed that PLL induced necrosis but not apoptosis. The proinflammatory cytokine, tumor necrosis factor (TNF), was detected in supernatants from monocytes stimulated with PLL. The TNF response was partly inhibited with antibodies against CD14, which is a well-known receptor for lipopolysaccharide (LPS). Bactericidal permeability increasing protein (BPI) and a lipid A analogue (B-975), which both inhibit LPS, did not inhibit PLL from stimulating monocytes to TNF production. This indicates that PLL and LPS bind to different sites on monocytes, but because they both are inhibited by a p38 MAP kinase inhibitor, they seem to have a common element in the signal transducing pathway. These results suggest that PLL may provoke inflammatory responses either directly or indirectly through its necrosis inducing abilities. By combining soluble PLL and alginate both the toxic and TNF inducing effects of PLL were reduced. The implications of these data are to use alginate microcapsules with low amounts of PLL for transplantation purposes. PMID- 28866942 TI - Remyelination of Demyelinated CNS Axons by Transplanted Human Schwann Cells: The Deleterious Effect of Contaminating Fibroblasts. AB - Areas of demyelination can be remyelinated by transplanting myelin-forming cells. Schwann cells are the naturally remyelinating cells of the peripheral nervous system and have a number of features that may make them attractive for cell implantation therapies in multiple sclerosis, in which spontaneous but limited Schwann cell remyelination has been well documented. Schwann cells can be expanded in vitro, potentially affording the opportunity of autologous transplantation; and they might also be spared the demyelinating process in multiple sclerosis. Although rat, cat, and monkey Schwann cells have been transplanted into rodent demyelinating lesions, the behavior of transplanted human Schwann cells has not been evaluated. In this study we examined the consequences of injecting human Schwann cells into areas of acute demyelination in the spinal cords of adult rats. We found that transplants containing significant fibroblast contamination resulted in deposition of large amounts of collagen and extensive axonal degeneration. However, Schwann cell preparations that had been purified by positive immunoselection using antibodies to human low affinity nerve growth factor receptor containing less than 10% fibroblasts were associated with remyelination. This result indicates that fibroblast contamination of human Schwann cells represents a greater problem than would have been appreciated from previous studies. PMID- 28866943 TI - Enhanced Survival of Porcine Neural Xenografts in Mice Lacking CD1d1, But No Effect of NK1.1 Depletion. AB - Transplantation of embryonic porcine neurons may restore neurological function in patients with Parkinson's disease, if immunological rejection could be prevented. This study was performed to investigate the role of natural killer cells (NK cells) and NK1.1+ T cells (NK T cells) in the rejection of neural xenografts. A cell suspension was prepared from the ventral mesencephalon of 26 - 27-day-old pig embryos, and 2 MUl was implanted in the right striata of mutant CD1d1 null (CD1.1-/-) mice, NK1.1-depleted mice, and controls. The CD1.1-/- mice are deficient in NK T cells and the antigen-presenting molecule CD1d1. Graft survival and host responses were determined immunohistochemically using markers for dopamine neurons, CD4-, CD8- cells, microglia, and macrophages. At 2 weeks, the grafts were significantly larger in CD1.1-/- mice, 0.09 +/- 0.02 MUl (mean +/- SEM), compared with controls, 0.05 +/- 0.01 MUl. There was no significant difference between NK1.1-depleted mice, 0.02 +/- 0.01 MUl, and controls. At 5 weeks, two grafts were still present in the CD1-/- mice, whereas only scars remained in the controls and in the NK1.1-depleted mice. Immune reactions were strong at 2 weeks and less pronounced at 5 weeks in all groups. Microglial activation was lower in NK-depleted mice than in the controls at 2 weeks. In contrast to organ xenografting, NK1.1+ cells do not seem to be important mediators of the rejection of discordant cellular neural xenografts. However, our results suggest that the antigen-presenting molecule CD1d1 may be involved in the rejection process. PMID- 28866944 TI - Posterior Segment Approach for Subretinal Transplantation or Injection in the Canine Model. AB - A posterior segment approach for cell transplantation or injection into the subretinal space of the dog has been developed. Controlled penetration to the subretinal space was achieved using a 29-gauge injection cannula, either blunted or with a 30 degrees sharpened bevel, and partially ensheathed with moveable plastic tubing. Depending on the injection volume used, the retina detached, and the fluid was reabsorbed within 1 - 3 weeks, although for smaller volumes the retina reattached within a matter of days. The optimal injection volume used was between 100 and 150 MUl, or two injections of 55 MUl each. By ophthalmoscopy following the surgery, it was possible to serially monitor the injection site and retinal bleb through fundus photography. Light microscopy demonstrates the distribution of stable, viable RPE cells in the subretinal space up to 6 months. The transplantation technique developed for the dog is atraumatic and free from any major surgical or clinical complications. It can be readily used to deliver cells or fluids to localized regions of the subretinal space. PMID- 28866945 TI - Influence of Donor Age on Mouse Islet Characteristics and Transplantation. AB - Old donor age has been considered as a risk factor and relative contraindication for transplantation. This study was designed to investigate the influence of donor age on islet characteristics and transplantation. Islets isolated from 8 (I A)-, 32 (I-B)-, or 64 (I-C)-week-old C57BL/6 mice were studied for number, size, insulin content, and secretion. After syngeneically transplanting 300 islets under the kidney capsule of strep-tozotocin-diabetic mice (R-A, R-B, and R-C, respectively), we measured recipients' metabolic parameters as well as the beta cell mass and insulin content of the graft. Eight-week-old donors had better glucose tolerance than 32- and 64-week-old donors. However, 64-week-old donors had more pancreatic insulin content than 8- and 32-week-old donors. I-B and I-C were greater in number, larger in size, and higher in insulin content than I-A. But perifusion study showed I-C secreted less insulin, albeit with a similar stimulation index compared with that of I-A and I-B. After transplantation, the fall of blood glucose in R-C was faster than that in R-A and R-B. At 12 weeks, the recipients' blood glucose, body weight, HbA1c, and the beta-cell mass and insulin content of the graft were comparable in all groups. However, R-C had better glucose tolerance than R-A. During follow-up, R-A and R-B maintained lifelong normoglycemia and their glucose tolerance did not deteriorate. These data indicate that islets isolated from donors with different ages have different characteristics and effects on transplantation. The islets isolated from aged donors are functioning well and can be a potential source for transplantation; however, because we transplanted a large islet mass from the aged donors, the role of the islet dose needs to be further clarified. PMID- 28866946 TI - Bridging a Patient with Acute Liver Failure to Liver Transplantation by the AMC Bioartificial Liver. AB - Recently a phase I clinical trial has been started in Italy to bridge patients with acute liver failure (ALF) to orthotopic liver transplantation (OLT) by the AMC-bioartificial liver (AMC-BAL). The AMC-BAL is charged with 10 * 109 viable primary porcine hepatocytes isolated from a specified pathogen-free (SPF) pig. Here we report a patient with ALF due to acute HBV infection. This patient was treated for 35 h by two AMC-BAL treatments and was bridged to OLT. There was improvement of biochemical and clinical parameters during the treatment. No severe adverse events were observed during treatment and follow-up of 15 months after hospital discharge. Possible porcine endogenous retrovirus (PERV) activity could not be detected in the patient's blood or blood cells up to 12 months after treatment. PMID- 28866947 TI - Decellularized Native and Engineered Arterial Scaffolds for Transplantation. AB - More than 570,000 coronary artery bypass grafts are implanted each year, creating an important demand for small-diameter vascular grafts. For patients who lack adequate internal mammary artery or saphenous vein, tissue-engineered arteries may prove useful. However, the time needed to tissue engineer arteries (7 weeks or more) is too long for many patients. Decellularized cadaveric human arteries are another possible source of vascular conduit, but limited availability and the potential for disease transmission limit their widespread use. In contrast, decellularized tissue-engineered arteries could serve as grafts for immediate implantation, as scaffolds onto which patients' cells could be seeded, or as carriers for genetically engineered cells to aid cell transplantation. The goal of this study was to quantify the effects of decellularization on vascular matrix and mechanical properties. Specifically, we compared cellular elimination, extracellular matrix retention, and mechanical characteristics of porcine carotid arteries before and after treatment with three decellularization methods. In addition, for the first time, tissue-engineered arteries were decellularized. Decellularized native arteries were also used as a scaffold onto which vascular cells were seeded. These studies identified a decellularization method for native and engineered arteries that maximized cellular elimination, without greatly compromising mechanical integrity. We showed that engineered tissues could be decellularized, and demonstrated the feasibility of reseeding decellularized vessels with vascular cells. PMID- 28866948 TI - Characterization of Long-Term Survival of Syngeneic Hepatocytes in Rat Peritoneum. AB - Hepatocyte transplantation is a potential therapy for both acute and chronic hepatic insufficiency and also for treatment of inborn errors of metabolism affecting the liver. The peritoneum is one site for implantation and has several advantages: cells implanted there can be easily identified and observed, and it has a relatively large capacity. Long-term survival using "pure" hepatocytes in the peritoneum have been disappointing. We hypothesized that cotransplantation of hepatocytes with nonparenchymal cells would help maintain differentiated hepatocyte function. Rat liver cells transplanted intraperitoneally into August rats were sacrificed at 7 days, 1, 3, 6, 9, and 12 months and analyzed for presence, basal proliferation, and functionality of hepatocytes. To demonstrate that ectopic hepatocytes remained susceptible to exogenous growth factors affecting cell proliferation, rats 9 and 12 months after transplantation were stimulated with tri-iodothyronine and KGF. Hepatocytes were identified 7 days to >12 months, by H&E and immunohistochemically, as ectopic islands in the omental fat. Functionality was confirmed by glycogen deposition. Basal proliferation in 7 day rats was 28.0 +/- 10/1000 hepatocytes in ectopic islands (cf. 5.70 +/- 2.7/1000 in recipient liver). Proliferation in ectopic islands was greater than host liver. Growth factor-stimulated proliferation in ectopic islands induced a 70-fold increase in DNA synthesis. In conclusion, hepatocytes transplanted with nonparenchymal cells survive, proliferate, and function in the peritoneum of normal rats, and respond to exogenous growth stimuli. Their survival and proliferation in the presence of a normal functioning liver has implications for the potential use of the peritoneal site clinically for supplementation of liver function in metabolic disorders. PMID- 28866949 TI - Annexin A10 contributes to chronic constrictive injury-induced pain through activating ERK1/2 signalling in rats. AB - PURPOSE: The current study aims at investigating the downstream targets of spinal Annexin A10 in modulating neuropathic pain. MATERIALS AND METHODS: Paw withdrawal latency and paw withdrawal threshold were measured to evaluate the pain associated behaviour in rats. The expression of spinal Annexin A10, phosphorylated-extracellular regulated kinase 1/2 and extracellular regulated kinase were detected by western blotting. The level of tumour necrosis factor alpha and interleukine-1beta was tested by enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Chronic constrictive injury caused pain hypersensitivity in rats, along with increased expression of spinal Annexin A10, phosphorylated extracellular regulated kinase 1/2, tumour necrosis factor-alpha and interleukine 1beta in rats. Knockdown of spinal Annexin A10 suppressed the chronic constrictive injury-induced hyperalgesia, and inhibited the chronic constrictive injury-induced increased expression of phosphorylated-extracellular regulated kinase 1/2, tumour necrosis factor-alpha and interleukine-1beta in the spinal cord. Inhibition of spinal extracellular regulated kinase activation decreased the release of tumour necrosis factor-alpha and interleukine-1beta, but did not change the increased expression of Annexin A10 caused by chronic constrictive injury. CONCLUSIONS: Annexin A10 contributed to the development of neuropathic pain by activating spinal extracellular regulated kinase signalling and the subsequent release of tumour necrosis factor-alpha and interleukine-1beta in the spinal cord. PMID- 28866950 TI - Can antioxidant's reactive oxygen species (ROS) scavenging capacity contribute to aged seed recovery? Contrasting effect of melatonin, ascorbate and glutathione on germination ability of aged maize seeds. AB - It is well known that antioxidants such as AA (reduced ascorbate), glutathione (GSH) (reduced glutathione) and melatonin can delay seed ageing. Can they recover aged seed? Artificial aged maize seeds were obtained and their reduced germination rate (GR) and high lipid peroxidation were recorded. Exogenous melatonin was applied on these aged seeds and enhanced GR was observed. However, treatment with other antioxidants such as AA, GSH or DMTU (dimethyl thiourea) did not significantly improve or even reduce the GR of aged seeds. In addition, melatonin improved germination ability of theses aged seeds can be significantly impaired by DDC (diethyldithiocarbamic acid, a specific inhibitor of superoxide dismutase or superoxide dismutase (SOD)) and ATZ (aminotriazol, a specific inhibitor of catalase or CAT). In a further study, we found that melatonin but not other antioxidants (AA, GSH and DMTU) significantly induced CAT and SOD activities of aged seeds after imbibition. Accordingly, melatonin significantly reduced lipid peroxidation in aged seeds than that of other antioxidants. Taken together, these data suggest that melatonin induced antioxidant enzyme but not its direct reactive oxygen species (ROS) scavenging capacity contributing to recovery of aged maize seeds. PMID- 28866951 TI - Best practices, new perspectives and the perfect emollient: optimizing the management of contact dermatitis. AB - Contact dermatitis (CD) is caused by environmental agents, irritants, and allergens that penetrate the epidermis and lead to inflammation. An intact skin barrier prevents penetration and is important in maintaining healthy skin. Classical diagnosis of CD is made using the patch test, and traditional treatment strategies for CD promote skin barrier integrity and resolve the inflammatory component of the condition. This can be achieved by using emollient-based therapy, which is most important for skin barrier repair, and in addition to topical glucocorticosteroids, which are used in severe cases of CD and are most effective in reducing inflammation. Preventative measures, such as irritant and allergen avoidance in the workplace, also play a pivotal role in effective CD management. Moreover, CD management necessitates a holistic approach that incorporates prevention, barrier repair, and inflammatory resolution to ensure optimized efficacy. It is also important to consider potential barriers to optimal management when evaluating individuals with CD, such as limited patient education or poor access to care. Finally, key literature and our own clinical practice experience have highlighted the value of patient preference, as well as safety, efficacy and simplicity, in building the perfect emollient. PMID- 28866952 TI - Optical flow and image segmentation analysis for noninvasive precise mapping of microwave thermal ablation in X-ray CT scans - ex vivo study. AB - PURPOSE: To develop image processing algorithms for noninvasive mapping of microwave thermal ablation using X-ray CT. METHODS: Ten specimens of bovine liver were subjected to microwave ablation (20-80 W, 8 min) while scanned by X-ray CT at 5 s intervals. Specimens were cut and manually traced by two observers. Two algorithms were developed and implemented to map the ablation zone. The first algorithm utilises images segmentation of Hounsfield units changes (ISHU). The second algorithm utilises radial optical flow (ROF). Algorithm sensitivity to spatiotemporal under-sampling was assessed by decreasing the acquisition rate and reducing the number of acquired projections used for image reconstruction in order to evaluate the feasibility of implementing radiation reduction techniques. RESULTS: The average radial discrepancy between the ISHU and ROF contours and the manual tracing were 1.04+/-0.74 and 1.16+/-0.79mm, respectively. When diluting the input data, the ISHU algorithm retained its accuracy, ranging from 1.04 to 1.79mm. By contrast, the ROF algorithm performance became inconsistent at low acquisition rates. Both algorithms were not sensitive to projections reduction, (ISHU: 1.24+/-0.83mm, ROF: 1.53+/-1.15mm, for reduction by eight fold). Ablations near large blood vessels affected the ROF algorithm performance (1.83+/-1.30mm; p < 0.01), whereas ISHU performance remained the same. CONCLUSION: The two suggested noninvasive ablation mapping algorithms can provide highly accurate contouring of the ablation zone at low scan rates. The ISHU algorithm may be more suitable for clinical practice as it appears more robust when radiation dose reduction strategies are employed and when the ablation zone is near large blood vessels. PMID- 28866953 TI - Fake bad scale: the case of the missing construct, a response to Larrabee, Bianchini, Boone, and Rohling (2017). AB - The 'Commentary' of Drs. Larrabee, Bianchini, Boone, and Rohling (2017) attributes to us a view of the Fake Bad/Symptom Validity Scale (FBS/FBS-r) that is wholly erroneous, a view we do not hold and have never taken. In doing so, the authors have confused the thrust of our article with the assertions made in an earlier article which preceded publication of the FBS. This earlier article held that many physical and cognitive symptoms/complaints observed in personal injury plaintiffs are most parsimoniously understood as manifestations of the stresses that may routinely accompany plaintiffs' involvement in such litigation. In this response, I therefore, wish to clarify this misunderstanding and to elaborate upon several of the issues raised in our article. PMID- 28866954 TI - Are patients comprehending? A critical assessment of online patient educational materials. AB - PURPOSE: The primary aim of this study was to evaluate the readability, understandability, suitability and actionability of online psoriasis patient educational materials. A secondary aim was to identify areas for improvement. MATERIALS AND METHODS: We conducted an evaluation study to assess online psoriasis patient educational materials from the American Academy of Dermatology and National Psoriasis Foundation available in July 2017. We used two validated assessment tools specific to online healthcare materials. Outcomes were expressed as percentages, where higher percentages corresponded to higher quality materials. RESULTS: Overall, the educational materials had a mean understandability score (72.7%) that was understandable; a suitability score (58.8%) that was adequate; a reading grade level (10.5) that was not readable; and an actionability score (54.7%) that was not actionable. Areas of improvement include reading grade level, visual aids, word choice, specific steps for actions and cultural appropriateness. CONCLUSIONS: Online psoriasis patient educational materials are understandable and suitable, but they are written above the American Medical Association and National Institutes of Health's recommended 6th 8th grade reading level and are not actionable. Materials can benefit from decreasing reading grade level, including more visual elements, incorporating more actionable items and being culturally inclusive. PMID- 28866955 TI - Cross-country analysis of faecal sludge dewatering. AB - Dewatering of faecal sludge (FS) is indispensable for adequate FS management. However, comprehensive knowledge is lacking on FS dewatering performance. This study compared the dewatering performance of FS from different countries and onsite sanitation technologies, to assess influential characteristics on dewatering, and to compare dewatering performance of FS with wastewater sludge. We collected 73 FS samples from septic tanks, lined pit latrines, unlined pit latrines and johkasou tanks in Uganda, Vietnam and Japan, and 18 samples of wastewater sludge in Switzerland. Capillary suction time (CST) and total solids (TS) of centrifuged sludge (%TSfinal) were determined as metrics of dewatering rate and dewaterability, respectively, together with relevant sludge characteristics. Data were analysed by bootstrapping comparison of median results of each sample category and by bootstrapping multiple regression analysis to quantify the relative importance of sludge characteristics on dewatering performance. Results showed that the dewatering rate was significantly different between FS from different technologies, whereas dewaterability was significantly different within the same technology. FS had a significantly lower dewatering rate than wastewater sludge. In contrast, FS dewaterability was greater than wastewater sludge. However, this could be attributed to higher concentrations of sand in FS. Electrochemical properties such as NH4-N and surface charge had the strongest correlation to dewatering rate, and solid properties such as sand content and total volatile solids to dewaterability. The results identify potential characteristics that could explain and predict the high variability of FS dewatering performance that is observed in the field. PMID- 28866956 TI - Youth experiences in accessing sexual healthcare services in Vietnam. AB - Poor sexual and reproductive health outcomes among youth are reflective of the many barriers members of this group face in accessing health services. This study provides an in-depth account of the unique challenges that young people face in accessing sexual healthcare services in Vietnam. We surveyed 130 men and women aged 18-24 years at two major reproductive health sites in Ho Chi Minh City. We identified and explored seven domains: health insurance status, modern contraception use, HIV/STI testing, cervical cancer screening, unintended pregnancy, reproductive coercion and the patient-provider relationship. Attitudes towards the national health insurance system suggest that it does not facilitate access to healthcare. Despite widespread and affordable services, fears, fallacies and fixed social mores created formidable barriers for unmarried youth to access sexual and reproductive health services in Vietnam. PMID- 28866957 TI - Nanocarriers for brain specific delivery of anti-retro viral drugs: challenges and achievements. AB - HIV/AIDS is a global pandemic and the deleterious effects of human immunodeficiency virus in the brain cannot be overlooked. Though the current anti retro viral therapy is able to reduce the virus load in the peripheral tissues of the body, the inability of the anti-retro viral drugs to cross the blood brain barrier, as such, limits its therapeutic effect in the brain. The development of newer, successful nanoparticulate drug delivery systems to enhance the feasibility of the anti-retro viral drugs to the brain, offers a novel strategy to treat the AIDS-related neuronal degradation. This review summarised the neuropathogenesis of neuroAIDS, the challenges and achievements made in the delivery of therapeutics across the BBB and the use of nanocarriers as a safe and effective way for delivering anti-retro viral drugs to the brain. PMID- 28866958 TI - Perinatal outcome of pregnancies complicated with extreme birth weights at term. AB - OBJECTIVE: The objective of this study is to investigate whether an abnormal birthweight at term, either small for gestational age (SGA, < 5th centile for gestational age) or large for gestational age (LGA, > 95th centile for gestational age), is a risk factor for perinatal complications as compared with birthweight appropriate for gestational age (AGA). METHODS: A population-based retrospective cohort analysis of all singleton pregnancies delivered between 1991 and 2014 at Soroka Medical Center. Congenital malformations and multiple pregnancies were excluded. A multivariable generalized estimating equation regression model was used to control for maternal clusters and other confounders. RESULTS: During the study period, 228,242 births met the inclusion criteria, of them 91% were AGA (n = 207,652), 4.7% SGA, and 4.3% LGA. SGA significantly increased the risk for perinatal mortality (aOR 5.6, 95%CI 4.5-6.8) and low 5-min Apgar scores (aOR 2.2, 95%CI 2.0-2.4), while LGA did not. SGA and LGA were both significant risk factors for cesarean delivery. LGA was significantly associated with shoulder dystocia and post-partum hemorrhage (aOR =13.6, 95%CI 10.9-17.0, and aOR 1.7, 95%CI 1.2-2.6, respectively). CONCLUSIONS: Extreme birthweights at term are significantly associated with adverse maternal and neonatal outcomes. As opposed to SGA, LGA is not independently associated with perinatal mortality. PMID- 28866959 TI - A comparison of computerized adaptive testing and fixed-length short forms for the Prosthetic Limb Users Survey of Mobility (PLUS-MTM). AB - BACKGROUND: New health status instruments can be administered by computerized adaptive test or short forms. The Prosthetic Limb Users Survey of Mobility (PLUS MTM) is a self-report measure of mobility for prosthesis users with lower limb loss. This study used the PLUS-M to examine advantages and disadvantages of computerized adaptive test and short forms. OBJECTIVES: To compare scores obtained from computerized adaptive test to scores obtained from fixed-length short forms (7-item and 12-item) in order to provide guidance to researchers and clinicians on how to select the best form of administration for different uses. STUDY DESIGN: Cross-sectional, observational study. METHODS: Individuals with lower limb loss completed the PLUS-M by computerized adaptive test and short forms. Administration time, correlations between the scores, and standard errors were compared. RESULTS: Scores and standard errors from the computerized adaptive test, 7-item short form, and 12-item short form were highly correlated and all forms of administration were efficient. Computerized adaptive test required less time to administer than either paper or electronic short forms; however, time savings were minimal compared to the 7-item short form. CONCLUSION: Results indicate that the PLUS-M computerized adaptive test is most efficient, and differences in scores between administration methods are minimal. The main advantage of the computerized adaptive test was more reliable scores at higher levels of mobility compared to short forms. Clinical relevance Health-related item banks, like the Prosthetic Limb Users Survey of Mobility (PLUS-MTM), can be administered by computerized adaptive testing (CAT) or as fixed-length short forms (SFs). Results of this study will help clinicians and researchers decide whether they should invest in a CAT administration system or whether SFs are more appropriate. PMID- 28866960 TI - Blood pressure effects of adiposity in non-overweight children aged 6-17 years. AB - BACKGROUND: Obesity is a well-established risk factor of elevated blood pressure; however, the relationships between normal weight status and the risk of hypertension and pre-hypertension are not clear. AIM: The aim of this study is to describe the blood pressure effects of adiposity in non-overweight children. METHODS AND RESULTS: In total, 588 097 non-overweight children aged 6-17 years were included from the National Surveys on Students' Constitution and Health. A non-linear relationship was found between age- and gender-standardised body mass index (BMI) z-score and pre-hypertension and hypertension, respectively. The odds ratios and 95% confidence intervals [ORs (95% CIs)] of pre-hypertension were 0.61 (0.59-0.63), 0.67 (0.65-0.68), 0.83 (0.83-0.84), 1.00 (reference), 1.13 (1.12 1.14), 1.18 (1.16-1.20) and 1.20 (1.18-1.22) for BMI z-scores of -1.2, -1.0, 0.5, 0 (reference), 0.5, 0.7 and 0.8, respectively. The ORs (95% CIs) of hypertension were 0.56 (0.54-0.58), 0.62 (0.61-0.64), 0.81 (0.80-0.82), 1.00 (reference), 1.17 (1.16-1.18), 1.23 (1.22-1.5) and 1.27 (1.24-1.29) for BMI z scores of -1.2, -1.0, -0.5, 0 (reference), 0.5, 0.7 and 0.8, respectively. The above-mentioned associations were consistent in sub-group analysis by age, gender and height. CONCLUSIONS: Non-linear relationships of BMI z-scores with pre hypertension and hypertension were found in non-overweight children. Interventions to control blood pressure are also important in non-overweight children. PMID- 28866961 TI - Mathematical modelling of Pb2+, Cu2+, Ni2+, Zn2+, Cr6+ and Cd2+ ions adsorption from a synthetic acid mine drainage onto chitosan derivative in a packed bed column. AB - Studies on the adsorption of toxic metal ions in batch mode using modified chitosan beads have been reported by several authors in literature; for large scale operations, packed bed column studies are performed to generate data that are directly applicable in real wastewater treatment. In this work, the application potential of chitosan derivative for the uptake of Pb2+, Cu2+, Ni2+, Zn2+, Cr6+, and Cd2+ ions from aqueous solution in a packed bed adsorption column was investigated. On this note, the adsorbent was characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and Scanning electron microscope (SEM); the effect of breakthrough parameters such as influent concentration, bed height, and feed flow rate was determined. The experimental data were fitted to mathematical column models, namely Bed Depth Service Time (BDST), Yoon-Nelson and Thomas model. The removal efficiency, breakthrough and exhaustion time increased with an increase in bed height but decreased with an increase in the flow rate and influent concentration. The mathematical models applied in this study were successful in describing experimental data. Desorption studies were performed with no loss in the mass of the beads, and the breakthrough and exhaustion time were found to be the same on reusing the beads. Abbreviations: Ch-b: chitosan coated bentonite; GXXB: grafted cross-linked chitosan beads; MMBB: multi metal binding biosorbent; PFOLG: panosized ferric oxide loaded glycidyl; MPSD: Marquardt's percent standard deviation. PMID- 28866962 TI - In situ provision of drinking water to grazing dairy cows improves milk production. AB - AIMS: To determine the effect of providing water within the area grazed by dairy cows on milk yield and quality, compared to requiring cows to walk to a distant water trough, on a dairy farm in the Pampa region of Argentina during summer. METHODS: Holstein dairy cows were allocated to two herds with similar parity, days in milk and milk production. They were grazed in one paddock that was divided in two, with a fixed water trough at one end. Cows were moved twice daily to grazing plots within the paddock. Control cows (n=66) could only access water from the fixed trough, whereas supplemented cows (n=67) also received water from a mobile trough within the grazing plot. Milk production of each cow, and water consumption of the two herds were measured daily over 62 days. Milk composition for each herd was determined weekly from Days 18 to 60 of the study, and grazing behaviour was observed between 08:00 and 16:00 hours on Days 11-15, 19-22 and 39 43. RESULTS: Over the 62 days of the study, supplemented cows produced 1.39 (SE 0.11) L/cow/day more milk than Control cows (p=0.027). Estimated mean daily water intake was 50.4 (SE 2.1) L/cow/day for supplemented cows and 58.2 (SE 2.7) L/cow/day for Control cows (p=0.004). Percentage total solids in milk was higher for supplemented (12.5 (SE 0.06)%) than Control (12.4 (SE 0.04)%) cows (p=0.047). During the periods of behavioural observation, a higher percentage of cows in the water supplemented than the Control herd were observed in the grazing area (p=0.012). CONCLUSIONS AND CLINICAL RELEVANCE: This preliminary study demonstrated that provision of water to dairy cows within the grazing plot was beneficial for milk production and composition, and may be associated with longer periods spent within the grazing area, during hot weather in the Pampa region of Argentina. PMID- 28866963 TI - A single-chamber microbial fuel cell for rapid determination of biochemical oxygen demand using low-cost activated carbon as cathode catalyst. AB - The biochemical oxygen demand (BOD) is widely used for the evaluation of water and wastewater quality. However, the conventional method to measure BOD is time consuming and requires complicated processes. In this study, a Microbial fuel cell (MFC)-based BOD sensor was developed by using low-cost activated carbon as the cathode catalyst. The sensor was calibrated with an aerated nutrient medium containing sodium acetate as the BOD source. When the sensor was operated with an external resistance of 1 K Omega, linear correlation (R2 = 0.9965) was obtained for BOD concentrations ranging from 80 to 1280 mg/L in a reaction time of 50 h. Besides acetate, glucose/glutamic acid (GGA) and ethanol could also be analyzed by the sensor. In a low concentration range (200 mg/L), the relationship between GGA solution concentration and output voltage was in accord with Monod growth kinetics. PMID- 28866964 TI - Effects of soy isoflavones on the concentration of hyaluronic acid in the vagina of type 1 diabetic rats. AB - OBJECTIVE: To assess the effects of isoflavones and 17beta-estradiol on the vaginal epithelium extracellular matrix and hyaluronic acid (HA) in the diabetic rat model. METHODS: Sixty adult, virgin, female rats underwent ovariectomy, then randomization into six groups of ten animals each: GI, sham ovariectomized control animals; GII, sham ovariectomized control diabetic animals; GIII, control ovariectomized rats receiving propylene glycol vehicle; GIV, control ovariectomized diabetic animals receiving propylene glycol vehicle; GV, diabetic ovariectomized animals treated with soy isoflavones (150 mg/kg by gavage); GVI, ovariectomized diabetic rats treated with estrogen (17beta-estradiol, 10 mg/kg, subcutaneously). Treatment took place over 30 consecutive days. After euthanasia, a portion of the vagina was immersed in liquid nitrogen for RT-qPCR and Western blotting. Another portion was processed for paraffin embedding. Sections were stained with hematoxylin & eosin for histomorphometry and Picro Sirius Red for collagen quantification. RESULTS: Vaginal epithelium histomorphometry in GIII (15.3 +/- 1.1 um) and GIV (14.5 +/- 1.8 um) was thinner than in GV (41.3 +/- 1.5 um) and GVI (74.3 +/- 1.6 um). There was an increase in collagen content in GV (84.1 +/- 1.2 um) and GVI (88.2 +/- 1.7 um). HA quantification was higher in GV (0.38 +/- 1.1 MUg/mg) and GVI (0.49 +/- 1.4 MUg/mg) when compared with GIII (0.12 +/- 1.1 MUg/mg) and GIV (0.10 +/- 1.2 MUg/mg), p < 0.05. CONCLUSIONS: Soy isoflavones increase hyaluronic acid concentration in the vagina of diabetic ovariectomized rats. Such findings might help to attenuate the effects of vulvovaginal atrophy in women. PMID- 28866965 TI - Perfusion with carbon monoxide does not affect extracellular glutamate in dialysates of the hippocampus of freely moving mice. AB - Carbon monoxide (CO) produces several neurological effects, including cognitive, mood, and behavioral disturbance. Glutamate is thought to play a particularly important role in learning and memory. Thus, the present study was aimed at investigating the local effect of CO on the glutamate level in the hippocampus of mice using in vivo reverse microdialysis. Mice were perfused with Ringer's solution (control) or CO (60-125 MUM) in Ringer's solution into the hippocampus via microdialysis probe. Dialysate samples were collected every 20 min, and then analyzed with high-performance liquid chromatography coupled to an electrochemical detector. The result revealed that the perfusion with CO had no significant effect on glutamate levels (p = 0.316) as compared to the control group. This finding does not support a local CO rise as the cause of the increased glutamate level in the hippocampus of mice. PMID- 28866966 TI - Construction of nanoscale liposomes loaded with melatonin via supercritical fluid technology. AB - Melatonin-loaded liposomes (MLL) were successfully prepared using rapid expansion of supercritical solution technology. The effects of supercritical pressure on encapsulation efficiency (EE) and average particle size were then analysed. Meanwhile, temperature, formation time and ethanol concentration in the products were studied and optimised based on the response surface methodology (RSM). An in vitro simulated digestion model was also established to evaluate the release performance of MLL. The results showed that 140 bar was the best pressure for maximising the EE value using RSM optimisation, reaching up to 82.2%. MLL characterisations were performed using analytic techniques including infrared spectroscopy, transmission electron microscopy, a laser scattering particle size analyser and gas chromatograph-mass spectrometer. The size distribution was uniform, with an average diameter of 66 nm. Stability tests proved that MLL maintained good preservation duration, and residual solvent experiments indicated that only 1.03% (mass ratio) of ethanol remained in the products. Simulated release experiments indicated the slow release feature in early digestive stages and more thorough characteristics in later stages of simulated digestion. PMID- 28866968 TI - Glycaemic control in diabetic ketoacidosis: Too much of a good thing? PMID- 28866967 TI - A humanisation approach for the management of Joint Hypermobility Syndrome/Ehlers Danlos Syndrome-Hypermobility Type (JHS/EDS-HT). AB - Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome-Hypermobility Type (JHS/EDS HT) is a complex and multisystemic condition which significantly impacts on a person's health and well-being and is challenging for health professionals (HPs) to manage. People with JHS/EDS-HT and HPs recognise the individual nature and the complexities of the condition. There is a requirement to understand the condition within the context of the individual human dimensions of illness and healing. The aim of this paper is to explore the management of this condition using a theoretical model referred to as the Humanisation Framework. It is suggested that using the philosophical dimensions of this framework will empower HPs and those with JHS/EDS-HT to work together to proactively manage this condition. The eight dimensions of the Humanisation Framework facilitate an experiential understanding of the person within their context and environment, providing a constructive adjunct to the evidence-based management of those with JHS/EDS-HT. The humanisation framework was developed for health and social care and uses the philosophy behind well-being and what makes well-being possible. This paper explores how HPs may use aspects of the framework to understand the condition and empower and motivate those with JHS/EDS-HT to be active participants in their own well-being. PMID- 28866969 TI - A scoping review of use of wearable devices to evaluate outcomes in survivors of critical illness. AB - OBJECTIVE: Wearable devices using new technology may be a cost-effective method to assess functional outcomes in survivors of critical illness. Our primary objective was to review the extent to which wearable devices such as smartphones, pedometers, accelerometers and global positioning systems have been used to evaluate outcomes in survivors of an intensive care unit admission. DESIGN: We included studies of patients surviving an ICU admission and which measured outcomes using wearable devices. We performed a scoping review of studies found by searching the CINAHL, Embase, MEDLINE and PubMed databases. RESULTS: The seven studies we identified were published in or after 2012 and were predominantly descriptive (n = 6) with one randomised controlled trial. All studies described outcomes in cohorts of relatively few participants (range, 11-51 participants). Duration to follow-up was mostly short, at a median time of 3 months after ICU discharge (range, in-hospital to 27 years). All studies used accelerometers to monitor patient movement: physical activity (n = 5), sleep quality (n = 1), and infant movement (n = 1). The accelerometers were bi-axial (n = 3), uni-axial (n = 2) combined uni-axial (n = 1) and tri-axial (n = 1). Common outcomes evaluated were the number of participants walking for < 30 min/day, mean daily step count and walking speed. CONCLUSIONS: Wearable devices have infrequently been used to measure physical activity in survivors of critical illness and all identified studies were published recently, which suggests that the use of wearable devices for research may be increasing. To date, only accelerometry has been reported, and the wide variation in methodologies used and the outcomes measured limits synthesis of these data. PMID- 28866970 TI - Calprotectin as an early biomarker of bacterial infections in critically ill patients: an exploratory cohort assessment. AB - BACKGROUND: Calprotectin is the most abundant protein in the cytosolic fraction of neutrophils, and neutrophil degranulation is a major response to bacterial infections. OBJECTIVES: To assess the value of plasma calprotectin as an early marker of bacterial infections in critically ill patients and compare it with the corresponding values for procalcitonin (PCT), C-reactive protein (CRP) and white blood cell count (WBC). METHODS: We measured daily plasma calprotectin levels in 110 intensive care unit patients using a newly developed turbidimetric assay run on clinical chemistry analysers. The likelihood of infection was determined according to the International Sepsis Forum criteria. RESULTS: Overall, 58 patients (52.7%) developed a suspected or confirmed bacterial infection. Plasma calprotectin predicted such infections within 24 hours with an area under the receiver operating characteristics curve (ROC area) of 0.78 (95% CI, 0.68-0.89). The ROC area for calprotectin was significantly greater than the corresponding ROC areas for WBC (P < 0.001) and PCT (P = 0.02) but only marginally better than the ROC area for CRP (0.71; 95% CI, 0.68-0.89). CONCLUSION: Plasma calprotectin appears to be a useful early marker of bacterial infections in critically ill patients, with better predictive characteristics than WBC and PCT. PMID- 28866971 TI - Rapid response team calls that overlap in time: incidence, consequences and patient outcomes. AB - OBJECTIVE: To investigate overlap rapid response team (RRT) calls, factors associated with overlap calls, and their impact on RRT call times and patient outcomes. DESIGN AND SETTING: Review of prospectively collected, linked clinical and administrative datasets, at a public adult tertiary hospital during July 2013 to May 2016. RESULTS: There were 11 669 RRT calls to 7223 patients, of which 10 868 calls (93.1%) were to inpatients. The median number of daily calls was 12 (interquartile range [IQR], 9-15 calls; range, 2-29 calls). The median number of daily calls per 1000 hospital admissions was 56.3 (IQR, 41.3- 78.9 calls/1000 admissions; range, 8.3-231.5 calls/1000 admissions), and the median proportion of the day spent at RRT calls was 22.8% (IQR, 16.9%-30.5%). In total, 4575 (39.2%) calls overlapped. Overlap calls, compared with non-overlap calls, had similar patient characteristics, but a longer response time (4 min v 3 min; P < 0.001) and scene time (20 min v 34 min; P < 0.001). The daily number of calls correlated with the number of overnight-stay hospital admissions (r = 0.104; P = 0.001), but not with the total number of hospital admissions (r = -0.035; P = 0.258). The number of overlap calls correlated with the number of RRT calls (r = 0.786; P < 0.001), and also correlated with the proportion of the day spent at RRT calls (r = 0.762; P < 0.001). Overlap calls, compared with non-overlap calls, were more likely to result in an ICU admission (484 calls [11.2%] v 571 calls [8.7%]; P < 0.001). In contrast, efferent limb failure (815 calls [17.8%] v 1195 calls [16.8%]; P = 0.389) and hospital mortality (496 calls [19.3%] v 781 calls [19.6%]; P = 0.823) was similar for overlap and nonoverlap calls, respectively. CONCLUSIONS: Overlap RRT calls are common and influenced by overall RRT and hospital activity. They are more likely to be associated with longer response and scene times and unanticipated ICU admissions. PMID- 28866972 TI - Comparison of continous-wave Doppler ultrasound monitor and echocardiography to assess cardiac output in intensive care patients. AB - BACKGROUND: Continuous-wave Doppler (CWD) ultrasound through the left ventricular outflow tract is one modality used for non-invasive cardiac output measurement. The ultrasonic cardiac output monitor (USCOM) is a relatively new monitor which uses a small, transcutaneous ultrasound probe to measure cardiac output with CWD via the suprasternal window. It is faster and less complex to train new users than conventional echocardiography. In addition to stroke volume (SV), the USCOM can calculate stroke volume variation (SVV) and the Smith-Madigan inotropy index (SMII), which is an estimate of the pre-load independent contractility of the myocardium. OBJECTIVE: To assess the level of agreement between cardiac output measured with conventional echocardiography and with USCOM. METHODS: A prospective, observational, multicentre trial of patients admitted to the intensive care units of two hospitals. After excluding patients with aortic stenosis, any patient undergoing a clinically indicated echocardiogram also underwent a subsequent USCOM study for comparison. RESULTS: We enrolled 121 patients in the study, with aortic stenosis the main reason for patient exclusion. Of the study patients, 63% were mechanically ventilated, 84% were in sinus rhythm, and the mean age of the study cohort was 66 years (SD, 17 years). There was a very strong correlation between SV as measured by the USCOM and by echocardiography. The mean difference in SV was 0.33 mL (SD, 5.62 mL), r2 = 0.956, and Bland-Altman analysis confirmed no significant bias with acceptable limits of agreement between the methods. Patients who were fluid responsive had an SVV cut point on the receiver operating characteristic curve of 21%, and sensitivity and specificity of 95%. A low SMII (< 1.1 watts/m2) calculated with the USCOM did not correlate well with low cardiac output status, with a sensitivity of only 69%. CONCLUSIONS: SV (and thus cardiac output) measured using the USCOM correlated well with echocardiographic cardiac output measurement, which suggests that the USCOM could be a valuable haemodynamic tool for assessment of cardiac output and fluid responsiveness in critically ill patients if patients with aortic stenosis are excluded. Inotropy, as a parameter of low cardiac output, was not useful in this cohort of patients. PMID- 28866973 TI - Identification and assessment of potentially high-mortality intensive care units using the ANZICS Centre for Outcome and Resource Evaluation clinical registry. AB - PURPOSE: A hospital's highest-risk patients are managed in the intensive care unit. Outcomes are determined by patients' severity of illness, existing comorbidities and by processes of care delivered. The Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcome and Resource Evaluation (CORE) manages a binational clinical registry to benchmark performance, and report and assess ICUs which appear to have worse outcomes than others. METHODS: A descriptive retrospective cohort study was undertaken to detail processes, outcomes, limitations and practical lessons learnt from monitoring ICU performance throughout Australia and New Zealand. All ICUs contributing to the ANZICS Adult Patient Database between 2009 and 2014 were included. A potential outlier ICU was defined as one with a statistically significantly higher standardised mortality ratio (SMR) than its peer group. RESULTS: There were 757 188 admissions to 168 ICUs. Of these, 27 ICUs (16%) were identified as potential outlier ICUs at least once. Data quality problems led to inaccurate or artificially elevated SMRs at 16/27 ICUs. Variation in diagnostic casemix partly or completely explained the elevated SMR at 15/27 ICUs. At nine ICUs where data quality and casemix differences did not explain the elevated SMR, process-of-care problems were identified. CONCLUSIONS: A combination of routine monitoring techniques, statistical analysis and contextual interpretation of findings is required to ensure potential outlier ICUs are appropriately identified. This ensures engagement and understanding from clinicians and jurisdictional health departments, while contributing to the improvement of ICU practices throughout Australia and New Zealand. PMID- 28866974 TI - The Plasma-Lyte 148 v Saline (PLUS) study protocol: a multicentre, randomised controlled trial of the effect of intensive care fluid therapy on mortality. AB - BACKGROUND: 0.9% sodium chloride (saline) is the most commonly administered resuscitation fluid on a global basis but emerging evidence suggests that its high chloride content may have important adverse effects. OBJECTIVE: To describe the study protocol for the Plasma- Lyte 148 v Saline study, which will test the hypothesis that in critically ill adult patients the use of Plasma-Lyte 148 (a buffered crystalloid solution) for fluid therapy results in different 90-day all cause mortality when compared with saline. DESIGN AND SETTING: We will conduct this multicentre, blinded, randomised controlled trial in approximately 50 intensive care units in Australia and New Zealand. We will randomly assign 8800 patients to either Plasma-Lyte 148 or saline for all resuscitation fluid, maintenance fluid and compatible drug dilution therapy while in the ICU for up to 90 days after randomisation. OUTCOME MEASURES: The primary outcome is 90-day all cause mortality; secondary outcomes include mean and peak creatinine concentration, incidence of renal replacement therapy, incidence and duration of vasoactive drug treatment, duration of mechanical ventilation, ICU and hospital length of stay, and quality of life and health services use at 6 months. RESULTS AND CONCLUSIONS: The PLUS study will provide high-quality data on the comparative safety and efficacy of Plasma-Lyte 148 compared with saline for resuscitation and compatible crystalloid fluid therapy in critically ill adult patients. PMID- 28866975 TI - Influence of changing endotracheal tube cuff management on antibiotic use for ventilator-associated pneumonia in a tertiary intensive care unit. AB - BACKGROUND: Routine deflation of the endotracheal tube (ETT) cuff of critically ill patients receiving MV is common in Australia and New Zealand. Literature about ventilatorassociated pneumonia (VAP) and antibiotic use rates with different ETT cuff maintenance practices is lacking. OBJECTIVE: To determine the impact of a change in ETT cuff maintenance from a minimal leak technique to pressure manometry on the administration of antibiotics for VAP. DESIGN, SETTING AND PARTICIPANTS: A prospective, pre- post observational study conducted in a metropolitan tertiary referral intensive care unit. We analysed data from 178 patients receiving MV for > 48 hours during 13 weeks of minimal leak test ETT cuff technique (pre-intervention, n = 92) or 13 weeks of cuff pressure manometry (postintervention, n = 86), separated by 3 weeks' "wash-out". MAIN OUTCOME MEASURES: Primary outcome was the number of patients receiving antibiotics for the indication of VAP. Secondary outcomes were incidence of ventilatorassociated surveillance events, lengths of stay (LOSs) and mortality. RESULTS: Antibiotics were administered for VAP in 24 patients (26.1%) in the pre-intervention period compared with 11 post-intervention patients (12.8%). The univariate antibiotic administraion rate per 100 ventilation days was 15.3% (95% CI, 12.6%-18.4%) v 6.8% (95% CI, 4.9%- 9.3%), and the incident rate ratio (IRR) was 0.45 (95% CI, 0.31-0.64); P < 0.001). After adjustment for ventilation duration, IRR was 0.55 (95% CI, 0.24-1.27); P = 0.160. The ventilator-associated complication incidence rate was lower in the post-intervention group (11.4% v 16.3%; IRR, 0.70 [95% CI, 0.51-0.95]; P = 0.018). After adjustment for duration of MV, IRR was 0.66 (95% CI, 0.25-1.70); P = 0.387. Antibiotic administration for VAP was associated with increased ICU and hospital LOSs, but not with mortality. CONCLUSIONS: ETT cuff pressure manometry is associated with a reduced rate of antibiotic administration for a diagnosis of VAP compared with a minimal leak test technique. PMID- 28866977 TI - Intensity of early correction of hyperglycaemia and outcome of critically ill patients with diabetic ketoacidosis. AB - OBJECTIVES: To determine the impact of the intensity of early correction of hyperglycaemia on outcomes in patients with diabetic ketoacidosis (DKA) admitted to the intensive care unit. METHODS: We studied adult patients with DKA admitted to 171 ICUs in Australia and New Zealand from 2000 to 2013. We used their blood glucose levels (BGLs) in the first 24 hours after ICU admission to determine whether intensive early correction of hyperglycemia to <= 180 mg/dL was independently associated with hypoglycaemia, hypokalaemia, hypo-osmolarity or mortality, compared with partial early correction to > 180 mg/dL as recommended by DKA-specific guidelines. RESULTS: Among 8553 patients, intensive early correction of BGL was applied to 605 patients (7.1%). A greater proportion of these patients experienced hypoglycaemia (20.2% v 9.1%; P < 0.001) and/or hypo osmolarity (29.4% v 22.0%; P < 0.001), but not hypokalaemia (16.7% v 15.6%; P = 0.47). Overall, 11 patients (1.8%) in the intensive correction group and 112 patients (1.4%) in the partial correction group died (P = 0.42). However, after adjustment for illness severity, partial early correction of BGL was independently associated with a lower risk of hypoglycaemia (odds ratio [OR], 0.38; 95% CI, 0.30-0.48; P < 0.001), lower risk of hypo-osmolarity (OR, 0.80; 95% CI, 0.65-0.98; P < 0.03) and lower risk of death (OR, 0.44; 95% CI, 0.22-0.86; P = 0.02). CONCLUSIONS: In a large cohort of patients with DKA, partial early correction of BGL according to DKA-specific guidelines, when compared with intensive early correction of BGL, was independently associated with a lower risk of hypoglycaemia, hypo-osmolarity and death. PMID- 28866976 TI - A cross-sectional survey of Australian and New Zealand public opinion on methods totriage intensive care patients in an influenza pandemic. AB - BACKGROUND AND OBJECTIVE: An influenza pandemic has the potential to overwhelm intensive care resources, but the views of the general public on how resources should be allocated in such a scenario were unknown. We aimed to determine Australian and New Zealand public opinion on how intensive care unit beds should be allocated during an influenza pandemic. DESIGN, SETTING, AND PARTICIPANTS: A postal questionnaire was sent to 4000 randomly selected registered voters; 2000 people each from the Australian Electoral Commission and New Zealand Electoral Commission rolls. MAIN OUTCOME MEASURE: The respondents' preferred method to triage ICU patients in an influenza pandemic. Respondents chose from six methods: use a "first in, first served" approach; allow a senior doctor to decide; use pre determined health department criteria; use random selection; use the patient's ability to pay; use the importance of the patient to decide. Respondents also rated each of the triage methods for fairness. RESULTS: Australian respondents preferred that patients be triaged to the ICU either by a senior doctor (43.2%) or by pre-determined health department criteria (38.7%). New Zealand respondents preferred that triage be performed by a senior doctor (45.9%). Respondents from both countries perceived triage by a senior doctor and by pre-determined health department criteria to be fair, and the other four methods of triage to be unfair. CONCLUSION: In an influenza pandemic, when ICU resources would be overwhelmed, survey respondents preferred that ICU triage be performed by a senior doctor, but also perceived the use of pre-determined triage criteria to be fair. PMID- 28866978 TI - Peripheral venoarterial extracorporeal membrane oxygenation for severe hyperlactataemia after cardiac surgery: a pilot study. AB - BACKGROUND: Severe hyperlactataemia in patients after cardiac surgery is associated with poor prognosis and implies possible splanchnic hypoperfusion. Peripheral venoarterial extracorporeal membrane oxygenation (splanchnic ECMO) may be more effective at reducing lactic acidosis for these patients. OBJECTIVE: To investigate whether splanchnic ECMO attenuates hyperlactataemia and liver enzyme release in these patients, despite them having a cardiac index > 2 L/min/m2 and a mixed venous oxygen saturation > 55%. DESIGN AND PARTICIPANTS: Retrospective matched case- control study of patients treated with splanchnic ECMO for hyperlactataemia. Seven patients who had had cardiac surgery were treated with splanchnic ECMO compared with seven matched control patients. RESULTS: We observed a mean decrease in lactate levels from 9.9 mmol/L (SD, 2.9 mmol/L) to 1.4 mmol/L (SD, 0.6 mmol/L) in patients receiving 48 hours of splanchnic ECMO, compared with a mean of 10.4 mmol/L (SD, 2.8 mmol/L) to 4.4 mmol/L (SD, 5 mmol/L) during 48 hours in control patients (P < 0.0001). Normalisation of lactate levels (to < 2 mmol/L) was achieved within a mean of 16.3 hours (SD, 14.6 hours) with splanchnic ECMO, compared with 38.3 hours (SD, 23.8 hours) in the control group (P = 0.029). The median increase in alanine aminotransferase level with splanchnic ECMO was 68% (range, -84% to 2015%) compared with 158% (range: 0% 6024%) (not significant) in control patients. CONCLUSION: In a selected cohort of patients who had had cardiac surgery with severe post-operative hyperlactataemia, despite an acceptable cardiac index and a mixed venous oxygen saturation, splanchnic ECMO appeared to reduce overall lactate levels and time to normalisation of lactataemia. PMID- 28866979 TI - Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer's disease and down syndrome. AB - BACKGROUND: There is still a substantial unmet need for less invasive and lower cost blood-based biomarkers to detect brain Alzheimer's disease (AD) pathology. This study is aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181) is informative in the diagnosis of AD. METHODS: We have developed a novel ultrasensitive immunoassay to quantify plasma p-tau181, and measured the levels of plasma p-tau181 in three cohorts. RESULTS: In the first cohort composed of 20 AD patients and 15 age-matched controls, the plasma levels of p-tau181 were significantly higher in the AD patients than those in the controls (0.171 +/- 0.166 pg/ml in AD versus 0.0405 +/- 0.0756 pg/ml in controls, p = 0.0039). The percentage of the subjects whose levels of plasma p tau181 exceeded the cut-off value (0.0921 pg/ml) was significantly higher in the AD group compared with the control group (60% in AD versus 16.7% in controls, p = 0.0090). In the second cohort composed of 20 patients with Down syndrome (DS) and 22 age-matched controls, the plasma concentrations of p-tau181 were significantly higher in the DS group (0.767 +/- 1.26 pg/ml in DS versus 0.0415 +/- 0.0710 pg/ml in controls, p = 0.0313). There was a significant correlation between the plasma levels of p-tau181 and age in the DS group (R2 = 0.4451, p = 0.0013). All of the DS individuals showing an extremely high concentration of plasma p-tau181 (> 1.0 pg/ml) were older than the age of 40. In the third cohort composed of 8 AD patients and 3 patients with other neurological diseases, the levels of plasma p tau181 significantly correlated with those of CSF p-tau181 (R2 = 0.4525, p = 0.023). CONCLUSIONS: We report for the first time quantitative data on the plasma levels of p-tau181 in controls and patients with AD and DS, and these data suggest that the plasma p-tau181 is a promising blood biomarker for brain AD pathology. This exploratory pilot study warrants further large-scale and well controlled studies to validate the usefulness of plasma p-tau181 as an urgently needed surrogate marker for the diagnosis and disease progression of AD. PMID- 28866980 TI - Parasitology should not be abandoned: data from outpatient parasitological testing in Guangdong, China. AB - Over the past six decades, the Chinese government made parasitoses with a high disease burden, including soil-transmitted nematode infections, malaria, leishmaniasis, filariasis, and schistosomiasis, a public health priority because they were seen to be crucial impediments to the development of rural areas. As a result, these debilitating parasitic diseases that used to be widely prevalent have been well controlled or eliminated. Consequently, less attention has been paid to parasitic infection during the rapid development of the economy, especially in developed areas. However, our investigations conducted in the parasitological laboratory of Sun Yat-sen University (Guangzhou, Guangdong, China) show that emerging parasitic diseases still threaten many people's health, with 340 of 880 outpatients (38.6%) receiving a diagnosis of parasitic disease, among whom 201 (59.1%) had clonorchiasis and 120 (35.3%) had taeniasis/cysticercosis. Furthermore, our doctors are not equipped with sufficient parasitology knowledge because this discipline is not able to maintain attraction. Many parasitic infections that result in severe consequences are treatable and preventable, but the phenomena of misdiagnosis and missed diagnosis are common and merit attention. PMID- 28866981 TI - Carpal spasm in a girl as initial presentation of celiac disease: a case report. AB - BACKGROUND: Celiac disease is an immune-mediated disorder elicited by ingestion of gluten in genetically susceptible persons. This disorder is characterized by specific histological changes of the small intestine mucosa resulting in malabsorption. This case was written up as it was an unusual and dramatic presentation of celiac disease. CASE PRESENTATION: We report the case of a 3-year old Albanian girl who presented at our clinic with carpal spasms and hand paresthesia. A physical examination at admission revealed a relatively good general condition and body weight of 10.5 kg (10 percentile). Carpal spasms and paresthesias of her extremities were present. Neuromuscular irritability was demonstrated by positive Chvostek and Trousseau signs. Blood tests showed severe hypocalcemia with a total serum calcium of 1.2 mmol/L (normal range 2.12 to 2.55 mmol/L), ionized calcium of 0.87 (normal range 1.11 to 1.30 mmol/L), and 24-hour urine calcium excretion of 9.16 mmol (normal range female <6.2 mmol/day). Among other tests, screening for celiac disease was performed: antigliadin immunoglobulin A, anti-tissue transglutaminase, and anti-endomysial immunoglobulin A antibodies were positive. A duodenal biopsy revealed lymphocyte infiltration, crypt hyperplasia, and villous atrophy compatible with celiac disease grade IIIb according to the Marsh classification. Following the diagnosis of celiac disease, human leukocyte antigen typing was performed, giving a definite diagnosis of celiac disease. She was started on a gluten-free diet. Due to failure to follow a gluten-free diet, episodes of carpal spasms appeared again. Unfortunately, at the age of 7 years she presents with delayed psychophysical development. CONCLUSIONS: Although hypocalcemia is a common finding in celiac disease, hypocalcemic carpal spasm is a rare initial manifestation of the disease. Therefore, the possibility of celiac disease should be considered in patients with repeated carpal spasms that seem unduly difficult to treat. This should be evaluated even in the absence of gastrointestinal symptoms since hypocalcemia and its manifestation may present as initial symptoms of celiac disease even in young children. PMID- 28866982 TI - Protein profile of leprosy patients with plantar ulcers from the Eastern Amazon region. AB - BACKGROUND: Studies investigating the nutritional status of patients with leprosy and plantar ulcers are sparse. Therefore, the objective of this study was to describe the protein profile of leprosy patients with plantar ulcers from the Eastern Amazon region. METHODS: A case record form was created for 75 patients with leprosy (31 with plantar ulcers and 44 without plantar ulcers) with the following data: sociodemographic characteristics, clinical form of leprosy, presence or absence of plantar ulcers, and nutritional assessment using anthropometry consisting of the measurement of body mass index, arm circumference, arm muscle circumference, and triceps skinfold. Levels of blood albumin, transferrin, and C-reactive protein (CRP) were also measured. Data regarding protein intake were obtained using a Food Frequency Questionnaire. RESULTS: Plantar ulcers occurred more frequently in male patients (67.7%), patients aged 40-49 years (mean +/- SD: 47.3 +/- 8.0 years), and patients receiving 300 or 600 USD (71.0%). The mean weight and height of patients were 71.6 +/- 11.4 kg and 1.62 +/- 0.1 m, respectively. High levels of CRP were detected in 51.6% of leprosy patients with plantar ulcers and only 9.1% of patients without plantar ulcers (P < 0.001). Nutritional depletion of transferrin was observed in 14.3% of patients with paucibacillary leprosy and 44.3% of patients with multibacillary leprosy (P = 0.0447). Most patients had normal levels of serum albumin (74.2% with plantar ulcers and 77.3% without plantar ulcers). CONCLUSIONS: Most leprosy patients with plantar ulcers have normal levels of serum albumin and transferrin and high CRP levels, which indicates the presence of an inflammatory process. Our findings suggest the need to monitor patients with leprosy to prevent the occurrence of plantar ulcers and to provide adequate treatment for patients with existing plantar ulcers. PMID- 28866983 TI - Patterns of tsetse abundance and trypanosome infection rates among habitats of surveyed villages in Maasai steppe of northern Tanzania. AB - BACKGROUND: Changes of land cover modify the characteristics of habitat, host vector interaction and consequently infection rates of disease causing agents. In this paper, we report variations in tsetse distribution patterns, abundance and infection rates in relation to habitat types and age in the Maasai Steppe of northern Tanzania. In Africa, Tsetse-transmitted trypanosomiasis negatively impacted human life where about 40 million people are at risk of contracting the disease with dramatic socio-economical consequences, for instance, loss of livestock, animal productivity, and manpower. METHODS: We trapped tsetse flies in dry and wet seasons between October 2014 and May 2015 in selected habitats across four villages: Emboreet, Loiborsireet, Kimotorok and Oltukai adjacent to protected areas. Data collected include number and species of tsetse flies caught in baited traps, PCR identification of trypanosome species and extraction of monitored Normalized Difference Vegetation Index (NDVI) data from Moderate Resolution Imaging Spectrometer (MODIS). RESULTS: Our findings demonstrate the variation of tsetse fly species abundance and infection rates among habitats in surveyed villages in relation to NDVI and host abundance. Results have shown higher tsetse fly abundance in Acacia-swampy ecotone and riverine habitats for Emboreet and other villages, respectively. Tsetse abundance was inconsistent among habitats in different villages. Emboreet was highly infested with Glossina swynnertoni (68%) in ecotone and swampy habitats followed by G. morsitans (28%) and G. pallidipes (4%) in riverine habitat. In the remaining villages, the dominant tsetse fly species by 95% was G. pallidipes in all habitats. Trypanosoma vivax was the most prevalent species in all infected flies (95%) with few observations of co-infections (with T. congolense or T. brucei). CONCLUSIONS: The findings of this study provide a framework to mapping hotspots of tsetse infestation and trypanosomiasis infection and enhance the communities to plan for effective control of trypanosomiasis. PMID- 28866984 TI - Transmission of Opisthorchis viverrini, Schistosoma mekongi and soil-transmitted helminthes on the Mekong Islands, Southern Lao PDR. AB - BACKGROUND: Prevalence of Opisthorchis viverrini, Schistosoma mekongi and soil transmitted helminths (STH) remains high in Lao People's Democratic Republic (Lao PDR), despite control efforts including mass-drug administration, education and communication campaigns. New approaches are required to advance helminth control. METHODS: An ecohealth study was conducted on two Mekong islands in Southern Laos. Demographic and behavioural data were collected by questionnaire. Human and animal reservoir stools were examined. Bithynia spp. and Neotricula aperta snails were examined using shedding. Fresh water fish were examined using digestion technique. Multivariate random-effects analysis was used to find risk factors associated with helminth infections. RESULTS: Human infection rates with O. viverrini, hookworm, S. mekongi, Trichuris trichiura, Ascaris lumbricoides and Taenia spp. were 60.7%, 44.1%, 22.2%, 4.1%, 0.6% and 0.1%, respectively. Heavy intensity infections were 4.2%, 3.6% and 1.8% for O. viverrini, S. mekongi and hookworm, respectively. O. viverrini and S. mekongi infection rates among dogs and cats were 25.0% and 14.7%, respectively. Of the cats tested, 53.1% were infected with O. viverrini. Prevalence of O. viverrini and S. mekongi in snails was 0.3% and 0.01%, respectively. Overall prevalence of O. viverrini infection in fresh water fish was 26.9%, with the highest infection rates occurring in Hampala dispa (87.1%), Cyclocheilichthys apogon (85.7%) and Puntius brevis (40.0%). Illiteracy and lower socioeconomic status increased the risk of O. viverrini infection, while those aged 10-16 years and possessing latrines at home were less likely to be infected. Household dogs and cats that consumed raw fish were significantly and positively associated with O. viverrini infection of the household members. For S. mekongi, children under 9 years old were exposed significantly to this infection, compared to older age groups. CONCLUSIONS: There is a pressing need to design and implement an integrated helminth control intervention on the Mekong Islands in southern Lao PDR. Given the highly dynamic transmission of O. viverrini, S. mekongi, STH and extended multiparasitism, annual mass-drug administration is warranted along with environmental modifications, health education and improved access to clean water and adequate sanitation to consolidate morbidity control and move towards elimination. TRAIL REGISTRATION NUMBER: Our findings presented here are from a cross-sectional study, therefore, it has not been registered. PMID- 28866985 TI - Effects of cognitive remediation on negative symptoms dimensions: exploring the role of working memory. AB - BACKGROUND: Recent theories suggest that poor working memory (WM) may be the cognitive underpinning of negative symptoms in people with schizophrenia. In this study, we first explore the effect of cognitive remediation (CR) on two clusters of negative symptoms (i.e. expressive and social amotivation), and then assess the relevance of WM gains as a possible mediator of symptom improvement. METHOD: Data were accessed for 309 people with schizophrenia from the NIMH Database of Cognitive Training and Remediation Studies and a separate study. Approximately half the participants received CR and the rest were allocated to a control condition. All participants were assessed before and after therapy and at follow up. Expressive negative symptoms and social amotivation symptoms scores were calculated from the Positive and Negative Syndrome Scale. WM was assessed with digit span and letter-number span tests. RESULTS: Participants who received CR had a significant improvement in WM scores (d = 0.27) compared with those in the control condition. Improvements in social amotivation levels approached statistical significance (d = -0.19), but change in expressive negative symptoms did not differ between groups. WM change did not mediate the effect of CR on social amotivation. CONCLUSIONS: The results suggest that a course of CR may benefit behavioural negative symptoms. Despite hypotheses linking memory problems with negative symptoms, the current findings do not support the role of this cognitive domain as a significant mediator. The results indicate that WM improves independently from negative symptoms reduction. PMID- 28866986 TI - Post-fall reporting in aged acute inpatient mental health units: an 18-month observational cohort study. AB - BACKGROUND: Despite the high risk of falling for people with severe mental illness, there is limited falls research in mental health settings. Therefore, the objective of this observational cohort study was to conduct a focused post fall review of fall episodes within aged acute inpatient mental health units at one of Australia's largest publicly funded mental health organizations. METHODS: A post-fall reporting tool was developed to collect intrinsic and extrinsic fall risk factors among three aged acute mental health inpatient units over an 18 month period. Descriptive and inferential analyses were conducted to describe fall risk factors and predictors of fall risk. RESULTS: There were a total of 115 falls, of which the tool was used for 93 (80.9%) episodes. Falls occurred most often in consumer's bedroom/bathroom and were unwitnessed. Intrinsic risk factors were most often attributed to postural drop and losing balance during walking. However, that was in contrast to consumer's who self-reported feeling dizzy as the reason of the fall. CONCLUSIONS: Based on the cohort, future falls could be reduced by targeting those aged above 82 years, or with a diagnosis of dementia. Recurrent falls during admission could be reduced by targeting those with psychotic illness and males with a diagnosis of dementia. A clearer dialogue among consumers and clinical staff reporting about fall episodes may support future remedial interventions and inform programs to reduce fall risk and assist the challenge of describing unwitnessed falls in aged acute inpatient mental health settings. PMID- 28866987 TI - Helminth composition and prevalence of indigenous and invasive synanthropic murid rodents in urban areas of Gauteng Province, South Africa. AB - Although synanthropic rodents such as the indigenous species, Mastomys coucha, and the invasive species, Rattus norvegicus, R. rattus and R. tanezumi, are well known to be hosts to various micro- and macroparasites, their helminth parasite fauna is poorly studied in South Africa. In an attempt to remedy the situation, the aim of the present study was to investigate the helminth fauna of these sympatric rodent species, which were obtained from the informal settlements of Alexandra, Tembisa, Diepsloot and residential suburbs of Pretoria and Hammanskraal, Gauteng Province, South Africa. Helminths were recovered from the urinary bladder, liver and gastrointestinal tract and were identified morphologically and molecularly. The recovered nematodes were all rodent-specific and included Aspiculuris tetraptera, Eucoleus sp., Heterakis spumosa, Mastophorus muris, Nippostrongylus brasiliensis, Protospirura sp., Strongyloides ratti, Syphacia obvelata, Syphacia muris, Trichuris sp. and Trichosomoides crassicauda. Syphacia obvelata, a commensal nematode of laboratory rodents, was recovered from indigenous M. coucha. Strobilar stages of cestodes recovered included Hymenolepis diminuta, Hymenolepis nana and Inermicapsifer madagascariensis. Recovered metacestodes were strobilocerci of Hydatigera taeniaeformis from all three invasive Rattus species and coenurostrobilocerci of Hydatigera parva from M. coucha. An acanthocephalan, Moniliformis moniliformis, was recovered from R. rattus only. All rodent species examined showed high helminth infection prevalence (>=70%) with equal or higher nematode than cestode prevalence. Mastomys coucha, however, showed significantly lower cestode prevalence than Rattus species where they co-occur. Interspecific transmission of helminths likely occurs between invasive and indigenous rodents, and these rodents harbour several helminths that have zoonotic implications. PMID- 28866988 TI - A new generation computerised metacognitive cognitive remediation programme for schizophrenia (CIRCuiTS): a randomised controlled trial. AB - BACKGROUND: Cognitive remediation (CR) is a psychological therapy, which improves cognitive and social functioning in people with schizophrenia. It is now being implemented within routine clinical services and mechanisms of change are being explored. We designed a new generation computerised CR programme, CIRCuiTS (Computerised Interactive Remediation of Cognition - a Training for Schizophrenia), to enhance strategic and metacognitive processing, with an integrated focus on the transfer of cognitive skills to daily living. This large trial tested its feasibility to be delivered in therapist-led and independent sessions, and its efficacy for improved cognitive and social functioning. METHODS: A two arm single blind randomised superiority trial comparing CIRCuiTS plus treatment-as-usual (TAU) with TAU alone in 93 people with a diagnosis of schizophrenia. Cognitive, social functioning and symptom outcomes were assessed at pre- and post-therapy and 3 months later. RESULTS: 85% adhered to CIRCuiTS, completing a median of 28 sessions. There were significant improvements in visual memory at post-treatment (p = 0.009) and follow-up (p = 0.001), and a trend for improvements in executive function at post-treatment (p = 0.056) in favour of the CIRCuiTS group. Community function was also differentially and significantly improved in the CIRCuiTS group at post-treatment (p = 0.003) but not follow-up, and was specifically predicted by improved executive functions. CONCLUSIONS: CIRCuiTS was beneficial for improving memory and social functioning. Improved executive functioning emerges as a consistent predictor of functional gains and should be considered an important CR target to achieve functional change. A larger-scale effectiveness trial of CIRCuiTS is now indicated. PMID- 28866989 TI - The mismatch between observational measures and residents' perspectives on the retail food environment: a mixed-methods approach in the Heart Healthy Hoods study. AB - OBJECTIVE: To gain a deeper understanding of the retail food environment by investigating similarities and differences between objective measures and residents' perspectives. DESIGN: The study incorporated Geographic Information System (GIS)-based measures, in-store surveys and the results from a larger photovoice project. We combined these data using a convergent parallel mixed methods approach. SETTING: We conducted this study in a low-income neighbourhood in Madrid (Spain) in 2016. SUBJECTS: We assessed healthy food availability, accessibility and affordability using GIS-based measures and in-store audits. We also analysed the photographs and discussions from twelve participants who engaged in a photovoice project on their food environment. RESULTS: Quantitative results depicted a widely served and highly accessible retail food environment, in which supermarkets scored highest in terms of healthy food availability (36.5 out of 39) and 98.9 % of residents could access a healthy food store within a walking travel distance of less than 15 min. Qualitative results showed that participants preferred small local businesses over supermarkets, and revealed built environment obstacles for elderly residents. They also highlighted how the socio-economic context constrained residents' food choices. CONCLUSIONS: People's experienced retail food environment is different from the one quantitatively analysed. Results show the potential of using a mixed-methods approach to enrich food environment research and enhance public health interventions. PMID- 28866990 TI - Structural validity and internal consistency of the Qualidem in people with severe dementia. AB - BACKGROUND: Since its development, the Qualidem has had items that were considered unsuited for people with very severe dementia. This study attempted to investigate the applicability of all Qualidem items in people with all stages of dementia severity. METHODS: Four data sets that contained Qualidem observations on people with dementia were combined. Dementia severity was categorized based on the Global Deterioration Scale (GDS), with a dichotomization of very severe dementia (GDS 7) and others (GDS 1-6). Unidimensional latent-trait models (Mokken scaling) were estimated to fit the Qualidem responses in the overall sample and the dichotomized groups. Scalability was assessed using coefficients of homogeneity (Loevinger's H), while reliability was assessed with Cronbach's alpha and rho. RESULTS: Combining the four databases resulted in 4,354 Qualidem measurements. The scalability of all scales was considered acceptable in the overall sample, as well is in the subgroups (all H > 0.3). Additionally, the reliability was good-excellent in the scales: "positive affect," "positive self image," "care relationship," and "negative affect." Reliability was questionable acceptable for "feeling at home," "social relations," "social isolation," and "restless tense behavior." Reliability was poor for "having something to do." CONCLUSIONS: Statistical considerations allow using all Qualidem items in all dementia stages. Future research should determine balance of statistical- versus conceptual-based reasoning in this academic debate. PMID- 28866991 TI - Bacillus iocasae sp. nov., isolated from Pacmanus hydrothermal field, Manus Basin. AB - A novel bacterial strain S36T was isolated from the deep-sea sediment collected from Pacmanus hydrothermal field, Manus Basin. The strain was Gram-stain positive, aerobic, rod-shaped, endospore-forming, and motile. It was able to grow at 16-50 degrees C, pH 6.0-10.0, and in the presence of 0-11 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequence indicated that strain S36T was a member of genus Bacillus and shares the highest sequence identity with Bacillus herbersteinensis D-1,5aT (97.0 %). The value of DNA-DNA hybridization between strain S36T and B. herbersteinensis D-1,5aT was 22.8 %. The cell wall diagnostic diamino acid of strain S36T was meso-diaminopimelic acid and the polar lipid profile of strain S36T contained diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. The predominant respiratory quinine was MK-7. The major cellular fatty acids were iso-C15 : 0 and anteiso-C15 : 0. The genomic DNA G+C content of strain S36T was 43.0 mol%. On the basis of phylogenetic analysis, DNA-DNA hybridization, and phenotypic characteristics, it was concluded that strain S36T represents a novel species of the genus Bacillus, for which the name Bacillus iocasae sp. nov. was proposed. The type strain is S36T (=KCTC 33864T=DSM 104297T=CGMCC 1.16030T). PMID- 28866992 TI - Promicromonospora callitridis sp. nov., an endophytic actinobacterium isolated from the surface-sterilized root of an Australian native pine tree. AB - A new strain of the genus Promicromonospora, CAP94T, was isolated from the surface sterilized root of Callitrispreissii (Australian native pine tree). This strain was a Gram-stain-positive, aerobic actinobacterium with hyphae breaking up into fragments which were non-motile, rod-like, coccoid elements. Phylogenetic evaluation based on 16S rRNA gene sequence analysis placed this isolate as a member of the family Promicromonospora ceae, and most closely to Promicromonospora sukumoe NBRC 14650T (99.4 %), Promicromonospora kroppenstedtii DSM 19349T (99.2 %) and Promicromonosporaaerolata V54AT (99.1 %). Chemotaxonomic data including cell-wall components, major menaquinone and major fatty acids confirmed the affiliation of strain CAP94T to the genus Promicromonospora. The results of the phylogenetic analysis, including physiological and biochemical studies in combination with DNA-DNA hybridization, allowed the genotypic and phenotypic differentiation of strain CAP94T and the closest species with validly published names. The name proposed for the new species is Promicromonospora callitridis sp. nov. The type strain is CAP94T (=DSM 103339T=TBRC 6025T). PMID- 28866993 TI - Winogradskyella flava sp. nov., isolated from the brown alga, Sargassum fulvellum. AB - An aerobic, gliding and yellow-pigmented bacterium, designated strain SFD31T, was isolated from brown alga collected from the South Sea, Republic of Korea. Cells were Gram-stain-negative, and catalase- and oxidase-positive. The neighbour joining phylogenetic tree based on 16S rRNA gene sequences showed that strain SFD31T forms an independent lineage within the genus Winogradskyella. Strain SFD31T was related distantly to Winogradskyella echinorum KMM 6211T (97.9 %, 16S rRNA gene sequence similarity), Winogradskyellalitoriviva KMM 6491T (97.4 %), Winogradskyellapulchriflava EM106T (97.2 %) and Winogradskyellaeckloniae EC29T (96.9 %). The major fatty acids of strain SFD31T were iso-C15 : 0, iso-C15 : 1 G, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and unknown 13.565. The only isoprenoid quinone of the isolate was menaquinone 6. The major polar lipids were phosphatidylethanolamine, four unidentified aminolipids and two unidentified lipids. The DNA G+C content of strain SFD31T was 36.0 mol%. Phenotypic characteristics distinguished strain SFD31T from the related species of the genus Winogradskyella. On the basis of the evidence presented in this study, a novel species, Winogradskyella flava sp. nov., is proposed for strain SFD31T (=KCTC 52348T=JCM 31798T). PMID- 28866994 TI - Psychromarinibacter halotolerans gen. nov., sp. nov., isolated from seawater of the Yellow Sea. AB - A Gram-stain-negative, strictly aerobic, motile, non-gliding, oxidase-positive, catalase-positive, rod-shaped bacterium, designated strain YBW34T, was isolated from seawater from the bottom of the Yellow Sea at station H12 (-73m in depth). Growth occurred at 10-45 degrees C (optimum 28 degrees C), in the presence of 1 12 % NaCl (w/v, optimum 4 %) and at pH 6.0-8.0 (optimum pH 7.0). The major fatty acids (>10 %) were C18 : 1 omega7c and C16 : 0. The major polar lipids comprised phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine and three unidentified aminolipids. The major respiratory quinone was ubiquinone-10 (Q-10). The DNA G+C content of strain YBW34T was 64.2 mol%. The most closely related species was Tropicimonas isoalkanivorans JCM 14837T with 95.8 % sequence similarity in Alphaproteobacteria. It showed 16S rRNA gene sequence similarities of 93.03-95.49, 93.03-95.49 and 95.31-95.32 % to species of genera Rhodovulum, Lutimaribacter and Oceanicola, respectively. Nevertheless, strain YBW34T formed a distinct lineage in the trees which did not join the genera mentioned above in the phylogenetic dendrogram based on 16S rRNA gene sequences. The phenotypic, chemotaxonomic and phylogenetic data indicated that strain YBW34T represents a novel genus and species, for which the name Psychromarinibacter halotolerans gen. nov., sp. nov. is proposed. The type strain is YBW34T (=JCM 31462T=KCTC 52366T=MCCC 1K03203T). PMID- 28866995 TI - Nocardioides taihuensis sp. nov., isolated from fresh water lake sediment. AB - A novel actinobacterial strain, designated X17T, was isolated from the sediment of Taihu Lake in China and its taxonomic position was investigated by using a polyphasic approach. The isolate formed milky-white colonies comprising aerobic, Gram-stain-positive, rod-shaped cells. Phylogenetic analysis based on the 16S rRNA gene sequences revealed that the organism belonged to the genus Nocardioides and consistently formed a distinct cluster with Nocardioides agariphilus JCM 16020T and Nocardioides islandensis MSL 26T, sharing 95.5 and 94.8 % 16S rRNA gene sequence similarities, respectively. The genomic DNA G+C content was 69.9 mol%. Chemotaxonomically, the isolate contained ll-diaminopimelic acid in the cell-wall peptidoglycan, MK-8 (H4) as the predominant menaquinone, and diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol as the polar lipids found in the cell wall. The major fatty acids were 18 : 1 omega9c (38.6 %), 16 : 0 iso (20.3 %), 15 : 0 iso (6.8 %) and 18 : 0 (5.8 %). Based on its physiological, biochemical and chemotaxonomic characteristics, the strain represents a novel species of the genus Nocardioides, for which the name Nocardioides taihuensis sp. nov. (type strain X17T=CGMCC 4.7318T=NBRC 112321T) is proposed. PMID- 28866996 TI - Novosphingobium ipomoeae sp. nov., isolated from a water convolvulus field. AB - A bacterial strain designated Tese-5T was isolated from a water convolvulus field in Taiwan and characterized using the polyphasic taxonomic approach. Strain Tese 5T was an aerobic, Gram-stain-negative, non-motile, rod-shaped bacterium and formed bright yellow coloured colonies. Strain Tese-5T grew at 15-35 degrees C (optimum, 30 degrees C), with 0-1.0 % NaCl (optimum, 0-0.5 %) and at pH 5.5-7 (optimum, pH 6). The major fatty acids (>10 %) of strain Tese-5T were C18 : 1omega7c, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0. The polar lipid profile comprised phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylcholine, phosphatidylmonomethylethanolamine, phosphatidyldimethylethanolamine and sphingoglycolipid. The major polyamine was spermidine. The major isoprenoid quinone was Q-10. The DNA G+C content was 65.7 mol%. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Tese-5T belonged to the genus Novosphingobium and showed the highest levels of sequence similarity to Novosphingobium chloroacetimidivorans BUT-14T and Novosphingobium mathurense SM117T (96.3 %). Phenotypic characteristics of the novel strain also differed from those of the closest-related species of the genus Novosphingobium. On the basis of the genotypic, chemotaxonomic and phenotypic data, strain Tese-5T represents a novel species in the genus Novosphingobium, for which the name Novosphingobium ipomoeaesp. nov. is proposed. The type strain is Tese-5T (=BCRC 80904T=LMG 28838T=KCTC 42656T). PMID- 28866997 TI - Kushneria konosiri sp. nov., isolated from the Korean salt-fermented seafood Daemi-jeot. AB - A halophilic bacterial strain, X49T, was isolated from the Korean traditional salt-fermented seafood Daemi-jeot. X49T was an obligately aerobic, Gram-stain negative, motile, oval or rod-shaped (0.5-1.0*1.2-3.2 um) bacterium. After 2 days of growth, colonies on Marine agar medium were orange and circular with entire margins. X49T growth was detected at 10-37 degrees C and pH 4.5-8.5 in the presence of 0-26 % (w/v) NaCl. The 16S rRNA gene sequence of strain X49T was most similar to that of the type strain of Kushneria marisflavi SW32T and shared a sequence similarity of 94.7-98.6 % with type strains of species of the genus Kushneria. The predominant fatty acids were C16 : 0, C18 : 1omega7c and C12 : 0 3OH. The major isoprenoid quinone was Q9 (93 %), and minor quinones were Q8 (4 %) and Q10 (3 %). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylserine, two unidentified aminolipids, two unidentified phospholipids and two unidentified lipids. The genomic DNA G+C content was 59.1 mol%. The level of the ANI value between strain X49T and K. marisflavi SW32T, the most closely related species of the genus Kushneria, was 89.32 %. Based on the low ANI value, strain X49T and its reference strains represent genotypically distinct species. Based on this polyphasic taxonomic analysis, strain X49T represents a novel species of the genus Kushneria. The name Kushneria konosiri sp. nov. is proposed and the type strain is X49T (=KACC 14623T=JCM 16805T). PMID- 28866998 TI - Amylibacter cionae sp. nov., isolated from the sea squirt Ciona savignyi. AB - A Gram-stain-negative, non-motile, aerobic and rod-shaped bacterial strain, designated H-12T, was isolated from a sea squirt (Ciona savignyi) collected from Tsingtao Port, Jiaozhou Bay, China, and its taxonomic position was investigated. Strain H-12T grew optimally at 25-30 degrees C, at pH 7.0-8.0 and in the presence of 3.0-4.0 % (w/v) NaCl. The 16S rRNA gene sequence of strain H-12T exhibited the highest similarity to that of the type strain of Amylibacter marinus (95.3 %). A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain H-12T clustered with the type strain of A. marinus. The predominant ubiquinone in strain H-12T was identified as Q-10. The major fatty acids of strain H-12T were C18 : 1omega7c and C18 : 1omega7c 11 methyl. The major polar lipids detected in strain H-12T were phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, one unidentified aminolipid, two unidentified phospholipids and five unidentified lipids. The DNA G+C content of strain H-12T was 52.7 mol%. On the basis of phylogenetic, chemotaxonomic and phenotypic properties, strain H-12T is considered to represent a novel species within the genus Amylibacter, for which the name Amylibacter cionae sp. nov. is proposed. The type strain is H-12T (=KCTC 52581T=CGMCC 1.15880T). PMID- 28866999 TI - Caulobacter hibisci sp. nov., isolated from rhizosphere of Hibiscus syriacus L. (Mugunghwa flower). AB - A Gram-stain-negative, smooth, bright yellow-pigmented, aerobic, catalase- and oxidase-positive and rod-shaped bacterial strain was isolated from rhizosphere of Hibiscus syriacus L. (Mugunghwa flower) located in Kyung Hee University, Yongin, Gyeonggi, South Korea. Cells were dimorphic, non-motile or non-stalked, and motile by means of peritrichous flagellum. The strain, named THG-AG3.4T, grew at 15-35 degrees C, at pH 6.5-9.0 and in the presence of 0-1.5 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain THG AG3.4T was most closely related to Caulobacter segnis ATCC 21756T (98.64 % similarity), Caulobacter vibrioides CB51T (98.57 %) and Caulobacter henricii ATCC 15253T (97.41 %). The DNA G+C content of strain THG-AG3.4T was 64.0 mol%. In DNA DNA hybridization, the DNA-DNA relatedness between strain THG-AG3.4T and its closest phylogenetic neighbour was below 55.0 %. The predominant isoprenoid quinone detected in strain THG-AG3.4T was ubiquinone-10 (Q-10). The major polar lipids were found to be an unidentified lipid, two unidentified phosphoglycolipids, five unidentified glycolipids, eight unidentified aminolipids and phosphatidylglycerol. The major fatty acids were C16 : 0, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). Thus, based on the report of the phenotypic, genotypic and phylogenetic characterization of strain THG-AG3.4T, it has been concluded that the isolate represents a novel species of the genus Caulobacter, for which the name Caulobacter hibisci sp. nov. is proposed. The type strain is THG-AG3.4T (=KACC 18849T=CCTCC AB 2016077T). PMID- 28867000 TI - Desulfovibrio senegalensis sp. nov., a mesophilic sulfate reducer isolated from marine sediment. AB - Several strains of sulfate-reducing bacteria were isolated from marine sediments recovered from Hann Bay (Senegal). All were related to members of the genus Desulfovibrio. A strictly anaerobic, mesophilic and moderately halophilic strain designated BLaC1T was further characterized. Cells of strain BLaC1T stained Gram negative and were 0.5 um wide and 2-4 um long, motile, rod-shaped and non-spore forming. The four major fatty acids were anteiso-C15 : 0, iso-C15 : 0, iso-C17 : 0 and anteiso-C17 : 0. Growth was observed from 15 to 45 degrees C (optimum 40 degrees C) and at pH 5.5-8 (optimum pH 7.5). The salinity range for growth was 5 65 g NaCl l-1 (optimum 30 g l-1). Yeast extract was required for growth. Strain BLaC1T was able to grow on lactate and acetate in the presence of sulfate as an electron acceptor. Sulfate, thiosulfate and sulfite could serve as terminal electron acceptors, but not fumarate, nitrate or elemental sulfur. The DNA G+C content was 55.8 mol%. 16S rRNA gene sequence analysis assigned strain BLaC1T to the family Desulfovibrionaceae; its closest relative was Desulfovibrio oxyclinae DSM 19275T (93.7 % similarity). On the basis of 16S rRNA gene sequence comparisons and physiological characteristics, strain BLaC1T is proposed as representing a novel species of Desulfovibrio, with the name Desulfovibrio senegalensis sp. nov. The type strain is BLaC1T (=DSM 101509T=JCM 31063T). PMID- 28867001 TI - Microvirga indica sp. nov., an arsenite-oxidizing Alphaproteobacterium, isolated from metal industry waste soil. AB - A novel Gram-stain-negative bacterium, strain S-MI1bT, belonging to the genus Microvirga was isolated from a metal industry waste soil sample in Pirangut village, Pune District, Maharashtra, India. Cells were non-spore-forming, small rod-shapes, motile and strictly aerobic with light-pink colonies. The strain grew in 0-7.0 % (w/v) NaCl and at 25-45 degrees C, with optimal growth at 40 degrees C. The predominant fatty acids detected were summed feature 8 (C18 : 1 omega7c and/or C18 : 1 omega6c) and C19 : 0 cyclo omega8c. The predominant isoprenoid quinone was Q-10. The G+C content was 67.2 mol% and DNA-DNA relatedness values between strain S-MI1bTand Microvirga subterranea DSM 14364T and Microvirgaaerophila 5420S-12T were 53.9 and 54.8 %, respectively. Phylogenetic analysis, based on 16S rRNA gene sequences, indicated that strain S-MI1bT is a member of the genus Microvirga, with greatest sequence similarities of 97.7 and 97.4 % with M. subterranea DSM 14364T and M.aerophila 5420S-12T, respectively. Phylogenetic analysis showed that strain S-MI1bT forms a clade with the type strain of M. subterranea DSM 14364T, and was readily distinguishable from it due to various phenotypic characteristics. The combination of genotypic and phenotypic data suggests that the isolate represents a novel species of the genus Microvirga, for which the name Microvirga indica sp. nov. is proposed. The type strain is S-MI1bT (=NCIM-5595T=KACC 18792T=BCRC 80972T). PMID- 28867002 TI - Lactobacillus cerevisiae sp. nov., isolated from a spoiled brewery sample. AB - A Gram-stain-positive, non-motile, rod-shaped bacterium, designated TUM BP 140423000-2250T (=DSM 100836T=LMG 29073T), was isolated from spoiled beer. This bacterium did not form spores, and was catalase-negative and facultatively anaerobic. Its taxonomic position was determined in a polyphasic study. The 16S rRNA gene sequence similarity data showed that the strain belonged to the Lactobacillus genus with the nearest neighbours being Lactobacillus koreensis DCY50T (sequence similarity 99.5 %), Lactobacillus yonginensis THK-V8T (99.2 %) and Lactobacillus parabrevis LMG 11984T (98.7 %). Sequence comparisons of additional phylogenetic markers, pheS and rpoA, confirmed the 16S rRNA gene sequence tree topology. The maximum rpoA sequence similarity was 92.3 % with L. yonginensis THK-V8T. The DNA G+C content of the isolate was 50.0 mol%. The DNA DNA relatedness showed that strain TUM BP 140423000-2250T could be clearly distinguished from L. koreensis DCY 50T (30.8+/-0.4 %) and L. yonginensis THK-V8T (23.6+/-5.9 %). The major fatty acids were C18 : 1omega9c, summed feature 7 (comprised of C19 : 0 cyclo omega10c/C19 : 1omega6c) and C16 : 0. Based on phenotypic and genotypic studies, the authors propose classifying the new isolate as a representative of a novel species of the genus Lactobacillus, Lactobacillus cerevisiae sp. nov. The type strain is deposited at the Research Centre Weihenstephan for Brewing and Food Quality as TUM BP 140423000-2250T (=DSM 100836T=LMG 29073T). PMID- 28867003 TI - Phreatobacter stygius sp. nov., isolated from pieces of wood in a lava cave and emended description of the genus Phreatobacter. AB - An aerobic, Gram-negative, catalase-positive, oxidase-positive bacterium, designated strain YC6-17T, was isolated from pieces of wood collected at the bottom of Youngcheon Cave in Jeju, Republic of Korea. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain YC6-17T formed a tight cluster with Phreatobacter oligotrophus DSM 25521T (98.1 % sequence similarity) and was distinctly separate from other taxa of the order Rhizobiales. Cells were motile rods and showed growth at 10-30 degrees C, pH 6-8 and 2 % NaCl. Colonies were smooth, circular, convex and pale yellow in colour. The predominant ubiquinone was Q-10. The predominant fatty acids were C18 : 1omega7c, 11-methyl-C18 : 1omega7c, summed feature 3 and C16 : 0. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, two glycolipids and a lipid. The DNA G+C content was 64.4 mol%. DNA-DNA relatedness between strain YC6-17T and the closest relative was 15.6+/-7.9 %. Based on combined data from phenotypic characterization and DNA-DNA hybridization as well as phylogenetic analysis, it was suggested that the isolate represents a novel species of the genus Phreatobacter, for which the name Phreatobacter stygius sp. nov. is proposed. The type strain is strain YC6-17T (=KCTC 52518T=DSM 103734T). PMID- 28867004 TI - General practitioner and registrar involvement in refugee health: exploring needs and perceptions. AB - Objective Despite the recognition that refugees should have equitable access to healthcare services, this presents considerable challenges, particularly in rural and regional areas. Because general practitioners (GPs) are critical to resettlement for refugees and play a crucial role in understanding their specific health and social issues, it is important to know more about the needs of GPs.Methods In-depth interviews were conducted with 14 GPs and GP registrars who trained with a New South Wales regional training provider with the aim of assessing the needs and attitudes of GPs in treating refugees and the perceived effect that refugees have on their practice.Results The interviews, while acknowledging well-recognised issues such as language and culture, also highlighted particular issues for rural and regional areas, such as employment and community support. International medical graduates identified with resettlement problems faced by refugees and are a potential resource for these patients. A need for greater information for GPs regarding services available to help manage refugees in rural and regional areas and greater access to those services was demonstrated.Conclusions Issues such as time, costs, language and culture were recognised as challenges in providing services for refugees. GPs highlighted particular issues for rural and regional areas in addressing refugee health, such as finding jobs, problems with isolation and the effect of lack of anonymity in such communities. These social factors have implications for the health of the refugees, especially psychological health, which is also challenged by poor resources.What is known about the topic? Providing refugees equitable access to healthcare services presents considerable challenges, particularly in rural and regional areas. Time, language and culture are commonly reported barriers in providing services for this population group.What does this paper add? There are particular issues for rural and regional areas in addressing refugee health, including finding jobs, problems with isolation and the effect of lack of anonymity in rural communities. These social factors have implications for the health of refugees, especially psychological health, which is also challenged by a paucity of services. The findings of this study suggest that international medical graduate doctors identified with resettlement problems faced by refugees and may be an important resource for these patients. This study highlights the awareness, empathy and positive attitudes of GPs in regional and rural areas in their approach to treating patients with a refugee background.What are the implications for practitioners? International medical graduates often identify with resettlement problems faced by refugees and are an important resource for these patients. A need for greater information for GPs regarding services available to help manage refugees in rural and regional areas and greater access to those services was demonstrated. PMID- 28867005 TI - Review and analysis of the Mental Health Nurse Incentive Program. AB - Objective The aim of the present study was to review and synthesise research on the Mental Health Nurse Incentive Program (MHNIP) to ascertain the benefits and limitations of this initiative for people with mental illness, general practitioners, mental health nurses and the wider community.Methods An electronic and manual search was made of the research literature for MHNIP in May 2017. Features of studies, including cohorts and findings, were tabulated and cross study patterns in program processes and outcomes were closely compared.Results Seventeen reports of primary research data have been released. Triangulation of data from different cohorts, regions and design show that the program has been successful on the primary objectives of increased access to primary mental health care, and has received positive feedback from all major stakeholders. Although the program has been broadly beneficial to consumer health, there are inequities in access for people with mental illness.Conclusions The MHNIP greatly benefits the health of people with mental illness. Larger and more representative sampling of consumers is needed, as well as intensive case studies to provide a more comprehensive and effective understanding of the benefits and limitations of the program as it evolves with the establishment of primary health networks.What is known about the topic? The MHNIP is designed to increase access to mental health care in primary care settings such as general practice clinics. Studies have reported favourable views about the program. However, research is limited and further investigation is required to demonstrate the strengths and limitations of the program.What does this paper add? All studies reviewed reported that the MHNIP had positive implications for people with severe and persistent mental illness. Qualitative research has been most prevalent for mental health nurse views and research on Health of the Nation Outcome Scale scores for recipients of the program. There is more research on system dimensions than on person-centred care. Mental health consumers, carers and families have been neglected in the establishment, engagement and evaluation of the MHNIP.What are the implications for practitioners? A more systematic, national-level research program into the MHNIP is required that is centred more on the experiences of people with mental illness. PMID- 28867006 TI - Anti-inflammatory treatment and risk of depression in 91,842 patients with acute coronary syndrome and 91,860 individuals without acute coronary syndrome in Denmark. AB - BACKGROUND: We examined if treatment with acetylsalicylic acid (ASA), non-steroid anti-inflammatory drugs (NSAID), or statins after acute coronary syndrome (ACS) are associated with decreased risk of depression. METHOD: This register-based cohort study included all individuals with a first-time hospital admissions with an ACS diagnosis registered between January 2001 to December 2009 (N=91,842) and a comparable reference population without ACS (N=91,860). Information of ASA, NSAID, and statin use were retrieved from a national prescription register. The study population was followed for hospitalization with depression or receiving prescription of antidepressant medication for up to one year after ACS or study entry (early depression) or one to twelve years after ACS or study entry (late depression). RESULTS: ASA use after ACS was associated with decreased risk of early depression with hazard ratios (HR) of 0.89 (95% confidence interval 0.85 0.93) but not with late depression 0.96 (0.90-1.01). The corresponding HRs for statin were 0.90 (0.86-0.94) and 0.86 (0.82-0.90). In the non-ACS population, statin use was not associated with neither early nor late depression (HRs 1.04 (0.96-1.12) and 1.00 (0.95-1.06)), while ASA was associated with increased risk of late (HR 1.09 (1.04-1.14)) but not early depression (HR 1.03 (0.97-1.09)). In both populations, NSAID use was associated with increased risk of late but not early depression. CONCLUSION: Use of ASA or statins were associated with decreased risk of depression in ACS patients but not in individuals without ACS, while use of NSAID was associated with increased risk of late depression in both populations. PMID- 28867007 TI - The association between left ventricular global strain and coronary artery disease. PMID- 28867008 TI - Letter to "Clinical impact of admission hyperglycemia on in-hospital mortality in acute myocardial infarction patients" by Kim E J et al. PMID- 28867009 TI - Sex differences in the effect of diabetes mellitus on platelet reactivity and coronary thrombosis: From the Assessment of Dual Antiplatelet Therapy with Drug Eluting Stents (ADAPT-DES) study. AB - BACKGROUND: Whether the consequences of diabetes mellitus (DM) are worse for women than for men treated with drug-eluting stents (DES) and antiplatelet therapy remain unclear. METHODS: Patients from the Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents study were stratified according to sex and DM status. We investigated the sex-specific effect of DM on high on clopidogrel platelet reactivity (HPR), defined as a P2Y12 reaction units >=208, and the adjusted association of DM on the 2-year risk for coronary thrombotic events (CTE), defined as spontaneous myocardial infarction or definite or probable stent thrombosis. RESULTS: Out of 8582 patients included in the study, 829 were women with DM (9.6%) and 1954 were men with DM (16.2%). The prevalence of insulin-treated DM (ITDM) was greater in women (p<0.0001). By multivariable logistic regression, DM was associated with a greater likelihood of HPR that was uniform between sexes (pint=0.88). Following adjustment for baseline variables and HPR, in women a stepwise increase in risk for CTEs was observed in the transition from no DM to non-ITDM (NITDM) (adjusted hazard ratio [adjHR]: 1.31; 95% CI: 0.78-2.18) to ITDM (adjHR: 2.69; 95% CI: 1.23-3.45). This increase in risk associated with subtypes of DM was of smaller magnitude in men (for NITDM, adjHR: 1.04; 95% CI: 0.77-1.39; for ITDM, adjHR: 1.46; 95% CI: 1.05-2.03; pint=0.016). CONCLUSIONS: In a population treated with DES and antiplatelet therapy, the risk for CTE associated with DM seems to be greater in women and was independent of HPR. PMID- 28867010 TI - Mid-term clinical outcomes of ABSORB bioresorbable vascular scaffold versus everolimus-eluting stent for coronary bifurcation lesions. AB - BACKGROUND: Data regarding bioresorbable vascular scaffolds (BVS) use in coronary bifurcation lesions are limited. The aim of this study was to compare mid-term clinical outcomes of all-comer patients treated with BVS versus everolimus eluting stents (EES) for bifurcation lesions. METHODS: A total of 351 non-left main bifurcation lesions in 323 all-comer patients were treated either with BVS (166 bifurcations in 147 patients) or EES (185 bifurcations in 176 patients). The study endpoint was propensity-score adjusted target lesion failure (TLF) defined as the composite of cardiac death, target vessel myocardial infarction and clinically driven target lesion revascularization. RESULTS: Intravascular ultrasound and/or optical coherence tomography were more frequently utilized in the BVS group as compared to the EES one (89.8% versus 13.5%, p<0.001). In the BVS group, both predilation (97.6%) and postdilation (100%) of the main branch were performed in almost all-cases. Provisional single-stenting strategy was more frequently used in the BVS group (79.5% versus 68.1%, p=0.016). At the median follow-up of 698days, there was no significant difference in the propensity score adjusted analysis for TLF (HR: 1.19, 95% CI: 0.47 to 3.03, p=0.718). A similar result was obtained when performing propensity-score matched analysis. CONCLUSIONS: BVS use for coronary bifurcation lesions in real world patients was associated with comparable TLF rates up to 2-year follow-up as compared to EES. The high incidence of intravascular imaging guidance, meticulous lesion preparation, and aggressive postdilation of BVS treated lesions may have played a role in achieving equivalence to EES. PMID- 28867011 TI - TAVR with mechanically expandable prostheses: Is balloon aortic valvuloplasty really necessary? AB - BACKGROUND: The fully retrievable and repositionable Lotus Valve System uses a unique mechanical expansion mechanism. Balloon aortic valvuloplasty (BAV) is recommended before valve deployment. There are no studies focusing on feasibility and efficacy of Lotus Valve implantation without previous BAV. METHODS AND RESULTS: Thirty consecutive patients (63.3% female; mean age, 80+/-6.2years) underwent transcatheter aortic valve replacement (TAVR) with the Lotus Valve without preparatory BAV. Mean baseline aortic valve area was 0.41+/-0.14cm2/m2; mean transvalvular gradient was 50.2+/-16.2mmHg. All patients were successfully implanted, with 96.6% device success (VARC-2 definition) and 0% intra-procedural mortality. Partial and full valve repositioning were performed in 11 (36.7%) and 2 (6.7%) cases, respectively. Mean 30-day transprosthetic gradient was 11.3+/ 3.6mmHg, with an effective aortic orifice area of 1.0+/-0.2cm2/m2, and more than mild paravalvular leakage (PVL) in only one patient. At 30days, cardiac mortality was 3.3%, and 96.3% of subjects were NYHA Class I or II. The rate of life threatening bleeding was 10%; one patient experienced disabling stroke. Ten patients underwent new pacemaker implantation (38%). CONCLUSIONS: TAVR with the mechanically expandable Lotus Valve seems feasible without performing preparatory BAV. Valve hemodynamics at 30-days were favorable, and clinical outcomes were similar to studies employing routine preparatory BAV. PMID- 28867012 TI - To know the radiation dose and the fluoroscopy time of each cardiac procedure is of great importance. PMID- 28867013 TI - Alcohol and incident atrial fibrillation - A systematic review and meta-analysis. AB - BACKGROUND: Whilst high levels of alcohol consumption are known to be associated with atrial fibrillation (AF), it is unclear if any level of alcohol consumption can be recommended to prevent the onset of the condition. The aim of this review is to characterise the association between chronic alcohol intake and incident AF. METHODS AND RESULTS: Electronic literature searches were undertaken using PubMed and Embase databases up to 1 February 2016 to identify studies examining the impact of alcohol on the risk of incident AF. Prospective studies reporting on at least three levels of alcohol intake and published in English were eligible for inclusion. Studies of a retrospective or case control design were excluded. The primary study outcome was development of incident AF. Consistent with previous studies, high levels of alcohol intake were associated with an increased incident AF risk (HR 1.34, 95% CI 1.20-1.49, p<0.001). Moderate levels of alcohol intake were associated with a heightened AF risk in males (HR 1.26, 95% CI 1.04 1.54, p=0.02) but not females (HR 1.03, 95% CI 0.86-1.25, p=0.74). Low alcohol intake, of up to 1 standard drink (SD) per day, was not associated with AF development (HR 0.95, 95% CI 0.85-1.06, p=0.37). CONCLUSIONS: Low levels of alcohol intake are not associated with the development of AF. Gender differences exist in the association between moderate alcohol intake and AF with males demonstrating greater increases in risk, whilst high alcohol intake is associated with a heightened AF risk across both genders. PMID- 28867014 TI - Atrial fibrillation as a risk factor for worse outcome in acute coronary syndrome. PMID- 28867015 TI - Is subcutaneous implantable cardioverter-defibrillator testing effective and safe for patients with hypertrophic cardiomyopathy? PMID- 28867016 TI - Reply to: Is subcutaneous implantable cardioverter-defibrillator testing effective and safe for patients with hypertrophic cardiomyopathy? PMID- 28867017 TI - Letter to the editor: "The frailty syndrome is associated with adverse health outcomes in very old patients with stable heart failure: A prospective study in six Spanish hospitals". PMID- 28867018 TI - Cardiac pericyte is promising target for ischemic heart diseases: Role of Notch3. PMID- 28867019 TI - A potential and novel therapeutic approach to ischemic heart diseases: Notch3. PMID- 28867020 TI - Skeletal muscle exercise training in pulmonary arterial hypertension. PMID- 28867021 TI - Pentraxin-3 and its further clinical implications in women with preeclampsia. PMID- 28867022 TI - Cardiac magnetic resonance evaluation of left ventricular functional, morphological, and structural features in children and adolescents vs. young adults with isolated left ventricular non-compaction. AB - AIM: To investigate the left ventricular (LV) functional, morphological, and structural features revealed by cardiac magnetic resonance (CMR) in children/adolescents with isolated LV non-compaction (iLVNC), and to compare them with those observed in young adults with iLVNC and healthy controls. METHODS: 56 subjects were included: 12 children/adolescents (mean age 15+/-3years, 75% male) and 20 young adults (mean age 35+/-7years, 75% male) with first diagnosis of iLVNC, 12 healthy children/adolescents (mean age 15+/-3years, 75% male) and 12 healthy young adults (mean age 34+/-8years, 75% male). CMR with late gadolinium enhancement (LGE) imaging was performed to evaluate LV function, extent of LV trabeculation, and presence/extent of LV LGE, a surrogate of myocardial fibrosis. Tissue-tracking analysis was applied to assess LV global longitudinal (GLS), circumferential (GCS) and radial (GRS) strain. RESULTS: The extent of LVNC and the presence/extent of LV LGE in children/adolescents and young adults with iLVNC were similar. Compared to healthy subjects, young adults with iLVNC had significantly lower LVEF; conversely, no significant difference in this parameter was observed between children/adolescents with iLVNC and healthy subjects. However, compared to healthy subjects, LV strain parameters were lower in both children/adolescents and young adults with iLVNC. CONCLUSIONS: Complete phenotypic expression, subclinical impairment of myocardial deformation properties, and cardiac injury occur early in iLVNC patients, being already noticeable in the pediatric age group. The application of CMR myocardial deformation imaging permits earlier detection of LV functional impairment in children/adolescents with iLVNC, which would otherwise be missed with standard CMR imaging. PMID- 28867023 TI - Machine learning for prediction of 30-day mortality after ST elevation myocardial infraction: An Acute Coronary Syndrome Israeli Survey data mining study. AB - BACKGROUND: Risk scores for prediction of mortality 30-days following a ST segment elevation myocardial infarction (STEMI) have been developed using a conventional statistical approach. OBJECTIVE: To evaluate an array of machine learning (ML) algorithms for prediction of mortality at 30-days in STEMI patients and to compare these to the conventional validated risk scores. METHODS: This was a retrospective, supervised learning, data mining study. Out of a cohort of 13,422 patients from the Acute Coronary Syndrome Israeli Survey (ACSIS) registry, 2782 patients fulfilled inclusion criteria and 54 variables were considered. Prediction models for overall mortality 30days after STEMI were developed using 6 ML algorithms. Models were compared to each other and to the Global Registry of Acute Coronary Events (GRACE) and Thrombolysis In Myocardial Infarction (TIMI) scores. RESULTS: Depending on the algorithm, using all available variables, prediction models' performance measured in an area under the receiver operating characteristic curve (AUC) ranged from 0.64 to 0.91. The best models performed similarly to the Global Registry of Acute Coronary Events (GRACE) score (0.87 SD 0.06) and outperformed the Thrombolysis In Myocardial Infarction (TIMI) score (0.82 SD 0.06, p<0.05). Performance of most algorithms plateaued when introduced with 15 variables. Among the top predictors were creatinine, Killip class on admission, blood pressure, glucose level, and age. CONCLUSIONS: We present a data mining approach for prediction of mortality post-ST-segment elevation myocardial infarction. The algorithms selected showed competence in prediction across an increasing number of variables. ML may be used for outcome prediction in complex cardiology settings. PMID- 28867024 TI - Impact of stroke volume assessment by integrating multi-detector computed tomography and Doppler data on the classification of aortic stenosis. AB - BACKGROUND: The prevalence of low flow low gradient (LFLG) severe aortic stenosis (AS) may be overrated due to underestimation of stroke volume in two-dimensional (2D) echocardiography. The implications of 3D imaging on stroke volume calculation for AS classification have not been elucidated. Integrating multi detector computed tomography (MDCT) and Doppler data may improve diagnostic accuracy in patients with LFLG AS. METHODS: A total of 186 patients with severe AS evaluated for transcatheter aortic valve replacement were classified according to indexed stroke volume (SVI, cut-off 35mL/m2) and mean transaortic pressure gradient (cut-off 40mmHg). SVI was calculated using a) the biplane Simpson's method, b) left ventricular outflow tract (LVOT) velocity time integral (VTI) and LVOT diameter determined by 2D echocardiography, or c) LVOT VTI and LVOT area planimetered by MDCT. RESULTS: SVI assessed by the biplane Simpson's method was smaller than that obtained from 2D echocardiography LVOT diameter (29.5+/-0.6 vs 34.9+/-0.8mL/m2, p<0.001). The latter was smaller than SVI calculated by integrating MDCT and Doppler data (47.5+/-1.4mL/m2, p<0.001). LFLG and paradoxical LFLG severe AS were diagnosed in 42.5% and 27.4% of patients using the biplane Simpson's method, in 30.1% and 16.7% using 2D echocardiography LVOT diameter, and in 17.2% and 8.1% when integrating MDCT and Doppler data. CONCLUSIONS: The prevalence of LFLG and paradoxical LFLG severe AS was overestimated by 2.5- and 3.4-fold based on 2D echocardiography alone. Integration of MDCT and Doppler data should be considered for stroke volume assessment in the classification of severe AS. PMID- 28867025 TI - Physical Activity in Patients with Cardiovascular Disease: Challenges in Measurement and Motivation. PMID- 28867026 TI - Transcatheter Pulmonary Valve Implantation Provides Effective Treatment. PMID- 28867027 TI - Macitentan in Pulmonary Arterial Hypertension Associated with Congenital Heart Defects. PMID- 28867028 TI - Corrigendum to 'National Heart Foundation of Australia & Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Management of Acute Coronary Syndromes 2016' Heart Lung and Circulation volume 25, (2016) 898 - 952. AB - Please note that on p.929 in 5.2.2.7, paragraph 3, the dose of dabigatran should read as BD rather than daily. We regret any inconvenience that this may have caused. PMID- 28867029 TI - Spectraplakins, versatile roles in physiology and pathology. PMID- 28867030 TI - Protocadherins and other atypical cadherins. PMID- 28867031 TI - [Guidelines for the management of the cerebral arterial ischemic stroke in at term or near-term newborns]. PMID- 28867032 TI - [Revelation of the circumstances of the accident vascular arterial ischemic brain in at term or near-term and referral]. AB - The neonatal arterial ischemic stroke is an emergency. Recurrent focal seizures, generally occurring in the first 24-72 hours after birth, are the commonest first clinical signs. When neonatal arterial ischemic stroke is suspected, optimal initial management involves careful supportive care including treatment of clinical and frequent or prolonged subclinical seizures, correction of the possible metabolic disorders and their prevention. Contrary to hypoxic ischemic encephalopathy, therapeutic hypothermia is not indicated. This newborn requires emergent transfer to a neonatal intensive care unit for the confirmation of the diagnosis by means of a specialized neonatal transport team. PMID- 28867033 TI - [Recommendations for imaging neonatal ischemic stroke]. AB - Neuroimaging is critical for the diagnosis of neonatal arterial ischemic stroke (NAIS) and for prognosis estimation. The purpose of this work is to define guidelines of clinical neuroimaging for the diagnosis of NAIS, for the optimization of the imaging timing and for the assessment of the prognostic value of each imaging technique. A systematic search of electronic databases (Medline via Pubmed) for studies whose title and abstract were focused on NAIS has been conducted. One hundred and ten articles were selected and their results were analyzed by three Senior Practitioners of pediatric radiology using common methodology for guidelines elaboration within the group of experts gathered by Scientific Societies in the field. MRI with a diffu si on-weighted sequence (DWI) and T1, T2, and T2*-weighted sequences must be performed in the case of suspected NAIS (no sedation is required). In the first hours after the injury, an acute ischemic lesion is characterized by a hypersignal on the diffusion-weighted sequence, with a decrease of the apparent coefficient of diffusion (ADC). The best time to evaluate the extent of the ischemic lesion is between day 2 and day 4 after injury, when the ADC decrease reaches its nadir. In the acute phase, US may be useful as first imaging at the bedside to exclude other pathologies like large space-occupying hemorrhages, but its specific added value on NAIS diagnosis or prognosis assessment is very low. CT scan has no added value in NAIS, compared to MRI. Motor outcome is correlated with the extent of the lesion and with the presence of a definite injury of the corticospinal tract, which is well seen on the diffusion sequence at the acute stage. A secondary atrophy within the mesencephalon (cerebral peduncles) is tied in with a high risk of hemiplegia. Visual outcome is more often compromised in the case of lesions of the posterior cerebral artery territory. PMID- 28867034 TI - [Neonatal arterial ischemic stroke: Which thrombotic biological risk factors to investigate and which practical consequences?] AB - All biological risk factors that have been previously identified to increase the risk of thrombosis in adults, have also been studied in neonates with arterial Ischemic Stroke (NAIS), but most studies were retrospective and included relatively low numbers of affected children. We therefore could not suggest recommendations with a strong level of evidence and only expert proposals potentially useful for clinical practice will be presented in this text. Despite these limitations, the extensive analysis of published data supported that factor V Leiden (FVL) and increased levels of Lp(a) could be significant risk factors for NAIS. Importantly, these 2 risk factors cannot be considered as having provoked NAIS, and moreover, they do not influence the prognosis and the immediate treatment. However, since the FVL may have an impact for the prescription of a thromboprophylaxis when the neonate will become adult, to look for its presence in affected patients may be justified. For clinical practice, the following propositions can be applied: 1. Routine testing for thrombophilia (AT, PC PS deficiency, FV Leiden or FII20210A) or for detecting other biological risk factors such as antiphospholipid antibodies, high FVIII, homocystein or Lp(a) levels, MTHFR thermolabile variant, should not be considered in neonates with NAIS. 2. Testing for FV Leiden can be performed in case of documented family history of venous thromboembolic disease. 3. Testing neonates for the presence of antiphospholipid antibodies (APA) is mandatory in case of clinical events suggesting antiphospholipid syndrome in the mother (vascular thrombosis, and/or pregnancy morbidity). 4. Routine testing for thrombophilia is not proposed in both parents in case of early death of the neonate, apart from APA in the mother. PMID- 28867035 TI - [Neonatal arterial ischemic stroke in term or near-term newborns: prevalence and risk factors]. AB - The general designation ischemic perinatal stroke includes several disease states that differ in pathophysiology, timing of occurrence and presentation. While it seems logical to assume that their prevalence and their risk factors depend primarily on the considered type of stroke, most studies used inconsistent definitions or included heterogeneous populations, which limits their accuracy. Given these biases, the French Society of Neonatology and the French Centre for Paediatric Stroke wished to update the knowledge in this domain, focusing on a specific form of perinatal stroke, i.e neonatal arterial ischemic stroke (NAIS) in term or near term newborns. A comprehensive analysis of published epidemiological data was dedicated to the following issues:Is the prevalence of NAIS well defined from epidemiological studies?What are the best recognized risk factors and is it possible to delineate a maternal and fetal population at risk for this condition?On July 31, 2015 a total of four hospitalized-based and five population-based studies, and six case-control studies were found. The conclusions are the following:The prevalence of NAIS in term or near term newborns varies from 6 to 17/100,000 live births (level of evidence 2). NAIS represents a half of total ischemic perinatal strokes (i.e. including those with delayed presentation as well) and one fourth of perinatal strokes (i.e. including cerebral haemorrhage stroke as well).Four sets of risk factors are consistent across different studies (level of evidence 3): (1) male sex, (2) obstetrical determinants (first pregnancy, caesarean section), and two peripartum complications: (3) intrapartum hypoxia and (4) materno-fetal/neonatal infection. Bacterial meningitis, cardiac disorders/procedures and invasive care such as extra-corporeal circulation carry a risk of NAIS as well.A registry could help refining epidemiological descriptive data. It could also be used to develop etiological studies focusing on pathophysiological hypotheses derived from the identified aforementioned risk factors. PMID- 28867036 TI - [Biological monitoring and other explorations in the acute phase of a neonatal arterial ischemic stroke (excluding hemostasis)]. AB - Neonatal monitoring and other explorations required just after neonatal arterial ischemic stroke (NAIS) diagnosis remain elusive. This review attempts to propose guidelines on this topic. During neonatal period, three major contexts related to NAIS emerge: 1) Metabolic disorders including hypoglycemia; 2) Early post-natal infections; 3) Cardio-vascular anomalies. Different patient profiles have been defined (typical, atypical and at risk profiles). According to these profiles, a final decisional tree including biological monitoring and complementary explorations has been suggested to caregivers. PMID- 28867037 TI - [Place of EEG in the management of arterial ischemic stroke newborn]. AB - The EEG has a key role in the management of neonatal seizures, which are the typical mode of revelation of neonatal ischemic stroke. The EEG should be started as soon as possible in case of suspected seizure. Some EEG features are evocative of neonatal stroke, typically asymmetry of background activity with the presence of focal spikes and focal seizures. The EEG should be prolonged and always associated with a video as pauci-symptomatic or subclinical seizures are frequent, including some status epilepticus. Video-EEG monitoring is therefore essential to judge the efficacy of anticonvulsant therapy. There is insufficient evidence so far to state if some EEG aspects are predictive of long-term cognitive and epileptic outcomes. PMID- 28867038 TI - [Therapeutic management of neonatal arterial cerebral infarction and neuroprotection perspectives]. AB - Neonatal seizure related to stroke is a common diagnostic feature. Their treatment, although widely debated even today must be initiated in case of status epilepticus, clinical seizures of more than 5 minutes duration or short (> 30 secondes) and repeated clinical seizures (2 or more per hour). The treatment of neonatal seizures is a challenge that remains only partially solved. It should take into account the etiology of seizures, type of brain lesions and clinical/electrical response to treatment after the first line treatment. It is based on using a single anti-epileptic at its maximum dosage, and if needed, on the association with another anti-epileptic drug with a different mechanism of action. Phenobarbital remains the most commonly used drug for initial treatment of neonatal seizures and for which the most clinical experience has been accumulated. The lack of randomized controlled trials makes difficult recommendations about the optimal duration of treatment, but most experts agree that once arrested seizures, the duration of treatment should be as short as possible because of its potential risk on the developing brain. Novel neuroprotective strategies for reducing impact of neonatal stroke or promoting brain repair remain for the moment the concept stage, pre-clinical or parcel clinical data. PMID- 28867039 TI - [Long term outcome of perinatal stroke]. AB - Neonatal Arterial Ischemic Stroke (NAIS) affects 6-17 newborns on 100 000-birth term neonates, most of these children keeping long-term motor and cognitive impairments. Based on a literature review, the objectives of this paper are to describe motor and cognitive outcomes after a NAIS and to propose a consensual monitoring of these children to improve their management. About 30 % of children after a NAIS will develop a unilateral cerebral palsy requiring a management by a team with expertise in physical medicine and rehabilitation. Unlike adults, especially after a left NAIS, children will not present aphasia but between 50 and 90 % will present disorders of speech and language in expression and/or reception. After NAIS, the global intellectual efficiency is usually preserved except when the size of the lesion is very important or when severe epilepsy occurs. Several studies are also in favor of vulnerability in visuospatial functions. To quantify impairments, activity limitations and participation restrictions resulting from this NAIS, early and at least yearly evaluations with reliable tools must be carried out systematically until puberty. A multidisciplinary team with a longitudinal follow-up, in all the different developmental dimensions, must conduct these evaluations in term of motor skills, cognitive impairment, behavior, autonomy, quality of life, and participation. Consequences on family functioning need to be evaluate in order to help children and family coping with this event. PMID- 28867040 TI - [Brain plasticity and early rehabilitative care for children after neonatal arterial cerebral infarction]. AB - Currently, in the literature of the evidence based medicine, little data are available to confirm the benefit and the specific procedures of an early intervention for a neonatal arterial ischemic stroke. However, data about the effect of an early physical rehabilitation program on the cerebral plasticity, and preliminary results of clinical studies in children with cerebral palsy strongly suggest the benefit of an early rehabilitation with a multidisciplinary approach. The type of the rehabilitation and its frequency must be determined because a wide variability in the practices exists. A comprehensive care, of the children and his family is necessary to limit the orthopaedics but also the social consequences of a neonatal stroke. PMID- 28867042 TI - Correction to Lancet Glob Health 2015; 3: e316-23. PMID- 28867041 TI - Correction to Lancet Glob Health 2015; 3: e324-31. PMID- 28867043 TI - Genes, Brain, and Language: A brief introduction to the Special Issue. PMID- 28867044 TI - Letter in response to commentary by Small and Cronin. PMID- 28867045 TI - Response to letter by Grohskopf et al. in response to commentary by Small and Cronin. PMID- 28867046 TI - Peritoneal dialysis catheter placement as a mode of renal replacement therapy: Long-term results from a tertiary academic institution. AB - BACKGROUND: Peritoneal dialysis as a mode of renal replacement therapy still has not been embraced widely as an alternative to hemodialysis. Furthermore, there is marked variability in peritoneal dialysis catheter insertion techniques and perioperative management within the United States. After the publication of best demonstrated practices for peritoneal dialysis catheter placement, the utilization of peritoneal dialysis has increased significantly at our institution. We detail the long-term success of peritoneal dialysis catheter placement after the adoption of best-demonstrated practices. METHODS: Retrospective chart review was performed on all patients who underwent laparoscopic peritoneal dialysis catheter placement using the best-demonstrated practice technique from January 2005 through December 2015. Preoperative patient demographic information, intraoperative variables, 30-day morbidity and mortality, and long-term catheter durability outcomes were investigated. RESULTS: A total of 457 patients met inclusion criteria. Four (0.9%) patients experienced an immediate postoperative complication requiring return to the operating room. There were no perioperative mortalities. A total of 298 (65.2%) patients were available for long-term follow-up; 221 (74.2%) patients are still alive, 76 (25.6%) patients are still undergoing peritoneal dialysis, 63 (21.1%) patients transitioned from peritoneal dialysis to hemodialysis, and 88 (29.5%) patients have undergone kidney transplantation. Based on Kaplan-Meier survival plots, 30% of patients will transition from peritoneal dialysis to hemodialysis after 5.5 years of peritoneal dialysis and the median time from commencing peritoneal dialysis to kidney transplantation is 5.6 years. CONCLUSION: Based on our institutional data, the adoption of best-demonstrated practices should provide long-term and reliable access to the peritoneal cavity. We recommend the adoption of these techniques to facilitate long-term peritoneal dialysis catheter survival. PMID- 28867047 TI - Birth and Death of Histone mRNAs. AB - In metazoans, histone mRNAs are not polyadenylated but end in a conserved stem loop. Stem-loop binding protein (SLBP) binds to the stem-loop and is required for all steps in histone mRNA metabolism. The genes for the five histone proteins are linked. A histone locus body (HLB) forms at each histone gene locus. It contains factors essential for transcription and processing of histone mRNAs, and couples transcription and processing. The active form of U7 snRNP contains the HLB component FLASH (FLICE-associated huge protein), the histone cleavage complex (HCC), and a subset of polyadenylation factors including the endonuclease CPSF73. Histone mRNAs are rapidly degraded when DNA replication is inhibited by a 3' to 5' pathway that requires extensive uridylation of mRNA decay intermediates. PMID- 28867049 TI - Nonsurgical Treatment of Ankle Arthritis. AB - Nonsurgical treatment of ankle arthritis can be a short-term fix or a long-term solution. An understanding of the biomechanics of the ankle is helpful in the successful use of orthotics and bracing. Pharmacologic and/or biologic treatments can be used exclusively or in concert with mechanical interventions to decrease pain, improve function, and potentially extend the life span of an arthritic ankle. PMID- 28867050 TI - Ankle Arthrodiastasis with Circular External Fixation for the Treatment of Posttraumatic Ankle Arthritis. AB - Ankle arthrodiastasis provides an alternative surgical treatment of the mild to moderate posttraumatic ankle arthritis. Ankle arthrodesis or ankle implant arthroplasty is usually reserved for the end-stage ankle arthritis and after conservative treatment options have been implicated for a long period of time. Ankle joint destructive procedures are often considered for the older and less active population with strict selected surgical criteria and prolonged rehabilitation. In either ankle joint-sparing or ankle destructive procedures, lower extremity deformity correction will need to be addressed before or at the time of index surgery for the overall patient's successful outcome. PMID- 28867051 TI - Arthroscopic Treatment of Ankle Arthritis. AB - Ankle arthritis can be broadly classified as primary arthritis (nontraumatic degeneration) or secondary arthritis (post-traumatic degeneration). A good understanding of the anatomic features and presentations associated with each will assist the surgeon in determining the best course of action for each patient. Many variations of both primary and secondary arthritis can be treated conservatively; however, there are many times when conservative therapy is not adequate. In these cases, ankle arthroscopy may be considered before a joint fusion or replacement. Here, the authors discuss the common types of ankle arthritis, their presentations, and treatment success with ankle arthroscopy. PMID- 28867052 TI - Supramalleolar Osteotomies. AB - Distal tibial malalignment can result from posttraumatic malunion, physeal disturbances, congenital or metabolic diseases, and degenerative arthritis. Malalignment leads to an altered load distribution across the joint leading to early ankle joint arthritis. If a substantial part of the joint is salvageable, ankle fusion or joint replacement is not always the best option. Realignment of the distal tibia with a joint-sparing supramalleolar osteotomy is a valuable procedure in correcting deformity at the distal tibia. The goal of a supramalleolar osteotomy is to restore axial alignment. Several studies have demonstrated the successes of the osteotomy in improving function and relieving pain. PMID- 28867053 TI - Osteochondral Autograft and Allograft Transplantation in the Talus. AB - Large, symptomatic, focal chondral, and osteochondral lesions of the ankle are treated with osteochondral autograft/allograft transplantation (OAT) procedure, a reconstructive bone grafting technique that uses one or more cylindrical osteochondral grafts from an area of low impact or allograft source and transplants them into the prepared defect site on the talus. This technique allows defects to be filled with mature, hyaline articular cartilage. Acute or chronic chondral or osteochondral lesions can be debilitating; provided here is a review of osteochondral autograft or allograft transplantation. OAT shows a trend toward greater longevity and durability and improved outcomes in high-demand patients. PMID- 28867054 TI - Advances in Ankle Cartilage Repair. AB - Repair of osteochondral lesions of the talus can be difficult. Smaller lesions respond well to simple arthroscopy and microfracture, whereas larger cystic lesions may require allograft talus replacement or ankle fusions. The lesions in between are more difficult to treat. Autologous chondrocyte implantation and matrix-associated autologous chondrocyte implantation have shown promising results. Future research may include new techniques, pharmacologic intervention, and cell-based therapies, and may be better served with prospective observational studies instead of costly randomized controlled studies. A representative example of arthroscopic implantation is given. PMID- 28867056 TI - Arthroscopic Ankle Arthrodesis: An Update. AB - Arthroscopic ankle arthrodesis provides an alternative to open techniques. Advancements in arthroscopic techniques and instrumentation have made the procedure easier to perform. Arthroscopic ankle arthrodesis has demonstrated faster rates of union, fewer complications, reduced postoperative pain, and shorter hospital stays. Sound surgical techniques, particularly with regard to joint preparation, are critical for success. Comorbidities such as increased body mass index, history of smoking, malalignment, and posttraumatic arthritis should be considered when contemplating arthroscopic ankle arthrodesis. Although total ankle replacement continues to grow in popularity, arthroscopic ankle arthrodesis remains a viable alternative for management of the end-stage arthritic ankle. PMID- 28867048 TI - Signaling and Gene Regulatory Networks in Mammalian Lens Development. AB - Ocular lens development represents an advantageous system in which to study regulatory mechanisms governing cell fate decisions, extracellular signaling, cell and tissue organization, and the underlying gene regulatory networks. Spatiotemporally regulated domains of BMP, FGF, and other signaling molecules in late gastrula-early neurula stage embryos generate the border region between the neural plate and non-neural ectoderm from which multiple cell types, including lens progenitor cells, emerge and undergo initial tissue formation. Extracellular signaling and DNA-binding transcription factors govern lens and optic cup morphogenesis. Pax6, c-Maf, Hsf4, Prox1, Sox1, and a few additional factors regulate the expression of the lens structural proteins, the crystallins. Extensive crosstalk between a diverse array of signaling pathways controls the complexity and order of lens morphogenetic processes and lens transparency. PMID- 28867055 TI - Open Ankle Arthrodesis. AB - First described in 1879, ankle arthrodesis is a procedure that has undergone significant advancements not only in technique but also in technology and fixation. Surgeon preference has often dictated those changes with regard to incisional approaches, fixation methods, and use of bone graft and biologics but one constant has always remained: open ankle arthrodesis is a predictable, time tested procedure with consistent results when performed in appropriate patients. This article highlights the changes that have occurred since the introduction of this procedure and provides a brief overview of the preferred technique. PMID- 28867057 TI - Current Concepts Regarding Total Ankle Replacement as a Viable Treatment Option for Advanced Ankle Arthritis: What You Need to Know. AB - Much of the current literature suggests that total ankle replacement (TAR) is no longer an inferior or fringe treatment for advanced ankle arthritis compared with ankle fusion, but rather a viable option for recalcitrant arthritic ankle pathology in the correct patient population. In this article, current concepts associated with successful outcomes for TAR are discussed with an emphasis on ankle joint anatomy and biomechanics, preoperative planning and patient selection, understanding pathomechanics and soft tissue balancing, as well as the surgeon's learning curve. PMID- 28867058 TI - Complex Total Ankle Arthroplasty. AB - Total ankle arthroplasty is a viable surgical technique for the treatment of end stage degenerative joint disease. With continued advancement in prosthetic design, refined surgical techniques, and improved outcomes, the indications for total ankle replacement have expanded to include cases of increasing complexity. With meticulous preoperative planning and exacting execution, many frontal plane deformities and cases of avascular necrosis can now be successfully addressed at the time of prosthesis implantation or in a staged procedure. PMID- 28867059 TI - Revision Total Ankle Arthroplasty. AB - With total ankle arthroplasty, documented complications can be categorized chronologically into intraoperative, postoperative, and late complications. Factors such as patient selection, surgeon experience, implant features, and prosthetic device selection can influence functional outcomes as well as incidence of complications. Even with impeccable surgical technique and optimal patient selection, complications that require revision may still arise and the most common complications with revision solutions are discussed in this article. PMID- 28867060 TI - Surgical Complications of Ankle Joint Arthrodesis and Ankle Arthroplasty Procedures. AB - Total ankle arthroplasty (TAA) and ankle arthrodesis (AA) are complicated surgeries that carry a learning curve with them. Complications are an aspect of all surgeries that must be considered. Surgeons must be prepared to handle these complications. The most important things are early identification and treatment of these complications. Treating complications is a combination of medicines, conservative measures, and most importantly surgical intervention. Recent studies have shown a decrease in complications of TAA and AA over the past 10 years. Carefully identifying the complications early and treating patients right away are imperative to increasing the outcomes for these patients. PMID- 28867061 TI - The Evolution of Arthritis Treatment in the Foot and Ankle: A Change in the Gold Standard? PMID- 28867062 TI - Home-based delivery of XR-NTX in youth with opioid addiction. AB - Early experience with relapse prevention medications in the treatment of opioid addiction in youth has been positive, but barriers to effectiveness and broader adoption have included problems with adherence and retention, and lack of evidence or consensus about implementation. In particular there is relatively little known about either the effectiveness of extended release naltrexone (XR NTX) in youth, or optimal models of care for its delivery. The purpose of this study is to report on a pilot initiative to improve the effectiveness of XR-NTX by delivering doses at home with assertive outreach to patients enrolled in a community treatment outpatient program. This is a naturalistic case series based on retrospective chart abstractions of 14 young adults (mean age=20.5), who enrolled in the pilot program, and in particular, the 9 who received home-based doses of XR-NTX. They are compared to a historical group of patients (n=21) prior to the pilot, who were referred to receive standard clinic-based doses of XR-NTX. Home-based administration was viewed favorably by patients and families. Although the small sample size is not amenable to statistical analysis, patients in the home based group, compared to the historical clinic-based group, received a greater number of doses overall and over 16 weeks of treatment, had longer retention, and attended similar numbers of clinic-based counseling sessions. These preliminary findings suggest that home-based delivery of XR-NTX and assertive outreach are feasible and promising in this critical target population, may compare favorably to clinic-based treatment as usual, and should be explored further in more rigorous evaluations. PMID- 28867063 TI - Preface to the proceedings of the Workshop on Eosinophils in Allergy and Related Diseases 2016. PMID- 28867064 TI - Increased DNA Methylation of ABCB1, CYP2D6, and OPRM1 Genes in Newborn Infants of Methadone-Maintained Opioid-Dependent Mothers. AB - OBJECTIVE: To investigate whether in utero opioid exposure, which has been linked to adverse neurodevelopmental and social outcomes, is associated with altered DNA methylation of opioid-related genes at birth. STUDY DESIGN: Observational cohort study of 21 healthy methadone-maintained opioid-dependent mother-infant dyads consecutively delivered at >36 weeks of gestation, and 2 comparator groups: smoking, "deprived" opioid-naive mother-infant dyads (n = 17) and nonsmoking, "affluent" opioid-naive mother-infant dyads (n = 15). DNA methylation of ABCB1, CYP2D6, and OPRM1 genes for mothers and babies was determined from buccal swabs. Plasma methadone concentrations were additionally measured for methadone maintained opioid-dependent mothers. RESULTS: DNA methylation for ABCB1 and CYP2D6 was similar in opioid-naive infants compared with their mothers, but was less for OPRM1 (3 +/- 1.6% vs 8 +/- 1%, P < .0005). Opioid-exposed newborns had similar DNA methylation to their mothers for all genes studied and greater methylation of ABCB1 (18 +/- 4.8% vs 3 +/- 0.5%), CYP2D6 (92 +/- 1.2% vs 89 +/- 2.4%), and OPRM1 (8 +/- 0.3% vs 3 +/- 1.6%) compared with opioid-naive newborns (P < .0005 for all 3 genes). Infant DNA methylation was not related to birth weight, length of hospital stay, maternal smoking, dose or plasma concentration of methadone at delivery, or postcode of residence. CONCLUSIONS: In utero exposure to opioids is associated with increased methylation of opioid-related genes in the newborn infant. It is not clear whether these findings are due to opioid exposure per se or other associated lifestyle factors. PMID- 28867066 TI - Pathogen imaging applications. PMID- 28867065 TI - Prenatal Risk Factors for PHACE Syndrome: A Study Using the PHACE Syndrome International Clinical Registry and Genetic Repository. AB - The cause of PHACE syndrome is unknown. In a study of 218 patients, we examined potential prenatal risk factors for PHACE syndrome. Rates of pre-eclampsia and placenta previa in affected individuals were significantly greater than in the general population. No significant risk factor differences were detected between male and female subjects. PMID- 28867067 TI - Corrigendum to: "Prunetin signals via G protein coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated activation of MAPK signaling induces Runx2 expression in osteoblasts to promote bone regeneration" [J Nutr Biochem 2015; 26 (12): 1491-501]. PMID- 28867069 TI - Reply by Authors. PMID- 28867068 TI - Retraction notice to "Polysaccharide from Angelica sinensis ameliorates high-fat diet and STZ-induced hepatic oxidative stress and inflammation in diabetic mice by activating Sirt1-AMPK pathway" [JNB 43 (2017) 88-97]. PMID- 28867070 TI - Editorial Comment. PMID- 28867071 TI - Editorial Comment. PMID- 28867072 TI - Editorial Comment. PMID- 28867074 TI - Association of covered metallic stents with cholecystitis and stent migration in malignant biliary stricture. AB - BACKGROUND AND AIMS: ERCP with self-expandable metallic stent (SEMS) placement provides reliable and durable relief of malignant biliary obstruction. Our objective was to compare efficacy and adverse outcomes between uncovered SEMSs (USEMSs) and covered SEMSs (CSEMSs). METHODS: A retrospective cohort study was performed of all consecutive patients who underwent ERCP with SEMS placement for the management of a malignant bile duct stricture. Comparative analyses on clinical success, patency duration, stent dysfunction, and adverse outcomes were performed. Univariate and multivariable analyses were performed to identify factors associated with stent dysfunction. RESULTS: Six hundred forty-five patients underwent SEMS placement for the management of malignant bile duct stricture from 2008 to 2016. CSEMSs and USEMSs had similar rates of clinical success in relief of bile duct obstruction (93.0% vs 92.1%, respectively; P = .69) and patency duration (546.7 vs 557.9 days, P = .14). Among those with an intact gallbladder, the incidence of acute cholecystitis was higher in the CSEMS group compared with the USEMS group (7.8% vs 1.2%; P < .001). In the multivariable analysis, CSEMS use was associated with increased risk of stent migration (hazard ratio, 10.7; 95% confidence interval, 4.1-27.7). CONCLUSIONS: CSEMSs and USEMSs have similar clinical success rates and patency durations in management of malignant bile duct stricture. CSEMSs, however, are associated with increased rates of migration and cholecystitis. Comparable efficacy and superior safety profile of USEMSs render a compelling argument for its place as the preferred choice of SEMSs in the management of malignant biliary stricture. PMID- 28867073 TI - Metal stents versus plastic stents for the management of pancreatic walled-off necrosis: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Endoscopic transluminal drainage of symptomatic walled-off necrosis (WON) is a good management option, although the optimal choice of drainage site stent is unclear. We performed a systematic review and meta analysis to compare metal stents (MSs) and plastic stents (PSs) in terms of WON resolution, likelihood of resolution after 1 procedure, and adverse events. METHODS: An expert librarian queried several databases to identify studies that assessed WON management, and selection was according to a priori criteria. Publication bias, heterogeneity, and study quality were evaluated with the appropriate tools. We performed single and 2-arm meta-analyses for noncomparative and comparative studies using event rate random-effects model and odds ratio (OR)/difference in means, respectively. RESULTS: We included 41 studies involving 2213 patients. In 2-arm study meta-analysis, WON resolution was more likely with MSs compared with PSs (OR, 2.8; 95% confidence interval, 1.7-4.6; P < .001). Resolution with a single endoscopic procedure was similar between stents (47% vs 44%), although for those cases requiring more than 1 intervention, the MS group had fewer interventions, favored by a mean difference of -.9 procedures (95% CI, 1.283 to -.561). In single-arm study meta-analysis, when compared with PSs, MS use was associated with lower bleeding (5.6% vs 12.6%; P = .02), a trend toward lower perforation and stent occlusion (2.8% vs 4.3%, P = .2, and 9.5% vs 17.4%, P = .07), although with higher migration (8.1% vs 5.1%; P = .1). CONCLUSION: Evidence suggests that MSs are superior for WON resolution, with fewer bleeding events, trend toward less occlusion and perforation rate, but increased migration rate compared with PSs. PMID- 28867075 TI - Isolation of new ligands for orphan receptor MRGPRX1-hemorphins LVV-H7 and VV-H7. AB - The human MAS-related G protein-coupled receptor X1 (MRGPRX1) is a member of the GPCR family. The receptor is primate specific and expressed in the sensory neurons of dorsal root ganglion and trigeminal ganglion, where it is considered to be involved in the pain perception. The MRGPRX1 has unusual binding mechanism, as it is activated by several different ligands as well as several different fragments of precursor proteins. Thus, we hypothesize that it is activated by several unknown compounds as well since the receptor is still classified as orphan. Here, we describe the isolation of two novel endogenous ligands for the MRGPRX1 from human platelet preparation. The isolated ligands are hemoglobin beta chain fragments, known members of the hemorphin family. PMID- 28867076 TI - Paleoclimate determines diversification patterns in the fossorial snake family Uropeltidae Cuvier, 1829. AB - Understanding how and why diversification rates vary across evolutionary time is central to understanding how biodiversity is generated and maintained. Recent mathematical models that allow estimation of diversification rates across time from reconstructed phylogenies have enabled us to make inferences on how biodiversity copes with environmental change. Here, we explore patterns of temporal diversification in Uropeltidae, a diverse fossorial snake family. We generate a time-calibrated phylogenetic hypothesis for Uropeltidae and show a significant correlation between diversification rate and paleotemperature during the Cenozoic. We show that the temporal diversification pattern of this group is punctuated by one rate shift event with a decrease in diversification and turnover rate between ca. 11Ma to present, but there is no strong support for mass extinction events. The analysis indicates higher turnover during periods of drastic climatic fluctuations and reduced diversification rates associated with contraction and fragmentation of forest habitats during the late Miocene. Our study highlights the influence of environmental fluctuations on diversification rates in fossorial taxa such as uropeltids, and raises conservation concerns related to present rate of climate change. PMID- 28867078 TI - The 11th International Food Data Conference (IFDC). PMID- 28867077 TI - Characteristics of patients with hepatitis B virus and hepatitis C virus dual infection in a Western European country: Comparison with monoinfected patients. AB - : The epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is continuously evolving. Updated data on dual HBV and HCV infection are still needed. AIMS: To assess the main characteristics of patients with HBV and HCV dual infection, to compare these with those of patients infected with either HBV or HCV and, among patients with dual infection, to assess fibrosis according to HCV replication. METHODS: Data of 23 patients with dual infection were compared to data from 92 age and sex-matched HBV or HCV monoinfected patients. RESULTS: Patients with dual infection were more often immigrants from Africa or Asia than HCV or HBV patients (52% vs. 20% and 22%, respectively, P=0.01). Intravenous drug use was the route of transmission in 22% of patients with dual infection, which was less frequent than in HCV patients (41%) but more frequent than in HBV patients (0%). Extensive fibrosis or cirrhosis was as frequent among dual-infected patients as among those with HCV or chronic hepatitis B infection (19% vs. 29% vs. 14%, respectively, P=0.4), even when fibrosis stage was reported considering the duration of infection. In dual infected patients, the prevalence of extensive fibrosis or cirrhosis was similar in patients with and without detectable HCV RNA (18% vs. 20%). CONCLUSIONS: Patients with HBV and HCV dual infection were more often immigrants from Africa or Asia and had similar fibrosis stages than HCV or HBV monoinfected patients. In patients with dual infection, extensive fibrosis or cirrhosis was not associated with HCV replication. PMID- 28867079 TI - The New Zealand Food Composition Database: A useful tool for assessing New Zealanders' nutrient intake. AB - A country-specific food composition databases is useful for assessing nutrient intake reliably in national nutrition surveys, research studies and clinical practice. The New Zealand Food Composition Database (NZFCDB) programme seeks to maintain relevant and up-to-date food records that reflect the composition of foods commonly consumed in New Zealand following Food Agricultural Organisation of the United Nations/International Network of Food Data Systems (FAO/INFOODS) guidelines. Food composition data (FCD) of up to 87 core components for approximately 600 foods have been added to NZFCDB since 2010. These foods include those identified as providing key nutrients in a 2008/09 New Zealand Adult Nutrition Survey. Nutrient data obtained by analysis of composite samples or are calculated from analytical data. Currently >2500 foods in 22 food groups are freely available in various NZFCDB output products on the website: www.foodcomposition.co.nz. NZFCDB is the main source of FCD for estimating nutrient intake in New Zealand nutrition surveys. PMID- 28867080 TI - Dietary nutritional profile and phenolic compounds consumption in school children of highlands of Argentine Northwest. AB - The objective of this work was to assess dietary patterns and consumption of phenolic compounds from fruits and vegetables byschoolchildren of high altitude regions from northwest of Argentina. A nutritional survey including food frequency consumption, 24-h dietary recall and anthropometric measurements was applied to 241 children from 6 to 12years old. The amounts of the different classes of phenolic compounds were established from Food Composition Tables available in phenol-explorer website. Statistics analyses were performed using IBM SPSS 20.0. Nutritional status assessment showed underweight (2.2%), low weight (12.7%), overweight (12.7%) and obesity (7.4%). Mean intake of phenolic compounds was 412mg/day. Most consumed foods were infusions and sugar products, consumption of vegetables, fruits and dairy products were low compared to recommendations for this age. Considering that polyphenols have protective health effects, its low consumption could be a risk of development of chronic non communicable diseases. PMID- 28867081 TI - Is sodium and potassium content of commonly consumed processed packaged foods a cause of concern? AB - Processed foods are the major contributors towards sodium intake thereby pre disposing individuals towards risk of Diet Related Non-communicable Diseases (DR NCDs). There is paucity of data on sodium and potassium content of processed packaged foods in India. The sodium and potassium content of the most commonly consumed processed packaged foods (n=154) was analyzed by AOAC 969.23 method using Flame Photometer. Highest analyzed mean sodium content was found in soups (4823+/-1674mg/100g, range=3220 to 8000mg/100g) while the potassium content was highest in chips with a mean of 778+/-260mg/100g and ranged between 360 and 1220mg/100g. A higher potassium to sodium ratio is desirable for good health, however only 20% of the analyzed products were found to have the same. Therefore, there is a need to monitor the sodium and potassium content of the processed packaged foods and to reformulate the products to bring about favorable potassium to sodium ratio. PMID- 28867082 TI - A methodology to compile food metrics related to diet sustainability into a single food database: Application to the French case. AB - The holistic approach required to assess diet sustainability is hindered by lack of comprehensive databases compiling relevant food metrics. Those metrics are generally scattered in different data sources with various levels of aggregation hampering their matching. The objective was to develop a general methodology to compile food metrics describing diet sustainability dimensions into a single database and to apply it to the French context. Each step of the methodology is detailed: indicators and food metrics identification and selection, food list definition, food matching and values assignment. For the French case, nutrient and contaminant content, bioavailability factors, distribution of dietary intakes, portion sizes, food prices, greenhouse gas emission, acidification and marine eutrophication estimates were allocated to 212 commonly consumed generic foods. This generic database compiling 279 metrics will allow the simultaneous evaluation of the four dimensions of diet sustainability, namely health, economic, social and environmental, dimensions. PMID- 28867083 TI - USDA's National Food and Nutrient Analysis Program (NFNAP) produces high-quality data for USDA food composition databases: Two decades of collaboration. AB - For nearly 20years, the National Food and Nutrient Analysis Program (NFNAP) has expanded and improved the quantity and quality of data in US Department of Agriculture's (USDA) food composition databases (FCDB) through the collection and analysis of nationally representative food samples. NFNAP employs statistically valid sampling plans, the Key Foods approach to identify and prioritize foods and nutrients, comprehensive quality control protocols, and analytical oversight to generate new and updated analytical data for food components. NFNAP has allowed the Nutrient Data Laboratory to keep up with the dynamic US food supply and emerging scientific research. Recently generated results for nationally representative food samples show marked changes compared to previous database values for selected nutrients. Monitoring changes in the composition of foods is critical in keeping FCDB up-to-date, so that they remain a vital tool in assessing the nutrient intake of national populations, as well as for providing dietary advice. PMID- 28867084 TI - The contribution of processed pork meat products to total salt intake in the diet. AB - Consumption of processed meats is reported to be the second largest contributor to total dietary sodium intake. This study aims to describe the contribution of commonly consumed processed pork products to total salt intake. A large variation was found in the sodium content between similar products. Sodium content (mg/100g) for bacon ranged from 558 to 1570, russians from 762 to 1403, viennas from 480 to 1340 and ham from 696 to 1360 respectively. When converting sodium content from 100g to serving size, different products contributed the most sodium to the diet. A serving size of brawn (125g uncooked) will contribute on average 983mg sodium to total sodium intake. Pork bangers will contribute the lowest amount of sodium (~400mg) to the diet (~4% of RDI). Reported daily intake are smaller than indicated serving sizes and the contribution of processed meat to sodium intake can be predicted to be lesser than expected. PMID- 28867085 TI - A systematic review of food composition tools used for determining dietary polyphenol intake in estimated intake studies. AB - Translating food intake data into phytochemical outcomes is a crucial step in investigating potential health benefits. The aim of this review was to examine the tools for determining dietary-derived polyphenol intakes for estimated intake studies. Published studies from 2004 to 2014 reporting polyphenol food composition information were sourced with 157 studies included. Six polyphenol subclasses were identified. One quarter of studies (n=39) reported total flavonoids intake with 27% reporting individual flavonoid compounds. Assessing multiple compounds was common with approximately 10% of studies assessing seven (n=13), six (n=12) and five (n=14) subclasses of polyphenol. There was no pattern between reported flavonoids compounds and subclass studied. Approximately 60% of studies relied on publicly accessible food composition data to estimate dietary polyphenols intake with 33% using two or more tools. This review highlights the importance of publicly accessible composition databases for estimating polyphenol intake and provides a reference for tools available globally. PMID- 28867086 TI - Biochemical and nutritional characterization of coconut (Cocos nucifera L.) haustorium. AB - Study was conducted to determine the biochemical constituents in coconut (Cocos nucifera L.) haustorium, a spongy tissue formed during coconut germination. Results indicated that 100g of dried coconut haustorium contained 1.05+/-0.2% ash, 44.2+/-4.6% soluble sugar, 24.5+/-3.2% starch, 5.50+/-0.3% protein, 1.99+/ 0.9% fat, 5.72+/-0.4% soluble dietary fibre, 20.3+/-1.9% insoluble dietary fibre, and 146+/-14.3mg phenolics. Mineral profiling showed that it contained 145+/-8.6, 104+/-9.6, 33.9+/-8.2, 30.9+/-1.9, 9.45+/-2.1, 0.292+/-0.1, 2.53+/-0.2 and 1.20+/ 0.1mg of K, Mg, Ca, P, Mn, Cu, Fe and Zn, respectively. Antioxidant activity assay indicated that 100g haustorium was equivalent to 1918+/-173, 170+/-20.4, 72.8+/-14.7 and 860+/-116mg of Trolox as measured by CUPRAC, FRAP, DPPH and ABTS, respectively. Amino acid score indicated that methionine+cysteine (57.6%), phenylalanine+tyrosine (32.6%), leucine (45.7%) and isoleucine (68%) are found less in haustorium. Further studies needed in developing nutritionally balanced formulations using coconut haustorium, which will be useful for lactose intolerant children. PMID- 28867087 TI - Advances in food composition tables in Japan-Standard Tables Of Food Composition in Japan - 2015 - (Seventh Revised Edition). AB - The latest version of the Standard Tables of Food Composition in Japan-2015- comprises the main food composition table (Standard Tables of Food Composition in Japan-2015-[Seventh revised Edition)) and three supplementary books. The supplementary books are Standard Tables of Food Composition in Japan - 2015 - (Seventh Revised Edition) - Amino Acids -, Standard Tables of Food Composition in Japan - 2015 - (Seventh Revised Edition) - Fatty Acids - and Standard Tables of Food Composition in Japan - 2015 - (Seventh Revised Edition) - Available Carbohydrates, Polyols and Organic Acids-. We believe understanding these food composition tables can give greater insight into Japan's gastronomic culture and changes in eating habits. We expect them to play important roles as part of the East Asia food composition tables. PMID- 28867088 TI - Effects of processing methods on nutrient and antinutrient composition of yellow yam (Dioscorea cayenensis) products. AB - There is dearth of documented information on nutrient retention of Dioscorea cayenensis products. This study was carried out to evaluate effects of processing methods on nutrient and antinutrient retention of yellow yam products. Fresh Dioscorea cayenensis tubers were purchased from Bodija market in Ibadan, peeled, cut into small pieces, divided into nine portions. One portion was treated as raw sample, and others processed into local delicacies. All nine samples were analysed for proximate, mineral, vitamin and antinutrient composition using AOAC methods. Data were analysed using ANOVA at p=0.05. Raw yam contained 66.79g moisture, 2.62g crude protein, 0.27g lipid, 0.17g fibre, 0.63g ash, 29.69g carbohydrates, 262.30mg potassium, 61.53mg magnesium, 0.79mg iron, 0.39mg zinc, and yielded 108.26kcal energy with insignificant vitamin content/100g edible portion. Processing significantly improved macronutrients and energy content with significant reduction in all antinutrients of products (p<0.05). The yam products can serve as staple source of energy to consumers. PMID- 28867089 TI - FoodCASE: A system to manage food composition, consumption and TDS data. AB - Food and nutrition scientists, nowadays, need to manage an increasing amount of data regarding food composition, food consumption and Total Diet Studies (TDS). The corresponding datasets can contain information about several thousand different foods, in different versions from different studies. FoodCASE is a system that has been developed to manage these different datasets. It also support flexible means of linking between datasets and generally provide support for the different processes involved in the acquisition, management and processing of data. In this paper, the most important concepts to implement existing guidelines and standards for proper food data management are presented, as well as different use cases of data import and proofs of concepts demonstrating the ability to manage data in FoodCASE. PMID- 28867090 TI - Nutrients and natural toxic substances in commonly consumed Jerusalem artichoke (Helianthus tuberosus L.) tuber. AB - This study determined nutrients, chemical contaminants, (insecticide residues and heavy metals), and natural toxic substances (nitrate, nitrite, cyanide, oxalate, phytate, and trypsin inhibitor) in tubers of Jerusalem artichokes-Kaentawan in the Thai language-grown in four major provinces in Thailand. They were purchased, prepared, homogenized, and freeze-dried for further analysis using standard methods. All Kaentawan samples contained considerable amounts of fructans and dietary fiber (15.4+/-0.2gand3.2+/-0.8g/100gfresh weight [FW], respectively), as well as potassium and iron (339+/-61and0.32+/-0.05mg/100gFW, respectively). All samples had very low amounts of insecticide residues (37 compounds), cyanide, and trypsin inhibitor, as well as Pb, Cd, nitrate, and nitrite (0.82+/-0.09, 0.10+/ 0.02, 1.9-17.5, and 0.01-0.24mgkg-1FW, respectively), in addition to oxalate and phytate (14+/-9and0.17+/-0.02mg/100gFW, respectively). This study's data can be used for food composition databases and for safety consumption. PMID- 28867091 TI - Food synergies for improving bioavailability of micronutrients from plant foods. AB - Plant foods are endowed with micronutrients but an understanding of bioavailability is essential in countries primarily dependent on plant based foods. Bioavailability depends majorly on food synergies. This review examines the nature of certain food synergies and methods to screen and establish it as a strategy to control micronutrient deficiency in the populations. Strong evidence on the synergistic effect of inclusion of vitamin C rich fruits and non vegetarian foods in enhancing the bioavailability of iron has been demonstrated. Fat is found to be synergistic for vitamin A absorption. Red wine and protein have been explored for zinc absorption and effect of fat has been studied for vitamin D. Methods for screening of bioavailability, and biomarkers to demonstrate the synergistic effects of foods are required. Translation of food synergy as a strategy requires adaptation to the context and popularization of intelligent food synergies. PMID- 28867092 TI - Development, features and application of DIET ASSESS & PLAN (DAP) software in supporting public health nutrition research in Central Eastern European Countries (CEEC). AB - In order to meet growing public health nutrition challenges in Central Eastern European Countries (CEEC) and Balkan countries, development of a Research Infrastructure (RI) and availability of an effective nutrition surveillance system are a prerequisite. The building block of this RI is an innovative tool called DIET ASSESS & PLAN (DAP), which is a platform for standardized and harmonized food consumption collection, comprehensive dietary intake assessment and nutrition planning. Its unique structure enables application of national food composition databases (FCDBs) from the European food composition exchange platform (28 national FCDBs) developed by EuroFIR (http://www.eurofir.org/) and in addition allows communication with other tools. DAP is used for daily menu and/or long-term diet planning in diverse public sector settings, foods design/reformulation, food labelling, nutrient intake assessment and calculation of the dietary diversity indicator, Minimum Dietary Diversity-Women (MDD-W). As a validated tool in different national and international projects, DAP represents an important RI in public health nutrition epidemiology in the CEEC region. PMID- 28867093 TI - The nutritional composition of Zespri(r) SunGold Kiwifruit and Zespri(r) Sweet Green Kiwifruit. AB - The composition of kiwifruit is important for understanding the nutritional value of kiwifruit for consumption. Our aim was to develop a reference nutritional composition profile for a gold-fleshed kiwifruit Zespri(r) SunGold Kiwifruit and a green-fleshed kiwifruit Zespri(r) Sweet Green Kiwifruit. Ten representative single-replicate (10 growers) samples, each containing 40 fruit, were prepared for both kiwifruit varieties. Samples were analysed for macronutrients, minerals, and vitamins. The analytical results reveal that the nutrient composition of SunGold and Sweet Green are largely similar to other commercially available kiwifruits. However, a key difference is the elevated levels of vitamin C in SunGold (161mg/100g edible flesh) and Sweet Green, (150mg/100g), compared to 85mg/100g commonly found for the green 'Hayward' variety. Levels of dietary fibre, potassium, vitamin E, and folate are similar to other commercial kiwifruit Zespri(r) Gold Kiwifruit ('Hort16A') and Green Kiwifruit ('Hayward'), confirming kiwifruit as a good source of these nutrients. PMID- 28867094 TI - Antioxidant properties of selected fruit cultivars grown in Sri Lanka. AB - Extracts of twenty locally available Sri Lankan fruits were analysed for 2,2 diphenyl-1-picrylhydrazyl (DPPH) scavenging activity, ferrous reducing antioxidant power (FRAP), total phenolic content (TPC), total flavonoid content (TFC) and vitamin C content. The results showed that gooseberry (Phyllanthus emblica 'local') exhibited the highest DPPH scavenging activity (111.25mg ascorbic acid equivalent antioxidant capacity (AEAC)/g), FRAP (1022.05MUmol FeSO4/g), TPC (915.7mg gallic acid equivalents (GAE)/100g), TFC (873.2mg catechin equivalents (CE)/100g) and vitamin C (136.8mg ascorbic acid equivalents (AAE)/100g), respectively. Sugar apple (Annona squamosa 'local') and star fruit (Averrhoa carambola 'Honey Sweet') obtained the second and third highest antioxidant activities in terms of rankings of FRAP, DPPH activities, TPC, TFC and vitamin C content. Strong correlation between vitamin C, TPC and TFC with FRAP and DPPH showed their contribution to antioxidant capacity. Among the selected fruits, underutilized fruit cultivar gooseberry showed the highest overall antioxidant potential. PMID- 28867095 TI - Detection of aflatoxin M1 in milk using spectroscopy and multivariate analyses. AB - Aflatoxin M1 (AFM1), a potentially carcinogenic compound, is found in milk obtained from animals that consume contaminated feed. Spectra of bovine milk, spiked with AFM1 (0, 0.02, 0.04, 0.06, 0.08 and 0.1MUg/l) were acquired using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectrometer. Spectra revealed significant differences among pure and AFM1 spiked samples in spectral regions 1800-650cm-1 and 3689-3499cm-1, which may be attributed to complex chemical structure of AFM1. Principal component analysis (PCA) showed clear clustering of samples (p?0.05). The models could successfully classify (>86%) and detect even 0.02MUg/l AFM1 in milk (p?0.05) using SIMCA. AFM1 was best predicted in wavenumber range of 1800-650cm-1 with coefficient of determination (R2) of 0.99 and 0.98, for calibration and validation, respectively, using partial least square (PLS) regression. The study indicated feasibility of ATR FTIR spectroscopy and chemometrics in rapid detection and quantification of AFM1 in milk. PMID- 28867096 TI - The role of traditional foods in food-based dietary guidelines - A South African case study on maas (cultured milk). AB - With the revision of the South African food-based dietary guidelines (FBDGs) a new guideline specifically recommending the daily consumption of dairy products including maas (cultured milk) was introduced. This paper aims to evaluate the relevance of including maas as a traditional food product in the FBDGs. It was found that maas is a culturally relevant and traditional food product in South Africa. The nutrient profile of maas has changed notably over time since the first nutrient analysis was performed in 1995. The health benefits of maas, together with its popularity and its cultural relevance as part of the South African diet, make maas a suitable traditional food product to be included in the South African FBDGs. PMID- 28867097 TI - Nutritional composition in relation to glycemic potential of popular Indian rice varieties. AB - Diabetes, a chronic hyperglycemic disorder, is a public health concern in India. High glycemic carbohydrate foods are linked to higher risk of diabetes. The chemical composition and in vivo glycemic potential of popular Indian rice varieties namely Jaya, Lalat, NDR-97, PR-113, Salivahana, Sasyasree, Savithri, Tellahamsa, Triguna, Varalu and one hybrid DRRH-3, having wide agronomical and grain morphological features were studied. Nutrient composition varied prominently among different varieties. Resistant starch (RS) content (2.03-2.91%) correlated negatively with the glycemic index (GI) (r=-0.674; p<=0.05) and contributed for 45.5% of GI variability. Lalat, an aromatic traditional rice variety, with 2.91% RS and 27.9% amylose was the only one eliciting low GI of 50 and glycemic load (GL) of 13 while the rest exhibited GI ranging from 70 by Savitri to 80 by Salivahana. Identification of Lalat as a low GI variety is of significance in the dietary prevention and management of diabetes. PMID- 28867098 TI - The nutrient content of selected South African lamb and mutton organ meats (offal). PMID- 28867099 TI - EuroFIR Guideline on calculation of nutrient content of foods for food business operators. AB - This paper presents a Guideline for calculating nutrient content of foods by calculation methods for food business operators and presents data on compliance between calculated values and analytically determined values. In the EU, calculation methods are legally valid to determine the nutrient values of foods for nutrition labelling (Regulation (EU) No 1169/2011). However, neither a specific calculation method nor rules for use of retention factors are defined. EuroFIR AISBL (European Food Information Resource) has introduced a Recipe Calculation Guideline based on the EuroFIR harmonized procedure for recipe calculation. The aim is to provide food businesses with a step-by-step tool for calculating nutrient content of foods for the purpose of nutrition declaration. The development of this Guideline and use in the Czech Republic is described and future application to other Member States is discussed. Limitations of calculation methods and the importance of high quality food composition data are discussed. PMID- 28867100 TI - Biodiversity of Andean potatoes: Morphological, nutritional and functional characterization. AB - Andean potatoes (Solanum tuberosum andigenum) are a staple food for Andean population; there is great biodiversity but only few varieties are cultivated nowadays. In order to contribute to biodiversity conservation of Andean potatoes, information about their morphological, nutritional and functional characteristics was generated. In gene bank (INTA-Balcarce), varieties collected from regional producers were preserved. Forty-four genotypes were multiplied and characterized. Morphological characteristics; proximate composition and functional compounds were analyzed. Cluster analysis separated them into 3 groups according to distinguishing characteristics, which define industrial or nutritional applications. Group 2 was characterized by higher content of macronutrients and Group 3 with the highest antioxidant activity, both would be advisable for direct consumption. Genotype CS 1418 had big size and oval form so it could be destined to potato chips industry. Knowledge on nutritional and functional properties of genotypes contributes to promoting the cultivation depending on properties and also to preserve biodiversity. PMID- 28867101 TI - Capsaicinoids, amino acid and fatty acid profiles in different fruit components of the world hottest Naga king chilli (Capsicum chinense Jacq). AB - The world hottest Naga king chilli is cultivated and consumed in Northeast India. Capsaicinoids, amino acids and fatty acids were studied in fruit and fruit components of Naga king chilli. Capsaicinoid content was increased in each ripening stage and maximum level was observed at red color fruits. Total protein and fat content of placenta was 19.41 and 20.36% respectively. Capsaicinoids of placenta (7.35+/-2.241%) was higher followed by seed (3.83+/-1.358%) and pericarp (2.91+/-0.667%). Similarly, essential amino acid content was also higher in placenta compared to other components. Amino acid score ranged from 37 to 38 with cystine and methionine as limiting amino acid. Low level of palmitic, stearic and alpha-linolenic acid and very high level of linoleic acid were found in seeds. Total polyunsaturates of seeds were higher followed by whole fruit. Naga king chilli is unique due to its high capsaicinoid content and it offers potential crop for the future exploitation. PMID- 28867102 TI - Chemical composition and antioxidant activities of some indigenous spices consumed in Nigeria. AB - The chemical compositions and antioxidant capacities of seven spices consumed in Southern Nigeria were determined. They were purchased from majors markets in the study area. Edible portions of the spices were ground into fine powder and their nutrient and phytochemical compositions determined using standard methods. Antioxidant activity were determined on aqueous extract using standard assays, namely, 1,1-diphenyl-2picrylhydrazyl (DPPH) free radical ability and ferric reducing antioxidant potential (FRAP). The spices were rich in macro-and micro nutrients. Ricinodendron heudelotii had the highest protein (30.6%) and fat (24.6%) contents. Tetrapleura tetraptera had the least fat content. The total phenol, flavonoid and vitamin C contents differed significantly (p<0.001) from each other. Aframomum citratum had the highest amount of total phenol, flavonoid and DPPH scavenging ability, while Afrostyrax lepidophyllus had the best FRAP. The spices have good nutrient profile and antioxidant potentials. Their increased consumption is recommended and use as functional foods needs to be exploited. PMID- 28867103 TI - Recipe standardization, nutrient composition and sensory evaluation of waterleaf (Talinum triangulare) and wild spinach (Gnetum africanum) soup "afang" commonly consumed in South-south Nigeria. AB - One hundred recipes of waterleaf and wild spinach soup (afang) consumed among the Ibibios in South-south Nigeria were collected through interview and questionnaire from indigenous homemakers and food sellers, harmonized, standardized, prepared and their nutrient content calculated. Mean weights of ingredients were calculated to obtain the control recipe. Major ingredients in the soup were analyzed chemically. Edible portions, retention factors to be applied in recipe calculation were determined. Sensory evaluation was conducted on five of the most preferred recipes on a nine-point hedonic scale. Edible coefficients of major foods ranged between 0.32 and 0.95. Significant changes (p<0.05) in nutrients were observed between raw and cooked ingredients and recipes. Afang soup had 67.9% moisture; protein, 12.7% and energy, 169kcal. Fat contributed 57% of the total energy. Consumption of adequate quantities of afang soup will contribute substantially to Recommended Nutrient Intake of protein and micronutrients which will further increase with additional fish/meat. PMID- 28867104 TI - The bioavailability of iron, zinc, protein and vitamin A is highly variable in French individual diets: Impact on nutrient inadequacy assessment and relation with the animal-to-plant ratio of diets. AB - Nutritional adequacy depends on nutrient intakes and bioavailability which strongly varies with the plant- or animal-origin of foods. The aim was to estimate iron, zinc, protein and vitamin A bioavailability from individual diets, and investigate its relation with the animal-to-plant ratio (A/P) of diets. Bioavailability was estimated in 1899 French diets using diet-based algorithms or food-group specific conversion factors. Nutrient inadequacy was estimated based on i) bioavailability calculated in each individual diet and ii) average bioavailability assumed for Western-diets. Mean iron absorption, zinc absorption, protein quality and beta-carotene conversion factor were 13%, 30%, 92%, and 17:1, respectively. Bioavailability displayed a high variability between individual diets, poorly explained by their A/P. Using individual bioavailability led to different inadequacy prevalence than with average factors assumed for Western diets. In this population, the A/P does not seem sufficient to predict nutrient bioavailability and the corresponding recommended intakes. Nutritional adequacy should be assessed using bioavailability accounting for individual diets composition. PMID- 28867105 TI - Study on evaluation of starch, dietary fiber and mineral composition of cookies developed from 12 sorghum cultivars. AB - The study aimed to identify best cultivars suitable for sorghum cookies accordingly nutrient and mineral compositions were evaluated. Protein and fat content of cookies were ranged from 5.89+/-0.04 to 8.27+/-0.21% and 21.03+/-0.01 to 23.08+/-0.03% respectively. The starch content of cookie ranged between 47.06+/-0.01 and 42.15+/-0.03% and dietary fiber was reported highest in CSH14 (9.27+/-0.01%). The highest Mg (56.24+/-0.03mg/100g) P (255.54+/-0.03mg/100g), and K (124.26+/-0.02mg/100g) content were found in C43 cultivar. CSV18R was reported highest iron content (1.23+/-0.01mg/100g). The sensory scores for overall acceptability of cookies were highest in CSH23, CSH13R and CSV18R cultivars which are rich in dietary fiber and minerals. Normally the hybrids are high yielders and the grain price/qt is 20% lower than varieties. It is implied the raw material costs of two identified cultivars (CSH23 & CSH13R) would help the industry to reduce overall cost of production and offer a better profit margins over the varieties. PMID- 28867106 TI - Application of dietary fiber method AOAC 2011.25 in fruit and comparison with AOAC 991.43 method. AB - AOAC 2011.25 method enables the quantification of most of the dietary fiber (DF) components according to the definition proposed by Codex Alimentarius. This study aimed to compare the DF content in fruits analyzed by the AOAC 2011.25 and AOAC 991.43 methods. Plums (Prunus salicina), atemoyas (Annona x atemoya), jackfruits (Artocarpus heterophyllus), and mature coconuts (Cocos nucifera) from different Brazilian regions (3 lots/fruit) were analyzed for DF, resistant starch, and fructans contents. The AOAC 2011.25 method was evaluated for precision, accuracy, and linearity in different food matrices and carbohydrate standards. The DF contents of plums, atemoyas, and jackfruits obtained by AOAC 2011.25 was higher than those obtained by AOAC 991.43 due to the presence of fructans. The DF content of mature coconuts obtained by the same methods did not present a significant difference. The AOAC 2011.25 method is recommended for fruits with considerable fructans content because it achieves more accurate values. PMID- 28867107 TI - Fatty acid profile of edible oils and fats consumed in India. AB - A total 320 samples of edible oils and fats (Oils-236; Vanaspati- 45; Ghee-39) were sampled from 107 sampling sites in India and were evaluated for their fatty acid profile. This is the first comprehensive report on fatty acids profile of fats & oil commonly consumed in India. Every variety of edible oil showed its own unique fatty acid profile with significant variation within each individual fatty acid. Pure safflower oil exhibited the highest total TPUFA (76.78%) while the highest TSFA was noticed for coconut oil (90.84%). High level of erucic acid in the range of 48.5 to 54.2% was observed in mustard oil.. Groundnut and rice bran oils showed TPUFA/TSFA ratio closer to WHO recommended value. Several vanaspati samples exhibited trans fatty acid beyond the permitted limit while trace amount of the same was also detected in ghee. PMID- 28867108 TI - The important role of food composition in policies and programmes for better public health: A South African case study. AB - Most governments have committed to the set of Sustainable Development Goals established by the United Nations (UN) to be achieved by 2030. Subsequently the governments have drafted, or are in process of drafting, policies and programmes which aim to answer to these global requests. South Africa provides a unique case study: despite economic growth, undernutrition has not improved when compared to other industrialised nations, while at the same time, diet-related non communicable diseases and obesity have exponentially increased. Access to healthy food is a constitutional right of all South Africans, and towards increasing food security and improving population health, various policies, programmes and regulations have been developed and implemented by the government to rectify the situation. The paper presents an overview of food composition within these public health policies, programmes and regulations and unpacks the important role of accurate food composition data. PMID- 28867109 TI - Proton Pump Inhibitor-related Mortality: Let Us Not Be Dead Wrong. PMID- 28867110 TI - PET/Computed Tomography Scanning and Precision Medicine: Esophageal Cancer. AB - Esophageal cancer commonly has a poor prognosis, which requires an accurate diagnosis and early treatment to improve outcome. Other modalities for staging, such as endoscopic ultrasound imaging and computed tomography (CT) scans, have a role in diagnosis and staging. However, PET with fluorine-18 fluoro-2-deoxy-d glucose/CT (FDG PET/CT) scanning allows for improved detection of distant metastatic disease and can help to prevent unnecessary interventions that would increase morbidity. FDG PET/CT scanning is valuable in the neoadjuvant chemotherapy assessment and predicting survival outcomes subsequent to surgery. FDG PET/CT scanning detects recurrent disease and metastases in follow-up. PMID- 28867111 TI - Molecular Imaging and Precision Medicine in Uterine and Ovarian Cancers. AB - Gynecologic cancer is a heterogeneous group of diseases both functionally and morphologically. Today, PET coupled with computed tomography (PET/CT) or PET/MR imaging play a central role in the precision medicine algorithm of patients with gynecologic malignancy. In particular, PET/CT and PET/MR imaging are molecular imaging techniques that not only are useful tools for initial staging and restaging but provide anatomofunctional insight and can serve as predictive and prognostic biomarkers of response in patients with gynecologic malignancy. PMID- 28867113 TI - Precision Medicine and PET-Computed Tomography in Pediatric Malignancies. AB - Fluorine-18 fluorodeoxyglucose (18F-FDG) PET-computed tomography (CT) plays a significant role in diagnosis, staging, therapy selection, and therapy assessment of multiple pediatric malignancies and facilitating precision medicine delivery in pediatric patients. In patients with Hodgkin lymphoma, interim fludeoxyglucose 18F-FDG PET/CT is highly sensitive and specific for predicting survival and multiple trials with FDG PET/CT-based adaptive therapies are currently ongoing. It is superior to iodine-131 metaiodobenzylguanidine (131I-MIBG) scintigraphy and bone scintigraphy for detecting metastases in neuroblastoma patients and sarcoma patients. It may predict histologic differentiation and neoadjuvant therapy assessment in Wilms tumor. PMID- 28867112 TI - PET-Computed Tomography and Precision Medicine in Pancreatic Adenocarcinoma and Pancreatic Neuroendocrine Tumors. AB - 18F-FDG PET/CT has been described as an accurate tool for initial diagnosis of pancreatic adenocarcinoma. It differentiates benign from malignant causes; detects local and, especially, distant spread of disease; and is a very good predictor of patient prognosis. Pancreatic neuroendocrine tumors are rare tumors that originate from the islet cells of the pancreas. Currently, 68Ga-DOTA-labeled somatostatin analogs are considered the best modality for detection of well differentiated neuroendocrine tumors. 18F-FDG PET/CT has a role in patients with poorly differentiated tumors. Recent studies have demonstrated improved survival in patients with metastatic neuroendocrine tumors treated with radiolabeled somatostatin analogs. PMID- 28867114 TI - PET/Computed Tomography and Precision Medicine: Gastric Cancer. AB - Gastric cancer is a disease with low survival rates and high morbidity, requiring accurate and prompt diagnosis and treatment. Although limited in the evaluation of the primary tumor as such, the metabolic information of primary tumors in an 18F-FDG PET/CT study can assist in surgical and treatment planning and differentiating gastric cancers. It detects nodal disease with good specificity and positive predictive value, thus enabling appropriate therapy for individual patients. It provides valuable information about distant metastases, altering therapy decisions. It has reasonably good performance in detecting recurrent disease and in the follow-up of patients. PMID- 28867116 TI - Precision Medicine and PET/Computed Tomography in Cardiovascular Disorders. AB - PET/computed tomography (CT) can evaluate the metabolic and anatomic involvement of a variety of inflammatory, infectious, and malignant cardiovascular disorders. PET/CT is useful in evaluating coronary vasculature, hibernating myocardium, cardiac sarcoidosis, cardiac amyloidosis, cerebrovascular disease, acute aortic syndromes, cardiac and vascular neoplasms, cardiac and vascular infections, and vasculitis. Novel targeted radiopharmaceutical agents and novel use of established techniques show promise in diagnosing and monitoring cardiovascular diseases. PMID- 28867115 TI - Precision Medicine and PET/Computed Tomography in Melanoma. AB - Recent advances in genomic profiling and sequencing of melanoma have provided new insights into the development of the basis for molecular biology to more accurately subgroup patients with melanoma. The development of novel mutation targeted and immunomodulation therapy as a major component of precision oncology has revolutionized the management and outcome of patients with metastatic melanoma. PET imaging plays an important role in noninvasively assessing the tumor biological behavior, to guide individualized treatment and assess response to therapy. This review summarizes the recent genomic discoveries in melanoma in the era of targeted therapy and their implications for functional PET imaging. PMID- 28867117 TI - PET/Computed Tomography and Precision Medicine: Musculoskeletal Sarcoma. AB - Skeletal and soft tissue sarcomas need early and accurate diagnosis, staging, and treatment for optimal outcome. 18F-FDG PET/computed tomography (CT) is indicated in staging of patients with high-grade sarcomas and acts as a surrogate marker of histopathologic grade, guiding biopsy to most aggressive portion of the tumor. Pretherapy and posttherapy 18F-FDG PET/CT metabolic parameters are reliable indicators of survival in patients with sarcoma with an important role in posttreatment response assessment, enabling the treatment plan to be modified in nonresponders. 18F-FDG PET/CT is particularly useful in the evaluation of molecular targeted therapies, which induce metabolic change before structural change. PMID- 28867118 TI - The Role of PET/MR Imaging in Precision Medicine. AB - Fluorodeoxyglucose PET and PET/computed tomography have gained acceptance in the evaluation of disease. Nontargeted tracers have been used in the diagnosis of certain malignancies but may not be sensitive or specific enough to become standard of care. Newer targeted PET tracers have been developed that target disease-specific biomarkers, and allow accurate and sensitive detection of disease. Combined with the capabilities of MR imaging to evaluate soft tissue, precision imaging with PET/MR imaging can change the diagnosis. This article discusses specific areas in which precision imaging with nontargeted and targeted diagnostic agents can change the diagnosis and treatment. PMID- 28867119 TI - Precision Medicine and PET/Computed Tomography: Emerging Themes for Future Clinical Practice. PMID- 28867120 TI - How does one detect scientific fraud - but avoid false accusations? PMID- 28867121 TI - Hierarchical signaling transduction of the immune and muscle cell crosstalk in muscle regeneration. AB - The muscle regeneration is a complicated bioprocess that involved in many cell types, including necrotic muscle cells, satellite cells, mesenchymal cells, pericytes, immune cells, and other cell types present at the injury site. Immune cells involved in both innate and adaptive immune responses regulate the progress of muscle regeneration. In this review, we discussed the roles of different immune cells in muscle regeneration. The immune cells regulate muscle regeneration through cytokine production, cell-cell contacts, and general immune environment regulation. We also describe the current known mechanism of how immune cells regulating muscle regeneration. PMID- 28867122 TI - Sexual dimorphism in dermatoglyphic traits and fluctuating asymmetry in Bulgarians from northeast Bulgaria. AB - In parallel with the development of dermatoglyphics as a method of identification, data have been accumulated on the characteristics of fingerprints related to sex and ethnic origin which make up the statistical basis of this study. The aims of the present study are to determine phenotype variations in the asymmetry of dermatoglyphics in both sexes within the scope of the entire hand skin ridge system; to investigate correlations between the phenotypes; and, to assess the fluctuating asymmetry among the Bulgarian population from the region of northwest Bulgaria. The sample consists of 894 unrelated, clinically healthy individuals (480 females and 414 males) aged 18-50 years, who live in towns and villages in the northwest provinces. Finger and palmar prints were collected using rolled print (inked) method. Twenty dermatoglyphics variables of fingers and hands, separately for right and left hands and jointly for both hands, were statistically assessed. The material was processed by SPSS 12 software. The results of the present study show distinctive sexual differences. Higher values in males are recorded in finger ridge counts, the Furuhata and Cummins indices, the palm ridge counts and the overall ridge counts in all interdigital areas. Males have higher frequency values in patterns Hy, Th/III and Th/IV. PMID- 28867123 TI - Comparison of Outcomes in Patients Having Acute Myocardial Infarction With Versus Without Sickle-Cell Anemia. AB - Sickle-cell disease (SCD) affects millions worldwide. Sickle-cell anemia (SCA), the most severe form of this disease, is the most common inherited blood disorder in the United States. There are limited data on the incidence, clinical characteristics, and outcomes of acute myocardial infarction (AMI) in these patients. Using data from the National Inpatient Sample database, we matched cases (AMI with SCA) with controls (AMI without SCA) in a 1:1 ratio for age, gender, race, and year of admission. We compared both groups in terms of clinical characteristics and inpatient outcomes and performed a logistic regression with mortality as the primary outcome. Using weighted samples, we also described trends of SCA in the general population of patients with AMI. Of the 2,386,657 admissions with AMI, SCA was reported in 501 (0.02%) patients, and 495 were successfully matched to controls. Patients with SCA were less likely to have risk factors for coronary artery disease than those without SCA. Patients with SCA were more likely to develop pneumonia, respiratory failure, and acute renal failure, and require mechanical ventilation, hemodialysis for acute renal failure and blood transfusion. In-hospital mortality was significantly higher in patients with SCA. In a multivariate analysis, SCA was an independent predictor of mortality (odds ratio 3.49; 95% confidence interval 1.99 to 6.12; p = < .001). In conclusion, myocardial infarction occurs in patients with SCA at a relatively early age. These patients do not typically have the traditional risk factors for the acute coronary syndrome. Mortality in these patients is significantly higher in age-, gender-, and race-matched controls. PMID- 28867124 TI - Effect of Nonalcoholic Fatty Liver Disease on In-Hospital and Long-Term Outcomes in Patients With ST-Segment Elevation Myocardial Infarction. AB - Nonalcoholic fatty liver disease (NAFLD) is a risk factor for coronary artery disease. We investigated the effect of NAFLD grade on in-hospital and long-term outcomes in patients with ST-segment elevation myocardial infarction (STEMI). The study group consisted of 360 patients with STEMI. The patients were classified according to the grade of the NAFLD using ultrasonography. Based on this classification, all patients were divided into 4 subgroups as grade 0 (no fatty liver disease), grade 1, grade 2, and grade 3. Hierarchical logistic regression and Cox proportional regression analysis were used to establish the relation between NAFLD grade and outcomes. In-hospital mortality for grade 0, 1, 2, and 3 NAFLDs were 4.7%, 8.3%, 11.3%, and 33.9%, respectively. Three-year mortality for grade 0, 1, 2, and 3 NAFLDs were 5.6%, 7.8%, 9.5%, and 33.3%, respectively. In the multivariable hierarchical logistic regression analysis, in-hospital mortality risks were higher for patients with grade 3 NAFLD (odds ratio 4.2). In a multivariable Cox proportional regression analysis, the mortality risk was higher for patients with grade 3 NAFLD (hazard ratio 4.0). In conclusion, in patients with STEMI, the presence of NAFLD is associated with unfavorable clinical outcomes. Among these patients, grade 3 NAFLD had the highest mortality rates. The present study supports NAFLD screening in patients with STEMI. PMID- 28867125 TI - Comparison of Benefit of Successful Percutaneous Coronary Intervention for Chronic Total Occlusion in Patients With Versus Without Reduced (<=40%) Left Ventricular Ejection Fraction. AB - Successful recanalization of chronic total occlusions (CTO) has been associated with improved survival. Data on outcomes in patients with left ventricular (LV) systolic dysfunction undergoing percutaneous coronary intervention for CTO, however, are scarce. Between January 2005 and December 2013, a total of 2,002 consecutive patients undergoing elective CTO percutaneous coronary intervention at a tertiary care center were divided into patients with (LV ejection fraction <= 40%) and without (LV ejection fraction > 40%) LV systolic dysfunction as defined by transthoracic echocardiography. The primary end point was all-cause mortality. Median follow-up was 2.6 (1.1 to 3.1) years. A total of 348 (17.4%) patients had LV dysfunction. All-cause mortality was higher in patients with LV dysfunction (30.2%) than in those with normal LV function (8.2%, p <0.001), and associations remained significant after adjustment for baseline differences (adjusted hazard ratio [HR] 3.39, 95% confidence interval [CI] 2.57 to 4.47, p <0.001). Successful CTO recanalization was independently associated with reduced all-cause mortality, with similar relative risk reductions in both the preserved (6.6% vs 16.9%, adjusted HR 0.48, 95% CI 0.34 to 0.70, p <0.001) and the reduced LV function groups (26.2% vs 45.2%, adjusted HR 0.63, 95% CI 0.41 to 0.98, p = 0.04, interaction p = 0.28). In conclusion, irrespective of LV function, successful CTO recanalization is associated with a clear survival benefit. PMID- 28867126 TI - Early Ventricular Tachycardia or Fibrillation in Patients With ST Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention and Impact on Mortality and Stent Thrombosis (from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction Trial). AB - The prevalence and impact of early ventricular arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]) occurring before mechanical revascularization for acute ST segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention are poorly understood. We sought to investigate the association between early VT/VF and long-term clinical outcomes using data from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial. Among 3,602 patients with STEMI, 108 patients (3.0%) had early VT/VF. Baseline clinical characteristics were similar in patients with versus without early VT/VF. Patients with early VT/VF had shorter symptom-to-balloon times and lower left ventricular ejection fraction and underwent more frequent thrombectomy compared with patients without early VT/VF. Adjusted 3-year rates of all-cause death (15.7% vs 6.5%; adjusted hazard ratio 2.62, 95% confidence interval 1.48 to 4.61, p <0.001) and stent thrombosis (13.7% vs 5.7%; adjusted hazard ratio 2.74, 95% confidence interval 1.52 to 4.93, p <0.001) were significantly higher in patients with early VT/VF compared with patients without early VT/VF. In conclusion, in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial, VT/VF occurring before coronary angiography and revascularization in patients with STEMI was strongly associated with increased 3-year rates of death and stent thrombosis. Further investigation into the mechanisms underlying the increased risk of early stent thrombosis in patients with early VT/VF is required. PMID- 28867127 TI - Utilization of Standard and Target-Specific Oral Anticoagulants Among Adults in the United Kingdom With Incident Atrial Fibrillation. AB - New oral anticoagulants (OACs) and updated risk stratification have the potential to improve the quality of care for patients with atrial fibrillation (AF). To describe the time from AF diagnosis to the initiation of an OAC, characteristics associated with treatment, and the incidence of switching OACs, we conducted this retrospective cohort study of 23,018 adults with incident AF receiving care between 2010 and 2014 in 647 primary care practices participating in the United Kingdom Clinical Practice Research Datalink. In patients with moderate to high stroke risk (CHA2DS2-VASc >= 2), the median time from diagnosis to OAC initiation decreased from 10 to 2 months. Among 980 at very low stroke risk (CHA2DS2-VASc = 0), 29% received OAC prescriptions after 90 days. Being prescribed an OAC was associated with a history of stroke or transient ischemic attack (relative risk 1.3); severe dementia or psychosis was most associated with not being prescribed an OAC (relative risk 0.3). After 1 year, the risk of OAC switching was higher for patients initiating dabigatran (19%) than warfarin (6%), rivaroxaban (8%), or apixaban (9%). The prescribing of OACs in moderate-to-high-risk patients in the United Kingdom increased annually; 1/3 of very low-risk patients were prescribed OACs contrary to guidance. In conclusion, future research should refine decision making tools to minimize the unwanted effects of underutilization and overutilization of OACs. PMID- 28867128 TI - Severely Impaired Cardiorespiratory Fitness in Patients With Recently Decompensated Systolic Heart Failure. AB - Hospital admission for decompensated heart failure marks a critical inflection point in a patient's health. Despite the improvement in signs or symptoms during hospitalization, patients have a high likelihood of readmission, reflecting a lack of resolution of the underlying condition. Surprisingly, no studies have characterized the cardiorespiratory fitness of such patients. Fifty-two patients (38 [73%] male, age 57 [52 to 65] years, left ventricular ejection fraction 31% [24 to 38]) underwent cardiopulmonary exercise testing 4 (1 to 10) days after hospital discharge, when stable and without overt signs of volume overload. Transthoracic Doppler echocardiography, measurement of N-terminal pro-B natriuretic peptide, and quality of life were also assessed. Aerobic exercise capacity was severely reduced: peak oxygen consumption (pVO2) was 14.1 (11.2 to 16.3) ml/kg/min. Ventilatory inefficiency as indicated by the minute ventilation carbon dioxide production relation (VE/VCO2 slope) >30 and oxygen uptake efficiency slope <2.0 was noted in 41 (77%) and 39 (75%) patients, respectively. Forty-five (87%) patients had 1 of 2 high-risk features (pVO2 < 14 ml/kg/min or VE/VCO2 >30). Perceived functional capacity, measured by the Duke Activity Status Index, was also severely reduced and correlated with pVO2. N-terminal pro-B natriuretic peptide levels and early transmitral velocity/early mitral annulus velocity (E/e') ratio at echocardiography showed a modest correlation with lower pVO2. In conclusion, patients with recently decompensated systolic heart failure demonstrate severe impairment in cardiorespiratory fitness, severely limiting quality of life. PMID- 28867129 TI - Frequency of Cholesterol Crystals in Culprit Coronary Artery Aspirate During Acute Myocardial Infarction and Their Relation to Inflammation and Myocardial Injury. AB - Cholesterol crystals (CCs) have been associated with plaque rupture through mechanical injury and inflammation. This study evaluated the presence of CCs during acute myocardial infarction (AMI) and associated myocardial injury, inflammation, and arterial blood flow before and after percutaneous coronary intervention. Patients presenting with AMI (n = 286) had aspiration of culprit coronary artery obstruction. Aspirates were evaluated for crystal content, size, composition, and morphology by scanning electron microscopy, crystallography, and infrared spectroscopy. These were correlated with inflammatory biomarkers, cardiac enzymes, % coronary stenosis, and Thrombolysis in Myocardial Infarction (TIMI) blush and flow grades. Crystals were detected in 254 patients (89%) and confirmed to be cholesterol by spectroscopy. Of 286 patients 240 (84%) had CCs compacted into clusters that were large enough to be measured and analyzed. Moderate to extensive CC content was present in 172 cases (60%). Totally occluded arteries had significantly larger CC clusters than partially occluded arteries (p <0.05). Patients with CC cluster area >12,000 um2 had significantly elevated interleukin-1 beta (IL-1beta) levels (p <0.01), were less likely to have TIMI blush grade of 3 (p <0.01), and more likely to have TIMI flow grade of 1 (p <0.01). Patients with recurrent AMI had smaller CC cluster area (p <0.04), lower troponin (p <0.02), and IL-1beta levels (p <0.04). Women had smaller CC clusters (p <0.04). Macrophages in the aspirates were found to be attached to CCs. Coronary artery aspirates had extensive deposits of CCs during AMI. In conclusion, presence of large CC clusters was associated with increased inflammation (IL-1beta), increased arterial narrowing, and diminished reflow following percutaneous coronary intervention. PMID- 28867130 TI - Follow-up to Age 4 Years of Treatment of Type 1 Retinopathy of Prematurity Intravitreal Bevacizumab Injection versus Laser: Fluorescein Angiographic Findings. AB - PURPOSE: To compare structural outcome at age 4 years of eyes treated with intravitreal injection of bevacizumab with fellow eyes treated with conventional laser photoablation in type 1 retinopathy of prematurity (ROP). DESIGN: Single, randomized, controlled trial. PARTICIPANTS: All inborn babies with type 1 zone 1 ROP at the Neonatal Intensive Care Unit of the Catholic University, Rome, from September 1, 2009, to March 31, 2012. METHODS: In 21 infants (42 eyes), 1 eye was randomized to receive an intravitreal injection of 0.5 mg bevacizumab; the fellow eye underwent conventional laser photoablation. Digital retinal imaging and fluorescein angiography (FA) were performed at an average of 4 years after treatment in follow-up after these studies performed at treatment and 9 months. MAIN OUTCOME MEASURES: Fluorescein angiograms were examined by 2 experts to document retinal and choroidal findings. RESULTS: Among the 20 bevacizumab treated eyes available at 4 years of age, all showed abnormalities at the periphery (avascular area, vessel leakage, shunts, abnormal vessel branching, and tangles) or the posterior pole (hyperfluorescent lesions, absence of foveal avascular zone). These lesions were not observed in the majority of the lasered eyes. Among the 19 laser-treated eyes, leakage was noted in 1 eye, shunts and tangles were noted in 3 eyes, and macular abnormalities were noted in 3 eyes. CONCLUSIONS: Fluorescein angiography has shown potentially serious and long-term ocular effects that are present more commonly after treatment with bevacizumab for acute-phase ROP than after laser. PMID- 28867131 TI - Posterior Vitreous Detachment and the Posterior Hyaloid Membrane. AB - PURPOSE: Despite posterior vitreous detachment being a common ocular event affecting most individuals in an aging population, there is little consensus regarding its precise anatomic definition. We investigated the morphologic appearance and molecular composition of the posterior hyaloid membrane to determine whether the structure clinically observed enveloping the posterior vitreous surface after posterior vitreous detachment is a true basement membrane and to postulate its origin. Understanding the relationship between the vitreous (in both its attached and detached state) and the internal limiting membrane of the retina is essential to understanding the cause of rhegmatogenous retinal detachment and vitreoretinal interface disorders, as well as potential future prophylactic and treatment strategies. DESIGN: Clinicohistologic correlation study. PARTICIPANTS: Thirty-six human donor globes. METHODS: Vitreous bodies identified to have posterior vitreous detachment were examined with phase contrast microscopy and confocal microscopy after immunohistochemically staining for collagen IV basement membrane markers, in addition to extracellular proteins that characterize the vitreoretinal junction (fibronectin, laminin) and vitreous gel (opticin) markers. The posterior retina similarly was stained to evaluate the internal limiting membrane. Findings were correlated to the clinical appearance of the posterior hyaloid membrane observed during slit-lamp biomicroscopy after posterior vitreous detachment and compared with previously published studies. MAIN OUTCOME MEASURES: Morphologic appearance and molecular composition of the posterior hyaloid membrane. RESULTS: Phase-contrast microscopy consistently identified a creased and distinct glassy membranous sheet enveloping the posterior vitreous surface, correlating closely with the posterior hyaloid membrane observed during slit-lamp biomicroscopy in patients with posterior vitreous detachment. Immunofluorescent confocal micrographs demonstrated the enveloping membranous structure identified on phase-contrast microscopy to show positive stain results for type IV collagen. Immunofluorescence of the residual intact internal limiting membrane on the retinal surface also showed positive stain results for type IV collagen. CONCLUSIONS: The results of this study provide immunohistochemical evidence that the posterior hyaloid membrane is a true basement membrane enveloping the posterior hyaloid surface. Because this membranous structure is observed only after posterior vitreous detachment, the results of this study indicate that it forms part of the internal limiting membrane when the vitreous is in its attached state. PMID- 28867132 TI - Symbiont dynamics during thermal acclimation using cnidarian-dinoflagellate model holobionts. AB - Warming oceans menace reef ecosystems by disrupting symbiosis between cnidarians and Symbiodinium zooxanthellae, thus triggering bleach episodes. Temperature fluctuations promote adjustments in physiological variables and symbiont composition, which can cause stress responses, but can also yield adaptation if fitter host-symbiont homeostasis are achieved. To understand such processes manipulative studies are required, but many reef-building cnidarians pose limitations to experimental prospects. We exposed Exaiptasia anemones to Gradual Thermal Stress (GTS) and Heat Shock (HS) exposures and monitored chlorophyll and symbiont dynamics to test the phenotypic plasticity of these photosynthetic holobionts. GTS enhanced chlorophyll concentrations and decreased Symbiodinium proliferation. A recovery period after GTS returned chlorophyll to lower concentrations and symbiont divisions to higher rates. HS triggered a stress response characterized by intense symbiont declines through degradation and expulsion, algal compensatory proliferation, and chlorophyll accumulation. Anemones pre-exposed to GTS displayed more acute signs of symbiont paucity after HS, demonstrating that recurrent stress does not always induce bleaching resistance. Our study is the first documenting Symbiodinium C and D, along with the predominant Clade B1 in Exaiptasia anemones. C subclades found in outdoor specimens faded under laboratory exposures. Clade D emerged after HS treatments, and especially after GTS pre-exposure. This highlights the thermotolerance of D subclades found in E. pallida and shows that bleaching-recovery can involve shifts of background symbiont phylotypes. This study enlightens the capability of Exaiptasia anemones to acclimate to gradually increased temperatures, and explores into how thermal history influences in subsequent stress tolerance in symbiotic cnidarians. PMID- 28867134 TI - Experimental study on titanium wire drawing with ultrasonic vibration. AB - Titanium and its alloys have been widely used in aerospace and biomedical industries, however, they are classified as difficult-to-machine materials. In this paper, ultrasonic vibration is imposed on the die to overcome the difficulties during conventional titanium wire drawing processes at the room temperature. Numerical simulations were performed to investigate the variation of axial stress within the contacting region and study the change of the drawing stress with several factors in terms of the longitudinal amplitude and frequency of the applied ultrasonic vibration, the diameter reduction ratio, and the drawing force. An experimental testing equipment was established to measure the drawing torque and rotational velocity of the coiler drum during the wire drawing process. The result indicates the drawing force increases with the growth of the drawing velocity and the reduction ratio, whether with or without vibrations. Application of either form of ultrasonic vibrations contributes to the further decrease of the drawing force, especially the longitudinal vibration with larger amplitude. SEM was employed to detect the surface morphology of the processed wires drawn under the three circumstances. The surface quality of the drawn wires with ultrasonic vibrations was apparently improved compared with those using conventional method. In addition, the longitudinal and torsional composite vibration was more effective for surface quality improvement than pure longitudinal vibration, however, at the cost of weakened drawing force reduction effect. PMID- 28867133 TI - Natural marine bacteria as model organisms for the hazard-assessment of consumer products containing silver nanoparticles. AB - Scarce information is available regarding the fate and toxicology of engineered silver nanoparticles (AgNPs) in the marine environment, especially when compared to other environmental compartments. Hence, the antibacterial activity of the NM 300 AgNPs (OECD programme) and a household product containing colloidal AgNPs (Mesosilver) was investigated using marine bacteria, pure cultures and natural mixed populations (microcosm approach). Bacterial susceptibility to AgNPs was species-specific, with Gram negative bacteria being more resistant than the Gram positive species (NM-300 concentration used ranged between 0.062 and 1.5 mg L-1), and the Mesosilver product was more toxic than the NM-300. Bacterial viability and the physiological status (O2 uptake measured by respirometry) of the microbial community in the microcosm was negatively affected at an initial concentration of 1 mg L-1 NM-300. The high chloride concentrations in the media/seawater led to the formation of silver-chloro complexes thus enhancing AgNP toxicity. We recommend the use of natural marine bacteria as models when assessing the environmental relevant antibacterial properties of products containing nanosilver. PMID- 28867135 TI - Adsorption of sulfamethoxazole and sulfapyridine antibiotics in high organic content soils. AB - Many antibiotics, including sulfonamides, are being frequently detected in soil and groundwater. Livestock waste is an important source of antibiotic pollution, and sulfonamides may be present along with organic-rich substances. This study aims to investigate the sorption reaction of two sulfonamides, sulfamethoxazole (SMZ) and sulfapyridine (SPY) in two organic-rich sorbents: a commercial peat soil (38.41% carbon content) and a composted manure (24.33% carbon content). Batch reactions were conducted to evaluate the impacts of pH (4.5-9.5) and background ions (0.001 M-0.1 M CaCl2) on their sorption. Both linear partitioning and Freundlich sorption isotherms fit the reaction well. The n values of Freundlich isotherm were close to 1 in most conditions suggesting that the hydrophobic partition is the major adsorption mechanism. In terms of SMZ, Kd declined with increases in the pH. SPY has a pyridine group that is responsible for adsorption at high pH values, and thus, no significant trend between Kd and pH was observed. At high pH ranges, SPY sorption deviated significantly from linear partitioning. The results suggested the sorption mechanism of these two sulfonamide antibiotics tended to be hydrophobic partitioning under most of the experimental conditions, especially at pH values lower than their corresponding pKa2. The fluorescence excitation emission matrix and dissolved organic carbon leaching test suggested composted manure has higher fulvic acid organics and that peat soil has higher humus-like organics. Small organic molecules showed stronger affinity toward sulfonamide antibiotics and cause the composted manure to exhibit higher sorption capacity. Overall, this study suggests that the chemical structure and properties of sulfonamides antibiotics and the type of organic matter in soils will greatly influence the fate and transport of these contaminants into the environment. PMID- 28867136 TI - Prostascore: A Simplified Tool for Predicting Outcomes among Patients with Treatment-naive Advanced Prostate Cancer. AB - AIMS: To develop and internally validate a new simplified model 'prostascore' to help predict the outcomes of treatment-naive patients with advanced prostate cancer. PATIENTS AND METHODS: Through the SEER*Stat program, the Surveillance, Epidemiology and End Results (SEER) database was queried for eligible records spanning the period from 2010 to 2013. The resulting group of patients was equally divided into two sets: training group (to guide model development) and validation group (to validate the model prediction). Multivariate analysis for the candidate prognostic factors (extent of extra-prostatic disease, prostate specific antigen [PSA] level and grade) was conducted through a Cox proportional model. Prostascore was then calculated for each patient. Cancer-specific and overall survival analyses according to prostascore were conducted through Kaplan Meier analysis/Log-rank testing. RESULTS: In total, 8727 patients with treatment naive advanced prostate cancer and complete baseline data were identified in the period from 2010 to 2013. The following factors were associated with better cancer-specific survival in the training set (isolated regional nodal disease, lower PSA level and lower grade group; P < 0.0001). After assignment of a prostascore for each patient, cancer-specific survival was compared according to the score. Pairwise comparisons between all different scores were conducted. For cancer-specific survival evaluation according to the prostascore model, P values for pairwise comparisons among different score points were significant (P < 0.05) in the validation set. CONCLUSION: Prostascore is an easy and reliable tool for predicting the outcomes of patients with treatment-naive advanced prostate cancer. Further validation within the context of other treatment settings and population-based cohorts is recommended. PMID- 28867137 TI - Invasion Science in the Developing World: A Response to Ricciardi et al. PMID- 28867138 TI - Winning Arguments: Coexistence Not Competition: A Reply to Saul et al. PMID- 28867140 TI - Channel 7-7 PMR: A Radio Communication Initiative in Mountain-Related Emergencies in Spain. PMID- 28867139 TI - Bite Wounds Caused by a Wild Boar: A Case Report. AB - A 74-year-old man was attacked by a wild boar while on his way home from his farm in the daytime in winter 2017 on the rural Izu peninsula. He did not provoke the boar; however, hunters were hunting animals in the mountains near the farm around the same time. The boar bit his left leg, and the man fell to the ground. The boar continued biting the man's left leg, and the man delivered a few kicks to the boar's face with his right leg. The boar then bit his right foot and ran away. The man was taken to a hospital, and a physical examination revealed 3 bite wounds on his left leg and right foot. The wounds were irrigated with sterilized saline and closed with sutures under local anesthesia. He received antibiotics and a tetanus toxoid booster. The next day, his wounds were found to be infected, and pus was drained from them. After these treatments, his wounds healed successfully. Animal bite wounds are frequently contaminated. Accordingly, in addition to early proper wound treatment, close observation of the wound is required for both the early detection of any signs of infection and early medical intervention, including appropriate drainage of pus and irrigation as necessary. PMID- 28867141 TI - Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes. AB - Haploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. Here we exploit this property and develop a method to specifically identify genes with significant spatial clustering patterns of de novo mutations in large cohorts. We apply our method to a dataset of 4,061 de novo missense mutations from published exome studies of trios with intellectual disability and developmental disorders (ID/DD) and successfully identify 15 genes with clustering mutations, including 12 genes for which mutations are known to cause neurodevelopmental disorders. For 11 out of these 12, NHI mutation mechanisms have been reported. Additionally, we identify three candidate ID/DD associated genes of which two have an established role in neuronal processes. We further observe a higher intolerance to normal genetic variation of the identified genes compared to known genes for which mutations lead to HI. Finally, 3D modeling of these mutations on their protein structures shows that 81% of the observed mutations are unlikely to affect the overall structural integrity and that they therefore most likely act through a mechanism other than HI. PMID- 28867142 TI - Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder. AB - Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations. We developed a robust and sensitive SNV PMM calling approach integrating complementary callers, logistic regression modeling, and additional heuristics. In our high-confidence call set, we identified 470 PMMs in children, increasing the proportion of mosaic SNVs to 22%. Probands have a significant burden of synonymous PMMs and these mutations are enriched for computationally predicted impacts on splicing. Evidence of increased missense PMM burden was not seen in the full cohort. However, missense burden signal increased in subcohorts of families where probands lacked nonsynonymous germline mutations, especially in genes intolerant to mutations. Parental mosaic mutations that were transmitted account for 6.8% of the presumed de novo mutations in the children. PMMs were identified in previously implicated high-confidence neurodevelopmental disorder risk genes, such as CHD2, CTNNB1, SCN2A, and SYNGAP1, as well as candidate risk genes with predicted functions in chromatin remodeling or neurodevelopment, including ACTL6B, BAZ2B, COL5A3, SSRP1, and UNC79. We estimate that PMMs potentially contribute risk to 3%-4% of simplex ASD case subjects and future studies of PMMs in ASD and related disorders are warranted. PMID- 28867143 TI - Text4baby Influenza Messaging and Influenza Vaccination Among Pregnant Women. AB - INTRODUCTION: Pregnant women are at risk for severe influenza-related complications; however, only 52% reported receiving an influenza vaccination during the 2013-2014 influenza season. Text4baby, a free national text service, provides influenza vaccination education and reminders to pregnant women. This study examined reported influenza vaccination during pregnancy among Text4baby participants who reported receiving influenza messages and women who reported never participating in Text4baby. METHODS: Opt-in Internet Panel Surveys (April 2013 and 2014) of pregnant women collected demographic and other characteristics; influenza vaccination knowledge, attitudes, and behaviors; and Text4baby participation. Women aged 18-49 years, pregnant anytime from October to January (N=3,321) were included. Text4baby influenza message recallers reported receiving Text4baby influenza messages during their current/most recent pregnancy (n=377). Text4baby non-participants reported never receiving Text4baby messages (n=2,824). Multivariable logistic regression was performed (2014-2016) controlling for demographic and other characteristics, high-risk conditions, and provider recommendation and offer to vaccinate. Adjusted prevalence ratios (APRs) were calculated. Random sampling was assumed for this non-probability sample. RESULTS: Text4baby recallers were more likely than non-participants to report influenza vaccination regardless of receipt of provider recommendation and/or offer to vaccinate (provider recommendation/offer APR=1.29, 95% CI=1.21, 1.37, provider recommendation/no offer APR=1.52, 95% CI=1.07, 2.17). Among women receiving neither a provider recommendation nor offer to vaccinate, Text4baby recallers were more than three times as likely to report influenza vaccination compared with non-participants (APR=3.39, 95% CI=2.03, 5.67). CONCLUSIONS: Text4baby status was associated with higher influenza vaccination, especially among women whose provider did not recommend or offer the vaccine. Encouraging Text4baby enrollment may help ensure influenza vaccination is given to protect mothers and infants. PMID- 28867144 TI - Editorial Comment. PMID- 28867145 TI - Author Reply. PMID- 28867146 TI - Research methods must find ways of accommodating clinical reality, not ignoring it: the need for pragmatic trials. PMID- 28867147 TI - LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis. AB - A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dbetah promoter mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination. PMID- 28867148 TI - Variation, Indispensability, and Masking in the M protein. AB - The M protein is the major surface-associated virulence factor of group A Streptococcus (GAS) and an antigenically variable target of host immunity. How selection pressures to escape immune recognition, maintain indispensable functions, and mask vulnerabilities have shaped the sequences of the >220M protein types is unclear. Recent experiments have shed light on this question by showing that, hidden within the antigenic variability of many M protein types, are sequence patterns conserved for recruiting human C4b-binding protein (C4BP). Other host factors may be recruited in a similar manner by conserved but hidden sequence patterns in the M protein. The identification of such patterns may be applicable to the development of a GAS vaccine. PMID- 28867149 TI - Establishing the role of rare coding variants in known Parkinson's disease risk loci. AB - Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks. PMID- 28867150 TI - [Consensus on Perioperative Transesophageal Echocardiography of the Brazilian Society of Anesthesiology and the Department of Cardiovascular Image of the Brazilian Society of Cardiology]. AB - Through the Life Cycle of Intraoperative Transesophageal Echocardiography (ETTI/SBA) the Brazilian Society of Anesthesiology, together with the Department of Cardiovascular Image of the Brazilian Society of Cardiology (DIC/SBC), createded a task force to standardize the use of intraoperative transesophageal echocardiography by Brazilian anesthesiologists and echocardiographers based on scientific evidence from the Society of Cardiovascular Anesthesiologists/American Society of Echocardiography (SCA/ASE) and the Brazilian Society of Cardiology. PMID- 28867151 TI - [Axillary local anesthetic spread after the thoracic interfacial ultrasound block - a cadaveric and radiological evaluation]. AB - BACKGROUND: Oral opioid analgesics have been used for management of peri- and postoperative analgesia in patients undergoing axillary dissection. The axillary region is a difficult zone to block and does not have a specific regional anesthesia technique published that offers its adequate blockade. METHODS: After institutional review board approval, anatomic and radiological studies were conducted to determine the deposition and spread of methylene blue and local anesthetic injected respectively into the axilla via the thoracic inter-fascial plane. Magnetic Resonance Imaging studies were then conducted in 15 of 34 patients scheduled for unilateral breast surgery that entailed any of the following: axillary clearance, sentinel node biopsy, axillary node biopsy, or supernumerary breasts, to ascertain the deposition and time course of spread of solution within the thoracic interfascial plane in vivo. RESULTS: Radiological and cadaveric studies showed that the injection of local anesthetic and methylene blue via the thoracic inter-fascial plane, using ultrasound guide technique, results in reliable deposition into the axilla. In patients, the injection of the local anesthetic produced a reliable axillary sensory block. This finding was supported by Magnetic Resonance Imaging studies that showed hyper-intense signals in the axillary region. CONCLUSIONS: These findings define the anatomic characteristics of the thoracic interfascial plane nerve block in the axillary region, and underline the clinical potential of this novel nerve block. PMID- 28867152 TI - Cognitive and affective empathy among adolescent siblings of children with a physical disability. AB - BACKGROUND: This study is a continuation of research on possible psychosocial benefits resulting from exposure to sibling with disability present in the family system. The issue seems to be especially important in Poland because of growing number of children with a disability and inconsistent results of previously performed studies. OBJECTIVE: The main aim of this study was to examine the differences in the intensity of cognitive and affective empathy in adolescents who either have or do not have siblings with physical disability. The authors hypothesized that the increased exposure to individual with disability should result in positive attitude towards such people and this tendency should be manifested in elevated empathy and compassion. METHODS: The study was carried out between September and November 2016. To meet the goals set to the study, a sample of 292 students from public middle and high schools were assessed using self report demographic questionnaire and measure of empathy (IRI). The participants were between 13 and 19 years old. Among them 128 had a disabled sibling (Group T) and 164 constituted a comparative group (Group C). Interpretation of results is based on descriptive statistics. RESULTS: Participants having a disabled sibling showed significantly higher scores related both to cognitive and affective empathy. Some significant differences were also noted in relation to participants' gender and age. CONCLUSIONS: Exposure to individuals with physical disability in family context may facilitate development of positive psychosocial traits including elevated empathy and compassion in nondisabled siblings. Data analysis also showed significantly greater empathic and altruistic tendencies in females that in males. PMID- 28867153 TI - Rethinking informal payments by patients in Europe: An institutional approach. AB - The aim of this paper is to explain informal payments by patients to healthcare professionals for the first time through the lens of institutional theory as arising when there are formal institutional imperfections and asymmetry between norms, values and practices and the codified formal laws and regulations. Reporting a 2013 Eurobarometer survey of the prevalence of informal payments by patients in 28 European countries, a strong association is revealed between the degree to which formal and informal institutions are unaligned and the propensity to make informal payments. The association between informal payments and formal institutional imperfections is then explored to evaluate which structural conditions might reduce this institutional asymmetry, and thus the propensity to make informal payments. The paper concludes by exploring the implications for tackling such informal practices. PMID- 28867154 TI - Could serum S100B be a predictor of neuronal damage and clinical poor outcomes associated with the use of synthetic cannabinoids? S100B to predict neuronal damage of SC in the ED. AB - AIM: This study aims to evaluate the serum S100B levels to predict neuronal damage and poor clinical outcomes associated with the use of synthetic cannabinoids. METHOD: Thirty patients identified as synthetic cannabinoid users and 30 healthy controls were included in the study. S100B levels were compared between healthy controls and synthetic cannabinoid users. The following were considered to be composite outcomes: the need for endotracheal intubation, incidence of seizures, the need for intensive care unit admission, and in hospital mortality. Clinical and laboratory findings associated with composite clinical outcomes were examined. RESULTS: The mean S100B level was 19.3 (95% CI: 17.7 to 21.4) pg/mL in patients who use synthetic cannabinoid, and 15.9 (95% CI: 15 to 16.9) pg/mL in the controls; mean df: -3.6 (95% CI: -5.6 to -1.6). In patients with and without composite clinical outcomes, the mean S100B level measured 24.5 (95% CI: 21.2 to 27.9) pg/mL and 17.4 (95% CI: 15.8 to 18.4) pg/mL, respectively; mean df: -7.4 (95% CI: -10.2 to -4.6). With the cut-off value for S100B set at 20pg/mL based on the highest sensitivity, the sensitivity, specificity, PPV, and NPV for S100B were 89.9%, 52.0%, 44.4%, and 91.9%, respectively; odds ratio: 13.2, 95% CI (2.1 to 28.1). CONCLUSION: Our data suggest that serum S100B levels are elevated in patients using synthetic cannabinoids. These results show that S100B can help clinicians stratify risk or may have a role in excluding those with neuronal damage. PMID- 28867155 TI - The boundaries of fetal cardiac intervention: Expand or tighten? AB - Fetal cardiac intervention (FCI) is a relatively new and continually evolving field, and, for select cardiac defects, offers the potential to alter the progression of the disease and improve outcomes. It is a procedure that requires a collaborative effort between maternal-fetal medicine, interventional cardiology and fetal echo/ultrasound specialists, as well as fetal and maternal anesthesiologists, nursing specialists, and social workers. This article reviews the most recently reported data and advances in FCI. Currently, FCI is most frequently performed in fetuses with severe aortic stenosis (AS) with evolving hypoplastic left heart syndrome (eHLHS), established HLHS with intact or highly restrictive atrial septum (IAS), and pulmonary atresia with intact ventricular septum (PA-IVS) with evolving hypoplastic right heart syndrome (eHRHS). The goal of FCI for eHLHS and eHRHS is to promote a postnatal biventricular circulation with, theoretically, the potential for better long-term outcomes. In HLHS with IAS the aim is to improve survival. Contemporary data for FCI demonstrate limited maternal risks and improving technical success. With experience, FCI in severe AS with eHLHS has shown improved rates of biventricular outcome and early survival. Limited data for PA-IVS show promise for improving postnatal biventricular outcomes; however, for HLHS with IAS, FCI has yet to clearly demonstrate improved survival. FCI has an evolving role in the management of congenital heart defects. Ongoing analysis of disease progression, patient selection and postnatal outcomes, in conjuncture with technologic innovations and a multicenter collaborative approach, is essential as the field expands. PMID- 28867156 TI - [Sexual risk behaviours and PAP testing in university women vaccinated against human papillomavirus]. AB - AIM: To estimate the association between the human papillomavirus (HPV) vaccine and sexual risk behaviour, as well as the participation in the Cervical Cancer Screening Program (CCSP). DESIGN: Cross-sectional study. LOCATION: School of Medicine and Health Sciences, School of Law, and School of Economics and Business (University of Oviedo). PARTICIPANTS: Female university students. MAIN MEASUREMENTS: Information was collected about contraceptive methods, sexual behaviours, HPV knowledge, and participation in the CCSP. Furthermore, proportions and odds ratio (OR) were estimated with their corresponding 95% confidence intervals (95%CI). RESULTS: Approximately two-thirds (67.7%) of the sample was vaccinated against HPV, and 216 women (65.3%) were sexually active. Barrier contraceptive methods were used by 67.6% during their current intimate relationships, being less frequent in non-vaccinated women (54.9% vs. 75.4% in vaccinated female students) (P=.002). The risk of having at least one sexual risk behaviour was higher in non-vaccinated women: OR2.29 (95%CI: 1.29-4.07). In addition, the probability of having a PAP test within the CCSP was higher in non vaccinated women: OR2.18 (95%CI: 1.07-4.47). CONCLUSIONS: The prevalence of sexual risk behaviours in non-vaccinated women is elevated, and it is related to the lack of use of barrier contraceptive methods. The vaccination against HPV could affect sexual behaviours and the participation in the CCSP. Therefore, the information received by young people about contraceptive methods, sexually transmitted diseases, and cancer prevention should be reinforced. PMID- 28867157 TI - [Fine-tuning of antithrombotic therapy in patients with non-valvular atrial fibrillation. The AFINVA register]. AB - OBJECTIVE: To determine whether antithrombotic treatment (ATT) in patients with non-valvular atrial fibrillation in a health area complies with the recommendations of current clinical guidelines. DESIGN: Prospective observational study. LOCATION: Primary Health Care Centres and Cardiology Department of a Health Department of the Valencian Community, Spain. PARTICIPANTS: A total of 505 patients with nonvalvular atrial fibrillation were included in the study. MAIN MEASUREMENTS: ATT was deemed to be inappropriate in patients with a CHA2DS2-VASc score >=1 and who were not under oral anticoagulation, in patients treated with antivitaminK drugs, and poor control of oral anticoagulation, or with antiplatelet therapy inappropriately associated with anticoagulation, and in patients on ATT with a CHA2DS2-VASc score=0. RESULTS: The median age was 77.4+/ 10years. The ATT was considered inadequate in 58% of cases. Factors independently associated with inadequate ATT were age (OR: 1.02 [1-1.04]; P=.029), hypothyroidism (OR: 1.98 [1.14-3.43]; P=.015), ischaemic heart disease (OR: 1.3 [1.15-2.59]; P=.008) and paroxysmal non-valvular AF (OR: 2.11 [1.41-3.17]; P<.0001). CONCLUSIONS: These data underline the high prevalence of inadequate ATT in daily practice, as well its different causes. PMID- 28867158 TI - Acylglycerol Kinase: Mitochondrial Protein Transport Meets Lipid Biosynthesis. AB - The carrier translocase (TIM22 complex) inserts hydrophobic proteins into the mitochondrial inner membrane. Recently, the acylglycerol kinase (AGK) mutated in Sengers syndrome was identified as a novel subunit of the human TIM22 complex. This finding reveals an exciting link between mitochondrial protein and lipid biogenesis. PMID- 28867160 TI - Children with nocturnal enuresis and attention deficit hyperactivity disorder: A separate entity? AB - INTRODUCTION: There is ongoing debate about whether nocturnal enuresis (NE) is affected by the presence of attention deficit hyperactivity disorder (ADHD) in children. Clarifying this relationship could categorize them as a separate entity, potentially requiring a different management from enuretic children without ADHD. AIMS: To study whether (1) children with ADHD exhibited greater severity of enuresis and associated voiding symptoms compared with children without ADHD, (2) whether there was a difference in enuretic response to treatment between children with/without ADHD, (3) whether previously prescribed medication for ADHD affected severity of enuresis or voiding symptoms, and response to treatment. METHODS: Data on all consecutive children seen with primary NE and ADHD and age- and gender-matched children with NE without ADHD over the course of 2 years were extracted from our database. Controls were identified using a random number generator to choose patients within each age/gender group. Changes in Dysfunctional Voiding Scoring System (DVSS) and Bristol scores were assessed before and after treatment for NE using repeated measures ANOVAs. Number of weekly wet nights was compared between the groups before and after the treatment of enuresis. Children with more than a 50% decrease in number of wet nights per week were categorized as responding to treatment. RESULTS: Compared with controls, ADHD children (N = 95) had significantly more severe voiding symptoms, NE and constipation (Table). No significant differences were found between children on ADHD medication (63.2%) and those who were not on ADHD medication (36.8%) on any of the demographic and pre-treatment clinical parameters. Similar enuretic response rates to behavioral modification alone were seen in both study (13.5%) and control (12.8%) groups (p = 0.73). Response to pharmacological treatment was seen in nine patients with ADHD (42.9%) and in six (20.7%) controls, with pharmacological intervention being significantly more effective than behavioral modification for patients with ADHD (p = 0.012). Additionally, no difference was found between ADHD patients on and off ADHD medication in terms of response to enuresis treatment. CONCLUSION: In children with primary NE, the presence of ADHD was associated with more severe NE, voiding symptoms and constipation. The severity of voiding symptoms and/or NE was unrelated to the use of stimulant medication. The response to behavioral modification was comparable in both groups. However, patients with ADHD were significantly more responsive to medication for NE compared with behavioral modification, indicating a possible benefit for earlier pharmacological treatment for enuresis in this population subgroup. PMID- 28867159 TI - New Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma. AB - Pheochromocytomas and paragangliomas (PPGLs) belong to the family of neural crest cell-derived neoplasms. In up to 70% of cases they are associated with germline and somatic mutations in 15 well-characterized PPGL driver or fusion genes. PPGLs can be grouped into three main clusters, where cluster 1 includes PPGLs characterized by a pseudohypoxic signature. Although cluster 1 tumors share several common features, they exhibit unique behaviors. We present here unique insights into the imaging phenotypes of cluster 1 PPGLs based on glucose uptake, catecholamine metabolism, and somatostatin receptor expression. Recent data suggest that succinate is a major player in the imaging phenotype of succinate dehydrogenase-deficient PPGLs. This review emphasizes the emerging stromal cell succinate interaction and highlights new perspectives in PPGL theranostics. PMID- 28867161 TI - Hyaluronidase Injection in the Vocal Folds for Vocal Hemorrhage, Reinke Edema, and Hyaluronic Acid Overinjection: A Novel Application in the Larynx. AB - Hyaluronidase (HAase) injection into the vocal folds is an off-label use of an enzyme for liquefaction of hyaluronic acid (HA). HAase injection was performed in 14 cases in 13 patients. Office and operative injections of HAase were performed. The indications were five cases of overinjection of HA, six cases of Reinke edema and polypoid corditis, and three cases of acute vocal hemorrhage with early fusiform polyp formation. All the patients tolerated the HAase without complications. Significant voice improvements were noted between pre- and postinjection procedures as evaluated by a self-rating of voice by the Voice Handicap Index-10. A marked decrement in the mass on the side of the injection of HAase was noted in all groups successfully injected upon viewing by videostroboscopy. HAase prevented an additional operative phonosurgery in 10 patients. In conclusion, HAase injection can be used in the vocal folds with good effect in patients. The indications are polypoid corditis with overproduction of HA, acute vocal hemorrhage, and correction of iatrogenic HA overinjection. PMID- 28867162 TI - DCTN1 variation in pathologically-confirmed PSP and CBD tauopathy. PMID- 28867163 TI - Tongue tremor as a manifestation of atypical Parkinsonism treated with coaxial deep brain stimulation of thalamus and subthalamic area. PMID- 28867164 TI - Venom Peptides: Improving Specificity in Cancer Therapy. AB - Venom peptides (VPs) exhibit high specificity and selectivity towards cancer cells, with effects on cell proliferation, invasion, migration, and angiogenesis, as well as modulating immune responses. Studying VPs can help the design of more specific peptide drugs for targeted cancer therapy. PMID- 28867165 TI - Antitumor Antibodies Can Drive Therapeutic T Cell Responses. AB - The classical view of therapeutic monoclonal antibodies (mAbs) against tumor associated antigens (TAAs) is that their mechanism of action is dominated by signal blocking or the cytotoxicity of Fc-driven innate immune effector functions. We review here a mounting body of evidence that anti-TAA mAbs are capable of profoundly synergizing with T cell-directed immunotherapies such as checkpoint blockade and adoptive cell therapy. Two key components account for this synergy: (i) a self-vaccinal effect mediated by dendritic cells (DCs); and (ii) an inflammatory repolarization of the tumor microenvironment. Efficient exploitation of these mechanisms has tremendous therapeutic potential. PMID- 28867167 TI - Pediatric Acute Megakaryoblastic Leukemia: Multitasking Fusion Proteins and Oncogenic Cooperations. AB - Pediatric leukemia presents specific clinical and genetic features from adult leukemia but the underpinning mechanisms of transformation are still unclear. Acute megakaryoblastic leukemia (AMKL) is the malignant accumulation of progenitors of the megakaryocyte lineage that normally produce blood platelets. AMKL is diagnosed de novo, in patients showing a poor prognosis, or in Down syndrome (DS) patients with a better prognosis. Recent data show that de novo AMKL is primarily associated with chromosomal alterations leading to the expression of fusions between transcriptional regulators. This review highlights the most recurrent genetic events found in de novo pediatric AMKL patients and, based on recent functional analyses, proposes a mechanism of leukemogenesis common to de novo and DS-AMKL. PMID- 28867166 TI - Targeting Inflammation to Improve Tumor Drug Delivery. AB - Inefficient delivery of drugs is a main cause of chemotherapy failure in hypoperfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness, and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on anti-angiogenic drugs, whereas stress alleviation is based on stroma-depleting agents. We present here an alternative approach to normalize tumor vasculature, taking into account that malignant tumors tend to develop at sites of chronic inflammation. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyperpermeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or inflammation resolution mediators, as an alternative means to increase tumor drug delivery might prove promising. PMID- 28867168 TI - The Unfolded Protein Response in Immunogenic Cell Death and Cancer Immunotherapy. AB - The unfolded protein response (UPR) is a conserved pathway that is stimulated when endoplasmic reticulum (ER) proteostasis is disturbed or lost. Accumulating evidence indicates that chronic activation of the UPR supports the main hallmarks of cancer by favoring cancer cell-autonomous and nonautonomous processes, which ultimately foster the immunosuppressive and protumorigenic microenvironment. However, certain forms of therapy-induced ER stress can elicit immunogenic cancer cell death (ICD), which enables the release of key immunostimulatory or danger signals, eventually driving efficient antitumor immunity. In this review, after a brief discussion of the interplay between ER stress and protumorigenic inflammation, we review the relevance of therapy-mediated ER stress pathways in evoking ICD and how they could be used to optimize current immunotherapy approaches against cancer. PMID- 28867171 TI - Correction in the Article by Kirchhof et al. "2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS". Rev Esp Cardiol. 2017;70:50.e1-e84. PMID- 28867170 TI - Assessment of pit latrines in a peri-urban community in KwaZulu-Natal (South Africa) as a source of antibiotic resistant E. coli strains. AB - Due to the frequent use of antibiotics and recurring illnesses related to multidrug-resistant (MDR) bacteria in South Africa, we determined if MDR Escherichia coli were present in pit latrine fecal sludge samples obtained from a peri-urban community in KwaZulu-Natal, South Africa. The abundance of E. coli in pit latrine samples was established using a most probable number (MPN) method with species confirmation done using biochemical tests and polymerase chain reaction (PCR). Forty-four randomly selected E. coli pit latrine isolates were further characterized, using the European committee on antimicrobial susceptibility testing (EUCAST) disk diffusion method to establish antibiotic resistance profiles for these E. coli isolates. The resulting MPN values for E. coli ranged from one to 6.2 log10 MPN per gram of fresh pit latrine fecal sludge. While only 3 out of 44 E. coli pit latrine isolates showed no resistance to any of the 12 tested antibiotics, most isolates were resistant to two or more antibiotics. The majority of isolates showed resistance to at least one of the two tested aminoglycosides, one isolate showed resistance to the carbapenem ertapenem, and although resistance was not detected for tigecycline four pit latrine E. coli isolates showed intermediate resistance to this antibiotic. However, about 14% of the E. coli pit latrine isolates were categorized as MDR, all of which showed resistance to four or more antibiotics. The presence of MDR E. coli strains in pit latrine samples demonstrates that these facilities are potential sources for MDR bacteria. PMID- 28867169 TI - Nitric Oxide: The Forgotten Child of Tumor Metabolism. AB - Nitric oxide (NO) is a signaling molecule with pleiotropic physiological roles in normal cells and pathophysiological roles in cancer. NO synthetase expression and NO synthesis are linked to altered metabolism, neoplasticity, invasiveness, chemoresistance, immune evasion, and ultimately to poor prognosis of cancer patients. Exogenous NO in the microenvironment facilitates paracrine signaling, mediates immune responses, and triggers angiogenesis. NO regulates posttranslational protein modifications, S-nitrosation, and genome-wide epigenetic modifications that can have both tumor-promoting and tumor-suppressing effects. We review mechanisms that link NO to cancer hallmarks, with a perspective of co-targeting NO metabolism with first-line therapies for improved outcome. We highlight the need for quantitative flux analysis to study NO in tumors. PMID- 28867172 TI - Untreated unruptured aneurysm: Natural history at long-term. AB - BACKGROUND AND OBJECTIVES: Although the diagnosis of unruptured intracranial aneurysm (IA) has become more frequent, its natural history and management still remain controversial. A better comprehension of its evolution could optimize our therapeutic strategies. The aim of our study was to evaluate, in a cohort of patients with untreated unruptured IA based on the proposition of multidisciplinary staff meetings, the proportion of bleeding, death and cardiovascular events during a long-term prospective follow-up. PATIENTS AND METHODS: This longitudinal study concerned a series of patients with unruptured IA collected over a period of 8 years (2006-2014) identified from a prospectively collected database including all patients with unruptured IA discussed during multidisciplinary staff meetings in the neurosurgery department at Rouen University Hospital. Clinical endpoints were the rupture rate, incidence of death or occurrence of noticeable pathological event defined by any event leading to death, admission to the intensive care unit or challenging the vital prognosis. RESULTS: After a mean follow-up delay of 46.9+/-18.7 months, the IA remained stable in 73 patients (98.6%) out of 74. The rate of rupture per aneurysm year of follow-up was 0.3%, the rate of cardiovascular events was 2.1% and the death rate was 2.8% per year of follow-up. DISCUSSION: In this study, we emphasize the important incidence of adverse events in these patients, which has to be taken into account before proposing a prophylactic IA exclusion. The low incidence of IA rupture confirmed the decision of conservative treatment made during a multidisciplinary staff meeting. PMID- 28867174 TI - Post-transcriptional regulation of gene expression. PMID- 28867173 TI - Different processing of CAPA and pyrokinin precursors in the giant mealworm beetle Zophobas atratus (Tenebrionidae) and the boll weevil Anthonomus grandis grandis (Curculionidae). AB - Capa and pyrokinin (pk) genes in hexapods share a common evolutionary origin. Using transcriptomics and peptidomics, we analyzed products of these genes in two beetles, the giant mealworm beetle (Zophobas atratus; Tenebrionidae) and the boll weevil (Anthonomus grandis grandis; Curculionidae). Our data revealed that even within Coleoptera, which represents a very well-defined group of insects, highly different evolutionary developments occurred in the neuropeptidergic system. These differences, however, primarily affect the general structure of the precursors and differential processing of mature peptides and, to a lesser degree, the sequences of the active core motifs. With the differential processing of the CAPA-precursor in Z. atratus we found a perfect example of completely different products cleaved from a single neuropeptide precursor in different cells. The CAPA precursor in abdominal ganglia of this species yields primarily periviscerokinins (PVKs) whereas processing of the same precursor in neurosecretory cells of the subesophageal ganglion results in CAPA-tryptoPK and a novel CAPA-PK. Particularly important was the detection of that CAPA-PK which has never been observed in the CNS of insects before. The three different types of CAPA peptides (CAPA-tryptoPK, CAPA-PK, PVK) each represent potential ligands which activate different receptors. In contrast to the processing of the CAPA precursor from Z. atratus, no indications of a differential processing of the CAPA precursor were found in A. g. grandis. These data suggest that rapid evolutionary changes regarding the processing of CAPA precursors were still going on when the different beetle lineages diverged. The sequence of the single known PVK of A. g. grandis occupies a special position within the known PVKs of insects and might serve asa basis to develop lineage-specific peptidomimetics capable of disrupting physiological processes regulated by PVKs. PMID- 28867175 TI - Thrombo-hemorrhagic liability in children with congenital heart diseases. AB - BACKGROUND: The precise mechanisms of the increased incidence of hemostatic abnormalities in congenital heart disease (CHD) have not been determined. The aim of the study was to evaluate some indicators of activation of platelets and vascular endothelial cells in patients with CHD, evaluation of bleeding liability of these patients, and correlation with the clinical presentation of these patients. METHODS: This work was carried out on 20 patients with cyanotic congenital heart diseases (CCHD), 20 patients with acyanotic congenital heart diseases (ACHD), and 20 healthy children who served as the control group, aged between 1 and 10years. All were subjected to full clinical examination, complete blood count, oxygen saturation, echocardiography, bleeding and coagulation times, PT, PTT, FDPs, plasma soluble P-selectin, E-selectin, and platelet factor 4 (PF4). RESULTS: There was significant prolongation of PT and PTT, and there was a significant lowering of platelet counts. These results were obtained in CCHD and ACHD, but were more significant in CCHD patients. There was a significant elevation in PF4 (55.0+/-25.5ng/mL), P-selectin (128.9+/-42.44ng/dL), and E selectin (9461.5+/-1701.24pg/mL) levels in children with CCHD as compared to those with ACHD (PF4, 21+/-7.94ng/mL; P-selectin, 80.1+/-13.2ng/mL; E-selectin, 7969.6+/-2127.5pg/mL), and significant increase in both groups when compared to the control group (PF4, 8.1+/-4.7ng/mL; P-selectin, 27.83+/-9.73ng/mL; E selectin, 6750.00+/-3204.00pg/mL). There was a significant negative correlation between oxygen saturation, plasma P-selectin (r=-0.865), E-selectin (r=-0.401), and PF4 (r=-0.792) in patients with CCHD. CONCLUSION: Patients with CHD-both cyanotic and acyanotic-have variable degrees of increased liability for both thrombosis and hemorrhage that represents some sort of adaptation to preserve hemostasis and to protect these patients against the clinical presentation of both thrombosis and bleeding. This is to say that CHD patients have their own point of balance between thrombogenicity and bleeding liability. Wide-scale studies are needed to detect the normal levels of different thrombohemorrhagic parameters of these patients. PMID- 28867176 TI - A Study Demonstrating the Quantitative Relationship Between Internal Thoracic Artery Length and Free Flow. AB - BACKGROUND: The left internal thoracic artery (LITA) is the most commonly used arterial bypass conduit in coronary artery bypass graft (CABG) patients and inadequate LITA flow can result in an increase in morbidity and mortality. In this study, we evaluated the effect of excision of the distal spasmodic segment of the LITA on the free flow in CABG patients. METHODS: This study consisted of 47 patients who underwent elective CABG performed with or without other cardiac surgery, between July 2015 and December 2015. Excised LITA length was shorter than 15mm in group 1, between 15mm and 30mm in group 2 and longer than 30mm in group 3. Left ITA free flow was measured for 60seconds into a container before and after the distal LITA excision. The inter-measurement differences were calculated for the three groups. Thereafter, the comparison was performed in terms of free flow difference amongst the three groups. RESULTS: The mean difference of LITA free flow was 27.6+/-22.7ml/minute in group 1, 35.4+/ 26.7ml/minute in group 2, and 52.6+/-26.1ml/minute in group 3. There were significant differences in terms of free flow difference between the groups (p=0.008). Also, differences were statistically significant in group 1 versus group 3 (p=0.003) and group 2 versus group 3 (p=0.038) in the intergroup comparisons. CONCLUSIONS: The distal part of the LITA has more spasmodic potential than other segments. This spasm may result in low flow of LITA grafts. Therefore, an as long as possible excision of the distal LITA segment may be required to avoid the spasmodic effect. PMID- 28867177 TI - Postoperative Lung Torsion With Retained Viability: The Presentation and Surgical Indications. AB - BACKGROUND: We review our experience with postoperative lung torsion with retained viability. METHODS: A total of 2165 patients underwent pulmonary resection (lobectomy or segmentectomy) at our institution between 1 January, 1986, and 31 March, 2017. Eight (0.3%, six males and two females: median age, 68 years) had lung torsion with retained viability. RESULTS: The right upper lobe was resected in seven patients, while the left upper segment was resected in one patient. The lung torsion with retained viability was the right middle lobe in seven patients and the left lingular segment in one patient. A bronchoscopic examination was performed in four patients to diagnose the pulmonary torsion; however, it demonstrated no specific findings. Subsequently, computed tomography (CT) was performed in all the patients, and lung torsion was diagnosed in all the patients based on the CT findings. None of the patients showed any symptoms when lung torsion was diagnosed in them. The diagnosis of pulmonary torsion was made at a median of 4 days (range, 1-22 days) after the initial surgery. Six patients underwent detorsion of the affected lung, while one patient had a lobectomy, and one patient received conservative management. The lungs of all patients in which detorsion was performed adequately re-expanded. Frequent pneumonia in the viable torsed lung was diagnosed as a cause of death in the one patient who received conservative management. CONCLUSION: The timely decision to follow a surgical approach for lung torsion with retained viability can lead to a satisfactory outcome. PMID- 28867178 TI - Associations of ERAP1 coding variants and domain specific interaction with HLA C*06 in the early onset psoriasis patients of India. AB - Interferon-gamma-induced aminopeptidase ERAP1 trims peptides within the endoplasmic reticulum so that they can be loaded onto MHC class I and presented to the CD8+ T-cells. ERAP1 association and its interaction with HLA-C*06 is controversial across different populations. We have investigated the association and possible functional role of non-synonymous SNPs at different exons of ERAP1 (rs26653: Arg127Pro, rs30187: Lys528Arg and rs27044: Gln730Glu) and their interactions with HLA-C*06 in psoriasis. Significant associations of HLA-C*06 (OR=5.47, P<2.2*10-16), rs30187 (OR 1.35, P=7.4*10-4) and rs27044 (OR=1.24, P=5.8*10-3) were observed. All three ERAP1 SNPs showed significant association only for HLA-C*06 positive patients, while rs30187 and rs27044 showed significant association only for early onset patients (rs30187: OR=1.47, P=9.6*10-5; rs27044: OR=1.36, P=3.3*10-4). No differential expression of ERAP1 was observed either between paired uninvolved and involved skin tissues of psoriasis patients or between non-risk and risk variants in the involved skin. Significant epistatic interaction was observed between HLA-C*06 and the SNP (rs27044) located at the peptide-binding cavity of ERAP1. Evolutionary conservation analysis among mammals showed confinement of Lys528 and Gln730 within highly conserved regions of ERAP1 and suggested the possible detrimental effect of this allele in ERAP1 regulation. PMID- 28867179 TI - RAGE maintains high levels of NFkappaB and oncogenic Kras activity in pancreatic cancer. AB - Oncogenic KRas activity is central to several cancer types including pancreatic ductal adenocarcinoma (PDAC) but has been determined to be "undruggable". Recent studies have indicated that oncogenic KRas is not constitutively active but relies on a feed-forward stimulatory mechanism involving NFkappaB mediated inflammation. In the current study, we investigated the role of the receptor for advanced glycation end-products (RAGE) in maintaining oncogenic signaling in PDAC. We observed that there was a shift in the levels of specific RAGE isoforms and altered cellular localization in PDAC. Furthermore, inhibition of RAGE using a pharmacological antagonist, FPS-ZM1, or a blocking antibody, decreased phosphorylation of IKBalpha and inhibited Erk activity down-stream of Kras in PDAC cell lines. In vivo, inhibition of RAGE using FPS-ZM1 reduced the growth of PDAC syngeneic orthotopic xenografts and prolonged survival. These data indicate that RAGE plays a central role in maintaining inflammatory signaling in PDAC that benefits tumor growth. These observations support the development of approaches to inhibit the carcinogenic actions of Kras indirectly by blocking the mechanisms which maintain its activity. PMID- 28867180 TI - Lactoferrin promotes autophagy via AMP-activated protein kinase activation through low-density lipoprotein receptor-related protein 1. AB - Lactoferrin (LF) is a multifunctional, iron-binding glycoprotein in mammalian secretions, such as breast milk, and has several beneficial effects for human health. However, how these effects are exerted at the cellular level is still largely unknown. In this study, we investigated the effects of LF on autophagy activity in NIH/3T3 mouse fibroblasts. LF from bovine milk was found to increase LC3-I to LC3-II conversion and LC3-positive cytosolic punctate structures because of increased autophagy flux. Knockdown of the putative LF receptor low-density receptor-related protein 1 (LRP1) completely abolished LC3 conversion in cells by LF treatment. Moreover, exposure to LF increased the phosphorylation levels of AMPK in cells, and treatment of dorsomorphin, a pharmacological inhibitor of AMPK signaling, attenuated LC3 conversion by LF. Therefore, we concluded that the beneficial effects of LF might be due to an increase of autophagy activity via AMPK signaling through the LRP1 receptor. These findings provide a novel insight into the physiological role of LF for the maintenance of cellular and tissue homeostasis. PMID- 28867181 TI - Insulin upregulates GRIM-19 and protects cardiac mitochondrial morphology in type 1 diabetic rats partly through PI3K/AKT signaling pathway. AB - Insulin is involved in the development of diabetic heart disease and is important in the activities of mitochondrial complex I. However, the effect of insulin on cardiac mitochondrial nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1 subunit of retinoic-interferon-induced mortality 19 (GRIM-19) has not been characterized. The aim of this study was to investigate the effect of insulin on the mitochondrial GRIM-19 in the hearts of rats with streptozotocin (STZ)-induced type 1 diabetes. Protein changes of GRIM-19 were evaluated by western blotting and reverse transcription-quantitative polymerase chain reaction. Furthermore, the effects of insulin on mitochondrial complex I were detected in HeLa cells and H9C2 cardiac myocytes. During the development of diabetic heart disease, the cardiac function did not change within the 8 weeks, but the mitochondrial morphology was altered. The hearts from the rats with STZ induced diabetes exhibited reduced expression of GRIM-19. Prior to the overt cardiac dilatation, mitochondrial alterations were already present. Following subcutaneous insulin injection, it was demonstrated that GRIM-19 protein was altered, as well as the mitochondrial morphology. The phosphoinositide 3-kinase inhibitor LY294002 had an effect on insulin signaling in H9C2 cardiacmyocytes, and decreased the level of GRIM-19 by half compared with that in the insulin group. The results indicate that insulin is essential for the control of cardiac mitochondrial morphology and the GRIM-19 expression partly via PI3K/AKT signaling pathways. PMID- 28867183 TI - Indomethacin inhabits the NLRP3 inflammasome pathway and protects severe acute pancreatitis in mice. AB - Clinical studies have confirmed that indomethacin (Indo) can reduce the incidence and severity of post-endoscopicretrogradecholangio-pancreatography pancreatitis (PEP) effectively. However, the role of Indo on severe acute pancreatitis (SAP) is not clear. In the present study, we aimed to explore the effects of Indo treatment on SAP model induced by caerulein combined with lipopolysaccharide. After intraperitoneal injection of Indo in mice, both the severity of SAP and the serum levels of amylase, lipase, and proinflammatory cytokines were decreased. Furthermore, the mRNA and protein levels of NLRP3 inflammasome pathway (NLRP3,ASC and IL-1beta) in pancreatic tissues were down-regulated. In vitro experiments, by isolating the pancreatic acinar cells (PACs) from mice, we found that Indo significantly reduced lactate dehydrogenase(LDH) excretion, increased the cell activity, and inhibited the NLRP3 inflammasome pathway of PACs. Taken together, our data showed that Indo could protect pancreatic acinar cell from injury by inhabiting NLRP3 pathway and decreased the severity of SAP accordingly. PMID- 28867182 TI - Deficiency of KLF4 compromises the lung function in an acute mouse model of allergic asthma. AB - Asthma is a chronic inflammatory disease of the airways and the mechanisms are not fully understood. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of monocytes, granulocyte and myeloid cells at early stage of differentiation. They possess phenotypic plasticity and regulate airway inflammation. We recently reported that Kruppel-like factor 4 (KLF4) regulates MDSC differentiation into fibrocytes, emerging effectors in chronic inflammation. However, the role of KLF4 in asthma is not known. Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine and a key initiator of allergic airway inflammation. Given the fact that TSLP promotes Th2 cytokine production that increases MDSC differentiation into fibrocytes, we postulate that KLF4 regulates asthma in a TSLP-dependent manner. In this study, we utilized a model of allergic asthma with ovalbumin challenge (OVA). We found that upon OVA treatment the wild type mice had increased MDSC infiltration into the lung, up regulation of KLF4 and TSLP gene expression, and higher levels of Th2 cytokines including IL4 and IL13. Consistently, lack of KLF4 expression in monocytes and lung epithelial cells resulted in decreased TSLP expression and lower levels of Th2 cytokines in mice, and fibrocyte generation was compromised. KLF4 deficiency in these cells also led to decreased airway hyperresponsiveness (AHR), a cardinal feature of asthma, as assessed by whole body plethysmography. Moreover, lung fibrosis as measured by trichome staining was attenuated and the population of CD45 + COL1A1+ fibrocytes was diminished in this setting. Together, our results suggest that KLF4 regulates asthma development in a TSLP- and fibrocyte-dependent manner. PMID- 28867184 TI - Crystal structure and thermodynamic dissection of chitin oligosaccharide binding to the LysM module of chitinase-A from Pteris ryukyuensis. AB - We determined the crystal structure of a LysM module from Pteris ryukyuensis chitinase-A (PrLysM2) at a resolution of 1.8 A. Structural and binding analysis of PrLysM2 indicated that this module recognizes chitin oligosaccharides in a shallow groove comprised of five sugar-binding subsites on one side of the molecule. The free energy changes (DeltaGr degrees ) for binding of (GlcNAc)6, (GlcNAc)5, and (GlcNAc)4 to PrLysM2 were determined to be -5.4, -5,4 and -4.6 kcal mol-1, respectively, by ITC. Thermodynamic dissection of the binding energetics of (GlcNAc)6 revealed that the driving force is the enthalpy change (DeltaHr degrees = -11.7 +/- 0.2 kcal/mol) and the solvation entropy change ( TDeltaSsolv degrees = -5.9 +/- 0.6 kcal/mol). This is the first description of thermodynamic signatures of a chitin oligosaccharide binding to a LysM module. PMID- 28867185 TI - Effects of two-dimensional materials on human mesenchymal stem cell behaviors. AB - Graphene, a typical two-dimensional (2D) material, is known to affect a variety of stem cell behaviors including adhesion, spreading, growth, and differentiation. Here, we report for the first time the effects of four different emerging 2D materials on human adipose-derived mesenchymal stem cells (hADMSCs). Graphene oxide (GO), molybdenum sulfide (MoS2), tungsten sulfide (WS2), and boron nitride (BN) were selected as model two-dimensional materials and were coated on cell-culture substrates by a drop-casting method. Acute toxicity was not observed with any of the four different 2D materials at a low concentration range (<5 MUg/ml). Interestingly, the 2D material-modified substrates exhibited a higher cell adhesion, spreading, and proliferation when compared with a non-treated (NT) substrate. Remarkably, in the case of differentiation, the MoS2-, WS2-, and BN modified substrates exhibited a better performance in terms of guiding the adipogenesis of hADMSCs when compared with both NT and GO-modified substrates, based on the mRNA expression level (qPCR) and amount of lipid droplets (ORO staining). In contrast, the osteogenesis was found to be most efficiently induced by the GO-coated substrate (50 MUg/mL) among all 2D-material coated substrates. In summary, 2D materials could act as favorable sources for controlling the stem cell growth and differentiation, which might be highly advantageous in both biomedical research and therapy. PMID- 28867186 TI - Dietary beta-conglycinin prevents acute ethanol-induced fatty liver in mice. AB - Alcoholic fatty liver is the earliest stage of alcohol-induced liver disease leading to liver cirrhosis. beta-Conglycinin, one of the soy proteins, is known to prevent non-alcoholic fatty liver, hyperlipidemia and obesity. Therefore, we examined whether beta-conglycinin feeding has an effect on the prevention of acute ethanol-induced fatty liver in mice. Male C57BL/6J mice were fed with 20 energy% beta-conglycinin or casein for 4 weeks prior to ethanol administration and were then given ethanol or glucose, as a control, by gavage. Ethanol significantly increased liver triglyceride (TG) in mice fed casein due to the activation of peroxisome proliferator-activated receptor (PPAR) gamma2, a nuclear transcription factor known for regulating lipid metabolism and de novo lipogenesis. The liver TG of ethanol-administered beta-conglycinin-fed mice was significantly lower than that in those fed casein, although ethanol increased the amount of liver TG in mice fed beta-conglycinin. The increased levels of PPARgamma2 protein and its target gene CD36 in response to an ethanol were not observed in mice fed beta-conglycinin. Moreover, beta-conglycinin decreased the basal expression of de novo lipogenesis-related genes such as stearoyl-CoA desaturase-1, and therefore, the expressions of these genes were lower in the ethanol-administered beta-conglycinin-fed mice than in the casein-fed mice. In conclusion, beta-conglycinin supplementation appears to prevent the development of fatty liver in mice caused by ethanol consumption via the suppression of alcohol-induced activation of PPARgamma2 and the downregulation of the basal expression of de novo lipogenesis. PMID- 28867187 TI - Irisin stimulates cell proliferation and invasion by targeting the PI3K/AKT pathway in human hepatocellular carcinoma. AB - Irisin is a newly identified myokine that may be cancer-associated, and its impact on liver cancer is unclear. To understand the roles of irisin in liver cancer, we investigated its effect in HepG2 and SMCC7721 hepatocellular carcinoma cells, and the underlying mechanisms. We determined irisin levels in liver tissues and serum samples obtained from patients by using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Irisin levels in cancerous livers were significantly upregulated compared with those in control livers, but serum irisin levels remained unchanged. Additionally, we evaluated the effects of different concentrations of human recombinant modified and active (glycosylated) irisin (IM) or human recombinant nonmodified irisin (INM) on cell migration, proliferation, viability, and invasiveness. CCK8, transwell, and scratching assays demonstrated that irisin significantly increased cell proliferation, invasion, and migration through activation of the PI3K/AKT pathway. Irisin induced cell proliferation, migration, and invasion were blocked by a PI3K inhibitor (LY294002). Irisin also decreased the cytotoxicity of doxorubicin in HepG2 cells. These data indicate that increased irisin levels may have protective roles in liver cancer cells through partial activation of the PI3K/AKT pathway, which may facilitate liver cancer progression and decrease the sensitivity to chemotherapy. PMID- 28867188 TI - Disruption of the hydrogen bonding network determines the pH-induced non fluorescent state of the fluorescent protein ZsYellow by protonation of Glu221. AB - Many fluorescent proteins (FPs) exhibit fluorescence quenching at a low pH. This pH-induced non-fluorescent state of an FP serves as a useful indicator of the cellular pH. ZsYellow is widely used as an optical marker in molecular biology, but its pH-induced non-fluorescent state has not been characterized. Here, we report the pH-dependent spectral properties of ZsYellow, which exhibited the pH induced non-fluorescence state at a pH below 4.0. We determined the crystal structures of ZsYellow at pH 3.5 (non-fluorescence state) and 8.0 (fluorescence state), which revealed the cis-configuration of the chromophore without pH induced isomerization. In the non-fluorescence state, Arg95, which is involved in stabilization of the exited state of the chromophore, was found to more loosely interact with the carbonyl oxygen atom of the chromophore when compared to the interaction at pH 8.0. In the fluorescence state, Glu221, which is involved in the hydrogen bonding network around the chromophore, stably interacted with Gln42 and His202. By contrast, in the non-fluorescence state, the protonated conserved Glu221 residue exhibited a large conformational change and was separated from His202 by 5.46 A, resulting in breakdown of the hydrogen bond network. Our results provide insight into the critical role of the conserved Glu221 residue for generating the pH-induced non-fluorescent state. PMID- 28867189 TI - Modified high-throughput quantification of plasma microRNAs in heparinized patients with coronary artery disease using heparinase. AB - Heparin, a widely used anticoagulant in cardiovascular diseases, is notorious for its inhibitory effect on qRT-PCR-based detection. Heparinase I could degrade heparin in RNA. qRT-PCR-based TaqMan Low Density Array (TLDA) technology is commonly used for circulating microRNAs (miRNAs) profiling analysis. However, the effect of heparin contamination on inhibition of miRNAs TLDA amplification, as well as the method for removing heparin during this process, are not yet well investigated. We obtained the plasma RNA samples from patients undergoing percutaneous coronary intervention (PCI) before and after heparinization (n = 26). We found that heparin suppressed the miRNAs amplification by ~8 cycles in the TLDA assay, which was absolutely reversed after treating the RNA samples with heparinase I using the components from TLDA reverse transcription system. We further observed that heparin inhibited the miRNAs amplification by ~4 cycles in the qRT-PCR assay, which was also reversed by heparinase I using the similar method. Furthermore, we demonstrated that plasma miR-92a and miR-155 were differentially expressed in the patients undergoing PCI tested by TLDA assay, which was validated by qRT-PCR. In conclusion, we present a simple method for the removal of heparin with heparinase I, and for the subsequent successful miRNAs TLDA or RT-qPCR amplification. PMID- 28867190 TI - Modulation of RAB5A early endosome trafficking in response to KRas mediated macropinocytic fluxes in pancreatic cancer cells. AB - KRAS is the key mutated gene in pancreatic ductal adenocarcinoma (PDAC). Emerging evidence indicates that KRas modulates endocytic uptake. The present study aimed to explore the fate of early endosomal trafficking under the control of KRas expression in PDAC. Surprisingly, PANC-1 cells lacking KRas exhibited significantly enlarged early and late endosomes containing internalized dextran and epidermal growth factor. Endosome enlargement was accompanied by reduced endosomal degradation. Both KRas silencing and lysosomal blockade caused an upregulation of the master regulator of early endosome biogenesis, RAB5A, which is likely responsible for the expansion of the early endosomal compartment, because simultaneous KRAS/RAB5A knockdown abolished endosome enlargement. In contrast, early endosome shrinkage was seen in MIA PaCa-2 cells despite RAB5A upregulation, indicating that distinct KRas-modulated responses operate in different metabolic subtypes of PDAC. In conclusion, mutant KRAS promotes endosomal degradation in PDAC cell lines, which is impaired by KRAS silencing. Moreover, KRAS silencing activates RAB5A upregulation and drives PDAC subtype dependent modulation of endosome trafficking. PMID- 28867191 TI - Aging-related mitochondrial dysfunction facilitates the occurrence of serious arrhythmia after myocardial infarction. AB - BACKGROUND: During aging a mosaic of normal cells and cells with mitochondrial deficiency develops in various tissues including the heart. Whether this contributes to higher susceptibility for arrhythmia following myocardial infarction (MI) is unknown. METHODS AND RESULTS: Myocardial cryoinfarction was performed in 12-month-old transgenic mice with accelerated accumulation of deletions in mitochondrial DNA. Occurrence and pathogenesis of arrhythmia was investigated after two weeks. Holter-ECG recordings revealed higher rates of premature ventricular complexes (incidence > 10/24 h: 100% vs. 20%; p = 0.048) and more severe spontaneous arrhythmia during stress test in mutant mice with MI as compared to control mice with MI. Mice with mitochondrial dysfunction exhibited longer spontaneous AV-blocks (467 +/- 26 ms vs. 377 +/- 24 ms; p = 0.013), an increased probability for induction of ventricular tachycardia during in vivo electrophysiological investigation (22% vs. 9%; p = 0.044), and a reduced conduction velocity in the infarct borderzone (38.5 +/- 0.5 cm/s vs. 55.3 +/- 0.9 cm/s; p = 0.001). Furthermore, mutant mice exhibited a significant reduction of the phospho-Cx43/Cx43 ratio in right (0.59 +/- 0.04 vs. 0.85 +/- 0.01; p = 0.027) and left ventricular myocardium (0.72 +/- 0.01 vs. 0.86 +/- 0.02; p = 0.023). CONCLUSIONS: Aging-related cardiac mosaic respiratory chain dysfunction facilitates the occurrence of spontaneous and inducible cardiac arrhythmia after myocardial infarction and is associated with slowing of electrical impulse propagation in the infarct borderzone. PMID- 28867192 TI - Apigenin inhibits d-galactosamine/LPS-induced liver injury through upregulation of hepatic Nrf-2 and PPARgamma expressions in mice. AB - Apigenin is a natural flavonoid compound widely distributed in a variety of vegetables, medicinal plants and health foods. This study aimed to examine the protective effect of apigenin against d-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced mouse liver injury and to investigate the potential biochemical mechanisms. The results showed that after oral administration of apigenin 100-200 mg/kg for 7 days, the levels of serum alanine aminotransferase and aspartate aminotransferase were decreased, and the severity of liver injury was alleviated. Importantly, apigenin pretreatment increased the levels of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and peroxisome proliferator-activated receptor gamma (PPARgamma) protein expressions as well as superoxide dismutase, catalase, glutathione S-transferase and glutathione reductase activities, decreased the levels of hepatic nuclear factor-kappaB (NF-kappaB) protein expression and tumor necrosis factor-alpha. These findings demonstrated that apigenin could prevent the D-GalN/LPS-induced liver injury in mice, and its mechanisms might be associated with the increments of Nrf-2-mediated antioxidative enzymes and modulation of PPARgamma/NF-kappaB-mediated inflammation. PMID- 28867193 TI - TRIM25 is associated with cisplatin resistance in non-small-cell lung carcinoma A549 cell line via downregulation of 14-3-3sigma. AB - Lung cancer, in particular, non-small cell lung cancer (NSCLC), is the leading cause of cancer-related mortality. Cis-Diamminedichloroplatinum (cisplatin, CDDP) as first-line chemotherapy for NSCLC, but resistance occurs frequently. We previously reported that Tripartite motif protein 25 (TRIM25) was highly expressed in cisplatin-resistant human lung adenocarcinoma A549 cells (A549/CDDP) in comparison with its parental A549 cells. Herein, we take a further step to demonstrate the association of TRIM25 and cisplatin resistance and also the underlying mechanisms. Knockdown of TRIM25 by RNA interference in A549/CDDP cells decreased half maximal inhibitory concentration (IC50) values and promoted apoptosis in response to cisplatin, whereas overexpression of TRIM25 had opposite effects. More importantly, we found that concomitant knockdown of 14-3-3sigma and TRIM25 absolutely reversed the decreased MDM2, increased p53, increased cleaved Capsese3 and decreased IC50 value induced by knockdown of TRIM25 individually, suggesting that TRIM25 mediated cisplatin resistance primarily through downregulation of 14-3-3sigma. Our results indicate that TRIM25 is associated with cisplatin resistance and 14-3-3sigma-MDM2-p53 signaling pathway is involved in this process, suggesting targeting TRIM25 may be a potential strategy for the reversal of cisplatin resistance. PMID- 28867194 TI - Identification of an argpyrimidine-modified protein in human red blood cells from schizophrenic patients: A possible biomarker for diseases involving carbonyl stress. AB - Argpyrimidine (ARP) is an advanced glycation end product thought to be generated from a reaction between methylglyoxal and arginine residues in proteins. In this study, we observed marked accumulation of an approximately 56 kD protein, reactive to anti-ARP antibodies, in the red blood cells (RBCs) of some patients with refractory schizophrenia. This ARP-modified protein was purified from the blood of schizophrenic patients and identified as selenium binding protein 1 (SBP1) by LC-MS/MS. This is the first report of ARP-modified proteins accumulating in RBCs of patients with diseases involving carbonyl stress. We also observed high accumulation of ARP-modified SBP1 in the RBCs of patients with chronic kidney disease. Therefore, this modified protein may be a novel marker of carbonyl stress. PMID- 28867195 TI - Simultaneous targeting PI3K and PERK pathways promotes cell death and improves the clinical prognosis in esophageal squamous carcinoma. AB - PI3K pathway is an important anti-tumor target, but its effect and mechanism is not clear in esophageal squamous cell carcinoma (ESCC). By analysis of the Cancer Genome Atlas (TCGA) datasets, we found that PI3Ks level were significantly upregulated in human esophageal cancer tissues compared with that in non-cancer tissues. The alteration of PI3K can significantly affect the overall patient survival in ESCC but not in esophageal adenocarcinoma (EAC). We found that the classic PI3K inhibitor LY294002 obviously inhibited the canonical mammalian target of rapamycin (mTOR) pathway and restrained the growth of ESCC with less toxicity to normal cells. Besides, LY294002 inhibited noncanonical PKR-like ER kinase (PERK)/elF2alpha/ATF4 pathway as well. Both siRNA and the small molecule inhibitor GSK2656157 against PERK/elF2alpha/ATF4 pathway can significantly inhibit the growth of ESCC. More importantly, GSK2656157 aggravated the inhibitory effect of LY294002 on cell growth, colony formation, and apoptosis induction of ESCC. In addition of dual high expression of PI3K and PERK pathways in the ESCC patients, the difference of overall survival (OS) was more significant than using PI3K alone. These results indicated that dual targeting of PI3K and PERK pathways might improve clinical prognosis and enhance the treatment of ESCC patients. PMID- 28867196 TI - A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest. AB - Despite the development of new drugs for multiple myeloma (MM), the prognosis of MM patients with high-risk cytogenetic abnormalities such as t (4; 14) and del17p remains poor. We reported that a novel phenylphthalimide derivative, TC11, induced apoptosis of MM cells in vitro and in vivo, and TC11 directly bound to alpha-tubulin and nucleophosmin-1 (NPM1). However, TC11 showed low water solubility and poor pharmacokinetic properties. Here we synthesized a water soluble TC11-derivative, PEG(E)-TC11, in which HOEtO-TC11 is pegylated with PEG through an ester bond, and we examined its anti-myeloma activity. We observed that PEG(E)-TC11 and its hydrolyzed product, HOEtO-TC11, induced G2/M arrest and the apoptosis of MM cells. Intraperitoneal administration of PEG(E)-TC11 to xenografted mice revealed improved pharmacokinetic properties and significantly delayed tumor growth. TC11 and its derivatives did not bind to cereblon (CRBN), which is a responsible molecule for thalidomide-induced teratogenicity. These results suggest that PEG(E)-TC11 is a good candidate drug for treating high-risk MM. PMID- 28867197 TI - Litter size determines the number of melanin-concentrating hormone neurons in the medial preoptic area of Sprague Dawley lactating dams. AB - Melanin-concentrating hormone [MCH] is an important neuromodulator related to motivated behaviors. The MCH-containing neurons are mainly located in the lateral hypothalamic area, zona incerta, and incerto-hypothalamic area. In the medial preoptic area [MPOA], a key region for the regulation of maternal behavior, Pmch mRNA expression and MCH synthesis can be detected exclusively during the lactation period. As litter size affects different parameters of maternal physiology, the aim of this study was to verify whether litter size can modulate the number of MCH-containing neurons in the MPOA of lactating rats. The dams were divided into the following groups: postpartum day 12, 15, or 19, with a large, small or reduced litter. Our results show that the number of MCH-immunoreactive neurons in the MPOA is positively correlated with the number of pups in the litter and that artificially reducing the number of pups can also decrease the number of MCH-immunoreactive neurons in the MPOA. PMID- 28867198 TI - The emerging role of pore forming proteins in cell biology and development. PMID- 28867199 TI - Alternative polyadenylation in the regulation and dysregulation of gene expression. AB - Transcriptional control shapes a cell's transcriptome composition, but it is RNA processing that refines its expression. The untranslated regions (UTRs) of mRNA are hotspots for regulatory control. Features in these can impact mRNA stability, localisation and translation. Here we describe how alternative cleavage and polyadenylation can change mRNA fate by changing the length of its 3'UTR. PMID- 28867200 TI - Application of X-Ray Sensors for In-line and Noninvasive Monitoring of Mass Flow Rate in Continuous Tablet Manufacturing. AB - The progress in continuous downstream manufacturing of oral solid doses demands effective real-time process management, with monitoring at its core. This study evaluates the feasibility of using a commercial sensor to measure the mass flow rate of the particulates, a critical process variable in continuous manufacturing. The sensor independently measures X-ray attenuation and cross correlation velocimetry of particulate flow in real time. Steady-state flow rates of blends comprised primarily of acetaminophen and microcrystalline-cellulose are monitored using the sensor, with simultaneous weighing scale measurements, to calibrate the sensor and investigate the measurement accuracy. The free-fall flow measurement of the powder and granule blends in a conduit is linearly proportional to the X-ray attenuation. Relative standard deviations of ~3%-7% for 1 s monitoring are observed and a measurement error of approximately 5% suggests the usability of the sensor for real-time monitoring. The sensor measurement is robust for operational variations in composition, addition of lubricant or glidant and reuse of material for PAT tool calibration. The measurement relative standard deviations depend on particulate flow dynamics at the sensor location. This requires experimental evaluation for a given material at the sensor location, to capture the flow dynamics of the particulate stream through the sensor. PMID- 28867201 TI - The Influence of Mannitol Hemihydrate on the Secondary Drying Dynamics of a Protein Formulation: A Case Study. AB - The objective of this research was to study the atypical secondary drying dynamics observed during the freeze-drying of a formulation consisting of mannitol, disaccharide, and sodium chloride, where "bursts" of water vapor release were observed during secondary drying as detected by comparative pressure measurement. "Thief" samples were removed at the end of primary drying and during secondary drying as the shelf temperature was increased in a stepwise fashion. These samples were examined by X-ray powder diffraction and thermal analysis. From the X-ray powder diffraction data, we determined that mannitol crystallized predominantly as its hemihydrate. The physical state of mannitol changed from the hemihydrate form to anhydrous forms during secondary drying. Investigation of the effect of excipients on mannitol crystallization demonstrated that sodium chloride (at 225 mM, 1.3% w/v) had the greatest influence on hemihydrate crystallization, followed by trehalose and sucrose. However, only negligible hemihydrate formation was observed when mannitol was freeze-dried either by itself or in the presence of 150 mM sodium chloride and no hemihydrate in the presence of 75 mM sodium chloride. In general, a combination of a disaccharide and sodium chloride promoted the hemihydrate formation to a greater extent than the individual components. Comparative pressure measurement was demonstrated to be an effective tool to monitor mannitol hemihydrate dehydration during secondary drying. PMID- 28867202 TI - A Neural Basis for Contagious Yawning. AB - Contagious yawning, in which yawning is triggered involuntarily when we observe another person yawn, is a common form of echophenomena-the automatic imitation of another's words (echolalia) or actions (echopraxia) [1]. The neural basis for echophenomena is unknown; however, it has been proposed that it is linked to disinhibition of the human mirror-neuron system [1-4] and hyper-excitability of cortical motor areas [1]. We investigated the neural basis for contagious yawning using transcranial magnetic stimulation (TMS). Thirty-six adults viewed video clips that showed another individual yawning and, in separate blocks, were instructed to either resist yawning or allow themselves to yawn. Participants were videoed throughout and their yawns or stifled yawns were counted. We used TMS to quantify motor cortical excitability and physiological inhibition for each participant, and these measures were then used to predict the propensity for contagious yawning across participants. We demonstrate that instructions to resist yawning increase the urge to yawn and alter how yawns are expressed (i.e., full versus stifled yawns) but do not alter the individual propensity for contagious yawning. By contrast, TMS measures of cortical excitability and physiological inhibition were significant predictors of contagious yawning and accounted for approximately 50% of the variability in contagious yawning. These data demonstrate that individual variability in the propensity for contagious yawning is determined by cortical excitability and physiological inhibition in the primary motor cortex. PMID- 28867203 TI - Warming by 1 degrees C Drives Species and Assemblage Level Responses in Antarctica's Marine Shallows. AB - Forecasting assemblage-level responses to climate change remains one of the greatest challenges in global ecology [1, 2]. Data from the marine realm are limited because they largely come from experiments using limited numbers of species [3], mesocosms whose interior conditions are unnatural [4], and long-term correlation studies based on historical collections [5]. We describe the first ever experiment to warm benthic assemblages to ecologically relevant levels in situ. Heated settlement panels were used to create three test conditions: ambient and 1 degrees C and 2 degrees C above ambient (predicted in the next 50 and 100 years, respectively [6]). We observed massive impacts on a marine assemblage, with near doubling of growth rates of Antarctic seabed life. Growth increases far exceed those expected from biological temperature relationships established more than 100 years ago by Arrhenius. These increases in growth resulted in a single "r-strategist" pioneer species (the bryozoan Fenestrulina rugula) dominating seabed spatial cover and drove a reduction in overall diversity and evenness. In contrast, a 2 degrees C rise produced divergent responses across species growth, resulting in higher variability in the assemblage. These data extend our ability to expand, integrate, and apply our knowledge of the impact of temperature on biological processes to predict organism, species, and ecosystem level ecological responses to regional warming. PMID- 28867204 TI - Formation and Shaping of the Antirrhinum Flower through Modulation of the CUP Boundary Gene. AB - Boundary domain genes, expressed within or around organ primordia, play a key role in the formation, shaping, and subdivision of planar plant organs, such as leaves. However, the role of boundary genes in formation of more elaborate 3D structures, which also derive from organ primordia, remains unclear. Here we analyze the role of the boundary domain gene CUPULIFORMIS (CUP) in formation of the ornate Antirrhinum flower shape. We show that CUP expression becomes cleared from boundary subdomains between petal primordia, most likely contributing to formation of congenitally fused petals (sympetally) and modulation of growth at sinuses. At later stages, CUP is activated by dorsoventral genes in an intermediary region of the corolla. In contrast to its role at organ boundaries, intermediary CUP activity leads to growth promotion rather than repression and formation of the palate, lip, and characteristic folds of the closed Antirrhinum flower. Intermediary expression of CUP homologs is also observed in related sympetalous species, Linaria and Mimulus, suggesting that changes in boundary gene activity have played a key role in the development and evolution of diverse 3D plant shapes. PMID- 28867205 TI - Collective Growth in a Small Cell Network. AB - Theoretical studies suggest that many of the emergent properties associated with multicellular systems arise already in small networks [1, 2]. However, the number of experimental models that can be used to explore collective dynamics in well defined cell networks is still very limited. Here we focus on collective cell behavior in the female germline cyst in Drosophila melanogaster, a stereotypically wired network of 16 cells that grows by ~4 orders of magnitude with unequal distribution of volume among its constituents. We quantify multicellular growth with single-cell resolution and show that proximity to the oocyte, as defined on the network, is the principal factor that determines cell size; consequently, cells grow in groups. To rationalize this emergent pattern of cell sizes, we propose a tractable mathematical model that depends on intercellular transport on a cell lineage tree. In addition to correctly predicting the divergent pattern of cell sizes, this model reveals allometric growth of cells within the network, an emergent property of this system and a feature commonly associated with differential growth on an organismal scale [3]. PMID- 28867206 TI - Evolution of Vocal Diversity through Morphological Adaptation without Vocal Learning or Complex Neural Control. AB - The evolution of complex behavior is driven by the interplay of morphological specializations and neuromuscular control mechanisms [1-3], and it is often difficult to tease apart their respective contributions. Avian vocal learning and associated neural adaptations are thought to have played a major role in bird diversification [4-8], whereas functional significance of substantial morphological diversity of the vocal organ remains largely unexplored. Within the most species-rich order, Passeriformes, "tracheophones" are a suboscine group that, unlike their oscine sister taxon, does not exhibit vocal learning [9] and is thought to phonate with tracheal membranes [10, 11] instead of the two independent sources found in other passerines [12-14]. Here we show tracheophones possess three sound sources, two oscine-like labial pairs and the unique tracheal membranes, which collectively represent the largest described number of sound sources for a vocal organ. Birds with experimentally disabled tracheal membranes were still able to phonate. Instead of the main sound source, the tracheal membranes constitute a morphological specialization, which, through interaction with bronchial labia, contributes to different acoustic features such as spectral complexity, amplitude modulation, and enhanced sound amplitude. In contrast, these same features arise in oscines from neuromuscular control of two labial sources [15-17]. These findings are supported by a modeling approach and provide a clear example for how a morphological adaptation of the tracheophone vocal organ can generate specific, complex sound features. Morphological specialization therefore constitutes an alternative path in the evolution of acoustic diversity to that of oscine vocal learning and complex neural control. PMID- 28867207 TI - Lesions of the Head Direction Cell System Increase Hippocampal Place Field Repetition. AB - A central tenet of systems neuroscience is that the mammalian hippocampus provides a cognitive map of the environment. This view is supported by the finding of place cells, neurons whose firing is tuned to specific locations in an animal's environment, within this brain region. Recent work, however, has shown that these cells repeat their firing fields across visually identical maze compartments [1, 2]. This repetition is not observed if these compartments face different directions, suggesting that place cells use a directional input to differentiate otherwise similar local environments [3, 4]. A clear candidate for this input is the head direction cell system. To test this, we disrupted the head direction cell system by lesioning the lateral mammillary nuclei and then recorded place cells as rats explored multiple, connected compartments, oriented in the same or in different directions. As shown previously, we found that place cells in control animals exhibited repeated fields in compartments arranged in parallel, but not in compartments facing different directions. In contrast, the place cells of animals with lesions of the head direction cell system exhibited repeating fields in both conditions. Thus, directional information provided by the head direction cell system appears essential for the angular disambiguation by place cells of visually identical compartments. PMID- 28867208 TI - Inter-adipocyte Adhesion and Signaling by Collagen IV Intercellular Concentrations in Drosophila. AB - Sheet-forming Collagen IV is the main component of basement membranes, which are planar polymers of extracellular matrix underlying epithelia and surrounding organs in all animals. Adipocytes in both insects and mammals are mesodermal in origin and often classified as mesenchymal. However, they form true tissues where cells remain compactly associated. Neither the mechanisms providing this tissue level organization nor its functional significance are known. Here we show that discrete Collagen IV intercellular concentrations (CIVICs), distinct from basement membranes and thicker in section, mediate inter-adipocyte adhesion in Drosophila. Loss of these Collagen-IV-containing structures in the larval fat body caused intercellular gaps and disrupted continuity of the adipose tissue layer. We also found that Integrin and Syndecan matrix receptors attach adipocytes to CIVICs and direct their formation. Finally, we show that Integrin mediated adhesion to CIVICs promotes normal adipocyte growth and prevents autophagy through Src-Pi3K-Akt signaling. Our results evidence a surprising non basement membrane role of Collagen IV in non-epithelial tissue morphogenesis while demonstrating adhesion and signaling functions for these structures. PMID- 28867209 TI - Identification and molecular profiling of DC-SIGN-like from big belly seahorse (Hippocampus abdominalis) inferring its potential relevancy in host immunity. AB - Dendritic-cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) is a C-type lectin that functions as a pattern recognition receptor by recognizing pathogen associated molecular patterns (PAMPs). It is also involved in various events of the dendritic cell (DC) life cycle, such as DC migration, antigen capture and presentation, and T cell priming. In this study, a DC-SIGN-like gene from the big belly seahorse Hippocampus abdominalis (designated as ShDCS-like) was identified and molecularly characterized. The putative, complete ORF was found to be 1368 bp in length, encoding a protein of 462 amino acids with a molecular mass of 52.6 kDa and a theoretical isoelectric point of 8.26. The deduced amino acid sequence contains a single carbohydrate recognition domain (CRD), in which six conserved cysteine residues and two Ca2+-binding site motifs (QPN, WND) were identified. Based on pairwise sequence analysis, ShDCS-like exhibits the highest amino acid identity (94.6%) and similarity (97.4%) with DC-SIGN-like counterpart from tiger tail seahorse Hippocampus comes. Quantitative real-time PCR revealed that ShDCS like mRNA is transcribed universally in all tissues examined, but with abundance in kidney and gill tissues. The basal mRNA expression of ShDCS-like was modulated in blood cell, kidney, gill and liver tissues in response to the stimulation of healthy fish with lipopolysaccharides (LPS), Edwardsiella tarda, or Streptococcus iniae. Moreover, recombinant ShDCS-like-CRD domain exhibited detectable agglutination activity against different bacteria. Collectively, these results suggest that ShDCS-like may potentially involve in immune function in big belly seahorses. PMID- 28867210 TI - Membrane transporter research in times of countless structures. AB - Structural biology has advanced our understanding of membrane proteins like no other scientific discipline in the past two decades and the number of high resolution membrane transporter structures solved by X-ray crystallography has increased exponentially over this time period. Currently, single particle cryo-EM is in full swing due to a recent resolution revolution and permits for structural insights of proteins that were refractory to crystallization. It is foreseeable that multiple structures of many human transporters will be solved in the coming five years. Nevertheless, many scientifically important questions remain unanswered despite of available structures, as is illustrated in this article at the example of multidrug efflux pumps and ABC transporters. Structure-function studies likely continue to be a supporting pillar of membrane transporter research. However, there is a trend towards the "integrated structural biologist", whose research focusses on a biological question and who closely collaborates with other research groups specialized in spectroscopy techniques or molecular dynamics simulation. Future membrane protein research requires joint efforts from specialists of various disciplines to finally work towards a molecular understanding of membrane transport in the context of the living cell. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain. PMID- 28867211 TI - Autophagy inhibitors suppress environmental particulate matter-induced airway inflammation. AB - Particulate matter (PM) is a significant risk factor for airway injury. We have recently demonstrated a pivotal role of autophagy in mediating PM-induced airway injury. In the present study, we examined the possible effects of autophagy inhibitors spautin-1 and 3-Methyladenine (3-MA) in protection of PM-induced inflammatory responses. We observed that PM triggered autophagy in human bronchial epithelial (HBE) cells and in mouse airways. Spautin-1 or 3-MA inhibited PM-induced expression of inflammatory cytokines in HBE cells, and decreased the neutrophil influx and proinflammatory cytokines induced by PM in vivo. We further illustrated that autophagy inhibitors suppressed the inflammation responses via inhibition of the nuclear factor-kB (NF-kB) pathway. Thus, this study shows a paradigm that autophagy inhibitors effectively decrease the PM-induced airway inflammation via suppressing the NF-kB pathway, which may provide novel preventive and/or protective approaches for PM-related airway injury. PMID- 28867212 TI - miR-124 downregulates BACE 1 and alters autophagy in APP/PS1 transgenic mice. AB - One role of BACE 1 (Beta-site amyloid precursor protein cleaving enzyme 1) is to cleave the sequential amyloid precursor protein (APP) into beta-Amyloid (Abeta), the accumulation of which is an important participant in the formation of the amyloid plaques and neurofibrillary tangles of Alzheimer's disease (AD). Our previous study showed BACE 1, the potential functional downstream target of miR 124, to be connected to cell death in AD cell models. Recent studies have shown that autophagy is altered in AD, however, as to whether miR-124 is involved in this alteration is not clear. In this study, 7-month-old APP/PS1 transgenic mice were transfected with miR-124 lentiviral vectors, injected bilaterally into the dentate gyrus (DG) of mice hippocampi. Following 7 days of recovery, both behavior and biochemical pathology tests were implemented. The results demonstrated learning ability improvement and specific AD pathology alleviation. Meanwhile there was down-regulation of Bcl-2 to Bax ratio expression, increase in Beclin-1 and decreases in expression of LC3II, Atg5 and p62/SQSTMl. In view of this, we hypothesis that miR-124 conducts its neuroprotective effect through BACE 1 by regulation of autophagic pathways. PMID- 28867213 TI - Transgenerational pancreatic impairment with Igf2/H19 epigenetic alteration induced by p,p'-DDE exposure in early life. AB - The hypothesis of fetal origins indicates that exposures in early development could induce epigenetic modifications in the male germ-line, affecting the susceptibility of adult-onset disease for generations. p,p'-DDE, the primary metabolite of persistent organochlorine pesticide DDT, is highly correlated with impaired glucose tolerance (IGT) and a strong contributing factor to type 2 diabetes. In our previous study, ancestral p,p'-DDE exposure could induce transgenerational impaired male fertility with sperm Igf2 hypomethylation. It is still unknown whether this germline epigenetic defect would affect the somatic tissue endocrine pancreas. Gestating F0 generation females were exposed to p,p' DDE from gestation day 8 to 15. The F1 male offspring were mated with female to produce F2 progeny. F3 generation was obtained by intercrossing the control and treated male and female of F2 generation and divided as C?-C?, DDE?-DDE?, DDE?-C? and C?-DDE?. Results indicated that F1 offspring in p,p'-DDE group exhibited impaired glucose tolerance (IGT), abnormal insulin secretion, beta-cell dysfunction and altered Igf2 and H19 expression induced by Igf2/H19 hypomethylation, which could be transferred to the F3 offspring through the male germ line. IGT and abnormal insulin secretion were more obvious in males than those in females. Ancestral p,p'-DDE exposure could induce transgenerational pancreatic impairment with Igf2/H19 epigenetic defect. PMID- 28867214 TI - Lithium chloride inhibits StAR and progesterone production through GSK-3beta and ERK1/2 signaling pathways in human granulosa-lutein cells. AB - Lithium chloride (LiCl) is a widely-used medication to treat neurological disorders that has undesirable side effects on the female reproductive system. It has been show that LiCl can inhibit ovarian folliculogenesis, promote follicle atresia and suppress steroid hormone production in rodents. However, the effects of LiCl on human ovarian steroidogenesis remain completely unknown. In this study, both primary and immortalized human granulosa-lutein (hGL) cells were used to investigate the effects of LiCl on progesterone production and its related enzyme expression as well as the underlying mechanisms. Our results showed that LiCl significantly down-regulated the steroidogenic acute regulatory protein (StAR) expression and subsequent progesterone production in hGL cells. Additionally, LiCl induced the phosphorylation of GSK-3beta and ERK1/2 but not AKT or CREB. Knockdown of endogenous GSK-3beta or inhibition of ERK1/2 partially reversed LiCl-induced down-regulation of StAR. Furthermore, by using dual inhibition approaches, the results showed that both GSK-3beta and ERK1/2 signaling mediated the regulatory effect of LiCl on StAR expression. Our findings deepen our understanding of the pathological effects and the underlying molecular mechanisms of how lithium might affect the female reproductive system. PMID- 28867215 TI - Development of a questionnaire to evaluate asthma control in Japanese asthma patients. AB - BACKGROUND: The asthma control questionnaires used in Japan are Japanese translations of those developed outside Japan, and have some limitations; a questionnaire designed to optimally evaluate asthma control levels for Japanese may be necessary. The present study was conducted to validate the Japan Asthma Control Survey (JACS) questionnaire in Japanese asthma patients. METHODS: A total of 226 adult patients with mild to severe persistent asthma were enrolled and responded to the JACS questionnaire, asthma control questionnaire (ACQ), and Mini asthma quality of life questionnaire (Mini AQLQ) at Weeks 0 and 4. The reliability, validity, and sensitivity/responsiveness of the JACS questionnaire were evaluated. RESULTS: The intra-class correlation coefficients (ICCs) were within the range of 0.55-0.75 for all JACS scores, indicating moderate/substantial reproducibility. For internal consistency, Cronbach's alpha coefficients ranged from 0.76 to 0.92 in total and subscale scores, which were greater than the lower limit of internal consistency. As for factor validity, the cumulative contribution ratio of four main factors was 0.66. For criterion related validity, the correlation coefficients between the JACS total score and ACQ5, ACQ6, and Mini AQLQ scores were -0.78, -0.78, and 0.77, respectively, showing a significant correlation (p < 0.0001). CONCLUSIONS: The JACS questionnaire was validated in terms of reliability and validity. It will be necessary to evaluate the therapeutic efficacy measured by the JACS questionnaire and calculate cutoff values for the asthma control status in a higher number of patients. CLINICAL TRIAL REGISTRATION: UMIN000016589. PMID- 28867216 TI - The effect of phosphorylation on the salt-tolerance-related functions of the soybean protein PM18, a member of the group-3 LEA protein family. AB - Enzymatically driven post-translated modifications (PTMs) usually happen within the intrinsically disordered regions of a target protein and can modulate variety of protein functions. Late embryogenesis abundant (LEA) proteins are a family of the plant intrinsically disordered proteins (IDPs). Despite their important roles in plant stress response, there is currently limited knowledge on the presence and functional and structural effects of phosphorylation on LEA proteins. In this study, we identified three phosphorylation sites (Ser90, Tyr136, and Thr266) in the soybean PM18 protein that belongs to the group-3 LEA proteins. In yeast expression system, PM18 protein increased the salt tolerance of yeast, and the phosphorylation of this protein further enhanced its protective function. Further analysis revealed that Ser90 and Tyr136 are more important than Thr266, and these two sites might work cooperatively in regulating the salt resistance function of PM18. The circular dichroism analysis showed that PM18 protein was disordered in aqueous media, and phosphorylation did not affect the disordered status of this protein. However, phosphorylation promoted formation of more helical structure in the presence of sodium dodecyl sulfate (SDS) or trifluoroethanol (TFE). Furthermore, in dedicated in vitro experiments, phosphorylated PM18 protein was able to better protect lactate dehydrogenase (LDH) from the inactivation induced by the freeze-thaw cycles than its un- or dephosphorylated forms. All these data indicate that phosphorylation may have regulatory effects on the stress-tolerance related function of LEA proteins. Therefore, further studies are needed to shed more light on functional and structural roles of phosphorylation in LEA proteins. PMID- 28867218 TI - Editor's perspectives - September 2017. PMID- 28867217 TI - In utero and lactational exposure to metformin induces reproductive alterations in male rat offspring. AB - Metformin (MET) is prescribed for the treatment of type 2 diabetes mellitus and gestational diabetes. Although MET crosses the placenta, it is considered safe throughout gestation. However, it has been shown in humans that maternal exposure to MET increases sex hormone binding globulin levels in newborns, and in rats it decreases the testosterone concentration at gestational day (GD) 16.5. Therefore, the present study evaluated if maternal exposure to MET could interfere with reproductive parameters of male offspring. Wistar female rats were treated with MET 293mg/kg/day, by gavage from GD0 to GD21 (METG) or GD0 until lactational day (LD) 21 (METGL) and the control groups received water. Sexual behavior of male offspring was affected in both MET groups. However, a decrease in the sperm count was observed only in METGL group. These results suggest that MET exposure induced alterations in reproductive parameters of male offspring in adulthood depending on exposure time. PMID- 28867219 TI - A short note on a present-day benthic recovery status in the formerly heavily polluted Idefjord (Sweden/Norway). AB - Idefjord (Skagerrak, North Sea) has had a long pollution history due to a heavy exposure to effluents from sawmills and pulp and paper industry, which had a detrimental effect on fjord life. Earlier we presented a paper on the pollution history and benthic recovery in the fjord by studying sediment geochemistry (TOC and heavy metals) and benthic foraminifera in the sediment cores taken in the inner and the outer Idefjord. At that stage the foraminiferal (~benthic recovery) record was limited to years 2000 (inner fjord) and 2002 (outer fjord), in contrast to pollutant data reaching all the way up to 2014. In this short note we extend the foraminiferal record to year 2014 and fill the gap in the benthic recovery in the inner and the outer fjord over the last 12years. The results show that both inner and outer fjord inlets currently undergo a steady benthic recovery reflected in comeback of transitional and pre-pollution benthic foraminiferal species after 2000-2002 and towards 2014. The recovery is also supported by increasing faunal diversity, low dominance and since 2000-2002 re appearance of calcareous foraminiferal species (Bulimina marginata, Elphidium spp., Epistominella vitrea, Hyalinea balthica and Lagena spp), which all disappeared during the period of maximum effluent discharges. At the same time, detection of opportunistic newcomers (e.g. Stainforthia fusiformis) and persisting absence of some transitional species such as Ammoscalaria tenuimargo suggests a recolonization by foraminiferal population with a different species composition as compared to the original pre-pollution community either due to changed environmental conditions or/and increased competition. PMID- 28867220 TI - A bibliometric analysis of global research in Oropouche. PMID- 28867221 TI - Measles and more: Apps, blogs and clips on measles outbreaks and vaccination. PMID- 28867222 TI - Inter-airway structural heterogeneity interacts with dynamic heterogeneity to determine lung function and flow patterns in both asthmatic and control simulated lungs. AB - Asthma is a disease involving both airway remodelling (e.g. thickening of the airway wall) and acute, reversible airway narrowing driven by airway smooth muscle contraction. Both of these processes are known to be heterogeneous, and in this study we consider a new theoretical model which considers the interactions of both mechanisms: structural heterogeneity (variation in airway remodelling) and dynamic heterogeneity (emergent variation in airway narrowing and flow). By integrating both types of inter-airway heterogeneity in a full human lung geometry, we are able to draw several insights regarding the mechanisms underlying observed ventilation heterogeneity. We show that: (1) bimodal ventilation distributions are driven by paradoxical contraction/dilation patterns for airways of all sizes; (2) structural heterogeneity differences between asthmatic and control subjects significantly influences resulting lung function, and observed ventilation heterogeneity patterns; and (3) individual airway dilation probabilities are uncorrelated with prior airway remodelling of that airway. PMID- 28867223 TI - Protein-protein interaction site predictions with minimum covariance determinant and Mahalanobis distance. AB - Protein-protein interaction site (PPIS) prediction must deal with the diversity of interaction sites that limits their prediction accuracy. Use of proteins with unknown or unidentified interactions can also lead to missing interfaces. Such data errors are often brought into the training dataset. In response to these two problems, we used the minimum covariance determinant (MCD) method to refine the training data to build a predictor with better performance, utilizing its ability of removing outliers. In order to predict test data in practice, a method based on Mahalanobis distance was devised to select proper test data as input for the predictor. With leave-one-validation and independent test, after the Mahalanobis distance screening, our method achieved higher performance according to Matthews correlation coefficient (MCC), although only a part of test data could be predicted. These results indicate that data refinement is an efficient approach to improve protein-protein interaction site prediction. By further optimizing our method, it is hopeful to develop predictors of better performance and wide range of application. PMID- 28867224 TI - Optional interactions and suspicious behaviour facilitates trustful cooperation in prisoners dilemma. AB - In evolutionary game theory interactions between individuals are often assumed obligatory. However, in many real-life situations, individuals can decide to opt out of an interaction depending on the information they have about the opponent. We consider a simple evolutionary game theoretic model to study such a scenario, where at each encounter between two individuals the type of the opponent (cooperator/defector) is known with some probability, and where each individual either accepts or opts out of the interaction. If the type of the opponent is unknown, a trustful individual accepts the interaction, whereas a suspicious individual opts out of the interaction. If either of the two individuals opt out both individuals remain without an interaction. We show that in the prisoners dilemma optional interactions along with suspicious behaviour facilitates the emergence of trustful cooperation. PMID- 28867225 TI - Laser microdissection hyphenated with high performance gel permeation chromatography-charged aerosol detector and ultra performance liquid chromatography-triple quadrupole mass spectrometry for histochemical analysis of polysaccharides in herbal medicine: Ginseng, a case study. AB - This study establishes a new combinatorial approach for histochemical analysis of polysaccharides in herbal medicines using laser microdissection followed by high performance gel permeation chromatography coupled with charged aerosol detector and ultra-performance liquid chromatography hyphenated with triple quadrupole mass spectrometry. Ginseng was employed as a study model. Tissue-specific qualitative and quantitative characterization of ginseng polysaccharides was performed by determining their molar masses and monosaccharide compositions in three macro-dissected parts (rhizome, main and branched roots) and five micro dissected tissues (cork, cortex, xylem, phloem and resin canal). The results showed that ginseng "flesh" (xylem, phloem and resin canal) contained more polysaccharides with larger molecular weights and higher ratios of glucose residue, whereas ginseng "skin" (cork and cortex) had fewer polysaccharides with smaller molecular weights and higher ratios of non-glucose constituents (e.g. galacturonic acid, galactose, arabinose and rhamnose). These findings suggested that the polysaccharides of the "flesh" were predominantly starch-like glucans, while those of the "skin" were of a higher proportion of acidic pectins. The revealed histologic distribution and accumulation pattern of ginseng polysaccharides contributes to the scientific understanding of ginseng regarding the biosynthesis and transportation of polysaccharides, medicinal quality evaluation as well as empirical clinical application. PMID- 28867226 TI - Structural analysis of a sulfated galactan from the tunic of the ascidian Microcosmus exasperatus and its inhibitory effect of the intrinsic coagulation pathway. AB - Several bioactive sulfated galactans have been isolated from the tunic of different species of ascidians. The biological activity of this kind of polysaccharides has been related with the presence and position of sulfate groups, and by the chemical composition of this kind of polysaccharides. A sulfated galactan (1000RS) was isolated from the tunic of the Brazilian ascidia Microcosmus exasperatus through proteolytic digestion, ethanol precipitation, dialysis and freeze-thaw cycles. Homogeneity and molecular weight were estimated by using size exclusion chromatography. Monosaccharide composition and type of linkage were assessed by Gas chromatography coupled to mass spectrometry and the sulfate content was quantified through gelatin/BaCl2 method. These experiments along with NMR and FTIR analysis allowed to claim that the galactan backbone is mainly composed of 4-linked alpha-l-Galp units. In addition, they permitted to establish that some of the galactose residues are sulfated at the 3-position. This sulfated polysaccharide, which has an average molecular mass of 439.5kDa, presents anticoagulant effect in a dose-dependent manner through the inhibition of the intrinsic coagulation pathway. PMID- 28867227 TI - Improving the stability of chondroitinase ABC I via interaction with gold nanorods. AB - Chondroitinase ABC I (cABC I) cleaves glycosaminoglycan chains which are responsible for most of the inhibition of axon regrowth in spinal cord injury. The application of chondroitinase ABC I (cABC I) in damaged nervous tissue is found to prune glycosaminoglycan chains of proteoglycans and facilitate axon regeneration. However, a limiting factor for such application is the enzyme's instability. In this study, the structure and activity of cABC I have been investigated upon interaction with various concentrations of Gold nanorods. The enzyme preserved its major activity with increase in substrate affinity in the presence of the nanostructures. Analysis of circular dichroism spectropolarimetry data showed that secondary structural content of the enzyme slightly increased. The complex form of the enzyme also showed higher storage stability. Fluorescence studies indicated that enzyme obtained more rigidity in its structure. Taking higher stability of enzyme upon interaction, result of this investigation interaction paves the way for utilizing tiny plasmonic nanostructures for fruitful applications in biomedicine. PMID- 28867228 TI - Chitosan-titanium dioxide-glucantime nanoassemblies effects on promastigote and amastigote of Leishmania major. AB - The purpose of the present study was to design nanoassemblies of chitosan titanium dioxide (TiO2) nanoparticles (NPs) loaded with glucantime for using their synergistic effects and enhancing the toxic effects of glucantime on Leishmania parasites. The nanoassemblies were prepared by electrostatic interactions and optimized by a response surface central composite design. The effects of glucantime, chitosan and TiO2 NPs amounts were studied on the particle size, zeta potential, loading efficiency, and release efficiency of drug from nanoassemblies. The conjugation of TiO2/chitosan-glucantime was verified by UV spectroscopy and changes in surface charge of NPs. The anti-promastigots effect of glucantime loaded in TiO2/chitosan nanoassemblies was studied by tripan blue dye test and their anti-amastigotes effect by counting the average number of parasites per infected J774 macrophages in 100 cells. The optimized formulation obtained by using 12.5mg glucantime, 25mg chitosan and 6mg TiO2 NPs. Although TiO2 NPs alone were effective more than negative control in reduction of promastigots and amastigotes but they didn't show significant difference compared with free glucantime (p>0.05). However, at the concentration of 50MUg/mL and after 72h exposure nanoassemblies decreased the proliferation of L. major promastigotes and amastigotes 13 and 4-fold, respectively compared with glucantime alone. PMID- 28867229 TI - Efficient removal of anionic dye (Congo red) by dialdehyde microfibrillated cellulose/chitosan composite film with significantly improved stability in dye solution. AB - A novel composite film with efficient removal of anionic dye (Congo red) was developed using chitosan and dialdehyde microfibrillated cellulose nano fibrils. Microfibrillated cellulose with three dimensional network structure was prepared from microcrystalline cellulose by high-pressure homogenization. Then it was surface modified by periodate to prepare dialdehyde microfibrillated cellulose (DAMFC). DAMFC/chitosan composite films were prepared by solvent-casting. During the compounding of DAMFC with chitosan, a Schiff base was formed through the reaction between the aldehyde groups of DAMFC and amino groups of chitosan. A giant network structure was therefore formed. The addition of DAMFC resulted in remarkably increased adsorption capacity of the chitosan material as well as drastically improved stability in dye solution. The adsorption performance was investigated with respect to pH, temperature, contact time, and the initial dye concentration. The possible adsorption mechanism was proposed. Various isotherm models have been used to fit the data, and kinetic parameters were evaluated. PMID- 28867230 TI - Studies on structure and antioxidant properties of a heteroglycan isolated from wild edible mushroom Lentinus sajor-caju. AB - A water-soluble heteroglycan (PS-I) isolated from the aqueous extract of a wild edible mushroom Lentinus sajor-caju showed average molecular weight ~1.79*105Da. The structure of the polysaccharide was determined using chemical and 1D/2D NMR experiments. Acid hydrolysis indicated the presence of d-glucose, d-galactose, d mannose, and l-fucose in a molar ratio of nearly 4:4:1:1 respectively. The presence of terminal Fucp, terminal Galp, (1->3)-Glcp, (1->6)-Galp, (1->6)-Glcp, (1->4,6)-Galp, and (1->2,4)-Manp moieties were established from methylation analysis. The chemical and NMR analyses indicated that the PS-I was a heteroglycan composed of a repeating unit with backbone chain of three (1->6) alpha-d-galactopyranosyl residues, two (1->6)-beta-d-glucopyranosyl residues, one (1->4)-alpha-d-mannopyranosyl residue, and two (1->3)-beta-d-glucopyranosyl residues where one (1->6)-alpha-d-galactopyranosyl residue was branched at O-4 position with terminal alpha-l-fucopyranosyl residue and (1->4)-alpha-d mannopyranosyl residue was branched at O-2 position with terminal alpha-d galactopyranosyl residue and the structure was proposed as; The PS-I is a moderate antioxidant compound which showed DPPH radical scavenging activity, hydroxyl radical scavenging activity, ABTS radical scavenging property, reducing power, and ferrous ion chelating ability. PMID- 28867231 TI - Protective effects of polysaccharide from Dendrobium nobile against ethanol induced gastric damage in rats. AB - Dendrobium nobile is a medicinal herb in traditional China and Southeast Asian countries. Employing a rat model of ethanol-induced gastric ulcer, we examined the protective effect of polysaccharide (JCP) extracted from Dendrobium nobile and explored the related mechanisms. Oral administration with 100mg/kg and 300mg/kg body weight JCP for days can significant prevent the formation of gastric ulcer. Moreover, JCP pretreatment could alleviate ethanol-induced histological damage, antioxidant activities, the level of epidermal growth factor, gastric concentration of prostaglandin E, and regulate the signaling pathways of mitogen-activated protein kinases and matrix metalloproteinases. This study investigated the ethanol-induced gastric ulcer protective effect of JCP for the first time, and elucidated that the protective mechanisms. PMID- 28867232 TI - New composite materials prepared by calcium phosphate precipitation in chitosan/collagen/hyaluronic acid sponge cross-linked by EDC/NHS. AB - Nowadays, fabrication of composite materials based on biopolymers is a rising field due to potential for bone repair and tissue engineering application. Blending of different biopolymers and incorporation of inorganic particles in the blend can lead to new materials with improved physicochemical properties and biocompatibility. In this work 3D porous structures called scaffolds based on chitosan, collagen and hyaluronic acid were obtained through the lyophilization process. Scaffolds were cross-linked by EDC/NHS. Infrared spectra for the materials were made, the percentage of swelling, scaffolds porosity and density, mechanical parameters, thermal stability were studied. Moreover, the scaffolds were used as matrixes for the calcium phosphate in situ precipitation. SEM images were taken and EDX analysis was carried out for calcium and phosphorous content determination in the scaffold. In addition, the adhesion and proliferation of human osteosarcoma SaOS-2 cells was examined on obtained scaffolds. The results showed that the properties of 3D composites cross-linked by EDC/NHS were altered after the addition of 1, 2 and 5% hyaluronic acid. Mechanical parameters, thermal stability and porosity of scaffolds were improved. Moreover, calcium and phosphorous were found in each kind of scaffold. SEM images showed that the precipitation was homogeneously carried in the whole volume of samples. Attachment of SaOS-2 cells to all modified materials was better compared to unmodified control and proliferation of these cells was markedly increased on scaffolds with precipitated calcium phosphate. Obtained materials can provide the support useful in tissue engineering and regenerative medicine. PMID- 28867233 TI - Preparation and biocompatibility of crosslinked poly(3-hydroxyundecenoate). AB - A sticky polymer, poly(3-hydroxyundecenoate) (PHU), was produced by Pseudomonas oleovorans when nonanoate and undecenoate were used as carbon sources. Crosslinked PHU (CL-PHU) was prepared by heating using benzoyl peroxide as a crosslinker. According to the degree of crosslinking in the polymer, three types of CL-PHU were prepared: CL-PHU50, CL-PHU60 and CL-PHU70. Fourier transform infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry results suggested that crosslinking of PHU was successfully achieved by heat, which increased the crosslinking density and decreased stiffness and flexibility of the polymer. Water contact angle measurements revealed no differences of hydrophilicity as the crosslinking density. Slight morphological changes of CL-PHU film surfaces were observed by atomic force microscopy. Chinese hamster ovary cells were used to investigate the biocompatibility of CL-PHU films using poly(l-lactide) surfaces as control. Surface properties of the film, such as roughness and adhesive force, enhanced the adhesion and proliferation of cells on the films. CL-PHU might be useful for cell compatible biomedical applications. PMID- 28867235 TI - Optimization of angelica sinensis polysaccharide-loaded Poly (lactic-co glycolicacid) nanoparticles by RSM and its immunological activity in vitro. AB - In this study, angelica sinensis polysaccharide (ASP) was encapsulated into the Poly (lactic-co-glycolicacid) (PLGA) to constitute the ASP-PLGA. The aim of the study is to obtain optimal encapsulation efficiency of ASP-PLGA by optimizing the preparation conditions and investigate the immunological enhancement activity of ASP-PLGA. To obtain the optimal processing parameters, the parameters, such as the ratio of organic phase (o) to internal water phase (w1), the ratio of external water phase (w2) to organic phase (o) and the concentration of Pluronic F68 (F68) (w/v) were examined through response surface methodology (RSM). The optimum preparation conditions of ASP-PLGA for maximizing encapsulation efficiency (EE) was as follows:ratio of organic phase (o) to internal water phase (w1) at 10:1, ratio of external water phase (w2) to organic phase (o) at 11:1, the concentration of F68 at 0.8% and the experimental EE 67.89+/-0.48% was achieved. In addition, the results showed that ASP-PLGA could significantly promote the lymphocytes proliferation and increase the ratio of CD4+ to CD8+ T cells compared with ASP and blank PLGA. This study provided strong evidence that the immunological enhancement of ASP was significantly improved through establishing a drug delivery system with PLGA. PMID- 28867234 TI - Structural studies and nociceptive activity of a native lectin from Platypodium elegans seeds (nPELa). AB - A native lectin (nPELa), purified from seeds of the species Platypodium elegans, Dalbergieae tribe, was crystallized and structurally characterized by X-ray diffraction crystallography and bioinformatics tools. The obtained crystals diffracted to 1.6A resolution, and nPELa structure were solved through molecular substitution. In addition, nPELa has a metal binding site and a conserved carbohydrate recognition domain (CRD) similar to other Dalbergieae tribe lectins, such as PAL (Pterocarpus angolensis) and CTL (Centrolobium tomentosum). Molecular docking analysis indicated high affinity of this lectin for different mannosides, mainly trimannosides, formed by alpha-1,3 or alpha-1,6 glycosidic bond, as evidenced by the obtained scores. In addition, molecular dynamics simulations were performed to demonstrate the structural behavior of nPELa in aqueous solution. In solution, nPELa was highly stable, and structural modifications in its carbohydrate recognition site allowed interaction between the lectin and the different ligands. Different modifications were observed during simulations for each one of the glycans, which included different hydrogen bonds and hydrophobic interactions through changes in the relevant residues. In addition, nPELa was evaluated for its nociceptive activity in mice and was reported to be the first lectin of the Dalbergieae tribe to show CRD-dependent hypernociceptive activity. PMID- 28867236 TI - The Refractory Endometrium is Still Refractory. PMID- 28867237 TI - [Neurosyphilis: A retrospective study of 13 cases at Strasbourg University Hospital]. AB - OBJECTIVE: After a decade of constant decline, the number of syphilis cases has been steadily increasing since the 2000s, particularly in HIV infected patients. Neurosyphilis is a rare manifestation of this sexually transmitted disease for which we performed a retrospective study and analyzed clinical manifestations. PATIENTS AND METHODS: We reviewed retrospectively all the neurosyphilis cases admitted to Strasbourg University Hospital between 2004 and 2014. We included and analyzed 13 patients admitted during this period who met the diagnostic criteria for neurosyphilis. RESULTS: Nine of 13 patients had isolated visual manifestations; three (23.1%) experienced posterior uveitis, two (15.4%), panuveitis, and 4 (30.8%) had papillitis. Out of five patients (38.5%) who were HIV positive, three (60%) had a CD4 cell count above 400/mm3 at the time of diagnosis of neurosyphilis. All patients received parenteral penicillin G or cephalosporin, and 5/13 (38.5%) received systemic corticotherapy. CONCLUSION: Ophthalmologists appear as key players in the identification, management and follow-up of neurosyphilis, since ocular findings are key diagnostic features in these patients. PMID- 28867238 TI - Energy evaluation of low-level control in UAVs powered by lithium polymer battery. AB - Nowadays, the energetic cost of flying in electric-powered UAVs is one of the key challenges. The continuous evolution of electrical energy storage sources is overcome by the great amount of energy required by the propulsion system. Therefore, the on-board energy is a crucial factor that needs to be further analyzed. In this work, different control strategies applied to a generic UAV propulsion system are considered and a lithium polymer battery dynamic model is included as the propulsion system energy source. Several simulations are carried out for each control strategy, and a quantitative evaluation of the influence of each control law over the actual energy consumed by the propulsion system is reported. This energy, which is delivery by the battery, is next compared against a well-known control-effort-based index. The results and analysis suggest that conclusions regarding energy savings based on control effort signals should be drawn carefully, because they do not directly represent the actual consumed energy. PMID- 28867239 TI - Pole-placement Predictive Functional Control for under-damped systems with real numbers algebra. AB - This paper presents the new algorithm of PP-PFC (Pole-placement Predictive Functional Control) for stable, linear under-damped higher-order processes. It is shown that while conventional PFC aims to get first-order exponential behavior, this is not always straightforward with significant under-damped modes and hence a pole-placement PFC algorithm is proposed which can be tuned more precisely to achieve the desired dynamics, but exploits complex number algebra and linear combinations in order to deliver guarantees of stability and performance. Nevertheless, practical implementation is easier by avoiding complex number algebra and hence a modified formulation of the PP-PFC algorithm is also presented which utilises just real numbers while retaining the key attributes of simple algebra, coding and tuning. The potential advantages are demonstrated with numerical examples and real-time control of a laboratory plant. PMID- 28867240 TI - New strategies for targeting and treatment of multi-drug resistant Staphylococcus aureus. AB - Staphylococcus aureus is a major cause of bacterial infection in humans, and has been notoriously able to acquire resistance to a variety of antibiotics. An example is methicillin-resistant S. aureus (MRSA), which despite having been initially associated with clinical settings, now is one of the key causative agents of community-acquired infections. Antibiotic resistance in S. aureus involves mechanisms ranging from drug efflux to increased expression or mutation of target proteins, and this has required innovative approaches to develop novel treatment methodologies. This review provides an overview of the major mechanisms of antibiotic resistance developed by S. aureus, and describes the emerging alternatives being sought to circumvent infection and proliferation, including new generations of classic antibiotics, synergistic approaches, antibodies, and targeting of virulence factors. PMID- 28867241 TI - Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance. AB - Intrinsic anticancer drug resistance appearing prior to chemotherapy as well as acquired resistance due to drug treatment, remain the dominant impediments towards curative cancer therapy. Hence, novel targeted strategies to overcome cancer drug resistance constitute a key aim of cancer research. In this respect, targeted nanomedicine offers innovative therapeutic strategies to overcome the various limitations of conventional chemotherapy, enabling enhanced selectivity, early and more precise cancer diagnosis, individualized treatment as well as overcoming of drug resistance, including multidrug resistance (MDR). Delivery systems based on nanoparticles (NPs) include diverse platforms enabling a plethora of rationally designed therapeutic nanomedicines. Here we review NPs designed to enhance antitumor drug uptake and selective intracellular accumulation using strategies including passive and active targeting, stimuli responsive drug activation or target-activated release, triggered solely in the cancer cell or in specific organelles, cutting edge theranostic multifunctional NPs delivering drug combinations for synergistic therapy, while facilitating diagnostics, and personalization of therapeutic regimens. In the current paper we review the recent findings of the past four years and discuss the advantages and limitations of the various novel NPs-based drug delivery systems. Special emphasis is put on in vivo study-based evidences supporting significant therapeutic impact in chemoresistant cancers. A future perspective is proposed for further research and development of complex targeted, multi-stage responsive nanomedical drug delivery systems for personalized cancer diagnosis and efficacious therapy. PMID- 28867243 TI - A mechanopharmacology approach to overcome chemoresistance in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly chemoresistant malignancy. This chemoresistant phenotype has been historically associated with genetic factors. Major biomedical research efforts were concentrated that resulted in the identification of subtypes characterized by specific genetic lesions and gene expression signatures that suggest important biological differences. However, to date, these distinct differences could not be exploited for therapeutic interventions. Apart from these genetic factors, desmoplasia and tumor microenvironment have been recognized as key contributors to PDAC chemoresistance. However, while several strategies targeting tumor-stroma have been explored including drugs against members of the Hedgehog family, they failed to meet the expectations in the clinical setting. These unsatisfactory clinical results suggest that, an important link between genetics and the influence of tumor microenvironment on PDAC chemoresistance remains to be elucidated. In this respect, mechanobiology is an emerging multidisciplinary field that encompasses cell and developmental biology as well as biophysics and bioengineering. Herein we provide a comprehensive overview of the key players in pancreatic cancer chemoresistance from the perspective of mechanobiology, and discuss novel experimental avenues such as elastic micropillar arrays that could provide fresh insights for the development of mechanobiology-targeted therapeutic approaches (know as mechanopharmacology) to overcome anticancer drug resistance in pancreatic cancer. PMID- 28867244 TI - Angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers in acute ST-segment elevation myocardial infarction patients with diabetes mellitus undergoing percutaneous coronary intervention. AB - BACKGROUND: Diabetes Mellitus (DM) is an important factor of adverse cardiovascular events in acute ST-segment elevation myocardial infarction (STEMI) patients. Renin-angiotensin-aldosterone system (RAAS) inhibitors is associated with improved clinical outcomes, however, there are limited data comparing the effectiveness of two different RAAS inhibitors in STEMI patients with DM undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS: A total of 3811 eligible STEMI patients with DM were enrolled in Korea Acute Myocardial Infarction Registry (KAMIR). They were stratified into two groups: Angiotensin converting enzyme inhibitors (ACEI) group (n=2691) and angiotensin receptor blockers (ARB) group (n=1120). To adjust baseline confounding factors, we performed propensity score matching (PSM) analysis and evaluated individual and composite major clinical outcomes between the two groups up to 2years. RESULTS: After PSM, a total of 1049 well-matched pairs were generated. Baseline clinical, angiographic and procedural characteristics were well-balanced between the two groups. The incidence of death, recurrent myocardial infarction (MI), revascularization and major adverse cardiac events (MACE) were not significantly different between the two groups up to 2years, CONCLUSION: In the present study, ACEI and ARB showed comparable effectiveness and safety on individual and composite clinical outcomes in STEMI patients with DM who underwent successful PCI with DES at least up to 2years. PMID- 28867242 TI - Can microbial cells develop resistance to oxidative stress in antimicrobial photodynamic inactivation? AB - Infections have been a major cause of disease throughout the history of humans on earth. With the introduction of antibiotics, it was thought that infections had been conquered. However, bacteria have been able to develop resistance to antibiotics at an exponentially increasing rate. The growing threat from multi drug resistant organisms calls for intensive action to prevent the emergence of totally resistant and untreatable infections. Novel, non-invasive, non-antibiotic strategies are needed that act more efficiently and faster than current antibiotics. One promising alternative is antimicrobial photodynamic inactivation (APDI), an approach that produces reactive oxygen species when dyes and light are combined. So far, it has been questionable if bacteria can develop resistance against APDI. This review paper gives an overview of recent studies concerning the susceptibility of bacteria towards oxidative stress, and suggests possible mechanisms of the development of APDI-resistance that should at least be addressed. Some ways to potentiate APDI and also to overcome future resistance are suggested. PMID- 28867245 TI - Proposal of a novel clinical score to predict heart failure incidence in long term survivors of acute coronary syndromes. AB - INTRODUCTION: HF remains a frequent complication following MI and adversely affects prognosis. The objective of this study was to identify predictors of HF following MI and to design a risk score for its prediction. METHODS: Retrospective study of all consecutive patients admitted for MI. Primary end point was time to incident HF. Patients with previous history of HF were excluded. Death was modelled as competing risk. RESULTS: 5737 patients were included. Mean age was 66.32+/-12.80. During a median follow-up of 47.0months (23.0-73.0), 686 patients (12%) developed HF. Age, diabetes mellitus, peripheral artery disease, renal insufficiency, chronic obstructive pulmonary disease, persistent atrial fibrillation, haemoglobin, troponin peak, diuretic at admission, ventricular function, and revascularization were independent predictors for HF development. According to this multivariate regression analysis, we developed a novel score that allows for the identification of patients at high (>=16), medium (9-15) and low risk (<9) for HF development, with an AUC of 0.77 (IC 95%, 0.76-0.78; p=0.008). CONCLUSIONS: Clinical comorbidities were determinant for the development of HF following MI. A simple score effectively categorize patients into low, intermediate, and high-risk. This could be important in order to intensify medical treatment or consider additional interventions. PMID- 28867246 TI - Response to the Letter to the Editor regarding ''Statistical verification on the effect of hearing loss on speech-evoked auditory brainstem response''. PMID- 28867247 TI - Yin Yang-1 suppresses pancreatic ductal adenocarcinoma cell proliferation and tumor growth by regulating SOX2OT-SOX2 axis. AB - The transcription regulator Yin Yang-1 (YY1) serves as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). However, the function of YY1 in proliferation of PDAC cells remains to be clarified. In this study, we found that overexpression of YY1 suppressed proliferation and decreased the expression of long non-coding RNA (lncRNA) SOX2OT and its potential target gene SOX2 in PDAC cells. Luciferase reporter, electrophoretic mobility shift (EMSA), and chromatin immunoprecipitation (ChIP) assays revealed binding of YY1 to the SOX2OT promoter. Moreover, YY1 suppressed PDAC cell proliferation through SOX2OT transcriptional inhibition and subsequent decreased SOX2 expression. In addition, YY1 expression was statistically negatively correlated with SOX2OT and SOX2 expression in PDAC tissues and lower level expression of SOX2OT predicted better outcome in PDAC patients. These results confirmed the anti-proliferation effect of YY1 on PDAC cells, which was associated with SOX2 down-regulation in a SOX2OT-dependent mechanism. Although other undiscovered mechanisms may be involved in the YY1 mediated tumor suppression role, the present study suggests that SOX2OT may act as a tumor promotor in PDAC and may represent a valuable diagnostic and therapeutic target. PMID- 28867248 TI - Roles of RNA methylation by means of N6-methyladenosine (m6A) in human cancers. AB - Reversible methylation by means of N6-methyladenosine (m6A) is the most prevalent internal modification in mammalian mRNA. This RNA chemical mark is created by proteins that are m6A "writers" and can be reversed by proteins that are m6A "erasers" (i.e., demethylases). Some other proteins serving as "readers" can recognize m6A-containing mRNA and regulate downstream molecular mechanisms accordingly. Although m6A bases in RNA perform critical functions in important biological processes, their roles in cancer biology and cancer stem cells remain largely unknown. In this review, we focus on the m6A-associated mechanisms and modification landscapes in several major malignant tumors. Global and detailed analyses were both conducted on relevant high-throughput sequencing data. Possible interventions against m6A demethylases are also explored in this review, which may be advantageous for the treatment of m6A related cancers. PMID- 28867250 TI - Extensor Retinaculum Reconstruction Using the Wide-Awake Approach. AB - De Quervain tenosynovitis is often treated by simple release of the first compartment. However, patients can suffer from persistent postoperative problems, including "clumsy" use of the thumb, as a result of redislocation or bowstringing of the extensor pollicis brevis/abductor pollicis longus tendons or irritation of the superficial branch of the radial nerve. Here we describe our method for first compartment reconstruction, in which the flaps are sutured after double-flap incision of the compartment. Because the tendons can become recompressed or redislocate if the sutures are too tight or loose, respectively, we achieve proper tension by suturing the flaps with the patient fully awake, under local anesthesia, and without a tourniquet. This allows the patient to actively move the thumb during the procedure, in turn enabling the surgeon to confirm the presence or absence of dislocation or stenosis. We describe the details of the local anesthesia, compartment incision and reconstruction, and how to avoid disturbing the superficial branch of the radial nerve in patients with de Quervain tenosynovitis during surgery. These procedures can be broadly applied without the need for specialized equipment and can be used for a variety of different procedures in which intraoperative surgical judgment is required to optimize function. PMID- 28867249 TI - Night Orthosis After Surgical Correction of Dupuytren Contractures: A Systematic Review. AB - PURPOSE: To determine the role of night orthosis use after surgical correction of Dupuytren contracture. METHODS: We searched MEDLINE, EMBASE, CINAHL, AMED, OTSeeker, and CENTRAL for articles published from inception of the databases to August 2015. Assessment was undertaken by 2 independent reviewers (O.A.S. and S.A.). Methodological quality of randomized controlled trials was assessed using the Cochrane risk of bias tool and the Newcastle-Ottawa instrument. RESULTS: Seven studies met the standard for inclusion in this review. A total of 659 patients across these 7 studies were included in the analysis, with follow-up ranging from 3 to 72 months. None of the included studies assessed recurrence. The analysis revealed no significant improvement in range of motion of hand joints for patients who received a static night orthosis after Dupuytren surgery compared with patients without an orthosis. Similarly, no differences were found in patient-reported functional status across the 2 groups. CONCLUSIONS: The current literature does not appear to support the use of static night orthosis in addition to hand therapy after surgical correction of Dupuytren contracture. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28867251 TI - Dorsal Plate Fixation of Scapular Fracture. AB - Scapular fractures are uncommon injuries. When they occur, they are usually treated nonsurgically. However, certain indications remain for operative intervention for the treatment of these injuries. In this article, we review some operative indications as well as the surgical technique. We present a case to demonstrate the indications and surgical technique of treatment. As with most surgical approaches, technique is critical to minimize morbidity and maximize functional outcome. Using these techniques, operative management of scapular fractures can be successful. PMID- 28867252 TI - Genetics of human autoimmunity: From genetic information to functional insights. AB - Genome-wide association studies have identified hundreds of risk variants associated with human autoimmune diseases. Recent evidence suggests that a substantial portion of them affect gene expression in specific cell types. To obtain the functional insights of GWAS findings, comprehensive characterization of genetic variants in human genome is a key task. In parallel with GWAS, many researches in functional genomics have been conducted in the past decade, and our understandings of cell type-specific gene regulatory system have been substantially improved. In this review, we will introduce the main research topics in functional genomics, and explain their utility to understand biological mechanisms of autoimmune diseases. PMID- 28867254 TI - The sneaking ligand approach for cell type-specific modulation of intracellular signalling pathways. AB - Small molecules interfering with intracellular signalling pathways are used in the treatment of multiple diseases including RA. However, small molecules usually affect signalling in most cell types, not only in those which need to be targeted. This general inhibition of signalling pathways causes often adverse effects, which could be avoided by cell type-specific inhibitors. For cell-type specific modulation of signal transduction, we developed the sneaking ligand fusion proteins (SLFPs). SLFPs contain three domains: (1) the binding domain mediating cell type-specific targeting and endocytosis; (2) the endosomal release sequence releasing the effector domain into the cytoplasm; (3) the effector domain modulating signalling. Using our SLFP NF-kappaB inhibitor termed SLC1 we demonstrated that cell-type-specific modulation of intracellular signalling pathways is feasible, that endothelial NF-kappaB activation is critical for arthritis and peritonitis and that SLFPs help to identify disease-relevant pathways in defined cell types. Hence, SLFPs may improve risk-benefit ratios of therapeutic interventions. PMID- 28867255 TI - Editorial overview: Membranes. PMID- 28867253 TI - Estrogen decreases tight junction protein ZO-1 expression in human primary gut tissues. AB - Females have a higher prevalence of most autoimmune diseases; however, the mechanism is unknown. In this study, we examined the expression of tight junction protein zonula occludens 1 (ZO-1) and estrogen receptor (ER)-alpha/beta in human primary gut tissues by immunohistochemistry, immunofluorescence and qPCR. The expression of ZO-1 and ER-beta but not ER-alpha was present in both male and female gut tissues. There was no sex difference in ER-beta expression, but ZO-1 expression was decreased in females compared to males. In vitro, estrogen treatment decreased ZO-1 mRNA and protein expression, ZO-1 promoter activity, IL 6 production, and NF-kappaB activation in human primary gut tissues or the Caco-2 cells, but increased the ER-beta expression in Caco-2 cells. Consistently, plasma IL-6 levels in females were reduced relative to males in vivo. Our finding indicates that estrogen may play a role in gut tight junction expression and permeability. PMID- 28867256 TI - Timing of Intubation in Acute Respiratory Failure Associated With Sepsis: A Mixed Methods Study. AB - OBJECTIVE: To analyze bedside clinicians' perspectives regarding the decision process to optimize timing of intubation in sepsis-associated acute respiratory failure. PARTICIPANTS AND METHODS: This mixed methods study was conducted from March 1, 2015, through June 30, 2016. Using qualitative research methods, factors that influenced variability in the decision to intubate were organized into categories and used to build a theoretical explanatory model grounded in current practice variance. All coding schemes were independently reviewed for accuracy and consistency. Themes and findings were then refined with member checking by feedback from individuals and from an anonymous questionnaire until saturation was achieved. RESULTS: The practice of intubation varied according to 3 domains: (1) patient factors included the nature of the acute illness, comorbidities, clinical presentation, severity, trajectory, and values and preferences; (2) clinician factors included background, training, experience, and practice style; and (3) system factors included workload, policies and protocols, hierarchy, communications, culture, and team dynamics. In different contexts, intubation was considered early (elective), just in time (urgent), or late (rescue). The initial assessment, initial decision, and reassessment mattered. CONCLUSION: Recognizing that the variability in both the decision to intubate and its timing depends on many factors, and not on clinical criteria alone, should render the clinician more attentive to the eventual progression of the acute respiratory failure. PMID- 28867257 TI - Oropharyngeal candidiasis prevalence among HIV-infected patients at the teaching hospital of Treichville (Abidjan, Cote d'Ivoire). AB - AIM OF THE STUDY: The aim of this study was to determine the mycological profile of oropharyngeal candidiasis among HIV-infected patients from Internal Medicine, Infectious and Tropical Diseases, and Pneumo-Phthisiology Diseases departments of the Teaching Hospital of Treichville in Abidjan, Cote d'Ivoire. PATIENTS AND METHODS: This was a cross-sectional study carried out on patients with lesions suggestive of oropharyngeal candidiasis from October 2010 to April 2011. Oral swabs were cultured, and Candida species were identified using a germ tube test, a chlamydospore formation assay, and the API 20C system. RESULTS: A total of 286 patients were included, among whom 99.1% were infected with HIV. The prevalence of oropharyngeal candidiasis was 79.4% (CI95%=74.4-83.8). Five different species of Candida were identified, with the predominant species being Candida albicans (95.2%). Most affected patients were female (54.6%, P<0.0001) between the ages of 30 and 45 (78.4%, P<0.0001). The most lesion types observed were thrush (87.8%). Patients infected with HIV1 (95.6%), with a primary school level of education (52.8%), under antiretroviral therapy (88.5%) and with tuberculosis as an associated pathology (62.5%) were the most commonly affected. Patients were mostly under ART first line treatment (86.4%) and at the beginning of the treatment (86.4%). CONCLUSION: Oropharyngeal candidiasis is frequent among HIV infected patients. Better and early management of this vulnerable population should allow for a reduction in the high prevalence observed. PMID- 28867258 TI - Risk factors for suboptimal drug concentration of posaconazole oral suspension in patients with hematologic malignancy. AB - Absorption of posaconazole oral suspension is influenced by several factors including diet, medications, and mucosal integrity. However, there are few prospective data about which is the most important modifiable factor in routine clinical practice. We prospectively analyzed clinical risk factors associated with low posaconazole trough concentrations in 114 patients receiving anticancer chemotherapy due to acute myeloid leukemia or myelodysplastic syndrome who received posaconazole oral suspension. In multivariate analyses, risk factors for drug level<500ng/mL included low calorie intake, mucositis>=grade 2, H2 blocker famotidine and proton-pump inhibitor. The only significant risk factor for drug level<700ng/mL was famotidine use (adjusted relative risk, 3.18; 95% confidence interval, 1.07-9.11; P=0.038). In conclusion, medication of H2 blocker famotidine should be cautious in patients with hematologic malignancy receiving posaconazole suspension. PMID- 28867259 TI - Early and Late CNS Inflammation in Alzheimer's Disease: Two Extremes of a Continuum? AB - In 1990 it was reported that individuals receiving NSAIDs (non-steroidal anti inflammatory drugs) showed a markedly reduced prevalence of Alzheimer's disease (AD) compared to the overall population. Large epidemiological studies corroborated this assertion and provoked numerous prospective AD clinical trials with a variety of NSAIDs, all of which demonstrated lack of efficacy. It is postulated that the explanation for the success of NSAIDS in preventing AD onset when given at preclinical stages, and for their failure when administered after AD clinical presentation, lies in the changing nature of central nervous system (CNS) inflammation in the decades-long continuum of AD pathology. Early disease aggravating CNS inflammation might start decades before the presentation of severe cognitive impairments or dementia, and the nature of this process will co evolve with the neuropathological progression from preclinical to clinical AD stages. This early CNS inflammation should be considered a promising therapeutic target as we continue searching for an unequivocal diagnosis of AD preclinical stages. PMID- 28867260 TI - Screening for ADHD in adults with cystic fibrosis: Prevalence, health-related quality of life, and adherence. AB - BACKGROUND: International guidelines recommend depression and anxiety screening in individuals with cystic fibrosis (CF), but Attention-Deficit Hyperactivity Disorder (ADHD) remains understudied. METHODS: Adults with CF (n=53) were screened using the Adult ADHD Self-Report Scale-v1.1 Symptom Checklist (ASRS v1.1), Cystic Fibrosis Questionnaire-Revised (CFQ-R), and a self-report measure of treatment adherence. RESULTS: Elevated ADHD symptoms on the ASRS-v1.1 screener were reported by 15% of participants. Self-reported adherence, Body Mass Index in kg/m2 (BMI), and Forced Expiratory Volume in 1 Second, Percent Predicted (FEV1%pred) did not differ between participants with vs. without elevated ADHD scores. Three CFQ-R scales, Physical Functioning, Role Functioning, and Respiratory Symptoms, were significantly lower in participants with elevated ADHD screens (unadjusted p<0.05). This difference remained statistically significant for the Role Functioning and Respiratory Symptoms scales following correction for multiple comparisons. CONCLUSIONS: The highly specific screening tool ASRS-v1.1 can ascertain previously undetected ADHD symptoms in adults with CF. ADHD was substantially more prevalent than expected in this population. Elevated ASRS-v1.1 screens correlated with poorer Health-Related Quality of Life (HRQoL) in some domains, but not with BMI, FEV1%pred, or self-reported CF treatment adherence. Additional research will elucidate the impact of ADHD and its treatment on HRQoL, CF self-care and health outcomes. PMID- 28867261 TI - Histologically Proven Myocardial Carcinoid Metastases: The Value of Multimodality Imaging. AB - We present a case of a patient with intramyocardial metastases from a carcinoid tumor. These findings were detected using cardiovascular magnetic resonance imaging, with functional metabolic activity analyzed using nuclear imaging and confirmed by histologic findings at surgical biopsy. This case highlights the value of cardiovascular magnetic resonance imaging and the importance of multimodality imaging. PMID- 28867262 TI - Persistent Hypoxemia After Acute Myocardial Infarction: An Unexpected Culprit. AB - Hypoxemia after myocardial infarction (MI) is usually explained by common culprits, including congestive heart failure, pre-existing lung disease, and pulmonary infection. We report a case of a 60-year-old woman who experienced severe persistent hypoxemia caused by a patent foramen ovale in the setting of anterior MI complicated by a contained left ventricular rupture. PMID- 28867263 TI - Effects of Hyperthyroidism on Coronary Artery Disease: A Computed Tomography Angiography Study. AB - BACKGROUND: Changes in thyroid hormone concentration can negatively affect the cardiovascular system. Subclinical hyperthyroidism has been linked to an increase of cardiovascular heart disease, however, clinical effects and significance are still uncertain. Therefore, we analyzed coronary computed tomography angiographies of patients with overt and subclinical hyperthyroidism for quantitative parameters and plaque morphology. METHODS: Seven hundred forty-four (47.1% female) patients who underwent coronary computed tomography angiography were stratified into 3 groups: 51 patients with overt, 74 patients with subclinical hyperthyroidism, and 619 patients with euthyroidism. Analysis included grades of stenosis (no stenosis = 0, mild < 50%, intermediate 50%-70%, or high-grade > 70%) and plaque types (noncalcified, mixed, and calcified), segment involvement score (SIS), noncalcified SIS, and high-risk plaque features (napkin ring sign, low attenuation plaque, spotty calcifications, positive remodelling). RESULTS: Patients with overt and subclinical hyperthyroidism had more high-grade stenoses (39.2% vs 37.8% vs 24.2%; P = 0.007) and a higher coronary calcium score (456.5 vs 199.5 vs 155.9; P < 0.0001). Also, a total higher plaque burden has been found (SIS: 3.3 vs 3.2 vs 2.2; P < 0.0001; noncalcified SIS (1.2 vs 1.1 vs 0.6; P < 0.0001)). Patients with overt hyperthyroidism, followed by those with subclinical hyperthyroidism, had the most high-risk plaque features: napkin ring (21.6% vs 9.5% vs 6.0%, P < 0.0001), low attenuation plaque (35.3% vs 27% vs 8.7%, P < 0.0001), spotty calcification (35.3% vs 18.9% vs 19.1%, P = 0.02), and positive remodelling (37.3% vs 37.8% vs 25.5%, P = 0.02). After a mean follow-up of 168 months, significantly more revascularizations were documented for hyperthyroid patients. CONCLUSIONS: Patients with subclinical and overt hyperthyroidism showed more high-grade coronary stenoses, plaque burden, and high-risk plaque features than patients with euthyroidism, which indicates that an increase of thyroid hormones might lead to coronary vascular degeneration and plaque instability. PMID- 28867264 TI - Implantable Cardioverter-Defibrillators in Sudden Cardiac Death Survivors: Are We Doing All We Can? PMID- 28867265 TI - Implantable Cardioverter Defibrillator Implantation Rates After Out of Hospital Cardiac Arrest: Are the Rates Guideline-Concordant? AB - BACKGROUND: Clinical practice guidelines recommend implantable cardioverter defibrillators (ICDs) for the secondary prevention of sudden death after a cardiac arrest not from a reversible cause, but "real world" implantation rates are not well described. METHODS: Adults with out of hospital cardiac arrest attended by Emergency Medical Services are captured in the Toronto Regional RescuNET database. We analyzed those who survived to hospital discharge and collected data on age, sex, initial rhythm, ST-elevation myocardial infarction (STEMI) on presenting electrocardiogram (ECG), in-hospital revascularization, neurologic status (Modified Rankin Scale [MRS]) at discharge, and admission hospital type. To estimate 'indicated' ICD implantation rates, "likely ICD eligible" patients were defined as having an initial shockable rhythm, no STEMI on presenting ECG, no revascularization, and good neurologic status (MRS 0-3). "Not likely ICD-eligible" patients were defined as having a STEMI on presenting ECG, revascularization, or poor neurologic status (MRS 4-5). RESULTS: In the 1238 adults (2011-2014) analyzed, the overall ICD implantation rate was 23.9%. Two hundred fifty-six patients were "likely ICD-eligible," of whom 146 (57.0%) received an ICD. The implantation rate for "not likely ICD-eligible" patients was 16.7% (112 of 670). ICD eligibility could not be determined for 312 patients, of whom 38 (12.2%) received an ICD. Admission to a hospital with ICD implantation facilities was associated with a higher probability of ICD implantation (odds ratio, 2.85; 95% confidence interval, 1.40-5.82). CONCLUSIONS: Postcardiac arrest ICD implantation rates in eligible patients are lower than expected. Implementation strategies to monitor guideline adherence after out of hospital cardiac arrest are warranted. PMID- 28867266 TI - Low SIRT3 expression contributes to tumor progression, development and poor prognosis in human pancreatic carcinoma. AB - SIRT3, an important mitochondrial protein, may act as either an oncogene or tumor suppressor depending on the tumor-type. The aim of this study was to investigate the expression of SIRT3 in pancreatic carcinoma (PC) and its clinical association in PC patients. Immunohistochemistry was adopted to investigate the expression of SIRT3 in cancer and corrresponding adjacent non-cancer tissues across 79 patients with PC. The log-rank test and Cox hazard model were used to estimate the relationship between SIRT3 expression and prognosis. The staining results revealed that SIRT3 negative expression was more common in cancer tissues than in adjacent non-cancer tissues (P<0.001). Chi-square tests indicated that the expression of SIRT3 correlated with T status (p<0.001) and tumor stage (p=0.013). Kaplan-Meier analysis showed that negative SIRT3 expression is linked to a poor prognosis in PC patients. Multivariate analysis identified SIRT3 expression as an independent predictor for PC outcome both in the whole cohort and several subgroups of PC patients. Our results indicate that down-regulated SIRT3 may contribute to tumor progression and gloomy prognosis in PC patients and may sever as a novel prognostic marker. PMID- 28867268 TI - Control of HIV epidemic: improve access to testing and ART. PMID- 28867269 TI - Easing Concerns About the Low FODMAP Diet in Patients With Irritable Bowel Syndrome. PMID- 28867270 TI - Is a Biosimilar Interchangeable With an Originator? PMID- 28867267 TI - Testing and linkage to HIV care in China: a cluster-randomised trial. AB - BACKGROUND: Multistage, stepwise HIV testing and treatment procedures can result in lost opportunities to provide timely antiretroviral therapy (ART). Incomplete engagement of patients along the care cascade translates into high preventable mortality. We aimed to identify whether a structural intervention to streamline testing and linkage to HIV health care would improve testing completeness, ART initiation, and viral suppression and reduce mortality. METHODS: We did a cluster randomised, controlled trial in 12 hospitals in Guangxi, China. All hospitals were required to be level 2A county general hospitals and ART delivery sites. We selected the 12 most similar hospitals in terms of structural characteristics, past patient caseloads, and testing procedures. Hospitals were randomly assigned (1:1) to either the One4All intervention or standard of care. Hospitals were randomised in a block design and stratified by the historical rate of testing completeness of the individual hospital during the first 6 months of 2013. We enrolled patients aged 18 years or older who were identified as HIV-reactive during screening in study hospitals, who sought inpatient or outpatient care in a study hospital, and who resided in the study catchment area. The One4All strategy incorporated rapid, point-of-care HIV screening and CD4 counts, and in-parallel viral load testing, to promote fast and complete diagnosis and staging and provide immediate ART to eligible patients. Participants in control hospitals received standard care services. All enrolled patients were assessed for the primary outcome, which was testing completeness within 30 days, defined as completion of three required tests and their post-test counselling. Safety assessments were hospital admissions for the first 90 days and deaths up to 12 months after enrolment. This trial is registered with ClinicalTrials.gov, number NCT02084316. FINDINGS: Between Feb 24 and Nov 25, 2014, we enrolled 478 patients (232 in One4All, 246 in standard of care). In the One4All group, 177 (76%) of 232 achieved testing completeness within 30 days versus 63 (26%) of 246 in the standard-of-care group (odds ratio 19.94, 95% CI 3.86-103.04, p=0.0004). Although no difference was observed between study groups in the number of hospital admissions at 90 days, by 12 months there were 65 deaths (28%) in the in the One4All group compared with 115 (47%) in the standard-of-care group (Cox proportional hazard ratio 0.44, 0.19-1.01, p=0.0531). INTERPRETATION: Our study provides strong evidence for the benefits of a patient-centred approach to streamlined HIV testing and treatment that could help China change the trajectory of its HIV epidemic, and help to achieve the goal of an end to AIDS. FUNDING: US National Institute on Drug Abuse Clinical Trials Network and China's National Health and Family Planning Commission. PMID- 28867271 TI - Maximizing the Diagnostic Yield of Endoscopic Ultrasound-Guided Fine-Needle Aspiration Biopsy. PMID- 28867272 TI - ROCKing the Field of Intestinal Fibrosis or Between a ROCK and a Hard Place? PMID- 28867274 TI - Enhanced Reprocessing of Duodenoscopes: Is Doing More Better? PMID- 28867275 TI - Risk for Hepatocellular Carcinoma After Hepatitis C Virus Antiviral Therapy With Direct-Acting Antivirals: Case Closed? PMID- 28867276 TI - Pediatric Liver Transplantation: An Asymmetrical War for Access to Livers. PMID- 28867277 TI - Progress in PD-1-based Immunotherapy: New Mechanistic Insight May Provide Expanded Hope for Application to Colon and Gastrointestinal Cancers. PMID- 28867278 TI - Disparities Among Gastrointestinal Disorders in Research Funding From the National Institutes of Health. PMID- 28867279 TI - Investigating hominin carnivory in the Okote Member of Koobi Fora, Kenya with an actualistic model of carcass consumption and traces of butchery on the elbow. AB - Previous zooarchaeological analysis at Koobi Fora indicates that Okote Member hominins were the primary agents of bone assemblage formation, gained early access to large and small mammal flesh, and consumed both high- and low-ranked carcass parts. The discovery of additional butchered specimens prompted the re analysis presented here of three large and well-preserved zooarchaeological assemblages from the Okote member, GaJi14, FwJj14N and FwJj14S, to revisit paleoecological hypotheses about tool-assisted carnivory. Cow and goat limb butchery documenting the skeletal location of cut marks created by skinning, defleshing, and disarticulation was used to build an actualistic model to infer hominin consumption of distinct carcass resources. Archaeological specimens were assigned to early (defleshing limbs), middle (defleshing ribs, viscera, vertebrae, and head) and late (metapodial tendon removal, element disarticulation, long bone fragmentation) carcass consumption stages, and the incidence of these butchery behaviors was examined for specimens and minimum number of element and individual aggregates. Elbow specimens, where traces of defleshing, disarticulation, and percussion co-occur, offer a sequential view of carcass consumption behaviors that is free from fragmentation bias. Classification trees populated with actualistic data were used to identify defleshing and disarticulation cut mark clusters on archaeological elbow portions by their location, cut mark count, median length, and median cross-sectional width. Actualistically-informed configurational analysis offers high-resolution behavioral reconstruction of the butchered sub-assemblage and should be integrated with assemblage-scale zooarchaeological methods. These experiments highlight the bias for detecting butchery traces of early carcass access, because defleshing cut marks are abundant and introduced to dense midshaft portions, whereas disarticulation cut marks are rare and occur on epiphyseal portions, which are often deleted by density-mediated destruction. Butchery trace interpretation across multiple analytical scales confirms a flexible carnivorous paleoecological role for Okote hominins that included primary and secondary access to carcass resources from large and small mammals. PMID- 28867280 TI - Interaction between childhood maltreatment on immunogenetic risk in depression: Discovery and replication in clinical case-control samples. AB - Major depressive disorder (MDD) is a prevalent disorder with moderate heritability. Both MDD and interpersonal adversity, including childhood maltreatment, have been consistently associated with elevated inflammatory markers. We investigated interaction between exposure to childhood maltreatment and extensive genetic variation within the inflammation pathway (CRP, IL1b, IL-6, IL11, TNF, TNFR1, and TNFR2) in relation to depression diagnosis. The discovery RADIANT sample included 262 cases with recurrent DSM-IV/ICD-10 MDD, and 288 unaffected controls. The replication Munster cohort included 277 cases with DSM IV MDD, and 316 unaffected controls. We identified twenty-five single nucleotide polymorphisms (SNPs) following multiple testing correction that interacted with childhood maltreatment to predict depression in the discovery cohort. Seven SNPs representing independent signals (rs1818879, rs1041981, rs4149576, rs616645, rs17882988, rs1061622, and rs3093077) were taken forward for replication. Meta analyses of the two samples presented evidence for interaction with rs1818879 (IL6) (RD=0.059, SE=0.016, p<0.001), with the replication Munster sample approaching statistical significance in analyses restricted to recurrent MDD and controls following correction for multiple testing (q=0.066). The CRP locus (rs3093077) showed a similar level of evidence for interaction in the meta analysis (RD=0.092, SE=0.029, p=0.002), but less compelling evidence in the replication sample alone (recurrent MDD q=0.198; all MDD q=0.126). Here we present evidence suggestive of interaction with childhood maltreatment for novel loci in IL-6 (rs1818879) and CRP (rs3093077), increasing risk of depression. Replication is needed by independent groups, targeting these specific variants and interaction with childhood maltreatment on depression risk. PMID- 28867282 TI - TRIF contributes to epileptogenesis in temporal lobe epilepsy during TLR4 activation. AB - Increasing evidence indicates that inflammatory processes play a crucial role in the etiopathology of epilepsy and seizure disorders. The Toll/IL-1R domain containing adapter-inducing IFN-beta (TRIF) activated several transcriptions leading to the production of pro-inflammatory cytokines in the central nervous system, which suggests a potential role for TRIF in the epileptogenesis of epilepsy. In this study, we investigated the roles of TRIF in human and mice epileptogenic tissues. Western blot and immunohistochemistry assays showed that the expression of TRIF was significantly upregulated in neurons and glial cells in both human epileptic tissues and mouse models, and positively correlated with seizure frequency. TRIF expression positively correlated with high-mobility group box 1 (HMGB1) expression. In TRIF-deficient mice, electroencephalograms displayed a significant decrease in seizure frequency and duration time, while KA induced seizures compared with wild-type (WT) mice. The number and duration time of spontaneous seizures were also decreased in the chronic KA-induced TRIF-deficient mouse models. In TLR4-deficient hippocampal neurons and mouse models, TRIF expression was lower compared with WT mice during HMGB1 and KA stimulation. Meanwhile, in KA-induced TRIF-deficient mouse models, microglia activation was significantly suppressed; pro-inflammatory factors including IL-1beta, TNF-alpha, iNOS, HMGB1 and IFN-beta were reduced; and the survival of the neurons in the hippocampus increased compared with WT mice. Our findings suggested that TRIF may be involved in the epileptogenesis of temporal lobe epilepsy, which would make it a potential therapeutic target for the treatment of epilepsy. PMID- 28867281 TI - Childhood victimization and inflammation in young adulthood: A genetically sensitive cohort study. AB - OBJECTIVE: Childhood victimization is an important risk factor for later immune related disorders. Previous evidence has demonstrated that childhood victimization is associated with elevated levels of inflammation biomarkers measured decades after exposure. However, it is unclear whether this association is (1) already detectable in young people, (2) different in males and females, and (3) confounded by genetic liability to inflammation. Here we sought to address these questions. METHOD: Participants were 2232 children followed from birth to age 18years as part of the Environmental Risk (E-Risk) Longitudinal Twin Study. Childhood victimization was measured prospectively from birth to age 12years. Inflammation was measured through C-reactive protein (CRP) levels in dried blood spots at age 18years. Latent genetic liability for high inflammation levels was assessed through a twin-based method. RESULTS: Greater exposure to childhood victimization was associated with higher CRP levels at age 18 (serum equivalent means were 0.65 in non-victimized Study members, 0.74 in those exposed to one victimization type, and 0.81 in those exposed to poly-victimization; p=0.018). However, this association was driven by a significant association in females (serum-equivalent means were 0.75 in non-victimized females, 0.87 in those exposed to one type of victimization, and 1.19 in those exposed to poly victimization; p=0.010), while no significant association was observed in males (p=0.19). Victimized females showed elevated CRP levels independent of latent genetic influence, as well as childhood socioeconomic status, and waist-hip ratio and body temperature at the time of CRP assessment. CONCLUSION: Childhood victimization is associated with elevated CRP levels in young women, independent of latent genetic influences and other key risk factors. These results strengthen causal inference about the effects of childhood victimization on inflammation levels in females by accounting for potential genetic confounding. PMID- 28867283 TI - Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression. AB - The incidence of depression is approximately 2-fold greater in women than men but the biological mechanisms underlying this phenomenon remain unclear. One potential mechanism that has been understudied is immune function, which is modulated by sex hormones and differs considerably between males and females. The immune-regulating kynurenine pathway previously has been implicated in the pathogenesis of mood disorders. In particular, a decreased ratio of neuroprotective (kynurenic acid; KynA) to neurotoxic (3-hydroxykynurenine; 3HK and quinolinic acid; QA) kynurenine pathway metabolites has been reported in several mood disorder subtypes. Yet there is a paucity of research investigating sex differences in the kynurenine pathway in the context of depression. Similarly, oral contraceptive (OC) use has been shown to be a risk factor for depression but to our knowledge this epidemiological relationship has not been considered within the framework of immune dysfunction. Here, we compared the concentrations of c-reactive protein (CRP) and kynurenine pathway metabolites in a combined sample of subjects with major depressive disorder (MDD), bipolar disorder (BD), and healthy controls (HC) comprising 130 men and 350 women. CRP was measured in a CLIA-certified hospital laboratory. Kynurenine metabolites were quantified using high performance liquid chromatography with tandem mass spectrometry. Estradiol and progesterone were quantified with the Mesoscale Discovery (MSD) platform. After controlling for diagnosis, age, sex, BMI, analysis batch, and self-reported childhood trauma we found that women had significantly lower KynA/3HK and KynA/QA ratios than men, and that these results were driven by a decrease in KynA. There was no significant difference between males and females in the concentration of CRP. Further, women taking OC showed significantly higher levels of CRP and lower ratios of KynA/3HK and KynA/QA compared with women on no form of contraception. Moreover, among women using OC, progesterone concentrations were positively correlated with KynA, KynA/3HK, and KynA/QA. Although preliminary, our results indicate that on average, healthy women show the same pattern of kynurenine pathway metabolism as that observed in subjects with depression. This finding raises the possibility that a reduction in KynA concentrations in women may constitute a vulnerability factor that partly explains the higher incidence of depression in females. Further, the significant association between OC use and reduced KynA as well as increased CRP, could conceivably partially account for the epidemiological association between OC use and depression. Nonetheless, because of the cross-sectional nature of this study, these hypotheses need to be more rigorously tested with longitudinal designs and/or large epidemiological studies. PMID- 28867284 TI - CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein. AB - BACKGROUND: Recent studies have implicated inflammatory processes in the pathophysiology of posttraumatic stress disorder (PTSD). C-reactive protein (CRP) is a widely-used measure of peripheral inflammation, but little is known about the genetic and epigenetic factors that influence blood levels of C-reactive protein (CRP) in individuals with PTSD. METHODS: Participants were 286 U.S. military veterans of post-9/11 conflicts (57% with current PTSD). Analyses focused on single nucleotide polymorphisms (SNPs) in the CRP gene and DNA methylation at cg10636246 in AIM2-a locus recently linked to CRP levels through results from a large-scale epigenome-wide association study. RESULTS: PTSD was positively correlated with serum CRP levels with PTSD cases more likely to have CRP levels in the clinically-elevated range compared to those without a PTSD diagnosis. Multivariate analyses that controlled for white blood cell proportions, genetic principal components, age and sex, showed this association to be mediated by methylation at the AIM2 locus. rs3091244, a functional SNP in the CRP promoter region, moderated the association between lifetime trauma exposure and current PTSD severity. Analyses also revealed that the top SNPs from the largest genome-wide association study of CRP conducted to date (rs1205 and rs2794520) significantly interacted with PTSD to influence CRP levels. CONCLUSIONS: These findings provide new insights into genetic and epigenetic mechanisms of inflammatory processes in the pathophysiology of PTSD and point to new directions for biomarker identification and treatment development for patients with PTSD. PMID- 28867285 TI - Mating in the Closest Living Relatives of Animals Is Induced by a Bacterial Chondroitinase. AB - We serendipitously discovered that the marine bacterium Vibrio fischeri induces sexual reproduction in one of the closest living relatives of animals, the choanoflagellate Salpingoeca rosetta. Although bacteria influence everything from nutrition and metabolism to cell biology and development in eukaryotes, bacterial regulation of eukaryotic mating was unexpected. Here, we show that a single V. fischeri protein, the previously uncharacterized EroS, fully recapitulates the aphrodisiac-like activity of live V. fischeri. EroS is a chondroitin lyase; although its substrate, chondroitin sulfate, was previously thought to be an animal synapomorphy, we demonstrate that S. rosetta produces chondroitin sulfate and thus extend the ancestry of this important glycosaminoglycan to the premetazoan era. Finally, we show that V. fischeri, purified EroS, and other bacterial chondroitin lyases induce S. rosetta mating at environmentally relevant concentrations, suggesting that bacteria likely regulate choanoflagellate mating in nature. PMID- 28867286 TI - Load Adaptation of Lamellipodial Actin Networks. AB - Actin filaments polymerizing against membranes power endocytosis, vesicular traffic, and cell motility. In vitro reconstitution studies suggest that the structure and the dynamics of actin networks respond to mechanical forces. We demonstrate that lamellipodial actin of migrating cells responds to mechanical load when membrane tension is modulated. In a steady state, migrating cell filaments assume the canonical dendritic geometry, defined by Arp2/3-generated 70 degrees branch points. Increased tension triggers a dense network with a broadened range of angles, whereas decreased tension causes a shift to a sparse configuration dominated by filaments growing perpendicularly to the plasma membrane. We show that these responses emerge from the geometry of branched actin: when load per filament decreases, elongation speed increases and perpendicular filaments gradually outcompete others because they polymerize the shortest distance to the membrane, where they are protected from capping. This network-intrinsic geometrical adaptation mechanism tunes protrusive force in response to mechanical load. PMID- 28867288 TI - Geography of Genetics and Genomics Research Funding in Africa. AB - An estimated U.S. $300 billion is spent each year on medical research. What proportion of this goes to genomics and genetics research in Africa? Until recently, this type of question was nearly impossible to answer. The World RePORT database, sponsored by the Heads of International Research Organizations (HIRO) and managed by the National Institutes of Health (NIH), provides a first attempt at answering questions on the distribution of research funding by geography and research organization. In this journal issue on the Human Heredity and Health in Africa (H3Africa), we explore the geography of biomedical research funding in the genomics field with special emphasis on Africa. Using World RePORT, we identified 185 research projects in genetics and genomics in Africa in 2015 with total funding exceeding U.S. $216 million. These numbers are likely incomplete and more efforts at collating data from funder organizations is needed. A comprehensive snapshot of funders' portfolios will be invaluable to research investigators and policy makers in the identification of research gaps and analysis of allocation priorities to facilitate evidence-based decision-making for public-research funding organizations. PMID- 28867287 TI - Dynamic Control of X Chromosome Conformation and Repression by a Histone H4K20 Demethylase. AB - Chromatin modification and higher-order chromosome structure play key roles in gene regulation, but their functional interplay in controlling gene expression is elusive. We have discovered the machinery and mechanism underlying the dynamic enrichment of histone modification H4K20me1 on hermaphrodite X chromosomes during C. elegans dosage compensation and demonstrated H4K20me1's pivotal role in regulating higher-order chromosome structure and X-chromosome-wide gene expression. The structure and the activity of the dosage compensation complex (DCC) subunit DPY-21 define a Jumonji demethylase subfamily that converts H4K20me2 to H4K20me1 in worms and mammals. Selective inactivation of demethylase activity eliminates H4K20me1 enrichment in somatic cells, elevates X-linked gene expression, reduces X chromosome compaction, and disrupts X chromosome conformation by diminishing the formation of topologically associating domains (TADs). Unexpectedly, DPY-21 also associates with autosomes of germ cells in a DCC-independent manner to enrich H4K20me1 and trigger chromosome compaction. Our findings demonstrate the direct link between chromatin modification and higher order chromosome structure in long-range regulation of gene expression. PMID- 28867289 TI - A New Age for African-Driven Genomics Research: Human Heredity and Health in Africa (H3Africa). PMID- 28867290 TI - Modified adductor sling technique: A surgical therapy for patellar instability in skeletally immature patients. AB - BACKGROUND: Due to open femoral physis the therapy of patellar instability in skeletally immature patients is challenging. We developed a modified surgical technique of the 'Adductor-Sling-Approach' by Sillanpaa. The purpose of this study was to evaluate the clinical outcome of the operative technique and to analyse the reasons for failure. METHODS: Thirty 'modified adductor sling' reconstructions in 28 patients were included in the study. From 2010 to 2016 modified adductor sling reconstruction was performed by looping the gracilis or semitendinosus tendon around the adductor magnus tendon and attaching it at the medial facet of the patella. Clinical outcome was retrospectively evaluated at a mean follow up of 25.6months (range 12-43). The evaluation also included subjective International Knee Documentation Committee (IKDC), Lysholm Score, Kujala Score and Tegner Activity Score. RESULTS: The average age at the time of operation was 15.10years (range 11-17). Eighty-seven percent of the patients, who underwent the modified adductor sling technique, gained a stable patella and excellent results in postoperative scores. Recurrent dislocation occurred in four of 30 cases (13%). Analysis showed that possible reasons for failure of the tendon graft could be maltracking of the patella due to patella alta, trochlear dysplasia or an elevated tibial tuberosity to trochlear groove distance. CONCLUSION: The modified adductor sling technique for MPFL reconstruction in children and adolescents showed elevated redislocation rates. Only in absence of additional patellofemoral maltracking, caused by elevated tibial tubercle to trochlear groove distance (>15mm), patella alta or especially severe trochlear dysplasia, the modified adductor sling technique could be recommended. PMID- 28867291 TI - Cancer recurrence after solid organ transplantation: A systematic review and meta analysis. AB - Solid organ transplant recipients (SOTR) with a pre-transplant malignancy (PTM) have been thought to be at high risk of cancer recurrence. However, recent population-based studies report cancer recurrence rates in SOTR similar to those of non-transplant patients. A systematic search was performed in MEDLINE, EMBASE, and Cochrane Library to identify studies reporting cancer recurrence in SOTR with PTM. Quality assessment was performed using a validated tool for assessing the quality of an observational study with no control group designed by the Institute of Health Economics. Overall and site-specific recurrence rates per person-year were pooled using generalized linear random/mixed-effects meta-analysis models and an exact likelihood approach based on a binomial and Poisson distribution. Meta-regressions, subgroup and sensitivity meta-analyses were used to explore sources of heterogeneity. Fifty-seven eligible studies were identified and 39 were included in the meta-analysis. The pooled recurrence rate was 1.6 (95% CI 1.0-2.6) per 100 person-year for all studies, and 1.1 (95% CI 0.5-2.7) when restricted to population-based studies. The recurrence rate was higher for kidney (2.4 per 100 person-year, 95% CI 1.0-5.6) compared with liver (1.0 per 100 person year, 95% CI 0.4-2.6), and cardiothoracic recipients (1.3 per 100 person-year, 95% CI 0.6-2.7). Time from cancer diagnosis to transplantation (TCT) <= 5 years was associated with greater risk of cancer recurrence compared to TCT > 5 years (risk ratio: 2.80, 95% CI 1.12-7.01). In conclusion, the risk of cancer recurrence in recipients with PTM is considerably lower than historic reports used to establish recommendations for listing patients with PTM. Evidence to support minimum cancer remission times before transplantation is limited. PMID- 28867292 TI - Single-Molecule Imaging Reveals How Mre11-Rad50-Nbs1 Initiates DNA Break Repair. AB - DNA double-strand break (DSB) repair is essential for maintaining our genomes. Mre11-Rad50-Nbs1 (MRN) and Ku70-Ku80 (Ku) direct distinct DSB repair pathways, but the interplay between these complexes at a DSB remains unclear. Here, we use high-throughput single-molecule microscopy to show that MRN searches for free DNA ends by one-dimensional facilitated diffusion, even on nucleosome-coated DNA. Rad50 binds homoduplex DNA and promotes facilitated diffusion, whereas Mre11 is required for DNA end recognition and nuclease activities. MRN gains access to occluded DNA ends by removing Ku or other DNA adducts via an Mre11-dependent nucleolytic reaction. Next, MRN loads exonuclease 1 (Exo1) onto the free DNA ends to initiate DNA resection. In the presence of replication protein A (RPA), MRN acts as a processivity factor for Exo1, retaining the exonuclease on DNA for long range resection. Our results provide a mechanism for how MRN promotes homologous recombination on nucleosome-coated DNA. PMID- 28867293 TI - Global Inhibition with Specific Activation: How p53 and MYC Redistribute the Transcriptome in the DNA Double-Strand Break Response. AB - In response to stresses, cells often halt normal cellular processes, yet stress specific pathways must bypass such inhibition to generate effective responses. We investigated how cells redistribute global transcriptional activity in response to DNA damage. We show that an oscillatory increase of p53 levels in response to double-strand breaks drives a counter-oscillatory decrease of MYC levels. Using RNA sequencing (RNA-seq) of newly synthesized transcripts, we found that p53 mediated reduction of MYC suppressed general transcription, with the most highly expressed transcripts reduced to a greater extent. In contrast, upregulation of p53 targets was relatively unaffected by MYC suppression. Reducing MYC during the DNA damage response was important for cell-fate regulation, as counteracting MYC repression reduced cell-cycle arrest and elevated apoptosis. Our study shows that global inhibition with specific activation of transcriptional pathways is important for the proper response to DNA damage; this mechanism may be a general principle used in many stress responses. PMID- 28867294 TI - The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence. AB - YTHDF2 binds and destabilizes N6-methyladenosine (m6A)-modified mRNA. The extent to which this branch of m6A RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of m6A in these upregulated genes. In summary, the m6A-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development. PMID- 28867296 TI - Device-assisted transdermal drug delivery. AB - Transdermal drug delivery is a prospective drug delivery strategy to complement the limitations of conventional drug delivery systems including oral and injectable methods. This delivery route allows both convenient and painless drug delivery and a sustained release profile with reduced side effects. However, physiological barriers in the skin undermine the delivery efficiency of conventional patches, limiting drug candidates to small-molecules and lipophilic drugs. Recently, transdermal drug delivery technology has advanced from unsophisticated methods simply relying on natural diffusion to drug releasing systems that dynamically respond to external stimuli. Furthermore, physical barriers in the skin have been overcome using microneedles, and controlled delivery by wearable biosensors has been enabled ultimately. In this review, we classify the evolution of advanced drug delivery strategies based on generations and provide a comprehensive overview. Finally, the recent progress in advanced diagnosis and therapy through customized drug delivery systems based on real-time analysis of physiological cues is highlighted. PMID- 28867295 TI - Asthma Outcomes and Management During Pregnancy. AB - Asthma during pregnancy poses a common, increasingly prevalent threat to the health of women and their children. The present article reviews recent insights gained from the epidemiology of asthma during pregnancy, demonstrating the many short- and long-term risks to mother and fetus incurred by poorly controlled maternal asthma. We further discuss emerging evidence that active management of asthma during pregnancy can positively influence and perhaps completely mitigate these poor outcomes. Recent high-quality trials examining best methods for asthma treatment are reviewed and synthesized to offer an evidence-based pathway for comprehensive treatment of asthma in the outpatient setting. Safe and effective medications, as well as nonpharmacologic interventions, for asthma during pregnancy are discussed, and treatment options for related conditions of pregnancy, including depression, rhinitis, and gastroesophageal reflux, are presented. Throughout, we emphasize that an effective treatment strategy relies on a detailed patient evaluation, patient education, objective measurement of asthma control, and frequent and supportive follow-up. The cardiovascular and respiratory physiology of pregnancy is reviewed, as well as its implications for the management of patients with asthma, including patients requiring intubation and mechanical ventilation. For the situation when outpatient asthma management has failed, an approach to the critically ill pregnant patient with status asthmaticus is detailed. Multidisciplinary teams that include pulmonary specialists, obstetricians, primary care providers, nurses, pharmacists, and asthma educators improve the care of pregnant women with asthma. PMID- 28867297 TI - Nomogram to predict non-home discharge following pancreaticoduodenectomy in a national cohort of patients. AB - BACKGROUND: Despite the development of pathways to enhance recovery and discharge to home, a significant proportion of patients are discharged to inpatient facilities after pancreaticoduodenectomy (PD). The aim of this study was to determine the rate of non-home discharge (NHD) following PD in a national cohort of patients and to develop predictive nomograms for NHD. METHODS: The National Surgical Quality Improvement Program was used to construct and validate pre- and postoperative nomograms for NHD following PD. RESULTS: A total of 6856 patients who underwent PD were identified, of which 927 (13.5%) had an NHD. The independent preoperative predictors of NHD were being female, older age, higher BMI, low serum albumin, >10% weight loss, ASA class III/IV, and being diagnosed with a bile duct/ampullary neoplasm or neuroendocrine tumor. A preoperative nomogram was constructed with a concordance index of 0.77. When postoperative variables were added to the model, the concordance index increased to 0.82. The postoperative predictors of NHD were return to the operating room, length of stay of >=14 days, and any inpatient complications. CONCLUSIONS: These nomograms could be useful risk assessment tools to predict NHD after PD and therefore facilitate patient counseling and improve resource utilization and discharge planning. PMID- 28867299 TI - Solute concentration at a well in non-Gaussian aquifers under constant and time varying pumping schedule. AB - Our study is keyed to the analysis of the interplay between engineering factors (i.e., transient pumping rates versus less realistic but commonly analyzed uniform extraction rates) and the heterogeneous structure of the aquifer (as expressed by the probability distribution characterizing transmissivity) on contaminant transport. We explore the joint influence of diverse (a) groundwater pumping schedules (constant and variable in time) and (b) representations of the stochastic heterogeneous transmissivity (T) field on temporal histories of solute concentrations observed at an extraction well. The stochastic nature of T is rendered by modeling its natural logarithm, Y=lnT, through a typical Gaussian representation and the recently introduced Generalized sub-Gaussian (GSG) model. The latter has the unique property to embed scale-dependent non-Gaussian features of the main statistics of Y and its (spatial) increments, which have been documented in a variety of studies. We rely on numerical Monte Carlo simulations and compute the temporal evolution at the well of low order moments of the solute concentration (C), as well as statistics of the peak concentration (Cp), identified as the environmental performance metric of interest in this study. We show that the pumping schedule strongly affects the pattern of the temporal evolution of the first two statistical moments of C, regardless the nature (Gaussian or non-Gaussian) of the underlying Y field, whereas the latter quantitatively influences their magnitude. Our results show that uncertainty associated with C and Cp estimates is larger when operating under a transient extraction scheme than under the action of a uniform withdrawal schedule. The probability density function (PDF) of Cp displays a long positive tail in the presence of time-varying pumping schedule. All these aspects are magnified in the presence of non-Gaussian Y fields. Additionally, the PDF of Cp displays a bimodal shape for all types of pumping schemes analyzed, independent of the type of heterogeneity considered. PMID- 28867298 TI - Transcriptional and epigenetic analyses of the DMD locus reveal novel cis-acting DNA elements that govern muscle dystrophin expression. AB - The dystrophin gene (DMD) is the largest gene in the human genome, mapping on the Xp21 chromosome locus. It spans 2.2Mb and accounts for approximately 0,1% of the entire human genome. Mutations in this gene cause Duchenne and Becker Muscular Dystrophy, X-linked Dilated Cardiomyopathy, and other milder muscle phenotypes. Beside the remarkable number of reports describing dystrophin gene expression and the pathogenic consequences of the gene mutations in dystrophinopathies, the full scenario of the DMD transcription dynamics remains however, poorly understood. Considering that the full transcription of the DMD gene requires about 16h, we have investigated the activity of RNA Polymerase II along the entire DMD locus within the context of specific chromatin modifications using a variety of chromatin-based techniques. Our results unveil a surprisingly powerful processivity of the RNA polymerase II along the entire 2.2Mb of the DMD locus with just one site of pausing around intron 52. We also discovered epigenetic marks highlighting the existence of four novel cis-DNA elements, two of which, located within intron 34 and exon 45, appear to govern the architecture of the DMD chromatin with implications on the expression levels of the muscle dystrophin mRNA. Overall, our findings provide a global view on how the entire DMD locus is dynamically transcribed by the RNA pol II and shed light on the mechanisms involved in dystrophin gene expression control, which can positively impact on the optimization of the novel ongoing therapeutic strategies for dystrophinopathies. PMID- 28867300 TI - Percolation characteristics of solvent invasion in rough fractures under miscible conditions. AB - Surface roughness and flow rate effects on the solvent transport under miscible conditions in a single fracture are studied. Surface replicas of seven different rocks (marble, granite, and limestone) are used to represent different surface roughness characteristics each described by different mathematical models including three fractal dimensions. Distribution of dyed solvent is investigated at various flow rate conditions to clarify the effect of roughness on convective and diffusive mixing. After a qualitative analysis using comparative images of different rocks, the area covered by solvent with respect to time is determined to conduct a semi-quantitative analysis. In this exercise, two distinct zones are identified, namely the straight lines obtained for convective (early times) and diffusive (late times) flow. The bending point between these two lines is used to point the transition between the two zones. Finally, the slopes of the straight lines and the bending points are correlated to five different roughness parameters and the rate (Peclet number). It is observed that both surface roughness and flow rate have significant effect on solvent spatial distribution. The largest area covered is obtained at moderate flow rates and hence not only the average surface roughness characteristic is important, but coessentially total fracture surface area needs to be considered when evaluating fluid distribution. It is also noted that the rate effect is critically different for the fracture samples of large grain size (marbles and granite) compared to smaller grain sizes (limestones). Variogram fractal dimension exhibits the strongest correlation with the maximum area covered by solvent, and display increasing trend at the moderate flow rates. Equations with variogram surface fractal dimension in combination with any other surface fractal parameter coupled with Peclet number can be used to predict maximum area covered by solvent in a single fracture, which in turn can be utilized to model oil recovery, waste disposal, and groundwater contamination processes in the presence of fractures. PMID- 28867302 TI - Comparison of the efficiency of different newcastle disease virus reverse genetics systems. AB - Rescue of negative-sense single-stranded RNA viruses ((-)ssRNA virus), generally requires the handling of a large number of plasmids to provide the virus genome and essential components for gene expression and genome replication. This constraint probably renders reverse genetics of (-)ssRNA virus more complex and less efficient. Some authors have shown that the fewer the plasmids, the more efficient reverse genetics is for segmented RNA virus. However, it is not clear if the same applies for (-)ssRNA, such as Newcastle disease virus (NDV). To address this issue, six variants of NDV reverse genetic systems were established by cloning combinations of NP, P and L genes, mini-genome or full-genome in 4, 3, 2 and 1 plasmid. In terms of mini-genome and full-genome rescue, we showed that only the 2-plasmid system, assembling three support plasmids together, was able to improve the rescue efficiency over that of the conventional 4-plasmid system. These results may help establish and/or improve reverse genetics for other mononegaviruses. PMID- 28867304 TI - Pharmaconutrition with intravenous selenium in intensive care: Back to basics? PMID- 28867303 TI - Treatment with a GLP-1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders. AB - Cognitive deficits are a core feature across psychiatric disorders. Emerging evidence indicates that metabolic pathways are highly relevant for the substrates and phenomenology of the cognitive domain. Herein, we aimed to determine the effects of liraglutide, a GLP-1R agonist, on brain structural/volumetric parameters in adults with a mood disorder. This is the secondary analysis of a 4 week, pilot, proof-of-concept, open-label study. Participants (N=19) exhibiting impairments in executive function with either major depressive disorder (MDD) or bipolar disorder (BD) were recruited. Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy. Structural magnetic resonance imaging (MRI) scanning was obtained at baseline and endpoint. Results showed that at endpoint there was significant weight loss (mean: 3.15%; p<0.001). Changes in frontal and striatal volumes were significantly correlated with changes in body mass index (BMI), indicating the weight loss was associated with volume increase in most regions (e.g. r=-0.561, p=0.042 in the left superior frontal area). After adjusting for intracranial volume, age, gender, and BMI, we observed significant changes from baseline to endpoint in multiple regions (e.g. RR: 1.011, p=0.049 in the left rostral middle frontal area). Changes in regional volumes were associated with improvement in executive function (e.g. r=0.698, p=0.003 for the right superior frontal area). Adjunctive liraglutide results in clinically significant weight loss, with corresponding improvement in cognitive function; changes in cognitive function were partially moderated by changes in brain morphometry, underscoring the interrelationship between weight and brain structure/function. PMID- 28867305 TI - The effect of hospital teaching status on outcomes in bariatric surgery. AB - BACKGROUND: Studies have shown conflicting effects of resident involvement on outcomes after laparoscopic bariatric surgery. Resident involvement may be a proxy for a teaching environment in which multiple factors affect patient outcomes. However, no study has examined outcomes of laparoscopic bariatric surgery based on hospital teaching status. OBJECTIVE: To compare outcomes after laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) between teaching hospitals (THs) and nonteaching hospitals (NTHs). SETTING: Retrospective review of a national database in the United States. METHODS: The Nationwide Inpatient Sample database (2011-2013) was reviewed for obese patients who underwent LRYGB or LSG. Patient demographic characteristics and outcomes were analyzed according to hospital teaching status. Primary outcome measures included risk-adjusted inpatient mortality and serious morbidity. RESULTS: We analyzed 32,449 LRYGBs and 26,075 LSGs. There were 35,160 (60.1%) cases performed at THs and 23,364 (39.9%) cases performed at NTHs. At THs, the distribution of LRYGB versus LSG cases was 20,461 (58.2%) versus 14,699 (41.8%), respectively; at NTHs, the distribution was 11,988 (51.3%) versus 11,376 (48.7%), respectively. For LRYGB, there were no significant differences between THs versus NTHs in mortality (AOR 1.14; P = 0.99), but there was an increase in odds of serious morbidity at THs (AOR 1.36; P<0.001). For LSG, there were no significant differences between THs versus NTHs for mortality (AOR 1.15; P = 0.99) or serious morbidity (AOR 1.03; P = 0.99). CONCLUSIONS: There is an association between THs and increased serious morbidity for LRYGB, but hospital teaching status has no effect on morbidity or mortality after LSG. Further research is warranted to elucidate the reasons for these associations. PMID- 28867306 TI - Comment on: Fat mass, fat-free mass, and resting metabolic rate in weight-stable sleeve gastrectomy patients compared with weight-stable nonoperated subjects. PMID- 28867301 TI - Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. AB - NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-epsilon, impairing insulin receptor activation and insulin-stimulated glycogen synthesis. Peripheral insulin resistance indirectly influences hepatic glucose and lipid metabolism by increasing flux of substrates that promote lipogenesis (glucose and fatty acids) and gluconeogenesis (glycerol and fatty acid-derived acetyl-CoA, an allosteric activator of pyruvate carboxylase). Weight loss with diet or bariatric surgery effectively treats NAFLD, but drugs specifically approved for NAFLD are not available. Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR gamma, PPAR alpha/delta, FXR and analogs for FGF-21, and GLP-1). Others specifically inhibit key enzymes involved in lipid synthesis (e.g., mitochondrial pyruvate carrier, acetyl-CoA carboxylase, stearoyl-CoA desaturase, and monoacyl- and diacyl glycerol transferases). Finally, a novel class of liver-targeted mitochondrial uncoupling agents increases hepatocellular energy expenditure, reversing the metabolic and hepatic complications of NAFLD. PMID- 28867307 TI - [Cardiological vision of functional exploration during exercise]. PMID- 28867308 TI - [Use of endobronchial ultrasound in the management of cryptogenic haemoptysis]. AB - Currently about 50% of cases of haemoptysis are thought to be cryptogenic. Haemorrhage from the pulmonary arterial system is rare and usually due to aneurysms or pseudoaneurysms, the radiological diagnosis of which is often difficult. We report here the case of a patient admitted with a heavy haemoptysis in whom the thoracic CT scan did not reveal the diagnosis. Bronchoscopy with endobronchial ultrasound showed a vascular malformation of a branch of the pulmonary artery allowing a radiological embolisation. This case underlines the importance of bronchoscopy and the role of ultrasound in the diagnosis of haemoptysis, considered ideopathic, complicating vascular malformations. PMID- 28867309 TI - B-cell activating factor BAFF reflects patients' immunological risk profile after kidney transplantation. AB - The B-cell activating factor BAFF plays an important role in the development and maturation of B-lymphocytes, which can contribute to the generation of donor specific antibodies and thus may influence graft function and graft survival. Inconsistent data on the role of BAFF levels after renal transplantation for the formation of donor-specific antibodies and the contribution for allograft rejection exist. The aim of the current study was to determine to what extent the degree of pre-immunization is reflected by each patient's BAFF levels before transplantation and in the follow-up. Furthermore, the impact of BAFF on allograft rejection frequency as well as severity and resulting allograft function over time was analyzed. Additionally, the impact of viral infections on BAFF levels after transplantation - as a potential confounder - was examined. For this purpose, a group of pre-sensitized patients (PRA>0%, (52+/-24% on average), n=40) was compared with non-sensitized patients (PRA=0%, n=62) and in a subsequent analysis stratification in accordance to the detected BAFF level was performed. Pre-sensitized patients had significantly higher BAFF levels before transplantation and suffered significantly more often from early steroid resistant, mainly antibody-mediated rejections. A result which was confirmed also in highly sensitized patients with PRA levels >50%. Additionally, in the follow up patients with either rising BAFF levels over time or BAFF levels above the median also had significantly more often antibody mediated rejections. Additionally, patients with BAFF levels above detected median even displayed impaired creatinine values as well as an induced eGFR slope up to month 48 after transplantation. The occurrence of viral infections (CMV, BKV) was only an additional influencing factor in the absence of concomitant allograft rejections. Therefore, the B-cell proliferation factor BAFF appears not only to reflect the immunological risk profile of patients in the context of kidney transplantation, it may possibly be further developed as a predictor of patients with an increased risk profile for subsequent allograft rejection and impaired allograft function. PMID- 28867310 TI - Effects of Patients' Affect on Adverse Procedural Events during Image-Guided Interventions. AB - PURPOSE: To assess how a patient's affect on presentation relates to the likelihood of adverse events during their subsequent interventional image-guided procedures. MATERIALS AND METHODS: A secondary analysis was performed of an existing dataset from a clinical trial with 230 patients who underwent percutaneous peripheral vascular and renal interventions and who had completed the positive affect (PA) negative affect (NA) schedule (PANAS) before their procedures. Summary PANAS scores were split over the median and used to classify the participants into those with high vs low PA and high vs low NA. Associations between affect and the absence or presence of adverse medical events were examined by two-sided Fisher exact tests. RESULTS: Patients with high baseline NA were significantly more likely to have adverse events during their procedures than those with low baseline NA (18% vs 8%; P = .030). High baseline PA was not associated with a significantly higher frequency of subsequent adverse events compared with low PA (15% vs 9%; P = .23). Patients with high NA requested and received significantly more sedative and opioid agents than those with low NA (2.0 vs 1.0 units requested [P = .0009]; 3.0 vs 1.0 units received [P = .0004]). PA levels did not affect medication use. CONCLUSIONS: High NA, but not PA, was associated with an increased likelihood of adverse events. Improving patients' NA before procedures seems a more suitable target than attempting to boost PA to improve the procedural experience. PMID- 28867311 TI - Distal technologies and type 1 diabetes management. AB - Type 1 diabetes requires intensive self-management to avoid acute and long-term health complications. In the past two decades, substantial advances in technology have enabled more effective and convenient self-management of type 1 diabetes. Although proximal technologies (eg, insulin pumps, continuous glucose monitors, closed-loop and artificial pancreas systems) have been the subject of frequent systematic and narrative reviews, distal technologies have received scant attention. Distal technologies refer to electronic systems designed to provide a service remotely and include heterogeneous systems such as telehealth, mobile health applications, game-based support, social platforms, and patient portals. In this Review, we summarise the empirical literature to provide current information about the effectiveness of available distal technologies to improve type 1 diabetes management. We also discuss privacy, ethics, and regulatory considerations, issues of global adoption, knowledge gaps in distal technology, and recommendations for future directions. PMID- 28867312 TI - Models of Mortality and Morbidity in Severe Traumatic Brain Injury: An Analysis of a Singapore Neurotrauma Database. AB - OBJECTIVE: Current prognostic models for traumatic brain injury (TBI) are developed from diverse historical data sets. We aimed to construct a prognostication tool for patients with severe TBI, as this group would benefit most from an accurate model. METHODS: Model development was based on a cohort of 300 patients with severe TBI (Glasgow Coma Scale score <=8) consecutively admitted to a neurosurgical intensive care unit at the National Neuroscience Institute (NNI), Singapore, between February 2006 and December 2009. We analyzed prospectively collected data of admission characteristics using univariate and multivariate logistic regressions to predict 14-day and 6-month mortality and 6 month unfavorable outcome. Comparison with Corticosteroid Randomization After Significant Head Injury (CRASH) and Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) models was done using Akaike information criterion. RESULTS: Two prediction models, NNI Clinical (age, Glasgow Coma Scale score, pupillary reactivity) and NNI+ (NNI Clinical model with addition of obliteration of third ventricle or basal cisterns, presence of subdural hemorrhage, hypoxia, and coagulopathy), were derived from this data set. Both models predicted well across 3 outcome measures with area under the curve values of 0.84-0.91, with adequate calibration. Comparison with CRASH and IMPACT models showed better performance by both derived models with lower Akaike information criterion and higher area under the curve values. CONCLUSIONS: Two accurate prognostic models, NNI Clinical and NNI+, were developed from our cohort of patients with severe TBI. Both models are specific to severe TBI and could be better alternatives to current available models. External validation is required to assess performance of models in a different setting. PMID- 28867313 TI - Residual Deformity After Anterior Cervical Discectomy and Fusion for Unstable Hangman's Fractures. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) is a commonly used surgery for unstable hangman's fractures. This study investigated the rate of residual deformity after ACDF for these fractures and the effect of residual deformity on clinical and radiologic outcomes. METHODS: A retrospective analysis of 28 patients with unstable hangman's fractures treated with ACDF was undertaken. The angulation and anterior translation between C2-C3 were measured on lateral radiographs at the time of admission, after skull traction, in the initial postoperative period, and at final follow-up. Residual deformity after surgery was defined as significant angulation (>=6 degrees ) and/or translation (>=3 mm). Patients were divided into 2 groups: with and without residual deformity. Follow-up evaluation included clinical and radiologic outcomes. RESULTS: Mean follow-up time was 22 months. The group with residual deformity included 7 patients with an angulation of >=11 degrees and/or translation of >=4 mm after skull traction. The remaining 21 patients without residual deformity had an angulation of <11 degrees and translation of <4 mm after skull traction. Neck pain and neurologic deficits improved significantly in all patients after surgery. No significant changes of alignment of middle and lower cervical vertebrae were observed. CONCLUSIONS: Residual deformity after ACDF for unstable hangman's fractures is not rare, and it seems to have no significant effect on clinical outcome during short-term follow-up. A severe deformity between C2-C3 after skull traction may be a predictor of residual deformity. PMID- 28867314 TI - Prognostic Factors and Comparison of Conservative Treatment, Percutaneous Vertebroplasty, and Open Surgery in the Treatment of Spinal Metastases from Lung Cancer. AB - BACKGROUND: Spinal metastases from lung cancer could result in life-threatening consequences. Few studies report the prognostic factors and compare different treatments in patients with spinal metastases from lung cancer. METHODS: From 2005 to 2014, we retrospectively reviewed and studied 140 patients with spinal metastases from lung cancer according to different treatments. To estimate overall survival and identify prognostic factors for survival, the Kaplan-Meier method and Cox regression analysis were adopted. In addition, the Kaplan-Meier method was used to compare different treatments for overall survival. RESULTS: All patients in a conservative group and a percutaneous vertebroplasty group died at a median survival time of 7 months for both groups. As for patients in the open-surgery group, 42 patients died at a median of 11 months, and 7 patients who were still alive at the time of this study were followed for a median of 29 months. Multivariate analysis suggested that better survival was significantly associated with American Spinal Injury Association grade D/E on admission, American Spinal Injury Association grade E after surgery, Eastern Cooperative Oncology Group performance status 1-2, and adjuvant radiation therapy in all 3 groups. In addition, Kaplan-Meier analysis showed that the overall survival rate of the open-surgery group (14.3%) was better than that of conservative group (0%) and the percutaneous vertebroplasty group (0%). CONCLUSIONS: A better overall survival outcome might be achieved by a series of comprehensive and individualized treatments and personalized treatment. PMID- 28867316 TI - Endoscopic Endonasal Surgery for Treatment of Pituitary Apoplexy: 16 Years of Experience in a Specialized Pituitary Center. AB - OBJECTIVE: Symptomatic pituitary apoplexy is a rare but life-threatening condition caused by sudden hemorrhage or infarction of a pituitary adenoma. In the current study, we aim to evaluate the clinical presentation, management, and clinical outcomes in a cohort of patients who were treated for this condition in our center in the last 16 years. METHODS: We performed a retrospective analysis of all patients who underwent endoscopic endonasal surgery for treatment of symptomatic pituitary apoplexy between 2001 and 2016 in our center. RESULTS: A total of 39 patients were included in the study, mean age of 54.9 years (range, 18-70 years) and mean follow-up 5.1 years (range, 0.6-16 years). Most of the patients had nonfunctioning adenomas (32 patients). Headache (89%), visual impairment (79%), and hypopituitarism (86%) were the most common preoperative findings. Surgical treatment led to gross total resection in 31 patients (79.4%). During follow-up, visual fields and oculomotor improvement was observed in 23 (74.1%) and 21 (67.7%) of the patients, respectively. Intractable headache also improved in all patients. Hypopituitarism was present in 77% of patients after surgery. In this series, no cerebrospinal fluid leak, vascular injury, or infection was observed. There was no postoperative mortality. CONCLUSIONS: The endoscopic endonasal transsphenoidal approach is an effective modality to treat pituitary apoplexy with a high rate of success and minimal risk in selected cases. Although reversion of preoperative visual deficits is often observed, hormonal deficits tend to persist, and require long-term hormonal therapy, even after successful endoscopic endonasal surgical resection. PMID- 28867315 TI - Soluble Fms-Like Tyrosine Kinase 1 (sFlt-1) and Risk of Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: The molecular mechanisms underlying cerebral vasospasm and delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) are incompletely understood. We hypothesized that circulating antiangiogenic factors, such as soluble Fms-like tyrosine kinase 1 (sFlt-1) and soluble transforming growth factor beta coreceptor, soluble endoglin (sEng), are important markers of their pathophysiology. METHODS: We performed a prospective study in patients with aSAH and measured cerebrospinal fluid and serum levels of sFlt-1 and sEng on postbleed day 1 and 6 and correlated levels with incidence and severity of cerebral vasospasm and DCI. RESULTS: Twenty-seven patients with aSAH were enrolled in the study. Severe angiographic vasospasm was present in 14.8% of patients and DCI occurred in 33.3%. Serum sFlt1 levels were increased on postbleed day 6 in patients who developed vasospasm. However, on postbleed day 1, there were no differences in patients who developed vasospasm. Increased serum sFlt-1 levels on postbleed day 1 were found to predict the development of severe angiographic vasospasm with an area under the curve of 0.818 with an optimal cutoff value of 95 pg/mL. Alterations in sFlt1 were not associated with DCI. Serum and cerebrospinal fluid sEng levels did not correlate with vasospasm or DCI. CONCLUSIONS: Serum levels of sFlt-1 are increased in patients with aSAH who are at risk for severe vasospasm. Further studies with larger sample sizes are needed to evaluate whether sFlt-1 levels may predict onset of severe vasospasm and DCI. PMID- 28867317 TI - Extensive Mirror-Image Neurofibromas of Entire Spine Resulting in Spastic Tetraplegia. AB - Neurofibromatosis 1 (NF1) is associated with increased incidence of spinal tumors including neurofibromas. The majority of NF1-associated spine neurofibromas are asymptomatic; however, a minority of patients will experience neurologic symptoms that can range from mild paresthesia, radiculopathy, myelopathy, and focal weakness to quadriplegia in extreme cases. We present a 21-year-old male diagnosed with NF1 in infancy and followed for multiple mirror-image neurofibromas involving the entire spine. He was asymptomatic until age 14 when he developed neck pain and progressive tetraplegia with magnetic resonance imaging showing severe cord compression secondary to bilateral C2 neurofibromas. Emergent cervical decompression was performed at C1-C3 along with debulking of bilateral neurofibromas. Postoperatively he regained full strength with no signs of myelopathy several years postoperatively. This case demonstrates a dramatic neuroimaging finding and emphasizes the potential for significant neurologic deterioration in previously asymptomatic NF1 patients, highlighting the need for long-term follow-up. PMID- 28867318 TI - Regression of Recurrent High-Grade Glioma with Temozolomide, Dexamethasone, and Levetiracetam: Case Report and Review of the Literature. AB - BACKGROUND: Treatment options for recurrent glioma of the brain include chemotherapy, radiotherapy, surgery, and palliation. Temozolomide appears to be effective in patients with recurrent high-grade gliomas. CASE DESCRIPTION: A middle-aged woman presented with a high-grade glioma of corpus callosum. The tumor, a grade 3 anaplastic oligodendroglioma, was excised, and chemoradiotherapy was administered. The patient presented with significant recurrence 5 years later. Repeat surgery and radiation were suggested but refused. She was given temozolomide and dexamethasone intermittently, and levetiracetam was continued. Magnetic resonance imaging performed at 10-month follow-up showed 90% remission. CONCLUSIONS: There are a few reports in the literature of similar response to temozolomide and levetiracetam. Similar reports give more hope in the treatment of recurrent high grade glioma. PMID- 28867320 TI - Complete Reversibility of the Chiari Type II Malformation After Postnatal Repair of Myelomeningocele. AB - OBJECTIVE: It was believed that Chiari type II malformation (CM-II) was always present in a myelomeningocele (MMC). In fact, it is associated in about 80% of cases. Improvement of the hindbrain herniation after prenatal closure of MMC has challenged the idea that this condition was irreversible. Only 2 studies report ascent of the cerebellar tonsil after postnatal closure. This work aimed to study a large group of patients with MMC who benefited from a postnatal repair to evaluate the rate of long-term total reversibility of CM-II. METHODS: Sixty-one patients were included. Mean time of follow-up was 8.1 years. The presence of CM II after closure of the MMC was assessed on the most recent brain scan available for each patient. RESULTS: Forty-seven patients (77%) had a CM-II at birth (confirmed before the MMC repair). There was a significant correlation between the level of the malformation and the presence of a CM-II at birth (P = 0.003). After MMC closure, only 28 (45.9%) patients had a remaining CM-II. The reversibility rate was 40.4%. The reversibility was higher in lower level malformations (P = 0.004). The number of patients treated for hydrocephalus was significantly higher in the group of patients with remaining CM-II (P = 0.004). Only 11.5% of the children needed surgery for a symptomatic CM-II. CONCLUSIONS: MMC is not always associated with CM-II. The outcome of CM-II has improved. Postnatal closure can reverse the CM-II. This must be kept in mind when analyzing the result of prenatal series. PMID- 28867319 TI - Transfer of Learning from Practicing Microvascular Anastomosis on Silastic Tubes to Rat Abdominal Aorta. AB - OBJECTIVE: Learning to perform microvascular anastomosis is difficult. Laboratory practice models using artificial vessels are frequently used for this purpose. However, the efficacy of such practice models has not been objectively assessed for the performance of microvascular anastomosis during live surgical settings. This study was conducted to assess the transfer of learning from practicing microvascular anastomosis on tubes to anastomosing rat abdominal aorta. METHODS: Ten surgeons without any experience in microvascular anastomosis were randomly assigned to an experimental or a control group. Both groups received didactic and visual training on end-to-end microvascular anastomosis. The experimental group received 24 sessions of hands-on training on microanastomosis using Silastic tubes. Next, both groups underwent recall tests on weeks 1, 2, and 8 after training. The recall test consisted of completing an end-to-end anastomosis on the rat's abdominal aorta. Anastomosis score, the time to complete the anastomosis, and the average time to place 1 stitch on the vessel perimeter were compared between the 2 groups. RESULTS: Compared with the control group, the experimental group did significantly better in terms of anastomosis score, total time, and per-stitch time. The measured variables showed stability and did not change significantly between the 3 recall tests. CONCLUSION: The skill of microvascular anastomosis is transferred from practicing on Silastic tubes to rat's abdominal aorta. Considering the relative advantages of Silastic tubes to live rodent surgeries, such as lower cost and absence of ethical issues, our results support the widespread use of Silastic tubes in training programs for microvascular anastomosis. PMID- 28867321 TI - Cytotoxic and Apoptogenic Effects of Cyanidin-3-Glucoside on the Glioblastoma Cell Line. AB - OBJECTIVE: Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary cerebral tumor. The median survival time is 15 months despite maximum treatment because the tumor is resistant to most therapeutic modalities. Several studies have indicated chemopreventive and chemotherapeutic activity of cyanidin 3-glucoside (C3G) as an anthocyanin component. We aimed to illustrate the cytotoxic and apoptogenic effects of C3G in the U87 cell line (human GBM cell line). METHODS: Cytotoxic activity was evaluated using the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide tetrazolium assay after treatment with C3G at different concentrations in the U87 cell line. Cisplatin was used as a positive control for 24 and 48 hours. The percentage of apoptotic cells was determined using an Annexin V/propidium iodide assay, and the expression of bax, bcl2, and p53 genes was assessed using real-time polymerase chain reaction. RESULTS: Treatment of U87 cells with 40 MUg/mL of C3G resulted in 32% apoptotic cells after 24 hours. To further confirm that C3G treatment induced apoptosis in U87 cells, RNA expression of bax, bcl2, and p53 genes was investigated after treatment. Real-time polymerase chain reaction indicated that the expression of bax and p53 increased, whereas the expression of bcl2 decreased. CONCLUSIONS: C3G had an apoptogenic effect in the GBM cell line. New information regarding the therapeutic effects of C3G in GBM could ultimately lead to the production of new drugs. PMID- 28867322 TI - Recurrent Bleeding After Perimesencephalic Hemorrhage. AB - BACKGROUND: Perimesencephalic hemorrhage (PMH) is a type of subarachnoid hemorrhage with excellent long-term outcomes. Only 1 well-documented case of in hospital rebleeding after PMH is described in the literature, which occurred after initiating antithrombotic treatment because of myocardial ischemia. We describe a patient with PMH without antithrombotic treatment who had 2 episodes of recurrent bleeding on the day of ictus. To validate the radiologic findings, we conducted a case-control study. Six neuroradiologists and 2 neuroradiology fellows performed a blinded assessment of serial unenhanced head computed tomography (CT) scans of 8 patients with a perimesencephalic bleeding pattern (1 index patient, 6 patients with PMH, 1 patient with perimesencephalic bleeding pattern and basilar artery aneurysm) to investigate a potential increase in amount of subarachnoid blood. CASE DESCRIPTION: A 56-year-old woman with a perimesencephalic bleeding pattern and negative CT angiography had 2 episodes after the onset headache with a sudden increase of the headache. Blinded assessment of serial head CT scans of 8 patients with a perimesencephalic bleeding pattern identified the patient who was clinically suspected to have 2 episodes of recurrent bleeding to have an increased amount of subarachnoid blood on 2 subsequent CT scans. CONCLUSIONS: Recurrent bleeding after PMH may also occur in patients not treated with antithrombotics. Even after early rebleeding, the prognosis of PMH is excellent. PMID- 28867323 TI - Endoscopic Middle Cranial Fossa Reconstruction with a Subtemporal Keyhole. AB - BACKGROUND: Skull base reconstruction is an essential technique for repairing cerebrospinal fluid (CSF) leakage. A reliable method for middle cranial fossa (MCF) reconstruction with minimal invasiveness has not been reported. An initial case of endoscopic MCF reconstruction with a subtemporal keyhole is described. CASE DESCRIPTION: A 57-year-old man developed severe meningitis and was diagnosed with spontaneous CSF leakage from bone defects on the tegmen tympani. Endoscopic MCF reconstruction with a subtemporal keyhole was carried out. Three skin incisions, including 1 subtemporal incision for a subtemporal keyhole and 2 temporal line incisions on the superior temporal line, were made, and a 0-degree endoscope was introduced into the subcutaneous space. The deep temporal fascia (DTF) was bluntly dissected and separated from the superficial temporal fascia and the temporal muscle, and the DTF was incised to shape a pedicled flap under endoscopic view. Blood supply to the pedicled DTF flap was confirmed with indocyanine green angiography. A subtemporal keyhole was then made, and a 30 degree endoscope was used to explore the extradural space of the MCF floor, visualizing the bone defects on the tegmen tympani. The vascularized DTF flap passed easily through the subtemporal keyhole and adequately overlaid the bone defects. The patient's postoperative course was uneventful, and the CSF leakage disappeared without mastication problems. CONCLUSIONS: This purely endoscopic technique using a vascularized DTF flap provided reliable MCF reconstruction through a subtemporal keyhole. This technique is also expected to be applicable for MCF reconstruction after subtemporal keyhole surgery for skull base tumors. PMID- 28867324 TI - Surgical Management and Outcomes of Intracranial Chondromas: a Single-Center Case Series of 66 Patients. AB - OBJECTIVE: Management of intracranial chondromas (ICDs) is difficult. This study aims to propose a tailored management strategy based on our management of ICDs. METHODS: A retrospective review was performed in 66 patients who received surgical operations at our institute. Clinical charts and radiographs were reviewed, follow-up was performed, and adverse factors for progression-free survival (PFS) and overall survival were evaluated. RESULTS: The preoperative and postoperative Karnofsky performance status was 81.8 and 72.3, respectively. The mean tumor size was 3.5 cm. Gross total resection was achieved in 15 patients (22.7%). Six patients (10.3%) received postoperative radiation. After a mean follow-up duration of 85.5 months, recurrence occurred to 15 patients (28.8%) with surgery alone, and no recurrence was observed in patients receiving postoperative radiotherapy. Six patients (10.3%) died due to tumor progression. The risk factors affecting the PFS included age <33 years (hazard rate [HR] 6.876; 95% confidence interval [CI] 1.599-29.560; P = 0.010), tumor size >=3.1 cm (HR 6.138; 95% CI 1.259-29.926; P = 0.025), tumor with evident atypia/mitotic activity (HR 4.672; 95% CI 1.352-16.152; P = 0.015), and partial resection (HR 12.841; 95% CI 3.004-54.896; P = 0.001). In all patients, the PFS rate was 75% at 5 years and 64% at 10 years; in addition, the overall survival rate was 93% at 5 years and 83% at 10 years. CONCLUSIONS: The therapeutic strategy for ICDs should be individualized and should consider preoperative variables. Gross total resection was attempted if the tumors were resectable; otherwise, subtotal resection was an alternative. In patients with partial resection and evident atypia/mitotic activity, consultation with an oncologist for radiotherapy was recommended. PMID- 28867325 TI - Neuroprotective Effects of Valproic Acid in a Rat Model of Cauda Equina Injury. AB - BACKGROUND: Histone deacetylase inhibitors, including valproic acid (VPA), are promising therapeutic interventions in neurological disorders and play an important role in synaptic activity and neuronal function. METHODS: A total of 30 rats were randomly allocated to 3 groups: sham, control, and VPA. The rats in the VPA and control groups received laminectomy at the L4 level of the vertebrae and silicone gel implantation into the epidural spaces L5 and L6. Rats in the sham group only received laminectomy at the L4 level of vertebrae without any implantation. VPA (300 mg/kg in saline) was administered 2 hours before the surgery. After the surgery, the VPA group received further VPA injections at 300 mg/kg twice a day for 1 week. The same volume of saline was injected in the control group. Neurobehavioral tests using the Basso, Beattie, Bresnahan scale and the oblique board test were performed for 1 week starting at 2 hours before surgery up to day 7 after surgery. At day 7 after surgery, tissues from the compressed cauda equina (L5-L6) were subjected to hematoxylin and eosin, luxol fast blue, or immunofluorescence staining, whereas the terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end label assay staining was performed on the tissue from the dorsal root ganglions and the lumbar segment of the spinal cord proximal to the compressed cauda equina (L5-L6). RESULTS: The behavioral results suggested a significant improvement in the lower limb motor function in the VPA group compared with controls (P < 0.05). Furthermore, histologic assessment revealed a significant reduction in nerve fibers showing Wallerian degeneration and demyelinating lesions in the VPA group, in addition to an increased myelination compared with the control group (P < 0.05). The terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end label assay staining revealed a significant decrease in the number of apoptotic neurons in the spinal cord anterior horn and dorsal root ganglions in the VPA group compared with controls (P < 0.05). CONCLUSIONS: Our data demonstrated that VPA could alleviate cauda equina injury, reduce apoptotic cells, and improve motor recovery, suggesting a neuroprotective effect in acute cauda equina syndrome. PMID- 28867326 TI - Decompressive Cranioplasty in a Patient with Osteopetrosis. AB - BACKGROUND: Osteopetrosis is a heterogeneous group of uncommon congenital disorders that causes bony sclerosis and remodeling. Patients who are symptomatic can show significant neurologic consequences with the involvement of cranial nerves and symptoms of increased intracranial pressure (ICP). CASE DESCRIPTION: We report an unusual case of a 26-year-old woman with an autosomal-dominant type of osteopetrosis who presented with headache and severe visual deterioration, both attributed to increased ICP. A hemicranioplasty was preformed, resulting in the resolution of her symptoms of ICP and stabilization of her vision. Postoperative imaging showed expansion of the ventricles and the subarachnoid spaces with an improvement of the associated cerebellar herniation. CONCLUSIONS: In conclusion, in patients with symptomatic osteopetrosis, cranioplasty can be considered as an option to treat high ICP-related symptoms. PMID- 28867327 TI - On Protecting Young People's Brains. PMID- 28867328 TI - The Volume of the Third Ventricle as a Prognostic Marker for Shunt Dependency After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Hydrocephalus is a common sequelae of aneurysmal subarachnoid hemorrhage (aSAH). However, in daily routine it is difficult to predict a patient's need for ventricular shunt placement in the course of the disease. OBJECTIVE: The purpose of this study was to identify radiologic predictors for development of a shunt-dependent hydrocephalus after aSAH. METHODS: A cohort of 217 patients with aSAH with adequate pretreatment computed tomography (CT) imaging was retrospectively reviewed. All variables, including demographic data, treatment, and initial CT imaging were gathered and grading was performed using Hunt and Hess, Graeb, LeRoux, and modified Fisher scores. Analysis of the radiographic parameters consisted of straight measurement and three-dimensional volumetry using manual segmentation. Univariate and multivariate statistical analyses were performed to identify predictive parameters. RESULTS: Of 217 patients, 36 (17.5%) required a ventricular shunt (VS). A receiver operating characteristic analysis between the volume of the third ventricle and shunt dependent hydrocephalus showed a significant cutoff at a volume of 2.3 cm3 with a 4.3-fold higher risk for shunt dependency (P < 0.001). However, the treatment modality and classification according to the mentioned scores were not associated with the need for VS after aSAH. In univariate and multivariate analysis, the volume of the third ventricle on admission remained a significant prognostic marker for the need of a VS. CONCLUSIONS: Our data suggest that the volume of the third ventricle in the initial CT is a strong predictor for shunt dependency after aSAH. PMID- 28867329 TI - Patchy Parasitized Skin Governs Leishmania donovani Transmission to Sand Flies. AB - Doehl et al. have combined empirical data with computer simulation to demonstrate that RAG-2 mice intravenously infected with Leishmania donovani form heterogeneous skin parasite patches that govern infectiousness to sand flies. This model provides a much-needed tool to explore the relevance of asymptomatic and symptomatic visceral leishmaniasis patients as infection reservoirs. PMID- 28867330 TI - Silencing of juvenile hormone epoxide hydrolase gene (Nljheh) enhances short wing formation in a macropterous strain of the brown planthopper, Nilaparvata lugens. AB - The rice brown planthopper, Nilaparvata lugens, is an important migratory pest in many rice planting areas of Asia. The typical wing dimorphism of N. lugens gives them flexibility to adapt to different environmental cues. As an important hormone in the insect's endocrine regulation, juvenile hormone (JH) has previously been shown to participate in the wing morph determination of N. lugens. In this paper, we investigated the possible wing morph determination roles of two JH metabolic enzymes, JH esterase (JHE) and JH epoxide hydrolase (JHEH). A 1957-bp full-length cDNA sequence encoding JHEH in N. lugens (NlJHEH) was first cloned from a hemipteran insect. Except for an uncertain transmembrane segment prediction, the deduced 454-amino-acid sequence of Nljheh has all of the conserved domains of JHEHs such as the H147GWP150, Tyr293 and Tyr368 motif corresponding to the oxyanion hole and the residues Asp222, Glu398, and His425 in the catalytic triad. qRT-PCR results showed that both Nljhe and Nljheh had different expression timeframes between a predominantly brachypterous strain (BS) and a macropterous strain (MS) of N. lugens, indicating that these two enzymes may participate in wing dimorphism regulation in brown planthopper. Silencing Nljheh expression by dsRNA injection enhanced short wing formation in the macropterous strain of N. lugens, while the brachypterizing individuals were mainly females. Compared to the dsgfp injection control, silencing Nljhe had no brachypterizing effect. Our results indicated that NlJHEH plays an important role in the wing morph determination of N. lugens. PMID- 28867331 TI - Reference ranges for serum S100B neuroprotein specific to infants under four months of age. AB - BACKGROUND: Minor head traumatisms are a common reason for consultation in paediatric emergency departments. The diagnosis of traumatic brain injuries involves performing a cranial computed tomography (CCT), associated with a risk of cancer due to the radiation. The serum S100B is an effective biomarker used to reduce reliance on CCT. While reference ranges have been determined, the limited number of cases regarding infants less than 4months of age has not allowed this biomarker to be used with this age group. Our study aimed to determine reference ranges for serum S100B based on a larger number of infants from birth to 4months of age. METHODS: Three centres included infants coming to the hospital for whom blood samples were taken. These samples were analysed to determine the upper reference values based on the 95th percentile. RESULTS: 135 samples were analysed. The upper reference value was 0.51MUg/L for children aged 0 to 4months. There was no effect of the gender. CONCLUSIONS: This study provides serum S100B reference ranges based on the largest group of neurologically healthy 0 to 4 month-old infants analysed to date. Reliable reference values of S100B for children are now determined. It is the first step towards validation of thresholds for studies integrating S100B into a clinical decision rule for MHT in children. PMID- 28867332 TI - Editorial overview: Paleovirology: the genomic fossil record, and consequences of ancient viral infections. PMID- 28867333 TI - Crimean-Congo haemorrhagic fever: "What is not sought is not found". PMID- 28867334 TI - Antihypertensive overtreatment in people 80 years old and older. AB - BACKGROUND AND OBJECTIVE: To study the proportion of patients older than 80 years old with hypertension and pharmacological overtreatment. PATIENTS AND METHODS: Cross-sectional simulation study, including 281 patients older than 80 years old of primary prevention, randomly selected, with good control of hypertension (systolic blood pressure<150mmHg, diastolic blood pressure<90mmHg), treated with a maximum of 3 medications. Overtreatment was considered if at least one medication could be removed and good control persisted, calculating how the blood pressure would raise with Law's meta-analysis, which estimates blood pressure reductions by pre-treatment levels, number and dose of medications. RESULTS: The average age was 85.3 years (64.8% women). A percentage of 33.6 were taking one medication, 46.3% 2 and 22.1% 3, with the most prescribed being thiazides (69.4%), ACE inhibitors (51.3%), ARBs (23.4%), calcium antagonists (21%) and beta blockers (19.6%). Overtreatment was 90.7%, with 2 medications being able to be removed in 63.1% of cases and 3 in 43.1%. Polypharmacy (OR 2.47; 95% CI 1.07 5.69; P=.033) was associated with a greater likely removal of at least one medication. CONCLUSIONS: The proportion of patients with overtreatment is high. Changing good control criteria could contribute to a reasoned deprescription. PMID- 28867335 TI - Home blood pressure vs. clinic blood pressure measurement-based follow up in type ii diabetics: Effect on 24-h ambulatory BP and albuminuria. Randomised trial. AB - BAKGROUND AND OBJECTIVE: To compare the efficacy of two strategies of blood pressure (BP) measurement-based follow-up in hypertension and albuminuria control. PATIENTS AND METHODS: Multicentre, prospective, randomised, open trial with a parallel-group design. Nineteen primary care centres and a hospital clinic participated. Adult type 2 diabetics with systolic BP >=140mmHg without relevant renal disease were randomised to one of two follow-up strategies: 1) standard follow up, with a clinic BP target <140/90mmHg and 2) self-monitoring home BP (SMHBP)-based follow up, with a BP target <135/85mmHg. Biochemical standard blood variables, albuminuria, and 24-h ambulatory BP monitoring were performed at entry, 12 and 24 months. The main outcome measurement was 24-h ambulatory systolic BP variation. Albuminuria change was analysed as a secondary outcome. RESULTS: 116 patients were analysed (mean age: 66.8 years). Mean systolic ambulatory 24- h BP change in two years was 3.9mmHg (95% CI 1.8-6.1). We did not find significant differences between both groups (p=0.706). Similarly, no differences were found when we compared other ambulatory BP values. Initial albuminuria was similar in both groups and did not significantly changed throughout the follow-up period. CONCLUSION: In type 2 diabetics without relevant nephropathy a SMHBP- based follow up was equivalent to a standard clinic-based BP follow up in BP and albuminuria control. PMID- 28867336 TI - Plasmatic levels of N-terminal pro-atrial natriuretic peptide in preeclamptic patients and healthy normotensive pregnant women. AB - BACKGROUND AND OBJECTIVE: To compare plasma N-terminal pro-atrial natriuretic peptide concentrations in preeclamptic patients and healthy normotensive pregnant women. METHODS: A cases-controls study was done with 180 patients at Hospital Central Dr. Urquinaona, Maracaibo, Venezuela, that included 90 preeclamptic patients (group A; cases) and 90 healthy normotensive pregnant women selected with the same age and body mass index similar to group A (group B; controls). Blood samples were collected one hour after admission and prior to administration of any medication in group A to determine plasma N-terminal pro-atrial natriuretic peptide and other laboratory parameters. RESULTS: Plasma N-terminal pro-atrial natriuretic peptide concentrations in group A (mean 1.01 [0.26] pg/mL) showed a significant difference when compared with patients in group B (mean 0.55 [0.07] pg/mL; P<.001]. There was no significant correlation with systolic and diastolic blood pressure values in preeclamptic patients (P=ns). A cut-off value of 0.66ng/mL had an area under the curve of 0.93, sensitivity of 87.8%, specificity of 83.3%, a positive predictive value of 84.0% and a negative predictive value of 87.2%, with a diagnostic accuracy of 85.6%. CONCLUSION: Preeclamptic patients have significantly higher concentrations of plasma N terminal pro-atrial natriuretic peptide compared with healthy normotensive pregnant women, with high predictive values for diagnosis. PMID- 28867337 TI - Ethics in clinical research: Contributions of the new version of the Council for International Organizations of Medical Sciences guidelines. PMID- 28867338 TI - Anti-N-methyl-D-aspartate-receptor encephalitis due to ovarian teratoma. PMID- 28867339 TI - Multimodal neural correlates of cognitive control in the Human Connectome Project. AB - Cognitive control is a construct that refers to the set of functions that enable decision-making and task performance through the representation of task states, goals, and rules. The neural correlates of cognitive control have been studied in humans using a wide variety of neuroimaging modalities, including structural MRI, resting-state fMRI, and task-based fMRI. The results from each of these modalities independently have implicated the involvement of a number of brain regions in cognitive control, including dorsal prefrontal cortex, and frontal parietal and cingulo-opercular brain networks. However, it is not clear how the results from a single modality relate to results in other modalities. Recent developments in multimodal image analysis methods provide an avenue for answering such questions and could yield more integrated models of the neural correlates of cognitive control. In this study, we used multiset canonical correlation analysis with joint independent component analysis (mCCA + jICA) to identify multimodal patterns of variation related to cognitive control. We used two independent cohorts of participants from the Human Connectome Project, each of which had data from four imaging modalities. We replicated the findings from the first cohort in the second cohort using both independent and predictive analyses. The independent analyses identified a component in each cohort that was highly similar to the other and significantly correlated with cognitive control performance. The replication by prediction analyses identified two independent components that were significantly correlated with cognitive control performance in the first cohort and significantly predictive of performance in the second cohort. These components identified positive relationships across the modalities in neural regions related to both dynamic and stable aspects of task control, including regions in both the frontal-parietal and cingulo-opercular networks, as well as regions hypothesized to be modulated by cognitive control signaling, such as visual cortex. Taken together, these results illustrate the potential utility of multi-modal analyses in identifying the neural correlates of cognitive control across different indicators of brain structure and function. PMID- 28867341 TI - Phase-synchronization-based parcellation of resting state fMRI signals reveals topographically organized clusters in early visual cortex. AB - Resting-state fMRI is widely used to study brain function and connectivity. However, interpreting patterns of resting state (RS) fMRI activity remains challenging as they may arise from different neuronal mechanisms than those triggered by exogenous events. Currently, this limits the use of RS-fMRI for understanding cortical function in health and disease. Here, we examine the phase synchronization (PS) properties of blood-oxygen level dependent (BOLD) signals obtained during visual field mapping (VFM) and RS with 7T fMRI. This data-driven approach exploits spatiotemporal covariations in the phase of BOLD recordings to establish the presence of clusters of synchronized activity. We find that, in both VFM and RS data, selecting the most synchronized neighboring recording sites identifies spatially localized PS clusters that follow the topographic organization of the visual cortex. However, in activity obtained during VFM, PS is spatially more extensive than in RS activity, likely reflecting stimulus driven interactions between local responses. Nevertheless, the similarity of the PS clusters obtained for RS and stimulus-driven fMRI suggest that they share a common neuroanatomical origin. Our finding justifies and facilitates direct comparison of RS and stimulus-evoked activity. PMID- 28867340 TI - BDNF Val66Met polymorphism tunes frontolimbic circuitry during affective contextual learning. AB - Adaptive learning impairments are common in cognitive and behavioral disorders, but the neurogenetic mechanisms supporting human affective learning are poorly understood. We designed a higher-order contextual learning task in which healthy participants genotyped for the Val66Met polymorphism of the brain derived neurotropic factor gene (BDNF) were required to choose the member of a picture pair most congruent with the emotion in a previously-viewed facial expression video in order to produce an advantageous monetary outcome. Functional magnetic resonance imaging (fMRI) identified frontolimbic blood oxygenation level dependent (BOLD) reactivity that was associated with BDNF Val66Met genotype during all three phases of the learning task: aversive and reward-predictive learning, contextually-challenging decision-making, and choice-related monetary loss-avoidance and gain outcomes. Relative to Val homozygotes, Met carriers showed attenuated ventromedial prefrontal response to predictive affective cues, dorsolateral prefrontal signaling that depended on decision difficulty, and enhanced ventromedial prefrontal reactivity that was specific to loss-avoidance. These findings indicate that the BDNF Val66Met polymorphism is associated with functional tuning of behaviorally-relevant frontolimbic circuitry, particularly involving the ventromedial prefrontal cortex, during higher-order learning. PMID- 28867342 TI - Thresholds of Toxicological Concern for cosmetics-related substances: New database, thresholds, and enrichment of chemical space. AB - A new dataset of cosmetics-related chemicals for the Threshold of Toxicological Concern (TTC) approach has been compiled, comprising 552 chemicals with 219, 40, and 293 chemicals in Cramer Classes I, II, and III, respectively. Data were integrated and curated to create a database of No-/Lowest-Observed-Adverse-Effect Level (NOAEL/LOAEL) values, from which the final COSMOS TTC dataset was developed. Criteria for study inclusion and NOAEL decisions were defined, and rigorous quality control was performed for study details and assignment of Cramer classes. From the final COSMOS TTC dataset, human exposure thresholds of 42 and 7.9 MUg/kg-bw/day were derived for Cramer Classes I and III, respectively. The size of Cramer Class II was insufficient for derivation of a TTC value. The COSMOS TTC dataset was then federated with the dataset of Munro and colleagues, previously published in 1996, after updating the latter using the quality control processes for this project. This federated dataset expands the chemical space and provides more robust thresholds. The 966 substances in the federated database comprise 245, 49 and 672 chemicals in Cramer Classes I, II and III, respectively. The corresponding TTC values of 46, 6.2 and 2.3 MUg/kg-bw/day are broadly similar to those of the original Munro dataset. PMID- 28867343 TI - Assessment of clinical symptoms in household contacts of confirmed pertussis cases. AB - OBJECTIVES: We assessed the value of the clinical symptoms included in the case definition of pertussis in household contacts of laboratory-confirmed cases. METHODS: A prospective epidemiological study was made in two Spanish regions. Household contacts were identified for each confirmed case reported during 2012 and 2013. Two clinical samples were taken to determine the presence or absence of Bordetella pertussis by culture or real-time PCR. Clinical variables, age and vaccination status were recorded. Positive and negative likelihood ratios (PLR, NLR) were estimated for each symptom. RESULTS: 2852 household contacts of 688 confirmed cases were reported. 178 household contacts with clinical symptoms were analyzed: 150 were laboratory confirmed and 28 were not. The clinical symptom with the highest PLR in comparison with the NLR was paroxysmal cough(PLR 4.76; 95% CI 1.91-11.87 and NLR 0.37; 95% CI 0.28-0.49). The contrast between the PLR and NLR was especially important for persons aged <18 years (PLR 7.08; 95% CI 1.10-45.74 and NLR 0.32; 95% CI 0.21-0.49). CONCLUSIONS: The clinical symptoms of pertussis are poor predictors of pertussis disease, independently of the vaccination status. Differences were observed between persons aged <18 years and adults. To adopt the appropriate treatment and control measures, rapid laboratory confirmation by PCR of all household contacts of confirmed cases who present any clinical symptoms compatible with pertussis should be recommended. PMID- 28867344 TI - NK Cell Alloreactivity against KIR-Ligand-Mismatched HLA-Haploidentical Tissue Derived from HLA Haplotype-Homozygous iPSCs. AB - HLA haplotype-homozygous (HLA-homo) induced pluripotent stem cells (iPSCs) are being prepared to be used for allogeneic transplantation of regenerated tissue into recipients carrying an identical haplotype in one of the alleles (HLA hetero). However, it remains unaddressed whether natural killer (NK) cells respond to these regenerated cells. HLA-C allotypes, known to serve as major ligands for inhibitory receptors of NK cells, can be classified into group 1 (C1) and group 2 (C2), based on their binding specificities. We found that the T cells and vascular endothelial cells regenerated from HLA-homo-C1/C1 iPSCs were killed by specific NK cell subsets from a putative HLA-hetero-C1/C2 recipient. Such cytotoxicity was canceled when target cells were regenerated from iPSCs transduced with the C2 gene identical to the recipient. These results clarify that NK cells can kill regenerated cells by sensing the lack of HLA-C expression and further provide the basis for an approach to prevent such NK cell-mediated rejection responses. PMID- 28867345 TI - A PITX3-EGFP Reporter Line Reveals Connectivity of Dopamine and Non-dopamine Neuronal Subtypes in Grafts Generated from Human Embryonic Stem Cells. AB - Development of safe and effective stem cell-based therapies for brain repair requires an in-depth understanding of the in vivo properties of neural grafts generated from human stem cells. Replacing dopamine neurons in Parkinson's disease remains one of the most anticipated applications. Here, we have used a human PITX3-EGFP embryonic stem cell line to characterize the connectivity of stem cell-derived midbrain dopamine neurons in the dopamine-depleted host brain with an unprecedented level of specificity. The results show that the major A9 and A10 subclasses of implanted dopamine neurons innervate multiple, developmentally appropriate host targets but also that the majority of graft derived connectivity is non-dopaminergic. These findings highlight the promise of stem cell-based procedures for anatomically correct reconstruction of specific neuronal pathways but also emphasize the scope for further refinement in order to limit the inclusion of uncharacterized and potentially unwanted cell types. PMID- 28867346 TI - Germline Stem Cell Activity Is Sustained by SALL4-Dependent Silencing of Distinct Tumor Suppressor Genes. AB - Sustained spermatogenesis in adult males and fertility recovery following germ cell depletion are dependent on undifferentiated spermatogonia. We previously demonstrated a key role for the transcription factor SALL4 in spermatogonial differentiation. However, whether SALL4 has broader roles within spermatogonia remains unclear despite its ability to co-regulate genes with PLZF, a transcription factor required for undifferentiated cell maintenance. Through development of inducible knockout models, we show that short-term integrity of differentiating but not undifferentiated populations requires SALL4. However, SALL4 loss was associated with long-term functional decline of undifferentiated spermatogonia and disrupted stem cell-driven regeneration. Mechanistically, SALL4 associated with the NuRD co-repressor and repressed expression of the tumor suppressor genes Foxl1 and Dusp4. Aberrant Foxl1 activation inhibited undifferentiated cell growth and survival, while DUSP4 suppressed self-renewal pathways. We therefore uncover an essential role for SALL4 in maintenance of undifferentiated spermatogonial activity and identify regulatory pathways critical for germline stem cell function. PMID- 28867347 TI - Functional Enterospheres Derived In Vitro from Human Pluripotent Stem Cells. AB - Intestinal organoids derived from human pluripotent stem cells (hPSCs) are valuable in vitro research models that enable simplified access to human gastrointestinal tissues. Here, we report the in vitro generation of enterospheres (hEnS) from hPSC-derived gastrointestinal epithelial precursors. hEnS are cystic spheroids with a simple uniform structure composed entirely of intestinal epithelium. hEnS express markers of mature brush border cells and share a transcriptome profile similar to that of more mature intestinal organoids. Modulation of signaling cues enables control of hEnS growth and differentiation, including long-term propagation. We show that hEnS can be exploited for functional studies: hEnS display an innate immune response when treated with enteric pathogens, and transgenic modification of hEnS with a fluorescence cell-cycle reporter enables hEnS-forming stem cell enrichment. Our work establishes hEnS as an accessible and tractable in vitro modeling system for studying human gastrointestinal biology. PMID- 28867349 TI - Engineering Escherichia coli membrane phospholipid head distribution improves tolerance and production of biorenewables. AB - Economically competitive microbial production of biorenewable fuels and chemicals is often impeded by toxicity of the product to the microbe. Membrane damage is often identified as a major mechanism of this toxicity. Prior efforts to strengthen the microbial membrane by changing the phospholipid distribution have largely focused on the fatty acid tails. Herein, a novel strategy of phospholipid head engineering is demonstrated in Escherichia coli. Specifically, increasing the expression of phosphatidylserine synthase (+pssA) was found to significantly increase both the tolerance and production of octanoic acid, a representative membrane-damaging solvent. Tolerance of other industrially-relevant inhibitors, such as furfural, acetate, toluene, ethanol and low pH was also increased. In addition to the increase in the relative abundance of the phosphoethanolamine (PE) head group in the +pssA strain, there were also changes in the fatty acid tail composition, resulting in an increase in average length, percent unsaturation and decreased abundance of cyclic rings. This +pssA strain had significant changes in: membrane integrity, surface potential, electrochemical potential and hydrophobicity; sensitivity to intracellular acidification; and distribution of the phospholipid tails, including an increase in average length and percent unsaturation and decreased abundance of cyclic rings. Molecular dynamics simulations demonstrated that the +PE membrane had increased resistance to penetration of ethanol into the hydrophobic core and also the membrane thickness. Further hybrid models in which only the head group distribution or fatty acid tail distribution was altered showed that the increase in PE content is responsible for the increase in bilayer thickness, but the increased hydrophobic core thickness is due to altered distribution of both the head groups and fatty acid tails. This work demonstrates the importance of consideration of the membrane head groups, as well as a modeling approach, in membrane engineering efforts. PMID- 28867348 TI - Cellular Computations Underlying Detection of Gaps in Sounds and Lateralizing Sound Sources. AB - In mammals, acoustic information arises in the cochlea and is transmitted to the ventral cochlear nuclei (VCN). Three groups of VCN neurons extract different features from the firing of auditory nerve fibers and convey that information along separate pathways through the brainstem. Two of these pathways process temporal information: octopus cells detect coincident firing among auditory nerve fibers and transmit signals along monaural pathways, and bushy cells sharpen the encoding of fine structure and feed binaural pathways. The ability of these cells to signal with temporal precision depends on a low-voltage-activated K+ conductance (gKL) and a hyperpolarization-activated conductance (gh). This 'tale of two conductances' traces gap detection and sound lateralization to their cellular and biophysical origins. PMID- 28867350 TI - Health Disparities in Adolescent Bariatric Surgery: Nationwide Outcomes and Utilization. AB - PURPOSE: Bariatric surgery represents an appropriate treatment for adolescent severe obesity, but its utilization remains low in this patient population. We studied the impact of race and sex on preoperative characteristics, outcomes, and utilization of adolescent bariatric surgery. METHODS: Retrospective analysis (2007-2014) of adolescent bariatric surgery using the Bariatric Outcomes Longitudinal Database, a national database that collects bariatric surgical care data. We assessed the relationships between baseline characteristics and outcomes (weight loss and remission of obesity-related conditions [ORCs]). Using the National Health and Nutrition Examination Survey and U.S. census data, we calculated the ratio of severe obesity and bariatric procedures among races and determined the ratio of ratios to assess for disparities. RESULTS: About 1,539 adolescents underwent bariatric surgery. Males had higher preoperative body mass index (BMI; 51.8 +/- 10.5 vs. 47.1 +/- 8.7, p < .001) and higher rates of obstructive sleep apnea and dyslipidemia. Blacks had higher preoperative BMI (52.4 +/- 10.6 vs. 47.3 +/- 8.3; 48.7 +/- 8.8; 48.2 +/- 12.1 kg/m2; whites, Hispanics, and others, respectively p < .001) and higher rates of hypertension, obstructive sleep apnea, and asthma. Weight loss and ORCs remission rates did not differ between sexes or races after accounting for the rate of severe obesity in each racial group. White adolescents underwent bariatric surgery at a higher proportion than blacks and Hispanics (2.5 and 2.3 times higher, respectively). CONCLUSIONS: Preoperative characteristics vary according to race and sex. Race and sex do not impact 12-month weight loss or ORC's remission rates. Minority adolescents undergo bariatric surgery at lower-than-expected rates. PMID- 28867351 TI - Body Mass Index z-Scores and Weight Status Predict Conduct Disorder Symptoms in Adolescents. AB - PURPOSE: The goal of the study was to examine whether baseline body mass index (BMI) z-scores and weight status predicted conduct disorder (CD) symptoms in 368 adolescents (15-17 years). METHODS: Participants in the 10th and 11th grades completed self-report questionnaires at baseline and at a 2-year follow-up. Baseline BMI z-scores and weight status were derived from self-reports of height and weight. CD symptoms were assessed using a symptom checklist. Covariates included baseline demographics, depressive symptoms, alcohol consumption, drug use, and a retrospective report of CD symptoms before age 15 years. RESULTS: A cubic association was observed between baseline BMI z-scores and follow-up CD symptoms (p = .047), such that a positive association emerged only among adolescents with BMI z-scores of greater than ~1.5. Adolescents who were obese at baseline reported more follow-up CD symptoms than nonoverweight adolescents (p = .008). Higher baseline BMI z-scores were associated with increased odds of endorsing probable CD at follow-up (p's < .03). Obese adolescents were more likely to report the presence of probable CD at follow-up than overweight and nonoverweight adolescents (p's <= .01). CONCLUSIONS: Findings suggest that nutritional status, particularly high BMI z-scores and obese weight status, may contribute to elevated CD symptoms during adolescence, which should be dually addressed in screening and intervention efforts. PMID- 28867352 TI - Health Concerns of Transgender and Gender Nonconforming Youth and Their Parents Upon Presentation to a Transgender Clinic. AB - PURPOSE: The purpose of the study was to determine the frequency of specific health concerns identified by transgender and gender nonconforming patients and their parents at initial clinic visit. METHODS: Checklists were developed in an iterative process and distributed to both patients and parents at their initial visit to a transgender clinic. Retrospective chart review and secondary data analyses were performed to determine the number of items endorsed, frequency with which each item was endorsed, and provider domain of each item endorsed: physician, social work, or both physician and social work. RESULTS: Checklists were collected from 118 patients and 103 parents. Patients endorsed a mean of 8.4 concerns (range 0-22) and parents 7.9 concerns (range 0-20). The most commonly endorsed patient concerns included use of gender-affirming hormones, steps for transition, gender-affirming surgery, restroom/dressing room use, and legal issues. Common parent concerns included general resources, child safety at school, acute mental health concerns, restroom/dressing room use, and steps for transition. Of the concerns endorsed by patients, 44% were in the social work domain, 37% in the physician domain, and 19% in both the social work and physician domain. Of the concerns endorsed by parents, 40% were in the social work domain, 31% in the physician domain, and 29% in the social work and physician domain. CONCLUSIONS: Although patients and parents had similar numbers of concerns, they primarily focused on different topics. Youth were more interested in hormones and transition, while parents were more interested with transition and acceptance. Many concerns for both patients and parents fell within the social work domain. PMID- 28867353 TI - Cessation of Injecting and Preceding Drug Use Patterns Among a Prospective Cohort of Street-Involved Youth. AB - PURPOSE: Injection drug use is prevalent among street-involved youth, but patterns of cessation are poorly described. We identified drug use patterns preceding injection cessation among street-involved youth. METHODS: From September 2005 to May 2015, we collected data from the At-Risk Youth Study, a prospective cohort of street-involved youth in Vancouver, Canada, and limited the sample to actively injecting youth. The primary outcome was cessation of injecting self-reported at semiannual follow-up visits. We used Cox regression to identify drug use patterns preceding cessation. RESULTS: Among 383 youth, 65% were male, mean age was 22.3 (standard deviation, 2.5; range, 15-30) years, and 171 (45%) ceased injecting for 6 months or more (crude incidence density 22 per 100 person-years; 95% confidence interval [CI], 19-26). Youth who ceased were less likely to have injected daily (adjusted hazard ratio [AHR], .40; 95% CI, .28 .56), injected heroin (AHR, .40; 95% CI, .29-.56), or injected crystal methamphetamine (AHR, .43; 95% CI, .31-.59) before cessation. Noninjection heroin use was positively associated with injection cessation (AHR, 1.52; 95 CI, 1.12 2.08). Addiction treatment was not associated with cessation. At the time of cessation, 101 (59%) youth continued to use "hard" noninjection drugs such as heroin and crystal methamphetamine. CONCLUSIONS: Periods of injection cessation were common but frequently accompanied by ongoing noninjection drug use. Findings indicate that trajectories of injection drug use among youth are complex and highlight the need to further explore relationships between ongoing noninjection drug use and injection cessation. PMID- 28867354 TI - Development of a simple and economical diagnostic test for canine leishmaniasis. AB - Visceral leishmaniasis is a public health problem worldwide. The early diagnosis in dogs is crucial, since they are an epidemiologically relevant reservoir of the disease. The aim of a field study is to early identify the disease allowing rapid intervention to reduce its effects. We propose an immunoagglutination test as a visual in situ method for diagnosis of canine visceral leishmaniasis. Latex protein complexes were sensitized by covalent coupling of a chimeric recombinant antigen of Leishmania spp. onto polystyrene latex with carboxyl functionality. The reaction time and the antigen concentration under which the immunoagglutination assay shows greater discrimination between the responses of a positive control serum and a negative control serum were determined. Then, the latex-protein complexes were evaluated as a visual diagnostic tool with a panel of 170 sera. The test may be read between 2 and 5 min and can be performed even using sera with elevated concentration of lipids, bilirubin or with variable percentage of hemolysis. The sensitivity, the specificity and the diagnostic accuracy were 78%; 100% and >80%, respectively. The visual immunoagglutination test is of potential application as a method for field studies because it shows results in less than 5 min, it is easy to implement and does not require sophisticated equipment. PMID- 28867355 TI - The relationship between physical activity and vitamin D status in postpartum lactating and formula-feeding women. AB - Existing research shows an association between physical activity levels and vitamin D status in the elderly, men, women, children, and adolescent populations. This association has not yet been investigated in postpartum women. We hypothesized that based on the relationship between vitamin D and physical activity found in other populations, greater physical activity levels in postpartum women will be associated with higher serum 25(OH)D levels. A post hoc analysis of 286 postpartum women with self reported physical activity data from the America on the Move survey, and measured circulating serum 25(OH)D (measured by RIA) as an indicator of vitamin D status, was gathered at baseline (4-6 weeks postpartum), 4 months, and 7 months postpartum. The data were analyzed using SAS 9.4 (Cary, NC). 39.9% of women at visit 1 (baseline), 52.8% of women at visit 4 (month 4), and 55.9% of women at visit 7 (month 7) were meeting the NIH recommendation of 150min of moderate intensity (3-6 METs) physical activity per week. Significant differences were seen in physical activity by race (p=0.007). Caucasians were more likely to meet the standard recommendation than African Americans or Hispanics. Using multiple regression models to examine associations between duration of physical activity and 25(OH)D concentration, controlling for race, BMI, feeding type, and METs, it was found that at visit 1, an increase in physical activity was associated with an increase in 25(OH)D of 1.3nmol/L (p=0.03) and achieving at least 2.5h/wk of physical activity had a trending association with an increase in 25(OH)D of 7.23nmol/L (p=.05). At visit 4 (also controlling for treatment group and sun exposure) achieving at least 1.5h/wk of physical activity was associated with an increase in 25(OH)D of 11.73nmol/L (p=.04). By visit 7, no association between physical activity and maternal 25(OH)D was observed. In a repeated measures, mixed model analysis predicting maternal 25(OH)D during the study, achieving at least the recommended 150min per week of physical activity (>2.5h) was not significantly associated with vitamin D status (pNS). While no definitive conclusions can be drawn regarding precise levels of physical activity influencing 25(OH)D levels in postpartum women, the data suggest that increased activity during the first 4 months after birth is associated with improved vitamin D status. Additional research is needed because of the inconsistency seen at visit 7. PMID- 28867356 TI - Relationship of SULT1A1 copy number variation with estrogen metabolism and human health. AB - Human cytosolic sulfotransferase 1A1 (SULT1A1) is considered to be one of the most important SULT isoforms for metabolism, detoxification, and carcinogenesis. This theory is driven by observations that SULT1A1 is widely expressed in multiple tissues and acts on a wide range of phenolic substrates. SULT1A1 is subject to functional common copy number variation (CNV) including deletions or duplications. However, it is less clear how SULT1A1 CNV impacts health and disease. To better understand the biological role of SULT1A1 in human health, we genotyped CNV in 14,275 Marshfield Clinic patients linked to an extensive electronic health record. Since SULT1A1 is linked to steroid metabolism, select serum steroid hormones were measured in 100 individuals with a wide spectrum of SULT1A1 CNV genotypes. Furthermore, comprehensive phenome-wide association studies (PheWAS) were conducted using diagnostic codes and clinical text data. For the first time, individuals homozygous null for SULT1A1 were identified in a human population. Thirty-six percent of the population carried >2 copies of SULT1A1 whereas 4% had <=1 copy. Results indicate SULT1A1 CNV was negatively correlated with estrone-sulfate to estrone ratio predominantly in males (E1S/E1; p=0.03, r=-0.21) and may be associated with increased risk for common allergies. The effect of SULT1A1 CNV on circulating estrogen metabolites was opposite to the predicted CNV-metabolite trend based on enzymatic function. This finding, and the potential association with common allergies reported herein, warrants future studies. PMID- 28867357 TI - Serum prolidase enzyme activity in obese subjects and its relationship with oxidative stress markers. AB - BACKGROUND: The relationship between increased serum enzyme activity of prolidase and increased rate of collagen turnover in the arterial wall has been asserted in previous studies. Collagen reflects much of the strength to the connective tissue involved in the arterial wall. Atherosclerosis is very common vessel disease and oxidative stress plays a pivotal role in the etiopathogenesis. Our objective was to examine the serum enzyme activity of prolidase and its possible relationships with oxidative stress parameters in obese subjects. METHODS: Our present study was conducted 27 obese subjects and 26 age-matched healthy control subjects. The serum enzyme activity of prolidase in all study population was evaluated spectrophotometrically. Oxidative stress levels in obese subjects were analyzed with total antioxidant capacity (TAC) and total oxidant status (TOS) as well as oxidative stress index (OSI). RESULTS: Obese subjects have higher serum TOS and OSI indicators as well as prolidase activity than those in control subjects (for all; p<0.001). Moreover, obese subjects have lower levels of TAC than in those in healthy subjects (p<0.001). In the Pearson's correlation analysis, enzyme activity of prolidase was positively related with TOS (p<0.001, r=0.529) and OSI (p<0.001, r=0.519) as well as BMI (p<0.001, r=0.692) and inversely related with TAC (p<0.05, r=-0.405) in obese subjects. CONCLUSIONS: Increased serum prolidase activity and decreased antioxidant levels are likely to be a results of increased of oxidative stress levels in obese subjects. The significantly correlation between increased oxidative stress and increased prolidase activity may play a pivotal role in etiopathogenesis of atherosclerotic cardiovascular diseases in obese subjects. PMID- 28867358 TI - Radiation-Induced Large Vessel Cerebral Vasculopathy in Pediatric Patients With Brain Tumors Treated With Proton Radiation Therapy. AB - PURPOSE: The purpose of this research was to evaluate the incidence, time to development, imaging patterns, risk factors, and clinical significance of large vessel cerebral vasculopathy in pediatric patients with brain tumors treated with proton radiation therapy. METHODS AND MATERIALS: A retrospective study was performed on 75 consecutive pediatric patients with primary brain tumors treated with proton radiation therapy. Radiation-induced large vessel cerebral vasculopathy (RLVCV) was defined as intracranial large vessel arterial stenosis or occlusion confirmed on magnetic resonance angiography, computed tomographic angiography, catheter angiography, or a combination of these within an anatomic region with previous exposure to proton beam therapy and not present before radiation therapy. Clinical records were used to determine the incidence, timing, radiation dose to the large vessels, and clinical significance associated with the development of large vessel vasculopathy in these patients. RESULTS: RLVCV was present in 5 of 75 (6.7%) patients and included tumor pathologic features of craniopharyngioma (n=2), ATRT (n=1), medulloblastoma (n=1), and anaplastic astrocytoma (n=1). The median time from completion of radiation therapy to development was 1.5 years (mean, 3.0 years; range, 1.0-7.5 years). Neither mean age at the time of radiation therapy (5.1 years) nor mean radiation therapy dose to the large vessels (54.5 Gy) was a statistically significant risk factor. Four of the 5 patients with RLVCV presented with acute stroke and demonstrated magnetic resonance imaging evidence of acute infarcts in the expected vascular distributions. Angiography studies demonstrated collateral vessel formation in only 2 of the patients with RLVCV. No patients demonstrated acute hemorrhage or aneurysm. Two patients were treated with pial synangiomatosis surgery. CONCLUSIONS: RLVCV can occur in pediatric patients with brain tumors treated with proton radiation therapy. Further studies are necessary to determine potential risk factors for large vessel vasculopathy with proton radiation therapy in comparison with conventional photon radiation therapy. PMID- 28867359 TI - Novel heterozygous NOTCH3 pathogenic variant found in two Chinese patients with CADASIL. AB - NOTCH3 mutations have been described to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Here, we report 2 CADASIL patients from a Chinese family. Whole genome sequencing was performed on the two CADASIL patients. The novel variant c.128G>C in exon 2 of NOTCH3 was identified and confirmed through PCR-Sanger sequencing (Human Genome Variation Society nomenclature: HGVS: NOTCH3 c.128G>C; p.Cys43Ser). The heterozygous NOTCH3 variant cause a cysteine to serine substitution at codon 43. According to the variant interpretation guideline of American College of Medical Genetics and Genomics (ACMG), this variant was classified as "pathogenic". Other variants in HTRA1, COL4A1 and COL4A2 were also found, they were classified as "benign". PMID- 28867360 TI - The use of TMZ embedded hydrogels for the treatment of orthotopic human glioma xenografts. AB - The current treatment of glioblastoma multiforme (GBM) is limited by the restricted arsenal of agents which effectively cross the blood brain barrier (BBB). For example, only a fraction of temozolomide (TMZ) administered systemically is available for therapeutic effect because of the BBB and the instability of TMZ under physiologic conditions. A novel approach to overcome this obstacle is to bypass the BBB and locally deliver chemotherapeutic agents directly to the tumor mass. We have explored the loading of TMZ into a novel hydrogel matrix, which can be delivered in liquid form and then solidifies in situ and releases chemotherapy as the matrix dissolves. Here, we tested the effect of amphiphilic diblock copolypeptide hydrogels (DCHs) of 180-poly-lysine and 20-poly-leucine (K180L20) on TMZ using Glioblastoma models. In both the in vitro model, which involved treatment of a human glioblastoma GSC line suspended as neurospheres, and in vivo using an orthotopic glioma xenograft mouse model, we found that K180L20 could safely enhance the efficacy of TMZ. This technique may offer the opportunity to 'coat' the inner lining of the cavity following glioma resection with a slow-release TMZ and potentially decrease recurrence. Future studies in larger animals are needed to delineate this effect. PMID- 28867361 TI - Diphtheric encephalitis and brain neuroimaging features. AB - We report a rare case of paediatric diphtheria complicated with encephalitis. A 6 year-old boy who did not receive his scheduled diptheria-tetanus-pertusis vaccination presented with one episode of generalised convulsive seizure. His illness was preceded by a 3day history of fever associated with enlarged exudative tonsils with a pseudomembrane. He was commenced on intravenous penicillin and oral erythromycin. However, he developed progressive encephalopathy with focal neurological deficit which required intubation on day 5 of illness. Throat swab polymerase chain reaction for diphtheria toxin A and B were positive and diphtheria antitoxin was given. Magnetic resonance imaging (MRI) of brain showed T2-weighted hyperintensities over the anterior cingulate gyri, insular cortex and cerebellum. This is the first reported MRI finding of diphtheric encephalitis. Our report highlights the importance of neuroimaging in diagnosing diphtheric encephalitis particularly in cases with unremarkable cerebrospinal findings. PMID- 28867362 TI - Riluzole-induced recurrent pancreatitis. AB - Riluzole is the only drug approved for the treatment of patients with Amyotrophic Lateral Sclerosis (ALS). It is well tolerated, being the most frequent adverse effects asthenia, nausea and reversible increase of liver enzymes levels. Severe adverse effects are extremely rare. We report for the first time, two patients with sporadic limb-onset ALS who developed recurrent acute pancreatitis (AP), with portal vein thrombosis as complication, during treatment with riluzole. We suggest that AP should be considered asa probable rare and severe side effect of treatment with riluzole in patients with ALS. We believe that in patients who develop AP during treatment with riluzole, its withdrawn may prevent recurrent AP and should be discussed with patients. PMID- 28867363 TI - Methoxetamine produces rapid and sustained antidepressant effects probably via glutamatergic and serotonergic mechanisms. AB - Depression afflicts around 16% of the world's population, making it one of the leading causes of disease burden worldwide. Despite a number of antidepressants available today, the delayed onset time and low remission rate of these treatments are still a major challenge. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown to produce rapid and sustained antidepressant effects and has paved the way for a new generation of glutamate-based antidepressants. Methoxetamine (MXE) is a ketamine analogue that acts as an NMDA receptor antagonist and a serotonin reuptake inhibitor. However, no studies have evaluated the antidepressant effects of MXE. Here, we assessed whether MXE produces antidepressant effects and explored possible mechanisms underlying its effects. Mice were treated with MXE (2.5, 5, or 10 mg/kg) and their behavior was evaluated 30 min and 24 h later in an array of behavioral experiments used for screening antidepressant drugs. A separate group of mice were treated with NBQX, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin, a 5HT2 receptor antagonist, before MXE (5 mg/kg) administration in the forced swimming test (FST). We also investigated the effect of MXE on glutamatergic- and serotonergic-related genes in the mouse hippocampus using quantitative real-time PCR. MXE produced antidepressant effects 30 min after treatment that persisted for 24 h. Both NBQX and ketanserin blocked the antidepressant effects of MXE in the FST. MXE also altered hippocampal glutamatergic- and serotonergic gene expressions. These results suggest that MXE has rapid and sustained antidepressant effects, possibly mediated by the glutamatergic and serotonergic system. PMID- 28867365 TI - Correction. PMID- 28867366 TI - Assessment of saliva, hair and toenails as biomarkers of low level exposure to manganese from drinking water in children. AB - We evaluated hair, toenails, and saliva (whole and supernatant) as biomarkers of exposure to manganese (Mn) in 274 school age children (6-13 years) consuming well water in southeastern New Brunswick, Canada. Mn concentrations in tap water ranged from <0.03 to 1046MUgL-1 (geometric mean 5.96MUgL-1). The geometric mean of Mn intake resulting from the consumption of water was 0.25 (0-34.95) MUg kg 1day-1. Both Mn concentration in water and Mn intake were significantly correlated with Mn in hair (r=0.60 and r=0.53, respectively), Mn in toenail (r=0.29 and r=0.37 respectively) and to a lesser extent with Mn in saliva supernatant (r=0.14 and r=0.18, respectively). Mn in whole saliva did not correlate with Mn in water or Mn intake. Both Mn in hair and Mn in toenail allowed to discriminate the most exposed group from the least exposed group, based on Mn in water and Mn intake from water. In this group of children with low level Mn exposure, Mn concentrations in hair, and toenails reflected reasonably well Mn exposure from drinking water, whereas Mn content in saliva correlated less strongly. PMID- 28867367 TI - Clinical analysis of the approximate, 3-dimensional, biological effective dose equation in multiphase treatment plans. AB - A multiphase, approximate biological effective dose (BEDA) equation was introduced because most treatment planning systems (TPS) are incapable of calculating the true BED (BEDT). This work investigates the accuracy and precision of the multiphase BEDA relative to the BEDT in clinical cases. Ten patients with head and neck cancer and 10 patients with prostate cancer were studied using their treatment plans from Pinnacle3 9.2 (Philips Medical, Fitchburg, WI). The organs at risk (OARs) that were studied are the normal brain, left and right optic nerves, optic chiasm, spinal cord, brainstem, bladder, and rectum. BEDA and BEDT distributions were calculated using MATLAB 2010b (MathWorks, Natick, MA) and analyzed on a voxel basis for percent error, percent error volume histograms (PEVHs), Pearson correlation coefficient, and Bland Altman analysis. The maximum BED values that were calculated using the BEDA and BEDT methods were also analyzed. BEDA was found to always underestimate BEDT. The accuracy and precision of BEDA distributions varied between the organs: for optic chiasm and brainstem, 50% of the patients had an overall BEDA percent error of <1%; for left and right optic nerves, rectum, and bladder, 60% to 70% of the patients had an overall BEDA percent error of <1%; and for normal brain and spinal cord, 80% of the patients had an overall BEDA percent error of <1%. BEDA distributions had maximum errors ranging from 2% to 11%, with the 11% error occurring for bladder. BEDA produced much more accurate maximum BED values with adjacent organs such as normal brain, bladder, and rectum. This study has shown that BEDA can calculate BED distributions with acceptable accuracy under certain circumstances. However, its consistency and accuracy strongly depend on the dose distributions of the different treatment phases. One should be cautious when using BEDA. PMID- 28867368 TI - Plant ESCRT Complexes: Moving Beyond Endosomal Sorting. AB - The endosomal sorting complex required for transport (ESCRT) machinery is an ancient system that deforms membrane and severs membrane necks from the inside. Extensive evidence has accumulated to demonstrate the conserved functions of plant ESCRTs in multivesicular body (MVB) biogenesis and MVB-mediated membrane protein sorting. In addition, recent exciting findings have uncovered unique plant ESCRT components and point to emerging roles for plant ESCRTs in non endosomal sorting events such as autophagy, cytokinesis, and viral replication. Plant-specific processes, such as abscisic acid (ABA) signaling and chloroplast turnover, provide further evidence for divergences in the functions of plant ESCRTs during evolution. We summarize the multiple roles and current working models for plant ESCRT machinery and speculate on future ESCRT studies in the plant field. PMID- 28867364 TI - Cell-based and pharmacological neurorestorative therapies for ischemic stroke. AB - Ischemic stroke remains one of most common causes of death and disability worldwide. Stroke triggers a cascade of events leading to rapid neuronal damage and death. Neuroprotective agents that showed promise in preclinical experiments have failed to translate to the clinic. Even after decades of research, tPA remains the only FDA approved drug for stroke treatment. However, tPA is effective when administered 3-4.5 h after stroke onset and the vast majority of stroke patients do not receive tPA therapy. Therefore, there is a pressing need for novel therapies for ischemic stroke. Since stroke induces rapid cell damage and death, neuroprotective strategies that aim to salvage or replace injured brain tissue are challenged by treatment time frames. To overcome the barriers of neuroprotective therapies, there is an increasing focus on neurorestorative therapies for stroke. In this review article, we provide an update on neurorestorative treatments for stroke using cell therapy such as bone marrow derived mesenchymal stromal cells (BMSCs), human umbilical cord blood cells (HUCBCs) and select pharmacological approaches including Minocycline and Candesartan that have been employed in clinical trials. This review article discusses the present understanding of mechanisms of neurorestorative therapies and summarizes ongoing clinical trials. This article is part of the Special Issue entitled 'Cerebral Ischemia'. PMID- 28867369 TI - [Oral anticoagulation in atrial fibrillation: What is the guideline for using new drugs?] AB - OBJECTIVE: To assess whether there are differences between atrial fibrillation (AF) patients initiating new direct-acting oral anticoagulants (DOAC) therapy and vitamin K antagonist (VKA) therapy in an emergency service. METHODS: Descriptive, observational, prospective study. We enrolled patients with AF who were visited in a hospital emergency service over one year. RESULTS: This study included 492 patients with AF, and 189 subjects received anticoagulant therapy, 104 with VKA (55%), and 85 with DOAC (45%). The VKA group: mean age 76.1 years, male 50.9% and female 49.1%, CHA2DS2-VASc mean 3.2+/-1.3 points, and a HAS-BLED mean of 1.9+/ 0.8 points. The DOAC group: mean age 73.4 years, male 37.6% and female 63.3%, CHA2DS2-VASc mean 3.1+/-1.6 points, and a HAS-BLED mean of 1.7+/-0.8 points. On analysing the medical history, 17.3% of patients in the VKA group had a previous stroke, and 13.5% significant valve disease, as well as 7.1 and 1.2% of patients, respectively, in the DOAC group. In the analysis of the DOAC types, 24.2% of patients in the dabigatran group had a previous stroke, 22.7% in the rivaroxaban group had ischaemic heart disease. CONCLUSIONS: Patients with AF who start on treatment in emergency services with VKA or with DOAC show a similar profile of age, gender, CHA2DS2-VASc score, and HAS-BLED score. The patients with a history of valvular or ischaemic heart disease received more VKA than DOAC. When the patient has a history of stroke, the DOAC more used is dabigatran, and in patients with ischaemic heart disease it is preferred to give rivaroxaban. PMID- 28867370 TI - Transport mechanism of chitosan-N-acetylcysteine, chitosan oligosaccharides or carboxymethyl chitosan decorated coumarin-6 loaded nanostructured lipid carriers across the rabbit ocular. AB - To facilitate the hydrophobic drugs modeled by coumarin-6 (Cou-6) acrossing the cornea to the anterior chamber of the rabbit eye, chitosan (CS) derivatives including chitosan-N-acetyl-l-cysteine (CS-NAC), chitosan oligosaccharides (COS) and carboxymethyl chitosan (CMCS) modified nanostructured lipid carriers (NLCs) were designed and characterized. We found that, with similar size distribution and positivecharges, different CS derivatives based on NLCs led to distinctive delivery performance. In vivo precorneal retention study on rabbits revealed that these CS derivatives coating exhibited a stronger resistant effect than Cou-6 eye drops and Cou-6-NLC (P<0.05), moreover, the AUC(0-infinity), Cmax and MRT(0 infinity) of them followed the sequence of CMCS-Cou-6-NLC= 2mm and w>= 10mm. Comparison of suture retention and mode I crack opening tests reveals a linear correlation between break starting strength and tearing energy. This suggests that the defect created by the needle and the load applied by the suture thread lead to a fracture mechanics problem, which dominates the initiation of failure. PMID- 28867372 TI - Key themes and future prospects in translational multiple system atrophy research. AB - Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder with a highly variable clinical presentation. Unfortunately, there exists no effective therapy that can improve the course of the disease and symptomatic treatment options remain limited. Although significant progress in research has improved our understanding of MSA, knowledge gaps still remain. Thus, a global network focusing on different research areas is required to face this fatal disease. PMID- 28867373 TI - Etelcalcetide (AMG 416), a peptide agonist of the calcium-sensing receptor, preserved cortical bone structure and bone strength in subtotal nephrectomized rats with established secondary hyperparathyroidism. AB - Sustained elevation of parathyroid hormone (PTH) is catabolic to cortical bone, as evidenced by deterioration in bone structure (cortical porosity), and is a major factor for increased fracture risk in chronic kidney disease (CKD). Etelcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces PTH levels in subtotal nephrectomized (Nx) rats and in hemodialysis patients with secondary hyperparathyroidism (SHPT) in clinical studies; however, effects of etelcalcetide on bone have not been determined. In a rat model of established SHPT with renal osteodystrophy, etelcalcetide or vehicle was administered by subcutaneous (s.c.) injection to subtotal Nx rats with elevated PTH (>750pg/mL) once per day for 6weeks. Sham-operated rats receiving vehicle (s.c.) served as non-SHPT controls. Prior to treatment, significant increases in serum creatinine (2-fold), blood urea nitrogen (BUN, 3-fold), PTH (5-fold), fibroblast growth factor-23 (FGF23; 13-fold) and osteocalcin (12-fold) were observed in SHPT rats compared to non-SHPT controls. Elevations in serum creatinine and BUN were unaffected by treatment with vehicle or etelcalcetide. In contrast, etelcalcetide significantly decreased PTH, FGF23 and osteocalcin, whereas vehicle treatment did not. Cortical bone porosity increased and bone strength decreased in vehicle-treated SHPT rats compared to non-SHPT controls. Cortical bone structure improved and energy to failure was significantly greater in SHPT rats treated with etelcalcetide compared to vehicle. Mineralization lag time and marrow fibrosis were significantly reduced by etelcalcetide. In conclusion, etelcalcetide reduced bone turnover, attenuated mineralization defect and marrow fibrosis, and preserved cortical bone structure and bone strength by lowering PTH in subtotal Nx rats with established SHPT. PMID- 28867374 TI - Automatic registration of 2D histological sections to 3D microCT volumes: Trabecular bone. AB - Histomorphometry and microCT are the two dominant imaging techniques to study bone structure and quality to evaluate repair, regeneration, and disease. These two methods are complementary; where histology provides highly resolved tissue properties on a cellular level in 2D, microCT provides spatial information of bone micro-structure in 3D. For this reason, both of these modalities are commonly used in bone studies. As it is not trivial to combine the images of these two modalities, the two methods are typically applied to different specimens within a study. However, we believe that applying both imaging modalities to the same specimen with a suitable fusion strategy may further strengthen the value of each modality. Therefore, we propose a registration method to align 2D histology slices with a 3D microCT volume, without any prior knowledge of the sectioning direction. In a preprocessing step, bone is extracted from both images. Then, we use a strategy for initializing potential locations, and an iterative approach for searching for an ideal fitting plane using Radon based rigid transforms and feature-based affine alignments. The algorithm was tested and validated with simulated and real data. For the latter, microCT images of trabecular bone with 76 corresponding histological sections acquired from decalcified and calcified specimens were used. The registration resulted in 94.7% acceptable solutions as defined by a registration orientation error of less than 3 degrees . Average registration accuracy of the acceptable results was 0.6 degrees , leading to a target registration error for our method of 106.3MUm, computed based on landmarks annotated by an observer. This corresponds roughly to 10pixels in the images; although, the relation to actual visible structures that provide the features to register, is arguably more relevant. PMID- 28867375 TI - Calcified plaque modification alters local drug delivery in the treatment of peripheral atherosclerosis. AB - BACKGROUND: Calcific atherosclerosis is a major challenge to intraluminal drug delivery in peripheral artery disease (PAD). OBJECTIVES: We evaluated the effects of orbital atherectomy on intraluminal paclitaxel delivery to human peripheral arteries with substantial calcified plaque. METHODS: Diagnostic angiography and 3 D rotational imaging of five fresh human lower limbs revealed calcification in all main arteries. The proximal or distal segment of each artery was treated using an orbital atherectomy system (OAS) under simulated blood flow and fluoroscopy. Explanted arterial segments underwent either histomorphometric assessment of effect or tracking of 14C-labeled or fluorescent-labeled paclitaxel. Radiolabeled drug quantified bulk delivery and fluorescent label established penetration of drug over finer spatial domain in serial microscopic sections. Results were interpreted using a mathematical model of binding diffusion mediated arterial drug distribution. RESULTS: Lesion composition affected paclitaxel absorption and distribution in cadaveric human peripheral arteries. Pretreatment imaging calcium scores in control femoropopliteal arterial segments correlated with a log-linear decline in the bulk absorption rate constant of 14C-labeled, declining 5.5-fold per calcified quadrant (p=0.05, n=7). Compared to controls, OAS-treated femoropopliteal segments exhibited 180MUm thinner intima (p<0.001), 45% less plaque calcification, and 2 log orders higher paclitaxel bulk absorption rate-constants. Correspondingly, fluorescent paclitaxel penetrated deeper in OAS-treated femoropopliteal segments compared to controls, due to a 70% increase in diffusivity (p<0.001). CONCLUSIONS: These data illustrate that calcified plaque limited intravascular drug delivery, and controlled OAS treatment of calcific plaques resulted in greater drug permeability and improved adjunct drug delivery to diseased arteries. PMID- 28867376 TI - A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo. AB - Antibody-drug conjugates are generally believed to crucially rely on internalization into cancer cells for therapeutic activity. Here, we show that a non-internalizing antibody-drug conjugate, based on the F16 antibody specific to the alternatively spliced A1 domain of tenascin-C, mediates a potent therapeutic activity when equipped with the anthracycline PNU159682. The peptide linker, connecting the F16 antibody in IgG format at a specific cysteine residue to the drug, was stable in serum but could be efficiently cleaved in the subendothelial extracellular matrix by proteases released by the dying tumor cells. The results indicate that there may be a broader potential applicability of non-internalizing antibody-drug conjugates for cancer therapy than what had previously been assumed. PMID- 28867377 TI - Ultrasound-induced mild hyperthermia improves the anticancer efficacy of both Taxol(r) and paclitaxel-loaded nanocapsules. AB - We study the influence of ultrasound on paclitaxel-loaded nanocapsules in vitro and in vivo. These nanocapsules possess a shell of poly(dl-lactide-co-glycolide) poly(ethylene glycol) (PLGA-PEG) and a liquid core of perfluorooctyl bromide (PFOB). In vitro experiments show that mechanical effects such as cavitation are negligible for nanocapsules due to their small size and thick and rigid shell. As the mechanical effects were unable to increase paclitaxel delivery, we focused on the thermal effects of ultrasound in the in vivo studies. A focused ultrasound sequence was therefore optimized in vivo under magnetic resonance imaging guidance to obtain localized mild hyperthermia with high acoustic pressure. Ultrasound-induced mild hyperthermia (41-43 degrees C) was then tested in vivo in a subcutaneous CT-26 colon cancer murine model. As hyperthermia is applied, an inhibition of tumor growth for both paclitaxel-loaded nanocapsules and the commercial formulation of paclitaxel, namely Taxol(r) have been observed (p<0.05). Ultrasound-induced mild hyperthermia at high acoustic pressure appears as an interesting strategy to enhance cytotoxic efficacy locally. PMID- 28867379 TI - Staged hybrid repair of mega aortic syndrome: Good...but not great. PMID- 28867380 TI - Homemade fenestrated stent-graft for thoracic endovascular aortic repair of zone 2 aortic lesions. AB - OBJECTIVE: The aim of this retrospective analysis was to evaluate the outcomes of homemade fenestrated stent-grafts for thoracic endovascular aortic repair of zone 2 aortic lesions. METHODS: From November 2013 to January 2017, 24 patients underwent thoracic endovascular aortic repair with left subclavian artery revascularization using a homemade fenestrated stent-graft to preserve the patency of the left subclavian artery. Elective cases accounted for 54% (n = 13) of the sample. Indications included acute complicated type B aortic dissection (n = 9), degenerative aneurysm (n = 9), penetrating aortic ulcer (n = 5), and intramural hematoma (n = 1). Routine postoperative follow-up imaging with computed tomography angiography was performed to assess thoracic endovascular aortic repair and left subclavian artery fenestration patency and endoleak. RESULTS: Median duration for stent-graft modification was 16 minutes (range, 14 17 minutes). The technical success rate was 100%. One patient had a distal type I endoleak requiring additional stent-graft placement. One patient had partial coverage of the left common carotid artery requiring left common carotid artery stenting. One patient had a stroke without permanent sequelae (4.1%). Overall mortality was 0%. All left subclavian arteries were patent. Two type III endoleaks required additional left subclavian artery covered stent placement. One type II endoleak is currently observed. During a mean follow-up of 13.2 +/- 2 months, there were no conversions to open surgical repair, aortic rupture, paraplegia, or retrograde dissection. CONCLUSIONS: The use of a homemade fenestrated stent-graft for thoracic endovascular aortic repair of zone 2 aortic lesions is both feasible and effective for left subclavian artery revascularization during thoracic endovascular aortic repair involving a spectrum of thoracic aortic pathology. Durability concerns will need to be assessed in additional studies with long-term follow-up. PMID- 28867378 TI - Autologous fat transplants to deliver glitazone and adiponectin for vasculoprotection. AB - The insulin sensitizing glitazone drugs, rosiglitazone (ROS) and pioglitazone (PGZ) both have anti-proliferative and anti-inflammatory effects and induce adipose tissue (fat) to produce the vaso-protective protein adiponectin. Stenosis due to intimal hyperplasia development often occurs after placement of arteriovenous synthetic grafts used for hemodialysis. This work was performed to characterize the in vitro and in vivo effects of ROS or PGZ incorporation in fat and to determine if fat/PGZ depots could decrease vascular hyperplasia development in a porcine model of hemodialysis arteriovenous graft stenosis. Powdered ROS or PGZ (6-6000MUM) was mixed with fat explants and cultured. Drug release from fat was quantified by HPLC/MS/MS, and adiponectin and monocyte chemotactic protein-1 (MCP-1) levels in culture media were measured by ELISA. The effect of conditioned media from the culture of fat with ROS or PGZ on i) platelet-derived growth factor-BB (PDGF-BB)-stimulated proliferation of human venous smooth muscle cells (SMC) was measured by a DNA-binding assay, and ii) lipopolysaccharide (LPS)-induced human monocyte release of tumor necrosis factor alpha (TNFalpha) was assessed by ELISA. In a porcine model, pharmacokinetics of PGZ from fat depots transplanted perivascular to jugular vein were assessed by HPLC/MS/MS, and retention of the fat depot was monitored by MRI. A porcine model of synthetic graft placed between carotid artery and ipsilateral jugular vein was used to assess effects of PGZ/fat depots on vascular hyperplasia development. Both ROS and PGZ significantly induced the release of adiponectin and inhibited release of MCP-1 from the fat. TNF production from monocytes stimulated with LPS was inhibited 50-70% in the presence of media conditioned by fat alone or fat and either drug. The proliferation of SMC was inhibited in the presence of media conditioned by fat/ROS cultures. Fat explants placed perivascular to the external jugular vein were retained, as confirmed by MRI at one week after placement. PGZ was detected in the fat depot, in the external jugular vein wall and in adjacent tissue at clinically relevant levels, whereas levels in plasma were below detection. External jugular vein exposed to fat incorporated with PGZ had increased adiponectin expression compared to vein exposed to fat alone. However, the development of hyperplasia within the arteriovenous synthetic grafts was unchanged by treatment with fat/PGZ depots compared to no treatment. PMID- 28867381 TI - Using the National Cancer Database to create a scoring system that identifies patients with early-stage esophageal cancer at risk for nodal metastases. AB - OBJECTIVES: Endoscopic resection is gaining popularity as a treatment for early stage esophageal adenocarcinoma, particularly for T1a tumors. The goal of this study was to create a scoring system to reflect the risk of nodal metastases in early-stage esophageal adenocarcinoma to be used after endoscopic resection to better individualize treatment. METHODS: The National Cancer Database was queried for patients with T1a or T1b esophageal adenocarcinoma who underwent esophagectomy. We identified variables affecting nodal metastases using multivariable logistic regression, which we then used to create a scoring system. We stratified the model for T1a or T1b tumors, tested model discrimination, and validated the models by refitting in 1000 bootstrap samples. C-statistics greater than 0.7 were considered relevant. RESULTS: We identified 1283 patients with T1a or T1b tumors; 146 had nodal metastases (11.4%). Tumor category (pT1a vs pT1b), grade, and size and the presence of angiolymphatic invasion significantly affected the risk of nodal metastases. We assigned points to each variable and added them to get a risk score. In patients with T1a tumors, less than 3% of patients with a risk score of 3 or less had nodal metastases, whereas 16.1% of patients with a risk score of 5 or greater had nodal metastases. In patients with T1b tumors, less than 5% of patients with a risk score of 2 or less had nodal metastases, whereas 41% of patients with a score of 6 or greater had nodal metastases (c-statistic = 0.805). CONCLUSIONS: The proposed scoring system seems to be useful in discriminating risk of nodal metastases in patients with T1a or T1b esophageal adenocarcinoma and may be useful in directing patients who received endoscopic resection to esophagectomy or careful follow-up. PMID- 28867382 TI - Diaphragm plication: When and why to do it. PMID- 28867383 TI - Protective effects of kinetin against aluminum chloride and D-galactose induced cognitive impairment and oxidative damage in mouse. AB - Increasing evidence indicates that aluminum exposure and oxidative stress play crucial roles in the initiation and development of Alzheimer's disease (AD). Aluminum chloride (AlCl3) and d-galactose (d-gal) combined treatment of mice is considered as an easy and cheap way to obtain an animal model of AD. Kinetin is a plant cytokinin, which is also reported to exert neuro-protective effects in vivo and in vitro. Thus, in this study, neuro-protective effects of kinetin were investigated in an AD model of mice induced by AlCl3 and d-gal. The Morris water maze (MWM) test was performed to directly evaluate neuro-protective effects of kinetin on the memory and spatial learning abilities, while the histopathological changes were examined by hematoxylin and eosin (H & E) staining method. To further investigate mechanisms involved, Al content in cortex and hippocampus was determined. In addition, related detection kits were used to determine acetylcholine (ACh) content and activity of acetylcholinesterase (AChE). Activities of anti-oxidative enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), and the content of heme oxygenase-1 (HO-1) were also measured. Besides, the content of oxidative damage bio-markers including 8-iso-prostaglandin F (8-iso-PGF), advanced glycation end products (AGEs) and 8-hydroxy-2-deoxyguanosine (8-OHdG) were determined by ELISA kits. Finally, the distribution of beta-amyloid protein 1-42 (Abeta1-42) was detected by immunohistochemistry (IHC), while the expression levels of amyloidogenic proteins including beta-amyloid precursor protein (APP), beta secretase, gamma-secretase and Abeta1-42 were detected by western blotting (WB) method. Results showed that kinetin improved performance in MWM test, attenuated histopathological changes, reduced Al level in cortex and hippocampus, increased ACh content and decreased AChE activity. In addition, kinetin elevated activities of anti-oxidative enzymes and reduced the levels of oxidative damage biomarkers in AD model of mice. Furthermore, kinetin also increased the content of HO-1, and inhibited the distribution of Abeta1-42 and the expressions of amyloidogenic proteins (APP, beta-secretase, gamma-secretase and Abeta1-42) in brain tissue of AD mice. Our results indicate that kinetin has neuro-protective effects on the AD model of mice induced by AlCl3 and d-gal, suggesting that kinetin may be a candidate drug for treatment of AD. PMID- 28867385 TI - Olfactory conditioned same-sex partner preference in female rats: Role of ovarian hormones. AB - The dopamine D2-type receptor agonist quinpirole (QNP) facilitates the development of conditioned same-sex partner preference in males during cohabitation, but not in ovariectomized (OVX) females, primed with estradiol benzoate (EB) and progesterone (P). Herein we tested the effects of QNP on OVX, EB-only primed females. Females received a systemic injection (every four days) of either saline (Saline-conditioned) or QNP (QNP-conditioned) and then cohabited for 24h with lemon-scented stimulus females (CS+), during three trials. In test 1 (female-female) preference was QNP-free, and females chose between the CS+ female and a novel female. In test 2 (male-female) they chose between the CS+ female and a sexually experienced male. In test 1 Saline-conditioned females displayed more hops & darts towards the novel female, but QNP-conditioned females displayed more sexual solicitations towards the CS+ female. In test 2 Saline-conditioned females displayed a clear preference for the male, whereas QNP-conditioned females displayed what we considered a bisexual preference. We discuss the effect of dopamine and ovarian hormones on the development of olfactory conditioned same sex preference in females. PMID- 28867384 TI - Downregulations of TRPM8 expression and membrane trafficking in dorsal root ganglion mediate the attenuation of cold hyperalgesia in CCI rats induced by GFRalpha3 knockdown. AB - BACKGROUND: Cold hyperalgesia is an intractable sensory abnormality commonly seen in peripheral neuropathies. Although glial cell line-derived neurotrophic factor family receptor alpha3 (GFRalpha3) is required for the formation of pathological cold pain has been revealed, potential transduction mechanism is poorly elucidated. We have previously demonstrated the contribution of enhanced activity of transient receptor potential melastatin 8 (TRPM8) to cold hyperalgesia in neuropathic pain using a rat model of chronic constriction injury (CCI) to the sciatic nerve. Recently, the enhancement of TRPM8 activity is attributed to the increased TRPM8 plasma membrane trafficking. In addition, TRPM8 can be sensitized by the activation of GFRalpha3, leading to increased cold responses in vivo. The aim of this study was to investigate whether GFRalpha3 could influence cold hyperalgesia of CCI rats via modulating TRPM8 expression and plasma membrane trafficking in dorsal root ganglion (DRG). METHODS: Mechanical allodynia, cold and heat hyperalgesia were measured on 1day before CCI and the 1st, 4th, 7th, 10th and 14th day after CCI. TRPM8 total expression and membrane trafficking as well as GFRalpha3 expression in DRG were detected by immunofluorescence and western blot. Furthermore, GFRalpha3 small interfering RNA (siRNA) was intrathecally administrated to reduce GFRalpha3 expression in DRG, and the effects of GFRalpha3 knockdown on CCI-induced behavioral sensitization as well as TRPM8 total expression and membrane trafficking in both mRNA and protein levels were investigated, and the change in coexpression of TRPM8 with GFRalpha3 was also evaluated. Then, the effect of GFRalpha3 activation with artemin on pain behavior of CCI rats pretreated with the selective TRPM8 antagonist RQ-00203078 was observed. RESULTS: Here we found that TRPM8 total expression and plasma membrane trafficking as well as GFRalpha3 expression in DRG were initially increased on the 4th day after CCI, and maintained at the peak level from the 10th to the 14th day, which entirely conformed with the induction and maintenance of behavioral-reflex facilitation following CCI. The coexpression of TRPM8 with GFRalpha3, which was mainly located in peptidergic C-fibers DRG neurons, was also increased after CCI. Downregulation of GFRalpha3 protein in DRG attenuated CCI induced cold hyperalgesia without affecting mechanical allodynia and heat hyperalgesia, and reduced the upregulations of TRPM8 total expression and plasma membrane trafficking as well as coexpression of TRPM8 with GFRalpha3 induced by CCI. Additionally, the inhibition of TRPM8 abolished the influence of GFRalpha3 activation on cold hyperalgesia after CCI. CONCLUSION: Our results demonstrate that GFRalpha3 knockdown specially inhibits cold hyperalgesia following CCI via decreasing the expression level and plasma membrane trafficking of TRPM8 in DRG. GFRalpha3 and its downstream mediator, TRPM8, represent a new analgesia axis which can be further exploited in sensitized cold reflex under the condition of chronic pain. PMID- 28867386 TI - ALDH7A1 is a protein that protects Atlantic salmon against Aeromonas salmonicida at the early stages of infection. AB - Aldehyde dehydrogenases (ALDHs) belong to a super-family of detoxifying proteins and perform a significant role in developing epithelial homeostasis, protecting cells from toxic aldehydes and drug resistance. However, the activity and function of these detoxifying proteins remain unknown, especially in fish. In our research, we aimed to study functions of aldehyde dehydrogenase 7A1 (ALDH7A1) in Atlantic salmon infected by Aeromonas salmonicida. Recombinant ALDH7A1 (rALDH7A1) was verified by SDS-PAGE and western blot. The molecular mass of the deduced amino acid sequence of rALDH7A1 is 58.9 kDa with an estimated pI of 7.09. Only a low complexity region (141yvegvgevqeyvdv153) without a signal peptide existed in rALDH7A1. Results of ELISA indicated that rALDH7A1 exhibited apparent binding activities with A. salmonicida and its expression was highest in fish kidney. A Real-Time PCR (qRT-PCR) assay in kidneys confirmed that fish in this experiment were authentically infected and bacterial loads in rALDH7A1-adminsitered fish were significantly reduced at an early stage of infection. Meanwhile, we found the mRNA expression of NF-kbeta, P-38 MAPK, caspase-3 and TNF-alpha were mainly up-regulated at 72 h in the kidneys and livers of highly infected fish injected with rALDH7A1, and the same variation trend existed in fish spleens at 12 h. Consistent with these observations, neutralization experiments in vivo indicated that rALDH7A1 could obviously reduce the death rate compared to the BSA and control group. Taken together, we concluded that rALDH7A1 could act in host immune defense against bacterial infection and decrease the mortality rate of Atlantic salmon at early stages of infection with A. salmonicida. PMID- 28867388 TI - Using Engineered Bacteria to Characterize Infection Dynamics and Antibiotic Effects In Vivo. AB - Synthetic biology has focused on engineering microbes to synthesize useful products or to serve as living diagnostics and therapeutics. Here we utilize a host-derived Escherichia coli strain engineered with a genetic toggle switch as a research tool to examine in vivo replicative states in a mouse model of chronic infection, and to compare in vivo and in vitro bacterial behavior. In contrast to the effect of antibiotics in vitro, we find that the fraction of actively dividing bacteria remains relatively high throughout the course of a chronic infection in vivo and increases in response to antibiotics. Moreover, the presence of non-dividing bacteria in vivo does not necessarily lead to an antibiotic-tolerant infection, in contrast to expectations from in vitro experiments. These results demonstrate the utility of engineered bacteria for querying pathogen behavior in vivo, and the importance of validating in vitro studies of antibiotic effects with in vivo models. PMID- 28867387 TI - Deciphering the Origin and Evolution of Hepatitis B Viruses by Means of a Family of Non-enveloped Fish Viruses. AB - Hepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome organization with extensive gene overlap. Remarkably, the ~1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via protein-primed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras. PMID- 28867389 TI - Legionella pneumophila Modulates Mitochondrial Dynamics to Trigger Metabolic Repurposing of Infected Macrophages. AB - The intracellular bacteria Legionella pneumophila encodes a type IV secretion system (T4SS) that injects effector proteins into macrophages in order to establish and replicate within the Legionella-containing vacuole (LCV). Once generated, the LCV interacts with mitochondria through unclear mechanisms. We show that Legionella uses both T4SS-independent and T4SS-dependent mechanisms to respectively interact with mitochondria and induce mitochondrial fragmentation that ultimately alters mitochondrial metabolism. The T4SS effector MitF, a Ran GTPase activator, is required for fission of the mitochondrial network. These effects of MitF occur through accumulation of mitochondrial DNM1L, a GTPase critical for fission. Furthermore mitochondrial respiration is abruptly halted in a T4SS-dependent manner, while T4SS-independent upregulation of cellular glycolysis remains elevated. Collectively, these alterations in mitochondrial dynamics promote a Warburg-like phenotype in macrophages that favors bacterial replication. Hence the rewiring of cellular bioenergetics to create a replication permissive niche in host cells is a virulence strategy of L. pneumophila. PMID- 28867390 TI - Capillary moving-boundary isotachophoresis with electrospray ionization mass spectrometric detection and hydrogen ion used as essential terminator: Methodology for sensitive analysis of hydroxyderivatives of s-triazine herbicides in waters. AB - Capillary isotachophoresis (ITP) is an electrophoretic technique offering high sensitivity due to permanent stacking of the migrating analytes. Its combination with electrospray-ionization mass-spectrometric (ESI-MS) detection is limited by the narrow spectrum of ESI-compatible components but can be compensated by experienced system architecture. This work describes a methodology for sensitive analysis of hydroxyderivatives of s-triazine herbicides, based on implementation of the concepts of moving-boundary isotachophoresis and of H+ as essential terminating component into cationic ITP with ESI-MS detection. Theoretical description of such kind of system is given and equations for zone-related boundary mobilities are derived, resulting in a much more general definition of the effective mobility of the terminating H+ zone than used so far. Explicit equations allowing direct calculation for selected simple systems are derived. The presented theory allows prediction of stacking properties of particular systems and easy selection of suitable electrolyte setups. A simple ESI compatible system composed of acetic acid and ammonium with H+ and ammonium as a mixed terminator was selected for the analysis of 2-hydroxyatrazine and 2 hydroxyterbutylazine, degradation products of s-triazine herbicides. The proposed method was tested with direct injection without any sample pretreatment and provided excellent linearity and high sensitivity with limits of detection below 100ng/L (0.5nM). Example analyses of unspiked and spiked drinking and river water are shown. PMID- 28867391 TI - Are there differences in lipid peroxidation and immune biomarkers between major depression and bipolar disorder: Effects of melancholia, atypical depression, severity of illness, episode number, suicidal ideation and prior suicide attempts. AB - BACKGROUND: There is evidence that major depression (MDD) and bipolar disorder (BD) are accompanied by activated immune & oxidative (I&O) pathways. METHODS: To compare I&O biomarkers between MDD and BD we assessed serum levels of thiobarbituric acid reactive substances (TBARS; a lipid peroxidation marker), soluble interleukin-2 receptor (sIL-2R), sIL-6R, IL-alpha, sIL-1R antagonist (sIL 1RA), tumor necrosis factor receptor 60kDa/80kDa (sTNFR60/R80) in 114 MDD and 133 BD patients, and 50 healthy controls. We computed z-unit weighted indices reflecting the 5 cytokine receptor levels (zCytR), cell-mediated immunity (zCMI) and I&O pathways (zCMI+TBARS). RESULTS: There are no significant differences in biomarkers between MDD and BD. BD/MDD with atypical features is characterized by increased sIL-6R and TBARS, whereas melancholia is associated with higher TBARS and lower sTNFR60 levels. Severity of illness, as measured with the Hamilton Depression Rating Scale, is correlated with increased sIL-6R, sTNFR80, TBARS, zCytR and zCMI+TBARS. The number of episodes the year prior to blood sampling is positively associated with sTNFR80, TBARS, zCMI, zCMI+TBARS, while number of hospitalizations is positively associated with sIL-1RA. Prior suicidal attempts are associated with increased sIL-1RA, IL-1alpha, zCMI, TBARS and zCMI+TBARS, while TBARS is associated with current suicidal ideation. CONCLUSIONS: There are no I&O biomarker differences between MDD and BD. Atypical depression is associated with increased IL-6 trans-signaling and lipid peroxidation. Severity of depression, number of episodes and suicidal attempts are associated with activated I&O pathways. Increased TBARS is the single best predictor of BD/MDD, atypical depression, melancholia and current suicidal ideation. PMID- 28867392 TI - Effects of alprazolam treatment on anxiety-like behavior induced by color stimulation in adult zebrafish. AB - It has been reported that the use of certain stimuli can lead to anxiety-like behavior in zebrafish. Moreover, visual stimulation of zebrafish is becoming a popular tool. Here we evaluated the effects of six colors combinations and alprazolam, a benzodiazepine which is widely used in the treatment of anxiety disorders, on the behavior of adult zebrafish in a two-chambered apparatus, which chambers were illuminated by red/yellow, green/blue, red/green, green/yellow, red/blue and blue/yellow light. The following parameters were measured: time spent in the zone, number of entries to the zone, time of freezing, distance traveled and average speed in the zone. We report that the adult zebrafish spent more time in the red zone compared to yellow or green as well as in the yellow or blue compared to green. The zebrafish displayed a concomitant increase in time freezing in the red zone compared to yellow or green as well as in the yellow or blue compared to green. Moreover, average speed was decreased in the red zone compared to yellow or green and in the yellow zone compared to green. Treatment with alprazolam significantly affected the behavior of the zebrafish, e.g., following alprazolam administration time spent in the zone and time freezing were longer in the green zone than in red. Based on these observations, we suggest that light color combinations could be effective to manipulate zebrafish behavior and could be useful in neuropsychopharmacological studies, perhaps to study anxiety-like behavior and the effects of anxiolytic agents. PMID- 28867393 TI - Reprint of "Epidemiology of brucellosis, Q Fever and Rift Valley Fever at the human and livestock interface in northern Cote d'Ivoire". AB - Northern Cote d'Ivoire is the main livestock breeding zone and has the highest livestock cross-border movements in Cote d'Ivoire. The aim of this study was to provide updated epidemiological data on three neglected zoonotic diseases, namely brucellosis, Q Fever and Rift Valley Fever (RVF). We conducted three-stage cross sectional cluster surveys in livestock and humans between 2012 and 2014 in a random selection of 63 villages and a sample of 633 cattle, 622 small ruminants and 88 people. We administered questionnaires to capture risk factors and performed serological tests including the Rose Bengal Plate Test (RBPT), Brucella spp. indirect and competitive ELISAs, Coxiella burnetii indirect ELISA and RVF competitive ELISA. The human seroprevalence for Brucella spp. was 5.3%. RBPT positive small ruminants tested negative by the indirect ELISA. The seroprevalence of Brucella spp. in cattle adjusted for clustering was 4.6%. Cattle aged 5-8 years had higher odds of seropositivity (OR=3.5) than those aged <=4years. The seropositivity in cattle was associated with having joint hygromas (OR=9), sharing the pastures with small ruminants (OR=5.8) and contact with pastoralist herds (OR=11.3). The seroprevalence of Q Fever was 13.9% in cattle, 9.4% in sheep and 12.4% in goats. The seroprevalence of RVF was 3.9% in cattle, 2.4% in sheep and 0% in goats. Seropositive ewes had greater odds (OR=4.7) of abortion than seronegative ones. In cattle, a shorter distance between the night pens and nearest permanent water bodies was a protective factor (OR=0.1). The study showed that the exposure to the three zoonoses is rather low in northern Cote d'Ivoire. Within a One Health approach, cost-benefit and cost-effectiveness of control measures should be assessed for an integrated control. PMID- 28867394 TI - Reprint of "Modelling the influence of temperature and rainfall on malaria incidence in four endemic provinces of Zambia using semiparametric Poisson regression". AB - Although malaria morbidity and mortality are greatly reduced globally owing to great control efforts, the disease remains the main contributor. In Zambia, all provinces are malaria endemic. However, the transmission intensities vary mainly depending on environmental factors as they interact with the vectors. Generally in Africa, possibly due to the varying perspectives and methods used, there is variation on the relative importance of malaria risk determinants. In Zambia, the role climatic factors play on malaria case rates has not been determined in combination of space and time using robust methods in modelling. This is critical considering the reversal in malaria reduction after the year 2010 and the variation by transmission zones. Using a geoadditive or structured additive semiparametric Poisson regression model, we determined the influence of climatic factors on malaria incidence in four endemic provinces of Zambia. We demonstrate a strong positive association between malaria incidence and precipitation as well as minimum temperature. The risk of malaria was 95% lower in Lusaka (ARR=0.05, 95% CI=0.04-0.06) and 68% lower in the Western Province (ARR=0.31, 95% CI=0.25 0.41) compared to Luapula Province. North-western Province did not vary from Luapula Province. The effects of geographical region are clearly demonstrated by the unique behaviour and effects of minimum and maximum temperatures in the four provinces. Environmental factors such as landscape in urbanised places may also be playing a role. PMID- 28867395 TI - Nanoformulated copper/zinc superoxide dismutase exerts differential effects on glucose vs lipid homeostasis depending on the diet composition possibly via altered AMPK signaling. AB - Evidence suggests that superoxide dismutase 1 (SOD1) promotes glucose vs lipid metabolism depending on the diet type. We recently reported that nanoformulated SOD1 (Nano) improved lipid metabolism without altering glucose homeostasis in high-fat (HF) diet-fed mice. Here, we sought to determine the effects and potential mechanisms of Nano in modulating glucose and lipid homeostasis in mice fed a normal chow diet (CD) vs HF diet. Mice were fed a CD or a HF diet (45%) for 10 wk and injected with Nano once every 2 days for 15 days. The fasting glucose level was lower (P < 0.05) in CD + Nano-treated mice compared to control. Conversely, blood glucose was not altered but serum triglycerides were lower in HF + Nano-treated mice. Genes involved in fatty acid synthesis were reduced by Nano in the skeletal muscle of CD but not of HF diet-fed mice. Adenosine monophosphate-activated protein kinase (AMPK), which promotes both glucose and lipid metabolism depending on the fuel availability, is activated by Nano in CD fed mice. Moreover, Nano increased phosphorylation of ACC, a downstream target of AMPK, in both CD and HF diet-fed mice. Nano increased mitochondrial respiration in C2C12 myocytes in the presence of glucose or fatty acid, and this effect is inhibited by Compound C, an AMPK inhibitor. Our data suggest that Nano promotes glucose and lipid metabolism in CD and HF diet-fed mice, respectively, and this effect is mediated partly via AMPK signaling. PMID- 28867396 TI - The Healthy Hearts and Kidneys (HHK) study: Design of a 2*2 RCT of technology supported self-monitoring and social cognitive theory-based counseling to engage overweight people with diabetes and chronic kidney disease in multiple lifestyle changes. AB - Patients with complex chronic diseases usually must make multiple lifestyle changes to limit and manage their conditions. Numerous studies have shown that education alone is insufficient for engaging people in lifestyle behavior change, and that theory-based behavioral approaches also are necessary. However, even the most motivated individual may have difficulty with making lifestyle changes because of the information complexity associated with multiple behavior changes. The goal of the current Healthy Hearts and Kidneys study was to evaluate, different mobile health (mHealth)-delivered intervention approaches for engaging individuals with type 2 diabetes (T2D) and concurrent chronic kidney disease (CKD) in behavior changes. Participants were randomized to 1 of 4 groups, receiving: (1) a behavioral counseling, (2) technology-based self-monitoring to reduce information complexity, (3) combined behavioral counseling and technology based self-monitoring, or (4) baseline advice. We will determine the impact of randomization assignment on weight loss success and 24-hour urinary excretion of sodium and phosphorus. With this report we describe the study design, methods, and approaches used to assure information security for this ongoing clinical trial. Clinical Trials.gov Identifier: NCT02276742. PMID- 28867398 TI - Visual and ocular motor outcomes in children with posterior fossa tumors. AB - PURPOSE: To describe the clinical characteristics and visual and ocular motor outcomes of a large cohort of pediatric patients treated for tumors of the posterior cranial fossa. METHODS: The medical records of all patients with posterior fossa tumors evaluated by the ophthalmology services at two large tertiary care academic hospitals between 2005 and 2011 were reviewed retrospectively. Data abstracted for each study patient included demographic information, presenting signs and symptoms, pathologic diagnosis, and results of the most recent ophthalmology examination. RESULTS: A total of 139 patients were included. Visual outcomes were categorized as "good" (bilateral acuity of 20/20 20/40) in 101 patients (72.7%), "fair" (<20/40-20/200 in one or both eyes) in 12 patients (8.6%), or "poor" (<20/200 in one or both eyes) in 9 patients (6.5%). Patients with medulloblastoma and ependymoma had a significantly greater risk of a poor or fair visual outcome than those with juvenile pilocytic astrocytoma (both P < 0.05), independent of age and sex. Thirty-two patients (23.0%) developed nystagmus, and 59 patients (42.4%) developed strabismus. Twenty-four patients (17.3%) underwent eye muscle surgery for persistent strabismus. CONCLUSIONS: The majority of patients had good visual outcomes, although ocular motor abnormalities were common. Tumor type was a significant risk factor for permanent vision loss. PMID- 28867397 TI - Factors associated with atypical postoperative drift following surgery for consecutive exotropia. AB - PURPOSE: To evaluate the associations of clinical and surgical factors with atypical postoperative drift following surgery for consecutive exotropia. METHODS: A total of 66 patients with consecutive exotropia (>=10Delta at distance), after historical surgery for esotropia were retrospectively identified at a tertiary medical center. All patients underwent unilateral lateral rectus recession (on adjustable suture) with medial rectus advancement and/or resection. Immediate postoperative target angle was 4Delta-10Delta of esotropia at distance, anticipating mild postoperative exodrift. Actual postoperative drift was calculated as change in distance deviation from immediately postadjustment to 6 weeks. Typical drift was defined as 0Delta-9Delta of exodrift. Excessive exodrift was defined as >=10Delta. Esodrift was defined as 1Delta or more. Univariate and multiple logistic regression analyses were performed to evaluate for associations with a wide range of clinical and surgical factors. RESULTS: Overall there was a median exodrift (4Delta, quartiles 0Delta-10Delta). Of the 66 patients, 18 (27%) showed excessive exodrift; 15 (23%), esodrift. In multiple logistic analyses, larger preoperative distance exodeviation was associated with excessive exodrift (P = 0.01), and non-normal medial rectus attachment status (abnormal [stretched scar, pseudo-tendon], attached to pulley, or behind pulley) was associated with esodrift (P = 0.02). CONCLUSIONS: Approximately half of patients show atypical drift following unilateral surgery for consecutive exotropia, with larger preoperative distance exodeviation associated with exodrift and non-normal medial rectus muscle status with esodrift. Knowing these associations may help when counseling patients regarding surgical outcomes. PMID- 28867399 TI - Neuro-oculo-cutaneous cavernous hemangiomas: a CCM1 mutation-associated phakomatosis. AB - Evaluation for intracranial lesions in a patient with retinal cavernous hemangiomas is vital for early recognition of this heritable and potentially life threatening disease. We report a case of a highly penetrant but variably expressed form of cerebral cavernous malformation syndrome with cerebral, cutaneous, and retinal cavernomas in a family found to harbor a nonsense mutation of the CCM1 gene. PMID- 28867400 TI - Looking to the future: Introducing palliative care in the cardiorespiratory population. PMID- 28867402 TI - Plasmodium simium: a Brazilian focus of anthropozoonotic vivax malaria? PMID- 28867401 TI - Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epidemiological investigation. AB - BACKGROUND: Malaria was eliminated from southern and southeastern Brazil over 50 years ago. However, an increasing number of autochthonous episodes attributed to Plasmodium vivax have recently been reported from the Atlantic Forest region of Rio de Janeiro state. As the P vivax-like non-human primate malaria parasite species Plasmodium simium is locally enzootic, we performed a molecular epidemiological investigation to determine whether zoonotic malaria transmission is occurring. METHODS: We examined blood samples from patients presenting with signs or symptoms suggestive of malaria as well as from local howler monkeys by microscopy and PCR. Samples were included from individuals if they had a history of travel to or resided in areas within the Rio de Janeiro Atlantic Forest, but not if they had malaria prophylaxis, blood transfusion or tissue or organ transplantation, or had travelled to known malaria endemic areas in the preceding year. Additionally, we developed a molecular assay based on sequencing of the parasite mitochondrial genome to distinguish between P vivax and P simium, and applied this assay to 33 cases from outbreaks that occurred in 2015, and 2016. FINDINGS: A total of 49 autochthonous malaria cases were reported in 2015-16. Most patients were male, with a mean age of 44 years (SD 14.6), and 82% lived in urban areas of Rio de Janeiro state and had visited the Atlantic Forest for leisure or work-related activities. 33 cases were used for mitochondrial DNA sequencing. The assay was successfully performed for 28 samples, and all were shown to be P simium, indicative of zoonotic transmission of this species to human beings in this region. Sequencing of the whole mitochondrial genome of three of these cases showed that P simium is most closely related to P vivax parasites from South America. The malaria outbreaks in this region were caused by P simium, previously considered to be a monkey-specific malaria parasite, related to but distinct from P vivax, and which has never conclusively been shown to infect people before. INTERPRETATION: This unequivocal demonstration of zoonotic transmission, 50 years after the only previous report of P simium in people, leads to the possibility that this parasite has always infected people in this region, but that it has been consistently misdiagnosed as P vivax because of an absence of molecular typing techniques. Thorough screening of local non-human primates and mosquitoes (Anopheline) is required to evaluate the extent of this newly recognised zoonotic threat to public health and malaria elimination in Brazil. FUNDING: Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado de Rio de Janeiro, The Brazilian National Council for Scientific and Technological Development (CNPq), JSPS Grant-in-Aid for scientific research, Secretary for Health Surveillance of the Brazilian Ministry of Health, Global Fund, Fundacao de amparo a pesquisa do estado de Minas Gerais (Fapemig), and PRONEX Program of the CNPq. PMID- 28867403 TI - Optimization of the monitoring of landfill gas and leachate in closed methanogenic landfills. AB - Monitoring of the gas and leachate parameters in a closed landfill is a long-term activity defined by national legislative worldwide. Serbian Waste Disposal Law defines the monitoring of a landfill at least 30 years after its closing, but the definition of the monitoring extent (number and type of parameters) is incomplete. In order to define and clear all the uncertainties, this research focuses on process of monitoring optimization, using the closed landfill in Zrenjanin, Serbia, as the experimental model. The aim of optimization was to find representative parameters which would define the physical, chemical and biological processes in the closed methanogenic landfill and to make this process less expensive. Research included development of the five monitoring models with different number of gas and leachate parameters and each model has been processed in open source software GeoGebra which is often used for solving optimization problems. The results of optimization process identified the most favorable monitoring model which fulfills all the defined criteria not only from the point of view of mathematical analyses, but also from the point of view of environment protection. The final outcome of this research - the minimal required parameters which should be included in the landfill monitoring are precisely defined. PMID- 28867404 TI - Manure from biochar, bentonite and zeolite feed supplemented poultry: Moisture retention and granulation properties. AB - Feeding treatments were imposed in two feeding trials involving Cobb broiler and Bond Brown layer birds. Three feed additives (biochar, bentonite and zeolite) were supplied at four rates (0, 1, 2 and 4% w/w) in feed, as previously considered in the context of animal production, was considered in the context of Excreta chemical and water retention properties and granulation characteristics of decomposed excreta (manure) were characterised. At field capacity (- 0.01 MPa), manure produced from control and 4% bentonite diets contained significantly (p = 0.001) more water (at 1.93 and 2.44% v/v water, respectively) than zeolite and biochar treatments. Manure mesoporosity was significantly (p = 0.015) higher in 2 and 4% bentonite treatments than other feed additives. Fresh excreta from layer birds on the control diet contained 6% w/dw N and 35% C, which was decreased to 2.6% N and 28% C after decomposition, with C:N ratio changing from 5.9 to 12.1. Ammonia loss was higher from biochar and zeolite manures than control or bentonite, associated with higher pH in the biochar and zeolite manures. More N was unaccounted from bentonite manure than other treatments, presumably lost as N2O or N2, a result linked to its higher moisture content and its enhanced rate of denitrification. The highest proportion of granules in the size class desired for fertilizer spreading was achieved using decomposed manure from the 1 and 2% w/w biochar treatments of the broiler trial, and 1 and 2% zeolite and 4% biochar treatments of the layer trial. Thus the feed amendments improved poultry manure in specific ways. PMID- 28867405 TI - Attitudes of Chinese community members and psychiatrists towards forensic psychiatric assessments. AB - The aim of this study was to investigate the attitudes of Chinese community members and psychiatrists towards forensic psychiatric assessments. A questionnaire designed to record attitudes toward the current forensic psychiatric assessment procedures and the disposal of mentally ill offenders was developed and distributed via a mobile App. A total of 134 community members and 132 psychiatrists voluntarily completed the questionnaire. Most of responders agreed that the department of public-security has the right to apply for a forensic psychiatric assessment but should not be held solely by that department. Community members were less significantly confident in the validation of forensic psychiatric opinions than were the psychiatrists. A significantly higher proportion of community members than psychiatrists considered that offenders judged Not Criminally Responsible on Account of Mental Disorder (NCRMD) should be punished as would be sane people. In addition, only a minority of responders supported that NCRMD should not be held criminally responsible. Our results indicate that both groups have comments on the current distribution of right of startup of forensic psychiatric assessments. Compared to psychiatrists, community members have lower confidence in the validation of forensic psychiatric assessment and have stricter attitudes toward the disposal of offenders with psychiatric disorders. PMID- 28867406 TI - Self-reported sleep problems among the elderly: A latent class analysis. AB - The present study utilized a person-centered approach to examine the different profiles of problem sleepers in a community sample of elderly. In addition, this study also explores how demographic and psychiatric variables may be related to these different profiles of sleep problems. A total of 515 participants (Mean age = 67 years, SD = 5) were administered self-report measures of sleep problems, depression and anxiety. Among them, 230 who reported significant problems in any of five selected sleep components were entered into a latent class analysis. The remaining 285 participants were assigned to a comparison control group. The profiles of 'inadequate sleep', 'disturbed sleep', 'trouble falling asleep' and 'multiple problems' were identified. The 'multiple problems' group had significantly higher levels of depression and anxiety relative to the control group. Regression analyses indicated that these different profiles had contributed to a significant increase in variance explained in anxiety but not depression levels, on top of the severity of sleep problems and demographic variables. Although sleep problems occur among the elderly with considerable heterogeneity, they can generally be classified into four different profiles. Furthermore, the inclusion of sleep problem profiles can significantly enhance the prediction of anxiety symptoms. PMID- 28867407 TI - Childhood adversities and clinical symptomatology in first-episode psychosis. AB - In addition to severe traumatic experiences, milder, more common childhood adversities reflecting psychosocial burden may also be common in people with psychotic disorders and have an effect on symptomatology and functioning. We explored eleven negative childhood experiences and their influence on clinical symptoms among young adults with first-episode psychosis (FEP, n = 75) and matched population controls (n = 51). Individuals with FEP reported more adversities than controls. Specifically serious conflicts within the family, bullying at school, maternal mental health problems, and one's own and parents' serious illness during childhood were experienced by the patients more often than by controls. In the FEP group, the severity of adversity was associated with increased anxiety, manic, and obsessive-compulsive symptoms, but not with the severity of positive psychotic symptoms. Adversity produced a more pronounced effect on symptoms in male patients than in female patients. To conclude, in line with earlier studies of more chronic psychosis, a majority of the participants with FEP reported exposure to childhood adversities, with the FEP group reporting more adversities than controls. High levels of mood and anxiety symptoms in patients with FEP may be related to cumulative exposure to childhood adversities. This should be taken into account in the treatment for FEP. PMID- 28867408 TI - Associations between a history of traumatic brain injuries and conduct disorder during youth in a population sample of Canadian adults. AB - This study describes the association between history of traumatic brain injury (TBI) and childhood symptoms of conduct disorder (CD). Data were based on telephone interviews with 6048 respondents derived from the 2011-2013 cycles of a representative cross-sectional survey of adults aged 18+ years in Ontario, Canada. TBI was defined as loss of consciousness for at least 5min or overnight hospitalization due to injury symptoms. Symptoms of CD before 15 years of age were assessed using five items based on the DSM-IV. Adults who reported a history of TBI reported odds 3 times higher for possible CD before 15 years of age. Odds remained significant even when age, sex, marital status, income, and education were statistically controlled. The nature of this data precludes determining if TBI occurred before or following CD symptoms. Nonetheless, the co-occurrence of a history of TBI with symptoms of CD supports the recommendation that practitioners be vigilant in assessing the history of both CD and TBI when diagnosing and treating one of these conditions. These findings do not exclude the possibility that TBI during childhood or youth may be interfering with brain development and could co-occur with conduct behaviors in both the short and long term. PMID- 28867409 TI - What characteristics are associated with earlier onset of first depressive episodes: A 16-year follow-up of a national population-based cohort. AB - This study examined characteristics associated with earlier onset of first depressive episodes. A nationally representative Canadian sample was randomly selected and followed from 1994 to 2011. At baseline complete data on depression history (Yes/No) and related diseases was available for 12,227 study subjects. Proportional hazard models were used. Meta-analyses were also applied to sync results across studies. Being younger, a woman, a Caucasian, a regular smoker, and having a chronic disease were significantly associated with the expedited trajectory for the onset of the first depressive episode. People were at the greater risk of having earlier onset of first depressive episodes at the 2-year follow-up (p < 0.001), with the risk declining after four years (p < 0.001). Women and men had different sets of characteristics associated with earlier onset of first depressive episodes. In meta-analyses, those having a chronic disease (HRpooled = 1.31) and being a woman (HRpooled = 1.43) were more likely to have earlier onset of first depressive episodes. This study provides solid evidence on the timing effect of these characteristics on first depressive episodes. Approaches focused on these identified risk characteristics should be prioritized to reduce the risk and postpone the onset of major depressive episode. PMID- 28867410 TI - Boar variability in sperm cryo-tolerance after cooling of semen in different long term extenders at various temperatures. AB - This study investigated individual boar variability in the quality of pre-freeze (PF) and post-thaw (PT) semen cooled in different long-term (LT) extenders and for different holding times (HT). Sperm rich fractions were diluted with Androhep(r) Plus (AHP), Androstar(r) Plus (ASP), Safecell(r) Plus (SCP) and TRIXcell(r) Plus (TCP) extenders, stored for 2h at 17 degrees C (HT 1) and additionally for 24h at 10 degrees C (HT 2) and the samples were subsequently evaluated and frozen. Besides the analysis of CASA sperm variables, mitochondrial membrane potential (MMP), plasma membrane integrity (PMI), normal apical ridge (NAR) acrosome integrity, and viability (YO-PRO-1-/PI-) of sperm were assessed in the PF and PT semen. Results indicated that boar, extender and HT group affected the sperm quality characteristics. There were great variations in PMOT and the sperm motion patterns of the PF semen among the boars. Differences in the HT groups of the PF semen, with respect to the sperm membrane integrity, were less marked among the boars. Consistent variations in TMOT and PMOT in the PT semen were observed among the boars, being greater in the HT 2 group. Most of the CASA analyzed sperm motion patterns were greater in the HT 2 group of the PT semen. Furthermore, sperm MMP, PMI and viability were greater in the HT 2 group of the PT semen in most of the boars, while consistent differences were observed among the boars for sperm NAR acrosome integrity in either HT group. The significant effect of the cryopreservation process on the sperm membrane proteome was evident from the number of protein bands, detected in the electrophoretic profiles of sperm of the HT 1 and HT 2 groups. The electrophoretic profiles of the PF and PT semen among boars with poor and good semen freezability, however, differed with respect to the abundance and types of sperm membrane-associated proteins. The overall results of this study provided evidence that there are differences among boars in response to the different cooling regimens, and that cooling of extended semen for a 24-h period at 10 degrees C modulated the functions of sperm in an extender-dependent manner, rendering the cells less susceptible to cryo-induced damage. It is suggested that the findings of this study have the potential to improve the technology of boar semen cryopreservation. PMID- 28867411 TI - Toxic shock syndrome in paediatric thermal injuries: A case series and systematic literature review. AB - BACKGROUND: Toxic shock syndrome (TSS) is a rare, but potentially life threatening complication of thermal injuries in children. The study objective was to systematically review the literature on paediatric TSS after burns or scalds, and describe our experience with this condition in Switzerland. METHODS: All tertiary paediatric healthcare centres managing burns and scalds in Switzerland were inquired. A systematic literature review was performed using EMBASE (1947 2016), MEDLINE (1946-2016), Web of Science (1900-2016) and Google Scholar in October 2016. Data on patient characteristics, symptoms, laboratory parameters, management and outcome were extracted from paper and electronic patient charts. Descriptive statistics were performed. RESULTS: The literature review revealed 25 articles describing 59 cases observed in 10 countries (UK, USA, Hungary, Austria, Sweden, Denmark, Israel, Japan, Spain, Switzerland) from 1985 to 2016. The patient age ranged from 8 months to 8 years at the time point of TSS-diagnosis. The injured total body surface area ranged from <1% to 41%. Forty-one patients suffered from scalds, 6 from burns and in 12 cases the type of injury was not specified. The TSS-diagnosis was made 1-7days after thermal injury. Nineteen children underwent admission to the Intensive Care Unit. Six children died from TSS. In Switzerland, we identified 11 consecutive cases between 07/2001 and 06/2011 (median age 15 months, range 9 months-14 years; 9 male, 2 female; 3 burns, 8 scalds; 7% median total body surface area (TBSA), range 2-30%). Diagnosis of TSS was made on day 5 after injury in median (range 3-34 days). Eight of eleven patients received intensive care. Survivors (10/11) suffered no long-term sequelae besides scars. One 13-month old boy died 3days after a 7%-TBSA scald. CONCLUSIONS: Toxic shock syndrome is an important complication of paediatric burns in Switzerland and several other countries world-wide. Diagnosis and management remain challenging. Awareness among treating clinicians is crucial for a favourable outcome. PMID- 28867412 TI - Somatosensory amplification - An old construct from a new perspective. AB - The paper reviews and summarizes the history and the development of somatosensory amplification, a construct that plays a substantial role in symptom reports. Although the association with negative affect has been supported by empirical findings, another key elements of the original concept (i.e. body hypervigilance and the tendency of focusing on mild body sensations) have never been appropriately addressed. Recent findings indicate that somatosensory amplification is connected with phenomena that do not necessarily include symptoms (e.g. modern health worries, or expectations of symptoms and medication side effects), and also with the perception of external threats. In conclusion, somatosensory amplification appears to refer to the intensification of perceived external and internal threats to the integrity of the body ("somatic threat amplification") rather than amplification of perceived or actual bodily events only. Practical implications of this new approach are also discussed. PMID- 28867413 TI - Vagal withdrawal and psychological distress during ventilator weaning and the related outcomes. AB - OBJECTIVE: This study investigated the associations between changes in autonomic nervous system (ANS) function, psychological status during the mechanical ventilation (MV) weaning process, and weaning outcomes. METHODS: In this prospective study, we recruited 67 patients receiving MV for >24h at a medical center in northern Taiwan. Patients' ANS function, represented by heart rate variability (HRV), the rapid shallow breathing index (RSBI), anxiety, fear, and dyspnea, was repeatedly measured 10min before and 30min after undergoing a weaning trial. Forty-nine patients capable of sustaining a 2-h weaning trial were successfully weaned. RESULTS: Compared with the failed group, the success group showed significantly smaller decreases in high-frequency HRV (HRV-HF) and smaller increases in RSBI (per 10 breaths/min/L), fear, dyspnea, and anxiety in response to the weaning trial (odds ratio [OR]=2.19, 0.81, 0.69, 0.66, and 0.77, respectively; p<0.05). Multivariate analyses revealed that low-frequency HRV before weaning (OR=2.32; 95% confidence interval [CI]=1.13-4.78, p=0.02), changes in HRV-HF (OR=3.33; 95% CI=1.18-9.44, p=0.02), and psychological fear during the weaning process (OR=0.50; 95% CI=0.27-0.92, p=0.03) were three independent factors associated with 2-h T-piece weaning success. CONCLUSIONS: ANS responses and psychological distress during weaning were associated with T-piece weaning outcomes and may reflect the need for future studies to utilize these factors to guide weaning processes and examine their impact on outcomes. PMID- 28867414 TI - Is the practice of yoga or meditation associated with a healthy lifestyle? Results of a national cross-sectional survey of 28,695 Australian women. AB - OBJECTIVES: To examine the relationship between yoga/meditation practice and health behavior in Australian women. METHODS: Women aged 19-25years, 31-36years, and 62-67years from the Australian Longitudinal Study on Women's Health (ALSWH) were surveyed regarding smoking, alcohol or drug use, physical activity and dietary behavior; and whether they practiced yoga/meditation on a regular basis. Associations of health behaviors with yoga/meditation practice were analyzed using multiple logistic regression modelling. RESULTS: 11,344, 8200, and 9151 women aged 19-25years, 31-36years, and 62-67years, respectively, were included of which 29.0%, 21.7%, and 20.7%, respectively, practiced yoga/meditation. Women practicing yoga/meditation were significantly more likely to report at least moderate physical activity levels (OR=1.50-2.79), to follow a vegetarian (OR=1.67 3.22) or vegan (OR=2.26-3.68) diet, and to report the use of marijuana (OR=1.28 1.89) and illicit drugs in the last 12 months (OR=1.23-1.98). CONCLUSIONS: Yoga/meditation practice was associated with higher physical activity levels, a higher likelihood of vegetarian or vegan diet use, and a higher likelihood of drug use. While health professionals should keep the potential vulnerability of yoga/meditation practitioners to drug use in mind, the positive associations of yoga/meditation with a variety of positive health behaviors warrant its consideration in preventive medicine and healthcare. PMID- 28867415 TI - Gender differences in mental and physical health conditions in U.S. veterans: Results from the National Health and Resilience in Veterans Study. AB - OBJECTIVES: To characterize gender differences in the prevalence of mental and physical health conditions and evaluate the moderating effect of assaultive trauma on risk for these conditions in a nationally representative sample of male and female U.S. veterans. METHODS: Cross-sectional data were analyzed from 3157 U.S. veterans from the National Health and Resilience in Veterans Study. Multivariable logistic regression analyses assessed gender differences in health outcomes and evaluated physical and sexual trauma as possible moderators of these outcomes. RESULTS: Compared to male veterans, female veterans had higher prevalence estimates of lifetime posttraumatic stress (OR=3.33) and lifetime and current major depressive (ORs=2.10 and 2.76, respectively) disorders, and lifetime histories of arthritis, migraine headaches, and osteoporosis (ORs ranging 2.14-9.74), but lower prevalence estimates of lifetime nicotine dependence (OR=0.46), lifetime and current alcohol use (ORs=0.19 and 0.36, respectively) and lifetime drug use (OR=0.39) disorders, and lifetime histories of diabetes, heart attack, and high blood pressure (ORs ranging 0.05-0.49). The elevation in risk associated with physical and sexual assault was greater for males than females for numerous health conditions (but greater for females for posttraumatic stress disorder). CONCLUSIONS: Results provide a comprehensive assessment and characterization of gender differences in mental and physical health conditions and risk conferred by assaultive trauma for certain conditions in U.S. veterans. PMID- 28867416 TI - Negative affect as mediator between emotion regulation and medically unexplained symptoms. AB - BACKGROUND: Research on emotion regulation (ER) in medically unexplained physical symptoms (MUS) is rare. PURPOSE: The goal of this study was to compare ER skills between MUS-patients without comorbid depression, MUS-patients with comorbid depression (MUS+MDD), patients with major depressive disorder (MDD), and healthy controls. Additionally, we examined the mediating effect of depression and anxiety on the relationship between ER and somatization. METHODS: The Emotion Regulation Skills Questionnaire (ERSQ) and other self-report measures were completed by 138 MUS-patients, 114 MUS+MDD-patients, 106 MDD-patients, and 100 healthy controls. Multiple mediation analyses were applied to investigate the role of depression and anxiety as potential mediators. RESULTS: A MANCOVA and post-hoc test with age, sex and education as covariates indicated that ER skills of the MUS-group were lower than the controls (p<0.001-p=0.047), but higher than the MDD- and MUS+MDD-group (p<0.001-p=0.042). ER skills of the MDD-group and MUS+MDD-group did not differ (p=0.78-p=0.99), but were lower than controls (p<0.001-p=0.011). In the MUS-groups depression and anxiety had a mediating effect on the relationship between ER and somatization (b=-0.23, 95% bias corrected CI: -0.30, -0.17). The direct effect of ER on somatization was no longer significant when controlling for the mediating variables (b=0.07, p=0.083). CONCLUSIONS: Our study reveals that patients with MUS+MDD have higher deficits in ER skills than MUS patients without MDD. Additionally, deficits in ER in MUS-patients are influenced by depression and anxiety. This indicates that MUS patients with comorbid mental disorders might benefit from an emotion regulation training. PMID- 28867418 TI - Predicting grief intensity after recent perinatal loss. AB - OBJECTIVE: The Perinatal Grief Intensity Scale (PGIS) was developed for clinical use to identify and predict intense grief and need for follow-up after perinatal loss. This study evaluates the validity of the PGIS via its ability to predict future intense grief based on a PGIS score obtained early after a loss. METHODS: A prospective observational study was conducted with 103 international, English speaking women recruited at hospital discharge or via the internet who experienced a miscarriage, stillbirth, or neonatal death within the previous 8weeks. Survey data were collected at baseline using the PGIS and the Perinatal Grief Scale (PGS). Follow-up data on the PGS were obtained 3months later. Data analysis included descriptive statistics, Cronbach's alpha, receiver operating characteristic curve analysis, and confirmatory factor analysis. RESULTS: Cronbach's alphas were >=0.70 for both instruments. PGIS factor analysis yielded three factors as predicted, explaining 57.7% of the variance. The optimal cutoff identified for the PGIS was 3.535. No difference was found when the ability of the PGIS to identify intense grief was compared to the PGS (p=0.754). The PGIS was not inferior to the PGS (AUC=0.78, 95% CI 0.68-0.88, p<0.001) in predicting intense grief at the follow-up. A PGIS score>=3.53 at baseline was associated with increased grief intensity at Time 2 (PGS: OR=1.97, 95% CI 1.59-2.34, p<0.001). CONCLUSIONS: The PGIS is comparable to the PGS, has a lower response burden, and can reliably and validly predict women who may experience future intense grief associated with perinatal loss. PMID- 28867417 TI - Increased psychiatric morbidity in women with complete androgen insensitivity syndrome or complete gonadal dysgenesis. AB - OBJECTIVE: Knowledge concerning mental health outcomes is important to optimize the health of individuals with disorders or differences of sex development (DSD). Thus, the aim of this study was to estimate if the prevalence of psychiatric morbidity in adult women diagnosed with complete androgen insensitivity syndrome (CAIS) or complete gonadal dysgenesis (46,XY GD and 46,XX GD) differs from that in women with premature ovarian insufficiency (POI) or age-matched population controls. METHODS: This cross-sectional study was conducted at the Karolinska University Hospital, Stockholm, Sweden, and included 33 women with different DSDs: 20 CAIS, 6 46,XY GD, 7 46,XX GD, 21 women with POI and 61 population derived controls. Psychiatric morbidity was assessed using the Mini International Neuropsychiatric Interview plus (MINI+). To complement the MINI+, three self report questions were used to evaluate current and previous psychiatric history. Results are presented as p values and estimated risks (odds ratio [OR], 95% confidence intervals [CI]) of psychiatric conditions among women with CAIS or GD in comparison with women with POI and age-matched population-derived controls. RESULTS: Twenty-eight of the 33 women (85%) with CAIS or GD met the criteria for at least one psychiatric disorder according to the MINI+, with depression and anxiety disorders being most common. This was significantly higher compared with population controls (52%) (OR 5.1, 95% CI 1.7-14.9), but not compared to women with POI, who had a high frequency of psychiatric diagnoses (76%). CONCLUSION: The increased psychiatric morbidity in women with CAIS and GD highlights the need for clinical awareness of the psychiatric vulnerability in these patients. PMID- 28867419 TI - Increased incidence of psychiatric disorders in immune-mediated inflammatory disease. AB - OBJECTIVE: Although psychiatric comorbidity is known to be more prevalent in immune-mediated inflammatory diseases (IMID) than in the general population, the incidence of psychiatric comorbidity in IMID is less understood, yet incidence is more relevant for understanding etiology. METHODS: Using population-based administrative (health) data, we conducted a retrospective cohort study over the period 1989-2012 in Manitoba, Canada. We identified 19,572 incident cases of IMID including 6119 persons with inflammatory bowel disease (IBD), 3514 persons with multiple sclerosis (MS), 10,206 persons with rheumatoid arthritis (RA), and 97,727 age-, sex- and geographically-matched controls. After applying validated case definitions, we estimated the incidence of depression, anxiety disorder, bipolar disorder and schizophrenia in each of the study cohorts. Using negative binomial regression models, we tested whether the incidence rate of psychiatric comorbidity was elevated in the individual and combined IMID cohorts versus the matched cohorts, adjusting for sex, age, region of residence, socioeconomic status and year. RESULTS: The relative incidence of depression (incidence rate ratio [IRR] 1.71; 95%CI: 1.64-1.79), anxiety (IRR 1.34; 95%CI: 1.29-1.40), bipolar disorder (IRR 1.68; 95%CI: 1.52-1.85) and schizophrenia (IRR 1.32; 95%CI: 1.03-1.69) were elevated in the IMID cohort. Depression and anxiety affected the MS population more often than the IBD and RA populations. CONCLUSIONS: Individuals with IMID, including IBD, MS and RA are at increased risk of psychiatric comorbidity. This increased risk appears non-specific as it is seen for all three IMIDs and for all psychiatric disorders studied, implying a common underlying biology for psychiatric comorbidity in those with IMID. PMID- 28867420 TI - A comparative prospective cohort study of women following childbirth: Mothers of low birthweight infants at risk for elevated PTSD symptoms. PMID- 28867421 TI - DSM-5 illness anxiety disorder and somatic symptom disorder: Comorbidity, correlates, and overlap with DSM-IV hypochondriasis. AB - OBJECTIVE: To investigate the reliability, validity and utility of DSM-5 illness anxiety disorder (IAD) and somatic symptom disorder (SSD), and explore their overlap with DSM-IV Hypochondriasis in a health anxious sample. METHODS: Treatment-seeking patients with health anxiety (N=118) completed structured diagnostic interviews to assess DSM-IV Hypochondriasis, DSM-5 IAD, SSD, and comorbid mental disorders, and completed self-report measures of health anxiety, comorbid symptoms, cognitions and behaviours, and service utilization. RESULTS: IAD and SSD were more reliable diagnoses than Hypochondriasis (kappa estimates: IAD: 0.80, SSD: 0.92, Hypochondriasis: 0.60). 45% of patients were diagnosed with SSD, 47% with IAD, and 8% with comorbid IAD/SSD. Most patients with IAD fluctuated between seeking and avoiding care (61%), whereas care-seeking (25%) and care-avoidant subtypes were less common (14%). Half the sample met criteria for DSM-IV Hypochondriasis; of those, 56% met criteria for SSD criteria, 36% for IAD, and 8% for comorbid IAD/SSD. Compared to IAD, SSD was characterized by more severe health anxiety, somatic symptoms, depression, and higher health service use, and higher rates of major depressive disorder, panic disorder and agoraphobia. CONCLUSIONS: DSM-5 IAD and SSD classifications reliably detect more cases of clinically significant health anxiety than DSM-IV Hypochondriasis. The differences between IAD and SSD appear to be due to severity. Future research should explore the generalizability of these findings to other samples, and whether diagnostic status predicts treatment response and long-term outcome. PMID- 28867422 TI - Serum albumin levels and depression in people living with Human Immunodeficiency Virus infection: a cross-sectional study. AB - BACKGROUND: Lower serum albumin levels and depression are common among HIV infected persons. High serum albumin levels may provide protection against depression through its defensive role in inflammation and infection. We tested the hypothesis of an independent relationship between serum albumin levels and depressive symptoms in a cohort of HIV-infected persons. METHODS: A cross sectional survey was conducted among 310 HIV-infected persons (176 men and 134 women) aged 20-60years residing in the Kathmandu Valley, Nepal. The bromocresol green method was used to measure serum albumin levels and the Beck Depression Inventory method was used to measure depressive symptoms, with a cut off score of 20 or higher indicating likely depression. The relationship between serum albumin levels and depressive symptoms was assessed using both multiple linear regression analysis and multiple logistic regression analysis, with adjustment for sociodemographic, cardiovascular, life-style, and HIV-related clinical and treatment confounding factors. RESULTS: Serum albumin levels were inversely associated with depressive symptoms scores (beta for 1 unit change in serum albumin levels: beta=-3.91; p=0.001) for the total participant sample. This inverse association was significant in both men (beta=-3.93; p=0.009) and women (beta=-4.47; p=0.03). A significantly decreased risk of depression was observed among participants with the highest serum albumin levels, with odds ratio and 95% CI for those with >5.0g/dL versus <4.0g/dL of 0.22 (0.06-0.80) (p=0.01). CONCLUSION: Serum albumin levels were inversely associated with depressive symptoms scores in HIV-infected persons. PMID- 28867423 TI - Comparing the Patient Health Questionnaire - 15 and the Somatic Symptom Scale - 8 as measures of somatic symptom burden. AB - PURPOSE: The Patient Health Questionnaire - 15 (PHQ-15) and the Somatic Symptom Scale - 8 (SSS-8) are self-report measures which assess somatic symptom burden. The present study investigates whether the two measures are comparable in terms of their psychometric properties and estimates of symptom burden. METHOD: Item characteristics, reliability, symptom severity and construct validity with regard to other relevant psychological, health-related quality of life and disability measures were compared for the PHQ-15m and the SSS-8 in 294 primary care patients who participated in a randomized comparative effectiveness trial targeting pain and mood symptoms. RESULTS: The reliabilities of the PHQ-15m and the SSS-8 were alpha=0.66 and alpha=0.72, respectively. Both measures were highly correlated (r=0.79). All item characteristics were comparable and both instruments showed the same pattern of correlations with instruments measuring depression, anxiety, pain, quality of life and impairment (r=0.25 to 0.53). A 1-point score increase (worsening of somatic symptoms) on either instrument resulted in a 3.7% to 3.9% increase in the number of disability days reported for the last four weeks. Using the same severity thresholds (5: low, 10: medium, 15: high), both measures identified nearly identical subgroups of patients with regard to health-related quality of life and disability. CONCLUSION: The PHQ-15m and the SSS-8 are comparable measures in terms of reliability and validity and severity classifications. These findings are in line with previous results and support the use of the SSS-8 as a valuable and short alternative to the original PHQ-15 in settings with limited assessment time. PMID- 28867424 TI - Psychosocial and behavioral factors in acetaminophen-related acute liver failure and liver injury. AB - OBJECTIVES: Acetaminophen overdoses result in nearly 500 deaths annually and a much larger number of hospitalizations. Suicidal overdoses are exceeded in number in the United States by unintentional overdoses. We evaluated clinical, demographic and psychosocial factors among unintentional and intentional overdose patients whose acetaminophen (APAP) toxicity had resulted in acute liver failure. We hypothesized that APAP overdose patients would be more likely to suffer from behavioral health issues and display higher impulsivity scores than the general population. METHODS: Within 4days of admission and initial recovery of alertness, we administered a detailed questionnaire that included questions on APAP intake (e.g., dose taken, intent, other substances ingested), the Mini International Neuropsychiatric Interview modules on depression, alcohol use, substance use, and pain disorders and The Barratt Impulsiveness Scale-11. RESULTS: The group included 44 intentional (single time point ingestions with the intent to self harm) and 51 unintentional (multiple time point ingestions to manage pain or other condition) APAP patients enrolled in the Acute Liver Failure Study Group registry between 2007 and 2013. Both groups were characterized by similar frequencies of chronic pain, depressive symptoms at time of ingestion and alcohol and substance use disorders, all at higher rates than the general population. Overall, APAP patients scored higher than the general population for Non-planning aspects of impulsivity, with no apparent differences between other impulsivity scores or between intentional and unintentional APAP patients. CONCLUSIONS: Depression, mismanagement of problematic chronic pain, frequent substance abuse, and increased impulsivity appear to provide the substrate for many APAP overdoses. PMID- 28867425 TI - The association between substantiated childhood maltreatment, asthma and lung function: A prospective investigation. AB - BACKGROUND: Asthma reflects multiple and likely complex causal pathways. We investigate the possibility that childhood maltreatment is one such causal pathway. Childhood maltreatment can be interpreted as a form of early life adversity and like other life adversities may predict a range of negative health outcomes, including asthma. METHODS: A total of 3762 young adults (52.63% female) from the Mater Hospital-University of Queensland Study of Pregnancy (MUSP) participated in this study. MUSP is a prospective Australian birth cohort study of mothers consecutively recruited during their first antenatal clinic visit at Brisbane's Mater Hospital from 1981 to 1983. The study followed both mother-child dyads to the age of 21years after birth. Participants reported whether they had been diagnosed by a physician with asthma by the 21-year follow-up. Trained research assistants also performed gender- and height-standardized lung function tests using a Spirobank G spirometer system attached to a laptop computer. We linked this dataset with data obtained from the child protection services and which comprised all substantiated cases of childhood maltreatment in the MUSP cohort. Substantiations of childhood maltreatment included children in an age range of 0-14years. RESULTS: The experience of any childhood maltreatment, particularly emotional abuse, was independently associated with self-reported physician-diagnosed asthma by the 21-year follow-up. The association was no longer significant after adjustment for a range of confounders and covariates in neglected children. Childhood maltreatment, including multiple events, was not associated with lung function in adjusted models. CONCLUSIONS: Childhood maltreatment, including emotional abuse, was associated with lifetime ever asthma. This was in contrast to the absence of an association with objective measures of lung function. More research is indicated on the effect of childhood maltreatment on lung function using objective measures. In the meantime, there should be a greater awareness of the potential impact of childhood maltreatment on the potential to develop asthma, as well as of the possibility that asthma in adulthood may precede childhood maltreatment. PMID- 28867426 TI - Alexithymia as a health risk and resilience factor. PMID- 28867427 TI - Prevalence and effectiveness of psychiatric treatments for patients with IBD: A systematic literature review. AB - OBJECTIVES: Higher prevalence of psychiatric disorders, such as anxiety and depression, has been found in people with Crohn's disease and Ulcerative Colitis compared to the general population. Nowadays, international guidelines advocate psychotherapy and psycho-pharmacological treatments as playing an important role in IBD care. The main goal of this systematic literature review was summarize the evidence on the utilization and effectiveness of treatments for depression and anxiety in persons with IBD. METHODS: A systematic literature review was conducted using three different electronic databases: MEDLINE, PsychINFO, and EMBASE to identify studies reporting the prevalence and efficacy of psycho pharmacological and psychotherapeutic treatments for IBD. A quality appraisal was conducted using several scales as appropriate for each study design. A narrative synthesis was also performed. RESULTS: Forty-three studies were included. Although a high rate of psychoactive drug use was found in people with IBD, a low proportion of IBD patients have access to psychiatric referral. 1/3 of the studies found that psychotherapy was effective for improving the quality of life, perception of stress, anxiety and depression as well as disease. Antidepressants proved effective in reducing disease activity, gastrointestinal symptoms, anxiety and depression. CONCLUSION: Our results suggest that psychiatric treatment should be implemented in IBD care. However, further studies are needed to confirm the findings of our systematic review. PMID- 28867428 TI - Epidemiological evaluation of the Patient Health Questionnaire-2 in a pregnant population. AB - INTRODUCTION: The Patient Health Questionnaire-2 (PHQ-2) is a commonly used 2 item screening tool for depressive symptoms among pregnant women in primary care settings. However, its validity has not been assessed for large-scale epidemiological studies. Therefore, the aim of this study was to provide an epidemiological evaluation of the PHQ-2 among pregnant women. METHOD: A total of 3033 pregnant women participating in the PRegnancy and Infant DEvelopment Study completed the PHQ-2 as well as the Hospital Anxiety Depression Scale-Depression (HADS-D) or the Edinburgh Depression Scale (EDS) three times throughout pregnancy. The validity of the PHQ-2 was assessed with the HADS-D/EDS as reference standard. RESULTS: Sensitivity and specificity of the PHQ-2 were 69-84% and 79-84%, respectively. The positive predictive values (range 19-26%) were substantially lower than the negative predictive values (96-99%). CONCLUSION: Despite the relatively high number of false-positive screens, initial screening for depression by two questions only may enhance routine evaluation of depressive symptoms among pregnant women. PMID- 28867429 TI - Comparison of sodium hydroxide and calcium hydroxide pretreatments of giant reed for enhanced enzymatic digestibility and methane production. AB - NaOH pretreatment with leachate reuse and Ca(OH)2 pretreatment were compared for improved enzymatic digestibility and biogas production from giant reed, a promising energy crop. The NaOH pretreatment with leachate reuse increased glucose yields during enzymatic hydrolysis by 2.6-fold, and methane yields during anaerobic digestion by 1.4- to 1.6-fold. However, NaOH pretreatment had a negative net benefit (i.e., revenue from increased energy production minus chemical cost). Pretreatment with 7-20% Ca(OH)2 not only improved glucose yield and methane yield by up to 2.3-fold and 1.4-fold, respectively, but also obtained a net benefit of $1.1-5.8/tonne dry biomass. Thus, Ca(OH)2 pretreatment was shown to be more feasible than NaOH pretreatment for biogas production from giant reed. PMID- 28867430 TI - Thoughts About Journals, Altruism, Impact Factors, Marijuana, and the Physician Labeling Rule. PMID- 28867431 TI - Race and postoperative complications following urologic cancer surgery: An ACS NSQIP analysis. AB - PURPOSE: Racial disparities in complication rates have been demonstrated for a variety of surgical procedures. We hypothesized that African American (AA) patients experience higher postoperative complication rates than whites following urologic oncology procedures. MATERIALS AND METHODS: Patients in American College of Surgeons National Surgical Quality Improvement Program who underwent radical prostatectomy (RP), radical or partial nephrectomy (RN/PN), and radical cystectomy (RC) between 2005 and 2013 were included. Complications were grouped as minor (Clavien I-II), major (Clavien III-IV), or death (Clavien V). A 30-day complication rates and disparities in preoperative comorbidity burden were compared by race. After adjustment for comorbidity burden, multivariable logistic regression was performed to test the association between race and risk of complication. RESULTS: Of 38,642 patients included in the analysis, 90% were white and 10% were AA. In unadjusted analysis, there were no significant differences in complication rates between AA and white patients for any Clavien grade in the procedures queried (RP: P = 0.07; RN/PN: P = 0.70; RC: P = 0.12). After controlling for a higher comorbidity burden among AA patients, AA race was again not independently associated with 30-day postoperative complications for RP (odds ratio [OR] = 1.08, 95% CI: 0.92-1.29), RN/PN (OR = 0.98, 95% CI: 0.84 1.13), or RC (OR = 1.10, 95% CI: 0.84-1.43). CONCLUSION: Despite a higher comorbidity burden, AA patients in American College of Surgeons National Surgical Quality Improvement Program are not at increased risk of 30-day postoperative complications following major urologic cancer surgery. These findings suggest that comorbidity burden, as opposed to race, is most strongly associated with the risk of postoperative complications. To minimize perioperative risk, clinicians should strive to preoperatively optimize medical comorbidities in all patients undergoing urologic cancer surgery. PMID- 28867432 TI - Use of administrative data for comparative effectiveness research in the treatment of non-prostate genitourinary malignancies. AB - Comparative effectiveness research (CER) is imperative for objective and balanced assessment of treatment outcomes. CER that uses administrative databases (AD-CER) affords unique opportunities for large scale data analyses that potentially transcend limitations of small institutional datasets. Prostate cancer has received much attention from the AD-CER research community, whereas non-prostate genitourinary malignancies are less well-studied. The objective of this article is to review the currently available AD-CER that has been published in the non prostate genitourinary malignancies space. PMID- 28867434 TI - Avery D. Weisman, M.D. PMID- 28867433 TI - Epidemiology of Back Pain in Young and Middle-Aged Adults: A Longitudinal Population Cohort Survey From Age 27-50 Years. AB - BACKGROUND: Back pain is extremely common and a huge burden for both individuals and health care services. OBJECTIVE: The aim was to determine the prevalence and incidence of lumbar and cervical back pain over 23 years and to quantify associations with concomitant disorders. METHODS: Data on lumbar and cervical back pain, and mental disorders from the Zurich study, collected between 1986 (age men: 27/women: 28 years) and 2008 (age 49/50) were analyzed. Epidemiological parameters were representative rates for the general population. Associations were quantified by odds ratios (ORs). RESULTS: Of 499 subjects, 68.9% ever experienced lumbar pain and 60.7% ever experienced cervical back pain; the 23 year prevalences were 66.9% and 54.9% and the 23-year incidences 52.3% and 48.9% for lumbar and cervical back pain, respectively. Annual prevalences varied between 28.4% and 47.2% for lumbar and 18.3% and 54.7% for cervical back pain; the corresponding annual incidences varied by 5.8-13.3% (lumbar) and 7.8-12.6% (cervical). Lumbar back pain was significantly associated with cardiovascular disease (OR = 4.58), obesity (OR = 3.99), asthma spectrum (OR = 5.76), tranquillizer dependence (OR = 5.84), and other comorbidities (ORs = 1.47-3.27). Significant associations with cervical back pain were observed for specific phobia (OR = 5.10), panic attacks (OR = 4.79), and other comorbidities (ORs = 1.61-2.62). CONCLUSIONS: This study contributes to the refinement of epidemiological data on lumbar and cervical back pain. Some associations with treatable disorders were high, which may offer hope for the indirect management of lumbar and cervical back pain. PMID- 28867435 TI - Inhaled corticosteroids and pneumonia risk - Revised knowledge. PMID- 28867436 TI - Effects of diosmetin on nine cytochrome P450 isoforms, UGTs and three drug transporters in vitro. AB - Diosmetin (3', 5, 7-trihydroxy-4'-methoxyflavone), a natural flavonoid from traditional Chinese herbs, has been used in various medicinal products because of its anticancer, antimicrobial, antioxidant, estrogenic and anti-inflammatory activity. However, flavonoids could affect the metabolic enzymes and cause drug drug interactions (DDI), reducing the efficacy of co-administered drugs and potentially resulting in serious adverse reactions. To evaluate its potential to interact with co-administered drugs, the IC50 value of phase I cytochrome P450 enzymes (CYPs), phase II UDP-glucuronyltransferases (UGTs) and hepatic uptake transporters (organic cation transporters (OCTs), organic anion transporter polypeptides (OATPs) and Na+-taurocholate cotransporting polypeptides (NTCPs)) were examined in vitro by LC-MS/MS. Diosmetin showed strong inhibition of CYP1A2 in a concentration-dependent manner. The intensity of the inhibitory effect was followed by CYP2C8, CYP2C9, CYP2C19 and CYP2E1. For CYP2A6, CYP2B6, CYP2D6 and CYP3A4, diosmetin was found to have no significant inhibitory effects, and the induction effect on CYPs was not significant. For UGTs, diosmetin had a minimal inhibitory effect. In addition, the inhibitory effects of diosmetin on OATP and OCT1 were weak, and it had little effect on NTCP. This finding indicated that drug-drug interactions induced by diosmetin may occur through co-administration of drugs metabolized by CYP1A2. PMID- 28867437 TI - Quinacrine induces the apoptosis of human leukemia U937 cells through FOXP3/miR 183/beta-TrCP/SP1 axis-mediated BAX upregulation. AB - Quinacrine, which is clinically used as an antimalarial drug, has anti-cancer activity. However, mechanism underlying its cytotoxic effect remains to be completely elucidated. In the present study, we investigated the cytotoxic effect of quinacrine on human leukemia U937 cells. Quinacrine-induced apoptosis of U937 cells was accompanied with ROS generation, mitochondrial depolarization, and BAX upregulation. Quinacrine-treated U937 cells showed ROS-mediated p38 MAPK activation and ERK inactivation, which in turn upregulated FOXP3 transcription. FOXP3-mediated miR-183 expression decreased beta-TrCP mRNA stability and suppressed beta-TrCP-mediated SP1 degradation, thus increasing SP1 expression in U937 cells. Upregulated SP1 expression further increased BAX expression. BAX knock-down attenuated quinacrine-induced mitochondrial depolarization and increased the viability of quinacrine-treated cells. Together, our data indicate that quinacrine-induced apoptosis of U937 cells is mediated by mitochondrial alterations triggered by FOXP3/miR-183/beta-TrCP/SP1 axis-mediated BAX upregulation. PMID- 28867438 TI - Neuromuscular paralysis by the basic phospholipase A2 subunit of crotoxin from Crotalus durissus terrificus snake venom needs its acid chaperone to concurrently inhibit acetylcholine release and produce muscle blockage. AB - BACKGROUND AND PURPOSE: Crotoxin (CTX), a heterodimeric phospholipase A2 (PLA2) neurotoxin from Crotalus durissus terrificus snake venom, promotes irreversible blockade of neuromuscular transmission. Indirect electrophysiological evidence suggests that CTX exerts a primary inhibitory action on transmitter exocytosis, yet contribution of a postsynaptic action of the toxin resulting from nicotinic receptor desensitization cannot be excluded. Here, we examined the blocking effect of CTX on nerve-evoked transmitter release measured directly using radioisotope neurochemistry and video microscopy with the FM4-64 fluorescent dye. EXPERIMENTAL APPROACH: Experiments were conducted using mice phrenic-diaphragm preparations. Real-time fluorescence video microscopy and liquid scintillation spectrometry techniques were used to detect transmitter exocytosis and nerve evoked [3H]-acetylcholine ([3H]ACh) release, respectively. Nerve-evoked myographic recordings were also carried out for comparison purposes. KEY RESULTS: Both CTX (5MUg/mL) and its basic PLA2 subunit (CB, 20MUg/mL) had biphasic effects on nerve-evoked transmitter exocytosis characterized by a transient initial facilitation followed by a sustained decay. CTX and CB reduced nerve-evoked [3H]ACh release by 60% and 69%, respectively, but only the heterodimer, CTX, decreased the amplitude of nerve-evoked muscle twitches. CONCLUSION AND IMPLICATIONS: Data show that CTX exerts a presynaptic inhibitory action on ACh release that is highly dependent on its intrinsic PLA2 activity. Given the high safety margin of the neuromuscular transmission, one may argue that the presynaptic block caused by the toxin is not enough to produce muscle paralysis unless a concurrent postsynaptic inhibitory action is also exerted by the CTX heterodimer. PMID- 28867439 TI - Mixed-methods investigation of women's experiences with second-trimester abortion care in the Midwest and Northeast United States. AB - OBJECTIVE(S): We studied women's experiences seeking and receiving second trimester abortion care in two geographically and legislatively different settings to inform ways to improve abortion care access and services. STUDY DESIGN: We conducted in-depth interviews with women who obtained second-trimester abortion care. Themes from the interviews were then used to inform a self administered survey, which was completed by 108 women who received second trimester abortion care in the Northeast and Midwest. We calculated descriptive statistics and used chi-squared and t-tests to compare responses. RESULTS: We interviewed eight women and surveyed 108 women. Most interviewees and 65.2% of survey respondents reported difficulties accessing care. Although most interview and survey respondents had insurance, a slight majority reported difficulty funding care. All interviewees and 57.9% of survey respondents reported positive experiences with providers, with many interviewees and 62.0% of survey respondents saying their abortion care was better than their usual health care. Most interviewees and 75.8% of survey respondents reported pain as low to moderate, and the majority of participants reported it was the same or less than expected. Knowledge about abortion restrictions was low. Most interviewees and 68.4% survey respondents disagreed with restrictions on insurance coverage of abortion. Common recommendations to improve experiences were to ensure travel and financial support and to decrease wait times at clinics. There were few regional differences among outcomes. CONCLUSION(S): Women seeking second-trimester abortion in these locations reported positive abortion experiences. However, they had to overcome significant obstacles to obtain care. IMPLICATIONS: This is the first study to systematically research women's second-trimester care experiences in two different regions of the United States. Regardless of location, women experienced barriers due to policies that impose gestational age restrictions, limit provider availability (consequently increasing wait times), and increase costs. Policy change to reduce these barriers is critical to improve access to and experiences with second trimester abortion care. PMID- 28867440 TI - Etonogestrel implant migration to the vasculature, chest wall, and distant body sites: cases from a pharmacovigilance database. AB - OBJECTIVE: To describe clinical outcomes of etonogestrel implant patients with migration to the vasculature, chest wall and other distant body sites spontaneously reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. STUDY DESIGN: We performed a standardized Medical Dictionary for Regulatory Activities (MedDRA) query in the FAERS database (through November 15, 2015), with reports coded with one or more MedDRA preferred terms that indicate complications with device placement or migration of the device from the original site of insertion to the vasculature, chest wall and other distant body sites. We excluded any cases previously described in the medical literature. RESULTS: We identified 38 cases of pronounced etonogestrel implant migration. Migration locations included the lung/pulmonary artery (n=9), chest wall (n=1), vasculature at locations other than the lung/pulmonary artery (n=14) and extravascular migrations (n=14) to other body sites (e.g., the axilla and clavicle/neck line/shoulder). The majority of cases were asymptomatic and detected when the patient desired implant removal; however, seven cases reported symptoms such as pain, discomfort and dyspnea in association with implant migration. Three cases also describe pulmonary fibrosis and skin reactions as a result of implant migration to the vasculature, chest wall and other distant body sites. Sixteen cases reported surgical removal in an operating room setting. CONCLUSIONS: Our FAERS case series demonstrates etonogestrel implant migration to the vasculature, chest wall and other body sites distant from the site of original insertion. IMPLICATIONS STATEMENT: As noted by the sponsor in current prescribing information, a key determinant in the risk for etonogestrel contraceptive implant migration appears to be improper insertion technique. Although migration of etonogestrel implants to the vasculature is rare, awareness of migration and education on proper insertion technique may reduce the risk. PMID- 28867441 TI - Tweeting PP: an analysis of the 2015-2016 Planned Parenthood controversy on Twitter. AB - OBJECTIVES: We analyzed Twitter tweets and Twitter-provided user data to give geographical, temporal and content insight into the use of social media in the Planned Parenthood video controversy. METHODOLOGY: We randomly sampled the full Twitter repository (also known as the Firehose) (n=30,000) for tweets containing the phrase "planned parenthood" as well as group-defining hashtags "#defundpp" and "#standwithpp." We used demographic content provided by the user and word analysis to generate charts, maps and timeline visualizations. Chi-square and t tests were used to compare differences in content, statistical references and dissemination strategies. RESULTS: From July 14, 2015, to January 30, 2016, 1,364,131 and 795,791 tweets contained "#defundpp" and "#standwithpp," respectively. Geographically, #defundpp and #standwithpp were disproportionally distributed to the US South and West, respectively. Word analysis found that early tweets predominantly used "sensational" words and that the proportion of "political" and "call to action" words increased over time. Scatterplots revealed that #standwithpp tweets were clustered and episodic compared to #defundpp. #standwithpp users were more likely to be female [odds ratio (OR) 2.2, confidence interval (CI) 2.0-2.4] and have fewer followers (median 544 vs. 1578, p<.0001). #standwithpp and #defundpp did not differ significantly in their usage of data in tweets. #defundpp users were more likely to link to websites (OR 1.8, CI 1.7-1.9) and to other online dialogs (mean 3.3 vs. 2.0 p<.0001). CONCLUSION: Social media analysis can be used to characterize and understand the content, tempo and location of abortion-related messages in today's public spheres. Further research may inform proabortion efforts in terms of how information can be more effectively conveyed to the public. IMPLICATIONS: This study has implications for how the medical community interfaces with the public with regards to abortion. It highlights how social media are actively exploited instruments for information and message dissemination. Researchers, providers and advocates should be monitoring social media and addressing the public through these modern channels. PMID- 28867442 TI - Does information about abortion safety affect Texas voters' opinions about restrictive laws? A randomized study. AB - OBJECTIVE: The objective was to assess whether information about abortion safety and awareness of abortion laws affect voters' opinions about medically unnecessary abortion regulations. STUDY DESIGN: Between May and June 2016, we randomized 1200 Texas voters to receive or not receive information describing the safety of office-based abortion care during an online survey about abortion laws using simple random assignment. We compared the association between receiving safety information and awareness of recent restrictions and beliefs that ambulatory surgical center (ASC) requirements for abortion facilities and hospital admitting privileges requirements for physicians would make abortion safer. We used Poisson regression, adjusting for political affiliation and views on abortion. RESULTS: Of 1200 surveyed participants, 1183 had complete data for analysis: 612 in the information group and 571 in the comparison group. Overall, 259 (46%) in the information group and 298 (56%) in the comparison group believed that the ASC requirement would improve abortion safety (p=.008); 230 (41%) in the information group and 285 (54%) in the comparison group believed that admitting privileges would make abortion safer (p<.001). After multivariable adjustment, the information group was less likely to report that the ASC [prevalence ratio (PR): 0.82; 95% confidence interval (CI): 0.72-0.94] and admitting privileges requirements (PR: 0.76; 95% CI: 0.65-0.88) would improve safety. Participants who identified as conservative Republicans were more likely to report that the ASC (82%) and admitting privileges requirements (83%) would make abortion safer if they had heard of the provisions than if they were unaware of them (ASC: 52%; admitting privileges: 47%; all p<.001). CONCLUSIONS: Informational statements reduced perceptions that restrictive laws make abortion safer. Voters' prior awareness of the requirements also was associated with their beliefs. IMPLICATIONS: Informational messages can shift scientifically unfounded views about abortion safety and could reduce support for restrictive laws. Because prior awareness of abortion laws does not ensure accurate knowledge about their effects on safety, it is important to reach a broad audience through early dissemination of information about new regulations. PMID- 28867443 TI - Association of Hormonal Contraception with depression in the postpartum period. AB - OBJECTIVES: Studies have demonstrated an association between hormonal contraception use with subsequent depression and antidepressant use. This association has not been assessed among postpartum women. STUDY DESIGN: This study is a secondary analysis of insurance records from 75,528 postpartum women enrolled in the US military medical system, who delivered between October 2012 and September 2014. Our analyses excluded women who used antidepressants or had a diagnosis of depression in the 24months prior to delivery. We assessed the relationship of hormonal contraception use with subsequent antidepressant use or diagnosis with depression in the first 12months postpartum using Cox proportional hazards regression, with a time dependent covariate measuring exposure to hormonal contraception. RESULTS: Antidepressants were prescribed to 7.8% of women and 5.0% were diagnosed with depression. In multivariable analysis adjusting for demographics, both antidepressant use and diagnosis with depression were associated with: younger age, lower socioeconomic status, and a history of military service. Compared to women with no hormonal contraceptive use, use of etonogestrel containing contraception was associated with a higher risk of antidepressant use (Implant: adjHR:1.22(95%CI:1.06-1.41), p<0.001; Ring:1.45(1.16 1.80), p=0.001). Use of norethindrone-only pills was associated with a lower risk of antidepressant use (0.58(0.52-0.64), p<0.001) and depression diagnosis (0.56(0.49-0.64), p<0.001). Use of a levonorgestrel intrauterine system was associated with a lower risk of depression diagnoses (0.65(0.52-0.82), p<0.001). CONCLUSION: The risk of major depression diagnosis and antidepressant use in the postpartum period varies with the type of hormonal contraception used. Further research is required to describe the mechanisms of these relationships. PMID- 28867444 TI - Use of Breast Magnetic Resonance Imaging and Ultrasonography for Identifying Nonpalpable Axillae Metastases in Newly Diagnosed Breast Cancer Patients. AB - BACKGROUND: The metastasis of axillary lymph node (ALNs) is a critical step in the initial cancer staging of newly diagnosed breast cancer (BC) patients. Various imaging modalities can enhance the sensitivity of clinical examination in assessing the ALN status. PATIENTS AND METHODS: We enrolled 135 patients with BC, confirmed via histopathology, including 4 bilateral BC cases. A total of 139 ipsilateral ALNs adjacent to the breast lesion were examined via physical examination, ultrasonography (US), and magnetic resonance imaging (MRI); of these, 100 were nonpalpable ALNs, as determined by experienced breast surgeons and physicians. The relative size parameters on MRI and US images were recorded. Receiver operating characteristic (ROC) analyses were conducted, and the area under the ROC curve (AUC) was compared. RESULTS: Of 139 ALNs, 67 (48%) were malignant and 72 (52%) were benign on pathological examination. In all of the ALNs, the US short diameter appeared to be the most discriminative quantitative measurement for detecting positive findings (AUC, 0.854). In nonpalpable ALNs as well, the US short diameter exhibited the greatest discriminability (AUC, 0.746). However, the 2-dimensional and 3-dimensional parameters on MRI did not exhibit any significant differences between the enrolled and nonpalpable ALNs (P > .05). CONCLUSION: The shortest diameter on US exhibited better discriminative ability than MRI for predicting positive ALNs in nonpalpable axillae. Moreover, the 2 dimensional and 3-dimensional parameters on MRI did not differ in terms of discriminability. PMID- 28867445 TI - Changing Natural History of HER2-Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies. AB - BACKGROUND: Given the wide adoption of human epidermal growth factor receptor 2 (HER2)-targeted therapies for advanced HER2-positive breast cancer, we studied the natural history of patients with HER2-positive breast cancer brain metastases (BCBM) over time. PATIENTS AND METHODS: Patients with HER2-positive BCBM identified from a prospectively maintained database at the University of North Carolina were divided into 3 cohorts by year of BCBM diagnosis. Cohorts were selected by year of HER2-targeted therapy US Food and Drug Administration approval. Overall survival (OS), time to first metastasis, time to BCBM, and BCBM survival were estimated by the Kaplan-Meier method. Associations between OS after BCBM and clinical variables were assessed by Cox proportional hazards regression models. RESULTS: One hundred twenty-three patients were identified. Median age was 51 years, and 58% were white and 31% African American. OS from initial breast cancer diagnosis improved over time: 3.6 years (95% confidence interval [CI], 2.8 6.1) in the 1998-2007 cohort, 6.6 years (95% CI, 4.5-8.6) in the 2008-2012 cohort, and 7.6 years (95% CI, 4.4-9.6) in the 2013-2015 cohort (P = .05). While time from initial diagnosis to first metastasis did not differ (P = .12), time to BCBM increased over time (2.6 years [95% CI, 1.3-3.5] for 1998-2007; 2.6 years [95% CI, 2.1-4.3] for 2008-2012, and 3.3 years [95% CI, 2.2-6] for 2013-2015; P = .05). Although OS from BCBM did not significantly differ by cohort, patients who received HER2-targeted therapy after BCBM had a prolonged OS (2.1 years [95% CI, 1.6-2.6] vs. 0.65 years [95% CI, 0.4-1.3]; P = .001). CONCLUSION: OS from initial breast cancer diagnosis significantly improved over time for patients with HER2 positive breast cancer who develop BCBM, now exceeding 7 years; survival from BCBM diagnosis may now exceed 2 years. PMID- 28867447 TI - Quality Improvement Efforts in Radical Cystectomy: From Prehab to Rehab. PMID- 28867446 TI - European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. AB - CONTEXT: The European Association of Urology (EAU) Guidelines Panel on Upper Urinary Tract Urothelial Carcinoma (UTUC) has prepared updated guidelines to aid clinicians in the current evidence-based management of UTUC and to incorporate recommendations into clinical practice. OBJECTIVE: To provide an overview of the EAU guidelines on UTUC as an aid to clinicians. EVIDENCE ACQUISITION: The recommendations provided in the current guidelines are based on a thorough review of available UTUC guidelines and articles identified following a systematic search of Medline. Data on urothelial malignancies and UTUC were searched using the following keywords: urinary tract cancer; urothelial carcinomas; upper urinary tract, carcinoma; renal pelvis; ureter; bladder cancer; chemotherapy; ureteroscopy; nephroureterectomy; adjuvant treatment; instillation; recurrence; risk factors; and survival. References were weighted by a panel of experts. EVIDENCE SYNTHESIS: Owing to the rarity of UTUC, there are insufficient data to provide strong recommendations (ie, grade A). However, the results of recent multicentre studies are now available, and there is a growing number of retrospective articles in UTUC. The 2017 tumour, node, metastasis (TNM) classification is recommended. Recommendations are given for diagnosis and risk stratification, as well as for radical and conservative treatment; prognostic factors are also discussed. A single postoperative dose of intravesical mitomycin after radical nephroureterectomy reduces the risk of bladder tumour recurrence. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk tumours and two functional kidneys. CONCLUSIONS: These guidelines contain information on the management of individual patients according to a current standardised approach. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen, based on the proposed risk stratification of these tumours. PATIENT SUMMARY: Urothelial carcinoma of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis; appropriate diagnosis and management is most important. We present recommendations based on current evidence for optimal management. PMID- 28867448 TI - Moisture-induced phase separation and recrystallization in amorphous solid dispersions. AB - Active Pharmaceutical Ingredients (APIs) are often dissolved in polymeric matrices to control the gastrointestinal dissolution and to stabilize the amorphous state of the API. During the pharmaceutical development of new formulations, stability studies via storage at certain temperature and relative humidity (RH) have to be carried out to verify the long-term thermodynamic stability of these formulations against unwanted recrystallization and moisture induced amorphous-amorphous phase separation (MIAPS). This study focuses on predicting the MIAPS of API/polymer formulations at elevated RH. In a first step, the phase behavior of water-free formulations of ibuprofen (IBU) and felodipine (FEL) combined with the polymers poly(vinyl pyrrolidone) (PVP), poly(vinyl acetate) (PVAC) and poly (vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) was determined experimentally by differential scanning calorimetry (DSC). The phase behavior of these water-free formulations was modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Based on this, the API solubility and MIAPS in the above-mentioned formulations at humid conditions was predicted in perfect agreement with the results of two-year lasting stability studies at 25 degrees C/0% RH and 40 degrees C/75% RH. MIAPS was predicted and also experimentally found for the FEL/PVP, FEL/PVPVA64 and IBU/PVP formulations, whereas MIAPS was neither predicted nor measured for the IBU/PVPVA64 system and PVAC-containing formulations. It was thus shown that the results of time consuming long-term stability tests can be correctly predicted via thermodynamic modeling with PC-SAFT. PMID- 28867449 TI - Advances in intravesical drug delivery systems to treat bladder cancer. AB - Chemotherapeutic agents administered intravesically to treat bladder cancer have limited efficacy due to periodic dilution and wash-out during urine formation and elimination. This review describes the pathophysiology, prevalence and staging of bladder cancer, and discusses several formulation strategies used to improve drug residence within the bladder. These include the use of amphiphilic copolymers, mucoadhesive formulations, hydrogels, floating systems, and liposomes. Various in vitro and in vivo models recently employed for intravesical drug delivery studies are discussed. Some of the challenges that have prevented the clinical use of some promising formulations are identified. PMID- 28867450 TI - Modeling of the burst release from PLGA micro- and nanoparticles as function of physicochemical parameters and formulation characteristics. AB - A substantial drug release from poly(lactic-co-glycolic) acid (PLGA) micro- and nanoparticles can occur in the first hours of immersion, which is referred to as burst release. A strong burst release (when not intentional) is to be avoided as it decreases the efficacy of the treatment and could be dangerous to the host. In this work we analyze the total amount of drug released during burst and respective kinetics in relation to formulations characteristics, experimental conditions and drug molecular properties in 154 drug release experiments with 41 different drugs by partial least squares (PLS) and decision tree regression. The model created enables to quantify to which degree the physicochemical parameters control the burst release from PLGA particles. Our analysis shows that the amount of drug released during burst is mostly influenced by the formulation characteristics and the synthesis parameters, whereas the drug release kinetics is also influenced by the molecular properties of the drug. The variables that significantly influence the amount and kinetics of the burst release are discussed in detail and compared with findings from other researchers. The final regression models are shown to predict the release profile of a new drug, opening the possibility to be applied to systematically manipulate the burst release by means of designing an optimized drug delivery system. PMID- 28867451 TI - Postprandial triglyceride responses and endothelial function in prediabetic first degree relatives of patients with diabetes. AB - BACKGROUND: Only a few studies have reported on postprandial lipid responses and endothelial function in prediabetic subjects. None of the study has compared role of familial predisposition in determining postprandial endothelial dysfunction and postprandial hypertriglyceridemia in subjects with prediabetes. OBJECTIVE: The objective was to study the postprandial triglyceride (PPTG) responses and endothelial function in prediabetic first-degree relatives of patients with diabetes. METHODS: Thirty-nine subjects were recruited on the basis of oral glucose tolerance test into 3 groups: group 1, prediabetic subjects who had a first-degree relative with diabetes; group 2, prediabetic subjects without family history of diabetes; and group 3, normal glucose tolerance subjects without family history of diabetes. Oral fat challenge test was performed in all study subjects and PPTG responses were measured up to 8 hours. Postprandial endothelial function after 4 hours of fat challenge was estimated by flow-mediated dilation. RESULTS: Postprandial endothelial dysfunction was greatest in group 1 and significantly higher in group 1 compared with group 2 (P < .001) and group 2 compared with group 3 (P < .001). PPTG responses (TG-AUC, TG-peak, TG-6 hour, and TG-8 hour) were significantly higher in group 1 compared with groups 2 and 3. However, they were similar between groups 2 and 3. Endothelial function showed significant negative correlation with TG-6 hour and TG-8 hour. CONCLUSION: Prediabetic subjects respond to fat challenge with a greater degree of TG response and endothelial dysfunction compared with normal glucose tolerance subjects especially if they have a first-degree relative with diabetes. This may contribute to enhanced cardiovascular risk reported in prediabetic individuals. PMID- 28867452 TI - The role of osteoprotegerin in the crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases. AB - Among the numerous molecules that are being studied for their potential utility as biomarkers of cardiovascular diseases, much interest has been shown in the superfamily of tumor necrosis factor (TNF) receptors. Members of this family include osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappaB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). These signals may be expressed and regulated, and their functions could be involved in several physiological and pathological processes. The relationship between bone regulatory proteins and vascular biology has attracted attention, and it has been suggested that OPG may mediate vascular calcification and cardiometabolic diseases. OPG is steadily released from vascular endothelial cells in response to inflammatory stimuli, suggesting that it plays a modulatory role in vascular injury, inflammation, and atherosclerosis. Vascular calcification, a hallmark of atherosclerosis, is similar to bone remodeling. It is an actively regulated mechanism that includes both inductive and inhibitory processes. There is a temporal link between the development of osteoporosis and vascular calcification, which is particularly marked in post-menopausal women and the elderly. The precise nature of the link between bone metabolism, vascular calcification and cardiovascular disease is largely unknown but increasing evidence suggests that the triad of RANK/RANKL/OPG may be important in the initiation of various diseases. An increased release of OPG is associated with increased cardiovascular risk and it is suggested that increased OPG levels resulting from vascular damage correspond to a protective mechanism. Circulating OPG levels could be used as independent biomarkers of cardiovascular disease in patients with acute or chronic cardiometabolic disease and thus an improved prognosis. PMID- 28867453 TI - The effect of indocyanine green loaded on a novel nano-graphene oxide for high performance of photodynamic therapy against Enterococcus faecalis. AB - BACKGROUND: Recently developed photodynamic therapy (PDT) has gained attention for achieving effective root canal disinfection. Using an optimized nontoxic photosensitizer (PS), such as indocyanine green (ICG), is an imperative part of this technique. Therefore, the objective of the current study was to improve ICG photodynamic properties through incorporation of ICG into nano-graphene oxide (NGO) in order to produce NGO-ICG as a new PS and also to assess the antimicrobial effects of NGO-ICG against Enterococcus faecalis after photodynamic therapy. MATERIALS AND METHODS: NGO-ICG was synthesized based on oxidation of graphite flakes and direct loading of ICG onto NGO. NGO-ICG formation was confirmed using the Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), and UV-vis spectrometry. The antimicrobial and anti biofilm potential of NGO-ICG-PDT against E. faecalis was assessed via colony forming unit and crystal violet assays, respectively. RESULTS: FT-IR, SEM and UV vis spectrometry confirmed successful synthesis of NGO-ICG containing 200MUg/mL of ICG. NGO-ICG-PDT at an energy density of 31.2J/cm2 showed a significant reduction (2.81 log) in the count of E. faecalis (P<0.05). NGO-ICG-PDT significantly reduced the biofilm formation ability of E. faecalis up to 99.4% (P<0.05). The overall antimicrobial and anti-biofilm potential of NGO-ICG-PDT was higher than PDT based on ICG (1000MUg/mL) (47% and 21%, respectively). CONCLUSION: Because NGO-ICG-PDT showed a significant reduction in the number and biofilm formation ability of E. faecalis at low ICG concentrations (200MUg/mL), it could be a new approach to adjuvant treatment of endodontic infections. PMID- 28867454 TI - Cetuximab with radiotherapy as an alternative treatment for advanced squamous cell carcinoma of the temporal bone. AB - The prognosis of advanced temporal bone cancer is poor, because complete surgical resection is difficult to achieve. Chemoradiotherapy is one of the available curative treatment options; however, its systemic effects on the patient restrict the use of this treatment. A 69-year-old female (who needed peritoneal dialysis) presented at our clinic with T4 left external auditory canal cancer and was treated with cetuximab plus radiotherapy (RT). The primary lesion showed complete response. The patient is currently alive with no evidence of disease two years after completion of the treatment and does not show any late toxicity. This is the first advanced temporal bone cancer patient treated with RT plus cetuximab. Cetuximab plus RT might be a treatment alternative for patients with advanced temporal bone cancer. PMID- 28867455 TI - Role of adjuvant radiotherapy in FIGO stage IIIC endometrial carcinoma: Treatment outcomes and prognostic factors in 52 irradiated patients. AB - BACKGROUND: To retrospectively review the postoperative radiotherapy treatment outcomes and the prognostic factors for the International Federation of Gynecology and Obstetrics (FIGO) stage IIIC endometrial carcinoma. METHODS: Fifty two patients who were newly diagnosed and previously untreated FIGO stage IIIC endometrial carcinoma over a 33-year period (September 1983 to April 2015) were retrospectively reviewed. They had received radical surgery followed by adjuvant radiotherapy with or without adjuvant chemotherapy. Those excluded patients had initial distant metastasis disease, palliative intent or incomplete adjuvant radiotherapy. Different subgroups of the stage III patients were compared statistically in terms of their rates of overall survival (OS), loco-regional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS). RESULTS: The median follow up duration was 51.5 months (range, 5-298). The loco regional recurrence was found in 4 patients and distant metastasis in 15 patients. Comparing stage IIIC1 vs. IIIC2 patients, their 5-year OS were 69.9% vs. 55% (p = 0.0954), LRRFS 90.3% vs. 94.4% (p = 0.6151), and DMFS 82.5% vs. 53.3% (p = 0.0080). The FIGO stage was a significant factor for DMFS (hazard ratio [HR], 5.440, 95% confidence interval [95% CI] 1.379-21.451, p = 0.0155), but only marginal for OS (HR, 2.137, 95% CI 0.930-4.913, p = 0.0738). The ECOG performance status was marginal significant for DMFS (HR, 4.777, 95% CI 0.976 23.378, p = 0.0536). CONCLUSION: Adjuvant radiotherapy decreased loco-regional recurrence and had good local control in FIGO stage IIIC endometrial carcinoma. The stage IIIC2 patients showed a greater tendency of distant metastases and poorer overall survival rate when compared to patients of stage IIIC1. PMID- 28867456 TI - Antimicrobial activity of bitespiramycin, a new genetically engineered macrolide. AB - The antimicrobial activity of bitespiramycin (BT) against Chlamydia trachomatis (Ct), Chlamydia pneumoniae (Cp), Ureaplasma urealyticum (Uu), and Mycoplasma pneumoniae (Mp), was compared with those of azithromycin (AZM) and acetylspiramycin (AT-SP) in vitro. Furthermore, the anti-Mp activities of BT and AZM were evaluated in a hamster model. The activities of BT in vitro were similar to those of AZM but were more effective than those of AT-SP. BT effectively inhibited Mp infection at a dose of 200mg/kg in a hamster model. PMID- 28867457 TI - Natural protective immunity against grass pollen allergy is maintained by a diverse spectrum of response types. PMID- 28867459 TI - Reimbursement of radiotherapy in Germany. AB - Reimbursement of radiotherapy in Germany is mainly based on a certain fixed fee for treatment planning and patient set up in addition to payment per fraction. This applies to outpatient care for patients with public health insurance or private health insurance. Payment per fraction has a considerable influence on reimbursement of inpatients as well. The advantage of payment per fraction is the simplicity and transparency. The disadvantage is an inadequate reimbursement for new treatment modalities like hypofractionation or stereotactic body radiotherapy. PMID- 28867458 TI - Allergen sensitization in a birth cohort at midchildhood: Focus on food component IgE and IgG4 responses. PMID- 28867460 TI - [Doses to organs at risk in conformational radiotherapy and stereotaxic irradiation: The heart]. AB - Radiation therapy of breast cancer, Hodgkin lymphoma, lung cancer and others thoracic irradiations induce an ionizing radiation dose to the heart. Irradiation of the heart, associated with patient cardiovascular risk and cancer treatment induced cardiotoxicity, increase cardiovascular mortality. The long survival after breast or Hodgkin lymphoma irradiation requires watching carefully late treatment toxicity. The over-risk of cardiac events is related to the dose received by the heart and the irradiated cardiac volume. The limitation of cardiac irradiation should be a priority in the planning of thoracic irradiations. Practices have to be modified, using modern techniques to approach of the primary objective of radiotherapy which is to optimize the dose to the target volume, sparing healthy tissues, in this case the heart. We have reviewed the literature on cardiac toxicity induced by conformational tridimensional radiation therapy, intensity-modulated radiation therapy or stereotactic body radiation therapy, in order to evaluate the possibilities to limit cardiotoxicity. Finally, we summarise the recommendations on dose constraints to the heart and coronary arteries. PMID- 28867461 TI - The Development of Practice Guidelines for a Palliative Care Multidisciplinary Case Conference. AB - CONTEXT: In Ontario, we identified that few hospitals have developed multi disciplinary case conferences or forums for discussion of patients with palliative care issues. OBJECTIVE: We describe the process of creating a province wide standards document for palliative care multidisciplinary case conferences (pMCCs). METHODS: A provincial survey and a multidisciplinary cancer conference symposium identified pMCCs as a priority. A literature search focusing on pMCCs and their implementation was completed as well as a current state assessment (survey and interviews) to understand challenges with existing pMCCs in Ontario. A working group was then assembled to draft a recommendation report that was finalized by an expert panel. RESULTS: A total of 22 articles were identified and 10 were used by the working group to create a framework for the pMCC guideline. The current state assessment identified substantial variability in pMCC structure and function. The expert panel made recommendations about meeting format (multidisciplinary discussion encouraged), frequency (at least every two weeks), type of cases to present, attendees (palliative care, nursing, primary care, social work, and community nursing), provider roles and responsibilities, and institutional requirements (pMCC coordinator, meeting room and videoconference capability). All patients (not just those with cancer) with palliative care needs were to be discussed at the pMCC, and pMCCs should serve as a crucial link between the hospital and community. CONCLUSION: We have described the process of creating the first pMCC guideline. A key component of this guideline is that pMCCs should serve as a link between the hospital and community. PMID- 28867462 TI - Use of cone beam computed tomography to assess significant imaging findings related to mandibular third molar impaction. AB - OBJECTIVE: The aim of the study was to identify risk factors for pathoses related to mandibular third molars observed in cone beam computed tomography. STUDY DESIGN: Cone beam computed tomography volumes of 410 mandibular third molars were assessed by 3 observers, according to the angulation and position of the third molar in relation to the second molar. In addition, pathoses (marginal bone loss, resorption of the second molar, increased follicular space and lingual bone perforation) were assessed. Logistic regression analyses were used to test whether the angulation and position of the third molar were risk factors for pathoses. RESULTS: On average, 41% of second molars had resorption; mesioangulated (odds ratio [OR] 11-107; P < .001) and horizontally positioned (OR 13-120; P < .001) third molars located cervically at the second molar (OR 2-3; P < .027) significantly increased the risk. On average, 49% of second molars had marginal bone loss; mesioangulated (OR 16-85; P < .001) and horizontally positioned (OR 61-573; P < .001) third molars increased the risk. For the third molar, an increased follicular space was seen in 25% of cases; distal (OR 5-9; P < .001) and vertical positions (OR 5; P < .002) increased the risk. Lingual bone perforation was not related to a specific angulation. CONCLUSIONS: Specific angulations of the mandibular third molar are risk factors for marginal bone loss and resorption of the second molar. PMID- 28867463 TI - Oral lichen sclerosus-a review of clinical presentation, treatment, and clinical outcomes. AB - OBJECTIVE: The aim of this study was to evaluate the disease involvement, treatment and response, and malignant potential of oral lichen sclerosus (LS). STUDY DESIGN: We conducted a review of the literature of 37 cases of oral LS. We looked specifically for the following data: patient demographic characteristics, disease involvement, treatment, response to treatment, duration of follow-up, symptoms, risk factors for oral malignancy, and malignant transformation. RESULTS: The most common area of oral involvement included the labial mucosa (67.6%). Of patients with oral LS, 38.5% reported symptoms, and 35.1% exhibited extraoral manifestations. Patients were less likely to receive treatment when asymptomatic (62.5%) than when symptomatic (80%). Topical steroids were more efficacious (66.7%) compared with other treatments. Risk factors for malignancy were found in 25% of patients. No patient had malignant transformation of oral lesions at follow-up (mean follow-up 22.1 months; median 12 months). CONCLUSIONS: More data and longer follow-up are required to determine the long-term clinical outcomes of oral LS. PMID- 28867464 TI - Is cone beam computed tomography accurate for postoperative evaluation of implants? An in vitro study. AB - OBJECTIVE: The aim of this study was to evaluate the accuracy of cone beam computed tomography (CBCT) for evaluation of the bone-implant interface in comparison with periapical radiography. STUDY DESIGN: Titanium implants were inserted in 74 bovine rib blocks in intimate contact with bone walls and with a gap of 0.125 mm (simulating failure in the osseointegration process). Periapical radiographs were taken with conventional film, and CBCT scans were acquired with i-CAT (0.2 mm and 0.125 mm voxel) and Kodak (0.2 mm and 0.076 mm voxel) units. Three examiners evaluated the images using a 5-point scale. Diagnostic accuracy was analyzed through sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC) with 95% confidence intervals (CIs). Intra- and interexaminer agreements were analyzed through Kendall's concordance test. RESULTS: Intra- and interexaminer agreements showed satisfactory results. The greatest accuracy was observed with conventional radiography (AUC = 0.963; CI 95% = 0.891-0.993). I-CAT 0.125-mm images showed good accuracy (AUC = 0.885; CI 95% = 0.790-0.947), with no significant difference compared with conventional radiography. Kodak images had high specificity and low sensitivity, presenting more false-negative results. CONCLUSIONS: Conventional radiography showed the highest accuracy for assessment of the bone-implant interface. However, CBCT (i CAT; 0.125-mm voxel), if available or if performed for preoperative assessment of another implant site, may provide similar accuracy. PMID- 28867465 TI - Effect of gum chewing on ameliorating ileus following colorectal surgery: A meta analysis of 18 randomized controlled trials. AB - BACKGROUND AND OBJECTIVE: Chewing gum, as an alternative to sham feeding, had been shown to hasten the recovery of gut function following abdominal surgery. However, conclusions remained contradictory. We sought to conduct an updated meta analysis to evaluate the efficacy of gum chewing in alleviating ileus following colorectal surgery. METHODS: We searched PubMed, EMBASE, and Cochrane Library Databases through February 2017 to identify randomized controlled trials (RCTs) evaluating the efficacy of the additional use of chewing gum following colorectal surgery. After screening for inclusion, data extraction, and quality assessment, meta-analysis was conducted by the Review Manager 5.3 software. The outcomes of interest were the time to first flatus, time to first bowel movement, length of hospital stay, and some clinically relevant parameters. We also performed subgroup analyses according to the type of surgical approaches or on trials that adopted enhanced recovery after surgery (ERAS) protocol or sugared gum. RESULTS: A total of 18 RCTs, involving 1736 patients, were included. Compared with standardized postoperative care, Chewing gum resulted in a shorter passage to first flatus [WMD = -8.81, 95%CI: (-13.45, -4.17), P = 0.0002], earlier recovery of bowel movement [WMD = -16.43, 95%CI: (-22.68, -10.19), P < 0.00001], and a reduction in length of hospital stay [WMD = -0.89, 95%CI: (-1.72, -0.07), P = 0.03]. Chewing gum was also associated with a lower risk of postoperative ileus [OR = 0.41, 95%CI: (0.23, 0.73), P = 0.003]. No evidence of significant advantages in overall postoperative complication, nausea, vomiting, bloating, readmission and reoperation towards the addition of chewing gum was observed. Subgroup analyses all favored gum chewing. However, the findings are hampered by the significant heterogeneity between trials. CONCLUSIONS: Based on current evidence, chewing gum offers an inexpensive, well-tolerated, safe and effective method to ameliorate ileus following colorectal surgery. However, tightly controlled, randomized and considerably larger multicenter trials are warranted to further validate our findings. PMID- 28867466 TI - Diffuse large B-cell lymphoma of the lung in a patient with nonspecific interstitial pneumonia. PMID- 28867467 TI - Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis. AB - OBJECTIVE: To assess the efficacy and side effects of methotrexate and leflunomide in patients with rheumatoid arthritis (RA) as the first disease modifying antirheumatic drug (DMARD). METHODS: We performed a systematic review and meta-analysis of clinical studies that included patients who took methotrexate, leflunomide, placebo or another DMARD for RA treatment. A systematic review yielded 1971 articles from databases; once completely reviewed, 73 trials that completed inclusion criteria were selected. In structured workshops for discussion and assessment of each article, 6 could be meta-analyzed for the primary and secondary outcomes: achievement of American College of Rheumatology (ACR) 20 and its core set components; and change of serum C-reactive protein (CRP) levels, Health Assessment Questionnaire Disability Index (HAQ-Di), liver enzyme aspartate transaminase/alanine transaminase ratio, new gastrointestinal (GI) side effects and infections. RESULTS: A total of 1984 patients were included: 986 took leflunomide and 998 methotrexate. The probability of achieving ACR 20 had an odds ratio (OR) of 0.88 (95% confidence interval [CI] 0.74, 1.06) with a trend toward favoring methotrexate; reduction of the swollen joint count was greater for methotrexate: mean difference=0.82 (95%CI 0.24, 1.39); tender joint count, physician global assessment, HAQ-Di, and serum CRP levels revealed no significant difference between groups. Increased liver enzymes were more frequent in the leflunomide group, OR=0.38 (95%CI 0.27, 0.53), and new GI complaints were more common with methotrexate (OR=1.44; 95%CI 1.17, 1.79). There was no difference in the incidence of non-severe infections. CONCLUSION: Leflunomide used as the first DMARD in RA seemed to be as efficacious as methotrexate; only the reduction of swollen joint count was more marked for methotrexate. Leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints. PMID- 28867468 TI - Lipidation of BmAtg8 is required for autophagic degradation of p62 bodies containing ubiquitinated proteins in the silkworm, Bombyx mori. AB - p62/Sequestosome-1 (p62/SQSTM1, hereafter referred to as p62) is a major adaptor that allows ubiquitinated proteins to be degraded by autophagy, and Atg8 homologs are required for p62-mediated autophagic degradation, but their relationship is still not understood in Lepidopteran insects. Here it is clearly demonstrated that the silkworm homolog of mammalian p62, Bombyx mori p62 (Bmp62), forms p62 bodies depending on its Phox and Bem1p (PB1) and ubiquitin-associated (UBA) domains. These two domains are associated with Bmp62 binding to ubiquitinated proteins to form the p62 bodies, and the UBA domain is essential for the binding, but Bmp62 still self-associates without the PB1 or UBA domain. The p62 bodies in Bombyx cells are enclosed by BmAtg9-containing membranes and degraded via autophagy. It is revealed that the interaction between the Bmp62 AIM motif and BmAtg8 is critical for the autophagic degradation of the p62 bodies. Intriguingly, we further demonstrate that lipidation of BmAtg8 is required for the Bmp62-mediated complete degradation of p62 bodies by autophagy. Our results should be useful in future studies of the autophagic mechanism in Lepidopteran insects. PMID- 28867469 TI - TmSR-C, scavenger receptor class C, plays a pivotal role in antifungal and antibacterial immunity in the coleopteran insect Tenebrio molitor. AB - Scavenger receptors (SRs) constitute a family of membrane-bound receptors that bind to multiple ligands. The SR family of proteins is involved in removing cellular debris, oxidized low-density lipoproteins, and pathogens. Specifically, class C scavenger receptors (SR-C) have also been reported to be involved in phagocytosis of gram-positive and -negative bacteria in Drosophila and viruses in shrimp. However, reports are unavailable regarding the role of SR-C in antifungal immune mechanisms in insects. In this study, a full-length Tenebrio molitor SR-C (TmSR-C) sequence was obtained by 5'- and 3'-Rapid amplification of cDNA ends polymerase chain reaction (RACE-PCR). The TmSR-C full-length cDNA comprised 1671 bp with 5'- and 3'-untranslated regions of 23- and 107-bp, respectively. TmSR-C encodes a putative protein of 556 amino acid residues that is constitutively expressed in all tissues of late instar larvae and 2-day-old adults, with the highest transcript levels observed in hemocytes of larvae and adults. TmSR-C mRNA showed a 2.5-fold and 3-fold increase at 24 and 6 h after infection with Candida albicans and beta-glucan, respectively. Immunoassay with TmSR-C polyclonal antibody showed induction of the putative protein in the cytosols of hemocytes at 3 h after inoculation of C. albicans. RNA interference (RNAi)-based gene silencing and phagocytosis assays were used to understand the role of TmSR-C in antifungal immunity. Silencing of TmSR-C transcripts reduced the survivability of late instar larvae at 2 days post-inoculation of C. albicans, Escherichia coli, or Staphylococcus aureus. Furthermore, in TmSR-C-silenced larvae, there was a decline in the rate of microorganism phagocytosis. Taken together, results of this study suggest that TmSR-C plays a pivotal role in phagocytosing not only fungi but also gram-negative and -positive bacteria in T. molitor. PMID- 28867470 TI - Collateral Circulation in Chronic Aortic Occlusive Disease. PMID- 28867471 TI - Commentary to "Outcome After Turndown for Elective Abdominal Aortic Aneurysm Surgery". PMID- 28867472 TI - Symmetrical Peripheral Gangrene. PMID- 28867473 TI - Commentary on "Follow-up on Small Abdominal Aortic Aneurysms Using Three Dimensional Ultrasound: Volume Versus Diameter". PMID- 28867474 TI - Fecal immunological blood test is more appealing than the guaiac-based test for colorectal cancer screening. AB - BACKGROUND: The reasons for participation in fecal immunological testing (FIT) of subjects who were previously non-respondents to guaiac fecal occult blood testing (g-FOBT) have not been assessed. POPULATION AND METHODS: We aimed to determine the reasons for current compliance with FIT among non-responders to g-FOBT, termed "converts?, in a French district. A questionnaire was returned by 170 converts aged from 55 to 75 years (response rate 75.2% after exclusions). RESULTS: The major barriers to participation in screening with g-FOBT were test related: the test was perceived as complicated (24%) and it required three consecutive stools (28%). Among the test-related major determinants of FIT compliance was the perception that the test was less complicated than previous test (30%) and that a unique stool sample was required (29%). Among the non-test related major determinants of FIT compliance were the perception that the general practitioner was more convincing (31%) and the feeling to be more concerned because of age (21%). The reasons for compliance among converts did not differ according to age, sex, and rural or urban residence. CONCLUSIONS: Our study demonstrated that the simplicity of FIT and the endorsement of practitioners were both major motivations for FIT compliance among non-respondents in at least two previous consecutive campaigns. PMID- 28867475 TI - Fibroblast growth factor 15 deficiency increases susceptibility but does not improve repair to acetaminophen-induced liver injury in mice. AB - The leading cause of acute liver failure (ALF) is hepatotoxicity from acetaminophen (APAP) overdose. However, limited options are available to treat this ALF so stimulating liver regeneration maybe a potential treatment. Our previous study has shown that fibroblast growth factor 15 (FGF15) plays a crucial role in liver regeneration, but the roles of FGF15 in liver injury and repair following APAP-overdose are unknown. In this study, treatment of FGF15 knockout (KO) male mice with APAP at 200, 250, or 300mg/kg significantly increased the degree of liver injury compared to wild type (WT) mice. To determine the effects of FGF15 deficiency on liver repair following APAP overdose, a similar degree of liver injury was first obtained 24h after treatment of WT and Fgf15 KO mice with APAP at different dosage. Fgf15 KO mice did not differ from WT mice in liver repair following similar degree of liver injury. In conclusion, we showed that FGF15 deficiency renders mice more susceptible to APAP-induced liver injury but did not seem to affect liver repair or regeneration. This study suggests that in contrast to the critical role that FGF15 plays in promoting liver regeneration following partial hepatectomy, this intestine factor is less involved in liver repair after APAP-induced liver injury. PMID- 28867476 TI - Using scenarios and personas to enhance the effectiveness of heuristic usability evaluations for older adults and their care team. AB - OBJECTIVE: Using heuristics to evaluate user experience is a common methodology for human-computer interaction studies. One challenge of this method is the inability to tailor results towards specific end-user needs. This manuscript reports on a method that uses validated scenarios and personas of older adults and care team members to enhance heuristics evaluations of the usability of commercially available personal health records for homebound older adults. MATERIALS AND METHODS: Our work extends the Chisnell and Redish heuristic evaluation methodology by using a protocol that relies on multiple expert reviews of each system. It further standardizes the heuristic evaluation process through the incorporation of task-based scenarios. RESULTS: We were able to use the modified version of the Chisnell and Redish heuristic evaluation methodology to identify potential usability challenges of two commercially available personal health record systems. This allowed us to: (1) identify potential usability challenges for specific types of users, (2) describe improvements that would be valuable to all end-users of the system, and (3) better understand how the interactions of different users may vary within a single personal health record. CONCLUSIONS: The methodology described in this paper may help designers of consumer health information technology tools, such as personal health records, understand the needs of diverse end-user populations. Such methods may be particularly helpful when designing systems for populations that are difficult to recruit for end-user evaluations through traditional methods. PMID- 28867477 TI - Research priority setting in Barrett's oesophagus and gastro-oesophageal reflux disease. AB - The incidence of gastro-oesophageal reflux disease and Barrett's oesophagus is increasing. Barrett's oesophagus is the main precursor to oesophageal adenocarcinoma, which has a poor prognosis. In view of the vast potential burden of these diseases on patients and health-care resources, there is a real need to define and focus research efforts. This priority setting exercise aimed to produce a list of the top ten uncertainties in the field that reflect the priorities of patients and health-care providers. We adopted the robust and transparent methodologies previously outlined by the James Lind Alliance. This qualitative approach firstly involves an ideas gathering survey that, once distilled, generates a longlist of research uncertainties. These uncertainties are then prioritised via an interim ranking survey and a final workshop to achieve consensus agreement. The initial 629 uncertainties, generated from a survey of 170 individual respondents (47% professional, 53% non-professional) and one workshop, were narrowed down to the final top ten uncertainties of priority for future research. These priorities covered a range of issues, including a need for improved patient risk stratification, alternative diagnostic and surveillance tests, efficacy of a dedicated service for Barrett's oesophagus, cost effectiveness and appropriateness of current surveillance, advances in development of non-drug treatments for gastro-oesophageal reflux disease, safety of long-term drug treatment, and questions regarding the durability and role of different endoscopic therapies for dysplastic Barrett's oesophagus. This is the first patient-centred assessment of priorities for researchers in this chronic disease setting. We hope that recognition and dissemination of these results will shape the future direction of research and translate into meaningful gains for patients. PMID- 28867478 TI - Hemidesmosomal linker proteins regulate cell motility, invasion and tumorigenicity in oral squamous cell carcinoma derived cells. AB - BPAG1e and Plectin are hemidesmosomal linker proteins which anchor intermediate filament proteins to the cell surface through beta4 integrin. Recent reports indicate that these proteins play a role in various cellular processes apart from their known anchoring function. However, the available literature is inconsistent. Further, the previous study from our laboratory suggested that Keratin8/18 pair promotes cell motility and tumor progression by deregulating beta4 integrin signaling in oral squamous cell carcinoma (OSCC) derived cells. Based on these findings, we hypothesized that linker proteins may have a role in neoplastic progression of OSCC. Downregulation of hemidesmosomal linker proteins in OSCC derived cells resulted in reduced cell migration accompanied by alterations in actin organization. Further, decreased MMP9 activity led to reduced cell invasion in linker proteins knockdown cells. Moreover, loss of these proteins resulted in reduced tumorigenic potential. SWATH analysis demonstrated upregulation of N-Myc downstream regulated gene 1 (NDRG1) in linker proteins downregulated cells as compared to vector control cells. Further, the defects in phenotype upon linker proteins ablation were rescued upon loss of NDRG1 in linker proteins knockdown background. These data together indicate that hemidesmosomal linker proteins regulate cell motility, invasion and tumorigenicity possibly through NDRG1 in OSCC derived cells. PMID- 28867479 TI - Combining 2D angiogenesis and 3D osteosarcoma microtissues to improve vascularization. AB - Angiogenesis is now well known for being involved in tumor progression, aggressiveness, emergence of metastases, and also resistance to cancer therapies. In this study, to better mimic tumor angiogenesis encountered in vivo, we used 3D culture of osteosarcoma cells (MG-63) that we deposited on 2D endothelial cells (HUVEC) grown in monolayer. We report that endothelial cells combined with tumor cells were able to form a well-organized network, and that tubule-like structures corresponding to new vessels infiltrate tumor spheroids. These vessels presented a lumen and expressed specific markers as CD31 and collagen IV. The combination of 2D endothelial cells and 3D microtissues of tumor cells also increased expression of angiogenic factors as VEGF, CXCR4 and ICAM1. The cell environment is the key point to develop tumor vascularization in vitro and to be closer to tumor encountered in vivo. PMID- 28867480 TI - Vagus nerve stimulation produces a hippocampal formation theta rhythm in anesthetized rats. AB - Vagus nerve stimulation (VNS) has been used for years to treat patients with drug resistant epilepsy. In the present study, the effect of different stimulation protocols of VNS on the hippocampal formation (HPC) type II theta field potentials were evaluated in anesthetized rats. The following theta parameters were analysed: power, frequency and duration of theta epochs. We documented for the first time the presence of HPC type II theta in response to the application of VNS. A VNS-induced theta rhythm appeared in different experimental protocols and, depending on the current intensity, could occur directly during VNS (brief effect) or after vagal stimulation (delayed effect), using lower intensity stimuli. PMID- 28867481 TI - Lesions of the central amygdala and ventromedial medulla reduce bladder hypersensitivity produced by acute but not chronic foot shock. AB - Both acute and chronic stress has been shown to exacerbate symptoms of chronic visceral pain conditions such as interstitial cystitis. Studies using animal models support these findings in that both acute and chronic exposure to foot shock-induced stress (FS) augment nociceptive reflex responses to urinary bladder distension (UBD). Only a few studies have examined the neural substrates mediating these phenomena and it is not clear whether acute and chronic stress engage the same or different substrates to produce bladder hypersensitivity. The present studies examined the role of two important central nervous system structures - the amygdala (AMG) and the ventromedial medulla (VMM) - in mediating/modulating hypersensitivity evoked by acute versus chronic FS using responses to graded UBD in adult, female Sprague-Dawley rats. Bladder hypersensitivity produced by acute FS was significantly reduced by either bilateral central AMG or VMM lesions using measures generated by graded UBD, but these lesions had no significant effects using the same measures on bladder hyperalgesia produced by chronic FS. Our findings provide evidence that neural substrates underlying bladder hypersensitivity produced by chronic stress differ from those produced by acute stress. These findings suggest that while the AMG and VMM participate in pain processing during periods of limited exposure to stress, prolonged stress may recruit a new set of neural substrates not initially activated by acute exposure to stress. PMID- 28867483 TI - Construction of a versatile expression library for all human single-pass transmembrane proteins for receptor pairings by high throughput screening. AB - Interactions between protein ligands and receptors play crucial roles in cell cell signalling. Most of the human cell surface receptors have been identified in the post-Human Genome Project era but many of their corresponding ligands remain unknown. To facilitate the pairing of orphan receptors, 2762 sequences encoding all human single-pass transmembrane proteins were selected for inclusion into a mammalian-cell expression library. This expression library, consisting of all the individual extracellular domains (ECDs), was constructed as a Fab fusion for each protein. In this format, individual ECD can be produced as a soluble protein or displayed on cell surface, depending on the applied heavy-chain Fab configuration. The unique design of the Fab fusion concept used in the library led to not only superior success rate of protein production, but also versatile applications in various high-throughput screening paradigms including protein protein binding assays as well as cell binding assays, which were not possible for any other existing expression libraries. The protein library was screened against human coagulation factor VIIa (FVIIa), an approved therapeutic for the treatment of hemophilia, for binding partners by AlphaScreen and ForteBio assays. Two previously known physiological ligands of FVIIa, tissue factor (TF) and endothelial protein C receptor (EPCR) were identified by both assays. The cell surface displayed library was screened against V-domain Ig suppressor of T-cell activation (VISTA), an important immune-checkpoint regulator. Immunoglobulin superfamily member 11 (IgSF11), a potential target for cancer immunotherapy, was identified as a new and previously undescribed binding partner for VISTA. The specificity of the binding was confirmed and validated by both fluorescence activated cell sorting (FACS) and surface plasmon resonance (SPR) assays in different experimental setups. PMID- 28867484 TI - Secondary cerebral abscess of an ischemic stroke treated by thrombectomy. PMID- 28867485 TI - Mechanisms of action of cannabidiol in adoptively transferred experimental autoimmune encephalomyelitis. AB - Cannabidiol (CBD) is one of the most important compounds in Cannabis sativa, lacks psychotropic effects, and possesses a high number of therapeutic properties including the amelioration of experimental autoimmune encephalomyelitis (EAE). The aim of this study was to analyse the relative efficacy of CBD in adoptively transferred EAE (at-EAE), a model that allows better delineation of the effector phase of EAE. Splenocytes and lymph nodes from mice with actively induced EAE were cultured in the presence of MOG35-55 and IL-12 and inoculated intraperitoneally in recipient female C57BL/6J mice. The effects of CBD were evaluated using clinical scores and magnetic resonance imaging (MRI). In the central nervous system, the extent of cell infiltration, axonal damage, demyelination, microglial activation and cannabinoid receptors expression was assessed by immunohistochemistry. Lymph cell viability, apoptosis, oxidative stress and IL-6 production were measured in vitro. Preventive intraperitoneal treatment with CBD ameliorated the clinical signs of at-EAE, and this improvement was accompanied by a reduction of the apparent diffusion coefficient in the subiculum area of the brain. Inflammatory infiltration, axonal damage, and demyelination were reduced, and cannabinoid receptor expression was modulated. Incubation with CBD decreased encephalitogenic cell viability, increasing early apoptosis and reactive oxygen species (ROS) and decreasing IL-6 production. The reduction in viability was not mediated by CB1, CB2 or GPR55 receptors. CBD markedly improved the clinical signs of at-EAE and reduced infiltration, demyelination and axonal damage. The CBD-mediated decrease in the viability of encephalitogenic cells involves ROS generation, apoptosis and a decrease in IL-6 production and may contribute to the therapeutic effect of this compound. PMID- 28867482 TI - Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons. AB - Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant. PMID- 28867486 TI - YAP/TAZ Orchestrate VEGF Signaling during Developmental Angiogenesis. AB - Vascular endothelial growth factor (VEGF) is a major driver of blood vessel formation. However, the signal transduction pathways culminating in the biological consequences of VEGF signaling are only partially understood. Here, we show that the Hippo pathway effectors YAP and TAZ work as crucial signal transducers to mediate VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium-specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton and that activated YAP/TAZ induce a transcriptional program to further control cytoskeleton dynamics and thus establish a feedforward loop that ensures a proper angiogenic response. Lack of YAP/TAZ also results in altered cellular distribution of VEGFR2 due to trafficking defects from the Golgi apparatus to the plasma membrane. Altogether, our study identifies YAP/TAZ as central mediators of VEGF signaling and therefore as important regulators of angiogenesis. PMID- 28867488 TI - Quaking RNA-Binding Proteins Control Early Myofibril Formation by Modulating Tropomyosin. AB - Skeletal muscle contraction is mediated by myofibrils, complex multi-molecular scaffolds structured into repeated units, the sarcomeres. Myofibril structure and function have been extensively studied, but the molecular processes regulating its formation within the differentiating muscle cell remain largely unknown. Here we show in zebrafish that genetic interference with the Quaking RNA-binding proteins disrupts the initial steps of myofibril assembly without affecting early muscle differentiation. Using RNA sequencing, we demonstrate that Quaking is required for accumulation of the muscle-specific tropomyosin-3 transcript, tpm3.12. Further functional analyses reveal that Tpm3.12 mediates Quaking control of myofibril formation. Moreover, we identified a Quaking-binding site in the 3' UTR of tpm3.12 transcript, which is required in vivo for tpm3.12 accumulation and myofibril formation. Our work uncovers a Quaking/Tpm3 pathway controlling de novo myofibril assembly. This unexpected developmental role for Tpm3 could be at the origin of muscle defects observed in human congenital myopathies associated with tpm3 mutation. PMID- 28867487 TI - Arp2/3 Complex Is Required for Macrophage Integrin Functions but Is Dispensable for FcR Phagocytosis and In Vivo Motility. AB - The Arp2/3 complex nucleates branched actin, forming networks involved in lamellipodial protrusion, phagocytosis, and cell adhesion. We derived primary bone marrow macrophages lacking Arp2/3 complex (Arpc2-/-) and directly tested its role in macrophage functions. Despite protrusion and actin assembly defects, Arpc2-/- macrophages competently phagocytose via FcR and chemotax toward CSF and CX3CL1. However, CR3 phagocytosis and fibronectin haptotaxis, both integrin dependent processes, are disrupted. Integrin-responsive actin assembly and alphaM/beta2 integrin localization are compromised in Arpc2-/- cells. Using an in vivo system to observe endogenous monocytes migrating toward full-thickness ear wounds we found that Arpc2-/- monocytes maintain cell speeds and directionality similar to control. Our work reveals that the Arp2/3 complex is not a general requirement for phagocytosis or chemotaxis but is a critical driver of integrin dependent processes. We demonstrate further that cells lacking Arp2/3 complex function in vivo remain capable of executing important physiological responses that require rapid directional motility. PMID- 28867489 TI - Optomechanical devices for deep plasma cancer proteomics. AB - Most of the cancer deaths could be avoided by early detection of the tumor when it is confined to its primary site and it has not metastasized. To this aim, one of the most promising strategies is the discovery and detection of protein biomarkers shed by the young tumor to the bloodstream. Proteomic technologies, mainly mass spectrometry and multiplexed immunoassays, have rapidly developed during last years with improved limits of detection and multiplexing capability. Unfortunately, these developments together major investments and large international efforts have not resulted into new useful protein biomarkers. Here, we analyze the potential and limitations of current proteomic technologies for detecting protein biomarkers released into circulation by the tumor. We find that these technologies can hardly probe the deepest region of the plasma proteome, at concentrations below the pg/mL level, where protein biomarkers for early cancer detection may exist. This clearly indicates the need of incorporating novel ultrasensitive techniques to the proteomic tool-box that can cover the inaccessible regions of the plasma proteome. We here propose biological detectors based on nanomechanical systems for discovery and detection of cancer protein biomarkers in plasma. We review the modes of operation of these devices, putting our focus on recent developments on nanomechanical sandwich immunoassays and nanomechanical spectrometry. The first technique enables reproducible immunodetection of proteins at concentrations well below the pg/mL level, with a limit of detection on the verge of 10 ag/mL. This technology can potentially detect low abundance tumor-associated proteins in plasma at the very early stages of the tumor. The second technique enables the identification of individual intact proteins by two physical coordinates, the mass and stiffness, instead of the mass-to-charge ratio of the protein constituents. This technology enormously simplifies the identification of proteins and it can provide useful information on interactions and posttranslational modifications, that otherwise is lost in mass spectrometry. PMID- 28867490 TI - Theoretical evaluation of ADMET properties for coumarin derivatives as compounds with therapeutic potential. AB - Coumarins have received a considerable attention in the last three decades as the lead structures for the discovery of orally administrated chemotherapeutics. Despite of the large amounts of in vitro activity information, relatively a little is known about their bioavailability in vivo. This paper presents an evaluation of drug-likeness of 31 coumarin derivatives on the basis of Lipinski's rule of five, and computed ADMET parameters (adsorption, distribution, metabolism, elimination and toxicity). Nine compounds which were predicted as showing the cardiotoxicity, were examined as hERG K+ channel blockers using in silico approach. Additionally, an impact of the acetyl group at benzene ring on pharmacokinetic profile was scrutinized for the tested coumarin derivatives. None of the analyzed coumarins violated the Lipinski's rule of five for orally administered drugs, and all tested compounds will remain in the qualitative likelihood of crossing the blood-brain barrier. 7-O-Alkilaminocoumarins showed no hepatotoxicity, but introduction of the nitrile or the amidine groups increased the levels of the hepatoxicity markers. Computed parameters of toxicity revealed cardiotoxic potency of twenty-five tested compounds. The proposed hERG K+ channel binding simulations helped in the understanding the molecular basis of coumarins cardiotoxicity. The presented theoretical studies explained some aspects of coumarin pharmacokinetics and identified the positive effect of the acetoxy substituent on the tested parameters. PMID- 28867491 TI - The prenylated phenolic natural product isoglycycoumarin is a highly selective probe for human cytochrome P450 2A6. AB - Prenylated phenolic compounds are an important class of bioactive natural products. One major in vivo metabolic pathway of these compounds is hydroxylation at terminal methyl of the isoprenyl group. This study aims to identify the P450 isozyme catalyzing this metabolic reaction. In human liver microsomes, 16 out of 24 screened compounds could be metabolized into their hydroxylated derivatives. Chemical inhibition assays using 11 isozyme specific inhibitors indicated the hydroxylation reactions of 12 compounds were primarily catalyzed by cytochrome P450 2A6 (CYP2A6). In particular, CYP2A6 was the major enzyme participating in the metabolism of isoglycycoumarin (IGCM). The product of IGCM was obtained and identified as licopyranocoumarin (4"-hydroxyl isoglycycoumarin) using NMR spectroscopic analysis. The Km values for human liver microsomes and recombinant human CYP2A6 were 7.98 and 10.14MUM, respectively. According to molecular docking analysis, the catalytic mechanism may involve cyclized isoprenyl group of IGCM entering the active cavity of CYP2A6. These results demonstrate that IGCM could serve as an ideal isozyme selective probe to evaluate CYP2A6 activities. PMID- 28867492 TI - 7th European rotavirus biology conference, Cork/Ireland, 18-21 June 2017. PMID- 28867493 TI - Taking the defensive: Immune control of Zika virus infection. AB - ZIKV is a neurotropic mosquito-borne flavivirus that has recently emerged in the Americas and is a pathogen of significant public health concern across the world. ZIKV was first isolated in Uganda in 1947 and remained dormant in Africa and Asia for decades, with sporadic outbreaks characterized by a mild self-limiting disease in humans. The emergence of ZIKV in the Americas corresponded with enhanced disease severity and congenital Zika syndrome, a phenotype characterized by severe microcephaly, brain anomalies, ocular anomalies, congenital contractures and neurological impairments. In less than two years, a collective effort led by the scientific research community has uncovered many new facets to the once rarely discussed ZIKV. In this review, we highlight the known immune parameters that correlate with protective immunity to ZIKV infection, including pattern recognition receptors, interferons, humoral and cell-mediated responses, as well as countermeasures utilized by ZIKV to inhibit host antiviral immune responses. PMID- 28867494 TI - Targeting human breast cancer cells by an oncolytic adenovirus using microRNA targeting strategy. AB - MicroRNA-targeting strategy is a promising approach that enables oncolytic viruses to replicate in tumor cells but not in normal cells. In this study, we targeted adenoviral replication toward breast cancer cells by inserting ten complementary binding sites for miR-145-5p downstream of E1A gene. In addition, we evaluated the effect of increasing miR-145 binding sites on inhibition of virus replication. Ad5-control and adenoviruses carrying five or ten copies of miR145-5p target sites (Ad5-5miR145T, Ad5-10miR145T) were generated and inoculated into MDA-MB-453, BT-20, MCF-7 breast cancer cell lines and human mammary epithelial cells (HMEpC). Titer of Ad5-10miR145T in HMEpC was significantly lower than Ad5-control titer. Difference between the titer of these two viruses at 12, 24, 36, and 48h after infection was 1.25, 2.96, 3.06, and 3.77 log TCID50. No significant difference was observed between the titer of both adenoviruses in MDA-MB-453, BT-20 and MCF-7 cells. The infectious titer of adenovirus containing 10 miR-145 binding sites in HMEpC cells at 24, 36, and 48h post-infection was 1.7, 2.08, and 4-fold, respectively, lower than the titer of adenovirus carrying 5 miR-145 targets. Our results suggest that miR-145-targeting strategy provides selectivity for adenovirus replication in breast cancer cells. Increasing the number of miRNA binding sites within the adenoviral genome confers more selectivity for viral replication in cancer cells. PMID- 28867496 TI - Draft genome sequence of multidrug-resistant Staphylococcus haemolyticus IPK_TSA25 harbouring a Staphylococcus aureus plasmid, pS0385-1. AB - OBJECTIVES: Staphylococcus haemolyticus is the second most frequently isolated coagulase-negative staphylococci from blood cultures. Moreover, multidrug resistance associated with the genome flexibility of S. haemolyticus has been increasingly reported worldwide. Here we report the draft genome sequence of multidrug-resistant S. haemolyticus IPK_TSA25 isolated from a building surface in South Korea. METHODS: Genomic DNA of S. haemolyticus IPK_TSA25 was sequenced using the PacBio RS II sequencing platform. Generated reads were assembled using PacBio SMRT Analysis 2.3.0. The draft genome was annotated and antibiotic resistance genes were identified. RESULTS: The genome of 2517398bp contains various antibiotic resistance genes associated with resistance to beta-lactams, aminoglycosides and macrolides. Genome analysis also revealed chromosomal integration of the full-length Staphylococcus aureus plasmid pS0385-1 containing a tetracycline resistance gene. CONCLUSIONS: The genome sequence reported in this study will provide valuable information to understand the flexibility of the S. haemolyticus genome, which facilitates acquisition of antibiotic resistance genes and contributes to the dissemination of antibiotic resistance by this emerging pathogen. PMID- 28867495 TI - Healthcare Policy Statement on the Utility of Coronary Computed Tomography for Evaluation of Cardiovascular Conditions and Preventive Healthcare: From the Health Policy Working Group of the Society of Cardiovascular Computed Tomography. AB - The rising cost of healthcare is prompting numerous policy and advocacy discussions regarding strategies for constraining growth and creating a more efficient and effective healthcare system. Cardiovascular imaging is central to the care of patients at risk of, and living with, heart disease. Estimates are that utilization of cardiovascular imaging exceeds 20 million studies per year. The Society of Cardiovascular CT (SCCT), alongside Rush University Medical Center, and in collaboration with government agencies, regional payers, and industry healthcare experts met in November 2016 in Chicago, IL to evaluate obstacles and hurdles facing the cardiovascular imaging community and how they can contribute to efficacy while maintaining or even improving outcomes and quality. The summit incorporated inputs from payers, providers, and patients' perspectives, providing a platform for all voices to be heard, allowing for a constructive dialogue with potential solutions moving forward. This article outlines the proceedings from the summit, with a detailed review of past hurdles, current status, and potential solutions as we move forward in an ever-changing healthcare landscape. PMID- 28867498 TI - The triumph of HIV treatment: another new antiretroviral. PMID- 28867497 TI - Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380 1489): a double-blind, multicentre, phase 3, randomised controlled non inferiority trial. AB - BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug-drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine. METHODS: We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged >=18 years) who were previously untreated (HIV-1 RNA >=500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (<=100 000 copies per mL, >100 000 to <=400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per MUL, 50-199 cells per MUL, or >=200 cells per MUL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. All participants who received one dose of study drug were included in primary efficacy and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02607930. FINDINGS: Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92.4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93.0% of patients (n=293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference -0.6%, 95.002% CI -4.8 to 3.6; p=0.78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p<0.0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p<0.0001). INTERPRETATION: At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non inferior to coformulated dolutegravir, abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting. FUNDING: Gilead Sciences. PMID- 28867499 TI - Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. AB - BACKGROUND: Integrase strand transfer inhibitors (INSTIs) coadministered with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) are recommended as first-line treatment for HIV, and coformulated fixed-dose combinations are preferred to facilitate adherence. We report 48-week results from a study comparing initial HIV-1 treatment with bictegravir-a novel INSTI with a high in vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug interactions-coformulated with the NRTI combination emtricitabine and tenofovir alafenamide as a fixed-dose combination to dolutegravir administered with coformulated emtricitabine and tenofovir alafenamide. METHODS: In this randomised, double-blind, multicentre, placebo controlled, non-inferiority trial, HIV-infected adults were screened and enrolled at 126 outpatient centres in 10 countries in Australia, Europe, Latin America, and North America. Participants were previously untreated adults (HIV-1 RNA >=500 copies per mL) with estimated glomerular filtration rate of at least 30 mL/min. Chronic hepatitis B virus or hepatitis C co-infection was allowed. We randomly assigned participants (1:1) to receive oral fixed-dose combination bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or dolutegravir 50 mg with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg, with matching placebo, once a day for 144 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm), with a prespecified non inferiority margin of -12%. This study is registered with ClinicalTrials.gov, number NCT02607956. FINDINGS: Between Nov 11, 2015, and July 15, 2016, 742 participants were screened for eligibility, of whom 657 were randomly assigned to treatment (327 with bictegravir, emtricitabine, and tenofovir alafenamide fixed dose combination [bictegravir group] and 330 with dolutegravir plus emtricitabine and tenofovir alafenamide [dolutegravir group]). 320 participants who received the bictegravir regimen and 325 participants who received the dolutegravir regimen were included in the primary efficacy analyses. At week 48, HIV-1 RNA <50 copies per mL was achieved in 286 (89%) of 320 participants in the bictegravir group and 302 (93%) of 325 in the dolutegravir group (difference -3.5%, 95.002% CI -7.9 to 1.0, p=0.12), showing non-inferiority of the bictegravir regimen to the dolutegravir regimen. No treatment-emergent resistance to any study drug was observed. Incidence and severity of adverse events were similar between groups, and few participants discontinued treatment due to adverse events (5 [2%] of 320 in the bictegravir group and 1 [<1%] 325 in the dolutegravir group). Study drug related adverse events were less common in the bictegravir group than in the dolutegravir group (57 [18%] of 320 vs 83 [26%] of 325, p=0.022). INTERPRETATION: At 48 weeks, virological suppression with the bictegravir regimen was achieved and was non-inferior to the dolutegravir regimen in previously untreated adults. There was no emergent resistance to either regimen. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated compared with the dolutegravir regimen. FUNDING: Gilead Sciences Inc. PMID- 28867500 TI - Review of combinations of experimental and computational techniques to identify and understand genes involved in innate immunity and effector-triggered defence. AB - The innate immune system includes a first layer of defence that recognises conserved pathogen-associated molecular patterns that are essential for microbial fitness. Resistance (R) gene-based recognition of pathogen effectors, which function in modulation or avoidance of host immunity, activates a second layer of plant defence. In this review, experimental and computational techniques are considered to improve understanding of the plant immune system. Biocomputation contributes to discovery of the molecular genetic basis of host resistance against pathogens. Sequenced genomes have been used to identify R genes in plants. Resistance gene enrichment sequencing based on conserved protein domains has increased the number of R genes with nucleotide-binding site and leucine-rich repeat domains. Network analysis will contribute to an improved understanding of the innate immune system and identify novel genes for partial disease resistance. Machine learning algorithms are expected to become important in defining aspects of the immune system that are less well characterised, including identification of R genes that lack conserved protein domains. PMID- 28867501 TI - Stem cell transplantation for Huntington's diseases. AB - Therapeutic approaches based on stem cells have received considerable attention as potential treatments for Huntington's disease (HD), which is a fatal, inherited neurodegenerative disorder, caused by progressive loss of GABAergic medium spiny neurons (MSNs) in the striatum of the forebrain. Transplantation of stem cells or their derivatives in animal models of HD, efficiently improved functions by replacing the damaged or lost neurons. In particular, neural stem cells (NSCs) for HD treatments have been developed from various sources, such as the brain itself, the pluripotent stem cells (PSCs), and the somatic cells of the HD patients. However, the brain-derived NSCs are difficult to obtain, and the PSCs have to be differentiated into a population of the desired neuronal cells that may cause a risk of tumor formation after transplantation. In contrast, induced NSCs, derived from somatic cells as a new stem cell source for transplantation, are less likely to form tumors. Given that the stem cell transplantation strategy for treatment of HD, as a genetic disease, is to replace the dysfunctional or lost neurons, the correction of mutant genes containing the expanded CAG repeats is essential. In this review, we will describe the methods for obtaining the optimal NSCs for transplantation-based HD treatment and the differentiation conditions for the functional GABAergic MSNs as therapeutic cells. Also, we will discuss the valuable gene correction of the disease stem cells by the CRISPR/Cas9 system for HD treatment. PMID- 28867502 TI - Continuous liquid feeding: New method to study pesticides toxicity in Drosophila melanogaster. AB - Fly fruit Drosophila melanogaster (DM) has been extensively employed as an in vivo model system to study pesticides toxicity. Pesticide administration to the fly traditionally involves feeding in an agar-gelled feed fly's medium (AM). However, AM method has several limitations such as uncertainty regarding the bioavailability and amount of pesticides ingested. And also high manipulation of the treated flies. We developed a new method of exposure the flies to pesticides, called Continuous Liquid Feeding (CLF). This method successfully delivers food to the flies at much higher concentrations than the AM method, and requires little manipulation of flies under treatment. PMID- 28867503 TI - A generic approach for simultaneous measurements of total antibody and cleavable antibody-conjugated drug by LC/MS/MS. AB - The current industry practice for antibody-drug conjugate (ADC) bioanalysis includes quantification of total antibody and antibody-conjugated drug. Here, we report a novel 2-in-1 approach for measuring total antibody and protease cleavable conjugated drug Monomethyl Auristatin E (MMAE) concurrently. This allows for the determination of the DAR (Drug Antibody Ratio) for in vivo samples, with a 3-orders linear range based on total antibody concentration from 0.1 to 100 MUg/mL. Our generic, concurrent method has been cross-validated with the previously established methods in an animal study. This novel approach is applicable to all human IgG1 ADCs with papain cleavable conjugated drug in preclinical studies. PMID- 28867504 TI - College tanning behaviors, attitudes, beliefs, and intentions: A systematic review of the literature. AB - Despite well-established links between exposure to ultraviolet radiation (UVR) and skin cancer, UVR-based tanning behaviors persist among college students. Understanding tanning motivations, perceptions, barriers, and demographic characteristics of this population is critical to modifying these behaviors, but is limited by variability in study design, sample size, and outcomes measured in the current literature. To help clarify the tanning behaviors of this population and provide a concise reference for future studies, this review examines existing reports to determine the comparability of tanning behaviors across multiple U.S. college populations. A systematic review of the literature was performed in July 2016 to identify studies investigating tanning behaviors among U.S. college students. Twenty-three studies met inclusion criteria. High rates of indoor tanning (IT) and outdoor tanning (OT) were found among college students. Key motivators included appearance, emotion, health perceptions, and the influence of parents, peers, and the media. Misconceptions regarding skin protection, low rates of sun protective behaviors, and tanning dependence were barriers against safe UVR exposure. Understudied demographic factors may account for variance in observed tanning behaviors, emphasizing the need for standardization efforts to consistently identify trends associated with geographical region, age, year in college, and sex. The findings presented in this review reaffirm that college students are at high risk for tanning-associated skin cancer, emphasizing the critical need for effective, targeted interventions. Improved interventions will reduce the burden of skin cancer within this group, ultimately contributing to longer, healthier lives. PMID- 28867505 TI - Dose-response in a high density three-dimensional liver device with real-time bioenergetic and metabolic flux quantification. AB - Real-time dose-response curves for fructose have been non-invasively determined in primary rat hepatocyte alginate spheroids cultured in a NMR-compatible fluidized-bed bioreactor. Using 13C-labeled glucose and glycine culture medium, fructose dose was compared to glucose uptake and glycogen synthesis rate using 13C NMR spectroscopy, and to ATP and fructose-1-phosphate concentration using 31P NMR spectroscopy. A highly efficient multicoaxial perfusion system maintains high density 3-D hepatocyte cultures, permitting 13C and 31P NMR spectral time courses with 1min time points. The perfusion system was turned off to demonstrate its efficiency and effect on the metabolites. Within 16min, glycogen plummeted, lactate became the largest 13C-glucose metabolite via anaerobic glycolysis, while glutathione was the largest 13C-glycine metabolite. ATP depletion and fructose-1 phosphate formation demonstrated a dose response with a 3h EC50 of 19mM+/-8.9mM and 17.4mM+/-3.7mM, respectively. Computational modeling of mass transfer corroborated experimental results and helped determine the optimal bioreactor loading densities, oxygen concentration, and perfusion rates to maintain physiologically-relevant nutrient levels. The total bioreactor plus perfusion loop has a dead volume of 2ml, and contains 5 million hepatocytes. Due to the non invasive measurements, there is a reduction of animal tissue by an order-of magnitude, depending on the number of time points in an experiment. This dynamic flux approach may have generic utility for dose-response studies monitoring multiple metabolic reactions in other primary mammalian cells, such as human, that have strict oxygen demands. PMID- 28867506 TI - Gait disturbance and lower limb pain in a patient with PIK3CA-related disorder. AB - Post-zygotic activating mutations in PIK3CA and other genes encoding members of PI3K-AKT-mTOR pathway have been found in various overgrowth syndromes that have been grouped together as PIK3CA-related overgrowth spectrum (PROS). We report a female patient with gait disturbance, leg pain, isolated macrodactyly of the foot, and mild intellectual disability. Imaging of the lower limb showed a lipoblastoma of the right thigh. A mosaic gain-of-function mutation in the catalytic domain of PIK3CA (c.3140 A > G; p.His1047Arg) was detected in the adipose tissue and in skin cultured fibroblasts from the macrodactyly but not in blood. The leg pain and the severe walking disturbance improved slightly over time and serial MRI of the lower limbs suggested that the size of the lipoblastoma relative to the lower limb muscles or to the whole lower limb was unchanged as consequence of limb growth. This case report illustrates that pain and gait disturbance can be features of PROS and highlights the need of better knowledge about the natural history of the disease. PMID- 28867507 TI - Immunization of mice with Borrelia burgdorferi lp54 gene encoded recombinant proteins does not provide protection against tick transmitted infectious challenge. AB - The Borrelia burgdorferi outer surface membrane proteins BBA65, BBA66, BBA69, BBA70, and BBA73 were tested for their ability to confer protection against B. burgdorferi infection challenge. Mice were immunized with recombinant forms of the proteins singly or in combinations. Following initial protein inoculation and booster injections, seroconversion was confirmed prior to B. burgdorferi challenge by tick bite. Despite mice having high antibody titers for each antigen, no significant protections against the challenge infections were observed. These results demonstrate that these recombinant proteins were not protective and reflects the challenges confronted to identify effective novel vaccine candidates for Lyme disease. PMID- 28867509 TI - Do It Fast: Immediate Functional Testing of Membrane Pumps Expressed into Nanodiscs. PMID- 28867508 TI - Influenza epidemiology and immunization during pregnancy: Final report of a World Health Organization working group. AB - From 2014 to 2017, the World Health Organization convened a working group to evaluate influenza disease burden and vaccine efficacy to inform estimates of maternal influenza immunization program impact. The group evaluated existing systematic reviews and relevant primary studies, and conducted four new systematic reviews. There was strong evidence that maternal influenza immunization prevented influenza illness in pregnant women and their infants, although data on severe illness prevention were lacking. The limited number of studies reporting influenza incidence in pregnant women and infants under six months had highly variable estimates and underrepresented low- and middle-income countries. The evidence that maternal influenza immunization reduces the risk of adverse birth outcomes was conflicting, and many observational studies were subject to substantial bias. The lack of scientific clarity regarding disease burden or magnitude of vaccine efficacy against severe illness poses challenges for robust estimation of the potential impact of maternal influenza immunization programs. PMID- 28867511 TI - Glutamine and citrulline concentrations reflect nitric oxide synthesis in the human nervous system. AB - INTRODUCTION: Although citrulline is produced by nitric oxide (NO) synthase upon activation of the NMDA glutamate receptor, nitrite and nitrate (NOx) concentration is considered the best marker of NO synthesis, as citrulline is also metabolised by other enzymes. This study analyses the correlation between human cerebrospinal fluid NOx and citrulline concentrations in order to determine the extent to which citrulline reflects NO synthesis and glutamatergic neurotransmission. METHODS: Participants were patients with acute neurological diseases undergoing lumbar puncture (n=240). NOx and amino acid concentrations were determined by HPLC. RESULTS: NOx concentrations did not vary significantly where infection (p=0,110) or inflammation (p=0,349) were present. Multiple regression analysis showed that NOx concentration was correlated with glutamine (r=-0,319, p<0,001) and citrulline concentrations (r=0,293, p=0,005) but not with the citrulline/arginine ratio (r=-0,160, p=0,173). ANCOVA confirmed that NOx concentration was correlated with citrulline concentration (F=7,6, p=0,007) but not with the citrulline/arginine ratio (F=2,2, p=0,136), or presence of infection (F=1,8, p=0,173) or inflammation (F=1,4, p=0,227). No association was found between NOx and arginine or glutamate concentrations. CONCLUSION: The results suggest that CSF citrulline concentration reflects NOx synthesis to some extent, despite the contribution of other metabolic pathways. In addition, this study shows that glutamine is an important modulator of NO synthase activity, and that arginine and glutamate are not correlated with NOx. PMID- 28867512 TI - Comment on: "The outcomes of overlay myringoplasty: Endoscopic versus microscopic approach". PMID- 28867513 TI - Clinical and Prognostic Implications of Methods and Partition Values Used to Assess Left Atrial Volume by Two-Dimensional Echocardiography. AB - BACKGROUND: The 2015 American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations for chamber quantification suggest new abnormality threshold and severity partition values for left atrial (LA) volume that are equally valid for the biplane method of disk (MOD) summation and the area-length method (ALM). However, they have never been clinically validated. Thus, we compared the clinical and prognostic impact of LA volume assessed by MOD and ALM by using both the 2015 and 2005 abnormality thresholds. METHODS: In a retrospective study of 467 patients with sinus rhythm and various cardiac conditions (median age 61 years, 68% men), maximal LA volumes were measured with MOD and ALM. Patients were followed for 3.7 +/- 1.1 years to record both all cause mortality and cardiac death. RESULTS: Applying the 2015 cutoff values, 21% of patients with dilated LA according to the 2005 recommendations were reclassified as normal. Severity of LA dilatation was reclassified in 48% (222/467) patients. ALM provided significantly larger LA volumes than MOD (41 [32; 58] mL/m2 vs 39 [30; 55] mL/m2; P = .0150), reclassifying 18% (84/467) of patients. Patients who died had larger LA volumes measured with both MOD (57 [38; 77] mL/m2 vs 37 [30; 51] mL/m2; P < .0001) and ALM (58 [40; 82] mL/m2 vs 40 [32; 54] mL/m2; P < .0001). Regardless of the method used, LA volume was a significant factor associated with mortality, with both the 2015 and 2005 cutoff values providing similar prognostic power. CONCLUSIONS: The use of 2015 partition values and different methods of LA volume measurement leads to significant changes in patients' clinical profiles. LA enlargement is an important prognostic indicator independent of cutoff values and methods used. Care should be taken to ensure consistent measurements and interpretation of two-dimensional echocardiography LA volume during patient follow-up. PMID- 28867514 TI - How Accurate Is Rapid Antigen Testing for Group A Streptococcus in Children With Pharyngitis? PMID- 28867515 TI - Morphometric parameters of the optic disc in normal and glaucomatous eyes based on time-domain optical coherence tomography image analysis. AB - BACKGROUND AND OBJECTIVE: Assessment of optic disc morphology is essential in diagnosis and management of visual impairment. The aim of this study was to evaluate associations between optic disc morphometric parameters, i.e., size and shape, and age, gender, and ocular axial length in normal and glaucomatous eyes based on time-domain optical coherence tomography image analysis. MATERIALS AND METHODS: It was a case-control study of 998 normal and 394 eyes with primary open angle glaucoma that underwent an ophthalmological examination and time-domain optical coherence topography scanning. Areas and shapes of the disc, cup, and neuroretinal rim were analyzed. RESULTS: The shape of the optic disc did not differ between the study groups, i.e., normal and glaucomatous case groups, but the disc area of the primary open angle glaucoma group was significantly larger. The shape of the small disc was significantly different, but the shape of the medium and the large disc did not differ between the study groups. The central area of the disc, i.e., cup area was significantly larger in the case group and its shape was significantly different between the study groups. No significant differences in the area of the cup and its shape, nerve fibers on the edge of the disc, i.e., neuroretinal rim area, were found between the study groups of the small discs. There were significant associations between age, gender, and ocular axial length and morphometric parameters of the optic disc. CONCLUSIONS: Informative results with regard to the size and shape due to various ocular characteristics between the healthy control group and patients suffering with primary open angle glaucoma were obtained. Both study groups were significant in size, which makes the findings interesting and important contribution in the field. PMID- 28867516 TI - Modelling the neuromotor abnormalities of psychotic illness: Putative mechanisms and systems dysfunction. AB - Limitations in access to antipsychotic-naive patients and in the incisiveness of studies that can be conducted on them, together with the inevitability of subsequent antipsychotic treatment, indicate an enduring role for animal models that can inform on the pathobiology of neuromotor abnormalities in schizophrenia and related psychotic illness. This review focusses particularly on genetically modified mouse models that involve genes associated with risk for schizophrenia and with mechanisms implicated in the neuromotor abnormalities evident in psychotic patients, as well as developmental models that seek to mirror the trajectory, phenomenology and putative pathophysiology of psychotic illness. Such abnormalities are inconsistent and subtle in mice mutant for some schizophrenia risk genes but more evident for others. The phenotype of dopaminergic and glutamatergic mutants indicates the involvement of these mechanisms, informs on the roles of specific receptor subtypes, and implicates the interplay of cortical and subcortical processes. Developmental models suggest a criticality in the timing of early adversity for diversity in the relative emergence of psychological symptoms vis-a-vis neuromotor abnormalities in the overall psychosis phenotype. These findings elaborate current concepts of dysfunction in a neuronal network linking the cerebral cortex, basal ganglia, thalamus and cerebellum. Both findings in model systems and clinical evidence converge in indicating that any distinction between 'psychomotor' and 'neuromotor' abnormality is artificial and arbitrary due to a unitary origin in developmentally determined systems/network dysfunction that underlies the lifetime trajectory of psychotic illness. PMID- 28867517 TI - Schizophrenia and creativity: A meta-analytic review. AB - The present study investigated the relationship between creativity and schizophrenia with a 3-level multilevel meta-analytic approach. Analyses with 200 effect sizes obtained from 42 studies found a mean effect size of r=-0.324, 95%CI [-0.42, -0.23]. Further analyses focused on moderators and indicated that the relationship between schizophrenia and creativity is moderated by type of creativity measure, the content of creativity measure, the severity of schizophrenia, and patient status. The negative mean effect size was stronger with semantic-category or verbal-letter fluency tasks than the divergent thinking or associational measures. Performance on verbal measures of creativity was significantly lower than the nonverbal measures. When effect sizes were compared at different levels of severity, a stronger and more negative mean effect size was obtained at chronic schizophrenia than acute and early onset levels. Studies that involved inpatients had a significantly higher (more negative) mean effect size than those involving outpatients. When these findings are considered along with previous meta-analyses on the link between creativity and psychoticism and schizotypy, creativity and psychopathology seem to have an inverted-U relationship. A mild expression of schizophrenia symptoms may support creativity but a full demonstration of the symptoms undermines it. PMID- 28867518 TI - Personality traits in recent-onset-of-psychosis patients compared to a control sample by gender. AB - Personality traits in recent onset of psychosis (ROP) patients are an under researched area. Our aim was to examine clinical and clinically significant personality traits in ROP patients compared with a healthy control sample by gender. Data were obtained from 94 ROP patients and a control sample matched in gender and age. The Millon Clinical Multiaxial Inventory and a sociodemographic scale were used. T for independent samples, U-Mann-Whitney and Fisher tests were applied to make comparisons. All personality traits were significantly higher in ROP than control participants in the general sample, except histrionic, narcissistic, and compulsive traits which were higher in controls. Clinically significant schizoid, avoidant, dependent and antisocial personality traits were more common in the ROP than the control participants. However, histrionic clinically significant trait was more common in the control sample. In relation to the males and female samples, more significant differences were found in the male sample in comparison to their control counterparts than in the female sample. These results highlight the importance of the study of clinical personality traits in patients with ROP and the importance of viewing these differences in relation to gender because of the possible therapeutic implications. PMID- 28867519 TI - Striatal dysfunction in patients with schizophrenia and their unaffected first degree relatives. AB - Despite empirical findings showing that patients with schizophrenia and their unaffected first-degree relatives have deficits in processing monetary incentives, it is unclear whether similar deficits could be demonstrated for affective incentives. Twenty-six patients with schizophrenia and 26 age and gender matched healthy controls; 23 unaffected first-degree relatives and 23 matched healthy controls were recruited to complete a Monetary Incentive Delay (MID) task and an Affective Incentive Delay (AID) task in a 3-Tesla MRI scanner. Hypoactivation in the dorsal striatum when anticipating monetary incentives were found in patients with schizophrenia and their unaffected first-degree relatives compared with healthy controls. Furthermore, patients with schizophrenia showed hyperactivation in the ventral striatum when receiving both monetary and affective incentives. These findings suggest that disorganized striatal function, regardless of incentive types, may be present in patients with schizophrenia and before the onset of illness in their first-degree unaffected relatives. PMID- 28867520 TI - Comparison of the iAssist Handheld Guidance System to Conventional Instruments for Mechanical Axis Restoration in Total Knee Arthroplasty. AB - BACKGROUND: Recent advances in total knee arthroplasty (TKA) include an intelligent instrument system designed to provide intraoperative guidance to reduce mechanical alignment errors. Internal position-sensing technology is integrated into microelectronic pods that attach to cutting blocks. The purpose of this prospective, randomized study was to determine whether this iAssist system enables the surgeon to make more accurate bone resections and better restore the mechanical axis compared to conventional instruments in TKA. METHODS: We randomized patients undergoing TKA into 2 groups. Group I (n = 25) underwent TKA assisted by the iAssist guidance system, group II (n = 25) underwent TKA using conventional instruments. Preoperative and postoperative mechanical axes were measured from full-length lower extremity radiographs to evaluate alignment. Additional surgical parameters were also assessed, including tourniquet time and blood loss. RESULTS: Patient demographics and preoperative mechanical axis alignments were similar between the groups. Postoperatively, 4.0% of patients had greater than 3 degrees of tibial or femoral component mal-alignment in the guidance-assisted cohort, compared with 36.0% in the conventional group (P < .05). Additionally, group I showed significant improvement in variance seen in both the femoral mechanical axis (1.65 degrees +/- 0.17 degrees vs 2.23 degrees +/- 0.33 degrees , P < .005) and tibial mechanical axis (1.28 degrees +/- 0.13 degrees vs 1.71 degrees +/- 0.24 degrees , P < .005) compared to group II. There were no significant differences in tourniquet time (P = .86) or blood loss (P = .39) between groups. CONCLUSION: Use of the iAssist system in TKA results in an improved postoperative mechanical axis and decreased alignment variability compared to conventional instruments, without significantly increasing operative time. PMID- 28867521 TI - Vacuolar ATPase in phago(lyso)some biology. AB - Many eukaryotic cells ingest extracellular particles in a process termed phagocytosis which entails the generation of a new intracellular compartment, the phagosome. Phagosomes change their composition over time and this maturation process culminates in their fusion with acidic, hydrolase-rich lysosomes. During the maturation process, degradation and, when applicable, killing of the cargo may ensue. Many of the events that are pathologically relevant depend on strong acidification of phagosomes by the 'vacuolar' ATPase (V-ATPase). This protein complex acidifies the lumen of some intracellular compartments at the expense of ATP hydrolysis. We discuss here the roles and importance of V-ATPase in intracellular trafficking, its distribution, inhibition and activities, its role in the defense against microorganisms and the counteractivities of pathogens. PMID- 28867522 TI - Do amyloid structures formed by Staphylococcus aureus phenol-soluble modulins have a biological function? AB - Phenol-soluble modulins (PSMs) are alpha-helical, amphipathic peptides that have multiple functions in staphylococcal physiology and virulence. Recent research has suggested that PSMs form amyloid fibrils and amyloids are involved in PSM mediated phenotypes such as cytolysis and biofilm stability. While we observed PSM amyloid formation using electron microscopy and dye assays, there were no apparent differences in the production of extracellular fibrous material between a PSM-deficient strain and the isogenic wild-type strain. Furthermore, we detected no correlation between cytolytic or pro-inflammatory activities with the propensity of PSM derivatives to form amyloids. In addition, we propose a model based on our finding of non-specific attachment of PSMs to DNA, which we here report results in resistance to DNase digestion, explaining previous findings on PSM-mediated biofilm stability without the necessity to assume amyloid involvement. Collectively, our results indicate that PSM amyloid formation may not be of major relevance for known key biological functions of PSMs. Intriguingly, however, we found that amyloid-forming capacity of PSMalpha3 allows almost no amino acid exchanges, suggesting importance of amyloid formation in possibly yet unknown functions of PSMs. PMID- 28867523 TI - Drip-and-Ship Thrombolytic Therapy for Acute Ischemic Stroke. AB - BACKGROUND: Neuroendovascular therapy is a common treatment for patients with acute ischemic stroke of the anterior circulation who fail to respond to recombinant tissue plasminogen activator. However, although most hospitals can provide recombinant tissue plasminogen activator therapy, many cannot perform neuroendovascular therapy. Thus, use of a drip-and-ship treatment-liaison system allowing recombinant tissue plasminogen activator-treated patients to be transferred to facilities offering neuroendovascular therapy is important. METHODS: We retrospectively analyzed 16 drip-and-ship patients transferred to our hospital for additional neuroendovascular therapy after they received intravenous recombinant tissue plasminogen activator at prior hospitals between June 2009 and March 2017. RESULTS: The mean patient age was 68 +/- 17 years. Ten patients had cardiogenic embolism and 6 had atherothrombosis. Additional neuroendovascular therapy was performed in 14 patients. Median National Institute of Health Stroke Scale and diffusion-weighted image-Alberta Stroke Program Early Computed Tomography Scores before recombinant tissue plasminogen activator therapy were 14 and 8, respectively. Occluded or stenotic lesions of the cerebral arteries were detected by magnetic resonance angiography in the internal carotid artery (n = 4), middle cerebral artery (n = 10), and basilar artery (n = 3) (1 patient had tandem lesions). Mean intervals from onset-to-recombinant tissue plasminogen activator, recombinant tissue plasminogen activator-to-our hospital (door), door to-puncture, and onset-to-recanalization were 166, 65, 32, and 334 minutes, respectively. No patients showed symptomatic intracranial hemorrhage. CONCLUSIONS: Magnetic resonance imaging/angiography performed in previous hospitals allows initiation of reperfusion therapy immediately after transfer. Thus, drip-and-ship plus neuroendovascular therapy is a safe and useful system for treatment of patients with acute infarcts. PMID- 28867524 TI - Severity of White Matter Lesions Correlates with Subcortical Diffusion-Weighted Imaging Abnormalities and Predicts Stroke Risk. AB - BACKGROUND AND PURPOSE: The severity of white matter lesions (WMLs) has been strongly linked to small-vessel diseases or lacunar infarction. The present study aimed to investigate the correlation between severity of WMLs and distribution of diffusion-weighted imaging (DWI) hyperintensities, and to explore whether the severity of WMLs is an independent neuroimaging predictor of stroke risk after transient symptoms with infarction (TSI). METHODS: We evaluated the presence and severity of WMLs on fluid-attenuated inversion recovery sequences using the age related white matter changes scale and the location and size of hyperintensities on DWI sequences, respectively, in a prospective cohort study of TSI patients. The primary end point was recurrent stroke within 90 days. RESULTS: A total of 191 consecutive TSI patients were eligible for inclusion in the present analysis. The average age of the patients was 57.3 +/- 12.8 years. DWI abnormalities occurred more often in the deep white matter with increasing severity of WMLs (P < .001). During 90-day follow-up, Kaplan-Meier analysis showed that recurrent stroke was correlated to the severity of WMLs (P = .01). The Cox proportional hazards model revealed that WMLs were predictive of recurrent stroke (hazard ratio, 1.748; 95% confidence interval, 1.16-2.634; P = .008). CONCLUSIONS: Severe WMLs were correlated with DWI hyperintensities in the deep white matter in TSI patients and contributed to an increased risk of recurrent stroke. PMID- 28867525 TI - A customised digitally engineered solution for fixed dental rehabilitation in severe bone deficiency: A new innovative line extension in implant dentistry. AB - OBJECTIVES: Numerous procedures including soft and hard tissue reconstructions are necessary to allow for final implant-borne dental rehabilitation in patients with severe alveolar atrophy or resected jaws. In these cases, customised digitally engineered patient solutions for fixed or removable dental rehabilitation provide an innovative line extension to conventional implant dentistry. MATERIAL AND METHODS: A wax-up was performed on plaster models that were scanned by 3D laser. The generated stereolithographic files were then fused with the preoperative 3D imaging data. The individualised "dental" patient solutions were designed digitally and comprised a skeletonised anchorage system and a suprastructure connection system. Insertion of the implants was performed on an outpatient basis. Conventional implant-supported prosthodontic rehabilitation was performed. RESULTS: This digital planning algorithm can be applied to manufacture individualised patient solutions. Similar to conventional implant-supported dentures, these implants can be equipped with individual suprastructure connection systems for internal conical connection, ball-retained attachment, and external conical (telescopic) connection. CONCLUSIONS: In patients with severe atrophy or resected jaws, particularly following ablative tumour surgery, customised digitally engineered solutions allow for an innovative, less invasive line extension to conventional implant dentistry. When conventional implant dentistry reaches its limits, they still offer a strategy for implant-borne dental rehabilitation. PMID- 28867527 TI - Is babesiosis the most common transfusion transmitted infection in the United States of America? The answer is not simple! PMID- 28867528 TI - Corrigendum to 'U.S. Population Data for 29 Autosomal STR Loci' [Forensic Sci. Int. Genet. 7 (2013) e82-e83]. PMID- 28867526 TI - From Original Antigenic Sin to the Universal Influenza Virus Vaccine. AB - Antibody responses are essential for protection against influenza virus infection. Humans are exposed to a multitude of influenza viruses throughout their lifetime and it is clear that immune history influences the magnitude and quality of the antibody response. The 'original antigenic sin' concept refers to the impact of the first influenza virus variant encounter on lifelong immunity. Although this model has been challenged since its discovery, past exposure, and likely one's first exposure, clearly affects the epitopes targeted in subsequent responses. Understanding how previous exposure to influenza virus shapes antibody responses to vaccination and infection is critical, especially with the prospect of future pandemics and for the effective development of a universal influenza vaccine. PMID- 28867529 TI - One hundred and forty five total laparoscopic pancreatoduodenectomies: A single centre experience. AB - INTRODUCTION: Laparoscopic pancreatoduodenectomy (LPD) remains one of the most challenging minimal invasive operations today. PATIENTS AND METHODS: Between January 2007 and December 2016, 197 patients were scheduled for LPD but 162 patients (from January 2007 to July 2016) were analysed in this cohort series. RESULTS: Total LPD concerned for 162 patients (five patients did not undergo PD and 12 underwent conversion): standard LPD in 104 patients (66%), and laparoscopic pylorus-preserving PD in 41 patients (26%). Median operative time was 415 (240-765) min. Median blood loss was 200 (50-2100) ml. Twelve patients required blood transfusion. Clinically relevant pancreatic fistula (ISGPF grades B and C) occurred in 21 (13%) patients: 16 (10.0%) grade B, and 5 (3%) grade C. Grades B and C delayed gastric emptying occurred in five patients each. Grades B and C post-pancreatectomy bleeding occurred in 9 (5.7%) and 3 (1.9%) patients, respectively. LPD was performed for 18 (11.4%) benign and 139 (88.5%) malignant lesions. Superior mesenteric and/or portal vein involvement required major venous resection in eight patients. The 90-day mortality 5.0%. The median overall survival for pancreatic ductal adenocarcinoma was 22.5 months. CONCLUSION: Morbidity and mortality for LPD are comparable to open procedures rates in the literature. Laparoscopic major venous resection is feasible and safe. PMID- 28867530 TI - Clinical and microbiological profile of diabetic foot ulcer patients in a tertiary care hospital. AB - AIM: To evaluate the clinical and microbiological profile of diabetic foot ulcer patients admitted to a tertiary care hospital. METHODOLOGY: This study recruited 120 diabetic foot ulcer patients of all grade. Their medical records were evaluated retrospectively. RESULTS: We found that median age of patient was 60(52, 67.75) years. 68.3% of patients were males. Median duration of diabetes mellitus was 15(10, 20) years. Mean HbA1C and fasting glucose was 10.3+/-2.3 and 167.6+/-52.42 respectively. Neuropathy (35%) and peripheral vascular disease (23.3%) was major micro vascular and macro vascular complication associated. Different locations of ulcers were toe (23.3%), sole (20%), dorsum (18.3%), shin (16.6%), heel (13.3%), and ankle (8.3%). Bacterial infection was seen in 81.66% patients out of which 23.3% had poly microbial infection. CONCLUSION: Diabetic foot ulcer patient had poor blood glucose control with elevated HbA1C and fasting blood glucose level. Neuropathy and peripheral vascular disease, hypertension were major complications. Staphylococcus aureus, Pseudomonas aeruginosa were common infecting bacteria. PMID- 28867531 TI - [Acute management of ischemic stroke in 2017]. AB - Acute management of ischemic stroke is a burning topic in 2017 since stroke represents the leading cause of acquired handicap in adults. Over the last past years, major improvement took place, especially with the demonstration of the efficacy of mechanical thrombectomy, thus needing to better organize care pathways, and optimize access to neurologists and interventional neuroradiology platforms. Intensive care stroke units remain the pivotal place of patients' management. A multidisciplinary coordination is required, with continuous teaching of all the actors involved in stroke management, so as to increase the number of patients who could benefit from available active treatments. PMID- 28867532 TI - [Eosinophilia heralding the diagnosis of eosinophilic fasciitis (Shulman's disease)]. AB - INTRODUCTION: Eosinophilic fasciitis or Shulman's disease is characterized, in its typical form, by palpable thickening of the skin and soft tissues, blood hypereosinophilia and fascia lesions. We hereby report a case of eosinophilic fasciitis in which hypereosinophilia preceded for several months the clinical signs of fasciitis. CASE REPORT: A 64-year-old woman, with a history of Little's syndrome with motor disability, was admitted in internal medicine for eosinophilia. For almost three months, no origin to the eosinophilia was found. The secondary onset of an edema and pain located on four limbs led to the diagnosis of eosinophilic fasciitis. Muscle magnetic resonance imaging was supportive and the muscle histological analysis confirmed the diagnosis of eosinophilic fasciitis. Treatment with steroids induced a rapid normalization of the eosinophilia and edema. CONCLUSION: In this case report, eosinophilia was preceding the clinical cutaneous signs that led to the diagnosis of eosinophilic fasciitis. It is likely to believe that myalgias, frequently found in the onset of eosinophilic fasciitis, may have been hidden by the history of infantile encephalopathy. The diagnosis of eosinophilic fasciitis must be kept in mind of physicians in the investigation of an eosinophilia, even though cutaneous signs are lacking. PMID- 28867533 TI - [Primary intestinal lymphangiectasia (Waldmann's disease)]. AB - Primary intestinal lymphangiectasia (PIL), Waldmann's disease, is a rare disorder of unknown etiology characterized by dilated intestinal lacteals leading to lymph leakage into the small-bowel lumen and responsible for protein-losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. PIL is generally diagnosed before 3 years of age but may be diagnosed in older patients. The main symptom is bilateral lower limb edema. Edema may be moderate to severe including pleural effusion, pericarditis or ascites. Protein-losing enteropathy is confirmed by the elevated 24-h stool alpha1-antitrypsin clearance and diagnosis by endoscopic observation of intestinal lymphangiectasia with the corresponding histology of biopsies. Videocapsule endoscopy may be useful when endoscopic findings are not contributive. Several B-cell lymphomas of the gastrointestinal tract or with extra-intestinal localizations were reported in PIL patients. A long-term strictly low-fat diet associated with medium-chain triglyceride and liposoluble vitamin supplementation is the cornerstone of PIL medical management. Octreotide, a somatostatin analog, have been proposed with an inconsistent efficacy in association with diet. Surgical small-bowel resection is useful in the rare cases with segmental and localized intestinal lymphangiectasia. A prolonged clinical and biological follow-up is recommended. PMID- 28867534 TI - [Vitamin K antagonist-induced necrotic leg ulcer, without protein C and S deficiencies]. AB - INTRODUCTION: Patients treated by vitamin K antagonists (VKA) represent 1% of the population in France. We report a case of atypical necrotic leg ulcers induced by VKA. CASE REPORT: A 84-year-old woman was referred to our dermatology department because of necrotic leg ulcers that developed for the past 5weeks, and appeared spontaneously after the introduction of a VKA, fluindione. The etiological assessment was non contributive, in particular the search for thrombophilic factors. The skin biopsy found an aspect compatible with pyoderma gangrenosum. The outcome was favorable after discontinuing the fluindione and the switch to apixaban. A complete healing was obtained in 5months. CONCLUSION: We report an original case of necrotic leg ulcers induced by VKA without deficit of protein C or S, with a pyoderma like histology. Reported cases of ulcers induced by VKA are uncommon and the physiopathology is not well known. The involvement of VKA should be evoked in case of necrotic leg ulcer without specific etiology found. PMID- 28867536 TI - Nitric oxide and CaMKII: Critical steps in the cardiac contractile response To IGF-1 and swim training. AB - Cardiac adaptation to endurance training includes improved contractility by a non yet clarified mechanism. Since IGF-1 is the main mediator of the physiological response to exercise, we explored its effect on cardiac contractility and the putative involvement of nitric oxide (NO) and CaMKII in control and swim-trained mice. IGF-1 increased cardiomyocyte shortening (128.1+/-4.6% vs. basal; p?0.05) and accelerated relaxation (time to 50% relengthening: 49.2+/-2.0% vs. basal; p?0.05), effects abrogated by inhibition of: AKT with MK-2206, NO production with the NO synthase (NOS) inhibitor L-NAME and the specific NOS1 inhibitor nitroguanidine (NG), and CaMKII with KN-93. In agreement, an increase in NO in response to IGF-1 (133.8+/-2.2%) was detected and prevented by both L-NAME and NG but not KN-93, suggesting that CaMKII activation was downstream NO. In addition, we determined CaMKII activity (P-CaMKII) and phosphorylation of its target, Thr17 PLN. IGF-1, by a NO-dependent mechanism, significantly increased both (227.2+/ 29.4% and 145.3+/-5.4%, respectively) while no changes in the CaMKII phosphorylation site of ryanodine receptor were evident. The improvement in contractility induced by IGF-1 was associated with increased Ca2+ transient amplitude, rate of decay and SR content. Interestingly, this response was absent in cardiomyocytes from transgenic mice that express a CaMKII inhibitory peptide (AC3-I strain). Moreover, AC3-I mice subjected to swim training did develop physiological cardiac hypertrophy but not the contractile adaptation. Therefore, we conclude that NO-dependent CaMKII activation plays a critical role in the improvement in contractility induced by IGF-1 and exercise training. Interestingly, this pathway would not contribute to the adaptive hypertrophy. PMID- 28867535 TI - Innate Lymphoid Cell Immunometabolism. AB - Innate lymphoid cells (ILCs) are tissue-resident "first responders" of the immune system that function to protect epithelial barriers against pathogens and maintain tissue homeostasis. However, because ILCs are finely tuned to perturbations within tissue microenvironments, they can also contribute to host pathology when upstream activating signals are dysregulated. Recent work has demonstrated that the crosstalk between ILCs and their environment has a significant impact on host metabolism in health and disease. In this brief review, we summarize recent studies that demonstrate the ability of ILCs to influence tissue and systemic metabolism, as well as how ILC biology can be regulated by environmental changes in host metabolism. We also highlight studies showing how ILC-intrinsic metabolism influences their activation, proliferation, and homeostasis. Finally, this review discusses the challenges and open questions in the rapidly expanding field of immunometabolism. PMID- 28867537 TI - Thermal injury of the skin induces G-CSF-dependent attenuation of EPO-mediated STAT signaling and erythroid differentiation arrest in mice. AB - Inflammation-mediated impairment of erythropoiesis plays a central role in the development of the anemia of critical illness (ACI). ACI develops despite elevation of endogenous erythropoietin (EPO), does not respond to exogenous erythropoietin (EPO) supplementation, and contributes significantly to transfusion requirements in burned patients. We have reported previously that the reduction of red blood cell mass in the bone marrow of a burn-injured ACI mouse model is granulocyte colony-stimulating factor (G-CSF) dependent. Given that elevated G-CSF levels also have been associated with lower hemoglobin levels and increased transfusion requirements in trauma victims, we postulated that G-CSF mediates postburn EPO resistance. In ACI mice, we found that bone marrow erythroid differentiation, viability, and proliferation are impaired after thermal injury of the skin. These changes in the marrow were associated with attenuated phosphorylation of known EPO-responsive signaling nodes, signal transducer and activator of transcription 5 (STAT5) Y694 and STAT3 S727, in bone marrow erythroid cells and developed despite highly elevated levels of endogenous EPO. Severely blunted STAT5 Y694 phosphorylation in bone marrow erythroid cells after exogenous EPO supplementation confirmed that EPO signaling was impaired in ACI mice. Importantly, parenteral administration of anti-G-CSF largely rescued postburn bone marrow erythroid differentiation arrest and EPO signaling in erythroid cells. Together, these data provide strong evidence for a role for G CSF in the development of ACI after burn injury through suppression of EPO signaling in bone marrow erythroid cells. PMID- 28867538 TI - Attention bias modification reduces neural correlates of response monitoring. AB - The error-related negativity (ERN) is an electrophysiological response to errors. Individual differences in the ERN have been posited to reflect sensitivity to threat and linked with risk for anxiety disorders. Attention bias modification is a promising computerized intervention that has been shown to decrease threat biases and anxiety symptoms. In the present study, we examined the impact of a single session of attention bias modification, relative to a control task, on the neural correlates of response monitoring, including the ERN, correct response negativity (CRN), and their difference (i.e., the ERN - CRN or DeltaERN). The final sample included 60 participants who first completed a flanker task to elicit the ERN and CRN, and were then randomly assigned to attention bias modification (n=30) or a control task (n=30). After completing the attention bias modification or control task, participants completed the same flanker task to again elicit the ERN and CRN. Among participants who completed attention bias modification training, the ERN, CRN, and DeltaERN decreased from the pre- to post training assessment. In contrast, in participants who completed the control task, the CRN, ERN, and DeltaERN did not differ between the pre- and post-training assessment. The presents study suggests that a single session of attention bias modification reduces neural correlates of response monitoring, including error related brain activity. These results also support attention bias modification as a potential mechanistic-based intervention for the prevention and treatment of anxiety pathology. PMID- 28867539 TI - Fear acquisition and liking of out-group and in-group members: Learning bias or attention? AB - The present study explores the notion of an out-group fear learning bias that is characterized by facilitated fear acquisition toward harm-doing out-group members. Participants were conditioned with two in-group and two out-group faces as conditioned stimuli. During acquisition, one in-group and one out-group face was paired with an aversive shock whereas the other in-group and out-group face was presented without shock. Psychophysiological measures of fear conditioning (skin conductance and pupil size) and explicit and implicit liking exhibited increased differential responding to out-group faces compared to in-group faces. However, the results did not clearly indicate that harm-doing out-group members were more readily associated with fear than harm-doing in-group members. In contrast, the out-group face not paired with shock decreased conditioned fear and disliking at least to the same extent that the shock-associated out-group face increased these measures. Based on these results, we suggest an account of the out-group fear learning bias that relates to an attentional bias to process in group information. PMID- 28867540 TI - Finding hidden treasures in old drugs: the challenges and importance of licensing generics. AB - Identifying new indications for existing drugs creates new therapeutic options while bypassing much of the costs and time involved with bringing a new drug to market. The rediscovery of a generic drug, however, is a challenging pursuit because there is no formal regulatory approach and a lack of economic interest by pharmaceutical companies. This played a part in the re-registration of thioguanine as a rescue drug for the treatment of patients with inflammatory bowel disease in The Netherlands. In this article, we aim to underline the importance of drug rediscovery, the difficulties of this procedure in Europe and we attempt to suggest conceivable solutions. PMID- 28867541 TI - miR-107-mediated decrease of HMGCS2 indicates poor outcomes and promotes cell migration in hepatocellular carcinoma. AB - Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) has been implicated in human cancers, but its role and clinical significance in hepatocellular carcinoma (HCC) remain unknown. Here, we show that HMGCS2 is downregulated and exhibits antimetastatic potential in HCC. Low expression of HMGCS2 was associated with poor tumor differentiation, vascular invasion and worse overall and disease-free survivals in two independent cohorts consisting of 743 cases. In vitro data demonstrated HMGCS2 overexpression suppressed, whereas HMGCS2 silence promoted HCC cell migration via Epithelial-Mesenchymal Transition (EMT) process and the activation of ERK/c-Jun signaling pathway. Inhibition of ERK phosphorylation by PD098059 markedly attenuated the malignant phenotypes mediated by HMGCS2 siRNA. Furthermore, miR-107 was identified as an upstream regulator of HMGCS2 via directly targeting the 3'-UTR of HMGCS2 mRNA. Collectively, our findings suggest HMGCS2 serve as a promising prognostic biomarker and exert anti-tumor activity towards HCC, and therefore provide a potential target for HCC clinical intervention. PMID- 28867542 TI - Use Only as Directed. PMID- 28867543 TI - Clinical outcomes of hypofractionated radiation therapy for choroidal metastases: Symptom palliation, tumor control, and survival. AB - PURPOSE: External beam radiation therapy (RT) is an effective palliative treatment for patients with choroidal metastases and is aimed at preserving vision and obtaining local tumor control. Delivery of 30 to 40 Gy in 2-Gy daily fractions is a standard approach at many centers. This study reports the outcomes of a hypofractionated schedule of 20 Gy in 5 fractions in this palliative setting. METHODS AND MATERIALS: We conducted a retrospective review of patients who were treated with RT (20 Gy in 5 fractions) for choroidal metastases between January 1999 and November 2012. The primary outcome measures were change in visual acuity and tumor response. Secondary outcomes included toxicities of RT, tumor control, and overall survival (OS) from diagnosis of choroidal metastases. Univariate and multivariable Cox regression modeling was used to investigate the predictors for OS. RESULTS: Fifty-five patients with 71 affected eyes were included. Decreased vision was the presenting symptom in 43 eyes (61%). Visual acuity improved from a median of 20/70 at baseline to 20/40 at last follow-up and remained stable or improved in 56 eyes (80%). Tumor regression was observed in 64 eyes (91%) with complete response in 47 eyes (67%). Local progression occurred in 4 eyes (6%). The median survival after diagnosis of choroidal metastases was 13 months. No acute complications were observed in 49 patients (89%). Mild acute toxicities included transitory dryness in 5 patients and episcleritis in 1 patient. Cataracts, retinopathy, optic neuropathy, pigmentary maculopathy, and neovascular glaucoma developed in 4 eyes (6%), 1 eye, 7 eyes (10%), 5 eyes (7%), and 1 eye, respectively. No variables were statistically significantly associated with OS. CONCLUSIONS: A short fractionation schedule of 20 Gy in 5 fractions is a well-tolerated treatment that effectively preserves vision and gains local tumor control for many patients with choroidal metastases. This hypofractionated approach would help reduce the burden of a longer treatment course in this palliative patient population. PMID- 28867544 TI - Standardization of radiation therapy dose for locally advanced non-small cell lung cancer through changes to a lung cancer clinical pathway in a large, integrated comprehensive cancer center network. AB - PURPOSE: The results of Radiation Therapy Oncology Group (RTOG) 0617, which randomized patients with stages IIIA/IIIB non-small cell lung cancer (NSCLC) to definitive chemoradiation therapy to 60 Gy versus 74 Gy, demonstrated a detrimental survival impact with high-dose radiation therapy. We evaluated the impact of changes to a provider-driven clinical pathway (CP) guiding management of NSCLC on practice throughout our cancer center network. METHODS AND MATERIALS: In 2001, we implemented a CP for management of stage IIIA/IIIB NSCLC with definitive chemoradiation therapy. In 2013, the CP for NSCLC was amended (amendment 1) to allow a dose range of 60 to 74 Gy. The CP was amended (amendment 2) in January 2016 to specify a dose range of 60 to 70 Gy. Higher doses were considered off-pathway and subject to peer review. Data from decisions entered from 2012 to 2016 were obtained. RESULTS: From 2012 until publication of RTOG 0617 in February 2015, the median prescription dose was 66 Gy delivered in 1.8 to 2.1 Gy fractions. Doses <=66 Gy were prescribed for 52% of patients. From February 2015 to September 2016, the median prescription dose was 60 Gy, and 91% of prescription doses were <=66 Gy. After amendment 2, 99% of decisions were <=66 Gy. Dose <=66 Gy was associated with treatment following publication of 0617 (P < .001) and treatment after amendment 2 (P < .001). On multivariable analysis, treatment after amendment 2 was associated with dose <=66 Gy (odds ratio, 9.9; 95% confidence interval, 5.2-19.0; P < .001). The percentage of lung receiving 20 Gy was lower following publication of 0617 (P < .001). There was no difference in the percentage of heart receiving 40 Gy. CONCLUSIONS: CPs eliminate variations in practice that lead to inferior outcomes. Recognizing that our CP for definitive treatment of patients with locally advanced NSCLC allowed heterogeneous dose prescriptions, we modified the CP based on the publication of RTOG 0617. We found that the CP was a tool to ensure patients receive evidence-based care across a large cancer center network. PMID- 28867545 TI - Never too old: A single-institution experience of stereotactic body radiation therapy for patients 90 years and older with early stage lung cancer. AB - PURPOSE: To report on the patient, tumor, and treatment characteristics of patients aged 90 years or older who were treated with lung stereotactic body radiation therapy (SBRT) for early stage lung cancer and the resulting clinical outcomes. METHODS AND MATERIALS: We surveyed our institutional review board approved prospective lung SBRT data registry for patients aged 90 years or older who were treated for early stage lung cancer to determine the rates of local failure, progression-free survival, and overall survival as well as treatment related toxicity. RESULTS: For the 2004 to 2016 time period, 19 patients (of a total of 1268 lung SBRT cases) were identified. The median age at treatment was 91.6 years (range, 90-97 years). Most patients were female (52.6%) and former smokers (78.9%). The median tumor size was 2.1 cm (range, 1.5-5.4 cm). Tissue was obtained for diagnosis in 68.4% of patients, with the predominant histology being adenocarcinoma (42.2%). Six patients (31.6%) had central lesions. The median follow-up for all patients was 17.3 months. The median SBRT schedule was 50 Gy in 5 fractions over 5 consecutive days and was used in 9 cases (47.4%). The median pre-SBRT and 6-month post-SBRT pulmonary testing showed that the forced expiratory volume in one second, as the percent predicted, was 81.9 and 84.5 and the diffusing capacity of the lungs for carbon monoxide, as the percent predicted, was 66.5 and 67, respectively. No grade 3 or higher toxicities were observed. The 2-year rates of local failure, progression-free survival, and overall survival were 5.6%, 48.6%, and 47.8%, respectively. CONCLUSIONS: Lung SBRT appears to be safe and effective in nonagenarians with stage I lung cancer. The absence of high-grade toxicities and mortality warrants its consideration as the primary curative modality in this population. PMID- 28867546 TI - Reirradiation of thoracic cancers with intensity modulated proton therapy. AB - PURPOSE: Reirradiation of thoracic malignancies is a treatment challenge, with concerns for toxicity and the inability to deliver definitive doses. Intensity modulated proton therapy (IMPT) may allow safe delivery of a higher dose of radiation to the tumor while minimizing toxicities. METHODS AND MATERIALS: Between 2011 and 2016, 27 patients who received IMPT for reirradiation of thoracic malignancies with definitive intent were retrospectively analyzed. Patients were included if they received a prior thoracic radiation course. All doses were recalculated to an equivalent dose in 2-Gy fractions (EQD2). Patients received IMPT to a median dose of 66 EQD2 Gy (range, 43.2-84 Gy) for recurrence of thoracic cancer (93%) or sequentially after a course of thoracic stereotactic ablative radiation therapy (7%). RESULTS: Twenty-two patients (81%) were treated for non-small cell lung cancer. The median time to reirradiation was 29.5 months. At a median follow-up for all patients of 11.2 months (25.9 surviving patients), the median overall survival was 18.0 months, with a 1-year overall survival of 54%. Four patients (15%) experienced an in-field local failure (LF), with a 1 year freedom from LF rate of 78%. The 1-year freedom from locoregional failure and 1-year progression-free survival rates were 61% and 51%, respectively. Patients who received 66 EQD2 Gy or higher had improved 1-year freedom from LF (100% vs 49%; P = .013), 1-year freedom from locoregional failure (84% vs 23%; P = .035), and 1-year progression-free survival (76% vs 14%; P = .050). Reirradiation was well tolerated, with only 2 patients (7%) experiencing late grade 3 pulmonary toxicity, and none with grade 3 or higher esophagitis. There were no grade 4-5 toxicities. CONCLUSIONS: These data represent the largest series of patients treated with IMPT for definitive reirradiation of thoracic cancers. They demonstrate that IMPT provided durable local control with minimal toxicity and suggest that higher doses may improve outcomes. PMID- 28867547 TI - Stereotactic radiosurgery for treatment of multiple brain metastases: Remembering to spare the hippocampus?: In Regard to Zhang et al. PMID- 28867548 TI - Treatment of bilateral breast cancer and regional nodes using an opposed lateral beam arrangement. PMID- 28867549 TI - The upper and lower segments of subscapularis muscle have different roles in glenohumeral joint functioning. AB - Subscapularis muscle is divided into two independent segments, upper and lower (USUB and LSUB), but the role of each segment in glenohumeral functioning is unclear. We compared the electromyographic (EMG) activity of USUB and LSUB during a variety of shoulder movements, with and without an external translation force. Intramuscular electrodes were inserted in USUB and LSUB segments of 20 adults without pathology and EMG activity was measured in stabilization trials (with and without an anterior or posterior directed force at the humerus and isometric rotations) and two shoulder positions (shoulder neutral, abduction). Maximal voluntary isometric contraction (MVIC) trials were performed in abduction, internal and external rotation of the shoulder. In MVIC trials, USUB showed higher activity during internal rotation (p=0.03), whereas LSUB showed higher activity during external rotation (p<0.01). In stabilization trials, the interaction effects were significant for muscle segment*condition (p<0.01), and approached significance for muscle segment*position (p=0.06). In the neutral position, the pattern of activity for LSUB was similar to USUB. In the abducted position the LSUB, unlike USUB, was more active during external rotation (p=0.06) and also showed increased activity in response to the posterior directed force at the humerus (p=0.04). Our results suggest that USUB primarily acts asan agonist for internal rotation. In contrast LSUB was particularly active in external rotation in the abducted position and demonstrated increased EMG activity in response to the posteriorly directed force at the humerus in that position, suggesting more of a role in glenohumeral stabilization. PMID- 28867551 TI - Stable Positioning of Unc13 Restricts Synaptic Vesicle Fusion to Defined Release Sites to Promote Synchronous Neurotransmission. AB - Neural information processing depends on precisely timed, Ca2+-activated synaptic vesicle exocytosis from release sites within active zones (AZs), but molecular details are unknown. Here, we identify that the (M)Unc13-family member Unc13A generates release sites and show the physiological relevance of their restrictive AZ targeting. Super-resolution and intravital imaging of Drosophila neuromuscular junctions revealed that (unlike the other release factors Unc18 and Syntaxin-1A) Unc13A was stably and precisely positioned at AZs. Local Unc13A levels predicted single AZ activity. Different Unc13A portions selectively affected release site number, position, and functionality. An N-terminal fragment stably localized to AZs, displaced endogenous Unc13A, and reduced the number of release sites, while a C-terminal fragment generated excessive sites at atypical locations, resulting in reduced and delayed evoked transmission that displayed excessive facilitation. Thus, release site generation by the Unc13A C terminus and their specific AZ localization via the N terminus ensure efficient transmission and prevent ectopic, temporally imprecise release. PMID- 28867550 TI - Neurotransmitter Switching Regulated by miRNAs Controls Changes in Social Preference. AB - Changes in social preference of amphibian larvae result from sustained exposure to kinship odorants. To understand the molecular and cellular mechanisms of this neuroplasticity, we investigated the effects of olfactory system activation on neurotransmitter (NT) expression in accessory olfactory bulb (AOB) interneurons during development. We show that protracted exposure to kin or non-kin odorants changes the number of dopamine (DA)- or gamma aminobutyric acid (GABA)-expressing neurons, with corresponding changes in attraction/aversion behavior. Changing the relative number of dopaminergic and GABAergic AOB interneurons or locally introducing DA or GABA receptor antagonists alters kinship preference. We then isolate AOB microRNAs (miRs) differentially regulated across these conditions. Inhibition of miR-375 and miR-200b reveals that they target Pax6 and Bcl11b to regulate the dopaminergic and GABAergic phenotypes. The results illuminate the role of NT switching governing experience-dependent social preference. VIDEO ABSTRACT. PMID- 28867553 TI - Cepstral analysis of normal and pathological voice in Spanish adults. Smoothed cepstral peak prominence in sustained vowels versus connected speech. AB - INTRODUCTION AND OBJECTIVES: In recent years, the use of cepstral measures for acoustic evaluation of voice has increased. One of the most investigated parameters is smoothed cepstral peak prominence (CPPs). The objectives of this paper are to establish the usefulness of this acoustic measure in the objective evaluation of alterations of the voice in Spanish and to determine what type of voice sample (sustained vowels or connected speech) is the most sensitive in evaluating the severity of dysphonia. METHOD: Forty subjects participated in this study 40, 20 controls and 20 with dysphonia. Two voice samples were recorded for each subject (one sustained vowel/a/and four phonetically balanced sentences) and the CPPs was calculated using the Praat programme. Three raters perceptually evaluated the voice sample with the Grade parameter of GRABS scale. RESULTS: Significantly lower values were found in the dysphonic voices, both for/a/(t[38]= 4.85, P<.000) and for phrases (t[38] = 5,75, P<.000). In relation to the type of voice sample most suitable for evaluating the severity of voice alterations, a strong correlation was found with the acoustic-perceptual scale of CPPs calculated from connected speech (rs = -0.73) and moderate correlation with that calculated from the sustained vowel (rs = -0,56). CONCLUSION: The results of this preliminary study suggest that CPPs is a good measure to detect dysphonia and to objectively assess the severity of alterations in the voice. PMID- 28867552 TI - Connexin 43-Mediated Astroglial Metabolic Networks Contribute to the Regulation of the Sleep-Wake Cycle. AB - Astrocytes produce and supply metabolic substrates to neurons through gap junction-mediated astroglial networks. However, the role of astroglial metabolic networks in behavior is unclear. Here, we demonstrate that perturbation of astroglial networks impairs the sleep-wake cycle. Using a conditional Cre-Lox system in mice, we show that knockout of the gap junction subunit connexin 43 in astrocytes throughout the brain causes excessive sleepiness and fragmented wakefulness during the nocturnal active phase. This astrocyte-specific genetic manipulation silenced the wake-promoting orexin neurons located in the lateral hypothalamic area (LHA) by impairing glucose and lactate trafficking through astrocytic networks. This global wakefulness instability was mimicked with viral delivery of Cre recombinase to astrocytes in the LHA and rescued by in vivo injections of lactate. Our findings propose a novel regulatory mechanism critical for maintaining normal daily cycle of wakefulness and involving astrocyte-neuron metabolic interactions. PMID- 28867554 TI - Characterization of atrazine binding to dissolved organic matter of soil under different types of land use. AB - Atrazine is widely used in agriculture. In this study, dissolved organic matter (DOM) from soils under four types of land use (forest (F), meadow (M), cropland (C) and wetland (W)) was used to investigate the binding characteristics of atrazine. Fluorescence excitation-emission matrix-parallel factor (EEM-PARAFAC) analysis, two-dimensional correlation spectroscopy (2D-COS) and Stern-Volmer model were combined to explore the complexation between DOM and atrazine. The EEM PARAFAC indicated that DOM from different sources had different structures, and humic-like components had more obvious quenching effects than protein-like components. The Stern-Volmer model combined with correlation analysis showed that log K values of PARAFAC components had a significant correlation with the humification of DOM, especially for C3 component, and they were all in the same order as follows: meadow soil (5.68)>wetland soil (5.44)>cropland soil (5.35)>forest soil (5.04). The 2D-COS further confirmed that humic-like components firstly combined with atrazine followed by protein-like components. These findings suggest that DOM components can significantly influence the bioavailability, mobility and migration of atrazine in different land uses. PMID- 28867555 TI - Lexical access in semantic variant PPA: Evidence for a post-semantic contribution to naming deficits. AB - The most salient clinical symptom of semantic variant primary progressive aphasia (PPA) is a profound and pervasive anomia. These patients' naming impairments have been shown to reflect in large part a domain-general deterioration of conceptual knowledge that impacts both linguistic and non-linguistic processing. However, it is possible that post-semantic stages of lexical access may also contribute to naming deficits. To clarify the stages at which lexical access breaks down in semantic variant PPA, eleven French-speaking patients were asked to name objects, and were then queried for semantic, lexical-syntactic, and word form information pertaining to the items they could not name. Specifically, our goal was to determine whether patients can access intermediate representations known as lemmas, which mediate the arbitrary mapping between semantic representations and word forms (phonological and orthographic forms). The French language was chosen for this study because nouns in French are marked for grammatical gender, a prototypical type of lexical-syntactic information, represented at the level of the lemma. Access to word form information is also dependent on lemma access under some theoretical views. We found that six of the eleven patients showed partial access to either lexical-syntactic properties of unnamed items (grammatical gender), word form information (initial letter), or both. Access to these types of information suggests that a lemma has been retrieved, implying a breakdown at the post-semantic stage of word form retrieval. Our results suggest that although degraded conceptual knowledge is the main cause of naming deficits in semantic variant PPA, in some patients, a post-semantic component also contributes to the impairment. PMID- 28867556 TI - Neoantigen Vaccines Pass the Immunogenicity Test. AB - Neoantigens arising from tumor-specific genomic alterations constitute authentic non-self antigens and represent a new class of targets for cancer immunotherapy. Recent reports on various vaccine platforms targeting neoantigens suggest a basis for precision therapies customized to each patient's tumor mutational profile. PMID- 28867557 TI - Imaging the spatial distribution of radiofrequency field, sample and temperature in MAS NMR rotor. AB - We investigate using nutation experiments the spatial distribution of radiofrequency (rf) field, sample, temperature and cross-polarization transfer efficiency in 1.3 mm rotor. First, two-dimensional (2D) 1H nutation experiments on silicone thin cylinders in the presence of B0 field gradient generated by shim coils are used to image the spatial distribution of rf field inside the rotor. These experiments show that the rf field is asymmetrical with respect to the center of the rotor. Moreover, they show the large inhomogeneity that still remains across the sample when using spacers, and that even in this case, the rf field close to the drive cap is decreased to ca. only 20% of its maximum value. Such 2D nutation experiment in the presence of B0 field gradient are also employed to demonstrate the migration of adamantane sample from the center of the rotor to its ends during Magic-Angle Spinning (MAS). Furthermore, 2D 1H nutation experiments on nickelocene exhibiting temperature-dependent isotropic chemical shift provides insights into the temperature distribution inside rotor. Finally three-dimensional (3D) 1H -> 13C Cross-Polarization under MAS (CPMAS) nutation experiment indicates that only nuclei subject to the largest rf field contribute to the CPMAS transfer, when using rf field of constant amplitude on both channels. Such high selectivity allows the determination of accurate dipolar coupling constants in the Cross-Polarization with Variable Contact (CP-VC) experiment under fast MAS, at the expense of low sensitivity. Conversely when using ramped-amplitude on the 1H channel during the CPMAS transfer, nuclei subject to smaller rf field contributes to the transfer, which increases the sensitivity of CPMAS experiment but does not allow an accurate determination of dipolar coupling constants using CP-VC experiment. PMID- 28867558 TI - Dose-volume histogram analysis of brainstem necrosis in head and neck tumors treated using carbon-ion radiotherapy. AB - BACKGROUND AND PURPOSE: We aimed to evaluate the relationship between brainstem necrosis and dose-volume histograms in patients with head and neck tumors after carbon-ion radiotherapy. MATERIAL AND METHODS: We evaluated 85 patients with head and neck tumors who underwent carbon-ion radiotherapy and were followed-up for >=12months. Brainstem necrosis was evaluated using the Common Terminology Criteria for Adverse Events (version 4.0). RESULTS: The median follow-up was 24months, and four patients developed grade 1 brainstem necrosis, with 2-year and 3-year cumulative rates of 2.8% and 6.5%, respectively. Receiver operating characteristic curve analysis revealed the following significant cut-off values: a maximum brainstem dose of 48Gy (relative biological effectiveness [RBE]), D1cm3 of 27Gy (RBE), V40Gy (RBE) of 0.1cm3, V30Gy (RBE) of 0.7cm3, and V20Gy (RBE) of 1.4cm3. Multivariate analysis revealed that V30Gy (RBE) was most significantly associated with brainstem necrosis. The 2-year cumulative rates were 33% and 0% for V30Gy (RBE) of >=0.7cm3 and <0.7cm3, respectively (p<0.001). CONCLUSIONS: The present study indicated that the dose constraints might help minimize brainstem necrosis after carbon-ion radiotherapy. PMID- 28867559 TI - Fighting back against the dilution of the Comprehensive Geriatric Assessment. PMID- 28867560 TI - Prevalence and characteristics of opioid-related deaths involving alcohol in Ontario, Canada. AB - BACKGROUND: While it is well known that patients receiving opioids should refrain from alcohol consumption, little is known about the involvement of alcohol in opioid-related deaths. METHODS: We conducted a population-based analysis of opioid-related deaths in Ontario with and without alcohol involvement between 1993 and 2013, and reported rates overall and stratified by manner of death. We compared the characteristics of individuals who died of an opioid overdose based on the presence or absence of alcohol involvement. RESULTS: The rate of opioid related deaths increased 288% from 11.9 per million (95% confidence interval (CI) 9.8-13.9 per million) in 1993-46.2 per million (95% CI 42.6-49.8 per million) in 2013. The rate of opioid-related deaths without alcohol involvement increased 388% from 7.4 per million to 36.1 per million, while deaths involving alcohol increased by 125% from 4.5 per million to 10.1 per million. Therefore, although the annual number of opioid-related deaths involving alcohol rose, the proportion of opioid-related deaths involving alcohol declined from 37.8% in 1993-21.9% by 2013. Generally, opioid-related deaths involving alcohol were less likely to involve other central nervous system depressants, and more likely to occur among men and those with a history of alcohol use disorder. CONCLUSIONS: Although the relative contribution of alcohol in opioid-related deaths has declined, 1 in 5 fatal opioid overdoses still involved alcohol in 2013. Our findings highlight the ongoing need for targeted messaging around risks of opioids alone, and in combination with alcohol and other CNS depressants. PMID- 28867561 TI - Depressive Symptoms and Low Sexual Desire after Radical Prostatectomy: Early and Long-Term Outcomes in a Real-Life Setting. AB - PURPOSE: We assessed the rate and predictors of depressive symptoms and impaired sexual desire in patients who underwent open or robot-assisted radical prostatectomy. MATERIALS AND METHODS: A total of 811 patients completed IIEF (International Index of Erectile Function) and BDI (Beck Depression Inventory) preoperatively, and 6, 12, 24 and 36 months postoperatively. Rates and predictors of depressive symptoms and impaired sexual desire were assessed with descriptive statistics and logistic regression models. RESULTS: We analyzed data on 416 patients treated with robot-assisted radical prostatectomy and 395 who underwent open radical prostatectomy. Overall the incidence of patients with postoperative BDI scores suggestive of depressive symptoms ranged between 26.3% at 6 months and 36.7% at 36 months. BDI scores were significantly higher in open than in robot assisted radical prostatectomy cases at every analyzed postoperative time point (all p <0.01). Patients treated with robot-assisted radical prostatectomy showed higher IIEF-EF (Erectile Function) domain scores and a greater proportion of them experienced erectile function recovery at each time point compared to those treated with open radical prostatectomy (all p <0.005). Postoperatively the rate of impaired sexual desire ranged between 40.9% at 6 months and 34.1% at 24 months. IIEF-SD (Sexual Domain) scores were significantly lower in open radical prostatectomy cases at every followup (all p <0.02). Age, open radical prostatectomy and postoperative erectile dysfunction were independent predictors of BDI scores and impaired sexual desire. CONCLUSIONS: One of 3 men surgically treated for prostate cancer still report depressive symptoms months after surgery. Patients who undergo robot-assisted radical prostatectomy reported lower depressive symptoms than those treated with open radical prostatectomy. Sexual desire was highly affected after radical prostatectomy with greater impairment reported by patients who underwent open radical prostatectomy. PMID- 28867562 TI - Long-Term Antitumor Activity and Safety of Enzalutamide Monotherapy in Hormone Naive Prostate Cancer: 3-Year Open Label Followup Results. AB - PURPOSE: A phase 2 study of enzalutamide monotherapy in patients with hormone naive prostate cancer demonstrated high prostate specific antigen response rates at 25 weeks, 1 year and 2 years with minimal effects on total body bone mineral density and favorable safety. In this followup analysis we evaluated enzalutamide antitumor activity and safety at 3 years. MATERIALS AND METHODS: In a single arm analysis 67 patients with hormone naive prostate cancer and noncastrate testosterone (230 ng/dl or greater) received enzalutamide 160 mg per day orally until disease progression or unacceptable toxicity. The primary end point was the prostate specific antigen response (80% or greater decline from baseline). RESULTS: No patients discontinued treatment during year 3. Of 42 patients with prostate specific antigen assessments at 3 years 38 (90.5%, 95% CI 77.4-97.3) maintained a prostate specific antigen response. Of 26 patients with metastases at baseline 17 (65.4%) had a complete or partial response as the best overall response during 3 years. In patients who completed the 3-year visit minimal mean changes from baseline were observed in total body bone mineral density or bone mineral density of the femoral neck, trochanter, spine L1-L4 or forearm (range 2.7% to -0.1%). At 3 years total body fat had increased a mean of 16.5%, total lean body mass had decreased a mean of -6.5% and global health status had minimally decreased from baseline. Common adverse events were gynecomastia, fatigue, hot flush and nipple pain. CONCLUSIONS: Enzalutamide antitumor activity was maintained in patients with hormone naive prostate cancer at 3 years. Overall bone mineral density, global health status and safety results were similar to those at 2 years. PMID- 28867563 TI - Expression and activation of Daphnia pulex Caspase-3 are involved in regulation of aging. AB - Death-mediating proteases such as Caspases have been implicated in aging. Remarkably, active Caspase-3 can trigger widespread damage and degeneration, playing a key role in causing cell death. In order to explore the relationship between Caspase-3 and aging in Daphnia pulex, we cloned and analyzed the full length cDNA sequence of its Caspase-3 gene. Both mRNA expression and activity of D. pulex Caspase-3 increased with age. Moreover, different forms of Caspase-3 appeared with aging. The expression of casp3-L was higher and decreased with age, while that of casp3-S was weak and increased with age, consistent with the trend in Caspase-3 activity. Mhc mRNA expression declined over time and was negatively correlated with age and Caspase-3. In situ hybridization results showed that Caspase-3 mRNA was expressed in different growth and reproduction stages, and its expression levels in embryos and larva were lower than that in adult D. pulex. Western blot analysis revealed the presence of Caspase-3 in the form of zymogens with a molecular weight of ~36kDa. Overall, this study explored age-associated gene regulation to provide a basis for the molecular mechanism of D. pulex reproductive conversion. PMID- 28867564 TI - Different histories of two highly variable LTR retrotransposons in sunflower species. AB - In the Helianthus genus, very large intra- and interspecific variability related to two specific retrotransposons of Helianthus annuus (Helicopia and SURE) exists. When comparing these two sequences to sunflower sequence databases recently produced by our lab, the Helicopia family was shown to belong to the Maximus/SIRE lineage of the Sirevirus genus of the Copia superfamily, whereas the SURE element (whose superfamily was not even previously identified) was classified as a Gypsy element of the Ogre/Tat lineage of the Metavirus genus. Bioinformatic analysis of the two retrotransposon families revealed their genomic abundance and relative proliferation timing. The genomic abundance of these families differed significantly among 12 Helianthus species. The ratio between the abundance of long terminal repeats and their reverse transcriptases suggested that the SURE family has relatively more solo long terminal repeats than does Helicopia. Pairwise comparisons of Illumina reads encoding the reverse transcriptase domain indicated that SURE amplification may have occurred more recently than that of Helicopia. Finally, the analysis of population structure based on the SURE and Helicopia polymorphisms of 32 Helianthus species evidenced two subpopulations, which roughly corresponded to species of the Helianthus and Divaricati/Ciliares sections. However, a number of species showed an admixed structure, confirming the importance of interspecific hybridisation in the evolution of this genus. In general, these two retrotransposon families differentially contributed to interspecific variability, emphasising the need to refer to specific families when studying genome evolution. PMID- 28867565 TI - Molecular mapping and genetic analysis of a QTL controlling spike formation rate and tiller number in wheat. AB - Spike formation rate (SR), which is based on maximum tiller number per unit area and spike number per unit area, is an important yield-related trait in wheat. Increasing the spike formation rate reduces growth competition and wastage of photosynthate from ineffective tillers. Unfortunately, research studies involving quantitative trait locus (QTL) mapping for wheat spike formation rate are limited. In the present study, a set of 371 recombinant inbreed line (RIL) population, which were derived from 1BL/LRS wheat-rye translocation lines CN18 and T1208, was analysed by simple sequence repeat (SSR) markers. Genetic analysis showed that a stable and major QTL (QSR.sicau-4D) for spike formation rate was localized to chromosome 4D and explained 18.24% and 24.48% of the observed phenotypic variance in 2015 and 2016, respectively. This QTL was closely linked to SSR marker Xcfd23, and the genetic distance between the flank markers was 3.28cM. Furthermore, QSR.sicau-4D might be a novel pleiotropic QTL, which also controlled maximum tiller number per unit area (QMTN.sicau-4D) and tiller number during pre-winter per unit area (QTNW.sicau-4D). The marker Xcfd23 associated with SR may be utilized in marker-assisted selection in wheat breeding. PMID- 28867566 TI - Activity analysis of LTR12C as an effective regulatory element of the RAE1 gene. AB - Ribonucleic acid export 1 (RAE1) plays an important role in the export of mature mRNAs from the nucleus to the cytoplasm. Long terminal repeats (LTRs) became integrated into the human genome during primate evolution. One such repeat element, LTR12C, lies within a predicted regulatory region located upstream of the RAE1 gene. We examined the transcriptional activity of LTR12C by using the luciferase assay, and showed that the tandem repeat region (TRR) located within LTR12C was required for its regulatory function. A bioinformatics analysis revealed that the LTR12C element had multiple transcription factor binding sites specific for nuclear transcription factor Y (NF-Y), and the promoter activity of LTR12C was significantly decreased after NF-Y knockdown. Additionally, we discovered novel data indicating that LTR12C was initially inserted into the gorilla genome. Taken together, our results reveal that the TRR of LTR12C has powerful regulatory activity due to its NF-Y binding sites, and the integration of the LTR12C element into the primate genome during evolution may have affected RAE1 transcription. PMID- 28867567 TI - Epilepsy & Behavior in social media: Top published papers in 2016. PMID- 28867568 TI - Psychogenic nonepileptic seizures in patients with surgically treated temporal lobe epilepsy: Presurgical and de novo postsurgical occurrence. AB - Whether occurring before or after an epilepsy surgery, psychogenic nonepileptic seizures (PNES) impact treatment options and quality of life of patients with epilepsy. We investigated the frequency of pre- and postsurgical PNES, and the postsurgical Engel and psychiatric outcomes in patients with drug-resistant temporal lobe epilepsy (TLE). We reviewed 278 patients with mean age at surgery of 37.1+/-12.4years. Postsurgical follow-up information was available in 220 patients, with average follow-up of 4years. Nine patients (9/278 or 3.2%) had presurgical documented PNES. Eight patients (8/220 or 3.6%) developed de novo PNES after surgery. Pre- and postsurgery psychiatric comorbidities were similar to the patients without PNES. After surgery, in the group with presurgical PNES, five patients were seizure-free, and three presented persistent PNES. In the group with de novo postsurgery PNES, 62.5% had Engel II-IV, and 37.5% had Engel I. All presented PNES at last follow-up. Presurgical video-EEG monitoring is crucial in the diagnosis of coexisting PNES. Patients presenting presurgical PNES and drug-resistant TLE should not be denied surgery based on this comorbidity, as they can have good postsurgical epilepsy and psychiatric outcomes. Psychogenic nonepileptic seizures may appear after TLE surgery in a low but noteworthy proportion of patients regardless of the Engel outcome. PMID- 28867569 TI - Quality of life one year after epilepsy surgery. AB - BACKGROUND: The aim of surgery for medically intractable epilepsy was to achieve seizure freedom and improve overall quality of life (QOL) in patients. This investigation looked at changes in QOL one year after epilepsy surgery and the relationship of changes to mood, language, and seizure outcomes. METHOD: Depressive symptoms, QOL, and naming were measured in 25 patients with temporal lobe epilepsy before and one year after dominant temporal lobe resection. The Quality of Life in Epilepsy-89 (QOLIE-89), Beck Depression Inventory II (BDI-II), and Boston Naming Test (BNT) were used, respectively, and seizure outcome was reported according to the Engel classifications. Minimum clinically important differences (MCID) and reliable change indices (RCI) were used to assess the proportion of patients who achieved meaningful improvement or worsening in the respective areas of functioning, and the relationship between outcomes was evaluated. Changes on the 17 individual items of the QOLIE-89 were also assessed. RESULTS: Overall, there was a significant improvement in QOL, reduction in depressive symptoms, and decline in naming one year after surgery. Positive clinically important improvement in QOL was achieved in 76% of patients, meaningful reduction of depressive symptoms was achieved in 20%, and clinically important naming declines were observed in 48% of the cohort. Sixteen patients were seizure-free one year after surgery, but there was no significant correlation between changes in QOL and seizure outcome, depressive symptoms, or naming. CONCLUSION: The results in the reported cohort of patients showed that surgical treatment of temporal lobe epilepsy in the dominant hemisphere resulted in clinically meaningful improvement in overall QOL and declines in naming but no significant reduction of mood disturbance. PMID- 28867570 TI - Epilepsy Foundation of the Netherlands (Stichting Epilepsie Instellingen Nederland [SEIN]), Heemstede and Zwolle, The Netherlands. PMID- 28867571 TI - Epilepsy Center Bethel, Bielefeld, Germany. PMID- 28867572 TI - Pharmacokinetic and pharmacodynamic interaction of hydroalcoholic extract of Ocimum sanctum with valproate. AB - For effective control of seizures, antiepileptic drugs (AEDs) are administered at higher dose which is associated with several adverse effects. This study envisaged antiepileptic and neuroprotective potential of Tulsi, a commonly used herb for its immunomodulatory property. The optimal dose of Ocimum sanctum hydroalcoholic extract (OSHE) was determined using maximal electroshock seizure (MES)- and pentylenetetrazol (PTZ)-induced seizure models in Wistar rats (200 250g) after administering OSHE (200-1000mg/kg) orally for 14days. For interaction study, OSHE optimal dose in combination with maximum and submaximal therapeutic doses of valproate was administered for 14days. Serum levels of valproate were estimated using HPLC for pharmacokinetic study. For pharmacodynamic interaction, antiepileptic effect on above seizure models, neurobehavioral effect using Morris water maze, passive avoidance and elevated plus maze tests, and antioxidant capacity were assessed. Ocimum sanctum hydroalcoholic extract 1000mg/kg was found to be optimal providing 50% protection against both MES- and PTZ-induced seizures. Combination of OSHE with valproate did not alter antiepileptic efficacy of valproate significantly. However, the combination showed better memory retention potential in neurobehavioral tests and protection against oxidative stress compared with valproate-alone-treated groups. Pharmacokinetic parameters did not reveal any significant change in combination group compared with valproate alone. Ocimum, although having per se antiepileptic action, did not affect antiepileptic action of valproate in combination. However, combination treatment has an edge over valproate alone-better neurobehavioral function and reduced oxidative stress-predicting adjuvant potential of Ocimum in epilepsy treatment. PMID- 28867573 TI - The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany. PMID- 28867574 TI - Decline in word-finding: The objective cognitive finding most relevant to patients after mesial temporal lobe epilepsy surgery. AB - PURPOSE: The purpose of this study was to investigate the following: i) the objective impairment in neuropsychological tests that were associated with the subjective perception of cognitive function decline in Brazilian patients who underwent mesial temporal lobe epilepsy (MTLE) surgery and ii) the predictive variables for those impaired objective neuropsychological tests. METHODS: Forty eight adults with MTLE (27 right HS and 23 male) were divided according to their perception of changes (Decline or No-decline) of cognitive function domain of the QOLIE-31 questionnaire applied before and 1year after the ATL. The mean (SD) of changes in the raw score difference of the neuropsychological tests before and after the ATL was compared between Decline and No-decline groups. Receiver Operating Characteristic curves, sensitivity, specificity, and predictive values were used to assess the optimum cutoff points of neuropsychological test score changes to predict patient-reported subjective cognitive decline. KEY FINDINGS: Six (12.5%) patients reported a perception of cognitive function decline after ATL. Among the 25 cognitive tests analyzed, only changes in the Boston Naming Test (BNT) were associated with subjective cognitive decline reported by patients. A reduction of >=8 points in the raw score of BNT after surgery had 91% of sensitivity and 45% specificity for predicting subjective perception of cognitive function decline by the patient. Left side surgery and age older than 40years were more associated with an important BNT reduction with overall accuracy of 91.7%, 95% predictive ability for no impairment, and 75% for impairment of cognitive function. SIGNIFICANCE: Impairment in word-finding seems to be the objective cognitive finding most relevant to Brazilian patients after mesial temporal lobe epilepsy surgery. Similar to American patients, the side of surgery and age are good predictors for no decline in the BNT, but shows a lower accuracy to predict its decline. If replicated in other populations, the results may have wider implications for the surgical management of patients with drug resistant MTLE. PMID- 28867575 TI - Filadelfia, Danish Epilepsy Center, Dianalund, Denmark. PMID- 28867576 TI - Neurocysticercosis-related epilepsy. PMID- 28867577 TI - Biological properties of cardiac mesenchymal stem cells in rats with diabetic cardiomyopathy. AB - : Cardiomyopathy is a major outcome in patients with diabetes mellitus (DM) and contributes to the high morbidity/mortality observed in this disease. AIMS: To evaluate several biological properties of cardiac mesenchymal stem cells (cMSCs) in a rat model of streptozotocin-induced DM with concomitant diabetic cardiomyopathy. MAIN METHODS: After 10weeks of DM induction, diabetic and control rats were assessed using ECG and ventricular hemodynamics monitoring. Then, the hearts were excised and processed for histology and for extracting non cardiomyocytic cells. A pool of these cells was plated for a colony forming units fibroblasts (CFU-F) assay in order to estimate the number of cMSCs. The remaining cells were expanded to assess their proliferation rate as well as their osteogenic and adipogenic differentiation ability. KEY FINDINGS: DM rats presented intense hyperglycemia and changes in ECG, LV hemodynamic, cardiac mass index and fibrosis, indicating presence of DCM. The CFU-F assay revealed a higher number of cardiac CFU-Fs in DM rats (10.4+/-1.1CFU-F/105 total cells versus 7.6+/ 0.7CFU-F/105 total cells in control rats, p<0.05), which was associated with a significantly higher proliferative rate of cMSCs in DM rats. In contrast, cMSCs from DM rats presented a lower capacity to differentiate into both osteogenic (20.8+/-4.2% versus 10.1+/-1.0% in control rats, p<0.05) and adipogenic lineages (4.6+/-1.0% versus 1.3+/-0.5% in control rats, p<0.05). SIGNIFICANCE: The findings suggest, for the first time, that in chronic DM rats with overt DCM, cMSCs increase in number and exhibit changes in several functional properties, which could be implicated in the pathogenesis of diabetic cardiomyopathy. PMID- 28867578 TI - Streptozotocin-induced hippocampal astrogliosis and insulin signaling malfunction as experimental scales for subclinical sporadic Alzheimer model. AB - AIMS: Insulin signaling malfunction has recently been suggested as a preliminary event involved in the etiology of Sporadic Alzheimer's disease (SAD). In order to develop insulin resistance-related SAD model, rats were treated with streptozotocin, intracerebroventricularly (icv-STZ). Nevertheless, given the lack of knowledge regarding sub-clinical stages of SAD, the current challenging issue is establishing a practical pre-clinical SAD model. Despite some proposed mechanisms, such as insulin malfunction, neuroinflammation, and gliosis, icv-STZ mechanism of action is not fully understood yet and Streptozotocin-induced rat model of Alzheimer has still major shortcomings. MAIN METHODS: Using three STZ doses (0.5, 1, and 3mg/kg) and three testing time (short-term, medium-term and long-term), we sought the best dose of STZ in order to mimic the characteristic feature of sAD in rats. So, we conducted a series of fifteen-week follow-up cognitive and non-cognitive studies. Besides, IR, tau and ChAT mRNA levels were measured, along with histological analysis of astrocyte, dark neuron numbers, and pyramidal layer thickness, in order to compare the effects of different doses of icv-STZ. KEY FINDINGS: STZ 3mg/kg caused cognitive and insulin signaling disturbance from the very first testing-time. STZ1-injected animals, however, showed an augmented hippocampal astrocyte numbers in a short time; they, also, were diagnosed with disturbed insulin signaling in medium-term post icv-STZ injection. Moreover, behavioral, molecular and histological impairments induced by 0.5mg/kg icv-STZ were slowly progressing in comparison to high doses of STZ. SIGNIFICANCE: STZ1 and 0.5mg/kg-treated animals are, respectively, suggested as a suitable experimental model of MCI, and sub-clinical stage. PMID- 28867579 TI - SOCS2 exacerbates myocardial injury induced by ischemia/reperfusion in diabetic mice and H9c2 cells through inhibiting the JAK-STAT-IGF-1 pathway. AB - AIMS: This study aimed to investigate potential candidates and molecular mechanisms of myocardial ischemia/reperfusion (I/R) injury (MIRI) in type 2 diabetes mellitus. MAIN METHODS: Type 2 diabetic and myocardial I/R mouse models were established with a high fat-diet (HFD) for 24weeks and subjecting to global ischemia/reperfusion for 1h/3h, respectively. Microarray analysis was applied to screen differentially expressed genes (DEGs) in the hearts of these mice. Moreover, H9c2 cells were treated with high glucose (HG) and/or hypoxia and reoxygenation (H/R). Subsequently, the expression of suppressor of cytokine signaling 2 (SOCS2) was knocked down by siRNA followed by the above treatments. Then, the cell lipid peroxidation and apoptosis-related indicators (malondialdehyde, MDA, and lactate dehydrogenase, LDH, cleaved-caspase-3; glucose regulated protein 78, GRP78;), Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway-related proteins (p-JAK2 and p-STAT5b) and insulin-like growth factor-1 (IGF-1) were detected. KEY FINDINGS: The mRNA levels of selected DEGs, such as Angptl4, Gadd45b, Rnf122 and SOCS2, showed a high degree of correlation with the microarray data. In addition, the levels of SOCS2, caspase-3, GRP78, LDH and MDA were increased, while the IGF-1 level was down-regulated in cells treated with HG and/or H/R compared to untreated cells (p<0.05). However, SOCS2 knockdown elevated the expression levels of IGF-1, p-JAK2 and p-STAT5b, as well as caspase-3, GRP78, LDH and MDA. SIGNIFICANCE: This research suggests that overexpressed SOCS2 might exacerbates MIRI in type 2 diabetes mellitus by inhibiting the expression of IGF-1 via the JAK-STAT signaling pathway. PMID- 28867580 TI - Ethanol potentiates heat response in the carotid artery via TRPV1. AB - AIM: Ethanol is one of the most widely used recreational drugs in the world. At high concentrations, it can induce carotid artery vasoconstriction. Hyperthermia potentiates its effects resulting in carotid artery vasoconstriction at any concentration. The aim of this study is to investigate the interaction between ethanol and heating and to understand the underlying mechanisms leading to their synergistic effect. MATERIALS AND METHODS: Isometric tension of rabbit carotid artery ring segments suspended in organ baths filled with Krebs solution was recorded. Different concentrations of ethanol were examined at 37 degrees C and during temperature elevation to39-43 degrees C. Capsaicin and capsazepine were used to examine the mechanism of action of ethanol. KEY FINDINGS: Ethanol induced contraction at 37 degrees C when the concentration reached 100mM. Contraction was observed at any concentration at higher temperatures. Ethanol potentiated heat induced contraction. Capsaicin, the vanilloid receptor subtype1 (TRPV1) agonist, potentiated the vasoconstriction due to heating. While capsazepine, TRPV1 antagonist, abolished the effect of ethanol and its potentiation of heating induced contraction, but it did not abolish the heating effect. SIGNIFICANCE: Ethanol's mechanism of action and its effect on heating induced-vasoconstriction of the carotid artery is being mediated by TRPV1. The combination of ethanol and hyperthermia can lead to a synergistic effect on carotid vasoconstriction. This effect may induce brain damage and heat stroke. Development of new drugs act as TRPV1 antagonist can be used to prevent these fatal effects. PMID- 28867581 TI - High pressure balloon dilatation of the ureterovesical junction in primary obstructive megaureter: Infectious morbidity. AB - INTRODUCTION: The objective of this study is to investigate the infectious morbidity associated with high-pressure balloon dilatation (HPBD) and an indwelling double J stent, in primary obstructive megaureter. METHODS: We reviewed the cases of 12 patients undergoing endoscopic treatment for primary obstructive megaureter from January 2012 to January 2015. The characteristics of the infection and data concerning the patient and the intervention were analyzed. RESULTS: The frequency of preoperative urinary tract infection (UTI) was 58%. The procedure was feasible in 100% of cases. Two patients required a second dilatation. One patient underwent Cohen's ureteral reimplantation after failure of the second dilatation. The frequency of postoperative UTI was 25%. All these infections occurred in patients with a double J stent. None of the patients had UTI after stent removal. None of the patients developed postoperative vesicoureteral reflux (VUR) after HPBD. CONCLUSION: Endoscopic balloon dilatation has been shown to have good short- mid- and long-term outcomes. In our experience, the morbidity of this procedure mostly results from infections, exclusively related to the use of a double J stent. The placement of a double J stent has a significant medical and economic impact. A definitive decision about the utility of double J stents will require studies of further dilatation without the placement of a double J stent. LEVEL OF EVIDENCE: 4. PMID- 28867582 TI - [Pathological findings of visible and non-visible tumors on multiparametric magnetic resonance imaging (MRI) prior to radical prostatectomy]. AB - INTRODUCTION: As urologists are questioned about the overtreatment of localized prostate cancer, multiparametric MRI can diagnose significant prostate cancer thanks to targeted biopsies. However, some tumors cannot be detected by MRI. What are the pathological characteristics of those tumors? MATERIALS AND METHODS: We have selected 144 consecutive patients treated with radical prostatectomy for clinically localized prostate cancer diagnosed on systematic and targeted biopsies (Koelis(r)) according to multiparametric MRI findings. On MRI, each suspicious area was graded according to the PI-RADS score v1.0. On radical prostatectomy specimen, tumor foci with a Gleason score greater than 3+3 and/or a tumor volume greater than 0,5cm3 were considered significant. The grade-four tumoral volume was calculated by multiplying the tumoral volume by grade 4 tumoral percentage. RESULTS: Two hundred and seventy seven tumors were identified. A hundred and thirty nine were non-visible on MRI. They had a significantly lower volume (0.15cm3 versus 1.45cm3, P<0.0001) and a Gleason score significantly lower (P<0.0001) than apparent tumors. 17.3% of non-apparent tumors were significant. Moreover, the grade-four tumoral volume of significant non apparent tumors was significantly lower than that of significant apparent tumors (0.11cm3 versus 0.66cm3, P<0.0001). CONCLUSION: Non-apparent prostate tumors on multiparametric MRI have a Gleason score, a tumor volume - and consequently - a grade 4 tumor volume significantly lower than apparent tumors. LEVEL OF PROOF: 4. PMID- 28867583 TI - [Hybrid operating room: For what?] AB - Hybrid operating rooms (HOR) are rooms that mix interventional radiology and surgical equipments. They are usually used in heart, vascular, orthopedic and neurosurgery, and make it possible to consider new minimally invasive procedures in urology. Thanks to these, we developed a new partial nephrectomy technique without renal pedicle clamping and without ischemia. Renal cancer is now diagnosed at localized stage in most of the cases, and its treatment is mostly based on nephron sparing surgery. However, the hemorrhagic character of this intervention requires a renal pedicle clamping whose long-term consequences on renal function are discussed. It also exposes to a classical complication: the renal artery pseudoaneurysm. Therefore, we developed a new laparoscopic partial nephrectomy technique without clamping or approach of renal pedicle, by a selective embolization of tumor vessels through an endovascular route, immediately before the surgery. HOR allowed the combination of the two procedures in the same time and space unit. Tumor staining by Bleu Patente also aids the surgeon in its spotting. HOR allow a new approach in localized renal cancer management, and should be used in many other urologic surgeries in years to come. They represent a technological advancement by combining interventional radiologists and surgeons' expertise. PMID- 28867584 TI - Coalition for Global Clinical Surgical Education: The Alliance for Global Clinical Training. AB - OBJECTIVE: Assessment of the effect of the collaborative relationship between the high-income country (HIC) surgical educators of the Alliance for Global Clinical Training (Alliance) and the low-income country surgical educators at the Muhimbili University of Health and Allied Sciences/Muhimbili National Hospital (MUHAS/MNH), Dar Es Salaam, Tanzania, on the clinical global surgery training of the HIC surgical residents participating in the program. DESIGN: A retrospective qualitative analysis of Alliance volunteer HIC faculty and residents' reports, volunteer case lists and the reports of Alliance academic contributions to MUHAS/MNH from 2012 to 2017. In addition, a survey was circulated in late 2016 to all the residents who participated in the program since its inception. RESULTS: Twelve HIC surgical educators provided rotating 1-month teaching coverage at MUHAS/MNH between academic years 2012 and 2017 for a total of 21 months. During the same time period 11 HIC residents accompanied the HIC faculty for 1-month rotations. HIC surgery residents joined the MUHAS/MNH Department of Surgery, made significant teaching contributions, performed a wide spectrum of "open procedures" including hand-sewn intestinal anastomoses. Most had had either no or limited previous exposure to hand-sewn anastomoses. All of the residents commented that this was a maturing and challenging clinical rotation due to the complexity of the cases, the limited resources available and the ethical and emotional challenges of dealing with preventable complications and death in a resource constrained environment. CONCLUSIONS: The Alliance provides an effective clinical global surgery rotation at MUHAS/MNH for HIC Surgery Departments wishing to provide such an opportunity for their residents and faculty. PMID- 28867585 TI - Protein phosphorylation and its role in the regulation of Annexin A2 function. AB - BACKGROUND: Annexin A2 (AnxA2) is a multifunctional protein involved in endocytosis, exocytosis, membrane domain organisation, actin remodelling, signal transduction, protein assembly, transcription and mRNA transport, as well as DNA replication and repair. SCOPE OF REVIEW: The current knowledge of the role of phosphorylation in the functional regulation of AnxA2 is reviewed. To provide a more comprehensive treatment of this topic, we also address in depth the phosphorylation process in general and discuss its possible conformational effects. Furthermore, we discuss the apparent limitations of the methods used to investigate phosphoproteins, as exemplified by the study of AnxA2. MAJOR CONCLUSIONS: AnxA2 is subjected to complex regulation by post-translational modifications affecting its cellular functions, with Ser11, Ser25 and Tyr23 representing important phosphorylation sites. Thus, Ser phosphorylation of AnxA2 is involved in the recruitment and docking of secretory granules, the regulation of its association with S100A10, and sequestration of perinuclear, translationally inactive mRNP complexes. By contrast, Tyr phosphorylation of AnxA2 regulates its role in actin dynamics and increases its association with endosomal compartments. Modification of its three main phosphorylation sites is not sufficient to discriminate between its numerous functions. Thus, fine-tuning of AnxA2 function is mediated by the joint action of several post-translational modifications. GENERAL SIGNIFICANCE: AnxA2 participates in malignant cell transformation, and its overexpression and/or phosphorylation is associated with cancer progression and metastasis. Thus, tight regulation of AnxA2 function is an integral aspect of cellular homeostasis. The presence of AnxA2 in cancer cell derived exosomes, as well as the potential regulation of exosomal AnxA2 by phosphorylation or other PTMs, are topics of great interest. PMID- 28867586 TI - Application of cation-modified sulfur nanoparticles as an efficient sorbent for separation and preconcentration of carbamazepine in biological and pharmaceutical samples prior to its determination by high-performance liquid chromatography. AB - A simple and rapid solid phase extraction procedure using a mini-column packed with modified sulfur nanoparticles as a new, efficient and reusable sorbent has been developed for the preconcentration of carbamazepine prior to its determination by high performance liquid chromatography. This method is based on the retention of carbamazepine by modified sulfur nanoparticles which are quite efficient for fast adsorption and desorption of carbamazepine. An HPLC system including C18, 250*4.6mm column, methanol-acidic water (pH=2.6 by acetic acid) (60:40) as mobile phase and UV detector (lambda=276nm) was used. The effects of multiple experimental conditions such as the effect of pH, type and volume of buffer, type and volume of eluent, sample and eluent flow rate, sorbent amount and interfering ions, on the analytical performance of the method were investigated. The calibration curve was linear in the range of 0.5-200ngmL-1 and LOD of the proposed method was found to be 0.16ngmL-1. The procedure was successfully applied for the determination of carbamazepine in pharmaceutical samples, human plasma and breast milk. PMID- 28867587 TI - Cerebellar pathology in childhood-onset vs. adult-onset essential tremor. AB - Although the incidence of ET increases with advancing age, the disease may begin at any age, including childhood. The question arises as to whether childhood onset ET cases manifest the same sets of pathological changes in the cerebellum as those whose onset is during adult life. We quantified a broad range of postmortem features (Purkinje cell [PC] counts, PC axonal torpedoes, a host of associated axonal changes [PC axonal recurrent collateral count, PC thickened axonal profile count, PC axonal branching count], heterotopic PCs, and basket cell rating) in 60 ET cases (11 childhood-onset and 49 adult-onset) and 30 controls. Compared to controls, childhood-onset ET cases had lower PC counts, higher torpedo counts, higher heterotopic PC counts, higher basket cell plexus rating, and marginally higher PC axonal recurrent collateral counts. The median PC thickened axonal profile count and median PC axonal branching count were two to five times higher in childhood-onset ET than controls, but the differences did not reach statistical significance. Childhood-onset and adult-onset ET had similar PC counts, torpedo counts, heterotopic PC counts, basket cell plexus rating, PC axonal recurrent collateral counts, PC thickened axonal profile count and PC axonal branching count. In conclusion, we found that childhood-onset and adult-onset ET shared similar pathological changes in the cerebellum. The data suggest that pathological changes we have observed in the cerebellum in ET are a part of the pathophysiological cascade of events in both forms of the disease and that both groups seem to reach the same pathological endpoints at a similar age of death. PMID- 28867588 TI - Light deprivation produces distinct morphological orchestrations on RGCs and cortical cells in a depressive-like YFP-H mouse model. AB - Neural physiological functions and synaptic changes underlying the pathogenesis of depression have obtained great achievements. However, neuronal morphological changes under a depressive state have not been well understood yet. Here a depressive-like YFP-H transgenic mouse model was produced by light deprivation (LD), and morphological changes of retinal ganglion cells (RGCs) and primary visual and auditory cortical layer 5 pyramidal cells (L5PCs) were investigated. Three distinct RGC subtypes were identified based on soma- and dendritic field (DF) size. RGA cells were highlighted by large soma and medium-sized to large DF. RGB cells were characterized by small- to medium-sized soma and small- to medium sized DF. RGC cells were typical of small- to medium-sized soma and large DF. LD showed cell-type-specific morphological orchestrations on RGCs and predominantly promoted the dendritic growth of RGA cells, leaving no significant effect on RGB and RGC cells. LD produced a consistently suppressed effect on the morphology of primary visual and auditory cortical L5PCs. LD enhanced the dendritic spine density of primary visual cortical L5PCs, implying a compensation mechanism underlying morphological changes in individual cortical L5PCs. The increased morphological complexity of RGA cells and the simplified morphology of cortical L5PCs suggest a broad range of neuronal morphological "cross-modal plasticity" among different brain areas. Our observations in morphological changes of RGCs and cortical L5PCs under a depressive-like state will provide some insights into the pathogenesis of depression at a single neuronal morphological level. PMID- 28867589 TI - Maternal swimming exercise during pregnancy attenuates anxiety/depressive-like behaviors and voluntary morphine consumption in the pubertal male and female rat offspring born from morphine dependent mothers. AB - This study was designed to examine whether maternal swimming exercise during pregnancy would attenuate prenatally morphine-induced anxiety, depression and voluntary consumption of morphine in the pubertal male and female rat offspring. Pregnant rats during the development of morphine dependence were allowed to swim (30-45min/d, 3days per a week) on gestational days 11-18. Then, the pubertal male and female rat offspring were tested for the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that male and female rat offspring born of the swimmer morphine-dependent mothers exhibited an increase in EPM open arm time and entries, higher levels of sucrose preference than their sedentary control mothers. Voluntary consumption of morphine was less in the male and female rat offspring born of the swimmer morphine-dependent mothers as compared with their sedentary control mothers during three periods of the intake of drug. Thus, swimming exercise in pregnant morphine dependent mothers decreased anxiety, depressive-like behavior and also the voluntary morphine consumption in the pubertal male and female offspring, which may prevent prenatally morphine-induced behavioral sensitization in offspring. PMID- 28867590 TI - Grip force control and hand dexterity are impaired in individuals with diabetic peripheral neuropathy. AB - Diabetic peripheral neuropathy (DPN) affects the sensory function of the hands and, consequently, may negatively impact hand dexterity, maximum grip strength (GSMax), and hand grip force (GF) control during object manipulation. The aims of this study were to examine and compare the GF control during a simple holding task as well as GSMax and hand dexterity of individuals with DPN and healthy controls. Ten type 2 diabetic individuals diagnosed with DPN and ten age- and gender-matched healthy controls performed two traditional timed hand dexterity tests (i.e., nine-hole peg test and Jebsen-Taylor hand function test), a GSMax test, and a GF control test (i.e., hold a instrumented handle). The results indicated that individuals with DPN and controls produced similar GSMax. However, individuals with DPN took longer to perform the hand dexterity tests and set lower safety margin (exerted lower GF) than controls when holding the handle. The findings showed that mild to moderate DPN did not significantly affect maximum hand force generation, but does impair hand dexterity and hand GF control, which could impair the performance of daily living manipulation tasks and put them in risk of easily dropping handheld objects. PMID- 28867592 TI - Prevalence of Cryptosporidium species and subtypes in paediatric oncology and non oncology patients with diarrhoea in Jordan. AB - Cryptosporidiosis is a protozoan parasitic disease which affects human and animals worldwide. In adult immunocompetent individuals, cryptosporidiosis usually results in acute and self-limited diarrhoea; however, it can cause life threatening diarrhoea in children and immunocompromised individuals. In the present study, we compared the prevalence of Cryptosporidium species and gp60 subtypes amongst paediatric oncology patients with diarrhoea (n=160) from King Hussein Medical Centre for Cancer in Jordan, and non-oncology paediatric patients with diarrhoea (n=137) from Al-Mafraq paediatric hospital. Microscopy results using modified acid fast staining identified a significantly (p<=0.05) higher prevalence of Cryptosporidium in paediatric oncology patients with diarrhoea (14.4% - 23/160), compared to non-oncology paediatric patients with diarrhoea only (5.1% - 7/137). With the exception of one sample, all microscopy-positive samples (n=29) and an additional 3/30 microscopy-negative controls were typed to species and subtype level at the 18S and gp60 loci, respectively. All Cryptosporidium positives were typed as C. parvum. Of the 22 typed Cryptosporidium positives from the paediatric oncology patients, 21 were subtyped as IIaA17G2R1 and one as IIaA16G2R1 C. parvum subtypes. The 7 typed positives from the paediatric patients from Al-Mafraq hospital were subtyped as IIaA17G2R1 (n=5) and IIaA16G2R1 (n=2). The 3 additional positives from the 30 microscopy negative control samples were subtyped as IIaA17G2R1. The high prevalence of the IIaA17G2R1 subtype, particularly amongst oncology patients, suggests that an outbreak of cryptosporidiosis may have been occurring in oncology patients during the collection period (April to December, 2016). New therapies for cryptosporidiosis in immunocompromised patients are urgently required. PMID- 28867591 TI - Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced nitric oxide production and vasorelaxation in rabbit mesenteric arteries. AB - Stimulation of calcium-sensing receptors (CaSR) by increasing the external calcium concentration (Ca2+]o) induces endothelium-dependent vasorelaxation through nitric oxide (NO) production and activation of intermediate Ca2+ activated K+ currents (IKCa) channels in rabbit mesenteric arteries. The present study investigates the potential role of heteromeric TRPV4-TRPC1 channels in mediating these CaSR-induced vascular responses. Immunocytochemical and proximity ligation assays showed that TRPV4 and TRPC1 proteins were expressed and co localised at the plasma membrane of freshly isolated endothelial cells (ECs). In wire myography studies, increasing [Ca2+]o between 1 and 6mM induced concentration-dependent relaxations of methoxamine (MO)-induced pre-contracted tone, which were inhibited by the TRPV4 antagonists RN1734 and HC067047, and the externally-acting TRPC1 blocking antibody T1E3. In addition, CaSR-evoked NO production in ECs measured using the fluorescent NO indicator DAF-FM was reduced by RN1734 and T1E3. In contrast, [Ca2+]o-evoked perforated-patch IKCa currents in ECs were unaffected by RN1734 and T1E3. The TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent relaxation of MO-evoked pre-contracted tone and increased NO production, which were inhibited by the NO synthase inhibitor L NAME, RN1734 and T1E3. GSK activated 6pS cation channel activity in cell-attached patches from ECs which was blocked by RN1734 and T1E3. These findings indicate that heteromeric TRPV4-TRPC1 channels mediate CaSR-induced vasorelaxation through NO production but not IKCa channel activation in rabbit mesenteric arteries. This further implicates CaSR-induced pathways and heteromeric TRPV4-TRPC1 channels in regulating vascular tone. PMID- 28867593 TI - Brucella suis biovar 2 multi locus sequence type ST16 in wild boars (Sus scrofa) from Abruzzi region, Italy. Introduction from Central-Eastern Europe? AB - Porcine brucellosis occurs in many countries where pigs are farmed, often representing an underrated problem. B. suis biovar 2 is the most common isolate in Europe, with high prevalence reported in wild boars in which it is generally isolated in the absence of gross lesions. In the last five years, we tested for Brucella spp. 389 lymph nodes of wild boars collected during hunting seasons or during necropsy procedures. In this paper, we describe the first case of isolation of B. suis biovar 2 from a wild boar aborted foetus, and we analyse the genomic relationships with B.suis biovar 2 strains isolated in the past five years in Abruzzi Region, Central Italy. The genetic fingerprint revealed that the isolates under study belong to the MLST ST16 and to the MLVA11 Gt 57, similar to the Central-Eastern European strains. Massive restocking (for hunting purpose) of wild boars from Eastern Europe have been done since 1950 in Italy contributing to the increasing of population size and distribution, as well as to the interbreeding between these foreign breeds and the local population. The contamination of pastures with infected material such as aborted wild boars foetuses can increase the risk of transmission of Brucella among wild and domestic animals. The contact of B. suis with domestic ruminants may also cause serological reactions to brucellosis serological testing, and even unapparent infection, thus hampering the efforts made in the brucellosis eradication campaign. PMID- 28867594 TI - Serotype and MLST-based inference of population structure of clinical Streptococcus pneumoniae from invasive and noninvasive pneumococcal disease. AB - Streptococcus pneumoniae is an important human pathogen causing various diseases. In this study, S. pneumoniae from invasive (IPD) and noninvasive pneumococcal disease (NIPD) were studied by serotype and multilocus sequence typing (MLST) for population structure characteristics. A total of 169 clinical S. pneumoniae, containing 63 IPD and 106 NIPD strains, were analyzed. 19F, 19A, 6A, 6B, 1, 14 and 23F were the dominant serotypes in both IPD and NIPD strains. By MLST, 169 strains were divided into 85 sequence types (STs) with an index of discrimination (IOD) value of 0.9606. The seven predominant STs were ST271, ST320, ST876, ST3173, ST236, ST81 and ST342, which were mainly associated with serotypes 19F, 19A, 14, 6A, 19F, 1, and 1/23F, respectively. The 63 IPD strains were divided into 20 serotypes (IOD=0.9135) and 44 STs (IOD=0.9795); the 106 NIPD strains were divided into 16 serotypes (IOD=0.8334) and 49 STs (IOD=0.9430). In conclusion, the serotypes and ST distribution of IPD and NIPD strains analyzed in this study are similar to the profiles observed in other cities of China, suggesting that the clinical S. pneumoniae isolates were derived from clones generally circulating in China. The strains showed a variety of serotypes and STs, and the IPD strains showed higher serotype and genetic diversity than NIPD strains. PMID- 28867595 TI - Mitochondrial Ferredoxin Determines Vulnerability of Cells to Copper Excess. AB - The essential micronutrient copper is tightly regulated in organisms, as environmental exposure or homeostasis defects can cause toxicity and neurodegenerative disease. The principal target(s) of copper toxicity have not been pinpointed, but one key effect is impaired supply of iron-sulfur (FeS) clusters to the essential protein Rli1 (ABCE1). Here, to find upstream FeS biosynthesis/delivery protein(s) responsible for this, we compared copper sensitivity of yeast-overexpressing candidate targets. Overexpression of the mitochondrial ferredoxin Yah1 produced copper hyper-resistance. 55Fe turnover assays revealed that FeS integrity of Yah1 was particularly vulnerable to copper among the test proteins. Furthermore, destabilization of the FeS domain of Yah1 produced copper hypersensitivity, and YAH1 overexpression rescued Rli1 dysfunction. This copper-resistance function was conserved in the human ferredoxin, Fdx2. The data indicate that the essential mitochondrial ferredoxin is an important copper target, determining a tipping point where plentiful copper supply becomes excessive. This knowledge could help in tackling copper-related diseases. PMID- 28867596 TI - Relationship between aluminum stress and caffeine biosynthesis in suspension cells of Coffea arabica L. AB - Toxicity by aluminum is a growth-limiting factor in plants cultivated in acidic soils. This metal also promotes signal transduction pathways leading to the biosynthesis of defense compounds, including secondary metabolites. In this study, we observed that Coffea arabica L. cells that were kept in the dark did not produce detectable levels of caffeine. However, irradiation with light and supplementation of the culture medium with theobromine were the best conditions for cell maintenance to investigate the role of aluminum in caffeine biosynthesis. The addition of theobromine to the cells did not cause any changes to cell growth and was useful for the bioconversion of theobromine to caffeine. During a short-term AlCl3-treatment (500MUM) of C. arabica cells kept under light irradiation, increases in the caffeine levels in samples that were recovered from both the cells and culture media were evident. This augmentation coincided with increases in the enzyme activity of caffeine synthase (CS) and the transcript level of the gene encoding this enzyme (CS). Together, these results suggest that actions by Al and theobromine on the same pathway lead to the induction of caffeine biosynthesis. PMID- 28867597 TI - Overexpression of suppressors of cytokine signaling 1 regulate the proliferation and differentiation of rat-derived neural stem cells. AB - Neural stem cells are a reliable resource in various neural tissue repair and neurodegenerative diseases. Increasing evidence has demonstrated that Suppressor of cytokine signaling proteins (SOCS) was involved in the nervous system development. The universality and diversity of SOCS also suggested their important roles in neurogenesis and nerve regeneration. In this study, we employed a lentiviral vector to investigate the impacts of overexpression SOCS1 on the proliferation and differentiation of rat-derived NSCs. Cells infected with LV-EGFP-SOCS1 showed a prominent increased cell number, diameter, and metabolic activity compared with other groups. Immunofluorescence analysis revealed the proportion of cells positive for microtubule associated protein-2 (MAP2) or myelin basic protein (MBP) was significantly increased in LV-EGFP-SOCS1 group while the proportion of glial fibrillary acidic protein (GFAP)-positive cells in LV-EGFP-SOCS1 group was significantly decreased compare to LV-EGFP and PBS group. Moreover, Western blot results were consistent with immunofluorescence results which indicated that overexpression of SOCS1 could promote neuronal and oligodendrocyte differentiations of NSCs but inhibit astrocyte differentiation of NSCs. In conclusion, our findings provided evidence that SOCS1 could promote the proliferation of NSCs and affect the differentiation of NSCs, providing a potential target for NSCs transplantation strategies. PMID- 28867598 TI - Intracranial and hierarchical perspective on dietary plasticity in mammals. AB - The effect of dietary properties on craniofacial form has been the focus of numerous functional studies, with increasingly more work dedicated to the importance of phenotypic plasticity. As bone is a dynamic tissue, morphological variation related to differential loading is well established for many masticatory structures. However, the adaptive osteogenic response of several cranial sites across multiple levels of bony organization remains to be investigated. Here, rabbits were obtained at weaning and raised for 48 weeks until adulthood in order to address the naturalistic influence of altered loading on the long-term development of masticatory and non-masticatory elements. Longitudinal data from micro-computed tomography (MUCT) scans were used to test the hypothesis that variation in cortical bone formation and biomineralization in masticatory structures is linked to increased stresses during oral processing of mechanically challenging foods. It was also hypothesized that similar parameters for neurocranial structures would be minimally affected by varying loads as this area is characterized by low strains during mastication and reduced hard-tissue mechanosensitivity. Hypotheses were supported regarding bone formation for maxillomandibular and neurocranial elements, though biomineralization trends of masticatory structures did not mirror macroscale findings. Varying osteogenic responses in masticatory elements suggest that physiological adaptation, and corresponding variation in skeletal performance, may reside differentially at one level of bony architecture, potentially affecting the accuracy of behavioral and in silico reconstructions. Together, these findings underscore the complexity of bone adaptation and highlight functional and developmental variation in determinants of skull form. PMID- 28867599 TI - The postoperative venous thromboembolism (TREVO) study - risk and case mortality by surgical specialty. AB - INTRODUCTION AND OBJECTIVES: Venous thromboembolism, risk of which is increased in surgical patients, is a preventable cause of morbidity and death. The primary objective of this study was to estimate the incidence of symptomatic postoperative venous thromboembolism in adults at a tertiary university hospital, overall and by surgical specialty. The secondary objective was to analyze severity of and mortality from thromboembolic events. METHODS: We performed a retrospective study to identify cases of in-hospital postoperative venous thromboembolism, encoded by the International Classification of Diseases, Ninth Revision, according to the Joint Commission International criteria. Adult patients admitted for surgery in 2008-2012 were included. RESULTS: Among 67 635 hospitalizations, 90 cases of postoperative symptomatic venous thromboembolism were identified, corresponding to an incidence of 1.33/1000 admissions (95% confidence interval [CI] 1.1-1.6/1000). Neurosurgery had the highest risk (4.07/1000), followed by urological surgery and general surgery (p<0.001). There were 50 cases of pulmonary embolism, 11 of which were fatal. Of the 90 cases, 12.2% occurred under neuraxial anesthesia and 55.1% in patients with American Society of Anesthesiology III physical status. At least 37.7% of patients with events received a prophylactic dose of injectable anticoagulant postoperatively. The overall risk decreased from 2008 to 2012. Venous thromboembolism-associated mortality during hospitalization was 21.1% (95% CI 13.6-30.4). CONCLUSIONS: The incidence of postoperative symptomatic venous thromboembolism was 1.33/1000. Neurosurgery showed the greatest risk. Mortality was 21.1%. PMID- 28867600 TI - Mission (almost) impossible. PMID- 28867601 TI - Hydralazine vs nifedipine for acute hypertensive emergency in pregnancy: a randomized controlled trial. AB - BACKGROUND: There is a paucity of good quality evidence regarding the best therapeutic option for acute control of blood pressure during acute hypertensive emergency of pregnancy. OBJECTIVE: We sought to compare the efficacy of intravenously administered hydralazine and oral nifedipine for acute blood pressure control in acute hypertensive emergency of pregnancy. STUDY DESIGN: In this double-blind, randomized, controlled trial, pregnant women (>=24 weeks period of gestation) with sustained increase in systolic blood pressure of >=160 mm Hg or diastolic blood pressure of >=110 mm Hg were randomized to receive intravenous hydralazine injection in doses of 5, 10, 10, and 10 mg and a placebo tablet or oral nifedipine (10 mg tablet up to 4 doses) and intravenous saline injection every 20 minutes until the target blood pressure of 150 mm Hg systolic and <=100 mm Hg diastolic was achieved. Crossover treatment was administered if the initial treatment failed. The primary outcome of the study was time necessary to achieve target blood pressure. The secondary outcomes were the number of dosages required, adverse maternal and neonatal effects, and perinatal outcome. RESULTS: From December 2014 through September 2015, we enrolled 60 patients. The median time to achieve target blood pressure was 40 minutes in both groups (intravenous hydralazine and oral nifedipine) (interquartile interval 5 and 40 minutes, respectively, P = .809). The median dose requirement in both groups was 2 (intravenous hydralazine and oral nifedipine) (interquartile range 1 and 2 doses, respectively, P = .625). Intravenous hydralazine was associated with statistically significantly higher occurrence of vomiting (9/30 vs 2/30, respectively, P = .042). No serious adverse maternal or perinatal side effects were witnessed in either group. CONCLUSION: Both intravenous hydralazine and oral nifedipine are equally effective in lowering of blood pressure in acute hypertensive emergency of pregnancy. PMID- 28867602 TI - A phase-3, double-blind, placebo-controlled study of the effectiveness and safety of single oral doses of secnidazole 2 g for the treatment of women with bacterial vaginosis. AB - BACKGROUND: A novel single oral dose granule formulation of secnidazole 2 g, a 5 nitroimidazole with a longer half-life (~17 hours) than metronidazole (~8 hours), is being developed to treat bacterial vaginosis. OBJECTIVE: We sought to evaluate the effectiveness and safety of single-dose secnidazole 2 g compared to placebo for the treatment of women with bacterial vaginosis. STUDY DESIGN: In all, 189 women with bacterial vaginosis were randomized 2:1 to receive a single oral dose of secnidazole 2 g (N = 125) or matched placebo (N = 64) at 21 centers in the United States. The primary endpoint was the proportion of clinical outcome responders, defined as those with: (1) normal vaginal discharge; (2) negative 10% potassium hydroxide whiff test; and (3) <20% clue cells of total epithelial cell count on microscopic examination of the vaginal wet mount, using saline at the test of cure/end of study visit (study days 21-30). Secondary efficacy analyses included clinical cure rates, defined as: (1) responders with normal discharge or abnormal discharge not consistent with bacterial vaginosis after treatment; (2) negative potassium hydroxide whiff tests; and (3) clue cells <20% assessed at the interim visit (study days 7-14), and test of cure/end of study (study days 21 30). In addition, based on the 2016 US Food and Drug Administration draft guidance, patients with baseline Nugent scores 7-10 were evaluated for clinical cure using the following clinical assessments on study days 7-14: (1) resolution of the abnormal vaginal discharge; (2) a negative potassium hydroxide whiff test; and (3) clue cells <20%. The study was designed and powered to demonstrate the efficacy of single-dose secnidazole 2 g compared to placebo; safety and tolerability were also assessed. Due to a prespecified institutional review board approved protocol calling for withdrawal of randomized, treated patients with a Nugent score <4 or with a separate sexually transmitted infection, this modified intent-to-treat population was the primary analysis population. Statistical comparisons used a stratified Cochran-Mantel-Haenszel test with a .05 level of significance (2-sided). RESULTS: Single-dose secnidazole 2 g was superior to placebo for the primary and all secondary efficacy measures in the modified intent-to-treat population, with clinical outcome responder rates of 53.3% (57/107) vs 19.3% (11/57; P < .001). Clinical cure rates, based on an alternate definition of responder, which accounted for resolution of abnormal discharge consistent with bacterial vaginosis, were consistent with the clinical outcome responder rate analysis (58.9% vs 24.6%; P < .001) for single-dose secnidazole 2 g vs placebo. Clinical cure rates based on the 2016 US Food and Drug Administration guidance were 64.0% vs 26.4% for single-dose secnidazole 2 g vs placebo. Based on the investigator's clinical assessment at the test of cure/end of study visit, significantly more patients receiving single-dose secnidazole 2 g vs placebo required no additional bacterial vaginosis treatment (68.0% [68/100] vs 29.6% [16/54]; P < .001). Adverse events considered by the investigator to be related to study drug occurred in only 20.0% of single-dose secnidazole 2 g treated patients vs 10.9% of placebo patients, and they included diarrhea (4.0% vs 1.6%), headache (4.0% vs 3.1%), nausea (4.8% vs 1.6%), and vulvovaginal candidiasis (4.0% vs 3.1%). CONCLUSION: Single-dose secnidazole 2 g was superior to placebo on all primary and secondary outcomes and was well tolerated; these results support its role for the treatment of women with bacterial vaginosis. PMID- 28867603 TI - Molecular Signatures for Tumor Classification: An Analysis of The Cancer Genome Atlas Data. AB - Cancer classification in the clinic is primarily based on histological analysis in the proper clinical context, often supplemented by immunohistochemical and molecular studies. Recent genomic studies have shown the potential of integrated multiomics platforms for molecular classification. We performed unsupervised analyses of molecular platforms in The Cancer Genome Atlas data (n = 6,216 samples) in comparison with tumor type. Our data showed that mRNA signatures and DNA methylation signatures mapped to histological diagnosis with high accuracy (95% and 88%, respectively) as individual platforms. The accuracy of mRNA signatures alone for classification and subtype identification was comparable to accuracies reported in the previously published Pan-Cancer 12 analysis. When combined, mRNA and methylation revealed a set of outliers for which the mRNA- and methylation-based molecular signatures concordantly differed from the original histological diagnosis. A subset remained consistent as outliers after using alternative classification and clustering algorithms and analysis of an independent molecular platform (miRNA). Overall, our results indicate that unsupervised approaches with individual genomic platforms, especially gene expression and DNA methylation, provide substantial classification information and identify occasional outlier cases in which the molecular signature is distinct from signatures expected for a given histological diagnosis. Identification of cases in which the molecular signature correlates with a specific histology that differs from initial impressions may prompt reconsideration of tumor classification in specific cases. PMID- 28867604 TI - Characterization and Genomic Localization of a SMAD4 Processed Pseudogene. AB - Like many clinical diagnostic laboratories, the Yorkshire Regional Genetics Service undertakes routine investigation of cancer-predisposed individuals by high-throughput sequencing of patient DNA that has been target-enriched for genes associated with hereditary cancer. Accurate diagnosis using such reagents requires alertness regarding rare nonpathogenic variants that may interfere with variant calling. In a cohort of 2042 such cases, we identified 5 that initially appeared to be carriers of a 95-bp deletion of SMAD4 intron 6. More detailed analysis indicated that these individuals all carried one copy of a SMAD4 processed gene. Because of its interference with diagnostic analysis, we characterized this processed gene in detail. Whole-genome sequencing and confirmatory Sanger sequencing of junction PCR products were used to show that in each of the 5 cases, the SMAD4 processed gene was integrated at the same position on chromosome 9, located within the last intron of the SCAI gene. This rare polymorphic processed gene therefore reflects the occurrence of a single ancestral retrotransposition event. Compared to the reference SMAD4 mRNA sequence NM_005359.5 (https://www.ncbi.nlm.nih.gov/nucleotide), the 5' and 3' untranslated regions of the processed gene are both truncated, but its open reading frame is unaltered. Our experience leads us to advocate the use of an RNA-seq aligner as part of diagnostic assay quality assurance, since this allows recognition of processed pseudogenes in a comparatively facile automated fashion. PMID- 28867605 TI - High-Throughput and Sensitive Quantification of Circulating Tumor DNA by Microfluidic-Based Multiplex PCR and Next-Generation Sequencing. AB - Circulating tumor DNA (ctDNA) has potential to serve as a biomarker for noninvasive monitoring of treatment response and disease progression. However, broad clinical applicability of ctDNA has been limited by the low sensitivity, throughput, and patient coverage offered by existing ctDNA detection methods. Herein, we report the adaptation and characterization of the microfluidics multiplex PCR sequencing technology for high-throughput and sensitive quantitation of ctDNA. A multiplex PCR preamplification step was developed and incorporated into the microfluidics multiplex PCR sequencing work flow to enable low-input ctDNA analysis with enhanced sensitivity. An empirical bayesian model was developed to characterize both position and substitution-associated system errors specific to this platform and provided a tailored approach to greatly enhance the confidence and accuracy of variant calling for ctDNA analysis. Clinical validation of this platform for ctDNA mutation detection demonstrated an overall sensitivity of 92% and specificity of 100% when using mutation calls in the matched tumor tissues as a benchmark. Finally, we established an early proof of concept of clinical utility of this ctDNA work flow for monitoring disease progression using clinical trial samples. Our novel ctDNA work flow provides a high-throughput and sensitive platform that can be implemented in clinical trials for mutation detection and disease monitoring from plasma ctDNA. PMID- 28867607 TI - Tanshinone IIA ameliorates apoptosis of myocardiocytes by up-regulation of miR 133 and suppression of Caspase-9. AB - To explore the potential protective effect of Tanshinone IIA on myocardial cell apoptosis and elucidate the underlying molecular mechanisms. The rat heart cell H9c2 was treated by either H2O2 or doxorubicin (DOX) to mimic oxidative stress and DNA damage conditions in vivo. Cell growth was monitored by optical microscope observation or CCK-8 counting kit. The relative expression of miR-133 and U6 snoRNA was semi-quantitated by RT-PCR or real-time PCR. Cell apoptosis was analyzed by flow cytometry with Annexin V/PI double staining. The microRNA binding sites were predicted by online bioinformatics tools. The regulatory effect of miR-133 on caspase-9 was measured by luciferase reporter assay. Apoptosis pathway factors were analyzed by immunoblotting. Our data demonstrated that Tanshinone IIA significantly ameliorated myocardial apoptosis induced by either H2O2 or DOX. The protective effect was likely mediated by up-regulation of miR-133. We further identified Caspase-9 as the target of miR-133. Tanshinone IIA treatment significantly reversed down-regulation of miR-133 under harsh conditions and in turn suppressed evoking of Caspase-9 and related apoptotic effectors, which consequently contributed to the improvement of myocardial injury. In conclusion, Tanshinone IIA ameliorated myocardial apoptosis via restoration of miR-133 and suppression Caspase-9 signaling cascade, which underlies its well-proven clinical benefit and warrants larger scale clinical applications. PMID- 28867606 TI - Similar precipitated withdrawal effects on intracranial self-stimulation during chronic infusion of an e-cigarette liquid or nicotine alone. AB - The FDA recently extended their regulatory authority to electronic cigarettes (ECs). Because the abuse liability of ECs is a leading concern of the FDA, animal models are urgently needed to identify factors that influence the relative abuse liability of these products. The ability of tobacco products to induce nicotine dependence, defined by the emergence of anhedonia and other symptoms of nicotine withdrawal following cessation of their use, contributes to tobacco abuse liability. The present study compared the severity of precipitated withdrawal during chronic infusion of nicotine alone or nicotine-dose equivalent concentrations of three different EC refill liquids in rats, as indicated by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Because these EC liquids contain constituents that may enhance their abuse liability (e.g., minor alkaloids), we hypothesized that they would be associated with greater withdrawal effects than nicotine alone. Results indicated that the nicotinic acetylcholine receptor antagonist mecamylamine precipitated elevations in ICSS thresholds in rats receiving a chronic infusion of nicotine alone or EC liquids (3.2mg/kg/day, via osmotic pump). Magnitude of this effect did not differ between formulations. Our findings indicate that nicotine alone is the primary CNS determinant of the ability of ECs to engender dependence. Combined with our previous findings that nicotine alone and these EC liquids do not differ in other preclinical addiction models, these data suggest that product standards set by the FDA to reduce EC abuse liability should primarily target nicotine, other constituents with peripheral sensory effects (e.g. flavorants), and factors that influence product appeal (e.g., marketing). PMID- 28867608 TI - Activation of PPARgamma inhibits HDAC1-mediated pulmonary arterial smooth muscle cell proliferation and its potential mechanisms. AB - The downstream targets of histone deacetylase 1 (HDAC1) mediation of platelet derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and it is also unknown whether activation of peroxisome proliferator-activated receptor gamma (PPARgamma) modulates HDAC1 and its down-stream targets in PASMCs. The present study aims to address these issues. Our results showed that PDGF dose- and time-dependently induced PASMC proliferation, and this was accompanied by an increase of HDAC1 and cyclin-dependent kinase 4 (CDK4) protein expression as well as a reduction of microRNA-124 (miR-124). Pre-silencing of HDAC1 with small interfering RNA (siRNA) abolished PDGF-induced miR-124 down-regulation, CDK4 protein up-regulation, and PASMC proliferation. In addition, over-expression of miR-124 reversed CDK4 protein elevation and PASMC proliferation caused by PDGF. We further found that pre-incubation of PASMCs with pioglitazone, an agonist of PPARgamma receptors, significantly increased PPARgamma expression and activity, and blocked PDGF stimulated cell proliferation by regulating HDAC1-mediated miR-124 and CDK4 expression. Our study indicates that HDAC1/miR-124/CDK4 axis plays an important role in PDGF-induced PASMC proliferation, and activation of PPARgamma inhibits PASMC proliferation by acting on HDAC1 pathway. PMID- 28867609 TI - AMPK attenuates ventricular remodeling and dysfunction following aortic banding in mice via the Sirt3/Oxidative stress pathway. AB - Although recent findings have suggested that AMP-activated protein kinase (AMPK) exerts inhibitory effects on cardiac remodeling secondary to hypertension, the mechanism and optimal duration of treatment remain unknown. Mice with descending aortic banding (AB) or subjected to sham operation received subcutaneous injection of either AICAR (0.5mgg-1day-1) or vehicle over 4 week periods. At the end of 4 week treatment, left ventricular (LV) remodeling and function were evaluated with histological analysis and echocardiography. Collagen deposition within the LV myocardium was detected with Masson's trichrome staining. Collagen I, Collagen III, Smad 2, Smad 3, NOX2, NOX4 and Sirt3 (an important antioxidant factor) within the LV tissue were also evaluated. Compared with the sham group, the vehicle-treated AB group exhibited significant elevations in cardiac remodeling and heart failure, characterized by an increase in LV weight relative to body weight, an increase in the area of collagen deposition, an increase in LV end-diastolic diameter, an increase in mitral E inflow velocity to mitral A inflow velocity and increases in the gene expressions of the fibrosis markers Collagen I, III and Smad 2, 3 mRNA and decreases in EF and fractional shortening. AMPK attenuate the cardiac remodeling parameters and improve cardiac function. Moreover, the expressions of NOX2, NOX4 were significantly elevated in vehicle treated AB group. AMPK was able to significantly inhibit NOX2, NOX4 expression, while activate Sirt3 expression. AMPK significantly attenuated hypertension induced Ventricular remodeling and dysfunction, which may be mediated by the Sirt3/Oxidative stress signaling pathway. PMID- 28867610 TI - Muscle Lim Protein and myosin binding protein C form a complex regulating muscle differentiation. AB - Muscle Lim Protein (MLP) is a protein with multiple functional roles in striated muscle physiology and pathophysiology. Herein, we demonstrate that MLP directly binds to slow, fast, and cardiac myosin-binding protein C (MyBP-C) during myogenesis, as shown by yeast two-hybrid and a range of protein-protein interaction assays. The minimal interacting domains involve MLP inter-LIM and MyBP-C [C4]. The interaction is sensitive to cytosolic Ca2+ concentrations changes and to MyBP-C phosphorylation by PKA or CaMKII. Confocal microscopy of differentiating myoblasts showed MLP and MyBP-C colocalization during myoblast differentiation. Suppression of the complex formation with recombinant MyBP-C [C4] peptide overexpression, inhibited myoblast differentiation by 65%. Suppression of both MLP and MyBP-C expression in myoblasts by siRNA revealed negative synergistic effects on differentiation. The MLP/MyBP-C complex modulates the actin activated myosin II ATPase activity in vitro, which could interfere with sarcomerogenesis and myofilaments assembly during differentiation. Our data demonstrate a critical role of the MLP/MyBP-C complex during early myoblast differentiation. Its absence in muscles with mutations or aberrant expression of MLP or MyBP-C could be directly implicated in the development of cardiac and skeletal myopathies. PMID- 28867611 TI - ErbB3 interacts with Hrs and is sorted to lysosomes for degradation. AB - The ErbB family of receptor tyrosine kinases mediates activation of a wide network of signaling pathways. ErbB3 has weak kinase activity, but its six docking sites for the p85 subunit of phosphoinositide 3-kinase make it an important contributor to proliferative signaling. ErbB3 has a relatively short half-life but the exact mechanisms controlling its turnover are unclear as contradictory reports exist. ErbB-mediated signaling is, however, negatively regulated by endocytosis of the receptors, followed by either recycling or degradation. Our previous studies showed that ErbB3 can be endocytosed and degraded in the absence of its ligand heregulin. However, binding of heregulin increased the degradation rate. In the current study we have investigated in more detail the trafficking and degradation of ErbB3 in the presence or absence of heregulin. We report that ErbB3 is internalized by clathrin-mediated endocytosis both in the presence and absence of heregulin. Moreover, we show that both proteasomal and lysosomal activity regulate ErbB3 degradation. Although steady state expression of ErbB3 is regulated by proteasomal activity to a large extent, probably linked to a previously identified ER-localized quantity control, the results indicate that internalization, both constitutive and ligand-induced, causes lysosomal degradation of ErbB3. Furthermore, we show that ErbB3 interacts with the ESCRT-0 subunit Hrs both in the presence and absence of heregulin. This indicates an ESCRT-mediated sorting of ErbB3 to late endosomes and lysosomes, and in line with this we show that impaired ESCRT function leads to an endosomal accumulation of ErbB3. PMID- 28867612 TI - Achieving a Graded Immune Response: BTK Adopts a Range of Active/Inactive Conformations Dictated by Multiple Interdomain Contacts. AB - Capturing the functionally relevant forms of dynamic, multidomain proteins is extremely challenging. Bruton's tyrosine kinase (BTK), a kinase essential for B and mast cell function, has stubbornly resisted crystallization in its full length form. Here, nuclear magnetic resonance and hydrogen-deuterium exchange mass spectrometry show that BTK adopts a closed conformation in dynamic equilibrium with open, active conformations. BTK lacks the phosphotyrosine regulatory tail of the SRC kinases, yet nevertheless achieves a phosphotyrosine independent C-terminal latch. The unique proline-rich region is an internal "on" switch pushing the autoinhibited kinase toward its active state. Newly identified autoinhibitory contacts in the BTK pleckstrin homology domain are sensitive to phospholipid binding, which induces large-scale allosteric changes. The multiplicity of these regulatory contacts suggests a clear mechanism for gradual or "analog" kinase activation as opposed to a binary "on/off" switch. The findings illustrate how previously modeled information for recalcitrant full length proteins can be expanded and validated with a convergent multidisciplinary experimental approach. PMID- 28867613 TI - High-Resolution Cryo-EM Maps and Models: A Crystallographer's Perspective. AB - The appearance of ten high-resolution cryoelectron microscopy (cryo-EM) maps of proteins, ribosomes, and viruses was compared with the experimentally phased crystallographic electron density maps of four proteins. We found that maps calculated at a similar resolution by the two techniques are quite comparable in their appearance, although cryo-EM maps, even when sharpened, seem to be a little less detailed. An analysis of models fitted to the cryo-EM maps indicated the presence of significant problems in almost all of them, including incorrect geometry, clashes between atoms, and discrepancies between the map density and the fitted models. In particular, the treatment of the atomic displacement (B) factors was meaningless in almost all analyzed cryo-EM models. Stricter cryo-EM structure deposition standards and their better enforcement are needed. PMID- 28867614 TI - Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis. AB - Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill >500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds. Our PRS-drug co-crystal structures reveal remarkable active site plasticity that accommodates diversely substituted compounds, an enzymatic feature that can be leveraged for refining drug-like properties of quinazolinones on a per parasite basis. A compound we termed In-5 exhibited a unique double conformation, enhanced drug-like properties, and cleared malaria in mice. It thus represents a new lead for optimization. Collectively, our data offer insights into the structure-guided optimization of quinazolinone-based compounds for drug development against multiple human eukaryotic pathogens. PMID- 28867615 TI - Structure of the Human Mitochondrial Ribosome Studied In Situ by Cryoelectron Tomography. AB - Mitochondria maintain their own genome and its corresponding protein synthesis machine, the mitochondrial ribosome (mitoribosome). Mitoribosomes primarily synthesize highly hydrophobic proteins of the inner mitochondrial membrane. Recent studies revealed the complete structure of the isolated mammalian mitoribosome, but its mode of membrane association remained hypothetical. In this study, we used cryoelectron tomography to visualize human mitoribosomes in isolated mitochondria. The subtomogram average of the membrane-associated human mitoribosome reveals a single major contact site with the inner membrane, mediated by the mitochondria-specific protein mL45. A second rRNA-mediated contact site that is present in yeast is absent in humans, resulting in a more variable association of the human mitoribosome with the inner membrane. Despite extensive structural differences of mammalian and fungal mitoribosomal structure, the principal organization of peptide exit tunnel and the mL45 homolog remains invariant, presumably to align the mitoribosome with the membrane-embedded insertion machinery. PMID- 28867616 TI - The Mammalian Proteasome Activator PA28 Forms an Asymmetric alpha4beta3 Complex. AB - The heptameric proteasome activator (PA) 28alphabeta is known to modulate class I antigen processing by docking onto 20S proteasome core particles (CPs). The exact stoichiometry and arrangement of its alpha and beta subunits, however, is still controversial. Here we analyzed murine PA28 complexes regarding structure and assembly. Strikingly, PA28alpha, PA28beta, and PA28alphabeta preparations form heptamers, but solely PA28alpha and PA28alphabeta associate with CPs. Co expression of alpha and beta yields one unique PA28alphabeta species with an unchangeable subunit composition. Structural data on PA28alpha, PA28beta, and PA28alphabeta up to 2.9 A resolution reveal a PA28alpha4beta3 complex with an alternating subunit arrangement and a single alpha-alpha interface. Differential scanning fluorimetry experiments and activity assays classify PA28alpha4beta3 as most stable and most active, indicating that this assembly might represent the physiologically relevant species. Together, our data resolve subunit composition and arrangement of PA28alphabeta and clarify how an asymmetric heptamer can be assembled from two highly homologous subunits. PMID- 28867617 TI - Total reference air kerma can accurately predict isodose surface volumes in cervix cancer brachytherapy. A multicenter study. AB - PURPOSE: To demonstrate that V60 Gy, V75 Gy, and V85 Gy isodose surface volumes can be accurately estimated from total reference air kerma (TRAK) in cervix cancer MRI-guided brachytherapy (BT). METHODS AND MATERIALS: 60 Gy, 75 Gy, and 85 Gy isodose surface volumes levels were obtained from treatment planning systems (VTPS) for 239 EMBRACE study patients from five institutions treated with various dose rates, fractionation schedules and applicators. An equation for estimating VTPS from TRAK was derived. Furthermore, a surrogate Point A dose (Point A*) was proposed and tested for correlation with V75 Gy. RESULTS: Predicted volumes Vpred = 4965 (TRAK/dref) 3/2 + 170 (TRAK/dref) - 1.5 gave the best fit to VTPS. The difference between VTPS and predicted volumes was 0.0% +/- 2.3%. All volumes were predicted within 10%. The prediction was valid for (1) high-dose rate and pulsed dose rate, (2) intracavitary vs. intracavitary/interstitial applicators, and (3) tandem-ring, tandem-ovoid, and mold. Point A* = 14 TRAK was converted to total EQD2 and showed high correlation with V75 Gy. CONCLUSIONS: TRAK derived Isodose surface volumes may become a tool for assessment of treatment intensity. Furthermore, surrogate Point A* doses can be applied for both intracavitary and intracavitary/interstitial BT and can be used to compare treatments across fractionation schedules. PMID- 28867618 TI - Leucine responsive regulatory protein is involved in methionine metabolism and polyamine homeostasis in acetic acid bacterium Komagataeibacter europaeus. AB - The leucine responsive regulatory protein (Lrp) is a global transcription factor that regulates the expression of genes involved in amino acid metabolism. To identify metabolic pathways and related genes under the control of Lrp in the acetic acid bacterium Komagataeibacter europaeus, the Kelrp null mutant (KGMA7110), which requires supplementation of all 20 amino acids for normal growth, was cultivated in minimal media containing or lacking particular amino acids. The results confirmed that KGMA7110 was auxotrophic for methionine and its catabolites S-adenosylmethionine (SAM) and spermidine (SPD). Quantitative reverse transcription PCR analysis revealed lower metK (SAM synthetase) and mdtI (SPD efflux pump) expression in KGMA7110 than in wild-type KGMA0119. By contrast, these genes were significantly up-regulated in the Kelrp mutant lacking the putative C-terminal ligand-sensing domain (KGMA7203), indicating abnormal regulation of target genes by the KeLrp variant in KGMA7203. KGMA7110 (0.69+/ 0.27 MUM) and KGMA7203 (4.90+/-0.61 MUM) excreted lower and higher quantities of SPD, respectively, than KGMA0119 (2.28+/-0.26 MUM). This was attributed to imbalanced carbon flow caused by Kelrp disruption that respectively attenuated and stimulated metK and mdtI expression. These findings indicate that KeLrp plays a key role in SAM biosynthesis and intracellular polyamine homeostasis in K. europaeus. PMID- 28867619 TI - Effect of sub-MIC of vancomycin and clindamycin alone and in combination with ceftazidime on Clostridium difficile surface layer protein A (slpA) gene expression. AB - Clostridium difficile (C.difficile) infection is often established in the presence of antibiotics and probably antibiotics can influence surface layer protein A (slpA) expression as a colonization factor. The aim of this study is to evaluate the effect of vancomycin (VAN), clindamycin (CLI) alone and in combination with ceftazidime (CAZ) on slpA gene expression to determine whether such antibiotics can have any effect on slpA expression. About ~106 CFU/mL was inoculated to medium containing an appropriate concentration of antibiotics alone and in combination. After 24 and 48 h incubation under anaerobic condition, 3 mL of culture was excluded and centrifuged in 8000 * g per 3 min. The pellet was washed and used for RNA extraction. The RNA extraction, Dnase I treatment and cDNA synthesis was performed by RNA extraction, Dnase I, and cDNA synthesis kits, respectively. The real-time PCR were carried out by sybrGreen methods and data were analyzed based on comparative DeltaDeltaCT. All antibiotics alone and in combination, except VAN/CAZ in clinical isolate, decreased the level of slpA gene expression in the 24-h incubation. While the expression profile of slpA was different in the 48-h incubation period. The VAN and CLI decreased the slpA expression, although the template of expression is closed to control medium. CAZ alone and in combination increased slpA expression. C. difficile may down regulate slpA expression in the early stages of growth in sub-inhibitory concentration of antibiotics. But, over time C. difficile increases or over expresses the slpA expression level. Consequently C. difficile binds strongly to epithelial cells and continues to survive in the presence of sub-MIC concentration of antibiotics. This effect is observed especially with regard to CAZ and probably other third generation cephalosporins or in combination therapy with VAN or CLI, which are prescribed in the clinic. CAZ can interfere with the anti-down regulatory feature of VAN, CLI, and maybe other antibiotics. PMID- 28867620 TI - Complete genome sequence analysis of the fish pathogen Flavobacterium columnare provides insights into antibiotic resistance and pathogenicity related genes. AB - We analyzed here the complete genome sequences of a highly virulent Flavobacterium columnare Pf1 strain isolated in our laboratory. The complete genome consists of a 3,171,081 bp circular DNA with 2784 predicted protein-coding genes. Among these, 286 genes were predicted as antibiotic resistance genes, including 32 RND-type efflux pump related genes which were associated with the export of aminoglycosides, indicating inducible aminoglycosides resistances in F. columnare. On the other hand, 328 genes were predicted as pathogenicity related genes which could be classified as virulence factors, gliding motility proteins, adhesins, and many putative secreted proteases. These genes were probably involved in the colonization, invasion and destruction of fish tissues during the infection of F. columnare. Apparently, our obtained complete genome sequences provide the basis for the explanation of the interactions between the F. columnare and the infected fish. The predicted antibiotic resistance and pathogenicity related genes will shed a new light on the development of more efficient preventional strategies against the infection of F. columnare, which is a major worldwide fish pathogen. PMID- 28867621 TI - Genetic variation among Clostridium perfringens isolated from food and faecal specimens in Lagos. AB - BACKGROUND: Clostridium perfringens is an anaerobic Gram-positive bacterium which is commonly present in the gastrointestinal tract of man and animals and causes enteritic diseases in animals and food poisoning in humans. Previous studies have looked at the epidemiological relationship between C. perfringens isolates from outbreak source. In this study, the genetic diversity of C. perfringens strains from non-outbreak food and faecal specimens was investigated for epidemiological purposes. METHODS: We analyzed thirty-eight (38) Clostridium perfringens strains isolated from food and faecal specimens in Lagos State. Bacterial identification was done using colonial morphology, Gram stain reaction, conventional biochemical tests and PCR. Genetic analysis was performed using arbitrary primed polymerase chain reaction (AP-PCR) technique with oligonucleotide primer of random sequences (OPA-3) to determine the genetic diversity of C. perfringens. The distance between the different bands produced were analyzed using numerical taxonomy and multivariate system software (NTSYS). RESULTS: Seventeen (44.7%) C. perfringens strains showed at least one polymorphic DNA patterns when genotyped. However, this method identified polymorphisms among the C. perfringens species from which four genetic groups (1, 2, 3 and 4) were established. CONCLUSIONS: Our findings suggest that there may be faecal contamination of food products and similar clones of Clostridium perfringens may be incriminated. PMID- 28867622 TI - Association of IFNG gene polymorphisms with pulmonary tuberculosis but not with spinal tuberculosis in a Chinese Han population. AB - Spinal tuberculosis (STB) is an extrapulmonary form of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb), which accounts for around 2% of all TB cases and can lead to spine degeneration. It is widely accepted that host genetic factors participate in the pathogenesis of active TB, but the factors controlling which TB form will manifest after Mtb infection remain unknown. We hypothesized that a genetic difference may exist between the development of STB and pulmonary tuberculosis (PTB). Here, three single nucleotide polymorphisms (SNPs) in the IFNG gene (rs2069718), IRGM gene (rs10065172), and MBL2 gene (rs11003125) were genotyped among 183 PTB patients, 177 STB patients, and 360 healthy controls from the Chinese Han population. We found that rs2069718 genotypes were significantly associated with PTB (TT, p = 0.007; CT, p = 0.008) but not STB, and the TT genotype (p = 0.046) of rs2069718 were less common in PTB than in STB. In contrast, neither PTB nor STB were found to be associated with rs10065172 and rs11003125. Overall, we found a difference in the rs2069718 genetic distribution between the STB and PTB patients in a Chinese Han population. The rs2069718 TT genotype was associated with a protective role in PTB but not STB development during active Mtb infection. PMID- 28867623 TI - Colonization, resistance to bile, and virulence properties of Escherichia coli strains: Unusual characteristics associated with biliary tract diseases. AB - Escherichia coli is the species that is most frequently isolated from bile of patients with biliary tract diseases. This study was aimed to investigate any association between resistance and virulence properties of these isolates with occurrence of the diseases. A total of 102 bile samples were obtained from patients subjected to endoscopic retrograde cholangiopancreatography for different biliary diseases. Clinical data were collected and culture of the bile samples was done on selective media. Resistance of characterized Escherichia coli isolates to deoxycholate sodium (0-7%) and nineteen antibiotics was determined and PCR using 16 pairs of primers targeting stx1, stx2, exhA, eae, bfp, agg, pcvd432, lt, st, ipaH, pic, pet, ast, set, sen, and cdtB genes was done. Our results showed a statistically significant association between E. coli colonization and existence of common bile duct and gallbladder stones (p value 0.028). Out of the 22 E. coli strains (22/102) multidrug resistance phenotype was present in 95.45%. None of the strains belonged to common E. coli pathotypes. However, bfp + EhxA-hly, bfp + astA, bfp + EhxA-hly + pic, and EhxA-hly + pic + astA, bfp, and astA genotypes were detected in these strains. bfp (7/22, 31.8%) and astA (5/22, 22.7%) were among most frequent virulence factors in these strains. Results of this study showed significant association between colonization of E. coli and choledocholithiasis. Unusual existence of virulence gene combinations in these strains and their resistance to DOC and multiple classes of antibiotics could be considered as possible causes of their persistence in this harsh microenvironment. PMID- 28867624 TI - Effect of aminoglycosides on the pathogenic characteristics of microbiology. AB - Infections caused by pathogen remain to be one of the most important global health issues, and scientists are devoting themselves to seeking effective treatments. Aminoglycoside antibiotics are one kind of widely used antibiotics because of the good efficiency and broad antimicrobial-spectrum. However, it causes some unexpected effects on the pathogenic characteristics of microbiology during the treatment, such as drug resistance and biofilm promotion. Drug resistance is partly due to antibiotics abuse. Simultaneously, aminoglycoside is documented to make divergent effects on biofilm based on their concentrations. Here, we review the mechanism of drug resistance caused by long-term use of aminoglycoside antibiotics, the effects of antibiotic concentration on biofilm formation and the negative effects on intestinal flora to provide theoretical supports for rational use of antibiotics. PMID- 28867625 TI - Inhibition of cervical cancer cell metastasis by benzothiazole through up regulation of E-cadherin expression. AB - The present study was aimed to investigate the effect of benzothiazole on the invasive and metastasis potential of HeLa DH cervical cancer cells and the underlying mechanism. HeLa DH cervical cells were cultured with 5, 10, 15, 20, 25 and 30 MUM concentrations of benzothiazole for 48 h. Benzothiazole treatment did not induce any cytotoxic effect on HeLa DH cells after 48 h of incubation. The results from wound healing assay revealed that migration potential of HeLa DH cells was reduced to 4% on treatment with 20 MUM concentration of benzithiazole compared to 99% in the control cells. The invasion potential of HeLa DH cells was reduced to 13% on treatment with 20 MUM concentration of benzithiazole. Inhibition of HeLa DH cell migration was also significantly (p < 0.002) higher in the benzithiazole treated cell cultures compared to the control cells. HeLa DH cervical cancer cells on treatment with various concentrations of benzithiazole for 48 h showed a significant (p < 0.05) increase in the expression of E-cadherin in a dose dependent manner. Among the various concentrations of benzithiazole used, western blot assay revealed that the increase in E-cadherin was maximum at 20 MUM. Analysis of the levels of mRNA corresponding to E-cadherin by RT-qPCR showed significant increase in HeLa DH cervical cancer cells on treatment with 20 MUM concentration of benzithiazole. Thus benzithiazole treatment suppresses the invasive and metastasis potential of HeLa DH cervical cells through upregulation of E-cadherin expression. Therefore, benzithiazole has a potential to be used for the treatment of cervical cancer. PMID- 28867626 TI - Enhanced cytopathic effect of Japanese encephalitis virus strain SA14-14-2: Probable association of mutation in amino acid of its envelope protein. AB - Japanese encephalitis (JE) is a mosquito-borne viral disease. It is a global public health concern since it causes an acute encephalitis syndrome (AES). A large number of JE/AES cases are reported to occur in areas with established or developing JE vaccination program. Partial vaccine coverage and emergence of new variants of Japanese encephalitis virus (JEV) might be playing an important role. The envelope protein (E) of JEV is a major antigenic determinant and responsible for immunogenic responses as well as membrane fusion and virion assembly. In the present study, we have characterized the JEV live attenuated vaccine strain SA14 14-2 in baby hamster kidney cells (BHK-21). The vaccine strain showed enhanced replication following its passage in BHK-21 cells. Nucleotide sequence analysis of the E protein gene of the cell-culture adapted vaccine strain showed an important point mutation. The mutation in the E protein gene was identical to its wild-type parent strain SA14. This study suggests the possibility of reversion mutation and exaltation of vaccine strains following adaptation in the host cells. PMID- 28867627 TI - Effect of organic acids on biofilm formation and quorum signaling of pathogens from fresh fruits and vegetables. AB - Organic acids are known to be used as food preservatives due to their antimicrobial potential. This study evaluated the ability of three organic acids, namely, acetic acid, citric acid and lactic acid to manage E. coli and Salmonella sp. from fresh fruits and vegetables. Effect of these organic acids on biofilm forming ability and anti-quorum potential was also investigated. The effect of organic acids on inactivation of E. coli and Salmonella sp. on the surface of a selected vegetable (cucumber) was determined. The minimum inhibitory concentration of the organic acids were found to be 1.5, 2 and 0.2% in E. coli while it was observed to be 1, 1.5 and 1% in Salmonella sp. for acetic, citric and lactic acids respectively. Maximum inhibition of biofilm formation was recorded at 39.13% with lactic acid in E. coli and a minimum of 22.53% with citric acid in Salmonella sp. EPS production was affected in E. coli with lactic acid showing reduction by 13.42% while citric acid and acetic acid exhibited only 6.25% and 10.89% respectively. Swimming and swarming patterns in E. coli was notably affected by both acetic and lactic acids. Lactic and acetic acids showed higher anti-quorum sensing (QS) potential when compared to citric acid. 2% lactic acid showed a maximum inhibition of violacein production by 37.7%. Organic acids can therefore be used as potential quorum quenching agents in food industry. 2% lactic acid treatment on cucumber demonstrated that it was effective in inactivating E. coli and Salmonella sp. There was 1 log reduction in microbial count over a period of 6 days after the lactic acid treatment. Thus, organic acids can act as effective potential sanitizers in reducing the microbial load associated with fresh fruits and vegetables. PMID- 28867628 TI - Molecular and phenotypic characterization of endophytic bacteria isolated from sulla nodules. AB - In the current study, bacterial diversity was investigated in root nodules of Sulla pallida and Sulla capitata. The isolates were analyzed on the basis of their phenotypic and molecular characteristics. The phylogenetic analysis based on 16S rRNA and housekeeping genes (recA and atpD) showed that the isolated bacteria related to Sinorhizobium, Neorhizobium, Phyllobacterium, Arthrobacter, Variovorax and Pseudomonas genera. This is the first report of Neorhizobium genus associated with Hedysarum genus. Phenotypically, all strains tolerate the elevated temperature of 40 degrees C, and salt stress at a concentration of 2%. In addition, the isolates failed to induce nodulation on their original host; and the symbiotic genes could not be amplified, suggesting that these strains are endophytic bacteria. PMID- 28867629 TI - A nanobiosensing method based on force measurement of antibody-antigen interaction for direct detection of enterovirus 71 by the chemically modified atomic force microscopic probe. AB - Hand, Foot and mouth disease (HFMD) is a common disease with high infectivity for children, and enterovirus 71 (EV71) is one of the main pathogens to cause the type of illness. Therefore, the aim of this study was to propose a rapid and effective technique for detecting EV71 directly based on the mechanism of biological intermolecular force by using atomic force microscopy (AFM). At first, we coated EV71 particles on the mica surface and made the EV71 antibodies (anti EV71) fixed on the AFM tip by means of several chemical procedures. Then, AFM chemically modified tip was applied to measure the unbinding forces between EV71 and anti-EV71 by contact mode. Finally, by using AFM imaging calculating software, the EV71 particle size (mean+/-SD) was 31.36+/-3.87 nm (n = 200) and this result was concordance with previous literature. Besides, the force (mean+/ SD) between EV71 antigen and antibody complex was 336.9+/-64.7 pN. The force (mean+/-SD) between anti-EV71 and non-specific specimens was 47.1+/-15.1 pN and was significantly smaller (P < 0.05). Apparently, the results show that we can precisely identify EV71 infection among the samples by measuring the force magnitude and observing the occurrence of EV71/anti-EV71 unbinding events. Therefore, the combination of AFM system and the chemically modified tip has the potential to be a rapid and effective method for detecting EV71 directly. PMID- 28867630 TI - Indole reduces the expression of virulence related genes in Vibrio splendidus pathogenic to sea cucumber Apostichopus japonicus. AB - Indole is a metabolite of tryptophan that can be synthesized by various bacteria. In the present study, production of indole by Vibrio splendidus Vs was determined using Kovac's reagent, and m/z was further determined by HPLC-MS. Extracellular indole reached a maximum concentration of 160 MUM, when OD600 of V. splendidus Vs was approximately 0.9. In addition, glucose could reduce indole level, and 1% (m/v) glucose could reduce the mRNA level of tnaA, the gene encoding tryptophanase, down to 0.2%. To investigate the effects of indole on the mRNA levels of virulence related genes of V. splendidus Vs, mRNA levels of vsm, vsh and ABC respectively related to protease activity, haemolytic activity and ABC transporter ATP-binding protein were determined. Exogenous indole supplemented at a concentration of 125 MUMU could respectively down regulate the mRNA level of vsm, vsh and ABC to 16%, 13% and 11%. Meanwhile, indole could alter the expressions of immune related gene in Apostichopus japonicus. When coelomocytes were co-cultured with exogenous indole at a concentration of 125 MUMU, the mRNA level of Ajp105 and AjLBP/BPI1, were up regulated by 1.6-fold and 2.1-fold, respectively. Combined all the results in our study suggested that indole could alter the expressions of the virulence related genes in pathogenic V. splendidus Vs as well as the immune related genes in A. japonicus. PMID- 28867631 TI - The apoptotic impact of nisin as a potent bacteriocin on the colon cancer cells. AB - Nisin is a polycyclic peptide containing 34 amino acids produced by Lactococcus lactis during fermentation. Recently, researchers considered nisin as an anticancer peptide. Herein, the authors aim to evaluate the nisin effects on the apoptosis stimulation in the colon cancer cell line. The SW480 cells were exposed to discrepant concentrations of nisin and the cell viability as well as the expression of bcl-2 and bax genes and proteins were surveyed by the MTT assay, Real-Time PCR and western blotting method, respectively. Furthermore, the Ethidium bromide/Acridine orange staining was performed to visualize apoptotic cells. 4000, 3000, 2500 and 2000 MUg/ml of nisin led to significant anti proliferative impact and augmentation apoptotic index (bax/bcl-2 ratio) both at mRNA and protein levels (p < 0.05). Furthermore, the apoptotic impacts were demonstrated after Ethidium bromide/Acridine orange (EB/AO) staining to have a dose dependent manner. Our outcome suggested that nisin could induce apoptosis via intrinsic pathways and lead to cancerous cell death. PMID- 28867632 TI - Extraction, isolation and characterization of bioactive compounds from chloroform extract of Carica papaya seed and it's in vivo antibacterial potentiality in Channa punctatus against Klebsiella PKBSG14. AB - The relative efficacy of the isolated pure compound, extracted from Carica papaya seed has been tested against live fish, Channa punctatus infected with pathogenic strains of KlebsiellaPKBSG14 (gene bank accession no.KJ162158) at a dose of 0.75 CFU/ml in vivo. The isolated compound has been characterized by chromatography and mass spectroscopy studies using FTIR, 1HNMR and 13c NMR to identify as well as to determine the nature of the pure compound. This study revealed the extracted biological molecule is oleic acid, a long chained saturated fatty acid (LFAs) with a molecular formula C18H34O2. Later this compound was analyzed for its efficacy as an antibacterial agent in vivo through cytotoxicological and genotoxicological assays. A dose of 0.5 mg/kg and 1 mg/kg b.w of isolated pure oleic acid has been tested and it showed effective result in regard to DNA fragmentation, comet tail length and toxicity biomarkers like ROS generation. The results of in vivo studies showed similar effects on spleen cells with regard to cell viability by PI staining, cell cycle analysis and also Annexin-FITC assay. Thus, the overall results suggest that oleic acid increases drug bioavailability and thereby has a better chemo-preventive action against bacterial infection in vivo. PMID- 28867633 TI - Borrelia burgdorferi basic membrane protein A could induce chemokine production in murine microglia cell line BV2. AB - Lyme neuroborreliosis is a nervous system infectious disease caused by Borrelia burgdorferi (B. burgdorferi). It has been demonstrated that cytokines induced by B. burgdorferi are related to Lyme neuroborreliosis. Microglia is known as a key player in the immune responses that occur within the central nervous system. In response to inflammation, it will be activated and generate cytokines and chemokines. Experiments in vitro cells have showed that B. Burgdorferi membrane protein A (BmpA), a major immunogen of B. Burgdorferi, could induce Lyme arthritis and stimulate human and murine lymphocytes to produce inflammatory cytokines. In our study, the murine microglia BV2 cell line was used as a cell model to explore the stimulating effects of recombinant BmpA (rBmpA); Chemokine chip, ELISA and QPCR technology were used to measure the production of chemokines from microglial cells stimulated by rBmpA. Compared with the negative control group, CXCL2, CCL22, and CCL5 concentrations in the cell supernatant increased significantly after the rBmpA stimulation; the concentration of these chemokines increased with rBmpA concentration increasing; the mRNA expression levels of chemokines (CXCL2, CCL22, and CCL5) in murine BV2 cells increased significantly with 10 MUg/mL and 20 MUg/mL rBmpA stimulation; CXCL13 was not change after the rBmpA stimulation. Our study shows that chemokines, such as CXCL2, CCL22, and CCL5 were up-regulated by the rBmpA in the BV2 cells. The production of chemokines in Lyme neuroborreliosis may be mainly from microglia cells and the rBmpA may be closely related with the development of Lyme neuroborreliosis. PMID- 28867634 TI - Two potential uses for silver nanoparticles coated with Solanum nigrum unripe fruit extract: Biofilm inhibition and photodegradation of dye effluent. AB - Silver nanoparticle was green synthesized involving the unripe fruit extracts of Solanum nigrum (Sn-AgNPs). The synthesized Sn-AgNPs was bio-physically characterized by UV-Vis spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and Transmission electron microscopy (TEM). UV-Vis recorded the absorbance spectra at 443 nm. XRD analysis clearly demonstrated the crystalline nature of Sn-AgNPs with Bragg's reflection peaks at 111, 200, 220 and 311 lattice planes. The FTIR spectrum of Sn-AgNPs showed strong bands at 3432, 1555, 1455, 862 and 406 cm-1 which corresponds at O-H, C-H, C-C, C-OH and C-N groups respectively. TEM exhibited the spherical shape of Sn-AgNPs with particle size between 20 and 30 nm. The antibacterial effects of Sn-AgNPs were tested on clinically important biofilm forming Gram positive (Bacillus pumulis and Enterococcus faecalis) and Gram negative (Proteus vulgaris and Vibrio parahaemolyticus) bacteria. The greater inhibition of B. pumulis and E. faecalis was observed at 100 MUg mL-1 of Sn-AgNPs compared to P. vulgaris and V. parahaemolyticus. The biofilm inhibition potential of Sn-AgNPs was greater against Gram positive bacteria than that of Gram negative bacteria. Furthermore, Sn-AgNPs effectively degraded the industrial effluent methyl orange dye by photocatalysis. It is concluded that Sn-AgNPs could be used as an effective therapeutics against the biofilm of clinically important bacteria. The green synthesized Sn-AgNPs can be employed to degrade dye effluents and prevent environmental pollution as well. PMID- 28867635 TI - Effect of human placental extract in the management of biofilm mediated drug resistance - A focus on wound management. AB - Management of infectious wounds, particularly chronic wounds and burn injuries, is a matter of global concern. Worldwide estimates reveal that, billions of dollars are being spent annually for the management of such chronic ailments. Evidently, bacterial biofilms pose a greater problem in the effective management of infection in chronic wounds, since most of the currently available antibiotics are unable to act on the microorganisms residing inside the protected environment of the biofilms. Accordingly, in the present study, we have attempted to evaluate the anti-biofilm properties of human placental extract (PLX) and also other virulence factors that are mediated via the quorum sensing (QS) signalling system. PLX is well known for its anti inflammatory action and it has been shown earlier some anti microbial and enzymatic activity also. PLX was found to produce significant inhibition of biofilm formation and also decreased the levels of pyoverdin and pyocyanin. The microscopic analysis (both light microscopy and atomic force microscopy) of biofilms was also used for substantiating the findings from spectrophotometric (crystal violet estimation) and fluorescence analysis (resazurin uptake). PLX pre-treatment decreased the hydrophobicity of gram-positive and gram negative cells, indicating the effect of placental extract on adherence property of planktonic cell, serving as an indicator for its antibiofilm effect on microorganisms. The reduced extracellular DNA (eDNA) content in biofilm matrix following treatment with PLX also indicates the effectiveness of placenta extract on bacterial adherence, which in turn serves as evidence substantiating the antibiofilm effects of the PLX. Furthermore, PLX was also found to be significantly effective in the in vitro wound biofilm model. Thus the present study, the first of its kind with PLX, establishes the therapeutic benefit of the same particularly in infected wounds, opening up newer avenue for further exploration. PMID- 28867636 TI - Characterization of vaginal microbiota of endometritis and healthy sows using high-throughput pyrosequencing of 16S rRNA gene. AB - Endometritis is one of major challenges in reproduction infections caused by bacteria in sows. Understanding of the vaginal bacterial community between endometritis and healthy sows serves as a critical step to develop more effective ways to improve reproduction ability in pig industry. The aim of the present study is to evaluate and compare the vaginal microbiota of endometritis and healthy sows using high-throughput pyrosequencing of 16S rRNA gene. The main bacterium found at the phylum level were Firmicutes (60.88% vs. 45.86%), Proteobacteria (20.45% vs. 32.19%) and Bacteroidetes (9.19% vs. 12.99%) for healthy and endometritis sows, respectively. Most notable difference at the phylum level was the Proteobacteria which occupied high abundance in the endometritis sows but less abundance in the healthy sows. At the genus level, the highest abundant were Bacillus (27.13% vs. 16.15%), Paenibacillus (14.78% vs. 8.92%), Alkaliphilus (3.99% vs. 2.87%) and Cronobacter (4.04% vs. 2.37%), in healthy and endometritis sows, respectively. Notable differences were Escherichia Shigella, Bacteroides, Fusobacterium and Clostridium_sensu_stricto_1 which were more abundant in the endometritis than the healthy sows respectively. The present results for the first time demonstrate vaginal microbial community of sows and indicate that endometritis affected the vaginal microbiota of sow. PMID- 28867638 TI - Zebrafish: A promising in vivo model for assessing the delivery of natural products, fluorescence dyes and drugs across the blood-brain barrier. AB - The blood brain barrier (BBB) is the network of capillaries that controls the passage of substances from the blood into the brain and other parts of the central nervous system (CNS). As this barrier is the major obstacle for drug delivery into CNS, a credible BBB model is very necessary to assess the BBB permeability of novel neuroactive compounds including thousands of bioactive compounds which have been extracted from medicinal plants and have the potential for the treatment of CNS diseases. Increasing reports indicated that zebrafish has emerged as a timely, reproducible model for BBB permeability assessment. In this review, the development and functions of the BBB in zebrafish, such as its anatomical morphology, tight junctions, drug transporters and enzyme expression, are compared with those in mammals. The studies outlined in this review describe the utilization of the zebrafish as a BBB model to investigate the permeability and distribution of fluorescent dyes and drugs. Particularly, this review focuses on the use of zebrafish to evaluate the delivery of natural products and nanosized drug delivery systems across the BBB. Due to the highly conserved nature of both the structure and function of the BBB between zebrafish and mammals, zebrafish has the potential to be developed as a model for assessing and predicting the permeability of BBB to novel compounds. PMID- 28867637 TI - Sinomenine-induced histamine release-like anaphylactoid reactions are blocked by tranilast via inhibiting NF-kappaB signaling. AB - Zhengqing Fengtongning (ZQFTN), the pharmaceutical preparation of sinomenine (SIN) derived from the medicinal plant Sinmenium acutum, is well-known in China as an effective treatment for rheumatoid arthritis (RA). However, its histamine release anaphylactoid reactions (HRARs) occur often in some patients. Therefore, it is desirable to establish effective clinical protocols to manage such HRARs. In the study, rat models with systemic HRARs and local HRARs of the skin were established. The level of vascular permeability and mast cell numbers was determined by quantitative analysis using Evans blue dye and histological assays. The levels of histamine, leukotriene B4 (LTB4) and IL-33 in plasma were detected by UHPLC-SPE-MS, ELISA and immunohistochemistry assays, respectively. The results demonstrated that SIN significantly induced both systemic and local HRARs in rats, showing significant decrease of body temperature, increases in vascular permeability in skin, injury of lung tissues and mast cell infiltration and IL-33 expression in skin and lung tissues. Mechanistic study showed that tranilast could prevent SIN-triggered HRARs via inhibition of H1 receptor gene expression and NF-kappaB signaling. Our findings provide evidence that mast cell membrane stabilizers and H1 receptor blockers effectively prevent SIN-induced HRARs, and cromolyn, cetirizine and tranilast can be used in the clinic for the management of HRARs induced by ZQFTN. PMID- 28867639 TI - Animal models of pulmonary arterial hypertension: A systematic review and meta analysis of data from 6126 animals. AB - Numerous animal models of pulmonary hypertension are currently available. A systematic review and meta-analysis was performed of a number of experimental studies of disease induction based on several animal models. A meta-analysis was performed of 291 publications discussing the efficacy of 611 interventions to introduce disease pulmonary hypertension in 6126 animals. A meta-regression analysis was done to assess the effect of prolonged periods of disease induction on the outcomes. A random-effects meta-analysis was used to assess the impact of study characteristics and seek evidence of publication bias. A more pronounced worsening in hemodynamics or right ventricle hypertrophy was observed in animals exposed to Sugen combined with hypoxia, or left pneumonectomy followed by monocrotaline. Chronic hypoxia induced the poorest, but the most stable, response to disease induction with regard to elevated hemodynamic parameters, right ventricle hypertrophy and wall thickening. The greatest elevation of right ventricle systolic pressure was observed in animals exposed to isoflurane and the weakest to chloral hydrate. This result was true for different animal models and lengths of induction of pulmonary hypertension. Publication bias was found for all the crucial parameters. Development of pulmonary hypertension depends on the choice of animal model. Classic models, especially these related to chronic hypoxia, provoke a less severe response with regard to poorer hemodynamics and myocardial hypertrophy. The outcome of disease development can be strongly determined by the duration of induction, detailed experimental conditions and anesthesia procedure. PMID- 28867640 TI - Development and Validation of a Teaching Module for Echocardiographic Scoring of Rheumatic Mitral Stenosis. AB - BACKGROUND: The Wilkins score and commissural calcification scores predict outcomes after percutaneous balloon mitral valvuloplasty. However, many cardiologists are inadequately trained in their application-both in the United States where the incidence of rheumatic heart disease has fallen and in rheumatic heart disease endemic countries where training infrastructure is weak. OBJECTIVES: This study sought to develop a computer-based educational module teaching 2 scoring systems for rheumatic mitral stenosis and to validate the module among cardiology fellows in the United States and Uganda. METHODS: We developed a module organized into 3 sets of 10 echocardiograms each. The module was completed by 13 cardiology fellows from 2 academic centers in the United States and 1 in Uganda. Subject answers were compared with a score assigned by 2 experts in echocardiography. The primary outcome was change in subjects' accuracy from set 1 to set 3, measured by mean absolute deviation from expert scores. Secondary outcomes included change in interoperator variability and individual subject bias from set 1 to set 3. RESULTS: The mean absolute deviations from expert scores in sets 1 and 3 were 2.09 and 1.82 for the Wilkins score (possible score range 0 to 16) and 1.13 and 0.94 for the commissural calcification score (possible score range 0 to 4). The change from set 1 to set 3 was statistically significant only for 1 of the Wilkins component scores (leaflet calcification, p < 0.001.) No change was seen in the interoperator variability. Individual subject bias in assigning the total Wilkins score was reduced from set 1 to set 3. CONCLUSIONS: Use of this module has the potential to enhance the training of cardiologists in the echocardiographic assessment of mitral stenosis. Modified versions of this module or similar ones should be tested in targeted populations of cardiology trainees with the most exposure to mitral stenosis interventions. PMID- 28867641 TI - A comparison of the management of blunt splenic injury in children and young people-A New South Wales, population-based, retrospective study. AB - : The importance and safety of non-operative management (NOM) of Blunt Splenic Injury (BSI) has been established in children and adults over recent decades. However, studies have shown higher operation rates in adults. There is international evidence that when children are managed in adult centres, operation rates are higher while adolescents in paediatric centres, are operated on in line with paediatric guidelines. This difference between children and young adults, and the factors responsible, have not been examined in New South Wales (NSW). OBJECTIVE: To use NSW hospital and mortality data to compare the characteristics of BSI in patients aged 0-16 to those aged 17-25, and determine factors related to operative management (OM) and splenic salvage in each group. METHODS: Patients age 0-25 between July 2000 and December 2011, with a diagnosis of BSI, were identified in the NSW Admitted Patient Data Collection, and linked to deaths data from Registry of Births Deaths and Marriages and Bureau of Statistics. Operation rate was compared between the two groups. Univariable analysis was used to determine factors associated with OM. Multivariable logistic regression with stepwise elimination was then performed to determine likelihood of OM according to age group, adjusting for potential confounders. RESULTS: 1986 cases were identified, with 422 (21.2%) managed operatively - 101/907 children (11.1%) and321/1079 (29.7%)young adults(p<0.001). Of these, 59 (58%) children underwent splenectomy compared with 233 (73%) young adults (p<0.001). OM increased significantly after the age of 12 (p=0.03), and the percentage almost tripled in the teenage years, coinciding with a higher proportion admitted to adult centres. OM doubled again in young adults(p<0.001), all of whom were managed away from paediatric centres. On multivariable analysis, factors significantly associated with operation included age over 16 (OR 2.82, 95%CI 2.10-3.81), splenic injury severity, associated thoracic, liver, pancreatic and hollow viscus injury, and blood transfusion. CONCLUSION: While Paediatric Surgeons have wholeheartedly adopted non-operative management, away from paediatric centres, it is possible children and young people in NSW are undergoing operation unnecessarily. Further evaluation of the surgeon attitudes and institutional factors involved in the management of injured children and young people within the broad NSW trauma system is required. PMID- 28867642 TI - Phonomyography as a non-invasive continuous monitoring technique for muscle ischemia in an experimental model of acute compartment syndrome. AB - BACKGROUND: In acute compartment syndrome (ACS), clinicians have difficulty diagnosing muscle ischemia provoked by increased intra-compartmental pressure in a timely and non-invasive manner. Phonomyography records the acoustic signal produced by muscle contraction. We hypothesize that alterations in muscle contraction caused by muscle ischemia can be detected with phonomyography, serving as a potential non-invasive technique in the detection of ACS. METHODS: The left hind limb of 15 Sprague-Dawley rats was submitted to a reversible ischemic model of limb injury for 30min and 1, 2, 4, 6h (3 rats in each group). The right limb served as control. Phonomyography microphones were placed over the posterior calf of both limbs and the sciatic nerve was stimulated percutaneously at 10-min intervals to evaluate muscle contraction. Histopathological analysis of muscles and nerves biopsies was performed and correlation was made between duration of injury, phonomyography output and degree of muscle and nerve necrosis. RESULTS: There was a statistically significant decrease in the phonomyography signal output in the ischemic limb that correlated with the duration of ischemia and histological findings of muscle and nerve necrosis. The phonomyography signal decrease and histological findings were respectively: 55.5% (n=15;p=0.005) with rare muscle and nerve necrosis at 30min, 65.6% (n=12;p=0.005) with 5-10% muscle necrosis at 1h, 68.4% (n=9;p=0.015) with 100% muscle necrosis and little nerve damage at 2h, 72.4% (n=6;p=0.028) with 100% muscle necrosis and severe nerve damage at 4h, and 92.8% (n=3;p=0.109) with 100% muscle necrosis and severe nerve degeneration at 6h. CONCLUSION: Changes in phonomyography signal are observed in early ischemic injury prior to the onset of nerve or muscle necrosis. Therefore, phonomyography could serve as a non-invasive technique to detect early ischemic muscle changes in acute compartment syndrome. CLINICAL RELEVANCE: The detection of abnormal muscle contraction in a timely fashion and non-invasive manner is of interest in clinical settings where the presence of ischemia is not easy to diagnose. PMID- 28867643 TI - Subtrochanteric fractures of the femur. Treatment with locking intramedullary nailing. An experience without C-Arc. The guide-wire stopping method for verify distal locking is described. AB - OBJECTIVE: Evaluate the results of treatment of subtrochanteric fracture with interlocked intramedullary nail and describe a technical for accurate and secure verification of distal locking position when we do surgery without arc-C. METHODS: A case series where was reviewed the results in 49 patients with subtrochanteric fracture and treated locking intramedullary nailing. The AO and Russell-Taylor Classification were used. The statistic procedure was done with SPSS program. The traumatic hip scale of Sander et al. was used for final evaluation. Technical for doing distal locking is detailed. RESULTS: This series evaluated 49 patients: 35 male and 14 female patients. The mean age was 36 years old (range: 18-86 years). Traffic accidents and gunshot wounds were injury forms most frequent. There were not transoperative complications. The surgical time was between 90 and 120min (mean: 108min). The mean follow-up was 24 months (range: 18 36 months). According to Sanders score, it was reported 22 excellent results, 20 good results and 7 regular results. All distal locking procedures were successfully performed. CONCLUSION: Although this series consists in a few numbers of patients, we recommend the placement of interlocked intramedullary nail (Closs-MB Bioimpianti(r) and Orthosintese(r)) in subtrochanteric fractures. This device allows placement of distal locking through the insertion frame with safety and precision, even in surgery rooms without arc-C. The guide-wire stopping method allows the verification of distal locking in an objective, accurate, safe and reproducible way. PMID- 28867644 TI - Fracture-related infection: A consensus on definition from an international expert group. AB - Fracture-related infection (FRI) is a common and serious complication in trauma surgery. Accurately estimating the impact of this complication has been hampered by the lack of a clear definition. The absence of a working definition of FRI renders existing studies difficult to evaluate or compare. In order to address this issue, an expert group comprised of a number of scientific and medical organizations has been convened, with the support of the AO Foundation, in order to develop a consensus definition. The process that led to this proposed definition started with a systematic literature review, which revealed that the majority of randomized controlled trials in fracture care do not use a standardized definition of FRI. In response to this conclusion, an international survey on the need for and key components of a definition of FRI was distributed amongst all registered AOTrauma users. Approximately 90% of the more than 2000 surgeons who responded suggested that a definition of FRI is required. As a final step, a consensus meeting was held with an expert panel. The outcome of this process led to a consensus definition of FRI. Two levels of certainty around diagnostic features were defined. Criteria could be confirmatory (infection definitely present) or suggestive. Four confirmatory criteria were defined: Fistula, sinus or wound breakdown; Purulent drainage from the wound or presence of pus during surgery; Phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens; Presence of microorganisms in deep tissue taken during an operative intervention, as confirmed by histopathological examination. Furthermore, a list of suggestive criteria was defined. These require further investigations in order to look for confirmatory criteria. In the current paper, an overview is provided of the proposed definition and a rationale for each component and decision. The intention of establishing this definition of FRI was to offer clinicians the opportunity to standardize clinical reports and improve the quality of published literature. It is important to note that the proposed definition was not designed to guide treatment of FRI and should be validated by prospective data collection in the future. PMID- 28867645 TI - 5-Fluorouracil induces inflammation and oxidative stress in the major salivary glands affecting salivary flow and saliva composition. AB - This study aimed to elucidate the effect of 5-fluorouracil (5-FU) on the histological aspects of the major salivary glands, salivary flow and saliva composition using an established oral mucositis model in hamsters. Oral mucositis was induced by two intraperitoneal administrations of 5-FU in two consecutive days (60 and 40mg/kg), followed by cheek pouch mucosa scratch, on day 4. The Pilocarpine-stimulated salivary flow was measured 4 and 10days after the first 5 FU injection. Salivary glands were harvested for histopathological analysis, measurement of inflammatory cells, quantification of pro-inflammatory cytokines (TNF-alpha and IL-1beta), investigation of cell death and cell proliferation. Oxidative stress and oxidative defense system were also investigated in the salivary gland tissues using MDA (malondialdehyde), nitrite, non-protein sulfhydryl groups (NP-SH), SOD (superoxide dismutase) and CAT (catalase). In addition, the CAT and lysozyme activities and the IgA and SOD levels were evaluated in the saliva samples. 5-FU significantly reduced the pilocarpine stimulated salivary flow rate on the 4th experimental day, associated with an increase in the SOD levels in saliva. Recovery of the salivary flow and SOD were observed on day 10, when an increase in the saliva lysozyme levels was detected. In addition, 5-FU promoted vacuolization in parotid (P) and periductal edema in submandibular (SM) gland, combined with an increase in the inflammatory cells influx, mostly observed on the 4th day in SM gland and on 4th and 10th days in P. Oxidative stress was found mostly on day 10 in SM, SL and P glands, associated with release of proinflammatory cytokines, observed in SM and SL glands, but not in P. 5-FU induces an inflammatory response in the major salivary glands, most observed ten days after its first injection, which may contribute to the major salivary glands hypofunction, leading to alterations in the salivary flow rate and composition. PMID- 28867646 TI - The MCU complex in cell death. AB - During the 60s, the notion that positively charged Ca2+ ions are rapidly accumulated in energized mitochondria has been first established. In the following decades, mitochondrial Ca2+ homeostasis was shown to control cell metabolism, cell survival and other cell-specific functions through different mechanism. However, the molecular identity of the molecules controlling this process remained a mystery until just few years ago, when both mitochondrial Ca2+ uptake and release systems were genetically dissected. This finally opened the possibility to develop genetic model to directly test the contribution of mitochondrial Ca2+ homeostasis to cellular functions. Although the picture is still far from being clear, we here summarize and critically evaluate the current knowledge on how mitochondrial Ca2+ handling controls cell death. PMID- 28867648 TI - Tendon injury and repair - A perspective on the basic mechanisms of tendon disease and future clinical therapy. AB - : Tendon is an intricately organized connective tissue that efficiently transfers muscle force to the bony skeleton. Its structure, function, and physiology reflect the extreme, repetitive mechanical stresses that tendon tissues bear. These mechanical demands also lie beneath high clinical rates of tendon disorders, and present daunting challenges for clinical treatment of these ailments. This article aims to provide perspective on the most urgent frontiers of tendon research and therapeutic development. We start by broadly introducing essential elements of current understanding about tendon structure, function, physiology, damage, and repair. We then introduce and describe a novel paradigm explaining tendon disease progression from initial accumulation of damage in the tendon core to eventual vascular recruitment from the surrounding synovial tissues. We conclude with a perspective on the important role that biomaterials will play in translating research discoveries to the patient. STATEMENT OF SIGNIFICANCE: Tendon and ligament problems represent the most frequent musculoskeletal complaints for which patients seek medical attention. Current therapeutic options for addressing tendon disorders are often ineffective, and the need for improved understanding of tendon physiology is urgent. This perspective article summarizes essential elements of our current knowledge on tendon structure, function, physiology, damage, and repair. It also describes a novel framework to understand tendon physiology and pathophysiology that may be useful in pushing the field forward. PMID- 28867647 TI - Inhibitory effects of melatonin on titanium particle-induced inflammatory bone resorption and osteoclastogenesis via suppression of NF-kappaB signaling. AB - : Wear debris-induced peri-implant osteolysis challenges the longevity of implants. The host response to wear debris causes chronic inflammation, promotes bone resorption, and impairs bone formation. We previously demonstrated that melatonin enhances bone formation and attenuates wear debris-induced bone loss in vivo. However, whether melatonin inhibits chronic inflammation and bone resorption at sites of wear debris-induced osteolysis remains unclear. In this study, we examined the potential inhibitory effects of melatonin on titanium particle-induced inflammatory osteolysis in a murine calvarial model and on RANKL induced osteoclastic formation in bone marrow-derived macrophages. We found that the exogenous administration of melatonin significantly inhibited wear debris induced bone resorption and the expression of inflammatory cytokines in vivo. Additionally, melatonin inhibited RANKL-induced osteoclast differentiation, F actin ring formation, and osteoclastic resorption in a concentration-dependent manner in vitro. We also showed that melatonin blocked the phosphorylation of IkappaB-alpha and p65, but not IKKalpha, and significantly inhibited the expression of NFATc1 and c-Fos. However, melatonin had no effect on MAPK or PI3K/AKT signaling pathways. These results provide novel mechanistic insight into the anti-inflammatory and anti-bone resorptive effects of melatonin on wear debris-induced bone loss and provide an evidence-based rationale for the protective effects of melatonin as a treatment for peri-implant osteolysis. STATEMENT OF SIGNIFICANCE: Wear debris-induced chronic inflammation, osteoclastic activation and osteoblastic inhibition have been identified as critical factors of peri-implant bone loss. We previously demonstrated that melatonin, a bioactive indolamine secreted mainly by the pineal gland, activates Wnt/beta-catenin signaling pathway and enhances bone regeneration at osteolytic site in vivo. In the current study, we further demonstrated that melatonin significantly suppresses wear debris-induced bone resorption and inflammatory cytokine expression in vivo. In addition, melatonin inhibits receptor activator of nuclear factor kappa-B ligand induced osteoclast formation and osteoclastic bone resorption in vitro. Meanwhile, we found that melatonin mediates its anti inflammation and anti-bone resorption effects by abrogating nuclear factor kappa B activation. These results further support the protective effects of melatonin on wear debris-induced peri-implant bone loss, and strongly suggest that melatonin could be considered as a potential candidate for the prevention and treatment of wear debris-induced osteolysis and subsequent aseptic loosening. PMID- 28867649 TI - Synthesis and characterization of arginine-NIPAAm hybrid hydrogel as wound dressing: In vitro and in vivo study. AB - : A multi-functional hybrid hydrogel P(M-Arg/NIPAAm) with temperature response, anti-protein adsorption and antibacterial properties was prepared and applied as wound dressing. The hydrogel was carried out by free radical copolymerization of methacrylate arginine (M-Arg) and N-isopropyl acrylamide (NIPAAm) monomers using N,N'-methylene bisacrylamide as a crosslinker, and ammonium persulfate/N,N,N', N' tetramethylethylenediamine as the redox initiator. To endow the antimicrobial property, chlorhexidine diacetate (CHX) was preloaded into the hydrogel and polyhexamethylene guanidine phosphate (PHMG) was grafted on the hydrogel surface, respectively. The antimicrobial property of two series of hydrogels was evaluated and compared. The successful synthesis of M-Arg, PHMG and hydrogels was proved by 13C NMR, 1H NMR and FTIR spectroscopy. The hydrogel morphology characterized by scanning electron microscopy confirmed that the homogeneous porous and interconnected structures of the hydrogels. The swelling, protein adsorption property, in vitro release of CHX, antimicrobial assessment, cell viability as well as in vivo wound healing in a mouse model were studied. The results showed the nontoxicity and antimicrobial P(M-Arg/NIPAAm) hydrogel accelerated the full thickness wound healing process and had the potential application in wound dressing. STATEMENT OF SIGNIFICANCE: Despite the zwitterionic characteristic and biocompatible property of arginine based hydrogels, the brittle behavior and non transparency still remain as a significant problem for wound dressing. Furthermore promoting the antibacterial property of the zwitterionic hydrogel is also necessary to prevent the bacterial colonization and subsequent wound infection. Therefore, we created a hybrid hydrogel combined methacrylate arginine (M-Arg) and N-isopropyl acrylamide (NIPAAm). NIPAAm improves transparency and mechanical property as well as acts as a temperature-response drug release system. Additionally, chlorhexidine (CHX) was preloaded into the hydrogels and polyhexamethylene guanidine phosphate (PHMG) was grafted on the hydrogel surface, respectively, which make the hydrogel useful as a favorable antibacterial dressing. The hybrid hydrogel has a combination effect of biocompatibility, environmentally responsive transformation behavior, biodegradability, anti protein adsorption and antimicrobial properties. This report proposes the preparation of P(M-Arg/NIPAAm) hydrogel that has a great potential for wound healing. PMID- 28867650 TI - A postoperative anti-adhesion barrier based on photoinduced imine-crosslinking hydrogel with tissue-adhesive ability. AB - : Postoperative adhesion is a serious complication that can further lead to morbidity and/or mortality. Polymer anti-adhesion barrier material provides an effective precaution to reduce the probability of postoperative adhesion. Clinical application requires these materials to be easily handled, biocompatible, biodegradable, and most importantly tissue adherent to provide target sites with reliable isolation. However, currently there is nearly no polymer barrier material that can fully satisfy these requirements. In this study, based on the photoinduced imine-crosslinking (PIC) reaction, we had developed a photo-crosslinking hydrogel (CNG hydrogel) that composed of o nitrobenzyl alcohol (NB) modified carboxymethyl cellulose (CMC-NB) and glycol chitosan (GC) as an anti-adhesion barrier material. Under light irradiation, CMC NB generated aldehyde groups which subsequently reacted with amino groups distributed on GC or tissue surface to form a hydrogel barrier that covalently attached to tissue surface. Rheological analysis demonstrated that CNG hydrogel (30mg/mL polymer content) could be formed in 30s upon light irradiation. Tissue adhesive tests showed that the tissue adhesive strength of CNG hydrogel (30mg/mL) was about 8.32kPa-24.65kPa which increased with increasing CMC-NB content in CNG hydrogel. Toxicity evaluation by L929 cells demonstrated that CNG hydrogel was cytocompatible. Furthermore, sidewall defect-cecum abrasion model of rat was employed to evaluate the postoperative anti-adhesion efficacy of CNG hydrogel. And a significantly reduction of tissue adhesion (20% samples with low score adhesion) was found in CNG hydrogel treated group, compared with control group (100% samples with high score adhesion). In addition, CNG hydrogel could be degraded in nearly 14days and showed no side effect on wound healing. These findings indicated that CNG hydrogel can effectively expanded the clinical treatments of postoperative tissue adhesion. STATEMENT OF SIGNIFICANCE: In this study, a tissue adhesive photo-crosslinking hydrogel (CNG) was developed based on photo-induced imine crosslinking reaction (PIC) for postoperative anti-adhesion. CNG hydrogel showed the features of easy and convenient operation, fast and controllable gelation, suitable gel strength, good biocompatibility, and most importantly strong tissue adhesiveness. Therefore, it shows very high performance to prevent postoperative tissue adhesion. Overall, our study provides a more suitable hydrogel barrier material that can overcome the shortcomings of current barriers for clinical postoperative anti-adhesion. PMID- 28867651 TI - Effects of cavity reconstruction on morbidity and quality of life after canal wall down tympanomastoidectomy. AB - INTRODUCTION: Canal wall down tympanomastoidectomy is commonly used to treat advanced chronic otitis media or cholesteatoma. The advantages of canal wall down mastoidectomy are excellent exposure for disease eradication and postoperative control of residual disease; its disadvantages include the accumulation of debris requiring life-long otological maintenance and cleaning, continuous ear drainage, fungal cavity infections, and the occurrence of dizziness and vertigo by changing temperature or pressure. OBJECTIVE: To evaluate whether cavity-induced problems can be eliminated and patient comfort can be increased with mastoid cavity reconstruction. METHODS: In total, 11 patients who underwent mastoid cavity reconstruction between March 2013 and June 2013 comprised the study group, and 11 patients who had dry, epithelialized CWD cavities were recruited as the control group. The study examined three parameters: epithelial migration, air caloric testing, and the Glasgow Benefit Inventory. Epithelial migration, air caloric testing, and the Glasgow Benefit Inventory were evaluated in the study and control groups. RESULTS: The epithelial migration rate was significantly faster in study group (1.63+/-0.5mm/week) than control group (0.94+/-0.37mm/week) (p=0.003, p<0.05). The mean slow component velocity of nystagmus of the study group (13.33+/-5.36 degrees /s) was significantly lower when compared to control group (32.11+/-9.12 degrees /s) (p=0.018). The overall the Glasgow Benefit Inventory score was -7.21, and the general subscale, physical and social health scores were -9.71, -21.09, and +20.35, respectively in the control group. These were +33.93, +35.59, +33.31, and +29.61, respectively in the study group. All but the social health score improved significantly (0.007, 0.008, 0.018, and 0.181, respectively). CONCLUSIONS: Cavity reconstruction improves epithelial migration, normalizes caloric responses and increases the quality of life. Thus, cavity rehabilitation eliminates open-cavity-induced problems by restoring the functional anatomy of the ear. PMID- 28867652 TI - The neuropsychology and neurobiology of late-onset schizophrenia and very-late onset schizophrenia-like psychosis: A critical review. AB - OBJECTIVE: The current review discusses neuropsychological profiles and the longitudinal course of cognitive dysfunction in Late Onset Schizophrenia (LOS) and Very-late-onset schizophrenia-like psychosis (VLOSLP), and attempts to clarify its neurobiological underpinnings. METHOD: A systematic literature search resulted in 29 publications describing original research on the neuropsychology of LOS/VLOSLP and 46 studies focussing on neurobiology. RESULTS: Although mildly progressive cognitive impairment is usually present, only a subgroup of LOS/VLOSLP develops dementia during a 10-year follow-up succeeding the onset of psychosis. This coincides with the absence of neuropathological evidence for neurodegeneration in many cases. Cognitive deterioration is characterized by deficits in (working) memory, language, psychomotor speed and executive functioning. Underlying neurobiological changes encompass white matter pathology, increased ventricle-to-brain ratio (VBR) with coinciding atrophy and hypo metabolism of frontal, temporal and subcortical areas. CONCLUSIONS: Multiple changes in neurobiology and cognition contributing to LOS/VLOSLP may reflect stress-related accelerated brain aging rather than neurodegenerative pathology. Their involvement in the onset of illness, however, might be inversely proportional to pre-existing (psychosocial and/or genetic) vulnerability to psychosis. PMID- 28867653 TI - Comprehensive review: Computational modelling of schizophrenia. AB - Computational modelling has been used to address: (1) the variety of symptoms observed in schizophrenia using abstract models of behavior (e.g. Bayesian models - top-down descriptive models of psychopathology); (2) the causes of these symptoms using biologically realistic models involving abnormal neuromodulation and/or receptor imbalance (e.g. connectionist and neural networks - bottom-up realistic models of neural processes). These different levels of analysis have been used to answer different questions (i.e. understanding behavioral vs. neurobiological anomalies) about the nature of the disorder. As such, these computational studies have mostly supported diverging hypotheses of schizophrenia's pathophysiology, resulting in a literature that is not always expanding coherently. Some of these hypotheses are however ripe for revision using novel empirical evidence. Here we present a review that first synthesizes the literature of computational modelling for schizophrenia and psychotic symptoms into categories supporting the dopamine, glutamate, GABA, dysconnection and Bayesian inference hypotheses respectively. Secondly, we compare model predictions against the accumulated empirical evidence and finally we identify specific hypotheses that have been left relatively under-investigated. PMID- 28867654 TI - Preterm behavioral epigenetics: A systematic review. AB - Behavioral epigenetics is revealing new pathways that lead individuals from early adversity exposures to later-in-life detrimental outcomes. Preterm birth constitutes one of the major adverse events in human development. Preterm infants are hospitalized in the Neonatal Intensive Care Unit (NICU) where they are exposed to life-saving yet pain-inducing procedures and to protective care. The application of behavioral epigenetics to the field of preterm studies (i.e., Preterm Behavioral Epigenetics, PBE) is rapidly growing and holds promises to provide valid insights for research and clinical activity. Here, the evidence of the epigenetic correlates of prenatal adversities, NICU-related environment and development of preterm infants is systematically reviewed. The findings suggest that a number of prenatal adverse (e.g., maternal depression and stress) and post natal (e.g., NICU-related pain-related stress) events affect the developmental trajectories of preterm infants and children via epigenetic alterations of imprinted and stress-related genes. Nonetheless, the potential epigenetic vestiges of early care and protective interventions in NICU have not been investigated yet and this represents a fascinating challenge for future PBE research. PMID- 28867655 TI - Cosmetic genital surgery in children and adolescents. AB - Clinicians are faced with increasing requests for female cosmetic genital surgery and prominent amongst these is labiaplasty. The implications of labiaplasty in adolescence are explored with emphasis on what is known about normal genital appearances, pubertal development, anatomy and physiology and the options for surgical intervention including risks and implications. Faced with what is known to date on female cosmetic genital surgery then such interventions should be avoided in adolescence in the absence of defined medical indications until at least the age of 18 years. PMID- 28867656 TI - Possible Contribution of Fibrocytes to Increased Type I Collagen Synthesis during the Early Stage of Dermal Wound Repair in Human Skin. PMID- 28867657 TI - Imbalance of Mitochondrial Respiratory Chain Complexes in the Epidermis Induces Severe Skin Inflammation. AB - Accumulation of large-scale mitochondrial DNA (mtDNA) deletions and chronic, subclinical inflammation are concomitant during skin aging, thus raising the question of a causal link. To approach this, we generated mice expressing a mutant mitochondrial helicase (K320E-TWINKLE) in the epidermis to accelerate the accumulation of mtDNA deletions in this skin compartment. Mice displayed low amounts of large-scale deletions and a dramatic depletion of mtDNA in the epidermis and showed macroscopic signs of severe skin inflammation. The mtDNA alterations led to an imbalanced stoichiometry of mitochondrial respiratory chain complexes, inducing a unique combination of cytokine expression, causing a severe inflammatory phenotype, with massive immune cell infiltrates already before birth. Altogether, these data unraveled a previously unknown link between an imbalanced stoichiometry of the mitochondrial respiratory chain complexes and skin inflammation and suggest that severe respiratory chain dysfunction, as observed in few cells leading to a mosaic in aged tissues, might be involved in the development of chronic subclinical inflammation. PMID- 28867658 TI - Identification and characterization of a potent and biologically-active PDE4/7 inhibitor via fission yeast-based assays. AB - We previously constructed a collection of fission yeast strains that express various mammalian cyclic nucleotide phosphodiesterases (PDEs) and developed a cell-based high throughput screen (HTS) for small molecule PDE inhibitors. Here we describe a compound, BC54, that is a selective inhibitor of enzymes from the cAMP-specific PDE4 and PDE7 families. Consistent with the biological effect of other PDE4 and PDE7 inhibitors, BC54 displays potent anti-inflammatory properties and is superior to a combination of rolipram (a PDE4 inhibitor) and BRL50481 (a PDE7A inhibitor) for inducing apoptosis in chronic lymphocytic leukemia (CLL) cells. We further exploited PKA-regulated growth phenotypes in fission yeast to isolate two mutant alleles of the human PDE4B2 gene that encode enzymes possessing single amino acid changes that confer partial resistance to BC54. We confirm this resistance to both BC54 and rolipram via yeast-based assays and, for PDE4B2T407A, in vitro enzyme assays. Thus, we are able to use this system for both chemical screens to identify biologically-active PDE inhibitors and molecular genetic studies to characterize the interaction of these molecules with their target enzymes. Based on its potency, selectivity, and effectiveness in cell culture, BC54 should be a useful tool to study biological processes regulated by PDE4 and PDE7 enzymes. PMID- 28867659 TI - t-Darpp stimulates protein kinase A activity by forming a complex with its RI regulatory subunit. AB - t-Darpp is the truncated form of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (Darpp-32) and has been demonstrated to confer resistance to trastuzumab, a Her2-targeted anticancer agent, via sustained signaling through the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt pathway and activation of protein kinase A (PKA). The mechanism of t-Darpp-mediated PKA activation is poorly understood. In the PKA holoenzyme, when the catalytic subunits are bound to regulatory subunits RI or RII, kinase activity is inhibited. We investigated PKA activity and holoenzyme composition in cell lines overexpressing t-Darpp (SK.tDp) or a T39A phosphorylation mutant (SK.tDpT39A), as well as an empty vector control cell line (SK.empty). We also evaluated protein protein interactions between t-Darpp and PKA catalytic (PKAc) or regulatory subunits RI and RII in those cell lines. SK.tDp cells had elevated PKA activity and showed diminished association of RI with PKAc, whereas SK.tDpT39A cells did not have these properties. Moreover, wild type t-Darpp associates with RI. Concurrent expression of Darpp-32 reversed t-Darrp's effects on PKA holoenzyme state, consistent with earlier observations that Darpp-32 reverses t-Darpp's activation of PKA. Together, t-Darpp phosphorylation at T39 seems to be crucial for t-Darpp-mediated PKA activation and this activation appears to occur through an association with RI and sequestering of RI away from PKAc. The t-Darpp-RI interaction could be a druggable target to reduce PKA activity in drug-resistant cancer. PMID- 28867660 TI - Effects of smear layer removal agents on the physical properties and microstructure of mineral trioxide aggregate cement. AB - OBJECTIVE: To compare the effect of QMix (Dentsply Sirona), 7% maleic acid (MA), and 17% ethylenediaminetetraacetic acid (EDTA) on the microhardness, flexural strength and microstructure of mineral trioxide aggregate (MTA; ProRoot MTA, Dentsply Sirona). METHODS: Forty MTA specimens were divided into four groups: [I] QMix [II] 7% MA [III] 17% EDTA and [IV] distilled water (control). After treatment with 5mL of the respective solution for 1min, the specimens were tested for microhardness using a Knoop hardness tester. Forty additional specimens were similarly treated and evaluated for the flexural strength using a universal testing machine. For microstructure evaluation, MTA specimens were treated in a similar manner and examined by X-ray diffractometry and scanning electron microscopy (SEM). RESULTS: For microhardness, there were no differences between distilled water, QMix and EDTA groups. However, MTA exposed to distilled water had higher microhardness than MA. When compared with QMix and EDTA, MA had lower microhardness; there was no difference between EDTA and QMix. For flexural strength, distilled water group had higher flexural strength than the other agents. There were no differences between EDTA vs MA and EDTA vs QMix. Specimens treated with QMix had higher flexural strength than MA. X-ray diffraction indicated that EDTA inhibited hydration of MTA. For SEM, all the tested agents altered the microstructure of MTA when compared to distilled water. CONCLUSION: MA had more detrimental effect on the physical properties of MTA and EDTA was more detrimental to the hydration of MTA. CLINICAL SIGNIFICANCE: The present study highlights the effect of newer chelating agents on the physical properties and microstructure of MTA. Preventing the deterioration of MTA is important for its long term success in endodontic procedures. PMID- 28867661 TI - Influence of specimens' geometry and materials on the thermal stresses in dental restorative materials during thermal cycling. AB - OBJECTIVES: Thermal cycling is widely used to simulate the aging of restorative materials corresponding to the changes of temperature in the oral cavity. However, test parameters present in literature vary considerably, which prevents comparison between different reports. The aim of this work is to assess the influence of the specimens' geometry and materials on the thermal stresses developed during thermal cycling tests. MATERIALS AND METHODS: Finite elements method was used to simulate the conditions of thermal cycling tests for three different sample geometries: a three-points bending test sample, a cylinder rod and more complex shape of a restoration crown. Two different restorative systems were considered: all-ceramic (zirconia coupled with porcelain) and metal-ceramic (CoCrMo alloy coupled with porcelain). The stress state of each sample was evaluated throughout the test cycle. RESULTS: The results show that the sample geometry has great influence on the stress state, with difference of up to 230% in the maximum stress between samples of the same composition. The location of maximum stress also changed from the interface between materials to the external wall. CONCLUSIONS: Maximum absolute stress values were found to vary between 2 and 4MPa, which might not be critical even for ceramics. During multi-cycle testing these stresses would cause different fatigue in various locations. The zirconia-based specimens and zirconia-based restoration (crown) exhibited the most similar stress states. Thus it might be recommended to use these geometries for fast screening of the materials for this type of restorations. CLINICAL SIGNIFICANCE: The selection of specimens' geometry and materials should be carefully considered when aging conditions close to clinical ones want to be simulated. PMID- 28867663 TI - High-density peptide microarray exploration of the antibody response in a rabbit immunized with a neurotoxic venom fraction. AB - Polyvalent snakebite antivenoms derive their therapeutic success from the ability of their antibodies to neutralize venom toxins across multiple snake species. This ability results from a production process involving immunization of large mammals with a broad suite of toxins present in venoms. As a result of immunization with this wide range of toxins, many polyvalent antivenoms have a high degree of cross-reactivity to similar toxins in other snake venoms - a cross reactivity which cannot easily be deconvoluted. As a proof of concept, we aimed at exploring the opposite scenario by performing a high-throughput evaluation of the extent of cross-reactivity of a polyclonal mixture of antibodies that was raised against only a single snake venom fraction. For this purpose, a venom fraction containing short neurotoxin 1 (SN-1; Uniprot accession number P01416, three-finger toxin (3FTx) family), which is the medically most important toxin from the notorious black mamba (Dendroaspis polylepis), was employed. Following immunization of a rabbit, a specific polyclonal antibody response was confirmed by ELISA and immunodiffusion. Subsequently, these antibodies were investigated by high-density peptide microarray to reveal linear elements of recognized epitopes across 742 3FTxs and 10 dendrotoxins. This exploratory study demonstrates in a single immunized animal that cross-reactivity between toxins of high similarity may be difficult to obtain when immunizing with a single 3FTx containing venom fraction. Additionally, this study explored the influence of employing different lengths of peptides in high-density peptide microarray experiments for identification of toxin epitopes. Using 8-mer, 12-mer, and 15-mer peptides, a single linear epitope element was identified in SN-1 with high precision. PMID- 28867662 TI - High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers. AB - OBJECTIVES: Fosfomycin is increasingly being prescribed for treatment of uncomplicated urinary tract infections in an era of emerging drug resistance. Surprisingly, little is known of the urinary concentrations of fosfomycin and its interindividual variation after the standard single 3-g oral dose. We aimed to gain more insight into urinary fosfomycin pharmacokinetics to evaluate its effectiveness. METHODS: Three grams of fosfomycin trometamol was administered to 40 healthy female volunteers with an estimated mean glomerular filtration rate of >90 mL/min/1.73m2. Urine samples were collected from every urination during 48 hours, and then twice daily for up to 7 days. Time, volume, and pH were recorded. Concentrations were quantified with UPLC-MS/MS. Effectiveness was evaluated based on urinary concentrations and the target MIC of E. coli, the most common uropathogen. RESULTS: A high interindividual variability was found. Peak concentration was 1982.0 +/- 1257.4 mg/L, urinary half-life 12.4 +/- 5.7 hours, and excretion rate over 48 hours 29.9 +/- 7.1 mg/h. Recovery was 44.5 +/- 12.6% after 48 hours and 47.0 +/- 10.4% after 7 days. Concentrations remained above the EUCAST breakpoint of 32 mg/L in 100% of the volunteers over the first 24 hours, 67.5% for 48 hours, and 30% for 72 hours. A high urinary output was associated with low urinary concentrations and consequently reduced time > MIC, AUC0 7days/MIC, and Cmax/MIC values. CONCLUSIONS: Considerable interindividual variability observed in the pharmacokinetics of fosfomycin signifies a risk for inadequate drug exposure in a significant proportion of the population. The current dosing regimen should therefore be reevaluated. PMID- 28867664 TI - Reliability and Validity of Subjective Measures of Aerobic Intensity in Adults With Spinal Cord Injury: A Systematic Review. AB - OBJECTIVE: To systematically synthesize and appraise research regarding test retest reliability or criterion validity of subjective measures for assessing aerobic exercise intensity in adults with spinal cord injury (SCI). DATA SOURCES: Electronic databases (Pubmed, PsychINFO, SPORTDiscus, EMBASE, and CINAHL) were searched from inception to January 1, 2016. STUDY SELECTION: Studies involving at least 50% of participants with SCI who performed an aerobic exercise test that included measurement of subjective and objective intensity based on test-retest reliability or criterion validity protocols. DATA EXTRACTION: Characteristics were extracted on study design, measures, participants, protocols, and results. Each study was evaluated for risk of bias based on strength of the study design and a quality checklist score (COnsensus-based Standards for the selection of health Measurement INstruments [COSMIN]). DATA SYNTHESIS: The 7 eligible studies (1 for reliability, 6 for validity) evaluated overall, peripheral and/or central ratings of perceived exertion (RPE) on a scale of 6-20 (RPE 6-20). No eligible studies were identified for other subjective intensity measures. The evidence for reliability and validity were synthesized separately for each measure and were assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Overall, very low GRADE confidence ratings were established for reliability and validity evidence generalizable to the entire population with SCI and various upper-body and lower-body modalities. There was low confidence for the evidence showing that overall RPE 6-20 has acceptable validity for adults with SCI and high fitness levels performing moderate to vigorous-intensity upper body aerobic exercise. CONCLUSIONS: Health care professionals and scientists need to be aware of the very low to low confidence in the evidence, which currently prohibits a strong clinical recommendation for the use of subjective measures for assessing aerobic exercise intensity in adults with SCI. However, a tentative, conditional recommendation regarding overall RPE 6-20 seems applicable, depending on participants' fitness level as well as the exercise intensity and modality used. LEVEL OF EVIDENCE: NA. PMID- 28867666 TI - Unilateral Lower Extremity Pain Due to Malignancy Managed With Cordotomy: A Case Report. AB - : Cancer pain management is comprehensive, and it generally begins with pharmacotherapy in a step-wise approach per analgesic guidelines established decades ago by the World Health Organization. This analgesic ladder involves the prescribing of co-analgesics, adjuvants, and opioids, with each step depending on pain severity. Although the majority of cancer pain responds to this strategy, there exist patients who do not respond adequately or experience significant side effects or intolerance to pain medications. It is in these patients whom clinicians consider interventional approaches. One approach to manage unremitting unilateral malignant pain includes evaluation for cordotomy, which is an approach that has been effective in such cases. We present a patient with breast cancer metastatic to the pelvis, with associated severe pelvic and right lower limb pain. Due to progressive disease, her pain worsened despite aggressive opioid dose escalations. She ultimately underwent percutaneous left anterolateral cervical cordotomy for malignant right leg pain, resulting in complete resolution of leg pain. We propose that, in select patients with neoplasm-related pain, cordotomy may prove very effective. LEVEL OF EVIDENCE: V. PMID- 28867665 TI - Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy. AB - BACKGROUND: Pharmacogenomic variability can contribute to differences in pharmacokinetics and clinical responses. Pediatric patients with cerebral palsy with genetic variations have not been studied for these potential differences. OBJECTIVE: To determine the genetic sources of variation in oral baclofen clearance and clinical responses. DESIGN: Pharmacogenomic add-on study to determine variability in oral baclofen clearance and clinical responses. SETTING: Multicenter study based in academic pediatric cerebral palsy clinics. PARTICIPANTS: A total of 49 patients with cerebral palsy who had participated in an oral baclofen pharmacokinetic/pharmacodynamic study. METHODS OR INTERVENTIONS: Of 53 participants in a pharmacokinetic/pharmacodynamic trial, 49 underwent genetic analysis of 307 key genes and 4535 single-nucleotide polymorphisms involved in drug absorption, distribution, metabolism, and excretion. Associations between genotypes and phenotypes of baclofen disposition (weight corrected and allometrically scaled clearance) and clinical endpoints (improvement from baseline in mean hamstring Modified Tardieu Scale scores from baseline for improvement of R1 spastic catch) were determined by univariate analysis with correction for multiple testing by false discovery rate. MAIN OUTCOME MEASUREMENTS: Primary outcome measures were the genotypic and phenotypic variability of oral baclofen in allometrically scaled clearance and change in the Modified Tardieu Scale angle compared to baseline. RESULTS: After univariate analysis of the data, the SNP of ABCC9 (rs11046232, heterozygous AT versus the reference TT genotype) was associated with a 2-fold increase in oral baclofen clearance (mean 0.51 +/- standard deviation 0.05 L/h/kg for the AT genotype versus 0.25 +/- 0.07 L/h/kg for the TT genotype, adjusted P < .001). Clinical responses were associated with decreased spasticity by Modified Tardieu Scale in allelic variants with SNPs ABCC12, SLC28A1, and PPARD. CONCLUSIONS: Genetic variation in ABCC9 affecting oral baclofen clearance highlights the need for continued studies of genetic polymorphisms to better characterize variable drug response in children with cerebral palsy. Single-nucleotide polymorphisms in ABCC12, SLC28A1, and PPARD were associated with varied responses, which warrants further investigation to determine their effect on spasticity. LEVEL OF EVIDENCE: II. PMID- 28867667 TI - Long-Term Effects of Orthoses Use on the Changes of Foot and Ankle Joint Motions of Children With Spastic Cerebral Palsy. AB - BACKGROUND: Orthoses commonly are prescribed to children with cerebral palsy (CP) to provide foot correction and to improve ambulatory function. Immediate effects of ankle foot orthosis (AFOs) have been investigated, but long-term kinematic effects are lacking clinical evidence. OBJECTIVE: To determine changes in 3 dimensional ankle and foot segment motion in pediatric patients with CP between initial and follow-up visits (18-month average time differences) in both barefoot gait and gait with their AFO. We also investigated intravisit changes between barefoot and AFO gait. DESIGN: A prospective cohort study. SETTING: Children's Hospital of Wisconsin, Department of Orthopaedic Surgery, Medical College of Wisconsin. PATIENTS: A total of 23 children with CP, mean age 10.5 years (6.2 18.1 years) were clinically prescribed either a solid ankle foot orthotic (SAFO), hinged ankle foot orthotic (HAFO), or supramalleolar orthotic. METHODS: Holes were cut in the study orthoses so that electromagnetic markers could be directly placed on the skin. A 6-foot segment model was used. OUTCOME MEASUREMENTS: Kinematic and kinetic data were recorded for each patient's initial and follow-up visit (18-month follow-up average, 15-20 months range). RESULTS: For the SAFO group (gait with AFO), a significant decrease in dorsiflexion was found between the initial and third visit (P = .008). Furthermore, the SAFO group (barefoot gait) had an increased eversion at the midfoot for most of the gait cycle (P < .008). Sagittal forefoot range of motion was reduced for all 3 groups between the barefoot and AFO groups. CONCLUSION: The use of AFOs long term either maintained or improved foot deformities or dysfunction. LEVEL OF EVIDENCE: Level II. PMID- 28867668 TI - MRI protocol optimization for quantitative DCE-MRI of the spine. AB - PURPOSE: In this study we systematically investigated different Dynamic Contrast Enhancement (DCE)-MRI protocols in the spine, with the goal of finding an optimal protocol that provides data suitable for quantitative pharmacokinetic modelling (PKM). MATERIALS AND METHODS: In 13 patients referred for MRI of the spine, DCE MRI of the spine was performed with 2D and 3D MRI protocols on a 3T Philips Ingenuity MR system. A standard bolus of contrast agent (Dotarem - 0.2ml/kg body weight) was injected intravenously at a speed of 3ml/s. Different techniques for acceleration and motion compensation were tested: parallel imaging, partial Fourier imaging and flow compensation. The quality of the DCE MRI images was scored on the basis of SNR, motion artefacts due to flow and respiration, signal enhancement, quality of the T1 map and of the arterial input function, and quality of pharmacokinetic model fitting to the extended Tofts model. RESULTS: Sagittal 3D sequences are to be preferred for PKM of the spine. Acceleration techniques were unsuccessful due to increased flow or motion artefacts. Motion compensating gradients failed to improve the DCE scans due to the longer echo time and the T2* decay which becomes more dominant and leads to signal loss, especially in the aorta. The quality scoring revealed that the best method was a conventional 3D gradient-echo acquisition without any acceleration or motion compensation technique. The priority in the choice of sequence parameters should be given to reducing echo time and keeping the dynamic temporal resolution below 5s. Increasing the number of acquisition, when possible, helps towards reducing flow artefacts. In our setting we achieved this with a sagittal 3D slab with 5 slices with a thickness of 4.5mm and two acquisitions. CONCLUSION: The proposed DCE protocol, encompassing the spine and the descending aorta, produces a realistic arterial input function and dynamic data suitable for PKM. PMID- 28867669 TI - COnstrained Data Extrapolation (CODE): A new approach for high definition vascular imaging from low resolution data. AB - PURPOSE: To introduce a new approach to reconstruct high definition vascular images using COnstrained Data Extrapolation (CODE) and evaluate its capability in estimating vessel area and stenosis. MATERIALS AND METHODS: CODE is based on the constraint that the full width half maximum of a vessel can be accurately estimated and, since it represents the best estimate for the width of the object, higher k-space data can be generated from this information. To demonstrate the potential of extracting high definition vessel edges using low resolution data, both simulated and human data were analyzed to better visualize the vessels and to quantify both area and stenosis measurements. The results from CODE using one fourth of the fully sampled k-space data were compared with a compressed sensing (CS) reconstruction approach using the same total amount of data but spread out between the center of k-space and the outer portions of the original k-space to accelerate data acquisition by a factor of four. RESULTS: For a sufficiently high signal-to-noise ratio (SNR) such as 16 (8), we found that objects as small as 3 voxels in the 25% under-sampled data (6 voxels when zero-filled) could be used for CODE and CS and provide an estimate of area with an error <5% (10%). For estimating up to a 70% stenosis with an SNR of 4, CODE was found to be more robust to noise than CS having a smaller variance albeit a larger bias. Reconstruction times were >200 (30) times faster for CODE compared to CS in the simulated (human) data. CONCLUSION: CODE was capable of producing sharp sub-voxel edges and accurately estimating stenosis to within 5% for clinically relevant studies of vessels with a width of at least 3pixels in the low resolution images. PMID- 28867670 TI - Reduced distortion artifact whole brain CBF mapping using blip-reversed non segmented 3D echo planar imaging with pseudo-continuous arterial spin labeling. AB - PURPOSE: To implement and evaluate interleaved blip-up, blip-down, non-segmented 3D echo planar imaging (EPI) with pseudo-continuous arterial spin labeling (pCASL) and post-processing for reduced susceptibility artifact cerebral blood flow (CBF) maps. MATERIALS AND METHODS: 3D EPI non-segmented acquisition with a pCASL labeling sequence was modified to include alternating k-space coverage along phase encoding direction (referred to as "blip-reversed") for alternating dynamic acquisitions of control and label pairs. Eight volunteers were imaged on a 3T scanner. Images were corrected for distortion using spatial shifting transformation of the underlying field map. CBF maps were calculated and compared with maps obtained without blip reversal using matching gray matter (GM) images from a high resolution 3D scan. Additional benefit of using the correction for alternating blip-up and blip-down acquisitions was assessed by comparing to corrected blip-up only and corrected blip-down only CBF maps. Matched Student t test of overlapping voxels for the eight volunteers was done to ascertain statistical improvement in distortion. RESULTS: Mean CBF value in GM for the eight volunteers from distortion corrected CBF maps was 50.8+/-9.9ml/min/100 gm tissue. Corrected CBF maps had 6.3% and 4.1% more voxels in GM when compared with uncorrected blip up (BU) and blip down (BD) images, respectively. Student t-test showed significant reduction in distortion when compared with blip-up images and blip-down images (p<0.001). When compared with corrected BU and corrected BD only CBF maps, BU and BD corrected maps had 2.3% and 1% more voxels (p=0.006 and 0.04, respectively). CONCLUSION: Pseudo-continuous arterial spin labeling with non segmented 3D EPI acquisition using alternating blip-reversed k-space traversal and distortion correction provided significantly better matching GM CBF maps. In addition, employing alternating blip-reversed acquisitions during pCASL acquisition resulted in statistically significant improvement over corrected blip up and blip-down CBF maps. PMID- 28867671 TI - The development and optimisation of 3D black-blood R2* mapping of the carotid artery wall. AB - PURPOSE: To develop and optimise a 3D black-blood R2* mapping sequence for imaging the carotid artery wall, using optimal blood suppression and k-space view ordering. METHODS: Two different blood suppression preparation methods were used; Delay Alternating with Nutation for Tailored Excitation (DANTE) and improved Motion Sensitive Driven Equilibrium (iMSDE) were each combined with a three dimensional (3D) multi-echo Fast Spoiled GRadient echo (ME-FSPGR) readout. Three different k-space view-order designs: Radial Fan-beam Encoding Ordering (RFEO), Distance-Determined Encoding Ordering (DDEO) and Centric Phase Encoding Order (CPEO) were investigated. The sequences were evaluated through Bloch simulation and in a cohort of twenty volunteers. The vessel wall Signal-to-Noise Ratio (SNR), Contrast-to-Noise Ratio (CNR) and R2*, and the sternocleidomastoid muscle R2* were measured and compared. Different numbers of acquisitions-per-shot (APS) were evaluated to further optimise the effectiveness of blood suppression. RESULTS: All sequences resulted in comparable R2* measurements to a conventional, i.e. non-blood suppressed sequence in the sternocleidomastoid muscle of the volunteers. Both Bloch simulations and volunteer data showed that DANTE has a higher signal intensity and results in a higher image SNR than iMSDE. Blood suppression efficiency was not significantly different when using different k space view orders. Smaller APS achieved better blood suppression. CONCLUSION: The use of blood-suppression preparation methods does not affect the measurement of R2*. DANTE prepared ME-FSPGR sequence with a small number of acquisitions-per shot can provide high quality black-blood R2* measurements of the carotid vessel wall. PMID- 28867673 TI - BMP7 dose-dependently stimulates proliferation and cadherin-11 expression via ERK and p38 in a murine metanephric mesenchymal cell line. AB - BMP7 is expressed in ureteric buds and cap mesenchyme of the fetal kidney, mediating branching morphogenesis and survival and priming of metanephric mesenchyme. Although dose-dependent effects of BMP7 in collecting duct cells have been reported, studies in metanephric mesenchymal cells are lacking. We examined the effects of BMP7 on MAP kinase activation, proliferation, and expression of cadherins in a metanephric mesenchymal cell line MS7 by thymidine incorporation, immunoblot analysis, and quantitative real-time PCR The levels of phosphorylated ERK (P-ERK) and phosphorylated p38 (P-p38) were not altered at 10 min, 1 h, and 6 h with low-dose BMP7 (0.25 nmol/L), but were increased at 24 h. At 24 h, P-ERK was increased with low-dose BMP7, but not by intermediate- (1 nmol/L) or high dose (10 nmol/L) BMP7, whereas p38 was activated by intermediate-dose BMP7. Cell proliferation of MS7 was significantly increased by low- and intermediate-dose BMP7 and decreased by high-dose BMP7. A p38 inhibitor SB203580 5 MUmol/L or a MEK inhibitor PD98059 5 MUmol/L abolished BMP7-stimulated proliferation. Expression of cadherin-11, an adhesion molecule known to promote cell migration and compaction, was upregulated by intermediate-dose BMP7. BMP7-induced cadherin-11 expression was inhibited by cotreatment with SB203580 and PD98059. Finally, in metanephroi cultured with siRNA for cadherin-11, the number and thickness of cap mesenchyme were reduced. In conclusion, BMP7 exerts differential effects depending on the concentration; it may expand mesenchymal cells in the stroma where BMP7 concentration is low and may upregulate cadherin-11 promoting condensation around the tip of ureteric buds. PMID- 28867674 TI - Acute changes in extracellular volume fraction in skeletal muscle monitored by 23Na NMR spectroscopy. AB - In this article, we induced acute changes in extracellular volume fraction in skeletal muscle tissue and compared the sensitivity of a standard 1H T2 imaging method with different 23Na-NMR spectroscopy parameters within acquisition times compatible with clinical investigations. First, we analyzed the effect of a short ischemia on the sodium distribution in the skeletal muscle. Then, the lower leg of 21 healthy volunteers was scanned under different vascular filling conditions (vascular draining, filling, and normal condition) expected to modify exclusively the extracellular volume. The first experiment showed no change in the total sodium content during a 15 min ischemia, but the intracellular weighted 23Na signal slowly decreased. For the second part, significant variations of total sodium content, sodium distribution, and T1 and T2* of 23Na signal were observed between different vascular filling conditions. The measured sodium distribution correlates significantly with sodium T1 and with the short and long T2* fractions. In contrast, significant changes in the proton T2w signal were observed only in three muscles. Altogether, the mean T2w signal intensity of all muscles as well as their mean T2 did not vary significantly with the extracellular volume changes. In conclusion, at the expense of giving up spatial resolution, the proposed 23Na spectroscopic method proved to be more sensitive than standard 1H T2 approach to monitor acute extracellular compartment changes within muscle tissue. PMID- 28867675 TI - Resting sympathetic activity is associated with the sympathetically mediated component of energy expenditure following a meal. AB - Individuals with high plasma norepinephrine (NE) levels at rest have a smaller reduction in resting energy expenditure (REE) following beta-adrenergic blockade. If this finding extends to the response to a meal, it could have important implications for the role of the sympathetic nervous system in energy balance and weight gain. We hypothesized high muscle sympathetic nerve activity (MSNA) would be associated with a low sympathetically mediated component of energy expenditure following a meal. Fourteen young, healthy adults completed two visits randomized to continuous saline (control) or intravenous propranolol to achieve systemic beta-adrenergic blockade. Muscle sympathetic nerve activity and REE were measured (indirect calorimetry) followed by a liquid mixed meal (Ensure). Measures of energy expenditure continued every 30 min for 5 h after the meal and are reported as an area under the curve (AUC). Sympathetic support of energy expenditure was calculated as the difference between the AUC during saline and beta-blockade (AUCPropranolol-AUCSaline, beta-REE) and as a percent (%) of control (AUCPropranolol/AUCSaline * 100). beta-REE was associated with baseline sympathetic activity, such that individuals with high resting MSNA (bursts/100 heart beats) and plasma NE had the greatest sympathetically mediated component of energy expenditure following a meal (MSNA: beta-REE R = -0.58, P = 0.03; %REE R = -0.56, P = 0.04; NE: beta-REE R = -0.55, P = 0.0535; %REE R = -0.54, P = 0.0552). Contrary to our hypothesis, high resting sympathetic activity is associated with a greater sympathetically mediated component of energy expenditure following a liquid meal. These findings may have implications for weight maintenance in individuals with varying resting sympathetic activity. PMID- 28867680 TI - Coexistence of a Double-Chambered Right Ventricle With Ebstein-Like Anomaly and Right Ventricular Apical Hypoplasia - Usefulness of Multimodality Imaging. PMID- 28867677 TI - C-X-C chemokine receptor type 4 (CXCR4) is a key receptor for chicken primordial germ cell migration. AB - In mammals, germ cells originate outside of the developing gonads and follow a unique migration pattern through the embryonic tissue toward the genital ridges. Many studies have attempted to identify critical receptors and factors involved in germ cell migration. However, relatively few reports exist on germ cell receptors and chemokines that are involved in germ cell migration in avian species. In the present study, we investigated the specific migratory function of C-X-C chemokine receptor type 4 (CXCR4) in chicken primordial germ cells (PGCs). We induced loss-of-function via a frameshift mutation in the CXCR4 gene in chicken PGCs using clustered regularly interspaced short palindromic repeat CRISPR-associated protein 9 (CRISPR/Cas9) genome editing. The migratory capacity of CXCR4 knockout PGCs was significantly reduced in vivo after transplantation into recipient embryos. However, CXCR4-expressing somatic cell lines, such as chicken DT40 and DF1, failed to migrate into the developing gonads, suggesting that another key factor(s) is necessary for targeting and settlement of PGCs into the genital ridges. In conclusion, we show that CXCR4 plays a critical role in the migration of chicken germ cells. PMID- 28867679 TI - A 2-base insertion in exon 5 is a common mutation of the TP53 gene in dogs with histiocytic sarcoma. AB - Canine histiocytic sarcoma (HS) is a malignancy originating from the histiocytic cell lineage and characterized by poor response to chemotherapy and short survival time. Mutation of the TP53 gene and its association with poor prognosis has been reported in several canine tumors. However, the mutation of this gene has not been investigated in canine HS. The aim of this study was to examine a TP53 gene mutation in dogs with HS. Aberrations of the TP53 gene were examined by polymerase chain reaction-single strand conformational polymorphism analysis and DNA sequence analysis, revealing mutations of the TP53 gene in 12 (46%) of 26 dogs affected by HS. The incidence of the TP53 gene mutation was relatively high in canine HS compared with other canine tumors. Among these mutations, 10 of 12 dogs (83%) with a TP53 gene mutation harbored the same mutation: a 2-base (AT) insertion in exon 5, resulting in the introduction of a stop codon (c.446_447insAT, p.Tyr150SerfsX8). Further studies are needed to examine the functional change due to the mutation and its association with the pathogenesis of canine HS. PMID- 28867678 TI - Effects of zinc supplementation on Shiga toxin 2e-producing Escherichia coli in vitro. AB - Swine edema disease is caused by Shiga toxin (Stx) 2e-producing Escherichia coli (STEC). Addition of highly concentrated zinc formulations to feed has been used to treat and prevent the disease, but the mechanism of the beneficial effect is unknown. The purpose of the present study was to investigate the effects of highly concentrated zinc formulations on bacterial growth, hemolysin production, and an Stx2e release by STEC in vitro. STEC strain MVH269 isolated from a piglet with edema disease was cultured with zinc oxide (ZnO) or with zinc carbonate (ZnCO3), each at up to 3,000 ppm. There was no effect of zinc addition on bacterial growth. Nonetheless, the cytotoxic activity of Stx2e released into the supernatant was significantly attenuated in the zinc-supplemented media compared to that in the control, with the 50% cytotoxic dose values of 163.2 +/- 12.7, 211.6 +/- 33.1 and 659.9 +/- 84.2 after 24 hr of growth in the presence of ZnO, ZnCO3, or no supplemental zinc, respectively. The hemolytic zones around colonies grown on sheep blood agar supplemented with zinc were significantly smaller than those of colonies grown on control agar. Similarly, hemoglobin absorbance after exposure to the supernatants of STEC cultures incubated in sheep blood broth supplemented with zinc was significantly lower than that resulting from exposure to the control supernatant. These in vitro findings indicated that zinc formulations directly impair the factors associated with the virulence of STEC, suggesting a mechanism by which zinc supplementation prevents swine edema disease. PMID- 28867676 TI - A Varroa destructor protein atlas reveals molecular underpinnings of developmental transitions and sexual differentiation. AB - Varroa destructor is the most economically damaging honey bee pest, weakening colonies by simultaneously parasitizing bees and transmitting harmful viruses. Despite these impacts on honey bee health, surprisingly little is known about its fundamental molecular biology. Here, we present a Varroa protein atlas crossing all major developmental stages (egg, protonymph, deutonymph, and adult) for both male and female mites as a web-based interactive tool (http://foster.nce.ubc.ca/varroa/index.html). We used intensity-based label-free quantitation to find 1,433 differentially expressed proteins across developmental stages. Enzymes for processing carbohydrates and amino acids were among many of these differences as well as proteins involved in cuticle formation. Lipid transport involving vitellogenin was the most significantly enriched biological process in the foundress (reproductive female) and young mites. In addition, we found that 101 proteins were sexually regulated and functional enrichment analysis suggests that chromatin remodeling may be a key feature of sex determination. In a proteogenomic effort, we identified 519 protein-coding regions, 301 of which were supported by two or more peptides and 169 of which were differentially expressed. Overall, this work provides a first-of-its-kind interrogation of the patterns of protein expression that govern the Varroa life cycle and the tools we have developed will support further research on this threatening honey bee pest. PMID- 28867672 TI - Phagocytosis and Inflammation: Exploring the effects of the components of E cigarette vapor on macrophages. AB - E-cigarettes are perceived as harmless; however, evidence of their safety is lacking. New data suggests E-cigarettes discharge a range of compounds capable of physiological damage to users. We previously established that cigarette smoke caused defective alveolar macrophage phagocytosis. The present study compared the effect E-cigarette of components; E-liquid flavors, nicotine, vegetable glycerine, and propylene glycol on phagocytosis, proinflammatory cytokine secretion, and phagocytic recognition molecule expression using differentiated THP-1 macrophages. Similar to CSE, phagocytosis of NTHi bacteria was significantly decreased by E-liquid flavoring (11.65-15.75%) versus control (27.01%). Nicotine also decreased phagocytosis (15.26%). E-liquid, nicotine, and E-liquid+ nicotine reduced phagocytic recognition molecules; SR-A1 and TLR-2. IL 8 secretion increased with flavor and nicotine, while TNFalpha, IL-1beta, IL-6, MIP-1alpha, MIP-1beta, and MCP-1 decreased after exposure to most flavors and nicotine. PG, VG, or PG:VG mix also induced a decrease in MIP-1alpha and MIP 1beta We conclude that E-cigarettes can cause macrophage phagocytic dysfunction, expression of phagocytic recognition receptors and cytokine secretion pathways. As such, E-cigarettes should be treated with caution by users, especially those who are nonsmokers. PMID- 28867682 TI - Surgical Outcomes of Isolated Coronary Artery Bypass Grafting for Acute Coronary Syndrome - Based on the Japan Adult Cardiovascular Surgery Database. AB - BACKGROUND: The present study aimed to clarify the current use and outcomes of coronary artery bypass grafting (CABG) for acute coronary syndrome (ACS) based on the Japan Adult Cardiovascular Surgery Database (JACVSD) in stratified risk categories, and also to provide guidance on selection of optimal surgical strategies for ACS.Methods and Results:From January 2008 through December 2012, 7,867 isolated CABG procedures for ACS were identifiedfrom the JACVSD. Patients were stratified into 3 subgroups (<2%, 2-9.9%, >=10%) according to preoperative risk estimations based on this database. Off- and on-pump CABG surgical outcomes were evaluated in each subgroup. Off-pump CABG (OPCAB) was the predominant surgical strategy in all subgroups. The proportion of on-pump beating CABG increased in the higher-risk groups. Although average observed mortality rates were compatible with preoperative estimated risk in all subgroups, those after OPCAB were significantly lower in the medium (2-9.9%) risk group with lower incidence of major complications. In the low (<2%) and high (>=10%) risk groups, observed mortality rates did not show statistically significant differences between off- and on-pump CABG. CONCLUSIONS: In this study in Japan, OPCAB was mainly performed in patients with ACS, particularly those with estimated risk <10%, with lower mortality rates, whereas on-pump beating CABG was selected for higher-risk patients with ACS, with reasonable mortality rates. PMID- 28867681 TI - Effect of Intensive and Standard Pitavastatin Treatment With or Without Eicosapentaenoic Acid on Progression of Coronary Artery Calcification Over 12 Months - Prospective Multicenter Study. AB - BACKGROUND: The effect of lipid-lowering agents on progression of coronary artery calcification (CAC) remains unclear. We evaluated the effects of pitavastatin 2 mg/day (PIT2), pitavastatin 4 mg/day (PIT4), and PIT2 combined with eicosapentaenoic acid (PIT2+EPA) on CAC progression.Methods and Results:This prospective multicenter study in Japan included patients with an Agatston score of 1-999, hypercholesterolemia, and no evidence of cardiovascular disease. Patients were allocated into PIT2, PIT4, or PIT2+EPA groups. The primary outcome was the annual percent change in Agatston score in all patients. In total, 156 patients who had multi-detector row computed tomography without any artifacts were included in the primary analysis. Pitavastatin did not significantly reduce the annual progression rate of the Agatston score (40%; 95% CI: 19-61%). The annual progression rate of Agatston score in the PIT2 group was not significantly different from that in the PIT4 group (34% vs. 42%, respectively; P=0.88) or the PIT2+EPA group (34% vs. 44%, respectively; P=0.80). On post-hoc analysis the baseline ratio of low- to high-density lipoprotein cholesterol was a significant predictor of non-progression of Agatston score by pitavastatin (OR, 2.17; 95% CI: 1.10-44.12; P=0.02). CONCLUSIONS: Pitavastatin does not attenuate progression of CAC. Intensive pitavastatin treatment and standard treatment with EPA does not reduce progression of CAC compared with standard treatment. PMID- 28867683 TI - MicroRNA-134 Promotes the Development of Atherosclerosis Via the ANGPTL4/LPL Pathway in Apolipoprotein E Knockout Mice. AB - AIMS: Atherosclerosis is the most common cause of cardiovascular disease, such as myocardial infarction and stroke. Previous study revealed that microRNA (miR)-134 promotes lipid accumulation and proinflammatory cytokine secretion through angiopoietin-like 4 (ANGPTL4)/lipid lipoprotein (LPL) signaling in THP-1 macrophages. METHODS: ApoE KO male mice on a C57BL/6 background were fed a high fat/high-cholesterol Western diet, from 8 to 16 weeks of age. Mice were divided into four groups, and received a tail vein injection of miR-134 agomir, miR-134 antagomir, or one of the corresponding controls, respectively, once every 2 weeks after starting the Western diet. After 8 weeks we measured aortic atherosclerosis, LPL Activity, mRNA and protein levels of ANGPTL4 and LPL, LPL/ low-density lipoprotein receptor related protein 1 Complex Formation, proinflammatory cytokine secretion and lipid levels. RESULTS: Despite this finding, the influence of miR-134 on atherosclerosis in vivo remains to be determined. Using the well-characterized mouse atherosclerosis model of apolipoprotein E knockout, we found that systemic delivery of miR-134 agomir markedly enhanced the atherosclerotic lesion size, together with a significant increase in proinflammatory cytokine secretion and peritoneal macrophages lipid contents. Moreover, overexpression of miR-134 decreased ANGPTL4 expression but increased LPL expression and activity in both aortic tissues and peritoneal macrophages, which was accompanied by increased formation of LPL/low-density lipoprotein receptor-related protein 1 complexes in peritoneal macrophages. However, an opposite effect was observed in response to miR-134 antagomir. CONCLUSIONS: These findings suggest that miR-134 accelerates atherogenesis by promoting lipid accumulation and proinflammatory cytokine secretion via the ANGPTL4/LPL pathway. Therefore, targeting miR-134 may offer a promising strategy for the prevention and treatment of atherosclerotic cardiovascular disease. PMID- 28867686 TI - Impact of fatty liver disease and metabolic syndrome on incident type 2 diabetes; a population based cohort study. AB - Fatty liver disease and metabolic syndrome (MetS) are both shown to increase the risk of type 2 diabetes. The aim of this study was to investigate the combined effect of fatty liver and MetS on incident diabetes. In this cohort study of 17,810 participants, fatty liver was diagnosed by abdominal ultrasonography and MetS was defined by a joint interim statement. We divided the participants into four groups according to the presence of fatty liver and/or MetS. Type 2 diabetes was defined as HbA1c >=6.5%, fasting plasma glucose >=7.0 mmol/L or treatment for diabetes. During the follow up examination (median 5.1 years), 804 participants developed diabetes. Compared with non-MetS without fatty liver, hazard ratios (HR) for incident diabetes after adjusting for age, body mass index, smoking status, exercise habit, alcohol consumption, family history of diabetes logarithm of alanine aminotransferase and fasting plasma glucose, were as follow: 2.35 (95 % CI 1.91-2.89, p<0.001) in non-MetS with fatty liver, 1.70 (95% CI 1.30-2.20, p<0.001) in MetS without fatty liver, and 2.33 (95% CI 1.85-2.94, p<0.001) in MetS with fatty liver. In addition, adjusted HRs for incident diabetes compared with MetS without fatty liver were 1.39 (95% CI 1.07-1.80, p=0.012) in non-MetS with fatty liver and 1.38 (95% CI 1.07-1.79, p=0.013) in MetS with fatty liver. Fatty liver affects more on the risk of incident diabetes than MetS. To prevent the further risk of diabetes, we should pay more attention to fatty liver. PMID- 28867687 TI - Rapid exacerbation of renal function after administration of hydroxyethyl starch in a dog. AB - Hydroxyethyl starches (HES) are commonly used synthetic colloidal solution in veterinary medicine. Despite of possible adverse effect to kidney injury in human, there is no report about nephrotoxic effects of HES in dogs. HES was administered to a Golden retriever (4-year-old, intact male) with ascites in order to increase plasma osmolality. Initially, the dog was mild azotemic, however, kidney function was rapidly deteriorated after several days of HES administration. Finally, histopathological examination revealed remarkable osmotic nephrosis. In the case reported herein, acute kidney injury was remarkably developed after HES administration. Clinical and histopathologic findings of acute kidney injury support nephrotoxic effects of HES to a dog. PMID- 28867685 TI - Analysis of fecal short chain fatty acid concentration in miniature dachshunds with inflammatory colorectal polyps. AB - Short chain fatty acids (SCFAs) play an important role in the maintenance of colonic homeostasis, and their depletion has been reported in various gastrointestinal disorders. Inflammatory colorectal polyps (ICRPs) are a recently recognized disease specific to miniature dachshunds (MDs), and fecal dysbiosis with a reduction of SCFA-producing bacteria has been reported with this disease. Therefore, this study was performed based on the hypothesis that a reduced SCFA concentration associates with the development of ICRPs. We recruited 11 ICRP affected MDs and 25 control MDs. Their fecal SCFA concentrations and bacterial proportions were quantified using high performance liquid chromatography and quantitative real-time PCR, respectively. The feces of ICRP-affected MDs contained lower amounts of propionic acid and lower proportions of Bifidobacterium than the feces of control MDs. Furthermore, fecal proportions of Bifidobacterium, Firmicutes and Lactobacillus exhibited significant positive correlations with fecal concentrations of total SCFAs and/or propionic acid; fecal Escherichia coli proportions correlated negatively with fecal concentrations of total SCFAs, as well as acetic, propionic and butyric acid. This result indicates an association between fecal dysbiosis and fecal SCFA concentrations; these phenomena may contribute to ICRP pathogenesis in MDs. Potential therapeutic targeting of the reduced propionic acid concentration using probiotics, prebiotics or SCFA enemas merits further study. PMID- 28867689 TI - ANGPTL2 - A New Causal Player in Accelerating Heart Disease Development in the Aging. AB - In parallel with the increase in the number of elderly people worldwide, the number of patients with heart disease is also rapidly increasing. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are strongly associated with adverse health outcomes that decrease productivity in later years. Recently, ANGPTL2, a secreted glycoprotein and member of the angiopoietin like protein family, has received attention as a causal player in the development of CVD and HF. Prolonged ANGPTL2 autocrine/paracrine signaling in vascular tissue leads to chronic inflammation and pathologic tissue remodeling, accelerating CVD development. Excess ANGPTL2 autocrine/paracrine signaling induced in the pathologically stressed heart accelerates cardiac dysfunction by decreasing myocardial energy metabolism. Conversely, ANGPTL2 inactivation in vascular tissue and the heart delays development or progression of CVD and HF, respectively. Moreover, there is increased evidence for an association between elevated circulating ANGPTL2 levels and CVD and HF. Interestingly, ANGPTL2 expression is also associated with cellular senescence, which may promote premature aging and development of aging-associated diseases, including CVD and HF. Overall, ANGPTL2 autocrine/paracrine signaling is a new factor in accelerating heart disease development in the aging. Here, we focus on current topics relevant to ANGPTL2 function in heart disease. PMID- 28867688 TI - Aminoglycoside susceptibility of Pasteurella multocida isolates from bovine respiratory infections in China and mutations in ribosomal protein S5 associated with high-level induced spectinomycin resistance. AB - Twenty-three isolates of Pasteurella multocida were tested for susceptibility to six aminoglycoside agents and screened by polymerase chain reaction for the presence of aminoglycoside resistance genes. In addition, mutations in the resistance-determining region of strains showing a high level of induced resistance to spectinomycin strains were examined. Susceptibility testing showed that all of the isolates were resistant to at least two types of aminoglycosides, and that the most effective antimicrobial was spectinomycin. The resistance genes aphA1, strB and aacA4 were present in all 23 isolates. In the three induced spectinomycin-resistant strains, a 9-bp deletion in rpsE that encodes ribosomal protein S5 was detected. PMID- 28867684 TI - Neutralizing epitopes of RSV and palivizumab resistance in Japan. AB - Respiratory Syncytial Virus (RSV) is one of the most important viral pathogen related to acute lower respiratory infection in young children. The virus surface envelope contains the G, F, and SH proteins as spike proteins. The F protein is considered to be a major antigenic target for the neutralizing (NT) epitope as only the F protein is essential for cell infection among the three viral envelope proteins, and it is more highly conserved than the G protein. Recently, four antigenic targets related to NT activity have been reported;site I, site II, site IV, and site zero (0). Site II is the target for palivizumab used throughout the world to suppress severe RSV infection as passive immunity in high-risk children since 1998. Under the recent conditions in which indications for palivizumab administered subjects are being expanded, palivizumab-resistant mutations have been confirmed overseas in children with RSV infection, although they remain infrequent. Therefore, continuous genetic analysis of the palivizumab-binding region of the F protein is necessary. In addition, as vaccine development progresses, RSV infection control is expected to improve greatly over the next decade. PMID- 28867691 TI - Huge Metastatic Gastrointestinal Stromal Tumor Occupying the Right Ventricle. PMID- 28867690 TI - Effects of Calcium-Channel Blocker Benidipine-Based Combination Therapy on Cardiac Events - Subanalysis of the COPE Trial. AB - BACKGROUND: The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was conducted to compare the effects of regimens combining the dihydropyridine calcium-channel blocker benidipine with each of 3 secondary agent types (an angiotensin-receptor blocker (ARB), a beta-blocker and a thiazide) in Japanese hypertensive outpatients who did not achieve target blood pressure (<140/90 mmHg) with benidipine 4 mg/day alone. The analysis included 3,293 patients (ARB, 1,110; beta-blocker, 1,089; thiazide, 1,094) with a median follow-up of 3.61 years. The main results of the COPE trial demonstrated that the incidences of hard cardiovascular composite endpoints and fatal or non-fatal strokes were significantly higher in the benidipine/beta-blocker group than in the benidipine/thiazide group.Methods and Results:We further evaluated the treatment effects on different cardiac events among the 3 benidipine-based regimens.We observed a total of 50 cardiac events, 4.2 per 1000 person-years. The incidences of total cardiac events and each cardiac event were similarly low among the 3 treatment groups. Unadjusted and multi-adjusted hazard ratios for total cardiac events showed no significant difference among the 3 treatment groups. CONCLUSIONS: This subanalysis of the COPE trial demonstrated that blood pressure-lowering regimens combining benidipine with an ARB, beta-blocker or thiazide diuretic were similarly effective for the prevention of cardiac events in Japanese hypertensive outpatients. PMID- 28867692 TI - Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 37, Number 7, July 25, 2017. PMID- 28867696 TI - Convergent Synthesis of Fused Ring Systems in Large Polycyclic Ethers. AB - This article reviews our studies on the oxiranyl anion-based, [X+2+Y]-type convergent strategy for the synthesis of polycyclic ether natural products. The strategy is noteworthy for its flexibility, which allows for the generation of different-sized fused ring systems based on a ring expansion reaction. For a precise understanding of this key ring expansion, we first focused on the reaction mechanism, in which an equatorial attack of TMS-diazomethane was determined to be the crucial step. In the later part of this review, the application of our oxiranyl anion-based strategy to large fused ring systems is described. The advantageous flexibility is highlighted in the divergent synthesis of five octacyclic ethers involving the CDEFGHIJ-ring skeleton of yessotoxin and its ring-modified analogs. Total synthesis of gymnocin-A was achieved using the oxiranyl anion convergent strategy, which furnished its large system of fourteen contiguous ether rings. PMID- 28867694 TI - Development of Biologically Active Compounds on the Basis of Phosphonic and Phosphinic Acid Functionalities. AB - Phosphonic and phosphinic acids, especially alpha-heteroatom-substituted ones, possess unique structural and physical features which enable them to act as hydrotically stable analogs to biological phosphates in biological processes. They also act as mimetics in the transition state of the protease-induced hydrolysis of dipeptides. The first half of this review focuses on selected new synthetic methods developed by our research group for the stereoselective synthesis of alpha-heteroatom-substituted phosphonic and phosphinic acid derivatives, including modified nucleotide analogs and phosphinyl dipeptide isosteres. In the latter half, this review summarizes the utility of difluoromethylenephosphonic acids and phosphonic acid esters in the development of enzyme inhibitors against protein tyrosine phosphatases, sphingomyelinases, purine nucleoside phosphorylases and thrombin. The enzyme inhibitors developed were used as probes to elucidate signal transductions and the mechanisms of enzyme actions. The findings of the studies are briefly described. PMID- 28867695 TI - Development of a Prodrug of Levofloxacin to Avoid Chelation with Al3+ and of Pemetrexed Dimedoxomil Esters for Oral Administration. AB - An ethoxycarbonyl 1-ethyl hemiacetal ester of levofloxacin (LVFX-EHE) avoids insoluble chelate formation with metal-containing drugs in the intestinal tract and is rapidly hydrolyzed to the parent drug. Furthermore, the minimum inhibitory concentration confirms that LVFX-EHE is less likely to cause pseudomembranous colitis because of less susceptibility to normal intestinal bacteria flora. Pemetrexed dimedoxomil, the prodrug of pemetrexed, was synthesized via reaction with medoxomil bromide after modification of L-glutamate with the tert butyloxycarbonyl protecting group (BOC), followed by hydrolysis of the BOC moiety with trifluoroacetic acid (TFA) in CH2Cl2 at a temperature of 0 degrees C for 2 h. A serum pemetrexed concentration of >2 MUg/mL was observed after oral administration of pemetrexed dimedoxomil at a dose of 60 mg/kg to rats. PMID- 28867693 TI - Mild thyroid peroxidase deficiency caused by TPO mutations with residual activity: Correlation between clinical phenotypes and enzymatic activity. AB - Thyroid peroxidase (TPO) deficiency, caused by biallelic TPO mutations, is a well established genetic form of congenital hypothyroidism (CH). More than 100 patients have been published, and the patients have been diagnosed mostly in the frame of newborn screening (NBS) programs. Correlation between clinical phenotypes and TPO activity remains unclear. Here, we report clinical and molecular findings of two unrelated TPO mutation-carrying mildly hypothyroid patients. The two patients were born at term after an uneventful pregnancy and delivery, and were NBS negative. They sought medical attention due to goiter at age 8 years. Evaluation of the thyroid showed mild elevation of serum TSH levels, normal or slightly low serum T4 levels, high serum T3 to T4 molar ratio, high serum thyroglobulin levels, and high thyroidal 123I uptake. We performed next generation sequencing-based genetic screening, and found that one patient was compound heterozygous for two novel TPO mutations (p.Asp224del; c.820-2A>G), and the other was homozygous for a previously known mutation (p.Trp527Cys). In vitro functional analyses using HEK293 cells showed that the two amino acid-altering mutations (p.Asp224del and p.Trp527Cys) caused partial loss of the enzymatic activity. In conclusion, we report that TPO mutations with residual activity are associated with mild TPO deficiency, which is clinically characterized by marked goiter, mild TSH elevation, high serum T3 to T4 molar ratio, and high serum thyroglobulin levels. Our findings illuminate the hitherto under-recognized correlation between clinical phenotypes and residual enzymatic activity among patients with TPO deficiency. PMID- 28867697 TI - Studies of Neuronal Gene Regulation Controlling the Molecular Mechanisms Underlying Neural Plasticity. AB - The regulation of the development and function of the nervous system is not preprogramed but responds to environmental stimuli to change neural development and function flexibly. This neural plasticity is a characteristic property of the nervous system. For example, strong synaptic activation evoked by environmental stimuli leads to changes in synaptic functions (known as synaptic plasticity). Long-lasting synaptic plasticity is one of the molecular mechanisms underlying long-term learning and memory. Since discovering the role of the transcription factor cAMP-response element-binding protein in learning and memory, it has been widely accepted that gene regulation in neurons contributes to long-lasting changes in neural functions. However, it remains unclear how synaptic activation is converted into gene regulation that results in long-lasting neural functions like long-term memory. We continue to address this question. This review introduces our recent findings on the gene regulation of brain-derived neurotrophic factor and discusses how regulation of the gene participates in long lasting changes in neural functions. PMID- 28867698 TI - Meta-analysis on the Influence of Antifungal Spectrum on Effectiveness of Empirical Antifungal Therapy for Febrile Neutropenia. AB - We conducted a meta-analysis to investigate the influence of antifungal spectrum on the effectiveness and adverse events of empirical antifungal therapy for febrile neutropenia. We searched PubMed and Cochrane Central Register of Controlled Trials (Central), and identified randomized controlled trials reporting mortality, efficacy, adverse events, and hepatic and renal dysfunction. Five trials assessed the efficacy and adverse events of agents with antifungal spectrum covering and those not covering Aspergillus. There were no differences in mortality [risk ratio (RR); 0.79, 95% confidence interval (Cl); 0.60-1.02], efficacy ratio (RR; 1.01, 95%Cl; 0.91-1.12), adverse event ratio (RR; 0.23, 95%Cl; 0.04-1.23), and hepatic dysfunction ratio (RR; 0.81, 95%Cl; 0.59-1.12) between two groups. Antifungals with no activity against Aspergillus were associated with lower renal dysfunction ratio (RR; 0.27, 95%Cl; 0.10-0.71). Five trials compared agents with antifungal spectrum covering versus those not covering Mucor. There were no difference in mortality (RR; 1.24, 95%Cl; 0.98 1.57), efficacy ratio (RR; 1.09, 95%Cl; 0.91-1.30), and hepatic dysfunction ratio (RR; 0.98, 95%Cl; 0.66-1.45) between two groups. Antifungals with no activity against Mucor were associated with lower adverse event ratio (RR; 0.60, 95%Cl; 0.47-0.77) and renal dysfunction ratio (RR; 0.25, 95%Cl; 0.13-0.49). Presence or absence of activity against Aspergillus or Mucor is not associated with mortality or efficacy ratio. Amphotericin B with activity against Aspergillus and Mucor has a higher adverse event ratio. Depending on the case, selection of antifungal drugs considering efficacy and side effects is necessary. PMID- 28867699 TI - Frequency of Acute Kidney Injury Caused by Tazobactam/Piperacillin in Patients with Pneumonia and Chronic Kidney Disease: A Retrospective Observational Study. AB - Tazobactam/piperacillin (TAZ/PIPC) is a combination antibiotic frequently used to treat pneumonia. It has recently been reported that TAZ/PIPC worsens renal function in patients with existing renal impairment. Creatinine clearance is generally between 10 and 40 mL/min in Japanese patients, so TAZ/PIPC is given at a dose of 2.25 g three times daily or 4.5 g twice daily. If pneumonia is severe or intractable, the dose frequency may be increased to 2.25 g four times daily and 4.5 g three times daily. We examined the effect of these different dosing regimens on renal function. We studied a cohort of 57 patients with impaired renal function hospitalized with pneumonia and treated with TAZ/PIPC between January 2015 and November 2016. Patients were classified into four groups according to TAZ/PIPC dose: 2.25 g three times daily (Group A); 2.25 g four times daily (B); 4.5 g twice daily (C) and 4.5 g three times daily (D). We examined the frequency of acute kidney injury (AKI) and treatment effectiveness. In Groups A, B, C and D, AKI occurred in 5.6%, 0.0%, 25.0% and 38.5% of patient. In groups C and D, hydration and dose reduction were required to address early signs of impending AKI. Our findings suggest that the higher TAZ/PIPC dose of 4.5 g was responsible for the decline in renal function, even if the dose frequency was reduced. PMID- 28867700 TI - Increase of Anti-oxidative Capacity during Differentiation of 3T3-L1 Preadipocytes into Adipocytes. AB - Cells have developed ingenious defense mechanisms in response to oxidative stress. Here, we evaluated changes in anti-oxidative capacity during differentiation of 3T3-L1 preadipocytes into adipocytes. When 3T3-L1 preadipocytes were treated with H2O2 (0.10-2.0 mM) for 21 h, cell viability decreased in response to H2O2 concentration, with an LD50 of approximately 0.35 mM H2O2. In the cells undergoing differentiation at 2 and 6 d, LD50 increased to 1.0 and >2.0 mM H2O2, respectively. These results indicate that resistance to oxidative stress dramatically increased with progression of differentiation of preadipocytes into adipocytes. Catalase activity and GSH content increased in the differentiated cells at 6 d, whereas superoxide dismutase and glutathione peroxidase activities were slightly lower in adipocytes than in preadipocytes. Moreover, knockdown of catalase or depletion of intracellular GSH enhanced the sensitivity to H2O2. When GSH was added to the cells depleted of intracellular GSH, the antioxidant capacity recovered. Autophagy was increased in differentiated adipocytes but was not affected by H2O2 treatment. Therefore, these results suggest that the increase in intracellular catalase activity and GSH content played a role in the increased anti-oxidative capacity of differentiated 3T3-L1 adipocytes. PMID- 28867701 TI - A Metabolic Study on the Biochemical Effects of Chiral Illegal Drugs in Rats Using 1H-NMR Spectroscopy. AB - Considering the pharmacological effects of chiral drugs, enantiopure drugs may differ from their racemic mixture formulation in efficacy, potency, or adverse effects. Levomethorphan (LVM) and Dextromethorphan (DXM) act on the central nervous system and exhibit different pharmacological features. LVM, the l stereoisomer of methorphan, shows many similarities to opiates such as heroin, morphine and codeine, including the potential for addiction, while the d stereoisomer, DXM, does not have the same opioid effect. In the present study, NMR-based metabolomics were performed on the urine of rats treated with these stereoisomers, and showed significant differences in metabolic profiles. In urine within 24 h after treatment of these samples, levels of citrate, 2-oxoglutarate, creatine, and dimethylglycine were higher in LVM-treated rats than in DXM-treated rats. While urinary levels of hippurate and creatinine gradually increased over 72 h in DXM-treated rats, these metabolites were decreased in the urine by 48-72 h after treatment with LVM. The levels of these changed metabolites may provide the first evidence for different cellular responses to the metabolism of stereoisomers. PMID- 28867702 TI - Relationship between Hydrogen-bond Conditions of Surface Adsorbed Water and Interparticle Binding Force on Pharmaceutical Tablets. AB - Influence of water contents to the pharmaceutical tablet strength is known empirically, and participation of hydrogen bonding force among adsorbed water molecules has been presumed. However, the detailed mechanisms of hydrogen bonding phenomena have not been reported. In this study, the hydrogen bonds states of the surface adsorbed waters on the excipient particles of the tablets were focused upon, and the relationship to the interparticle binding force determined by the Rumpf equation was discussed using a near-infrared spectroscopy (NIR). As for the results, NIR peaks of OH groups of surface water were shifted by a humidity change, and the degrees of the peak shifts correlated to interparticle binding force. PMID- 28867703 TI - Patient Preference for Aggressive Medication Therapies with Potentially Stronger Adverse Drug Reactions Revealed Using a Scenario-based Survey. AB - Some patients do not inform healthcare professionals of adverse drug reactions (ADRs) because they fear termination of aggressive medication therapies. Preferences for aggressive medication therapies may differ between patients and pharmacists. The goal of this study was to estimate whether pharmacists were able to accurately assess patient preference for aggressive medication therapies with potentially stronger ADRs. A cross-sectional study was conducted of hospitalized patients (35 to 74 years of age) receiving oral medications for a chronic disease or systemic chemotherapy at three hospitals in Japan. We estimated the extent of agreement between patient responses and pharmacist predictions using a scenario based investigation (1) to examine the choice between an aggressive medication therapy and the standard therapy, and (2) to assess increased life expectancy as a result of aggressive medication therapy. The extent of agreement was estimated using the kappa statistic. Of 113 patients, 43 (38.1%) chose the aggressive medication therapy. Pharmacists correctly predicted the choice of 25 (58.1%) of these patients [kappa 0.32 (95% confidence interval 0.15-0.50)]. Of 111 patients, 42 (37.8%) expected one additional life expectancy year. However, pharmacists predicted that as many as 36 (85.7%) of these patients would require more years of added life expectancy before choosing an aggressive medication therapy [kappa 0.24 (0.08-0.40)]. Agreement between patients and pharmacists on the choice of aggressive medication therapy was generally poor. Pharmacists should make an effort to identify patients who might prefer more aggressive medication therapies with potentially stronger ADRs in order to minimize ADR risk. PMID- 28867704 TI - Evaluation of Retinal Function in Streptozotocin-induced Diabetic Rats by Using the Electroretinography and Immunohistochemistry Methods. AB - Streptozotocin-induced diabetic rat (STZ rat) was used in many studies for the diabetic mellitus. In this study, we demonstrated whether the electroretinograms (ERG) was changed in the retina of STZ rats. In addition, we investigated the histopathological alteration in the retina of STZ rats by using the immunological method. The 100 mg/kg of STZ was injected continuously for 2 d (100 mg/kg*2). The insulin level was decreased, and the glucose level was enhanced 14 d after the injection of STZ. Moreover, the levels of a-wave, b-wave and OP amplitude were decreased in the rat at 14 d after the injection of STZ. Although, the damage and apoptosis was not observed in the retinal ganglion cell of STZ rats by the immunological experiment using the phospho-H2A.X and cleaved caspase-3, the distance between cell and cell was increased in both of outer- and inner- nuclear (granule) layer in retina of STZ rats. In conclusion, we showed that the enhanced thickening in retina was caused by the injection of excessive STZ. The thickening in retina of STZ rats may lead to the dysfunction of retina, resulting in the decrease in ERG. These findings provide significant information that can be used in the design of a model of diabetic retinopathy. PMID- 28867707 TI - Development of Batch and Flow Immobilized Catalytic Systems with High Catalytic Activity and Reusability. AB - My mission in catalysis research is to develop highly active and reusable supported catalytic systems in terms of fundamental chemistry and industrial application. For this purpose, I developed three types of highly active and reusable supported catalytic systems. The first type involves polymeric base supported metal catalysts: Novel polymeric imidazole-Pd and Cu complexes were developed that worked at the mol ppm level for a variety of organic transformations. The second involves catalytic membrane-installed microflow reactors: Membranous polymeric palladium and copper complex/nanoparticle catalysts were installed at the center of a microtube to produce novel catalytic membrane-immobilized flow microreactor devices. These catalytic devices mediated a variety of organic transformations to afford the corresponding products in high yield within 1-38 s. The third is a silicon nanowire array-immobilized palladium nanoparticle catalyst. This device promoted a variety of organic transformations as a heterogeneous catalyst. The Mizoroki-Heck reaction proceeded with 280 mol ppb (0.000028 mol%) of the catalyst, affording the corresponding products in high yield. PMID- 28867706 TI - Secondhand Smoking Is Associated with Poor Mental Health in Korean Adolescents. AB - In Korea, the prevalence of depression is increasing in adolescents and the most common cause of death of adolescents has been reported as suicide. At a time of increasing predicament of mental health of adolescents, there are few studies on whether secondhand smoking is associated with mental health in adolescents. The objective of this study was to determine whether exposure to secondhand smoke is associated with mental health-related variables, such as depression, stress, and suicide, in Korean adolescents. Data from the eleventh Korea youth risk behavior web-based survey, a nationally representative survey of 62,708 participants (30,964 males and 31,744 females), were analyzed. For students of aged 12 to 18 years, extensive data including secondhand smoking, mental health, sociodemographic variables, and physical health were collected. Chi-square analysis, multiple logistic regression analysis and ordered logistic regression analysis were performed to estimate the association and dose-response relation between secondhand smoking and mental health. Compared with the non-exposed group, the odds ratios (OR) of depression, stress, suicidal ideation, suicidal planning and suicidal attempt in the secondhand smoking exposed group were 1.339, 1.192, 1.303, 1.437 and 1.505, respectively (all P < 0.001). When subjects were classified into two secondhand smoke exposure groups, with increasing secondhand smoking experience, higher was the OR for each mental health related variable, in a dose-response relation. Our findings suggest that secondhand smoking is associated with poor mental health such as depression, stress, and suicide, showing a dose-response relation in Korean adolescents. PMID- 28867705 TI - Validating the Effectiveness of Switching the Vancomycin TDM Analysis Software Based on the Predictive Accuracy. AB - Based on the predictive performance in our previous study, we switched the therapeutic drug monitoring (TDM) analysis software for dose setting of vancomycin (VCM) from "Vancomycin MEEK TDM analysis software Ver2.0" (MEEK) to "SHIONOGI-VCM-TDM ver.2009" (VCM-TDM) in January 2015. In the present study, our aim was to validate the effectiveness of the changing VCM TDM analysis software in initial dose setting of VCM. The enrolled patients were divided into two groups, each having 162 patients in total, who received VCM with the initial dose set using MEEK (MEEK group) or VCM-TDM (VCM-TDM group). We compared the rates of attaining the therapeutic range (trough value; 10-20 MUg/mL) of serum VCM concentration between the groups. Multivariate logistic regression analysis was performed to confirm that changing the VCM TDM analysis software was an independent factor related to attaining the therapeutic range. Switching the VCM TDM analysis software from MEEK to VCM-TDM improved the rate of attaining the therapeutic range by 21.6% (MEEK group: 42.6% vs. VCM-TDM group: 64.2%, p<0.01). Patient age >=65 years, concomitant medication (furosemide) and the TDM analysis software used VCM-TDM were considered to be independent factors for attaining the therapeutic range. These results demonstrated the effectiveness of switching the VCM TDM analysis software from MEEK to VCM-TDM for initial dose setting of VCM. PMID- 28867708 TI - Substrate Specific Silver(I)-Catalyzed Cycloisomerization of Diene Involving Alkyl Rearrangements: Syntheses of 1,2,5,6-Tetrahydrocuminic Acid, p-Menth-3-en-7 ol, and p-Menth-3-en-7-al. AB - The novel cationic Ag(I)-catalyzed cycloisomerization, which is associated with alkyl rearrangements, from dimethyl 2-allyl-2-prenylmalonate (1) to dimethyl 4 isopropylcyclohex-3-ene-1,1-dicarboxylate (2) has been developed. Derivatization from the diester 2 into the diol 3 and its X-ray crystallographic analysis determined the structure. The mechanisms of the novel reaction were investigated by isotopic experiments, which supported the unusual alkyl shifts. In addition, the product 2 was used for the total syntheses of three natural products, 1,2,5,6 tetrahydrocuminic acid (12), p-menth-3-en-7-ol (13), and p-menth-3-en-7-al (14) in short steps. PMID- 28867710 TI - Design, Synthesis and Biological Evaluation of Oxindole-Based Chalcones as Small Molecule Inhibitors of Melanogenic Tyrosinase. AB - The enzyme tyrosinase regulates melanogenesis and skin hyperpigmentation by converting L-3,4-dihydroxyphenylalanine (L-DOPA) into dopaquinone, a key step in the melanin biosynthesis. The present work deals with design and synthesis of various oxindole-based chalcones as monophenolase and diphenolase activity inhibitors of tyrosinase. Among the screened compounds, 4-hydroxy-3 methoxybenzylidene moiety bearing chalcone (7) prepared by one pot reaction of oxindole and vanillin displayed the highest activity against tyrosinase with IC50s of 63.37 and 59.71 uM in monophenolase and diphenolase activity assays, respectively. In molecular docking studies, chalcone 7 also showed the highest binding affinity towards the enzyme tyrosinase while exhibiting the lowest estimated free energy of binding, among all the ligands docked. PMID- 28867709 TI - Neuroprotective Effect of Corydalis ternata Extract and Its Phytochemical Quantitative Analysis. AB - The tubers of Corydalis ternata have been used to treat cardiovascular diseases such as hypertension and cardiac arrhythmia. Its active components have anticholinesterase, antiamnesic, and anti-inflammatory activities, and analgesic effects. In the present study, we performed quantitative analyses of the two components of C. ternata, coptisine and berberine, using HPLC. A 70% ethanol extract of C. ternata was prepared and the two components were separated using a C-18 analytical column on a gradient solvent system of acetonitrile and 0.1% (v/v) aqueous trifluoroacetic acid. Recordings were performed at a UV wavelength of 265 nm for two standard components. The established analytical method showed high linearity (correlation coefficient (r)=1.0000) and proper precision (0.49 3.88%), accuracy (97.88-102.7%), and recovery (95.12-103.79%) for two standard components. The amount of the coptisine and berberine was 4.968+/-0.089 mg/g and 3.73+/-0.075 mg/g, respectively. In addition, we investigated the effects of coptisine and berberine on acetylcholinesterase activity and amyloid-beta aggregation, which are major biomarkers of dementia. Coptisine and berberine decreased acetylcholinesterase activity in a dose-dependent manner (IC50=0.74 and 0.48 uM, respectively). The C. ternata extract exerted an antioxidant activity by stimulating the radical scavenging activity of 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) (ABTS), but not 2,2-diphenyl-1 picrylhydrazyl (DPPH). Furthermore, the C. ternata extract reversed the hydrogen peroxide-induced death of HT22 hippocampal cells, indicating its neuroprotective effect. Our results suggest the potential of C. ternata as a therapeutic agent against dementia via the inhibition of acetylcholinesterase activity and neuronal cell death. PMID- 28867711 TI - Four New Lignans and IL-2 Inhibitors from Magnoliae Flos. AB - Four new lignans, a furofuran lignan medioresinol B (10) and three tetrahydrofuran lignans kobusinol C (16), 7'-methoxy magnostellin A (21), and mangnostellin D (23), along with 19 known lignans, were isolated from the flower buds of Magnolia biondii PAMP. The structures of the isolates were elucidated using spectroscopic analysis, mainly one- and two-dimensional NMR, high resolution-MS, and circular dichroism techniques as well as Mosher's esterification method. The anti-allergic effects of the isolated compounds were evaluated by analyzing the inhibition of interleukin-2 (IL-2) expression in Jurkat T-cells. Compounds 11-14 reduced IL-2 expression in a dose-dependent manner. PMID- 28867713 TI - Stereo-Selective Preparation of Teneraic Acid, trans-(2S,6S)-Piperidine-2,6 dicarboxylic Acid, via Anodic Oxidation and Cobalt-Catalyzed Carbonylation. AB - Teneraic acid (piperidine-2,6-dicarboxylic acid) is a naturally occurring imino acid that comprises three stereoisomers due to its two asymmetric centers at C2 and C6. The configuration of natural teneraic acid is reported to correspond to trans-(2S,6S). However, a few studies are focused on the stereospecific synthesis of trans-(2S,6S)-teneraic acid. The present study investigates a convenient synthetic method that includes regiospecific anodic oxidation and stereospecific cobalt-catalyzed carbonylation to obtain trans-(2S,6S)-teneraic acid. Methyl (S) N-benzoyl-alpha-methoxypipecolate, the key intermediate that displays a structure that corresponds to an intermediate (N-alpha-hydroxyalkyl amide) of intramolecular amidocarbonylation, was obtained via an anodic oxidation of methyl (S)-N-benzoylpipecolate. Subsequently, cobalt-catalyzed carbonylation converted the methyl (S)-N-benzoyl-alpha-methoxypipecolate to trans-(2S,6S)-N-benzoyl teneraic acid dimethyl ester in good optical purity (>95% enantiomeric excess (ee)) and modest yield (63%). Finally, de-protection occurred via acidic hydrolysis to obtain trans-(2S,6S)-teneraic acid. The stereochemistry of synthesized teneraic acid was confirmed as corresponding to trans-(2S,6S) by comparing its physical properties with those of a cis-meso-isomer and those of a trans-(2S,6S)-isomer that were reported in previous studies. PMID- 28867712 TI - Effect of the External Lubrication Method for a Rotary Tablet Press on the Adhesion of the Film Coating Layer. AB - External lubrication is a useful method which reduces the adhesion of powder to punches and dies by spraying lubricants during the tableting process. However, no information is available on whether the tablets prepared using an external lubrication system can be applicable for a film coating process. In this study, we evaluated the adhesion force of the film coating layer to the surface of tablets prepared using an external lubrication method, compared with those prepared using internal lubrication method. We also evaluated wettability, roughness and lubricant distribution state on the tablet surface before film coating, and investigated the relationship between peeling of the film coating layer and these tablet surface properties. Increasing lubrication through the external lubrication method decreased wettability of the tablet surface. However, no change was observed in the adhesion force of the film coating layer. On the other hand, increasing lubrication through the internal lubrication method, decreased both wettability of the tablet surface and the adhesion force of the film coating layer. The magnesium stearate distribution state on the tablet surface was assessed using an X-ray fluorescent analyzer and lubricant agglomerates were observed in the case of the internal lubrication method. However, the lubricant was uniformly dispersed in the external lubrication samples. These results indicate that the distribution state of the lubricant affects the adhesion force of the film coating layer, and external lubrication maintained sufficient lubricity and adhesion force of the film coating layer with a small amount of lubricant. PMID- 28867714 TI - Ethereal C-O Bond Cleavage Mediated by Ni(0)-Ate Complex: A DFT Study. AB - Density functional theory calculations were performed to explore the mechanism of Ni-catalyzed cross-coupling reactions involving organo-lithium and -zinc reagents through ethereal C-O bond cleavage. Based on this work, together with our previous mechanistic study on etheric Kumada-Tamao reaction, we identify and characterize a novel catalytic cycle for cross-coupling mediated by Ni(0)-ate complex. PMID- 28867717 TI - Effects of Tripterygium wilfordii Induction Therapy to IgA Nephropathy Patients with Heavy Proteinuria. AB - Although some new drugs have been developed, Tripterygium wilfordii HOOK F. (TWHF) has the merits of relatively lower price and fewer side effects. Unfortunately, the efficacy and safety of the TWHF (especially dosage 120 mg/d) in the immunoglobulin A (IgA) nephropathy (IgAN) are still lacking. A cohort study including 49 IgAN patients with heavy proteinuria who received induction therapy was undertaken. Patients were divided into three groups: Prednisone (PRE), conventional-dose TWHF (CTW) and double-dose TWHF (DTW). The clinical features, laboratory data, histological manifestations and outcomes of the groups were compared. We found that urinary protein excretion and rates of elevated n acetyl-beta-D-glucosaminidase (NAG) and retinol binding protein (RBP) were prominent in all groups. Neither histopathological changes nor the rates of renal insufficiency were significantly different among groups. Patients in the PRE (69.2%) and DTW groups (87.5%) achieved complete remission; none of the CTW group did. Furthermore, the total remission rate of the DTW group was substantially higher than that of the CTW group. The degree of hypoproteinemia, improved considerably in the PRE and DTW groups. Treatment was well tolerated in all patients, and no serious adverse events were observed. Our findings suggested that induction therapy with double dose TWHF significantly improved response rates in IgAN patients with heavy proteinuria, and did not considerably increase side effects. PMID- 28867715 TI - New Iridoids from Scrophularia ningpoensis. AB - Five new compounds including five iridoids (1-5) and six known compounds were isolated from the rhizomes of Scrophularia ningpoensis. Their structures were determined by extensive NMR and IR, MS spectroscopic data analyses. The anti inflammatory, antibacterial, antifungal, and cytotoxic activities of the isolated compounds were evaluated. Compound 11 exhibited significant inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophage cells. PMID- 28867716 TI - Identification of Characteristic Phenolic Constituents in Mousouchiku Extract Used as Food Additives. AB - Mousouchiku extract is prepared from the bamboo-sheath of Phyllostachys heterocycla MITF. (Poaceae), and is registered as a food manufacturing agent in the List of Existing Food Additives in Japan. This study describes the chromatographic evaluation of characteristic components of this extract to obtain the chemical data needed for standardized specifications. We isolated 12 known compounds from this extract: 5-hydroxymethyl-2-furfural, 4-hydroxybenzoic acid, trans-p-coumaric acid, trans-ferulic acid, N,N'-diferuloylputrescine, 4' hydroxypropiophenone, beta-arbutin, tachioside, isotachioside, 3,4' dihydroxypropiophenone 3-O-glucoside, koaburaside, and (+)-lyoniresinol 9'-O glucoside. Moreover, a new propiophenone glycoside, propiophenone 4'-O-(6-beta-D xylosyl)-beta-D-glucoside (propiophenone 4'-O-primeveroside), was isolated. The structure of each isolated compound was elucidated based on NMR and MS data or direct HPLC comparisons with authentic samples. Among the isolates, (+) lyoniresinol 9'-O-glucoside was found to be the major ingredients of the extract as observed using HPLC analysis. However, 2,6-dimethoxy-1,4-benzoquinone, which is considered the main constituent of mousouchiku extract, was only detected as a trace constituent and not isolated in this study. PMID- 28867719 TI - ER Stress and Disease: Toward Prevention and Treatment. AB - Secretory and membrane proteins are synthesized in ribosomes, then mature in the endoplasmic reticulum (ER), but if ER function is impaired, immature defective proteins accumulate in the ER. This situation is called ER stress: in response, a defensive mechanism called the unfolded protein response (UPR) is activated in cells to reduce the defective proteins. During the UPR, the ER transmembrane sensor molecules inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and RNA-dependent protein kinase (PKR)-like ER kinase (PERK) are activated, stress signals are transduced to the outside of the ER, and various cell responses, including gene induction, occur. In ER-associated degradation (ERAD), one type of UPR, defective proteins are eventually expelled from the ER and degraded in the cytoplasm through the ubiquitin proteasome system. Since ER stress has been reported to have relationships with neurodegenerative diseases, diabetes, metabolic syndromes, and cancer, it is the focus of increased attention from the perspectives of elucidating pathogenic mechanisms, and in the development of therapeutics. PMID- 28867720 TI - Chronic Rapamycin Treatment Improved Metabolic Phenotype but Inhibited Adipose Tissue Browning in High-Fat Diet-Fed C57BL/6J Mice. AB - Rapamycin (Rap) has been demonstrated to affect lipid metabolism through stimulating lipolysis, inhibiting de novo lipogenesis and reducing adiposity. In the present study, we investigated rapamycin exposure's influence on adipose tissue browning in high-fat diet-induced fatty mice. Four-week old C57BL/6J mice were fed normal chow or high-fat diet for a period of 6 weeks and then divided into three groups: (1) Nor group: mice fed with normal chow; (2) high fat diet (HFD) group: fatty mice fed with high-fat diet; (3) Rap group: high-fat diet-fed fatty mice treated intragastrically with rapamycin at a dose of 2.5 mg/kg per day for 5 weeks. Body weights and food intakes of the mice were recorded weekly. At the end of the study, blood samples were collected for glucose, lipid and insulin evaluations. Adipose tissues were weighed and lipid contents were monitored. Moreover, real-time PCR and Western blotting were applied to detect the expression levels of beige and brown fat marker genes in white adipose tissue (WAT) and brown adipose tissue (BAT). Our data demonstrated that Rap exposure significantly ameliorated metabolic defects including hyperglycaemia, dyslipidaemia and insulin resistance in the fatty mice. Furthermore, Rap treatment led to decreased tissue weights and lipid contents both in WAT and BAT. Remarkably, expression levels of BAT marker genes including uncoupling protein-1 (UCP-1), cell death-inducing DNA fragmentation factor-alpha-like effector A (CIDEA), PR-domain containing protein-16 (PRDM16) and peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha) were significantly down regulated in Rap-treated fatty mice. This report demonstrates Rap exposure is capable of inhibiting adipose tissue browning in high-fat diet-induced fatty mice, and provides evidence for deeper understanding of Rap's influence on lipid homeostasis. PMID- 28867721 TI - Inhibitory Effect of Oxethazaine on Midazolam Metabolism in Rats. AB - There have been few reports concerning to the drug-drug interactions (DDIs) with OTC drugs although an increase in the use of OTC drugs in recent years. This current study was conducted to clarify the DDIs through CYP3A inhibition by oxethazaine (OXZ), an antacid available as an OTC drug. Midazolam (MDZ) was used as a probe drug for CYP3A activity. In an in vivo study, a single oral dose of OXZ (50 mg/kg) was administered to rats 30, 60, or 120 min before oral MDZ administration (15 mg/kg). Serum concentrations of MDZ were analyzed by HPLC, and its pharmacokinetic parameters were compared with a water-treated control group. The inhibitory effect of OXZ on MDZ 1'-hydroxylation (MDZ 1'-OH) activity was investigated in vitro using rat liver and intestinal microsomes. Pretreatment of OXZ 120 min before MDZ administration significantly increased the area under the serum concentration-time curve (AUC0-infinity) of MDZ six-fold compared to the control group without a change in elimination half-life (t1/2). In contrast, OXZ pretreatment 30 or 60 min before MDZ administration did not show any remarkable change in MDZ pharmacokinetic parameters. The in vitro study showed that OXZ inhibited MDZ 1'-OH activity in a concentration-dependent manner both in liver and intestinal microsomes. These results suggested that OXZ increases serum MDZ concentration presumably by the inhibition of liver and/or intestinal CYP3A activity. OXZ was predicted to cause the DDIs mediated by CYP3A inhibition, although this effect depended on the dose interval. PMID- 28867718 TI - Role of mast cells in bronchial contraction in nonallergic obstructive lung pathology. AB - The role of mast cells in contractile bronchial smooth muscle activity has been evaluated in a model of chronic obstructive pulmonary disease induced in rats that were intermittently exposed to nitrogen dioxide (NO2) for 60 days. Starting from the 31st day, one group of rats inhaled sodium cromoglycate before exposure to NO2 to stabilize mast cell membranes. The second group (control) was not treated. Isometric smooth muscle contraction was analysed in isolated bronchial samples in response to nerve and smooth muscle stimulation. Histological analysis revealed large numbers of mast cells in lung tissue of COPD model rats. The inhibition of mast cell degranulation by sodium cromoglycate prevented the development of nerve-stimulated bronchial smooth muscle hyperactivity in COPD model rats. Histamine or adenosine-induced hyperactivity on nerve stimulation was also inhibited by sodium cromoglycate in bronchial smooth muscle in both control and COPD model rats. This suggests that the mechanism of contractile activity enhancement of bronchial wall smooth muscle cells may be mediated through the activation of resident mast cells transmembrane adenosine receptors resulting in their partial degranulation, with the released histamine acting upon histamine H1 receptors which trigger reflex pathways via intramural ganglion neurons. PMID- 28867723 TI - The Inhibitory Effect of Telmisartan on the Metabolism of Arachidonic Acid by CYP2C9 and CYP2C8: An in Vitro Study. AB - Epoxyeicosatorienoic acids (EETs) are generated from arachidonic acid (AA) by CYPs. EETs comprise four regioisomers (14,15-, 11,12-, 8,9-, and 5,6-EET). EETs show potent physiological effects, including vasodilation, anti-inflammation, myocardial preconditioning, and anti-platelet aggregation effects. We recently demonstrated that telmisartan, one of angiotensin II receptor blockers, inhibits AA metabolism by CYP enzymes, including CYP2C8, CYP2C9, and CYP2J2. We conducted studies of AA metabolism using recombinant CYP enzymes to estimate the inhibition constant and the type of inhibition by telmisartan of CYP2C9 and CYP2C8. The contribution ratio (CR) of each CYP enzyme was investigated using human liver microsomes. Dixon and Lineweaver-Burk plots indicated that telmisartan is a mixed inhibitor of both CYP2C9 and CYP2C8; telmisartan did not show a time-dependent inhibition toward these CYP enzymes. Based on the CRs, both CYP2C9 and CYP2C8 are the key enzymes in the metabolism of AA in the human liver. Uptake of telmisartan in the liver by organic anion transporting polypeptide (OATP) 1B3 and the non linear metabolism in gastrointestinal tract augment the potential of the drug to inhibit the CYP enzymes in the liver. PMID- 28867722 TI - The Standardized Extract of Juniperus communis Alleviates Hyperpigmentation in Vivo HRM-2 Hairless Mice and in Vitro Murine B16 Melanoma Cells. AB - In European folk medicine, the fruits of Juniperus communis are used in the treatment of skin-related disorders such as skin infection, itching, and psoriasis. Previously, we reported that the EtOAc fraction of J. communis (EAJC) contained tyrosinase inhibition properties in vitro non-cellular experiment. The aim of this study was to evaluate anti-melanogenic effect of standardized EAJC on a hyperpigmentation animal model. Therapeutic effects of EAJC toward skin hyperpigmentation were confirmed by both in vivo experiment and in vitro cell based assay. Skin depigmenting effect was detected by topical treatment of EAJC for 11 d to HRM-2 melanin-possessing hairless mice. Histologic findings including significantly decreased melanin depositions could be observed in dorsal skin samples of EAJC-treated group. In addition, the EAJC (50 ug/mL) attenuated melanin production through down-regulation of tyrosinase activity and protein expression in B16 murine melanoma cells. According to the phytochemical analysis, EAJC was found to contain hypolaetin-7-O-beta-D-xylopyranoside and isoscutellarein-7-O-beta-D-xylopyranoside as main components. Hypolaetin-7-O-beta D-xylopyranoside was responsible for the skin-lightening effect of EAJC by reducing the number of melanocytes in dorsal skins of HRM-2 mice. The present study provided direct experimental evidence for skin-lightening effect of EAJC in UV-irradiated hairless mouse model. Therapeutic attempts with the J. communis might be useful in the management of skin pigmentation-related diseases. PMID- 28867724 TI - Justicia procumbens Extract (DW2008) Selectively Suppresses Th2 Cytokines in Splenocytes and Ameliorates Ovalbumin-Induced Airway Inflammation in a Mouse Model of Asthma. AB - DW2008 is an anhydrous ethanol extract of Justicia procumbens produced by Dong Wha Pharmaceutical, Inc., Co. as a candidate anti-asthmatic drug. In this study, DW2008 selectively reduced T helper 2 (Th2) cytokines in mouse splenocytes and ameliorated ovalbumin-induced airway inflammation by downregulating pulmonary infiltration of differential inflammatory cells and Th2 cytokines more than a decoction or ethanol extract of J. procumbens did in a mouse asthma model. DW2008 also significantly inhibited airway hyperresponsiveness and reduced the thickness of the airway epithelium. HPLC analysis showed that the major peaks (justicidin A and B) of DW2008 were higher than those of the other extracts. Justicidin A and B significantly suppressed Th2 cytokine levels in mouse spleen cells and exhibited a protective effect in ovalbumin-induced airway inflammation. Our findings indicate that DW2008 effectively inhibits allergic airway inflammatory reactions and airway hyperresponsiveness in a mouse model of asthma, suggesting its potential as an anti-asthmatic agent. PMID- 28867727 TI - Influence of Japanese Regulatory Action on Denosumab-Related Hypocalcemia Using Japanese Adverse Drug Event Report Database. AB - The anti-receptor activator of nuclear factor kappa-B ligand (RANKL) antibody, Denosumab (DEN), was approved in April 2012 in Japan, but a Dear Healthcare Professional Letter of Rapid Safety Communication was released in September, 2012 by the regulatory authority because of the severe hypocalcemia risks. Currently, the effectiveness of this regulatory action has not been evaluated and, therefore, this study aimed to assess its impact on DEN-induced hypocalcemia using the Japanese Adverse Drug Event Report database (JADER). The case reports from April 2012 to September 2014 were collected from the JADER, which included 151642 adverse events for the primary suspected drugs. The reporting odds ratio (ROR) of hypocalcemia as a signal of the target adverse event was analyzed for DEN and zoledronic acid (ZOL, a reference drug). Changes in RORs were compared between the pre- (Pre, April 2012 to September 2012) and post- (Post 1, October 2012 to September 2013 and Post 2, October 2013 to September 2014) periods of the regulatory action. A decrease in the hypocalcemia ROR was observed for DEN in the post-periods, especially Post 2. Multivariate logistic regression analysis showed a significant decrease in hypocalcemia signal in Post 1 (p=0.0306 vs. Pre) and Post 2 (p=0.0054 vs. Pre). ZOL caused no significant changes in ROR of hypocalcemia, and none of the drugs caused ROR changes in jaw osteonecrosis (a reference adverse event). This study suggests that the regulatory action against hypocalcemia in DEN effectively decreased hypocalcemia signal. Further studies using medical information databases are needed to confirm this result. PMID- 28867726 TI - Short Chain Fatty Acid Acetate Protects against Ethanol-Induced Acute Gastric Mucosal Lesion in Mice. AB - Short chain fatty acids acetate and propionate have been demonstrated protective function in the intestinal mucosa. However, their impact on gastric mucosa has not yet been elucidated. The current study aimed to investigate the potential protective effects of acetate and propionate against ethanol-induced gastric mucosal lesion and the underlying mechanism in mice. ICR mice were orally treated with acetate and propionate, respectively, 30 min prior to the establishment of gastric mucosal injury model by challenge with absolute ethanol. The gastric samples were collected for the detection of oxidative, inflammatory and apoptotic related parameters. Acetate, but not propionate, attenuated the severity of gastric mucosal damage as evidenced by the gross changes of gastric mucosa, pathological aberrations. Acetate alleviated oxidative stress as shown by the increase in glutathione (GSH) content and superoxide dismutase (SOD) activities, and the decrease of malondialdehyde (MDA) level. The elevated concentrations of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6, and the activation of nuclear factor-kappaB (NF-kappaB) p65 by ethanol stimulation was also reduced by acetate. Moreover, the anti-inflammatory factors, IL-4, LXA4 and IL-10, were up-regulated in acetate treated group. With respect to gastric mucosal apoptosis, acetate suppressed caspase-3 activity and BAX expression in favor of cell survival. These favorable actions were maybe associated with up regulation of the gastric MUC5AC, the key defense factor of gastric mucosal system. These findings accentuate the gastroprotective actions of acetate in ethanol-induced gastric injury which were mediated via concerted multi-prolonged actions, including suppression of gastric oxidation, inflammation and apoptosis and promotion of MUC5AC expression. PMID- 28867728 TI - Development of a High-Throughput Assay for Inhibitors of the Polo-Box Domain of Polo-Like Kinase 1 Based on Time-Resolved Fluorescence Energy Transfer. AB - Although enzyme-linked immunosorbent assay (ELISA) technology has been widely accepted for binding assays against the polo-box domain (PBD) of polo-like kinase 1 (Plk1), these assays have a limitation-related heterogeneous procedure, such as multiple incubations and washing steps to apply high-throughput screenings (HTSs). In the present study, a Plk1-PBD binding assay based on time-resolved fluorescence energy transfer (TR-FRET) was developed for HTS of PBD-binding inhibitors. The TR-FRET-based Plk1-PBD binding assay is sensitive and robust and can be miniaturized into the 384-well plate-based format. Compared with the ELISA based Plk1-PBD binding assay (Z' factor, 0.53; signal-to-background ratio, 4.19), the TR-FRET-based Plk1-PBD binding assay improved the Z' factor (0.72) and signal to-background ratio (8.16). Using TR-FRET based Plk1-PBD binding assay, pilot library screening of 1019 natural compounds was conducted and five hit compounds such as haematoxylin, verbascoside, menadione, lithospermic acid and (1,3 dioxolo[4,5-g]isoquinolinium 5,6,7,8-tetrahydro-4-methoxy-6,6-dimethyl-5-[2-oxo-2 (2-pyridinyl)ethyl]-iodide) (DITMD) were identified as Plk1-PBD inhibitor. In a functional assay to validate the hit compounds, five hit compounds exhibited suppression of HeLa cells proliferation. These results suggest that TR-FRET-based Plk1-PBD binding assay can be applied for an efficient and less time-consuming HTS of compound libraries. PMID- 28867725 TI - Wound Healing Effect of Slightly Acidic Electrolyzed Water on Cutaneous Wounds in Hairless Mice via Immune-Redox Modulation. AB - Acidic electrolyzed water is an innovative sanitizer having a wide-spectrum of applications in food industry, and healthcare industry but little is known on its effect and mechanism in wound healing. The study was conducted to identify the effect and mechanism of slightly acidic electrolyzed water (SAEW) on cutaneous wounds in hairless mice. SAEW (pH: 5-6.5, oxidation reduction potential: 800 mV, chlorine concentration: 25 ppm) was prepared through electrolysis of water and was applied to the wounds of hairless mice three times a day for seven days. Wound size, immune response and oxidative stress were explored and compared to conventional agents such as Betadine and alcohol. We found that SAEW-treated group showed the highest wound reduction percentage (p<0.01). Antioxidant activities such as glutathione peroxidase, catalase and myeloperoxidase activities of SAEW group surpassed the total reactive oxygen species in skin. Nuclear factor erythroid-2-related-factor-2 and aryl hydrocarbon receptor were upregulated in SAEW group. Further, SAEW recruited the production of intracellular calcium and promoted its utilization for faster healing. In line, SAEW treatment decreased pro-inflammatory cytokines [interleukin (IL)-1beta, IL 6, keratinocyte chemoattractant, and tumor necrosis factor-alpha] in serum. Other hallmarks of wound healing, matrixmetalloproteinases (MMP)1 and MMP9 were also upregulated. Collectively, our study indicates that SAEW is effective in wound healing of hairless mice via immune-redox modulation, and heals better/faster than conventional agents. PMID- 28867730 TI - Up-Regulation of the Voltage-Gated KV2.1 K+ Channel in the Renal Arterial Myocytes of Dahl Salt-Sensitive Hypertensive Rats. AB - Salt-sensitive hypertension induces renal injury via decreased blood flow in the renal artery (RA), and ion channel dysfunction in RA myocytes (RAMs) may be involved in the higher renal vascular resistance. We examined the effects of several voltage-gated K+ (KV) channel blockers on the resting tension in endothelium-denuded RA strips and delayed-rectifier K+ currents in RAMs of Dahl salt-sensitive hypertensive rats (Dahl-S) fed with low- (Dahl-LS) and high-salt diets (Dahl-HS). The tetraethylammonium (TEA)-induced contraction in RA strips were significantly larger in Dahl-HS than Dahl-LS. Correspondingly, TEA-sensitive KV currents were significantly larger in the RAMs of Dahl-HS than Dahl-LS. Among the TEA-sensitive KV channel subtypes, the expression levels of KV2.1 transcript and protein were significantly higher in the RA of Dahl-HS than Dahl-LS, while those of KV1.5, KV7.1, and KV7.4 transcripts was comparable in two groups. KV2.1 currents detected as the guangxitoxin-1E-sensitive component were larger in the RAMs of Dahl-HS than Dahl-LS. These suggest that the up-regulation of the KV2.1 channel in RAMs may be involved in the compensatory mechanisms against decreased renal blood flow in salt-sensitive hypertension. PMID- 28867729 TI - Comparison of Clinical Advantage between Topiroxostat and Febuxostat in Hemodialysis Patients. AB - To determine the response of hemodialysis (HD) patients to topiroxostat after a switch from febuxostat, we evaluated the efficacy, tolerability, and serum concentration of topiroxostat in HD patients after the switch. In this 16-month prospective observational study, we assessed the serum uric acid (UA) levels, other laboratory data, and serum topiroxostat concentrations of 10 HD patients who had been receiving febuxostat at a dose of 10 mg/d for over 1 year. No statistical difference was observed between the tolerability index at baseline and 16 months after the switch to topiroxostat. Serum UA after the switch in all patients (attained serum UA levels of <=6 mg/dL) was 5.6+/-1.7 mg/dL (60%) at baseline, 4.9+/-0.5 mg/dL (100%) at 6 months and 5.7+/-0.4 mg/dL (50%) at 16 months (p=0.25), respectively. In patients with baseline serum UA levels >6 mg/dL, serum UA was significantly reduced at 6 and 16 months compared with baseline. Minimum serum concentrations of serum topiroxostat were lower than the limit of quantification (<25 ng/mL). Our results indicate that a switch from febuxostat 10 mg/d to topiroxostat 40 mg/d might reduce serum UA levels, with no change in other clinical laboratory data over the long term. These effects were more frequent in patients with high serum UA levels. Furthermore, topiroxostat therapy was more cost effective than febuxostat therapy. Thus, topiroxostat therapy could be a better treatment option for HD patients who develop high serum UA levels after febuxostat 10 mg/d administration. PMID- 28867731 TI - FOXA1 Induces E-Cadherin Expression at the Protein Level via Suppression of Slug in Epithelial Breast Cancer Cells. AB - Epithelial-to-mesenchymal transition (EMT) is an important process during embryonic development and tumor progression by which adherent epithelial cells acquire mesenchymal properties. Forkhead box protein A1 (FOXA1) is a transcriptional regulator preferentially expressed in epithelial breast cancer cells, and its expression is lost in mesenchymal breast cancer cells. However, the implication of this biased expression of FOXA1 in breast cancer is not fully understood. In this study, we analyzed the involvement of FOXA1 in EMT progression in breast cancer, and found that stable expression of FOXA1 in the mesenchymal breast cancer MDA-MB-231 cells strongly induced the epithelial marker E-cadherin at the mRNA and protein levels. Furthermore, stable expression of FOXA1 was found to reduce the mRNA and protein expression of Slug, a repressor of E-cadherin expression. FOXA1 knockdown in the epithelial breast cancer MCF7 cells reduced E-cadherin protein expression without decreasing its mRNA expression. In addition, FOXA1 knockdown in MCF7 cells up-regulated Slug mRNA and protein expression. Notably, similar to FOXA1 knockdown, stable expression of Slug in MCF7 cells reduced E-cadherin protein expression without decreasing its mRNA expression. Taken together, these results suggest that although FOXA1 can induce E-cadherin mRNA expression, it preferentially promotes E-cadherin expression at the protein level by suppressing Slug expression in epithelial breast cancer, and that the balance of this FOXA1-Slug axis regulates EMT progression. PMID- 28867732 TI - Comparison between Antiemetic Effects of Palonosetron and Granisetron on Chemotherapy-Induced Nausea and Vomiting in Japanese Patients Treated with R CHOP. AB - In the present study, the antiemetic effect of palonosetron, not combined with dexamethasone and aprepitant, on chemotherapy-induced nausea and vomiting was evaluated in patients with malignant lymphoma receiving first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, and was compared to that of granisetron. A total of 74 patients with non-Hodgkin lymphoma were included in this study (April 2007 to December 2015). Palonosetron (0.75 mg) or granisetron (3 mg) was intravenously administered before R-CHOP therapy. The proportions of patients with complete response (CR) during the overall (0-120 h after the start of R-CHOP therapy), acute (0-24 h) and delayed (24-120 h) phases were evaluated. CR was defined as no vomiting and no use of antiemetic rescue medication. A total of 32 and 42 patients were treated with palonosetron and granisetron, respectively. The CR rate in the palonosetron group was significantly higher than that in the granisetron group during the delayed phase (90.6 and 61.9%, respectively; p=0.007). Logistic regression analysis showed that use of palonosetron improved the CR rate during the delayed phase, compared to use of granisetron. Female sex, age less than 60 years, no habitual alcohol intake, and Eastern Cooperative Oncology Group performance status (ECOG PS) score of 1 were significant risk factors associated with non-CR. The findings of this study suggested the superiority of palonosetron to granisetron, without accompanying dexamethasone and aprepitant, for chemotherapy-induced nausea and vomiting in patients with malignant lymphoma. PMID- 28867733 TI - 13C-Acetic Acid Breath Test Monitoring of Gastric Emptying during Disease Progression in Diabetic Rats. AB - Gastric motility disturbance is commonly found in long-standing hyperglycemia. Both delayed and rapid gastric emptying has been reported in diabetes. However, very few studies have followed the changes in gastric emptying during disease progression in diabetes because of technical limitations. 13C-Acetic acid breath test is a validated method which is non-invasive and can be used repeatedly or serially to evaluate gastric emptying changes in animal. We investigated the gastric emptying changes in different stages of diabetes using 13C-acetic acid breath test, as well as its related mechanisms involving interstitial cells of Cajal (ICCs), and stem cell factor (SCF) in streptozotocin-induced diabetic rats. The results showed that gastric emptying was accelerated at the early stage (12 weeks of diabetes) whereas intramuscular ICCs (ICC-IM) networks were not different from normal group. At long-term stage (28 weeks of diabetes), gastric emptying had returned to normal pattern with no delayed. ICC-IM networks were decreased in the diabetic group compared to 12th weeks, and were lower than in the normal group at the same time point. SCF levels were constantly high in the diabetic group than in the normal group. This result indicated that 13C-acetic acid breath test is useful to track the alteration in gastric emptying during disease progression. The change of gastric emptying was not found to be significantly associated with ICC-IM. Elevated SCF may help to preserve ICC-IM, especially in the early phase of diabetes. PMID- 28867734 TI - Curcumin beta-D-Glucuronide Plays an Important Role to Keep High Levels of Free Form Curcumin in the Blood. AB - Curcumin, a polyphenol derived from the rhizome of the naturally occurring plant Curcuma longa, has various pharmacological actions such as antioxidant and anti inflammatory effects. In this paper, we evaluated the role of its internal metabolite, curcumin beta-D-glucuronide (curcumin monoglucuronide, CMG), by investigating curcumin kinetics and metabolism in the blood. Firstly, we orally administered highly bioavailable curcumin to rats to elucidate its kinetics, and observed not only the free-form of curcumin, but also, curcumin in a conjugated form, within the portal vein. We confirmed that curcumin is conjugated when it passes through the intestinal wall. CMG, one of the metabolites, was then orally administered to rats. Despite its high aqueous solubility compared to free-form curcumin, it was not well absorbed. In addition, CMG was injected intravenously into rats in order to assess its metabolic behavior in the blood. Interestingly, high levels of free-form curcumin, thought to be sufficiently high to be pharmacologically active, were observed. The in vivo antitumor effects of CMG following intravenous injection were then evaluated in tumor-bearing mice with the HCT116 human colon cancer cell line. The tumor volume within the CMG group was significantly less than that of the control group. Moreover, there was no significant loss of body weight in the CMG group compared to the control group. These results suggest that CMG could be used as an anticancer agent without the serious side effects that most anticancer agents have. PMID- 28867735 TI - Effects of Ascorbyl-2-phosphate Magnesium on Human Keratinocyte Toxicity and Pathological Changes by Sorafenib. AB - Hand-foot skin reaction is recognized as one of the most common adverse events related to multiple tyrosine kinase inhibitors, but an effective prevention method has not been identified. The chief aim of this study was to find a mechanism-based preventive method for the skin toxicity induced by sorafenib using vitamin C derivatives. The effects of ascorbyl-2-phosphate magnesium (P-VC Mg) on the molecular and pathological changes induced by sorafenib were investigated in human keratinocyte HaCaT cells. The cell growth inhibition and apoptotic effects of sorafenib were attenuated by P-VC-Mg. Moreover, P-VC-Mg inhibited the decrease of signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of apoptosis suppressors treated by sorafenib. HaCaT cells transfected with the STAT3 dominant-negative form (STAT3DN) and STAT3 small interfering RNA (siRNA) combined with P-VC-Mg did not exhibit the attenuation of cell growth inhibition. Interestingly, after exposure to sorafenib in a three dimensional (3D) skin model assay, the basal layer was significantly thickened and the granular and spinous layers became thinner. In contrast, after exposure to sorafenib with P-VC-Mg, the thickness of the basal, granular, and spinous layers was similar to that of the control image. These findings suggest that P-VC-Mg attenuates sorafenib-induced apoptosis and pathological changes in human keratinocyte cells and in the 3D skin model mediated by the maintenance of STAT3 activity. PMID- 28867736 TI - Triterpenoids Isolated from Alnus japonica Inhibited LPS-Induced Inflammatory Mediators in HT-29 Cells and RAW264.7 Cells. AB - Alnus japonica (Betulaceae) is a broad-leaved tree easily found in damp regions within the mountains of Korea and Japan. Four triterpenoids (1-4) from the fruits of A. japonica, including the newly isolated 3beta-hydroxy-lanost-9(11),23(24) dien-25,26-diol (3), inhibited the lipopolysaccharide (LPS)-induced expression of the chemotactic cytokine interleukin (IL)-8 and nitric oxide (NO) production in HT-29 colon epithelial cells and RAW264.7 macrophages, respectively. Among these triterpenoids, compound 4, which showed the most potent inhibitory activity, effectively down-regulated LPS-induced protein expression of inducible nitric oxide synthase (iNOS) in RAW264.7 cells and in HT-29 cells. Also, compound 4 concentration-dependently inhibited the levels of LPS-induced pro-inflammatory cytokines, IL-1beta and IL-6 in macrophage cells. These triterpenoids isolated from A. japonica fruits are thought to contribute to the anti-inflammatory activities of macrophage and colon epithelial cells, which are important for regulating the colon immune system. They are expected to be potential candidates for therapeutic agents against inflammatory bowel disease. PMID- 28867737 TI - Fluorescence Analysis of the Mitochondrial Effect of a Plasmalemmal Na+/Ca2+ Exchanger Inhibitor, SEA0400, in Permeabilized H9c2 Cardiomyocytes. AB - We investigated the effect on mitochondrial Ca2+ of SEA0400, an inhibitor of the Na+/Ca2+ exchanger (NCX) which reduces mitochondrial Ca2+ overload during myocardial ischemia, in digitonin-permeabilized H9c2 cells expressing the mitochondrial-targeted Ca2+ indicator, yellow cameleon 3.1. The elevation of mitochondrial Ca2+ concentration caused by an increase in extramitochondrial Ca2+ concentration was inhibited by carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) or ruthenium red, but enhanced by CGP-37157, a mitochondrial NCX inhibitor. SEA0400 had no effect on mitochondrial Ca2+ under normal and ischemic conditions. Thus, the mitochondria-protective effects of SEA0400 could be explained by inhibition of plasmalemmal NCX but not mitochondrial NCX. PMID- 28867740 TI - Investigation on the Interactions between Various Drugs and Aojiru (Green Juice) Using a Simple Centrifugation Method. AB - The objective of this study was to evaluate the interactions between various drugs and aojiru (green juice), a popular health food in Japan, using a simple centrifugation method. The mixture of drug solution and aojiru suspension was gently shaken and centrifuged. The drug concentration in the supernatant fluid was then determined by HPLC. The concentration of rhodamine 123 (Rho-123), a model compound, in the supernatant fluid significantly decreased after mixing with aojiru, indicating extensive binding of Rho-123 to the insoluble components of aojiru. When administered into rat small intestinal loops together with aojiru, the plasma Rho-123 concentrations became much smaller than those when administered alone. This result strongly suggested that a strong interaction observed in vitro was well reflected in modulated absorption. Among seven drugs tested, chlorpromazine and imipramine exerted binding properties to aojiru similar to or greater than Rho-123. As a small part of both Rho-123 and imipramine was released when the aojiru precipitate was resuspended, their binding to aojiru was considered to be tight. The binding of diltiazem, fexofenadine, glibenclamide, metformin, and norfloxacin to aojiru was much weaker or almost negligible compared with that of chlorpromazine and imipramine. The present results suggest that aojiru can decrease the intestinal absorption of some clinically relevant drugs through tight binding in the small intestine and that the present centrifugation method is useful for predicting in vivo interactions between drugs and aojiru. PMID- 28867741 TI - Inhibitory Potency of Marketed Drugs for Ulcerative Colitis and Crohn's Disease on PEPT1. AB - We investigate the inhibitory effect of marketed drugs for treatment of inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) on the uptake transporters of peptide transporter 1 (PEPT1), which are up-regulated under the inflamed condition. The uptake transport of glycylsarcosine, a typical substrate for PEPT1, was reduced to 60% only by 5 aminosalicylate at the clinically relevant concentration among tested marketed drugs in PEPT1 transfected HEK293 cell lines. These findings suggest that the inhibition of PEPT1, which were up-regulated in inflamed or non-inflamed site on UC and CD patients, contribute to the clinical effect of commercially available drugs for IBD patients through the inhibition of uptake of antigenic proinflammatory oligopeptides such as formyl-methionine (Met)-leucine (Leu) phenylalanine (Phe) via PEPT1. PMID- 28867742 TI - Effect of Infectious Diseases on the Pathogenesis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions. Recent studies have revealed that the prevalence of SJS/TEN is associated with genetic backgrounds, such as polymorphisms in human leukocyte antigens (HLAs). However, non-genetic factors contributing to the etiology of SJS/TEN are largely unknown. This study aimed to assess the involvement of concurrent infection on the pathological states of SJS/TEN, examining the severity of cutaneous symptoms and ocular involvement as well as the time to onset in drug-induced SJS/TEN patients. We recruited 257 Japanese SJS/TEN patients from June 2006 to September 2013 through a nationwide case collection network and participating hospitals and reviewed the clinical information including patient backgrounds, primary disease and medication status. Association between infection and pathological states of SJS/TEN was assessed using univariate and multivariate analyses. The concurrent infectious group of SJS/TEN patients showed a significantly higher rate of exhibiting severer dermatological and ophthalmological phenotypes and an earlier onset of SJS/TEN than the non-infectious group. Our results suggest that the infection could be a risk factor to cause severer symptoms and earlier onset of SJS/TEN. PMID- 28867739 TI - Inhibitory Effects of Juices Prepared from Individual Vegetables on CYP3A4 Activity in Recombinant CYP3A4 and LS180 Cells. AB - Human intestinal absorption and drug metabolism vary to a large extent among individuals. For example, CYP3A4 activity has large individual variation that cannot be attributed to only genetic differences. Various flavonoids in vegetables, such as kaempferol and quercetin, possess inhibitory effects, and some vegetable and fruit juices have also been found to inhibit CYP3A4 activity. Therefore, differences in daily intake of flavonoid-containing vegetables may induce individual variation in intestinal bioavailability. To identify a vegetable that strongly inhibits CYP3A4, we investigated the effects of juices, prepared from individual vegetables, on CYP3A4 activity using recombinant CYP3A4 and LS180 cells in this study. Nine vegetable juices (cabbage, Japanese radish, onion, tomato, eggplant, carrot, Chinese cabbage, green pepper, and lettuce), were prepared and recombinant CYP3A4 and LS180 cells were used for evaluation of CYP3A4 activity. Metabolism to 6beta-hydroxytestosterone by recombinant CYP3A4 was strongly inhibited by cabbage, onion, and green pepper juices, and cabbage and green pepper juices significantly inhibited CYP3A4 activity in a preincubation time-dependent manner. In addition, CYP3A4 activity in LS180 cells was significantly inhibited by cabbage and onion juices. In conclusion, this study showed that juices prepared from some individual vegetables could significantly inhibit CYP3A4 activity. Therefore, variation in the daily intake of vegetables such as cabbage and onion may be one of the factors responsible for individual differences in intestinal bioavailability. PMID- 28867738 TI - Characterization of beta-Estradiol 3-Glucuronidation in Rat Brain. AB - beta-Estradiol is conjugated by uridine 5'-diphosphate-glucuronosyltransferase (UGT) 1A to 3-glucuronide in the human liver. UGT1A has been found in the brain; therefore, UGT1A may be involved in beta-estradiol 3-glucuronidation in the brain. In the present study, we aimed to characterize the beta-estradiol 3 glucuronidation reaction in the rat brain. beta-Estradiol 3-glucuronidation was detected in eight rat brain regions (cerebellum, frontal cortex, parietal cortex, piriform cortex, hippocampus, medulla oblongata, striatum, and thalamus). beta Estradiol 3-glucuronidation in the cerebellum was fitted to the Hill equation (S50=8.0 uM, n=1.1). In inhibition experiments, beta-estradiol 3-glucuronidation was inhibited to 73.6% in the cerebellum by 50 uM bilirubin, whereas it was reduced to 20.5% with 5 uM bilirubin in the liver. Unlike in the liver, Ugt1a1 may not be the main isoform catalyzing this glucuronidation in the brain. Serotonin and acetaminophen at 10 mM inhibited glucuronidation to 1.17 and 25.5%, respectively, in the cerebellum. In induction experiments, the administration of beta-naphthoflavone, carbamazepine, and phenobarbital did not increase beta estradiol 3-glucuronidation in the brain except for phenobarbital in the striatum. In addition, beta-estradiol 3-glucuronidation was not correlated with serotonin or acetaminophen glucuronidation in the brain, suggesting that Ugt1a6 and Ugt1a7 are not major isoforms of beta-estradiol 3-glucuronidation in the rat brain. In the present study, although we were unable to identify the isoform responsible for beta-estradiol 3-glucuronidation, we confirmed that beta estradiol could be metabolized to glucuronide in the brain under a different metabolic profile from that in the liver. PMID- 28867743 TI - Effects of Capsaicin Coadministered with Eicosapentaenoic Acid on Obesity-Related Dysregulation in High-Fat-Fed Mice. AB - Obesity-induced inflammation contributes to the development of metabolic disorders such as insulin resistance, type 2 diabetes, fatty liver disease, and cardiovascular disease. In this study, we investigated whether the combination of eicosapentaenoic acid (EPA) and capsaicin could protect against high-fat diet (HFD)-induced obesity and related metabolic disorders. The experiments were performed using male C57BL/6J mice that were fed one of the following diets for 10 weeks: standard chow (5.3% fat content) (normal group), a HFD (32.0% fat content) (HFD group), or a HFD supplemented with either 4% (w/w) EPA (EPA group) or a combination of 4% (w/w) EPA and 0.01% (w/w) capsaicin (EPA+Cap group). Our results indicated that the body, fat and liver tissue weights and levels of serum glucose, insulin, total cholesterol, triglyceride, high-density lipoprotein cholesterol, aspartate aminotransferase, and alanine aminotransferase were significantly higher in HFD group mice than in normal group mice (p<0.05 in all cases). However, the body and fat tissue weights and serum glucose levels and homeostasis model assessment of insulin resistance were significantly lower in EPA+Cap group mice group than in HFD and EPA group mice (p<0.05 in all cases). Thus, our study suggests that the combination of EPA and capsaicin might be beneficial for delaying the progression of obesity-related metabolic dysregulation and subsequent complications. PMID- 28867744 TI - Limited Azithromycin Localization to Rabbit Meibomian Glands Revealed by LC-MS Based Bioanalysis and DESI Imaging. AB - Meibomian gland dysfunction (MGD) is the leading cause of dry eye, and although it affects approximately 4% of the population, treatment options remain limited. Topical azithromycin is one of the most promising pharmacological agents because of its multiple mechanisms of action and long sustainability. Azithromycin is frequently used as an off-label medication in the U.S. However, although azithromycin is presumed to act directly on meibomian gland cells, the mechanisms of action that contribute to its clinical efficacy remain unclear because no studies using a pharmacokinetic approach have been performed. Therefore, we aimed to clarify whether topical azithromycin reaches the meibomian glands sufficiently to generate a biological effect. We measured azithromycin concentrations in rabbit meibomian glands collected using a recently developed method. Moreover, we also visualized the azithromycin micro-distribution using desorption electrospray ionization (DESI) imaging. Azithromycin concentration in the meibomian glands reached only 0.8 ug/g tissue following a single application of a 1% azithromycin ophthalmic solution and was 1000-fold lower than the concentration in conjunctival epithelium. Similarly, no signal was observed in the meibomian glands on DESI images. Our results clearly demonstrated that topical azithromycin had limited access to the meibomian glands and was predominantly distributed in ocular surface tissues such as the palpebral conjunctiva and lid margins. These findings provide new insight into the clinical responses to topical azithromycin therapy and will aid in the further development of effective drugs with more suitable pharmacokinetic properties. PMID- 28867745 TI - Non-toxic Level of Acetaminophen Potentiates Carbon Tetrachloride-Induced Hepatotoxicity in Mice. AB - A wide range of medications are routinely used to maintain and improve human health. Hence, it is essential that we understand and predict adverse effects caused by the combined use of multiple medications. In the present study, we investigated whether the combination of carbon tetrachloride (CCl4) and acetaminophen (APAP) had a detrimental effect on the liver. Mice injected with APAP (100 mg/kg) showed no significant changes in hepatic injury markers (alanine aminotransferase and aspartate aminotransferase), histopathological findings, pro inflammatory cytokine levels, or hepatic oxidative stress. In contrast, a single injection of CCl4 (15 mg/kg) led to a significant increase in hepatic injury, in addition to an increase in pro-inflammatory cytokine levels and oxidative stress. Co-administration of APAP and CCl4 resulted in exacerbation of these hepatic injuries. Our results suggest that a non-toxic dose of APAP has the potential to increase CCl4-induced liver damage and oxidative stress. PMID- 28867746 TI - Modulation of Unfolded Protein Response by Methylmercury. AB - Methylmercury (MeHg) results in cell death through endoplasmic reticulum (ER) stress. Previously, we reported that MeHg induces S-mercuration at cysteine 383 or 386 in protein disulfide isomerase (PDI), and this modification induces the loss of enzymatic activity. Because PDI is a key enzyme for the maturation of nascent protein harboring a disulfide bond, the disruption in PDI function by MeHg results in ER stress via the accumulation of misfolded proteins. However, the effects of MeHg on unfolded protein response (UPR) sensors and their signaling remain unclear. In the present study, we show that UPR is regulated by MeHg. We found that MeHg specifically attenuated inositol-requiring enzyme 1alpha (IRE1alpha)-x-box binding protein 1 (XBP1) branch, but not the protein kinase RNA like endoplasmic reticulum kinase (PERK) and activating transcriptional factor 6 (ATF6) branches. Treatment with GSK2606414, a specific PERK inhibitor, significantly inhibited MeHg-induced cell death. These findings suggest that MeHg exquisitely regulates UPR signaling involved in cell death. PMID- 28867747 TI - Involvement of Carrier-Mediated Transport at the Blood-Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain. AB - Spermine is the end-product in the polyamine biosynthetic pathway, and its excess accumulation induces neuroexcitatory responses and neurotoxicity. The purpose of this study was to elucidate the involvement of transport systems at the brain barriers in the clearance of spermine. In vivo rat spermine elimination from brain parenchyma across the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCSFB) was assessed by intracerebral and intracerebroventricular administration techniques, respectively. To characterize spermine transport at the BCSFB, a transport study using rat choroid plexus was performed. After the intracerebral microinjection of [3H]spermine, no time dependent decrease in [3H]spermine in the ipsilateral cerebrum was observed, suggesting the low contribution of the BBB to spermine clearance from the brain. In contrast, the [3H]spermine concentration in the CSF after intracerebroventricular administration was time-dependently decreased with an elimination rate constant of 0.352 min-1, and the elimination clearance of [3H]spermine was 6.6-fold greater than that of [14C]D-mannitol, reflecting bulk flow of the CSF. This [3H]spermine elimination was attenuated by co administration of unlabeled excess spermine, indicating carrier-mediated elimination of spermine from the CSF. [3H]Spermine transport into the choroid plexus was strongly inhibited by unlabeled spermine, other polyamines (spermidine and putrescine), and organic cation transporter substrates such as corticosterone and 1-methyl-4-phenylpyridinium. However, other substrates/inhibitors for organic cation transporters (decynium-22 and tetraethylammonium) had little effect. Consequently, our study indicates that transporting molecules at the BCSFB, distinct from typical organic cation transporters, are involved in spermine clearance from the CSF. PMID- 28867748 TI - Higher incidence of nasopharyngeal carcinoma in some regions in the world confers for interplay between genetic factors and external stimuli. AB - Nasopharyngeal carcinoma (NPC) is a rare variety of head and neck cancers. The risk factors include three major causes: genetic factors, viral infection, and environmental and dietary factors. The types of NPC show strong ethnic and geographic variations. The keratinizing and non-keratinizing types are prevalent in the lower incidence regions like North America and Europe; whereas the undifferentiated type is mostly found in the regions with higher incidences like China, North Africa, Arctic, and Nagaland of North-East India. These suggest a possible major role of the internal genetic factors for generation and promotion of this disease. Viral infections might accelerate the process of carcinogenesis by helping in cellular proliferation and loss of apoptosis. Diet and other environmental factors promote these neoplastic processes and further progression of the disease occurs. PMID- 28867749 TI - Nanoemulsion: A suitable nanodelivery system of clove oil for anesthetizing Nile tilapia. AB - Clove oil ethanolic solution (CL-EtOH) have always been used for fish anesthesia. However, ethanol causes major side effect of fish hypersensivity. In this study, clove oil loaded nanoemulsion (CLN) was developed in order to enhance water miscibility of clove oil without using ethanol in the preparations. The obtained CLN was characterized in terms of droplet size, size distribution expressed as polydispersity index (PDI), and zeta potential. The anesthetic effect of CLN in comparison with CL-EtOH on Oreochromis niloticus (Nile tilapia) was investigated. The results showed that the best CLN was composed of 20% w/w clove oil and 15% w/w polysorbate 20. This CLN has internal droplet size of 63.2 +/- 1.0 nm, PDI of 0.31 +/- 0.04, and zeta potential of - 30.3 +/- 8.1 mV. GC-MS analysis indicated that eugenol was the main compound in clove oil. It was found that the induction time to anesthesia for Nile tilapia that received this CLN was shorter than that received CL-EtOH at the same eugenol concentration. The results of this study showed the potential of nanoemulsion on water miscible and efficacy enhancing of clove oil without using ethanol. The obtained CLN from this study is a promising formulation for fish aquaculture where fish sedation is required. PMID- 28867750 TI - Effects of Alpinia galanga oil on anesthesia and stress reduction in Oreochromis niloticus. AB - Oreochromis niloticus (Nile tilapia) is one widely cultured fish in Thailand. Handling processes and transportation causes high stress in Nile tilapia. This study explores anesthetic effect and stress reduction of Alpinia galanga oil (AGO) on Nile tilapia. The anesthetic activity was evaluated by the time for fish induction to anesthesia and full recovery. It was found that the suitable dose of AGO that caused desirable anesthesia of Nile tilapia was 700 mg/L. This dose gave induction and recovery times of approximately 257 and 438 sec, respectively. Blood glucose and plasma cortisol of the fish anesthetized with AGO showed nearly normal levels indicating that the fish stress during handling was not increased. Study on loading densities of fish mimicked general fish transportation and showed that loading density of fish was a crucial factor on fish stress. The highest water quality was found in the lowest loading density of fish. Water containing AGO at a concentration of 150 mg/L showed significantly higher potential for reducing fish activity and water improvement than without AGO. Therefore, AGO is a promising natural edible plant oil for anesthesia in Nile tilapia. PMID- 28867751 TI - T-786C variation in the promoter sequence of human eNOS gene markedly influences its expression level. AB - This study investigated the role of the T-786C polymorphism (SNP) in the 5' flanking sequence of the endothelial nitric oxide synthase gene (eNOS) on its expression level in vascular endothelium with the ultimate goal of shedding more light on the mechanisms by which genetic variations of eNOS might affect the vascular level of nitric oxide (NO). Sequences in the 5'-flanking region of eNOS gene were PCR-amplified using genomic DNA templates isolated from blood samples collected from cardiovascular disease (CVD) patients. Two sequence-versions carrying the same SNP site were used; a short (345 bp) and an extended one (1,594 bp), numbered relative to the translational start site. All sequences were cloned into a promoter-less vector (pGL3-basic), which carries the firefly luciferase gene as a reporter. Genotyping of the T-786C polymorphism was performed using Sanger sequencing of the insert region. Luminescence levels were then recorded 24 48 h after transfecting human endothelial cell line (EA.hy926). Three genotypes were identified in the subject samples; TT, TC, or CC. The highest expression levels associated with the TT genotype, followed by the TC genotype, then the CC genotype. The extended sequence version produced higher expression levels compared to the shorter version. Our results provide evidence that the T allele at the T-786C SNP site of the eNOS gene results in increased expression of the enzyme, and consequently might provide a protective mechanism from CVD. The extended promoter sequence of eNOS resulted in higher expression of the gene, suggesting the presence of some essential binding sites for transcription enhancing proteins. PMID- 28867752 TI - Genotyping of CYP2C9 and VKORC1 polymorphisms predicts south Indian patients with deep vein thrombosis as fast metabolizers of warfarin/acenocoumarin. AB - Deep vein thrombosis (DVT) is a life-threatening disease. Warfarin and acenocoumarol are anticoagulants used to treat DVT and vary among individuals in terms of treatment response/toxicity. Single nucleotide polymorphisms (SNPs) in CYP2C9 and VKORC1 play a role in the pharmacokinetics and dynamics of warfarin and acenocoumarol and they determine the efficacy of treatment by controlling drug clearance in treated individuals. The aim of the current study was to genotype the critical SNPs of CYP2C9 and VKORC1 genes in a south Indian population in order to understand the metabolizer phenotype of patients with DVT. CYP2C9 (rs1799853, rs1057910, rs1057909, rs28371686) and VKORC1 (rs9923231) SNPs were genotyped in 124 cases of DVT. Genomic regions of these SNPs from genomic DNA were amplified with PCR and directly sequenced using Sanger sequencing except for the SNP rs1799853, which was detected using Sau96I restriction endonuclease based digestion of variant alleles. Among south Indian patients with DVT, 6.5% (8/124) had the rs1799853 SNP of CYP2C9 and 11% (14/124) had the rs1057910 SNP while 16% (20/124) had the rs9923231 SNP of VKORC1 which were associated with the response to warfarin treatment. None of the patients tested positive for poor drug metabolizing genotypes of the CYP2C9 gene and only 1.6% of the south Indian population was sensitive to warfarin treatment. Genotyping results suggest that a relatively greater amount of the therapeutic drug is required to achieve/maintain the international normalized ratio (INR) in south Indian patients with DVT. PMID- 28867754 TI - Sushi repeat-containing protein X-linked 2 promotes angiogenesis through the urokinase-type plasminogen activator receptor dependent integrin alphavbeta3/focal adhesion kinase pathways. AB - Sushi repeat-containing protein X-linked 2 (SRPX2) is a newly identified chondroitin sulfate proteoglycan that is markedly elevated in multiple solid tumors. It is also suggested that SRPX2 is associated with angiogenesis. A conditioned medium of SRPX2 overexpressing colorectal cancer (CRC) cells and SRPX2 recombinant protein was used to evaluate the effect of secretory SRPX2 on the angiogenesis ability of human umbilical vein endothelial cells (HUVECs) and the involved molecular mechanisms. It was revealed that the activity of SRPX2 is dependent on the urokinase-type plasminogen activator receptor and cooperation of the integrin alphavbeta3 co-receptor. Subsequent studies showed that both PI3K/Akt and Ras/MAPK pathways and phosphorylation of focal adhesion kinase is involved in the intracellular signaling pathway of SRPX2/uPAR. This study suggests that SRPX2 promotes angiogenesis of HUVECs through the cooperation of the uPAR and integrin/FAK pathway. PMID- 28867753 TI - The alpha7 nicotinic acetylcholine receptor positive allosteric modulator attenuates lipopolysaccharide-induced activation of hippocampal IkappaB and CD11b gene expression in mice. AB - We have reported that 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H cyclopentan[c]quinoline-8-sulfonamide (TQS), alpha7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) reduces lipopolysaccharide (LPS)-induced hyperalgesia and allodynia in mice. The objective of the present study was to determine the effects of TQS on LPS-induced activation of hippocampal inhibitor of kappaB (IkappaB) and cluster of differentiation 11b (CD11b) gene expression involving hyperalgesia and allodynia in mice. We also examined the effects of TQS on microglial phenotype following LPS administration. Pretreatment of TQS (4 mg/kg) reduced the expressions of IkappaB and CD11b mRNA. Pretreatment of methyllycaconitine (3 mg/kg), an alpha7 nAChR antagonist, reversed TQS-induced decrease in IkappaB and CD11b mRNA expressions in the hippocampus indicating the involvement of alpha7 nAChR. In addition, TQS (4 mg/kg) reversed the LPS-induced microglial morphological changes. These results suggest that TQS reduces LPS-induced IkappaB and CD11b gene expression and microglial activation associated with hyperalgesia and allodynia by targeting microglial alpha7 nAChR in the hippocampus. PMID- 28867755 TI - Successful treatment of three patients with organizing pneumonia associated with rheumatoid arthritis using clarithromycin and prednisolone. AB - Macrolides have anti-inflammatory effects and have been used to treat diffuse panbronchiolitis, bronchiectasis, and cystic fibrosis. Lately, several cases of cryptogenic organizing pneumonia (COP) and radiotherapy-related organizing pneumonia (OP) that were successfully treated with macrolides considering their anti-inflammatory effects were reported. We report three cases of OP associated with rheumatoid arthritis (RA) successfully treated with clarithromycin (CAM) and prednisolone (PSL). Case 1: A 70-year-old woman suffering from RA was admitted with cough and severe dyspnea. She was diagnosed with OP associated with RA on the basis of computed tomography (CT) findings and transbronchial lung biopsy results. She was successfully treated with PSL and cyclosporine A. At the exacerbation of OP, she was successfully treated with CAM and PSL. Case 2: A 74 year-old man suffering from COP visited our department with arthralgia and articular swellings. He was diagnosed with RA, which was thought to be associated with OP. He was successfully treated with CAM and PSL. Case 3: A 54-year-old man suffering from RA presented with an exacerbation of arthralgia and articular swellings and cough. He was diagnosed with OP associated with RA on the basis of CT findings. He was successfully treated with CAM and PSL. The present cases suggest that CAM and PSL treatment may be effective in some cases of OP associated with RA. PMID- 28867756 TI - Successful treatment with clarithromycin and/or tacrolimus for two patients with polymyalgia rheumatica. AB - Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease in the elderly. Glucocorticoids (GCs) remain the mainstay of treatment. GC therapy usually dramatically improves the clinical picture, but approximately one-third of patients experience disease recurrence when the dose is reduced. Moreover, long term use of GCs causes adverse reactions. Macrolide antibiotics have anti inflammatory action. Several recent studies have reported the successful treatment of rheumatoid arthritis (RA) and PMR treated using clarithromycin (CAM), a macrolide, because of its anti-inflammatory action. Tacrolimus (TAC) has been indicated as a treatment for RA in patients who failed to respond to methotrexate. Recently, a case of RA was successfully treated using CAM and TAC according to one report. Reported here are two cases of PMR treated using CAM and/or TAC. Case 1: A 73-year-old man suffering from PMR was successfully treated with prednisolone (PSL) and CAM. Because his muscle pain disappeared, CAM was discontinued. However, the pain returned after that discontinuation, so CAM was successfully administered again. Case 2: An 83-year-old man suffering from PMR was successfully treated with PSL and CAM. Because muscle pain disappeared, the CAM dosage was halved. The pain returned after the dosage was reduced, so the CAM dosage was successfully resumed and the PSL dosage was reduced. When the PSL dosage was reduced, muscle pain recurred. Because the PSL and CAM dosages were not successfully increased, TAC was also administered and was found to be effective at treating muscle pain. These two cases suggest that CAM and/or TAC are effective at treating PMR. PMID- 28867757 TI - Visual field improvement in non-arteritic posterior ischemic optic neuropathy in a patient treated with intravenous prostaglandin E1 and steroids. AB - Non-arteritic posterior ischemic optic neuropathy (NA-PION) is a disorder of reduced blood flow to the retrobulbar optic nerve. There is usually an acute loss of visual acuity and field. Previous studies have noted an improvement in visual acuity and in ocular and retrobulbar blood flow with the use of a potent vasodilator of the microcirculation, prostaglandin E1 (PGE1), and steroids. The current report describes immediate improvement in the visual fields and visual acuity in a patient with NA-PION treated with intravenous PGE1 and steroids 66 hours after onset. An 89-year-old white female was first seen in December 2016 with a sudden loss of vision in the right eye. After a complete eye exam and visual fields, the patient was diagnosed with NA-PION. Treatment was immediately started with steroids and intravenous PGE1. This was repeated once again the next morning. Visual acuity in the right eye improved from 1/10 + 1 to 7/10 + 3 at 5 days. The mean deviation of the visual field improved from - 7.10 decibels (dB) with a central scotoma of - 22 dB to - 2.97 dB with a central scotoma of - 19 dB. After 2 weeks, her visual acuity was 7/10 + 1 and visual field testing of the right eye revealed a mean deviation of - 2.54 dB with a central scotoma of - 9 dB. The left eye was unchanged. In cases of NA-PION, PGE1 and steroids should be considered to immediately restore blood flow to help improve visual acuity and visual fields. PMID- 28867758 TI - Catalytic Ethanol Dehydration to Ethylene over Nanocrystalline chi- and gamma Al2O3 Catalysts. AB - The study is aimed to investigate the combination of nanocrystalline gamma- and chi- alumina that displays the attractive chemical and physical properties for the catalytic dehydration of ethanol. The correlation between the acid density and ethanol conversion was observed. The high acid density apparently results in high catalytic activity, especially for the equally mixed gamma- and chi- phase alumina (G50C50). In order to obtain a better understanding on how different catalysts would affect the ethylene yield, one of the most powerful techniques such as X-ray photoelectron spectroscopy (XPS) was performed. Hence, the different O 1s surface atoms can be identified and divided into three types including lattice oxygen (O, 530.7 eV), surface hydroxyl (OH, 532.1 eV) and lattice water (H2O, 532.9 eV). It was remarkably found that the large amount of O 1s surface atoms in lattice water can result in increased ethylene yield. In summary, the appearance of metastable chi-alumina structure exhibited better catalytic activity and ethylene yield than gamma- alumina. Thus, the introduction of metastable chi- alumina structure into gamma- alumina enhanced catalytic activity and ethylene yield. As the result, it was found that the G50C50 catalyst exhibits the ethylene yield (80%) at the lowest reaction temperature ca. 250 degrees C among other catalysts. PMID- 28867759 TI - Development and Optimization of Orally and Topically Applied Liquid Crystal Drug Formulations. AB - Liquid crystal (LC)-forming lipids represent an important class of biocompatible amphiphiles and their application extends to cosmeceutical, dietary, and pharmaceutical technologies. In the present study, we aimed to develop strategies for designing and optimizing oral and topical LC formulations by evaluating their in vitro and in vivo drug absorption performances. C17-Monoglycerol ester (MGE) was used as a LC-forming lipid. p-Amino benzoic acid, methyl PABA, ethyl PABA, and sodium fluorescein were selected as drug models with different physiochemical properties. Various oral and topical LC formulations were designed based on changes in the LC forming lipid contents in the formulations and entrapped with different physiochemical properties of the drugs. The LC phase structures were evaluated using small-angle X-ray scattering (SAXS). The drug-release profiles from LC formulations were determined using a dialysis membrane method. In vivo oral absorption of LC formulations was conducted in Wistar rats. Furthermore, the skin penetration of drugs from LC formulations was investigated by in vitro skin permeation studies. As a result, although the release profile was influenced by changes in MGE concentration, it was more dramatically influenced by changes in the physiochemical properties of the entrapped drugs. Drug absorption after oral and topical administration of LC formulations was dramatically affected by the concentration of MGE. The concentration of LC-forming lipid and the physiochemical properties of entrapped drugs are key issues for good performance of the LC formulations in various pharmaceutical applications. The present results could enable researchers to manipulate LC formulation approaches intended to improve the oral absorption and skin permeation of drugs. PMID- 28867760 TI - In vitro Study of Serial Changes to Carmustine Wafers (Gliadel) with MR Imaging and Computed Tomography. AB - PURPOSE: Implantation of carmustine wafers (Gliadel) in vivo is accompanied by characteristic serial changes on MRI and CT, such as transient hyperintensity of the wafers on T1-weighted images (T1WIs) and considerable gas accumulation in surgical resection cavities. The purpose of this study was to evaluate intrinsic imaging changes to carmustine wafers in vitro. METHODS: Three phantoms simulating a surgical resection cavity were constructed. Each contained either a carmustine wafer fixed with oxidized regenerated cellulose and fibrin sealant, an unfixed carmustine wafer, or a fixed polyethylene control disk, immersed in phosphate buffered saline. Image acquisition of the phantoms was performed on MRI and CT until 182 days after construction. The radiological appearances of the object in each phantom were assessed by visual evaluation and quantification of the region of interest. The volume of gas around the objects at 24 h after constructing the phantoms was also measured. RESULTS: The carmustine wafers showed low signal intensities on T1WIs and T2-weighted images (T2WIs), and high densities on CT images at 24 h. The signal intensities and CT densities gradually approximated those of saline over a period of months. However, the carmustine wafers never showed hyperintensity on T1WIs in vitro. The fixed carmustine wafer showed slower radiological changes, as compared to the unfixed wafer. The gas volume around the fixed carmustine wafer was greater than that around the fixed control disk. CONCLUSION: Changes to the carmustine wafers probably reflected penetration of fluid inside and degradation of the hydrophobic matrix. Reported transient hyperintensity of wafers on T1WIs in vivo is regarded as the result of biological reactions, whereas the initial production of gas is considered as an intrinsic characteristic of wafers. PMID- 28867762 TI - Development and Validation of HPLC-DAD and UHPLC-DAD Methods for the Simultaneous Determination of Guanylhydrazone Derivatives Employing a Factorial Design. AB - Guanylhydrazones are molecules with great pharmacological potential in various therapeutic areas, including antitumoral activity. Factorial design is an excellent tool in the optimization of a chromatographic method, because it is possible quickly change factors such as temperature, mobile phase composition, mobile phase pH, column length, among others to establish the optimal conditions of analysis. The aim of the present work was to develop and validate a HPLC and UHPLC methods for the simultaneous determination of guanylhydrazones with anticancer activity employing experimental design. Precise, exact, linear and robust HPLC and UHPLC methods were developed and validated for the simultaneous quantification of the guanylhydrazones LQM10, LQM14, and LQM17. The UHPLC method was more economic, with a four times less solvent consumption, and 20 times less injection volume, what allowed better column performance. Comparing the empirical approach employed in the HPLC method development to the DoE approach employed in the UHPLC method development, we can conclude that the factorial design made the method development faster, more practical and rational. This resulted in methods that can be employed in the analysis, evaluation and quality control of these new synthetic guanylhydrazones. PMID- 28867761 TI - SMAD2 Inactivation Inhibits CLDN6 Methylation to Suppress Migration and Invasion of Breast Cancer Cells. AB - The downregulation of tight junction protein CLDN6 promotes breast cancer cell migration and invasion; however, the exact mechanism underlying CLDN6 downregulation remains unclear. CLDN6 silence is associated with DNA methyltransferase 1 (DNMT1) mediated DNA methylation, and DNMT1 is regulated by the transforming growth factor beta (TGFbeta)/SMAD pathway. Therefore, we hypothesized that TGFbeta/SMAD pathway, specifically SMAD2, may play a critical role for CLDN6 downregulation through DNA methyltransferase 1 (DNMT1) mediated DNA methylation. To test this hypothesis, we blocked the SMAD2 pathway with SB431542 in two human breast cancer cell lines (MCF-7 and SKBR-3). Our results showed that treatment with SB431542 led to a decrease of DNMT1 expression and the binding activity for CLDN6 promoter. The methylation level of CLDN6 promoter was decreased, and simultaneously CLDN6 protein expression increased. Upregulation of CLDN6 inhibited epithelial to mesenchymal transition (EMT) and reduced the migration and invasion ability of both MCF-7 and SKBR-3 cells. Furthermore, knocked down of CLDN6 abolished SB431542 effects on suppression of EMT associated gene expression and inhibition of migration and invasion. Thus, we demonstrated that the downregulation of CLDN6 is regulated through promoter methylation by DNMT1, which depends on the SMAD2 pathway, and that CLDN6 is a key regulator in the SMAD2/DNMT1/CLDN6 pathway to inhibit EMT, migration and invasion of breast cancer cells. PMID- 28867763 TI - Utilization of Fishery Processing By-Product Squid Pens for alpha-Glucosidase Inhibitors Production by Paenibacillus sp. AB - The supernatants (the solution part received after centrifugation) of squid pens fermented by four species of Paenibacillus showed potent inhibitory activity against alpha-glucosidases derived from yeast (79-98%) and rats (76-83%). The inhibition of acarbose-a commercial antidiabetic drug, used against yeast and rat alpha-glucosidases-was tested for comparison; it showed inhibitory activity of 64% and 88%, respectively. Other chitinolytic or proteolytic enzyme-producing bacterial strains were also used to ferment squid pens, but no inhibition activity was detected from the supernatants. Paenibacillus sp. TKU042, the most active alpha-glucosidase inhibitor (aGI)-producing strain, was selected to determine the optimal cultivation parameters. This bacterium achieved the highest aGI productivity (527 ug/mL) when 1% squid pens were used as the sole carbon/nitrogen source with a medium volume of 130 mL (initial pH 6.85) in a 250 mL flask (48% of air head space), at 30 degrees C for 3-4 d. The aGI productivity increased 3.1-fold after optimization of the culture conditions. Some valuable characteristics of Paenibacillus aGIs were also studied, including pH and thermal stability and specific inhibitory activity. These microbial aGIs showed efficient inhibition against alpha-glucosidases from rat, yeast, and bacteria, but weak inhibition against rice alpha-glucosidase with IC50 values of 362, 252, 189, and 773 ug/mL, respectively. In particular, these aGIs showed highly stable activity over a large pH (2-13) and temperature range (40-100 degrees C). Various techniques, including: Diaoin, Octadecylsilane opened columns, and preparative HPLC coupled with testing bioactivity resulted in isolating a main active compound; this major inhibitor was identified as homogentisic acid (HGA). Notably, HGA was confirmed as a new inhibitor, a non sugar-based aGI, and as possessing stronger activity than acarbose with IC50, and maximum inhibition values of 220 MUg/mL, 95%, and 1510 MUg/mL, 65%, respectively. These results suggest that squid pens, an abundant and low-cost fishery processing by-product, constitute a viable source for the production of antidiabetic materials via fermentation by strains of Paenibacillus. This fermented product shows promising applications in diabetes or diabetes related to obesity treatment due to their stability, potent bioactivity, and efficient inhibition against mammalian enzymes. PMID- 28867764 TI - Fluorescent Polymer Incorporating Triazolyl Coumarin Units for Cu2+ Detection via Planarization of Ict-Based Fluorophore. AB - A novel fluorescent polymer with pendant triazolyl coumarin units was synthesized through radical polymerization. The polymer showed reasonable sensitivity and selectivity towards Cu2+ in acetonitrile in comparison to other tested metal ions with a significant quenching effect on fluorescence and blue shifting in the range of 20 nm. The blue shift was assigned to the conformation changes of the diethylamino group from the coumarin moiety which led to planarization of the triazolyl coumarin units. The possible binding modes for Cu2+ towards the polymer were determined through the comparison of the emission responses of the polymer, starting vinyl monomer and reference compound, and the triazole ring was identified as one of the possible binding sites for Cu2+. The detection limits of the polymer and vinyl monomer towards Cu2+ were determined from fluorescence titration experiments and a higher sensitivity (35 times) was observed for the polymer compared with its starting monomer. PMID- 28867765 TI - Breakfast Cereal Consumption and Obesity Risk amongst the Mid-Age Cohort of the Australian Longitudinal Study on Women's Health. AB - Obesity affects 27.5% of Australian women. Breakfast cereal consumption has been proposed to be protective against obesity. This study investigated the association of breakfast cereal consumption with the risk of developing obesity (Body Mass Index (BMI) >= 30 kg/m2) over 12 years among mid-age participants in the Australian Longitudinal Study on Women's Health (ALSWH). Dietary data were obtained at S3 and obesity incidence at S4-S7. Women were excluded if: dietary data were incomplete, energy intake was <4500 or >20,000 kJ/day, or they reported being overweight or obese at S3. Logistic regressions with discrete time survival analysis investigated the association between breakfast cereal intake and incident obesity and were adjusted for: area of residency, income, smoking, physical activity, hypertension, dietary intakes and a discrete measure of time. There were 308 incident cases of obesity. Any breakfast cereal intake was not associated with incident obesity (Odds Ratio (OR): 0.92; p = 0.68). Oat-based cereal (OR: 0.71; p = 0.01), muesli (OR: 0.57; p = 0.00) and All-Bran (OR: 0.62; p = 0.01) intakes were associated with a significant reduction in obesity risk. Among this cohort, muesli on its own, or as part of oat-based cereals, and All Bran, were associated with a reduction in obesity. This effect may be due to particular characteristics of these cereal eaters, but the relationship warrants further investigation. PMID- 28867766 TI - Impact of Dietary Protein and Gender on Food Reinforcement. AB - Recent evidence suggests that increasing dietary protein may alter reward-driven eating behavior. However, the link between protein and food reinforcement is not known. We sought to determine the extent to which increasing dietary protein alters food reinforcement in healthy adults. In a randomized crossover study, 11 women (age = 25 +/- 7 years; Body Mass Index (BMI) = 21 +/- 2 kg/m2) and 10 men (age = 22 +/- 2 years; BMI = 24 +/- 2 kg/m2) consumed normal (15%) and high (30%) protein meals. Food reinforcement was assessed using a computer-based choice task (operant responding with concurrent log2(x) reinforcement schedules) 4 h after lunch. We found that food reinforcement was greater in men than women (p < 0.05) and greater for sweet than savory snack foods (p < 0.02). Gender interacted with dietary protein level (p = 0.03) and snack food type (p < 0.0001). Specifically, we found that increasing dietary protein decreased the reinforcing value of savory foods in women. The reinforcing value for sweet foods did not interact with dietary protein or gender. These results demonstrate the differential effects of dietary protein on the reinforcing value for energy-dense, highly palatable snack foods. PMID- 28867771 TI - GPS Satellite Orbit Prediction at User End for Real-Time PPP System. AB - This paper proposed the high-precision satellite orbit prediction process at the user end for the real-time precise point positioning (PPP) system. Firstly, the structure of a new real-time PPP system will be briefly introduced in the paper. Then, the generation of satellite initial parameters (IP) at the sever end will be discussed, which includes the satellite position, velocity, and the solar radiation pressure (SRP) parameters for each satellite. After that, the method for orbit prediction at the user end, with dynamic models including the Earth's gravitational force, lunar gravitational force, solar gravitational force, and the SRP, are presented. For numerical integration, both the single-step Runge Kutta and multi-step Adams-Bashforth-Moulton integrator methods are implemented. Then, the comparison between the predicted orbit and the international global navigation satellite system (GNSS) service (IGS) final products are carried out. The results show that the prediction accuracy can be maintained for several hours, and the average prediction error of the 31 satellites are 0.031, 0.032, and 0.033 m for the radial, along-track and cross-track directions over 12 h, respectively. Finally, the PPP in both static and kinematic modes are carried out to verify the accuracy of the predicted satellite orbit. The average root mean square error (RMSE) for the static PPP of the 32 globally distributed IGS stations are 0.012, 0.015, and 0.021 m for the north, east, and vertical directions, respectively; while the RMSE of the kinematic PPP with the predicted orbit are 0.031, 0.069, and 0.167 m in the north, east and vertical directions, respectively. PMID- 28867767 TI - Arid1b Haploinsufficiency Causes Abnormal Brain Gene Expression and Autism Related Behaviors in Mice. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that include poor social communication, restricted interests, and repetitive behaviors. Several ASD mouse models exhibit impaired social interaction, anxiety-like behavior, and elevated perseveration. Large-scale whole exome sequencing studies identified many genes putatively associated with ASD. Like chromodomain helicase DNA binding protein 8 (CHD8), the most frequently mutated gene in individuals with ASD, the candidate gene AT-rich interaction domain 1B (ARID1B) encodes a chromatin remodeling factor. Arid1b heterozygous knockout (hKO) mice exhibited ASD-like traits related to social behavior, anxiety, and perseveration, in addition to associated features reported in some cases of ASD, such as reduced weight, impaired motor coordination, and hydrocephalus. Hydrocephalus was present in 5 of 91 hKO mice, while it was not observed in wild-type littermates (0 of 188). Genome-wide gene expression patterns in Arid1b hKO mice were similar to those in ASD patients and Chd8 haploinsufficient mice, an ASD model, and to developmental changes in gene expression in fast-spiking cells in the mouse brain. Our results suggest that Arid1b haploinsufficiency causes ASD-like phenotypes in mice. PMID- 28867776 TI - Multi Ray Model for Near-Ground Millimeter Wave Radar. AB - A quasi-optical multi-ray model for a short-range millimeter wave radar is presented. The model considers multi-path effects emerging while multiple rays are scattered from the target and reflected to the radar receiver. Among the examined scenarios, the special case of grazing ground reflections is analyzed. Such a case becomes relevant when short range anti-collision radars are employed in vehicles. Such radars operate at millimeter wavelengths, and are aimed at the detection of targets located several tens of meters from the transmitter. Reflections from the road are expected to play a role in the received signal strength, together with the direct line-of-sight beams illuminated and scattered from the target. The model is demonstrated experimentally using radar operating in the W-band. Controlled measurements were done to distinguish between several scattering target features. The experimental setup was designed to imitate vehicle near-ground millimeter wave radars operating in vehicles. A comparison between analytical calculations and experimental results is made and discussed. PMID- 28867773 TI - Analysis of Differences in Phenology Extracted from the Enhanced Vegetation Index and the Leaf Area Index. AB - Remote-sensing phenology detection can compensate for deficiencies in field observations and has the advantage of capturing the continuous expression of phenology on a large scale. However, there is some variability in the results of remote-sensing phenology detection derived from different vegetation parameters in satellite time-series data. Since the enhanced vegetation index (EVI) and the leaf area index (LAI) are the most widely used vegetation parameters for remote sensing phenology extraction, this paper aims to assess the differences in phenological information extracted from EVI and LAI time series and to explore whether either index performs well for all vegetation types on a large scale. To this end, a GLASS (Global Land Surface Satellite Product)-LAI-based phenology product (GLP) was generated using the same algorithm as the MODIS (Moderate Resolution Imaging Spectroradiometer)-EVI phenology product (MLCD) over China from 2001 to 2012. The two phenology products were compared in China for different vegetation types and evaluated using ground observations. The results show that the ratio of missing data is 8.3% for the GLP, which is less than the 22.8% for the MLCD. The differences between the GLP and the MLCD become stronger as the latitude decreases, which also vary among different vegetation types. The start of the growing season (SOS) of the GLP is earlier than that of the MLCD in most vegetation types, and the end of the growing season (EOS) of the GLP is generally later than that of the MLCD. Based on ground observations, it can be suggested that the GLP performs better than the MLCD in evergreen needleleaved forests and croplands, while the MLCD performs better than the GLP in shrublands and grasslands. PMID- 28867770 TI - Peri-Urbanism in Globalizing India: A Study of Pollution, Health and Community Awareness. AB - This paper examines the intersection between environmental pollution and people's acknowledgements of, and responses to, health issues in Karhera, a former agricultural village situated between the rapidly expanding cities of New Delhi (India's capital) and Ghaziabad (an industrial district in Uttar Pradesh). A relational place-based view is integrated with an interpretive approach, highlighting the significance of place, people's emic experiences, and the creation of meaning through social interactions. Research included surveying 1788 households, in-depth interviews, participatory mapping exercises, and a review of media articles on environment, pollution, and health. Karhera experiences both domestic pollution, through the use of domestic waste water, or gandapani, for vegetable irrigation, and industrial pollution through factories' emissions into both the air and water. The paper shows that there is no uniform articulation of any environment/health threats associated with gandapani. Some people take preventative actions to avoid exposure while others do not acknowledge health implications. By contrast, industrial pollution is widely noted and frequently commented upon, but little collective action addresses this. The paper explores how the characteristics of Karhera, its heterogeneous population, diverse forms of environmental pollution, and broader governance processes, limit the potential for citizen action against pollution. PMID- 28867769 TI - Transgenic Cotton Plants Expressing the HaHR3 Gene Conferred Enhanced Resistance to Helicoverpa armigera and Improved Cotton Yield. AB - RNA interference (RNAi) has been developed as an efficient technology. RNAi insect-resistant transgenic plants expressing double-stranded RNA (dsRNA) that is ingested into insects to silence target genes can affect the viability of these pests or even lead to their death. HaHR3, a molt-regulating transcription factor gene, was previously selected as a target expressed in bacteria and tobacco plants to control Helicoverpa armigera by RNAi technology. In this work, we selected the dsRNA-HaHR3 fragment to silence HaHR3 in cotton bollworm for plant mediated-RNAi research. A total of 19 transgenic cotton lines expressing HaHR3 were successfully cultivated, and seven generated lines were used to perform feeding bioassays. Transgenic cotton plants expressing dsHaHR3 were shown to induce high larval mortality and deformities of pupation and adult eclosion when used to feed the newly hatched larvae, and 3rd and 5th instar larvae of H. armigera. Moreover, HaHR3 transgenic cotton also demonstrated an improved cotton yield when compared with controls. PMID- 28867772 TI - Detection of Tetrodotoxin Shellfish Poisoning (TSP) Toxins and Causative Factors in Bivalve Molluscs from the UK. AB - Tetrodotoxins (TTXs) are traditionally associated with the occurrence of tropical Pufferfish Poisoning. In recent years, however, TTXs have been identified in European bivalve mollusc shellfish, resulting in the need to assess prevalence and risk to shellfish consumers. Following the previous identification of TTXs in shellfish from southern England, this study was designed to assess the wider prevalence of TTXs in shellfish from around the coast of the UK. Samples were collected between 2014 and 2016 and subjected to analysis using HILIC-MS/MS. Results showed the continued presence of toxins in shellfish harvested along the coast of southern England, with the maximum concentration of total TTXs reaching 253 ug/kg. TTX accumulation was detected in Pacific oysters (Crassostreagigas), native oysters (Ostreaedulis) common mussels (Mytilusedulis) and hard clams (Mercenariamercenaria), but not found in cockles (Cerastodermaedule), razors (Ensis species) or scallops (Pectenmaximus). Whilst the highest concentrations were quantified in samples harvested during the warmer summer months, TTXs were still evident during the winter. An assessment of the potential causative factors did not reveal any links with the phytoplankton species Prorocentrumcordatum, instead highlighting a greater level of risk in areas of shallow, estuarine waters with temperatures above 15 degrees C. PMID- 28867775 TI - Remote Marker-Based Tracking for UAV Landing Using Visible-Light Camera Sensor. AB - Unmanned aerial vehicles (UAVs), which are commonly known as drones, have proved to be useful not only on the battlefields where manned flight is considered too risky or difficult, but also in everyday life purposes such as surveillance, monitoring, rescue, unmanned cargo, aerial video, and photography. More advanced drones make use of global positioning system (GPS) receivers during the navigation and control loop which allows for smart GPS features of drone navigation. However, there are problems if the drones operate in heterogeneous areas with no GPS signal, so it is important to perform research into the development of UAVs with autonomous navigation and landing guidance using computer vision. In this research, we determined how to safely land a drone in the absence of GPS signals using our remote maker-based tracking algorithm based on the visible light camera sensor. The proposed method uses a unique marker designed as a tracking target during landing procedures. Experimental results show that our method significantly outperforms state-of-the-art object trackers in terms of both accuracy and processing time, and we perform test on an embedded system in various environments. PMID- 28867777 TI - Poverty and Child Behavioral Problems: The Mediating Role of Parenting and Parental Well-Being. AB - The detrimental impact of poverty on child behavioral problems is well established, but the mechanisms that explain this relationship are less well known. Using data from the Families in Germany Study on parents and their children at ages 9-10 (middle childhood), this study extends previous research by examining whether or not and to what extent different parenting styles and parents' subjective well-being explain the relationship between poverty and child behavior problems. The results show that certain parenting styles, such as psychological control, as well as mothers' life satisfaction partially mediate the correlation between poverty and child behavioral problems. PMID- 28867778 TI - Nurse Perceptions of Artists as Collaborators in Interprofessional Care Teams. AB - Increased attention is being given to interprofessional collaboration in healthcare, which has been shown to improve patient satisfaction, patient safety, healthcare processes, and health outcomes. As the arts and artists are being more widely incorporated into healthcare settings throughout the world, professional artists are contributing to interprofessional care teams. A secondary directed content analysis of interviews with 31 nurses on a medical-surgical care unit investigated the roles and impacts of professional artists on the interprofessional care team. The investigation utilized established domains of interprofessional care, including values and ethics, roles and responsibilities, interprofessional communication, and teams and teamwork, and created the domain of quality of care. Findings suggest that artists are valued by nurses as members of the interprofessional care team, that they enhance the provision of patient centered care, and that they improve quality of care by providing holistic dimensions of caring, including cognitive and social engagement, and meaningful interaction. The presence of artists on interprofessional teams provides a cost effective and welcome resource for clinical staff and builds a culture in which creativity and interdisciplinary collaboration are more highly valued and activated. PMID- 28867774 TI - Intrachromosomal Rearrangements in Rodents from the Perspective of Comparative Region-Specific Painting. AB - It has long been hypothesized that chromosomal rearrangements play a central role in different evolutionary processes, particularly in speciation and adaptation. Interchromosomal rearrangements have been extensively mapped using chromosome painting. However, intrachromosomal rearrangements have only been described using molecular cytogenetics in a limited number of mammals, including a few rodent species. This situation is unfortunate because intrachromosomal rearrangements are more abundant than interchromosomal rearrangements and probably contain essential phylogenomic information. Significant progress in the detection of intrachromosomal rearrangement is now possible, due to recent advances in molecular biology and bioinformatics. We investigated the level of intrachromosomal rearrangement in the Arvicolinae subfamily, a species-rich taxon characterized by very high rate of karyotype evolution. We made a set of region specific probes by microdissection for a single syntenic region represented by the p-arm of chromosome 1 of Alexandromys oeconomus, and hybridized the probes onto the chromosomes of four arvicolines (Microtus agrestis, Microtus arvalis, Myodes rutilus, and Dicrostonyx torquatus). These experiments allowed us to show the intrachromosomal rearrangements in the subfamily at a significantly higher level of resolution than previously described. We found a number of paracentric inversions in the karyotypes of M. agrestis and M. rutilus, as well as multiple inversions and a centromere shift in the karyotype of M. arvalis. We propose that during karyotype evolution, arvicolines underwent a significant number of complex intrachromosomal rearrangements that were not previously detected. PMID- 28867780 TI - Litter Accumulation and Nutrient Content of Roadside Plant Communities in Sichuan Basin, China. AB - It is widely recognized that feedbacks exist between plant litter and plant community species composition, but this relationship is difficult to interpret over heterogeneous conditions typical of modified environments such as roadways. Given the need to expedite natural recovery of disturbed areas through restoration interventions, we characterized litter accumulation and nutrient content (i.e., organic carbon, total N, and P) and quantified their association with key plant species. Plant species cover and litter characteristics were sampled at 18 successional forest plant communities along major roadways in Sichuan Basin, western China. Variation in litter across communities was assessed with principal component analysis (PCA) and species with the highest correlation to PCA axes were determined with Pearson's r coefficients. Plant communities with the longest time since road construction (i.e., 70 years) were distinctly different in litter total N and organic carbon compared to plant communities with a shorter disturbance history. We encountered 59 plant species across sampling plots, but only four rare species (i.e., frequency < 5) were strongly correlated with litter characteristics (p < 0.01); none of which were the most abundant where they occurred. These results highlight the importance of site-specific factors (i.e., geographic location, disturbance age) regulating plant litter across heavily disturbed landscapes and how litter characteristics and rare plant species are correlated. PMID- 28867779 TI - Identification and Analysis of Amygdalin, Neoamygdalin and Amygdalin Amide in Different Processed Bitter Almonds by HPLC-ESI-MS/MS and HPLC-DAD. AB - Processing is a traditional pharmacy technology based on traditional Chinese medicine theory. The traditional Chinese medicine (TCM) ingredients should be processed before being used as a medicine. Processed bitter almonds are widely used in the clinic in TCM for the treatment of cough and asthma. In this work the amygdalin profile of three producing areas in China was determined, with respect to three differently processed bitter almond products: raw, stir-fried and scalded. Identification of the compounds was done by using high performance liquid chromatography coupled to electrospray ionization mass spectrometry (HPLC ESI-MS/MS). Results indicated that amygdalin, neoamygdalin and amygdalin amide were identified in the different processed bitter almonds. Meanwhile, amygdalin was used as a standard to calculate the quantification of amygdalin and the concentration ratio of neoamygdalin and total amygdalin by HPLC-DAD. The data suggested that composition of amygdalin isomers in bitter almonds was influenced by the processing method. It also gives a new understanding of the processing principle of bitter almonds. Moreover, the classification of different processed bitter almonds can be achieved on the basis of amygdalin isomers levels. PMID- 28867768 TI - Keratinocyte Differentiation-Dependent Human Papillomavirus Gene Regulation. AB - Human papillomaviruses (HPVs) cause diseases ranging from benign warts to invasive cancers. HPVs infect epithelial cells and their replication cycle is tightly linked with the differentiation process of the infected keratinocyte. The normal replication cycle involves an early and a late phase. The early phase encompasses viral entry and initial genome replication, stimulation of cell division and inhibition of apoptosis in the infected cell. Late events in the HPV life cycle include viral genome amplification, virion formation, and release into the environment from the surface of the epithelium. The main proteins required at the late stage of infection for viral genome amplification include E1, E2, E4 and E5. The late proteins L1 and L2 are structural proteins that form the viral capsid. Regulation of these late events involves both cellular and viral proteins. The late viral mRNAs are expressed from a specific late promoter but final late mRNA levels in the infected cell are controlled by splicing, polyadenylation, nuclear export and RNA stability. Viral late protein expression is also controlled at the level of translation. This review will discuss current knowledge of how HPV late gene expression is regulated. PMID- 28867782 TI - The Canadian Atlas of Child and Youth Injury: Mobilizing Injury Surveillance Data to Launch a National Knowledge Translation Tool. AB - Child and youth injury prevention research in Canada has lagged behind other Organisation for Economic Co-operation and Development nations, despite existing surveillance systems and longitudinal data. A critical need to improve access to the available data, as well as need to tailor its display and interpretation, was identified by injury prevention stakeholders involved in research, policy, and practice. The Canadian Atlas of Child and Youth Injury Prevention ("the Atlas") was developed to address this need. Following a series of iterative consultation meetings and a pilot testing session, the Atlas was scaled up with national data. Two testing sessions were held to evaluate the tools. The Atlas is comprised of three main components: data, indicators, and visualizations. The accessibility of the dashboard is enhanced by customization of data visualizations and data outputs to suit the user's needs. Overall feedback indicated that the tools were easy to use, and that the interface was intuitive and visually appealing. The Canadian Atlas of Child and Youth Injury Prevention provides readily accessible information to injury prevention practitioners, policy makers and researchers, helping to chart pathways to success in improving the child and youth injury prevention system in Canada. PMID- 28867783 TI - The Mouse Papillomavirus Infection Model. AB - The mouse papillomavirus (MmuPV1) was first reported in 2011 and has since become a powerful research tool. Through collective efforts from different groups, significant progress has been made in the understanding of molecular, virological, and immunological mechanisms of MmuPV1 infections in both immunocompromised and immunocompetent hosts. This mouse papillomavirus provides, for the first time, the opportunity to study papillomavirus infections in the context of a small common laboratory animal for which abundant reagents are available and for which many strains exist. The model is a major step forward in the study of papillomavirus disease and pathology. In this review, we summarize studies using MmuPV1 over the past six years and share our perspectives on the value of this unique model system. Specifically, we discuss viral pathogenesis in cutaneous and mucosal tissues as well as in different mouse strains, immune responses to the virus, and local host-restricted factors that may be involved in MmuPV1 infections and associated disease progression. PMID- 28867786 TI - Proposal and Evaluation of BLE Discovery Process Based on New Features of Bluetooth 5.0. AB - The device discovery process is one of the most crucial aspects in real deployments of sensor networks. Recently, several works have analyzed the topic of Bluetooth Low Energy (BLE) device discovery through analytical or simulation models limited to version 4.x. Non-connectable and non-scannable undirected advertising has been shown to be a reliable alternative for discovering a high number of devices in a relatively short time period. However, new features of Bluetooth 5.0 allow us to define a variant on the device discovery process, based on BLE scannable undirected advertising events, which results in higher discovering capacities and also lower power consumption. In order to characterize this new device discovery process, we experimentally model the real device behavior of BLE scannable undirected advertising events. Non-detection packet probability, discovery probability, and discovery latency for a varying number of devices and parameters are compared by simulations and experimental measurements. We demonstrate that our proposal outperforms previous works, diminishing the discovery time and increasing the potential user device density. A mathematical model is also developed in order to easily obtain a measure of the potential capacity in high density scenarios. PMID- 28867785 TI - Patch-Clamp Recording from Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Improving Action Potential Characteristics through Dynamic Clamp. AB - Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for studying inherited cardiac arrhythmias and developing drug therapies to treat such arrhythmias. Unfortunately, until now, action potential (AP) measurements in hiPSC-CMs have been hampered by the virtual absence of the inward rectifier potassium current (IK1) in hiPSC-CMs, resulting in spontaneous activity and altered function of various depolarising and repolarising membrane currents. We assessed whether AP measurements in "ventricular-like" and "atrial-like" hiPSC CMs could be improved through a simple, highly reproducible dynamic clamp approach to provide these cells with a substantial IK1 (computed in real time according to the actual membrane potential and injected through the patch-clamp pipette). APs were measured at 1 Hz using perforated patch-clamp methodology, both in control cells and in cells treated with all-trans retinoic acid (RA) during the differentiation process to increase the number of cells with atrial like APs. RA-treated hiPSC-CMs displayed shorter APs than control hiPSC-CMs and this phenotype became more prominent upon addition of synthetic IK1 through dynamic clamp. Furthermore, the variability of several AP parameters decreased upon IK1 injection. Computer simulations with models of ventricular-like and atrial-like hiPSC-CMs demonstrated the importance of selecting an appropriate synthetic IK1. In conclusion, the dynamic clamp-based approach of IK1 injection has broad applicability for detailed AP measurements in hiPSC-CMs. PMID- 28867781 TI - Low Docosahexaenoic Acid, Dihomo-Gamma-Linolenic Acid, and Arachidonic Acid Levels Associated with Long-Term Mortality in Patients with Acute Decompensated Heart Failure in Different Nutritional Statuses. AB - The clinical significance of polyunsaturated fatty acids (PUFAs) in acute decompensated heart failure (ADHF) in various nutritional statuses remains unclear. For this study, we enrolled 267 patients with ADHF admitted to the cardiac intensive care unit at Juntendo University hospital between April 2012 and March 2014. The association between long-term mortality, the geriatric nutritional risk index (GNRI), and levels of PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), dihomo-gamma-linolenic acid (DGLA), and arachidonic acid (AA) was investigated. The median age was 73 (64-82) years, and mortality was 29% (62 patients). The event-free survival rates for all-cause death were higher in patients with high PUFA levels or GNRI than in those with low PUFA levels or GNRI (p < 0.05 for all). In particular, high DGLA in the low GNRI group and high DHA or AA in the high-GNRI group were associated with high event-free survival (p < 0.05 for all). After accounting for confounding variables, DHA, DGLA, and AA, but not EPA, were associated with long-term mortality (p < 0.01 for all). This study concludes that in patients with ADHF, decreased levels of DHA, DGLA, and AA are independently associated with long-term mortality in the various nutritional statuses. PMID- 28867787 TI - Iodine Intakes of Victorian Schoolchildren Measured Using 24-h Urinary Iodine Excretion. AB - Mandatory fortification of bread with iodized salt was introduced in Australia in 2009, and studies using spot urine collections conducted post fortification indicate that Australian schoolchildren are now replete. However an accurate estimate of daily iodine intake utilizing 24-h urinary iodine excretion (UIE MUg/day) has not been reported and compared to the estimated average requirement (EAR). This study aimed to assess daily total iodine intake and status of a sample of primary schoolchildren using 24-h urine samples. Victorian primary school children provided 24-h urine samples between 2011 and 2013, from which urinary iodine concentration (UIC, MUg/L) and total iodine excretion (UIE, MUg/day) as an estimate of intake was determined. Valid 24-h urine samples were provided by 650 children, mean (SD) age 9.3 (1.8) years (n = 359 boys). The mean UIE of 4-8 and 9-13 year olds was 94 (48) and 111 (57) MUg/24-h, respectively, with 29% and 26% having a UIE below the age-specific EAR. The median (IQR) UIC was 124 (83,172) MUg/L, with 36% of participants having a UIC < 100 MUg/L. This convenience sample of Victorian schoolchildren were found to be iodine replete, based on UIC and estimated iodine intakes derived from 24-h urine collections, confirming the findings of the Australian Health Survey. PMID- 28867790 TI - Development of Embedded EM Sensors for Estimating Tensile Forces of PSC Girder Bridges. AB - The tensile force of pre-stressed concrete (PSC) girders is the most important factor for managing the stability of PSC bridges. The tensile force is induced using pre-stressing (PS) tendons of a PSC girder. Because the PS tendons are located inside of the PSC girder, the tensile force cannot be measured after construction using conventional NDT (non-destructive testing) methods. To monitor the induced tensile force of a PSC girder, an embedded EM (elasto-magnetic) sensor was proposed in this study. The PS tendons are made of carbon steel, a ferromagnetic material. The magnetic properties of the ferromagnetic specimen are changed according to the induced magnetic field, temperature, and induced stress. Thus, the tensile force of PS tendons can be estimated by measuring their magnetic properties. The EM sensor can measure the magnetic properties of ferromagnetic materials in the form of a B (magnetic density)-H (magnetic force) loop. To measure the B-H loop of a PS tendon in a PSC girder, the EM sensor should be embedded into the PSC girder. The proposed embedded EM sensor can be embedded into a PSC girder as a sheath joint by designing screw threads to connect with the sheath. To confirm the proposed embedded EM sensors, the experimental study was performed using a down-scaled PSC girder model. Two specimens were constructed with embedded EM sensors, and three sensors were installed in each specimen. The embedded EM sensor could measure the B-H loop of PS tendons even if it was located inside concrete, and the area of the B-H loop was proportionally decreased according to the increase in tensile force. According to the results, the proposed method can be used to estimate the tensile force of unrevealed PS tendons. PMID- 28867788 TI - High Throughput Identification of Antimicrobial Peptides from Fish Gastrointestinal Microbiota. AB - Antimicrobial peptides (AMPs) are a group of small peptides, which are secreted by almost all creatures in nature. They have been explored in therapeutic and agricultural aspects as they are toxic to many bacteria. A considerable amount of work has been conducted in analyzing 16S and metagenomics of the gastrointestinal (GI) microbiome of grass carp (Ctenopharyngodon idellus). However, these datasets are still untapped resources. In this present study, a homologous search was performed to predict AMPs from our newly generated metagenome of grass carp. We identified five AMPs with high similarities to previously reported bacterial toxins, such as lantibiotic and class II bacteriocins. In addition, we observed that the top abundant genus in the GI microbiota of the grass carp was generally consistent with the putative AMP-producing strains, which are mainly from Lactobacillales. Furthermore, we constructed the phylogenetic relationship of these putative AMP-producing bacteria existing in the GI of grass carp and some popular commercial probiotics (commonly used for microecologics), demonstrating that they are closely related. Thus, these strains have the potential to be developed into novel microecologics. In a word, we provide a high-throughput way to discover AMPs from fish GI microbiota, which can be developed as alternative pathogen antagonists (toxins) for microecologics or probiotic supplements. PMID- 28867784 TI - The Complex Interplay between DNA Injury and Repair in Enzymatically Induced Mutagenesis and DNA Damage in B Lymphocytes. AB - Lymphocytes are endowed with unique and specialized enzymatic mutagenic properties that allow them to diversify their antigen receptors, which are crucial sensors for pathogens and mediators of adaptive immunity. During lymphocyte development, the antigen receptors expressed by B and T lymphocytes are assembled in an antigen-independent fashion by ordered variable gene segment recombinations (V(D)J recombination), which is a highly ordered and regulated process that requires the recombination activating gene products 1 & 2 (RAG1, RAG2). Upon activation by antigen, B lymphocytes undergo additional diversifications of their immunoglobulin B-cell receptors. Enzymatically induced somatic hypermutation (SHM) and immunoglobulin class switch recombination (CSR) improves the affinity for antigen and shape the effector function of the humoral immune response, respectively. The activation-induced cytidine deaminase (AID) enzyme is crucial for both SHM and CSR. These processes have evolved to both utilize as well as evade different DNA repair and DNA damage response pathways. The delicate balance between enzymatic mutagenesis and DNA repair is crucial for effective immune responses and the maintenance of genomic integrity. Not surprisingly, disturbances in this balance are at the basis of lymphoid malignancies by provoking the formation of oncogenic mutations and chromosomal aberrations. In this review, we discuss recent mechanistic insight into the regulation of RAG1/2 and AID expression and activity in lymphocytes and the complex interplay between these mutagenic enzymes and DNA repair and DNA damage response pathways, focusing on the base excision repair and mismatch repair pathways. We discuss how disturbances of this interplay induce genomic instability and contribute to oncogenesis. PMID- 28867791 TI - The Non-Linear Relationship between BMI and Health Care Costs and the Resulting Cost Fraction Attributable to Obesity. AB - This study aims to analyse the non-linear relationship between Body Mass Index (BMI) and direct health care costs, and to quantify the resulting cost fraction attributable to obesity in Germany. Five cross-sectional surveys of cohort studies in southern Germany were pooled, resulting in data of 6757 individuals (31-96 years old). Self-reported information on health care utilisation was used to estimate direct health care costs for the year 2011. The relationship between measured BMI and annual costs was analysed using generalised additive models, and the cost fraction attributable to obesity was calculated. We found a non-linear association of BMI and health care costs with a continuously increasing slope for increasing BMI without any clear threshold. Under the consideration of the non linear BMI-cost relationship, a shift in the BMI distribution so that the BMI of each individual is lowered by one point is associated with a 2.1% reduction of mean direct costs in the population. If obesity was eliminated, and the BMI of all obese individuals were lowered to 29.9 kg/m2, this would reduce the mean direct costs by 4.0% in the population. Results show a non-linear relationship between BMI and health care costs, with very high costs for a few individuals with high BMI. This indicates that population-based interventions in combination with selective measures for very obese individuals might be the preferred strategy. PMID- 28867789 TI - Multiple Antibiotic-Resistant, Extended Spectrum-beta-Lactamase (ESBL)-Producing Enterobacteria in Fresh Seafood. AB - Members of the family Enterobacteriaceae include several human pathogens that can be acquired through contaminated food and water. In this study, the incidence of extended spectrum beta-lactamase (ESBL)-producing enterobacteria was investigated in fresh seafood sold in retail markets. The ESBL-positive phenotype was detected in 169 (78.60%) isolates, with Escherichia coli being the predominant species (53), followed by Klebsiella oxytoca (27), and K. pneumoniae (23). More than 90% of the isolates were resistant to third generation cephalosporins, cefotaxime, ceftazidime, and cefpodoxime. Sixty-five percent of the isolates were resistant to the monobactam drug aztreonam, 40.82% to ertapenem, and 31.36% to meropenem. Resistance to at least five antibiotics was observed in 38.46% of the isolates. Polymerase Chain Reaction (PCR) analysis of ESBL-encoding genes detected blaCTX, blaSHV, and blaTEM genes in 76.92%, 63.3%, and 44.37% of the isolates, respectively. Multiple ESBL genes were detected in majority of the isolates. The recently discovered New Delhi metallo-beta-lactamase gene (blaNDM-1) was detected in two ESBL+ isolates. Our study shows that secondary contamination of fresh seafood with enteric bacteria resistant to multiple antibiotics may implicate seafood as a potential carrier of antibiotic resistant bacteria and emphasizes an urgent need to prevent environmental contamination and dissemination of such bacteria. PMID- 28867792 TI - Soluble Epoxide Hydrolase Inhibitory Activity of Components Isolated from Apios americana Medik. AB - A new compound 1, 5-methoxy-2,5,7,4'-tetrahydroxy-coumaronochromone, along with seven known compounds (2-8), were isolated from Apios americana using open column chromatography. Their structures were established based on an analysis of 1D and 2D NMR, and MS spectra. Among these, two compounds 1 and 2 showed inhibitory activity on soluble epoxide hydrolase (sEH) at a concentration below 50 MUM. The respective competitive (1) and mixed (2) inhibitors were revealed to have Ki values of 21.0 +/- 0.8 and 14.5 +/- 1.5 MUM, based on the Dixon plot. The potential inhibitor (2) was visually presented in a predicted binding pose in the receptor by molecular docking. Additionally, molecular dynamics were performed for a detailed understanding of their complex by Gromacs 4.6.5 package. PMID- 28867794 TI - Understanding Adolescents' Categorisation of Animal Species. AB - Categorisations are a means of investigating cognitive maps. The present study, for the first time, investigates adolescents' spontaneous categorisation of 34 animal species. Furthermore, explicit evaluations of 16 selected animals in terms of their perceived utility and likeability were analysed. 105 British adolescents, 54% female, mean age 14.5 (SD = 1.6) participated in the study. Results of multidimensional scaling (MDS) techniques indicate 3-dimensional data representation regardless of gender or age. Property fittings show that affect and perceived utility of animals explain two of the MDS dimensions, and hence partly explain adolescents' categorisation. Additionally, hierarchical cluster analyses show a differentiation between farm animals, birds, pet animals, and wild animals possibly explaining MDS dimension 3. The results suggest that utility perceptions predominantly underlie adolescents' categorisations and become even more dominant in older adolescents, which potentially has an influence on attitudes to animals with implications for animal welfare, conservation, and education. PMID- 28867795 TI - Development and Validation of a Reproducible and Label-Free Surface Plasmon Resonance Immunosensor for Enrofloxacin Detection in Animal-Derived Foods. AB - This study describes the development of a reproducible and label-free surface plasmon resonance (SPR) immunosensor and its application in the detection of harmful enrofloxacin (ENRO) in animal-derived foods. The experimental parameters for the immunosensor construction and regeneration, including the pH value (4.5), concentration for coating ENRO-ovalbumin conjugate (ENRO-OVA) (100 MUg.mL-1), concentration of anti-ENRO antibody (80 nM) and regeneration solution (0.1 mol.L 1 HCl) were evaluated in detail. With the optimized parameters, the proposed SPR immunosensor obtained a good linear response to ENRO with high sensitivity (IC50: 3.8 ng.mL-1) and low detection limit (IC15: 1.2 ng.mL-1). The proposed SPR immunosensor was further validated to have favorable performances for ENRO residue detection in typical animal-derived foods after a simple matrix pretreatment procedure, as well as acceptable accuracy (recovery: 84.3-96.6%), precision (relative standard deviation (n = 3): 1.8-4.6%), and sensitivity (IC15 <= 8.4 ng.mL-1). Each SPR chip for analysis can be reused at least 100 times with good stability and the analysis cycle containing the steps of sample uploading/chip regeneration/baseline recovery can be completed within 6 min (one cycle) and auto-operated by a predetermined program. These results demonstrated that the proposed SPR immunosensor provided an effective strategy for accurate, sensitive, and rapid detection for ENRO residue, which has great potential for routine analysis of large numbers of samples for measuring different types of compounds. PMID- 28867796 TI - Evaluating the Tensile Properties of Aluminum Foundry Alloys through Reference Castings-A Review. AB - The tensile properties of an alloy can be exploited if detrimental defects and imperfections of the casting are minimized and the microstructural characteristics are optimized through several strategies that involve die design, process management and metal treatments. This paper presents an analysis and comparison of the salient characteristics of the reference dies proposed in the literature, both in the field of pressure and gravity die-casting. The specimens produced with these reference dies, called separately poured specimens, are effective tools for the evaluation and comparison of the tensile and physical behaviors of Al-Si casting alloys. Some of the findings of the present paper have been recently developed in the frame of the European StaCast project whose results are complemented here with some more recent outcomes and a comprehensive analysis and discussion. PMID- 28867793 TI - Diet, Gut Microbiome and Epigenetics: Emerging Links with Inflammatory Bowel Diseases and Prospects for Management and Prevention. AB - Inflammatory bowel diseases (IBD) represent a growing public health concern due to increasing incidence worldwide. The current notion on the pathogenesis of IBD is that genetically susceptible individuals develop intolerance to dysregulated gut microflora (dysbiosis) and chronic inflammation develops as a result of environmental triggers. Among the environmental factors associated with IBD, diet plays an important role in modulating the gut microbiome, influencing epigenetic changes, and, therefore, could be applied as a therapeutic tool to improve the disease course. Nevertheless, the current dietary recommendations for disease prevention and management are scarce and have weak evidence. This review summarises the current knowledge on the complex interactions between diet, microbiome and epigenetics in IBD. Whereas an overabundance of calories and some macronutrients increase gut inflammation, several micronutrients have the potential to modulate it. Immunonutrition has emerged as a new concept putting forward the importance of vitamins such as vitamins A, C, E, and D, folic acid, beta carotene and trace elements such as zinc, selenium, manganese and iron. However, when assessed in clinical trials, specific micronutrients exerted a limited benefit. Beyond nutrients, an anti-inflammatory dietary pattern as a complex intervention approach has become popular in recent years. Hence, exclusive enteral nutrition in paediatric Crohn's disease is the only nutritional intervention currently recommended as a first-line therapy. Other nutritional interventions or specific diets including the Specific Carbohydrate Diet (SCD), the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyol (FODMAP) diet and, most recently, the Mediterranean diet have shown strong anti inflammatory properties and show promise for improving disease symptoms. More work is required to evaluate the role of individual food compounds and complex nutritional interventions with the potential to decrease inflammation as a means of prevention and management of IBD. PMID- 28867797 TI - Flavonoid-Rich Extract of Paulownia fortunei Flowers Attenuates Diet-Induced Hyperlipidemia, Hepatic Steatosis and Insulin Resistance in Obesity Mice by AMPK Pathway. AB - The flavonoid-rich extract from Paulownia fortunei flowers (EPF) has been reported to prevent obesity and other lipid metabolism disease. However, the mechanism of its protective effects is not yet clear. The objective of this study was to investigate molecular factors involved in the hypoglycemic and hypolipidemic effects of EPF in obese mice fed a high-fat diet (HFD). Male h ICR (Institute of Cancer Research) mice were fed a HFD containing or not containing the EPF (50 or 100 mg/kg) for eight weeks. EPF reduced body weight gain, lipid accumulation in livers and levels of lipid, glucose and insulin in plasma as well as reduced insulin resistance as compared with the HFD group. EPF significantly decreased serum aminotransferase activity of the HFD group. We observed that EPF administration significantly increased the level of AMP-activated kinase (AMPK) phosphorylation and prevented fat deposits in livers and HepG2 cells, but these effects were blocked by compound C (an AMPK inhibitor). The protective effects of EPF were probably associated with the decrease in HMGCR, SREBP-1c and FAS expressions and the increase in CPT1 and phosphor-IRS-1 expressions. Our results suggest that EPF might be a potential natural candidate for the treatment and/or prevention of overweight and hepatic and metabolic-related alterations induced by HFD. PMID- 28867798 TI - Vitamin C Status and Cognitive Function: A Systematic Review. AB - Vitamin C plays a role in neuronal differentiation, maturation, myelin formation and modulation of the cholinergic, catecholinergic, and glutaminergic systems. This review evaluates the link between vitamin C status and cognitive performance, in both cognitively intact and impaired individuals. We searched the PUBMED, SCOPUS, SciSearch and the Cochrane Library from 1980 to January 2017, finding 50 studies, with randomised controlled trials (RCTs, n = 5), prospective (n = 24), cross-sectional (n = 17) and case-control (n = 4) studies. Of these, 36 studies were conducted in healthy participants and 14 on cognitively impaired individuals (including Alzheimer's and dementia). Vitamin C status was measured using food frequency questionnaires or plasma vitamin C. Cognition was assessed using a variety of tests, mostly the Mini-Mental-State-Examination (MMSE). In summary, studies demonstrated higher mean vitamin C concentrations in the cognitively intact groups of participants compared to cognitively impaired groups. No correlation between vitamin C concentrations and MMSE cognitive function was apparent in the cognitively impaired individuals. The MMSE was not suitable to detect a variance in cognition in the healthy group. Analysis of the studies that used a variety of cognitive assessments in the cognitively intact was beyond the scope of this review; however, qualitative assessment revealed a potential association between plasma vitamin C concentrations and cognition. Due to a number of limitations in these studies, further research is needed, utilizing plasma vitamin C concentrations and sensitive cognitive assessments that are suitable for cognitively intact adults. PMID- 28867799 TI - Could Pomegranate Juice Help in the Control of Inflammatory Diseases? AB - Fruits rich in polyphenols, such as pomegranates, have been shown to have health benefits relating to their antioxidant and anti-inflammatory properties. Using data obtained from PubMed and Scopus, this article provides a brief overview of the therapeutic effects of pomegranate on chronic inflammatory diseases (CID) such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), metabolic and cardiovascular disorders, and other inflammatory-associated conditions, with an emphasis on fruit-derived juices. Most studies regarding the effects of pomegranate juice have focused on its ability to treat prostate cancer, diabetes, and atherosclerosis. However, pomegranate juice has shown therapeutic potential for many other illnesses. For instance, a small number of human clinical trials have highlighted the positive effects of pomegranate juice and extract consumption on cardiovascular health. The beneficial effects of pomegranate components have also been observed in animal models for respiratory diseases, RA, neurodegenerative disease, and hyperlipidaemia. Furthermore, there exists strong evidence from rodent models suggesting that pomegranate juice can be used to effectively treat IBD, and as an anti-inflammatory agent to treat CID. The effects of pomegranate intake should be further investigated by conducting larger and more well-defined human trials. PMID- 28867800 TI - Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes NaV1.9, NaV1.7 and NaV1.1. AB - Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA) to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC50 concentrations in the low nanomolar range. P-CTX-1 induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels. In contrast, lidocaine and tetrodotoxin (TTX) reduce CGRP release by 53-75%, with the remaining fraction involving L-type and T type voltage-gated calcium channels (VGCC). Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC) NaV1.9, but not NaV1.8 or NaV1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes NaV1.7 and NaV1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics. PMID- 28867801 TI - An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet. AB - Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by a rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for treatment of various cholinergic deficiencies, including Alzheimer's disease and myasthenia gravis. In a previous high throughput screening campaign, we identified the dye crystal violet (CV) as an inhibitor of AChE. Herein, we show that CV displays a significant cooperativity for binding to AChE, and the molecular basis for this observation has been investigated by X-ray crystallography. Two monomers of CV bind to residues at the entrance of the active site gorge of the enzyme. Notably, the two CV molecules have extensive intermolecular contacts with each other and with AChE. Computational analyses show that the observed CV dimer is not stable in solution, suggesting the sequential binding of two monomers. Guided by the structural analysis, we designed a set of single site substitutions, and investigated their effect on the binding of CV. Only moderate effects on the binding and the cooperativity were observed, suggesting a robustness in the interaction between CV and AChE. Taken together, we propose that the dimeric cooperative binding is due to a rare combination of chemical and structural properties of both CV and the AChE molecule itself. PMID- 28867803 TI - Palladium-Catalyzed Dehydrogenative Coupling: An Efficient Synthetic Strategy for the Construction of the Quinoline Core. AB - Palladium-catalyzed dehydrogenative coupling is an efficient synthetic strategy for the construction of quinoline scaffolds, a privileged structure and prevalent motif in many natural and biologically active products, in particular in marine alkaloids. Thus, quinolines and 1,2-dihydroquinolines can be selectively obtained in moderate-to-good yields via intramolecular C-H alkenylation reactions, by choosing the reaction conditions. This methodology provides a direct method for the construction of this type of quinoline through an efficient and atom economical procedure, and constitutes significant advance over the existing procedures that require preactivated reaction partners. PMID- 28867804 TI - FVIIa-sTF and Thrombin Inhibitory Activities of Compounds Isolated from Microcystis aeruginosa K-139. AB - The rise of bleeding and bleeding complications caused by oral anticoagulant use are serious problems nowadays. Strategies that block the initiation step in blood coagulation involving activated factor VII-tissue factor (fVIIa-TF) have been considered. This study explores toxic Microcystis aeruginosa K-139, from Lake Kasumigaura, Ibaraki, Japan, as a promising cyanobacterium for isolation of fVIIa sTF inhibitors. M. aeruginosa K-139 underwent reversed-phase solid-phase extraction (ODS-SPE) from 20% MeOH to MeOH elution with 40%-MeOH increments, which afforded aeruginosin K-139 in the 60% MeOH fraction; micropeptin K-139 and microviridin B in the MeOH fraction. Aeruginosin K-139 displayed an fVIIa-sTF inhibitory activity of ~166 uM, within a 95% confidence interval. Micropeptin K 139 inhibited fVIIa-sTF with EC50 10.62 uM, which was more efficient than thrombin inhibition of EC50 26.94 uM. The thrombin/fVIIa-sTF ratio of 2.54 in micropeptin K-139 is higher than those in 4-amidinophenylmethane sulfonyl fluoride (APMSF) and leupeptin, when used as positive controls. This study proves that M. aeruginosa K-139 is a new source of fVIIa-sTF inhibitors. It also opens a new avenue for micropeptin K-139 and related depsipeptides as fVIIa-sTF inhibitors. PMID- 28867806 TI - How Stress Treatments Influence the Performance of Biodegradable Poly(Butylene Succinate)-Based Copolymers with Thioether Linkages for Food Packaging Applications. AB - Biodegradable poly(butylene succinate) (PBS)-based random copolymers containing thioether linkages (P(BSxTDGSy)) of various compositions have been investigated and characterized from the gas barrier, thermal, and mechanical point of view, after food contact simulants or thermal and photoaging processes. Each stress treatment was performed on thin films and the results obtained have been compared to the same untreated film, used as a standard. Barrier properties with different gases (O2 and CO2) were evaluated, showing that the polymer chemical composition strongly influenced the permeability behavior. The relationships between the diffusion coefficients (D) and solubility (S) with polymer composition were also investigated. The results highlighted a correlation between polymer chemical structure and treatment. Gas transmission rate (GTR) mainly depending on the performed treatment, as GTR increased with the increase of TDGS co-unit amount. Thermal and mechanical tests allowed for the recording of variations in the degree of crystallinity and in the tensile properties. An increase in the crystallinity degree was recorded after contact with simulant liquids and aging treatments, together with a molecular weight decrease, a slight enhancement of the elastic modulus and a decrement of the elongation at break, proportional to the TDGS co-unit content. PMID- 28867805 TI - Cytotoxic Activity of Origanum Vulgare L. on Hepatocellular Carcinoma cell Line HepG2 and Evaluation of its Biological Activity. AB - The potential of plant essential oils (EOs) in anticancer treatment has recently received many research efforts to overcome the development of multidrug resistance and their negative side effects. The aims of the current research are to study (i) the cytotoxic effect of the crude EO extracted from Origanum vulgare subsp hirtum and its main constituents (carvacrol, thymol, citral and limonene) on hepatocarcinoma HepG2 and healthy human renal cells HEK293; (ii) the antibacterial and phytotoxic activities of the above EO and its main constituents. Results showed that cell viability percentage of treated HepG2 by EO and its main constituents was significantly decreased when compared to untreated cells. The calculated inhibition concentration (IC50) values for HepG2 were lower than healthy renal cells, indicating the sort of selectivity of the studied substances. Citral is not potentially recommended as an anticancer therapeutic agent, since there are no significant differences between IC50 values against both tested cell lines. Results showed also that oregano EO and its main constituents have a significant antibacterial activity and a moderate phytotoxic effect. The current research verified that oregano EO and its main constituents could be potentially utilized as anticancer therapeutic agents. PMID- 28867802 TI - Design of Artificial Riboswitches as Biosensors. AB - RNA aptamers readily recognize small organic molecules, polypeptides, as well as other nucleic acids in a highly specific manner. Many such aptamers have evolved as parts of regulatory systems in nature. Experimental selection techniques such as SELEX have been very successful in finding artificial aptamers for a wide variety of natural and synthetic ligands. Changes in structure and/or stability of aptamers upon ligand binding can propagate through larger RNA constructs and cause specific structural changes at distal positions. In turn, these may affect transcription, translation, splicing, or binding events. The RNA secondary structure model realistically describes both thermodynamic and kinetic aspects of RNA structure formation and refolding at a single, consistent level of modelling. Thus, this framework allows studying the function of natural riboswitches in silico. Moreover, it enables rationally designing artificial switches, combining essentially arbitrary sensors with a broad choice of read-out systems. Eventually, this approach sets the stage for constructing versatile biosensors. PMID- 28867807 TI - Synthesis of Glycosides by Glycosynthases. AB - The many advances in glycoscience have more and more brought to light the crucial role of glycosides and glycoconjugates in biological processes. Their major influence on the functionality and stability of peptides, cell recognition, health and immunity and many other processes throughout biology has increased the demand for simple synthetic methods allowing the defined syntheses of target glycosides. Additional interest in glycoside synthesis has arisen with the prospect of producing sustainable materials from these abundant polymers. Enzymatic synthesis has proven itself to be a promising alternative to the laborious chemical synthesis of glycosides by avoiding the necessity of numerous protecting group strategies. Among the biocatalytic strategies, glycosynthases, genetically engineered glycosidases void of hydrolytic activity, have gained much interest in recent years, enabling not only the selective synthesis of small glycosides and glycoconjugates, but also the production of highly functionalized polysaccharides. This review provides a detailed overview over the glycosylation possibilities of the variety of glycosynthases produced until now, focusing on the transfer of the most common glucosyl-, galactosyl-, xylosyl-, mannosyl-, fucosyl-residues and of whole glycan blocks by the different glycosynthase enzyme variants. PMID- 28867808 TI - Approaches for Studying Autophagy in Caenorhabditis elegans. AB - Macroautophagy (hereafter referred to as autophagy) is an intracellular degradative process, well conserved among eukaryotes. By engulfing cytoplasmic constituents into the autophagosome for degradation, this process is involved in the maintenance of cellular homeostasis. Autophagy induction triggers the formation of a cup-shaped double membrane structure, the phagophore, which progressively elongates and encloses materials to be removed. This double membrane vesicle, which is called an autophagosome, fuses with lysosome and forms the autolysosome. The inner membrane of the autophagosome, along with engulfed compounds, are degraded by lysosomal enzymes, which enables the recycling of carbohydrates, amino acids, nucleotides, and lipids. In response to various factors, autophagy can be induced for non-selective degradation of bulk cytoplasm. Autophagy is also able to selectively target cargoes and organelles such as mitochondria or peroxisome, functioning as a quality control system. The modification of autophagy flux is involved in developmental processes such as resistance to stress conditions, aging, cell death, and multiple pathologies. So, the use of animal models is essential for understanding these processes in the context of different cell types throughout the entire lifespan. For almost 15 years, the nematode Caenorhabditis elegans has emerged as a powerful model to analyze autophagy in physiological or pathological contexts. This review presents a rapid overview of physiological processes involving autophagy in Caenorhabditis elegans, the different assays used to monitor autophagy, their drawbacks, and specific tools for the analyses of selective autophagy. PMID- 28867809 TI - Revisiting the Latency of Uridine Diphosphate-Glucuronosyltransferases (UGTs)-How Does the Endoplasmic Reticulum Membrane Influence Their Function? AB - Uridine diphosphate-glucuronosyltransferases (UGTs) are phase 2 conjugation enzymes mainly located in the endoplasmic reticulum (ER) of the liver and many other tissues, and can be recovered in artificial ER membrane preparations (microsomes). They catalyze glucuronidation reactions in various aglycone substrates, contributing significantly to the body's chemical defense mechanism. There has been controversy over the last 50 years in the UGT field with respect to the explanation for the phenomenon of latency: full UGT activity revealed by chemical or physical disruption of the microsomal membrane. Because latency can lead to inaccurate measurements of UGT activity in vitro, and subsequent underprediction of drug clearance in vivo, it is important to understand the mechanisms behind this phenomenon. Three major hypotheses have been advanced to explain UGT latency: compartmentation, conformation, and adenine nucleotide inhibition. In this review, we discuss the evidence behind each hypothesis in depth, and suggest some additional studies that may reveal more information on this intriguing phenomenon. PMID- 28867810 TI - Longitudinal Study-Based Dementia Prediction for Public Health. AB - The issue of public health in Korea has attracted significant attention given the aging of the country's population, which has created many types of social problems. The approach proposed in this article aims to address dementia, one of the most significant symptoms of aging and a public health care issue in Korea. The Korean National Health Insurance Service Senior Cohort Database contains personal medical data of every citizen in Korea. There are many different medical history patterns between individuals with dementia and normal controls. The approach used in this study involved examination of personal medical history features from personal disease history, sociodemographic data, and personal health examinations to develop a prediction model. The prediction model used a support-vector machine learning technique to perform a 10-fold cross-validation analysis. The experimental results demonstrated promising performance (80.9% F measure). The proposed approach supported the significant influence of personal medical history features during an optimal observation period. It is anticipated that a biomedical "big data"-based disease prediction model may assist the diagnosis of any disease more correctly. PMID- 28867812 TI - Design and Analysis of the Measurement Characteristics of a Bidirectional Decoupling Over-Constrained Six-Dimensional Parallel-Mechanism Force Sensor. AB - The measurement of large forces and the presence of errors due to dimensional coupling are significant challenges for multi-dimensional force sensors. To address these challenges, this paper proposes an over-constrained six-dimensional force sensor based on a parallel mechanism of steel ball structures as a measurement module. The steel ball structure can be subject to rolling friction instead of sliding friction, thus reducing the influence of friction. However, because the structure can only withstand unidirectional pressure, the application of steel balls in a six-dimensional force sensor is difficult. Accordingly, a new design of the sensor measurement structure was designed in this study. The static equilibrium and displacement compatibility equations of the sensor prototype's over-constrained structure were established to obtain the transformation function, from which the forces in the measurement branches of the proposed sensor were then analytically derived. The sensor's measurement characteristics were then analysed through numerical examples. Finally, these measurement characteristics were confirmed through calibration and application experiments. The measurement accuracy of the proposed sensor was determined to be 1.28%, with a maximum coupling error of 1.98%, indicating that the proposed sensor successfully overcomes the issues related to steel ball structures and provides sufficient accuracy. PMID- 28867811 TI - Development and Evaluation of Topical Gabapentin Formulations. AB - Topical delivery of gabapentin is desirable to treat peripheral neuropathic pain conditions whilst avoiding systemic side effects. To date, reports of topical gabapentin delivery in vitro have been variable and dependent on the skin model employed, primarily involving rodent and porcine models. In this study a variety of topical gabapentin formulations were investigated, including Carbopol(r) hydrogels containing various permeation enhancers, and a range of proprietary bases including a compounded Lipoderm(r) formulation; furthermore microneedle facilitated delivery was used as a positive control. Critically, permeation of gabapentin across a human epidermal membrane in vitro was assessed using Franz type diffusion cells. Subsequently this data was contextualised within the wider scope of the literature. Although reports of topical gabapentin delivery have been shown to vary, largely dependent upon the skin model used, this study demonstrated that 6% (w/w) gabapentin 0.75% (w/w) Carbopol(r) hydrogels containing 5% (w/w) DMSO or 70% (w/w) ethanol and a compounded 10% (w/w) gabapentin Lipoderm(r) formulation were able to facilitate permeation of the molecule across human skin. Further pre-clinical and clinical studies are required to investigate the topical delivery performance and pharmacodynamic actions of prospective formulations. PMID- 28867813 TI - Application of Dynamic Analysis in Semi-Analytical Finite Element Method. AB - Analyses of dynamic responses are significantly important for the design, maintenance and rehabilitation of asphalt pavement. In order to evaluate the dynamic responses of asphalt pavement under moving loads, a specific computational program, SAFEM, was developed based on a semi-analytical finite element method. This method is three-dimensional and only requires a two dimensional FE discretization by incorporating Fourier series in the third dimension. In this paper, the algorithm to apply the dynamic analysis to SAFEM was introduced in detail. Asphalt pavement models under moving loads were built in the SAFEM and commercial finite element software ABAQUS to verify the accuracy and efficiency of the SAFEM. The verification shows that the computational accuracy of SAFEM is high enough and its computational time is much shorter than ABAQUS. Moreover, experimental verification was carried out and the prediction derived from SAFEM is consistent with the measurement. Therefore, the SAFEM is feasible to reliably predict the dynamic response of asphalt pavement under moving loads, thus proving beneficial to road administration in assessing the pavement's state. PMID- 28867814 TI - Identification of Potential High-Risk Habitats within the Transmission Reach of Oncomelania hupensis after Floods Based on SAR Techniques in a Plane Region in China. AB - Schistosomiasis japonica is an infectious disease caused by Schistosoma japonicum, and it remains endemic in China. Flooding is the main hazard factor, as it causes the spread of Oncomelania hupensis, the only intermediate host of Schistosoma japonicum, thereby triggering schistosomiasis outbreaks. Based on multi-source real-time remote sensing data, we used remote sensing (RS) technology, especially synthetic aperture radar (SAR), and geographic information system (GIS) techniques to carry out warning research on potential snail habitats within the snail dispersal range following flooding. Our research result demonstrated: (1) SAR data from Sentinel-1A before and during a flood were used to identify submerged areas rapidly and effectively; (2) the likelihood of snail survival was positively correlated with the clay proportion, core area standard deviation, and ditch length but negatively correlated with the wetness index, NDVI (normalized difference vegetation index), elevation, woodland area, and construction land area; (3) the snail habitats were most abundant near rivers and ditches in paddy fields; (4) the rivers and paddy irrigation ditches in the submerged areas must be the focused of mitigation efforts following future floods. PMID- 28867815 TI - Determinants of FDI Localization in China: A County-Level Analysis for the Pharmaceutical Industry. AB - Foreign direct investments (FDIs) have been widely recognized as a crucial feature of the Chinese industrial development process. Over the past decades, China has been attracting huge amounts of inward FDIs as a consequence of both spontaneous market dynamics and place-based preferential policies at the sub national level. However, the Chinese market exhibits large dissimilarities in terms of FDI localization across territories that are worth investigating at a more disaggregated level. In this regards, our study explores the determinants of attraction of inward FDIs in China, at the county level. It focuses on the pharmaceutical industry and attempts to assess whether factors related to location advantages, agglomeration dynamics, information cost effects and environmental regulation costs affect foreign firms' localization choices as well as invested amounts in that location. By means of discrete choice models, our paper confirms the findings of the prevalent literature about the positive effects of location advantages on pharmaceutical FDI attraction. Different from our expectations, a higher proportion of foreign enterprises do not stimulate significant effects on FDI localization, while preferential policies and sectoral agglomeration are positively correlated with the localization of pharmaceutical foreign firms. Finally, our results suggest that investing firms tend to avoid areas with strict environment regulation. PMID- 28867816 TI - Dairy Product Consumption Interacts with Glucokinase (GCK) Gene Polymorphisms Associated with Insulin Resistance. AB - Dairy product intake and a person's genetic background have been reported to be associated with the risk of type 2 diabetes (T2D). The objective of this study was to examine the interaction between dairy products and genes related to T2D on glucose-insulin homeostasis parameters. A validated food frequency questionnaire, fasting blood samples, and glucokinase (GCK) genotypes were analyzed in 210 healthy participants. An interaction between rs1799884 in GCK and dairy intake on the homeostasis model assessment of insulin resistance was identified. Secondly, human hepatocellular carcinoma cells (HepG2) were grown in a high-glucose medium and incubated with either 1-dairy proteins: whey, caseins, and a mixture of whey and casein; and 2-four amino acids (AA) or mixtures of AA. The expression of GCK related genes insulin receptor substrate-1 (IRS-1) and fatty acid synthase (FASN) was increased with whey protein isolate or hydrolysate. Individually, leucine increased IRS-1 expression, whereas isoleucine and valine decreased FASN expression. A branched-chain AA mixture decreased IRS-1 and FASN expression. In conclusion, carriers of the A allele for rs1799884 in the GCK gene may benefit from a higher intake of dairy products to maintain optimal insulin sensitivity. Moreover, the results show that whey proteins affect the expression of genes related to glucose metabolism. PMID- 28867817 TI - Vesico-Adnexal Fistula Treated with Transurethral Embolization Under Fluoroscopic Guidance. AB - BACKGROUND Vesico-adnexal fistulae are rare. Potential causes of such fistulae include infection, endometriosis, and iatrogenic causes following pelvic surgeries. To the best of our knowledge, only 3 cases of vesico-adnexal fistulae have been reported, and all these patients were treated surgically by removing the involved adnexa, excising the fistulous duct, and suturing the bladder. We describe the first case of vesico-adnexal fistula that developed after pelvic surgery, and it was successfully treated by transurethral embolization under fluoroscopic guidance. CASE REPORT Our patient was a 27-year-old woman with a history of hysterectomy. She presented to our institution with urethral discharge and a recurrent urinary tract infection. The cystogram showed a fistula tract connecting the urinary bladder and left adnexal cystic cavity. She was treated conservatively with antibiotics and prolonged Foley catheterization to allow for spontaneous closure of the fistula; however, conservative management failed. The patient was successfully treated with transurethral embolization of the tract under fluoroscopic guidance. CONCLUSIONS In such a rare scenario with limited treatment options, interventional radiology offers an alternative minimally invasive treatment strategy. PMID- 28867818 TI - Knowledge and Awareness of Cervical Cancer, Human Papillomavirus (HPV), and HPV Vaccine Among HPV-Infected Chinese Women. AB - BACKGROUND It is important to understand the knowledge that various groups of a population have about cervical cancer and human papillomavirus (HPV) and their attitudes toward HPV vaccination, as it will ultimately influence their decision making for or against the acceptability of vaccines and other preventive methods. This study was designed to determine the level of knowledge and awareness about cervical cancer, HPV, and the HPV vaccine among Chinese women in Yunnan province. MATERIAL AND METHODS A survey was conducted in Yunnan province by the Laboratory of Molecular Virology in collaboration with the Yunnan First People's Hospital in Feb 2015. A total of 388 women were recruited and asked to participate in a questionnaire-based interview that collected information related to their awareness and knowledge about: (1) cervical cancer, (2) HPV and HPV vaccine and willingness to have their children receive vaccination, and (3) demographic characteristics. RESULTS A total of 388 HPV-positive women were included; 300/388 (73.3%) were Han, and 88/388 (22.7%) were other ethnicities. Overall, 204/388 (52.6%) of the women were aware of cervical cancer, with a significant difference between Han women and women of other ethnic groups (168/388, 56.0% and 36/88, 40.9%; P=0.015). Overall, 26.5% of the women were aware of the role of HPV in cervical cancer; 29.0% of the Han women and 18.2% of women of other ethnic groups were aware of this role of HPV (P=0.05). The knowledge that HPV infection leads to cervical cancer was higher among Han women (29.0%) compared to women of other ethnicities (18.2%). Knowledge about the HPV vaccine was very low in all ethnic groups, but the Han women were more willing to allow their children to be vaccinated before they become sexually active. A similar difference has also been found in women from various regions. CONCLUSIONS Although level of awareness and knowledge about cervical cancer was moderate, knowledge and awareness of HPV and the HPV vaccine was very low. Targeted communication is very important among populations in which knowledge gaps exist in order to promote dialogue about the vaccine among patients and their healthcare providers. PMID- 28867820 TI - Microbiome: The microbiota maintains oxygen balance in the gut. PMID- 28867821 TI - The Exposome: A New Frontier for Education. AB - The historic debate of nature vs. nurture has emerged as a central yin-yang of contemporary health and disease research. The Human Genome Project provided the capability to define the nature of an individual by one's genetic sequence. But tools are not available to sequence lifelong exposures (i.e., the nurture of an individual). Many believe that nurture has an even greater role than genetics in determining lifelong success, health, and well-being. In contemporary terminology, the cumulative measure of environmental influences and associated biological responses throughout the life span is termed the "exposome." This includes all external exposures from the environment, diet, behavior, societal influences and infections, and also cumulative biological responses to exposures and endogenous processes. Pursuit of a Human Exposome Project is a vision worthy of our youth: development of strategies and tools will require the brightest and most imaginative. Incorporation of the exposome into education curricula will foster discussion, development of interest, improvement of skills, and promotion of critical thinking to prepare students for civically engaged lives, ongoing study, and future career opportunities. The long-term vision is that sequencing the exposome will support better understanding of healthful and harmful lifelong exposures and lead to improved opportunity for the health and prosperity of all. PMID- 28867822 TI - Detection of Buckminsterfullerene emission in the diffuse interstellar medium. AB - Emission of fullerenes in their infrared vibrational bands has been detected in space near hot stars. The proposed attribution of the diffuse interstellar bands at 9577 and 9632 A to electronic transitions of the buckminsterfullerene cation (i.e. [Formula: see text]) was recently supported by new laboratory data, confirming the presence of this species in the diffuse interstellar medium (ISM). In this letter, we present the detection, also in the diffuse ISM, of the 17.4 and 18.9 MUm emission bands commonly attributed to vibrational bands of neutral C60. According to classical models that compute the charge state of large molecules in space, C60 is expected to be mostly neutral in the diffuse ISM. This is in agreement with the abundances of diffuse C60 we derive here from observations. We also find that C60 is less abundant in the diffuse ISM than in star-forming regions, supporting the theory that C60 can be formed in these regions. PMID- 28867823 TI - Studying Sex: A Content Analysis of Sexuality Research in Counseling Psychology. AB - Using a sex positive framework, the authors conducted a 61-year (1954-2015) content analysis of sexuality research in the flagship counseling psychology journals, the Journal of Counseling Psychology and The Counseling Psychologist. Given counseling psychology's core strengths- and multiculturalism-related values, this study aimed to uncover which human sexuality topics were published most, whether publications aligned with a sex positive, neutral, or negative discourse, what methodologies were used, and differences in how populations were investigated across race. Researchers used an integrative approach to content analysis and human coding (Neuendorf, 2011). Results highlighted that out of 188 articles meeting criteria, a slight majority (38.05%) focused on sexual orientation, identity, and minorities topics. Only 4.78% utilized a sex-positive perspective. Quantitative and conceptual pieces were most published, and publications disproportionately focused on primarily White populations. When people of color were included, the discourse was sex negative. Implications for research and practice are discussed. PMID- 28867824 TI - Faecal-wood biomass co-combustion and ash composition analysis. AB - Fuel blending is a widely used approach in biomass combustion, particularly for feedstocks with low calorific value and high moisture content. In on-site sanitation technologies, fuel blending is proposed as a pre-treatment requirement to reduce moisture levels and improve the physiochemical properties of raw faeces prior to drying. This study investigates the co-combustion performance of wood dust: raw human faeces blends at varying air-to-fuel ratios in a bench-scale combustor test rig. It concludes with ash composition analyses and discusses their potential application and related problems. The study shows that a 50:50 wood dust (WD): raw human faeces (FC) can reduce moisture levels in raw human faeces by ~40% prior to drying. The minimum acceptable blend for treating moist faeces without prior drying at a combustion air flow rate of 14-18 L/min is 30:70 WD: FC. For self-sustained ignition and flame propagation, the minimum combustion temperature required for conversion of the fuel to ash is ~400 degrees C. The most abundant elements in faecal ash are potassium and calcium, while elements such as nickel, aluminium and iron are in trace quantities. This suggests the potential use of faecal ash as a soil conditioner, but increases the tendency for fly ash formation and sintering problems. PMID- 28867819 TI - Gliding motility powers invasion and egress in Apicomplexa. AB - Protozoan parasites have developed elaborate motility systems that facilitate infection and dissemination. For example, amoebae use actin-rich membrane extensions called pseudopodia, whereas Kinetoplastida are propelled by microtubule-containing flagella. By contrast, the motile and invasive stages of the Apicomplexa - a phylum that contains the important human pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis) - have a unique machinery called the glideosome, which is composed of an actomyosin system that underlies the plasma membrane. The glideosome promotes substrate-dependent gliding motility, which powers migration across biological barriers, as well as active host cell entry and egress from infected cells. In this Review, we discuss the discovery of the principles that govern gliding motility, the characterization of the molecular machinery involved, and its impact on parasite invasion and egress from infected cells. PMID- 28867825 TI - "Epidemiological Follow-up 15 Years After Presumably False Diagnoses of Breast Cancer" - A Statement by the German Senology Society. PMID- 28867826 TI - Comment on the Article "Epidemiological Follow-up 15 Years After the Breast Cancer Scandal in Essen" (Hauth et al.). PMID- 28867827 TI - Application of a Two-Sinker Densimeter for Phase-Equilibrium Measurements: A New Technique for the Detection of Dew Points and Measurements on the (Methane + Propane) System. AB - We explore a novel method for determining the dew-point density and dew-point pressure of fluid mixtures and compare it to traditional methods. The (p, rho, T, x) behavior of three (methane + propane) mixtures was investigated with a two sinker magnetic suspension densimeter over the temperature range of (248.15 to 293.15) K; the measurements extended from low pressures into the two-phase region. The compositions of the gravimetrically prepared mixtures were (0.74977, 0.50688, and 0.26579) mole fraction methane. We analyzed isothermal data by: (1) a "traditional" analysis of the intersection of a virial fit of the (p vs. rho) data in the single-phase region with a linear fit of the data in the two-phase region; and (2) an analysis of the adsorbed mass on the sinker surfaces. We compared these to a traditional isochoric experiment. We conclude that the "adsorbed mass" analysis of an isothermal experiment provides an accurate determination of the dew-point temperature, pressure, and density. However, a two sinker densimeter is required. PMID- 28867828 TI - The spectral invariant approximation within canopy radiative transfer to support the use of the EPIC/DSCOVR oxygen B-band for monitoring vegetation. AB - EPIC (Earth Polychromatic Imaging Camera) is a 10-channel spectroradiometer onboard DSCOVR (Deep Space Climate Observatory) spacecraft. In addition to the near-infrared (NIR, 780 nm) and the 'red' (680 nm) channels, EPIC also has the O2 A-band (764+/-0.2 nm) and B-band (687.75+/-0.2 nm). The EPIC Normalized Difference Vegetation Index (NDVI) is defined as the difference between NIR and 'red' channels normalized to their sum. However, the use of the O2 B-band instead of the 'red' channel mitigates the effect of atmosphere on remote sensing of surface reflectance because O2 reduces contribution from the radiation scattered by the atmosphere. Applying the radiative transfer theory and the spectral invariant approximation to EPIC observations, the paper provides supportive arguments for using the O2 band instead of the red channel for monitoring vegetation dynamics. Our results suggest that the use of the O2 B-band enhances the sensitivity of the top-of-atmosphere NDVI to the presence of vegetation. PMID- 28867830 TI - Effects of mine strata thermal behavior and mine initial temperatures on mobile refuge alternative temperature. AB - Federal regulations require the installation of refuge alternatives (RAs) in underground coal mines. Mobile RAs have a limited ability to dissipate heat, and heat buildup can lead to a life-threatening condition as the RA internal air temperature and relative humidity increase. The U.S. National Institute for Occupational Safety and Health (NIOSH) performed heat testing on a 10-person tent type training RA and contracted ThermoAnalytics Inc. to develop a validated thermal simulation model of the tested RA. The model was used to examine the effects of the constant mine strata temperature assumption, initial mine air temperature, initial mine strata surface temperature (MSST), initial mine strata temperature at depth (MSTD) and mine strata thermal behavior on RA internal air temperature using 117 W (400 Btu/h) of sensible heat input per simulated miner. For the studied RA, when the mine strata temperature was treated as a constant, the final predicted RA internal air temperature was 7.1 degrees C (12.8 degrees F) lower than it was when the mine strata thermal behavior was included in the model. A 5.6 degrees C (10.0 degrees F) increase in the initial MSST resulted in a 3.9 degrees C (7.1 degrees F) increase in the final RA internal air temperature, whereas a 5.6 degrees C (10 degrees F) increase in the initial MSTD yielded a 1.4 degrees C (2.5 degrees F) increase in the final RA internal air temperature. The results indicate that mine strata temperature increases and mine strata initial temperatures must be accounted for in the physical testing or thermal simulations of RAs. PMID- 28867829 TI - pH-Responsive Schizophrenic Diblock Copolymers Prepared by Polymerization-Induced Self-Assembly. AB - Polymerization-induced self-assembly (PISA) is used for the highly convenient and efficient preparation of ampholytic diblock copolymer nanoparticles directly in acidic aqueous solution. Cationic nanoparticles comprising a protonated polyamine stabilizer block and a hydrophobic polyacid core-forming block are formed at pH 2. Micelle inversion occurs at pH 10 to produce anionic nanoparticles with an ionized polyacid stabilizer block and a hydrophobic polyamine core-forming block. Macroscopic precipitation occurs at around pH 6-7, which lies close to the isoelectric point of this ampholytic diblock copolymer. Incorporation of fluorescein and rhodamine dye labels into the acid and amine blocks, respectively, leads to dual-color bifluorescent self-reporting pH-responsive nanoparticles. PMID- 28867831 TI - Quick fixes to improve workers' health: Results using engineering assessment technology. AB - Personal respirable dust sampling and the evaluation of control technologies have been providing exposure information to the mining industry but not necessarily in a way that shows how technology can be integrated to provide organizational support and resources for workers to mitigate dust sources on site. In response, the U.S. National Institute for Occupational Safety and Health (NIOSH) used previously developed Helmet-CAM technology to design and engage in a behavioral/engineering cooperative intervention to initiate and enhance mine site conversations about the risks and potential occurrences of respirable silica dust exposures on the job as well as provide impetus and solutions for mitigating higher sources of dust. The study involved 48 workers from five mine sites, who agreed to participate between April 2015 and September 2016. Using the Helmet-CAM in this series of longitudinal interventions revealed several exposure trends in respirable silica dust sources and, in many cases, simple quick-fix strategies to reduce their sources. This paper focuses on several specific identified sources of dust that were elevated but could be reduced through basic engineering fixes, low-cost resources, and supportive communication from management to remind and engage workers in protective work practices. PMID- 28867832 TI - Elderly and technology tools: a fuzzyset qualitative comparative analysis. AB - The number of senior citizens is growing globally and governments are striving to find innovative solutions to deal with complex care demands of this part of the population. Technology has been an answer to this situation; however, it is very important that the elderly accept and actually use the technology. This paper empirically tests the senior technology acceptance model using the fsQCA method to analyse data with a sample of 811 seniors aged 60 and over living in Sweden. The results revealed that the necessary conditions for high "perceived ease of use" and "perceived usefulness" are gerontechnology self-efficacy, gerontechnology anxiety, and cognitive abilities; however, each of these is not sufficient on its own. Self-reported health conditions and physical function also play a peripheral role in achieving the desired outcome. Theoretical and managerial implications are discussed at the end of the paper. PMID- 28867833 TI - A recommendation for applied researchers to substantiate the claim that ordinal variables are the product of underlying bivariate normal distributions. AB - A simulation study was carried out to study the behaviour of the polychoric correlation coefficient in data not compliant with the assumption of underlying continuous variables. Such data can produce relatively high estimated polychoric correlations (in the order of .62). Applied researchers are prone to accept these artefacts as input for elaborate modelling (e.g., structural equation models) and inferences about reality justified by sheer magnitude of the correlations. In order to prevent this questionable research practice, it is recommended that in applications of the polychoric correlation coefficient, data is tested with goodness-of-fit of the BND, that such statistic is reported in published applications, and that the polychoric correlation is not applied when the test is significant. PMID- 28867834 TI - Estimation of leaf area index and its sunlit portion from DSCOVR EPIC data: Theoretical basis. AB - This paper presents the theoretical basis of the algorithm designed for the generation of leaf area index and diurnal course of its sunlit portion from NASA's Earth Polychromatic Imaging Camera (EPIC) onboard NOAA's Deep Space Climate Observatory (DSCOVR). The Look-up-Table (LUT) approach implemented in the MODIS operational LAI/FPAR algorithm is adopted. The LUT, which is the heart of the approach, has been significantly modified. First, its parameterization incorporates the canopy hot spot phenomenon and recent advances in the theory of canopy spectral invariants. This allows more accurate decoupling of the structural and radiometric components of the measured Bidirectional Reflectance Factor (BRF), improves scaling properties of the LUT and consequently simplifies adjustments of the algorithm for data spatial resolution and spectral band compositions. Second, the stochastic radiative transfer equations are used to generate the LUT for all biome types. The equations naturally account for radiative effects of the three-dimensional canopy structure on the BRF and allow for an accurate discrimination between sunlit and shaded leaf areas. Third, the LUT entries are measurable, i.e., they can be independently derived from both below canopy measurements of the transmitted and above canopy measurements of reflected radiation fields. This feature makes possible direct validation of the LUT, facilitates identification of its deficiencies and development of refinements. Analyses of field data on canopy structure and leaf optics collected at 18 sites in the Hyytiala forest in southern boreal zone in Finland and hyperspectral images acquired by the EO-1 Hyperion sensor support the theoretical basis. PMID- 28867835 TI - Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via a Catalytic Enantioselective Allylic Alkylation Strategy. AB - Rapid access to enantioenriched spirocycles possessing a 1,4-dicarbonyl moiety spanning an all-carbon quaternary stereogenic spirocenter was achieved using a masked bromomethyl vinyl ketone reagent. The developed protocol entails an enantioselective palladium-catalyzed allylic alkylation reaction followed by a one-pot unmasking/RCM sequence that provides access to the spirocyclic compounds in good yields and selectivities. PMID- 28867837 TI - Syphilis screening and treatment: integration with HIV services. PMID- 28867838 TI - Addressing vulnerability of pregnant refugees. PMID- 28867839 TI - Public health round-up. PMID- 28867841 TI - Promoting evidence-based health care in Africa. AB - Countries with major public health challenges do not always base their health care decisions on the best available scientific evidence. Charles Shey Wiysonge tells Fiona Fleck how he and his colleagues are trying to change that. PMID- 28867840 TI - Providing family planning services to women in Africa. AB - Access to contraceptives in Africa has not increased at the same pace as elsewhere in the world. Some African nations are investing in family planning services to reduce fertility rates, improve economic development and their population's health. Tatum Anderson reports. PMID- 28867842 TI - Pneumococcal conjugate vaccines and hospitalization of children for pneumonia: a time-series analysis, South Africa, 2006-2014. AB - OBJECTIVE: To assess the impact of immunization with pneumococcal conjugate vaccines on all-cause pneumonia hospitalizations among children in Soweto, South Africa. METHODS: We used data collected at the Chris Hani Baragwanath Hospital in Soweto between 2006 and 2014 - i.e. before and after April 2009, when a pneumococcal conjugate vaccine was first included in South Africa's routine immunization programme. Using a Bayesian generalized seasonal autoregressive moving-average model and the data collected in 2006-2008, we estimated the numbers of children that would have been hospitalized for pneumonia between 2010 and 2014 if no pneumococcal conjugate vaccines had been used. These estimates were then compared with the corresponding numbers of hospitalizations observed. FINDINGS: Between 2006 and 2014, 26 778 children younger than five years - including 3388 known to be infected with human immunodeficiency virus (HIV) - were admitted to the study hospital for pneumonia. We estimated that, for the children known to be infected with HIV and for the other children, pneumococcal conjugate vaccines reduced the numbers of hospitalizations for pneumonia in 2014 by 33% (50% credible interval, CrI: 6 to 52) and 39% (50% CrI: 24 to 50), respectively. In the study hospital in 2012-2014, as a result of immunizations with these vaccines, there were an estimated 3100 fewer pneumonia hospitalizations of children younger than five years. CONCLUSION: In our study hospital, following the introduction of pneumococcal conjugate vaccines into the national immunization programme, there were significant reductions in pneumonia hospitalizations among children. PMID- 28867844 TI - A guide to aid the selection of diagnostic tests. AB - In recent years, a wide range of diagnostic tests has become available for use in resource-constrained settings. Accordingly, a huge number of guidelines, performance evaluations and implementation reports have been produced. However, this wealth of information is unstructured and of uneven quality, which has made it difficult for end-users, such as clinics, laboratories and health ministries, to determine which test would be best for improving clinical care and patient outcomes in a specific context. This paper outlines a six-step guide to the selection and implementation of in vitro diagnostic tests based on Medecins Sans Frontieres' practical experience: (i) define the test's purpose; (ii) review the market; (iii) ascertain regulatory approval; (iv) determine the test's diagnostic accuracy under ideal conditions; (v) determine the test's diagnostic accuracy in clinical practice; and (vi) monitor the test's performance in routine use. Gaps in the information needed to complete these six steps and gaps in regulatory systems are highlighted. Finally, ways of improving the quality of diagnostic tests are suggested, such as establishing a model list of essential diagnostics, establishing a repository of information on the design of diagnostic studies and improving quality control and postmarketing surveillance. PMID- 28867843 TI - Estimated economic impact of vaccinations in 73 low- and middle-income countries, 2001-2020. AB - OBJECTIVE: To estimate the economic impact likely to be achieved by efforts to vaccinate against 10 vaccine-preventable diseases between 2001 and 2020 in 73 low and middle-income countries largely supported by Gavi, the Vaccine Alliance. METHODS: We used health impact models to estimate the economic impact of achieving forecasted coverages for vaccination against Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae and yellow fever. In comparison with no vaccination, we modelled the costs - expressed in 2010 United States dollars (US$) - of averted treatment, transportation costs, productivity losses of caregivers and productivity losses due to disability and death. We used the value-of-a-life-year method to estimate the broader economic and social value of living longer, in better health, as a result of immunization. FINDINGS: We estimated that, in the 73 countries, vaccinations given between 2001 and 2020 will avert over 20 million deaths and save US$ 350 billion in cost of illness. The deaths and disability prevented by vaccinations given during the two decades will result in estimated lifelong productivity gains totalling US$ 330 billion and US$ 9 billion, respectively. Over the lifetimes of the vaccinated cohorts, the same vaccinations will save an estimated US$ 5 billion in treatment costs. The broader economic and social value of these vaccinations is estimated at US$ 820 billion. CONCLUSION: By preventing significant costs and potentially increasing economic productivity among some of the world's poorest countries, the impact of immunization goes well beyond health. PMID- 28867845 TI - A data platform to improve rabies prevention, Sri Lanka. AB - PROBLEM: In Sri Lanka, rabies prevention initiatives are hindered by fragmented and delayed information-sharing that limits clinicians' ability to follow patients and impedes public health surveillance. APPROACH: In a project led by the health ministry, we adapted existing technologies to create an electronic platform for rabies surveillance. Information is entered by trained clinical staff, and both aggregate and individual patient data are visualized in real time. An automated short message system (SMS) alerts patients for vaccination follow-up appointments and informs public health inspectors about incidents of animal bites. LOCAL SETTING: The platform was rolled out in June 2016 in four districts of Sri Lanka, linking six rabies clinics, three laboratories and the public health inspectorate. RELEVANT CHANGES: Over a 9-month period, 12 121 animal bites were reported to clinics and entered in the registry. Via secure portals, clinicians and public health teams accessed live information on treatment and outcomes of patients started on post-exposure prophylaxis (9507) or receiving deferred treatment (2614). Laboratories rapidly communicated the results of rabies virus tests on dead mammals (328/907 positive). In two pilot districts SMS reminders were sent to 1376 (71.2%) of 1933 patients whose contact details were available. Daily SMS reports alerted 17 public health inspectors to bite incidents in their area for investigation. LESSONS LEARNT: Existing technologies in low-resource countries can be harnessed to improve public health surveillance. Investment is needed in platform development and training and support for front-line staff. Greater public engagement is needed to improve completeness of surveillance and treatment. PMID- 28867846 TI - Integrated morbidity management for lymphatic filariasis and podoconiosis, Ethiopia. AB - PROBLEM: Lymphatic filariasis and podoconiosis are the major causes of tropical lymphoedema in Ethiopia. The diseases require a similar provision of care, but until recently the Ethiopian health system did not integrate the morbidity management. APPROACH: To establish health-care services for integrated lymphoedema morbidity management, the health ministry and partners used existing governmental structures. Integrated disease mapping was done in 659 out of the 817 districts, to identify endemic districts. To inform resource allocation, trained health extension workers carried out integrated disease burden assessments in 56 districts with a high clinical burden. To ensure standard provision of care, the health ministry developed an integrated lymphatic filariasis and podoconiosis morbidity management guideline, containing a treatment algorithm and a defined package of care. Experienced professionals on lymphoedema management trained government-employed health workers on integrated morbidity management. To monitor the integration, an indicator on the number of lymphoedema-treated patients was included in the national health management information system. LOCAL SETTING: In 2014, only 24% (87) of the 363 health facilities surveyed provided lymphatic filariasis services, while 12% (44) provided podoconiosis services. RELEVANT CHANGES: To date, 542 health workers from 53 health centres in 24 districts have been trained on integrated morbidity management. Between July 2013 and June 2016, the national health management information system has recorded 46 487 treated patients from 189 districts. LESSONS LEARNT: In Ethiopia, an integrated approach for lymphatic filariasis and podoconiosis morbidity management was feasible. The processes used could be applicable in other settings where these diseases are co-endemic. PMID- 28867848 TI - Regulating the stem cell industry: needs and responsibilities. PMID- 28867847 TI - Monetary incentives for provision of syphilis screening, Yunnan, China. AB - PROBLEM: Early detection of syphilis-infected people followed by effective treatment is essential for syphilis prevention and control. APPROACH: Starting in 2010 the local health authority in Yunnan province, China, developed a network of 670 service sites for syphilis testing, diagnosis and treatment or for testing only with referral for further diagnosis and treatment. Point-of-care tests for syphilis and syphilis interventions were integrated into the existing human immunodeficiency virus (HIV) prevention and control programme. To improve the syphilis services, a pay-for-performance scheme was introduced in which providers were paid for testing and treating patients. LOCAL SETTING: Yunnan province is the region hardest hit by HIV infection and disproportionately burdened with syphilis cases in China. RELEVANT CHANGES: The proportion of attendees at voluntary counselling and testing clinics who were tested for syphilis increased from 46.2% (32 877/71 162) in 2010 to 98.2% (68 012/69 259) in 2015. Syphilis infected cases treated with the recommended therapy increased from 26.6% (264/993) in 2010 to 82.5% (453/549) in 2015 at designated testing, diagnosis and treatment sites. LESSONS LEARNT: The strategy greatly increased the uptake of syphilis testing and treatment among people at risk. Introduction of point-of care tests for syphilis increased coverage of the testing services. Introduction of a pay-for-performance scheme seemed to motivate health-care providers to undertake syphilis intervention services. PMID- 28867849 TI - Heavy Metal Uptake by Herbs. V. Metal Accumulation and Physiological Effects Induced by Thiuram in Ocimum basilicum L. AB - Basil (Ocimum basilicum L.) is extensively cultivated as either an important spice and food additive or a source of essential oil crucial for the production of natural phenylpropanoids and terpenoids. It is frequently attacked by fungal diseases. The aim of the study was to estimate the impact of thiuram contact time on the uptake of manganese, cobalt, nickel, copper, zinc, cadmium, and lead by Ocimum basilicum L. The relevant plant physiological parameters were also investigated. Two farmland soils typical for the Polish rural environment were used. Studies involved soil analyses, bioavailable, and total forms for all investigated metals, chlorophyll content, and gas exchange. Atomic absorption spectrometry was used to determine concentration of all elements. Analysis of variance proved hypothesis that thiuram treatment of basil significantly influences metal transfer from soil and their concentration in roots and aboveground parts. This effect is mostly visible on the 14th day after the fungicide administration. Thiuram modifies mycoflora in the rhizosphere zone and subsequently affects either metal uptake from the soil environment or their further migration within the basil plant. Notable, those changes are more evident for basil planted in mineral soil as compared to organic soil with higher buffering capacity. PMID- 28867850 TI - Audiovisual perceptual learning with multiple speakers. AB - One challenge for speech perception is between-speaker variability in the acoustic parameters of speech. For example, the same phoneme (e.g. the vowel in "cat") may have substantially different acoustic properties when produced by two different speakers and yet the listener must be able to interpret these disparate stimuli as equivalent. Perceptual tuning, the use of contextual information to adjust phonemic representations, may be one mechanism that helps listeners overcome obstacles they face due to this variability during speech perception. Here we test whether visual contextual cues to speaker identity may facilitate the formation and maintenance of distributional representations for individual speakers, allowing listeners to adjust phoneme boundaries in a speaker-specific manner. We familiarized participants to an audiovisual continuum between /aba/ and /ada/. During familiarization, the "b-face" mouthed /aba/ when an ambiguous token was played, while the "D-face" mouthed /ada/. At test, the same ambiguous token was more likely to be identified as /aba/ when paired with a stilled image of the "b-face" than with an image of the "D-face." This was not the case in the control condition when the two faces were paired equally with the ambiguous token. Together, these results suggest that listeners may form speaker-specific phonemic representations using facial identity cues. PMID- 28867851 TI - Linking pesticides and human health: a geographic information system (GIS) and Landsat remote sensing method to estimate agricultural pesticide exposure. AB - Accurate pesticide exposure estimation is integral to epidemiologic studies elucidating the role of pesticides in human health. Humans can be exposed to pesticides via residential proximity to agricultural pesticide applications (drift). We present an improved geographic information system (GIS) and remote sensing method, the Landsat method, to estimate agricultural pesticide exposure through matching pesticide applications to crops classified from temporally concurrent Landsat satellite remote sensing images in California. The image classification method utilizes Normalized Difference Vegetation Index (NDVI) values in a combined maximum likelihood classification and per-field (using segments) approach. Pesticide exposure is estimated according to pesticide treated crop fields intersecting 500 m buffers around geocoded locations (e.g., residences) in a GIS. Study results demonstrate that the Landsat method can improve GIS-based pesticide exposure estimation by matching more pesticide applications to crops (especially temporary crops) classified using temporally concurrent Landsat images compared to the standard method that relies on infrequently updated land use survey (LUS) crop data. The Landsat method can be used in epidemiologic studies to reconstruct past individual-level exposure to specific pesticides according to where individuals are located. PMID- 28867852 TI - Risk and Emotion Among Healthy Volunteers in Clinical Trials. AB - Theorized as objective or constructed, risk is recognized as unequally distributed across social hierarchies. Yet the process by which social forces shape risk and risk emotions remains unknown. The pharmaceutical industry depends on healthy individuals to voluntarily test early-stage, investigational drugs in exchange for financial compensation. Emblematic of risk in late modernity, Phase I testing is a rich site for examining how class and race shape configurations of emotion and risk. Using interview data from 178 healthy trial participants, this article examines emotion and risk as mutually constituting processes linked to biographical context and social structure. Biographical events like economic insecurity and incarceration influence how risk is felt by providing comparative experiences of felt risk and felt benefits. Such events, in turn, are structured by class-based and racial inequalities, linking class and race positions to primary emotional experiences of risk. PMID- 28867854 TI - Predatory Conferences in the Field of Ayurveda and Alternative Medicine: Need for Quality Checks. PMID- 28867855 TI - An Open Label, Randomized, Comparative, Parallel Group, Multicenter, Prospective, Interventional, Clinical Study to Evaluate Efficacy and Safety of "AHPL/AYTOP/0113" in Comparison with "Framycetin Sulphate Cream" in Acute Wounds. AB - OBJECTIVES: The main objective of the present study was to assess efficacy and safety of AHPL/AYTOP/0113 cream, a polyherbal formulation in comparison with Framycetin sulphate cream in acute wounds. METHODOLOGY: It was an open label, randomized, comparative, parallel group and multi-center clinical study. Total 47 subjects were randomly assigned to Group-A (AHPL/AYTOP/0113 cream) and 42 subjects were randomly assigned to Group-B (Framycetin sulphate cream). All the subjects were advised to apply study drug, thrice daily for 21 days or up to complete wound healing (whichever was earlier). All the subjects were called for follow up on days 2, 4, 7, 10, 14, 17 and 21 or up to the day of complete wound healing. Data describing quantitative measures are expressed as mean +/- SD. Comparison of variables representing categorical data was performed using Chi square test. RESULTS: Group-A subjects took significantly less (P < 0.05) i.e., (mean) 7.77 days than (mean) 9.87 days of Group-B subjects for wound healing. At the end of the study, statistically significant better (P < 0.05) results were observed in Group-A than Group-B in mean wound surface area, wound healing parameters and pain associated with wound. Excellent overall efficacy and tolerability was observed in subjects of both the groups. No adverse event or adverse drug reaction was noted in any subject of both the groups. CONCLUSION: AHPL/AYTOP/0113 cream proved to be superior to Framycetin sulphate cream in healing of acute wounds. PMID- 28867853 TI - Are rash impulsive and reward sensitive traits distinguishable? A test in young adults. AB - Adolescents and young adults are characterized as prone to risky behavior with a wide range of traits identified as predictors of individual differences in this behavior. Here we test a crucial difference between traits that reflect rash impulsivity, the tendency to engage in risky behavior without consideration of consequences, versus reward sensitivity, the tendency to be attracted to novel and rewarding experience. To test the validity of this distinction, we examined the factorial structure of eight risk-related traits in a sample of 899 18 to 22 year-olds. We predicted that rash impulsive traits would be separable in structure from reward sensitive traits and would uniquely predict relatively maladaptive risk-taking (e.g., drug use). In addition, we predicted that reward sensitive traits would be related to both adaptive (e.g., entering competitions) and maladaptive risk behaviors. Results revealed a factorial structure that distinguished these traits, with rash impulsive and reward sensitive traits uniquely predictive of different forms of risk-taking. The results suggest that it is possible to distinguish traits that reflect these two forms of risk-taking with implications for the measurement and interpretation of risk propensities in youth. PMID- 28867856 TI - Physicochemical Screening and Shelf Life Evaluation of Kunkumadi Ghrta Prepared using Kesara and Nagakesara. AB - INTRODUCTION: Kunkumadi Ghrta (KG) is an Ayurvedic formulation commonly recommended in skin disorders, especially Mukhadusika (Acne vulgaris). Kesara (stigma of Crocus sativus Linn.) is a prime ingredient in the formulation. However, due to high cost and increased adulteration in Kesara, 'Nagakesara' (Mesua ferrea Linn.) is suggested by Ayurvedic experts as a substitute. Nagakesara is relatively lower in cost and possesses similar therapeutic attributes to that of Kesara. Recent studies have established standard manufacturing procedures and clinical efficacies of Kesarayukta (with Kesara) Kunkumadi Ghrta (KKG) and Nagakesara yukta (with Nagakesara) Kunkumadi Ghrta (NKG) in Mukhadusika. In spite of wide utility of KG in Ayurvedic practice, no published work on its shelf life is available so far. AIMS AND OBJECTIVES: To establish the physicochemical profile and evaluate the shelf life of KKG and NKG. MATERIALS AND METHODS: Total three batches of KKG and NKG each were prepared in the laboratory by adopting Ayurvedic classical guidelines and the findings were systematically recorded. Comparative differences in organoleptic characters (colour, odour, taste, touch) and values of different physicochemical parameters (Ash value, pH value, Total solid content, Specific gravity, Refractive index, Loss on drying, Acid value, Iodine value, Saponification value, Peroxide value and Rancidity tests) of raw materials [herbal ingredients, Go Ghrta, Murcchita Ghrta (MG)] as well as finished products (KKG and NKG) were recorded. Long term (real time) shelf life testing was carried out at the intervals i.e., at 0, 3, 6, 9 and 16 months. High performance thin layer chromatography (HPTLC) analysis of samples was also carried out. RESULTS AND CONCLUSION: The average percentage loss in final product was 10.18% in KKG and 7.58% in NKG. The shelf life of MG, KKG and NKG is 16 months. After 16 months, Go Ghrta showed negative rancidity test, while MG, KKG and NKG showed positive rancidity, indicative of onset of deterioration after 16 months. Present findings validate the Ayurvedic principles stipulating medicated Ghrta to have a shelf life of 16 months. Chromatographic study showed few differences between KKG and NKG samples. Data obtained by present study may be considered as standard for future researches. PMID- 28867858 TI - Evaluation of Cyavanaprasa on Health and Immunity related Parameters in Healthy Children: A Two Arm, Randomized, Open Labeled, Prospective, Multicenter, Clinical Study. AB - CONTEXT: Cyavanaprasa (CP) is an Ayurvedic immune booster formulation that confers vigor and vitality while delaying the ageing process. Benefits of CP have been studied widely in adult population. OBJECTIVES: Current study assessed beneficial effects of CP on health and immunity related parameters in healthy children. METHODS: This study was a 6 month long two armed, randomized, open labeled, prospective clinical study. School going healthy children between ages of 5-12 years were randomized to receive orally daily either CP (approx. 6 g) followed by a cup of milk (100 - 200 ml) or cup of milk only twice a day while continuing with their normal/routine diet. Results were analyzed based on number of episodes, severity, duration of illness (infections and allergies) and number of absent days due to illness during the study duration and changes in levels of energy, physical fitness, strength, stamina and quality of life in children which were recorded in subject diary by their parents/Legally Acceptable Representative (LAR). RESULTS: 702 participants were randomized, out of which 627 completed the study (CP n = 313; Control n = 314). Results of immunity (episodes of infections or allergy related conditions) showed more than 2 times protection from immunity related illness in CP Group as compared to the control. CP also showed better percentage improvement in energy levels, physical fitness, strength, stamina and quality of life assessed through KIDSCREEN QOL-27 questionnaires in children. CONCLUSION: Regular consumption of CP for a period of six months could significantly improve immunity, energy levels, physical fitness, strength, stamina and quality of life in school going healthy children. STUDY REGISTRATION: Clinical Trail Registry of India vide CTRI/2015/02/005574, Dated 24 February 2015. PMID- 28867857 TI - Ethnopharmacological based Evaluation of Anogeissus pendula Edgew Extracts for Antioxidant and Hepatoprotective Potential. AB - BACKGROUND: Anogeissus pendula has various reported ethnomedicinal uses and is reported to contain phenolic compounds which have antioxidant potential. AIM: The present study was undertaken to evaluate the in vitro antioxidant potential and in vivo hepatoprotective activity along with the oxidative stress parameters of stem bark and leaves of Anogeissus pendula for the first time. SETTINGS AND DESIGN: Albino rats were divided into seven groups of six animals each. Healthy control (Group I) and toxic control (Group II) received the vehicle. Group III, IV, V, VI and VII were treated with silymarin (100 mg/kg body weight, orally) and two hydro-alcoholic extracts i.e., APB (stem bark) and APL (leaves) at doses of 200 and 400 mg/kg b. w., orally, respectively. Hepatotoxicity was induced by allyl alcohol. MATERIALS AND METHODS: Albino Wistar rats of either sex between 8 12 weeks old were used. The plant parts were collected from Sawai Madhopur (Rajasthan, India) and extracted with hydro-alcoholic solvent to get two extracts i.e., APB (stem bark) and APL (leaves) which were investigated for the in vitro antioxidant potential through DPPH radical and H2O2 scavenging assay along with in vivo hepatoprotective potential through allyl alcohol induced hepatotoxicity. STATISTICAL ANALYSIS: Statistical comparisons between different groups were done by using one-way ANOVA followed by the Bonferroni test. P < 0.05 was considered significant. RESULTS AND CONCLUSIONS: APB showed more potent activity than APL in case of in vitro antioxidant potential with IC50 of 44.29 MUg/ml in DPPH radical scavenging activity and 53.09 MUg/ml in hydrogen peroxide scavenging assay. Both the extracts revealed antioxidant and hepatoprotective potentials in a dose dependent manner but more significant results were obtained in case of APB at 400 mg/kg. More amounts of phytoconstituents might be the reason behind the more significant activity of extract of stem bark than that of the leaves. PMID- 28867859 TI - Pharmacognostical and Phytochemical Studies of Helleborus niger L Root. AB - BACKGROUND: Helleborus niger L (Ranunculaceae) is used Ayurvedic and Unani systems and other herbal medicine systems. The roots of H. niger have a good medicinal value. AIMS: To conduct a pharmacognostical and phytochemical study of H. niger. MATERIALS AND METHODS: The pharmacognostical studies on roots including parameters such as taxonomical, macroscopic, microscopic characters, physico chemical, ultra-violet analysis and phytochemical studies are established. RESULTS: Macroscopically, the roots are brownish-black in colour, cylindrical in shape, feeble odour, slightly acrid taste with irregularly branched. Microscopically the root showed the presence of epidermis, air-chambers, fissure periderm, periderm, inner cortex, pith, phloem, xylem, vessels and xylem vessels. Microscopic examination of the powder showed the presence of parenchyma cells, parenchyma mass, periderm, cell inclusion, laticifer, lateral wall pith, perforation, xylem bundle and xylem elements. Ultra-violet and ordinary light analyses with different reagents were conducted to identify the drug in powder form. Physico-chemical evaluation established, Ash values - Total, acid insoluble, water soluble and sulphated ash values were 7.3%, 4.1%, 3.7% and 5.2%, respectively. Extractive values - Alcohol soluble, water soluble and ether soluble extractive values were 22.8%, 7.4% and 5.6%, respectively. Loss on drying was 3.3%. Preliminary phytochemical screening showed the presence of carbohydrate, glycoside, saponins, flavonoid, phytosterols, tannins and phenolic compounds. CONCLUSIONS: The results of the study can serve as a valuable resource of pharmacognostic and phytochemical information. This will serve as appropriate, standards for discovery of this plant material in future investigations and applications and also contribute towards establishing pharmacopoeial standards. PMID- 28867861 TI - Effect of Integrative Naturopathy and Yoga in a Patient with Rheumatoid Arthritis Associated with Type 2 Diabetes and Hypertension. AB - A 54-year old married woman was diagnosed with rheumatoid arthritis in 2002, essential hypertension in 2008, type-2 diabetes in 2011 and gangrene over 2nd toe of right foot. She underwent conventional management in private hospitals. Her symptoms, began with moderate to severe pain associated with swelling, stiffness (more in the morning) in multiple joints especially over small joints. In July 2014 she visited our college hospital with the complaints of pain, mild swelling and stiffness over multiple joints associated with poor quality of sleep (QOS) and quality of life (QOL). Subject received integrative Naturopathy and Yoga therapies (INYT) with conventional medicine daily for 10-days. After 10-days, improvements in pain, blood sugar, depression, anxiety, stress, QOS, QOL, blood analysis with normal blood pressure (BP) was observed. This suggests that INYT could be considered as an adjuvant to conventional medicine in RA associated with type-2 diabetes and essential hypertension. PMID- 28867860 TI - Ayurvedic Management of Recurrent Abortions due to Uterine Fibroid. AB - Uterine fibroids are present in 30-70% of women of reproductive age. Uterine fibroids distort the uterine cavity. Therefore there is consensus of a negative impact on both the clinical pregnancy and delivery rates.[2] In addition, studies have also reported an increased risk of spontaneous miscarriage with submucosal fibroids. In biomedicine, myomectomy is considered the treatment of choice and Assisted Reproductive Technology is advised to overcome infertility. In Harita Samhita treatment is given for recurrent abortion (Garbhasravi). In this study, considering pitta dosa and altered uterine receptivity (ksetra dusti) as causative factors, purgation (virecana karma) was done, enema (yoga basti) was given after post purgation protocol (samsarjana karma). After body purification (sodhana), garbhasthapaka drugs were given to the patient for one month. Patient conceived in the second month with this treatment. In Antenatal Care, haematinics and calcium supplements and month wise Ayurvedic medication (Masanumasika kasaya) were given for nine months. Elective caesarean section as done after GA 38 weeks (USG) followed by inj. Wymesone 8 mg. The procedure uneventful. Thus proving Ayurvedic management of recurrent abortion due to uterine fibroid. It is cost effective and improves and normalises uterine receptive environment. PMID- 28867862 TI - Good Pharmacovigilance Practice: Accountability of Ayurvedic Pharmaceutical Companies. PMID- 28867863 TI - Does stimulating various coping strategies alleviate loneliness? Results from an online friendship enrichment program. AB - Loneliness stems from a mismatch between the social relationships one has and those one desires. Loneliness often has severe consequences for individuals and society. Recently, an online adaptation of the friendship enrichment program (FEP) was developed and tested to gain insight in its contribution to the alleviation of loneliness. Three loneliness coping strategies are introduced during the program: network development, adapting relationship standards, and reducing the importance of the discrepancy between actual and desired relationships. Data were collected among 239 participants aged 50-86. Loneliness was measured four times using a multi-item scale, and on various days with a single, direct question. Loneliness assessed with the scale declined during and after the program. Scores on loneliness assessed for a specific day, however, are more ambiguous. Despite the immediate positive effect of conducting assignments, we did not observe a decline in the single loneliness item score over the course of the program. The online FEP seems to reduce loneliness in general, but these effects are not visible on today's loneliness. Nevertheless, the online intervention to reduce loneliness is a valuable new contribution to the collection of loneliness interventions. PMID- 28867864 TI - Stability of Lactobacillus rhamnosus GG incorporated in edible films: Impact of anionic biopolymers and whey protein concentrate. AB - The incorporation of probiotics and bioactive compounds, via plasticised thin layered hydrocolloids, within food products has recently shown potential to functionalise and improve the health credentials of processed food. In this study, choice of polymer and the inclusion of whey protein isolate was evaluated for their ability to stabalise live probiotic organisms. Edible films based on low (LSA) and high (HSA) viscosity sodium alginate, low esterified amidated pectin (PEC), kappa-carrageenan/locust bean gum (kappa-CAR/LBG) and gelatine (GEL) in the presence or absence of whey protein concentrate (WPC) were shown to be feasible carriers for the delivery of L. rhamnosus GG. Losses of L. rhamnosus GG throughout the drying process ranged from 0.87 to 3.06 log CFU/g for the systems without WPC, losses were significantly reduced to 0 to 1.17 log CFU/g in the presence of WPC. Storage stability (over 25d) of L. rhamnosus GG at both tested temperatures (4 and 25 degrees C), in descending order, was kappa-CAR/LBG > HSA > GEL > LSA = PEC. In addition, supplementation of film forming agents with WPC led to a 1.8- to 6.5-fold increase in shelf-life at 4 degrees C (calculated on the WHO/FAO minimum requirements of 6 logCFU/g), and 1.6-4.3-fold increase at 25 degrees C. Furthermore probiotic films based on HSA/WPC and kappa-CAR/LBG/WPC blends had both acceptable mechanical and barrier properties. PMID- 28867865 TI - Mowing exacerbates the loss of ecosystem stability under nitrogen enrichment in a temperate grassland. AB - 1. Global reactive nitrogen (N) is projected to further increase in the coming years. Previous studies have demonstrated that N enrichment weakens the temporal stability of the ecosystem and the primary productivity through decreased biodiversity and species asynchrony. Mowing is a globally common practise in grasslands; and infrequent mowing can maintain or increase plant diversity under N enrichment conditions. However, it is unclear how infrequent mowing affects ecosystem stability in the face of N enrichment. 2. By independently manipulating the frequency (twice vs. monthly additions per year) and rate (i.e. 0, 1, 2, 3, 5, 10, 15, 20, and 50 g N m-2 year-1) of NH4NO3 inputs and mowing (unmown vs. mown) over 3 years (2011-2013) in a temperate grassland of northern China, we aimed to examine the interactive effects of N enrichment and mowing on ecosystem stability. 3. The results show that mowing maintained a positive relationship between species richness and ecosystem stability despite N addition, but that it exacerbated the negative effects of N addition on ecosystem stability. Mowing increased mean primary productivity and plant species richness, but it also increased the synchrony of population fluctuations and the variability of primary productivity under N enrichment, thereby contributing to a decline in the ecosystem stability. 4. Thus, our study reveals that infrequent mowing can buffer the negative effects of N enrichment on biodiversity to some extent and further increase the primary productivity, but it exacerbates the loss of ecosystem stability with N enrichment, thereby threatening local and/or semiarid regional food security. PMID- 28867866 TI - Comparative investigation of stimulus-evoked rod outer segment movement and retinal electrophysiological activity. AB - Transient retinal phototropism (TRP) has been observed in rod photoreceptors activated by oblique visible light flashes. Time-lapse confocal microscopy and optical coherence tomography (OCT) revealed rod outer segment (ROS) movements as the physical source of TRP. However, the physiological source of TRP is still not well understood. In this study, concurrent TRP and electroretinogram (ERG) measurements disclosed a remarkably earlier onset time of the ROS movements (<=10 ms) than that (~38 ms) of the ERG a-wave. Furthermore, low sodium treatment reversibly blocked the photoreceptor ERG a-wave, which is known to reflect hyperpolarization of retinal photoreceptors, but preserved the TRP associated rod OS movements well. Our experimental results and theoretical analysis suggested that the physiological source of TRP might be attributed to early stages of phototransduction, before the hyperpolarization of retinal photoreceptors. PMID- 28867868 TI - Inter-comparison of Low-cost Sensors for Measuring the Mass Concentration of Occupational Aerosols. AB - Low-cost sensors are effective for measuring the mass concentration of ambient aerosols and secondhand smoke in homes, but their use at concentrations relevant to occupational settings has not been demonstrated. We measured the concentrations of four aerosols (salt, Arizona road dust, welding fume, and diesel exhaust) with three types of low-cost sensors (a DC1700 from Dylos and two commodity sensors from Sharp), an aerosol photometer, and reference instruments at concentrations up to 6500 MUg/m3. Raw output was used to assess sensor precision and develop equations to compute mass concentrations. EPA and NIOSH protocols were used to assess the mass concentrations estimated with low-cost sensors compared to reference instruments. The detection efficiency of the DC1700 ranged from 0.04% at 0.1 MUm to 108% at 5 MUm, as expected, although misclassification of fine and coarse particles was observed. The raw output of the DC1700 had higher precision (lower coefficient of variation, CV = 7.4%) than that of the two sharp devices (CV = 25% and 17%), a finding attributed to differences in manufacturer calibration. Aerosol type strongly influenced sensor response, indicating the need for on-site calibration to convert sensor output to mass concentration. Once calibrated, however, the mass concentration estimated with low-cost sensors was highly correlated with that of reference instruments (R2=0.99). These results suggest that the DC1700 and Sharp sensors are useful in estimating aerosol mass concentration for aerosols at concentrations relevant to the workplace. PMID- 28867867 TI - Computer-Assisted Adjuncts for Aneurysmal Morphologic Assessment: Toward More Precise and Accurate Approaches. AB - Neurosurgeons currently base most of their treatment decisions for intracranial aneurysms (IAs) on morphological measurements made manually from 2D angiographic images. These measurements tend to be inaccurate because 2D measurements cannot capture the complex geometry of IAs and because manual measurements are variable depending on the clinician's experience and opinion. Incorrect morphological measurements may lead to inappropriate treatment strategies. In order to improve the accuracy and consistency of morphological analysis of IAs, we have developed an image-based computational tool, AView. In this study, we quantified the accuracy of computer-assisted adjuncts of AView for aneurysmal morphologic assessment by performing measurement on spheres of known size and anatomical IA models. AView has an average morphological error of 0.56% in size and 2.1% in volume measurement. We also investigate the clinical utility of this tool on a retrospective clinical dataset and compare size and neck diameter measurement between 2D manual and 3D computer-assisted measurement. The average error was 22% and 30% in the manual measurement of size and aneurysm neck diameter, respectively. Inaccuracies due to manual measurements could therefore lead to wrong treatment decisions in 44% and inappropriate treatment strategies in 33% of the IAs. Furthermore, computer-assisted analysis of IAs improves the consistency in measurement among clinicians by 62% in size and 82% in neck diameter measurement. We conclude that AView dramatically improves accuracy for morphological analysis. These results illustrate the necessity of a computer assisted approach for the morphological analysis of IAs. PMID- 28867869 TI - Porous Polyurethane Foam for Use as a Particle Collection Substrate in a Nanoparticle Respiratory Deposition Sampler. AB - Porous polyurethane foam was evaluated to replace the eight nylon meshes used as a substrate to collect nanoparticles in the Nanoparticle Respiratory Deposition (NRD) sampler. Cylindrical (25-mm diameter by 40-mm deep) foam with 110 pores per inch was housed in a 25-mm-diameter conductive polypropylene cassette cowl compatible with the NRD sampler. Pristine foam and nylon meshes were evaluated for metals content via elemental analysis. The size-selective collection efficiency of the foam was evaluated using salt (NaCl) and metal fume aerosols in independent tests. Collection efficiencies were compared to the nanoparticulate matter (NPM) criterion and a semi-empirical model for foam. Changes in collection efficiency and pressure drop of the foam and nylon meshes were measured after loading with metal fume particles as measures of substrate performance. Substantially less titanium was found in the foam (0.173 MUg sampler-1) compared to the nylon mesh (125 MUg sampler-1), improving the detection capabilities of the NRD sampler for titanium dioxide particles. The foam collection efficiency was similar to that of the nylon meshes and the NPM criterion (R2 = 0.98, for NaCl), although the semi-empirical model underestimated the experimental efficiency (R2 = 0.38). The pressure drop across the foam was 8% that of the nylon meshes when pristine and changed minimally with metal fume loading (~ 19 mg). In contrast, the pores of the nylon meshes clogged after loading with ~ 1 mg metal fume. These results indicate that foam is a suitable substrate to collect metal (except for cadmium) nanoparticles in the NRD sampler. PMID- 28867870 TI - Effect of an edge at cup rim on contact stress during micro-separation in ceramic on-ceramic hip joints. AB - Alumina ceramic total hip joint bearings have shown superior wear properties. The joint bearing may undergo adverse conditions such as micro-separation causing head contact on the cup rim. As a transition, an edge is formed between the cup bearing and the rim. The aim of this study was to predict the effect of the edge on contact stresses in order to better understand the mechanisms of wear. A finite element contact model was developed under the conditions of the head displacements 0.5-2 mm and vertical loads 0.5-3 kN. The edge contact produced the most severe stresses capable of causing elevated wear and damage to ceramic bearings. The study shows that the bearing design should be considered in association with clinical conditions to eliminate severe stress. PMID- 28867871 TI - Mapping regional risks from climate change for rainfed rice cultivation in India. AB - Global warming is predicted to increase in the future, with detrimental consequences for rainfed crops that are dependent on natural rainfall (i.e. non irrigated). Given that many crops grown under rainfed conditions support the livelihoods of low-income farmers, it is important to highlight the vulnerability of rainfed areas to climate change in order to anticipate potential risks to food security. In this paper, we focus on India, where ~ 50% of rice is grown under rainfed conditions, and we employ statistical models (climate envelope models (CEMs) and boosted regression trees (BRTs)) to map changes in climate suitability for rainfed rice cultivation at a regional level (~ 18 * 18 km cell resolution) under projected future (2050) climate change (IPCC RCPs 2.6 and 8.5, using three GCMs: BCC-CSM1.1, MIROC-ESM-CHEM, and HadGEM2-ES). We quantify the occurrence of rice (whether or not rainfed rice is commonly grown, using CEMs) and rice extent (area under cultivation, using BRTs) during the summer monsoon in relation to four climate variables that affect rice growth and yield namely ratio of precipitation to evapotranspiration (PER), maximum and minimum temperatures (Tmax and Tmin ), and total rainfall during harvesting. Our models described the occurrence and extent of rice very well (CEMs for occurrence, ensemble AUC = 0.92; BRTs for extent, Pearson's r = 0.87). PER was the most important predictor of rainfed rice occurrence, and it was positively related to rainfed rice area, but all four climate variables were important for determining the extent of rice cultivation. Our models project that 15%-40% of current rainfed rice growing areas will be at risk (i.e. decline in climate suitability or become completely unsuitable). However, our models project considerable variation across India in the impact of future climate change: eastern and northern India are the locations most at risk, but parts of central and western India may benefit from increased precipitation. Hence our CEM and BRT models agree on the locations most at risk, but there is less consensus about the degree of risk at these locations. Our results help to identify locations where livelihoods of low-income farmers and regional food security may be threatened in the next few decades by climate changes. The use of more drought-resilient rice varieties and better irrigation infrastructure in these regions may help to reduce these impacts and reduce the vulnerability of farmers dependent on rainfed cropping. PMID- 28867872 TI - Investigation of the influence of oxygen plasma on supported silver nanoparticles. AB - Silver deposition precursor molecule trimethylphosphine(hexafluoroacetylacetonato)silver(I) [(hfac)AgP(CH3)3] was used to deposit silver onto water-modified (hydroxyl-terminated) solid substrates. A silicon wafer was used as a model flat surface, and water-predosed ZnO nanopowder was investigated to expand the findings to a common substrate material for possible practical applications. Following the deposition, oxygen plasma was used to remove the remaining organic ligands on a surface and to investigate its effect on the morphology of chemically deposited silver nanoparticles and films. A combination of microscopic and spectroscopic techniques including electron microscopy and x-ray photoelectron spectroscopy was used to confirm the change in the morphology of the deposited material consistent with Ostwald ripening as a result of plasma treatment. Particle agglomeration was observed on the surfaces, and the deposited metallic silver was oxidized to Ag2O following plasma treatment. The fluorine-containing ligands were completely removed. This result suggests that chemical vapor deposition can be used to deposit silver in a very controlled manner onto a variety of substrates using different topography methods and that the post-treatment with oxygen plasma is effective in preparing materials deposited for potential practical applications. PMID- 28867874 TI - Neuromechanics and Pathophysiology of Diffuse Axonal Injury in Concussion. AB - Our research on concussion-induced axonal injury may lead to identification of biomarkers that enable noninvasive diagnosis and treatment. PMID- 28867875 TI - SCALING LIMITS OF A MODEL FOR SELECTION AT TWO SCALES. AB - The dynamics of a population undergoing selection is a central topic in evolutionary biology. This question is particularly intriguing in the case where selective forces act in opposing directions at two population scales. For example, a fast-replicating virus strain outcompetes slower-replicating strains at the within-host scale. However, if the fast-replicating strain causes host morbidity and is less frequently transmitted, it can be outcompeted by slower replicating strains at the between-host scale. Here we consider a stochastic ball and-urn process which models this type of phenomenon. We prove the weak convergence of this process under two natural scalings. The first scaling leads to a deterministic nonlinear integro-partial differential equation on the interval [0, 1] with dependence on a single parameter, lambda. We show that the fixed points of this differential equation are Beta distributions and that their stability depends on lambda and the behavior of the initial data around 1. The second scaling leads to a measure-valued Fleming-Viot process, an infinite dimensional stochastic process that is frequently associated with a population genetics. PMID- 28867873 TI - New Developments in Cardiac Arrest Management. PMID- 28867876 TI - Novel nuclear barcode regions for the identification of flatfish species. AB - The development of an efficient seafood traceability framework is crucial for the management of sustainable fisheries and the monitoring of potential substitution fraud across the food chain. Recent studies have shown the potential of DNA barcoding methods in this framework, with most of the efforts focusing on using mitochondrial targets such as the cytochrome oxidase 1 and cytochrome b genes. In this article, we show the identification of novel targets in the nuclear genome, and their associated primers, to be used for the efficient identification of flatfishes of the Pleuronectidae family. In addition, different in silico methods are described to generate a dataset of barcode reference sequences from the ever growing wealth of publicly available sequence information, replacing, where possible, labour-intensive laboratory work. The short amplicon lengths render the analysis of these new barcode target regions ideally suited to next-generation sequencing techniques, allowing characterisation of multiple fish species in mixed and processed samples. Their location in the nucleus also improves currently used methods by allowing the identification of hybrid individuals. PMID- 28867877 TI - Scientific Responsibility and Development. PMID- 28867878 TI - Childhood Maltreatment and Health Impact: The Examples of Cardiovascular Disease and Type 2 Diabetes Mellitus in Adults. AB - Child maltreatment is associated with increased risk for an array of mental and physical health problems. We reviewed studies examining associations of child maltreatment, assessed either alone or in combination with other adversities, with cardiovascular disease (CVD) and Type 2 Diabetes. PubMed was searched for relevant studies until December, 2015. Forty publications met inclusion criteria. Consistent positive associations were noted across a range of childhood adversities. Child maltreatment was associated with CVD (myocardial infarction, stroke, ischemic heart disease, coronary heart disease) in 91.7% of studies, with diabetes in 88.2% of studies, and with blood pressure/hypertension in 61.5% of studies. Inclusion of mental disorders tended to attenuate associations. Sex related differences were under-examined. Implications for future research and intervention efforts are discussed. PMID- 28867879 TI - Uterus Transplant: Does It Have Legs? PMID- 28867880 TI - Calcium: A Nutrient in Pregnancy. PMID- 28867881 TI - Influence of Research on Health Policy and Clinical Practice. AB - Clinical research is a type of biomedical research conducted to aid and support the development of knowledge wherein there is involvement of patient. One of the key duties of healthcare professionals is to involve in research and change existing practice, when there is robust evidence in favour of new strategies that can have better patient care. Knowledge derived from research and experience may be of little value unless it is put into practice. Evidence-based medicine (EBM) is the diligent, clear, and wise use of current best research evidence in making decisions about clinical care of patients. The practice of EBM is incorporating clinician's expertise with the best available clinical evidence from research. It leads to improved patient outcomes and promote critical thinking and reflective practice. Effective research utilization can enhance policy decisions, resource allocation for programmes, and decisions about how to deliver those services. PMID- 28867882 TI - Visibility of Strings After Postplacental Intracesarean Insertion of CuT380A and Cu375 Intrauterine Contraceptive Device: A Randomized Comparative Study. AB - OBJECTIVES: To compare the incidence of visible strings after postplacental intracesarean insertion of Cu375 and CuT380A intrauterine contraceptive devices (IUD). METHODS: This was a prospective, randomized comparative study. A total of 100 women fulfilling the inclusion and exclusion criteria underwent postplacental intracesarean insertion of either Cu375 IUD or CuT380A IUD. Women were followed up at 1, 6 weeks and 3 months after IUD insertion and were questioned about IUD expulsion or removal at each visit. The cervix was inspected to visualize the IUD strings. Data were analyzed by Chi-square test. RESULTS: At 6-week follow-up, 97.9% women in group A versus 41.7% women in group B had strings visible at the cervical os and at 3 months 100% women in group A versus only 47.9% women in group B (p < 0.001) had visible strings of IUD. CONCLUSION: Both Cu375 and CuT380A IUD are safe postpartum method of contraception but Cu375 if used for intracesarean IUD insertion increases the incidence of visible IUD strings. Hence, it avoids radiological investigations and invasive procedures at follow-up visits required to locate the IUD when strings are not visible. CTRI No. CTRI/2015/09/006221. PMID- 28867883 TI - Examining the Use of Magnesium Sulfate to Treat Pregnant Women with Preeclampsia and Eclampsia: Results of a Program Assessment of Emergency Obstetric Care (EmOC) Training in India. AB - BACKGROUND: The aim of this study is to examine rates of magnesium sulfate utilization by emergency obstetric care trainees to treat preeclampsia-eclampsia in India. Secondarily, structural barriers are identified which limit the use of magnesium sulfate, highlighting limitations of emergency obstetric care training, which is a commonly implemented intervention in resource-poor settings. METHODS: Trainees' curriculum specified magnesium sulfate treatment for eclampsia and severe preeclampsia. Case records were analyzed for preeclampsia-eclampsia diagnosis, magnesium sulfate utilization, delivery route, and maternal and neonatal outcomes from 13,238 reported deliveries between 2006 and 2012 across 75 district hospitals in 12 Indian states. RESULTS: Of 1320 cases of preeclampsia eclampsia, 322 (24.4%) had eclampsia. Magnesium sulfate was given to 12.9% of preeclamptic and 54.3% of eclamptic women, with lower usage rates in rural communities. Among the 1308 women with preeclampsia-eclampsia, only 24 deaths occurred (1.8%). In contrast, among the 17,179 women without preeclampsia eclampsia, there were 95 reported deaths (0.6%). Both maternal mortality ratios were found to be much higher than the Millennium Development Goal target of 0.15%. Magnesium sulfate administration was associated with a higher death rate in preeclamptic but not eclamptic women, representing possible confounding by severity. CONCLUSION: To optimize resources spent on emergency obstetric care training, the consistent availability of magnesium sulfate should be improved in India. Increasing drug availability, implementing clinical guidelines around its administration, and training health-care providers on the identification and treatment of preeclampsia-eclampsia could lead to notable improvements in maternal and infant mortality. PMID- 28867884 TI - Comparison of Diagnostic Accuracy of Non-fasting DIPSI and HbA1c with Fasting WHO Criteria for Diagnosis of Gestational Diabetes Mellitus. AB - BACKGROUND: To compare diagnostic accuracy of non-fasting DIPSI and HbA1c with fasting WHO 1999 as gold standard for diagnosis of gestational diabetes mellitus (GDM). METHODS: Pregnant women attending antenatal clinic underwent a 2-h 75-gm GCT in non-fasting state (DIPSI). HbA1c was also determined at the same sitting. A 2-h 75-gm GCT was repeated for all women after 72 h in a fasting state (WHO criteria). GDM was diagnosed if plasma glucose was >=140 mg/dl by either test or if HbA1C >=6%. RESULTS: Of the 800 women evaluated, 51 were diagnosed as GDM by WHO criteria, 63 by DIPSI, and 40 by HbA1c. The sensitivity of DIPSI test with respect to WHO 1999 was 98.04% and specificity 98.26%. The diagnostic accuracy was 98.25%. The area under the ROC curve for DIPSI was 0.988 (p < 0.001) (95% confidence interval: 0.960-1.000). The sensitivity of HbA1c with respect to WHO GTT was 47.06%, specificity 97.86%, and diagnostic accuracy 94.63%. The ROC curve between WHO GTT and HbA1c covered an area of 0.805 (p < 0.01) (95% confidence interval: 0.731-0.879). CONCLUSIONS: Non-fasting DIPSI criteria had high diagnostic accuracy compared to gold-standard WHO GTT and can be an effective and practical alternative to the latter. HbA1c had a low sensitivity although the specificity was good and therefore is not a suitable test for screening GDM. PMID- 28867885 TI - Serious Visual (Ocular) Complications in Pre-eclampsia and Eclampsia. AB - INTRODUCTION: Complete loss of vision is an uncommon ocular complication of pre eclampsia/eclampsia. The conditions which lead to visual loss in pre-eclampsia include cortical blindness, retinal detachment, retinal vascular thrombosis and optic nerve atrophy. OBJECTIVES: The objective was to describe the cause, clinical course and prognosis in blindness complicating pre-eclampsia. METHODOLOGY: This is a prospective observational study conducted at the Govt. Hospital for Women and Children, Chennai, from January 2006 to December 2010. Sixteen women who were diagnosed with blindness complicating pre-eclampsia were analysed for the cause of blindness, clinical details and prognosis. RESULTS: The incidence of blindness among women with pre-eclampsia and eclampsia was 0.17%. The cause of visual loss was cortical blindness in 14 patients and retinal detachment in two patients. Blindness manifested predominantly in the intrapartum and postpartum period in 13/16 cases (81.25%). Seven patients (43.75%) suffered from severe pre-eclampsia, and nine patients (56.25%) suffered from eclampsia. HELLP syndrome, gestational diabetes mellitus (GDM) and anaemia were seen in two patients each. Seven patients also presented with motor deficits. CT scan imaging showed cortical vein thrombosis in five cases, arterial infarcts in two cases, widespread hypodense areas in the occipito-parietal region in six cases. In patients with cortical blindness, recovery of vision occurred within 10 days. CONCLUSION: Cortical blindness and retinal detachment are rare complications of pre-eclampsia and eclampsia. The prognosis is usually good especially with cortical blindness where the loss of vision is transient. The mainstay of management is effective treatment of pre-eclampsia/eclampsia along with termination of pregnancy. PMID- 28867886 TI - Study of Effect of Vitamin D Supplementation on the Clinical, Hormonal and Metabolic Profile of the PCOS Women. AB - INTRODUCTION: Insulin resistance is one of the most common features of polycystic ovary syndrome, and some studies suggest that vitamin D deficiency may have role in insulin resistance. OBJECTIVE: To study the effect of vitamin D supplementation on the clinical, hormonal and metabolic profile of the PCOS women. STUDY DESIGN: Randomized, placebo-controlled, interventional, double-blind study. MATERIALS AND METHODS: PCOS women were evaluated and enrolled after considering inclusion and exclusion criteria. They were randomized by block randomization with sealed envelope system done in two groups. In the study group (n = 25), patients were supplemented with vitamin D 60,000 IU weekly for 12 weeks, whereas control group (n = 25) was given placebo weekly for the same period. Both the groups were compared pre- and post-supplementation for variables like clinical profile, biochemical profile and metabolic profile. Statistical analysis was performed by the SPSS program for Windows, version 10.1 (SPSS, Chicago, IL). RESULT: In the study (n = 50), PCOS patients were enrolled; 34 patients (68%) were vitamin D deficient (<=20 ng/ml) out of which 10 patients (29%) were severely deficient (<10 ng/ml). Twelve patients (24%) were vitamin D insufficient showing high prevalence of vitamin D deficiency in the PCOS women. The difference in mean serum fasting glucose pre- and post-supplementation of vitamin D in study group was found to be statistically significant with p value of 0.041. There was significant difference seen in insulin resistance (IR) (2.38 +/- 4.88-1.00 +/- 0.58, p = 0.003), serum fasting insulin (10.34 +/- 20.00-5.00 +/- 3.25, p = 0.021), and increase in insulin sensitivity determined by QUICKI (0.37 +/- 0.04-0.394 +/- 0.009, p = 0.001) after supplementation with vitamin D. CONCLUSION: The study concluded that there was a beneficial effect of vitamin D supplementation on ovulatory dysfunctions and blood pressure. Post supplementation, there were decrease in insulin resistance and increase in insulin sensitivity. In the study decreased serum fasting insulin level and fasting blood sugar after vitamin D supplementation suggest underlying role of vitamin D in glucose homeostasis. PMID- 28867887 TI - Unilateral Versus Bilateral Laparoscopic Ovarian Drilling Using Thermal Dose Adjusted According to Ovarian Volume in CC-Resistant PCOS, A Randomized Study. AB - OBJECTIVE: This study aimed to evaluate the efficacy of unilateral laparoscopic ovarian drilling versus bilateral laparoscopic ovarian drilling with thermal dose adjusted according to ovarian volume in clomiphene citrate (CC)-resistant PCOS patients in terms of endocrine changes, menstrual cycle resumption, ovulation and pregnancy rates. PATIENTS AND METHODS: This study was conducted in the Department of Obstetrics and Gynecology, Zagazig university hospitals. One hundred CC resistant PCOS patients were divided into two groups. Group (I) (50 patients) underwent unilateral laparoscopic ovarian drilling with thermal dose adjusted according to ovarian volume (60 J/cm3 of ovarian tissue), and group (II) (50 patients) underwent bilateral laparoscopic ovarian drilling using the same previously mentioned thermal dose. Endocrinal changes and menstrual cycle resumption were assessed within 8 weeks postoperatively, but the ovulation and pregnancy rates were estimated after 6-month follow-up period. RESULTS: There was no statistically significant difference between the two groups as regards demographic data (p > 0.05). As regards menstruation cycle resumption (62.5 vs. 81%) (p = 0.047), total ovulation rate (54.2 vs. 78.7%) (p = 0.011) and cumulative pregnancy rate (33.3 vs. 55.3%) (p = 0.031), there was statistically significant difference between both groups. After drilling, there were highly statistically significant decrease in the mean serum levels of luteinizing hormone (LH) and significant decrease in the mean serum levels of testosterone in both groups. Mean serum level of follicle stimulating hormone (FSH) did not change significantly in both groups after drilling. CONCLUSION: Bilateral laparoscopic ovarian drilling with thermal dose adjusted according to ovarian volume is more effective than the right-sided unilateral technique with thermal dose adjusted according to ovarian volume in terms of menstrual cycle resumption, ovulation and cumulative pregnancy rates in CC-resistant PCOS patients. PMID- 28867889 TI - Massive Maternal Haemorrhage: A Rare Case of Ruptured Uterine Varix. AB - Haemoperitoneum anytime during pregnancy is a rare but catastrophic event. With advancement in antenatal and intrapartum care, the maternal survival has improved manyfold. Management involves immediate resuscitation with volume correction followed by surgery, mostly laparotomy. This case is of a booked primigravida, with otherwise uneventful pregnancy, who suffered a massive haemoperitoneum. On laparotomy, the only cause found was a small uterine varix on the posterior uterine surface. The patient survived after multiple transfusions, but it led to a fresh stillborn baby. Immediate action is the only answer to improving maternal and foetal survival. PMID- 28867888 TI - Efficacy of Combined Cabergoline and Metformin Compared to Metformin Alone on Cycle Regularity in Patients with Polycystic Ovarian Disease with Hyperprolactinemia: A Randomized Clinical Trial. AB - PURPOSE: Polycystic ovarian syndrome (PCOS) is a common reproductive disorder. Increasing serum prolactin in these patients could be detected in both follicular and luteal phase of the normal and stimulated cycles. Hyperprolactinemia affects the hypothalamic-pituitary-ovarian axis causing anovulation and abnormal uterine bleeding. In this study, the efficacy of combined cabergoline and metformin therapy was compared to metformin therapy alone in patients with PCOS on the body mass index, androgen profile and menstrual cycle regulation. METHODS: Two hundred and fifty patients with polycystic ovarian syndrome (PCOS) with increased serum prolactin were randomly allocated into two groups: group (1) received oral metformin tablet 1000 mg per day and cabergoline 0.5 g tablet weekly for 3 months as a case group, and group (2) received oral metformin tablet 1000 mg per day and a placebo tablet weekly for 3 months as the control group (n = 123). Body mass index (BMI), menstrual cycle regularity, serum testosterone, serum prolactin and dehydroepiandrosterone sulfate (DHEAS) level were compared before and after treatment in both groups. RESULTS: There was significant decrease in body mass index and improvement of androgenic profile in both groups after treatment. In group (1), there was significant improvement in cycle regularity and significant decrease in serum prolactin level post-treatment. CONCLUSIONS: The use of cabergoline in addition to metformin had more favorable effect on cycle regularity and prolactin level in patients with polycystic ovarian syndrome with hyperprolactinemia than the use of metformin alone. PMID- 28867890 TI - An Unusual Case of Vaginal Bleeding in an 18-Year-Old Female. PMID- 28867891 TI - Easy Balloon: The Easiest to Assemble Condom Balloon Uterine Tamponade for Primary Level of Health Care Centres. PMID- 28867892 TI - Self-Medication for Abortion: Safety Issues. PMID- 28867893 TI - Incubating Integrative Medicine in India through PMO's Atal Incubator Scheme of Niti Aayog. AB - BACKGROUND: Incubation centers are considered important tools to advance in a field of activity with multidisciplinary approach. The idea of incubation emerged long time back but it is actively pursued by funding agencies as a medium to propel community development. India's fast developing economy had limited tryst with Integrative Medicine until Indian Prime Minister, Narendra Modi, role modelled for Yoga in Chandigarh on the occasion of International Yoga Day. Integrative Medicine is a growing field and widely accepted as a cost-effective problem solving method that simplifies the management of incurable and complex disorders where modern medicine has little to offer. SUMMARY: Development of integrative medicine health incubator is the key to development of multidisciplinary program that offers to reduce the cost of healthcare, out of pocket expenses and emphasizes on preventive healthcare as means to achieve a healthy population in a developing country like India. KEY MESSAGE: Incubation center may become practical solution for many health problems in singular platform for healthier society by integrating traditional and modern medicine. PMID- 28867894 TI - Policy Research for Assessment of Quality Assurance Practices in Skill Development of Doctoral Programs in Medical Institutes. PMID- 28867895 TI - Estrous Cycle Phase-Dependent Changes in Anxiety- and Depression-Like Profiles in the Late Adolescent Wistar-Kyoto Rat. AB - BACKGROUND: Depression often manifests during adolescence when the development and networking of social and emotional brain areas is being influenced by hormones. The Wistar Kyoto (WKY) rat has been proposed as an animal model of adolescent depression with various face, construct, and predictive validities for clinical depression having been established. PURPOSE: The influence of the estrous cycle on anxiety- and depression-like behaviors in female adolescents may be tested out further using this model. METHODS: Female adolescent WKY rats were tested for anxiety- and depression-like behaviors in the elevated plus maze and forced swim test (FST) during different phases of the estrous cycle with inbred, age-, and phase-matched Wistar rats as controls. RESULTS: Wistars in proestrus estrus demonstrated reduced anxiety levels. WKY also demonstrated increased open arm time and entries and closed arm time, but less than Wistars, and as closed arm entries remained unaffected, it did not translate into a lowering of the anxiety levels. Risk taking and risk assessment behaviors were not affected by estrous phases in WKY, though exploratory behavior was reduced in proestrus estrus. In Wistars, increased risk taking and decreased risk assessment behaviors were observed during proestrus-estrus. Increased immobility in the FST, indicative of learned helplessness was not influenced by phase in the WKY, which was at variance with Wistars that demonstrated phase-specific differences. CONCLUSION: Results indicate a masking effect of indicative hormones in this putative model of adolescent depression, with implications for an unravelling of the steroid milieu in predisposed adolescent depression and for taking phase specific time windows into account for therapeutic interventions. PMID- 28867896 TI - Neonatal Lipopolysaccharide Infection Causes Demyelination and Behavioral Deficits in Adult and Senile Rat Brain. AB - BACKGROUND: Neonatal bacterial infections have been reported to cause white matter loss, although studies concerning the influence of infection on the expression of myelin and aging are still in their emerging state. PURPOSE: The present study aimed to investigate the effects of perinatal lipopolysaccharide (LPS) exposure on the myelination at different age points using histochemical and immunocytochemical techniques and the relative motor coordination. METHODS: A rat bacterial infection model was established by exposing the neonatal rats with LPS (0.3 mg/kg body weight, i.p., on postnatal day (PND) 3 followed by a booster at PND 5) and its impact was studied on the myelination and motor coordination in young, adult, and senile rats. RESULTS: The results obtained suggest that the administration of LPS induces demyelination, predominantly in cortex and corpus callosum. Low expression level of myelin oligodendrocyte glycoprotein (MOG) was observed at all time points, with prominence at 12, 18, and 24 months of age. In addition, reduced staining with luxol fast blue stain was also recorded in the experimentals. With the increasing demyelination and declining motor ability, LPS exposure also seemed to accelerate normal aging symptoms. CONCLUSION: There is a direct correlation of myelin damage and poor motor coordination with age. This would provide a better incite to understand inflammation-associated demyelinating changes in age-associated neurodegenerative disorders. Since, no long-term studies on behavioral impairments caused by LPS-induced demyelination in the central nervous system has been reported so far, this work would help in the better understanding of the long-term pathological effects of bacterial-induced demyelination. PMID- 28867897 TI - Extrapyramidal Symptoms Probably Related to Risperidone Treatment: A Case Series. AB - BACKGROUND: Atypical antipsychotics, like risperidone purportedly, score over their typical counterparts in terms of their lower propensity toward producing extrapyramidal symptoms (EPS). However, recent studies have furnished evidence to the contrary. Hereby, we present a case series implicating risperidone as the causative agent for EPS. METHODS: As a part of the pharmacovigilance programme of India, the authors have assessed 10 physician-reported cases of EPS among the 1,830 patients who were prescribed risperidone within the time period of January 2012-December 2014 in a tertiary care hospital in South India. Causality, severity, and preventability assessments of adverse reaction were done as per Naranjo's, Hartwig's, and Thornton'scale respectively. RESULTS: Of the 10 cases, a dose-dependent occurrence of EPS was noted in all and the time duration for development of EPS ranged from 1 week to 2 years. Four patients developed EPS at a dose of 6-8 mg, 4 developed at a dose of 4-6 mg, and the remaining 2 developed at 2 and 1 mg. CONCLUSION: A strong temporal correlation between risperidone and EPS was noted in all cases. High doses produced EPS early, whereas moderate to low doses produced EPS at a later date. Thus, cautious use and close monitoring are warranted in the chronic use of risperidone. PMID- 28867898 TI - Cortical Oligodendrocytes in Kaolin-Induced Hydrocephalus in Wistar Rat: Impact of Degree and Duration of Ventriculomegaly. AB - BACKGROUND: Oligodendrocytes are critical to the function of the brain. They generate the myelin sheath which ensures saltatory conduction, which is a more energy saving and efficient means of axonal impulse transmission. Ventriculomegaly results in neuronal degeneration and astrogliosis. PURPOSE: The effect of the degree of ventriculomegaly on oligodendrocyte in kaolin-induced hydrocephalus and the timeline have not been extensively documented, hence this study. METHODS: A total of 81 rats that were 3 weeks old were divided into 4 groups each consisting of control and experimental subgroups. Kaolin suspension was intracisternally injected to induce hydrocephalus and the animal sacrificed post-induction at 1, 2, 3, and 4 weeks. Two 1-mm-thick coronal slices at optic chiasma level were fixed in 10% buffered formal-saline and Karnovsky's fixative for light and transmission electron microscopy (TEM), respectively. The former slices were processed and stained with hematoxylin and eosin for glial density, cortical thickness, and oligodendrocyte evaluations. Subcortical white matter region of the latter were processed by conventional techniques for TEM. RESULTS: Compared with their corresponding control rats, thickness of the dorsolateral cortex was significantly reduced across the 2-4 week post-induction (WPI), glial density was significantly increased in the mild and moderate ventriculomegaly subgroups 1 WPI but only in mild ventriculomegaly subset 2 WPI. In the 4 WPI group, there was significant increase in glial density across the 3 ventriculomegaly subsets. Early hydropic changes of oligodendrocytes were noted in the inner pyramidal layer mostly in the 4 WPI experimental rats. Dilation of the endoplasmic reticulum precedes that of mitochondria, while mitochondrial crista disruption was noted in the 3 and 4 WPI rats. The nuclear membrane of the oligodendrocytes was progressively deformed from the 2nd to 4th WPI. CONCLUSION: This study reported degenerative changes of oligodendrocytes and its organelles in kaolin-induced hydrocephalus. Degeneration was worse with duration and in the deep cortical layers. PMID- 28867899 TI - Homology Modeling and Protein Interaction Map of CHRNA7 Neurogenesis Protein. AB - CHRNA7 is a neurodevelopmental protein involved in differentiation and neurogenesis, which is also named as nicotinic acetylcholine receptors, cholinergic receptor, nicotinic, alpha 7 (neuronal). The protein encoded by this gene forms a homo-oligomeric channel. It is a major component of brain nicotinic receptors displays that are blocked by and sensitive to alpha-bungarotoxin. Studies reports involvement of CHRNA7 protein in different neurological diseases. Non-availability of 3-dimensional (3D) structure leads the study toward structure 3D prediction along with its interaction analysis. The current paper is focused on the structure prediction through homology modeling of CHRNA7 along with binding site prediction using Schrodinger software suite. In continuation of the study, protein-protein interaction analysis is carried out by using string database. Tertiary structure along with binding sites was obtained, and visualized CHRAN7 protein have interaction with CHRNA protein family along with JAK2, AKT1, PICK1 protein that are involved in neurological disease. Structure formation analysis is an important aspect of proteomics studies. Hence, this predicted structure can be used for further advance studies and drug designing. Protein interaction analysis shows that CHRNA7 protein also interact with AKT1 protein which regulate neuronal differentiation and development, that signifies the role of CHRNA7 protein in neurological diseases. PMID- 28867900 TI - Diagnostic Markers of Autoimmune Neuropathological Diseases. PMID- 28867901 TI - Primary Intracranial Extraskeletal Mesenchymal Chondrosarcoma: Clinical Mimicry as Glomus Jugulare. AB - BACKGROUND: Extraskeletal mesenchymal chondrosarcoma (ESMCS) is an unusual pathologic variant of chondrosarcoma. There are no specific clinicoradiographic parameters to distinguish it from other intracranial pathologies. The diagnosis can be established only on the basis of histopathology, which may pose significant challenges in certain unusual locations. PURPOSE: In this case, we discuss the pitfalls in diagnosis, management, and major characteristics of ESMCS with a review of current literature. METHODS AND RESULTS: A 47-year-old female patient presented with a jugular foramen tumor which was misdiagnosed as glomus jugulare tumor for which she received primary gamma knife radiosurgery at 2 instances. But unfortunately, the patient died because of the increase in size of the lesion associated with necrosis. Autopsy analysis revealed a highly cellular tumor, rich in sarcomatous cells, and well-differentiated cartilages consistent with ESMCS. CONCLUSION: A definite preoperative diagnosis of ESMCS is crucial though difficult especially when located at complex sites like jugular foramen and clinicoradiological mimicry. The most crucial step in the management of ESMCS is accurate diagnosis with critical evaluation of clinical, radiological, and histopathological parameters and realization of highly variable clinical course of the disease. PMID- 28867903 TI - Hand Surgeons-More Need of the Hour. PMID- 28867902 TI - Adenoid Cystic Carcinoma Presenting as Abducens Nerve Palsy Secondary to Cavernous Sinus Lesion. AB - BACKGROUND: We report a 61-year-old who presented with a right-sided abducens nerve palsy secondary to a middle cranial fossa adenoid cystic carcinoma (ACC) extending into the cavernous sinus. PURPOSE: This case represents a unique presentation of intracranial ACC with a large middle cranial fossa mass and only a small extracranial component. METHODS: Review of the literature was undertaken to identify cases of intracranial ACC and their range of presentations. RESULTS: Our results show that this is the first reported case of an ACC presenting mostly as an intracranial mass with an isolated cranial nerve lesion. CONCLUSION: Our case highlights the importance of a broad differential diagnosis, particularly in circumstances where there are atypical features of lesions on radiographic imaging. PMID- 28867904 TI - Versatility of Free Cutaneous Flaps for Upper Extremity Soft Tissue Reconstruction. AB - The goals of upper extremity soft tissue reconstruction should go well beyond providing coverage and restoring function. As the field of reconstructive microsurgery has evolved, free cutaneous flaps (FCFs) are gaining wider application. The advantages of FCF include minimizing donor-site morbidity by preserving the muscle and fascia, improving versatility of flap design, and superior aesthetic results. This review highlights the application of anterolateral thigh, superficial circumflex iliac artery, deep inferior epigastric perforator, superficial inferior epigastric artery, and flow-through flaps for reconstruction of upper extremity defects. These flaps share several qualities in common: well-concealed donor sites, preservation of major arteries responsible of providing inflow to distal extremity, and potential for a two-team approach (donor and recipient sites). While the choice of flaps should be decided based on individual patient and defect characteristics, FCF should be considered as excellent options to achieve the goals of upper extremity reconstruction. PMID- 28867905 TI - Motor Examination in the Diagnosis of Carpal Tunnel Syndrome. AB - The relative importance and use of motor evaluation to diagnose carpal tunnel syndrome (CTS) is not clear. Because the ulnar nerve is not affected in CTS, we evaluated comparing the strength of the median-nerve innervated muscles to the ulnar innervated muscles in the same patient, through manual muscle testing (MMT) and a handheld dynamometer. Our purpose was to evaluate whether this method, which takes into account patient-dependent factors that would affect both groups of muscles equally, can provide better assessment of CTS. A retrospective case control review of MMT and dynamometer-measured strength for CTS was performed. The study was performed retrospectively but prior to surgery or other treatment. There were 28 cases (CTS) and 14 controls (without CTS). Positive nerve conduction tests defined cases. MMT of the thenar musculature was found to be unreliable as a test for CTS. Comparisons to ulnar nerve innervated muscle strength did not improve sensitivity or specificity of the MMT examination. Use of the dynamometer improved sensitivity and specificity of motor testing in CTS over MMT. Motor evaluation is important for the diagnosis of CTS, but further study is warranted, specifically to define the method of motor evaluation and delineate the subgroup of patients (predominantly thenar motor presentation) that would benefit most from motor testing and motor-focused treatment. PMID- 28867906 TI - Open Carpal Tunnel Release Outcomes: Performed Wide Awake versus with Sedation. AB - Background Carpal tunnel release (CTR) is the most common surgery of the hand, and interest is growing in performing it under local anesthesia without tourniquet. To better understand differences, we hypothesized that patients undergoing CTR under wide-awake local anesthesia with no tourniquet (WALANT) versus sedation (monitored anesthesia care [MAC]) would not result in a difference in outcome. Methods Consecutive cases of electrodiagnostically confirmed open CTR across multiple surgeons at a single center were prospectively enrolled. Data included demographic data, visual analog scale, Levine-Katz carpal tunnel syndrome scale, QuickDASH questionnaire, customized Likert questionnaire, and complications. Results There were 81 patients enrolled in the WALANT group and 149 patients in the MAC group. There were no reoperations in either group or any epinephrine-related complications in the WALANT group. Disability and symptom scores did not differ significantly between WALANT and sedation groups at 2 weeks or 3 months. Average postoperative QuickDASH, Levine-Katz, and VAS pain scales were the same in both groups. Both groups of patients reported high levels of satisfaction at 91 versus 96% for the WALANT versus MAC groups, respectively ( p > 0.05). Patients in each group were likely to request similar anesthesia if they were to undergo surgery again. Conclusion Patients undergoing open CTR experienced similar levels of satisfaction and outcomes with either the WALANT or MAC techniques. There was no statistically significant difference between either group relative to the tested outcome measures. These data should facilitate surgeons and patients' choosing freely between WALANT and MAC techniques relative to complications and outcomes. PMID- 28867907 TI - Preemptive Analgesia in Thumb Basal Joint Arthroplasty: Immediate Postoperative Pain with Preincision versus Postincision Local Anesthesia. AB - Purpose Currently no guidelines exist for the timing of the injection of anesthetics in surgeries performed under general anesthesia to minimize postoperative pain. To better understand the role of timing of the injection of local anesthesia in hand surgery performed under general anesthesia, we evaluated the effect of pre- versus postincisional local analgesic injection on immediate postoperative pain experience. We hypothesize that the preincisional (preemptive) injection will result in decreased immediate postoperative pain experience and analgesic use when compared with postincisional injection. Methods Consecutive cases of thumb basal joint arthroplasty performed over a 4-year period were retrospectively reviewed. During the first half of the study period, the surgical site was infiltrated with 0.5% bupivacaine at the completion of surgery following closure. During the second half of the study period, the surgical site was infiltrated with 0.5% bupivacaine prior to skin incision. Data collected included patient demographics, immediate postoperative recovery room (PACU) pain scores, and postoperative opioid consumption in morphine equivalents. Results Two-tailed t -test identified no significant difference between the pre- and postincision cohorts relative to PACU entrance pain scores and time spent in the PACU. PACU exit pain scores were significantly lower in the preincision cohort. The mean PACU pain score was also significantly lower in the preincision cohort. PACU opioid consumption, converted into morphine equivalents, was found to be 211 mg in the preincision versus 299 mg in the postincision cohort. Conclusion The preincisional (preemptive) injection of local anesthesia was found to result in lower pain scores during and upon exit of the PACU as compared with the postclosure group. In addition, the preincision cohort also trended toward lower opioid consumption while in the PACU. Consideration should be given to the routine use of preincision injection of local anesthesia to maximize pain relief in a multimodal pain strategy in hand surgical patients. Level of Evidence Therapeutic level III. PMID- 28867908 TI - Using the Rasch Model to Develop a Measure of Participation Capturing the Full Range of Participation Characteristics for the Patients with Hand Injuries. AB - Objective The purpose of this paper was to report on the first step in the development of a new instrument to measure participation including the full range of its characteristics. Methods The 30-item participation behavior questionnaire (PBQ) was developed from four main sources (a literature review of the theatrical basis of participation, available participation measures, and interviews with patients and experts about participation). Item selection and the reliability and validity of the measure were explored using Rasch measurement modeling for analysis. Participants A total of 404 individuals referred to rehabilitation after hand, wrist, or upper extremity surgery to reduce impairment from trauma, at least 2 months post-injury. Results An initial pool of 100 items; reflecting 14 characteristics of participation was initially reduced to 91 items after review by 15 participation experts and then further reduced to 30 items by three rounds of Rasch analysis removing misfitting items. The final PBQ has a person reliability of 0.91 with separation of 3.22, indicating it can reliably differentiate four levels of participation. There are no misfitting items and the instrument is unidimensional. All 14 characteristics of participation were retained in the PBQ, and none of the 30 items refer specifically to upper extremity issues. Conclusion The 30 participation behavior items of the PBQ show promise of being a psychometrically sound measure of participation. Further research is needed to validate the PBQ in samples of people with a range of other disabilities. PMID- 28867909 TI - Survival Rate of Limb Replantation in Different Age Groups. AB - Revascularization of damaged limbs/digits is technically feasible, but indications for surgical replantation remain controversial. The authors analyzed the survival rate of upper limb amputations and the associated factors in different age groups. They grouped 371 limb/digit amputees (average age, 44 years; range, 2-85 years) treated in their hospital during the past 10 years into three groups based on age (young, <= 15 years, n = 12; adult, 16-64 years, n = 302; elderly, >= 65 years, n = 57) and analyzed their injury type (extent of injury and stump status), operation method, presence of medical complications (Charlson comorbidity index), and survival rate. There were 168 replantations, and the overall replantation survival rate was 93%. The Charlson comorbidity index of the replantation patients was 0 in 124 cases; 1 in 32; 2 in 9; and 3 in 3, but it did not show any significant difference in survival rate after replantation. Eight elderly patients (14%) did not opt for replantation. Younger patients tended to undergo replantation, but they had lower success rates due to their severe injury status. The results of this study show that the survival rate of replantation in elderly patients is equal to that in adults. Stump evaluation is important for survival, but the presence of medical complications is not associated with the overall survival rate. PMID- 28867910 TI - Hook Plate Fixation for the Thumb Ulnar Collateral Ligament Fracture-Avulsion. AB - During a taekwondo competition, a 20-year-old female competitor injured her left thumb. There was pain, swelling, and tenderness at the ulnar side of the metacarpophalangeal joint. Plain radiography demonstrated an avulsion fracture with a small-size fragment at the base of the proximal phalanx. A mini hook plate was used to repair the lesion. The patient was satisfied with the results and returned to her sports activities after 2 months. PMID- 28867911 TI - Prolonged Bleeding after a Single Leech Application in Pediatric Hand Surgery. AB - Use of the medicinal leech in microsurgery is common place for venous decongestion and can be associated with the need for transfusion over time and multiple applications. Here the authors present a case of profound, ongoing, life threatening bleeding after a single leech application in pediatric microscopic surgery. There are no reports of such profound bleeding in the literature, and this case serves as a warning of the need for close surveillance in this subset of patients. PMID- 28867912 TI - Deep Inferior Epigastric Perforator Free Flaps for Use in Complicated Groin Wound Repair: A Case Report of Severe Groin Scar Contracture and Review of Pedicled and Free Flaps in Groin Wound Repair. AB - The use of pedicled and free flaps for tissue transfer and coverage has become a common practice in modern plastic surgery. An area that presents considerable challenge for tissue coverage is the groin. Defects in this area are complicated by issues such as prior surgery; scar contracture; extension of the defect beyond the borders of the groin; radiation damage; high probability of infection; and involvement of vital underlying structures, the genitalia, and perineal and perianal area. Therefore, the choice of donor site and flap usage is often difficult. Multiple methods of tissue transfer closure have been reported in the literature for repair of such defects and are reviewed in the following text. Here the authors present the case of a 30-year-old Caucasian woman born with a congenital giant hairy nevus of her left lower back, buttock, posterior thigh, and flank, who underwent wide local excision and skin grafting as a newborn. After several operations, the closure broke down and was left to heal by secondary intention. She has since developed excessive scar tissue leading to pain with ambulation secondary to scar contracture involving her labia majora. In this report, the wound was repaired with a free DIEP flap with excellent result and resolution of all symptoms. PMID- 28867913 TI - The Adipofascial Nerve Patch as an Alternative to Grafting in Partial Transection of a Peripheral Nerve. PMID- 28867914 TI - An Unusual Case of Posterolateral Rotatory Instability of the Elbow. PMID- 28867915 TI - Optimizing the Sequence of Zone 1 Extensor Tendon Repair. PMID- 28867916 TI - A Method to Facilitate "Nonsticking" of Regular Bipolar Forceps. AB - Electrosurgery using a bipolar cautery is very common, especially in surgical fields with surrounding vital structures. However, the tissue tends to stick to the bipolar forceps due to the heat cautery, which makes the tips stick together. When forceps tips are stuck to the cauterized tissue, surgeons have to spend time separating the tips. Also, when surgeons separate the tips, a cauterized bleeder may rebleed. Some bipolar forceps with nonstick coatings have been developed to reduce the sticking problem. However, for some surgeons or institutes, these nonstick bipolar forceps may be unavailable. The authors describe an easy method to reduce the occurrence of sticking forceps tips if regular bipolar forceps are used. PMID- 28867917 TI - Identifying Associations Between Brain Imaging Phenotypes and Genetic Factors via A Novel Structured SCCA Approach. AB - Brain imaging genetics attracts more and more attention since it can reveal associations between genetic factors and the structures or functions of human brain. Sparse canonical correlation analysis (SCCA) is a powerful bi-multivariate association identification technique in imaging genetics. There have been many SCCA methods which could capture different types of structured imaging genetic relationships. These methods either use the group lasso to recover the group structure, or employ the graph/network guided fused lasso to find out the network structure. However, the group lasso methods have limitation in generalization because of the incomplete or unavailable prior knowledge in real world. The graph/network guided methods are sensitive to the sign of the sample correlation which may be incorrectly estimated. We introduce a new SCCA model using a novel graph guided pairwise group lasso penalty, and propose an efficient optimization algorithm. The proposed method has a strong upper bound for the grouping effect for both positively and negatively correlated variables. We show that our method performs better than or equally to two state-of-the-art SCCA methods on both synthetic and real neuroimaging genetics data. In particular, our method identifies stronger canonical correlations and captures better canonical loading profiles, showing its promise for revealing biologically meaningful imaging genetic associations. PMID- 28867918 TI - Occupational Health and Safety in Ethiopia: A review of Situational Analysis and Needs Assessment. AB - BACKGROUND: The current rapid economic development has brought changes in workplaces in developing countries, including Ethiopia. The organization of occupational health and safety services is not yet resilient enough to handle the growing demands for workers' health in the context of industrialization. There is limited information on the gaps and needs of occupational health services in workplaces in Ethiopia. OBJECTIVES: The present review article describes the existing profile of occupational safety and health services in Ethiopia and identifies the current gaps and needs in the services. METHODS: Secondary data sources were reviewed using a structured checklist to explore the status of occupational safety, health services and related morbidity. Local literature was consulted in order to describe the type and prevalence of work related hazards, patterns of industries and of workforce. Published articles were searched in Google, Google scholar, PUBMED, and HINARI databases. Relevant heads of stakeholder organizations and experts were interviewed to verify the gaps that were synthesized using desk review. RESULTS: Ethiopia is an agrarian country that is industrializing rapidly with a focus on construction, manufacturing, mining, and road infrastructure. An estimated work force of about two million is currently engaged in the public and private sectors. Males constitute the majority of this workforce. Most of the workforce has basic primary education. Commonly observed hazards in the workplace include occupational noise and dust of various types in manufacturing sectors and chemical exposures in the flower industry. Injury in both the agriculture and the manufacturing sectors is another workplace hazard commonly observed in the country. A lack of information made assessing workplace exposures in detail difficult. The prevalence of noise exposure was found to be high with the potential to seriously impact hearing capacity. Exposure to dust in textile and cement factories greatly exceeded international permissible limits. There is a high level of workplace injuries that often leads to an extended loss of productive working days. Occupational safety and health services were found to be inadequately organized. There is limited practice in exposure assessment and monitoring. This happens to be true despite the existing favorable environment in areas of policies and regulations. CONCLUSION AND RECOMMENDATION: There is a severe scarcity of peer-reviewed literature related to workplace exposures and their impact on workplace health and safety. Limited adequately skilled manpower is available. The internal infrastructural capacity is weak and cannot help to identify and assess hazards in the workplace. Monitoring system and laboratory investigation is limited despite the presence of favorable policy and regulatory frameworks. Addressing these gaps is of immediate concern. PMID- 28867919 TI - Review of Climate Change and Health in Ethiopia: Status and Gap Analysis. AB - BACKGROUND: This review assessed Ethiopia's existing situation on issues related to the environment, climate change and health, and identifies gaps and needs that can be addressed through research, training, and capacity building. METHODS: The research was conducted through a comprehensive review of available secondary data and interviewing key informants in various national organizations involved in climate change adaptation and mitigation activities. RESULTS: Climate change related health problems, such as mortality and morbidity due to floods and heat waves, vector-borne diseases, water-borne diseases, meningitis, and air pollution related respiratory diseases are increasing in Ethiopia. Sensitive systems such as agriculture, health, and water have been affected, and the effects of climate change will continue to magnify without the right adaptation and mitigation measures. Currently, research on climate change and health is not adequately developed in Ethiopia. Research and other activities appear to be fragmented and uncoordinated. As a result, very few spatially detailed and methodologically consistent studies have been made to assess the impact of climate in the country. There has often been a lack of sufficient collaboration among organizations on the planning and execution of climate change and health activities, and the lack of trained professionals who can perform climate change and health-related research activities at various levels. CONCLUSION: Firstly, there is a lack of organized structure in the various organizations. Secondly, there is inadequate level of inter-sectoral collaboration and poor coordination and communication among different stakeholders. Thirdly, there are no reliable policy guidelines and programs among organizations, agencies and offices that target climate change and health. Fourth, the existing policies fail to consider the gender and community-related dimensions of climate change. Fifth, the monitoring and evaluation efforts exerted on climate change and health activities are not strong enough to address the climate change and health issues in the country. PMID- 28867920 TI - Health Effects of Environmental Exposures, Occupational Hazards and Climate Change in Ethiopia: Synthesis of Situational Analysis, Needs Assessment and the Way Forward. AB - BACKGROUND: The burden of diseases caused by environmental and occupational health hazards and the effects of global climate change are of growing concerns in Ethiopia. However, no adequate information seems to be available on the current situation. This means there is a critical gap in research, policy framework and implementation in the country. OBJECTIVE: The purpose of this paper was to synthesize evidence from a systematic situational analysis and needs assessment to help establish a hub for research and training on three major themes and their related policy frameworks: air pollution and health, occupational health and safety and climate change and health. METHODS: The methods used in this work include a systematic review of secondary data from peer reviewed literature, thesis reports from academia, government and national statistical reports. Limited primary data based on key informant interviews held with major stakeholders were also used as sources of data. FINDINGS: Exposures to high levels of indoor and outdoor air pollutants were found to be major sources of public health challenges. Lack of occupational safety and health due to agricultural activities and exposure to industries was found to be substantial. Worse is the growing fear that climate change will pose increasingly significant multidimensional challenges to the environment and public health. Across all three areas of focus, there was a paucity of information on local scientific evidence. There is also very limited trained skilled manpower and physical infrastructure to monitor the environment and enforce regulatory guidelines. Research, policy frameworks and regulatory mechanisms were among the cross cutting issues that needed urgent attention. CONCLUSIONS: Critical gaps were observed in research and training across the three themes. Also, there is a limitation in implementing the link between policy and related regulations in the environment and health. PMID- 28867921 TI - Nanogels as a Basis for Network Construction. AB - Reactive nanogels with diverse chemical and physical compositions were synthesized using solution free radical polymerization. Conventional monomer resins show a reduction in polymerization shrinkage and stress as well as improved bond strength when nanogels are used as a filler. Nanogels dispersed in inert solvent at appropriate concentrations form macroscopic networks with chemical compositions that are not directly available from the starting monomers. PMID- 28867922 TI - General Bahr-Esseen inequalities and their applications. AB - We study the Bahr-Esseen inequality. We show that the Bahr-Esseen inequality holds with exponent p if it holds with exponent [Formula: see text] for the truncated and centered random variables. The Bahr-Esseen inequality is also true if the truncated random variables are acceptable. We then apply the results to obtain weak and strong laws of large numbers and complete convergence. PMID- 28867923 TI - On the spectral norms of r-circulant matrices with the biperiodic Fibonacci and Lucas numbers. AB - In this paper, we present new upper and lower bounds for the spectral norms of the r-circulant matrices [Formula: see text] and [Formula: see text] whose entries are the biperiodic Fibonacci and biperiodic Lucas numbers, respectively. Finally, we obtain lower and upper bounds for the spectral norms of Kronecker and Hadamard products of Q and L matrices. PMID- 28867924 TI - Estimating the Size of a Large Network and its Communities from a Random Sample. AB - Most real-world networks are too large to be measured or studied directly and there is substantial interest in estimating global network properties from smaller sub-samples. One of the most important global properties is the number of vertices/nodes in the network. Estimating the number of vertices in a large network is a major challenge in computer science, epidemiology, demography, and intelligence analysis. In this paper we consider a population random graph G = (V, E) from the stochastic block model (SBM) with K communities/blocks. A sample is obtained by randomly choosing a subset W ? V and letting G(W) be the induced subgraph in G of the vertices in W. In addition to G(W), we observe the total degree of each sampled vertex and its block membership. Given this partial information, we propose an efficient PopULation Size Estimation algorithm, called PULSE, that accurately estimates the size of the whole population as well as the size of each community. To support our theoretical analysis, we perform an exhaustive set of experiments to study the effects of sample size, K, and SBM model parameters on the accuracy of the estimates. The experimental results also demonstrate that PULSE significantly outperforms a widely-used method called the network scale-up estimator in a wide variety of scenarios. PMID- 28867925 TI - Adolescent Physiological and Behavioral Patterns of Emotion Dysregulation Predict Multisystemic Therapy Response. AB - This study examined whether physiological and behavioral indicators of emotion dysregulation assessed over the course of Multisystemic Therapy (MST) were related to treatment response. Participants were 180 ethnically diverse adolescents (n=120 males), ranging in age from 12 to 17 years. Treatment response was assessed through therapist report and official arrest records. Changes in cortisol reactivity and changes in scores on a behavioral dysregulation subscale of the Child Behavior Checklist were used as indicators of emotion dysregulation. Hierarchical linear modeling analyses examined whether a less favorable treatment response was associated with cortisol reactivity measures (a) collected early in treatment and (b) over the course of treatment, as well as with behavioral reports of emotion dysregulation reported (c) early in treatment, and (d) over the course of treatment. Sex was explored as a moderator of these associations. Results indicated that both cortisol and behavioral indices of emotion dysregulation early in treatment and over the course of therapy predicted treatment responsiveness. This relationship was moderated by sex: girls were more likely to evidence a pattern of increasing emotion regulation prior to successful therapy response. The results lend further support to the notion of incorporating emotion regulation techniques into treatment protocols for delinquent behavior. PMID- 28867926 TI - Quantum dot light emitting devices for photomedical applications. AB - While OLEDs have struggled to find a niche lighting application that can fully take advantage of their unique form factors as thin, flexible, lightweight and uniformly large-area luminaire, photomedical researchers have been in search of low-cost, effective illumination devices with such form factors that could facilitate widespread clinical applications of photodynamic therapy (PDT) or photobiomodulation (PBM). Although existing OLEDs with either fluorescent or phosphorescent emitters cannot achieve the required high power density at the right wavelength windows for photomedicine, the recently developed ultrabright and efficient deep red quantum dot light emitting devices (QLEDs) can nicely fit into this niche. Here, we report for the first time the in-vitro study to demonstrate that this QLED-based photomedical approach could increase cell metabolism over control systems for PBM and kill cancerous cells efficiently for PDT. The perspective of developing wavelength-specific, flexible QLEDs for two critical photomedical fields (wound repair and cancer treatment) will be presented with their potential impacts summarized. The work promises to generate flexible QLED-based light sources that could enable the widespread use and clinical acceptance of photomedical strategies including PDT and PBM. PMID- 28867927 TI - Sarcopenia and the New ICD-10-CM Code: Screening, Staging, and Diagnosis Considerations. PMID- 28867928 TI - Improving Veteran Access to Treatment for Hepatitis C Virus Infection: Addressing social issues and treatment barriers significantly increases access to HCV care, and many veterans successfully start therapy with the help of additional support staff. PMID- 28867929 TI - Statistical Learning of Multiple Structures by 8-Month-Old Infants. PMID- 28867930 TI - MR Safe Robot, FDA Clearance, Safety and Feasibility Prostate Biopsy Clinical Trial. AB - Compatibility of mechatronic devices with the MR environment has been a very challenging engineering task. After over a decade of developments, we report the successful translation to clinical trials of our MR Safe robot technology. MrBot is a 6-degree-of-freedom, pneumatically actuated robot for transperineal prostate percutaneous access, built exclusively of electrically nonconductive and nonmagnetic materials. Its extensive pre-clinical tests have been previously reported. Here, we present the latest technology developments, an overview of the regulatory protocols, and technically related results of the clinical trial. The FDA has approved the MrBot for the biopsy trial, which was successfully performed in 5 patients. With no trajectory corrections, and no unsuccessful attempts to target a site, the robot achieved an MRI based needle targeting accuracy of 2.55 mm. To the best of our knowledge, this is the first robot approved by the FDA for the MR environment. The results confirm that it is possible to perform safe and accurate robotic manipulation in the MRI scanner, and the development of MR Safe robots is no longer a daunting technical challenge. PMID- 28867931 TI - Targeted next-generation sequencing analysis identifies novel mutations in families with severe familial exudative vitreoretinopathy. AB - PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a genetically and clinically heterogeneous disease, characterized by failure of vascular development of the peripheral retina. The symptoms of FEVR vary widely among patients in the same family, and even between the two eyes of a given patient. This study was designed to identify the genetic defect in a patient cohort of ten Chinese families with a definitive diagnosis of FEVR. METHODS: To identify the causative gene, next-generation sequencing (NGS)-based target capture sequencing was performed. Segregation analysis of the candidate variant was performed in additional family members by using Sanger sequencing and quantitative real-time PCR (QPCR). RESULTS: Of the cohort of ten FEVR families, six pathogenic variants were identified, including four novel and two known heterozygous mutations. Of the variants identified, four were missense variants, and two were novel heterozygous deletion mutations [LRP5, c.4053 DelC (p.Ile1351IlefsX88); TSPAN12, EX8Del]. The two novel heterozygous deletion mutations were not observed in the control subjects and could give rise to a relatively severe FEVR phenotype, which could be explained by the protein function prediction. CONCLUSIONS: We identified two novel heterozygous deletion mutations [LRP5, c.4053 DelC (p.Ile1351IlefsX88); TSPAN12, EX8Del] using targeted NGS as a causative mutation for FEVR. These genetic deletion variations exhibit a severe form of FEVR, with tractional retinal detachments compared with other known point mutations. The data further enrich the mutation spectrum of FEVR and enhance our understanding of genotype phenotype correlations to provide useful information for disease diagnosis, prognosis, and effective genetic counseling. PMID- 28867932 TI - A DNA dot hybridization model for molecular diagnosis of parasitic keratitis. AB - PURPOSE: Developing a DNA dot hybridization model for diagnosing parasitic keratitis. METHODS: Newly designed oligonucleotide probes for detecting Acanthamoeba and microsporidia were tested with target reference strains of Acanthamoeba (n = 20) and microsporidia (n = 3), and non-target microorganisms, including bacteria (n = 20) and fungi (n = 20). These probes, which had passed the preliminary tests, were then assembled as a parasite dot hybridization (PDH) model for assessing 33 clinical samples from patients with clinically suspected Acanthamoeba and microsporidia keratitis, including eight positives for Acanthamoeba, 13 positives for microsporidia, and 12 negatives for both pathogens. RESULTS: Two probes for detecting Acanthamoeba and two for detecting microsporidia passed the tests using target and non-target strains and then were assembled in the PDH model. For clinical samples, one Acanthamoeba-positive sample (proved with pathology) was falsely negative according to the PDH assay. The sensitivity and specificity of the PDH assay for diagnosing Acanthamoeba keratitis were 87.5% and 100%, respectively, while the sensitivity and specificity for diagnosing microsporidia keratitis were 100%. The infectious agent of all clinical samples of microsporidia keratitis was identified as Vittaforma corneae with DNA sequencing, while those of Acanthamoeba keratitis were caused by four species of Acanthamoeba, with Acanthamoeba castellanii found in four samples (50%, 4/8). CONCLUSIONS: The PDH model has the potential to be a molecular assay for diagnosing Acanthamoeba and microsporidia keratitis. However, a prospective clinical study might be needed before the model is adopted in routine clinical practice. PMID- 28867933 TI - Anxiety disorders: a review of current literature. AB - Anxiety disorders are the most prevalent psychiatric disorders. There is a high comorbidity between anxiety (especially generalized anxiety disorders or panic disorders) and depressive disorders or between anxiety disorders, which renders treatment more complex. Current guidelines do not recommend benzodiazepines as first-line treatments due to their potential side effects. Selective serotonin reuptake inhibitors and selective serotonin norepinephrine reuptake inhibitors are recommended as first-line treatments. Psychotherapy, in association with pharmacotherapy, is associated with better efficacy. Finally, a bio-psycho-social model is hypothesized in anxiety disorders. PMID- 28867935 TI - The history of generalized anxiety disorder as a diagnostic category. AB - From the 19th century into the 20th century, the terms used to diagnose generalized anxiety included "pantophobia" and "anxiety neurosis." Such terms designated paroxysmal manifestations (panic attacks) as well as interparoxysmal phenomenology (the apprehensive mental state). Also, generalized anxiety was considered one of numerous symptoms of neurasthenia, a vaguely defined illness. Generalized anxiety disorder (GAD) appeared as a diagnostic category in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) in 1980, when anxiety neurosis was split into GAD and panic disorder. The distinct responses these two disorders had to imipramine therapy was one reason to distinguish between the two. Since the revised DSM-III (DSM-III-R), worry about a number of life circumstances has been gradually emphasized as the distinctive symptom of GAD. Thus, a cognitive aspect of anxiety has become the core criterion of GAD. The validity of GAD as an independent category has been questioned from DSM-III up to preparation of DSM-5. Areas of concern have included the difficulty to establish clear boundaries between GAD and (i) personality dimensions, (ii) other anxiety-spectrum disorders, and (iii) nonbipolar depression. The National Institute of Mental Health has recently proposed the Research Domain Criteria (RDoC), a framework destined to facilitate biological research into the etiology of mental symptoms. Within the RDoC framework, generalized anxiety might be studied as a dimension denominated "anxious apprehension" that would typically fit into the research domain called "negative valence systems" and the more specific construct termed "potential threat." PMID- 28867934 TI - Treatment of anxiety disorders. AB - Anxiety disorders (generalized anxiety disorder, panic disorder/agoraphobia, social anxiety disorder, and others) are the most prevalent psychiatric disorders, and are associated with a high burden of illness. Anxiety disorders are often underrecognized and undertreated in primary care. Treatment is indicated when a patient shows marked distress or suffers from complications resulting from the disorder. The treatment recommendations given in this article are based on guidelines, meta-analyses, and systematic reviews of randomized controlled studies. Anxiety disorders should be treated with psychological therapy, pharmacotherapy, or a combination of both. Cognitive behavioral therapy can be regarded as the psychotherapy with the highest level of evidence. First line drugs are the selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors. Benzodiazepines are not recommended for routine use. Other treatment options include pregabalin, tricyclic antidepressants, buspirone, moclobemide, and others. After remission, medications should be continued for 6 to 12 months. When developing a treatment plan, efficacy, adverse effects, interactions, costs, and the preference of the patient should be considered. PMID- 28867936 TI - Cultural aspects of anxiety disorders in India. AB - Cultural factors have influenced the presentation, diagnoses, and treatment of anxiety disorders in India for several centuries. This review covers the antecedents, prevalence, phenomenology, and treatment modalities of anxiety disorders in the Indian cultural context. It covers the history of the depiction of anxiety in India and the concept of culture in the classification of anxiety disorders, and examines the cultural factors influencing anxiety disorders in India. We review the prevalence and phenomenology of various disorders, such as generalized anxiety disorder, panic disorder, social anxiety, and phobic disorder, as well as culture-specific syndromes such as dhat and koro in India. Finally, the review examines the wide range of therapeutic modalities practiced in India, such as faith healing, psychotherapy, ayurveda, psychopharmacology, Unani medicine, homeopathy, yoga, meditation, and mindfulness. We conclude by emphasizing the significance of cultural factors in making relevant diagnoses and offering effective and holistic treatments to individuals with anxiety disorders. PMID- 28867937 TI - Epidemiology of anxiety disorders: from surveys to nosology and back. AB - On the basis of epidemiological survey findings, anxiety disorders are the most prevalent mental disorders around the world and are associated with significant comorbidity and morbidity. Such surveys rely on advances in psychiatric nosology and may also contribute usefully to revisions of the nosology. There are a number of questions at the intersection of psychiatric epidemiology and nosology. This review addresses the following: What is the prevalence of anxiety disorders and how do we best explain cross-national differences in prevalence estimates? What are the optimal diagnostic criteria for anxiety disorders, and how can epidemiological data shed light on this question? What are the comorbidities of anxiety disorders, and how do we best understand the high comorbidities seen in these conditions? What is the current treatment gap for anxiety disorders, and what are the implications of current understandings of psychiatric epidemiology and nosology for policy-making relevant to anxiety disorders? Here, we emphasize that anxiety disorders are the most prevalent of the psychiatric conditions, and that rather than merely contrasting cross-national prevalence in anxiety disorders, it is more productive to delineate cross-national themes that emerge about the epidemiology of these conditions. We discuss that optimizing diagnostic criteria for anxiety disorders is an iterative process to which epidemiological data can make a crucial contribution. Additionally, high comorbidity in anxiety disorders is not merely artefactual; it provides key opportunities to explore pathways to mental disorders and to intervene accordingly. Finally, work on the epidemiology and nosology of anxiety disorders has provided a number of important targets for mental health policy and for future integrative work to move between bench and bedside, as well as between clinic and community. PMID- 28867938 TI - Environmental transmission of generalized anxiety disorder from parents to children: worries, experiential avoidance, and intolerance of uncertainty. AB - Generalized anxiety disorder (GAD) runs in families. Building on recent theoretical approaches, this review focuses on potential environmental pathways for parent-to-child transmission of GAD. First, we address child acquisition of a generalized pattern of fearful/anxious and avoidant responding to potential threat from parents via verbal information and via modeling. Next, we address how parenting behaviors may contribute to maintenance of fearful/anxious and avoidant reactions in children. Finally, we consider intergenerational transmission of worries as a way of coping with experiential avoidance of strong negative emotions and with intolerance of uncertainty. We conclude that parents with GAD may bias their children's processing of potential threats in the environment by conveying the message that the world is not safe, that uncertainty is intolerable, that strong emotions should be avoided, and that worry helps to cope with uncertainty, thereby transmitting cognitive styles that characterize GAD. Our review highlights the need for research on specific pathways for parent-to child transmission of GAD. PMID- 28867939 TI - Biological markers of generalized anxiety disorder. AB - Generalized anxiety disorder (GAD) is a prevalent and highly disabling mental health condition; however, there is still much to learn with regard to pertinent biomarkers, as well as diagnosis, made more difficult by the marked and common overlap of GAD with affective and anxiety disorders. Recently, intensive research efforts have focused on GAD, applying neuroimaging, genetic, and blood-based approaches toward discovery of pathogenetic and treatment-related biomarkers. In this paper, we review the large amount of available data, and we focus in particular on evidence from neuroimaging, genetic, and neurochemical measurements in GAD in order to better understand potential biomarkers involved in its etiology and treatment. Overall, the majority of these studies have produced results that are solitary findings, sometimes inconsistent and not clearly replicable. For these reasons, they have not yet been translated into clinical practice. Therefore, further research efforts are needed to distinguish GAD from other mental disorders and to provide new biological insights into its pathogenesis and treatment. PMID- 28867940 TI - Genetics of generalized anxiety disorder and related traits. AB - This review serves as a systematic guide to the genetics of generalized anxiety disorder (GAD) and further focuses on anxiety-relevant endophenotypes, such as pathological worry fear of uncertainty, and neuroticism. We inspect clinical genetic evidence for the familialityl heritability of GAD and cross-disorder phenotypes based on family and twin studies. Recent advances of linkage studies, genome-wide association studies, and candidate gene studies (eg, 5-HTT, 5-HT1A, MAOA, BDNF) are outlined. Functional and structural neuroimaging and neurophysiological readouts relating to peripheral stress markers and psychophysiology are further integrated, building a multilevel disease framework. We explore etiologic factors in gene-environment interaction approaches investigating childhood trauma, environmental adversity, and stressful life events in relation to selected candidate genes (5-HTT, NPSR1, COMT, MAOA, CRHR1, RGS2), Additionally, the pharmacogenetics of selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor treatment are summarized (5 HTT, 5-HT2A, COMT, CRHR1). Finally, GAD and trait anxiety research challenges and perspectives in the field of genetics, including epigenetics, are discussed. PMID- 28867941 TI - Affective neuroimaging in generalized anxiety disorder: an integrated review. AB - Affective neuroimaging has contributed to our knowledge of generalized anxiety disorder (GAD) through measurement of blood oxygenation level-dependent (BOLD) responses, which facilitate inference on neural responses to emotional stimuli during task-based functional magnetic resonance imaging (fMRI). In this article, the authors provide an integrated review of the task-based affective fMRI literature in GAD. Studies provide evidence for variable presence and directionality of BOLD abnormalities in limbic and prefrontal regions during reactivity to, regulation of, and learning from emotional cues. We conclude that understanding the sources of this variability is key to accelerating progress in this area. We propose that the cardinal symptom of GAD-worry-predominantly reflects stimulus-independent mental processes that impose abnormal, inflexible functional brain configurations, ie, the overall pattern of information transfer among behaviorally relevant neural circuits at a given point in time. These configurations that are inflexible to change from the incoming flux of environmental stimuli may underlie inconsistent task-based findings. PMID- 28867942 TI - Behavioral methods to study anxiety in rodents. AB - Stress is a precipitating factor for anxiety-related disorders, which are among the leading forms of psychiatric illness and impairment in the modern world. Rodent-based behavioral tests and models are widely used to understand the mechanisms by which stress triggers anxiety-related behaviors and to identify new treatments for anxiety-related disorders. Although substantial progress has been made and many of the key neural circuits and molecular pathways mediating stress responsiveness have been characterized, these advances have thus far failed to translate into fundamentally new treatments that are safer and more efficacious in humans. The purpose of this article is to describe methods that have been historically used for this type of research and to highlight new approaches that align with recent conceptualizations of disease symptomatology and that may ultimately prove to be more fruitful in facilitating the development of improved therapeutics. PMID- 28867944 TI - Cognitive-behavioral therapy for generalized anxiety. AB - As a form of therapy, cognitive behavioral therapy (CBT) is more than a mere "toolbox." CBT allows us to better understand how the human mind is functioning because it is based on neuroscience and experimental and scientific psychology. At the beginning, the Diagnostic and Statistical Manual of Mental Disorders (DSM) was "nontheoretical," but nowadays (the most recent version being DSM-5), it is increasingly based on CBT paradigms (with the insertion of important notions such as cognitions and behaviors). This Brief Report presents what we currently know about generalized anxiety disorder (GAD) and how we can treat this condition by nonpharmaceutical means. In the last few years, GAD theories have evolved, becoming more precise about the cognitive functioning of GAD sufferers. Here, we look at current theoretical models and the main techniques of therapeutic care, as well as the advances in research about the "transdiagnostic" process and GAD in childhood. CBT is an effective treatment for GAD, typically leading to reductions in worry, and a study has shown that such therapy is equal to pharmaceutical treatment and more effective 6 months after study completion. PMID- 28867945 TI - Genetic, Biochemical, Nutritional and Antimicrobial Characteristics of Pomegranate (Punica granatum L.)?Grown in Istria. AB - This study characterises the genetic variability of local pomegranate (Punica granatum L.) germplasm from the Slovenian and Croatian areas of Istria. The bioactive components and antioxidant and antimicrobial properties of ethanol and water extracts of different parts of pomegranate fruit were also determined, along with their preliminary nutritional characterisation. Twenty-six different genotypes identified with microsatellite analysis indicate the great diversity of pomegranate in Istria. The pomegranate fruit ethanol extracts represent rich sources of phenolic compounds (mean value of the mass fraction in exocarp and mesocarp expressed as gallic acid is 23 and 16 mg/g, respectively). The ethanol extracts of pomegranate exocarp and mesocarp showed the greatest antimicrobial activity against Candida albicans, Candida parapsilosis, Rhodotorula mucilaginosa, Exophiala dermatitidis and Staphylococcus aureus, and the same water extracts against S. aureus and Escherichia coli. To the best of our knowledge, this study represents the first report of the characterisation of pomegranate genetic resources from Istria at different levels, including the molecular, chemical, antimicrobial and nutritional properties. PMID- 28867946 TI - Recombinant Xylanase from Bacillus tequilensis BT21: Biochemical Characterisation and Its Application in the Production of Xylobiose from Agricultural Residues. AB - Bacterial strain Bacillus tequilensis BT21 isolated from marine sediments was found to produce extracellular xylanase. The xynBT21 gene encoding xylanase enzyme was cloned and expressed in Escherichia coli. The gene encoded a protein consisting of 213 amino acid residues with calculated molecular mass of 23.3 kDa. Purified recombinant xylanase had optimum activity at 60 degrees C and pH=6. The enzyme was highly stable in alkaline pH, at pH=7 it remained 100% active for 24 h, while its activity increased at pH=8 and 9 during incubation. B. tequilensis BT21 xylanase had alkaline pI of 9.4 and belongs to glycosyl hydrolase family 11. The mode of action of XynBT21 on beechwood xylan and xylooligosaccharides was studied. It hydrolysed xylooligosaccharides and beechwood xylan yielding mainly xylobiose (X2) with a small amount of xylose (X1), indicating that XynBT21 was probably an endo-acting xylanase. Enzymatic hydrolysis using wheat bran as a substrate revealed that xylanase reported here has the potential to produce xylobiose from wheat bran. Xylooligosaccharides, especially xylobiose, have strong bifidogenic properties and are increasingly used as a prebiotic. This is the first report that describes this novel xylanase enzyme from marine B. tequilensis BT21 used for the release of xylobiose from wheat bran. PMID- 28867943 TI - Oxytocin and social functioning. AB - Social anxiety is a form of anxiety characterized by continuous fear of one or more social or performance situations. Although multiple treatment modalities (cognitive behavioral therapy, selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors, benzodiazepines) exist for social anxiety, they are effective for only 60% to 70% of patients. Thus, researchers have looked for other candidates for social anxiety treatment. Our review focuses on the peptide oxytocin as a potential therapeutic option for individuals with social anxiety. Animal research both in nonprimates and primates supports oxytocin's role in facilitation of prosocial behaviors and its anxiolytic effects. Human studies indicate significant associations between social anxiety and oxytocin receptor gene alleles, as well as social anxiety and oxytocin plasma levels. In addition, intranasal administration of oxytocin in humans has favorable effects on social anxiety symptomology. Other disorders, including autism, schizophrenia, and anorexia, have components of social anxiety in their pathophysiology. The therapeutic role of oxytocin for social dysfunction in these disorders is discussed. PMID- 28867947 TI - Lactobacillus casei Encapsulated in Soy Protein Isolate and Alginate Microparticles Prepared by Spray Drying. AB - This article presents a novel formulation for preparation of Lactobacillus casei 01 encapsulated in soy protein isolate and alginate microparticles using spray drying method. A response surface methodology was used to optimise the formulation and the central composite face-centered design was applied to study the effects of critical material attributes and process parameters on viability of the probiotic after microencapsulation and in simulated gastrointestinal conditions. Spherical microparticles were produced in high yield (64%), narrow size distribution (d50=9.7 um, span=0.47) and favourable mucoadhesive properties, with viability of the probiotic of 11.67, 10.05, 9.47 and 9.20 log CFU/g after microencapsulation, 3 h in simulated gastric and intestinal conditions and four month cold storage, respectively. Fourier-transform infrared spectroscopy confirmed the probiotic stability after microencapsulation, while differential scanning calorimetry and thermogravimetry pointed to high thermal stability of the soy protein isolate-alginate microparticles with encapsulated probiotic. These favourable properties of the probiotic microparticles make them suitable for incorporation into functional food or pharmaceutical products. PMID- 28867948 TI - Biogas Production from Brewer's Yeast Using an Anaerobic Sequencing Batch Reactor. AB - Renewable energy sources are becoming increasingly important in the beverage and food industries. In the brewing industry, a significant percentage of the used raw materials finishes the process as secondary resource or waste. The research on the anaerobic digestion of brewer's yeast has been scarce until recent years. One of the reasons for this is its use as a secondary resource in the food industry and as cattle feed. Additionally, market value of brewer's yeast is higher than its energy value. Due to the increase of energy prices, brewer's yeast has become of interest as energy substrate despite its difficult degradability in anaerobic conditions. The anaerobic co-digestion of brewer's yeast and anaerobically treated brewery wastewater was studied using a pilot scale anaerobic sequencing batch reactor (ASBR) seeded with granular biomass. The experiments showed very good and stable operation with an organic loading rate of up to 8.0 kg/(m3.day), and with a maximum achieved organic loading rate of 13.6 kg/(m3.day) in a single cycle. A specific biogas productivity of over 0.430 m3/kg of the total chemical oxygen demand (COD) inserted, and total COD removal efficiencies of over 90% were achieved. This study suggests that the brewer's yeast can be successfully digested in an ASBR without adverse effects on the biogas production from brewer's yeast/wastewater mixtures of up to 8% (by volume). By using the brewer's yeast in the ASBR process, the biogas production from brewery wastewater could be increased by 50%. PMID- 28867949 TI - Hybrid Drying of Carrot Preliminary Processed with Ultrasonically Assisted Osmotic Dehydration. AB - In this paper the kinetics of osmotic dehydration of carrot and the influence of this pretreatment on the post-drying processes and the quality of obtained products are analysed. Osmotic dehydration was carried out in the aqueous fructose solution in two different ways: with and without ultrasound assistance. In the first part of the research, the kinetics of osmotic dehydration was analysed on the basis of osmotic dewatering rate, water loss and solid gain. Next, the effective time of dehydration was determined and in the second part of research samples were initially dehydrated for 30 min and dried. Five different procedures of drying were established on the grounds of convective method enhanced with microwave and infrared radiation. The influence of osmotic dehydration on the drying kinetics and final product quality was analysed. It was found that it did not influence the drying kinetics significantly but positively affected the final product quality. Negligible influence on the drying kinetics was attributed to solid uptake, which may block the pores, hindering heat and mass transfer. It was also concluded that the application of microwave and/or infrared radiation during convective drying significantly influenced the kinetics of the final stage of drying. A proper combination of aforementioned techniques of hybrid drying allows reducing the drying time. Differences between the particular dehydration methods and drying schedules were discussed. PMID- 28867950 TI - Extracellular Alkaline Lipase from a Novel Fungus?Curvularia sp. DHE 5: Optimisation of Physicochemical Parameters, Partial Purification and Characterisation. AB - Thirty isolated fungal strains were screened for lipase production using Phenol Red plates, containing tributyrin as lipidic substrate, and a novel fungus identified genetically as Curvularia sp. DHE 5 was found as the most prominent strain. Various agro-industrial substrates were evaluated as inert supports for lipase production in solid-state fermentation. The highest yield of lipase ((83.4+/-2.2) U/g on dry mass basis) was reported with wheat bran medium after seven days of fermentation at pH=7.0, temperature of 30 degrees C, 70% moisture content, inoculum size of 1.27.107 spore/mL and 2% olive oil as an inducer. Supplementation of the medium with 0.05% KCl as an ion source further increased lipase production to (88.9+/-1.2) U/g on dry mass basis. The enzyme was partially purified through ammonium sulphate fractionation (40%) followed by dialysis, and its optimum pH and temperature were reported at 8.0 and 50 degrees C, respectively, with remarkable pH and thermal stability. PMID- 28867951 TI - Brewery Waste Reuse for Protease Production by Lactic ?Acid Fermentation. AB - This study evaluated the use of three solid brewery wastes: brewer's spent grain, hot trub and residual brewer's yeast, as alternative media for the cultivation of lactic acid bacteria to evaluate their potential for proteolytic enzyme production. Initially, a mixture experimental design was used to evaluate the effect of each residue, as well as different mixtures (with the protein content set at 4%) in the enzyme production. At predetermined intervals, the solid and liquid fractions were separated and the extracellular proteolytic activity was determined. After selecting the best experimental conditions, a second experiment, factorial experimental design, was developed in order to evaluate the protein content in the media (1 to 7%) and the addition of fermentable sugar (glucose, 1 to 7%). Among the wastes, residual yeast showed the highest potential for the production of extracellular enzymes, generating a proteolytic extract with 2.6 U/mL in 3 h. However, due to the low content of the fermentable sugars in the medium, the addition of glucose also had a positive effect, increasing the proteolytic activity to 4.9 U/mL. The best experimental conditions of each experimental design were reproduced for comparison, and the enzyme content was separated by ethanol precipitation. The best medium produced a precipitated protein with proteolytic activity of 145.5 U/g. PMID- 28867952 TI - Production of gamma-Decalactone by Yeast Strains under ?Different Conditions. AB - gamma-Decalactone is a flavour compound that when obtained by biotechnological production using microorganisms is classified as natural. The aim of this study is to evaluate various conditions for gamma-decalactone production by tropical yeast strains Yarrowia lipolytica CCMA 0242 and Lindnera saturnus CCMA 0243. The growth of and gamma-decalactone production by Y. lipolytica CCMA 0242 were higher in castor oil than in glycerol. gamma-Decalactone production in single batch or fed-batch fermentation did not differ significantly. The gamma-decalactone production by L. saturnus CCMA 0243 was better at initial pH=5, while the production by Y. lipolytica CCMA 0242 was better at initial pH=6. The yeast L. saturnus CCMA 0243 produced more gamma-decalactone than Y. lipolytica CCMA 0242 under the same fermentation conditions. The crude glycerol was not an alternative substrate for gamma-decalactone production by Y. lipolytica CCMA 0242. Castor oil at volume fraction of 30% showed better results as a substrate. The strain L. saturnus CCMA 0243 showed better results of gamma-decalactone production. This yeast species can be considered an alternative producer of gamma-decalactone in biotechnological processes. PMID- 28867953 TI - Tween(r) 20-Enhanced Bioreduction of Acetophenones ?Promoted by Daucus carota Root. AB - The effect of surfactants on the bioreduction of acetophenones mediated by carrot (Daucus carota) root was investigated. Among the tested surfactants, Tween(r) 20 slightly improved the conversion. The amount of surfactant was optimised, and the presented methodology was applied to other substituted acetophenones, which led to the preparation of their respective optically enriched 1-phenylethanols with high conversion levels and high enantioselectivities. PMID- 28867954 TI - Evaluation of Solasonine Content and Expression Patterns ?of SGT1 Gene in Different Tissues of Two Iranian Eggplant (Solanum melongena L.) Genotypes. AB - Eggplant (Solanum melongena L.) is one of the most consumed vegetables in the world. The eggplant glycoalkaloids (GAs) are toxic secondary metabolites that may have detrimental effects on human health, particularly if the magnitudes of GAs are higher than the recommended food safety level (200 mg per kg of fresh mass). In this study, the content of solasonine compound and the expression patterns of solasodine galactosyltransferase (SGT1) gene were assessed in different tissues (mature leaves, flower buds, young, mature, and physiologically ripe fruits) of two Iranian eggplant genotypes (D1 and J10) under field conditions. The maximum mass fraction of solasonine in D1 was detected in flower buds (135.63 ug/g), followed by leaf (113.29 ug/g), physiologically ripe fruit (74.74 ug/g), young fruit (61.33 ug/g), and mature fruit (21.55 ug/g). Comparing both genotypes, the genotype of bitter fruits (J10) contained higher mass fraction of solasonine, as one of the main factors for producing bitter flavour of the plant. Regarding the expression profiles of SGT1, in both genotypes, the activity of the gene was increased nearly parallel with the concentration of solasonine. In the J10 genotype, transcript level of the gene was significantly higher than the genotype of sweet fruits (D1). Although both D1 and J10 genotypes are possibly recommendable for human food consumption, D1 is more suitable for daily diet. PMID- 28867955 TI - Effect of Microwave-Assisted Extraction on the Phenolic Compounds and Antioxidant Capacity of Blackthorn Flowers. AB - This research was undertaken to investigate the influence of extraction parameters during microwave-assisted extraction on total phenolic content, total flavonoids, total hydroxycinnamic acids and total flavonols of blackthorn flowers as well as to evaluate the antioxidant capacity by two different methods (2,2 diphenyl-1-picrylhydrazyl free radical scavenging capacity and ferric reducing antioxidant power assays). The investigated extraction parameters were: solvent type and volume fraction of alcohol in solvent (50 and 70% aqueous solutions of ethanol and methanol), extraction time (5, 15 and 25 min) and extraction temperature (40, 50 and 60 degrees C) controlled by microwave power of 100, 200 and 300 W. Multivariate analysis of variance (MANOVA) was used to evaluate the differences at a 95% confidence level (p<=0.05). The obtained results show that aqueous solution of ethanol was more appropriate solvent for extraction of phenolic compounds (total flavonoids, total hydroxycinnamic acids and total flavonols) than aqueous solution of methanol. The amount of phenolic compounds was higher in 70% aqueous solution of ethanol or methanol, while higher antioxidant capacity was observed in 50% aqueous solution of methanol. Higher temperature of extraction improved the amount of phenolic compounds and also antioxidant capacity determined by 2,2-diphenyl-1-picrylhydrazyl free radical scavenging capacity assay. Extensive duration of extraction (15- to 25-minute interval) has a significant effect only on the increase of total phenolic content, while specific phenolic compound content and antioxidant capacity were the highest when microwave extraction time of 5 min was applied. PMID- 28867957 TI - Synthesis of the Galactosyl Derivative of Gluconic Acid With the Transglycosylation Activity of beta-Galactosidase. AB - Bionic acids are bioactive compounds demonstrating numerous interesting properties. They are widely produced by chemical or enzymatic oxidation of disaccharides. This paper focuses on the galactosyl derivative of gluconic acid as a result of a new method of bionic acid synthesis which utilises the transglycosylation properties of beta-galactosidase and introduces lactose as a substrate. Products obtained in such a process are characterised by different structures (and, potentially, properties) than those resulting from traditional oxidation of disaccharides. The aim of this study is to determine the effect of selected parameters (concentration and ratio of substrates, dose of the enzyme, time, pH, presence of salts) on the course of the reaction carried out with the enzymatic preparation Lactozym, containing beta-galactosidase from Kluyveromyces lactis. Research has shown that increased dry matter content in the baseline solution (up to 50%, by mass per volume) and an addition of NaCl contribute to higher yield. On the other hand, reduced content of the derivative is a result of increased pH from 7.0 to 9.0 and an addition of magnesium and manganese salts. Moreover, exceeding the beta-galactosidase dose over approx. 35 000 U per 100 g of lactose also leads to reduced yield of the process. The most favourable molar ratio of sodium gluconate to lactose is 2.225:0.675. Depending on the conditions of the synthesis, the product concentration ranged between 17.3 and 118.3 g/L of the reaction mixture, which corresponded to the mass fraction of 6.64-23.7% of dry matter. The data obtained as a result of the present study may be useful for designing an industrial process. PMID- 28867956 TI - MEGGASENSE - The Metagenome/Genome Annotated Sequence Natural Language Search Engine: A Platform for ?the Construction of Sequence Data Warehouses. AB - The MEGGASENSE platform constructs relational databases of DNA or protein sequences. The default functional analysis uses 14 106 hidden Markov model (HMM) profiles based on sequences in the KEGG database. The Solr search engine allows sophisticated queries and a BLAST search function is also incorporated. These standard capabilities were used to generate the SCATT database from the predicted proteome of Streptomyces cattleya. The implementation of a specialised metagenome database (AMYLOMICS) for bioprospecting of carbohydrate-modifying enzymes is described. In addition to standard assembly of reads, a novel 'functional' assembly was developed, in which screening of reads with the HMM profiles occurs before the assembly. The AMYLOMICS database incorporates additional HMM profiles for carbohydrate-modifying enzymes and it is illustrated how the combination of HMM and BLAST analyses helps identify interesting genes. A variety of different proteome and metagenome databases have been generated by MEGGASENSE. PMID- 28867958 TI - Relationships Between Bioactive Compound Content and?the Antiplatelet and Antioxidant Activities of Six Allium Vegetable Species. AB - Allium sp. vegetables are widely consumed for their characteristic flavour. Additionally, their consumption may provide protection against cardiovascular disease due to their antiplatelet and antioxidant activities. Although antiplatelet and antioxidant activities in Allium sp. are generally recognised, comparative studies of antiplatelet and antioxidant potency among the main Allium vegetable species are lacking. Also, the relationship between organosulfur and phenolic compounds and these biological activities has not been well established. In this study, the in vitro antiplatelet and antioxidant activities of the most widely consumed Allium species are characterised and compared. The species total organosulfur and phenolic content, and the HPLC profiles of 11 phenolic compounds were characterised and used to investigate the relationship between these compounds and antiplatelet and antioxidant activities. Furthermore, antiplatelet activities in chives and shallot have been characterised for the first time. Our results revealed that the strongest antiplatelet agents were garlic and shallot, whereas chives had the highest antioxidant activity. Leek and bunching onion had the weakest both biological activities. Significantly positive correlations were found between the in vitro antiplatelet activity and total organosulfur (R=0.74) and phenolic (TP) content (R=0.73), as well as between the antioxidant activity and TP (R=0.91) and total organosulfur content (R=0.67). Six individual phenolic compounds were associated with the antioxidant activity, with catechin, epigallocatechin and epicatechin gallate having the strongest correlation values (R>0.80). Overall, our results suggest that both organosulfur and phenolic compounds contribute similarly to Allium antiplatelet activity, whereas phenolics, as a whole, are largely responsible for antioxidant activity, with broad variation observed among the contributions of individual phenolic compounds. PMID- 28867959 TI - Structural features and seismotectonic implications of coseismic surface ruptures produced by the 2016 Mw 7.1 Kumamoto earthquake. AB - Field investigations and analyses of satellite images and aerial photographs reveal that the 2016 Mw 7.1 (Mj 7.3) Kumamoto earthquake produced a ~40-km surface rupture zone striking NE-SW on central Kyushu Island, Japan. Coseismic surface ruptures were characterized by shear faults, extensional cracks, and mole tracks, which mostly occurred along the pre-existing NE-SW-striking Hinagu Futagawa fault zone in the southwest and central segments, and newly identified faults in the northeast segment. This study shows that (i) the Hinagu-Futagawa fault zone triggered the 2016 Kumamoto earthquake and controlled the spatial distribution of coseismic surface ruptures; (ii) the southwest and central segments were dominated by right-lateral strike-slip movement with a maximum in site measured displacement of up to 2.5 m, accompanied by a minor vertical component. In contrast, the northeast segment was dominated by normal faulting with a maximum vertical offset of up to 1.75 m with a minor horizontal component that formed graben structures inside Aso caldera; (iii) coseismic rupturing initiated at the jog area between the Hinagu and Futagawa faults, then propagated northeastward into Aso caldera, where it terminated. The 2016 Mw 7.1 Kumamoto earthquake therefore offers a rare opportunity to study the relationships between coseismic rupture processes and pre-existing active faults, as well as the seismotectonics of Aso volcano. PMID- 28867960 TI - Estimating the upper limit of prehistoric peak ground acceleration using an in situ, intact and vulnerable stalagmite from Plavecka priepast cave (Detrekoi zsomboly), Little Carpathians, Slovakia-first results. AB - Earthquakes hit urban centres in Europe infrequently, but occasionally with disastrous effects. Obtaining an unbiased view of seismic hazard (and risk) is therefore very important. In principle, the best way to test probabilistic seismic hazard assessments (PSHAs) is to compare them with observations that are entirely independent of the procedure used to produce PSHA models. Arguably, the most valuable information in this context should be information on long-term hazard, namely maximum intensities (or magnitudes) occurring over time intervals that are at least as long as a seismic cycle. The new observations can provide information of maximum intensity (or magnitude) for long timescale as an input data for PSHA studies as well. Long-term information can be gained from intact stalagmites in natural caves. These formations survived all earthquakes that have occurred over thousands of years, depending on the age of the stalagmite. Their 'survival' requires that the horizontal ground acceleration (HGA) has never exceeded a certain critical value within that time period. Here, we present such a stalagmite-based case study from the Little Carpathians of Slovakia. A specially shaped, intact and vulnerable stalagmite in the Plavecka priepast cave was examined in 2013. This stalagmite is suitable for estimating the upper limit of horizontal peak ground acceleration generated by prehistoric earthquakes. The critical HGA values as a function of time going back into the past determined from the stalagmite that we investigated are presented. For example, at the time of Joko event (1906), the critical HGA value cannot have been higher than 1 and 1.3 m/s2 at the time of the assumed Carnuntum event (~340 AD), and 3000 years ago, it must have been lower than 1.7 m/s2. We claimed that the effect of Joko earthquake (1906) on the location of the Plavecka priepast cave is consistent with the critical HGA value provided by the stalagmite we investigated. The approach used in this study yields significant new constraints on the seismic hazard, as tectonic structures close to Plavecka priepast cave did not generate strong earthquakes in the last few thousand years. The results of this study are highly relevant given that the two capitals, Vienna and Bratislava, are located within 40 and 70 km of the cave, respectively. PMID- 28867961 TI - Potential immunotoxic effects of trichloroethylene-induced IV allergic reaction in renal impairment. AB - Trichloroethylene (TCE) is known to induce allergic contact dermatitis and subsequent occupational medicamentosa-like dermatitis (OMLD) with multi-system injuries, including liver, kidney, and skin injuries. However, the mechanisms underlying immune system dysfunction that result in organ injury have not yet been clearly elucidated. In the present study, we measured the levels of secreted cytokines by effect or T cells in TCE-treated guinea pigs to better understand the contribution of allergic disorders in renal injuries. We immunized guinea pigs with trichloroethylene using the Guinea Pig Maximization Test (GPMT) and scored the inflammation on the guinea pigs' skin. The kidney function and ultra structural changes in the kidneys were detected using biochemical methods and electron microscopy. The deposition of cytokines was determined using immunohistochemistry. The sensitization rate was 63.16% in the TCE-sensitized groups. The electron microscopy results showed tubular epithelial cell mitochondrial swelling, vacuolar degeneration, and atrophy of the microvillus in the sensitized groups. A high degree of cytokine deposition was observed in the renal tubular proximal epithelial cells in the TCE-sensitized groups. As observed in this study, the variation in the level of immune system activation not only indicates that TCE can largely magnify the immune reaction but also suggests a potential role of immune dysfunction in renal impairment. PMID- 28867963 TI - Phase space of modified Gauss-Bonnet gravity. AB - We investigate the evolution of non-vacuum Friedmann-Lemaitre-Robertson-Walker (FLRW) spacetimes with any spatial curvature in the context of Gauss-Bonnet gravity. The analysis employs a new method which enables us to explore the phase space of any specific theory of this class. We consider several examples, discussing the transition from a decelerating into an acceleration universe within these theories. We also deduce from the dynamical equations some general conditions on the form of the action which guarantee the presence of specific behaviours like the emergence of accelerated expansion. As in f(R) gravity, our analysis shows that there is a set of initial conditions for which these models have a finite time singularity which can be an attractor. The presence of this instability also in the Gauss-Bonnet gravity is to be ascribed to the fourth order derivative in the field equations, i.e., is the direct consequence of the higher order of the equations. PMID- 28867964 TI - Weights and importance in composite indicators: Closing the gap. AB - Composite indicators are very popular tools for assessing and ranking countries and institutions in terms of environmental performance, sustainability, and other complex concepts that are not directly measurable. Because of the stakes that come with the media attention of these tools, a word of caution is warranted. One common misconception relates to the effect of the weights assigned to indicators during the aggregation process. This work presents a novel series of tools that allow developers and users of composite indicators to explore effects of these weights. First, the importance of each indicator to the composite is measured by the nonlinear Pearson correlation ratio, estimated by Bayesian Gaussian processes. Second, the effect of each indicator is isolated from that of other indicators using regression analysis, and examined in detail. Finally, an optimisation procedure is proposed which allows weights to be fitted to agree with pre-specified values of importance. These three tools together give developers considerable insight into the effects of weights and suggest possibilities for refining and simplifying the aggregation. The added value of these tools are shown on three case studies: the Resource Governance Index, the Good Country Index, and the Water Retention Index. PMID- 28867962 TI - Vaccine research and development: tuberculosis as a global health threat. AB - One of the aims of the World Health Organisation (WHO) Millennium Development Goals (MDG) is to reduce the number of cases of tuberculosis (TB) infection by the year 2015. However, 9 million new cases were reported in 2013, with an estimated 480,000 new cases of multi-drug resistant tuberculosis (MDR-TB) globally. Bacille Calmette-Guerin (BCG) is the most available and currently used candidate vaccine against tuberculosis; it prevents childhood TB, but its effectiveness against pulmonary TB in adults and adolescents is disputed. To achieve the goal of the WHO MDG, the need for a new improved vaccine is of primary importance. This review highlights several articles that have reported vaccine development. There are about 16 TB vaccines in different phases of clinical trials at the time of writing, which include recombinant peptide/protein, live-attenuated and recombinant live-attenuated, protein/adjuvant, viral-vectored, and immunotherapeutic vaccine. Further studies in reverse vaccinology and massive campaigns on vaccination are needed in order to achieve the target for TB eradication by 2050. PMID- 28867965 TI - Play as third space between home and school: Bridging cultural discourses. AB - This article examines play as a conceptual third space that serves as a bridge between home and school discourses. Using sociocultural theories and an interpretivist framework, 19 immigrant mothers and their children in Canada were interviewed about their play experiences at home and in preschools. The findings reveal that children and teachers utilise play as third space in various ways. Although there is some cultural dissonance experienced by children, this study illustrates ways that children use play as a bridge between home and school and explores strategies that teachers use in supporting children's use of play as third space. As children navigate these two cultural sites, they accumulate funds of knowledge and life experiences, which then meet, interact and perhaps fuse together in the conceptual third space. The conclusion proposes that 'play as third space' can be used as a conceptual framework for educators and practitioners to support children's transition from home to school and assist children who experience discontinuities. PMID- 28867966 TI - Investigation of the Evolution of Crystal Size and Shape during Temperature Cycling and in the Presence of a Polymeric Additive Using Combined Process Analytical Technologies. AB - Crystal size and shape can be manipulated to enhance the qualities of the final product. In this work the steady-state shape and size of succinic acid crystals, with and without a polymeric additive (Pluronic P123) at 350 mL, scale is reported. The effect of the amplitude of cycles as well as the heating/cooling rates is described, and convergent cycling (direct nucleation control) is compared to static cycling. The results show that the shape of succinic acid crystals changes from plate- to diamond-like after multiple cycling steps, and that the time required for this morphology change to occur is strongly related to the type of cycling. Addition of the polymer is shown to affect both the final shape of the crystals and the time needed to reach size and shape steady-state conditions. It is shown how this phenomenon can be used to improve the design of the crystallization step in order to achieve more efficient downstream operations and, in general, to help optimize the whole manufacturing process. PMID- 28867967 TI - Achalasia. PMID- 28867969 TI - An Overview of Achalasia and Its Subtypes. AB - Achalasia is one of the most studied esophageal motility disorders. However, the pathophysiology and reasons that patients develop achalasia are still unclear. Patients often present with dysphagia to solids and liquids, regurgitation, and varying degrees of weight loss. There is significant latency prior to diagnosis, which can have nutritional implications. The diagnosis is suspected based on clinical history and confirmed by esophageal high-resolution manometry testing. Esophagogastroduodenoscopy is necessary to rule out potential malignancy that can mimic achalasia. Recent data presented in abstract form suggest that patients with type II achalasia may be most likely, and patients with type III achalasia may be least likely, to report weight loss compared to patients with type I achalasia. Although achalasia cannot be permanently cured, palliation of symptoms is possible in over 90% of patients with the treatment modalities currently available (pneumatic dilation, Heller myotomy, or peroral endoscopic myotomy). This article reviews the clinical presentation, diagnosis, and management options in patients with achalasia, as well as potential insights into histopathologic differences and nutritional implications of the subtypes of achalasia. PMID- 28867968 TI - Advances and Future Directions in the Treatment of Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Liver transplant is considered the gold standard for curative therapy for HCC when patients are not candidates for surgical resection or ablation. Because a subset of patients with HCC have a survival rate with liver transplantation that is comparable to that of cirrhotic patients without tumors, the organ allocation system allows for increased priority for transplant in potential recipients within the Milan criteria. With the recent change in the Model for End-Stage Liver Disease exception point allocation, patients with HCC will now need to wait at least 6 months before being awarded extra points. This extension leads to increased time on the transplant waiting list and underscores the importance of locoregional therapy to contain the tumor burden. Fortunately, there has been significant progress in therapy for HCC in the past few decades, namely due to advances in interventional radiology, radiotherapy, and expanded surgical and transplant criteria. Recent advances in immunotherapy also provide promising options for patients who are not candidates for other therapies. This article highlights the major therapeutic options for HCC, including surgical resection, liver transplant, thermal and nonthermal ablation, chemoembolization, radiotherapy, and systemic chemotherapy, as well as discusses the evidence supporting these approaches. PMID- 28867971 TI - Treatment of Alcoholic Liver Disease. PMID- 28867970 TI - Occurrence and Recurrence of Hepatocellular Carcinoma After Successful Direct Acting Antiviral Therapy for Patients With Chronic Hepatitis C Virus Infection. AB - Chronic hepatitis C virus (HCV) infection has generally been associated with a slightly increased risk of developing hepatocellular carcinoma (HCC). For the past several decades, most patients with chronic HCV cirrhosis have been treated with pegylated interferon and ribavirin therapies, which were known to achieve sustained virologic response (SVR) but also carried their own side effects and toxicities. The recent implementation of direct-acting antiviral (DAA) treatments revealed an increased efficacy in difficult-to-treat populations and higher adherence rates given the all-oral nature of the regimens. However, while these regimens are excellent in terms of improving the side-effect profile and achieving SVR at a higher rate and in a shorter time frame than interferon and ribavirin, some researchers are now discovering an increased rate of de novo and recurrent HCC in patients with HCV cirrhosis compared to interferon treatment protocols. Although other studies were not able to reproduce similar findings, the question as to the role of DAA therapy in HCC occurrence after achieving SVR in patients with HCV cirrhosis continues to persist. Possible theories as to the mechanisms behind tumor relapse after DAA therapy include alterations of immunosurveillance and gene expression, a protective and antineoplastic effect from inflammation secondary to chronic HCV infection that is then abolished with DAA therapy, and delay in radiographic identification of previously undetectable tumors. This article reviews the current literature regarding concern for the possible increase of HCC after DAA therapy. PMID- 28867972 TI - Peroral Endoscopic Myotomy for the Management of Esophageal Disorders. PMID- 28867973 TI - Vaccination of Patients With Inflammatory Bowel Disease. PMID- 28867974 TI - The Effect of Digital Health Technology on Patient Care and Research. PMID- 28867976 TI - Health Maintenance in Inflammatory Bowel Disease. PMID- 28867977 TI - GASTRO-HEP News. PMID- 28867975 TI - Serous Microcystic Adenoma of the Pancreas. PMID- 28867978 TI - When Not to Pouch: Important Considerations for Patient Selection for Ileal Pouch Anal Anastomosis. AB - Ileal pouch-anal anastomosis (IPAA) is the preferred surgical treatment for patients who undergo colectomy and wish to avoid a permanent ileostomy. The overall outcomes are positive, with an improved quality of life and stable long term pouch retention. However, certain conditions or disease states may be at a higher risk of pouch dysfunction or failure. For example, obese patients have an increased risk for postoperative complications. In addition, women with a history of obstetric complications and elderly patients with a history of sphincter damage or dysfunction may be at an increased risk for postoperative incontinence, although quality-of-life indices do not necessarily correlate with incontinence scores. Advanced age itself is not a contraindication to pouch surgery, and elderly patients can be considered for IPAA based on individual functionality and comorbidities. Pelvic radiation may lead to pouch dysfunction. Finally, patients with Crohn's disease and indeterminate colitis may have increased complications with IPAA, but highly specific patient selection leads to good rates of pouch retention. This article examines several clinical scenarios that require careful thought prior to considering IPAA. PMID- 28867979 TI - Approach to Incomplete Colonoscopy: New Techniques and Technologies. AB - Colonoscopy is the most widely used screening modality for the detection and removal of colon polyps and for the prevention of colorectal cancer. To identify all colon lesions and reduce the risk of colorectal cancer, it is important to perform a complete colonoscopy. The success of screening colonoscopy depends upon several parameters, including bowel preparation and adenoma detection rate. Incomplete colonoscopy rates vary from 4% to 25% and are associated with higher rates of interval proximal colon cancer. This article reviews the potential causes of and preventive measures for incomplete colonoscopy, as well as techniques and technologies that may improve the rate of complete colonoscopy. PMID- 28867981 TI - Review of Regorafenib for the Treatment of Hepatocellular Carcinoma. PMID- 28867980 TI - The Enigma of Hepatitis E Virus. AB - Globally, hepatitis E virus (HEV) is the most common cause of acute viral hepatitis. HEV is endemic in many developing countries, yet it is far more common in industrialized, nonendemic countries than previously recognized. Nonetheless, HEV remains poorly characterized and is frequently unidentified or misdiagnosed by clinicians. Manifestation of disease, source of infection, and route of transmission vary by HEV genotype and epidemiology in endemic and nonendemic settings worldwide. HEV infection can be acute or chronic, further complicating the presentation, diagnosis, prognosis, and natural history of disease. However, accurate identification and diagnosis of HEV has important implications for patient management, disease control, prevention efforts, and characterization of mechanisms of transmission and epidemiology. Acute HEV infection is rarely diagnosed in industrialized, nonendemic countries; however, recent seroprevalence data collected using modern, highly sensitive testing assays demonstrate a surprisingly high prevalence of anti-HEV antibodies in these settings, suggesting common subclinical or unrecognized infection. These data suggest widespread underestimation of the global burden, population seroprevalence, and importance of HEV infection. Enhanced capacity for disease recognition, accurate diagnosis, and clinical awareness are critical to improving the management and reducing the burden of HEV infection worldwide. PMID- 28867982 TI - Endoscopic Ultrasound-Guided Fine-Needle Aspiration Vs Fine-Needle Biopsy. PMID- 28867983 TI - Health Maintenance Assessment for Patients With Inflammatory Bowel Disease. PMID- 28867984 TI - Management of Autoimmune Hepatitis in Pregnant Women. PMID- 28867985 TI - Acetic Acid Chromoendoscopy in the Setting of Neoplastic Barrett Esophagus. PMID- 28867987 TI - Remote sensing monitoring of land restoration interventions in semi-arid environments with a before-after control-impact statistical design. AB - Restoration interventions to combat land degradation are carried out in arid and semi-arid areas to improve vegetation cover and land productivity. Evaluating the success of an intervention over time is challenging due to various constraints (e.g. difficult-to-access areas, lack of long-term records) and the lack of standardised and affordable methodologies. We propose a semi-automatic methodology that uses remote sensing data to provide a rapid, standardised and objective assessment of the biophysical impact, in terms of vegetation cover, of restoration interventions. The Normalised Difference Vegetation Index (NDVI) is used as a proxy for vegetation cover. Recognising that changes in vegetation cover are naturally due to environmental factors such as seasonality and inter annual climate variability, conclusions about the success of the intervention cannot be drawn by focussing on the intervention area only. We therefore use a comparative method that analyses the temporal variations (before and after the intervention) of the NDVI of the intervention area with respect to multiple control sites that are automatically and randomly selected from a set of candidates that are similar to the intervention area. Similarity is defined in terms of class composition as derived from an ISODATA classification of the imagery before the intervention. The method provides an estimate of the magnitude and significance of the difference in greenness change between the intervention area and control areas. As a case study, the methodology is applied to 15 restoration interventions carried out in Senegal. The impact of the interventions is analysed using 250-m MODIS and 30-m Landsat data. Results show that a significant improvement in vegetation cover was detectable only in one third of the analysed interventions, which is consistent with independent qualitative assessments based on field observations and visual analysis of high resolution imagery. Rural development agencies may potentially use the proposed method for a first screening of restoration interventions. PMID- 28867986 TI - Ecdysteroids: production in plant in vitro cultures. AB - Ecdysteroids are secondary metabolites, widely distributed in the animal and plant kingdoms. They have a wide range of pharmacological effects in vertebrates, including mammals, most of which are beneficial for humans. Therefore, they have become compounds of interest for the pharmaceutical industry due to their adaptogenic, anabolic, hypoglycaemic, hypocholesterolaemic and antimicrobial activities, which are still being researched. Nowadays, ecdysteroids are present as active ingredients in bodybuilding supplements. Because of their complex structures, their chemical synthesis seems unprofitable and impractical. Due to high content of ecdysteroids in many plants, they are primarily obtained by extraction of the plant material. Plant in vitro cultures provide an alternative source of these compounds, helping to avoid problems associated with field production-such as variable yield or dependence on environmental factors, as well as limited availability of natural resources. Plant cell and tissue cultures may be suggested as alternatives for the production of plant biomass rich in pharmaceutically active ecdysteroids. Moreover, the use of common biotechnological strategies, such as elicitation or precursor feeding, may further increase the yield and improve production of these compounds. In this paper, we describe general information about ecdysteroids: their structure, biosynthesis, distribution, role in plants, and we review recent studies on micropropagation of ecdysteroid-producing plants and cell cultures, and potential ability of ecdysteroids enhancement in in vitro cultures. PMID- 28867988 TI - Identification of weak and gender specific effects in a short 3 weeks intervention study using barley and oat mixed linkage beta-glucan dietary supplements: a human fecal metabolome study by GC-MS. AB - INTRODUCTION: Mixed-linkage (1->3),(1->4)-beta-d-glucans (BG) reduce cholesterol level and insulin response in humans. Despite this, their role in human metabolism and a mode of action remains largely unknown. OBJECTIVES: To investigate the effects of three structurally different BG on human fecal metabolome in a full cross-over intervention using GC-MS metabolomics. METHODS: Over three weeks of intervention, young healthy adults received food supplemented with BG from oat, two different BG from barley or a non-fiber control in a full cross-over design. Untargeted metabolomics and short chain fatty acid analysis was performed on day three fecal samples. ANOVA-simultaneous component analysis was applied to partition the data variation according to the study design, and PLS-DA was used to select most discriminative metabolite markers. RESULTS: Univariate and multivariate data analysis revealed a dominating effect of inter individual variances followed by a gender effect. Weak effects of BG intake were identified including an increased level of gamma-amino-butyrate and palmitoleic acid in males and a decreased level of enterolactone in females. Barley and oat derived BG were found to influence the human fecal metabolome differently. Barley BG increased the relative level of formate in males and isobutyrate, isovalerate, 2-methylbutyrate in females. In total 15, 3 and 11 human fecal metabolites were significantly different between control vs. BG, control vs. oat BG, and barley BG vs. oat BG, respectively. CONCLUSIONS: The study show that human fecal metabolome largely reflects individual (~28% variation) and gender (~15% variation) differences, whereas the treatment effect of the BG (~8% variation) only manifests in a few key metabolites (primarily by the metabolites: d-2 aminobutyric acid, palmitoleic acid, linoleic acid and 11-eicosenoic acid). PMID- 28867990 TI - ECG Parameters for Malignant Ventricular Arrhythmias: A Comprehensive Review. AB - Many studies showed electrocardiogram (ECG) parameters are useful for predicting fatal ventricular arrhythmias (VAs). However, the studies have several shortcomings. Firstly, all studies lack of effective way to present behavior of various ECG parameters prior to the occurrence of the VAs. Secondly, they also lack of discussion on how to consider the parameters as abnormal. Thirdly, the reports do not include approaches to increase the detection accuracy for the abnormal patterns. The purpose of this study is to address the aforementioned issues. It identifies ten ECG parameters from various sources and then presents a review based on the identified parameters. From the review, it has been found that the increased risk of VAs can be represented by presence and certain abnormal range of the parameters. The variation of parameters range could be influenced by either gender or age. This study also has discovered the facts that averaging, outliers elimination and morphology detection algorithms can contribute to the detection accuracy. PMID- 28867991 TI - Video Voiding Device for Diagnosing Lower Urinary Tract Dysfunction in Men. AB - We introduce a novel diagnostic Visual Voiding Device (VVD), which has the ability to visually document urinary voiding events and calculate key voiding parameters such as instantaneous flow rate. The observation of the urinary voiding process along with the instantaneous flow rate can be used to diagnose symptoms of Lower Urinary Tract Dysfunction (LUTD) and improve evaluation of LUTD treatments by providing subsequent follow-up documentations of voiding events after treatments. The VVD enables a patient to have a urinary voiding event in privacy while a urologist monitors, processes, and documents the event from a distance. The VVD consists of two orthogonal cameras which are used to visualize urine leakage from the urethral meatus, urine stream trajectory, and its break-up into droplets. A third, lower back camera monitors a funnel topped cylinder where urine accumulates that contains a floater for accurate readings regardless of the urine color. Software then processes the change in level of accumulating urine in the cylinder and the visual flow properties to calculate urological parameters. Video playback allows for reexamination of the voiding process. The proposed device was tested by integrating a mass flowmeter into the setup and simultaneously measuring the instantaneous flow rate of a predetermined voided volume in order to verify the accuracy of VVD compared to the mass flowmeter. The VVD and mass flowmeter were found to have an accuracy of +/-2 and +/-3% relative to full scale, respectively. A VVD clinical trial was conducted on 16 healthy male volunteers ages 23-65. PMID- 28867992 TI - Analysis of Locking Self-Taping Bone Screws for Angularly Stable Plates. AB - Paper focuses on biomechanics, specifically on locking cortical bone screws in angularly stable plates used for the treatment of bone fractures in the medical fields of traumatology and orthopaedics. During extraction of titanium-alloy implants, problems are encountered in an effort to loosen some locking bone screws from the locking holes of an angularly stable plate and the subsequent stripping of the internal hexagon of the screw head. The self-locking of the screw-plate threaded joint was verified by calculation and the effect of the angle of the thread on the head of the locking cortical bone screw on self locking was evaluated. The magnitude of the torque, causing the stripping of the internal hexagon (the Inbus type head) of a locking cortical bone screw with a shank diameter of 3.5 mm from Ti6Al4 V titanium alloy to ISO 5832-3, was determined experimentally. Also, it was experimentally found that the rotation of the screwdriver end with a hexagonal tip inside the locking cortical bone screw head during stripping of the internal hexagon causes strain of the screw head perimeter and thereby an increase of thread friction. The effect of tightening torque on the possibility of loosening of the locking cortical bone screw from the locking hole of an angularly stable plate was assessed experimentally. From the evaluation of five alternative shapes of locking cortical bone screw heads in terms of the acting stress and generated strains, it follows that the best screw is the screw with the Torx type head, which demonstrates the lowest values of reduced stress and equivalent plastic strain. Based on experiments and simulations the authors recommend that all global producers of locking cortical bone screws for locking holes of angularly stable plates use the Torx type heads, and not heads of the Inbus type or the Square, PH, PZ types. PMID- 28867989 TI - Exhaled breath analysis: a review of 'breath-taking' methods for off-line analysis. AB - BACKGROUND: The potential of exhaled breath sampling and analysis has long attracted interest in the areas of medical diagnosis and disease monitoring. This interest is attributed to its non-invasive nature, access to an unlimited sample supply (i.e., breath), and the potential to facilitate a rapid at patient diagnosis. However, progress from laboratory setting to routine clinical practice has been slow. Different methodologies of breath sampling, and the consequent difficulty in comparing and combining data, are considered to be a major contributor to this. To fulfil the potential of breath analysis within clinical and pre-clinical medicine, standardisation of some approaches to breath sampling and analysis will be beneficial. OBJECTIVES: The aim of this review is to investigate the heterogeneity of breath sampling methods by performing an in depth bibliometric search to identify the current state of art in the area. In addition, the review will discuss and critique various breath sampling methods for off-line breath analysis. METHODS: Literature search was carried out in databases MEDLINE, BIOSIS, EMBASE, INSPEC, COMPENDEX, PQSCITECH, and SCISEARCH using the STN platform which delivers peer-reviewed articles. Keywords searched for include breath, sampling, collection, pre-concentration, volatile. Forward and reverse search was then performed on initially included articles. The breath collection methodologies of all included articles was subsequently reviewed. RESULTS: Sampling methods differs between research groups, for example regarding the portion of breath being targeted. Definition of late expiratory breath varies between studies. CONCLUSIONS: Breath analysis is an interdisciplinary field of study using clinical, analytical chemistry, data processing, and metabolomics expertise. A move towards standardisation in breath sampling is currently being promoted within the breath research community with a view to harmonising analysis and thereby increasing robustness and inter-laboratory comparisons. PMID- 28867995 TI - Does Spatial Navigation Have a Blind-Spot? Visiocentrism Is Not Enough to Explain the Navigational Behavior Comprehensively. PMID- 28867993 TI - Impact of Prefrontal Theta Burst Stimulation on Clinical Neuropsychological Tasks. AB - Theta burst stimulation (TBS) protocols hold high promise in neuropsychological rehabilitation. Nevertheless, their ability to either decrease (continuous, cTBS) or increase (intermittent, iTBS) cortical excitability in areas other than the primary motor cortex, and their consistency modulating human behaviors with clinically relevant tasks remain to be fully established. The behavioral effects of TBS over the dorsolateral prefrontal cortex (dlPFC) are particularly interesting given its involvement in working memory (WM) and executive functions (EF), often impaired following frontal brain damage. We aimed to explore the ability of cTBS and iTBS to modulate WM and EF in healthy individuals, assessed with clinical neuropsychological tests (Digits Backward, 3-back task, Stroop Test, and Tower of Hanoi). To this end, 36 participants were assessed using the four tests 1 week prior to stimulation and immediately following a single session of either cTBS, iTBS, or sham TBS, delivered to the left dlPFC. No significant differences were found across stimulation conditions in any of the clinical tasks. Nonetheless, in some of them, active stimulation induced significant pre/post performance modulations, which were not found for the sham condition. More specifically, sham stimulation yielded improvements in the 3-back task and the Color, Color-Word, and Interference Score of the Stroop Test, an effect likely caused by task practice. Both, iTBS and cTBS, produced improvements in Digits Backward and impairments in 3-back task accuracy. Moreover, iTBS increased Interference Score in the Stroop Test in spite of the improved word reading and impaired color naming, whereas cTBS decreased the time required to complete the Tower of Hanoi. Differing from TBS outcomes reported for cortico-spinal measures on the primary motor cortex, our analyses did not reveal any of the expected performance differences across stimulation protocols. However, if one considers independently pre/post differences for each individual outcome measure and task, either one or both of the active protocols appeared to modulate WM and EF. We critically discuss the value, potential explanations, and some plausible interpretations for this set of subtle impacts of left dlPFC TBS in humans. PMID- 28867994 TI - An Antioxidant Screen Identifies Candidates for Protection of Cochlear Hair Cells from Gentamicin Toxicity. AB - : Reactive oxygen species are important elements in ototoxic damage to hair cells (HCs), appearing early in the damage process. Higher levels of natural antioxidants are positively correlated with resistance to ototoxins and many studies have shown that exogenous antioxidants can protect HCs from damage. While a very wide variety of antioxidants with different characteristics and intracellular targets exist, most ototoxicity studies have focused upon one or a few well-characterized compounds. Relatively little research has attempted to determine the comparative efficacy of large variety of different antioxidants. This has been in part due to the lack of translation between cell culture and in vivo measures of efficacy. To circumvent this limitation, we used an in vitro assay based on micro-explants from the basal and middle turns of the neonatal mouse organ of Corti to screen a commercial redox library of diverse antioxidant compounds for their ability to protect mammalian HCs from a high dose of the ototoxic antibiotic gentamicin. The library included several antioxidants that have previously been studied as potential treatments for HC damage, as well as many antioxidants that have never been applied to ototoxicity. The micro-explants were treated with 200 MUM gentamicin alone, gentamicin plus one of three dosages of a redox compound, the highest dosage of compound alone, or were untreated. HC counts were determined before the gentamicin insult and at 1, 2, and 3 days afterward to evaluate the HC survival. From a total of 81 antioxidant compounds, 13 exhibited significant protection of HCs. These included members of a variety of antioxidant classes with several novel antioxidants, not previously tested on HCs, appearing to alleviate the damaging gentamicin effect. Some compounds previously shown to be protective of HCs were correspondingly protective in this in vitro screen, while others were not. Finally, one of the three pro-oxidant compounds included in the library as well as six antioxidants exhibited evidence of toxicity in the absence of gentamicin. The results demonstrate the wide variability in the ability of antioxidants to protect HCs from high-dose gentamicin damage, and identify promising candidate leads for further study as potential drug targets. HIGHLIGHTS: * A medium-throughput assay based on micro explants of the organ of Corti was developed to screen mammalian cochlear hair cells for protection from damage by ototoxins.* Eighty one antioxidants and 3 pro oxidants were evaluated for hair cell protection from high-dose gentamicin.* Thirteen antioxidants were significantly protective, while 6 proved to be damaging.* The use of a common assay permitted an evaluation of the relative capacity of different antioxidants for the protection of hair cells. PMID- 28867996 TI - Neural Signatures of Rational and Heuristic Choice Strategies: A Single Trial ERP Analysis. AB - In multi-attribute choice, people use heuristics to simplify decision problems. We studied the use of heuristic and rational strategies and their electrophysiological correlates. Since previous work linked the P3 ERP component to attention and decision making, we were interested whether the amplitude of this component is associated with decision strategy use. To this end, we recorded EEG when participants performed a two-alternative choice task, where they could acquire decision cues in a sequential manner and use them to make choices. We classified participants' choices as consistent with a rational Weighted Additive rule (WADD) or a simple heuristic Take The Best (TTB). Participants differed in their preference for WADD and TTB. Using a permutation-based single trial approach, we analyzed EEG responses to consecutive decision cues and their relation to the individual strategy preference. The preference for WADD over TTB was associated with overall higher signal amplitudes to decision cues in the P3 time window. Moreover, the preference for WADD was associated with similar P3 amplitudes to consecutive cues, whereas the preference for TTB was associated with substantial decreases in P3 amplitudes to consecutive cues. We also found that the preference for TTB was associated with enhanced N1 component to cues that discriminated decision alternatives, suggesting very early attention allocation to such cues by TTB users. Our results suggest that preference for either WADD or TTB has an early neural signature reflecting differences in attentional weighting of decision cues. In light of recent findings and hypotheses regarding P3, we interpret these results as indicating the involvement of catecholamine arousal systems in shaping predecisional information processing and strategy selection. PMID- 28867997 TI - Autism Spectrum Disorder Related Functional Connectivity Changes in the Language Network in Children, Adolescents and Adults. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disability with global implication. Altered brain connectivity in the language network has frequently been reported in ASD patients using task-based functional magnetic resonance imaging (fMRI) compared to typically developing (TD) participants. Most of these studies have focused on a specific age group or mixed age groups with ASD. In the current study, we investigated age-related changes in functional connectivity related measure, degree centrality (DC), in the language network across three age groups with ASD (113 children, 113 adolescents and 103 adults) using resting state fMRI data collected from the autism brain imaging data exchange repository. We identified regions with significant group-wise differences between ASD and TD groups for three age cohorts using DC based on graph theory. We found that both children and adolescents with ASD showed decreased DC in Broca's area compared to age-matched TD groups. Adults with ASD showed decreased DC in Wernicke's area compared to TD adults. We also observed increased DC in the left inferior parietal lobule (IPL) and left middle temporal gyrus (MTG) for children with ASD compared to TD children and for adults with ASD compared to TD adults, respectively. Overall, functional differences occurred in key language processing regions such as the left inferior frontal gyrus (IFG) and superior temporal gyrus (STG) related to language production and comprehension across three age cohorts. We explored correlations between DC values of our findings with autism diagnostic observation schedule (ADOS) scores related to severity of ASD symptoms in the ASD group. We found that DC values of the left IFG demonstrated negative correlations with ADOS scores in children and adolescents with ASD. The left STG showed significant negative correlations with ADOS scores in adults with ASD. These results might shed light on the language network regions that should be further explored for prognosis, diagnosis, and monitoring of ASD in three age groups. PMID- 28867999 TI - Time-Varying Networks of Inter-Ictal Discharging Reveal Epileptogenic Zone. AB - The neuronal synchronous discharging may cause an epileptic seizure. Currently, most of the studies conducted to investigate the mechanism of epilepsy are based on EEGs or functional magnetic resonance imaging (fMRI) recorded during the ictal discharging or the resting-state, and few studies have probed into the dynamic patterns during the inter-ictal discharging that are much easier to record in clinical applications. Here, we propose a time-varying network analysis based on adaptive directed transfer function to uncover the dynamic brain network patterns during the inter-ictal discharging. In addition, an algorithm based on the time varying outflow of information derived from the network analysis is developed to detect the epileptogenic zone. The analysis performed revealed the time-varying network patterns during different stages of inter-ictal discharging; the epileptogenic zone was activated prior to the discharge onset then worked as the source to propagate the activity to other brain regions. Consistence between the epileptogenic zones detected by our proposed approach and the actual epileptogenic zones proved that time-varying network analysis could not only reveal the underlying neural mechanism of epilepsy, but also function as a useful tool in detecting the epileptogenic zone based on the EEGs in the inter-ictal discharging. PMID- 28867998 TI - Functional Magnetic Resonance Imaging and Functional Near-Infrared Spectroscopy: Insights from Combined Recording Studies. AB - Although blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) is a widely available, non-invasive technique that offers excellent spatial resolution, it remains limited by practical constraints imposed by the scanner environment. More recently, functional near infrared spectroscopy (fNIRS) has emerged as an alternative hemodynamic-based approach that possesses a number of strengths where fMRI is limited, most notably in portability and higher tolerance for motion. To date, fNIRS has shown promise in its ability to shed light on the functioning of the human brain in populations and contexts previously inaccessible to fMRI. Notable contributions include infant neuroimaging studies and studies examining full-body behaviors, such as exercise. However, much like fMRI, fNIRS has technical constraints that have limited its application to clinical settings, including a lower spatial resolution and limited depth of recording. Thus, by combining fMRI and fNIRS in such a way that the two methods complement each other, a multimodal imaging approach may allow for more complex research paradigms than is feasible with either technique alone. In light of these issues, the purpose of the current review is to: (1) provide an overview of fMRI and fNIRS and their associated strengths and limitations; (2) review existing combined fMRI-fNIRS recording studies; and (3) discuss how their combined use in future research practices may aid in advancing modern investigations of human brain function. PMID- 28868000 TI - Fiberweb: Diffusion Visualization and Processing in the Browser. AB - Data visualization is one of the most important tool to explore the brain as we know it. In this work, we introduce a novel browser-based solution for medical imaging data visualization and interaction with diffusion-weighted magnetic resonance imaging (dMRI) and tractography data: Fiberweb. It uses a recent technology, WebGL, that has yet to be fully explored for medical imaging purposes. There are currently very few software tools that allow medical imaging data visualization in the browser, and none of these tools support efficient data interaction and processing, such as streamlines selection and real-time deterministic and probabilistic tractography (RTT). With Fiberweb allowing these types of interaction, it is no longer the case. We show results of the visualization of medical imaging data, and demonstrate that our new RTT probabilistic algorithm can compare to a state of the art offline algorithm. Overall, Fiberweb pushes the boundary of interaction combined with scientific visualization, which opens great perspectives for quality control and neurosurgical navigation on browser-based mobile and static devices. PMID- 28868001 TI - Efficacy and Tolerability of Polyphenon E in "Difficult-to-Treat" Multiple Genital Warts in an HIV-Positive Male Subject. AB - A 55-year-old man, nonsmoker, with a HIV-positive history came to our attention in February 2017. He was on treatment with StribildTM, 1 capsule daily (150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 245 mg tenofovir disoproxil). The CD4+/CD8+ cellular count was 326/uL (normal values: 404-1,612); the CD3+/CD8+ cellular count was 819/uL (normal values: 220-1,219). The CD4/CD8 ratio was 0.40 (normal value: >1). Several typical genital wart lesions were present at the penis shaft and at the level of the neck and the corona of glans. These lesions were present for 2 years. Several cryotherapy sessions (a total of 10 procedures) had been performed with partial success. At the initial visit a total of 5 lesions were present. Treatment with topical Polyphenon E 10% 3 times a day was prescribed and started. After 1 month of treatment the lesions were reduced to 2. Treatment was very well tolerated. After 8 weeks of treatment no more lesions were observed and therefore a complete clearance was obtained. Local tolerability was evaluated to be very good by the patient. PMID- 28868002 TI - Scabies Associated with Granulomatous Dermatitis. AB - Scabies is a relatively common parasitic infection, which has sometimes been associated with the formation of granuloma annulare. We report the case of an 86 year-old female who developed a non-necrotizing granulomatous dermatitis after a scabies infestation. This case highlights the importance of considering scabies in the differential diagnosis when granulomatous dermatitis is noted histologically that cannot be explained by other causes. PMID- 28868003 TI - Wells' Syndrome Successfully Treated with Colchicine. AB - Eosinophilic cellulitis is an uncommon, inflammatory and chronic disorder of unknown etiology. Corticosteroids are currently considered as the first-line treatment but they are not without significant disadvantages such as contraindications in steroid-resistant cases and patients with frequent recurrences. We report a patient suffering from Wells' syndrome with a 24-year history of symptomatic and generalized skin lesions. After consultation in our department, treatment with colchicine 1 mg/day was prescribed resulting in large clinical improvement. No side effects have been recorded. To our knowledge, this is an original disease approach. Although small, our clinical experience supports the inclusion of colchicine in the drug armamentarium when treating patients suffering from Wells' syndrome. Indeed, its excellent safety profile makes it very attractive for patients with frequent recurrent episodes who need secure options for the medium- and long-term disease control. PMID- 28868004 TI - A Disease-Modifying Approach for Advanced Hidradenitis Suppurativa (Regimen with Metformin, Liraglutide, Dapsone, and Finasteride): A Case Report. AB - Hidradenitis suppurativa (HS) is a challenging skin disease with limited therapeutic options. Obesity and metabolic syndrome are being increasingly implicated and associated with younger ages and greater metabolic severity. A 19 year-old female with an 8-year history of progressively debilitating cicatricial HS disease presented with obesity, profound anemia, leukocytosis, increased platelet count, hypoalbuminemia, and elevated liver enzymes. A combination of metformin, liraglutide, levonorgestrel-ethinyl estradiol, dapsone, and finasteride was initiated. Acute antibiotic use for recurrences and flares could be slowly discontinued. Over the course of 3 years on this regimen, the liver enzymes normalized in 1 year, followed in2 years by complete resolution of the majority of the hematological and metabolic abnormalities. The sedimentation rate reduced from over 120 to 34 mm/h. She required 1 surgical intervention for perianal disease after 9 months on the regimen. Flares greatly diminished in intensity and duration, with none in the past 6 months. Right axillary lesions have completely healed with residual disease greatly reduced. Chiefly abdominal lesions are persistent. She was able to complete high school from home, start a job, and resume a normal life. Initial weight loss of 40 pounds was not maintained. The current regimen is being well tolerated and continued. PMID- 28868005 TI - Extrafacial Granuloma Faciale: A Case Report and Brief Review. AB - Granuloma faciale (GF) is a rare, inflammatory, cutaneous disorder of unknown aetiology. It presents clinically as one or several well-circumscribed violaceous papules, plaques, and nodules almost exclusively confined to the facial region. Rarely, extrafacial lesions can occur, most often on sun-exposed sites. We report a case of extrafacial GF in a 63-year-old male with indolent lymphoma, who presented with plaques involving the right preauricular region and left posterior axilla. The clinical and histopathological findings were consistent with GF. Our case highlights the importance of performing skin biopsies in patients with persistent erythematous plaques and nodules, particularly to exclude important malignant and granulomatous differential diagnoses. PMID- 28868006 TI - Sweet's Syndrome Arising in a Scar. AB - Acute febrile neutrophilic dermatosis (Sweet's syndrome) is an uncommon inflammatory cutaneous disorder. It presents with lesions which are tender, erythematous, edematous papules and under histologic examination show dense neutrophilic infiltration of the dermis. These lesions are often accompanied by leukocytosis and fever. This paper reports a unique case of acute febrile neutrophilic dermatosis presenting as a Koebner response to a linear scar. PMID- 28868007 TI - The Use of Intralesional Steroids in a Case of Localized Pemphigus Foliaceus. AB - A 37-year-old South-Asian male presented to our clinic with a crusty, verrucous like, scaly plaque of the left ala of the nose. After ruling out infectious and other epidermal bullous diseases, we finalized a diagnosis of localized pemphigus foliaceus, an exceptionally rare disorder with only 15 cases reported in the literature to date. The hyperkeratotic lesions responded favorably to a 3-week regimen of triamcinolone ointment and a onetime intralesional triamcinolone 2.5 mg/mL injection. PMID- 28868008 TI - Epidermolytic Acanthoma on Fingers, Mimicking Flat Warts. AB - Epidermolytic acanthoma (EA) is a benign cutaneous condition. It is characterized by warty or flat-topped, keratotic papules that show epidermolytic hyperkeratosis in histology. EA has been described to occur in various locations, namely the trunk, face, and genitoscrotal area. However, it has not been previously reported to involve the palmar area. To the best of our knowledge, we present the first reported case of EA involving the palms and fingers. PMID- 28868009 TI - Good Tolerance to Full-Dose Crizotinib in a Patient with Anaplastic Lymphoma Receptor Tyrosine Kinase-Rearranged Lung Adenocarcinoma and Preexisting Renal Impairment. AB - BACKGROUND: Crizotinib is an approved tyrosine kinase inhibitor in the treatment of advanced-stage non-small-cell lung cancer patients with anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement. Renal dysfunction after crizotinib administration was recently reported, but the physiopathological explanation and the safety in patients with preexisting renal dysfunction are still not clear. CASE PRESENTATION: A 44-year-old female and current smoker was diagnosed with a stage IV lung adenocarcinoma and treated with five lines of chemotherapy during a 4-year period of time. While she developed symptomatic tumor progression with deterioration of her performance status and renal dysfunction after these five lines of treatment, we discovered that her lung cancer was ALK-rearranged. We therefore proposed a treatment with full-dose crizotinib despite the renal impairment (creatinine clearance: 33 mL/min/1.73 m2) of unknown origin. A renal function worsening occurred after the initiation of crizotinib but we did not reduce the dose as recommended and this did not induce further deterioration. During the 15 months under crizotinib, the patient had a good general status, no clinically noticeable side effect, and a stable renal dysfunction, which even improved after the initial worsening and almost returned to the baseline (pre crizotinib) status. CONCLUSION: This case report suggests that full-dose crizotinib may be continued even in patients with severe renal dysfunction and deterioration at treatment initiation, in parallel to careful follow-up of renal function and particular attention to avoid the use of concomitant nephrotoxic drugs. PMID- 28868010 TI - Clinical Benefit from Trametinib in a Patient with Appendiceal Adenocarcinoma with a GNAS R201H Mutation. AB - We report the case of a patient with appendiceal adenocarcinoma with mucinous peritoneal carcinomatosis who was treated with trametinib upon identification of a GNAS R201H mutation by comprehensive genomic profiling. The molecular pathology of appendiceal neoplasms is reviewed, and the mechanistic basis underlying the clinical benefit as well as the subsequent course on trametinib that were observed in this patient are discussed. PMID- 28868011 TI - Esophagobronchial Fistula in a Patient with Squamous Cell Carcinoma of the Lung: A Case Report. AB - A 73-year-old man was referred to our hospital after a 2-week history of bloody sputum and cough. Computed tomography (CT) images of the chest showed a mass grouped with mediastinal lymph nodes, and bronchoscopy showed a projecting mass in the right main bronchus. After a transbronchial biopsy, the patient was diagnosed with squamous cell carcinoma (T4N2M0 stage IIIB). The patient was treated with systemic chemotherapy, consisting of cisplatin (40 mg/m2, days 1 and 8) and docetaxel (30 mg/m2, days 1 and 8), and concurrent thoracic irradiation at a daily dose of 2 Gy. On day 35 of treatment, the patient complained of a sore throat and cough. A CT of the chest showed punctate low-attenuation foci between the esophagus and bronchus. Gastrointestinal endoscopy and bronchoscopy demonstrated a fistula in the middle intrathoracic esophagus and the left main bronchus. The patient's symptoms gradually improved, and the fistula was closed after the suspension of chemoradiotherapy. Radiotherapy was resumed and completed on day 82. However, on day 108, he developed a fever and cough, and a tumor with fistula was revealed in the right main bronchus. He had an esophageal stent inserted, but he later died of sudden hemoptysis. PMID- 28868013 TI - Efficacy of Paclitaxel in a Patient with Inoperable Pulmonary Vein Leiomyosarcoma. AB - Pulmonary vein leiomyosarcoma is extremely rare and has a poor prognosis. Surgical resection with a wide margin seems to offer the only chance of cure. The role of adjuvant therapy is controversial, and the exact efficacy of chemotherapy has not been observed. In this report, we present an 18-year-old male patient with pulmonary vein leiomyosarcoma in whom the use of paclitaxel (PAX) proved to be effective. Because the tumor originated from the left superior pulmonary vein and diffused into the left atrial wall and the junction of the right superior pulmonary vein and left atrium, the en bloc excision of the tumor was impossible. The first-line chemotherapy, including ifosfamide, doxorubicin, and dacarbazine, in conjugation with radiation therapy could not demonstrate any effect on the tumor size. However, the following PAX-containing regimen provided complete regression of the tumor. After PAX-based high-dose chemotherapy with autologous peripheral blood stem cell transplantation, the patient showed complete remission for 2 years. Although he suffered metastatic recurrences and died 4 years after the onset of symptoms, our patient's clinical course clearly reveals the efficacy of PAX. PMID- 28868012 TI - Treatment of Primary and Metastatic Multifocal Mucosal Melanoma of the Oral Cavity with Imatinib. AB - BACKGROUND: Mucosal melanoma of the oral cavity is a rare entity and accounts for less than 1-3% of all melanomas. Contrary to cutaneous melanoma, primary oral melanoma more commonly harbors mutations in c-KIT. METHODS: A 64-year-old man presented with asymptomatic, multiple, brown-to-black macules in the oral cavity. A biopsy was taken and histopathology exhibited mucosal melanoma. In molecular analysis, a c-KIT mutation was proven and a CT scan revealed pulmonary metastases. Due to the multifocality of the lesions, the metastases, and the mutation status, a therapy with imatinib was initiated. RESULTS: After 1 year of therapy, progressive disease in the lung was noticed. Therefore, the therapy was switched to a PD-1 antagonist and a CTL-4 antibody. CONCLUSIONS: Our case suggests that imatinib may be considered as first-line treatment for both locally advanced and distant primary multifocal oral melanoma, for which surgery or radiotherapy of the primary tumor is impossible. PMID- 28868015 TI - Chronic Oxaliplatin-Based Chemotherapy in a Primary Ampullary Adenocarcinoma Patient without Significant Peripheral Neuropathy: Case Report and Literature Review. AB - Peripheral neuropathy is the most common dose-limiting toxicity associated with oxaliplatin. We report on a 61-year-old female patient with advanced primary ampullary adenocarcinoma who received 35 cycles of FOLFIRINOX (5-fluorouracil, irinotecan, and oxaliplatin) chemotherapy. The patient has tolerated this treatment without developing significant peripheral neuropathy. PMID- 28868014 TI - First-Line Treatment with Carboplatin plus nab-Paclitaxel and Maintenance Monotherapy with nab-Paclitaxel for a Thymic Carcinoma: A Case Report. AB - Thymic carcinomas are rare malignant tumors, located in the anterior mediastinum. For the treatment of these carcinomas, several chemotherapy regimens have been suggested, including carboplatin plus paclitaxel. However, because of the rarity of these tumors, the standard chemotherapy regimen has not yet been established. Here, we report a case of thymic carcinoma that responded to first-line carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) therapy with continuation maintenance nab-paclitaxel monotherapy. A 78-year-old male presented to a hospital with the chief complaint of dyspnea. Cardiomegaly was detected on chest X-ray scans, and marked pericardial effusion was observed by echocardiography. Chest computed tomography scans revealed the presence of a mediastinal mass, pericardial thickening, and pericardial effusion. The serum levels of the tumor marker CYFRA 21-1 (cytokeratin-19 fragment) were elevated. Eventually, he was diagnosed with squamous cell carcinoma of the thymus, which was staged as cT4N3M0 or stage IV (according to the tumor-node-metastasis classification). Chemotherapy with carboplatin on day 1 and nab-paclitaxel on days 1, 8, and 15, every 4 weeks was initiated. After the administration of 4 cycles of this regimen, the tumor diameter appeared reduced, and the serum CYFRA 21-1 levels were normalized. After a 1-month interval, the serum CYFRA 21-1 levels increased again; therefore, maintenance nab-paclitaxel monotherapy was initiated. At the end of the treatment, the patient experienced a progression free survival of 10.3 months. Carboplatin plus nab-paclitaxel may be an appropriate alternative first-line treatment for thymic carcinomas. Additionally, maintenance nab-paclitaxel monotherapy may prolong the progression-free survivals of patients with thymic carcinomas. PMID- 28868016 TI - Relapsed Multiple Myeloma Presenting as Intracranial Plasmacytoma and Malignant Pericardial Effusion following Recent Allogeneic Stem Cell Transplantation. AB - Although rare, both central nervous system and pericardial involvement of myeloma have been well described in the literature. Their simultaneous occurrence in relapsed disease, however, has not been previously reported. This case describes a 54-year-old female who was treated for high-risk multiple myeloma with multiregimen chemotherapy and allogeneic hematopoietic stem cell transplantation. Four months after transplant, she was found to have relapsed disease manifesting as an extraosseous, intracranial plasmacytoma and simultaneous malignant pericardial effusion. Her disease characteristics, treatment course, radiologic and pathologic findings are described in detail, and we review the previous literature to determine the various aspects of her disease that may have contributed to her aggressive clinical course. PMID- 28868017 TI - Natural Killer Cell Lymphoblastic Leukaemia/Lymphoma: Case Report and Review of the Recent Literature. AB - Natural killer (NK) cell lymphoblastic leukaemia/lymphoma is a rare haemopoietic tumour currently defined in the 2008 WHO classification under the category of acute leukaemias of ambiguous lineage. A diagnosis of this type of leukaemia is considered in cases expressing CD56 along with immature T-cell-associated markers such as CD2 and CD7 with absence of B-cell and myeloid markers; in addition, blastic plasmacytoid dendritic cell leukaemia should be excluded. Prior to 2008, these precursor NK cell lymphoblastic leukaemias/lymphomas were categorized as myeloid/NK cell acute leukaemia with a phenotype identical to acute myeloid leukaemia with minimal differentiation. While the new classification has merit in having excluded myeloid expression, there is still persistent confusion in the literature and on a practical level with regard to precursor NK cell neoplasms. There is a paucity of recent case reports in the literature after the new WHO classification of this neoplasm. Due to the rarity of this neoplasm, an accurate pathological diagnosis is often difficult. In this article, we describe a case of precursor NK cell lymphoblastic leukaemia/lymphoma presenting with unique morphological features and conflicting immunophenotypes. We also review all case reports of this neoplasm after the WHO 2008 classification. PMID- 28868018 TI - Spinal Cord Compression Secondary to Metastatic Sinonasal Undifferentiated Carcinoma. AB - Sinonasal undifferentiated carcinoma (SNUC) is a rare malignancy of the upper airways and anterior skull base that carries a poor prognosis. The tumor is known to be invasive into the surrounding structures of the skull base and brain. To date, there is only one existing case report documenting drop metastasis to the intradural extramedullary spinal cord. To the best of our knowledge, we present the second case of metastatic SNUC to the spine. This report describes a 59-year old male with a history of head and neck SNUC who presented with thoracic back pain and bilateral lower extremity paresis. Neuroimaging demonstrated an extradural thoracic mass with severe spinal cord compression. The patient underwent thoracic laminectomy and fusion for decompression of the spinal cord and internal stabilization. The pathology returned as SNUC. The patient was subsequently lost to follow-up from our institution. Metastatic SNUC is rare. We discuss the relevant clinical imaging and review the literature. Such a malignancy portends a very poor prognosis. PMID- 28868019 TI - Cystoid Macular Edema during Treatment with Paclitaxel and Bevacizumab in a Patient with Metastatic Breast Cancer: A Case Report and Literature Review. AB - We present a case of a metastatic breast cancer patient with cystoid macular edema (CME) occurring during treatment with paclitaxel and bevacizumab. She had a history of neoadjuvant chemotherapy and partial mastectomy plus axillary lymph node dissection for stage IIB left-breast cancer. Twenty-four months later, she was diagnosed with multiple bone metastases and underwent chemotherapy with paclitaxel and bevacizumab. Thirty-three months after the initiation of the chemotherapy, she noticed bilateral blurred vision. The retinal thickening with macular edema was observed by optical coherence tomography, resulting in a diagnosis of CME. With cessation of paclitaxel and administrating ocular instillation of a nonsteroidal anti-inflammatory drug, her macular edema gradually reduced and disappeared in a month. While CME caused by chemotherapy is very rare, taxane may cause ocular adverse events such as CME. It is important to urge patients to consult an ophthalmologist promptly when they have visual complaints during taxane chemotherapy. PMID- 28868020 TI - Erdheim-Chester Disease: The Importance of Information Integration. AB - BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis disorder that utilizes the RAS-RAF-MEK-ERK pathway. It has a highly variable clinical presentation, where virtually any organ can be involved, thus having the potential of posing a great diagnostic challenge. Over half of the reported cases have the BRAF V600E mutation and have shown a remarkable response to vemurafenib. CASE PRESENTATION: We describe herein a patient with a history of stroke-like symptoms and retroperitoneal fibrosis that on initial pathology raised the possibility of IgG4-related disease. However, the patient was refractory to high-dose steroids and progressed further, developing an epicardial soft tissue mass and recurrent neurological symptoms. Integration of the above findings with new information at another hospital about a radiological history of symmetrical lower extremities long bone lesions raised the differential diagnosis of ECD. Molecular analysis of formalin-fixed paraffin-embedded tissue of both of the patient's retroperitoneal biopsies (the second one of which had shown a small focus of foamy histiocytes, CD68+/CD1a-) was positive for BRAF mutation, confirming the diagnosis of ECD. The patient demonstrated a dramatic and sustained metabolic response to vemurafenib on follow-up positron emission tomography scans. CONCLUSION: This case highlights the need for developing a high index of suspicion for presentations of retroperitoneal fibrosis that could represent IgG4-related disease but fail to respond to steroids. When unusual multisystem involvement occurs, one should consider a diagnosis of a rare histiocytosis. Vemurafenib appears to be an effective treatment for even advanced cases of both ECD and Langerhans histiocytosis bearing the BRAF V600E mutation. PMID- 28868021 TI - A Case of Recurrent Breast Cancer Identified by Pulmonary Tumor Thrombotic Microangiopathy. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare, cancer-related, pulmonary complication that causes hypoxia and pulmonary hypertension. We report on a 42-year-old woman who was diagnosed with recurrent breast cancer that was detected due to the presence of PTTM. Eleven months after surgery for heterochronous bilateral cancer of the left breast, she developed progressive dyspnea but computerized tomography showed no pulmonary thromboembolism, and a transthoracic echocardiography revealed mild pulmonary hypertension. She was diagnosed with PTTM by cytology from pulmonary artery catheterization and perfusion lung scintigraphy. Also, the patients complained of back pain after admission, bone scintigraphy showed multiple bone metastases. Despite the early diagnosis of PTTM, her platelet count decreased, her performance status rapidly deteriorated, and her dyspnea worsened. Thus, we could not treat her with chemotherapy. She died due to respiratory failure 19 days after admission. To the best of our knowledge, this is the first report of recurrent breast cancer identified by the manifestation of PTTM. Although PTTM is a rare phenomenon, it should be considered in the differential diagnosis of acute dyspnea or pulmonary hypertension in patients with breast cancer. Furthermore, upon diagnosis, the patient should be referred to a cardiologist as soon as possible. PMID- 28868022 TI - Successful Yttrium-90 Microsphere Radioembolization for Hepatic Metastases of Prostate Cancer. AB - Prostate cancer is the most common solid tumor malignancy worldwide with an estimated 180,000 new cases of prostate cancer and 26,000 deaths in the USA in 2016. Although significant advances in the treatment of prostate cancer have recently been made, the treatment of metastatic disease remains a challenge. With visceral metastases marking more advanced tumor stages, liver involvement is associated with the worst prognosis. So far, no locoregional treatment regimens for the management of liver metastases of prostatic cancer exist. Herein, we report for the first time a successful treatment of hepatic metastases of prostatic cancer using radioembolization with selective intra-arterial administration of Yttrium-90 resin microspheres. PMID- 28868023 TI - Next-Generation Sequencing in Order to Better Characterize a BRCA Variant of Uncertain Significance. AB - BRCA germline mutations are the most common predisposing factor in familial breast-ovarian cancer syndrome families. However, many screened patients are identified as harboring BRCA variants of uncertain significance (VUS), rather than carrying deleterious germline mutations [Calo et al.: Cancers 2010; 2:1644 1660]. While such VUSs are typically reclassified as benign polymorphisms, this may occur years after the VUS is first identified [Murray et al.: Genet Med 2011; 13; 998-1005]. Loss of heterozygosity (LOH) of BRCA is nearly always the gatekeeper event in inherited BRCA-related breast cancer and LOH of BRCA is rare in sporadic cancers [Osorio et al.: Int J Cancer 2002; 99:305-309]. Here, we describe a patient identified as carrying a germline BRCA VUS. Tumor next generation sequencing (NGS) demonstrated a very high mutation allelic frequency for that BRCA VUS, consistent with LOH. This case illustrates that since BRCA LOH is the typical mechanism of transformation in inherited BRCA-related breast cancers, NGS might be used to suggest that the BRCA VUS is actually cancer predisposing in a particular family. As a result, this may help patients make more informed decisions regarding screening and prophylactic therapy, long before official reclassification of the VUS occurs. PMID- 28868024 TI - Isolated Splenic Metastasis from Non-Small-Cell Lung Cancer: A Case Report and Review of the Literature. AB - Metastases to the spleen are rare but have been reported for different tumor entities, including breast cancer, lung cancer, colorectal cancer, ovarian cancer, and melanoma. As an isolated event, splenic metastasis from non-small cell lung cancer (NSCLC) is exceedingly rare. Until now, only 28 cases have been reported in the medical literature. We report the case of a 66-year-old woman with NSCLC (adenocarcinoma) who presented with a synchronous, isolated splenic metastasis. Operative removal of both primary tumor and metastasis was not possible due to multiple comorbidities. Therefore, treatment was limited to combined systemic chemotherapy and simultaneous radiation of the primary tumor, which led to partial remission of the disease. Isolated metastasis to the spleen in NSCLC has been reported only 28 times in the medical literature, most often in male patients with right-sided lung tumors, most of which were adenocarcinomas. The majority of patients were asymptomatic with respect to splenic metastasis. About half of the reported cases were isolated metachronous splenic metastases. Splenectomy seems to confer a survival advantage. We review the pertinent medical literature. PMID- 28868025 TI - The Effectiveness of Trastuzumab Combined with Sequential Chemotherapy for Metastatic Gastric Carcinoma with Overexpression of HER2. AB - Metastatic gastric carcinoma is a mortal disease with a median survival of barely 10 months. An approximate 20% of the cases overexpress HER2, and among them, the combination of chemotherapy with trastuzumab is actually the first-line palliative treatment. However, after progression, sequential strategies of chemotherapy while maintaining trastuzumab have been barely researched. We report the case of a patient with a diagnosis of adenocarcinoma in the gastroesophageal junction with overexpression of HER2, in stage IV, treated with sequential chemotherapy and trastuzumab, who survived more than 5 years during the metastatic phase maintaining a good quality of life. PMID- 28868026 TI - Ultrasound-Guided Transoral Videolaryngoscopic Surgery for Retropharyngeal Lymph Node Metastasis of Papillary Thyroid Cancer. AB - BACKGROUND: Endoscopic-assisted transoral surgery, including transoral robotic surgery for metastatic retropharyngeal lymph node (RPN) from well-differentiated thyroid cancer, has been reported to reduce the complications resulting from transcervical and transmandibular approaches. However, the narrow working space and difficulty identifying RPN are problematic. To solve these issues, several studies have used intraoperative ultrasound in endoscopic-assisted transoral surgery. However, the type of ultrasonography suitable for this purpose remains unclear. CASE PRESENTATION: A 60-year-old female with thyroid papillary carcinoma (T4aN1bM0) initially underwent total thyroidectomy and paratracheal and selective neck dissections (D2a), with resectional management of recurrent laryngeal nerve, trachea, and esophagus. Three years later, she was diagnosed with left retropharyngeal and upper mediastinal lymph node metastases of papillary thyroid cancer. Transoral videolaryngoscopic surgery was performed with a combination of ultrasonography with a flexible laparoscopic transducer manipulated with forceps for identifying RPN intraoperatively. Due to the transducer's small size and thin, flexible cable, the transducer interrupted the procedure in spite of the narrowness of oral cavity. RPN was resected completely without adverse events. CONCLUSION: We performed intraoperative ultrasound-guided endoscopic transoral surgery for metastatic RPN from papillary thyroid cancer and achieved complete resection as well as preservation of swallowing function. PMID- 28868027 TI - Recurrent Meningioma of the Cervical Spine, Successfully Treated with Liposomal Doxorubicin. AB - There is no standard systemic treatment for persons with recurrent meningioma who have exhausted surgery and radiation options. Liposomal doxorubicin is a cytotoxic chemotherapy which is sustainable and tolerable, with activity against a range of solid tumors. There exists one reported case of metastatic meningioma effectively treated with liposomal doxorubicin. We report a second case. Our patient, a 35-year-old man with recurrent meningioma compressing the cervical spinal cord received liposomal doxorubicin for 22 months with clinical improvement, minimal toxicity, and slow regression of his tumor. He is well and without progression 18 months after stopping chemotherapy and 4 years after his last progression event. PMID- 28868028 TI - Primary Cystic Pleuropulmonary Synovial Sarcoma Presenting as Recurrent Pneumothorax. AB - Primary pleuropulmonary synovial sarcomas are quite rare, representing 0.1-0.5% of all pulmonary malignancies. We report an entirely cystic monophasic synovial sarcoma in a 25-year-old male who presented with recurrent pneumothorax and no evidence of a mass lesion on imaging. The purpose of this case report is to increase awareness of neoplasms clinically presenting as a pneumothorax with no imagining evidence of a mass-forming lesion and emphasize the significance of fluorescent in situ hybridization testing in nontypical synovial sarcoma cases. PMID- 28868029 TI - Thrombosis of the Vein of Galen: Pitfalls, Metamorphosis, and Paroxysmal Sympathetic Hyperactivity. AB - Isolated thrombosis of the vein of Galen is a rare and serious entity with few cases reported in the literature. We report the case of a previously healthy 18 year-old male who was admitted after developing headache and subsequently worsening mental status, requiring endotracheal intubation for airway protection. During his admission he developed symptoms of severe paroxysmal sympathetic hyperactivity and posturing. The computed tomography and magnetic resonance imaging of the brain showed bilateral thalamic lesions. The magnetic resonance angiography and digital arteriography revealed a thrombosis of the deep cerebral venous system (vein of Galen). We call attention to a case with rapid symptom progression and specific radiological findings, with atypical clinical course, characterized by paroxysmal sympathetic hyperactivity, but with good clinical functional outcome. PMID- 28868030 TI - Association of Posterior Reversible Encephalopathy Syndrome and Transient Apical Ballooning Syndrome (Takotsubo): First Case Report of a Man and Review of the Literature. AB - INTRODUCTION: An association of posterior reversible encephalopathy syndrome (PRES) and takotsubo is rare. We present the first case of a male patient. CASE REPORT: A 69-year-old man presented to the hospital in a persistent comatose state following a generalized tonic-clonic seizure with high blood pressure. The electrocardiogram revealed transient left bundle branch block. Troponin and BNP were elevated. Cardiac ultrasound showed large apical akinesia with altered left ventricular ejection fraction, and the left ventriculogram showed characteristic regional wall motion abnormalities involving the mid and apical segments. Brain MRI showed bilateral, cortical, and subcortical vasogenic edema predominant in the posterior right hemisphere. The lumbar puncture and cerebral angiography were normal. Paraclinical abnormalities were reversible within 2 weeks with a clinical recovery in 3 months, confirming the takotsubo and the PRES diagnoses. DISCUSSION: Several theories hypothesize the underlying pathophysiology of takotsubo or PRES. Circulating catecholamines are up to 3 times higher in patients with takotsubo causing impaired microcirculation and apical hypokinesia. An association of both takotsubo and asthma crisis and PRES and asthma crisis underlines the role of catecholamines in the occurrence of these disorders. CONCLUSION: Early recognition of this rare association, in which heart and neurological damage may require rapid intensive care support, is needed. PMID- 28868031 TI - Optical Coherence Tomography Angiography: Employing a Novel Technique for Investigation in Vogt-Koyanagi-Harada Disease. AB - PURPOSE: To report a case of Vogt-Koyanagi-Harada (VKH) disease and describe the imaging findings by means of optical coherence tomography angiography (OCTA). METHODS: Medical and ophthalmological history, ophthalmological examination, laboratory evaluation, B-scan ultrasonography, fluorescein and indocyanine angiography, and optical coherence tomography (OCT) were performed at baseline, as well as OCTA. RESULTS: A 50-year-old healthy female presented with decreased vision in both eyes. A Topcon DRI OCT Triton Plus swept source OCT system was used to visualize and evaluate the retinal and choroidal vascular plexus. Patchy and confluent dark areas in the superficial and deep retinal capillary plexus and choriocapillaris corresponded to areas of hypoperfusion, analyzed as areas of ischemia. CONCLUSIONS AND IMPORTANCE: VKH disease is characterized by ocular, neurological, and integumentary findings in its complete form. We present a case of incomplete disease in a 50-year-old female evaluated by means of OCTA which is a novel technique that provides depth-resolved images of the retina and choroidal microvasculature without dye injection that allows better visualization and detailed evaluation of the retinal and choroidal vascular plexus. PMID- 28868032 TI - Spironolactone for Secondary Central Serous Chorioretinopathy: A Challenge Rechallenge Case. AB - Central serous chorioretinopathy (CSCR) is potentially sight-threatening and has been associated with corticosteroid use. CSCR secondary to steroid use can sometimes be challenging to treat, especially if continuing steroid use is medically necessary. In this case report we demonstrate the efficacy of spironolactone as an effective agent in countering CSCR secondary to steroid use. This challenge-rechallenge case may be helpful to clinicians in delineating a treatment paradigm for these patients. PMID- 28868033 TI - Sturge-Weber Syndrome Associated with Monolateral Ocular Melanocytosis, Iris Mammillations, and Diffuse Choroidal Haemangioma. AB - We present the case of a 12-year-old boy with Sturge-Weber syndrome and ocular melanocytosis who presented with bilateral naevus flammeus of the face and hyperpigmentation of the right iris associated with ipsilateral iris mammillations. The patient had glaucoma and a diffuse choroidal haemangioma of the right eye. Optical coherence tomography of the anterior segment confirmed iris hyper-pigmentation and did not show abnormalities of the chamber angle structures. B-scan ultrasonography and enhanced depth imaging optical coherence tomography were performed and showed a marked difference in thickness and reflectance between the right and left choroid. Visual field examinations with perimetry showed early defects in the right eye. Peripapillary optical coherence imaging showed borderline values of retinal nerve fibre layer thickness reduction in the right eye. Sturge-Weber syndrome associated with ocular melanocytosis and iris mammillations is an extremely rare condition. This paper highlights the role of multi-imaging methods in the enhanced evaluation of rare diseases towards choosing the most appropriate management strategies and improving the follow-up of patients over time. PMID- 28868034 TI - Correction of High Astigmatism after Penetrating Keratoplasty with Toric Multifocal Intraocular Lens Implantation. AB - After penetrating keratoplasty (PK), high astigmatism is often induced, being frequently about 4-6 dpt. According to the entity and typology of astigmatism, different methods of correction can be used. Selective suture removal, relaxing incisions, wedge resections, compression sutures, photorefractive keratectomy, and laser-assisted in situ keratomileusis can reduce corneal astigmatism and ametropia, but meanwhile they can cause a reduction in the corneal integrity and cause an over- or undercorrection. In case of moderate-to-high regular astigmatisms, the authors propose a toric multifocal intraocular lens (IOL) implantation to preserve the corneal integrity (especially in PK after herpetic corneal leukoma keratitis). We evaluated a 45-year-old patient who at the age of 30 was subjected to PK in his left eye due to corneal leukoma herpetic keratitis, which led to high astigmatism (7.50 dpt cyl. 5 degrees ). The patient was subjected to phacoemulsification and customized toric multifocal IOL implantation in his left eye. The correction of PK-induced residual astigmatism with a toric IOL implantation is an excellent choice but has to be evaluated in relation to patient age, corneal integrity, longevity graft, and surgical risk. It seems to be a well-tolerated therapeutic choice and with good results. PMID- 28868035 TI - A Novel Stress-Diathesis Model to Predict Risk of Post-operative Delirium: Implications for Intra-operative Management. AB - Introduction: Risk assessment for post-operative delirium (POD) is poorly developed. Improved metrics could greatly facilitate peri-operative care as costs associated with POD are staggering. In this preliminary study, we develop a novel stress-diathesis model based on comprehensive pre-operative psychiatric and neuropsychological testing, a blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) carbon dioxide (CO2) stress test, and high fidelity measures of intra-operative parameters that may interact facilitating POD. Methods: The study was approved by the ethics board at the University of Manitoba and registered at clinicaltrials.gov as NCT02126215. Twelve patients were studied. Pre-operative psychiatric symptom measures and neuropsychological testing preceded MRI featuring a BOLD MRI CO2 stress test whereby BOLD scans were conducted while exposing participants to a rigorously controlled CO2 stimulus. During surgery the patient had hemodynamics and end-tidal gases downloaded at 0.5 hz. Post-operatively, the presence of POD and POD severity was comprehensively assessed using the Confusion Assessment Measure -Severity (CAM-S) scoring instrument on days 0 (surgery) through post-operative day 5, and patients were followed up at least 1 month post-operatively. Results: Six of 12 patients had no evidence of POD (non-POD). Three patients had POD and 3 had clinically significant confusional states (referred as subthreshold POD; ST-POD) (score >= 5/19 on the CAM-S). Average severity for delirium was 1.3 in the non-POD group, 3.2 in ST-POD, and 6.1 in POD (F-statistic = 15.4, p < 0.001). Depressive symptoms, and cognitive measures of semantic fluency and executive functioning/processing speed were significantly associated with POD. Second level analysis revealed an increased inverse BOLD responsiveness to CO2 pre-operatively in ST-POD and marked increase in the POD groups when compared to the non-POD group. An association was also noted for the patient population to manifest leucoaraiosis as assessed with advanced neuroimaging techniques. Results provide preliminary support for the interacting of diatheses (vulnerabilities) and intra operative stressors on the POD phenotype. Conclusions: The stress-diathesis model has the potential to aid in risk assessment for POD. Based on these initial findings, we make some recommendations for intra-operative management for patients at risk of POD. PMID- 28868037 TI - BH3 Mimetics for the Treatment of Prostate Cancer. AB - Despite improved diagnostic and therapeutic intervention, advanced prostate cancer (PC) remains incurable. The acquired resistance of PC cells to current treatment protocols has been traced to apoptosis resistance based on the upregulation of anti-apoptotic proteins of the Bcl-2 family. The use of BH3 mimetics, mimicking pro-apoptotic activator or sensitizer proteins of the intrinsic apoptotic pathway, is therefore a promising treatment strategy. The present review gives an overview of preclinical and clinical studies with pan- and specific BH3 mimetics as sensitizers for cell death and gives an outlook how they could be effectively used for the therapy of advanced PC in future. PMID- 28868036 TI - Baicalin Alleviates Lipopolysaccharide-Induced Liver Inflammation in Chicken by Suppressing TLR4-Mediated NF-kappaB Pathway. AB - As a kind of potent stimulus, lipopolysaccharide (LPS) has the ability to cause cell damage by activating toll-like receptor(TLR)4, then nuclear factor kappa B (NF-kappaB) translocates into the nucleus and changes the expression of related inflammatory genes. Baicalin is extracted from Radix Scutellariae, which possesses anti-inflammation, antioxidant and antibacterial properties. However, the effects of it on LPS-induced liver inflammation have not been fully elucidated. This study aims to investigate the anti-inflammatory effects of Baicalin on the LPS-induced liver inflammation and its underlying molecular mechanisms in chicken. The results of histopathological changes, serum biochemical analysis, NO levels and myeloperoxidase activity showed that Baicalin pretreatment ameliorated LPS-induced liver inflammation. ELISA and qPCR assays showed that Baicalin dose-dependently suppressed the production of IL-1beta, IL 6, and TNF-alpha. Furthermore, the mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were significantly decreased by Baicalin. TLR4 is an important sensor in LPS infection. Molecular studies showed that the expression of TLR4 was inhibited by Baicalin pretreatment. In addition, Baicalin pretreatment inhibited NF-kB signaling pathway activation. All results demonstrated the protective effects of Baicalin pretreatment against LPS-induced liver inflammation in chicken via negative regulation of inflammatory mediators through the down-regulation of TLR4 expression and the inhibition of NF-kB activation. PMID- 28868038 TI - Quantitative Comparison of Effects of Dofetilide, Sotalol, Quinidine, and Verapamil between Human Ex vivo Trabeculae and In silico Ventricular Models Incorporating Inter-Individual Action Potential Variability. AB - Background:In silico modeling could soon become a mainstream method of pro arrhythmic risk assessment in drug development. However, a lack of human-specific data and appropriate modeling techniques has previously prevented quantitative comparison of drug effects between in silico models and recordings from human cardiac preparations. Here, we directly compare changes in repolarization biomarkers caused by dofetilide, dl-sotalol, quinidine, and verapamil, between in silico populations of human ventricular cell models and ex vivo human ventricular trabeculae. Methods and Results:Ex vivo recordings from human ventricular trabeculae in control conditions were used to develop populations of in silico human ventricular cell models that integrated intra- and inter-individual variability in action potential (AP) biomarker values. Models were based on the O'Hara-Rudy ventricular cardiomyocyte model, but integrated experimental AP variability through variation in underlying ionic conductances. Changes to AP duration, triangulation and early after-depolarization occurrence from application of the four drugs at multiple concentrations and pacing frequencies were compared between simulations and experiments. To assess the impact of variability in IC50 measurements, and the effects of including state-dependent drug binding dynamics, each drug simulation was repeated with two different IC50 datasets, and with both the original O'Hara-Rudy hERG model and a recently published state-dependent model of hERG and hERG block. For the selective hERG blockers dofetilide and sotalol, simulation predictions of AP prolongation and repolarization abnormality occurrence showed overall good agreement with experiments. However, for multichannel blockers quinidine and verapamil, simulations were not in agreement with experiments across all IC50 datasets and IKr block models tested. Quinidine simulations resulted in overprolonged APs and high incidence of repolarization abnormalities, which were not observed in experiments. Verapamil simulations showed substantial AP prolongation while experiments showed mild AP shortening. Conclusions: Results for dofetilide and sotalol show good agreement between experiments and simulations for selective compounds, however lack of agreement from simulations of quinidine and verapamil suggest further work is needed to understand the more complex electrophysiological effects of these multichannel blocking drugs. PMID- 28868039 TI - Relaxin-2 in Cardiometabolic Diseases: Mechanisms of Action and Future Perspectives. AB - Despite the great effort of the medical community during the last decades, cardiovascular diseases remain the leading cause of death worldwide, increasing their prevalence every year mainly due to our new way of life. In the last years, the study of new hormones implicated in the regulation of energy metabolism and inflammation has raised a great interest among the scientific community regarding their implications in the development of cardiometabolic diseases. In this review, we will summarize the main actions of relaxin, a pleiotropic hormone that was previously suggested to improve acute heart failure and that participates in both metabolism and inflammation regulation at cardiovascular level, and will discuss its potential as future therapeutic target to prevent/reduce cardiovascular diseases. PMID- 28868041 TI - Self-esteem Modulates the P3 Component in Response to the Self-face Processing after Priming with Emotional Faces. AB - The self-face processing advantage (SPA) refers to the research finding that individuals generally recognize their own face faster than another's face; self face also elicits an enhanced P3 amplitude compared to another's face. It has been suggested that social evaluation threats could weaken the SPA and that self esteem could be regarded as a threat buffer. However, little research has directly investigated the neural evidence of how self-esteem modulates the social evaluation threat to the SPA. In the current event-related potential study, 27 healthy Chinese undergraduate students were primed with emotional faces (angry, happy, or neutral) and were asked to judge whether the target face (self, friend, and stranger) was familiar or unfamiliar. Electrophysiological results showed that after priming with emotional faces (angry and happy), self-face elicited similar P3 amplitudes to friend-face in individuals with low self-esteem, but not in individuals with high self-esteem. The results suggest that as low self-esteem raises fears of social rejection and exclusion, priming with emotional faces (angry and happy) can weaken the SPA in low self-esteem individuals but not in high self-esteem individuals. PMID- 28868042 TI - Cognitive Behavioral Therapy vs. Eye Movement Desensitization and Reprocessing for Treating Panic Disorder: A Randomized Controlled Trial. AB - Objective: Cognitive Behavioral Therapy (CBT) is an effective intervention for patients with panic disorder (PD). From a theoretical perspective, Eye Movement Desensitization and Reprocessing (EMDR) therapy could also be useful in the treatment of PD because: (1) panic attacks can be experienced as life threatening; (2) panic memories specific to PD resemble traumatic memories as seen in posttraumatic stress disorder (PTSD); and (3) PD often develops following a distressing life event. The primary objective of this Randomized Controlled Trial (RCT), was to compare EMDR therapy with CBT for PD and determine whether EMDR is not worse than CBT in reducing panic symptoms and improving Quality Of Life (QOL). Methods: Two-arm (CBT and EMDR) parallel RCT in patients with PD (N = 84). Patients were measured at baseline (T1), directly after the last therapy session (T2), and 3 months after ending therapy (T3). Non-inferiority testing (linear mixed model with intention-to-treat analysis) was applied. Patients were randomly assigned to 13 weekly 60-min sessions of CBT (N = 42) or EMDR therapy (N = 42). Standard protocols were used. The primary outcome measure was severity of PD at T3, as measured with the Agoraphobic Cognitions Questionnaire (ACQ), the Body Sensations Questionnaire (BSQ), and the Mobility Inventory (MI). The secondary outcome measure was QOL, as measured with the World Health Organization Quality of Life short version (WHOQOL-Bref), at T3. Results: The severity of PD variables ACQ and BSQ showed non-inferiority of EMDR to CBT, while MI was inconclusive (adjusted analyses). Overall QOL and general health, Psychological health, Social relationships, and Environment showed non-inferiority of EMDR to CBT, while Physical health was inconclusive. Conclusion: EMDR therapy proved to be as effective as CBT for treating PD patients. Trial Registration: Dutch Trial Register, Nr. 3134 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3134. PMID- 28868043 TI - Metabolomics Profiling As a Diagnostic Tool in Severe Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a complex disease with a multifaceted pathophysiology. Impairment of energy metabolism is a key component of secondary insults. This phenomenon is a consequence of multiple potential mechanisms including diffusion hypoxia, mitochondrial failure, and increased energy needs due to systemic trauma responses, seizures, or spreading depolarization. The degree of disturbance in brain metabolism is affected by treatment interventions and reflected in clinical patient outcome. Hence, monitoring of these secondary events in peripheral blood will provide a window into the pathophysiological course of severe TBI. New methods for assessing perturbation of brain metabolism are needed in order to monitor on-going pathophysiological processes and thus facilitate targeted interventions and predict outcome. Circulating metabolites in peripheral blood may serve as sensitive markers of pathological processes in TBI. The levels of these small molecules in blood are less dependent on the integrity of the blood-brain barrier as compared to protein biomarkers. We have recently characterized a specific metabolic profile in serum that is associated with both initial severity and patient outcome of TBI. We found that two medium-chain fatty acids, octanoic and decanoic acids, as well as several sugar derivatives are significantly associated with the severity of TBI. The top ranking peripheral blood metabolites were also highly correlated with their levels in cerebral microdialyzates. Based on the metabolite profile upon admission, we have been able to develop a model that accurately predicts patient outcome. Moreover, metabolomics profiling improved the performance of the well-established clinical prognostication model. In this review, we discuss metabolomics profiling in patients with severe TBI. We present arguments in support of the need for further development and validation of circulating biomarkers of cerebral metabolism and for their use in assessing patients with severe TBI. PMID- 28868044 TI - Merkel Cell Carcinoma with Distant Metastasis to the Clivus Causing Symptoms Mimicking Tolosa-Hunt Syndrome: A Case Report and Literature Review. AB - Merkel cell carcinoma (MCC) is an uncommon but highly malignant neuroendocrine tumor of the skin. MCC can metastasize, but involvement of the central nervous system is rare. Here, we report a case of rapidly progressing metastatic MCC to the clivus and bilateral cavernous sinus in an immunocompromised patient. This case is unique in that it is the first case report showing MCC metastasis to the clivus from a distant site. It also demonstrates that a MCC metastasis can masquerade with symptoms of Tolosa-Hunt syndrome. A literature review on MCC with CNS metastasis is presented. PMID- 28868040 TI - Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs. AB - A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug's properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine ("Kratom"), synthetic cannabinoids (e.g., "Spice"), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, gamma hydroxybutyrate, gamma-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications. PMID- 28868046 TI - A Novel Saccadic Strategy Revealed by Suppression Head Impulse Testing of Patients with Bilateral Vestibular Loss. AB - OBJECTIVE: We examined the eye movement response patterns of a group of patients with bilateral vestibular loss (BVL) during suppression head impulse testing. Some showed a new saccadic strategy that may have potential for explaining how patients use saccades to recover from vestibular loss. METHODS: Eight patients with severe BVL [vestibulo-ocular reflex (VOR) gains less than 0.35 and absent otolithic function] were tested. All patients were given the Dizziness Handicap Inventory and questioned about oscillopsia during abrupt head movements. Two paradigms of video head impulse testing of the horizontal VOR were used: (1) the classical head impulse paradigm [called head impulse test (HIMPs)]-fixating an earth-fixed target during the head impulse and (2) the new complementary test paradigm-fixating a head-fixed target during the head impulse (called SHIMPs). The VOR gain of HIMPs was quantified by two algorithms. RESULTS: During SHIMPs testing, some BVL patients consistently generated an inappropriate covert compensatory saccade during the head impulse that required a corresponding large anti-compensatory saccade at the end of the head impulse in order to obey the instructions to maintain gaze on the head-fixed target. By contrast, other BVL patients did not generate this inappropriate covert saccade and did not exhibit a corresponding anti-compensatory saccade. The latencies of the covert saccade in SHIMPs and HIMPs were similar. CONCLUSION: The pattern of covert saccades during SHIMPs appears to be related to the reduction of oscillopsia during abrupt head movements. BVL patients who did not report oscillopsia showed this unusual saccadic pattern, whereas BVL patients who reported oscillopsia did not show this pattern. This inappropriate covert SHIMPs saccade may be an objective indicator of how some patients with vestibular loss have learned to trigger covert saccades during head movements in everyday life. PMID- 28868045 TI - Primary Blast-Induced Changes in Akt and GSK3beta Phosphorylation in Rat Hippocampus. AB - Traumatic brain injury (TBI) due to blast from improvised explosive devices has been a leading cause of morbidity and mortality in recent conflicts in Iraq and Afghanistan. However, the mechanisms of primary blast-induced TBI are not well understood. The Akt signal transduction pathway has been implicated in various brain pathologies including TBI. In the present study, the effects of simulated primary blast waves on the phosphorylation status of Akt and its downstream effector kinase, glycogen synthase kinase 3beta (GSK3beta), in rat hippocampus, were investigated. Male Sprague-Dawley (SD) rats (350-400 g) were exposed to a single pulse shock wave (25 psi; ~7 ms duration) and sacrificed 1 day, 1 week, or 6 weeks after exposure. Total and phosphorylated Akt, as well as phosphorylation of its downstream effector kinase GSK3beta (at serine 9), were detected with western blot analysis and immunohistochemistry. Results showed that Akt phosphorylation at both serine 473 and threonine 308 was increased 1 day after blast on the ipsilateral side of the hippocampus, and this elevation persisted until at least 6 weeks postexposure. Similarly, phosphorylation of GSK3beta at serine 9, which inhibits GSK3beta activity, was also increased starting at 1 day and persisted until at least 6 weeks after primary blast on the ipsilateral side. In contrast, p-Akt was increased at 1 and 6 weeks on the contralateral side, while p-GSK3beta was increased 1 day and 1 week after primary blast exposure. No significant changes in total protein levels of Akt and GSK were observed on either side of the hippocampus at any time points. Immunohistochemical results showed that increased p-Akt was mainly of neuronal origin in the CA1 region of the hippocampus and once phosphorylated, the majority was translocated to the dendritic and plasma membranes. Finally, electrophysiological data showed that evoked synaptic N-methyl-d-aspartate (NMDA) receptor activity was significantly increased 6 weeks after primary blast, suggesting that increased Akt phosphorylation may enhance synaptic NMDA receptor activation, or that enhanced synaptic NMDA receptor activation may increase Akt phosphorylation. PMID- 28868047 TI - In Premature Newborns Intraventricular Hemorrhage Causes Cerebral Vasospasm and Associated Neurodisability via Heme-Induced Inflammasome-Mediated Interleukin-1 Production and Nitric Oxide Depletion. AB - BACKGROUND: Intraventricular hemorrhage (IVH) occurs in 60-70% of neonates weighing 500-750 g and 10-20% of those weighing 1,000-1,500 g. All forms of IVH have been associated with neurocognitive deficits. Both subarachnoid and IVHs have been associated with delayed vasospasm leading to neurological deficits. Pathways linking hemoglobin release from blood clots to vasospasm include heme induced activation of inflammasomes releasing interleukin-1 (IL-1) that can cause calcium dependent and independent vasospasm. Free hemoglobin is a potent scavenger of nitric oxide (NO). Depletion of NO, a potent endogenous vasodilator, has been associated with features of vasospasm. HYPOTHESIS: In premature newborns, IVH causes cerebral vasospasm and associated neurodisability via heme induced increased inflammasome-mediated IL-1 production and NO depletion. CONFIRMATION OF HYPOTHESIS AND IMPLICATIONS: This hypothesis could be confirmed in the IVH animal model with visualization of any associated vasospasm by angiography and in newborns with IVH by transcranial Doppler ultrasonography and correlation with cerebrospinal fluid IL-1 and NO metabolite levels. Confirmation of the role of heme in activation of inflammasomes causing IL-1 production and NO binding could be achieved by measuring the effect of heme scavenging interventions on IL-1 levels and levels of NO metabolites. In addition to removal of the accumulated blood of an IVH by drainage, irrigation, and fibrinolytic therapy intrathecal application of vasodilators and heme scavenging agents like haptoglobin and haemopexin and systemic treatment with inhibitors of inflammasomes like telmisartan could be used to prevent and treat cerebral vasospasm, and thus reduce the risk of associated brain injury in premature neonates. PMID- 28868048 TI - Extracellular Vesicles from Adipose Tissue-A Potential Role in Obesity and Type 2 Diabetes? AB - Adipose tissue plays a key role in the development of insulin resistance and its pathological sequelae, such as type 2 diabetes and non-alcoholic fatty liver disease. Dysfunction in the adipose tissue response to storing excess fatty acids as triglyceride can lead to adipose tissue inflammation and spillover of fatty acids from this tissue and accumulation of fatty acids as lipid droplets in ectopic sites, such as liver and muscle. Extracellular vesicles (EVs) are released from adipocytes and have been proposed to be involved in adipocyte/macrophage cross talk and to affect insulin signaling and transforming growth factor beta expression in liver cells leading to metabolic disease. Furthermore EV produced by adipose tissue-derived mesenchymal stem cells (ADSC) can promote angiogenesis and cancer cell migration and have neuroprotective and neuroregenerative properties. ADSC EVs have therapeutic potential in vascular and neurodegenerative disease and may also be used to target specific functional miRNAs to cells. Obesity is associated with an increase in adipose-derived EV which may be related to the metabolic complications of obesity. In this review, we discuss our current knowledge of EV produced by adipose tissue and the potential impact of adipose tissue-derived EV on metabolic diseases associated with obesity. PMID- 28868049 TI - Identification of Secondary Metabolite Gene Clusters in the Pseudovibrio Genus Reveals Encouraging Biosynthetic Potential toward the Production of Novel Bioactive Compounds. AB - Increased incidences of antimicrobial resistance and the emergence of pan resistant 'superbugs' have provoked an extreme sense of urgency amongst researchers focusing on the discovery of potentially novel antimicrobial compounds. A strategic shift in focus from the terrestrial to the marine environment has resulted in the discovery of a wide variety of structurally and functionally diverse bioactive compounds from numerous marine sources, including sponges. Bacteria found in close association with sponges and other marine invertebrates have recently gained much attention as potential sources of many of these novel bioactive compounds. Members of the genus Pseudovibrio are one such group of organisms. In this study, we interrogate the genomes of 21 Pseudovibrio strains isolated from a variety of marine sources, for the presence, diversity and distribution of biosynthetic gene clusters (BGCs). We expand on results obtained from antiSMASH analysis to demonstrate the similarity between the Pseudovibrio-related BGCs and those characterized in other bacteria and corroborate our findings with phylogenetic analysis. We assess how domain organization of the most abundant type of BGCs present among the isolates (Non ribosomal peptide synthetases and Polyketide synthases) may influence the diversity of compounds produced by these organisms and highlight for the first time the potential for novel compound production from this genus of bacteria, using a genome guided approach. PMID- 28868050 TI - Biofilm Formation by Pseudallescheria/Scedosporium Species: A Comparative Study. AB - Pseudallescheria/Scedosporium species are medically important fungi that are present in soil and human impacted areas and capable of causing a wide spectrum of diseases in humans. Although little is known about their pathogenesis, their growth process and infection routes are very similar to those of Aspergillus species, which grow as biofilms in invasive infections. All nine strains tested here displayed the ability to grow as biofilms in vitro and to produce a dense network of interconnected hyphae on both polystyrene and the surfaces of central venous catheters, but with different characteristics. Scedosporium boydii and S. aurantiacum clinical isolates were able to form biofilms faster than the corresponding environmental strains, as evidenced in kinetic assays for S. boydii and CLSM for S. aurantiacum. Biofilms formed by Pseudallescheria/Scedosporium species had significantly higher resistance to the class of antifungal azole than was observed in planktonic cells, indicating a protective role for this structure. In addition, the clinical S. aurantiacum isolate that formed the most robust biofilms was also more virulent in a larvae Galleria mellonella infection model, suggesting that the ability to form biofilms enhances virulence in Pseudallescheria/Scedosporium species. PMID- 28868051 TI - Distinct Seasonal Patterns of Bacterioplankton Abundance and Dominance of Phyla alpha-Proteobacteria and Cyanobacteria in Qinhuangdao Coastal Waters Off the Bohai Sea. AB - Qinhuangdao coastal waters in northern China are heavily impacted by anthropogenic and natural activities, and we anticipate a direct influence of the impact on the bacterioplankton abundance and diversity inhabiting the adjacent coastal areas. To ascertain the anthropogenic influences, we first evaluated the seasonal abundance patterns and diversity of bacterioplankton in the coastal areas with varied levels of natural and anthropogenic activities and then analyzed the environmental factors which influenced the abundance patterns. Results indicated distinct patterns in bacterioplankton abundance across the warm and cold seasons in all stations. Total bacterial abundance in the stations ranged from 8.67 * 104 to 2.08 * 106 cells/mL and had significant (p < 0.01) positive correlation with total phosphorus (TP), which indicated TP as the key monitoring parameter for anthropogenic impact on nutrients cycling. Proteobacteria and Cyanobacteria were the most abundant phyla in the Qinhuangdao coastal waters. Redundancy analysis revealed significant (p < 0.01) influence of temperature, dissolved oxygen and chlorophyll a on the spatiotemporal abundance pattern of alpha-Proteobacteria and Cyanobacteria groups. Among the 19 identified bacterioplankton subgroups, alpha-Proteobacteria (phylum Proteobacteria) was the dominant one followed by Family II (phylum Cyanobacteria), representing 19.1 55.2% and 2.3-54.2% of total sequences, respectively. An inverse relationship (r = -0.82) was observed between the two dominant subgroups, alpha-Proteobacteria and Family II. A wide range of inverse Simpson index (10.2 to 105) revealed spatial heterogeneity of bacterioplankton diversity likely resulting from the varied anthropogenic and natural influences. Overall, our results suggested that seasonal variations impose substantial influence on shaping bacterioplankton abundance patterns. In addition, the predominance of only a few cosmopolitan species in the Qinhuangdao coastal wasters was probably an indication of their competitive advantage over other bacterioplankton groups in the degradation of anthropogenic inputs. The results provided an evidence of their ecological significance in coastal waters impacted by seasonal inputs of the natural and anthropogenic matter. In conclusion, the findings anticipate future development of effective indicators of coastal health monitoring and subsequent management strategies to control the anthropogenic inputs in the Qinhuangdao coastal waters. PMID- 28868052 TI - High-Resolution Microbiome Profiling for Detection and Tracking of Salmonella enterica. AB - 16S rRNA community profiling continues to be a useful tool to study microbiome composition and dynamics, in part due to advances in next generation sequencing technology that translate into reductions in cost. Reliable taxonomic identification to the species-level, however, remains difficult, especially for short-read sequencing platforms, due to incomplete coverage of the 16S rRNA gene. This is especially true for Salmonella enterica, which is often found as a low abundant member of the microbial community, and is often found in combination with several other closely related enteric species. Here, we report on the evaluation and application of Resphera Insight, an ultra-high resolution taxonomic assignment algorithm for 16S rRNA sequences to the species level. The analytical pipeline achieved 99.7% sensitivity to correctly identify S. enterica from WGS datasets extracted from the FDA GenomeTrakr Bioproject, while demonstrating 99.9% specificity over other Enterobacteriaceae members. From low diversity and low-complexity samples, namely ice cream, the algorithm achieved 100% specificity and sensitivity for Salmonella detection. As demonstrated using cilantro and chili powder, for highly complex and diverse samples, especially those that contain closely related species, the detection threshold will likely have to be adjusted higher to account for misidentifications. We also demonstrate the utility of this approach to detect Salmonella in the clinical setting, in this case, bloodborne infections. PMID- 28868053 TI - Inherent Immunogenicity or Lack Thereof of Pluripotent Stem Cells: Implications for Cell Replacement Therapy. AB - Donor-specific induced pluripotent stem cells (iPSCs) offer opportunities for personalized cell replacement therapeutic approaches due to their unlimited self renewal potential and ability to differentiate into different somatic cells. A significant progress has been made toward generating iPSC lines that are free of integrating viral vectors, development of xeno-free culture conditions, and differentiation of pluripotent stem cells (PSCs) into functional somatic cell lineages. Since donor-specific iPSC lines are genetically identical to the individual, they are expected to be immunologically matched and these iPSC lines and their cellular derivatives are not expected to be immunologically rejected. However, studies in mouse models, utilizing rejection of teratomas as a model, have claimed that syngenic iPSC lines, especially the iPSC lines derived with integrating viral vectors, could be inherently immunogenic. This manuscript reviews current understanding of inherent immunogenicity of PSC lines, especially that of the human iPSC lines and their cellular derivatives, and strategies to overcome it. PMID- 28868055 TI - Investigation of the Influence of Leaf Thickness on Canopy Reflectance and Physiological Traits in Upland and Pima Cotton Populations. AB - Many systems for field-based, high-throughput phenotyping (FB-HTP) quantify and characterize the reflected radiation from the crop canopy to derive phenotypes, as well as infer plant function and health status. However, given the technology's nascent status, it remains unknown how biophysical and physiological properties of the plant canopy impact downstream interpretation and application of canopy reflectance data. In that light, we assessed relationships between leaf thickness and several canopy-associated traits, including normalized difference vegetation index (NDVI), which was collected via active reflectance sensors carried on a mobile FB-HTP system, carbon isotope discrimination (CID), and chlorophyll content. To investigate the relationships among traits, two distinct cotton populations, an upland (Gossypium hirsutum L.) recombinant inbred line (RIL) population of 95 lines and a Pima (G. barbadense L.) population composed of 25 diverse cultivars, were evaluated under contrasting irrigation regimes, water limited (WL) and well-watered (WW) conditions, across 3 years. We detected four quantitative trait loci (QTL) and significant variation in both populations for leaf thickness among genotypes as well as high estimates of broad-sense heritability (on average, above 0.7 for both populations), indicating a strong genetic basis for leaf thickness. Strong phenotypic correlations (maximum r = 0.73) were observed between leaf thickness and NDVI in the Pima population, but not the RIL population. Additionally, estimated genotypic correlations within the RIL population for leaf thickness with CID, chlorophyll content, and nitrogen discrimination ([Formula: see text] = -0.32, 0.48, and 0.40, respectively) were all significant under WW but not WL conditions. Economically important fiber quality traits did not exhibit significant phenotypic or genotypic correlations with canopy traits. Overall, our results support considering variation in leaf thickness as a potential contributing factor to variation in NDVI or other canopy traits measured via proximal sensing, and as a trait that impacts fundamental physiological responses of plants. PMID- 28868054 TI - Therapeutic Antibodies against Intracellular Tumor Antigens. AB - Monoclonal antibodies are among the most clinically effective drugs used to treat cancer. However, their target repertoire is limited as there are relatively few tumor-specific or tumor-associated cell surface or soluble antigens. Intracellular molecules represent nearly half of the human proteome and provide an untapped reservoir of potential therapeutic targets. Antibodies have been developed to target externalized antigens, have also been engineered to enter into cells or may be expressed intracellularly with the aim of binding intracellular antigens. Furthermore, intracellular proteins can be degraded by the proteasome into short, commonly 8-10 amino acid long, peptides that are presented on the cell surface in the context of major histocompatibility complex class I (MHC-I) molecules. These tumor-associated peptide-MHC-I complexes can then be targeted by antibodies known as T-cell receptor mimic (TCRm) or T-cell receptor (TCR)-like antibodies, which recognize epitopes comprising both the peptide and the MHC-I molecule, similar to the recognition of such complexes by the TCR on T cells. Advances in the production of TCRm antibodies have enabled the generation of multiple TCRm antibodies, which have been tested in vitro and in vivo, expanding our understanding of their mechanisms of action and the importance of target epitope selection and expression. This review will summarize multiple approaches to targeting intracellular antigens with therapeutic antibodies, in particular describing the production and characterization of TCRm antibodies, the factors influencing their target identification, their advantages and disadvantages in the context of TCR therapies, and the potential to advance TCRm-based therapies into the clinic. PMID- 28868057 TI - Selenium-Induced Toxicity Is Counteracted by Sulfur in Broccoli (Brassica oleracea L. var. italica). AB - Selenium (Se) is an essential micronutrient for humans. Increasing Se content in food crops offers an effective approach to enhance the consumption of Se in human diets. A thoroughly understanding of the effects of Se on plant growth is important for Se biofortification in food crops. Given that Se is an analog of sulfur (S) and can be toxic to plants, its effect on plant growth is expected to be greatly affected by S nutrition. However, this remains to be further understood. Here, we evaluated the influence of Se treatments on broccoli (Brassica oleracea L. var. italica) growth when S was withheld from the growth nutrient solution. We found that Se was highly toxic to plants when S nutrition was poor. In contrast to Se treatments with adequate S nutrition that slightly reduced broccoli growth, the same concentration of Se treatments without S supplementation dramatically reduced plant sizes. Higher Se toxicity was observed with selenate than selenite under low S nutrition. We examined the bases underlying the toxicity. We discovered that the high Se toxicity in low S nutrition was specifically associated with an increased ratio of Se in proteins verse total Se level, enhanced generation of reactive oxygen species, elevated lipid peroxidation causing increased cell membrane damage, and reduced antioxidant enzyme activities. Se toxicity could be counteracted with increased supplementation of S, which is likely through decreasing non-specific integration of Se into proteins and altering the redox system. The present study provides information for better understanding of Se toxicity and shows that adequate S nutrition is important to prevent Se toxicity during biofortification of crops by Se fertilization. PMID- 28868056 TI - A Combined Association Mapping and Linkage Analysis of Kernel Number Per Spike in Common Wheat (Triticum aestivum L.). AB - Kernel number per spike (KNPS) in wheat is a key factor that limits yield improvement. In this study, we genotyped a set of 264 cultivars, and a RIL population derived from the cross Yangmai 13/C615 using the 90 K wheat iSelect SNP array. We detected 62 significantly associated signals for KNPS at 47 single nucleotide polymorphism (SNP) loci through genome-wide association analysis of data obtained from multiple environments. These loci were on 19 chromosomes, and the phenotypic variation attributable to each one ranged from 1.53 to 39.52%. Twelve (25.53%) of the loci were also significantly associated with KNPS in the RIL population grown in multiple environments. For example, BS00022896_51-2ATT , BobWhite_c10539_201-2DAA , Excalibur_c73633_120-3BGG , and Kukri_c35508_426-7DTT were significantly associated with KNPS in all environments. Our findings demonstrate the effective integration of association mapping and linkage analysis for KNPS, and underpin KNPS as a target trait for marker-assisted selection and genetic fine mapping. PMID- 28868058 TI - Melatonin Enhances Phenolics Accumulation Partially via Ethylene Signaling and Resulted in High Antioxidant Capacity in Grape Berries. AB - This study assessed the primary impacts of exogenous melatonin (MT) treatment on grape berry metabolism. Exogenous MT treatment increased the endogenous MT content and modified berry ripening. Transcriptomic analysis revealed that the processes of polyphenol metabolism, carbohydrate metabolism and ethylene biosynthesis and signaling were the three most significantly altered biological processes upon MT treatment. Further experiments verified that MT treatment increased the contents of total anthocyanins, phenols, flavonoids and proanthocyanidins in berries. Additionally, the contents of 18 of the 22 detected individual phenolic compounds were enhanced by MT treatment; particularly, the resveratrol content was largely increased concomitantly with the up-regulation of STS gene expression. Meanwhile, MT treatment enhanced the antioxidant capacity of berries. On the other hand, it was indicated that ethylene participated in the regulation of polyphenol metabolism and antioxidant capacity under MT treatment in grape berries. In summary, MT enhances the polyphenol content and antioxidant capacity of grape berries partially via ethylene signaling. PMID- 28868059 TI - Integrating Early Transcriptomic Responses to Rhizotoxins in Rice (Oryza sativa. L.) Reveals Key Regulators and a Potential Early Biomarker of Cadmium Toxicity. AB - As sessile organisms, plants were constantly challenged with biotic and abiotic stresses. Transcriptional activation of stress-responsive genes is a crucial part of the plant adaptation to environmental changes. Here, early response of rice root to eight rhizotoxic stressors: arsenate, copper, cadmium, mercury, chromate, vanadate, ferulic acid and juglone, was analyzed using published microarray data. There were 539 general stress response (GSR) genes up-regulated under all eight treatments, including genes related to carbohydrate metabolism, phytohormone balance, and cell wall structure. Genes related to transcriptional coactivation showed higher Ka/Ks ratio compared to the other GSR genes. Network analysis discovered complicated interaction within GSR genes and the most connected signaling hubs were WRKY53, WRKY71, and MAPK5. Promoter analysis discovers enriched SCGCGCS cis-element in GSR genes. Moreover, GSR genes tend to be intronless and genes with shorter total intron length were induced in a higher level. Among genes uniquely up-regulated by a single stress, a phosphoenolpyruvate carboxylase kinase (PPCK) was identified as a candidate biomarker for detecting cadmium contamination. Our findings provide insights into the transcriptome dynamics of molecular response of rice to different rhizotoxic stress and also demonstrate potential use of comparative transcriptome analysis in identifying a novel potential early biomarker. PMID- 28868060 TI - Absorption Kinetics and Subcellular Fractionation of Zinc in Winter Wheat in Response to Nitrogen Supply. AB - Nitrogen (N) is critical for zinc (Zn) absorption into plant roots; this in turn allows for Zn accumulation and biofortification of grain in winter wheat (Triticum aestivum L.), an important food crop. However, little is known about root morphology and subcellular Zn distribution in response to N treatment at different levels of Zn supply. In this study, two nutrient solution culture experiments were conducted to examine Zn accumulation, Zn absorption kinetics, root morphology, and Zn subcellular distribution in wheat seedlings pre-cultured with different N concentrations. The results showed positive correlations between N and Zn concentrations, and N and Zn accumulation, respectively. The findings suggested that an increase in N supply enhanced root absorption and the root-to shoot transport of Zn. Nitrogen combined with the high Zn (Zn10) treatment increased the Zn concentration and consequently its accumulation in both shoots and roots. The maximum influx rate (Vmax), root length, surface area, and volume of 14-d-old seedlings, and root growth from 7 to 14 d in the medium N (N7.5) treatment were higher, but the Michaelis constant (Km) and minimum equilibrium concentrations (Cmin) in this treatment were lower than those in the low (N0.05) and high (N15) N treatments, when Zn was supplied at a high level (Zn10). Meanwhile, there were no pronounced differences in the above root traits between the N0.05Zn0 and N7.5Zn10 treatments. An increase in N supply decreased Zn in cell walls and cell organelles, while it increased Zn in the root soluble fraction. In leaves, an increase in N supply significantly decreased Zn in cell walls and the soluble fraction, while it increased Zn in cell organelles under Zn deficiency, but increased Zn distribution in the soluble fraction under medium and high Zn treatments. Therefore, a combination of medium N and high Zn treatments enhanced Zn absorption, apparently by enhancing Zn membrane transport and stimulating root development in winter wheat. An increase in N supply was beneficial in terms of achieving a balanced distribution of Zn subcellular fractions, thus enhancing Zn translocation to shoots, while maintaining normal metabolism. PMID- 28868062 TI - Genetic Mapping of the Leaf Number above the Primary Ear and Its Relationship with Plant Height and Flowering Time in Maize. AB - The leaf number above the primary ear (LA) is a major contributing factor to plant architecture in maize. The yield of leafy maize, which has extra LA compared to normal maize, is higher than normal maize in some regions. One major concern is that increasing LA may be accompanied by increased plant height and/or flowering time. Using an F2:3 population comprising 192 families derived from a leafy maize line and a normal maize line, an association population comprising 437 inbred maize lines, and a pair of near-isogenic maize lines, we mapped the quantitative trait loci (QTL) associated with LA and assessed its genetic relationship with flowering time and plant height. Ten QTL with an additive and dominant effect, 18 pairs of interacting QTL in the F2:3 population and seventeen significant SNPs in the association population were detected for LA. Two major QTL, qLA3-4 and qLA7-1, were repeatedly detected and explained a large proportion of the phenotypic variation. The qLA3-4 was centered on lfy1, which is a dominant gene underlying extra leaves above the ear in leafy maize. Four LA QTL were found to overlap with flowering time and/or plant height, which suggested that these QTL might have a pleiotropic effect. The pleiotropy of the lfy1 locus on LA, flowering time and plant height were validated by near-isogenic line analysis. These results enhance our understanding of the genetic architecture affecting maize LA and the development of maize hybrids with increased LA. PMID- 28868063 TI - A Rapid and Efficient Method to Obtain Photosynthetic Cell Suspension Cultures of Arabidopsis thaliana. AB - Photosynthetic cell suspension cultures are a useful experimental system to analyze a variety of physiological processes, bypassing the structural complexity of the plant organism in toto. Nevertheless, cell cultures containing functional chloroplasts are quite difficult to obtain, and this process is usually laborious and time-consuming. In this work a novel and rapid method to set up photosynthetic cell suspension cultures from the model plant Arabidopsis thaliana was developed. The direct germination of Arabidopsis seeds on a sucrose containing agarized culture medium supplemented with 0.25 MUg/ml 6 benzylaminopurine and 0.5 MUg/ml 2,4-dichlorophenoxyacetic acid caused the straightforward formation of green calli at the level of seedling hypocotyls. The subsequent transfer of these calli in liquid culture medium containing the same concentrations of phytohormones and gradually decreasing sucrose levels allowed for the establishment of chloroplast-containing cell suspension cultures, containing functional chloroplasts, in a much faster way than previously described procedures. Pulse amplitude modulation analyses, measurements of oxygen evolution and electron transport rate, together with confocal and electron microscopy observations, confirmed the photosynthetic efficiency of these cell suspension cultures. The described procedure lends itself as a simple and effective way to obtain a convenient tool for a wide array of structural and functional studies on chloroplasts. PMID- 28868061 TI - Genome-Wide Identification and Expression Analysis of NRAMP Family Genes in Soybean (Glycine Max L.). AB - The NRAMP (natural resistance-associated macrophage protein) family of genes has been widely characterized in organisms ranging from bacteria to yeast, plants, mice, and humans. This gene family plays vital roles in divalent metal ion transport across cellular membranes. As yet, comprehensive analysis of NRAMP family genes has not been reported for soybean. In this study, bioinformatics analysis was conducted to identify 13 soybean NRAMP genes, along with their gene structures, phylogenetic relationships, and transmembrane domains. Expression analysis suggests that GmNRAMP genes function in numerous tissues and development stages. Moreover, soybean NRAMP genes were differentially regulated by deficiencies of N, P, K, Fe, and S, along with toxicities of Fe, Cu, Cd, and Mn. These results indicate that GmNRAMP genes function in many nutrient stress pathways, and might be involved in crosstalk among nutrient stress pathways. Subcellular localization analysis in Arabidopsis protoplasts confirmed the tonoplast or plasma membrane localization of selected soybean NRMAP proteins. Protein-protein interaction analysis found that the networks of three GmNRAMP proteins which putatively interact with nodulin-like proteins, almost distinct from the network that is common to the other 10 soybean NRAMP proteins. Subsequent qRT-PCR results confirmed that these three GmNRMAP genes exhibited enhanced expression in soybean nodules, suggesting potential functions in the transport of Fe or other metal ions in soybean nodules. Overall, the systematic analysis of the GmNRAMP gene family reported herein provides valuable information for further studies on the biological roles of GmNRAMPs in divalent metal ion transport in various soybean tissues under numerous nutrient stresses and soybean rhizobia symbiosis. PMID- 28868065 TI - Control of Glyphosate-Resistant Common Ragweed (Ambrosia artemisiifolia L.) in Glufosinate-Resistant Soybean [Glycine max (L.) Merr]. AB - Common ragweed emerges early in the season in Nebraska, USA and is competitive with soybean; therefore, preplant herbicides are important for effective control. Glyphosate has been used as a preplant control option; however, confirmation of glyphosate-resistant (GR) common ragweed in Nebraska necessitates evaluating other herbicide options. The objectives of this study were to (1) evaluate the efficacy of preplant (PP) herbicides followed by (fb) glufosinate alone or in tank-mixture with imazethapyr, acetochlor, or S-metolachlor applied post emergence (POST) for control of GR common ragweed in glufosinate-resistant soybean; (2) their effect on common ragweed density, biomass, and soybean yield; and (3) the partial economics of herbicide programs. A field experiment was conducted in a grower's field infested with GR common ragweed in Gage County, Nebraska, USA in 2015 and 2016. Preplant herbicide programs containing glufosinate, paraquat, 2,4-D, dimethenamid-P, cloransulam-methyl, or high rates of flumioxazin plus chlorimuron-ethyl provided 90-99% control of common ragweed at 21 d after treatment (DAT). The aforementioned PP herbicides fb a POST application of glufosinate alone or in tank-mixture with imazethapyr, acetochlor, or S-metolachlor controlled GR common ragweed 84-98% at soybean harvest, reduced common ragweed density (<=20 plants m-2) and biomass by >=93%, and secured soybean yield 1,819-2,158 kg ha-1. The PP fb POST herbicide programs resulted in the highest gross profit margins (US$373-US$506) compared to PP alone (US$91) or PRE fb POST programs (US$158). The results of this study conclude that effective and economical control of GR common ragweed in glufosinate-resistant soybean is achievable with PP fb POST herbicide programs. PMID- 28868064 TI - Hydrogen Peroxide Is Involved in beta-Cyclodextrin-hemin Complex-Induced Lateral Root Formation in Tomato Seedlings. AB - Although previous results showed that beta-cyclodextrin-hemin complex (beta-CDH) could induce tomato lateral root (LR) formation, the corresponding downstream messengers are still not fully understood. In this report, similar to the inducing effects of exogenously applied hydrogen peroxide (H2O2), we discovered that beta-CDH elicited RBOH1 transcript upregulation, endogenous H2O2 accumulation, and thereafter tomato LR development. Above responses were sensitive to dimethylthiourea (DMTU) and ascorbic acid (AsA), two membrane permeable scavengers of H2O2, showing that accumulation of H2O2 and LR formation were significantly blocked. The test with diphenyleneiodonium (DPI; the inhibitor of NADPH oxidase) revealed that H2O2 mainly produced by NADPH oxidase, might be involved in LR formation triggered by beta-CDH. qPCR combined with pharmacological and anatomical analyses showed that beta-CDH-modulated several marker genes responsible for LR formation, such as CYCA3;1, CYCA2;1, CYCD3;1, and CDKA1 (four cell cycle regulatory genes), ARF7 and RSI-1 (two auxin signaling genes), LAX3 (an auxin influx carrier), IAA14 (encoding a member of the Aux/IAA protein family), PIN3 and PIN7 (two auxin efflux carriers), isocitrate dehydrogenase [NADP], NADH-cytochrome b5 reductase 1, and L-ascorbate oxidase homolog genes (two reactive oxygen species-associated genes and one LR formation related gene), were causally related to above H2O2 signaling. Particularly, representative proteins related to H2O2 metabolism and lateral rooting, were specifically induced in beta-CDH-treated tomato seedlings. Overall, the results clearly suggested a vital role of H2O2 in the beta-CDH-induced tomato LR formation, and beta-CDH-elicited H2O2-related target proteins responsible for LR formation might be, at least partially, regulated at transcriptional and translational levels. PMID- 28868066 TI - Distinguishing Depressive Pseudodementia from Alzheimer Disease: A Comparative Study of Hippocampal Volumetry and Cognitive Tests. AB - BACKGROUND AND AIM: Depressive pseudodementia (DPD) is a condition which may develop secondary to depression. The aim of this study was to contribute to the differential diagnosis between Alzheimer disease (AD) and DPD by comparing the neurocognitive tests and hippocampal volume. MATERIALS AND METHODS: Patients who met criteria of AD/DPD were enrolled in the study. All patients were assessed using the Wechsler Memory Scale (WMS), clock-drawing test, Stroop test, Benton Facial Recognition Test (BFRT), Boston Naming Test, Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS). Hippocampal volume was measured by importing the coronal T1-weighted magnetic resonance images to the Vitrea 2 workstation. RESULTS: A significant difference was found between the AD and DPD groups on the WMS test, clock-drawing test, Stroop test, Boston Naming Test, MMSE, GDS, and left hippocampal volume. A significant correlation between BFRT and bilateral hippocampal volumes was found in the AD group. No correlation was found among parameters in DPD patients. CONCLUSIONS: Our results suggest that evaluation of facial recognition and left hippocampal volume may provide more reliable evidence for distinguishing DPD from AD. Further investigations combined with functional imaging techniques including more patients are needed. PMID- 28868067 TI - Cerebrospinal Fluid Apolipoprotein E Levels in Delirium. AB - BACKGROUND/AIMS: Delirium and the apolipoprotein E epsilon4 allele are risk factors for late-onset Alzheimer disease (LOAD), but the connection is unclear. We looked for an association. METHODS: Inpatients with delirium (n = 18) were compared with LOAD outpatients (n = 19), assaying blood and cerebrospinal fluid (CSF) using multiplex ELISA. RESULTS: The patients with delirium had a higher Confusion Assessment Method (CAM) score (5.6 +/- 1.2 vs. 0.0 +/- 0.0; p < 0.001) and Delirium Index (13.1 +/- 4.0 vs. 2.9 +/- 1.2; p = 0.001) but a lower Mini Mental State Examination (MMSE) score (14.3 +/- 6.8 vs. 20.8 +/- 4.6; p = 0.003). There was a reduction in absolute CSF apolipoprotein E level during delirium (median [interquartile range]: 9.55 MUg/mL [5.65-15.05] vs. 16.86 MUg/mL [14.82 20.88]; p = 0.016) but no differences in apolipoprotein A1, B, C3, H, and J. There were no differences in blood apolipoprotein levels, and no correlations between blood and CSF apolipoprotein levels. CSF apolipoprotein E correlated negatively with the CAM score (r = -0.354; p = 0.034) and Delirium Index (r = 0.341; p = 0.042) but not with the Acute Physiology and Chronic Health Evaluation (APACHE) index, or the MMSE or Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). CONCLUSION: Reduced CSF apolipoprotein E levels during delirium may be a mechanistic link between two important risk factors for LOAD. PMID- 28868068 TI - Assessing Capacity in the Elderly: Comparing the MoCA with a Novel Computerized Battery of Executive Function. AB - BACKGROUND/AIMS: Clinicians are increasingly being asked to provide their opinion on the decision-making capacity of older adults, while validated and widely available tools are lacking. We sought to identify an online cognitive screening tool for assessing mental capacity through the measurement of executive function. METHODS: A mixed elderly sample of 45 individuals, aged 65 years and older, were screened with the Montreal Cognitive Assessment (MoCA) and the modified Cambridge Brain Sciences Battery. RESULTS: Two computerized tests from the Cambridge Brain Sciences Battery were shown to provide information over and above that obtained with a standard cognitive screening tool, correctly sorting the majority of individuals with borderline MoCA scores. CONCLUSIONS: The brief computerized battery should be used in conjunction with standard tests such as the MoCA in order to differentiate cognitively intact from cognitively impaired older adults. PMID- 28868070 TI - Coronary heart disease incidence and competing risks: an important issue. PMID- 28868069 TI - Urinary Neutrophil Gelatinase-Associated Lipocalin as a Predictor of Acute Kidney Injury, Severe Kidney Injury, and the Need for Renal Replacement Therapy in the Intensive Care Unit. AB - BACKGROUND: Recent attempts were made to identify early indicators of acute kidney injury (AKI) in order to accelerate treatment and hopefully improve outcomes. This study aims to assess the value of urinary neutrophil gelatinase associated lipocalin (uNGAL) as a predictor of AKI, severe AKI, and the need for renal replacement therapy (RRT). METHODS: We conducted a prospective study and included adults admitted to our intensive care unit (ICU) at King Abdulaziz University Hospital (KAUH), between May 2012 and June 2013, who had at least 1 major risk factor for AKI. They were followed up throughout their hospital stay to identify which potential characteristics predicted any of the above 3 outcomes. We collected information on patients' age and gender, the Acute Physiology And Chronic Health Evaluation, version II (APACHE II) score, the Sepsis-Related Organ Failure Assessment (SOFA) score, serum creatinine and cystatin C levels, and uNGAL. We compared ICU patients who presented with any of the 3 outcomes with others who did not. RESULTS: We included 75 patients, and among those 21 developed AKI, 18 severe AKI, and 17 required RRT. Bivariate analysis revealed intergroup differences for almost all clinical variables (e.g., patients with AKI vs. patients without AKI); while multivariate analysis identified mean arterial pressure as the only predictor for AKI (p < 0.001) and the SOFA score (p = 0.04) as the only predictor for severe AKI. For RRT, day 1 maximum uNGAL was the stronger predictor (p < 0.001) when compared to admission diagnosis (p = 0.014). Day 1 and day 2 maximum uNGAL levels were good and excellent predictors for future RRT, but only fair to good predictors for AKI and severe AKI. CONCLUSIONS: Maximum urine levels of uNGAL measured over the first and second 24 h of an ICU admission were highly accurate predictors of the future need for RRT, however less accurate at detecting early and severe AKI. PMID- 28868071 TI - Verapamil and vasospastic angina: underuse in the elderly population. PMID- 28868072 TI - Usefulness of coronary flow reserve measured by transthoracic coronary Doppler ultrasound in the elderly. PMID- 28868073 TI - Antithrombotic treatment tailoring and risk score evaluation in elderly patients diagnosed with an acute coronary syndrome. AB - Age is an important prognostic factor in the outcome of acute coronary syndromes (ACS). A substantial percentage of patients who experience ACS is more than 75 years old, and they represent the fastest-growing segment of the population treated in this setting. These patients present different patterns of responses to pharmacotherapy, namely, a higher ischemic and bleeding risk than do patients under 75 years of age. Our aim was to identify whether the currently available ACS ischemic and bleeding risk scores, which has been validated for the general population, may also apply to the elderly population. The second aim was to determine whether the elderly benefit more from a specific pharmacological regimen, keeping in mind the numerous molecules of antiplatelet and antithrombotic drugs, all validated in the general population. We concluded that the GRACE (Global Registry of Acute Coronary Events) risk score has been extensively validated in the elderly. However, the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) bleeding score has a moderate correlation with outcomes in the elderly. Until now, there have not been head-to head scores that quantify the ischemic versus hemorrhagic risk or scores that use the same end point and timeline (e.g., ischemic death rate versus bleeding death rate at one month). We also recommend that the frailty score be considered or integrated into the current existing scores to better quantify the overall patient risk. With regard to medical treatment, based on the subgroup analysis, we identified the drugs that have the least adverse effects in the elderly while maintaining optimal efficacy. PMID- 28868074 TI - Update on pharmacological treatment of acute coronary syndrome without persistent ST segment elevation myocardial infarction in the elderly. AB - The increase in cardiovascular disease prevalence with ageing has been attributed to several age-related changes such as changes in the vascular wall elasticity, the coagulation and haemostatic system and endothelial dysfunction, among other causes. There is a 50% increased mortality risk per 10-year increase in age starting at 65 years old. Here, we aimed to discuss pharmacological treatment in acute coronary syndrome (ACS) without persistent ST segment elevation myocardial infarction in the elderly. The main aim of ACS treatment in elderly people is at preventing ischemia, myocardial damage and complications. A meta-analysis suggests that invasive revascularization therapy is probably most useful in older patients. Dual antiplatelet therapy is currently the standard of care post-ACS. Platelet P2Y12 inhibitors are among the most commonly used medications worldwide, due to their established benefits in the treatment and prevention of arterial thrombosis. The main recommendation is to tailor antithrombotic treatment, considering body weight, renal function (Class I, level C) and careful evaluation of life expectancy, comorbidities, risk/benefit profile, quality of life and frailty when invasive strategies are considered (Class IIa, level A) on top of the different recommendations given for a general non ST elevation ACS population. It is obvious that potent P2Y12 inhibitors will continue to play an important role in pharmacological treatment for elderly ACS patients in the future. PMID- 28868075 TI - Determinants of invasive strategy in elderly patients with non-ST elevation myocardial infarction. AB - BACKGROUND: Knowledge gaps across literature prevent current guidelines from providing the profile of elderly patients most likely to derive benefit from invasive strategy (IS) in non ST-elevation myocardial infarction (NSTEMI). Furthermore, the benefit of IS in a real-world elderly population with NSTEMI remains unclear. The aims of this study were to determine factors that lead the cardiologist to opt for an IS in elderly patients with NSTEMI, and to assess the impact of IS on the 6-month all-cause mortality. METHODS: This multicenter prospective study enrolled all consecutive patients aged >= 75 years old who presented a NSTEMI and were hospitalized in cardiology intensive care unit between February 2014 and February 2015. Patients were compared on the basis of reperfusion strategy (invasive or conservative) and living status at six months, in order to determine multivariate predictors of the realization of an IS and multivariate predictors of 6-month mortality. RESULTS: A total of 141 patients were included; 87 (62%) underwent an IS. The strongest independent determinants of IS were younger age [odds ratio (OR): 0.85, 95%-confidence interval (CI): 0.78 0.92; P < 0.001) and lower "Cumulative Illness Rating Scale-Geriatric" number of categories score (OR: 0.83, 95%CI: 0.73-0.95; P = 0.002). IS was not significantly associated with 6-month survival (OR: 0.80, 95%CI: 0.27-2.38; P = 0.69). CONCLUSIONS: In real-world elderly patients with NSTEMI, younger patients with fewer comorbidities profited more often from an IS. However, IS did not modify 6-month all-cause mortality. PMID- 28868076 TI - Glycation of high-density lipoprotein triggers oxidative stress and promotes the proliferation and migration of vascular smooth muscle cells. AB - BACKGROUND: In type 2 diabetes mellitus (T2DM), high-density lipoprotein (HDL) impairs its anti-atherogenic properties and even develops to a pro-inflammatory and pro-atherogenic phenotype because of abnormal compositions and modifications. In this study, we examined the effects and the related mechanisms of glycation of HDL on the proliferation and migration of vascular smooth muscle cells (VSMCs). METHODS & RESULTS: Glycated HDL (G-HDL) was modified with D-glucose (25 mmol/L) in vitro. Diabetic HDL (D-HDL) was isolated from T2DM patients. Rat VSMCs were isolated from the thoracic aortas. Human VSMCs were obtained from ScienCell Research Laboratories. Alpha-actin was detected through immunofluorescence. VSMC proliferation was assayed by Cell Count. VSMC migration was determined by transwell chamber and scratch-wound assay. Intracellular reactive oxygen species (ROS) was detected based on ROS-mediated 2',7'-dichlorofluorescein (DCFH-DA) fluorescence. Compared to native HDL (N-HDL), G-HDL remarkably promoted VSMC proliferation and migration in the dose and time-dependent manners. In addition, G-HDL enhanced ROS generation in VSMCs. However, the ROS scavenger, N acetylcysteine, efficiently decreased ROS production and subsequently inhibited the proliferation of VSMCs induced by G-HDL. Similarly, D-HDL from T2DM patients also promoted ROS release and VSMC proliferation and migration. CONCLUSIONS: HDL either glycated in vitro or isolated from T2DM patients triggered VSMC proliferation, migration, and oxidative stress. These results might partly interpret the higher morbidity of cardiovascular disease in T2DM patients. PMID- 28868077 TI - Acute myocardial infarction in patients of nephrotic syndrome: a case series. PMID- 28868078 TI - Clinical features of aortic dissection associated with Takayasu's arteritis. PMID- 28868079 TI - Two case of preoperative bridging therapy for patients undergoing non-cardiac surgery after coronary stent implantation. PMID- 28868080 TI - Effect of Living Arrangement on the Health Status of Elderly in India: Findings from a national cross sectional survey. AB - Epidemiological studies show strong association between lack/inadequate family support with increased mortality and poor health among the elderly. This study examined the effect of living arrangement on elderly health status by analysing the data of 39,694 persons aged 60 and above included in India's second National Family Health Survey conducted in 1998-1999. Results indicate that elderly who are living alone are likely to suffer more from both chronic illnesses, such as asthma and tuberculosis, and acute illnesses, such as malaria and jaundice, than those elderly who are living with their family, even after controlling for the effects of a number of socio-economic, demographic, environmental and behavioural confounders. The findings have important programme and policy implications for countries such as India, which has the second largest elderly population in the world. There is a strong need for the implementation of specific public support systems and health care strategies focused on the elderly population in general and elderly living alone in particular. PMID- 28868082 TI - The Influence of Tai Chi Exercise on Proprioception in Patients with Knee Osteoarthritis: Results from a Pilot Randomized Controlled Trial. AB - PURPOSE: Previous long-term observational studies found that Tai Chi practitioners had better knee-joint proprioceptive acuity versus controls in an older population. We evaluated the effects of Tai Chi for knee-joint proprioception in knee osteoarthritis (OA) in a randomized controlled trial. METHODS: We randomized 40 eligible individuals (age > 55, BMI <= 40 kg/m2 with knee pain on most days of the previous month and tibiofemoral OA (K/L grade >=2) to Tai Chi (10 modified forms from classical Yang style) or to an attention control (stretching and wellness education). The 60 minute intervention sessions occurred twice-weekly for 12 weeks. The knee joint proprioception was measured using a BiometricsTM electrogoniometer with an ADU301 angle display unit during each assessment visit. Three test angles (30, 45 and 60 degrees) were evaluated with each subject in a sitting position taken as neutral (0 degrees). The mean error (absolute angle error) between the actual and replicated angles was calculated for each of the three test angles. The Tai Chi and control groups were compared by intention-to-treat using t-tests. RESULTS: The participants had a mean age of 65 y (SD 7.8), a mean disease duration of 10 y (SD 7.6), a mean BMI of 30.0 kg/m2 (SD 4.8), and median K/L grade 4; 75% were female, 70% were white. The participants in the Tai Chi intervention exhibited significantly improved proprioception at 30 degrees, but not at 45 or 60 degrees, at 12 weeks. Patients who continued Tai Chi practice after 12 weeks also reported no significant improvements in knee proprioception at 24 and 48 weeks. CONCLUSION: Tai Chi appears to be beneficial for knee proprioception in people with severe knee OA at a 30 degree test angle immediately following 12 weeks of practice. However, we were unable to demonstrate that Tai Chi has any long-term effects on knee proprioception, nor were we able to find any effects on proprioception at larger test angles (45 and 60 degrees). Standardized and reproducible measures for knee proprioception should be explored in future research. PMID- 28868081 TI - Cognitive Performance in Euthymic Patients with Bipolar Disorder vs Healthy Controls: A Neuropsychological Investigation. AB - OBJECTIVES: Cognitive impairment may affect patients with Bipolar Disorder (BD) beyond the acute episodes, qualifying as a potential endophenotype. However, which cognitive domains are specifically affected in euthymic patients with BD and the potential influence of confounding factors (e.g., age and concomitant pharmacological treatment) are still a matter of debate. The present study was, therefore, conducted to assess cognitive performance across specific domains in euthymic bipolar patients, not older than 50 years (to avoid potential age related bias) versus healthy controls (HCs). METHODS: A cognitive task battery, including the Wisconsin Card Test, Span Attention Test, Tower of London, Trail Making Test, Verbal Fluency Test, Matrices Scores and N-Back, was administered to 62 subjects (30 bipolar patients and 32 matched HCs) and differences between the groups analyzed. RESULTS: Bipolar patients performed significantly worse than HCs in the Span Forward task, in the expression of Verbal Fluency Test (Category) and in the N-Back task (all p<.05), with marginal differences between BD I and BD II patients. CONCLUSION: The present study pointed out significant differences in terms of cognitive performance between euthymic bipolar patients and HCs, supporting the notion that specific cognitive functions may remain impaired even after the resolution of the acute episodes in subjects suffering from BD. Future studies on larger samples are warranted to confirm the present results and further explore potential differences in cognitive impairment across specific bipolar subtypes. PMID- 28868083 TI - Complex forearm deformities: operative strategy in posttraumatic pathology. AB - Complex posttraumatic forearm deformities have a significant impact on the integrity of the upper extremity leading to pain, instability in both the proximal and/or distal radioulnar articulation, and reduced range of forearm motion. Corrective osteotomy or more advanced procedures for malunited fractures or other posttraumatic deformities of the upper extremity, especially in the forearm are challenging procedures. In this review we will discuss the essential aspects of anatomy and pathomechanics, clinical and radiological assessment and the pathway from preoperative planning to the actual deformity correction surgery, either with one-stage correction or using gradual lengthening with external fixation ("callotasis techniques") and finally the functional outcome we can expect for our patients. In addition we will analyze the modern computer assisted techniques available to date. PMID- 28868084 TI - Statistical and histological analysis of tumors of the upper extremity. AB - BACKGROUND: Tumors of the upper extremity are common and usually benign. The most commonly diagnosed are ganglion cysts: specific, non-neoplastic swellings localized mostly around the wrist. OBJECTIVE: The objective of this retrospective study was to determine the proportion of various types of nonganglionic hand tumors operated on at the authors' institution in 2014. METHODS: A total of 246 patients, 141 women (57 %) and 105 men (43 %), with a mean age of 53 years and with tumorsof the upper extremity, were identified and treated in the authors' institution in 2014. RESULTS: Almost half of the lesions were localized in the fingers (n = 119, 48 %), followed by the wrist (n=49, 20 %), metacarpus (n = 40, 16 %), and more proximal parts (n = 38, 16 %). The time between the patients noticing the lesion and surgery was a mean of 4 years (range, 1 month to 30 years). The most common lesion was giant cell tumor of the tendon sheath (n = 58, 23 %), followed by lipoma (n = 40, 16 %), epidermal cyst (n = 23, 9 %), enchondroma (n=16, 6 %), hemangioma (n = 14, 6 %), fibroma (n = 11, (4 %), glomus tumor (n = 10, (4 %), and rheumatoid nodule (n = 10, (4 %). Two cases of malignant fibrosarcoma were identified incidentally. CONCLUSION: A brief review of the literature is made referring to the data presented here. PMID- 28868085 TI - Revision of reversed shoulder arthroplasty: Is a reoperation possible? AB - INTRODUCTION: As the number of reversed shoulder arthroplasty (RSA) procedures increases, the revision rate will also increase. In case of severe bone insufficiency, instability or infection of the primary RSA, revision to another RSA is preferable but not always possible. Hemiarthroplasty (HA), spacers and resection arthroplasty (RA) have been described in this indication. MATERIALS AND METHODS: Between 2004 and 2016, 20 shoulders in 19 patients were treated at Ghent University Hospital for failed revision of RSA. Nine received a megahead prosthesis, a spacer was implanted in 6, and 5 underwent RA. RESULTS: Indications for implantation of a megahead prosthesis were loosening RSA (n = 5), infection (n = 4), dislocation (n = 1) and nerve irritation (n = 1). Improvement of range of motion was observed. Anterosuperior migration of the prosthesis was noted in 2 patients. Another 2 patients were ultimately revised to RSA. Seven permanent spacers were implanted for infection, of which 2 remain in place till today. The other 5 were revised to RSA. Of the 5 patients treated with RA, 3 were revised further on to RSA, resulting in pain relief and regain of function. DISCUSSION: Our study shows that a megahead prosthesis has better functional results than RA, but is inferior to RSA. Due to increasing surgical experience and improving technique, 9 patients could ultimately be reconverted to another RSA. A review of current literature is presented. In HA and RA, the functional results are poor, and pain relief is uncertain. Results of spacers are variable and can be satisfactory. Arthrodesis is a last resort. CONCLUSION: In our case series study, a hemiarthroplasty can be performed in case of failure of RSA. However, the results are inferior to another RSA. PMID- 28868086 TI - Subacromial spacer implantation for massive rotator cuff tears: Clinical outcome of arthroscopically treated patients. AB - BACKGROUND: Massive rotator cuff tears (MRCT) can be treated arthroscopically by partial reconstruction, tenotomy/tenodesis of the long head of the biceps, and debridement. A new treatment option is the additional implantation of a biodegradable spacer (InSpace Balloon(r); ISB) into the subacromial space, which reduces subacromial shear forces to keep the humeral head centered in the glenoid. The aim of this study is to investigate the clinical outcome of patients with MRCT who were treated arthroscopically with or without an additional ISB. METHODS: The clinical outcome of patients treated with conventional arthroscopic techniques (n = 11, group A, partial repair, biceps tenotomy, and debridement) and that of patients treated with a supplementary ISB (n = 12, group B) was retrospectively analyzed. Preoperatively and postoperatively, shoulder function was assessed with the Constant and American Shoulder and Elbow Surgeons (ASES) scores. At follow-up after a mean of 22 months, patients filled out a questionnaire about their subjective satisfaction. RESULTS: Preoperative shoulder function was lower in patients treated with an ISB (ASES score: group A, 59.1; group B, 31.5; Constant score: group A, 60.7; group B, 36.8). At follow-up, both groups had improved shoulder function (Constant score: group A, 60.7-77.6; p < 0.001; group B, 36.8-69.5; p < 0.001; ASES score: group A, 59.1-88.6; p < 0.001; group B, 31.5-85.7; p < 0.001). Patients in both groups were subjectively satisfied with their outcome. CONCLUSION: The ISB is a feasible treatment option for MRCT, providing subjective pain relief and improved shoulder function. Further studies with larger patient collectives and longer follow-up are needed to confirm whether it is a safe and cost-effective treatment. PMID- 28868088 TI - Chondral defects of the glenohumeral joint: Long-term outcome after microfracturing of the shoulder. AB - INTRODUCTION: An increasing number of young patients are diagnosed with chondral lesions. Minimally invasive surgical techniques are important in order to delay progression of the early stages of osteoarthritis and the need for total joint replacement. MATERIALS AND METHODS: Patients (n = 32) who had received microfracturing of the shoulder were retrospectively enrolled, of whom 5 had received shoulder replacements after a mean time of 47 months. Of these patients, 23 completed the Disabilities of the Arm, Shoulder and Hand (DASH) and Constant Murley Scores in addition to an additional subjective questionnaire. Patients were then clinically examined and received x-ray analysis of the operated shoulder. Data from an additional 4 patients were acquired by telephone interview. RESULTS: Mean follow-up was 105 months. Of the included patients, 13/27 patients reported no pain, 12/27 patients moderate pain. Of these 12, 6/27 reported pain only at night and 3/27 only during rest. Concerning the outcome of surgery, 19/27 patients were "satisfied" or "very satisfied". There was a statistically significant increase in internal rotation, but no further differences in the range of motion pre- and postoperatively. Patients without any signs of osteoarthritis before surgery showed statistically significantly better outcomes. There was a statistically significant increase in radiological signs of osteoarthrosis in pre- versus postoperative patients. Patients with bipolar lesions showed statistically significantly poorer Subjective Shoulder Value (SSV) results. CONCLUSION: Even though microfracturing does not prevent radiographic progression, microfracture of the glenohumeral joint might be worth considering as part of a treatment regimen for younger patients who may not yet be treated with arthroplasty. PMID- 28868087 TI - Use of shoulder pacemaker for treatment of functional shoulder instability: Proof of concept. AB - BACKGROUND: Functional shoulder instability (polar type III) is caused by underactivity of rotator cuff and periscapular muscles, which leads to subluxation or dislocation during shoulder movement. While surgical treatment has shown no benefits, aggravates pain, and frequently diminishes function even further, conservative treatment is often ineffective as well. OBJECTIVES: The aim was to investigate the effectiveness of a "shoulder pacemaker" device that stimulates underactive muscles in patients with functional instability during shoulder movement in order to re-establish glenohumeral stability. PATIENTS AND METHODS: Three patients with unsuccessfully treated functional shoulder instability causing pain, emotional stress, as well as limitations during daily activities and sports participation were enrolled in this pilot project. The device was used to stimulate the external rotators of the shoulder and retractors of the scapula. Pain level, subjective shoulder instability, range of motion, visible aberrant muscle activation, and signs of dislocation were compared when the device was switched on and off. RESULTS: No changes were observed when the device was attached but switched off. When the device was switched on, all patients were able to move their arms freely without pain, discomfort, or subjective or objective signs of instability. All patients rated this as an excellent experience and volunteered to train further with the device. No complications were observed. CONCLUSION: The electric stimulation of hypoactive rotator cuff and periscapular muscles by means of the shoulder pacemaker successfully re-establishes stability in patients with functional shoulder instability during the time of application. VIDEO ONLINE: The online version of this article (doi: 10.1007/s11678-017-0399-z) contains the video: "The Shoulder Pacemaker: treatment of functional shoulder instability with pathological muscle activation pattern". Video by courtesy of P. Moroder, M. Minkus, E. Bohm, V. Danzinger, C. Gerhardt and M. Scheibel, Charite Universitatsmedizin Berlin 2017, all rights reserved. PMID- 28868089 TI - Humeral bone grafting in stemless shoulder arthroplasty. PMID- 28868090 TI - Post-processing reproducibility of the structural characteristics of the common carotid artery in a Flemish population. AB - INTRODUCTION: Common carotid artery (CCA) intima-media thickness (IMT), lumen diameter, and maximum plaque thickness were assessed on ultrasound images. The objective of the study was to evaluate the intra- and inter-reader reproducibility of the measurements following a standardised protocol. METHODS: Two readers performed the off-line measurements on B-mode ultrasound images of the distal CCA, in a randomly selected subset (n = 60) from a Flemish population cohort (FLEMENGHO). We calculated the coefficient of variation, the interclass correlation coefficient (ICC) and reproducibility according to the Bland-Altman method. RESULTS: The intra-reader bias for the measurements of left and right side CCA IMT were -0.003 +/- 0.04 mm (p = 0.55) and 0.01 +/- 0.04 mm (p = 0.03), respectively. The intra-reader bias of the lumen diameter was -0.04 +/- 0.25 mm (p = 0.27) for the left and 0.02 +/- 0.22 mm (p = 0.45) for the right side. The measurements for the maximum plaque thickness showed no intra-reader differences with bias 0.07 +/- 0.2 mm (p = 0.26) for the left and -0.03 +/- 0.2 mm (p = 0.55) for the right side. The inter-reader analysis showed good reproducibility for the left and right side CCA IMT with bias 0.004 +/- 0.06 mm (p = 0.57) and -0.008 +/- 0.05 mm (p = 0.19), respectively, but the lumen diameter measurements showed inter-reader differences, with bias 0.17 +/- 0.27 mm (p < 0.0001) for the left and 0.10 +/- 0.21 mm (p = 0.0006) for the right side. The inter-reader bias for the maximum plaque thickness were 0.07 +/- 0.2 mm (p = 0.21) and -0.1 +/- 0.4 mm (p = 0.26) for the left and right side, respectively. CONCLUSION: The results demonstrated a reliable reproducibility of carotid wall structural measurements, allowing for an adequate further analysis of the entire population cohort. PMID- 28868091 TI - Non-invasive Raman Spectroscopy and Quantitative Real-Time PCR Distinguish Among Undifferentiated Human Mesenchymal Stem Cells and Redifferentiated Nucleus Pulposus Cells and Chondrocytes In Vitro. AB - BACKGROUND: The most common cause of lower back pain is the pathological degeneration of the nucleus pulposus (NP). Promising NP regeneration strategies involving human mesenchymal stem cells (hMSCs) would require specific markers to confirm successful differentiation into the NP lineage and to distinguish the articular cartilage (AC). OBJECTIVE: We sought specific NP mRNA markers that are upregulated in native NP cells but not in dedifferentiated NP cells, undifferentiated hMSCs or chondrocytes. We also considered the suitability of non invasive Raman spectroscopy to distinguish among these classes of cells. METHOD: We used quantitative real-time PCR and Raman spectroscopy to analyse undifferentiated hMSCs in monolayers and embedded in hydrogels, and compared the results with dedifferentiated and redifferentiated human NP and AC cells. RESULTS: The redifferentiation of NP cells induced the expression of annexin A3 (ANXA3), collagen type II (COL2) and proteoglycan mRNAs, whereas the redifferentiation of AC cells only induced proteoglycan expression. Redifferentiated NP cells expressed higher levels of ANXA3, COL2, paired box 1 (PAX1) and OCT4 mRNA than redifferentiated AC cells. Redifferentiated NP cells and undifferentiated hMSC-TERT cells expressed similar amount of OCT4 mRNA, indicating that only ANXA3, COL2 and PAX1 are promising markers for redifferentiated NP cells. Raman spectra clearly differed among the three cell types and highlighted their differentiation status. CONCLUSION: We recommend ANXA3, COL2 and PAX1 as markers to determine the success of hMSC-based differentiation to regenerate NP cells. Raman spectroscopy can be used to determine cell type and differentiation status especially in the context of clinical trials. PMID- 28868092 TI - The Spectrum of Familial Hypercholesterolemia (FH) in Saudi Arabia: Prime Time for Patient FH Registry. AB - BACKGROUND: Familial hypercholesterolemia (FH) is a life-threatening inherited condition. Untreated patients have the risk to develop raised plasma levels of cholesterol, atherosclerosis and cardiovascular disease (CVD). If diagnosed and treated early in life, the pathological consequences due to atherosclerosis could be avoided and patients with FH can have an anticipated normal life. Mounting evidence suggests that FH is underdiagnosed and undertreated in all populations. The underlying molecular basis of FH is the presence of mutations in one or more genes in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB) or proprotein convertase subtilisin/kexin 9 (PCSK9). However, their prevalence is largely unknown in Saudi Arabia but given the high rates of consanguinity, the prevalence appears to be higher. Furthermore, the high prevalence of obesity and diabetes mellitus in Saudi Arabia increases the vascular disease burden in FH cases by adding additional CVD risk factors. OBJECTIVE: This article explores the spectrum of FH-causing mutations in the highly consanguineous Saudi community, the need for establishing the Saudi FH registry, the challenges in creating gene databases, and cascade screening. CONCLUSION: The establishment of FH registry and genetic testing should raise awareness not only among healthcare professionals, but the general population as well. It also helps to provide the best treatment regimen in a cost effective manner to this under-recognised population of FH patients. PMID- 28868095 TI - A Mechanistic Account of Wide Computationalism. AB - The assumption that psychological states and processes are computational in character pervades much of cognitive science, what many call the computational theory of mind. In addition to occupying a central place in cognitive science, the computational theory of mind has also had a second life supporting "individualism", the view that psychological states should be taxonomized so as to supervene only on the intrinsic, physical properties of individuals. One response to individualism has been to raise the prospect of "wide computational systems", in which some computational units are instantiated outside the individual. "Wide computationalism" attempts to sever the link between individualism and computational psychology by enlarging the concept of computation. However, in spite of its potential interest to cognitive science, wide computationalism has received little attention in philosophy of mind and cognitive science. This paper aims to revisit the prospect of wide computationalism. It is argued that by appropriating a mechanistic conception of computation wide computationalism can overcome several issues that plague initial formulations. The aim is to show that cognitive science has overlooked an important and viable option in computational psychology. The paper marshals empirical support and responds to possible objections. PMID- 28868094 TI - Pressure Ulcer Risk Evaluation in Critical Patients: Clinical and Social Characteristics. AB - BACKGROUND: Pressure ulcers increase hospital stays and treatment costs due to their complications. Therefore, recognizing factors that contribute to pressure ulcer risk are important to patient safety. OBJECTIVE: To evaluate the association between the scores of the Waterlow, Braden, and Norton scales and clinical and social characteristics in critically ill patients. METHOD: A cross sectional study of 78 patients in an adult intensive care unit of a university hospital in Northeastern Brazil was conducted from July to December 2015. Data included social and clinical information and the risk factors of the Braden, Norton and Waterlow scales. Data were analysed by the descriptive and inferential statistics. RESULTS: Most of the participants were female, adults and elderly people with brown skin colour, low education levels and insufficient income. Most of them showed a high risk for developing pressure ulcers using the three evaluated scales. Age, smoking status, diabetes and hypertension were associated with scores on the Waterlow, Braden and Norton scales. CONCLUSION: Age, use of the tobacco, diabetes and hypertension were associated with the risk of pressure ulcers in ICU patients. PMID- 28868093 TI - On the Cellular and Molecular Mechanisms of Drug-Induced Gingival Overgrowth. AB - INTRODUCTION: Gingival overgrowth has been linked to multiple factors such as adverse drug effects, inflammation, neoplastic processes, and hereditary gingival fibromatosis. Drug-induced gingival overgrowth is a well-established adverse event. In early stages, this gingival enlargement is usually located in the area of the interdental papilla. Histologically, there is an increase in the different components of the extracellular matrix. OBJECTIVE: The aim of this manuscript is to describe and analyze the different cellular and molecular agents involved in the pathogenesis of Drug-induced gingival overgrowth. METHOD: A literature search of the MEDLINE/PubMed database was conducted to identify the mechanisms involved in the process of drug-induced gingival overgrowth, with the assistance of a research librarian. We present several causal hypotheses and discuss the advances in the understanding of the mechanisms that trigger this gingival alteration. RESULTS: In vitro studies have revealed phenotypic cellular changes in keratinocytes and fibroblasts and an increase of the extracellular matrix with collagen and glycosaminoglycans. Drug-induced gingival overgrowth confirms the key role of collagenase and integrins, membrane receptors present in the fibroblasts, due to their involvement in the catabolism of collagen. The three drug categories implicated: calcineuron inhibitors (immunosuppressant drugs), calcium channel blocking agents and anticonvulsant drugs appear to present a multifactorial pathogenesis with a common molecular action: the blockage of the cell membrane in the Ca2+/Na+ ion flow. The alteration of the uptake of cellular folic acid, which depends on the regulated channels of active cationic transport and on passive diffusion, results in a dysfunctional degradation of the connective tissue. Certain intermediate molecules such as cytokines and prostaglandins play a role in this pathological mechanism. The concomitant inflammatory factor encourages the appearance of fibroblasts, which leads to gingival fibrosis. Susceptibility to gingival overgrowth in some fibroblast subpopulations is due to phenotypic variability and genetic polymorphism, as shown by the increase in the synthesis of molecules related to the response of the gingival tissue to inducing drugs. The authors present a diagram depicting various mechanisms involved in the pathogenesis of drug-induced gingival overgrowth. CONCLUSION: Individual predisposition, tissue inflammation, and molecular changes in response to the inducing drug favor the clinical manifestation of gingival overgrowth. PMID- 28868096 TI - Are there Special Mechanisms of Involuntary Memory? AB - Following the precedent set by Dorthe Berntsen's 2009 book, Involuntary Autobiographical Memory, this paper asks whether the mechanisms responsible for involuntarily recollected memories are distinct from those that are responsible for voluntarily recollected ones. Berntsen conjectures that these mechanisms are largely the same. Recent work has been thought to show that this is mistaken, but the argument from the recent results to the rejection of Berntsen's position is problematic, partly because it depends on a philosophically contentious view of voluntariness. Berntsen herself shares this contentious view, but the defenders of her position can easily give it up. This paper explains how and why they should. PMID- 28868097 TI - Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM. AB - Hypertrophic cardiomyopathy (HCM) is a common disease in pet cats, affecting 10 15% of the pet cat population. The similarity to human HCM, the rapid progression of disease, and the defined and readily determined endpoints of feline HCM make it an excellent natural model that is genotypically and phenotypically similar to human HCM. The Maine Coon and Ragdoll cats are particularly valuable models of HCM because of myosin binding protein-C mutations and even higher disease incidence compared to the overall feline population. The cat overcomes many of the limitations of rodent HCM models, and can provide enhanced translation of information from in vitro and induced small animal models to human clinical trials. Physicians and veterinarians working together in a collaborative and interdisciplinary approach can accelerate the discovery of more effective treatments for this and other cardiovascular diseases affecting human and veterinary patients. PMID- 28868098 TI - Does Right Ventricular Dysfunction Predict Mortality in Hemodynamically Stable Patients With Acute Pulmonary Embolism? AB - BACKGROUND: Acute pulmonary embolism (APE) is directly responsible for 100,000 deaths annually. Right ventricular dysfunction (RVD) on admission is considered a poor prognostic factor in these patients, though existing evidence of its significance in predicting mortality in hemodynamically stable patients is still unclear. We attempted to clarify this association by doing a retrospective review. METHODS: We retrospectively reviewed electronic medical records of hemodynamically stable patients older than 18 years of age with APE who were admitted to a tertiary care hospital in rural Upstate New York from July 2014 to July 2016. One hundred thirty-four patients were reviewed in two groups: patients who presented with computed tomography (CT) or echocardiographic evidence of RVD, and those without RVD. To identify differences in mortality between the two groups, the Chi-square/Fisher's exact test and t-tests were used. All variables with P < 0.2 in the initial analysis were included in a stepwise multivariable logistic regression model to predict RVD. RESULTS: No statistically significant difference was found in 30-day mortality between the groups (7.8% in RVD and 5.3% in no RVD, P = 0.563). The overall prevalence of RVD was found to be 57% (77/134). Troponin elevation (53.2% in RVD group vs. 19.3 in the no RVD group with P < 0.01) and central location of thrombus (53.1% vs. 32.1% with P = 0.016) were more prevalent in RVD group. A marginally significant difference was found in length of hospital stay among those with RVD versus no RVD (7.13 days vs. 5.46 days; P = 0.061). The multivariable analysis shows that the odds of RVD were greater for patients with elevated troponin levels (odds ratio = 7.8). CONCLUSION: There was no difference in 30-day mortality in hemodynamically stable patients with APE having RVD compared to patients with no RVD. On the basis of this study, we do not suggest the routine use of systemic fibrinolysis in hemodynamically stable patients with radiographic evidence of RVD alone. PMID- 28868099 TI - Relationship Between Hemorheology Assessed Using Microchannel Array Flow Analyzer and Kidney Function in Hypertensive Patients. AB - BACKGROUND: Kidney function is known to be closely associated with the pathogenesis of hypertension. In contrast, hemorheology assessed using microchannel array flow analyzer (MC-FAN) has demonstrated the significance of cardiovascular risk factors in recent clinical studies. The present cross sectional study aimed to clarify the relationship between hemorheology assessed by MC-FAN and kidney function in hypertensive patients from the perspective of primary prevention of cardiovascular events. METHODS: In total, 453 outpatients undergoing treatment for hypertension (176 men and 277 women; mean age +/- standard deviation: 65 +/- 13 years) with no history of cardiovascular disease were enrolled. Whole blood passage time (WBPT) was measured using MC-FAN as a marker of hemorheology, and the relationships with various clinical parameters including kidney function were examined. RESULTS: A significant correlation was observed between WBPT and the parameters of kidney function such as estimated glomerular filtration rate (r = -0.14, P < 0.01), urinary albumin excretion (r = 0.40, P < 0.001), and renal resistive index (r = 0.44, P < 0.001). Furthermore, multivariate analysis demonstrated urinary albumin excretion, renal resistive index, skin autofluorescence, derivatives of reactive oxygen metabolites, and hematocrit as independent variables for WBPT as a subordinate factor. CONCLUSIONS: The results of the present study indicate that hemorheology assessed by the MC-FAN is significantly associated with markers of kidney function, such as albuminuria and increased renovascular resistance, in hypertensive patients. PMID- 28868100 TI - Safety and Feasibility of Transcatheter Interruption of Ruptured Sinus of Valsalva Aneurysm Using the Cocoon Duct Occluder: Immediate Results and Mid-Term Follow-Up. AB - BACKGROUND: Limited data are available regarding safety and feasibility of transcatheter interruption of ruptured sinus of Valsalva aneurysm (RSOVA) using the Cocoon duct occluder (CDO) with immediate and mid-term follow-up result. METHODS: Transcatheter closure (TCC) was successfully done among eight patients, whereas five cases, not amenable to TCC, were referred for surgical correction among 13 consecutive patients of RSOVA at LPS Institute of Cardiology, Kanpur between January 2010 and March 2015. RESULTS: Their mean age was 26.1 +/- 6.9 years. Sites of rupture were from right coronary sinus (RCS) to right atrium (RA) in one (12.5%), right ventricle in one (12.5%), and non-coronary sinus to RA in six patients (75%). The defects (9 - 17 mm) were closed by CDO (12/10 - 20/18 mm) with 100% procedural success. During follow-up (9 - 26 months), there was no residual shunt, progression of AR, infective endocarditis or device embolization. CONCLUSION: TCC of RSOVA appears to be a safe and feasible alternative to surgical therapy, with high technical success and excellent mid-term follow-up. PMID- 28868101 TI - Chest Pain Due to Pericardial Effusion as Initial Presenting Feature of Rheumatoid Arthritis: Case Report and Review of the Literature. AB - Pericardial effusions are not uncommon in rheumatoid arthritis (RA); however, they are rarely the presenting symptom of the disease. We describe a 55-year-old female who presented to the emergency department with complaints of chest pain and dyspnea on exertion. Initial workup revealed a medium-sized pericardial effusion. The wide spectrum of etiologies, including infectious and non infectious disease, was explored. Eventually, after ruling out an array of disease states, rheumatologic workup was positive for RA. The initial presentation in our case was atypical due to absence of small joint polyarthritis and other common symptoms of RA. In difficult cases, extensive workup including laboratory tests, electrocardiography, echocardiography and imaging studies can aid in narrowing the causes of pericardial effusion. This case demonstrates that pericardial effusion could be an early presenting feature of RA, even in the absence of more common symptoms, and should be considered in differential diagnosis. PMID- 28868102 TI - A Novel Electrocardiographic Sign of an ST-Segment Elevation Myocardial Infarction-Equivalent: De Winter Syndrome. AB - Patients with de Winter syndrome, also termed anterior ST-segment elevation myocardial infarction (STEMI)-equivalent, represent 2% of all patients with acute anterior myocardial infarctions admitted to emergency departments (EDs). STEMI equivalents do not present with classical electrocardiogram (ECG) changes but exhibit a critical stenosis of the left anterior descending (LAD) coronary artery. This is under-recognized by clinicians and is therefore associated with high morbidity and mortality. Here, we report a rare case of a novel, typical, STEMI-equivalent ECG pattern without obvious ST-segment elevation in a 34-year old female who presented to our ED with substantial chest pain and a large, acute, transmural anterior myocardial infarction caused by acute occlusion of the LAD coronary artery. However, she presented as a non-STEMI case. A definite diagnosis of de Winter syndrome was made on the basis of clinical and ECG findings. PMID- 28868103 TI - Ischemic Stroke in a Patient With Quadricuspid Aortic Valve and Patent Foramen Ovale. AB - Quadricuspid aortic valve (QAV) is a rare congenital aortic valve abnormality. It is less common as compared to bicuspid or unicuspid aortic valve abnormality. QAV causes aortic regurgitation usually in the fifth to sixth decade of life. We present a rare case of a female patient with cryptogenic stroke due to a QAV and a patent foramen ovale (PFO). The patient underwent transcatheter closure of PFO, as there was no clear indication for surgery for her valve. Surgical removal remains the method of choice for the treatment of the QAV before left ventricular decompensation occurs. PMID- 28868104 TI - Parvovirus B19 Myocarditis of Fulminant Evolution. AB - Myocarditis is an inflammation of the myocardium. Clinical presentation ranges from non-specific systematic symptoms to fulminant collapse and sudden death. Sudden death occurs at rates of 8.6-12% and cardiomyopathy at 9%. In active myocarditis, there is inflammatory cellular infiltrate with myocardial necrosis. The disease is distinguished by clinical presentation in fulminant and non fulminant myocarditis. We present a rare case of a parvovirus B19-induced fulminant viral myocarditis in a young female. The patient presented with acute onset heart failure mimicking a myocardial infarction, followed by non-specific symptoms that had been misdiagnosed as urinary tract infection. PMID- 28868105 TI - Primary Fusiform Superior Vena Cava Aneurysm. AB - Superior vena cava (SVC) aneurysms are rare mediastinal vascular lesions. We report a case of a 42-year-old female, who presented to the outpatient department with features suggestive of lower respiratory tract infection. Chest X-ray showed abnormal contour and widening of right border of mediastinum. Computed tomography (CT) thorax revealed fusiform aneurysmal ectasia of SVC measuring 4.5 * 5.5 * 8.9 cm without internal thrombosis or dissecting flap. Management options include observation with follow-up and in some cases anticoagulation and surgical excision may be considered. The general consensus is that fusiform variety can be managed conservatively in view of the low risk of complications. The saccular aneurysms may need to be managed with anticoagulation therapy or surgically in view of the possible risk for thrombus formation and pulmonary embolism. Since in our case it was an asymptomatic primary fusiform SVC aneurysm, patient was advised for conservative management and follow-up. PMID- 28868106 TI - Monitoring bacterial biofilms with a microfluidic flow chip designed for imaging with white-light interferometry. AB - There is a need for imaging and sensing instrumentation that can monitor transitions in a biofilm structure in order to better understand biofilm development and emergent properties such as anti-microbial resistance. Herein, we describe the design, manufacture, and use of a microfluidic flow cell to visualize the surface structure of bacterial biofilms with white-light interferometry (WLI). The novel imaging chip enabled the use of this non disruptive imaging method for the capture of high resolution three-dimensional profile images of biofilm growth over time. The fine axial resolution (3 nm) and the wide field of view (>1 mm by 1 mm) enabled the detection of biofilm formation as early as 3 h after inoculation of the flow cell with a live bacterial culture (Pseudomonas fluorescens). WLI imaging facilitated the monitoring of the early stages of biofilm development and subtle variations in the structure of mature biofilms. Minimally-invasive imaging enabled the monitoring of biofilm structure with surface metrology metrics (e.g., surface roughness). The system was used to observe a transition in the biofilm structure that occurred in response to exposure to a common antiseptic. In the future, WLI and the biofilm imaging cell described herein may be used to test the effectiveness of biofilm-specific therapies to combat common diseases associated with biofilm formation such as cystic fibrosis and periodontitis. PMID- 28868107 TI - A simple and reusable bilayer membrane-based microfluidic device for the study of gradient-mediated bacterial behaviors. AB - We have developed a user-friendly microfluidic device for the study of gradient mediated bacterial behaviors, including chemotaxis. This device rapidly establishes linear concentration gradients by exploiting solute diffusion through porous membranes in the absence of convective flows. As such, the gradients are created rapidly and can be sustained for long time periods (e.g., hours), sufficient to evaluate cell phenotype. The device exploits a unique simple bilayer configuration that enables rapid setup and quick reproducible introduction of cells. Its reusability represents an additional advantage in that it need not be limited to settings with microfluidics expertise. We have successfully demonstrated the applicability of this tool in studying the chemotactic response of Escherichia coli to glucose. When coupled with our recent Python program, quantified metrics such as speed, ratio of tumble to run, and effective diffusivity can be obtained from slow frame rate videos. Moreover, we introduce a chemotaxis partition coefficient that conveniently scores swimming behavior on the single-cell level. PMID- 28868108 TI - Integrated dielectrophoretic and surface plasmonic platform for million-fold improvement in the detection of fluorescent events. AB - We present an integrated dielectrophoretic (DEP) and surface plasmonic technique to quantify ~1 pM of fluorescent molecules in low conductivity buffers. We have established a DEP force on target molecules to bring those molecules and place them on the nanometallic structures (hotspots) for quantification through surface plasmonic effects. Our results show that the DEP is capable of placing the fluorescent molecules on the hotspots, which are depicted as a significant reduction in the fluorescence lifetime of those molecules. To efficiently integrate the DEP and plasmonic effects, we have designed and utilized pearl shaped interdigitated electrodes (PIDEs) in experiments. These electrodes generate 2-3 times higher DEP force than traditional interdigitated electrodes. Therefore, high-throughput assays can be developed. The nanometallic structures were strategically fabricated in the periphery of PIDEs for smooth integration of DEP and plasmonic detection. With the introduction of DEP, about 106-fold improvement was achieved over existing plasmonic-based detection. Therefore, this simple addition to the existing surface plasmonic-based detection will enable the disease related protein detection. PMID- 28868109 TI - Rapid evaporation-driven chemical pre-concentration and separation on paper. AB - Airflow-enhanced evaporation is investigated as a method for rapid chemical preconcentration on a thin porous substrate. The mechanism is described by combining 1D models of capillary rise, chromatography, and pervaporation concentration. It is shown that the effective length of the column can be shorter than its actual length, allowing concentrate to be held at a stagnation point and then released for separation, and that the Peclet number, which determines the concentration performance, is determined only by the substrate properties. The differential equations are solved dynamically, and it is shown that faster concentration can be achieved during capillary filling. Experiments are carried out using chromatography paper in a ducted airflow, and concentration is quantified by optical imaging of water-soluble food dyes. Good agreement with the model is obtained, and concentration factors of ~100 are achieved in 10 min using Brilliant Blue FCF. Partial separation of Brilliant Blue from Tartrazine is demonstrated immediately following concentration, on a single unpatterned substrate. The mechanism may provide a method for improving the sensitivity of lab-on-paper devices. PMID- 28868110 TI - Erratum: "Quick chip assay using locked nucleic acid modified epithelial cell adhesion molecule and nucleolin aptamers for the capture of circulating tumor cells" [Biomicrofluidics 9(5), 054110 (2015)]. AB - [This corrects the article DOI: 10.1063/1.4930983.]. PMID- 28868111 TI - S-1 induced hepatic steatosis in patients with pancreatic cancer: Retrospective analysis. AB - AIM: To determine whether S-1 induces hepatic steatosis in patients being treated for pancreatic cancer. METHODS: This retrospective study evaluated 22 patients who received oral S-1 as a first-line treatment for pancreatic cancer between January 2008 and July 2015 at the Ishikawa Prefectural Central Hospital. Patients underwent abdominal computed tomography (CT) scans before chemotherapy and within 3 mo from the start of treatment. CT numbers of the liver and spleen were measured before and after S-1 administration. Steatosis was diagnosed when the ratio of the CT number of the liver to that of the spleen (liver/spleen ratio) was < 0.9. RESULTS: Median patient age was 68 years (range, 48-85 years), and median body mass index was 21 kg/m2 (range, 18-27 kg/m2). Of the 22 patients, six (27%) regularly consumed alcohol, and five (23%) had liver metastases. The mean ratio of CT number of the liver to the spleen was significantly higher before administration of S-1 (1.27 vs 1.09, P = 0.012) compared with after. Of the 22 patients, five (23%) had hepatic steatosis and 17 (77%) did not. The pretreatment demographic and clinical characteristics of these two groups showed no significant differences. The relationship between liver/spleen ratio and alanine transaminase activity in these patients. A statistically significant inverse correlation was observed (r = -0.417, P < 0.027). CONCLUSION: Of the 22 patients with pancreatic cancer, five (23%) experienced S-1 induced hepatic steatosis. Care should be taken during S-1 treatment of patients with pancreatic cancer. PMID- 28868112 TI - Does the discrepancy in histologic differentiation between a forceps biopsy and an endoscopic specimen necessitate additional surgery in early gastric cancer? AB - AIM: To investigate the clinicopathological variables in early gastric cancer (EGC) patients in relation to differentiation discrepancy. METHODS: The data of 265 specimens from 240 patients with EGC, who had undergone radical operation at Hallym University Sacred Heart Hospital from 2010 to 2015, were retrospectively analyzed. We evaluated clinical, endoscopic, and histopathological data according to histological discrepancy. RESULTS: Clinically significant discrepancy rate showed the difference in differentiated type (well and moderately differentiated) and undifferentiated type (poorly differentiated and signet ring cell) between endoscopic biopsies and postoperative specimens was 9.4% (25/265). There were no differences in tumor location, size, gross pattern, and number of biopsies. Specimens having histological discrepancy showed more submucosal invasion (72.0% vs 49.6%, P = 0.033) and lymph node involvement (24.0% vs 7.9%, P = 0.009) than specimens having non-discrepancy. The rate of a positive epidermal growth factor receptor status was higher in specimens having discrepancy than in specimens having non-discrepancy (81.0% vs 55.4%, P = 0.035). CONCLUSION: The discordance of histologic differentiation is associated with higher submucosal invasion and lymph node metastases in EGC. Patients have histological discrepancy may require additional surgical treatments. PMID- 28868113 TI - Gastric xanthoma is a predictive marker for metachronous and synchronous gastric cancer. AB - AIM: To investigate predictive markers for metachronous and synchronous gastric cancer (GC), which can develop after endoscopic submucosal dissection (ESD). METHODS: A total of 352 patients underwent ESD for early GC at NTT West Osaka Hospital between June 2006 and February 2016. Exclusion criteria were as follows: Remnant stomach, unknown Helicobacter pylori status, and endoscopic observation of the whole stomach outside our hospital. We analyzed data from 192 patients comprising 109 patients with solitary GC (Group A) and 83 with metachronous and synchronous GC (Group B). We retrospectively investigated the clinicopathological and endoscopic characteristics, and endoscopic risk score as predictive markers for GC. RESULTS: The median age of Group B [72 years (interquartile range 63-78)] was significantly higher than that of Group A [66 years (interquartile range 61 74), respectively, P = 0.0009]. The prevalence of intestinal metaplasia in Group B tended to be higher than that in Group A (57.8% vs 45.0%, P = 0.08). The prevalence of gastric xanthoma (GX) in Group B was significantly higher than that in Group A (54.2% vs 32.1%, P = 0.003). The atrophy score in Group B was significantly higher than that in Group A (P = 0.005). Multivariate analysis revealed that higher age and the presence of GX were independently related to metachronous and synchronous GC [OR = 1.04 (1.01-1.08), P = 0.02; and OR = 2.11 (1.14-3.99), P = 0.02, respectively]. CONCLUSION: The presence of GX is a useful predictive marker for metachronous and synchronous GC. PMID- 28868114 TI - Impact of tumour histological subtype on chemotherapy outcome in advanced oesophageal cancer. AB - AIM: To investigate the impact of histology on outcome in advanced oesophageal cancer treated with first-line fluoropyrimidine-based chemotherapy. METHODS: Individual patient data were pooled from three randomised phase III trials of fluoropyrimidine-based chemotherapy +/- platinum/anthracycline in patients with advanced, untreated gastroesophageal adenocarcinoma or squamous cell carcinoma (SCC) randomised between 1994 and 2005. The primary endpoint was overall survival of oesophageal cancer patients according to histology. Secondary endpoints were response rates and a toxicity composite endpoint. RESULTS: Of the total 1836 randomised patients, 973 patients (53%) were eligible (707 patients with gastric cancer were excluded), 841 (86%) had adenocarcinoma and 132 (14%) had SCC. There was no significant difference in survival between patients with adenocarcinoma and SCC, with median overall survivals of 9.5 mo vs 7.6 mo (HR = 0.85, 95%CI: 0.70-1.03, P = 0.09) and one-year survivals of 38.8% vs 28.2% respectively. The overall response rate to chemotherapy was 44% for adenocarcinoma vs 33% for SCC (P = 0.01). There was no difference in the frequency of the toxicity composite endpoint between the two groups. CONCLUSION: There was no significant difference in survival between adenocarcinoma and SCC in patients with advanced oesophageal cancer treated with fluoropyrimidine-based chemotherapy despite a trend for worse survival and less chemo-sensitivity in SCC. Tolerance to treatment was similar in both groups. This analysis highlights the unmet need for SCC-specific studies in advanced oesophageal cancer and will aid in the design of future trials of targeted agents. PMID- 28868115 TI - Catching and Correcting Unreported, Under-Reported Accidents (Near-Misses) among Healthcare Provider in Thailand. AB - OBJECTIVES: Latent errors in an incident reporting system pose threats to accident and near-miss prevention in hospitals. The aims of this study were to gain insight into the incident reporting system by exploring and investigating the refinement of unreported and under-reported (near-miss) patterns and by estimating under-reported annual hospital accidents over three months in one hospital. METHODS: Sequential mixed-method research was undertaken using both qualitative and quantitative approaches. 120 health care providers were selected from 13 departments of a selected study hospital. Self-reported questionnaires, information from annual reports and focus group interviews among stakeholders were employed. Based on a quantitative mixed-model approach, estimation of lost cases from near-miss incidents was made. RESULTS: In 2015, 20% of accidents had been reported to the hospital center while under-reported accidents and near-miss incidents by self-report over 3 months equaled 18% and 25.9%, respectively. Recent trends were positive, driven by changing values about incident reporting. However, confusion and fear still remain among practitioners about near-miss reporting due to old beliefs. This study confirms that incident reporting needs improvement so that there is an enhanced organizational culture of safety, raised awareness for individual reporting, and recovery of lost cases using mixed-model estimation of near-misses. PMID- 28868117 TI - Thiadiazoles: the appropriate pharmacological scaffolds with leishmanicidal and antimalarial activities: a review. AB - Leishmaniasis and malaria are serious public health problems in tropical and sub tropical regions worldwide. Development of drug-resistant strains has disrupted efforts to control the spread of these diseases in the world. The conventional antiparasitic chemotherapy still suffers from side effects and drug resistance. Therefore, the development of novel antimalarial and leishmanicidal drugs remains a critical topic to combat against these diseases. Five-membered heterocyclic systems have possessed antiparasitic activity such as thiadiazole scaffold which is a prevalent and an important heterocyclic ring. For this purpose, the authors introduce a series of synthetic thiadiazole derivatives with antileishamanial activity. Also, the authors searched a number of sources and articles to find thiadiazole derivatives with antileishamnial and antimalarial activity. Then all of the findings were reviewed. 5-nitroheteroaryl-1,3,4-Thiadiazole derivatives with different substituents at position 2 of the thiadiazole ring (8, 10-11) presented the best antileishmanial activity with low toxicity compared with reference drug. Also, 1,3,4-thiadiazole-2-sulfonamide derivative (18) showed excellent inhibitory activity against pfCA as a special enzyme in Plasmodium falciparum. Thiadiazole scaffold has the suitable physicochemical and pharmacokinetic properties and still stays as a therapeutic target for the development of a novel lead in the medicinal chemistry. Therefore, the current review provides a brief summary of medicinal chemistry of thiadiazole ring and introduces novel leads possessing this nucleus with antimalarial and antileishmanial activities. PMID- 28868116 TI - Bio-effectiveness of the main flavonoids of Achillea millefolium in the pathophysiology of neurodegenerative disorders- a review. AB - The Achillea millefolium L. (Yarrow) is a common herb which is widely being used, worldwide. Achillea is being used for treatment of many disorders since centuries. It is considered safe for supplemental use and flavonoids such as kaempferol, luteolin and apigenin are of main constituents present in Achillea. Most of both antioxidant and anti-inflammatory properties of this herb have been attributed to its flavonoid content. Oxidative and inflammatory processes play important roles in pathogenesis of neurodegenerative diseases. Present review was aimed to review the latest literature evidences regarding application of Achillea and/or its three main flavonoid constituents on epilepsy, Alzheimer's disease, multiple sclerosis, Parkinson's disease and stroke. PMID- 28868118 TI - Effects of left prefrontal transcranial direct current stimulation on the acquisition of contextual and cued fear memory. AB - OBJECTIVES: Behavioral and neuroimaging studies have shown that transcranial direct current stimulation, as a non-invasive neuromodulatory technique, beyond regional effects can modify functionally interconnected remote cortical and subcortical areas. In this study, we hypothesized that the induced changes in cortical excitability following the application of cathodal or anodal tDCS over the left frontal cortex as pre-training would affect functional connectivity in resting-state circuits of fear memory and consequently could improve or disturb the acquisition of fear memory. MATERIALS AND METHODS: In order to evaluate the polarity-dependent effects of tDCS on the acquisition of fear memory and the functional connectivity, we applied left prefrontal anodal or cathodal stimulation at 200 MUA for one session to healthy mice for the durations of 20 and 30 min prior to fear conditioning. RESULTS: Our results revealed that the administration of left prefrontal anodal (for both 20 and 30 min durations) and cathodal (at 30 min duration) tDCS impaired the acquisition of both contextual and cued fear memory. In addition, we did not observe a direct correlation between stimulation duration and the efficacy of tDCS on the acquisition of contextual and cued fear memory. CONCLUSION: In this study, the impairments of both contextual and cued memory further confirmed the previous studies reporting that the administration of transcranial stimulation would affect the activity of deeper structures like amygdala and hippocampus as the main components of the fear memory circuit in acquisition, storage, and expression of the memory. PMID- 28868119 TI - Coumarin derivatives bearing benzoheterocycle moiety: synthesis, cholinesterase inhibitory, and docking simulation study. AB - OBJECTIVES: To investigate the efficiency of a novel series of coumarin derivatives bearing benzoheterocycle moiety as novel cholinesterase inhibitors. MATERIALS AND METHODS: Different 7-hydroxycoumarin derivatives were synthesized via Pechmann or Knoevenagel condensation and conjugated to different benzoheterocycle (8-hydroxyquinoline, 2-mercaptobenzoxazole or 2 mercaptobenzimidazole) using dibromoalkanes 3a-m: Final compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by Ellman's method. Kinetic study of AChE inhibition and ligand-protein docking simulation were also carried out for the most potent compound 3b. RESULTS: Some of the compounds revealed potent and selective activity against AChE. Compound 3b containing the quinoline group showed the best activity with an IC50 value of 8.80 MUM against AChE. Kinetic study of AChE inhibition revealed the mixed-type inhibition of the enzyme by compound 3b. Ligand-protein docking simulation also showed that the flexibility of the hydrophobic five carbons linker allows the quinoline ring to form pi-pi interaction with Trp279 in the PAS. CONCLUSION: We suggest these synthesized compounds could become potential leads for AChE inhibition and prevention of AD symptoms. PMID- 28868120 TI - Novel cilostamide analogs, phosphodiesterase 3 inhibitors, produce positive inotropic but differential lusitropic and chronotropic effects on isolated rat atria. AB - OBJECTIVES: Recently, we showed that some new synthetic compounds structurally related to cilostamide (4-(1,2-dihydro-2-oxoquinolin-6-hydroxy)- N-cyclohexyl-N methylbutanamide), a selective phosphodiesterase 3 (PDE3) inhibitor, produce inotropic effect comparable to that of IBMX (3-isobutyl-1-methylxanthine), a non selective PDE inhibitor, but with differential chronotropic effect. In this investigation, we compared the pharmacological effects of these compounds as potential cardiotonic agents using the spontaneously beating atria model. MATERIALS AND METHODS: In each experiment, rats were treated with reserpine. The atrium was isolated and mounted in an organ bath. We assessed chronotropic and inotropic effects using cumulative log concentration-response curves of isoprenaline alone or in combination of each test-compound. RESULTS: Majority of test compounds augment atria contraction force (ACF) significantly but with different potencies on atrium contraction rate. Cilostamide, MCPIP ([4-(4-methyl piperazin-1-yl)-4-oxobutoxy)-4-methylquinolin-2(1H)-one]), methyl carbostyril compounds- (mc1), mc2 and mc5 increased the isoprenaline effect on ACF synergistically. But, mc6 failed to potentiate the effect of isoprenalin; mc3 and mc4 did not increase ACF, which may be because of their higher hydrophilic nature. It was interesting that mc2, alone or in combination with isoprenaline, produced the highest inotropic effect while it did not affect the basal contraction rate and almost blocked the isoprenaline chronotropic effect. CONCLUSION: Combination of mc2 with isoprenaline had synergistic effect on inotropic effect, but this combination reduced isoprenaline chronotropic effect; therefore, these effects cannot be related to reducing B-adrenergic receptors activity. These compounds showed different effects; probably all of them were not mediated via PDE3 inhibition and other mechanisms are involving. PMID- 28868121 TI - Melatonin upregulates ErbB1 and ErbB4, two primary implantation receptors, in pre implantation mouse embryos. AB - OBJECTIVES: To evaluated the effects of melatonin on early embryo competence and the expression rate of the primary implantation receptors (ErbB1 and ErbB4). MATERIALS AND METHODS: Two-cell mouse embryos were cultured in 3 groups: simple media, melatonin-treated (10-9 M melatonin) and Luzindole-treated (10-9 M luzindole). Then, the rate of ErbB1 and ErbB4 gene and protein expression, the level of intracellular ROS, antioxidant capacity, and also the number of cells were evaluated and compared with the fourth group in vivo developed blastocysts (control group). RESULTS: We concluded that melatonin significantly up-regulated the ErbB1 and ErbB4 gene and protein expression, decreased intracellular ROS, increased the total antioxidant capacity, and also elevated the cell numbers in the melatonin-treated group compared with the other groups (P<= 0.05). CONCLUSION: The use of melatonin may be a helpful factor in improving the embryo quality and enhancing the expression of ErbB1 and ErbB4, two important implantation-related genes and proteins. PMID- 28868122 TI - Allicin attenuates tunicamycin-induced cognitive deficits in rats via its synaptic plasticity regulatory activity. AB - OBJECTIVES: To illuminate the functional effects of allicin on rats with cognitive deficits induced by tunicamycin (TM) and the molecular mechanism of this process. MATERIALS AND METHODS: 200-250 g male SD rats were divided into three groups at random: control group (n=12), TM group (5 MUl, 50 MUM, ICV, n=12), and allicin treatment group (180 mg/kg/d with chow diet, n=12). After 16 weeks of allicin treatment, the learning ability and memory were tested using novel object recognition (NOR) testing on rats with 72 hr TM treatment (5 MUl, 50 MUM, ICV); meanwhile, the variation of field excitatory postsynaptic potential (fEPSP) in the Schaffer Collateral (SC)-CA1 synapse was detected by extracellular electrophysiological recordings and the morphology of dendritic spine was observed by Golgi staining as well as detecting several synaptic plasticity related proteins by Western blot. RESULTS: The density of dendritic spine was increased significantly in allicin-treated groups and the correspondence slope of fEPSP in TM-induced cognitive deficits group was enhanced and expression of synaptophysin and glutamate receptor-1(GluR1) in hippocampal neurons was up regulated. CONCLUSION: The results indicate that allicin plays an important role in synaptic plasticity regulation. These finding showed that allicin could be used as a pharmacologic treatment in TM-induced cognitive deficits. PMID- 28868123 TI - Orthotopic liver transplantation from cardiac death donors in the mouse: a new model and evaluation of cardiac death time. AB - OBJECTIVES: The goal of this research was to develop a mouse orthotopic liver transplantation (LTx) model from donor-after-cardiac-death (DCD) grafts. MATERIALS AND METHODS: Mice were randomly assigned to the experimental group or the sham group. The mice in the experimental group were divided into three groups according to the warm ischemia time (WIT) of liver graft: normal LTx, WIT 30 minute (min) +LTx and WIT 45 min +LTx. The descending aorta was clamped using a miniature aortic clamp to simulate cardiac arrest in the DCD grafts. Subsequently, the grafts were orthotopically transplanted into C57BL/6 mice. The 7-day survival rate, serum alanine aminotransferase (ALT), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6) mRNA level, tumor necrosis factor-alpha (TNF-alpha) mRNA level, as well as hepatic pathologic alterations were observed. RESULTS: The 7-day survival rate was markedly lower in the WIT 45 min+LTx group than that in the normal LTx group (25% versus 100%, P-value<0.05), with no significant difference between the WIT 30 min +LTx and normal LTx group (75% versus 100%, P-value>0.05). Serum ALT level of WIT 45 min+LTx group was markedly higher than that of normal LTx and WIT 30 min+LTx group (P-value<0.01). There were significant differences in necrosis and apoptosis among the three groups (P value<0.05). The expression of iNOS, IL-6 mRNA and TNF-alpha mRNA in WIT 45 min +LTx group all increased significantly compared with the normal LTx and WIT 30 min+LTx group. CONCLUSION: The DCD LTx model is feasible in the mouse and would provide many advantages for biomedical research on LTx from DCD grafts. PMID- 28868124 TI - Neuroprotective role of curcumin on the hippocampus against the structural and serological alterations of streptozotocin-induced diabetes in Sprague Dawely rats. AB - OBJECTIVES: Diabetes mellitus causes impaired memory and cognitive functions. The hippocampus plays a key role in memory and learning. Curcumin attenuates diabetic nephropathy in vivo. Curcumin has shown a neurogenic effect and cognition enhancing potential in aged rats. The aim of this study is to evaluate the possible protective role of curcumin on the histological and serological changes of the hippocampus in diabetic rats. MATERIALS AND METHODS: Forty albino rats were divided into four groups, ten rats each. Group 1 control rats, group 2 rats received curcumin orally (200 mg/kg/day for six weeks), group 3 rats were injected intraperitoneally with streptozotocin (STZ) (100 mg/kg, single dose), group 4 received a single injection of STZ and received curcumin orally for six weeks. Paraffin sections of hippocampus were prepared and stained with hematoxylin and eosin stain, and immnunohistochemical staining for GFAP and caspase-3. Morphometrical and statistical analyses were performed. Glycemic status and parameters of oxidative stress was measured. RESULTS: Examination of hippocampus of diabetic rats showed disorganization of small pyramidal cells in CA1, many cellular losses in the pyramidal cells of CA3, many degenerated granule cells in the dentate gyrus. GFAP positive astrocyte and caspase-3 positive neuron counts were significantly increased. There were significant serum glucose elevation and significant lowered levels of oxidative stress parameters as compared to control rats. Curcumin administration improved the structural and serological alterations of the hippocampus with significant reduction in serum glucose level. CONCLUSION: Curcumin ameliorates the deterious effect of diabetes on the hippocampus through its antioxidant, antiapoptotic and anti-inflammatory efficacies. PMID- 28868125 TI - Restoration of correct splicing in IVSI-110 mutation of beta-globin gene with antisense oligonucleotides: implications and applications in functional assay development. AB - OBJECTIVES: The use of antisense oligonucleotides (AOs) to restore normal splicing by blocking the recognition of aberrant splice sites by the spliceosome represents an innovative means of potentially controlling certain inherited disorders affected by aberrant splicing. Selection of the appropriate target site is essential in the success of an AO therapy. In this study, in search for a splice model system to facilitate the evaluation of AOs to redirect defective splicing of IVSI-110 beta-globin intron, an EGFP-based IVSI-110 specific cellular reporter assay system has been developed and a number of AOs were tested in this cellular splicing assay. MATERIALS AND METHODS: A recombinant plasmid (pEGFP/I 110) carrying the EGFP gene interrupted by a mutated human beta-globin intron 1 (IVSI-110) was developed and transfected into K562 cells. A number of AOs with a 2'-O-methyl oligoribonucleotide (2'-O-Me) backbone system were systematically tested in this cellular splicing assay. RESULTS: The mutation in the intron causes aberrant splicing of EGFP pre-mRNA, preventing translation of EGFP; however, treatment of the cells with specific concentration of a sequence specific 2'-O-Me AO targeted to the aberrant splice site induced correct splicing and resulted in restoring of EGFP activity. CONCLUSION: This cellular splicing assay provides a novel functional assay system in assessing the cellular delivery efficiency of AOs and therapeutic effect of AOs in restoration of aberrant splicing. PMID- 28868126 TI - Repeated systemic administration of the cinnamon essential oil possesses anti anxiety and anti-depressant activities in mice. AB - OBJECTIVES: The present study aimed to evaluate the putative antidepressant and anti-anxiety effects of the cinnamon essential oil when administered acute (for 3 doses) and sub-acute (for 14 days) to mice. MATERIALS AND METHODS: In an acute experimental study, forced swim test (FST) was conducted to evaluate the antidepressant-like behavior of animals treated with the intraperitoneal (IP) essential oil of cinnamon in triple doses (0.5, 1, and 2 mg/kg). In a sub-acute study (14 days in 24-hr intervals) antidepressant-like effects of essential oil (0.5, 1, and 2 mg/kg) with the same route were assessed in FST and tail suspension test (TST). Anti-anxiety and motor activities were evaluated using elevated plus-maze (EPM) and open field tests, respectively. Determination of different constituents within the sample oil was via gas chromatography-mass spectrometry (GC-MS) analysis. RESULTS: Repetitive administration of cinnamon essential oil (0.5, 1, 2 mg/kg) during 14 days significantly decreased the time of immobility in both FST and TST as compared to the control group. Mice treated with oil at the dose of 2 mg/kg spent a longer time and had more entries into the open arms of EPM as compared with the vehicle-treated ones. According to GC-MS analysis, 46 chemical compounds were identified in the studied cinnamon essential oil with the main constituent being trans-cinnamaldehyde (87.32%). CONCLUSION: Cinnamon essential oil might be used as an adjunctive therapy in improving symptoms of depressive and anxiety disorders. However, dose-response effects need further evaluation. Trans-cinnamaldehyde might be responsible for the beneficial effect observed. PMID- 28868127 TI - Mori cortex prevents kidney damage through inhibiting expression of inflammatory factors in the glomerulus in streptozocin-induced diabetic rats. AB - OBJECTIVES: It has been widely reported that Mori cortex extract (MCE) is used for the treatment of diabetes mellitus in traditional medicine. The present study was designed to investigate its mechanism of action in the treatment of diabetic nephropathy (DN). We assessed whether MCE preventive treatment ameliorates kidney damage in high-fat diet and streptozotocin (STZ)-induced type 2 diabetic rats. MATERIALS AND METHODS: Rats were fed a high-fat diet and injected with STZ. MCE was given to rats daily at 10 g/kg. Fasting blood glucose (FBG) and postprandial plasma glucose were measured. Blood and urine biochemical parameters, renal tissue morphology, and inflammation were investigated. RESULTS: Prevention with MCE significantly decreased FBG and homoeostasis model assessment (HOMA) of IR (HOMA-IR) levels and increased insulin levels in diabetic rats. MCE prevention significantly decreased levels of KW/BW, BUN, Cr, and 24 hr urinary protein. MCE inhibited glomerular basement membrane thickening, tubular epithelial cell hypertrophy, and glomerular capillary dilation. MCE also prevented the disappearance of bowman's space and renal tubular lumen and decreased collagen deposition in rat kidney. Moreover, MCE reduced the levels of inflammatory factors (MCP-1 and TNF-alpha) and fibrosis factors (collagen IV and fibronectin). CONCLUSION: MCE prevents DN through inhibition of inflammation and fibrosis in a rat model. It might provide a safe and effective way to prevent DN. PMID- 28868128 TI - Design of peptides interfering with iron-dependent regulator (IdeR) and evaluation of Mycobacterium tuberculosis growth inhibition. AB - OBJECTIVES: Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), stayed a global health thread with high mortality rate. Since TB has a long-term treatment, it leads high risk of drug resistant development, and there is an urgent to find new drugs. The aim of this study was designing new inhibitors for a new drug target, iron dependent regulator, IdeR. MATERIALS AND METHODS: Based on the interaction most populated amino acids of IdeR to the related gene operators, 50 short peptides were modeled. Bonding affinity of short peptides toward DNA were studied by docking. Top 10 best predicted bonding affinity were selected. DNA binding assay, microplate alamar blue assay, colony counting, quantitative real time- PCR (qRT-PCR) of IdeR corresponding genes, cell wall-associated mycobactin and whole-cell iron estimation were done to prove the predicted mechanism of in silico potent constructs. RESULTS: Amongst the 10 synthesized short peptide candidates, glycine-valine-proline-glycine (GVPG) and arginine-proline-arginine (RPR) inhibited Mtbin vitro at 200 MUM concentration. qRT-PCR showed mbtB 58-fold over expression that resulted in Mtb growth inhibition. Cell wall-associated mycobactin and whole-cell iron estimation confirmed the results of qRT-PCR. CONCLUSION: We introduced two new lead compounds to inhibit Mtb that are promising for the development of more potent anti-tubercular therapies. PMID- 28868129 TI - Does the human immune system ever really become "senescent"? AB - Like all somatic tissues, the human immune system changes with age. This is believed to result in an increased frequency of, and susceptibility to, infectious disease and to contribute to a wide range of non-communicable age associated diseases in later life, especially cancer, cardiovascular disease, and autoimmunity. The majority of studies addressing immune ageing has been cross sectional, but limited longitudinal studies are contributing to a better understanding of age-associated changes, as opposed to differences, and their clinical relevance. However, intriguing differences are emerging that implicate highly context-dependent immune ageing processes, mitigating against current generalisations concerning human immunosenescence and indicating the necessity for detailed comparisons of different populations, even those that would appear quite similar at first glance. PMID- 28868130 TI - Bacterial lipids: powerful modifiers of the innate immune response. AB - The innate immune system serves as a first line of defense against microbial pathogens. The host innate immune response can be triggered by recognition of conserved non-self-microbial signature molecules by specific host receptor proteins called Toll-like receptors. For bacteria, many of these molecular triggers reside on or are embedded in the bacterial membrane, the interface exposed to the host environment. Lipids are the most abundant component of membranes, and bacteria possess a unique set of lipids that can initiate or modify the host innate immune response. Bacterial lipoproteins, peptidoglycan, and outer membrane molecules lipoteichoic acid and lipopolysaccharide are key modulators of the host immune system. This review article will highlight some of the research emerging at the crossroads of bacterial membranes and innate immunity. PMID- 28868132 TI - Comprehensive comparison of Pacific Biosciences and Oxford Nanopore Technologies and their applications to transcriptome analysis. AB - Background: Given the demonstrated utility of Third Generation Sequencing [Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT)] long reads in many studies, a comprehensive analysis and comparison of their data quality and applications is in high demand. Methods: Based on the transcriptome sequencing data from human embryonic stem cells, we analyzed multiple data features of PacBio and ONT, including error pattern, length, mappability and technical improvements over previous platforms. We also evaluated their application to transcriptome analyses, such as isoform identification and quantification and characterization of transcriptome complexity, by comparing the performance of PacBio, ONT and their corresponding Hybrid-Seq strategies (PacBio+Illumina and ONT+Illumina). Results: PacBio shows overall better data quality, while ONT provides a higher yield. As with data quality, PacBio performs marginally better than ONT in most aspects for both long reads only and Hybrid Seq strategies in transcriptome analysis. In addition, Hybrid-Seq shows superior performance over long reads only in most transcriptome analyses. Conclusions: Both PacBio and ONT sequencing are suitable for full-length single-molecule transcriptome analysis. As this first use of ONT reads in a Hybrid-Seq analysis has shown, both PacBio and ONT can benefit from a combined Illumina strategy. The tools and analytical methods developed here provide a resource for future applications and evaluations of these rapidly-changing technologies. PMID- 28868133 TI - Achieving good adherence to inhaled corticosteroids after weighing canisters of asthmatic children. AB - Background: The metered-dose inhalers (MDIs) currently available for inhaled corticosteroid delivery do not offer an integrated dose counter; therefore, it is difficult to evaluate adherence of patients. The present authors developed a linear regression equation using canister weight to calculate the number of doses actuated from the MDIs. This study aimed to assess medical adherence after the integration of regular weighing of the canisters into the routine service. Methods: A cohort study was carried out between May 2013 and April 2014. Children aged less than 8 years with a diagnosis of asthma were recruited. The duration of adherence assessment was 24 weeks. Participants had a regular schedule every 8 weeks to obtain a new FLIXOTIDE(r) 125 inhaler. Parents were asked to collect the discarded MDI canisters, which were then weighed by a laboratory scale. The weight of each canister was replaced in the regression equation to calculate the number of doses actuated from the MDIs. Results: A total of 52 asthmatic children participated in the study. The median age was 52.7 months. At the end of 24 weeks, 44, 33, and 23 discarded MDI canisters were collected from visits 1, 2, and 3, respectively. The median percentages of adherence were 96.8%, 96.3%, and 96.3%, respectively. In 11 discarded canisters (11%), the remaining medication was more than 30% of the labeled doses. Approximately 90% of the participants had no asthma exacerbation during 24-week study period. Conclusion: High adherence rates were achieved after integration of canister weighing into the asthma care service. PMID- 28868131 TI - Circulating tumor cells: silent predictors of metastasis. AB - Circulating tumor cells (CTCs) were added to the arsenal of clinical testing in 2004 for three cancer types: metastatic breast, prostate, and colorectal cancer. CTCs were found to be an independent prognostic indicator of survival for these three diseases. Multiple enrichment/isolation strategies have been developed and numerous assay applications have been performed using both single and pooled captured/enriched CTCs. We have reviewed the isolation techniques and touched on many analyses. The true utility of a CTC is that it acts as a "silent" predictor of metastatic disease. The mere presence of a single CTC is an indication that disease has spread from the primary site. Comments and suggestions have been set forth for CTCs and cell-free DNA to be used as a screening panel for the early detection of disease recurrence and metastatic spread, providing the opportunity for early intervention with curative intent to treat metastatic disease. PMID- 28868134 TI - Arkas: Rapid reproducible RNAseq analysis. AB - The recently introduced Kallisto pseudoaligner has radically simplified the quantification of transcripts in RNA-sequencing experiments. We offer cloud scale RNAseq pipelines Arkas-Quantification, which deploys Kallisto for parallel cloud computations, and Arkas-Analysis, which annotates the Kallisto results by extracting structured information directly from source FASTA files with per contig metadata and calculates the differential expression and gene-set enrichment analysis on both coding genes and transcripts. The biologically informative downstream gene-set analysis maintains special focus on Reactome annotations while supporting ENSEMBL transcriptomes. The Arkas cloud quantification pipeline includes support for custom user-uploaded FASTA files, selection for bias correction and pseudoBAM output. The option to retain pseudoBAM output for structural variant detection and annotation provides a middle ground between de novo transcriptome assembly and routine quantification, while consuming a fraction of the resources used by popular fusion detection pipelines. Illumina's BaseSpace cloud computing environment, where these two applications are hosted, offers a massively parallel distributive quantification step for users where investigators are better served by cloud-based computing platforms due to inherent efficiencies of scale. PMID- 28868135 TI - Improved deconvolution of very weak confocal signals. AB - Deconvolution is typically used to sharpen fluorescence images, but when the signal-to-noise ratio is low, the primary benefit is reduced noise and a smoother appearance of the fluorescent structures. 3D time-lapse (4D) confocal image sets can be improved by deconvolution. However, when the confocal signals are very weak, the popular Huygens deconvolution software erases fluorescent structures that are clearly visible in the raw data. We find that this problem can be avoided by prefiltering the optical sections with a Gaussian blur. Analysis of real and simulated data indicates that the Gaussian blur prefilter preserves meaningful signals while enabling removal of background noise. This approach is very simple, and it allows Huygens to be used with 4D imaging conditions that minimize photodamage . PMID- 28868136 TI - The menstrual cycle affects recognition of emotional expressions: an event related potential study. AB - BACKGROUND: Several studies have investigated the relationship between behavioral changes and the menstrual cycle in female subjects at a reproductive age. The present study investigated the relationship between the menstrual cycle and emotional face recognition by measuring the N170 component of ERPs. METHODS: We measured N170 of twelve women in both follicular phase and late luteal phase who were presented with human facial expressions as stimuli (happy and angry). RESULTS: In the follicular phase, participants showed a significantly larger response to happy male facial expressions. In the late luteal phase, participants had longer reaction times to all emotional stimuli, and a significantly reduced response to happy faces, especially happy male facial expressions (P<0.001). CONCLUSIONS: Our findings suggest that the menstrual cycle modulates early visual cognitive processing, and highlight the importance of considering the menstrual cycle phase in studies that investigate emotion and cognition. PMID- 28868137 TI - Case Report: Nicolau syndrome due to etofenamate injection. AB - Nicolau syndrome, also known as embolia cutis medicomentosa, is a rare complication characterized by tissue necrosis that occurs after injection of drugs. The exact pathogenesis is uncertain, but there are several hypotheses, including direct damage to the end artery and cytotoxic effects of the drug. Severe pain in the immediate postinjection period and purplish discoloration of the skin with reticulate pigmentary pattern is characteristic of this syndrome. Diagnosis is mainly clinical and there is no standard treatment for the disease. Etofenamate is a non-steroidal anti-inflammatory drug and a non-selective cyclooxygenase inhibitor. Cutaneous adverse findings caused by etofenamate are uncommon. Herein, we present a case with diagnosis of Nicolau syndrome due to etofenamate injection, which is a rare occurrence. PMID- 28868138 TI - Analytical challenges of untargeted GC-MS-based metabolomics and the critical issues in selecting the data processing strategy. AB - Background: A challenge of metabolomics is data processing the enormous amount of information generated by sophisticated analytical techniques. The raw data of an untargeted metabolomic experiment are composited with unwanted biological and technical variations that confound the biological variations of interest. The art of data normalisation to offset these variations and/or eliminate experimental or biological biases has made significant progress recently. However, published comparative studies are often biased or have omissions. Methods: We investigated the issues with our own data set, using five different representative methods of internal standard-based, model-based, and pooled quality control-based approaches, and examined the performance of these methods against each other in an epidemiological study of gestational diabetes using plasma. Results: Our results demonstrated that the quality control-based approaches gave the highest data precision in all methods tested, and would be the method of choice for controlled experimental conditions. But for our epidemiological study, the model based approaches were able to classify the clinical groups more effectively than the quality control-based approaches because of their ability to minimise not only technical variations, but also biological biases from the raw data. Conclusions: We suggest that metabolomic researchers should optimise and justify the method they have chosen for their experimental condition in order to obtain an optimal biological outcome. PMID- 28868139 TI - The choice between surgical scrubbing and sterile covering before or after induction of anaesthesia: A prospective study. AB - Background: Day surgery is increasing, and safe and effective logistics are sought. One part of the in-theatre logistics commonly discussed is whether surgical scrub and sterile covering should be done before or after induction of anaesthesia. The aim of the present study was to compare the impact of surgical scrub and sterile covering before vs. after the induction of anaesthesia in male patients scheduled for open hernia repair. Methods: This is a prospective randomised study. Sixty ASA 1-3 patients scheduled for open hernia repair were randomised to surgical scrub and sterile covering before or after induction of anaesthesia; group "awake" and group "anaesthetised", respectively. Patients and theatre nurses were asked about their experiences and willingness to have the same logistics on further potential surgeries, through a survey provided before post-surgery. Duration of anaesthesia, surgery, theatre time, recovery room stay and time to discharge was studied. Results: There was no difference in the patients' assessment of quality of care, and only one patient in the awake group would prefer to be anaesthetised on a future procedure. All nurses found pre anaesthesia scrubbing acceptable as routine. The duration of anaesthesia was shorter and doses of propofol and remifentanil were reduced by 10 and 13%, respectively, in the awake group. Time in recovery area was significantly reduced in the awake group (p<0.05), but time to discharge was not different. Conclusion: Surgical scrub and sterile covering before the induction of anaesthesia can be done safely and without jeopardising patients' quality of care. PMID- 28868140 TI - Bioconductor workflow for single-cell RNA sequencing: Normalization, dimensionality reduction, clustering, and lineage inference. AB - Novel single-cell transcriptome sequencing assays allow researchers to measure gene expression levels at the resolution of single cells and offer the unprecendented opportunity to investigate at the molecular level fundamental biological questions, such as stem cell differentiation or the discovery and characterization of rare cell types. However, such assays raise challenging statistical and computational questions and require the development of novel methodology and software. Using stem cell differentiation in the mouse olfactory epithelium as a case study, this integrated workflow provides a step-by-step tutorial to the methodology and associated software for the following four main tasks: (1) dimensionality reduction accounting for zero inflation and over dispersion and adjusting for gene and cell-level covariates; (2) cell clustering using resampling-based sequential ensemble clustering; (3) inference of cell lineages and pseudotimes; and (4) differential expression analysis along lineages. PMID- 28868141 TI - We need a NICE for global development spending. AB - With aid budgets shrinking in richer countries and more money for healthcare becoming available from domestic sources in poorer ones, the rhetoric of value for money or improved efficiency of aid spending is increasing. Taking healthcare as one example, we discuss the need for and potential benefits of (and obstacles to) the establishment of a national institute for aid effectiveness. In the case of the UK, such an institute would help improve development spending decisions made by DFID, the country's aid agency, as well as by the various multilaterals, such as the Global Fund, through which British aid monies is channelled. It could and should also help countries becoming increasingly independent from aid build their own capacity to make sure their own resources go further in terms of health outcomes and more equitable distribution. Such an undertaking will not be easy given deep suspicion amongst development experts towards economists and arguments for improving efficiency. We argue that it is exactly because needs matter that those who make spending decisions must consider the needs not being met when a priority requires that finite resources are diverted elsewhere. These chosen unmet needs are the true costs; they are lost health. They must be considered, and should be minimised and must therefore be measured. Such exposition of the trade-offs of competing investment options can help inform an array of old and newer development tools, from strategic purchasing and pricing negotiations for healthcare products to performance based contracts and innovative financing tools for programmatic interventions. PMID- 28868142 TI - Recent advances in understanding and treating chronic granulomatous disease. AB - A number of recent advances have been made in the epidemiology and treatment of chronic granulomatous disease. Several reports from developing regions describe the presentations and progress of local populations, highlighting complications due to Bacillus Calmette-Guerin vaccination. A number of new reports describe complications of chronic granulomatous disease in adult patients, as more survivors reach adulthood. The complications experienced by X-linked carriers are particularly highlighted in three new reports, confirming that infection and inflammatory or autoimmune conditions are more common and severe than previously recognised. Finally, definitive treatment with haematopoietic stem cell transplantation and gene therapy is reviewed. PMID- 28868143 TI - Recent advances in understanding basophil functions in vivo. AB - Basophils are mainly known as pro-inflammatory effector cells associated with allergy and helminth infections. Although they were identified over 130 years ago, their in vivo functions are still poorly understood. New insights into basophil development and function have been gained by the development of various transgenic mouse lines and staining techniques to detect and purify these cells from different organs. Several studies over the past few years have identified unexpected functions for basophils, including immunomodulatory properties and interactions with other immune cells. Here, I summarize and discuss the main findings. PMID- 28868145 TI - Co-delivery of paclitaxel and cisplatin with biocompatible PLGA-PEG nanoparticles enhances chemoradiotherapy in non-small cell lung cancer models. AB - Chemoradiotherapy (CRT) with paclitaxel (PTX) and cisplatin (CP) is part of the standard of care for patients with locally advanced non-small cell lung cancer (NSCLC). Despite the high treatment intensity, many patients still develop local recurrence after treatment. Thus, there is a strong need to further improve CRT for lung cancer. One strategy is to co-deliver cytotoxic chemotherapy agents using biocompatible nanoparticles (NPs) which can limit off-target tissue toxicity and improve therapeutic efficacy. Herein, we report the development of dual-drug loaded nanoformulations that improve the efficacy of CRT for NSCLC by co-encapsulation of cisplatin (CP) and PTX in PLGA-PEG NPs. Mice bearing NSCLC xenografts given the dual-drug loaded NPs during CRT showed greater inhibition of tumor growth than free drug combinations or combinations of single-drug loaded NPs. These results indicate that using a NP co-delivery strategy for this common CRT regimen may improve clinical responses in NSCLC patients. PMID- 28868144 TI - Inhibition of IL-17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections. AB - Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), has been shown to have significant efficacy in the treatment of moderate to severe psoriasis, psoriatic arthritis and ankylosing spondylitis. Blocking critical mediators of immunity may carry a risk of increased opportunistic infections. Here we present clinical and in vitro findings examining the effect of secukinumab on Mycobacterium tuberculosis infection. We re-assessed the effect of secukinumab on the incidence of acute tuberculosis (TB) and reactivation of latent TB infection (LTBI) in pooled safety data from five randomized, double-blind, placebo-controlled, phase 3 clinical trials in subjects with moderate to severe plaque psoriasis. No cases of TB were observed after 1 year. Importantly, in subjects with a history of pulmonary TB (but negative for interferon-gamma release and receiving no anti-TB medication) or positive for latent TB (screened by interferon-gamma release assay and receiving anti-TB medication), no cases of active TB were reported. Moreover, an in vitro study examined the effect of the anti-tumor necrosis factor-alpha (TNFalpha) antibody adalimumab and secukinumab on dormant M. tuberculosis H37Rv in a novel human three-dimensional microgranuloma model. Auramine-O, Nile red staining and rifampicin resistance of M. tuberculosis were measured. In vitro, anti-TNFalpha treatment showed increased staining for Auramine-O, decreased Nile red staining and decreased rifampicin resistance, indicative of mycobacterial reactivation. In contrast, secukinumab treatment was comparable to control indicating a lack of effect on M. tuberculosis dormancy. To date, clinical and preclinical investigations with secukinumab found no evidence of increased M. tuberculosis infections. PMID- 28868146 TI - A hydrogel sealant for the treatment of severe hepatic and aortic trauma with a dissolution feature for post-emergent care. PMID- 28868147 TI - Intra-body microwave communication through adipose tissue. AB - The human body can act as a medium for the transmission of electromagnetic waves in the wireless body sensor networks context. However, there are transmission losses in biological tissues due to the presence of water and salts. This Letter focuses on lateral intra-body microwave communication through different biological tissue layers and demonstrates the effect of the tissue thicknesses by comparing signal coupling in the channel. For this work, the authors utilise the R-band frequencies since it overlaps the industrial, scientific and medical radio (ISM) band. The channel model in human tissues is proposed based on electromagnetic simulations, validated using equivalent phantom and ex-vivo measurements. The phantom and ex-vivo measurements are compared with simulation modelling. The results show that electromagnetic communication is feasible in the adipose tissue layer with a low attenuation of ~2 dB per 20 mm for phantom measurements and 4 dB per 20 mm for ex-vivo measurements at 2 GHz. Since the dielectric losses of human adipose tissues are almost half of ex-vivo tissue, an attenuation of around 3 dB per 20 mm is expected. The results show that human adipose tissue can be used as an intra-body communication channel. PMID- 28868148 TI - Automatic disease diagnosis using optimised weightless neural networks for low power wearable devices. AB - Low-power wearable devices for disease diagnosis are used at anytime and anywhere. These are non-invasive and pain-free for the better quality of life. However, these devices are resource constrained in terms of memory and processing capability. Memory constraint allows these devices to store a limited number of patterns and processing constraint provides delayed response. It is a challenging task to design a robust classification system under above constraints with high accuracy. In this Letter, to resolve this problem, a novel architecture for weightless neural networks (WNNs) has been proposed. It uses variable sized random access memories to optimise the memory usage and a modified binary TRIE data structure for reducing the test time. In addition, a bio-inspired-based genetic algorithm has been employed to improve the accuracy. The proposed architecture is experimented on various disease datasets using its software and hardware realisations. The experimental results prove that the proposed architecture achieves better performance in terms of accuracy, memory saving and test time as compared to standard WNNs. It also outperforms in terms of accuracy as compared to conventional neural network-based classifiers. The proposed architecture is a powerful part of most of the low-power wearable devices for the solution of memory, accuracy and time issues. PMID- 28868149 TI - Speech reconstruction using a deep partially supervised neural network. AB - Statistical speech reconstruction for larynx-related dysphonia has achieved good performance using Gaussian mixture models and, more recently, restricted Boltzmann machine arrays; however, deep neural network (DNN)-based systems have been hampered by the limited amount of training data available from individual voice-loss patients. The authors propose a novel DNN structure that allows a partially supervised training approach on spectral features from smaller data sets, yielding very good results compared with the current state-of-the-art. PMID- 28868150 TI - Electrocardiograph signal denoising based on sparse decomposition. AB - Noise in ECG signals will affect the result of post-processing if left untreated. Since ECG is highly subjective, the linear denoising method with a specific threshold working well on one subject could fail on another. Therefore, in this Letter, sparse-based method, which represents every segment of signal using different linear combinations of atoms from a dictionary, is used to denoise ECG signals, with a view to myoelectric interference existing in ECG signals. Firstly, a denoising model for ECG signals is constructed. Then the model is solved by matching pursuit algorithm. In order to get better results, four kinds of dictionaries are investigated with the ECG signals from MIT-BIH arrhythmia database, compared with wavelet transform (WT)-based method. Signal-noise ratio (SNR) and mean square error (MSE) between estimated signal and original signal are used as indicators to evaluate the performance. The results show that by using the present method, the SNR is higher while the MSE between estimated signal and original signal is smaller. PMID- 28868151 TI - Motion artefact removals for wearable ECG using stationary wavelet transform. AB - Wearable Electrocardiogram (ECG) is attracting much attention in daily healthcare applications. From the viewpoint of long-term use, it is desired that the electrodes are non-contact with the human body. In this study, the authors propose an algorithm using the stationary wavelet transform (SWT) to remove motion artefact superimposed on ECG signal when using non-contact capacitively coupling electrodes. The authors evaluate the effect on motion artefact removal of this algorithm by applying it to various ECG signals with motion artefacts superimposed. As a result, the correlation coefficients of ECG signals with respect to the clean ones have been improved from 0.71 to 0.88 on median before and after motion artefact removal, which demonstrates the validity of the proposed SWT-based algorithm. PMID- 28868152 TI - Dedicated real-time monitoring system for health care using ZigBee. AB - Real-time monitoring systems (RTMSs) have drawn considerable attentions in the last decade. Several commercial versions of RTMS for patient monitoring are available which are used by health care professionals. Though they are working satisfactorily on various communication protocols, their range, power consumption, data rate and cost are really bothered. In this study, the authors present an efficient embedded system based wireless health care monitoring system using ZigBee. Their system has a capability to transmit the data between two embedded systems through two transceivers over a long range. In this, wireless transmission has been applied through two categories. The first part which contains Arduino with ZigBee will send the signals to the second device, which contains Raspberry with ZigBee. The second device will measure the patient data and send it to the first device through ZigBee transceiver. The designed system is demonstrated on volunteers to measure the body temperature which is clinically important to monitor and diagnose for fever in the patients. PMID- 28868153 TI - Role for 2D image generated 3D face models in the rehabilitation of facial palsy. AB - The outcome for patients diagnosed with facial palsy has been shown to be linked to rehabilitation. Dense 3D morphable models have been shown within the computer vision to create accurate representations of human faces even from single 2D images. This has the potential to provide feedback to both the patient and medical expert dealing with the rehabilitation plan. It is proposed that a framework for the creation and measuring of patient facial movement consisting of a hybrid 2D facial landmark fitting technique which shows better accuracy in testing than current methods and 3D model fitting. PMID- 28868154 TI - SMARCD1 regulates senescence-associated lipid accumulation in hepatocytes. AB - Previously, we have identified 16 senescence-associated genes by a subtractive proteomic analysis using presenescent and senescent human fibroblast cells, TIG 1. The aim of this study was to clarify the role of SMARCD1, one of the identified genes, also known as BAF60a, in hepatic senescence. SMARCD1 is a member of the SWI/SNF chromatin remodeling complex family, and regulates the transcription of target genes through the alterations of chromatin structure. We demonstrated that the reduced expression of SMARCD1 triggers cellular senescence and induces the accumulation of lipids, suggesting that SMARCD1 acts as a mediator in these processes. Furthermore, palmitic acid treatment and high-fat diet led to a significant reduction of SMARCD1 expression, and consequently induced cellular senescence and lipid accumulation in HepG2 cells and mouse liver, respectively. The results obtained here suggest that dietary nutrient associated impaired expression of SMARCD1 triggers cellular senescence and lipid accumulation, indicating a potential application of SMARCD1 in the prevention of lifestyle-related diseases. PMID- 28868156 TI - Post-traumatic syringomyelia with holocord involvement: a case report. AB - INTRODUCTION: Syringomyelia is a disorder in which a cyst, or syrinx, develops within the spinal cord. Historically, syringomyelia in post-traumatic spinal cord injury has been uncommon; however, its diagnosis has been increasing due to the advances in medical technology. Syringomyelia that involves the entire spinal cord, or holocord, is rare after traumatic spinal cord injury, with only a few cases reported in the literature. CASE PRESENTATION: We present a case of a 57 year-old male who had a motorcycle accident 30 years ago resulting in a spinal cord injury, who presented a rapid decline in the function of his left upper extremity. Imaging studies were reviewed to reveal an expansive T2 hyperintense intramedullary spinal cord lesion from C1 inferiorly to the conus medullaris. The patient underwent a T6-T7 laminectomy for the placement of a syringosubarachnoid shunt. The patient was then transferred to acute inpatient rehabilitation where he underwent an intense course of therapy for 3 weeks while being monitored closely by physiatrists. DISCUSSION: The patient was able to make significant recovery and was successfully discharged home. There are a limited number of reports published about post-traumatic holocord syringomyelia. It is important to recognize this diagnosis during follow-up visits with spinal cord injury patients. PMID- 28868157 TI - Response to 'Foix-Alajouanine is another differential diagnosis in longitudinal myelitis thought to be a case of multiple sclerosis or neuromyelitis optica'. PMID- 28868155 TI - Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation. AB - Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss. PMID- 28868158 TI - Near miss for big red: a unique case of penetrating glass injury of the thoracic spine and posterior mediastinum. AB - INTRODUCTION: A 42-year-old female with no significant comorbidities presented to our care with a penetrating glass injury to her mid-thoracic spine after falling backwards onto a table. CASE PRESENTATION: A large fragment of glass was protruding from her spine, and multi-planar computed tomography imaging revealed protrusion through the thoracic spinal vertebrae with the glass shards located 2 mm from the aortic lumen. The management of this patient posed several challenges, including initial care of the patient, evaluation of potentially affected structures and the appropriate sequence of therapeutic interventions. After multidisciplinary discussion, our trauma, thoracic and neurosurgical teams formulated a diagnostic workup and two-step surgical approach to address her injuries. DISCUSSION: Here we present the approach used by our team to successfully manage this type of injury. We hope this case report represents a platform for future discussion on best management approaches in patients presenting with the low-velocity penetrating thoracic, spinal and posterior mediastinal trauma. PMID- 28868159 TI - The effects of residential dual diagnosis treatment on alcohol abuse. AB - This multi-center study of dual diagnosis (DD) programs involved 804 residential patients with co-occurring alcohol and mental health disorders. The Addiction Severity Index was administered at admission and at one, six, and 12 months after discharge. Repeated measures analysis showed the intoxication rate per month stabilized between months six and 12 with 68% still in remission and an 88% mean reduction from baseline (F = 519, p < .005). A comparison between patients with and without weekly relapse produced significant differences in hospitalization (odds ratio 11.3:1; 95% C.I., 5.5 to 23.2). Eight ANCOVAs used mean intoxication days per month after discharge as the outcome variable, pre-admission intoxication days per month as a covariate, and eight variables associated with relapse (e.g. depression) as factors. Patients with these factors at admission did not have significantly higher intoxication rates after discharge than patients without them. This suggests that these DD programs successfully integrated treatment of both disorders and explained their effectiveness. Co occurring DSM IV mood disorders such as anxiety and depression as well as drug abuse involving opioids or cocaine fell between 66 and 95% at months one, six, and twelve. PMID- 28868160 TI - Analyses of Impact of Needle Surface Properties on Estimation of Needle Absorption Spectrum: Case Study with Coniferous Needle and Shoot Samples. AB - Leaf scattering spectrum is the key optical variable that conveys information about leaf absorbing constituents from remote sensing. It cannot be directly measured from space because the radiation scattered from leaves is affected by the 3D canopy structure. In addition, some radiation is specularly reflected at the surface of leaves. This portion of reflected radiation is partly polarized, does not interact with pigments inside the leaf and therefore contains no information about its interior. Very little empirical data are available on the spectral and angular scattering properties of leaf surfaces. Whereas canopy structure effects are well understood, the impact of the leaf surface reflectance on estimation of leaf absorption spectra remains uncertain. This paper presents empirical and theoretical analyses of angular, spectral, and polarimetric measurements of light reflected by needles and shoots of Pinus koraiensis and Picea koraiensis species. Our results suggest that ignoring the leaf surface reflected radiation can result in an inaccurate estimation of the leaf absorption spectrum. Polarization measurements may be useful to account for leaf surface effects because radiation reflected from the leaf surface is partly polarized, whereas that from the leaf interior is not. PMID- 28868161 TI - Reconstructing Historical VOC Concentrations in Drinking Water for Epidemiological Studies at a U.S. Military Base: Summary of Results. AB - A U.S. government health agency conducted epidemiological studies to evaluate whether exposures to drinking water contaminated with volatile organic compounds (VOC) at U.S. Marine Corps Base Camp Lejeune, North Carolina, were associated with increased health risks to children and adults. These health studies required knowledge of contaminant concentrations in drinking water-at monthly intervals delivered to family housing, barracks, and other facilities within the study area. Because concentration data were limited or unavailable during much of the period of contamination (1950s-1985), the historical reconstruction process was used to quantify estimates of monthly mean contaminant-specific concentrations. This paper integrates many efforts, reports, and papers into a synthesis of the overall approach to, and results from, a drinking-water historical reconstruction study. Results show that at the Tarawa Terrace water treatment plant (WTP) reconstructed (simulated) tetrachloroethylene (PCE) concentrations reached a maximum monthly average value of 183 micrograms per liter (MUg/L) compared to a one-time maximum measured value of 215 MUg/L and exceeded the U.S. Environmental Protection Agency's current maximum contaminant level (MCL) of 5 MUg/L during the period November 1957-February 1987. At the Hadnot Point WTP, reconstructed trichloroethylene (TCE) concentrations reached a maximum monthly average value of 783 MUg/L compared to a one-time maximum measured value of 1400 MUg/L during the period August 1953-December 1984. The Hadnot Point WTP also provided contaminated drinking water to the Holcomb Boulevard housing area continuously prior to June 1972, when the Holcomb Boulevard WTP came on line (maximum reconstructed TCE concentration of 32 MUg/L) and intermittently during the period June 1972 February 1985 (maximum reconstructed TCE concentration of 66 MUg/L). Applying the historical reconstruction process to quantify contaminant-specific monthly drinking-water concentrations is advantageous for epidemiological studies when compared to using the classical exposed versus unexposed approach. PMID- 28868162 TI - Cigarette Smoke Alters the Hematopoietic Stem Cell Niche. AB - Effects of tobacco smoke on hematologic derangements have received little attention. This study employed a mouse model of cigarette smoke exposure to explore the effects on bone marrow niche function. While lung cancer is the most widely studied consequence of tobacco smoke exposure, other malignancies, including leukemia, are associated with tobacco smoke exposure. Animals received cigarette smoke exposure for 6 h/day, 5 days/week for 9 months. Results reveal that the hematopoietic stem and progenitor cell (HSPC) pool size is reduced by cigarette smoke exposure. We next examined the effect of cigarette smoke exposure on one supporting cell type of the niche, the mesenchymal stromal cells (MSCs). Smoke exposure decreased the number of MSCs. Transplantation of naive HSPCs into irradiated mice with cigarette smoke exposure yielded fewer numbers of engrafted HSPCs. This result suggests that smoke-exposed mice possess dysfunctional niches, resulting in abnormal hematopoiesis. Co-culture experiments using MSCs isolated from control or cigarette smoke-exposed mice with naive HSPCs in vitro showed that MSCs from cigarette smoke-exposed mice generated marked expansion of naive HSPCs. These data show that cigarette smoke exposure decreases in vivo MSC and HSC number and also increases pro-proliferative gene expression by cigarette smoke-exposed MSCs, which may stimulate HSPC expansion. These results of this investigation are clinically relevant to both bone marrow donors with a history of smoking and bone marrow transplant (BMT) recipients with a history of smoking. PMID- 28868165 TI - Serum Vitamin D Level at ICU Admission and Mortality. AB - OBJECTIVE: Vitamin D is a fat-soluble vitamin that plays a major role in the regulation of bone and calcium metabolism and has effects on the immune and cardiovascular systems. Vitamin D deficiency is commonly seen in the general population as well as in critically ill patients and is reported to be associated with increased mortality and morbidity. Our aim was to determine the relationship between vitamin D level at ICU admission and mortality. METHODS: A total of 491 patients admitted to the ICU between January 2014 and January 2015 were evaluated retrospectively. The patients who were under 18 years old, had elective surgery, or whose serum vitamin D levels and outcomes were unknown were excluded. The patient's age, gender, APACHE II score, number of organ dysfunction, serum vitamin D level at ICU admission and outcomes were recorded. RESULTS: Vitamin D level was low (<25 ng dL-1) in 166 (77.1%) of the patients. In non-survivor patients, APACHE II score and the number of organ dysfunction were significantly higher than the survivor patients (p<0.001 and p<0.001). There was a negative correlation between vitamin D level and APACHE II score (r2=0.04, p=0.006). In multivariate analyses, the likelihood of mortality was increased 9.8-fold (range 4.2-17.6) and 8.9-fold (range 3.9-14.1) with an APACHE II score >=24 and the number of organ dysfunction >=2, respectively (p<0.001 and p<0.001). CONCLUSION: Vitamin D deficiency is commonly seen in intensive care patients. Although it is not an independently decisive factor for mortality, it might be related with poor clinical status at ICU admission. The APACHE II score and number of organ dysfunction are still important parameters for increased mortality. PMID- 28868164 TI - WHO Needs High FIO2? AB - World Health Organization and the United States Center for Disease Control have recently recommended the use of 0.8 FIO2 in all adult surgical patients undergoing general anaesthesia, to prevent surgical site infections. This recommendation has arisen several discussions: As a matter of fact, there are numerous studies with different results about the effect of FIO2 on surgical site infection. Moreover, the clinical effects of FIO2 are not limited to infection control. We asked some prominent authors about their comments regarding the recent recommendations. PMID- 28868163 TI - New insights into the vitamin D requirements during pregnancy. AB - Pregnancy represents a dynamic period with physical and physiological changes in both the mother and her developing fetus. The dramatic 2-3 fold increase in the active hormone 1,25(OH)2D concentrations during the early weeks of pregnancy despite minimal increased calcium demands during that time of gestation and which are sustained throughout pregnancy in both the mother and fetus suggests an immunomodulatory role in preventing fetal rejection by the mother. While there have been numerous observational studies that support the premise of vitamin D's role in maintaining maternal and fetal well-being, until recently, there have been few randomized clinical trials with vitamin D supplementation. One has to exhibit caution, however, even with RCTs, whose results can be problematic when analyzed on an intent-to-treat basis and when there is high non-adherence to protocol (as if often the case), thereby diluting the potential good or harm of a given treatment at higher doses. As such, a biomarker of a drug or in this case "vitamin" or pre-prohormone is better served. For these reasons, the effect of vitamin D therapies using the biomarker circulating 25(OH)D is a far better indicator of true "effect." When pregnancy outcomes are analyzed using the biomarker 25(OH)D instead of treatment dose, there are notable differences in maternal and fetal outcomes across diverse racial/ethnic groups, with improved health in those women who attain a circulating 25(OH)D concentration of at least 100 nmol.L-1 (40 ng.mL-1). Because an important issue is the timing or initiation of vitamin D treatment/supplementation, and given the potential effect of vitamin D on placental gene expression and its effects on inflammation within the placenta, it appears crucial to start vitamin D treatment before placentation (and trophoblast invasion); however, this question remains unanswered. Additional work is needed to decipher the vitamin D requirements of pregnant women and the optimal timing of supplementation, taking into account a variety of lifestyles, body types, baseline vitamin D status, and maternal and fetal vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genotypes. Determining the role of vitamin D in nonclassical, immune pathways continues to be a challenge that once answered will substantiate recommendations and public health policies. PMID- 28868166 TI - Day-Time Isoflurane Administration Suppresses Circadian Gene Expressions in Both the Brain and a Peripheral Organ, Liver. AB - OBJECTIVE: The aim of this study is to investigate the effects of light and administration time of isoflurane on circadian gene expression in the brains and liver tissues of rats kept in light-dark cycle. METHODS: Seventy two 15-days-old rats pups were divided into four groups. All animals were exposed to 1.5% concentration of isoflurane or to 6 L min-1 O2 for six hours between Zeitgeber Time (ZT) 0-ZT06 (day-time administration) or ZT12-ZT18 (night-time administration). Rats were sacrificed after six hours of anaesthesia with four hour time intervals. Total RNA was isolated from brains and liver tissues. Circadian gene expression was examined using quantitative real-time Reverse transcription polymerase chain reaction (RT-PCR). RESULTS: BMAL1, CLOCK, PER2 and CRY2 gene expression levels were markedly suppressed after day-time anaesthesia in the both brain and liver, but night-time administration caused only temporary suppression of gene expression. CONCLUSION: The effect of isoflurane on the circadian clock is time-dependent, and administered isoflurane anaesthesia at night had minimal effect on clock gene expression. Additionally, when the treated animals were kept in a regular light-dark cycle, isoflurane-induced phase shift was not observed, possibly because of the light. PMID- 28868167 TI - Comparing the Effects of Combined General/Epidural Anaesthesia and General Anaesthesia on Serum Cytokine Levels in Radical Cystectomy. AB - OBJECTIVE: Surgical stress combined with general anaesthesia (GA) suppresses the immune system and leads to cancer cell growth and premature metastasis in major oncological interventions. Epidural analgesia decreases the need for inhalation agents and opioids during surgery by suppressing sympathetic and neuroendocrine responses in the postoperative period. This study aimed to compare the effects of combined general/epidural anaesthesia (GEA)+patient-controlled epidural analgesia (PCEA) and GA+IV patient-controlled analgesia (PCA) on serum tumour necrosis factor-alpha TNF-alpha), interleukin-1 beta (IL-1beta) and interferon-gamma (IFN gamma) levels in patients undergoing radical cystectomy. METHODS: Sixty-five patients were enrolled in this prospective study. Patients were randomly enrolled to the GEA group, i.e., combined GEA+ PCEA (0.1% bupivacaine+1 MUg mL-1 fentanyl), and the GA group, namely combined GA+IV PCA (0.03 mg mL-1 morphine). To evaluate the cytokine response, blood samples were collected at preoperative, postoperative 1st and 24th hours. RESULTS: There was no statistically significant difference in serum TNF-alpha, IL-1beta and IFN-gamma levels between groups GA and GEA at preoperative and postoperative 1st hour and 24th hour. Total remifentanil consumption was significantly lower and length of hospital stay was significantly shorter in the GEA group than in the GA group (p<0.05). CONCLUSION: There is no difference between two anaesthesia methods in terms of serum cytokine levels; however, combined GEA+PCEA technique appeared to be superior to GA+IV PCA because of lower intraoperative narcotic analgesic consumption and shorter hospital stay. PMID- 28868168 TI - Validity of Pulse Pressure Variation (PPV) Compared with Stroke Volume Variation (SVV) in Predicting Fluid Responsiveness. AB - OBJECTIVE: Static monitors for assessing the fluid status during major surgeries and in critically ill patients have been gradually replaced by more accurate dynamic monitors in modern-day anaesthesia practice. Pulse pressure variation (PPV) and systolic pressure variation (SPV) are the two commonly used dynamic indices for assessing fluid responsiveness. METHODS: In this prospective observational study, 50 patients undergoing major surgeries were monitored for PPV and SPV: after the induction of anaesthesia and after the administration of 500 mL of isotonic crystalloid bolus. Following the fluid bolus, patients with a cardiac output increase of more than 15% were classified as responders and those with an increase of less than 15% were classified as non-responders. RESULTS: There were no significant differences in the heart rate (HR), mean arterial pressure (MAP), PPV, SVV, central venous pressure (CVP) and cardiac index (CI) between responders and non-responders. Before fluid bolus, the stroke volume was significantly lower in responders (p=0.030). After fluid bolus, MAP was significantly higher in responders but there were no significant changes in HR, CVP, CI, PPV and SVV. In both responders and non-responders, PPV strongly correlated with SVV before and after fluid bolus. CONCLUSION: Both PPV and SVV are useful to predict cardiac response to fluid loading. In both responders and non-responders, PPV has a greater association with fluid responsiveness than SVV. PMID- 28868169 TI - Relieving Pain After Arthroscopic Knee Surgery: Ultrasound-Guided Femoral Nerve Block or Adductor Canal Block? AB - OBJECTIVE: To compare the analgesic effects of femoral nerve block (FNB) and adductor canal block (ACB) after arthroscopic knee surgery. METHODS: This was a prospective randomised clinical trial that enrolled 92 patients undergoing arthroscopic knee surgery. Ultrasound-guided FNB or ACB was performed immediately after surgery for pain relief. Visual analogue scale (VAS) scores and modified sedation-agitation scale (SAS) were recorded and analysed immediately following block and at 3, 6, 12 and 24 hours. The satisfaction level was also evaluated using a Likert-based patient questionnaire. RESULTS: VAS scores decreased to 4.1+/-0.8 from 5.6+/-1.2 immediately after any nerve block, and within 3 hours, they continued to decrease to 2.0+/-0.6 in the FNB group and 3.4+/-1.0 in the ACB group (P=0.014). More patients in the FNB group were satisfied with the quality of the pain control compared to the ACB group. Additionally, patients in the ACB group required more supplemental analgesia compared to the FNB group. CONCLUSION: This study demonstrated that patients with FNB had denser analgesia after arthroscopic knee surgery and had less analgesic requirement compared with ACB. Greater satisfaction scores also reflected superior analgesia in patients receiving FNB. PMID- 28868170 TI - Clinical Experiences with the FRONT Formula for Pre-Operative Airway Assessment and Documentation: a Multi-Centre Study. AB - OBJECTIVE: The prediction of difficult airway is one of the most important challenges before general anaesthesia. This study aimed to assess the clinical usefulness of the FRONT score, a recently developed scoring system to predict and document airway difficulties. METHODS: This multi-centre, inter-observer, prospective and double-blinded study included 976 patients from two university centres. The pre-operative evaluation of the patients was performed by a pre operative team of anaesthesiologists (team A) who evaluated and scored the expected difficulty of airway management. An intra-operative team of evaluators (team B) working independently of team A, performed the actual instrumentation of the airway and scored the actual findings. Both teams used the FRONT scoring system and worked independently of each other to ensure blinded assessments. The statistical analysis of the pre- and intra-operative FRONT scores was performed in an off-line blinded manner. RESULTS: Our results show a fair and promising association between pre-operative composite FRONT score and that observed at the induction phase (Spearman=0.43). Among the score components, the best correlation was observed for the F and R components (kappa=0.44 and 0.36, respectively), and the worse correlation was observed for the O and T components (kappa=0.25 and 0.24, respectively). CONCLUSION: The FRONT formula for the prediction and documentation of the airway status is a simple and effective method for assessing and defining airway management difficulties. Further prospective studies are required to assess the sensitivity and specificity of the system. PMID- 28868171 TI - Complication of Peribulbar Block: Brainstem Anaesthesia. AB - Peribulbar block is used to obtain anaesthesia and akinesia of the eye by injecting a local anaesthetic around the musclecone. A patient scheduled for cataract surgery received peribulbar block with 6 mL of 2% lidocaine hydrochloride. Following the injection, confusion, hypotension and dilatation of the contralateral pupil rapidly progressed to loss of consciousness and respiratory arrest. The patient was intubated and mechanically ventilated for 30 min. The patient regained her consciousness, was extubated and transferred to the intensive care unit for further follow-up. Although brainstem anaesthesia because of peribulbar block is very rare, this procedure should be performed with complete monitorisation and resuscitation equipment. PMID- 28868172 TI - Unique Liver Disease of Pregnancy Requiring Anaesthesia Support: A Case with Severe Hyperemesis Gravidarum. AB - Hyperemesis gravidarum (HG) is one of the common unique liver diseases that occurs during pregnancy. Mild cases can be spontaneously resolved in time but severe cases usually require supportive medical treatment to relieve symptoms. Moreover, differential diagnosis may be required in severe cases that manifest with persistent nausea-vomiting, dehydration and weight loss refractory to treatment. Thus, to rule out any gastrointestinal pathology, this case was referred to the outpatient anaesthesia clinic after the first unsuccessful awake endoscopy attempt without sedation. Therefore, anaesthetic support for endoscopy of a pregnant woman with severe HG was presented in this case report. PMID- 28868173 TI - Analysis of the Alarms From a Blood Purification Machine During Continuous Haemodiafiltration. PMID- 28868174 TI - Comment on: Comparison of Intraabdominal and Trocar Site Local Anaesthetic Infiltration Efficacy on Postoperative Analgesia After Laparoscopic Cholecystectomy. PMID- 28868175 TI - Re: Comment on: Comparison of Intraabdominal and Trocar Site Local Anaesthetic Infiltration on Postoperative Analgesia After Laparoscopic Cholecystectomy. PMID- 28868176 TI - Passive Smoking Also Affects Recovery from Anaesthesia. PMID- 28868177 TI - Re: Passive Smoking Also Affects Recovery from Anaesthesia. PMID- 28868178 TI - A 45-Year-Old Woman with Acute Interstitial Pneumonia (Hamman-Rich Syndrome). PMID- 28868179 TI - Fatty liver without a large "belly": Magnified review of non-alcoholic fatty liver disease in non-obese patients. AB - Nonalcoholic fatty liver disease (NAFLD) is well described as a common cause of chronic liver disease, mostly in the obese population. It refers to a spectrum of chronic liver disease that starts with simple steatosis than progresses to nonalcoholic steatohepatitis and cirrhosis in patients without significant alcohol consumption. NAFLD in the non-obese population has been increasingly reported and studied recently. The pathogenesis of nonobese NAFLD is poorly understood and is related to genetic predisposition, most notably patatin-like phospholipase domain-containing 33 G allele polymorphism that leads to intrahepatic triglyceride accumulation and insulin resistance. Non-obese NAFLD is associated with components of metabolic syndrome and, especially, visceral obesity which seems to be an important etiological factor in this group. Dietary factors and, specifically, a high fructose diet seem to play a role. Cardiovascular events remain the main cause of mortality and morbidity in NAFLD, including in the non-obese population. There is not enough data regarding treatment in non-obese NAFLD patients, but similar to NAFLD in obese subjects, lifestyle changes that include dietary modification, physical activity, and weight loss remain the mainstay of treatment. PMID- 28868180 TI - Acute and chronic hepatobiliary manifestations of sickle cell disease: A review. AB - Sickle cell disease (SCD) is a common hemoglobinopathy which can affect multiple organ systems in the body. Within the digestive tract, the hepatobiliary system is most commonly affected in SCD. The manifestations range from benign hyperbilirubinemia to overt liver failure, with the spectrum of acute clinical presentations often referred to as "sickle cell hepatopathy". This is an umbrella term referring to liver dysfunction and hyperbilirubinemia due to intrahepatic sickling process during SCD crisis leading to ischemia, sequestration and cholestasis. In this review, we detail the pathophysiology, clinical presentation and biochemical features of various acute and chronic hepatobiliary manifestations of SCD and present and evaluate existing evidence with regards to management of this disease process. We also discuss recent advances and controversies such as the role of liver transplantation in sickle cell hepatopathy and highlight important questions in this field which would require further research. Our aim with this review is to help increase the understanding, aid in early diagnosis and improve management of this important disease process. PMID- 28868181 TI - Oral spore-based probiotic supplementation was associated with reduced incidence of post-prandial dietary endotoxin, triglycerides, and disease risk biomarkers. AB - AIM: To determine if 30-d of oral spore-based probiotic supplementation could reduce dietary endotoxemia. METHODS: Apparently healthy men and women (n = 75) were screened for post-prandial dietary endotoxemia. Subjects whose serum endotoxin concentration increased by at least 5-fold from pre-meal levels at 5-h post-prandial were considered "responders" and were randomized to receive either placebo (rice flour) or a commercial spore-based probiotic supplement [Bacillus indicus (HU36), Bacillus subtilis (HU58), Bacillus coagulans, and Bacillus licheniformis, and Bacillus clausii] for 30-d. The dietary endotoxemia test was repeated at the conclusion of the supplementation period. Dietary endotoxin (LAL) and triglycerides (enzymatic) were measured using an automated chemistry analyzer. Serum disease risk biomarkers were measured using bead-based multiplex assays (Luminex and Milliplex) as secondary, exploratory measures. RESULTS: Data were statistically analyzed using repeated measures ANOVA and a P < 0.05. We found that spore-based probiotic supplementation was associated with a 42% reduction in endotoxin (12.9 +/- 3.5 vs 6.1 +/- 2.6, P = 0.011) and 24% reduction in triglyceride (212 +/- 28 vs 138 +/- 12, P = 0.004) in the post-prandial period Placebo subjects presented with a 36% increase in endotoxin (10.3 +/- 3.4 vs 15.4 +/- 4.1, P = 0.011) and 5% decrease in triglycerides (191 +/- 24 vs 186 +/- 28, P = 0.004) over the same post-prandial period. We also found that spore-based probiotic supplementation was associated with significant post-prandial reductions in IL-12p70 (24.3 +/- 2.2 vs 21.5 +/- 1.7, P = 0.017) and IL-1beta (1.9 +/- 0.2 vs 1.6 +/- 0.1, P = 0.020). Compared to placebo post supplementation, probiotic subject had less ghrelin (6.8 +/- 0.4 vs 8.3 +/- 1.1, P = 0.017) compared to placebo subjects. CONCLUSION: The key findings of the present study is that oral spore-based probiotic supplementation reduced symptoms indicative of "leaky gut syndrome". PMID- 28868182 TI - Assessment of serum angiogenic factors as a diagnostic aid for small bowel angiodysplasia in patients with obscure gastrointestinal bleeding and anaemia. AB - AIM: To assess the use of serum levels of angiopoietin-1 (Ang1), Ang2 and tumor necrosis factor-alpha (TNFalpha) as predictive factors for small bowel angiodysplasia (SBA). METHODS: Serum samples were collected from patients undergoing capsule endoscopy for any cause of obscure gastrointestinal bleeding (OGIB) or anaemia. Based on small bowel findings patients were divided into 3 groups: (1) SBA; (2) other bleeding causes; and (3) normal, according to diagnosis. Using ELISA technique we measured serum levels of Ang1, Ang2 and TNFalpha and compared mean and median levels between the groups based on small bowel diagnosis. Using receiver operator curve analysis we determined whether any of the factors were predictive of SBA. RESULTS: Serum samples were collected from a total of 120 patients undergoing capsule endoscopy for OGIB or anaemia: 40 with SBA, 40 with other causes of small bowel bleeding, and 40 with normal small bowel findings. Mean and median serum levels were measured and compared between groups; patients with SBA had significantly higher median serum levels of Ang2 (3759 pg/mL) compared to both other groups, with no significant differences in levels of Ang1 or TNFalpha based on diagnosis. There were no differences in Ang2 levels between the other bleeding causes (2261 pg/mL) and normal (2620 pg/mL) groups. Using Receiver Operator Curve analysis, an Ang2 level of > 2600 pg/mL was found to be predictive of SBA, with an area under the curve of 0.7. Neither Ang1 or TNFalpha were useful as predictive markers. CONCLUSION: Elevations in serum Ang2 are specific for SBA and not driven by other causes of bleeding and anaemia. Further work will determine whether Ang2 is useful as a diagnostic or prognostic marker for SBA. PMID- 28868183 TI - Effect of replenishment of vitamin D on survival in patients with decompensated liver cirrhosis: A prospective study. AB - AIM: To assess the vitamin D (VD) deficiency as a prognostic factor and effect of replenishment of VD on mortality in decompensated cirrhosis. METHODS: Patients with decompensated liver cirrhosis were screened for serum VD levels. A total of 101 VD deficient patients (< 20 ng/mL) were randomly enrolled in two groups: Treatment group (n = 51) and control group (n = 50). Treatment group received VD treatment in the form of intramuscular cholecalciferol 300000 IU as loading dose and 800 IU/d oral as maintenance dose along with 1000 mg oral calcium supplementation. The VD level, clinical parameters and survival of both the groups were compared for 6-mo. RESULTS: Prevalence of vitamin D deficiency (VDD) in decompensated CLD was 84.31%. The mean (SD) age of the patients in the treatment group (M:F: 40:11) and control group (M:F: 37:13) were 46.2 (+/- 14.93) years and 43.28 (+/- 12.53) years, respectively. Baseline mean (CI) VD (ng/mL) in control group and treatment group were 9.15 (8.35-9.94) and 9.65 (8.63-10.7), respectively. Mean (CI) serum VD level (ng/mL) at 6-mo in control group and treatment group were 9.02 (6.88-11.17) and 29 (23-35), respectively. Over the period of time the VD, calcium and phosphorus level was improved in treatment group compared to control group. There was non-significant trend seen in greater survival (69% vs 64%; P > 0.05) and longer survival (155 d vs 141 d; P > 0.05) in treatment group compared to control group. VD level had no significant association with mortality (P > 0.05). In multivariate analysis, treatment with VD supplement was found significantly (P < 0.05; adjusted hazard ratio: 0.48) associated with survival of the patients over 6-mo. CONCLUSION: VD deficiency is very common in patients of decompensated CLD. Replenishment of VD may improve survival in patients with decompensated liver cirrhosis. PMID- 28868184 TI - Multiple endocrine neoplasia 2B: Differential increase in enteric nerve subgroups in muscle and mucosa. AB - Multiple endocrine neoplasia 2B (MEN2B) is a rare syndrome caused by an activating mutation of the RET gene, leading to enteric gangliomatosis. This child presented with constipation at 1-mo old, was diagnosed with MEN2B by rectal biopsy at 4 mo, had thyroidectomy at 9 mo and a colectomy at 4 years. We studied the extent of neuronal and nerve fibre proliferation and which classes of enteric nerves are affected by examining the colon with multiple neuronal antibodies. Resected transverse colon was fixed, frozen, sectioned and processed for fluorescence immunohistochemistry labelling with antibodies against TUJ1, Hu, ChAT, NOS, VIP, SP and CGRP and cKit. Control transverse colon was from the normal margin of Hirschsprung (HSCR) colon (4-year-old) and a child with familial adenomatous polyposis (FAP, 12 year). Myenteric ganglia were increased in size to as wide as the circular muscle. There was a large increase in nerve cells and nerve fibres. ChAT-, NOS-, VIP- and SP-immunoreactive nerve fibres all increased in the myenteric ganglia. NOS-IR nerves preferentially increased in the muscle, while VIP and SP increased in submucosal ganglia and mucosal nerve fibres. The density of ICC was normal. RET overactivation in MEN2B lead to a large increase in intrinsic nerve fibres in the myenteric and submucosal ganglia, with a relative increase in NOS-IR nerve fibres in the circular muscle and VIP and SP in the submucosal ganglia and mucosa. The changes were associated with severe constipation resulting in colectomy at 4 years. PMID- 28868185 TI - T2 vertebrectomy with combined anterior and posterior arthrodesis for treatment of a solitary plasmacytoma. AB - BACKGROUND: Plasma cell neoplasmas are a heterogenous group of neoplastic tumor lesions occurring secondary to disordered proliferation of cells from a monocyte lineage. Plasmacytoma is a rare lesion that accounts for 5% of all plasma cell neoplasms. The current recommended treatment for solitary plasmacytoma is moderate dose radiation therapy. For patients who are suffering from axial back pain, spinal instability, radiculopathy, or bowel/bladder dysfunction secondary to spinal cord compression, surgical intervention with spinal decompression and stabilization can be used as an adjuvant to radiation therapy. CASE DESCRIPTION: We report a patient who presented with worsening axial and bilateral upper extremity pain. He was found to have a locally aggressive tumor involving the vertebral body of T2. After a repeat magnetic resonance imaging (MRI) and a computed tomography (CT)-guided biopsy, the diagnosis of a solitary plasmacytoma was confirmed. It destroyed over 90% of the T2 vertebral body, resulted in 22 degrees of local kyphosis, and caused spinal cord compression. The tumor was treated with a T2 vertebrectomy, posterior arthrodesis from C5-T4, and anterior arthrodesis from T1-3. CONCLUSIONS: Solitary plasmacytomas of the vertebral bodies are difficult lesions to treat secondary to their location and risk of neurologic compromise. Surgical intervention with tumor resection and adjuvant chemotherapy or radiation is the recommended treatment option. PMID- 28868186 TI - Salvage gamma knife radiosurgery in the management of dysembryoplastic neuroepithelial tumors: Long-term outcome in a single-institution case series. AB - BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNT/DNET) are rare epileptogenic tumors. Microsurgery remains the best treatment option, although case reports exist on the use of gamma knife radiosurgery (GKRS) in selected cases. We investigated the long-term outcome of GKRS-treated DNTs at our institution in the context of current diagnostic and treatment options. CASE DESCRIPTIONS: We conducted a retrospective review of three consecutive adult patients (>=18 years) treated with salvage GKRS between 2002 and 2010 at Karolinska University Hospital, Stockholm, Sweden. The case series was supplemented by a review of current literature. A 20-year-old male underwent subtotal resection (STR) in 1997 and 2002 of DNT resulting in temporary control of intractable epilepsy despite antiepileptic drug treatment (AED). Long-term seizure control was obtained after GKRS of two separate residual DNT components along the surgical margin (2005 and 2010). A 27-year-old male undergoing gross total resection of the contrast-enhancing portion of a DNT (1999) resulted in temporary control of intractable epilepsy despite AEDs; lasting clinical control of seizures was achieved in 2002 after GKRS of a small, recurrent DNT component. A 28-year-old male underwent STR of DNT (1994 and 2004) resulting in temporary control of intractable epilepsy. Lasting seizure control was gained after GKRS of a residual tumor (2005). CONCLUSION: GKRS as performed in our series was effective in terms of tumor and seizure control. No adverse radiation effects were recorded. Prospective studies are warranted to establish the role of GKRS in the treatment of DNTs. PMID- 28868188 TI - Impact of body mass index on 30-day outcomes after spinopelvic fixation surgery. AB - BACKGROUND: Obesity is one of the most prevalent chronic diseases associated with degenerative spinal disease. There is limited evidence regarding the short-term outcome of patients with elevated BMI following spinopelvic fixation surgery. METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database from 2013 to 2014. Inclusion criteria included: adults, aged 18 and older, who underwent all-cause spinopelvic fixation surgery. Primary outcome measures were 30-day readmission, reoperation, and major complication rates. Logistic regression analysis was used to assess the effect of elevated body mass index (BMI) on 30-day outcome. RESULTS: A total of 618 patients met inclusion criteria stratified into levels of BMI: 11.2% were Class 2 obese and 10.3% were Class 3 obese. Significant differences were found between the classes for the incidence of revision surgery, reoperations, and deep wound infections. However, there were no significant increases in readmissions and major complications rates, and only Class 3 obese patients had significantly higher odds of reoperation than those who were not obese. CONCLUSION: Significant differences between all classes of obesity regarding revision surgery, reoperation, and deep wound infection rates were found. Class 3 obese patients had significantly higher odds of reoperation, most likely attributed to the greater number/severity of preoperative comorbidities. PMID- 28868187 TI - Tumor cerebri: Metastatic renal cell carcinoma with dural venous sinus compression leading to intracranial hypertension; a case report. AB - BACKGROUND: Pseudotumor cerebri (PTC), also known as idiopathic intracranial hypertension (IIH), is a condition associated with increased intracranial pressure (ICP) in the absence of radiographic findings such as mass lesions or cerebral edema. CASE DESCRIPTION: We describe a case of progressive headache and visual disturbances attributed to PTC that resulted from subacute superior sagittal sinus (SSS) stenosis by a metastatic tumor. CONCLUSIONS: Venous outflow obstruction often presents with an acute symptomatology including infarcts, hemorrhages, and seizures, but only rarely does it cause the progressive development of raised ICP. The sinister presentation of our patient's pathology stemmed from local mass effect caused by a tumor that has hitherto not been reported to cause intracranial hypertension (IH) and was best elucidated using magnetic resonance venography (MRV). PMID- 28868189 TI - Spontaneous rupture of a secondary pituitary abscess causing acute meningoencephalitis: Case report and literature review. AB - BACKGROUND: Pituitary abscess (PA) is an uncommon finding that is rarely diagnosed preoperatively. If not properly treated it is associated with high morbidity and mortality rates. Nowadays standard diagnostic procedures allow early detection and successful treatment of this lesion in a high number of cases and mortality has been significantly reduced in recent years. PA arising de novo in a healthy gland are defined as primary, whereas those complicating a pre existing disease of the hypophysis are called secondary abscesses. CASE DESCRIPTION: We present a case of a secondary PA mimicking a large pituitary adenoma extending in the nasal cavity, which was wrongly diagnosed as such. The abscess showed an unexpected evolution in 48 h from presentation due to a sudden, extensive intracranial leakage of pus. CONCLUSIONS: To our knowledge, it is rare to find PA showing a rapid evolution like this, and in the literature only one previous case of a PA not reaching medical or surgical therapy was reported. In that case, hypothalamus involvement was identified as the cause of death. This should be the first case reported of a spontaneous PA rupture causing acute meningoencephalitis. Along with a short review of the literature on the major features of PA, we also tried to identify some features which could be supportive of a diagnosis of secondary PA. PMID- 28868190 TI - Upward migration and peroral extrusion of a peritoneal shunt catheter: Case report and review of the literature. AB - BACKGROUND: Various complications after ventriculoperitoneal (VP) shunt surgery have been reported, but peroral extrusion of peritoneal catheter is an extremely rare complication, and only 20 cases have been reported since 1987. The pathophysiology still remains unclear and the management is challenging. CASE DESCRIPTION: A 5-year-old boy presented with a catheter coming out of his mouth. The boy had a posterior fossa tumor surgery and had VP shunt insertion 1 year earlier. Clinical signs and imaging studies showed that the distal end of the catheter had perforated the gaster and migrated upward and extruded through the mouth. Emergency removal of the shunt and proper treatment were done and he made uneventful recovery. CONCLUSION: Peroral extrusion of VP shunt is extremely rare. Clinicians should be aware of this complication. With early diagnosis and proper management, the prognosis for good recovery is excellent, with only two deaths being reported in the literature. Complication of shunt extrusion is difficult to avoid, but knowing the risk factors, pathophysiology and proper management will decrease the morbidity and mortality of such cases. PMID- 28868191 TI - Solitary aneurysm of the filum terminale artery: A case report and review of the literature. AB - BACKGROUND: We report a rare case of aneurysmal dilatation of filum terminale artery after resection of filum terminal myxopapillary ependymoma. CASE DESCRIPTION: The authors report a rare aneurysmal dilatation of the filum terminale artery following removal of a filum terminal myxopapillary ependymoma in a 10-year-old male. The patient presented with 6-month history of increasing back pain without a focal neurological deficit. Magnetic resonance (MR) showed an intradural filum terminale lesion that was completely excised. Three months later, the MR again revealed a lesion involving the filum terminale. During the second surgery, however, an aneurysmal dilation of the filum artery was found, which was coagulated and resected. Following the secondary surgery, the patient's symptoms gradually resolved, and he remains intact. CONCLUSION: Although rare, a true aneurysm after spinal surgery should be considered among the differential diagnostic consideration in the region of the filum terminale. PMID- 28868192 TI - Giant cavernous carotid aneurysm causing pituitary dysfunction: Pituitary function recovery with high-flow bypass. AB - BACKGROUND: Giant internal carotid artery (ICA) aneurysms extending into the sellar region, mimicking pituitary tumors, and causing pituitary dysfunction are relatively rare. Open surgery or endovascular treatment can treat these aneurysms, but achieving recovery of endocrine function is difficult. CASE DESCRIPTION: A 56-year-old man presented with giant aneurysm of the ICA causing pituitary impairment, leading to disturbance of consciousness due to hyponatremia. High-flow bypass from the cervical external carotid artery to the middle cerebral artery and ligation of the ICA at the cervical portion were performed. One year after the operation, his pituitary function recovered well; he was followed up as an outpatient without hormonal replacement therapy for 8 years after the operation. CONCLUSION: Giant ICA aneurysm causing pituitary dysfunction is relatively rare, but it is important to consider in the differential diagnosis for hypopituitarism. Treatment with high-flow bypass using radial artery graft can achieve both prevention of aneurysm rupture and recovery of pituitary function. PMID- 28868193 TI - Cervical cancer metastasis to the brain: A case report and review of literature. AB - BACKGROUND: Intracranial metastasis from cervical cancer is a rare occurrence. METHODS: In this study we describe a case of cervical cancer metastasis to the brain and perform an extensive review of literature from 1956 to 2016, to characterize clearly the clinical presentation, treatment options, molecular markers, targeted therapies, and survival of patients with this condition. RESULTS: An elderly woman with history of cervical cancer in remission, presented 2 years later with a right temporo-parietal tumor, which was treated with surgery and subsequent stereotactic radiosurgery (SRS) to the resection cavity. She then returned 5 months later with a second solitary right lesion; she again underwent surgery and SRS to the resection cavity with no signs of recurrence 6 months later. According to the reviewed literature, the most common clinical presentation included females with median age of 48 years; presenting symptoms such as headache, weakness/hemiplegia/hemiparesis, seizure, and altered mental status (AMS)/confusion; multiple lesions mostly supratentorially located; poorly differentiated squamous cell carcinoma; and additional recurrences at other sites. The best approach to treatment is a multimodal plan, consisting of SRS or whole brain radiation therapy (WBRT) for solitary brain metastases followed by chemotherapy for systemic disease, surgery and WBRT for solitary brain lesions without systemic disease, and SRS or WBRT followed by chemotherapy for palliative care. The overall prognosis is poor with a mean and median survival time from diagnosis of brain metastasis of 7 and 4.6 months, respectively. CONCLUSION: Future efforts through large prospective randomized trials are warranted to better describe the clinical presentation and identify more effective treatment plans. PMID- 28868194 TI - Spinal epidural hematoma mimicking subarachnoid hemorrhage: A case study. AB - BACKGROUND: Spontaneous spinal epidural hematoma (SSEH) is a rare spinal cord disorder requiring urgent diagnosis and prompt treatment to prevent irreversible neurological damage. Subarachnoid hemorrhage (SAH), usually presenting with headache and neck stiffness, is also a worldwide neurosurgical emergency. In this case study, a patient on clopidogrel presented with an SSEH mimicking a spontaneous SAH. CASE DESCRIPTION: A 74-year-old female presented with severe headache and neck pain which ultimately attributed to a cervicothoracic SSEH resulting in cord compression. Notably, there was a long delay in establishing the diagnosis of SSEH as her symptoms mimicked a SAH. Although the patient ultimately underwent spinal surgery followed by intense rehabilitation, the diagnostic delay resulted in a poor neurological outcome. CONCLUSIONS: Patients with spontaneous cervicothoracic epidural hematomas may occasionally present with symptoms of severe headache and neck pain/stiffness mimicking an SAH. Long diagnostic delays in establishing SSEH may result in irreversible cord damage. PMID- 28868195 TI - Spontaneous resolved cervical spine epidural hematoma: A case report. AB - BACKGROUND: Cervical spine epidural hematomas (CSEH) are rare, and surgical intervention is typically required. Here, we present the rare case of a CSEH resulting from chiropractic manipulation successfully treated conservatively. CASE DESCRIPTION: A 44-year-old female with cervical myelopathy presented with a mild quadriparesis following manipulation by a chiropractor. Although magnetic resonance (MR) documented a CSEH, the lesion was treated nonsurgically as the patient refused operative intervention. Four days later, the patient demonstrated spontaneous improvement. Furthermore, the 1-month post manipulation cervical MR showed resolution of the CSEH mass effect, and her myelopathy fully resolved. CONCLUSION: Few studies document the efficacy of conservative treatment of CSEH. In this case, a patient with cervical myelopathy presented with a mild quadriparesis following chiropractic manipulation. Although MR documented a CSEH, she refused surgery, but fortunately improved neurologically within the next 4 days and was intact within 1 postoperative month. We recommend performing more powerful studies with large sample size to better define criteria for conservative vs. surgical treatment of CSEH. PMID- 28868196 TI - Novel approach to continuous neurophysiological monitoring during surgery of peripheral nerve tumors. AB - BACKGROUND: Intraoperative neurophysiological monitoring (IONM) with nerve action potential (NAP) can be useful during peripheral nerve surgery. However, current methodologies are not optimized for continuous recording of the NAP. The use of newer electrodes may make it possible to more conveniently obtain continuous recordings of the NAP during surgery. METHODS: After localizing the nerve of interest and dissecting it from the adjacent soft tissue, two APS(r) (Automatic Periodic Stimulation) electrodes, originally designed for stimulation of the vagus nerve during thyroid surgery, are placed on the nerve on either sides of the tumor for stimulation and recording using two subdermal electroencephalogram (EEG) needles as anode and reference, respectively. Both monopolar and bipolar recordings can be used as appropriate. Anesthesia regime comprised sevoflurane or total intravenous anesthesia (TIVA). No muscle relaxant after intubation, local anesthesia, or blood pressure cuff is used during the surgery. RESULTS: Twelve patients (6 male, 6 female) with peripheral nerve tumors (motor, sensitive, or mixed nerves) or tumors affecting the peripheral nerves were monitored in our center since 2014 (mean age: 50 years; 28-79). In 10 patients, the NAP was monitored without experiencing any changes from the beginning till the end of the surgery; in these patients, no postoperative deficit was adverted. In the last 2 patients, who departed from a complete neurological deficit, no NAP was recorded at the baseline or during the surgery, and they did not experience any neurological improvement. CONCLUSION: The vagus nerve stimulation electrodes open new possibilities in peripheral nerve IONM. We have used them for continuous monitoring without additional problems with the traditional probes. PMID- 28868197 TI - Combined simultaneous transcranial and endoscopic endonasal resection of sphenoorbital meningioma extending into the sphenoid sinus, pterygopalatine fossa, and infratemporal fossa. AB - BACKGROUND: Sphenoorbital meningiomas are surgically challenging because of their nature to extend to adjacent structures. Here, we describe a case of recurrent sphenoorbital meningioma extending into the sphenoid sinus, pterygopalatine fossa, and infratemporal fossa, which was resected using combined simultaneous transcranial and endoscopic endonasal approaches. CASE DESCRIPTION: A 62-year-old man who had 15 years earlier undergone partial resection of a left sphenoorbital meningioma presented with a 1-year history of progressive proptosis of the left eye. Magnetic resonance imaging (MRI) showed a Gd-enhancing tumor occupying the left sphenoid wing and orbital lateral wall and extending into extracranial structures such as the sphenoid sinus, pterygopalatine fossa, and infratemporal fossa as well as adjacent structures such as the cavernous sinus and superior orbital fissure (SOF). Based on the MRI findings of tumor extension into the sphenoid sinus with broad continuity, the risk of postoperative cerebrospinal fluid (CSF) leakage through the large defect in the sphenoid sinus was considered high. Subtotal resection using combined simultaneous transzygomatic and endoscopic endonasal approaches was performed, leaving residual tumor in the cavernous sinus and SOF. The large skull base defect between the middle fossa and sphenoid sinus was covered with a free graft of fascia lata from the transcranial side and with a vascularized nasoseptal flap from the endonasal side. No CSF rhinorrhea and no neurological deficits developed postoperatively. CONCLUSION: Combined simultaneous transcranial and endoscopic endonasal approaches may become a safe and feasible alternative for sphenoorbital meningioma with a large skull base defect penetrating to the paranasal sinus. PMID- 28868199 TI - Intradural angiomatous meningioma arising from a thoracic nerve root. AB - BACKGROUND: Spinal intradural meningiomas that arise purely from a nerve root without dural attachments are extremely rare. Spinal meningiomas arise from arachnoidal cap cells in the spinal canal, and growth of these tumors exerts pressure on the spinal cord and nerve roots. CASE DESCRIPTION: A patient presented with a lesion at the T3-T4 level that resembled a schwannoma on magnetic resonance imaging. During surgery, the tumor originated from a spinal nerve root. Pathologically, it was an angiomatous meningioma (AM). CONCLUSIONS: In a review of the literature, we discuss the pathogenesis and surgical strategy for diagnosing and treating these extremely rare AM lesions. PMID- 28868198 TI - Malignant squamous cell carcinoma arising in a previously resected cerebellopontine angle epidermoid. AB - BACKGROUND: Malignant squamous cell differentiation of an epidermoid cyst can carry a significantly poor prognosis and very little is known about this entity. CASE DESCRIPTION: We present the case of a 35-year-old lady, with primary malignant squamous cell carcinoma (SCC) arising from a previously partially resected cerebellopontine angle epidermoid cyst almost 5 years after initial resection. We also review the relevant literature. CONCLUSION: The imaging findings, histopathology, and management of a malignant SCC arising from a benign epidermoid cyst are discussed with recommendation for increased surveillance and follow-up, even for classically accepted benign lesions. PMID- 28868200 TI - The open access video collection project "Hernesniemi's 1001 and more microsurgical videos of Neurosurgery": A legacy for educational purposes. AB - BACKGROUND: Neurosurgical educational programs and courses are helpful to improve the quality of training. Moreover, nowadays, online activities may represent a very useful tool to globally enhance neurosurgical education. The "Hernesniemi's 1001 and more microneurosurgical videos" project aims to show the microsurgical style developed by the senior author and his TEAMs in more than 40 years of experience. METHODS: More than 1100 high-definition videos of microneurosurgical operations performed by the senior author were carefully edited. These videos illustrate the philosophy of "simple, clean, fast and preserving the normal anatomy" while offering a step by step guide of different neurosurgical procedures. RESULTS: All the aforementioned material is well organized in an electronic videobook, freely available in Surgical Neurology International. The book also includes comments of great current neurosurgeons and writings of the authors and editors. CONCLUSION: We are sure that our project will be able to instill in and spread across the neurosurgical community the microneurosurgical style of the senior author, thus representing an efficient educational tool for surgeons all around the world. PMID- 28868201 TI - Never say never again: A bone graft infection due to a hornet sting, thirty-nine years after cranioplasty. AB - BACKGROUND: Cranioplasty (CP) is a widespread surgical procedure aimed to restore skull integrity and physiological cerebral hemodynamics, to improve neurological functions and to protect the underlying brain after a life-saving decompressive craniectomy (DC). Nevertheless, CP is still burdened by surgical complications, among which early or late graft infections are the most common outcome threatening ones. CASE DESCRIPTION: We report the case of 48-year-old man admitted to our neurosurgical unit because of a painful right frontal swelling and 1-week purulent discharge from a cutaneous fistula. He had been undergone frontal CP because of severe traumatic brain injury (TBI) when he was 9-year-old. Since then, his medical history has been being unremarkable without any surgical or infective complication of the graft for 39 years, until he was accidentally stung by a hornet in the frontal region. After the CT scan and laboratory findings had evidenced a probable infection of the graft, the patient was treated by vancomycin and cefepime before he underwent surgical revision of its former CP, with the removal of the graft and the debridement of the surgical field. Subsequent bacteriological tests revealed Staphylococcus aureus as causal agent of that infection. CONCLUSION: This case illustrates an anecdotal example of very late CP infection, due to an unpredictable accident. Due to lack of consensus on risk factors and on conservative or surgical strategy in case of graft infection, we aimed to share our surgical experience. PMID- 28868202 TI - A thoracic vertebral localization of a metastasized cutaneous Merkel cell carcinoma: Case report and review of literature. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor, which may be related to sun exposure. It can metastasize to lungs, liver and bone, leading to severe morbidity and mortality. Vertebral metastases from MCC are rare. The authors report the tenth case in the literature, a 59-year-old patient with MCC, which was primarily localized in the scalp, and later provoked distant metastasis to the thoracic spinal column. CASE DESCRIPTION: A 59-year-old woman was admitted at our Unit of Neurosurgery with a 4-month history of progressive and severe dorsal back pain, without neurological signs. The patient had been surgically treated for a recidivated MCC in the occipital region in 2007, 2011, and 2013. (In 2013, the surgical treatment also included lateral cervical lymph node dissection). Chemotherapy and radiotherapy had come after the treatments. Magnetic resonance imaging (MRI) of the dorsal spine showed metastatic vertebral involvement with cord impingement of the T7-T8 levels. A total body CT scan revealed lungs and liver metastases, besides vertebral district. After a multidisciplinary consult a palliative surgery was decided and a posterior dorsal approach was employed: Radiofrequency (RF) thermoablation was followed by the injection of cement of T7 and T8 and transpedicle fixation T5-T9. The postoperative course was uneventful and followed by a further adjuvant therapy. CONCLUSION: Spinal metastases from MCC are described in literature only exceptionally. The clinical course is presented, along with a review of literature. PMID- 28868203 TI - Titanium versus polyetheretherketone implants for vertebral body replacement in the treatment of 77 thoracolumbar spinal fractures. AB - BACKGROUND: Titanium and polyetheretherketone (PEEK) implants have been used in spinal surgery with low rejection rates. Compared to titanium, PEEK has many advantages, including a density more similar to that of bone, radiolucency, and a lack of artifacts in computed tomography (CT) and magnetic resonance imaging (MRI). In this study, we evaluated the effectiveness of PEEK cages as an alternative to titanium for bone fusion after fractures of the thoracolumbar spine. We also propose a classification to the impaction index. METHODS: We evaluated 77 patients with fractures of the thoracic or lumbar spine who were treated by anterior fixation with titanium cages (TeCorp(r)) in 46 (59.7%) patients or PEEK (Verte-stak(r)) in 31 (40.3%) patients from 2006 to 2012 (Neurological Hospital of Lyon). RESULTS: The titanium group achieved 100% fusion, and the PEEK group achieved 96.3% fusion. The titanium systems correlated with higher impact stress directed toward the lower and upper plateaus of the fused vertebrae; there were no nonunions for those treated with titanium group. Nevertheless, there was only one in the PEEK group. There was no significant difference in the pain scale outcomes for patients with +/-10 degrees of the sagittal angle. Statistically, it is not possible to associate the variation of sagittal alignment or the impaction with symptoms of pain. The complication rate related to the implantation of cages was low. CONCLUSIONS: Titanium and PEEK are thus equally effective options for the reconstruction of the anterior column. PEEK is advantageous because its radiolucency facilitates the visualization of bone bridges. PMID- 28868204 TI - Impact of low coagulation factor XIII activity in patients with chronic subdural hematoma associated with cerebrospinal fluid hypovolemia: A retrospective study. AB - BACKGROUND: Cerebrospinal fluid hypovolemia (CSFH) is sometimes associated with chronic subdural hematomas (CSHs). Affected patients often develop enlargement and recurrence of the CSH, even if appropriate treatments such as epidural blood patch (EBP) and/or burr-hole surgery for the CSH are performed. This situation may lead to subclinical coagulopathy, including low coagulation factor XIII (CFXIII) activity. We retrospectively analyzed whether CFXIII activity was involved in the development of CSHs and post-treatment exacerbation of CSHs in patients with CSFH. METHODS: We diagnosed CSFH by radioisotope (RI), magnetic resonance imaging (MRI) and computed tomography (CT) findings, and CSH by CT and/or MRI findings. The plasma CFXIII activity was assessed on admission. All patients with CSFH initially received conservative treatments. When these treatments were ineffective, the patients underwent EBP and/or CSH surgery according to previously reported therapeutic strategies. RESULTS: Among 206 patients with CSFH, 19 developed CSHs. Fourteen patients with a thin hematoma underwent EBP and three with a thick hematoma underwent CSH surgery immediately after EBP on the same day. We were unable to diagnose two patients with CSFH at the time of admission, and one of these two patients underwent repeated CSH surgery before obtaining the correct diagnosis. Seven patients (36.8%) developed CSH exacerbation after the treatment. The CFXIII activity was significantly lower in patients with than without a CSH (42.1% vs. 12.8%, respectively; P = 0.003). The CFXIII activity was significantly lower in patients with than without post treatment CSH exacerbation (P = 0.046). All five patients with low CFXIII activity who developed CSH exacerbation received intravenous injection of CFXIII and had no recurrence of CSH after the additional treatment. CONCLUSION: In patients with CSFH, low CFXIII activity is one of the risk factors for both the development of a CSH and the post-treatment exacerbation CSH. PMID- 28868205 TI - Moving in and Out: Dispersion of Cells in Self-Generated Gradients. AB - Migrating cells can influence the direction of their own migration by metabolizing chemoattractants present in their environment. This is illustrated by the dispersal of melanoma cells, which break down lysophosphatidic acid and generate a gradient with increasing concentrations of lysophosphatidic acid distant from the tumor. Melanoma cells can then disperse away from the tumor as they migrate in the self-generated lysophosphatidic acid gradient. Thus, dispersal of tumor cells during invasion of the surrounding stroma might be driven by chemotaxis of cells along self-generated chemoattractant gradients. PMID- 28868206 TI - A Hybrid Algorithm for Non-negative Matrix Factorization Based on Symmetric Information Divergence. AB - The objective of this paper is to provide a hybrid algorithm for non-negative matrix factorization based on a symmetric version of Kullback-Leibler divergence, known as intrinsic information. The convergence of the proposed algorithm is shown for several members of the exponential family such as the Gaussian, Poisson, gamma and inverse Gaussian models. The speed of this algorithm is examined and its usefulness is illustrated through some applied problems. PMID- 28868207 TI - Host non-inflammatory neutrophils mediate the engraftment of bioengineered vascular networks. AB - Notwithstanding remarkable progress in vascular network engineering, implanted bioengineered microvessels largely fail to form anastomoses with the host vasculature. Here, we demonstrate that implants containing assembled human vascular networks (A-Grafts) fail to engraft due to their inability to engage non inflammatory host neutrophils upon implantation into mice. In contrast, unassembled vascular cells (U-Grafts) readily engage alternatively polarized neutrophils, which in turn serve as indispensable mediators of vascular assembly and anastomosis. The depletion of host neutrophils abrogated vascularization in U Grafts, whereas an adoptive transfer of neutrophils fully restored vascularization in myeloid-depleted mice. Neutrophil engagement was regulated by secreted factors and was progressively silenced as the vasculature matured. Exogenous addition of factors from U-Grafts reengaged neutrophils and enhanced revascularization in A-Grafts, a process that was recapitulated by blocking Notch signaling. Our data suggest that the pro-vascularization potential of neutrophils can be harnessed to improve the engraftment of bioengineered tissues. PMID- 28868208 TI - Pedicled Latissimus Dorsi Flap for Shoulder Soft-Tissue Reconstruction After Excision of a Musculoskeletal Neoplasm. PMID- 28868209 TI - Oral Glycine and Sodium Thiosulfate for Lethal Cyanide Ingestion. AB - OBJECTIVE: Accidental or intentional cyanide ingestion is an-ever present danger. Rapidly acting, safe, inexpensive oral cyanide antidotes are needed that can neutralize large gastrointestinal cyanide reservoirs. Since humans cannot be exposed to cyanide experimentally, we studied oral cyanide poisoning in rabbits, testing oral sodium thiosulfate with and without gastric alkalization. SETTING: University research laboratory. SUBJECTS: New Zealand white rabbits. INTERVENTIONS: Seven animal groups studied; Groups 1-5 received high dose oral NaCN (50 mg, >LD100) and were treated immediately with oral (via nasogastric tube): 1) saline, 2) glycine, 3) sodium thiosulfate or 4) sodium thiosulfate and glycine, or 5) after 2 min with intramuscular injection of sodium nitrite and sodium thiosulfate plus oral sodium thiosulfate and glycine. Groups 6-7 received moderate dose oral NaCN (25 mg, LD70) and delayed intramuscular 6) saline or 7) sodium nitrite-sodium thiosulfate. MEASUREMENTS AND MAIN RESULTS: All animals in the high dose NaCN group receiving oral saline or glycine died very rapidly, with a trend towards delayed death in glycine-treated animals; saline versus glycine treated animals died at 10.3+3.9 and 14.6+5.9 min, respectively (p=0.13). In contrast, all sodium thiosulfate-treated high dose cyanide animals survived (p<0.01), with more rapid recovery in animals receiving both thiosulfate and glycine, compared to thiosulfate alone (p<0.03). Delayed intramuscular treatment alone in the moderate cyanide dose animals increased survival over control animals from 30% to 71%. Delayed treatment in high dose cyanide animals was not as effective as immediate treatment, but did increase survival time and rescued 29% of animals (p<0.01 versus cyanide alone). CONCLUSIONS: Oral sodium thiosulfate with gastric alkalization rescued animals from lethal doses of ingested cyanide. The combination of oral glycine and sodium thiosulfate may have potential for treating high dose acute cyanide ingestion and merits further investigation. The combination of systemic and oral therapy may provide further options. PMID- 28868210 TI - Stroke Investigative Research and Education Network: Public Outreach and Engagement. AB - Stroke is becoming a leading cause of disability and death, and a major public health concern in Sub-Saharan Africa (SSA). The Stroke Investigative Research and Education Network (SIREN) seeks to comprehensively characterize the genomic, sociocultural, economic, and behavioral risk factors for stroke and to build effective teams for research to address and decrease the burden of stroke and other non-communicable diseases in SSA. One of the first steps to address this goal was to effectively engage the communities that suffer high burdens of disease in SSA. This paper describes the process of SIREN project's community engagement activities in Ghana and Nigeria. The aims of community engagement (CE) within SIREN are to: i) elucidate information about knowledge, attitudes, beliefs, and practices (KABP) about stroke and its risk factors from individuals of African ancestry in SSA; ii) educate the community about stroke and ways to decrease disabilities and deaths from stroke; and iii) recruit 3000 control research subjects to participate in a case-control stroke study. CE focused on three-pronged activities-constitution and interaction with Community Advisory Board (CABs), Focus Group Discussions (n=27) and community education and outreach programs (n=88). FGDs and outreach programs indicate that knowledge of stroke, as well as risk factors and follow-up evidence-based care is limited and often late. Almost all indicated that genetic testing could help health provider's better treat stroke and help scientists better understand the causes of stroke. Over 7000 individuals have received education on cardiovascular risk factors and about 5,000 have been screened for cardiovascular risk factors during the outreaches. The CE core within SIREN is a first of its kind public outreach engagement initiative to evaluate and address perceptions about stroke and genomics by patients, caregivers, and local leaders in SSA and has implications as a model for assessment in other high stroke risk populations. PMID- 28868212 TI - High-Density Mapping of Brain Slices using a Large Multi-Functional High-Density CMOS Microelectrode Array System. AB - We present a CMOS-based high-density microelectrode array (HD-MEA) system that enables high-density mapping of brain slices in-vitro with multiple readout modalities. The 4.48*2.43 mm2 array consists of 59,760 micro-electrodes at 13.5 um pitch (5487 electrodes/mm2). The overall system features 2048 action potential, 32 local-field-potential and 32 current recording channels, 32 impedance-measurement and 28 neurotransmitter-detection channels and 16 voltage/current stimulation channels. The system enables real-time and label-free monitoring of position, size, morphology and electrical activity of brain slices. PMID- 28868211 TI - Considerations When Using Predictive Equations to Estimate Energy Needs Among Older, Hospitalized Patients: A Narrative Review. AB - The aim of this narrative review was to summarize the accuracy of predictive equations used to estimate energy expenditure in older, hospitalized adults. More than 50% of patients admitted to intensive care units are older adults. Currently accepted prediction equations used to determine energy intake in the older, hospitalized patient were not specifically developed for the aging population. Rates of multimorbidity, polypharmacy and malnutrition, conditions that influence energy expenditure, are higher in older adults compared to younger adults. For these reasons, current equations may not accurately assess energy needs in this population. As the evidence demonstrating the importance of nutritional supplementation in older, hospitalized adults grows, more accurate energy assessment methods that account for age-related conditions are needed to predict nutritional requirements. PMID- 28868213 TI - Geochemical characterization of Lucaogou Formation and its correlation of tight oil accumulation in Jimsar Sag of Junggar Basin, Northwestern China. AB - With the constant consumption of conventional oil and gas resources, unconventional oil and gas resources with great resource potential such as tight oil have gradually been valued and become the new exploration area. Jimsar Sag is the key tight oil exploration and development block in Junggar Basin of Northwestern China. Based on the data sets of geology, oil production test, logging, rock thin section, and geochemistry of Permian Lucaogou Formation (LCG), we studied the geochemical characteristics of hydrocarbon source rocks and their relation to the tight oil accumulation. Organic matter abundance of source rocks is high, the types of organic matter are mainly type I and type II, and the organic matter maturation is in the low mature stage to mature stage. Results of oil source correlation showed that the crude oil of sweet spots was mainly derived from the source rocks in the interior of the sweet spots. The LCG tight oil is mainly distributed in the plane where the source rocks have great thickness and the TOC is higher than 3.5%. It shows that the source rocks have obvious controlling on the occurrence and accumulation of tight oil. PMID- 28868214 TI - Allelic variation at high-molecular weight and low-molecular weight glutenin subunit genes in Moroccan bread wheat and durum wheat cultivars. AB - Glutenin is a major protein fraction contributing to the functional properties of gluten and dough. The glutenin constitutes 30-40% of the protein in wheat flour and about half of that in gluten. It is essential to identify correct glutenin alleles and to improve wheat quality by selecting alleles that exert favorable effects. Moroccan wheat cultivars are unique in West Asia and North Africa region, since many of them possess resistance to Hessian fly, a pest, which is becoming important in other countries in the region. Hence, these cultivars are being used as donor for the resistance in the breeding program. Here, we determine the allelic variation in high-molecular weight glutenin subunits (HMW GS) and low-molecular weight glutenin subunits (LMW-GS) in Moroccan cultivars of bread and durum wheat using the gene-specific PCR markers. In 20 cultivars of bread wheat, 9 different allele variants were detected at HMW-GS and 13 different allele variants were detected at LMW-GS, in which the alleles Glu-A1b (2*), Glu B1i (17 + 18), Glu-B1c (7*/7 + 9), Glu-D1d (5 + 10), Glu-A3c, Glu-B3 h, and Glu D3b were the most frequents. In 26 cultivars of durum wheat, less allelic variation was found: seven different allele variants at HMW-GS and six different allele variants at LMW-GS were identified, in which the major alleles were Glu A1c (null), Glu-B1b (7 + 8), Glu-B1e (20), Glu-A3c, and Glu-B3d. The mean value of the genetic diversity for the glutenin loci was 0.502 in bread wheat and 0.449 in durum wheat. Most of the glutenin alleles carried by Moroccan bread wheat cultivars impart good bread-making quality. Most of the durum wheat glutenin alleles were related to low strength dough or poor quality and need to be improved. To improve quality of Moroccan durum wheat, essentially, Glu-A1c and Glu-B3d alleles of the genes should be replaced with the better alleles through breeding. PMID- 28868215 TI - RAPD and ISSR marker assessment of genetic diversity in Citrullus colocynthis (L.) Schrad: a unique source of germplasm highly adapted to drought and high temperature stress. AB - Citrullus colocynthis (L.) Schrad. (Cucurbitaceae) shows high levels of variation in fruit color, fruit stripe pattern, seed coat color, and size. Thirty-eight accessions of C. colocynthis plants from different parts of semi-arid Rajasthan were collected and genetic diversity was assessed using random-amplified polymorphic DNA (RAPD) and inter-simple sequence repeat (ISSR) markers. Out of 65 RAPD decamer primers, 50 primers produced 549 scorable bands of which 318 were polymorphic. Polymorphic banding patterns with the number of amplified fragments varied from 5 (OPA-08 and OPF-9) to 19 (OPT-20) in the molecular size range of 150-6000 bp. Percent polymorphism ranged from 22.2% (OPA-09) to 83.3% (OPE-12) with 55.14% polymorphism. Out of the 20 ISSR primers screened, 13 primers produced 166 amplification products, of which 99 were polymorphic. The number of bands amplified per primer varied between 9 (UBC-807, 802) and 16 (UBC-803, 812) with average band size between 250 and 4000 bp. Percent polymorphism ranged from 45.4% (UBC-815) to 73.3% (UBC-814) with 65.05% polymorphism. Dendrogram constructed on the basis of RAPD + ISSR polymorphism separated the accessions into four distinct clusters at 72% variation with Jaccard's similarity coefficient ranging from minimum 0.64 to 0.95. The matrices for RAPD and ISSR were also compared using Mantel's test and obtained correlation value (r = 0.7947). Discriminating power of RAPD and ISSR markers was assessed by calculating polymorphic information content, multiplex ratio, marker index, and resolving power. Approx. 50% RAPD and ISSR markers showed PIC value and heterozygosity (H) >= 0.50, indicating marker as informative. The primers that showed higher polymorphism had higher RP, MR, and MI values. PMID- 28868216 TI - Molecular and phytochemical analysis of wild type and olive cultivars grown under Saudi Arabian environment. AB - This study aimed to assess genetic variability at molecular and phytochemical levels among the four most commonly grown olive cultivars and the wild-type olive of Saudi Arabia. Sixty-six and 80 amplicons were generated from 9 random amplified polymorphic DNA (RAPD) and inter simple sequence repeats (ISSR) primers, each, producing an average of 95.9 and 86.44% polymorphism for the two markers, respectively. The PIC values were 82.2% for the RAPD and 85.4% for the ISSR markers and the discrimination power for both the markers was 11.1%. The UPGMA cluster analysis based on the RAPD and ISSR data resulted in the aggregation of cultivars and wild accession with a good bootstrapping value according to their origin. Furthermore, a total of 199 compounds were identified in the cultivars based on peak area, retention time, and molecular formula using GC-MS analyses of methanolic and ethanolic extracts. These compounds were classified according to their chemical class; most of them were fatty acids, alcoholic compounds, carboxylic acids, aldehydes, heterocyclic compounds, ketones, alkanes, and phenols. Genetic and phytochemical distances were significantly correlated, based on the Mantel test. The Saudi wild accession also had high numbers of fatty acids and their esters, and can be used in breeding programs for generating new genotypes with interesting characters. PMID- 28868217 TI - Simultaneous saccharification and viscosity reduction of cassava pulp using a multi-component starch- and cell-wall degrading enzyme for bioethanol production. AB - In this study, an efficient ethanol production process using simultaneous saccharification and viscosity reduction of raw cassava pulp with no prior high temperature pre-gelatinization/liquefaction step was developed using a crude starch- and cell wall-degrading enzyme preparation from Aspergillus aculeatus BCC17849. Proteomic analysis revealed that the enzyme comprised a complex mixture of endo- and exo-acting amylases, cellulases, xylanases, and pectina ses belonging to various glycosyl hydrolase families. Enzymatic hydrolysis efficiency was dependent on the initial solid loading in the reaction. Reduction in mixture viscosity was observed with a rapid decrease in complex viscosity from 3785 to 0.45 Pa s with the enzyme dosage of 2.19 mg/g on a dried weight basis within the first 2 h, which resulted from partial destruction of the plant cell wall fiber and degradation of the released starch granules by the enzymes as shown by scanning electron microscopy. Saccharification of cassava pulp at an initial solid of 16% (w/v) in a bench-scale bioreactor resulted in 736.4 mg glucose/g, which is equivalent to 82.92% glucose yield based on the total starch and glucan in the substrate, after 96 h at 40 degrees C. Simultaneous saccharification and fermentation of cassava pulp by Saccharomyces cerevisiae with the uncooked enzymatic process led to a final ethanol concentration of 6.98% w/v, equivalent to 96.7% theoretical yield based on the total starch and cellulose content. The results demonstrated potential of the enzyme for low-energy processing of cassava pulp in biofuel industry. PMID- 28868218 TI - Optimization of the secretory expression of recombinant human C-reactive protein in Pichia pastoris. AB - Human C-reactive protein (CRP), a classical human acute-phase plasma protein, is not only a sensitive systemic inflammatory marker but also an independent risk predictor of cardiovascular diseases. However, existing heterologous expression systems for expressing CRP is not efficient and cost-effective for large-scale industrial production of CRP to meet the growing market demand for CRP. This study aims to improve the secretion of recombinant CRP by Pichia pastoris via optimizing signal peptides, promoters and carbon sources. The CRP genes with encoding four different signal peptides were designed and synthesized. The genes were cloned into pPICZalphaA or pPICZ B, respectively via splicing by overlap extension polymerase chain reaction (SOE-PCR) technology and expressed in P. pastoris X-33, regulated by the alcohol oxidase I promoter (pAOX1). The CRP led by the alpha-mating factor secretion signal peptide (alpha-MF) was secreted at the highest level in these signal peptides. Then, a constitutive construct and expression of the CRP genes were achieved by switching to the glyceraldehyde-3 phosphate dehydrogenase promoter (pGAP). Subsequently, different carbon sources and at different concentrations were used to further improve the secretion of CRP. The expression of CRP with the alpha-MF driven by the pGAP gave the highest yield of secreted CRP, about 3 mg/l of culture on the optimized culture conditions. The purified recombinant CRP exhibited good immunoreactivity determined by ELISA with anti-human CRP monoclonal antibody. The efficient engineering strategy established in this work might provide potential uses in large-scale industrial production of human CRP in the future. PMID- 28868220 TI - Evaluation of stress effects of copper oxide nanoparticles in Brassica napus L. seedlings. AB - Rapid growth of nanotechnology has enabled the production and use of engineered nanoparticles (ENPs) in several industries as well as in agriculture areas. This has raised ecotoxicological concerns due to the release of ENPs to the environment. In the present study, we investigated the effects of interactions of copper oxide nanoparticles (CuO NPs) on physiological, biochemical, and molecular indices in seedlings of an important oil seed crop Brassica napus L. The seedlings were treated with 0, 20, 50, 100, 200, 400, and 500 mg/L of CuO NPs for 14 days in half-strength semi-solid Murashige and Skoog medium. The CuO NPs treatment significantly reduced shoot and root growth as well as plant biomass. Shortening and thickening of primary and lateral roots and inhibition of lateral root growth was observed at higher concentrations. An increase in reactive oxygen species generation, and malondialdehyde accumulation was observed. Histochemical staining of roots with propidium iodide and aniline blue indicated cell death and callose formation in roots. Transcriptional modulation of genes related to oxidative stress viz. CuZn superoxide dismutase, catalase, and ascorbate peroxidase was observed. Element content analysis showed an increase in Cu content and decrease in Fe, Mn, and Zn contents. Overall, exposure to CuO NPs caused oxidative injury, cell death, callose formation, and decreased the micro nutrient contents in B. napus seedlings. PMID- 28868219 TI - Appraisal of biochemical classes of radioprotectors: evidence, current status and guidelines for future development. AB - The search for efficient radioprotective agents to protect from radiation-induced toxicity, due to planned or accidental radiation exposure, is still ongoing worldwide. Despite decades of research and development of widely different biochemical classes of natural and derivative compounds, a safe and effective radioprotector is largely unmet. In this comprehensive review, we evaluated the evidence for the radioprotective performance of classical thiols, vitamins, minerals, dietary antioxidants, phytochemicals, botanical and bacterial preparations, DNA-binding agents, cytokines, and chelators including adaptogens. Where radioprotection was demonstrated, the compounds have shown moderate dose modifying factors ranging from 1.1 to 2.7. To date, only few compounds found way to clinic with limited margin of dose prescription due to side effects. Most of these compounds (amifostine, filgratism, pegfilgrastim, sargramostim, palifermin, recombinant salmonella flagellin, Prussian blue, potassium iodide) act primarily via scavenging of free radicals, modulation of oxidative stress, signal transduction, cell proliferation or enhance radionuclide elimination. However, the gain in radioprotection remains hampered with low margin of tolerance. Future development of more effective radioprotectors requires an appropriate nontoxic compound, a model system and biomarkers of radiation exposure. These are important to test the effectiveness of radioprotection on physiological tissues during radiotherapy and field application in cases of nuclear eventualities. PMID- 28868221 TI - The persistence and performance of phosphate-solubilizing Gluconacetobacter liquefaciens qzr14 in a cucumber soil. AB - The persistence and performance of plant growth-promoting microorganisms (PGPMs) in soil are considered critical features for effectiveness, yet they are poorly understood. Here, we investigated the colonization and activity of a new PGPM, phosphate-solubilizing Gluconacetobacter liquefaciens qzr14, in a pot culture experiment using cucumber as test crop for 20 days. The number of G. liquefaciens and bacterial diversity in the rhizosphere and bulk soil were monitored by real time PCR and DGGE, respectively. Soil phosphorus and cucumber biomass were also examined. G. liquefaciens qzr14 effectively colonized the rhizosphere soil (bacterial density ranging from 2.70 * 108 to 1.18 * 109 copies per gram dry soil). G. liquefaciens qzr14 inoculation had significantly positive effects on bacterial diversity (BD) of the rhizosphere and bulk soil and the ratio of soluble phosphorus to total phosphorus (SP/TP). The number of G. liquefaciens in the rhizosphere soil was significantly related to SP/TP and the BD of the rhizosphere and bulk soil. BD in rhizosphere soil was significantly related to SP/TP and BD in bulk soil. Based on the results of correlation analysis, we inferred that the introduced G. liquefaciens qzr14 effectively colonized the rhizosphere of cucumber, and then expanded its bacterial community by solubilizing soil phosphorus. The expanded bacterial communities might promote cucumber growth by some new functions. PMID- 28868222 TI - Linkage disequilibrium based association mapping of micronutrients in common bean (Phaseolus vulgaris L.): a collection of Jammu & Kashmir, India. AB - Micronutrient deficiencies are of major concern in human health and plant metabolism. Iron (Fe), zinc (Zn), iodine (I), selenium (Se) are regarded as micronutrients having major impact on human health. More than 50% of populations mainly from developing countries are suffering from one or the other micronutrient malnutrition. Ensuring adequate supply of these micronutrients through diet consisting of staple foods, such as common bean (Phaseolus vulgaris L.) is must. Here, we evaluated common bean genotypes that were collected from various regions of Jammu and Kashmir, India for Fe, Zn and protein contents and used SSRs to identify the markers associated with these traits. We found significant variation among genotypes for Fe, Zn and protein contents. Genotype R2 was having 7.22 mg 100 g-1 of Fe content, genotype K15 with 1.93 mg 100 g-1 of Zn content and genotype KS6 with 31.6% of protein content. Diversity study was done using both cluster and structure based approach. Further, association mapping analysis using General Linear Method (GLM) approach was done to identify SSRs associated with accumulation of Fe, Zn and protein. 13 SSRs were identified that significantly (p < 0.05) showed association with Fe, Zn and protein contents in common bean. The markers associated with Fe were located on chromosome no. 2, 5, 6, 7, 9 and 10, markers associated with Zn were located on chromosome no. 1, 3, 5, 7 and 10 whereas only one marker located on chromosome no. 4 was found associated with protein content. These findings will provide potential opportunity to improve Fe and Zn concentrations in common bean, through molecular breeding. PMID- 28868223 TI - Enzymatic saccharification of seaweeds into fermentable sugars by xylanase from marine Bacillus sp. strain BT21. AB - Enzymatic hydrolysis of seaweed biomass was studied using xylanase produced from marine bacteria Bacillus sp. strain BT21 through solid-state fermentation of wheat bran. Three types of seaweeds, Ahnfeltia plicata, Padina tetrastromatica and Ulva lactuca, were selected as representatives of red, brown, and green seaweeds, respectively. Seaweed biomass was pretreated with hot water. The efficiency of pretreated biomass to release reducing sugar by the action of xylanase as well as the type of monosaccharide released during enzyme saccharification of seaweed biomass was studied. It was seen that pretreated biomass of seaweed A. plicata, U. lactuca, and P. tetrastroma, at 121 degrees C for 45 min, followed by incubation with 50 IU xylanase released reducing sugars of 233 +/- 5.3, 100 +/- 6.1 and 73.3 +/- 4.1 ug/mg of seaweed biomass, respectively. Gas chromatography analysis illustrated the release of xylose, glucose, and mannose during the treatment process. Hot water pre-treatment process enhanced enzymatic conversion of biomass into sugars. This study revealed the important role of xylanase in saccharification of seaweed, a promising feedstock for third-generation bioethanol production. PMID- 28868224 TI - Characterization of Acanthosicyos horridus and Citrullus lanatus seed oils: two melon seed oils from Namibia used in food and cosmetics applications. AB - The physicochemical characteristics, fatty acid, tocopherol, stigmasterol, beta sitosterol, and 1H NMR profiles of Citrullus lanatus and Acanthosicyos horridus melon seed oils were determined and compared among different extraction methods (cold pressing, traditional, and Soxhlet). The oil content was 40.2 +/- 3.45 and 37.8 +/- 7.26% for C. lanatus and A. horridus, respectively. Significant differences (p < 0.05) were observed among the different extraction methods in the characteristics studied. Physicochemical characteristics of the melon seed oils were saponification value, 180.48-189.86 mg KOH/g oil; iodine value, 108.27 118.62 g I2/100 g oil; acid value, 0.643-1.63 mg KOH/g oil; peroxide value; 1.69 2.98 mequiv/kg oil; specific gravity, 0.901-0.922; and refractive indices, 1.4676 1.4726. The dominant tocopherol was gamma-tocopherol with total tocopherol in the range 27.61-74.39 mg/100 g. The dominant fatty acid was linoleic acid in the range 52.57-56.96%. The favorable oil yield, physicochemical characteristics, tocopherol, and fatty acid composition have the potential to replace or improve major commercial vegetable oils and to be used for various applications in the food industry and nutritive medicines. PMID- 28868226 TI - Recurrent gastric ulcer and cholangitis caused by ectopic drainage of the bile duct into the stomach. AB - We report a case of recurrent gastritis with pyloric stenosis and cholangitis due to a rare variation in bile duct anatomy. A 72-year-old female patient showed recurrent gastral ulcers and biliary colic with cholangitis caused by gallstones in the main bile duct with an ectopic orifice in the prepyloric region and concurrent inflammatory pyloric stenosis. After temporarily successful endoscopic treatment with stenting and pyloric dilatation, the patient suffered from recurrent cholangitis. Finally, the abnormal biliary anatomy required surgical treatment with biliodigestive anastomosis. PMID- 28868225 TI - Pleomorphic rhabdomyosarcoma infiltrating thoracic spine in a 59-year-old female patient: Case report. AB - Rhabdomyosarcoma (RMS) represents a malignant tumor of skeletal muscle cells arising from rhabdomyoblasts. RMS represents the most common soft tissue sarcoma in children. In adults it is uncommon and accounts for less than 1% of all malignant solid tumors. While treatment protocols are well known for children, there is no standardized regimen in adults. This is one reason, why the outcome in adults is worse than in children. We present the case of a 59-year-old female patient with pleomorphic rhabdomyosarcoma (PRMS) infiltrating the thoracic spine. Multimodality treatment was performed including en-bloc resection, adjuvant multidrug chemotherapy and radiation beam therapy. The patient was tumor free and had no relapse within 6 month follow-up. PMID- 28868227 TI - A case of severe acute necrotizing pancreatitis in a 38-year-old woman postpartum due to a parathyroid adenoma. AB - Lethal necrotizing pancreatitis postpartum due to primary hyperparathyroidism caused by a parathyroid adenoma can be considered as a rarity. Due to the unspecific clinical signs and uncommonness this disorder may be overseen very easily. The reported case illustrates the very importance of early diagnosis of this endocrine disorder in pregnancy in order to avoid a lethal course. PMID- 28868228 TI - Large thoracic defect due to shotgun violation - surgical emergency management. AB - Shotgun injuries from a short distance (<3 m) may cause massive bleeding and tissue destruction. Only immediate aggressive (surgical) therapy prevents lethal outcome. We report about a 27-year-old patient, who was wounded on the left chest wall by a straight-cut shotgun from a short distance. In cases of this special traumatic pattern damage control measures are necessary. The measures should take place in preclinical emergency management (by the on-site emergency physician). We report about the emergency management from admission to our hospital and the following surgical treatment until discharge from the hospital. PMID- 28868229 TI - A Very Unlikely Finding in a Male Child: Urethral Prolapse. AB - Urethral prolapse is a disease of prepubertal black girls and postmenopausal women with an unknown cause. It may be congenital in origin or an acquired condition. It has never been reported in males. We report a 10-year-old Caucasian boy who presented because of recurrent right undescended testis. He had been operated on for bilateral undescended testes 7 years ago in another hospital, and circumcision was done during the same operation. The boy complained of a weak urinary stream during voiding. The physical examination was consistent with recurrent right undescended testis. Penile examination showed a circumferential urethral prolapse around the meatus. The urethral meatal appearance was apparent right after the circumcision. An orchiopexy operation as well as circumferential excision of the perimeatal urethral tissue with primary repair was done. The pathological examination of the specimen revealed keratinized stratified squamous epithelium consistent with urethral mucosa. The postoperative course was uneventful, and the patient urinates normally at the 8 postoperative month with a normal uroflowmetry study. This is the first report of urethral prolapse in a male. Because circumcision is a widely employed practice in many cultures, it is unlikely to be a predisposing factor. It is a benign condition that can be cured with simple resection and anastomosis. PMID- 28868230 TI - Sternal Fracture in Children: Diagnosis by Ultrasonography. AB - Because of its subcutaneous location, the sternum can be examined sonographically using a linear scanner. We report about two children who experienced blunt chest trauma. Anterior-posterior chest X-rays were normal. Ultrasonic imaging confirmed a fracture of the sternum with dorsal displacement of the distal fragment (by 0.97 cm) in the first child and a transverse fracture of the body of the sternum without displacement in the second child. In both children, pericardial effusion was excluded by sonography. The displaced fracture of the sternum was confirmed by magnetic resonance imaging (MRI), which ruled out concomitant injuries of the soft tissues adjacent to the sternum. Both sternum fractures were managed nonoperatively. These cases serve to emphasize the importance of sonography that represents an ionizing radiation free, noninvasive, efficient, and safe imaging modality to diagnose fractures of the sternum in children while also enabling the assessment of the pericardium. PMID- 28868231 TI - Laser Speckle Contrast Imaging to Evaluate Bowel Lesions in Neonates with NEC. AB - Background Necrotizing enterocolitis (NEC) is the most frequent surgical emergency in newborns. Intestinal ischemia is considered a factor that precedes the development of NEC lesions. Laser speckle contrast imaging (LSCI) can be used to assess tissue microcirculation. We evaluated if LSCI may help to detect intestinal regions with reduced microcirculation in NEC. Case Report A male patient (gestational age, 26 [3/7] weeks; birth weight, 600 g) showed clinical signs of NEC 28 days after birth. X-ray revealed pneumatosis intestinalis and portal gas. Laparotomy showed NEC lesions with signs of transmural ischemia in the terminal ileum and cecum. Surgical resection lines (RLs) were marked, followed by LSCI measurements and resection of the bowel between the two RLs. Post hoc LSCI analyses were conducted on both sides of the proximal and distal RL. Low-flux values, indicating reduced microcirculation, were found in the macroscopically assessed necrotic bowel at the proximal RL, whereas higher flux values, indicating sufficient microcirculation, were found in the macroscopically assessed normal bowel. Discussion This study is the first description of intra abdominal use of LSCI to evaluate tissue microcirculation in relation to NEC lesions. LSCI could be a valuable tool to distinguish between ischemic and nonischemic bowel in neonates undergoing surgery for NEC. PMID- 28868232 TI - Penile Reconstruction with Skin Grafts and Dermal Matrices: Indications and Management. AB - Introduction The penis eventually needs specific cutaneous coverage in the context of reconstructive procedures following trauma or congenital anomalies. Local flaps are the first choice but are not always available after multiple previous procedures. In these cases, skin graft and dermal matrices should be considered. Materials and Methods This study was a retrospective review of the past 4 years of four patients with severe loss of penile shaft skin who underwent skin reconstruction. Dermal matrices and skin grafts were utilized. Dermal matrices were placed for a median of 4.5 weeks (3.0-6.0 weeks). The skin graft was harvested from the inner thigh region for split-thickness skin graft (STSG) and the inguinal region for full-thickness skin graft (FTSG). Results The four patients presented with complete loss of skin in the penile shaft. One patient had a vesical exstrophy, one had a buried penis with only one corpus cavernosum, one had a wide congenital lymphedema of the genitalia, and one had a lack of skin following circumcision at home. They underwent reconstruction with three patients undergoing split-thickness skin graft; two dermal matrices; and one full thickness graft, respectively, thereby achieving a good cosmetic and functional result. There were no complications, and all the patients successfully accepted the graft. Conclusion Dermal matrices and skin grafts may serve as effective tools in the management of severe penile skin defects unable to be covered with local flaps. PMID- 28868233 TI - Intestinal Perforation during the Stabilization Period in a Preterm Infant with Congenital Diaphragmatic Hernia. AB - Background Delayed surgery after stabilization of infants with congenital diaphragmatic hernia (CDH) is an accepted strategy. However, the evidence favoring delayed versus immediate surgical repair is limited. We present an extremely rare case of a very low-birth-weight infant with prenatally diagnosed left-sided CDH and unexpected transmural bowel perforations developing within the postnatal stabilization period. Case Report A neonate born at 31st week of gestation with a birth weight of 1,470 g with antenatally diagnosed left-sided CDH presented with bowel dilation leading to transmural bowel perforations on the 2nd day of life. Meconium pleuroperitonitis resulted in severe systemic inflammatory response syndrome, pulmonary hypertension, multiple organ failure, and death. Conclusion In neonates with CDH deteriorating under standard postnatal management, intestinal perforation, and early surgical intervention should be considered. PMID- 28868234 TI - How gambling harms experienced by Pacific people in New Zealand amplify when they are culture-related. AB - Pacific people in New Zealand are a minority ethnic population identified in national prevalence studies as having the highest risk of developing gambling problems. As earlier studies identified some links between culture and gambling for this population, our study aimed to deepen understanding of these links and their role in explaining the disproportionate gambling harms experienced by Pacific people. To achieve this aim we employed intersectionality as a theoretical framework to explore the culture-gambling intersection for this population group. We analysed data from a subset of focus groups conducted for a broad study of gambling harms in New Zealand. The subset was selected based on the presence of individuals knowledgeable about Pacific people's gambling behaviours, including staff from Pacific problem gambling treatment services who provided examples from a cultural perspective. We identified themes at a latent level via an interpretive process to identify underlying cultural contexts of gambling harms. Findings indicated that whilst harms experienced by Pacific people were similar to those identified amongst the general population, the cultural contexts in which some harms manifested were complex. This paper contributes to the existing knowledge base about gambling harms for Pacific people in relation to six culture-gambling intersecting themes that emerged from the data: collectivism, gift-giving, gambling-based fundraising, patriarchy, beliefs about blessings, and sports celebrities. Findings are discussed in relation to the current knowledge of gambling and conceptualisations of gambling harm within Pacific communities. Implications for culturally appropriate harm minimisation strategies and prevention interventions for this population are suggested. PMID- 28868236 TI - Management Strategies and Outcomes for VHL-related Craniospinal Hemangioblastomas. AB - Hemangioblastomas are rare and benign tumors accounting for less than 2% of all central nervous system (CNS) tumors. The vast majority of hemangioblastomas occur sporadically, whereas a small number of cases, especially in younger patients, are associated with Von Hippel-Lindau (VHL) syndrome. It is thought that loss of tumor suppressor function of the VHL gene results in stabilization of hypoxia inducible factor alpha with downstream activation of cellular proliferative and angiogenic genes that promote tumorigenesis. VHL-related hemangioblastomas predominantly occur in the cerebellum and spine. Lesions are often diagnosed on contrast-enhanced craniospinal MRIs, and the diagnosis of VHL occurs through assessment for germline VHL mutations. Surgical resection remains the primary treatment modality for symptomatic or worrisome lesions, with excellent local control rates and neurological outcomes. Stereotactic radiotherapy can be employed in patients who are deemed high risk for surgery, have multiple lesions, or have non-resectable lesions. Given the tendency for development of either new or multiple lesions, close radiographic surveillance is often recommended for asymptomatic lesions. PMID- 28868235 TI - Design of Injectable Materials to Improve Stem Cell Transplantation. AB - Stem cell-based therapies are steadily gaining traction for regenerative medicine approaches to treating disease and injury throughout the body. While a significant body of work has shown success in preclinical studies, results often fail to translate in clinical settings. One potential cause is the massive transplanted cell death that occurs post injection, preventing functional integration with host tissue. Therefore, current research is focusing on developing injectable hydrogel materials to protect cells during delivery and to stimulate endogenous regeneration through interactions of transplanted cells and host tissue. This review explores the design of targeted injectable hydrogel systems for improving the therapeutic potential of stem cells across a variety of tissue engineering applications with a focus on hydrogel materials that have progressed to the stage of preclinical testing. PMID- 28868237 TI - Examining the relationship between burnout and empathy in healthcare professionals: A systematic review. AB - OBJECTIVE: Empathy and burnout are two related yet distinct constructs that are relevant to clinical healthcare staff. The nature of their relationship is uncertain and this review aimed to complete a rigorous, systematic exploration of the literature investigating the relationship between burnout and empathy in healthcare staff. DESIGN: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. DATA SOURCES: Search terms (Burnout OR Burn-out OR "Burn out") AND (Empathy OR Empath*) enabled identification of studies investigating burnout and empathy in healthcare staff, using five electronic data bases (MEDLINE, PsycINFO, CINAHL Plus, PubMed, and SCOPUS). Manual searching amongst reference lists of eligible articles was also completed. REVIEW METHODS: Databases were searched for studies published in the English language, from inception to February 2017. Key inclusion criteria were: 1) participants who were nurses or medical professionals, 2) full written manuscript in English, 3) use of the Maslach Burnout Inventory to assess burnout and a standardized outcome measure for empathy, 4) quantitative methodology exclusively. RESULTS: Ten eligible studies were reviewed. Of those, seven were conducted in countries where English was not the first language. Eight of the studies provided empirical support for a negative relationship between empathy and burnout. One study provided support for a positive relationship between burnout and empathy. One study reported contradictory evidence with positive and negative correlations between different subscales of the empathy and burnout measures. In general, the quality of the studies was assessed to be good. However, some of the studies failed to provide information pertaining to sample size, with the reporting of data less than adequate from one study. CONCLUSIONS: There was consistent evidence for a negative association between burnout and empathy. This review avoided a common English-speaking country bias of some areas of the literature. Given that all of the studies reviewed were cross sectional, further research is necessary to establish causality. PMID- 28868238 TI - MiR-9 Promotes Apoptosis Via Suppressing SMC1A Expression in GBM Cell Lines. AB - OBJECTIVE: Glioblastomas multiforme (GBM) is the most malignant brain cancer, which presented vast genomic variation with complicated pathologic mechanism. METHOD: MicroRNA is a delicate post-transcriptional tuner of gene expression in the organisms by targeting and regulating protein coding genes. MiR-9 was reported as a significant biomarker for GBM patient prognosis and a key factor in regulation of GBM cancer stem cells. To explore the effect of miR-9 on GBM cell growth, we over expressed miR-9 in U87 and U251 cells. The cell viability decreased and apoptosis increased after miR-9 overexpression in these cells. To identify the target of miR-9, we scanned miR-9 binding site in the 3'UTRs region of expression SMC1A (structural maintenance of chromosomes 1A) genes and designed a fluorescent reporter assay to measure miR-9 binding to this region. Our results revealed that miR-9 binds to the 3'sUTR region of SMC1A and down-regulated SMC1A expression. RESULT: Our results indicated that miR-9 was a potential therapeutic target for GBM through triggering apoptosis of cancer cells. PMID- 28868239 TI - Is the association between offspring intelligence and parents' educational attainment influenced by schizophrenia or mood disorder in parents? AB - Results from twin, family, and adoption studies all suggest that general intelligence is highly heritable. Several studies have shown lower premorbid intelligence in individuals before the onset of both mood disorders and psychosis, as well as in children and adolescents at genetic high risk for developing schizophrenia. Based on these findings, we aim to investigate if the association between educational achievement in parents and intelligence in their offspring is influenced by schizophrenia or mood disorder in parents. In a large population-based sample of young adult male conscripts (n = 156,531) the presence of a mental disorder in the parents were associated with significantly lower offspring scores on a test of general intelligence, the Borge Priens Prove (BPP), and higher educational attainment in parents was significantly associated with higher BPP test scores in offspring. A significant interaction suggested that the positive association between maternal education and offspring intelligence was stronger in offspring of mothers with schizophrenia compared to the control group (p = 0.03). The associations between parental education and offspring intelligence are also observed when restricting the sample to conscripts whose parents are diagnosed after 30 years of age. In conclusion, findings from this study show a more positive effect of education on offspring intelligence in mothers with schizophrenia compared to mothers from the control group. This effect could have both environmental and genetic explanations. PMID- 28868240 TI - JAK3-mediated phosphorylation of EZH2: a novel mechanism of non-canonical EZH2 activation and oncogenic function. PMID- 28868241 TI - Targeting cancer with tumor-specific therapeutic strategies-metabolic reprogramming beyond the Warburg effect. PMID- 28868243 TI - Highly active antiretroviral therapy dysregulates proliferation and differentiation of human pre-adipocytes. AB - AIM: To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome. METHODS: Preadipocytes from healthy donors were assessed for proliferation and differentiation in the presence of nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) individually and in combination. Effects on proliferation were assessed with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and effects on differentiation were assessed from glycerol-3-phosphate dehydrogenase (GP DH) activity and quantitation of Oil Red O staining for intracellular lipid. Data were analyzed with a randomized block ANOVA with post hoc Fisher's Least Significant Difference test. RESULTS: Preadipocyte proliferation was inhibited by a combination of NNRTI + NRTI (14% at 48 h, P < 0.001) and PI + NRTI (19% at 48 h, P < 0.001) with additional suppression when ritonavir (RTV) was added (26% at 48 h). The drug combination of atazanavir (ATV) + RTV + emtricitabine (FTC) + tenofovir (TDF) had the greatest inhibitory effect on proliferation at 48 h. Preadipocyte differentiation was most significantly reduced by the efavirenz + FTC + TDF assessed either by GPDH activity (64%) or lipid accumulation (39%), P < 0.001. Combining NRTIs with a PI (ATV + FTC + TDF) significantly suppressed differentiation (GPDH activity reduced 29%, lipid accumulation reduced by 19%, P < 0.01). This effect was slightly greater when a boosting amount of RTV was added (ATV + FTC + TDF + RTV, P < 0.001). CONCLUSION: Although combination antiretroviral therapy is clinically more efficacious than single drug regimens, it also has a much greater inhibitory effect on preadipocyte proliferation and differentiation. PMID- 28868242 TI - Additional attention to combination antiretroviral therapy-related lipodystrophy. AB - The occurrence of lipodystrophy in patients taking anti-human immunodeficiency virus (HIV) medications is a serious problem as it is irreversible even after drug withdrawal. Although it was first recognized in patients taking proteinase inhibitors, other types of anti-HIV agents can also cause lipodystrophy. In a recent publication by Jones et al entitled "Highly active antiretroviral therapy dysregulates proliferation and differentiation of human pre-adipocytes" in World Journal of Virology, it was reported that simultaneous treatment of human subcutaneous adipocytes with anti-HIV drugs with different mechanisms of action synergistically exerted anti-adipogenesis effects in vitro, warning us to take utmost care in every case receiving combination antiretroviral therapy (cART). For elucidation of the molecular basis for cART-related lipodystrophy, multi faceted approaches should be taken, based on a deeper understanding of the development and organization of adipose tissues. PMID- 28868244 TI - Poor Quality Embryos Hamper the Development of High Quality Ones. PMID- 28868245 TI - Isolation, Culture and Characterization of Human Sertoli Cells by Flow Cytometry: Development of Procedure. AB - BACKGROUND: The sertoli cells in the testis create unique and safe environment to protect seminiferous tubules from auto antigens and invading pathogens. These cells produce the survival factor of the blood-testis barrier and produce special materials such as androgen binding proteins and contribute to the coordinated action of spermatogenesis. Given that the sertoli cells play an essential role in spermatogenesis and the lack of these cells leads to the disruption of spermatogenesis, it is necessary to investigate the behavior and performance of these cells. To achieve this goal, the cells must first be extracted. The aim of this study was to develop a procedure to isolate, culture, and characterize human sertoli cells. METHODS: In order to isolate the sertoli cells of azoospermia patients who underwent (testicular sperm extraction) TESE surgery, washing up and multi_stage enzyme digestion of single cells, culture on petri dishes impregnated with datura stramonium lectin agglutinin (DSA) were done and then the cells were passaged for several times and isolated. For more purification, flow cytometry method with FSH receptor antibody was used. Immunocytochemistry assays and Elisa test for identification of these cells were employed. RESULTS: The purification method resulted in more than 97% purity. The nature of sertoli cells was confirmed by morphology evaluation, detecting anti-mullerian hormone in sertoli cell culture media and the presence of FSH receptor on sertoli cells. CONCLUSION: This study introduced and applied a method to isolate, culture, and purify human sertoli cells with high purity which made possible further researches on these cells. PMID- 28868246 TI - Antimicrobial Properties of Amniotic and Chorionic Membranes: A Comparative Study of Two Human Fetal Sacs. AB - BACKGROUND: There is evidence of antibacterial properties of human chorioamniotic layer. However, the distinctive contribution of its individual parts, amniotic and chorionic membranes, to these effects is still unknown. The aim of present study was comparison of the antibacterial effects between amniotic and chorionic membranes. METHODS: Chorioamniotic layer was removed from placenta belonging to 43 healthy mothers whose infants were delivered by caesarean section. Their amniotic and chorionic fetal tissues were manually peeled in sterile conditions. The antibacterial effects of all membrane samples were evaluated on 8 standard strains of bacterial collection using disk diffusion method on bacteriologic media. Results of bacterial growth inhibition in the presence of amniotic or chorionic membranes were measured and recorded as median+/-IQR. For data analysis and statistical comparison of samples, Kruskal-Wallis and Mann-Whitney U-test were applied using SPSS (v. 18). RESULTS: Amniotic and chorionic membranes significantly showed different level of growth inhibitory effects on 8 bacterial strains including seven pathogens: E. coli, Bacillus cereus, Klebsiella pneumonia, Streptococcus pyogenes, Pseudomonas aeruginosa, Staphylococcus aureus, Shigella flexneri and one probiotic: Lactobacillus plantarum (p=0.018 and p<0.001, respectively). The number of bacterial growth inhibition zones around chorionic membranes was more than of what found around amniotic membranes. CONCLUSION: The superiority of antibacterial effects of the chorionic membrane compared with the amniotic membrane can represent the key role of maternal part in placenta in protecting the fetus against possible infections. The antimicrobial effect of amniotic and chorionic membranes is significantly different on various bacteria. PMID- 28868247 TI - Vitrification Increased Vacuolization of Human Spematozoa: Application of MSOME Technology. AB - BACKGROUND: Sperm vitrification is a technique of ice and cryoprotectant free cryopreservation by direct plunging of sperm suspension into liquid nitrogen (LN2). The aim of this study was to investigate the influence of cryoprotectant free-vitrification on human sperm fine structure by MSOME technology and the fertility potential by zona binding assay (ZBA). METHODS: 20 normo-ejaculates were prepared by swim up technique, and supernatants were divided into two parts of fresh and vitrified groups. For vitrification, sperm was dropped into LN2. Sperm motility, morphology, viability and MSOME were evaluated for each sample. In MSOM morphologically normal sperm (class 1), <=2 small vacuoles (class 2), and one large vacuole or >2 small vacuoles (class 3) were evaluated. Also, fertility potential was evaluated by zona binding assay. Data was analyzed using paired t test or Willcoxon's test and p-value <0.05 was considered significant. RESULTS: Vitrification significantly reduced both progressive motility, viability and morphology. Also, normal morphology of spermatozoa decreased significantly after vitrification. In MSOME evaluation, normal motile spermatozoa (Class 1) decreased from 23.00+/-12.44 to 16.00.56+/-10.79 after vitrification (p=0.008). Although spermatozoa classes 2 and 3 were increased, the difference was not significant. Moreover, fertility potential of motile spermatozoa was reduced after vitrification (9.0+/-13.87 vs. 13.40+/-22.73; p=0.07). CONCLUSION: Vitrification increased the rate of vacuolization in motile sperm head. Therefore, MSOME technology is recommended for assessment of sperm fine morphology in ICSI program used cryopreserved spermatozoa. PMID- 28868248 TI - The Window of Implantation Is Closed by Estrogen via Insulin-Like Growth Factor 1 Pathway. AB - BACKGROUND: The opening and closing of the implantation window is important for successful pregnancy in eutherians. The recent study demonstrated that the window of uterine receptivity was prepared by the sole action of progesterone in mice, but the mechanism to close the window remained to be elucidated. METHODS: The pregnant mice were ovariectomized on the evening on the third day of pregnancy with a single injection of medroxyprogesterone acetate to induce delayed implantation (DI). Several treatments were applied to DI mice. The uterine receptivity after treatment was assessed by examining cell proliferation in the uterine luminal epithelium (LE). The gene expressions in the endometrium were investigated by RNA-seq. The p<0.05 was considered significant. RESULTS: Cell proliferation in the LE ceased only when the window of implantation was open. Estrogen (E2) stimulated cell proliferation in the LE rendered the uterus refractory. The high throughput gene expression analysis by RNA-Seq showed that the insulin-like growth factor 1 (IGF1) pathway was the candidate to close the implantation window under E2. In vivo administration of IGF1 to delayed implantation mice resulted in proliferation in the LE cells. CONCLUSION: This study demonstrated that the window of uterine receptivity was closed by E2, which was mediated by the IGF1 pathway. PMID- 28868249 TI - Should Subclinical Hypothyroidism Be an Exclusion Criterion for the Diagnosis of Polycystic Ovary Syndrome? AB - BACKGROUND: The purpose of the study was to examine whether patients with subclinical hypothyroidism (SCH) should be excluded before making a diagnosis of polycystic ovary syndrome (PCOS). METHODS: Seven hundred sixteen patients, 462 with true PCOS, 31 with PCOS-SCH, and 223 normal cycling women were enrolled. Clinical, metabolic, and hormonal parameters among the groups were investigated. Continuous variables were compared by one-way analysis of variance. Proportions were compared using Z test. Fisher test was used to compare categorical variables. Simple correlation was performed using Spearman's coefficient. Correlation between thyroid stimulating hormone (TSH) and dependent variables were performed using backward multiple regression. The significance level was set at 0.05. RESULTS: True polycystic ovary and polycystic ovary with subclinical hypothyroidism patients presented similar anthropometrical parameters. C-peptide was higher in polycystic ovary patients than in the other groups (p=0.014). Prevalence of glucose intolerance (p=0.186) and insulin resistance (p=0.293) was not statistically different in polycystic ovary and polycystic ovary with subclinical hypothyroidism. TSH levels showed positive correlation with lean body mass (p=0.032), total cholesterol (p=0.046, insulin (p=0.048) and prolactin (p=0.047). Backward multiple regression model retained TC, insulin, and PRL as predictors of TSH levels (p=0.011). CONCLUSION: Anthropometric parameters and ovary morphology were similar in both PCOS and PCOS-with-SCH patients. Regarding hormones, only C-peptide was higher in PCOS group. TSH correlated with total cholesterol, insulin, and prolactin. Before PCOS diagnosis, the exclusion criterion thyroid dysfunction should be standardized and subclinical hypothyroidism should not exclude a diagnosis of PCOS. PMID- 28868251 TI - Maternal and Fetal Tuberous Sclerosis: Do We Know Enough as an Obstetrician? AB - BACKGROUND: Tuberous sclerosis, also known as tuberous sclerosis complex (TSC), is a rare genetic condition that mainly causes hamartomas to develop in different parts of the body. TSC, an autosomal dominant trait with variable penetrance, can adversely affect maternal and fetal outcome. CASE PRESENTATION: In this paper, a case of maternal and fetal tuberous sclerosis having fetal cardiac rhabdomyoma detected in utero at 26 weeks was reported who subsequently had fetal demise at 31 weeks. CONCLUSION: Tuberous sclerosis is a rare genetic condition that mainly causes development of hamartomas. In tuberous sclerosis, a cardiac rhabdomyoma is the only sign that can be detected prenatally. In maternal tuberous sclerosis, fetal ECHO is advisable after 24 weeks. A pregnancy complicated by maternal or fetal tuberous sclerosis deserves careful observation and the fetus should undergo prenatal fetal Doppler echocardiography and if possible magnetic resonance imaging for evaluation of other fetal structures including brain and renal parenchyma, so that parents can be counseled regarding its future prognostic implications. Tuberous sclerosis can lead to poor fetal outcome including intrauterine fetal death; hence regular antenatal follow up is required. Genetic counseling is recommended for couples who have a family history of tuberous sclerosis and who want to have children. Prenatal diagnosis is available for families with a known gene mutation or history of this condition. PMID- 28868250 TI - The Relationship Between Uterine Artery two-dimensional Color Doppler Measurement and Pregnancy Outcome: A Prospective Observational Study. AB - BACKGROUND: The purpose of the study was to evaluate the role of uterine blood flow parameters measured by uterine artery two-dimensional (2D)-power color doppler (PCD) ultrasound in predicting fertility outcomes in women undergoing IVF ET cycles. METHODS: In this prospective observational study, a total of 188 infertile women who underwent IVF-ET cycles were investigated. Uterine artery 2D PD measurements were taken during early follicular phase and on day of trigger. Pulsatility Index (PI), Resistant Index (RI), Peak Systolic Velocity (PSV), and Systolic/Diastolic ratio (S/D) were measured. Statistical correlation was sought between the doppler parameters and fertility outcomes. RESULTS: The pregnancy rate was 40.43% (76/188). The women who conceived (n= 76) (Group A) were found to have mean age of 31.2+/-3.9 years whereas the non-pregnant group of women (n=112) (Group B) had mean age of 31.45+/-4.25 years. The mean PI measurements subsequently during early follicular phase and on the day of hCG trigger between group A and group B were comparable (2.09+/-1.15 versus 1.9+/-0.95; p=0.385 and 1.86+/-1.12 versus 2.03+/-1.0; p=0.192, respectively). No significant changes in the uterine artery PSV values and S/D values and RI were noted during the cycle. CONCLUSION: Uterine artery doppler evaluation in women undergoing IVF cycles was not predictive of the pregnancy outcomes. PMID- 28868252 TI - The Importance of Fertility Preservation Counseling in Patients with Gynecologic Cancer. PMID- 28868253 TI - Relationships between Regional Radiation Doses and Cognitive Decline in Children Treated with Cranio-Spinal Irradiation for Posterior Fossa Tumors. AB - Pediatric posterior fossa tumor (PFT) survivors who have been treated with cranial radiation therapy often suffer from cognitive impairments that might relate to IQ decline. Radiotherapy (RT) distinctly affects brain regions involved in different cognitive functions. However, the relative contribution of regional irradiation to the different cognitive impairments still remains unclear. We investigated the relationships between the changes in different cognitive scores and radiation dose distribution in 30 children treated for a PFT. Our exploratory analysis was based on a principal component analysis (PCA) and an ordinary least square regression approach. The use of a PCA was an innovative way to cluster correlated irradiated regions due to similar radiation therapy protocols across patients. Our results suggest an association between working memory decline and a high dose (equivalent uniform dose, EUD) delivered to the orbitofrontal regions, whereas the decline of processing speed seemed more related to EUD in the temporal lobes and posterior fossa. To identify regional effects of RT on cognitive functions may help to propose a rehabilitation program adapted to the risk of cognitive impairment. PMID- 28868255 TI - Resection of Gliomas with and without Neuropsychological Support during Awake Craniotomy-Effects on Surgery and Clinical Outcome. AB - BACKGROUND: During awake craniotomy for tumor resection, a neuropsychologist (NP) is regarded as a highly valuable partner for neurosurgeons. However, some centers do not routinely involve an NP, and data to support the high influence of the NP on the perioperative course of patients are mostly lacking. OBJECTIVE: The aim of this study was to investigate whether there is a difference in clinical outcomes between patients who underwent awake craniotomy with and without the attendance of an NP. METHODS: Our analysis included 61 patients, all operated on for resection of a presumably language-eloquent glioma during an awake procedure. Of these 61 cases, 47 surgeries were done with neuropsychological support (NP group), whereas 14 surgeries were performed without an NP (non-NP group) due to a language barrier between the NP and the patient. For these patients, neuropsychological assessment was provided by a bilingual resident. RESULTS: Both groups were highly comparable regarding age, gender, preoperative language function, and tumor grades (glioma WHO grades 1-4). Gross total resection (GTR) was achieved more frequently in the NP group (NP vs. non-NP: 61.7 vs. 28.6%, P = 0.04), which also had shorter durations of surgery (NP vs. non-NP: 240.7 +/- 45.7 vs. 286.6 +/- 54.8 min, P < 0.01). Furthermore, the rate of unexpected tumor residuals (estimation of the intraoperative extent of resection vs. postoperative imaging) was lower in the NP group (NP vs. non-NP: 19.1 vs. 42.9%, P = 0.09), but no difference was observed in terms of permanent surgery-related language deterioration (NP vs. non-NP: 6.4 vs. 14.3%, P = 0.48). CONCLUSION: We need professional neuropsychological evaluation during awake craniotomies for removal of presumably language-eloquent gliomas. Although these procedures are routinely carried out with an NP, this is one of the first studies to provide data supporting the NP's crucial role. Despite the small group size, our study shows statistically significant results, with higher rates of GTR and shorter durations of surgery among patients of the NP group. Moreover, our data emphasize the common problem of language barriers between the surgical and neuropsychological team and patients requiring awake tumor resection. PMID- 28868256 TI - Multiparametric MRI and [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging Is a Potential Prognostic Imaging Biomarker in Recurrent Glioblastoma. AB - PURPOSE/OBJECTIVES: Multiparametric advanced MR and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging may be important biomarkers for prognosis as well for distinguishing recurrent glioblastoma multiforme (GBM) from treatment-related changes. METHODS/MATERIALS: We retrospectively evaluated 30 patients treated with chemoradiation for GBM and underwent advanced MR and FDG PET for confirmation of tumor progression. Multiparametric MRI and FDG-PET imaging metrics were evaluated for their association with 6-month overall (OS) and progression-free survival (PFS) based on pathological, radiographic, and clinical criteria. RESULTS: 17 males and 13 females were treated between 2001 and 2014, and later underwent FDG-PET at suspected recurrence. Baseline FDG-PET and MRI imaging was obtained at a median of 7.5 months [interquartile range (IQR) 3.7 12.4] following completion of chemoradiation. Median follow-up after FDG-PET imaging was 10 months (IQR 7.2-13.0). Receiver-operator characteristic curve analysis identified that lesions characterized by a ratio of the SUVmax to the normal contralateral brain (SUVmax/NB index) >1.5 and mean apparent diffusion coefficient (ADC) value of <=1,400 * 10-6 mm2/s correlated with worse 6-month OS and PFS. We defined three patient groups that predicted the probability of tumor progression: SUVmax/NB index >1.5 and ADC <=1,400 * 10-6 mm2/s defined high-risk patients (n = 7), SUVmax/NB index <=1.5 and ADC >1,400 * 10-6 mm2/s defined low risk patients (n = 11), and intermediate-risk (n = 12) defined the remainder of the patients. Median OS following the time of the FDG-PET scan for the low, intermediate, and high-risk groups were 23.5, 10.5, and 3.8 months (p < 0.01). Median PFS were 10.0, 4.4, and 1.9 months (p = 0.03). Rates of progression at 6 months in the low, intermediate, and high-risk groups were 36, 67, and 86% (p = 0.04). CONCLUSION: Recurrent GBM in the molecular era is associated with highly variable outcomes. Multiparametric MR and FDG-PET biomarkers may provide a clinically relevant, non-invasive and cost-effective method of predicting prognosis and improving clinical decision making in the treatment of patients with suspected tumor recurrence. PMID- 28868257 TI - Serum miRNAs as Biomarkers for the Diagnosis and Prognosis of Thyroid Cancer: A Comprehensive Review of the Literature. AB - BACKGROUND/OBJECTIVES: Thyroid cancer is the most common endocrine malignancy and accounts for 1% of cancers. In recent years, there has been much interest in the feasibility of using miRNAs or miRNA panels as biomarkers for the diagnosis of thyroid cancer. miRNAs are noncoding RNAs with 21-23 nucleotides that are highly conserved during evolution. They have been proposed as regulators of gene expression, apoptosis, cancer, and cell growth and differentiation. METHODS: The Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO), and Web of Science were searched. RESULTS: The serum level of miRNAs (miRNA-375, 34a, 145b, 221, 222, 155, Let-7, 181b) can be used as molecular markers for the diagnosis and prognosis of thyroid cancer in the serum samples of patients with thyroid glands. CONCLUSIONS: Given that most common methods for the screening of thyroid cancer cannot detect the disease in its early stages, identifying miRNAs that are released in the bloodstream during the gradual progression of the disease is considered a key method in the early diagnosis of thyroid cancers. PMID- 28868254 TI - Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate. AB - The tight cross talk between two essential organelles of the cell, the endoplasmic reticulum (ER) and mitochondria, is spatially and functionally regulated by specific microdomains known as the mitochondria-associated membranes (MAMs). MAMs are hot spots of Ca2+ transfer between the ER and mitochondria, and emerging data indicate their vital role in the regulation of fundamental physiological processes, chief among them mitochondria bioenergetics, proteostasis, cell death, and autophagy. Moreover, and perhaps not surprisingly, it has become clear that signaling events regulated at the ER-mitochondria intersection regulate key processes in oncogenesis and in the response of cancer cells to therapeutics. ER-mitochondria appositions have been shown to dynamically recruit oncogenes and tumor suppressors, modulating their activity and protein complex formation, adapt the bioenergetic demand of cancer cells and to regulate cell death pathways and redox signaling in cancer cells. In this review, we discuss some emerging players of the ER-mitochondria contact sites in mammalian cells, the key processes they regulate and recent evidence highlighting the role of MAMs in shaping cell-autonomous and non-autonomous signals that regulate cancer growth. PMID- 28868258 TI - Thyroid Autoimmunity and Thyroid Cancer: Review Focused on Cytological Studies. AB - The association between Hashimoto thyroiditis (HT) and papillary thyroid carcinoma (PTC) has been originally suggested by retrospective pathological studies and has recently been re-evaluated and proposed on the basis of several fine-needle aspiration cytology (FNAC) studies. In FNAC studies, the association between HT and PTC is based on the comparison of anti-thyroid autoantibodies (ATA) (anti-thyroperoxidase [TPOAb] and anti-thyroglobulin [TgAb]), thyroid function (TSH), and cytology with histology of thyroid nodules and lymphocytic thyroid infiltration (LTI) of operated thyroid glands. Most of the pathological studies found a high prevalence rate of PTC in HT. In most FNAC studies, the risk ratio of PTC in HT patients was evaluated using multivariate statistical analysis: increased TSH levels represented the main and common independent risk factor of malignancy, although it resulted not consistently related to HT. On the other hand, several studies provided a positive relationship between ATA and PTC, particularly with TgAb. Two recent FNAC studies from the same referral center clearly demonstrated an independent risk for thyroid malignancy conferred by both TPOAb and TgAb, confirming the role of increased TSH levels, and found a significant association between PTC and ATA and diffuse LTI at histology. These studies are consistent with the hypothesis that autoimmune thyroid inflammation and increased serum TSH concentration may be involved in thyroid tumor growth. The complex relationship between HT and PTC, which involves immunological/hormonal pathogenic links, needs to be further investigated with prospective studies. PMID- 28868260 TI - TPOAb and Thyroid Function Are Not Associated with Breast Cancer Outcome: Evidence from a Large-Scale Study Using Data from the Taxotere as Adjuvant Chemotherapy Trial (TACT, CRUK01/001). AB - BACKGROUND: Small-scale studies correlated the presence of thyroid autoimmunity with both improved or worsened breast cancer outcome. OBJECTIVES: We aimed to clarify this association in a large cohort using the phase III, randomized, controlled Taxotere as Adjuvant Chemotherapy Trial (TACT, CRUK01/001). METHODS: TACT women >18 years old with node-positive or high-risk node-negative early breast cancer (pT1-3a, pN0-1, M0), with stored plasma (n = 1,974), taken 15.5 (median; IQR 7.0-24.0) months after breast surgery were studied. Patients had also received chemotherapy (100%), radiotherapy (1,745/1,974; 88.4%), hormonal therapy (1,378/ 1,974; 69.8%), or trastuzumab (48/1,974; 2.4%). History of thyroid diseases and/or related treatments was not available. The prognostic significance of autoantibodies to thyroid peroxidase (TPOAb; positive >=6 kIU/L), free-thyroxine and thyrotropin (combined: euthyroid, hypothyroid, hyperthyroid) was evaluated for disease-free survival (DFS), overall-survival (OS), and time-to recurrence (TTR), with Cox regression models in univariate and multivariable analyses. The extended median follow-up was 97.5 months. RESULTS: No difference in DFS was found by TPOAb status (unadjusted hazard ratio [HR]: 0.97, 95%CI: 0.78 1.19; p = 0.75) and/or thyroid function (unadjusted HR [hypothyroid vs. euthyroid]: 1.15, 95% CI: 0.79-1.68; p = 0.46; unadjusted HR [hyperthyroid vs. euthyroid]: 1.14, 95% CI: 0.82-1.61; p = 0.44). Similar results were obtained for OS, TTR, multivariable analyses, when TPOAb titre by tertiles was considered, and in a subgroup of 123 patients with plasma collected before adjuvant treatments. CONCLUSIONS: No evidence for a prognostic role of TPOAb and/or thyroid function in moderate-to-high-risk early breast cancer was found in the largest and longest observational study to date. PMID- 28868259 TI - Radioiodine Ablation following Thyroidectomy for Differentiated Thyroid Cancer: Literature Review of Utility, Dose, and Toxicity. AB - Management recommendations for differentiated thyroid cancer are evolving. Total thyroidectomy is the backbone of curative-intent therapy, with radioiodine ablation (RAI) of the thyroid remnant routinely performed, in order to facilitate serologic surveillance and reduce recurrence risk. Several single-institution series have identified patient subsets for whom recurrence risk is sufficiently low that RAI may not be indicated. Further, the appropriate dose of RAI specific to variable clinicopathologic presentations remains poorly defined. While recent randomized trials demonstrated equivalent thyroid remnant ablation rates between low- and high-dose RAI, long-term oncologic endpoints remain unreported. While RAI may be employed to facilitate surveillance following total thyroidectomy, cancer recurrence risk reduction is not demonstrated in favorable-risk patients with tumor size <=1 cm without high-risk pathologic features. When RAI is indicated, in patients without macroscopic residual disease or metastasis, the evidence suggests that the rate of successful remnant ablation following total thyroidectomy is equivalent between doses of 30-50 mCi and doses >=100 mCi, with fewer acute side effects; however, in the setting of subtotal thyroidectomy or when preablation diagnostic scan uptake is >2%, higher doses are associated with improved ablation rates. Historical series demonstrate conflicting findings of long-term cancer control rates between dose levels; long-term results from modern series have yet to be reported. For high-risk patients, including those with positive surgical margins, gross extrathyroidal extension, lymph node involvement, subtotal thyroidectomy, or >5% uptake, higher-dose RAI therapy appears to provide superior rates of ablation and cancer control. PMID- 28868261 TI - Nonalcoholic Fatty Liver Disease Is Not Associated with Thyroid Hormone Levels and Hypothyroidism: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Whether hypothyroidism is related to nonalcoholic fatty liver disease (NAFLD) is unclear. Thyroid dysfunction is closely related with components of metabolic syndrome. Given the hepatic manifestation of metabolic syndrome, several studies have investigated the association between NAFLD and thyroid dysfunction and have demonstrated inconsistent results. Thus, we conducted a systematic review and meta-analysis to better characterize the association between NAFLD and thyroid dysfunction. METHODS: MEDLINE and Embase were searched through July 2016. The primary outcome was the association between NAFLD and subclinical, overt, and overall hypothyroidism. The secondary outcome was the difference in thyroid hormone levels (free triiodothyronine [FT3], free thyroxine [FT4], or thyroid-stimulating hormone [TSH]) between NAFLD patients and non-NAFLD controls. Pooled odds ratios (OR) and 95% CI were calculated using a random effects model. All continuous data are summarized as the mean difference along with 95% CI. RESULTS: Data were extracted from 14 studies involving 7,191 NAFLD patients and 30,003 controls. NAFLD was not associated with subclinical, overt, or overall hypothyroidism compared with non-NAFLD controls. Patients who had NAFLD did not show a significant difference in FT3, FT4, or TSH compared with non NAFLD controls. CONCLUSIONS: Our meta-analysis demonstrates no significant association between NAFLD and subclinical, overt, or overall hypothyroidism, and we also found no significant difference in thyroid hormone levels between participants with and without NAFLD. PMID- 28868262 TI - A Cervical Schwannoma Masquerading as a Thyroid Nodule. AB - BACKGROUND: We present a case of a cervical schwannoma, likely originating from the pharyngeal plexus of the vagal nerve. The lesion masqueraded as a thyroid nodule and magnetic resonance imaging (MRI) assisted in preoperative diagnosis. We review the radiographic characteristics of nerve sheath tumors on MRI as well as the diagnostic cytologic stains which can enhance the possibility of a correct preoperative diagnosis. CASE: We describe a 60-year-old female with dysphagia and a neck mass consistent with a nodular goiter. The patient's history, diagnostic images, cytology, pathology, and surgical management are presented and analyzed. The preoperative diagnosis of a cervical schwannoma was suspected by the use of MRI which led to additional specialized cytologic stains. CONCLUSION: Pharyngeal wall schwannomas are important to consider in the differential diagnosis of thyroid nodules when fine needle aspiration cytology indicates cells of neural origin. Imaging by MRI can assist in identifying lesions of neural origin masquerading as thyroid nodules. PMID- 28868263 TI - Next Generation Sequencing and Association Studies in Familial Nonmedullary Thyroid Carcinoma: Let's Choose Appropriate Controls. PMID- 28868264 TI - The Role of Long Non Coding RNAs in the Repair of DNA Double Strand Breaks. AB - DNA double strand breaks (DSBs) are abrasions caused in both strands of the DNA duplex following exposure to both exogenous and endogenous conditions. Such abrasions have deleterious effect in cells leading to genome rearrangements and cell death. A number of repair systems including homologous recombination (HR) and non-homologous end-joining (NHEJ) have been evolved to minimize the fatal effects of these lesions in cell. The role of protein coding genes in regulation of these pathways has been assessed previously. However, a number of recent studies have focused on evaluation of non-coding RNAs participation in DNA repair. We performed a computerized search of the Medline/ Pubmed databases with key words: DNA repair, homologous recombination, non-homologues end joining and long non-coding RNA (LncRNA). The existing data highlight the role of long non coding RNAs in DSB repair as well as dysregulation in their expression which would lead to pathological conditions such as cancer. The specific mechanism of their contribution in DNA repair pathways has been elucidated for a few of them. LncRNAs participate in several steps of DNA repair pathways and regulate the expression of key components of these pathways including p53 tumor suppressor gene. PMID- 28868265 TI - MeDIP Real-Time qPCR has the Potential for Noninvasive Prenatal Screening of Fetal Trisomy 21. AB - This study aimed to verify the reliability of the 7 tissue differentially methylated regions used in the methylated DNA immunoprecipitation (MeDIP) real- time quantitative polymerase chain reaction (real-time qPCR) based approach of fetal DNA in maternal blood to diagnosis of fetal trisomy 21. Forty pregnant women with high risk pregnancy who were referred after first or second trimester screening tests, were selected randomly. For each sample whole DNA extraction (mother and fetus), fragmentation of DNA, immunoprecipitation of methylated DNA and real- time qPCR using 7 primer pairs was performed. D-value for each sample was calculated using the following formula D = -4.908+ 0.254 XEP1+ 0.409 XEP4+ 0.793 XEP5+ 0.324 XEP6+ 0.505 XEP7+ 0.508 XEP9+ 0.691 XEP12. In all normal cases, D value was negative, while it was positive in all trisomy cases. Therefore, all normal and trisomy 21 cases were classified correctly which correspond to 100% specificity and 100% sensitivity for this method. The MeDIP real-time qPCR method has provided the opportunity for noninvasive prenatal diagnosis of fetal trisomy 21 to be potentially employed into the routine practice of diagnostic laboratories. PMID- 28868266 TI - Evaluation of Placental mir-155-5p and Long Non-coding RNA sONE Expression in Patients with Severe Pre-eclampsia. AB - It has been well documented that preeclampsia (PE) has a common etiological background, but little is known about its linkage at the molecular level.Non- coding RNAs are critical posttranscriptional regulators ofgene expression. This study was performed to determine whether PE is associated with alterations in placental non-coding RNAs expression. MicroRNA (miR)-155-5p and long non-coding RNA (lnc)sONE expression, in placentas collected sequentially from 59 patients with PE and 40 normotensive pregnancies were measured using real-time PCR.The relationship between miR-155-5p and lncsONE expressions was analyzed statistically. miR-155-5p expression was increased (fold change =1.6, P=0.04), while lncsONE expression was not significantly changed (fold change =1.1, P=0.68), in placentas from patients compared with control group.miR-155-5p was upregulated in placentas from patients with PE and may have influenced eNOS expression. These findings indicate that miRNA-155-5p may be involved in PE pathogenesis and could be a potential biomarker for this disease. PMID- 28868267 TI - Analysis of Two CDKN2B-AS Polymorphisms in Relation to Coronary Artery Disease Patients in North of Iran. AB - Coronary artery disease (CAD) including myocardial infarction (MI) as its complication, is one of the most common heart diseases worldwide and also in Iran, with extremely elevated mortality. CAD is a multifactorial disorder. Twin and family studies at different loci have demonstrated that genetic factors have an important role in the progression of CAD. Many studies have reported a significant association of CDKN2B-AS, also known as ANRIL which is located within the p15, p16, p14 gene cluster at 9p21 locus, with cardiovascular diseases as well as many other diseases like diabetes and cancers. This study investigated two polymorphisms rs10757274 and rs1333042 of CDKN2B-AS gene at 9p21 locus. 205 subjects, comprising 102 controls and 103 CAD patients were genotyped by TaqMan probe real time PCR technique and haplotypes were examined. This study confirmed the association of rs10757274 variants with CAD in Iranian patients (P= 0.003) but genotype and allele distributions of CAD and control groups showed no significant association for the rs1333042. However, frequency of the [G;G] haplotype of these two SNPs was significantly higher in CAD group (P= 0.0002, Odds Ratio = 3.1, 95% CI = 1.7-5.7). Our finding suggests that [G; G] haplotype of rs10757274 and rs1333042 may be considered as a genetic risk factor for susceptibility to CAD in Iranian patients. PMID- 28868268 TI - Effect of Concentrated Apple Extract on Experimental Colitis Induced by Acetic Acid. AB - Reactive oxygen and nitrogen species (ROS/RNS) play a crucial role in inflammatory bowel disease (IBD) exacerbating the chronic inflammatory process. Endogenous and diet antioxidants can neutralize these compounds. The apple is widely consumed, with several antioxidant activity compounds. The present study evaluated the effects of concentrated apple extract (CAE) in acetic acid induced colitis. 29 Wistar male rats were randomized into 5 groups. G1-Sham/saline solution, G2-CAE/control, G3-acetic acid/control, G4-curative- CAE treatment and G5-preventive-CAE treatment. Eight days later, the animals were euthanized and the colonic segment resected for macroscopic and histological analysis. Gene expression was evaluated for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), catalase and copper and zinc superoxide dismutase (CuZnSOD) by quantitative real time PCR, while protein expression was assessed for iNOS, COX-2 and 8-hydroxy-20-deoxyguanosine (8-OHdG) via immunohistochemistry. The groups G3, G4 and G5 had weight loss, while G5 had weight increase at the end of the experiment. The treatment with CAE reduced the macroscopic and microscopic injury, decreased iNOS mRNA expression and increased CuZnSOD mRNA expression in animals with induced acetic acid-colitis. The findings of the present study suggest that CAE treatment exerts an antioxidant role by downregulating iNOS and upregulating CuZnSOD. PMID- 28868269 TI - Determination of Bacteriocin Genes and Antibacterial Activity of Lactobacillus Strains Isolated from Fecal of Healthy Individuals. AB - Lactobacillus species play a major role in gastrointestinal (GI) tract function, intestinal microbiota balance, and the immune system activity by exerting a strong activity against many intestinal pathogens. The aim of this study was to isolate Lactobacillus species from fecal samples, investigate their antimicrobial properties, and characterize their bacteriocin encoding genes. 48 fecal samples were grown in MRS broth and then MRS agar. The colonies grown in MRS agar were selected and identified by PCR. 72 Lactobacillus species were obtained from 434 lactic acid bacteria (LAB) strains. Approximately 40% of all Lactobacillus isolates had antimicrobial activity against one or more microorganisms and 17.4% of them were active against all four indicator bacteria. The frequency of bacteriocin encoding genes were 5 (6.9%), 3 (4.1%) and 5 (6.9%) for Gassericin A, Plantaricin S and Laf operon, respectively. pH alteration had no effect on antibacterial activity, but in the alkaline range these activities were reduced and the strains showed the highest antibacterial activity after 48 h incubation. These data indicate that the majority of isolates were susceptible to GI tract or belonged to other bacterial forms such as viable but nonculturable (VBNC). The detection of bacteriocin encoding genes in about only 6% of all Lactobacillus isolates seems to be due to the existence of many other bacteriocin encoding genes in Lactobacillus species which were not tested. Further study of the bacteriocin gene clusters, types, subtypes and the probiotic effect of these strains will contribute to a better characterization of these isolates. PMID- 28868270 TI - Torque Teno Virus (TTV) Among beta-Thalassemia and Haemodialysis Patients in Mazandaran Province (North of Iran). AB - Torque Teno virus (TTV) is a transfusion transmitted virus that seems to be involved in several complications such as acute respiratory diseases, liver diseases, AIDS, cancer, and autoimmune reactions. In the present study the frequency of TTV was investigated among beta- thalassemia (BT) and haemodialysis (HD) patients (high risk patients for TTV) in Mazandaran province, Iran. DNA was extracted from the serum of 82 BT and 100 HD patients, and nested PCR method was applied to detect TTV DNA. The aspartate transaminase(AST) and alanine transaminase (ALT) enzyme levels in BT patients were measured using photometric assay. The mean age of BT and HD patients as 23.4+/-5.4 and 48.8+/-8.2 years, respectively. 21% of HD and 26.8% of BT patients were infected with TTV, respectively. The frequency of TTV was not significantly different between two groups of patients and there was no significant correlation between sex and TTV infection. The mean AST and ALT levels in TTV positive BT patients was not significantly higher than TTV negative cases. The present study showed that TTV prevalence in BT patients with recurrent blood transfusion was not significantly higher than HD patients. The investigation of TTV prevalence in healthy individuals is recommended to identify if transfusion or dialysis is associated with higher TTV infection. Besides, although TTV infection did not change the AST and ALT enzymes in BT patients, the liver involvement may still exist in these patients. PMID- 28868271 TI - Prenatal Diagnosis of Mosaic Tetrasomy 18p in a Case without Sonographic Abnormalities. AB - Small supernumerary marker chromosomes (sSMC) are still a major problem in clinical cytogenetics as they cannot be identified or characterized unambiguously by conventional cytogenetics alone. On the other hand, and perhaps more importantly in prenatal settings, there is a challenging situation for counseling how to predict the risk for an abnormal phenotype, especially in cases with a de novo sSMC. Here we report on the prenatal diagnosis of a mosaic tetrasomy 18p due to presence of an sSMC in a fetus without abnormal sonographic signs. For a 26 year-old, gravida 2 (para 1) amniocentesis was done due to consanguineous marriage and concern for Down syndrome, based on borderline risk assessment. Parental karyotypes were normal, indicating a de novo chromosome aberration of the fetus. FISH analysis as well as molecular karyotyping identified the sSMC as an i(18)(pter->q10:q10->pter), compatible with tetrasomy for the mentioned region. Cordocentesis was done due to normal sonography and the results from amniocentesis were confirmed. The parents opted for pregnancy termination and post mortem examination now noted, low anterior hairline, large philtrum, low-set posteriorly rotated malformed ears with prominent antihelix, lower limbs joint contracture and digital anomalies, including long and narrow toes with clinodactyly of the 1st and 5th toes and postaxial polydactyly of one hand. De novo i(18p) can be considered as a special case in the sense that the major relevant phenotypes mentioned for it, i.e. feeding difficulties, abnormalities in muscle tone and developmental/mental retardation, cognitive and behavioral characteristics, recurrent otitis media and seizures, are mostly postnatal. This emphasizes the necessity to determine the nature of a de novo euchromatic marker chromosome, especially in cases with normal ultrasound result and the suitability of a cordocentesis in order to better predicting the pregnancy outcome and parental counseling. PMID- 28868272 TI - Readiness for Radiological and Nuclear Events among Emergency Medical Personnel. AB - BACKGROUND: Among medical providers, even though radiological and nuclear events are recognized as credible threats, there is a lack of knowledge and fear about the medical consequences among medical personnel which could significantly affect the treatment of patients injured and/or contaminated in such scenarios. This study was conducted to evaluate the relative knowledge, willingness to respond, and familiarity with nuclear/radiological contamination risks among U.S. and Japanese emergency medical personnel. METHODS: An institutional review board approved anonymous paper survey was distributed at various medical and disaster conferences and medicine courses in Japan and in the U.S. The surveys were written in Japanese and English and collected information on the following four categories: generalized demographics, willingness to manage, knowledge of disaster systems, and contamination risks. RESULTS: A total of 418 surveys were completed and collected. Demographics showed that physicians and prehospital responders were the prevalent survey responders. The majority of responders, despite self-professed disaster training, were still very uncomfortable with and unaware how to respond to a radiological/nuclear event. CONCLUSION: Despite some educational coverage in courses and a limited number of disaster events, it is concluded that there is a lack of comfort and knowledge regarding nuclear and radiological events among the medical community. It is recommended that considerable development and subsequent distribution is needed to better educate and prepare the medical community for inevitable upcoming radiological/nuclear events. PMID- 28868273 TI - Obesity, Underweight, and Smoking Are Associated with Worse Cardiorespiratory Fitness in Finnish Healthy Young Men: A Population-Based Study. AB - BACKGROUND: Obesity and smoking are strongly associated with worse cardiorespiratory fitness (CRF). Most previous studies that have examined the association of body composition with CRF have neither assessed non-linearity nor separately examined the effects of underweight. Thus, very little is known on how underweight affects CRF. Possible joint effects of obesity and smoking on CRF have not been adequately explored. AIMS: We examined the association between body mass index (BMI) and smoking with CRF in 1,629 Finnish army conscripts. We focused on non-linear effects of BMI in order to assess the importance of underweight. We also examined whether the cooccurrence of obesity and smoking potentiates their deleterious effects on CRF. METHODS: We used the Cooper's 12 minute run test (12MR) to measure CRF. The 12MR score was analyzed as continuous (linear, polynomial, and restricted cubic spline regression) and categorical. In categorical analyses, we used binary logistic regression with the 12MR score in two groups (low = lowest quintile vs. intermediate/high = quintiles 2-5) and multinomial logistic regression with the 12MR score in three groups (low = lowest quintile, intermediate = quintiles 2 and 3, and high = quintiles 4 and 5). RESULTS: Non-linearity in the spline model was statistically significant (p < 0.001). In addition, the non-linear models had a clearly better fit than the linear one in terms of Akaike Information Criterion and R-squared values. There was a statistically significant interaction between smoking and BMI (p < 0.01). In the categorical analysis, overweight/obese regular smokers were at a particularly high risk of not achieving high CRF. CONCLUSION: In healthy young men, not only overweight/obesity but also underweight may be associated with worse CRF. This provides a potential mechanism for the previously reported association between underweight and increased mortality. The cooccurrence of overweight/obesity and regular smoking may have a deleterious effect on CRF. PMID- 28868274 TI - Advancing Physical Therapy Practice through Curriculum Revision: The Malawi Experience. AB - Challenged health systems are a motivation for health education reform. Although resources-limited areas cover our planet, sub-Saharan Africa has the highest disease burden, yet the lowest health-care provider and medical school density of any region in the world. Malawi is among the most under-resourced countries in the world. While much of the data focus on dental, medical, and psychiatric service provision, physical therapists are also in short supply. Among the barriers to achieving the recommended standards for physical therapist education, African physiotherapists (the term for "physical therapists" in Africa) identify limited training opportunities, limited research education, and limited resources and funding. The purpose of this article is to describe an international partnership for strengthening the Malawian physiotherapist workforce capacity through curriculum revision in the Department of Physiotherapy at the University of Malawi's College of Medicine. PMID- 28868275 TI - Recurrent Orbital Solitary Fibrous Tumor in a 12-Year-Old. AB - PURPOSE: To report the clinical features and pathology of orbital solitary fibrous tumors and present a case of a recurrence in a 12-year-old boy. METHODS: Case Report. RESULTS: A 12-year-old boy presented to our institution with double vision in upgaze for 6 months. Examination revealed 3 mm of left-sided proptosis, hypoglobus, and -3 impairment of supraduction. Magnetic resonance imaging of the orbits showed an avidly enhancing mass within the superolateral aspect of the orbit. Biopsy revealed a solitary fibrous tumor with STAT6 and CD34 positivity. Positron emission tomography-computed tomography was negative for metastatic disease. The tumor underwent excision. However, 4 months postoperatively, imaging revealed changes consistent with recurrence. A repeat lateral orbitotomy with orbital rim marginotomy was performed with complete gross excision of the tumor. The patient remains tumor-free 22 months after reoperation. CONCLUSION: Orbital solitary fibrous tumor rarely occurs in the pediatric population. Despite initial complete gross tumor excision, this case represents the youngest individual with a recurrence to the authors' knowledge. This case of rapid recurrence may have been due to tumor seeding at the time of initial biopsy or other factors. This case increases the known spectrum of orbital solitary fibrous tumors. PMID- 28868276 TI - Uveal Melanoma Regression after Brachytherapy: Relationship with Chromosome 3 Monosomy Status. AB - AIM: The objective was to evaluate the relationship between the regression rate of ciliary body melanoma and choroidal melanoma after brachytherapy and chromosome 3 monosomy status. METHODS: We conducted a prospective and consecutive case series of patients who underwent biopsy and brachytherapy for ciliary/choroidal melanoma. Tumor biopsy performed at the time of radiation plaque placement was analyzed with fluorescence in situ hybridization to determine the percentage of tumor cells with chromosome 3 monosomy. The regression rate was calculated as the percent change in tumor height at months 3, 6, and 12. The relationship between regression rate and tumor location, initial tumor height, and chromosome 3 monosomy (percentage) was assessed by univariate linear regression (R version 3.1.0). RESULTS: Of the 75 patients included in the study, 8 had ciliary body melanoma, and 67 were choroidal melanomas. The mean tumor height at the time of diagnosis was 5.2 mm (range: 1.90-13.00). The percentage composition of chromosome 3 monosomy ranged from 0-20% (n = 35) to 81 100% (n = 40). The regression of tumor height at months 3, 6, and 12 did not statistically correlate with tumor location (ciliary or choroidal), initial tumor height, or chromosome 3 monosomy (percentage). CONCLUSION: The regression rate of choroidal melanoma following brachytherapy did not correlate with chromosome 3 monosomy status. PMID- 28868277 TI - Extramedullary Relapse of Acute Myelogenous Leukemia Presenting as a Large Serous Retinal Detachment. AB - BACKGROUND/AIMS: To describe the rare presentation of a large, unilateral, serous retinal detachment as an extramedullary manifestation of acute myelogenous leukemia (AML) recurrence without bone marrow or central nervous system involvement after more than 1 year of follow-up. METHODS: Case report. RESULTS: A teenage patient with AML, previously treated with multiple courses of systemic chemotherapy, radiation, and bone marrow transplant, presented with acute vision loss. Ophthalmic workup revealed a large, unilateral, bullous, serous retinal detachment. Ultimately, he underwent subretinal fluid biopsy, which was found to be positive for leukemic blast cells. Cytologic markers matched his initial bone marrow biopsy, and therefore were diagnostic of extramedullary AML relapse. CONCLUSIONS: Leukemia can cause various ophthalmic manifestations. Autopsy studies suggest that choroidal infiltration is relatively common, but clinical progression to serous retinal detachment is quite uncommon. Furthermore, serous retinal detachment is generally shallow, posterior, and much more often reported in acute lymphocytic leukemia. The ophthalmologist plays a critical role in identifying leukemic ocular involvement. This case demonstrates the potential for ocular biopsy to secure the diagnosis of extramedullary relapse in order to initiate prompt treatment and systemic workup. PMID- 28868278 TI - Conjunctival Melanoma during Pregnancy. AB - PURPOSE: To describe the clinical and histopathological features of a conjunctival melanoma (CM) during early pregnancy. PROCEDURES: A 37-year-old, 20 week pregnant primigravida was referred to the Sheffield Ocular Oncology Service with a rapidly growing lesion arising from the right superior conjunctival fornix, noted from the first trimester of pregnancy. This was associated with pain and bloody discharge. Incisional biopsy confirmed the clinical suspicion of invasive CM. She was treated by primary surgical excision and cryotherapy under local anaesthesia. RESULTS: Histology of the excised specimen showed an invasive malignant melanoma with surrounding in situ conjunctival changes arising from a naevus. The melanoma was 10.5 mm thick, focally necrotic, and had a mitotic count of 11/mm2 focally. The patient responded well to surgical treatment. She gave birth to a healthy boy, and the placenta showed no evidence of metastatic melanoma. There has been no recurrence or distant metastasis during 5 years of follow-up. CONCLUSION: CM during pregnancy is extremely rare. Because of possible transformation to malignant melanoma, we recommend close monitoring of females known to have pigmented conjunctival lesions of the conjunctiva during pregnancy. PMID- 28868279 TI - Dural Arteriovenous Fistula Presenting with Purely Contralateral Ophthalmic Manifestations. AB - PURPOSE: To report a case of dural arteriovenous fistula presenting with purely contralateral ophthalmic manifestations. DESIGN: Interventional case report. RESULTS: A 70-year-old male presenting with right-sided proptosis, injection, and choroidal effusions with a completely quiet fellow eye was found to have a left sided dural arteriovenous fistula. After recognition on cerebral angiography, successful endovascular embolization was achieved, along with complete resolution of the contralateral ocular signs. CONCLUSIONS: Entirely unilateral ocular signs suggestive of an intracranial arteriovenous fistula may herald the presence of a contralateral vascular lesion. PMID- 28868280 TI - Optic Disc Pyogenic Granuloma. AB - AIM: The aim of this paper was to report a rare presentation of adenoid cystic carcinoma. METHOD: This is a case report presenting clinical, radiographic, and histopathologic findings. RESULTS: A 72-year-old female with no reported ocular symptoms was found to have an incidental right orbital mass on imaging. Additional studies revealed multiple liver lesions, which were biopsied and found to be consistent with adenoid cystic carcinoma. She was then referred to the ophthalmology service, where ocular examination demonstrated 2.5 mm of right proptosis with elevation and abduction deficits. Diplopia could be elicited in extreme upgaze and right lateral gaze. An excisional biopsy of the orbital mass was performed, with histopathology confirming the diagnosis of primary adenoid cystic carcinoma of the lacrimal gland, thereby also supporting the initial suspicion that the hepatic adenoid cystic carcinoma lesions represented metastases. CONCLUSION: The authors describe a rare presentation of adenoid cystic carcinoma of the lacrimal gland, initially asymptomatic, with metastatic lesions restricted to the liver at the time of diagnosis. Three previous cases of adenoid cystic carcinoma with isolated metastatic hepatic lesions at the time of diagnosis have been reported; all of these cases localized the primary tumor to the salivary glands. PMID- 28868281 TI - Multiple Pigmented Conjunctival Lesions following Intravitreal Injections in a Patient with Uveal Melanoma. AB - PURPOSE: This paper reports a case of pigmented conjunctival lesions after intravitreal injections in a patient who received brachytherapy for uveal melanoma. METHODS: Clinical and histopathological examination of the pigmented conjunctival lesions was performed. RESULTS: A 57-year-old male who was treated with brachytherapy for uveal melanoma developed radiation retinopathy. Following intravitreal anti-vascular endothelial growth factor (VEGF) injections, 2 pigmented conjunctival spots appeared at the injection sites. After excision of the lesions, histopathology showed pigment-loaded macrophages, with no signs of active tumour cells. CONCLUSION: Two conjunctival lesions that appeared following uveal melanoma brachytherapy and anti-VEGF injections were excised under suspicion of tumour seeding. Histopathology, however, showed aggregates of pigment-loaded macrophages. PMID- 28868282 TI - Growth of Uveal Melanoma following Intravitreal Bevacizumab. AB - PURPOSE: Typically treatment of large melanomas (by Collaborative Ocular Melanoma Study criteria) is restricted to enucleation, due to size constraints for plaque brachytherapy. Because primary and metastatic uveal melanoma cells are inhibited by bevacizumab (an anti-vascular endothelial growth factor), this prospective study evaluated the impact of intravitreal bevacizumab on large uveal melanomas that were destined for enucleation. Size reduction by bevacizumab would potentially salvage these eyes by making them eligible for treatment with plaque brachytherapy. PROCEDURES: Two patients with large uveal melanoma were each treated with one intravitreous injection of bevacizumab (1.25 mg/0.05 mL). RESULTS: Both tumors displayed paradoxical growth 1 week following the injection, with confirmed growth 1 week later (increase from baseline of 1.1 mm in one eye and 3.1 mm in the other eye). Both eyes were enucleated and monosomy 3 and vasculogenic mimicry patterns were identified in both tumors. At 9 years follow up, both patients were alive and metastasis free. CONCLUSION: These patients demonstrate that neoadjuvant intravitreous bevacizumab does not decrease the size of large uveal melanomas and may, in fact, result in their paradoxical growth. This observation supports a cautious approach in the use of intravitreous bevacizumab for uveal melanoma, particularly in the neoadjuvant setting. PMID- 28868283 TI - Uveal Ganglioneuroma due to Germline PTEN Mutation (Cowden Syndrome) Presenting as Unilateral Infantile Glaucoma. AB - PURPOSE: Uveal ganglioneuroma is a rare tumor that usually occurs in association with neurofibromatosis type 1. Here, we present a rare case of a uveal ganglioneuroma leading to a diagnosis of the tumor predisposition condition Cowden syndrome. PROCEDURES: A 5-year-old girl with unilateral refractory glaucoma secondary to diffuse iris and choroidal thickening developed a blind, painful eye. Enucleation was performed, and histopathology revealed infiltration of the entire uveal tract by neoplastic spindle cells containing admixed ganglion cells diagnostic of uveal ganglioneuroma. Targeted next-generation sequencing of 510 cancer-associated genes was performed on tumor tissue and peripheral blood. RESULTS: A germline nonsense mutation in the PTEN gene was found, accompanied by loss of heterozygosity in the tumor. A diagnosis of Cowden syndrome was made, for which the family sought genetic counseling and initiated the recommended cancer screening. CONCLUSIONS: A novel association is found between uveal ganglioneuroma and Cowden syndrome, emphasizing the value of genetic tissue testing in managing patients with rare ocular tumors. PMID- 28868284 TI - Eye Salvage with Combination of Intravitreal and Intracameral Melphalan Injection for Recurrent Retinoblastoma with Anterior Chamber Involvement: Report of a Case. AB - AIMS: Herein we report successful eye salvage following combined intravitreal and intracameral administration of melphalan for anterior chamber recurrence of retinoblastoma. METHODS: A 12-month-old boy was referred with a sporadic bilateral retinoblastoma staged as group D and V in the right eye and group E and V in the left eye. Treatment initially involved 6 cycles of 3 drugs followed by focal treatments. The left eye was enucleated. Three months after the end of systemic chemotherapy, multiple recurrent lesions were noted in the ciliary body and the anterior chamber. A series of intravitreal (IVT) and intracameral (IC) injections of melphalan combined with a 7th cycle of systemic chemotherapy was performed. The therapeutic schedule alternated: week A an IVT of melphalan (30 MUg/0.1 mL) for a total of 4 versus week B IC injections of melphalan (15 MUg/0.05 mL) 4 IC in total. Each injection was preceded by an anterior chamber. Cryotherapy to the injection punctures was systematically performed. RESULTS: Rapidly, iris and ciliary body nodules regressed completely based on clinical and ultrasound biomicroscopic examinations. After 3 years of follow-up, the patient has shown no evidence of recurrence. CONCLUSION: In our patient, combined IVT and IC administration of melphalan proved highly efficacious in eradicating the ciliary body and anterior chamber disease and salvage of his one remaining functional eye. PMID- 28868286 TI - Clinical and Spectral-Domain Optical Coherence Tomography Appearance of Optic Disc Melanocytoma: A New Classification and Differentiation from Pigmented Choroidal Lesions. AB - AIMS: The aim of this paper was to compare the features of both the classic, darkly pigmented and the atypical, more lightly pigmented optic disc melanocytoma with those of pigmented choroidal lesions. METHODS: We analyzed the spectral domain optical coherence tomography (SD-OCT) features of 9 eyes with optic disc melanocytoma and compared them with those of choroidal melanoma and nevus. RESULTS AND CONCLUSION: We identified 2 categories of SD-OCT findings in optic disc melanocytoma: (a) type 1, the typical, prominent, hyperpigmented lesion with SD-OCT findings of a hyperreflective, disorganized overlying retina and a posterior hyporeflective shadow, and (b) the less common, atypical, minimally pigmented type 2 lesion overlaid by a relatively well-organized retina that lacks a posterior hyporeflective shadow. Choroidal lesions were characterized by tumor confined beneath the clearly visible hyperreflective line of the photoreceptor and retinal pigment epithelium, with minimal disorganization of the overlying retina. PMID- 28868285 TI - Systemic BRAF/MEK Inhibitors as a Potential Treatment Option in Metastatic Conjunctival Melanoma. AB - AIM: In this review, we outline similarities between conjunctival and skin melanoma as well as the effectiveness of combined BRAF/MEK inhibition in melanoma, and discuss the applicability of these agents in conjunctival melanoma. METHODS: The study provides a PubMed literature review. RESULTS: Conjunctival melanoma and skin melanoma are genetically and phenotypically related. Both tumors typically harbor BRAF mutations in more than 50% of cases. New targeted therapies in metastatic skin melanoma include selective inhibition of BRAF and MEK. Combined BRAF/MEK inhibition has revolutionized the treatment of metastatic skin melanoma, significantly improving patients' prognoses. While these new substances have been investigated extensively in the treatment of skin melanoma, comparable studies in conjunctival melanoma do not exist owing to the rarity of the malignancy. CONCLUSIONS: The application of combined BRAF/MEK inhibition in metastatic or unresectable conjunctival melanoma shows great potential for improving patients' prognoses. Future studies are needed to investigate the assumed benefit. PMID- 28868287 TI - Intracameral Chemotherapy (Melphalan) for Aqueous Seeding in Retinoblastoma: Bicameral Injection Technique and Related Toxicity in a Pilot Case Study. AB - BACKGROUND: The anterior chamber has been shown by pharmacokinetic studies to represent a sanctuary never achieving a tumoricidal dose with the present administration routes, such as systemic, intra-arterial, or intravitreal injections. METHOD: A novel intracameral chemotherapy technique is described to control aqueous seeding in a pilot unilateral group E retinoblastoma case with primary aqueous seeding. Anterior segment toxicity was carefully monitored. RESULTS: Control of the retinal tumor and vitreous seeding was achieved by intra arterial and intravitreal chemotherapies. Sterilization of the aqueous was achieved after a first cycle of 7 melphalan injections in the anterior chamber, but relapse was noted 3.5 months later. This relapse was finally controlled with a second cycle of 6 intracameral injections targeting the posterior chamber. Corneal endothelial cell density remained stable over the injection period. Heterochromia and a progressive cataract developed, which required cataract surgery. At 5 years' follow-up, the patient is tumor free with normal vision (20/20 in both eyes), full binocularity, and no metastasis. CONCLUSIONS: The present bicameral injection technique appears to be safe and effective with limited toxicity. Melphalan-induced side effects were noted on the iris and lens but with no impact on the final visual function. PMID- 28868288 TI - Uveal Melanoma with Histopathologic Intratumoral Heterogeneity Associated with Gene Expression Profile Discordance. AB - PURPOSE: To report a case of intratumoral gene expression profile discordance in a malignant uveal melanoma, associated with intratumoral heterogeneity based upon histopathologic features. METHODS: The clinical history, fundus findings, imaging and histopathologic features, and DecisionDx-UM gene expression profile results (Castle Biosciences, Inc., Phoenix, AZ, USA) of the tumor were reviewed. RESULTS: A trans-retinal fine-needle aspiration biopsy was performed for a thin, pigmented choroidal tumor in a 33-year-old man. Cells obtained from this biopsy were tested using the DecisionDx-UM gene expression profile test and the tumor was classified as class 1A. Cytology confirmed melanoma. The patient subsequently elected to undergo enucleation. On microscopic examination of the globe, the tumor was composed primarily of spindle B cells, but had a focal area composed of epithelioid cells. This portion of the tumor was subsequently tested and demonstrated a class 1B gene expression profile. CONCLUSION: Intratumoral discordance in gene expression profile results has been described in uveal melanomas. Here we demonstrate that this discordance may be associated in some cases with intratumoral heterogeneity based upon histopathologic features. PMID- 28868289 TI - Pathophysiological Mechanisms in Sclerosing Skin Diseases. AB - Sclerosing skin diseases represent a large number of distinct disease entities, which include systemic sclerosis, localized scleroderma, and scleredema adultorum. These pathologies have a common clinical appearance and share histological features. However, the specific interplay between cytokines and growth factors, which activate different mesenchymal cell populations and production of different extracellular matrix components, determines the biomechanical properties of the skin and the clinical features of each disease. A better understanding of the mechanisms underlying these events is prerequisite for developing novel targeted therapeutic approaches. PMID- 28868290 TI - Coffee with High but Not Low Caffeine Content Augments Fluid and Electrolyte Excretion at Rest. AB - BACKGROUND: Low levels of caffeine ingestion do not induce dehydration at rest, while it is not clear if larger doses do have an acute diuretic effect. The aim of the present investigation was to examine the acute effect of low and high levels of caffeine, via coffee, on fluid balance in habitual coffee drinkers (at least one per day) at rest. METHODS: Ten healthy adults (eight males and two females; age: 27 +/- 5 years, weight: 89.5 +/- 14.8 kg, height: 1.75 +/- 0.08 m, and body mass index: 29.1 +/- 4.4 kg m-2) ingested 200 mL of water (W), coffee with low caffeine (3 mg kg-1, LCAF), or coffee with high caffeine (6 mg kg-1, HCAF) on three respective separate occasions. All sessions were performed at 09:00 in the morning in a counterbalanced, crossover manner, at least 5 days apart. Subjects remained in the laboratory while urine samples were collected every 60 min for 3 h post ingestion. RESULTS: Absolute caffeine consumption was 269 +/- 45 and 537 +/- 89 mg for the LCAF and HCAF, respectively. Coffee ingestion at the HCAF trial induced greater diuresis during the 3-h period (613 +/- 101 mL, P < 0.05), when compared to W (356 +/- 53 mL) and LCAF (316 +/- 38 mL). In addition, cumulative urinary osmotic excretion was significantly greater in the HCAF (425 +/- 92 mmol, P < 0.05), as compared to the W (249 +/- 36 mmol) and LCAF (177 +/- 16 mmol) trials. CONCLUSION: The data indicate that caffeine intake of 6 mg kg-1 in the form of coffee can induce an acute diuretic effect, while 3 mg kg-1 do not disturb fluid balance in healthy casual coffee drinking adults at rest. PMID- 28868291 TI - Rare Renal Diseases Can Be Used as Tools to Investigate Common Kidney Disorders. AB - BACKGROUND: The prevention and slowing of chronic kidney disease still represent major challenges in nephrology. To this end, a major contribution may come from the extensive knowledge on the molecular pathways involved in the pathogenesis of rare kidney diseases, since it is now possible to shed light on several aspects of these pathologies thanks to the introduction of new technologies, including next-generation sequencing. SUMMARY: In steroid-resistant nephrotic patients, a genetic background has been demonstrated in both children and adults; individualized mutations have been correlated with glomerular filtration barrier alterations. In addition, studies on genetic tubulopathies expressing hypertensive phenotypes can provide useful information for a correct diagnostic and therapeutic approach in patients with essential hypertension and a poor responsiveness to therapy. KEY MESSAGE: This review deals with the pathogenesis of rare glomerular diseases and tubulopathies associated with hypertension, highlighting the importance of the study of rare diseases to better understand the molecular basis of more common and complex disorders leading to end-stage renal disease. PMID- 28868292 TI - Hereditary Podocytopathies in Adults: The Next Generation. AB - Idiopathic nephrotic syndrome may have two underlying mechanisms: either (1) an alteration of the immune system resulting in the production of a putative circulating factor of glomerular permeability; or (2) mutations in the structural genes of the glomerular filtration barrier in which case patients are typically multidrug resistant and do not recur after transplantation. The latter forms have been recently recognized as "hereditary podocytopathies." In the past few years, positional cloning approaches that allow the identification of gene mutations underlying diseases whose pathophysiology is unknown and animal models have helped decipher the pathophysiological mechanisms of the glomerular filtration process. Recently, the advent of next-generation sequencing (NGS) techniques has greatly facilitated the identification of numerous novel causative genes in hereditary podocytopathies. Moreover, it has revealed mutations in unexpected genes and has widened the phenotypes associated with podocyte gene mutations. The list of genes mutated in hereditary podocytopathies is constantly evolving and consists to date of more than 40 genes. However, the most recently identified genes are extremely rarely mutated and may concern only a couple of families worldwide. These discoveries provided crucial insight into the pathophysiological mechanisms linking podocyte proteins to kidney function. This review will focus on monogenic podocytopathies affecting adult patients. PMID- 28868293 TI - The Kidney in Bardet-Biedl Syndrome: Possible Pathogenesis of Urine Concentrating Defect. AB - BACKGROUND: The ciliopathies are a growing number of disorders caused by mutations in genes involved in the function of the primary cilium. Bardet-Biedl syndrome (BBS) belongs to this group of disorders. In this setting, kidney dysfunction is highly variable, and urine concentrating defect, a common feature of multiple ciliopathies, has been described as the most frequent defect. Here we review the mechanism of urine concentration and describe the possible mechanism underling this defect in ciliopathies and especially BBS, based on the current body of literature. SUMMARY: Active Na+ absorption along the thick ascending limb of the loop of Henle (TAL) is critical for generating the corticomedullary osmotic gradient, and the countercurrent anatomical arrangement of the 2 branches of the loop of Henle enhances this gradient. The vasa recta, paralleling the loop of Henle, operate into the countercurrent mechanism, minimizing washout of solutes from the interstitium. Final water reabsorption is mediated by the aquaporin 2 (AQP2) water channels along the distal nephron, and it is under hormonal control. Several studies demonstrated that hyposthenuria in BBS patients relies on kidney resistance to desmopressin, suggesting a renal origin. We recently showed that the majority of hyposthenuric BBS patients have also a defect regarding maximal urine dilution. Independent studies showed that BBS10 deficiency caused AQP2 mistrafficking in vitro; accordingly, we demonstrated impaired urinary AQP2 excretion in BBS patients with combined concentrating and diluting defect. Whether receptor signaling pathways or downstream events cause AQP2 deregulation is still unclear. In addition, reduced urinary uromodulin excretion in BBS patients opens the possibility that TAL dysfunction may also play a pathogenic role. KEY MESSAGE: Impaired water handling in BBS is associated with AQP2 mistrafficking. The potential role of additional factors, such as the dissipation of the medullary osmotic gradient due to TAL dysfunction and/or structural anomalies, remains to be elucidated. PMID- 28868294 TI - Integration of Proteomics and Metabolomics in Exploring Genetic and Rare Metabolic Diseases. AB - BACKGROUND: Inherited metabolic disorders or inborn errors of metabolism are caused by deficiency of enzymatic activities in the catabolism of amino acids, carbohydrates, or lipids. These disorders include aminoacidopathies, urea cycle defects, organic acidemias, defects of oxidation of fatty acids, and lysosomal storage diseases. Inborn errors of metabolism constitute a significant proportion of genetic diseases, particularly in children; however, they are individually rare. Clinical phenotypes are very variable, some of them remain asymptomatic, others manifest metabolic decompensation in neonatal age, and others encompass mental retardation at later age. The clinical manifestation of these disorders can involve different organs and/or systems. Some disorders are easily managed if promptly diagnosed and treated, whereas in other cases neither diet, vitamin therapy, nor transplantation appears to prevent multi-organ impairment. SUMMARY: Here, we discuss the principal challenges of metabolomics and proteomics in inherited metabolic disorders. We review the recent developments in mass spectrometry-based proteomic and metabolomic strategies. Mass spectrometry has become the most widely used platform in proteomics and metabolomics because of its ability to analyze a wide range of molecules, its optimal dynamic range, and great sensitivity. The fast measurement of a broad spectrum of metabolites in various body fluids, also collected in small samples like dried blood spots, have been facilitated by the use of mass spectrometry-based techniques. These approaches have enabled the timely diagnosis of inherited metabolic disorders, thereby facilitating early therapeutic intervention. Due to its analytical features, proteomics is suited for the basic investigation of inborn errors of metabolism. Modern approaches enable detailed functional characterization of the pathogenic biochemical processes, as achieved by quantification of proteins and identification of their regulatory chemical modifications. KEY MESSAGE: Mass spectrometry-based "omics" approaches most frequently used to study the molecular mechanisms underlying inherited metabolic disorders pathophysiology are described. PMID- 28868295 TI - Urinary Mitochondrial DNA Level as a Biomarker of Acute Kidney Injury Severity. AB - BACKGROUND: Mitochondrial dysfunction contributes to the pathogenesis of acute kidney injury (AKI). The urinary mitochondrial DNA (mtDNA) level was previously shown to predict renal function recovery in AKI following cardiac surgery. Herein, we determine whether urinary mtDNA is a marker of severity and predictor of recovery in AKI due to other etiologies. METHODS: We recruited 107 AKI patients. The urinary mtDNA level was measured, the severity of AKI was quantified, and patients were followed for 90 days. RESULTS: The urinary mtDNA level had modest but statistically significant correlations with the peak serum creatinine level (Spearman's r = -0.248, p = 0.010) and the duration of hospital stay (r = -0.217, p = 0.025). Patients who required temporary dialysis also tended to have higher urinary mtDNA levels than those without dialysis (22.6 +/- 4.5 vs. 24.9 +/- 5.7 cycles, p = 0.06). There was no definite relation between the urinary mtDNA level and renal function recovery. CONCLUSION: The urinary mtDNA level is a marker of AKI severity, as reflected by its significant correlation with the peak serum creatinine level, duration of hospital stay, and probably the need for temporary dialysis. Our result suggests that urinary mtDNA has the potential to serve as a biomarker of AKI. PMID- 28868296 TI - Hemodialysis Arteriovenous Access Occlusion Using the Amplatzer Vascular Plug in Patients with Intractable Arm Edema. AB - OBJECTIVES: Vascular occlusion of hemodialysis arteriovenous access (AVA) using an Amplatzer vascular plug (AVP; St. Jude Medical, St. Paul, MN, USA) is an arising and alternative practice in selected patients; however, few reported cases can be found in the literature. Herein, we report on our experience with endovascular treatment of complicated AVA. MATERIALS AND METHODS: From September 2015 to December 2016, 3 patients at our clinic underwent an occlusion of hemodialysis AVA with 2 different Amplatzer vascular plugs: 2 patients with type II and 1 patient with type IV. Of these, 1 patient was treated for an autologous radiocephalic fistula, the second patient was treated for an autologous brachiocephalic fistula located at the elbow, and the third was, instead, treated for a radiocephalic forearm fistula. The reason for closing the AVA in all patients was due to the presence of dialysis-associated steal syndrome with critical hand ischemia and intractable ipsilateral edema. RESULTS: All AVAs were treated using an AVP. No plug migration, access revascularization, persistent ischemia, nor other complications were observed. CONCLUSION: This report suggests that the use of AVP for embolization of complicated AVA is a safe and reasonable alternative to open surgery in selected patients. PMID- 28868297 TI - A Toddler Presenting with Pulmonary Renal Syndrome. AB - Pulmonary renal syndrome refers to an association of pulmonary and glomerular disease and includes disorders, such as the ANCA-associated vasculitides, anti glomerular basement membrane antibody disease, systemic lupus erythematosus, and IgA vasculitis (Henoch-Schonlein purpura). We present the medical history of a 26 month-old boy with an extensive purpuric rash, involving the limbs, trunk, and face, who developed clinically significant pulmonary hemorrhage and renal involvement. Rapid recognition of this rare but potentially life-threatening condition is crucial. In this report, we discuss the differential diagnosis, diagnostic studies, and treatment options to consider when facing a young child presenting with a pulmonary renal syndrome. PMID- 28868298 TI - Case Report of Spontaneous Remission of Biopsy-Proven Idiopathic Immune Complex Mediated Membranoproliferative Glomerulonephritis. AB - Membranoproliferative glomerulonephritis (MPGN) is a histopathologic diagnosis causing microscopic hematuria, nephrotic range proteinuria, and chronic renal failure. Current understanding divides pathogenesis into two broad categories: immune complex mediated and complement mediated (now termed C3 glomerulopathy). The term idiopathic immune complex-mediated MPGN would apply to a patient without an identifiable source of immune complex production and no evidence of C3 glomerulopathy. Presented is a patient with idiopathic immune complex mediated MPGN and her clinical course. The patient opted for conservative therapy with losartan, carvedilol, chlorthalidone, and atorvastatin. Nephrotic range proteinuria of 8.7 g per day resolved over 5 months, with improvement of serum from 3.3 to 1.2 mg/dL. Remission continues at follow-up 21 months after biopsy. For idiopathic immune complex-mediated MPGN, resorting to empiric immunosuppression therapy may not be the best option. As this patient demonstrates, a conservative approach of blood pressure control with anti-renin angiotensin agents, control of lipids, and watchful follow-up can be successful. PMID- 28868299 TI - Tubuloreticular Inclusions in the Absence of Systemic Lupus Erythematosus and HIV Infection: A Report of Three Pediatric Cases. AB - Tubuloreticular inclusions (TRIs) are subcellular structures located within the cisternae of endoplasmic reticulum. Formation of TRIs has been linked to the exposure of excess interferon (IFN), either from endogenous or exogenous sources. In renal disease, TRIs have been most commonly associated with systemic lupus erythematosus (SLE), and human immunodeficiency virus-associated nephropathy (HIVAN). Case reports of patients with renal biopsies showing TRIs without underlying SLE or HIV are infrequent in adults, and to our knowledge none have been reported in children. We report 3 pediatric cases in which the renal biopsy showed TRIs on electron microscopy without underlying SLE or HIV infection. The first patient presented at 2 years of age with nephrotic syndrome and renal failure. His renal biopsy revealed focal segmental glomerulosclerosis and TRIs. The second patient presented at 6 months of age with infantile nephrotic syndrome, and his renal biopsy revealed membranous glomerulopathy and TRIs. The last patient presented at 4 years of age with acute kidney injury of unclear etiology leading to chronic kidney disease. Her biopsy revealed acute and chronic tubulointerstitial nephritis with TRIs. Despite extensive evaluation in all 3 patients, including testing for HIV infection and SLE, we could not identify an underlying etiology to explain the presence of TRIs. In conclusion, renal biopsy with TRIs in the absence of underling SLE and HIV remains obscure. We propose a possible role for excess IFN triggered by an abnormal immune response to common viral infections in the formation of TRIs and renal injury. PMID- 28868300 TI - AA Amyloidosis and Atypical Familial Mediterranean Fever with Exon 2 and 3 Mutations. AB - A 54-year-old Japanese man presented with recurrent abdominal pain, fever lasting >5 days, and renal failure. AA amyloidosis was proven by renal and gastric biopsy. Symptoms subsided with the administration of colchicine, but a subsequent recurrence of symptoms did not respond to colchicine. Mediterranean fever gene (MEFV) analysis showed that he was heterozygous for mutations in exon 2 (E148Q/R202Q) and exon 3 (P369S/R408Q), although he had none of the exon 10 mutations known to be closely related to AA amyloidosis. He did not respond to infliximab, but tocilizumab therapy was successful. The present case is a rare report of AA amyloidosis associated with familial Mediterranean fever in Japan. PMID- 28868301 TI - Dynamic Lumbosacral Magnetic Resonance Imaging in a Dog with Tethered Cord Syndrome with a Tight Filum Terminale. AB - A 1-year and 11-month- old English Cocker Spaniel was evaluated for clinical signs of progressive right pelvic limb lameness and urinary incontinence. Neurological examination was suggestive of a lesion localized to the L4-S3 spinal cord segments. No abnormalities were seen on magnetic resonance imaging (MRI) performed in the dog in dorsal recumbency and the hips in a neutral position and the conus medullaris ended halfway the vertebral body of L7. An MRI of the hips in extended and flexed positions demonstrated minimal displacement of the conus medullaris in the cranial and caudal directions, respectively. Similar to the images in neutral position, the conus medullaris ended halfway the vertebral body of L7 in both the extended and flexed positions. In comparison, an MRI of the hips in neutral, extended, and flexed positions performed in another English Cocker Spaniel revealed obvious cranial displacement of the conus medullaris with the hips in extension and caudal displacement with hips in flexion. A standard dorsal lumbosacral laminectomy was performed. Visual inspection of the vertebral canal revealed excessive caudal traction on the conus medullaris. After sectioning the distal aspect of the filum terminale, the conus medullaris regained a more cranial position. A neurological examination 4 weeks after surgery revealed clinical improvement. Neurological examinations at 2, 4, 7, and 12 months after surgery did not reveal any abnormalities, and the dog was considered to be clinically normal. Tethered cord syndrome with a tight filum terminale is a very rare congenital anomaly and is characterized by an abnormally short and inelastic filum terminale. Therefore, this disorder is associated with abnormal caudal traction on the spinal cord and decreased physiological craniocaudal movements of the neural structures within the vertebral canal. Although further studies are necessary to evaluate and quantify physiological craniocaudal movement of the spinal cord and conus medullaris in neurologically normal dogs, the results of this report suggest further exploration of dynamic MRI to demonstrate decreased craniocaudal displacement of the conus medullaris in dogs with tethered cord syndrome with a tight filum terminale. PMID- 28868302 TI - Electrolyte Disturbances Are Associated with Non-Survival in Dogs-A Multivariable Analysis. AB - Electrolyte disorders have been individually associated with mortality in small populations of dogs and cats with specific conditions, but the associations and interactions between electrolyte disturbances and outcome have not been evaluated in a large, heterogeneous population. It was hypothesized that abnormalities of sodium, chloride, potassium, and calcium concentrations would be independently and proportionately associated with death from natural causes and with all-cause mortality in dogs. An electronic database containing 33,117 electrolyte profiles was constructed to retrospectively assess the association between disorders of sodium, potassium, corrected chloride, and ionized calcium concentrations with non-survival and with death excluding euthanasia by multivariable modeling. A second database containing 11,249 records was used to validate the models constructed from the first database. All four electrolytes assessed had non linear U-shaped associations with case fatality rates, wherein concentrations clustered around the reference interval had the lowest case fatality rates, while progressively abnormal concentrations were associated with proportionately increased risk of non-survival (AUROC 0.624) or death (AUROC 0.678). Multivariable modeling suggested that these electrolyte disturbances were associated with non-survival and with death from natural causes independent of each other. This study suggests that measurement of electrolyte concentrations is an important component of the assessment of dogs in emergency rooms or intensive care units. Future studies should focus on confirming these associations in a prospective manner accounting for disease severity. PMID- 28868304 TI - Treatment of sepsis: What is the antibiotic choice in bacteremia due to carbapenem resistant Enterobacteriaceae? AB - Sepsis is one of the major challenges of today. Although gram-positive bacteria related infections are more prevalent in hospital setting, the highest mortality rate is associated with gram-negative microorganisms especially Enterobacteriaceae. Enterobacteriaceae, including Escherichia coli, Klebsiella spp., Proteus spp., Enterobacter spp. and Serratia spp. Resistance to beta lactams in Enterobacteriaceae is primarily attributed to the production of B lactamase enzymes with subsequent antibiotic hydrolysis and to a lesser extent by alteration of efflux pump or porins expression. Carbapenem resistant Enterobacteriaceae (CRE) and Acinetobacter baumannii are the most notorious pathogens due to the high incidence of morbidity and mortality especially in the immunocompromised patients in the intensive care unit. The most appropriate antimicrobial therapy to treat CRE is still controversial. Combination therapy is preferred over monotherapy due to its broad-spectrum coverage of micro-organisms, due to its synergetic effect and to prevent development of further resistance. Current suggested therapies for CRE resistance as well as promising antibiotics that are currently under investigation for winning the war against the emerging CRE resistance are reviewed and discussed. PMID- 28868305 TI - Vertebroplasty and delayed subdural cauda equina hematoma: Review of literature and case report. AB - Vertebroplasy is considered an alternative and effective treatment of painful oncologic spine disease. Major complications are very rare, but with high morbidity and occur in less than 1% of patients who undergo vertebroplasty. Spinal subdural hematoma (SDH) is an extremely rare complication, usual developing within 12 h to 24 h after the procedure. We report the case of a tardive SDH in an oncologic patient who underwent VP for Myxoid Liposarcoma metastasis. Trying to explain the pathogenesis, we support the hypothesis that both venous congestion of the vertebral venous plexus of the vertebral body and venous congestion due to a traumatic injury can provoke SDH. To our best knowledge, only 4 cases of spinal subdural hematoma following a transpedicular vertebroplasty have been previously described in International literature and only one of them occurred two weeks after that surgical procedures. Percutaneous verteboplasty is a well-known treatment of pain oncologic spine disease, used to provide pain relief and improvement of quality life and is considered a simple surgical procedure, involving a low risk of complications, but related to high morbidity, such as SDH. Therefore it has to be performed by experienced and skilled surgeons, that should also recognize possible risk factors, making SDH more risky. PMID- 28868306 TI - Pseudotumoral acute cerebellitis associated with mumps infection in a child. AB - Pseudotumoral cerebellitis in childhood is an uncommon presentation of cerebellitis mimicking a brain tumor. It often follows an inflammatory or infectious event, particularly due to varicella virus. Patients could have a wide clinical spectrum on presentation. Some patients may be asymptomatic or present at most with mild cerebellar signs, whereas others may suffer severe forms with brainstem involvement and severe intracranial hypertension mimicking tumor warranting surgical intervention. Imaging techniques especially multimodal magnetic resonance imaging represent an interesting tool to differentiate between posterior fossa tumors and acute cerebellitis. We describe a case of pseudotumoral cerebellitis in a 6-year-old girl consequent to mumps infection and review the literature on this rare association. PMID- 28868307 TI - Atlanto-axial langerhans cell histiocytosis in a child presented as torticollis. AB - Langerhans cell histiocytosis (LCH) is a rare condition mostly seen in children and adolescents. Eosinophilic granuloma (EG) is one of its three clinical entities and is considered as a benign osteolytic lesion. Many reports of patients with spine histiocytosis are well documented in the literature but it is not the case of atlantoaxial localization. We report here a new observation of atlantoaxial LCH in a 4-year-old boy revealed by persistent torticollis. He was successfully treated with systemic chemotherapy and surgery. Inter-body fusion packed by autologous iliac bone was performed with resolution of his symptoms. It is known that conservative treatment is usually sufficient and surgery should be reserved for major neurologic defects in spine EG. In atlantoaxial lesion, surgical treatment should be frequently considered. PMID- 28868303 TI - Adjuvants to local anesthetics: Current understanding and future trends. AB - Although beneficial in acute and chronic pain management, the use of local anaesthetics is limited by its duration of action and the dose dependent adverse effects on the cardiac and central nervous system. Adjuvants or additives are often used with local anaesthetics for its synergistic effect by prolonging the duration of sensory-motor block and limiting the cumulative dose requirement of local anaesthetics. The armamentarium of local anesthetic adjuvants have evolved over time from classical opioids to a wide array of drugs spanning several groups and varying mechanisms of action. A large array of opioids ranging from morphine, fentanyl and sufentanyl to hydromorphone, buprenorphine and tramadol has been used with varying success. However, their use has been limited by their adverse effect like respiratory depression, nausea, vomiting and pruritus, especially with its neuraxial use. Epinephrine potentiates the local anesthetics by its antinociceptive properties mediated by alpha-2 adrenoreceptor activation along with its vasoconstrictive properties limiting the systemic absorption of local anesthetics. Alpha 2 adrenoreceptor antagonists like clonidine and dexmedetomidine are one of the most widely used class of local anesthetic adjuvants. Other drugs like steroids (dexamethasone), anti-inflammatory agents (parecoxib and lornoxicam), midazolam, ketamine, magnesium sulfate and neostigmine have also been used with mixed success. The concern regarding the safety profile of these adjuvants is due to its potential neurotoxicity and neurological complications which necessitate further research in this direction. Current research is directed towards a search for agents and techniques which would prolong local anaesthetic action without its deleterious effects. This includes novel approaches like use of charged molecules to produce local anaesthetic action (tonicaine and n butyl tetracaine), new age delivery mechanisms for prolonged bioavailability (liposomal, microspheres and cyclodextrin systems) and further studies with other drugs (adenosine, neuromuscular blockers, dextrans). PMID- 28868309 TI - Aortic Root Reconstruction with a New Dacron Graft Featuring Prefabricated Coronary Side Branches: Lessons Learned from the Cabrol Procedure. AB - BACKGROUND: Coronary button reimplantation can represent a technical challenge of aortic root reconstruction that can be associated with significant morbidity and mortality. With the goal of simplifying coronary reimplantation and reducing the incidence of related complications, we designed a new Dacron graft with prefabricated coronary branches to minimize coronary artery mobilization and prevent the potential mechanical complications of reattachment to the body of the graft. METHODS: Between June 2010 and May 2012, we implanted the graft in eight patients (six males, two females) ranging in age from 42-68 years (mean, 54 years). Six procedures were modified Bentall reconstructions, and two procedures were valve-sparing root replacements using the reimplantation technique. RESULTS: There were no complications and no morbidity or mortality related to coronary reattachment. All patients were alive and doing well at a mean follow-up of 26 months (range, 17-38 months). At an extended mean follow-up of 42 months (range, 25-56 months), one patient died of stroke-related complications. No radiologic or clinical evidence of impairment of coronary perfusion was identified in any patient. CONCLUSIONS: The use of this new graft model may simplify the technique of root reconstruction and potentially lower the incidence of mechanical complications related to coronary button reimplantation. PMID- 28868308 TI - Phosphodiesterases 3 and 4 Differentially Regulate the Funny Current, If, in Mouse Sinoatrial Node Myocytes. AB - Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3',5'-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac "funny current" (If) is among the cAMP sensitive effectors that drive pacemaking in SAMs. If is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them. PKA activity is required for signaling between beta adrenergic receptors (betaARs) and HCN channels in SAMs but the mechanism that constrains cAMP signaling to a PKA-dependent pathway is unknown. Phosphodiesterases (PDEs) hydrolyze cAMP and form cAMP signaling domains in other types of cardiomyocytes. Here we examine the role of PDEs in regulation of If in SAMs. If was recorded in whole-cell voltage-clamp experiments from acutely isolated mouse SAMs in the absence or presence of PDE and PKA inhibitors, and before and after betaAR stimulation. General PDE inhibition caused a PKA independent depolarizing shift in the midpoint activation voltage (V1/2) of If at rest and removed the requirement for PKA in betaAR-to-HCN signaling. PDE4 inhibition produced a similar PKA-independent depolarizing shift in the V1/2 of If at rest, but did not remove the requirement for PKA in betaAR-to-HCN signaling. PDE3 inhibition produced PKA-dependent changes in If both at rest and in response to betaAR stimulation. Our results suggest that PDE3 and PDE4 isoforms create distinct cAMP signaling domains that differentially constrain access of cAMP to HCN channels and establish the requirement for PKA in signaling between betaARs and HCN channels in SAMs. PMID- 28868311 TI - Occlusive Shrinkage of Ovation Endograft Presenting as Acute Lower Limb Ischemia: Effective Endovascular Management. AB - The aim of this report is to describe the imaging and successful treatment of an acute shrinkage of the Ovation Abdominal Stent Graft System. The Ovation Prime system utilizes a polymer-filled sealing ring that is cast in situ at the margin of the aneurysm; however, the residual endograft inner volume after ring filling may reduce volume and graft flow. Nevertheless, there are no reports about severe complications using the Ovation Prime system. A 75-year-old male presented to our hospital for acute lower limb ischemia. The patient reported a previous endograft for abdominal aortic aneurysm 1 month previously, which utilized the Ovation device. Computed tomography (CT) angiography demonstrated a critical narrowing of the endograft at the site of the proximal sealing rings. We decided on urgent treatment, delivering a covered stent graft (CP STENT NUMEDTM). Intraoperative intravascular ultrasound showed effective compaction of the proximal rings. Nine month follow-up with CT angiography demonstrated good patency without ring recoil of the endograft. This is the first report of endovascular treatment for an acute and symptomatic shrinkage of proximal rings in the Ovation trivascular endograft. Angiographic and intravascular ultrasound findings showed that covered stenting is effective and that the ring polymer is safely moldable. PMID- 28868313 TI - Page for the General Public. PMID- 28868312 TI - A Case of Primary Aortoduodenal Fistula and Abdominal Aortic Aneurysm in a Patient with Chronic Q Fever. AB - A 70-year-old man was successfully treated for an aortoduodenal fistula originating from a Q fever-related abdominal aortic aneurysm. He had no known history of contact with cattle or sheep. Although the combination of abdominal aortic aneurysm and aortoduodenal fistula is rare, one should be suspicious of Q fever infection as the causative agent, and additional medical treatment should be initiated. PMID- 28868314 TI - Cause of Death Following Surgery for Acute Type A Dissection: Evidence from the Canadian Thoracic Aortic Collaborative. AB - BACKGROUND: Surgery confers the best chance of survival following acute Type A dissection (ATAD), yet perioperative mortality remains high. Although perioperative risk factors for mortality have been described, information on the actual causes of death is sparse. In this study, we aimed to characterize the inciting events causing death during surgical repair of ATAD. METHODS: Nine centers participated in the study. We included all patients who died following surgical repair for ATAD between January 2007 and December 2013. An aortic surgeon at each site determined the primary cause of death from seven predetermined categories: cardiac, stroke, hemorrhage, other organ ischemia (peripheral, renal, or visceral), multiorgan failure, sepsis, or other causes. Additional characteristics and variables were analyzed to delineate potential modifiable factors for mortality. RESULTS: Of the 692 surgeries for ATAD, there were 123 deaths (17.8% mortality rate). Mean age at death was 66 years. Events contributing to death were: cardiac (25%), stroke (22%), hemorrhage (21%), multiorgan failure (12%), other organ ischemia (11%), sepsis (4%), and other causes (5%). Neurologic injury at presentation was a predictor of stroke as the inciting cause of death (p = 0.04). Peripheral, renal, or visceral ischemia at presentation was highly predictive of death due to these presenting ischemic conditions (p = 0.004). We found no associations between cardiogenic shock, tamponade, or cardiopulmonary bypass duration and cardiac death. CONCLUSION: Operative mortality for ATAD remains high in Canada. Nearly 70% of deaths arise from cardiac failure, stroke, or hemorrhage. Therefore, novel surgical, hybrid, and endovascular strategies should target these three areas. PMID- 28868310 TI - Genes Associated with Thoracic Aortic Aneurysm and Dissection: An Update and Clinical Implications. AB - Thoracic aortic aneurysm (TAA) is a lethal disease, with a natural history of enlarging progressively until dissection or rupture occurs. Since the discovery almost 20 years ago that ascending TAAs are highly familial, our understanding of the genetics of thoracic aortic aneurysm and dissection (TAAD) has increased exponentially. At least 29 genes have been shown to be associated with the development of TAAD, the majority of which encode proteins involved in the extracellular matrix, smooth muscle cell contraction or metabolism, or the transforming growth factor-beta signaling pathway. Almost one-quarter of TAAD patients have a mutation in one of these genes. In this review, we provide a summary of TAAD-associated genes, associated clinical features of the vasculature, and implications for surgical treatment of TAAD. With the widespread use of next-generation sequencing and development of novel functional assays, the future of the genetics of TAAD is bright, as both novel TAAD genes and variants within the genes will continue to be identified. PMID- 28868316 TI - A Rare and Late Complication After Left Ventricular Assist Device Explantation. AB - Late complications can arise after explantation of a left ventricular assist device. We report the case of a patient who presented at the age of 19 years with peri-partum cardiomyopathy and was initially managed with a biventricular support device, which was subsequently upgraded to an ambulatory left ventricular assist device. This was successfully explanted after myocardial recovery via a minimally invasive approach 7 months later. The patient re-presented 5 years following explantation with hemoptysis. At redo sternotomy, a 10-cm remnant of the outflow graft was found to be eroding the surface of the right lung. The conduit was excised and the stump oversewn. Eleven months later, she presented again with hemoptysis, and a pseudo-aneurysm was identified on the computed tomography scan. She underwent urgent open repair with peripheral cannulation and deep hypothermic total circulatory arrest. The Dacron stump was found to be partially dehisced, leaving a 2-3 cm defect in the ascending aorta. The defect was repaired with a bovine pericardial patch. The patient made a good recovery and was successfully discharged. PMID- 28868315 TI - Impact of Thoracic Endovascular Repair on Pulsatile Aortic Strain in Acute Type B Aortic Dissection: Preliminary Results. AB - BACKGROUND: The impact of thoracic endovascular aortic repair (TEVAR) on pulsatile aortic strain remains undetermined in patients with Type B aortic dissection (TBAD). Therefore, we quantified pulsatile aortic strain in TBAD patients and control subjects. METHODS: We retrospectively analyzed two TBAD patients from our database with cardiac-gated computed tomography angiography imaging available before and after TEVAR and two control subjects (67- and 76 year-old males). Patient 1 (54-year-old female) presented with acute TBAD, and Patient 2 (55-year-old male) had Marfan syndrome and ruptured acute TBAD. Custom developed software was used to compute aortic length, diameter, and area during the cardiac cycle. Pulsatile strain was calculated as systolic increments of length and circumference divided by corresponding diastolic values. RESULTS: Before TEVAR, pulsatile longitudinal strain of the thoracic aorta was lower in TBAD patients (1.4-1.7%) than in control subjects (2.1-4.5%). After TEVAR, pulsatile longitudinal strain increased proximal to the stent-graft by 65% in the arch of Patient 1 and by 70% in the ascending aorta of Patient 2. Pulsatile circumferential strain was elevated in false lumen patency (4.4-6.2%) compared with thrombosed false lumen (1.4-2.1%) or control subjects (0.9-3.3%). Following TEVAR, circumferential measurements within stented segments were deemed unreliable due to artifacts. CONCLUSIONS: TEVAR led to a considerable increase of pulsatile longitudinal strain proximal to the stent-grafts, and TBAD was associated with longitudinally stiffer aortas, which may be part of the pathophysiology of TEVAR-related complications such as retrograde dissection and aneurysmal dilatation. These preliminary data call for larger prospective studies. PMID- 28868317 TI - Aorto-Cutaneous Fistula and False Aneurysm of the Ascending Aorta Five Years after its Prosthetic Replacement for Stanford Type A Acute Aortic Dissection. AB - Aorto-cutaneous fistula and false aneurysm of the ascending aorta in patients who previously underwent Stanford Type A acute aortic dissection are rare and severe complications. Surgical correction remains a demanding challenge. In a case of false aneurysm rupture during redo sternotomy, selective cannulation of the right axillary and left carotid arteries allowed an efficient method of cerebral perfusion. PMID- 28868318 TI - Complete Shrinkage of the Obliterated False Lumen After Open and Endovascular Chronic Aortic Dissection Stanford Type A Repair. AB - A 48-year-old man was admitted to our hospital with chronic aortic dissection Stanford Type A. His diagnosis was confirmed by chest multi-detector computed tomography (CT). The patient underwent combined (i.e., hybrid) open and endovascular repair (frozen elephant trunk) in a one-stage operation with moderate hypothermic circulatory arrest and antegrade cerebral perfusion. His postoperative course was uneventful, and he was discharged home on postoperative day 9. At 2-year follow-up, chest CT angiography revealed complete shrinkage of the obliterated false lumen in the distal aortic arch and descending thoracic aorta. PMID- 28868319 TI - Management of Iatrogenic Injury to the Inferior Vena Cava and Right Common Iliac Artery for Drainage of Psoas Abscess. AB - Iatrogenic simultaneous inferior vena cava (IVC) and iliac vessel injury is a rare entity. Ligation of the IVC in a life-threatening situation is well reported in the literature. Our case demonstrates that such a clinical situation requires optimization of fluid volume and management of sequelae such as deep vein thrombosis. PMID- 28868320 TI - Page for the General Public. PMID- 28868321 TI - List of Upcoming Meetings. PMID- 28868322 TI - Viability and Tissue Quality of Cartilage Flaps From Patients With Femoroacetabular Hip Impingement: A Matched-Control Comparison. AB - BACKGROUND: Chondrolabral damage is commonly observed in patients with cam-type femoroacetabular impingement (FAI). Chondral flap reattachment has recently been proposed as a possible preservation technique. PURPOSE/HYPOTHESIS: The purpose of this study was to determine the viability and tissue quality of chondral flaps from patients with FAI at the time of arthroscopy. It was hypothesized that chondral flaps from patients with cam lesions of the hip would exhibit less viability and greater tissue degeneration than would those of a matched control group. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Patients with cam-type FAI who were treated with hip arthroscopy between 2014 and 2016 were asked to participate in this study. The cartilage lesions were localized and classified intraoperatively according to Beck classification. A chondral flap (study group) and a cartilage sample (control group) were obtained from each patient for histologic evaluation. Cellular viability and tissue quality were examined and compared in both groups. Cellular viability was determined with live/dead staining, and tissue quality was evaluated using safranin O/fast green, hematoxylin and eosin (H&E) staining, and immunohistochemistry for collagen II. Osteoarthritis Research Society International (OARSI) grading was used for quality assessment, and Image J software was used to calculate the percentage of tissue viability and Col II stain. RESULTS: A total of 10 male patients with a mean age of 38.4 years (range, 30-55 years) were enrolled. All chondral flaps were classified as Beck grade 4. The mean cellular viability of the chondral flaps was reduced (54.6% +/- 25.6%), and they were found to be degenerated (OARSI grade, 4 +/- 1.27). Control samples also had reduced viability (38.8% +/- 30.3%) and were degenerative (OARSI grade, 3.5 +/- 1.38). There was no statistically significant intergroup difference for viability (P = .203) or OARSI grade (P = .645), nor was there an intragroup correlation between viability and OARSI grade (P > .05). A significant negative correlation (r = -0.9, P = .035) was found between OARSI grade and collagen II percentage scale in 5 selected samples. CONCLUSION: Despite appearing normal macroscopically, the chondral flaps from patients with cam-type FAI displayed loss of viability and tissue degeneration. In addition, control samples obtained away from the injury area also displayed cartilage damage and degeneration. Careful consideration should be taken when attempting to reattach the chondral flap. PMID- 28868323 TI - Fetal Alcohol Exposure: The Common Toll. AB - Alcohol has always been present in human life, and currently it is estimated that 50% of women of childbearing age consume alcohol. It has become increasingly clear over the last years that alcohol exposure during fetal development can have detrimental effects on various organ systems, and these effects are exerted by alcohol through multiple means, including effects on free radical formation, cellular apoptosis, as well as gene expression. Fetal alcohol exposure can lead to a spectrum of short term as well as long-term problems, with Fetal Alcohol Syndrome being on the more severe end of that spectrum. This syndrome is morbid, yet preventable, and is characterized by midfacial hypoplasia, thin upper lip, widely spaced small eyes, long smooth philtrum and inner epicanthal folds. Other findings include growth restriction as well as various neurodevelopmental abnormalities. This article is the first comprehensive review combining the molecular as well as the gross physiological and anatomical effects of alcohol exposure during pregnancy on various organ systems in the body. Our knowledge of these various mechanisms is crucial for our understanding of how alcohol exposure during fetal development can lead to its detrimental effects. PMID- 28868324 TI - From structure to structural dynamics: Ahmed Zewail's legacy. AB - In this brief tribute to Ahmed Zewail, we highlight and place in the historical context, several of the major achievements that he and his colleagues have made in Femtochemistry (of which he was the principal instigator) and his introduction of ultrafast electron scattering, diffraction, microscopy and spectroscopy. By achieving a sub-picosecond temporal resolution, coupled with a picometer spatial resolution, he revolutionised our understanding of the corpus of chemical, physical, biological and materials science systems. PMID- 28868325 TI - Active control of bright electron beams with RF optics for femtosecond microscopy. AB - A frontier challenge in implementing femtosecond electron microscopy is to gain precise optical control of intense beams to mitigate collective space charge effects for significantly improving the throughput. Here, we explore the flexible uses of an RF cavity as a longitudinal lens in a high-intensity beam column for condensing the electron beams both temporally and spectrally, relevant to the design of ultrafast electron microscopy. Through the introduction of a novel atomic grating approach for characterization of electron bunch phase space and control optics, we elucidate the principles for predicting and controlling the phase space dynamics to reach optimal compressions at various electron densities and generating conditions. We provide strategies to identify high-brightness modes, achieving ~100 fs and ~1 eV resolutions with 106 electrons per bunch, and establish the scaling of performance for different bunch charges. These results benchmark the sensitivity and resolution from the fundamental beam brightness perspective and also validate the adaptive optics concept to enable delicate control of the density-dependent phase space structures to optimize the performance, including delivering ultrashort, monochromatic, high-dose, or coherent electron bunches. PMID- 28868326 TI - Evolution of Vertebrate Solute Carrier Family 9B Genes and Proteins (SLC9B): Evidence for a Marsupial Origin for Testis Specific SLC9B1 from an Ancestral Vertebrate SLC9B2 Gene. AB - SLC9B genes and proteins are members of the sodium/lithium hydrogen antiporter family which function as solute exchangers within cellular membranes of mammalian tissues. SLC9B2 and SLC9B1 amino acid sequences and structures and SLC9B-like gene locations were examined using bioinformatic data from several vertebrate genome projects. Vertebrate SLC9B2 sequences shared 56-98% identity as compared with ~50% identities with mammalian SLC9B1 sequences. Sequence alignments, key amino acid residues and conserved predicted transmembrane structures were also studied. Mammalian SLC9B2 and SLC9B1 genes usually contained 11 or 12 coding exons with differential tissue expression patterns: SLC9B2, broad tissue distribution; and SLC9B1, being testis specific. Transcription factor binding sites and CpG islands within the human SLC9B2 and SLC9B1 gene promoters were identified. Phylogenetic analyses suggested that SLC9B1 originated in an ancestral marsupial genome from a SLC9B2 gene duplication event. PMID- 28868327 TI - Near-Field Optical Drilling of Sub-lambda Pits in Thin Polymer Films. AB - Under UV illumination, polymer films can undergo chain scission and contract. Using this effect, tightly focused laser light is shown to develop runaway near field concentration that drills sub-100 nm pits through a thin film. This subwavelength photolithography can be controlled in real time by monitoring laser scatter from the evolving holes, allowing systematic control of the void diameter. Our model shows how interference between the substrate and film together with near-field focusing by the evolving crevice directs this formation and predicts minimum pit sizes in films of 100 nm thickness on gold substrates. The smallest features so far are 60 nm diameter pits using 447 nm light focused onto polystyrene through a *100 objective (NA = 0.8). Such arrays of pits can be easily used as masks for fabricating more complex nanostructures, such as plasmonic nanostructures and biomicrofluidic devices. This demonstration shows the potential for harnessing near-field feedback in optical direct-writing for nanofabrication. PMID- 28868328 TI - Creating a RAW264.7 CRISPR-Cas9 Genome Wide Library. AB - The bacterial clustered regularly interspaced short palindromic repeats (CRISPR) Cas9 genome editing tools are used in mammalian cells to knock-out specific genes of interest to elucidate gene function. The CRISPR-Cas9 system requires that the mammalian cell expresses Cas9 endonuclease, guide RNA (gRNA) to lead the endonuclease to the gene of interest, and the PAM sequence that links the Cas9 to the gRNA. CRISPR-Cas9 genome wide libraries are used to screen the effect of each gene in the genome on the cellular phenotype of interest, in an unbiased high throughput manner. In this protocol, we describe our method of creating a CRISPR Cas9 genome wide library in a transformed murine macrophage cell-line (RAW264.7). We have employed this library to identify novel mediators in the caspase-11 cell death pathway (Napier et al., 2016); however, this library can then be used to screen the importance of specific genes in multiple murine macrophage cellular pathways. PMID- 28868329 TI - Active Cdk5 Immunoprecipitation and Kinase Assay. AB - Cdk5 activity is regulated by the amounts of two activator proteins, p35 and p39 (Tsai et al., 1994; Zheng et al., 1998; Humbert et al., 2000). The p35-Cdk5 and p39-Cdk5 complexes have differing sensitivity to salt and detergent concentrations (Hisanaga and Saito, 2003; Sato et al., 2007; Yamada et al., 2007; Asada et al., 2008). Cdk5 activation can be directly measured by immunoprecipitation of Cdk5 with its bound activator, followed by a Cdk5 kinase assay. In this protocol, buffers for cell lysis and immunoprecipitation are intended to preserve both p35- and p39-Cdk5 complexes to assess total Cdk5 activity. Cells are lysed and protein concentration is determined in the post nuclear supernatant. Cdk5 is immunoprecipitated from equal amounts of total protein between experimental groups. Washes are then performed to remove extraneous proteins and equilibrate the Cdk5-activator complexes in the kinase buffer. Cdk5 is then incubated with histone H1, a well-established in vitro target of Cdk5, and [gamma-32P]ATP. Reactions are resolved by SDS-PAGE and transferred to membranes for visualization of H1 phosphorylation and immunoblot of immunoprecipitated Cdk5 levels. We have used this assay to establish p39 as the primary activator for Cdk5 in the oligodendroglial lineage. However, this assay is amenable to other cell lineages or tissues with appropriate adjustments made to lysis conditions. PMID- 28868330 TI - Aldicarb-induced Paralysis Assay to Determine Defects in Synaptic Transmission in Caenorhabditis elegans. AB - Aldicarb treatment causes an accumulation of acetylcholine in the synaptic cleft of the neuromuscular junction, resulting in sustained muscle activation and eventually paralysis. Aldicarb-induced paralysis assay is an easy and fast method to determine whether synaptic transmission of a C. elegans mutant of interest is altered. This assay is based on the correlation of the rate of neurotransmitter release with the rate of paralysis. In this protocol, we describe a method for simultaneously assessing the aldicarb sensitivity of animals with different genotypes. PMID- 28868331 TI - Mass Spectrometry-based in vitro Assay to Identify Drugs that Influence Cystine Solubility. AB - Cystinuria is a rare genetic disorder characterized by recurrent, painful kidney stones, primarily composed of cystine, the dimer of the amino acid cysteine (Sumorok and Goldfarb, 2013). Using a mouse model of cystinuria, we have recently shown that administration of drugs that increase cystine solubility in the urine can be a novel therapeutic strategy for the clinical management of the disease (Zee et al., 2017). There is a large unmet need in the field for developing new drugs for cystinuria. To that end, here we describe a simple in vitro cystine solubility assay that is amenable for screening compounds to identify potential drugs that may influence cystine solubility. The assay includes preparing a supersaturated solution of cystine, incubating this solution with drug(s) of choice, and finally using high pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to quantify the amount of cystine precipitated under various conditions. PMID- 28868332 TI - Primary Culture System for Germ Cells from Caenorhabditis elegans Tumorous Germline Mutants. AB - The Caenorhabditis elegans germ line is an important model system for the study of germ stem cells. Wild-type C. elegans germ cells are syncytial and therefore cannot be isolated in in vitro cultures. In contrast, the germ cells from tumorous mutants can be fully cellularized and isolated intact from the mutant animals. Here we describe a detailed protocol for the isolation of germ cells from tumorous mutants that allows the germ cells to be maintained for extended periods in an in vitro primary culture. This protocol has been adapted from Chaudhari et al., 2016. PMID- 28868333 TI - Rapid Profiling Cell Cycle by Flow Cytometry Using Concurrent Staining of DNA and Mitotic Markers. AB - The flow cytometric quantitation of DNA content by DNA-binding fluorochrome, propidium iodide (PI) is the most widely used method for cell cycle analysis. However, the commonly used methods are time-consuming and labor-intensive and are incompatible with staining of mitotic markers by fluorescent-labeled antibodies. Here, we report an optimized simple protocol for rapid and simultaneous analysis of characteristic mitotic phosphorylated proteins and DNA content, permitting the quantification of cells in mitosis, G1, S and G2 stage in a single assay. The protocol detailed here employs detergent-based hypotonic solution to rapidly permeabilize cells and allows simultaneous staining of DNA with PI and mitotic marker, phospho-Histone H3, with specific antibody within 20 min. The protocol requires only inexpensive and commercial available reagents and also enables a rapid and complete analysis of cell cycle profile. PMID- 28868334 TI - Loading of Extracellular Vesicles with Chemically Stabilized Hydrophobic siRNAs for the Treatment of Disease in the Central Nervous System. AB - Efficient delivery of oligonucleotide therapeutics, i.e., siRNAs, to the central nervous system represents a significant barrier to their clinical advancement for the treatment of neurological disorders. Small, endogenous extracellular vesicles were shown to be able to transport lipids, proteins and RNA between cells, including neurons. This natural trafficking ability gives extracellular vesicles the potential to be used as delivery vehicles for oligonucleotides, i.e., siRNAs. However, robust and scalable methods for loading of extracellular vesicles with oligonucleotide cargo are lacking. We describe a detailed protocol for the loading of hydrophobically modified siRNAs into extracellular vesicles upon simple co-incubation. We detail methods of the workflow from purification of extracellular vesicles to data analysis. This method may advance extracellular vesicles-based therapies for the treatment of a broad range of neurological disorders. PMID- 28868335 TI - Fundamental Bounds for Sequence Reconstruction from Nanopore Sequencers. AB - Nanopore sequencers are emerging as promising new platforms for high-throughput sequencing. As with other technologies, sequencer errors pose a major challenge for their effective use. In this paper, we present a novel information theoretic analysis of the impact of insertion-deletion (indel) errors in nanopore sequencers. In particular, we consider the following problems: (i) for given indel error characteristics and rate, what is the probability of accurate reconstruction as a function of sequence length; (ii) using replicated extrusion (the process of passing a DNA strand through the nanopore), what is the number of replicas needed to accurately reconstruct the true sequence with high probability? Our results provide a number of important insights: (i) the probability of accurate reconstruction of a sequence from a single sample in the presence of indel errors tends quickly (i.e., exponentially) to zero as the length of the sequence increases; and (ii) replicated extrusion is an effective technique for accurate reconstruction. We show that for typical distributions of indel errors, the required number of replicas is a slow function (polylogarithmic) of sequence length - implying that through replicated extrusion, we can sequence large reads using nanopore sequencers. Moreover, we show that in certain cases, the required number of replicas can be related to information-theoretic parameters of the indel error distributions. PMID- 28868336 TI - Long-Term Outcomes of Gastric Endoscopic Submucosal Dissection: Focus on Metachronous and Non-Curative Resection Management. AB - INTRODUCTION: Endoscopic submucosal dissection (ESD) is an effective treatment for gastric superficial neoplasms and curative in 80-85% of the patients. The aims of this study were to identify risk factors for non-curative resection and metachronous development, and to evaluate patient management and outcome after non-curative resection. METHODS: In this single-centre study, the outcome of consecutive patients submitted to gastric ESD was assessed during a minimum follow-up of 18 months. Univariate analysis and multivariate logistic regression were performed to identify risk factors. RESULTS: ESD was performed in 194 lesions (164 patients) between 2005 and 2014. The median follow-up was 40 months. En bloc and complete resection rates were 95.3 and 93.8%, respectively. Male sex, larger tumor size, longer procedural time, and more advanced histology were associated with a non-curative resection (p < 0.05), but only carcinoma detected in biopsies before resection was identified as a significant risk factor on multivariate analysis. Metachronous lesions occurred in 18.4%, and the incidence rate was 4.7 lesions/100 person-years. Older age at diagnosis was identified as the only predictor of metachronous development in logistic regression. In the non curative resection group, survival did not differ between patients allocated to surveillance and those submitted to gastrectomy; 75% of gastrectomy specimens showed no residual lesion. CONCLUSIONS: The risk factors identified for non curative resection help to improve patient selection and patient information. Older patients had an increased risk for the development of metachronous lesions. In patients with non-curative resections, individualized patient management and surveillance seems to be an adequate option in selected cases. PMID- 28868337 TI - The adolescent brain at risk for substance use disorders: a review of functional MRI research on motor response inhibition. AB - Youth with family history (FH+) of substance use disorders (SUDs) are at increased risk for developing SUDs. Similarly, childhood attention deficit hyperactivity disorder (ADHD) is considered to be a risk factor for developing SUDs. Recent research has suggested a close association between SUDs and impaired inhibitory control. As such, it is crucial to examine common and distinct neural alterations associated with inhibitory control in these at-risk groups, particularly prior to the initiation of heavy substance use. This paper reviews the functional magnetic resonance imaging (fMRI) literature of inhibitory control in these two at-risk youth populations (FH+ and ADHD), specifically considering studies that used motor response inhibition tasks (Go/No-Go or Stop Signal). Across the selected fMRI studies, we discovered no common alteration in the at risk groups, but found neural alterations specific to each at-risk group. In FH+ youth and youth who transitioned into heavy substance use, blunted activation in the lateral part of the frontal pole (FP-lat) was most reliably observed. Importantly, longitudinal studies indicate that the blunted FP-lat activation may predict later SUDs, irrespective of the presence of FH+. In regards to ADHD, blunted activation was observed in the right dorsal anterior cingulate cortex (dACC) and left caudate. Of note, similar blunted dACC activation was also reported by one FH+ study, and thus, we cannot preclude a possibility that the right dACC activity may be a potential common alteration in both at-risk groups, particularly given a limited number of FH+ studies in the current review. Research challenges remain, and large-scale, longitudinal efforts will help determine the neurobiological markers predictive of SUDs among at-risk adolescents, including those with FH+, as well as those with ADHD and other psychiatric disorders. PMID- 28868338 TI - The role of literacy in the association between educational attainment and depressive symptoms. AB - There is a consistent association between education and depressive symptoms, but research on the mechanisms to explain this association remains limited. No study has formally evaluated the extent to which the association between education and depressive symptoms is mediated through a foundational skill such as literacy. Inverse odds ratio weighting (IORW) was used to estimate total, natural direct, and natural indirect effects in examining literacy as a mediator of the association between education and depressive symptoms. Health and Retirement Study participants born in the U.S. between 1900 and 1947 were interviewed biennially for up to 12 years (N = 16,718). Literacy was assessed with a brief vocabulary measure. Depressive symptoms were measured using the 8-item Centers for Epidemiologic Studies-Depression (CES-D) scale. Decomposition estimates were derived using regression analyses of repeated measures of depressive symptoms. Standard errors were obtained using a nonparametric bootstrap with the individual as the independent unit to account for dependence of observations within an individual. In a large cohort of older Americans, a one standard deviation difference in educational attainment (~ 3 years) was associated with a 0.35-point decrement in CES-D score (95% CI: -0.38, -0.32). This decrement represents a 0.22 standard deviation difference in depressive symptoms. Using IORW, the estimated effect of education on depressive symptoms mediated through literacy was -0.10 (95% CI: -0.18, -0.01), which represents 28% of the total effect. Education confers many benefits; as demonstrated by this study for depressive symptoms, one important benefit is literacy. PMID- 28868339 TI - Low-frequency and low-intensity ultrasound irradiation to the forearm improves an index of arterial stiffness in subjects with type 2 diabetes and hypertension. AB - OBJECTIVES: The arterial pressure-volume index (API) is a non-invasive assessment of arterial stiffness, and is suggested as a useful predictor of future cardiovascular events. The aim of the present study was to determine the effects of low-frequency and low-intensity ultrasound applied to the forearm for 10 min on the API in Japanese subjects with type 2 diabetes and hypertension. METHODS: We examined the effects of low-frequency and low-intensity ultrasound (800 kHz, 25 mW/cm2) applied to the forearm for 10 min on the API, blood pressure (BP) and pulse rate in 40 Japanese subjects (13 men and 27 women; mean age +/- SE, 70 +/- 2 years) with type 2 diabetes and hypertension, who had the API > 30 and systolic BP > 140 mmHg at a clinic visit. We also examined the effects of the ultrasound irradiation for 10 min on the API, BP and pulse rate in 33 Japanese subjects (11 men and 22 women; mean age +/- SE, 65 +/- 2 years) with type 2 diabetes and hypertension, who had the API > 30 and systolic BP (SBP) < 140 mmHg. RESULTS: The API, systolic BP and pulse rate in the ultrasound treatment group was significantly lower than the baseline values in the subjects who had the API > 30 and either the baseline of systolic BP > 140 mmHg or systolic BP < 140 mmHg. CONCLUSIONS: The low-frequency and low-intensity ultrasound irradiation to the forearm for 10 min might be useful as a preventive application for arterial stiffness in subjects with type 2 diabetes and hypertension. PMID- 28868340 TI - E-Selectin and SDF-1 regulate metastatic trafficking of breast cancer cells within the bone. AB - E-selectin is a key mediator of breast cancer cell (BCC) metastatic entry into the bone and stromal-derived factor 1 (SDF-1) is a critical molecular anchor for BCCs within discrete pro-dormancy bone marrow (BM) niches. Small-molecule inhibitors blocked metastatic entry and mobilized established disease from BM, suggesting a new treatment strategy to prevent breast cancer relapse. PMID- 28868341 TI - Flick the cancer stem cells' switch to turn cancer off. AB - Tumors are organized in a cellular hierarchy with a population of cancer stem cell (CSC) driving cancer progression and resistance to treatment. Recently, we identified miR-600 as a bimodal switcher that balances breast CSC-fate from a self-renewing to a differentiation state, with a direct impact on tumor progression. PMID- 28868342 TI - PSMA redirects MAPK to PI3K-AKT signaling to promote prostate cancer progression. AB - Increased Prostate Specific Membrane Antigen expression promotes tumor progression in prostate epithelium by dysregulating the beta1-integrin/type I insulin-like growth factor receptor axis, resulting in a shift in signaling from the less aggressive mitogen-activated protein kinase-extracellular signal regulated kinases 1 and 2 pathway to the pro-survival protein kinase B(AKT)/phosphatidylinositol 3-kinase pathway. PMID- 28868343 TI - Disentangling PTEN-cooperating tumor suppressor gene networks in cancer. AB - We have recently performed a whole-body, genome-wide screen in mice using a single-copy inactivating transposon for the identification of Pten (phosphatase and tensin homolog)-cooperating tumor suppressor genes (TSGs). We identified known and putative TSGs in multiple cancer types and validated the functional and clinical relevance of several promising candidates for human prostate cancer. PMID- 28868344 TI - Early detection of the aflatoxin B1 mutational fingerprint: A diagnostic tool for liver cancer. AB - Using duplex-consensus sequencing technology, we recently identified the characteristic high-resolution mutational spectrum of the liver carcinogen aflatoxin B1 in a mouse model, many months before aflatoxin-induced tumors are detectable. The diagnostic power of this spectrum is then demonstrated by accurately identifying, among the sequenced human liver tumors, the subset of cancers associated with aflatoxin B1 exposure. PMID- 28868345 TI - Deregulated MITF sumoylation: A route to melanoma. AB - Metastatic melanoma is a deadly form of skin cancer. Extraordinary breakthroughs have been recently achieved in the treatment of the disease,1 leading to objective increase in patient survival. However, early detection of potential dangerous melanocytic lesions remains the best strategy to avoid metastatic dissemination, which is still the main cause of death in melanoma patients. In 2011, our team identified a germline mutation in microphthalmia-associated transcription factor (MITFE318K ) that predisposes carriers to melanoma. Recently, we demonstrated that this mutation interfered with oncogene-induced senescence, one of the first events that should be overcome to allow melanoma development. Therefore, our works provide important clues on the early steps of melanomagenesis and as such might be useful for prevention or early therapeutic interventions in at risk-patients. PMID- 28868346 TI - Heterogeneity among Lgr5-positive colon stem cells. AB - Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is considered a representative marker of intestinal stem cells from both non-tumor and tumor tissues. However, it remains unclear whether all or only a fraction of Lgr5 positive cells behave as stem cells. Recently, we reported that Lgr5-positive cells from non-tumor and tumor tissues can be classified into overlapping yet distinct groups and that the tumor-specific groups are associated with tumorigenic capability, suggesting that these cells could represent targets for therapeutic intervention. PMID- 28868347 TI - Major effect of transcytosis on nano drug delivery to pancreatic cancer. AB - We demonstrated that activated transcytosis is a major mechanism to complement the classic enhanced permeability and retention effect in pancreatic cancer. This was achieved by using an iRGD peptide that triggers transcytosis pathway at the tumor site. Co-administration of unconjugated iRGD substantially improved the effect of the chemotherapeutics delivering nanocarrier, and resulted in survival improvement in mice. Since the iRGD effect is commensurate with neuropilin-1 expression on tumor vasculature, it is necessary to contemplate a personalized approach to implement this technology. PMID- 28868348 TI - Targeting pseudokinase TRIB3 brings about a new therapeutic option for acute promyelocytic leukemia. AB - Pseudokinase tribbles (Trib) family, Trib1 and Trib2, but not Trib3, act as oncogene to drive acute leukemia by destabilizing the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) and inhibiting myeloid differentiation. A recent study identifies pseudokinase TRIB3 as an important factor in acute promyelocytic leukemia (APL) progression and therapy resistance. Targeting TRIB3 may provide a novel therapeutic approach for APL. PMID- 28868349 TI - Tumor-initiating CD49f cells are a hallmark of chemoresistant triple negative breast cancer. AB - Taxanes are mainstay treatment of triple negative breast cancer (TNBC) patients but resistance often develops. Using TNBC patient-derived orthoxenografts (PDX) we have recently discovered that a CD49f+ chemoresistant population with tumor initiating ability is present in sensitive tumors and expands in tumors that have acquired resistance. Importantly, sensitivity to taxanes is recovered after long term drug interruption. The characterization of this chemoresistant CD49f+ cells provides a unique opportunity to identify novel targets for the treatment of chemoresistant TNBC. PMID- 28868350 TI - The answer's in the tail: MYC mRNA has a metabolic sensor that supports cancer chemoresistance. AB - Our recent study shows that the translation of MYC mRNA (mRNA) is controlled by its 3' untranslated region (UTR) in a process that depends on the availability of glutamine and levels of cellular nucleotides. Metabolic feedback protects cells from a lethal glutamine addiction and may compromise metabolic targeting of glutamine metabolism. PMID- 28868351 TI - The cell-of-origin dictates the genomic landscape of breast cancers. AB - Aberrant cell proliferation induced by activated oncogenes triggers oxidative stress and uncontrolled DNA replication, promoting genomic instability. We recently reported that human mammary stem cells exhibit the unique capacity to withstand an oncogenic activation by dint of an anti-oxidant program driven by the ZEB1 transcription factor. This pre-emptive program prevents the onset of chromosomal instability, leading to the development of tumors with unique pathological features. PMID- 28868353 TI - Dual epigenetic modifiers for cancer therapy. AB - Epigenetic drug discovery is an emerging strategy for the treatment of cancer and other pathologies. Here, we discuss our recent discovery of first-in-class dual reversible inhibitors of the histone methyltransferase activity of G9a/EHMT2 and DNA methyltransferases showing in vivo efficacy in human tumors. Current and future investigation lines are presented. PMID- 28868352 TI - SWI/SNF tumor suppressor gene PBRM1/BAF180 in human clear cell kidney cancer. AB - Mutations within chromatin modulating protein complexes have dominated the novel cancer gene landscape. However, little is known about how individual aberrations contribute to cancer formation. A novel Pbrm1 kidney cancer mouse model examining the role of Pbrm1 provides much needed clue concerning how SWI/SNF complexes might function as tumor suppressors. PMID- 28868354 TI - Differential dynamic microscopy of bidisperse colloidal suspensions. AB - Research tasks in microgravity include monitoring the dynamics of constituents of varying size and mobility in processes such as aggregation, phase separation, or self-assembly. We use differential dynamic microscopy, a method readily implemented with equipment available on the International Space Station, to simultaneously resolve the dynamics of particles of radius 50 nm and 1 MUm in bidisperse aqueous suspensions. Whereas traditional dynamic light scattering fails to detect a signal from the larger particles at low concentrations, differential dynamic microscopy exhibits enhanced sensitivity in these conditions by accessing smaller wavevectors where scattering from the large particles is stronger. Interference patterns due to scattering from the large particles induce non-monotonic decay of the amplitude of the dynamic correlation function with the wavevector. We show that the position of the resulting minimum contains information on the vertical position of the particles. Together with the simple instrumental requirements, the enhanced sensitivity of differential dynamic microscopy makes it an appealing alternative to dynamic light scattering to characterize samples with complex dynamics. PMID- 28868356 TI - On/off switchable electronic conduction in intercalated metal-organic frameworks. AB - The electrical properties of metal-organic frameworks (MOF) have attracted attention for MOF as electronic materials. We report on/off switchable electronic conduction behavior with thermal responsiveness in intercalated MOF (iMOF) with layered structure, 2,6-naphthalene dicarboxylate dilithium, which was previously reported as a reversible Li-intercalation electrode material. The I-V response of the intercalated sample, which was prepared using a chemically reductive lithiation agent, exhibits current flow with sufficiently high electronic conductivity, even though it displays insulating characteristics in the pristine state. Calculations of band structure and electron hopping conduction indicate that electronic conduction occurs in the two-dimensional pi-stacking naphthalene layers when the band gap is decreased to 0.99 eV and because of the formation of an anisotropic electron hopping conduction pathway by Li intercalation. The structure exhibiting electronic conductivity remains stable up to 200 degrees C and reverts to an insulating structure, without collapsing, at 400 degrees C, offering the potential for a shutdown switch for battery safety during thermal runaway or for heat-responsive on/off switching electronic devices. PMID- 28868357 TI - THE ENDOCRINOPATHIES OF MALE ANOREXIA NERVOSA: CASE SERIES. AB - OBJECTIVE: Anorexia nervosa (AN) is a serious disorder with associated morbidity and mortality, most commonly diagnosed in females. Existing literature on male anorexia is sparse, and a review of the endocrine effects of AN in males has not previously been published. Our objective is to highlight the clinical characteristics of AN in males as a routinely overlooked cause of multiple endocrinopathies and systemic illness in hospitalized patients. METHODS: We present 4 cases (2 cases at The Mount Sinai Hospital; 2 cases at Long Island Jewish Hospital) of young men with hormonal dysfunction due to underlying AN. Pertinent de-identified data were collected from a chart review of cases seen on the endocrinology consult service at both hospitals. Institutional Review Board approval was not required for an observational report of the cases presented. RESULTS: Four young men with AN demonstrated evidence of multiple systemic complications from severe caloric and protein malnutrition. Varying degrees of endocrinopathies were present, including hypogonadotropic hypogonadism, hypercortisolemia, and nonthyroidal illness syndrome, resulting in bradycardia, gastroparesis, hypothermia, acute systolic heart failure, and erectile dysfunction. Ages at diagnosis were 20, 24, 23, and 20 years, with mean age 21.75 years. Most of the clinical effects from these endocrinopathies resolved with improved caloric intake and nutrition, although symptoms of hypogonadism persisted. CONCLUSION: This small case series highlights the importance of AN as a potential cause of multiple endocrinopathies in males. The heterogeneous presentations and varying degrees of clinical manifestations in our cohort emphasize the challenge in diagnosis. Increased awareness of AN in males is vital, as its prevalence is likely underestimated and appropriate diagnosis and treatment can ameliorate the metabolic dysfunction in a majority of cases. Further studies on males with eating disorders are needed to help guide diagnostic and therapeutic decisions. PMID- 28868358 TI - GLYCOGENIC HEPATOPATHY: A COMPLICATION OF UNCONTROLLED DIABETES. AB - OBJECTIVE: To describe a case of hepatomegaly and elevated transaminases in a patient with glycogenic hepatopathy (GH) as a complication of uncontrolled diabetes. METHODS: Clinical, laboratory, and pathological information are described. RESULTS: An 18-year-old male with uncontrolled type 1 diabetes and recurrent diabetic ketoacidosis (DKA) presented with abdominal distention and severe hyperglycemia. Physical examination revealed massive hepatomegaly. Laboratory evaluation showed anion-gap metabolic acidosis, ketonuria, and markedly elevated aspartate and alanine amino transaminases (AST = 1,162 IU/L and ALT = 598 IU/L, respectively). Despite resolution of DKA with insulin infusion, transaminases continued to increase (peak AST = 3,725 U/L, ALT = 1,049 U/L) with no signs of liver failure (normal coagulation profile and albumin level). Abdominal ultrasonography revealed an enlarged liver with moderate echogenicity, consistent with steatosis. Extensive evaluation for causes of hepatitis including toxic, autoimmune, genetic, and infectious diseases was unrevealing. Liver biopsy showed no signs of nonalcoholic fatty liver disease (NAFLD), such as fibrosis, steatosis, or portal inflammation. However, swollen hepatocytes with glycogen accumulation consistent with GH were seen. CONCLUSION: GH can present as hepatomegaly and elevated liver transaminases in patients with uncontrolled diabetes. Clinicians should consider GH in patients with uncontrolled diabetes after ruling out other common causes. Liver ultrasound cannot differentiate this condition from the more commonly seen NAFLD. Although liver biopsy remains a gold standard, evaluation with magnetic resonance imaging may be considered as a less invasive alternative in the appropriate clinical setting. PMID- 28868355 TI - Stability of gene expression in human T cells in different gravity environments is clustered in chromosomal region 11p15.4. AB - In the last decades, a plethora of in vitro studies with living human cells contributed a vast amount of knowledge about cellular and molecular effects of microgravity. Previous studies focused mostly on the identification of gravity responsive genes, whereas a multi-platform analysis at an integrative level, which specifically evaluates the extent and robustness of transcriptional response to an altered gravity environment was not performed so far. Therefore, we investigated the stability of gene expression response in non-activated human Jurkat T lymphocytic cells in different gravity environments through the combination of parabolic flights with a suborbital ballistic rocket and 2D clinostat and centrifuge experiments, using strict controls for excluding all possible other factors of influence. We revealed an overall high stability of gene expression in microgravity and identified olfactory gene expression in the chromosomal region 11p15.4 as particularly robust to altered gravity. We identified that classical reference genes ABCA5, GAPDH, HPRT1, PLA2G4A, and RPL13A were stably expressed in all tested gravity conditions and platforms, while ABCA5 and GAPDH were also known to be stably expressed in U937 cells in all gravity conditions. In summary, 10-20% of all transcripts remained totally unchanged in any gravitational environment tested (between 10-4 and 9 g), 20-40% remained unchanged in microgravity (between 10-4 and 10-2 g) and 97-99% were not significantly altered in microgravity if strict exclusion criteria were applied. Therefore, we suppose a high stability of gene expression in microgravity. Comparison with other stressors suggests that microgravity alters gene expression homeostasis not stronger than other environmental factors. PMID- 28868359 TI - Immune Mediator Pharmacogenomics: TCL1A SNPs and Estrogen-Dependent Regulation of Inflammation. AB - This review describes the important functional implications of TCL1A single nucleotide polymorphisms (SNPs) discovered during pharmacogenomic studies of aromatase inhibitor-induced musculoskeletal adverse events that were subsequently shown to influence the expression of cytokines, chemokines, toll-like receptors (TLR), and NF-kappaB in a SNP and estrogen-dependent fashion. Functional genomic studies of these SNPs led to the discovery of novel mechanisms that may contribute to disease pathophysiology and which may also increase our understanding of pharmacogenomic aspects of regulation of the expression of inflammatory mediators. Specifically, TCL1A expression was induced by estrogens in a SNP-dependent fashion, resulting in downstream effects on the expression of immune mediators that included IL17RA, IL17A, CCR6, CCL20 TLR2, TLR7, TLR9, TLR10 and NF-kappaB. These observations have potential implications for inflammatory diseases such as rheumatoid arthritis-a disease for which two thirds of patients are women. Strikingly, this genomic phenomenon could be "reversed" by estrogen receptor antagonist treatment-once again in a SNP-dependent, i.e., in a pharmacogenomic fashion. Specifically, differential SNP-dependent effects on estrogen receptor binding to estrogen response elements before and after estrogen receptor blockade might be associated with mechanisms underlying the SNP genotype and estrogen-dependent regulation of TCL1A and the expression of downstream immune mediators. Furthermore, this SNP and estrogen-dependent phenotypic response could be "reversed" by SERM treatment. These observations could potentially open the way to understand, predict and even pharmacologically manipulate the expression of selected immune mediators in a SNP-dependent fashion. PMID- 28868360 TI - GE - A New Path! PMID- 28868361 TI - Evaluating Disability in Inflammatory Bowel Diseases: A Step Forward for Improved Care. PMID- 28868362 TI - Disability in Inflammatory Bowel Disease: Translation to Portuguese and Validation of the "Inflammatory Bowel Disease - Disability Score". AB - BACKGROUND: Inflammatory bowel disease (IBD) has a physical, psychological and social impact, often compromising the patient's ability to perform daily activities. Recently a new measurement for disability in IBD was developed. The Inflammatory Bowel Disease-Disability Score (IBD-DS) comprises the following domains: mobility, self-care, major daily life activities, gastrointestinal related problems, mental health and interaction with the environment. The aim of our study was to translate to Portuguese and to validate the IBD-DS. METHODS: Eighty-five patients, 55 with Crohn's disease (CD) and 30 with ulcerative colitis (UC), completed the Portuguese version of the IBD-DS and the short inflammatory bowel disease questionnaire (SIBDQ-10 questions). Disease activity was assessed using the Harvey-Bradshaw (HB) for CD and partial Mayo score (pMayo) for UC. Pearson's correlation coefficient was used to assess the correlation between the IBD-DS and SIBDQ. The Student's t-test was used to compare the mean of IBD-DS between active and inactive disease. Statistical analysis was performed with SPSS 21.0 and the statistical level of significance (alpha) was established at 5%. RESULTS: In our study, a significant negative correlation between the IBD-DS and the SIBDQ was observed (r = -0.858, p < 0.001 for CD and r = -0.933, p < 0.001 for UC). There was a statistically significant difference of the mean of IBD-DS between inactive vs. active disease (93.78 vs. 117.57, p = 0.016 for CD and 78.96 vs. 137.14, p < 0.001 for UC). CONCLUSION: The Portuguese version of the inflammatory bowel disease-disability score has a strong correlation with patients' quality of life and clinical disease activity and was shown to be a valid tool to measure disability in patients with inflammatory bowel disease. PMID- 28868363 TI - Polyglandular Syndrome Type III and Severe Peripheral Neuropathy: An Unusual Association. AB - INTRODUCTION: Polyglandular syndrome is characterized by the association of autoimmune, organ-specific, endocrine and non-endocrine diseases. OBJECTIVE: To present a case of polyglandular syndrome type III (b) accompanied by pernicious anemia and autoimmune thyroiditis. METHOD: Report the clinical case of a young patient that developed progressive and disabling peripheral neuropathy framework, triggered by vitamin B12 deficiency. DISCUSSION: It was proven that atrophic gastritis with positive intrinsic anti-factor was responsible for the framework of pernicious anemia, which in turn dangerously reduced the serum levels of vitamin B12, leading to myelopathy. There was a progressive neurological improvement after parenteral cyanocobalamin replacement, keeping the patient at ambulatory, under maintenance therapy. CONCLUSION: The importance of suspecting on polyglandular syndrome in the presence of autoimmune frameworks is important, especially those involving diabetes, thyroiditis, atrophic gastritis, pernicious anemia, vitiligo, among others. PMID- 28868364 TI - Hepatic Actinomycosis. AB - Actinomycosis is a rare disorder caused by an anaerobic gram-positive bacillus (Actinomyces), predominantly by the Actinomyces israelii species. Only 20% of cases show an abdominal manifestation, the appendix and ileocecal valve being the most frequent locations. Definitive diagnosis is based on microbiological cultures, microscopy or macroscopy examination. Nevertheless, histological examination of the percutaneous biopsy and blood microbiological cultures are rarely positives. Preoperative diagnosis is hampered by the lack of specific clinical and imaging manifestations, which often mimic malignancy. The rate of preoperative diagnosis is less than 10%, however, the outcome is excellent, with a low mortality rate. The authors describe the case of a patient who was diagnosed with primary hepatic actinomycosis only by a histological examination of the surgical specimen of left hepatectomy extended to segments V and VIII, for suspected malignant lesion. This case demonstrates the difficulties in diagnosing hepatic actinomycosis. PMID- 28868365 TI - The Clinical Significance of Autoantibodies in Hepatitis C Patients Submitted to Interferon Treatment. AB - Hepatitis C virus is associated with several immune-mediated phenomena, presented usually as extra-hepatic hepatitis C manifestations. A predisposition to autoimmunity associated with the presence of baseline autoantibodies has been demonstrated in interferon mediated autoimmune diseases. We report a male patient, 34 years old, with genotype 1, chronic hepatitis C (hepatitis C viremia 1.432.463 UI/mL) and family history of psoriasis. He had high levels of transaminases and immunology showed positive antinuclear antibodies (1/320) and anti-smooth-muscle antibodies, with elevated immunoglobulin G (1740 mg/dL). Liver biopsy revealed a F1/2 Metavir score, histologic activity index of 3 and mild piecemeal necrosis. Antiviral treatment was started with peg-interferon alpha2a 180 mcg plus ribavirin 1200 mg, and the patient had rapid virologic response, normalization of transaminases, negativation of antinuclear antibodies positivity and decrease of immunoglobulin levels. However, at week 22, he developed psoriatic-like eczema and arthritis with functional limitation. Due to suspicion of latent psoriatic arthritis not previously diagnosed, he was started on methotrexate 10 mg/weekly with improvement of psoriatic plaques, arthritis and functional limitation. Patient achieved sustained virologic response, with normal transaminases and no significant changes in immunology. Post-treatment median hepatic elastography was 3.6 kPa. Autoimmunity in hepatitis C infection is not limited to surrogate autoantibody seropositivity, but may embrace the full spectrum of autoimmune disorders. PMID- 28868366 TI - Accidental Ingestion of Dentistry Material - Report of Cases and Challenges from the Pediatrician Point of View. AB - INTRODUCTION: Aspiration or ingestion of foreign bodies may occur during dental procedures. Diagnosis and management of these accidents is sometimes challenging. The authors present a small series of clinical cases. CASE 1: Adolescent observed due to suspected accidental bracket ingestion, not visible on x-ray, removed by upper digestive endoscopy. CASE 2: Adolescent observed after accidental ingestion of a dental file. Conflicting results in image exams and absence of object progression led to enteroscopy for extraction. CASE 3: Adolescent observed due to accidental ingestion of a surgical blade, visualized on image study but not accessible by endoscopy, resulting in latter spontaneous elimination. DISCUSSION: Image study is frequently useful when metallic object ingestion is suspected, but has some limitations. In some cases, mucosal protections must be used during removal procedures. Prevention of such accidents is the best approach, using appropriate protections to secure airway and digestive tract during dental procedures. PMID- 28868367 TI - A Case of Obstructive Jaundice. PMID- 28868368 TI - Gastric Mixed Adenoneuroendocrine Carcinoma. PMID- 28868369 TI - Sloughing Esophagitis: A Rare Cause of Dysphagia. PMID- 28868370 TI - Single-balloon Enteroscopy Assisted Endoscopic Retrograde Cholangiopancreatography with the Rendezvous Technique. PMID- 28868371 TI - Inactive Carriers of Hepatitis B Virus: A Never Ending Story. PMID- 28868372 TI - Endoscopic Submucosal Dissection of Early Gastric Cancer: Yes, We Need to Calculate Procedure Times! PMID- 28868373 TI - Hepatitis B Virus Inactive Carriers: Which Follow-up Strategy? AB - INTRODUCTION: The natural history of patients with inactive hepatitis B virus (HBV) is still unclear, persisting doubts about the optimal management of these patients. AIM: To evaluate the long-term outcome in a cohort of hepatitis B inactive carriers. METHODS: We conducted a retrospective study in a cohort of 100 HBV inactive carriers (categorized after quarterly determinations of serum ALT and HBV DNA over one year) and analyzed the results of serial determinations of HBV DNA and alanine transaminase (ALT). The HBV DNA was quantified by Cobas TaqMan(r). We used the Spearman's rank correlation coefficient to evaluate the correlation between the serum ALT and HBV DNA. RESULTS: We studied 100 HBV inactive carriers (53% females, mean age 48.7 +/- 13.8 years, range 16-77 year). Vertical transmission was identified in 18%. The mean follow-up time was 4.6 +/- 2.5 (2-13) years. Two patients had transient elevation of ALT (alcohol and drugs). We observed clearance of hepatitis B surface antigen (HBsAg) in four patients (4%) and biological and virological reactivation in 10% (from the 4th year of follow-up). Mild lesions were found in the 12 patients in whom liver biopsy was performed; genotypes A and D predominated. Viral load and serum ALT levels were unremarkable in 90% of the patients. There was no significant correlation (p > 0.05) between the values of ALT and HBV DNA throughout the follow-up. CONCLUSION: The management strategy, using both patterns of biochemical and virologic activity, seems adequate. The lack of correlation between the values of ALT and HBV DNA caveat its effectiveness and the stability of the levels of HBV DNA and ALT in most patients suggests that the prognosis of the inactive carriers, when defined accurately, is mostly benign. Further studies, including ones with new tests available, are needed to standardize and improve the management of this group of patients. PMID- 28868374 TI - Endoscopic Submucosal Dissection of Gastric Superficial Lesions: Predictors for Time of Procedure in a Portuguese Center. AB - BACKGROUND: Endoscopic submucosal dissection (ESD), an endoscopic technique used for treatment of gastric superficial lesions, has been gaining importance on western countries. Procedural times have an impact on various outcomes. AIM: To define which factors from patients, lesions and procedure can predict longer procedural times. METHODS: In a cohort of 127 lesions resected by ESD with IT knife, after using needle-knife for submucosal layer access, by experienced gastroenterologists, characteristics from the patient (age, gender, presence of co-morbidities, usage and suspension of anti-platelet drugs and general physical condition), lesion (size, histopathological diagnosis at biopsy, location, macroscopic type and submucosal invasion) and procedure (adverse events) were retrospectively analyzed for its impact on time of procedure. Univariate and multivariate analysis were performed. RESULTS: Lesions larger than 20 mm (p < 0.001), on the upper third of the stomach (p = 0.035) and with an ASA score of 3 (p = 0.031) were considered influential factors for a longer procedure time and specifically for a time of procedure longer than 90 min. Existence of intra procedure adverse events was also a predictor for a procedure time >90 min. Lesion's size >20 mm and location in the upper third were independently associated with a procedure time longer than 90 min (OR 4.91 [95%CI 2.29-10.50] and OR 18.26 [95%CI 2.02-164.78], respectively). CONCLUSION: The time of procedure of ESD for gastric superficial lesions is influenced by size of lesion (>20 mm) and location (upper third of stomach), which predict a time longer than 90 min. This can be useful for better management of workflow, operation, training of teams and anesthesic procedures. PMID- 28868375 TI - A Large Gastric Inflammatory Fibroid Polyp. AB - Inflammatory fibroid polyp (IFP) is an unusual benign gastrointestinal subepithelial tumor (SET). The endosonographic (EUS) features of IFPs were sporadically reported on imaging tips or small case series study. However, the differential diagnosis and optimal treatment of gastric IFP is still challenging. We report an unusual case of a large erosioned and prolapsing gastric submucosal lesion, presenting primarily with obstructive symptoms ("ball valve syndrome") and anemia. On EUS examination, a 50 mm SET in the distal antrum was seen, with hypoechoic but heterogeneous echo-pattern, located in the second and third sonographic layers of the gastric wall (deep mucosal and submucosal). The fourth (muscle) layer was intact; no peri-lesional adenopathies were identified. A decision was made to proceed to endoscopic treatment because of the mentioned symptoms. Histopathologic evaluation of the resected specimen with immunohistochemical staining was consistent with the diagnosis of IFP. IFP rarely reach these large dimensions or cause symptoms. Despite its benign etiology, endoscopic resection was important in both establishing a histologic diagnosis and treatment. EUS was crucial in the differential diagnosis. The literature concerning IFP is also reviewed. PMID- 28868376 TI - Portal Hypertensive Biliopathy: An Infrequent Cause of Biliary Obstruction. AB - INTRODUCTION: Biliary obstruction is usually caused by choledocholithiasis. However, in some circumstances, alternative or concurring unusual ethiologies such as portal hypertensive biliopathy (PHB) must be considered. CLINICAL CASE: We present the case of a 36-year-old female complaining of jaundice and pruritus. Liver function tests were compatible with biliary obstruction and the ultrasound scan of the abdomen showed dilatation of the intrahepatic biliary ducts, a dilated common bile duct (CBD) and biliary calculi. The computed tomography of the abdomen revealed a portal cavernoma encasing the CBD. DISCUSSION: Portal cavernoma, the hallmark of extrahepatic portal venous obstruction, can cause PHB. When symptomatic, chronic cholestasis is present if a dominant stricture exists whereas biliary pain and acute cholangitis occur when choledocholithiasis prevails. Management must be individualized and usually includes endoscopic therapy to address choledocholithiasis and shunt surgery for definitive treatment. PMID- 28868377 TI - Schwannoma-A Rare Subepithelial Lesion of the Colon. AB - Schwannoma is a benign tumor arising from Schwann cells that form the neural sheath. Primary schwannoma of the colon is rare and a few cases have been reported. We report a case of schwannoma of the colon and present the differential diagnosis that must be considered in the evaluation of colonic subepithelial lesions. PMID- 28868378 TI - Pneumoperitoneum after Percutaneous Endoscopic Gastrostomy. PMID- 28868379 TI - Perforated Rectal Haematoma Induced by a Cleansing Enema Tip. PMID- 28868380 TI - Incidental Diagnosis of Mantle Lymphoma Made by Sigmoidoscopy. PMID- 28868381 TI - A New Method for Distal Repositioning of a Misplaced Esophageal Stent. PMID- 28868382 TI - Preoperative Aerobic Capacity - Is There a Role for Routine Evaluation in Liver Transplantation? PMID- 28868383 TI - Bariatric Analysis and Reporting Outcome System (BAROS): Toward the Uniform Assessment of Bariatric Surgery Outcomes. PMID- 28868384 TI - Pre-Transplant Aerobic Capacity and Prolonged Hospitalization After Liver Transplantation. AB - INTRODUCTION: Patients with end stage liver disease (ESLD) referred for liver transplantation (LT) are forwarded to pulmonary evaluation before being operated. ESLD is associated with muscle wasting, reduced exercise tolerance and aerobic capacity. OBJECTIVES: We assessed the association between aerobic capacity (AC), liver disease severity and postoperative LT outcomes in a series of LT candidates in a university affiliated hospital in Brazil. METHODS: Pre-LT oxygen uptake at peak (pre-VO2peak), liver disease severity, and early pos-LT outcomes such as length of intensive care unit (ICU) stay, <5 and >=5 days and hospitalization, <20 and >=20 days and postoperative mortality were compared. Pre-VO2peak was measured through the cardiopulmonary exercise testing (CPET). Severity of liver disease was estimated by the Model for End-Stage Liver Disease (MELD) categorization into MELD < 18 and MELD >= 18 groups. Student's t-test was used to compare these groups. A logistic regression model was built to verify the effect of those variables on the length of ICU stay, length of hospitalization and postoperative mortality. RESULTS: A total of 47 patients were include in analysis. Pre-VO2peak was similar to that of healthy sedentary individuals (75 +/ 18%) and worse in the MELD >= 18 group as compared to the MELD < 18 group (19.51 +/- 7.87 vs 25.21 +/- 8.76 mL/kg/min, respectively; p = 0.048). According to the multivariate analysis, only a lower pre-VO2peak (<20.09 +/- 4.83 mL/kg/min) was associated to a greater length of hospitalization (p = 0.01). CONCLUSIONS: In LT candidates, a reduced pre-VO2peak may predict a higher risk of greater pos-LT length of hospitalization. The length of ICU stay and postoperative mortality were not associated with variables studied. This finding should be evaluated in other studies before making specific recommendations about a routine use of CPET in LT candidates. PMID- 28868385 TI - Impact of Bariatric Surgery on Patients from Goias, Brazil, Using the BAROS Method - A Preliminary Study. AB - INTRODUCTION: As obesity is currently a major public health problem, bariatric surgery has been widely indicated due to the difficulties involved in the clinical management of obese adults. OBJECTIVES: Assess the quality-of-life (QOL) of patients who had undergone Roux-en-Y Gastric Bypass (RYGB) in the State of Goias, Brazil, where as yet no studies have been published on the QOL of patients who underwent bariatric surgery. METHODS: A retrospective study, using the Bariatric Analysis and Reporting Outcome System (BAROS), was carried out in Goiania and Rio Verde, Goias, Brazil, with 50 over 18-year-old patients of both genders, who had undergone RYGB and had at least three months of postoperative time. RESULTS: Before RYGB, 48% of the individuals were classified as morbidly obese. Average weight and body mass index (BMI) of the 50 patients interviewed were 119.37 +/- 18.44 kg and 43.54 +/- 5.33 kg/m2, respectively. By contrast, after the RYGB these parameters decreased significantly to 78.01 +/- 11.06 kg and 28.46 +/- 3.61 kg/m2, respectively, mainly from the 3rd to 85th month of postoperative time (p < 0.0001). As well as that, 78% reported having presented preoperative comorbidities, especially hypertension (44%), rheumatism (34%), dyslipidemia (24%) and diabetes (20%). However, after surgery, the resolution rates were 77, 24, 100 and 100%, respectively, for these same clinical conditions. In terms of QOL, some patients reported feeling better (8%) or much better (92%) after RYGB. The outcome of the BAROS method for those patients was classified as fair (2%), good (8%), very good (24%) and excellent (66%). CONCLUSIONS: Preliminary results indicated that RYGB could be a successful surgical procedure to promote satisfactory and sustained reduction in the body measurements of morbidly obese patients from Goias, Brazil. Furthermore, the final BAROS score showed improvements in associated comorbidity and also in the QOL of these patients. PMID- 28868386 TI - New Trends in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disease of the gastrointestinal (GI) tract. In the past decade a shift in the treatment paradigm of IBD has ensued. The availability of drugs capable of inducing mucosal healing, combined with the recognition that IBD is not an intermittent disease, but rather a progressive one causing bowel damage and disability, led us to a more stringent strategy. Tailored therapy with more aggressive treatment in high risk patients, treating beyond symptoms, intervening early before damage occurs, optimizing therapeutic regimens, and actively pursuing sustained remission and sustained control of inflammation are strategies that are slowly being incorporated in our clinical practice. Furthermore, new drugs targeting different immunological pathways, such as vedolizumab, have recently been approved and therefore more therapeutic resources for patients failing anti-tumour necrosis factor alpha (anti-TNFalpha) agents will be available. The future years look promising for IBD. Hopefully the new trends in IBD management, combined with new drugs, will make possible to change the course of disease and provide better therapy and quality of life for patients suffering from this disabling disease. PMID- 28868388 TI - Panniculitis - A Rare Manifestation of Acute Pancreatitis. AB - Pancreatic panniculitis is a rare skin disorder that occurs in 2-3% of pancreatic diseases, mostly associated with acute or chronic pancreatitis. Its pathophysiology is still unclear, but the release of pancreatic enzymes in circulation can be responsible for this disorder. The typical histological features are adipocyte necrosis with neutrophils infiltrate and typical "ghost cells". Its treatment, clinical course and prognosis are usually related with the pancreatic disease. We present a case of a 39-year-old man who presented with fever, abdominal pain, nausea and vomiting after a copious alcohol ingestion. Acute alcohol-induced pancreatitis was diagnosed. 9 days after admission he developed tender erythematous subcutaneous nodules, whose biopsy was consistent with pancreatic panniculitis. There was clinical and laboratory improvement with supportive treatment as well as skin nodules regression. Although pancreatic panniculitis is a rare condition, physicians must be aware of it to avoid delay in the diagnosis. PMID- 28868389 TI - Meckel's Diverticulum: A Rare Cause of Overt Obscure Gastrointestinal Bleeding in an Adult Male. PMID- 28868387 TI - The Importance of Alternative Diagnostic Modalities in the Diagnosis of Small Bowel Tumors After a Negative Capsule Endoscopy. AB - Capsule endoscopy is widely accepted as the preferred diagnostic test in the evaluation of small bowel diseases, especially in the setting of obscure gastrointestinal bleeding. It has revolutionized small bowel examination and has improved the detection of small bowel tumors. However, small bowel tumors are sometimes missed by capsule endoscopy. Furthermore, there are several recent reports comparing capsule endoscopy with other diagnostic modalities, such as double balloon enteroscopy and CT/RM enterography, that challenge the reportedly high negative predictive value of capsule endoscopy in detecting small bowel tumors. We report the case of a patient with overt obscure gastrointestinal bleeding due to a gastrointestinal stromal tumor diagnosed by CT enterography after two negatives capsule endoscopies. This case shows that capsule endoscopy may overlook significant life threatening lesions and highlights the importance of using other diagnostic modalities after a negative capsule endoscopy, especially in patients with a high index of suspicion for small bowel tumoral pathology or persistent/recurrent bleeding. PMID- 28868391 TI - Hematochezia in a Patient with Renal Failure and Hyperkalemia. PMID- 28868390 TI - Rapid Progression of Multifocal Hepatic Epithelioid Hemangioendothelioma. PMID- 28868392 TI - Secondary Aortoesophageal Fistula Due to Thoracic Aortic Stent Graft: Is There a Role for Endoscopic Intervention? PMID- 28868393 TI - Burkitt's Lymphoma Diagnosed by Colonoscopy in Immunocompetent Patient. PMID- 28868394 TI - The Vanishing Frontiers of Therapeutic Enteroscopy. PMID- 28868395 TI - Genetic Variations and Gastric Cancer Risk. PMID- 28868396 TI - Endoscopic Mucosal Resection of Jejunal Polyps using Double-Balloon Enteroscopy. AB - BACKGROUND: There are only two single case reports describing double-balloon enteroscopy (DBE)-assisted endoscopic mucosal resection (EMR) of the jejunum. The aim of this case series was to evaluate the feasibility and utility of DBE assisted EMR in patients with familial and non-familial jejunal polyps. PATIENTS AND METHODS: Observational, open-label, retrospective, single-arm case series in two hospitals. RESULTS: Eight patients underwent DBE assisted jejunal EMR. Median age of patients was 42 years (range 24-62 years), male: female ratio 1.5:1. DBE was done through the antegrade (i.e. oral) route in all patients. Four patients had FAP; two had Peutz-Jeghers syndrome, one had a sporadic adenoma and one had a bleeding jejunal polyp, which on histological examination turned out to be lipoma. 3/8 underwent piece-meal EMR. No immediate adverse events occurred. CONCLUSIONS: This is the first case series presenting the technical details, feasibility and outcomes of EMR of the small bowel. EMR of the jejunum is feasible and safe during DBE. PMID- 28868398 TI - Imagiological Diagnosis of Gastrointestinal Diseases - Diagnostic Criteria of Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of neoplastic morbidity and mortality worldwide, and despite recent treatment advances, the prognosis remains dismal, with a 5-year mortality rate of 85%. The surveillance and timely diagnosis is therefore of crucial importance in order to improve survival rates and alleviate the health burden imposed by the HCC. Previously, HCC diagnosis warranted liver biopsy, an invasive process with limited diagnostic accuracy. In the past 15 years, HCC diagnosis based solely on imaging criteria was accepted by all the major national and international guidelines, and is now widely employed across the globe. Current European guidelines for the HCC diagnosis support the use of both dynamic contrasted computer tomography as well as magnetic resonance imaging for the non-invasive diagnosis of HCC for nodules >1 cm in a cirrhotic liver. The non-invasive diagnosis of HCC depends on radiological hallmarks, such as homogeneous contrast uptake during the arterial phase and wash-out during the venous and late phases, but while such tumoral behaviour is frequent in nodules >2 cm, high-end equipment and superior expertise is often needed for the correct diagnosis of early HCC. Nevertheless, the accuracy of imaging techniques for the diagnosis of HCC is permanently improving, and supports the progressively reduced need for liver biopsy during liver nodule workout in a cirrhotic liver. PMID- 28868397 TI - Association Between IL-4 and IL-6 Expression Variants and Gastric Cancer Among Portuguese Population. AB - INTRODUCTION: Multiple studies have reported strong associations between Helicobacter pylori (Hp) inflammation and gastric cancer (GC) development. Altered expressions of pro/anti-inflammatory cytokines have a crucial role in Hp and GC proliferation. Although there are many studies related to cytokines polymorphisms involvement in GC risk, the role of Interleukin-4 (IL-4) and Interleukin-6 (IL-6) in gastric inflammation process is not yet clarified. AIM: This study aimed to investigate the impact of common IL-4 and IL-6 polymorphisms in GC development risk among Portuguese population. METHODS: A total of 100 GC biopsies (50 with intestinal type, IGC, 50 with diffuse type, DGC) and 50 chronic gastritis cases, used as control group, were included in this case-control study. IL-4 and IL-6 common polymorphisms were genotyped by PCR-SSP, using commercially available kits. RESULTS: IL-4 low producer genotypes, IL-4-590TT (OR = 6.7; 95% CI 1.4-32.4) and IL-4-1098GG (OR = 4.4; 95% CI 1.7-16.9) were found associated with IGC and DGC, respectively. We also verified that IL-4 TTT haplotype was linked with both IGC (OR = 5.8; 95% CI 2.3-14.4) and DGC (OR = 2.3; 95% CI 1.0 5.5) groups. Concerning IL-6 results, IL-6-174CG genotype showed a higher prevalence among IGC cases (OR = 7.3; 95% CI 2.7-20.3), and IL-6-174CC (OR = 3.8; 95% CI 1.7-8.7) showed upper prevalence within DGC subjects. Finally, IL-6 174/nt565CG haplotype showed a significant association with both IGC (OR = 7.3; 95% CI 2.7-20.3) and DGC (OR = 7.9; 95% CI 4.2-14.9). CONCLUSION: IL-6 and IL-4 expression variants seem to have an important role in GC risk mechanisms. This study provides preliminary evidence that IL-4 and IL-6 polymorphisms, although not directly linked to the disease, may be useful tools in the study of this multifactorial disease. PMID- 28868400 TI - Upper Gastrointestinal Hemorrhage as an Unexpected Feature of Hepatocellular Carcinoma. PMID- 28868401 TI - Duodenal and Colonic Metastases of Ovarian Neoplasm. PMID- 28868399 TI - Endoscopic Ultrasound in the Diagnosis and Staging of Pancreatic Cancer. AB - Pancreatic cancer is one of the digestive cancers with the poorest prognosis, so an early and correct diagnosis is of utmost importance. With the development of new therapeutic options an accurate staging is essential. Endoscopic ultrasonography (EUS) has a major role in all stages of the management of these patients. EUS has a high accuracy in the diagnosis of pancreatic adenocarcinoma and the possibility to perform fine-needle aspiration/biopsy (FNA/FNB) increases the diagnostic yield of EUS. There is still no consensus on the several technical aspects of FNA, namely on the rapid on-site evaluation (ROSE), the diameter and type of needle, the number of passes and the use of stylet and suction. Contrast enhanced EUS (CE-EUS) and EUS elastography (EUS-E) have been used in recent years as an adjunct to EUS-FNA. Given the higher sensitivity of these techniques a negative cytology by EUS-FNA should not exclude malignancy when CE-EUS and/or EUS E are suggestive of pancreatic neoplasia. EUS remains one of the main methods in the staging of pancreatic adenocarcinoma, namely to further evaluate patients with non-metastatic disease that appears resectable on initial imaging. EUS is crucial for an accurate preoperative evaluation of pancreatic cancer which is essential to choose the correct management strategy. The possibility to obtain samples from suspicious lesions or lymph nodes, by means of EUS-guided fine needle aspiration as well as the use of contrast-enhanced and elastography, makes EUS an ideal modality for the diagnosis and staging of pancreatic cancer. PMID- 28868402 TI - Aspiration of Capsule Endoscopy. PMID- 28868403 TI - Duodenal Variceal Bleeding Successfully Treated by Endoscopic N-butyl-2 cyanoacrylate Injection. PMID- 28868404 TI - A Challenge, an Ambition. PMID- 28868405 TI - Endoscopic Submucosal Dissection in the Treatment of Gastrointestinal Superficial Lesions: Follow the Guidelines! PMID- 28868406 TI - Predictors of Severity and In-Hospital Mortality for Acute Pancreatitis: Is There Any Role for C-Reactive Protein Determination in the First 24 Hours? PMID- 28868407 TI - Endoscopic Submucosal Dissection for Gastrointestinal Superficial Lesions: Initial Experience in a Single Portuguese Center. AB - INTRODUCTION: Endoscopic submucosal dissection (ESD) is a minimally invasive organ-sparing endoscopic technique which allows en bloc resection of premalignant and early malignant lesions of the gastrointestinal tract regardless of size. In spite of the promising results, mainly from Japanese series, ESD is still not being widely used in western countries. This study aims to report the feasibility, safety and effectiveness of ESD technique for treating premalignant and early malignant gastrointestinal (GI) lesions (esophagus, gastric and rectum) in a Portuguese center. PATIENT AND METHODS: From December 2011 to November 2014, 34 GI lesions were treated by ESD. The location, en bloc and pathological complete resection (R0) rates, procedure time, complications and local recurrence were retrospectively evaluated. RESULTS: From 34 resected lesions, 18 were gastric (GL), 15 were rectal (RL) and one esophageal (EL). En bloc resection for each location was 17/18 (94%), 11/15 (73%) and 1/1 respectively. R0 was achieved in 16/18 (89%) GL, 9/15 (60%) RL and 1/1 EL. Mean resection time was 67 min for GL, 142 min for RL and 40 min for EL. Complications included immediate (6%) and delayed (3%) minor bleeding but no perforation. One local residual lesion from a RL was reported in the follow-up, effectively treated with an endoscopic technique. Disease-specific survival was 100% over a mean follow-up period of 14 months. CONCLUSION: ESD has shown to be a safe and feasible resection method, achieving high R0, low recurrence and complication rates. Our results are similar to those reported in other international series. PMID- 28868408 TI - C-Reactive Protein at 24 Hours after Hospital Admission may have Relevant Prognostic Accuracy in Acute Pancreatitis: A Retrospective Cohort Study. AB - INTRODUCTION: C-reactive protein (CRP) and Bedside Index for Severity in Acute Pancreatitis (BISAP) have been used in early risk assessment of patients with AP. OBJECTIVES: We evaluated prognostic accuracy of CRP at 24 hours after hospital admission (CRP24) for in-hospital mortality (IM) in AP individually and with BISAP. MATERIALS AND METHODS: This retrospective cohort study included 134 patients with AP from a Portuguese hospital in 2009-2010. Prognostic accuracy assessment used area under receiver-operating characteristic curve (AUC), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: Thirteen percent of patients had severe AP, 26% developed pancreatic necrosis, and 7% died during index hospital stay. AUCs for CRP24 and BISAP individually were 0.80 (95% confidence interval (CI) 0.65-0.95) and 0.77 (95% CI 0.59-0.95), respectively. No patients with CRP24 <60 mg/l died (P = 0.027; negative predictive value 100% (95% CI 92.3-100%)). AUC for BISAP plus CRP24 was 0.81 (95% CI 0.65-0.97). Change in NRInonevents (42.4%; 95% CI, 24.9-59.9%) resulted in positive overall NRI (31.3%; 95% CI, -36.4% to 98.9%), but IDInonevents was negligible (0.004; 95% CI, -0.007 to 0.014). CONCLUSIONS: CRP24 revealed good prognostic accuracy for IM in AP; its main role may be the selection of lowest risk patients. PMID- 28868410 TI - Neuroendocrine Rectal Tumors: Main Features and Management. AB - The incidence of neuroendocrine tumors of the rectum has been increasing in the last decades, partly due to improved investigation. They are mostly well differentiated small tumors with a rather good overall prognosis. In the last few years, some aspects of neuroendocrine tumors have been evolving. In 2010, the World Health Organization proposed a new classification, indicating that these tumors, as a category, should be considered malignant. Afterwards the European Neuroendocrine Tumor Society published their guidelines for the management of colorectal neoplasms. Treatment algorithm is mainly based on tumor size and grading and, in general, well-differentiated rectal tumors <2 cm can be endoscopically resected. Endorectal ultrasound plays a particularly important role by accurately assessing tumor size and depth of invasion prior to resection. There are no specific recommendations on the optimal endoscopic resection method, but data from recent studies suggests that modified endoscopic mucosal resection techniques and endoscopic submucosal dissection have superior complete resection rates. PMID- 28868409 TI - Management of Patients with Hereditary Colorectal Cancer Syndromes. AB - Colorectal cancer (CRC) is one of the most important causes of death in the world. Hereditary CRC is found in 5-10% of CRC patients. In this review, we will focus on the major forms of hereditary CRC and their management according to the most recent literature available. PMID- 28868411 TI - Finding a Needle in a Haystack: The Diagnosis of a Rectal Neuroendocrine Tumor by Transrectal Prostate Biopsy. AB - INTRODUCTION: Prostate biopsy, usually performed by a transrectal approach, is executed when there is a suspicion of prostate cancer. Neuroendocrine tumors (NETs) are epithelial neoplasms with predominant neuroendocrine differentiation and only 19% of them are localized in the rectum. CASE REPORT: The authors describe a 73-year-old man without a significant past medical history that underwent a prostate biopsy because of urinary complaints and elevated serum levels of prostate specific antigen. The histology revealed a well-differentiated NET characterized as a low-grade tumor (G1). A total colonoscopy revealed a 5 mm sessile rectal polyp and in the splenic flexure a sessile lesion with central ulceration with 5 cm with histological features compatible with an adenocarcinoma. CONCLUSION: This is the first case reported in the literature of a rectal NET diagnosed by transrectal prostate biopsy. This case is particularly unique because the diagnosis of the NET lead to the subsequent timely detection of a colonic adenocarcinoma. PMID- 28868413 TI - Endoscopic Ultrasound and Anal Pain: The Key to Diagnosis. PMID- 28868412 TI - Anal Pain and Constipation - Beyond the Obvious. PMID- 28868414 TI - Left-Sided Portal Hypertension: A Clinical Challenge. PMID- 28868415 TI - Left-Sided Portal Hypertension: A Sinister Entity. AB - INTRODUCTION: Sinistral, or left-sided, portal hypertension (SPH) is a rare entity, with multiple potential causes. Gastrointestinal variceal bleeding and hypersplenism are its' major clinical manifestations. The main aim of the present study is to summarize the clinical features of patients with SPH. PATIENTS AND METHODS: This was a retrospective analysis of consecutive patients with present or previous diagnosis of SHP, observed in a Gastroenterology Department, in a period of 2 years. Patients with clinical, radiological or laboratory alterations suggestive of cirrhosis were excluded. Causes of SPH, clinical manifestations and outcomes were registered. Potential factors associated with gastrointestinal bleeding were analyzed. RESULTS: In the study period a total of 22 patients (male - 17; mean age - 59.6 +/- 10.6 years) with SHP were included. Clinical manifestations were: asymptomatic/unspecific abdominal pain (n = 14); gastrointestinal bleeding (n = 8). Eleven (50%) patients had increased aminotransferases, GGT and/or alkaline phosphatase although liver function was normal in all of them. Causes of SPH were chronic pancreatitis (n = 7), acute pancreatitis (n = 7), pancreatic cancer (n = 4), pancreatic surgery (n = 3) and arteriovenous malformation (n = 1). All patients had gastric and/or esophageal varices and seven had splenomegaly. Five (22.7%) had thrombocytopenia, associated with hypersplenism. Five patients (22.7%) were submitted to endoscopic treatment and eight were submitted to splenic artery embolization and/or splenectomy. There were no cases of variceal rebleeding and two patients died. Patients without liver enzymes elevation had a higher probability of gastrointestinal bleeding (87.5% vs. 28.6%; p = 0.024). CONCLUSIONS: Acute and chronic pancreatitis are the major causes of SHP. Gastrointestinal bleeding is the most important clinical manifestation and patients without liver enzyme elevation seem more prone to bleed. Specific treatment is seldom performed or needed. PMID- 28868416 TI - Systematic Review of the Relation Between Intestinal Microbiota and Toll-Like Receptors in the Metabolic Syndrome: What Do We Know So Far? AB - INTRODUCTION: Metabolic syndrome is an emerging problem in developed countries and presents itself as a potential threat worldwide. The role of diabetes, dyslipidaemia and hepatic steatosis as pivotal components of the metabolic syndrome is well known. However, their common persistent chronic inflammation and its potential cause still elude. This systematic review aims to present evidence of the mechanisms that link the intestinal microbioma, innate immunity and metabolic syndrome. METHODS: A comprehensive research was made using PubMed database and 35 articles were selected. RESULTS: We found that metabolic syndrome is associated to increased levels of innate immunity receptors, namely, Toll-like receptors, both in intestine and systemically and its polymorphisms may change the risk of metabolic syndrome development. Microbioma dysbiosis is also present in metabolic syndrome, with lower prevalence of Bacteroidetes and increased prevalence of Firmicutes populations. The data suggest that the link between intestinal microbiota and Toll-like receptors can negatively endanger the metabolic homeostasis. CONCLUSION: Current evidence suggests that innate immunity and intestinal microbiota may be the hidden link in the metabolic syndrome development mechanisms. In the near future, this can be the key in the development of new prophylactic and therapeutic strategies to treat metabolic syndrome patients. PMID- 28868417 TI - Leaping Forward in the Treatment of Clostridium Difficile Infection: Update in 2015. AB - In recent years, significant advances in the treatment of Clostridium difficile infection (CDI) have risen. We review the most relevant updated recommendations in the current standard of care of CDI and discuss emerging therapies, including antibiotic, alternative therapies (probiotics, toxin-binding resins, immunotherapy) and new data on fecal transplantation. Upcoming surgical options and other rescue therapies for severe refractory disease are also addressed. Although oral metronidazole is a first-line therapy for non-severe CDI, emerging data have demonstrated its inferiority relatively to vancomycin, particularly in the setting of recurrent and/or severe infection. After a CDI recurrence for the first time, fidaxomicin has been shown to be associated with lower likelihood of CDI recurrence compared to vancomycin. Fecal transplantation is now strongly recommended for multiple recurrent CDI and may have a role in refractory disease. Oral, frozen stool capsules may simplify fecal transplantation in the future, with preliminary promising results. Diverting loop ileostomy combined with colonic lavage is a potential alternative to colectomy in severe complicated CDI. Potential alternative therapies requiring further investigation include toxin binding resins and immunotherapy. PMID- 28868419 TI - Duodenal Subepithelial Lesion? An Unexpected Endoscopic Ultrasound Finding. PMID- 28868420 TI - Unusual Retained Rectal Foreign Body. PMID- 28868418 TI - Nutrition in Chronic Liver Disease. AB - Protein-calorie malnutrition is a transversal condition to all stages of chronic liver disease. Early recognition of micro or macronutrient deficiencies is essential, because the use of nutritional supplements reduces the risk of complications. The diet of patients with chronic liver disease is based on a standard diet with supplements addition as necessary. Restrictions may be harmful and should be individualized. Treatment management should aim to maintain an adequate protein and caloric intake and to correct nutrient deficiencies. The large majority of patients with grade I/II hepatic encephalopathy can tolerate a regular diet. Protein restriction can aggravate malnutrition and is not recommended, except in cases of hepatic encephalopathy unresponsive to optimized therapy. PMID- 28868421 TI - Brunner's Gland Hamartoma - A Rare Cause of Upper Gastrointestinal Bleeding. PMID- 28868422 TI - RDW as a Surrogate Marker for Active Crohn's Disease: Potential Utility. PMID- 28868423 TI - Real-Time Elastography in the Assessment of Advanced Fibrosis in Chronic Hepatitis C: Is It Here to Stay? PMID- 28868424 TI - Can Red Cell Distribution Width Be Used as a Marker of Crohn's Disease Activity? AB - INTRODUCTION: Recently, it has been suggested an association between red cell distribution width (RDW) and Crohn's disease activity index (CDAI), but its use is not yet performed in daily clinical practice. OBJECTIVES: To determine whether RDW can be used as a marker of Crohn's disease (CD) activity. METHODS: This was a cross-sectional study including patients with CD, observed consecutively in an outpatient setting between January 1st and September 30th 2013. Blood cell indices, erythrocyte sedimentation rate (ESR), and C-reactive protein were measured. CD activity was determined by CDAI (active disease if CDAI >= 150). Associations were analyzed using logistic regression (SPSS version 20). RESULTS: 119 patients (56% female) were included in the study with a mean age of 47 years (SD 15.2). Twenty patients (17%) had active disease. The median RDW was 14.0 (13 15). There was an association between RDW and disease activity (p = 0.044). After adjustment for age and gender, this association remained consistent (OR 1.20, 95% CI 1.03-1.39, p = 0.016). It was also found that the association between RDW and disease activity was independent of hemoglobin and ESR (OR 1.36, 95% CI 1.08 1.72, p = 0.01) and of biologic therapy (OR 1.19, 95% CI 1.03-1.37, p = 0.017). A RDW cutoff of 16% had a specificity and negative predictive value for CDAI >= 150 of 88% and 86%, respectively. CONCLUSION: In this study, RDW proved to be an independent and relatively specific marker of CD activity. These results may contribute to the implementation of this simple parameter, in clinical practice, aiming to help therapeutic decisions. PMID- 28868425 TI - Diagnostic Performance of Real-Time Elastography in the Assessment of Advanced Fibrosis in Chronic Hepatitis C. AB - BACKGROUND AND AIMS: Since liver fibrosis index (LFI) was developed by Fujimoto et al., real-time elastography (RTE) has become a promising non-invasive technique to assess fibrosis in chronic hepatitis C (CHC). The aims of this study were to compare the diagnostic performance of RTE versus laboratory tests to predict advanced fibrosis (METAVIR scoring system: F >= 3) in patients with CHC, using liver biopsy (LB) as the reference standard; and to evaluated the impact of patient anthropometric features on RTE histogram acquisition. METHODS: This prospective study included 37 patients with CHC scheduled for LB. Aspartate aminotransferase (AST)/alanine aminotransferase (AST) ratio, AST/platelet ratio index (APRI), and Fibrosis-4 index (FIB-4) were calculated from recent (<=6 months) laboratory data. RTE was performed by two independent operators blind to each other' findings and to LB results, using Hitachi HI-VISION Avius ultrasound system. According to Hitachi RTE software, liver elasticity was evaluated through the LFI. Percutaneous ultrasound-assisted LB was performed in the same day of RTE. All LB specimens were analyzed by an expert pathologist blind to RTE results. Hepatic fibrosis was staged according to METAVIR scoring system. The diagnostic performance of the LFI, AST/ALT ratio, APRI and FIB-4 for predicting advanced fibrosis was assessed using area under receiver-operating characteristic curve (AUROC), sensitivity, specificity, positive-predictive and negative predictive (NPV) values. RESULTS: Thirty-seven LB were performed without complications. The distribution according to METAVIR scoring system was F0-1 in 13 patients (35%), F2 in 13 (35%), F3 in 9 (25%) and F4 in 2 (5%). Thirty-seven RTE procedures were performed. Histogram acquisition was successfully achieved in 32 patients (86%). Abdominal wall thickness >=23 mm was associated with no histogram acquisition (p = 0.018). Using the optimal cut-off value of 2.38, the AUROC for the LFI was 0.73. The AUROC for the AST/ALT ratio, APRI and FIB-4 were 0.62, 0.79, and 0.82, respectively. CONCLUSIONS: The LFI calculated by RTE showed a very good diagnostic performance to predict advanced fibrosis in CHC, with remarkable sensitivity and NPV (both 100%). PMID- 28868426 TI - Biopsies in Gastrointestinal Endoscopy: When and How. AB - Gastrointestinal endoscopy and the acquisition of tissue samples are essential for the diagnosis and treatment of various diseases of the digestive system. However, given the differences between the recommendations and the clinical practice, the inexorable increase of requests for endoscopic examinations and the financial burden associated with it, it is crucial that we concentrate on the challenge that endoscopic biopsies represent. In this review we describe the available evidence in the literature, including the more recent published guidelines, on when or not to perform endoscopic biopsies in upper and lower endoscopy, focusing on the precise diagnosis of the most common gastrointestinal diseases that motivate endoscopic examinations and on the rational use of available resources without compromising proper management of patients. PMID- 28868427 TI - Contrast-Enhanced Cross Sectional Imaging and Capsule Endoscopy: New Perspectives for a Whole Picture of the Small Bowel. AB - Small bowel evaluation is a challenging task and has been revolutionized by high quality contrasted sectional imaging (CT enterography - CTE) and magnetic resonance enterography (MRE) as well as by small bowel capsule endoscopy (SBCE). The decision of which technique to employ during the investigation of small bowel diseases is not always simple or straightforward. Moreover, contraindications may preclude the use of these techniques in some patients, and although they are noninvasive procedures, may present with various complications. SBCE plays a crucial role in the investigation of both obscure gastrointestinal bleeding and Crohn's disease, but it is also useful for surveillance of patients with Peutz Jeghers syndrome, while CTE is very accurate in small bowel tumours and in established Crohn's Disease, and its use in patients presenting with gastrointestinal bleeding is increasing. MRE, an expensive and not widely available technique, is essential for the study of patients with Crohn's Disease, and presents an attractive alternative to SBCE in Peutz-Jeghers syndrome surveillance. These diagnostic modalities are often not competitive but synergistic techniques. Knowing their characteristics, strengths and limitations, indications, contraindications and potential complications, as well as the adaptation to local availability and expertise, is essential to better select which procedures to perform in each patient, both safely and effectively, in order to optimize management and improve patient outcomes. PMID- 28868428 TI - Endoscopic Scores for Evaluation of Crohn's Disease Activity at Small Bowel Capsule Endoscopy: General Principles and Current Applications. AB - The small bowel is affected in the vast majority of patients with Crohn's Disease (CD). Small bowel capsule endoscopy (SBCE) has a very high sensitivity for the detection of CD-related pathology, including early mucosal lesions and/or those located in the proximal segments of the small bowel, which is a major advantage when compared with other small bowel imaging modalities. The recent guidelines of European Society of Gastrointestinal Endoscopy (ESGE) and European Crohn's and Colitis Organisation (ECCO) advocate the use of validated endoscopic scoring indices for the classification of inflammatory activity in patients with CD undergoing SBCE, such as the Lewis Score or the Capsule Endoscopy Crohn's Disease Activity Index (CECDAI). These scores aim to standardize the description of lesions and capsule endoscopy reports, contributing to increase inter-observer agreement and enabling a stratification of the severity of the disease. On behalf of the Grupo de Estudos Portugues do Intestino Delgado (GEPID) - Portuguese Small Bowel Study Group, we aimed to summarize the general principles and clinical applications of current endoscopic scoring systems for SBCE in the setting of CD, covering the topic of suspected CD as well as the evaluation of disease extent (with potential prognostic and therapeutic impact), evaluation of mucosal healing in response to treatment and evaluation of post-surgical recurrence in patients with previously established diagnosis of CD. PMID- 28868429 TI - Impacted Foreign Body Causing Acute Malignant Colonic Obstruction. AB - Malignant colorectal obstruction is a serious complication of advanced cancers. The obstruction can be caused by colorectal cancer, adjacent organ cancer or distant metastases. Rectal metastases from gastric cancer are rare. Foreign body ingestion is not a rare event and the majority of them causes no symptoms or complications. Nevertheless, they are likely to stop at any narrowing or angulation of the intestinal lumen. The authors describe a rare clinical presentation of an impacted foreign body in a pathological narrowing secondary to rectal metastasis of a gastric neoplasia that caused an acute malignant colonic obstruction. After endoscopic removal of the foreign body, there was complete resolution of symptoms avoiding surgery or palliative stenting. This case report highlights the need of careful inspection of colonic malignant strictures before stenting to exclude other causes of colonic obstructions, as an impacted foreign body. PMID- 28868430 TI - Endoscopic Treatment of Early Gastric Obstruction After Sleeve Gastrectomy: Report of Two Cases. AB - Morbid obesity is an epidemic and complex disease which imposes a multidisciplinary approach. Laparoscopic sleeve gastrectomy has become a frequent procedure given its efficacy and safety compared to other surgical options. However, it isn't free from complications. Lax gastric fixation or incorrect positioning of the stomach during surgery can result in early gastric outlet obstruction caused by a volvulus-like mechanism by rotation of the stomach around its anatomic axes. This report refers to two cases of post sleeve gastric torsion resulting in persisting vomiting after initiating oral intake. The diagnosis was confirmed by upper gastrointestinal-contrast study and gastroscopy. In both cases, a fully covered self-expandable metallic stent was inserted which prompted the gastric lumen to become permeable resulting in symptomatic resolution. The stents were removed endoscopically after two and three months. Beyond more than three years of follow-up, the patients remain asymptomatic and no recurring "stenosis" was noticed. In these cases the use of fully covered self-expandable metallic stents demonstrated to be effective and safe in the treatment of post sleeve gastric torsion. PMID- 28868431 TI - Trichobezoar - A Rare Cause of Abdominal Mass and Gastric Outlet Obstruction. AB - The authors present the clinical case of a 14-year old girl with weight loss, anorexia, epigastric abdominal pain and postprandial vomiting with 5 months duration. There was a background of trichophagia for 2 years without evidence of alopecia or psychiatric history. The physical examination revealed an epigastric mass motionless, stony, with poorly defined limits, painful on palpation and about 7 cm diameter. Abdominal ultrasonography showed thickening of the gastric wall and antrum with gastric distension. The abdominal tomography scan and endoscopic examination revealed the presence of a bulky trichobezoar occupying almost the entire gastric lumen. It was decided to undergo gastrotomy and extraction of the bezoar. The postoperative period was uneventful. PMID- 28868432 TI - Gelatinous Ascites: A Characteristic Finding of a Rare Entity. PMID- 28868433 TI - Fistulizing Gastric GIST. PMID- 28868434 TI - To Stent or Not to Stent in Colorectal Cancer: That is Still the Question in Gastroenterology! PMID- 28868435 TI - Sprue-Like Enteropathy Associated With Olmesartan: A New Kid on the Enteropathy Block. PMID- 28868436 TI - Acute Treatment of Malignant Colorectal Occlusion: Real Life Practice. AB - INTRODUCTION: Colorectal cancer presents itself as acute bowel occlusion in 10 40% of patients. There are two main therapeutic approaches: urgent surgery and endoluminal placement self-expandable metallic stents (SEMS). AIMS AND METHODS: This study intended to better clarify the risk/benefit ratio of the above mentioned approaches. We conducted a retrospective longitudinal multicenter study, including 189 patients with acute malignant colorectal occlusion, diagnosed between January 2005 and March 2013. RESULTS: Globally (85 patients - 35 bridge-to-surgery and 50 palliative), SEMS's technical success was of 94%. Palliative SEMS had limited clinical success (60%) and were associated with 40% of complications. SEMS occlusion (19%) was the most frequent complication, followed by migration (9%) and bowel perforation (7%). Elective surgery after stenting was associated with a higher frequency of primary anastomosis (94% vs. 76%; p = 0.038), and a lower rate of colostomy (26% vs. 55%; p = 0.004) and overall mortality (31% vs. 57%; p = 0.02). However, no significant differences were identified concerning postoperative complications. Regarding palliative treatment, no difference was found in the complications rate and overall mortality between SEMS and decompressive colostomy/ileostomy. In this SEMS subgroup, we found a higher rate of reinterventions (40% vs. 5%; p = 0.004) and a longer hospital stay (14, nine vs. seven, three days; p = 0.004). CONCLUSION: SEMS placement as a bridge-to-surgery should be considered in the acute treatment of colorectal malignant occlusion, since it displays advantages regarding primary anastomosis, colostomy rate and overall mortality. In contrast, in this study, palliative SEMS did not appear to present significant advantages when compared to decompressive colostomy. PMID- 28868437 TI - Reevaluation of Self-Expanding Metal Stents as a Bridge to Surgery for Acute Left Sided Malignant Colonic Obstruction: Six Years Experience. AB - INTRODUCTION: Self-expanding metal stents (SEMS) as a bridge to surgery have been used as an alternative for acute malignant left-sided colonic obstruction. However, the benefits are uncertain. The European Society of Gastrointestinal Endoscopy no longer recommends their use in patients with low surgical risk because of the risk of tumor recurrence. METHODS: Patients admitted for acute malignant left-sided colonic obstruction who underwent SEMS as a bridge to elective surgery or urgent surgery were retrospectively evaluated. Postoperative morbidity/mortality, stent complications and survival were recorded. Our aim was to compare the outcome between preoperative SEMS and direct emergent surgery in acute left-sided malignant colonic obstruction. RESULTS: 42 patients were included (SEMS group: 27 and surgery group: 15). There were no differences between groups in relation to age, ASA classification and tumor stage. The technical success of SEMS was 88.9% and the clinical success was 85.2%. There were three SEMS related perforations. In the surgery group, the stoma rate was higher (86.7% vs 25.9%, p < 0.001) and there was a trend for a lower length of hospital stay (18.9 days vs 26.3 days, p = 0.051). SEMS verses surgery group: There were no differences in the rate of temporary stoma (57.1% vs 61.5%, p = 0.84), definitive stoma (42.8% vs 38.5%, p = 0.84), success of primary anastomosis (86.7% vs 66.7%, p = 0.22) and Clavien-Dindo classification (>=III: 36% vs 58.2% p = 0.24). Overall survival at 1/5 years was identical in the two groups 100%/56% in the SEMS group vs 93%/43% in the surgery group, p = 0.14), as well as tumor recurrence at 3/5 years (24%/50% vs 20%/36% respectively, p = 0.68). CONCLUSIONS: SEMS are associated with a lower overall stoma rate and a higher primary anastomosis rate. However, there are no differences in complications, overall survival and recurrence between the groups. PMID- 28868438 TI - The Role of Emergency Endoscopy in Small Bowel Bleeding: A Review. AB - There is no consensus on the timing and management of emergency overt obscure gastrointestinal bleeding. Emergency capsule endoscopy and balloon-assisted enteroscopy have a high diagnostic and therapeutic yield in these situations. Most lesions detected by small bowel endoscopy are amenable to endoscopic haemostasis, although some lesions still require surgery or interventional radiology. The management of these patients is varied, and doubt persists about which technique should be preferred as first-line treatment. This narrative review analyses the usefulness and impact of small bowel endoscopic techniques in the emergency setting for severe overt obscure gastrointestinal bleeding. PMID- 28868439 TI - Olmesartan-Induced Enteropathy: An Unusual Cause of Villous Atrophy. AB - We report a case of a 63-year-old-man presenting with chronic diarrhea and weight loss while on olmesartan treatment for hypertension. Investigation showed multiple nutritional deficiencies associated with diffuse intestinal villous atrophy. Serologies for celiac disease were negative and other causes of villous atrophy were excluded. Olmesartan as a precipitant agent was suspected and withdrawn. Clinical improvement occurred in days with no need for other therapeutic measures. Follow-up at three months showed clinical remission and almost complete recovery of intestinal atrophy. Olmesartan is an angiotensin receptor blocker commonly prescribed for the management of hypertension. Spruelike enteropathy associated with this drug is a recently described entity with few cases reported. It presents with chronic diarrhea and intestinal villous atrophy and should be included in its differential diagnosis. This case intends to alert clinicians for the possibility of this event in a patient on treatment with this drug. PMID- 28868440 TI - Enteropathy Associated with Olmesartan. AB - The recognition of an enteropathy caused by olmesartan is recent. It was first described in 2012 by the Mayo Clinic, which presented 22 clinical cases. Olmesartan is a highly prescribed drug and the differential diagnosis of a sprue like enteropathy is very wide, so it is important to be aware of this pathology. We report a case of a 67-years-old man, with arterial hypertension under treatment with olmesartan, with a 4-months history of diarrhea and weight lost. He was admitted three times in our Department during this period of time. An initial diagnosis was made of lymphocytic colitis but he did not respond to treatment with corticosteroids. There was a high suspicion of celiac disease, so the patient started a gluten-free diet but still there were no symptomatic changes. The patient underwent several blood and imaging tests which were negative. Due to the suspicion of an enteropathy caused by drugs, olmesartan was stopped and the patient showed a significant improvement of his symptoms. The exact pathophysiology of this entity remains to be elucidated. It may affect all gastrointestinal tract and mimic a refractory celiac disease as well as a lymphocytic colitis due to similar symptoms and histology. It is expected more cases like this in the future due to high use of olmesartan in current clinical practice. So, it is important to all gastroenterologists to be aware of this pathology and take it into consideration when putting together a differential diagnosis. PMID- 28868441 TI - Olmesartan-Induced Sprue Like Enteropathy. AB - Chronic diarrhoea is a common clinical problem in gastroenterology practice and often it is difficult to diagnose the cause. Villous atrophy is not specific and the rarer possibility of drug-induced enteritis should always be considered. Olmesartan has recently been described as a cause of drug-induced enteropathy characterized by chronic diarrhoea and varying degrees of duodenal mucosa atrophy resembling celiac disease. We describe two cases of sprue-like enteropathy in patients treated with olmesartan for arterial hypertension several years before the onset of symptoms. Patients presented severe diarrhoea and significant weight loss, and both had histological evidence of intestinal villous atrophy. The clinical signs completely resolved after drug withdrawal. Olmesartan-induced enteropathy is a new clinical entity that must be included in the differential diagnosis of villous atrophy with negative celiac serology. The clinical and histological alterations easily and completely resolve after drug discontinuation, restoring quality of life to patients and avoiding unnecessary investigation. PMID- 28868442 TI - Refractory Celiac Disease Type II: A Case Report that Demonstrates the Diagnostic and Therapeutic Challenges. AB - Refractory celiac disease is an uncommon but serious complication of celiac disease. We describe a case of a severe refractory celiac disease type II, complicated with ulcerative jejunoileitis, in a 68 years old female, unresponsive to consecutive treatments with budesonide, prednisolone, cladribine and autologous stem cell transplantation. The patient maintained severe malnutrition, advanced osteoporosis, anaemia, vitamin deficiencies and hydro-electrolytic imbalances, necessitating consecutive hospitalizations for total parenteral nutrition. The patient also developed life-threatening complications, namely respiratory and urinary septic shock and also episodes of haemorrhagic shock secondary to ulcerative jejunoileitis. The progression to enteropathy associated T-cell lymphoma was never demonstrated, but the patient died 7 years after the diagnosis due to a septic shock secondary to a nosocomial pneumonia and osteomyelitis related to a spontaneous hip fracture. This case highlights the difficulties in the diagnostic process, therapeutic management and surveillance of this rare condition associated with very poor prognosis. PMID- 28868443 TI - Intraluminal Duodenal ("Windsock") Diverticulum: A Rare Cause of Gastrointestinal Bleeding. PMID- 28868444 TI - Extensive Esophageal Ulceration in a Renal Transplant Patient. PMID- 28868445 TI - Successful Endoscopic Removal of a Kerh-Tube Placed in an Iatrogenic Esophageal Perforation: Push to Pull. PMID- 28868446 TI - GE - Into the Future. PMID- 28868447 TI - A Bugs Battle on Behalf of the Liver. PMID- 28868448 TI - Acute or Recurrent Abdominal Pain: The Eyes Can Only See What the Mind Knows! PMID- 28868449 TI - Microbiota Modulation With Synbiotic Decreases Liver Fibrosis in a High Fat Choline Deficient Diet Mice Model of Non-Alcoholic Steatohepatitis (NASH). AB - BACKGROUND: Gut microbiota may play a role in non-alcoholic steatohepatitis (NASH). Previous studies showed that prebiotics and probiotics might halt the progression of steatohepatitis. AIM: To clarify the potential effect of Synbiotic 2000(r)Forte (Synb) in preventing or ameliorating diet induced steatohepatitis, particularly in fibrosis progression and how this intervention correlates with gut microbiota composition and endotoxinemia. METHODS: Twenty-seven C57BL/6 mice were divided into three groups: chow diet (CD, n = 7); high-fat choline deficient diet (HFCD, n = 10) and HFCD diet supplemented with Synbiotic 2000(r)Forte (four probiotic strains and four prebiotics mixture) (HFCD + Synb, n = 10). At 6 and 18 weeks, blood samples (lipopolysaccharides assay - LPS), cecal feaces (gut microbiota) and liver tissue (histology) were collected for analysis. RESULTS: Both HCFD diet mice developed steatohepatitis with ballooning at 6 and 18 weeks, opposite to CD. Comparison of histological scores in HFCD and HFCD + Synb, at 6 and 18 weeks showed no significant difference regarding steatosis, inflammation, or ballooning. Evaluating fibrosis with Sirius Red, and degree of smooth-muscle cell activation, HFCD mice had significantly more fibrosis; addition of Synb significantly reduced fibrosis at 6 weeks and 18 weeks. Serum endotoxin levels were similarly increased in HFCD and HFCD + Synb at week 6; however at week 18 HFCD + Synb had significantly lower endotoxin levels than HFCD. Gut microbiota of HFCD vs CD, showed no significant differences regarding the phyla Firmicutes and Bacteroidetes, either at 6 or 18 weeks; Proteobacteria increased at 6 week (3.3) and 18 week (7.5), while the addition of Synb resulted in a decrease at week 18 ( 3.90). Fusobacteria markedly increase at week 18 (10.0), but less so with the addition of Synb (5.2). CONCLUSION: Synbiotic 2000(r)Forte is able to modulate the mouse gut microbiota reducing the degree of fibrosis while simultaneously decreasing endotoxemia. PMID- 28868452 TI - Isolated Visceral Angioedema Induced by Angiotensin-Converting Enzyme Inhibitor. AB - Visceral angioedema is a rare complication of therapy with angiotensin-converting enzyme (ACE) inhibitors. Clinical presentation includes nausea, vomiting, abdominal pain and diarrhea. Early detection of this entity can prevent recurrent episodes and unnecessary invasive procedures, including surgery. This article describes a 46-year-old-woman who presented to the emergency department with abdominal pain, associated with nausea and vomiting. She had been taking ramipril for 15 days. A computed tomography was performed which revealed thickening of a jejunal segment, with submucosal edema. ACE inhibitor-associated angioedema was suspected and the medication was discontinued, with resolution of symptoms in 48 h. After 7 months of follow-up, the patient is asymptomatic. Despite of its rarity, ACE inhibitor-induced small-bowel angioedema should be included in the differential diagnosis when patients receiving ACE inhibitor therapy present with abdominal complaints. PMID- 28868451 TI - Anti-TNF Withdrawal in Inflammatory Bowel Disease. AB - The introduction of the anti-tumor necrosis factoralpha agents (anti-TNFalpha) in clinical practice has greatly advanced the treatment of inflammatory bowel disease. The use of these medications results in durable remission in a subset of patients, preventing surgery and hospitalizations. However, there are some concerns about safety and costs associated with their long-term use. Therefore, anti-TNF withdrawal has emerged as an important consideration in clinical practice. Herein our goal was to discuss the available evidence about anti TNFalpha discontinuation in IBD that could inform the clinician on the expected rates of relapse, the potential predictors of relapse, as well the response to re treatment. PMID- 28868453 TI - Visceral Angioedema Induced by Angiotensin Converting Enzyme Inhibitor: Case Report. AB - INTRODUCTION: Intestinal angioedema is a rare adverse effect of angiotensin converting enzyme inhibitors. CLINICAL CASE: A 42-year old woman presented to the Emergency Department complaining of diffuse abdominal pain, predominantly in the right quadrants, with no other associated symptoms. She had been started on perindopril plus indapamide 72 h before the admission for arterial hypertension. There was no other relevant background. Physical examination suggested peritoneal irritation on the lower quadrants of the abdomen and right flank. Laboratory tests were relevant for mild leukocytosis. Abdomen ultrasound and contrast enhanced computed tomography scan showed moderate amount of fluid in the pelvic excavation and small intestine wall thickening. She was admitted for observation. Once the hypothesis of intestinal angioedema was admitted, angiotensin converting enzyme inhibitor was withheld and no other-directed therapy was instituted. Within 24 h she showed clinical, analytic and imaging improvement, thus supporting this diagnosis. CONCLUSION: The diagnosis of intestinal angioedema induced by angiotensin converting enzyme inhibitor can be challenging and time consuming due to its rarity and nonspecific symptoms, which may lead to underdiagnosis of this entity. PMID- 28868450 TI - Endoscopic Management of Foreign Bodies in the Upper Gastrointestinal Tract: An Evidence-Based Review Article. AB - Gastrointestinal foreign bodies (FB) are comprised of food bolus impaction and intentionally or unintentionally ingested or inserted true FB. Food bolus impaction and true FB ingestion represent a recurrent problem and a true challenge in gastrointestinal endoscopy. More than 80-90% of the ingested true FB will pass spontaneously through the gastrointestinal tract without complications. However, in 10-20% of the cases an endoscopic intervention is deemed necessary. True FB ingestion has its greatest incidence in children, psychiatric patients and prisoners. On the other hand, food bolus impaction typically occurs in the elderly population with an underlying esophageal pathology. The most serious situations, with higher rates of complications, are associated with prolonged esophageal impaction, ingestion of sharp and long objects, button batteries and magnets. Physicians should recognize early alarm symptoms, such as complete dysphagia, distressed patients not able to manage secretions, or clinical signs of perforation. Although many papers are yearly published regarding this subject, our knowledge is mainly based on case-reports and retrospective series. Herein, the authors summarize the existing evidence and propose an algorithm for the best approach to FB ingestion. PMID- 28868454 TI - Groove Pancreatitis with Biliary and Duodenal Stricture: An Unusual Cause of Obstructive Jaundice. AB - INTRODUCTION: Groove pancreatitis is an uncommon cause of chronic pancreatitis that affects the groove anatomical area between the head of the pancreas, duodenum, and common bile duct. CLINICAL CASE: A 67-year-old man with frequent biliary colic and an alcohol consumption of 30-40 g/day was admitted to the hospital complaining of jaundice and pruritus. Laboratory analysis revealed cholestasis and the ultrasound scan showed intra-hepatic biliary ducts dilatation, middle third cystic dilatation of common bile duct, enlarged Wirsung and pancreatic atrophy. The magnetic resonance cholangiopancreatography showed imaging findings compatible with groove pancreatitis. An esophagogastroduodenoscopy later excluded duodenal neoplasia. He was submitted to a Roux-en-Y cholangiojejunostomy because of common bile duct stricture. Five months later a gastrojejunostomy was performed due to a duodenal stricture. The patient remains asymptomatic during follow-up. DISCUSSION: Groove pancreatitis is a benign cause of obstructive jaundice, whose main differential diagnosis is duodenal or pancreatic neoplasia. When this condition causes duodenal or biliary stricture, surgical treatment can be necessary. PMID- 28868455 TI - A Rare Cause of Proximal Intestinal Obstruction. PMID- 28868457 TI - Pediatric Crohn's Disease and Surgery: Another Tool for the Treatment of a Complex Disease. PMID- 28868456 TI - Massive Gastrointestinal Bleeding from an Ectopic Varix in a Non-Cirrhotic Patient: Angiographic Approach Following Endoscopic Treatment Failure. PMID- 28868458 TI - Iatrogenic Perforations During Colonoscopy In a Portuguese Population: A Study Including In and Out-Of-Hospital Procedures. AB - INTRODUCTION: The risk of iatrogenic perforations in colonoscopy is not negligible. Experience with endoscopic closure of perforations is increasing and new devices for this purpose are being released, making endoscopy a therapeutic option. National data regarding iatrogenic perforations is scarce and the burden of iatrogenic perforations in out-hospital procedures is poorly characterized in the literature. OBJECTIVE: Evaluation of iatrogenic perforations rate during colonoscopy, their characteristics, management and prognosis. METHODS: Retrospective study of all patients with perforations secondary to in-hospital and non-hospital colonoscopies treated in a tertiary hospital between 01-01-2006 and 01-10-2014. Demographic, endoscopic, radiological and therapeutic data were analyzed. RESULTS: Fifty-three perforations were identified, 20 occurring in colonoscopies performed in non-hospital environment (45% with therapeutic procedures) and 33 occurring in-hospital procedures (73% in therapeutic colonoscopies; representing 0.12% of all colonoscopies carried out in-hospital). Patients: male in 56%, average age of 71 years, history of previous abdominopelvic surgery in 31% and diverticulosis in 10%. Colonoscopy: elective in 93%, under deep sedation in 21%, with less than excellent/good bowel preparation in 56%. A resident was the first performer in 10 cases. Perforations: average size of 21 mm (4-130 mm), diagnosed during the procedure in 51% of cases and occurred in rectum-sigmoid transition in 58.5%. Regarding therapeutics, all patients with perforation occurring in non-hospital colonoscopies were managed by surgery. Concerning treatment of those in our unit: 2-conservative, 12-endoscopic (10 successfully), 21-surgical (including the 2 cases with failure of the endoscopic approach). Comparing endoscopic treatment (n = 10, G1) versus surgery (n = 21; G2): perforation size - 9 mm (G1) versus 28 mm (G2); perforation location - 7/10 in rectum-sigmoid (G1) versus 8/21 in rectum-sigmoid and 10/21 transverse/ascending colon/hepatic angle (G2). Morbidity: 1 infection in G1 and 13 complications in G2 (infection, hemorrhage, fistula). Mortality: no deaths in G1 and 2 deaths at 30 days due to septic shock in G2. CONCLUSION: Perforations in colonoscopy are rare in our clinical practice. Endoscopic closure was effective, though limited to perforations found during the procedure. The mortality was relatively low and endoscopic management did not seem to worsen it. An additional effort is necessary in order to detect perforations during colonoscopy. PMID- 28868459 TI - Surgery in Pediatric Crohn Disease: Case Series from a Single Tertiary Referral Center. AB - INTRODUCTION: There is a recognized increase of lifelong surgery risk in Crohn disease (CD). Outcome data concerning surgery in children, particularly in the biological era, are limited. AIM: To characterize the clinical profile and the clinical outcome in children and adolescents with CD who underwent surgical intervention, in a single tertiary referral center. METHODS: Retrospective, cross sectional study, including pediatric patients with CD undergoing intra-abdominal surgery in the last 11 years. RESULTS: Included eight of 50 CD total patients (16%); six female; median age at CD diagnosis of 12.0 years; Paris classification: (a) location: ileocolonic (5), colonic (1), upper disease (1), ileocolonic/upper disease (1); (b) behavior: stricturing (4), nonstricturing nonpenetrating (2), penetrating (1), both penetrating and stricturing disease (1); growth delay (2). Six children received thiopurines, five mesalazine, three corticosteroids and four anti-TNF therapy, preoperatively. Surgery followed diagnosis by a median of 2.9 years. Median PCDAI at the time of surgery was 35.0. Elective surgery was performed in six patients and emergency surgery in two, without major complications. Five children received anti-TNF and three thiopurines post-operatively. Within the follow-up period (median 1.7 years), relapse occurred in one child (3.2 years after intervention); the remaining seven patients persist in clinical remission. Median PCDAI in the last evaluation was 6.3. Weight and height recovery was observed in seven patients, at last follow up. CONCLUSION: Surgical treatment of CD is a valid alternative in selected cases, contributing to the resolution of acute complications and maintenance of remission, allowing disease-free interval and nutritional recovery. PMID- 28868461 TI - Disseminated Tuberculosis in an Immunocompetent Patient: The Answer is in the Liver. AB - Tuberculosis, a chronic infectious disease caused by Mycobacterium tuberculosis, may invade all organs but mainly affect the lungs. We report a case of disseminated tuberculosis with hepatic, pericardial and pleural involvement and a review of the relevant literature. A 64-year-old Portuguese male was admitted with epigastric and right upper quadrant pain associated with low grade fever, fatigue, nausea, anorexia, weight loss (6 kg) and mild jaundice. A chest X-ray showed cardiomegaly and a computed tomographic scan of the thorax and abdomen revealed a mild left pleural effusion, a thickened pericardium with signs of incipient calcification and hepatomegaly. The echocardiogram suggested the diagnosis of constrictive pericarditis. Liver biopsy revealed granulomatous lesions with central caseating necrosis. Tuberculosis is usually associated with atypical clinical manifestations. Imaging examination combined with histopathological features, a high index of clinical suspicion and improvement with antibacilar therapeutic are necessary to confirm a diagnosis, especially in the cases of extrapulmonary tuberculosis. PMID- 28868460 TI - Large Colorectal Lesions: Evaluation and Management. AB - In the last years, a distinctive interest has been raised on large polypoid and non-polypoid colorectal tumors, and specially on flat neoplastic lesions >=20 mm tending to grow laterally, the so called laterally spreading tumors (LST). Real or virtual chromoendoscopy, endoscopic ultrasound or magnetic resonance should be considered for the estimation of submucosal invasion of these neoplasms. Lesions suitable for endoscopic resection are those confined to the mucosa or selected cases with submucosal invasion <=1000 MUm. Polypectomy or endoscopic mucosal resection remain a first-line therapy for large colorectal neoplasms, whereas endoscopic submucosal dissection in high-volume centers or surgery should be considered for large LSTs for which en bloc resection is mandatory. PMID- 28868462 TI - Mucosal Prolapse Polyp Mimicking Rectal Malignancy: A Case Report. AB - Mucosal prolapse polyps (MPPs) are rare inflammatory lesions that are part of the mucosal prolapse syndrome. We present the case of a 40-year-old male with history of constipation referred to our institution with suspected rectal malignancy due to hematochezia and a palpable rectal mass. Colonoscopy revealed a 25 mm wide lesion suggestive of subepithelial origin but with marked erythema and erosion in the mucosa. Crypt dilatation and distortion, mixed inflammatory infiltrate and fibrosis were apparent on histological evaluation after bite-on-bite biopsies. Due to the initial suspicion of malignancy, resection was decided after discussion with the patient. However, due to non-elevation partial resection was performed allowing the diagnosis of MPP. Hematochezia ceased after obstipation treatment and endoscopic follow-up showed maintenance of the lesion with the same characteristics except for reduced dimension. MPP may mimic neoplastic lesions and should be considered in the differential diagnosis of rectal masses. History, endoscopy and histological characteristics are all necessary and important in the diagnosis of MPP. PMID- 28868464 TI - Genital Ischemia in a Patient Under Terlipressin Therapy. PMID- 28868463 TI - Caustic Esophageal Stenosis: A Case Report of Endoscopic Dilation With a Dynamic Stent. AB - INTRODUCTION: The management of esophageal strictures has evolved from surgical treatment to the endoscopic dilation and, more recently, esophageal stenting. CLINICAL CASE: We describe a case of a two-year-old boy with a double stenosis of the esophagus resulting from accidental ingestion of strong alkaline liquid. After several unsuccessful endoscopic dilations for three years and even topical mitomicin, it was decided to place a dynamic stent developed by the Digestive Surgery and Endoscopic Unit of the Bambino Gesu Hospital, Rome. The stent is a custom silicon device built coaxially on a nasogastric tube that is inserted after stricture dilations, by endoscopic guidance, and then fixed outside the nose. The device was removed after seven weeks with good clinical outcome (no dysphagia more than a year of follow-up). CONCLUSION: This case confirms that the dynamic stent is a simple device that may avoid aggressive surgical substitution in cases of refractory strictures. PMID- 28868465 TI - Endoscopic View of Embolization Coil in a Duodenal Ulcer. PMID- 28868466 TI - Obstructive Jaundice Due to Foreign Body in the Bile Duct: An Unusual Finding. PMID- 28868467 TI - Hepatocellular Carcinoma: Portuguese Data in Chronic Hepatitis B Patients on Antiviral Therapy and Treatment Results With Sorafenib. PMID- 28868468 TI - Hepatocellular Carcinoma in Chronic Hepatitis B Patients on Third Generation Nucleos(t)ides Analogs: Risk Factors and Performance of a Risk Score. AB - OBJECTIVE: To investigate hepatocellular carcinoma (HCC) incidence, risk factors and the performance of baseline REACH-B risk score in a Portuguese chronic hepatitis B (CHB) population on antiviral therapy. METHODS: Retrospective study of CHB patients who were treated with tenofovir or entecavir for at least 12 months. Multivariate analysis was performed to identify factors associated with HCC. The Kaplan-Meier method was used to estimate the cumulative incidence of HCC at 1, 3 and 5 years on therapy. The performance of the REACH-B score at baseline was assessed. RESULTS: One hundred and twenty patients initiated nucleos(t)ide analogs (NUC) therapy (age, 47 +/- 14 years-old; 83 male; 11% had cirrhosis; 71% tenofovir; 73% HBeAg-negative; 61% treatment-naive). After a median time under NUC of 39 months, 9 patients (7.5%) developed HCC. The calculated cumulative incidence rates of HCC at 1, 3 and 5 years on therapy were 5.1%, 7.3% and 8.8%, respectively. Independent predictors for HCC occurrence: age and cirrhosis at baseline. Diagnostic accuracy of baseline REACH-B score in predicting HCC development: AUC 0.738, 95%CI: 0.521-0.955. The cutoff value of 8 points had a sensitivity, specificity, positive predictive value and negative predictive value of 75%, 52%, 6% and 98%, respectively in predicting HCC occurrence during therapy. CONCLUSIONS: Older age and cirrhosis at baseline were independent predictors for HCC development. Discriminatory performance of baseline REACH-B score was limited. PMID- 28868469 TI - Hepatocellular Carcinoma Treatment With Sorafenib: Real-Life Evaluation of Prognostic Factors and a Practical Clue for Patient Management. AB - INTRODUCTION: Sorafenib chemotherapy is the first-line therapy for patients with hepatocellular carcinoma (HCC) in an advanced stage. The aim of this study was to evaluate prognostic factors of survival in HCC patients treated with sorafenib, in real-life clinical practice. MATERIAL AND METHODS: Retrospective study of HCC patients who initiated treatment with sorafenib, following assessment and indication from the multidisciplinary group. RESULTS: There were included 36 patients, mostly male (89%) and with a mean age of 65 years. The main etiologies were chronic hepatitis C (44%) and alcoholic liver disease (36%). Twenty patients (56%) were classified as Child-Pugh A and 16 patients (44%) as Child-Pugh B. Half of the patients group were staged as BCLC C and the remaining as BCLC B. Significant adverse events were observed in 15 patients (42%) and were associated with longer survival (21.5 vs. 3.2 months, p < 0.001). The most frequent adverse events were diarrhea and palmar-plantar syndrome. Median survival was 17.3 months for Child-Pugh A versus 3.2 months for Child-Pugh B patients (p = 0.001). Within Child-Pugh A, median OS was 21.5 months for BCLC B patients and 15.7 months for BCLC C patients (p = 0.001). DISCUSSION AND CONCLUSIONS: The main prognostic factors beyond Child-Pugh class and BCLC stage included the occurrence of significant adverse events. Being related to increased time of exposure to the drug, it points out the need of dose reducing instead of discontinuation whenever significant adverse events occur. PMID- 28868470 TI - Treating Gastric Antral Vascular Ectasia - When Argon Therapy Is Not Enough. AB - Gastric antral vascular ectasia (GAVE) is a capillary-type vascular malformation of the gastric antrum and an infrequent cause of chronic gastrointestinal blood loss and iron deficiency anemia. The authors describe a case report of GAVE in a female cirrhotic patient presenting with severe symptomatic iron deficiency anemia. After failure of argon plasma coagulation (APC), the patient was treated with endoscopic band ligation (EBL) with resolution of anemia, without new episodes of rebleeding and no need for further hospitalizations or transfusion requirements. Even though APC is the current treatment of choice for GAVE recurrence-free survival at one year is achieved in less than 50% of the patients and failed therapy has been described in up to 14% of the patients. EBL has been reported to be a relatively easy technique for GAVE therapy and has been shown to be safe and effective with lower complication rates in comparison with APC. This technique may in the future be used as the initial endoscopic treatment to eradicate GAVE. PMID- 28868471 TI - Cystic Pancreatic Lymphangioma - Diagnostic Role of Endoscopic Ultrasound. AB - Pancreatic cystic lymphangiomas are rare benign lesions that arise from lymphatic vessels, accounting for less than 0.2% of all pancreatic cysts. Typically it is asymptomatic and discovery occurs during imaging exams for non-pancreatic disease. In the past, a definite diagnosis was made through surgery, with complete resection of all tumoral tissue to prevent recurrence. Nowadays, the development of endoscopic ultrasound (EUS) made it possible to identify these cysts combining morphologic ultrasound features, macroscopic aspirated fluid appearance, biochemical and cytological evaluation of the sample. We report two cases of cystic pancreatic lymphangioma diagnosed through EUS, allowing conservative management without surgery. These cases show that cystic pancreatic lymphangioma should be considered in the differential diagnosis of cystic pancreatic lesions and that EUS is an important tool for their recognition. PMID- 28868473 TI - Colonic Intussusception Caused by Colonic Lipoma. PMID- 28868472 TI - Tracheitis - A Rare Extra-Intestinal Manifestation of Ulcerative Colitis in Children. AB - INTRODUCTION: Inflammatory bowel disease may cause both intestinal and extraintestinal manifestations. Respiratory symptoms in ulcerative colitis are rare and tracheal involvement is exceedingly rare in children. CASE 1: Sixteen year-old female with a 4-week-complaint of abdominal pain, bloody diarrhea, fever and cough. The investigation was consistent with the diagnosis of concomitant ulcerative colitis/coinfection to Escherichia coli. On day 4 respiratory signs persisted so azithromycin and inhaled corticosteroids were added. By day 6 she progressed to respiratory failure and was diagnosed with necrotic tracheitis so started on intravenous steroids with fast clinical improvement. CASE 2: Twelve year-old male adolescent with ulcerative colitis and sclerosing cholangitis started dry cough and throat pain 10 days after diagnosis. Laboratory investigations showed increased inflammatory signs and normal chest X-ray. He started treatment with azithromycin without clinical improvement and on day five he presented dyspnea and fever. Laryngeal fibroscopy suggested tracheitis and so systemic steroids where added with fast clinical and analytic improvement. DISCUSSION: Tracheitis should be suspected if there are persistent respiratory symptoms even when exams are normal. Early recognition and early treatment are essential for a good prognosis preventing progression to respiratory failure. PMID- 28868474 TI - Kaposi's Sarcoma - An Unusual Cause of Upper Gastrointestinal Bleeding. PMID- 28868475 TI - Idiopathic Pneumatosis Intestinalis, Radiological and Endoscopic Images. PMID- 28868476 TI - The Lymphoma Hidden in Actinomycosis. PMID- 28868477 TI - Intestinal Obstruction Due to Malrotation of Midgut and Right Paraduodenal Hernia. PMID- 28868478 TI - Small Bowel GIST: Clinical Presentation as Intussusception and Obscure Bleeding. PMID- 28868479 TI - Skin Metastases: The Visible Face of a Disastrous Unusual Finding. PMID- 28868480 TI - Self-Expandable Metal Stent as a Bridge to Surgery for Obstructing Colonic Cancer: Still a Hot Topic for Debate. PMID- 28868481 TI - The Role of Endoscopic Ultrasound in the Diagnostic Assessment of Subepithelial Lesions of the Upper Gastrointestinal Tract. AB - INTRODUCTION: The identification of subepithelial lesions is a relatively frequent finding at endoscopy however their natural history is not well known. Our aim was to analyze the role of endoscopic ultrasound (EUS) in the diagnostic approach of subepithelial lesions of the upper gastrointestinal tract. METHODS: Retrospective study which included 324 patients undergoing upper radial EUS for evaluation of subepithelial lesions from 2008 to 2014. The EUS features, presumptive diagnosis and management decision were analyzed. RESULTS: 324 patients included, 60% with gastric subepithelial lesions, 28% oesophageal and 12% from the duodenum. Based on EUS features the presumptive diagnosis was: 25% gastrointestinal stromal tumor, 21% lipoma, 19% leiomyoma, 17% pancreatic rest, 7% submucosa cysts, 1% granular cell tumors, 1% carcinoids, 1% mucosa lesions and 8% not defined. After EUS the suggested approach was no follow-up in 45%, follow up with re-examination with EUS in 35% and additional tissue sampling or endoscopic/surgical resection in 20%. The latter was based on EUS features of risk at the diagnosis (53%), such as size >=2 cm, hypoechogenicity, heterogeneity, lobulation, calcifications, cystic component and regional adenopathies; impossibility to define a presumptive diagnosis (39%) or EUS features change at follow-up (8%). The combination of multiple features correlated with a higher probability of this recommended strategy (p < 0.001), in 100% when 4 or more features were present. Among the 33 patients who underwent fine needle aspiration, in 66% the result was inconclusive. During follow-up, none of the patients who were managed with surveillance radial EUS presented complications. CONCLUSION: EUS is the method of choice in the study of subepithelial lesions of the upper gastrointestinal tract, in most cases defining a diagnosis. The need for a definitive diagnosis or therapeutic approaches can be based on ultrasound risk features, presented, in the majority, at presentation. This study shows that EUS is capable of safely and accurately define those subepithelial lesions that can be managed only with surveillance ultrasound while waiting for better results with fine needle aspiration. PMID- 28868482 TI - Self-Expandable Metal Stents for Colorectal Cancer: From Guidelines to Clinical Practice. AB - INTRODUCTION: Colonic self-expandable metal stent placement is widely used for palliation of obstructive colorectal cancer. The European recommendations for stent placement as a bridge to elective surgery in obstructive colorectal cancer were recently reviewed. The aim of this study was to evaluate the efficacy and safety of stent placement in obstructive colorectal cancer and to discuss these recent guidelines. MATERIALS AND METHODS: Demographic characteristics, procedure indications, complications and final outcome in patients with obstructive colorectal cancer who underwent endoscopic stent placement between January 2012 and June 2015 were retrospectively analyzed. Statistical analysis was performed with SPSS V22. RESULTS: Thirty-six patients were included, 20 (56%) women, mean age 70.6 +/- 10.9 years. Stent placement as a bridge to elective surgery was performed in 75% (n = 27) of patients and with palliation intent in 25% (n = 9). In 94% (n = 34) of procedures, technical and clinical success was achieved. A total of eleven (11%) complications were observed: 2 migrations and 9 perforations. No procedure related death was recorded. When stents were placed as a bridge to surgery, average time between endoscopic procedure and surgery was 11.7 +/- 9.4 days (excluding three patients who underwent neoadjuvant chemotherapy). Six perforations were recorded in this group: one overt and five silent (three during surgery and two after histopathological examination of the resected specimen). Twenty-one patients underwent adjuvant chemotherapy. During the follow-up period of 14.7 +/- 10.9 months recurrence was observed in five patients. None of the recurrence occurred in the group of patients with perforation. CONCLUSIONS: In this study, stent placement was an effective procedure in obstructive colorectal cancer. It was mainly used as a bridge to elective surgery. However, a significant rate of silent perforation was observed, which may compromise the oncological outcome of these potentially curable patients. Prospective real life studies are warranted for a better definition of actual recommendations. PMID- 28868483 TI - Ampullary Metastasis From Breast Cancer: A Rare Cause of Obstructive Jaundice. AB - Breast cancer is the most common tumor in women and the first cause of death for malignancy in the female. Bile ducts are not among the common sites of metastasis from breast cancer. Few cases of obstructive jaundice due to metastatic breast cancer have been described in the literature and they mostly resulted from widespread liver metastases that eventually involved the bile ducts. We report an exceptional case of ampullary metastasis in the absence of liver metastases. Sporadic reports have been published about the involvement of the ampulla by breast cancer metastasis. This case emphasizes the need to consider this diagnosis in women presenting with obstructive jaundice, especially when there is a clinical possibility of breast cancer. PMID- 28868484 TI - Acute Hepatitis in the DRESS Syndrome. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, idiosyncratic reaction characterized by diffuse maculopapular rash, facial edema, lymphadenopathy, fever, eosinophilia and/or other leukocyte abnormalities, and involvement of internal organs as liver, kidney, heart and lung. Diagnosing this entity is specifically complicated due to the multiplicity of organs involved. DRESS syndrome must be recognized promptly and the causative drug withdrawn in order to improve patient outcomes. Indeed, it is a potentially life-threatening condition, with a reported mortality between 5 and 20%. We describe a case of a 22-year old woman admitted to our hospital with acute diffuse, pruritic rash associated with crampy abdominal pain, vomiting, diarrhea and fever three weeks after starting sulfasalazine therapy. Initially, laboratory parameters revealed normal white blood cell count and normal liver enzymes, but during hospitalization, eosinophilia developed and liver enzymes, including transaminases and cholestatic parameters, dramatically increased. The diagnostic of DRESS syndrome was made and sulfasalazine was withdrawn and as there were signs of disease severity, systemic corticotherapy was initiated, with gradually improvement of the rash and symptoms resolution. The patient was discharged home after thirty days of hospitalization. PMID- 28868486 TI - Giant Pancreatic Cyst: An Unusual Entity. PMID- 28868485 TI - Drug-Induced Acute Pancreatitis and Pseudoaneurysms: An Ominous Combination. AB - Rupture of pseudoaneurysms is rare but can be life-threatening complications of acute or chronic pancreatitis, usually due to enzymatic digestion of vessel walls crossing peripancreatic fluid collections. We report the case of a 40 year-old female, with multisystemic lupus and anticoagulated for prior thrombotic events, admitted for probable cyclosporine-induced acute pancreatitis. Hemodynamic instability occurred due to abdominal hemorrhage from two pseudoaneurysms inside an acute peri-pancreatic collection. Selective angiography successfully embolized the gastroduodenal and pancreatoduodenal arteries. The hemorrhage recurred two weeks later and another successful embolization was performed and the patient remains well to date. The decision to restart anticoagulants and to suspend cyclosporine was challenging and required a multidisciplinary approach. Despite rare, bleeding from a pseudoaneurysm should be considered when facing a patient with pancreatitis and sudden signs of hemodynamic instability. PMID- 28868487 TI - Upper Gastrointestinal Kaposi's Sarcoma in an HIV-Infected Patient. PMID- 28868488 TI - Small Bowel Stricture Mimicking Megacolon in a Patient with Crohn's Disease. PMID- 28868489 TI - Liver Abscess Associated Sepsis Caused by Fish Bone Ingestion. PMID- 28868490 TI - Two Synchronous Pseudoinvasive Adenomas: Twice the Caution? PMID- 28868491 TI - Polidocanol Injection for the Treatment of Rectal Ulcer with Large Vessel After Hemorrhoidal Band Ligation. PMID- 28868492 TI - Unusual Endoscopic Removal of a Curious Foreign Body. PMID- 28868493 TI - Ulcerous Esophagitis in a Young Immunocompetent Patient. PMID- 28868494 TI - Small Bowel Obstruction Seven Years After Video Capsule Retention. PMID- 28868495 TI - Sprue-Like Enteropathy Associated with Olmesartan: An Unrecognized Emerging Drug Induced Enteropathy? PMID- 28868497 TI - Influence of Hematocrit and Total-Spot Volume on Performance Characteristics of Dried Blood Spots for Newborn Screening. AB - Dried blood spots (DBS) have been used in newborn screening (NBS) tests for over 50 years. The Newborn Screening Quality Assurance Program (NSQAP) at the Centers for Disease Control and Prevention (CDC) conducted studies to assess the individual impacts of hematocrit and total-spot volume on characteristics of DBS samples. Per-punch serum volumes decreased 27%, RBC volumes more than doubled, absorption times increased over 300%, and spot diameters decreased marginally between the hematocrits of 40% to 65%. Per-punch serum and RBC volumes decreased logarithmically with lowering total-spot volumes. Patient hematocrit is an uncontrollable variable and inevitably affects the resulting punch from a DBS sample. It may be possible, though, to identify samples that fall outside of an acceptable range by noting certain physical characteristics of the DBS. PMID- 28868498 TI - Non-derivatized Assay for the Simultaneous Detection of Amino Acids, Acylcarnitines, Succinylacetone, Creatine, and Guanidinoacetic Acid in Dried Blood Spots by Tandem Mass Spectrometry. AB - Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive genetic disorder which results in global developmental delay and intellectual disability. There is evidence that early treatment prevents intellectual disability and seizures. GAMT deficiency is now being discussed as a potential addition to the U.S. Recommended Uniform Screening Panel (RUSP); the availability of suitable screening methods must be considered. A neonatal screening derivatized method to quantify creatine (CRE) and guanidinoacetic acid (GAA) in dried blood spots by tandem mass spectrometry (MS/MS) has been described. Its key feature is the ability to detect CRE and GAA in the same extract generated from neonatal DBS during amino acids (AA) and acylcarnitines (AC) analysis. More laboratories are adopting non-derivatized MS/MS screening methods. We describe an improved, non-derivatized DBS extraction and MS/MS analytical method (AAAC-GAMT) which incorporates quantitation of CRE and GAA into routine analysis of amino acids, acylcarnitines, and succinylacetone. The non-derivatized AAAC-GAMT method performs comparably to the stand-alone GAMT and non-derivatized AAAC screening methods, evidencing its potential suitability for high-throughput GAMT neonatal screening. PMID- 28868496 TI - Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes. AB - It is well established that NADH/NAD+ redox balance is heavily perturbed in diabetes, and the NADH/NAD+ redox imbalance is a major source of oxidative stress in diabetic tissues. In mitochondria, complex I is the only site for NADH oxidation and NAD+ regeneration and is also a major site for production of mitochondrial reactive oxygen species (ROS). Yet how complex I responds to the NADH/NAD+ redox imbalance and any potential consequences of such response in diabetic pancreas have not been investigated. We report here that pancreatic mitochondrial complex I showed aberrant hyperactivity in either type 1 or type 2 diabetes. Further studies focusing on streptozotocin (STZ)-induced diabetes indicate that complex I hyperactivity could be attenuated by metformin. Moreover, complex I hyperactivity was accompanied by increased activities of complexes II to IV, but not complex V, suggesting that overflow of NADH via complex I in diabetes could be diverted to ROS production. Indeed in diabetic pancreas, ROS production and oxidative stress increased and mitochondrial ATP production decreased, which can be attributed to impaired pancreatic mitochondrial membrane potential that is responsible for increased cell death. Additionally, cellular defense systems such as glucose 6-phosphate dehydrogenase, sirtuin 3, and NQO1 were found to be compromised in diabetic pancreas. Our findings point to the direction that complex I aberrant hyperactivity in pancreas could be a major source of oxidative stress and beta cell failure in diabetes. Therefore, inhibiting pancreatic complex I hyperactivity and attenuating its ROS production by various means in diabetes might serve as a promising approach for anti diabetic therapies. PMID- 28868499 TI - The future of robotics. PMID- 28868500 TI - Epidemiology and economics of nephrolithiasis. AB - Nephrolithiasis is a disease common in both the Western and non-Western world. Several population based studies have demonstrated a rising prevalence and incidence of the disease over the last several decades. Recurrence occurs frequently after an initial stone event. The influence of diet on the risk of nephrolithiasis is important, particularly dietary calcium and fluid intake. An increasing intake of dietary calcium and fluid are consistently associated with a reduced risk of incident nephrolithiasis in both men and women. Increasing evidence suggests that nephrolithiasis is associated with systemic diseases like obesity, diabetes, and cardiovascular disease. Nephrolithiasis places a significant burden on the health care system, which is likely to increase with time. PMID- 28868501 TI - The role of metastasis-directed therapy and local therapy of the primary tumor in the management of oligometastatic prostate cancer. AB - Oligometastasis has been proposed as an intermediate stage of cancer spread between localized disease and widespread metastasis. Oligometastatic malignancy is now being diagnosed more frequently as the result of improvements in diagnostic modalities such as functional imaging. The importance of oligometastasis in managing metastatic prostate cancer is that it is possible to treat with a curative aim by metastasis-directed or local therapy in selected patients. Many studies have shown that these aggressive treatments lead to improved survival in other oligometastatic malignancies. However, few studies have shown definitive benefits of metastasis-directed or local therapy in oligometastatic prostate cancer. Review of the available studies suggests that stereotactic radiotherapy (RT) of metastatic lesions in oligorecurrent disease is a feasible and safe modality for managing oligometastatic prostate cancer. Also, stereotactic RT can delay the start of androgen deprivation therapy. Many retrospective studies of metastatic prostate cancer have shown that patients undergoing local therapy seem to have superior overall and cancer-specific survival compared with patients not receiving local therapy. Ongoing prospective randomized trials would be helpful to evaluate the role of local therapy in oligometastatic prostate cancer. PMID- 28868502 TI - Analysis of closed medical litigation in urology. AB - PURPOSE: The objective of this study was to provide a descriptive understanding of the characteristics of malpractice litigation related to urology by examining court cases. MATERIALS AND METHODS: A total of 6,074 court cases related to medical malpractice litigation filed between 2005 and 2010 were received from the Lower Courts, the Appellate Courts, and the Supreme Court of Korea. Of the received cases, 34 urology-related civil proceedings were analyzed. The following information was compiled and investigated from the cases: background, age and sex of patient, categorization of the defendant, opinion of the court, amount claimed and awarded in damages, type of medical treatment involved, and negative effects resulting from the medical accident. RESULTS: The average amount in damages paid out to plaintiffs in this research was 27,186,504+/-32,371,008 Korean won (KRW) (range, 1,000,000-100,000,000 KRW). A total of 9 of the 34 analyzed cases (26.5%) ruled in favor of the plaintiff, with all 9 cases involving a surgery. An analysis of the surgery sites further revealed that the penis was the most frequently litigated over site of surgery, making up 14 of the 35 sites (40.0%). CONCLUSIONS: Information regarding urology malpractice lawsuits should be made available to help prevent further disputes and litigation. Continuous efforts must be expended in the prevention of accidents and disputes, alongside research into urology-related cases beyond 2010. Extensive cause analysis and recurrence prevention methods must also be researched to enhance overall patient safety. PMID- 28868503 TI - Does T1- and diffusion-weighted magnetic resonance imaging give value-added than bone scintigraphy in the follow-up of vertebral metastasis of prostate cancer? AB - PURPOSE: To evaluate the effectiveness of limited Magnetic Resonance (MR) images including T1- and diffusion-weighted image (DWI) for monitoring vertebral metastasis in patients with prostate cancer. MATERIALS AND METHODS: From July 2014 to November 2016, patients diagnosed with spinal metastasis from prostate cancer using 99mTc bone scintigraphy were enrolled. Regardless of the primary local therapy, the changes in spinal metastasis were followed up using bone scan and biparametric MR (T1+DWI). All tests were followed up for more than 3 months. RESULTS: Among the 14 follow-ups of 10 patients, 6 and 10 (including all progressed cases on bone scan) follow-ups were determined to show progressive disease using bone scan and biparametric MR, respectively. Otherwise, we could have predicted neurologic sequela earlier using biparametric MR. Examination time for biparametric MR was 15 minutes, and it was 4 hours for bone scan, respectively. CONCLUSIONS: Although bone scan has been considered the standard test for bony metastasis in men with prostate cancer, limited MR including T1 and DWI has an additional benefit in monitoring spinal metastasis in patients who are already diagnosed as having spinal metastasis. The limited MR is more sensitive in detecting progressive disease. In addition, it can reduce neurologic complications caused by spinal metastasis. PMID- 28868504 TI - Patient-reported quality of life recovery curves after robotic prostatectomy are similar across body mass index categories. AB - PURPOSE: To assess the impact of body mass index (BMI) on postoperative recovery curve of urinary and sexual function after robotic-assisted laparoscopic prostatectomy (RALP). We hypothesized that overweight and obese men have different recovery curves than normal weight men. MATERIALS AND METHODS: We reviewed preoperative and postoperative surveys from 691 men who underwent RALP from 2004-2014 in an integrated healthcare delivery system. Survey instruments included: sexual health inventory for men (SHIM), urinary behavior, leakage, and incontinence impact questionnaire (IIQ). A repeated measures analysis with autoregressive covariance structure was employed with linear splines with 2 knots for the time factor. We fit unadjusted and adjusted models and stratified by BMI (under/normal weight, overweight, and obese). Adjusted models included age, race/ethnicity, smoking status, diabetes, operation length, prostate-specific antigen, pathologic stage, nerve-sparing status, and surgery year. RESULTS: Mean age was 59 years. Most men were overweight (43%) and obese (42%). There were no significant differences in mean baseline SHIM, urinary behavior, leakage, and IIQ scores by BMI category. All groups had initial steep declines in urinary and sexual function in the first 3 months after RALP. There were no significant differences in postoperative urinary and sexual function score curves by BMI category. CONCLUSIONS: The pattern of urinary and sexual function recovery was similar across all BMI categories. Overweight and obese men may be counseled that urinary and sexual function recovery curves after surgery is similar to that of normal weight men. PMID- 28868505 TI - Radiological noninvasive assessment of ureteral stone impaction into the ureteric wall: A critical evaluation with objective radiological parameters. AB - PURPOSE: To determine the predictive value of certain radiological parameters for an objective asssessment of the presence of ureteral stone impaction. MATERIALS AND METHODS: Seventy-nine patients with a single proximal ureteral stones were retrieved from the departmental database. Both clinical and particularly radiological data of all cases were well evaluated on this aspect. In addition to the time period between the first colic attack and definitive management; diameter of proximal ureter and renal pelvis, longitudinal and transverse stone size, Hounsfied unit (HU) of the stone and lastly ureteral wall thickness at the impacted stone site were all carefully evaluated and noted. RESULTS: Patients had a single proximal ureteral stone. While mean age of the cases was ranged 20 to 78 years; mean stone size was 15.62+/-4.26 mm. Evaluation of our data demonstrated that although there was a statistically significant correlation between ureteral wall thickness and patients age, transverse diameter of the stone, ureteral diameter just proximal to the stone, renal pelvic diameter and the duration of renal colic attacks; no correlation could be demonstrated between patients sex and the HU of the stone. CONCLUSIONS: Prediction of the presence and degree of proximal ureteral stone impaction is a challenging issue and our data indicated a highly significant correlation between ureteral wall thickness and the some certain radiological as well as clinical parameters evaluated which will give an objective information about the presence of impaction which may in turn be helpful in the follow-up and also management plans of such calculi. PMID- 28868506 TI - Ultrasound-guided percutaneous nephrolithotomy: Advantages and limitations. AB - PURPOSE: The use of ultrasound in percutaneous nephrolithotomy (PCNL) has not been shown to translate to better clinical and stone outcomes. To compare the operative outcomes, postoperative outcomes and complication rates of ultrasound guided access PCNL (USGA-PCNL) versus fluoroscopy-guided access PCNL (FGA-PCNL). MATERIALS AND METHODS: A total of 184 consecutive patients who underwent PCNL from July 2008 to September 2014 were identified from our PCNL database. Seventy two patients underwent USGA-PCNL and 112 FGA-PCNL. RESULTS: The patients were similar in age, sex, race, American Society of Anesthesiologists physical status classification, mean largest stone diameters, side of PCNL, number of stones and the degree of hydronephrosis between both groups. There were higher rates of upper pole (5.6% vs. 3.6%), mid pole (8.3% vs. 2.7%) and multiple pole punctures (4.2% vs. 0%) in USGA-PCNL compared to FGA-PCNL (p=0.027). There was no difference in the stone free rates of both groups in univariate analysis. Those who had FGA-PCNL were 2.26 (95% confidence interval, 1.09-4.75; p=0.029) times more likely to require a second-look procedure compared to USGA-PCNL on univariate analysis but not on multivariate analysis. There were no differences in Clavien-Dindo complications. No patient in the USGA-PCNL group experienced organ injuries during puncture compared to 1 patient in the FGA-PCNL group who had pneumothorax requiring urgent chest tube insertion. CONCLUSIONS: The use of ultrasonography to guide access puncture during PCNL eliminates the risk of inadvertent organ injuries. Similar operative and stone outcomes show that the learning curve for USGA is minimal compared to conventional FGA. PMID- 28868507 TI - Evaluation of the incidence and risk factors associated with persistent frequency in interstitial cystitis/bladder pain syndrome and the efficacy of antimuscarinic treatment. AB - PURPOSE: To investigate the incidence and risk factors associated with persistent urinary frequency, and to evaluate the efficacy of antimuscarinic treatment. MATERIALS AND METHODS: Interstitial cystitis/bladder pain syndrome (IC/BPS) patients complaining of persistent urinary frequency despite improved pain were evaluated. Before initial conventional treatment, each patient completed a voiding diary and symptom questionnaires. After conventional treatment, patients were divided according to the presence of pain and frequency. Improved pain was defined as lesser than 3 points in visual analogue scale, and persistent urinary frequency as >10 times/d. Risk factors for persistent frequency were identified through multivariate analysis. The efficacy of antimuscarinic treatment was assessed by the mean change of frequency. RESULTS: Of 171 IC/BPS patients treated with conventional therapy, 132 had improved pain after 3 months, but 72 had persistent frequency (72 of 132, 54.5%). Patients with persistent frequency had lower voided volume (p=0.008), lower maximal flow rate (p<0.001), lower maximal bladder capacity (p=0.003), and more frequent micturition (p<0.001) at baseline compared to those with improved frequency. Patients who took antimuscarinic agents showed slightly decreased urinary frequency, from 14.6 times/d to 13.5 times/d (p=0.438) after 3 months of medication. No patients showed more than a 20% decrease in frequency with antimuscarinics. CONCLUSIONS: About half of the patients with IC/BPS showed persistent frequency, with poor voiding function identified as a risk factor; antimuscarinic treatment was not effective in these patients. PMID- 28868508 TI - Can men with prostates sized 80 mL or larger be managed conservatively? AB - PURPOSE: To analyze the long-term clinical outcomes of men with large prostate sizes of 80 mL and greater who were managed conservatively. MATERIALS AND METHODS: We retrospectively analyzed men with prostate sizes of 80 mL and greater from our electronic hospital database. Clinical parameters such as age, International Prostate Symptom Score (IPSS), quality of life (QoL) scoring, serum prostate-specific antigen (PSA), uroflowmetry variables, and transabdominal ultrasound findings were evaluated. These parameters were compared at entry to our study and at the patient's latest follow-up visit. RESULTS: For the 50 men included in our analysis, mean age was 68 years, median PSA was 9.9 ng/mL, and median prostate volume was 94 mL. Seven men underwent upfront prostate surgery, whereas the other 43 were managed conservatively, predominantly with pharmacotherapy (98%). Only serum PSA, QoL scores, and postvoid residual urine demonstrated a significant reduction at the end of a median follow-up period of 62 months. Fourteen men (33%) were considered to have progressed clinically, with 8 experiencing retention of urine and 6 having symptomatic deterioration. Of the 35 men who were still receiving conservative treatment at the end of the follow up period, 24 men (69%) had a peak flow rate of 10 mL/s or greater, a QoL score of 3 or less, and mild to moderate (IPSS, 0-19) symptoms. CONCLUSIONS: Although the incidence of clinical progression in men with prostate sizes of 80 mL and greater is high, there is still a role for conservative management with pharmacotherapy. PMID- 28868509 TI - "Targeted" prophylaxis: Impact of rectal swab culture-directed prophylaxis on infectious complications after transrectal ultrasound-guided prostate biopsy. AB - PURPOSE: To assess the prevalence of fluoroquinolone resistance among patients undergoing transrectal ultrasound (TRUS)-guided prostate biopsy and the impact of rectal swab culture-directed antibiotic prophylaxis on postbiopsy infectious complications. MATERIALS AND METHODS: We prospectively analyzed all patients undergoing TRUS-guided prostate biopsy from April 2013 to February 2015. Antibiotic prophylaxis was tailored to the results of rectal swab cultures. If the organism was fluoroquinolone-sensitive, oral ciprofloxacin 500 mg with tinidazole 600 mg was prescribed. If the organism was fluoroquinolone-resistant, then a culture-directed antibiotic was prescribed. In both cases the antibiotic was continued for 3 days. All patients were followed for 14 days after biopsy to record infectious complications. RESULTS: A total of 247 patients were included, and Escherichia coli was isolated on rectal swab cultures in 99.5% of the patients. Of these, 41.7% harbored fluoroquinolone-resistant E. coli. Piperacillin/tazobactam was the most common culture-directed antibiotic prescribed (59.3%), with amoxicillin/clavulanic being the second most common (25.5%) for the fluoroquinolone-resistant group. Only 2 patients (0.9%) developed postbiopsy fever and none had sepsis. CONCLUSIONS: Colonization of rectal flora with fluoroquinolone-resistant E. coli was seen in 40% of men undergoing prostate biopsy. Targeted prophylaxis, which uses the results of prebiopsy rectal swab culture to direct antibiotic prophylaxis, results in low rates of postbiopsy infections. PMID- 28868510 TI - Retroperitoneal fibrosis-clinical presentation and outcome analysis from urological perspective. AB - PURPOSE: To study clinical presentation, laboratory results, imaging findings and treatment options and outcomes of retroperitoneal fibrosis (RPF). To determine whether it follows the same natural course and response to treatment in the Asian population as in the Western world. MATERIALS AND METHODS: Medical records of patients diagnosed with RPF on imaging and histopathology between February 2010 and April 2016 were reviewed. RESULTS: Of the 21 patients analyzed, mean age at presentation was 50.81 years. The male to female ratio was 0.9:1. Pain was most common presenting complaint (95.23% cases), almost 85% cases were idiopathic and rests were postradiation induced. The median creatinine level was 1.8 mg/dL. The mean erythrocyte sedimentation rate (ESR) was 53.2 mm/h. Hydronephrosis was present in all patients and 47.6% had atrophic kidneys. Diffuse retroperitoneal mass was present in 61.1%. Ureterolysis with lateralization, omental wrapping or gonadal pedicle wrap was done in 17 cases. Two patients underwent uretero ureterostomy. One patient underwent ileal replacement of ureter, and one ileal conduit. Eighteen patients received concurrent medical treatment, 11 were given tamoxifen, 2 steroids (Prednisolone), and five were given both. Of the 20 patients with follow-up, 70% had complete symptomatic relief; ESR improvement was seen in 77.8%. Follow-up ultrasound showed resolved and decreased hydronephrosis in 20% and 55% respectively. One patient had treatment failure and 17.65% had disease recurrence. CONCLUSIONS: RPF is a rare disease with varied presentation and outcomes. The male to female ratio may be equal in Asians and smoking could be lesser contributing factor. More Asian cohort studies are required to support same. PMID- 28868511 TI - Optimization of urinary dipstick pH: Are multiple dipstick pH readings reliably comparable to commercial 24-hour urinary pH? AB - PURPOSE: Accurate measurement of pH is necessary to guide medical management of nephrolithiasis. Urinary dipsticks offer a convenient method to measure pH, but prior studies have only assessed the accuracy of a single, spot dipstick. Given the known diurnal variation in pH, a single dipstick pH is unlikely to reflect the average daily urinary pH. Our goal was to determine whether multiple dipstick pH readings would be reliably comparable to pH from a 24-hour urine analysis. MATERIALS AND METHODS: Kidney stone patients undergoing a 24-hour urine collection were enrolled and took images of dipsticks from their first 3 voids concurrently with the 24-hour collection. Images were sent to and read by a study investigator. The individual and mean pH from the dipsticks were compared to the 24-hour urine pH and considered to be accurate if the dipstick readings were within 0.5 of the 24-hour urine pH. The Bland-Altman test of agreement was used to further compare dipstick pH relative to 24-hour urine pH. RESULTS: Fifty-nine percent of patients had mean urinary pH values within 0.5 pH units of their 24 hour urine pH. Bland-Altman analysis showed a mean difference between dipstick pH and 24-hour urine pH of -0.22, with an upper limit of agreement of 1.02 (95% confidence interval [CI], 0.45-1.59) and a lower limit of agreement of -1.47 (95% CI, -2.04 to -0.90). CONCLUSIONS: We concluded that urinary dipstick based pH measurement lacks the precision required to guide medical management of nephrolithiasis and physicians should use 24-hour urine analysis to base their metabolic therapy. PMID- 28868512 TI - CORRIGENDUM: Correction of the Figure. Robot-assisted radical prostatectomy has lower biochemical recurrence than laparoscopic radical prostatectomy: Systematic review and meta-analysis. AB - [This corrects the article on p. 152 in vol. 58.]. PMID- 28868513 TI - Evaluation of Renal Blood Flow in Chronic Kidney Disease Using Arterial Spin Labeling Perfusion Magnetic Resonance Imaging. AB - INTRODUCTION: Chronic kidney disease (CKD) is known to be associated with reduced renal blood flow. However, data to-date in humans is limited. METHODS: In this study, non-invasive arterial spin labeling (ASL) MRI data was acquired in 33 patients with diabetes and stage-3 CKD, and 30 healthy controls. RESULTS: A significantly lower renal blood flow both in cortex (108.4+/-36.4 vs. 207.3+/ 41.8; p<0.001, d=2.52) and medulla (23.2+/-8.9 vs. 42.6+/-15.8; p<0.001, d=1.5) was observed. Both cortical (rho=0.67, p<0.001) and medullary (rho=0.62, p<0.001) blood flow were correlated with eGFR, and cortical blood flow was found to be confounded by age and BMI. However, in a subset of subjects that were matched for age and BMI (n=6), the differences between CKD and control subjects remained significant both in cortex (107.4+/-42.8 vs. 187.51+/-20.44; p=0.002) and medulla (15.43+/-8.43 vs. 39.18+/-11.13; p=0.002). A threshold value to separate healthy and CKD was estimated to be Cor_BF=142.9 and Med_BF=24.1. CONCLUSION: These results support the use of ASL in the evaluation of renal blood flow in patients with moderate level of CKD. Whether these measurements can identify subjects at risk of progressive CKD requires further longitudinal follow-up. PMID- 28868514 TI - CD161 Expression on Mucosa-Associated Invariant T Cells is Reduced in HIV Infected Subjects Undergoing Antiretroviral Therapy Who Do Not Recover CD4+ T Cells. AB - BACKGROUND: Mucosa-associated invariant T (MAIT) cells are a recently identified class of innate-like T cells that are involved in the mucosal immune response. MAIT cells are characterized by expression of TCR Valpha7.2 and CD161. In HIV infection, there is a profound early loss of MAIT cells from the circulation that never fully recovers, even after prolonged viral control with antiretroviral therapy (ART). METHODS: We analyzed PBMCs from fresh whole blood from HIV negative or ART-treated HIV-positive donors with full (Immune Success) or impaired (Immune Failure) CD4+ T- cell recovery by flow cytometry for T-cell markers, TCR Valpha7.2, and CD161. The PBMCs were cultured with or without TCR mediated stimulation, and CD161 expression was assessed on Valpha7.2+ T cells. Interferon-gamma (IFNgamma) production was assessed by intracellular cytokine staining. RESULTS: We found a decrease in the percentage of CD3+ T cells that expressed CD161 and the percentage of Valpha7.2+ T cells that expressed CD161, in HIV-infected individuals. We also found a significant increase in the percentage of T cells that were Valpha7.2+CD161- in immune failure compared to controls, accompanied by an increase in the percentage of Valpha7.2+CD161- T cells that express CD8+ in donors with immune failure, but not immune success. After TCR stimulation in vitro, Valpha7.2+ T cells reduced expression of CD161, yet Valpha7.2+CD161- cells from immune failure donors retained the ability to express IFNgamma on stimulation. CONCLUSIONS: Our findings suggest that in immune failure patients, the reduction in peripheral MAIT cells is due, at least in part, to a loss in CD161 expression, and is not merely the result of trafficking into mucosal tissues or cell death. These CD161- cells retain their function. PMID- 28868515 TI - Comparison of wildfire smoke estimation methods and associations with cardiopulmonary-related hospital admissions. AB - Climate forecasts predict an increase in frequency and intensity of wildfires. Associations between health outcomes and population exposure to smoke from Washington 2012 wildfires were compared using surface monitors, chemical-weather models, and a novel method blending three exposure information sources. The association between smoke particulate matter <=2.5 MUm in diameter (PM2.5) and cardiopulmonary hospital admissions occurring in Washington from 1 July to 31 October 2012 was evaluated using a time-stratified case-crossover design. Hospital admissions aggregated by ZIP code were linked with population-weighted daily average concentrations of smoke PM2.5 estimated using three distinct methods: a simulation with the Weather Research and Forecasting with Chemistry (WRF-Chem) model, a kriged interpolation of PM2.5 measurements from surface monitors, and a geographically weighted ridge regression (GWR) that blended inputs from WRF-Chem, satellite observations of aerosol optical depth, and kriged PM2.5. A 10 MUg/m3 increase in GWR smoke PM2.5 was associated with an 8% increased risk in asthma-related hospital admissions (odds ratio (OR): 1.076, 95% confidence interval (CI): 1.019-1.136); other smoke estimation methods yielded similar results. However, point estimates for chronic obstructive pulmonary disease (COPD) differed by smoke PM2.5 exposure method: a 10 MUg/m3 increase using GWR was significantly associated with increased risk of COPD (OR: 1.084, 95%CI: 1.026-1.145) and not significant using WRF-Chem (OR: 0.986, 95%CI: 0.931 1.045). The magnitude (OR) and uncertainty (95%CI) of associations between smoke PM2.5 and hospital admissions were dependent on estimation method used and outcome evaluated. Choice of smoke exposure estimation method used can impact the overall conclusion of the study. PMID- 28868517 TI - Chart review versus an automated bioinformatic approach to assess real-world crizotinib effectiveness in ALK-positive NSCLC. PMID- 28868516 TI - Analysis of Human Endogenous Retrovirus Expression in Multiple Sclerosis Plaques. AB - BACKGROUND: It has been suggested that Human endogenous retroviruses (HERVs) are associated with multiple sclerosis (MS) pathogenesis. The objective of this study was to broadly evaluate the expression of HERV core (GAG) and envelope (ENV) genes in diseased brain white matter samples from MS patients compared to normal controls. METHODS: Twenty-eight HERV GAG and 88 ENV gene sequences were retrieved, classified by phylogeny, and grouped into clades. Consensus qPCR primers were designed for each clade, and quantitative PCR was performed on 33 MS and 9 normal control frozen brain samples. MS samples included chronic progressive (n=5), primary progressive (n=4), secondary progressive (n=14), relapsing remitting (n=3) and unclassified confirmed MS cases (n=7). The levels of GAG and ENV RNA within each of the samples were quantitated and normalized using the neuronal reference gene RPL19. Expression differences were analyzed for MS vs control. RESULTS: Expression of GAG clades 1A, 3B, and 3C mapping to HERV-E and HERV-K were significantly increased compared to controls, while GAG clade 3A expression was decreased. Expression of HERV ENV clades 2, 3A, 3B, mapping to RTVL, HERV-E and HERV-K and MSRV (HERV-W), were significantly increased in the MS group. However, the relative expression differences between the MS and control groups were small, differing less than 1.5-fold. CONCLUSION: Expression of GAG and ENV mapping to HERV-E, RTVL and HERV-K10 families were significantly increased in the MS group. However, the relative expression differences between the MS and control groups were small, differing less than 1.5-fold. These results indicate that the expression of HERV GAG and ENV regions do not differ greatly between MS and controls in these frozen brain samples. PMID- 28868518 TI - Associations of alpha-thalassemia and BCL11A with stroke in Nigerian, United States, and United Kingdom sickle cell anemia cohorts. AB - Alpha-thalassemia and the BCL11A rs1427407 T allele are commonly observed in sickle cell anemia (SCA) patients and are associated with reduced hemolysis and higher hemoglobin F levels, respectively. We investigated whether a high-risk genetic profile, defined as SCA patients who did not inherit either alpha thalassemia or the BCL11A rs1427407 T allele, had stronger associations with clinical and laboratory variables than the individual genetic components in the University of Ibadan cohort (n=249). We then replicated our findings in SCA cohorts from the University of Illinois at Chicago (UIC)(n=260) and Walk Treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy (Walk-PHaSST)(n=387). High-risk was associated with higher reticulocytes (15.0% vs. 7.8%, P=0.08) and stroke history (6% vs. 1%, P=0.02) than standard risk patients and these associations were more significant than the individual genetic components in the University of Ibadan cohort. These findings were replicated in high-risk patients from UIC and Walk-PHaSST for reticulocytes (UIC: 13.5% vs. 11.8%, P=0.03; Walk-PHaSST: 9.6% vs. 8.2%, P=0.0003) and stroke history (UIC: 32% vs. 22%, P=0.07; Walk-PHaSST: 14% vs. 7%, P=0.01). On combined analysis, high-risk had strong associations with increased markers of hemolysis (hemoglobin beta= -0.29, 95%CI: -0.50 to -0.09; P=0.006; reticulocyte% beta=2.29, 95%CI: 1.31 to 3.25; P=1x10-5) and stroke history (OR=2.0, 95%CI: 1.3 to 3.0; P=0.0002), but no association with frequent vaso-occlusive crises (>=3/year). A high-risk genetic profile is associated with increased hemolysis and stroke history in three independent cohorts. This profile may help identify patients to prioritize for hydroxyurea and for closer monitoring strategies for stroke. PMID- 28868519 TI - Dynamic Change of Transcription Pausing through Modulating NELF Protein Stability Regulates Granulocytic Differentiation. AB - The NELF complex is a metazoan-specific factor essential for establishing transcription pausing. Although NELF has been implicated in cell fate regulation, the cellular regulation of NELF and its intrinsic role in specific lineage differentiation remains largely unknown. Using mammalian hematopoietic differentiation as a model system, here we identified a dynamic change of NELF mediated transcription pausing as a novel mechanism regulating hematopoietic differentiation. We found a sharp decrease of NELF protein abundance upon granulocytic differentiation and a subsequent genome-wide reduction of transcription pausing. This loss of pausing coincides with activation of granulocyte-affiliated genes and diminished expression of progenitor markers. Functional studies revealed that sustained expression of NELF inhibits granulocytic differentiation, whereas NELF depletion in progenitor cells leads to premature differentiation towards the granulocytic lineage. Our results thus uncover a previously unrecognized regulation of transcription pausing by modulating NELF protein abundance to control cellular differentiation. PMID- 28868520 TI - Family Dynamics May Influence an Individual's Substance Use Abstinence Self Efficacy. AB - BACKGROUND: Previous work on substance use suggests the influence of family dynamics on emotion regulation. OBJECTIVE: The present study examined the role of family in substance use recovery. It is of importance to examine whether conflict with various family members influences an individual's abstinence self-efficacy. METHODS: We examined individual abstinence self-efficacy scores and lifetime conflict with mother, father, and siblings in a sample of 200 women who had been justice involved. RESULTS: We found that conflict with mother was the best predictor of abstinence self-efficacy compared to conflict with father and conflict with siblings. Individuals who indicated having conflict with mother over their lifetime had lower confidence that they could abstain from use in potentially emotionally triggering situations. CONCLUSIONS/IMPORTANCE: These findings suggest that family dynamics, specifically lifetime conflict with mother, do play a role in an individual's confidence to regulate emotions in high risk relapse situations without turning to substances. Limitations include using abstinence self-efficacy as a proxy for emotion regulation and not directly measuring emotion regulation. Examining family relationships may be especially important in the treatment of women in recovery from substance use. PMID- 28868521 TI - An Out-of-Core GPU based dimensionality reduction algorithm for Big Mass Spectrometry Data and its application in bottom-up Proteomics. AB - Modern high resolution Mass Spectrometry instruments can generate millions of spectra in a single systems biology experiment. Each spectrum consists of thousands of peaks but only a small number of peaks actively contribute to deduction of peptides. Therefore, pre-processing of MS data to detect noisy and non-useful peaks are an active area of research. Most of the sequential noise reducing algorithms are impractical to use as a pre-processing step due to high time-complexity. In this paper, we present a GPU based dimensionality-reduction algorithm, called G-MSR, for MS2 spectra. Our proposed algorithm uses novel data structures which optimize the memory and computational operations inside GPU. These novel data structures include Binary Spectra and Quantized Indexed Spectra (QIS). The former helps in communicating essential information between CPU and GPU using minimum amount of data while latter enables us to store and process complex 3-D data structure into a 1-D array structure while maintaining the integrity of MS data. Our proposed algorithm also takes into account the limited memory of GPUs and switches between in-core and out-of-core modes based upon the size of input data. G-MSR achieves a peak speed-up of 386x over its sequential counterpart and is shown to process over a million spectra in just 32 seconds. The code for this algorithm is available as a GPL open-source at GitHub at the following link: https://github.com/pcdslab/G-MSR. PMID- 28868522 TI - Primary Care Provider Management of Congenital Hypothyroidism Identified Through Newborn Screening. AB - OBJECTIVE: To assess Primary Congenital Hypothyroidism (CH) management patterns and feasibility of providing long-term care for patients with CH identified through newborn screening by Primary Care Providers (PCPs) in California and Hawaii. STUDY DESIGN: A survey was mailed to all physicians (N=823) listed as the referral doctor for confirmed patients with CH identified through newborn screening programs in both states between 01/01/2009-12/31/2013. Information was collected on CH management patterns, barriers to providing care, and knowledge on CH treatment. Descriptive statistics and bivariate logistic regression results were reported. RESULTS: 206 PCPs completed the survey. Among these, 78% currently have patients with CH and 91% indicated willingness to provide long-term care to new patients with CH. Among PCPs currently caring for patients with CH, 17% managed CH by themselves with limited assistance from endocrinologists; 63% were involved in managing CH but endocrinologists played a larger role than PCPs; 19% were not involved in CH care. Only 49% of PCPs correctly answered questions regarding recommended follow-up frequencies and 23% knew the correct age for a trial off levothyroxine for suspected transient CH. Top two perceived barriers to providing long-term care included "need guidance or support from endocrinologists" (61%) and "not familiar with CH treatment guidelines" (28%). CONCLUSION: The majority of PCPs surveyed are willing to provide long-term care to patients with CH, but need support from endocrinologists and increased knowledge about current treatment guidelines. PMID- 28868523 TI - Design Features in Games for Health: Disciplinary and Interdisciplinary Expert Perspectives. AB - Games for health (G4H) aim to improve health outcomes and encourage behavior change. While existing theoretical frameworks describe features of both games and health interventions, there has been limited systematic investigation into how disciplinary and interdisciplinary stakeholders understand design features in G4H. We recruited 18 experts from the fields of game design, behavioral health, and games for health, and prompted them with 16 sample games. Applying methods including open card sorting and triading, we elicited themes and features (e.g., real-world interaction, game mechanics) around G4H. We found evidence of conceptual differences suggesting that a G4H perspective is not simply the sum of game and health perspectives. At the same time, we found evidence of convergence in stakeholder views, including areas where game experts provided insights about health and vice versa. We discuss how this work can be applied to provide conceptual tools, improve the G4H design process, and guide approaches to encoding G4H-related data for large-scale empirical analysis. PMID- 28868524 TI - Divergent Specificity Development of IgG1 and IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem). AB - We have shown that although the IgG response in fogo selvagem (FS) is mainly restricted to desmoglein (Dsg) 1, other keratinocyte cadherins are also targeted by FS patients and healthy control subjects living in the endemic region of Limao Verde, Brazil (endemic controls). Evaluating nonpathogenic IgG1 and pathogenic IgG4 subclass responses to desmosomal proteins may reveal important differences between pathogenic and nonpathogenic responses, and how these differences relate to the pathogenic IgG4 response and resultant FS. In this study, we tested by ELISA >100 sera from each FS patient, endemic control, and nonendemic control for IgG1 and IgG4 autoantibodies to keratinocyte cadherins besides Dsg1. IgG1 and IgG4 subclass responses in endemic controls are highly correlated between Dsg1 and other keratinocyte cadherins. This correlation persists in the IgG1 response among FS patients, but diminishes in IgG4 response, suggesting that IgG1 binds highly conserved linear epitopes among cadherins, whereas IgG4 binds mainly specific conformational epitopes on Dsg1. A confirmatory test comparing serum samples of 11 individuals before and after their FS onset substantiated our findings that IgG1 recognizes primarily linear epitopes on Dsg1 both before and after disease onset, whereas IgG4 recognizes primarily linear epitopes before disease onset, but recognizes more conformational epitopes on Dsg1 after the onset of disease. This study may provide a mechanism by which a specificity convergence of the IgG4 response to unique Dsg1 epitopes, most likely conformational pathogenic epitopes, leads to the onset of FS disease. PMID- 28868526 TI - Programs to Recruit and Retain a More Diverse Workforce in Biomedical Sciences Research. AB - To improve overall healthcare and to reduce health disparities, efforts must focus on increasing the diversity of personnel trained in the biomedical sciences. Here, we describe the development, implementation, and relative outcomes of three pipeline training programs in biomedical sciences research designed to increase workforce diversity institutionally, regionally, and nationally. We report on their effectiveness in improving the recruitment and retention of underrepresented minorities with the long-term goal of remedying health inequities and disparities. PMID- 28868525 TI - Potential Contributions of the Tobacco Nicotine-Derived Nitrosamine Ketone to White Matter Molecular Pathology in Fetal Alcohol Spectrum Disorder. AB - BACKGROUND: Fetal alcohol spectrum disorder (FASD) is associated with long-term deficits in cognitive and motor functions. Previous studies linked neurodevelopmental abnormalities to increased oxidative stress and white matter hypotrophy. However, similar effects occur with low-dose nitrosamine exposures, alcohol abuse correlates with cigarette smoking, and tobacco smoke contains tobacco-specific nitrosamines, including NNK. HYPOTHESIS: Tobacco smoke exposure is a co-factor in FASD. DESIGN: Long Evans rat pups were i.p. administered ethanol (2 g/kg) on postnatal days (P) 2, 4, 6 and/or NNK (2 mg/kg) on P3, P5, and P7 to simulate third trimester human exposures. Oligodendroglial myelin associated, neuroglial, and relevant transcription factor mRNA transcripts were measured using targeted PCR arrays. RESULTS: Ethanol and NNK differentially altered the expression of immature and mature oligodendroglial, neuronal and astrocytic structural and plasticity-associated, and various transcription factor genes. NNK's effects were broader and more pronounced than ethanol's, and additive or synergistic effects of dual exposures impacted expression of all four categories of genes investigated. CONCLUSION: Developmental exposures to alcohol and NNK (via tobacco smoke) contribute to sustained abnormalities in brain white matter structure and function via distinct but overlapping alterations in the expression of genes that regulate oligodendrocyte survival, maturation and function, neuroglial structural integrity, and synaptic plasticity. The results support the hypothesis that smoking may contribute to brain abnormalities associated with FASD. PMID- 28868527 TI - Alterations of Cholesterol Metabolism in Inflammation-Induced Atherogenesis. AB - Vascular inflammation is central to the pathogenesis of the atherosclerotic lesion. In the setting of hypercholesterolemia, vascular inflammation accelerates the accumulation of cholesterol within arterial smooth muscle cells, macrophages, and other immune cells. In disorders such as obesity, diabetes, and thrombosis, a myriad of interactions between sterol metabolites and inflammatory mediators exacerbate cholesterol deposition in the vessel wall, leading to the well-known consequences of stroke, transient ischemic attack, myocardial infarction, and peripheral vascular insufficiency. This review highlights emerging concepts in the regulation of cholesterol synthesis, the lipolytic enzymes involved in cholesterol utilization, and the therapies that successfully modulate vascular inflammation. In addition, developments relating to the role of inflammasomes in the management of cholesterol-mediated inflammation are discussed. PMID- 28868528 TI - The National Environmental Public Health Tracking Network Access to Parks Indicator: A National County-Level Measure of Park Proximity. AB - Parks and recreation departments and public health organizations both work to improve the well-being of their communities. Measuring residential proximity to parks could be a specific area of shared interest, given that proximity to parks is needed for walking access, and the use of parks is, in turn, associated with many physical, social, and mental health benefits. The CDC's publicly available National Environmental Public Health Tracking Network (NEPHTN) Access to Parks Indicator (API) focuses on one major component of access, residential proximity to parks. The API uses a commercial parks database and U.S. Census data to estimate the number and percentage of individuals in the U.S. that live within a half-mile of a park boundary, a measure commonly used to represent park proximity. The API is calculated at the state and county levels and is available for all states and counties in the U.S. Using estimates from the API, we examined the distribution of residential proximity to parks by geography and race/ethnicity. Additionally, we evaluated differences in park proximity by rural/urban status of counties. In 2010, 39% of the total U.S. population lived within a half-mile of a park. This percentage varied widely between states, ranging from 9% in West Virginia to 67% in Hawaii and 88% in the District of Columbia (DC). Park proximity was lowest among non-Hispanic whites (34.2%) and highest among individuals belonging to the non-Hispanic other race category (52.0%). Metropolitan counties had the highest percentage of residents living within a half-mile of a park (43.3%); the percentage was lower in non metropolitan counties adjacent to a metropolitan county (15.0%) and non metropolitan counties not adjacent to a metropolitan county (18.5%). Park proximity was higher in metropolitan counties with a larger population size and in non-metropolitan counties with a higher degree of urbanization. The NEPHTN Access to Parks Indicator provides an opportunity to understand park proximity in counties and states throughout the U.S., including identifying disparities that may exist between population subgroups and comparing geographic areas. Parks and recreational professionals can use this information to compare their county or state to other geographic areas and, in combination with local data on parks within their jurisdiction, inform decisions to improve the distribution of parks and the well-being of their communities. PMID- 28868529 TI - The Development of the Mother-Infant Mutualistic Screening Scale. AB - BACKGROUND: The integrity of a mother-infant dyad is essential for the proper development of maternal behavior and infant growth/ development. At present, there is a lack of objective approaches to monitor mother-infant behavioral exchanges. OBJECTIVES: This is an exploratory prospective study designed to evaluate the Mother-Infant Mutualistic Screening Scale (MIMSS), a novel observational tool focused on monitoring the mutual/ reciprocal sensitivity and responsiveness that mother and infant express toward one another's behaviors/ actions during the obligatory setting of daily meal times. METHODS: Mother-infant interactions were assessed from videotaped feeding sessions conducted under recurrent naturalistic observations. Data were collected from 27 mother-preterm infant singleton dyads at 6 and 12 month corrected age (CA). Four levels of MIMSS are defined: Level I - both mother and infant are not responsive (NR) to one another's actions; Level II - mother is not responsive (NR) to infant, but infant is responsive (R) to mother; Level III - mother is responsive (R) to infant, but infant is not responsive (NR) to mother; Level IV - both mother and infant are responsive (R) to one another. RESULTS: Inter- and intra-rater reliability between two raters was 93% and >= 85%, respectively. At 6 and 12 month CA, 78% and 81% of the dyads were at a MIMSS Level IV, respectively. A change in mother infant reciprocal behavioral responses or MIMSS levels was observed in 9 of the dyads between these two ages. No association was observed between MIMSS levels and infant growth/ development as monitored by percentile Weight, Length, and Weight by Length at both corrected ages. CONCLUSIONS: The MIMSS is easy to use with high inter- and intra-rater reliabilities. With the ability to differentiate between mother and infant reciprocal behavioral responses toward one another's actions, MIMSS can help health professionals assess the quality of mother-infant interactions and identify the partner(s) who may benefit from individualized assistance. Although MIMSS uses mealtime as a recurrent setting, it offers a conceptual frame work for evaluating co-regulatory processes under different contexts. PMID- 28868530 TI - Addressing Health Disparities in Idiopathic Dilated Cardiomyopathy. PMID- 28868531 TI - A Control Theory Model of Smoking. AB - We present a heuristic control theory model that describes smoking under restricted and unrestricted access to cigarettes. The model is based on the allostasis theory and uses a formal representation of a multiscale opponent process. The model simulates smoking behavior of an individual and produces both short-term ("loading up" after not smoking for a while) and long-term smoking patterns (e.g., gradual transition from a few cigarettes to one pack a day). By introducing a formal representation of withdrawal- and craving-like processes, the model produces gradual increases over time in withdrawal- and craving-like signals associated with abstinence and shows that after 3 months of abstinence, craving disappears. The model was programmed as a computer application allowing users to select simulation scenarios. The application links images of brain regions that are activated during the binge/intoxication, withdrawal, or craving with corresponding simulated states. The model was calibrated to represent smoking patterns described in peer-reviewed literature; however, it is generic enough to be adapted to other drugs, including cocaine and opioids. Although the model does not mechanistically describe specific neurobiological processes, it can be useful in prevention and treatment practices as an illustration of drug using behaviors and expected dynamics of withdrawal and craving during abstinence. PMID- 28868533 TI - PET-based bisBODIPY photosensitizers for highly efficient excited triplet state and singlet oxygen generation: tuning photosensitizing ability by dihedral angles. AB - Herein, four covalent BODIPY heterodimers that differ by dihedral angles were shown to be highly efficient excited triplet state (T1) photosensitizers (PSs) for singlet oxygen formation with a quantum yield (PhiDelta) of up to 0.94 as compared to their respective monomers, which had only negligible PhiDelta of ca. 0.060. More interestingly, these PSs generate T1via charge recombination mechanism rather than traditional inter-system crossing. The photosensitizing ability of dimers is easily tuned by either the dihedral angle (between the two linked BODIPYs) or solvent polarity. Laser flash photolysis, time-resolved and steady state fluorescence, quantum chemical calculation, as well as thermodynamic analysis were employed to study the associated photophysical process to reveal the T1 formation mechanism: photo-induced electron transfer (PET) followed by charge recombination. Due to its heavy-atom-free nature, polarity selectivity, high efficiency, and easy tunability, this PET-based PS and its mechanism are very useful in developing new PS for photodynamic therapy of tumors, photobiology, and organic photochemistry. PMID- 28868532 TI - [Ocular Surface Reconstruction with Cultivated Limbal Epithelial Cells in Limbal Stem Cell Deficiency: One-year Follow-up Results]. AB - PURPOSE: To evaluate the 1-year follow-up results of cultivated limbal epithelial cell (CLEC) transplantation in unilateral limbal stem cell deficiency (LSCD). MATERIAL AND METHOD: One-year follow-up results of five unilateral LSCD patients who had undergone CLEC transplantation were evaluated. Parameters for this evaluation were: fluorescein staining of ocular surface, corneal vascularization and status of epithelium with slit lamp, and visual acuity. 1.5-mm limbal biopsy was performed from the superior limbus of the healthy eyes, broke into two equal pieces, expanded on human amniotic membrane (hAM) and inserts for 14 days until getting 20 mm in size. CLECs on hAMs were used directly, and cells on inserts were used after detachment procedure. The symblepharon and pannus tissues were removed, superficial keratectomy was performed. CLEC on hAMs were transplanted with the epithelial side up onto the bare corneal stroma, sutured to the conjunctiva with 10-0 nylon sutures. Free CLEC layer from insert was placed on hAM as a second layer, additional hAM was used as a protective layer all over other tissues. RESULTS: Median age was 44.4 years (14-71). The etiology was chemical burn in all patients. Median duration of symptoms was 10 years (2-18), median follow-up period was 12.6 (12-12.5) months. Preoperative best corrected visual acuities (BCVA) were light perception in three patients, counting fingers at 50 cm in one patient and 3/10 in one patient. Visions were improved in all patients. Postoperative BCVA 12 months after the surgery were between counting fingers at 3 meters to 6/10. There was a temporary hemorrhage between the two layers of hAMs in one patient at the early postoperative period. Peripheral corneal vascularization has occurred in three patients, in patient corneal vascularization has reached to the paracentral area. DISCUSSION: CLEC transplantation is an efficient treatment option for unilateral LSCD in mid-long term. PMID- 28868534 TI - Importance of the alignment of polar pi conjugated molecules inside carbon nanotubes in determining second-order non-linear optical properties. AB - We employed density functional theory (DFT) calculations with dispersion corrections to investigate energetically preferred alignments of certain p,p' dimethylaminonitrostilbene (DANS) molecules inside an armchair (m,m) carbon nanotube (n * DANS@(m,m)), where the number of inner molecules (n) is no greater than 3. Here, three types of alignments of DANS are considered: a linear alignment in a parallel fashion and stacking alignments in parallel and antiparallel fashions. According to DFT calculations, a threshold tube diameter for containing DANS molecules in linear or stacking alignments was found to be approximately 1.0 nm. Nanotubes with diameters smaller than 1.0 nm result in the selective formation of linearly aligned DANS molecules due to strong confinement effects within the nanotubes. By contrast, larger diameter nanotubes allow DANS molecules to align in a stacking and linear fashion. The type of alignment adopted by the DANS molecules inside a nanotube is responsible for their second order non-linear optical properties represented by their static hyperpolarizability (beta0 values). In fact, we computed beta0 values of DANS assemblies taken from optimized n * DANS@(m,m) structures, and their values were compared with those of a single DANS molecule. DFT calculations showed that beta0 values of DANS molecules depend on their alignment, which decrease in the following order: linear alignment > parallel stacking alignment > antiparallel stacking alignment. In particular, a linear alignment has a beta0 value more significant than that of the same number of isolated molecules. Therefore, the linear alignment of DANS molecules, which is only allowed inside smaller diameter nanotubes, can strongly enhance their second-order non-linear optical properties. Since the nanotube confinement determines the alignment of DANS molecules, a restricted nanospace can be utilized to control their second-order non-linear optical properties. These DFT findings can assist in the design of nanotube-based materials exhibiting stronger non-linear optical properties. PMID- 28868535 TI - Configurable microfluidic platform for investigating therapeutic delivery from biomedical device coatings. AB - Advanced biomedical device coatings have shown significant promise in delivery of therapeutics (e.g., small-molecule drugs, proteins) for a wide range of medical interventions ranging from targeted cancer therapy to management of atherosclerosis. In order to accelerate the development of such coatings, there is a need for tools to investigate the loading capacity and release kinetics with high temporal resolution and in a variety of physiological conditions. To address this need, we report a microfluidic platform, where the coating on a substrate can be mounted onto the microchannel and the device can be configured in two physiologically-relevant modes: (i) flow-mode allows for monitoring the release from the coating in contact with a liquid flowing at a specific rate, modeling the case of a drug-eluting stent. (ii) Static-mode, where the channel is filled with a stationary gel, mimics the case of drug-eluting brain implant. We demonstrate the utility of the platform with a fluorescein-loaded nanoporous gold coating and monitor in real-time the release kinetics both under deionized water infusion and an agarose gel-filled channel via fluorescence microscopy coupled to a LabVIEW-based interface. PMID- 28868536 TI - Using molecular vibrations to probe exciton delocalization in films of perylene diimides with ultrafast mid-IR spectroscopy. AB - Ultrafast vibrational spectroscopy in the mid-infrared was used to directly probe the delocalization of excitons in two different perylenediimide (PDI) derivatives that are predicted to preclude the formation of excimers, which can act as trap sites for excited state energy in organic semiconductors. We identified vibrational modes within the conjugated C-C stretch modes of PDI molecules whose frequencies reported the interactions of molecules within delocalized excitonic states. The vibrational linewidths of these modes, which we call intermolecular coordinate coupled (ICC) modes, provided a direct probe of the extent of exciton delocalization among the PDI molecules, which was confirmed using X-ray diffraction and electro-absorption spectroscopy. We show that a slip-stacked geometry among the PDI molecules in their crystals promotes delocalized charge transfer (CT) excitons, while localized Frenkel excitons tend to form in crystals with helical, columnar stacking geometries. Because all molecules possess vibrational modes, the use of ultrafast mid-infrared spectroscopy to measure ICC vibrational modes offers a new approach to examine exciton delocalization in a variety of small molecule electron acceptors for optoelectronic and organic photovoltaic applications. PMID- 28868537 TI - Alternating current electrothermal modulated moving contact line dynamics of immiscible binary fluids over patterned surfaces. AB - In this paper, we report the results of our numerical study on incompressible flow of a binary system of two immiscible fluids in a parallel plate capillary using alternating current electrothermal kinetics as the actuation mechanism for flow. The surfaces of the capillary are wetted with two different alternating wettability patches. The dynamic motion of the interface of the two fluids is tracked using a phase-field order parameter-based approach. The results exhibit a stick-slip behavior involving acceleration and deceleration of the interface due to the interplay of electrothermal (Coulomb and dielectric) and surface tension forces. Controlling the interface motion through effective tuning of the chemical characteristics of the surfaces and forcing parameters was explored in detail. Finally, we were able to find a critical value of the dimensionless strength of the alternating current electrothermal force above which the interface "breaks", resulting in the formation of isolated droplets. These results have the potential to improve fundamental understanding and design optimization of various biomedical and physiological systems that involve flow of two or more immiscible fluids over chemically wetted surfaces. PMID- 28868538 TI - Radicals derived from acetaldehyde and vinyl alcohol. AB - Vinyl alcohol and acetaldehyde are isoelectronic products of incomplete butanol combustion. Along with the radicals resulting from the removal of atomic hydrogen or the hydroxyl radical, these species are studied here using ab initio methods as complete as coupled cluster theory with single, double, triple, and perturbative quadruple excitations [CCSDT(Q)], with basis sets as large as cc pV5Z. The relative energies provided herein are further refined by including corrections for relativistic effects, the frozen core approximation, and the Born Oppenheimer approximation. The effects of anharmonic zero-point vibrational energies are also treated. The syn conformer of vinyl alcohol is predicted to be lower in energy than the anti conformer by 1.1 kcal mol-1. The alcoholic hydrogen of syn-vinyl alcohol is found to be the easiest to remove, requiring 84.4 kcal mol-1. Five other radicals are also carefully considered, with four conformers investigated for the 1-hydroxyvinyl radical. Beyond energetics, we have conducted an overhaul of the spectroscopic literature for these species. Our results also provide predictions for fundamental modes yet to be reported experimentally. To our knowledge, the nu3 (3076 cm-1) and nu4 (2999 cm-1) C-H stretches for syn vinyl alcohol and all but one of the vibrational modes for anti-vinyl alcohol (nu1-nu14) are yet to be observed experimentally. For the acetyl radical, nu6 (1035 cm-1), nu11 (944 cm-1), nu12 (97 cm-1), and accounting for our changes to the assignment of the 1419.9 cm-1 experimental mode, nu10 (1441 cm-1), are yet to be observed. We have predicted these unobserved fundamentals and reassigned the experimental 1419.9 cm-1 frequency in the acetyl radical to nu4 rather than to nu10. Our work also strongly supports reassignment of the nu10 and nu11 fundamentals of the vinoxy radical. We suggest that the bands assigned to the overtones of these fundamentals were in fact combination bands. Our findings may be useful in constructing improved combustion models of butanol and in spectroscopically characterizing these molecules further. PMID- 28868539 TI - Simple contact mechanics model of the vertebrate cartilage. AB - We study a simple contact mechanics model of the vertebrate cartilage, which includes (bulk) osmotic effects. The surface roughness power spectrum of a pig cartilage is obtained from the measured surface topography. Using the Reynolds equations with fluid flow factors, calculated using the Persson contact mechanics theory and the Bruggeman effective medium theory, we show how the area of contact and the average interfacial separation change with time. We found that in most cases the contact area percolates, resulting in islands of confined fluid which carry most of the external load. Most importantly, we find that the pressure in the area of real contact is nearly independent of the external load, and well below 1 MPa. This allows the surfaces in the area of "real contact", to be separated (at nanometer range separation distance) by osmotic repulsion, resulting in a very small (breakloose) friction force observed even after a long time of stationary contact. PMID- 28868540 TI - Synthesis of circular and triangular gold nanorings with tunable optical properties. AB - This communication describes a robust wet-chemical synthetic strategy for the preparation of monodispersed circular and triangular gold nanorings. The localized surface plasmon resonance of the nanorings can be tuned by controlling the outer diameter and ridge thickness of the nanorings. PMID- 28868541 TI - Photoinduced dimerization of a photosensory DNA-binding protein EL222 and its LOV domain. AB - EL222 is a blue light sensor protein consisting of a light-oxygen-voltage (LOV) domain (EL-LOV domain) at the N-terminus and a helix-turn-helix DNA-binding domain at the C-terminus. EL222 acts as a light dependent transcriptional factor. The photochemical reactions of EL222 and the light sensing properties of the LOV domain were investigated. Concentration dependent experiments revealed that the EL-LOV domain is in equilibrium between the dimer and the monomer in the dark state, and the main photoreaction is the dimerization reaction between a monomer in the ground state and that in the excited state. The equilibrium constant and the intrinsic rate constants of dimerization were determined. EL222 was found to also exhibit photoinduced dimerization even in the absence of target DNA, although the yield of the reaction was low (~0.08 compared with that of the EL LOV domain). This observation suggests that there are inhomogeneous conformations, open and closed types, of EL222 in solution. PMID- 28868542 TI - Iodine-doped sumanene and its application for the synthesis of chalcogenasumanenes and silasumanenes. AB - The synthesis of an iodine-doped sumanene, which represents the first example of halogen-doped buckybowls, is described. Pristine trithiasumanene, trisilasumanene and the hitherto unknown parent triselenasumanene, three interesting heterobuckybowls with significant synthetic challenges, were efficiently prepared from the iodine-doped sumanene through non-pyrolytic conditions. This work demonstrates the high potential of hypervalent iodines embedded in extended pi conjugated systems for the synthesis of novel curved and planar polycyclic aromatic hydrocarbons. PMID- 28868543 TI - Capture of Xe and Ar atoms by quantized vortices in 4He nanodroplets. AB - We present a computational study, based on time-dependent Density Functional theory, of the real-time interaction and trapping of Ar and Xe atoms in superfluid 4He nanodroplets either pure or hosting quantized vortex lines. We investigate the phase-space trajectories of the impurities for different initial conditions and describe in detail the complex dynamics of the droplets during the capture of the impurities. We show that the interaction of the incoming atom with the vortex core induces large bending and twisting excitations of the vortex core lines, including the generation of helical Kelvin waves propagating along the vortex core. We have also calculated the stationary configurations of a 4He droplet hosting a 6-vortex array whose cores are filled with Ar atoms. As observed in recent experiments, we find that doping adds substantial rigidity to the system, such that the doped vortex array remains stable, even at low values of the angular velocities where the undoped vortices would otherwise be pushed towards the droplet surface and be expelled. PMID- 28868544 TI - Photoinduced reversible spin-state switching of an FeIII complex assisted by a halogen-bonded supramolecular network. AB - The organization of a molecular FeIII complex embedded in a halogen-bonded 2D network is chemically tuned to trigger temperature- and light-induced spin-state switching. We attribute the associated magnetic properties and the unprecedented photoswitching effect to the optimized structural confinement provided by the presence of the supramolecular host framework. PMID- 28868545 TI - Topological vacancies in spherical crystals. AB - Understanding geometric frustration of ordered phases in two-dimensional condensed matter on curved surfaces is closely related to a host of scientific problems in condensed matter physics and materials science. Here, we show how two dimensional Lennard-Jones crystal clusters confined on a sphere resolve geometric frustration and form pentagonal vacancy structures. These vacancies, originating from the combination of curvature and physical interaction, are found to be topological defects and they can be further classified into dislocational and disclinational types. We analyze the dual role of these crystallographic defects as both vacancies and topological defects, illustrate their formation mechanism, and present the phase diagram. The revealed dual role of the topological vacancies may find applications in the fabrication of robust nanopores. This work also shows the promising potential of exploiting richness in both physical interactions and substrate geometries to create new types of crystallographic defects, which have strong connections with the design of crystalline materials. PMID- 28868546 TI - Enhancement of the photocatalytic activity of rhenium(i) complexes by encapsulation in light-harvesting soft nanotubes. AB - Dye-assembled soft nanotubes with controlled-diameter nanochannels functioned as light-harvesting antennae to strongly enhance the photocatalytic activity of Re(i) complexes encapsulated in their nanochannels. PMID- 28868547 TI - Investigation of a common gene expression signature in gastrointestinal cancers using systems biology approaches. AB - According to GLOBOCAN 2012, the incidence and the mortality rate of colorectal, stomach and liver cancers are the highest among the total gastrointestinal (GI) cancers. Here we aimed to find the common genes and pathways that are simultaneously deregulated in these three malignancies using systems biology approaches. Here we conducted a differential expression analysis on high-quality gene expression datasets of gastric cancer (GC), colorectal cancer (CRC) and hepatocellular carcinoma (HCC). To address the inter gene correlations that were neglected in differential expression studies, we also applied differential co expression analysis on the understudied datasets. The common significant differentially expressed genes (DEGs) among the three cancers were used for further regulatory and PPI network construction. In parallel the regulatory roles of miRNAs and lncRNAs in the common DEGs were investigated. 23 common DEGs were detected between GC, CRC and HCC. Two cases of potential feed forward loops were identified in the constructed TF-target regulatory network, indicating the probable cross-talk between biological pathways. The result of a vulnerability test on the common PPI network resulted in the finding of three candidates, the simultaneous targeting of which will disintegrate the main parts of the network. The results of the differential co-expression study led to the identification of respectively 7 and 1 common differentially co-expressed pairs of genes between GC and CRC and between CRC and HCC. The results of the differential expression study introduced new common players in CRC, GC and HCC and provided better insights into the molecular characteristics of these GI malignancies. Moreover, we concluded that differential co-expression studies are an essential complement for differential expression studies that just take single differentially expressed genes into account. PMID- 28868549 TI - Progress in bio-inspired sacrificial bonds in artificial polymeric materials. AB - Mimicking natural structures has been highly pursued in the fabrication of synthetic polymeric materials due to its potential in breaking the bottlenecks in mechanical properties and extending the applications of polymeric materials. Recently, it has been revealed that the energy dissipating mechanisms via sacrificial bonds are among the important factors which account for strong and tough attributes of natural materials. Great progress in synthesis of polymeric materials consisting of sacrificial bonds has been achieved. The present review aims at (1) summarizing progress in the mechanics and chemistry of sacrificial bond bearing polymers, (2) describing the mechanisms of sacrificial bonds in strengthening/toughening polymers based on studies by single-molecule force spectroscopy, chromophore incorporation and constitutive laws, (3) presenting synthesis methods for sacrificial bonding including dual-crosslink, dual/multiple network, and sacrificial interfaces, (4) discussing the important advances in engineering sacrificial bonding into hydrogels, biomimetic structures and elastomers, and (5) suggesting future works on molecular simulation, viscoelasticity, construction of sacrificial interfaces and sacrificial bonds with high dissociative temperature. It is hoped that this review will provide guidance for further development of sacrificial bonding strategies in polymeric materials. PMID- 28868550 TI - Calculation and experimental measurement of paramagnetic NMR parameters of phenolic oximate Cu(ii) complexes. AB - We present a strategy for predicting the unusual 1H and 13C shifts in NMR spectra of paramagnetic bisoximato copper(ii) complexes using DFT. We demonstrate good agreement with experimental measurements, although 1H-13C correlation spectra show that a combined experimental and theoretical approach remains necessary for full assignment. PMID- 28868551 TI - Cavitation to fracture transition in a soft solid. AB - When a soft solid such as rubber, gel and soft tissue is subject to hydrostatic tension, a small cavity inside the solid expands. For a neo-Hookean solid, when the hydrostatic tension approaches a critical value: 2.5 times its shear modulus, the initially small cavity can expand unboundedly. Such a phenomenon is usually referred to as cavitation instability in soft solids. Several recent experiments have shown that fractures may occur in the material when the hydrostatic tension is far below the critical value. In this article, we study a spherical cavity with a ring crack on its wall and inside a neo-Hookean elastomer subject to hydrostatic tension. We compute the energy release rate associated with the extension of the ring crack, for both pressure-control and (cavity) volume control loading modes. We find that for the pressure-control mode, the energy release rate increases with the increase of the crack size as well as the magnitude of pressure; for the (cavity) volume-control mode, with a fixed cavity volume, the energy release rate increases with the increase of the crack size when the crack is short; the energy release rate maximizes for an intermediate crack size, and decreases with the increase of crack size when the crack is long. The results obtained in this article may be helpful for understanding cavitation to-fracture transition in soft solids subject to different loading conditions. PMID- 28868548 TI - Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4). AB - Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17beta-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers. PMID- 28868552 TI - Synthesis of ribosyl-ribosyl-adenosine-5',5'',5'''(triphosphate)-the naturally occurring branched fragment of poly(ADP ribose). AB - Poly-adenosine diphosphate ribose (PAR) is a branched biopolymer that occurs as a result of post-translational modification of proteins. In 1981 Miwa et al. determined the structure of enzymatically prepared branched PAR. We present the first synthesis of the same branched PAR fragment and have shown by NMR that the structure proposed by Miwa is correct. PMID- 28868554 TI - Highly flexible and transparent dielectric elastomer actuators using silver nanowire and carbon nanotube hybrid electrodes. AB - We demonstrate a dielectric elastomer actuator (DEA) with a high areal strain value of 146% using hybrid electrodes of silver nanowires (AgNWs) and single walled carbon nanotubes (SWCNTs). The addition of a very small amount of SWCNTs (~35 ng mm-2) to a highly resistive AgNW network resulted in a remarkable reduction of the electrode sheet resistance by three orders, increasing the breakdown field by 183% and maximum strain, while maintaining the reduction of optical transmittance within 11%. The DEA based on our transparent and stretchable hybrid electrodes can be easily fabricated by a simple vacuum filtration and transfer process of the electrode film on a pre-strained dielectric elastomer membrane. We expect that our approach will be useful in the future for fabricating stretchable and transparent electrodes in various soft electronic devices. PMID- 28868555 TI - Validation of density functionals for pancake-bonded pi-dimers; dispersion is not enough. AB - pi-Stacking pancake bonding between radicals poses special challenges to density functional theories (DFTs) due to their shorter than van der Waals contact distances, their multireference singlet ground states and the concurrently important dispersion interactions. We examined over 50 DFTs including 22 with dispersion corrections on four different pi-dimerized pancake-bonded systems exploring the performances of these DFTs in the very short intermolecular contact regime. We examined crucial energetic as well as geometric parameters against available high-level multireference average quadratic coupled cluster (MR-AQCC) results. Overall we did not find an omnipotent DFT applicable for all four pancake-bonded pi-dimers. However, some DFTs were found to perform well for each individual system: M05-2X and PBE0-MBD are the only DFTs that work well for the phenalenyl pi-dimer; BLYP is the only appropriate DFT for the 1,2,4,6 thiatriazine pi-dimer; O3LYP works best on the double pancake-bonded 1,3,2,4,6 dithiatriazine pi-dimer with a few acceptable ones and MN15L is the best method for K+TCNE- pi-dimer in addition to a few acceptable ones. We believe our findings can deliver insights towards the design and characterization of the pancake-bond based materials and the development of new DFTs. PMID- 28868553 TI - Origins of the enhanced affinity of RNA-protein interactions triggered by RNA phosphorodithioate backbone modification. AB - The well-characterized interaction between the MS2 coat protein and its cognate RNA hairpin was used to evaluate changes in affinity as a result of phosphorodithioate (PS2) replacing phosphate by biolayer interferometry (BLI). A structure-based analysis of the data provides insights into the origins of the enhanced affinity of RNA-protein interactions triggered by the PS2 moiety. PMID- 28868556 TI - The electronic properties of three popular high spin complexes [TM(acac)3, TM = Cr, Mn, and Fe] revisited: an experimental and theoretical study. AB - The occupied and unoccupied electronic structures of three high spin TM(acac)3 (TM = Cr, Mn, and Fe) complexes (I, II, and III, respectively) were studied by revisiting their literature vapour-phase He(i) and, when available, He(ii) photoemission (PE) spectra and by means of original near-edge X-ray absorption fine structure (NEXAFS) spectroscopic data recorded at the O K-edge (OK-edge) and TM L2,3-edges (TML2,3-edges). The assignments of the vapour-phase He(i)/He(ii) PE spectra were guided by the results of spin-unrestricted non-relativistic Slater transition state calculations, while the OK-edge and TML2,3-edge spectroscopic pieces of evidence were analysed by exploiting the results of spin-unrestricted scalar-relativistic time-dependent density functional theory (DFT) and DFT/ROCIS calculations, respectively. Although the actual symmetry (D3, in the absence of any Jahn-Teller distortion) of the title molecules allowed an extensive mixing between TM t2g-like and eg-like atomic orbitals, the use of the Nalewajski-Mrozek TM-O bond multiplicity index combined with a thorough analysis of the ground state (GS) outcomes allowed the assessment of the TM-O bond weakening associated with the progressive TM 3d-based eg-like orbital filling. The experimental information provided by OK-edge spectra was rather poor; nevertheless, the combined use of symmetry, orbitals and spectra allowed us (i) to rationalise minor differences characterizing spectral features along the series, (ii) to quantify the contribution provided by the ligand-to-metal-charge-transfer (LMCT) excitations to the different spectral features, and (iii) to recognize the t2g /eg-like nature of the TM 3d-based orbitals involved in LMCT transitions. As far as the TML2,3-edge spectra and the DFT/ROCIS results were concerned, the lowest lying I,IIL3 spectral features included states having either the GS spin multiplicity (S(I) = 3/2, S(II) = 2) or, at higher excitation energies (EEs), states with DeltaS = +/-1. In contrast to that, only states with DeltaS = 0, -1 significantly contributed to the IIIL3 spectral pattern. Along the whole series, the L3 higher EE side was systematically characterized by states involving TM2p > pi4 MLCT excitations; as such, coupled-single excitations with DeltaS = 0 were involved in I and II, while single MLCT TM2p -> pi4 transitions with DeltaS = -1 were involved in III. PMID- 28868557 TI - Latest advances in supercapacitors: from new electrode materials to novel device designs. AB - Notably, many significant breakthroughs for a new generation of supercapacitors have been reported in recent years, related to theoretical understanding, material synthesis and device designs. Herein, we summarize the state-of-the-art progress toward mechanisms, new materials, and novel device designs for supercapacitors. Firstly, fundamental understanding of the mechanism is mainly focused on the relationship between the structural properties of electrode materials and their electrochemical performances based on some in situ characterization techniques and simulations. Secondly, some emerging electrode materials are discussed, including metal-organic frameworks (MOFs), covalent organic frameworks (COFs), MXenes, metal nitrides, black phosphorus, LaMnO3, and RbAg4I5/graphite. Thirdly, the device innovations for the next generation of supercapacitors are provided successively, mainly emphasizing flow supercapacitors, alternating current (AC) line-filtering supercapacitors, redox electrolyte enhanced supercapacitors, metal ion hybrid supercapacitors, micro supercapacitors (fiber, plane and three-dimensional) and multifunctional supercapacitors including electrochromic supercapacitors, self-healing supercapacitors, piezoelectric supercapacitors, shape-memory supercapacitors, thermal self-protective supercapacitors, thermal self-charging supercapacitors, and photo self-charging supercapacitors. Finally, the future developments and key technical challenges are highlighted regarding further research in this thriving field. PMID- 28868558 TI - Delayed release singlet oxygen sensitizers based on pyridone-appended porphyrins. AB - A new type of porphyrin photosensitizer capable of generating singlet oxygen upon irradiation, storing it through binding to pyridone subunits, followed by slow release at 20-40 degrees C, is reported. The timescale of singlet oxygen release can be varied depending on the pyridone group substitution pattern, forming endoperoxides of different stabilities. Modified tetra- and octa-substituted pyridone-porphyrins showed solubility in water, allowing for straightforward delivery into cells. The effect of delayed singlet oxygen formation due to endoperoxide decomposition was demonstrated on cancer cells in vitro. PMID- 28868559 TI - Anharmonic vibrational effects in linear and two-dimensional electronic spectra. AB - For the description of vibrational effects in electronic spectra, harmonic vibrations are a convenient and widespread model. However, spectra of larger organic molecules in solution usually exhibit signs of vibrational anharmonicity, as revealed by deviation from the mirror image symmetry between linear absorption and emission spectra of the harmonic case. For perylene and terylene, two molecules with rigid Pi-electron systems and strong vibrational-electronic coupling, we employ a simple but effective theoretical model, which introduces cubic anharmonicity in the potentials of electronic surfaces. Vibrational anharmonicity is then readily quantified based on the experimentally measured peak ratio of the first vibronic progression peaks in linear absorption and emission. This method is straightforward but not applicable if emission from the initially excited state is short lived. For such a case, we employ two dimensional electronic spectroscopy in the visible as a comprehensive time resolved technique for the experimental determination of the vibrational anharmonicity of pinacyanol iodide, a solvated dye molecule exhibiting ultrafast excited state isomerization. We show that the ratio between certain cross peak amplitudes in two-dimensional electronic spectra is a direct measure of vibrational anharmonicity. PMID- 28868560 TI - Nickel-catalyzed direct C-H trifluoroethylation of heteroarenes with trifluoroethyl iodide. AB - A highly selective nickel-catalyzed C-H trifluoroethylation of heteroarenes was developed with the assistance of a monodentate directing group. This protocol provides efficient access to various trifluoroethyl-substituted heteroarenes, including indoles, pyrroles, furans, and thiophenes, with commercially available CF3CH2I as an alkylation reagent. This robust catalytic procedure is scalable and tolerates a broad range of functional groups. Moreover, multifluoroalkylation of indoles is also viable. PMID- 28868561 TI - Aqueous-solution-processable metal oxides for high-performance organic and perovskite solar cells. AB - Poly(3,4-ethylene dioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) is a widely utilized hole-transporting material (HTM) in planar photovoltaic devices, such as organic solar cells (OSCs) and perovskite solar cells (PSCs). However, the hygroscopic nature of PEDOT:PSS aqueous dispersions may restrict their future application. Therefore, it is necessary to develop other effective and stable HTMs to achieve high-performance photovoltaic devices. Herein, we demonstrate a facile route to deposit solution-processed MoO3, GeO2, V2O5 and CrO3 thin films as hole-transporting layers by directly dissolving their commercial powders in deionized water. Among these, the solution-processed V2O5 (sV2O5) film exhibited the highest work function of 5.2 eV, and the best hydrophobicity, with a contact angle of 77.2 degrees . The sV2O5-based OSCs and PSCs presented power conversion efficiencies (PCEs) of 8.36% and 14.13%, respectively. Notably, the PEDOT:PSS V2O5 composite HTM based device obtained a maximum PCE of 18.03% with a Voc exceeding 1.0 V. These aqueous-solution-processed HTMs have potential applications in green and low-cost photovoltaic devices by virtue of their simple and ecofriendly preparations. PMID- 28868562 TI - Analyses of sizable ZFS and magnetic tensors of high spin metallocomplexes. AB - The fictitious spin-1/2 Hamiltonian approach is the putative method to analyze the fine-structure/hyperfine ESR spectra of high spin metallocomplexes having sizable zerofield splitting (ZFS), thus giving salient principal g-values far from around g = 2 without explicitly providing their ZFS parameters in most cases. Indeed, the significant departure of the g-values from g = 2 is indicative of the occurrence of their high spin states, but naturally they never agree with true g-values acquired by quantum chemical calculations such as sophisticated DFT or ab initio MO calculations. In this work, we propose facile approaches to determine the magnetic tensors of high spin metallocomplexes having sizable ZFS, instead of performing advanced high-field/high-frequency ESR spectroscopy. We have revisited analytical expressions for the relationship between effective g values and true principal g-values for high spins. The useful analytical formulas for the geff-gtrue relationships are given for S's up to 7/2. The genuine Zeeman perturbation formalism gives the exact solutions for S = 3/2, and for higher S's it is much more accurate than the pseudo-Zeeman perturbation approach documented so far (A. Abragam and B. Bleaney, Electron Paramagnetic Resonance of Transition Metal Ions, 1970; J. R. Pilbrow, J. Magn. Reson., 1978, 31, 479; F. Trandafir et al., Appl. Magn. Reson., 2007, 31, 553; M. Fittipaldi et al., J. Phys. Chem. B, 2008, 112, 3859), in which the E(Sx2 - Sy2) term is putatively treated to the second order. To show the usefulness of the present approach, we exploit FeIII(Cl)OEP (S = 5/2) (OEP: 2,3,7,8,12,13,17,18-octaethylporphyrin) and CoIIOEP (S = 3/2) well magnetically diluted in the diamagnetic host crystal lattice of NiIIOEP. The advantage of single-crystal ESR spectroscopy lies in the fact that the molecular information on the principal axes of the magnetic tensors is crucial in comparing with reliable theoretical results. In high spin states of metallocomplexes with sizable ZFS in pseudo-octahedral symmetry, their fine structure ESR transitions for the principal z-axis orientation appear in the lower field far from g = 2 at the X-band, disagreeing with the putative intuitive picture obtained using relevant ESR spectroscopy. A ReIII,IV dinuclear complex in a mixed valence state exemplifies the cases, whose fine-structure/hyperfine ESR spectra of the neat crystals have been analyzed in their principal-axis system. The DFT-based/ab initio MO calculations of the magnetic tensors for all the high spin entities in this work were carried out. PMID- 28868563 TI - Current progress in black phosphorus materials and their applications in electrochemical energy storage. AB - Recently, a new two-dimensional material, single- or few-layered black phosphorus (BP), has attracted considerable attention for applications in electronics, optoelectronics, and batteries due to its unique properties, including large specific surface area, anisotropy, and tunable and direct band gaps. In particular, contributions to electrochemical energy storage devices, such as lithium and sodium ion batteries and supercapacitors, have emerged. However, critical issues remain to be explored before scaled-up commercial production of BP, such as preparation, stability, and performance. Herein, we present the first review of recent progress in BP-based electrochemical energy storage device. The preparation and electrochemical properties of black phosphorus, recent advances, potential challenges, and relevant perspectives in electrochemical energy storage, and the potential of BP are discussed in this work. PMID- 28868564 TI - Nanoconfinement greatly speeds up the nucleation and the annealing in single-DNA collapse. AB - Manipulating and measuring single-molecule dynamics and reactions in nanofluidics is a rapidly growing field with broad applications in developing new biotechnologies, understanding nanoconfinement effects in vivo, and exploring new phenomena in confinement. In this work, we investigate the kinetics of DNA collapse in nanoslits using single T4-DNA (165.6 kbp) and lambda-DNA (48.5 kbp), with particular focus on the measurement of the nucleation and annealing times. Fixing the ethanol concentration at 35% and varying the slit height from 2000 to 31 nm, the nucleation time dramatically decreases from more than 1 hour to a few minutes or less. The increased collapsed rate results from the larger free energy experienced by coiled DNA in confinement relative to compacted DNA. Our results also shed light on other conformational transitions in confinement, such as protein folding. PMID- 28868566 TI - "Bone Morphogenic Protein augmentation for long bone healing" response to "Clinical need for bone morphogenetic protein". AB - We take advantage of the comments of Dr. Vukicevic et al. to clarify that the study focus did not include other diseases and locations than long bones; in this light, the articles that Dr. Vukicevic mentioned could not be selected. We would like to recognize the key contribution of Urist and the nice tribute of the International Orthopaedics heritage section on the BMPs discovery. While we could not refer to the latter, published after our search, we put emphasis on the steps of important discoveries that made BMPs available for clinical use, a road that started in 1965, when Urist showed that new bone formation could be induced by demineralized bone matrix, later identified as BMPs, and purified in the next three decades. In the past years, BMPs have been studied in several pre-clinical models. As this was not the focus of this systematic clinical review, only some pre-clinical papers were cited, aiming at underlining important aspects, such as the relationship between dosage and bone formation and the delivery material, which could influence BMPs release and effect, key factors requiring further studies to optimize BMPs augmentation, as mentioned in the discussion. While our article does not present the methodological strength of a meta-analysis, and while it was not possible to summarize the entire extensive literature on BMPs, we hope that our review could be useful to summarize the available evidence in terms of both BMPs augmentation potential and complications for the treatment of long bones affected by fractures, non-union, and osteonecrosis. PMID- 28868565 TI - Comparison of the Amplification Refractory Mutation System, Super Amplification Refractory Mutation System, and Droplet Digital PCR for T790 M Mutation Detection in Non-small Cell Lung Cancer after Failure of Tyrosine Kinase Inhibitor Treatment. AB - Plasma mutation detection has the advantages of non-invasiveness and accessibility. Here, we evaluated three methods, the amplification refractory mutation system (ARMS), second-generation ARMS (SuperARMS), and droplet digital PCR (ddPCR), to assess their concordance and feasibility for the detection of mutations in plasma samples. Non-small lung cancer patients with stage IIIB/IV that were resistant to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment were enrolled. Blood samples were collected within 14 days after TKI resistance. Each sample was simultaneously assessed by the three methods. In total, 169 patients were enrolled; 54.4% were female, 72.2% were diagnosed with stage IV disease; and 97.6% had adenocarcinoma. T790 M mutations were detected in 42 (24.8%) of the 169 samples using ARMS, one of which carried the T790 M alone, 22 that also encoded exon 19 deletions, and 19 with L858R mutations. For the SuperARMS assay, 59 (34.9%) samples exhibited the T790 M mutation, and 110 (65.1%) showed no detectable T790 M mutation. ddPCR showed that 61 (36.1%) samples contained the T790 M mutation, whereas 108 (63.9%) were not positive. T790 M abundance ranged from 0.04% to 38.2%. The median T790 M abundance was 0.15% for total samples and 2.98% for T790 M mutation samples. The overall concordance was 78.7% (133/169) among ARMS, SuperARMS, and ddPCR. Compared with patients with stage III disease, patients with stage IV disease exhibited a higher T790 M mutation detection rate (28.7% vs. 14.9% by ARMS; 37.7% vs. 27.7% by SuperARMS; and 41.8% vs. 21.3% by ddPCR). Liquid biopsy showed promise and has the advantages of non-invasiveness and accessibility. T790 M detection based on circulating tumor DNA showed high concordance. Compared with non-digital platforms, ddPCR showed higher sensitivity and provided both frequency and abundance information, which might be important for treatment decisions. PMID- 28868567 TI - Gait analysis of patients with an off-the-shelf total knee replacement versus customized bi-compartmental knee replacement. AB - INTRODUCTION: Newer TKR designs have been introduced to the market with the aim of overcoming common sizing problems with older TKR designs. Furthermore, since a sizable percentage of patients with OA present with disease limited to the medial/lateral knee compartment in addition to the patellofemoral joint, for whom, a customized bi-compartmental knee replacement (BKR) is available as a treatment option. To date, there is very little information regarding knee strength and mechanics during gait for patients implanted with these modern TKR and BKR designs. The purpose of the study was to evaluate knee strength and mechanics during walking for patients with either a modern off the shelf TKR or a customized BKR and compare these findings to a cohort of healthy controls. METHODS: Twelve healthy controls, eight BKR, and nine TKR patients participated in the study. Maximal isometric knee strength was evaluated. 3D kinematic and kinetic analyses were conducted for level walking. RESULTS: The TKR knee exhibited less peak extensor torque when compared to, both the BKR and control limbs (p < 0.05). The TKR knee had less extensor moment at stance than both the BKR and control knees (p < 0.05). Both the BKR and control knees displayed larger internal rotation at stance than that of the TKR knee (p < 0.05). DISCUSSION AND CONCLUSION: This study suggests that, for patients that exhibit isolated OA of the tibiofemoral joint, using a customized BKR implant is a viable treatment option and may contribute to superior mechanical advantages. PMID- 28868568 TI - Referral to cancer genetic counseling: do migrant status and patients' educational background matter? AB - Participation rates in cancer genetic counseling differ among populations, as patients with a lower educational background and migrant patients seem to have poorer access to it. We conducted a study to determine the present-day educational level and migrant status of counselees referred to cancer genetic counseling. We assessed personal characteristics and demographics of 731 newly referred counselees. Descriptive statistics were used to describe these characteristics. The results show that about 40% of the counselees had a high educational level and 89% were Dutch natives. Compared to the Dutch population, we found a significant difference in educational level (p = < 0.01) and migrant status (p = < 0.001). This suggests disparities in cancer genetic counseling and as a result of that, suboptimal care for vulnerable groups. Limited health literacy is likely to pose a particular challenge to cancer genetic counseling for counselees with a lower education or a migrant background. Our study points to considerable scope for improvement in referring vulnerable groups of patients for cancer genetic counseling. PMID- 28868569 TI - Genetic analysis of 12 X-STR loci in the Serbian population from Vojvodina Province. AB - The analysis of 12 X-STR loci included in the Investigator(r) Argus X-12 kit was performed on a sample of 325 unrelated persons from Vojvodina Province, Republic of Serbia. No significant differences were observed in the allele frequencies in males and females. Heterozygosity values among the studied loci ranged from 67.62 to 94.28%. All loci in female individuals were consistent with the Hardy-Weinberg equilibrium test. The combined power of discrimination values in male and female individuals was 0.9999999994 and 0.999999999999999, respectively. The combined mean exclusion chance was 0.999998 in deficiency cases, 0.9999999977 in normal trio cases, and 0.9999994 in duo cases. Loci DXS10135 and DXS10101 were found to be most polymorphic. The haplotype diversity was found to be greater than 0.993 for all linkage groups. The exact test for pairwise linkage disequilibrium for the 12 loci in the male samples showed significant linkage disequilibrium for the DXS10103-DXS10101 and DXS10134-DXS10146 pairs of loci. The results from the current study confirmed that the panel of 12 X-STR loci is highly polymorphic and informative and can be implemented as a powerful tool in deficient paternity testing and kinship analysis, as well as a useful complement tool of autosomal short tandem repeats (STRs) in forensic investigation. Population differentiation analyses indicated significant differences in genetic structure between the Serbian population and the geographically and ethno-linguistically distant populations, while genetic homogeneity was present in populations with similar geographic origin. PMID- 28868570 TI - Effects of pH, initial Pb2+ concentration, and polyculture on lead remediation by three duckweed species. AB - Various geographical duckweed isolates have been developed for phytoremediation of lead. The Pb2+ removal efficiency of Lemna aequinoctialis, Landoltia punctata, and Spirodela polyrhiza was investigated in monoculture and polyculture at different levels of pH and initial Pb2+ concentrations. L. aequinoctialis was not sensitive to the tested pH but significantly affected by initial Pb2+ concentration, whereas synergistic effect of pH and initial Pb2+ concentration on removal efficiency of L. punctata and S. polyrhiza was found. Although the majority of polycultures showed median removal efficiency as compared to respective monocultures, some of the polycultures achieved higher Pb2+ removal efficiencies and can promote population to remove Pb2+. Besides, the three duckweed strains could be potential candidates for Pb2+ remediation as compared to previous reports. Conclusively, this study provides useful references for future large-scale duckweed phytoremediation. PMID- 28868571 TI - Erratum to: comparison between inflammation-related markers in peri-implant crevicular fluid and clinical parameters during osseointegration in edentulous jaws. PMID- 28868572 TI - Upregulation of Treg-Related Genes in Addition with IL6 Showed the Significant Role for the Distant Metastasis in Colorectal Cancer. AB - T helper 17 (Th17) and T regulatory (Treg) cytokines appear to be contributing greatly to colorectal cancer (CRC) development and progression. The aim of the current study was to investigate the expression of Foxp3; IL10; TGFB1; IL17A; IL6 and NOS2 genes in tumor tissue, regional positive lymph nodes and distant metastasis obtained from 26 patients with advanced CRC. Quantitative real-time polymerase chain reaction (qPCR) was performed for mRNA detection by TaqMan gene expression assay. In distant metastasis, IL6 was strongly expressed, over 7.5 fold, followed by Treg-related genes Foxp3; IL10 and TGFB1 in contrast to IL17A and NOS2. The similar pattern of expression was observed in positive regional lymph node in addition to significant down-regulation of NOS2 (RQ = 0.287; p = 0.011) and a trend for the elevation of IL17A. In tumor tissue, Fopx3 was significantly upregulated and Foxp3 mRNA positively correlated with TGFB1 in all investigated tissue types. In tumor tissue, expression of IL17A was correlated with NOS2 (r = 0.68; p = 0.005), while in distant metastasis IL10 was in strong relation with TGFB1 and IL6. In addition, a reverse correlation between IL6 and NOS2 (r = -0.66; p = 0.009), was observed in distant metastasis. The simultaneous expression of given Treg and Th17-related genes found both in the primary tumor and in the regional lymph nodes appears to provide suitable microenvironment sufficient for promoting metastatic growth. The upregulation of Foxp3; IL10, TGFB1 and IL6 might be a transcriptional profile hallmark for colorectal metastases. PMID- 28868573 TI - Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies. AB - Background Polymeric micellar paclitaxel (PM-paclitaxel) is a novel Cremophor EL free, nanoparticle-encapsulated paclitaxel formulation administered through intravenous injection. The primary objective of this phase I trial was to determine the first cycle dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PM-paclitaxel. Secondary objectives included the evaluation of the safety, antitumor activity, and pharmacokinetic (PK) profile of PM-paclitaxel in patients with advanced malignancies. Methods The PM-paclitaxel dose was escalated from 175 mg/m2 (level 1) to 435 mg/m2 (level 5). PM-paclitaxel was intravenously administered to patients for 3 h without premedication on day 1 of a 21-day cycle. Results Eighteen patients with confirmed advanced malignancies received PM paclitaxel. DLT included grade 4 neutropenia (four patients) and grade 3 numbness (one patient), which occurred in one of the six patients who received 300 mg/m2 (level 3) PM-paclitaxel and all three patients who were treated with 435 mg/m2 PM paclitaxel. Thus, the MTD of PM-paclitaxel was determined as 390 mg/m2 (level 4). Acute hypersensitive reactions were not observed. Partial response was observed in six of 18 patients (33.3%), three of whom had prior exposure to paclitaxel chemotherapy. The peak concentration and area under the curve values of paclitaxel increased with increasing dosage, indicating that PM-paclitaxel exhibits linear PKs. Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300 mg/m2. PMID- 28868574 TI - Racial minority group interest in direct-to-consumer genetic testing: findings from the PGen study. AB - There is little information regarding direct-to-consumer (DTC) personal genetic testing (PGT) in non-White racial minorities. Using a web-based survey, we compared the pretest interests and attitudes toward DTC-PGT of racial minority and White DTC-PGT customers of 23andMe and Pathway Genomics using chi-square tests and multinomial regression. Data were available for 1487 participants (1389 White, 44 Black, and 54 Asian). Survey responses were similar across racial groups, although a greater proportion of Blacks compared to Whites reported being "very interested" in genetic information related to traits (91.9 vs. 70.8%, p = 0.009). A greater proportion of Asians compared to Whites reported that a "very important" consideration for pursuing DTC-PGT was limited information about their family health history (58.0 vs. 37.5%, p = 0.002). While a number of significant differences between groups were observed in unadjusted analyses, they did not remain significant after adjustment. This study provides a preliminary view of the interests for purchasing DTC-PGT among customers with racial minority backgrounds. PMID- 28868575 TI - Co-contaminant effects on ofloxacin adsorption onto activated carbon, graphite, and humic acid. AB - Given their voluminous application, significant amounts of fluoroquinolones are discharged into the environment through wastewater effluent. Adsorption has been shown to be a critical process controlling the environmental behaviors of fluoroquinolones. Competition between ofloxacin (OFL) and naphthalene (NAP)/bisphenol A (BPA) and their adsorption on activated carbon (AC), graphite (GP), and humic acid (HA) were investigated. The suppressed adsorption of OFL was observed on AC and GP, but not on HA, by NAP or BPA. Moreover, for AC, the competition by NAP was slightly stronger than that by BPA. However, for GP, the competition with BPA was higher than that with NAP. These observations indicate that competitive adsorption of OFL with respect to NAP/BPA depends on the degree of overlap of adsorption sites, as interpreted by the following: (i) AC can provide overlapping adsorption sites for OFL, BPA, and NAP, which include non specific adsorption sites, such as hydrophobic sites, pi-pi interactions, and micropore filling; (ii) pi-pi interactions and hydrogen bonding might be responsible for the strong competitive adsorption between BPA and OFL on GP; and (iii) OFL adsorbs on HA through specific adsorption force-electrostatic attraction, with which NAP and BPA cannot compete. PMID- 28868576 TI - Choice between delayed food and immediate opioids in rats: treatment effects and individual differences. AB - RATIONALE: Addiction involves maladaptive choice behavior in which immediate drug effects are valued more than delayed nondrug rewards. OBJECTIVES AND METHODS: To model this behavior and extend our earlier work with the prescription opioid oxycodone, we allowed rats to choose between immediate intravenous delivery of the short-acting opioid remifentanil and delayed delivery of highly palatable food pellets. Treatment drugs were tested on a baseline where remifentanil was preferred over food. RESULTS: Treatment with a high dose of the opioid antagonist naltrexone decreased but did not reverse the preference for remifentanil. Treatment with the serotonin 5-HT2C agonist lorcaserin decreased remifentanil and food self-administration nonselectively. Across conditions in which the alternative to delayed food was either a moderate dose of oxycodone, a moderate or high dose of remifentanil, a smaller more immediate delivery of food, or timeout with no primary reinforcement, choice was determined by both the length of the delay and the nature of the alternative option. Delayed food was discounted most steeply when the alternative was a high dose of remifentanil, which was preferred over food when food was delayed by 30 s or more. Within subject comparisons showed no evidence for trait-like impulsivity or sensitivity to delay across these conditions. CONCLUSIONS: Choice was determined more by the current contingencies of reinforcement than by innate individual differences. This finding suggests that people might develop steep delay-discounting functions because of the contingencies in their environment, and it supports the use of contingency management to enhance the relative value of delayed nondrug reinforcers. PMID- 28868577 TI - X-chromosomal STR-based genetic structure of Sichuan Tibetan minority ethnicity group and its relationships to various groups. AB - The X-chromosomal short tandem repeats (STRs) with more informative than autosomal STRs in some complicated biological relationships identification due to its specific mode of genetic transmission can be used as a complementary tool in forensic case practices. In this study, we presented the population genetic data of 19 X-STRs, consisting of DXS10174, DXS10075, DXS10079, DXS101, DXS10101, DXS10103, DXS10134, DXS10135, DXS10148, DXS10159, DXS10162, DXS10164, DXS6789, DXS6809, DXS7132, DXS7423, DXS7424, DXS8378, and HPRTB loci, in a sample of 235 individuals of Tibetan nationality from Sichuan province, Southwest China. All 19 X-STR loci were consistent with Hardy-Weinberg equilibrium. The results showed that the combined power of discrimination in females and males are 0.999999999999999999997 and 0.9999999999997, respectively. In addition, the mean paternity exclusion chances based on the formula of MECKruger, MECKishida, and MECDesmarais as well as MECDesmarais Duo are 0.99999991, 0.9999999999924, 0.9999999999929, and 0.999999985, respectively. In summary, our findings suggested that the AGCU X19 kit can be considered to serve as a high polymorphic information tool for forensic identification and kinship testing in the Sichuan Tibetan population. Furthermore, population genetic structure investigation between Sichuan Tibetan population and other 19 populations using PCA, MDS, and phylogenetic tree illustrated that significant genetic difference was observed between the Sichuan Tibetan and Malay, as well as the Xinjiang Uyghur population. PMID- 28868578 TI - Management of pulmonary neuroendocrine tumors. AB - Neuroendocrine tumors (NETs) of the lung are divided into 4 major types: small cell lung cancer (SCLC), large cell neuroendocrine carcinoma (LCNEC), atypical carcinoid (AC) or typical carcinoid (TC). Each classification has distinctly different treatment paradigms, making an accurate initial diagnosis essential. The inconsistent clinical presentation of this disease, however, makes this difficult. The objective of this manuscript is to detail the diagnosis and management of the well differentiated pulmonary carcinoid (PC) tumors. A multidisciplinary approach to work up and treatment should be utilized for each patient. A multimodal radiological work-up is used for diagnosis, with contrast enhanced CT predominantly utilized and functional imaging techniques. A definitive diagnosis is based on tissue findings. Surgical management remains the mainstay of therapy and can be curative. In those with advanced disease, medical treatments consist of somatostatin analog (SSA) therapy, targeted therapy, chemotherapy or peptide receptor radionuclide therapy. SSAs are the standard of care in those with metastatic NETs, using either Octreotide long acting repeatable (LAR) or lanreotide as reasonable options, despite a scarcity of prospective data in PCs. Targeted therapies consist of everolimus which is approved for use in PCs, with various studies showing mixed results with other targeted agents. Additionally, radionuclide therapy may be used and has been shown to increase survival and to reduce symptoms in some studies. Prospective trials are needed to determine other strategies that may be beneficial in PCs as well as sequencing of therapy. Successful diagnosis and optimal treatment relies on a multidisciplinary approach in patients with lung NETs. Clinical trials should be used in appropriate patients. PMID- 28868580 TI - Quantitative sequence characterization for repetitive DNA content in the supernumerary chromosome of the migratory locust. AB - Repetitive DNA is a major component in most eukaryotic genomes but is ignored in most genome sequencing projects. Here, we report the quantitative composition in repetitive DNA for a supernumerary (B) chromosome, in the migratory locust (Locusta migratoria), by Illumina sequencing of genomic DNA from B-carrying and B lacking individuals and DNA obtained from a microdissected B chromosome, as well as the physical mapping of some elements. B chromosome DNA of 94.9% was repetitive, in high contrast with the 64.1% of standard (A) chromosomes. B chromosomes are enriched in satellite DNA (satDNA) (65.2% of B-DNA), with a single satellite (LmiSat02-176) comprising 55% of the B. Six satDNAs were visualized by FISH on the B chromosome, and the only A chromosome carrying all these satellites was autosome 9, pointing to this chromosome, along with autosome 8 (which shares histone genes with the B) as putative ancestors of the B chromosome. We found several transposable elements (TEs) showing nucleotidic variation specific to B-carrying individuals, which was also present in B carrying transcriptomes. Remarkably, an interstitial region of the B chromosome included a 17 kb chimera composed of 29 different TEs, suggesting reiterative TE insertion in this B chromosome region. PMID- 28868579 TI - Bacillus safensis with plant-derived smoke stimulates rice growth under saline conditions. AB - Salinity is a worldwide environmental problem of agricultural lands. Smoke and plant growth-promoting bacteria (PGPR) are individually used to improve plant growth, but the combined effects of these have not been studied yet under saline conditions. The combined effect of plant growth-promoting bacteria Bacillus safensis and plant-derived smoke Cymbopogon jwarancusa was studied under different salinity level as 50, 100, and 150 mM on rice (cv. Basmati-385). Smoke dilutions of C. jwarancusa (C-500 and C-1000) and bacterial culture of B. safensis were used to soak seeds for 10 h. It was observed that the salt concentration decreases the germination percentage, vegetative growth, ion contents (K+ and Ca2+), and photosynthetic pigments (Chl "a," Chl "b," and carotene) while an increase occurred in Na+, total soluble protein (TSP), proline, total soluble sugar, catalase (CAT), and peroxidase (POD) contents. The combined effect of B. safensis and smoke primed seeds increased the germination percentage, seedling growth, ion contents (K+, Ca2+), and photosynthetic pigments (Chl "a," Chl "b," carotene) and reduced the Na+ ion content, total soluble protein, proline content, total soluble sugar, CAT, and POD activity by lowering the drastic effect of salt stress. It was concluded that combined effect of smoke and PGPR is more effective than individual effect. PMID- 28868581 TI - In human brain ornithine transcarbamylase (OTC) immunoreactivity is strongly expressed in a small number of nitrergic neurons. AB - There is recent evidence for ornithine transcarbamylase (OTC) expression in adult human brain. We decided to immunocytochemically map OTC throughout brain, and to further characterize OTC-immunopositive neurons. By using double immunolabeling technique for OTC and neuronal nitric oxide synthase (nNOS) OTC protein expression was revealed in a small subset of nitrergic (nNOS) neurons. Since citrulline (the reaction product of OTC) enhances the bioavailability of L arginine, the substrate of nNOS, it is conceivable that OTC activity supports NO production in nitrergic neurons. PMID- 28868582 TI - Still sour about lactic acidosis years later: role of metformin in heart failure. AB - Metformin remains a widely-used, first-line pharmacotherapy agent for patients with type 2 diabetes mellitus because of its efficacy, mild side effects, and affordability.However, use of this medication has traditionally been shunned by clinicians in patient populations that are considered at risk of lactic acidosis, such as those with heart failure. The underutilization of metformin can largely be attributed to the historical stigma of its biguanide predecessor, phenformin, and its association with lactic acidosis. Despite various studies finding low rates of lactic acidosis and the United States Federal Drug Administration's subsequent removal of heart failure from metformin's contraindication labeling in 2006, this oral hypoglycemic remains underutilized in this patient population. In addition to reports of the safe use of metformin in the heart failure population, a multitude of studies have also additionally suggested a modest reduction in mortality and morbidity. Metformin's role should be strongly reconsidered in the armamentarium of diabetes management in heart failure patients. PMID- 28868583 TI - Von Willebrand factor protects against acute CCl4-induced hepatotoxicity through phospho-p38 MAPK signaling pathway inhibition. AB - The blood glycoprotein von Willebrand factor (vWF) is involved in coagulopathy and inflammation; however, its role in the pathogenesis of acute liver failure, as suggested by its higher expression levels in such patients, remains unknown. In this study, vWF-knockout (KO) mice showed more severe carbon tetrachloride (CCl4)-induced liver injury than wild-type mice. Patients with acute liver injury also showed elevated vWF protein activity and expression in liver tissues, as compared to healthy individuals. Using the mouse model and cultured human umbilical vein endothelial cells (HUVECs), CCl4 was found to directly increase vWF protein expression through interaction with the highly expressed vWF receptor, GPIbalpha. Microarray analysis revealed that the genes showing the most differential expression in response to CCl4-induced liver injury and vWF deficiency were related to the MAPK signaling pathway. Subsequent inhibition of vWF protein activity in HUVECs led to activation of the MAPK signal pathway and elevated production of FGL2, and treatment with a phospho-p38 inhibitor suppressed the CCl4-induced production of FGL2. Exposure of liver sinusoidal endothelial cells isolated from the vWF-KO acute liver injury model mice to phospho-p38 inhibitor also decreased FGL2 expression. The vWF/GPIbalpha axis plays a protective role against development of acute liver injury by attenuating FGL2 production through the MAPK signaling pathway. Collectively, these data provide insight into the pathogenesis of acute liver injury and a potential novel strategy for its treatment. PMID- 28868584 TI - Urgent Care Centre's: "Urgent Need of the Hour?" PMID- 28868585 TI - Spectrum of ANCA-Associated Vasculitis. PMID- 28868586 TI - The Correlation Between Inferior Vena Cava Diameter Measured by Ultrasonography and Central Venous Pressure. AB - OBJECTIVE: To find a correlation between inferior vena cava (IVC) diameters, IVC compressibility index (CI) and central venous pressure (CVP). METHODS: Prospective observational study was done at pediatric intensive care unit (PICU) of Kalawati Saran Children's Hospital (KSCH). Fifty children aged 5-18 y, presenting with shock were enrolled for the study. IVC diameters, CI and relevant clinical data were noted at enrollment, 30 min, 1 h, 6 h, and 12 h. Central line was placed at the time of admission. RESULTS: Of 50 children enrolled, 28 were boys, with a mean age of 11 y. More than 80% of cases were diagnosed as septic shock. Mean maximum and minimum IVC diameter of 8.3 +/- 2 mm and 3.7 +/- 1.7 mm, respectively CI 58.2 +/- 7% and CVP of 5.4 +/- 1.5 cm of H2O was observed at admission. CVP and IVC diameters showed a serial improvement with treatment; CI showed a serial decrease with treatment. Heart rate (HR) and systolic blood pressure (SBP) also showed a serial improvement at 12 h (p < 0.05). CVP showed a positive correlation with IVC diameter (r +0.312; p < 0.05), and a negative correlation with CI (r -0.343; p < 0.05). CONCLUSIONS: Effective fluid resuscitation improves IVC diameters with a decrease in CI. IVC diameter has a positive correlation to CVP and CI has a negative correlation to CVP. PMID- 28868587 TI - Preparation, characterization and toxicity evaluation of amphotericin B loaded MPEG-PCL micelles and its application for buccal tablets. AB - Oral candidiasis or thrush is a fungal infection due to Candida albicans, causing discomfort in areas inside mouth or tongue. The clinical application of antifungal reagent amphotericin B (AMB), which is believed to offer a better treatment for oral candidiasis, is greatly compromised by its toxicities (mainly nephrotoxicity) and poor solubility. In order to overcome these issues, we characterized AMB-loaded MPEG-PCL micelles in vitro and in vivo. In addition, the antifungal activities of AMB/MPEG-PCL micelles-loaded buccal tablet were also evaluated in vitro. We found that micelles system could significantly improve the solubility of AMB yet reduce the overall toxicity, while the buccal tablet system is capable to suppress C. albicans biofilm formation. Furthermore, the toxicity of the buccal tablet system is also reduced compared with other standard preparations. Therefore, the prepared tablet with AMB-loaded MPEG-PCL micelles as oral topical preparations has the potential to improve current treatment of superficial oral C. albicans infections. PMID- 28868588 TI - Maternal vitamin D and offspring trabecular bone score. AB - : No studies have explored the relationship with maternal vitamin D (25(OH)D) in pregnancy and offspring trabecular bone score (TBS). Our data suggest that maternal 25(OH)D in early pregnancy, but not late, may be associated with offspring TBS in boys. These data act as hypothesis-generating findings for confirmation in larger, longer-term studies. INTRODUCTION: Trabecular bone score (TBS), a novel tool derived from dual-energy X-ray absorptiometry (DXA), reflects the microarchitecture of the vertebrae. It has been shown to predict fracture independent of standard DXA parameters in adult populations. Previously, we demonstrated that maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy is associated with offspring bone mineral content at age 11 years. However, associations with TBS have not been explored, thus we aimed to determine associations between maternal 25(OH)D and offspring TBS. METHODS: Data were collected from the Vitamin D in Pregnancy (VIP) study. Venous blood samples were taken at recruitment and at 28-32 weeks' gestation. Maternal 25(OH)D was measured by radioimmunoassay. Offspring (n = 195, n = 181 with complete measures) underwent spine DXA (GE Lunar), at age 11 years (median = 10.9 (IQR 10.9-11.4)). TBS was calculated using TBS iNsight software. RESULTS: Offspring of mothers with sufficient 25(OH)D levels (>=50 nmol/L) at recruitment had a higher TBS (1.363 vs. 1.340, p = 0.04). In multivariable linear regression models, after adjustment for child relative lean mass, sex and pubertal stage, a 10 nmol/L increase in maternal 25(OH)D was associated with a 0.005 (95% CI 0.000, 0.010, p = 0.04) increase in TBS. However when stratified by sex (p for interaction = 0.16), the association was significant in boys, but not girls. There were no associations with TBS and maternal 25(OH)D at 28-32 weeks. CONCLUSIONS: We speculate that maternal 25(OH)D in early pregnancy may be associated with TBS in offspring at age 11 in boys. These hypothesis-generating findings warrant confirmation with larger interventional and long-term follow-up studies. PMID- 28868589 TI - Heavy metals in the soils and plants from a typical restored coal-mining area of Huainan coalfield, China. AB - This study was conducted to pursue the heavy metals in the soil and plants of a typical restored coal-mining area, China. The average concentrations of Cu, Zn, Cr, Ni, and Pb in soil were 26.4, 76.1, 188.6, 34.3, and 50.2 mg kg-1, respectively, implying a significant accumulation of Cr, Ni, and Pb compared with the background values. Contamination factor indicates that the soil underwent none to medium pollution by Cu and Zn, medium to strong by Cr, none to strong by Pb, and medium pollution by Ni while the pollution load index means that the soil was subjected to intermediate contamination. Based on the critical threshold values to protect the plants, the investigated metals were unable to affect the plants. One-way ANOVA analysis shows that Cu, Zn, and Pb in plants varied with plant tissues. Cu-Cr, Cu-Ni, Zn-Ni, Zn-Pb, Cr-Ni, and Ni-Pb pairs had significant positive correlation both in soil and in plants due to the similar soil characteristics and plant physiologies. Correspondence analysis indicates that Pb was more likely to be accumulative in stems and leaves. In addition, the levels of Cu and Cr in plant followed an order of roots > stems > leaves; Zn and Ni leaves >= stems > roots; and Pb followed stems >= leaves > roots. Generally, this study suggests that the plants like Ligustrum lucidum Aiton and Weigela hortensis, which are capable of accumulating Cr, Ni, and Pb, should be the predominant species in the studied area. PMID- 28868590 TI - Effect of culturing temperatures on cadmium phytotoxicity alleviation by biochar. AB - Biochar produced from rice straw at 400 degrees C (RS400) was prepared to determine its alleviating effect on Cd phytotoxicity to wheat seedlings under different cultivation temperatures and pH. A hydroponic system (pH 4.3) and a loam soil slurry system were designed to respectively simulate acidic and neutral soil condition, and cultivation at increasing temperatures (20, 25, and 30 degrees C) were performed to evaluate the greenhouse effect. The root and shoot elongation and the Cd concentration in root and solution were measured; furthermore, batch experiments for Cd adsorption were undertaken. An increasing inhibition of the root by Cd addition was observed at increasing temperatures. The inhibition rate was 50.50 and 20.80% in hydroponic system and slurry system at 25 degrees C, respectively; however, the corresponding inhibition rates of root were significantly decreased to 25.5 and 3.5% with addition of RS400. This is mainly attributed to the reduction of Cd migration into the roots by RS400, which decreased Cd bioavailability. The mechanism behind the reduced Cd bioavailability is attributed to the Cd adsorption and the strong buffering capacity of acidity by RS400. Therefore, biochar could be a potential amendment for the remediation of Cd-contaminated soil even at increasing culturing temperatures. PMID- 28868591 TI - Early CT scanning in the emergency department in patients with penetrating injuries: does it affect outcome? AB - BACKGROUND: To be a level I trauma center in the Netherlands a computed tomography (CT) scanner in the emergency department (ED) is considered desirable, as it is presumed that this optimizes the diagnostic process and that therapy can be directed based on these findings. Aim of this study was to assess the effects of implementing a CT scanner in the ED on outcomes in patients with penetrating injuries. METHODS: In this retrospective descriptive study, patients with penetrating injuries (shot and/or stab wounds), presented between 2000 and 2014 were analysed using the hospital's electronic database, and data from the West Netherlands trauma registry and the financial department. RESULTS: 405 patients were included: performing a CT scan upon arrival increased significantly from 26.7 to 67.0% (p = 0.00) after implementation of a CT scanner in the ED, with the mean cost of a CT being 96.85 euros. Overall mortality decreased from 6.9 to 3.7%, although not statistically significant. Intensive care unit admission (ICU admission) and median hospital length of stay (H-LOS) decreased from 30.9 to 24.5% resp. 3.2 to 1.8 days (p <= 0.05). Overall mortality, adjusted for injury severity score (ISS), revised trauma score (RTS), and types of injuries, did not change significantly. CONCLUSION: Patients with penetrating injuries more often received a CT scan on admission after implementation of a CT scanner in the ED. Early CT scanning is useful since it significantly reduces ICU-admissions and decreases H-LOS. It is a cheap and non-invasive diagnostic tool with significant clinical impact, resulting in directed treatment, and improvement of outcomes. PMID- 28868592 TI - Early stage primary cranial vault lymphoma in a 50-year-old man: presenting as only sclerosis and mimicking osteoma. PMID- 28868593 TI - Mutation in the AGK gene in two siblings with unusual Sengers syndrome. AB - Sengers syndrome is a rare autosomal recessive metabolic disorder caused by lack of acylglycerol kinase due to mutations in the AGK gene. It is characterized by congenital cataract, hypertrophic cardiomyopathy, myopathy and lactic acidosis. Two clinical forms have been described: a severe neonatal form, and a more benign form displaying exercise intolerance. We describe two siblings with congenital cataract, cardiomyopathy, hypotonia, intellectual disability and lactic acidosis. Whole exome sequencing revealed a homozygous c.1035dup mutation in the two siblings, supporting a diagnosis of Sengers syndrome. Our patients presented an intermediate form with intellectual deficiency, an unusual feature in Sengers syndrome. This permitted a prenatal diagnosis for a following pregnancy. PMID- 28868594 TI - Chain of events analysis for a scuba diving fatality. AB - INTRODUCTION: A scuba diving fatality usually involves a series of related events culminating in death. Several studies have utilised a chain of events-type analysis (CEA) to isolate and better understand the accident sequence in order to facilitate the creation of relevant countermeasures. The aim of this research was to further develop and better define a process for performing a CEA to reduce potential subjectivity and increase consistency between analysts. METHODOLOGY: To develop more comprehensive and better-defined criteria, existing criteria were modified and a template was created and tested using a CEA. Modifications comprised addition of a category for pre-disposing factors, expansion of criteria for the triggers and disabling agents present during the incident, and more specific inclusion criteria to better encompass a dataset of 56 fatalities. Four investigators (raters) used both the previous criteria and this template, in randomly assigned order, to examine a sample of 13 scuba diver deaths. Individual results were scored against the group consensus for the CEA. Raters' agreement consistency was compared using the Index of Concordance and intra-class correlation coefficients (ICC). RESULTS: The template is presented. The index of concordance between the raters increased from 62% (194/312) using the previous criteria to 82% (257/312) with use of this template indicating a substantially higher inter-rater agreement when allocating criteria. The agreement in scoring with and without template use was also quantified by ICC which were generally graded as low, illustrating a substantial change in consistency of scoring before and after template use. CONCLUSION: The template for a CEA for a scuba diving fatality improves consistency of interpretation between users and may improve comparability of diving fatality reports. PMID- 28868595 TI - Heat deactivation of the stonefish Synanceia horrida venom - implications for first-aid management. AB - OBJECTIVES: To investigate the effects of temperature and hot water immersion time on neutralising venom lethality of the Australian estuarine stonefish (Synanceia horrida). DESIGN: Depths of the spines were measured while venom was extracted from S. horrida individuals. The venom was then exposed to temperatures of 4 degrees C, 37.0 degrees C, 40.1 degrees C, 42.3 degrees C, 45.0 degrees C, 47.7 degrees C, 55.2 degrees C, and 60.0 degrees C for either five or 20 minutes incubation periods. Venom samples were added to cultured human cardiomyocytes and cell viability curves were produced using the ACEA's xCELLigence real-time cell monitoring system. MAIN OUTCOME MEASURES: Determination of venom lethality on cardiomyocytes at a range of temperatures. RESULTS: The average depth of the spine required to go into a victims' flesh before the venom gland compressed and expelled venom was 18 mm. Cardiomyocytes exposed to heat-treated venom for five minutes required higher temperatures to neutralise 99% of the venom, namely 44.6 degrees C in comparison to 42.1 degrees C with an incubation time of 20 minutes. CONCLUSION: This study supports the use of hot water immersion therapy in the treatment of S. horrida stings. It is suggested that due to the depth of the puncture wound longer incubation times should be sought to allow heat to penetrate the deeper portions of the dermis and effectively begin venom deactivation. PMID- 28868596 TI - Decompressing rescue personnel during Australian submarine rescue operations. AB - INTRODUCTION: Personnel rescuing survivors from a pressurized, distressed Royal Australian Navy (RAN) submarine may themselves accumulate a decompression obligation, which may exceed the bottom time limits of the Defense and Civil Institute of Environmental Medicine (DCIEM) Air and In-Water Oxygen Decompression tables (DCIEM Table 1 and 2) presently used by the RAN. This study compared DCIEM Table 2 with alternative decompression tables with longer bottom times: United States Navy XVALSS_DISSUB 7, VVAL-18M and Royal Navy 14 Modified tables. METHODS: Estimated probability of decompression sickness (PDCS), the units pulmonary oxygen toxicity dose (UPTD), the volume of oxygen required and the total decompression time were calculated for hypothetical single and repetitive exposures to 253 kPa air pressure for various bottom times and prescribed decompression schedules. RESULTS: Compared to DCIEM Table 2, XVALSS_DISSUB 7 single and repetitive schedules had lower estimated PDCS, which came at the cost of longer oxygen decompressions. For single exposures, DCIEM schedules had PDCS estimates ranging from 1.8% to 6.4% with 0 to 101 UPTD and XVALSS_DISSUB 7 schedules had PDCS of less than 3.1%, with 36 to 350 UPTD. CONCLUSIONS: The XVALSS_DISSUB 7 table was specifically designed for submarine rescue and, unlike DCIEM Table 2, has schedules for the estimated maximum required bottom times at 253 kPa. Adopting these tables may negate the requirement for saturation decompression of rescue personnel exceeding DCIEM limits. PMID- 28868597 TI - Decompressing recompression chamber attendants during Australian submarine rescue operations. AB - INTRODUCTION: Inside chamber attendants rescuing survivors from a pressurised, distressed submarine may themselves accumulate a decompression obligation which may exceed the limits of Defense and Civil Institute of Environmental Medicine tables presently used by the Royal Australian Navy. This study assessed the probability of decompression sickness (PDCS) for medical attendants supervising survivors undergoing oxygen-accelerated saturation decompression according to the National Oceanic and Atmospheric Administration (NOAA) 17.11 table. METHODS: Estimated probability of decompression sickness (PDCS), the units pulmonary oxygen toxicity dose (UPTD) and the volume of oxygen required were calculated for attendants breathing air during the NOAA table compared with the introduction of various periods of oxygen breathing. RESULTS: The PDCS in medical attendants breathing air whilst supervising survivors receiving NOAA decompression is up to 4.5%. For the longest predicted profile (830 minutes at 253 kPa) oxygen breathing at 30, 60 and 90 minutes at 132 kPa partial pressure of oxygen reduced the air breathing-associated PDCS to less than 3.1 %, 2.1% and 1.4% respectively. CONCLUSIONS: The probability of at least one incident of DCS among attendants, with consequent strain on resources, is high if attendants breathe air throughout their exposure. The introduction of 90 minutes of oxygen breathing greatly reduces the probability of this interruption to rescue operations. PMID- 28868598 TI - Turkish recreational divers: a comparative study of their demographics, diving habits, health and attitudes towards safety. AB - INTRODUCTION: In Turkey, scuba diving has become more popular and accessible in the past decade and there has been a commensurate rise in the number of certified divers. This new generation of recreational divers has not been described in detail previously. The aim of this study was to profile this group, while investigating any gender differences and making comparisons with the global diving community. METHODS: Turkish dive club members and diving forum/blog readers were invited to complete an online questionnaire investigating their demography, medical issues and diving history and habits. RESULTS: The questionnaire was completed by 303 female and 363 male divers. Significant differences were found between the sexes in terms of demographics, diving experience and attitudes toward safety. Previous or ongoing medical conditions were reported by 100 female divers and 141 males. Only 29% of females and 22% of males had been examined by a physician trained to conduct assessments of fitness to dive. Female divers did not report problems while diving during menstruation or while taking oral contraceptives. There was no significant difference in the occurrence of decompression sickness (DCS) and DCS-like symptoms between the sexes. CONCLUSION: This is the largest study to date conducted on recreational divers in Turkey and so carries some value. It profiles their physical and behavioral attributes as well as differences in diving practices between the sexes in Turkey. Our findings should have implications for medical screening and dive training standards. PMID- 28868599 TI - Diving with pre-existing medical conditions. AB - INTRODUCTION: This is the second report based on a survey of Divers Alert Network Asia-Pacific (DAN AP) members who dive with cardiovascular and respiratory conditions and diabetes. It examines the medical management of the divers' conditions, any diving modifications used to mitigate the risk and outcomes. METHODOLOGY: An online cross-sectional survey was sent to 833 divers who had declared a targeted medical condition when applying for DAN AP membership between July 2009 and August 2013. RESULTS: Two-hundred-and-sixty-eight respondents (32%) provided sufficient information on their conditions to be included in the analyses. These included ischaemic heart disease (31), arrhythmias (20), cardiac septal defects (31), other cardiac conditions (10), hypertension (127), diabetes (25), asthma (40) and pneumothorax (5). Forty-nine per cent had sought specialist diving medical advice about their condition and 23% reported modifying their diving practices to mitigate their risk. The cohort had completed 183,069 career dives, 57,822 of these since being diagnosed with their medical condition. There were 27 individuals who reported having decompression illness (25 of whom were subsequently diagnosed with a persistent foramen ovale), and two individuals who experienced an arrhythmia during diving. CONCLUSIONS: Some DAN AP members are diving with medical conditions which could potentially impact the safety of their diving. A minority modified their diving practices to mitigate the risk of their condition and approximately half sought specialist diving medical advice. The incidence of diving-related problems precipitated by known and managed pre existing health conditions seems low but further studies of larger cohorts and incorporating fatality data would be necessary to confirm this. These results are limited by the 32% response rate and potential for bias towards selection of those most careful with their health. PMID- 28868600 TI - A pleural vacuum relief device for pleural drain unit use in the hyperbaric environment. AB - INTRODUCTION: When a standard water-seal pleural drain unit (PDU) is used under hyperbaric conditions there are scenarios where excessive negative intrapleural pressure (IPP) and/or fluid reflux can be induced, risking significant morbidity. We developed and tested a pleural vacuum relief (PVR) device which automatically manages these risks, whilst allowing more rapid hyperbaric pressure change rates. METHODS: The custom-made PVR device consists of a one-way pressure relief valve connected in line with a sterile micro filter selected for its specific flow capacity. The PVR device is designed for connection to the patient side sampling port of a PDU system, allowing inflow of ambient air whenever negative pressure is present, creating a small, controlled air leak which prevents excessive negative pressure. The hyperbaric performance of a Pleur-Evac A-6000 intercostal drain was assessed with and without this added device by measuring simulated IPP with an electronic pressure monitor connected at the patient end of the PDU. IPP readings were taken at 10, 15, 20 and 30 cmH2O of suction (set on the drain unit) at compression rates of 10, 30, 60, 80, 90 and 180 kPa.min-1 to a pressure of 280 kPa. RESULTS: At any compression rate of > 10 kPa.min-1, the negative IPP generated by the Pleur-Evac A-6000 alone was excessive and resulted in back flow through the PDU water seal. By adding the PVR device, the generated negative IPP remains within a clinically acceptable range, allowing compression rates of at least 30 kPa.min-1 with suction settings up to -20 cmH2O during all phases of hyperbaric treatment. CONCLUSIONS: The PDU PVR device we have developed works well, minimising attendant workload and automatically avoiding the excessive negative IPPs that can otherwise occur. This device should only be used with suction. PMID- 28868601 TI - Periorbital emphysema after a wet chamber dive. AB - Although periorbital emphysema (PE) is commonly associated with orbital fractures, it may develop without any fracture or significant trauma in circumstances such as post-surgery, infection, forceful nose blowing, sneezing, and weight lifting. We report on a healthy military diver who developed PE following a wet chamber dive. A diagnosis of PE secondary to sinus barotrauma was reached. He was treated conservatively without medication and his symptoms recovered completely within 10 days. To the best of our knowledge, only five cases of diving-related PE have been reported in the literature. Analysis of these cases and ours revealed that facial trauma, repeated forceful Valsalva manoeuvres and recent upper respiratory tract infection are probable risk factors for diving-related PE. PMID- 28868602 TI - Ruptured tympanic membrane from underwater impact with an Atlantic salmon, Salmo salar. AB - An unusual case of tympanic membrane rupture in a diver due to impact from an Atlantic salmon, Salmo salar is described. The diver was treated conservatively and the injury fully healed by eight weeks after which the diver successfully returned to diving. The author contends that the appearances of such traumatic perforations differ from barotrauma in divers secondary to ear clearing problems on descent. PMID- 28868603 TI - Proliferative retinopathy during hyperbaric oxygen treatment. AB - A 43-year-old male with type 2 diabetes mellitus, treated with insulin for 28 years and with an HbA1c of 7.9% six months prior, suffered from bilateral plantar ulcers refractory to specialised wound care. He underwent a planned 40 sessions of hyperbaric oxygen treatment (HBOT) at 243 kPa for 90 minutes. Consent was given for this report. The patient's ophthalmic history included bilateral proliferative diabetic retinopathy (PDR) identified on routine diabetic eye screening three years previously. This was treated with pan-retinal photocoagulation (PRP). Three months before starting HBOT, he underwent phacoemulsification and intra-ocular lens insertion of his left eye, having had the same procedure done to his right eye a year prior, without complication. He was reviewed again one week prior to his first HBOT and fundoscopy confirmed non proliferative diabetic retinopathy (NPDR) without evidence of PDR. The patient had a routine follow up by the ophthalmologist following his fifth HBOT when fundoscopic examination revealed pre-retinal haemorrhage, a form of PDR, in his left eye. This was treated with PRP at the time. His visual acuity, 6/9 bilaterally, had not changed, nor did he describe any changes in his visual field despite these findings. He was seen three weeks later (following 12 further HBOT) when fundoscopy showed worsening proliferative changes, this time in both eyes. Bevacizumab was injected at the time and fill-in PRP performed the following week. His visual acuity remained unchanged in both eyes. At this point, HBOT was withheld to allow the proliferative phase of the patients' retinopathy to remit. The potentially adverse effects of hyperbaric oxygen to the retinal vasculature of diabetic patients was postulated in 1994 following a similar experience, albeit without a baseline fundoscopic examination. In particular, the concern was of accelerating the proliferative process of retinopathy with subsequent irreversible loss of vision. Thereafter, routine screening and treatment of all diabetic patients for PDR was adopted at our facility. Until now, there have been no further cases of NPDR evolving into PDR at three-month review following HBOT. Indeed, a brief literature search using the terms "retinopathy", "complications", "adverse effects", "vitreous", "hemorrhage", "haemorrhage", "hyperbaric" and "oxygen" has not found any other cases described. In a double blind, randomised trial (meeting abstract only) of 15 diabetic patients with both NPDR and PDR, patients in neither the HBOT (243 kPa for 90 min) nor the control arm had evidence of neovascularisation nor worsening of their proliferative retinopathy at three-month follow up. The significance of PDR following cataract surgery has also been considered. A review article consistently found that NPDR progression occurred in up to a third of such patients. Despite this, there were no cases of NPDR progressing to PDR at 12-month follow up. Whether this patient's sudden progression to PDR was related to HBOT, recent cataract surgery or another unknown factor is unclear. However, the temporal relationship to 17 HBOT is difficult to explain and appears more rapid than available data regarding vascular regrowth in wound healing would suggest. PMID- 28868604 TI - The tick-derived rBmTI-A protease inhibitor attenuates the histological and functional changes induced by cigarette smoke exposure. AB - INTRODUCTION: Smoking is the main risk factor for chronic obstructive pulmonary disease development and cigarette smoke (CS) exposure is considered an important approach to reproduce in rodents this human disease. We have previously shown that in an elastase-induced model of emphysema, the administration of a protease inhibitor (rBmTI-A) prevented and attenuated tissue destruction in mice. Thus, in this study we aimed to verify the effects of rBmTI-A administration on the physiopathological mechanisms of CS-induced emphysema. METHODS: Mice (C57BL/6) were exposed to CS or room air for 12 weeks. In this period, 3 nasal instillations of rBmTI-A inhibitor or its vehicle were performed. After euthanasia, respiratory mechanics were evaluated and lungs removed for analysis of mean linear intercept, volume proportion of collagen and elastic fibers, density of polymorphonuclear cells, macrophages, and density of positive cells for MMP-12, MMP-9, TIMP-1 and gp91phox. RESULTS: The rBmTI-A administration improved tissue elastance, decreased alveolar enlargement and collagen fibers accumulation to control levels and attenuated elastic fibers accumulation in animals exposed to CS. There was an increase of MMP-12, MMP-9 and macrophages in CS groups and the rBmTIA only decreased the number of MMP-12 positive cells. Also, we demonstrated an increase in gp91phox in CS treated group and in TIMP-1 levels in both rBmTI-A treated groups. CONCLUSION: In summary, the rBmTI-A administration attenuated emphysema development by an increase of gp91phox and TIMP-1, accompanied by a decrease in MMP-12 levels. PMID- 28868605 TI - Development of digastric muscles in human foetuses: a review and findings in the flexor digitorum superficialis muscle. AB - The digastricus and omohyoideus muscles are digastric muscles with two muscle bellies. An insertion tendon of the posterior belly becomes an intermediate tendon in digastricus muscles, whereas a single band-like muscle in omohyoideus muscles may later be interrupted by an intermediate tendon, possibly due to muscle cell death caused by mechanical stress. In human foetuses, an intermediate tendon provides the temporal origins of the tensor veli palatini and tensor tympani muscles. Some reptiles, including snakes, carry multiple series of digastric-like axial muscles, in which each intersegmental septum is likely to become an intermediate tendon. These findings indicate that many pathways are involved in the development of digastric muscles. A review of these morphologies suggested that the flexor digi-torum superficialis (FDS) muscle was a digastric muscle, although the intermediate tendon may not be visible in the surface view in adults. The present observations support the hypothesis that the proximal anlage at the elbow develops into a deep muscle slip to a limited finger, while the distal anlage at the wrist develops into the other slips. The findings suggest that, in the FDS muscle, the proximal and distal bellies of the embryonic digastric muscle fuse together to form a laminar structure, in which muscle slips accumulate from the palmar to the deep side of the forearm. (Folia Morphol 2018; 77, 2: 362-370). PMID- 28868606 TI - The influence of post-fixation on visualising vimentin in the retina using immunofluorescence method. AB - BACKGROUND: Post-fixation of sections is especially required for cryostat sections of fresh frozen tissues. Vimentin is an intermediate filament in both fibrillary and non-fibrillary form, expressed in Muller's cells and astrocytes of the retina. Our aim was to determine the best post-fixation method for visualising vimentin in archival mouse eyes. MATERIALS AND METHODS: We used an archival mouse eye, slightly pre-fixed with paraformaldehyde and stored at -80 degrees C for 4 years. We tried three fixatives (pa-raformaldehyde [PFA], alcohol/acetic acid [AAA] and methanol) for post-fixation of eye sections. RESULTS: We showed that post-fixation alters the labelling properties of vimentin expressed in the retina. In the sections with no post-fixation, vimentin positivity was observed in and around the nuclei in non-fibrillary form. In PFA post-fixed sections, the vimentin in the retina was not observed as fibrils. Positivity was observed in the nuclei and in perinuclear regions of the cells. In AAA post-fixed sections, positive labelling was observed around the nuclei as fibrils. In methanol post-fixed sections, labelling was observed around the nuclei as fibrils. CONCLUSIONS: We conclude that post-fixation with AAA is more convenient for immunofluorescent labelling of vimentin in the retina for slightly PFA pre-fixed and long-term stored retina. (Folia Morphol 2018; 77, 2: 246-252). PMID- 28868608 TI - Incidental imaging findings of congenital rib abnormalities - a case series and review of developmental concepts. AB - BACKGROUND: Congenital rib abnormalities are found in approximately 2% of the general population. Usually, they occur in isolation and are rarely symptomatic, but they can also be associated with other malformations. MATERIALS AND METHODS: We reviewed imaging examinations performed over a period of 2 years (2014-2015), enabling us to identify isolated rib abnormalities in 6 adult patients. RESULTS: The case series consisted in 3 cases with bilateral cervical ribs and 1 case each with bifid rib, costal fusion and rib pseudarthrosis. In all patients, the costal anomalies were discovered incidentally. All rib malformations were detected at thoracic radiography, except for the rib pseudarthrosis, which was identified at computed tomography (CT) scan. Differential diagnosis was made between cer-vical ribs and abnormalities of the C7 transverse process and of the first rib, while the other costal malformations were distinguished from tumoural, traumatic or inflammatory lesions of the chest wall, lung and pleura. Considering the existing knowledge on rib development, we suggest a classification of the most common types of rib malformations in three categories: (I) results of homeotic transforma-tion, referring to numerical aberrations; (II) segmentation errors, including costal fusion and bridging; (III) anomalies of resegmentation, resulting in bifid ribs. CONCLUSIONS: It is important that radiologists are familiarised with the imaging features of rib abnormalities, since these anomalies can be misinterpreted as lesions with different implications. We are convinced that the developmental classification proposed in this paper can contribute to a better understanding of this pathology. (Folia Morphol 2018; 77, 2: 386-392). PMID- 28868609 TI - How automated image analysis techniques help scientists in species identification and classification? AB - Identification of taxonomy at a specific level is time consuming and reliant upon expert ecologists. Hence the demand for automated species identification incre ased over the last two decades. Automation of data classification is primarily focussed on images while incorporating and analysing image data has recently become easier due to developments in computational technology. Research ef-forts on identification of species include specimens' image processing, extraction of identical features, followed by classifying them into correct categories. In this paper, we discuss recent automated species identification systems, mainly for categorising and evaluating their methods. We reviewed and compared different methods in step by step scheme of automated identification and classification systems of species images. The selection of methods is influenced by many variables such as level of classification, number of training data and complexity of images. The aim of writing this paper is to provide researchers and scientists an extensive background study on work related to automated species identification, focusing on pattern recognition techniques in building such systems for biodiversity studies. (Folia Morphol 2018; 77, 2: 179-193). PMID- 28868610 TI - Examination of foramen tympanicum: an anatomical study using cone-beam computed tomography. AB - BACKGROUND: The foramen tympanicum (FT) is an osseous dehiscence of the temporal bone and usually closes by the age of 5 years. The foramen is located posteromedial to the temporomandibular joint and anteroinferior of the external auditory canal. The aim of this study is to define the prevalence, location and size of the foramen. MATERIALS AND METHODS: We retrospectively examined 200 cone beam computed tomography (CBCT) images (400 ears). We used a CBCT dental imaging system (GALILEOS, Sirona Dental Systems, Bensheim, Germany) working at 15-30 mA and 98 kV. We noted size and location (unilateral and bilateral) of the present FT. RESULTS: Foramen tympanicum was determined in 11.5% of 200 patients (they had FT at least on one side of the head). This was bilateral in 5 (2.5%) patients. Prevalence of the FT was significintly higher in females (8%) than in males (3.5%). FT was found more frequently on the left side (7.5%) than on the right side (4%). Mean axial diameter was 1.13 mm (range 0.23-4.43 mm), and mean sagittal diameter was 1.44 mm (range 0.22-3.99 mm). CONCLUSIONS: Considering that FT was present in 11.75% of patients, radiologists and clinicians should be aware of the possible presence of this defect. It is known that this developmental dehiscence may cause herniation of temporomandibular joint, formation of salivary otorrhea, and spread of tumour or infection to the infratemporal fossa from external auditory canal. This study showed that CBCT may be preferred for imaging these conditions. (Folia Morphol 2018; 77, 2: 335-339). PMID- 28868611 TI - Simvastatin exerts antiproliferative and differentiating effects on MG63 osteoblast-like cells: Morphological and immunocytochemical study. AB - BACKGROUND AND OBJECTIVE: Current evidence suggests that statins exert an anabolic effect on bone and may therefore impact on osteogenic differentiation and proliferation. These effects can be useful for their use in guided bone regeneration. The objective of this study was to determine the in vitro effects of simvastatin on the differentiation and proliferation of MG63 human osteoblast tumor cells. MATERIAL AND METHODS: MG63 human osteosarcoma cells were cultured in the presence of simvastatin or solvent alone for 72 hours, and their proliferation was assessed by MTT assay. Cells from the culture were prepared for light, transmission and scanning electron microscopy studies. immunocytochemical was used to analyze the differentiation and proliferation markers Musashi-1, Ki 67, CD56 and CD44. RESULTS: Cultured MG63 control cells showed spheroid morphology with numerous secretion vesicles accumulated on the surface, observing no cytoplasmic projections with intercellular connections. However, cells cultured with simvastatin had a polygonal and spindle-shaped morphology, with cytoplasmic projections that interconnected cells. There were numerous microvilli like filamentous projections on the surface with no defined pattern. At 72 hours of culture, CD56, Ki-67 and Musashi-1 expression was significantly reduced (P < .001) in simvastatin-treated cells. CD44 expression was intense in both groups and was not affected by simvastatin treatment. CONCLUSION: MG63 cells cultured with simvastatin for 72 hours undergo morphological and surface changes. Simvastatin treatment exerts antiproliferative and differentiating effects on these cells as well as promoting recovery of cellular homeostasis. PMID- 28868612 TI - The Volume-Outcome Relationship Revisited: Practice Indeed Makes Perfect. AB - OBJECTIVE: To examine the causal effect of a hospital's experience with treating hip fractures (volume) on patient treatment outcomes. DATA SOURCES: We use a full sample of administrative data from German hospitals for 2007. The data provide detailed information on patients and hospitals. We also reference the hospitals' addresses and the zip codes of patients' place of residence. STUDY DESIGN: We apply an instrumental variable approach to address endogeneity concerns due to reverse causality and unobserved patient heterogeneity. As instruments for case volume, we use the number of potential patients and number of other hospitals in the region surrounding each hospital. PRINCIPAL FINDINGS: Our results indicate that after applying an instrumental variables (IV) regression of volume on outcome, volume significantly increases quality. CONCLUSIONS: We provide evidence for the practice-makes-perfect hypothesis by showing that volume is a driving factor for quality. PMID- 28868613 TI - Is Good Enough for Our Peers Good Enough for Policy Makers? PMID- 28868614 TI - Resveratrol in the foodomics era: 1:25,000. AB - Resveratrol is probably the most investigated plant secondary metabolite ever. An epidemiological study known as the French paradox showed a correlation between red wine intake and low mortality due to coronary heart diseases, and the red wine substance resveratrol was claimed to play a key role. Since then, several hundred resveratrol studies have been conducted to demonstrate its antioxidant and other beneficial properties. In the foodomics era, considering a complex foodome including over 25,000 substances that make up the human diet, it appears to be outdated to pursue the hunt for biological activities one function/compound at a time. First, nature is multivariate, and the effect of any one molecule will have to be modulated by its carrying matrix, its bioavailability, and synergies with other molecules. Second, a large number of targeted studies have the tendency to become biased, as they tend to retain only the data that the researchers think are relevant and thus increase the chances of spurious correlations. In this concise review, we retrace the research toward a more inductive, holistic, and multivariate path. PMID- 28868616 TI - Kinematic evaluation of penetration and aspiration in laryngeal elevating and descending periods. AB - OBJECTIVES: It is important to evaluate swallowing movements by dividing them into periods of laryngeal closure and release. The purpose of this study was to evaluate penetration-aspiration (PA) according to human pathophysiology and to identify the factors for predicting PA. STUDY DESIGN: Case-control study. METHODS: Eighty-one patients with complaints of dysphagia caused by various etiologies were enrolled in this study. Videofluoroscopic swallowing studies were conducted, and the spatial and temporal factors were analyzed by computer assisted motion analysis. RESULTS: The initiation of laryngeal vestibule closure in the laryngeal elevating period and its duration in the laryngeal descending period were significant factors for evaluating PA. CONCLUSION: A knowledge of the delay of laryngeal vestibule closure in the laryngeal elevating period and its short duration in the laryngeal descending period could make it easier to evaluate the risk of PA. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:806-811, 2018. PMID- 28868617 TI - Prophylactic immunization with human papillomavirus vaccines induces oral immunity in mice. AB - OBJECTIVE: Although it has been shown that prophylactic vaccination can induce genital immunity, there is inadequate information on human papillomavirus (HPV) vaccine-induced oral immunity, which is of particular interest due to HPV associated oropharyngeal malignancies and recurrent respiratory papillomatosis. Therefore, we assessed the efficacy of various HPV vaccines against oral HPV pseudovirus (PsV) infection in mice. STUDY DESIGN: Preclinical scientific investigation. METHODS: C57BL/6 mice were vaccinated three times at 2-week intervals with either Gardasil (Merck, Kenilworth, NJ) (50 uL intramuscular injection) or a candidate pan-HPV L2 vaccine with alum adjuvant (25 ug subcutaneous injection). Additional mice were immunized with passive transfer of either Gardasil (Merck) human antisera or nonimmunized sera (100 uL intraperitoneal injection). All vaccinated and naive control mice were then challenged with HPV16 E6E7 luciferase PsV in the oral mucosa. Visualization of HPV PsV infection was monitored through in vivo luciferase imaging. RESULTS: Oral luciferase-expressing HPV16 PsV infection was not detected in Gardasil (Merck), L2 vaccine, and Gardasil (Merck) antisera-immunized mice, whereas robust luciferase expression was observed in all control mice. An in vitro neutralization assay from sera of Gardasil-vaccinated (Merck) mice confirmed that vaccine efficacy was due to neutralizing antibodies. CONCLUSION: Oral HPV16 PsV infection in mice was completely prevented with all methods of prophylactic HPV immunization. These findings provide preliminary evidence that human vaccines induce protection against oral HPV infection, which has significant public health implications for HPV-associated oropharyngeal malignancies. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E16-E20, 2018. PMID- 28868618 TI - Reduction of [11 C]CO2 to [11 C]CO using solid supported zinc. AB - A new method for the reduction of no-carrier-added [11 C]carbon dioxide into [11 C]carbon monoxide ([11 C]CO) is described, in which the reductant (zinc) is supported on fused silica particles. Using this setup, which allows for a reduction temperature (485 degrees C) well above the melting point for zinc (420 degrees C), radiochemical yields of up to 96% (decay-corrected) were obtained. A slight decrease in radiochemical yield was observed upon repeated [11 C]CO productions (93 +/- 3%, n = 20). The methodology is convenient and efficient and provides a straightforward path to no-carrier-added production of [11 C]CO. PMID- 28868619 TI - Contact lens technology to 2020 and beyond: a review of recent patent literature. AB - Contact lenses have been a common means of vision correction for more than half a century. Recent developments raise the possibility that the next several years will see the range of applications in which they are used broaden considerably, with an associated expansion in both the number and type of individuals who consider them to be a valuable option. To describe this new landscape, a review of recent patent submissions covering the period 1 January 2014 to 1 February 2017 was undertaken. The results show that in the main, areas where contact lenses will be applied include drug delivery, visual augmentation and biosensing. PMID- 28868620 TI - An oblique bitoric rigid contact lens fitting for the management of lens subluxation in Marfan syndrome. PMID- 28868615 TI - Mechanisms of weight loss and improved metabolism following bariatric surgery. AB - Bariatric surgery is increasingly recognized as one of the most effective interventions to help patients achieve significant and sustained weight loss, as well as improved metabolic and overall health. Unfortunately, the cellular and physiological mechanisms by which bariatric surgery achieves weight loss have not been fully elucidated, yet are critical to understanding the central role of the intestinal tract in whole-body metabolism and to developing novel strategies for the treatment of obesity. In this review, we provide an overview of potential mechanisms contributing to weight loss, including effects on regulation of energy balance and both central and peripheral nervous system regulation of appetite and metabolism. Moreover, we highlight the importance of the gastrointestinal tract, including alterations in bile acid physiology, secretion of intestinally derived hormones, and the microbiome, as a potent mediator of improved metabolism in postbariatric patients. PMID- 28868621 TI - Aerosols: A Sustainable Route to Functional Materials. AB - Sustainability is an increasingly important topic in the design and manufacture of materials, with the need to reduce the environmental impact of producing materials being of paramount significance. A competing interest to this is the ability to produce functional materials in large volumes from a fast, on-line process, which can be integrated easily into existing industrial setups. Herein, we present aerosol-assisted chemical vapour deposition (AACVD) routes to advanced functional materials. We will show that by careful design of precursors and manipulation of deposition conditions, it is possible to achieve high sustainability whilst maintaining fast growth rates and large scale production of thin film functional materials. PMID- 28868622 TI - Proliferation inhibition of cisplatin-resistant ovarian cancer cells using drugs screened by integrating a metabolic model and transcriptomic data. AB - OBJECTIVES: If screening to find effective drugs is possible, the inhibition of proliferation using existing drugs can be a practical strategy to control the drug resistance of cancer. Development of a system-oriented strategy to find effective drugs was the main aim of this research. MATERIALS AND METHODS: An algorithm (transcriptional regulated flux balance analysis [TRFBA]) integrating a generic human metabolic model with transcriptomic data was used to identify genes affecting the growth of drug-resistant cancer cells. Drugs that inhibit activation of the target genes were found and their effect on the proliferation was experimentally evaluated. RESULTS: Experimental assessments demonstrated that TRFBA improves the prediction of cancer cell growth in comparison with previous algorithms. The algorithm was then used to propose the system-oriented strategy to search drugs effective in limiting the growth rate of the cisplatin-resistant A2780 epithelial ovarian cancer cell. Experimental evaluations resulted in the selection of azathioprine, terbinafine, hydralazine and sodium valproate that appropriately inhibit the proliferation of resistant cancer cells while minimally affecting normal cells. Furthermore, experimental data indicate that the selected drugs are synergistic and can be used in combination therapies. CONCLUSIONS: The proposed strategy was successful to identify drugs effective on the viability of resistant cancer cells. This strategy can enhance the potency of treatments for drug-resistant cancer cells and provides the possibility of using existing drugs. PMID- 28868623 TI - Short-term language switching training tunes the neural correlates of cognitive control in bilingual language production. AB - The present study investigated how language switching experience would modulate the neural correlates of cognitive control involved in bilingual language production. A group of unbalanced Chinese-English bilinguals undertook an 8-day cued picture naming training during which they named pictures in either of their languages based on visually presented cues. Participants' brain activation was scanned before and after the training in the same task. Behavioral results revealed a significant training effect such that switch costs were reduced after training. fMRI results showed that after training, activation of brain areas associated with cognitive control including the anterior cingulated cortex and the caudate was reduced. Besides, the activation reduction in the left dorsal anterior cingulated cortex positively correlated with the reduction in switch costs in response time and this training effect could be transferred to untrained stimuli. These findings suggest that neural correlates of cognitive control, especially that of the conflict monitoring process, in bilingual language production could be modulated by short-term language switching training. Hum Brain Mapp 38:5859-5870, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28868624 TI - Employment insecurity and employees' health in Denmark. AB - We use register data for Denmark (IDA) merged with the Danish Work Environment Cohort Survey (1995, 2000, and 2005) to estimate the effect of perceived employment insecurity on perceived health for a sample of Danish employees. We consider two health measures from the SF-36 Health Survey Instrument: a vitality scale for general well-being and a mental health scale. We first analyse a summary measure of employment insecurity. Instrumental variables-fixed effects estimates that use firm workforce changes as a source of exogenous variation show that 1 additional dimension of insecurity causes a shift from the median to the 25th percentile in the mental health scale and to the 30th in that of energy/vitality. It also increases by about 6 percentage points the probability to develop severe mental health problems. Looking at single insecurity dimensions by naive fixed effects, uncertainty associated with the current job is important for mental health. Employability has a sizeable relationship with health and is the only insecurity dimension that matters for the energy and vitality scale. Danish employees who fear involuntary firm internal mobility experience worse mental health. PMID- 28868625 TI - Competency-based assessment in surgeon-performed head and neck ultrasonography: A validity study. AB - OBJECTIVE: Head and neck ultrasonography (HNUS) increasingly is used as a point of-care diagnostic tool by otolaryngologists. However, ultrasonography (US) is a very operator-dependent image modality. Hence, this study aimed to explore the diagnostic accuracy of surgeon-performed HNUS and to establish validity evidence for an objective structured assessment of ultrasound skills (OSAUS) used for competency-based assessment. STUDY DESIGN: A prospective experimental study. METHODS: Six otolaryngologists and 11 US novices were included in a standardized test setup for which they had to perform focused HNUS of eight patients suspected for different head and neck lesions. Their diagnostic accuracy was calculated based on the US reports, and two blinded raters assessed the video-recorded US performance using the OSAUS scale. RESULTS: The otolaryngologists obtained a high diagnostic accuracy on 88% (range 63%-100%) compared to the US novices on 38% (range 0-63%); P < 0.001. The OSAUS score demonstrated good inter-case reliability (0.85) and inter-rater reliability (0.76), and significant discrimination between otolaryngologist and US novices; P < 0.001. A strong correlation between the OSAUS score and the diagnostic accuracy was found (Spearman's rho, 0.85; P < P 0.001), and a pass/fail score was established at 2.8. CONCLUSION: Strong validity evidence supported the use of the OSAUS scale to assess HNUS competence with good reliability, significant discrimination between US competence levels, and a strong correlation of assessment score to diagnostic accuracy. An OSAUS pass/fail score was established and could be used for competence-based assessment in surgeon-performed HNUS. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:1346-1352, 2018. PMID- 28868626 TI - Columnar Lithium Metal Anodes. AB - The rechargeable lithium metal anode is of utmost importance for high-energy density batteries. Regulating the deposition/dissolution characteristics of Li metal is critical in both fundamental researches and practical applications. In contrast to gray Li deposits featured with dendritic and mossy morphologies, columnar and uniform Li is herein plated on lithium-fluoride (LiF)-protected copper (Cu) current collectors. The electrochemical properties strongly depended on the microscale morphologies of deposited Li, which were further embodied as macroscale colors. The as-obtained ultrathin and columnar Li anodes contributed to stable cycling in working batteries with a dendrite-free feature. This work deepens the fundamental understanding of the role of LiF in the nucleation/growth of Li and provides emerging approaches to stabilize rechargeable Li metal anodes. PMID- 28868627 TI - Hydroxyurea prescription, availability and use for children with sickle cell disease in Italy: Results of a National Multicenter survey. AB - BACKGROUND: The number of patients with sickle cell disease (SCD) has increased in Italy in the past decade due to immigration. In spite of the established efficacy of hydroxyurea (HU) in childhood, population-based data regarding its prescription and effectiveness come mainly from studies performed in adults or outside Europe. POPULATION AND METHODS: The Hydroxyurea in SCD: A Large Nation wide Cohort Study from Italy was a retrospective cohort study of adult and pediatric patients with SCD attending 32 centers. Pediatric data are analyzed separately. RESULTS: Out of 504 children followed in 11 centers, 206 (40%) were on HU (194 SS/Sbeta degrees , 12 SC/Sbeta+); 74% came from Sub-Saharian Africa and 18% from Europe. HU therapy indications for SS/Sbeta degrees patients were as follows: 57% painful vaso-occlusive crisis, acute chest syndrome or both, 24% anemia, 8% anemia, and other reasons (the majority had Hb <= 8-8.5 g/dl, revealing scarce acceptance of low Hb values by pediatric hematologist). Mean starting dose was 15.5 mg/kg, and dose at full regimen was 17.1 mg/kg. Mean age at HU therapy was 7.68 years, although it was lower for SS/Sbeta degrees patients. Only 10% started HU before 3 years. In 92%, 500 mg capsule was used; in 6%, the galenic was used; and in 2%, 100 mg tablet was used. Significant reduction of clinical events and inpatients admissions, with improvement in hematological parameters, was observed for SS/Sbeta degrees patients and a trend toward improvement for SC/Sbeta+ patients was also observed. CONCLUSIONS: HU effectiveness is demonstrated in a national cohort of children with SCD living in Italy, even at a lower dose than recommended, revealing good adherence to a treatment program by a socially vulnerable group of patients such as immigrants. PMID- 28868629 TI - AFM Imaging of Hybridization Chain Reaction Mediated Signal Transmission between Two DNA Origami Structures. AB - Signal transfer is central to the controlled exchange of information in biology and advanced technologies. Therefore, the development of reliable, long-range signal transfer systems for artificial nanoscale assemblies is of great scientific interest. We have designed such a system for the signal transfer between two connected DNA nanostructures, using the hybridization chain reaction (HCR). Two sets of metastable DNA hairpins, one of which is immobilized at specific points along tracks on DNA origami structures, are polymerized to form a continuous DNA duplex, which is visible using atomic force microscopy (AFM). Upon addition of a designed initiator, the initiation signal is efficiently transferred more than 200 nm from a specific location on one origami structure to an end point on another origami structure. The system shows no significant loss of signal when crossing from one nanostructure to another and, therefore, has the potential to be applied to larger multi-component DNA assemblies. PMID- 28868628 TI - Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells. AB - Emerging evidence indicates a link between the increased proportion of regulatory T cells (Tregs ) and reduced survival in patients who have been diagnosed with cancer. Cancer stem cells (CSCs) have been indicated to play a vital role in tumour initiation, drug resistance and recurrence. However, the relationship between Tregs and CSCs remains largely unknown. Here, we sorted out ovarian cancer stem-like side population (SP) cells and CD133+ cells to investigate the influence of ovarian CSCs on Tregs . Among the various immune-related molecules that we assessed, C-C motif chemokine ligand 5 (CCL5) was the most elevated in ovarian CSCs relative to that in the non-CSCs. The expression of its receptor, C C motif chemokine receptor 5 (CCR5), was also increased on the surface of Tregs in ovarian cancer patients. This receptor-ligand expression profile indicated that ovarian CSCs recruit Tregs via CCL5-CCR5 interactions. We further assessed the expression of interleukin (IL)-10 in Tregs cultured with different cancer cells. Tregs cultured in conditioned medium (CM) from ovarian CD133+ cells expressed a higher level of IL-10 than Tregs cultured in CM from CD133- cells, indicating that Tregs exert pronounced immune-inhibitory functions in CSC-rich environments. Furthermore, co-culture with ovarian cancer cell lines induced the expression of matrix metalloproteinase-9 (MMP9) in Tregs which, in turn, enhanced the degradation of the extracellular matrix and enabled the invasion of tumour cells, thereby facilitating tumour metastasis. For the first time, to our knowledge, our findings describe the relationship between ovarian CSCs and Tregs , and demonstrated that these two cell populations co-operate to promote tumour immune tolerance and enhance tumour progression. PMID- 28868630 TI - A model-based conditional power assessment for decision making in randomized controlled trial studies. AB - Conditional power based on summary statistic by comparing outcomes (such as the sample mean) directly between 2 groups is a convenient tool for decision making in randomized controlled trial studies. In this paper, we extend the traditional summary statistic-based conditional power with a general model-based assessment strategy, where the test statistic is based on a regression model. Asymptotic relationships between parameter estimates based on the observed interim data and final unobserved data are established, from which we develop an analytic model based conditional power assessment for both Gaussian and non-Gaussian data. The model-based strategy is not only flexible in handling baseline covariates and more powerful in detecting the treatment effects compared with the conventional method but also more robust in controlling the overall type I error under certain missing data mechanisms. The performance of the proposed method is evaluated by extensive simulation studies and illustrated with an application to a clinical study. PMID- 28868631 TI - Finite element analysis of customized implant in mandibular reconstruction after tumor resection with and without using customized surgical osteotomy guide. AB - OBJECTIVES: The aim of this work was to compare different 12 cases (3 patients * 4 cases = 12 cases) with varying gaps between implant and bone by analyzing the effect of these gaps on implant and screws using FEM. METHODS: In each patient's case 1 using CSOG and in case 2, 3, and 4 without using CSOG tumor cutting was done. Hence in each patient zero gaps at case 1 and overcutting at case 2, 3, and 4 have obtained at different locations. RESULTS: FEM results reveal that in each patient's case 4 (maximum gap) was more susceptible to loosening of the screws due to higher strains (37%) and implant failure due to higher stress (28%) concentration under the same loading conditions when compared with case 1 (zero gap). CONCLUSIONS: The study reveals that mandibular reconstruction with implant placement using CSOG can significantly enhance the stability and safety of the implant. PMID- 28868632 TI - Intellectually disabled and addicted: a call for evidence based tailor-made interventions. PMID- 28868633 TI - A 5-year randomized trial on the safety and efficacy of pimecrolimus in atopic dermatitis: a critical appraisal. AB - AIM: The PETITE study (Sigurgeirsson et al.) aimed to compare safety and efficacy of pimecrolimus 1% cream (PIM) and low-to-medium-potency topical corticosteroids (TCS) in children with mild-to-moderate atopic dermatitis (AD). SETTING AND DESIGN: Participants of this 5-year drug-company sponsored multicentre, open label, parallel-group trial were recruited between April 2004 and October 2005. No details are reported regarding the study sites. STUDY EXPOSURE: Infants aged >= 3 to < 12 months with mild-to-moderate AD were randomly assigned in a 1 : 1 ratio to receive either PIM or a low- or medium-potency TCS cream/ointment for 5 years. No information on specific TCS products used was provided. The topical treatment was applied twice daily 'until complete AD clearance or for as long as allowed by the label of the specific TCS', and was reinitiated at the occurrence of first signs and symptoms of AD flares. In the PIM group, exacerbations not controlled by PIM were treated with short-term TCSs. OUTCOMES: Adverse events (AEs) and serious AEs (SAEs) were recorded 'during clinic visits'. In a proportion of the patients, various immunological assessments including antibody titres to common vaccine antigens, immunoglobulin levels, B and T lymphocyte cell counts, and T-cell proliferation tests were performed. The children's growth was assessed by measuring height and weight. AD severity was measured using the Investigator Global Assessment (IGA) score and the percentage of the total body surface area affected. No specific information was provided on the number and scheduling of study visits. Primary outcomes were the incidence of AEs 'of primary clinical interest' and those with a crude incidence of >= 5% in either treatment group. Secondary outcome was 'long-term efficacy' defined as IGA <= 1 at week 3 and year 5. RESULTS: Patients in the PIM group experienced significantly more AEs [bronchitis (P = 0.02), infected eczema (P <= 0.001), impetigo (P = 0.045), nasopharyngitis (P = 0.04)]. No significant differences were seen for the other AEs. The overall incidence of SAEs was slightly higher for PIM (20.5% vs. 17.3%; P = 0.046). The proportion of participants with IGA <= 1 at year 5 was 88.7% for PIM and 92.3% for TCS, a success rate difference of 3.6% (95% confidence interval 0.8-6.4) favouring TCS. CONCLUSIONS: Sigurgeirsson et al. conclude that the long-term management of mild-to-moderate AD in children with both TCS and PIM is safe, and that PIM has similar efficacy to TCS. Further, they conclude that their data support the use of PIM as a first-line treatment of mild-to-moderate AD in children. PMID- 28868634 TI - Effects of video-feedback intervention on harmonious parent-child interaction and sensitive discipline of parents with intellectual disabilities: A randomized controlled trial. AB - BACKGROUND: This study tested whether video-feedback intervention based on attachment and coercion theory increased harmonious parent-child interaction and sensitive discipline of parents with mild intellectual disabilities or borderline intellectual functioning. METHODS: Observer ratings of video-recorded structured interaction tasks at home formed pretest, post-test, and 3-month follow-up outcome data in a randomized controlled trial with 85 families. Repeated measures analyses of variance and covariance were conducted to test for the intervention effect and possible moderation by IQ and adaptive functioning. RESULTS: The intervention effect on harmonious parent-child interaction was conditional on parental social adaptive behaviour at pretest, with lower adaptive functioning associated with stronger intervention benefit at post-test and follow-up compared to care as usual. Intervention effects were not conditional on parental IQ. Intervention effects for sensitive discipline were not found. CONCLUSION: Although the video-feedback intervention did not affect observed parenting for the average parent, it may benefit interaction between children and parents with lower parental adaptive functioning. PMID- 28868635 TI - Usefulness of the lymphocyte positional parameters in the Sysmex XN haematology analyser in lymphoproliferative disorders and mononucleosis syndrome. AB - INTRODUCTION: The lymphocyte positional parameters included in Sysmex XN have been suggested as useful means to differentiate lymphoproliferative disorders (LPD), mononucleosis syndrome (MNS) and other lymphocytoses. METHODS: We evaluated Sysmex XN analysers, which supply 6 lymphocyte positional parameters that can be measured in the WDF scattergram: LY-X, LY-Y, LY-Z, LY-WX, LY-WY and LY-WZ. RESULTS: We collected 301 samples from normal controls, polyclonal lymphocytosis, MNS and LPD. MNS and monoclonal expansion of T granular lymphocyte (T-GL) diagnostic groups accumulated higher numbers of significant differences in the mean values in comparison with the other groups. We propose a new algorithm that can differentiate T-GL cases from other diagnostic groups with an SE of 67.5%, an SP of 98.2%, a PPV of 87.1% and an NPV of 94.3%. Another algorithm showed its efficiency to differentiate MNS cases from other diagnostic groups with an SE of 63.6%, an SP of 97.5%, a PPV of 70.0% and an NPV of 96.7%. In 38.5% of all cases, the analyser did not generate any morphologic flag. Abnormal results in lymphocyte positional parameters were useful to detect 72.5% of these samples. CONCLUSION: The lymphocyte positional parameters provided by Sysmex XN analysers are useful to differentiate expansions of T-GLs from other LPD and to differentiate MNS cases from other diagnostic groups. In addition, these parameters are very useful for detecting changes in the lymphocytes that make it necessary to review blood smears in samples without morphological flagging. PMID- 28868636 TI - Plasma levels of haemostatic factors in patients with pulmonary embolism on admission and seven months later. AB - INTRODUCTION: With the exception of D-dimer, not much is known about the plasma levels of haemostatic factors during acute venous thromboembolism (VTE) compared to their basic levels in a stable phase. The goal of this study was to examine how plasma levels of factor V, VIII, XIIIa, von Willebrand factor antigen (vWF:Ag), fibrinogen, thrombomodulin evolve from the point of diagnosis of acute VTE to the end of standard treatment period. METHODS: Sixty-three consecutive patients (mean 57, range 18-86 years, 33 females) with acute pulmonary embolism (PE) were included. Laboratory samples were collected upon arrival (acute phase) and seven months later (stable phase). Fifteen similar aged individuals served as controls. RESULTS: Plasma levels of factor XIIIa (87.5% vs 117.7%, P < .001) and soluble thrombomodulin (36.6 vs 47.5 ng/L, P < .001) were lower, whereas plasma levels of vWF:Ag (2.66 vs 2.01 IU/mL, P < .001) and fibrinogen (4.3 vs 3.9 g/L, P < .05) were higher on admission compared to the stable phase. In the stable phase, vWF:Ag (2.01 vs 1.43 IU/mL, P < .01) and soluble thrombomodulin (47.5 vs 38.0 ng/mL, P < .05), but not FXIIIa levels, were higher in PE patients compared to healthy controls. CONCLUSION: This study confirms the concept of FXIIIa consumption during acute phase of VTE by showing its intraindividual normalization during the follow-up. vWF:Ag, known to be associated with the risk of VTE, was constantly elevated in the majority of the patients. Soluble thrombomodulin levels were lower in acute phase compared to stable phase, a finding which significance needs to be evaluated in the future. PMID- 28868637 TI - Clinical performance of self-assembling peptide P11 -4 in the treatment of initial proximal carious lesions: A practice-based case series. AB - AIM: The aim of the present study was to investigate the clinical performance of self-assembling peptide P11 -4 on non-cavitated initial proximal carious lesions 12 months after treatment. METHODS: Twenty-six patients, aged between 18 and 65 years, with 35 carious lesions were included in this practice-based, uncontrolled, prospective case series. The opacity and size of the proximal lesions were evaluated visually at baseline and at day 360 using standardized single-tooth or bite-wing and digital-subtraction radiography. Pairwise evaluation of images was carried out in a randomized and blinded manner with respect to the time point. RESULTS: Twelve months after treatment of the proximal carious lesions, the visual evaluation showed a predominant shift toward regression of the initial lesions. Radiographic assessment yielded regression of the caries in 17 of 28 cases; four of 28 were regarded as unchanged, and seven of 28 lesions showed progression of the carious lesion. Combined assessment of clinical radiographs and digital subtraction radiographs confirmed the radiographic assessment, with 20 of 28 lesions showing total or partial regression, four unchanged, and four progressing. CONCLUSION: Radiographic and digital subtraction analyses suggest that initial proximal carious lesions can regress after treatment with P11 -4, but additional factors might influence the overall treatment outcome. PMID- 28868638 TI - A Simple Local Correlation Energy Functional for Spherically Confined Atoms from ab Initio Correlation Energy Density. AB - We propose a simple method of calculating the electron correlation energy density ec (r) and the correlation potential Vc (r) from second-order Moller-Plesset amplitudes and its generalization for the case of a configuration interaction wavefunction, based on Nesbet's theorem. The correlation energy density obtained by this method for free and spherically confined Be and He atoms was employed to fit a local analytical density functional based on Wigner's functional. The functional is capable of producing a strong increase in the correlation energy with decreasing confined radius for the Be atom. PMID- 28868639 TI - Advanced immunocapture of milk-borne Salmonella by microfluidic magnetically stabilized fluidized bed. AB - The success of microfluidic immunocapture based on magnetic beads depends primarily on a sophisticated microscale separation system and on the quality of the magnetic immunosorbent. A microfluidic chip containing a magnetically stabilized fluidized bed (MUMSFB), developed for the capture and on-chip amplification of bacteria, was recently described by Pereiro et al.. The present work shows the thorough development of anti-Salmonella magnetic immunosorbents with the optimal capture efficiency and selectivity. Based on the corresponding ISO standards, these parameters have to be high enough to capture even a few cells of bacteria in a proper aliquot of sample, e.g. milk. The selection of specific anti-Salmonella IgG molecules and the conditions for covalent bonding were the key steps in preparing an immunosorbent of the desired quality. The protocol for immunocapturing was first thoroughly optimized and studied in a batchwise arrangement, and then the carrier was integrated into the MUMSFB chip. The combination of the unique design of the chip (guaranteeing the collision of cells with magnetic beads) with the advanced immunosorbent led to a Salmonella cell capture efficiency of up to 99%. These high values were achieved repeatedly even in samples of milk differing in fat content. The rate of nonspecific capture of Escherichia coli (i.e. the negative control) was only 2%. PMID- 28868640 TI - Finding "hard to find" literature on hard to find groups: A novel technique to search grey literature on refugees and asylum seekers. AB - There is a lack of information on how to execute effective searches of the grey literature on refugee and asylum seeker groups for inclusion in systematic reviews. High-quality government reports and other grey literature relevant to refugees may not always be identified in conventional literature searches. During the process of conducting a recent systematic review, we developed a novel strategy for systematically searching international refugee and asylum seeker related grey literature. The approach targets governmental health departments and statistical agencies, who have considerable access to refugee and asylum seeker populations for research purposes but typically do not publish findings in academic forums. Compared to a conventional grey literature search strategy, our novel technique yielded an eightfold increase in relevant high-quality grey sources that provided valuable content in informing our review. Incorporating a search of the grey literature into systematic reviews of refugee and asylum seeker research is essential to providing a more complete view of the evidence. Our novel strategy offers a practical and feasible method of conducting systematic grey literature searches that may be adaptable to a range of research questions, contexts, and resource constraints. PMID- 28868641 TI - Synthesis and Magnetic Properties of Trioxytriphenylamine Dimers in their Di(radical cationic) States. AB - Three structural isomers of trioxytriphenylamine (TOT) dimers, 4,4''' bis(2,2':6',2":6",6-trioxytriphenylamine) (4), 3,3'''-bis(2,2':6',2":6",6 trioxytriphenylamine) (5), and 3,4'''-bis(2,2':6',2":6",6-trioxytriphenylamine) (6), have been prepared and their electronic and magnetic properties in their di(radical cationic) states have been investigated. These di(radical cationic) species can be handled under ambient conditions because of their high stability under aerated conditions even in solution. The X-ray crystal structure analysis demonstrated that the TOT moieties of all the di(radical cation)s have planar structures similar to that of the parent TOT radical cation 3+ . The UV/Vis spectra of the di(radical cation)s show characteristic absorptions depending on the connecting pattern. Thus, in the long-wavelength region (600-900 nm), 42+ exhibits strong and broad characteristic absorptions, whereas compounds 52+ and 62+ exhibit weak absorptions. Notably, in the 450-600 nm region, 52+ displays very similar absorptions (with twice the intensity) to 3+ , whereas small differences were observed for 62+ . Finally, we investigated in detail the magnetic properties of the corresponding di(radical cation)s by electron spin resonance spectroscopy and magnetic susceptibility measurements, which indicated intramolecular exchange interactions with a singlet ground state and a large singlet-triplet (S-T) gap for 42+ , a singlet ground state and a small S-T gap for 52+ , and a triplet ground state for 62+ . PMID- 28868642 TI - Assessing risk of bias in randomized controlled trials of methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). AB - To test how reliable the tool recommend by Cochrane Collaboration for assessing risk of bias systematic reviews of randomized clinical trials is in the context of methylphenidate for children and adolescents with attention deficit hyperactivity disorder. Confirmatory factor analysis was used to evaluate a unidimensional model for the 7 indicators, applied to 184 Randomized Clinical Trial (RCTs) within a 2015 Cochrane systematic review titled "Methylphenidate for children and adolescents with attention deficit hyperactivity disorder." A unidimensional model resulted in excellent adequacy indices, but only 2 indicators had very high factor loadings and low measurement errors. In terms of content, the 7 indicators showed poor reliability (omega = 0.642); however, the set of indicators was precise in evaluating studies with a high amount of bias risk. The Cochrane model of risk of bias as it is, exhibited good fit indices but the majority of the items were not reliable to adequately capture risk of bias in the context of clinical trials of methylphenidate for ADHD. PMID- 28868643 TI - Comparison of radiography and computed tomography to evaluate fractures of the canine tarsus. AB - Detection and accurate classification of traumatic tarsal fractures are important for identifying cases requiring surgical intervention. The aim of this prospective, experimental, methods comparison study was to directly compare the accuracy, sensitivity, and specificity of tarsal computed tomography (CT), ten view and two-view digital radiographs for detecting traumatic fractures of the canine tarsus. The working hypothesis was that tarsal fractures would be detected with higher accuracy, sensitivity, and specificity using CT imaging compared to radiography, and a ten-view would be superior to a two-view radiographic study. Ten cadaver hind limbs of medium to large dogs received a CT scan and ten-view radiographic study before and after induction of fractures with a hydraulic press. All bones included in the radiographic images were assessed for fractures by two observers and gross dissection was used as the gold standard. The two-view radiographic study (dorsoplantar, lateromedial) was created from the ten-view study and reviewed 2 years later. All limbs sustained fractures, the most common locations were the talus and calcaneus (n = 7). The sensitivity of CT was greater than ten-view radiographic study (77% vs. 57%), while the specificity was similar (97% vs. 98%). The sensitivity and specificity of the ten-view and two-view radiograph studies were similar (57% vs. 55%; both 98%). Computed tomography images were reassessed postdissection to determine if failure to identify fractures resulted from observer error. Overall, CT was better than radiography for detecting fractures of the canine tarsus, however there was little improvement with ten-view compared to two-view radiographic studies. PMID- 28868645 TI - Parallel trade of pharmaceuticals: The Danish market for statins. AB - This paper investigates and quantifies the impact of parallel trade in markets for pharmaceuticals. The paper develops a structural model of demand and supply using data on price, sales, and the characteristics of statins in Denmark and simulates outcomes under a complete ban of parallel imports, keeping other regulatory schemes unchanged. There are two sets of key results. The first set focuses on price effects. On average, prices increase more in markets where the molecule has lost patent protection; wholesale prices for both generic and original products increase after competition from parallel importers is removed, but the final price paid by consumers (after deducting reimbursement) increases more for original products than for generics because most changes in wholesale prices are absorbed by the prevailing reimbursement rules. The second set of results reports the effects on market participants. My model takes into consideration consumers' preferences, allowing them to substitute between products. Prohibiting parallel imports induces consumers to substitute towards original products for which they have stronger preferences. In sum, banning parallel imports leads to (a) an increase in variable profits for original producers and a decrease for generic firms, (b) an increase in governmental health-care expenditures, and (c) a decrease in the welfare of Danish patients and firms. PMID- 28868644 TI - Plant-like bacterial expansins play contrasting roles in two tomato vascular pathogens. AB - Expansin proteins, which loosen plant cell walls, play critical roles in normal plant growth and development. The horizontal acquisition of functional plant-like expansin genes in numerous xylem-colonizing phytopathogenic bacteria suggests that bacterial expansins may also contribute to virulence. To investigate the role of bacterial expansins in plant diseases, we mutated the non-chimeric expansin genes (CmEXLX2 and RsEXLX) of two xylem-inhabiting bacterial pathogens, the Actinobacterium Clavibacter michiganensis ssp. michiganensis (Cmm) and the beta-proteobacterium Ralstonia solanacearum (Rs), respectively. The Cmm DeltaCmEXLX2 mutant caused increased symptom development on tomato, which was characterized by more rapid wilting, greater vascular necrosis and abundant atypical lesions on distant petioles. This increased disease severity correlated with larger in planta populations of the DeltaCmEXLX2 mutant, even though the strains grew as well as the wild-type in vitro. Similarly, when inoculated onto tomato fruit, DeltaCmEXLX2 caused significantly larger lesions with larger necrotic centres. In contrast, the Rs DeltaRsEXLX mutant showed reduced virulence on tomato following root inoculation, but not following direct petiole inoculation, suggesting that the RsEXLX expansin contributes to early virulence at the root infection stage. Consistent with this finding, DeltaRsEXLX attached to tomato seedling roots better than the wild-type Rs, which may prevent mutants from invading the plant's vasculature. These contrasting results demonstrate the diverse roles of non-chimeric bacterial expansins and highlight their importance in plant-bacterial interactions. PMID- 28868646 TI - Long-term pulmonary disease among Swiss childhood cancer survivors. AB - BACKGROUND: Pulmonary diseases are potentially severe late complications of childhood cancer treatment that increase mortality risk among survivors. This nationwide study assesses the prevalence and incidence of pulmonary diseases in long-term childhood cancer survivors (CCS) and their siblings, and quantifies treatment-related risks. METHODS: As part of the Swiss Childhood Cancer Survivor Study, we studied CCS who were diagnosed between 1976 and 2005 and alive at least 5 years after diagnosis. We compared prevalence of self-reported pulmonary diseases (pneumonia, chest wall abnormalities, lung fibrosis, emphysema) between CCS and their siblings, calculated cumulative incidence of pulmonary diseases using the Kaplan-Meier method, and determined risk factors using multivariable logistic regression. RESULTS: CCS reported more pneumonias (10% vs. 7%, P = 0.020) and chest wall abnormalities (2% vs. 0.4%, P = 0.003) than siblings. Treatment with busulfan was associated with prevalence of pneumonia (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.1-14.9), and thoracic surgery was associated with chest wall abnormalities and lung fibrosis (OR 4.1, 95% CI 1.6 10.7 and OR 6.3, 95% CI 1.7-26.6). Cumulative incidence of any pulmonary disease after 35 years of follow-up was 21%. For pneumonia, the highest cumulative incidence was seen in CCS treated with both pulmotoxic chemotherapy and radiotherapy to the thorax (23%). CONCLUSION: This nationwide study in CCS found an increased risk for pulmonary diseases, especially pneumonia, while still young, which indicates that CCS need long-term pulmonary follow-up. PMID- 28868647 TI - Symplastic epididymal leiomyoma with bizarre cytology. PMID- 28868648 TI - Improvement of Electrochemical Water Oxidation by Fine-Tuning the Structure of Tetradentate N4 Ligands of Molecular Copper Catalysts. AB - Two copper complexes, [(L1)Cu(OH2 )](BF4 )2 [1; L1=N,N'-dimethyl-N,N'-bis(pyridin 2-ylmethyl)-1,2-diaminoethane] and [(L2)Cu(OH2 )](BF4 )2 [2, L2=2,7-bis(2 pyridyl)-3,6-diaza-2,6-octadiene], were prepared as molecular water oxidation catalysts. Complex 1 displayed an overpotential (eta) of 1.07 V at 1 mA cm-2 and an observed rate constant (kobs ) of 13.5 s-1 at eta 1.0 V in pH 9.0 phosphate buffer solution, whereas 2 exhibited a significantly smaller eta (0.70 V) to reach 1 mA cm-2 and a higher kobs (50.4 s-1 ) than 1 under identical test conditions. Additionally, 2 displayed better stability than 1 in controlled potential electrolysis experiments with a faradaic efficiency of 94 % for O2 evolution at 1.58 V, when a casing tube was used for the Pt cathode. A possible mechanism for 1- and 2-catalyzed O2 evolution reactions is discussed based on the experimental evidence. These comparative results indicate that fine-tuning the structures of tetradentate N4 ligands can bring about significant change in the performance of copper complexes for electrochemical water oxidation. PMID- 28868650 TI - Joint Meeting of the Federation of European Physiological Societies and the Austrian Physiological Society with Participation of the Czech, French, Italian, Slovak, Slovenian, Swiss and Turkish Physiological Societies, Vienna, Austria, September 13th-15th, 2017. PMID- 28868649 TI - Microscopic findings in EUS-guided fine needle (SharkCore) biopsies with type 1 and type 2 autoimmune pancreatitis. AB - The International Consensus Diagnostic Criteria (ICDC) for the diagnosis of autoimmune pancreatitis (AIP) include the histological criterion that is based on either pancreatic core needle biopsies (CNBs) or surgical specimens. However, CNBs are difficult to obtain by endoscopic ultrasound (EUS). EUS fine-needle aspiration (EUS-FNA) cytology is usually not sufficient for the diagnosis of AIP, but may sometimes contain tissue microfragments. Another approach is EUS-guided histological fine-needle biopsy (EUS-FNB), using needles such as the SharkCore or ProCore needle. Published data regarding EUS-guided SharkCore FNB for the diagnosis of AIP are lacking. We aimed to describe our histological findings in one type 1 and two type 2 AIP patients who underwent EUS SharkCore FNB. The EUS FNBs of two patients fulfilled the histological level 2 ICDC for type 1 AIP or type 2 AIP. The EUS-FNB of one patient fulfilled the histological level 1 ICDC for type 2 AIP. The tissue cylinders and fragments measured 55, 28 and 17 mm in total. At least histological level 2 ICDC were fulfilled in all cases, and our findings regarding the utility of EUS SharkCore FNB for the diagnosis of AIP are therefore promising, but further studies based on larger numbers of patients are warranted. PMID- 28868651 TI - The effects of preterm birth on visual development. AB - Children born very preterm are at a greater risk of abnormal visual and neurological development when compared to children born at full term. Preterm birth is associated with retinopathy of prematurity (a proliferative retinal vascular disease) and can also affect the development of brain structures associated with post-retinal processing of visual information. Visual deficits common in children born preterm, such as reduced visual acuity, strabismus, abnormal stereopsis and refractive error, are likely to be detected through childhood vision screening programs, ophthalmological follow-up or optometric care. However, routine screening may not detect other vision problems, such as reduced visual fields, impaired contrast sensitivity and deficits in cortical visual processing, that may occur in children born preterm. For example, visual functions associated with the dorsal visual processing stream, such as global motion perception and visuomotor integration, may be impaired by preterm birth. These impairments can continue into adolescence and adulthood and may contribute to the difficulties in learning (particularly reading and mathematics), attention, behaviour and cognition that some children born preterm experience. Improvements in understanding the mechanisms by which preterm birth affects vision will inform future screening and interventions for children born preterm. PMID- 28868652 TI - Challenges of treatment of acutely ill patients enrolled in a managed alcohol program. PMID- 28868653 TI - Metabonomic analysis of serum reveals antifatigue effects of Yi Guan Jian on fatigue mice using gas chromatography coupled to mass spectrometry. AB - Yi Guan Jian (YGJ), one of the most commonly used traditional Chinese medicines, has been reported to possess significant antifatigue effects. However, the mechanisms underlying its antifatigue effects remain largely unresolved. In this study, a metabonomics approach, involving gas chromatography coupled to mass spectrometry and a multivariate statistical technique, was developed to estimate the extent to which YGJ alleviated the exhausting swimming-induced fatigue of mice. High-dose treatment with YGJ significantly extended the swimming time of fatigued mice. Significant alterations of metabolites involving amino acids, organic acids and carbohydrates were observed in the serum of fatigued mice, which were reversed by YGJ treatment while biochemical indexes returned to normal. These metabolic changes suggest that the antifatigue effect of YGJ is associated with the impairement of amino acid, organic acids and carbohydrates. It also appears that YGJ can induce significant metabolic alterations independent of the exhausting swimming-induced metabolic changes. The significantly altered metabolites induced by YGJ intervention include l-2-amino-acetoacetate, taurine, fumaric acid, malic acid, oxoadipic acid and l-aspartate, all of which are associated with antifatigue properties. This suggests that YGJ exerts chemopreventive effects via antifatigue mechanisms. PMID- 28868655 TI - Hydrosulfonylation Reaction with Arenesulfonyl Chlorides and Tetrahydrofuran: Conversion of Terminal Alkynes into Cyclopentylmethyl Sulfones. AB - An efficient and simple radical chain reaction to convert terminal alkynes into arenesulfonylmethylcyclopentanes is described. The reaction involves a radical addition-translocation-cyclization process and necessitates solely the use of readily available arenesulfonyl chlorides in tetrahydrofuran. Interestingly, this radical-mediated C-H activation process took place with a high level of retention of configuration when an enantiomerically pure starting material was used. PMID- 28868654 TI - Impact of the OATP1B1 c.521T>C single nucleotide polymorphism on the pharmacokinetics of exemestane in healthy post-menopausal female volunteers. AB - WHAT IS KNOWN AND OBJECTIVE: OATP1B1 mediates the transport of a diverse range of amphiphilic organic compounds that include bile acids, steroid conjugates and hormones. This retrospective pharmacogenetic study was conducted to assess the impact of the OATP1B1 c.521T>C single nucleotide polymorphism (SNP) on the pharmacokinetics of the steroidal aromatase inhibitor drug exemestane in healthy volunteers. METHODS: Exemestane (25 mg) was administered orally to 14 healthy post-menopausal women. All of the 14 subjects were sampled for pharmacokinetic (PK) analyses and retrospectively genotyped for OATP1B1 c.521T>C (rs 4149056). RESULTS AND DISCUSSION: Of the 14 subjects enrolled in the study, five were carriers of the minor C allele (OATP1B1 c.521TC+CC) and the remaining nine were carriers of the OATP1B1 c.521TT genotype. PK was assessed over 8 hours post dosing. Our results showed statistically significant differences (P=.04) in the plasma exemestane AUC0-8 between the OATP1B1 genotype groups. Our data also showed statistically significant differences (P=.04) in the plasma AUC0-8 of 17 hydroexemestane (the major biologically active metabolite) between the OATP1B1 genotype groups. WHAT IS NEW AND CONCLUSION: Our data suggest that the OAPTP1B1 c.521T>C SNP may influence exemestane pharmacokinetics in humans. PMID- 28868657 TI - Three-Dimensional Hierarchical Architectures Derived from Surface-Mounted Metal Organic Framework Membranes for Enhanced Electrocatalysis. AB - Inspired by the rapid development of metal-organic-framework-derived materials in various applications, a facile synthetic strategy was developed for fabrication of 3D hierarchical nanoarchitectures. A surface-mounted metal-organic framework membrane was pyrolyzed at a range of temperatures to produce catalysts with excellent trifunctional electrocatalytic efficiencies for the oxygen reduction, hydrogen evolution, and oxygen evolution reactions. PMID- 28868656 TI - Paradoxical prognostic impact of TERT promoter mutations in gliomas depends on different histological and genetic backgrounds. AB - AIMS: The purpose of this study was to explore the clinical significance of telomerase reverse transcriptase (TERT) promoter mutations in gliomas. METHODS AND RESULTS: We used DNA sequencing data to analyze 887 gliomas for TERT promoter mutations based on histological and genetic backgrounds. TERT promoter mutations were detected in 39.6% of low-grade gliomas, 40.3% of anaplastic gliomas, 44.7% of primary glioblastomas, 29.4% of secondary glioblastomas, and in 29.7% of Proneural, 38.6% of Neural, 41.8% of Classical, and 41.6% of Mesenchymal subtypes. Frequency of C250T mutation in recurrent gliomas was approximately half that in newly diagnosed gliomas. TERT exhibited improved prognosis when co occurred with isocitrate dehydrogenase 1 (IDH1) and 1p19q alteration, but experienced inverse survival in the Mesenchymal subtype or tumor protein p53 (TP53) and epidermal growth factor receptor (EGFR) alteration. Furthermore, the five subtypes were classified based on the prognostic impact of the TERT mutation with different genetic backgrounds of glioma. CONCLUSION: We describe the TERT promoter mutation spectrum according to the histological, genetic, and molecular subtypes of glioma, which may aid in glioma subtype classification and have clinical implications. PMID- 28868658 TI - Bisoprolol-induced thrombocytopenia: A case report. AB - WHAT IS KNOWN AND OBJECTIVE: Thrombocytopenia, not associated with bone marrow primary disease, is a common clinical problem. The possibility of drug-induced thrombocytopenia must be considered, especially in hospitalized patients. Drugs can cause thrombocytopenia by several mechanisms including direct bone marrow or other organ toxicity, and immune reactions. CASE DESCRIPTION: We describe a patient presenting with thrombocytopenia likely related to bisoprolol. WHAT IS NEW AND CONCLUSION: We report a case of bisoprolol-induced thrombocytopenia which resolved with drug discontinuation and steroid therapy. We review the mechanisms involved in drug-induced immune thrombocytopenia. PMID- 28868659 TI - Evaluating the heat-aggression hypothesis: The role of temporal and social factors in predicting baseball related aggression. AB - We examined the role that season progression and social threats play in the heat aggression hypothesis within Major League Baseball put forward by Reifman, Larrick, and Fein (1991). Box score data from 38,870 Major League Baseball games between the years of 2000 and 2015 was used to test the heat-aggression relationship, while accounting for temporal and social factors that may be simultaneously exerting influence on player behavior. Controlling for a number of other variables, we observed that the effect of temperature on aggressive behavior is partially contingent on the point of the season in which the game took place. Aggressive behavior was also more likely to occur when teams played divisional (compared to league and inter-league) rivals, however this relationship was contingent on season progression. We provide potential boundary conditions relating to the heat-aggression relationship, indicating this may not be a ubiquitous phenomenon. PMID- 28868660 TI - In vivo whole-blood T2 versus HbO2 calibration by modulating blood oxygenation level in the femoral vein through intermittent cuff occlusion. AB - PURPOSE: To investigate the feasibility of estimating calibration constants (K and T2o ) in vivo for converting whole-blood T2 to blood hemoglobin oxygen saturation (HbO2 ) according to the Luz-Meiboom model, 1/T2=1/T2o+K(1-HbO2)2, where K and T2o are relaxivity and transverse relaxation time of fully saturated blood, respectively. METHODS: A range of HbO2 values was achieved in the superficial femoral vein with intermittent cuff occlusion in seven healthy adults (four males) to establish a calibration curve between blood T2 and HbO2 at 1.5T. HbO2 was derived via MR susceptometry, a technique previously validated, and the transverse relaxation time was quantified with an optimized T2 -prepared balanced steady-state free precession pulse sequence. To evaluate the accuracy of the in vivo calibration method, T2 and HbO2 were quantified in the superior sagittal sinus in six additional subjects and compared with susceptometry. RESULTS: Two sets of gender-specific calibration constants were derived, one for each gender corresponding to hematocrits of 0.47 +/- 0.02 for males and 0.38 +/- 0.01 for females, yielding K/T2o = 41 Hz/260 ms and 26 Hz/280 ms, respectively. The in vivo calibration returned physiologically plausible superior sagittal sinus SvO2 values (65 +/- 5% HbO2 ), and there was no significant difference between the results from the two methods (average difference -0.3% HbO2 ). CONCLUSION: The results show feasibility of performing in vivo calibration for converting whole blood T2 to HbO2 . The proposed approach bypasses the involved and cumbersome processes associated with in vitro calibration. Magn Reson Med 79:2290-2296, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28868661 TI - Cost-Effectiveness Analysis of Long-Term Intermittent Self-Catheterization with Hydrophilic-Coated and Uncoated Catheters in Patients with Spinal Cord Injury in Japan. AB - OBJECTIVES: To evaluate the cost effectiveness of disposable, hydrophilic-coated catheters in Japan. METHODS: A Markov decision model previously applied in a European study was used to evaluate the cost effectiveness of intermittent self catheterization (ISC) with hydrophilic-coated catheters in Japanese spinal cord injury (SCI) patients suffering from chronic urinary retention from a lifetime perspective. To adjust the model to a Japanese setting, relevant Japanese data regarding the baseline risk of urinary tract infection (UTI), the average age at onset of SCI, costs, and general mortality were extracted from published literature, national statistics, or the opinions of Japanese experts. The direct medical costs, quality-adjusted life years (QALYs) and life years gained (LYG) were calculated from the payers' perspective. An annual discount rate of 2% was applied to both the costs and the effects. RESULTS: The incremental cost of hydrophilic-coated catheters was 1 279 886 yen (US$ 10 578 at an exchange rate of US$ 1 = 121 yen) per SCI patient, but they yielded an additional 0.334 QALYs and 0.781 LYG compared with uncoated catheters. The incremental cost-effectiveness ratio (ICER) of hydrophilic-coated catheters vs. uncoated catheters was 3 826 351 yen/QALY (US$ 31 623/QALY) gained and 1 639 562 yen/LYG (US$ 13 550/LYG). CONCLUSIONS: The ICER of 3.8 million yen (US$ 31 405) falls well within the Japanese societal willingness to pay per QALY gained; therefore, hydrophilic coated catheters can be considered highly cost-effective in Japan compared with uncoated catheters. However, because of the lack of relevant studies, a number of key parameters could not be based on Japanese data, and further research among people with SCI in Japan is recommended. PMID- 28868663 TI - Coping and Help-Seeking Behaviors for Management of Urinary Incontinence. AB - OBJECTIVES: To describe the coping strategies and help-seeking behaviors of women and men with urinary incontinence (UI). METHODS: In cross-sectional study, 156 women and 106 men Turkish with UI were interviewed using a questionnaire covering 29 questions. RESULTS: It was determined that 50.6% of women and 34.0% of men seek help in first for treatment of UI. Forty eight percent of men consulted a physician in the first 6 months after the UI occurred, 44.9% of women consulted a physician 2-5 years later after the UI occurred. Coping behaviors of both groups for management of the UI were as follows: keeping feet warm, performing hot application to perineum, reducing the amount of daily drinking water, using pad, cloth pads, restricting physical activity, refraining from social life and praying etc. CONCLUSIONS: While women mostly do not prefer to seek medical advice for UI, men tend to go to doctors more often than women. Except for treatment seeking behaviors, both men and women are practicing coping methods for the management of UI such as going frequently to the toilet, keeping feet warm, hot application to perineum etc. PMID- 28868664 TI - Profile of consumers and their partners of a perinatal and infant mental health (PIMH) service in Australia. AB - The perinatal period is a time of great vulnerability for many women, in particular those with a range of psychosocial vulnerabilities and mental health risk factors. This paper outlines the psychosocial and mental health profile of consumers and their partners of a perinatal and infant mental health (PIMH) service in Australia. To establish the consumer profile, we analysed client vulnerabilities and demographical information maintained over a 6-year period for 406 consumers. Consumer information, including mental health problems, psychosocial vulnerabilities and demographical information, was entered into a standalone database by the allocated clinicians upon service allocation and throughout treatment. The women accepted by PIMH presented with an average of nine different vulnerabilities. Frequently endorsed risk factors included depression (72.66%), anxiety (71.43%), comorbid depression and anxiety (58.13%), self-harm (past, 7.88%, present, 16.26%), a history of family mental health issues (39.66%), childhood trauma (57.88%), limited support (68.84%), relationship conflict with partners (38.92%) and financial stress (47.29%). The women's partners also presented with a range of vulnerabilities, in particular childhood trauma (34.11%) and mental health issues (30.81%). This study contributes to our understanding of the profile of vulnerable women in the perinatal period, and in particular contributes to the literature by highlighting that in addition to depression, anxiety, self-harm and trauma are also significant in PIMH service delivery. PMID- 28868665 TI - The impact of the non-invasive follicular thyroid neoplasm with papillary-like nuclear feature terminology in the routine diagnosis of thyroid tumours. AB - BACKGROUND: Due to the recent proposal of the non-invasive follicular thyroid neoplasm with papillary-like nuclear feature (NIFTP) category, the authors analyse the state of the art in the challenging diagnosis of follicular thyroid neoplasms in routine practice. METHODS AND RESULTS: A consecutive series of 200 histological diagnoses, with complete cytological correlation, was analysed following the introduction of the NIFTP definition. The study was conducted in a general hospital with a high prevalence of thyroid benign nodules that accounted for approximately 60% of surgically-treated nodules. The significant incidence of the new NIFTP category was 7%. Concurrently, a gradual decrease of the follicular variant of papillary thyroid carcinoma (fvPTC) was observed (3.5%). When evaluating the FNA biopsies within the NIFTP group, despite the systematic evaluation of nuclear crowding, enlargement, irregularities and clearing, the final cytological class was often indeterminate for malignancy (Thy3/III-IV, 71%). At histology, the application of the semiquantitative NIFTP score for the evaluation of the PTC-like nuclear features was able to discriminate benign lesions (score 0/1) from fvPTC (score 2/3). A certain degree of overlapping still persisted between NIFTP and fvPTC (score 2) or between NIFTP and benign lesions (score 1). CONCLUSIONS: In the routine evaluation of FNA biopsies, the presence of subtle and questionable PTC-like nuclear features still remains a controversial aspect of the diagnostic workflow. Given that the NIFTP category was introduced to stratify the low-risk group of thyroid tumours more precisely, pathologists should force themselves to apply the nuclear score rigorously and to classify cases assigned a score of 1 as benign proliferations. PMID- 28868667 TI - Preparation of novel deuterated cyclosporin A standards for quantitative LC-MS analysis. PMID- 28868666 TI - Interactions among symbionts operate across scales to influence parasite epidemics. AB - Parasite epidemics may be influenced by interactions among symbionts, which can depend on past events at multiple spatial scales. Within host individuals, interactions can depend on the sequence in which symbionts infect a host, generating priority effects. Across host individuals, interactions can depend on parasite phenology. To test the roles of parasite interactions and phenology in epidemics, we embedded multiple cohorts of sentinel plants, grown from seeds with and without a vertically transmitted symbiont, into a wild host population, and tracked foliar infections caused by three common fungal parasites. Within hosts, parasite growth was influenced by coinfections, but coinfections were often prevented by priority effects among symbionts. Across hosts, parasite phenology altered host susceptibility to secondary infections, symbiont interactions and ultimately the magnitude of parasite epidemics. Together, these results indicate that parasite phenology can influence parasite epidemics by altering the sequence of infection and interactions among symbionts within host individuals. PMID- 28868668 TI - Green and Chamomile Teas, but not Acarbose, Attenuate Glucose and Fructose Transport via Inhibition of GLUT2 and GLUT5. AB - SCOPE: High glycaemic sugars result in blood-glucose spikes, while large doses of post-prandial fructose inundate the liver, causing an imbalance in energy metabolism, both leading to increased risk of metabolic malfunction and type 2 diabetes. Acarbose, used for diabetes management, reduces post-prandial hyperglycaemia by delaying carbohydrate digestion. METHODS AND RESULTS: Chamomile and green teas both inhibited digestive enzymes (alpha-amylase and maltase) related to intestinal sugar release, as already established for acarbose. However, acarbose had no effect on uptake of sugars using both differentiated human Caco-2 cell monolayers and Xenopus oocytes expressing human glucose transporter-2 (GLUT2) and GLUT5. Both teas effectively inhibited transport of fructose and glucose through GLUT2 inhibition, while chamomile tea also inhibited GLUT5. Long term incubation of Caco-2/TC7 cells with chamomile tea for 16 h or 4 days did not enhance the observed effects, indicating that inhibition is acute. Sucrase activity was directly inhibited by green tea and acarbose, but not chamomile. CONCLUSION: These findings show that chamomile and green teas are potential tools to manage absorption and metabolism of sugars with efficacy against high sugar bolus stress inflicted, for example, by high fructose syrups, where the drug acarbose would be ineffective. PMID- 28868669 TI - Attributes of Bio-Oss(r) and Moa-Bone(r) graft materials in a pilot study using the sheep maxillary sinus model. AB - BACKGROUND AND OBJECTIVE: The aim of this pilot study was to characterize surface morphology and to evaluate resorption and osseous healing of two deproteinated bovine bone graft materials after sinus grafting in a large animal model. MATERIAL AND METHODS: Surfaces of a novel particulate bovine bone graft, Moa Bone(r) were compared with Bio-Oss(r) using scanning electron microscopy. Six sheep then had maxillary sinus grafting bilaterally, covered with BioGide(r) . Grafted maxillae were harvested after 4, 6 and 12 weeks. Healing was described for half of each site using resin-embedded ground sections. For the other half, paraffin-embedded sections were examined using tartrate resistant acid phosphatase staining for osteoclast activity, runt-related transcription factor2 immunohistochemistry for pre-osteoblasts and osteoblasts and proliferating cell nuclear antigen for proliferative cells. RESULTS: Moa-Bone(r) had a smoother, more porous fibrous structure with minimal globular particles compared with Bio Oss(r) . After 4 weeks, woven bone formed on both grafts and the Moa-Bone(r) particles also showed signs of resorption. After 12 weeks, Moa-Bone(r) continued to be resorbed, however Bio-Oss(r) did not; both grafts were surrounded by maturing lamellar bone. Moa-Bone(r) was associated with earlier evidence of runt related transcription factor 2-positive cells. Moa-Bone(r) but not Bio-Oss(r) was associated with strong tartrate resistant acid phosphatase-positive osteoclasts on the graft surface within resorption lacunae at both 4 and 6 weeks post grafting. CONCLUSION: Both materials supported osseous healing and maturation without inflammation. Moa-Bone(r) showed marked osteoclast activity after 4 and 6 weeks and demonstrated positive attributes for grafting, if complete remodeling of the graft within the site is desired. Further optimization of Moa-Bone(r) for maxillofacial applications is warranted. PMID- 28868670 TI - Practising drinking, practising health. PMID- 28868671 TI - The Oxidation of Hydrophobic Aromatic Substrates by Using a Variant of the P450 Monooxygenase CYP101B1. AB - The cytochrome P450 monooxygenase CYP101B1, from a Novosphingobium bacterium is able to bind and oxidise aromatic substrates but at a lower activity and efficiency than norisoprenoids and monoterpenoid esters. Histidine 85 of CYP101B1 aligns with tyrosine 96 of CYP101A1, which, in the latter enzyme forms the only hydrophilic interaction with its substrate, camphor. The histidine residue of CYP101B1 was mutated to phenylalanine with the aim of improving the activity of the enzyme for hydrophobic substrates. The H85F mutant lowered the binding affinity and activity of the enzyme for beta-ionone and altered the oxidation selectivity. This variant also showed enhanced affinity and activity towards alkylbenzenes, styrenes and methylnaphthalenes. For example the rate of product formation for acenaphthene oxidation was improved sixfold to 245 nmol per nmol CYP per min. Certain disubstituted naphthalenes and substrates, such as phenylcyclohexane and biphenyls, were oxidised with lower activity by the H85F variant. Variants at H85 (A and G) designed to introduce additional space into the active site so as to accommodate these larger substrates did not improve the oxidation activity. As the H85F mutant of CYP101B1 improved the oxidation of hydrophobic substrates, this residue is likely to be in the substrate binding pocket or the access channel of the enzyme. The side chain of the histidine might interact with the carbonyl groups of the favoured norisoprenoid substrates of CYP101B1. PMID- 28868672 TI - Comment on 'Small sample GEE estimation of regression parameters for longitudinal data'. AB - In longitudinal studies, the generalized estimating equation (GEE) estimator of the parameters of a marginal model is known to be consistent even if the working intra-subject covariance matrix is incorrectly specified. Recently, a small sample correction for the bias of the GEE estimator has been proposed. We show that this correction formula relies on the correct specification of the working intra-subject covariance matrix. We provide a revised formula that is valid under misspecification and develop the R package 'BCgee' to ease the practical use of the formula. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28868673 TI - Erratum. PMID- 28868674 TI - A new species of Astyanax (Characiformes: Characidae) from Dolina Agua Milagrosa, Rio Paraguai basin, Mato Grosso, Brazil. AB - A new species of Astyanax is described from the upper Rio Paraguai basin, Mato Grosso State, Brazil. The new species can be distinguished from congeners by having the body intensely yellowish in life (v. silvery, reddish or lightly yellow) and by morphometric and meristics traits. Astyanax dolinae n. sp. cannot be assigned to any of the Astyanax species complex currently recognized for the genus. It is only known from the Dolina Agua Milagrosa, a karstic sinkhole lake, entirely fed by groundwater, surrounded by Cerrado, the savannah-like vegetation of central South America. PMID- 28868675 TI - Can We Develop a Permanent Pulsatile Rotary Blood Pump? Yes, We Can. AB - Active U.S. participation in the development of artificial heart technology began in 1966 with the award of six contracts. Since that beginning, and continuing to this day, we have been asking the same question, "Can we develop a system to take the place of a natural heart?" There are four formidable barriers that must be overcome before success can be achieved: technological development (Can the system perform as designed?); economic challenges (Can we finance the development?); regulatory hurdles (Can we get it approved for general use?); and acceptance (Will it be used, and will society accept it for what it is?). After 30 years, all but the last barrier has been overcome. PMID- 28868676 TI - A Ferrofluidic Seal Specially Designed for Rotary Blood Pumps. AB - One of the key technologies required for rotary blood pumps is sealing of the motor shaft. A ferrofluidic seal was developed for an axial flow pump. The seal body was composed of a plastic magnet and two pole pieces. This seal was formed by injecting ferrofluid into the gap between the pole pieces and the motor shaft. To contain the ferrofluid in the seal and to minimize the possibility of ferrofluid making contact with blood, a shield with a small cavity was provided on the pole piece. Sealing pressure of the seal was measured. The sealing pressure was maintained at more than 23.3 kPa (175 mm Hg) for a motor speed up to 11,000 rpm. The specially designed ferrofluidic seal for sealing out liquids is useful for axial flow blood pumps. PMID- 28868677 TI - Biventricular Bypass with Oxygenation for Postcardiotomy Ventricular Failure. AB - Between January 1984 and March 1995, biventricular bypass (BVB) with oxygenation was used in 17 patients for postcardiotomy ventricular failure at the Heart Institute of Japan, Tokyo Women's Medical College. Of the 17 patients, 12 (70.6%) were weaned from the circulatory support, and 8 (47.1%) were discharged from the hospital. The time interval from the end of cardiopulmonary bypass to the start of BVB was significantly shorter in weaned patients than in unweaned patients. The duration on support also has been shortened significantly in the last 6 years, compared with the earlier 6 years. Causes of death were severe heart failure or ventricular arrhythmia in 6 patients and multiple organ failure in 3 patients. These results suggest that early application and timely weaning from biventricular bypass with oxygenation might be the effective circulatory support of choice for treatment of postcardiotomy ventricular failure. PMID- 28868678 TI - Hemodynamic System Analysis of Intraarterial Microaxial Pumps In Vitro and In Vivo. AB - Because of the lack of a sophisticated pump management system, the performance of the Hemopump in patients cannot be assessed successfully. To clarify the interrelationship between an intravascular nonpulsatile pump and a pulsating ventricle, an in vitro study was set up under controlled conditions. Before these in vitro experiments, a series of in vivo experiments were performed in sheep using Hp31 cannulae. As anticipated, the resulting pulsatile pump flow was a function of the momentary pressure difference across the pump. This varying pump flow showed a significant flow loop hysteresis, indicating that the pressure difference across the pump is not the only parameter governing momentary pump flow of a rotary pump operating at constant speed in a pulsatile environment. Furthermore, flow in the Hp31 was significantly influenced by the inflow situation, blood supply, size of the ventricular cavity, and shape and position of the inflow cannula within the ventricle. Pulsatile flow conditions with good as well as impaired inflow into the pump were accordingly simulated in vitro to verify the in vivo measurements, to characterize the various inflow conditions, and to discuss methods of improved pump management. As a result of the in vivo and in vitro experiments, one can rely on the measurement of nonpulsatile in vitro flow and pressure differences across the pump to characterize the momentary pump flow for good inflow conditions into the pump. For these situations, the flow hysteresis produced, caused by fluid inertia within the pump and cannula, can be neglected. In contrast, for an impaired inflow situation, the calculated pump flow based on pressure difference measurements can be misleading. Consequently, an improved pump management system is required to adjust the pump speed, the pump performance, to any kind of impaired inflow. PMID- 28868679 TI - Transcutaneous Energy Transfer with Voltage Regulation for Rotary Blood Pumps. AB - Rotary blood pumps often require a constant operating voltage. To meet this requirement and to eliminate the need for percutaneous leads, a voltage-regulated transcutaneous energy transfer (TET) system has been developed. Voltage regulation is achieved by using a transcutaneous infrared feedback control loop operating on a 890 nanometer (nm) wavelength. In vitro testing of the system developed has shown that output voltage can be maintained to within 0.2 V of nominal (14.5 V) for delivered powers up to 50 watts (W) and coil separations of between 3 and 10 mm. Power transfer efficiencies were determined to be from 68% to 72% over the tested range of coil separations and output currents from 1.5 to 3.6 amperes (A). This system has demonstrated acceptable performance in regulating output voltage while transferring power inductively without using percutaneous connections. By integrating this type of TET system with an implanted rotary blood pump, the quality of life for the device recipient could be improved. PMID- 28868680 TI - Numerical Simulation of Nonpulsatile Left Ventricular Bypass. AB - A computer simulation was carried out to investigate the influence of nonpulsatile left ventricular assistance on hemodynamics. A simulation circuit was constructed to represent the circulatory system. A source of current was added to denote the nonpulsatile blood pump. The left and right ventricles were replaced by variable compliances. Left heart failure was simulated by decreasing the amount of compliance change of the left ventricle. We introduced a pulsatility indicator (PI) to clarify the pulsatility characteristics in the hemodynamics; this PI was defined as the ratio of the pulse pressure (PP) to the mean aortic pressure (AoP). When nonpulsatile bypass flow increased, the mean AoP, tension time index (TTI), and diastolic pressure time index (DPTI) increased, and cardiac output, PP, and PI decreased. When assisted flow increased with the constant total flow rate, the mean AoP and DPTI changed little; the PP, TTI, and PI decreased, and the endocardial viability rate increased. The PI would be helpful in evaluating the effect of pulsatility. PMID- 28868682 TI - Role of the BioMedicus Pump and Distal Aortic Perfusion in Thoracoabdominal Aortic Aneurysm Repair. AB - We reviewed the role of the BioMedicus pump in the reduction of neurologic complications following the repair of Type 1 and Type 2 thoracoabdominal aortic aneurysms. Since 1991, we have used several different methods for the repair of thoracoabdominal aortic aneurysms including simple cross-clamping, selective use of the BioMedicus pump, cardiopulmonary bypass with or without profound hypothermia, and most recently, distal aortic perfusion using the BioMedicus pump combined with cerebral spinal fluid drainage. This latter method has been the most promising in rectifying the side effects of aortic clamping and in providing the time necessary for thorough thoracoabdominal aortic aneurysm repair. On our service, the ongoing study of the BioMedicus pump and distal aortic perfusion in conjunction with cerebral spinal fluid drainage has shown that these adjuncts can extend the tolerance of the spinal cord to ischemia and lower the overall rate of neurologic complications for Type 1 and Type 2 thoracoabdominal aortic aneurysm repairs to a rate of 5% (early results) and 3% (late results). We highly recommend distal aortic perfusion using the BioMedicus pump combined with cerebral spinal fluid drainage for thoracoabdominal aortic aneurysm repair. PMID- 28868681 TI - Extracorporeal Membrane Oxygenation as a Bridge to Cardiac Transplantation in Children. AB - The feasibility and efficacy of extracorporeal membrane oxygenation (ECMO) as a bridge to cardiac transplantation was examined in 6 pediatric patients who suffered irreversible myocardial failure after undergoing surgery for congenital heart defects. The mean time of ECMO support was 260.5 h, range, 101-402 h. Three patients underwent transplantation, 2 of whom are long-term survivors. Progressive hypotension as a result of capillary leak syndrome precluded further ECMO support in the other 3 patients. Overall, 2 of the 6 patients survived. Major complications were encountered in 4 patients including bleeding in 2, a seizure in 1, and renal failure in 3, 2 of whom recovered renal function after transplantation. Infection did not occur in any of the 6 patients. Exchanging ECMO components was performed with no difficulties; these exchanges included a centrifugal pump once for 2 patients and a membrane oxygenator once for 3 patients. Our results indicate that ECMO can safely keep critically ill pediatric transplant candidates alive for more than 1 week with a low incidence of multiple organ failure. PMID- 28868683 TI - Clinical Application of a Newly Developed Autoflow Control System for the Terumo Centrifugal Pump: From External Control to Built-in Direct Control. AB - We have developed an autoflow control system for the Terumo Capiox centrifugal pump, the SP-101. First, we made an external control system regulated by a personal computer through a serial communications line. Although an in vivo experiment using a goat showed excellent performance in regulating the flow, a communication error that caused an abrupt and instantaneous flow fluctuation was noted occasionally. Therefore, we incorporated a check-sum function to solve this problem. After this improvement, 5 patients safely underwent cardiopulmonary bypass using a pump having this autoflow control. As the next step for more practical usage, we developed a built-in autoflow control system in which the control device is entirely incorporated into the console without a communications line. This system demonstrated better response and reliability than the external control system and was applied successfully in 3 patients. In conclusion, this autoflow mode will expand the usage of centrifugal pumps through improved handling. PMID- 28868685 TI - A Magnetically Suspended and Hydrostatically Stabilized Centrifugal Blood Pump. AB - A magnetically suspended centrifugal blood pump intended for application as a long-term implantable ventricular assist device has been built and tested. The rotor is freely suspended in the blood by magnetic and hydrostatic restoring forces. This design obviates the need for bearings and shaft seals, and eliminates the problems of reliability and thrombogenicity associated with them. The positional stability and hydrodynamic performance of the pump has been characterized in vitro at flows of up to 10 L/min at physiologic pressures. Radial position control is realized by an analog electronic feedback control system. The pressure distribution in the fluid surrounding the rotor provides dynamic control in the axial direction with no active feedback. Rotor excursion is less than 50 microns (MU) when the housing receives an impulse peaking at an acceleration of 40 g or upon sudden blockage of the flow. In vitro blood measurements indicate an acceptable level of hemolysis compared with that of a standard centrifugal pump. PMID- 28868687 TI - The Cleveland Clinic Rotodynamic Pump Program. AB - The Cleveland Clinic Foundation has developed a unique rotodynamic blood pump for future use as a permanent implant. This pump is small (2.5 +/- 2.5 inches) and requires an electric input power of 7 watts to produce 5 L/min of blood flow against 100 mm Hg at 3,000 rpm. Initial in vivo testing has confirmed in vitro function and shown low hemolysis. Endurance bench testing has exceeded 12 months of continuous function. This pump is the basis of an innovative ventricular assist system in which power is supplied by a tranocutaneous electrical transmission system, and pacer technology is used for both control logic and telemetry functions. The resulting system will be completed and tested under an NHLBI contract during the next 5 years. PMID- 28868686 TI - Controller for an Axial Flow Blood Pump. AB - A rotary blood pump inherently provides only one noninvasive "observable'" parameter (motor current) and allows for only one "controllable" parameter (pump speed). To maintain the systemic circulation properly, the pump speed must be controlled to sustain appropriate outlet Hows and perfusion pressure while preventing pulmonary damage caused by extremes in preload. Steady-state data were collected at repeated intervals during chronic trials of the Nimbus AxiPump (Nimbus, Inc., Rancho Cordova, California, U.S.A.) in sheep (n = 7) and calves (n = 12). For each data set, the pump speed was increased at increments of 500 rpm until left ventricular and left atrial emptying was observed by left atrial pressure diminishing to zero. The effect of decreasing preload was evaluated perioperatively by inferior vena cava occlusion at a constant pump speed. Fourier analysis established a relationship between changes in the pump preload and the power spectra of the pump current waveform. Based on these results, a control method was devised to avoid ventricular collapse and maintain the preload within a physiologic range. The objective of this controller is the minimization of the second and third harmonic of the periodic current waveform. This method is intended to provide a noninvasive regulation of the pump by eliminating the need for extraneous transducers. PMID- 28868688 TI - ISRP Presidential Address: Is It Really Possible To Support or Replace a Human Heart with a Mechanical Pump-a Human Heart-with all its Historical, Philosophical, and Emotional Importance? PMID- 28868689 TI - Development of a Pivot Bearing Supported Sealless Centrifugal Pump for Ventricular Assist. AB - Since 1991, in our laboratory, a pivot bearing-supported, sealless, centrifugal pump has been developed as an implantable ventricular assist device (VAD). For this application, the configuration of the total pump system should be relatively small. The C1E3 pump developed for this purpose was anatomically compatible with the small-sized patient population. To evaluate an-tithrombogenicity, ex vivo 2 week screening studies were conducted instead of studies involving an intracorpore-ally implanted VADs using calves. Five paracorporeal LVAD studies were performed using calves for longer than 2 weeks. The activated clotting time (ACT) was maintained at approximately 250 s using heparin. All of the devices demonstrated trouble-free performances over 2 weeks. Among these 5 studies, 3 implantations were subjected to 1-month system validation studies. There were no device-induced thrombus formations inside the pump housing, and plasma-free hemoglobin levels in calves were within the normal range throughout the experiment (35, 34, and 31 days). There were no incidents of system malfunction. Subsequently, the mass production model was fabricated and yielded a normalized index of hemolysis of 0.0014, which was comparable to that of clinically available pumps. The wear life of the impeller bearings was estimated at longer than 8 years. In the next series of in vivo studies, an implantable model of the C1E3 pump will be fabricated for longer term implantation. The pump-actuator will be implanted inside the body; thus the design calls for substituting plastic for metallic parts. PMID- 28868690 TI - Can We Develop a Nonpulsatile Permanent Rotary Blood Pump? Yes, We Can. AB - For many years, it was thought that nonpulsatile perfusion produced physiological and circulatory abnormalities. Since 1977, Yukihiko Nose and his colleagues have challenged this misconception. Toward that end, they did show that if a 20% higher blood flow uses more than that required for a pulsatile blood pump, then there would be no circulatory or physiological abnormalities. These experimental findings confirm that there is no difference in clinical outcome using either a pulsatile or nonpulsatile blood pump. Furthermore, the nonpulsatile rotary blood pump demonstrates efficient and reliable performance in various clinical situations. The nonpulsatile blood pump is a simple and reliable design that is manufactured easily and that has several desirable features. There is no need to incorporate heart valves, which are the most thrombogenic and blood trauma inducing component. A continuous flow pump does not require a large orifice inflow conduit and proves to be easier to implant in patients with minimal damage to the myocardium. There is no need to incorporate a compliance volume-shifting device, which is essential for a pulsatile blood pump. The nonpulsatile device is a continuous blood pumping system; therefore, the control system is simpler and more reliable than that of a pulsatile pump. Because of the rotary blood pump's structure, only one moving part is necessary for the blood-pumping motion. By using durable components for this moving part, a durable system becomes possible. Because the electrical motor operates continuously, the on-and-off motion required for a pulsatile pump is not necessary; therefore, it is a more efficient and durable system. Thus, this group is working on the development of a nonpulsatile blood pump as a permanently implantable assist device. To achieve this goal, it is necessary to incorporate seven features into the system: small size, atraumatic features, antithrombogenic features, antiinfection features, a simple and durable design, and low energy requirement with easy controllability. PMID- 28868691 TI - A Teaspoon Pump for Pumping Blood with High Hydraulic Efficiency and Low Hemolysis Potential. AB - Virtually all blood pumps contain some kind of rubbing, sliding, closely moving machinery surfaces that are exposed to the blood being pumped. These valves, internal bearings, magnetic bearing position sensors, and shaft seals cause most of the problems with blood pumps. The original teaspoon pump design prevented the rubbing, sliding machinery surfaces from contacting the blood. However, the hydraulic efficiency was low because the blood was able to "slip around" the rotating impeller so that the blood itself never rotated fast enough to develop adequate pressure. An improved teaspoon blood pump has been designed and tested and has shown acceptable hydraulic performance and low hemolysis potential. The new pump uses a nonrotating "swinging" hose as the pump impeller. The fluid enters the pump through the center of the swinging hose; therefore, there can be no fluid slip between the revolving blood and the revolving impeller. The new pump uses an impeller that is comparable to a flexible garden hose. If the free end of the hose were swung around in a circle like half of a jump rope, the fluid inside the hose would rotate and develop pressure even though the hose impeller itself did not "rotate"; therefore, no rotating shaft seal or internal bearings are required. PMID- 28868692 TI - Tandem Operation of a Turbo Blood Pump (BP-80-Type Centrifugal Pump) to Reduce Hemolysis. AB - When operating turbo blood pumps in tandem, the strength of shear stress is reduced, but the exposure duration of the stress is increased. The purpose of this experiment was to compare the degree of contribution of these two factors on hemolysis as well as to evaluate the effectiveness of the tandem operation of turbo blood pumps. Tandem operation of two Bio-pumps (BP-80; Medtronics Bio medicus, Inc., Eden Prairie, Minnesota, U.S.A.) were compared with single operation of a BP-80 in in vitro hemolysis tests in three different driving conditions, that is, pumping heads of 200, 350, and 500 mm Hg under a pump flow rate of 5 L/min. The Allen's hemolytic indexes of the tandem operation at pumping heads of 200, 350, and 500 mm Hg were 0.014, 0.020, and 0.080 mg/dl, respectively. The hemolytic indexes of the single operation at pumping heads of 200, 350, and 500 mm Hg were 0.014, 0.056, and 0.12 mg/dl, respectively. These results indicate that tandem operation is a useful method of reducing hemolysis with the BP-80 under high pumping heads and that the effect on hemolysis of exposure to higher shear stresses may be more serious than that of longer durations of exposure to shear stress in turbo blood pumps. PMID- 28868693 TI - Findlay Implantable Two-Stage Centrifugal Pump. AB - The Findlay centrifugal pump is unique in its two-stage pumping mechanisms and in its complementary interrelationship of the stages to each other and to the exit system, and it forms an extremely efficient unit. The first stage is a lift force pump as an inlet. The second and major stage is a shear force pump. Twenty-six prototypes, many multiply modified, have been hand fabricated, and most have had classic pump function analyses. Six pumps have demonstrated minimal hemolysis (3.5-5 h). At modest rotation speeds, it pumps water up to 10 L/min. Forty-four acute studies in normal dogs have been performed with the Findlay pump in a ventricular assist system. Blood flows through the pump ranged from 1.2 to 4.5 L/min. The conclusion is that the Findlay pump has the ability to operate with low blood damage, performs at acceptable rotational speed with reasonable hydraulic and mechanical efficiency, and is small and implantable. PMID- 28868694 TI - Development of a Centrifugal Pump with Improved Antithrombogenicity and Hemolytic Property for Chronic Circulatory Support. AB - A centrifugal pump with a unique structure has been developed for chronic support. The pump is driven by a magnetic coupling and has no rotating shaft, no seal around the rotating part, and a balancing hole at the center of the impeller and the thrust bearing. The pump was improved in stepwise fashion to realize good antithrombogenicity and low hemolysis. The first pump, the National Cardiovascular Center (NCVC)-O, had an impeller with 4 rectangular and curved vanes; 6 triangularly shaped curved vanes were employed in the second model, the NCVC-1, to reduce trauma to the blood. In the third design, the NCVC-2, the central hole was enlarged, and the thrust bearing shoulder was rounded so that blood washing was enhanced around the impeller; stream lines also were smoothed for improved antithrombogenicity. The hemolytic property of the device was evaluated in vitro with heparinized fresh goat blood; hemolysis indexes of the NCVC-0, -1, and -2 were 0.05, 0.01, and 0.006 g per 100 L, respectively. Antithrombogenicity of the pumps was examined in animal experiments as a left heart bypass device in goats weighing 52-75 kg. Six NCVC-0 pumps were driven for 14 to 33 (22.0 +/- 7.6) days in goats receiving the antiplatelet drug cilostazol orally. Four NCVC-I pumps ran for 1 to 80 (28.5 +/- 30.6) days with the same drug regimen in 2 cases and with no anticoagulation therapy in 2 cases. After 3 preliminary 1-week tests of NCVC-2 pumps in animals, the pump was installed in 3 goats; 2 pumps were still running on the 182nd and 58th pumping day. Intracorporeal implantation also was attempted successfully. The results indicate that this pump has promising features for chronic support although longer term and additional evaluations are necessary. PMID- 28868695 TI - Application of Computational Fluid Dynamics Techniques to Blood Pumps. AB - Present-day computational fluid dynamics (CFD) techniques can be used to analyze the behavior of fluid flow in a variety of pumps. CFD can be a powerful tool during the design stage for rapid virtual prototyping of different designs, analyzing performance parameters, and making design improvements. Computational flow solutions provide information such as the location and size of stagnation zones and the local shear rate. These parameters can be correlated to the extent of hemolysis and thrombus formation and are critical to the success of a blood pump. CFD-ACE, an advanced commercial CFD code developed by CFD Research Corporation, has been applied to fluid flows in rotary machines, such as axial flow pumps and inducers. Preprocessing and postprocessing tools for efficient grid generation and advanced graphical flow visualization are integrated seamlessly with CFD-ACE. The code has structured multiblock grid capability, non Newtonian fluid treatment, a variety of turbulence models, and an Eulerian Lagrangian particle tracking model. CFD-ACE has been used successfully to study the flow characteristics in an axial flow blood pump. An unstructured flow solver that greatly automates the process of grid generation and speeds up the flow simulation is under development. PMID- 28868696 TI - Greetings from the Honorary President of the International Society of Rotary Blood Pumps. PMID- 28868697 TI - A New Supportive Method for Aortic Aneurysm Surgery: Centrifugal Left Heart Bypass Combined with an Oxygenator and a Heat Exchanger. AB - A new supportive method of centrifugal left heart bypass with oxygenation was performed in 25 patients and compared with standard left heart bypass in 45 patients. Femoro-femoral bypass was selected in another 6 patients because of the presence of a left atrial adhesion. Intraoperative complications related to standard left heart bypass, hypoxia, hypothermia, and ventricular fibrillation, were eliminated by using this method. This supportive method maintained good hemodynamics and improved the surgical result of extended thoracoabdominal aortic replacement. Hospital deaths decreased from 6.7% to 3.2%. PMID- 28868699 TI - Clinical Experience of Percutaneous Cardiopulmonary Support. AB - Recently, percutaneous cardiopulmonary support (PCPS) combined with femoro femoral bypass without reservoir has become valued because of its quick and easy application. We developed a fully preconnected compact integrated cardiopulmonary bypass (CPB) unit (priming volume of 250 ml) with a blind pore membrane oxygenator (Kuraray Menox) for PCPS. From 1990 to 1995, PCPS was performed in 49 patients of whom 26 were weaned from support. In most cases, we applied this CICU in patients with no active bleeding (22 patients); in patients with active bleeding (n = 13), we used Medtron-ic's heparin-bonded close chest support pack (CCSP). Of these, PCPS was performed uneventfully for 2 h (median) in 8 elective cases; all of these patients were weaned or were switched to a left ventricular assist system (LVAS). In 8 urgent cases, such as those with low cardiac output syndrome, PCPS was performed for 4 days (median), 1 was weaned, and 2 CICU were cases switched to other procedures. In 32 cases of shock, 5 CICU patients were weaned, and 3 of them survived. Eight patients including 5 CICU patients and 1 CCSP patient were switched to operation or LVAS, and 2 CICU patients remain alive. From these data, PCPS has been shown to support the patient's circulation in the acute phase and earn time to switch to operation or LVAS; the quick and easy set-up of the CICU can improve the clinical results. The use of the Medtronic device broadened the indication for PCPS. The CCSP enlarged the indication of PCPS but could not improve the results. To improve the results, a heparin-bonded surface is desired. PMID- 28868698 TI - Clinical Experience with the Nikkiso Centrifugal Pump. AB - The Nikkiso HPM-15 is a minimally sized centrifugal pump. Preliminary results regarding clinical use of this pump for cardiopulmonary bypass (CPB) procedures have been reported previously. Recently, we have managed some additional cases using a newly developed controller. This article reports our clinical experiences with the use of this pump. We have managed 23 cases with a Nikkiso centrifugal pump. Twenty-two patients underwent CPB and 1 patient with fulminant viral myocarditis underwent percutaneous cardiopulmonary support (PCPS). With this pump, the circuit was extremely easy to prepare and deaeration was achieved readily. Hemodynamics during CPB and PCPS were stable in all cases. The increase in serum-free hemoglobin levels during CPB with this pump was as low as that seen in preliminary tests. A decrease in the platelet count was observed after the initiation of CPB with this pump; however, platelet counts returned to preoperative values 7 days after surgery. Moreover, urine output during CPB with this pump was as high as that seen in preliminary tests. No abnormalities in renal or liver function occurred during CPB. It appears that this new centrifugal pump is safe and easy to operate, and we conclude that it is useful for CPB and PCPS. PMID- 28868700 TI - Clinical Use of Centrifugal Pumps and the Roller Pump in Open Heart Surgery: A Comparative Evaluation. AB - Centrifugal pumps have been used widely as the main pump in open heart surgery to reduce damage to blood elements and to reduce the activation of the coagulation system. The purpose of this study was the evaluation and comparison of the effects of two types of centrifugal pumps and of one type of roller pump on blood elements, the coagulation system, complements, and immunoglobulins. Two types of centrifugal pumps (Lifestream; St. Jude Medical, Chelmsford, Massachusetts; and BP-80; Medtronic, BioMedicus, Inc., Eden Prairie, Minnesota, U.S.A.) and one roller pump (Mera Co.) were used separately as the main pump for cardio-pulmonary bypass (CPB) in 29 patients. Platelet counts, lactate dehydrogenase, antithrombin III, thrombin-antithrombin complex (TAT), complements (C3, C4, and CH50) and immunoglobulins G, A, and M values were measured before and after CPB and compared. Values, except those for TAT, showed no significant difference among the three groups. The TAT values increased less in each of the centrifugal pump groups than in the roller pump group. This finding suggests that thrombin synthesis might be suppressed by the use of a centrifugal pump. PMID- 28868701 TI - A Calf Model for Left Ventricular Centrifugal Mechanical Assist. AB - The increased use of centrifugal mechanical assist (CMA) for treatment of refractory postcardiotomy cardiogenic shock highlights the need for experimental testing to improve clinical results. This report describes the preoperative conditioning, anesthetic and surgical technique, and postoperative management of a reliable calf model refined in this laboratory for in vivo sub-chronic (96 h) testing of CMA. Holstein bull calves (2 to 3 months old; mean body weight, 78 kg; n = 35) were instrumented for left ventricular CMA; 4 of these calves were sham operated controls. Anesthetic recovery and postoperative restraint were accomplished in a specially designed crate to which each calf was preconditioned extensively. Younger calves were more readily conditioned and more tolerant of postoperative restraint than older calves. One calf died of ventricular fibrillation in-traoperatively. One calf that had been heparinized developed uncontrollable hemothorax and died 12 h postoperatively. One calf prematurely dislodged his aortic cannula 15 h postoperatively and exsanguinated. Six calves developed pelvic limb paresis or paralysis because of lumbar spinal cord thromboembolism by 36 h postoperatively, and 3 of these calves were sacrificed by 42 h postoperatively. Fifteen calves required sedation in the first 12 h after the operation. Tachycardia associated with bottle feeding occurred in 15 calves. Second-degree atrioventricular block was noted frequently during deep relaxation. Postmortem examination demonstrated the absence of surgical wound and distant infection, security of cannulae in all but the calf that prematurely dislodged the aortic cannula, absence of thrombus formation at cannu-lation sites, and presence of thromboembolism in 51% of the calves. The incidence of thromboembolic lesions was not influenced by the need for chemical restraint, by the occurrence of feeding-associated tachycardia, or by the presence of atrioventricular block. There were no thromboembolic lesions in any of the sham-operated controls. PMID- 28868702 TI - Clinical Comparative Study of Cardiopulmonary Bypass with Nikkiso and BioMedicus Centrifugal Pumps. AB - The Nikkiso centrifugal pump was evaluated in elective adult open heard surgery in comparison with the BioMedicus pump. Ten patients using the Nikkiso pump (Group N), and 10 patients using the BioMedicus pump (Group B) were examined for (or to determine) hemato-biologic parameters and patient outcome data as well as pump controllability. During cardiopulmonary bypass (CPB), both pumps maintained systemic perfusion satisfactorily without any mechanical adverse event. Rotation speed of the Nikkiso centrifugal pump (3,580 +/- 100 rpm) was significantly higher than that of the BioMedicus pump (3,170 +/- 100 rpm; p < 0.05) whereas changes in free plasma hemoglobin, platelet count, blood urea nitrogen, and creatinine levels showed no significant differences between the two groups. Urine output in Group N for 30 min after the initiation of CPB (7.10 +/- 1.50 ml/kg/h) was significantly higher than that in Group B (3.23 +/- 0.46 ml/kg/h; p < 0.05). Patient outcome data were similar in both groups, such as duration of intensive care unit stay, hospital stay, postoperative intubation time, amount of postoperative bleeding, and amount of blood transfused. These equivalent results with the BioMedicus pump suggested that the Nikkiso pump can be used in open heart surgery as a reliable and atraumatic CPB pump. PMID- 28868703 TI - The Heart-Hemopump Interaction: A Study of Hemopump Flow as a Function of Cardiac Activity. AB - The Hemopump is a useful left ventricular assist device. Because it is a rotary blood pump, the pump performance is not constant and is dependent on the cardiac cycle. We measured the static flow delivered by the pump at varying pressure heads (DeltaP) in a mock circulation. These data are compared to the pump performance in vivo. On the basis of these results, 5 sheep were instrumented for continuous Hemopump flow measurement as well as left ventricular and aortic pressure measurements. The Hemopump flow was relayed instantaneously to the pressure head. Low filling and ventricular failing (through intravenous administration of a beta-blocker) conditions were applied. The in vivo measured flows also are pressure head dependent, but the flow curve shows hysteresis resulting in a loop during each cardiac cycle. The in vivo peak flows (AP = 0) are similar to the in vitro data. The in vivo means flows (A 50 mm Hg) are similar to the in vitro data for the lower pump speeds but are less than that at the higher pump speeds (3.74 +/- 0.55 L/min in vivo at Speed 7 versus 4.6 L/min in vitro). Low filling interrupts the AP-flow loop and reduces flow. In the failing ventricle, AP increases and flow is reduced. The cannula leaks and results in aortic insufficiency (0.36 +/- 0.05 L/min) when the pump is turned off. Several conclusions have been drawn from these tests: Cardiac activity is beneficial for the pump performance as well as when the aortic pressure curve is nonpulsatile; the longer the systolic phase, the higher the pump flow; the pump should never be turned off in clinical use; and filling is important for the pump's performance. PMID- 28868705 TI - Summary of the Third Congress of the International Society for Rotary Blood Pumps, Houston, Texas, U.S.A., 1995. PMID- 28868704 TI - Effect of Pulsatile and Nonpulsatile Assist on Heart and Kidney Microcirculation with Cardiogenic Shock. AB - To estimate microcirculation of the heart and kidney in pulsatile and nonpulsatile-assisted circulation, a comparison study was done using a swine model. Acute myocardial infarction was made by ligation of the left coronary artery branches. After cardiogenic shock, animals were divided into 3 groups as follows: Group C (n = 6), no assist provided; Group NP (n = 6), assisted by a nonpulsatile pump (Bio-Medicus BP-80); Group P (n = 6), supported by a pulsatile pump (Nippon Zeon). Left coronary artery flow, endocardial and epicardial regional flows, and renal cortex and medulla tissue blood flows were measured. Left coronary artery flow and endocardial and epicardial tissue blood flows decreased in cardiogenic shock, and they recovered to the control level soon after support in both Group N and Group P. Renal medulla and cortex tissue blood flows decreased in cardiogenic shock, and these flows did not recover in either Group N or P. However, cortex blood flow in Group P did improve, but it did not improve in Group N. These results suggested that pulsatile assist was more effective than nonpulsatile assist for microcirculation after cardiogenic shock to avoid deterioration of major organ functions. PMID- 28868706 TI - Comparative Hemolysis Study of Clinically Available Centrifugal Pumps. AB - Centrifugal pumps have become important devices for cardiopulmonary bypass and circulatory assistance. Five types of centrifugal pumps are clinically available in Japan. To evaluate the blood trauma caused by centrifugal pumps, a comparative hemolysis study was performed under identical conditions. In vitro hemolysis test circuits were constructed to operate the BioMedicus BP-80 (Medtronic, BioMedicus), Sams Delphin (Sarns/3M Healthcare), Isoflow (St. Jude Medical [SJM]), HPM-15 (Nikkiso), and Capiox CX-SP45 (Terumo). The hemolysis test loop consisted of two 1.5 m lengths of polyvinyl chloride tubing with a 3/8 -inch internal diameter, a reservoir with a sampling port, and a pump head. All pumps were set to flow at 6 L/min against the total pressure head of 120 mm Hg. Experiments were conducted simultaneously for 6 h at room temperature (21o C) with fresh bovine blood. Blood samples for plasma-free hemoglobin testing were taken, and the change in temperature at the pump outlet port was measured during the experiment. The mean pump rotational speeds were 1,570, 1,374, 1,438, 1,944, and 1,296 rpm, and the normalized indexes of hemolysis were 0.00070, 0.00745, 0.00096, 0.00066, 0.00090 g/100 L for the BP-80, Sarns, SJM, Nikkiso, and Terumo pumps, respectively. The change in temperature at the pump outlet port was the least for the Nikkiso pump (1.8o C) and the most with the SJM pump (3.8o C). This study showed that there is no relationship between the pump rotational speed (rpm) and the normalized index of hemolysis in 5 types of centrifugal pumps. The pump design and number of impellers could be more notable factors in blood damage. PMID- 28868707 TI - Characteristics of a Blood Pump Combining the Centrifugal and Axial Pumping Principles: The Spiral Pump. AB - Two well-known centrifugal and axial pumping principles are used simultaneously in a new blood pump design. Inside the pump housing is a spiral impeller, a conically shaped structure with threads on the surface. The worm gears provide an axial motion of the blood column through the threads of the central cone. The rotational motion of the conical shape generates the centrifugal pumping effect and improves the efficiency of the pump without increasing hemolysis. The hydrodynamic performance of the pump was examined with a 40% glycerin-water solution at several rotation speeds. The gap between the housing and the top of the thread is a very important factor: when the gap increases, the hydrodynamic performance decreases. To determine the optimum gap, several in vitro hemolysis tests were performed with different gaps using bovine blood in a closed circuit loop under two conditions. The first simulated condition was a left ventricular assist device (LVAD) with a flow rate of 5 L/min against a pressure head of 100 mm Hg, and the second was a cardiopulmonary bypass (CPB) simulation with a flow rate of 5 L/min against 350 mm Hg of pressure. The best hemolysis results were seen at a gap of 1.5 mm with the normalized index of hemolysis (NIH) of 0.0063 +/ 0.0020 g/100 L and 0.0251 +/- 0.0124 g/100 L (mean +/- SD; n = 4) for LVAD and CPB conditions, respectively. PMID- 28868708 TI - Pharmacologically Induced Heart Failure for the Evaluation of Circulatory Assistance. AB - For the evaluation of the hemodynamic interaction between the natural heart and an assist device, a reversible pharmacological model based on the channel blocker Verapamil under hyperkalemia, was developed for deterioration of left ventricular function. Four calves weighing 70-90 kg underwent standard implantation for left atrioaortal assist (BioMedicus, BP-80), pump anesthesia (oxygen/isoflurane [1%]; 8 mg/kg of BW/h keta-mine), and of ventricular demand pacing at 120 bpm. Left atrial pressure (LAP), ventricular pressure (LVP), aortic pressure (AoP), pulmonary arterial (Qpulm) pressures, and graft flow (Qgraft) were monitored. The hemodynamic effects of anesthetic overdose (2% Isoflurane) were compared with those of Verapamil (Isoptin: 0.2 mg/kg BW/h 5 mmol/kg of BW/h of KC1) medication. Both regimens caused a decrease in AoP to <=50%. For Isoflurane, a slight reduction in cardiac output (CO) of 10% at a nearly constant LAP and a strong decrease of the peripheral resistance (Rperi) of 35% could be seen where Isoptin caused a significant reduction in CO of 40% at an increased LAP (+ 25%) and changes in Rperi of <10%. Because the vascular tonus remains nearly constant, the hemodynamic effects are controllable and reversible (antagonized with calcium chloride); thus we conclude that Verapamil administration under hyperkalemia conditions is a proper model for mimicking congestive heart failure with low systemic side effects. PMID- 28868709 TI - Prototype Continuous Flow Ventricular Assist Device Supported on Magnetic Bearings. AB - This article describes a prototype continuous flow pump (CFVAD2) fully supported in magnetic bearings. The pump performance was measured in a simulated adult human circulation system. The pump delivered 6 L/min of flow at 100 mm Hg of differential pressure head operating at 2,400 rpm in water. The pump is totally supported in 4 magnetic bearings: 2 radial and 2 thrust. Magnetic bearings offer the advantages of no required lubrication and large operating clearances. The geometry and other properties of the bearings are described. Bearing parameters such as load capacity and current gains are discussed. Bearing coil currents were measured during operation in air and water. The rotor was operated in various orientations to determine the actuator current gains. These values were then used to estimate the radial and thrust forces acting on the rotor in both air and water. Much lower levels of force were found than were expected, allowing for a very significant reduction in the size of the next prototype. Hemolysis levels were measured in the prototype pump and found not to indicate damage to the blood cells. PMID- 28868710 TI - Wear-Resistant, Hemocompatible Ti-Nb-Zr and Zr-Nb Alloys to Improve Blood Pump Design and Performance. AB - Over the past several years, we have developed novel titanium-niobium-zirconium (Ti-Nb-Zr) alloys to address the long-term performance needs of orthopedic implants. The unique properties of these alloys also render them promising candidates for blood pumps. These properties include excellent biocompatibility in combination with high strength and toughness, and low elastic modulus (low stiffness). Additionally, these metal alloys are readily hot or cold worked into complex shapes including wire, foil, tubing, and bar. They are readily machined and polished, and they can be surface oxidized to form a hard, wear-resistant, low-friction ceramic surface layer. In this diffusion-hardened condition, oxygen also hardens the underlying metal to optimize the bone between the ceramic oxide surface and the tough metal substrate. Unlike metal surfaces, oxidative wear, which can alter surface energy, friction, and hemocompatibility, does not occur. Consequently, the combined benefits of a stable, wear-resistant, low-friction ceramic surface layer with the toughness, strength, formability, and thermal conductivity of metal may provide improvements in the design and performance of blood pumps and peripheral graft and percutaneous (power) components of the pump. PMID- 28868711 TI - Prediction of Hemolysis in Turbulent Shear Orifice Flow. AB - This study proposes a method of predicting hemolysis induced by turbulent shear stress (Reynolds stress) in a simplified orifice pipe flow. In developing centrifugal blood pumps, there has been a serious problem with hemolysis at the impeller or casing edge; because of flow separation and turbulence in these regions. In the present study, hemolysis caused by turbulent shear stress must occur at high shear stress levels in regions near the edge of an orifice pipe flow. We have computed turbulent shear flow using the low-Reynolds number k epsilon model. We found that the computed turbulent shear stress near the edge was several hundreds times that of the laminar shear stress (molecular shear stress). The peak turbulent shear stress is much greater than that obtained in conventional hemolysis testing using a viscometer apparatus. Thus, these high turbulent shear stresses should not be ignored in estimating hemolysis in this blood flow. Using an integrated power by shear force, it is optimimal to determine the threshold of the turbulent shear stress by comparing computed stress levels with those of hemolysis experiments of pipe orifice blood flow. PMID- 28868712 TI - Relationship Between Pump Speed Design and Hemolysis in an Axial Flow Blood Pump. AB - In an attempt to reduce the hemolysis caused by axial flow blood pumps, we investigated whether the specific speed should be kept within the standard engineering range or whether pump speed should be minimized, thus making the specific speed beyond the standard range. Four pumps with 11.8 mm diameter impellers were designed to accommodate a flow of 5 L/min and a head of 100 mm Hg. The pumps were tested at 4 speeds: A, 14,000; B, 18,000; C, 22,000; and D, 26,000 rpm. Pump performance data were obtained, and the maximum point of total pump efficiency was found for each pump. The maximum efficiencies were A, 50%; B, 58%; C, 52%; and D, 53%. The specific speed of each pump recorded at the maximum efficiency point was calculated as A, 899; B, 954; C, 1,218; and D, 1,951 rpm. Hemolytic tests were performed with fresh goat blood in a closed, mock-loop circuit. Hemolytic indexes were A, 0.036; B, 0.22; C, 0.35; and D, 0.66. We have concluded that decreased hemolysis is correlated with a lower pump speed and that the specific speed for the lowest pump speed is less than the standard range. Having a specific speed outside the standard range was not correlated with reduced total pump efficiency. PMID- 28868713 TI - Coronary Microcirculation During Left Heart Bypass with a Centrifugal Pump. AB - To estimate coronary microcirculation during left heart bypass (LHB), we performed an experimental comparison study of LHB and intraaortic balloon pumping (1ABP). LHB was performed with a BioMedicus BP-80 pump supporting half of the flow of cardiac output whereas the IABP was pumped in a 1:1 mode for cardiogenic shock in a swine model. Coronary circulations were analyzed by electromagnetic flowmeter, pulsed Doppler velocimeter, and laser Doppler flowmeter. Left ventricular end-diastolic pressure (LVEDP) was reduced significantly by LHB. Although there was no significant difference in epicardial flow between the LHB and IABP groups, endocardial flow was increased significantly by LHB. In the LHB group, the systolic reverse wave of the coronary velocity called a myocardial invalid circulation was reduced remarkably. There was a significant inverse correlation between endocardial flow and LVEDP. These results suggested that LHB was more effective for myocardial microcirculation than was IABP. PMID- 28868714 TI - Evolution Toward the Development of Totally Implantable Rotary Blood Pumps. PMID- 28868715 TI - Effects of Surface Roughness on Mechanical Hemolysis. AB - Previous in vitro hemolysis test results showed that an inlet taper or a round corner in the leading edge of a stenotic connector played an important role in the reduction of hemolysis. However, computational fluid dynamics (CFD) analysis of these results indicated that the shear rate and hemolysis level were not always related to each other. Then, further research was performed, focusing on the effects of surface roughness on hemolysis. The results thus far can be summarized as threefold. First, the rate of hemolysis occurring at an abrupt change in the stenotic section was different if the longitudinal length of the stenosis was changed. The level of plasma-free hemoglobin after 6 h of circulation was decreased from 280 mg/dl to 70 mg/dl when the longitudinal length was shortened from 15 mm to 1 mm. Second, a comparison of hemolysis rates in identical stenotic connectors with differing surface roughness (Ra = 0.45 and 1.35 u.m) revealed that a smooth surface achieved as much as an 80% reduction in the rate of hemolysis. Third, the in vitro hemolysis results obtained were further defined through CFD analysis. PMID- 28868716 TI - Basic Performance of a Miniature Intraventricular Axial Pump. AB - A miniature intraventricular axial pump for left ventricular (LV) support is under development. This pump was designed for placement in the LV cavity by insertion through the LV apex with the outlet located at the ascending aorta via the aortic valve. The basic hydro-dynamic characteristics represented as a relationship between pump head (H) and flow (Q) showed a negative linear relationship under a constant head. This characteristic was generally the same as that obtained by other axial rotation pumps. However, the actual H-Q relationship was represented as anticlockwise "loops" caused by the contraction of the natural LV. The comparative in vitro data on these H-Q loops showed that the shape of the loops was changed drastically by the connecting condition between the pump and natural cardiovascular system. PMID- 28868717 TI - Estimating Mechanical Blood Trauma in a Centrifugal Blood Pump: Laser Doppler Anemometer Measurements of the Mean Velocity Field. AB - A laser Doppler anemometer (LDA) was used to obtain the mean velocity and the Reynolds stress fields in the inner channels of a well-known centrifugal vaneless pump (Bio-pump). Effects of the excessive flow resistance against which an occlusive pump operates in some surgical situations, such as cardiopulmonary bypass, are illustrated. The velocity vector field obtained from LDA measurements reveals that the constraint-forced vortex provides pumping action in a restricted area in the core of the pump. In such situations, recirculating zones dominate the flow and consequently increase the damage to blood cells and raise the risk of thrombus formation in the device. Reynolds normal and shear stress fields were obtained in the entry flow for the channel formed by two rotating cones to illustrate the effects of flow disturbances on the potential for blood cell damage. PMID- 28868718 TI - Using Hybrid Magnetic Bearings to Completely Suspend the Impeller of a Ventricular Assist Device. AB - Clinically available blood pumps and those under development suffer from poor mechanical reliability and poor biocompatibility related to anatomic fit, hemolysis, and thrombosis. To alleviate these problems concurrently in a long term device is a substantial challenge. Based on testing the performance of a prototype, and on our judgment of desired characteristics, we have configured an innovative ventricular assist device, the CF-VAD4, for long-term use. The design process and its outcome, the CFVAD4 system configuration, is described. To provide unprecedented reliability and biocompatibility, magnetic bearings completely suspend the rotating pump impeller. The CFVAD4 uses a combination of passive (permanent) and active (electric) magnetic bearings, a mixed flow impeller, and a slotless 3-phase brushless DC motor. These components are shaped, oriented, and integrated to provide a compact, implantable, pancake-shaped unit for placement in the left upper abdominal quadrant of adult humans. PMID- 28868719 TI - New Method of Evaluating Sublethal Damage to Erythrocytes by Blood Pumps. AB - We recently proposed a new concept, the total destruction time of erythrocytes, to indicate sublethal damage to erythrocytes by blood pumps. In this article, results of additional experiments concerning this new concept are reported. Five paired in vitro hemolysis tests with bovine blood were conducted using a cone type centrifugal pump (Group A) and an impeller-type pump (Group B). A total pressure head of 100 mm Hg was applied. The factors evaluated were the normalized index of hemolysis and the total destruction time, or the pumping duration, required to raise the level of the plasma-free hemoglobin to 50% of the total hemoglobin. The morphologic change of the erythrocytes also was analyzed. The percentage of crenated cells was calculated from blood smear specimens 1 min after starting the pumps and 2 h before the total destruction time of Group A in each experiment. Although there was no statistical difference in the normalized index of hemolysis between the two groups, the total destruction time of Group A erythrocytes was significantly shorter than that of Group B (18.9 +/- 4.5 h and 33.7 +/- 9.9 h in Group A and group B, respectively; p < 2). The rate of crenated erythrocytes was higher in Group A than in Group B at a point 2 h before the total destruction time of Group A. The total destruction time values seem to define a good method for establishing sublethal traumatic damage to erythrocytes in blood pumps. PMID- 28868720 TI - Comparison of Centrifugal and Roller Pump Hemolysis Rates at Low Flow. AB - We compared in vitro rates of hemolysis for a recently developed centrifugal pump with a conventional roller pump (10-10-00; Stockert, Munich, Germany). Flow rates of 0.3 L/min and 1 L/min and a pressure of 200 mm Hg were chosen to simulate conditions during neonatal extracorporeal membrane oxygenation (ECMO). There was no significant difference in hemolysis rates between centrifugal and roller pumps (p = 0.57) nor between high and low flow (p = 0.86). The centrifugal pump caused no more blood trauma than the roller pump at the low-flow/high-pressure conditions required for neonatal ECMO. The Nikkiso pump is superior to roller pumps in size and priming volume (25 ml) and may permit development of a smaller and simpler ECMO system. PMID- 28868721 TI - Experiences of Postcardiotomy Assist: Pneumatic Ventricular Assist Device or Venoarterial Bypass with Percutaneous Cardiopulmonary Support. AB - From October 1982 to the present, 16 patients have been supported by a pneumatic ventricular assist device (VAD). Since April 1990, we have introduced a venoarterial bypass (VAB) with percutaneous cardiopulmonary support (PCPS) system. This PCPS system was used in 12 patients. The long-term survival rate of PCPS cases (41%) was much better than that of VAD cases (19%). The main cause of death in VAD cases was multiple organ failure (MOF). Although VAB was initiated more recently than VAD, the duration on support was longer in the VAD group than in the VAB group. Because of the longer support duration and the presence of many patients with MOF, coagulopathy deteriorated more readily in the VAD group than in the VAB group. In the case of postcardiotomy cardiopulmonary bypass weaning or low-output syndrome (LOS), the VAB with PCPS system should be applied first under intraaortic balloon pumping assist because of its simplicity and low cost. Thereafter, VAD should be applied in cases refractory to VAB support. PMID- 28868722 TI - Subchronic Use of the St. Jude Centrifugal Pump as a Mechanical Assist Device in Calves. AB - The purpose of this experiment was to study the effects of the St. Jude Lifestream centrifugal pump on hemodynamic and hematologic parameters and the incidence of postmortem findings in a subchronic ex vivo left ventricular assist animal model. Five calves were implanted with the pump as a left ventricular assist device (left atrial to thoracic aorta bypass) and studied for 96 h of continuous pumping under identical conditions. Heparin (100 IU/kg) was administered only in the initial saline pump prime. Throughout the protocol, mean arterial and central venous pressures averaged 102.1 +/- 4.6 and 3.4 +/- 2.2 mm Hg, respectively. Pump flow was 47.8 +/- 8.4 ml/kg/min at a mean pump speed of 1,676.3 +/- 106.1 rpm. No clinical abnormalities or mechanical malfunctions attributable to the pump were detected during the 96 h of continuous pumping for each calf. Mean plasma-free hemoglobin after 96 h was 3.9 +/- 3.7 u, mol/L (p = 0.337 compared to baseline). At post mortem, renal infarctions were detected in 1 calf. No other pump-associated lesions were detected in any of the other calves. We have concluded that the St. Jude Lifestream centrifugal pump functions reliably during 96 h of continuous left heart bypass in a calf model. PMID- 28868724 TI - Study of Secondary Flow in Centrifugal Blood Pumps Using a Flow Visualization Method with a High-Speed Video Camera. AB - Four pump models with different vane configurations were evaluated with flow visualization techniques using a high-speed video camera. These models also were evaluated through in vivo hemolysis tests using bovine blood. The impeller having the greatest fluid velocity relative to the impeller, the largest velocity variance, and the most irregular local flow patterns in the flow passage caused the most hemolysis. Even if the pumps were operated at almost the same speed (rpm) at the same output, the impeller showing more irregular flow patterns had a statistically greater rate of hemolysis. This fact confirms that the existence of local irregular flow patterns in a centrifugal blood pump deteriorates its hemolytic performance. Thus, to optimize the design of the pump, it is very important to examine the secondary flow patterns in the centrifugal blood pump in detail using flow visualization with a high-speed video camera. PMID- 28868723 TI - Less Blood Damage in the Impeller Centrifugal Pump: A Comparative Study with the Roller Pump in Open Heart Surgery. AB - A centrifugal pump with an impeller (Nikkiso Centrifugal Pump, Model HPM15; Nikkiso Co. Ltd.) was applied to cardiopulmonary bypass (CPB) in 14 patients who underwent elective coronary artery bypass grafting. Serum hemoglobin level, platelet count, and serum p-thromboglobulin (pTG) level were measured during CPB. The results were compared with those obtained in a comparative roller pump (RP) group (n = 10). There was no difference in the time on CPB between the NP (109 min) and RP (121 min) groups. The serum pTG level (ng/ ml) was lower in the NP group than in the RP group (obtained 90 min after the initiation of CPB). The plasma-free hemoglobin level also was lower in the NP group than in the RP group (obtained 90 min after the initiation of CPB, 120 min after the initiation of CPB, immediately after the termination of CPB, 3 h after termination of CPB; p < 0.01). There was no significant difference in platelet depletion. The HPM15 pump showed excellent hemodynamic performance with less blood trauma compared with the roller pump in its clinical application to open heart surgery. PMID- 28868725 TI - Subchronic Centrifugal Mechanical Assist in an Unheparinized Calf Model. AB - The purpose of this study was to determine whether the major centrifugal pumps currently in use in the United States (Medtronic, BioMedicus BioPump and Carmeda coated BioPump, Sams 3M centrifugal pump, and St. Jude Medical Lifestream) could function as left mechanical assist devices in the subchronic (72 h) unheparinized calf model. Calves were instrumented for left atrial to aorta ex vivo assist, and the pump flow was set at 3.5 +/- 0.4 L/min. Two calves (Sarns 3M and St. Jude) survived 72 h of pumping without clinical complications. The other 2 calves died at 62 and 66 h (Medtronic Bio-Pump and Carmeda-coated BioPump, respectively); both had pelvic limb paralysis. The seal of the Sarns 3M pump head ruptured after approximately 36 h of pumping and required replacement. On postmortem examination, pump-associated thromboembolic lesions were detected in 3 of the 4 calves in one or more of the following organs: kidney, pancreas, abomasum, duodenum, ileum, spleen, and lumbar spinal cord. The calf with the Sarns 3M pump had no discernable lesions. Because of the clinical abnormalities and postmortem lesions in the unheparinized calf model, it was suggested that anticoagulation is necessary for conducting centrifugal mechanical assist studies in calves using presently available technology. PMID- 28868726 TI - Evaluation of the Wear of the Pivot Bearing in the Gyro C1E3 Pump. AB - To estimate the lifetime of the pivot bearing system of the sealless centrifugal Gyro C1E3 pump, pivot bearing wear phenomena of the C1E3 were studied. The pivot bearing system consisted of a male and female pivot made of ceramics and ultrahigh molecular weight polyethylene (UHMWPE), respectively. First, many pumping tests were performed with the C1E3 under various pumping conditions, and the effects of impeller position and fluid on wear were analyzed. Through these preliminary tests, it was found that the wear progress of the pivot bearing consisted of initial wear and stationary wear. Most of this initial wear is caused by the plastic deformation of the polyethylene female pivot. It also was observed that bovine blood was almost comparable to water in its effect on the stationary wear rate at the same rotational speed. Based on these results, a long term pumping test was performed with the C1E3, and initial and stationary wear rates were determined. At the same time, the maximal loosening distance (LDmax) (permissible total wear) of the C1E3 was determined experimentally from hemolytic and hydraulic performance perspectives. By using experimentally determined parameters the lifetime of the pivot bearing system of the C1E3 pump was estimated for various pumping conditions. The lifetime of the pivot bearing system of the C1E3 was typically 10 years for right ventricular assist, 8 years for left ventricular assist, and 5 years for cardiopulmonary bypass. PMID- 28868727 TI - Fluctuations of the Hemodynamic Derivatives During Left Ventricular Assistance Using Oscillated Blood Flow. AB - To analyze the autonomic nervous system during left heart bypass with a vibrating flow pump (VFP), fluctuations in hemodynamic derivatives were evaluated by the spectral analysis method using fast fourier transform methodology. After the left pleural cavity was opened through the fourth intercostal space under general anesthesia, a VFP was implanted as the left heart bypass device in chronic animal experiments using 3 healthy adult goats. Hemodynamic parameters with and without VFP assistance were recorded on magnetic tape in awake animals and were analyzed by computer through an analog to digital convertor. Power spectral analysis was performed on a beat-to-beat basis for the evaluation of the fluctuations. During left heart bypass with the VFP, Mayer wave fluctuations were decreased significantly although respiratory waves were not changed significantly. These results suggest that sympathetic nervous system modulation was changed under the influences of the left heart bypass with VFP. By using this analysis methodology, truly physiologic ventricular assistance may be achieved. PMID- 28868728 TI - High-Resolution Fluorescent Particle-Tracking Flow Visualization within an Intraventricular Axial Flow Left Ventricular Assist Device. AB - Flow visualization is typically applied in blood pump development to both confirm the design expectations and identify regions that may be predisposed to blood element deposition and trauma. Rotary pumps, in particular, place high demands on the technique chosen to visualize the flow given the limited visual accessibility of the flow path and the high impeller speeds. Fluorescent image-tracking velocimetry currently is used at the University of Pittsburgh Medical Center to visualize flow accurately inside of these pumps both qualitatively and quantitatively. Flow patterns under steady conditions within an intraventricular axial flow, left ventricular assist pump (prototype No. 7, SUN Medical Technology Research Corporation, Nagano, Japan) were investigated using this technique. The flow fields at the impeller-stator interface and at the pump outlet were given specific attention. This allowed the assessment of the fluid dynamics throughout the hydrodynamic design limits of the pump. PMID- 28868729 TI - Greetings from the Honorary Congress President of the International Society for Rotary Blood Pumps. PMID- 28868730 TI - Macromolecule mapping of the brain using ultrashort-TE acquisition and reference based metabolite removal. AB - PURPOSE: To develop a practical method for mapping macromolecule distribution in the brain using ultrashort-TE MRSI data. METHODS: An FID-based chemical shift imaging acquisition without metabolite-nulling pulses was used to acquire ultrashort-TE MRSI data that capture the macromolecule signals with high signal to-noise-ratio (SNR) efficiency. To remove the metabolite signals from the ultrashort-TE data, single voxel spectroscopy data were obtained to determine a set of high-quality metabolite reference spectra. These spectra were then incorporated into a generalized series (GS) model to represent general metabolite spatiospectral distributions. A time-segmented algorithm was developed to back extrapolate the GS model-based metabolite distribution from truncated FIDs and remove it from the MRSI data. Numerical simulations and in vivo experiments have been performed to evaluate the proposed method. RESULTS: Simulation results demonstrate accurate metabolite signal extrapolation by the proposed method given a high-quality reference. For in vivo experiments, the proposed method is able to produce spatiospectral distributions of macromolecules in the brain with high SNR from data acquired in about 10 minutes. We further demonstrate that the high dimensional macromolecule spatiospectral distribution resides in a low dimensional subspace. This finding provides a new opportunity to use subspace models for quantification and accelerated macromolecule mapping. Robustness of the proposed method is also demonstrated using multiple data sets from the same and different subjects. CONCLUSION: The proposed method is able to obtain macromolecule distributions in the brain from ultrashort-TE acquisitions. It can also be used for acquiring training data to determine a low-dimensional subspace to represent the macromolecule signals for subspace-based MRSI. Magn Reson Med 79:2460-2469, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28868731 TI - Modulating Crystallinity of Graphitic Carbon Nitride for Photocatalytic Oxidation of Alcohols. AB - Exploiting efficient photocatalysts with strengthened structure for solar-driven alcohol oxidation is of great significance. The photocatalytic performance of graphitic carbon nitrides can be considerably promoted by modulating its crystallinity. Results confirmed that a high crystallinity accelerates the separation and transfer of photogenerated charge carriers, thus providing more free charges for photoredox reactions. More importantly, the high crystallinity facilitated the adsorption of benzyl alcohol and desorption of benzaldehyde and simultaneously lowered the energy barrier for O2 activation. As a result, the crystalline carbon nitride exhibited a roughly twelvefold promotion with respect to the normal carbon nitride. The remarkable enhancement of activity can be attributed to the synergistic effects of increased electron-hole separation and increased surface reaction kinetics. These findings will open up new opportunities to modulate the structure of polymers for a wide variety of organic reactions. PMID- 28868732 TI - Morphology quiz: Renal disease and cytopathology. PMID- 28868734 TI - A Supplement to TRANSFUSION Abstract Presentations from the AABB Annual Meeting San Diego, CA, October 7-10, 2017. PMID- 28868733 TI - National study of parental confidence in general practitioners. AB - AIM: To assess a national sample of Australian parental confidence in general practitioner (GP) care for illness and injury for their children. METHODS: Cross sectional, internet-based survey of a national, representative sample of parents of children birth - 17 years in Australia was used. Purposeful recruitment was used to achieve a national, representative sample of 2100 Australian parents, reflective of demographic and geographic distribution based on census data. Parents were asked to indicate their degree of confidence in a GP to handle medical problems as well as their preference for, and use of, paediatric speciality care for their children. RESULTS: Fewer than half of parents (44%) reported that they were completely confident in a GP to provide general care as defined as 'can handle almost all general health issues for my child'. A slightly greater proportion of parents (56%) were completely confident in a GP to provide care for minor injuries, defined as injuries not requiring an X-ray. Greater confidence in general care was seen among parents >40 years of age and those whose GP is always bulk billed. CONCLUSIONS: Parental confidence in GPs is an important issue. Our findings that fewer than half of parents are completely confident in their GP to provide general care to their child may be an influencing factor on current health-care utilisation trends. The potential implications of low parental confidence in GPs are greater numbers of emergency department presentations for children with lower urgency conditions and increased referrals of children for specialty care. PMID- 28868736 TI - Case of peripheral T-cell lymphoma, not otherwise specified, presenting dyshidrosis-like eruptions as the first clinical manifestation. PMID- 28868735 TI - Micronuclei and other erythrocyte nuclear abnormalities in fishes from the Great Lakes Basin, USA. AB - Biological markers (biomarkers) sensitive to genotoxic and mutagenic contamination in fishes are widely used to identify exposure effects in aquatic environments. The micronucleus assay was incorporated into a suite of indicators to assess exposure to genotoxic and mutagenic contamination at five Great Lakes Areas of Concern (AOCs), as well as one non-AOC (reference) site. The assay allowed enumeration of micronuclei as well as other nuclear abnormalities for both site and species comparisons. Erythrocyte abnormality data was also compared to skin and liver tumor prevalence and hepatic transcript abundance. Erythrocyte abnormalities were observed at all sites with variable occurrence and severity among sites and species. Benthic-oriented brown bullhead (Ameiurus nebulosus) and white sucker (Catostomus commersonii) expressed lower rates of erythrocyte abnormalities, but higher rates of skin and liver neoplasms, when compared to pelagic-oriented largemouth bass (Micropterus salmoides) or smallmouth bass (Micropterus dolomieu) at the same site. The reduced erythrocyte abnormalities, increased transcript abundance associated with Phase I and II toxicant responsive pathways, and increased neoplastic lesions among benthic-oriented taxa may indicate the development of contaminant resistance of these species to more acute effects. Environ. Mol. Mutagen. 58:570-581, 2017. (c) 2017 This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. PMID- 28868737 TI - Response to "An unbalanced study that lacks power: a caution about IPTAS". PMID- 28868738 TI - Evidence for a more restrictive hematocrit trigger for neonates with respiratory failure requiring ECMO. PMID- 28868740 TI - An unbalanced study that lacks power: a caution about IPTAS. PMID- 28868741 TI - It's time to step up to the plate and BAT. PMID- 28868742 TI - A life-threatening transfusion reaction. PMID- 28868743 TI - Partial D in an obstetrical patient presenting as a mixed field on Rh typing. PMID- 28868744 TI - A putative spermidine synthase interacts with flagellar switch protein FliM and regulates motility in Helicobacter pylori. AB - The flagellar motor is an important virulence factor in infection by many bacterial pathogens. Motor function can be modulated by chemotactic proteins and recently appreciated proteins that are not part of the flagellar or chemotaxis systems. How these latter proteins affect flagellar activity is not fully understood. Here, we identified spermidine synthase SpeE as an interacting partner of switch protein FliM in Helicobacter pylori using pull-down assay and mass spectrometry. To understand how SpeE contributes to flagellar motility, a speE-null mutant was generated and its motility behavior was evaluated. We found that deletion of SpeE did not affect flagellar formation, but induced clockwise rotation bias. We further determined the crystal structure of the FliM-SpeE complex at 2.7 A resolution. SpeE dimer binds to FliM with micromolar binding affinity, and their interaction is mediated through the beta1' and beta2' region of FliM middle domain. The FliM-SpeE binding interface partially overlaps with the FliM surface that interacts with FliG and is essential for proper flagellar rotational switching. By a combination of protein sequence conservation analysis and pull-down assays using FliM and SpeE orthologues in E. coli, our data suggest that FliM-SpeE association is unique to Helicobacter species. PMID- 28868745 TI - Improved clonality detection in B-cell lymphoma using a semi-nested modification of the BIOMED-2 PCR assay for IGH rearrangement: A paraffin-embedded tissue study. AB - The BIOMED-2 PCR protocol for targeting the IGH gene is widely employed for detecting clonality in B-cell malignancies. Unfortunately, the detection of clonality with this method is not very sensitive when paraffin sections are used as a DNA source. To increase the sensitivity, we devised a semi-nested modification of a JH consensus primer. The clonality detection rates of three assays were compared: the standard BIOMED-2, BIOMED-2 assay followed by BIOMED-2 re-amplification, and BIOMED-2 assay followed by semi-nested BIOMED-2. We tested more than 100 cases using paraffin-embedded tissues of various B-cell lymphomas, and found that the clonality detection rates with the above three assays were 63.9%, 79.6%, and 88.0%, respectively. While BIOMED-2 re-amplification was significantly more sensitive than the standard BIOMED-2, the semi-nested BIOMED-2 was significantly more sensitive than both the standard BIOMED-2 and BIOMED-2 re amplification. An increase in sensitivity was observed in all lymphoma subtypes examined. In conclusion, tumor clonality may be detected in nearly 90% of B-cell lymphoma cases with semi-nested BIOMED-2. This ancillary assay may be useful when the standard BIOMED-2 fails to detect clonality in histopathologically suspected B-cell lymphomas. PMID- 28868746 TI - Corrigendum. AB - In Pathology International vol 62 iss 1, the authors would like to draw the reader's attention to the error: On page 28, College of Veterinary Medicine, Seoul National University, Seoul, Korea was not included as an affiliation for author, Jun Won Park. The corrected author affiliation list is: Hee Seok Lee,1 * Jun Won Park,1,4 * Oleg Chertov,2 Simona Colantonio,2 John T. Simpson,2 Matthew J. Fivash,3 Chong Woo Yoo,1 Geon Kook Lee,1 Jae Ill Zo,1 Heung Tae Kim1 and Hark Kyun Kim11 National Cancer Center, Goyang, Korea and 2 Protein Chemistry Laboratory Advanced Technology Program, SAIC-Frederick, Inc. and 3 Data Management Systems Inc., National Cancer Institute at Frederick, Frederick, Maryland, USA and 4 College of Veterinary Medicine, Seoul National University, Seoul, Korea The authors apologize for this error and any confusion it may have caused. PMID- 28868747 TI - A case of mucin-producing urothelial-type adenocarcinoma of the prostate showing immunoreactivity for NKX3.1, a specific marker of prostatic tissue. PMID- 28868748 TI - Egg cases of the graytail skate Bathyraja griseocauda and the cuphead skate Bathyraja scaphiops from the south-west Atlantic Ocean. AB - Egg cases of Bathyraja griseocauda were larger (140-142 mm in length) than those of Bathyraja scaphiops (88-90 mm in length) and their surface was relatively smooth, without denticles, prickles or any ornamentation. Egg cases of B. scaphiops had a relative coarse surface, covered with prickles of similar size. An identification key for the all described egg cases from Bathyraja occurring in the south-west Atlantic Ocean is provided. PMID- 28868749 TI - Molecular and morphological analyses revealed a cryptic species of dojo loach Misgurnus anguillicaudatus (Cypriniformes: Cobitidae) in Japan. AB - Although it has been reported that populations of the Japanese dojo loach Misgurnus anguillicaudatus (Cypriniformes: Cobitidae) belong to two distinct mitochondrial (mt)DNA (Type I and Type II), the taxonomic status of the species remains unresolved. To address this question, nuclear DNA and morphological analyses were performed on M. anguillicaudatus population in the Nakaikemi Wetland, where Type I and Type II lineages are sympatric. Results suggest the existence of a cryptic species (Type I) within the Japanese dojo loach. PMID- 28868750 TI - Life in a bubble: the role of the labyrinth organ in determining territory, mating and aggressive behaviours in anabantoids. AB - The anabantoids are a group of c. 137 species of air-breathing freshwater fishes found in Africa and southern Asia. All anabantoids have a pair of suprabranchial chambers that each house an air-breathing organ known as the labyrinth apparatus: a complex bony structure lined with thin, highly vascularised respiratory epithelium. The labyrinth apparatus allows anabantoids to extract oxygen from air and is a morpho-physiological innovation that has had a dramatic influence on the behaviour of these fishes. Air-breathing influences a wide range of anabantoid behaviours, including territorial displays, courtship and breeding and parental care and also equips these fishes to persist in hypoxic and polluted water. These traits also make anabantoids successful invaders of novel habitats, a global problem compounded by their popularity in the aquarium trade. By reviewing the functionality and evolution of air breathing in anabantoids, this review aims to examine the role of the labyrinth apparatus in modulating behaviour within this group. The anabantoids are a fascinating group and have often been cited as a model organism due to the stereotypical and easily identifiable behaviours that they adopt during social interactions. They also provide a unique opportunity to further our understanding about how fishes adapt their behaviour in response to an extreme environment, whilst limited by their own physiological constraints. PMID- 28868752 TI - Severe cutaneous aluminum reaction to quadrivalent human papillomavirus vaccine treated with cyclosporin. PMID- 28868751 TI - Reductive Coupling of Acrylates with Ketones and Ketimines by a Nickel-Catalyzed Transfer-Hydrogenative Strategy. AB - Nickel-catalyzed coupling of benzyl acrylates with activated ketones and imines provides gamma-butyrolactones and lactams, respectively. The benzyl alcohol byproduct released during the lactonization/lactamization event is relayed to the next cycle where it serves as the reductant for C-C bond formation. This strategy represents a conceptually unique approach to transfer-hydrogenative C-C bond formation, thus providing examples of reductive heterocyclizations where hydrogen embedded within an alcohol leaving group facilitates turnover. PMID- 28868754 TI - Size does matter: what is the corneo-limbal diameter? AB - This review surveys available literature for corneal and limbal dimensions. With modern scleral lenses, these measures have become central to determining the overall size of a lens for satisfactory fitting. In general, published values are not based on a definition of what is being measured. In addition, the most widely accepted average corneal diameter measurement, 11.7 * 10.6 mm, emanates from one source published more than 50 years ago. This value was not based on a measurement but appears to be the cumulative impression of measurements from seven studies conducted between 67 and 127 years ago. Furthermore, in most instances, if at all stated, quoted measures are based on horizontal visible iris diameter, providing limited acknowledgement of limbal width and its inclusion as part of the corneal diameter. The corneo-scleral sulcus from one side to the other has been measured, giving a larger diameter, but may include at least part of the limbus. More objective measurements are possible with modern ophthalmic instrumentation but the lack of structural definition and low magnification resolution with these techniques raises concerns with the accuracy of the results. Measurement of the horizontal visible iris diameter does not include the limbal width, which means that the horizontal visible iris diameter is an underestimate of the true corneo-limbal diameter. This review concludes that the width of the limbus has been neither structurally defined nor accurately measured and that there is a need for the development of new protocols for determining the dimensions of the average cornea and limbus. It is predicted that more accurate measures will indicate that to vault across cornea with limbus and provide excellent comfort, the average cornea will need a lens to have a diameter of 16.0 mm or larger. PMID- 28868753 TI - A "spaghetti sign" in feline abdominal radiographs predicts spleno-systemic collateral circulation. AB - A well-defined, tortuous, and tubular soft tissue opaque structure has been observed within the left mid abdominal cavity in digital radiographs of some cats. Authors hypothesized that this radiographic "spaghetti sign" is a predictor for spleno-systemic collateral circulation. The purpose of this multicenter, retrospective, descriptive study was to further characterize radiographic "spaghetti signs" in a group of cats and compare these signs with results of ultrasonography or computed tomography (CT). A multiinstitutional database was reviewed for radiographic reports describing the presence of a tubular tortuous structure within the left abdominal cavity of feline patients. Patients were included if additional abdominal ultrasound or CT studies were available. Imaging studies and medical records were retrieved and reviewed by a board-certified veterinary radiologist, and characteristics were recorded. Eighteen cats met the inclusion criteria. The presence of a tortuous vessel consistent with spleno systemic collateral circulation was observed by ultrasonography or CT examinations in all patients with a "spaghetti sign" on abdominal radiographs. All patients were spayed females. One cat showed ultrasonographic imaging features consistent with portal hypertension. In conclusion, findings supported the hypothesis that a radiographic "spaghetti sign" is a predictor of spleno systemic collateral circulation in feline patients and should be distinguished from other signs such as focal loss of serosal detail or a space occupying lesion. PMID- 28868755 TI - Matrix-Metalloproteinase-2 Predicts Arteriovenous Fistula Failure in Hemodialysis Patients. AB - In hemodialysis patients the principal cause of arteriovenous fistula dysfunction is stenosis. Matrix-metalloproteinase-2 is implicated in the pathophysiological mechanism of stenosis development. Our study tried to assess the clinical impact of this protease on arteriovenous fistula survival. Seventy-nine prevalent dialysis patients with functional arteriovenous fistulas were included in the study. The presence of stenosis and the serum levels of matrix-metalloproteinase 2 were determined at the beginning of the study. The patency of the arteriovenous fistulas was followed- up for two years. In multivariate regression; matrix metalloproteinase-2 was a significant predictor of vascular access loss (HR = 1.104, 95%CI 1.033-1.179, P = 0.003). Patients with a level of matrix metalloproteinase-2 lower than 50 ng/mL had a better survival of the arteriovenous fistulas. Matrix-metalloproteinase-2 was an even stronger predictor of fistula failure in the stenosis group (HR = 1.076, 95%CI 1.027-1.127, P = 0.002). In our study matrix-metalloproteinase-2 has a predictive value for arteriovenous fistula failure. PMID- 28868756 TI - The contribution of microbial biotechnology to economic growth and employment creation. AB - Our communication discusses the profound impact of bio-based economies - in particular microbial biotechnologies - on SDG 8: Promote sustained, inclusive and sustainable economic growth, full and productive employment and decent work for all. A bio-based economy provides significant potential for improving labour supply, education and investment, and thereby for substantially increasing the demographic dividend. This, in turn, improves the sustainable development of economies. PMID- 28868757 TI - Depression in early adolescence: Contributions from relational aggression and variation in the oxytocin receptor gene. AB - Interpersonal stress arising from relational aggression (RA)-the intentional effort to harm others via rejection and exclusion-may increase risk for depression in youth. Biological vulnerabilities related to the hormone oxytocin, which affects social behavior and stress responses, may exacerbate this risk. In a community sample of 307 youth (52% female; age range = 10-14 years), we tested whether (1) the association between RA and subsequent depressive symptoms was mediated through social problems and (2) a single nucleotide polymorphism (rs53576) in the oxytocin receptor gene (OXTR) moderated this indirect association between RA and depression, where GG homozygotes are predicted to be more sensitive to the effects of social problems than A-allele carriers. Youth reported RA and depressive symptoms were measured using a structured interview and a questionnaire, respectively. DNA was extracted from saliva collected with Oragene kits. Consistent with the interpersonal theory of depression, the association between relational aggression and subsequent depressive symptoms was mediated by social problems. This indirect effect was further moderated by rs53576 genotype, such that GG homozygotes showed a stronger mediation effect than A-carriers. These results suggest that rs53576 variants confer vulnerability for depression within the context of interpersonal risk factors, such that youth with the GG genotype may be particularly sensitive to the social consequences resulting from RA. PMID- 28868758 TI - Programmed cell death ligand 1 (PD-L1) expression is not a predominant feature in Ewing sarcomas. AB - BACKGROUND: Programmed cell death 1 (PD-1) receptor engagement on T cells by its ligand programmed cell death ligand 1 (PD-L1) is a key mechanism of immune escape, and antibody blockade of the interaction has emerged as an effective immunotherapeutic strategy in some cancers. The role and relevance of the PD-1 checkpoint in Ewing sarcoma (EwS) is not yet understood. PROCEDURE: Here, we investigated expression of PD-L1 and PD-1 in EwS by immunohistochemistry analysis of pretherapeutic tumor biopsies and in tumor xenografts following treatment with human T cells engineered to express a chimeric antigen receptor (CAR) against the tumor-associated antigen GD2 . PD-L1 surface expression in EwS cell lines was assessed by flow cytometry. RESULTS: PD-L1 expression was not detectable on tumor cells in any of the 60 EwS biopsies. Infiltrating PD-L1 positive T cells were found in one tumor, and four biopsies contained PD-1-positive T cells. Of 13 EwS cell lines, none constitutively expressed PD-L1 on the cell surface. Interferon gamma cytokine stimulation induced upregulation of the ligand on all cell lines. Adoptive therapy with CAR gene-modified T cells in a mouse model did not induce PD-L1 expression in EwS xenografts despite tumor infiltration with PD-1+ CD3+ T cells. CONCLUSIONS: EwS cells can upregulate PD-L1 under inflammatory conditions, but do not express the ligand in the pretherapeutic tumor microenvironment or postexposure to CAR T cells. PD-1 checkpoint blockade alone is thus unlikely to evoke potent immune responses against EwS. Identification of the relevant immune evasion strategies in EwS will be vital for the development of effective immune targeting strategies. PMID- 28868759 TI - From Food Waste to Efficient Bifunctional Nonprecious Electrocatalyst. AB - Synergy between graphitic nanocarbon, obtainable from food waste through cracking of biomethane, and iron oxide nanoparticles provides access to efficient bifunctional electro catalysts. Dissolution of potassium-intercalated graphitic nanocarbons yields graphenide solutions with calibrated, small lateral size reduced graphenes that are used subsequently as reducing agents of iron metal salts. This results in the strong binding of small size (2-5 nm) nanoparticles on the carbon framework homogeneously within the composite material, accessibility of the catalytic centers, and good conductivity provided by the underlying carbon framework. The iron oxide nanocarbon electrocatalyst performances are highlighted by the overall overpotential of approximately 1 V needed to reach the benchmark threshold of 10 mA cm-2 for the oxygen reduction reaction and the particular activity towards oxygen evolution reaction (eta~0.4 V at 10 mA cm-2 ), comparable to that of the precious RuO2 and IrO2 catalysts. This iron oxide/nanocarbon electrocatalyst is versatile, remarkably active, stable, and truly sustainable. PMID- 28868760 TI - Cannabis use among two national samples of Aboriginal and Torres Strait Islander tobacco smokers. AB - INTRODUCTION AND AIMS: There is a concern that cannabis use is an important barrier to reducing Aboriginal and Torres Strait Islander smoking. We investigate the associations of cannabis use and tobacco smoking and quitting in two large national samples. DESIGN AND METHODS: The 2012-2013 National Aboriginal and Torres Strait Islander Health Survey was a national stratified random household survey conducted between April 2012 and February 2013, and included 2580 adult Aboriginal and Torres Strait Islander smokers. The Talking About The Smokes Project interviewed a national quota sample of 1301 Aboriginal and Torres Strait Islander adult smokers between August 2013 and August 2014. Both surveys asked about tobacco smoking and quitting, cannabis use and socio-demographic factors. RESULTS: Both surveys estimated that cannabis use is common among Aboriginal and Torres Strait Islander smokers (National Aboriginal and Torres Strait Islander Health Survey: 32%, Talking About The Smokes: 24%). Both surveys found a higher prevalence of cannabis use among smokers who were male, younger, unemployed or who more frequently consumed five or more alcoholic drinks in a day. However, the two surveys provided inconsistent evidence about whether cannabis use is associated with not quitting smoking tobacco. DISCUSSION AND CONCLUSIONS: We did not find consistent evidence in this setting that cannabis use is an obstacle to quitting tobacco smoking. Nevertheless, we would still recommend that clinicians counselling Aboriginal and Torres Strait Islander tobacco smokers about quitting talk about cannabis use because its use is common and almost all mix it with tobacco. PMID- 28868761 TI - Relationship between the retinacula cutis and sagging facial skin. AB - BACKGROUND: Sagging skin is one of the most concerning esthetic issues for elderly individuals. Although reduced skin elasticity has been reported as the cause of sagging skin, a loss of skin elasticity alone is insufficient to explain sagging facial skin. This study investigated the mechanisms underlying sagging skin, with a focus on the subcutaneous network of collagenous fibers known as the retinacula cutis (RC). METHODS: To evaluate the structure of the RC noninvasively, tomographic images of the face were obtained using magnetic resonance imaging (MRI). The RC was identified by comparing MRI results with histological specimens of human skin. A descriptive scale was used to evaluate the degree of sagging, and a device equipped with a 6-mm-diameter probe was used to measure the elasticity of deeper skin layers and evaluate the physical properties of the skin. RESULTS: The density of RC in subcutaneous tissue correlated negatively with sagging scores and positively with elasticity. CONCLUSION: These results imply that a sparse RC structure contributes to a reduction in the elasticity of subcutaneous tissue, resulting in a greater degree of sagging facial skin. These findings are expected to contribute to the understanding of the mechanisms underlying sagging skin. PMID- 28868762 TI - Repairing Nanoparticle Surface Defects. AB - Solar devices based on semiconductor nanoparticles require the use of conductive ligands; however, replacing the native, insulating ligands with conductive metal chalcogenide complexes introduces structural defects within the crystalline nanostructure that act as traps for charge carriers. We utilized atomically thin semiconductor nanoplatelets as a convenient platform for studying, both microscopically and spectroscopically, the development of defects during ligand exchange with the conductive ligands Na4 SnS4 and (NH4 )4 Sn2 S6 . These defects can be repaired via mild chemical or thermal routes, through the addition of L type ligands or wet annealing, respectively. This results in a higher-quality, conductive, colloidally stable nanomaterial that may be used as the active film in optoelectronic devices. PMID- 28868763 TI - Cascade Reductive Etherification of Bioderived Aldehydes over Zr-Based Catalysts. AB - An efficient one-pot catalytic cascade sequence has been developed for the production of value-added ethers from bioderived aldehydes. Etherification of 5 (hydroxymethyl)furfural with different aliphatic alcohols over acidic Zr montmorillonite (Zr-Mont) catalyst produced a mixture of 5-(alkoxymethyl)furfural and 2-(dialkoxymethyl)-5-(alkoxymethyl)furan. The latter was selectively converted back into 5-(alkoxymethyl)furfural by treating it with water over the same catalyst. The synthesis of 2,5-bis(alkoxymethyl)furan was achieved through a cascade sequence involving etherification, transfer hydrogenation, and re etherification over a combination of acidic Zr-Mont and the charge-transfer hydrogenation catalyst [ZrO(OH)2 ]. This catalyst combination was further explored for the cascade conversion of 2-furfuraldehyde into 2 (alkoxymethyl)furan. The scope of this strategy was then extended for the reductive etherification of lignin-derived arylaldehydes to obtain the respective benzyl ethers in >80 % yield. Additionally, the mixture of Zr-Mont and ZrO(OH)2 does not undergo mutual destruction, which was proved by recycling experiments and XRD analysis. Both the catalysts were thoroughly characterized using BET, temperature-programmed desorption of NH3 and CO2 , pyridine-FTIR, XRD, inductively coupled plasma optical emission spectroscopy, and X-ray photoelectron spectroscopy techniques. PMID- 28868764 TI - The role of increased glucose on neurovascular dysfunction in patients with the metabolic syndrome. AB - Metabolic syndrome (MetS) causes autonomic alteration and vascular dysfunction. The authors investigated whether impaired fasting glucose (IFG) is the main cause of vascular dysfunction via elevated sympathetic tone in nondiabetic patients with MetS. Pulse wave velocity, muscle sympathetic nerve activity (MSNA), and forearm vascular resistance was measured in patients with MetS divided according to fasting glucose levels: (1) MetS+IFG (blood glucose >=100 mg/dL) and (2) MetS IFG (<100 mg/dL) compared with healthy controls. Patients with MetS+IFG had higher pulse wave velocity than patients with MetS-IFG and controls (median 8.0 [interquartile range, 7.2-8.6], 7.3 [interquartile range, 6.9-7.9], and 6.9 [interquartile range, 6.6-7.2] m/s, P=.001). Patients with MetS+IFG had higher MSNA than patients with MetS-IFG and controls, and patients with MetS-IFG had higher MSNA than controls (31+/-1, 26+/-1, and 19+/-1 bursts per minute; P<.001). Patients with MetS+IFG were similar to patients with MetS-IFG but had higher forearm vascular resistance than controls (P=.008). IFG was the only predictor variable of MSNA. MSNA was associated with pulse wave velocity (R=.39, P=.002) and forearm vascular resistance (R=.30, P=.034). In patients with MetS, increased plasma glucose levels leads to an adrenergic burden that can explain vascular dysfunction. PMID- 28868765 TI - Cleft lip and palate with lip pits and ankyloblepharon. PMID- 28868766 TI - Increased doses of inhaled corticosteroids during home management of asthma flare ups do not reduce the need for systemic steroids. PMID- 28868768 TI - Antibiotic prophylaxis for infective endocarditis: A systematic review and meta analysis. PMID- 28868767 TI - Use of Nicotine Replacement Therapy in Young People Entering Custody in New South Wales, Australia. PMID- 28868769 TI - Cleft lip and palate with lip pits and ankyloblepharon. PMID- 28868770 TI - Efficacy of World Health Organization Guideline in Facility-Based Reduction of Mortality in Severely Malnourished Children From Low and Middle Income Countries. PMID- 28868771 TI - Coeliac disease and psychological symptoms. PMID- 28868772 TI - Unusual Presentation of an Odontogenic Cyst in a Child. PMID- 28868773 TI - Deliberate salt poisoning. PMID- 28868774 TI - Children in research. PMID- 28868775 TI - Clinical analysis of the factors that influence disease progression of differentiated thyroid carcinoma in children. AB - AIM: To investigate the factors that influence disease progression of paediatric patients with differentiated thyroid carcinoma. METHODS: A total of 34 patients under 18 years of age with differentiated thyroid carcinoma (32 papillary and 2 follicular; 9 males and 25 females; 19 cases younger than 15 years old and 15 cases 15-18 years old) treated in our department from June 2009 to August 2015 were retrospectively reviewed. All of the patients underwent a total thyroidectomy or near-total thyroidectomy, central node dissection and/or lateral neck dissection, radioactive iodine treatment and thyroid-stimulating hormone suppressive therapy. A univariate analysis was conducted by log-rank to evaluate the factors that influenced progression-free survival of differentiated thyroid carcinoma in these patients. RESULTS: The median progression-free survival time of all patients was 23 months, ranging from 4 to 72 months. Progression of pulmonary metastatic disease was observed in two cases, a recurrence in the thyroid bed was found in one case, and thyroglobulin significantly increased in four cases. In the univariate analysis, the factor that influenced progression free survival of differentiated thyroid carcinoma was multifocality (P = 0.040), and independently, age, gender, tumour size, pathological type, degree of infiltration, lymph node metastasis and pulmonary metastasis had no significant influence on progression-free survival (P > 0.05). CONCLUSION: Multifocality was the factor that influenced the progression-free survival of differentiated thyroid carcinoma patients under 18 years of age. PMID- 28868776 TI - Ten tips for young (and old) doctors. PMID- 28868777 TI - The Racp Evolve General Paediatrics List. PMID- 28868779 TI - Survival comparison of patients with cystic fibrosis in Canada and the USA. PMID- 28868778 TI - Seizures and chorioretinal lacunae in an infant. PMID- 28868780 TI - Meta-Analysis of Sleep Duration and Obesity in Children: Fixed Effect Model or Random Effect Model? PMID- 28868781 TI - Long-term outcomes for large for gestational age infants born at term. AB - AIM: Large for gestational age (LGA) babies have increased risks for short-term outcomes such as shoulder dystocia, neonatal hypoglycaemia and longer hospital stay. Little is known of long-term health, development and educational outcomes of LGA babies. The aim of this study was to determine the long-term health, mortality, development and educational outcomes for infants born LGA at term. METHODS: A population-based record linkage study of live singletons born at term (37-41 weeks of gestation) in New South Wales, Australia, from 2001 to 2006. RESULTS: This study compared 49 439 LGA (>90th percentile for birthweight, gestational age and sex) and 400 418 appropriate size for gestational age (AGA; 10th-90th percentile) infants. LGA infants had increased risk of birth and neonatal outcomes and hospitalisations, for brachial plexus injury after the neonatal period, and for all causes from 1 to 5 years of age. There were no differences in mortality up to 5 years of age or hospitalisations for type 1 diabetes in childhood. LGA infants had lower rates of developmental vulnerability (in kindergarten) and showed a significant trend (chi2 for trend <0.0001) to fewer low scores and more high scores in reading and numeracy (in Year 3) compared with AGA. After adjusting for potential confounders, only the relative risk for higher reading scores was statistically significant. CONCLUSIONS: LGA infants show positive long-term health, development and educational outcomes. Concerns for LGA infants still remain in the perinatal period as a result of birth trauma; however, these complications usually do not persist in postnatal and early childhood. PMID- 28868783 TI - Seizures and chorioretinal lacunae in an infant. PMID- 28868782 TI - Successful Use of Enzyme Replacement Therapy in Infantile Hypophosphatasia. PMID- 28868784 TI - Direct fitness benefits explain mate preference, but not choice, for similarity in heterozygosity levels. AB - Under sexual selection, mate preferences can evolve for traits advertising fitness benefits. Observed mating patterns (mate choice) are often assumed to represent preference, even though they result from the interaction between preference, sampling strategy and environmental factors. Correlating fitness with mate choice instead of preference will therefore lead to confounded conclusions about the role of preference in sexual selection. Here we show that direct fitness benefits underlie mate preferences for genetic characteristics in a unique experiment on wild great tits. In repeated mate preference tests, both sexes preferred mates that had similar heterozygosity levels to themselves, and not those with which they would optimise offspring heterozygosity. In a subsequent field experiment where we cross fostered offspring, foster parents with more similar heterozygosity levels had higher reproductive success, despite the absence of assortative mating patterns. These results support the idea that selection for preference persists despite constraints on mate choice. PMID- 28868785 TI - Incomplete initial nutation diffusion imaging: An ultrafast, single-scan approach for diffusion mapping. AB - PURPOSE: Diffusion MRI is confounded by the need to acquire at least two images separated by a repetition time, thereby thwarting the detection of rapid dynamic microstructural changes. The issue is exacerbated when diffusivity variations are accompanied by rapid changes in T2 . The purpose of the present study is to accelerate diffusion MRI acquisitions such that both reference and diffusion weighted images necessary for quantitative diffusivity mapping are acquired in a single-shot experiment. METHODS: A general methodology termed incomplete initial nutation diffusion imaging (INDI), capturing two diffusion contrasts in a single shot, is presented. This methodology creates a longitudinal magnetization reservoir that facilitates the successive acquisition of two images separated by only a few milliseconds. The theory behind INDI is presented, followed by proof of-concept studies in water phantom, ex vivo, and in vivo experiments at 16.4 and 9.4 T. RESULTS: Mean diffusivities extracted from INDI were comparable with diffusion tensor imaging and the two-shot isotropic diffusion encoding in the water phantom. In ex vivo mouse brain tissues, as well as in the in vivo mouse brain, mean diffusivities extracted from conventional isotropic diffusion encoding and INDI were in excellent agreement. Simulations for signal-to-noise considerations identified the regimes in which INDI is most beneficial. CONCLUSIONS: The INDI method accelerates diffusion MRI acquisition to single-shot mode, which can be of great importance for mapping dynamic microstructural properties in vivo without T2 bias. Magn Reson Med 79:2198-2204, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28868787 TI - Cytological diagnostic clues in poorly differentiated squamous cell carcinomas of the breast: Streaming arrangement, necrotic background, nucleolar enlargement and cannibalism of cancer cells. AB - OBJECTIVE: Squamous cell carcinoma (SCC) is a rare histological type of breast cancer. The cytological diagnosis of non-keratinising, poorly differentiated SCC is often difficult, and distinguishing it from invasive ductal carcinoma or apocrine carcinoma (AC) is especially challenging. We aimed to define the diagnostic cytological features of poorly differentiated SCC of the breast. METHODS: We studied the cytological findings of poorly differentiated SCC (n=10) and compared them to those of IDC (n=15) and AC (n=14). The following six cytological features were evaluated: streaming arrangement, nucleolar enlargement, dense nuclei, cannibalism, atypical keratinocytes and necrotic background. RESULTS: SCC exhibited significantly higher frequencies of streaming arrangement (70% vs 6.7%, P=.002), nucleolar enlargement (80% vs 27%, P=.02), and necrotic background (80% vs 36%, P=.002) than invasive ductal carcinoma. The detection of two or three of these features yielded a higher sensitivity (80%) and specificity (93%) for the diagnosis of SCC. Streaming arrangement (70% vs 0%, P<.001), cannibalism (60% vs 0%, P=.002), and a necrotic background (80% vs 36%, P=.047) were all significantly more frequent in SCC than in AC. When distinguishing SCC from AC, the presence of two or three of these features yielded a high sensitivity (80%) and specificity (100%). CONCLUSIONS: Cytological features such as a streaming arrangement, a necrotic background, nucleolar enlargement and cannibalism are useful indicators for the diagnosis of SCC of the breast. As such, greater attention should be paid to these morphological features in daily clinical practice. PMID- 28868786 TI - Effect of Formamidinium/Cesium Substitution and PbI2 on the Long-Term Stability of Triple-Cation Perovskites. AB - Altering cation and anion ratios in perovskites has proven an excellent means of tuning the perovskite properties and enhancing the performance. Recently, methylammonium/formamidinium/cesium triple-cation mixed-halide perovskites have demonstrated efficiencies up to 22 %. Similar to the widely explored methylammonium lead halide, excess PbI2 is added to these perovskite films to enhance their performances. The excess PbI2 is known to be beneficial for the performance. However, its impact on stability is less well known. Triple-cation perovskites deploy excess PbI2 up to 8 %. Thus, it is imperative to analyze the role of excess PbI2 in the degradation kinetics. In this study, the amount of PbI2 in the triple-cation perovskite films is varied and the degradation kinetics monitored by X-ray diffraction and optical absorption spectroscopy. The inclusion of excess PbI2 is shown to adversely affect the stability of the material. Faster degradation kinetics are observed for samples with higher PbI2 contents. However, samples with excess PbI2 also showed superior properties such as enhanced grain sizes and better optical absorption. Thus, careful management of the PbI2 quantity is required to obtain better stability and alternative pathways should be explored to achieve better device performance rather than adding excess PbI2 . PMID- 28868788 TI - Constructing arabinofuranosidases for dual arabinoxylan debranching activity. AB - Enzymatic conversion of arabinoxylan requires alpha-L-arabinofuranosidases able to remove alpha-L-arabinofuranosyl residues (alpha-L-Araf) from both mono- and double-substituted D-xylopyranosyl residues (Xylp) in xylan (i.e., AXH-m and AXH d activity). Herein, SthAbf62A (a family GH62 alpha-L-arabinofuranosidase with AXH-m activity) and BadAbf43A (a family GH43 alpha-L-arabinofuranosidase with AXH d3 activity), were fused to create SthAbf62A_BadAbf43A and BadAbf43A_SthAbf62A. Both fusion enzymes displayed dual AXH-m,d and synergistic activity toward native, highly branched wheat arabinoxylan (WAX). When using a customized arabinoxylan substrate comprising mainly alpha-(1 -> 3)-L-Araf and alpha-(1 -> 2) L-Araf substituents attached to disubstituted Xylp (d-2,3-WAX), the specific activity of the fusion enzymes was twice that of enzymes added as separate proteins. Moreover, the SthAbf62A_BadAbf43A fusion removed 83% of all alpha-L Araf from WAX after a 20 hr treatment. 1 H NMR analyses further revealed differences in SthAbf62A_BadAbf43 rate of removal of specific alpha-L-Araf substituents from WAX, where 9.4 times higher activity was observed toward d alpha-(1 -> 3)-L-Araf compared to m-alpha-(1 -> 3)-L-Araf positions. PMID- 28868789 TI - The phenylephrine concentration-response relationship for blood pressure after nasal delivery in children. AB - BACKGROUND: Intranasal phenylephrine is commonly used to vasoconstrict the nasal mucosa, reducing bleeding associated with nasotracheal intubation or endoscopic sinus surgery. There are few data quantifying either absorption pharmacokinetics or phenylephrine concentration effect on blood pressure in children. METHODS: Published observations of plasma concentration and blood pressure changes after phenylephrine nasal administration (0.1 mL kg-1 , 0.25% or 0.5%) in children (n = 52, 2-12 years, 10-40 kg) were pooled with those in adults (23-81 years) given phenylephrine 2.5% (n = 10) and 10% (n = 10) eyedrops. Further pharmacokinetic (PK) data were available from healthy volunteers given oral phenylephrine 10 mg alone, with blood for concentration assay taken at 5, 15, 30, 45 minutes and 1, 2, 3, 6 hours (n = 28). Intravenous time-concentration data were available from four healthy volunteers given phenylephrine 1 mg and who had blood taken for assay on 17 occasions over the subsequent 4 hours. Data were analyzed using an integrated pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed effects models. Allometry, scaled to a 70-kg person, was used for PK size standardization. Effect was described using an EMAX model. RESULTS: A two compartment model was used to fit PK data while an additional compartment, linked by an equilibration half-time (T1/2 keo), was used to describe effect. PK parameter estimates for the nasal formulation were clearance (CL) 160 L h-1 , central volume of distribution (V1) 13.3 L, intercompartment clearance (Q) 25.3 L h-1 , peripheral volume of distribution (V2) 225 L, absorption half-time (Tabs) 6.2 minutes, absorption lag time (Tlag) 1.5 minutes, and bioavailability (F) 0.183. Bioavailability and absorption of the ophthalmic solution were concentration dependent (F 0.13, Tabs 5.5 minutes for 2.5% solution; F 0.15, Tabs 9.6 minutes for 10% solution). Absorption of the oral formulation was slow (Tabs 48 minutes) with poor bioavailability (F 0.0128). The pediatric PD interrogation revealed a baseline mean arterial pressure of 60 mm Hg, a maximum effect (EMAX ) of 25 mm Hg, and an EC50 of 10.3 MUg L-1 . The effect on vasculature was immediate and T1/2 keo was not estimable. CONCLUSION: Absorption of phenylephrine through the nasal mucosa was rapid and similar to the ophthalmic formulation. Bioavailability was also similar to the ophthalmic formulation. The maximum effect (EMAX ) in children was half that in adults (EMAX 50 mm Hg). PMID- 28868791 TI - Predicting hemispheric dominance for language production in healthy individuals using support vector machine. AB - We used a Support Vector Machine (SVM) classifier to assess hemispheric pattern of language dominance of 47 individuals categorized as non-typical for language from their hemispheric functional laterality index (HFLI) measured on a sentence minus word-list production fMRI-BOLD contrast map. The SVM classifier was trained at discriminating between Dominant and Non-Dominant hemispheric language production activation pattern on a group of 250 participants previously identified as Typicals (HFLI strongly leftward). Then, SVM was applied to each hemispheric language activation pattern of 47 non-typical individuals. The results showed that at least one hemisphere (left or right) was found to be Dominant in every, except 3 individuals, indicating that the "dominant" type of functional organization is the most frequent in non-typicals. Specifically, left hemisphere dominance was predicted in all non-typical right-handers (RH) and in 57.4% of non-typical left-handers (LH). When both hemisphere classifications were jointly considered, four types of brain patterns were observed. The most often predicted pattern (51%) was left-dominant (Dominant left-hemisphere and Non Dominant right-hemisphere), followed by right-dominant (23%, Dominant right hemisphere and Non-Dominant left-hemisphere) and co-dominant (19%, 2 Dominant hemispheres) patterns. Co-non-dominant was rare (6%, 2 Non-Dominant hemispheres), but was normal variants of hemispheric specialization. In RH, only left-dominant (72%) and co-dominant patterns were detected, while for LH, all types were found, although with different occurrences. Among the 10 LH with a strong rightward HFLI, 8 had a right-dominant brain pattern. Whole-brain analysis of the right dominant pattern group confirmed that it exhibited a functional organization strictly mirroring that of left-dominant pattern group. Hum Brain Mapp 38:5871 5889, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28868792 TI - Circular interpretation of regression coefficients. AB - The interpretation of the effect of predictors in projected normal regression models is not straight-forward. The main aim of this paper is to make this interpretation easier such that these models can be employed more readily by social scientific researchers. We introduce three new measures: the slope at the inflection point (bc ), average slope (AS) and slope at mean (SAM) that help us assess the marginal effect of a predictor in a Bayesian projected normal regression model. The SAM or AS are preferably used in situations where the data for a specific predictor do not lie close to the inflection point of a circular regression curve. In this case bc is an unstable and extrapolated effect. In addition, we outline how the projected normal regression model allows us to distinguish between an effect on the mean and spread of a circular outcome variable. We call these types of effects location and accuracy effects, respectively. The performance of the three new measures and of the methods to distinguish between location and accuracy effects is investigated in a simulation study. We conclude that the new measures and methods to distinguish between accuracy and location effects work well in situations with a clear location effect. In situations where the location effect is not clearly distinguishable from an accuracy effect not all measures work equally well and we recommend the use of the SAM. PMID- 28868790 TI - Insulin regulation of gluconeogenesis. AB - The coordinated regulation between cellular glucose uptake and endogenous glucose production is indispensable for the maintenance of constant blood glucose concentrations. The liver contributes significantly to this process by altering the levels of hepatic glucose release, through controlling the processes of de novo glucose production (gluconeogenesis) and glycogen breakdown (glycogenolysis). Various nutritional and hormonal stimuli signal to alter hepatic gluconeogenic flux, and suppression of this metabolic pathway during the postprandial state can, to a significant extent, be attributed to insulin. Here, we review some of the molecular mechanisms through which insulin modulates hepatic gluconeogenesis, thus controlling glucose production by the liver to ultimately maintain normoglycemia. Various signaling pathways governed by insulin converge at the level of transcriptional regulation of the key hepatic gluconeogenic genes PCK1 and G6PC, highlighting this as one of the focal mechanisms through which gluconeogenesis is modulated. In individuals with compromised insulin signaling, such as insulin resistance in type 2 diabetes, insulin fails to suppress hepatic gluconeogenesis, even in the fed state; hence, an insight into these insulin-moderated pathways is critical for therapeutic purposes. PMID- 28868794 TI - Canine demodicosis: a retrospective study of a veterinary hospital population in California, USA (2000-2016). AB - BACKGROUND: Demodex spp. are cutaneous mites that cause clinical disease when present in increased numbers. There is an association in some dogs with underlying systemic disease or immunosuppressive medications. HYPOTHESIS/OBJECTIVES: Retrospective study to document breed predisposition, identify any concurrent diseases or underlying immunosuppressive conditions, and to determine the frequency of demodicosis recurrence after treatment completion. ANIMALS: There were 431 dogs with demodicosis presented to a veterinary teaching hospital in California, USA, from 2000 to 2016. METHODS: Inclusion in this study required a diagnosis of demodicosis based on direct demonstration of the mite. Records were reviewed for signalment, disease history, potential underlying aetiologies, diagnosed concurrent diseases, medications and demodicosis treatment. Analyses were performed to evaluate for potential breed predispositions and because of the large number of dogs with allergic dermatoses, analyses for this diagnosis as a disease associated with demodicosis was also performed. E-mailed surveys and follow-up telephone calls were used to assess for information about disease recurrence. RESULTS: The pit bull terrier group and West Highland white terrier, based on calculated odds ratio, were breeds predisposed to developing demodicosis. For dogs with demodicosis, allergic dermatoses was an associated disease. Relapse or recurrence of disease after treatment was uncommon, affecting 11% of the dogs with long-term follow-up. CONCLUSIONS/CLINICAL IMPORTANCE: This study identified, in dogs attending the institution based in California, USA, breed predilections for canine demodicosis and associated concomitant diseases. It also revealed a low occurrence of disease relapse, recurrence or persistence. PMID- 28868793 TI - Chronic steroid-response pancytopenia and increased bone density due to thromboxane synthase deficiency. AB - Diagnosis of bone marrow failure (BMF) disorders is challenging but essential for optimal patient management. Here, we report a young adult from nonconsanguineous parents with progressive pancytopenia since childhood, bone pain, increased bone density, and haphazard ossification replacing hematopoiesis within the bone marrow. Sequencing revealed two novel biallelic variants of unknown significance within the thromboxane A synthase gene, TBXAS1 (c.266T > C; c.989T > C), bioinformatically predicted to disrupt the protein. TBXAS1 mutations result in Ghosal hematodiaphyseal dysplasia (OMIM 231095), the autosomal recessive syndrome associated with abnormal bone structure and BMF. Identification of the genetic defect prompted steroid therapy leading to resolution of symptoms. PMID- 28868795 TI - Ultra-Low Doses of Naltrexone Enhance the Antiallodynic Effect of Pregabalin or Gabapentin in Neuropathic Rats. AB - Preclinical Research Treatment of neuropathic pain is an area of largely unmet medical need. Pregabalin and gabapentin are anticonvulsants widely used for the treatment of neuropathic pain. Unfortunately, these drugs are only effective in 50-60% of the treated patients. In addition, both drugs have substantial side effects. Several studies have reported that ultralow doses of opioid receptor antagonists can induce analgesia and enhance the analgesic effect of opioids in rodents and humans. The objective of the present study was to assess the antiallodynic synergistic interaction between gabapentinoids and naltrexone in rats. Oral administration of pregabalin (ED50 = 2.79 +/- 0.16 mg/kg) or gabapentin (ED50 = 21.04 +/- 2.87 mg/kg) as well as intrathecal naltrexone (ED50 = 0.11 +/- 0.02 ng) reduced in a dose-dependent manner tactile allodynia in rats. Maximal antiallodynic effects (~100%) were reached with 30 mg/kg of pregabalin, 300 mg/kg of gabapentin or 0.5 ng of naltrexone. Co-administration of pregabalin or gabapentin and naltrexone in a fixed-dose ratio (1:1) remarkably reduced spinal nerve ligation-induced tactile allodynia showing a synergistic interaction. The data indicate that combinations of pregabalin or gabapentin and ultra-low doses of naltrexone are able to reduce tactile allodynia in neuropathic rats with lower doses that those used when drugs are given individually and with an improved side effects profile. Drug Dev Res 78 : 371-380, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28868797 TI - Effect of blood contamination on the compressive strength of three calcium silicate-based cements. AB - The aim of this study was to investigate the effect of human blood exposure on the compressive strength of various calcium silicate-based cements. Two hundred and eighty-eight customised cylindrical moulds were randomly divided into three groups according to material used: ProRoot MTA, Biodentine or CEM cement (n = 96). Each group was divided into two subgroups according to exposure conditions: PBS or blood. Then, the compressive strength of the specimens was measured after 6 h, 24 h, 72 h and 7 days. The compressive strength of CEM cement could not be measured after 6 and 24? h regardless of the exposure conditions nor could the compressive strength of 6 h blood-exposed ProRoot MTA. The compressive strength of blood-exposed ProRoot MTA was only significantly lower after 6 h, but no difference was seen at other time intervals. Blood exposed did adversely affected the compressive strength of Biodentine. The compressive strength of all groups significantly increased over time (P < 0.005). PMID- 28868796 TI - IgE autoreactivity in bullous pemphigoid: eosinophils and mast cells as major targets of pathogenic immune reactants. AB - BACKGROUND: Bullous pemphigoid (BP) is an autoimmune disease characterized by tense blisters that are usually preceded by urticarial eruptions. Affected patients exhibit IgG and/or IgE autoantibodies against BP180 and/or BP230. Their relative importance in disease pathogenesis has not been fully elucidated. OBJECTIVES: The aim of this study was to provide a better characterization of the circulating and tissue-resident IgE in patients with BP at the serological, structural and functional levels. METHODS: Sera (n = 19) and skin (n = 33) from patients with BP were analysed via enzyme-linked immunosorbent assay (ELISA) and immunofluorescence, respectively. RESULTS: The results obtained show that many patients with BP exhibit elevated IgE levels in the serum and in the skin. In the skin, it is very rarely and only sparsely found along the basement membrane zone, but is prominently present on mast cells and eosinophils. At least a portion of these IgE antibodies are BP-specific, as evidenced by serum ELISA and by the colocalization of BP180 and FcepsilonRI-bound IgE on mast cells and/or eosinophils. An important role of these immune reactants can be inferred from our additional finding that cross-linking of IgE, derived from BP sera, on FcepsilonRI-expressing rat basophils with BP180 results in robust degranulation of these cells. CONCLUSIONS: We propose the existence of a disease pathway alternative to IgG and complement that may well be responsible for some of the clinical features of this autoimmune disease. PMID- 28868799 TI - Low mitochondrial diversity in native Italian pig breeds is consistent with the occurrence of strong population bottlenecks. PMID- 28868798 TI - Feeding frequency in infancy and dental caries in childhood: a prospective cohort study. AB - OBJECTIVES: Feeding patterns in infancy are plausible contributors to dental caries later in childhood, yet relatively few cohort studies have examined potential dietary risk factors at this age. This study aimed to investigate the associations between feeding frequency at age 12 months and caries prevalence at age 3 years. METHODS: In this prospective birth cohort of 345 Brazilian children, all foods and drinks consumed at age 12 months, including bottle-use and breastfeeding, were recorded using two 24-hour infant dietary recalls with mothers. The prevalence of early childhood caries (ECC) and severe ECC (S-ECC) at age 38 months were compared in groups defined according to 12-month feeding frequency, using regression models to adjust for sociodemographic characteristics and total carbohydrate intake. RESULTS: Independent of other variables, compared with children with infrequent bottle-use and breastfeeding at 12 months, at 38 months the ECC prevalence was 1.8-times higher in children breastfed more than three times/day (P = 0.001), 1.4-times higher in children bottle-fed more than three times/day (P = 0.07) and 1.5-times higher with combined high frequency of bottle and breastfeeding together (P = 0.04), but the association with consumption of other foods or drinks more than five times/day [risk ratio (RR) = 1.2; P = 0.10] was not statistically significant. Prevalence of S-ECC was significantly associated with frequent breastfeeding (RR = 2.4; P < 0.001) and with greater frequency of consumption of other foods or drinks (RR = 1.7, P = 0.001). CONCLUSIONS: High-frequency feeding in late infancy, including both bottle use and breastfeeding, were positively associated with dental caries in early childhood, suggesting possible early-life targets for caries prevention. PMID- 28868800 TI - Clinical characteristics of laryngeal versus nonlaryngeal amyloidosis. AB - OBJECTIVES/HYPOTHESIS: Amyloidosis represents a heterogeneous group of disorders marked by abnormal protein formation and deposition. Laryngeal amyloidosis is rare and classically thought to remain isolated with little risk of systemic involvement or associated malignancy. This study sought to further characterize differences in clinical characteristics between patients with laryngeal and nonlaryngeal amyloidosis. STUDY DESIGN: Retrospective case-control study. METHODS: The Stanford Translational Research Integrated Database Environment was searched to identify patients with biopsy-confirmed laryngeal amyloidosis and patients with amyloidosis without laryngeal involvement on endoscopy. Mann Whitney U and chi2 tests were used for statistical analysis. RESULTS: Of 865 patients treated for amyloidosis between 1996 and 2016, 22 (2.5%) patients with biopsy-proven laryngeal amyloidosis were identified. An additional 22 patients with amyloidosis of a different organ and negative laryngoscopy-and therefore without laryngeal amyloidosis-were identified as controls. Compared to these controls with nonlaryngeal amyloidosis, patients with laryngeal amyloidosis were younger (mean age 52.8 years vs. 68.4 years, P < .0006), and 18% had additional organ involvement. Immunoglobulin light-chain amyloidosis was the most common subtype in both groups of patients. Eighty-six percent of patients with laryngeal amyloidosis required surgical excision, and of these patients, over 30% required multiple excisions. CONCLUSIONS: There is a significant rate (18%) of multiorgan involvement in patients with laryngeal amyloidosis, which contradicts conventional concepts that this is an isolated disorder. This finding could have a significant impact on the evaluation and management of patients with laryngeal amyloidosis. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:670-674, 2018. PMID- 28868801 TI - Exciting news about the 2016 Impact Factor and JOPM performance. PMID- 28868802 TI - Case of lymph node primary perivascular epithelioid cell tumor associated with leukoderma. PMID- 28868803 TI - Epidemiology of contact lens-induced infiltrates: an updated review. AB - Corneal infiltrative events (CIEs) are well established as a risk associated with soft contact lens wear. The incidence of symptomatic CIEs during extended soft lens wear ranges from 2.5 to six per cent; when asymptomatic CIEs are included, the incidence can be as high as 20-25 per cent. In daily soft lens wear, the annual incidence of symptomatic CIEs is about three per cent. There are various accepted methods of categorising CIEs, and a scoring system based on clinical signs and symptoms is a good approach to grade severity. Lens-related risk factors include extended wear, silicone hydrogel material, the use of multipurpose solutions, bacterial bioburden and reusable lenses. Recent studies report that daily disposable lenses reduce the risk of CIEs. PMID- 28868805 TI - Formation of Palladium eta2 -Bound Chalcogenoketones across a Pd+ -C- Bond. AB - A series of chalcogen analogues encompassing a ketone and chalcogenoketones [{PC(=E)P}Pd(PMe3 )] (E=O, S, Se, Te) was generated from a nucleophilic palladium carbene compound, [{PC(sp2 )P}Pd(PMe3 )] ([PC(sp3 )HP]=bis[2 (diisopropylphosphino)-phenyl]methyl, iPr2 P-C6 H4 -CH-C6 H4 -PiPr2 ). The thio-, seleno-, and telluroketone were all synthesized by means of an atom transfer from the respective chalcogens. The ketone analogue, however, required the use of nitrobenzene or nitrosobenzene as the oxygen-atom transfer agent. PMID- 28868804 TI - Prevalence and socioeconomic characteristics of alcohol disorders among men and women in the Eastern Cape Province, South Africa. AB - There is growing concern about alcohol problems in low- and middle-income countries. More research is required, particularly among the younger generation. The aim of this study was to investigate the prevalence of alcohol disorders and associated socioeconomic characteristics among young men and women living in the Eastern Cape Province, South Africa. This was a cross-sectional population-based study of 977 participants (52% male and 48% female) aged 18-40, the majority of whom lived in low-income areas. Data collection was carried out in 2012 by trained fieldworkers. The Mini International Neuropsychiatric Interview (DSM-IV) was used to investigate the prevalence of alcohol dependence (increased tolerance to alcohol, failed attempt to cut down, risk of physical and mental effects) and alcohol abuse (harmful use, consistent intoxication, risk behaviour, physically hazardous, social problems). A high 12-month prevalence of alcohol dependence was found (26.5% in total; 39.0% among men and 19.1% among women) as well as of alcohol abuse (9% in total; 19.0% among men and 6.0% among women). Few socioeconomic differences emerged among the men, except older men (OR 1.94, CI 1.11-3.42) and those supported by social grants (OR 2.28, CI 1.06-4.93), who presented higher odd ratios for alcohol dependence than the reference groups. Among the women, more differences emerged: women who were widowed/single (OR 2.35, CI 1.20-4.62), had no education (OR 3.41, CI 1.04-11.21), had a low income (OR 3.26, CI 1.55-6.80) and had no social support from friends when ill presented higher odd ratios (OR 1.73, CI 1.07-2.80). In the adjusted model, marital status and low income remained statistically significant. With regard to alcohol abuse, fewer socioeconomic differences emerged. Interventions need to address the early onset of alcohol misuse in order to meet both current needs and long-standing mental and physical illness. PMID- 28868806 TI - Validity of maximum isometric tongue pressure as a screening test for physical frailty: Cross-sectional study of Japanese community-dwelling older adults. AB - AIM: Maximum isometric tongue pressure (MIP) seems to have a diagnostic value for oral phase dysphagia. The present study aimed to examine the association between MIP and frailty, and to assess the screening validity of MIP for physical frailty. METHODS: We carried out a cross-sectional study, and enrolled participants aged >=60 years from Japanese national medical check-ups in 2015 and 2016. The Fried frailty phenotype model was used. We analyzed odds ratios (OR) and 95% confidence intervals (CI) of physical frailty using one standard deviation increments of tongue pressure. Receiver operating characteristic curves were obtained to predict physical frailty using MIP values. RESULTS: Out of 1603 participants, 968 were categorized as non-frail, 605 as pre-frail and 30 as frail. In logistic regression analysis, one standard deviation increment of MIP significantly differentiated frail and pre-frail: the OR for frail with one standard deviation increment in MIP was 0.37 (95% CI 0.26-0.54, P < 0.001), and the OR for pre-frail was 0.63 (95% CI 0.57-0.70, P < 0.001). The area under the receiver operating characteristic curve for predicting frailty with MIP score was as high as 0.776 (95% CI 0.689-0.862). A point of MIP 35 kPa had a sensitivity of 90.0%, specificity of 40.4%, a positive likelihood ratio of 1.5 and a negative likelihood ratio of 0.2 for predicting frailty. CONCLUSIONS: MIP performance is independently associated with frailty. MIP also can be used as a simple screening tool for frailty. Geriatr Gerontol Int 2018; 18: 240-249. PMID- 28868807 TI - Correlates of concealment behavior among couples coping with cancer: Actor partner model. AB - OBJECTIVES: Contextual self-concealment in the psychooncology literature has been found to be associated with elevated distress. The current study aimed to understand the dyadic relationships of an individual's perception of spousal support and dispositional perspective-taking with own and partner's levels of self-concealment behavior, among couples coping with cancer. METHODS: A subsample of 61 heterosexual couples coping with cancer was taken from a large-scale cross sectional study. Patients and their spouses independently completed measures of perceived spousal support, perspective-taking, and contextual self-concealment. Dyadic data were analyzed by using the actor-partner interdependence model both for couples in which the woman was the patient and also for couples in which the man was the patient. RESULTS: Perceived spousal support negatively predicted contextual self-concealment, regardless of gender and role. Implications of perspective-taking for concealment behavior were dependent on role and gender. A female patient's perspective-taking was associated with a reduction in her own and her spouse's concealment behavior. A male spouse's perspective-taking was associated with an increase in his own and his spouse's concealment behavior. A female spouse's perspective-taking negatively predicted patient's concealment behavior, but not her own. CONCLUSIONS: Findings stress the important roles played by spousal support and perspective-taking in communication patterns between couples affected by cancer. Although the perception of support from one's spouse seems to reduce the need to conceal cancer-related issues, interventions that focus on couples' communication should address the differential implications of perspective-taking, as they can lead to either more or less self-concealment among couples, depending on role and gender. PMID- 28868808 TI - Biphasic Synergistic Gel Materials with Switchable Mechanics and Self-Healing Capacity. AB - A fabrication strategy for biphasic gels is reported, which incorporates high internal-phase emulsions. Closely packed micro-inclusions within the elastic hydrogel matrix greatly improve the mechanical properties of the materials. The materials exhibit excellent switchable mechanics and shape-memory performance because of the switchable micro- inclusions that are incorporated into the hydrogel matrix. The produced materials demonstrated a self-healing capacity that originates from the noncovalent effect of the biphasic heteronetwork. The aforementioned characteristics suggest that the biphasic gels may serve as ideal composite gel materials with validity in a variety of applications, such as soft actuators, flexible devices, and biological materials. PMID- 28868809 TI - Color Tuning in Garnet Oxides: The Role of Tetrahedral Coordination Geometry for 3 d Metal Ions and Ligand-Metal Charge Transfer (Band-Gap Manipulation). AB - We explored garnet-structured oxide materials containing 3d transition-metal ions (e.g., Co2+ , Ni2+ , Cu2+ , and Fe3+ ) for the development of new inorganic colored materials. For this purpose, we synthesized new garnets, Ca3 Sb2 Ga2 ZnO12 (I) and Ca3 Sb2 Fe2 ZnO12 (II), that were isostructural with Ca3 Te2 Zn3 O12 . Substitution of Co2+ , Ni2+ , and Cu2+ at the tetrahedral Zn2+ sites in I and II gave rise to brilliantly colored materials (different shades of blue, green, turquoise, and red). The materials were characterized by optical absorption spectroscopy and CIE chromaticity diagrams. The Fe3+ -containing oxides showed band-gap narrowing (owing to strong sp-d exchange interactions between Zn2+ and the transition-metal ion), and this tuned the color of these materials uniquely. We also characterized the color and optical absorption properties of Ca3 Te2 Zn3-x Cox O12 (0=1 month after ECS and for >=6 months after PES. RESULTS: At 5 years follow-up, no significant differences were found in TVF (ECS 24% vs. PES 29%, risk difference 95% confidence interval (RDCI) -17.3% to 7.4%). Between 2 and 5 years after the index procedure, low numbers of TVF were observed in ECS compared with PES (ECS 4% vs. PES 16%, RDCI 20.8% to -2.3%). There was no definite stent thrombosis in ECS compared with four patients in the PES group. CONCLUSION: This is the first randomized study providing very long-term clinical efficacy and safety of the ECS in lesions carrying a high risk of restenosis. At 5 years follow-up, TVF rates in ECS group are numerically lower compared with PES due to an increase of events between 2 and 5 years after the index procedure. PMID- 28868811 TI - The distribution of total vitamin B12, holotranscobalamin, and the active vitamin B12 fraction in the first 5 weeks postpartum. AB - INTRODUCTION: Total vitamin B12 levels decrease significantly during pregnancy and recover to normal values within 8-week postpartum. Holotranscobalamin (holoTC) reflects the active part of vitamin B12 and has been shown to remain constant during pregnancy and postpartum. A mechanism of redistribution of vitamin B12 is suggested, with a shift toward holoTC if there is insufficient total vitamin B12 available. Our objective was to examine vitamin B12 deficiency and the active vitamin B12 fraction in postpartum women. METHODS: Total vitamin B12 and holoTC were measured in 171 women within 48 hours (T0) and at 5 weeks (T5) postpartum. Vitamin B12 deficiency was defined as total vitamin B12 < 180 pmol/L or holoTC <32 pmol/L. The active vitamin B12 fraction was defined as holoTC/total vitamin B12. RESULTS: Without intervention, vitamin B12 deficiency based on both serum total vitamin B12 and holoTC changed from 75% and 60%, to respectively 10% and 6% at T5. The fraction of active vitamin B12 was significant higher in vitamin B12 deficient women at both time points and across time (P < .0001 and P = .002). A high fraction of active vitamin B12 was only present in women with total vitamin B12 deficiency at T0. At T5, no high vitamin B12 fraction was found. CONCLUSION: The changes in total vitamin B12 levels seem to be based on a physiological changes rather than vitamin B12 deficiency. The results of this study confirm the hypothesis that a shift toward the metabolic active vitamin B12 (holoTC) occurs in women with insufficient available total vitamin B12. PMID- 28868812 TI - Application of three hygrometers under different skin conditions in dogs: dry, moist and haired skin. AB - BACKGROUND: Hydration is one parameter of skin barrier function. The Skicon 200EX(r) and Corneometer CM825(r) are hygrometers used to measure skin hydration in humans based on different measurement methods. The ASA-MX3(r) is a hygrometer used to obtain measurements at haired skin sites in humans. HYPOTHESIS/OBJECTIVES: To validate three hygrometers to measure skin dryness in dogs. ANIMALS: Six clinically normal research dogs. METHODS: In vivo evaluation of three hygrometers for three different skin types was performed. Measurement of hydration was performed at five different regional sites. Dry and moist skin were induced by treatment with a sorbent and petrolatum, respectively, and measurements were collected for 120 min. Skin sites with three different hair lengths were evaluated to determine whether hair would interfere with hydration measurements. RESULTS: All three hygrometers obtained measurements at the nonhaired skin sites, except the ASA-MX3(r) hygrometer at the ear site. At the dry skin sites the Skicon-200EX(r) hygrometer detected a significant decrease of water content for longer than the other devices. At the moist skin sites the Corneometer CM825(r) and ASA-MX3(r) hygrometers showed a significant increase in water content. The ASA-MX3(r) hygrometer was the only device that could obtain measurements at sites with hair. CONCLUSIONS AND CLINICAL IMPORTANCE: The Skicon 200EX(r) hygrometer was the most sensitive for detecting skin dryness, whereas the Corneometer CM825(r) and ASA-MX3(r) hygrometers detected an emollient effect. Only the ASA-MX3(r) could provide measurements at the haired sites. This study may assist in the selection of a hygrometer based on the purpose of use. PMID- 28868813 TI - Insomnia in nursing students and related factors: A cross-sectional study. AB - AIM: The aim of this study is to determine the factors affecting insomnia in nursing students. METHODS: This study was conducted with 379 nursing students, studying at a university in western Anatolia/Turkey between 2014 and 2015 as a descriptive and cross-sectional analytic study. Data of the survey were collected using the Personal Inquiry Form, Pittsburgh Sleep Quality Index, Insomnia Severity Index, Trait Anxiety Inventory and the Beck Depression Inventory, and a self-administered questionnaire. RESULTS: The Insomnia Severity Index score for the students is 11.51 +/- 5.04 on average. It was found that as anxiety and depression increased, the Insomnia Severity Index score for the students also increased and there was a weak positive correlation. Also, a moderate positive correlation between sleep quality and insomnia severity was found. Significant correlations were found between some of the socio-demographic characteristics (lower socio-economic situation, irregular bedtime, and smoking) and insomnia, sleep quality, anxiety, and depression. CONCLUSION: Anxiety, depression, irregular bedtime, and lower socio-economic situation are factors that make falling asleep difficult. PMID- 28868814 TI - Exposure to secondhand smoke, exclusive breastfeeding and infant adiposity at age 5 months in the Healthy Start study. AB - BACKGROUND: Infant adiposity may be influenced by several environmental risk factors, but few studies have explored these interactions. OBJECTIVE: To examine the interaction between exposure to secondhand smoke and breastfeeding exclusivity on adiposity at age 5 months. METHODS: We studied 813 mother offspring pairs from the longitudinal Healthy Start study. Fat mass and fat-free mass were measured by air displacement plethysmography. Linear regression analyses were used to estimate the association between household smokers (none, any) with fat mass, fat-free mass, percent fat mass, weight-for-age z-score, weight-for-length z-score and BMI-for-age z-score as separate outcomes. Interaction terms between household smokers and breastfeeding exclusivity (<5 months, >=5 months) were added to separate models. RESULTS: The combination of exposure to secondhand smoke and a lack of exclusive breastfeeding was associated with increased adiposity at age 5 months. For example, within the not exclusively breastfed strata, exposure to secondhand smoke was associated with increased fat mass (0.1 kg; 95% CI: 0.0-0.2; P = 0.05). Conversely, within the exclusively breastfed strata, there was virtually no difference in fat mass between exposed and non-exposed infants (coefficient: -0.1; 95% CI: -0.3-0.1; P = 0.25). CONCLUSIONS: Our findings may inform new public health strategies with potential relevance for both smoking cessation and obesity prevention. PMID- 28868815 TI - The Role of the Urologist in Men's Health. PMID- 28868816 TI - Hypertension and Male Fertility. AB - As the age of paternity rises in the developed world, issues of chronic disease may affect prospective fathers. Given the high prevalence of hypertension, researchers have begun to explore the relationship between hypertensive disease and male fertility. The current literature suggests an association between hypertension and semen quality. The use of various antihypertensive medications has also been linked to impaired semen parameters, making it difficult to discern whether the association exists with hypertension or its treatment. Further investigation is warranted to determine whether the observed associations are causal. PMID- 28868817 TI - Incidence of De Novo Erectile Dysfunction after Urethroplasty: A Prospective Observational Study. AB - PURPOSE: De novo erectile dysfunction (ED) is a known complication after urethroplasty. Incidence and natural history of de novo ED after urethroplasty is underreported. We assessed the incidence of de novo ED after urethroplasty. MATERIALS AND METHODS: Consecutive consenting urethroplasty (n=48) patients aged 21 to 50 years from February 2014 to July 2016 with normal preoperative erectile function as determined by an International Index of Erectile Function-5 (IIEF-5) score >=22 were included and interviewed at 3, 6, and 12 months. RESULTS: In patients with anterior stricture (n=40), substitution urethroplasty (SU) was performed in 22 patients (55.0%) and end-to-end anastomotic urethroplasty (EEAU) in 18 patients (45.0%). Their mean IIEF-5 score was 24.15+/-0.8 preoperatively, 20.10+/-4.2 at 3 months (p<0.001), 22.70+/-2.3 at 6 months (p=0.0012), and 23.70+/-1.7 at 12 months (p=0.03), showing a recovery of erectile function with time. All 8 patients with pelvic fracture urethral injury (PFUI) underwent progressive perineal urethroplasty. Their mean IIEF score was 24.0+/-1.2 preoperatively, 18.8+/-5.4 at 3 months (p=0.002), 20.9+/-3.5 at 6 months (p=0.37), and 22.0+/-1.5 at 12 months (p=0.427). The incidence of ED was similar at 1 year postoperatively between patients with anterior stricture and PFUI and between patients who underwent EEAU or SU for anterior stricture. CONCLUSIONS: Incidence of ED at 1 year after PFUI is similar to that after surgery for anterior stricture in patients with normal preoperative erectile function. Among the cases of anterior stricture, recovery was better with SU at 3 months and was similar between SU and EEAU at 1 year. PMID- 28868818 TI - Evaluation of Impact of Voiding Posture on Uroflowmetry Parameters in Men. AB - PURPOSE: To evaluate the impact of voiding position on uroflowmetry parameters and to assess its potential clinical implications. MATERIALS AND METHODS: We conducted a prospective study from 2013 to 2015 and included men between 18 and 77 years old who were either healthy volunteers with an International Prostate Symptom Score (IPSS) <=7 or men with benign prostate enlargement that were on alpha-blocker medication and had an IPSS <10. Participants underwent uroflowmetry and post-void residual urine (PVRU) measurements twice, once in a sitting position and once in a standing position. The participants were divided into 4 groups based on age (35 years or younger, 36 to 50 years, 51 to 60 years, and older than 60 years). RESULTS: A total of 740 men with a mean age of 40.35 years were evaluated. There was no significant difference in uroflowmetry parameters until the age of 50 years between the voiding positions. However, in those older than 50 years, PVRU volume was significantly lower in the sitting position than the standing position, whereas voiding time was significantly higher in the sitting position than the standing position. Other uroflowmetry parameters, including maximal and average urine flow rates, were non-significant. CONCLUSIONS: The voiding position plays an important role in the uroflowmetry parameters of elderly men. Voiding in the sitting position was found to be optimal for elderly men, whereas the role of the voiding position in healthy young men could not be determined. More research is needed to further study this issue. PMID- 28868819 TI - Erectile Dysfunction in Men with and without Lower Urinary Tract Symptoms in Nigeria. AB - PURPOSE: Much attention has been focused in recent decades on the effects of erectile dysfunction (ED) secondary to lower urinary tract symptoms (LUTS), potentially underestimating its effects in men without LUTS. This study aimed to compare the prevalence and predictors of ED in men with and without LUTS. MATERIALS AND METHODS: The International Index of Erectile Function questionnaire was administered to 303 patients between January 2014 and June 2016. Within this sample, 147 patients with LUTS (cases) were compared to 156 men without LUTS who were matched for age, level of education, and occupation (controls). RESULTS: The mean age was 66.03+/-9.64 years and 65.78+/-8.61 years for the cases and controls, respectively. The prevalence of ED was 64.6% and 73.7% (odds ratio [OR], 1.54; 95% confidence interval [CI], 0.94~2.51) in the case cohort and controls, respectively (p=0.086). There was no difference in the prevalence of impaired erectile function (p=0.067), impaired orgasmic function (p=0.108), impaired sexual desire (p=0.291), impaired intercourse satisfaction (p=0.869), or impaired overall satisfaction (p=0.191). Multivariate logistic regression analysis showed that being currently employed was a significant predictor of ED both in men with LUTS (OR, 8.08; 95% CI, 1.51~9.27; p=0.004) and in men without LUTS (OR, 7.00; 95% CI, 1.49~14.51; p=0.008). Being married only predicted for impaired EF in men without LUTS (OR, 6.34; 95% CI, 1.40~15.20; p<0.05). CONCLUSIONS: ED was not found to be more prevalent in men with LUTS. Being employed was a predictor of ED in both groups of men, while being married was also a predictor of ED in men without LUTS. PMID- 28868820 TI - Loupe-Assisted Vasovasostomy Using a Prolene Stent: A Simpler Vasectomy Reversal Technique. AB - PURPOSE: Microsurgical vasovasostomy is associated with high patency and pregnancy rates, but is difficult and requires significant effort and time to learn. Therefore, we assessed a simplified loupe-assisted vasovasostomy method using a Prolene stent. MATERIALS AND METHODS: The medical records of 82 patients who underwent loupe-assisted vasovasostomy with a Prolene stent by a single surgeon between January 2004 and December 2015 were reviewed. The association between the vasal obstructive interval (VOI) and the success rate was evaluated. RESULTS: The average age at the time of vasovasostomy was 39.8 years (range, 29~57 years). The mean VOI was 6.6 years (range, 1~19 years). The mean operation time was 87.0 minutes (range, 55.0~140.0 minutes). The overall patency and natural pregnancy rates were 90.2% and 45.1%, respectively. The success rate decreased as time after vasectomy increased (odds ratio, 0.869; 95% confidence interval, 0.760~0.993; p=0.039). The cases were divided into 2 groups according to the mean VOI: group A (>7 years) and group B (<=7 years), with 31 cases (37.8%) and 51 cases (62.2%), respectively. The patency and pregnancy rates of group A were 80.6% and 51.6%, respectively, while those of group B were 96.1% and 41.2%, respectively. CONCLUSIONS: Loupe-assisted vasovasostomy using a Prolene stent is a safe and effective method. PMID- 28868821 TI - Paraffin Granuloma Associated with Buried Glans Penis-Induced Sexual and Voiding Dysfunction. AB - A paraffinoma is a type of inflammatory lipogranuloma that develops after the injection of an artificial mineral oil, such as paraffin or silicon, into the foreskin or the subcutaneous tissue of the penis for the purpose of penis enlargement, cosmetics, or prosthesis. The authors experienced a case of macro paraffinoma associated with sexual dysfunction, voiding dysfunction, and pain caused by a buried glans penis after a paraffin injection for penis enlargement that had been performed 35 years previously. Herein, this case is presented with a literature review. PMID- 28868823 TI - Depression and Mortality in Type 2 Diabetes Mellitus. PMID- 28868822 TI - The Effectiveness of Green Tea or Green Tea Extract on Insulin Resistance and Glycemic Control in Type 2 Diabetes Mellitus: A Meta-Analysis. AB - Green tea or green tea extract (GT/GTE) has been demonstrated to reduce insulin resistance and improve glycemic control. However, evidence for this health beneficial effect is inconsistent. This systematic review evaluated the effect of GT/GTE on insulin resistance and glycemic control in people with pre diabetes/type 2 diabetes mellitus (T2DM). Ovid MEDLINE, Embase, AMED, Web of Science, and the Cochrane Library were searched up to April 2017 for randomised controlled trials of participants with pre-diabetes or T2DM, where the intervention was GT/GTE. Meta-analysis was performed to assess the standardised mean difference (SMD) in biomarkers of insulin resistance and glycemic control between GT/GTE and placebo groups. Six studies (n=382) were pooled into random effects meta-analysis. Overall, no differences were found between GT/GTE and the placebo for glycosylated hemoglobin (HbA1c: SMD, -0.32; 95% confidence interval [CI], -0.86 to 0.23), homeostatic model assessment for insulin resistance (HOMA IR: SMD, 0.10; 95% CI, -0.17 to 0.38), fasting insulin (SMD, -0.25; 95% CI, -0.64 to 0.15), and fasting glucose (SMD, -0.10; 95% CI, -0.50 to 0.30). No evidence support the consumption of GT/GTE could reduce the levels of HbA1c, HOMA-IR, fasting insulin, or fasting glucose in people with pre-diabetes/T2DM. However, the studies included were small and of varying quality. PMID- 28868824 TI - Comparison of Glucose Area Under the Curve Measured Using Minimally Invasive Interstitial Fluid Extraction Technology with Continuous Glucose Monitoring System in Diabetic Patients. AB - BACKGROUND: Continuous glucose monitoring (CGM) is reported to be a useful technique, but difficult or inconvenient for some patients and institutions. We are developing a glucose area under the curve (AUC) monitoring system without blood sampling using a minimally invasive interstitial fluid extraction technology (MIET). Here we evaluated the accuracy of interstitial fluid glucose (IG) AUC measured by MIET in patients with diabetes for an extended time interval and the potency of detecting hyperglycemia using CGM data as a reference. METHODS: Thirty-eight inpatients with diabetes undergoing CGM were enrolled. MIET comprised a pretreatment step using a plastic microneedle array and glucose accumulation step with a hydrogel patch, which was placed on two sites from 9:00 AM to 5:00 PM or from 10:00 PM to 6:00 AM. IG AUC was calculated by accumulated glucose extracted by hydrogel patches using sodium ion as standard. RESULTS: A significant correlation was observed between the predicted AUC by MIET and CGM in daytime (r=0.76) and nighttime (r=0.82). The optimal cutoff for the IG AUC value of MIET to predict hyperglycemia over 200 mg/dL measured by CGM for 8 hours was 1,067.3 mg.hr/dL with 88.2% sensitivity and 81.5% specificity. CONCLUSION: We showed that 8-hour IG AUC levels using MIET were valuable in estimating the blood glucose AUC without blood sampling. The results also supported the concept of using this technique for evaluating glucose excursion and for screening hyperglycemia during 8 hours in patients with diabetes at any time of day. PMID- 28868825 TI - Effects of High-Dose alpha-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea. AB - BACKGROUND: Diabetic cardiac autonomic neuropathy (CAN) is one of the important complications of diabetes. It is characterized by reduced heart rate variability (HRV). METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, 75 patients were randomly assigned to one of two groups. One group (n=41) received alpha-lipoic acid (ALA) at an oral dose of 600 mg/day for the first 12 weeks and then 1,200 mg/day for the next 12 weeks. The other group (n=34) received placebo treatment for 24 weeks. CAN was assessed by measuring HRVs in people with diabetes. RESULTS: Most of the baseline measures for HRVs were similar between the ALA and placebo groups. Although there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial, we found a positive tendency in some of the HRV parameters of the ALA group. The standard deviations of normal-to-normal RR intervals in the standing position increased by 1.87 ms in the ALA group but decreased by -3.97 ms in the placebo group (P=0.06). The power spectrum of the low frequency (LF) band in the standing position increased by 15.77 ms2 in the ALA group, whereas it declined by -15.04 ms2 in the placebo group (P=0.08). The high frequency/LF ratio in the upright position increased by 0.35 in the ALA group, whereas it declined by -0.42 in the placebo group (P=0.06). There were no differences between the two groups regarding rates of adverse events. CONCLUSION: Although a slight improvement tendency was seen in HRV in the ALA group, there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial. However, the high oral dose of ALA was well tolerated. PMID- 28868826 TI - Determinants of Long-Term Durable Glycemic Control in New-Onset Type 2 Diabetes Mellitus. AB - BACKGROUND: Long-term durable glycemic control is a difficult goal in the management of type 2 diabetes mellitus (T2DM). We evaluated the factors associated with durable glycemic control in a real clinical setting. METHODS: We retrospectively reviewed the medical records of 194 new-onset, drug-naive patients with T2DM who were diagnosed between January 2011 and March 2013, and were followed up for >2 years. Glycemic durability was defined as the maintenance of optimal glycemic control (glycosylated hemoglobin [HbA1c] <7.0%) for 2 years without substitution or adding other glucose-lowering agents. Clinical factors and glycemic markers associated with glycemic durability were compared between two groups: a durability group and a non-durability group. RESULTS: Patients in the durability group had a higher baseline body mass index (26.1 kg/m2 vs. 24.9 kg/m2) and lower HbA1c (8.6% vs. 9.7%) than the non-durability group. The initial choice of glucose-lowering agents was similar in both groups, except for insulin and sulfonylureas, which were more frequently prescribed in the non-durability group. In multiple logistic regression analyses, higher levels of education, physical activity, and homeostasis model assessment of beta-cell function (HOMA beta) were associated with glycemic durability. Notably, lower HbA1c (<7.0%) at baseline and first follow-up were significantly associated with glycemic durability (adjusted odds ratio [OR], 7.48; 95% confidence interval [CI], 2.51 to 22.3) (adjusted OR, 9.27; 95% CI, 1.62 to 53.1, respectively), after adjusting for confounding variables including the types of glucose-lowering agents. CONCLUSION: Early achievement of HbA1c level within the glycemic target was a determinant of long-term glycemic durability in new-onset T2DM, as were higher levels of education, physical activity, and HOMA-beta. PMID- 28868827 TI - Depression and Mortality in People with Type 2 Diabetes Mellitus, 2003 to 2013: A Nationwide Population-Based Cohort Study. AB - BACKGROUND: Previous reports have demonstrated a bidirectional relationship between depression and diabetes mellitus (DM), accentuating a need for more intensive depression screening in DM patients. There is a relative paucity of data on the mortality of depressed DM patients in Korea. METHODS: Retrospective data from January 2003 to December 2013 were collected for adult type 2 diabetes mellitus (T2DM) patients older than 30 years using the National Health Information database maintained by the Korean National Health Insurance Service (NHIS). Demographic characteristics were analyzed with descriptive statistics, and the annual prevalence of depression was estimated. Mortality rates and hazard ratios for each age group (stratified into six age groups) of patients diagnosed with T2DM in 2003 were estimated using a Cox proportional hazard method, with the Kaplan-Meier cumulative survival curve showing the overall survival rates according to the T2DM status until the given year of 2013. RESULTS: The annual prevalence of depression was consistently higher in T2DM group from 2003 to 2013. The mortality hazard ratio was higher in the depressed in all age groups, and the risk was higher in male groups and in younger-aged groups. CONCLUSION: Depression was significantly associated with a high mortality risk in T2DM patients; hence, a more systematic surveillance of T2DM patients to identify risk factors for depression might contribute significantly to reducing mortality risk in this group of patients. PMID- 28868828 TI - In Vitro Effect of Fatty Acids Identified in the Plasma of Obese Adolescents on the Function of Pancreatic beta-Cells. AB - BACKGROUND: The increase in circulating free fatty acid (FFA) levels is a major factor that induces malfunction in pancreatic beta-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6]). METHODS: From fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic syndrome; obese without metabolic syndrome; and normal weight without metabolic syndrome. MIN6 cells were treated for 24 or 48 hours with the three FFA profiles, and glucose-stimulated insulin secretion, cell viability, mitochondrial function and antioxidant activity were evaluated. RESULTS: The high FFA content and high polyunsaturated omega6/omega3 ratio, present in plasma of obese adolescents with metabolic syndrome had a toxic effect on MIN6 cell viability and function, increasing oxidative stress and decreasing glucose-dependent insulin secretion. CONCLUSION: These results could help to guide nutritional management of obese young individuals, encouraging the increase of omega-3-rich food consumption in order to reduce the likelihood of deterioration of beta-cells and the possible development of type 2 diabetes mellitus. PMID- 28868829 TI - Factors Associated with Improved Glycemic Control by Direct-Acting Antiviral Agent Treatment in Egyptian Type 2 Diabetes Mellitus Patients with Chronic Hepatitis C Genotype 4. AB - BACKGROUND: The association of chronic hepatitis C virus (HCV) infection with type 2 diabetes mellitus (T2DM) was first reported in 1994. Little is known about the effect of direct-acting antiviral agents (DAAs) on glycemic control in T2DM patients. The aim of the present study was to evaluate the factors associated with improved glycemic control (IGC) by DAA treatment in Egyptian T2DM patients with chronic HCV genotype 4 infection. METHODS: This study included 460 T2DM patients with chronic HCV genotype 4 infection. Four hundred patients received DAAs and 60 patients did not receive DAAs. Patients with sustained virological response after 3 months of DAAs (378 patients) were allocated into two groups: first group included 292 patients (77.2%) with IGC and second group included 86 patients (22.8%) with non-improved glycemic control (NIGC). RESULTS: In IGC group, 78 patients (26.7%) needed to decrease the dose of antidiabetic treatment. There were no significant differences between IGC and NIGC groups as regards age, sex, and body mass index. The percentage of patients with positive family history of T2DM, those with Child B class and duration of T2DM were significantly higher in NIGC group compared to IGC. CONCLUSION: Diabetic patients receiving DAAs should be closely monitored for reduction of antidiabetic drugs especially insulin and sulfonylurea to avoid hypoglycemic events. Improvement of glycemic control with DAAs is more in patients without family history of T2DM, short duration of diabetes mellitus, and mild liver disease. PMID- 28868830 TI - Letter: The Effect of 12 Weeks Aerobic, Resistance, and Combined Exercises on Omentin-1 Levels and Insulin Resistance among Type 2 Diabetic Middle-Aged Women (Diabetes Metab J 2017;41:205-12). PMID- 28868831 TI - Response: The Effect of 12 Weeks Aerobic, Resistance, and Combined Exercises on Omentin-1 Levels and Insulin Resistance among Type 2 Diabetic Middle-Aged Women (Diabetes Metab J 2017;41:205-12). PMID- 28868832 TI - Combined Cataract Extraction With Pars Plana Vitrectomy and Metallic Intraocular Foreign Body Removal Through Sclerocorneal Tunnel Using a Novel "Magnet Handshake" Technique. AB - PURPOSE: To study the outcomes of combined cataract extraction with pars plana vitrectomy (PPV) and metallic intraocular foreign body (IOFB) removal through a sclerocorneal tunnel using the "magnetic handshake" technique. DESIGN: A retrospective review. METHODS: Retrospective review of case records of 14 patients from 2010 to 2016 with metallic IOFB and traumatic cataract was performed. Cataract extraction was combined with PPV. Two intraocular magnets (IOMs) introduced through 20-gauge vitrectomy port and sclerocorneal tunnel helped achieve safe delivery of IOFB outside the globe by the "magnetic handshake" technique. RESULTS: All patients were males with a mean age of 33.04 years. A final best corrected visual acuity (BCVA) of 20/60 or better was noted in 10 (71.42%) of 14 patients. Final reattachment with more than 1 surgery was achieved in 13 (92.85%) patients. Postoperative complications included retinal detachment (RD) and phthisis bulbi in 1 (14.28%) patient each. CONCLUSIONS: Combined cataract extraction with PPV and metallic IOFB removal through sclerocorneal tunnel using the "magnet handshake" technique gives good visual and surgical outcomes. PMID- 28868833 TI - Evaluation of Interleukin-17 and Interleukin-23 in Pterygium: Immunohistochemistry Study. AB - PURPOSE: To compare the interleukin-17 (IL-17) and interleukin-23 (IL-23) positive cell counts between pterygium and normal conjunctiva. DESIGN: A case control study. METHODS: This study received ethical approval (NMRR Research ID 23957) and informed consent was obtained from all participants. It involved 20 participants with 20 samples of pterygium and 20 samples of normal conjunctiva that were obtained from the same eye of each participant. All the participants underwent history taking, slit lamp examination, and pterygium excision surgery. Both samples underwent immunohistochemistry procedure. Pretreatment procedure was conducted using heat-induced epitope retrieval with PT link, subsequently followed by EnVision FLEX staining procedure and incubation with anti-IL-17 antibody and anti-IL-23 antibody. Slides were examined in high-power fields (400x) for both samples in 3 different fields. Total positive stained cell counts in all 3 fields with IL-17 and IL-23 between pterygium and normal conjunctiva were analyzed by using Wilcoxon signed rank test. RESULTS: IL-17 positive cell counts for normal conjunctiva showed mean 196.10 +/- 80.487 but for pterygium was 331.10 +/- 108.416. As for IL-23, the mean for positive cell counts for normal conjunctiva was 62.10 +/- 33.462 and IL-23 positive cell counts for pterygium showed mean 102.95 +/- 41.378. Both IL-17 and IL-23 were significantly increased in pterygium compared with normal conjunctiva (P < 0.001). CONCLUSIONS: Both IL 17 and IL-23 were found to be significantly higher in the pterygium group than in the normal conjunctiva group with P < 0.001 by Wilcoxon signed rank test. PMID- 28868834 TI - Recurrent Vulvovaginal Candidiasis: Could It Be Related to Cell-Mediated Immunity Defect in Response to Candida Antigen? AB - Background: Recurrent vulvovaginal candidiasis (RVVC) is a common cause of morbidity affecting millions of women worldwide. Patients with RVVC are thought to have an underlying immunologic defect. This study has been established to evaluate cell-mediated immunity defect in response to candida antigen in RVVC cases. MATERIALS AND METHODS: Our cross-sectional study was performed in 3 groups of RVVC patients (cases), healthy individuals (control I) and known cases of chronic mucocutaneous candidiasis (CMC) (control II). Patients who met the inclusion criteria of RVVC were selected consecutively and were allocated in the case group. Peripheral blood mononuclear cells were isolated and labeled with CFSE and proliferation rate was measured in exposure to candida antigen via flow cytometry. RESULTS: T lymphocyte proliferation in response to candida was significantly lower in RVVC cases (n=24) and CMC patients (n=7) compared to healthy individuals (n=20, <0.001), but no statistically significant difference was seen between cases and control II group (P>0.05). Family history of primary immunodeficiency diseases (PID) differed significantly among groups (P=0.01), RVVC patients has family history of PID more than control I (29.2 vs. 0%, P=0.008) but not statistically different from CMC patients (29.2 vs. 42.9%, P>0.05). Prevalence of atopy was greater in RVVC cases compared to healthy individuals (41.3 vs. 15%, P=0.054). Lymphoproliferative activity and vaginal symptoms were significantly different among RVVC cases with and without allergy (P=0.01, P=0.02). CONCLUSION: Our findings revealed that T cells do not actively proliferate in response to Candida antigen in some RVVC cases. So it is concluded that patients with cell-mediated immunity defect are more susceptible to recurrent fungal infections of vulva and vagina. Nonetheless, some other cases of RVVC showed normal function of T cells. Further evaluations showed that these patients suffer from atopy. It is hypothesized that higher frequency of VVC in patients with history of atopy might be due to allergic response in mucocutaneous membranes rather than a functional impairment in immune system components. PMID- 28868835 TI - Association of CYP1A1*2A Polymorphism with Idiopathic Non-Obstructive Azoospermia in A South Indian Cohort. AB - Background: Infertility is the inability of a couple to conceive after one and a half years of unprotected sex. Male infertility, which accounts for almost half of infertility cases, is considered as a major problem all over the world. The aim of this study was to investigate the association of CYP1A1 polymorphisms with idiopathic non-obstructive azoospermia in a South Indian cohort. MATERIALS AND METHODS: An experimental study was conducted with idiopathic nonobstructive azoospermia. A total of 120 infertile and 80 fertile samples were collected, and DNA was then extracted from all samples. The CYP1A1*2A polymorphism genotyping was carried out by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The genotype distribution of CYP1A1*2A polymorphism showed significant difference between patients and controls. Moreover, the CC genotype was associated with decreased risk of idiopathic non obstructive azoospermia in comparison with the TT and TC genotypes. CONCLUSION: The current experimental study identified that the CT genotype of CYP1A1*2A polymorphism may contribute to the pathogenesis of male infertility in the South Indian population. PMID- 28868836 TI - Comparative Expression Analysis of HSP70, HSP90, IL-4, TNF, KITLG and KIT receptor Gene between Varicocele-Induced and Non-Varicocele Testes of Dog. AB - Background: This study was designed to create an experimental varicocele model by a simple surgical procedure in dog with minimum invasion and to investigate the effect of varicocele-induced infertility on the expression of six related genes (HSP90, HSP70, IL- 4, TNF, KITLG and KIT receptor). MATERIALS AND METHODS: In this experimental study, the proximal part of the pampiniform plexus of dog testes was partially occluded without abdominal incision which was confirmed by venographic examination. To evaluate varicocele in its acute form, dogs were castrated after 15 days and testes were dissected. Histopathologic evaluation was undertaken and the relative expression of the six genes was assessed by quantitative realtime polymerase chain reaction (PCR). RESULTS: Microscopic changes showed tubule degeneration. The Johnson score was significantly decreased in the varicocele testes when compared with non-varicocele testes. Expressions of HSP90, TNF, KITLG and the KIT-receptor gene were significantly downregulated (P=0.029, 0.047, 0.004 and 0.035 respectively) in varicocele-induced testes while HSP70 was upregulated (P=0.018). IL-4 did not show differential expression (P=0.377). CONCLUSION: We conclude that partial occlusion of the proximal part of the pampiniform plexus induces varicocele in the testis of dog. Differential expression of the mentioned genes may be responsible for the pathophysiology of varicocele and related subfertility. PMID- 28868837 TI - Physically Active Men Show Better Semen Parameters than Their Sedentary Counterparts. AB - Background: The quality of semen depends upon several factors such as environment, life style, physical activity, age, and occupation. The aim of this study was to analyze and compare the conventional and functional semen parameters in men practicing vigorous physical activity to those of sedentary men. MATERIALS AND METHODS: In this descriptive cross-sectional study, semen samples of 17 physically active men and 15 sedentary men were collected for analysis. Semen analysis was performed according to the World Health Organization (WHO) guidelines, while functional parameters were evaluated by flow cytometry. RESULTS: Results showed that several semen parameters (semen volume, viability, progressive motility, total motility, normal morphology, and moribund cells) were superior in the physically active group in comparison with the sedentary group. Semen parameters such as viability, progressive motility and total motility, as well as the percentage of moribund spermatozoa were significantly different between both groups. However, sperm DNA damage, lipid peroxidation and mitochondrial potential were not significantly different among the groups. CONCLUSION: Nevertheless, the physical activity shows better semen parameters than sedentary group. Taken together, our results demonstrate that regular physical activity has beneficial impact in sperm fertility parameters and such a life style can enhance the fertility status of men. PMID- 28868839 TI - Effect of Grape Seed Extract on Lipid Profile and Expression of Interleukin-6 in Polycystic Ovarian Syndrome Wistar Rat Model. AB - Background: Polycystic ovary syndrome (PCOS) is a common but complex endocrine disorder and is the major cause of anovulation and consequent subfertility. In this study the effect of grape seed extract (GSE) on triglyceride (TG), total cholesterol (TC), highdensity lipoprotein-cholestrol (HDL-C), low-density lipoprotein-cholestrol (LDL-C) and interleukin-6 (IL-6) in PCOS Wistar rats were assessed. MATERIALS AND METHODS: In this experimental study, 84 adult female Wistar rats were divided into 7 groups (n=12) including control (intact), Sham (estradiol valerate solvent injection), control PCOS and 4 experimental PCOS groups. To induce the syndrome, a single subcutaneous injection of 2 mg estradiol valerate was applied. In experimental groups, PCOS rats were treated with different doses of 50, 75, 100 and 200 mg/kg body weight (BW) GSE by intraperitoneal injection for 10 consecutive days. After harvesting blood serum, TG was measured by Glycerol-3-phosphate Oxidase-Peoxidase (GPOPAP), TC by Cholesterol Oxidase-Peroxidase (CHOD-PAP), and HDL-C by sedimentation method, LDL C by Friedwald calculation and IL-6 by ELISA method. The serum values of each parameter were analyzed using one-way ANOVA at P<=0.05. RESULTS: In all experimental groups significant decrease of visceral fat was obvious as compared with control PCOS group. LDL-C, TC and IL-6 levels in experimental groups, particularly at dose of 50 mg/kg of GSE, were significantly decreased as compared with PCOS group. However, HDL-C levels were not significantly changed. CONCLUSION: According to the findings of this study, it can be concluded that GSE with its effects on serum TC, LDL-C and IL-6 could reduce the effects of dyslipidemia and inflammation in PCOS rats and improve systemic symptoms of PCOS. PMID- 28868838 TI - Aluminium-Induced Oxidative Stress, Apoptosis and Alterations in Testicular Tissue and Sperm Quality in Wistar Rats: Ameliorative Effects of Curcumin. AB - Background: Reproductive toxicity is a major challenge associated with aluminum (Al) exposure. No studies have evaluated the possible effects of curcumin (CUR) on Al-induced reproductive dysfunction. Therefore, this study investigated the effects of CUR treatment on Al-induced reproductive damage. MATERIALS AND METHODS: In this experimental study, 40 male Wistar rats were allocated to the five groups (n=8) based on the treatment they received: no treatment (control), solvent [dimethyl sulfoxide (DMSO) or distilled water], CUR 10 mg/kg body weight (BW), Al chloride 10 mg/kg BW, and CUR+Al chloride (10 mg/kg BW/each alone). Treatments were performed by intraperitoneal (IP) injections for 28 days. The left testis was assessed for histopathological analysis as well as the incidence of germ cell apoptosis. One-way analysis of variance (ANOVA) followed by the Tukey's test was used. P<0.05 was considered significant. RESULTS: Significant reductions in body and testis weight; plasma testosterone and luteinizing hormone levels; sperm count, motility, morphology, and viability; germinal epithelium thickness; seminiferous tubules diameter; as well as, superoxide dismutase activity were observed in rats treated with Al. Moreover, Al exposure caused significant increments in the lumen diameter of tubules, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and malondialdehyde (MDA) levels compared to the control group. However, in rats receiving CUR+Al, CUR significantly reversed the adverse effects of Al on testis and sperm quality. No significant differences in follicle-stimulating hormone (FSH) levels and nuclear diameter of spermatogonia were detected among all groups. CONCLUSION: It can be concluded that Al causes reproductive dysfunction by creating oxidative damage. CUR, on the other hand, reduces the toxic effects of Al and improves the antioxidant status and sperm quality in male rats. PMID- 28868840 TI - Predicting Implantation Outcome of In Vitro Fertilization and Intracytoplasmic Sperm Injection Using Data Mining Techniques. AB - Background: In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are two important subsets of the assisted reproductive techniques, used for the treatment of infertility. Predicting implantation outcome of IVF/ICSI or the chance of pregnancy is essential for infertile couples, since these treatments are complex and expensive with a low probability of conception. MATERIALS AND METHODS: In this cross-sectional study, the data of 486 patients were collected using census method. The IVF/ICSI dataset contains 29 variables along with an identifier for each patient that is either negative or positive. Mean accuracy and mean area under the receiver operating characteristic (ROC) curve are calculated for the classifiers. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios of classifiers are employed as indicators of performance. The state-of-art classifiers which are candidates for this study include support vector machines, recursive partitioning (RPART), random forest (RF), adaptive boosting, and one-nearest neighbor. RESULTS: RF and RPART outperform the other comparable methods. The results revealed the areas under the ROC curve (AUC) as 84.23 and 82.05%, respectively. The importance of IVF/ICSI features was extracted from the output of RPART. Our findings demonstrate that the probability of pregnancy is low for women aged above 38. CONCLUSION: Classifiers RF and RPART are better at predicting IVF/ICSI cases compared to other decision makers that were tested in our study. Elicited decision rules of RPART determine useful predictive features of IVF/ICSI. Out of 20 factors, the age of woman, number of developed embryos, and serum estradiol level on the day of human chorionic gonadotropin administration are the three best features for such prediction. PMID- 28868841 TI - Factors that Influence The Occurrence of Multiple Pregnancies after Intracytoplasmic Injection Cycles with Two or Three Fresh Embryo Transfers. AB - Background: Multiple pregnancies are an important complication of assisted reproductive technology (ART). The present study aims to indentify the risk factors for multiple pregnancies independent of the number of transferred embryos. MATERIALS AND METHODS: This retrospective study reviewed the medical records of patients who underwent intracytoplasmic sperm injection (ICSI) cycles in Royan Institute between October 2011 and January 2012. We entered 12 factors that affected the number of gestational sacs into the poisson regression (PR) model. Factors were obtained from two study populations-cycles with double embryo transfer (DET) and cycles that transferred three embryos (TET). We sought to determine the factors that influenced the number of gestational sacs. These factors were entered into multivariable logistic regression (MLR) to identify risk factors for multiple pregnancies. RESULTS: A total of 1000 patients referred to Royan Institute for ART during the study period. We included 606 eligible patients in this study. PR analysis demonstrated that the quality of transferred embryos and woman's age had a significant effect on the number of observed sacs in patients who underwent ICSI with DET. There was no significant predictive variable for multiple pregnancies according to MLR analysis. Our findings demonstrated that both regression models (PR and MLR) had the same outputs. A significant relation existed between age and fertilization rate with multiple pregnancies in patients who underwent ICSI with TET. CONCLUSION: Single embryo transfer (SET) should be considered with the remaining embryos cryopreserved to prevent multiple pregnancies in women younger than 35 years of age who undergo ICSI cycles with high fertilization rates and good or excellent quality embryos. However, further prospective studies are necessary to evaluate whether SET in women with these risk factors can significantly decrease multiple pregnancies and improve cycle outcomes. PMID- 28868842 TI - Effect of Marital Relationship Enrichment Program on Marital Satisfaction, Marital Intimacy, and Sexual Satisfaction of Infertile Couples. AB - Background: Infertile couples only think of having children during their sexual intercourse, and their constant concern about this issue increases their stress level. Psychosocial and social stress leads to decreased life satisfaction, increased marital problems, and reduced sexual confidence. This study aims to determine the effect of enrichment program on marital and sexual satisfaction as well as marital intimacy among infertile couples. MATERIALS AND METHODS: This randomized controlled clinical trial was conducted on 50 infertile couples in 2013 in Hamedan. The marital relationship enrichment program was taught to the experimental group during seven 90 minutes sessions. Enrich marital satisfaction, Linda Berg sexual satisfaction, and marital intimacy questionnaires were completed by both groups in 3 pretest steps immediately after the end of training sessions, and 8 weeks later. The results were analyzed in STATA11 software using t test, Chi-square, ANCOVA, RM-ANOVA, and Bonferroni post-hoc test. To check the data normality, Kolmogorov-Smirnov test was used. P<0.05 was considered significant. RESULTS: Comparison of mean scores related to pretest on the one hand and immediately after the test in 8 week later on the other hand showed marital relationship enrichment program significantly increased marital and sexual satisfaction (P<0.001). Also, mean score of marital intimacy immediately after the test (P=0.04) and 8 weeks after the test (P<0.001) significantly increased in comparison with the pretest under the influence of the program. CONCLUSION: Enrichment training can increase marital intimacy and also marital and sexual satisfaction in infertile couples (Registration Number: IRCT201604299014N97). PMID- 28868843 TI - Correlation of The Etiology of Infertility with Life Satisfaction and Mood Disorders in Couples who Undergo Assisted Reproductive Technologies. AB - Background: This study compared common psychological symptoms and life satisfaction in husbands and wives according to infertility diagnosis. MATERIALS AND METHODS: We conducted this cross-sectional study on 248 infertile couples between November 1, 2014 and February 28, 2015 at Royan Institute, Tehran, Iran. Participants answered three questionnaires. First, they completed a demographic questionnaire followed by the Hospital Anxiety and Depression Scale (HADS, 14 item self-report instrument) composed of two sub-scales: anxiety (HADS-A) and depression (HADS-D). Participants also completed the Satisfaction with Life Scale (SLWS) comprised of 5 items. Both our questionnaires were validated for the Iranian population. RESULTS: In couples with male factor infertility, wives had a significantly higher mean score for anxiety compared to their husbands (P<0.001). When the cause of infertility was female factor, the wives appeared significantly more anxious (P<0.001) and depressed (P=0.004) than their husbands. Male patients, those with unknown and female factors, expressed greater satisfaction with life compared to other male patients (P=0.022). Significantly greater depression existed among the couples in which the wives' educational levels was above their husbands (P=0.045). CONCLUSION: Our findings showed that when the infertility etiology was male factor, female factors or unexplained, wives showed significantly higher anxiety than their husbands. In couples diagnosed with female factor infertility, wives showed significantly more depression than their husbands. PMID- 28868844 TI - Desired Numbers of Children, Fertility Preferences and Related Factors among Couples Who Referred to Pre-Marriage Counseling in Alborz Province, Iran. AB - Background: The Islamic Republic of Iran has experienced a dramatic decrease in fertility rates in the past three decades. One of the main issues in the field of fertility is the couple's preferences and the desire to bear children. This study aimed to determine desired number of children, fertility preference, and related factors among people referring pre-marriage counseling to clarify their presumed behavior in case of fertility. MATERIALS AND METHODS: This study was a descriptive analytic cross-sectional survey, conducted during 8 months. The participants were 300 couples came to pre-marriage counseling centers of two health centers of Karaj and asked to complete a 22 items questionnaire about of demographic characteristics, participants' interest, preference about fertility, and economic situation. RESULTS: Majority of the males were between the ages of 20-30 years (66.6%) while majority of the females were below 25 years of age (57%). About 17 percent of men and 22.3 percent of women stated that they want to have 1 child and equally 52.7 percent of men and 52.7 percent of women wanted to have 2 children. The only factor that contributed to the female participant's decision for a desirable number of children was the number of siblings that they have. In male participants with an increasing age at marriage and aspiration for higher educational level, the time interval between marriage and the birth of the first child has increased. There was a convergence in desired number of children in male and female participants. CONCLUSION: Majority of the participants express their desire to have only one or two children in future but in considering the fact that what one desires does not always come into reality, the risk of reduced fertility is generally present in the community. Appropriate policies should be implemented in order to create a favorable environment for children. PMID- 28868845 TI - Tehran Survey of Potential Risk Factors for Multiple Births. AB - Background: The multiple pregnancy incidence is increasing worldwide. This increased incidence is concerning to the health care system. This study aims to determine the frequency of multiple pregnancy and identify factors that affect this frequency in Tehran, Iran. MATERIALS AND METHODS: This cross-sectional study included 5170 mothers in labor between July 6-21, 2015 from 103 hospitals with Obstetrics and Gynecology Wards. The questionnaire used in this study consisted of five parts: demographic characteristics; information related to pregnancy; information related to the infant; information regarding the multiple pregnancy; and information associated with infertility. We recruited 103 trained midwives to collect data related to the questionnaire from eligible participants through an interview and medical records review. Frequencies and odds ratios (OR) for the association between multiple pregnancy and the selected characteristics (maternal age, economic status, history of multiple pregnancy in first-degree relatives, and reproductive history) were computed by multiple logistic regression. Stata software, version 13 (Stata Corp, College Station, TX, USA) was used for all statistical analyses. RESULTS: Multiple pregnancy had a prevalence of 1.48% [95% confidence interval (CI): 1.19-1.85]. After controlling for confounding variables, we observed a significant association between frequency of multiple pregnancy and mother's age (OR=1.04, 95% CI: 1.001-1.09, P=0.044), assisted reproductive technique (ART, OR=6.11, 95% CI: 1.7- 21.97, P=0.006), and history of multiple pregnancy in the mother's family (OR=5.49, 95% CI: 3.55-9.93, P=0.001). CONCLUSION: The frequency of multiple pregnancy approximated results reported in previous studies in Iran. Based on the results, we observed significantly greater frequency of multiple pregnancy in older women, those with a history of ART, and a history of multiple pregnancy in the mother's family compared to the other variables. PMID- 28868846 TI - Personhood and Moral Status of The Embryo: It's Effect on Validity of Surrogacy Contract Revocation according to Shia Jurisprudence Perspective. AB - Background: One of the most controversial issues related to the human embryo is the determination of the moment when an embryo is considered a human being and acquires a moral status. Although personhood and moral status are frequently mentioned in medical ethics, they are considered interdisciplinary as concepts that shape the debate in medical law (fiqh) since their consequences are influential in the way which the parents and other individuals behave towards the embryo. MATERIALS AND METHODS: This analytical-descriptive research gathered relevant data in a literature search. After a description of the fundamentals and definitions, we subsequently analyzed juridical texts and selected one of the viewpoints that regarded the surrogacy contract revocation. RESULTS: The surrogacy contract is a contract based upon which two sides (infertile couple and surrogate mother) involved in making the contract are obligated to fulfill its terms. Therefore, contract revocation can be surveyed from three perspectives: mutual revocation (iqala), legal unilateral wills (khiar al-majlis, khiar al ayb), and contractual wills (khiar al-shart). CONCLUSION: Revocation of a surrogacy contract either by the genetic parents, surrogate or the fertility clinic is allowed by Muslim jurists only when the embryo lacks personhood. Based on Islamic teachings, the termination of a surrogacy contract in and after the sixteenth week of pregnancy, when the embryo acquires a human soul (ensoulment), is not allowed. However religious thought emphasizes the moral status of the fetus before the sixteenth week and states that optional termination of the surrogacy contract is not permitted while the fetus becomes a human being. PMID- 28868847 TI - Fertility Preservation in Iranian Cancer Patients: A Continuing Neglect. PMID- 28868848 TI - [Inheritance and innovation of traditional processing technology of Chinese medicine]. AB - To discuss the inheritance and innovation study of Chinese medicine processing technology from three aspects: inheritance, standardization and industrial innovation development, propose "three lacks" in inheritance, "six lacks of standardization, and one lack of unity" in standardization, and "three emphasizing and three despising aspects" in industrial innovation, and propose feasible solutions for the above mentioned problems, providing a good foundation for inheritance and innovation of Chinese medicine processing. PMID- 28868849 TI - [Advance on chemical compounds of Tibetan medicinal plants of Aconitum genus]. AB - It was estimated that about 60 species and 15 varieties of genus Aconitum are distributed in China.These plants contain various kinds of chemical compounds, and the main compounds are diterpenoid alkaloids. In addition, there are flavonoids, phenolic acid and others.So far, phytochemical studies showed 339 compounds.This paper summarized the chemical compounds to provide the theoretical basis for the use of Tibetan medicinal plants of Aconitum genus. PMID- 28868850 TI - [Application of drug-target prediction technology in network pharmacology of traditional Chinese medicine]. AB - In recent years, network pharmacology has been developed rapidly, and especially, the concept of "network target" has brought a new era in the field of traditional Chinese medicine (TCM). The integrity and systematicness emphasized in network pharmacology comply with the characteristics of holistic view and treatment in Chinese medicine. It can provide deeper insights into the underlying mechanisms of TCM theories, including the illustration on action mechanism of Chinese medicine, selection of pharmacodynamic materials and the combination principles of various Chinese herbs, etc. Therefore, this theory is more suitable for TCM academic characteristics and practical conditions. The key problem in network pharmacology is how to efficiently and quickly identify the interactions between large amounts of drugs and target proteins. As an efficient and high throughput way, drug-target prediction technology can reduce costs, quickly predict the component targets, and provide foundation for the application of TCM network pharmacology. In view of the large amount of compounds and target databases, different prediction methods and technologies have been developed, and used to predict the drug-target interactions. Many virtual screening technologies have been successfully applied to network pharmacology. Based on different prediction principles, drug-target prediction technology can be generally divided into four types: ligand-based prediction, receptor-based prediction, machine learning and combined prediction. In this paper, we are going to review the prediction methods of drug-target interactions and give acomprehensive elaboration of their application in network pharmacology of TCM, hoping to provide beneficial references for various Chinese medicine researchers. PMID- 28868851 TI - [Evaluation for heavy metal pollution of soil and herb from main producing area of Phellodendron amurense in China]. AB - In order to evaluate the heavy metal potential pollution of soil and medicinal materials in main producing area of Phellodendron amurense, we collected 32 soil samples and 32 herb samples from northeast and north of China covering four provinces. In this study, the detection of heavy metal contents was conducted by ICP emission spectroscopy and atomic fluorescence spectrometry. The results showed that the soil from all areas of Ph amurense generally reached the national standard. As, Hg, Cr, Cd, Pb and Cu content of herb samples met the requirtment of the national standard except Hg content exceeding standard slight in a few samples. The reason of excessive Hg was the ability of Hg accumulation in Ph. amurense and atmospheric environment was polluted. So, national standard and Good Agricultural Practice (GAP) must be carried out severely in Ph. amurense resources production. PMID- 28868852 TI - [Identification of Notopterygium seeds using DNA barcoding method]. AB - In order to guarantee the species correction of Notopterygium seeds, a molecular identification method with ITS2 as DNA barcode has been verified. In this study, 27 samples of Notopterygium seeds were collected from the main producing area of Notopterygium. The morphological characteristics of the Notopterygium seeds were firstly surveyed. Then the DNA extraction, PCR amplification, DNA sequencing and DNA assembly were carried out. The species identification for a Notopterygium seed was implemented through distance method, NJ-tree method and the DNA barcoding system for traditional Chinese medicine (www.tcmbarcode.cn). The results showed that the seeds of N. incisum and N. franchetii had similar morphological characteristics and were difficult to distinguish clearly based on morphological descriptions. With the results of molecular identification, 24 samples were genuine including 13 N. incisum seeds samples and 11 N. franchetii genuine seeds samples. In conclusion, DNA barcode technology can accurately and efficiently identify the species of Notopterygium seeds. Furthermore, this study will provide a new method for germplasm resources identification of medicinal materials and supplies some guidelines for establishing Chinese herbal seeds and seedlings quality standards. PMID- 28868853 TI - [In vitro autotetraploid induction and analysis on DNA methylation diversity of Platycodon grandiflorum]. AB - In order to investigate the epigenetic variations between diploid and autotetraploid of Platycodon grandiflorus. The diploid buds of P. grandiflorus were soaked in the mixture of different concentration colchicines and 0.002 g*mL 1 dimethyl sulphoxide (DMSO).The identification of autotetraploid plants were based on morphological characteristics, chromosome number and flow cytometry. And then the level and pattern of DNA methylation explored by using the technology of methylation sensitive amplified polymorphism (MSAP).The result demonstrated that the buds soaked in 0.2% colchicines and 0.002 g*mL -1 DMSO solution for 12 h was ideal conditions to induce autotetraploid of P. grandiflorus, with induction rate of 32.0%.The diploid and tetraploid plants existed distinctly differences in morphological indexes.Totally,1 586 bands were amplified by 20 pairs of selective primers, of which 764 and 822 bands were detected in diploid and autotetraploid respectively. The total methylation ratio,full methylation ratio and hemimethylated ratio were 91.25%,61.25% and 30.65% in diploid of P. grandiflorus,respectively.However,the total methylation ratio,full methylation ratio and hemimethylated ratio of autotetraploid of P. grandiflorus were 86.13%,54.38% and 31.75%, respectively. Compared with diploid, the genomic DNA total methylate ratio and full methylation ratio of autotetration plants decreased by 6.02% and 7.14%.But the hemimethylated ratio of autotetraploid was higher than that of diploid, which more than 1.6%. All this results indicated that DNA methylation patterns have adjusted during the polyploidy process.. PMID- 28868854 TI - [Progress on molecular biology of Isaria farinosa, pathogen of host of Ophiocordyceps sinensis during the artificial culture]. AB - Isaria farinosa is the pathogen of the host of Ophiocordyceps sinensis. The present research has analyzed the progress on the molecular biology according to the bibliometrics, the sequences (including the gene sequences) of I. farinosa in the NCBI. The results indicated that different country had published different number of the papers, and had landed different kinds and different number of the sequences (including the gene sequences). China had published the most number of the papers, and had landed the most number of the sequences (including the gene sequences). America had landed the most numbers of the function genes. The main content about the pathogen study was focus on the biological controlling. The main content about the molecular study concentrated on the phylogenies classification. In recent years some protease genes and chitinase genes had been researched. With the increase of the effect on the healthy of O. sinensis, and the whole sequence and more and more pharmacological activities of I. farinosa being made known to the public, the study on the molecular biology of the I. farinosa would be deeper and wider. PMID- 28868855 TI - [International research trends of pharmacognosy on molecular level --based on analysis of SCI literature]. AB - The techniques and methods of molecular biology have been widely applied in pharmacognosy fields. International development trends of pharmacognosy studies on molecular level were analyzed by bibliometric methods using the SCIE database on Web of Science, the literature distribution, national distribution, agency distribution, periodicals distribution, and hot research topics were described using multivariate statistical analysis and multidimensional scaling analysis method,etc. The number of international pharmacognosy literature on molecular level is increasing year by year. USA, China and Japan have close cooperation, and focus on molecular identification and genetic diversity. Chinese scientists issued high-impact factor journals papers and high citations amount in the international forefront. The international pharmacognosy research on molecular level has developed rapidly. Chinese research has a significant influence.The molecular mechanism of the formation of Dao-di Herbs may become the next hotspot. PMID- 28868856 TI - [Analysis of different dosage forms of Xiasangju granules on fingerprints and models using high performance liquid chromatography]. AB - To establish the fingerprints of Xiasangju granules (with sugar and non-sugar forms) by HPLC, and provide reference for their identification and effective quality control. High performance liquid chromatography (HPLC) method was used to collect the fingerprints of 20 batches of non-sugar Xiasangju granules and 34 batches of sugar type Xiasangju granules. Their main different components were classified and screened by mode identification methods (principal component analysis, PCA, and orthogonal partial least squares discriminate analysis, OPLS DA). The principal components were identified by comparing with reference standards. The fingerprints of Xiasangju granules (sugar type and non-sugar type) were established. PCA could not fully classify the two types of granules, while OPLS-DA could obviously classify these two different types of Xiasangju granules. Six components showed greatest difference between two types of granules, including salviaflaside, luteoloside and linarin. The developed mode identification method is helpful to control the overall quality of Xiasangju granules, and it provides an effective approach to quality evaluation. PMID- 28868857 TI - [Near infrared spectrum monitoring of scale up process for macroporous resin purification of Grardeniae extract]. AB - To establish a fast detection method during the purifying process of the extracts from Grardeniae using macroporous resin based on near infrared spectroscopy. First, the ethanol eluent was collected from the purification process of small size sample; and near infrared (NIR) spectrum was collected. Then the content of the geniposide was determined by HPLC method, and partial least squares (PLS) method was used to establish the quantitative model to predict the content of geniposide by NIR spectrum. This model was used to supervise the changes of geniposide concentrations in ethanol eluent during medium scale process. Experimental results showed that the NIR small scale model can accurately predict the concentrations of geniposide in the production process of medium scale. However, with the proceeding of batch processes, the prediction performance of the model was decreased, so model updating method was employed to maintain the model. After twice updates, the NIR quantitative model can accurately predict the concentrations of the geniposide during medium scale process. Therefore, through model updates, the established NIR quantitative model can be applied in different scales of macroporous resin purification processes, to improve the data utilization efficiency of small scale process and save the cost of rebuilding the quantitative model of medium scale. PMID- 28868858 TI - [Quality comparison andstructural characteristics of material basic composition of Danshen injection from different manufacturers]. AB - HPLC was used to analyze the chromatographic fingerprints and determine the contents of tanshinol, protocatechuic acid, protocatechuic aldehyde, caffeic acid, isoferulic acid, lithospermic acid, rosmarinic acid, salvianolic acid B, salvianolic acid A, and salvianolic acid C in Danshen injection from 10 different manufacturers. The significant differences of phenolic compounds in Danshen injection from ten manufacturers were investigated by using F test. The results showed that the similarity degree of Danshen injection from ten manufacturers was above 0.9 and there was significant difference in mass fraction of phenolic compounds between the samples from different manufacturers. The analysis of mass fraction of effective phenolic components and their structural ratios in Danshen injection from the different manufacturers showed significant differences, indicating that the Danshen injection available in market had different curative effects and with significant differences in structural ratios. PMID- 28868859 TI - [Preparation and in vitro dissolution of magnolol solid dispersion]. AB - In this study, solid dispersion system of magnolol in croscarmellose sodium was prepared by using the solvent evaporation method, in order to increase the drug dissolution. And its dissolution behavior, stability and physical characteristics were studied. The solid dispersion was prepared with magnolol and croscarmellose sodium, with the proportion of 1?5, the in vitro dissolution of magnolol solid dispersion was up to 80.66% at 120 min, which was 6.9 times of magnolol. The results of DSC (differential scanning calorimetry), IR (infra-red) spectrum and SEM (scanning electron microscopy) showed that magnolol existed in solid dispersion in an amorphous form. After an accelerated stability test for six months, the drug dissolution and content in magnolol solid dispersion showed no significant change. So the solid dispersion prepared with croscarmellose sodium as the carrier can remarkably improve the stability and dissolution of magnolol. PMID- 28868860 TI - [Optimization of flash-type extraction technology of alisol B 23-acetate from Alismatis Rhizoma by response surface methodology]. AB - Response surface methodology was used to optimize and obtain the optimal flash type extraction technology of alisol B 23-acetate from Alismatis Rhizoma. With the extraction rate of alisol B 23-acetate as an indicator, single-factor test was used to investigate the effect of ethanol volume fraction, liquid-solid ratio, extraction times and extracting time on the extraction rate of alisol B 23 acetate.The results were combined with Box-Benhnken design and response surface analysis to optimize the technology parameters for extraction process of Alismatis Rhizoma and obtain the optimal flash-type extraction technology under the following conditions: ethanol volume fraction 80%, liquid-solid ratio 12?1, extraction 4 times, 114 s/time. Flash-type extraction technology of alisol B 23 acetate by response surface methodology is stable, time-saving, efficient, and with the advantages of room temperature extraction and no component damage, so it can be used for massive production. PMID- 28868862 TI - [Studies on chemical constituents of rhizomes of Smilax trinervula]. AB - The chemical constituents were separated and purified from the 70% ethanol extract of Smilax trinervulaby various chromatographic methods including silica gel, Sephadex LH-20, MCI and preparative HPLC. Their structures were obtained and identified by analysis of the spectroscopic data. Compounds 1-11 were separated from this genus for the first time. Compound 12 was obtained from S. trinervula for the first time. PMID- 28868861 TI - [A new biflavone from needles of Taxus canadensis]. AB - The presentstudy is to investigate the chemical constituents of needles of Taxus canadensis. The constituent was isolated by various chromatographic methods, and the chemical structure was elucidated on the basis of spectral analysis. A new biflavone was isolated and identified as 3"'-hydroxy-4"', 7 dimethylamentoflavone. PMID- 28868863 TI - [Chemical constituents from medical and edible plants of Rosa roxburghii]. AB - Rosa roxburghii, a kind of the medical and edible plants belonging to the Rosaceae family, is widely distributed in the southwest districts of China, especially Guizhou province. Now, by reason of the extensive bioactivities, the plant is widely used in the field of food, health product, drug, and so on. In the course of our continuing search for the bioactive constituents, thirteen compounds were isolated from R. roxburghii, and their structures were determined on the basis of physicochemical property, spectroscopic data and comparison with the literatures, as 2-oxo pomolic acid(1), 1beta-hydroxyeuscaphic acid(2), euscaphic acid(3), arjunic acid(4), tormentic acid(5), kaiiichigeside F1(6), rosamultin(7), arjunetin(8), 2alpha, 3alpha, 19alpha-trihydroxy-olean-12-en-28 oic acid 28-O-beta-D-glucopyranoside(9), 2alpha, 3alpha, 19alpha, 24 tetrahydroxyolean-12-en-28-oic-acid 28-O-beta-D-glucopyranosyl ester(10), pyrogallic acid (11), daucosterol(12), and 1, 2-decanediol(13). Compounds 9 and 10 were firstly obtained from Rosaceae family, and compounds 1,4,5,9-11,13 were isolated from this plant for the first time. PMID- 28868864 TI - [Research on certified reference material of emodin in rhubarb and its alcohol extract, water extract]. AB - The certified reference materials (CRMs) of emodin in rhubarb and its alcohol extract, water extract were developed by using quantity transfer technology from single chemical composition to the complex systems. The CRM of emodin was used for quantity transfer, and high performance liquid chromatography (HPLC) method was used to determine the contents of emodin in different matrix composition. By establishing mathematical model and calculating the parts of uncertainty, the uncertainty values were finally gotten. CRMs of emodin in rhubarb, alcohol extract and water extract were accomplished. The content values of emodin were 0.40% +/-0.03%, 1.15%+/-0.18%, 0.16%+/-0.08% (k=2,P=0.95), respectively. The established method for quantity transfer has successfully solved the technical problems that the value of active ingredient of traditional Chinese medicine can't be traced to SI units. The series of CRMs are assigned as grade primary reference materials, which are useful for quality control of the emodin content, also provide the accurate and reliable CRM, materials standard and standard methods. PMID- 28868865 TI - [Analysis on characteristic constituents of crude Aconitum carmichaelii in different regions based on UPLC-Q-TOF-MS]. AB - As a representative variety of hypertoxic herbs, aconite has a very high medicinal value but certain security risks. With the advance of urbanization and industrial transfer and upgrading, traditional geo-authentic regions and emerging regions have gradually coexisted. However, there are significant differences in the geographical distribution, ecological environment and growing cycle in these areas, which may cause intraspecific variations in chemical components, and then affect herb quality and clinical efficacy. Furthermore, there was still lack of in-depth study on characteristic constituents of aconite genuineness. In this paper, an UPLC-Q-TOF-MS was used to investigate the chemical ingredients in Jiangyou aconite, Hanzhong aconite, Butuo aconite and Weishan aconite. The results suggested that using unsupervised PCA method, Jiangyou aconite was similar with Hanzhong aconite in chemical ingredients, but significantly different from ones in emerging regions. Using PLS-DA method, seven characteristic constituents were identified, in which Butuo aconite and Weishan aconite had higher contents of mesaconitine and fuziline, while Jiangyou aconite and Hanzhong aconite had higher contents of hypaconitine, neoline, carmichaeline, and songorine. Based on basic toxicity of each ingredient, we can find that hypaconitine and mesaconitine were the key toxicity factors to distinguish Jiangyou aconite, Butuo aconite, and Weishan aconite. The toxicity of geo authentic Jiangyou aconite was lower than that of Butuo aconite and Weishan aconite. The lower toxicity in geo-authentic Jiangyou aconite was beneficial for ensuring clinical drug safety, which may be one of the important reasons for the formation of genuine aconite. These results provide new reference data to reveal the formation mechanism of genuine aconite from the perspective of plant secondary metabolite diversity. PMID- 28868866 TI - [Mechanism of geniposide in improving free fatty acid metabolism in rats with non alcoholic fatty liver disease]. AB - To observe the effect of geniposide on non-alcoholic fatty liver disease (NAFLD), and discuss the mechanism of geniposide for NAFLD from the aspect of free fatty acid, forty healthy Wistar male rats were randomly divided into normal group, model group, geniposide and Xuezhikang group. The rats in normal group were fed with normal diets, and the rats in other 3 groups were given with high-fat diet for 8 weeks to induce the NAFLD models. From the week 5 to end of week 8, the rats in geniposide and Xuezhikang group were intervened with corresponding medicines. The body weight, liver wet weight, and fat weight of the rats were recorded. Visual and pathological changes in hepatic tissues were observed with HE staining. The contents of TG, FFA, FAS, AMPK, ACCase and Malonyl-CoA in hepatic tissue, contents of CHO and LDL-C in serum and activities of AST and ALT in serum were detected by using corresponding methods. The results showed that the body weight, liver wet weight, and fat weight of the rats, CHO, LDL-C, ALT and AST levels in serum, TG, FFA, FAS, ACCase and Malonyl-CoA levels in hepatic tissues of the rats in model group were significantly higher than those in normal group (P<0.01), while AMPK activity was significantly lower than that of the normal group (P<0.01), with obvious visual and pathological steatosis in hepatic tissues, and inflammatory injury occurred in model group. Compared with the model group, body weight of the rat, fat weight, levels of FFA in hepatic tissues, ALT and AST activities in serum, liver wet weight, TG, FAS, ACCase and Malonyl-CoA levels were significantly decreased in geniposide group (P<0.01), while the AMPK activity in hepatic tissues was significantly increased (P<0.05),with improvement in visual and pathological performance. Compared with the model group, liver wet weight, fat weight, TG and FFA levels in hepatic tissues, and LDL-C level in serum were significantly decreased in Xuezhikang group (P<0.05). Compared with Xuezhikang group, the body weight of rat, fat weight and FFA level in hepatic tissues were significantly lower in geniposide group (P<0.01), but with no significant difference in other aspects. These findings indicated that geniposide was highly effective in improving the pharmacological effect of NAFLD induced by high-fat diet, and the mechanism was achieved through AMPK-ACCase-Malonyl-CoA-FFA axis. PMID- 28868868 TI - [Effects of ginseng, notoginseng, and Chuanxiong Rhizoma extracts on cytoskeleton protein of replicative senescence vascular smooth muscle cells]. AB - To observe the effect of extracts of ginseng, notoginseng, and Chuanxiong Rhizome on the cytoskeleton protein F-actin and G-actin of the replicative senescence vascular smooth muscle cells, with human aortic smooth muscle cells (HASMC) as the research object, and the replicative senescence 9th generation cells as the senescence models, the experiment was divided into youth group (5th generation cells), model group (9th generation cells), Chinese medicine low dose group (100 mg*L-1), middle dose group (200 mg*L-1), and high dose group (400 mg*L-1) and resveratrol group (10 MUmol*L-1). The intervention time was 48 h. beta Galactosidase specific staining method was used to calculate the ratio of blue dyeing cells. CCK-8 method was used to detect the cells proliferation. The flow cytometry was used to analyze the cell cycle. Immunofluorescent staining was used to observe morphological changes of F-actin and G-actin. The western blot assay was used to determine the expression of F-actin protein. Compared with the model group, the Chinese medicine groups and resveratrol group significantly reduced the number of blue dyeing cells, improved the ability of cells proliferation, reduced the number of cells in G0/G1 phase, increased the number of cells in S phase, and reduced the protein expression of F-actin and the formation of stress fibers, with obvious intervention effect and statistically significant difference. Therefore, the replicative senescence vascular smooth muscle cells can be used as the models for senescence research, with significant changes in morphology and protein expression of cytoskeleton protein F-actin and G-actin in the process of cells aging. The extracts of ginseng, notoginseng, and Chuanxiong Rhizome have obvious intervention effect on F-actin and G-actin, and it might be indirectly associated with delaying the aging of blood vessels. PMID- 28868867 TI - [Apoptosis mechanism of taxol combined with resveratrol on human laryngeal carcinoma Hep-2 cells]. AB - Laryngeal cancer is one of the most common malignant tumors in the respiratory tumors, and its incidence ranks second highest in the respiratory tumors. Resveratrol (Res) is a kind of polyphenols, which can inhibit nucleotides can inhibit the growth of liver cancer cells, gastric cancer cells, pancreatic cells and other tumor cells by inhibiting ribonucleotide reductase in the cells. Taxol (Tax) is a kind of secondary metabolites of Taxus chinensis, which has anti-tumor activity for breast cancer, cervical cancer, ovarian cancer and other tumors by inhibiting cellular microtubule depolymerization. But at present the effects of resveratrol combined with taxol on human laryngeal carcinoma cell strain Hep-2 and their underlying molecular mechanisms are rarely reported. After human laryngeal cancer cell Hep-2 cells were processed with resveratrol (Res) and taxol (Tax), CCK-8 assay was used to evaluate the effect of these two herbs on the proliferation of cancer cells; AO/PI staining and JC-1 were used to detect Hep-1 cells apoptosis; the expression of Bax, Bcl-2, PARP, TRIB3, and XIAP genes was detected by real time quantitative PCR; the activity of caspase-3 and caspase-8 was determined with quantitative fluorescence method. The experimental results showed that compared with Tax, Res medication alone, joint group significantly enhanced inhibition of Hep-2 cells activity, decreased the dosage of Tax, increased the expression of Bax and PARP, TRIB3, reduced the expression of the Bcl-2 and XIAP, and promoted the activity of caspase-3 and caspase-8. The test results showed that compared with the single medication, combined group could significantly increase the inhibitory effect on Hep-2 cells, significantly reduce Tax dosage, increase expressions of Bax, PARP, TRIB3, reduce expressions of Bcl 2, XIAP, and promote activity of caspase-3, caspase-8. This indicated apoptosis of human laryngeal carcinoma cell strain Hep-2 may be induced with Res, Tax, and the combination of these two herbs by mitochondria pathway. It provides valuable clue for further research on combination of Res and Tax for the treatment of laryngeal cancer, and expanding the combined application of Res and Tax. PMID- 28868869 TI - [Evaluation of nephrotoxicity induced by total terpenoids from Alismatis Rhizoma on HK-2 cells in vitro and its induction of apoptosis]. AB - To evaluate the nephrotoxicity of total terpenoids from Alismatis Rhizoma on human kidney proximal tubular cells (HK-2), explore the iraction in inducing apoptosis of HK-2 cells, and provide reference for the research of controversial nephrotoxicity of total terpenoids from Alismatis Rhizoma, HK-2 cells were used and cells viability was measured by MTT colorimetric method. An assessment of cells apoptosis was also conducted by using flow cytometry. Meanwhile western blot assay was used to detect the protein expressions of caspase-3, Bcl-2, Bcl xl, Kim-1, clusterin and TFF-3. At last, q-PCR was used to detect the mRNA expressions of caspase-3, Bcl-2, Bcl-xl, Kim-1, clusterin and TFF-3. The flow cytometry results showed that cells apoptosis rate was (37.48+/-1.76)%, (26.91+/ 1.91)% and (25.61+/-2.05)% respectively after treating with total terpenoids (6.25*10-5, 3.125*10-5, 1.562 5*10-5 g*mL-1). Western blot results showed that Bcl-2 and Bcl-xl protein levels were significantly decreased after treating with total terpenoids (6.25*10-5, 3.125*10-5, 1.562 5*10-5 g*mL-1), while the protein expression of caspase-3 was significantly increased. q-PCR results were the same with western blot results, that mRNA expressions of Bcl-2 and Bcl-xl were significantly decreased while mRNA expression of caspase-3 was significantly increased after treating with total terpenoids (6.25*10-5, 3.125*10-5, 1.562 5*10 5 g*mL-1). Western blot results and q-PCR results showed that both mRNA and protein expressions of Kim-1, clusterin and TFF-3 were significantly increased after treating with total terpenoids from Alismatis Rhizoma (6.25*10-5, 3.125*10 5, 1.562 5*10-5 g*mL-1). HK-2 cells in vitro evaluation results showed that, total terpenoids from Alismatis Rhizoma may have nephrotoxicity effect, but further study is still needed for verification; meanwhile, they could induce HK-2 cells apoptosis, providing basis for nephrotoxicity study and safe application of Alismatis Rhizoma. PMID- 28868870 TI - [Inhibitory effect of ilexpernoside C from Ilex pernyi on aggregated LDL-induced foam cells formation]. AB - The aggregation of macrophage-derived foam cells on vascular wall is considered to be a main cause of atherosclerosis. In the present study, we evaluated the inhibitory effect of the compound ilexpernoside C (IC1) extracted from Ilex pernyi (Aquifoliaceae) on foam cell formation in THP-1 macrophages cells which were induced by low density lipoproteins aggregates (LDL aggregates). Results showed that IC1 could significantly inhibit the formation of foam cells. The analysis on related receptors of foam cells indicated that IC1 could significantly decrease the expression of low density lipoprotein-related receptor 1(LRP1). Therefore, these findings indicated that IC1 inhibited the formation of foam cells by inhibiting endocytosis of macrophages, thus it may act as a potential anti-atherosclerotic agent. PMID- 28868871 TI - [Inhibitory effect of different species of hydroxygenkwanin on UGTs and UGT1A1 activities]. AB - To predit the mechanism of metabolic drug-drug interactions of hydroxygenkwanin with other drugs, we investigated the inhibition inhibitory effect of hydroxygenkwanin on UGTs and UGT1A1 activities of different liver microsomes. In the present study, 4-nitrophenol (4-NP) and beta-estradiol were elected as substrates to determine activities of UGTs and UGT1A1 by UV and HPLC, respectively. The results showed that, hydroxygenkwanin significantly inhibited UGTs activity in rat, mouse and human liver microsomes. UGT1A1 activity was inhibited by hydroxygenkwanin to varying degrees, with IC50 about 190, 10.93, 20.07, 76.31 MUmol*L-1 in mouse liver microsome(MLM), rat liver microsome (RLM) and recombinant UGT1A1, and human liver microsome (HLM), respectively. The inhibition types were competitive inhibition (RLM, HLM) and linear mixed-typed linear inhibition (recombinant UGT1A1). The order for the inhibitory intensity was RLM>rUGT1A1>HLM>MLM. In conclusion, hydroxygenkwanin has an inhibitory effect on UGTs and UGT1A1 activities of different liver microsomes, with differences in species, indicating its potential drug interactions based on UGT1A1 enzyme. This study aims to provide a reliable experimental basis for its further research and development of hydroxygenkwanin, and provide theoretical reference for the clinic drug combination research. PMID- 28868872 TI - [HTRF-based high-throughput PGE2 release prohibition model and application in discovering traditional Chinese medicine active ingredients]. AB - Prostaglandin (PG) E2 is an active substance in pathological and physiological mechanisms, such as inflammation and pain. The in vitro high-throughput assay for screening the inhibitors of reducing PEG2 production is a useful method for finding out antiphlogistic and analgesic candidates. The assay was based on LPS induced PGE2 production model using a homogeneous time-resolved fluorescence(HTRF) PGE2 testing kit combined with liquid handling automation and detection instruments. The critical steps, including the cell density optimization and IC50 values determination of a positive compound, were taken to verify the stability and sensibility of the assay. Low intra-plate, inter-plate and day-to-day variability were observed in this 384-well, high-throughput format assay. Totally 5 121 samples were selected from the company's traditional Chinese medicine(TCM) material base library and used to screen PGE2 inhibitors. In this model, the cell plating density was 2 000 cells for each well; the average IC50 value for positive compounds was (7.3+/-0.1) MUmol; the Z' factor for test plates was more than 0.5 and averaged at 0.7. Among the 5 121 samples, 228 components exhibited a PGE2 production prohibition rate of more than 50%, and 23 components exhibited more than 80%. This model reached the expected standards in data stability and accuracy, indicating the reliability and authenticity of the screening results. The automated screening system was introduced to make the model fast and efficient, with a average daily screening amount exceeding 14 000 data points and provide a new model for discovering new anti-inflammatory and analgesic drug and quickly screening effective constituents of TCM in the early stage. PMID- 28868873 TI - [Regulations of berberine on gene expression of BMP4 transcriptional pathways to improve visceral white adipose tissues insulin resistance in type 2 diabetic hamsters]. AB - To study the effects of berberine on the gene mRNA expressions of BMP4 transcriptional pathways and brown/white adipose tissue conversion transcriptional pathways in visceral white adipose tissues(VWAT) in type 2 diabetic hamsters and explore the relevant mechanisms. The obese insulin resistant hamster model were induced by using high-fat diet, and then the type 2 diabetic hamster model was created through injection with low-dose streptozotocin in the obese insulin-resistant hamster model. After the modeling, the hamsters were randomly divided into normal control, obese insulin-resistant, type 2 diabetic and berberine-treated diabetic groups. After the nine-week treatment, real-time quantitative PCR was used to measure the changes in gene mRNA expressions of VWAT BMP4 transcriptional pathways, brown/white adipose tissue conversion transcriptional pathways and their target genes in different groups. The results showed that the gene mRNA expressions of BMP4, BMPRII, BMPRlA, Smad1, Smad5, Smad8, p38/MAPK, ATF2, PRDM16, C/EBPbeta, PGC1alpha, PPARgamma and brown adipose tissue-specific genes was decreased and that of Smad6, Smurf1 and white adipose tissue-specific genes was increased in VWAT of model hamsters. Treatment with berberine regulated BMP4 transcriptional pathways and brown adipose tissue transcriptional pathways and induced the gene mRNA expression of brown adipose tissue-specific genes in VWAT to develop browning gene phenotype of white adipose tissues, and then improved fat-induced insulin resistance. These findings indicated that BMP4 transcriptional pathways involved in the formation of fat induced visceral white adipose tissues insulin resistance (FIVWATIR) and the browning molecular mechanism of white adipose tissues induced by berberine. PMID- 28868874 TI - [LC-LTQ-Orbitrap analysis on chemical constituents in Scrophulariae Radix extract and their metabolites in rat plasma]. AB - Chemical constituents in extract of Scrophulariae Radix and their metabolites in rat plasma after oral administration were identified by HPLC-LTQ-Orbitrap. Samples were separated by a Venusil MP C18 column using a binary gradient elution. The information on the total ion chromatogram, the extraction chromatogram and the mass spectrogram in a negative mode were synthetically analyzed by comparing the retention time, MS and MS/MS spectra with literature data and some of reference standards to conduct a qualitative study on constituents of Radix Scrophulariae extract in vivo and in vitro. Totally 37 compounds from Scrophularia ningpoensis extract were detected including 12 iridoid glycosides, 20 phenylpropanoids and 5 unknown compounds. In vivo, harpagide, harpagoside and angoroside C were confirmed to enter into the blood in prototype forms. Besides, another 2 prototype compounds and 2 metabolites were detected in rat plasma after oral administration of S. ningpoensis extract. The results are beneficial for the determination of bioactive substances of S. ningpoensis and significant for further studies on S. ningpoensis. PMID- 28868875 TI - [Data mining analysis of regularity of formulas containing Salviae Miltiorrhizae Radix et Rhizoma-Carthami Flos medicin pair in Dictionary of Chinese Medicine Prescription]. AB - In this study, formulas containing Salviae Miltiorrhizae Radix et Rhizoma Carthami Flos in the database of Dictionary of Chinese Medicine Prescription (DCMP) were extracted by using traditional Chinese medicine inheritance support system (TCMISS). The drugs pairs and formula composition rules were analyzed with data mining methods, such as association rules, improved mutual information method and complex system entropy clustering. Totally 39 formulas were included in this study and involved 280 Chinese medicines. The top 5 Chinese medicines most frequently used were Danggui (Angelica sinensis), Chuanxiong (Ligusticum chuanxiong), Xiangfu (Cyperi Rhizoma), Baishao(Radix Paeoniae Alba), Taoren(Prunus persica) and Shengdihuang (Radix Rehmanniae Recens). Six core medicinal pairs were obtained through clustering analysis, namely Danshen (Salviae Miltiorrhizae Radix et Rhizoma)-Xiangfu (Cyperi Rhizoma)-Honghua (Carthami Flos), Danshen (Salviae Miltiorrhizae Radix et Rhizoma)-Baishao (Radix Paeoniae Alba)-Honghua (Carthami Flos), Danshen (Salviae Miltiorrhizae Radix et Rhizoma)-Danggui (A. sinensis)-Xiagnfu (Cyperi Rhizoma)-Honghua (Carthami Flos), Danshen (Salviae Miltiorrhizae Radix et Rhizoma)-Danggui (A. sinensis)-Baishao (Radix Paeoniae Alba)-Honghua (Carthami Flos), Honghua (Carthami Flos)-Danshen (Salviae Miltiorrhizae Radix et Rhizoma)-Baishao (Radix Paeoniae Alba)-Danggui (A. sinensis), Danshen (Salviae Miltiorrhizae Radix et Rhizoma)-Baishao (Radix Paeoniae Alba)-Honghua (Carthami Flos)-Danggui (A. sinensis). The support degree was set at 11 (38.46%), with a confidence coefficient of 80%, and then 38 associated pairs were screened. These results suggested that Salviae Miltiorrhizae Radix et Rhizoma, Carthami Flos is often combined with herbs for activating blood and promoting circulation of qi to treat gynecopathy, stasis blood pain syndrome, stroke and other syndromes. PMID- 28868876 TI - [Effect of Quyu Huatan decoction on lipid metabolism and hormone levels of patients with polycystic ovary syndrome]. AB - To study the effect of prescription for removing blood stasis and resolving phlegm on lipid metabolism and hormone levels of patients with polycystic ovary syndrome. Totally 93 cases of patients with polycystic ovary syndrome treated in our hospital from March 2013 to July 2014 were randomly divided into control group and observation group. The observation group was treated by oral administration of Quyu Huatan decoction, while the control group was treated with metformin. The result indicated that the total effective rate of the observation group was significantly higher than that of the control group(chi2=632, P<0.05). After treatment, the score of syndrome for traditional Chinese medicine in the observation group was significantly lower than the control group(t=13.865,P<0.05). After treatment, the levels of TG, BMI, TC in the observation group were significantly lower than the control group(P<0.05), and the difference of HDL between the two groups were not significantly. After treatment, the levels of FSH, LH and T in the observation group were significantly lower than those in the control group(P<0.05). After treatment, FBG and INS in the two groups were significantly decreased(P<0.05); the FBG in the observation group was significantly lower than that in the control group(t=3.981, P<0.05), and the INS level in the observation group was significantly higher than that in the control group(t=6.472, P<0.05). In this study, we can find that the Quyu huatan decoction for removing blood stasis and resolving phlegm has a better clinical efficacy in the treatment of polycystic ovary syndrome. It not only ameliorates the secretion of variety sex hormone, but also regulates the body's metabolism of glucose and lipid, so it is worth clinical promotion and application. PMID- 28868877 TI - [Meta-analysis on effect of Shenfu injection in treating angina pectoris]. AB - To systematically evaluate the efficiency and safety of Shenfu injection in treating patients with angina pectoris. Retrievals were made in Embase, Pubmed, Cochrane Library, Clinical Trials.gov, CNKI, CBM, VIP and Wanfang (before September 2015) for randomized or semi-randomized controlled trials reporting data of Shenfu injection in the adjuvant treatment of angina pectoris. The quality of included trials was evaluated according to tool evaluation at cochrane.org. STATA version 12.0 was applied for Meta analysis after quality assessment of included studies. Finally, a total of 17 studies, including 16 randomized controlled trials (RCTs) and 1 controlled clinical trial (CCT) involving 1 309 patients, met the inclusion criteria, of which 659 patients received Shenfu injection treatment. Meta-analysis results showed that Shenfu injection treatment group significantly improved angina pectoris symptoms (OR=3.38, 95%CI: 2.47-4.64, P=0.000) and ischemic ST-T changes in electrocardiogram (OR=3.30, 95%CI: 2.22-4.90, P=0.000), compared with control group. In the Meta-regression analysis, the average age of patients was positively correlated with the improved clinical (beta=0.17) and electrocardiogram (beta=1.15) efficacies. Major complication rate of Shenfu injection was 3.4%, and no serious adverse events were reported. Current clinical evidence in this study proved that Shenfu injection could significantly improve clinical symptoms and ECG ischemic changes for angina pectoris patients, with a good safety. PMID- 28868878 TI - [Spleen, liver and kidney-strengthening formula combined with polyethylene glycol interferon in treatment of chronic hepatitis B]. AB - To observe the clinical efficacy of spleen, liver and kidney-strengthening formula combined with polyethylene glycol interferon in the treatment of HBeAg positive chronic hepatitis B(HP-HBV).One hundred and twenty-six patients with HP HBV, who were treated in the hospital from June 2012 to December 2014, were selected and injected with polyethylene glycol interferon alpha-2a(or alpha-2b). The treatment course for the patients lasted for 24 weeks. Base on the level of HBV-DNA, patients are divided into response group and poor response group. According to random number table, the poor response group were randomized into control group and test group. Patients in the control group were injected with polyethylene glycol interferon alpha-2a(or alpha-2b), and patients in the test group were treated with spleen, liver and kidney-strengthening formula combined with polyethylene glycol interferon. Clinical efficacies of the 2 groups were observed, and changes in the level of HBeAg, ALT and HBV-DNA were observed before treatment and at the 24th week after treatment, and virological and serological response, biochemical responses, integral clinical symptoms and signs, adverse reactions were observed after 48 weeks of treatment.After 24 weeks of treatment, the response group was significantly better than the poor response group in HBeAg, ALT and the level of HBV-DNA(P<0.05). After 48 weeks of treatment, there was statistical significance in HBV-DNA negative conversion rate, HBeAg negative conversion rate between the 2 groups(P<0.05), and the test group was better in the two indicators. And the test group was significantly lower than the control group in clinical symptoms and signs score at the 48th week after treatment(P<0.05), with a significantly lower adverse reaction rate than the control group(P<0.05).Combination of spleen, liver and kidney-strengthening formula and polyethylene glycol interferon alpha-2a was effective and safe in the treatment of chronic hepatitis B, and so worth promoting in clinic. PMID- 28868879 TI - [Framework on drug interactions between herbal medicine and western medicine: building I/II/III class pathways of interactions]. AB - Combined use of Chinese medicine and western medicine is one of the hot spots in the domestic medical and academic fields for many years. There are lots of involved reports and studies on interaction problems due to combined used of Chinese medicine and western medicine, however, framework understanding is still rarely seen, affecting the clinical rationality of drug combinations. Actually, the inference ideas of drug interactions in clinical practice are more extensive and practical, and the overall viewpoint and pragmatic idea are the important factors in evaluating the rationality of clinical drug combinations. Based on above points, this paper systemically analyzed the existing information and examples, deeply discuss the embryology background (environment and action mechanism of interactions), and principally divided the interactions into three important and independent categories. Among the three categories, the first category (Iapproach) was defined as the physical/chemical reactions after direct contact in vivo or in vitro, such as the combination of Chinese medicine injections and western medicine injections (in vitro), combination of bromide and Chinese medicines containing cinnabar (in vivo). The evaluation method for such interactions may be generalized theory of Acid-Base reaction. The second category (II approach) was defined as the interactions through the pharmacokinetic process including absorption (such as the combination of aspirin and Huowei capsule), distribution (such as the combination of artosin and medicinal herbs containing coumarin), metabolism (such as the combination of phenobarbital and glycyrrhiza) and excretion (such as the combination of furadantin and Crataegi Fructus). The existing pharmacokinetic theory can act as the evaluation method for this type of interaction. The third category (III approach) was defined as the synergy/antagonism interactions by pharmacological effects or biological pathways. The combination of warfarin and Salvia miltiorrhiza is an example for synergy interaction, while the combination of guanethidine and ephedra is an example for anatagonism interaction. The repeated application of Chinese and western medicine compound preparations and same type of western medicine also belongs to this approach. The receptor competition theory under the view of the overall pathways might act as the evaluation method for this type of interactions. Above all, the research framework on interactions between Chinese medicine and western medicine was proposed, providing overall thinking and support for the essential study on combined application of Chinese medicine and western medicine. PMID- 28868880 TI - [Application of "Fu Yang and activating blood circulation" in treatment of unstable angina pectoris patients]. AB - Coronary heart disease(CHD) has become a major public health problem in the world, while the unstable angina (UA) is one of an important type. Hypofunction of yang qi in chest and cardiac blood stasis has been considered as the basic pathogenesis of UA.According to the deficiency of yang and blood stasis run through the process of CHD, fu yang and activating blood circulation could be main treatment. Wenxin decoction which has the function of fu yang and activating blood circulation, not only can effectively improve the symptoms of angina pectoris, the ischemic ECG, but also can significantly improve blood rheology, blood lipids and so on. So deepening the theory of "fu yang and activating blood circulation" and the application of "Wenxin decoction" in the treatment of UA would have an important clinical value for improving the therapeutic efficacy of CHD. PMID- 28868881 TI - [Current status and sustainable development countermeasures of Anoectochilus roxburghii]. AB - The current status of the domestic manufacturing and sales markets of Anoectochilus roxburghii were investigated and analyzed in the study. Some problems in the A. roxburghii industry were revealed and a variety of sustainable development countermeasures were also proposed. The main problems of A. roxburghii industry are the lack of protection for wild resources, the lag in the speed of variety breeding, the insufficient research on the quality systems, the low level of industry and product innovation capability, as well as the relatively low market cognition and brand competence. Therefore, strengthening the protection for breeding resources, establishing a dynamic monitoring system, promoting the variety breeding, constructing a propagation system for improved varieties, enhancing the quality of medicinal herbs, accelerating the adjustment of product structure, upgrading the industry technology, strengthening brand competence and expanding the market, will be the effective methods to realize the sustainable development of A. roxburghii industry. PMID- 28868883 TI - Lysosomal-Targeted Two-Photon Fluorescent Probe to Sense Hypochlorous Acid in Live Cells. AB - A two-photon reversible fluorescent probe L1 was designed and synthesized. The fluorescence intensity of the probe solution was strong, while the fluorescence of the solution was obviously quenched and the color of the solution was changed after the addition of hypochlorous acid, indicating this is "naked-eye sensor" for the detection of HClO. The probe showed great selectivity for hypochlorous acid over other reactive oxygen species (ROS) and anions. Fluorescence titration experiments showed that the probe has a low detection limit of 0.674 MUM. Because of a morpholine group introduced to the naphathalimide framework, probe L1 was successfully applied to detect intracellular HClO in lysosome. PMID- 28868882 TI - Graphene-Titanium Interfaces from Molecular Dynamics Simulations. AB - Unraveling the physical and chemical properties of graphene-metal contacts is a key step toward the development of graphitic electronic nanodevices. Although many studies have revealed the way that various metals interact with graphene, few have described the structure and behavior of large pieces of graphene-metal nanostructures under different conditions. Here, we present the first classical molecular dynamics study of graphene-titanium (G-Ti) structures, with and without substrates. Physical and chemical properties of equilibrium structures of G-Ti interfaces with different amounts of titanium coverage are investigated. Adhesion of Ti films on graphene is shown to be enhanced by the vacancies in graphene or the electrostatic influence of substrates. The dynamics of pristine G-Ti structures at different temperatures on planar and nonplanar substrates are investigated, and the results show that G-Ti interfaces are thermally stable, that is, not prone to any reaction toward the formation of titanium carbide. PMID- 28868884 TI - Effects of Free Energy and Solvent on Rates of Intramolecular Electron Transfer in Organic Radical Anions. AB - Rates of intramolecular electron transfer from a 1,1'-biphenylyl radical anion to six different acceptors on an androstane scaffold are examined with the aid of a theory that was developed recently to include effects of vibrational relaxations and dephasing. The electronic-interaction matrix element and other parameters needed for the theory are obtained by quantum-mechanical/molecular-mechanical simulations of the reactions in five solvents ranging from iso-octane to methyltetrahydrofuran. Intramolecular vibrational modes that are coupled to electron transfer are resolved in simulations in iso-octane and cyclohexane. The energies and coupling factors for these modes allow extension of the theory to incorporate transitions to and from excited vibrational levels. The calculated rates of electron transfer agree well with experimental measurements from the literature, except for reactions in which excited electronic states of the products become important. PMID- 28868885 TI - Cobalt/Copper-Cocatalyzed Synthesis of Imidazo[1,2-a:3,4-a']dipyridiniums from 2H [1,2'-Bipyridin]-2-ones and 2-Bromoacetophenones. AB - A cobalt/copper-cocatalyzed facile synthesis of imidazo[1,2-a:3,4 a']dipyridiniums from 2H-[1,2'-bipyridin]-2-ones and 2-bromoacetophenones is presented. This strategy provides an alternative to the imidazo[1,2-a:3,4 a']dipyridinium synthesis by employing readily available substrates and a simple procedure, which would render this method potentially useful in organic synthesis. PMID- 28868887 TI - Controllable Preparation of CuFeMnO4 Nanospheres as a Novel Multifunctional Affinity Probe for Efficient Adsorption and Selective Enrichment of Low-Abundance Peptides and Phosphopeptides. AB - A facile solvothermal method for the synthesis of multifunctional magnetic CuFeMnO4 nanospheres affinity probe (NSAP) with controllable morphology and size was developed for the first time. The CuFeMnO4 nanospheres combine the brilliant features of Cu2+, Fe3+, and Mn2+ ions, so their multifunction performances are embodied by strong coordination to carboxyl and amine groups of peptides (Cu2+ and Fe3+), special affinity to phosphate groups of phosphopeptides (Fe3+ and Mn2+), and high magnetic responsiveness in a magnetic field. Their potential as an affinity probe was evaluated for highly effective enrichment, rapid magnetic separation of low-abundance peptides (neutral condition), and effective selective capture of phosphopeptides (acid condition) from various complex biosamples. Notably, CuFeMnO4 NSAP was explored for highly selective capture and isolation of phosphopeptides from A549 cells after exposure to ZnO nanoparticles for different times. Consequently, we put forward a new nanospinel ferrite-based protocol here to analyze and identify the phosphoproteins/phosphopeptides involved in cellular signaling pathways in response to exogenous stimulation. PMID- 28868886 TI - Gastrointestinal Absorption and Metabolic Dynamics of Jujuboside A, A Saponin Derived from the Seed of Ziziphus jujuba. AB - Jujuboside A (JuA), an active saponin, is responsible for the anxiolytic and sedative effects of Zizyphi Spinosae Semen (ZSS). In this study, the gastrointestinal absorption and metabolic dynamics of JuA were investigated in vivo and in vitro. The results showed that the bioavailability was 1.32% in rats, indicating only a trace amount of JuA was able to be absorbed. Further investigation revealed that its poor bioavailability was not caused by malabsorption but by the metabolic process. JuA was hydrolyzed largely in the stomach before being absorbed into the different parts of the intestine (especially duodenum and colon), and the gastric environment played a vital role in this process. Furthermore, the metabolites, jujuboside B (JuB) and jujubogenin, exhibited significant effects on the expression and activation of gamma-amino-butyric acid A (GABA(A)) receptors. Our findings demonstrate that the metabolites of the saponin, not the original molecule, should be responsible for the specific bioactivities. PMID- 28868888 TI - Selective Micellar Extraction of Ultratrace Levels of Uranium in Aqueous Samples by Task Specific Ionic Liquid Followed by Its Detection Employing Total Reflection X-ray Fluorescence Spectrometry. AB - A task specific ionic liquid (TSIL) bearing phosphoramidate group, viz., N propyl(diphenylphosphoramidate)trimethylammonium bis(trifluoromethanesulfonyl)imide, was synthesized and characterized by 1H NMR, 13C NMR, 31P NMR, and IR spectroscopies, elemental (C H N S) analysis, and electrospray ionization mass spectrometry (ESI-MS). Using this TSIL a cloud point extraction (CPE) or micelle mediated extraction procedure was developed for preconcentration of uranium (U) in environmental aqueous samples. Total reflection X-ray fluorescence spectrometry was utilized to determine the concentration of U in the preconcentrated samples. In order to understand the mechanism of the CPE procedure, complexation study of the TSIL with U was carried out by isothermal calorimetric titration, liquid-liquid extraction, 31P NMR and IR spectroscopies, and ESI-MS. The developed analytical technique resulted in quantitative extraction efficiency of 99.0 +/- 0.5% and a preconcentration factor of 99 for U. The linear dynamic range and method detection limit of the procedure were found to be 0.1-1000 ng mL-1 and 0.02 ng mL-1, respectively. The CPE procedure was found to tolerate a higher concentration of commonly available interfering cations and anions, especially the lanthanides. The developed analytical method was validated by determining the concentration of U in a certified reference material, viz., NIST SRM 1640a natural water, which was found to be in good agreement at a 95% confidence limit with the certified value. The method was successfully applied to the U determination in three natural water samples with <=4% relative standard deviation (1sigma). PMID- 28868889 TI - Recruiting Practices for Change Initiatives Is Hard: Findings From EvidenceNOW. AB - Engaging primary care practices in initiatives designed to enhance quality, reduce costs, and promote safety is challenging as practices are already participating in numerous projects and mandated programs designed to improve care delivery and quality. Recruiters must expand their recruitment tools to engage today's practices in quality improvement. Using grant proposals, online diaries, observational site visits, and interviews with key stakeholders, the authors identify successful practice recruitment strategies in the EvidenceNOW initiative, which aimed to recruit approximately 1500 small- to medium-sized primary care practices. Recruiters learned they needed to articulate how participation in EvidenceNOW aligned with other initiatives and could help practices succeed with federal and state initiatives, recognition programs, and existing or future payment requirements. Recruiters, initiative leaders, and funders must now consider how their efforts align with ongoing initiatives to successfully recruit and engage practices, ease practice burden, and encourage participation in efforts that support practice transformation. PMID- 28868890 TI - Autoimmunity, Autonomic Neuropathy, and the HPV Vaccination: A Vulnerable Subpopulation. PMID- 28868891 TI - Anticholinergic burden in older inpatients on psychotropic medication: do we care? AB - OBJECTIVES: This quality activity explored the prescribing patterns in an Older Persons Mental Health Inpatient Unit in order to establish whether the Anticholinergic Cognitive Burden Scale (ACB Scale) score on admission was reviewed to minimise anticholinergic cognitive burden (ACB) while maintaining therapeutic effects. METHODS: A retrospective electronic chart review of 50 discharged patients for any documented ACB review by the treating team, as well as the ACB Scale scores on admission and discharge. FINDINGS: ACB was rarely considered. On average, the total ACB Scale scores on admission and discharge were high. At the time of discharge, the proportion of patients on at least one anticholinergic medication had significantly increased, and only 10% of patients were on no anticholinergic medication. Approximately 50% of patients had an increased ACB Scale score by discharge as opposed to only 8% who had reduced scores. CONCLUSIONS: Anticholinergic polypharmacy should be minimised when prescribing to the elderly population to reduce potential anticholinergic burden. PMID- 28868893 TI - Five-Year Multicenter Study of Clinical Tests of Neonatal Purulent Meningitis. AB - This study aimed to provide more data support for early diagnosis and treatment of neonatal purulent meningitis through retrospective analysis of its clinical diagnosis and treatment, pathogen distribution, and drug resistance in 5 third class A hospitals in Southwest and Northwest China from January 2011 to December 2015. It was found that both the positive rates of blood and cerebrospinal fluid culture were low, and Escherichia coli should be the main pathogenic bacteria. Drug-resistant strains with varying degrees to the third generation of cephalosporin antibiotics have appeared currently. PMID- 28868894 TI - A Pilot Study of Trauma-Focused Cognitive-Behavioral Therapy Delivered via Telehealth Technology. AB - Significant barriers exist in access to evidence-based, trauma-focused treatment among youth from economically disadvantaged backgrounds, those living in rural areas, and belonging to a racial and ethnic minority group, despite the high prevalence rates of trauma exposure among these underserved groups. The present study is proof-of-concept pilot of trauma-focused cognitive-behavioral therapy (TF-CBT) delivered to underserved trauma-exposed youth ( N = 15) via telehealth technology (i.e., via one-on-one videoconferencing), aimed at addressing barriers in access to TF treatment. This pilot study provides preliminary evidence of the ability to successfully deliver TF-CBT via a telehealth delivery format. Results demonstrated clinically meaningful symptom change posttreatment (large effect sizes for youth-reported ( d = 2.93) and caregiver-reported ( d = 1.38) reduction in posttraumatic stress disorder symptoms), with no treatment attrition (0% dropout). These findings are promising in showing treatment effects that are comparable with TF-CBT delivered in an in-person, office-based setting and an important first step in determining how to best address the mental health needs of trauma-exposed youth with barriers in access to care. PMID- 28868892 TI - Home-based pulmonary rehabilitation for people with COPD: A qualitative study reporting the patient perspective. AB - This study aimed to document the perspective of patients with chronic obstructive pulmonary disease (COPD) who underwent home-based pulmonary rehabilitation (HBPR) in a clinical trial. In this qualitative study, open-ended questions explored participants' views regarding HBPR. Thirteen semi-structured interviews were analysed using a thematic analysis approach. Major themes from interviews included the positive impact of HBPR on physical fitness, breathing and mood. Participants valued the flexibility and convenience of the programme. Participants also highlighted the importance of social support received, both from the physiotherapist over the phone and from family and friends who encouraged their participation. Reported challenges were difficulties in initiating exercise, lack of variety in training and physical incapability. While most participants supported the home setting, one participant would have preferred receiving supervised exercise training at the hospital. Participants also reported that HBPR had helped establish an exercise routine and improved their disease management. This study suggests that people with COPD valued the convenience of HBPR, experienced positive impacts on physical fitness and symptoms and felt supported by their community and programme staff. This highly structured HBPR model may be acceptable to some people with COPD as an alternative to centre-based pulmonary rehabilitation. PMID- 28868895 TI - In-Law Preferences in China and in Cyprus: Differences and Similarities. AB - Across different times and cultures, parents exercise considerable influence over their children's mate choices. When they do so, parents are looking for specific traits in a prospective daughter- and son-in-law. Using a sample of 674 parents, the current research investigated in-law preferences in China. Participants rated 88 different traits, which were clustered in 10 different preference domains. In law preferences were found to be contingent on the sex of the in-law and the sex of the parent. The data from the current study were compared with data from a different study which took place in the Republic of Cyprus. It was found that preferences varied in the two samples, but specific cultural differences were identified. It was also found that for both samples, the 10 different domains clustered in two supra-domains. The first supra-domain, where personality traits clustered, was preferred more by both Chinese and Greek-Cypriot parents than the second domain, where the rest of the traits clustered. PMID- 28868896 TI - Stock Photographs Do Not Comply With Infant Safe Sleep Guidelines. AB - We evaluated images in popular stock photography websites for adherence with American Academy of Pediatrics (AAP) guidelines for safe infant sleep practices. Three top stock photo websites were used to collect photographs generated from key phrases. All images depicting an infant sleep environment were analyzed for consistency with AAP guidelines. Descriptive statistics, chi-square and z test of proportions, were conducted. A total of 1233 of 1947 stock photographs showed sleeping infants on a flat surface. In all, 627 (50.8%) photographs showed the infant in the supine position and 79 (5%) of all infant sleep environments were adherent with AAP recommendations. Bedding inconsistent with safe sleep recommendations was identified in 1133 images (71.3%), with blankets noted in 49.5%. Images depicting sleeping infants on stock photography sites do not routinely adhere to AAP recommendations. Media messages inconsistent with health care messages create confusion and misinformation about infant sleep safety and may lead inadvertently to unsafe practices. PMID- 28868897 TI - Recurrent Sterile Abscesses After Immunization With Aluminum-Adjuvant Based Vaccines. PMID- 28868899 TI - Rate of Change of Premeal Glucose Measured by Continuous Glucose Monitoring Predicts Postmeal Glycemic Excursions in Patients With Type 1 Diabetes: Implications for Therapy. AB - BACKGROUND: Patients with type 1 diabetes routinely utilize a single premeal fingerstick glucose to determine premeal insulin doses. Continuous glucose monitoring (CGM) provides much richer glycemic trend information, including glycemic slope (GS). How to incorporate this information into dosing decisions remains an open question. METHODS: We examined the relationship between premeal GS and postmeal glycemic excursions in 240 individuals with type 1 diabetes receiving CGM augmented insulin pump therapy. Over 23.5 million CGM values were synchronized with 264 500 meals. CGM values were integrated 2 hours premeal to compute GS and 2 hours postmeal to compute glycemic excursion outcomes. Postmeal hyperglycemia (integrated CGM glucose >180 mg/dL*hr) and postmeal hypoglycemic events (any CGM glucose < 70 mg/dL) were tabulated according to positive/negative premeal GS and according to GS bins commonly displayed as rate-of-change arrows on CGM devices. RESULTS: Positive versus negative premeal GS was associated with a 2.28-fold (95% CI 2.25-2.32) risk of postmeal hyperglycemia. Negative versus positive premeal GS was associated with a 2.36-fold (95% CI 2.25-2.43) increase in one or more postprandial hypoglycemic events. Premeal GS in the bin currently displayed as "no change" on existing CGM devices (-1 to 1 mg/dL/min), conferred a 1.82-fold (95% CI 1.79-1.86) risk of postprandial hyperglycemia when positive and a 2.06-fold (95% CI 1.99-2.15) increased risk of postprandial hypoglycemia when negative. CONCLUSION: Premeal GS predicts postmeal glycemic excursions and may help inform insulin dosing decisions. Rate-of-change arrows on existing devices obscure clinically actionable glycemic trend information from CGM users. PMID- 28868898 TI - The tumour suppressor CDKN2A/p16INK4a regulates adipogenesis and bone marrow dependent development of perivascular adipose tissue. AB - The genomic CDKN2A/B locus, encoding p16INK4a among others, is linked to an increased risk for cardiovascular disease and type 2 diabetes. Obesity is a risk factor for both cardiovascular disease and type 2 diabetes. p16INK4a is a cell cycle regulator and tumour suppressor. Whether it plays a role in adipose tissue formation is unknown. p16INK4a knock-down in 3T3/L1 preadipocytes or p16INK4a deficiency in mouse embryonic fibroblasts enhanced adipogenesis, suggesting a role for p16INK4a in adipose tissue formation. p16INK4a-deficient mice developed more epicardial adipose tissue in response to the adipogenic peroxisome proliferator activated receptor gamma agonist rosiglitazone. Additionally, adipose tissue around the aorta from p16INK4a-deficient mice displayed enhanced rosiglitazone-induced gene expression of adipogenic markers and stem cell antigen, a marker of bone marrow-derived precursor cells. Mice transplanted with p16INK4a-deficient bone marrow had more epicardial adipose tissue compared to controls when fed a high-fat diet. In humans, p16INK4a gene expression was enriched in epicardial adipose tissue compared to other adipose tissue depots. Moreover, epicardial adipose tissue from obese humans displayed increased expression of stem cell antigen compared to lean controls, supporting a bone marrow origin of epicardial adipose tissue. These results show that p16INK4a modulates epicardial adipose tissue development, providing a potential mechanistic link between the genetic association of the CDKN2A/B locus and cardiovascular disease risk. PMID- 28868900 TI - Natural resistance of Sri Lankan village chicken to Salmonella gallinarum infection. AB - 1. An experiment was conducted to compare the natural resistance of an indigenous breed of local village chickens to Salmonella gallinarum with two commercial breeds: ISA Brown and ISA White layers under experimental conditions. 2. A total of 72 chickens from each of these breeds were randomly distributed to 4 pens to provide equal numbers of two replicate pens maintained as infected and control (uninfected). All chickens in infected groups were inoculated orally with 1 * 108 CFU (1 ml dose) of a field isolate of S. gallinarum, at the age of 8 and 16 weeks given over 5 consecutive days. Growth performance, clinical signs, gross pathological lesions and antibody responses were measured. 3. A significantly higher mortality was observed in the brown layers compared with the white layers, and clinical signs and mortality were absent in village chickens. However, a large number of birds with gross lesions and high antibody titres were detected in village chickens, indicating that birds had the disease subclinically. Commercial breeds had a significantly higher body weight, feed intake and feed conversion efficiency. 4. There was a significantly lower proportion of positive reactors in village chickens in the whole-blood agglutination test (35%) compared to brown (100%) and white (90%) layers even after the second inoculation. Uninfected birds were negative in all groups. The indirect enzyme-linked immunosorbent assay confirmed these observations. 5. These results suggest that the indigenous breed had superior natural resistance to S. gallinarum than the commercial breeds. PMID- 28868901 TI - Assessment and biomonitoring indoor environment of buildings. AB - Ensuring hygiene and health protection is one of the basic construction requirements. Such requirements are examined when commissioning new constructions and examining defects in constructions already in use. One substantial defect is biocorrosion which represents a synergistic process with a complex variety of factors. It is caused by biochemical manifestations of various micro-organisms (micromycetes). Micromycetes producing mycotoxins therefore play an important role regarding the so-called 'Sick Building Syndrome' that has become a global problem nowadays. The case study presented here aims to demonstrate the effectiveness of the diagnostic methods used in assessing the presence of micromycetes in a building's internal atmosphere and on the internal surfaces of a construction built using traditional construction methods. The methodology of comparing methods is based on their effectiveness, taking into account the identification of type and intensity of micromycetes presence in the air and on the material surfaces in the monitored areas. PMID- 28868902 TI - Differences Between Sleep Logs and Actigraphy Combined With Electroencephalography in Adults With Sleep Disturbances. AB - BACKGROUND: Actigraphy plus single-channel electroencephalography (EEG) has a high agreement with polysomnography and is considered a simple method for monitoring sleep at home. No studies, however, have evaluated its agreement with sleep logs. PURPOSE: A sleep log was compared to a single-channel EEG in adults with sleep disturbances. The determinants of the agreement between the two recording methods were explored. METHOD: This prospective comparison substudy included 71 participants aged 22-67 years sampled from a previous study of nonpharmacological therapy for sleep disturbances. The participants concurrently used a sleep log and a single-channel EEG machine for 6 days to measure their sleep at home. Total sleep time (TST) and sleep onset latency (SOL) were compared. RESULTS: Correlations between measurements were .43 for TST ( p < .001) and .30 ( p < .01) for SOL. Bland-Altman analysis revealed that the mean bias between methods was 81.54 min (standard deviation [ SD] = 66.72 min) for TST and 5.58 min ( SD = 25.38 min) for SOL. SDs for both TST and SOL were higher for the sleep log than for EEG. A multivariate linear regression model demonstrated that age (standardized coefficient beta = .42, p = .001) was a significant predictor of the mean difference in SOL measurements, accounting for 13.7% of the total variance in the mean difference. CONCLUSION: Sleep log and single-channel EEG sleep measures are distinct from one another, and age predicts the mean level of disagreement between the two measures in adults with sleep disturbances. PMID- 28868903 TI - Toward 90-90-90: identifying those who have never been tested for HIV and differences by sex in Lesotho. AB - To reach HIV epidemic control it is important to ensure that those who have never been tested access HIV testing and counseling (HTC) particularly in the context of a generalized HIV epidemic. Using data from the 2014 Lesotho Demographic Health Survey bivariate and multivariate logistic regressions were conducted to determine the associations between never tested for HIV and key socio-cognitive characteristics by sex. Marginal probabilities at the means were calculated for the socio-cognitive variables for men and women to ascertain the magnitude of the differences in the likelihood of never being tested by sex. We stratified by gender and controlled for age, education, religion, marital status, place of residence, and years circumcised (for men only). Results indicate that more men than women have never been tested (chi2 = 461.16, p < 0.001); and, among men, acceptance of gender based violence (Odds ratio [OR]: 1.44, p < 0.001), holding discriminatory attitudes (OR: 1.50, p < 0.001), and not having basic HIV prevention knowledge (OR: 1.53, p < 0.001) were significantly associated with never being tested. The likelihood of never being tested among those who had these three socio-cognitive characteristics was much higher among men (0.56, p < 0.001) than women (0.20, p < 0.001). Given the strong sex differential, there is an urgent need for strategies specifically targeting men in order to effectively promote HTC uptake among them. Additionally, results suggest that those strategies should integrate strategies to address GBV acceptance, HIV prevention knowledge, and HIV discrimination or link men to programs addressing these. PMID- 28868904 TI - The Dynamics of Catastrophic and Impoverishing Health Spending in Indonesia: How Well Does the Indonesian Health Care Financing System Perform? AB - Our study examines the incidence and intensity of catastrophic and impoverishing health spending in Indonesia. A panel data set was used from 4 waves of the Indonesian Family Life Surveys 1993, 1997, 2000, and 2007. Catastrophic health expenditure was measured by calculating the ratio of out-of-pocket payments to household income. Then, we calculated poverty indicators as a measure of impoverishing spending in the health care financing system. Head count, overshoot, and mean positive overshoot for each given threshold in 2000 were lower than other surveyed periods; otherwise, fraction headcount in 2007 of households were the higher. Between 1993 and 2007, the percentage of households in poverty decreased, both in gross and net of health payments. However, in each year, the percentages of households in poverty using net health payments were higher than the gross. The estimates of poverty gap, normalized poverty gap, and normalized mean positive gap decreased across the survey periods. The health care financing system performance has shown positive evidence for financial protection offerings. A sound relationship between improvements of health care financing performance and the existing health reform demonstrated a mutual reinforcement, which should be maintained to promote equity and fairness in health care financing in Indonesia. PMID- 28868905 TI - Hope, recovery and symptoms: the importance of hope for people living with severe mental illness. AB - OBJECTIVES: Hope is an important part of recovery from severe mental illness. Our aim was to assess hope and its correlation with symptoms in people living with severe mental illness. METHODS: We used validated questionnaires to assess hope, social isolation, quality of life and symptoms among 60 people living with severe mental illness. RESULTS: Hope scores were significantly lower than those reported for many community groups. There was a negative association between psychiatric symptoms and levels of hope. CONCLUSIONS: Some people living with enduring severe mental illness in the Australian community feel hopeless. Being hopeful and initiating recovery are evidently difficult when symptoms remain severe. Appropriate acknowledgement and support for patients and their families is required. PMID- 28868906 TI - Therapeutic application of contrast ultrasound in ST elevation myocardial infarction: Role in coronary thrombosis and microvascular obstruction. AB - In the past few decades, cardiac ultrasound has become a widely available, easy to-use diagnostic tool in many scenarios in acute cardiac care. The introduction of microbubbles extended its diagnostic value. Not long thereafter, several investigators explored the therapeutic potential of contrast ultrasound on thrombus dissolution. Despite large improvements in therapeutic options, acute ST elevation myocardial infarction remains one of the main causes of mortality and morbidity in the western world. The therapeutic effect of contrast ultrasound on thrombus dissolution might prove to be a new, effective treatment strategy in this group of patients. With the recent publication of human studies scrutinising the therapeutic options of ultrasound and microbubbles in ST elevation myocardial infarction, we have entered a new stage in this area of research. This therapeutic effect is based on biochemical effects both at macrovascular and microvascular levels, of which the exact working mechanisms remain to be elucidated in full. This review will give an up-to-date summary of our current knowledge of the therapeutic effects of contrast ultrasound and its potential application in the field of ST elevation myocardial infarction, along with its future developments. PMID- 28868907 TI - New Device for Intrinsic Hand Muscle Strength Measurement: An Alternative to Strain Gauge Handheld Dynamometer. AB - An accurate measurement of intrinsic hand muscle strength (IHMS) is required by clinicians for effective clinical decision-making, diagnosis of certain diseases, and evaluation of the outcome of treatment. In practice, the clinicians use Intrins-o-meter and Rotterdam Intrinsic Hand Myometer for IHMS measurement. These are quite bulky, expensive, and possess poor interobserver reliability (37-52%) and sensitivity. The purpose of this study was to develop an alternative lightweight, accurate, cost-effective force measurement device with a simple electronic circuit and test its suitability for IHMS measurement. The device was constructed with ketjenblack/deproteinized natural rubber sensor, 1-MOmega potential divider, and Arduino Uno through the custom-written software. Then, the device was calibrated and tested for accuracy and repeatability within the force range of finger muscles (100 N). The 95% limit of agreement in accuracy from 1.95 N to 2.06 N for 10 to 100 N applied load and repeatability coefficient of +/ 1.91 N or 6.2% was achieved. Furthermore, the expenditure for the device construction was around US$ 53. For a practical demonstration, the device was tested among 16 participants for isometric strength measurement of the ulnar abductor and dorsal interossei. The results revealed that the performance of the device was suitable for IHMS measurement. PMID- 28868908 TI - [One year persistence of free and fixed dose combinations of perindopril/amlodipine]. AB - INTRODUCTION: In management of hypertension patient adherence is one of the most important factors. In hypertension the cardiovascular risk reduction can be reached only by prolonged and effective pharmacotherapy. AIM: To evaluate the persistence of one-year treatment of free and fixed-dose combination of perindopril/amlodipine in hypertension. METHOD: Information from the National Health Insurance of Hungary prescriptions database on pharmacy claims between October 1, 2012 and September 30, 2013 was analysed. Authors identified patients who filled prescriptions for free and fixed-dose combination of perindopril/amlodipine, prescribed for the first time for hypertension. Patients have not received antihypertensive therapy with similar active substances during the one year before. Apparatus of survival analysis was used, where "survival" was the time to abandon the medication. As it was available to month precision, discrete time survival analysis was applied. RESULTS: 109,248 patients met the inclusion criteria. Combination antihypertensive therapy with perindopril/amlodipine was started with a free or a fixed-dose combination of these agents in 19,365 and 89,883 patients, respectively. One year persistence rate in patients taking perindopril/amlodipine as a free combination was 27.15%, whereas it was 46.89% in those on the fixed-dose combination. Mean duration of persistence was 177.6 days in patients on the perindopril/amlodipine free, whereas 245.7 days on fixed-dose combination. Actual rate of discontinuation was approximately twice higher with the treatment of free, compared with the use of the fixed-dose combination (hazard ratio =1.94 [95% CI: 1.91-1.98], p<0.001). Orv Hetil. 2017; 158(36): 1421-1425. PMID- 28868909 TI - [Recognizing complicated grief from a doctor's point of view]. AB - By reviewing two bereavement support group cases I wish to demonstrate the important role a doctor, also receptive of his patients' non-verbal signals, has in the early recognition of complicated grief and halted grief process. Doctors are aware of individual traumas and destinies, and general practitioners are familiar with the details of their patients' life and home circumstances, could be catalysts for the continuation of the halted grief process. They discover the real cause of trauma behind several psychosomatic symptoms. For professionals working with bereavement support groups and meeting a number of different manifestations of the experience of absence and loss in people facing complicated grief (by its former, stigmatizing term: pathological or distorted grief), synchronizing the work of such heterogeneous groups of people, who have diverse loss history and individual (grief) habitus, is a real professional challenge. In such a work process the activity of doctors and health care workers can be supportive and could facilitate progress. Orv Hetil. 2017; 158(36): 1426-1431. PMID- 28868910 TI - [Orbital compartment syndrome. The most frequent cause of blindness following facial trauma]. AB - INTRODUCTION: Although orbital compartment syndrome is a rare condition, it is still the most common cause of blindness following simple or complicated facial fractures. Its pathomechanism is similar to the compartment syndrome in the limb. Little extra fluid (blood, oedema, brain, foreign body) in a non-space yielding space results with increasingly higher pressures within a short period of time. Unless urgent surgical intervention is performed the blocked circulation of the central retinal artery will result irreversible ophthalmic nerve damage and blindness. Aim, material and method: A retrospective analysis of ten years, 2007 2017, in our hospital among those patients referred to us with facial-head trauma combined with blindness. RESULTS: 571 patients had fractures involving the orbit. 23 patients become blind from different reasons. The most common cause was orbital compartment syndrome in 17 patients; all had retrobulbar haematomas as well. 6 patients with retrobulbar haematoma did not develop compartment syndrome. Compartment syndrome was found among patient with extensive and minimal fractures such as with large and minimal haematomas. Early lateral canthotomy and decompression saved 7 patients from blindness. CONCLUSION: We can not predict and do not know why some patients develop orbital compartment syndrome. Compartment syndrome seems independent from fracture mechanism, comminution, dislocation, amount of orbital bleeding. All patients are in potential risk with midface fractures. We have a high suspicion that orbital compartment syndrome has been somehow missed out in the recommended textbooks of our medical universities and in the postgraduate trainings. Thus compartment syndrome is not recognized. Teaching, training and early surgical decompression is the only solution to save the blind eye. Orv Hetil. 2017; 158(36): 1410-1420. PMID- 28868911 TI - [Geza Sas (1937-2017)]. PMID- 28868913 TI - [Biopsychosocially informed therapy of symptoms related to premature ovarian failure]. AB - The basic legal conditions for pursuing medical activities in Hungary require that psychologists be employed at certain somatic departments. In the Hungarian medical practice, however, attitudes recognizing the potential role of psychological factors in the course of diseases are not widely present. The modern psychosomatic approach to healing includes biological, psychological and social factors that may predispose one to, precipitate or perpetuate a medical condition. This case study of a 35-year-old woman reports on a therapy in which the symptoms were indicative of both premature ovarian failure and anxiety, influencing each other in a bidirectional way. Therapy also included interventions on physical (hormonal therapy, Jacobson's progressive relaxation technique) and psychological levels (cognitive behavioral interventions). This case management is an example for how physician-psychologist collaboration serves the best interests of patients. Orv Hetil. 2017; 158(36): 1432-1435. PMID- 28868914 TI - [Comparison of laparoscopic and open radical hysterectomies in the surgical treatment of cervical cancer]. AB - INTRODUCTION: Cervical cancer is one of the most common causes of death among women with malignant tumours. The two most common ways of surgical technique of early stage cervical cancer is the laparoscopy and the laparotomy. AIM: Our aim was to compare the intra- and postoperative results of total laparoscopic radical hysterectomy and abdominal radical hysterectomy. METHOD: Ten nerve sparing laparoscopic and 11 abdominal radical hysterectomies were performed from June 2016 until June 2017 because of early stage cervical cancer. Results were analysed retrospectively. RESULTS: There was no significant difference between the two groups in the length of the operation, in blood loss and in intra- and postoperative complications. Significantly more lymph nodes were harvested by abdominal surgery and the length of hospitalisation was significantly shorter in the laparoscopy group. CONCLUSION: Results of total laparoscopic radical hysterectomy are comparable and not worse than abdominal radical hysterectomy. Laparoscopic way may have a priority because of the general advantages of laparoscopic surgery in the surgical treatment of early stage cervical cancer. Orv Hetil. 2017; 158(36): 1403-1409. PMID- 28868915 TI - Detection of Subclinical Peripheral Artery Ischemia in Healthy Male Smokers by an Ankle-Brachial Index After Exercise: Sasayama Study. AB - We investigated the relationship between smoking and the risk of nonnormal (<=0.99) ankle-brachial index (ABI) at rest and after ankle plantar flexion exercise in healthy male community dwellers. A cross-sectional study was performed including 228 Japanese men aged 40 to 64 years without a history of cardiovascular diseases. Participants were classified as never, ex-, and current smokers. We estimated the multivariate-adjusted odds ratios (ORs) for nonnormal ABI of ex- and current smokers in relation to never smokers after adjusting for age and other confounding factors. At rest, the prevalence of nonnormal ABI was not significantly different by smoking status. After exercise, the prevalence of nonnormal ABI increased from 1.8% to 11.5% in ex-smokers and from 3.8% to 17.0% in current smokers, while the prevalence did not significantly change in never smokers. The multivariate-adjusted OR for nonnormal ABI after ankle plantar flexion exercise, in relation to never smokers, was 3.85 (95% confidence interval [CI]: 0.79-18.9) for ex-smokers and 6.97 (95% CI: 1.32-36.7) for current smokers. Our results suggest that ABI after ankle plantar flexion exercise is useful for early detection of subclinical peripheral artery ischemia in male smokers without typical symptoms. PMID- 28868916 TI - Peripheral Artery Disease: To Screen or Not Screen, That Is the Question! PMID- 28868917 TI - Mutuality and heart failure self-care in patients and their informal caregivers. AB - BACKGROUND: Heart failure is a progressive condition characterized by frequent hospitalizations for exacerbated symptoms. Informal family caregivers may help patients improve self-care, which may in turn reduce hospitalizations. However, little is known about how mutuality, defined as the quality of the patient caregiver relationship, and caregiver burden affect self-care. OBJECTIVE: This study examines the associations among mutuality, patient self-care confidence (beliefs in abilities to engage in self-care behaviors) and maintenance (behaviors such as medication adherence, activity, and low salt intake), caregiver confidence in and maintenance of patient care, and caregiver perceived burden. METHODS: This study used cross-sectional baseline data from a multi-site randomized clinical trial of a symptom and psychosocial care intervention. Patient-caregiver dyads ( N=99) completed self-report surveys of mutuality and self-care confidence and maintenance, and caregivers completed a measure of caregiver burden. Path analysis, with actor (effects within a person) partner (effects across the dyad) interdependence model paths and regression models were used to examine the associations among mutuality, caregiver burden, and self care. RESULTS: The majority of patients ( M age=66, 21% female) and caregivers ( M age=57, 81% female) were spouses (60%). The path model demonstrated significant actor effects; patients and caregivers with better mutuality were more confident in patient self-care ( p<.05). Partner effects were not significant. Regression models indicated that caregivers with greater mutuality reported less perceived burden ( p<.01). CONCLUSIONS: Mutuality in patient-caregiver dyads is associated with patient self-care and caregiver burden and may be an important intervention target to improve self-care and reduce hospitalizations. PMID- 28868918 TI - Successful use of palliative inotrope therapy in end-stage cardiac ATTR amyloidosis. PMID- 28868919 TI - Three new kavalactone dimers from Piper methysticum (kava). AB - Three new dimeric kavalactones, designated as diyangonins A-C (1-3), along with two known analogs were isolated from the roots of Piper methysticum. Their structures were elucidated by means of extensive analysis of their 1D, 2D NMR, and mass spectroscopic data. All these dimers possess a skeleton featuring a cyclobutane ring connecting two kavalactone units in head-to-tail or head-to-head mode. Compounds 1-5 were evaluated for their cytotoxic activities against human tumor cell lines. PMID- 28868921 TI - The dual task effect on gait in adults with intellectual disabilities: is it predictive for falls? AB - PURPOSE: Falling is an important health issue in adults with intellectual disabilities. Their cognitive and motor limitations may result in difficulties with dual tasking (walking and talking), which increases fall risk. Therefore, we assessed the dual task effect on gait in adults with intellectual disabilities, if this dual task effect is predictive for falls, and if this is more predictive than regular walking. METHOD: Gait characteristics of 31 adults with intellectual disabilities without Down syndrome were assessed with the GAITRite at comfortable speed and during dual tasking (conversation). Falls were collected over a three month follow-up period. RESULTS: During dual tasking, participants walked slower, with a lower cadence, increased stride time, and shorter stride lengths. They spend less time in swing and single support phase than at comfortable speed. Also swing and single support time became more variable. The dual task effect and walking at comfortable speed were not predictive for falls, although medium effect sizes were found. CONCLUSIONS: Dual tasking affects gait in adults with intellectual disabilities. This is an important finding for safe community participation, and must be considered while interacting with adults with intellectual disabilities during daily activities. Possible negative consequences of distractors should be kept in mind. More research is needed to better understand the predictive value of gait for falls. Implications for Rehabilitation Having a conversation while walking affects the gait pattern of adults with intellectual disabilities, possible negative consequences of distractors should be kept in mind. The dual task effect on the width of the gait pattern and stride time variability had the largest effect sizes with future falls, this potential relationship should be kept in mind in clinical practice. The dual task effect on gait is important to consider with regard to safe community participation. Future studies are needed to better understand the predictive value of gait for falls, and for cutoff points to be used in clinical practice. PMID- 28868920 TI - Albidosides H and I, two new triterpene saponins from the barks of Acacia albida Del. (Mimosaceae). AB - Two new triterpene saponins, albidosides H (1) and I (2), along with the three known saponins were isolated from the barks of Acacia albida. Their structures were elucidated on the basis of extensive 1D- and 2D-NMR studies and mass spectrometry. Albidosides H (1) and I (2) were assayed for their cytotoxicity against HeLa and HL60 cells using MTT method. PMID- 28868922 TI - Second-Look Arthroscopic Evaluation and Clinical Outcome After Supramalleolar Osteotomy for Medial Compartment Ankle Osteoarthritis. AB - BACKGROUND: The aim of this study was to evaluate the clinical and radiologic outcomes of medial compartment ankle osteoarthritis after supramalleolar osteotomy (SMO) without the bone marrow stimulation procedure and confirm cartilage recovery by second-look arthroscopy. METHODS: Twenty-two ankles that were followed for more than 1 year after SMO were retrospectively reviewed. Visual analog scale pain scores and American Orthopaedic Foot & Ankle Society ankle-hindfoot scores were used for functional evaluations. The tibial anterior surface angle and tibial lateral surface angle were measured on radiographs, and ankle osteoarthritis was classified by Takakura stage. Among the 22 patients, 21 underwent ankle arthroscopy prior to SMO, and second-look arthroscopy was performed in 16 patients 1 year postoperatively. Tibiotalar cartilage regeneration was evaluated according to the modified Outerbridge classification for the 14 patients who had undergone SMO without the bone marrow stimulation procedure. RESULTS: The mean visual analog scale and American Orthopaedic Foot & Ankle Society scores significantly improved from 6.5 preoperatively to 1.1 postoperatively and from 60.7 preoperatively to 87.1 postoperatively, respectively ( P < .05). The mean tibial anterior surface and tibial lateral surface angles significantly improved from 83.5 degrees and 76.9 degrees preoperatively to 93.8 degrees and 80.2 degrees postoperatively, respectively ( P < .05). All preoperative Takakura stage IIIa cases and IIIb case improved to postoperative stage II. On second-look arthroscopy, cartilage regeneration of the medial compartment of the tibiotalar joint was observed in 12 of 14 patients (85%), whereas cartilage deterioration was not observed in any patient. CONCLUSIONS: SMO without the bone marrow stimulation procedure for medial ankle osteoarthritis demonstrated cartilage regeneration in the medial tibiotalar joint in most patients by second-look arthroscopy, as well as satisfactory clinical and radiologic outcomes. LEVEL OF EVIDENCE: Level IV, case series. PMID- 28868923 TI - Two thymol derivatives from the flower buds of Lonicera japonica and their antibacterial activity. AB - A new monoterpenoid, 7-acetyl-8,9-dihydroxy thymol (1), together with a known one 7,8-dihydroxy-9-buyryl thymol (2), were isolated from the dried flower buds of Lonicera japonica Thunb. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analyses. The potential antibacterial effects of these compounds on Staphylococcus aureus, Escherichia coli, Micrococcus luteus, and Bacillus cereus were evaluated. Interestingly, both compounds 1 and 2 exhibited significant antibacterial activities with IC50 values range from 27.64 +/- 2.26 to 128.58 +/- 13.26 MUg/mL. PMID- 28868924 TI - Is instrument-free molecular detection possible? PMID- 28868925 TI - Structural changes in S. epidermidis biofilms after transmission between stainless steel surfaces. AB - Transmission is a main route for bacterial contamination, involving bacterial detachment from a donor and adhesion to receiver surfaces. This work aimed to compare transmission of an extracellular polymeric substance (EPS) producing and a non-EPS producing Staphylococcus epidermidis strain from biofilms on stainless steel. After transmission, donor surfaces remained fully covered with biofilm, indicating transmission through cohesive failure in the biofilm. Counter to the numbers of biofilm bacteria, the donor and receiver biofilm thicknesses did not add up to the pre-transmission donor biofilm thickness, suggesting more compact biofilms after transmission, especially for non-EPS producing staphylococci. Accordingly, staphylococcal density per unit biofilm volume had increased from 0.20 to 0.52 MUm-3 for transmission of the non-EPS producing strain under high contact pressure. The EPS producing strain had similar densities before and after transmission (0.17 MUm-3). This suggests three phases in biofilm transmission: (1) compression, (2) separation and (3) relaxation of biofilm structure to its pre-transmission density in EPS-rich biofilms. PMID- 28868926 TI - A novel chloro-substituted pentenamide from the fruiting bodies of Amanita virgineoides. AB - One unusual chloro-substituted pentenamide, (3R)-4-chloro-3-hydroxy-4-pentenamide (1), together with 11 known compounds (2-12) were isolated from the fruiting bodies of Amanita virgineoides. The structure of 1 including the absolute configuration was characterized by extensive spectroscopic analyses and quantum calculation. Compound 1 displayed no obvious activity against herpes simplex virus (HSV), human enterovirus 71 (EV71) or coxsackievirus B3 (CVB3). PMID- 28868927 TI - Measuring a critical stress for continuous prevention of marine biofouling accumulation with aeration. AB - When cleaning the hull of a ship, significant shear stresses are needed to remove established biofouling organisms. Given that there exists a link between the amount of time that fouling accumulates and the stress required to remove it, it is not surprising that more frequent grooming requires less shear stress. Yet, it is unclear if there is a minimum stress needed to prevent the growth of macrofouling in the limit of continuous grooming. This manuscript shows that single bubble stream aeration provides continuous grooming and prevents biofouling accumulation in regions where the average wall stress exceeds ~0.01 Pa. This value was found by comparing observations of biofouling growth from field studies with complementary laboratory measurements that probe the associated flow fields. These results suggest that aeration and other continuous grooming systems must exceed a wall stress of 0.01 Pa to prevent macrofouling accumulation. PMID- 28868928 TI - Xanthones isolated from Gentianella acuta and their protective effects against H2O2-induced myocardial cell injury. AB - In the present study, two new xanthones, (5'S,8'S)-1,3,5,8-tetrahydroxyxanthone(7 >2')-1,3,5,8-tetrahydroxy-5',6',7',8'-tetrahydroxanthone (1), 5-hydroxy-3,4,6 trimethoxyxanthone-1-O-beta-D-glucopyranoside (2), and eight known xanthones (3 10) were isolated from the whole plants of Gentianella acuta. Their structures were identified by the spectroscopic analyses (HR-ESI-MS, and 1D and 2D NMR). Meanwhile, cell-protective effects against H2O2-induced H9c2 cardiomyocyte injury and cytotoxic activities of compounds 1-10 were also determined. PMID- 28868929 TI - Voices and Views of Congolese Refugee Women: A Qualitative Exploration to Inform Health Promotion and Reduce Inequities. AB - Refugees have recently been thrust into the spotlight worldwide. The strikingly negative rhetoric currently surrounding refugees calls for increased action from public health educators. In 2016, the largest proportion of refugees to the United States came from the Democratic Republic of Congo. This presents the opportunity to explore health needs as Congolese refugees resettle in the United States, with women taking priority due to health disparities linked to gender based discrimination, trauma, sexual and gender-based violence, lower literacy rates, and less access to learning English. Insight into experiences of Congolese women in the United States is critical for the proactive development of socioculturally relevant health promotion rather than reaction interventions once health inequities are exacerbated. Therefore, to better understand perceptions and experiences of Congolese women in Indianapolis related to health and health care, a community-based participatory research study with an anthropological approach was conducted in collaboration with a refugee resettlement agency utilizing photovoice and semistructured interviews. Sixteen women participated in six photovoice sessions and home-based interviews. Selected photos, photo stories, and interview transcripts were analyzed using ethnographic content analysis. Major themes were health care system issues, social support, and daily experiences of health. Findings provide needed insight into the sociocultural context of health for Congolese refugees in the United States for both health educators and resettlement agencies. Findings also revealed specific priority areas for culturally tailoring health education and assets on which to build when promoting health for this population. Additionally, lessons were learned about the power of an anthropological, community-based participatory research approach to qualitative research for promoting health equity. PMID- 28868931 TI - Emerging inhaled long-acting beta-2 adrenoceptor agonists for the treatment of COPD. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD), characterized by persistent and partially reversible airflow obstruction, is a leading cause of morbidity and mortality worldwide. Long-acting inhaled bronchodilators form the backbone for the maintenance therapy for this disease. The ultra-long-acting beta2-agonists (ultra-LABAs) represent novel pharmacologic agents with interesting potential benefits as stand-alone therapy or in combination with other therapies for the treatment of COPD. Areas covered: In this review, we will focus newly developed ultra-LABAs, describing currently available evidence of their clinical effect and safety, their comparison relative to older long-acting beta2-agonists, and their potential niche in the maintenance treatment of COPD. We also provide an overview of the current landscape of available LABAs, and discuss the present understanding of the disease, and suggest possible future directions for COPD therapy. Expert opinion: Ultra-LABAs are pivotal bronchodilators in the maintenance therapy of COPD as monotherapy or in combination with other agents. Their long-acting effect permits once daily dosing and their improved delivery using novel devices and their safety profile represent an important advancement in management of this disease. PMID- 28868932 TI - The development and feasibility of an online aphasia group intervention and networking program - TeleGAIN. AB - PURPOSE: Aphasia group therapy offers many benefits, however people with aphasia report difficulty accessing groups and speech-language pathologists are faced with many challenges in providing aphasia group therapy. Telerehabilitation may offer an alternative service delivery option. An online aphasia group therapy program - Telerehabilitation Group Aphasia Intervention and Networking (TeleGAIN) - has been developed according to the guidelines of the Medical Research Council (MRC) framework for complex interventions. The purpose of this paper is to describe the development of TeleGAIN and the results of a pilot trial to determine feasibility and acceptability. METHOD: The development of TeleGAIN was informed through literature reviews in relevant topic areas, consideration of expert opinion and application of the social cognitive theory. TeleGAIN was then modelled through a feasibility pilot trial with four people with aphasia. RESULT: TeleGAIN appeared to be feasible and acceptable to participants and able to be implemented as planned. Participant satisfaction with treatment was high and results suggested some potential for improvements in language functioning and communication-related quality of life. CONCLUSION: TeleGAIN appeared to be feasible and acceptable, however the study highlighted issues related to technology, clinical implementation and participant-specific factors that should be addressed prior to a larger trial. PMID- 28868930 TI - Multicomponent synthesis of some new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane dithiocarbamates and their in vitro anti-proliferative activity against CaSki, MDA-MB-231 and SK-Lu-1 tumour cells as apoptosis inducing agents without necrosis. AB - Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5 diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile. PMID- 28868933 TI - Comparison of vacuum and non-vacuum urine tubes for urinary sediment analysis. AB - Urine collection systems with aspiration system for vacuum tubes are becoming increasingly common for urinalysis, especially for microscopic examination of the urine. In this study, we aimed to examine whether vacuum aspiration of the urine sample has any adverse effect on sediment analysis by comparing results from vacuum and non-vacuum urine tubes. The study included totally 213 urine samples obtained from inpatients and outpatients in our hospital. Urine samples were collected to containers with aspiration system for vacuum tubes. Each sample was aliquoted to both vacuum and non-vacuum urine tubes. Urinary sediment analysis was performed using manual microscope. Results were evaluated using chi-square test. Comparison of the sediment analysis results from vacuum and non-vacuum urine tubes showed that results were highly concordant for erythrocyte, leukocyte and epithelial cells (gamma values 1, 0.997, and 0.994, respectively; p < .001). Results were also concordant for urinary casts, crystals and yeast (kappa values 0.815, 0.945 and 1, respectively; p < .001). The results show that in urinary sediment analysis, vacuum aspiration has no adverse effect on the cellular components except on casts. PMID- 28868934 TI - Business model framework applications in health care: A systematic review. AB - It has proven to be a challenge for health care organizations to achieve the Triple Aim. In the business literature, business model frameworks have been used to understand how organizations are aligned to achieve their goals. We conducted a systematic literature review with an explanatory synthesis approach to understand how business model frameworks have been applied in health care. We found a large increase in applications of business model frameworks during the last decade. E-health was the most common context of application. We identified six applications of business model frameworks: business model description, financial assessment, classification based on pre-defined typologies, business model analysis, development, and evaluation. Our synthesis suggests that the choice of business model framework and constituent elements should be informed by the intent and context of application. We see a need for harmonization in the choice of elements in order to increase generalizability, simplify application, and help organizations realize the Triple Aim. PMID- 28868935 TI - Risk-reduction and treatment of chemotherapy-induced peripheral neuropathy. AB - INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN), a common adverse effect of several chemotherapeutic agents, has a significant impact on quality of life and may even compromise treatment efficacy, requiring chemotherapy dose reduction or discontinuation. CIPN is predominantly related with sensory rather than motor symptoms and the most common related cytotoxic agents are platinum compounds, taxanes and vinca alkaloids. CIPN symptoms may resolve after treatment cessation, but they can also be permanent and continue for years. Areas covered: We present an overview of CIPN pathophysiology, clinical assessment, prevention and treatment identified through a Pubmed search. Expert commentary: No substantial progress has been made in the last few years within the field of prevention and/or treatment of CIPN, in spite of remarkable efforts. Continuous research could expand our knowledge about chemotherapeutic-specific neuropathic pathways and eventually lead to the conception of innovative and targeted agents for the prevention and/or treatment of this debilitating chemotherapy adverse effect. PMID- 28868936 TI - Perceptions of Using Sit-to-Stand Desks in a Middle School Classroom. AB - The purpose of this study was to explore the feasibility of sit-to-stand desks in a middle school classroom. Participants used sit-to-stand desks during health class. Momentary time sampling was used for physical activity and behavioral observations. Results indicate students sat 37%, stood 59%, and walked 4% of the time. Misbehaviors occurred 4% of the observed period. The following themes emerged: focus, freedom, distractions, and design. Sit-to-stand desks appear to encourage standing during instruction while simultaneously limiting misbehaviors. Students indicated some distractions but were generally positive toward desk implementation and suggested they supported learning behaviors. The teacher echoed most of the student themes. PMID- 28868938 TI - Exploring and explaining the "Santa Claus effect": cross-sectional study of jollity in 21 European countries. AB - BACKGROUND: Christmas "is the season to be jolly" but, despite many recent studies of happiness and wellbeing, the population distribution of jollity is unknown. AIMS: To assess levels of jollity across Europe, hypothesising the existence of a "Santa Claus effect" whereby Mr. Claus, a long-established resident of Scandinavia, increases jollity through his social network. METHODS: Cross-sectional analysis of data from 37 966 participants in the European Society Survey (Round 7, 2014/2015) across 21 European countries. RESULTS: Jollity has independent associations with satisfaction with health and income, male gender, younger age, and country of residence. Each one-point increase in satisfaction with health (on a 5-point scale) corresponds to a 0.79-point increase in jollity (23-point scale); each one-point increase in satisfaction with income (4-point scale) corresponds to a 0.76-point increase in jollity. Switzerland is the jolliest country in Europe. CONCLUSIONS: The jolliest European is likely to be a young Swiss male who is satisfied with his income and health. If there is a Santa Claus effect acting to increase jollity, it probably acts not just in Scandinavia but across Mr. Claus's broad network of contacts and admirers in many countries. PMID- 28868937 TI - Ameliorative effect of nicotine exposure on insulin resistance is accompanied by decreased cardiac glycogen synthase kinase-3 and plasminogen activator inhibitor 1 during oral oestrogen-progestin therapy. AB - CONTEXT: Cigarette smoking is considered to be a major risk factor for the development of diabetes and cardiovascular disease. Oestrogen-progestin combined oral contraceptive (COC) use has been associated with adverse cardiometabolic events. OBJECTIVE: We hypothesized that nicotine would ameliorate insulin resistance (IR) that is accompanied by decreased cardiac glycogen synthase kinase 3 (GSK-3) and plasminogen activator inhibitor-1 (PAI-1). METHODS: Female Wistar rats received (po) low-(0.1 mg/kg) or high-nicotine (1.0 mg/kg) with or without COC containing 5.0 ug levonorgestrel plus 1.0 ug ethinylestradiol daily for 8 weeks. RESULTS: Data showed that COC treatment or nicotine exposure led to IR, glucose deregulation, atherogenic dyslipidemia, increased corticosterone, aldosterone, cardiac and circulating GSK-3 values and PAI-1. However, these effects with the exception of corticosterone and aldosterone were ameliorated in COC + nicotine-exposed rats. CONCLUSION: Amelioration of IR induced by COC treatment is accompanied by decreased circulating PAI-1, cardiac PAI-1 and GSK-3 instead of circulating aldosterone and corticosterone. PMID- 28868939 TI - Characterization of a suboptimal IVF population and clinical outcome after two IVF cycles. AB - The number of oocytes retrieved in in vitro fertilization (IVF) cycles is an independent factor influencing pregnancy rate (PR), and optimal number of oocytes would be between 10 and 15. This has led to the hypothesis that the identification of a suboptimal group of responders beforehand (4-9 oocytes retrieved) would allow physicians to optimize their PR. A retrospective observational study counting on 735 women doing an IVF treatment in our center was performed. Multivariable logistic regression was used to analyze the relationship between anti-Mullerian hormone (AMH) and antral follicle count (AFC), within suboptimal and optimal responders. We also analyzed the outcome of those patients with an estimated high probability of having an optimal response and the second cycles of those who did not get pregnant in the first cycle to observe the main significant traits that made them change from one group of responders to the other. Main results are that suboptimal responders account for almost half of our patients. Ovarian reserve markers (AMH and AFC) are significantly different in optimal and suboptimal responders, even when adjusted by age. There is a significant difference in the cumulative PR between both groups. Interestingly, 18.9% shifted from suboptimal to optimal response, and 36.9% from optimal to suboptimal. PMID- 28868940 TI - Vigilance on use of drugs, herbal products, and food supplements during pregnancy: focus on fosfomycin. AB - PURPOSE: Urinary tract infection (UTI) is defined as a common bacterial infection that can lead to significant morbidity such as stricture, fistula, abscess formation, bacteremia, sepsis, pyelonephritis, and kidney dysfunction with a mortality rates reported of 1% in men and 3% in women because of development of pyelonephritis. UTIs are more common in women and the 33% of them require antimicrobials treatment for at least one episode by the age of 24 years. UTIs are the most common infections observed during pregnancy and up to 30% of mothers with not treated asymptomatic bacteriuria may develop acute pyelonephritis which consequently can be associated to adverse maternal and fetal outcomes. All bacteriuria in pregnancy should be treated with antimicrobial treatments being safe for both the mother and the fetus. Approximately one every four women receives prescription of antibiotic treatment during pregnancy, nearly 80% of all the prescription medications during gestation. The use of fosfomycin to treat cystitis in pregnancy generally considered safe and effective. Even though use on antibiotics for urinary tract infections is considered generally safe for the fetus and mothers, this opinion is not based on specific studies monitoring the relationship of among urinary infections, consumption of antibiotics, and pregnancy outcomes. MATERIALS AND METHODS: On this basis we decided to analyze data from the database of our multicenter study PHYTOVIGGEST, reporting data from 5362 pregnancies, focusing on use of fosfomycin. Principal outcomes of pregnancy in women treated with fosfomycin were taken into consideration. RESULTS: Women who have been treated with urinary antibiotics during the pregnancy were 183. With respect to the total number of pregnancies of our sample, these women represented the percentage of 3.49% (187/5362). Analysis of different outcomes of pregnancy such as gestational age, neonatal weight, and neonatal Apgar index did not show any significant difference. At the same time, analysis of data of pregnancy complicancies (such as urgent cesarean delivery, use of general anesthesia, need to induce labor) did not show any difference in women taking fosfomycin during pregnancy and those not taking it. CONCLUSIONS: Our data, based on a large number of pregnancies, confirm the safety use of fosfomycin use in pregnancy. PMID- 28868942 TI - MYC immunohistochemical and cytogenetic analysis are required for identification of clinically relevant aggressive B cell lymphoma subtypes. AB - Accurate subclassification of aggressive B cell lymphomas (ABCLs) requires integration of morphologic, immunohistochemical (IHC), and cytogenetic information. Optimal strategies have not been well defined for diagnosis of high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBLwR) and double expressor lymphomas with MYC and BCL2 protein overexpression. One hundred and eighty seven ABCLs were investigated with complete IHC and FISH analysis. Morphologic and IHC analysis was insufficient to identify clinically relevant HGBLwR. Approximately, 75% of cases classified as HGBLwR showed conventional DLBCL morphologic features. Fourteen percent of MYC-rearranged cases were negative by IHC. Conversely, 60% of cases positive for MYC by IHC did not demonstrate a MYC rearrangement. Analysis by FISH without MYC and BCL2 IHC would miss 41 cases of double expressor lymphoma. Complete IHC and FISH analysis is recommended in the evaluation of all ABCLs. PMID- 28868941 TI - Do rhomboid flaps provide more elongation than Z-plasty flaps? An experimental study. AB - BACKGROUND AND AIM: A Z-plasty flap is one of the most widely used geometric relaxation methods to release contracture bands. A rhomboid flap is a lesser used geometric relaxation method than a Z-plasty flap. This study aimed to determine the length and rate of elongation provided by rhomboid and Z-plasty flaps. METHODS: Bilateral contracture bands were created in the inguinal skins of rats. A rhomboid flap was planned for the right side of the inguinal region, and a single Z-plasty flap was planned for the left side. The length and rate of elongation provided by the two flaps were calculated after completing the procedures and were compared using Student's t-test. RESULTS: Experimental contracture bands disappeared in both the inguinal regions after creating rhomboid and Z-plasty flaps. The mean postoperative elongation of the contracture band was 1.4 +/- 0.119 and 2.47 +/- 0.281 cm using the rhomboid and Z-plasty flaps, respectively. The difference was statistically significant (p < .001). CONCLUSION: Z-plasty flaps provide more elongation than rhomboid flaps and also appear to be better options for releasing linear contracture bands. However, rhomboid flaps may be used as alternatives when Z-plasty flaps cannot be used and in regions such as the axilla, genital region, nipple-areola, where their distortion effects should be avoided. PMID- 28868943 TI - Evaluation of pro-oxidant-antioxidant balance (PAB) and its association with inflammatory cytokines in polycystic ovary syndrome (PCOS). AB - Chronic low-grade inflammation has been suggested as a key contributor of the pathogenesis and development of polycystic ovary syndrome (PCOS). To investigate the association between oxidative stress status and inflammatory cytokines in follicular fluid of 21 PCOS women compared to 21 women with normal ovarian function who underwent intra-cytoplasmic sperm injection. Concentration of IL-6, IL-8, IL-10, and TNF-alpha was measured using sandwich ELISA. Oxidative stress was examined by measuring total oxidant status (TOS), malondialdehyde (MDA), total antioxidant capacity (TAC), and thiol groups. PCOS women had an elevated concentration of MDA and TOS compared to controls. Levels of TAC and thiol groups were lower in PCOS compared to controls. PCOS patients had a higher concentration of IL-6, IL-8, and TNF-alpha compared to controls. Concentration of IL-10 was lower in PCOS compared to controls. Significant correlations were found between MDA and TOS concentration with TNF-alpha and between IL-6 and MDA, IL-8 and TAC, IL-10 and TOS levels and also between IL-10 and TAC levels. TAC and thiol groups were negatively correlated with TNF-alpha. Increased oxidative stress in PCOS is associated with inflammation which is closely linked. Inflammation can induce production of inflammatory cytokines in this syndrome and directly stimulates excess ovarian androgen production. PMID- 28868944 TI - Prehypertension in early versus late pregnancy. AB - INTRODUCTION: Hypertensive disorders play a significant role in maternal morbidity and mortality. Limited data on prehypertension (preHTN) in pregnancy exist. We examine the risk of adverse outcomes in patients with preHTN in early (<20 weeks) versus late pregnancy (>20 weeks). MATERIALS AND METHODS: Retrospective cohort study of singleton gestations between August 2013 and June 2014. Patients were divided based on when they had the highest blood pressure in pregnancy, as defined per the Joint National Committee 7 (JNC-7). Groups were compared using chi2, Fisher's exact, Student's t-test, and Mann-Whitney U test with p < .05 used as significance. RESULTS: There were 125 control, 95 early preHTN, 136 late preHTN, and 21 chronic hypertension (CHTN). Early preHTN had an increased risk of pregnancy-related hypertension (PRH) (OR 12.26, p < .01) and composite adverse outcomes (OR 2.32, p < .01). Late preHTN had an increased risk for PRH (OR 4.39, p = .02) compared with normotensive and decreased risk for PRH (OR 0.26, p = .02), and composite adverse outcomes (OR 0.379, p = .04) compared with CHTN. Compared with late preHTN, early preHTN had more PRH (OR 2.85, p < .01), and composite adverse outcomes (OR 1.68, p = .04). CONCLUSIONS: Early prehypertension increases the risk of adverse obstetrical outcomes. Other than an increased risk of PRH, patients with late prehypertension have outcomes similar to normotensive women. PMID- 28868945 TI - Social phobia, depression and eating disorders during middle adolescence: longitudinal associations and treatment seeking. AB - BACKGROUND: Longitudinal associations between social phobia (SP), depression and eating disorders (EDs), and the impact of antecedent SP and depression on subsequent treatment seeking for EDs have rarely been explored in prospective adolescent population studies. AIM: We aimed to examine these associations in a large-scale follow-up study among middle adolescents. METHOD: We surveyed 3278 Finnish adolescents with a mean age of 15 years for these disorders. Two years later, 2070 were reached and again surveyed for psychopathology and treatment seeking. Longitudinal associations between the self-reported disorders and treatment-seeking patterns for self-acknowledged ED symptoms were examined in multivariate analyses, controlling for SP/depression comorbidity and relevant socioeconomic covariates. RESULTS: Self-reported anorexia nervosa (AN) at age 15 years predicted self-reported depression at age 17 years. Furthermore, self reported SP at age 15 years predicted not seeking treatment for bulimia nervosa (BN) symptoms, while self-reported depression at age 15 years predicted not seeking treatment for AN symptoms during the follow-up period. CONCLUSIONS: Adolescents with AN should be monitored for subsequent depression. Barriers caused by SP to help seeking for BN, and by depression for AN, should be acknowledged by healthcare professionals who encounter socially anxious and depressive adolescents, especially when they present with eating problems. PMID- 28868947 TI - Structural and discriminant validity of the tripartite model of mental well being: differential relationships with the big five traits. AB - BACKGROUND: The tripartite model of mental well-being offers a comprehensive account of the nature of mental well-being. According to this model, mental well being is composed of three distinct yet related dimensions of subjective (hedonic), psychological and social well-being. AIMS: The present study investigated the structural and discriminant validity of the three well-being factors. METHODS: A large American sample (N = 2732) was used. Data were analyzed using both Confirmatory Factor Analysis (CFA) and Exploratory Structural Equation Modeling (ESEM). RESULTS: It was found that the well-being variables loaded on three separate factors, indicating that the tripartite model was consistent with the data. Discriminant validity was further evidenced by moderate correlations between the latent factors, and differential relationships with the Big Five personality traits. ESEM proved to be a more appropriate approach for analyzing the data given the presence of cross-loadings. CONCLUSIONS: These results support adequate structural and discriminant validity for the dimensions of the tripartite model. PMID- 28868946 TI - Vitamin D receptor gene polymorphisms and risk of polycystic ovary syndrome in South Indian women. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive age women. Emerging evidence suggests that Vitamin D Receptor (VDR) might be a causal factor for characteristics associated with PCOS such as obesity and type 2 diabetes. Present study investigated association between VDR gene BsmI A/G (rs1544410), ApaI A/C (rs7975232) and TaqI T/C (rs731236) single nucleotide polymorphisms and PCOS risk in South Indian women. Genotyping of VDR gene SNPs was carried out in PCOS patients (n = 95) and controls (n = 130) by PCR-RFLP method and confirmed by sequencing analysis. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pairwise linkage disequilibrium (LD) were assessed by Haploview software. Results showed significantly increased frequencies of BsmI G/G (p = .0197), ApaI C/C (p = .048), TaqI C/C (p = .044) genotypes and BsmI G (p = .0181), ApaI C (p = .0092), TaqI C (p = .0066) alleles in patients compared to controls. In addition, the frequency of the 'BsmI G, ApaI C, TaqI C' haplotype was also significantly elevated in patients (p = .0087). In conclusion, the VDR gene BsmI A/G ApaI A/C TaqI T/C and haplotype may constitute an inheritable risk factor for PCOS in South Indian women. PMID- 28868948 TI - The effects of baicalein or baicalin on the colloidal stability of ZnO nanoparticles (NPs) and toxicity of NPs to Caco-2 cells. AB - Recent study suggested that the presence of phytochemicals in food could interact with nanoparticles (NPs) and consequently reduce the toxicity of NPs, which has been attributed to the antioxidant properties of phytochemicals. In this study, we investigated the interactions between ZnO NPs and two flavonoids baicalein (Ba) or baicalin (Bn) as well as the influence of the interactions on the toxicity of ZnO NPs to Caco-2 cells. The antioxidant properties of Ba and Bn were confirmed by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) (ABTS) assays, with Ba being stronger. However, the presence of Ba or Bn did not significantly affect cytotoxicity, intracellular superoxide or release of inflammatory cytokines of Caco-2 cells after ZnO NP exposure. When Ba was present, the cellular viability of Caco-2 cells after exposure to ZnO NPs was slightly increased, associated with a modest decrease of intracellular Zn ions, but these effects were not statistically different. Ba was more effective than Bn at changing the hydrodynamic sizes, Zeta potential and UV-Vis spectra of ZnO NPs, which indicated that Ba might increase the colloidal stability of NPs. Taken together, the results of the present study indicated that the anti-oxidative phytochemical Ba might only modestly protected Caco-2 cells from the exposure to ZnO NPs associated with an insignificant reduction of the accumulation of intracellular Zn ions. These results also indicated that when assessing the combined effects of NPs and phytochemicals to cells lining gastrointestinal tract, it might be necessary to evaluate the changes of colloidal stability of NPs altered by phytochemicals. PMID- 28868949 TI - Cytokine profile in gingival crevicular fluid and plasma of patients with aggressive periodontitis. AB - OBJECTIVE: This study aimed to determine the content of cytokines in gingival crevicular fluid (GCF) as well as in plasma of Sudanese patients with aggressive periodontitis (AgP) and healthy controls (HC). MATERIALS AND METHODS: Nineteen AgP patients and 19 HC were included. The mean probing pocket depth and clinical attachment level of the GCF sampled sites in patients were both >=5 mm. The GCF and plasma levels of 27 cytokines were determined using 27-multiplex fluorescent bead-based immunoassays. Ratios were calculated among cytokines of the T-helper cell subsets Th1 and Th2. Descriptive statistics, the Mann-Whitney U-test and Spearman's rho rank correlation coefficient analysis were used. RESULTS: Interferon-gamma was the only cytokine found in significantly lower levels in GCF of patients compared with HC. Levels of interleukin (IL)-10, IL-13, IL-1Ra, monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), granulocyte-colony-stimulating factor (G-CSF), and granulocyte-macrophage-CSF (GM-CSF) were significantly lower in plasma of AgP compared with HC. The ratios of Th1:Th2 in GCF and Treg:Th17 in plasma were significantly lower in AgP. CONCLUSIONS: The lower levels of cytokines detected systemically in plasma of AgP patients may have an impact on the immune response. The lower ratio of Th1:Th2 cytokines in GCF samples of AgP patients suggests a role for Th2 at the local site of disease. PMID- 28868951 TI - Experiences of flourishing and languishing during the first year at university. AB - BACKGROUND: The theoretical framework utilised in the current study included Keyes's mental health continuum, as well as the dimensions of emotional, psychological and social well-being. AIM: The aim of this study was to explore students experiences of flourishing and languishing during their first year at university. METHODS: A nominal group technique was utilised in order to obtain data regarding the experiences of 22 first-year students and was thereafter analysed by means of thematic analysis. RESULTS: Various dimensions of emotional, psychological and social well-being were highlighted as essential in experiencing either flourishing or languishing during students first year at university. Although students experienced both flourishing and languishing, it is evident that students are more vulnerable to languishing during the beginning of their university career. Facing the big unknown, being confronted with practical difficulties, finding academics overwhelming, experiencing social isolation and being a victim of crime were prominent. Students however, learn to flourish when they achieve academic mastery, experience personal growth and independence and secure a social support system. CONCLUSIONS: The first year is seen as fundamental to student success at university, therefore the promotion of mental health during this year can be valuable in ensuring flourishing experiences during students' academic journey. PMID- 28868950 TI - Comparison of serum inflammatory cytokine concentrations in familial Mediterranean fever and rheumatoid arthritis patients. PMID- 28868952 TI - An fMRI study of the effects on normal language areas when acupuncturing the Tongli (HT5) and Xuanzhong (GB39) acupoints. AB - Objective Functional magnetic resonance imaging (fMRI) analysis of the effects of acupuncturing the Tongli (HT5) and Tongli (HT5)-Xuanzhong (GB39) acupoints on the normal language areas with a view to providing a theoretical basis for using acupuncture to treat patients with aphasia. Methods This study enrolled healthy volunteers. The following acupoints were stimulated: right Tongli (HT5), right Tongli (HT5)-Xuanzhong (GB39), right Tongli (HT5) sham acupuncture, left Tongli (HT5), and left Tongli (HT5)-Xuanzhong (GB39) acupoints. Acupuncture stimulation was delivered whilst fMRI scanning of the brain was undertaken. Results Ten healthy volunteers (five males) were included in this study (mean age 44.5 +/- 2.5 years; range 40-55 years). Based on the statistical analyses, only acupuncturing the right Tongli (HT5) acupoint resulted in activation of multiple regions of the bilateral cerebral hemisphere that were closely related to the language regions. The right Tongli (HT5) stimulation had a laterality index of 0.0952; with the activated voxels on the left side language-related areas being greater than those on the right side. Conclusions Acupuncturing the right Tongli (HT5) acupoint results in activation of the bilateral language-related areas, so this acupoint might be useful for the acupuncture treatment of aphasia caused by cerebral infarction. PMID- 28868954 TI - Mutational frequencies of CD79B and MYD88 vary greatly between primary testicular DLBCL and gastrointestinal DLBCL. PMID- 28868953 TI - Preparation, characterization and in vitro evaluation of epsilon-polylysine loaded polymer blend microparticles for potential pancreatic cancer therapy. AB - Peptide active ingredients show great promise regarding the treatment of various health-endangering diseases. It is reported that L-lysine inhibits the proliferation of several tumour lines in vitro and in vivo. However, proteins and peptide drugs possess certain disadvantages such as in vivo instability and short biological half-life. On the grounds that drug delivery systems can overcome a wide spectrum of bioactive compounds issues, a biopolymeric blend-based microparticulated system capable of delivering epsilon-polylysine (PLL) was developed. PLL-loaded poly((L)Lactic acid)/poly(D,L-Lactide)-co-poly(ethylene glycol)-based microparticles (PLL-PB-MPs) were prepared and fully characterised exhibiting a narrow size distribution (1.2 +/- 0.12 um), high loading efficiency (81%) and improved thermal stability (Td from 250 degrees C to 291 degrees C). The cytotoxicity and antiproliferative effect of PLL-PB-MPs in pancreatic adenocarcinoma cell lines BxPC3 and MIA PaCa-2 were confirmed. Due to their physicochemical and biopharmaceutical properties, PB-MPs constitute a promising carrier to deliver bioactive peptides. PMID- 28868955 TI - Neurogenetics of Drosophila circadian clock: expect the unexpected. AB - Daily biological rhythms (i.e. circadian) are a fundamental part of animal behavior. Numerous reports have shown disruptions of the biological clock in neurodegenerative disorders and cancer. In the latter case, only recently we have gained insight into the molecular mechanisms. After 45 years of intense study of the circadian rhtythms, we find surprising similarities among species on the molecular clock that governs biological rhythms. Indeed, Drosophila is one of the most widely used models in the study of chronobiology. Recent studies in the fruit fly have revealed unpredicted roles for the clock machinery in different aspects of behavior and physiology. Not only the central pacemaker cells do have non-classical circadian functions but also circadian genes work in other cells and tissues different from central clock neurons. In this review, we summarize these new evidences. We also recapitulate the most basic features of Drosophila circadian clock, including recent data about the inputs and outputs that connect the central pacemaker with other regions of the brain. Finally, we discuss the advantages and drawbacks of using natural versus laboratory conditions. PMID- 28868956 TI - Intracytoplasmic filamentous inclusions and IGHV rearrangements in a patient with chronic lymphocytic leukemia. PMID- 28868957 TI - Development of the SOSS-D: a scale to measure stigma of occupational stress and burnout in medical doctors. AB - BACKGROUND: Occupational stress and burnout are highly prevalent among doctors, with stigma identified as a barrier to help-seeking in this population. However, there has been a lack of a standardised tool to measure stigma of occupational stress and burnout among doctors. AIMS: The aim of the current study was to develop and investigate the psychometric properties of the Stigma of Occupational Stress Scale for Doctors (SOSS-D). METHOD: An online questionnaire package was completed by 200 (38 male, 162 female) doctors. Participants completed measures relating to help-seeking intentions, general stigma, and the SOSS-D. RESULTS: Exploratory Factor Analysis was used to refine the scale to an 11-item version. The analysis revealed a three-factor structure, which explained 63.4% of variance. Factors related to perceived structural stigma, personal stigma and perceived other stigma. The internal consistency, convergent, discriminant and criterion validity of the scale were supported. CONCLUSIONS: The SOSS-D may assist educators and mental health professionals in measuring and assessing the efficacy of interventions designed to reduce stigma. As such, it is anticipated that the SOSS-D will be a useful instrument for understanding and addressing stigma of occupational stress and burnout among medical doctors, to improve help seeking behaviours in this population. PMID- 28868959 TI - Association between psychological and self-assessed health status and smartphone overuse among Korean college students. AB - BACKGROUND: Several studies suggest that subjective health status is closely related to various behavioral addictions, but there are few studies on smartphone overuse. AIM: This study investigated the associations between psychological and subjective health conditions and smartphone overuse in Korean college students. METHOD: A total of 608 college students participated in this study. We investigated the perceived psychological factors, such as stress, depression symptoms and suicidal ideation. Overall health status was evaluated with self assessed items, including usual health condition and EuroQol-visual analog scales (EQ-VAS) score. Smartphone overuse was evaluated as the Korean Smartphone Addiction Proneness Scale. RESULTS: Students with psychotic anxiety (i.e. stress, depression and suicidal ideation) showed significant associations with smartphone overuse, indicating an approximately twofold increased risk compared to those without psychological anxiety (all p < 0.05). Students who reported feeling that their usual health is not good were more likely to overuse smartphones than those who are in good health (OR = 1.98; 95% CI = 1.22-3.21). The EQ-VAS score, which indicates current self-assessed health status, also showed a similar result with general health status (OR = 2.14; 95% CI = 1.14-4.02). CONCLUSION: Negative conditions in self-perceived emotional or overall health condition are associated with the increased likelihood of smartphone overuse in Korean college students. PMID- 28868958 TI - Selective in vitro anti-melanoma activity of ursolic and oleanolic acids. AB - Products of natural origin have become important agents in the treatment of cancer, and the active principles of natural sources could be used in combination with chemotherapeutic agents to increase their effects and to minimize their toxicity. Oleanolic (OA) and ursolic (UA) acids are intensely studied for their promising anticancer potential. The aim of this study was focused on the in vitro toxicological effects induced by UA and OA human mesenchymal stem cells and on melanoma, one of the most frequent cancers whose incidence is increasing every year. The two compounds were tested for their cytotoxic, cell cycle arrest and pro-apoptotic effects on melanoma cells (A375 and B164A5) and mesenchymal stem cells. UA exerted a cytotoxic effect in a dose-dependent manner on melanoma cells, while OA's activity has been shown to be low or moderate. Both compounds produced alterations of the cell cycle, arresting cells in the G0/G1 phase. Furthermore, UA induced significant apoptosis through the bcl-2 genes family pathway, with the decrease of the bcl-2 gene expression. The two compounds exerted selective effects on melanoma cells with no effects on human mesenchymal stem cells. The presented results reveal the anticancer potential of UA on melanoma cells, with no detectable toxicity on the mesenchymal stem cells. PMID- 28868960 TI - E-Pain Reporter: A Digital Pain and Analgesic Diary for Home Hospice Care. AB - Informal hospice caregivers play a key role in managing patients' pain at home, but lack of adherence to doctor-prescribed analgesic regimens and medication errors are significant barriers to truly effective pain management. A digital pain diary may improve caregiver management of pain at home; however, most digital pain tools available today were developed without input from patients or caregivers. Accordingly, the purpose of this study was to develop a digital pain application (1) for hospice caregivers to record patient pain and analgesic use and (2) for nurses to monitor administration of analgesics by caregivers. Using advisory group methods, nurse case managers (n = 6), and informal caregivers (n = 3) helped us to convert a paper-based pain and analgesic diary into a digital format-the e-PAIN Reporter-and to refine the application. The e-PAIN Reporter provides information on patient pain assessment and pain management and reports to nurses in real time. Further testing is now needed to determine (1) the feasibility of using the e-PAIN Reporter and (2) its effectiveness in improving pain management for hospice patients. PMID- 28868962 TI - Prevalence of Mycoplasma genitalium and other sexually transmitted infections causing urethritis among high-risk heterosexual male patients in Estonia. AB - BACKGROUND: We aimed to evaluate the prevalence of sexually transmitted infections (STI, including Mycoplasma genitalium, Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis) among high-risk heterosexual male patients and to clarify their potency to cause complaints and inflammation. METHODS: The study group included 825 men (18.0-49.5 y) consulting andrologist at Tartu University Hospital (Estonia) due to subjectively perceived risk of STI. Patients completed STI risk behaviour questionnaire. First voided urine was analysed for white blood cells and STIs. RESULTS: In total 193 (23.4%) patients were positive for one or multiple STI. The prevalence of C. trachomatis, M. genitalium, N. gonorrhoeae, T. vaginalis and combined STI was 14.3%, 4.4%, 2.7%, 0.7% and 1.3%, respectively. N. gonorrhoeae had the highest potency to generate inflammatory reaction in first voided urine (100%) followed by C. trachomatis (72.0%), M. genitalium (63.9%) and T. vaginalis (33.3%). N. gonorrhoeae and T. vaginalis caused the highest mean number of complaints while half of T. vaginalis cases and nearly fifth of M. genitalium and C. trachomatis cases were asymptomatic. CONCLUSIONS: C. trachomatis has the highest prevalence among Estonian high-risk men but M. genitalium holds an important second place. Prevalence of combined STIs is low. N. gonorrhoeae has the highest potency to generate urethral inflammation followed by C. trachomatis and M. genitalium. The highest number of complaints is also associated with N. gonorrhoeae while half of T. vaginalis cases and nearly a fifth of M. genitalium and C. trachomatis cases are asymptomatic. PMID- 28868963 TI - Prolonged hospitalization, primary refractory disease, performance status and age are prognostic factors for survival in patients with diffuse large B-cell lymphoma and transformed indolent lymphoma undergoing autologous stem cell transplantation. AB - In patients with relapsed diffuse large B-cell lymphoma (DLBCL), high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is standard treatment. Here, we aim to identify factors associated with survival in patients undergoing ASCT. A total of 369 patients with relapsed DLBCL undergoing ASCT from 2000 to 2012 were identified in the Danish National Lymphoma Registry. Information on clinical and socioeconomic factors was obtained from medical records and national registries. Factors associated with survival were assessed using a Cox's proportional hazards model. Median overall survival was 6.8 years, median progression-free survival was 2.6 years, and treatment-related mortality at Day 100 was 6%. Factors associated with a significant adverse impact on survival were age, primary refractory disease, prolonged hospitalization during salvage treatment, and performance status >0 prior to conditioning therapy. Reconsideration of ASCT for those patients may be required in order to select the right patients for this toxic procedure. PMID- 28868961 TI - Serotonin-gated inward currents are three times more frequent in rat hairy skin sensory afferents than in those innervating the skeletal muscle. AB - Tight whole-cell patch clamp was performed in 191 DiI (1,1'-dioctadecyl-3,3,3'3' tetramethylindocarbocyanine perchlorate) retrogradely labeled rat sensory afferents from skin shoulders ( n = 93) and biceps femoris muscles ( n = 98). 5 HT-gated inward currents were evoked with 50-uM serotonin (5-HT; 5 hydroxytryptamine), and their frequency and current densities were compared between skin and skeletal muscle sensory afferents. To evaluate if 5-HT-gated inward currents coexist with other ligand-gated currents, the skin and skeletal muscle sensory afferents were also sequentially exposed to external solution at pH 6.8, ATP (50 uM), and capsaicin (1 uM). 5-HT evoked inward currents in 72% (67 of 93) of hairy skin sensory afferents and in only 24% (24 of 98) of skeletal muscle sensory afferents, and this difference was statistically significant ( p < 0.0000, chi-square test). The current densities obtained in hairy skin and skeletal muscle sensory afferents were not significantly different. They were 45.8 +/- 7.7 and -32.4 +/- 10.5 pA/pF, respectively (mean +/- SEM, p < 0.30734). These results indicate that 5-HT-gated inward currents are three times more frequently evoked in small- to medium-sized sensory afferents (25-40 um) innervating the hairy skin than on those innervating the skeletal muscle. When cells were gathered in two clusters, the difference was four times larger in the small-sized cluster (25-32 um) and two times larger in the medium-sized cluster (33-40 um). The results can be explained if the superficial somatic (cutaneous) nociceptive system is more exposed than the deep somatic nociceptive system (musculoskeletal) to physical and chemical stimuli inducing 5-HT-mediated inflammatory pain. PMID- 28868965 TI - The effects of UDP-sugars, UDP and Mg2+on uridine diphosphate glucuronosyltransferase activity in human liver microsomes. AB - 1. The UDP-glucuronosyltransferase (UGT) enzymes are important in the metabolism, elimination and detoxification of many xenobiotics and endogenous compounds. As extrapolation of in vitro kinetics of drug metabolizing enzymes to predict in vivo clearance rates becomes more sophisticated, it is important to ensure proper optimization of enzyme assays. The luminal location of the enzyme active site (i.e. latency), and the complexity of UGT kinetics, results in consistent under prediction of clearance of drugs metabolized by glucuronidation. 2. We examined inhibition of UGT activity in alamethicin-disrupted human liver microsomes (HLM) by uridine diphosphate (UDP), a UGT reaction product, and its reversal by Mg2+ ions. We also determined whether UDP-sugars other than the co-substrate UDP glucuronic acid (UDP-GlcA) affected glucuronidation. 3. We show that other UDP sugars do not significantly influence glucuronidation. We also demonstrate that UDP inhibits HLM UGT activity and that this is reversed by including Mg2+ in the assay. The Mg2+ effect can be offset using EDTA, and is dependent on the concentration of UDP-GlcA in the assay. 4. We propose that formation of a Mg2+ UDP complex prevents UDP from affecting the enzyme. Our results suggest that 5 mM UDP-GlcA and 10 mM Mg2+ be used for UGT assays in fully disrupted HLM. PMID- 28868964 TI - Poly-epsilon-caprolactone/chitosan nanoparticles provide strong adjuvant effect for hepatitis B antigen. AB - AIM: This work aims to investigate the adjuvant effect of poly-epsilon caprolactone/chitosan nanoparticles (NPs) for hepatitis B surface antigen (HBsAg) and the plasmid DNA encoding HBsAg (pRC/CMV-HBs). METHODS: Both antigens were adsorbed onto preformed NPs. Vaccination studies were performed in C57BL/6 mice. Transfection efficiency was investigated in A549 cell line. RESULTS: HBsAg adsorbed NPs generated strong anti-HBsAg IgG titers, mainly of IgG1 isotype, and induced antigen-specific IFN-gamma and IL-17 secretion by spleen cells. The addition of pRC/CMV-HBs to the HBsAg-adsorbed NPs inhibited IL-17 secretion but had minor effect on IFN-gamma levels. Lastly, pRC/CMV-HBs-loaded NPs generated a weak serum antibody response. CONCLUSION: Poly-epsilon-caprolactone/chitosan NPs provide a strong humoral adjuvant effect for HBsAg and induce a Th1/Th17-mediated cellular immune responses worth explore for hepatitis B virus vaccination. PMID- 28868966 TI - Core-shell hybrid nanostructured delivery platforms for advanced RNAi therapeutics. AB - AIM: Study was aimed at combining the advantages of nonclassical RNAi-triggering oligonucleotides with nanoparticle-based advanced delivery platforms for developing efficient therapeutic systems. MATERIALS & METHODS: We utilized a core shell hybrid nanostructured platform for effectively delivering nonclassical RNAi triggers, namely long double stranded interfering RNA and tripodal interfering RNA. Core-shell structure was prepared by stably anchoring thiol-modified cationic polymer on the surface of growing crystal gold (Au) seeds, and the resulting particles were further complexed with nonclassical RNAi candidates via electrostatic interactions. RESULTS: Our studies clearly demonstrated that the unique combination of nonclassical RNAi structures with an advanced core-shell hybrid nanostructured platform is an effective module for advanced RNAi-based therapeutic development. PMID- 28868967 TI - Optimization of toluene removal over W-doped TiO2 nano-photocatalyst under visible light irradiation. AB - This study outlines the optimization of photocatalytic degradation of toluene by W-doped TiO2 nanoparticles under visible light irradiation. Experiments were carried out based on the central composite design (CCD) methodology. W-TiO2 nanoparticles were synthesized with various tungsten contents at different calcination temperatures by the sol-gel method. The nanoparticles' characteristics were determined using appropriate techniques such as field emission scanning electron microscopy, particle size analysis, X-ray diffraction and energy-dispersive spectroscopy. The effect of different operational conditions of coating mass, initial toluene concentration, and exposure time on the toluene removal efficiency was investigated. Result showed that tungsten has a fundamental role in improving the photocatalytic activity of TiO2 under visible light, as well as improving its photoactivity under UV irradiation by decreasing the rate of electron/hole charge recombination. Analysis of the obtained data on toluene removal with a CCD approach illustrated that the quadratic model can effectively predict the toluene removal with coefficient of determination of R2 = 0.862. Tungsten content and exposure time affect the toluene removal efficiency more than other factors. Results showed that maximum toluene removal efficiency slightly depends on the initial concentration of toluene. At the initial toluene concentration of 4000 ppm, the optimum values of the calcination temperature, tungsten content, coating mass, and exposure time were 500 degrees C, 0.52 wt%, 11.7 g/m2, and 8 h, respectively, with 59% removal of toluene. PMID- 28868968 TI - Can regenerative medicine and nanotechnology combine to heal wounds? The search for the ideal wound dressing. AB - Skin is the outermost covering of the human body and at the same time the largest organ comprising 15% of body weight and 2 m2 surface area. Skin plays a key role as a barrier against the outer environment depending on its thickness, color and structure, which differ from one site to another. The four major types of problematic wounds include ulcers (diabetic, venous, pressure) and burn wounds. Developing novel dressings helps us to improve the wound healing process in difficult patients. Recent advances in regenerative medicine and nanotechnology are revolutionizing the field of wound healing. Antimicrobial activity, exogenous cell therapy, growth factor delivery, biodegradable and biocompatible matrix construction, all play a role in hi-tech dressing design. In the present review, we discuss how the principles of regenerative medicine and nanotechnology can be combined in innovative wound dressings. PMID- 28868969 TI - The impact of physical activity and sex differences on intraindividual variability in inhibitory performance in older adults. AB - It is well-known that processing speed and executive functions decline with advancing age. However, physical activity (PA) has a positive impact on cognitive performances in aging, specifically for inhibition. Less is known concerning intraindividual variability (iiV) in reaction times. This study aims to investigate the influence of PA and sex differences on iiV in inhibitory performance during aging. Healthy adults were divided into active and sedentary groups according to PA level. To analyse iiV in reaction times, individual mean, standard deviation and the ex-Gaussian parameters were considered. An interaction between activity level and sex was revealed, sedentary females being slower and more variable than sedentary men. No sex differences were found in the active groups. These results indicate that the negative impact of sedentariness on cognitive performance in older age is stronger for females. The present findings underline the need to consider sex differences in active aging approaches. PMID- 28868972 TI - Realizing the therapeutic potential of rare earth elements in designing nanoparticles to target and treat glioblastoma. AB - The prognosis of brain cancer glioblastoma (GBM) is poor, and despite intense research, there have been no significant improvements within the last decade. This stasis implicates the need for more novel therapeutic investigation. One such option is the use of nanoparticles (NPs), which can be beneficial due to their ability to penetrate the brain, overcome the blood-brain barrier and take advantage of the enhanced permeation and retention effect of GBM to improve specificity. Rare earth elements possess a number of interesting natural properties due to their unique electronic configuration, which may prove therapeutically advantageous in an NP formulation. The underexplored exciting potential for rare earth elements to augment the therapeutic potential of NPs in GBM treatment is discussed in this review. PMID- 28868971 TI - Mucoadhesive solid lipid microparticles for controlled release of a corticosteroid in the chronic obstructive pulmonary disease treatment. AB - AIM: Therapeutic efficacy of pulmonary diseases is often limited and drug delivery systems offer new solutions to clinical problems. Solid lipid microparticles (SLMs) are suggested as systems for the delivery of therapeutics to the lung as, because of their size, they are able to deposit into secondary bronchi. MATERIALS & METHODS: Here, we describe two novel different SLMs using chitosan and alginate such as mucoadhesive polymers and we also studied their biocompatibility and their effectiveness compared with the free drug in controlling senescence and inflammatory processes in cigarette smoke extracts. RESULTS: Data reported show that fluticasone propionate (FP)-loaded SLMs are more effective than FP alone in controlling oxidative stress. CONCLUSION: The therapeutic approach using FP-loaded microparticles could be a promising strategy for the treatment of the chronic inflammatory pulmonary diseases. PMID- 28868973 TI - Key compounds contributing to the fruity aroma characterization in Japanese raw soy sauce. AB - In order to clarify the aroma characteristics of raw soy sauce (RS), the application of gas chromatography-olfactometry analysis to the aroma concentrate from a RS revealed 76 aroma peaks, of which 25 peaks showed fruit-like aromas. Furthermore, the head space aromatic compounds of RS were analyzed with 32 peaks detected. Ethyl 2-methylpropanoate, ethyl butanoate, ethyl 2-methylbutanoate, ethyl 3-methylbutanoate, and ethyl 4-methylpentanoate were detected with higher flavor dilution factor (FD factor) than other aroma compounds by aroma extract dilution analysis. Quantitative analysis suggested that these compounds were common in all RS samples tested in this study, and were present at higher concentrations than their perception thresholds. The concentrations and the FD factors of these compounds were significantly decreased during the heating of the RS. Fruitiness is one of the key aroma characteristics of RS and the ethyl esters identified in this study are the key components contributing to this distinct aroma. PMID- 28868970 TI - The use of nanoparticulates to treat breast cancer. AB - Breast cancer is a major ongoing public health issue among women in both developing and developed countries. Significant progress has been made to improve the breast cancer treatment in the past decades. However, the current clinical approaches are invasive, of low specificity and can generate severe side effects. As a rapidly developing field, nanotechnology brings promising opportunities to human cancer diagnosis and treatment. The use of nanoparticulate-based platforms overcomes biological barriers and allows prolonged blood circulation time, simultaneous tumor targeting and enhanced accumulation of drugs in tumors. Currently available and clinically applicable innovative nanoparticulate-based systems for breast cancer nanotherapies are discussed in this review. PMID- 28868975 TI - Attachment representations of school-aged Korean children: comparing family drawing and narrative assessments in a clinical and a community sample. AB - This study explored the links between two different methods of assessing children's attachment representations, a narrative task (the Manchester Attachment Story Task, MCAST) and a drawing task (the Family Drawing Task, FDT), in a clinical sample of 51 and a community sample of 45 Korean children aged 7-9. In both samples, attachment classifications derived from the MCAST were related to attachment classifications and global ratings derived from the FDT. In addition, rates of insecure attachment determined by MCAST classifications and by FDT global scales indicative of insecure attachment were higher in the clinical sample than the community sample. Variations in attachment patterns for these Korean samples are discussed in relation to Korean child-rearing customs. Results of this study contribute to the cross-cultural validation of both of these instruments, as well as extending our understanding of patterns of attachment in Korea from infancy to middle childhood. PMID- 28868974 TI - Brain Changes Following Executive Control Training in Older Adults. AB - BACKGROUND: While older adults are able to attend to goal-relevant information, the capacity to ignore irrelevant or distracting information declines with advancing age. This decline in selective attention has been associated with poor modulation of brain activity in sensory cortices by anterior brain regions implicated in cognitive control. OBJECTIVE: Here we investigated whether participation in an executive control training program would result in improved selective attention and associated functional brain changes in a sample of healthy older adults (N = 24, age 60-85 years). METHODS: Participants were enrolled in a goal-oriented attentional self-regulation (GOALS) program (n = 11) or a brain health education workshop as an active control condition (n = 13). All participants performed a working memory task requiring attention to or suppression of visual stimuli based on goal-relevance during functional magnetic resonance imaging. RESULTS: We observed a pattern of enhanced activity in right frontal, parietal and temporal brain regions from pre- to posttraining in the GOALS intervention group, which predicted the selectivity of subsequent memory for goal-relevant stimuli. CONCLUSIONS: Executive control training in older adults alters functional activity in brain regions associated with attentional control, and selectively predicts behavioral outcome. PMID- 28868976 TI - New insight into the fouling behavior of hydrophobic and hydrophilic polypropylene membranes in integrated membrane bioreactors. AB - To investigate the effect of hydrophobic and hydrophilic polypropylene hollow fiber membranes (PPHFMs) applied in membrane bioreactors (MBR), the fouling behaviors of membrane surfaces and pores have been tested. The structural and morphological features on the membrane surface were characterized using attenuated total reflection-Fourier transform infrared spectroscopy, field emission scanning electron microscopy, atomic force microscope, energy dispersive X-ray spectroscopy and laser granularity distribution analysis. The results showed that significantly more polysaccharide, protein and inorganic ingredients were accumulated in the original membrane compared to the hydrophilic membrane. Furthermore, it was found that the pore size influenced the particle distribution and accumulation, such that smaller pore size membranes tended to contain fewer pollutants and a narrow size distribution. Under a constant flux of 11.5 L/m2 h, the transmembrane pressure (TMP) varied narrowly between 38 and 53 KPa. Alongside this, a relatively hydrophilic membrane (PP-g-AA) showed the characteristics of lower TMP in comparison to hydrophobic membranes (PP). Indeed, the flux recovery was 30% higher than those of the original PPHFM. This investigation broadens our understanding of membrane modifying and fouling behavior in integrated MBRs. PMID- 28868977 TI - Family members' and best friend's smoking influence on adolescent smoking differs between Eastern Finland and Russian Karelia. AB - AIMS: The aim of this study was to find out whether family members' (mother, father, siblings) and best friend's smoking is related to 9th grade pupils' daily smoking in Eastern Finland and in the Pitkaranta district, in the Republic of Karelia, Russia, and whether these relations have changed in these two culturally very different neighbourhood countries from 1995 to 2013. METHODS: Data comprised four cross-sectional studies in all schools of the Pitkaranta region and selected schools in Eastern Finland. In data analyses, structural equation modelling techniques were used. RESULTS: Our findings showed that best friend's smoking had the strongest influence on adolescents' smoking in both countries and study years (p < .01). The relations among family members were highly different between Pitkaranta and Eastern Finland, particularly in 2013. CONCLUSIONS: Results suggest that health promotion in schools should take into account cultural impacts and pay special attention to pupils who have family members and friends who smoke. PMID- 28868978 TI - Biotransformation of chromium (VI) in liquid effluents by resistant bacteria isolated from the Matanza-Riachuelo basin, in Argentina. AB - The aims of this investigation were to evaluate the bacterial resistance to zinc, copper, chromium (VI) and lead in surface water streams from Buenos Aires, Argentina; to select a chromium-resistant strain able to remove the metal in batch process and to evaluate the potential of this strain to remove chromium (VI) in liquid effluents. Bacterial resistance to the metals was evaluated by determining the minimal inhibitory concentration. The kinetic of chromium (VI) removal by one of the resistant strains was studied in nutrient broth with 50 and 100 mg L-1 of the metal, as well as an effluent from an electroplating industry. High resistance to all the metals under study was observed in the bacterial communities of the Matanza-Riachuelo basin. A chromium-resistant strain was isolated and identified as Microbacterium sp. It was able to remove 50 and 100 mg L-1 of Cr (VI) in 36 and 66 h respectively, with efficiency higher than 99%. Experiments with liquid effluents showed the ability of the strain to transform 150 mg L-1 of the metal in 84 h, with efficiency higher than 99%. These results show the potential of this native strain for the treatment of liquid effluents that contain chromium (VI). PMID- 28868979 TI - Ethical public health issues for the use of informal PrEP. AB - This article presents the phenomenon of the use of informal pre-exposure prophylaxis (PrEP), also known colloquially as 'wild PrEP'. The related ethical public health issues of the use of informal PrEP are discussed. From the approach of an ethical framework of risk reduction in public health, the main objective of this article is to encourage health-related practices and policies that do not stop the informal access to PrEP, but rather promote the wellbeing of users by providing them with the necessary knowledge and resources related to PrEP and HIV prevention (i.e. getting regularly tested for HIV if one is to take PrEP). As each country has its own policies with respect to PrEP and access to healthcare services, this article does not explore specific locations but rather highlights different global ethical key points on how to approach the use of informal PrEP with the goal of promoting HIV prevention among individuals at high risk for HIV infection. PMID- 28868980 TI - Nanoparticle-based strategies for cancer immunotherapy and immunodiagnostics. AB - Although recent successes in clinical trials are strengthening research focused on cancer immunology, the poor immunogenicity and off-target side effects of immunotherapeutics remain major challenges in translating these promising approaches to clinically feasible therapies in the treatment of a large range of tumors. Nanotechnology offers target-based approaches, which have shown significant improvements in the rapidly advancing field of cancer immunotherapy. Here, we first discuss the chemical and physical features of nanoparticulate systems that can be tuned to address the anticancer immune response, and then review recent, key examples of the exploited strategies, ranging from nanovaccines to NPs revising the tumor immunosuppressive microenvironment, up to immunotherapeutic multimodal NPs. Finally, the paper concludes by identifying the promising and outstanding challenges the field of emerging nanotechnologies is facing for cancer immunotherapy. PMID- 28868981 TI - Spectroscopic and molecular docking approaches for the investigation of molecular interactions between herbicide sulfosulfuron and bovine serum albumin. PMID- 28868982 TI - Professors Amiram Eldor and Yaakov Matzner. In Memory of Two Dear Friends and Colleagues. PMID- 28868983 TI - Zebrafish: from genes and neurons to circuits, behavior and disease. PMID- 28868984 TI - The New Kidney Donor Allocation System and Implications for Anesthesiologists. AB - Given potential disparity and limited allocation of deceased donor kidneys for transplantation, a new federal kidney allocation system was implemented in 2014. Donor organ function and estimated recipient survival in this system has implications for perioperative management of kidney transplant recipients. Early analysis suggests that many of the anticipated goals are being attained. For anesthesiologists, implications of increased dialysis duration and burdens of end stage renal disease include increased cardiopulmonary disease, challenging fluid, hemodynamic management, and central vein access. With no recent evidence to guide anesthesia care within this new system, we describe the kidney allocation system, summarize initial data, and briefly review organ systems of interest to anesthesiologists. As additional invasive and echocardiographic monitoring may be indicated, one consideration may be development of a dedicated anesthesiology team experienced in management and monitoring of complex patients, in a similar manner as has been done for liver transplant recipients. PMID- 28868985 TI - Use of two commercial caprine arthritis-encephalitis immunoenzymatic assays for screening of arthritic goats. AB - Roughly one-fourth of goats infected with small ruminant lentivirus (SRLV) develop caprine arthritis-encephalitis (CAE). We compared the profile of antibody response to surface glycoprotein (SU), and combined transmembrane glycoprotein and capsid protein (TM/CA) in SRLV-infected arthritic and asymptomatic goats, and determined the ability of 2 commercial ELISAs to distinguish between arthritic and asymptomatic goats. We used sera from 312 SRLV-seropositive dairy goats in a whole-virus ELISA; 222 were collected from arthritic goats and 90 from apparently healthy goats. Sera were screened with a competitive inhibition ELISA based on SU antigen (SU-ELISA) and an indirect ELISA based on TM and CA antigens (TM/CA ELISA). Receiver operating characteristic (ROC) curves were prepared for both ELISAs, and areas under the ROC curves (AUC) were compared. The proportion of goats with antibody response stronger to SU antigen than to TM/CA antigen was significantly higher among arthritic than asymptomatic goats (58.1% vs. 28.9%; p < 0.001). Antibody response to SU antigen was a good predictor of the arthritic form of CAE: AUC for SU-ELISA was 89.7% (95% CI: 85.2%, 94.2%), compared to 59.3% (95% CI: 51.9%, 66.8%) for TM/CA-ELISA ( p < 0.001). With the cutoff set at percentage of inhibition of 56%, SU-ELISA had sensitivity of 86.9% (95% CI: 81.9%, 90.7%) and specificity of 84.4% (95% CI: 75.6%, 90.5%) in discriminating between arthritic and asymptomatic goats. PMID- 28868986 TI - Evaluation of design alternatives for sewing scissors with respect to hand performance, discomfort and usability. AB - The effects of three re-designed models of sewing scissors on hand performance measures, discomfort and usability were investigated, and the results were compared with those of conventional scissors. Adjustments were made to the scissors handle with emphasis on more neutral wrist postures (bent handle - model A), correction of the thumb's position and movements (model B) and reducing hand/finger discomfort (model C) while working with the tool. The results showed some improvements in hand performance, muscular effort, usability and discomfort with model B compared to the conventional model. Better hand performance and usability and lower discomfort were recorded with model C compared to the conventional model. The results suggest that the correction of the thumb's position and movement (model B) or even reduced hand/finger discomfort (model C) are perhaps more important considerations in scissors design than improved wrist posture (model A) for improving users' performance and usability of the tool. PMID- 28868987 TI - TMJ symptoms reduce chewing amplitude and velocity, and increase variability. AB - OBJECTIVE: The null hypothesis was that mandibular amplitude, velocity, and variability during gum chewing are not altered in subjects with temporomandibular joint (TMJ) internal derangements (ID). METHODS: Thirty symptomatic subjects with confirmed ID consented to chew gum on their left and right sides while being tracked by an incisor-point jaw tracker. A gender and age matched control group (p > 0.67) volunteered to be likewise recorded. Student's t-test compared the ID group's mean values to the control group. RESULTS: The control group opened wider (p < 0.05) and chewed faster (p < 0.05) than the ID group. The mean cycle time of the ID group (0.929 s) was longer than the control group (0.751 s; p < 0.05) and more variable (p < 0.05). DISCUSSION: The ID group exhibited reduced amplitude and velocity but increased variability during chewing. The null hypothesis was rejected. Further study of adaptation to ID by patients should be pursued. PMID- 28868988 TI - Effects of resistance-guided high intensity interval functional electrical stimulation cycling on an individual with paraplegia: A case report. AB - BACKGROUND AND PURPOSE: Individuals with spinal cord injury (SCI) are more than twice as likely to develop and die from cardio-metabolic diseases as compared to able-bodied. This increased risk is thought to be in part due to accelerated muscle atrophy and reduced blood flow through sublesional arteries. Thus, strategies to recondition paralyzed skeletal muscles may help reduce cardio metabolic disease risk. The purpose of this case report was to examine the impact of a novel, resistance-guided, high intensity interval training functional electrical stimulation (RG-HIIT-FES) cycling program on cardio-metabolic health in people with chronic SCI. CASE DESCRIPTION: One adult female with chronic T10 SCI. INTERVENTION: A novel RG-HIIT-FES cycling program three times per week for 10 weeks. Measures of body composition and cardio-metabolic health (vascular endothelial function of the brachial artery via flow-mediated dilation) and HbA1c blood values were performed at baseline and following completion of the RG-HIIT FES program. OUTCOMES: Total body lean mass and legs lean mass increased 2.8% and 5.3% respectively while vastus lateralis thickness increased by 59.5%. Reactive hyperemia and flow mediated dilation change in brachial artery diameter increased by 11.1% and 147.7% following the program, respectively. HbA1c level changed minimally (5 to 4.9%). DISCUSSION: This case report suggests that RG-HIIT-FES cycling was an effective strategy to improve lean mass, and systemic vascular endothelial health in an individual with chronic SCI. PMID- 28868989 TI - Ergonomics investigation for orientation of the handles of wood routers. AB - OBJECTIVES: Improperly designed hand tools not only expose workers to potential health risks but also hamper their productivity. This study tries to improve the ergonomics of wood routing tasks, suggesting better handle orientations for hand held wood routers. METHODS: Seven different handle combinations were tested over two routing tasks (beading and dado) with regard to perceived discomfort, electromyography (EMG) of biceps brachii and extensor carpi radialis brevis and hand-arm vibrations (HAV). RESULTS: Handles with 30 degrees and 60 degrees inclinations were found more comfortable than previous 90 degrees handle inclinations for routing tasks. Perceived discomfort in the dado task was found to be significantly higher than in the beading task (p < 0.001); EMG activity also supported this observation. However, EMG data showed no significant difference for the different handles used in the study. No worthwhile reduction was obtained in HAV levels for the modified wooden handles compared to initial plastic handles. Relevance to industry. The ergonomic intervention in wood routers described in this article will contribute to the existing knowledge of ergonomics of handle design and will aid the designers/engineers to design such tool handles that may reduce the risk of work-related musculoskeletal disorders/hand-arm vibration syndrome in workers using wood routers. PMID- 28868991 TI - Sequence-dependent dynamical instability of the human prion protein: a comparative simulation study. AB - The present study aimed to explore the most probable regions of the human prion protein backbone for which the initial steps of conformational transitions as a result of intrinsic and extrinsic perturbing factors on the protein structure can be assigned. A total of 0.3-MUs molecular dynamics simulations on several analog structures of the protein have been performed. To mimic the impact of the extrinsic and intrinsic destructive parameters on the dynamical characteristics of the protein, mild acidic conditions and R208H mutation have been simulated. The findings indicated that distribution of conformational flexibilities along the protein chain was almost independent of the induced perturbing factors, and was mostly centralized on certain distinct parts of the structure comprising residues 132-145 and 187-203. Analyses also revealed that the segment comprising residues 187-203 may be considered as a peptide sequence, possessing high potential to start the initial steps of conformational rearrangements due to the induced physicochemical alterations. Sequence alignment and molecular dynamics data also revealed that segment 178-203 prefers to accommodate in extended structures rather than alpha-helices. Region 178-203 may be considered as a peptide switch capable of initiating the conformational transitions due to the introduced modifications and perturbing parameters. PMID- 28868990 TI - The effects of whole body vibration on pulse wave velocity in men with chronic spinal cord injury. AB - OBJECTIVE: A pilot study to evaluate the therapeutic potential of 40 weeks of passive standing with whole body vibration (PS-WBV) on central and peripheral arterial stiffness among men with chronic spinal cord injury (SCI). METHODS: Consenting participants were pre-screened to ensure safe participation. Fifteen individuals with chronic SCI were enrolled to participate in PS-WBV sessions three times per week for 40 weeks on a modified WAVE platform custom-fitted with an EASYStand 5000. Knee angle was set at 160 degrees , and vibration parameters were 45Hz frequency and 0.7mm displacement. Each 45-minute session of PS-WBV training was intermittent (60 seconds on and 120 seconds off). Aortic and leg pulse wave velocity (PWV) was measured at baseline, mid-point (20 weeks) and exit (40 weeks). RESULTS: Nine males (age 41+/-11 years, American Spinal Injury Association Impairment Scale A-D, neurological level of injury T4-T10, years post injury 12+/-8 years) completed the intervention. Aortic PWV was collected on n=7 at exit, and leg PWV was collected on n=6 at exit. No changes over time were found for either aortic PWV (P = 0.46) or leg PWV (P = 0.54). One possible study related serious adverse event occurred during study intervention: the development of a grade III pressure sore on the right proximal anterior shin (n=1). CONCLUSION: Forty weeks of PS-WBV in adults with SCI did not result in an observable change in arterial stiffness. PMID- 28868992 TI - Validity of Self-Reported Birth Weight: Results from a Norwegian Twin Sample. AB - The association between birth weight and later life outcomes is of considerable interest in life-course epidemiology. Research often relies on self-reported measures of birth weight, and its validity is consequently of importance. We assessed agreement between self-reported birth weight and official birth records for Norwegian twins born 1967-1974. The intraclass correlation between self reported birth weight and register-based birth weight was 0.91 in our final sample of 363 twins. It could be expected that 95% of self-reported birth-weight values will deviate from official records within a maximum of +446 grams and a minimum of -478 grams - around a mean deviation of 16 grams. Self-reported birth weight had a sensitivity of 0.78-0.89 and a positive predictive value of 0.59 0.85, and an overall weighted kappa of 0.71. We further assessed agreement by conducting two linear regression models where we respectively regressed self reported birth weight and register-based birth weight on adult body mass index, a known association. The two models were not significantly different; however, there were different levels of significance in parameter estimates that warrant some caution in using self-reported birth weight. Reliability of self-reported birth weight was also assessed, based on self-reports in another sample of twins born 1935-1960 who had reported their birth weight in two questionnaires 34 years apart. The intraclass correlation was 0.86, which indicates a high degree of reliability. In conclusion, self-reported birth weight, depending on context and age when birth weight was reported, can be cautiously used. PMID- 28868993 TI - STAKEHOLDER INVOLVEMENT THROUGHOUT HEALTH TECHNOLOGY ASSESSMENT: AN EXAMPLE FROM PALLIATIVE CARE. AB - OBJECTIVES: Internationally, funders require stakeholder involvement throughout health technology assessment (HTA). We report successes, challenges, and lessons learned from extensive stakeholder involvement throughout a palliative care case study that demonstrates new concepts and methods for HTA. METHODS: A 5-step "INTEGRATE-HTA Model" developed within the INTEGRATE-HTA project guided the case study. Using convenience or purposive sampling or directly / indirectly identifying and approaching individuals / groups, stakeholders participated in qualitative research or consultation meetings. During scoping, 132 stakeholders, aged >= 18 years in seven countries (England, Italy, Germany, The Netherlands, Norway, Lithuania, and Poland), highlighted key issues in palliative care that assisted identification of the intervention and comparator. Subsequently stakeholders in four countries participated in face-face, telephone and / or video Skype meetings to inform evidence collection and / or review assessment results. An applicability assessment to identify contextual and implementation barriers and enablers for the case study findings involved twelve professionals in the three countries. Finally, thirteen stakeholders participated in a mock decision-making meeting in England. RESULTS: Views about the best methods of stakeholder involvement vary internationally. Stakeholders make valuable contributions in all stages of HTA; assisting decision making about interventions, comparators, research questions; providing evidence and insights into findings, gap analyses and applicability assessments. Key challenges exist regarding inclusivity, time, and resource use. CONCLUSION: Stakeholder involvement is feasible and worthwhile throughout HTA, sometimes providing unique insights. Various methods can be used to include stakeholders, although challenges exist. Recognition of stakeholder expertise and further guidance about stakeholder consultation methods is needed. PMID- 28868994 TI - Fine-temporal forecasting of outbreak probability and severity: Ross River virus in Western Australia. AB - Health warnings of mosquito-borne disease risk require forecasts that are accurate at fine-temporal resolutions (weekly scales); however, most forecasting is coarse (monthly). We use environmental and Ross River virus (RRV) surveillance to predict weekly outbreak probabilities and incidence spanning tropical, semi arid, and Mediterranean regions of Western Australia (1991-2014). Hurdle and linear models were used to predict outbreak probabilities and incidence respectively, using time-lagged environmental variables. Forecast accuracy was assessed by model fit and cross-validation. Residual RRV notification data were also examined against mitigation expenditure for one site, Mandurah 2007-2014. Models were predictive of RRV activity, except at one site (Capel). Minimum temperature was an important predictor of RRV outbreaks and incidence at all predicted sites. Precipitation was more likely to cause outbreaks and greater incidence among tropical and semi-arid sites. While variable, mitigation expenditure coincided positively with increased RRV incidence (r 2 = 0.21). Our research demonstrates capacity to accurately predict mosquito-borne disease outbreaks and incidence at fine-temporal resolutions. We apply our findings, developing a user-friendly tool enabling managers to easily adopt this research to forecast region-specific RRV outbreaks and incidence. Approaches here may be of value to fine-scale forecasting of RRV in other areas of Australia, and other mosquito-borne diseases. PMID- 28868996 TI - Comparison of the Luminex NxTAG respiratory pathogen panel and a multiplex in house real-time PCR panel for the detection of respiratory viruses in symptomatic patients. AB - PURPOSE: To evaluate the Luminex NxTAG respiratory pathogen panel (NxTAG RPP) for the detection of respiratory viruses in clinical samples from patients with the symptoms of respiratory infection. METHODOLOGY: The NxTAG RPP was compared to an in-house multiplex real-time PCR panel (LDT) for the detection of respiratory viruses in 314 clinical samples from patients with the symptoms of respiratory infection. RESULTS: Thirty-one samples were negative in both tests and 193 samples contained a single virus that was detected in both tests. Polymicrobial infections were detected in 74 samples, with 268 samples overall having concordant results in both assays, and there were a total of 51 discordant results in 44 samples. Two samples were invalid in the NxTAG RPP assay and were excluded from the final analysis. The overall agreement between the NxTAG RPP and LDT was very high, as indicated by the Kappa coefficients, which ranged from 0.85 for metapneumovirus up to 0.96 for RSV A, and the overall percentage agreement values of 96.2 % for enterovirus/rhinovirus and 100 % for influenza A, influenza B, PIV 4 and RSV B. CONCLUSION: The NxTAG RPP is a sensitive and specific test for the detection of respiratory viruses and the high sample throughput and low hands-on time make the NxTAG RPP assay suitable for screening clinical samples for respiratory pathogens. PMID- 28868995 TI - Central line-associated bloodstream infections in Australian ICUs: evaluating modifiable and non-modifiable risks in Victorian healthcare facilities. AB - Central line-associated bloodstream infections (CLABSIs) in intensive care units (ICUs) result in poor clinical outcomes and increased costs. Although frequently regarded as preventable, infection risk may be influenced by non-modifiable factors. The objectives of this study were to evaluate organisational factors associated with CLABSI in Victorian ICUs to determine the nature and relative contribution of modifiable and non-modifiable risk factors. Data captured by the Australian and New Zealand Intensive Care Society regarding ICU-admitted patients and resources were linked to CLABSI surveillance data collated by the Victorian Healthcare Associated Infection Surveillance System between 1 January 2010 and 31 December 2013. Accepted CLABSI surveillance methods were applied and hospital/patient characteristics were classified as 'modifiable' and 'non modifiable', enabling longitudinal Poisson regression modelling of CLABSI risk. In total, 26 ICUs were studied. Annual CLABSI rates were 1.72, 1.37, 1.00 and 0.93/1000 CVC days for 2010-2013. Of non-modifiable factors, the number of non invasively ventilated patients standardised to total ICU bed days was found to be independently associated with infection (RR 1.07; 95% CI 1.01-1.13; P = 0.030). Modelling of modifiable risk factors demonstrated the existence of a policy for mandatory ultrasound guidance for central venous catheter (CVC) localisation (RR 0.51; 95% CI 0.37-0.70; P < 0.001) and increased number of sessional specialist full-time equivalents (RR 0.52; 95% CI 0.29-0.93; P = 0.027) to be independently associated with protection against infection. Modifiable factors associated with reduced CLABSI risk include ultrasound guidance for CVC localisation and increased availability of sessional medical specialists. PMID- 28868997 TI - DNA microarray assay and real-time PCR as useful tools for studying the respiratory tract Mycoplasma populations in young dairy calves. AB - PURPOSE: With more than 120 species, the genus Mycoplasma is one of the largest taxa in the class Mollicutes, a group of micro-organisms that are characterized by apparent simplicity and to which important animal pathogens belong. Mycoplasmabovis is the most frequently identified pathogenic Mycoplasma in cattle; however, the prevalence of other Mycoplasma species living in calves' airways is poorly understood. The aim of this work was to characterize the respiratory tract mycoplasma populations in calves on one of the largest dairy farms in Italy using a real-time PCR assay and a DNA microarray assay. METHODOLOGY: A total of 49 nasal swabs and 49 trans-tracheal aspirations from non vaccinated veal calves were analysed. Genomic DNA was extracted from the samples and then tested using a real-time PCR targeting the oppD gene of M. bovis and a DNA microarray that was able to identify more than 70 Mycoplasma species. RESULTS: Forty-two out of 49 calves tested positive for Mycoplasma spp. (85.7 %). None of the samples tested positive for M. bovis. A majority (73.5 %) of the 98 samples tested positive for M. dispar, while 8 samples tested positive for M. bovirhinis (8.2 %). CONCLUSION: Our results expand our knowledge regarding the diversity of Mycoplasma populations in the respiratory airways of very young veal calves and add data regarding M. bovis prevalence in the Italian cattle population. However, the importance of these species in the respiratory diseases of calves still remains to be determined. PMID- 28868998 TI - Conexibacter stalactiti sp. nov., isolated from stalactites in a lava cave and emended description of the genus Conexibacter. AB - A Gram-positive, strictly aerobic, non-sporulating, motile, rod-shaped bacterium, designated YC2-25T, was isolated from pieces of stalactites collected from a lava cave in Jeju, Republic of Korea. Colonies were circular, smooth, convex and cream to light yellow in colour. A neighbour-joining tree based on 16S rRNA gene sequences indicated that the organism belonged to the genus Conexibacter with the closest relatives being Conexibacter woesei (99.0 % sequence similarity) and Conexibacter arvalis (98.8 %). Meso-Diaminopimelic acid was the diagnostic diamino acid in the cell-wall peptidoglycan. The predominant menaquinone was MK 7(H4). The polar lipids were diphosphatidylglycerol, phosphatidylinositol, two phospholipids and four lipids. The predominant fatty acid was C18 : 1omega9c. The DNA G+C content was 70.3 %. On the basis of distant phenotypic characteristics and DNA-DNA hybridization data, strain YC2-25T (=KCTC 39840T=DSM 103719T) represents a novel species of the genus Conexibacter, for which the name Conexibacter stalactiti sp. nov. is proposed. PMID- 28868999 TI - Phylogenetically distant clade of Nostoc-like taxa with the description of Aliinostoc gen. nov. and Aliinostoc morphoplasticum sp. nov. AB - Nostoc is a complex and tough genus to differentiate, and its morphological plasticity makes it taxonomically complicated. Its cryptic diversity and almost no distinguishable morphological characteristics make this genus incredibly heterogeneous to evaluate on taxonomic scales. The strain NOS, isolated from a eutrophic water body, is being described as a new genus Aliinostoc with the strain showing motile hormogonia with gas vesicles as an atypical feature, which is currently considered as the diacritical feature of the genus but should be subjected to critical evaluation in the near future. The phylogenetic placement of Aliinostoc along with some other related sequences of Nostoc clearly separated this clade from Nostoc sensu stricto with high bootstrap support and robust topology in all the methods tested, thus providing strong proof of the taxa being representative of a new genus which morphologically appears to be Nostoc-like. Subsequent phylogenetic assessment using the rbcL, psbA, rpoC1 and tufA genes was done with the aim of facilitating future multi-locus studies on the proposed genus for better taxonomic clarity and resolution. Folding of the 16S-23S internal transcribed spacer region and subsequent comparisons with members of the genera Nostoc, Anabaena, Aulosira, Cylindrospermum, Sphaerospermopsis, Raphidiopsis, Desmonostoc and Mojavia gave entirely new secondary structures for the D1-D1' and box-B helix. Clear and separate clustering from Nostoc sensu stricto supports the establishment of Aliinostoc gen. nov. with the type species being Aliinostoc morphoplasticum sp. nov. in accordance with the International Code of Nomenclature for algae, fungi and plants. PMID- 28869000 TI - Similarities in intracellular transport of plant viral movement proteins BMB2 and TGB3. AB - The cell-to-cell transport of many plant viruses through plasmodesmata requires viral movement proteins (MPs) encoded by a 'triple gene block' (TGB) and termed TGB1, TGB2 and TGB3. TGB3 is a small integral membrane protein that contains subcellular targeting signals and directs both TGB2 and the helicase domain containing TGB1 protein to plasmodesmata-associated structures. Recently, we described a 'binary movement block' (BMB) coding for two MPs, BMB1 and BMB2. The BMB2 protein associates with endoplasmic reticulum (ER) membranes, accumulates at plasmodesmata-associated membrane bodies and directs the BMB1 helicase to these structures. TGB3 transport to cell peripheral bodies was previously shown to bypass the secretory pathway and involve a non-conventional mechanism. Here, we provide evidence that the intracellular transport of both poa semilatent virus TGB3 and hibiscus green spot virus BMB2 to plasmodesmata-associated sites can occur via lateral translocation along the ER membranes. Agrobacterium-mediated transient co-expression in Nicotiana benthamiana leaves revealed that green fluorescent protein (GFP)-fused actin-binding domains of Arabidopsis fimbrin (ABD2-GFP) and mouse talin (TAL-GFP) inhibited the subcellular targeting of TGB3 and BMB2 to plasmodesmata-associated bodies, which resulted in TGB3 and BMB2 accumulation in the cytoplasm in association with aberrant ER structures. Inhibition of COPII budding complex formation by the expression of a dominant negative mutant of the small GTPase Sar1 had no detectable effect on BMB2 subcellular targeting, which therefore could occur without exit from the ER in COPII transport vesicles. Collectively, the presented data support the current view that plant viral MPs exploit the ER:actin network for their intracellular transport. PMID- 28869001 TI - m6A RNA methylation, a new hallmark in virus-host interactions. AB - The role of m6A methylation of RNA has remained elusive for decades, but recent technological advances are now allowing the mapping of the m6A methylation landscape at nucleotide level. This has spurred an explosion in our understanding of the role played by RNA epigenetics in RNA biology. m6A modifications have been tied to almost every aspect of the mRNA life cycle and it is now clear that RNA virus genomes are subject to m6A methylation. These modifications play various roles in the viral replication cycle. This review will summarize recent breakthroughs concerning m6A RNA modification and their implications for cellular and viral RNAs. PMID- 28869002 TI - Mycobacterium eburneum sp. nov., a non-chromogenic, fast-growing strain isolated from sputum. AB - A polyphasic study was undertaken to establish the taxonomic position of a non chromogenic, rapidly growing Mycobacterium strain that had been isolated from sputum. The strain, CECT 8775T, has chemotaxonomic and cultural properties consistent with its classification in the genus Mycobacterium and was distinguished from the type strains of closely related mycobacterial species, notably from Mycobacterium paraense DSM 46749T, its nearest phylogenetic neighbour, based on 16S rRNA, hsp65 and rpoB gene sequence data. These organisms were also distinguished by a broad range of chemotaxonomic and phenotypic features and by a digital DNA-DNA relatedness value of 22.8 %. Consequently, the strain is considered to represent a novel species of Mycobacterium for which the name Mycobacterium eburneum sp. nov is proposed; the type strain is X82T (CECT 8775T=DSM 44358T). PMID- 28869003 TI - Pleomorphobacterium xiamenense Yin et al. 2013 is a later heterotypic synonym of Oceanicella actignis Albuquerque et al. 2012. AB - Pleomorphobacterium xiamenense CLWT was compared with Oceanicella actignis PRQ 67T to examine the taxonomic relationship between the two organisms. The 16S rRNA gene sequence comparison showed that the two strains had 99.9 % sequence similarity. Phylogenetic analysis showed the two strains formed an independent tight cluster, distinctly branching from the closely related species in the family Rhodobacteraceae. Whole genomic comparison between the two strains revealed a digital DNA-DNA hybridization estimate of 88.4 % and average nucleotide identity of 98.8 %, strongly supporting that the two strains represented a single species. In addition, neither strain displayed any striking difference in biochemical characteristics, fatty acid composition, and polar lipid profile. According to priority, Pleomorphobacterium xiamenense is reclassified as a later heterotypic synonym of Oceanicella actignis based on the phylogenetic relationship, whole genomic comparison, fatty acid composition and polar lipid profile, and other phenotypic and biochemical properties. PMID- 28869004 TI - Performance assessment of urine flow cytometry (UFC) to screen urines to reflex to culture in immunocompetent and immunosuppressed hosts. AB - PURPOSE: Urine flow cytometry (UFC) is an automated method to quantify bacterial and white blood cell (WBC) counts. We aimed to determine whether a threshold for these parameters can be set to use UFC as a sensitive screen to predict which urine samples will subsequently grow in culture. METHODOLOGY: Urines submitted to our microbiology laboratory at a tertiary care centre from 22 July 2015-17 February 2016 underwent UFC (Sysmex UF-1000i) analysis, regular urinalysis and urine culture. Positive urine cultures were defined as growth >=104 c.f.u. ml-1 of organisms associated with urinary tract infections. The correlation of UFC bacterial and WBC counts with urine culture was assessed using receiver operating characteristics curves. The sensitivity (SN), specificity (SP), negative predictive values (NPVs), positive predictive values (PPVs) and false negative rate (FNR) were calculated at various thresholds in immunocompetent and immunosuppressed patients. RESULTS: A total of 15 046 urine specimens were submitted, of which 14 908 were analysable in the study. The average time to UFC result from receipt in the laboratory was 0.76 h (+/-1.04). The test performance at a set threshold of UFC bacteria >=20 or WBC >5 was: SN=96.0 %, SP=39.2 %, PPV=47.0 %, NPV=94.5 % and FNR=4.0 %. This threshold eliminates 26 % of urine cultures. Immunosuppressed hosts had a lower sensitivity of 90.6 % and a higher FNR of 9.4 %. CONCLUSIONS: UFC is a rapid and sensitive method to screen out urine samples that will subsequently be negative and to reflex urines to culture that will subsequently grow. UFC results are available within 1 h from receipt and enable the elimination of culture when the set threshold is not met. PMID- 28869007 TI - [Kronisk infektion efter traumatisk sar]. PMID- 28869005 TI - Human interactome of the influenza B virus NS1 protein. AB - NS1 proteins of influenza A and B viruses share limited sequence homology, yet both are potent manipulators of host cell processes, particularly interferon (IFN) induction. Although many cellular partners are reported for A/NS1, only a few (e.g. PKR and ISG15) have been identified for B/NS1. Here, affinity purification and mass spectrometry were used to expand the known host interactome of B/NS1. We identified 22 human proteins as new putative targets for B/NS1, validating several, including DHX9, ILF3, YBX1 and HNRNPC. Consistent with two RNA-binding domains in B/NS1, many of the identified factors bind RNA and some interact with B/NS1 in an RNA-dependent manner. Functional characterization of several B/NS1 interactors identified SNRNP200 as a potential positive regulator of host IFN responses, while ILF3 exhibited dual roles in both IFN induction and influenza B virus replication. These data provide a resource for future investigations into the mechanisms underpinning host cell modulation by influenza B virus NS1. PMID- 28869006 TI - Amisulpride augmentation in clozapine-unresponsive schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical effectiveness and cost-effectiveness. AB - BACKGROUND: When treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice. OBJECTIVES: The main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia. DESIGN: The study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks. SETTINGS: The study was set in NHS multidisciplinary teams in adult psychiatry. PARTICIPANTS: Eligible participants were people aged 18-65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy. INTERVENTIONS: Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of 'responders', using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale. RESULTS: A total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between L329 and L2011; no difference in quality-adjusted life years (QALYs)] and possibly in the longer term. LIMITATIONS: The trial under recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants. CONCLUSIONS: The risk-benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride-clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride-clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings. TRIAL REGISTRATION: EudraCT number 2010-018963-40 and Current Controlled Trials ISRCTN68824876. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 49. See the NIHR Journals Library website for further project information. PMID- 28869008 TI - [Faecal microbiota transplantation for the treatment of bowel disease]. AB - Faecal microbiota transplantation (FMT) is the transferral of faeces from a healthy donor to a patient with a disease linked to disturbances in the gut microbiota. The treatment has been implemented at several hospitals in Denmark, and banks with frozen donor stool material have been established. The effect of FMT for recurrent Clostridium difficile infection is well-documented. FMT cannot be recommended for routine clinical use for inflammatory bowel disease and irritable bowel syndrome because of lack of data from clinical trials. PMID- 28869009 TI - [Hemifacial atrophy treated with lipofilling]. AB - Autologous lipofilling is a relatively new method of reconstructing congenital and acquired soft tissue defects. However, long-term results are unpredictable due to varying survival rate of the fat graft, and additional treatments are often required. We present a case of a 53-year-old woman who had a right hemifacial soft tissue deficit and received lipofilling twice with no complications and satisfactory cosmetic results. We consider conventional lipofilling to be safe and viable for facial soft tissue augmentation. PMID- 28869010 TI - [Simultaneous intestinal tuberculosis and adenocarcinoma]. AB - Intestinal tuberculosis is a rare diagnosis, which may often be mistaken for mb. Crohn or cancer. We present a case of a 57-year-old man, who was diagnosed with intestinal tuberculosis. Due to increased abdominal pain, a computed tomography was performed, revealing a growing sigmoidal tumour, and the biopsies taken showed an adenocarcinoma. Further histological tests revealed no spread of cancer, and the patient could receive curative surgery. While intestinal tuberculosis can appear similar to colon cancer, it may also as in this case be an intercurrent disease. PMID- 28869011 TI - [Nutrition and dietary supplement in chronic inflammatory bowel diesease]. AB - Nutrition and food items may improve or worsen symptoms in Crohn's disease and ulcerative colitis. Protein malnutrition and vitamin and mineral deficiencies are common, particularly deficiency of iron and vitamin D. Dietary fibres and omega-3 fatty acids are safe, but no evidence supports their use as treatment. The use of probiotics is not encouraged in patients with Crohn's disease, but it may maintain remission in ulcerative colitis. Curcumin, chamomile, and other herbal extracts are promising in the treatment of mild ulcerative colitis, but validation of products and monitoring of side effects are insufficient. PMID- 28869012 TI - [Erythropoietin treatment may improve cognition in neuropsychiatric disorders]. AB - Cognitive dysfunction is a core feature in a range of neuropsychiatric disorders which reduces patients' workforce capacity - the largest socio-economic cost of these disorders. Nevertheless, there is no clinically available medical treatment with robust and enduring efficacy on cognitive deficits in most neuropsychiatric conditions. Recent research has shown that erythropoietin may have beneficial effects on cognitive dysfunction across neuropsychiatric disorders, including bipolar and unipolar disorders, schizophrenia, Parkinson's disease and multiple sclerosis. PMID- 28869013 TI - [Challenges in the differential diagnoses of parkinsonism]. AB - Parkinsonism (PD) is the clinical syndrome of bradykinesia combined with rigidity and/or tremor at rest. These are the defining characteristics of PD, but they are present in many other diseases of the brain. The most frequent differential diagnosis of PD are the atypical parkinsonian syndromes and the conditions presenting with mainly lower body parkinsonism. Discrimination between these can be challenging, especially at early stages of the disease, but nevertheless of utmost importance, because treatment and prognosis vary. Diagnoses are clinical, as disease-specific biomarkers are still lacking. PMID- 28869014 TI - [Iliac haematoma as a differential diagnosis to lumbar disc herniation]. AB - After a fall without fracture an 83-year-old man who was treated with warfarin was admitted with severe groin pain on the left hip. A few days later he had reduced strength in hip flexion and knee extension, absent patellar tendon reflex, and decreased sensibility of the anterior thigh and the medial lower leg. A magnetic resonance imaging revealed a large haematoma in the left iliac muscle. Iliac haematoma-induced femoral nerve compression neuropathy is a rare condition but should be considered as a differential diagnosis for L4 root compression in patients, who are receiving anticoagulant therapy. PMID- 28869016 TI - [Fremmedlegeme i osofagus]. PMID- 28869015 TI - [Rat bite fever in a three-year-old child]. AB - Rat bite fever (RBF) is rare in Denmark. It can be very difficult to diagnose, as the causative agent is an extremely fastidious organism which needs microaerophilic conditions to grow. We report a case of arthritis in the right ankle due to Streptobacillus moniliformis in a three-year-old girl who fully recovered after 14-day treatment of intravenous administrated penicillin followed by four weeks of orally administrated amoxicillin. Social history revealed the presence of two domestic rats living in the child's home. As rodents are becoming more popular as pets, RBF must be considered in patients with a history of relevant exposure. PMID- 28869017 TI - ? PMID- 28869018 TI - ? PMID- 28869019 TI - [Treatment of recurrent posterior epistaxis]. AB - 30% of the patients presenting with epistaxis at emergency wards and otorhinolaryngeal specialist departments have posterior bleeding. Traditional treatment with packing often leads to initial treatment failure, and many patients experience recurrent bleeding within the following month. Recurrent posterior epistaxis should be treated with local electrocautery or endoscopic ligation of the sphenopalatine artery to reduce patient discomfort, hospital stay, risk of treatment failure and recurrence. PMID- 28869020 TI - [Administration of norepinephrine in peripheral venous catheter on surgical patients]. AB - Hypotension is a common event during surgery and can cause serious post-operative complication, but vasoactive drugs can stabilize the cardiovascular system and reduce the risk of post-operative complications. Norepinephrine is an ideal vasopressor. Due to the risk of extravasation and ischaemic tissue damage norepinephrine is often administered via a central venous catheter. Administration of norepinephrine via a peripheral venous catheter may be a safe alternative during surgery, if the drug is administered correctly. PMID- 28869021 TI - [Acute impact of the small intestine in a patient after gastric bypass surgery and alcohol intake]. AB - This case recounts the management of a patient, who had previously undergone laparoscopic gastric bypass surgery and was admitted with sudden onset of severe abdominal pain. A computed tomography suggested acute ischaemia of the Roux limb. A normal diagnostic laparoscopy was performed, and a subsequent upper endoscopy showed a severely inflamed Roux limb. The patient informed that he had accidentally ingested a single glass of strong liquor. The endoscopy was repeated a month after discharge and was normal. This case suggests a link between intake of strong liquor and local inflammation of the Roux limb. PMID- 28869022 TI - [Accidental find of scrotal tuberculosis on a computed tomography]. AB - The prevalence of tuberculosis in Denmark is low compared to many developing countries. It is most commonly found in socially marginalized communities. We present an unusual case of a man, who was referred to urological treatment as a computed tomography had showed a tumour with a suspicious process in the left scrotum and in relation to the left seminal vesicle. Histopathology of the testis showed granuloma formation. A Ziehl-Neelsen staining showed no acid-fast bacilli, but polymerase chain reaction revealed Mycobacterium tuberculosis. Antituberculous treatment was commenced. PMID- 28869023 TI - ? PMID- 28869024 TI - ? PMID- 28869025 TI - [Gastric aspiration therapy is a possible alternative to treatment of obesity]. AB - Aspiration therapy with AspireAssist is a novel endoscopic obesity treatment. Patients aspirate approximately 30% of an ingested meal through a draining system connected to a percutanous endoscopic gastrostomy tube. AspireAssist was recently approved by the US Food and Drug Administration, and it induces weight loss comparable to the weight loss observed after bariatric surgery, but with a lower risk of complications. Few clinical studies about the efficacy and safety of AspireAssist have been carried out and published. Thus, further intervention studies evaluating acute as well as long-term effects are warranted. PMID- 28869026 TI - [A Danish fetal alcohol spectrum disorders definition]. AB - The Danish Paediatric Society presents the first Danish definition of fetal alcohol spectrum disorders (FASD) in a new guideline. FASD is an umbrella term for conditions caused by prenatal alcohol exposure. To varying degrees, fetal alcohol damages manifest as physical defects, characteristic facial features and poor growth, as well as behavioural and cognitive disorders. It requires both somatic and psychological evaluation to identify these damages. Early diagnosis and identification of problems are important for prognosis as professional care has a positive preventive effect on comorbidities. PMID- 28869027 TI - [Evaluation and treatment of nipple secretion]. AB - Nipple secretion is a common condition; it can occur in men and women, and be uni or bilateral. It is related to hormonal changes, physical stimulation, intracerebral processes and certain drugs, and it is divided into three types: galactorrhoea, clear/bloody or viscous. Only the clear/bloody type is an indication of breast malignancy. Malignancy should always be ruled out in the presence of breast tumours. Treatment is determined by aetiology, and can vary from patient education, medications to surgery. PMID- 28869028 TI - [The use of anti-Mullerian hormone in fertility treatment]. AB - The need for fertility treatment in Denmark is increasing, one of the main causes being postponed parenthood. Ovarian reserve is determined by the anti-Mullerian hormone (AMH) level and by antral follicle count. Both tests can predict the ovarian response to gonadotropin treatment prior to in vitro fertilization (IVF) and are used to individualize ovarian stimulation to achieve an appropriate number of follicles and to avoid ovarian hyperstimulation. A new assay detects low values of AMH and may predict who will benefit from IVF, and who should be referred directly to oocyte donation. PMID- 28869030 TI - Use of coercion at Danish psychiatric wards by day of week and time of day. AB - INTRODUCTION: Mechanical restraint and other forms of coercion may be used under certain circumstances at psych-iatric wards. The use of coercion receives considerable focus, yet little is known about its diurnal distribution. We examined the initiation of mechanical restraint, sedative drug administration, physical retention, door locking and personal shielding by time of day and week. METHODS: Group 3 protocols in the national Register of Coercion for patients aged >= 18 years in the years 2010-2012 were analysed. The first coercive episode was internally compared with respect to type, shift and whether it had been initiated on weekdays or weekend days. The odds ratio for experiencing coercive episodes outside day shifts on weekdays was calculated and adjusted for sex, age and hospital. Episodes initiated after 24 hours of admission were also analysed. RESULTS: The dataset consisted of 68,619 records from 7,338 persons. The first coercive episode was mostly initiated during a day shift on a weekday (44.9%), but this differed markedly between types of coercion. Compared with locking of doors, the adjusted odds ratio of being subjected to coercion outside the day shift on weekdays was 3.32 (95% confidence interval (CI): 2.91-3.79) for mechanical restraint and 2.70 (95% CI: 2.32-3.16) for physical retention. This pattern persisted if the first episode was initiated at least 24 hours after admission. CONCLUSIONS: The initiation of coercion was lower during evenings, nights and weekends, but different coercive types and hospitals followed different diurnal patterns, which indicates unexplained variations. FUNDING: The establishment of the data set was funded by the Public Health Officers North. TRIAL REGISTRATION: not relevant. PMID- 28869029 TI - Validation of the Danish version of Inflammatory Bowel Disease Self-assessment Scale. AB - INTRODUCTION: The Inflammatory Bowel Disease Fatigue Self-assessment Scale (IBD F) is a multidimensional, disease-specific questionnaire. Patients with inflammatory bowel disease (IBD) took part in the development of the tool. The scale was developed in the UK and comprises 35 questions: five questions about the severity of fatigue and 30 questions about the impact of fatigue. The purpose of this study was to validate a Danish electronic version of the IBD-F in a Danish IBD population. METHODS: We included IBD outpatients regardless of disease activity. They were invited to answer the IBD-F, the Multidimensional Fatigue Inventory (MFI-20) and the health-related quality of life tool known as the Short Health Scale (SHS). Furthermore, we collected socio-demographic and disease data. A subsample was invited to answer the IBD-F again two weeks later. Spearman analysis was used to evaluate the correlations between the IBD-F, the MFI-20 and the SHS. Reliability was tested by intraclass coefficients. RESULTS: A total of 325 patients were invited, and 159 patients had complete data. The IBD-F correlated well with the MFI-20 fatigue tool for almost all dimensions. The correlation with the SHS was less marked. The following variables were associated with more fatigue: female, Crohn's disease, respondent unemployed and comorbidity. The test-retest reliability was excellent. CONCLUSION: The Danish version of the IBD-F is a valid tool for use in Danish patients with IBD. FUNDING: This study was funded in part by an unrestricted grant from Takeda, Denmark. TRIAL REGISTRATION: not relevant. PMID- 28869031 TI - Cost analysis of bariatric surgery in Denmark made with a decision-analytic model. AB - INTRODUCTION: Bariatric surgery offers effective obesity treatment. The aim of this study was to evaluate the cost-effectiveness of bariatric surgery in Denmark from a third-party payer perspective in the mid- (ten years) and long-term (lifetime). METHODS: A state-transition Markov model was developed in which patients may experience surgery, post-surgery complications, diabetes mellitus type 2, cardiovascular diseases or die. Transition probabilities, costs and utilities were informed by the literature. Three types of surgery were included: gastric bypass, sleeve gastrectomy and adjustable gastric banding. The impact of different surgical methods on BMI level was informed by the Danish Obesity Surgery Registry (Dansk Fedmekirurgiregister). RESULTS: In the ten-year base-case analysis, bariatric surgery led to a cost increment of 19,332 DKK and generated an additional 1.1 quality-adjusted life years (QALYs). In the course of a lifetime, surgery leads to savings of 36,403 DKK, an additional 0.7 life years and 2.9 QALYs. Bariatric surgery was cost-effective at ten years with an incremental cost-effectiveness ratio of 17,818 DKK per QALY and was dominant over conservative management in the course of a lifetime. Up to three years of delay in the provision of surgery resulted in a reduction of life years, a lower QALY gain and a minor decrease in healthcare costs. CONCLUSIONS: In Denmark, bariatric surgery is cost-effective at ten years and may produce a significant reduction in healthcare costs over the course of a lifetime in persons with severe obesity. FUNDING: Synergus AB received support for economic model development from Covidien AG (now part of Medtronic). TRIAL REGISTRATION: not relevant. PMID- 28869032 TI - Tissue - engineering as an adjunct to pelvic reconstructive surgery. AB - : This PhD-thesis is based on animal studies and comprises three original papers and unpublished data. The studies were con-ducted during my employment as a research fellow at the Department of Obstetrics and Gynecology, Herlev University Hospital, Denmark. New strategies for surgical reconstruction of pelvic organ pro lapse (POP) are warranted. Traditional native tissue repair may be associated with poor long-term outcome and augmentation with permanent polypropylene meshes is associated with frequent and severe adverse effects. Tissue-engineering is a regenerative strategy that aims at creating functional tissue using stem cells, scaffolds and trophic factors. The aim of this thesis was to investigate the potential adjunctive use of a tissue-engineering technique for pelvic reconstructive surgery using two synthetic biodegradable materials; methoxypolyethyleneglycol-poly(lacticco-glycolic acid) (MPEG-PLGA) and electrospun polycaprolactone (PCL) - with or without seeded muscle stem cells in the form of autologous fresh muscle fiber fragments (MFFs). To simulate different POP repair scenarios different animal models were used. In Study 1 and 2, MPEG PLGA was evaluated in a native tissue re-pair model and a partial defect model of the rat abdominal wall. We found that the scaffold was fully degraded after eight weeks. Cells from added MFFs could be traced and had resulted in the formation of new striated muscle fibers. Also, biomechanical changes were found in the groups with added MFFs. In Study 3, the long-term degradable electrospun PCL scaffold was evaluated in three rat abdominal wall models representing different loads on the scaffold. Surprisingly, cells from the MFFs did not survive. After eight weeks, a marked inflammatory foreign-body response was observed with numerous giant cells located between and around the PCL fibers which appeared not to be degraded. This response caused a considerable increase in the thickness of the mesh, resulting in a neotissue PCL construct with strength comparable to that of normal rat abdominal wall. The foreign-body inflammatory response did not differ between the groups in terms of cellularity, cell types or thickness, and no differences were found between groups when comparing biomechanical properties. In study 4, we modified a new transabdominal rabbit vaginal model to avoid the erosions known to occur following vaginal mesh implantation. A partial defect was created on the anterior vaginal wall in the vesico-vaginal space and on the anterior vaginal wall close to the cervix. This was a feasibility study aimed at obtaining results comparable to those seen in the rat model. The model was easy to perform and no vaginal erosions were observed. IN CONCLUSION: In two rat abdominal wall models, cells from autologous MFFs, seeded on the quickly degradable MPEG-PLGA scaf-fold, survived implantation and contributed to the regenerative process by forming extra striated muscle fibers and influencing the biomechanical properties of the regenerated tissue. Consequently, MFFs seeded on an MPEG-PLGA scaffold is a potentially advantageous cell-delivering strategy to regenerate tissue at pelvic reconstructive surgery. In three rat abdominal wall models, a long-term degradable PCL scaffold caused a marked foreign-body response and formed a neo-tissue PCL construct that provided biomechanical tissue reinforcement to the abdominal wall, even at maximal load. Consequently, the PCL scaffold might be beneficial in pelvic reconstructive surgery, providing initial biomechanical rein-forcement, although long-term studies showing the tissue response at full degradation are required. Cells from the MFFs did not survive in or around the neo-tissue PCL construct, possibly because of the massive inflammatory response. Consequently, as a scaffold material, with the purpose of delivering cells to a specific anatomical site, the PCL scaffold seems poor. A transabdominal rabbit vaginal model was feasible and might be advantageous in the evaluation of meshes used for pelvic reconstructive surgery, especially when long term studies are needed. PMID- 28869033 TI - Life course of children with parental multiple sclerosis. AB - BACKGROUND: The majority of persons with multiple sclerosis (MS) experience onset of MS between the ages of 20 and 40. Since two-thirds of the persons with MS are young women of childbearing age, parenthood is an essential issue during this period of life. The potential influence of parental MS on children arises from the varied symptoms of the chronic illness, which affect physical and cognitive abilities. MS disabilities and fatigue can restrict daily life and result in less energy for activities or job loss and thus worse conditions for the family. OBJECTIVES AND METHODS: This PhD thesis was designed to investigate whether parental MS influences children in different areas throughout the children's life course (i.e. education, employment, disability pension, and income) as well as to explore the experiences of having a parent with MS. We investigated the research question using two distinct METHODS: A quantitative method based on nationwide population-based Danish registers comparing a group of children with one biological parent with MS (termed 'MS offspring') with a matched group of children of parents without MS (termed 'reference cohort') up to 58 years of age (Papers I-II). A qualitative method based on phenomenological face-to-face interviews with young adults with parental MS (Paper III). The nationwide register-based epidemiological method complemented by a phenomenological interview method, the long time-span and the age groups of 'children' up to age 58 are original within this area of research. RESULTS: In Paper I, we investigated the educational achievements of 4,177 MS offspring compared with 33,416 reference children. MS off-spring achieved a higher grade point average in the final class of basic school, at age 15, although they achieved similar educational levels as did the reference children at ages 15 to 58. There was a trend toward more MS offspring women attaining health-related educations than did reference women at ages 21 to 58. In Paper II, we investigated employment and income of 2,456 MS offspring compared with 19,648 reference children. At age 30, the MS offspring were less often employed, and at ages 30 and 40 MS offspring more often received disability pension than did reference children. The mean income at the age interval of 45 to 49 years was similar. Analyzing whether the MS offspring earned more than DKK 250,000 annually (~ EUR 33,650), which is approximately double the level defined as poverty in Denmark in 2012, they earned above this level in annual gross personal in-come less frequently than did reference children. This income level was only sufficient for the bare necessities. In Paper III, we explored the experiences of children growing up with a parent with MS by interviewing 14 young adults between 18 and 25 years. The results in the interview study showed two essential themes: 'Caring' and 'Restraint'. Each essential theme emerged from four subthemes. Caring: Assuming responsibility; worry and guilt; choosing health-related educations; advantage of being responsible. Restraint: Concealing feelings and desires; anxiety and depression; shame; lack of openness and knowledge. All the young adults had experiences of the essential themes of caring and restraint. Half of the participants in the interview study were enrolled in a health-related education. CONCLUSION: Growing up with a parent with MS can have both beneficial and adverse influences on children late into adulthood. On the one hand, the educational achievements of MS offspring are either better or similar to those of reference children because they attained better grades and similar educational levels. Also, some of the young adults interviewed found advantages to having learned to be responsible. On the other hand, we found an ad-verse association regarding employment, disability pension, and income. Also, the young adults interviewed had experiences of caring for and of practicing restraint toward the parent with MS, the other parent, and siblings, with most participants continuing this pattern toward friends and partners. The results of caring and restraint might partly explain some of the associations found in the register-based studies. The children might continue taking care of their parents and striving to find a balance between helping others and fulfilling their own desires. This caregiver challenge might also partly explain the beneficial association between parental MS on education and the adverse association on employment. Thus, having a parent with MS might be associated with long-term socioeconomic influence on education, employment, disability pension, income, and social relations in children's life course: Parental MS influences children far into adulthood. PMID- 28869034 TI - Plasticity and function of human skeletal muscle in relation to disuse and rehabilitation: Influence of ageing and surgery. AB - In order to study the influence of disuse and aging on skeletal muscle homeostasis, different human models were employed. Effects of chronic disuse were investigated in elderly patients suffering from uni-lateral hip-osteoarthritis, whereas the effect of short-term disuse (4 and 14 days of unilateral lower limb immobilisation) was assessed in healthy young and old individuals. In summary, chronic muscle disuse in the elderly was associated with marked quantitative as well as qualitative neuromuscular impairments. More specifically, decreases were observed in muscle strength, quadriceps muscle size and myofibre area, muscle architecture, contractile properties and neuromuscular activation. Furthermore, substantial side-to-side differences in specific strength (MVC/LCSA) and normalised rapid muscle force capacity (RFD/CSA) were observed, indicating that a significant part of the observed changes in mechanical muscle function with disuse were explained by impairments in muscle quality. Importantly, within the first 4 days of immobility the ob-served atrophy responses did not seem affected by age, as manifested by comparable reductions in myofibre area in young and old individuals. However, in line with previous observations using various animal models, we observed a larger loss in muscle mass in young compared to older individuals after more prolonged immobilisation (14 days). Conversely, old individuals were more negatively affected with respect to neural function and rapid force characteristics than their young counterparts. Moreover, we showed that the initiation and regulation of human skeletal muscle atrophy with short term disuse is age-dependant. Based on the present experiments it can be concluded that a multitude of signalling pathways related to both muscle atrophy and protein synthesis are activated in the initial phase of disuse, which in turn lead to a rapid initial atrophy response (~1-4 days) in both young and old individuals followed by a gradually attenuated atrophy response at later time points (~2 weeks). Notably, during the first 1-2 days of immobility a parallel activation of the ubiquitin-proteasome pathway and the IGF-1/Akt pathway seem to occur along with a deactivation of PGC-1alpha and PGC-1beta, suggesting that cellular proteolysis plays an important role in the initiation of human disuse atrophy in both young and old muscle, whereas the concurrent regulation in protein synthesis signalling and proteolysis inhibition appears to affect young adults more pronouncedly compared to older adults. Gaining a better understanding of the ability of human skele-tal muscle to recover from disuse-induced atrophy has important implications for the development and implementation of effective countermeasures against physical frailty in the increasing population of elderly. Importantly therefore, the present experiments demonstrate that resistance training is highly effective of increasing maximal muscle strength and neuromuscular function in elderly post-operative patients. Importantly, these increases in mechanical muscle function were accompanied by gains in muscle size, architecture and in the expression of IGF-I mRNA splice variants, resembling that typically seen in young healthy individuals when exposed to resistance training. In contrast, these positive adaptations could not be achieved with the use of neuromuscular electrical stimulation or conventional rehabilitation efforts alone. Collectively, these findings strongly underline the importance of implementing resistive exercises in future rehabilitation programs for elderly individuals. In addition, comparing young and old able-bodied individuals, we observed that the magnitude and time-course of changes in mechanical muscle function during the recovery phase following short-term disuse were compromised in old compared to young individuals. Likewise, aged individuals demonstrated an impaired response to re-loading reflected by attenuated gains in myofibre area, in parallel with smaller increases in satellite cell number despite no age related differences were observed in factors known to promote skeletal muscle hypertrophy and myogenic stem cell proliferation (IGF-Ea, MGF, MyoD, myogenin, HGF). Moreover, an age-specific regulation in myostatin mRNA expression was observed, characterized by an amplified increase in aging skeletal muscle with immobilisation that was followed by less down-regulation during the subsequent phase of re-loading. In combination with an association observed between the changes in myostatin expression and satellite cell proliferation in the acute phase of re-loading, these data indicates that myostatin play an important role in the impaired ability of aged human skeletal muscle. PMID- 28869035 TI - A transgenic toolkit for visualizing and perturbing microtubules reveals unexpected functions in the epidermis. AB - The physiological functions of microtubules (MTs) are poorly understood in many differentiated cell types. We developed a genetic toolkit to study MT dynamics and function in diverse cells. Using TRE-EB1-GFP mice, we found that MT dynamics are strongly suppressed in differentiated keratinocytes in two distinct steps due to alterations in both growth rate and lifetime. To understand the functions of these MT populations, we developed TRE-spastin mice to disrupt MTs in specific cell types. MT perturbation in post-mitotic keratinocytes had profound consequences on epidermal morphogenesis. We uncoupled cell-autonomous roles in cell flattening from non-cell-autonomous requirements for MTs in regulating proliferation, differentiation, and tissue architecture. This work uncovers physiological roles for MTs in epidermal development, and the tools described here will be broadly useful to study MT dynamics and functions in mammals. PMID- 28869036 TI - Single methyl groups can act as toggle switches to specify transmembrane Protein protein interactions. AB - Transmembrane domains (TMDs) engage in protein-protein interactions that regulate many cellular processes, but the rules governing the specificity of these interactions are poorly understood. To discover these principles, we analyzed 26 residue model transmembrane proteins consisting exclusively of leucine and isoleucine (called LIL traptamers) that specifically activate the erythropoietin receptor (EPOR) in mouse cells to confer growth factor independence. We discovered that the placement of a single side chain methyl group at specific positions in a traptamer determined whether it associated productively with the TMD of the human EPOR, the mouse EPOR, or both receptors. Association of the traptamers with the EPOR induced EPOR oligomerization in an orientation that stimulated receptor activity. These results highlight the high intrinsic specificity of TMD interactions, demonstrate that a single methyl group can dictate specificity, and define the minimal chemical difference that can modulate the specificity of TMD interactions and the activity of transmembrane proteins. PMID- 28869037 TI - Mcm10 promotes rapid isomerization of CMG-DNA for replisome bypass of lagging strand DNA blocks. AB - Replicative helicases in all cell types are hexameric rings that unwind DNA by steric exclusion in which the helicase encircles the tracking strand only and excludes the other strand from the ring. This mode of translocation allows helicases to bypass blocks on the strand that is excluded from the central channel. Unlike other replicative helicases, eukaryotic CMG helicase partially encircles duplex DNA at a forked junction and is stopped by a block on the non tracking (lagging) strand. This report demonstrates that Mcm10, an essential replication protein unique to eukaryotes, binds CMG and greatly stimulates its helicase activity in vitro. Most significantly, Mcm10 enables CMG and the replisome to bypass blocks on the non-tracking DNA strand. We demonstrate that bypass occurs without displacement of the blocks and therefore Mcm10 must isomerize the CMG-DNA complex to achieve the bypass function. PMID- 28869039 TI - [Bilateral acute iris transillumination syndrome: Case report]. PMID- 28869038 TI - The genomic landscape of human cellular circadian variation points to a novel role for the signalosome. AB - The importance of natural gene expression variation for human behavior is undisputed, but its impact on circadian physiology remains mostly unexplored. Using umbilical cord fibroblasts, we have determined by genome-wide association how common genetic variation impacts upon cellular circadian function. Gene set enrichment points to differences in protein catabolism as one major source of clock variation in humans. The two most significant alleles regulated expression of COPS7B, a subunit of the COP9 signalosome. We further show that the signalosome complex is imported into the nucleus in timed fashion to stabilize the essential circadian protein BMAL1, a novel mechanism to oppose its proteasome mediated degradation. Thus, circadian clock properties depend in part upon a genetically-encoded competition between stabilizing and destabilizing forces, and genetic alterations in these mechanisms provide one explanation for human chronotype. PMID- 28869041 TI - Chest ultrasound for guiding lung recruitment maneuvers. PMID- 28869040 TI - The impact of obesity in the cardiac lipidome and its consequences in the cardiac damage observed in obese rats. AB - AIMS: To explore the impact of obesity on the cardiac lipid profile in rats with diet-induced obesity, as well as to evaluate whether or not the specific changes in lipid species are associated with cardiac fibrosis. METHODS: Male Wistar rats were fed either a high-fat diet (HFD, 35% fat) or standard diet (3.5% fat) for 6 weeks. Cardiac lipids were analyzed using by liquid chromatography-tandem mass spectrometry. RESULTS: HFD rats showed cardiac fibrosis and enhanced levels of cardiac superoxide anion (O2), HOMA index, adiposity, and plasma leptin, as well as a reduction in those of cardiac glucose transporter (GLUT 4), compared with control animals. Cardiac lipid profile analysis showed a significant increase in triglycerides, especially those enriched with palmitic, stearic, and arachidonic acid. An increase in levels of diacylglycerol (DAG) was also observed. No changes in cardiac levels of diacyl phosphatidylcholine, or even a reduction in total levels of diacyl phosphatidylethanolamine, diacyl phosphatidylinositol, and sphingomyelins (SM) was observed in HFD, as compared with control animals. After adjustment for other variables (oxidative stress, HOMA, cardiac hypertrophy), total levels of DAG were independent predictors of cardiac fibrosis while the levels of total SM were independent predictors of the cardiac levels of GLUT 4. CONCLUSIONS: These data suggest that obesity has a significant impact on cardiac lipid composition, although it does not modulate the different species in a similar manner. Nonetheless, these changes are likely to participate in the cardiac damage in the context of obesity, since total DAG levels can facilitate the development of cardiac fibrosis, and SM levels predict GLUT4 levels. PMID- 28869043 TI - Basilar artery thrombosis caused by vertebral dissection secondary to brachial plexus block. PMID- 28869042 TI - Hyperuricemia is associated with progression of chronic kidney disease in patients with reduced functioning kidney mass. AB - BACKGROUND AND OBJECTIVES: Hyperuricemia plays a major role in the development and progression of chronic kidney disease (CKD). Many large observational studies have indicated that increased serum uric acid level predicts the development and progression of CKD in some population, however this hypothesis has not been yet studied in patients with reduced renal mass. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective study with a cohort of 324 patients with reduced renal mass from an outpatient basis, followed during 60 (36-98) months. Demographics variables, cardiovascular factors, concomitant medications, albuminuria and uric acid levels were recorded yearly. The primary endpoint was the annual fall of estimated glomerular filtration rate (eGFR) by MDRD-4. The sample was divided into three successive groups (A1: patients with fall of eGFR lower than median, A2: greater than median, B: without fall of eGFR). Factors associated and predictors of kidney function decline were analyzed. RESULTS: One hundred and seventy out of 324 patients suffered a fall of eGFR (group A), (median of fall -1.6ml/min/1.73m2/year (-3.0, -0.7)). Male gender, albuminuria>100mg/day and higher pulse pressure were associated to progression in our cohort (group A). Hyperuricemia was more frequent among patients with higher kidney disease progression (group A2) (33% vs 49%, p=0.04) when comparing to lower progression (group A1). Adjusted Cox regression models showed that hyperuricemia, pulse pressure and albuminuria were independent predictors of kidney disease progression (HR 1.67 (1.06-2.63), p=0.023; 1.02 (1.01-1.03), p=0.001 and HR: 2.14 (1.26-3.64), p=0.005, respectively). Kidney disease progression was higher in patients with unilateral renal atrophy or agenesis than nephrectomy (log rank: 7.433, p=0.006). CONCLUSIONS: Hyperuricemia is independently associated with kidney disease progression in patients with reduce functioning renal mass. PMID- 28869044 TI - Stroke and temporal arteritis: A study of 6 cases. AB - INTRODUCTION: Though uncommon, ischaemic stroke due to temporal arteritis carries serious difficulties for diagnosis and subsequent management and requires a high level of suspicion. METHODS: We analysed a series of 6 patients with biopsy proven temporal arteritis presenting with ischaemic stroke. We discuss clinical characteristics, difficulties of assessment, short- and long-term progression, treatment, and the usefulness of new diagnostic techniques. RESULTS: Our sample of 6 patients had a mean age of 68.3 years; 50% were women. The majority of patients showed systemic symptoms. Anterior and posterior circulation were affected similarly. MRI angiography, Doppler sonography, and PET-CT proved to be very useful for diagnosis and treatment. Mean follow-up time was 26 months. Clinical outcomes were far from good: 33% scored>=3 on the modified Rankin scale, including one death. Two patients had recurrent stroke despite treatment with full doses of corticosteroids, and 2 underwent angioplasty. CONCLUSIONS: Stroke caused by giant cell arteritis is a serious and potentially severe condition which requires a high level of suspicion and early treatment with corticosteroids. New diagnostic techniques contribute to refining patient assessment and identifying the optimal treatment. Endovascular treatment may be a valid therapeutic option in selected patients. PMID- 28869045 TI - Anticipating disaster: Mechanical thrombectomy in patients with low NIHSS scores. PMID- 28869046 TI - Usefulness of brain SPECT imaging in the study of recurrent hypersomnia: Kleine Levin syndrome. PMID- 28869047 TI - Isolated sixth nerve palsy: An unusual manifestation of preeclampsia. PMID- 28869048 TI - Ecologists Winning Arguments: Ends Don't Justify the Means. A Response to Begon. PMID- 28869049 TI - [Digoxin: Does it have a rest at weekends?] PMID- 28869050 TI - Long-term voice outcome after thyroidectomy using energy based devices. AB - OBJECTIVE: Voice dysfunction is frequently reported after thyroidectomy even in absence of vocal fold paralysis. The energy-based devices such as Harmonic scalpel (HS) or LigaSure (LS) are commonly used in conventional thyroidectomy. The objective of this study was to investigate the long-term voice outcome after total thyroidectomy using energy based devices. METHODS: Patients who underwent total thyroidectomy with or without central neck dissection for papillary thyroid carcinoma using HS or LS from April 2012 to March 2013 were involved. The videolaryngostroboscopy, acoustic analysis, voice range profile, voice perceptual evaluation, and voice handicap index-30 were obtained preoperatively, 1 week, 1 month, 3 months, 6 months, and 1year after thyroidectomy. RESULTS: Total 92 patients (HS group: 58 cases; LS group: 34 cases) were enrolled in this study. Demographics, tumor stage, and extent of operation were not significantly different between the HS and LS group. None of the patients evidenced any abnormalities at the pre- or postoperative videolaryngostroboscopic examination. The voice range profile (highest frequency), voice perceptual evaluation (grade, rough, and breathy), and voice handicap index-30 (total, functional, physical, and emotional) showed significantly worse scores in early postoperative period (<1month), but gradually returned to preoperative values. The all parameters of acoustic analysis, voice range profile, voice perceptual evaluation, and voice handicap index-30 were not significantly different between the HS and LS group. CONCLUSION: The long-term voice change after thyroidectomy shows similar results regardless of the type of energy-based devices. PMID- 28869052 TI - Recent advances in design of electrochemical affinity biosensors for low level detection of cancer protein biomarkers using nanomaterial-assisted signal enhancement strategies. AB - The main advances in control and early diagnosis of cancer is greatly aided by low level detection of tumor markers in biological samples. Extensive efforts have been devoted to developing some ultrasensitive electrochemical biosensors for detection of cancer markers with high selectivity. These efforts include the development of the bioreceptors with high specificity and affinity, synthesis of novel signal amplifiers based on nanomaterials and the exploration of appropriate design strategies. Electrochemical measurement protocols are suitable for mass fabrication of miniaturized devices. They have a major role in the move towards rapid and simplified testing for point-of-care usage. This review discusses the remarkable advances of the last 6 years in the electrochemical affinity biosensors for determination of protein and glycoprotein tumor markers, with a particular focus on antibodies and aptamers as biorecognition probes. PMID- 28869051 TI - Emergency consultation for epistaxis: A bad predictor for overall health? AB - OBJECTIVE: To compare the mortality rate of a large epistaxis cohort with the fatalities of the general Swiss population and to evaluate significant risk factors for impending early death. METHODS: 568 patients out of an epistaxis cohort from a former study were contacted by mail to answer a questionnaire. Deceased patients were identified from March, 2007 through April, 2014. Death rates were compared to the general Swiss population. Different potential risk factors were evaluated by multivariate analysis. RESULTS: Thirty-four percent of the included patients (61 of total n=181) died during the observation period. The mean number of deaths per year was 8.7. Binary logistic regression identified anterior localization (p=0.027), comorbid endogenous bleeding predisposition including hemorrhagic hereditary telangiectasia (p=0.017) and age (p<0.01) as independent and significant risk factors for early death in epistaxis patients. A significantly higher mortality was found within our epistaxis cohort compared to the Swiss general population. CONCLUSION: With the present data a trivial event such as epistaxis, especially when anteriorly located, needs to be seen in a new light. Emergency consultation because of nose bleeding might be an unexpected bad predictor for mortality. Although conclusions need to be considered with caution due to the retrospective character of the study, we regard epistaxis as an independent alarm-signal. After an acute nose bleed requiring emergency consultation, active collaboration with the patient's general practitioner and additional efforts to check for the patient's general health might be more useful than so far assumed. PMID- 28869053 TI - Author's reply. PMID- 28869054 TI - Onsite defluoridation system for drinking water treatment using calcium carbonate. AB - Fluoride in drinking water has several effects on teeth and bones. At concentrations of 1-1.5 mg/L, fluoride can strengthen enamel, improving dental health, but at concentrations above 1.5 to 4 mg/L can cause dental fluorosis. At concentrations of 4-10 mg/L, skeletal fluorosis can occur. There are many areas of the world that have excessive fluoride in drinking water, such as China, India, Sri Lanka, and the Rift Valley countries in Africa. Treatment solutions are needed, especially in poor areas where drinking water treatment plants are not available. On-site or individual treatment alternatives can be attractive if constructed from common materials and if simple enough to be constructed and maintained by users. Advanced on-site methods, such as under sink reserve osmosis units, can remove fluoride but are too expensive for developing areas. This paper investigates calcium carbonate as a cost effective sorbent for an onsite defluoridation drinking water system. Batch and column experiments were performed to characterize F- removal properties. Fluoride sorption was described by a Freundlich isotherm model, and it was found that the equilibrium time was approximately 3 h. Calcium carbonate was found to have comparable F- removal abilities as the commercial ion exchange resins and possessed higher removal effectiveness compared to calcium containing eggshells and seashells. It was also found that the anion Cl- did not compete with F- at typical drinking water concentrations, having little impact on the effectiveness of the treatment system. A fluoride removal system is proposed that can be used at home and can be maintained by users. Through this work, we can be a step closer to bringing safe drinking water to those that do not have access to it. PMID- 28869055 TI - Corrigendum to "Factors influencing local ecological knowledge of forage resources: Ethnobotanical evidence from West Africa's savannas" [J. Environ. Manag., 188 (1 March 2017) 297-307]. PMID- 28869056 TI - Patients' autonomic activation during clinical interaction: A review of empirical studies. AB - OBJECTIVE: To investigate how patients' autonomic responses are related to verbal or non-verbal communication during clinical encounters. METHODS: The SCOPUS database was searched to identify papers. Studies were included if measures of autonomic arousal were related to patients' emotions or patient-clinician interaction during clinical consultations such as psychotherapy, counseling or medical interviews. The search was conducted according to PRISMA criteria. The included studies were assessed using the 16 item quality assessment tool QATSDD. RESULTS: A total of 24 publications were identified. The studies varied greatly in design and quality. However, a few trends could be observed across studies. Patients' expressions of emotions were associated with significant autonomic arousal. Clinician behavior affected arousal levels; and in a few studies, a patient centered way of presenting information was found to attenuate arousal level, interpreted as stress reduction. There was a general, but not consistent, trend in the reduction of arousal level over time within the consultation. Examples of individual differences in autonomic responses were found. CONCLUSION AND PRACTICE IMPLICATIONS: Increased awareness of potential impact of clinician behavior on patient' arousal level may be helpful for clinicians, in particular how different communication styles may augment or attenuate arousal in response to stressors. PMID- 28869057 TI - The social utility of clinical exome sequencing. AB - OBJECTIVE: Examine the presentation of clinical and social implications of exome sequencing findings during patient-geneticist interactions. METHODS: Video recordings of 34 returns of exome sequencing results with findings in an academic genetics clinic were examined using an inductive thematic analysis to distinguish categories of consequences. We then operationalized these categories for structured observation coding of parent or geneticist/genetic counselor-initiated mention of consequences, complemented with semi-structured interviews with 16 families. This allowed us to provide basic descriptive statistics including frequencies and bivariate analyses. Because variables were generally dichotomous, we used chi-square tests of independence. RESULTS: A total of 568 consequences of exome sequencing were discussed during the consultations, which can be grouped in two broad categories: clinical and social consequences. Clinical consequences related to the diagnosis, prognosis or treatment regimen of the test. Social consequences affect the family as a social unit and were not the reason for testing. CONCLUSION: Besides clinical consequences, patients and clinicians distinguish distinct and highly salient social consequences of exome findings during return of results consultations. PRACTICE IMPLICATIONS: Clinical geneticists have an opportunity to address the social utility of exome findings. PMID- 28869058 TI - Enrichment and physiological characterization of an anaerobic ammonium-oxidizing bacterium 'Candidatus Brocadia sapporoensis'. AB - We successfully enriched a novel anaerobic ammonium-oxidizing (anammox) bacterium affiliated with the genus 'Candidatus Brocadia' with high purity (>90%) in a membrane bioreactor (MBR). The enriched bacterium was distantly related to the hitherto characterized 'Ca. Brocadia fulgida' and 'Ca. Brocadia sinica' with 96% and 93% of 16S ribosomal RNA gene sequence identity, respectively. The bacterium exhibited the common structural features of anammox bacteria and produced hydrazine in the presence of hydroxylamine under anoxic conditions. The temperature range of anammox activity was 20-45 degrees C with a maximum activity at 37 degrees C. The maximum specific growth rate (MUmax) was 0.0082h-1 at 37 degrees C, corresponding to a doubling time of 3.5 days. The half-saturation constant (KS) for nitrite was 5+/-2.5MUM. The anammox activity was inhibited by nitrite (IC50=11.6mM) but not by formate and acetate. The major respiratory quinone was identified to be menaquinone-7 (MK-7). The enriched anammox bacterium shared nearly half of genes with 'Ca. Brocadia sinica' and 'Ca. Brocadia fulgida'. The enriched bacterium showed all known physiological characteristics of anammox bacteria and can be distinguished from the close relatives by its 16S rRNA gene sequence. Therefore, we proposed the name 'Ca. Brocadia sapporoensis' sp. nov. PMID- 28869059 TI - Soybeans inoculated with root zone soils of Canadian native legumes harbour diverse and novel Bradyrhizobium spp. that possess agricultural potential. AB - An assessment was made of the evolutionary relationships of soybean nodulating bacteria associated with legumes native to eastern Canada to identify potential new sources of soybean inoculant strains. Short season soybeans were used to selectively trap bacteria from root zone soils of four native legume species. Screening of more than 800 bacterial isolates from soybean root nodules by analysis of recA gene sequences followed by analyses of selected genotypes using six core and two symbiosis (nodC and nifH) gene sequences permitted identification of diverse taxa that included eight novel and four named Bradyrhizobium species as well as lineages attributed to the genera Afipia and Tardiphaga. Plant tests showed that symbionts related to four named species as well as a novel Bradyrhizobium lineage were highly efficient with regard to nitrogen fixation on soybeans relative to an inoculant strain. A new symbiovar (sv. septentrionalis) is proposed based on a group of four novel Bradyrhizobium spp. that possess distinctive nodC and nifH gene sequences and symbiotic characteristics. Evidence is provided for horizontal transfer of sv. septentrionalis symbiosis genes between novel Bradyrhizobium spp., a process that rendered recipient bacteria ineffective on soybeans. Diverse lineages of non symbiotic and symbiotic Bradyrhizobium spp. co-occured within monophyletic clusters in a phylogenetic tree of concatenated core genes, suggesting that loss and/or gain of symbiosis genes has occurred in the evolutionary history of the bacterial genus. Our data suggest that symbiont populations associated with legumes native to eastern Canada harbour elite strains of Bradyrhizobium for soybean inoculation. PMID- 28869060 TI - The effects of topical nitric oxide on healing of partial thickness porcine burns. AB - BACKGROUND: Nitric oxide is a wound mediator that promotes wound healing. We hypothesized that topical application of nitric oxide would speed reepithelialization, enhance angiogenesis, and reduce scar thickness in a partial thickness porcine burn model. METHODS: While under general anesthesia, 20 partial thickness burns were created on the backs of four female Yorkshire swine using a 2.5cm*2.5cm*7.5cm, 150-g aluminum bar, preheated to 80 degrees C and applied for 20s. The necrotic epidermis was removed and the burns were randomized to low, medium, and high concentrations of a novel nitric-oxide (NO) releasing drug or its ointment vehicle applied 3 times weekly for 28 days. Full thickness punch biopsies were performed at 8, 11, 14 and 28 days after injury to determine percentage wound reepithelialization and scar thickness using H&E staining and blood vessel density using CD31 staining. RESULTS: At day 11, the percentages (SD) wound reepithelialization were: control, 26.3 (34.6); low NO, 23.9 (36.9); medium NO, 43.3 (42.9); and high NO, 59.9 (43.6); ANOVA, P=0.02. The number of CD31 stained blood vessels at days 8 and 11 were greater in wounds treated with high dose NO vs. controls (48.1 vs. 22.9 [P<0.001] and 44.0 vs. 33.5 [P=0.05] per 1mm2 respectively). Scar thicknesses (SD) in mm at day 28 by treatment allocation were: control, 4.8 (1.2); low NO, 4.7 (1.2); medium NO, 4.3 (1.2); and high NO, 4.1 (1.0); P=0.22. CONCLUSIONS: Treatment of partial thickness porcine burns with high concentrations of topical NO resulted in earlier reepithelization and increased angiogenesis but not reduced scar thickness compared with its control vehicle in a partial thickness porcine burn model. PMID- 28869061 TI - Implant Arthroplasty for Proximal Interphalangeal, Metacarpophalangeal, and Trapeziometacarpal Joint Degeneration. AB - Arthritis of the hand can result from inflammatory arthritis, osteoarthritis (OA), or be posttraumatic and can cause pain and debilitation. Arthroplasty serves as 1 surgical option in the surgical management of arthritis and aims to create a pain-free joint with preservation of motion. Although implant arthroplasty of the proximal interphalangeal (PIP), metacarpophalangeal (MCP), and trapeziometacarpal (TMC) joints predictably produce pain relief and high satisfaction, it has historically suffered from high rates of complications. The hinged silicone prosthesis was 1 of the early implants and, in many cases, remains the gold standard. However, problems with deformity correction, implant fracture, and synovitis remain. Implants made of alternative materials such as metal-plastic and pyrocarbon have evolved; however, survivorship and reoperation rates remain a concern. This review details the evolution and current options available for small joint implant arthroplasty involving the MCP, PIP, and TMC joints. PMID- 28869062 TI - Supination Contractures in Brachial Plexus Birth Palsy: Long-Term Upper Limb Function and Recurrence After Forearm Osteotomy or Nonsurgical Treatment. AB - PURPOSE: Forearm osteotomy for supination deformity in brachial plexus birth palsy (BPBP) may lead to improved function of the upper limb. However, recurrence rates are high and limit satisfactory results. METHODS: We reviewed the long-term outcome of the entire upper limb of 22 BPBP patients with a supination contracture who were treated by forearm osteotomy and compared them with an age matched group that was treated nonsurgically (n = 28). Recurrence was defined as a passive pronation below 30 degrees . RESULTS: The median follow-up was 5.0 years (range, 1.5-14 years). The mean passive pronation after forearm osteotomy, including patients with recurrence at follow-up, improved from -1 degrees (SD, 9 degrees ) to 33 degrees (SD, 48 degrees ) at final follow-up, mean active wrist extension improved from 23 degrees (SD, 40 degrees ) to 41 degrees (SD, 38 degrees ). An overall improvement of wrist and hand strength was present. In patients without recurrence, pronation improved to a mean of 66 degrees (SD, 23 degrees ) at final follow-up. Recurrence of the supination contracture was present in 9 cases (41%) and was only present in patients with a single bone osteotomy. Recurrence was associated with lower age at surgery (recurrence mean, 4 [SD, 1.2] and no recurrence 8 [SD 4.5]), lower shoulder external rotation (recurrence mean, 28 [SD, 17] and no recurrence 49 [SD, 23]), and overall lower hand function at baseline. CONCLUSIONS: Forearm osteotomy improves forearm pronation and hand function. Recurrence should be considered as a potential complication after forearm osteotomy and is associated with young age and lower function of shoulder and hand. Single-bone osteotomy might also be a risk factor for recurrence. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28869063 TI - Nanoparticles and innate immunity: new perspectives on host defence. AB - The innate immune system provides the first line of defence against foreign microbes and particulate materials. Engineered nanoparticles can interact with the immune system in many different ways. Nanoparticles may thus elicit inflammation with engagement of neutrophils, macrophages and other effector cells; however, it is important to distinguish between acute and chronic inflammation in order to identify the potential hazards of nanoparticles for human health. Nanoparticles may also interact with and become internalised by dendritic cells, key antigen-presenting cells of the immune system, where a better understanding of these processes could pave the way for improved vaccination strategies. Nanoparticle characteristics such as size, shape and deformability also influence nanoparticle uptake by a plethora of immune cells and subsequent immune responses. Furthermore, the corona of adsorbed biomolecules on nanoparticle surfaces should not be neglected. Complement activation represents a special case of regulated and dynamic corona formation on nanoparticles with important implications in clearance and safety. Additionally, the inadvertent binding of bacterial lipopolysaccharide to nanoparticles is important to consider as this may skew the outcome and interpretation of immunotoxicological studies. Here, we discuss nanoparticle interactions with different cell types and soluble mediators belonging to the innate immune system. PMID- 28869064 TI - Multiple correspondence analysis as a strategy to explore the association between categories of qualitative variables related to oral-maxillofacial trauma and violent crimes at the community level. AB - The main objective of this study was to show the applicability of multiple correspondence analysis (MCA) in the detection and representation of underlying structures in large datasets used to investigate oral-maxillofacial lesions. A cross-sectional study was conducted involving the analysis of the medical forensic and social records of 992 people who experienced oral-maxillofacial trauma resulting from non-fatal violent crimes that occurred in the community. Based on the MCA results, two distinct victim profiles were identified. The first profile was characterized by adult men, victims of instruments of violence (such as firearms, knives, or mixed aggression), resulting in severe trauma, mainly affecting the upper or middle third of the face. The second profile was characterized by adolescent and young adult women, victims of aggression using physical force, resulting in soft tissue traumas, mainly affecting the lower third of the face or more than one region at the same time. MCA has been demonstrated to be a powerful tool for exploring complex data related to oral maxillofacial trauma, showing whether there is a relationship and how variables are related. This multivariate method can also be very valuable in the study of several outcomes in oral and maxillofacial surgery and supporting specialties. PMID- 28869065 TI - Isolated acetabular osteochondroma of the hip. AB - We present a case of isolated intra-acetabular osteochondroma in a 21 year-old male who presented with history of right hip pain for 5 years and difficulty in walking. Patient was managed with excision of intra-articular exostoses through surgical hip dislocation. Intra-articular hip osteochondromas can be a rare cause of hip pain in patients with unexplained etiology, and their diagnosis and management can be challenging. PMID- 28869066 TI - Neoadjuvant radiotherapy for myxoid liposarcomas: Oncologic outcomes and histopathologic correlations. AB - OBJECTIVE: The aim of this study was to evaluate the histopathological features of primary extremity myxoid liposarcoma before and after neoadjuvant radiation therapy, and to evaluate the oncological outcomes of the patients. METHODS: The study included 23 patients (16 men and 7 women with a mean age of 43 (24-69) years) with primary myxoid liposarcoma of the extremities, who were treated between January 1998 and December 2015. Inclusion criteria were histopathological confirmation of the diagnosis with both the initial biopsy and the resection specimen, and having undergone neoadjuvant radiotherapy. Demographic, clinical and histopathological data were evaluated. RESULTS: Over a mean follow-up time of 55.2 (8-139) months, 5 patients (21.7%) died secondary to disease progression, leaving 18 patients (78.3%) still alive at the time of last follow-up. Only one patient (4%) experienced local recurrence and six (26%) patients developed distant metastases. Disease-free survival at 5 and 10 years were 66%; whereas, overall patient survival at 5 and 10 years were 78.1% and 71.0%, respectively. Tumor size (>15 cm) and presence of metastasis were significantly associated with increased overall mortality. On histopathology, necrosis was present in 12/23 resection specimens. Hyalinization/fibrosis and residual viable tumor was present in all specimens. Adipocytic maturation/cytodifferentiation was seen in 8/23 patients. CONCLUSION: Neoadjuvant radiotherapy was effective for myxoid liposarcomas histopathologically, although these histopathological features did not affect the patients' oncological outcomes. Favorable oncological outcomes were obtained with neoadjuvant radiotherapy, surgical resection and chemotherapy. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 28869068 TI - Re: Silke Gillessen, Gerhardt Attard, Tomasz M. Beer, et al. Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol 2018;73:178-211. PMID- 28869067 TI - National Testing of the Nursing-Kids Intensity of Care Survey for Pediatric Long term Care. AB - PURPOSE: The purpose of this study is to test the Nursing-Kids Intensity of Care, a measure of the intensity of nursing care needs, defined as the quantity and type of direct and indirect care activities performed by caregivers in a national sample. DESIGN AND METHODS: A 40-item tool previously tested in a small sample was psychometrically tested on a sample of 116 children with complex medical conditions by 33 nurse raters across 11 pediatric sites. RESULTS: The Nursing Kids Intensity of Care tool demonstrated components of usability, feasibility, inter-rater, test-retest and internal consistency reliability and construct validity in the national study sample. CONCLUSIONS: Additional testing to further establish psychometric sufficiency and expanded use to quantify the intensity of nursing care needs of children with complex medical conditions in pediatric long term care settings is recommended. PRACTICE IMPLICATIONS: This novel measure could assist the nursing administrators, educators and staff of pediatric long term care facilities assess the intensity of care needs of their residents. PMID- 28869069 TI - Reply to Finn E. von Eyben, Irene Virgolini and Giandomenico Roviello's Letter to the Editor re: Silke Gillessen, Gerhardt Attard, Tomasz M. Beer, et al. Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol 2018;73:178-211. PMID- 28869070 TI - Natural attenuation of Fukushima-derived radiocesium in soils due to its vertical and lateral migration. AB - Processes of vertical and lateral migration lead to gradual reduction in contamination of catchment soil, particularly its top layer. The reduction can be considered as natural attenuation. This, in turn, results in a gradual decrease of radiocesium activity concentrations in the surface runoff and river water, in both dissolved and particulate forms. The purpose of this research is to study the dynamics of Fukushima-derived radiocesium in undisturbed soils and floodplain deposits exposed to erosion and sedimentation during floods. Combined observations of radiocesium vertical distribution in soil and sediment deposition on artificial lawn-grass mats on the Niida River floodplain allowed us to estimate both annual mean sediment accumulation rates and maximum sedimentation rates corresponding to an extreme flood event during Tropical Storm Etau, 6-11 September 2015. Dose rates were reduced considerably for floodplain sections with high sedimentation because the top soil layer with high radionuclide contamination was eroded and/or buried under cleaner fresh sediments produced mostly due to bank erosion and sediments movements. Rate constants of natural attenuation on the sites of the Takase River and floodplain of Niida River was found to be in range 0.2-0.4 year-1. For the site in the lower reach of the Niida River, collimated shield dose readings from soil surfaces slightly increased during the period of observation from February to July 2016. Generally, due to more precipitation, steeper slopes, higher temperatures and increased biological activities in soils, self-purification of radioactive contamination in Fukushima associated with vertical and lateral radionuclide migration is faster than in Chernobyl. In many cases, monitored natural attenuation along with appropriate restrictions seems to be optimal option for water remediation in Fukushima contaminated areas. PMID- 28869072 TI - Mid upper arm circumference and Powell-Tuck and Hennessy's equation correlate with body mass index and can be used sequentially in gastrostomy fed patients. AB - BACKGROUND & AIMS: Body Mass Index (BMI) is a simple and widespread method to assess undernutrition. However its use may be limited in bedridden patients. AIMS: 1) compare BMI, Mid Upper Arm Circumference (MUAC) and Powell-Tuck and Hennessy's regression equation for BMI (BMIPTH) in gastrostomy fed patients, 2) validate its correlation for sequential use and 3) select the best cut-off of MUAC and BMIPTH to predict risk of undernutrition. METHODS: Prospective study including adult patients who underwent endoscopic gastrostomy (PEG). BMI, MUAC and BMIPTH adjusted for sex and age were determined at the day of gastrostomy (0), first (1) and third (3) months of follow up. Correlations between BMI and MUAC and BMIPTH were calculated at all time-points using Spearman's test. MUAC's Area Under ROC (AUROC) to predict risk of undernutrition (BMI <= 18,5 kg/m2 in non-elderly (<65 years) and BMI <= 22,5 kg/m2 in elderly (>=65 years)) was calculated with DeLong method and Youden Index was used to select the best cut off for this outcome. RESULTS: 405 PEG patients were included (69,9% males, median age 62,9 +/- 15,3 years). Head and neck cancer and neurological disorders were the main indications for gastrostomy. BMI correlated moderately with BMIPTH0 (rho = 0.646-0.694), MUAC0 (rho = 0.669) and MUAC1 (rho = 0.699). BMI correlated strongly with BMIPTH1 (rho = 0.764-0.794), BMIPTH3 (rho = 0.714-0.732) and MUAC3 (rho = 0.725). MUAC and BMIPTH's accuracy was not significantly different to predict undernutrition neither in elderly (AUROC 0.835 +/- 0.033 Vs. 0.836 +/- 0.033 respectively, p = 0.319) nor in non-elderly patients (AUROC 0.857 +/- 0.027 Vs. 0.888 +/- 0.053 respectively, p = 0.256). MUAC <26 cm (positive predictive value (PPV) 83.5%) or BMIPTH <22 kg/m2 (PPV 83.5%) in elderly and MUAC <25 cm (PPV 90.7%) or BMIPTH <21 kg/m2 (PPV 91.7%) in non-elderly can accurately predict risk of undernutrition in PEG patients. CONCLUSIONS: MUAC and BMIPTH correlated with BMI not only at the day of PEG placement but also at the 1st and 3rd month of follow up and were equivalent to predict risk of undernutrition according to the new cut-offs defined for this population. PMID- 28869071 TI - Role of transplanted bone marrow cells in development of rotator cuff muscle fatty degeneration in mice. AB - BACKGROUND: Rotator cuff muscle fatty degeneration after a chronic tendon tear is an irreversible pathologic change associated with poor clinical outcomes of tendon repair, and its exact pathogenesis remains unknown. We sought to investigate the role of transplanted bone marrow cells in the development of fatty degeneration, specifically in adipocyte accumulation, using a mouse model. METHODS: Fourteen mice were divided into 2 bone marrow chimeric animal groups: bone marrow transplantation (BMT) group and reverse BMT group. For the BMT group, C57BL/6J wild-type mice underwent whole body irradiation followed by BMT into the retro-orbital sinus from green fluorescent protein (GFP)-transgenic donor mice. For the reverse BMT group, GFP-transgenic mice received BMT from C57BL/6J wild type donor mice after irradiation. The supraspinatus tendon, infraspinatus tendon, and suprascapular nerve were surgically transected 3 weeks after transplantation. The rotator cuff muscles were harvested 13 weeks after transplantation for histologic analysis and GFP immunohistochemistry. RESULTS: On histologic examination, both groups showed substantial fatty degeneration, fibrosis, and atrophy of the cuff muscles. The BMT group showed no noticeable GFP immunostaining, whereas the reverse BMT group showed significantly stronger GFP staining in most adipocytes (P < .001). However, both groups also showed that a small number of adipocytes originated from transplanted bone marrow cells. A small number of myocytes showed a large cytoplasmic lipid vacuole resembling adipocytes. CONCLUSIONS: This study's findings suggest that most adipocytes in fatty degeneration of the rotator cuff muscles originate from sources other than bone marrow-derived stem cells, and there may be more than 1 source for the adipocytes. PMID- 28869073 TI - Association of the rs10830963 polymorphism in melatonin receptor type 1B (MTNR1B) with metabolic response after weight loss secondary to a hypocaloric diet based in Mediterranean style. AB - BACKGROUND & AIMS: Some genetic variants within MTNR1B were related with fasting glucose levels or the increased prevalence of diabetes mellitus and obesity. The aims of the present investigation were to determine the influence of rs10830963 MTNR1B variant in relation to body weight loss, insulin resistance and adipokine levels in response to a hypocaloric diet with Mediterranean pattern. METHODS: A Caucasian population of 80 obese patients was studied before and after 12 weeks on a hypocaloric diet. Body weight, fat mass, waist circumference, blood pressure, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipoprotein levels and adipocytokines levels (leptin, adiponectin and resistin) were measured. Genotype of MTNR1B gene single nucleotide polymorphism (rs10830963) was evaluated. RESULTS: In total, 44 patients (55%) had the genotype CC, 27 patients CG (33.8%) and 9 patients GG (11.2%). With the dietary intervention body mass index, weight, fat mass, systolic blood pressure, leptin levels and waist circumference decreased in both groups. There were no significant differences between gender groups on the reported effects in each genotype group. However, the improvement of anthropometric parameters was higher in subjects with CC genotype than (GC + GG) genotype. After dietary intervention and in males with CC genotype, insulin levels (-5.3 +/- 4.8 UI/L vs 1.2 +/- 4.1 UI/L; p < 0.05) and HOMA-IR (-1.4 +/- 2.1 units vs 0.4 +/- 2.0 units; p < 0.05) decreased. In the group of females with CC genotype, insulin levels (-3.5 +/- 2.1 UI/L vs. -1.4 +/- 2.2 UI/L: p < 0.05) and HOMA-IR (-1.4 +/- 1.2 units vs. -0.1 +/- 1.3 units: p < 0.05) decreased, too. However, these parameters remained unchanged in (GC + GG) group. Fasting glucose levels were higher in patients in (GC + GG). CONCLUSIONS: This study showed the association of rs10830963 MTNR1B single nucleotide polymorphism with body weight loss and changes in fasting insulin levels and HOMA-IR in obese subjects. PMID- 28869074 TI - The Forgotten Ventricle. PMID- 28869076 TI - Reduction of the birth rate in Sao Paulo: a probable effect of the panic caused by the Zika-associated microcephaly epidemic. PMID- 28869075 TI - Heart Failure With Preserved Ejection Fraction: A Perioperative Review. PMID- 28869077 TI - Current approaches to the treatment of Parkinson's Disease. AB - Parkinson's Disease (PD) is the second most common neurodegenerative disorder. Clinical approaches to manage PD include symptomatic therapies, serving to compensate for the effects of dopaminergic neuronal deficits, as well as more recently a move toward disease modification, with the goal of slowing or stopping disease progression. This perspective surveys the approved therapies for PD treatment as well as provides a view of the ongoing clinical approaches aimed at improving outcomes for PD patients. PMID- 28869078 TI - Increasing access to thoracic organs from donors infected with hepatitis C: A previous challenge-now an opportunity. PMID- 28869079 TI - The challenging diagnosis of Chagas disease reactivation in endomyocardial biopsies from heart-transplanted patients. PMID- 28869080 TI - Altered chemokine receptor expression in the peripheral blood lymphocytes in polymyositis and dermatomyositis. AB - OBJECTIVE: To examine the expression of chemokine receptors in different peripheral blood T-cell subsets in patients with polymyositis (PM) and dermatomyositis (DM). METHODS: We used flow cytometry to measure the frequencies of chemokinereceptors CXCR3 and CCR4 expression in the CD4+ or CD8+ lymphocytes. Enzyme linked immunosorbent assays were also used to measure the concentrations of C-X-C motif chemokine 10 (CXCL10), thymus and activation regulated chemokine (TARC) and macrophage derived chemokine (MDC). RESULTS: Comparing to 20 healthy controls, %CD4+CXCR3+ and %CD8+CXCR3+ T cells significantly decreased in 33DM patients, and %CD8+CXCR3+ cells decreased in 24PM patients, but %CD4+CCR4+ and %CD8+CCR4+ cells did not significantly change in both the PM and DM patients. Accordingly, the Th1/Th2 polarization, analyzed as the balance obtained after dividing %CD4+CXCR3+ cells by %CD4+CCR4+ cells, showed a significant reduction in DM. The serum concentration of CXCR3+ ligand, CXCL10, significantly increased and negatively correlated with circulating %CD4+CXCR3+ cells in DM patients. There was no significant change of TARC and MDC in PM and DM patients. Furthermore, %CD4+CXCR3+ cells decreased more severely in the patients with interstitial lung disease. CONCLUSIONS: The present results indicate that the distributions of circulating CXCR3+ T-cells differ among the PM and DM cases. Our findings suggest a pathogenic difference between PM and DM. PMID- 28869081 TI - Differential regulation of IL-23 production in M1 macrophages by TIR8/SIGIRR through TLR4- or TLR7/8-mediated signaling. AB - Cross-talks between toll-like receptors (TLRs) including various negative regulatory mechanisms are many unknown. We investigated the differential mechanism of IL-23 production in M1 macrophages by single immunoglobulin interleukin-1 receptor-related (SIGIRR) molecule through TLR4 or TLR7/8. IL-12p40 production by M1 macrophages pretreated with human neutrophil elastase (HNE) was synergistically enhanced IL-12p40, but not IL-23 production, after exposure to lipopolysaccharide (LPS). LPS (a TLR4 agonist) induced a slight increase of IL-23 production, while Resiquimod (a TLR7/8 agonist) significantly enhanced IL-23 production. Expression of SIGIRR protein, a negative regulator of TLR4, was higher in M1 macrophages than in monocytes. Interestingly, SIGIRR siRNA induced a slight increment of IL-23 production after exposure of macrophages to LPS, while IL-23 production in response to Resiquimod was significantly upregulated by SIGIRR siRNA. Silencing SIGIRR enhanced IRF4 protein level determined by western blotting or ELISA. IRF4 siRNA dramatically restored IL-23 production after exposure to Resiquimod in macrophages transfected with SIGIRR siRNA. In conclusion, production of IL-23 is differentially regulated in M1 macrophages by SIGIRR through TLR4- or TLR7/8-mediated signaling. SIGIRR is both a negative regulator of TLR4 and a positive regulator of TLR7/8. PMID- 28869083 TI - Antifungal effect of cow's urine distillate on Candida species. AB - BACKGROUND: Increase in resistance of Candida species, to routinely used antifungal agents has necessitated the quest for new drugs. Few studies have revealed that cow's urine can suppress the growth of pathogenic fungi. However there is no published report on antifungal effects of cow's urine on clinical Candida isolates. OBJECTIVE: The present study aims at exploring the antifungal potential of cow's urine on clinical isolates of Candida species. MATERIALS AND METHODS: In this in-vitro experimental study four standard strains and 37 clinical isolates of Candida species were tested for their susceptibility to amphotericin B, fluconazole and voriconazole, by disk diffusion method. Detection of MIC of cow's urine for the Candida isolates was done by agar dilution method using 20-50% concentration of cow's urine. RESULTS: Clinical isolates of Candida albicans n = 22 (59.5%) Candida glabrata n = 6 (16.2%), Candida tropicalis n = 3 (8.1%) and other Candida species n = 6 were tested for their antifungal susceptibility. Among them, 18.9% were resistant to voriconazole, 24.3% to amphotericin B and 35.1% to fluconazole. Statistically significant association was observed between susceptibility of voriconazole and that of cow's urine (p = 0.045). C. albicans ATCC14053, Candida parapsilosis ATCC22019 and 75.7% of clinical isolates of Candida were susceptible to cow's urine. CONCLUSION: Cow's urine distillate has concentration dependent inhibitory effect on Candida species and is effective on the isolates that are either resistant or sensitive to the routinely used antifungal agents. PMID- 28869085 TI - Success rates and complications of autologous onlay bone grafts and sinus lifts in patients with congenital hypodontia and after trauma. AB - Autogenous bone remains the gold standard for augmentation of the alveolar ridge in congenital hypodontia and appreciable post-traumatic deformity. This generally reflects the volume of material required for such defects and the osteogenic potential of the grafts. Morbidity at the donor site and success rates may lead to autogenous grafts being superseded by xenografts or alloplastic materials in the future, but we know of little evidence to confirm this. All patients having augmentation of the alveolar ridge or sinus lift to enable subsequent placement of implants between 01 January 2009 and 31 December 2016 were identified from a prospectively-gathered database held at the Queen Elizabeth Hospital, Birmingham. Morbidity was recorded, with overall success defined as a graft that enabled subsequent placement of an implant. During this period the following grafts: calvarial (n=4), iliac crest (n=4), and ramus (n=149) were recorded, as well as 53 sinus lifts. Sinus lift augmentation with BioOss(r) had the highest success rate (51/53). Calvarial and iliac crest grafts had higher failure rates (2/4 and 3/4, respectively) than those from the mandibular ramus (6/149, 4%). Fifteen of 149 (10%) ramus grafts resulted in transient anaesthesia of the inferior alveolar nerve but no patients developed any permanent morbidity at the donor or recipient sites. Ramus grafts are a predictable method of bone augmentation with only transient morbidity at the donor site. Higher failure rates for extraoral grafts probably reflect their use in more challenging cases when more bone is required. Bilateral ramus grafts are an alternative to extraoral grafts and may be supplemented by bovine-derived particulate grafts with no appreciable increase in complications. PMID- 28869084 TI - UPAR targeted molecular imaging of cancers with small molecule-based probes. AB - Molecular imaging can allow the non-invasive characterization and measurement of biological and biochemical processes at the molecular and cellular levels in living subjects. The imaging of specific molecular targets that are associated with cancers could allow for the earlier diagnosis and better treatment of diseases. Small molecule-based probes play prominent roles in biomedical research and have high clinical translation ability. Here, with an emphasis on small molecule-based probes, we review some recent developments in biomarkers, imaging techniques and multimodal imaging in molecular imaging and highlight the successful applications for molecular imaging of cancers. PMID- 28869086 TI - Bacterial Tubulins: A Eukaryotic-Like Microtubule Cytoskeleton. AB - Ever since their discovery, bacterial tubulins, found in several Prosthecobacter species, have raised curiosity as they are closely related to eukaryotic tubulin. Deng and colleagues now present new evidence for the functional homology of the two cytoskeletal systems where in vitro reconstituted Btub-microtubules display eukaryote-like biochemical and dynamic properties. PMID- 28869082 TI - Development of botanicals to combat antibiotic resistance. AB - The discovery of antibiotics in the previous century lead to reduction in mortality and morbidity due to infectious diseases but their inappropriate and irrational use has resulted in emergence of resistant microbial populations. Alteration of target sites, active efflux of drugs and enzymatic degradations are the strategies employed by the pathogenic bacteria to develop intrinsic resistance to antibiotics. This has led to an increased interest in medicinal plants since 25-50% of current pharmaceuticals are plant derived. Crude extracts of medicinal plants could serve as an alternate source of resistance modifying agents owing to the wide variety of secondary metabolites. These metabolites (alkaloids, tannins, polyphenols etc.) could act as potentials for antimicrobials and resistance modifiers. Plant extracts have the ability to bind to protein domains leading to modification or inhibition protein-protein interactions. This enables the herbals to also present themselves as effective modulators of host related cellular processes viz immune response, mitosis, apoptosis and signal transduction. Thus they may exert their activity not only by killing the microorganism but by affecting key events in the pathogenic process, thereby, the bacteria, fungi and viruses may have a reduced ability to develop resistance to botanicals. The article is meant to stimulate research wherein the cidal activity of the extract is not the only parameter considered but other mechanism of action by which plants can combat drug resistant microbes are investigated. The present article emphasizes on mechanisms involved in countering multi drug resistance. PMID- 28869087 TI - [Chemical peels and management of skin aging]. AB - Chemical peels are an alternative and/or a complementary treatment to the surgical procedures for skin aging. The purpose of this article is to specify the procedures and the indications of the three principal types of chemical peels: alpha-hydroxy acids, trichloracetic acid, phenol-croton oil peel. The clinical examination will determine the depth of the lesions to treat and will take into consideration counter-indications and specific limits to each patient. Chemical peel is a four step procedure: pre-peel preparation, peeling itself, recovery phase and maintenance phase. The preparation is a very important phase which requires a thorough knowledge of cosmetics. This preparation can extend to any medical or surgical treatment for aging skin. Various techniques of peelings: superficial, medium, deep, combined and mosaic peel will be detailed. These procedures require a rigorous training and a distinct learning curve. The follow up will be specified as well as the management of the possible complications. PMID- 28869088 TI - Corrigendum to "Acute and sub-chronic oral toxicity studies of erythritol in Beagle dogs" [Food Chem. Toxicol. 105 (2017) 448-455]. PMID- 28869089 TI - Translating Economic Evidence for Public Health: Knowledge Brokers and the Interactive Systems Framework. PMID- 28869090 TI - SES, Chronic Kidney Disease, and Race in the U.S.: A Systematic Review and Meta analysis. AB - CONTEXT: The risk of chronic kidney disease (CKD) in the U.S. is higher in individuals with low SES than in those with high SES. However, differences in these risks between African Americans and whites are unclear. EVIDENCE ACQUISITION: Studies published through August 30, 2016 in Medline and EMBASE were searched. From the seven studies (1,775,267 participants) that met inclusion criteria, association estimates were pooled by race in meta-analysis. The ratio of association estimates and the corresponding 95% CIs for African Americans and whites were also pooled in meta-analysis. Additionally, meta-regression analysis was used to explore whether race is related to the strength of SES-CKD association. The analysis was conducted in September 2016. EVIDENCE SYNTHESIS: The risk of CKD in low-SES people was 58% higher in African Americans (relative risk=1.58, 95% CI=1.33, 1.84) and 91% higher in whites (relative risk=1.91, 95% CI=1.47, 2.35) compared with their high-SES counterparts. The relative risk of CKD in low SES (versus high SES) was lower in African Americans than in whites (relative risk ratio=0.71, 95% CI=0.65, 0.77). Results from meta-regression analyses also indicated that race is potentially related to the strength of the association between low SES and CKD (p for difference between whites and African Americans=0.001). CONCLUSIONS: The risk of CKD in low SES (versus high SES) is higher in whites than in African Americans. PMID- 28869091 TI - Potential Functional Benefit From Light Intensity Physical Activity in Knee Osteoarthritis. AB - INTRODUCTION: Knee pain may preclude participation in higher intensity physical activity in people with knee osteoarthritis and benefits of light activity are unclear. The effect of replacing sedentary time with light intensity activity on incident functional limitation 2 years later was investigated. METHODS: Included were people with or at high risk of knee osteoarthritis without baseline functional limitation using data from the Osteoarthritis Initiative collected between August 2008 and July 2010. Data were analyzed between May 2016 and August 2016 for time in sedentary, light, and moderate to vigorous physical activity from accelerometer monitoring. Incident functional limitation was defined as (1) slow gait speed <1.0 meters/second during a 20-meter walk, (2) Western Ontario and McMasters University Osteoarthritis Index physical function >=28, or (3) Short Form 12 Physical Component scale <40. RESULTS: Inclusion criteria were met by 1,873 people (mean age=65.0 [SD=9.0] years, mean BMI=28.4 [SD=4.7] kg/m2). Replacing 60 minutes/day of sedentary time with 60 minutes/day of light activity was associated with a 17% reduced risk for incident slow gait speed 2 years later (Hazard Ratio=0.83, 95% CI=0.70, 0.99) after adjustment. Approximately 5 minutes/day of moderate to vigorous physical activity would be necessary to receive the equivalent benefit of 60 minutes/day of light activity. Effects in secondary patient-reported outcomes did not reach statistical significance. CONCLUSIONS: Replacing sedentary time with light activity may reduce the risk of performance-based functional limitation. As expected, moderate to vigorous physical activity rather than light provided stronger risk reduction. When moderate to vigorous physical activity is not an option, pursuing light activity may be a beneficial alternative to being sedentary. PMID- 28869092 TI - Oral Health-Promoting School Environments and Dental Caries in Quebec Children. AB - INTRODUCTION: Dental caries are highly prevalent among children and have negative health consequences. Their occurrence may depend in part on school-based environmental or policy-related factors, but few researchers have explored this subject. This study aimed to identify oral health promoting school environment types and estimate their relation with 2-year dental caries incidence among Quebec children aged 8-10 years. METHODS: This study used data from two visits (completed in 2008 and 2011) of the QUALITY (Quebec Adipose Lifestyle Investigation in Youth) cohort, which recruited white children at risk of obesity and their families from Greater Montreal schools. Measures included school and neighborhood characteristics, and Decayed, Missing, Filled-Surfaces index scores. Principal component and cluster analyses, and generalized estimating equations were conducted. RESULTS: Data were available for 330 children attending 200 schools. Based on a series of statistical analyses conducted in 2016, the authors identified three distinct school environment types. Type 1 and 2 schools had strong healthy eating programs, whereas Type 3 had weak programs. Type 1 schools had favorable neighborhood food environments, whereas Type 2 and 3 had unfavorable ones. Adjusting for potential confounders, children attending Type 1 and 2 schools had 21% (incidence rate ratio=0.79, 95% CI=0.68, 0.90) and 6% (incidence rate ratio=0.94, 95% CI=0.83, 1.07) lower 2-year incidence of dental caries, respectively, compared with Type 3 schools. CONCLUSIONS: School-based oral health promotion programs combined with a favorable neighborhood can lower dental caries incidence in school children. PMID- 28869093 TI - The Guide to Community Preventive Services and Disability Inclusion. AB - INTRODUCTION: Approximately 40 million people in the U.S. identify as having a serious disability, and people with disabilities experience many health disparities compared with the general population. The Guide to Community Preventive Services (The Community Guide) identifies evidence-based programs and policies recommended by the Community Preventive Services Task Force (Task Force) to promote health and prevent disease. The Community Guide was assessed to answer the questions: are Community Guide public health intervention recommendations applicable to people with disabilities, and are adaptations required? METHODS: An assessment of 91 recommendations from The Community Guide was conducted for 15 health topics by qualitative analysis involving three data approaches: an integrative literature review (years 1980-2011), key informant interviews, and focus group discussion during 2011. RESULTS: Twenty-six recommended interventions would not need any adaptation to be of benefit to people with disabilities. Forty one recommended interventions could benefit from adaptations in communication and technology; 33 could benefit from training adaptations; 31 from physical accessibility adaptations; and 16 could benefit from other adaptations, such as written policy changes and creation of peer support networks. Thirty-eight recommended interventions could benefit from one or more adaptations to enhance disability inclusion. CONCLUSIONS: As public health and healthcare systems implement Task Force recommendations, identifying and addressing barriers to full participation for people with disabilities is important so that interventions reach the entire population. With appropriate adaptations, implementation of recommendations from The Community Guide could be successfully expanded to address the needs of people with disabilities. PMID- 28869094 TI - Effect of age and gender on the QTc-interval in healthy individuals and patients with long-QT syndrome. AB - Age- and gender-related differences in QTc-interval are most likely the result of changes in sex-specific hormones. Although the exact mechanisms and pathophysiology of sex hormones on the QTc-interval are not known, testosterone appears to shorten the QTc-interval. In females, however, there is a more complex interaction between progesterone and estrogen. In patients with an impaired repolarization, such as long-QT syndrome (LQTS), the effect of these sex hormones on the QTc-interval is more pronounced with a differing sensitivity between the LQTS genotypes. PMID- 28869096 TI - Profiling of experiential pleasure, emotional regulation and emotion expression in patients with schizophrenia. AB - BACKGROUND: Emotion deficits may be the basis of negative symptoms in schizophrenia patients and they are prevalent in these patients. However, inconsistent findings about emotion deficits in schizophrenia suggest that there may be subtypes. AIM: The present study aimed to examine and profile experiential pleasure, emotional regulation and expression in patients with schizophrenia. METHODS: A set of checklists specifically capturing experiential pleasure, emotional regulation, emotion expression, depressive symptoms and anhedonia were administered to 146 in-patients with schizophrenia and 73 demographically-matched healthy controls. Psychiatric symptoms and negative symptoms were also evaluated by a trained psychiatrist for patients with schizophrenia. RESULTS: Two-stage cluster analysis and discriminant function analysis were used to analyze the profile of these measures in patients with schizophrenia. We found a three cluster solution. Cluster 1 (n=41) was characterized by a deficit in experiential pleasure and emotional regulation, Cluster 2 (n=47) was characterized by a general deficit in experiential pleasure, emotional regulation and emotion expression, and Cluster 3 (n=57) was characterized by a deficit in emotion expression. Results of a discriminant function analysis indicated that the three groups were reasonably discrete. CONCLUSION: The present findings suggest that schizophrenia patients can be classified into three subtypes based on experiential pleasure, emotional regulation and emotion expression, which are characterized by distinct clinical representations. PMID- 28869097 TI - CBT in the prevention of psychosis and other severe mental disorders in patients with an at risk mental state: A review and proposed next steps. AB - Patients with an 'At risk mental state' (ARMS) for developing psychosis can be treated successfully with CBT to postpone and prevent the transition to a first psychotic episode. A characteristic of individuals that meet ARMS criteria is that they are still open for multiple explanations for extraordinary experiences. CBT aims to normalize extraordinary experiences with education and to prevent delusional explanations. The treatment is not only effective, but also cost saving in averting psychosis as well as in reducing disability adjusted life years at 18- and 48-month follow-up. Profiling within the ARMS group results in a personalized treatment. The screening and early treatment for ARMS fulfills all the criteria of the World Health Organization and is ready to be routine screening and treatment in mental health care. At the same time, ARMS patients are complex patients with multi-morbid disorders. Especially childhood trauma is associated to ARMS status, together with co-morbid PTSD, depression, substance abuse and anxiety disorders. Psychotic symptoms appear to be severity markers in other non-psychotic disorders. Preventing psychosis in ARMS patients should be broadened to also address other disorders and aim to reduce chronicity of psychopathology and improve social functioning in general. Several mechanisms play a part in psychopathology in ARMS patients such as stress sensitivity as a result of adverse experiences, dopamine sensitivity that is associated with salience and aggravates several cognitive biases, dissociation mediating between trauma and hallucinations, and low self-esteem and self-stigma. New avenues to treat the complexity of ARMS patients will be proposed. PMID- 28869095 TI - Biology and clinical relevance of noncoding sno/scaRNAs. AB - Small nucleolar RNAs (snoRNAs) are a group of noncoding RNAs that perform various biological functions, including biochemical modifications of other RNAs, precursors of miRNA, splicing, and telomerase activity. The small Cajal body associated RNAs (scaRNAs) are a subset of the snoRNA family and collect in the Cajal body where they perform their canonical function to biochemically modify spliceosomal RNAs prior to maturation. Failure of sno/scaRNAs have been implicated in pathology such as congenital heart anomalies, neuromuscular disorders, and various malignancies. Thus, understanding of sno/scaRNAs demonstrates the clinical value. PMID- 28869098 TI - Measurement of blood lactate, D-dimer, and activated prothrombin time improves prediction of in-hospital mortality in adults blunt trauma. PMID- 28869099 TI - Impact of implementation of the HEART pathway using an electronic clinical decision support tool in a community hospital setting. PMID- 28869100 TI - Rivaroxaban program for acute venous thromboembolism upon ED discharge, with focus on utility of commercially available dose pack. AB - OBJECTIVE: To evaluate the impact of a rivaroxaban discharge initiative on the efficacy and safety of acute venous thromboembolism treatment in emergency department patients. PRACTICE INNOVATION: Patients discharged on rivaroxaban from the emergency department were provided extensive counseling along with a commercially-available medication dose pack by the ED pharmacist. Patients were contacted by phone until they had obtained outpatient follow-up and remained adherent to anticoagulation beyond the initial first month of treatment. METHODS: In this retrospective chart review over a thirteen month period, efficacy and safety outcomes were compared between patients with intervention versus those who received usual care. Efficacy was defined by reduced 90-day readmission rates due to nonadherence or treatment failure, and improved medication adherence beyond the first month from discharge. Safety was determined by comparing 90-day readmission rates due to bleeding or adverse event. RESULTS: 41 patients received intervention with rivaroxaban, and 34 patients received usual care, with 76% prescribed rivaroxaban and remaining patients started on enoxaparin alone (6%) or enoxaparin plus warfarin (18%). Improved treatment efficacy in the intervention group was not found to be statistically significant. Safety outcomes were similar between the two groups. CONCLUSION: Home treatment of acute VTE, facilitated by medication dose pack, is a promising tactic to ensure both immediate and long term treatment efficacy and safety. Further studies are warranted to demonstrate clinical superiority of this intervention. PMID- 28869101 TI - Recycling of plastic waste: Screening for brominated flame retardants (BFRs). AB - Flame retardants are chemicals vital for reducing risks of fire and preventing human casualties and property losses. Due to the abundance, low cost and high performance of bromine, brominated flame retardants (BFRs) have had a significant share of the market for years. Physical stability on the other hand, has resulted in dispersion and accumulation of selected BFRs in the environment and receiving biota. A wide range of plastic products may contain BFRs. This affects the quality of waste plastics as secondary resource: material recycling may potentially reintroduce the BFRs into new plastic product cycles and lead to increased exposure levels, e.g. through use of plastic packaging materials. To provide quantitative and qualitative data on presence of BFRs in plastics, we analysed bromophenols (tetrabromobisphenol A (TBBPA), dibromophenols (2,4- and 2,6-DBP) and 2,4,6-tribromophenol (2,4,6-TBP)), hexabromocyclododecane stereoisomers (alpha-, beta-, and gamma-HBCD), as well as selected polybrominated diphenyl ethers (PBDEs) in samples of household waste plastics, virgin and recycled plastics. A considerable number of samples contained BFRs, with highest concentrations associated with acrylonitrile butadiene styrene (ABS, up to 26,000,000ngTBBPA/g) and polystyrene (PS, up to 330,000ng?HBCD/g). Abundancy in low concentrations of some BFRs in plastic samples suggested either unintended addition in plastic products or degradation of higher molecular weight BFRs. The presence of currently restricted flame retardants (PBDEs and HBCD) identified in the plastic samples illustrates that circular material flows may be contaminated for extended periods. The screening clearly showed a need for improved documentation and monitoring of the presence of BFRs in plastic waste routed to recycling. PMID- 28869102 TI - Quality improvement program of adult urinary tract infection management: Review and impact. AB - OBJECTIVE: A quality improvement program for adult urinary tract infection management was established to avoid unnecessary antibiotic treatment and to promote adequate prescription, associated with financial and time savings. METHODS: Management was integrated into a three-step approach: clinical diagnosis, bacteriological diagnosis, and therapeutic decision. For each step, areas for improvement were prioritized and implemented through corrective measures and key messages, measured by indicators. This program was applied to the whole hospital, which includes an emergency department and hospital units (672 beds). RESULTS: The diffusion of new recommendations on clinical diagnosis helped limit the use of Urine Dipstick Tests (UDT) and identify situations requiring the prescription of urine cytobacteriological test (UCBE) and antibiotic treatment: decreased annual consumption of UDTs (34%) and UCBEs (25%). The implementation of a new sampling system for UCBEs was associated with a 21% increase in conclusive analysis. Results of antimicrobial susceptibility testing were also optimized. Trainings on the proper use of antibiotics led to a 5.0% decline in global consumption. Only 23 antibiotic prescriptions for UTI resulted in pharmaceutical advice to prescribers in 2014. CONCLUSION: The program is part of a practice improvement strategy. Integrating the management of urinary tract infections into a global process helped improve each step of patient management. PMID- 28869103 TI - Clinical manifestations and STK11 germline mutations in Taiwanese patients with Peutz-Jeghers syndrome. AB - BACKGROUNDS: Clinical manifestations and molecular basis of Taiwanese patients with Peutz-Jeghers syndrome (PJS) were investigated to add the knowledge of phenotype and genotype of the disease. METHODS: Based on the Pathology Data Bank and the Colorectal Cancer Register, we collected their clinical data. The entire coding sequence of the STK11 gene was amplified and analyzed by sequencing using the genomic DNA. RESULTS: Fifteen patients diagnosed with PJS from 11 unrelated families were collected until 2015. The median age at the onset of symptoms was 19 years with intussusception as the most frequent presenting symptom. Ten patients developing 11 cancers at various anatomical sites, including two cases of sinonasal cancer, two lung cancers, two breast cancers, two rectal cancers, two gynecological cancers and one small bowel cancer. Five of the deceased patients had died of cancers. The median age of diagnosis of first cancer in the probands was 32 years. Seventy patients (7 of 10) diagnosed before age of 40. Mutations found in eight families included five novel mutations (exon 6, c.843 ins G; exon 8, c.2065 delete A; exon 8, c.G923A, nonsense; exon 6, c.748dupA; and mTOR c.5107dupA) and three previously reported mutations. The other three PJS families without detectable STK11 mutations did not develop malignancies so far. CONCLUSION: This is the first comprehensive study of patients with Peutz-Jeghers syndrome in the Taiwanese. We have demonstrated that the phenotype of Peutz Jeghers syndrome varies greatly among the patients. Patients with detectable STK11 mutations have very high risk of developing cancers. PMID- 28869104 TI - Diffusion Tensor Imaging of the Spinal Cord: Clinical Value, Investigational Applications, and Technical Limitations. AB - Although diffusion-weighted imaging (DWI) has become a mainstay in modern brain imaging, it remains less utilized in the evaluation of the spinal cord. Many studies have shown promise in using DWI and diffusion-tensor imaging (DTI) for evaluation of the spinal cord; however, application has been stalled by technical obstacles and artifacts, and questions remain regarding its clinical utility on an individual examination level. This review discusses the background, concepts, and technical aspects of DWI and DTI, specifically for imaging of the spinal cord. The clinical and investigational applications of spinal cord DTI, as well as the practical difficulties and limitations of DWI and DTI for the evaluation of the spinal cord are examined. PMID- 28869105 TI - Correlation between HBV protein preS2 and tumor markers of hepatocellular carcinoma. AB - BACKGROUND: Alpha-fetoprotein (AFP) and Glypican 3 (GPC3) are both oncogenes and reactivated in hepatocellular carcinoma (HCC). PreS2 has been proved to be an important transactivator in HCC. In this study, we aim to provide evidence that HBV protein preS2 is responsible for AFP and GPC3's reactivation in HCC. METHODS: Totally Sixty-three cases of HCC, aged 34-79, who were surgically treated and pathologically confirmed were enrolled. The levels of AFP in peripheral serum were detected with electrochemical luminescence method before surgery. Levels of GPC3 in HCC samples were evaluated by immunohistochemistry. Luciferase reporter assays were used to measure the effect of preS2 on AFP and GPC3 promoters. RESULTS: AFP level and GPC3 but not albumin were significantly higher in preS2 positive HCC samples than preS2-negative HCC samples. And the preS2 protein expression was positively related with serum AFP level and GPC3 expression. Furtherly, dual luciferase assay showed that preS2 activated AFP and GPC3 promoter activity. CONCLUSION: The expression of preS2 protein relates closely to HCC markers AFP and GPC3. PMID- 28869106 TI - Expression of STIM1 is associated with tumor aggressiveness and poor prognosis in breast cancer. AB - STIM1 has been confirmed a key role involving in breast cancer proliferation and metastasis in vitro studies and its value in breast cancer patients is still to be defined. In this study, we investigate the correlation between STIM1 expressions with clinicopathologic features and prognosis quantified by disease free survival (DFS) and overall survival (OS). To assess STIM1 expression, we conducted immunohistochemistry assays using breast cancer tissues encompassing a total of 165 breast cancer cases with detailed follow-up data and 40 cases of matched samples including cancer and adjacent normal tissues. STIM1 expression was present in 66.1% (109/165) of breast cancer cases which was significantly higher than adjacent non-tumor tissues. Larger tumors, lymphnode metastasis and negative estrogen receptor were positively associated with STIM1 overexpression. Furthermore, STIM1 expression was significantly associated with worse DFS (P=0.03) rather than OS in breast cancer patients. PMID- 28869107 TI - Molecular characterization of a series of solitary fibrous tumors, including immunohistochemical expression of STAT6 and NATB2-STAT6 fusion transcripts, using Reverse Transcriptase(RT)-Polymerase chain reaction(PCR) technique: An Indian experience. AB - A solitary fibrous tumor (SFT) is characterized by a diverse clinicopathologic spectrum. Recent studies have unraveled STAT6 as a useful diagnostic immunohistochemical (IHC) marker for a SFT and NAB2-STAT6 as its specific gene fusion transcript. Thirty-three SFTs were tested for STAT6 immunostaining by polymer detection technique. STAT6 immunoexpression was further graded, based on intensity (mild, moderate and strong) and percentage of immunopositive tumor cells, ranging from 1 to 25%(1+); 26-50%(2+); 51-75%(3+) and in more than 75%(4+) tumor nuclei. These cases along with 17 other tumors were tested for 8 variants of NAB2-STAT6, using qualitative endpoint reverse-transcriptase (RT)-PCR technique. RNA extraction was performed using Recover All Total nucleic acid extraction kit. The selected cases were screened for all the 8 fusion variants, using 8 primer pairs for NAB2 and STAT6 genes. Thirty-three SFTs occurred in 18 men and 15 women (M: F=1.2:1), with age varying from 13 to 74 years(average=49.6); across various body sites. Immunohistochemically, most SFTs (30/33) (90.9%) displayed moderate to strong immunostaining for STAT6, including 3+ and 4+ immunostaining patterns in 27/33 (81.8%) tumors. By RT-PCR, 30/33(90.9%) cases of SFT were positive for NAB2-STAT6 fusions, including NAB2ex4/STAT6ex2 (7cases), NAB2ex7/STAT6ex2 (7cases), NAB2ex6/STAT6ex3 (6cases), NAB2ex6/SAT6ex16 (4cases), NAB2ex3/STAT6ex19 (4cases), NAB2ex6/STAT6ex17 (single case), NAB2ex4/STAT6ex4 (single case) and NAB2ex6/STAT6ex18 (none). NAB2-STAT6 fusions were not observed in 9 cases of synovial sarcoma, 4 of Ewing sarcoma, 2 of MPNST and 2 cases of dedifferentiated liposarcomas (100% specificity). On comparing with clinical outcomes, more cases (7/11)(63.6%) of classic SFT were associated with favorable outcomes, while more cases(5/8)(62%) of atypical and malignant SFTs were associated with aggressive outcomes. This study reinforces high sensitivity and specificity of NAB2-STAT6 fusion and its correlation with strong and diffuse IHC expression of STAT6 in a SFT, irrespective of its occurrence in various body sites and its histopathologic types. NAB2ex4-STAT6ex2 and NAB2ex7-STAT6ex2 fusions were relatively more frequently observed in our patients. Atypical and malignant SFTs, together, were more frequently associated with relatively aggressive clinical outcomes. PMID- 28869108 TI - Cryopreservation of sperm in Grey mullet Mugil cephalus (Linnaeus, 1758). AB - The aim of this study was to document the effects of cryopreservation on sperm motility and viability in Grey mullet Mugil cephalus. Cryopreservation of sperm was attempted by using two extenders ringer solution for marine fish (RSMF) and V2 extender (V2E) and cryoprotectants dimethylacetamide (DMA), dimethylsulfoxide (DMSO), ethylene glycol (EG), glycerol (GLY), propylene glycol (PG) and methanol (MeOH). Cryoprotectants were assessed at different concentrations individually as well as in combination with varying equilibration times (10 and 30min). For optimization of freezing rate, four freezing protocols (-5, -10, -20 and -30 degrees C/min) were evaluated. After achieving final temperature, samples were plunged in liquid nitrogen (-196 degrees C) and stored for a week. Samples were subsequently thawed in a water bath at 30 degrees C for assessment of sperm motility and viability. Results indicated that cryomedium constituting of V2E extender+10% glycerol with a dilution ratio of 1:1 (sperm: cryomedium) at an equilibration time of 5 to- 10min and freezing rate of -20 degrees C/min was more desirable compared with other factors that were assessed. Use of this protocol resulted in retaining the greatest sperm motility grade 3.0+/-0.0 (50%-80% sperm movement, fast swimming) and 48.19+/-3.12% of sperm viability. The results of the present study, therefore, provide base-line data for establishing a protocol for sperm cryopreservation in M.cephalus. Further studies are, however, required for optimization of most suitable sperm cryopreservation protocol. PMID- 28869109 TI - The association between subclinical mastitis around calving and reproductive performance in grazing dairy cows. AB - The objective of this study was to evaluate the effect of subclinical mastitis (SCM) on calving-to-first-service interval (CFS), calving-to-conception interval (CC), and on the number of services per conception (S/C) in grazing Holstein and Normande cows. Primiparous (n=43) and multiparous (n=165) cows were selected from five dairy herds. Two composite milk samples were aseptically collected from each cow at drying-off, and then every week during the first postpartum month. One sample was used for somatic cell count (SCC), and the other one for bacteriological analysis. Cows were followed up to 300 d after calving. Non parametric and parametric survival models, and negative binomial regression were used to assess the association between SCM, evaluated by SCC and milk culture, and reproductive indices. Staphylococcus aureus, CNS, and Streptococcus uberis were the most frequent isolated pathogens. Subclinical mastitis in the first month of lactation was not associated with CFS; however, the CC interval was longer in cows with SCM compared to healthy cows, the former also had a higher number of S/C. PMID- 28869111 TI - Enhancement of sperm motility and viability by turmeric by-product dietary supplementation in roosters. AB - Improving sperm motility and viability are major goals to improve efficiency in the poultry industry. In this study, the effects of supplemental dietary turmeric by-product (TBP) from commercial turmeric production on sperm motility, viability, and antioxidative status were examined in domestic fowl. Mature Rhode Island Red roosters were divided into two groups - controls (groupC) without TBP administration and test subjects (groupT) fed a basal diet supplemented with 0.8g of TBP/day in a temperature-controlled rearing facility (Experiment 1) and 1.6g/day under heat stress (Experiment 2) for 4 weeks. In Experiment 1, TBP dietary supplementation increased the sperm motility variables straight-line velocity, curvilinear velocity, and linearity based on a computer-assisted semen analysis, 2 weeks following TBP supplementation. In Experiment 2, using flow cytometry, sperm viability at 3 and 4 weeks following TBP supplementation was greater in Group T than C, and this increase was consistent with a reduction in reactive oxygen species (ROS) production at 2 and 4 weeks. The results of both experiments clearly demonstrate that dietary supplementation with TBP enhanced sperm motility in the controlled-temperature conditions as well as sperm viability, and reduced ROS generation when heat stress prevailed. Considering its potential application in a range of environments, TBP may serve as an economical and potent antioxidant to improve rooster fertility. PMID- 28869110 TI - Anandamide exerts a suppressive effect on sperm binding to oviduct explants through CB1 receptors in the water buffalo (Bubalus bubalis). AB - An endocannabinoid system comprising of Anandamide (AEA) and its receptor has been shown to play a role in sperm acquisition of fertilizing potential and sperm oviduct interaction. In the present study, we assessed the effect of sperm pre treatment with AEA or co-incubation of sperm-oviduct explants with AEA in the presence or absence of CB1 receptor antagonist (SR141716A) on sperm-oviduct binding in the water buffalo. Cryopreserved spermatozoa from 3 Murrah buffalo bulls (3 ejaculates from each bull) were utilized for the study. Oviduct explants were prepared by overnight culture of epithelial cells in TCM- 199 and washed spermatozoa were added to the oviduct explants and incubated for 1h. Then, sperm oviduct explants were stained with a fluorescent stain (JC-1) and sperm binding index (BI - No. of bound spermatozoa/unit area of oviduct explants) was assessed. The results indicate that BI decreased significantly (P<0.05) when spermatozoa were either pre-treated with AEA (14.16+/-0.87) or sperm-oviduct explants were co incubated with AEA (16.27+/-0.86) at 1nM concentration compared to the control group (29.12+/-2.17), however such effect was not observed when AEA was used at 1MUM concentration. Incorporation of SR141716A in the incubation medium inhibited the suppressive effect of AEA on BI. It was concluded that AEA, at 1nM concentration, decreased the number of spermatozoa bound to the oviduct explants and the suppressive effect of AEA on sperm-oviduct binding was inhibited by CB1 receptor antagonist suggesting that the effect of AEA was mediated through CB1 receptor in the water buffalo. PMID- 28869112 TI - Activation of catalase activity by a peroxisome-localized small heat shock protein Hsp17.6CII. AB - Plant catalases are important antioxidant enzymes and are indispensable for plant to cope with adverse environmental stresses. However, little is known how catalase activity is regulated especially at an organelle level. In this study, we identified that small heat shock protein Hsp17.6CII (AT5G12020) interacts with and activates catalases in the peroxisome of Arabidopsis thaliana. Although Hsp17.6CII is classified into the cytosol-located small heat shock protein subfamily, we found that Hsp17.6CII is located in the peroxisome. Moreover, Hsp17.6CII contains a novel non-canonical peroxisome targeting signal 1 (PTS1), QKL, 16 amino acids upstream from the C-terminus. The QKL signal peptide can partially locate GFP to peroxisome, and mutations in the tripeptide lead to the abolishment of this activity. In vitro catalase activity assay and holdase activity assay showed that Hsp17.6CII increases CAT2 activity and prevents it from thermal aggregation. These results indicate that Hsp17.6CII is a peroxisome localized catalase chaperone. Overexpression of Hsp17.6CII conferred enhanced catalase activity and tolerance to abiotic stresses in Arabidopsis. Interestingly, overexpression of Hsp17.6CII in catalase-deficient mutants, nca1-3 and cat2 cat3, failed to rescue their stress-sensitive phenotypes and catalase activity, suggesting that Hsp17.6CII-mediated stress response is dependent on NCA1 and catalase activity. Overall, we identified a novel peroxisome-located catalase chaperone that is involved in plant abiotic stress resistance by activating catalase activity. PMID- 28869113 TI - Cold-induced retrotransposition of fish LINEs. AB - Classes of retrotransposons constitute a large portion of metazoan genome. There have been cases reported that genomic abundance of retrotransposons is correlated with the severity of low environmental temperatures. However, the molecular mechanisms underlying such correlation are unknown. We show here by cell transfection assays that retrotransposition (RTP) of a long interspersed nuclear element (LINE) from an Antarctic notothenioid fish Dissostichus mawsoni (dmL1) could be activated by low temperature exposure, causing increased dmL1 copies in the host cell genome. The cold-induced dmL1 propagation was demonstrated to be mediated by the mitogen-activated protein kinases (MAPK)/p38 signaling pathway, which is activated by accumulation of reactive oxygen species (ROS) in cold stressed conditions. Surprisingly, dmL1 transfected cells showed an increase in the number of viable cells after prolonged cold exposures than non-transfected cells. Features of cold inducibility of dmL1 were recapitulated in LINEs of zebrafish origin both in cultured cell lines and tissues, suggesting existence of a common cold-induced LINE amplification in fishes. The findings reveal an important function of LINEs in temperature adaptation and provid insights into the MAPK/p38 stress responsive pathway that shapes LINE composition in fishes facing cold stresses. PMID- 28869114 TI - Multidrug-Resistant Organisms in the Setting of Periprosthetic Joint Infection Diagnosis, Prevention, and Treatment. AB - BACKGROUND: Periprosthetic joint infection (PJI) is a rare yet challenging problem in total hip and knee arthroplasties. The management of PJI remains difficult primarily due to the evolution of resistance by the infecting organisms. METHODS: This review profiles acquired mechanisms of bacterial resistance and summarizes established and emerging techniques in PJI diagnosis, prevention, and treatment. RESULTS: New techniques in PJI diagnosis and prevention continue to be explored. Antibiotics combined with 1 or 2-stage revision are associated with the higher success rates and remain the mainstay of treatment. CONCLUSION: With higher prevalence of antibiotic-resistant organisms, novel antibiotic implant and wound care materials, improved methods for organism identification, and well-defined organism-specific treatment algorithms are needed to optimize outcomes of PJI. PMID- 28869115 TI - Wound Discharge After Pharmacological Thromboprophylaxis in Lower Limb Arthroplasty. AB - BACKGROUND: The benefits vs risk of pharmacological prophylaxis for thromboembolic disease in orthopedic patients remain controversial. Pharmacological thromboprophylaxis regimes are commonly used in this patient group. Few studies specifically examine wound complications attributable to this therapy. In this prospective trial, we investigated the effect of various regimens on postoperative wounds. METHODS: A prospective, observational, multicenter study involving patients undergoing elective hip or knee arthroplasty was undertaken. Patients were divided into 3 groups depending on thromboprophylaxis: no anticoagulation, aspirin, or low molecular weight heparin (LMWH) (enoxaparin). Surgical wounds were evaluated for each regime using the Southampton Wound Assessment Score. RESULTS: Over a 12-month period, 327 patients were enrolled with a mean age of 68.1 years (+/-11.2 years). There were 105 patients in the no anticoagulation group (32.1%), 97 patients in the aspirin group (29.7%), and 125 patients in the LMWH group (38.2%). Wound scores were evaluated for evidence and amount of discharge. The use of LMWH conferred a 4.92 times greater risk and aspirin a 3.64 times greater risk of wound discharge than no pharmacological thromboprophylaxis (P < .0001). There were no significant differences in the incidence of deep vein thrombosis or pulmonary embolus between groups either as an inpatient or postdischarge. CONCLUSION: There is a significant increase in the risk of wound discharge when aspirin or LMWH is used in arthroplasty patients. As potential complications of wound problems are significant, a more balanced view of risk vs benefit needs to be taken when prescribing thromboprophylaxis for this patient group. PMID- 28869116 TI - Teriparatide Administration Increases Periprosthetic Bone Mineral Density After Total Knee Arthroplasty: A Prospective Study. AB - BACKGROUND: Teriparatide is a currently available therapeutic agent for osteoporosis. Previous studies have reported that teriparatide affects periprosthetic bone mineral density (BMD) after total knee arthroplasty (TKA). However, little agreement has been reached concerning the treatment of periprosthetic BMD after TKA with teriparatide. Moreover, BMD in the femoral and tibial sides of the joints together has never been examined. We investigated the efficacy of teriparatide to inhibit BMD loss in the femoral and tibial side and considered complications such as migration and periprosthetic fractures after TKA. METHODS: Twenty-two knees in 17 patients were included in this study, and a control group of patients who underwent TKA was identified according to their medical records. Dual-energy X-ray absorptiometry was performed for different locations (knee, hip, and lumbar spine), and regions of interest were measured to estimate BMD at initiation of the study as a baseline reference, followed by subsequent measurements at 6 and 12 months. RESULTS: As a result of adjusting the difference between the BMDs of the 2 groups at initiation, there was a significant increase in R3 (posterior condyle) and R4 (lateral) at 6 months. Furthermore, there was a significant increase in R2 (anterior condyle), R3 (posterior condyle), and R6 (tibial diaphysis) at 12 months. The study group had a higher adjusted mean BMD in all regions than did the control group at 6 and 12 months. CONCLUSION: Teriparatide may be a reasonable treatment option for osteoporotic patients to preserve or improve periprosthetic BMD after TKA. PMID- 28869117 TI - Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices. AB - Thrombus formation is a major adverse event affecting patients implanted with ventricular assist devices (VADs). Despite anti-thrombotic drug administration, thrombotic events remain frequent within the first year post-implantation. Platelet activation (PA) is an essential process underling thrombotic adverse events in VAD systems. Indeed, abnormal shear forces, correlating with specific flow trajectories of VADs, are strong agonists mediating PA. To date, the ability to determine efficacy of anti-platelet (AP) agents under shear stress conditions is limited. Here, we present a novel microfluidic platform designed to replicate shear stress patterns of a clinical VAD, and use it to compare the efficacy of two AP agents in vitro. Gel-filtered platelets were incubated with i) acetylsalicylic acid (ASA) and ii) ticagrelor, at two different concentrations (ASA: 125 and 250 uM; ticagrelor: 250 and 500 nM) and were circulated in the VAD emulating microfluidic platform using a peristaltic pump. GFP was collected after 4 and 52 repetitions of exposure to the VAD shear pattern and tested for shear mediated PA. ASA significantly inhibited PA only at 2-fold higher concentration (250 uM) than therapeutic dose (125 uM). The effect of ticagrelor was not dependent on drug concentration, and did not show significant inhibition with respect to untreated control. This study demonstrates the potential use of microfluidic platforms as means of testing platelet responsiveness and AP drug efficacy under complex and realistic VAD-like shear stress conditions. PMID- 28869118 TI - Multicentric giant cell tumor of bone: Case series of 4 patients. AB - BACKGROUND: We aimed to retrospectively investigate patients with multicentric giant cell tumor (MCGCT) who were treated at our hospital and to clarify their clinical features, treatment policy, and follow-up method. METHODS: Four patients with two or more giant cell tumor (GCT) that occurred in the same patient were treated at our institution between 1978 and 2015. These patients were evaluated for the following: frequency, age of onset, number and site of occurrence, time to occurrence of the next lesion, treatment, recurrence, malignant transformation, metastasis, and oncological outcome. RESULTS: The rate of occurrence was 1.7%. The average age was 25.2 (17-44). The total number of lesions was three in two cases and two in two cases. All four cases had only one lesion during the initial visit. The most frequent site of occurrence was the proximal femur, followed by two lesions that occurred in the metaphysis. The interval between confirmation of the initial lesion and occurrence of the second lesion was in average 12.1 years (0.8-27.0). Initial presentations of lesions were treated by en bloc resection in one case and curettage in three cases. Local recurrences occurred in two cases that underwent curettage. The six lesions that occurred after the initial lesion were treated as follows: en bloc resection in four lesions, curettage and radiation therapy in one, and embolization and radiation therapy in one. Pathologically, no lesions presented malignancy. Pulmonary metastasis occurred in one case. The oncological outcome was NED in three cases and AWD in one case. CONCLUSIONS: No lesions were malignant, and by providing the same treatment as solitary GCT, the oncological outcome was good. It is unnecessary to be concerned of its risks and postoperatively conduct long term searches for focal lesions across the body. PMID- 28869120 TI - Ovaries and oogenesis in an epizoic dermapteran, Hemimerus talpoides (Dermaptera, Hemimeridae): Structural and functional adaptations to viviparity and matrotrophy. AB - The Dermaptera are traditionally classified in three taxa: the free living Forficulina and two viviparous (matrotrophic) groups, the Hemimerina and Arixeniina. Recent molecular and histological analyses suggest that both matrotrophic groups should be nested among the most derived taxon of the Forficulina, the Eudermaptera. We present results of ultrastructural analyses of ovary/ovariole morphology and oogenesis in a representative of the Hemimerina, Hemimerus talpoides (Walker, 1871). Our results strongly reinforce the idea that the Hemimerina should be classified within the Eudermaptera. We show additionally that the ovaries of the studied species are characterized by two peculiar modifications, i.e. the presence of numerous tracheoles in contact with the basement lamina covering the ovarioles, and an unusual development of the ovariole stalks. We believe that both characters are related to viviparity and unconventional "intra-ovariolar" embryo development. Finally, our study also indicates that the oocytes of H. talpoides reveal characters apparently associated with a matrotrophic type of embryo nourishment. They are completely yolkless and devoid of the typical, multilayered egg envelopes; instead, they comprise unconventional organelles (para-crystalline stacks of endoplasmic reticulum cisternae and translucent vacuoles) that seem to function after initiation of embryonic development. Thus, the ovaries as well as the oocytes of H. talpoides are characterized by an exceptional mixture of features shared with derived dermapterans and adaptations to matrotrophy. PMID- 28869121 TI - Exploring surface characterization and electrostatic property of Hybrid Pennisetum during alkaline sulfite pretreatment for enhanced enzymatic hydrolysability. AB - The surface characterization and electrostatic property of Hybrid Pennisetum (HP) after alkaline sulfite pretreatment were explored for enhanced enzymatic hydrolysability. The O/C ratio in HP increased from 0.34 to 0.60, and C1 concentration decreased from 62.5% to 31.6%, indicating that alkaline sulfite pretreatment caused poorer lignin but richer carbohydrate on HP surface. Zeta potential and sulfur element analysis indicated that more enzymes would preferably adsorb on the carbohydrate surface of alkaline sulfite pretreated HP because the lignin was sulfonated, which facilitated the decrease of non productive adsorption. Glucose yield of alkaline sulfite pretreated HP reached to 100% by synergistic action of cellulase and xylanase in the hydrolysis, which was significantly higher than that of NaOH pretreated, and the concentration of glucose released was 1.52times higher. The results suggested that alkaline sulfite pretreatment had potential for improving the HP hydrolysability, and the surface characterization and electrostatic property facilitated the enzymatic digestibility. PMID- 28869123 TI - Sequential high gravity ethanol fermentation and anaerobic digestion of steam explosion and organosolv pretreated corn stover. AB - The present work investigates the suitability of pretreated corn stover (CS) to serve as feedstock for high gravity (HG) ethanol production at solids-content of 24wt%. Steam explosion, with and without the addition of H2SO4, and organosolv pretreated CS samples underwent a liquefaction/saccharification step followed by simultaneous saccharification and fermentation (SSF). Maximum ethanol concentration of ca. 76g/L (78.3% ethanol yield) was obtained from steam exploded CS (SECS) with 0.2% H2SO4. Organosolv pretreated CS (OCS) also resulted in high ethanol concentration of ca. 65g/L (62.3% ethanol yield). Moreover, methane production through anaerobic digestion (AD) was conducted from fermentation residues and resulted in maximum methane yields of ca. 120 and 69mL/g volatile solids (VS) for SECS and OCS samples, respectively. The results indicated that the implementation of a liquefaction/saccharification step before SSF employing a liquefaction reactor seemed to handle HG conditions adequately. PMID- 28869119 TI - Does home-based pulmonary rehabilitation improve functional capacity, peripheral muscle strength and quality of life in patients with bronchiectasis compared to standard care? AB - BACKGROUND: Home-based pulmonary rehabilitation is a promising intervention that may help patients to overcome the barriers to undergoing pulmonary rehabilitation. However, home-based pulmonary rehabilitation has not yet been investigated in patients with bronchiectasis. OBJECTIVES: To investigate the effects of home-based pulmonary rehabilitation in patients with bronchiectasis. METHODS: An open-label, randomized controlled trial with 48 adult patients with bronchiectasis will be conducted. INTERVENTIONS: The program will consist of three sessions weekly over a period of 8 weeks. Aerobic exercise will consist of stepping on a platform for 20min (intensity: 60-80% of the maximum stepping rate in incremental step test). Resistance training will be carried out using an elastic band for the following muscles: quadriceps, hamstrings, deltoids, and biceps brachii (load: 70% of maximum voluntary isometric contraction). CONTROL: The patients will receive an educational manual and a recommendation to walk three times a week for 30min. All patients will receive a weekly phone call to answer questions and to guide the practice of physical activity. The home-based pulmonary rehabilitation group also will receive a home visit every 15 days. MAIN OUTCOME MEASURES: incremental shuttle walk test, quality of life, peripheral muscle strength, endurance shuttle walk test, incremental step test, dyspnea, and physical activity in daily life. The assessments will be undertaken at baseline, after the intervention, and 8 months after randomization. DISCUSSION: The findings of this study will determine the clinical benefits of home-based pulmonary rehabilitation and will contribute to future guidelines for patients with bronchiectasis. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT02731482). https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S00060X6&se ectaction=Edit&uid=U00028HR&ts=2&cx=1jbszg. PMID- 28869122 TI - Enhanced nitrogen and phosphorus removal from municipal wastewater in an anaerobic-aerobic-anoxic sequencing batch reactor with sludge fermentation products as carbon source. AB - An anaerobic-aerobic-anoxic sequencing batch reactor (AOA-SBR) using sludge fermentation products as carbon source was developed to enhance nitrogen and phosphorus removal in municipal wastewater with low C/N ratio (<4) and reduce sludge production. The AOA-SBR achieved simultaneous partial nitrification and denitrification (SND), aerobic phosphorus uptake and anoxic denitrification through the real-time control and the addition of sludge fermentation products. The average removal efficiencies of total nitrogen (TN), phosphorus (PO43--P) and chemical oxygen demand (COD) after 145-day operation were 88.8%, 99.3% and 81.2%, respectively. Nitrite accumulation ratio (NAR) reached 99.1% and sludge reduction rate reached 44.1-52.1%. Specifically, 34.4% of the TN removal was carried out by SND and 57.5% by denitrification. Illumina MiSeq sequencing indicated that ammonium-oxidizing bacteria (Nitrosomonas) were enriched and nitrite-oxidizing bacteria (Nitrospira) did not exist in AOA-SBR. The system demonstrated potential to solve the dual problem of insufficient carbon source and sludge reduction. PMID- 28869124 TI - Synergistic dye adsorption by biochar from co-pyrolysis of spent mushroom substrate and Saccharina japonica. AB - The potential of activating terrestrial biomass (spent mushroom substrate, SMS) with ash-laden marine biomass [kelp seaweed, KE] via co-pyrolysis in the field of adsorption was first investigated. KE biochar (KBC), SMS biochar (SMSBC), biochar (SK10BC) from 10%-KE added SMS, and biochar (ESBC) from KE-extract added SMS were used for the adsorption of cationic dye crystal violet (CV). ESBC had highest fixed carbon content (70.60%) and biochar yield (31.6%). SK10BC exhibited high ash content, abundant functional groups, coarser surface morphology and Langmuir maximum adsorptive capacity (610.1mg/g), which is 2.2 times higher than that of SMSBC (282.9mg/g). Biochar activated by a small amount of high ash-containing biomass such as seaweed via co-pyrolysis can serve as viable alternative adsorbent for cationic dye removal. PMID- 28869126 TI - Acclimatization of a mixed-animal manure inoculum to the anaerobic digestion of Axonopus compressus reveals the putative importance of Mesotoga infera and Methanosaeta concilii as elucidated by DGGE and Illumina MiSeq. AB - In this study, a multifarious microbial mix from different sources is acclimatized over a period of three months to digesting cowgrass, and the changes in the community structure are examined with both a traditional denaturing gradient gel electrophoresis method as well as a next generation sequencing MiSeq method. It is shown that the much more in depth analysis by Illumina gives more information about the relative abundance and thus putative importance of the role of various microbes, in particular the bacterium Mesotoga infera and the archaeon Methanosaeta concilii. PMID- 28869125 TI - Phenol biodegradation and microbial community dynamics in extractive membrane bioreactor (EMBR) for phenol-laden saline wastewater. AB - An extractive membrane bioreactor (EMBR) for phenol-laden saline wastewater was set up in this study to investigate the variations of phenol removal, extracellular polymeric substance (EPS) release and microbial community dynamics. The gradual release of phenol and the total separation of salt were achieved by silicon rubber tube membrane. Only phenol (55.6-273.9mg/L) was extracted into microorganism unit from wastewaters containing 1.0-5.0g/L phenol and 35.0g/L NaCl. After 82d of EMBR operation, maximal 273.9mg/L of phenol was removed in EMBR. Low concentration of phenol in wastewater (2.5g/L) played a favorable effect on the microbial community structure, community and dynamics. The enumeration of Proteobacteria (30,499 sequences) significantly increased with more released EPS (82.82mg/gSS) to absorb and degrade phenol, compared to the virgin data without phenol addition. However, high concentration of phenol showed adverse effects on EPS release, microbial abundance and biodiversity. PMID- 28869127 TI - Patient-Centered Assessment of the Value of Oral Contrast Material. AB - PURPOSE: The aim of this study was to measure the value of oral contrast material from the patient's point of view. METHODS: A prospective HIPAA-compliant survey was administered from August 30, 2016, to March 9, 2017, at two outpatient centers to consecutive outpatients immediately after oral contrast material consumption for abdominopelvic CT. The survey included validated measures of temporary health disutility and oral contrast-specific questions vetted by patient advocates with experience in survey design. Descriptive statistics were calculated. RESULTS: The response rate (93% [218 of 234]) and completion rate (100% [218 of 218]) were excellent. When given a hypothetical choice to not drink oral contrast, most subjects (89% [193 of 218]) stated that they would always drink it for fear of missing an important finding, and only 5 (2%) stated that they would never drink it regardless of risk. Twenty (9%) said that the decision to drink oral contrast would depend on the level of risk, with 18 (8%) indicating that they would accept a 0.01% to 1.00% risk for missing an important finding if they did not have to drink oral contrast. Most patients rated the oral contrast taste as tolerable (55% [120 of 218]); a minority rated it bad or terrible (10% [21 or 218]). Thirty-six subjects (17%) experienced concern or unease (8 minimal, 15 mild, 10 moderate, 3 extreme) when they learned that they had to drink oral contrast, and 36 (17%) experienced oral contrast-induced nausea or abdominal discomfort (10 minimal, 15 mild, 10 moderate, 1 extreme). CONCLUSIONS: If oral contrast material has any diagnostic benefit, most outpatients (89%) would rather drink it than accept any risk for missing an important finding. PMID- 28869128 TI - In Response to Avalanche Fatalities in the United States by Jekich et al. PMID- 28869129 TI - [Characteristics and cardiovascular events in a general population included in the RICARTO (RIesgo CARdiovascular TOledo) study: Data from the first 1,500 individuals included in the study]. AB - INTRODUCTION: The aim of this study was to assess cardiovascular risk (CVR) by investigating the prevalence of CVR factors (CVRF), target organ damage (TOD), and cardiovascular disease (CVD) in general population of the health area of Toledo, Spain. MATERIAL AND METHODS: Epidemiological and observational study that analysed a sample from the general population aged 18years or older, randomly selected from a database of health cards stratified by age and gender. Clinical history, physical examination, and complementary tests were performed. Total blood and serum samples were frozen at -85 degrees C to evaluate genetic studies in the future. Standard statistical analysis was performed. CVR was assessed by the SCORE scale calibrated for the Spanish population, and the Framingham Heart Study scale. RESULTS: A total of 1,500 individuals (mean age 49.1+/-15.8years, 55.6% women) were included. Prevalences: dyslipidaemia 56.9% (95% confidence interval [95% CI]: 54.3-59.4), hypertension 33.0% (95%CI: 30.6-35.4), diabetes mellitus 8.6% (95%CI: 7.17-10.1), smoking 24.2% (95%CI; 122.0-26.4), obesity 25.3% (95%CI; 23.1-27.5), and sedentary life-style 39.4% (95%CI; 36.9-41.8). No CVRF was reported in 21.1% of cases, and 18.6% had 3-5 CVRF. TOD: electrocardiographic left ventricular hypertrophy, 4.3%, peripheral artery disease, 10.1% (Doppler ultrasound), and 15.3% (oscillometric device), microalbuminuria, 4.3%, sub-clinical renal disease, 3.2%, and nephropathy in 3.8% (CKD-EPI). At least one CVD was reported in 9.2% of cases. A low CVR (SCORE) was present in 44.6% of individuals. CONCLUSIONS: Dyslipidaemia was found in 60% of individuals, 40% had a sedentary life-style, 30% with hypertension, 20% smoked, 20% obesity, and almost 10% with diabetes. More than a half of individuals have a moderate-high-very high risk. The prevalence of TOD and CVD are significant. PMID- 28869130 TI - [Onychomadesis in an immunocompetent adult patient]. PMID- 28869131 TI - In the Hunger Games, the Winner Takes Everything. AB - Entosis is an atypical form of cell death that occurs when a cell engulfs and kills another cell. A recent article by Overholtzer and colleagues indicates that glucose deprivation promotes entosis. AMP-activated protein kinase (AMPK) activation in the loser cells triggers their engulfment and elimination by winner cells, which endure starvation. PMID- 28869132 TI - Cementoblastoma: An updated analysis of 258 cases reported in the literature. AB - PURPOSE: To investigate the recurrence rate of cementoblastomas for different variables aside from the clinical/radiologic features. METHODS: An electronic search was undertaken in November/2016. Eligibility criteria included publications having enough clinical/radiological/histological information to confirm the diagnosis. RESULTS: 141 publications (258 cementoblastomas) were included. There was an equal sex distribution. There was a high prevalence in the second/third decades of life, in the posterior regions, and in mandibular first molars. Lesions were commonly associated with bone expansion (74.9%), presence of clinical symptoms (70.2%), vital teeth (78%), root resorption (59.8%). Observations not as frequent: cortical bone perforation (16.3%), inferior displacement of the mandibular canal (23.6%). Treatment was reported for 229 cases. Twenty (11.8%) out of 170 recurred. Preservation of the involved teeth and location seem to not influence the recurrence rate, but there was a 687% higher probability (odds ratio 7.875; p = 0.048) of recurrence for lesions associated with bone expansion, and a 217% higher probability (odds ratio 3.173; p = 0.023) of recurrence for lesions presenting cortical bone perforation. CONCLUSIONS: Although the recurrence rate of cementoblastomas is not as high as previously believed, it is a relevant phenomenon (11.8%). The presence of bone expansion and cortical bone perforation seem to influence the recurrence rate. PMID- 28869133 TI - Aesthetic facial perception and need for intervention in laterognathism in women of different ethnicities. AB - This study compared the perception of facial pleasantness and the need for intervention, as assessed by orthodontists, oral and maxillofacial (OMF) surgeons, and laypersons, in people of different ethnicities showing varying degrees of simulated laterognathism. Facial photographs were modified to simulate deviations in the lower face of women of African, Asian and Caucasian descent, ascending in two-degree steps from zero to eight degrees of deviation. Three groups of 20 individuals each (OMF surgeons, orthodontists, and laypersons) assessed the images and rated facial pleasantness on a numerical scale ranging from 0 to 10. The results showed that orthodontists and laypersons rated faces differently only after six and eight degrees of facial change. OMF surgeons rated faces statistically differently from laypersons in all degrees of deviation, and differently from orthodontists in faces with zero, two, and four degrees of deviation. Scores for Caucasian and Asian faces differed only at two degrees of deviation. On the other hand, Caucasian and African faces differed at two and four degrees of deviation, while African and Asian faces differed only at eight degrees. The results suggest that, as a group, OMF surgeons were able to detect all degrees of lower face deviation. Moreover, orthodontists and OMF surgeons seemed to agree in terms of need for facial intervention, and saw that need more often than laypersons. In addition, ethnicity also affected the perception of milder facial changes. PMID- 28869134 TI - Isolated INO as a presentation of midbrain paramedian area lacunar infarction in patients with diabetes. AB - The clinical features and pathogenesis of the pure midbrain infarction need to be described. Of 4257 stroke patients who were on the stroke registry between January 2000 and December 2015, 25 patients with pure midbrain infarctions, as demonstrated on diffusion-weighted magnetic resonance imaging, were enrolled. We analyzed the clinical features, MRI findings, and etiologic mechanisms of the infarctions. According to the distribution of each penetrating artery of the midbrain, we classified all the infarctions into paramedian (PM) area (13 patients), lateral area (10 patients), and PM and lateral areas (2 patients). In the lacunar infarction of the PM area group (8 patients), 6 patients had diabetes mellitus (DM), and 5 patients showed isolated anterior internuclear ophthalmoplegia (INO)-the ratio was much higher than that of the non-PM-lacunar infarction group. Patients with DM were more likely to develop lacunar infarction of the midbrain PM area than that of non-diabetics. Data suggest that isolated INO is a presentation of midbrain PM area lacunar infarction in patients with DM. PMID- 28869135 TI - Genetics of Alzheimer's disease: From pathogenesis to clinical usage. AB - Alzheimer's disease (AD) is the most common type of dementia and has caused a major global health concern. Understanding the etiology of AD can be beneficial for the diagnosis and intervention of this disease. Genetics plays a vital role in the pathogenesis of AD. Research methods in genetics such as the linkage analysis, study of candidate genes, genome-wide association study (GWAS), and next-generation sequencing (NGS) technology help us map the genetic information in AD, which can not only provide a new insight into the pathogenesis of AD but also be beneficial for early targeted intervention of AD. This review summarizes the pathogenesis as well as the diagnostic and therapeutic value of genetics in AD. PMID- 28869136 TI - Basilar Artery Dolichoectasia: Prevalence and Correlates With Markers of Cerebral Small Vessel Disease in Community-Dwelling Older Adults. AB - BACKGROUND: Basilar artery (BA) dolichoectasia has been associated with cerebral small vessel disease (SVD). However, studies have focused on stroke patients, and results cannot be extrapolated to the population at large. In this study, we aimed to assess prevalence of BA dolichoectasia and its association with SVD in community-dwelling older adults living in rural Ecuador. METHODS: Atahualpa residents aged >=60 years underwent brain magnetic resonance imaging and magnetic resonance angiography of intracranial vessels. Following Smoker's criteria, the mean BA diameter plus 2 standard deviation defined ectasia. In addition, a location lateral to the lateral margin of the clivus of dorsum sellae or a bifurcation at the third ventricle floor or higher defined dolichosis. Associations between BA abnormalities and imaging markers of SVD were assessed by the use of regression models adjusted for demographics and cardiovascular risk factors. RESULTS: Of 346 participants, 11 (3.2%) had ectasia, 40 (11.6%) had dolichosis, and 47 (13.6%) had dolichoectasia (ectasia, dolichosis, or both). BA diameter was only associated with severity of white matter hyperintensities (P = .038). Dolichosis was associated with deep cerebral microbleeds (P = .002) but not with white matter hyperintensities. Dolichoectasia was associated with both white matter hyperintensities (P = .031) and cerebral microbleeds (P = .001). There were no associations with lacunar infarcts or enlarged perivascular spaces in any model. CONCLUSIONS: Prevalence of BA dolichoectasia in this rural setting is similar to that reported in other populations. Associations with imaging markers of SVD differ according to whether the subject has ectasia or dolichosis. PMID- 28869137 TI - The optimal balance between quality and efficiency in proton radiography imaging technique at various proton beam energies: A Monte Carlo study. AB - Proton radiography is a novel imaging modality that allows direct measurement of the proton energy loss in various tissues. Currently, due to the conversion of so called Hounsfield units from X-ray Computed Tomography (CT) into relative proton stopping powers (RPSP), the uncertainties of RPSP are 3-5% or higher, which need to be minimized down to 1% to make the proton treatment plans more accurate. In this work, we simulated a proton radiography system, with position-sensitive detectors (PSDs) and a residual energy detector (RED). The simulations were built using Geant4, a Monte Carlo simulation toolkit. A phantom, consisting of several materials was placed between the PSDs of various Water Equivalent Thicknesses (WET), corresponding to an ideal detector, a gaseous detector, silicon and plastic scintillator detectors. The energy loss radiograph and the scattering angle distributions of the protons were studied for proton beam energies of 150MeV, 190MeV and 230MeV. To improve the image quality deteriorated by the multiple Coulomb scattering (MCS), protons with small angles were selected. Two ways of calculating a scattering angle were considered using the proton's direction and position. A scattering angle cut of 8.7mrad was applied giving an optimal balance between quality and efficiency of the radiographic image. For the three proton beam energies, the number of protons used in image reconstruction with the direction method was half the number of protons kept using the position method. PMID- 28869138 TI - Survival Outcomes of Radical Prostatectomy Versus Radiotherapy in Intermediate Risk Prostate Cancer: A NCDB Study. AB - BACKGROUND: Studies of various prostate cancer patient cohorts found men receiving external-beam radiotherapy (EBRT) had higher mortality than men undergoing radical prostatectomy (RP). Conversely, a recent clinical trial showed no survival differences between treatment groups. We used the National Cancer Data Base (NCDB) to evaluate overall survival in intermediate-risk (T2b-T2c or Gleason 7 [grade group II or III] or prostate-specific antigen 10-20 ng/mL) prostate cancer patients undergoing EBRT with or without androgen deprivation therapy (ADT), RP, or no initial treatment. PATIENTS AND METHODS: We analyzed 268,378 men with intermediate-risk prostate cancer from 2004 to 2012. Kaplan Meier estimates and multivariable Cox proportional hazards models were used to compare survival between treatments. RESULTS: After adjusting for patient and facility covariables, men receiving no initial treatment averaged greater adjusted mortality risk than men receiving EBRT (hazard ratio [HR], 1.71; 95% confidence interval [CI] 1.62-1.80; P < .001), EBRT + ADT (HR, 1.73; 95% CI 1.64 1.81; P < .001), or RP (HR, 4.18; 95% CI 3.94-4.43; P < .001). Men undergoing RP had significantly lower adjusted mortality risk than men receiving either EBRT (HR, 0.41; 95% CI 0.39-0.43; P < .001) or EBRT + ADT (HR, 0.41; 95% CI 0.39-0.43; P < .001). No difference was observed between men receiving EBRT or EBRT + ADT (HR, 1.01; 95% CI 0.97-1.05; P = .624). CONCLUSION: Men treated with RP experienced significantly lower overall mortality risk than EBRT with or without ADT and no treatment patients, regardless of patient, demographic, or facility characteristics. The results are limited by the lack of cancer-specific mortality in this database. PMID- 28869139 TI - Re: Cultural background, non-therapeutic circumcision and the risk of meatal stenosis and other urethral stricture disease: Two nationwide register-based cohort studies in Denmark 1977-2013. PMID- 28869140 TI - Median nerve ultrasound findings in systemic sclerosis patients: How do they relate to clinical features of the disease? PMID- 28869141 TI - Marine omega-3 fatty acids and cardiac death. PMID- 28869142 TI - Gene expression profile of estrogen receptors alpha and beta in rat brain during aging and following high fat diet. AB - The "sex-hormone" estrogen-17beta promotes several cognitive functions and is a master regulator of brain bioenergetics via the estrogen receptors alpha and beta (ERalpha and ERbeta). In this work, by using Real-Time PCR analysis, we evaluated the effect of aging and high fat diet (HFD) on ERalpha and ERbeta expression in rat hippocampus and cortex. In young rats, ERbeta is abundant in cortex and ERalpha in hippocampus. During the aging, in the cortex, we observe a general decrease in ERalpha and ERbeta expression; in hippocampus ERalpha increases and ERbeta decreases. ER expression patterns in rat brain are also affected by the administration of an HFD. In cortex, after 4weeks of HFD, ERbeta transcripts are down-regulated, whereas ERalpha levels remain unchanged; after 12weeks, both ERalpha and ERbeta expression is up-regulated. In the hippocampus, the level of ERbeta transcripts does not change following HDF, whereas ERalpha expression is affected by HDF, in a time-dependent manner: it increases after the 4-week treatment and decreases after 12weeks. Possible involvements of these receptors in the control of cortex and hippocampus functions during aging and in the modulation of energetic metabolism and feeding behaviour are discussed. PMID- 28869144 TI - Efficiency of using the day-of-implant CT for planning of SAVI APBI. AB - PURPOSE: The purpose of the study was to develop an optimized, efficient workflow for using the day-of-implant (DOI) CT for treatment planning of accelerated partial breast irradiation brachytherapy using the strut-adjusted volume implant (SAVI) device. METHODS AND MATERIALS: For 62 consecutive SAVI patients, a DOI CT was acquired and used for treatment planning. A "verification" CT was acquired 24 72 h after implant and immediately before the first fraction, then registered to the DOI CT. If the DOI CT-based plan was no longer optimal, a replan was performed. An array of metrics describing the geometry of the device and its relative position in the patient from the DOI CTs for these patients was collected. These metrics from the DOI CT were evaluated to determine what features could predict for the need to replan before the first treatment fraction. Logistical regression analysis including chi2 tests was used to determine if different factors correlated with replanning. RESULTS: Twenty-two of 62 patients (35%) required replanning. Only the presence of splayed struts, where splay was toward the skin, and the use of a nine strut ("8-1") SAVI were significantly correlated (p < 0.05) with replanning. Within these individual populations, no additional factors showed a significant statistical correlation for requiring replanning. CONCLUSIONS: For strut-based accelerated partial breast irradiation brachytherapy, it was feasible to treat with a plan based on the DOI CT for a majority (65%) of patients. Some factors correlate to needing replanning; recognizing these could be used to optimize treatment workflow for certain patients, increasing clinical efficiency while enhancing the quality of patient care. PMID- 28869143 TI - A novel urethral sparing technique for high-dose-rate prostate brachytherapy after transurethral resection of the prostate. AB - PURPOSE: The purpose of this study was to assess retrospectively the variability of the urethral dose optimized using a Foley catheter versus urethral contrast injected using a new modified triple-lumen catheter, in CT-based high-dose-rate (HDR) prostate brachytherapy of posttransurethral resection of prostate (TURP) patients. METHODS AND MATERIALS: At our institution, there were six post-TURP patients with prostate carcinoma between July 2014 and April 2016 who underwent transperineal interstitial HDR brachytherapy (16 needles). A custom modified triple-lumen catheter was placed to inject contrast into the TURP defect. Three dimensional optimal plans using inverse planning simulated annealing algorithm was generated according to radiation therapy oncology group dose requirements. Alternative plans were retroactively generated for comparison using standard technique based on a Foley catheter as a urethral constraint volume for each patient with the same weighting factors. We compared the dosimetry parameters in each planning using Wilcoxon's ranked sum nonparametric test. RESULTS: The median followup of all patients was 17.5 months. No significant genitourinary or gastrointestinal toxicity was noted using this technique. In the dosimetric analysis, the prostate V100 values and TURP urethral V100 were significantly different between plans with and without the contrast (V100 [mean]: 92.4 [%] vs. 94.4 [%], p = 0.046; TURP UV100 [mean]: 1.4 cc vs. 2.2 cc, p = 0.028). There were no statistical differences in the mean values of planning target volume V150%, V200%, and D90, and each bladder V75 and rectum V75. CONCLUSIONS: Post-TURP HDR brachytherapy with urethral contrast showed significantly more volume effect of the TURP defect than that with a Foley catheter alone. Better visualization of the TURP defect should lead to more accurate urethral sparing administration of HDR brachytherapy which is necessary to prevent urethral complication. PMID- 28869145 TI - The early diagnosis and management of mixed delirium in a patient placed on ECMO and with difficult sedation: A case report. AB - Delirium represents a serious problem that impacts the physical and cognitive prognosis of patients admitted to intensive care units and requires prompt diagnosis and management. This article describes the case and progress of a patient placed on Extracorporeal Membrane Oxygenation with difficult sedation criteria and an early diagnosis of mixed delirium. During the case report, we reflect on the pharmacological and non-pharmacological strategies employed to cope with delirium paying special attention to the non-use of physical restraint measures in order to preserve vital support devices (endotracheal tube or Extracorporeal Membrane Oxygenation cannula). The multimodal and multidisciplinary approach, focused on nursing interventions, strict Pain/Agitation/Delirium monitoring and pharmacological measures, as well as the implementation of measures according to the eCASH (early Comfort using Analgesia, minimal Sedatives and maximal Human Care) concept, were effective, resulting in a relatively short admission considering the severity of the patient's condition and the associated complications. Early independent ambulation was achieved prior to transfer to a hospitalisation unit. PMID- 28869146 TI - Intubation-associated pneumonia: An integrative review. AB - OBJECTIVE: This article aims to characterise intubation-associated pneumonia regarding its diagnosis, causes, risk factors, consequences and incidence. RESEARCH METHODOLOGY: Integrative literature review using database Pubmed and B on and webpages of organisations dedicated to this area of study. SETTING: The research took place between May and July 2015. After selection of the articles, according to established criteria, their quality was assessed and 17 documents were included. RESULTS: Evidence has demonstrated that intubation associated pneumonia has a multifactorial aetiology and one of its main causes is micro aspiration of gastric and oropharynx contents. Risk factors can be internal or external. The diagnostic criteria are based on clinical, radiological and microbiological data, established by several organisations, including the European Centres for Disease Control and Prevention, which are, however, still not accurate. In recent years, there has been a downward trend in the incidence in Europe. Nevertheless, it continues to have significant economic impact, as well as affecting health and human lives. CONCLUSIONS: Several European countries are committed to addressing this phenomenon through infection control and microbial resistance programmes; however there is a much to be done in order to minimise its effects. The lack of consensus in the literature regarding diagnosis criteria, risk factors and incidence rates is a limitation of this study. PMID- 28869147 TI - Challenges and factors likely to promote coping as anticipated by nurses preparing for a merger of intensive and intermediate care units. AB - OBJECTIVE: To describe challenges and factors that support coping as anticipated by nursing staff preparing for a merger of intensive and intermediate care units. RESEARCH METHODOLOGY: The method of empathy-based stories was employed to collect data from staff. The stories (n=20) were analysed using inductive content analysis. SETTING: Nursing staff from the cardiac observation and evaluation, intensive care and surgical observation units in a central hospital in Finland. FINDINGS: Participants anticipated challenges related to personal factors that affect coping at work, challenges in co-operation among nursing staff and problems associated with the new work context. Participants expected to need informational, concrete and social support from colleagues in future clinical nursing situations. CONCLUSION: Fostering peer support and team spirit is important to ensure staff co-operation and smooth care processes following restructuring. PMID- 28869148 TI - Estimation of critically ill patients' complaints by the nurse, the physician and the patient's family: A prospective comparative study. AB - OBJECTIVES: To evaluate the ability of the families of critically ill patients and of the intensive care team caring for the patient to communicate and accurately identify patients' complaints. DESIGN: The complaints of critically ill patients were evaluated by a psychologist using a list of 12 items. The same day as the patient interview, the psychologist collected an estimation of the patient's complaints from the family, the nurse and the physician. SETTING: 20 bed Intensive Care Unit in a large University Hospital. MAIN OUTCOME MEASURES: Patients' complaints. RESULTS: 51 patients were included. The most frequently reported complaints were insomnia, the inability to talk and presence of a tracheal tube. Patients reported a significantly higher prevalence of "misunderstanding" than that estimated by the nurses (55% vs 33%, p=0.045). The reported prevalence of "inability to talk" as the main complaint was significantly higher among patients than estimated by nurses and physicians (16% vs 2%, p=0.03 and 16% vs 2%, p=0.03 respectively). For the analysis of the individual complaints, there was a poor agreement between the patients and the other respondents. CONCLUSION: This study found that the estimation of critically ill patients' complaints by their families, nurses and physicians was largely suboptimal. PMID- 28869149 TI - The clinical surveillance process as carried out by expert nurses in a critical care context: A theoretical explanation. AB - BACKGROUND: Nursing Science presents surveillance as an indispensable component of patient safety. Although the literature defines surveillance fully, its implementation is not well understood. AIM: This research aims to formulate a theoretical explanation of the surveillance process that expert nurses employ in critical care. METHOD: To develop the theoretical explanation for the surveillance process of critical care nurses, Strauss and Corbin's (1998) grounded theory approach and Think Aloud Method (Fonteyn et al., 1993) were used with fifteen expert critical care nurses (n=15). FINDINGS: Surveillance in critical care is a continual process of collaborative vigilance that starts with the thought process and behaviour related to data collection, analysis and interpretation. The surveillance process comprises five key elements: 1) Managing the risk of complications; 2) Collecting data; 3) Detecting a problem; 4) Making a decision and 5) Working in synergy. CONCLUSION: In developing a theoretical explanation, this research leads to an understanding of the surveillance process performed by expert nurses in a critical care context. PMID- 28869150 TI - The association between hematological parameters and metabolic syndrome in Iranian men: A single center large-scale study. AB - AIMS: Some studies have demonstrated that metabolic syndrome is associated with hematological parameters. The present study explores the relationship between hematological parameters and numbers of metabolic syndrome conditions in Iranian men. METHODS: This cross-sectional study included 11,114 participants who were professional drivers of commercial motor vehicles, and were enrolled in the Iranian Health Surveys between 2014 and 2016. Diagnosis of metabolic syndrome was made according to International Diabetes Federation criteria. Clinical data, including anthropometric measurements and serum parameters, were collected. Odds ratios for hematological parameters and metabolic syndrome were calculated using binary logistic regression models. RESULTS: We found that hemoglobin; platelet, and white blood cell counts increased with increasing numbers of metabolic syndrome components (p<0.05 for all). The odds ratio of metabolic syndrome significantly increased across successive quartiles of platelet (1.00, 1.25, 1.29, and 1.51) and white blood cell counts (1.00, 1.51, 1.79, and 2.11) with the lowest quartile as the referent group. Similar associations for hemoglobin and hematocrit in the top quartile were also observed. We did not observe any significant difference in the mean of neutrophil count, mean platelet volume (MPV), red cell distribution width, or platelet distribution width among participants with or without metabolic syndrome. CONCLUSIONS: Our findings indicate that high levels of major hematological parameters such as hemoglobin, hematocrit, as well as platelet and white blood cell counts could be novel indicators for the development of metabolic syndrome. PMID- 28869151 TI - Energy expenditure, body composition, and prevalence of metabolic disorders in patients with Duchenne muscular dystrophy. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe muscular disease characterized by progressive loss of functional muscle mass followed by changes in body composition. AIM: To describe body composition, resting energy expenditure (REE), and metabolic disorders in DMD patients followed-up at a tertiary care center. To analyze the association with type of steroid and ambulatory status, and to compare obese DMD patients with patients with multifactorial obesity. POPULATION AND METHODS: A prospective, observational, cross-sectional study was conducted. Anthropometric measurements were taken, evaluating body composition with bioelectrical impedance analysis (BIA), REE with indirect calorimetry, and biochemical parameters in all DMD patients seen between June 2013 and April 2014. RESULTS: 63 boys between 5.4 and 18.7years of age were evaluated. Diagnosis of obesity ranged from 28% measuring body mass indexZ-score (BMIZ-score) to 70% using percentage of fat mass (%FM). Patients who had lost gait had a significantly higher %FM than those in whom gait was preserved (72% vs 46%, p<0.05). Insulin resistance was present in 29% associated with BMI Z-score and waist circumference and 40% had dyslipidemia associated with %FM, both of which were steroid independent. In obese DMD patients REE was lower than predicted and also lower than controls, and persist when dividing the patients into ambulators and non-ambulators. CONCLUSIONS: A high prevalence of obesity was observed. BMI-Z-score underestimates the degree of FM. No correlation was found between steroid type and body composition or metabolic disorders. No differences were found in REE between ambulators and non-ambulators. Obese DMD patients have a lower REE than controls. PMID- 28869152 TI - Effect of electronic education based on health promotion model on physical activity in diabetic patients. AB - BACKGROUND: By high prevalence of inactivity, particularly in diabetic patients, the need to effective interventions to promote physical activity is essential. The aim of this study was to determine the effects of education based on health promotion model (HPM) through multimedia on the physical activity in diabetic patients. METHOD: In this quasi-experimental study, 76 patients with type II diabetes were evaluated (40 patents in intervention group and 36 patients in control group). The intervention group members and a friend or a family member, that could be supportive in physical activity, received teaching CD based on health promotion model. Both group members at the beginning of the study, two weeks and three months after the training, completed questionnaires. After data collection, statistical analysis was conducted using independent T-test, chi square test, and repeated measurement of ANOVA. RESULTS: Finding showed that self efficacy (P<0.001), health status (p=0.032), benefits (P<0.001) and friends support in physical activity (P<0.001) were perceived to be higher, and barrier of physical activity (P<0.001) was perceived to be lower in multimedia group compared to control group 3 months after training. There was a significant difference in average of metabolic equivalent of task (MET) between two groups after the intervention (P<0.001). CONCLUSION: Planning of education based on the HPM and implementation through multimedia can change belief about physical activity and increase participation in physical activity. PMID- 28869154 TI - Hand hygiene in an era of healthcare complexity and antimicrobial resistance. PMID- 28869153 TI - A multi-faceted approach of a nursing led education in response to MERS-CoV infection. AB - BACKGROUND: The emergence of the Middle East respiratory syndrome-coronavirus (MERS-CoV) resulted in multiple healthcare associated outbreaks. In response, we developed a nurse-led program to screen and triage patients with MERS-CoV infection. METHODS: A formal educational program was implemented to ensure a standardized approach to care planning and delivery. The essential skills that were included were the use of Personal Protective Equipment (PPE) including gown, gloves, head cover and N95 mask, hand hygiene, the practice of donning and doffing and the collection of MERS-CoV nasopharyngeal specimens. RESULTS: A core group of nurses were identified from high-risk units. The education program consisted of four skill-days. Nurses were assigned a pre-course work from Mosby's Nursing Skills, an online skill module, donning and doffing of PPE, and the process for obtaining a nasopharyngeal swab. The skill lab incorporated multiple methods such group discussion, watching an on-line video, and a simulated demonstration and practice on a mannequin. In total, 450 nurses attended the Nasopharyngeal Skills Day and 1000 nurses received training. Donning and doffing PPE and N95 mask fit testing has become an annual mandatory competency requirement for staff in nursing and clinical services. CONCLUSION: The application of specified protocols minimizes the risks of cross infection, placing emphasis on patient and staff safety as well as expediting the patient to definitive treatment. Nurse educators have an instrumental role in training nurses and other healthcare providers on the specifics needed to identify, contain and manage patient presenting with MERS-CoV. PMID- 28869155 TI - Investigation of Chlamydia pneumoniae infection in Moroccan patients suffering from cardiovascular diseases. AB - Chlamydia pneumoniae is an intracellular bacterium responsible for respiratory diseases and is highly involved in cardiovascular disease development, mainly atherosclerosis. The main objective of our study was to evaluate C. pneumoniae prevalence in Moroccan patients suffering from cardiovascular diseases. A total of 115 patients with cardiovascular diseases were enrolled, and their clinical and behavioral information was recorded. Blood was sampled from all patients as well as the atheroma plaques from 36 patients undergoing surgery. Nested PCR was performed for C. pneumoniae DNA detection in both peripheral blood mononuclear cells (PBMCs) and atheroma plaques. Statistical analysis was performed using EpiInfo software. Data analysis showed cardiovascular disease dominance in men, with a sex ratio M/F of 3.4, a majority of tobacco users (52.2%), and many diabetics (44.3%). A significant difference between genders was shown for tobacco use (p<0.05). Positive cases for PBMCs and atheroma plaques were 61% and 86%, respectively, and a significant difference between PBMCs and atheroma plaque infection was identified (p=0.02). Data analysis also showed that 12% of patients presented only C. pneumoniae infection as a risk factor. Therefore, the high prevalence of C. pneumoniae suggests its involvement in atherosclerosis, and further investigation is recommended for confirmation. PMID- 28869156 TI - Molecular diagnosis of potentially human pathogenic Enterocytozoon bieneusi and Encephalitozoon species in exotic birds in Southwestern Iran. AB - Microsporidia are obligate intracellular parasites that produce spores. The infections caused by these parasites are mostly considered to be opportunistic in immunodeficient patients. Because of the zoonotic nature of microsporidia as well as the increasing prevalence of immunodeficiency diseases, the aim of this study was to evaluate the molecular diagnosis of Enterocytozoon bieneusi (E. bieneusi) and Encephalitozoon spp. in exotic birds in southwestern Iran. Initially, 816 stool specimens were collected and stained by modified trichrome (Weber) staining. The slides were explored using light microscopy. In the next stage, the extracted DNA was amplified using a multiplex/nested PCR method. RFLP with the Mnl1 restriction enzyme was used to differentiate the Encephalitozoon species in the products of the molecular analysis. Out of 816 samples, 138 and 181 cases were found to be positive by the staining and the multiplex/nested-PCR methods, respectively. Of the 181 samples, 103 and 78 samples were positive for E. bieneusi and Encephalitozoon spp., respectively. The Encephalitozoon species were 17 E. cuniculi, 52 E. intestinalis and 9 E. hellem. Of 103 E. bieneusi samples, 57, 39, 2 and 5 cases were detected as genotypes D, M, E and L, respectively. The results showed a relatively high prevalence of microsporidia in exotic birds, and according to the results of the genotyping, these birds can be an important source of microsporidiosis. It is essential that high-risk individuals, including patients with immunodeficiency diseases, receive accurate and valid information about the risk of direct and indirect contact with infected exotic birds. PMID- 28869157 TI - The contribution of long non-coding RNAs in Inflammatory Bowel Diseases. AB - Inflammatory bowel diseases (IBDs) are multifactorial autoimmune diseases with growing prevalence but the interaction between genetic, environmental and immunologic factors in their development is complex and remains obscure. There is great need to understand their pathogenetic mechanisms and evolve diagnostic and therapeutic tools. Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that are known to interfere in gene regulation but their roles and functions have not yet been fully understood. While they are widely investigated in cancers, little is known about their contribution in other diseases. There is growing evidence that lncRNAs play critical role in regulation of immune system and that they interfere in the pathogenetic mechanisms of autoimmune diseases, like IBDs. Recent studies have identified lncRNAs in the proximity of IBD-associated genes and single nucleotide polymorphisms within IBD associated lncRNAs as well. Furthermore, blood samples and pinch biopsies were also analyzed and a plethora of lncRNAs are found to be deregulated in Crohn's disease (CD), Ulcerative colitis (UC) or both. (Especially in UC samples the lncRNAs INFG-AS1 and BC012900 were found to be significantly up-regulated. Similarly, ANRIL, a lncRNA that nest different disease associated SNPs, is significantly down-regulated in inflamed IBD tissue.) This review aims at recording for the first time recent data about lncRNAs found to be deregulated in IBDs and discussing suggestive pathogenetic mechanisms and future use of lncRNAs as biomarkers. PMID- 28869158 TI - Re-bleeding rates and survival after early transjugular intrahepatic portosystemic shunt (TIPS) in clinical practice. AB - BACKGROUND: Early implantation (<72h) of a transjugular intrahepatic portosystemic shunt (TIPS) after acute variceal bleeding (AVB) improves survival in highly selected patients. METHODS: We retrospectively assessed bleeding control and survival of unselected cirrhotic patients undergoing early TIPS implantation within 72h. We compared the outcomes to patients meeting early TIPS criteria but receiving late TIPS within 3-28days after AVB and endoscopic/medical treatment. RESULTS: Forty-nine patients were included. Mean MELD was 14.4 (+/ 4.4). Thirteen patients (26.5%) presented characteristics that were exclusion criteria in previous early TIPS trials (age>75, CPS>13, HCC>Milan, previous beta blocker/band-ligation, renal insufficiency). Bare metal and PTFE-covered stents were used in n=32 (65.3%) and n=17 (34.7%) patients, respectively, and showed similar early re-bleeding rates (9.9% vs. 7.1%; p=0.6905) and bleeding-related mortality (25.0% vs. 23.5%; p=0.9906). However, overall re-bleeding rate was lower with PTFE-TIPS (7.7% vs. 64.2%; p=0.0044) over a median follow-up of 18.5 months with a tendency towards improved survival (median 70.5 vs. 13.8 months; p=0.204). Additional 68 patients meeting stringent criteria but receiving late TIPS also showed a favorable bleeding-related mortality (8.8%), which was not achieved in similar n=34 patients by a medical/endoscopic strategy with bleeding related mortality of 35.7%. CONCLUSIONS: An early TIPS strategy using covered stents and implementation of 'stringent criteria' results in a favorable outcome in patients with acute variceal bleeding. PMID- 28869159 TI - A Comparison of Objective Assessment Data for the United States and International Medical Graduates in a General Surgery Residency. AB - OBJECTIVE: To compare objective assessment scores between international medical graduates (IMGs) and United States Medical Graduates. Scores of residents who completed a preliminary year, who later matched into a categorical position, were compared to those who matched directly into a categorical position at the Mayo Clinic, Rochester. DESIGN: Postgraduate year (PGY) 1 to 5 residents participate in a biannual multistation, OSCE-style assessment event as part of our surgical training program. Assessment data were, retrospectively, reviewed and analyzed from 2008 to 2016 for PGY-1 and from 2013 to 2016 for PGY 2 to 5 categorical residents. SETTING: Academic medical center. PARTICIPANTS: Categorical PGY 1 to 5 General Surgery (GS) residents at Mayo Clinic Rochester, MN. RESULTS: A total of 86 GS residents were identified. Twenty-one residents (1 United States Medical Graduates [USMG] and 20 IMGs) completed a preliminary GS year, before matching into a categorical position and 68 (58 USMGs and 10 IMGs) residents, who matched directly into a categorical position, were compared. Mean scores (%) for the summer and winter multistation assessments were higher for PGY-1 trainees with a preliminary year than those without (summer: 59 vs. 37, p < 0.001; winter: 69 vs. 61, p = 0.05). Summer and winter PGY-2 scores followed the same pattern (74 vs. 64, p < 0.01; 85 vs. 71, p < 0.01). For the PGY 3 to 5 assessments, differences in scores between these groups were not observed. IMGs and USMGs scored equivalently on all assessments. Overall, junior residents showed greater score improvement between tests than their senior colleagues (mean score increase: PGY 1-2 = 18 vs. PGY 3-5 = 3, p < 0.001). CONCLUSIONS: Residents with a previous preliminary GS year at our institution scored higher on initial assessments compared to trainees with no prior GS training at our institution. The scoring advantage of an added preliminary year decreased as trainees progressed through residency. PMID- 28869160 TI - Evaluating the Use of Cleft Lip and Palate 3D-Printed Models as a Teaching Aid. AB - OBJECTIVE: Visualization tools are essential for effective medical education, to aid students understanding of complex anatomical systems. Three dimensional (3D) printed models are showing a wide-reaching potential in the field of medical education, to aid the interpretation of 2D imaging. This study investigates the use of 3D-printed models in educational seminars on cleft lip and palate, by comparing integrated "hands-on" student seminars, with 2D presentation seminar methods. SETTING: Cleft lip and palate models were manufactured using 3D-printing technology at the medical school. PARTICIPANTS: Sixty-seven students from two medical schools participated in the study. DESIGN: The students were randomly allocated to 2 groups. Knowledge was compared between the groups using a multiple choice question test before and after the teaching intervention. Group 1 was the control group with a PowerPoint presentation-based educational seminar and group 2 was the test group, with the same PowerPoint presentation, but with the addition of a physical demonstration using 3D-printed models of unilateral and bilateral cleft lips and palate. RESULTS: The level of knowledge gained was established using a preseminar and postseminar assessment, in 2 different institutions, where the addition of the 3D-printed model resulted in a significant improvement in the mean percentage of knowledge gained (44.65% test group; 32.16%; control group; p = 0.038). Student experience was assessed using a postseminar survey, where students felt the 3D-printed model significantly improved the learning experience (p = 0.005) and their visualization (p = 0.001). CONCLUSIONS: This study highlights the benefits of the use of 3D-printed models as visualization tools in medical education and the potential of 3D-printing technology to become a standard and effective tool in the interpretation of 2D imaging. PMID- 28869161 TI - Case report: A patient with malaria at the emergency department. PMID- 28869162 TI - A novel method for T2 quantification in presence of B1 inhomogeneities. AB - INTRODUCTION: T2 relaxometry as a quantitative MRI technique offers a more precise characterization of tissue, compared with qualitative T2 weighted imaging. The issue, however, is that in typically used T2 relaxometry sequences such as a multi-spin echo sequences, incorrect refocussing flip angles and B1 inhomogeneities cause inaccuracies in T2 determination. The work presented here within presents a new technique for modelling T2 decay curves and thereby correcting T2 times altered by inhomogeneities. MATERIALS AND METHODS: The proposed technique models the signal decay acquired by multi-spin echo sequences based on extended phase graph theory. We have then put this new correction technique to test under both noise free and noise affected simulated signal and compared it to other previously introduced correction methods. To compare the efficacy of the T2 correction techniques, it was applied to MRI data acquired at 9.4Tesla. RESULTS AND CONCLUSION: The results show that the proposed technique is able to minimize the systematic error in T2 relaxometry for a wide range of T2 times. Beyond that, the technique reveals the actual refocussing pulse angle in the respective voxel and reduces the error in So, which is mandatory if one aims for quantification of proton density. PMID- 28869163 TI - Biologically adapted radiation therapy. AB - The aim of biologically adapted radiotherapy (RT) is to shape or paint the prescribed radiation dose according to biological properties of the tumor in order to increase local control rates in the future. Human tumors are known to present with an extremely heterogeneous tissue architecture leading to highly variable local cell densities and chaotic vascular structures leading to tumor hypoxia and regions of increased radiation resistance. The goal of biologically adapted RT or dose painting is to individually adapt the radiation dose to biological features of the tumor as non-invasively assessed with functional imaging in order to overcome increased radiation resistance. This article discusses the whole development chain of biologically adapted RT from radio biologically relevant processes, functional imaging techniques to visualize tumor biology non-invasively and radiation prescription functions to the implementation of biologically adapted RT in clinical practice. PMID- 28869164 TI - The output factor correction as function of the photon beam field size - direct measurement and calculation from the lateral dose response functions of gas filled and solid detectors. AB - The first aim of this study has been to extend the systematic experimental study of the field size dependence of the output factor correction for three micro ionization chambers (PTW 31014, PTW 31022 and IBA Razor chamber), two silicon diodes (PTW 60017 and IBA Razor Diode) and the synthetic diamond detector microDiamond (PTW 60019) in a 6 MV photon beam down to an effective field side length of 2.6mm, and to summarize the present knowledge of this factor by treating it as a function of the dosimetric field size. In order to vary the dosimetric field size over this large range, output factors measurements were performed at source-to-surface distances of 60cm and 90cm. Since the output factors obtained with the organic scintillation detector Exradin W1 (Standard Imaging, Middleton, USA) at all field sizes closely agreed with those measured by EBT3 radiochromic films (ISP Corp, Wayne, USA), the scintillation detector served as the reference detector. The measured output correction factors reflect the influences of the volume averaging and density effects upon the uncorrected output factor values. In case of the microDiamond detector these opposing influences result in output factor correction values less than 1 for moderately small field sizes and larger than 1 for very small field sizes. Our results agree with most of the published experimental as well as Monte-Carlo simulated data within detector-specific limits of uncertainty. The dosimetric field side length has been identified as a reliable determinant of the output factor correction, and typical functional curve shapes of the field-size dependent output factor correction vs. dosimetric field side length have been associated with gas-filled, silicon diode and synthetic diamond detectors. The second aim of this study has been a novel, semi-empirical approach to calculate the field-size dependent output correction factors of small photon detectors by convolving film measured true dose profile data with measured lateral response functions of the detectors. To achieve this, the set of previously published 2D lateral dose response functions was complemented by those of the novel detectors PTW PinPoint chamber 31022 (PTW Freiburg, Freiburg, Germany), Razor chamber and Razor Diode (IBA Dosimetry, Schwarzenbruck, Germany). The output correction factors calculated from the lateral dose response functions closely fit with the directly measured output correction factors, thus supporting the latter by an independent method. PMID- 28869165 TI - Concurrent bariatric surgery and paraesophageal hernia repair: comparison of sleeve gastrectomy and Roux-en-Y gastric bypass. AB - BACKGROUND: Paraesophageal hernia (PEH) is a common condition that bariatric surgeons encounter. Expert opinion is split on whether bariatric surgery and PEH repair should be completed concurrently or sequentially. We hypothesized that concurrent bariatric surgery and PEH repair is safe. OBJECTIVES: We examined 30 day outcomes after concomitant PEH repair and bariatric surgery. SETTING: National database, United States. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database (2011-2014), we identified patients who underwent laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) with or without PEH repair. A propensity score-matching algorithm was used to compare patients who underwent either LRYGB or LSG with PEH repair. The primary outcome was overall morbidity. Secondary outcomes included mortality, serious morbidity, readmission, and reoperation. RESULTS: Of the 76,343 patients in this study, 5958 (7.80%) underwent PEH repair concurrently with bariatric surgery. The frequency of bariatric operations that included PEH repair increased over time (2.14% in 2010 versus 12.17% in 2014, P<.001). The rate of PEH/LSG was higher than PEH/LRYGB in 2014 (8.9 % versus 3.2%). There were no significant differences in outcomes between the matched cohort of PEH and non-PEH patients. Subgroup analysis showed significantly greater rates of morbidity (6.20% versus 2.69%, P<.001), readmission (6.33% versus 3.06%, P<.001), and reoperation (3.00% versus 1.05%, P<.001) for PEH/LRYGB versus PEH/LSG. CONCLUSIONS: A PEH repair at the time of bariatric surgery does not appear to be associated with increased morbidity or mortality. A concurrent approach to treat patients with severe obesity and PEH appears safe. PMID- 28869166 TI - Surgical management of enterolith ileus after Roux-en-Y gastric bypass. PMID- 28869167 TI - Determinants associated with the correction of glomerular hyper-filtration one year after bariatric surgery. AB - BACKGROUND: Increased adipokine production and hyperfiltration may explain the links between obesity and chronic kidney disease. Indeed, hyperfiltration may precede a subsequent accelerated decline of kidney function in these patients. Glomerular filtration rate decreases after bariatric surgery in young obese patients with hyperfiltration. OBJECTIVE: Our aim was to identify the factors associated with this decrease 1 year after bariatric surgery. SETTING: We used data from a prospective cohort of severely obese patients who underwent bariatric surgery in Nice University Hospital. METHODS: We analyzed 175 patients before and 1 year after bariatric surgery. Low-grade inflammation was evaluated by serum C reactive protein levels. Lean body mass and fat body mass were estimated by bioelectric impedance analysis. Body surface area was assessed by the Du Bois formula. Serum creatinine levels were used to estimate glomerular filtration rate by the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation. Glomerular filtration rate was de-adjusted from standard body surface area and then divided by lean body mass to calculate the decrease in hyperfiltration and to separate the patients into 2 groups: above or below the median decrease of hyperfiltration after bariatric surgery. RESULTS: The factors associated with a large correction of hyperfiltration were baseline C-reactive protein levels (10.0 +/- 5.8 mg/L versus 12.7 +/- 7.4 mg/L, P = .01) and brachial circumference (41 +/ 4 cm versus 44 +/- 5 cm, P = .006). A high fat mass reduction rate was significantly associated with a substantial hyperfiltration reduction after bariatric surgery (P<.001) independently of sex and surgical procedure. CONCLUSIONS: The correction of hyperfiltration is associated with a high reduction rate of fat mass after bariatric surgery but may be limited by low grade inflammation. PMID- 28869168 TI - ? AB - OBJECTIVES: The aim of this study was to assess the impact of the aggressiveness of cancer cells at the level of positive surgical margins (PSM) on the biochemical recurrence rate (BRR) by studying the Gleason score (GS) at this level. METHODS: We included all radical prostatectomy (RP) procedures performed from January 2007 to November 2011. All of the RP specimens with PSM were reviewed to determine the GS at the level of PSM. We compared the GS at PSM with BRR. RESULTS: A total of 658 RP were analysed, among which 16% had PSM. From the 101 patients with PSM included, 32% had biochemical recurrence (BR) with a median follow-up of 38 months. GS at PSM was significantly associated with earlier BR (P=0.008). Univariate analysis showed that GS at PSM (P=0.013), initial PSA (P<0.0001), pathologic GS (P<0.001), length of PSM (P=0.013), and seminal vesicle invasion (P<0.0001) were predictors of BR. Multivariate analysis confirmed that PSA greater than 10ng/mL and length of PSM greater than 3mm were independent prognostic factors for BR, but GS at the level of PSM was not. CONCLUSION: GS at PSM was not confirmed as an independent risk factor for BR. Initial PSA greater than 10ng/mL and length of PSM greater than 3mm were the sole independent predictors for BR. LEVEL OF PROOF: 4. PMID- 28869169 TI - [Temocillin and urinary tract infections]. AB - INTRODUCTION: Temocillin is an alternative to treat urinary tract infections with bacteria producing extended spectrum beta-lactamase (ESBL). The objective is to evaluate the use of temocillin in urinary tract infections. MATERIALS AND METHODS: A systematic review of literature was carried out according to PRISMA criteria. All national and international recommendations have been reviewed regarding the indication of the use of temocillin in urology. Data collection on the use of temocillin in urinary tract infection has been performed from the Cochrane, LILACS and the Medline database. The following keywords were used: temocillin, extended spectrum beta-lactamase, urinary tract infections, urine, prostate, epididymis, testis, diffusion, pharmacokinetics, pharmacodynamics. The selection was based on the methodology, language of publication (English/French), relevance to the topic and date of publication of the articles collected. The endpoint was to provide exhaustive scientific information allowing urologists to use this antibiotic in febrile urinary infections. RESULTS: Bacteria producing ESBL has a relatively high susceptible to temocillin, ranging from 61 % to 90 %. These rates would allow its use in probabilistic. The dosage recommended is currently, in the normo-renal patient, 4g per day by intermittent infusion or continuously after a loading dose of 2g. Some studies argue, particularly in case of difficult clinical situations or obese patients, for administration of high doses (6g/24h) rather continuous infusion. There is no evident relationship between high doses and side effects. With an excellent urinary and prostatic diffusion, temocilllin might be recommend for the treatment of ESBL prostatitis. CONCLUSION: Temocillin is known to have good urinary and prostatic diffusion. According to our results, this antibiotics is now a reliable alternative for the treatment of documented ESBL urinary tract infections. LEVEL OF EVIDENCE: 4. PMID- 28869170 TI - [Safety and feasibility of outpatient flexible ureteroscopy for urinary stones: A retrospective single-center study]. AB - AIM: Management of urolithiasis has changed over the past decades. Outpatient surgery has become a major issue for healthcare systems. The aim of this study was to assess the feasibility of outpatient flexible ureteroscopy. METHODS: A single-center retrospective study has been conducted including all patients who underwent an outpatient flexible ureteroscopy between January 2012 and December 2013. Failure of outpatient management was defined as length of hospital stay>12 hours or readmission within 48 hours after discharge. Univariate analysis was performed to seek for predictors of failure of outpatient management. RESULTS: One hundred and fifty-seven patients who underwent a total of 174 procedures were included. They were mostly men (57.5 %), with a mean body mass index of 25.2kg/m2 (+/-4.3). The stones were mostly unique (64.3 %), with a mean size of 14.2mm (+/ 11.2). Eighty patients had a double J stent preoperatively (46.5 %), and mean operative time was 64.2 minutes (+/-34.1). An ureteral access sheath was used in 39 procedures (22.4 %). A double J stent was left postoperatively in 103 patients (59.1 %). In total, 165 procedures (94.8 %) were performed successfully as outpatient surgery. On postoperative imaging, the stone-free rate was 69.5 %. Postoperative complications occurred in 3.4 % of cases and were mostly minor (i.e. Clavien 1-2; 83.3 %). Predictive factors of failed outpatient management were male gender (P=0.04), BMI (P=0.03), and anticoagulants intake (P=0.003). CONCLUSION: Outpatient flexible ureteroscopy for urinary stones is feasible and its low failure and complications rate may allow a wider spread of its use. LEVEL OF EVIDENCE: 4. PMID- 28869171 TI - [Physiological hydronephrosis in pregnancy: Occurrence and possible causes. An MRI study]. AB - INTRODUCTION: The etiology of the uretero-hydronephrosis in pregnancy is just hypothesis: hormonal or mechanical hypothesis, only investigated by echographic studies. MRI permits to visualize the entirety of the urinary tract, which can be helpful to find out a mechanical cause. METHODOLOGY: We have analysed the MRI of 100 asymptomatic pregnant women. We have determined the number and locations of the uretero-hydronephroses and researched whether there is any relationship between the uretero-hydronephrosis and certain abdominal structures. We focused on the psoas muscle and measured its depth, width and calculated its surface by a reproducible method. RESULTS: The analysis revealed that the uretero hydronephrosis was predominantly at the right side (63%) and in the majority of the cases limited to the kidney (42%) and/or the proximal third of the ureter (42%). We were able to rule out some proposed etiologies: a compression of the ureter between the uterus and the iliac or ovarian vessels; a protective effect of the left intestinal structures. A link was observed between the psoas muscle and the physiological uretero-hydronephrosis: the ipsilateral psoas muscle seemed smaller in pregnant women presenting a uretero-hydronephrosis. CONCLUSION: We have highlighted a link between a physiological uretero-hydronephrosis during pregnancy and a lesser developped psoas muscle. The hypothesis proposed is that a smaller psoas muscle would have a less protective effect of the ureter due to a lesser development. This study offers a practical conclusion: a left sided uretero-hydronephrosis during pregnancy and/or including the entirety of the ureter is more probably a pathological hydronephrosis. LEVEL OF EVIDENCE: 4. PMID- 28869172 TI - [Double J stent removal's cost estimate using a re-sterilizable fibroscope in a French private structure]. AB - : In front of the arrival of new devices intended to simplify the removal of double J stent, it poses the problem of the knowledge of the real cost of such an ablation under the current conditions of realization. MATERIAL AND METHOD: This is a monocentric economic evaluation of cost and remuneration needed data gathering of quotation (CCAM, GHS/SE, ...), estimate of the associated costs of wear and damping of the endoscopic equipments (endoscopes, cables, ...), estimate of the cost of sterilization, estimate of the associated costs to the intervention of staff (Auxiliary nurse [AS] and Nurse [IDE]) with timing of the various tasks. RESULTS: Quotation CCAM JCGE004 (48?) gives access to fixed price SE1 (73.71? for private clinic, and 75.89? for public institution) without hospitalization nor anaesthesia. The costs were reported to an act of single double J removal. Concerning the equipments: 4.42?HT for the fibroscopes, graspers, cable and light. The costs of sterilization were: 17.95?HT. The timed workforce's costs were: 7.61-9.51? for AS and 9.92-10.84? for IDE. The cost of consumable was about 1.37 ?HT, by excluding the common base from the extractions (1.876?HT). The total costs in France in 2016 were thus about 47.4 to 50.496? including all taxes. CONCLUSIONS: This estimate will be used certainly for reflection on the investments and the future studies of the economic impact of the new devices of extraction, by correlating it of course with the various maintenance contracts from each institution. LEVEL OF PROOF: 4. PMID- 28869173 TI - [Ablative therapy in kidney cancer: Indications]. AB - BACKGROUND: Ablative therapies (AT) in kidney cancer are rising. It's important to evaluate the situation of this therapy. The aim of this study is to identify the best indications for AT treatment for kidney cancer. METHODS: Review of literature using Medline and Embase databases. Study were selected based on scientific relevance. Clinical keys centered on the best requirements to indicate ablative therapies. RESULTS: AT is indicated according to specific tumor and patients criteria. A good initial evaluation is essential (imaging, pathology, renal function and general condition of the patient). AT gets the best results when applied to the following tumor criteria: solid tumor, length<3cm, exophytic localization, RENAL score<8. In few cases, AT could be discussed as an alternative to the reference treatment, sparing surgery: life expectancy evaluated between 3 and 7 years, chronic renal failure or single kidney, transplanted kidney, familial tumors. AT can be used in first line, post-surgery after local recurrence or for distant metastasis. Like every other innovative technic, indications of AT would be adjust with learning curve and cost effectiveness. CONCLUSION: AT have to be included as a valid treatment for kidney cancer<4cm. The respect of actual indications and collection of results of AT compared to surveillance and surgery, would determinate the evolution of AT indications in the future. PMID- 28869174 TI - Association between missing tooth count and mortality: A systematic review. AB - PURPOSE: The purpose of this review was to analyze existing literature on the relationship between tooth count and mortality by evaluating the findings in the context of methodological variations. We aimed at addressing the question of whether preserving natural teeth can impact mortality. STUDY SELECTION: PubMed, Web of Science and CINAHL databases were systematically searched using various combinations of related and synonymous keywords for "tooth count" and "mortality". The references of included articles were also evaluated for inclusion. Overall 49 studies found to be eligible were critically evaluated and their key findings were summarized. RESULTS: Studies were conducted in various continents and differed substantially in regards to their sample size, population, methodology, the definition of the tooth count variable, the confounders as well as the mediators accounted for in the analysis. Follow-up period ranged from 1 to 56 years. CONCLUSIONS: Although high variability in the studies precludes a definite conclusion about the relationship between number of teeth and mortality, the overall finding from this review is that reduced tooth count is associated with higher mortality. However the impact of factors such as smoking, health-care access, baseline co-morbidity and risk profile, dental and periodontal health, the presence of dental prosthesis as well as socio-economic status, in mediating whole or part of the association cannot be overlooked and needs further investigation using more standard methodologies. Any differences in males vs. females, as well as among different age groups, will also need further consideration in the future studies. PMID- 28869175 TI - Axillobifemoral bypass graft infection diagnosed with 18F-FDG PET/CT. PMID- 28869176 TI - 11C-PIB retention patterns in white and grey cerebral matter in idiopathic normal pressure hydrocephalus patients. A visual analysis. AB - OBJECTIVE: Cortical cerebral amyloid disease, a hallmark of Alzheimer's disease, has also been observed in idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to compare the 11C-PIB PET/CT retention pattern in iNPH patients and healthy subjects. MATERIAL AND METHODS: A comparison was made of the 11C-PIB PET/CT retention pattern in 13 iNPH patients selected for surgical deviation, compared to a normal control population. Images were visually analyzed and scored for gray matter and white matter (WM) from 1 to 4 (slight to very high PIB retention). The scoring was analyzed in both groups separately for infra- and supra-tentorial regions. A comprehensive clinical report was presented in terms of positive, negative, or equivocal. RESULTS: 11C-PIB PET/CT scan were reported as negative in 8, positive in 3, and equivocal in 2. Five of 13 patients showed at least one cortical area with PIB retention with an intensity higher than that observed in the control group. Overall, white matter (WM) PIB retention of iNPH scored lower than in the control group, showing a statistically significant difference in the infratentorial WM (92/104 vs 54/56; p<.05) and a tendency to be lower in the supratentorial regions (70/84 vs 122/156, p=.327), in particular in the upper periventricular region (25/28 vs 40/52; p=.134). CONCLUSIONS: The PIB retention pattern seems to be different in NPH, compared to normal subjects. PIB retention in WM of NPH appears less intense than in healthy subjects, and they show a higher degree of PIB retention in cortical regions. This deserves to be taken it into account. PMID- 28869178 TI - Review of the role of the sentinel node biopsy in neoadjuvant chemotherapy in women with breast cancer and negative or positive axillary node at diagnosis. AB - The role of the selective sentinel node biopsy (SNB) is increasing in relevance in breast cancer women with indication of neoadjuvant chemotherapy (NAC). The Radiosurgery Working Group of the SEMNIM is aware of the necessity of establishing the need for SNB before or after NAC, and also how to manage patients with axillary node-negative or node-positive. There is sufficient data to assess that the SNB with radioisotope techniques are feasible and safe in all these scenarios. An adequate axilla evaluation prior to surgery and the possibility of marking prior to NAC the nodes infiltrated must be the two main pillars to guarantee the success of the SNB. It has been shown that to incorporate the SNB in breast cancer women with indication of NAC increases the rate of a conservative treatment of the axilla that will be a clear benefit for these patients. PMID- 28869179 TI - [Discussion of the medico legal aspects of an unusual request for pregnancy termination]. PMID- 28869177 TI - Correlation of 18F-FDG uptake on PET/CT with Ki67 immunohistochemistry in pre treatment epithelial ovarian cancer. AB - OBJECTIVE: Standardised uptake value (SUV) and volumetric parameters such as metabolic tumour volume (MTV) and total lesion glycolysis (TLG) from 18F-FDG PET/CT are useful criteria for disease prognosis in pre-operative and post treatment epithelial ovarian cancer (EOC). Ki67 is another prognostic biomarker in EOC, associated with tumour aggressiveness. The aim of this study is to evaluate the association between 18F-FDG PET/CT measurements and Ki67 in pre treatment EOC to determine if PET/CT parameters could non-invasively predict tumour aggressiveness. MATERIAL AND METHODS: A pre-treatment PET/CT was performed on 18 patients with suspected or newly diagnosed EOC. Maximum SUV (SUVmax), mean SUV (SUVmean), whole-body MTV (wbMTV), and whole-body TLG (wbTLG) with a threshold of 30% and 40% of the SUVmax were obtained. Furthermore, Ki67 index (mean and hotspot) was estimated in tumour tissue specimens. Immunohistochemical findings were correlated with PET parameters. RESULTS: The mean age was 57.0 years old (standard deviation 13.6 years). A moderate correlation was observed between mean Ki67 index and SUVmax (r=0.392), SUVmean 30% (r=0.437), and SUVmean 40% (r=0.443), and also between hotspot Ki67 index and SUVmax (r=0.360), SUVmean 30% (r=0.362) and SUVmean 40% (r=0.319). There was a weaker correlation, which was inversely negative, between mean and hotspot Ki67 and volumetric PET parameters. However, no statistical significant differences were found for any correlations. CONCLUSIONS: SUVmax and SUVmean were moderately correlated with Ki67 index, whereas volumetric PET parameters overall, showed a weaker correlation. Thus, SUVmax and SUVmean could be used to assess tumour aggressiveness in pre-treatment EOC. PMID- 28869180 TI - [Observational study of a social device for women in precarious situations during pregnancy and post-partum]. AB - OBJECTIVES: To assess the impact of the Regional experimental accompanying nutrition and breast-feeding for pregnant women (PRENAP) 75 social device on the duration of postpartum hospitalization and breast-feeding for pregnant women in precarious situation. METHODS: A retrospective observational study took place between November 2013 and May 2015 in a type III Parisian maternity. Comparison of sociodemographic, perinatal and postpartum characteristics of women in precarious situations (no stable housing and no social care or universal medical coverage or state medical aid) was done according to whether they were included in the system PRENAP or not. RESULTS: Over the study period, 344 (4.6%) women in precarious situations gave birth in this maternity. Among these women, the women included in the PRENAP system were more frequently in a very unfavorable social situation than those who were not included. The inclusion in the PRENAP device did not reduce the hospitalization in post-partum. Breast-feeding was chosen more frequently by the women included in the PRENAP device. CONCLUSION: The PRENAP device seems to favor the use of breast-feeding, but is not associated with a diminution of the hospitalization time in post-partum. This social device, which seems to be beneficial in terms of social and medical support for women in precarious situations, deserves to be evaluated prospectively. PMID- 28869181 TI - [Impact of osteopathic manipulative therapy in patient with deep with colorectal endometriosis: A classification based on symptoms and quality of life]. AB - OBJECTIVES: A prospective study to evaluate the clinical impact of osteopathic manipulative therapy (OMT) on symptoms and quality of life (QOL) of patients with colorectal endometriosis. METHODS: Forty-six patients with colorectal endometriosis completed the SF-36 QOL and symptoms questionnaire before and after OMT. A comparison and clustering analysis was performed to identify subgroups of patient's profile and symptom classification. RESULTS: The mean age of the patients was 32+/-6.2 years. Prior surgery for endometriosis was recorded in 73.9 % of cases but none for deep infiltrating endometriosis. About three-quarters of the patients were nulliparous. The time between pre- and post-OMT completion of questionnaires was 28 days (15-63), A significant improvement in SF-36 QOL physical component summary (P<0.001) and mental component summary (P<0.001) was observed after OMT. Similarly, a significant improvement in gynecological, digestive and general symptoms values was observed. A clustering analysis allowed to identify four profiles of patients with colorectal endometriosis based on symptoms and a respective OMT gain of 30 %, 60 %, 64 % et 45 %. CONCLUSIONS: Our results support that OMT improve QOL and endometriosis symptoms of patients with colorectal endometriosis. Moreover, this symptom classification based on OMT gain can serve to design future randomized trial. PMID- 28869182 TI - [Predictive factors of conservative breast surgery after neoadjuvant chemotherapy for breast cancer]. AB - OBJECTIVES: The aim of our study was to evaluate the existence of predictive factors of conservative breast surgery after neoadjuvant chemotherapy (NAC) for breast cancer. METHODS: We included all women with invasive breast cancer who received NAC and underwent breast surgery between January 2007 and December 2013 in our institution. Univariable and multivariable analyses were performed to determine the association between clinical and histological factors and conservative breast surgery. RESULTS: During the study period, 229 women were included of whom 73 had breast conservative surgery (32%). At univariable analysis, significant predictive factors were age (OR 0.97 [CI 95% 0.95-0.99], P=0.02), radiological size (OR 0.97 [CI 95% 0.96-0.99], P<0.001), multifocality (OR 0.53 [CI 95% 0.27-1.05], P=0.06), breast inflammation (OR 0.15 [CI 95% 0.07 0.32], P<0.001) and the type of hormone receptors (P=0.12). In multivariable analysis, all these factors but age were significant factors and thus considered as independent predictive factors. CONCLUSION: This work permitted to identify independent predictive factors of breast conservative surgery after NAC for breast cancer that will be included in a risk scoring system that we aim to evaluate prospectively. PMID- 28869183 TI - Complete genome sequence of Pseudoalteromonas espejiana DSM9414T, an amino-acid requiring strain from seawater. AB - Strain DSM9414, the type strain of Pseudoalteromonas espejiana, is a Gram negative, and amino-acid-requiring stain isolated from seawater off the coast of Northern California. In this study, we report the complete genome sequence of Pseudoalteromonas espejiana DSM9414T. The genome (4,500,451bp; 40.3% G+C) is composed of two circular chromosomes: chromosome I is 3,720,756bp with 40.4% G+C content and chromosome II is 779,695bp with 39.8% G+C content. Genomic analysis showed that chromosome I encodes a complete set of ABC transporters responsible for branched-chain amino acids, whose homologous proteins were not discovered in other Pseudoalteromonas genomes released. This result indicated the tight dependence of extracellular amino acids for strain DSM9414T, which is consistent with its phenotype. The complete genome sequence of P. espejiana provides further genetic insights into the diversity of dependence on extracellular amino acids for Pseudoalteromonas species. PMID- 28869184 TI - The Treatment Landscape of Myelofibrosis Before and After Ruxolitinib Approval. AB - INTRODUCTION/BACKGROUND: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that presents with a heterogeneous clinical phenotype and prognosis. Before the US Food and Drug Administration approval of ruxolitinib, treatment options were varied and had limited effect. The increased use of ruxolitinib has drastically altered the MF treatment landscape. In this study, we aimed to clarify the clinical situations in which ruxolitinib is being used and analyze its effect on this landscape. PATIENTS AND METHODS: We retrospectively assessed treatment choices for MF patients treated at our institution (n = 309). This population was divided into 2 cohorts on the basis of a diagnosis before (cohort BR: n = 174) or after (cohort AR: n = 135) ruxolitinib approval. Cohorts were further stratified for comparison according to presenting clinical factors. RESULTS: Expectedly, the first-line use of ruxolitinib markedly increased after its approval. AR patients were less likely to receive erythropoiesis-stimulating agents (ESAs; P = .0003) and thalidomide (P = .003) than BR patients. In patients with MF-related symptoms and/or splenomegaly, increased use of ruxolitinib was associated with decreased use of first-line ESA (P = .03) or thalidomide (P = .03). In anemic patients, increased use of first-line ruxolitinib was associated with a decreased use of thalidomide (P = .007). In patients with severe leukocytosis, ruxolitinib use did not significantly increase and hydroxyurea was the preferred first-line agent. CONCLUSION: Overall, the increased use of ruxolitinib appears to have come predominantly at the expense of thalidomide and ESAs, while not having a large effect on the first-line use of hydroxyurea. PMID- 28869185 TI - Gait variability and motor control in patients with knee osteoarthritis as measured by the uncontrolled manifold technique. AB - Knee osteoarthritis (OA) causes pain, reduced muscular strength and stiffness of the affected joint. In response, the motor control mechanism is altered, potentially compromising stability during acts of daily living. Reduced walking stability can be quantified in terms of gait variability. This study therefore aimed to identify and quantify the effects of knee arthritis on gait variability. Fifty adults (25 males/25 females) with end-stage OA of the knee sufficiently symptomatic to require joint replacement, walked on a self-paced treadmill for 2min. A motion capture system was used to record 50 consecutive gait cycles from each patient. Kinematic variability of gait was analysed using the uncontrolled manifold technique (UCM). The position of the centre of mass (COM) was chosen as the task variable for the analysis. Results showed that our patient cohort were able to maintain a stable COM whilst walking, through adopting variable combinations of hip, knee and ankle kinematics. The greatest magnitudes of instability (based on the UCM ratios) occurred during initial contact and terminal stance. Active extension of the knee joint to approximately 5 degrees is required during these gait cycle events, meaning that these gait events are highly quadriceps dependent. This study identified and quantified components of the gait cycle where patients with knee OA are most unstable. Employment of this technique could therefore allow specific personalised prescription for prehabilitation and rehabilitation. PMID- 28869186 TI - Neural Noise Hypothesis of Developmental Dyslexia: (Trends in Cognitive Sciences 21, 434-448, 2017). PMID- 28869187 TI - Growth of Legionella anisa in a model drinking water system to evaluate different shower outlets and the impact of cast iron rust. AB - Legionella continues to be a problem in water systems. This study investigated the influence of different shower mixer faucets, and the influence of the presence of cast iron rust from a drinking water system on the growth of Legionella. The research is conducted using a model of a household containing four drinking water systems. All four systems, which contained standard plumbing components including copper pipes and a water heater, were filled with unchlorinated drinking water. Furthermore, all systems had three different shower faucets: (A) a stainless-steel faucet, (B) a brass-ceramic faucet, and (C) a brass thermostatic faucet. System 1 was solely filled with drinking water. System 2 was filled with drinking water, and cast iron rust. System 3 was contaminated with Legionella, and system 4 was contaminated with a Legionella, and cast iron rust. During a period of 34 months, 450 cold water samples were taken from 15 sample points of the four drinking water systems, and tested for Legionella according to the Dutch Standard (NEN 6265). In system 4, with added cast iron rust, the stainless-steel mixer faucet (A) had the highest concentration of Legionella at >4.3log10CFU/l (>20,000CFU/l) and was positive in 46.4% of samples. In contrast, the stainless-steel mixer faucet (A) of system 3 without cast iron rust showed 14.3% positive samples with a maximum concentration of 3.9log10CFU/l (7600CFU/l) Legionella. Additionally, both contaminated systems (3 and 4), with the brass thermostatic faucet (C), tested positive for Legionella. System 3 in 85.7% of the samples, with a maximum concentration of 4.38log10CFU/l (24,200CFU/l), and system 4 in 64.3% of the samples with a maximum concentration of 4.13log10CFU/l (13.400CFU/l). These results suggest that both the type of faucet used in a drinking water system and the presence or absence of cast iron rust influence the growth of Legionella. PMID- 28869188 TI - Risk assessment of environmental exposure to heavy metals in mothers and their respective infants. AB - Exposure to heavy metals can cause renal injury, which has been well documented in occupational exposure. Studies of low exposure in the general population, however, are still scarce, particularly for vulnerable populations such as mothers and young children. This study evaluated exposure to heavy metals, and biomarkers of renal function and oxidative stress in 944 lactating mothers and their infants and investigated the role of the interaction between heavy metals and oxidative stress in altering renal function. Mother and infant urine samples were analyzed to measure mercury (Hg), cadmium (Cd), and lead (Pb) concentrations for determining body-burden exposure; N-acetyl-beta-d-glucosaminidase (NAG), alpha1-microglobulin (alpha1-MG), albumin (ALB), and creatinine (Cr) concentrations for determining early renal injury; and 8-hydroxy-2-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) concentrations for determining oxidative stress. The median concentrclearlyations in mothers presented as MUg/g Cr (infants as MUg/l) for Hg, Cd, and Pb were 0.695 (0.716), 0.322 (0.343), and 3.97 (5.306) respectively. The mothers and their infants had clearly been exposed to heavy metals and had levels higher than the reference values reported for the general populations of USA, Germany, and Canada. Multiple regression analyses clearly demonstrated associations between urinary heavy metals in quartiles and several renal and oxidative biomarkers in mothers and to a lesser extent their infants. beta coefficients for urinary excretions of MDA, 8-OHdG, ALB, alpha1-MG, NAG, and Cr in mothers were high in the highest quartile of Hg (1.183-51.29MUg/g Cr or 1.732-106.95MUg/l), Cd (0.565-765.776MUg/g Cr or 0.785-1347.0MUg/l), and Pb (6.606-83.937MUg/g Cr or 9.459-80.826MUg/l), except Pb was not associated with ALB. Infants in the highest Pb quartile (9.293-263.098MUg/l) had the highest beta coefficients of urinary excretion of MDA, 8-OHdG, ALB, NAG, and Cr. Significant increasing trend in biomarkers across the quartiles of the three metals was seen in both mothers and infants (ptrend <0.001). A receiver operating characteristic analysis supported the predictive abilities of the four renal biomarkers in discriminating between low versus high metal quartiles. The interaction between heavy metals and oxidative stress contributed to the high excretions of renal biomarkers, but the mechanism remains unclear. These findings add to the limited evidence that low exposure to heavy metals in the general population is associated with alterations in renal function that could eventually progress to renal damage if exposure continues and that children are more susceptible due to the immaturity of their body organs. PMID- 28869189 TI - Status of small water supplies in the Nordic countries: Characteristics, water quality and challenges. AB - Access to safe water is essential for public health and is one of the most important prerequisites for good living and safe food production. Many studies have shown that non-compliance with drinking water quality standards in small water supply systems is much higher than in large systems. Nevertheless, people served by small water supply systems have the right to the same level of health protection. Actions are therefore needed to improve the situation. The objective of the present study was to carry out a baseline analysis of the situation in the Nordic region and provide recommendations for governmental policy and actions. Data were gathered on number of water supplies, population served, compliance with regulations and waterborne disease outbreaks from various sources in the Nordic countries. The collected data showed that there are about 12500 regulated water supplies, 9400 of which serve fewer than 500 persons. The number of unregulated and poorly regulated supplies is unknown, but it can be roughly estimated that these serve 10% of the Nordic population on a permanent basis or 2.6 million people. However, this does not tell the whole story as many of the very small water supplies serve transient populations, summerhouse dwellers and tourist sites, with many more users. Non-compliance regarding microbes is much higher in the small supplies. The population weighted average fecal contamination incidence rate in the Nordic region is eleven times higher in the smaller supplies than in the large ones, 0.76% and 0.07%, respectively. Registered waterborne disease outbreaks were also more frequent in the small supplies than in the large ones. PMID- 28869190 TI - Year-to-year variation in the density of Ixodes ricinus ticks and the prevalence of the rodent-associated human pathogens Borrelia afzelii and B. miyamotoi in different forest types. AB - The human pathogens Borrelia afzelii, which causes Lyme borreliosis and B. miyamotoi, which causes relapsing fever, both circulate between Ixodes ricinus ticks and rodents. The spatiotemporal dynamics in the prevalence of these pathogens have not yet been fully elucidated, but probably depend on the spatiotemporal population dynamics of small rodents. We aimed to evaluate the effect of different forest types on the density of infected nymphs in different years and to obtain more knowledge about the spatial and temporal patterns of ticks and tick-borne pathogens. We analysed unfed nymphal ticks from 22 stands of four different forest types in Belgium in 2009, 2010, 2013 and 2014 and found that the density of nymphs in general and the density of nymphs infected with B. afzelii and B. miyamotoi varied yearly, but without temporal variation in the infection prevalence. The yearly variation in density of infected nymphs in our study thus seems to be caused most by the variation in the density of nymphs, which makes it a good predictor of disease risk. The risk for rodent-associated tick-borne diseases also varied between forest types. We stress the need to elucidate the contribution of the host community composition to tick-borne disease risk. PMID- 28869191 TI - Co-infection with Babesia divergens and Anaplasma phagocytophilum in cattle (Bos taurus), Sweden. AB - Babesiosis is a severe disease in cattle worldwide. In Europe, the main causative agent of bovine babesiosis is Babesia divergens. In some areas, this species is reported to have declined or even disappeared, and its etiological role overtaken by other piroplasmid species. Moreover, co-infection with other tick-transmitted pathogens can be expected to complicate diagnosis in cattle. Hence, molecular identification of the causative agent of babesiosis should be a priority. Therefore, samples from 71 domestic cattle, 39 with clinical signs of babesiosis and 32 without, from southern Sweden were screened for Babesia spp. and Anaplasma spp. using molecular methods Babesia divergens was detected in 38 of the samples, and Anaplasma phagocytophilum in 17. Co-infections with both pathogens were frequent, occurring in 18% of the animals with a B. divergens infection. The possibility of co-infection should be considered in diagnosis and treatment of bovine babesiosis. PMID- 28869192 TI - Selection of yeast Saccharomyces cerevisiae promoters available for xylose cultivation and fermentation. AB - To efficiently utilize xylose, a major sugar component of hemicelluloses, in Saccharomyces cerevisiae requires the proper expression of varied exogenous and endogenous genes. To expand the repertoire of promoters in engineered xylose utilizing yeast strains, we selected promoters in S. cerevisiae during cultivation and fermentation using xylose as a carbon source. To select candidate promoters that function in the presence of xylose, we performed comprehensive gene expression analyses using xylose-utilizing yeast strains both during xylose and glucose fermentation. Based on microarray data, we chose 29 genes that showed strong, moderate, and weak expression in xylose rather than glucose fermentation. The activities of these promoters in a xylose-utilizing yeast strain were measured by lacZ reporter gene assays over time during aerobic cultivation and microaerobic fermentation, both in xylose and glucose media. In xylose media, PTDH3, PFBA1, and PTDH1 were favorable for high expression, and PSED1, PHXT7, PPDC1, PTEF1, PTPI1, and PPGK1 were acceptable for medium-high expression in aerobic cultivation, and moderate expression in microaerobic fermentation. PTEF2 allowed moderate expression in aerobic culture and weak expression in microaerobic fermentation, although it showed medium-high expression in glucose media. PZWF1 and PSOL4 allowed moderate expression in aerobic cultivation, while showing weak but clear expression in microaerobic fermentation. PALD3 and PTKL2 showed moderate promoter activity in aerobic cultivation, but showed almost no activity in microaerobic fermentation. The knowledge of promoter activities in xylose cultivation obtained in this study will permit the control of gene expression in engineered xylose-utilizing yeast strains that are used for hemicellulose fermentation. PMID- 28869193 TI - A search for microorganisms producing medium-chain alkanes from aldehydes. AB - Microorganisms with medium-chain alkane-producing activity are promising for the bio-production of drop-in fuel. In this study, we screened for microorganisms producing tridecane from tetradecanal. The activity of aldehyde decarbonylation was found in a wide range of microbes. In particular, the genus Klebsiella in the Enterobacteriaceae family was found to have a high ability to produce alkanes from aldehydes via enzyme catalyzed reaction. PMID- 28869194 TI - [How to manage a rectal cancer with synchronous liver metastases? A question of strategy]. AB - The prognosis of patients with rectal cancer and synchronous liver metastasis has improved thanks to chemotherapy and rectal and liver surgery progresses. However, there is no consensus about optimal management and practices remain heterogeneous. A curative treatment may be considered for 20 to 30% of patients with complete resection of metastasis and primary tumor after induction chemotherapy. To this end, a primary optimal evaluation by a multidisciplinary board including hepatic and colorectal surgeons is crucial. The therapeutic strategy associates chemotherapy, radiotherapy, hepatic and rectal surgery. The most threatening site guides the sequence of treatments. If hepatic resectability is uncertain, a "liver first" strategy associating induction chemotherapy and hepatic surgery is preferred. In non-resectable metastatic cases, chemotherapies with targeted therapies might lead to secondary resection for 30% of patients (conversion). This has changed our practice and triggers reconsidering resectability after chemotherapy. When metastases remain non-resectable, additional treatment focusing on primary tumor should control pelvic symptoms otherwise hardly impacting quality of life. Rectal surgery, short-course radiotherapy (5*5Gy), conformational long-course chemoradiotherapy or intensity modulated radiation therapy with dose escalation are options discussed in this review. PMID- 28869195 TI - [Proton therapy for head and neck cancers]. AB - The absence of exit dose and the sharp lateral penumbra are key assets for proton therapy, which are responsible for its dosimetric superiority over advanced photon radiotherapy. Dosimetric comparisons have consistently shown a reduction of the integral dose and the dose to organs at risk favouring intensity-modulated proton therapy (IMPT) over intensity-modulated radiotherapy (IMRT). The structures that benefit the most of these dosimetric improvements in head and neck cancers are the anterior oral cavity, the posterior fossa, the visual apparatus and swallowing structures. A number of publications have concluded that these dosimetric differences actually translate into reduced toxicities with IMPT, for example with regards to reduced weight loss or need for feeding tube. Patient survival is usually similar to IMRT series, except in base of skull or sinonasal malignancies, where a survival advantage of IMPT could exist. The goals of the present review is to describe the major characteristics of proton therapy, to analyse the clinical data with regards to head and neck cancer patients, and to highlight the issue of patient selection and physical and biological uncertainties. PMID- 28869196 TI - [Role of induction chemotherapy in head and neck cancer: Cons]. AB - The treatment of locally advanced head and neck squamous cell carcinoma is based on concomitant chemoradiotherapy. A sequential treatment combining induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF), followed by (chemo)radiotherapy is frequently used as part of laryngeal preservation strategies. Apart from this particular situation, the benefit in terms of survival of induction chemotherapy has been much discussed in recent years. In five recent randomized trials, chemoradiotherapy was compared with TPF induction chemotherapy followed by chemoradiotherapy. Of these five trials, four concluded that these treatments were similar. A single trial reports a benefit for induction chemotherapy but its methodology is highly debatable. After TPF chemotherapy, chemoradiotherapy is less well tolerated. In patients with significant lymph node invasion (N2b-c-N3), induction chemotherapy reduces the occurrence of distant metastasis. The HPV status should not influence the therapeutic decision. PMID- 28869197 TI - [Radiotherapy quality and risk manager role optimization in 2017]. AB - The quality and risk manager works in a regulated framework, which delimits its missions. Nevertheless, the variety among the centers generates heterogeneous situations regarding the positioning and the range of action. A well-defined framework is needed in order to ratify the legitimacy and the recognition of quality and risk manager's main function. PMID- 28869198 TI - [A randomized controlled trial of metastases-directed treatment in patients with metastatic prostate cancer using stereotactic body irradiation: A GETUG-AFU trial]. AB - The goal of treatment of metastatic prostate cancer remains palliation. The oligometastatic state could be the right time to intensify therapy by introducing metastases directed treatments. The aim of this trial was to evaluate the benefit of radiotherapy to all macroscopic metastatic sites and to the primary disease in patients with hormone sensitive oligometastatic prostate cancer. PMID- 28869199 TI - Reliability of measuring half-cycle cervical range of motion may be increased using a spirit level for calibration. AB - BACKGROUND: Assessments of range of motion (ROM) represent an essential part of clinical diagnostics. Ultrasonic movement analyses have been demonstrated to provide reliable results when analyzing complete amplitudes (e.g., flexion extension). However, due to subjective determination of the starting position, the assessment of half-cycle movements (e.g, flexion only) is less reproducible. OBJECTIVES: The present study aimed to examine the reliability of measuring half cycle cervical ROM using a spirit level for calibration. METHOD: 20 healthy subjects (30 +/- 12yrs, 7?, 13?) participated in the randomized, controlled, cross-over trial. In two testing sessions with one week of wash-out in between, cervical ROM was measured by means of an ultrasonic 3D movement analysis system using a test-retest design (baseline and 5 min post baseline). The sessions differed with reference to the mask carrying the ultrasound markers. It was removed during the 5 min break (mask off) or not (mask on). To determine the resting position, a bull's eye spirit level was used in each measurement. RESULTS: With ICC values of 0.90-0.98 (mask on, p < 0.001) and 0.90 to 0.97 (mask off, p < 0.001), both examined conditions demonstrated excellent test-retest reliability for separating the cycles regarding all movement planes. CONCLUSION: Cervical ROM during half-cycle movements can be assessed with excellent reliability using a spirit level. In contrast to subjective determination of the starting position, analyzing complete movement planes does not increase reliability. Using a defined and objective zero positioning allows the evaluation of repositioning tasks. PMID- 28869200 TI - Irreversible electroporation and thermal ablation of tumors in the liver, lung, kidney and bone: What are the differences? AB - Focal treatment with radiofrequency, microwave and cryoablation has been increasingly used for the treatment of tumors in patients who cannot undergo surgical resection and in select patients with early stage or oligometastatic disease. Each of these ablation modalities has a unique working principle and biophysics underlying the ablative effect, which largely determines the clinical indication for its application. Irreversible electroporation, a relatively new ablation technique with a predominantly nonthermal cell killing mechanism has emerged as an alternative treatment technique for tumors that are contraindicated for thermal ablation because of safety or efficacy considerations. Here, established thermal ablation techniques are compared with irreversible electroporation for treatment of tumors in the lung, liver, kidney and bone, and rationale is provided to guide selection of the most appropriate technique for each clinical setting. PMID- 28869201 TI - Cascading effects of attention disengagement and sensory seeking on social symptoms in a community sample of infants at-risk for a future diagnosis of autism spectrum disorder. AB - Recent work suggests sensory seeking predicts later social symptomatology through reduced social orienting in infants who are at high-risk for autism spectrum disorder (ASD) based on their status as younger siblings of children diagnosed with ASD. We drew on extant longitudinal data from a community sample of at-risk infants who were identified at 12 months using the First Year Inventory, and followed to 3-5 years. We replicate findings of Damiano et al. (in this issue) that a) high-risk infants who go on to be diagnosed with ASD show heightened sensory seeking in the second year of life relative to those who do not receive a diagnosis, and b) increased sensory seeking indirectly relates to later social symptomatology via reduced social orienting. We extend previous findings to show that sensory seeking has more clinical utility later in the second year of life (20-24 months) than earlier (13-15 months). Further, this study suggests that diminished attention disengagement at 12-15 months may precede and predict increased sensory seeking at 20-24 months. Findings add support for the notion that sensory features produce cascading effects on social development in infants at risk for ASD, and suggest that reduced attention disengagement early in life may set off this cascade. PMID- 28869202 TI - Short- and Long-term Functional Outcomes and Quality of Life after Radical Prostatectomy: Patient-reported Outcomes from a Tertiary High-volume Center. AB - BACKGROUND: Results from population-based studies and the Prostate Testing for Cancer and Treatment trial reported worse urinary continence (UC) and erectile function (EF) for radical prostatectomy (RP) patients compared with their radiation or active surveillance counterparts. OBJECTIVE: To investigate functional outcomes for patients undergoing RP in a high-volume center. DATA, SETTING, AND PARTICIPANTS: A total of 8573 consecutive RP patients (2008-2012) were analyzed. INTERVENTION: RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standardized questionnaires assessing EF, UC, and quality of life (QoL), were completed at baseline and annually thereafter. UC was defined as use of 0 or 1 safety pad/d, whereas the regular use of 1 pad/d was considered incontinent. EF was defined as >=3 points in the International Index of Erectile Function question two. QoL was assessed using the EORTC-QLQ-C30 Global Health/QoL item. Statistics relied on comparison of means and proportions. RESULTS AND LIMITATIONS: EF and UC rates significantly decreased after RP. Overall, 12-mo, 24 mo, and 36-mo EF rates were 45%, 51%, and 53%, but reached up to 65.7% in preoperatively potent patients with bilateral nerve sparing. At 36 mo, 13% reported problems in their partnership. However, at the same time point, 77% were satisfied with their sexual intercourse. UC rates were 89.1%, 91.3%, and 89.0% at 12-mo, 24-mo, and 36-mo postoperatively. Mean EORTC-QLQ-C30 scores ranged from 74 to 79 and remained constant compared to baseline. CONCLUSIONS: Although varying definitions hinder direct comparisons to other studies, functional outcomes seemed favorable for patients undergoing RP in a high-volume center and most patients reported excellent QoL. PATIENT SUMMARY: Results of functional outcomes (urinary continence and potency) after radical prostatectomy are better in a high volume center compared with those obtained from population-based data, and most patients report excellent quality of life after radical prostatectomy. PMID- 28869203 TI - Nephron-sparing Suture of Renal Parenchyma After Partial Nephrectomy: Which Technique to Go For? Some Best Practices. AB - : The quantity of the preserved parenchyma after partial nephrectomy is the result of interplay among various factors: the unmodifiable preoperative quality of the renal parenchyma and some technical modifiable aspects. Among the modifiable factors able to influence the quantity, the suture technique has gained paramount importance. Indeed, nowadays there is a consensus suggesting that one of the main predictors of the ultimate renal function is the minimal parenchymal volume loss: this is the sum of the healthy parenchyma excised with the tumour and the portion of the parenchyma devascularised by the renorrhaphy. The historical aim of a good suture was to avoid bleeding and urine leakage. A modern suture after partial nephrectomy should minimise the ischaemic effect on the renal parenchyma whenever possible. This has to be carried out with precision and based on the vascular anatomy of the kidney. PATIENT SUMMARY: In this report, we tried to describe the best practice for the suturing of renal parenchyma after conservative surgical treatment for small renal tumours. Indeed, the suture after the resection of a renal mass should minimise the ischaemic effect on the renal tissue whenever possible, maximising the functional outcomes. PMID- 28869204 TI - Safety of Live Robotic Surgery: Results from a Single Institution. AB - BACKGROUND: Live surgery events (LSEs) have become one of the most attended activities at surgical meetings and provide a unique opportunity for the audience to observe the decision-making process used by skilled and experienced surgeons in real time. However, there is an ongoing discussion on whether patients treated during LSE are at higher risk of complications. OBJECTIVE: To examine LSE outcomes for robot-assisted radical prostatectomy (RARP) and establish patient safety and efficacy. DESIGN, SETTING, AND PARTICIPANTS: From January 2008 to April 2016, >9000 patients underwent RARP at our institution, performed by a single surgeon. From this group, 36 patients underwent live RARP surgery (LS group) transmitted via video link from our institution to an external congress. A control group was obtained from our database to compare outcomes between the LS group and patients undergoing RARP under regular circumstances. The data were prospectively collected in a customized database and retrospectively analyzed. INTERVENTION: All patients underwent RARP performed by a single surgeon at our institution. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Postoperative outcomes were compared between the LS (n=36) and the control (n=108) groups using Student's t test and analysis of variance for continuous variables, and a two tailed Fisher's exact test for categorical variables. Statistical significance was set at p<0.05. RESULTS AND LIMITATIONS: There were no significant differences in baseline characteristics (age, body mass index, comorbidities, preoperative Gleason score, Sexual Health Inventory for Men score and American Urological Association symptom score) between the groups. The median console time was shorter for the LS group (73min, interquartile range [IQR] 70-79) than for the control group (78min, IQR 75-87; p=0.0371). No major complications were reported in either group, and only four minor complications were observed in the control group (p=0.2415). After median follow-up of 31 mo (IQR 18-50), only one patient (2.77%) in the LS group experienced biochemical recurrence, compared to four (3.71%) in the control group (p=0.7927). There was no significant difference in continence rates between the LS and control groups (97.22% vs 93.52%; p=0.7768). No differences in potency rate were evident by the end of the follow-up period (LS 69.44%, control group 70.37%; p=0.8432). The retrospective nature, the lack of randomization, and the single-institution experience are limitations of the study. CONCLUSIONS: In this series of live transmitted RARPs, perioperative results (oncological and functional outcomes and complications) were similar to those found in daily practice. After careful patient selection, LSEs are safe with minimal patient morbidity in the hands of an experienced surgeon working with a familiar surgical team. Further evaluation of the results from other surgeons at other centers is necessary. PATIENT SUMMARY: We investigated the safety of surgeries broadcast live from our institution. We found that outcomes were similar to those for patients undergoing surgery under regular circumstances in terms of the rate of complications and oncological and functional outcomes. We conclude that live transmitted surgery is safe in well-selected patients in the hands of an experienced surgeon. PMID- 28869205 TI - Ictal asystole in a patient with posterior reversible encephalopathy syndrome (PRES) and seizures. AB - We describe a case of ictal asystole in a patient with posterior reversible encephalopathy syndrome (PRES), which has never been described previously. Ictal asystole is rare and has possible serious medical consequences, including syncope, and may be a potential mechanism for sudden unexpected death in epilepsy (SUDEP). Awareness that PRES may be observed with recurrent ictal asystole may aid in the recognition and treatment of seizures in this condition and the prevention of asystole-associated complications. PMID- 28869207 TI - Effect of magnesium on the osteogenesis of normal human osteoblasts. AB - Biomaterials containing magnesium are used for implants and bone regeneration. However, mechanisms underlying the biologic effects of magnesium are still largely unknown and have not been examined on normal human osteoblasts. This study was designed to test the effect of supplemented Mg2+ concentrations between 0.5 mM and 16 mM on the osteogenic behaviors of normal human primary osteoblasts. Human primary osteoblasts were cultured in the groups with various concentrations of supplemented magnesium for various time intervals. Cell proliferation was measured using crystal violet staining. Degree of Alkaline Phosphatase (ALP) activity was measured by fluorometric assay. Expression of osteocalcin was measured by immunosorbent assay. Mineralization of cultures was determined by Alizarin Red S staining. Results showed that initial cell attachment efficiency was not affected by supplemented Mg2+ (P > 0.05). At 21 days, proliferation rates increased in groups containing 0.5 mM-4 mM supplemented Mg2+ and decreased in groups of supplemented 8 mM and 16 mM Mg2+. ALP activity and osteocalcin expression were upregulated in groups of supplemented Mg2+ between 0.5 mM-2.0 mM (P < 0.05), but downregulated in groups with supplemented Mg2+ concentrations of 4mM and above (P < 0.05). Cultures with 1 mM and 2 mM supplemented Mg2+ showed upregulated mineralization activity compared to the control (P < 0.05), but downregulated in groups with supplemented Mg2+ concentrations of 4 mM and above (P < 0.05). The present study based on an experimental design demonstrated the impact of 2 mM supplemented Mg2+ on induced-proliferation and differentiation of normal human osteoblasts. PMID- 28869206 TI - Serum magnesium and calcium levels in infertile women during a cycle of reproductive assistance. AB - Magnesium (Mg) and calcium (Ca) are essential cations for women's preconception health. It is well known that, in blood, the concentration of ionized form of these two cations is temporally altered during menstrual cycle, suggesting a correlation between sex steroid hormones and serum calcium and magnesium levels. Evidence from literature suggests that in assisted reproductive technology increasing estrogens during ovarian hyperstimulation may also modulate serum magnesium and calcium levels. Therefore, we first examined total serum magnesium and calcium levels during follicular phase in a large population of infertile patients who underwent intrauterine insemination (IUI). The results were compared to a group of fertile women. Successively, we studied the total serum magnesium and calcium concentrations in infertile patients before and after ovarian hyperstimulation for in vitro fertilization (IVF). Results highlight that total serum concentration of magnesium and calcium does not seem altered in infertile women. During stimulation with gonadotropins, the values of the two cations do not change significantly in ovarian-stimulated women. However, we found a downward trend in the total magnesium and calcium levels in relation to the rising estrogens. PMID- 28869208 TI - Factors associated with magnesemia in patients with chronic kidney disease. AB - Previous studies have indicated diabetes was associated with lower serum magnesium (Mg) level. Patients with renal impairment usually have higher Mg concentration due to reduced renal excretion. Whether Mg level in diabetics with chronic kidney disease (CKD) is altered remains undermined. In this study, we analyzed serum Mg concentration in patients with CKD and also compared diabetics with non-diabetics. Factors associated with Mg levels were explored. A total of 939 patients were included and 717 were with CKD. Their serum Mg concentration increased progressively, as their glomerular filtration rate (GFR) decreased in both diabetics and non-diabetics. Compared with non-diabetics, diabetes was significantly associated with lower serum Mg concentration in patients without CKD than in patients with CKD in all stages of disease. Multivariate regression analysis identified that both diabetes and serum albumin were independent factors of serum Mg concentration in patients without CKD. Age, diabetes, serum albumin concentration, GFR and macroproteinuria were significantly associated with serum Mg concentration in patients with early-stage CKD. In patients with moderate-to severe CKD, diabetes, serum albumin and GFR were independent factors related to the serum Mg level. PMID- 28869209 TI - Cost-effectiveness Analysis of an Aftercare Service vs Treatment-As-Usual for Patients with Severe Mental Disorders. AB - BACKGROUND: There have been claims that community mental health principles leads to the maintenance of better health and functioning in patients and can be more economical for patients with severe and chronic mental disorders. Economic evaluation studies have been used to assess the cost-effectiveness of national health programs, or to propose efficient strategies for health care delivery. AIMS OF THE STUDY: The current study is intended to test the cost-effectiveness of an Aftercare Service when compared with Treatment-As-Usual for patients with severe mental disorders in Iran. METHODS: This study was a parallel group randomized controlled trial. A total of 160 post-discharge eligible patients were randomized into two equal patient groups, Aftercare Service (that includes either Home Visiting Care, or Telephone Follow-up for outpatient treatment) vs Treatment As-Usual, using stratified balanced block randomization method. All patients were followed for 12 months after discharge. The perspective of the present study was the societal perspective. The outcome measures were the rate of readmission at the hospitals after discharge, psychotic symptoms, manic symptoms, depressive symptoms, illness severity, global functioning, quality of life, and patients' satisfaction with the services. The costs included the intervention costs and the patient and family costs in the evaluation period. RESULTS: There was no significant difference in effectiveness measures between the two groups. The Aftercare Service arm was about 66,000 US$ cheaper than Treatment-As-Usual arm. The average total cost per patient in the Treatment-As-Usual group was about 4651 USD, while it was reduced to 3823 US$ in the Aftercare Service group; equivalent to a cost reduction of about 800 USD per patient per year. DISCUSSION AND LIMITATIONS: Given that there was no significant difference in effectiveness measures between the two groups (slightly in favor of the intervention), the Aftercare Service was cost-effective. The most important limitation of the study was the relatively small sample size due to limited budget for the implementation of the study. A larger sample size and longer follow-ups are warranted. IMPLICATIONS FOR HEALTH CARE PROVISION, USE AND POLICIES: Considering the limited resources and equity concerns for health systems, the importance of making decisions about healthcare interventions based on cost-effectiveness evidence is increasing. Our results suggest that the aftercare service can be recommended as an efficient service delivery mode, especially when psychiatric bed requirements are insufficient for a population. IMPLICATIONS FOR FURTHER RESEARCH: Further research should continue the work done with a larger sample size and longer follow-ups to further establish the cost-effectiveness analysis of an aftercare service program compared with routine conventional care. PMID- 28869210 TI - The Affordable Care Act's Dependent Care Coverage Expansion and Behavioral Health Care. AB - BACKGROUND: In September 2010, the Affordable Care Act (ACA) extended dependent care coverage to individuals under the age of 26, allowing young adults to remain on their parent's private insurance. AIMS OF THE STUDY: This policy offers a natural experiment to examine the impact of expanded insurance coverage on mental health and substance use treatment utilization and payment composition. METHODS: Using National Survey on Drug Use and Health (NSDUH) and Medical Expenditure Panel Survey (MEPS) data between 2005 and 2014, this study employs a difference in-differences approach with 23-25 year olds as the treatment group and 27-30 year olds as the control group to examine the impact of the expansion on insurance coverage, behavioral health treatment utilization, and treatment payment source. RESULTS: Results indicate that the dependent care coverage expansion is associated with an increase in insurance coverage, greater mental health treatment utilization, and an increase in payment for behavioral health treatment by private insurance. DISCUSSION: This study shows that insurance coverage increased and financial barriers to getting behavioral health treatment fell. Improving access to care only led to increases in mental health treatment utilization, while substance use treatment utilization remained unchanged. IMPLICATIONS: The ACA succeeded in extending insurance benefits to a population that has been historically underinsured. Along with those benefits, young adults enjoyed greater access to behavioral health care and a measure of financial protection from high costs. While the evidence has yet to be presented for the full implementation of the ACA, if these results are typical of its other provisions, then the ACA will have achieved some of its most important objectives. PMID- 28869211 TI - Clinicians' Views on Therapeutic Outcomes of Systemic Interventions and on the Ability of the EQ-5D to Capture these Outcomes. AB - BACKGROUND: Systemic interventions focus on improvements of interactions between clients and their environments, and are increasingly used to treat adolescents with problems of substance use and delinquency. Clients' progress may include broad and non-medical effects. When performing economic evaluations of these interventions, the common outcome of costs per quality adjusted life year (cost/QALY) may not capture all of these effects. AIMS OF THE STUDY: The current study is an explorative study. It aims to investigate which outcomes clinicians consider relevant to the therapeutic success of systemic interventions and whether these, according to them, are sufficiently captured by the EQ-5D instrument. METHODS: Semi-structured interviews were performed with seven clinicians at two mental health institutions in the Netherlands. Clinicians were asked to list the most relevant outcomes of systemic interventions. They were asked whether they considered the EQ-5D dimensions to sufficiently capture these outcomes or if they missed aspects or outcome domains. RESULTS: The clinicians mentioned several broad effects relevant for the evaluation of systemic interventions. These were aspects of family functioning, parental functioning, social competencies, school attendance, etc. They considered several EQ-5D dimensions relevant (i.e. in particular 'usual activities' and 'anxiety/depression'), yet they indicated that the instrument lacked systemic dimensions (i.e. family relations and relations with others) and addiction related aspects. DISCUSSION: The interviewed clinicians considered several dimensions of the EQ-5D useful in evaluating effects of systemic interventions, yet they expressed the need to add additional dimensions particularly relevant to systemic aspects to the instrument when performing economic evaluations of systemic interventions. The explorative analysis was limited by the small number of interviewed clinicians. Furthermore, a relatively high proportion of clinicians were specialized in Multidimensional Family Therapy, a type of systemic intervention particularly used to treat adolescents with substance use disorders and related problems. Hence the importance of addiction-related improvements may have been over-emphasized in this group of respondents. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Practical implications of the current study may be the need for enhancements of the current health economic methodology for evaluating systemic interventions as to capture additional aspects specifically relevant to these interventions. This may lead to different choices in the use of instruments for the evaluation of treatment progress and success in clinical practice. IMPLICATIONS FOR HEALTH POLICIES: By improving the health economic toolkit to evaluate systemic interventions one may provide policy recommendations in line with the therapeutic goals of the interventions. IMPLICATIONS FOR FURTHER RESEARCH: Further research could be directed at investigating the suitability of other available instruments than the EQ-5D for economic evaluations of systemic interventions. PMID- 28869212 TI - Increased Mental Health Treatment Financing, Community-Based Organization's Treatment Programs, and Latino-White Children's Financing Disparities. AB - BACKGROUND: Latino child populations are large and growing, and they present considerable unmet need for mental health treatment. Poverty, lack of health insurance, limited English proficiency, stigma, undocumented status, and inhospitable programming are among many factors that contribute to Latino-White mental health treatment disparities. Lower treatment expenditures serve as an important marker of Latino children's low rates of mental health treatment and limited participation once enrolled in services. AIMS: We investigated whether total Latino-White expenditure disparities declined when autonomous, county-level mental health plans receive funds free of customary cost-sharing charges, especially when they capitalized on cultural and language-sensitive mental health treatment programs as vehicles to receive and spend treatment funds. Using Whites as benchmark, we considered expenditure pattern disparities favoring Whites over Latinos and, in a smaller number of counties, Latinos over Whites. METHODS: Using segmented regression for interrupted time series on county level treatment systems observed over 64 quarters, we analyzed Medi-Cal paid claims for per-user total expenditures for mental health services delivered to children and youth (under 18 years of age) during a study period covering July 1, 1991 through June 30, 2007. Settlement-mandated Medicaid's Early Periodic Screening, Diagnosis and Treatment (EPSDT) expenditure increases began in the third quarter of 1995. Terms were introduced to assess immediate and long term inequality reduction as well as the role of culture and language-sensitive community-based programs. RESULTS: Settlement-mandated increased EPSDT treatment funding was associated with more spending on Whites relative to Latinos unless plans arranged for cultural and language-sensitive mental health treatment programs. However, having programs served more to prevent expenditure disparities from growing than to reduce disparities. DISCUSSION: EPSDT expanded funding increased proportional expenditures for Whites absent cultural and language-sensitive treatment programs. The programs moderate, but do not overcome, entrenched expenditure disparities. These findings use investment in mental health services for Latino populations to indicate treatment access and utilization, but do not explicitly reflect penetration rates or intensity of services for consumers. IMPLICATIONS FOR POLICY: New funding, along with an expectation that Latino children's well documented mental health treatment disparities will be addressed, holds potential for improved mental health access and reducing utilization inequities for this population, especially when specialized, culturally and linguistically sensitive mental health treatment programs are present to serve as recipients of funding. IMPLICATIONS FOR RESEARCH: To further expand knowledge of how federal or state funding for community based mental health services for low income populations can drive down the longstanding and considerable Latino-White mental health treatment disparities, we must develop and test questions targeting policy drivers which can channel funding to programs and organizations aimed at delivering linguistically and culturally sensitive services to Latino children and their families. PMID- 28869213 TI - Two-probe STM experiments at the atomic level. AB - Direct characterization of planar atomic or molecular scale devices and circuits on a supporting surface by multi-probe measurements requires unprecedented stability of single atom contacts and manipulation of scanning probes over large, nanometer scale area with atomic precision. In this work, we describe the full methodology behind atomically defined two-probe scanning tunneling microscopy (STM) experiments performed on a model system: dangling bond dimer wire supported on a hydrogenated germanium (0 0 1) surface. We show that 70 nm long atomic wire can be simultaneously approached by two independent STM scanners with exact probe to probe distance reaching down to 30 nm. This allows direct wire characterization by two-probe I-V characteristics at distances below 50 nm. Our technical results presented in this work open a new area for multi-probe research, which can be now performed with precision so far accessible only by single-probe scanning probe microscopy (SPM) experiments. PMID- 28869214 TI - Critical and compensation behavior of a mixed spin-5/2 and spin-3/2 Ising antiferromagnetic system in a core/shell nanowire. AB - In this work, Monte Carlo simulations based on metropolis algorithm were performed to study the critical and compensation temperatures of a core-shell nanowire with spins [Formula: see text] and [Formula: see text], respectively, considering an Ising antiferromagnetic system. The influence of nearest neighbors exchange interactions and crystal field anisotropy on the critical and compensation behaviors of the system has been analyzed. The effects of the nanowire height in the critical and compensation temperatures were evaluated. The results show that, for a system with given values of exchange interaction constants and crystal field anisotropy, a compensation point only appears if two requirements are satisfied. First, the weight of the core magnetization in the total magnetization must be greater than the weight of the shell magnetization at zero temperature. And second, the exchange constant of shell ions must be greater than a certain value. This value is, at the same time, greater than the exchange constant of core ions. The critical and compensation temperatures are very sensitive to variations in the exchange constant of the shell ions and core ions, respectively, while the crystal field anisotropy affects both temperatures. PMID- 28869215 TI - Large scale calculations of thermoelectric transport coefficients: a case study of gamma-graphyne with point defects. AB - Defects such as vacancies and impurities could have profound effects on the transport properties of thermoelectric materials. However, it is usually quite difficult to directly calculate the thermoelectric properties of defect containing systems via first-principles method since very large supercell is required. In this work, based on the linear response theory and the kernel polynomial method, we present an efficient approach that can help to calculate the thermoelectric transport coefficients of a large system containing millions of atoms at arbitrary chemical potential and temperature. As a prototype example, we consider dilute vacancies and hydrogen impurities in a large scale gamma graphyne sheet and discuss their effects on the thermoelectric transport properties. PMID- 28869216 TI - In situ grown Ni9S8 nanorod/O-MoS2 nanosheet nanocomposite on carbon cloth as a free binder supercapacitor electrode and hydrogen evolution catalyst. AB - Transition metal sulfide nanostructure composites have received significant attention as energy conversion and storage devices. In this work, we report a three-dimension (3D) nanostructure with the Ni9S8 nanorods embedded in oxygen incorporated MoS2 (O-MoS2) nanosheets for supercapacitors and hydrogen evolution catalysts. The in situ grown Ni9S8/O-MoS2 nanocomposite on carbon cloth can be used as a free binder supercapacitor electrode and hydrogen evolution catalyst. The Ni9S8/O-MoS2 nanocomposite exhibits electrochemical behaviors with a specific capacitance of 907 F g-1 (at 2 A g-1) and good cycle stability after 1200 cycles due to its unique mutual embedding 3D nanostructure. Furthermore, the Ni9S8/O MoS2 nanocomposite also shows highly electrocatalytic features for hydrogen production with an onset overpotential of ~150 mV and a low Tafel slope of ~81 mV dec-1. The oxygen incorporation of MoS2 provides more active sites to participate in the catalytic process for the hydrogen evolution reaction. PMID- 28869217 TI - Single-molecule techniques in biophysics: a review of the progress in methods and applications. AB - Single-molecule biophysics has transformed our understanding of biology, but also of the physics of life. More exotic than simple soft matter, biomatter lives far from thermal equilibrium, covering multiple lengths from the nanoscale of single molecules to up to several orders of magnitude higher in cells, tissues and organisms. Biomolecules are often characterized by underlying instability: multiple metastable free energy states exist, separated by levels of just a few multiples of the thermal energy scale k B T, where k B is the Boltzmann constant and T absolute temperature, implying complex inter-conversion kinetics in the relatively hot, wet environment of active biological matter. A key benefit of single-molecule biophysics techniques is their ability to probe heterogeneity of free energy states across a molecular population, too challenging in general for conventional ensemble average approaches. Parallel developments in experimental and computational techniques have catalysed the birth of multiplexed, correlative techniques to tackle previously intractable biological questions. Experimentally, progress has been driven by improvements in sensitivity and speed of detectors, and the stability and efficiency of light sources, probes and microfluidics. We discuss the motivation and requirements for these recent experiments, including the underpinning mathematics. These methods are broadly divided into tools which detect molecules and those which manipulate them. For the former we discuss the progress of super-resolution microscopy, transformative for addressing many longstanding questions in the life sciences, and for the latter we include progress in 'force spectroscopy' techniques that mechanically perturb molecules. We also consider in silico progress of single-molecule computational physics, and how simulation and experimentation may be drawn together to give a more complete understanding. Increasingly, combinatorial techniques are now used, including correlative atomic force microscopy and fluorescence imaging, to probe questions closer to native physiological behaviour. We identify the trade-offs, limitations and applications of these techniques, and discuss exciting new directions. PMID- 28869218 TI - Novel boron channel-based structure of boron carbide at high pressures. AB - Boron carbide (B4C) is one of the hardest materials known to date. The extreme hardness of B4C arises from architecturally efficient B12 or B11C icosahedrons and strong inter-icosahedral B-C bonding. As an excellent material for use in ballistic armor, the mechanic limit of B4C and possible phase transitions under extreme stress conditions are of great interest. Here we systematically explored the post-icosahedral solid structures of B4C under high pressure, using an unbiased structure search method. A new structure composed of extended framework of B and zigzag chains of C is predicted to be stable above 96 GPa. The new structure was predicted to have a high Vickers hardness of 55 GPa and simultaneously to retain a metallic ground state. The exceptional mechanical properties found in this structure are attributed to strong sp 3 covalent network formed under extreme pressure conditions. The predicted structure represents a new type of superhard boron carbides that form under high pressure without the presence of boron icosahedrons, which encourages experimental exploration in this direction. PMID- 28869219 TI - Andrographolide sensitizes prostate cancer cells to TRAIL-induced apoptosis. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for anticancer therapy. The identification of small molecules that can establish the sensitivity of prostate cancer (PCa) cells to TRAIL-induced apoptosis is crucial for the targeted treatment of PCa. PC3, DU145, JAC-1, TsuPr1, and LNCaP cells were treated with Andrographolide (Andro) and TRAIL, and the apoptosis was measured using the Annexin V/PI double staining method. Real time-polymerase chain reaction (PCR) and Western blot analysis were performed to measure the expression levels of target molecules. RNA interference technique was used to down-regulate the expression of the target protein. We established a nude mouse xenograft model of PCa, which was used to measure the caspase-3 activity in the tumor cells using flow cytometry. In this research study, our results demonstrated that Andro preferentially increased the sensitivity of PCa cells to TRAIL-induced apoptosis at subtoxic concentrations, and the regulation mechanism was related to the up-regulation of DR4. In addition, it also increased the p53 expression and led to the generation of reactive oxygen species (ROS) in the cells. Further research revealed that the DR4 inhibition, p53 expression, and ROS generation can significantly reduce the apoptosis induced by the combination of TRAIL and Andro in PCa cells. In conclusion, Andro increases the sensitivity of PCa cells to TRAIL-induced apoptosis through the generation of ROS and up regulation of p53 and then promotes PCa cell apoptosis associated with the activation of DR4. PMID- 28869220 TI - Microdissection testicular extraction for a patient with transverse testicular ectopia and testicular fusion. PMID- 28869221 TI - Beyond epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) testing in advanced non-small cell lung cancer: Is the picture as "ROS1" as it appears? PMID- 28869222 TI - 2025 too short time to eliminate tuberculosis from India. PMID- 28869223 TI - ROS1 rearrangement and response to crizotinib in Stage IV non-small cell lung cancer. AB - BACKGROUND: The frequency of ROS1 rearrangement in non-small cell lung cancers has been reported from 1.6% to 2.3%. MATERIALS AND METHODS: We examined 105 lung adenocarcinoma patients for ROS1 rearrangement which were negative for EGFR and anaplastic lymphoma kinase. Clinical characteristics of ROS1 rearranged patients and their responses to crizotinib therapy were studied. RESULTS: Of the 105 patients, three cases were positive for ROS1 rearrangement by fluorescence in situ hybridization analysis. All of them showed heterogeneous pattern. All the 3 ROS1-positive patients were females in their forties and started on crizotinib. All of them responded to treatment. One of them developed resistance after 3 months. Another one showed marked systemic response but central nervous system lesions progressed. The third case is doing well till date with inactive lesions on positron emission tomography scan. CONCLUSIONS: The frequency of ROS1 rearrangement is low in non-small cell lung carcinoma, but their diagnosis offers patients an opportunity to receive highly effective targeted therapies. PMID- 28869224 TI - Evaluation of tuberculosis-associated chronic obstructive pulmonary disease at a tertiary care hospital: A case-control study. AB - CONTEXT: Irreversible airway obstruction is important sequelae of pulmonary tuberculosis (TB) that might contribute to a significant proportion of chronic obstructive pulmonary disease (COPD). India has the highest TB burden in the world. However, there are limited data on the prevalence and presentation of TB associated COPD from this region. AIMS: This study aims to evaluate the prevalence of TB-associated COPD among COPD patients presenting to a tertiary care hospital. SETTINGS AND DESIGN: It was a case-control study conducted in a tertiary care hospital. SUBJECTS AND METHODS: Stable COPD patients presenting to chest OPD and an equal number of healthy controls were enrolled. COPD patients were subjected to detailed clinical evaluation and lung function test. History of pulmonary TB was evaluated from both groups through self-reporting and/or checking previous records. TB-associated COPD patients were identified and their prevalence and distinguishing features evaluated. RESULTS: Of 74 COPD patients, 24 (32.4%) had previous history of pulmonary TB. The odds of having a previous TB in COPD patients was 3.96 (95% confidence interval: 1.64-9.55; P = 0.002) as compared to controls. Patients with TB-associated COPD were younger (P = 0.02), had lesser pack-years of smoking (P = 0.027) but had more number of hospitalizations (P = 0.01). The airflow limitation was similar in both groups. CONCLUSIONS: TB-associated COPD constitutes a significant proportion of COPD patients. It is a distinct clinical entity with preponderance in young. It may be associated with frequent hospitalizations as compared to other COPD patients. PMID- 28869226 TI - Inconsistency in the reporting of antitubercular drug susceptibility tests in an endemic region. AB - BACKGROUND: Individualized treatment for multidrug-resistant tuberculosis (MDR TB) is associated with improved outcomes. Therapy needs to be tailored to drug susceptibility testing (DST) results. We present our observations on the inconsistency in DST reporting in an endemic region with a high prevalence of MDR TB. METHODS: We retrospectively analyzed 118 DST reports from 10 different laboratories. OBSERVATIONS: Of 118 patients, only 79 (67%) had DST reports with results to all first-line drugs, a fluoroquinolone (excluding ciprofloxacin), all aminoglycosides, and a polypeptide. Twenty-one (18%) isolates did not have DST reports for all first-line drugs; 4 (3%) did not have DST reports for any second line drugs; 9 (8%) did not have DST reports for a fluoroquinolone; and 31 (26%) did not have DST reports for all second-line aminoglycosides and polypeptide. CONCLUSION: Inconsistencies were observed in several of the 118 DST reports. A case is made for sensitization toward standardization and completeness in TB DST reporting in India. PMID- 28869225 TI - Resection and anastomosis for benign tracheal stenosis: Single institution experience of 18 cases. AB - INTRODUCTION: Tracheal stenosis is a complex condition caused by altered inflammatory response to injury and subsequent excessive circumferential scar formation. Surgical resection, wherever possible, offers the best long-term results. Nonsurgical methods provide immediate relief to all can be curative in few but mostly serve as an excellent bridge to surgery in majority. The purpose of this study is to retrospectively evaluate the outcome following surgery for benign tracheal stenosis at our center. MATERIALS AND METHODS: This retrospective analysis was conducted on 18 patients who underwent resection and anastomosis for tracheal stenosis at our center between March 2012 and December 2015. Their records were analyzed for demography, history, clinical presentation, computed tomography, bronchoscopy details, preoperative interventions, indications for and details of surgery, the procedure performed, postoperative complications, and course during 6 months follow-up. RESULTS: The patients had a varied list of pathologies for which they were either intubated or tracheostomized. The length of stenosis ranged between 1 cm and 4 cm. The diameter of stenotic segment ranged between 0 mm and 10 mm. Average length of resected segment was 3 cm, and number of tracheal rings resected ranged from 2 to 9. Postoperative complications occurred in four patients (22.22%). All our patients were in the "excellent outcome" category at discharge as well as at 3 months follow-up. CONCLUSIONS: Surgical management of tracheal stenosis is challenging and requires multidisciplinary team approach. Thorough preoperative preparation and multidisciplinary planning regarding need for and timing of surgery, meticulous intraoperative technique, and aggressive postoperative care is key to successful surgery, which can provide long-lasting cure to these patients. PMID- 28869227 TI - A study on Beijing genotype in the clinical isolates of pulmonary drug-resistant tuberculosis. AB - BACKGROUND: Mycobacterium tuberculosis (MTB) Beijing strains are spread worldwide and are responsible for major outbreaks of tuberculosis (TB), sometimes spreading multidrug resistance (MDR). AIM: The aim of this study was to explore clinical features associated with the infection with Beijing strains among MDR patients of pulmonary TB in Lucknow and surrounding areas. MATERIALS AND METHODS: It was a hospital-based epidemiological study. Our study population was selected from all the newly diagnosed patients attending outpatient department and admitted patients of Department of Respiratory Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India. Those isolates which were characterized to be MTB by morphological and molecular techniques were tested for their resistance against the first-line drugs; after which each patient's isolate was genotyped. RESULTS: The results suggested that the presence of Beijing genotype in 31.78% of strains. CONCLUSION: Our results predicted that genotypic patterns reveal a large diversity among the MTB Beijing strain population. Increasing frequency of Beijing strains demands further research to unravel the factors behind its propensity to prevail. PMID- 28869228 TI - Symptom profile as assessed on delirium rating scale-revised-98 of delirium in respiratory intensive care unit: A study from India. AB - AIM: This study aimed to evaluate the phenomenology of delirium in patients admitted in a Respiratory Intensive Care Unit (RICU). METHODS: Consecutive patients admitted to RICU were screened for delirium using Richmond Agitation Sedation Scale (RASS), Confusion Assessment Method for ICU (CAM-ICU) assessment tool and those found positive for delirium were evaluated by a psychiatrist to confirm the diagnosis. Those with a diagnosis of delirium as per the psychiatrist were evaluated on Delirium Rating Scale-Revised-98 (DRS-R-98) to study phenomenology. RESULTS: All the 75 patients fulfilled the criteria of "acute onset of symptoms" and "presence of an underlying physical disorder" as per the DRS-R-98. Commonly seen symptoms of delirium included disturbances in attention (100%), thought process abnormality (100%), fluctuation in symptoms (97.33%) disturbance in, sleep-wake cycle, language disturbance (94.7%), disorientation (81.33%), and short-term memory impairments (73.33%). No patient had delusions and very few (5.3%) reported perceptual disturbances. According to RASS subtyping, hypoactive delirium was the most common subtype (n = 34; 45.33%), followed by hyperactive subtype (n = 28; 37.33%) and a few patients had mixed subtype of delirium (n = 13; 17.33%). Factor structure of DRS-R-98 symptoms yielded 3 factors (Factor-1: cognitive factor; Factor-2: motoric factor; Factor 3; thought, language, and fluctuation factor). CONCLUSION: The phenomenology of delirium in ICU patients is similar to non-ICU patients, but hypoactive delirium is the most common subtype. PMID- 28869229 TI - Endoscopic ultrasound-guided evaluation of the pleura and cases of pleural effusion. AB - The most efficient and cost-effective approach for the diagnosis of pleural exudates remains uncertain and is a subject of controversy. Essential factors to be considered include the respective diagnostic yields of thoracocentesis, closed pleural biopsy, and thoracoscopy. The role of endoscopic ultrasound (EUS) of the esophagus as a modality for the evaluation of pleural exudates has not yet been evaluated. The applied anatomy of the pleura has been discussed. The techniques involved in the EUS imaging of different aspects of the pleura in normal cases and in cases with pleural effusion are elaborated. The practical application of this knowledge can be useful in EUS-guided sampling of the pleural wall, pleural nodules, and in cases of pleural effusion. PMID- 28869230 TI - Three decades of transtracheal oxygen therapy: A review of the associated complications with an illustrative case presentation. AB - Transtracheal oxygen therapy is a well-established modality for improving oxygenation in patients with chronic obstructive pulmonary disease, sleep apnea, pulmonary fibrosis, and other conditions causing hypoxic respiratory failure. In spite of its proven track record, the device remains underutilized. This article reviews benefits and complications related to the use of this modality with an illustrative case presentation. PMID- 28869231 TI - How a mild influenza B infection can kill: A case of pulmonary hemorrhage. AB - Viral influenza is a seasonal infection associated with significant morbidity and mortality. Rapidly fatal hemorrhagic pneumonia has been described in previously healthy individuals with beta-hemolytic Streptococcus pneumoniae in a small series of patients, but it is not common in patients coinfected with influenza B and beta-hemolytic Streptococcus, particularly since influenza B is considered less pathogenic than influenza A. However, despite being uncommon, this coinfection seems to be associated with high morbidity and mortality, particularly in healthy individuals. We present a case of a 46-year-old previously healthy white woman presenting with 4 days of shortness of breath, sore throat, subjective fevers, and nonproductive cough with rapidly fatal hemorrhagic pneumonia confirmed to have Group A beta-hemolytic Streptococcus and influenza B coinfection. On admission, she had a temperature of 103 degrees F, room air oxygen saturation of 95%, a positive nasal swab for influenza B, and negative rapid strep test. Initial chest radiograph showed increased bibasilar interstitial markings. She was admitted to a regular floor and started on oseltamivir. Preliminary throat culture was positive for Group A beta-hemolytic Streptococcus and penicillin V was started. Respiratory status deteriorated requiring intubation and transfer to Intensive Care Unit. Subsequently, copious bleeding was noted in her endotracheal tube. A bedside bronchoscopy with bronchoalveolar lavage revealed a hemorrhagic pneumonitis. Despite aggressive efforts, she developed shock, arrested, and died Western District Office of the Chief Medical Examiner, Roanoke, VA, USA postadmission. Blood cultures, bronchoalveolar lavage, and postmortem pulmonary tissue grew Group A beta hemolytic Streptococcus, only resistant to erythromycin. PMID- 28869232 TI - To immunosuppress or not: Behcet's syndrome presenting as an eosinophilic pleural effusion. AB - Etiologic diagnosis of an eosinophilic pleural effusion (EPE) presents a diagnostic challenge when intrapleural air and blood have been ruled out as its proximate causes. Among the causes of EPE, those that require immunosuppression for the underlying disease include connective tissue diseases, sarcoidosis, vasculitis, and eosinophilic pneumonia. We present a case of clinically suspected Behcet's syndrome based on a 10-year history of recurrent multiple oral ulcers and human leukocyte antigen-B51 positivity who presented with only an EPE. Computed tomography pulmonary angiogram ruled out central thoracic vein thrombosis but was inconclusive in ruling out a subsegmental pulmonary embolism. The patient declined immunosuppressants and while on follow-up developed bilateral extensive acute lower limb deep venous thrombosis and pulmonary embolism. Upper infrarenal inferior vena cava demonstrated chronic thrombosis suggestive of its antecedent role in pulmonary embolism-related EPE during the first instance. Behcet's syndrome-related EPE can be associated with venous thromboembolism, and immunosuppressive therapy prevents the subsequent thrombotic episodes. PMID- 28869233 TI - Meropenem: A possible new culprit in eosinophilic lung diseases. AB - Eosinophilic lung diseases are a diverse group of pulmonary disorders with an extensive list of differential diagnoses. Multiple drugs particularly antibiotics can cause pulmonary eosinophilia with variable pulmonary manifestations. Cutaneous drug reactions are common. Diagnosis is usually made on clinical history and blood eosinophilia with an accumulation of eosinophils in alveolar spaces on histologic analysis. Imaging findings are nonspecific. Stopping the offending agent is often enough while a short course of corticosteroids can hasten recovery. We present a unique case of eosinophilic pneumonia due to meropenem that highlights the importance of keeping a low threshold of suspicion regarding the etiology of drug-induced lung diseases as the current list is not exhaustive, and new agents are being identified continuously. A 51-year-old African American woman presented with fever, dyspnea, and diffuse pustular rash. She had been treated with meropenem intravenously through a peripherally inserted central catheter for 6 weeks before presentation for Pseudomonas aeruginosa septic arthritis of the left knee. She had a temperature of 102.2 F and SpO2of 86% on room air. Chest roentgenogram had scattered infiltrates and chest tomography showed bilateral ground-glass opacities. Laboratory workup showed peripheral eosinophilia. Bronchoalveolar lavage revealed a white blood cell of 2230 with 89% eosinophils. Skin lesions' biopsies showed pustular dermatosis, compatible with acute drug-induced eosinophilic lung disease with skin involvement. As meropenem was the only medication she had been exposed to, it was stopped and systemic steroids were initiated with improvement in respiratory and clinical status and complete recovery on follow-up. PMID- 28869234 TI - Weaning difficulty in a near hanging patient: An unusual cause. AB - Suicidal hanging causes damage to the airways, neck blood vessels as well as soft tissue injuries. We report the development of tracheo-esophageal fistula in such a patient. Recurrent soiling of the airways and the resultant lung infection led to weaning failure. We highlight the approach to diagnosis and appropriate management in such a patient. PMID- 28869235 TI - Chronic obstructive pulmonary disease and tuberculosis. PMID- 28869236 TI - Catheter pinch-off syndrome. PMID- 28869237 TI - Nasal route for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA): An alternative modality in difficult oral bronchoscope insertion. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is usually performed under moderate sedation through the oral approach. Oral insertion is performed owing to the larger size of the EBUS bronchoscope as well as the delicate and rigid distal end with an integrated ultrasound transducer assembly. Nasal route for EBUS scope insertion has been described as a feasible alternative. We herein report a patient wherein inability to introduce the EBUS bronchoscope through the mouth necessitated nasal insertion of the bronchoscope to successfully perform EBUS-TBNA. We discuss the relevant issues comparing the nasal and oral introduction of the EBUS bronchoscope. PMID- 28869238 TI - Familial interstitial pulmonary fibrosis in two different families in India: A case series. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF), a chronic progressive interstitial lung disease (ILD), Occasionally, IPF occurs in families. Familial interstitial lung disease has been reported worldwide, limited information is available on the disease among Indian patients. CASE PRESENTATION: A 59-year-old woman presented with a 2-year history of progressive dyspnoea. Based on clinical and radiological features, our patient was diagnosed with idiopathic pulmonary fibrosis. Several family members of her first and second generations had died from respiratory failure. Her sister also diagnosed as IPF based on typical High resolution computed tomography (HRCT) finding though she was asymptomatic and came for screening. In addition, another male patient also had similar history and diagnosed as familial IPF based on HRCT and genetic testing in spite of significant occupational exposure. Genetic study revealed SFTPA1 gene was associated with susceptibility to idiopathic pulmonary fibrosis. CONCLUSION: Our report illustrates that asymptomatic screening of family member can uncover such a serious disease in patients with familial interstitial fibrosis. Otherwise, clinical, radiological, and histological features are indistinguishable from those of sporadic cases. Furthermore, our work highlights the importance of compiling a thorough family history in individuals presenting with cough and dyspnoea, particularly in younger patients identified with idiopathic pulmonary fibrosis. PMID- 28869239 TI - "Cannon-Ball" skin metastases as the presenting manifestation of lung adenocarcinoma. PMID- 28869241 TI - Tracheobronchopathia osteochondroplastica following laryngeal tuberculosis. PMID- 28869240 TI - Transudative chylothorax and pleural tuberculosis in a patient with Eisenmenger syndrome: An extraordinary coincidence. PMID- 28869242 TI - Unusual presentation of lung cancer as skeletal muscle and subcutaneous metastases. PMID- 28869243 TI - Superior mediastinal syndrome secondary to Pott's spine in a child. PMID- 28869245 TI - Clinicomicrobiological study of community-acquired pneumonia. PMID- 28869244 TI - An unusual pulmonary metastatic manifestation of gestational choriocarcinoma: A diagnostic dilemma. PMID- 28869246 TI - Cosmetic silicone injection causing pneumomediastinum and respiratory failure. PMID- 28869247 TI - Mycobacterium tuberculosis and nontuberculosis mycobacteria co-infection: Two cases from the sub-Himalayan region of North India in a year. PMID- 28869248 TI - Pre-eclampsia: Screening and aspirin therapy for prevention of pre-eclampsia. PMID- 28869249 TI - GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. AB - The gastrointestinal tract - the largest endocrine network in human physiology - orchestrates signals from the external environment to maintain neural and hormonal control of homeostasis. Advances in understanding entero-endocrine cell biology in health and disease have important translational relevance. The gut derived incretin hormone glucagon-like peptide 1 (GLP-1) is secreted upon meal ingestion and controls glucose metabolism by modulating pancreatic islet cell function, food intake and gastrointestinal motility, amongst other effects. The observation that the insulinotropic actions of GLP-1 are reduced in type 2 diabetes mellitus (T2DM) led to the development of incretin-based therapies - GLP 1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors - for the treatment of hyperglycaemia in these patients. Considerable interest exists in identifying effects of these drugs beyond glucose-lowering, possibly resulting in improved macrovascular and microvascular outcomes, including in diabetic kidney disease. As GLP-1 has been implicated as a mediator in the putative gut-renal axis (a rapid-acting feed-forward loop that regulates postprandial fluid and electrolyte homeostasis), direct actions on the kidney have been proposed. Here, we review the role of GLP-1 and the actions of associated therapies on glucose metabolism, the gut-renal axis, classical renal risk factors, and renal end points in randomized controlled trials of GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM. PMID- 28869250 TI - Hypertension: A new genetic clue to unravel the origins of pre-eclampsia. PMID- 28869252 TI - Chronic kidney disease: PLD4 regulates kidney fibrosis. PMID- 28869254 TI - The effect of comb architecture on complex coacervation. AB - Complex coacervation is a widely utilized technique for effecting phase separation, though predictive understanding of molecular-level details remains underdeveloped. Here, we couple coarse-grained Monte Carlo simulations with experimental efforts using a polypeptide-based model system to investigate how a comb-like architecture affects complex coacervation and coacervate stability. Specifically, the phase separation behavior of linear polycation-linear polyanion pairs was compared to that of comb polycation-linear polyanion and comb polycation-comb polyanion pairs. The comb architecture was found to mitigate cooperative interactions between oppositely charged polymers, as no discernible phase separation was observed for comb-comb pairs and complex coacervation of linear-linear pairs yielded stable coacervates at higher salt concentration than linear-comb pairs. This behavior was attributed to differences in counterion release by linear vs. comb polymers during polyeletrolyte complexation. Additionally, the comb polycation formed coacervates with both stereoregular poly(l-glutamate) and racemic poly(d,l-glutamate), whereas the linear polycation formed coacervates only with the racemic polyanion. In contrast, solid precipitates were obtained from mixtures of stereoregular poly(l-lysine) and poly(l-glutamate). Moreover, the formation of coacervates from cationic comb polymers incorporating up to ~90% pendant zwitterionic groups demonstrated the potential for inclusion of comonomers to modulate the hydrophilicity and/or other properties of a coacervate-forming polymer. These results provide the first detailed investigation into the role of polymer architecture on complex coacervation using a chemically and architecturally well-defined model system, and highlight the need for additional research on this topic. PMID- 28869255 TI - Correction: Enhancements in catalytic reactivity and selectivity of homobimetallic complexes containing heteroditopic ligands. AB - Correction for 'Enhancements in catalytic reactivity and selectivity of homobimetallic complexes containing heteroditopic ligands' by Mark R. D. Gatus et al., Dalton Trans., 2017, 46, 7457-7466. PMID- 28869256 TI - Regioselective hydrogenolysis of aryl ether C-O bonds by tungsten carbides with controlled phase compositions. AB - Evenly dispersed tungsten carbides with controlled phase compositions that exhibit an impressive capacity to carry out the regioselective hydrogenolysis of inert aryl ether C-O bonds instead of aliphatic C-O bonds to produce aromatic compounds are reported. PMID- 28869257 TI - The hydrophobic force for bubble-particle attachment in flotation - a brief review. AB - A deep understanding of the bubble-particle attachment is critical to flotation science and engineering. Historically, the so called "hydrophobic force" has been widely accepted to be the reason for bubble-particle attachment although its origin is still under debate now. In this paper, a number of representative mechanisms for the origin of hydrophobic attractions are reviewed, with the main focus being on solid-solid systems. Then we highlight the recent advances in the hydrophobic force measurement between bubble and particle. Quantitative description of the hydrophobic force in bubble-particle system has been achieved recently. This review is closed with a brief conclusion and perspective discussion. PMID- 28869258 TI - Effect of protic additives in Cu-catalysed asymmetric Diels-Alder cycloadditions of doubly activated dienophiles: towards the synthesis of magellanine-type Lycopodium alkaloids. AB - The pronounced beneficial effect of a precise amount of protic additive in an enantioselective Cu-catalysed Diels-Alder reaction is reported. This reaction, which employs a cyclic alkylidene beta-ketoester as a dienophile, represents one of the first examples of a transformation where these extremely versatile, though highly unstable reaction partners participate effectively in catalytic asymmetric cycloaddition with a functionalised diene. The cycloadduct was used as an intermediate towards the synthesis of magellanine-type Lycopodium alkaloids featuring a Stille cross-coupling of a highly congested enol triflate and a unique Meinwald rearrangement/cyclopropanation sequence. PMID- 28869253 TI - Organ-specific protection mediated by cooperation between vascular and epithelial barriers. AB - Immune privilege is a complex process that protects organs from immune-mediated attack and damage. It is accomplished by a series of cellular barriers that both control immune cell entry and promote the development of tolerogenic immune cells. In this Review, we describe the vascular endothelial and epithelial barriers in organs that are commonly considered to be immune privileged, such as the brain and the eye. We compare these classical barriers with barriers in the intestine, which share features with barriers of immune-privileged organs, such as the capacity to induce tolerance and to protect from external insults. We suggest that when intestinal barriers break down, disruption of other barriers at distant sites can ensue, and this may underlie the development of various neurological, metabolic and intestinal disorders. PMID- 28869259 TI - Anti-hyperlipidemic effect of rice bran polysaccharide and its potential mechanism in high-fat diet mice. AB - Hyperlipidemia occurs very often in modern society along with a high calorie intake and is regarded as one of the greatest risk factors for the prevalence of cardiac vascular disease (CVD). In this study, we investigated the anti hyperlipidemic effect of the rice bran polysaccharides (RBP) and its mechanism in a high fat diet animal model. 60 ICR mice were randomly divided into 3 groups, which included Control, HFD (high fat diet) and HFD + RBP, and each group included 20 mice. The control group was fed with a standard diet while the other two groups were fed with HFD. In addition, the HFD + RBP group was fed with 500 mg kg-1 of rice bran polysaccharides by intragastric administration while the other two groups were intragastrically administered with water. The results showed that RBP treatment for 10 weeks obviously decreased the body weight, liver weight and adipose tissues of mice; and it decreased the levels of total cholesterol (TC), triglycerides (TG) and low density lipoprotein-cholesterol (LDL c) in the plasma. H&E staining of the liver tissues showed that RBP treatment decreased the size of fat droplets compared with the HFD group. Microarray analysis revealed that RBP treatment results in 80 genes being up-regulated while 72 genes were down-regulated in the tissues of liver. IPA software analysis suggested that NF-kappaB may play a vital role in the lipid-lowering effect of RBP. Real-time quantitative PCR confirmed that the mRNA levels of PPAR-alpha, PPAR-gamma, PPAR-delta, SREBP-1C, FASN, ACC, SIRT and CD36, which are related to lipid metabolism, were significantly regulated by RBP supplementation compared to HFD. The western blot analysis further confirmed these altered expressions after RBP treatment. Taken together, these results suggest that the oral administration of RBP exerts lipid-lowering in high fat diet mice via regulating the lipid metabolism-related gene expression. PMID- 28869251 TI - Cardiac surgery-associated acute kidney injury: risk factors, pathophysiology and treatment. AB - Cardiac surgery-associated acute kidney injury (CSA-AKI) is the most common clinically important complication in adult patients undergoing open heart surgery, and is associated with increased mortality and morbidity. In patients in intensive care units, CSA-AKI is the second most common type of AKI after septic AKI. In this Review, we explore the definition of CSA-AKI, discuss its epidemiology and identify its risk factors. We discuss current theories of the pathophysiology of CSA-AKI and describe its clinical course. Furthermore, we introduce diagnostic tools with particular reference to novel biomarkers of AKI and their potential utility; we analyse currently applied interventions aimed at attenuating AKI in patients undergoing cardiac surgery; and describe evidence from randomized controlled trials aimed at preventing or treating CSA-AKI. Finally, we explore issues in the use of renal replacement therapy, its timing, its intensity and its preferred modalities in patients with CSA-AKI, and we discuss the prognosis of CSA-AKI in terms of patient survival and kidney recovery. PMID- 28869260 TI - Base-mediated diastereoselective [4 + 3] annulation of in situ generated ortho quinone methides with C,N-cyclic azomethine imines. AB - An efficient [4 + 3] annulation of 2-(1-tosylalkyl)phenols with C,N-cyclic azomethine imines via in situ generation of ortho-quinone methides (o-QMs) under mild basic reaction conditions is disclosed, furnishing biologically interesting seven-membered heterocyclic compounds with moderate to good yields and excellent diastereoselectivities. A gram-scale reaction is performed to demonstrate the potential in industrial application and two transition states are proposed to rationalize the outstanding diastereoselectivity. PMID- 28869261 TI - Microfluidic bead trap as a visual bar for quantitative detection of oligonucleotides. AB - We demonstrate a microfluidic bead trap capable of forming a dipstick-type bar visible to the naked eye for simple and quantitative detection of oligonucleotides. We use magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) that are connected and form MMPs-targets-PMPs when target oligonucleotides are present, leaving free PMPs with a number inversely proportional to the amount of targets. Using a capillary flow-driven microfluidic circuitry consisting of a magnetic separator to remove the MMPs-targets-PMPs, the free PMPs can be trapped at the narrowing nozzle downstream, forming a visual bar quantifiable based on the length of PMP accumulation. Such a power-free and instrument-free platform enables a limit of detection at 13 fmol (0.65 nM in 20 MUl, S/N = 3) of oligonucleotides and is compatible with single-nucleotide polymorphisms and operation in a complex bio-fluid. Moreover, using DNAzyme as the target oligonucleotide that catalyzes a specific hydrolytic cleavage in the presence of lead ions, we demonstrate a model application that detects lead ions with a limit of detection of 12.2 nM (2.5 MUg l-1), providing quantitative and visual detection of lead contamination at resource-limited sites. PMID- 28869262 TI - The effects of exfoliation, organic solvents and anodic activation on the catalytic hydrogen evolution reaction of tungsten disulfide. AB - The rational design of transition metal dichalcogenide electrocatalysts for efficiently catalyzing the hydrogen evolution reaction (HER) is believed to lead to the generation of a renewable energy carrier. To this end, our work has made three main contributions. At first, we have demonstrated that exfoliation via ionic liquid assisted grinding combined with gradient centrifugation is an efficient method to exfoliate bulk WS2 to nanosheets with a thickness of a few atomic layers and lateral size dimensions in the range of 100 nm to 2 nm. These WS2 nanosheets decorated with scattered nanodots exhibited highly enhanced catalytic performance for HER with an onset potential of -130 mV vs. RHE, an overpotential of 337 mV at 10 mA cm-2 and a Tafel slope of 80 mV dec-1 in 0.5 M H2SO4. Secondly, we found a strong aging effect on the electrocatalytic performance of WS2 stored in high boiling point organic solvents such as dimethylformamide (DMF). Importantly, the HER ability could be recovered by removing the organic (DMF) residues, which obstructed the electron transport, with acetone. Thirdly, we established that the HER performance of WS2 nanosheets/nanodots could be significantly enhanced by activating the electrode surface at a positive voltage for a very short time (60 s), decreasing the kinetic overpotential by more than 80 mV at 10 mA cm-2. The performance enhancement was found to arise primarily from the ability of a formed proton intercalated amorphous tungsten trioxide (a-WO3) to provide additional active sites and favourably modify the immediate chemical environment of the WS2 catalyst, rendering it more favorable for local proton delivery and/or transport to the active edge site of WS2. Our results provide new insights into the effects of organic solvents and electrochemical activation on the catalytic performance of two-dimensional WS2 for HER. PMID- 28869263 TI - Two-dimensional GeP3 as a high capacity electrode material for Li-ion batteries. AB - Two-dimensional (2D) materials are promising for use in lithium (Li) electrodes due to their high surface ratio. By using density functional theory (DFT) calculations, we investigate the adsorption and diffusion of Li on a newly predicted 2D GeP3 material [Nano Lett., 2016, 17, 1833]. The most favourable adsorption sites for Li are identified, and a semiconducting to metallic transition induced by Li adsorption is found, which indicates excellent electrical conductivity. The GeP3 monolayer has an estimated capacity of 648 mA h g-1, which is almost twice that of commercially used graphite (375 mA h g-1). During full Li intercalation, the GeP3 layer undergoes only 1.2% lattice parameter reduction. Moreover, GeP3 possesses the advantages of a small diffusion barrier (~0.5 eV) and low average open-circuit voltages (~0.4 V). Our results highlight a new class of promising anode materials, i.e. 2D phosphide, as potential rechargeable lithium batteries with ultrahigh-capacity, superior ionic conductivity, and low average open-circuit voltage. PMID- 28869264 TI - Synthesis of 2-aminoBODIPYs by palladium catalysed amination. AB - Palladium catalysed coupling of the 2-iodoBODIPY 3 with a range of anilines and a primary alkylamine succeeds in generating the corresponding 2-aminoBODIPYs. These 2-aminoBODIPY derivatives are non-emissive and quantum chemical calculations and electrochemistry are consistent with charge transfer from the amine substituent. Attenuation of this charge transfer pathway by conversion of the 1,2 phenylenediamine derivative 9 into the corresponding benzimidazolone 10 restores the fluorescence and has been used as the basis for a fluorescence sensor for phosgene. PMID- 28869265 TI - Tuning interfacial patterns of molecular bonds via surface morphology. AB - Many studies have demonstrated that the mechanical properties of the extracellular matrix can significantly influence the morphology, strength and lifetime of focal adhesions. However, how the morphology of the contact surface affects the pattern formation of the molecular bonds still remains largely unknown. Here, by simplifying the cell and extracellular matrix to two opposing elastic bodies and considering the lateral diffusion as well as the bonding/debonding of molecular bonds, we study the clustering behavior of receptor-ligand bonds between curved surfaces and the phase diagrams of cluster patterns. We reveal the important role of surface morphology and bond kinetics in regulating the patterns of bond clusters. We further investigate the segregation dynamics of the interfacial bonds under various loading speeds, and we show that the average interfacial stress is rate-dependent while the rupture stress is rate independent. Finally, we demonstrate that programmable patterning of bond clusters can be achieved through the designed surface morphology. PMID- 28869266 TI - NI(ii) phosphine and phosphide complexes supported by a PNP-pyrrole pincer ligand. AB - The reaction between [(PNpyrP)NiCl] (1, PNpyrP = 2,5-bis((di-iso-propylphosphino) methyl)-1H-pyrrolide) and TlPF6 in the presence of a monodentate phosphine ligand led to cationic nickel phosphine and phosphite complexes, [(PNpyrP)Ni(PHPh2)][PF6] (2), [(PNpyrP)Ni(PMe3)][PF6] (3), and [(PNpyrP)Ni{P(OMe)3}][PF6] (4). Compound 2 can be deprotonated resulting in the generation of a terminal phosphido complex, [(PNpyrP)Ni(PPh2)] (5). When 3 is subjected to a base, a methyl proton of PMe3 is abstracted to afford [(PNpyrP)Ni(CH2PMe2)] (6), containing a methylene bridge between Ni and the external phosphine. Compounds 2-6 were characterized by single crystal X-ray diffraction in addition to multi-nuclear NMR spectroscopy and elemental analysis. PMID- 28869267 TI - Multimodal imaging and photothermal therapy were simultaneously achieved in the core-shell UCNR structure by using single near-infrared light. AB - Core-shell nanostructures consisting of plasmonic materials and lanthanide-doped upconversion nanoparticles (UCNPs) show promising applications in theranostics including bio-imaging, diagnosis and therapy. However, some challenges still remain in the synthetic control because of the non-coordination between energy transfer and photothermal therapy (PTT). Herein, we developed a novel type of thermal-fluorescent core-shell hybrid nanocomposite incorporating rare-earth Yb3+ and Er3+ ion doped GdOF as the shell and gold nanorods (GNRs) as the core, creating upconversion nanorods (UCNRs) of GNRs@GdOF:Yb3+,Er3+. In order to facilitate the absorption or excretion of UCNRs in vivo, we designed gold nanorods with lower aspect ratios by reducing the amount of CTAB in the growth solution. More importantly, under 980 nm near-infrared (NIR) light irradiation, the green and red emissions of GdOF:Yb3+,Er3+ generally overlap with the visible absorbance of GNRs; by altering the contents of Yb3+ and Er3+ ions appropriately, the localized surface plasmon resonance (LSPR) absorption of low aspect ratio GNRs under 980 nm NIR laser excitation can be enhanced for improving the PTT efficiency. Furthermore, in vitro and in vivo assays reveal that the composite has excellent bio-compatibility and cancer therapy efficiency. This multi functional nanocomposite, which possesses upconversion luminescence and photothermal and biocompatibility properties, shows strong potential for application in bio-imaging and photothermal anti-cancer therapy. PMID- 28869268 TI - Multi-scale structural analysis of the A-site and oxygen deficient perovskite Sr11Mo4O23. AB - The long range average crystal structure, as well as the short and medium range structural features, of the A-site deficient and oxygen deficient perovskite Sr11Mo4O23 have been determined. Rietveld refinement of synchrotron X-ray and neutron powder diffraction data show that this compound is cubic with space group Fd3[combining macron]m and a lattice parameter of a = 16.4108 A. These findings contradict earlier reports of a tetragonal crystal structure. Sr11Mo4O23 appears to be isostructural with Ba11W4O23, except that the disordered coordination environment around one of the Mo sites seems to be a mixture of octahedral and square pyramidal instead of octahedral and tetrahedral. The short and medium range structural features have been inspected using the neutron pair distribution function (PDF). Short range correlations between the oxygen polyhedra surrounding the Mo(2) atom exist to avoid short O-O contacts. A model has been constructed which contains such correlations and is verified by reverse Monte Carlo (RMC) modeling of the PDF. The RMC refinements also give the distribution of inter atomic distances in this compound which reveals how the various atomic positions are correlated and over what length scales. These results are important for understanding the ionic conduction pathways. PMID- 28869269 TI - Mono-BHT heteroleptic magnesium complexes: synthesis, molecular structure and catalytic behavior in the ring-opening polymerization of cyclic esters. AB - Numerous heteroleptic 2,6-di-tert-butyl-4-methylphenolate (BHT) magnesium complexes have been synthesized by treatment of (BHT)MgBu(THF)2 with various alcohols. Molecular structures of the complexes have been determined by X-ray diffraction. The magnesium coordination number in [(BHT)Mg(MU-OBn)(THF)]2 (3) and [(BHT)Mg(MU-O-tert-BuC6H4)(THF)]2 (4) is equal to 4. Complexes formed from esters of glycolic and lactic acids, [(BHT)Mg(MU-OCH2COOEt)(THF)]2 (5) and [(BHT)Mg(MU OCH(CH3)COOCH2COOtBu)(THF)]2 (6) contain chelate fragments with pentacoordinated magnesium. Compounds 3-6 contain THF molecules coordinated to magnesium atoms. Complex {(BHT)Mg[MU-O(CH2)3CON(CH3)2]}2 (7) does not demonstrate any tendency to form an adduct with THF. It has been experimentally determined that complexes 3 and 5 are highly active catalysts of lactide polymerization. The activity of 4 is rather low, and complex 7 demonstrates moderate productivity. According to DOSY NMR experiments, compounds 3 and 5 retain their dimeric structures even in THF. The free energies of model dimeric [(DBP)Mg(MU-OMe)(Sub)]2 and monomeric (DBP)Mg(OMe)(Sub)2 products on treatment of [(DBP)Mg(MU-OMe)(THF)]2 with a series of sigma-electron donors (Sub) have been estimated by DFT calculations. These results demonstrate that the substitution of THF by Sub in a dimeric molecule is an energetically allowed process, whereas the dissociation of dimers is energetically unfavorable. DFT modeling of epsilon-CL and (dl)-lactide ROP catalyzed by dimeric and monomeric complexes showed that a cooperative effect of two magnesium atoms occurs within the ROP for binuclear catalytic species. A comparison of the reaction profiles for ROP catalyzed by binuclear and mononuclear species allowed us to conclude that the binuclear mechanism is favorable in early stages of ROP initiated by dimers 3 and 5. PMID- 28869271 TI - Understanding the influence of low-frequency vibrations on the hydrogen bonds of acetic acid and acetamide dimers. AB - Low-frequency vibrations coupled to high-frequency modes are known to influence the hydrogen bond strengths in a weakly interacting dimer. In this context, various acetic acid and acetamide dimers were analyzed using Moller-Plesset second-order perturbation (MP2) and density functional theory (DFT)-based approaches with explicit anharmonicity corrections. The computed low-frequency fundamentals as well as the high-frequency modes, which were found to be related to hydrogen bonding (OH/NH stretching modes), were analyzed and their computed intensities were correlated with their hydrogen-bond strengths/binding energies. There are similarities in the nature of eight low-frequency fundamentals of these two dimers, and the in-plane bending and stretch-bend fundamentals of the different dimers of these two species (in this low-frequency region) have specific roles in their relative stability order. The computed linear correlations were further verified against the results from coupled cluster calculations including triple excitation (CCSD(T)), Gaussian-G4 (G4), Gaussian-G2 MP2 (G2MP2) and complete basis set (CBS-QB3) methods of high accuracy energy calculations. As a consequence of such linear correlations, an additive property of local fragment energies (responsible for hydrogen bonding) was found to be a valid approximation to predict the binding energies of such dimers and the idea was found to be extendable to the other homologues of these acids/amides. PMID- 28869272 TI - Two-dimensional flow of driven particles: a microfluidic pathway to the non equilibrium frontier. AB - We discuss the basic physics of the flow of micron-scale droplets in 2D geometry. Our focus is on the use of droplet ensembles to look into fundamental questions of non-equilibrium systems, such as the emergence of dynamic patterns and irreversibility. We review recent research in these directions, which demonstrate that 2D microfluidics is uniquely set to study complex out-of-equilibrium phenomena thanks to the simplicity of the underlying Stokes flow and the accessibility of lab-on-chip technology. PMID- 28869270 TI - Proteomic and genetic analysis of the response of S. cerevisiae to soluble copper leads to improvement of the antimicrobial function of cellulosic copper nanoparticles. AB - Copper (Cu) was used in antiquity to prevent waterborne and food diseases because, as a broad-spectrum antimicrobial agent, it generates reactive oxygen species, ROS. New technologies incorporating Cu into low-cost biodegradable nanomaterials built on cellulose, known as cellulosic cupric nanoparticles or c CuNPs, present novel approaches to deliver Cu in a controlled manner to control microbial growth. We challenged strains of Saccharomyces cerevisiae with soluble Cu and c-CuNPs to evaluate the potential of c-CuNPs as antifungal agents. Cells exposed to c-CuNPs demonstrated greater sensitivity to Cu than cells exposed to soluble Cu, although Cu-resistant strains were more tolerant than Cu-sensitive strains of c-CuNP exposure. At the same level of growth inhibition, 157 MUM c CuNPs led to the same internal Cu levels as did 400 MUM CuSO4, offering evidence for alternative mechanisms of toxicity, perhaps through beta-arrestin dependent endocytosis, which was supported by flow cytometry and fluorescence microscopy of c-CuNPs distributed both on the cell surface and within the cytoplasm. Genes responsible for genetic variation in response to copper were mapped to the ZRT2 and the CUP1 loci. Through proteomic analyses, we found that the expression of other zinc (Zn) transporters increased in Cu-tolerant yeast compared to Cu sensitive strains. Further, the addition of Zn at low levels increased the potency of c-CuNPs to inhibit even the most Cu-tolerant yeast. Through unbiased systems biological approaches, we identified Zn as a critical component of the yeast response to Cu and the addition of Zn increased the potency of the c-CuNPs. PMID- 28869273 TI - Evolution of nanostructured single-phase CoSb3 thin films by low-energy ion beam induced mixing and their thermoelectric performance. AB - Skutterudites are emerging as potential candidates that show high efficiency and thus provide an ideal platform for research. The properties of nanostructured films of skutterudites are different from those of the corresponding bulk. The present study reports the evolution of nanostructured single-phase CoSb3 fabricated by using low-energy ion irradiation of Co/Sb bilayer films and subsequent annealing at an optimized temperature and their Seebeck coefficients (S). The effects of ion beam parameters with annealing on the phase evolution and nanostructure modifications were studied. An increase in Xe+ ion fluence resulted in complete mixing of Co/Sb on postannealing forming flower-like nanostructures of single phase CoSb3. The temperature-dependent electrical resistivity (rho) increases with the ion fluence because of defect creation which further increases on postannealing due to surface nanostructuring. The S of these films of CoSb3 is found to be higher and this is attributed to the formation of a uniform layer of nanostructured CoSb3 alloy thin film. The S and Hall coefficients of all these films are negative implying that they are n-type semiconductors. PMID- 28869274 TI - Probing the modulated formation of gold nanoparticles-beta-lactoglobulin corona complexes and their applications. AB - Understanding the interactions between proteins and nanoparticles (NPs) along with the underlying structural and dynamic information is of utmost importance to exploit nanotechnology for biomedical applications. Upon adsorption onto a NP surface, proteins form a well-organized layer, termed the corona, that dictates the identity of the NP-protein complex and governs its biological pathways. Given its high biological relevance, in-depth molecular investigations and applications of NPs-protein corona complexes are still scarce, especially since different proteins form unique corona patterns, making identification of the biomolecular motifs at the interface critical. In this work, we provide molecular insights and structural characterizations of the bio-nano interface of a popular food-based protein, namely bovine beta-lactoglobulin (beta-LG), with gold nanoparticles (AuNPs) and report on our investigations of the formation of corona complexes by combined molecular simulations and complementary experiments. Two major binding sites in beta-LG were identified as being driven by citrate-mediated electrostatic interactions, while the associated binding kinetics and conformational changes in the secondary structures were also characterized. More importantly, the superior stability of the corona led us to further explore its biomedical applications, such as in the smartphone-based point-of-care biosensing of Escherichia coli (E. coli) and in the computed tomography (CT) of the gastrointestinal (GI) tract through oral administration to probe GI tolerance and functions. Considering their biocompatibility, edible nature, and efficient excretion through defecation, AuNPs-beta-LG corona complexes have shown promising perspectives for future in vitro and in vivo clinical settings. PMID- 28869275 TI - Density functional study on the resistance to sulfur poisoning of Ptx (x = 0, 1, 4 and 8) modified alpha-Mo2C(0001) surfaces. AB - The tolerance of sulfur poisoning of alpha-Mo2C(0001) surfaces with different Pt coverages is investigated combining the density functional theory (DFT) results with thermodynamics data using the ab initio atomistic thermodynamic method. It is found that on Mo2C(0001), Pt clusters tend to form two dimensional planar structures instead of aggregating. The clean Mo2C(0001) surface interacts with sulfides very strongly and is susceptible to sulfur poisoning. With increasing the coverage of Pt on the Mo2C surface, the interaction between sulfur and substrate is weakened. The sulfur tolerance ability increases in the order of Mo2C ~ Pt1/Mo2C < Pt4/Mo2C < Pt8/Mo2C, where the coverage of Pt on the Mo2C plays a very effective role. The results provide theoretical guidance for designing Mo2C based catalysts with high activity and high sulfur resistance. PMID- 28869276 TI - Amniocentesis and chorionic villus sampling for prenatal diagnosis. AB - BACKGROUND: During pregnancy, fetal cells suitable for genetic testing can be obtained from amniotic fluid by amniocentesis (AC), placental tissue by chorionic villus sampling (CVS), or fetal blood. A major disadvantage of second trimester amniocentesis is that the results are available relatively late in pregnancy (after 16 weeks' gestation). Earlier alternatives are chorionic villus sampling (CVS) and early amniocentesis, which can be performed in the first trimester of pregnancy. OBJECTIVES: The objective of this review was to compare the safety and accuracy of all types of AC (i.e. early and late) and CVS (e.g. transabdominal, transcervical) for prenatal diagnosis. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (3 March 2017), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP; 3 March 2017), and reference lists of retrieved studies. SELECTION CRITERIA: All randomised trials comparing AC and CVS by either transabdominal or transcervical route. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included a total of 16 randomised studies, with a total of 33,555 women, 14 of which were deemed to be at low risk of bias. The number of women included in the trials ranged from 223 to 4606.Studies were categorized into six comparisons: 1. second trimester AC versus control; 2. early versus second trimester AC; 3. CVS versus second trimester AC; 4. CVS methods; 5. Early AC versus CVS; and 6. AC with or without ultrasound.One study compared second trimester AC with no AC (control) in a low risk population (women = 4606). Background pregnancy loss was around 2%. Second trimester AC compared to no testing increased total pregnancy loss by another 1%. The confidence intervals (CI) around this excess risk were relatively large (3.2% versus 2.3 %, average risk ratio (RR) 1.41, 95% CI 0.99 to 2.00; moderate-quality evidence). In the same study, spontaneous miscarriages were also higher (2.1% versus 1.3%; average RR 1.60, 95% CI 1.02 to 2.52; high-quality evidence). The number of congenital anomalies was similar in both groups (2.0% versus 2.2%, average RR 0.93, 95% CI 0.62 to 1.39; moderate-quality evidence).One study (women = 4334) found that early amniocentesis was not a safe early alternative compared to second trimester amniocentesis because of increased total pregnancy losses (7.6% versus 5.9%; average RR 1.29, 95% CI 1.03 to 1.61; high-quality evidence), spontaneous miscarriages (3.6% versus 2.5%, average RR 1.41, 95% CI 1.00 to 1.98; moderate quality evidence), and a higher incidence of congential anomalies, including talipes (4.7% versus 2.7%; average RR 1.73, 95% CI 1.26 to 2.38; high-quality evidence).When pregnancy loss after CVS was compared with second trimester AC, there was a clinically significant heterogeneity in the size and direction of the effect depending on the technique used (transabdominal or transcervical), therefore, the results were not pooled. Only one study compared transabdominal CVS with second trimester AC (women = 2234). They found no clear difference between the two procedures in the total pregnancy loss (6.3% versus 7%; average RR 0.90, 95% CI 0.66 to 1.23, low-quality evidence), spontaneous miscarriages (3.0% versus 3.9%; average RR 0.77, 95% CI 0.49 to 1.21; low-quality evidence), and perinatal deaths (0.7% versus 0.6%; average RR 1.18, 95% CI 0.40 to 3.51; low quality evidence). Transcervical CVS may carry a higher risk of pregnancy loss (14.5% versus 11.5%; average RR 1.40, 95% CI 1.09 to 1.81), but the results were quite heterogeneous.Five studies compared transabdominal and transcervical CVS (women = 7978). There were no clear differences between the two methods in pregnancy losses (average RR 1.16, 95% CI 0.81 to 1.65; very low-quality evidence), spontaneous miscarriages (average RR 1.68, 95% CI 0.79 to 3.58; very low-quality evidence), or anomalies (average RR 0.68, 95% CI 0.41 to 1.12; low quality evidence). We downgraded the quality of the evidence to low due to heterogeneity between studies. Transcervical CVS may be more technically demanding than transabdominal CVS, with more failures to obtain sample (2.0% versus 1.1%; average RR 1.79, 95% CI 1.13 to 2.82, moderate-quality evidence).Overall, we found low-quality evidence for outcomes when early amniocentesis was compared to transabdominal CVS. Spontaneous miscarriage was the only outcome supported by moderate-quality evidence, resulting in more miscarriages after early AC compared with transabdominal CVS (2.3% versus 1.3%; average RR 1.73, 95% CI 1.15 to 2.60). There were no clear differences in pregnancy losses (average RR 1.15, 95% CI 0.86 to 1.54; low-quality evidence), or anomalies (average RR 1.14, 95% CI 0.57 to 2.30; very low-quality evidence).We found one study that examined AC with or without ultrasound, which evaluated a type of ultrasound-assisted procedure that is now considered obsolete. AUTHORS' CONCLUSIONS: Second trimester amniocentesis increased the risk of pregnancy loss, but it was not possible to quantify this increase precisely from only one study, carried out more than 30 years ago.Early amniocentesis was not as safe as second trimester amniocentesis, illustrated by increased pregnancy loss and congenital anomalies (talipes). Transcervical chorionic villus sampling compared with second trimester amniocentesis may be associated with a higher risk of pregnancy loss, but results were quite heterogeneous.Diagnostic accuracy of different methods could not be assessed adequately because of incomplete karyotype data in most studies. PMID- 28869277 TI - Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson's disease. AB - OBJECTIVES: Cognitive decline is common in Parkinson's disease (PD), but the underlying mechanisms for this complication are incompletely understood. Genotypes affecting dopamine transmission may be of importance. This study investigates whether genotypes associated with reduced prefrontal dopaminergic tone and/or reduced dopamine D2-receptor availability (Catechol-O methyltransferase [COMT] Val158 Met genotype and DRD2 C957 T genotype) affect the development of cognitive deficits in PD. MATERIALS AND METHODS: One hundred and 34 patients with idiopathic PD, participating in a regional, population-based study of incident parkinsonism, underwent genotyping. After extensive baseline investigations (including imaging and biomarker analyses), the patients were followed prospectively during 6-10 years with neuropsychological evaluations, covering six cognitive domains. Cognitive decline (defined as the incidence of either Parkinson's disease mild cognitive impairment [PD-MCI] or dementia [PDD], diagnosed according to published criteria and blinded to genotype) was studied as the primary outcome. RESULTS: Both genotypes affected cognition, as shown by Cox proportional hazards models. While the COMT 158 Val/Val genotype conferred an increased risk of mild cognitive impairment in patients with normal cognition at baseline (hazard ratio: 2.13, P = .023), the DRD2 957 T/T genotype conferred an overall increased risk of PD dementia (hazard ratio: 3.22, P < .001). The poorer cognitive performance in DRD2 957 T/T carriers with PD occurred mainly in episodic memory and attention. CONCLUSIONS: The results favor the hypothesis that dopamine deficiency in PD not only relate to mild cognitive deficits in frontostriatal functions, but also to a decline in memory and attention. This could indicate that dopamine deficiency impairs a wide network of brain areas. PMID- 28869278 TI - Cerebral near-infrared spectroscopy monitoring for prevention of brain injury in very preterm infants. AB - BACKGROUND: Cerebral injury and long-term neurodevelopmental impairment is common in extremely preterm infants. Cerebral near-infrared spectroscopy (NIRS) enables continuous estimation of cerebral oxygenation. This diagnostic method coupled with appropriate interventions if NIRS is out of normal range (that is cerebral oxygenation within the 55% to 85% range) may offer benefits without causing more harms. Therefore, NIRS coupled with appropriate responses to abnormal findings on NIRS needs assessment in a systematic review of randomised clinical trials and quasi-randomised studies. OBJECTIVES: To evaluate the benefits and harms of interventions that attempt to alter cerebral oxygenation guided by cerebral NIRS monitoring in order to prevent cerebral injury, improve neurological outcome, and increase survival in preterm infants born more than 8 weeks preterm. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 8), MEDLINE via PubMed (1966 to 10 September 2016), Embase (1980 to 10 September 2016), and CINAHL (1982 to 10 September 2016). We also searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised clinical trials and quasi-randomised studies. SELECTION CRITERIA: Randomised clinical trials and quasi-randomised clinical studies comparing continuous cerebral NIRS monitoring for at least 24 hours versus blinded NIRS or versus no NIRS monitoring. DATA COLLECTION AND ANALYSIS: Two review authors independently selected, assessed the quality of, and extracted data from the included trials and studies. If necessary, we contacted authors for further information. We conducted assessments of risks of bias; risks of design errors; and controlled the risks of random errors with Trial Sequential Analysis. We assessed the quality of the evidence with GRADE. MAIN RESULTS: One randomised clinical trial met inclusion criteria, including infants born more than 12 weeks preterm. The trial employed adequate methodologies and was assessed at low risk of bias. One hundred and sixty-six infants were randomised to start continuous cerebral NIRS monitoring less than 3 hours after birth until 72 hours after birth plus appropriate interventions if NIRS was out of normal range according to a guideline versus conventional monitoring with blinded NIRS. There was no effect of NIRS plus guideline of mortality until term-equivalent age (RR 0.50, 95% CI 0.29 to 1.00; one trial; 166 participants). There were no effects of NIRS plus guideline on intraventricular haemorrhages: all grades (RR 0.93, 95% CI 0.65 to 1.34; one trial; 166 participants); grade III/IV (RR 0.57, 95% CI 0.25 to 1.31; one trial; 166 participants); and cystic periventricular leukomalacia (which did not occur in either group). Likewise, there was no effect of NIRS plus guideline on the occurrence of a patent ductus arteriosus (RR 1.96, 95% CI 0.94 to 4.08; one trial; 166 participants); chronic lung disease (RR 1.27, 95% CI 0.94 to 1.50; one trial; 166 participants); necrotising enterocolitis (RR 0.83, 95% CI 0.33 to 1.94; one trial; 166 participants); and retinopathy of prematurity (RR 1.64, 95% CI 0.75 to 3.00; one trial; 166 participants). There were no serious adverse events in any of the intervention groups. NIRS plus guideline caused more skin marks from the NIRS sensor in the control group than in the experimental group (unadjusted RR 0.31, 95% CI 0.10 to 0.92; one trial; 166 participants). There are no data regarding neurodevelopmental outcome, renal impairment or air leaks.The quality of evidence for all comparisons discussed above was assessed as very low apart from all-cause mortality and adverse events: these were assessed as low and moderate, respectively. The validity of all comparisons is hampered by a small sample of randomised infants, risk of bias due to lack of blinding, and indirectness of outcomes. AUTHORS' CONCLUSIONS: The only eligible randomised clinical trial did not demonstrate any consistent effects of NIRS plus a guideline on the assessed clinical outcomes. The trial was, however, only powered to detect difference in cerebral oxygenation, not morbidities or mortality. Our systematic review did not reach sufficient power to prove or disprove effects on clinical outcomes. Further randomised clinical trials with low risks of bias and low risks of random errors are needed. PMID- 28869279 TI - Life situation 5 years after subarachnoid haemorrhage. AB - OBJECTIVES: Subarachnoid haemorrhage (SAH) has high mortality and morbidity among survivors. SAH mainly affects young people and may result in long-term disabilities such as decreased Health-related Quality of Life (HRQoL), mental health and cognitive function. The aim of this study was to investigate the life situation 5 years after a SAH including physical/emotional status, participation and HRQoL. MATERIALS & METHODS: In this cross-sectional descriptive study, a mail survey was sent to all persons treated at a neurosurgery unit in Gothenburg, Sweden, for non-traumatic SAH in 2009-2010, approximately 5 years post-SAH. The survey included questions regarding HRQoL; EuroQol 5-Dimensions (EQ-5D), the impact of the SAH; Stroke Impact Scale (SIS), Occupational Gaps Questionnaire and participation in society; Impact of Participation and Autonomy (IPA). RESULTS: Forty-two 5 year survivors were sent the survey, of whom 26 (62%) responded (59 years old, range 33-85). The participants had generally low HRQoL and scored low in the domain of anxiety and depression. Many reported problems with emotions, fatigue, memory and executive function, but few problems with physical condition. However, nearly all participants reported to have an acceptable level of participation and 64% were independent in their daily life. CONCLUSIONS: In this 5-year follow-up after SAH, the participants reported to have a greater number of hidden disabilities compared to physical problems, whereas most had acceptable participation in society. A yearly follow-up after a SAH could be suggested aiming to improving the cognitive and mental health. PMID- 28869281 TI - Dogs don't always prefer their owners and can quickly form strong preferences for certain strangers over others. AB - The unique relationship between dog and owner has been demonstrated in several experimental procedures, including tests in which dogs are left alone or with a stranger, tests of dogs' appeasement or social approach when petted by their owner or a stranger, and their ability to learn when taught by their owner or a stranger. In all cases, dogs responded differently to their owner, which has been referred to as a specific attachment, and likely a product of a prolonged history of reinforcement. In the current study, we used a concurrent choice paradigm in which dogs could interact with two people, both of whom provided the same petting interaction, to test whether owned dogs would prefer their owner over a stranger and whether the familiarity of the testing context would influence preference. We also investigated whether shelter and owned dogs tested with two strangers would show a preference between strangers and whether that preference would be similar in magnitude to any preference between the owner and stranger. Owned dogs preferred to interact with their owners when in an unfamiliar context, but allocated more time to the stranger in a familiar context. Both shelter and owned dogs tested with two strangers showed a magnitude of preference for one stranger over the other similar to owned dogs' preference for owners in an unfamiliar context. These results parallel what has been found in strange situation tests with owned dogs tested with their owners, but the strength of preference shown for one of two strangers indicates dogs can form a preference for one person quickly. PMID- 28869282 TI - Percutaneous sclerotherapy using bleomycin for the treatment of vascular malformations. AB - BACKGROUND: Some vascular malformations are difficult to manage with surgical treatment. Thus, percutaneous sclerotherapy has been utilized with several advantages over surgical treatment. Bleomycin is one of several sclerosing agents used for the treatment of vascular malformations. OBJECTIVES: To evaluate therapeutic efficacy and safety of percutaneous sclerotherapy using bleomycin for the treatment of vascular malformations. METHODS: Thirty patients diagnosed with vascular malformations, including four with capillary malformations with nodular change, nine with lymphatic malformations, and 17 with venous malformations, were involved in the study. Patients received magnetic resonance imaging and pulmonary surveillance prior to the treatment. Clinical assessments for the degree of vascularity disappearance and adverse effects were performed by the investigator. RESULTS: Percutaneous sclerotherapy using bleomycin was performed in 3.2 sessions (mean) over 3 months (mean). Significant improvement was observed in 90.0% of all lesions. All lesions of capillary malformation with nodular change and lymphatic malformation demonstrated significant improvement, and 82.4% of lesions of venous malformation improved significantly. Seven patients (23.3%) complained of side effects including pain and headache. All occurred within 24 hours and were tolerable. CONCLUSIONS: Percutaneous sclerotherapy using bleomycin is effective and tolerable in the treatment of vascular malformation through a percutaneous approach. Therefore, it could be applied usefully for vascular malformations by dermatologists. PMID- 28869284 TI - Ultra-performance liquid chromatography-tandem mass spectrometry assay for determination of plasma nomegestrol acetate and estradiol in healthy postmenopausal women. AB - A highly sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry method is described for the simultaneous determination of nomegestrol acetate (NOMAC), a highly selective progestogen, and estradiol (E2), a natural estrogen in human plasma. NOMAC was obtained from plasma by solid-phase extraction, while E2 was first separated by liquid-liquid extraction with methyl tert-butyl ether followed by derivatization with dansyl chloride. Deuterated internal standards, NOMAC-d5 and E2-d4 were used for better control of extraction conditions and ionization efficiency. The assay recovery of the analytes was within 90-99%. The analytes were separated on UPLC BEH C18 (50 * 2.1 mm, 1.7 MUm) column using a mobile phase comprising of acetonitrile and 3.0 mm ammonium trifluoroacetate in water (80:20, v/v) with a resolution factor (Rs ) of 3.21. The calibration curves were linear from 0.01 to 10.0 ng/mL for NOMAC and from 1.00 to 1000 pg/mL for E2, respectively. The intra- and inter-batch precision was <=5.8% and the accuracy of quality control samples ranged from 96.7 to 103.4% for both analytes. The practical applicability of the method is demonstrated by analyzing samples from 18 healthy postmenopausal women after oral administration of 2.5 mg nomegestrol acetate and 1.5 mg estradiol film-coated tablets under fasting. PMID- 28869283 TI - Review article: the human intestinal virome in health and disease. AB - BACKGROUND: The human virome consists of animal-cell viruses causing transient infections, bacteriophage (phage) predators of bacteria and archaea, endogenous retroviruses and viruses causing persistent and latent infections. High throughput, inexpensive, sensitive sequencing methods and metagenomics now make it possible to study the contribution dsDNA, ssDNA and RNA virus-like particles make to the human virome, and in particular the intestinal virome. AIM: To review and evaluate the pioneering studies that have attempted to characterise the human virome and generated an increased interest in understanding how the intestinal virome might contribute to maintaining health, and the pathogenesis of chronic diseases. METHODS: Relevant virome-related articles were selected for review following extensive language- and date-unrestricted, electronic searches of the literature. RESULTS: The human intestinal virome is personalised and stable, and dominated by phages. It develops soon after birth in parallel with prokaryotic communities of the microbiota, becoming established during the first few years of life. By infecting specific populations of bacteria, phages can alter microbiota structure by killing host cells or altering their phenotype, enabling phages to contribute to maintaining intestinal homeostasis or microbial imbalance (dysbiosis), and the development of chronic infectious and autoimmune diseases including HIV infection and Crohn's disease, respectively. CONCLUSIONS: Our understanding of the intestinal virome is fragmented and requires standardised methods for virus isolation and sequencing to provide a more complete picture of the virome, which is key to explaining the basis of virome-disease associations, and how enteric viruses can contribute to disease aetiologies and be rationalised as targets for interventions. PMID- 28869285 TI - Microbiota: a mediator to transform glucosinolate precursors in cruciferous vegetables to the active isothiocyanates. AB - Isothiocyanates (ITCs), such as sulforaphane (SFN), exhibit powerful biological functions in fighting cancers, and cardiovascular and neurodegenerative diseases. They normally exist as glucosinolates (GLSs) in cruciferous vegetables, which are not themselves bioactive until they are degraded by myrosinase to form ITCs. Myrosinase coexists in the same plants but is normally kept apart from GLSs in different apparatus. A key point is that myrosinase is temperature sensitive and can be inactivated upon exposure to temperatures over 60 degrees , as typically occurs during cooking. However, studies using animal models and population trials have suggested that human gut bacteria might act like an 'organ' in that they can secrete their own myrosinase. In this review, the hydrolysis of GLS by myrosinase is discussed, with an important focus on the gut microflora and their myrosinase producing roles. (c) 2017 Society of Chemical Industry. PMID- 28869286 TI - Psychotherapy clients' recalled treatment experiences: A survey of perceived evidence-based practice elements. AB - Evidence-based practice (EBPs) elements can be observed across treatment approaches for commonly occurring problems. Little is known about the prevalence or pervasiveness of EBP elements from the routine client's perspective. We assessed psychotherapy clients' self-reported retrospective treatment experiences with regard to common EBP elements. Participants (N = 592) were consenting university undergraduate students who accessed a web survey that included (a) demographic items; (b) an item assessing the problem domain(s) of focus during their therapy; and (c) the presence/absence of 8 EBP elements and the extent to which they were a focus of their psychotherapy. Overall, routine psychotherapy clients recalled receiving a variety of EBP elements, the most common being a focus on positive emotions. Future work should continue to focus on clients' experience of psychotherapy elements, including what was/is most and least helpful to assist in the refinement and implementation of EBPs. PMID- 28869287 TI - Systematic review with meta-analysis: the association between hepatitis E seroprevalence and haemodialysis. AB - BACKGROUND: Hepatitis E virus (HEV) infection appears to be more common than previously thought. HEV seroprevalence in patients on maintenance haemodialysis (HD) is unclear with a range from 0% to 44%. In addition, risk factors of transmission of HEV in patients on haemodialysis are unknown. AIM: To perform a systematic review and meta-analysis of HEV seroprevalence in HD patients compared with controls. METHODS: A systematic search of several databases identified all observational studies with comparative arms. Two reviewers extracted data and assessed the methodological quality. A random-effects model was used for pooled odds ratio (OR) and 95% confidence interval (CI) of positive anti-HEV IgG in both groups. Heterogeneity and publication bias were assessed with appropriate tests. RESULTS: We identified 31 studies from 17 countries between 1994 and 2016. Sixteen studies were judged to have adequate quality and 15 to have moderate limitations. HEV infection was more prevalent in patients on haemodialysis compared with controls (OR 2.47, 95% CI 1.79-3.40, I2 = 75.2%, P < .01). We conducted several subgroup analyses without difference in results. Egger regression test did not suggest publication bias (P = .83). Specific risk factors of HEV transmission in patients on haemodialysis were not clearly identified. CONCLUSIONS: Hepatitis E virus infection is more prevalent in patients on haemodialysis compared with non-haemodialysis control groups. Further studies are needed to determine risk factors of acquisition, impact on health, and risk for chronic HEV especially among those patients going to receive organ transplantation. PMID- 28869288 TI - Exploring the mechanism of Jieduquyuziyin prescription on systemic lupus erythematosus by GC-MS-based urine metabolomics. AB - A urine metabolomics method based on gas chromatography-mass spectrometry was developed in order to investigate the metabolite characteristics of systemic lupus erythematosus (SLE) and the therapeutic effects of Jieduquyuziyin prescription. The urinary metabolic profiles in urine specimens of the SLE model mice (MRL/lpr) group, prednisone acetate-treated SLE mouse group, Jieduquyuziyin prescription-treated SLE mouse group, and control group (C57BL/6 J) after the administration were analyzed by gas chromatography-mass spectrometry. These metabolic profiles were then processed by multivariate analysis, in particular Mass Profiler Professional, SIMCA-P and partial least-squares discriminant analysis. According to the partial least-squares discriminant analysis results, the SLE model group and the control group were obviously separated, indicating that the incidence of SLE had a greater impact on the metabolic network, and the SLE model group had significant difference compared with the control group in urine metabolites. Eleven differential metabolites were identified to be related to SLE, and the results of differential metabolite identification showed that the metabolites were mainly related to energy metabolism and amino acid metabolism pathway. These results can provide an experimental basis for further exploring the mechanism of traditional Chinese medicine in the treatment of SLE. PMID- 28869289 TI - Quinoa Starch Characteristics and Their Correlations with the Texture Profile Analysis (TPA) of Cooked Quinoa. AB - : Starch characteristics significantly influence the functionality and end-use quality of cereals and pseudo-cereals. This study examined the composition and properties of starch from 11 pure varieties and 2 commercial samples of quinoa in relationship to the texture of cooked quinoa. Nearly all starch properties and characteristics differed among these samples. Results showed that total starch content of seeds ranged from 53.2 to 75.1 g/100 g apparent amylose content ranged from 2.7% to 16.9%; total amylose ranged from 4.7% to 17.3%; and the degree of amylose-lipid complex ranged from 3.4% to 43.3%. Amylose leaching ranged from 31 mg/100 g starch in "Japanese Strain" to 862 mg/100 g starch in "49ALC." "Japanese Strain" starch also exhibited the highest water solubility (4.5%) and the lowest swelling power (17). alpha-Amylase activity in "1ESP," "Col.#6197," "Japanese Strain," "QQ63," "Yellow Commercial," and "Red Commercial" (0.03 to 0.09 CU) were significantly lower than the levels of the other quinoa samples (0.20 to 1.16 CU). Additionally, gel texture, thermal properties, and pasting properties of quinoa starches were investigated. Lastly, correlation analysis showed that the quinoa samples with higher amylose content tended to yield harder, stickier, more cohesive, more gummy, and more chewy texture after cooking. A higher degree of amylose-lipid complex and amylose leaching were associated with softer and less chewy cooked quinoa TPA texture. Higher starch enthalpy correlated with firmer, more adhesive, more cohesive, and chewier texture. In sum, starch plays a significant role in the texture of cooked quinoa. PRACTICAL APPLICATION: The research determined starch characteristics among a diverse set of pure quinoa varieties and commercial samples, and identified the relationships between starch properties and cooked quinoa texture. The results can help breeders and food manufacturers to understand better the relationships among quinoa starch characteristics, cooked quinoa texture, and the best use of different cultivars. PMID- 28869290 TI - Gonioscopy in the dog: inter-examiner variability and the search for a grading scheme. AB - OBJECTIVES: To investigate inter-examiner variability in gonioscopic evaluation of pectinate ligament abnormality in dogs and to assess level of inter-examiner agreement for four different gonioscopy grading schemes. MATERIALS AND METHODS: Two examiners performed gonioscopy in 98 eyes of 49 Welsh springer spaniel dogs and estimated the percentage circumference of iridocorneal angle affected by pectinate ligament abnormality to the nearest 5%. Percentage scores assigned to each eye by the two examiners were compared. Inter-examiner agreement was assessed following assignment of the percentage scores to each of four grading schemes by Cohen's kappa statistic. RESULTS: There was a strong positive correlation between the results of the two examiners (R=0.91). In general, Examiner 1 scored individual eyes higher than Examiner 2, especially for eyes in which both examiners diagnosed pectinate ligament abnormality. A "good" level of agreement could only be achieved with a gonioscopy grading scheme of no more than three categories and with a relatively large intermediate bandwidth (kappa=0.68). CLINICAL SIGNIFICANCE: A three-tiered grading scheme might represent an improvement on hereditary eye disease schemes which simply classify dogs to be either "affected" or "unaffected" for pectinate ligament abnormality. However, the large intermediate bandwidth of this scheme would only allow for the additional detection of those dogs with marked progression of pectinate ligament abnormality which would be considered most at risk of primary closed-angle glaucoma. PMID- 28869291 TI - The client as the expert in psychotherapy: What clinicians and researchers can learn about treatment processes and outcomes from psychotherapy clients. AB - Clients are frequently recognized as perhaps having the largest impact on the eventual success or failure of treatment; however, researchers and clinicians alike often give inadequate attention to clients' perspectives on psychotherapy processes and outcomes. Researchers who do examine client variables in psychotherapy often conduct research about the client rather than from the client. The purpose of this article is to introduce a special issue focused on the client's perspective in psychotherapy. Specifically, the articles in this issue present case studies and quantitative and qualitative research that seek to (a) demonstrate how to tailor interventions according to the client's perspective and (b) identify common themes in clients' perspectives about their experiences in psychotherapy. PMID- 28869292 TI - Teaching conversational speech to children with autism spectrum disorder using text-message prompting. AB - The present study was designed to teach conversational speech using text-message prompts to children with autism spectrum disorder (ASD) in home play settings with siblings and peers. A multiple baseline design across children was used. Children learned conversational speech through the text-message prompts, and the behavior generalized across peers and settings. Maintenance of treatment gains was seen at 1-month follow-up probes. Social validity measures indicated that parents of typically developing children viewed the participants' conversational speech as much improved after the intervention. Results are discussed in terms of the efficacy of text-message prompts as a promising way to improve conversational speech for children with ASD. PMID- 28869293 TI - Living in the city: school friendships, diversity and the middle classes. AB - Much of the literature on the urban middle classes describes processes of both affiliation (often to the localities) and disaffiliation (often from some of the non-middle-class residents). In this paper, we consider this situation from a different position, drawing on research exploring whether and how children and adults living in diverse localities develop friendships with those different to themselves in terms of social class and ethnicity. This paper focuses on the interviews with the ethnically diverse, but predominantly white British, middle class parent participants, considering their attitudes towards social and cultural difference. We emphasize the importance of highlighting inequalities that arise from social class and its intersection with ethnicity in analyses of complex urban populations. The paper's contribution is, first, to examine processes of clustering amongst the white British middle-class parents, particularly in relation to social class. Second, we contrast this process, and its moments of reflection and unease, with the more deliberate and purposeful efforts of one middle-class, Bangladeshi-origin mother who engages in active labour to facilitate relationships across social and ethnic difference. PMID- 28869294 TI - Beta-blocker therapy is not associated with mortality after intracerebral hemorrhage. AB - BACKGROUND: Beta-blocker therapy has been suggested to have neuroprotective properties in the setting of acute stroke; however, the evidence is weak and contradictory. We aimed to examine the effects of pre-admission therapy with beta blockers (BB) on the mortality following spontaneous intracerebral hemorrhage (ICH). METHODS: Retrospective analysis of the Helsinki ICH Study database. RESULTS: A total of 1013 patients with ICH were included in the analysis. Patients taking BB were significantly older, had a higher premorbid mRS score, had more DNR orders, and more comorbidities as atrial fibrillation, hypertension, diabetes mellitus, ischemic heart disease, and heart failure. After adjustment for age, pre-existing comorbidities, and prior use of antithrombotic and antihypertensive medications, no differences in in-hospital mortality (OR 1.1, 95% CI 0.8-1.7), 12-month mortality (OR 1.3, 95% CI 0.9-1.9), and 3-month mortality (OR 1.2, 95% CI 0.8-1.7) emerged. CONCLUSION: Pre-admission use of BB was not associated with mortality after ICH. PMID- 28869296 TI - Growth and Sucrose Metabolism of Carrot Callus Strains with Normal and Low Acid Invertase Activity. AB - The properties of two strains of carrot (Daucus carota) callus are presented. One has a very low acid invertase activity which is accompanied by differences in morphology and metabolic rate, but not in growth rate. We conclude that one of the main functions of plant acid invertases is in controlling the levels of sugars which, by interaction with hormones, affect differentiation, both morphological and biochemical. The effect of tris on sucrose metabolizing enzymes, and the cause of the "sucrose effect" are considered. PMID- 28869297 TI - Mechanism of Action of the Herbicide 2-Chloro-3(4-chlorophenyl) Propionate and its Methyl Ester: Interaction with Cell Responses Mediated by Auxin. AB - Chlorfenprop-methyl (the herbicidal component of BIDISIN(r)), and to a lesser extent the free acid, chlorfenprop, inhibit auxin mediated cell responses in coleoptiles of Avena sativa L. and Zea mays L., such as cell elongation, auxin uptake, -transport and -metabolism, acidification of growth media, and binding of naphthyl-I-acetic acid to auxin-specific binding sites in homo-genates of corn coleoptiles. Within a very narrow concentration range (1 to 2MUM) chlorfenprop methyl arrests growth from 0 to 100% in sensitive cultivars. The compound displays neither auxin-nor anti-auxin-activity, and only the l(-)-enantiomer is active. The interaction of the herbicide with auxin at the level of membranes is proposed. PMID- 28869295 TI - The Clinical Potential of Senolytic Drugs. AB - Senolytic drugs are agents that selectively induce apoptosis of senescent cells. These cells accumulate in many tissues with aging and at sites of pathology in multiple chronic diseases. In studies in animals, targeting senescent cells using genetic or pharmacological approaches delays, prevents, or alleviates multiple age-related phenotypes, chronic diseases, geriatric syndromes, and loss of physiological resilience. Among the chronic conditions successfully treated by depleting senescent cells in preclinical studies are frailty, cardiac dysfunction, vascular hyporeactivity and calcification, diabetes mellitus, liver steatosis, osteoporosis, vertebral disk degeneration, pulmonary fibrosis, and radiation-induced damage. Senolytic agents are being tested in proof-of-concept clinical trials. To do so, new clinical trial paradigms for testing senolytics and other agents that target fundamental aging mechanisms are being developed, because use of long-term endpoints such as lifespan or healthspan is not feasible. These strategies include testing effects on multimorbidity, accelerated aging-like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age related loss of physiological resilience, and frailty. If senolytics or other interventions that target fundamental aging processes prove to be effective and safe in clinical trials, they could transform geriatric medicine by enabling prevention or treatment of multiple diseases and functional deficits in parallel, instead of one at a time. PMID- 28869298 TI - The Critical Oxygen Pressures for Respiration in Intact Plants. AB - Two methods for determining critical respiratory oxygen pressure in whole plants are described. By a polarographic method involving the use of cylindrical platinum electrodes the following critical oxygen pressures for root respiration were found: Rice (cv. Norin 36). 0.024 atm: Rice (cv. Norm 37). 0.026 atm: Eriophorum angustifolium. 0.02 atm. These values contrast markedly with those obtained in vitro, and support earlier criticisms of in vitro measurements: they call into question the use of such data in the modelling of root aeration. When the results were assessed by an electrical analogue system, it was concluded that the respiratory activity in the intact root does not follow the normally accepted hyperbolic relationship with oxygen partial pressure. The experimental data were simulated most closely by assuming the critical oxygen pressure to be a function of respiratory responses in the low porosity (high diffusional impedance) tissues of the root meristem and stele, and respiratory activity in the moderately porous root cortex to be unaffected at values greater than 0.001 atm. A critical oxygen pressure of 0.025-0.04 atm for E. angustifolium was found from analyses of the gas phase oxygen in the leaves of whole plants after submergence in the dark. It was concluded that the higher value found by this method was most likely a function of respiratory responses in root tissue remote from the leaf and should not be regarded as the critical oxygen pressure for leaf respiration. The form of the oxygen concentration vs. time plot again suggested a very much lower critical oxygen pressure for certain of the plant tissues. PMID- 28869299 TI - Photosynthesis of Conifers in Relation to Annual Growth Cycles and Dry Matter Production: I. Some C4 Characteristics in Photosynthesis of Japanese Larch (Larix leptolepis). AB - Observations that deciduous larch species can show annual growth increments equal to or greater than evergreen conifers, and that the saturating light intensity for photosynthesis in needles of Larix leptolepis was almost twice those for several evergreen conifers, led to a study of the photosynthetic mechanism in L. leptolepis. Several features of photosynthesis in L. leptolepis placed this species in an intermediate position between classical C3 and C4 plants. Incorporation of 14 C from 14 CO2 by enzyme preparations of larch needles was eight times greater with PEP as substrate than with ribulose bis phosphate; a chlorophyll a/b ratio of 3.5 was obtained; needles possessed a green starch containing endodermis but with little orientation of mesophyll cells to this "bundle sheath"; no clear ultrastructural dimorphism was observed between chloroplasts of mesophyll and endodermal cells; a CO2 -compensation point of 20 MUl-l-1 was recorded; and the first measurable product of photosynthesis appeared to be malate rather than phospho-glyceric acid. These results are discussed in relation to the deciduous habit of L. leptolepis and its high productivity in comparison with other conifers. PMID- 28869300 TI - Adaptation to Water Stress in Wheat. AB - Three experiments were designed to investigate to what extent adaptation to water stress take place. Wheat (Triticum aestivum L. cv. Kolibri) was grown in water culture at constant temperature, air humidity, and light intensity. When the plants were 16 days old, the potential of the root medium (psir ) was lowered by 1 bar every second day by means of polyethyleneglycol 1500 down to -4 or -7 bar and then remained at these levels. As a control one experiment was grown at -0.7 bar. By regression it was found that when psir was lowered by I bar, osmotic potential in leaf (psipi ) decreased 1.46 bar, and leaf water potential (psit ) 0.68 bar, which mean an increase of turgor of 0.78 bar. At the same time the leaf water content did fall 0.30 g per g dry matter. Specific transpiration rate increased significantly after psir was kept constant, but the increase in area of fresh leaves was strongly reduced due to wilting of old leaves. After an "adaptation" period during which psir remained at -0.7, -4, and -7 bar, respectively, for at least 1 week. psir was altered so as to cover the range from 0 to -14 bar and psipi , psir , transpiration and diffusion resistance in stomata (rs ) were measured. The levels of psipi and psi1 were lower (more negative) and turgor potential higher in plants grown at low psir . The transpiration in pre stressed plants showed less sensitivity to the alteration of psir than in the non stressed plants. The values of psir at which rs increased greatly, were found to be about -13, -15, and -18 bar for plants grown at -0.7, -4, and -7 bar, respectively. PMID- 28869301 TI - A Role for Auxin and Auxin Transport Inhibitors on the Ca Content of Artificially Induced Parthenocarpic Fruits. AB - Artificially induced parthenocarpic fruits of apples, pears and tomatoes, as well as seeded fruits treated with 2,3,5-triiodobenzoic acid, frequently show symptoms of Ca deficiency and a low Ca content. It was concluded that auxins, probably produced by the seeds, play a significant role in Ca translocation into fruits. Exogenous indoleacetic acid but not 4-chlorophenoxyacetic acid applications could replace the effect of seeds in this respect. Auxin transport, rather than auxin accumulation, seems to be necessary for Ca transport, as can be concluded from the effect of auxin transport inhibitors. PMID- 28869302 TI - Simultaneous Measurement of the Bioelectric Potential of the Cell Wall and the Vacuoles during the Oscillatory Response to the Nitella Cell. AB - Simultaneous measurements of bioelectric potentials of the vacuole and cell wall in cells of Nitella mucronata were made by inserting glass microelectrodes into the vacuole and cell wall respeclively. During the oscillation of the bioelectric potential of the vacuole. induced by sudden changes of the external bathing solution or by the impalement of the cell with a microelectrode. the cell wall potential also exhibited fluctuations of variable intensities in phase and concomitant with spikes of the vacuolar potential oscillation. However, the polarity of the pulses of the cell wall potential was reverse to that of the spikes of the vacuolar potential. These results suggest that the same event is registered at both sides of the plasmalemma membrane across which these phenomena are occurring. The results also support the voltage clamp and tracer flux measurements on these cells which indicate that during the generation of single action potentials, induced by current, the plasma lemma transiently increases its permeability to Cl- and K+ ions expelling them from the cell. The variable intensity of the transient hyperpolarizations of the cell wall potential is explained by the distance of the microelectrode in the cell wall from the plasmalemma. PMID- 28869304 TI - Isolation and Analysis of Protein Bodies from Cotyledons of Lablab purpureus and Phaseolus vulgaris (Leguminoseae). AB - Protein bodies, isolated by differential and isopycnic centrifugation, have been observed in transmission and scanning electron microscope and biochemically analysed. The powders of the axes and of the cotyledons contain numerous protein bodies, which in the scanning microscope appear to be surrounded by a more or less torn membrane. The proportion of intact, isolated protein bodies is influenced by the grinding methods, but even in the best conditions soaking disaggregates the majority of them. After isopycnic centrifugation, their debris gather in different density zones. Analyses of each zone have revealed that the caseinases are associated with particles of higher density than are peptidases and trypsin inhibitors. A minority population of small-size protein bodies resists the homogenization and fractioning modalities. A double origin of the protein bodies is considered. PMID- 28869303 TI - Incorporation of 5-Aminolevulinic Acid in the Chlorophyll-Protein Complexes of the Moss Ceratodon purpureus. AB - After one month of cultivation in the dark in inorganic medium the chloroplasts of protonemata of Ceratodon purpureus have larger grana than chloroplasts from light-grown cultures. Incubation of dark-grown material with ALA increases the chlorophyll content and chlorophyll a/b ratio. On polyacrylamide-gel electrophoresis, a preferential labelling of chlorophyll-protein complex I is obtained after treatment with (3 H) ALA in darkness. In contrast, in light, much higher activity is found in chlorophyll-protein complex II. The free pigment zone is highly labelled in both environments. PMID- 28869305 TI - The Effect of Root Formation on the Levels of Protein, Chlorophyll, RNA, DNA and Carbohydrates in Excised Cotyledons of Cucurbita pepo. AB - In attached cotyledons of Cucurbita pepo L. protein, chlorophyll, RNA, DNA and carbohydrates were found to increase to a maximum level 14 days after commencement of germination, followed by a sharp decline thereafter. Cotyledons excised and planted in a nutrient solution 14 days after sowing showed maximum levels of protein, chlorophyll, RNA, DNA and soluble and insoluble sugars 52 days after planting. The increase in these compounds coincides with the full development of the root system. Excision earlier or later than 14 days resulted in lower levels of protein and other compounds. The decrease in the level after 52 days was parallel to the senescing phase of the cotyledons. PMID- 28869306 TI - Carbon Dioxide as an Essential Requirement for Cultured Sycamore Cells. AB - Carbon dioxide (optimum concentration c. 1.0%) is essential to the initiation of the growth in suspension culture or on agar plates of cultured sycamore cells. By effective flushing of the cultures with CO2 -free air it is possible to demonstrate this requirement with initial cell densities up to 50 * 103 cells ml 1 . This growth-promoting activity of carbon dioxide is not related to any effect it may have on the pH of the culture medium. The cells fix applied carbon dioxide into organic and amino acids but attempts to replace the carbon dioxide requirement by non-toxic levels of organic or amino acids have not been successful. PMID- 28869307 TI - The State of Protochlorophyll and Chlorophyll in Corn Roots. AB - The protochlorophyll(ide) present in primary roots of dark-grown corn (Zea mays) seedlings has an in vivo absorption maximum at 634 nm. Red light converts the pigment to chlorophyll(ide) a with an absorption maximum at 675 nm. PMID- 28869308 TI - Environmentally Induced Changes in the Cell Walls of Tomato Leaves in Relation to Cell and Protoplast Release. AB - Factors involved in the isolation of protoplasts from the leaves of tomato plants grown over a wide range of environmental conditions have been studied. Increases in calcium pectate in summer grown ("hard") plants are suggested as a barrier to cell wall degradation. A one-step method involving the addition of sodium citrate to pectinase plus cellulase gives high yield of protoplasts from hard plants. Attempts to convert isolated palisade cells to protoplasts have failed. The plant culture conditions are described such that protoplasts may be isolated throughout the year using low enzyme concentrations. PMID- 28869309 TI - Resting heart rate, heart rate reserve, and metabolic syndrome in professional firefighters: A cross-sectional study. AB - BACKGROUND: Little is known about the associations of resting heart rate (RHR) and heart rate reserve (HRR) with metabolic syndrome (MetS) in firefighters. METHODS: For each of 288 professional firefighters, HRR was calculated as the difference between measured RHR and estimated maximum HR. For comparison, VO2 max based on a treadmill test was included. MetS was defined according to the NCEP/ATP III criteria. RESULTS: The prevalence of MetS was 14.2%. The average of RHR was 61.5 beat/min. Only 5.8% of the firefighters had RHR of >=80 beat/min. Between the firefighters in the lowest and highest quintiles, the prevalence ratios (95% confidence intervals) for MetS were 1.88 (0.71-4.94), 5.90 (1.74 20.02), and 8.03 (1.86-34.75) for RHR, HRR, and VO2 max, respectively. Both HRR and VO2 max, but not RHR, were significantly associated with MetS and its most component risk factors in middle-aged firefighters. CONCLUSIONS: HRR, a simple cardiovascular fitness measure, was inversely associated with MetS among middle aged professional firefighters. PMID- 28869310 TI - Chromatographic approaches for the characterization and quality control of therapeutic oligonucleotide impurities. AB - Phosphorothioate (PS) oligonucleotides are a rapidly rising class of drugs with significant therapeutic applications. However, owing to their complex structure and multistep synthesis and purification processes, generation of low-level impurities and degradation products are common. Therefore, they require significant investment in quality control and impurity identification. This requires the development of advanced methods for analysis, characterization and quantitation. In addition, the presence of the PS linkage leads to the formation of chiral centers which can affect their biological properties and therapeutic efficiency. In this review, the different types of oligonucleotide impurities and degradation products, with an emphasis on their origin, mechanism of formation and methods to reduce, prevent or even eliminate their production, will be extensively discussed. This review will focus mainly on the application of chromatographic techniques to determine these impurities but will also discuss other approaches such as mass spectrometry, capillary electrophoresis and nuclear magnetic resonance spectroscopy. Finally, the chirality and formation of diastereomer mixtures of PS oligonucleotides will be covered as well as approaches used for their characterization and the application for the development of stereochemically-controlled PS oligonucleotides. PMID- 28869311 TI - Factors underlying observed injury rate differences between temporary workers and permanent peers. AB - BACKGROUND: Temporary workers face increased risk of injury as compared to permanent workers in similar occupations. This study explores the role played by several potential risk factors. METHODS: Injured temporary and permanent workers, matched by industry, tenure and demographic characteristics, were interviewed to isolate the association of temporary employment with several injury risk factors. RESULTS: Temporary workers had higher workers' compensation claims rates than their permanent worker-peers. In interviews temporary workers a reported a lower frequency of exposure to hazards. However, they also reported being less likely to be equipped to cope with hazards by such countermeasures as experience screening, safety training and task control. CONCLUSION: Policies are needed to improve screening and training of temporary workers to assigned tasks, to discourage job-switching, to improve temporary workers' hazard awareness, to protect their right to report unsafe conditions. The responsibilities of agencies and host employers for ensuring the safety of their temporary workers need clarification in regulatory policy. PMID- 28869312 TI - Synthesis and Reactivity of a Scandium Terminal Hydride: H2 Activation by a Scandium Terminal Imido Complex. AB - Dihydrogen is easily activated by a scandium terminal imido complex containing the weakly coordinated THF. The reaction proceeds through a 1,2-addition mechanism, which is distinct from the sigma-bond metathesis mechanism reported to date for rare-earth metal-mediated H2 activation. This reaction yields a scandium terminal hydride, which is structurally well-characterized, being the first one to date. The reactivity of this hydride is reported with unsaturated substrates, further shedding light on the existence of the terminal hydride complex. Interestingly, the H2 activation can be reversible. DFT investigations further eludciate the mechanistic aspects of the reactivity of the scandium anilido terminal hydride complex with PhNCS but also on the reversible H2 activation process. PMID- 28869313 TI - What paediatric obesity treatment programmes work, and how can we measure their success? PMID- 28869315 TI - Strategy for Stereoselective Metal-free alpha-Functionalization of 2-Azaaryl Acetates with N-Boc Imines. AB - We report the first diastereo- and enantioselective formal Mannich reaction of 2 pyridyl acetates which gives rise to alpha- and beta-functionalized 2-substituted pyridines. Key for success is the previous azaarene N-oxide formation enabling alpha-carbon deprotonation by a mild bifunctional Bronsted base and subsequent reaction with N-Boc imines under almost perfect stereocontrol. PMID- 28869314 TI - Eosinophil-rich trichoblastic carcinoma with aggressive clinical course in a young man. AB - We present the case of a 35-year-old man who developed a follicular differentiated cutaneous carcinoma with an eosinophil-rich infiltrate and an aggressive clinical behavior. After an in-depth histopathological investigation the diagnosis of trichoblastic carcinoma was made. Over the course of the disease the patient developed a cutaneous in-transit metastasis as well as an axillary lymph node metastasis 18 months after the excision of the primary tumor on his back. Based on a literature review we discuss the different concepts behind the term "trichoblastic carcinoma" and we summarize the clinical and histological details of previously reported cases. Furthermore, we focus on the phenomenon of tumor-associated eosinophilia. PMID- 28869316 TI - Coupling and Dearomatization of Pyridines at a Transient eta2 Cyclopropene/Bicyclobutane Zirconocene Complex. AB - This paper reports on stereospecific coupling reactions between an eta2 cyclopropene ligand and pyridine derivatives, which are preferred to alternative C-H bond activation reactions. The dicyclopropylzirconocene complex [Cp2 Zr(c-C3 H5 )2 ] (1) eliminates cyclopropane to generate the eta2 cyclopropene/bicyclobutane intermediate [Cp2 Zr(eta2 -c-C3 H4 )] (A). A does not activate any pyridine C-H bonds, but rather pyridine inserts into a Zr-C bond of A, yielding an azazirconacycle with a dearomatized pyridyl group [Cp2 Zr{kappa2 N,C8 -(2-c-C3 H4 )-C5 H5 N}] (2). Kinetic data, isotopelabelling experiments, and DFT calculations indicate that the rate-determining step of this stereospecific reaction is cyclopropane elimination, and that the stability of the intermediate [Cp2 Zr(eta2 -c-C3 H4 )(NC5 H5 )] (A-py) governs the selectivity of the reaction. Complex 2 tautomerizes to [Cp2 Zr{kappa2 -N,C8 -(2-C3 H5 )-C5 H4 N}] (6) through a base-catalyzed proton migration accompanied by cyclopropyl opening and restoration of conjugation within the zirconacycle. PMID- 28869317 TI - Solid-State Reactions of Eicosaborate [B20 H18 ]2- Salts and Complexes. AB - A series of salts and complexes containing trans- and iso-isomers of octadecahydro-eicosaborate [B20 H18 ]2- dianion is synthesized and characterized using FTIR and 11 B NMR spectroscopies and X-ray diffraction techniques. Both isomers are found to act as four-, bi-, or zero-dentate ligands in reactions with copper(II), silver(I), and lead(II) through apical and/or equatorial boron atoms. Solid-state photo- and thermoinitiated reactions of octadecahydro-eicosaborate isomerization and solvent cleavage occurring in these compounds in a single crystal-to-single-crystal manner are studied in situ. In contrast with solutions, in solids the reaction of boron cluster transformation occurs rarely, thus, analysis of crystal packing allowed us to suggest some criteria of isomerization of macropolyhedral boranes in crystals. X-ray diffraction data are used to confirm reaction path of isomerization of the [B20 H18 ]2- dianion. PMID- 28869318 TI - Exercise for the prevention of low back and pelvic girdle pain in pregnancy: A meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVE: The effect of exercise in prevention of low back and pelvic girdle pain during pregnancy is uncertain. This study aimed to assess the effect of exercise on low back pain, pelvic girdle pain and associated sick leave. DATABASES AND DATA TREATMENT: Literature searches were conducted in PubMed, EMBASE, Cochrane Library, Google Scholar, ResearchGate and ClinicalTrials.gov databases from their inception through May 2017. Randomized controlled trials (RCTs) were eligible for inclusion in the review if they compared an exercise intervention with usual daily activities and at least some of the participants were free from low back pain and/or pelvic girdle pain at baseline. Methodological quality of included studies was evaluated using the Cochrane Collaboration's tool. A random-effects meta-analysis was performed, and heterogeneity and publication bias were assessed. RESULTS: Eleven randomized controlled trials (2347 pregnant women) qualified for meta-analyses. Exercise reduced the risk of low back pain in pregnancy by 9% (pooled risk ratio (RR) = 0.91, 95% CI 0.83-0.99, I2 = 0%, seven trials, N = 1175), whereas it had no protective effect on pelvic girdle pain (RR = 0.99, CI 0.81-1.21, I2 = 0%, four RCTs, N = 565) or lumbopelvic pain (RR = 0.96, CI 0.90-1.02, I2 = 0%, eight RCTs, N = 1737). Furthermore, exercise prevented new episodes of sick leave due to lumbopelvic pain (RR = 0.79, CI 0.64-0.99, I2 = 0%, three RCTs, N = 1168). There was no evidence of publication bias. CONCLUSION: Exercise appears to reduce the risk of low back pain in pregnant women, and sick leave because of lumbopelvic pain, but there is no clear evidence for an effect on pelvic girdle pain. SIGNIFICANCE: Exercise has a small protective effect against low back pain during pregnancy. PMID- 28869319 TI - Re: The impact of a novel transendometrial approach for caesarean myomectomy on obstetric outcomes of subsequent pregnancy: a longitudinal panel study: Novel transendometrial regimen for caesarean myomectomy on obstetric outcomes of subsequent pregnancy. PMID- 28869321 TI - Series test of cluster and network analysis for lupus nephritis, before and after IFN-K-immunosuppressive therapy. AB - AIM: The purpose was to screen potential targets of IFN-K-immunosuppressive therapy, which was used to offer effective information and resources for molecular targeted therapy. METHODS: The gene expression profile of GSE72747 was used to screen out significant differently expressed genes (DEGs). Series Test of Cluster (STC) analysis for DEGs was performed. For all DEGs, the Database for Annotation, Visualization, and Integrated Discovery was performed for Gene Ontology (GO) enrichment analysis. Pathway enrichment analysis of DEGs was performed based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Pathway was constructed based on the interactions in the KEGG database. The coexpression network and gene signal expression networks were constructed and analyzed. RESULTS: A total of 2193 DEGs were screened and eight significant profiles were identified. Significant GO terms included small molecule metabolic process, translation and apoptotic process. Metabolic pathways and Alzheimer's disease were significant KEGG pathways. Pathway relationship network of DEGs was constructed. MAPK signalling pathway, apoptosis and pathways in cancer were hub nodes. Gene co-expression network analysis was performed. VCP-interacting membrane protein and NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8 kDa were the hub nodes. Gene signal network was constructed with 162 nodes and 254 edges. Hub nodes were phospholipase C, beta 2. CONCLUSION: Screened DEGs including VIMP, NDUFAB1, SEC61G, PSMC2 might be potential targets for lupus nephritis treatment by involving in different functions and pathways, such as metabolic process and immune process. PMID- 28869320 TI - Spin Changes Accompany Ultrafast Structural Interconversion in the Ground State of a Cobalt Nitrosyl Complex. AB - Ultrafast, reversible intersystem crossing (ISC) is reported under ambient conditions for the electronic ground state of the pentacoordinate cobalt nitrosyl complexes, [CoX2 (NO)(PMePh2 )2 ] (X=Cl, Br), in solution. ISCs on such short timescales are more typically observed in electronically excited states reached by absorption of ultraviolet or visible light. Singlet and triplet electron spin states of the complex, corresponding to two different isomers, are populated at room temperature, and the two isomers exchange on a timescale of a few picoseconds. Ultrafast two-dimensional infrared spectroscopy observes the change in wavenumber of the NO ligand band accompanying the isomerization and associated ISC on the (spin) adiabatic ground potential energy surface. Comparison of the dynamics of the chloro- and bromo-complexes shows that inertial effects of the ligand motion have a greater effect than spin-orbit coupling on determining the forward and reverse isomerization and ISC rates. PMID- 28869322 TI - Attenuation of the anti-contractile effect of cooling in the rat aorta by perivascular adipose tissue. AB - In addition to providing mechanical support for blood vessels, the perivascular adipose tissue (PVAT) secretes a number of vasoactive substances and exerts an anticontractile effect. The main objective of this study was to find out whether the anticontractile effect of cooling in the rat aorta is affected by PVAT. Our hypothesis was that PVAT would enhance the anticontractile effect of cooling in the rat aorta. Aorta segments, with or without PVAT, were used in this investigation. Cumulative concentration-response curves were established for phenylephrine at 37 degrees C or 24 degrees C. Phenylephrine (10-9 M - 10-5 M) induced concentration-dependent contractions of aorta segments with or without PVAT at 37 degrees C. The maximum response, but not pD2 value, was reduced in aorta segments with PVAT. Cooling the tissues to 24 degrees C resulted in a significant reduction in the maximum response in aorta segments without PVAT with no change in pD2 values. However, the anticontractile effect of cooling was attenuated in the presence of PVAT with no significant (p > 0.05) change in either the maximum response or pD2 value. L-NAME potentiated PE-induced contractions and this was greater in aorta segments without PVAT at both temperatures. The expression of eNOS protein and basal tissue level of nitric oxide (NO) were greater in aorta segments with PVAT at both temperatures. However, PE significantly increased tissue levels of NO only in aorta segments without PVAT. We concluded that PVAT-induced loss of anticontractile effect of cooling against PE-induced contractions could be due to impaired generation of NO in aorta segments with PVAT. PMID- 28869323 TI - Main causes of hospitalization in people with Angelman syndrome. AB - BACKGROUND: The objective was to describe the main causes of hospitalization in people with Angelman syndrome (AS). METHOD: Population-based cross-sectional study in the Community of Madrid (CM), Spain. The information source for AS cases was the information system for rare diseases in the CM. Variables related to hospitalization, for the period 2006-2014, were the following: number of episodes, outcome, main cause, length of stay and type of admission. Main causes of hospitalization were described by age group and sex. RESULTS: The most frequent causes of hospitalization were the following: oral-dental care (28.9%), seizures (19.6%), orthopaedic problems (14.4%) and acute respiratory disorders (12.4%). The percentage of hospitalizations was higher for oral-dental care in women and for orthopaedic problems in men (p-value <.05). Hospitalizations for an acute respiratory disorder were higher in adults (p-value <.05). CONCLUSIONS: Some differences in the causes of hospitalization of people with AS were observed by sex and age. PMID- 28869325 TI - Epstein-Barr virus infection in children with renal transplantation: A single centre experience. AB - AIM: This study aimed to investigate the incidence, timing, manifestations, managements, and outcomes of Epstein-Barr virus (EBV) infection in paediatric renal transplant recipients in Korea. METHODS: We retrospectively evaluated 70 patients aged <18 years who had undergone renal transplantation between January 1990 and November 2014 at a single centre in Korea. EBV infection was diagnosed via serological test or real-time quantitative polymerase chain reaction (PCR). The diagnosis of post-transplant lymphoproliferative disorder (PTLD) was based on biopsy findings. RESULTS: In total, 21 patients (30.0% of renal transplant recipients) had EBV infection. EBV infection occurred at an average age of 12.6 +/- 4.5 (median, 12.0; range, 7.0-24.0 years, with a mean period of 28.3 +/- 27.2 (median, 14.0; range, 2.0-75.0) months for developing EBV infection after transplantation. EBV infection developed 12 times more frequently in pre transplant EBV-seronegative recipients. Eight patients (38% of EBV-infected patients) had EBV disease, and six patients (75% of patients with EBV disease) had PTLD. The maximum EBV PCR titer was greater in patients with EBV disease than in the asymptomatic EBV infection group. The main treatment for EBV infection was the reduction in immunosuppressants. Asymptomatic EBV infection resolved in approximately 80% of the patients. One patient (17% of the patients with PTLD) expired. The glomerular filtration rate did not deteriorate during the treatment of EBV infection. CONCLUSION: Regular EBV monitoring in renal transplant recipients is mandatory for early diagnosis and treatment of EBV infections and prevention of PTLD, especially in pre-transplant EBV IgG-negative patients. PMID- 28869324 TI - Mycophenolate mofetil-related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs. AB - MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant. PMID- 28869326 TI - Re: Montgomery and implications for clinical practice. PMID- 28869327 TI - Seasonal variation in effectiveness of the boar-operated system to deliver baits to wild boar. AB - BACKGROUND: Wild boar and feral pig numbers are growing worldwide and have substantial economic and environmental impacts. Bait-delivered pharmaceuticals such as disease vaccines, toxicants and contraceptives are advocated to mitigate these impacts. Effective campaigns based on these pharmaceuticals rely on optimising the target species' bait uptake, which may differ between seasons. We investigated seasonal differences in the use of Boar-Operated Systems (BOSs) by wild boar and non-target species in an English woodland. RESULTS: In a pre-trial phase (BOS left open), wild boar, wild mammals, birds, livestock and companion animals fed on the peanuts and maize used as bait in the BOS. During the trial (BOS closed), only wild boar consumed the baits. Wild boar visited and fed from a larger number of BOSs in spring than in summer or winter. No aggressive intra group interactions were recorded when wild boar fed from the BOSs but adult males were observed to monopolise two BOSs. Group size was highest in spring and bait uptake was lowest in winter. CONCLUSION: The study confirmed the species specificity of the BOS throughout the year and highlighted that, at least in this area, bait uptake by wild boar for baits delivered through the BOS would be maximised in spring. (c) 2017 Crown copyright. Pest Management Science (c) 2017 Society of Chemical Industry. PMID- 28869328 TI - Fluensulfone sorption and mobility as affected by soil type. AB - BACKGROUND: Fluensulfone is a fluoroalkenyl chemical with activity against multiple genera of plant-parasitic nematodes. The adsorption, desorption, and mobility of fluensulfone were evaluated on multiple soils from the USA in laboratory and column experiments. RESULTS: Adsorption data regressed to the logarithmic Freundlich equation resulted in isotherm values of 1.24 to 3.28. Soil adsorption of fluensulfone correlated positively with organic matter (0.67) and clay (0.34), but negatively with sand (-0.54). Fluensulfone soil desorption correlated to pH (0.38) and cation exchange capacity (0.44). Fluensulfone desorption from Arredondo sand soil was 26%, and from other soils ranged from 43 to 70%. In mobility experiments, fluensulfone in the leachate peaked at 3 h, gradually declining and becoming undetectable after 9 h. Recovery from leachate was 45% of the initial fluensulfone applied to the soil surface. In separate experiments, 30-cm-long soil columns were saturated with 1 L of water, and then segregated into three 10-cm sections. Fluensulfone recovery was 41, 34, 29, and 13% in Chualar sandy loam, Arredondo sand, Greenville sandy clay loam, and Tifton loamy sand, respectively, in the top 10-cm section. CONCLUSION: Data indicated that soil organic matter and clay contents will affect sorption, mobility, and dissipation of fluensulfone. (c) 2017 Society of Chemical Industry. PMID- 28869329 TI - A Multiple-Stimulus-Responsive Biomimetic Assembly Based on a Polyisocyanopeptide and Conjugated Polymer. AB - An assembly was fabricated and was revealed to be a multiple-stimulus-responsive biomimetic hybrid polymer architecture. It was constructed by the hydrophobic interactions between a conjugated polyfluorene that contained 2,1,3 benzothiadiazole units (PFBT) and a tri(ethylene glycol)-functionalized polyisocyanopeptide (3OEG-PIC). The introduction of PFBT to the polyisocyanopeptide (PIC) network allowed for the incorporation of responsiveness to multiple stimuli including temperature, CO2 , carbonic anhydrase, and nonlinear mechanics, which mimics natural processes and interactions. Furthermore, the light-harvesting and signal amplification characteristics of PFBT endowed the supramolecular assembly with the essential function of fluorescence monitoring for biological processes. PMID- 28869330 TI - Butyrate-Loaded Chitosan/Hyaluronan Nanoparticles: A Suitable Tool for Sustained Inhibition of ROS Release by Activated Neutrophils. AB - Tissue damage caused by excessive amounts of neutrophil-derived reactive oxygen species (ROS) occurs in many inflammatory diseases. Butyrate is a short-chain fatty acid (SCFA) with known anti-inflammatory properties, able to modulate several neutrophil functions. Evidence is provided here that butyrate inhibits neutrophil ROS release in a dose and time-dependent fashion. Given the short half life of butyrate, chitosan/hyaluronan nanoparticles are next designed and developed as controlled release carriers able to provide cells with a long lasting supply of this SCFA. Notably, while the inhibition of neutrophil ROS production by free butyrate declines over time, that of butyrate-loaded chitosan/hyaluronan nanoparticles (B-NPs) is sustained. Additional valuable features of these nanoparticles are inherent ROS scavenger activity, resistance to cell internalization, and mucoadhesiveness. B-NPs appear as promising tools to limit ROS-dependent tissue injury during inflammation. Particularly, by virtue of their mucoadhesiveness, B-NPs administered by enema can be effective in the treatment of inflammatory bowel diseases. PMID- 28869331 TI - Synthesis and structure-activity relationships of carbohydrazides and 1,3,4 oxadiazole derivatives bearing an imidazolidine moiety against the yellow fever and dengue vector, Aedes aegypti. AB - BACKGROUND: 1,3,4-Oxadiazole and imidazolidine rings are important heterocyclic compounds exhibiting a variety of biological activities. In this study, novel compounds with oxadiazole and imidazolidine rings were synthesized from 3 (methylsulfonyl)-2-oxoimidazolidine-1-carbonyl chloride and screened for insecticidal activities. The proposed structures of the 17 synthesized compounds were confirmed using elemental analysis, infrared (IR), proton nuclear magnetic resonance (1 H-NMR), and mass spectroscopy. RESULTS: None of the compounds showed larvicidal activity at the tested concentrations against first-instar Aedes aegypti larvae. However, nine compounds exhibited promising adulticidal activity, with mortality rates of >=80% at 5 ug per mosquito. Further dose-response bioassays were undertaken to determine median lethal dose (LD50 ) values. Compounds 1, 2b, 2c, 2d, 2 g, 3b, 3c, 3 g, and 3 h were effective, with typical LD50 values of about 5 - 10 ug per mosquito against female Ae. aegypti. Compounds 2c (bearing a nitro group on the aromatic ring; LD50 = 2.80 +/- 0.54 ug per mosquito) and 3 h (double halogen groups at 2,4 position on the phenyl ring; LD50 = 2.80 +/- 0.54 ug per mosquito) were the most promising compounds. CONCLUSION: Preliminary mode of action studies failed to show consistent evidence of either neurotoxic or mitochondria-directed effects. Further chemical synthesis within this series may lead to the development of new effective insecticides. (c) 2017 Society of Chemical Industry. PMID- 28869333 TI - Lung metastases of a uterine tumor resembling ovarian sex-cord tumor: Report of a rare case. AB - Uterine tumor resembling an ovarian sex-cord tumor (UTROSCT) is a rare type of uterine neoplasm. We present an extremely rare case of lung metastases from a UTROSCT focusing on the cytologic features. A 69-year-old Japanese woman was admitted to our hospital for further examination and treatment for abnormal shadows in the right lung field. She had a history of total hysterectomy for UTROSCT. Moreover, she underwent wedge resection of the right middle lobe for lung metastasis of UTROSCT in 2011. Enhanced chest computed tomography scan revealed a solid nodule 8 mm in diameter in the right upper lobe and a well demarcated 33-mm mass or nodule in the lower lobe. Under the diagnosis of metastatic tumors from UTROSCT, she underwent wedge resection of the right upper lobe and segmentectomy of the right S8. Cytologically, the stump smear from the resected tumors revealed round to short spindle-shaped neoplastic small cells arranged in sheets with poor cohesion and no cluster formation. The nuclei were irregular in shape, and the chromatin was finely granular, uniform, and increased. Mitotic figures were not observed. Necrosis was absent in the background. Histologically, the final diagnosis was UTROSCT group II. This is an unusual case of metastatic UTROSCT to the lung in which the cytologic features are described. PMID- 28869332 TI - Renin-angiotensin blockade in heart failure with preserved ejection fraction: a systematic review and meta-analysis. AB - Studies with angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in patients with heart failure with preserved ejection fraction (HFpEF) have yielded inconsistent results. To conduct a systematic review and meta-analysis of all evidence for ACE-I and ARBs in patients with HFpEF, we searched PubMed, Ovid SP, Embase, and Cochrane database to identify randomized trials and observational studies that compared ACE-I or ARBs against placebo or standard therapy in HFpEF patients. Random-effect models were used to pool the data, and I2 testing was performed to assess the heterogeneity of the included studies. A total of 13 studies (treatment arm = 8676 and control arm = 8608) were analysed. Pooled analysis of randomized trials for ACE-I and ARBs (n = 6) did not show any effect on all-cause mortality [relative risk (RR) = 1.02, 95% confidence interval (CI) = 0.93-1.11, P = 0.68, I2 = 0%], while results from observational studies showed a significant improvement (RR = 0.91, 95% CI = 0.87 0.95, P = 0.005, I2 = 81.5%). In pooled analyses of all studies, ACE-I showed a reduction of all-cause mortality (RR = 0.91, 95% CI = 0.87-0.95, P = 0.01). There was no reduction in cardiovascular mortality seen, but in pooled analysis of randomized trials, there was a trend towards reduced HF hospitalization risk (RR = 0.91, 95% CI = 0.83-1.01, I2 = 0%, P = 0.074). These data suggest that ACE-I and ARBs may have a role in improving outcomes of patients with HFpEF, underscoring the need for future research with careful patient selection, and trial design and conduct. PMID- 28869334 TI - Percutaneous thoracic duct intervention to treat plastic bronchitis related to Fontan palliation. AB - Plastic bronchitis is a life-threatening condition of airway obstructive cast formation. This pediatric case series from a high altitude center details the course of three patients after percutaneous thoracic duct interventions for refractory plastic bronchitis, with a follow-up interval of 3.5 years. In two patients, where cisterna chyli maceration (patients 2) or thoracic duct embolization (patient 3) was performed, a sustained clinical improvement is shown, with no subsequent cast recurrence. In patient 1, cisterna chyli maceration resulted in partial improvement. Herein, a favorable outcome is shown in pediatric patients with percutaneous thoracic duct interventions for plastic bronchitis at altitude. PMID- 28869335 TI - Generation and Evaluation of Novel Stromal Cell-Containing Tissue Engineered Artificial Stromas for the Surgical Repair of Abdominal Defects. AB - Repair of abdominal wall defects is one of the major clinical challenges in abdominal surgery. Most biomaterials are associated to infection and severe complications, making necessary safer and more biocompatible approaches. In the present work, the adequate mechanical properties of synthetic polymer meshes with tissue-engineered matrices containing stromal mesenchymal cells is combined to generate a novel cell-containing tissue-like artificial stroma (SCTLAS) for use in abdominal wall repair. SCTLAS consisting on fibrin-agarose hydrogels seeded with stromal cells and reinforced with commercial surgical meshes (SM) are evaluated in vitro and in vivo in animal models of abdominal wall defect. Inflammatory cells, collagen, and extracellular matrix (ECM) components are analyzed and compared with grafted SM. Use of SCTLAS results in less inflammation and less fibrosis than SM, with most ECM components being very similar to control abdominal wall tissues. Cell migration and ECM remodeling within SCTLAS is comparable to control tissues. The use of SCTLAS could contribute to reduce the side-effects associated to currently available SM and regenerated tissues are more similar to control abdominal wall tissues. Bioengineered SCTLAS could contribute to a safer treatment of abdominal wall defects with higher biocompatibility than currently available SM. PMID- 28869336 TI - High Photoluminescence Quantum Yields in Organic Semiconductor-Perovskite Composite Thin Films. AB - One of the obstacles towards efficient radiative recombination in hybrid perovskites is a low exciton binding energy, typically in the orders of tens of meV. It has been shown that the use of electron-donor additives can lead to a substantial reduction of the non-radiative recombination in perovskite films. Herein, the approach using small molecules with semiconducting properties, which are candidates to be implemented in future optoelectronic devices, is presented. In particular, highly luminescent perovskite-organic semiconductor composite thin films have been developed, which can be processed from solution in a simple coating step. By tuning the relative concentration of methylammonium lead bromide (MAPbBr3 ) and 9,9spirobifluoren-2-yl-diphenyl-phosphine oxide (SPPO1), it is possible to achieve photoluminescent quantum yields (PLQYs) as high as 85 %. This is attributed to the dual functions of SPPO1 that limit the grain growth while passivating the perovskite surface. The electroluminescence of these materials was investigated by fabricating multilayer LEDs, where charge injection and transport was found to be severely hindered for the perovskite/SPPO1 material. This was alleviated by partially substituting SPPO1 with a hole-transporting material, 1,3-bis(N-carbazolyl)benzene (mCP), leading to bright electroluminescence. The potential of combining perovskite and organic semiconductors to prepare materials with improved properties opens new avenues for the preparation of simple lightemitting devices using perovskites as the emitter. PMID- 28869337 TI - Rapid separation and simultaneous quantitative determination of 13 constituents in Psoraleae Fructus by a single marker using high-performance liquid chromatography with diode array detection. AB - Psoraleae Fructus is one of the most popular traditional Chinese medicines. Coumarins, flavonoids, and meroterpenes are the main contributors to the biological activity of Psoraleae Fructus. In this study, a new method for the quality control of Psoraleae Fructus was developed, through the quantitative analysis of multicomponents by single marker with diode array detector. Thirteen components, including psoralenoside, isopsoralenoside, psoralen, isopsoralen, psoralidin, neobavaisoflavone, bavachin, corylin, isobavachalcone, corylifol A, bavachinin, bavachalcone, and bakuchiol were rapidly separated and identified within 12 min by the newly developed method. The feasibility and reliability of this method were corroborated. The method was also compared to the external standard method and detection by corona charged aerosol detector. The results of percent difference (%) and cos (theta) have shown that there were no significant differences observed between the quantitative analysis of multicomponents by single marker and external standard method analyses; psoralen and isopsoralen were undetectable with the corona charged aerosol detector due to their but the sensitivity for all the compounds except bakuchiol detected by corona charged aerosol detector are higher than those obtained by diode array detector. In addition, the newly method developed was applied to the quality evaluation of Chinese patent medicines containing Psoraleae Fructus. PMID- 28869338 TI - Enhanced Biosynthesis of Hyaluronic Acid Using Engineered Corynebacterium glutamicum Via Metabolic Pathway Regulation. AB - Hyaluronic acid (HA) is a polysaccharide used in many industries such as medicine, surgery, cosmetics, and food. To avoid potential pathogenicity caused by its native producer, Streptococcus, efforts have been made to create a recombinant host for HA production. In this work, a GRAS (generally recognized as safe) strain, Corynebacterium glutamicum, is engineered for enhanced biosynthesis of HA via metabolic pathway regulation. Five enzymes (HasA-HasE) involved in the HA biosynthetic pathway are highlighted, and eight diverse operon combinations, including HasA, HasAB, HasAC, HasAD, HasAE, HasABC, HasABD, and HasABE, are compared. HasAB and HasABC are found to be optimal for HA biosynthesis in C. glutamicum. To meet the energy demand for HA synthesis, the metabolic pathway that produces lactate is blocked by knocking out the lactate dehydrogenase (LDH) gene using single crossover homologous recombination. Engineered C. glutamicum/Deltaldh-AB is superior and had a significantly higher HA titer than C. glutamicum/Deltaldh-ABC. Batch and fed-batch cultures of C. glutamicum/Deltaldh-AB are performed in a 5-L fermenter. Using glucose feeding, the maximum HA titer reached 21.6 g L-1 , more than threefolds of that of the wild-type Streptococcus. This work provides an efficient, safe, and novel recombinant HA producer, C. glutamicum/Deltaldh-AB, via metabolic pathway regulation. PMID- 28869339 TI - Anodic Dissolution of Al Current Collectors in Unconventional Solvents for High Voltage Electrochemical Double-Layer Capacitors. AB - This study investigated the anodic dissolution of Al current collectors in unconventional electrolytes for high voltage electrochemical double-layer capacitors (EDLCs) containing adiponitrile (ADN), 3-cyanopropionic acid methyl ester (CPAME), 2-methyl-glutaronitrile (2-MGN) as solvent, and tetraethylammonium tetrafluoroborate (Et4 NBF4 ) and tetraethylammonium bis(trifluoromethanesulfonyl)imide (Et4 NTFSI) as conductive salts. To have a comparison with the state-of-the-art electrolytes, the same salts were also used in combination with acetonitrile (ACN). The chemical-physical properties of the electrolytes were investigated. Furthermore, their impact on the anodic dissolution of Al was analyzed in detail as well as the influence of this process on the performance of high voltage EDLCs. The results of this study indicated that in the case of Et4 NBF4 -based electrolytes, the use of an alternative solvent is very beneficial for the realization of stable devices. When Et4 NTFSI is used, the reduced solubility of the complex Al(TFSI)3 appears to be the key for the realization of advanced electrolytes. PMID- 28869340 TI - Diagnostic utility of cardiac troponin T level in patients with cardiac amyloidosis. AB - AIM: The aim of this study was to evaluate the diagnostic utility of high sensitivity cardiac troponin T (hs-cTnT) levels in discriminating cardiac amyloidosis from patients with cardiac hypertrophy caused by aetiologies other than cardiac amyloidosis. METHODS AND RESULTS: Serum hs-cTnT levels were measured in 96 patients with cardiac amyloidosis (light chain: 23, wild-type transthyretin amyloidosis: 40, and mutated transthyretin amyloidosis: 33), and 91 patients with other causes of cardiac hypertrophy who were confirmed to have no cardiac amyloidosis by endomyocardial biopsy (control group). The diagnostic utility and cut-off value of hs-cTnT were evaluated by receiver operating characteristic analysis. The median hs-cTnT levels were higher in cardiac amyloidosis than the control group [0.048 (0.029-0.073) vs. 0.016 (0.010-0.031) ng/mL; P < 0.001]. High levels of hs-cTnT were suggestive of cardiac amyloidosis (cut-off value: 0.0312 ng/mL, sensitivity: 0.74, specificity: 0.76, area under the curve: 0.788; 95% confidence interval: 0.723-0.854, P < 0.001), compared with brain natriuretic peptide and E/e' ratio. The hs-cTnT levels were also useful in differentiating each type of amyloidosis from the control group. Multivariate analysis identified log hs-cTnT as an independent diagnostic factor for cardiac amyloidosis (odds ratio: 2.22; 95% confidence interval: 1.30-3.80; P = 0.004). CONCLUSIONS: High serum levels of hs-cTnT are highly suggestive of cardiac amyloidosis, allowing its differentiation from cardiac hypertrophy of other aetiologies. Further refined diagnostic approaches that include imaging modalities and histopathological examination are needed for these patients to avoid underdiagnosis of cardiac amyloidosis. PMID- 28869342 TI - High flow nasal cannula reduces carbon dioxide washout time: What can we pay attention to? PMID- 28869341 TI - (-)-Epigallocatechin-3-gallate Ameliorates Insulin Resistance and Mitochondrial Dysfunction in HepG2 Cells: Involvement of Bmal1. AB - SCOPE: Normal physiological processes require a robust biological timer called the circadian clock. Dysregulation of circadian rhythms contributes to a variety of metabolic syndrome, including obesity and insulin resistance. (-) Epigallocatechin-3-gallate (EGCG) has been demonstrated to possess antioxidant, anti-inflammatory, and cardioprotective bioactivities. The objective of this study was to explore whether the circadian clock is involved in the protective effect of EGCG against insulin resistance. METHODS AND RESULTS: The results demonstrated that EGCG reverses the relatively shallow daily oscillations of circadian clock genes transcription and protein expression induced by glucosamine in HepG2 cells. EGCG also alleviates insulin resistance by enhancing tyrosine phosphorylated levels of IRS-1, stimulating the translocation of GLUT2, and activating PI3K/AKT as well as AMPK signaling pathways in a Bmal1-dependent manner both in HepG2 cells and primary hepatocytes. Glucosamine-stimulated excessive secretions of ROS and depletions of mitochondrial membrane potential were notably attenuated in EGCG co-treated HepG2 cells, which consistent with the recovery in expression of mitochondrial respiration complexes. CONCLUSION: The results demonstrated that EGCG possesses a Bmal1-dependent efficacy against insulin resistance conditions by strengthening the insulin signaling and eliminating oxidative stress, suggesting that EGCG may serve as a promising natural nutraceutical for the regulation of metabolic disorders relevant to circadian clocks. PMID- 28869343 TI - Systematic reviews: Guidelines, tools and checklists for authors. PMID- 28869344 TI - Iliopsoas and intraperitoneal abscesses associated with pyoderma gangrenosum. PMID- 28869345 TI - Kerion celsi caused by Trichophyton erinacei from a hedgehog treated with terbinafine. PMID- 28869346 TI - Professor Stephania Jablonska, 1920-2017. PMID- 28869349 TI - Corrigendum. PMID- 28869350 TI - Utilizing lymphatic cell markers to visualize human lymphatic abnormalities. AB - In vivo visualization of the human lymphatic system is limited by the mode of delivery of tracing agents, depth of field and size of the area examined, and specificity of the cell markers used to distinguish lymphatic endothelium from the blood vessels and the surrounding tissues. These limitations are particularly problematic when imaging human lymphatic abnormalities. First, limited understanding of the lymphatic disease aetiology exists with respect to genetic causes and phenotypic presentations. Second, the ability of a tracer to reach the entire lymphatic network within the diseased tissue is suboptimal. Third, what is known about the expression of lymphatic endothelial cell (LEC) markers, such as podoplanin, lymphatic vessel endothelial hyaluronan receptor, Drosophila melanogaster homeobox gene prospero-1 and vascular endothelial growth factor receptor-3 in rodent lymphatic vessels and healthy human LECs may not necessarily apply in human lymphatic disease settings. The aim of this review is to highlight challenges in visualizing lymphatic vessels in human lymphatic abnormalities with respect to distribution patterns of the cellular markers currently employed to visualize abnormal human lymphatic vessels in experimental settings. Allowing for these limitations within new diagnostic visualization technologies is likely to improve our ability to image human lymphatic diseases. PMID- 28869351 TI - Ground plan of the larval nervous system in phoronids: Evidence from larvae of viviparous phoronid. AB - Nervous system organization differs greatly in larvae and adults of many species, but has nevertheless been traditionally used for phylogenetic studies. In phoronids, the organization of the larval nervous system depends on the type of development. With the goal of understanding the ground plan of the nervous system in phoronid larvae, the development and organization of the larval nervous system were studied in a viviparous phoronid species. The ground plan of the phoronid larval nervous system includes an apical organ, a continuous nerve tract under the preoral and postoral ciliated bands, and two lateral nerves extending between the apical organ and the nerve tract. A bilobed larva with such an organization of the nervous system is suggested to be the primary larva of the taxonomic group Brachiozoa, which includes the phyla Brachiopoda and Phoronida. The ground plan of the nervous system of phoronid larvae is similar to that of the early larvae of annelids and of some deuterostomians. The protostome- and deuterostome-like features, which are characteristic of many organ systems in phoronids, were probably inherited by phoronids from the last common bilaterian ancestor. The information provided here on the ground plan of the larval nervous system should be useful for future analyses of phoronid phylogeny and evolution. PMID- 28869352 TI - De novo transcriptome assembly and developmental mode specific gene expression of Pygospio elegans. AB - Species with multiple different larval developmental modes are interesting models for the study of mechanisms underlying developmental mode transitions and life history evolution. Pygospio elegans, a small, tube-dwelling polychaete worm commonly found in estuarine and marine habitats around the northern hemisphere, is one species with variable developmental modes. To provide new genomic resources for studying P. elegans and to address the differences in gene expression between individuals producing offspring with different larval developmental modes, we performed whole transcriptome Illumina RNA sequencing of adult worms from two populations and prepared a de novo assembly of the P. elegans transcriptome. The transcriptome comprises 66,233 unigenes, of which 33,807 contain predicted coding sequences, 26,448 have at least one functional annotation, and 3,076 are classified as putative long non-coding RNAs. We found more than 8,000 unigenes significantly differentially expressed between adult worms from populations producing either planktonic or benthic larvae. This comprehensive transcriptome resource for P. elegans adds to the available genomic data for annelids and can be used to uncover mechanisms allowing developmental variation in this and potentially other marine invertebrate species. PMID- 28869353 TI - The transition path from female workers to neotenic reproductives in the termite Reticulitermes labralis. AB - Termite workers are characterized by unique flexibility in that a worker can develop in one of three ways: remain a worker, become a soldier within two successive moults, or become a neotenic reproductive (NR) within a single moult. However, is it true that workers can transform into NRs within a single moult? Actually, the developmental pathways of workers turning into NRs remains unclear. In this study, we show for the first time that the female workers of Reticulitermes labralis develop into NRs after a pre-NRs stage. We found that a female worker became a NR after two successive moults, whereas the male workers copulated directly with queens without undergoing any moults. After the first moult led the female workers into the pre-NR stage, the length of their abdomens, seventh sternites and ovaries significantly increased. After the second moult from the pre-NRs stage into NRs, the follicle cells returned to normal, and a few oocytes and follicle cells underwent apoptosis. These results demonstrated that the female pre-NR type was a transitional type during the development of female workers to the NR caste, and the starting point for oogenesis resumption was the NR stage. We confirmed there were fundamental differences in the reproductive pathway of the male and female workers. Therefore, we determined that the transformation process of the female NRs from workers may be a very complex process, and the reproductive biology of the workers has great potential to provide important and spectacular insights into the evolution strategy of termites. PMID- 28869354 TI - Working memory network alterations in high-functioning adolescents with an autism spectrum disorder. AB - AIM: People with autism spectrum disorder (ASD) typically have deficits in the working memory (WM) system. WM is found to be an essential chain in successfully navigating in the social world. We hypothesize that brain networks for WM have an altered network integrity in ASD compared to controls. METHODS: Thirteen adolescents (one female) with autistic disorder (n = 1), Asperger's disorder (n = 7), or pervasive developmental disorder not otherwise specified (n = 5), and 13 typically developing healthy control adolescents (one female) participated in this study. Functional magnetic resonance imaging (MRI) was performed using an n back task and in resting state. RESULTS: The analysis of the behavioral data revealed deficits in WM performance in ASD, but only when tested to the limit. Adolescents with ASD showed lower binary global efficiency in the WM network than the healthy control group with n-back and resting-state data. This correlated with diagnostic scores for total problems, reciprocity, and language. CONCLUSION: Adolescents with higher-functioning autism have difficulty with the WM system, which is typically compensated. Functional MRI markers of brain network organization in ASD are related to characteristics of autism as represented in diagnostic scores. Therefore, functional MRI provides neuronal correlates for memory difficulties in adolescents with ASD. PMID- 28869355 TI - Black Pigment Gallstone Inspired Platinum-Chelated Bilirubin Nanoparticles for Combined Photoacoustic Imaging and Photothermal Therapy of Cancers. AB - Bilirubin (BR), a bile pigment that exerts potent antioxidant and anti inflammatory effects, is also a major constituent of black pigment gallstones found in bile ducts under certain pathological conditions. Inspired by the intrinsic metal-chelating power of BR found in gallstones, herein we report a cisplatin-chelated BR-based nanoparticle (cisPt@BRNP) for use as a new photonic nanomedicine for combined photoacoustic imaging and photothermal therapy of cancers. The cisPt@BRNPs were prepared by simply mixing cisplatin with BRNPs, yielding ca. 150-nm-size NPs. Upon near-IR laser irradiation at 808 nm, cisPt@BRNPs generated considerable heat and induced clear death of cancer cells in vitro. Following intravenous injection into human colon cancer-bearing mice, cisPt@BRNPs allowed effective tumor visualization by photoacoustic imaging and remarkable antitumor efficacy by photothermal therapy, suggesting their potential for use as a new photonic nanomedicine for cancer therapy. PMID- 28869356 TI - A Plant-Produced Candidate Subunit Vaccine Reduces Shedding of Enterohemorrhagic Escherichia coli in Ruminants. AB - Enterohemorrhagic Escherichia coli (EHEC) are commonly present in the gastrointestinal tract of cattle and cause serious infectious disease in humans. Immunizing cattle against EHEC is a promising strategy to decrease the risk of food contamination; however, veterinary vaccines against EHEC such as Econiche have not been widely adopted by the agricultural industry, and have been discontinued, prompting the need for more cost-effective EHEC vaccines. The objective of this project is to develop a platform to produce plant-made antigens for oral vaccination of ruminants against EHEC. Five recombinant proteins were designed as vaccine candidates and expressed transiently in Nicotiana benthamiana and transplastomically in Nicotiana tabacum. Three of these EHEC proteins, NleA, Stx2b, and a fusion of EspA accumulated when transiently expressed. Transient protein accumulation was the highest when EHEC proteins were fused to an elastin like polypeptide (ELP) tag. In the transplastomic lines, EspA accumulated up to 479 mg kg-1 in lyophilized leaf material. Sheep that were administered leaf tissue containing recombinant EspA shed less E. coli O157:H7 when challenged, as compared to control animals. These results suggest that plant-made, transgenic EspA has the potential to reduce EHEC shedding in ruminants. PMID- 28869357 TI - The moderator effect of commitment on the relations between satisfaction and motivation in Special Employment Centres. AB - BACKGROUND: Little is known about the relation between satisfaction, commitment and motivation among employees with mild intellectual disabilities. The present research analyses the moderated effect of commitment on the relation between satisfaction of employees with intellectual disabilities and their motivation. METHOD: Employees with legally recognized intellectual disabilities, following the Spanish law, answered a questionnaire. The present authors examined bivariate relations across all variables in the model. Subsequently, a moderator model was tested, using the Johnson-Neyman and the pick-a-point approximation. RESULT: There was a direct effect between employees' satisfaction and motivation (b = 2.4621; p < .0001). Commitment had a moderator effect on this relation (b = [ 3.36 to -0.30]; p < .001), especially for those employees with lower levels of commitment. CONCLUSIONS: Our research focuses on the antecedents of work motivation of employees with mild intellectual disabilities as full employees. So, our results help HR managers to increase employees' motivational levels, as one of the main objectives of healthy organizations. PMID- 28869358 TI - The role of respiratory tract infections and the microbiome in the development of asthma: A narrative review. AB - Asthma is a common disease in childhood, and might predispose for chronic obstructive respiratory morbidity in adolescence and adulthood. Various early life risk factors might influence the risk of wheezing, asthma, and lower lung function in childhood. Cohort studies demonstrated that lower respiratory tract infections in the first years of life are associated with an increased risk of wheezing and asthma, while the association with lung function is less clear. Additionally, the gut and airway microbiome might influence the risk of wheezing and asthma. The interaction between respiratory tract infections and the microbiome complicates studies of their associations with wheezing, asthma, and lung function. Furthermore, the causality behind these observations is still unclear, and several other factors such as genetic susceptibility and the immune system might be of importance. This review is focused on the association of early life respiratory tract infections and the microbiome with wheezing, asthma, and lung function, it is possible influencing factors and perspectives for future studies. PMID- 28869360 TI - Harnessing Microbial Cells Through Advanced Technologies and Conventional Strategies. PMID- 28869359 TI - Monitoring of hemostatic abnormalities in major orthopedic surgery patients treated with edoxaban by APTT waveform. AB - INTRODUCTION: An analysis of the activated partial thromboplastin time (APTT) in major orthopedic surgery patients receiving edoxaban for the prevention of venous thromboembolism (VTE) was carried out. METHODS: The APTT waveform was analyzed in the above patients to monitor edoxaban administration. RESULTS: Of these 99 patients, 12 exhibited deep vein thrombosis, and 25 had massive bleeding. An increased biphasic pattern of the APTT waveform was observed after the administration of edoxaban, but there were no significant differences between the patients with and without complications. The peak times of acceleration, velocity, and 1/2 fibrin formation were significantly prolonged after the administration of edoxaban, especially in patients with massive bleeding, and were moderately correlated with the anti-Xa activity. While the heights of velocity and acceleration peak 2 were lower in patients receiving warfarin treatment than in those receiving edoxaban, the widths of these parameters were significantly longer. The height of 1/2 fibrin formation and the width of acceleration peaks 1 and 2 and the velocity were significantly increased after the administration of edoxaban. CONCLUSION: The peak time of the APTT waveform was significantly prolonged after the administration of edoxaban. The analysis of the APTT waveform may therefore be useful for the prediction of the risk of massive bleeding. PMID- 28869361 TI - Development of multiple monolithic fiber solid-phase microextraction and liquid chromatography-tandem mass spectrometry method for the sensitive monitoring of aminoglycosides in honey and milk samples. AB - A simple and sensitive method for the simultaneous extraction and determination of six aminoglycosides in honey and milk samples was developed using multiple monolithic fiber solid-phase microextraction and liquid chromatography with tandem mass spectrometry. The multiple monolithic fibers based on poly(methacrylic acid-co-ethylenedimethacrylate) monolith as the extraction medium was used to concentrate target analytes. Because there were abundant carboxyl groups in the monolith, the monolithic fibers could extract aminoglycosides effectively through cation-exchange and hydrophobic interactions. To obtain optimum extraction performance, several extraction parameters including desorption solvent, adsorption and desorption time, pH value and ionic strength in sample matrix, were investigated in detail. Under the optimized extraction conditions, the limits of detection of the proposed method were 0.10-0.30 and 0.23-0.59 MUg/kg for honey and milk samples, respectively. Satisfactory linearity was achieved for analytes with the coefficients of determination above 0.99. At the same time, the developed method showed acceptable method repeatability and reproducibility. Finally, the proposed method was successfully applied to the determination of aminoglycosides in real honey and milk samples. Recoveries obtained for the determination of six target analytes in spiking samples ranged from 67.9 to 110%, and the relative standard deviations were in the range of 1.2 11%. PMID- 28869363 TI - Retrospectoscope: Are the peripheral airways in infants and young children disproportionately small, putting them at risk for severe respiratory illnesses? PMID- 28869362 TI - Self-Assembly of Thermoresponsive Recombinant Silk-Elastinlike Nanogels. AB - Recombinant silk-elastinlike protein polymers (SELPs) combine the biocompatibility and thermoresponsiveness of human tropoelastin with the strength of silk. Direct control over structure of these monodisperse polymers allows for precise correlation of structure with function. This work describes the fabrication of the first SELP nanogels and evaluation of their physicochemical properties and thermoresponsiveness. Self-assembly of dilute concentrations of SELPs results in nanogels with enhanced stability over micelles due to physically crosslinked beta-sheet silk segments. The nanogels respond to thermal stimuli via size changes and aggregation. Modifying the ratio and sequence of silk to elastin in the polymer backbone results in alterations in critical gel formation concentration, stability, aggregation, size contraction temperature, and thermal reversibility. The nanogels sequester hydrophobic compounds and show promise in delivery of bioactive agents. PMID- 28869364 TI - Nanocryl Coating of PMMA Complete Denture Base Materials to Prevent Scratching. AB - The surface of polymethylmethacrylate (PMMA) is vulnerable to indentation by hard objects that may contribute to abrade the material surface and subject it to wear. This phenomenon promotes an increase in the surface roughness leading to microbial colonisation which can endanger the general health of wearers and damage the intra-oral prosthesis. The aim of this study is to investigate the effect of three different nanocryl coating agents (Easy Glaze, G-Coat Plus and Formulation XP) on surface roughness and thickness of PMMA material after a simulating cleaning process utilizing an electric toothbrush and three different dentifrices (pastes and immersion). Acrylic uncoated discs were used as a control group. The results showed that the G-Coat Plus coating agent had less changes in the surface roughness and thickness layer whereas the immersion cleaner revealed less abrasion effect compared with the paste cleaners which could be considered the most suitable cleaner to provide lower abrasivenes and good removal of organic debris. However, using nanofilled sealants did not demonstrate significant improvement in reducing surface roughness p ? 0.05. Nevertheless, it could provide some protection against wearing to the acrylic resin surface during tooth brushing and may provide better resistance to microbial colonisation. PMID- 28869365 TI - Influence of Different Ceramic Systems on Marginal Misfit. AB - OBJECTIVE: the aim of this study was to evaluate the marginal misfit at the interface between a ceramic coping and its abutment. METHODS: Twenty-four specimens were made with solid abutments. The specimens were divided into 3 groups according to the ceramic system (n = 8): Lava (zirconia), IPS e.max Press (lithium disilicate), and IPS Empress Esthetic (leucite). All copings were cemented with resin luting agent (RelyX U200) and the marginal misfit were evaluated at 3 different times: initial, after cementation, and after mechanical cycling using a linear measuring microscope (Measuring Microscope STM-Olympus) at a magnification of 40x. All specimens were subjected to mechanical cycling (1 million cycles) by an universal testing machine (Instron 8800). The results were statistically analyzed using Analysis of Variance and Student's t-test (alpha = 0.05). RESULTS: all groups showed an increase in the marginal misfit after cementation. The lithium disilicate group demonstrated the lowest interacial gap values at each evaluation (p = 0.001). The zirconia and leucite groups showed similar interfacial gap values (initial, p = 0.244; and post cementation, p = 0.751). CONCLUSIONS: the cementation increase the marginal misfit, but the mechanical cycling did not influence the marginal misfit of the ceramics systems evaluated. PMID- 28869366 TI - Effect of Distance on Light Transmission Through Polymerized Resin Composite. AB - OBJECTIVE: Light transmittance of dental composites varies between products and shades, but also light curing units differ to each other in their irradiance and fiber optic structure of curing tip. The aim of this study was to investigate whether there is linear relationship between the distance of the curing tip to the resin composite and irradiance at lower surface of the resin composite. MATERIALS AND METHODS: Disks of 1 mm thickness (6mm diameter) were fabricated. Light transmittance (intensity) through the disk was measured at distance of 0, 2, 4, 6, 8, 10 mm from the light tip with two light curing units Elipar S10 (3M ESPE) and Silverlight (GC). Irradiance ratio (irradiance on the sensor surface without the composite disk / with the composite disk) was calculated and plotted against the distance of the light curing tip. Statistical analysis was carried out using analysis of covariance (ANCOVA, Tukey's, alpha =0.05). RESULTS: Irradiance ratio varied between 18% to 24% with Silverlight and 21% to 26% with Elipar S10 light curing units. There were statistically significant differences between the ratios with different distances of the light curing tip (p?0.05). Interestingly, the highest irradiance ratio for Elipar S10 unit was found with 4 mm distance of the tip, whereas Silverlight unit had the highest ratio with 6 mm distance. Out of two tested resin composites, the flowable composite showed higher irradiance ratio than regular packable resin composite. CONCLUSIONS: Increase of distance of the light curing tip from the composite surface decreased the absolute irradiance underneath of composite, as expected. However, there seemed to be device dependent optimal distance of 4-6 mm to reach the most efficient irradiance ratio through the composite resin keeping in mind that most efficient transmission of light through the material is reached by having light curing tip in contact to the material. PMID- 28869367 TI - Survival of Direct Posterior Composites With and Without a Bulk Fill Base. AB - OBJECTIVES: Direct composite restorations are increasingly popular and a flowable bulk-fill base material (SDR, Dentsply) claims to minimise stress through a more flexible polymerisation process. This retrospective audit of restorations placed in general practice compares SDR based restorations with conventional composite restorations. METHODS: Restorations were all placed by one operator using a similar clinical technique and were audited as Group G, placed with a conventional layering composite (G-aenial, GC) and Group S which had a bulk-fill base of SDR (Dentsply) and then were covered with G-aenial (GC). Data regarding survival, post-operative sensitivity and mode of failure were recorded and analysed. RESULTS: In total 54 Group S restorations and 71 Group G restorations were followed for a minimum of 24 months. Group S had a 92.6% survival and Group G 93%. Group S was more prone to failure by tooth fracture (p=0.033). In both groups failure was more likely in larger cavities, in both those with an increased number of surfaces (p?0.001) and cuspal coverage (p=0.004). CONCLUSIONS: There appears to be similar survival of the two techniques in the short-term although there were significantly more tooth fractures in teeth restored with SDR. PMID- 28869368 TI - 3D Metal Printing - Additive Manufacturing Technologies for Frameworks of Implant Borne Fixed Dental Prosthesis. AB - An edentulous patient was rehabilitated with maxillary metal-ceramic and mandibular metal-resin implant-supported fixed dental prosthesis (FDP). Metal frameworks of the FDPs were fabricated using 3D additive manufacturing technologies utilizing selective laser melting (SLM) and electron beam melting (EBM) processes. Both SLM and EBM technologies were employed in combination with computer numerical control (CNC) post-machining at the implant interface. This report highlights the technical and clinical protocol for fabrication of FDPs using SLM and EBM additive technologies. PMID- 28869369 TI - Minimally invasive percutaneous approach for the management of high grade spondylolisthesis. PMID- 28869370 TI - Disappearance of a synovial cyst after XLIF procedure. PMID- 28869371 TI - Quantitative analysis of cerebrospinal fluid dynamics at phase contrast cine-MRI: predictivity of neurosurgical "Shunt" responsiveness in patients with idiopathic normal pressure hydrocephalus. AB - BACKGROUND: Aqueductal stroke volume (ACSV) measured by phase-contrast cine (PCC) MRI has been proposed with controversy as a tool for the selection of patients with normal pressure hydrocephalus (NPH) as candidates for shunt-surgery. The aim of this study was to assess if PCC-MRI scan measurements of ACSV could select properly these patients. METHODS: We retrospectively reviewed charts and MRI of 38 shunted patients (72,16 +/-6,16 years). ACSV measurements were performed 7-30 days before shunt and at the first and sixth months after surgery. Normally distributed variables were compared in the two groups (improved/unimproved) by T test for baseline values and with repeated measures analysis of variance. RESULTS: 26 patients (68,4 %) improved after VPS (mean time of symptom onset was 8,15 +/-7,19 months). Mean preoperative ACSV value was 271,85 +/- 143,03, which decreased by 21,6 % (mean 213 +/- 125,14 ) at the first month and 40,3% sixth months after VPS (mean 162,15 +/- 91,5). 12 patients (31,6 %) did not improve (mean time of symptom onset was 29 +/- 5,62 months). Mean preoperative ACSV value was 79,83 +/- 31,24, decreased to 8,7 % (mean 72,83 +/-28,66 ) at first month after VPS, 21,2% (mean 62,83 +/- 31,12 ) after six months. We found statistical difference between preoperative ACSV of improved and unimproved patients (p<0,01), onset time of symptoms (p<0,01) and the changes in ACSV after one and six months in both groups (p<0,001). CONCLUSIONS: ACSV is useful to stratify patients with NPH after surgery (improved /not improved) suggesting to proceed with serial ACSV measurements before deciding treatment. PMID- 28869372 TI - Single level anterior cervical fusion. A new method to evaluate the real need of plate augmentation. PMID- 28869373 TI - Lipoxin A4 alleviates cerebral ischemia-reperfusion injury through up-regulating Nrf2. PMID- 28869374 TI - Application of esophageal radiography technique in the treatment of herniation of cervical disc with radiofrequency thermocoagulation and target ablation. PMID- 28869375 TI - Treatment strategies for craniopharyngiomas. AB - Craniopharyniomas arise from the sellar region and are particularly challenging because of their close proximity to critical neurovascular structures, including cranial nerves, brainstem, internal carotid arteries, posterior cerebral arteries, hypothalamus, and the pituitary gland. The tumors are benign on histology but can cause serious symptoms by compression of surrounding vital structures. While radical surgery and gross total resection (GTR) remains the first line treatment, choosing the optimal surgical approach is critical for the minimization of complications and post-operative morbidity. The extended endoscopic endonasal approach (EEEA) offers a direct route towards the sellar and suprasellar regions and has proven to be a safe and effective for GTR, with lower rates of complications and post-operative morbidity than open transcranial approaches. However, traditional transcranial approaches remain relevant in tumors with signficant lateral extension. Radiotherapy can be considered in cases of subtotal resection (STR) or if surgery is not possible, although progressive growth of cysts with neurological deterioration has been demonstrated no infrequently. Newly developed chemotherapy for papillary craniopharygniomas might expand treatment options in the future. PMID- 28869376 TI - Fluorinated Mesoporous Silica Nanoparticles for Binuclear Probes in 1H and 19F Magnetic Resonance Imaging. AB - The development of molecular and cellular magnetic resonance imaging (MRI) procedures has always represented a challenge because of the fact that conventional MRI contrast agents are not directly detected in vivo; in proton MRI (e.g., with the nucleus 1H), their local concentration is measured through the effect they exert on the signal of hydrogen protons present in their immediate vicinity. Because the contrast effects generated by conventional MRI probes superpose to and can often impede the anatomical information contained in 1H MRI images, new probes based on a nucleus other than 1H, are being developed. In this study, we report on the development of fluorinated mesoporous silica nanoparticles (MSNs), which could represent an interesting dual probe that allows two MRI modes: 1H for high-resolution anatomical information and 19F for the detection of MSNs used as drug delivery agents. MSNs were synthesized and covalently functionalized either with fluorosilane (FMSNs) or polyfluorosiloxane (polyFMSNs) to enable their detection in 19F MRI. Then, gadolinium chelates were grafted on the particles to enhance their detectability in 1H MRI. The physicochemical, textural, and relaxometric properties (1H and 19F relaxation times) of the nanoparticles were measured and compared. The 19F relaxation properties were found to be dependent on the concentration of fluorine; they were also highly sensitive to the presence of gadolinium. The shortest relaxation times were obtained with polyFMSNs. At clinical magnetic field strengths, high 1H relaxivities and low relaxometric ratios (r2/r1 = 1.45; 2.2 for nanoparticles entrapped in hydrogel) were found for both nanoparticle systems. Finally, the visibility of both systems was confirmed in 1H, and the detectability of polyFMSNs was confirmed in 19F MRI. This physicochemical and relaxometric study opens the door to the applications of fluorinated silica nanoparticles as theranostic materials allowing dual MRI (1H and 19F). PMID- 28869377 TI - Saccharomyces cerevisiae and Kluyveromyces marxianus Cocultures Allow Reduction of Fermentable Oligo-, Di-, and Monosaccharides and Polyols Levels in Whole Wheat Bread. AB - Fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) are small molecules that are poorly absorbed in the small intestine and rapidly fermented in the large intestine. There is evidence that a diet low in FODMAPs reduces abdominal symptoms in approximately 70% of the patients suffering from irritable bowel syndrome. Wheat contains relatively high fructan levels and is therefore a major source of FODMAPs in our diet. In this study, a yeast-based strategy was developed to reduce FODMAP levels in (whole wheat) bread. Fermentation of dough with an inulinase-secreting Kluyveromyces marxianus strain allowed to reduce fructan levels in the final product by more than 90%, while only 56% reduction was achieved when a control Saccharomyces cerevisiae strain was used. To ensure sufficient CO2 production, cocultures of S. cerevisiae and K. marxianus were prepared. Bread prepared with a coculture of K. marxianus and S. cerevisiae had fructan levels <=0.2% dm, and a loaf volume comparable with that of control bread. Therefore, this approach is suitable to effectively reduce FODMAP levels in bread. PMID- 28869378 TI - Synthesis of Imidazopyridines via Copper-Catalyzed, Formal Aza-[3 + 2] Cycloaddition Reaction of Pyridine Derivatives with alpha-Diazo Oxime Ethers. AB - The Cu-catalyzed, formal aza-[3 + 2] cycloaddition reaction of pyridine derivatives with alpha-diazo oxime ethers in trifluoroethanol was used to synthesize imidazopyridines via the release of molecular nitrogen and elimination of alcohol. These methods enabled modular synthesis of a wide range of N heterobicyclic compounds such as imidazopyridazines, imidazopyrimidines, and imidazopyrazines with an alpha-imino Cu-carbenoid generated from the alpha-diazo oxime ethers and copper. PMID- 28869379 TI - Droplet Formation by Confined Liquid Threads inside Microchannels. AB - A confined liquid thread can form monodisperse droplets near the exit of a microchannel, provided the continuous phase is able to enter the microchannel. A general model that accurately predicts the droplet size including the breakup position inside the microchannel is presented and is verified with experimental observations; breakup occurs as long as the capillary number (Ca) of the liquid thread is below a critical capillary number (Cacr); for cylindrical microchannels, it is derived that Cacr = 1/16. Below Cacr, the formed droplets at the exit of the microchannel have a diameter approximately two times the diameter of the liquid thread; around and above Cacr, the liquid thread remains stable and the formed droplets grow infinitely large. The presented controlled droplet generation method is a useful tool for producing monodisperse emulsions and has great potential for the food and pharmaceutical industry. PMID- 28869380 TI - Three-Dimensional Morphological and Chemical Evolution of Nanoporous Stainless Steel by Liquid Metal Dealloying. AB - Nanoporous materials, especially those fabricated by liquid metal dealloying processes, possess great potential in a wide range of applications due to their high surface area, bicontinuous structure with both open pores for transport and solid phase for conductivity or support, and low material cost. Here, we used X ray nanotomography and X-ray fluorescence microscopy to reveal the three dimensional (3D) morphology and elemental distribution within materials. Focusing on nanoporous stainless steel, we evaluated the 3D morphology of the dealloying front and established a quantitative processing-structure-property relationship at a later stage of dealloying. The morphological differences of samples created by liquid metal dealloying and aqueous dealloying methods were also discussed. We concluded that it is particularly important to consider the dealloying, coarsening, and densification mechanisms in influencing the performance determining, critical 3D parameters, such as tortuosity, pore size, porosity, curvature, and interfacial shape. PMID- 28869381 TI - MEEK MICROGRAFTING TECHNIQUE AND ITS USE IN THE TREATMENT OF SEVERE BURN INJURIES AT THE UNIVERSITY HOSPITAL OSTRAVA BURN CENTER. AB - BACKGROUND: Early necrectomy and skin autotransplantation are prerequisites for successful treatment of extensive burns. Insufficient autograft donor site availability is a limiting factor. The Meek micrografting technique, published by C. P. Meek in 1958, appears to be a potential solution. Skin grafts are cut into micrografts and expanded at a ratio of 1:3, 1:4, 1:6 or 1:9. Thus, even in cases with limited donor site availability, it is possible to cover large areas after necrectomy. MATERIAL AND METHODS: Meek micrografting was first used at the University Hospital Ostrava Burns Centre in 2013. To date, 14 operations have been performed in 4 patients with extensive burn trauma. Engraftment, healing rate, and subsequent scarring (with a particular focus on scar contracture formation) were observed postoperatively. RESULTS: The average micrograft success rate was 86.5%. The best success rates were observed in areas with deferred transplantation after necrectomy. Hypertrophic scarring occurred in both Meek and meshed transplant areas. No scar contractures requiring surgical management developed in micrografted areas. Surgical scar contracture release was required in 1 patient who underwent meshed graft transplantation. DISCUSSION: The Meek technique demonstrated significant advantages. Micrografts can be prepared with very small skin grafts, which is impossible with the mesh technique. Meshed grafts with expansion ratios of 1:3 or higher require allograft or xenograft coverage. In our experience, overlays were not necessary for micrografts with a 1:6 expansion ratio. Given that no serious scar contractures developed in micrografted areas, we speculate that micrografts may pose a lower risk for their development when compared to meshed grafts. The disadvantage of the Meek technique is greater economic demands. CONCLUSION: Meek micrografting is effective in the surgical management of deep burns in extensive thermal injuries with limited donor site availability... PMID- 28869382 TI - OUR EXPERIENCE WITH THE USE OF 40% BENZOIC ACID FOR NECRECTOMY IN DEEP BURNS. AB - INTRODUCTION: Chemical necrectomy of deep burns using 40% benzoic acid has been used extensively by the Department of Burns and Reconstructive Surgery at the University Hospital since its establishment in 1982. In spite of definite advantages for the patient and medical staff, hard data concerning benzoic acid absorption through skin necrosis and patient safety was missing. MATERIAL AND METHODS: We examined 22 burn patients in collaboration with the University Hospital Brno, Department of Clinical Biochemistry. The plasmatic levels of benzoic acid, hippuric acids and glycine, which is consumed during the metabolism of benzoic acid, were measured. Urine samples were collected to determine the total amount of hippuric acid that is excreted. We were able to determine the total amount of absorbed and excreted benzoic acid from these values. RESULTS: We consistently found that there was a rapid and short-term increase of plasmatic levels of benzoic acid (maximum 1.3 mmol/l). This value is about 5 times lower than the minimum toxic level of this acid (6.5 mmol/l). The same course has been observed in hippuric acid. The level of glycine dropped slightly, but was still within the normal range. DISCUSSION: Typical and atypical courses of the levels of both acids were discussed as well as the correlation of the dynamics of elimination with the extent of benzoic acid application in relationship with the clinical status of the patient. The effectiveness and safety of this method was evaluated. CONCLUSION: After summarizing the observations, it was demonstrated that chemical necrectomy using 40% benzoic acid is a selective method comparable with other types of sharp necrectomy. Chemical necrectomy is inexpensive, easy to perform and also reduces blood loss. Toxicity of absorbed benzoic acid is clinically negligible. Furthermore, benzoic acids antimycotic and antibacterial properties prevent the development of wound infection. PMID- 28869383 TI - EXPERIENCE WITH INTEGRA(r) AT THE PRAGUE BURNS CENTRE 2002-2016. AB - INTRODUCTION: Integra(r) dermal replacement has a wide spectrum of use both in burn medicine as well as in reconstructive plastic surgery and traumatology. Since 2002, it has been a part of surgical treatment of patients at Prague Burns Centre of the Kralovske Vinohrady Teaching Hospital. STUDY GROUP: Integra(r) was used in 47 patients in total between years 2002 and 2016. In this group there were 28 paediatric patients and 19 adult patients. Eleven children were operated during the reconstructive period, 8 children had an acute injury. There were 11 adult patients with Integra(r) applied within the trauma treatment, another 9 during reconstructive surgery. In 2016, we examined 11 patients treated by Integra(r), at least 2 years ago. The average time since the application was 9 years. All examined patients had Integra(r) primarily applied to treat an acute injury. METHOD: Scars after the application of Integra(r) were compared with scars after dermoepidermal grafts (DE) in respective patients. Evaluation was performed on the basis of subjective and objective assessment by means of the modified Vancouver Scale (VSS). Samples were submitted for a histological and immunohistochemical analysis. RESULTS: Areas with Integra(r) coverage scored 1.4 points on average on the VSS. The scars after dermoepidermal graft scored 4 points on the same scale. Subjective assessment of functional and cosmetic quality of scars by patients was better in all cases in comparison to DE grafting. Notable differences were found between scars following Integra(r) application and those after DE grafting on histological assessment, namely in the organization and quality of collagen and elastin fibres as well as in tissue revascularization. CONCLUSION: The Integra(r) artificial skin replacement is a part of surgical strategy in management of extensive burn trauma and plays an important role in reconstructive surgery. The resulting scar quality when using Integra(r) seems to be better than in DE grafting both from an objective and subjective points of view.. PMID- 28869384 TI - MICROMYCETES INFECTION IN PATIENTS WITH THERMAL TRAUMA. AB - GOAL: Determination of basic epidemiological parameters of burn patients with micromycetes infection. Identification of the most important micromycetes in burn patients. MATERIAL AND METHODS: Monocentre retrospective study enrolling all adult burn patients who were hospitalized between 2007 and 2015 and in whom micromycetes were isolated during hospitalization. ABSI index (Abbreviated Burn Severity Index) was used to evaluate severity of thermal trauma. Results were statistically analysed. RESULTS: There were 61 patients with thermal trauma identified in total during the period of observation, and there were yeast or fibrous fungi isolated. There were 37 males and 24 females (M:F ratio - 1.5:1) in this group. The average age of patients was 57.3 years (29 patients were aged up to 60 years, 32 patients were over the age of 60 years, inclusive). 6 patients died (lethality was 9.8%). The average extent of the burn area was 21.6% TBSA (median 14.0%). There were 90 strains of micromycetes cultured in total in these patients (79 yeasts, 11 fibrous fungi). Micromycetes were isolated from burn area in 30 patients, from the lower airways in 19 patients, from the urogenital area in 15 patients and from blood culture in 7 patients. Non-albicans Candida species were predominant among yeasts (60 strains); Candida albicans was isolated 16 times in total. Aspergillus fumigatus (4 isolations) and Fusarium species (2 isolations) were predominant species among fibrous fungi. CONCLUSION: We successfully identified the basic epidemiological parameters in burn patients with micromycetes infection, similarly to the most important yeasts and fibrous fungi causing infection in these patients. PMID- 28869385 TI - MICRONEEDLING - A FORM OF COLLAGEN INDUCTION THERAPY - OUR FIRST EXPERIENCES. AB - INTRODUCTION: Microneedling (percutaneous collagen induction therapy) is a new promising miniinvasive therapeutic method for the treatment of skin alterations of different aetiology, including burn scars. Since 2016, it is also available at our department. The microtraumatization of scars with the Dermaroller(r) leads to an activation of the healing cascade, activation of growth factors, which activate cell proliferation in the wound, increased synthesis and deposit of collagen - elastin complex with successive transformation of collagen III to collagen I, to neoangiogenesis and thus to accelerated scar remodelling. MATERIAL AND METHODS: In the pilot study conducted in 2016, the microneedling method with Dermaroller(r) with 2.5 mm needles was used in six patients (two males, four females; age 25-73 years) with stabilized scars after previous application of split thickness skin graft due to thermal injury. We repeated the microneedling procedure in three intervals approximately 6 to 8 weeks apart, with the use of topical anaesthesia. RESULTS: Preliminary results showed a subjective improvement of the scars. Objective evaluation with the Vancouver Scar Score showed an improvement of an average of two points before and after treatment. CONCLUSION: Our first clinical experience show that microneedling appears to be a suitable microinvasive method for the improvement of scar quality after burn trauma. PMID- 28869386 TI - [History, Present State and Perspectives of Czech Burns Medicine.] AB - Care for burn patients is defined in most developed countries as an independent multidisciplinary specialty (burn medicine) and it is concentrated to specialized units, which are sufficiently staffed with appropriate space area and equipment. Since the 50s of the previous century in the former Czechoslovakia, there were five such units, three of which were in the Czech Republic (Prague, Ostrava, Brno). The specialty successfully developed and achieved prestige also abroad, mainly due to uninterrupted contacts with the foreign units. Until approximately mid 90s of the previous century, an increasing trend of development accelerated (new technologies, better space area and equipment, acquisition of new knowledge from abroad, etc.). On the other hand, two negative tendencies occurred. These were negative economic balance of care for burn patients, which was due to the current system of financing healthcare, and a completely inappropriate system of postgraduate education for burn medicine specialty. These two factors cause that young doctors are not interested in the specialty and there is a risk of its stagnation in case that the units will not be at least in an even economical balance and will not be able to offer young doctors anything in terms of financial rewards and further professional growth. PMID- 28869387 TI - REPORT ON THE OBSERVER TRAINING AT BROOKE ARMY MEDICAL CENTER IN SAN ANTONIO, TEXAS, USA. AB - A short report describing the unique experience of visiting the famous Brooke Army Medical Center (BAMC) in San Antonio, Texas, USA and its Burn Center and Plastic Surgery Department in the period between June 27 and August 26, 2016. PMID- 28869388 TI - Proposal for a national triage system for the management of ventral hernias. AB - Ventral hernia disease is becoming increasingly prevalent and complex. Subspecialisation for patients with challenging conditions requiring surgery has been shown to improve postoperative outcomes. Worldwide, there is an emergence of specialist hernia centres using new and innovative techniques to repair large and complicated ventral hernias. After a national meeting of hernia experts, we present an algorithm to be used as a national triage system for patients with ventral hernias, with the aim of ensuring that patients are operated on by the most appropriate surgeon. Evidence-based clinical risk factors and ventral hernia parameters are used for risk stratification and patient triage. We hope that this algorithm will guide future ventral hernia management in the UK. PMID- 28869389 TI - The use of imaging in acute pancreatitis in United Kingdom hospitals: findings from a national quality of care study. AB - OBJECTIVE: To assess use of imaging in patients admitted to UK hospitals with acute pancreatitis (AP). METHODS: 4,479 patients had a diagnosis AP in the first 6 months of 2014. The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) selected patients with more severe AP for case review. Clinicians completed 712 questionnaires and case reviewers assessed 418 cases. The use of imaging in patients with AP is reported. RESULTS: The common causes of AP were gallstones (46.5%) and alcohol excess (22%) with no cause identified in 17.5%. Imaging was needed to diagnose AP in 12%. 60.1% of patients had one or more CT scan. The timing of the CT scan(s) was appropriate in 90% of patients. The number of CTs was appropriate in all except 6.6% (equally split between too many and too few). AP collection intervention was radiological in 49/613 and surgical in 23/613. 69.8% had an ultrasound scan which diagnosed gallstones in 46.4% and bile duct dilatation in 12.9%. At least 21% had ultrasound scan inappropriately omitted. The National Confidential Enquiry into Patient Outcome and Death recommends gallstones are excluded in all patients with AP, including suspected alcohol-related AP. 29.8% underwent magnetic resonance cholangio--pancreatography diagnosing gallstones in 62.4%, bile duct dilatation in 25.4% and common bile duct stones in 14.4%. 20.6% had recurrent pancreatitis with gallstones accounting for a third. 17% with gallstone AP had a cholecystectomy within the guideline recommended time period. CONCLUSION: Imaging is rarely required for the diagnosis of AP. CT is used responsibly in AP management. Imaging should be used more to exclude gallstones, including in presumed alcohol related AP. Increased diagnostic efforts will not reduce recurrent biliary AP unless matched by earlier gallstone treatment. Advances in knowledge: Whilst CT is used responsibly in AP greater use of other diagnostic modalities is required to identify reversible causes, in particular gallstones, in order to prevent recurrent AP. PMID- 28869390 TI - Approach to interpret images produced by new generations of multidetector CT scanners in post-operative spine. AB - OBJECTIVE: To reach a practical approach to interpret MDCT findings in post operative spine cases and to change the false belief of CT failure in the setting of instruments secondary to related artefacts. METHODS: We performed observational retrospective analysis of premier, early and late MDCT scans in 68 post-operative spine patients, with emphasis on instruments related complications and osseous fusion status. We used a grading system for assessment of osseous fusion in 35 patients and we further analysed the findings in failure of fusion, grade (D). RESULTS: We observed a variety of instruments related complications (mostly screws medially penetrating the pedicle) and osseous fusion status in late scans. We graded 11 interbody and 14 posterolateral levels as osseous fusion failure, showing additional instruments related complications, end plates erosive changes, adjacent segments spondylosis and malalignment. CONCLUSION: Modern MDCT scanners provide high quality images and are strongly recommended in assessment of the instruments and status of osseous fusion. In post-operative imaging of the spine, it is essential to be aware for what you are looking for, in relevance to the date of surgery. Advances in knowledge: Modern MDCT scanners allow assessment of instruments position and integrity and osseous fusion status in post-operative spine. We propose a helpful algorithm to simplify interpreting post-operative spine imaging. PMID- 28869391 TI - Expanding collaborative care: integrating the role of dietitians and nutrition interventions in services for people with mental illness. AB - OBJECTIVE: This article aims to draw mental health clinicians' attention to the connections between nutrition and mental health, and the roles that Accredited Practising Dietitians play in improving mental and physical health through dietary change. METHODS: Selective narrative review. RESULTS: Unhealthy dietary practices are common in high prevalence and severe mental illness. Epidemiological evidence demonstrates that nutrients and dietary patterns impact on mental health. In addition, poor physical health is well documented in people with mental illness and the greatest contributor to the mortality gap. Dietary intervention studies demonstrate improved mental and physical health outcomes. Accredited Practising Dietitians translate nutrition science into practical advice to improve the nutritional status of patients with mental illness, and prevent and manage comorbidities in a variety of care settings. CONCLUSIONS: Medical Nutrition Therapy offers opportunities to improve the physical and mental health of people living with mental illness. PMID- 28869392 TI - Intracranial pressure-induced optic nerve sheath response as a predictive biomarker for optic disc edema in astronauts. AB - A significant proportion of the astronauts who spend extended periods in microgravity develop ophthalmic abnormalities. Understanding this syndrome, called visual impairment and intracranial pressure (VIIP), has become a high priority for National Aeronautics and Space Administration, especially in view of future long-duration missions (e.g., Mars missions). Moreover, to ensure selection of astronaut candidates who will be able to complete long-duration missions with low risk of the VIIP syndrome, it is imperative to identify biomarkers for VIIP risk prediction. Here, we hypothesize that the optic nerve sheath response to alterations in intracranial pressure may be a potential predictive biomarker for optic disc edema in astronauts. If confirmed, this biomarker could be used for preflight identification of astronauts at risk for developing VIIP-associated optic disc edema. PMID- 28869393 TI - Ethics of clinical research in patients with ALS: is there a risk of exploitation? AB - Amyotrophic lateral sclerosis is the most common degenerative disease of the motor neuron network. Due to its inevitably fatal outcome, numerous attempts have been made to ameliorate its course. The emergence of every new technology has spurred research to see if it might benefit patients with ALS (PALS). This paper suggests a detailed road map to be followed when performing clinical research in PALS to satisfy the ethics requirements of the Declaration of Helsinki, expressed using the terminology of Beauchamp and Childress. The ethics principles that need to be satisfied are arranged in a hierarchical manner, each having to be satisfied before the next is approached: Justice; Beneficence, Nonmaleficence, Professional-Patient Relationship, and Respect for Autonomy. Study participants' autonomy can be respected only when all other principles have been addressed before PALS are approached to participate. Five 'red flags' are identified, which, if present, might indicate a risk that PALS may be exploited. PALS who are contemplating new treatments or clinical trials and their families will be assured that their best interests are the only ones that matter whenever adherence to established ethics principles and avoidance of known pitfalls are made explicit. PMID- 28869394 TI - Effect of age and sex in determining cognitive ability in Vanaraja chickens. AB - (1) To evaluate the cognitive ability of male and female Vanaraja birds, three hundred and sixty 1-d-old sexed chickens were reared under similar conditions in three treatment groups with 4 replicates in each group: 120 females in Treatment 1, 120 males in Treatment 2 and both males and females (60 + 60) as a mixed group in Treatment 3. (2) To assess learning ability, the birds were trained in T- and Y-mazes and tested at 3-week intervals in 4 test schedules (21, 42, 63 and 84 d). The birds were put into tonic immobility (TI) in each test schedule. (3) In each maze test, the latency to find the feed was regarded as a successful completion of the task. In the TI-test, the time taken to stabilise on a plane surface after swinging in the hanging cradle for 20-25 s was recorded. (4) The results indicated that male birds appeared to be cognitively superior to females in terms of learning and cognitive evolution in all the mazes, but by d 84, the females performed as well as the males. With increasing age, spatial memory gathering and processing improved. In the TI-test, the effect of sex or grouping system had no significant effect on the performance of birds at the various ages. PMID- 28869395 TI - MRI of suspected appendicitis during pregnancy: interradiologist agreement, indeterminate interpretation and the meaning of non-visualization of the appendix. AB - OBJECTIVE: To determine the degree of interradiologist agreement between the MRI features of appendicitis during pregnancy, the outcomes associated with an indeterminate interpretation and the negative predictive value of non visualization of the appendix. METHODS: Our study was approved by the institutional review board at the Washington University in St. Louis, Missouri (WUStL) and was HIPAA (Health Insurance Portability and Accountability Act of 1996)-compliant. The informed consent requirement was waived. Cases of suspected appendicitis during pregnancy evaluated using MRI were retrospectively identified using search queries. Scans were re-reviewed by two radiologists (7 and 9 years experience, respectively) to evaluate the interradiologist agreement of different MRI features of appendicitis during pregnancy (visualization of the appendix, appendiceal diameter, appendiceal wall thickening, periappendiceal fat stranding, fluid-filled appendix and periappendiceal fluid). The radiologists were blinded to patient outcome, patient intervention, laboratory data, demographic data and the original MRI reports. Clinical outcomes were documented by surgical pathology or clinical observation. Interradiologist agreement was analysed using Cohen's kappa, while patient demographic and clinical data was analysed using Student's t testing. RESULTS: 233 females with suspected appendicitis during pregnancy were evaluated using MRI over a 13-year period (mean age, 28.4 years; range, 17-38 years). There were 14 (6%) positive examinations for appendicitis during pregnancy, including 1 patient whose MRI was interpreted as negative, proven by surgical pathology. The presence of periappendiceal soft-tissue stranding and the final overall impression had the most interradiologist agreement (k = 0.81-1). There were no pregnant patients found to have acute appendicitis who had an indeterminate MR interpretation or when the appendix could not be visualized. CONCLUSION: The final impression by the two retrospectively reviewing radiologists of MR examinations performed for suspected appendicitis during pregnancy had near-perfect agreement. In patients where the appendix could not be visualized or in patients that were interpreted as indeterminate, no patients had acute appendicitis. Advances in knowledge: MR impression for suspected appendicitis in the pregnant patient has high interradiologist agreement, and a non-visualized appendix or lack of inflammatory findings at the time of MR, reliably excludes surgical appendicitis. PMID- 28869396 TI - Stereotactic/hypofractionated body radiation therapy as an effective treatment for lymph node metastases from colorectal cancer: an institutional retrospective analysis. AB - OBJECTIVE: The colorectal cancer (CRC) might present loco-regional recurrence, including lymph-node metastasis. Stereotactic body radiotherapy (SBRT) is a non invasive and well-tolerated ablative treatment. Aim of the present study is to evaluate efficacy and toxicity of SBRT with volumetric modulated arc therapy (VMAT) in this setting. METHODS: 35 patients presenting a total of 47 nodal recurrences from CRC, treated with VMAT-SBRT from 2008 to 2015, were selected. About three fourth of the treatments delivered 45 Gy in 6 daily fractions. End points were the detection of toxicities, overall survival (OS), local control (LC), disease progression free incidence (DPFI) and disease free survival (DFS). Tumour response was assessed according to the RECIST criteria. RESULTS: Only Grade 1 and 2 toxicities were recorded. Median follow-up was 15 months (range 2 68). Local relapse was reported in 6 patients, regional relapse in 10 patients. Complete remission was reported in 20 cases (53%), partial remission in 14 (37%). Rates of LC at 1, 2 and 3 years were 85.3, 75.0 and 75.0%, respectively. At 1 year the actuarial OS was 100%, at 2 and 3 years was 81.4%. Median DFS was estimated in 16 months, with an incidence of 69.4, 33.3 and 19.4% at 1, 2 and 3 years, respectively. CONCLUSION: The use of the VMAT-SBRT in lymph-node recurrence of CRC could prevent severe complications and achieve satisfying rates of disease control. Advances in knowledge: The use of VMAT-SBRT is a viable approach for lymph-node recurrence of CRC. PMID- 28869397 TI - Precision of cone beam CT to assess periodontal bone defects: a systematic review and meta-analysis. AB - OBJECTIVES: Evaluate the diagnostic validity of CBCT in measuring periodontal bone defects when compared with the reference standard (in situ measurement). METHODS: Studies in which the main objective was to evaluate the diagnostic validity of CBCT in measuring periodontal bone defects when compared with the reference standard were selected. Four databases were searched. The studies were selected by two independent reviewers. The methodology of selected studies was assessed using the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. The quality of evidence and strength of recommendation was assessed by The Grading of Recommendations Assessment Tool, Development and Evaluation. RESULTS: Using a selection process in two phases, 16 studies were identified and, in seven articles meta-analysis was performed. The results from these meta analyses showed that no difference between the measurements of CBCT and in situ for alveolar bone loss, and demonstrated a concordance of 82.82% between CBCT and in situ for the classification of the degree of furcation involvement. CONCLUSIONS: Based on a moderate level of evidence, CBCT could be useful for furcation involvement periodontal cases, but it should only be used in cases where clinical evaluation and conventional radiographic imaging do not provide the information necessary for an adequate diagnosis and proper periodontal treatment planning. PMID- 28869398 TI - Synthesis and evaluation of haloperidol metabolite II prodrugs as anticancer agents. AB - The use of haloperidol metabolite II (HP-metabolite II) prodrugs is an emerging strategy in the treatment of cancer. HP-metabolite II exhibits antiproliferative properties at micromolar concentrations inducing apoptosis in different types of cancer. Thus, the application of the prodrug approach appears as a useful method leading to much more desirable pharmacokinetic and pharmacodynamic properties. Some studies have shown that the esterification of the hydroxyl group of HP metabolite II with 4-phenylbutiric acid (4-PBA) or valproic acid enhances the anticancer therapeutic potency. The current progresses in the design, synthesis and evaluation of anticancer activity of HP metabolite II prodrugs will be discussed in this review. PMID- 28869399 TI - Clinical applications of textural analysis in non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer mortality worldwide. Treatment pathways include regular cross-sectional imaging, generating large data sets which present intriguing possibilities for exploitation beyond standard visual interpretation. This additional data mining has been termed "radiomics" and includes semantic and agnostic approaches. Textural analysis (TA) is an example of the latter, and uses a range of mathematically derived features to describe an image or region of an image. Often TA is used to describe a suspected or known tumour. TA is an attractive tool as large existing image sets can be submitted to diverse techniques for data processing, presentation, interpretation and hypothesis testing with annotated clinical outcomes. There is a growing anthology of published data using different TA techniques to differentiate between benign and malignant lung nodules, differentiate tissue subtypes of lung cancer, prognosticate and predict outcome and treatment response, as well as predict treatment side effects and potentially aid radiotherapy planning. The aim of this systematic review is to summarize the current published data and understand the potential future role of TA in managing lung cancer. PMID- 28869400 TI - Azide-alkyne cycloaddition en route to 4-aminoquinoline-ferrocenylchalcone conjugates: synthesis and anti-TB evaluation. AB - AIM: Tuberculosis is responsible for 9.6 million infections and 1.5 million deaths in 2015. The development of multidrug-resistant and extensively drug resistant strains has impeded the development of effective antitubercular therapy. Results/methodology: The present manuscript describes the synthesis of a series of 4-aminoquinoline-ferrocenylchalcone conjugates via Cu-promoted Huisgen's azide-alkyne cycloaddition reaction and evaluation of their antitubercular activities against mc26230 strain of Mycobacterium tuberculosis. The conjugate 11j proved to be the most potent of the synthesized conjugates with a minimum inhibitory concentration (MIC99) value of 30 MUM and proved to be noncytotoxic against HeLa cells. CONCLUSION: The synthesized conjugates can act as starting point for the development of new antitubercular agents. Synthesis and antitubercular evaluation of 1H-1,2,3-triazole-tethered 4-aminoquinoline ferrocenylchalcone conjugates. [Formula: see text]. PMID- 28869403 TI - Misdiagnosing Donald Trump. PMID- 28869401 TI - Clinical outcomes of multileaf collimator-based CyberKnife for spine stereotactic body radiation therapy. AB - OBJECTIVE: Stereotactic body radiotherapy (SBRT) for spinal metastases is becoming a prevalent therapeutic option. We aimed to evaluate the clinical feasibility and outcomes of the recently developed multileaf collimator (MLC) based CyberKnife (CK-M) for spine SBRT. METHODS: We reviewed 119 patients of 144 cases with 229 lesions treated with CK between November 2014 and March 2016. The lesion features, dosimetric parameters and clinical outcomes were compared between fixed cone collimator based CK (CK-F) and CK-M. RESULTS: Of 144 cases, 78 and 66 were treated with CK-F and CK-M, respectively. CK-M achieved an adequate target volume coverage that was comparable with CK-F (median 92 vs 90%; p = 0.03) even in larger targets (median 64.2 vs 46.7 cm3; p = 0.01), respectively. CK-M showed an improvement in the gradient index (p < 0.001) and no difference in conformity (p = 0.16). With CK-M, the median beam delivery time was significantly reduced by 30% (to 34 vs 48 min; p < 0.001). CK-M showed 1 year local control rates that were comparable to CK-F (77 vs 78%, respectively; p = 0.83). CONCLUSION: CK-M exhibits dosimetric data and local control that are comparable with CK-F, but with significant treatment time reduction. CK-M could be widely used in spine SBRT. Advances in knowledge: Given the recently developed MLC in CK, we aimed to evaluate the clinical feasibility and outcomes of MLC compared with fixed cone-based CK. MLC showed equivalent plan quality and significant treatment time reduction with comparable radiological control. We report here MLC as an effective and tolerable treatment option in CK. PMID- 28869402 TI - The epidemiology of back/neck/spine injuries in National Collegiate Athletic Association men's and women's ice hockey, 2009/2010 to 2014/2015. AB - This study describes the epidemiology of back/neck/spine injuries in National Collegiate Athletic Association (NCAA) men's and women's ice hockey. Data from 66 NCAA men's and 29 women's ice hockey programmes (total of 147 and 67 team seasons, respectively) were analysed from the NCAA Injury Surveillance Program during the 2009/2010-2014/2015 academic years. In the study period, 226 and 97 back/neck/spine injuries were reported in men and women, respectively, for injury rates of 0.56 and 0.65/1000 athlete exposures. Injury rates were higher in competitions than practices in men (injury rate ratio [IRR] = 4.22; 95% confidence interval [CI]: 3.24-5.49) and women (IRR = 2.49; 95% CI: 1.67-3.70). Most injuries occurred in the lower back/lumbar spine (men: 52.2%; women: 48.5%). There were notably low rates of fractures and severe spinal injuries for both sexes. This study enhances our understanding of the incidence, mechanisms and factors influencing these injuries and can ultimately lead to more effective injury prevention. PMID- 28869404 TI - Effect of wearing hearing protectors on the audibility of railway warning signals - an experimental study. AB - The effect of wearing hearing protectors on the audibility of warning signals has been evaluated for three specific railway-related jobs: track workers, train drivers and platform agents. Masked thresholds were measured in the laboratory, on railway agents with normal hearing, using warning signals and background noises typical of each job. Out of the 36 situations tested in total, statistical analyses showed that wearing earplugs improves the perception in 11 situations, deteriorates the perception in 10 situations and has no significant effect in 15 situations (as compared to no hearing protector). The deteriorations essentially concern signals which have no (or not enough) energy in the low-frequency range (f< 1500 Hz) when they have to be heard in background noises which dominate in the low-frequency range. To prevent the deteriorations, these signals could be modified by adding some energy in the low-frequency range (f< 1500 Hz). PMID- 28869406 TI - A Corrigendum to the SMART STROKES abstract supplement. PMID- 28869405 TI - A telehealth intervention to promote healthy lifestyles after stroke: The Stroke Coach protocol. AB - Rationale Recurrent stroke is prevalent and associated with high mortality rates, disability, and social and economic costs. Adequate management of risk factors may reduce recurrent stroke; however, many stroke survivors have poor control of risk factors. We have developed a theoretically sound and evidence-based lifestyle modification program called the Stroke Coach, a telephone-based self management program to improve control of risk factors. Hypothesis Individuals who participate in Stroke Coach will achieve more lifestyle improvements than individuals in an attention controlled Memory Training Program. Design In this single blind randomized controlled trial, 126 community-living stroke survivors will be randomized to Stroke Coach or the attention control group. Participants randomized to the six-month Stroke Coach will receive seven telephone lifestyle coaching sessions, self-management education and practice, and a self-monitoring kit, comprised of a health report card, with blood pressure and activity monitors. Study Outcomes The primary outcome will be measured using the Health Promoting Lifestyle Profile II. Secondary outcomes include behavioral and physiological risk factors, quality of life, cognitive status, health and social service use. Measurements will be taken at baseline, immediately after the intervention and six-month post-intervention. Summary The results of this trial will add to our understanding of the use of self-management to improve control of risk factors, and may facilitate the development of a larger trial evaluating the effect of Stroke Coach on endpoints such as recurrent stroke or cardiac events as the primary outcome. PMID- 28869407 TI - Characterization of feedback-resistant mevalonate kinases from the methanogenic archaeons Methanosaeta concilii and Methanocella paludicola. AB - The inhibition of mevalonate kinase (MVK) by downstream metabolites is an important mechanism in the regulation of isoprenoid production in a broad range of organisms. The first feedback-resistant MVK was previously discovered in the methanogenic archaeon Methanosarcinamazei. Here, we report the cloning, expression, purification, kinetic characterization and inhibition analysis of MVKs from two other methanogens, Methanosaetaconcilii and Methanocellapaludicola. Similar to the M. mazei MVK, these enzymes were not inhibited by diphosphomevalonate (DPM), dimethylallyl diphosphate (DMAPP), isopentenyldiphosphate (IPP), geranylpyrophosphate (GPP) or farnesylpyrophosphate (FPP). However, they exhibited significantly higher affinity to mevalonate and higher catalytic efficiency than the previously characterized enzyme. PMID- 28869408 TI - Involvement of signal peptidase I in Streptococcus sanguinis biofilm formation. AB - Biofilm accounts for 65-80 % of microbial infections in humans. Considerable evidence links biofilm formation by oral microbiota to oral disease and consequently systemic infections. Streptococcus sanguinis, a Gram-positive bacterium, is one of the most abundant species of the oral microbiota and it contributes to biofilm development in the oral cavity. Due to its altered biofilm formation, we investigated a biofilm mutant, DeltaSSA_0351, that is deficient in type I signal peptidase (SPase) in this study. Although the growth curve of the DeltaSSA_0351 mutant showed no significant difference from that of the wild-type strain SK36, biofilm assays using both microtitre plate assay and confocal laser scanning microscopy (CLSM) confirmed a sharp reduction in biofilm formation in the mutant compared to the wild-type strain and the paralogous mutant DeltaSSA_0849. Scanning electron microscopy (SEM) revealed remarkable differences in the cell surface morphologies and chain length of the DeltaSSA_0351 mutant compared with those of the wild-type strain. Transcriptomic and proteomic assays using RNA sequencing and mass spectrometry, respectively, were conducted on the DeltaSSA_0351 mutant to evaluate the functional impact of SPase on biofilm formation. Subsequently, bioinformatics analysis revealed a number of proteins that were differentially regulated in the DeltaSSA_0351 mutant, narrowing down the list of SPase substrates involved in biofilm formation to lactate dehydrogenase (SSA_1221) and a short-chain dehydrogenase (SSA_0291). With further experimentation, this list defined the link between SSA_0351-encoded SPase, cell wall biosynthesis and biofilm formation. PMID- 28869409 TI - The Rhodobacter capsulatus gene transfer agent is induced by nutrient depletion and the RNAP omega subunit. AB - Small bacteriophage-like particles called gene transfer agents (GTAs) that mediate DNA transfer between cells are produced by a variety of prokaryotes. The model GTA, produced by the alphaproteobacterium Rhodobacter capsulatus (RcGTA), is controlled by several cellular regulators, and production is induced upon entry into the stationary phase. We report that RcGTA production and gene transfer are stimulated by nutrient depletion. Cells depleted of organic carbon or blocked for amino acid biosynthesis increased RcGTA production and release from cells. Furthermore, cells lacking the sole RelA-SpoT homologue produced decreased levels of RcGTA, and the RNA polymerase omega (omega) subunit was required for appreciable production of RcGTA. PMID- 28869410 TI - Proposal to correct the generic name Flaviaesturariibacter Kang, Chun, Seo, Kim and Jahng 2015, 2212 to Flavaestuariibacter. Request for an Opinion. AB - The generic name Flaviaesturariibacter Kang, Chun, Seo, Kim and Jahng 2015, 2212 is malformed: being derived from the Latin noun aestuarium, ...aestuarii... instead of ...aesturarii... is required. Moreover, according to Appendix 9 of the Prokaryotic Code, a connecting vowel must be dropped when the following word element starts with a vowel. I therefore propose to correct the name Flaviaesturariibacter to Flavaestuariibacter. PMID- 28869411 TI - The presence of small joint contractures is a risk factor for survival in 439 patients with systemic sclerosis. AB - OBJECTIVES: Analysis of risk factors and mortality of 439 patients with systemic sclerosis (SSc) in a tertiary care centre. METHODS: The mean follow up time was 8.4+/-5.6 years. Lost to follow up rate was 6.4%. Female to male ratio was 366 to 73. Two hundred sixty patients had limited and 179 diffuse cutaneous SSc (dcSSc). A standard protocol including musculoskeletal examinations was used for the assessment of patients. RESULTS: By Kaplan-Meier analysis the overall 5-, 10- and 15 year survival were 88.2%, 79.9% and 73.6%, respectively. Univariate analysis showed that dcSSc, male gender, presence of small joint contractures, pulmonary interstitial, cardiac, oesophageal involvement, scleroderma renal crisis, arterial hypertension, anti-topoisomerase antibody, anemia, hypalbuminemia, coexistent malignancies and elevated erythrocyte sedimentation were associated with poor survival. Lack of giant capillaries, avascular zones or neo angiogenesis on capillaroscopy, and presence of anti-centromere antibodies were associated with favourable outcome. Multivariate regression analysis showed presence of small joint contractures, history of arterial hypertension, male gender, diffusing capacity of carbon monoxide <50%, right ventricular pressure >40 mmHg on echocardiography, less than 50% ejection fraction, anti-topoisomerase I positivity, anemia, and serum albumin concentration < 35 g/l as well as current or history of coexistent malignancy were independent poor prognostic factors. CONCLUSIONS: In addition to well-known factors predicting poor outcome in SSc, the presence of small joint contractures was a newly identi ed independent risk factor of mortality. Our data also confirmed a recent finding showing that history of arterial hypertension was also a poor prognostic factor. PMID- 28869412 TI - Prevalence of Takayasu's arteritis in Korea. PMID- 28869413 TI - Severe oesophageal disease and its associations with systemic sclerosis. AB - OBJECTIVES: Severe oesophageal disease in patients with systemic sclerosis (SSc), referred as scleroderma oesophagus, is characterised by ineffective or absent peristalsis along with hypotensive oesophagogastric junction (hEGJ). The associations between scleroderma oesophagus and different clinical and laboratory manifestations of SSc is still controversial. In this study we aimed to assess associations between scleroderma oesophagus, diagnosed by high resolution manometry (HRM), and other manifestations of disease. METHODS: Fifty-four consecutive SSc patients (49 women, mean age 50.6+/-11.6) with oesophageal symptoms underwent clinical interview, medical records review and HRM. HRMs were analysed according to the Chicago Classification in order to provide oesophageal motility diagnosis; EGJ <9 mmHg was considered hypotensive. Demographic characteristics, patient-reported symptoms, SSc subtypes, pulmonary fibrosis, cutaneous ulcers, and anti-Scl-70 positivity were compared between SSc patients with or without scleroderma oesophagus. Comparison was also performed in computed tomography (CT) findings of oesophageal lumen in 26 patients with available data. Oesophageal dilatation was deemed present when the diameter was >9 mm. RESULTS: Absent contractility was present in 37 (68.5%) patients; among these patients hEGJP was found in 32, thus 32/54 (59.2%) patients had classic scleroderma oesophagus. There were no associations with gender, age, oesophageal symptoms, skin involvement extent, anti-Scl-70, pulmonary fibrosis and cutaneous ulcers. Notably, oesophageal dilation on chest CT was more frequent in patients with scleroderma oesophagus compared to those without (77% vs. 7%, p=0.04, respectively). CONCLUSIONS: Scleroderma oesophagus diagnosed by HRM was present in less than 2/3 of symptomatic patients with SSc and associated only with oesophageal dilation in CT. Although further studies are needed, oesophageal dilation on chest CT may be a non-invasive alternative for evaluation of SSc patients with oesophageal symptoms. PMID- 28869415 TI - A novel iloprost administration method with portable syringe pump for the treatment of acral ulcers and Raynaud's phenomenon in systemic sclerosis patients. A pilot study (ILOPORTA). AB - OBJECTIVES: The objective of the study is to evaluate the feasibility, safety and efficacy of home infusion of iloprost with the new portable syringe pump Infonde(r), for the treatment of scleroderma-related Raynaud's phenomenon and digital ulcers. METHODS: 12 scleroderma patients were treated with iloprost at home, using the pump, with infusion cycles of 2 days per month (24 hours a day), for 6 months. RESULTS: The home treatment proved feasible since ten patients (83%) completed the entire infusion cycle, thus satisfying the feasibility target imposed by the protocol (75%). Side effects related to the device or venous access occurred in 3 out of 65 total 48-hour infusions (4.6%). They mostly consisted in phlebitis. No adverse events related to the device management were reported. Among the ten patients who completed the infusions, three showed a reduction in the number of ulcers, three maintained the same number, and four had no ulcers throughout the observation period. Patient's perception of their quality of life and wellness during home infusions, expressed with the Visual Analogue Scale (VAS) improved from 79/100 at the first infusion to 91/100 at the end of the study. All patients expressed a positive global judgment regarding this innovative method of iloprost infusion. CONCLUSIONS: The infusion of iloprost at home with Infonde(r) is feasible, safe and effective. Moreover, this approach presents potential advantages from the economic and organisational point of view. Because of the pilot design of our study, these results need to be confirmed in larger randomised trials. PMID- 28869414 TI - Expression of TREM-2 and its inhibitory effects on TNF-alpha induced inflammation in fibroblast-like synoviocytes via inhibiting p38 pathway activation. AB - OBJECTIVES: It is not clear whether TREM-2 (the "triggering receptor expressed on myeloid cells 2") is expressed in fibroblast-like synovial cells (FLSs). In this study, we aimed to determine the expression of TREM-2 in rheumatoid arthritis (RA)-FLSs and explore whether and how TREM-2 modulates the function of RA-FLSs. METHODS: Western blot and RT-PCR were used to detect the expression of TREM-2 in RA-FLSs, siRNA and lentivirus were used to down-regulate and up-regulate the expression of TREM-2 in RA-FLSs. Then mRNA expression of IL-1beta, IL-6, and MMP 13 was determined by RT-qPCR. Protein secretion of IL-1beta, IL-6, and MMP-13 in the supernatant was determined by ELISA assay; expression of cell signal transduction molecules was determined by western blot. RESULTS: A: Relative to OA FLSs, mRNA and protein expression levels of TREM-2 in RA-FLSs are significantly elevated. TREM-2 protein is mainly expressed in the cytoplasm of RA-FLSs; B: In RA, the expression of TREM-2 was reduced at first and then up-regulated after stimulation by TNF-alpha. TREM-2 also inhibited the activation of TNF-alpha induced of inflammation in RA-FLSs by the p38 pathway, which regulates the production of cytokines and matrix metalloproteinases. CONCLUSIONS: TREM-2 expressed in RA-FLSs and TNF-alpha mediated reduction of inflammatory reactions. These phenomena indicated that TREM-2 may be a potential target in the treatment of RA. PMID- 28869416 TI - Autologous stem cell transplantation in systemic sclerosis: a systematic review. AB - OBJECTIVES: Haematopoetic autologous stem cell transplantation (ASCT) has emerged as a treatment option for patients with refractory, severe autoimmune disease. This is a systematic review of the current literature on ASCT in adult patients with systemic sclerosis (SSc). METHODS: Original articles published between 2005 and 2016 that evaluated the use of ASCT in patients with SSc were reviewed with respect to the primary outcomes of overall and transplant related mortality (TRM) rates, and secondary outcomes of changes in modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), progression/event free survival (P/EFS) and quality of life measures. We also focussed on patient characteristics, the ASCT conditioning and mobilisation regimens used, and their relationship to patient outcome in each study. RESULTS: Of the 155 articles found, only 9 articles were suitable for review. There were 2 placebo-controlled trials (RCTs), ASTIS and ASSIST, and 7 observational and cohort studies. In general, patients undergoing ASCT had diffuse SSc with mRSS >14, and interstitial lung disease. The 2 RCTs showed a benefit in P/EFS (80-81%), FVC and quality of life measures in ASCT compared to monthly cyclophosphamide. All the studies showed an improvement in mRSS. TRM rates varied among studies, from 0 to 23%, with a trend to higher mortality rates in studies using higher doses of cyclophosphamide or myeloablative conditioning regimens. CONCLUSIONS: We conclude that ASCT is beneficial in some patients with SSc and that patient selection and conditioning regimens are critical determinants of prognosis and mortality post-ASCT. PMID- 28869418 TI - A meta-analysis of laninamivir octanoate for treatment and prophylaxis of influenza. AB - BACKGROUND: Laninamivir octanoate is a recently developed inhaled neuraminidase inhibitor for treating influenza virus infection. We performed meta-analyses to clarify the efficacy of laninamivir octanoate on influenza treatment and prevention. METHODS: MEDLINE and CENTRAL were searched to identify eligible studies. The log median time to event ratios (logMRs) and log odds ratios (logORs) were combined with meta-analysis. RESULTS: Nine studies in treatment settings and three studies in prophylaxis settings were eligible for this meta analysis. There was no significant difference between laninamivir octanoate and oseltamivir (8 studies, logMR 0.04, 95% CI [-0.05, 0.14]; P=0.36) or zanamivir (4 studies, logMR -0.01, 95% CI [-0.12, 0.11]; P=0.93) in alleviating fever. However, laninamivir octanoate was associated with significantly longer fever duration in treating H3N2 influenza as compared to oseltamivir (4 studies, logMR 0.29, 95% CI [0.00, 0.59]; P=0.047). Laninamivir octanoate was associated with significantly longer duration of fever as compared to peramivir (4 studies, logMR 0.46, 95% CI [0.14, 0.77]; P=0.004). Laninamivir octanoate significantly reduced the incidence of clinical influenza in post-exposure settings (3 studies, logOR 1.17, 95% CI [-1.72, -0.62]; P<0.001). CONCLUSIONS: Overall, the efficacy of laninamivir octanoate in treating influenza was comparable to that of oseltamivir or zanamivir, but it should be noted that laninamivir octanoate was associated with significantly longer fever duration in treating influenza H3N2 as compared to oseltamivir and oseltamivir-resistant mutations in seasonal influenza H1N1 might have affected the results. Peramivir may be superior to laninamivir in treating influenza. Laninamivir octanoate is effective in preventing influenza in post-exposure settings as compared to placebo. PMID- 28869417 TI - Efficacy of intensive hand physical therapy in patients with systemic sclerosis. AB - OBJECTIVES: To evaluate the efficacy of a three-week period of complex and intensive hand physical therapy on hand function in patients with systemic sclerosis (SSc). METHODS: Thirty-one patients with SSc were treated. Hand stretching exercises, ergotherapy supplemented with thermal and mud baths, whirlpool therapy and soft tissue massage were daily used during a three-week period. The control SSc group (n=22) received similar management for their large joints leaving out their hands. The primary outcomes of this study were the Health Assessment Questionnaire (HAQ) and the Disabilities of the Arm, Shoulder and Hand (DASH). Hand Anatomic Index (HAI), Cochin Hand Function (CHFT) and clinical characteristics were also assessed before starting the therapy and six months afterwards. RESULTS: Six months after the investigation period, only the group receiving hand physical therapy showed improvement in HAQ and DASH scores compared to the baseline values (p<0.05). The improvement in median HAQ value (25%-75% quartiles) reached the clinical meaningful rate (baseline 1.125/0.625 1.625/ versus 0.75/0.25-1.5/ at six months). Visual analogue scales of global pain (p<0.01) and Raynaud's phenomenon (p<0.05) also had better results than at baseline. HAI, gripping strength and CHFT also showed some improvement, but did not reach the significance level of change by the end of the six-month observation period. CONCLUSIONS: The complex physical therapy caused favourable changes in both the HAQ and the DASH indicating that this particular program had some long-term beneficial effect on hand function in patients with SSc. PMID- 28869419 TI - Sub-10 nm patterning with DNA nanostructures: a short perspective. AB - DNA is the hereditary material that contains our unique genetic code. Since the first demonstration of two-dimensional (2D) nanopatterns by using designed DNA origami ~10 years ago, DNA has evolved into a novel technique for 2D and 3D nanopatterning. It is now being used as a template for the creation of sub-10 nm structures via either 'top-down' or 'bottom-up' approaches for various applications spanning from nanoelectronics, plasmonic sensing, and nanophotonics. This perspective starts with an histroric overview and discusses the current state-of-the-art in DNA nanolithography. Emphasis is put on the challenges and prospects of DNA nanolithography as the next generation nanomanufacturing technique. PMID- 28869420 TI - Improved ultrasound transducer positioning by fetal heart location estimation during Doppler based heart rate measurements. AB - OBJECTIVE: Doppler ultrasound (US) is the most commonly applied method to measure the fetal heart rate (fHR). When the fetal heart is not properly located within the ultrasonic beam, fHR measurements often fail. As a consequence, clinical staff need to reposition the US transducer on the maternal abdomen, which can be a time consuming and tedious task. APPROACH: In this article, a method is presented to aid clinicians with the positioning of the US transducer to produce robust fHR measurements. A maximum likelihood estimation (MLE) algorithm is developed, which provides information on fetal heart location using the power of the Doppler signals received in the individual elements of a standard US transducer for fHR recordings. The performance of the algorithm is evaluated with simulations and in vitro experiments performed on a beating-heart setup. MAIN RESULTS: Both the experiments and the simulations show that the heart location can be accurately determined with an error of less than 7 mm within the measurement volume of the employed US transducer. SIGNIFICANCE: The results show that the developed algorithm can be used to provide accurate feedback on fetal heart location for improved positioning of the US transducer, which may lead to improved measurements of the fHR. PMID- 28869421 TI - A systemic view on the distribution of diet-derived methanol and hepatic acetone in mice. AB - Volatile organic compounds (VOCs) from breath can successfully be used to diagnose disease-specific pathological alterations in metabolism. However, the exact origin and underlying biochemical pathways that could be mapped to VOC signatures are mainly unknown. There is a knowledge gap regarding the contribution of tissues, organs, the gut microbiome, and exogenous factors to the 'sum signal' from breath samples. Animal models for human disease such as mutant mice provide the possibility to reproduce genetic predisposition to disease, thereby allowing in-depth analysis of metabolic and biochemical functions. We hypothesized that breath VOCs can be traced back to origins and organ-specific metabolic functions by combining breath concentrations with systemic levels detected in different organs and biological media (breath, blood, feces and urine). For this we fed C57Bl/6N mice a grain-based chow or a purified low-fat diet, thereby modifying the emission of methanol in breath whereas acetone levels were unaffected. We then measured headspace concentrations of both VOCs in ex vivo samples of several biological media. Cecum content especially was identified as a likely source of systemic methanol, whereas the liver showed highest acetone concentrations. Our findings are a first step to the systemic mapping of VOC patterns to metabolic functions in mice because differences between VOCs could be traced to different sources in the body. As a future aim, different levels of so called omics technologies (genomics, proteomics, metabolomics, and breathomics) could be mapped to metabolic pathways in multiple tissues, deepening our understanding of VOC metabolism and possibly leading to early non-invasive biomarkers for human pathologies. PMID- 28869422 TI - Rolling and pitching oscillating foil propulsion in ground effect. AB - In this paper, we investigate the effect of operating near a solid boundary on the forces produced by harmonically oscillating thrust-generating foils. A rolling and pitching foil was towed in a freshwater tank in a series of experiments with varying kinematics. Hydrodynamic forces and torques were measured in the freestream and at varying distances from a solid boundary, and changes in mean lift and thrust were found when the foil approached the boundary. The magnitude of this ground effect exhibited a strong nonlinear dependence on the distance between the foil and the boundary. Significant effects were found within three chord lengths of the boundary, and ground effect can be induced at greater distances from the boundary by biasing the tip of the foil toward the boundary. Lift coefficients changed by as much as [Formula: see text] at the closest approach to the ground, with changes [Formula: see text] [Formula: see text] for all cases across Strouhal numbers ranging from [Formula: see text] to [Formula: see text], and nominal maximum angle of attack ranging from [Formula: see text] to [Formula: see text]. The ubiquity of the ground effect in high thrust kinematics suggests that the ground effect can provide a passive obstacle avoidance capability for foil propelled vehicles. By comparison with previous experimental work, we find that the ground effect experienced by a high-aspect ratio rolling and pitching foil is a fully three-dimensional phenomenon, as it is not accurately predicted when two-dimensional flow and/or two-dimensional kinematics are enforced. While two-dimensional foil kinematics are more easily modeled for numerical studies, three-dimensional foil kinematics may be more practical for real world implementation in underwater vehicles. PMID- 28869423 TI - Advanced analyses of physiological signals in the neonatal intensive care unit. AB - Management and monitoring of infants within the neonatal intensive care unit represents a unique challenge. It involves an array of life-threatening diseases, procedures with potentially lifelong impacts, co-morbidities associated with preterm birth and risk of infection from prolonged exposure to the hospital environment. With the integration of monitoring systems and increasing accessibility of high-resolution data, there is a growing interest in the utility of advanced data analyses in predictive monitoring and characterising patterns of disease. Such analyses may offer an opportunity to identify infants at high risk of certain conditions and to detect the onset of disease prior to manifestation of clinical signs. This allows caregivers more time to respond and mitigate any abnormal or potentially fatal changes. We review techniques for variability analysis as they have been or have the potential to be applied to neonatal intensive care, the disease conditions in which they have been tested, and technical as well as clinical challenges relevant to their application. PMID- 28869424 TI - Repair of the calvarial defect in goat model using magnesium-doped porous hydroxyapatite combined with recombinant human bone morphogenetic protein-2. AB - Hydroxyapatite (HA) is a representative bone repairing biomaterial for its similar composition to human bones and teeth. However, pure HA is limited in application for some unwanted characteristic, such as it is brickle and weakness in degradation. In this study, we modified HA by doping magnesium (Mg) to the material and studied its property in vitro. Besides, we also evaluated the calvarial defect repair effect using MgHA combined with rhBMP-2 in goat model. According to our outcomes, HA composited Mg made the scaffold smooth and the pore regular. In vitro study, Mg could increase the Ca releasing, which may reflect a faster degradation property modified by Mg. And then, MgHA improved the cell viability and proliferation. Furthermore, MgHA could increase the expression of ALP, Collagen I and VEGF protein compared with pure HA (p<0.5, respectively). In the vivo study, MgHA showed a better bone defect healing effect in computed tomography (CT) evaluation compared with HA (p<0.05), but it was inferior to the MgHA/rhBMP-2 (p<0.05). Besides, in the histological analysis, MgHA/rhBMP-2 showed the most effective bone formation outcome (p<0.05), and the MgHA group was significant better than the pure HA group on osteogenesis (p<0.05). Furthermore, Collagen I and VEGF mRNA expression at 12 week in MgHA/rhBMP-2 group were also significat higher than other two groups. In conclusion, Mg had effects on bone formation and angiogenesis, and MgHA/rhBMP-2 had improved the bone defect repair effect. It is worthy of being recommended to bone tissue engineering. PMID- 28869425 TI - Effects of low oxygen dead space ventilation and breath-holding test in evaluating cerebrovascular reactivity: A comparative observation. AB - OBJECTIVE: This study aims to explore the application prospect of low oxygen dead space ventilation (LODSV) in evaluating vasomotor reactivity (VMR) by comparison between LODSV and breath-holding test (BHT). METHODS: Outpatient or inpatient patients who underwent transcranial Doppler sonography (TCD) were enrolled into this study. These patients successively underwent BHT and LODSV. The cooperation degree, tolerance conditions and adverse reactions in patients were recorded, and VMR was calculated, compared and analyzed. RESULTS: Patients had poor cooperation during BHT. Except for compensatory tachypnea after BHT, patients basically had no adverse reaction. The main manifestations of patients undergoing LODSV were deepened breathing and accelerated frequency in the end of the ventilation, and increased heart rate and a slight decline in pulse oxygen that rapidly recovered after ventilation. The increase rate of blood flow velocity in patients undergoing LODSV was significantly higher than in BHT (P<0.001), and its calculated VMR value was approximately 15% higher than BHT (P<0.001). BHT revealed a monophasic curve that slightly descends and rapidly increases, and LODSV revealed a curve that descends for a short time and slowly increases with a platform. CONCLUSION: LODSV can effectively eliminate the affect of poor cooperation in patients, and avoid intolerance caused by hypoxia. Hence, VMR value is more accurate than that determined by BHT; and this can reflect the maximum reaction ability of the blood vessels. Therefore, this method has higher clinical application value. PMID- 28869426 TI - EEG adaptive noise cancellation using information theoretic approach. AB - OBJECTIVE: In this paper, an adaptive method based on error entropy criterion is presented in order to eliminate noise from Electroencephalogram (EEG) signals. METHOD: Conventionally, the Mean-Squared Error (MSE) criterion is the dominant criterion deployed in the adaptive filters for this purpose. By deploying MSE, only second-order moment of the error distribution is optimized, which is not adequate for the noisy EEG signal in which the contaminating noises are typically non-Gaussian. By minimizing error entropy, all moments of the error distribution are minimized; hence, using the Minimum Error Entropy (MEE) algorithm instead of MSE-based adaptive algorithms will improve the performance of noise elimination. RESULTS: Simulation results indicate that the proposed method has a better performance compared to conventional MSE-based algorithm in terms of signal to noise ratio and steady state error. PMID- 28869427 TI - Study on the corrosion resistance and anti-infection of modified magnesium alloy. AB - In this paper, a low-cost and multifunctional hydroxyapatite (HA)/pefloxacin (PFLX) drug eluting layer is coated on magnesium (Mg) alloy through a simple hydrothermal and dip process. The drug PFLX could provide effective prevention for bone infection and inflammation due to its broad-spectrum antibacterial property. And HA would promote the growth of new bone and further improve the biocompatibility of implants. Besides, both PFLX and HA exhibits excellent corrosion protection for Mg alloy substrate. This coating is of great value for improving the application of Mg alloy as biomaterials. PMID- 28869428 TI - Preliminary studies of PVA/PVP blends incorporated with HAp and beta-TCP bone ceramic as template for hard tissue engineering. AB - Polyvinylalcohol (PVA) and Polyvinylpyrrolidone (PVP) blend incorporated with hydroxyapatite (HAp) and beta-tricalcium phosphate (beta-TCP) is electrospun as nanofibrous composite scaffolds to act as suitable template for bone tissue engineering. Microscopic and spectroscopic characterizations confirm uniform integration of the crystalline calcium phosphate ceramics in the scaffolds. PVA PVP blends are usually amorphous in nature and addition of phosphate ceramic particles specifically HAp elevates its crystalline behavior which is substantiated by XRD details. Further incorporation of ceramics is confirmed using FT-IR as characteristic PO43- groups for HAp and beta-TCP were observed in the distinguished composites. Single glass transition temperature is observed for pure and composite blends indicating the formation of highly miscible blends. Also, addition of these ceramics augments the thermal stability of the blend scaffolds. Biocompatibility of the prepared (PVA: PVP)-HAp and (PVA: PVP)-TCP scaffolds is assessed using MG-63 Osteoblast cell lines in the time interval of 1st, 4th and 7th day. The cell viability percentage for (PVA: PVP)-HAp is high compared to beta-TCP added blend composites, reinforcing the fact that scaffolds with good mechanical strength and enhanced porosity supports better cell adhesion. PMID- 28869429 TI - Testing of features for fatigue detection in EOG. AB - The article deals with the testing of features for fatigue detection in electrooculography (EOG) records. An optimal methodology for EOG signal acquisition is described; the Biopac data acquisition system was used. EOG signals were being recorded while 10 volunteers were watching prepared scenes. Three scenes were created for this purpose - a rotating ball, a video of driving a car, and a cross. Recorded EOG signals were processed and 20 features were extracted. The features involved blinks, slow eye movement (SEM), rapid eye movement (REM), eye instability, magnitude, and periodicity. These features were statistically tested and discussed in terms of fatigue detection ability. Some of the features were compared with published results. Finally, the best features - fatigue indicators - were selected. PMID- 28869430 TI - Increased intrinsic stiffness and mineralization in femurs of adult rats after high intensity treadmill running training. AB - BACKGROUND: Physical activity plays a tremendous role in determining bone mechanical behavior, which is superimposed to gravidity. OBJECTIVE: Compare the geometric and material responses of the rat femur to a high intensity treadmill running training of a relatively short duration, as assessed by 3-point mechanical test. METHODS: Mature male rats (180.0 +/- 30 g) were assigned (7 rats/group) to no exercise (NE) or treadmill exercise (EX). After a preconditioning period, the running speed was set at 45 cm.seg-1 during 2 wks, frequency 5 d/wk, 2-hour sessions/day. Body weight and weight of the crural quadriceps were registered at euthanasia. The right femur was mechanically tested through 3-point bending. The left femur was ashed to estimate bone mineral content. Geometric and material bone properties were estimated directly or calculated by appropriate equations. RESULTS: 1) Final body weight was 14% reduced in EX rats, while the crural quadriceps was 47% increased. Yield and fracture loads, and structural stiffness were significantly higher in the EX rats, as were the apparent elastic modulus, the bone mineral content and the degree of mineralization. Geometric properties were not affected. CONCLUSIONS: High intensity treadmill running training increases bone strength and stiffness by increasing material stiffness and mineralization, without affecting geometric bone parameters. PMID- 28869431 TI - A method to investigate the biomechanical alterations in Perthes' disease by hip joint contact modeling. AB - Perthes' disease is a destructive hip joint disorder characterized by malformation of the femoral head in young children. While the morphological changes have been widely studied, the biomechanical effects of these changes still need to be further elucidated. The objective of this study was to develop a method to investigate the biomechanical alterations in Perthes' disease by finite element (FE) contact modeling using MRI. The MRI data of a unilateral Perthes' case was obtained to develop the three-dimensional FE model of the hip joint. The stress and contact pressure patterns in the unaffected hip were well distributed. Elevated concentrations of stress and contact pressure were found in the Perthes' hip. The highest femoral cartilage von Mises stress 3.9 MPa and contact pressure 5.3 MPa were found in the Perthes' hip, whereas 2.4 MPa and 4.9 MPa in the healthy hip, respectively. The healthy bone in the femoral head of the Perthes' hip carries additional loads as indicated by the increase of stress levels around the necrotic-healthy bone interface. Identifying the biomechanical changes, such as the location of stress and contact pressure concentrations, is a prerequisite for the preoperative planning to obtain stress relief for the highly stressed areas in the malformed hip. This single-patient study demonstrated that the biomechanical alterations in Perthes' disease can be evaluated individually by patient-specific finite element contact modeling using MRI. A multi-patient study is required to test the strength of the proposed method as a pre-surgery planning tool. PMID- 28869432 TI - Validation of a computational knee joint model using an alignment method for the knee laxity test and computed tomography. AB - BACKGROUND: Computational models have been identified as efficient techniques in the clinical decision-making process. However, computational model was validated using published data in most previous studies, and the kinematic validation of such models still remains a challenge. Recently, studies using medical imaging have provided a more accurate visualization of knee joint kinematics. OBJECTIVE: The purpose of the present study was to perform kinematic validation for the subject-specific computational knee joint model by comparison with subject's medical imaging under identical laxity condition. METHODS: The laxity test was applied to the anterior-posterior drawer under 90 degrees flexion and the varus valgus under 20 degrees flexion with a series of stress radiographs, a Telos device, and computed tomography. The loading condition in the computational subject-specific knee joint model was identical to the laxity test condition in the medical image. RESULTS: Our computational model showed knee laxity kinematic trends that were consistent with the computed tomography images, except for negligible differences because of the indirect application of the subject's in vivo material properties. CONCLUSIONS: Medical imaging based on computed tomography with the laxity test allowed us to measure not only the precise translation but also the rotation of the knee joint. This methodology will be beneficial in the validation of laxity tests for subject- or patient-specific computational models. PMID- 28869433 TI - Treatment techniques on biocompatible titanium to modify the surface wetting properties. AB - The physical properties of biocompatible titanium surfaces were modified using different techniques of surface treatment. Particularly the measurements of roughness and wetting ability were controlled using six different techniques: polishing, sandblasting, acid attack, laser ablation, ion implantation and nanoparticle deposition. The titanium surface wetting can be modified drastically depending on the used treatment to enhance the hydrophilic or the hydrophobic behaviour of the metallic biocompatible surface. The study demonstrates that a linear relation between roughness and contact angle occurs. Possible applications to permanent or removable prosthesis titanium based are presented and discussed. PMID- 28869434 TI - Effects of neuromuscular electrical stimulation and Kinesio Taping applications in children with cerebral palsy on postural control and sitting balance. AB - BACKGROUND: Neurodevelopmental treatment (NDT), neuromuscular electrical stimulation (NMES), and Kinesio Taping (KT) applications are separately used to improve postural control and sitting balance in children with cerebral palsy (CP). OBJECTIVE: The aim of this study is to examine the combined effect of NDT, NMES and KT applications on postural control and sitting balance in children with CP. METHODS: Forty five children, in 3 groups, between the ages 5-12 years were included in the study. Group 1 received NDT; group 2 received NDT + NMES; and the group 3 received NDT + NMES + KT for 6 weeks. Sitting function evaluated by the sitting section of the gross motor function measure (GMFM), and postural control assessed with the seated postural control measurement (SPCM). RESULTS: Seating section of GMFM was improved significantly in all the groups; however, increases in the group 3 were higher than groups 1 and 2 (p= 0.001). While significant differences were observed in all groups in the SPCM posture (p< 0.001), function (p< 0.001), and the total scores (p< 0.001); the change in the third group was higher according to the comparison of the three groups within each other. CONCLUSIONS: Implementation of the NMES, and KT additionally to NDT improve the sitting posture, postural control, seating function, and gross motor function in children with CP. PMID- 28869435 TI - In vivo effects of limb movement on nerve stretch, strain, and tension: A systematic review. AB - BACKROUND: The mechanical behavior of the peripheral nervous system under elongation and tension has not been adequately established in vivo. OBJECTIVE: The purpose of this review is to investigate the mechanical behavior of the peripheral nervous system in vivo. METHODS: In vivo studies which evaluated the effects of limb movement and neurodynamic tests on peripheral nerve biomechanics were systematically searched in PubMed (Medline), the Cochrane Database, CINAHL, PEDro, Embase and Web of Science. Studies fulfilling the search criteria were assessed for methodological quality with a modified version of the Down & Blacks scale by two reviewers. RESULTS: This review includes the results of 22 studies, of which 15 examined limb movement influencing the median nerve, four the sciatic nerve, two the tibial nerve; and one each the ulnar and peroneal nerves respectively. Substantial nerve longitudinal and transverse excursion and changes in diameter were reported. Despite this, increased nerve strain was not a major finding. CONCLUSION: The heterogeneity of included studies, including wide variety of nerves tested, measurement location and joint position prevented comparisons between studies and also amalgamation of data. Limb movement induces complex biomechanical effects of which nerve elongation plays only a minor role. PMID- 28869436 TI - Design and analysis of a novel fall prevention device for lower limbs rehabilitation robot. AB - BACKGROUND: Most stroke survivors are suffering from physical motor impairments and confronting with the risk of falls, and well trunk stability is essential for balance during daily functional activities. OBJECTIVES: Current fall prevention devices have various limits to the efficient recovery of balance function of the trunk. To provide hemiplegic patients after stroke with the retraining of trunk position sense and a safety environment, a novel fall prevention device is proposed. METHODS: Firstly, the structure of the device is introduced and this work is a first effort towards restoring trunk balance function through retraining of trunk position sense. Secondly, the kinematic and static model of the device are developed. Lastly, kinematic and static analysis are carried out to study the motion characteristics, and a contrast experiment was derived to show the effectiveness of robot. RESULTS: No obvious difference in balance ability between two groups prior treatment (P> 0.05). Fugl-Meyer assessment in all the cases were improved in different extent (P< 0.05). The robot group had significantly higher Fugl-Meyer scores after treatment than the control group (P< 0.05). CONCLUSIONS: The results show that the fall prevention device has good kinematic dexterity within the prescribed workspace and markedly improves balance function. PMID- 28869437 TI - A 4-miRNAs signature predicts survival in glioblastoma multiforme patients. AB - BACKGROUND: Although O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation status is an important marker for glioblastoma multiforme (GBM), there is considerable variability in the clinical outcome of patients with similar methylation profles. OBJECTIVE: We examined whether a MicroRNA (miRNA) signature can be identified for predicting clinical outcomes and helping in treatment decisions. METHODS: The differentially expressed miRNAs were evaluated in 6 pairs of short- (? 450 days) and long-term survivors (> 450 days) by using microarray. Real time quantitative PCR (qRT-PCR) was applied to further verify screened miRNAs with a greater number of samples (n= 48). Meanwhile, functional interpretation of miRNA profile was carried out based on miRNA-target databases. In addition, MGMT promoter methylation status was tested by means of pyrosequencing (PSQ) testing. RESULTS: Six miRNAs were upregulated in the long term survival group (fold change ? 2.0, P< 0.05). The further verification by qRT PCR indicated that the increase in let-7g-5p, miR-139-5p, miR-17-5p and miR-9-3p level in long-term survivors was statistically significant. Kaplan-Meier survival analysis showed that high expression of a prognostic 4-miRNA signature was significantly associated with good patient survival (p= 0.0012). The signature regulated signaling pathways including Calcium, MAPK, ErbB, mTOR and cell cycle involved in carcinogenesis from glial progenitor cell to primary GBM. CONCLUSIONS: The 4-miRNA signature was identified as an independent prognostic biomarker that identified patients who have a favorable outcome. PMID- 28869439 TI - Epithelial-mesenchymal transition phenotypes of circulating tumor cells correlate with the clinical stages and cancer metastasis in hepatocellular carcinoma patients. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) plays a crucial role in circulating tumor cells (CTCs) dissemination and cancer metastasis. OBJECTIVE: To investigate the EMT phenotypes of CTCs in hepatocellular carcinoma (HCC) patients and the clinical utility in the early diagnosis of HCC metastasis and progression. METHODS: We retrospectively analyzed the count and EMT classification of CTCs detected by the CanPatrol(r) platform in 195 HCC patients. The clinical relevance with other pathological features was statistically evaluated. RESULTS: CTCs were detected in 95% of the 195 HCC patients with a range of 0-86 CTCs. Total CTCs numbers were correlated with BCLC stages, metastasis and serum AFP levels. The AUC of the ROC curve was 0.861 (95% CI: 0.782-0.940) in discriminating metastatic HCC patients with non-metastatic patients. Epithelial, hybrid and mesenchymal CTCs were found in about 53%, 83% and 57% patients, respectively. The proportion of hybrid and mesenchymal CTCs was associated with ages, BCLC stages, metastasis and AFP levels. Besides, recurrent HCC patients presented higher CTCs count and increased hybrid and mesenchymal CTCs. CONCLUSIONS: CTCs count and EMT classification are correlated with clinical stages and metastasis of HCC, suggesting that they may be potential markers for the early diagnosis of HCC metastasis and progression. PMID- 28869438 TI - Decreased expression of MUC1 induces apoptosis and inhibits migration in pancreatic cancer PANC-1 cells via regulation of Slug pathway. AB - MUC1, a membrane tethered mucin glycoprotein, is overexpressed in > 60% of human pancreatic cancers (PCs), and is associated with poor prognosis and enhanced metastasis. Here, we report the effect of silencing MUC1 expression on the growth, migration and invasive ability of pancreatic cancer cells, and explored its mechanisms. We observed that siRNA mediated suppression of the MUC1 expression significantly reduced invasive and migrative capability and induced apoptosis of the pancreatic cancer PANC-1 cells. We found that Slug was inhibited in the MUC1 siRNA transfected PANC-1 cells (MUC1 siRNA/PANC-1 cells). Expression of PUMA and E-cadherin was increased in the MUC1 siRNA/PANC-1 cells. PANC-1 cells overexpressing full long Slug gene (when transfected with Slug cDNA plasmid) significantly inhibited PUMA and E-cadherin expression in the MUC1 siRNA/PANC-1 cells. Silencing PUMA expression inhibited apoptosis in the MUC1 siRNA transfected PANC-1 cells (MUC1 siRNA/PANC-1 cells). Silencing E-cadherin expression restored the invasion and migration ability in the MUC1 siRNA/PANC-1 cells. We therefore concluded that silencing MUC1 expression inhibited migration and invasion, and induced apoptosis of PANC-1 cells via downregulation of Slug and upregulation of Slug dependent PUMA and E-cadherin expression. MUC1 could serve as a potential therapeutic target in pancreatic cancer. PMID- 28869440 TI - Downregulation of Piwil3 suppresses cell proliferation, migration and invasion in gastric cancer. AB - BACKGROUND: Gastric cancer is one of the most common malignancies worldwide. Recent studies reported that Piwil3 was overexpressed in various cancers, including gastric cancer (GC). This study was intended to investigate its function and mechanism in GC progress. METHODS: Quantitative real time PCR(RT PCR) and western blotting assays were utilized to measure mRNA and protein expression levels, respectively. SiRNA transfection was performed to suppress the expression of Piwil3. CCK-8 assay, cell invasion and migration assays were used to determine the cell proliferative, cell invasive and migratory ability. RESULTS: The expression of Piwil3 was significantly increased in GC tissues compared with matched normal tissues. The specific siRNA significantly inhibited the protein and mRNA expressions of Piwil3, and effectively inhibited the proliferation and induced G0/G1 phase arrest in GC cells. Downregulation of Piwil3 significantly suppressed the migration and invasion of GC cells. Moreover, the downregulation of Piwil3 also significantly suppressed the tumor volumes in nude mice. Mechanism investigation showed that the downregulation of Piwil3 significantly decreased the mRNA and protein expressions of metastasis-related genes, including RhoC, MTA1, MMP2 and MMP9, and also modulated the phosphorylation levels of JAK2 and STAT3 but not their protein levels. CONCLUSIONS: These findings indicate that overexpression of Piwil3 promotes the proliferation, migration and invasion of GC cells partially through JAK2/STAT3 signal pathway. PMID- 28869441 TI - Improvement of cytotoxicity of autologous CIKs from patients with breast cancer to MCF-7 cells by suppressed PD-1 expression. AB - OBJECTIVE: To investigate the improvement of cytotoxicity of autologous CIKs from patients with breast cancer to MCF-7 cells by suppressed PD-1 expression. METHODS: The Lentiviral Vector/PD-1 carrying the gene that can suppressed PD-1 was transferred to CIK cells from patients with breast cancer to inhibit PD-1 expression. The PD-1 protein were detected by RT-PCR and Western blot. The positive PD-1 of CIKs and PD-L1 of MCF-7 cells were detected by FCM, and cytotoxicity of CIKs to MCF-7 was assayed by CCK-8. RESULTS: The PD-1 positive CIKs with Lentiviral Vector/PD-1 transferred from patients with breast cancer were 16.02%, 14.36% and 14.64% at 14th, 21st and 28th day, obviously inhibited as compared to 50.54%, 74.50% and 73.36% in CIKs without transinfection (P< 0.05); the Lentiviral Vector/PD-1 decreased the PD-1 mRNA levels in CIK cells, and Lentiviral Vector/PD-1-transferred CIKs had lower PD-1 expression; CCK-8 detection showed that at 14th day, the cytotoxicity rates of CIKs with blank plasmids and those with PD-1 transfection to MCF-7 cells were 58.78% and 68.14%, respectively. CONCLUSION: MCF-7 cells have a strong PD-L1 expression at its surface, and inhibition of PD-1 expression can improve the cytotoxicity of CIK cells. PMID- 28869442 TI - Alpha-2-HS-glycoprotein plasma level decrease correlates with age in patients with myelodysplastic syndromes. AB - BACKGOUND: It has been indicated in plasma proteomic studies on different myelodysplastic syndrome (MDS) cohorts that alpha-2-HS-glycoprotein could be a promising MDS biomarker candidate. OBJECTIVE: The goal of this work was to estimate alpha-2-HS-glycoprotein (AHSG) plasma levels and its biomarker value in the low- and high-risk subgroups of MDS patients. METHODS: The level of AHSG was estimated for 115 plasma samples using ELISA. RESULTS: The AHSG plasma level was found to be decreased significantly (p= 2.59 * 10-7) in MDS patients (515 +/- 58 MUg/ml) when compared to healthy controls (579 +/- 64 MUg/ml). Pearson and Spearman correlation analyses showed that age is the principal factor affecting the AHSG plasma level, rather than risk/diagnosis in MDS. CONCLUSIONS: In this work we demonstrate that although the total plasma level of AHSG is decreased in myelodysplastic syndrome patients, in particular in advanced MDS, that decrease correlates more strongly with age than with diagnosis within our studied cohort. Thus, according to the AHSG data gathered so far, AHSG total plasma level does not seem to be a suitable MDS biomarker, but its particular proteoforms should be considered for the next steps in MDS research. PMID- 28869443 TI - Pregnancy-associated gigantomastia recurrence and ectopic breast after reduction mammaplasty: A case report. AB - It has been reported that majority of cases of gigantomastia, also known as breast hypertrophy and macromastia, occur during either pregnancy or puberty. Gigantomastia is a rare disorder that does not have a clear etiology or well established risk factors. We present a 26-year-old female patient who appeared to have pregnancy-associated gigantomastia recurrence, large accessory breast and, ectopic breast tissue at external genital three years after bilateral breast reduction surgery. The patient successively underwent bilateral mastectomy and vulvar tumor resection. Breast hypertrophy and progenital ectopic breast were pathologically confirmed. This the first case of gigantomastia reported worldwide. PMID- 28869444 TI - Plasma TuM2-PK correlates with tumor size, CRP and CA 15-3 in metastatic breast carcinomas; short versus long term follow up study of the Egyptian breast cancer patients. AB - BACKGROUND: The key regulator of tumor metabolome is the glycolytic isoenzyme M2 PK which favors the generation of nucleic acid via glutaminolysis as hypoxic adaptive mechanism in the tumor cells. AIM: The study aimed to evaluate the prognostic role of M2-PK, CRP, and CA 15-3 in preoperative and metastatic breast carcinomas. PATIENTS AND METHODS: The study included 70 females; 15 controls, 33 preoperative primary breast carcinomas clinically metastasis free, and 22 clinically diagnosed metastatic breast carcinomas. M2-PK and CA 15-3 were detected by ELISA. CRP was quantified using the CRP LATEX kit. RESULTS: TuM2-PK significantly increased in metastatic and preoperative groups when compared to controls (p= 0.049, p= 0.001); respectively. Both CRP and CA 15-3 were significantly increased in metastatic than the preoperative group (p= 0.002). CA 15-3 was significantly increased in both groups when compared to controls (p= 0.016; p< 0.001; respectively). TuM2-PK level significantly related to tumor size in metastatic group (p= 0.006) and with menstruation status (p= 0.039), and liver metastasis (p= 0.036) in preoperative group. TuM2-PK significantly correlated with CRP (r= 0.793, p= 0.004), and CA 15-3 (r= 0.568, p= 0.006) in the metastatic group.Metastatic group with TuM2-PK ? 15 U/ml had significantly higher survival rate than those with > 15 U/ml (chi2= 13.841, p< 0.001) within 3.3-4.2 but not after 10-20 years follow up period. Metastasis to bone and lymph nodes significantly increased in the metastatic than the preoperative group (p= 0.002, p= 0.013; respectively). Within 3.3-4.2 years, CA15.3 has the highest prognostic performance in metastatic group while both TuM2-PK and CRP have same specificity. On the other hand, TuM2-PK has the highest prognostic performance in preoperative group. After 20 years follow up period, there was neither significant difference in the performance of the three markers in predicting mortality in metastatic and preoperative groups nor in predicting metastasis in preoperative group. CONCLUSION: Current results document for the first time, a cross-talk between TuM2-PK and each of CRP and CA 15-3 in metastatic breast cancer. PMID- 28869445 TI - Clinical significance of serum 14-3-3 beta in patients with hepatocellular carcinoma. AB - OBJECTIVE: The 14-3-3 family of conserved regulatory proteins comprises the isoforms beta (beta), gamma (gamma), zeta (zeta), sigma (epsilon), tau (eta), and delta (sigma), which are overexpressed and associated with a high risk of metastasis and poor survival in hepatocellular carcinoma (HCC). In the present study, we investigated whether serum 14-3-3 isoforms are related to HCC progression and patient survival. METHODS: Serum samples from 63 HCC patients who underwent surgical reSection 104 HCC patients who received non-surgical anti-HCC treatments, 50 patients with liver cirrhosis alone, 45 patients with chronic hepatitis alone, and 50 healthy subjects were collected between January 2006 and December 2010. Serum levels of 14-3-3 (beta, epsilon, gamma, sigma, and zeta) isoforms were measured by ELISA. The correlation between 14-3-3 (beta and sigma) isoforms and clinicopathological factors was examined by logistic regression analysis. The feasibility of serum 14-3-3 beta for discriminating HCC patients was assessed by ROC curve analysis. Patient survival analyses were performed by Kaplan-Meier analyses and Cox regression models. RESULTS: Serum levels of 14-3-3 (beta and sigma) were significantly higher in HCC patients than in those with liver cirrhosis, chronic hepatitis, and healthy subjects (p< 0.05). There was no difference in the serum levels of 14-3-3 epsilon, gamma, and zeta between HCC and the other groups (p> 0.05). High levels of serum 14-3-3 beta were associated with vascular invasion (p= 0.016), TNM stage (p= 0.012), BCLC stage (p= 0.01), and early recurrence (p= 0.013). Patients with high levels of serum 14-3-3 beta had a poor prognosis. There was no significant association between 14-3-3 sigma levels and clinicopathological parameters. A significant independent association between serum 14-3-3 beta and HCC was observed by univariate and multivariate analysis (p< 0.05). Serum 14-3-3 beta could effectively discriminate HCC patients at a cut off point of 18.7 ng/mL, with 91.4% sensitivity and 75.3% specificity. CONCLUSIONS: Serum 14-3-3 beta is a potential biomarker for the diagnosis of early-stage HCC, and high levels of serum 14-3-3 beta were associated with metastasis and poor prognosis in HCC. PMID- 28869446 TI - bFGF in tumor tissue independently prognosticates disease outcome of a natural course of invasive breast cancer. AB - BACKGROUND: Basic fibroblast growth factor (bFGF) is a potent angiogenic and mitogenic factor that has been functionally predisposed to promote tumorigenesis, while literature data also associate bFGF with a favorable outcome of breast cancer. OBJECTIVE: In order to help resolve such controversy, this study set out to investigate the role of bFGF in breast cancer for the first time by use of the node-negative patient group with smaller tumors and without any systemic adjuvant therapy. This has allowed an increased homogeneity of the group and a far more reliable interpretation of results. METHODS: The study included 133 node-negative breast cancer patients with 33 distant metastasis events. bFGF levels were determined by ELISA in primary tumor tissue homogenates. RESULTS: bFGF in primary tumor tissue associated with favorable breast cancer outcome and its levels significantly and positively correlated with ER levels. CONCLUSIONS: The obtained results are relevant for the future prognostic research aimed at surpassing the currently achievable prognostic accuracies which are by far inadequate to allow reliable therapeutic decision making in breast cancer. PMID- 28869447 TI - High concentration of miR-133 is a useful marker for the diagnosis of lymphoma- associated hemophagocytic syndrome. AB - BACKGROUND: Lymphoma associated hemophagocytic syndrome (LAHS) is one of the major adult secondary hemophagocytic lymphohistiocytosis (HLH). Early diagnosis and treatment contribute to improved outcome. No enlarge lymph nodes can often delay the diagnosis of underlying lymphoma. OBJECTIVE: To find out criteria distinguishing LAHS from HLH induced by benign diseases. METHODS: clinical characteristic and laboratory feature of 31 patients with HLH (10 benign disease associated HLH and 21 LAHS) were analyzed retrospectively. RESULTS: No significantly differences were observed in the levels of LDH, IL-6, IL-10, TNF alpha; however, the level of CRP (C reactive protein) and the mean level of sIL-R (soluble interleukin-2 receptor) were higher in patients with LAHS than those with benign disease associated disease associated HLH while ferritin levels were higher in benign disease associated HLH than in LAHS. Consequently, the serum sIL 2R/ferritin ratio of patients with LAHS was markedly higher than that of patients with benign disease associated HLH (0.33 +/- 0.23 vs 5.82 +/- 3.26, P= 0.0001). In addition, we found out that the mean level of miR-133 (microRNA-133) was significant higher in LAHS than in benign disease associated HLH (18.83 +/- 10.44 vs 5.82 +/- 3.26, P? 0.0001). CONCLUSION: Serum miR-133 is a new very useful marker for diagnosing of LAHS, but it need further confirmation by further clinical studies. PMID- 28869448 TI - Large intergenic non-coding RNA-ROR as a potential biomarker for the diagnosis and dynamic monitoring of breast cancer. AB - BACKGROUND: Recent study has revealed that large intergenic non-coding RNA-ROR (linc-ROR) is aberrantly expressed in a number of cancers including breast cancer. However, whether circulating linc-ROR in plasma could be used for breast cancer diagnosis and dynamic monitoring is not clear. OBJECTIVE: The objective of this study is to determine if plasma linc-ROR could be applied as a biomarker for the diagnosis and dynamic monitoring of breast cancer. METHODS: We tested the expression levels of linc-ROR in 24 pairs of tissue samples and 96 plasma samples from breast cancer patients by quantitative real time-polymerase chain reaction (qRT-PCR), and analyzed the correlation between plasma linc-ROR levels and clinico-pathological characteristics. Receiver operating characteristic (ROC) curve was used to assess the diagnostic power of plasma linc-ROR, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)153 for breast cancer. Furthermore, we explored the monitoring values of plasma linc-ROR for breast cancer by analyzing the preoperative and postoperative plasma linc-ROR levels of the same patients. RESULTS: The expression levels of linc-ROR were significantly higher in breast cancer tissues and plasma than the levels in the control (P< 0.05). The linc-ROR expression levels in plasma were correlated with lymph node metastasis (P< 0.05), estrogen receptor (ER) (P< 0.05) and progesterone receptor (PR) (P< 0.05). The area under the ROC curve of plasma linc ROR was 0.758 (sensitivity 80.0%; specificity 73.3%), which was higher than CEA and CA153 values from the same patients obtained. Combination of the linc-ROR with the conventional biomarkers might produce better diagnostic ability. Additionally, the linc-ROR expression levels of plasma in postoperative patients were lower than those in preoperative patients (P< 0.05). CONCLUSION: Overexpressed linc-ROR may be a potential biomarker for the diagnosis and dynamic monitoring of breast cancer. PMID- 28869449 TI - Propofol-induced neurotoxicity in hESCs involved in activation of miR-206/PUMA signal pathway. AB - BACKGROUND AND OBJECTIVE: Studies in developing animals have demonstrated that when anesthetic agents, such as propofol, are early administered in life, it can lead to neuronal cell death and learning disabilities. However, the mechanisms causing these effects remains unknown. A recent report found that propofol could significantly upregulat miR-206 expression in the human ASCs. miR-206 could also induce apoptosis in human malignant cancers. Therefore, in this study, we hypothesized that propofol induces neurotoxicity in human embryonic stem cells (hESCs). METHODS: hESCs were exposed to propofol (50 MUM) for 6 hr and cell death was assessed using TUNEL staining, and cleaved caspase-3 expression. miR-206 was knocked down using antagomir. PUMA was knocked down using a small interfering RNA. microRNA-206 (miR-206) expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). PUMA protein expression was detected using western blot assay. RESULTS: hESCs exposed to propofol showed a significant increase in TUNEL positive cells and cleaved caspase-3 expression, followed by the upregulation of miR-206 and PUMA expression. Targeting PUMA inhibits propofol-induced cell apoptosis; miR-206 knockdown decreased propofol induced cell apoptosis, cleaved caspase-3 and PUMA expression. CONCLUSIONS: Propofol induce s cell death in hESC-derived neurons via activation of miR 206/PUMA signal pathway. PMID- 28869450 TI - IDH1 status is significantly different between high-grade thalamic and superficial gliomas. AB - BACKGROUND: While major progress has been made in diagnosis and treatment of gliomas based on molecules, molecular features of thalamic glioma have rarely been reported till now. OBJECTIVE: IDH1 mutation is important for prognosis of gliomas and represents a distinctive category of glioma. We intended to survey specific molecular abnormalities in high-grade thalamic gliomas (WHO III-IV). METHODS: We collected data of 50 and 93 newly diagnosed high-grade thalamic and superficial glioma patients respectively and conducted a comparative analysis of molecular characteristics between them. We analyzed expressions of molecules as follow: IDH1/2, P53, Ki-67, ATRX, PTEN, MMP9 and MGMT by Immunohistochemistry (IHC). Direct gene sequencing was performed to test the IDH1(R 132H) mutation. RESULTS: We found a significant difference of IDH1 mutation between those high grade gliomas, with 92% (46/50) of the thalamic tumors and 71% (66/93) of the superficial gliomas showing IDH1 wild-type (p= 0.004). It also showed that IDH1 mutation in superficial glioblastomas 18.6% (13/70) occurred more than thalamic glioblastomas 2.6% (1/39) (p= 0.017). As to high-grade superficial gliomas, there were 26 patients with IDH1 mutation, which contained 7, 13, and 6 high, moderate and low Ki-67 expression gliomas, respectively. The IDH1 wild-type group (62 patients), was composed of 29, 30, and 3 high, moderate and low Ki-67 expression gliomas, respectively. There was a significant distinction between the IDH1 mutation and Ki-67 expressions (p= 0.024). We also noted that the occurrence of low Ki-67 expressions 23.1% (6/26) in IDH1 mutation group was outnumbered than IDH1 wild-type group 4.8% (3/62) (p= 0.018). In addition, we found PTEN negative correlated with MMP9 negative in thalamic high-grade gliomas, whereas no such difference was found in superficial gliomas (p= 0.016). CONCLUSION: The rare occurrence of IDH1 mutant high-grade thalamic gliomas strongly suggested that the high-grade thalamic glioma is another distinct tumor entity as compared to the high-grade superficial gliomas. PMID- 28869451 TI - Spalt-like transcription factor 4 as a potential diagnostic and prognostic marker of colorectal cancer. AB - OBJECTIVE: The study aimed to investigate the role of spalt-like transcription factor 4 (SALL4) in the diagnosis and prognosis of colorectal cancer (CRC). METHODS: Between May 2008 and January 2010, 135 patients with CRC were recruited and subsequently assigned into the case group of the study. Additionally, 140 healthy individuals under identical conditions were selected as the control group. Venous blood was collected from all subjects. High expression of SALL4 was detected by immunohistochemistry, and SALL4 serum levels were detected using ELISA. A 5-year follow-up was conducted. A Kaplan-Meier curve was applied for analysis of survival rates, and a log-rank was used for univariate analysis. RESULTS: The case group exhibited largely positive expression levels of SALL4. Levels of SALL4 serum were much higher than those in the control group. The AUC value of CRC detected by serum SALL4 was 0.916 (95% CI was 0.881-0.951), which regarded 0.1255 MUcg/l to be the point of critical value. This result was in direct relation to data from the receiver operating characteristic curve (ROC). The sensitivity and specificity of serum SALL4 levels in the diagnosis of CRC were 85.9% and 85.7%, respectively. The AUC value of CRC detected by tissue SALL4 was 0.727 (95% CI was 0.666-0.789), 0.5 was regarded as the critical value. The sensitivity and specificity of SALL4 expression in CRC tissues regarding the diagnosis of CRC was determined to be 58.6% and 86.9% respectively. The levels of SALL4 expression in serum and tissues highlighted a correlation to lymph node metastasis (LNM), differentiation degree, Dukes staging and tumor node metastasis staging. Lower serum SALL4 levels were associated with higher survival rates in CRC patients. In accordance with a COX regression, LNM, differentiation degree and SALL4 levels were determined as being prognostic factors in patients with CRC (both P< 0.05). CONCLUSION: Our experimental data indicated that over expression of SALL4 was found in CRC and low expression of SALL4 was connected with high survival rate after surgery. Thus our study suggested that SALL4 could serve as a potential diagnostic and prognostic marker of CRC. PMID- 28869452 TI - MiR-135a-5p modulates biological functions of thyroid carcinoma cells via targeting VCAN 3'-UTR. AB - Thyroid carcinoma is one of the most frequent malignant tumors of the endocrine system, which accounts for nearly 1% population in newly diagnosed carcinoma worldwide and the incidence has an increasing tendency in recent years. To explore whether miR-135a-5p could affect the proliferation, invasion and migration of thyroid carcinoma cells by targeting VCAN. The expression levels of miR-135a-5p and VCAN were detected in human thyroid carcinoma tissues and cells, para-carcinoma tissues, as well as human normal thyroid cells using RT-qPCR and Western blot. In addition, dual-luciferase reporter gene assay, MTT assay, colony formation assay, wound healing assay, Transwell assay, flow cytometry analysis and in vivo tumorigenesis assay were also conducted. The results demonstrated that miR-135a-5p was down-regulated while VCAN was up-regulated both in thyroid carcinoma tissues and cells. Furthermore, the up-regulation of miR-135a-5p inhibited cell proliferation, invasion and migration of thyroid carcinoma. Dual luciferase reporter gene assay provided evidence indicating that miR-135a-5p targeted VCAN in thyroid carcinoma. MiR-135a-5p could inhibit cell proliferation, invasion and migration of thyroid carcinoma by targeting VCAN. MiR-135a-5p and VCAN might emerge as a target for the treatment of thyroid carcinoma. PMID- 28869454 TI - 36th Conference of the German Society for Clinical Microcirculation and Hemorheology. PMID- 28869453 TI - Bortezomib could down-regulate the expression of RANKL, inhibit cell proliferation and induce cell apoptosis in the human myeloma cell line RPMI 8226 by activating casepase-3. AB - OBJECTIVE: In spite of bortezomib being developed and demonstrated as a safe drug therapy for multiple myeloma (MM), the role of bortezomib-induced receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) in the MM cell lines remains to be understood. Thus the present study aims to explore the impact of bortezomib on RANKL expression, cell growth and apoptosis in human myeloma cell line RPMI 8226. METHODS: Four experiment groups were set according to different concentrations of bortezomib, namely blank group (treated with DMEM solution free of other drugs), low-dose group (treated with 10 nmol/L bortezomib), middle-dose group (treated with 20 nmol/L bortezomib) and high-dose group (treated with 40 nmol/L bortezomib). Western blotting was adopted to detect RANKL protein expression. MTT assay was performed to detect cell proliferation. Flow cytometry was used to analyze cell cycle and apoptosis. Spectrophotometry was applied to determine caspases-3 activity. RESULTS: Compared with the blank group, the RANKL protein expression, cell number at the S stage was reduced while cell inhibition rate, cell apoptosis rate and caspase-3 activity enhanced remarkably in the low dose, middle-dose and high-dose groups with dose-dependent manner. Compared with those treated with bortezomib (20 nmol/L and 40 nmol/L) for 6 h, the RANKL expression was down-regulated, cell inhibition rate was increased, cells at the S stage were reduced, cell apoptosis rate was enhanced, and caspase-3 activity elevated in the RPMI 8226 cells as treated with bortezomib for 24 h, with a dose- and time-dependent manner. CONCLUSIONS: Bortezomib could reduce the RANKL expression, inhibit cell proliferation and activate caspase-3 activity to induce cell apoptosis in RPMI 8266 cells. PMID- 28869455 TI - Influence of Ultrasound Microbubbles on kidney oxygen tension. AB - Ultrasound contrast agents (USCA) allows the dynamic detection of blood flow of both the macro and microvasculature. An obvious prerequisite for USCAs is the unhindered passage of clinically relevant dose levels through the microcirculation especially of the lungue, where they have to pass capillaries with diameters of around 4 MUm. While smaller microbubbles rapidly passed through the microcirculation along with the red blood cells, larger microbubbles, however, were observed to coalesce and interrupt the blood flow. Whether this might influence the tissue oxygen tension is unclear up to now.To examine this question a bolus of 2.4 ml SonoVueTM was injected into the suprarenal aorta at a flow rate of 10 ml/s (a dosage usually applied in the clinic). The pO2 in the outer medulla of the kidney was continuously measured using a flexible pO2 microcatheter. In addition, the SonoVueTM injection and its passage through the renal vasculature were documented by the CEUS technology to assess whether the microbubbles passed the kidney.The study revealed that SonoVueTM induced no changes of the mean oxygen partial pressure in the outer medulla which confirms that these microbubbles on their way through the medullar capillaries did not hinder the co-flow of blood through the renal microvessels in a big animal model with a renal morphology and function comparable to human kidneys. These results demonstrate that the CEUS diagnostic itself did not influence the system to be examined which is a most important prerequisite for any diagnostic method. PMID- 28869456 TI - Perfusion control of a partial revascularized hand via application of Indocyanine green (ICG) and Near-infrared Fluorescence Imaging. AB - BACKGROUND: Intra- and postoperative assessment of perfusion with near-infrared fluorescence imaging is commonly used among plastic surgeons to evaluate the quality of a microsurgical anastomosis in free flaps. OBJECTIVE: As microsurgical anastomosis can be monitored with near-infrared fluorescence imaging there is potential concerning revascularized fingers and hands with soft tissue depths not exceeding 7 mm above anastomosis. In a case of a severe crush injury of the hand more information about the perfusion was necessary as clinical assessment suspected loss of perfusion. METHODS: A 49-year old male suffered from a severe crush injury of his left hand with dissection of the ulnar superficial palmar arterial arch and a lesion of median nerve. After revascularization and reconstruction of the nerve, the patient developed postoperatively a loss of perfusion of thumb and index finger. An evaluation of the perfusion status was obtained by fluorescence imaging after intravenous application of ICG. RESULTS: After intravenous application of ICG the near-infrared imaging showed a delayed but sufficient perfusion of the hand so that a salvage surgery was not indicated. CONCLUSIONS: In scenarios of critical perfusion in revascularized fingers and hands, the perfusion control via application of ICG and near-infrared fluorescence imaging can be a helpful tool. PMID- 28869457 TI - Anti-inflammatory effects of a novel iron chelator, DIBI, in experimental sepsis. AB - BACKGROUND: Iron catalyzes the generation of reactive oxygen species (ROS) as part of the innate antimicrobial defense. During sepsis, the dysregulated systemic inflammatory response to infection, iron homeostasis becomes disrupted, generating an excess of ROS causing damage to tissues. This can be potentially suppressed using iron chelators that selectively bind iron to prevent its participation in ROS-related inflammatory reactions. OBJECTIVE: We hypothesize that administration of DIBI, a novel iron-chelator, attenuates the dysregulated systemic immune response and reduces tissue damage in experimental endotoxemia. METHODS: Five groups of animals (n = 5-10) were included in this study: control, untreated endotoxemia, and endotoxemia animals treated with either DIBI-A, MAHMP, or DIBI-B. Intravital microscopy was performed on the intestine of anesthesized mice to observe leukocyte endothelial interactions and evaluate the intestinal microcirculation. RESULTS: Treatment of endotoxemic mice with DIBI-B reduced the number of adhering leukocytes in submucosal collecting (V1) venules by 68%. DIBI B, MAHMP, and DIBI-A were able to restore functional capillary density (FCD) in the intestinal muscle layer by 74%, 44%, and 11%, respectively. CONCLUSIONS: DIBI B reduces leukocyte recruitment and improves FCD in experimental endotoxemia, outperforming other chelators tested. These findings suggest a potential role for DIBI-B as a candidate drug for sepsis treatment. PMID- 28869458 TI - Clinical significance of factor V Leiden and prothrombin G20210A-mutations in cerebral venous thrombosis - comparison with arterial ischemic stroke. AB - Cerebrovascular diseases are considered in a different way concerning their etiology with regard to arterial and venous occlusion. The role of thrombophilia in this context remains undetermined. For this reason, a case-control study was conducted including a total of 202 patients (154 females, 48 males) aged from 18 to 76 years (mean: 39.8 years) suffering either from cerebral sinus venous thrombosis (n = 101) or from arterial ischemic stroke (n = 101). Study groups were evaluated on the basis of age- and gender-matched pairs. Gene mutations of factor V-1691 (factor V Leiden) and prothrombin-20210 being considered as the most common thrombophilia markers were analyzed in this study. Factor V Leiden mutations were found in 16.8% of patients with cerebral sinus venous thrombosis (CVT) and in 17.8% of patients with arterial ischemic stroke (AIS), which was significantly more frequent than in controls at a rate of 4.95% (ORs: 3.89 and 4.16). Prothrombin-mutations were significantly more frequent in CVT at a rate of 14.9% versus 2.97% in controls (OR: 5.70). This does not apply for AIS showing a rate of 4.95% prothrombin-mutations. Rates of factor V Leiden-mutations are not different in CVT compared with AIS. In contrast, however, prothrombin-mutations were significantly more frequent in CVT than in AIS with a rate of 14.9% versus 4.95% (OR 3.35). Furthermore, 3 cases with combined heterozygosity of factor V Leiden- and prothrombin-mutation have been identified in CVT, but not in AIS or controls. All of the above mentioned mutations were exclusively heterozygous. We conclude from these data that thrombophilia in terms of factor V Leiden genotype is a risk factor for both CVT and AIS in equal measure. In contrast, prothrombin 20210-mutations were different playing a significant role in the pathogenesis of cerebral sinus vein thrombosis, but not in arterial ischemic stroke. Also, the combined occurrence of heterozygous prothrombin- and factor V Leiden-mutation clearly favors the emergence of cerebral sinus venous thrombosis. Therefore, in terms of thrombophilia such as investigated in this study, pathogenesis of arterial and venous occlusions in cerebrovascular disease has to be regarded as different. PMID- 28869460 TI - Folate receptor mediated genetic modification of human mesenchymal stem cells via folic acid-polyethylenimine-grafted poly(N-3-hydroxypropyl)aspartamide. AB - Mesenchymal stem cells (MSCs) are targeted as vehicles for cell mediated gene therapy. Here we report on a macromolecular carrier, which was designed aiming at successful targeted gene delivery into MSCs through the mediation of folate receptor and reduced cytotoxicity compared to established cationic polymer vector - polyethylenimine with a weight average molecular weight (Mw) of 25,000 Dalton (PEI25K). The carrier PHPA-PEI1800-FA was synthesized in a two-step procedure. PHPA-PEI1800 was prepared by grafting polyethylenimine with a Mw of 1800 Dalton (PEI1800) onto the alpha,beta-poly(N-3-hydroxypropyl)-D,L-aspartamide (PHPA) backbone. PHPA-PEI1800-FA was obtained by chemically conjugating folic acid onto PHPA-PEI1800. The grafting degree of PEI1800 was 3.9+/-0.2% in relation to the CH groups of PHPA and the molar ratio of folic acid conjugated to PEI1800 (chiFA) was 1.8+/-0.1 as calculated by NMR spectroscopy. The copolymers were biodegradable and exhibited lower cytotoxicity than PEI25K. Compared to PHPA PEI1800, PHPA-PEI1800-FA led to a significantly higher transfection efficiency in human MSCs, which could be attributed to the mediation of folate receptor during the transfection process as confirmed by folic acid competition assay. Both marker gene (GFP) and therapeutic gene (VEGF) were delivered into human MSCs from multi-donors using PHPA-PEI1800-FA. The percentage of GFP+ MSCs showed an average value of 2.85+/-1.60% but a large variation for different samples. The VEGF expression level of the PHPA-PEI1800-FA transfected cells was significantly higher than that of either untransfected or naked DNA transfected cells. Conclusively, PHPA-PEI1800-FA is a suitable vector to deliver genes into human MSCs through the interaction with folate receptor. PMID- 28869459 TI - Modulation of the mesenchymal stem cell migration capacity via preconditioning with topographic microstructure. AB - Controlling mesenchymal stem cells (MSCs) behavior is necessary to fully exploit their therapeutic potential. Various approaches are employed to effectively influence the migration capacity of MSCs. Here, topographic microstructures with different microscale roughness were created on polystyrene (PS) culture vessel surfaces as a feasible physical preconditioning strategy to modulate MSC migration. By analyzing trajectories of cells migrating after reseeding, we demonstrated that the mobilization velocity of human adipose derived mesenchymal stem cells (hADSCs) could be promoted by and persisted after brief preconditioning with the appropriate microtopography. Moreover, the elevated activation levels of focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) in hADSCs were also observed during and after the preconditioning process. These findings underline the potential enhancement of in vivo therapeutic efficacy in regenerative medicine via transplantation of topographic microstructure preconditioned stem cells. PMID- 28869461 TI - Effects of Tacrolimus or Sirolimus on the adhesion of vascular wall cells: Controlled in-vitro comparison study. AB - In drug eluting stents the cytostatic drugs Sirolimus or Tacrolimus are used to inhibit blood vessel restenosis by limiting the proliferation of smooth muscle cells. However, the cytostatic activity of both drugs was shown to be not cell specific and could also affect the stent endothelialisation, respectively. Currently, only limited in vitro data are available about the impact of Sirolimus and Tacrolimus on endothelial cell proliferation over a broad concentration range. To answer this question the following study was performed.Commercially obtained HUVEC were expanded with DMEM cell culture medium (GIBCO, Germany) supplemented with 5 vol% fetal calf serum on non-coated regular polystyrene-based 24-multiwell plates. For drug testings 2*104 cells/cm2 were seeded and grown for 24 h until 30-40% of the multiwell surfaces were covered and then exposed to Sirolimus (1.0*10-11 - 1.0*10-5 mol/l) or Tacrolimus (2.0*10-8 - 6.2*10-5 mol/l), both dissolved in DMSO. 12, 24 and 48 h after adding the drugs cell numbers per area were quantified by counting the cells in six wells with four fields of view per well, representing 0.6 mm2, using a confocal laser microscope.After 48 h of cell growth in the drug-free cell culture medium, the HUVEC number increased from 2.0*104 to 3.55*104 cells/cm2 (mean cell doubling time: 53.6 h, n = 6). At lower concentrations (<=2.0*10-6 mol/l) Tacrolimus reduced the number of adherent HUVEC significantly less than Sirolimus (p < 0.05). However, at higher concentrations (>=2.07*10-5 mol/l) the effect of Tacrolimus on the number of adherent endothelial cells was significantly greater than that of Sirolimus (p < 0.05). At the highest concentration applied (6.22*10-5 mol/l), Tacrolimus induced detachment of all HUVECs within 12 h after drug application. The number of adherent HUVEC decreased only slightly (about 9%) after Sirolimus application at the highest concentration (1.09*10-5 mol/l).These data show that in a non-flow model the cytostatic drug Tacrolimus reduced the number of adherent endothelial cells less than Sirolimus, as long as the drug concentration did not surpass 10-6 mol/l. At the limits of solubility, Sirolimus (1*10-5 mol/l) reduced the number of adherent endothelial cells less than Tacrolimus (6*10-5 mol/l), which induced detachment of endothelial cells. PMID- 28869462 TI - Applying XTT, WST-1, and WST-8 to human chondrocytes: A comparison of membrane impermeable tetrazolium salts in 2D and 3D cultures. AB - BACKGROUND: Tetrazolium-based assays are optimized to assess proliferation/toxicity of monolayer or suspension cells in microtiter plates. With regard to tissue engineering and regenerative medicine the need for in vivo like 3D microtissues has an increasing relevance. Applying tetrazolium-based assays to 3D culture systems is technically more challenging. The composed microenvironment may influence the assay standards, e.g. equal distribution of tetrazolium. OBJECTIVE: Evaluation of membrane-impermeable tetrazolium salt-based assays with regard to spheroid culture (3D) of human chondrocytes. METHODS: Chondrocytes were isolated from human articular cartilage. XTT, WST-1, and WST-8 were applied to monolayer cells (2D, varying cell numbers) and spheroids (3D, different sizes) in 96well plates. Formazan formation was measured spectrophotometrically after different incubation periods. Evaluation was done using phase contrast microsopy (toxicity), analyzing the correlation of cell number and absorbance signals (Gompertz function), and document signal over background ratio. RESULTS: In monolayer culture the assays showed a correlation between seeded cell numbers and absorption data. Spheroid sizes are directly related to the starting cell number. A correlation between size and absorbance was only detectable starting from 10,000 cells/aggregate. Phase contrast microscopy of monolayer cells revealed strong toxicity effects of the WST-1 (4 h) and XTT (8 h) assay and no signs of toxicity using WST-8. CONCLUSION: The WST-8 assay is non-toxic and revealed the highest sensitivity in comparison to the XTT or WST-1 assay. There is evidence, that only cells of the outer rim of spheroids are able to convert membrane-impermeable tetrazolium salts to formazans. PMID- 28869464 TI - Oxygen and Glucose Deprivation Alter Synaptic Distribution of Tau Protein: The Role of Phosphorylation. AB - Alterations in tau synaptic distribution are considered to underlie synaptic dysfunction observed in Alzheimer's disease (AD). In the present study, brain blood hypoperfusion was simulated in mouse brain slices, and tau levels and phosphorylation were investigated in total extracts, as well as in postsynaptic density fractions (PSDs) and non-PSDs obtained through differential extraction and centrifugation. Oxygen deprivation (OD) resulted in tau dephosphorylation at several AD-related residues and activation of GSK3beta and phosphatase PP2A. On the contrary, glucose deprivation (GD) did not affect total levels of cellular tau or its phosphorylation despite inactivation of GSK3beta. However, tau distribution in PSD and non-PSD fractions and the pattern of tau phosphorylation in these compartments is highly complex. In PSDs, tau was increased under GD conditions and decreased under OD conditions. GD resulted in tau dephosphorylation at Ser199, Ser262, and Ser396 while OD resulted in tau hyperphosphorylation at Ser199 and Ser404. In the non-PSD fraction, GD or OD resulted in lower levels of tau, but the phosphorylation status of tau was differentially affected. In GD conditions, tau was found dephosphorylated at Ser199, Thr205, and Ser404 and hyperphosphorylated at Ser262. However, in OD conditions tau was found hyperphosphorylated at Thr205, SerSer356, Ser396, and Ser404. Combined OD and GD resulted in degradation of cellular tau and dephosphorylation of PSD tau at Ser396 and Ser404. These results indicate that oxygen deprivation causes dephosphorylation of tau, while GD and OD differentially affect distribution of total tau and tau phosphorylation variants in neuronal compartments by activating different mechanisms. PMID- 28869463 TI - Risk Factors, Neuroanatomical Correlates, and Outcome of Neuropsychiatric Symptoms in Alzheimer's Disease. AB - BACKGROUND: An integrative model of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is lacking. OBJECTIVE: In this study, we investigated the risk factors, anatomy, biology, and outcomes of NPS in AD. METHODS: 181 subjects were included from the Alzheimer's Disease Neuroimaging Study (ADNI). NPS were assessed with the Neuropsychiatric Inventory Questionnaire at baseline and 6 months. NPI >3 was used as a threshold for NPS positivity. Three NPS courses were characterized: 1) minimal/absent (negative at 0 and 6 months, n = 77); 2) fluctuating (positive only at one time point, n = 53); 3) persistent (positive at both time points, n = 51). We examined the association between NPS course and family history of dementia, personal history of psychiatric disorders, cerebrospinal fluid biomarkers, atrophy patterns, as well as longitudinal cognitive and functional measures at 12 and 24 months (MMSE, CDR-SOB, FAQ). RESULTS: AD subjects with absent, fluctuating, or persistent NPS had similar CSF amyloid-beta and tau levels. AD subjects with minimal/absent NPS had less personal history of psychiatric disorders (35%) than those with fluctuating (57%; p = 0.015) or persistent NPS (47%, not significant). At 24 months, AD subjects with persistent NPS had worse cognitive (MMSE; p = 0.05) and functional (CDR-SOB; p = 0.016) outcomes. Dorsolateral prefrontal atrophy was seen in persistent NPS, but not in fluctuating NPS. CONCLUSIONS: Our results suggest that individuals with personal history of psychiatric disorders might be more vulnerable to develop NPS throughout the course of AD. The worst cognitive and functional outcomes associated with NPS in AD underscores the importance of monitoring NPS early in the disease course. PMID- 28869465 TI - Inflection Point in Course of Mild Cognitive Impairment: Increased Functional Connectivity of Default Mode Network. AB - The alteration of the default mode network (DMN) functional connectivity (FC) has been reported in patients with amnestic mild cognitive impairment (aMCI) as a predictor of Alzheimer's disease (AD). However, no studies exist that examined stage-dependent DMN FC changes throughout the course of aMCI. The present study aims to characterize patterns of DMN FC over three aMCI stages as first defined. Utilizing the extreme groups approach on the performance of memory tasks, aMCI subjects were divided into mild, moderate, and severe stages. Independent component analysis was used to assess DMN for individual patients in each of the three cross-sectionally defined stages. Instead of finding that continued monotonic decline was the case for the hippocampus volume, which we also investigated in this study, we observed an increase in DMN functional connectivity from mild aMCI to moderate aMCI and a decrease to severe aMCI, mainly in the left precuneus and superior parietal lobe. Moreover, the FC was significantly associated with cognitive performance. Though a longitudinal study is needed to confirm these results, our cross-sectional finding is that non linear FC changes in DMN could be a characteristic of prodromal early disease development. PMID- 28869467 TI - Potentially Inappropriate Medication, Anticholinergic Burden, and Mortality in People Attending Memory Clinics. AB - BACKGROUND: There is limited evidence regarding the association between potentially inappropriate medications (PIM) and mortality in older people with cognitive impairment. OBJECTIVE: To examine whether use of medications considered to be potentially inappropriate in older people with cognitive impairment (PIMcog) and anticholinergic cognitive burden (ACB) were associated with mortality in people who attended memory clinics. METHODS: Cross-sectional and longitudinal analyses of data from the Prospective Research In MEmory clinics (PRIME) study. Participants were community-dwelling people who attended nine memory clinics and had a diagnosis of mild cognitive impairment or dementia. PIMcog was defined as any medication considered potentially inappropriate for a person with cognitive impairment according to Beers or STOPP criteria. Anticholinergic burden was calculated using the ACB scale. Time-dependent Cox proportional hazards regression was used to analyze associations between PIMcog use/ACB score and all-cause mortality over a three-year follow-up period. The regression model included the baseline variables: age, gender, education, cognitive diagnoses, total number of medications, disease-burden, cognition, physical function, and neuropsychiatric symptoms. RESULTS: Of 964 participants, 360 (37.3%) used one or more PIMcog at some time during the study; most commonly anticholinergics and sedatives. 624 (64.7%) participants used a medication with potential or definite anticholinergic properties (ACB>0) at some point during the study. Both PIMcog use (adjusted hazard ratio: 1.42 95% CI: 1.12-1.80) and ACB score (adjusted hazard ratio: 1.18 95% CI: 1.06-1.32) were associated with mortality. CONCLUSION: Use of PIMcogs and medications with anticholinergic properties was common among memory clinic patients and both were associated with mortality. PMID- 28869466 TI - Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-beta and Amyloid beta Protein Precursor with Synapses. AB - Alzheimer's disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-beta (Abeta) have emerged as mediators of synapse dysfunction. Abeta binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Abeta and the amyloid-beta protein precursor (AbetaPP) in AD remain poorly understood. In addition, the relative roles of Abeta and AbetaPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Abeta/AbetaPP. We demonstrate that Abeta binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Abeta42 accumulates in both glutamatergic and GABAergic AbetaPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of gamma-secretase AbetaPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AbetaPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Abeta/AbetaPP in AD can be important for the development of more effective new therapies for this major disease of aging. PMID- 28869468 TI - Association of Gait Speed, Psychomotor Speed, and Dementia. AB - BACKGROUND: Gait speed (GS) and psychomotor speed (PS) could be considered as two different dimensions of age-related slowness and both measures are associated with higher risk of adverse health-related outcomes among elderly people. OBJECTIVE: To determine the association between GS, PS, and incident dementia among community-dwelling older adults. METHODS: Twelve-year longitudinal study of 1,265 participants in the Bordeaux Three-City Study, a French prospective cohort designed to determine the risk of dementia and cognitive impairment attributable to cardiovascular risk factors. Participants completed a battery of cognitive tests, including time to complete the Trail Making Test A, and a walking speed test. The incidence of dementia was determined over the 12-year follow-up period. Cox proportional hazards models with delayed entry were used to estimate the cumulative risk of dementia and were adjusted for sex, education, and ApoE4 genotype. RESULTS: Mean age of participants was 74.0 years (SD 4.8). Over the 12 year follow-up, 203 participants developed dementia. GS and PS were both independent predictors of incident all-cause dementia after 12 years of follow up. For a one SD increase of either GS or PS, the hazard ratio (HR) for Alzheimer's disease was 1.2 (95% CI = 1.02-1.32) and 1.4 (95% CI = 1.2-1.61), respectively; whereas for incident vascular dementia, the HR was 1.3 (95% CI = 1.05-1.71) and 1.5 (95% CI = 1.16-2.08), respectively. No significant interaction between GS and PS was observed. CONCLUSIONS: In older French people aged 65+, our findings showed that both low GS and PS were independently associated with risk of incident Alzheimer's disease and vascular dementia. PMID- 28869471 TI - Prevalence, Risk Factors, and Complaints Screening Tool Exploration of Subjective Cognitive Decline in a Large Cohort of the Chinese Population. AB - BACKGROUND: Substantial studies have reported the prevalence and the affecting factors of subjective cognitive decline (SCD). The complaints screening scale has also been used for probing. However, little is known in China. OBJECTIVE: To investigate the prevalence and risk factors of SCD, and explore an SCD complaints screening scale in China. METHODS: Stratified cluster random sampling was conducted. 2,689 residents aged 60-80 years completed questionnaire 1. 814 residents were included for clinical and neuropsychological evaluations. Two standards were used to make the diagnosis of mild cognitive impairment (MCI) and SCD, and a preliminary screening rate comparison was carried out. Finally, we assessed the risk factors of SCD and the correlation between the SCD questionnaire 9 (SCD-Q9) and the Auditory Verbal Learning Test-Long Delay Free Recall (AVLT-LR). RESULTS: 1) Standard 1 (ADNI2): the prevalence of SCD was 18.8% (95% CI = 14.7-22.9%) and zero conformed to six criteria (SCD plus). 2) Standard 2 (Jak/Bondi): the prevalence of SCD was 14.4% (95% CI = 10.7-18.1%). 3) Standard 1 had a relatively higher "false" positive rate, whereas Standard 2 had higher "false" negative rate. 4) Age, low education, fewer close friends, and daily drinking were independent risk factors for SCD progressing to MCI. 5) Total points of SCD-Q9 were negatively correlated to the value of AVLT-LR. CONCLUSIONS: The prevalence of SCD is high in the ShunYi District in Beijing, China. Age, low education, less social support, and daily drinking are independent risk factors. The brief SCD-Q9 can be used as a reference. PMID- 28869470 TI - The Cerebrospinal Fluid Abeta1-42/Abeta1-40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer's Disease in a Clinical Setting. AB - BACKGROUND: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-beta (Abeta) increases when the CSF Abeta1 42/Abeta1-40 ratio is used as compared to CSF Abeta1-42 levels alone. OBJECTIVE: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting. METHODS: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Abeta1-42, Abeta1-40, T-tau, P-tau181). RESULTS: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Abeta1-42/Abeta1-40 was applied compared to Abeta1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Abeta and [18F]AV45 PET increases when the CSF Abeta1-42/Abeta1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD. PMID- 28869469 TI - Trehalose Improves Cognition in the Transgenic Tg2576 Mouse Model of Alzheimer's Disease. AB - This study assessed the therapeutic utility of the autophagy enhancing stable disaccharide trehalose in the Tg2576 transgenic mouse model of Alzheimer's disease (AD) via an oral gavage of a 2% trehalose solution for 31 days. Furthermore, as AD is a neurodegenerative condition in which the transition metals, iron, copper, and zinc, are understood to be intricately involved in the cellular cascades leading to the defining pathologies of the disease, we sought to determine any parallel impact of trehalose treatment on metal levels. Trehalose treatment significantly improved performance in the Morris water maze, consistent with enhanced learning and memory. The improvement was not associated with significant modulation of full length amyloid-beta protein precursor or other amyloid-beta fragments. Trehalose had no effect on autophagy as assessed by western blot of the LC3-1 to LC3-2 protein ratio, and no alteration in biometals that might account for the improved cognition was observed. Biochemical analysis revealed a significant increase in the hippocampus of both synaptophysin, a synaptic vesicle protein and surrogate marker of synapses, and doublecortin, a reliable marker of neurogenesis. The growth factor progranulin was also significantly increased in the hippocampus and cortex with trehalose treatment. This study suggests that trehalose might invoke a suite of neuroprotective mechanisms that can contribute to improved cognitive performance in AD that are independent of more classical trehalose-mediated pathways, such as Abeta reduction and activation of autophagy. Thus, trehalose may have utility as a potential AD therapeutic, with conceivable implications for the treatment of other neurodegenerative disorders. PMID- 28869472 TI - Mitochondria in Excitatory and Inhibitory Synapses have Similar Susceptibility to Amyloid-beta Peptides Modeling Alzheimer's Disease. AB - Mitochondrial dysfunction is proposed to trigger memory deficits and synaptic damage at the onset of Alzheimer's disease (AD). However, it is unknown how mitochondria dysfunction might trigger synaptotoxicity and if a differential susceptibility of mitochondria located in synapses underlies the greater glutamatergic than GABAergic synaptotoxicity in early AD. Hippocampal synaptosomes (purified synapses) of a rat model of early AD, typified by selective memory deficits two weeks after intracerebroventricular injection of amyloid-beta peptides (Abeta1-42, 2 nmol), simultaneously displayed three mitochondria-associated deleterious alterations: 1) hampered metabolism (decreased MTT reduction); 2) increased oxygen radical production (increased hydrogen peroxide production); 3) increased caspase-3 activity. The direct exposure of hippocampal synaptosomes to Abeta1-42 (500 nM) similarly decreased mitochondrial membrane potential (TMRM+ fluorescence) and increased mitochondria derived oxygen radicals (MitoTraker(r)red-CM-H2Xros fluorescence) in individual glutamatergic (vesicular glutamate transporter-immunopositive) and GABAergic (vesicular GABA transporter-immunopositive) synaptosomes. However, significantly more glutamatergic than GABAergic synaptosomes were endowed with mitochondria (Tom20-immunopositive). These results indicate that dysfunctional mitochondria located in synapses can trigger synaptotoxicity through multifaceted mechanisms and that it is not the susceptibility of mitochondria to Abeta but more likely a different impact of dysfunctional mitochondria that underlies the greater sensitivity to synaptotoxicity of glutamatergic than GABA synapses in early AD. PMID- 28869474 TI - Cortical Metabolic and Cognitive Correlates of Disorientation in Alzheimer's Disease. AB - Orientation to time, date, and place is commonly utilized in clinical settings to aid in diagnosis, staging, and monitoring of Alzheimer's disease (AD). This study aimed to identify the cerebral metabolic correlates of orientation in patients with AD, and the degree to which regions associated with orientation overlap with memory-related structures. Eighty-five patients with a diagnosis of probable AD underwent fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological testing. Orientation items from the Dementia Rating Scale and recognition performance from the Consortium to Establish a Registry for AD (CERAD) Word List Learning test were correlated with cerebral glucose metabolism. Post-hoc analyses examined neuropsychological predictors of orientation. Better orientation performance related to greater cerebral metabolism in the bilateral middle-inferior temporal lobes, bilateral middle-posterior cingulate, left angular gyrus, and left middle occipital gyrus. In comparison, higher CERAD recognition discriminability score was associated with greater metabolic activity in left medial temporal lobe regions including the hippocampal and parahippocampal gyri, and the left fusiform gyrus. Post-hoc behavioral analyses revealed multiple cognitive functions to be related to orientation, including list learning, recognition memory, visuospatial functioning, attention, and language. Findings from the present study suggest that disorientation in AD results from dysfunction of a network of structures and cognitive abilities commonly found to be implicated in AD. The study supports the notion that memory is necessary but not sufficient for successful orientation. PMID- 28869473 TI - Neurocognitive and Behavioral Indexes for Identifying the Amnestic Subtypes of Mild Cognitive Impairment. AB - Early identification of amnestic mild cognitive impairment (aMCI) subtypes is important for early diagnosis and prognosis of Alzheimer's disease. Healthy, single-domain (sdaMCI) and multiple-domain aMCI (mdaMCI) participants performed an auditory-visual distraction-attention task. Event-related brain potentials (ERPs) were recorded while the participants performed the task to evaluate Go/NoGo N2 and P3 ERP components. The results showed the expected behavioral and cognitive decline in mdaMCI participants relative to controls (fewer hits, longer reaction times [RTs], slightly smaller Go-N2 and NoGo-N2 amplitudes), while sdaMCI participants showed some decline (slightly longer RTs, smaller Go- and NoGo-N2 amplitudes) along with some unexpected results (a late positive slow wave, PSW) and good levels of execution. In addition, some of these parameters proved to be useful markers. Thus, the number of hits was the best marker for diagnosing mdaMCI participants (distinguishing them from controls, from sdaMCI participants, and from both groups together), while the PSW amplitude was the best marker for diagnosing sdaMCI participants (distinguishing them from controls, and from control & mdaMCI participants). PMID- 28869475 TI - Effect of Attention Training in Mild Cognitive Impairment Patients with Subcortical Vascular Changes: The RehAtt Study. AB - BACKGROUND AND OBJECTIVE: Mild cognitive impairment (MCI) patients with small vessel disease (SVD) are at high dementia risk. We tested the effects of cognitive rehabilitation in these patients using the Attention Process Training II (APT-II) program in a single-blinded, randomized clinical trial. METHODS: Patients were randomized to APT-II or standard care and evaluated at baseline, 6, and 12 months with functional, quality of life, cognitive tests, and resting state functional MRI (rsfMRI). RESULTS: Forty-six patients were enrolled and 43 (mean+/-SD age 75.1+/-6.8) completed the study. No change was seen in functionality and quality of life between treated and non-treated patients. However, the Rey Auditory-Verbal Learning Test immediate recall showed a significant improvement in treated compared to non-treated group (change score 6 versus 12 months: 1.8+/-4.9 and -1.4+/-3.8, p = 0.021; baseline versus 12 months: 3.8+/-6.1 and 0.2+/-4.4, p = 0.032). A higher proportion of treated patients had stable/better evaluation compared to non-treated group on Visual search test (6 versus 12 months: 95% versus 71%, p = 0.038) and Rey-Osterrieth Complex Figure copy (6 versus 12 months: 95% versus 67%, p = 0.027). RsfMRI, performed in a subsample, showed that the difference between follow-up and baseline in synchronization of activity in cerebellar areas was significantly greater in treated than in non-treated patients. CONCLUSION: We were unable to show a significant effect in quality of life or functional status in treated patients with MCI and SVD. However, APT-II produces some beneficial effects in focused attention and working memory and seems to increase activity in brain circuits involved in cognitive processes. PMID- 28869477 TI - Persistence with Antihypertensive Drugs in Patients with Hypertension and Dementia in Germany. AB - BACKGROUND: Hypertension, a chronic disease resulting from aging and its related physiopathological dysregulations, is often associated with dementia. OBJECTIVE: The goal was to analyze the persistence with antihypertensive drugs in patients affected by both hypertension and dementia in Germany. METHODS: This study included hypertension patients who were initially treated with antihypertensive drugs in 1,262 general practices in Germany between January 2013 and December 2015 (index date). Patients with hypertension and comorbid dementia were matched (1 : 1) to patients without dementia by age, gender, type of residence (nursing home versus home-care setting), physician, and initial antihypertensive therapy, using a propensity score method. The primary outcome was the rate of patients without treatment discontinuation with antihypertensive drugs in cases and controls in the 12 months following the index date. Cox regressions were used to determine the impact of dementia on persistence with antihypertensive treatment. RESULTS: This study included 2,191 patients with hypertension and comorbid dementia and 2,191 patients with hypertension but without dementia. The mean age was 79.3 years (SD = 10.3 years) in both groups. Twelve months after initiation of antihypertensive therapy, 73.5% of cases and 69.5% of controls were persistent (p < 0.001). Dementia was associated with a significant decrease in the risk of non-persistence with antihypertensive drugs in the entire population (HR = 0.86, 95% CI: 0.79-0.93). This finding was corroborated in five different subgroups (age <=60 years, age 61-70 years, men, women, and patients living in home-care settings). CONCLUSIONS: Dementia was found to be a protective factor for persistence with antihypertensive drugs in Germany. PMID- 28869476 TI - Pazopanib Reduces Phosphorylated Tau Levels and Alters Astrocytes in a Mouse Model of Tauopathy. AB - Hyperphosphorylation and aggregation of tau protein is a critical factor in many neurodegenerative diseases. These diseases are increasing in prevalence, and there are currently no cures. Previous work from our group and others has shown that tyrosine kinase inhibitors (TKIs) can stimulate autophagy, decrease pathological proteins, and improve symptoms in models of neurodegeneration. Here we examined the role of pazopanib in mouse models that express either human mutant P301L tau (TauP301L) or triple mutant amyloid precursor protein (3x AbetaPP). The TauP301L mouse expresses P301L tau under the control of a prion promoter in both neurons and astrocytes, reminiscent of some human tauopathies. Pazopanib crosses the blood-brain barrier with no detectable peripheral off-side effects, and decreases p-tau in TauP301L mice. Pazopanib reaches a brain concentration sufficient for inhibition of several tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs). Further, pazopanib does not affect microglia but reduces astrocyte levels toward nontransgenic controls in TauP301L mice. Pazopanib does not alter amyloid beta levels or astrocytes in 3x-AbetaPP mice but modulates a number of inflammatory markers (IP-10, MIP 1alpha, MIP-1beta, and RANTES). These data suggest that pazopanib may be involved in p-tau clearance and modulation of astrocytic activity in models of tauopathies. PMID- 28869479 TI - Kynurenine Pathway Metabolites in Alzheimer's Disease. AB - BACKGROUND: Metabolites of tryptophan, produced via the kynurenine pathway (kynurenines), have been linked to Alzheimer's disease (AD) in small cohorts with conflicting results. OBJECTIVE: To compare differences in plasma kynurenine levels between AD and controls and identify potential associations with cognition. METHODS: The study included 65 histopathologically-confirmed AD patients and 65 cognitively-screened controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Cognition was assessed using the Cambridge Cognitive Examination (CamCog). Tryptophan, kynurenines, neopterin, and vitamin B6 forms were measured in plasma by liquid chromatography-tandem mass spectrometry. Non-parametric statistics, logistic regression and standardized robust regressions were applied with a false discovery rate of 0.05. RESULTS: Tryptophan, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid were lower in AD (Odds ratios (ORs) 0.24 -0.47; p-values <0.001 -0.01). Pyridoxal 5'phosphate did not differ between AD and controls. Kynurenine, anthranilic acid, quinolinic acid, and markers of immune activation (neopterin, kynurenine/tryptophan ratio, and the PAr index (Pyridoxic acid/(Pyridoxal 5'phosphate + Pyridoxal)) increased with age (beta 0.31 -0.51; p-values <0.001 0.006). Xanthurenic acid decreased with age (beta: -0.42, p < 0.001). Elderly AD patients with high quinolinic acid performed worse on the CamCog test, indicated by a significant age*quinolinic acid interaction (beta 0.21, p < 0.001). CONCLUSION: Plasma concentrations of several kynurenines were lower in patients with AD compared to controls. Low xanthurenic acid occurred in both AD and with aging. Inflammation-related markers were associated with age, but not AD. However, elevated QA was associated with poor cognition in older AD patients. PMID- 28869480 TI - Genetically-Predicted Adult Height and Alzheimer's Disease. AB - BACKGROUND: Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer's disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors. OBJECTIVE: To use a genetic approach to investigate the association between adult height and AD. METHODS: We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p < 5*10 8) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on AD were obtained from the International Genomics of Alzheimer's Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method. RESULTS: The odds ratio of AD was 0.91 (95% confidence interval, 0.86 0.95; p = 9.8*10-5) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86-0.97; p = 4.8*10-3). CONCLUSIONS: This finding suggests that biological processes that influence adult height may have a role in the etiology of AD. PMID- 28869482 TI - Intelligent Assistive Technology for Alzheimer's Disease and Other Dementias: A Systematic Review. PMID- 28869481 TI - Alzheimer's Disease Diagnosis Relies on a Twofold Clinical-Biological Algorithm: Three Memory Clinic Case Reports. AB - The International Working Group recently provided revised criteria of Alzheimer's disease (AD) proposing that the diagnosis of typical amnesic AD should be established by a clinical-biological signature, defined by the phenotype of an "amnesic syndrome of the hippocampal type" (ASHT) combined with positive in vivo evidence of AD pathophysiology in the cerebrospinal fluid (CSF) or on amyloid PET imaging. The application and clinical value of this refined diagnostic algorithm, initially intended for research purposes, is explored in three memory clinic cases presenting with different cognitive profiles including an ASHT, hippocampal atrophy, and CSF AD-biomarker data. The case reports highlight that the isolated occurrence of one of the two proposed AD criteria, ASHT or positive pathophysiological markers, does not provide a reliable diagnosis of typical AD. It is proposed that the twofold diagnostic IWG algorithm can be applied and operationalized in memory clinic settings to improve the diagnostic accuracy of typical amnesic AD in clinical practice. PMID- 28869478 TI - Tai Chi Chuan and Baduanjin Increase Grey Matter Volume in Older Adults: A Brain Imaging Study. AB - The aim of this study is to investigate and compare how 12-weeks of Tai Chi Chuan and Baduanjin exercise can modulate brain structure and memory function in older adults. Magnetic resonance imaging and memory function measurements (Wechsler Memory Scale-Chinese revised, WMS-CR) were applied at both the beginning and end of the study. Results showed that both Tai Chi Chuan and Baduanjin could significantly increase grey matter volume (GMV) in the insula, medial temporal lobe, and putamen after 12-weeks of exercise. No significant differences were observed in GMV between the Tai Chi Chuan and Baduanjin groups. We also found that compared to healthy controls, Tai Chi Chuan and Baduanjin significantly improved visual reproduction subscores on the WMS-CR. Baduanjin also improved mental control, recognition, touch, and comprehension memory subscores of the WMS CR compared to the control group. Memory quotient and visual reproduction subscores were both associated with GMV increases in the putamen and hippocampus. Our results demonstrate the potential of Tai Chi Chuan and Baduanjin exercise for the prevention of memory deficits in older adults. PMID- 28869483 TI - Obinutuzumab Plus Chlorambucil in a Patient with Severe Myasthenia Gravis and Chronic Lymphocytic Leukemia. AB - Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, characterized by fatigable weakness of the extraocular, bulbar, and limb musculature; prevalence is estimated at 14 to 32 per 100,000 in North America. Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, resulting from clonal expansion of B-cells in blood, marrow, and secondary lymphoid tissues. The simultaneous presentation of MG and CLL is exceedingly rare. This article presents the case of 71-year-old man diagnosed simultaneously with MG and CLL. His MG was severe and refractory to treatment; therefore, a strategy of treating his coexisting CLL with obinutuzumab and chlorambucil was pursued. Following 6 cycles of obinutuzumab and chlorambucil, his CLL is in remission and his MG is almost entirely undetectable. This is the first case report describing the use of obinutuzumab, a novel anti-CD20 monoclonal antibody, in a patient with concurrent MG and CLL. PMID- 28869484 TI - Efficient Skipping of Single Exon Duplications in DMD Patient-Derived Cell Lines Using an Antisense Oligonucleotide Approach. AB - BACKGROUND: Exon skipping strategies in Duchenne muscular dystrophy (DMD) have largely been directed toward altering splicing of exons flanking out-of-frame deletions, with the goal of restoring an open mRNA reading frame that leads to production of an internally deleted but partially functional dystrophin protein. OBJECTIVE: We sought to apply exon skipping to duplication mutations, assuming that the inherently limited efficiency of antisense oligonucleotide-induced exon skipping would more frequently skip a single copy of a duplicated exon, rather than both and result in significant amounts of wild-type DMD mRNA. METHODS: We tested this hypothesis in fibroblast cell lines derived from patients with a variety of single or multiple exon duplications that have been modified to allow transdifferentiation into a myogenic lineage. RESULTS: Using a variety of 2'O methyl antisense oligonucleotides, significant skipping was induced for each duplication leading to a wild-type transcript as a major mRNA product. CONCLUSIONS: This study provides another proof of concept for the feasibility of therapeutic skipping in patients carrying exon duplications in order to express wild-type, full-length mRNA, although careful evaluation of the skipping efficiency should be performed as some exons are easier to skip than others. Such a personalized strategy is expected to be highly beneficial for this subset of DMD patients, compared to inducing expression of an internally-deleted dystrophin. PMID- 28869485 TI - Nerve Conduction Studies as a Measure of Disease Progression: Objectivity or Illusion? AB - BACKGROUND: Clinical nerve conduction studies (NCS) are often used as a secondary outcome measure in therapeutic trials, but show a high degree of inter-trial variability even when technical factors known to affect the recorded responses are minimised. This raises the intriguing possibility that some of the observed variability may reflect true changes in nerve activity. OBJECTIVES: Our aim was determine how much variability these factors might produce, and how this might affect the results of commonly used neuropathy rating scales. METHODS: A standardised protocol was repeated over forty consecutive trials by the same operators in two healthy subjects. The protocol included recordings that shared either a stimulating or a recording electrode position, such that changes due to electrode position could be excluded, and hand temperature was closely controlled. RESULTS: Despite controlling for inter-operator differences, electrode position, and hand temperature, the variability in sensory nerve action potential (SNAP) amplitude was extremely high (Range 23 MUV, CoV = 10.7-18.8). This variability was greater than the change in amplitude needed to move a subject from point 0 to point 4 on the CMT neuropathy rating scale. Neither temperature or electrode position accounted for all of this variability, suggesting that additional as yet unidentified factors are responsible. CONCLUSION: Even under closely controlled conditions and sophisticated laboratory methods, test-to-test variability can be significant. The factors responsible for this variability may be difficult to control, limiting the utility of single nerve recordings as a trial outcome measure. PMID- 28869487 TI - rhBMP-2 in an injectable Gelfoam carrier enhances consolidation of the distracted callus in a sheep model. AB - BACKGROUND: A major problem associated with distraction osteogenesis is the long time required for consolidation. OBJECTIVE: The goal of this study was to determine whether a percutaneous injection of recombinant human bone morphogenetic protein-2 (rhBMP-2) in a Gelfoam carrier would enhance bone consolidation following distraction. METHODS: A unilateral tibial osteotomy combined with external stabilization was performed in 14 adult sheep. After a latency of four days, distraction was performed at 1.25 millimetres per day for 20 days. On days 23 and 30, the sheep received an injection of rhBMP-2/Gelfoam or buffer/Gelfoam. During the following 50 days, radiographs and in vivo torsional stiffness measurements were obtained weekly. The effect of rhBMP-2 treatment post mortem was assessed using destructive biomechanical testing, quantitative CT and DXA analysis. RESULTS: The in vivo stiffness measurements of the sheep treated with rhBMP-2 were significantly higher than those of the carrier control group (p< 0.05). These in vivo data were verified by post-mortem biomechanical testing and quantitative CT analysis. The maximum torsional moment observed was 55% greater in the sheep treated with rhBMP-2. CONCLUSIONS: These data support the potential use of rhBMP-2 in an injectable carrier for enhancing consolidation, as it may ultimately lead to shorter treatment times for patients undergoing distraction procedures. PMID- 28869486 TI - Efficacy of Idebenone to Preserve Respiratory Function above Clinically Meaningful Thresholds for Forced Vital Capacity (FVC) in Patients with Duchenne Muscular Dystrophy. AB - BACKGROUND: Patients with DMD experience progressive restrictive respiratory disease and eventual respiratory failure. Standard of care guidelines command changes in disease management when forced vital capacity percent of predicted (FVC% p) falls below clinically relevant thresholds. The Phase 3 DELOS trial in patients with DMD demonstrated that idebenone reduces the loss of peak expiratory flow and FVC compared to placebo (Buyse GM, et al.; Lancet 2015; 385 : 1748-57). OBJECTIVE: Post-hoc analyses were conducted to assess whether treatment with idebenone could reduce the risk of patients dropping below clinically meaningful thresholds of FVC% p. METHODS: The DELOS trial enrolled DMD patients 10-18 years of age not using glucocorticoids to receive idebenone (N = 31) or placebo (N = 33) for 12 months. Change from baseline in FVC and FVC% p was assessed by hospital spirometry and analyzed by mixed model of repeated measures and slope analysis and proportions of patients falling below clinically meaningful thresholds of FVC% p were compared. RESULTS: The change over 1 year in FVC and FVC% p showed a consistent pattern in favor of idebenone treatment across multiple analysis methods and fewer patients in the idebenone group declined by a margin of 10% or more in FVC and FVC% p compared to placebo. There were also fewer patients in the idebenone group (15%) with a decline below FVC% p of 50% compared to the placebo group (25%) and fewer patients in the idebenone group (28%) showed a decline below FVC% p of 50% or 40% or 30% compared to the placebo group (43%). CONCLUSIONS: These data added to the consistency and clinical meaningfulness of findings from the DELOS trial showing that idebenone can slow the loss of pulmonary function in patients with DMD. PMID- 28869488 TI - Sol-Gel Derived Active Material for Yb Thin-Disk Lasers. AB - A ytterbium doped active material for thin-disk laser was developed based on aluminosilicate and phosphosilicate glass matrices containing up to 30 mol% YbO1.5. Thick films and bulk samples were prepared by sol-gel processing. The structural nature of the base material was assessed by X-ray diffraction and Raman spectroscopy and the film morphology was evidenced by scanning electron microscopy. The photoluminescence (PL) properties of different compositions, including emission spectra and lifetimes, were also studied. Er3+ was used as an internal reference to compare the intensities of the Yb3+ PL peaks at ~ 1020 nm. The Yb3+ PL lifetimes were found to vary between 1.0 and 0.5 ms when the Yb concentration increased from 3 to 30 mol%. Based on a figure of merit, the best active material selected was the aluminosilicate glass composition 71 SiO2-14 AlO1.5-15 YbO1.5 (in mol%). An active disk, ~ 36 MUm thick, consisting of a Bragg mirror, an aluminosilicate layer doped with 15 mol% Yb and an anti-reflective coating, was fabricated. PMID- 28869489 TI - Photoswitchable Fluorescent Diarylethene Derivatives with Thiophene 1,1-Dioxide Groups: Effect of Alkyl Substituents at the Reactive Carbons. AB - Photoswitching and fluorescent properties of sulfone derivatives of 1,2-bis(2 alkyl-4-methyl-5-phenyl-3-thienyl)perfluorocyclopentene, 1-5, having methyl, ethyl, n-propyl, i-propyl, and i-butyl substituents at the reactive carbons (2- and 2'-positions) of the thiophene 1,1-dioxide rings were studied. Diarylethenes 1-5 underwent isomerization reactions between open-ring and closed-ring forms upon alternate irradiation with ultraviolet (UV) and visible light and showed fluorescence in the closed-ring forms. The alkyl substitution at the reactive carbons affects the fluorescent property of the closed-ring isomers. The closed ring isomers 2b-5b with ethyl, n-propyl, i-propyl, and i-butyl substituents show higher fluorescence quantum yields than 1b with methyl substituents. In polar solvents, the fluorescence quantum yield of 1b markedly decreases, while 2b-5b maintain the relatively high fluorescence quantum yields. Although the cycloreversion quantum yields of the derivatives with methyl, ethyl, n-propyl, and i-propyl substituents are quite low and in the order of 10-5, introduction of i-butyl substituents was found to increase the yield up to the order of 10-3. These results indicate that appropriate alkyl substitution at the reactive carbons is indispensable for properly controlling the photoswitching and fluorescent properties of the photoswitchable fluorescent diarylethenes, which are potentially applicable to super-resolution fluorescence microscopies. PMID- 28869490 TI - The Impact of Hemodialysis Frequency and Duration on Blood Pressure Management and Quality of Life in End-Stage Renal Disease Patients. AB - Cardiovascular complications are the most prominent causes of morbidity and mortality among chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients undergoing standard hemodialysis (HD) therapy. Cardiovascular disease risk is increased significantly through persistent hypertension and blood pressure (BP) fluctuation, which are the most common complications of CKD. It was hypothesized that an extended approach with lengthier and more frequent dialysis sessions, referred to in this paper as "extended hemodialysis" (EHD), can potentially lower and stabilize blood pressure, and consequently reduce the rate of morbidity and mortality. A greater reduction of volume (salt and water) with higher frequency can improve patient quality of life (QOL). Eleven papers, including clinical trials and systematic reviews were chosen and analyzed. The extracted data was used to evaluate the change in blood pressure levels between standard HD and EHD. Overall, the studies showed that EHD resulted in improved blood pressure management; therefore, we concluded that there will be a decrease in cardiovascular disease risk, stroke, and morbidity and mortality rate. There will be also an improvement in patient QOL due to beneficial effects of the EHD. PMID- 28869491 TI - Enhancing Youth Participation Using the PREP Intervention: Parents' Perspectives. AB - Pathways and Resources for Engagement and Participation (PREP), an innovative intervention aimed at modifying the environment and coaching youth/parents, was found to be effective in improving youth participation in chosen community activities. In order to complement existing quantitative evidence, this study examined parents' perspectives on the PREP approach. Twelve parents of youth with physical disabilities (12 to 18 years old) who received the PREP approach participated in individual semi-structured interviews following the 12-week intervention delivered by an occupational therapist. Thematic analysis revealed three inter-linked themes, the first of which was informative, describing the "nature of intervention", and led to two reflective themes: "multi-faceted effects of care" and "process of care". Parents highlighted the effect of the PREP intervention in a broad sense, extending beyond the accomplishment of the selected activities. This involved improvements on the physical, emotional, and social levels as well as in autonomy. Parents also discussed how their own needs were acknowledged through the intervention and recognized the unique role of the occupational therapist in supporting this process. The findings provide additional information about the usefulness of the PREP approach and describe the various benefits generated by a single intervention. Such knowledge can expand the therapeutic options for positive, health-promoting participation. PMID- 28869492 TI - The Lactate/Albumin Ratio: A Valuable Tool for Risk Stratification in Septic Patients Admitted to ICU. AB - The lactate/albumin ratio has been reported to be associated with mortality in pediatric patients with sepsis. We aimed to evaluate the lactate/albumin ratio for its prognostic relevance in a larger collective of critically ill (adult) patients admitted to an intensive care unit (ICU). A total of 348 medical patients admitted to a German ICU for sepsis between 2004 and 2009 were included. Follow-up of patients was performed retrospectively between May 2013 and November 2013. The association of the lactate/albumin ratio (cut-off 0.15) and both in hospital and post-discharge mortality was investigated. An optimal cut-off was calculated by means of Youden's index. The lactate/albumin ratio was elevated in non-survivors (p < 0.001). Patients with an increased lactate/albumin ratio were of similar age, but clinically in a poorer condition and had more pronounced laboratory signs of multi-organ failure. An increased lactate/albumin ratio was associated with adverse in-hospital mortality. An optimal cut-off of 0.15 was calculated and was associated with adverse long-term outcome even after correction for APACHE2 and SAPS2. We matched 99 patients with a lactate/albumin ratio >0.15 to case-controls with a lactate/albumin ratio <0.15 corrected for APACHE2 scores: The group with a lactate/albumin ratio >0.15 evidenced adverse in hospital outcome in a paired analysis with a difference of 27% (95%CI 10-43%; p < 0.01). Regarding long-term mortality, again, patients in the group with a lactate/albumin ratio >0.15 showed adverse outcomes (p < 0.001). An increased lactate/albumin ratio was significantly associated with an adverse outcome in critically ill patients admitted to an ICU, even after correction for confounders. The lactate/albumin ratio might constitute an independent, readily available, and important parameter for risk stratification in the critically ill. PMID- 28869493 TI - Vaccines against Botulism. AB - Botulinum neurotoxins (BoNT) cause the flaccid paralysis of botulism by inhibiting the release of acetylcholine from motor neurons. There are seven serotypes of BoNT (A-G), with limited therapies, and no FDA approved vaccine for botulism. An investigational formalin-inactivated penta-serotype-BoNT/A-E toxoid vaccine was used to vaccinate people who are at high risk of contracting botulism. However, this formalin-inactivated penta-serotype-BoNT/A-E toxoid vaccine was losing potency and was discontinued. This article reviews the different vaccines being developed to replace the discontinued toxoid vaccine. These vaccines include DNA-based, viral vector-based, and recombinant protein based vaccines. DNA-based vaccines include plasmids or viral vectors containing the gene encoding one of the BoNT heavy chain receptor binding domains (HC). Viral vectors reviewed are adenovirus, influenza virus, rabies virus, Semliki Forest virus, and Venezuelan Equine Encephalitis virus. Among the potential recombinant protein vaccines reviewed are HC, light chain-heavy chain translocation domain, and chemically or genetically inactivated holotoxin. PMID- 28869495 TI - What Can Synergetics Contribute to Embodied Aesthetics? AB - I deal with perception and action (e.g., movements) using results from synergetics, a comprehensive mathematical theory of the self-organized formation (emergence) of spatial, temporal, or functional structures in complex systems. I illustrate basic concepts such as order parameters (OPs), enslavement, complexity reduction, circular causality first by examples of well-known collective, spontaneous modes of human behavior such as rhythmic clapping of hands, and so forth, and then by face recognition. The role played by OPs depends on context. In the case of face (or pattern) recognition an OP represents the concept of an individual face (action of mind) and it enslaves the action (firing rates) of neurons (body). This insight allows me to interpret syndromes as order parameters playing their mind/body double role. I present criteria for the identification of OPs and discuss their general properties including error correction and remedy of deficiencies. Contact is made with a recent paper by Sabine Koch on embodied aesthetics. My approach includes the saturation of attention at various time scales (ambiguous figures/fashion). Adopting a psychological perspective, I discuss some ingredients of beauty such as proportionality and symmetry, but also the importance of irregularities. PMID- 28869496 TI - Electrochemical Properties of an Na4Mn9O18-Reduced Graphene Oxide Composite Synthesized via Spray Drying for an Aqueous Sodium-Ion Battery. AB - An aqueous sodium ion battery (ASIB) with metal Zn as anode and Na4Mn9O18-reduced graphene oxide (Na4Mn9O18-RGO) as cathode has been developed. In this work, spherical Na4Mn9O18-RGO composite particles were prepared via spray drying. The aqueous battery exhibits stable cyclability and high specific capacities. Typically, a high initial discharge capacity of 61.7 mAh.g-1 is attained at a high current rate of 4 C, and a stabilizing reversible capacity of 58.9 mAh.g-1 was obtained after 150 cycles. The network interlaced by RGO sheets provided fast electron conduction paths and structural stability to accommodate the mechanical stresses induced by sodium insertion and extraction, so the Na4Mn9O18-RGO electrode displayed superior electrochemical performance in the ASIB. PMID- 28869494 TI - "Dicing and Splicing" Sphingosine Kinase and Relevance to Cancer. AB - Sphingosine kinase (SphK) is a lipid enzyme that maintains cellular lipid homeostasis. Two SphK isozymes, SphK1 and SphK2, are expressed from different chromosomes and several variant isoforms are expressed from each of the isozymes, allowing for the multi-faceted biological diversity of SphK activity. Historically, SphK1 is mainly associated with oncogenicity, however in reality, both SphK1 and SphK2 isozymes possess oncogenic properties and are recognized therapeutic targets. The absence of mutations of SphK in various cancer types has led to the theory that cancer cells develop a dependency on SphK signaling (hyper SphK signaling) or "non-oncogenic addiction". Here we discuss additional theories of SphK cellular mislocation and aberrant "dicing and splicing" as contributors to cancer cell biology and as key determinants of the success or failure of SphK/S1P (sphingosine 1 phosphate) based therapeutics. PMID- 28869498 TI - TiO2 Nanobelt@Co9S8 Composites as Promising Anode Materials for Lithium and Sodium Ion Batteries. AB - TiO2 anodes have attracted great attention due to their good cycling stability for lithium ion batteries and sodium ion batteries (LIBs and SIBs). Unfortunately, the low specific capacity and poor conductivity limit their practical application. The mixed phase TiO2 nanobelt (anatase and TiO2-B) based Co9S8 composites have been synthesized via the solvothermal reaction and subsequent calcination. During the formation process of hierarchical composites, glucose between TiO2 nanobelts and Co9S8 serves as a linker to increase the nucleation and growth of sulfides on the surface of TiO2 nanobelts. As anode materials for LIBs and SIBs, the composites combine the advantages of TiO2 nanobelts with those of Co9S8 nanomaterials. The reversible specific capacity of TiO2 nanobelt@Co9S8 composites is up to 889 and 387 mAh.g-1 at 0.1 A.g-1 after 100 cycles, respectively. The cooperation of excellent cycling stability of TiO2 nanobelts and high capacities of Co9S8 nanoparticles leads to the good electrochemical performances of TiO2 nanobelt@Co9S8 composites. PMID- 28869497 TI - Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus. AB - Multicellular organisms have evolved multiple genetically programmed cell death pathways that are essential for homeostasis. The finding that many viruses encode cell death inhibitors suggested that cellular suicide also functions as a first line of defence against invading pathogens. This theory was confirmed by studying viral mutants that lack certain cell death inhibitors. Cytomegaloviruses, a family of species-specific viruses, have proved particularly useful in this respect. Cytomegaloviruses are known to encode multiple death inhibitors that are required for efficient viral replication. Here, we outline the mechanisms used by the host cell to detect cytomegalovirus infection and discuss the methods employed by the cytomegalovirus family to prevent death of the host cell. In addition to enhancing our understanding of cytomegalovirus pathogenesis we detail how this research has provided significant insights into the cross-talk that exists between the various cell death pathways. PMID- 28869499 TI - Antioxidant and Anti-Inflammatory Activities of Hydrolysates and Peptide Fractions Obtained by Enzymatic Hydrolysis of Selected Heat-Treated Edible Insects. AB - This study investigated the effect of heat treatment of edible insects on antioxidant and anti-inflammatory activities of peptides obtained by in vitro gastrointestinal digestion and absorption process thereof. The antioxidant potential of edible insect hydrolysates was determined as free radical-scavenging activity, ion chelating activity, and reducing power, whereas the anti inflammatory activity was expressed as lipoxygenase and cyclooxygenase-2 inhibitory activity. The highest antiradical activity against DPPH* (2,2-diphenyl 1-picrylhydrazyl radical) was noted for a peptide fraction from baked cricket Gryllodes sigillatus hydrolysate (IC50 value 10.9 ug/mL) and that against ABTS*+ (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical) was the highest for raw mealworm Tenebrio molitor hydrolysate (inhibitory concentration (IC50 value) 5.3 ug/mL). The peptides obtained from boiled locust Schistocerca gregaria hydrolysate showed the highest Fe2+ chelation ability (IC50 value 2.57 ug/mL); furthermore, the highest reducing power was observed for raw G. sigillatus hydrolysate (0.771). The peptide fraction from a protein preparation from the locust S. gregaria exhibited the most significant lipoxygenase and cyclooxygenase 2 inhibitory activity (IC50 value 3.13 ug/mL and 5.05 ug/mL, respectively). PMID- 28869500 TI - Using Naive Bayesian Analysis to Determine Imaging Characteristics of KRAS Mutations in Metastatic Colon Cancer. AB - Genotype, particularly Ras status, greatly affects prognosis and treatment of liver metastasis in colon cancer patients. This pilot aimed to apply word frequency analysis and a naive Bayes classifier on radiology reports to extract distinguishing imaging descriptors of wild-type colon cancer patients and those with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. In this institutional-review-board-approved study, we compiled a SNaPshot mutation analysis dataset from 457 colon adenocarcinoma patients. From this cohort of patients, we analyzed radiology reports of 299 patients (> 32,000 reports) who either were wild-type (147 patients) or had a KRAS (152 patients) mutation. Our algorithm determined word frequency within the wild-type and mutant radiology reports and used a naive Bayes classifier to determine the probability of a given word belonging to either group. The classifier determined that words with a greater than 50% chance of being in the KRAS mutation group and which had the highest absolute probability difference compared to the wild-type group included: "several", "innumerable", "confluent", and "numerous" (p < 0.01). In contrast, words with a greater than 50% chance of being in the wild type group and with the highest absolute probability difference included: "few", "discrete", and "[no] recurrent" (p = 0.03). Words used in radiology reports, which have direct implications on disease course, tumor burden, and therapy, appear with differing frequency in patients with KRAS mutations versus wild-type colon adenocarcinoma. Moreover, likely characteristic imaging traits of mutant tumors make probabilistic word analysis useful in identifying unique characteristics and disease course, with applications ranging from radiology and pathology reports to clinical notes. PMID- 28869501 TI - The Use of a Virtual Online Debating Platform to Facilitate Student Discussion of Potentially Polarising Topics. AB - The merits of students exchanging views through the so-called human continuum exercise (HCE) are well established. The current article describes the creation of the virtual human continuum (VHC), an online platform that facilitates the same teaching exercise. It also reports feedback on the VHC from veterinary science students (n = 38). First-year Doctor of Veterinary Medicine students at the University of Sydney, Australia, trialed the platform and provided feedback. Most students agreed or strongly agreed that the VHC offered: a non-threatening environment for discussing emotive and challenging issues; and an opportunity to see how other people form ideas. It also made them think about how to express their ideas and make arguments; and left them feeling more comfortable about expressing their views using it than they would discussing ideas face-to-face (98%, 84%, 79% and 76%, respectively). All respondents agreed or strongly agreed that the VHC encouraged them to consider other opinions. These data suggest that the transition of the HCE to an online platform facilitates dialogue on difficult ethical issues in a supportive environment. PMID- 28869502 TI - A Review of the Safety and Efficacy of Vaccines as Prophylaxis for Clostridium difficile Infections. AB - This review aims to evaluate the literature on the safety and efficacy of novel toxoid vaccines for the prophylaxis of Clostridium difficile infections (CDI) in healthy adults. Literature searches for clinical trials were performed through MEDLINE, ClinicalTrials.gov, and Web of Science using the keywords bacterial vaccines, Clostridium difficile, and vaccine. English-language clinical trials evaluating the efficacy and/or safety of Clostridium difficile toxoid vaccines that were completed and had results posted on ClinicalTrials.gov or in a published journal article were included. Six clinical trials were included. The vaccines were associated with mild self-reported adverse reactions, most commonly injection site reactions and flu-like symptoms, and minimal serious adverse events. Five clinical trials found marked increases in antibody production in vaccinated participants following each dose of the vaccine. Clinical trials evaluating C. difficile toxoid vaccines have shown them to be well tolerated and relatively safe. Surrogate markers of efficacy (seroconversion and geometric mean antibody levels) have shown significant immune responses to a vaccination series in healthy adults, indicating that they have the potential to be used as prophylaxis for CDI. However, more research is needed to determine the clinical benefits of the vaccines. PMID- 28869503 TI - An Adaptive Trajectory Clustering Method Based on Grid and Density in Mobile Pattern Analysis. AB - Clustering analysis is one of the most important issues in trajectory data mining. Trajectory clustering can be widely applied in the detection of hotspots, mobile pattern analysis, urban transportation control, and hurricane prediction, etc. To obtain good clustering performance, the existing trajectory clustering approaches need to input one or more parameters to calibrate the optimal values, which results in a heavy workload and computational complexity. To realize adaptive parameter calibration and reduce the workload of trajectory clustering, an adaptive trajectory clustering approach based on the grid and density (ATCGD) is proposed in this paper. The proposed ATCGD approach includes three parts: partition, mapping, and clustering. In the partition phase, ATCGD applies the average angular difference-based MDL (AD-MDL) partition method to ensure the partition accuracy on the premise that it decreases the number of the segments after the partition. During the mapping procedure, the partitioned segments are mapped into the corresponding cells, and the mapping relationship between the segments and the cells are stored. In the clustering phase, adopting the DBSCAN based method, the segments in the cells are clustered on the basis of the calibrated values of parameters from the mapping procedure. The extensive experiments indicate that although the results of the adaptive parameter calibration are not optimal, in most cases, the difference between the adaptive calibration and the optimal is less than 5%, while the run time of clustering can reduce about 95%, compared with the TRACLUS algorithm. PMID- 28869504 TI - Electrical Detection of Pneumococcus through the Nanoparticle Decoration Method. AB - A simple method of nanoparticle decoration can be used in the detection of pneumococcus. After the pneumococcal bacteria were captured by an antibody (pneumococcal C-polysaccharide (PnC) antibody) between the interdigitated electrodes, the gold nanoparticles conjugated with the PnC antibodies were let to bind onto an outer membrane of the bacteria. Upon successfully dense decoration, the bacteria surface will become conductive owing to the metal nanoparticles, and a distinctive conductance change between the electrodes can be observed. Since this success ratio, or the probability of the conductance change, reflects the concentration of the analyte, a number of repeated measurements can be used in the quantification of the bacteria. In this way, we have successfully detected S. pneumoniae in the range of 10-108 CFU/mL. The limit of detection in this work is lower than that in the commercial detection kit. We hope that the nanoparticle decoration method will play a role in the facile detection of various bacteria. PMID- 28869505 TI - A Survey on Data Quality for Dependable Monitoring in Wireless Sensor Networks. AB - Wireless sensor networks are being increasingly used in several application areas, particularly to collect data and monitor physical processes. Non functional requirements, like reliability, security or availability, are often important and must be accounted for in the application development. For that purpose, there is a large body of knowledge on dependability techniques for distributed systems, which provide a good basis to understand how to satisfy these non-functional requirements of WSN-based monitoring applications. Given the data-centric nature of monitoring applications, it is of particular importance to ensure that data are reliable or, more generically, that they have the necessary quality. In this survey, we look into the problem of ensuring the desired quality of data for dependable monitoring using WSNs. We take a dependability-oriented perspective, reviewing the possible impairments to dependability and the prominent existing solutions to solve or mitigate these impairments. Despite the variety of components that may form a WSN-based monitoring system, we give particular attention to understanding which faults can affect sensors, how they can affect the quality of the information and how this quality can be improved and quantified. PMID- 28869508 TI - An Effective Semantic Event Matching System in the Internet of Things (IoT) Environment. AB - IoT sensors use the publish/subscribe model for communication to benefit from its decoupled nature with respect to space, time, and synchronization. Because of the heterogeneity of communicating parties, semantic decoupling is added as a fourth dimension. The added semantic decoupling complicates the matching process and reduces its efficiency. Our proposed algorithm clusters subscriptions and events according to topic and performs the matching process within these clusters, which increases the throughput by reducing the matching time from the range of 16-18 ms to 2-4 ms. Moreover, the accuracy of matching is improved when subscriptions must be fully approximated, as demonstrated by an over 40% increase in F-score results. This work shows the benefit of clustering, as well as the improvement in the matching accuracy and efficiency achieved using this approach. PMID- 28869507 TI - Investigation on Eigenfrequency of a Cylindrical Shell Resonator under Resonator Top Trimming Methods. AB - The eigenfrequency of a resonator plays a significant role in the operation of a cylindrical shell vibrating gyroscope, and trimming is aimed at eliminating the frequency split that is the difference of eigenfrequency between two work modes. In this paper, the effects on eigenfrequency under resonator-top trimming methods that trim the top of the resonator wall are investigated by simulation and experiments. Simulation results show that the eigenfrequency of the trimmed mode increases in the holes-trimming method, whereas it decreases in the grooves trimming method. At the same time, the untrimmed modes decrease in both holes trimming and grooves-trimming methods. Moreover, grooves-trimming is more efficient than holes-trimming, which indicates that grooves-trimming can be a primary trimming method, and holes-trimming can be a precision trimming method. The rigidity condition after grooves-trimming is also studied to explain the variation of eigenfrequency. A femtosecond laser is employed in the resonator trimming experiment by the precise ablation of the material. Experimental results are in agreement with the simulation results. PMID- 28869506 TI - Critical Role of the Human ATP-Binding Cassette G1 Transporter in Cardiometabolic Diseases. AB - ATP-binding cassette G1 (ABCG1) is a member of the large family of ABC transporters which are involved in the active transport of many amphiphilic and lipophilic molecules including lipids, drugs or endogenous metabolites. It is now well established that ABCG1 promotes the export of lipids, including cholesterol, phospholipids, sphingomyelin and oxysterols, and plays a key role in the maintenance of tissue lipid homeostasis. Although ABCG1 was initially proposed to mediate cholesterol efflux from macrophages and then to protect against atherosclerosis and cardiovascular diseases (CVD), it becomes now clear that ABCG1 exerts a larger spectrum of actions which are of major importance in cardiometabolic diseases (CMD). Beyond a role in cellular lipid homeostasis, ABCG1 equally participates to glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase. Moreover, there is now a growing body of evidence suggesting that modulation of ABCG1 expression might contribute to the development of diabetes and obesity, which are major risk factors of CVD. In order to provide the current understanding of the action of ABCG1 in CMD, we here reviewed major findings obtained from studies in mice together with data from the genetic and epigenetic analysis of ABCG1 in the context of CMD. PMID- 28869509 TI - Anti-Inflammatory Effects of Curvularin-Type Metabolites from a Marine-Derived Fungal Strain Penicillium sp. SF-5859 in Lipopolysaccharide-Induced RAW264.7 Macrophages. AB - Chemical study on the extract of a marine-derived fungal strain Penicillium sp. SF-5859 yielded a new curvularin derivative (1), along with eight known curvularin-type polyketides (2-9). The structures of these metabolites (1-9) were established by comprehensive spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS). In vitro anti inflammatory effects of these metabolites were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Among these metabolites, 3-9 were shown to strongly inhibit LPS-induced overproduction of nitric oxide (NO) and prostaglandin E2 (PGE2) with IC50 values ranging from 1.9 MUM to 18.1 MUM, and from 2.8 MUM to 18.7 MUM, respectively. In the further evaluation of signal pathways involved in these effects, the most active compound, (10E,15S)-10,11 dehydrocurvularin (8) attenuated the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW264.7 macrophages. Furthermore, compound 8 was shown to suppress the upregulation of pro-inflammatory mediators and cytokines via the inhibition of the nuclear factor-kappaB (NF-kappaB) signaling pathway, but not through the mitogen-activated protein kinase (MAPK) pathway. Based on the comparisons of the different magnitude of the anti inflammatory effects of these structurally-related metabolites, it was suggested that the opening of the 12-membered lactone ring in curvularin-type metabolites and blocking the phenol functionality led to the significant decrease in their anti-inflammatory activity. PMID- 28869510 TI - A Hot-Polymer Fiber Fabry-Perot Interferometer Anemometer for Sensing Airflow. AB - This work proposes the first hot-polymer fiber Fabry-Perot interferometer (HPFFPI) anemometer for sensing airflow. The proposed HPFFPI is based on a single mode fiber (SMF) endface that is attached to a UV-cured polymer to form an ultracompact fiber Fabry-Perot microcavity. The proposed polymer microcavity was heated using a low-cost chip resistor with a controllable dc driving power to achieve a desired polymer's steady-state temperature (T) that exceeds the T of the surrounding environment. The polymer is highly sensitive to variations of T with high repeatability. When the hot polymer was cooled by the measured flowing air, the wavelength fringes of its optical spectra shifted. The HPFFPI anemometers have been experimentally evaluated for different cavity lengths and heating power values. Experimental results demonstrate that the proposed HPFFPI responses well in terms of airflow measurement. A high sensitivity of 1.139 nm/(m/s) and a good resolution of 0.0088 m/s over the 0~2.54 m/s range of airflow were achieved with a cavity length of 10 MUm and a heating power of 0.402 W. PMID- 28869511 TI - Analysis of Multi-Level Simultaneous Driving Technique for Capacitive Touch Sensors. AB - The signal-to-noise ratio (SNR) and driving levels of capacitive touch sensors determine the applicability of these sensors to thinner displays and sensor integrated modules. The simultaneous driving technique has been widely applied to capacitive touch sensors to cope with various types of environmental noise. A Hadamard matrix has been used to determine the driving code and multiplex capacitive signals required to increase the SNR and responsivity of touch sensors. Using multi-level Hadamard matrices, a new driving technique for sensing concurrent capacitive elements across multiple rows of a touch panel was developed. The technique provides more effective design choices than the existing bipolar driving method by supporting a variety of orders of matrices and regular capacity. The required TX voltage can be reduced by applying the Kronecker product for higher orders of simultaneous driving. A system model is presented for multiplexing capacitive signals to extract the SNR of the existing Hadamard matrices as well as one of the proposed multi-level sequences. In addition, the corresponding multi-level drivers and receivers were implemented to verify the theoretical expectations and simulation results of the proposed technique. PMID- 28869512 TI - The Application of a Novel Ceramic Liner Improves Bonding between Zirconia and Veneering Porcelain. AB - The adhesion of porcelain to zirconia is a key factor in the success of bilayered restorations. In this study, the efficacy of a novel experimental liner (EL) containing zirconia for improved bonding between zirconia and veneering porcelain was tested. Four ELs containing various concentrations (0, 3.0, 6.0, and 9.0 wt %) of zirconia were prepared. Testing determined the most effective EL (EL3 containing 3.0 wt % zirconia) in terms of shear bond strength value (n = 15). Three different bar-shaped zirconia/porcelain bilayer specimens were prepared for a three-point flexural strength (TPFS) test (n = 15): no-liner (NL), commercial liner (CL), and EL3. Specimens were tested for TPFS with the porcelain under tension and the maximum load was measured at the first sign of fracture. The strength data were analyzed using one-way ANOVA and Tukey's test (alpha = 0.05) as well as Weibull distribution. When compared to NL, the CL application had no effect, while the EL3 application had a significant positive effect (p < 0.001) on the flexural strength. Weibull analysis also revealed the highest shape and scale parameters for group EL3. Within the limitations of this study, the novel ceramic liner containing 3.0 wt % zirconia (EL3) significantly enhanced the zirconia/porcelain interfacial bonding. PMID- 28869514 TI - Capturing Complex 3D Human Motions with Kernelized Low-Rank Representation from Monocular RGB Camera. AB - Recovering 3D structures from the monocular image sequence is an inherently ambiguous problem that has attracted considerable attention from several research communities. To resolve the ambiguities, a variety of additional priors, such as low-rank shape basis, have been proposed. In this paper, we make two contributions. First, we introduce an assumption that 3D structures lie on the union of nonlinear subspaces. Based on this assumption, we propose a Non-Rigid Structure from Motion (NRSfM) method with kernelized low-rank representation. To be specific, we utilize the soft-inextensibility constraint to accurately recover 3D human motions. Second, we extend this NRSfM method to the marker-less 3D human pose estimation problem by combining with Convolutional Neural Network (CNN) based 2D human joint detectors. To evaluate the performance of our methods, we apply our marker-based method on several sequences from Utrecht Multi-Person Motion (UMPM) benchmark and CMU MoCap datasets, and then apply the marker-less method on the Human3.6M datasets. The experiments demonstrate that the kernelized low-rank representation is more suitable for modeling the complex deformation and the method consequently yields more accurate reconstructions. Benefiting from the CNN-based detector, the marker-less approach can be applied to more real-life applications. PMID- 28869515 TI - Characterizations of Anti-Alpha-Fetoprotein-Conjugated Magnetic Nanoparticles Associated with Alpha-Fetoprotein for Biomedical Applications. AB - In this work, we report characterizations of biofunctionalized magnetic nanoparticles (BMNPs) associated with alpha-fetoprotein (AFP) for biomedical applications. The example BMNP in this study is anti-alpha-fetoprotein (anti-AFP) conjugated onto dextran-coated Fe3O4 labeled as Fe3O4-anti-AFP, and the target is AFP. We characterize magnetic properties, such as increments of magnetization DeltaMH and effective relaxation time Deltataueff in the reaction process. It is found that both DeltaMH and Deltataueff are enhanced when the concentration of AFP, FAFP, increases. The enhancements are due to magnetic interactions among BMNPs in magnetic clusters, which contribute extra MH after the association with MH and in turn enhance taueff. The screening of patients carrying hepatocellular carcinoma (HCC) is verified via DeltaMH/MH. The proposed method can be applied to detect a wide variety of analytes. The scaling characteristics of DeltaMH/MH show the potential to develop a vibrating sample magnetometer system with low field strength for clinic applications. PMID- 28869516 TI - Level of Theory and Solvent Effects on DASA Absorption Properties Prediction: Comparing TD-DFT, CASPT2 and NEVPT2. AB - Donor-acceptor Stenhouse adducts (DASAs) are a very recent class of organic photoswitches that combine excellent properties, such as color and polarity change, a large structural modification, and excellent fatigue resistance. Despite their potential applications in different fields, very few studies have focused on rationalizing their electronic structure properties. Here, by means of different state-of-the-art theoretical methods, including solvent and vibrational effects, we show that while time dependent-density functional theory (TD-DFT) can qualitatively describe DASAs' excited states, multiconfigurational quantum chemistry methods along with dynamic electron correlation (CASPT2, NEVPT2) are required for a quantitative agreement with the experiment. This finding is reasoned based on the different charge transfer characteristics observed. Moreover, the TD-DFT computed two-photon absorption properties are reported and suggested to red-shift the absorption band, as required for biological applications. PMID- 28869517 TI - Eco-Friendly and Biodegradable Biopolymer Chitosan/Y2O3 Composite Materials in Flexible Organic Thin-Film Transistors. AB - The waste from semiconductor manufacturing processes causes serious pollution to the environment. In this work, a non-toxic material was developed under room temperature conditions for the fabrication of green electronics. Flexible organic thin-film transistors (OTFTs) on plastic substrates are increasingly in demand due to their high visible transmission and small size for use as displays and wearable devices. This work investigates and analyzes the structured formation of aqueous solutions of the non-toxic and biodegradable biopolymer, chitosan, blended with high-k-value, non-toxic, and biocompatible Y2O3 nanoparticles. Chitosan thin films blended with Y2O3 nanoparticles were adopted as the gate dielectric thin film in OTFTs, and an improvement in the dielectric properties and pinholes was observed. Meanwhile, the on/off current ratio was increased by 100 times, and a low leakage current was observed. In general, the blended chitosan/Y2O3 thin films used as the gate dielectric of OTFTs are non-toxic, environmentally friendly, and operate at low voltages. These OTFTs can be used on surfaces with different curvature radii because of their flexibility. PMID- 28869513 TI - Gene Drive for Mosquito Control: Where Did It Come from and Where Are We Headed? AB - Mosquito-borne pathogens place an enormous burden on human health. The existing toolkit is insufficient to support ongoing vector-control efforts towards meeting disease elimination and eradication goals. The perspective that genetic approaches can potentially add a significant set of tools toward mosquito control is not new, but the recent improvements in site-specific gene editing with CRISPR/Cas9 systems have enhanced our ability to both study mosquito biology using reverse genetics and produce genetics-based tools. Cas9-mediated gene editing is an efficient and adaptable platform for gene drive strategies, which have advantages over innundative release strategies for introgressing desirable suppression and pathogen-blocking genotypes into wild mosquito populations; until recently, an effective gene drive has been largely out of reach. Many considerations will inform the effective use of new genetic tools, including gene drives. Here we review the lengthy history of genetic advances in mosquito biology and discuss both the impact of efficient site-specific gene editing on vector biology and the resulting potential to deploy new genetic tools for the abatement of mosquito-borne disease. PMID- 28869518 TI - Combining Theory-Driven Evaluation and Causal Loop Diagramming for Opening the 'Black Box' of an Intervention in the Health Sector: A Case of Performance-Based Financing in Western Uganda. AB - Increased attention on "complexity" in health systems evaluation has resulted in many different methodological responses. Theory-driven evaluations and systems thinking are two such responses that aim for better understanding of the mechanisms underlying given outcomes. Here, we studied the implementation of a performance-based financing intervention by the Belgian Technical Cooperation in Western Uganda to illustrate a methodological strategy of combining these two approaches. We utilized a systems dynamics tool called causal loop diagramming (CLD) to generate hypotheses feeding into a theory-driven evaluation. Semi structured interviews were conducted with 30 health workers from two districts (Kasese and Kyenjojo) and with 16 key informants. After CLD, we identified three relevant hypotheses: "success to the successful", "growth and underinvestment", and "supervision conundrum". The first hypothesis leads to increasing improvements in performance, as better performance leads to more incentives, which in turn leads to better performance. The latter two hypotheses point to potential bottlenecks. Thus, the proposed methodological strategy was a useful tool for identifying hypotheses that can inform a theory-driven evaluation. The hypotheses are represented in a comprehensible way while highlighting the underlying assumptions, and are more easily falsifiable than hypotheses identified without using CLD. PMID- 28869520 TI - Multi-Scale Low-Entropy Method for Optimizing the Processing Parameters during Automated Fiber Placement. AB - Automated fiber placement (AFP) process includes a variety of energy forms and multi-scale effects. This contribution proposes a novel multi-scale low-entropy method aiming at optimizing processing parameters in an AFP process, where multi scale effect, energy consumption, energy utilization efficiency and mechanical properties of micro-system could be taken into account synthetically. Taking a carbon fiber/epoxy prepreg as an example, mechanical properties of macro-meso scale are obtained by Finite Element Method (FEM). A multi-scale energy transfer model is then established to input the macroscopic results into the microscopic system as its boundary condition, which can communicate with different scales. Furthermore, microscopic characteristics, mainly micro-scale adsorption energy, diffusion coefficient entropy-enthalpy values, are calculated under different processing parameters based on molecular dynamics method. Low-entropy region is then obtained in terms of the interrelation among entropy-enthalpy values, microscopic mechanical properties (interface adsorbability and matrix fluidity) and processing parameters to guarantee better fluidity, stronger adsorption, lower energy consumption and higher energy quality collaboratively. Finally, nine groups of experiments are carried out to verify the validity of the simulation results. The results show that the low-entropy optimization method can reduce void content effectively, and further improve the mechanical properties of laminates. PMID- 28869521 TI - A New Metre for Cheap, Quick, Reliable and Simple Thermal Transmittance (U-Value) Measurements in Buildings. AB - This paper deals with the thermal transmittance measurement focused on buildings and specifically in building energy retrofitting. Today, if many thermal transmittance measurements in a short time are needed, the current devices, based on the measurement of the heat flow through the wall, cannot carry out them, except if a great amount of devices are used at once along with intensive and tedious post-processing and analysis work. In this paper, from well-known physical laws, authors develop a methodology based on three temperatures measurements, which is implemented by a novel thermal transmittance metre. The paper shows its development step by step. As a result the developed device is modular, scalable, and fully wireless; it is capable of taking as many measurements at once as user needs. The developed system is compared working together on a same test to the currently used one based on heat flow. The results show that the developed metre allows carrying out thermal transmittance measurements in buildings in a cheap, quick, reliable and simple way. PMID- 28869519 TI - Differences in Sulfotyrosine Binding amongst CXCR1 and CXCR2 Chemokine Ligands. AB - Tyrosine sulfation, a post-translational modification found on many chemokine receptors, typically increases receptor affinity for the chemokine ligand. A previous bioinformatics analysis suggested that a sulfotyrosine (sY)-binding site on the surface of the chemokine CXCL12 may be conserved throughout the chemokine family. However, the extent to which receptor tyrosine sulfation contributes to chemokine binding has been examined in only a few instances. Computational solvent mapping correctly identified the conserved sulfotyrosine-binding sites on CXCL12 and CCL21 detected by nuclear magnetic resonance (NMR) spectroscopy, demonstrating its utility for hot spot analysis in the chemokine family. In this study, we analyzed five chemokines that bind to CXCR2, a subset of which also bind to CXCR1, to identify hot spots that could participate in receptor binding. A cleft containing the predicted sulfotyrosine-binding pocket was identified as a principal hot spot for ligand binding on the structures of CXCL1, CXCL2, CXCL7, and CXCL8, but not CXCL5. Sulfotyrosine titrations monitored via NMR spectroscopy showed specific binding to CXCL8, but not to CXCL5, which is consistent with the predictions from the computational solvent mapping. The lack of CXCL5 sulfotyrosine interaction and the presence of CXCL8-sulfotyrosine binding suggests a role for receptor post-translational modifications regulating ligand selectivity. PMID- 28869522 TI - Recombinant Botulinum Neurotoxin Hc Subunit (BoNT Hc) and Catalytically Inactive Clostridium botulinum Holoproteins (ciBoNT HPs) as Vaccine Candidates for the Prevention of Botulism. AB - There are few available medical countermeasures against botulism and the discontinuation of the pentavalent botulinum toxoid vaccine by the Centers for Disease Control and Prevention in 2011 has resulted in the need for a safe and effective prophylactic alternative. Advances in genetic engineering have resulted in subsequent vaccine efforts being primarily focused on the production of highly purified recombinant protein antigens representing one or more domains of the botulinum neurotoxin. Recombinant subunit vaccines based on the carboxy one-third of the toxin (Hc) developed in our lab against serotypes A-F have been shown to be safe and effective. However, in response to the identification of an ever increasing number of BoNT subtypes with significant amino acid heterogeneity, we have developed catalytically inactive BoNT holoproteins (ciBoNT HPs) in an attempt to elicit greater protective immunity to address these toxin variants. Here we report the production of ciBoNT/B1 HP, ciBoNT/C1 HP, ciBoNT/E1 HP and ciBoNT/F1 HP and compare the immunological and protective abilities of ciBoNT HPs and BoNT/A Hc, BoNT/B Hc, BoNT/C Hc, BoNT/E Hc and BoNT/F Hc vaccines when challenged with homologous and heterologous toxins. Our results suggest the ciBoNT HP vaccines exhibit superior potency after single vaccinations but multiple vaccinations with BoNT/Hc antigens resulted in increased survival rates at the toxin challenge levels used. PMID- 28869523 TI - An Optimum Specimen Geometry for Equibiaxial Experimental Tests of Reinforced Magnetorheological Elastomers with Iron Micro- and Nanoparticles. AB - The aim of this paper focused on obtaining the optimum cruciform geometry of reinforced magnetorheological elastomers (MRE) to perform homogeneous equibiaxial deformation tests, by using optimization algorithms and Finite Element Method (FEM) simulations. To validate the proposed specimen geometry, a digital image correlation (DIC) system was used to compare experimental result measurements with respect to those of FEM simulations. Moreover, and based on the optimum cruciform geometry, specimens produced from MRE reinforced with carbonyl-iron microparticles or iron nanoparticles were subjected to equibiaxial loading and unloading cycles to examine their Mullin's effect and their residual strain deformations. PMID- 28869524 TI - HPV16 E6 and E7 Upregulate Interferon-Induced Antiviral Response Genes ISG15 and IFIT1 in Human Trophoblast Cells. AB - Human papillomavirus (HPV) is suggested to infect trophoblasts in the placenta, and HPV infections are reported to be more prevalent in pregnancies with adverse outcomes. Results are however controversial, and studies investigating the molecular consequences of placental HPV infections are lacking. We studied HPV DNA localization in the placenta in cases of spontaneous abortion/spontaneous preterm delivery as well as in elective abortion/normal full-term delivery. Using in vitro assays, we investigated downstream effects of HPV16 E6 and E7 expression in trophoblast cells at the gene expression level in order to gain increased biological insight into the interaction between HPV and the cellular host. Fluorescent in situ hybridization (FISH), combined with fluorescent immunohistochemistry (FIHC) to target the trophoblast marker CK7 clearly showed, that HPV DNA resides within syncytiotrophoblast cells in the placenta. In vitro HPV16 E6 and E7-transfected trophoblasts were analyzed by RNA sequencing, and results were validated by reverse transcription real time polymerase chain reaction (RT-qPCR) for selected genes in cell lines, as well as in patient material. We show that HPV16 E6 and E7 upregulate interferon-induced antiviral response genes ISG15 and IFIT1 in a human trophoblast cell line two-days post transfection. This is a response that is not observed when assessing the gene expression levels of the same genes in HPV16-positive placenta samples. Investigations on viral activity find that HPV16 E6 and E7 are not transcribed in patients, possibly suggesting that HPV16 syncytiotrophoblast infection may be latent. We conclude that HPV localizes to syncytiotrophoblast cells of the placenta, and that active expression of HPV16 E6 and E7 induce an immediate interferon-induced antiviral response in trophoblast cells, which is not present in HPV-positive placenta samples, suggesting latent infection. PMID- 28869525 TI - Persimmon Fruit Powder May Substitute Indolbi, a Synthetic Growth Regulator, in Soybean Sprout Cultivation. AB - Soybean sprouts are a major food item in Korea. Various studies have been carried out to enhance their yield and nutritional values. The objective of the present study was to examine the influence of persimmon fruit powder and Indolbi, a synthetic plant growth regulator, on the yield and nutritional value of soybean sprouts. Seeds were soaked in tap water containing 0.5%, 1.0%, 2.5% and 5.0% (w/v) persimmon fruit powder and the samples were named as PT-1, PT-2, PT-3, and PT-4, respectively. The yield increment was almost doubled in PT-3 and PT-4 than in the Indolbi treated sprouts on basis of the control. Vitamin C, isoflavones, and total phenolic contents as well as antioxidant potentials (determined by 1,1 diphenyl-2-picrylhydrazyl and superoxide anion radical scavenging assays) were also significantly (p < 0.05) higher in PT-3 compared to the Indolbi treatment and the control. However, total free amino acid and magnesium contents of Indolbi applied sprouts were higher than in the fruit powder treatments. The overall results of the present study showed that persimmon fruit powder can be an option to enhance the yield and nutritional value of soybean sprouts since, due to potential health hazards, the use of synthetic chemicals like Indolbi is less preferred than the natural products. PMID- 28869526 TI - Modulation of Immunogenicity and Conformation of HA1 Subunit of Influenza A Virus H1/N1 Hemagglutinin in Tubular Immunostimulating Complexes. AB - The HA1 subunit of the influenza virus hemagglutinin (HA) is a valuable antigen for the development of vaccines against flu due to the availability of most antigenic sites which are conformational. Therefore, a novel adjuvanted antigen delivery system, tubular immunostimulating complexes (TI-complexes) comprising monogalactosyldiacylglycerol (MGDG) from different marine macrophytes as a lipid matrix for an antigen, was applied to enhance the immunogenicity of recombinant HA1 of influenza A H1N1 and to study the relation between its immunogenicity and conformation. The content of anti-HA1 antibodies and cytokines was estimated by ELISA after the immunization of mice with HA1 alone, and HA1 was incorporated in TI-complexes based on different MGDGs isolated from green algae Ulva lactuca, brown algae Sargassum pallidum, and seagrass Zostera marina. Conformational changes of HA1 were estimated by differential scanning calorimetry and intrinsic fluorescence. It was shown that the adjuvant activity of TI-complexes depends on the microviscosity of MGDGs, which differently influence the conformation of HA1. The highest production of anti-HA1 antibodies (compared with the control) was induced by HA1 incorporated in a TI-complex based on MGDG from S. pallidum, which provided the relaxation of the spatial structure and, likely, the proper presentation of the antigen to immunocompetent cells. PMID- 28869527 TI - Fine-Scale Spatial Variability of Pedestrian-Level Particulate Matters in Compact Urban Commercial Districts in Hong Kong. AB - Particulate matters (PM) at the pedestrian level significantly raises the health impacts in the compact urban environment of Hong Kong. A detailed investigation of the fine-scale spatial variation of pedestrian-level PM is necessary to assess the health risk to pedestrians in the outdoor environment. However, the collection of PM data is difficult in the compact urban environment of Hong Kong due to the limited amount of roadside monitoring stations and the complicated urban context. In this study, we measured the fine-scale spatial variability of the PM in three of the most representative commercial districts of Hong Kong using a backpack outdoor environmental measuring unit. Based on the measurement data, 13 types of geospatial interpolation methods were examined for the spatial mapping of PM2.5 and PM10 with a group of building geometrical covariates. Geostatistical modelling was adopted as the basis of spatial interpolation of the PM. The results show that the original cokriging with the exponential kernel function provides the best performance in the PM mapping. Using the fine-scale building geometrical features as covariates slightly improves the interpolation performance. The study results also imply that the fine-scale, localized pollution emission sources heavily influence pedestrian exposure to PM. PMID- 28869528 TI - The Spread of Helicoverpa armigera (Lepidoptera: Noctuidae) and Coexistence with Helicoverpa zea in Southeastern Brazil. AB - Helicoverpa armigera, one of the world's most destructive crop pests, was first documented in Brazil in 2013. Within a few months, this polyphagous insect had spread over the Northeast and Central-West of Brazil, causing great agricultural losses. With several reports of populations resistant to pesticides and Bt crops around the world, there is great concern about the spread of this pest in Brazil. There is confusion about the actual distribution of this species due to the high morphological similarity with the native corn earworm Helicoverpa zea, which may also coexist with H. armigera in the field. Our aims here were (i) to confirm its presence in the State of Minas Gerais, one of the most important agricultural regions in the country; and (ii) to assess the co-occurrence of this pest with the congeneric corn earworm H. zea. Using molecular screening, we confirmed the presence of H. armigera in Bt-crops of soybean and cotton, and non-Bt-crops of soybean, cotton and maize. Mixed infestations of H. armigera with H. zea were found in non-Bt maize (Vicosa, Southeastern Minas Gerais). These results highlight the need for adequate control strategies for H. armigera in Brazil, to deal with its polyphagous feeding habits, high dispersal capacity and possible risks of hybridization with congeneric species. PMID- 28869530 TI - Unexplained Dyspnea in a Young Adult with Epstein-Barr Virus Infectious Mononucleosis: Pulmonary Involvement or Co-Infection with Mycoplasma pneumoniae Pneumonia? AB - Clinically, in young immunocompetent adults, Epstein-Barr virus (EBV) usually manifests as infectious mononucleosis (IM). Typical clinical findings of EBV IM include fever, profound fatigue, pharyngitis, bilateral posterior cervical adenopathy, and splenomegaly. Respiratory involvement with EBV IM may occur, but is distinctly rare. We present a case of a 20 year old female who with classic EBV IM, but was inexplicably dyspneic and hypoxemic. Further diagnostic testing confirmed co-infection with Mycoplasma pneumoniae. As a non-zoonotic atypical community-acquired pneumonia (CAP), M. pneumoniae may rarely be accompanied by severe hypoxemia and even acute respiratory distress syndrome. She represented a diagnostic dilemma regarding the cause of her hypoxemia, i.e., due to EBV IM with pulmonary involvement or severe M. pneumoniae CAP. The patient slowly recovered with respiratory quinolone therapy. PMID- 28869529 TI - Different Covalent Immobilizations Modulate Lipase Activities of Hypocrea pseudokoningii. AB - Enzyme immobilization can promote several advantages for their industrial application. In this work, a lipase from Hypocrea pseudokoningii was efficiently linked to four chemical supports: agarose activated with cyanogen bromide (CNBr), glyoxyl-agarose (GX), MANAE-agarose activated with glutaraldehyde (GA) and GA crosslinked with glutaraldehyde. Results showed a more stable lipase with both the GA-crosslinked and GA derivatives, compared to the control (CNBr), at 50 degrees C, 60 degrees C and 70 degrees C. Moreover, all derivatives were stabilized when incubated with organic solvents at 50%, such as ethanol, methanol, n-propanol and cyclohexane. Furthermore, lipase was highly activated (4 fold) in the presence of cyclohexane. GA-crosslinked and GA derivatives were more stable than the CNBr one in the presence of organic solvents. All derivatives were able to hydrolyze sardine, acai (Euterpe oleracea), cotton seed and grape seed oils. However, during the hydrolysis of sardine oil, GX derivative showed to be 2.3-fold more selectivity (eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) ratio) than the control. Additionally, the types of immobilization interfered with the lipase enantiomeric preference. Unlike the control, the other three derivatives preferably hydrolyzed the R-isomer of 2-hydroxy-4 phenylbutanoic acid ethyl ester and the S-isomer of 1-phenylethanol acetate racemic mixtures. On the other hand, GX and CNBr derivatives preferably hydrolyzed the S-isomer of butyryl-2-phenylacetic acid racemic mixture while the GA and GA-crosslink derivatives preferably hydrolyzed the R-isomer. However, all derivatives, including the control, preferably hydrolyzed the methyl mandelate S isomer. Moreover, the derivatives could be used for eight consecutive cycles retaining more than 50% of their residual activity. This work shows the importance of immobilization as a tool to increase the lipase stability to temperature and organic solvents, thus enabling the possibility of their application at large scale processes. PMID- 28869531 TI - Potential Application of Eicosapentaenoic Acid Monoacylglyceride in the Management of Colorectal Cancer. AB - BACKGROUND: There is increasing evidence that marine omega-3 oils are involved in the reduction of cancer risk and progression. However, the anticancer effect of omega-3 monoglyceride on colorectal cancer has yet to be assessed. The goal of this study was to evaluate the anti-cancer effects of eicosapentaenoic acid monoglyceride (MAG-EPA) in HCT116 colorectal carcinoma cells. METHODS: The effect of MAG-EPA was evaluated in vitro on HCT116 cells and in vivo on mouse model of HCT116 xenograft. RESULTS: Our data reveal that MAG-EPA decreased cell proliferation and induced apoptosis in HCT116 cells. In a xenograft mouse model, daily per os administration of MAG-EPA reduced tumor growth. Furthermore, MAG-EPA treatments decreased EGFR, VEGFR, and AKT activation pathways and reduced VEGF and HIF1alpha expression levels in tumors. CONCLUSION: MAG-EPA may promote apoptosis and inhibit growth of tumors by suppressing EGFR and VEGFR activation pathways. Altogether, these data provide new evidence regarding the mode of action of MAG-EPA in colorectal cancer cells. PMID- 28869532 TI - CFTR-NHERF2-LPA2 Complex in the Airway and Gut Epithelia. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP- and cGMP-regulated chloride (Cl-) and bicarbonate (HCO3-) channel localized primarily at the apical plasma membrane of epithelial cells lining the airway, gut and exocrine glands, where it is responsible for transepithelial salt and water transport. Several human diseases are associated with altered CFTR channel function. Cystic fibrosis (CF) is caused by the absence or dysfunction of CFTR channel activity, resulting from mutations in the gene. Secretory diarrhea is caused by the hyperactivation of CFTR channel activity in the gastrointestinal tract. CFTR is a validated target for drug development to treat CF, and extensive research has been conducted to develop CFTR inhibitors for therapeutic interventions of secretory diarrhea. The intracellular processing, trafficking, apical membrane localization, and channel function of CFTR are regulated by dynamic protein-protein interactions in a complex network. In this paper, we review the current knowledge of a macromolecular complex of CFTR, Na+/H+ exchanger regulatory factor 2 (NHERF2), and lysophosphatidic acids (LPA) receptor 2 (LPA2) at the apical plasma membrane of airway and gut epithelial cells, and discuss its relevance in human physiology and diseases. We also explore the possibilities of targeting this complex to fine tune CFTR channel activity, with a hope to open up new avenues to develop novel therapies for CF and secretory diarrhea. PMID- 28869533 TI - Construction of a Fluorescent H2O2 Biosensor with Chitosan 6-OH Immobilized beta Cyclodextrin Derivatives. AB - In the present work, a fluorescent H2O2 biosensor was constructed by encapsulating fluorescent probe Rhodamine B (RhmB) in the hydrophobic cavity of the cyclodextrin (beta-CD) and immobilizing catalase (CAT) on the 2-NH2 of chitosan (CTS) in a chitosan 6-OH immobilized beta-cyclodextrin derivative (CTS-6 CD). The inclusion complex of CTS-6-CD to RhmB (CTS-6-CD-RhmB) was prepared by a solution method. Its structure and inclusion efficiency were determined by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and fluorescence spectroscopy (FL). CAT was immobilized on CTS-6-CD-RhmB to eventually form the functional membrane, CTS-6-CD-RhmB-CAT, via glutaraldehyde crosslinking, which was further characterized by FTIR and FL, and used as a H2O2 biosensor. The functional membrane was used to simultaneously oxidize and detect H2O2. The detection condition was optimized as pH 8, a reaction temperature of 25 degrees C, and an immobilized enzyme concentration of 2 * 10-4 mol/L. The fluorescence response of the biosensor exhibited a good linear relationship with the concentration of H2O2 in the range of 20 mMU-300 MUM and the detection limit of 10-8 mol/L. PMID- 28869534 TI - Tongue Sole CD209: A Pattern-Recognition Receptor that Binds a Broad Range of Microbes and Promotes Phagocytosis. AB - CD209 is an immune receptor that plays an important role in the initiation of innate immunity and activation of adaptive immunity in mammals. However, much less is known about the immunological function of CD209 in lower vertebrates. In the present study, we examined the immune effect of a CD209 homologue (CsCD209) from the teleost fish tongue sole Cynoglossus semilaevis. CsCD209 possesses a lectin domain that shares high levels of similarity with the lectin domains of human and mouse CD209. CsCD209 expression was most abundant in kidney and blood and was significantly upregulated during bacterial infection. CsCD209 exhibited a subcellular localization mainly on the cell surface of myelomonocytes. Recombinant CsCD209 displayed apparent binding capacities to a broad range of bacteria and fungi, and significantly promoted the phagocytosis of the bound bacteria by C. semilaevis leukocytes. Collectively, the results indicate that teleost CD209 serves as a pattern recognition receptor that exerts an influence on the phagocytosis process during pathogen infections. PMID- 28869536 TI - Video Synchronization With Bit-Rate Signals and Correntropy Function. AB - We propose an approach for the synchronization of video streams using correntropy. Essentially, the time offset is calculated on the basis of the instantaneous transfer rates of the video streams that are extracted in the form of a univariate signal known as variable bit-rate (VBR). The state-of-the-art approach uses a window segmentation strategy that is based on consensual zero mean normalized cross-correlation (ZNCC). This strategy has an elevated computational complexity, making its application to synchronizing online data streaming difficult. Hence, our proposal uses a different window strategy that, together with the correntropy function, allows the synchronization to be performed for online applications. This provides equivalent synchronization scores with a rapid offset determination as the streams come into the system. The efficiency of our approach has been verified through experiments that demonstrate its viability with values that are as precise as those obtained by ZNCC. The proposed approach scored 81 % in time reference classification against the equivalent 81 % of the state-of-the-art approach, requiring much less computational power. PMID- 28869535 TI - Mitochondrial-Targeted Antioxidant Maintains Blood Flow, Mitochondrial Function, and Redox Balance in Old Mice Following Prolonged Limb Ischemia. AB - Aging is a major factor in the decline of limb blood flow with ischemia. However, the underlying mechanism remains unclear. We investigated the role of mitochondrial reactive oxygen species (ROS) with regard to limb perfusion recovery in aging during ischemia. We performed femoral artery ligation in young and old mice with or without treatment with a scavenger of mitochondrial superoxide, MitoTEMPO (180 MUg/kg/day, from pre-operative day 7 to post-operative day (POD) 21) infusion using an implanted mini-pump. The recoveries of cutaneous blood flow in the ischemic hind limb were lower in old mice than in young mice but were improved in MitoTEMPO-treated old mice. Mitochondrial DNA damage appeared in ischemic aged muscles but was eliminated by MitoTEMPO treatment. For POD 2, MitoTEMPO treatment suppressed the expression of p53 and the ratio of Bax/Bcl2 and upregulated the expression of hypoxia-inducible factor-1alpha (HIF 1alpha) and vascular endothelial growth factor (VEGF) in ischemic aged skeletal muscles. For POD 21, MitoTEMPO treatment preserved the expression of PGC-1alpha in ischemic aged skeletal muscle. The ischemic soleus of old mice showed a lower mitochondrial respiratory control ratio in POD 21 compared to young mice, which was recovered in MitoTEMPO-treated old mice. Scavenging of mitochondrial superoxide attenuated mitochondrial DNA damage and preserved the mitochondrial respiration, in addition to suppression of the expression of p53 and preservation of the expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) in ischemic skeletal muscles with aging. Resolution of excessive mitochondrial superoxide could be an effective therapy to recover blood flow of skeletal muscle during ischemia in senescence. PMID- 28869537 TI - An Adaptive Classification Strategy for Reliable Locomotion Mode Recognition. AB - Algorithms for locomotion mode recognition (LMR) based on surface electromyography and mechanical sensors have recently been developed and could be used for the neural control of powered prosthetic legs. However, the variations in input signals, caused by physical changes at the sensor interface and human physiological changes, may threaten the reliability of these algorithms. This study aimed to investigate the effectiveness of applying adaptive pattern classifiers for LMR. Three adaptive classifiers, i.e., entropy-based adaptation (EBA), LearnIng From Testing data (LIFT), and Transductive Support Vector Machine (TSVM), were compared and offline evaluated using data collected from two able bodied subjects and one transfemoral amputee. The offline analysis indicated that the adaptive classifier could effectively maintain or restore the performance of the LMR algorithm when gradual signal variations occurred. EBA and LIFT were recommended because of their better performance and higher computational efficiency. Finally, the EBA was implemented for real-time human-in-the-loop prosthesis control. The online evaluation showed that the applied EBA effectively adapted to changes in input signals across sessions and yielded more reliable prosthesis control over time, compared with the LMR without adaptation. The developed novel adaptive strategy may further enhance the reliability of neurally controlled prosthetic legs. PMID- 28869538 TI - Experimental and Numerical Investigations on the Mechanical Characteristics of Carbon Fiber Sensors. AB - Carbon fiber-based materials possess excellent mechanical properties and show linear piezoresistive behavior, which make them good candidate materials for strain measurements. They have the potential to be used as sensors for various applications such as damage detection, stress analysis and monitoring of manufacturing processes and quality. In this paper, carbon fiber sensors are prepared to perform reliable strain measurements. Both experimental and computational studies were carried out on commercially available carbon fibers in order to understand the response of the carbon fiber sensors due to changes in the axial strain. Effects of parameters such as diameter, length, and epoxy hardener ratio are discussed. The developed numerical model was calibrated using laboratory-based experimental data. The results of the current study show that sensors with shorter lengths have relatively better sensitivity. This is due to the fact short fibers have low initial resistance, which will increase the change of resistance over initial resistance. Carbon fibers with low number of filaments exhibit linear behavior while nonlinear behavior due to transverse resistance is significant in fibers with large number of filaments. This study will allow researchers to predict the behavior of the carbon fiber sensor in real life and it will serve as a basis for designing carbon fiber sensors to be used in different applications. PMID- 28869540 TI - Secure Communications in CIoT Networks with a Wireless Energy Harvesting Untrusted Relay. AB - The Internet of Things (IoT) represents a bright prospect that a variety of common appliances can connect to one another, as well as with the rest of the Internet, to vastly improve our lives. Unique communication and security challenges have been brought out by the limited hardware, low-complexity, and severe energy constraints of IoT devices. In addition, a severe spectrum scarcity problem has also been stimulated by the use of a large number of IoT devices. In this paper, cognitive IoT (CIoT) is considered where an IoT network works as the secondary system using underlay spectrum sharing. A wireless energy harvesting (EH) node is used as a relay to improve the coverage of an IoT device. However, the relay could be a potential eavesdropper to intercept the IoT device's messages. This paper considers the problem of secure communication between the IoT device (e.g., sensor) and a destination (e.g., controller) via the wireless EH untrusted relay. Since the destination can be equipped with adequate energy supply, secure schemes based on destination-aided jamming are proposed based on power splitting (PS) and time splitting (TS) policies, called intuitive secure schemes based on PS (Int-PS), precoded secure scheme based on PS (Pre-PS), intuitive secure scheme based on TS (Int-TS) and precoded secure scheme based on TS (Pre-TS), respectively. The secure performances of the proposed schemes are evaluated through the metric of probability of successfully secure transmission ( P S S T ), which represents the probability that the interference constraint of the primary user is satisfied and the secrecy rate is positive. P S S T is analyzed for the proposed secure schemes, and the closed form expressions of P S S T for Pre-PS and Pre-TS are derived and validated through simulation results. Numerical results show that the precoded secure schemes have better P S S T than the intuitive secure schemes under similar power consumption. When the secure schemes based on PS and TS polices have similar P S S T , the average transmit power consumption of the secure scheme based on TS is lower. The influences of power splitting and time slitting ratios are also discussed through simulations. PMID- 28869539 TI - A Robust Deep-Learning-Based Detector for Real-Time Tomato Plant Diseases and Pests Recognition. AB - Plant Diseases and Pests are a major challenge in the agriculture sector. An accurate and a faster detection of diseases and pests in plants could help to develop an early treatment technique while substantially reducing economic losses. Recent developments in Deep Neural Networks have allowed researchers to drastically improve the accuracy of object detection and recognition systems. In this paper, we present a deep-learning-based approach to detect diseases and pests in tomato plants using images captured in-place by camera devices with various resolutions. Our goal is to find the more suitable deep-learning architecture for our task. Therefore, we consider three main families of detectors: Faster Region-based Convolutional Neural Network (Faster R-CNN), Region-based Fully Convolutional Network (R-FCN), and Single Shot Multibox Detector (SSD), which for the purpose of this work are called "deep learning meta architectures". We combine each of these meta-architectures with "deep feature extractors" such as VGG net and Residual Network (ResNet). We demonstrate the performance of deep meta-architectures and feature extractors, and additionally propose a method for local and global class annotation and data augmentation to increase the accuracy and reduce the number of false positives during training. We train and test our systems end-to-end on our large Tomato Diseases and Pests Dataset, which contains challenging images with diseases and pests, including several inter- and extra-class variations, such as infection status and location in the plant. Experimental results show that our proposed system can effectively recognize nine different types of diseases and pests, with the ability to deal with complex scenarios from a plant's surrounding area. PMID- 28869542 TI - Paint it Black: Using Change-Point Analysis to Investigate Increasing Vulnerability to Depression towards the End of Vincent van Gogh's Life. AB - This study investigated whether Vincent van Gogh became increasingly self-focused and thus vulnerable to depression-towards the end of his life, through a quantitative analysis of his written pronoun use over time. A change-point analysis was conducted on the time series formed by the pronoun use in Van Gogh's letters. We used time as a predictor to see whether there was evidence for increased self-focus towards the end of Van Gogh's life, and we compared this to the pattern in the letters written before his move to Arles. Specifically, we examined Van Gogh's use of first person singular pronouns (FPSP) and first person plural pronouns (FPPP) in the 415 letters he wrote while working as an artist before his move to Arles, and in the next 248 letters he wrote after his move to Arles until his death in Auvers-sur-Oise. During the latter period, Van Gogh's use of FPSP showed an annual increase of 0.68% (SE = 0.15, p < 0.001) and his use of FPPP showed an annual decrease of 0.23% (SE = 0.04, p < 0.001), indicating increasing self-focus and vulnerability to depression. This trend differed from Van Gogh's pronoun use in the former period (which showed no significant trend in FPSP, and an annual increase of FPPP of 0.03%, SE = 0.02, p = 0.04). This study suggests that Van Gogh's death was preceded by a gradually increasing self-focus and vulnerability to depression. It also illustrates how existing methods (i.e., quantitative linguistic analysis and change-point analysis) can be combined to study specific research questions in innovative ways. PMID- 28869541 TI - Spread of Tst-Positive Staphylococcus aureus Strains Belonging to ST30 Clone among Patients and Healthcare Workers in Two Intensive Care Units. AB - Staphylococcus aureus is a major cause of infections. Toxic shock syndrome toxin (TSST-1) and Panton-Valentine leukocidin (PVL) are associated with severe clinical syndromes. S. aureus colonizing isolates recovered from healthcare workers and patients in the intensive care unit (ICU) of a university hospital comprising Group A were compared with those from adult non-ICU carriers (Group B). mecA, lukS/lukF-PV (Panton-Valentine leukocidin, PVL), and tst (toxic shock syndrome toxin) gene carriage was detected by PCR. Clones were identified in all methicillin-resistant S. aureus (MRSA) and toxin-positive methicillin-susceptible strains (MSSA) by pulsed-field gel electrophoresis (PFGE), agr groups, and multi locus sequencing typing (MLST). Group A included 90 S. aureus isolates, whereas Group B 53. PVL was more frequently found among MRSA vs. MSSA (p < 0.001) and in strains of Group B as compared to Group A (p < 0.001), consistent with the spread of ST80-IV. Higher incidence of tst gene carriage was identified among MSSA vs. MRSA (P 0.005) belonging mainly to ST30, and Group A vs. Group B (P 0.002). The wide dissemination of ST80-IV mainly in the community is responsible for a high percentage of PVL-positive MRSA, while silent spread of tst-positive S. aureus clones among ICU patients and personnel poses a threat of hospital transmission and possible severe infections. PMID- 28869543 TI - Nitrogen-Doped Carbon Nanoparticles for Oxygen Reduction Prepared via a Crushing Method Involving a High Shear Mixer. AB - The disposal of agricultural wastes such as fresh banana peels (BPs) is an environmental issue. In this work, fresh BPs were successfully transformed into nitrogen-doped carbon nanoparticles (N-CNPs) by using a high shear mixer facilitated crushing method (HSM-FCM) followed by carbonization under Ar atmosphere. Ammonia-activated N-CNPs (N-CNPs-NH3) were prepared via subsequent ammonia activation treatments at a high temperature. The as-prepared N-CNPs and N CNPs-NH3 materials both exhibited high surface areas (above 700 m2/g) and mean particle size of 50 nm. N-CNPs-NH3 showed a relatively higher content of pyridinic and graphitic N compared to N-CNPs. In alkaline media, N-CNPs-NH3 showed superior performances as an oxygen reduction reaction (ORR) catalyst (E0 = -0.033 V, J = 2.4 mA/cm2) compared to N-CNPs (E0 = 0.07 V, J = 1.8 mA/cm2). In addition, N-CNPs-NH3 showed greater oxygen reduction stability and superior methanol crossover avoidance than a conventional Pt/C catalyst. This study provides a novel, simple, and scalable approach to valorize biomass wastes by synthesizing highly efficient electrochemical ORR catalysts. PMID- 28869545 TI - Hollow Au-Ag Alloy Nanorices and Their Optical Properties. AB - Hollow noble metal nanoparticles have excellent performance not only in surface catalysis but also in optics. In this work, the hollow Au-Ag alloy nanorices are fabricated by the galvanic replacement reaction. The dark-field spectrum points out that there is a big difference in the optical properties between the pure Ag nanorices and the hollow alloy nanorices that exhibit highly tunable localized surface plasmon resonances (LSPR) and that possess larger radiative damping, which is also indicated by the finite element method. Furthermore, the surface enhanced Raman scattering (SERS) and oxidation test indicate that hollow Au-Ag alloy nanorices show good anti-oxidation and have broad application prospects in surface-plasmon-related fields. PMID- 28869544 TI - Potential Roles of Intrinsic Disorder in Maternal-Effect Proteins Involved in the Maintenance of DNA Methylation. AB - DNA methylation is an important epigenetic modification that needs to be carefully controlled as a prerequisite for normal early embryogenesis. Compelling evidence now suggests that four maternal-effect proteins, primordial germ cell 7 (PGC7), zinc finger protein 57 (ZFP57), tripartite motif-containing 28 (TRIM28) and DNA methyltransferase (cytosine-5) 1 (DNMT1) are involved in the maintenance of DNA methylation. However, it is still not fully understood how these maternal effect proteins maintain the DNA methylation imprint. We noticed that a feature common to these proteins is the presence of significant levels of intrinsic disorder so in this study we started from an intrinsic disorder perspective to try to understand these maternal-effect proteins. To do this, we firstly analysed the intrinsic disorder predispositions of PGC7, ZFP57, TRIM28 and DNMT1 by using a set of currently available computational tools and secondly conducted an intensive literature search to collect information on their interacting partners and structural characterization. Finally, we discuss the potential effect of intrinsic disorder on the function of these proteins in maintaining DNA methylation. PMID- 28869546 TI - Energy-Efficient Optimal Power Allocation in Integrated Wireless Sensor and Cognitive Satellite Terrestrial Networks. AB - This paper proposes novel satellite-based wireless sensor networks (WSNs), which integrate the WSN with the cognitive satellite terrestrial network. Having the ability to provide seamless network access and alleviate the spectrum scarcity, cognitive satellite terrestrial networks are considered as a promising candidate for future wireless networks with emerging requirements of ubiquitous broadband applications and increasing demand for spectral resources. With the emerging environmental and energy cost concerns in communication systems, explicit concerns on energy efficient resource allocation in satellite networks have also recently received considerable attention. In this regard, this paper proposes energy-efficient optimal power allocation schemes in the cognitive satellite terrestrial networks for non-real-time and real-time applications, respectively, which maximize the energy efficiency (EE) of the cognitive satellite user while guaranteeing the interference at the primary terrestrial user below an acceptable level. Specifically, average interference power (AIP) constraint is employed to protect the communication quality of the primary terrestrial user while average transmit power (ATP) or peak transmit power (PTP) constraint is adopted to regulate the transmit power of the satellite user. Since the energy-efficient power allocation optimization problem belongs to the nonlinear concave fractional programming problem, we solve it by combining Dinkelbach's method with Lagrange duality method. Simulation results demonstrate that the fading severity of the terrestrial interference link is favorable to the satellite user who can achieve EE gain under the ATP constraint comparing to the PTP constraint. PMID- 28869547 TI - Dietary Protein and Amino Acid Profiles in Relation to Risk of Dysglycemia: Findings from a Prospective Population-Based Study. AB - Considering the limited knowledge on the effects of dietary amino acid intake on dysglycemia, we assessed the possible association of dietary protein and amino acid patterns with the risk of pre-diabetes in a prospective population-based study. Participants without diabetes and pre-diabetes (n = 1878) were recruited from the Tehran Lipid and Glucose Study and were followed for a mean of 5.8 years. Their dietary protein and amino acid intakes were assessed at baseline (2006-2008); demographic, lifestyle, and biochemical variables were evaluated at baseline and in follow-up examinations. Pre-diabetes was defined according to the American Diabetes Association criteria. Multivariate Cox proportional hazard regression models, adjusted for potential confounders, were used to estimate the risk of pre-diabetes across tertiles of dietary protein and amino acid pattern scores. The mean age of the participants (44.9% men) was 38.3 +/- 12.7 years at baseline. Three major amino acid patterns were characterized: (1) higher loads of lysine, methionine, valine, aspartic acids, tyrosine, threonine, isoleucine, leucine, alanine, histidine, and serine; (2) higher loads of glycine, cysteine, arginine, and tryptophan; and (3) higher loads of proline and glutamic acid. Dietary total protein intake Hazard Ratio (HR) = 1.13, 95% Confidence Interval (CI) = 0.92-1.38 and HR = 1.00, 95% CI = 0.81-1.23, in the second and third tertile, respectively) was not related to the development of pre-diabetes. The highest score of second dietary amino acid pattern tended to be associated with a decreased risk of pre-diabetes (HR = 0.81, 95% CI = 0.65-1.01), whereas the third pattern was related to an increased risk in the fully adjusted model (HR = 1.24, 95% CI = 1.02-1.52; p for trend = 0.05). These novel data suggest that the amino acid composition of an individual's diet may modify their risk of pre-diabetes. PMID- 28869548 TI - Polymethoxyflavones: Novel beta-Secretase (BACE1) Inhibitors from Citrus Peels. AB - Beta-site amyloid precursor protein (APP) cleaving enzyme1 (BACE1) catalyzes the rate-limiting step of amyloid-beta protein (Abeta) generation, and is considered as a prime target for Alzheimer's disease (AD). In search of a candidate for AD prevention, our efforts exploring the natural BACE1 inhibitor have led to the finding of nobiletin, tangeretin, and sinensetin-representative compounds of polymethoxyflavones (PMFs). Tangeretin exhibited the strongest BACE1 inhibition (IC50, 4.9 * 10-5 M), followed by nobiletin and sinensetin with IC50 values of 5.9 * 10-5 M and 6.3 * 10-5 M, respectively. In addition, all compounds reacted in a non-competitive manner with the substrate. Docking analysis results for complexes with BACE1 indicated that SER10 and THR232 residues of BACE1 hydrogen bonded with two oxygen atoms of tangeretin, while three additional BACE1 residues (ALA157, VAL336 and THR232) interacted with three oxygen atoms of nobiletin. Furthermore, sinensetin formed four hydrogen bonds through nitrogen atoms of TYR71, LYS75, and TRP76, and an oxygen atom of TYR198. Furthermore, the lowest energy conformations of the most proposed complexes of sinensetin, nobiletin, and tangeretin with BACE1 were -7.2, -7.0, and -6.8 kcal/mol, respectively. Taken together, our results suggest that these polymethoxyflavones (PMFs) might be considered as promising BACE1 inhibitory agents that could lower Abeta production in AD. PMID- 28869550 TI - Correction: Xingchen Zhou, et al. Whole Exome Sequencing in Psoriasis Patients Contributes to Studies of Acitretin Treatment Difference. Int. J. Mol. Sci. 2017, 18, 295. AB - We would like to submit the following correction to the published paper [1], the reason for this action is that the data in Table 3 were reanalyzed by one more accurate statistic method: On page 12, the sentence of paragraph three "OR and 95% CI were calculated by limited backward-LR (likelihood ratio) logistic regression analysis with adjustment by clinical variables" should be corrected into "OR and 95% CI were calculated by limited enter logistic regression analysis with adjustment by clinical variables".[...]. PMID- 28869549 TI - Microbiological Impact of the Use of Reclaimed Wastewater in Recreational Parks. AB - Reclaimed wastewater for irrigation is an opportunity for recovery of this natural resource. In this study, microbial risk from the use of treated wastewater for irrigation of recreational parks in the city of Chihuahua, evaluating the effect of distribution distance, season, and presence of storage tanks, was analyzed. Escherichia coli, Salmonella, and multidrug-resistant bacteria were recovered from samples of reclaimed water and soils at recreational parks in Chihuahua by the membrane filtration method, using selected agars for microbial growth. Samples were taken at three different seasons. No correlation in the presence of microbial indicators and multidrug-resistant bacteria (p > 0.05) was found between the distance from the wastewater treatment plant to the point of use. Presence of storage tanks in parks showed a significant effect (p < 0.05) with a higher level of E. coli. The highest count in wastewater occurred in summer. We isolated 392 multidrug-resistant bacteria from water and soil; cluster analysis showed that the microorganisms at each location were of different origins. Irrigation with reclaimed wastewater did not have a negative effect on the presence of microbial indicators of the quality of soils in the parks. However, the prevalence of multidrug-resistant bacteria still represents a potential risk factor for human health. PMID- 28869551 TI - An Energy-Efficient and Robust Multipath Routing Protocol for Cognitive Radio Ad Hoc Networks. AB - Routing in cognitive radio ad hoc networks (CRAHNs) is a daunting task owing to dynamic topology, intermittent connectivity, spectrum heterogeneity, and energy constraints. Other prominent aspects such as channel stability, path reliability, and route discovery frequency should also be exploited. Several routing protocols have been proposed for CRAHNs in the literature. By stressing on one of the aspects more than any other, however, they do not satisfy all requirements of throughput, energy efficiency, and robustness. In this paper, we propose an energy-efficient and robust multipath routing (ERMR) protocol for CRAHNs by considering all prominent aspects including residual energy and channel stability in design. Even when the current routing path fails, the alternative routing path is immediately utilized. In establishing primary and alternative routing paths, both residual energy and channel stability are exploited simultaneously. Our simulation study shows that the proposed ERMR outperforms the conventional protocol in terms of network throughput, packet delivery ratio, energy consumption, and end-to-end delay. PMID- 28869552 TI - Listeria monocytogenes Biofilms in the Wonderland of Food Industry. AB - The foodborne pathogen Listeria monocytogenes is a concern in food safety because of its ability to form biofilm and to persist in food industry. In this mini review, the issue represented by this pathogen and some of the latest efforts performed in order to investigate the composition of biofilms formed by L. monocytogenes are summarized. PMID- 28869554 TI - Design of Waveguide Bars for Transmitting a Pure Shear Horizontal Wave to Monitor High Temperature Components. AB - Guided wave technique could be a possible method for monitoring components working in high temperature above 350 degrees C. However, this would require the design of an appropriate waveguide bar to transmit the wave, so that its sensing part is not influenced by the high temperature. In the present study, the shape of waveguide bars is designed based on the analysis of wave source characteristics. The critical frequency-width and frequency-thickness products of waveguide bars are analyzed theoretically and numerically to transmit the zeroth shear horizontal wave SH0* in bars. The results show that waveguide bars can cut off all the other wave modes when their frequency-thickness products are smaller than the critical value fd*, and frequency-width products are not smaller than the critical value fw*. Six waveguide bars are designed and fabricated based on the design criteria, and an experiment system is set up to check their work performance. The testing results indicate that the wave signals of the SH0* mode propagate clearly in waveguide bars, and cut off all the other modes when the frequency-thickness products and frequency-width products of the bars meet the design criteria. It is also demonstrated that the dependency of the experimental group velocity of each waveguide bar on frequency is in good agreement with the numerical result. High-temperature experiments also validate the reliability of the designed waveguide bars. Therefore, the critical frequency-thickness product and frequency-width product can be the basis for the design of the waveguide bars. PMID- 28869555 TI - Poly(Neopentyl Glycol Furanoate): A Member of the Furan-Based Polyester Family with Smart Barrier Performances for Sustainable Food Packaging Applications. AB - In the last decade, there has been an increased interest from the food packaging industry toward the development and application of bioplastics, to contribute to the sustainable economy and to reduce the huge environmental problem afflicting the planet. In the present work, we focus on a new furan-based polyester, poly(neopentyl glycol 2,5-furanoate) (PNF) to be used for sustainable food packaging applications. The aromatic polyester was successfully synthesized with high molecular weight, through a solvent-free process, starting directly from 2,5 furandicarboxylic acid. PNF was revealed to be a material with good thermal stability, characterized by a higher Tg and Tm and a lower RAF fraction compared to poly(propylene 2,5-furanoate) (PPF), ascribable to the two methyl side groups present in PNF glycol-sub-unit. PNF's mechanical characteristics, i.e., very high elastic modulus and brittle fracture, were found to be similar to those of PPF and PEF. Barrier properties to different gases, temperatures and relative humidity were evaluated. From the results obtained, PNF was showed to be a material with very smart barrier performances, significantly superior with respect to PEF's ones. Lastly, PNF's permeability behavior did not appreciably change after contact with food simulants, whereas it got worse with increasing RH, due to the polar nature of furan ring. PMID- 28869553 TI - SGS3 Cooperates with RDR6 in Triggering Geminivirus-Induced Gene Silencing and in Suppressing Geminivirus Infection in Nicotiana Benthamiana. AB - RNA silencing has an important role in defending against virus infection in plants. Plants with the deficiency of RNA silencing components often show enhanced susceptibility to viral infections. RNA-dependent RNA polymerase (RDRs) mediated-antiviral defense has a pivotal role in resistance to many plant viruses. In RDR6-mediated defense against viral infection, a plant-specific RNA binding protein, Suppressor of Gene Silencing 3 (SGS3), was also found to fight against some viruses in Arabidopsis. In this study, we showed that SGS3 from Nicotiana benthamiana (NbSGS3) is required for sense-RNA induced post transcriptional gene silencing (S-PTGS) and initiating sense-RNA-triggered systemic silencing. Further, the deficiency of NbSGS3 inhibited geminivirus induced endogenous gene silencing (GIEGS) and promoted geminivirus infection. During TRV-mediated NbSGS3 or N. benthamiana RDR6 (NbRDR6) silencing process, we found that their expression can be effectively fine-tuned. Plants with the knock down of both NbSGS3 and NbRDR6 almost totally blocked GIEGS, and were more susceptible to geminivirus infection. These data suggest that NbSGS3 cooperates with NbRDR6 against GIEGS and geminivirus infection in N. benthamiana, which provides valuable information for breeding geminivirus-resistant plants. PMID- 28869556 TI - A New Monoterpene from the Leaves of a Radiation Mutant Cultivar of Perilla frutescens var. crispa with Inhibitory Activity on LPS-Induced NO Production. AB - The leaves of Perilla frutescens var. crispa (Lamiaceae)-known as 'Jureum-soyeop' or 'Cha-jo-ki' in Korean, 'ZI SU YE' in Chinese, and 'Shiso' in Japan-has been used as a medicinal herb. Recent gamma irradiated mutation breeding on P. frutescens var. crispa in our research group resulted in the development of a new perilla cultivar, P. frutescens var. crispa (cv. Antisperill; PFCA), which has a higher content of isoegomaketone. The leaves of PFCA were extracted by supercritical carbon dioxide (SC-CO2) extraction, and phytochemical investigation on this extract led to the isolation and identification of a new compound, 9 hydroxy-isoegomaketone [(2E)-1-(3-furanyl)-4-hydroxy-4-methyl-2-penten-1-one; 1]. Compound 1 exhibited inhibitory activity on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW264.7 cells with an IC50 value of 14.4 MUM. The compounds in the SC-CO2 extracts of the radiation mutant cultivar and the original plant were quantified by high-performance liquid chromatography with diode array detection. PMID- 28869557 TI - Magnetic Abrasive Machining of Difficult-to-Cut Materials for Ultra-High-Speed Machining of AISI 304 Bars. AB - This research proposes an optimized magnetic abrasive machining process that uses an ultra-high-speed system to perform precision machining on a workpiece. The system can process several microns of material, either for machining surface roughness or for machining a workpiece for a precise micro-diameter. The stainless steel workpieces have been machined using an ultra-high-speed magnetic abrasive machining (UHSMAM) process. The experiments were performed analyzing the accuracy of the machined workpiece diameter, using response surface methodology. The results obtained after machining have been analyzed to determine the effect of different process parameters such as machining speed, machining time, machining frequencies, inert gas in/out, magnetic pole types, and magnetic abrasive mesh size for the individual workpiece, as well as to study various interaction effects that may significantly affect the machining performance of the process. The obtained outcomes of the analysis for different workpieces have been critically compared to understand the effect of the considered process parameters based on the resulting mechanical properties. Regression analysis was used to confirm the stability of the micro-diameter and the processing efficiency. Atomic force microscope (AFM) micrographs were also obtained to study the surface morphology of the precision-machined workpiece. PMID- 28869558 TI - Event-Driven Observer-Based Smart-Sensors for Output Feedback Control of Linear Systems. AB - This paper deals with a recent design of event-driven observer-based smart sensors for output feedback control of linear systems. We re-design the triggering mechanism proposed in a previously reported system with the implementation of self-sampling data smart sensors; as a result, we improve its performance. Our approach is theoretically supported by using Lyapunov theory and numerically evidenced by controlling the inverted pendulum on the cart mechanism. PMID- 28869559 TI - Relationship between Degree of Deformation in Quartz and Silica Dissolution for the Development of Alkali-Silica Reaction in Concrete. AB - This paper presents research on the influence of quartz deformation in aggregates for the development of the alkali-silica reaction in concrete and its relationship with silica dissolution. The study also compares these characteristics with the field behavior of such rocks in concrete. The paper proposes parameters to classify the different degrees of deformation of quartz. Transmission electron microscopy showed the presence of walls even in slightly deformed quartz, which indicate the presence of the internal paths available to react with the alkaline concrete pore solutions and point to the potential development of an alkali-silica reaction. The presence of the deformation bands in the quartz grains leads to the alkali aggregate reaction occurring more rapidly. The visible spectrophotometer test was performed to evaluate the dissolution potential of the different samples of deformed quartz, which confirmed that the reactivity of the quartz increases as the deformation of the crystalline structure increases. The parameters established in the present study could be verified by analyzing the behavior of reactive and innocuous aggregates from the buildings. PMID- 28869560 TI - Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects. AB - Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS stimulated cells, thus demonstrating their potential as anti-inflammatory agents. PMID- 28869561 TI - Why is Aged Acetylcholinesterase So Difficult to Reactivate? AB - Organophosphorus agents are potent inhibitors of acetylcholinesterase. Inhibition involves successive chemical events. The first is phosphylation of the active site serine to produce a neutral adduct, which is a close structural analog of the acylation transition state. This adduct is unreactive toward spontaneous hydrolysis, but in many cases can be reactivated by nucleophilic medicinal agents, such as oximes. However, the initial phosphylation reaction may be followed by a dealkylation reaction of the incipient adduct. This reaction is called aging and produces an anionic phosphyl adduct with acetylcholinesterase that is refractory to reactivation. This review considers why the anionic aged adduct is unreactive toward nucleophiles. An alternate approach is to realkylate the aged adduct, which would render the adduct reactivatable with oxime nucleophiles. However, this approach confronts a considerable-and perhaps intractable-challenge: the aged adduct is a close analog of the deacylation transition state. Consequently, the evolutionary mechanisms that have led to transition state stabilization in acetylcholinesterase catalysis are discussed herein, as are the challenges that they present to reactivation of aged acetylcholinesterase. PMID- 28869562 TI - Comparative Programs for Arthropod, Disease and Weed Management in New York Organic Apples. AB - Organic apple production in the eastern US is small and is mostly based on existing varieties, which are susceptible to scab, and rootstocks, which are susceptible to fire blight. This requires numerous sprays per year of various pesticides to produce acceptable fruit. From 2014 to 2016, we tested different arthropod, disease and weed management programs in an advanced tall spindle high density production system that included disease-resistant cultivars and rootstocks, in an organic research planting of apples in Geneva, New York. Arthropod and disease management regimens were characterized as Advanced Organic, Minimal Organic, or Untreated Control. Results varied by year and variety, but, in general, the Advanced program was more effective than the Minimal program in preventing damage from internal-feeding Lepidoptera, plum curculio, and obliquebanded leafroller, and less effective than the Minimal program against damage by foliar insects. Both organic programs provided comparable control of sooty blotch, cedar apple rust, and fire blight, with some variability across cultivars and years. The advanced selection CC1009 and Modi seemed to possess complete resistance to cedar apple rust, while Pristine had partial resistance. For weed control, bark chip mulch, organic soap sprays, and limonene sprays tended to be most effective, while mechanical tillage and flame weeding had lower success. PMID- 28869564 TI - Phenolics Isolated from Aframomum meleguta Enhance Proliferation and Ossification Markers in Bone Cells. AB - Osteoporosis is a serious health problem characterized by decreased bone mineral density and deterioration of bone microarchitecture. Current antiosteoporotic agents exhibit a wide range of adverse effects; meanwhile, phytochemicals are effective and safer alternatives. In the current work, nine compounds belonging to hydroxyphenylalkane and diarylheptanoid groups were isolated from Aframomum meleguea seeds and identified as 6-gingerol (1), 6-paradol (2), 8 dehydrogingerdione (3), 8-gingerol (4), dihydro-6-paradol (5), dihydrogingerenone A (6), dihydrogingerenone C (7), 1,7-bis(3,4-dihydroxy-5-methoxyphenyl)heptane 3,5-diyl diacetate (8), and 1-(3,4-dihydroxy-5-methoxyphenyl)-7-(3,4 dihydroxyphenyl)heptane-3,5-diyl diacetate (9). The structures of isolated compounds were established by NMR and mass spectral data, in addition to referring to literature data. Exposure of MCF-7, MG-63, and SAOS-2 cells to subcytotoxic concentrations of the compounds under investigation resulted in accelerated proliferation. Among them, paradol was selected for further detailed biochemical analysis in SAOS-2 cells. DNA flowcytometric analysis of cell cycle distribution revealed that paradol did not induce any significant change in the proliferation index of SAOS-2 cells. Assessment of osteogenic gene expression revealed that paradol enhanced the expression of osteocyte and osteoblast-related genes and inhibited osteoclast and RUNX suppressor genes. Biochemically, paradol enhanced alkaline phosphatase activity and vitamin D content and decreased the osteoporotic marker acid phosphatase. In conclusion, paradol, which is a major constituents of A. melegueta seeds, exhibited potent proliferative and ossification characteristics in bone cells. PMID- 28869565 TI - The Variation of Oncidium Rosy Sunset Flower Volatiles with Daily Rhythm, Flowering Period, and Flower Parts. AB - Oncidium is an important ornamental crop worldwide, and in recent years, the characteristics of the flower aroma have become a concern for breeders. This study used headspace solid-phase microextraction (HS-SPME) and gas chromatography/mass spectrometry (GC-MS) analysis of the volatile compounds to study the aroma characteristics of Onc. Rosy Sunset. A total of 45 compounds were identified, with the major compound being linalool. Onc. Rosy Sunset had the highest odor concentration from 10:00 to 12:00 and lowest from 20:00 to 24:00. The inflorescence emitted the highest quantities of volatile compounds during stages 3-6, which then decreased with the aging of the flowers. In Onc. Rosy Sunset, the sepals and petals were the major parts for the floral fragrance emission, in which linalool content was the highest, whereas the lip and column had a different composition of major volatile compounds, of which benzaldehyde, beta-myrcene, and beta-caryophyllene dominated. PMID- 28869563 TI - Synergic Anti-Pruritus Mechanisms of Action for the Radix Sophorae Flavescentis and Fructus Cnidii Herbal Pair. AB - Radix Sophorae Flavescentis (RSF) and Fructus Cnidii (FC) compose a typical herbal synergic pair in traditional Chinese medicine (TCM) for pruritus symptom treatments. The mechanisms of action for the synergy are not understood. This paper aims at predicting the anti-pruritus targets and the main active ingredients for the RSF and FC herbal pair. We demonstrate that the RSF-FC herbal pair can be elucidated by mining the chemical structures of compounds derived from RSF and FC. Based on chemical structure data, the putative targets for RSF and FC were predicted. Additional putative targets that interact with the anti pruritus targets were derived by mapping the putative targets onto a PPI network. By examining the annotations of these proteins, we conclude that (1) RSF's active compounds are mainly alkaloids and flavonoids. The representative putative targets of the alkaloids are inflammation-related proteins (MAPK14, PTGS2, PTGS2, and F2) and pruritus-related proteins (HRH1, TRPA1, HTR3A, and HTR6). The representative putative targets of the flavonoids are inflammation-related proteins (TNF, NF-kappaB, F2, PTGS2, and PTGS2) and pruritus-related proteins (NR3C1 and IL2). (2) FC's active compounds are mainly coumarins. Their representative putative targets are CNS-related proteins (AChE and OPRK1) and inflammation-related proteins (PDE4D, TLR9, and NF-kappaB). (3) Both RSF and FC display anti-inflammatory effects, though they exhibit their anti-pruritus effects in different ways. Their synergy shows that RSF regulates inflammation related pruritus and FC regulates CNS-related pruritus. PMID- 28869566 TI - Dramatic Influence of Ionic Liquid and Ultrasound Irradiation on the Electrophilic Sulfinylation of Aromatic Compounds by Sulfinic Esters. AB - The sulfinylation reaction of aromatic and hetero-aromatic compounds with sulfinic esters as electrophiles has been investigated in different ionic liquids and by means of different Lewis acid salts in order to get moderate to good yields of asymmetrical sulfoxides. Mixtures of 1-butyl-3-methylimidazolium chloride and aluminum chloride were found to be the most efficient and recyclable reaction framework. Ultrasound sonication appeared to be the most useful and green activation method to afford the sulfoxides in yields better than or equivalent to those obtained under the longer-lasting conventional stirring conditions. PMID- 28869567 TI - Using Next Generation Sequencing to Identify and Quantify the Genetic Composition of Resistance-Breaking Commercial Isolates of Cydia pomonella Granulovirus. AB - The use of Cydia pomonella granulovirus (CpGV) isolates as biological control agents of codling moth (CM) larvae is important in organic and integrated pome fruit production worldwide. The commercially available isolates CpGV-0006, CpGV R5, and CpGV-V15 have been selected for the control of CpGV resistant CM populations in Europe. In infection experiments, CpGV-0006 and CpGV-R5 were able to break type I resistance and to a lower extent also type III resistance, whereas CpGV-V15 overcame type I and the rarely occurring type II and type III resistance. The genetic background of the three isolates was investigated with next generation sequencing (NGS) tools by comparing their nucleotide compositions to whole genome alignments of five CpGV isolates representing the known genetic diversity of the CpGV genome groups A to E. Based on the distribution of single nucleotide polymorphisms (SNPs) in Illumina sequencing reads, we found that the two isolates CpGV-0006 and CpGV-R5 have highly similar genome group compositions, consisting of about two thirds of the CpGV genome group E and one third of genome group A. In contrast, CpGV-V15 is composed of equal parts of CpGV genome group B and E. According to the identified genetic composition of these isolates, their efficacy towards different resistance types can be explained and predictions on the success of resistance management strategies in resistant CM populations can be made. PMID- 28869568 TI - Medicinal Plants Based Products Tested on Pathogens Isolated from Mastitis Milk. AB - Bovine mastitis a major disease that is commonly associated with bacterial infection. The common treatment is with antibiotics administered intramammary into infected quarters of the udder. The excessive use of antibiotics leads to multidrug resistance and associated risks for human health. In this context, the search for alternative drugs based on plants has become a priority in livestock medicine. These products have a low manufacturing cost and no reports of antimicrobial resistance to these have been documented. In this context, the main objective of this study was to determine the antimicrobial effect of extracts and products of several indigenous, or acclimatized plants on pathogens isolated from bovine mastitis. A total of eleven plant alcoholic extracts and eight plant derived products were tested against 32 microorganisms isolated from milk. The obtained results have shown an inhibition of bacterial growth for all tested plants, with better results for Everniaprunastri, Artemisiaabsinthium, and Lavandulaangustifolia. Moreover, E.prunastri, Populus nigra, and L. angustifolia presented small averages of minimum inhibitory and bactericidal concentrations. Among the plant-derived products, three out of eight have shown a strong anti microbial effect comparable with the effect of florfenicol and enrofloxacin, and better than individual plant extracts possibly due to synergism. These results suggest an important anti-microbial effect of these products on pathogens isolated from bovine mastitis with a possible applicability in this disease. PMID- 28869569 TI - Molecular Dynamic Analysis of Hyaluronic Acid and Phospholipid Interaction in Tribological Surgical Adjuvant Design for Osteoarthritis. AB - Tribological surgical adjuvants constitute a therapeutic discipline made possible by surgical advances in the treatment of damaged articular cartilage beyond palliative care. The purpose of this study is to analyze interactions between hyaluronic acid and phospholipid molecules, and the formation of geometric forms, that play a role in the facilitated lubrication of synovial joint organ systems. The analysis includes an evaluation of the pathologic state to detail conditions that may be encountered by adjuvants during surgical convalescence. The synovial fluid changes in pH, hyaluronic acid polydispersity, and phospholipid concentration associated with osteoarthritis are presented as features that influence the lubricating properties of adjuvant candidates. Molecular dynamic simulation studies are presented, and the Rouse model is deployed, to rationalize low molecular weight hyaluronic acid behavior in an osteoarthritic environment of increased pH and phospholipid concentration. The results indicate that the hyaluronic acid radius of gyration time evolution is both pH- and phospholipid concentration-dependent. Specifically, dipalmitoylphosphatidylcholine induces hydrophobic interactions in the system, causing low molecular weight hyaluronic acid to shrink and at high concentration be absorbed into phospholipid vesicles. Low molecular weight hyaluronic acid appears to be insufficient for use as a tribological surgical adjuvant because an increased pH and phospholipid concentration induces decreased crosslinking that prevents the formation of supramolecular lubricating forms. Dipalmitoylphosphatidylcholine remains an adjuvant candidate for certain clinical situations. The need to reconcile osteoarthritic phenotypes is a prerequisite that should serve as a framework for future adjuvant design and subsequent tribological testing. PMID- 28869570 TI - On Consistency Test Method of Expert Opinion in Ecological Security Assessment. AB - To reflect the initiative design and initiative of human security management and safety warning, ecological safety assessment is of great value. In the comprehensive evaluation of regional ecological security with the participation of experts, the expert's individual judgment level, ability and the consistency of the expert's overall opinion will have a very important influence on the evaluation result. This paper studies the consistency measure and consensus measure based on the multiplicative and additive consistency property of fuzzy preference relation (FPR). We firstly propose the optimization methods to obtain the optimal multiplicative consistent and additively consistent FPRs of individual and group judgments, respectively. Then, we put forward a consistency measure by computing the distance between the original individual judgment and the optimal individual estimation, along with a consensus measure by computing the distance between the original collective judgment and the optimal collective estimation. In the end, we make a case study on ecological security for five cities. Result shows that the optimal FPRs are helpful in measuring the consistency degree of individual judgment and the consensus degree of collective judgment. PMID- 28869571 TI - Value-Based Pricing and Reimbursement in Personalised Healthcare: Introduction to the Basic Health Economics. AB - 'Value-based' outcomes, pricing, and reimbursement are widely discussed as health sector reforms these days. In this paper, we discuss their meaning and relationship in the context of personalized healthcare, defined as receipt of care conditional on the results of a biomarker-based diagnostic test. We address the question: "What kinds of pricing and reimbursement models should be applied in personalized healthcare?" The simple answer is that competing innovators and technology adopters should have incentives that promote long-term dynamic efficiency. We argue that-to meet this social objective of optimal innovation in personalized healthcare-payers, as agents of their plan participants, should aim to send clear signals to their suppliers about what they value. We begin by revisiting the concept of value from an economic perspective, and argue that a broader concept of value is needed in the context of personalized healthcare. We discuss the market for personalized healthcare and the interplay between price and reimbursement. We close by emphasizing the potential barrier posed by inflexible or cost-based reimbursement systems, especially for biomarker-based predictive tests, and how these personalized technologies have global public goods characteristics that require global value-based differential pricing to achieve dynamic efficiency in terms of the optimal rate of innovation and adoption. PMID- 28869572 TI - Barriers to Effective Municipal Solid Waste Management in a Rapidly Urbanizing Area in Thailand. AB - This study focused on determining the barriers to effective municipal solid waste management (MSWM) in a rapidly urbanizing area in Thailand. The Tha Khon Yang Subdistrict Municipality is a representative example of many local governments in Thailand that have been facing MSWM issues. In-depth interviews with individuals and focus groups were conducted with key informants including the municipality staff, residents, and external organizations. The major influences affecting waste management were categorized into six areas: social-cultural, technical, financial, organizational, and legal-political barriers and population growth. SWOT analysis shows both internal and external factors are playing a role in MSWM: There is good policy and a reasonably sufficient budget. However, there is insufficient infrastructure, weak strategic planning, registration, staff capacity, information systems, engagement with programs; and unorganized waste management and fee collection systems. The location of flood prone areas has impacted on location and operation of landfill sites. There is also poor communication between the municipality and residents and a lack of participation in waste separation programs. However, external support from government and the nearby university could provide opportunities to improve the situation. These findings will help inform municipal decision makers, leading to better municipal solid waste management in newly urbanized areas. PMID- 28869574 TI - Incentivizing Verifiable Privacy-Protection Mechanisms for Offline Crowdsensing Applications. AB - Incentive mechanisms of crowdsensing have recently been intensively explored. Most of these mechanisms mainly focus on the standard economical goals like truthfulness and utility maximization. However, enormous privacy and security challenges need to be faced directly in real-life environments, such as cost privacies. In this paper, we investigate offline verifiable privacy-protection crowdsensing issues. We firstly present a general verifiable privacy-protection incentive mechanism for the offline homogeneous and heterogeneous sensing job model. In addition, we also propose a more complex verifiable privacy-protection incentive mechanism for the offline submodular sensing job model. The two mechanisms not only explore the private protection issues of users and platform, but also ensure the verifiable correctness of payments between platform and users. Finally, we demonstrate that the two mechanisms satisfy privacy protection, verifiable correctness of payments and the same revenue as the generic one without privacy protection. Our experiments also validate that the two mechanisms are both scalable and efficient, and applicable for mobile devices in crowdsensing applications based on auctions, where the main incentive for the user is the remuneration. PMID- 28869575 TI - Effects of a Transverse Field in Two Mixed-Spin Ising Bilayer Films. AB - The magnetic properties (phase diagrams and magnetizations) of two mixed-spin Ising bilayer films with a transverse field are investigated by the use of the effective field theory with correlations. The systems consist of two magnetic atoms where spin-1/2 atoms are directed to the z-direction and only spin-1 atoms are canted from the z-direction by applying a transverse field. We examined how magnetization sign reversal can be realized in the system, due to the effects of the transverse field on the spin-1 atoms. The compensation point phenomena are found in both systems, depending on the selections of physical parameters. However, the reentrant phenomena are found only for one of the two systems. PMID- 28869573 TI - Effects of Whey, Soy or Leucine Supplementation with 12 Weeks of Resistance Training on Strength, Body Composition, and Skeletal Muscle and Adipose Tissue Histological Attributes in College-Aged Males. AB - We sought to determine the effects of L-leucine (LEU) or different protein supplements standardized to LEU (~3.0 g/serving) on changes in body composition, strength, and histological attributes in skeletal muscle and adipose tissue. Seventy-five untrained, college-aged males (mean +/- standard error of the mean (SE); age = 21 +/- 1 years, body mass = 79.2 +/- 0.3 kg) were randomly assigned to an isocaloric, lipid-, and organoleptically-matched maltodextrin placebo (PLA, n = 15), LEU (n = 14), whey protein concentrate (WPC, n = 17), whey protein hydrolysate (WPH, n = 14), or soy protein concentrate (SPC, n = 15) group. Participants performed whole-body resistance training three days per week for 12 weeks while consuming supplements twice daily. Skeletal muscle and subcutaneous (SQ) fat biopsies were obtained at baseline (T1) and ~72 h following the last day of training (T39). Tissue samples were analyzed for changes in type I and II fiber cross sectional area (CSA), non-fiber specific satellite cell count, and SQ adipocyte CSA. On average, all supplement groups including PLA exhibited similar training volumes and experienced statistically similar increases in total body skeletal muscle mass determined by dual X-ray absorptiometry (+2.2 kg; time p = 0.024) and type I and II fiber CSA increases (+394 MUm2 and +927 MUm2; time p < 0.001 and 0.024, respectively). Notably, all groups reported increasing Calorie intakes ~600-800 kcal/day from T1 to T39 (time p < 0.001), and all groups consumed at least 1.1 g/kg/day of protein at T1 and 1.3 g/kg/day at T39. There was a training, but no supplementation, effect regarding the reduction in SQ adipocyte CSA (-210 MUm2; time p = 0.001). Interestingly, satellite cell counts within the WPC (p < 0.05) and WPH (p < 0.05) groups were greater at T39 relative to T1. In summary, LEU or protein supplementation (standardized to LEU content) does not provide added benefit in increasing whole-body skeletal muscle mass or strength above PLA following 3 months of training in previously untrained college aged males that increase Calorie intakes with resistance training and consume above the recommended daily intake of protein throughout training. However, whey protein supplementation increases skeletal muscle satellite cell number in this population, and this phenomena may promote more favorable training adaptations over more prolonged periods. PMID- 28869576 TI - Spatial Distribution and Fuzzy Health Risk Assessment of Trace Elements in Surface Water from Honghu Lake. AB - Previous studies revealed that Honghu Lake was polluted by trace elements due to anthropogenic activities. This study investigated the spatial distribution of trace elements in Honghu Lake, and identified the major pollutants and control areas based on the fuzzy health risk assessment at screening level. The mean total content of trace elements in surface water decreased in the order of Zn (18.04 MUg/L) > Pb (3.42 MUg/L) > Cu (3.09 MUg/L) > Cr (1.63 MUg/L) > As (0.99 MUg/L) > Cd (0.14 MUg/L), within limits of Drinking Water Guidelines. The results of fuzzy health risk assessment indicated that there was no obvious non carcinogenic risk to human health, while carcinogenic risk was observed in descending order of As > Cr > Cd > Pb. As was regarded to have the highest carcinogenic risk among selected trace elements because it generally accounted for 64% of integrated carcinogenic risk. Potential carcinogenic risk of trace elements in each sampling site was approximately at medium risk level (10-5 to 10 4). The areas in the south (S4, S13, and S16) and northeast (S8, S18, and S19) of Honghu Lake were regarded as the risk priority control areas. However, the corresponding maximum memberships of integrated carcinogenic risk in S1, S3, S10 S13, S15, and S18 were of relatively low credibility (50-60%), and may mislead the decision-makers in identifying the risk priority areas. Results of fuzzy assessment presented the subordinate grade and corresponding reliability of risk, and provided more full-scale results for decision-makers, which made up for the deficiency of certainty assessment to a certain extent. PMID- 28869577 TI - Forsythiae Fructus: A Review on its Phytochemistry, Quality Control, Pharmacology and Pharmacokinetics. AB - Forsythiae Fructus, as a traditional Chinese medicine, has been widely used both as a single herb and in compound prescriptions in Asia, mainly due to its heat clearing and detoxifying effects. Modern pharmacology has proved Forsythiae Fructus possesses various therapeutic effects, both in vitro and in vivo, such as anti-inflammatory, antibacterial and antiviral activities. Up to now, three hundred and twenty-one compounds have been identified and sensitive analytical methods have been established for its quality control. Recently, the pharmacokinetics of Forsythiae Fructus and its bioactive compounds have been reported, providing valuable information for its clinical application. Therefore, this systematic review focused on the newest scientific reports on Forsythiae Fructus and extensively summarizes its phytochemistry, pharmacology, pharmacokinetics and standardization procedures, especially the difference between the two applied types-unripe Forsythiae Fructus and ripe Forsythiae Fructus-in the hope of providing a helpful reference and guide for its clinical applications and further studies. PMID- 28869578 TI - Benthic Archives Reveal Recurrence and Dominance of Toxigenic Cyanobacteria in a Eutrophic Lake over the Last 220 Years. AB - Akinetes are resistant cells which have the ability to persist in sediment for several decades. We have investigated the temporal distribution of akinetes of two species, Dolichospermum macrosporum and Dolichospermum flos-aquae, in a sediment core sampled in Lake Aydat (France), which covers 220 years. The upper part, from 1907 to 2016, the number of akinetes fluctuated but stayed at high concentrations, especially for D. macrosporum in surface sediment (with the maximal value close to 6.105 akinetes g DW-1 of sediment), suggesting a recurrence of blooms of this species which was probably closely related to anthropic eutrophication since the 1960s. Before 1907, the abundance of akinetes of both species was very low, suggesting only a modest presence of these cyanobacteria. In addition, the percentage of intact akinetes was different for each species, suggesting different ecological processes in the water column. This percentage also decreased with depth, revealing a reduction in germination potential over time. In addition, biosynthetic genes of anatoxin-a (anaC) and microcystin (mcyA) were detected. First results show a high occurrence of mcyA all down the core. In contrast, anaC gene was mostly detected in the surface sediment (since the 1980s), revealing a potentially more recent occurrence of this cyanotoxin in Lake Aydat which may be associated with the recurrence of blooms of D. macrosporum and thus with anthropic activities. PMID- 28869580 TI - Association between Functional Movements Skills and Health Indicators in Children Aged between 9 and 12 Years Old. AB - Background: Children's health is a current concern and data suggests that poor fundamental movement skills (FMS) could be associated with poor health, which may or may not be mediated by low physical activity level. However, tools to assess FMS have not been standardized, and could consequently lead to different associations between FMS and health indicators. Objective: The primary objective of this study was to evaluate the associations between FMS and health indicators using two different FMS measurement tools often used in Canada. Methods: A total of 145 children between the ages of 9 to 12 were recruited from schools, after school programs, and summer camps in 2016. FMS were evaluated using the Passport for Life (bound, plank, run, kick, throw) and the PLAYbasic (run, hop, throw, kick, and balance). The association between each test and an average score for each tool were tests with health indicators including anthropometric measures, grip strength, cardiorespiratory fitness, and percent body fat. Results: Participants were composed of 54.2% boys aged 10.4 +/- 1.2 years with an average body mass index of 18.8 +/- 3.8 kg/m2. The association between the average score of both tools was 0.77 (p < 0.01), body mass index was significantly associated with 67% of FMS elements using the Passport for Life (r ranging from -0.18 to 0.32; p < 0.05), and 60% of FMS using the PLAYbasic (r ranging from -0.15 to 0.30; p < 0.05). There were no significant differences between the associations of the health indicators with FMS and either FMS assessment tool (Passport for Life and PLAYbasic) (p = 0.05). Average score of FMS was significantly associated with all health indicators using both PLAYbasic and Passport for Life (all p < 0.05). Conclusions: Health indicators in children are associated with FMS regardless of whether the Passport for Life or the PLAYbasic was used as the assessment tool. It is worth investigating if interventions that improve FMS lead to improvements in these health indicators. PMID- 28869581 TI - Seeing faces is necessary for face-domain formation. AB - Here we report that monkeys raised without exposure to faces did not develop face domains, but did develop domains for other categories and did show normal retinotopic organization, indicating that early face deprivation leads to a highly selective cortical processing deficit. Therefore, experience must be necessary for the formation (or maintenance) of face domains. Gaze tracking revealed that control monkeys looked preferentially at faces, even at ages prior to the emergence of face domains, but face-deprived monkeys did not, indicating that face looking is not innate. A retinotopic organization is present throughout the visual system at birth, so selective early viewing behavior could bias category-specific visual responses toward particular retinotopic representations, thereby leading to domain formation in stereotyped locations in inferotemporal cortex, without requiring category-specific templates or biases. Thus, we propose that environmental importance influences viewing behavior, viewing behavior drives neuronal activity, and neuronal activity sculpts domain formation. PMID- 28869579 TI - Exploring the Role of RGD-Recognizing Integrins in Cancer. AB - Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine. PMID- 28869583 TI - Parallel encoding of recent visual experience and self-motion during navigation in Drosophila. AB - Animal navigation requires multiple types of information for decisions on directional heading. We identified neural processing channels that encode multiple cues during navigational decision-making in Drosophila melanogaster. In a flight simulator, we found that flies made directional choices on the basis of the location of a recently presented landmark. This experience-guided navigation was impaired by silencing neurons in the bulb (BU), a region in the central brain. Two-photon calcium imaging during flight revealed that the dorsal part of the BU encodes the location of a recent landmark, whereas the ventral part of the BU tracks self-motion reflecting turns. Photolabeling-based circuit tracing indicated that these functional compartments of the BU constitute adjacent, yet distinct, anatomical pathways that both enter the navigation center. Thus, the fly's navigation system organizes multiple types of information in parallel channels, which may compactly transmit signals without interference for decision making during flight. PMID- 28869582 TI - Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion. AB - Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca2+ imaging in hippocampal area CA1 of wild type and Df(16)A+/- mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A+/- mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction. PMID- 28869585 TI - BRCA1 regulation on beta-hCG: a mechanism for tumorigenicity in BRCA1 defective breast cancer. AB - Human chorionic gonadotropin beta (beta-hCG) has been implicated in breast tumorigenesis. However, the role of this hormone is highly controversial as certain studies suggest it has anti-tumor properties while others have found it to be pro-tumorigenic. To unveil the truth, we have analyzed the expression of beta-hCG in breast cancer. We identified for the first time that beta-hCG expression is linked to BRCA1 status and its overexpression is seen in BRCA1 mutated breast cancer cells, BRCA1 conditional knockout mouse breast cancer tissues and BRCA1 floxed basal cell carcinoma (BCC) tissues. An analysis of three large, transcriptomic data sets from TCGA (The Cancer Genome Atlas) expression profile confirmed the inverse correlation between BRCA1 and beta-hCG in human breast cancer. Using ChIP and luciferase assays, we also demonstrated that the cancer cells with wild-type but not mutant BRCA1 directly repress the expression of beta-hCG by binding to its promoter. Further, beta-hCG promotes migration and invasion predominantly in BRCA1 mutant breast cancer cells. Interestingly, stable overexpression of beta-hCG in BRCA1 mutant but not wild-type breast cancer cells results in the formation of spheres even on monolayer cultures. The cells of these spheres show high expression of both EMT and stem cell markers. Since beta hCG belongs to a cysteine knot family of proteins like TGFbeta and TGFbeta signaling is deregulated in BRCA1 defective tumors, we checked whether beta-hCG can mediate signaling through TGFbetaRII in BRCA1 mutated cells. We found for the first time that beta-hCG can bind and phosphorylate TGFbetaRII, irrespective of LHCGR status and induce proliferation in BRCA1 defective cells. Our results confirmed that there exists a transcriptional regulation of BRCA1 on beta-hCG and BRCA1 mutation promotes beta-hCG mediated tumorigenesis through TGFbetaRII signaling. Thus inhibiting beta-hCG-TGFbetaRII could prove an effective treatment strategy for BRCA1 mutated tumors. PMID- 28869584 TI - An xQTL map integrates the genetic architecture of the human brain's transcriptome and epigenome. AB - We report a multi-omic resource generated by applying quantitative trait locus (xQTL) analyses to RNA sequence, DNA methylation and histone acetylation data from the dorsolateral prefrontal cortex of 411 older adults who have all three data types. We identify SNPs significantly associated with gene expression, DNA methylation and histone modification levels. Many of these SNPs influence multiple molecular features, and we demonstrate that SNP effects on RNA expression are fully mediated by epigenetic features in 9% of these loci. Further, we illustrate the utility of our new resource, xQTL Serve, by using it to prioritize the cell type(s) most affected by an xQTL. We also reanalyze published genome wide association studies using an xQTL-weighted analysis approach and identify 18 new schizophrenia and 2 new bipolar susceptibility variants, which is more than double the number of loci that can be discovered with a larger blood-based expression eQTL resource. PMID- 28869587 TI - Epigenetic foundations of pluripotent stem cells that recapitulate in vivo pluripotency. AB - In mammalian development, dynamic epigenetic reprogramming occurs in pre implantation embryos and primordial germ cells and plays a critical role in conferring pluripotency on embryonic cells. Pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, have been derived and maintained in vitro under culture conditions that include stimulators and inhibitors of extrinsic signaling. Recent advances in stem cell cultivation have opened the possibility of capturing naive pluripotency, which is reminiscent of the pluripotency of inner cell mass cells, in vitro. However, emerging evidence has revealed complexity of epigenetic regulation in pluripotent stem cells in vitro that reflects the developmental stage, gender, and species. In this review, we describe the developmental potential and epigenetic regulation of pluripotent stem cells in rodents and humans in vitro and discuss unsolved issues in developing strategies to capture in vivo pluripotency in vitro. PMID- 28869586 TI - Alterations in fatty acid metabolism in response to obesity surgery combined with dietary counseling. AB - BACKGROUND: The effects of obesity surgery on serum and adipose tissue fatty acid (FA) profile and FA metabolism may modify the risk of obesity-related diseases. METHODS: We measured serum (n=122) and adipose tissue (n=24) FA composition and adipose tissue mRNA expression of genes regulating FA metabolism (n=100) in participants of the Kuopio Obesity Surgery Study (KOBS, age 47.2+/-8.7 years, BMI 44.6+/-6.0, 40 men, 82 women) before and one year after obesity surgery. As part of the surgery protocol, all the subjects were instructed to add sources of unsaturated fatty acids, such as rapeseed oil and fatty fish, into their diet. The results were compared with changes in serum FA composition in 122 subjects from the Finnish Diabetes Prevention study (DPS) (age 54.3+/-7.1 years, BMI 32.2+/-4.6, 28 men, 94 women). RESULTS: The proportion of saturated FAs decreased and the proportion of n-3 and n-6 FAs increased in serum triglycerides after obesity surgery (all P<0.002). Weight loss predicted changes in quantitative amounts of saturated FAs, monounsaturated FAs, n-3 and n-6 FAs in triglycerides (P<0.002 for all). Moreover, the changes in adipose tissue FAs reflected the changes in serum FAs, and some of the changes were associated with mRNA expression of elongases and desaturases in adipose tissue (all P<0.05). In line with this the estimated activity of elongase (18:1 n-7/16:1 n-7) increased significantly after obesity surgery in all lipid fractions (all P<4 * 10-7) and the increase in the estimated activity of D5D in triglycerides was associated with higher weight loss (r=0.415, P<2 * 10-6). Changes in serum FA profile were similar after obesity surgery and lifestyle intervention, except for the change in the absolute amounts of n-3 FAs between the two studies (P=0.044). CONCLUSIONS: Beneficial changes in serum and adipose tissue FAs after obesity surgery could be associated with changes in endogenous metabolism and diet. PMID- 28869588 TI - Activation of pluripotent genes in hepatic progenitor cells in the transition of nonalcoholic steatohepatitis to pre-malignant lesions. AB - Nonalcoholic steatohepatitis is considered as a precancerous condition. However, hepatic carcinogenesis from NASH is poorly understood. This study aims to investigate the activation of pluripotent genes (c-Myc, Oct-4, KLF-4, and Nanog) and morphogenic gene (Gli-1) in hepatic progenitor cells from patient specimens and in an animal model to determine the possibility of normal stem/progenitor cells becoming the origin of NASH-HCC. In this study, expression of pluripotent and morphogenic genes in human NASH-HCC tissues was significantly upregulated compared to adjacent non-tumor liver tissues. After feeding high-fat/calorie diet plus high fructose/glucose in drinking water (HFC diet plus HF/G) for up to 12 months, mice developed obesity, insulin resistance, and steatohepatitis with significant necroptotic inflammation and fibrotic progression, as well as occurrence of hyperplastic nodules with dysplasia; and this model represents pathohistologically as a transition from NASH to NASH-HCC in a pre-carcinomatous stage. High expression of pluripotent and morphogenic genes was immunohistochemically visualized in the dysplasia areas of mouse liver, where there were many OV-6-positive cells, indicating proliferation of HOCs in NASH with fibrotic progression. Moreover, oncogenic transcription factors (c-Myc, KLF 4, and Nanog) were co-localized in these hepatic progenitor cells. In conclusion, pluripotent and morphogenic genes may contribute to the reprogramming of hepatic progenitor cells in driving these cells to be the origin of NASH-HCC in a steatotic and inflamed microenvironment. PMID- 28869589 TI - Stem cell therapies for myocardial infarction in clinical trials: bioengineering and biomaterial aspects. AB - Cardiovascular disease remains the leading cause of death and disability in advanced countries. Stem cell transplantation has emerged as a promising therapeutic strategy for acute and chronic ischemic cardiomyopathy. The current status of stem cell therapies for patients with myocardial infarction is discussed from a bioengineering and biomaterial perspective in this review. We describe (a) the current status of clinical trials of human pluripotent stem cells (hPSCs) compared with clinical trials of human adult or fetal stem cells, (b) the gap between fundamental research and application of human stem cells, (c) the use of biomaterials in clinical and pre-clinical studies of stem cells, and finally (d) trends in bioengineering to promote stem cell therapies for patients with myocardial infarction. We explain why the number of clinical trials using hPSCs is so limited compared with clinical trials using human adult and fetal stem cells such as bone marrow-derived stem cells. PMID- 28869591 TI - Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. AB - Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes. PMID- 28869592 TI - Reconstruction of enhancer-target networks in 935 samples of human primary cells, tissues and cell lines. AB - We propose a new method for determining the target genes of transcriptional enhancers in specific cells and tissues. It combines global trends across many samples and sample-specific information, and considers the joint effect of multiple enhancers. Our method outperforms existing methods when predicting the target genes of enhancers in unseen samples, as evaluated by independent experimental data. Requiring few types of input data, we are able to apply our method to reconstruct the enhancer-target networks in 935 samples of human primary cells, tissues and cell lines, which constitute by far the largest set of enhancer-target networks. The similarity of these networks from different samples closely follows their cell and tissue lineages. We discover three major co regulation modes of enhancers and find defense-related genes often simultaneously regulated by multiple enhancers bound by different transcription factors. We also identify differentially methylated enhancers in hepatocellular carcinoma (HCC) and experimentally confirm their altered regulation of HCC-related genes. PMID- 28869590 TI - Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. AB - To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid binding protein. PMID- 28869593 TI - How type II CRISPR-Cas establish immunity through Cas1-Cas2-mediated spacer integration. AB - CRISPR (clustered regularly interspaced short palindromic repeats) and the nearby Cas (CRISPR-associated) operon establish an RNA-based adaptive immunity system in prokaryotes. Molecular memory is created when a short foreign DNA-derived prespacer is integrated into the CRISPR array as a new spacer. Whereas the RNA guided CRISPR interference mechanism varies widely among CRISPR-Cas systems, the spacer integration mechanism is essentially identical. The conserved Cas1 and Cas2 proteins form an integrase complex consisting of two distal Cas1 dimers bridged by a Cas2 dimer. The prespacer is bound by Cas1-Cas2 as a dual-forked DNA, and the terminal 3'-OH of each 3' overhang serves as an attacking nucleophile during integration. The prespacer is preferentially integrated into the leader-proximal region of the CRISPR array, guided by the leader sequence and a pair of inverted repeats inside the CRISPR repeat. Spacer integration in the well-studied Escherichia coli type I-E CRISPR system also relies on the bacterial integration host factor. In type II-A CRISPR, however, Cas1-Cas2 alone integrates spacers efficiently in vitro; other Cas proteins (such as Cas9 and Csn2) have accessory roles in the biogenesis phase of prespacers. Here we present four structural snapshots from the type II-A system of Enterococcus faecalis Cas1 and Cas2 during spacer integration. Enterococcus faecalis Cas1-Cas2 selectively binds to a splayed 30-base-pair prespacer bearing 4-nucleotide 3' overhangs. Three molecular events take place upon encountering a target: first, the Cas1-Cas2 prespacer complex searches for half-sites stochastically, then it preferentially interacts with the leader-side CRISPR repeat, and finally, it catalyses a nucleophilic attack that connects one strand of the leader-proximal repeat to the prespacer 3' overhang. Recognition of the spacer half-site requires DNA bending and leads to full integration. We derive a mechanistic framework to explain the stepwise spacer integration process and the leader-proximal preference. PMID- 28869594 TI - An artificial transport metabolon facilitates improved substrate utilization in yeast. AB - Efficient substrate utilization is the first and most important prerequisite for economically viable production of biofuels and chemicals by microbial cell factories. However, production rates and yields are often compromised by low transport rates of substrates across biological membranes and their diversion to competing pathways. This is especially true when common chassis organisms are engineered to utilize nonphysiological feedstocks. Here, we addressed this problem by constructing an artificial complex between an endogenous sugar transporter and a heterologous xylose isomerase in Saccharomyces cerevisiae. Direct feeding of the enzyme through the transporter resulted in acceleration of xylose consumption and substantially diminished production of xylitol as an undesired side product, with a concomitant increase in the production of ethanol. This underlying principle could also likely be implemented in other biotechnological applications. PMID- 28869596 TI - GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP mediated degradation of Slug. AB - This corrects the article DOI: 10.1038/onc.2013.279. PMID- 28869595 TI - A toxic mutant huntingtin species is resistant to selective autophagy. AB - Protein misfolding is a common theme in neurodegenerative disorders including Huntington's disease (HD). The HD-causing mutant huntingtin protein (mHTT) has an expanded polyglutamine (polyQ) stretch that may adopt multiple conformations, and the most toxic of these is the one recognized by antibody 3B5H10. Here we show that the 3B5H10-recognized mHTT species has a slower degradation rate due to its resistance to selective autophagy in human cells and brains, revealing mechanisms of its higher toxicity. PMID- 28869597 TI - Atf3 deficiency promotes genome instability and spontaneous tumorigenesis in mice. AB - Mice lacking genes involving in the DNA-damage response (DDR) are often tumor prone owing to genome instability caused by oncogenic challenges. Previous studies demonstrate that activating transcription factor 3 (ATF3), a common stress sensor, can activate the tumor suppressor p53 and regulate expression of p53 target genes upon DNA damage. However, whether ATF3 contributes to the maintenance of genome stability and tumor suppression remains unknown. Here we report that Atf3-deficient (Atf3-/-) mice developed spontaneous tumors, and died significantly earlier than wild-type (Atf3+/+) mice. Consistent with these results, Atf3-/- mouse embryonic fibroblasts (MEFs) had more aberrant chromosomes and micronuclei, and were genetically unstable. Whereas we demonstrated that ATF3 activated p53 and promoted its pro-apoptotic activity in mouse thymi and small intestines, the chromosomal instability caused by Atf3 deficiency was largely dependent on the regulation of p53 by ATF3. Interestingly, loss of Atf3 also promoted spontaneous tumorigenesis in Trp53+/- mice, but did not affect tumor formation in Trp53-/- mice. Our results thus provide the first genetic evidence linking ATF3 to the suppression of the early development of cancer, and underscore the importance of ATF3 in the maintenance of genome integrity. PMID- 28869598 TI - RCC2 is a novel p53 target in suppressing metastasis. AB - RCC2 (also known as TD60) is a highly conserved protein involved in prognosis in colorectal cancer. However, its relationship with tumor development is less understood. Here we demonstrate a signaling pathway defining regulation of RCC2 and its functions in tumor progression. We report that p53 is a transcriptional regulator of RCC2 that acts through its binding to a palindromic motif in the RCC2 promoter. RCC2 physically interacts and deactivates a small GTPase Rac1 that is known to be involved in metastasis. We solved a high-resolution crystal structure of RCC2 and revealed one RCC1-like domain with a unique beta-hairpin that is requisite for RCC2 interaction with Rac1. p53 or RCC2 deficiency leads to activation of Rac1 and deterioration of extracellular matrix sensing (haptotaxis) of surface-bound gradients. Ectopic expression of RCC2 restores directional migration in p53-null cells. Our results demonstrate that p53 and RCC2 signaling is important for regulation of cell migration and suppression of metastasis. We propose that the p53/RCC2/Rac1 axis is a potential target for cancer therapy. PMID- 28869600 TI - FOXO3-mediated chemo-protection in high-stage neuroblastoma depends on wild-type TP53 and SESN3. AB - Forkhead box O class transcription factors are homeostasis regulators that control cell death, longevity and therapy-resistance. In neuroblastoma (NB), nuclear FOXO3 correlates with stage M disease and poor prognosis. To analyze whether FOXO3 contributes to drug-resistance in this childhood cancer, we investigated how different high-stage-derived NB cells respond to the activation of an ectopic FOXO3 allele. We found endogenous FOXO3 mostly localized to the nucleus-upon activation of an ectopic, 4OHT-activated FOXO3(A3)ER fusion protein two of the cell lines underwent apoptosis, whereas in the others FOXO3-activation even increased survival during drug-treatment. In the latter cell type, FOXO3 did not induce the BH3-only protein BCL2L11/BIM due to impaired binding of FOXO3 to the BIM-promoter, but still activated other FOXO3 targets. It was shown before that FOXO3 and TP53 physically interact with each other at two different regions the TP53-N-terminus binds to the FOXO3-DNA binding domain (DBD) and the FOXO3-C terminus interacts with the TP53-DBD. Interestingly, cell lines that undergo FOXO3-induced cell death carry homozygous point mutations in the TP53-DBD near the structural hotspot-mutation-site R175H, which abrogated FOXO3-TP53 interaction. In contrast, in FOXO3-death-resistant cells no point mutations in the TP53-DBD were found-in these cells FOXO3-TP53 complexes are formed and FOXO3 binding to the BIM-promoter, but not the induction of the detoxifying protein SESN3, were prevented, which in turn increased chemo-protection in this type of high-stage-derived NB cells. Our combined data suggest that FOXO3 steps in as a death inducer in case of TP53-mutation, whereas functional TP53 alters FOXO3 target-promoter-recognition, which prevents death induction by FOXO3 and instead increases chemo-protection and survival of NB cells. This novel mechanism may explain the low incidence of TP53 mutation in high-stage NB at diagnosis and suggests FOXO3 as a therapeutic target for this childhood malignancy. PMID- 28869599 TI - Taxane-mediated radiosensitization derives from chromosomal missegregation on tripolar mitotic spindles orchestrated by AURKA and TPX2. AB - Taxane-based radiochemotherapy is a central treatment option for various cancer entities in locally advanced stages. The therapeutic synergism of this combined modality approach due to taxane-mediated radiosensitization of cancer cells is well-known. However, the underlying molecular mechanisms remain largely elusive, and mechanism-derived predictive markers of taxane-based radiochemotherapy are currently not available. Here, we show that clinically relevant doses of Paclitaxel, the prototype taxane, stimulate a tripolar mode of mitosis leading to chromosomal missegregation and aneuploidization rather than interfering with cell cycle progression. This distinct mitotic phenotype was interlinked with Paclitaxel-mediated radiosensitization via overexpression of mitotic Aurora kinase A (AURKA) and its cofactor TPX2 whose knockdown rescued the bipolar mode of cell division and largely attenuated the radiosensitizing effects of Paclitaxel. In the cancer genome atlas (TCGA) lung adenocarcinoma cohort, high expression levels of AURKA and TPX2 were associated with specifically improved overall survival upon taxane-based radiochemotherapy, but not in case of non taxane-based radiochemotherapy, chemo- or radiotherapy only. Thus, our data provide insights into Paclitaxel-mediated radiosensitization on a mechanistic and molecular level and identify AURKA and TPX2 as the first potential mechanism based, predictive markers of taxane-based radiochemotherapy. PMID- 28869601 TI - Role of SMAD proteins in colitis-associated cancer: from known to the unknown. AB - Small mothers against decapentaplegic (SMAD) proteins are a family of signal transduction molecules in transforming growth factor beta (TGFbeta) ligand pathways that have been found to have a key role in the pathogenesis of inflammatory bowel disease (IBD). Long standing IBD predisposes individuals to colitis-associated colorectal cancer (CAC), an entity that possess unique characteristics compared to hereditary and sporadic cancer. The ligands of the TGFbeta super family along with SMADs have also been implicated in several aspects of colorectal cancer formation. SMAD proteins are shown to be involved in a number of potentially carcinogenic mechanisms such as altering gene transcription, controlling stem cell differentiation to causing epigenetic changes. Modulation of these proteins has emerged as a novel therapeutic intervention for IBD although its effect on carcinogenesis remains elusive. This account reviews available evidence linking SMAD proteins to CAC and explores the potential areas for future research in this area. PMID- 28869604 TI - Myc target gene, long intergenic noncoding RNA, Linc00176 in hepatocellular carcinoma regulates cell cycle and cell survival by titrating tumor suppressor microRNAs. AB - Hepatocellular carcinoma (HCC) is a frequent form of cancer with a poor prognosis and with limited possibilities for medical intervention. Recent evidence has accumulated that long noncoding RNAs (lncRNAs) are important regulators of disease processes including cancer. Chromatin remodeling in cancer cells may result in an unusual expression of lncRNAs and indeed it has been shown that more than 7000 unannotated lncRNAs are expressed in HCCs. We identified a novel long intergenic noncoding RNA, Linc00176, that plays a role in proliferation and survival of HCC. Linc00176 regulates expression of more than 200 genes by the sponge function for tumor suppressor miRNAs, miR-9 and miR-185. Linc00176 is expressed at a high level only in HCC, and is activated by Myc, Max and AP-4 transcription regulators. Myc also upregulates miR-9 and miR-185. In Linc00176 depleted HCC, these miRNAs were released from Linc00176 and downregulated their target mRNAs. Thus, depletion of Linc00176 disrupted the cell cycle and induced necroptosis in HCC via released tumor suppressor miRNAs. These data indicate that atypically expressed lncRNAs may be useful targets for cancer therapy. PMID- 28869602 TI - Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment. AB - DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small-molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe. PMID- 28869603 TI - A regulatory circuit composed of DNA methyltransferases and receptor tyrosine kinases controls lung cancer cell aggressiveness. AB - Overexpression of DNMT1 and KIT is prevalent in lung cancer, yet the underlying molecular mechanisms are poorly understood. While the deregulated activation of DNMT1 or KIT has been implicated in lung cancer pathogenesis, whether and how DNMT1 and KIT orchestrate lung tumorigenesis are unclear. Here, using human lung cancer tissue microarrays and fresh frozen tissues, we found that the overexpression of DNMT1 is positively correlated with the upregulation of KIT in tumor tissues. We demonstrated that DNMT1 and KIT form a positive regulatory loop, in which ectopic DNMT1 expression increases, whereas targeted DNMT1 depletion abrogates KIT signaling cascade through Sp1/miR-29b network. Conversely, an increase of KIT levels augments, but a reduction of KIT expression ablates DNMT1 transcription by STAT3 pathway leading to in-parallel modification of the DNA methylation profiles. We provided evidence that KIT inactivation induces global DNA hypomethylation, restores the expression of tumor suppressor p15INK4B through promoter demethylation; in turn, DNMT1 dysfunction impairs KIT kinase signaling. Functionally, KIT and DNMT1 co-expression promotes, whereas dual inactivation of them suppresses, lung cancer cell proliferation and metastatic growth in vitro and in vivo, in a synergistic manner. These findings demonstrate the regulatory and functional interplay between DNA methylation and tyrosine kinase signaling in propelling tumorigenesis, providing a widely applicable approach for targeting lung cancer. PMID- 28869605 TI - Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775 induced DNA damage and apoptosis. AB - Lung cancer treatment remains a challenge for clinical practice and new therapeutic approaches are urgently needed. Loss of functional WEE1 kinase causes DNA replication stress, DNA damage and unscheduled mitotic entry due to elevated CDK activity. The selective WEE1 inhibitor MK-1775 synergize with DNA-damaging agent to inhibit cancer cell growth. Here we report that inhibition of Sirt1 deacetylase through small interfering RNA or selective inhibitor Ex527 greatly enhances MK-1775-induced growth inhibition and apoptosis in human lung cancer cells. We further demonstrate that Sirt1 interacts and deacetylates homologous recombination (HR) repair machinery proteins, including NBS1 and Rad51. Inhibition of Sirt1 impairs HR repair activity, which causes unrepairable damage when combining MK-1775 and Ex527. Meanwhile, combination of MK-1775 and Ex527 induces cooperative antitumor activity in lung cancer xenograft model in vivo. Thus, our study provides a novel therapeutic strategy to optimize MK-1775 treatment efficiency in lung cancers. PMID- 28869606 TI - KCTD12 promotes tumorigenesis by facilitating CDC25B/CDK1/Aurora A-dependent G2/M transition. AB - Cell cycle dysregulation leads to uncontrolled cell proliferation and tumorigenesis. Understanding the molecular mechanisms underlying cell cycle progression can provide clues leading to the identification of key proteins involved in cancer development. In this study, we performed proteomics analysis to identify novel regulators of the cell cycle. We found that potassium channel tetramerization domain containing 12 (KCTD12) was significantly upregulated in M phase compared with S phase. We also found that KCTD12 overexpression not only facilitated the G2/M transition and induced cancer cell proliferation, but also promoted the growth of subcutaneous tumors and Ki-67 proliferation index in mice. Regarding the mechanism underlying these phenomena, cyclin-dependent kinase 1 (CDK1) was identified as an interacting partner of KCTD12 by immunoprecipitation and mass spectrometry analysis, which showed that KCTD12 activated CDK1 and Aurora kinase A (Aurora A) and that the effects of KCTD12 on CDK1 phosphorylation and cell proliferation were abrogated by cell division cycle 25B (CDC25B) silencing. In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer promoting effects. Furthermore, we analyzed the expression levels of various genes and the correlations between the expression of these genes and survival using tumor tissue microarray and Gene Expression Omnibus (GEO) data sets. The data showed that KCTD12 expression was significantly upregulated in cervical and lung cancers. More importantly, high KCTD12 expression was associated with larger tumor sizes, higher pathological stages and poor patient survival. Collectively, our study demonstrate that KCTD12 binds to CDC25B and activates CDK1 and Aurora A to facilitate the G2/M transition and promote tumorigenesis and that Aurora A phosphorylates KCTD12 at serine 243 to trigger a positive feedback loop, thereby potentiating the effects of KCTD12. Thus, the KCTD12-CDC25B-CDK1-Aurora A axis has important implications for cancer diagnoses and prognoses. PMID- 28869607 TI - MRPL33 and its splicing regulator hnRNPK are required for mitochondria function and implicated in tumor progression. AB - MRPL33 gene encodes a large mitoribosomal subunit protein, which may be involved in mitochondrial translation. Although two splice variants of MRPL33 have been described, its splicing regulation remains elusive. Here we observed that inclusion of alternative exon 3 was greatly promoted in a panel of human cancer cells. Depletion of the exon 3-containing long isoform of MRPL33 (MRPL33-L) led to impaired proliferation and increased apoptosis in cancer cell lines and in a xenograft model. MRPL33-L knockdown could also induce mitochondrial dysfunction including increased accumulation of reactive oxygen species, decreased ATP production and 16 S rRNA levels. We further showed that alternative splicing of MRPL33-L pre-mRNA is regulated by hnRNPK and that knocking down hnRNPK could phenocopy MRPL33-L depletion. More importantly, overexpression of MRPL33-L could increase tumorigenic potential of hnRNPK-depleted cancer cells, likely indicating that hnRNPK mediates tumorigenesis through splicing regulation of MRPL33 pre mRNA. Finally, we found that inclusion of MRPL33 exon 3 was promoted in human colorectal cancer tissues and this was correlated with hnRNPK levels. In summary, our findings underscore the biological significance of MRPL33-L and hnRNPK in the tumor formation and identifies hnRNPK as a critical splicing regulator of MRPL33 pre-mRNA in cancer cells. PMID- 28869608 TI - CNPY2 is a key initiator of the PERK-CHOP pathway of the unfolded protein response. AB - The unfolded protein response (UPR) in the endoplasmic reticulum (ER) is a highly conserved protein-quality-control mechanism critical for cells to make survival or-death decisions under ER-stress conditions. However, how UPR sensors are activated remains unclear. Here, we report that ER luminal protein canopy homolog 2 (CNPY2) is released from grp78 upon ER stress. Free CNPY2 then engages protein kinase R-like ER kinase (PERK) to induce expression of the transcription factor C/EBP homologous protein (CHOP), thereby initiating the UPR. Indeed, deletion of CNPY2 blocked the PERK-CHOP pathway and protected mice from UPR-induced liver damage and steatosis. Additionally, CNPY2 is transcriptionally upregulated by CHOP in a forward-feed loop to further enhance UPR signaling. These findings demonstrate the critical roles of CNPY2 in ER stress and suggest that CNPY2 is a potential new therapeutic target for UPR-related diseases such as metabolic disorders, inflammation and cancer. PMID- 28869609 TI - N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis. AB - RNA modifications are integral to the regulation of RNA metabolism. One abundant mRNA modification is N6-methyladenosine (m6A), which affects various aspects of RNA metabolism, including splicing, translation and degradation. Current knowledge about the proteins recruited to m6A to carry out these molecular processes is still limited. Here we describe comprehensive and systematic mass spectrometry-based screening of m6A interactors in various cell types and sequence contexts. Among the main findings, we identified G3BP1 as a protein that is repelled by m6A and positively regulates mRNA stability in an m6A-regulated manner. Furthermore, we identified FMR1 as a sequence-context-dependent m6A reader, thus revealing a connection between an mRNA modification and an autism spectrum disorder. Collectively, our data represent a rich resource and shed further light on the complex interplay among m6A, m6A interactors and mRNA homeostasis. PMID- 28869612 TI - Instilling defect tolerance in new compounds. PMID- 28869610 TI - Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas. AB - Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupre-Christol syndrome (BDCS) a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor suppressor properties of ACTRT1. PMID- 28869611 TI - Human-monoclonal-antibody therapy protects nonhuman primates against advanced Lassa fever. AB - There are no approved treatments for Lassa fever, which is endemic to the same regions of West Africa that were recently devastated by Ebola. Here we show that a combination of human monoclonal antibodies that cross-react with the glycoproteins of all four clades of Lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge. PMID- 28869613 TI - Age does not adversely influence outcomes among patients older than 60 years who undergo allogeneic hematopoietic stem cell transplant for AML and myelodysplastic syndrome. AB - Allogeneic hematopoietic stem cell transplant (AHSCT) outcomes data of older AML/myelodysplastic syndrome (MDS) patients are limited. We retrospectively evaluated consecutive patients ?60 years old with AML/MDS who underwent AHSCT between January 2005 and December 2014. The primary objectives were to determine nonrelapse mortality (NRM), relapse, relapse-free survival (RFS) and overall survival (OS) at 1 year post AHSCT. A total of 159 patients underwent AHSCT with a median age of 64 (range, 60-75) years. Of these, 103 patients (65%) had AML and 56 patients (35%) had MDS. At 1 year post AHSCT, grade III-IV acute GvHD and chronic GvHD occurred in 20.8% (95% confidence interval (CI), 14.9-27.5%) and 54.1% (95% CI, 46.0-61.5%) of patients, respectively. NRM, RFS, relapse rate and OS at 1 year post AHSCT were 25.3% (95% CI, 18.8-32.3%), 53.3% (95% CI, 46.1 61.7%), 21.4% (95% CI, 15.4-28.1%) and 56.4% (95% CI, 49.2-54.7%), respectively. High disease risk index was associated with poor RFS, OS and higher relapse rate (P<0.03), whereas non-thymoglobulin-based GvHD prophylaxis, higher comorbidity index (?3) and MDS were associated with higher NRM (P<0.03). Importantly, age did not have an adverse effect on NRM, relapse, RFS and OS. AHSCT was well tolerated. Hence, older age alone should not be considered a contraindication to AHSCT. PMID- 28869614 TI - Impact of cigarette smoking on survival after myeloablative allogeneic hematopoietic stem cell transplantation and contribution of invasive fungal infection. PMID- 28869616 TI - Successful bone marrow transplantation in two sisters with activated phosphoinositide 3-kinase delta syndrome 2. PMID- 28869615 TI - Acute and fatal cardiotoxicity following high-dose cyclophosphamide in a patient undergoing autologous stem cell transplantation for systemic sclerosis despite satisfactory cardiopulmonary screening. PMID- 28869619 TI - alphabeta-T-cell depleted donor lymphocyte infusion for leukemia relapse after allogeneic stem cell transplantation. PMID- 28869618 TI - Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms' tumor: a CIBMTR retrospective analysis. AB - Despite the marked improvement in the overall survival (OS) for patients diagnosed with Wilms' tumor (WT), the outcomes for those who experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and were reported to the Center for International Blood and Marrow Transplantation Research. The 5 year estimates for event-free survival (EFS) and OS were 36% (95% confidence interval (CI); 29-43%) and 45% (95 CI; 38-51%), respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. As attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus HDT followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. As disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy. PMID- 28869617 TI - A phase 1 trial of 90Y-Zevalin radioimmunotherapy with autologous stem cell transplant for multiple myeloma. AB - This phase 1 study (clinical trial NCT00477815) was conducted to determine the maximum tolerated dose (MTD) of yttrium-90 ibritumomab tiuxetan (90Y-Zevalin) with high dose melphalan (HDM) therapy in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). In a 3+3 trial design, 30 patients received rituximab 250 mg/m2 with indium-111 ibritumomab tiuxetan (111In Zevalin) for dosimetry (day -22); rituximab 250 mg/m2 with escalating doses of 90Y-Zevalin (day -14); melphalan 100 mg/m2 (days -2,-1) followed by ASCT (day 0) and sargramostim (GM-CSF, day 0) until neutrophil engraftment. Each patient's 111In-Zevalin dosimetry data were used to calculate the dose of 90Y-Zevalin (in mCi) to deliver 10, 12, 14, 16, 18 or 20 Gy to the liver. Dose limiting toxicities were seen in 3 patients. The overall response rate was 73% (22/30) with stringent complete response in 2 patients; complete response, 5; very good partial response, 12; and partial response, 3. The median PFS was 16.5 months and the median overall survival was 63.4 months. In MM, the MTD of 90Y-Zevalin with HDM is 18 Gy to the liver. The addition of radiation with novel delivery methods such as radioimmunotherapy combined with standard transplant regimens warrants further study. PMID- 28869620 TI - The influence of the cumulated deformation energy in the measurement by the DSI method on the selected mechanical properties of bone tissues. AB - PURPOSE: The goal of the study was to determine the influence of DSI test conditions, i.e., loading/unloading rates, hold time, and the value of the maximum loading force on selected mechanical properties of trabecular bone tissue. METHODS: The test samples were resected from a femoral head of a patient qualified for a hip replacement surgery. During the DSI tests hardness (HV, HM, HIT) and elastic modulus (EIT) of trabecular bone tissue were measured using the Micro Hardness Tester (MHT, CSEM). RESULTS: The analysis of the results of measurements and the calculations of total energy, i.e., elastic and inelastic (Wtotal, Welastic, Winelastic) and those of hardness and elasticity made it possible to assess the impact of the process parameters (loading velocity, force and hold time) on mechanical properties of bone structures at a microscopic level. CONCLUSIONS: The coefficient k dependent on the EIT/HIT ratio and on the stored energy (DeltaW = Wtotal - Welastic) is a measure of the material reaction to the loading and the deformation of tissue. PMID- 28869621 TI - Influence of fibre reinforcement on selected mechanical properties of dental composites. AB - PURPOSE: For splinting or designing adhesive bridges, reconstructive composite structures with increased mechanical properties owing to embedded reinforcement fibres are used. The aim of this article was to determine the influence of glass and aramid fibres on the mechanical strength of composites reinforced with these fibres. METHODS: Two polymer-ceramic microhybrid materials: Boston and Herculite were tested. Three types of reinforcement fibres were used: aramid (Podwiazka) with a single layer weave, a single layer weave glass fibre (FSO) and triple layer weave glass fibre (FSO evo). Tests were conducted in accordance with the requirements of ISO 4049:2009. The following material types were chosen for research: Boston, Boston + Podwiazka, Herculite, Herculite + Podwiazka, Herculite + FSO and Herculite + FSO evo. The scope of research included: flexural strength ?B, bending modulus of elasticity epsilonB and work to failure of the reinforced composite Wfb. Additionally, microscopic observations of fracture occurring in samples were made. RESULTS: In comparison: the Herculite (97.7 MPa) type with the Herculite + FSO evo (177.5 MPa) type was characterized by the highest strength. Fibre reinforcement resulted in decreasing the elasticity modulus: Herculite + reinforcement (6.86 GPa; 6.33 GPa; 6.11 GPa) in comparison with the Herculite (9.84 GPa) and respectively Boston + reinforcement (10.08 GPa) as compared with the Boston (11.81 GPa). CONCLUSIONS: Using glass fibres increases flexural strength of the test composites. Using aramid fibres does not change their strength. The elasticity modulus of the reinforced reconstructive structures decreases after application of either type of fibres. However, their resistance to the crack initiation increases. PMID- 28869622 TI - Spinal range of motion and plantar pressure in sport climbers. AB - PURPOSE: The aim of the study was to investigate the range of motion (ROM) of lumbar and thoracic articulations and static and dynamic plantar pressure in sport climbing athletes. METHODS: The sample included 30 sport climbers with a minimum of 2 years training experience and 30 physical education students who served as an active untrained control. ROM was assessed by a Saunders digital inclinometer and plantar pressure by a baropodometric platform. RESULTS: Mean spinal ROMs were greater in the sport climbers with an exception of extension, rotation, and lateral thoracic flexion, with a high degree of statistical significance obtained in the majority of the analyzed ROMs. The climbers exhibited increased mean forefoot pressure (smaller rearfoot pressure) in both the dominant and nondominant extremities, with significant intergroup differences found in dominant forefoot/rearfoot pressure distribution. CONCLUSIONS: Sport climbers present increased lumbar and thoracic ROM. The characteristics of climbing may also affect transverse arch structure and plantar pressure distribution. PMID- 28869623 TI - On influence of anodic oxidation on thrombogenicity and bioactivity of the Ti 13Nb-13Zr alloy. AB - PURPOSE: This paper reports on the results of investigations on the blood response to the modified of surfaces titanium alloys. METHODS: To enhance biocompatibility of the Ti-13Nb-13Zr alloy, anodisation was performed at 80 and 150 V. The oxidation process was carried out in a solution containing 4 mol dm-3 H3PO4 and 0.59 mol dm-3 Ca(H2PO2)2. RESULTS: The haemolytic activity of the titanium alloy surface was not altered much by the anodisation. The obtained values of the percentage of haemolysis were well below the levels required for the materials intended for blood contact. The clotting time of the blood was similar for the as-ground sample and the sample anodised at 80 V. For the sample anodised at 150 V the clotting time was shorter. The differences between these samples were observed in partial thromboplastin time after activation, prothrombin time and thrombin time, after 24 h. Extracts taken from the samples were not toxic towards the L-929 mouse fibroblast cells. CONCLUSIONS: The proposed treatment might be appropriate for the preparation of modified Ti-13Nb 13Zr surfaces intended for bone reconstruction or cardiovascular implants depending on process parameters. PMID- 28869624 TI - Computerized static posturography and laterality in children. Influence of age. AB - PURPOSE: The present study aims to explore relationships between footedness and posturographic assessment in children aged from 4 to 10. A real-time computerised device was used on a force plate for movement analysis. It requires a static posturography to assess postural control of children with the same handedness and footedness. METHODS: Thirty eight right-handed and right-footed children organized in three age groups of 4 to 6 years old, 6 to 8 years old and 8 to 10 years old participated in the study. Two statical tests, the Unilateral Stance (US) and the Weight Bearing Squat (WBS) were performed, jointly with a dynamic balance examination (Limits of Stability (LOS)). All these tests were executed to explore the body capability of the right/left side. RESULTS: The study demonstrated significant differences involving the right/left side among the three age groups. Better performance on the youngest children's right part and on the oldest children's left part was observed. Differences between the left and right sides of the body were noticeably revealed by posturographic assessments in right-handed and right-footed children. CONCLUSIONS: Age seemed to be a determinant for these outcomes. Maturation of the vestibular at the ages of 6 or 7 years might explain the observed differences between the youngest children and olderchildren. PMID- 28869625 TI - Phase composition and morphology characteristics of ceria-stabilized zirconia powders obtained via sol-gel method with various pH conditions. AB - PURPOSE: High purity, fine crystalline, degradation-free at low temperature powders have attracted special interest in CAD/CAM prosthetic dentistry full ceramic restorations. This study reports the preparation and characterisation of zirconia-ceria (0.9 ZrO2 0.1 CeO2) powders. Materials were obtained from zirconium-n-alkoxide and cerium nitrate hexahydrate in the pH 2-4 and 8-10. METHODS: Zirconia- ceria powders were obtained with the sol-gel method in a humid free environment. Thermal analysis (TGA/DTA) of the as-prepared materials was made for an assessment of its behaviour at elevated temperatures. Specimens were dried at 80 degrees C and calcinated in two stages: at 300 degrees C with soaking time 2.5 h and 850 degrees C with holding time 2.5 h, in order to evaluate the phase transformations. Thermal analyses of the as-dried powders were made for an assessment of its thermal behaviour during heat treatment up to 1000 degrees C. By X-ray diffraction (XRD), polymorphs of ZrO2 were identified. Additionally, scanning electron microscopy (SEM) and laser particle size distribution (PSD) were involved for characterisation of morphology of the powders. RESULTS: A correlation between the pH of the colloidal system and the morphology of the as-obtained powders were found. Based on analysis (SEM, PSD), structures were identified known as soft and hard agglomerates. CONCLUSIONS: It can be stated that differences found between powder morphology were dependent on the value pH used, which can be crucial for powder densification during sintering and compacting green bodies which, as a consequence, may be crucial for the lifetime of zirconia prostheses. Correlations between phase composition and pH are difficult to grasp, and require further, more sophisticated, studies. PMID- 28869626 TI - Chemical passivation as a method of improving the electrochemical corrosion resistance of Co-Cr-based dental alloy. AB - PURPOSE: The purpose of the study was to evaluate corrosion resistance of Wirobond C(r) alloy after chemical passivation treatment. METHODS: The alloy surface undergone chemical passivation treatment in four different media. Corrosion studies were carried out by means of electrochemical methods in saline solution. Corrosion effects were determined using SEM. RESULTS: The greatest increase in the alloy polarization resistance was observed for passive layer produced in Na2SO4 solution with graphite. The same layer caused the highest increase in corrosion current. Generally speaking, the alloy passivation in Na2SO4 solution with graphite caused a substantial improvement of the corrosion resistance. The sample after passivation in Na2SO4 solution without graphite, contrary to others, lost its protective properties along with successive anodic polarization cycles. The alloy passivation in Na3PO4 solution with graphite was the only one that caused a decrease in the alloy corrosion properties. The SEM studies of all samples after chemical passivation revealed no pit corrosion - in contrast to the sample without any modification. CONCLUSIONS: Every successive polarization cycle in anodic direction of pure Wirobond C(r) alloy enhances corrosion resistance shifting corrosion potential in the positive direction and decreasing corrosion current value. The chemical passivation in solutions with low pH values decreases susceptibility to electrochemical corrosion of Co-Cr dental alloy. The best protection against corrosion was obtained after chemical passivation of Wirobond C(r) in Na2SO4 solution with graphite. Passivation with Na2SO4 in solution of high pH does not cause an increase in corrosion resistance of WIROBOND C. Passivation process increases alloy resistance to pit corrosion. PMID- 28869627 TI - Somatotype variables related to strength and power output in male basketball players. AB - PURPOSE: The purpose of this study was to investigate the relationship between somatotype, muscular strength, power output measured in maximal cycle ergometer exercise bouts, and maximal power output and height of rise of the body mass centre (jump height) measured in akimbo counter movement jump (ACMJ), counter movement jump (CMJ) and spike jump (SPJ), in male basketball players. METHODS: Thirteen male basketball players (second division, age 19.4 +/- 0.8 years, body height 192.9 +/- 5.6 cm, body mass 88.8 +/- 8.6 kg, training experience 9.3 +/- 0.8 years) participated in the study. Somatotype was determined using the Heath Carter method. Maximal joint torques were measured under static conditions. Power output was measured in 2 maximal cycle ergometer exercise bouts, 10 seconds each, with increasing external loads equal to 7.5 and 10.0% of the body weight (BW). All jump trials (ACMJ, CMJ and SPJ) were performed on a force plate. RESULTS: The mean somatotype of basketball players amounted to: 2.8-4.2-3.2. The sum of the joint torques for left and right lower extremities (0.613), trunk (0.631) and all six measured muscle groups (0.647) were significantly correlated (p < 0.05) with the mesomorphic component. Endomorphic, mesomorphic and ectomorphic components were correlated insignificantly with values of maximal power and height of jump during ACMJ, CMJ and SPJ trials. The power output measured in maximal cycle ergometer exercise bouts with increasing external loads was significantly correlated (p < 0.05) with mesomorphy and ectomorphy. CONCLUSION: It can be assumed that basketball players' anthropometric characteristics can influence their level of performance but it is not a decisive factor. PMID- 28869628 TI - The influence of the acoustic stimulus on postural stability. AB - PURPOSE: The purpose of this study was to assess if 65 dB and 4000 Hz stimuli affect postural stability of young normally hearing people. METHODS: Posturography examinations belong to clinical tests which evaluate the motor skills. Posturography can be divided into static posturography and dynamic posturography. In both static and dynamic posturography patient stays on the platform with opened and closed eyes, but in the case of dynamic one, platform is unstable. In this study the Multitest Equilibre platform produced by FRAMIRAL was used. Patients took part in tests with opened and closed eyes, on stable and unstable platform. Additionally, patients were exposed to 65 dB and 4000 Hz acoustic stimuli. The sound pressure level, and frequency was belonging to the best audibly frequency range. RESULTS: Parameters such as velocity and surface were examined. The difference between velocity measured with acoustic stimuli and without acoustic stimuli was observed. On the other hand there was no difference in surface results. CONCLUSIONS: The statistically significant difference between velocity of patients center of gravity movements, measured on unstable platform, in the presence of 4000 Hz, 65 dB acoustic stimulus and without additional disturbances was observed. PMID- 28869629 TI - Experimental testing and constitutive modeling of the mechanical properties of the swine skin tissue. AB - PURPOSE: The aim of the study was an estimation of the possibility of using hyperelastic material models to fit experimental data obtained in the tensile test for the swine skin tissue. METHODS: The uniaxial tensile tests of samples taken from the abdomen and back of a pig was carried out. The mechanical properties of the skin such as the mean Young's modulus, the mean maximum stress and the mean maximum elongation were calculated. The experimental data have been used to identify the parameters in specific strain-energy functions given in seven constitutive models of hyperelastic materials: neo-Hookean, Mooney-Rivlin, Ogden, Yeoh, Martins, Humphrey and Veronda-Westmann. An analysis of errors in fitting of theoretical and experimental data was done. RESULTS: Comparison of load -displacement curves for the back and abdomen regions of skin taken showed a different scope of both the mean maximum loading forces and the mean maximum elongation. Samples which have been prepared from the abdominal area had lower values of the mean maximum load compared to samples from the spine area. The reverse trend was observed during the analysis of the values of elongation. An analysis of the accuracy of model fitting to the experimental data showed that, the least accurate were the model of neo- -Hookean, model of Mooney-Rivlin for the abdominal region and model of Veronda-Westmann for the spine region. CONCLUSIONS: An analysis of seven hyperelastic material models showed good correlations between the experimental and the theoretical data for five models. PMID- 28869630 TI - Deposition of phosphate coatings on titanium within scaffold structure. AB - PURPOSE: Existing knowledge about the appearance, thickness, and chemical composition of phosphate coatings on titanium inside porous structures is insufficient. Such knowledge is important for the design and fabrication of porous implants. METHODS: Metallic scaffolds were fabricated by selective laser melting of 316L stainless steel powder. Phosphate coatings were deposited on Ti sensors placed either outside the scaffolds or in the holes in the scaffolds. The electrochemically-assisted cathodic deposition of phosphate coatings was performed under galvanostatic conditions in an electrolyte containing the calcium and phosphate ions. The phosphate deposits were microscopically investigated; this included the performance of mass weight measurements and chemical analyses of the content of Ca2+ and ? 24 PO ions after the dissolution of deposits. RESULTS: The thicknesses of the calcium phosphate coatings were about 140 and 200 nm for isolated titanium sensors and 170 and 300 nm for titanium sensors placed inside pores. Deposition of calcium phosphate occurred inside the pores up to 150 mm below the scaffold surface. The deposits were rich in Ca, with a Ca/P ratio ranging from 2 to 2.5. CONCLUSIONS: Calcium phosphate coatings can be successfully deposited on a Ti surface inside a model scaffold. An increase in cathodic current results in an increase in coating thickness. Any decrease in the cathodic current inside the porous structure is slight. The calcium phosphate inside the pores has a much higher Ca/P ratio than that of stoichiometric HAp, likely due to a gradual increase in Ca fraction with distance from the surface. PMID- 28869631 TI - The Upper Limb Motion Deviation Index: A new comprehensive index of upper limb motion pathology. AB - PURPOSE: The aim of the research was to formulate a new index enabling assessment of the overall pathology of the upper limb movement. It defines the difference between the pathological movement and a normal movement pattern. METHODS: Methodology of determining the index is based on a mathematical algorithm for calculating the Gait Deviation Index which is based on advanced methods of image comparison. To calculate the ULMDI index, one must divide the analyzed movement into cycles appropriate to the nature of the movement (similarly in gait it is the gait cycle) and then determine kinematic quantities (courses of joint angles). RESULTS: A group of 23 healthy people (10 women: k1-k10 and 13 men: m1 m13) as the reference group and a group of 3 persons with mobility impairments (p1-p3) took part in the research. Time values of the angles of the joints on both upper limbs were registered and then ULMDI indexes were calculated. CONCLUSIONS: It has been shown that the developed ULMDI index allows to detect the deviations from the accepted norm in the performance of movements. The results showed that both the description of the motor dysfunction of examined person based on the diagnosis of the physician, a detailed analysis of kinematic waveforms received during the tests and the calculated values provide a coherent picture of the state of a human movement. The index analysis is less time consuming for the doctor, and the comparison of the results at various stages of therapy gives an objective picture of the rehabilitation progress. PMID- 28869633 TI - Optimal selection of dental implant for different bone conditions based on the mechanical response. AB - PURPOSE: Bone quality varies from one patient to another extensively. Young's modulus may deviate up to 40% of normal bone quality, which results into alteration of bone stiffness immensely. The prime goal of this study is to design the optimum dental implant considering the mechanical response at bone implant interfaces for a patient with specific bone quality. METHOD: 3D models of mandible and natural molar tooth were prepared from CT scan data, while dental implants were modelled using different diameter, length and porosity and FE analysis was carried out. Based on the variation in bone density, five different bone qualities were considered. First, failure analysis of implants, under maximum biting force of 250 N had been performed. Next, the implants that remained were selected for observation of mechanical response at bone implant interfaces under common chewing load of 120 N. RESULT: Maximum Von Mises stress did not surpass the yield strength of the implant material (TiAl4V). However, factor of safety of 1.5 was considered and all but two dental implants survived the design stress or allowable stress. Under 120 N load, distribution of Von Mises stress and strain at the boneimplant interface corresponding to the rest of the implants for five bone conditions were obtained and enlisted. CONCLUSION: Implants exhibiting interface strain within 1500-3000 microstrain range show the best bone remodelling and osseointegration. So, implant models having this range of interface strains were selected corresponding to the particular bone quality. A set of optimum dental implants for each of the bone qualities were predicted. PMID- 28869632 TI - Evaluation of reliability and concurrent validity of two optoelectric systems used for recording maximum vertical jumping performance versus the gold standard. AB - PURPOSE: The objective of this study was to evaluate the reliability and validity of two alternative systems used for jumping performance measurement. METHODS: Two groups of subjects were tested. The first group consisted of 15 male adults (21.3 +/- 1.7 years) and the second group consisted of 16 female volleyball players (17.2 +/- 0.9 years). We used three different systems of data collection in the study. Two of the used systems are based on optoelectric components. The Optojump Next system is referred to as the optoelectric system, and BTS Smart-E is refered to as the video system. Concurrent validity of these systems was verified with the use of "gold standard" which is force platform. All systems were used to estimate the height of vertical jumps. RESULTS: Both optoelectric systems turned out to be highly reliable with the ICCs = 0.98 for Optojump and 0.9 for BTS Smart. Their concurrent validity with the force platform data was also very high r = 0.99 and r = 0.97, respectively. CONCLUSIONS: Comparison of these two systems shows distinct differences between them. Out of the two systems, Optojump system is more suitable for quick and reliable sports testing while when BTS-Smart is better for research and clinical testing. PMID- 28869634 TI - The effects of an early intrahospital rehabilitation on weight bearing during lower extremity lengthening with Ilizarov method. AB - PURPOSE: Exerting axial pressure on the affected lower limb remains one of the most crucial elements of Ilizarov method. The objective was to determine the effects of an early intrahospital rehabilitation on weight bearing during lower extremity lengthening with Ilizarov method. METHODS: The study included 15 patients who underwent lower limb lengthening. The patients were tested on the third day after surgery using the pedobarographic platform. The tests were performed four times in the standing position: twice with the support of forearm crutches and twice without crutches. Patients were asked to either remain in the relaxed standing position (two tests) or use the lower limb equipped with Ilizarov apparatus to support the body weight (two tests). RESULTS: In relaxed stance average pressure with forearm crutches was 24.1% for affected limb, as compared to 75.9% for the healthy limb. In test without forearm crutches average pressure for affected limb was 26.1%, as compared to 73.9% for the healthy limb. Patients shifted body weight to the affected limb with forearm crutches on average, at the rate of 53.6%. In test without forearm crutches the affected limb was supporting the body weight at the rate of 48.26%. None of the patients was able to fully support the body weight on the affected leg. CONCLUSIONS: In spite of strict physiotherapy regimen, patients are neither able to equally distribute their body weight between the two lower limbs nor to shift their body weight to the limb equipped with Ilizarov apparatus. PMID- 28869635 TI - Assessing the impact of a targeted plyometric training on changes in selected kinematic parameters of the swimming start. AB - PURPOSE: The aim of this study was to analyse changes taking place within selected kinematic parameters of the swimming start, after completing a six-week plyometric training, assuming that the take-off power training improves its effectiveness. METHODS: The experiment included nine male swimmers. In the pre test the swimmers performed three starts focusing on the best performance. Next, a plyometric training programme, adapted from sprint running, was introduced in order to increase a power of the lower extremities. The programme entailed 75 minute sessions conducted twice a week. Afterwards, a post-test was performed, analogous to the pre-test. Spatio-temporal structure data of the swimming start were gathered from video recordings of the swimmer above and under water. RESULTS: Impulses triggered by the plyometric training contributed to a shorter start time (the main measure of start effectiveness) and glide time as well as increasing average take-off, flight and glide velocities including take-off, entry and glide instantaneous velocities. The glide angle decreased. CONCLUSIONS: The changes in selected parameters of the swimming start and its confirmed diagnostic values, showed the areas to be susceptible to plyometric training and suggested that applied plyometric training programme aimed at increasing take-off power enhances the effectiveness of the swimming start. PMID- 28869637 TI - Evaluation of functional and structural changes affecting the lumbar spine in professional field hockey players. AB - PURPOSE: The aim of this study was to evaluate functional and structural changes in the lumbar spine which occurred as a consequence of playing field hockey. METHODS: The research group consisted of 20 male professional field hockey players. Computed tomography scans were collected to define the radiological density of the vertebral bodies and to calculate Young's modulus. An electrogoniometer was used to measure the range of movement. Geometric parameters, such as Lumbar Lordosis Angle, Index of Lumbar Lordosis, Whitmann Ferguson Angle and Anterior Pelvic Tilt, were also measured. RESULTS: The values describing lumbar lordosis increased linearly with years of training and were significantly greater than those reported in the literature. Field hockey players displayed a larger range of flexion, side bending and rotation to the right. An analysis of radiological density discovered significantly high values. An analysis of Young's modulus showed that the vertebral bodies become more fragile. CONCLUSIONS: The results show that overuse changes in the lumbar spine of field hockey players are severe and highly correlated with years of training. PMID- 28869636 TI - Structure and corrosion resistance of Co-Cr-Mo alloy used in Birmingham Hip Resurfacing system. AB - PURPOSE: The endoprostheses made of cobalt-chromium-molybdenum (Co-Cr-Mo) alloys belong to the group of the most popular metallic implants used for reconstruction of hip joints. For such biomaterials, the primary goal is a correct and long-term functioning in the aggressive environment of body fluids. Therefore, the purpose of this study was to examine both the morphology and the corrosion resistance of implants made of the cobalt alloy used in Birmingham Hip Resurfacing (BHR) system (Smith & Nephew). For comparative purposes, the electrochemical studies were done for the nitrided stainless steel - Orthinox. METHODS: Observations of the microstructure of the material under investigation were performed by means of the optical metallographic microscope and the scanning electron microscope. Furthermore, Energy Dispersive X-ray Spectroscopy was used to analyse the chemical composition of the endoprosthesis. Characterisation and evaluation of electrochemical corrosion resistance of the selected alloys were performed by potentiodynamic polarisation tests. RESULTS: The structural studies confirmed that Co-Cr-Mo (BHR system) is characterised by a typical dendritic microstructure with carbide precipitates, mainly M23C6, within the interdendritic areas. The results of the polarisation measurements showed that the cobalt alloy investigated exhibits lower corrosion potential than Orthinox in the utilised environments (3% NaCl, simulated body fluid - Hank's Body Fluid). CONCLUSIONS: However, the high passivation ability of the Co-Cr-Mo alloy, as well as its resistance to the initiation and propagation of localised corrosion processes, indicate that this material is significantly more appropriate for long-term implants. PMID- 28869638 TI - Evaluation of the accuracy of the postural stability measurement with the Y Balance Test based on the levels of the biomechanical parameters. AB - PURPOSE: The study of dynamic balance involves tests that assess the muscle control of spatial changes of the position of the centre of gravity over the base of support. The purpose of this work was to determine the structure of the Y balance test and its accuracy based on the measurements of strength performance of the muscles acting on the knee joint as well as the flexibility and balance in boys aged 14 years. METHODS: The study included 43 schoolboys regularly participating in physical education lessons. The examination of postural stability was conducted with the use of the Y-balance test. The measurements of muscle strength and of resistance to fatigue of the extensors and flexors of knee joints in isometric contraction were performed on a measurement stand in a standard position with the use of tensometric sensors. The measurement of mobility range of the lower extremity joints was performed according to the SFTR. The examination of balance was performed with the use of the modified "Flamingo balance test". RESULTS: The factor structure of the Y-balance test results for the left and right lower extremities is similar and includes five principal independent factors that characterise the structure of analysed variables. They explain 76% and 74% of communality in total for the left and the right extremity, respectively. CONCLUSIONS: The extracted factor structure points to a hybrid structure of the Y-Balance Test and shows its accuracy in the measurements of the lower limb joint mobility and strength performance of knee joint extensors. PMID- 28869639 TI - Analysis of the influence of the transducer and its coupling layer on round window stimulation. AB - PURPOSE: In this work, a finite element study is proposed to evaluate the effects of the transducer and its coupling layer on the performance of round window (RW) stimulation. METHODS: Based on a set of micro-computer tomography images of a healthy adult's right ear and reverse engineering technique, a coupled finite element model of the human ear and the transducer was constructed and verified. Then, the effect of the cross-section of the transducer, the elastic modulus of the coupling layer, the mass of the transducer, and the preload of the transducer were studied. RESULTS: The increase of the transducer's cross-section area deteriorates the RW stimulation, especially at the lower frequencies. This adverse effect of the cross-section area's increase of the transducer can be reduced by adding a coupling layer between the transducer and the RW. However, the coupling layer's improvement on the RW stimulation is reduced with the increase of its elastic modulus. Moreover, the mass loading of the transducer decreases the RW stimulation's performance mainly at higher frequencies and applying a static preload on the transducer enhances its hearing compensating performance at higher frequencies. CONCLUSIONS: The influence of the transducer's mass, the mass of the transducer, the applied static preload and the properties of the coupling layer must be taken into account in the design of the RW stimulation type implantable middle ear hearing device. PMID- 28869640 TI - Renewable high-density spiro-fuels from lignocellulose-derived cyclic ketones. AB - Renewable high-density spiro-fuels are synthesized from lignocellulose-derived cyclic ketones for the first time, which show higher density, higher neat heat of combustion and lower freezing point compared with other biofuels synthesized from the same feedstock, and thus represent a new type of renewable high-density fuel attractive for practical applications. PMID- 28869641 TI - Multicomponent equiatomic rare earth oxides with a narrow band gap and associated praseodymium multivalency. AB - New multicomponent equiatomic rare earth oxides (ME-REOs) containing 3-7 rare earth elements (Ce, Gd, La, Nd, Pr, Sm and Y) in equiatomic proportions are synthesized using nebulized spray pyrolysis. All the systems crystallized as a phase pure fluorite type (Fm3[combining macron]m) structure in spite of the high chemical complexity. A nominal increase in the lattice parameter compared to CeO2 is observed in all ME-REOs. X-ray photoelectron spectroscopy performed on the ME REOs confirmed that all the constituent rare earth elements are present in the 3+ oxidation state, except for Ce and Pr which are present in 4+ and in a mixed (3+/4+) oxidation state, respectively. The presence of Ce4+ contributes substantially to the observed stability of the single phase structure. These new oxide systems have narrow direct band gaps in the range of 1.95-2.14 eV and indirect band gaps in the range of 1.40-1.64 eV, enabling light absorption over the entire visible spectral range. Furthermore, the oxygen vacancy concentration rapidly increases and then saturates with the number of rare earth elements that are incorporated into the ME-REOs. The lowering of the band gap is found to be closely related to the presence of multivalent Pr. Interestingly, the band gap values are relatively invariant with respect to the composition or thermal treatments. Considering the high level of oxygen vacancies present and the observed low band gap values, these new material systems can be of importance where the presence of oxygen vacancies is essential or in applications where a narrow band gap is desirable. PMID- 28869642 TI - The influence of functional groups on the ethylene polymerization performance of silsesquioxane-supported Phillips-type catalysts. AB - A series of silsesquioxane-supported Phillips-type molecular catalysts for ethylene polymerization were synthesized by introducing various functional groups in proximity to monoalkylated Cr(iii). They were moderately active in ethylene polymerization, while the performance was sensitive to the type of functional group. In particular, the presence of a lone pair near the active center was found to enhance the activity and expand the molecular weight distribution, which is plausibly due to alkylaluminum temporally captured by the lone pair. A similar result was never obtained by adding free molecules bearing a lone pair, and the fixation of the lone pair near the active site was essential. It was revealed that the design strategy based on the support functionalization can be transferred to SiO2-supported chromium catalysts. PMID- 28869643 TI - Carrier relaxation dynamics in type-II ZnO/CdSe quantum dot heterostructures. AB - Semiconductor heterostructures with type-II band alignment are well known for their engineering property of efficient charge separation in photogenerated carriers. Herein, type-II CdSe/ZnO core/shell quantum dot heterostructures with CdSe shells of different thicknesses have been synthesized and a study of carrier dynamics is carried out using femtosecond transient absorption and picosecond emission spectroscopy. Carrier lifetime measurements by transient emission spectroscopy have revealed reduced electron-hole overlap in the type-II localization regime of ZnO/CdSe heterostructures. Femtosecond transient absorption studies have revealed hot electron transfer from CdSe shell to ZnO core prior to electron cooling in the CdSe shell. In addition, a surface channel for the hole cooling process has been identified in the transient absorption measurements. Effects of carrier trapping at interfacial defect states and type II localization on carrier recombination have been recognized in our transient absorption and emission studies of ZnO/CdSe QDs heterostructure. PMID- 28869644 TI - Reactivity of a stable copper-dioxygen complex. AB - We report the isolation of a room temperature stable dipyrromethene Cu(O2) complex featuring a side-on O2 coordination. Reactivity studies highlight the unique ability of the dioxygen adduct for both hydrogen-atom abstraction and acid/base chemistry towards phenols, demonstrating that side-on superoxide species can be reactive entities. PMID- 28869645 TI - Visible light photocatalytic decarboxylative monofluoroalkenylation of alpha amino acids with gem-difluoroalkenes. AB - alpha-Amino acids are among the most common biologically active molecules in nature, and their functionalization has attracted much attention. In this communication, a novel, efficient and general visible-light photocatalytic decarboxylative monofluoroalkenylation of N-protected alpha-amino acids with gem difluoroalkenes is reported, affording the corresponding alpha-amino monofluoroalkenes which might find applications in medical chemistry and materials science. The reaction proceeded at room temperature with high efficiency and tolerance of various functional groups. PMID- 28869646 TI - Compositions and structures of niobium oxide cluster ions, NbmOn+/-, (m = 2-12), revealed by ion mobility mass spectrometry. AB - Herein, the compositions and geometrical structures of niobium oxide cluster ions were studied and compared with those of the lighter Group 5 counterpart vanadium oxide cluster ions by ion-mobility mass spectrometry (IM-MS). As a result of collision-induced dissociation in IM-MS, the compositions were found to be dependent on an odd and even number of niobium atoms, whereby the ions with (NbO2)(Nb2O5)(m-1)/2+ and (NbO3)(Nb2O5)(m-1)/2- were identified as stable compositions for an odd number of Nb atoms, whereas (Nb2O5)m/2+/- and (Nb2O6)(Nb2O5)(m-2)/2- were identified as stable compositions for an even number of Nb atom clusters. Furthermore, structural transitions were observed between m = 8 and 9 for cluster cations and m = 7 and 8 for cluster anions for experimental collision cross-sections (CCSs), which were determined from the arrival times in the ion-mobility measurements. Quantum chemical calculations were conducted on several structural candidates of these compositions for m = 2-12. For cluster cations with the sizes between m = 2 and 8 and cluster anions with m = 2-7, the structures were found to be similar to those of vanadium oxide cluster ions upon comparing the experimental CCSs with the theoretical CCSs of optimized structures. As compared to the vanadium oxide cluster ions, niobium oxide cluster cations with m >= 9 and anions with m >= 8 consisted of structures where some niobium atoms had more than five oxygen-atom coordination; thus, compact structures could be achieved in the case of niobium oxide cluster ions. PMID- 28869647 TI - Understanding the incomprehensible - patients' and spouses' experiences of comprehensibility before, at and after diagnosis of amyotrophic lateral sclerosis. AB - BACKGROUND: Previous studies have examined manageability and meaningfulness in amyotrophic lateral sclerosis (ALS), but there is a lack of studies examining the comprehensibility of ALS among patients and their spouses. AIM: This qualitative retrospective study aimed to illuminate patients' and spouses' experiences of comprehensibility in ALS from a long-term perspective, when symptoms appeared before diagnosis, and when the diagnosis was given and in life after diagnosis. METHODS: Individual semi-structured interviews with 14 patients and 13 spouses were performed. The transcribed interviews were subjected to qualitative content analysis. FINDINGS: Through the whole disease process, patients and spouses feared the unknown regardless of whether they comprehended the disease or not. They described that they before diagnosis felt uncertainty. It was problematic to comprehend what was wrong and what the deterioration implied. At the diagnosis, they described feelings of losing their foothold. Long-term after diagnosis, they still lived in fear and looked for reasons why they were afflicted. CONCLUSIONS: Findings of similar experiences in comprehensibility between patients and spouses strengthen the importance of support and information to both parties. Since they hovered between comprehensibility and incomprehensibility during the whole disease process, it is important that their questions, fears and worries are met, from the first visit at hospital and through the whole process. Multiprofessional teams, such as ALS teams and palliative teams can from a holistic perspective increase the possibility of meeting their needs in their unique situation. PMID- 28869648 TI - Site-specific distribution of claudin-based paracellular channels with roles in biological fluid flow and metabolism. AB - The claudins are a family of membrane proteins with at least 27 members in humans and mice. The extracellular regions of claudin proteins play essential roles in cell-cell adhesion and the paracellular barrier functions of tight junctions (TJs) in epithelial cell sheets. Furthermore, the extracellular regions of some claudins function as paracellular channels in the paracellular barrier that allow the selective passage of water, ions, and/or small organic solutes across the TJ in the extracellular space. Structural analyses have revealed a common framework of transmembrane, cytoplasmic, and extracellular regions among the claudin-based paracellular barriers and paracellular channels; however, differences in the claudins' extracellular regions, such as their charges and conformations, determine their properties. Among the biological systems that involve fluid flow and metabolism, it is noted that hepatic bile flow, renal Na+ reabsorption, and intestinal nutrient absorption are dynamically regulated via site-specific distributions of paracellular channel-forming claudins in tissue. Here, we focus on how site-specific distributions of claudin-2- and claudin-15-based paracellular channels drive their organ-specific functions in the liver, kidney, and intestine. PMID- 28869649 TI - Outlier identification in radiation therapy knowledge-based planning: A study of pelvic cases. AB - PURPOSE: The purpose of this study was to apply statistical metrics to identify outliers and to investigate the impact of outliers on knowledge-based planning in radiation therapy of pelvic cases. We also aimed to develop a systematic workflow for identifying and analyzing geometric and dosimetric outliers. METHODS: Four groups (G1-G4) of pelvic plans were sampled in this study. These include the following three groups of clinical IMRT cases: G1 (37 prostate cases), G2 (37 prostate plus lymph node cases) and G3 (37 prostate bed cases). Cases in G4 were planned in accordance with dynamic-arc radiation therapy procedure and include 10 prostate cases in addition to those from G1. The workflow was separated into two parts: 1. identifying geometric outliers, assessing outlier impact, and outlier cleaning; 2. identifying dosimetric outliers, assessing outlier impact, and outlier cleaning. G2 and G3 were used to analyze the effects of geometric outliers (first experiment outlined below) while G1 and G4 were used to analyze the effects of dosimetric outliers (second experiment outlined below). A baseline model was trained by regarding all G2 cases as inliers. G3 cases were then individually added to the baseline model as geometric outliers. The impact on the model was assessed by comparing leverages of inliers (G2) and outliers (G3). A receiver-operating-characteristic (ROC) analysis was performed to determine the optimal threshold. The experiment was repeated by training the baseline model with all G3 cases as inliers and perturbing the model with G2 cases as outliers. A separate baseline model was trained with 32 G1 cases. Each G4 case (dosimetric outlier) was subsequently added to perturb the model. Predictions of dose-volume histograms (DVHs) were made using these perturbed models for the remaining 5 G1 cases. A Weighted Sum of Absolute Residuals (WSAR) was used to evaluate the impact of the dosimetric outliers. RESULTS: The leverage of inliers and outliers was significantly different. The Area-Under-Curve (AUC) for differentiating G2 (outliers) from G3 (inliers) was 0.98 (threshold: 0.27) for the bladder and 0.81 (threshold: 0.11) for the rectum. For differentiating G3 (outlier) from G2 (inlier), the AUC (threshold) was 0.86 (0.11) for the bladder and 0.71 (0.11) for the rectum. Significant increase in WSAR was observed in the model with 3 dosimetric outliers for the bladder (P < 0.005 with Bonferroni correction), and in the model with only 1 dosimetric outlier for the rectum (P < 0.005). CONCLUSIONS: We established a systematic workflow for identifying and analyzing geometric and dosimetric outliers, and investigated statistical metrics for outlier detection. Results validated the necessity for outlier detection and clean-up to enhance model quality in clinical practice. PMID- 28869650 TI - Characterization of Extracellular Polymeric Substances Produced by Pseudomonas fragi Under Air and Modified Atmosphere Packaging. AB - Extracellular polymeric substances (EPS) play an important role in bacterial biochemical properties. The characteristics of EPS from 2 strains of Pseudomonas fragi cultured in meat aerobically (control) and in modified atmosphere packaging (MAP) were studied. The amount and components of EPS, the surface properties, and the effect on biofilm formation of several spoilage organisms were evaluated. The results showed that MAP inhibited the growth of the P. fragi strains. Compared with the control, more loose and less bound EPS (containing protein and carbohydrate) were produced by P. fragi in MAP samples. MAP also caused increased cell autoaggregation and surface hydrophobicity. After the removal of the EPS, the surface property changes were strain-dependent, suggesting that membrane compositions were also changed. In addition, the EPS displayed significant antibiofilm activity on Pseudomonas fluorescens and Serratia liquefaciens. In conclusion, P. fragi strains not only modified the amount, components, and surface properties of EPS but also changed the cell membrane compositions to adapt to MAP stress. Moreover, EPS may play an important role in microbial community competitions. PMID- 28869651 TI - Technical Note: Investigating the impact of field size on patient selection for the 1.5T MR-Linac. AB - PURPOSE: The 1.5 T Elekta MR-Linac, due to the construction of the system will have a maximum radiation field size in the superior-inferior patient direction of 22 cm at isocentre. The field size may impact on the patient groups which can be treated on the system. This technical note aims to address the question of which treatment sites will be affected by field size limitations on the MR-Linac. METHODS: Using historical data for 11 595 cases over 2 yr treated at the authors' institution, the proportion of plans that would fit the MR-Linac's field size was determined for eleven patient groups. In addition, cervix plans were analyzed to determine the length of the two Clinical Target Volumes (CTVs) and any overlap between them. RESULTS: With a 1 cm margin to allow for online plan adaption, 80% of all plans would be suitable for the MR-Linac due to the field size. This percentage increases to 100% for smaller tumor volumes such as prostate and brain. However, for cervix and three dose-level head and neck plans the percentage becomes 61% and 66%, respectively. CONCLUSION: The maximum radiation field size of the MR-Linac in the superior-inferior patient direction is 22 cm. With a 1 cm margin approximately 80% of all plans would be suitable for the MR Linac with the available field size, decreasing to 61% for larger tumor volumes. For cervix patients this may motivate investigations into treating each CTV with a separate isocentre, allowing for careful control of matching fields. PMID- 28869652 TI - Comparison of Laboratory-Developed and Commercial Monoclonal Antibody-Based Sandwich Enzyme-Linked Immunosorbent Assays for Almond (Prunus dulcis) Detection and Quantification. AB - : A commercially available monoclonal antibody (mAb)-based direct sandwich enzyme linked immunosorbent assay (ELISA) kit (BioFront Technologies, Tallahassee, Fla., U.S.A.) was compared with an in-house developed mAb 4C10-based ELISA for almond detection. The assays were comparable in sensitivity (limit of detection < 1 ppm full fat almond, limit of quantification < 5 ppm full fat almond), specificity (no cross-reactivity with 156 tested foods at a concentration of 100000 ppm whole sample), and reproducibility (intra- and interassay variability < 15% CV). The target antigens were stable and detectable in whole almond seeds subjected to autoclaving, blanching, frying, microwaving, and dry roasting. The almond recovery ranges for spiked food matrices were 84.3% to 124.6% for 4C10 ELISA and 81.2% to 127.4% for MonoTrace ELISA. The almond recovery ranges for commercial and laboratory prepared foods with declared/known almond amount were 30.9% to 161.2% for 4C10 ELISA and 38.1% to 207.6% for MonoTrace ELISA. Neither assay registered any false-positive or negative results among the tested commercial and laboratory prepared samples. PRACTICAL APPLICATION: Ability to detect and quantify trace amounts of almonds is important for improving safety of almond sensitive consumers. Two monoclonal antibody-based ELISAs were compared for almond detection. The information is useful to food industry, regulatory agencies, scientific community, and almond consumers. PMID- 28869653 TI - Purpuric Agave Dermatitis. PMID- 28869654 TI - Nursing roles and functions addressing relatives during in-hospital rehabilitation following stroke. Care needs and involvement. AB - RATIONALE: In the last decades, length of stay of in-hospital rehabilitation of patients with stroke has been significantly reduced. Health authorities expect relatives to be at disposal to convey the knowledge of everyday life and to provide emotional as well as practical support in relation to the patient. Caregivers require nurse assistance, support and to be seen as an essential partner in the care giving process. However, the nurses do not perceive that teaching of relatives is a task they should routinely undertake. This might indicate an ambiguity between the relatives' expectations and the actual contribution from nurses. AIM: This study describes nurses' experienced roles and functions addressing the relatives of patients with stroke during in-hospital rehabilitation. METHODOLOGICAL DESIGN: A phenomenological hermeneutic approach influenced by Paul Ricoeur. In a secondary analysis focus group, interviews of 19 randomly selected nurses from three different hospital settings were interpreted in three levels. The study was conducted in accordance with the ethical guidelines for nursing research in the Nordic countries. FINDINGS: The nurses expressed that they address the patient and the relatives and support the interaction between the patient and the relatives. Four themes occurred: the changed lives of relatives; shared life after stroke; noncooperating relatives; time for the relatives. CONCLUSION: Nurses experience their roles and functions addressing relatives after stroke as crucial, challenging and multifaceted. They acknowledged care needs of the relatives in their own right by addressing the relatives' vulnerability during in-hospital rehabilitation characterised by an existential threat to the physical as well as the shared life. The focus on the needs of relatives considering their expected future role was experienced as conflicting with restricting time frames and a healthcare system focusing on the individual patient. PMID- 28869655 TI - Intravenous-only or Intravenous Transitioned to Oral Antimicrobials for Enterobacteriaceae-Associated Bacteremic Urinary Tract Infection. AB - OBJECTIVES: To characterize antibiotic regimens utilized for bacteremic Enterobacteriaceae urinary tract infections and assess treatment failure associated with intravenous-only compared to intravenous transitioned to oral antibiotic treatment. DESIGN: Retrospective cohort. SETTINGS: Tertiary care academic medical center. PATIENTS: 241 adult patients hospitalized between July 1, 2010, and June 30, 2015, with positive blood and urine cultures with the same Enterobacteriaceae pathogen. MAIN RESULTS: Hospital days on antibiotics as well as length of stay were less in the group treated with any oral antibiotics (intravenous/oral, median 5 [IQR 3-7] days vs intravenous-only antibiotics 6 [4 10] days, p<0.001; length of stay for intravenous/oral 4.6 [3.1-7.8] days vs intravenous-only 7.1 [4.0-17.5] days, p<0.001). No statistically significant difference was found in the composite outcome of treatment failure in patients who received intravenous-only antibiotics versus intravenous/oral antibiotics for the treatment of bacteremic urinary tract infections (intravenous-only 3.8% [95% CI: 1.0-9.4%] failure; intravenous/oral 8.2% [95% CI: 4.1-14.1%] failure; p=0.19). CONCLUSIONS: Intravenous transitioned to oral treatment (intravenous/oral) was associated with a shorter length of stay and fewer hospital antibiotic days compared with intravenous-only therapy. Transitioning from intravenous to oral antibiotic therapy is a viable treatment option to consider for patients with bacteremic Enterobacteriaceae urinary tract infection. PMID- 28869656 TI - Immigrants' use of health care in their country of origin: the role of social integration, discrimination and the parallel use of health care systems. AB - AIMS: The objective of this study was to elucidate the utilisation of Russian health care by immigrants of Russian origin living in Finland (cross-border health care). The study examined the association of cross-border health care with social integration and discrimination. Moreover, it studied whether cross-border health care was used as an alternative to the host-country's healthcare system. METHODS: Data from the Finnish Migrant Health and Wellbeing Survey (Maamu) were utilised. The number of respondents of Russian origin was 545. The main analytical method was logistic regression. The outcome variable was based on a survey item on seeking physician's treatment or help abroad during the last 12 months. Social integration was measured multi-dimensionally, and the indicator was extracted by multiple correspondence analysis. Ethical approval for the study was obtained from the Ethical Committee of the Uusimaa Hospital Region. RESULTS: We found that 15.4% of the respondents had visited a physician in Russia during the last 12 months. 10.4% had experienced discrimination in Finnish health services during their stay in Finland. Stronger social integration predicted less frequent utilisation of cross-border health care. Experiences of discrimination or unfairness were associated with higher odds for seeking cross-border health care. Cross-border health care was typically used in parallel to the Finnish services. CONCLUSIONS: Our findings on integration and discrimination emphasise the importance of general integration policy as well as cultural competence in health care. Parallel use of healthcare systems entails both risks (e.g double medication, problems of follow-up) and opportunities (e.g. sense of agency), which should be further investigated. PMID- 28869657 TI - Self-reported personality traits are prospectively associated with proxy-reported behavioral and psychological symptoms of dementia at the end of life. AB - OBJECTIVE: Behavioral and psychological symptoms of dementia (BPSD) are among the most challenging aspects of Alzheimer disease for patients and their families. Previous studies have found associations between informant-reported retrospective personality and BPSD; we test whether prospective, self-reported personality predicts who will experience these symptoms. METHODS: Deceased participants from the Health and Retirement Study who had evidence of cognitive impairment at the end of life (N = 1988) were selected to examine whether self-reported five-factor model personality traits, measured up to 8 years before death, were associated with proxy-reported BPSD. RESULTS: Neuroticism was associated with increased risk of the 7 BPSD: got lost in familiar places, wandered off, were not able to be left alone, experienced hallucinations, suffered from depression, had periodic confusion, and an uncontrolled temper. These associations were not moderated by age, gender, race, or education. Conscientiousness was associated with fewer symptoms overall and especially with lower risk of getting lost in familiar places and not being able to be left alone. CONCLUSIONS: The present research indicates that self-reported personality, particularly Neuroticism, is associated prospectively with risk for a wide range of behavioral symptoms for individuals who had cognitive impairment at the end of life. The use of self-reported personality traits can help aid in identifying who is most at risk for behavioral symptoms. Such information may be useful for nonpharmacological interventions tailored to the individual's personality to reduce the prevalence and burden of these BPSD. PMID- 28869658 TI - Understanding life experiences of people affected by Crohn's disease in Spain. A phenomenological approach. AB - BACKGROUND AND OBJECTIVES: People affected by Crohn's disease must adapt their lives to their new chronic condition, and therefore, understanding such experience can be helpful in planning effective interventions for the affected ones. The aim of this study was to gain an insight into such experience and how they adapted in different areas of their lives, particularly in a family-centred culture such as the Spanish one. METHOD: A descriptive phenomenological study was conducted through in-depth interviews to 19 people diagnosed of Crohn's disease in the province of Alicante (Spain). Once the interviews were transcribed, data were analysed using Colaizzi's seven-step method. RESULTS: Five emergent themes were identified: self-protection against the unknown cause; self-training; learning to live with Crohn's disease; perceived losses associated to Crohn's disease; and relationship with others. The results portrayed a chronically ill patient who is unconscious about the chronicity and consequently must develop strategies to keep living a similar life like the one lived before. CONCLUSIONS: This study revealed that people affected by Crohn's disease struggle with the fact of being a chronic patient with uncertainty about the illness and need to learn living with a chronic condition that limits their daily lives. Furthermore, the lack of Crohn's disease a professional in charge of these people's Cares such as the specific nursing role existing in other countries support in the Spanish Health System determines the loneliness those diagnosed experience to cope with the new situation. PMID- 28869659 TI - Perceptions of family caregivers of cancer patients about the challenges of caregiving: a qualitative study. AB - BACKGROUND: The experience of caring for a family member with cancer is associated with several care-related problems and challenges for the caregiver. The comprehensive and in-depth understanding of the trials and tribulations of caregiving can be a step towards resolving the problems faced by family caregivers of these patients. AIM: The present study aimed to explore challenges faced by Iranian family caregivers of cancer patients. MATERIALS AND METHODS: The present qualitative study was conducted through in-depth semi-structured interviews held with 21 family caregivers of cancer patients selected through purposive sampling. Interviews continued until saturation of data. All interviews were recorded, transcribed and analysed through conventional content analysis. FINDING: The codes extracted from interviews produced four main themes, including 'confusion', 'uncertainty', 'disintegration' and 'setback', which collectively caused suffering for family caregivers. CONCLUSION: Care provided in an atmosphere of suffering and discontent diminishes caregiver's quality of life and quality of patient care. Health planners should therefore consider the challenges and sufferings faced by family caregivers and should seek to obviate them through appropriate plans. PMID- 28869660 TI - Pseudoxanthoma elasticum-like changes in nonuremic calciphylaxis: Case series and brief review of a helpful diagnostic clue. AB - Calciphylaxis is a rare syndrome of vascular calcification with thrombosis that occurs most often in patients with end-stage renal disease, and it frequently portends a guarded prognosis. Rarely, nonuremic calciphylaxis (NUC) may occur; in this context, a strongly supportive histology is crucial in establishing the diagnosis. Herein, we describe 2 cases of NUC associated with pseudoxanthoma elasticum-like changes, identified in both initial nondiagnostic and subsequent diagnostic biopsy specimens. This unusual but helpful histologic finding may support the early diagnosis and treatment of a potentially life-threatening disease in the context of subtle histopathologic vascular changes or in the absence of classic clinical or laboratory findings. PMID- 28869661 TI - Utilisation of formal and informal care and services at home among persons with dementia: a cross-sectional study. AB - BACKGROUND: The progression of dementia disease implies increasing needs for both informal and formal care and services but also risk of institutionalisation. To better adjust care and services in the phase preceding institutionalisation it is important to find out whether utilisation of formal and informal care and services is determined by increased needs and by who meets the needs. AIM: The aim was to compare persons with dementia (65+) with different levels of cognitive impairment, regarding utilisation of formal and informal care and service at home. METHODS: The participants consisted of 177 persons with dementia >=65 years old and at risk of nursing home admission, divided into groups according to their cognitive function. Structured interviews were conducted based on questionnaires about type and amount of formal and informal care utilised, as well as questions regarding cognitive impairment, dependency in activities of daily living (ADLs) and neuropsychiatric symptoms. To analyse the data, descriptive and comparative statistics were used. RESULTS: The findings revealed that the group with severe dementia used significantly more help with ADLs and supervision in terms of time (number of hours and days) provided by the informal caregiver, compared with the group with moderate dementia. Utilisation of formal care and services was highest in the group with the most severe cognitive impairments (Standardized Mini-Mental State Examination score of <9). The group with severe dementia were more dependent in ADLs and had more neuropsychiatric symptoms (hallucinations and motor disturbances). They were younger and more often cohabitated with the informal caregiver, compared with the group with moderate dementia. CONCLUSION: This study shows that in the phase preceding institutionalisation the ADL and supervision needs due to progression of dementia appear to tend to be met first and foremost by the informal caregivers. PMID- 28869662 TI - Parent Caring Response Scoring System: development and psychometric evaluation in the context of childhood cancer-related port starts. AB - RATIONALE: Multiple observational coding systems have been developed and validated to assess parent-child interactions during painful procedures. Most of these coding systems are neither theory-based nor do they well represent parent nonverbal behaviours. AIMS: Develop the Parent Caring Response Scoring System (P CaReSS) based on Swanson's Theory of Caring and test its psychometric properties in children in cancer port starts. METHODS: A hybrid approach of inductive and deductive coding was used to formulate the preliminary observational codes for the P-CaReSS. Twenty-nine children, each with one video-recording of port start available, were selected from the parent study (R01CA138981) to refine the P CaReSS, train coders and test inter-rater reliability. Videos of another 43 children were used to evaluate the construct validity of P-CaReSS. Per cent agreement and Cohen's kappa were used to present the inter-rater reliability. Spearman rank-order correlations were used to report the construct validity. RESULTS: The 18-item P-CaReSS includes three types of parent behaviours: verbal, nonverbal and emotional behaviours. These parent interaction behaviours comprise five caring domains - knowing, being with, doing for, enabling, and maintaining belief - and one noncaring domain. On average the per cent agreement was 0.82 for the P-CaReSS overall, with average per cent agreements above 0.80 for both verbal and nonverbal behaviours. Kappa coefficient was 0.81 for the emotional behaviour. The behavioural codes in the P-CaReSS showed significant correlations with independent ratings of parent distress, child distress and child cooperation. CONCLUSIONS: The P-CaReSS is a promising tool that can be used to evaluate parent verbal, nonverbal and emotional behaviours during cancer-related port starts. This observational tool can be used to guide the development of nursing interventions to help parents caring for their child during cancer procedures. PMID- 28869663 TI - Erratum. PMID- 28869664 TI - Young Children's Use of Surface and Object Information in Drawings of Everyday Scenes. AB - Pictorial symbols such as photographs, drawings, and maps are ubiquitous in modern cultures. Nevertheless, it remains unclear how children relate these symbols to the scenes that they represent. The present work investigates 4-year old children's (N = 144) sensitivity to extended surface layouts and objects when using drawings of a room to find locations in that room. Children used either extended surfaces or objects when interpreting drawings, but they did not combine these two types of information to disambiguate target locations. Moreover, children's evaluations of drawings depicting surfaces or objects did not align with their use of such information in those drawings. These findings suggest that pictures of all kinds serve as media in which children deploy symbolic spatial skills flexibly and automatically. PMID- 28869665 TI - Puberty Predicts Approach But Not Avoidance on the Iowa Gambling Task in a Multinational Sample. AB - According to the dual systems model of adolescent risk taking, sensation seeking and impulse control follow different developmental trajectories across adolescence and are governed by two different brain systems. The authors tested whether different underlying processes also drive age differences in reward approach and cost avoidance. Using a modified Iowa Gambling Task in a multinational, cross-sectional sample of 3,234 adolescents (ages 9-17; M = 12.87, SD = 2.36), pubertal maturation, but not age, predicted reward approach, mediated through higher sensation seeking. In contrast, age, but not pubertal maturation, predicted increased cost avoidance, mediated through greater impulse control. These findings add to evidence that adolescent behavior is best understood as the product of two interacting, but independently developing, brain systems. PMID- 28869666 TI - Comprehensive Guidance for Antibiotic Dosing in Obese Adults. AB - Physiologic alterations seen in obesity commonly impact the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics and may result in suboptimal dosing in this expanding but understudied population. Much of the published clinical and PK evidence to date consists of small patient populations and are retrospective with, not infrequently, heterogeneous results that in some cases are contradictory. In the last 10 years, additional antimicrobial PK/PD and clinical data encompassing prolonged infusion strategies and examination of critically ill populations have emerged to inform antimicrobial dosing in obesity. In this narrative review, we critically review literature on dosing, PK, and possible dosing strategies in obese adults. We searched PubMed, Scopus, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific antimicrobial names, obese, pharmacokinetics, and others. We reviewed articles, cross-referenced select cited references, and when applicable, referenced drug databases and package inserts to develop dosing recommendations. We provide an overall critical review of the available data regarding PK and dosing issues including dosing recommendations in both critically ill and noncritically ill patients with significant obesity. We developed dosing recommendations for 34 antimicrobials based on 121 articles of the 2336 identified by the search strategy. Although 11 of these do not appear to require dose adjustment, obesity specific dosing guidance is provided for the remaining 23 antimicrobials. Additional studies are needed to better understand and resolve discrepant published results regarding the PK of antibiotics to establish optimal dosing strategies in obese adults. Alternative dosing strategies, such as extended infusions, should be considered for time-dependent antibiotics (e.g., beta lactams) in obese patients to achieve PD targets reliably. Therapeutic drug monitoring across the spectrum of antimicrobials is of increasing importance in this and other populations to ensure optimized dosing. PMID- 28869667 TI - Children with ill parents: extent and nature of caring activities. AB - RATIONALE: Previous studies have shown that children may take on higher extents of caring activities if their parents are affected by severe illness or disability, especially when their parents lack access to formal and informal care. AIMS AND OBJECTIVES: This study examined the extent and nature of caring activities done by patients' children; differences in caring activities between different types of parental illness; factors associated with caring activities. DESIGN: An explorative cross-sectional multicentre study. METHODS: Parents as patients in specialised healthcare services, and their children, were recruited from five health trusts in Norway. The sample included 246 children aged 8-17 years and their 238 parents with severe physical illness (neurological disease or cancer) (n = 135), mental illness (n = 75) or substance abuse (n = 28). MAIN OUTCOME MEASURE: Multidimensional Assessment of Caring Activities (MACA-YC18). RESULTS: A large number of children with ill parents are performing various caring activities. Increased caring activities among children due to their parent's illness were confirmed by their parents, especially with regard to personal care. We found no significant differences in the extent of caring activities between illness types, but there were some differences in the nature of these activities. Factors significantly associated with the extent and nature of caring activities were as follows: better social skills and higher external locus of control among the children; and poorer physical parental health. Parent's access to home-based services was limited. STUDY LIMITATIONS: In recruitment of participants for the study, a sampling bias may have occurred. CONCLUSION: To promote coping and to prevent inappropriate or extensive caring activities among children with ill parents, there is a need for increased access to flexible home-based services adapted to the type of parental illness. PMID- 28869668 TI - Intermediate purification of CHO-derived recombinant human Factor IX using hydrophobic interaction membrane-based chromatography and its comparison to a sulfated resin. AB - This work investigated the use of hydrophobic interaction membrane chromatography for intermediate purification of recombinant human Factor IX (rFIX) produced by CHO cells. The first purification step was based on a strong anion exchange monolith, thus forming a purification process fully based on convective media, which allow operation at high flow rates and low pressure drops, as well as modular scale-up. Although the starting material was challenging (CHO cell culture supernatant harvested at 70% cell viability), the two-step purification process showed promising results, with a global purification factor of 298, a global recovery of 69%, and DNA and endotoxin levels close to regulatory limits. Final host cell DNA (68.8 ng per dose of 500 IU), endotoxins (60 EU per dose of 500 IU) and activated FIX (FIXa/FIX = 2.33%) were in levels close to those recommended by regulatory authorities. HCP removal was of 99.98%, decreasing from 9 424 358 ppm in the supernatant to a final HCP value of 2071 ppm. The use of a supernatant harvested at higher viability and/or the addition of a third polishing step focusing on HCP removal could allow meeting the desired HCP range of 50-100 ppm, as well as the regulatory requirements for the other critical contaminants. PMID- 28869669 TI - A two-step method for rapid characterization of electroosmotic flows in capillary electrophoresis. AB - The measurement of electroosmotic flow (EOF) is important in a capillary electrophoresis (CE) experiment in terms of performance optimization and stability improvement. Although several methods exist, there are demanding needs to accurately characterize ultra-low electroosmotic flow rates (EOF rates), such as in coated capillaries used in protein separations. In this work, a new method, called the two-step method, was developed to accurately and rapidly measure EOF rates in a capillary, especially for measuring the ultra-low EOF rates in coated capillaries. In this two-step method, the EOF rates were calculated by measuring the migration time difference of a neutral marker in two consecutive experiments, in which a pressure driven was introduced to accelerate the migration and the DC voltage was reversed to switch the EOF direction. Uncoated capillaries were first characterized by both this two-step method and a conventional method to confirm the validity of this new method. Then this new method was applied in the study of coated capillaries. Results show that this new method is not only fast in speed, but also better in accuracy. PMID- 28869670 TI - Pulmonary embolism in pregnant patients: Assessing organ dose to pregnant phantom and its fetus during lung imaging. AB - PURPOSE: The purpose of this study was to provide updated radiation dose from diagnostic exams performed for pregnant patients suspected of pulmonary embolism (PE) using the recently developed BREP phantoms of pregnant woman and the fetus. Also to challenge the validity of current recommendations suggest that ventilation/perfusion (V/Q) single photon emission computed tomography (SPECT) vs. computed tomography pulmonary angiography (CTPA) should be considered for diagnosis of PE in radiosensitive groups such as pregnant women. METHODS: The Monte Carlo calculations involving detailed geometrical simulation of pregnant women and the fetus were performed. RESULTS: The results showed that when radiation dose to the fetus is of concern, CTPA is more appropriate at early stages causes 50%-97% lower fetal doses for the first two trimesters of pregnancy. While for gestational periods more than 6 months, V/Q SPECT leads to a 15% lower fetal dose and thus, is less hazardous. The fetal dose from CTPA increases with gestational age, while that from V/Q SPECT decreases. Furthermore, the maximum amount of fetal dose is received by fetal skeleton (i.e., on average about 1.8 and 3.9 times larger dose from SPECT and CT, respectively). CONCLUSIONS: V/Q SPECT should not always be preferred for pregnant patients suspected of PE. This finding is in contrast with the guidance to choose the preferred modality based on the maternal effective dose. The reason of this issue was discussed in this paper based on chord length distributions (CLDs). The importance of considering fetal organs separately in MC calculations was also highlighted. PMID- 28869671 TI - Concussion in adolescence and risk of multiple sclerosis. AB - OBJECTIVE: To assess whether concussion in childhood or adolescence is associated with subsequent multiple sclerosis (MS) risk. Previous research suggests an association, but methodological limitations included retrospective data collection and small study populations. METHODS: The national Swedish Patient Register (hospital diagnoses) and MS Register were used to identify all MS diagnoses up to 2012 among people born since 1964, when the Patient Register was established. The 7,292 patients with MS were matched individually with 10 people without MS by sex, year of birth, age/vital status at MS diagnosis, and region of residence (county), resulting in a study population of 80,212. Diagnoses of concussion and control diagnoses of broken limb bones were identified using the Patient Register from birth to age 10 years or from age 11 to 20 years. Conditional logistic regression was used to examine associations with MS. RESULTS: Concussion in adolescence was associated with a raised risk of MS, producing adjusted odds ratios (95% confidence intervals) of 1.22 (1.05-1.42, p = 0.008) and 2.33 (1.35-4.04, p = 0.002) for 1 diagnosis of concussion and >1 diagnosis of concussion, respectively, compared with none. No notable association with MS was observed for concussion in childhood, or broken limb bones in childhood and adolescence. INTERPRETATION: Head trauma in adolescence, particularly if repeated, is associated with a raised risk of future MS, possibly due to initiation of an autoimmune process in the central nervous system. This further emphasizes the importance of protecting young people from head injuries. Ann Neurol 2017;82:554-561. PMID- 28869672 TI - Internal grant review to increase grant funding for junior investigators. PMID- 28869673 TI - Reply. PMID- 28869674 TI - Metalloproteinase 9 as a biomarker of progressive multifocal leukoencephalopathy development in multiple sclerosis patients receiving natalizumab. PMID- 28869675 TI - On establishing a grant pre-review process for new investigators. PMID- 28869678 TI - Bioinspired Redox-Active Catechol-Bearing Polymers as Ultrarobust Organic Cathodes for Lithium Storage. AB - Redox-active catechols are bioinspired precursors for ortho-quinones that are characterized by higher discharge potentials than para-quinones, the latter being extensively used as organic cathode materials for lithium ion batteries (LIBs). Here, this study demonstrates that the rational molecular design of copolymers bearing catechol- and Li+ ion-conducting anionic pendants endow redox-active polymers (RAPs) with ultrarobust electrochemical energy storage features when combined to carbon nanotubes as a flexible, binder-, and metal current collector free buckypaper electrode. The importance of the structure and functionality of the RAPs on the battery performances in LIBs is discussed. The structure optimized RAPs can store high-capacities of 360 mA h g-1 at 5C and 320 mA h g-1 at 30C in LIBs. The high ion and electron mobilities within the buckypaper also enable to register 96 mA h g-1 (24% capacity retention) at an extreme C-rate of 600C (6 s for total discharge). Moreover, excellent cyclability is noted with a capacity retention of 98% over 3400 cycles at 30C. The high capacity, superior active-material utilization, ultralong cyclability, and excellent rate performances of RAPs-based electrode clearly rival most of the state-of-the-art Li+ ion organic cathodes, and opens up new horizons for large-scalable fabrication of electrode materials for ultrarobust Li storage. PMID- 28869677 TI - Fibroblasts derived from patients with opsismodysplasia display SHIP2-specific cell migration and adhesion defects. AB - The SH2 domain containing inositol phosphatase 2 (SHIP2) dephosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, a lipid involved in the control of cell migration and adhesion. The INPPL1 gene that encodes SHIP2 has been found to be mutated in several cases of opsismodysplasia (OPS), a rare autosomal recessive chondrodysplasia characterized by growth plate defects and delayed bone maturation. Reported mutations often result in premature stop codons or missense mutations in SHIP2 catalytic domain. SHIP2 biochemical properties are known from studies in cancer cells; its role in endochondral ossification is unknown. Here, we report two novel mutations in the INPPL1 gene and show that cell migration is very much decreased in fibroblasts derived from three OPS patients as compared with control individuals. In contrast, cell adhesion on fibronectin is increased in OPS fibroblasts. An inhibitory effect on migration was also observed when normal fibroblasts were incubated in the presence of a SHIP2 competitive inhibitor. We conclude that both migration and adhesion are very much disrupted in OPS-derived fibroblasts. It is suggested that signaling events linked to migration and particularly to adhesion, which are lost in OPS patients, would prevent normal endochondral ossification. PMID- 28869676 TI - Alcohol improves cerebellar learning deficit in myoclonus-dystonia: A clinical and electrophysiological investigation. AB - OBJECTIVE: To characterize neurophysiological subcortical abnormalities in myoclonus-dystonia and their modulation by alcohol administration. METHODS: Cerebellar associative learning and basal ganglia-brainstem interaction were investigated in 17 myoclonus-dystonia patients with epsilon-sarcoglycan (SGCE) gene mutation and 21 age- and sex-matched healthy controls by means of classical eyeblink conditioning and blink reflex recovery cycle before and after alcohol intake resulting in a breath alcohol concentration of 0.08% (0.8g/l). The alcohol responsiveness of clinical symptoms was evaluated by 3 blinded raters with a standardized video protocol and clinical rating scales including the Unified Myoclonus Rating Scale and the Burke-Fahn-Marsden Dystonia Rating Scale. RESULTS: Patients showed a significantly reduced number of conditioned eyeblink responses before alcohol administration compared to controls. Whereas the conditioning response rate decreased under alcohol intake in controls, it increased in patients (analysis of variance: alcohol state * group, p = 0.004). Blink reflex recovery cycle before and after alcohol intake did not differ between groups. Myoclonus improved significantly after alcohol intake (p = 0.016). The severity of action myoclonus at baseline correlated negatively with the conditioning response in classical eyeblink conditioning in patients. INTERPRETATION: The combination of findings of reduced baseline acquisition of conditioned eyeblink responses and normal blink reflex recovery cycle in patients who improved significantly with alcohol intake suggests a crucial role of cerebellar networks in the generation of symptoms in these patients. Ann Neurol 2017;82:543-553. PMID- 28869679 TI - Direct Imaging of Superwetting Behavior on Solid-Liquid-Vapor Triphase Interfaces. AB - A solid-liquid-vapor interface dominated by a three-phase contact line usually serves as an active area for interfacial reactions and provides a vital clue to surface behavior. Recently, direct imaging of the triphase interface of superwetting interfaces on the microscale/nanoscale has attracted broad scientific attention for both theoretical research and practical applications, and has gradually become an efficient and intuitive approach to explore the wetting behaviors of various multiphase interfaces. Here, recent progress on characterizing the solid-liquid-vapor triphase interface on the microscale/nanoscale with diverse types of imaging apparatus is summarized. Moreover, the accurate, visible, and quantitative information that can be obtained shows the real interfacial morphology of the wetting behaviors of multiphase interfaces. On the basis of fundamental research, technical innovations in imaging and complicated multiphase interfaces of the superwetting surface are also briefly presented. PMID- 28869680 TI - Structural Analysis of Uranyl Complexation by the EF-Hand Motif of Calmodulin: Effect of Phosphorylation. AB - Better understanding of uranyl-protein interactions is a prerequisite to predict uranium chemical toxicity in cells. The EF-hand motif of the calmodulin site I is about thousand times more affine for uranyl than for calcium, and threonine phosphorylation increases the uranyl affinity by two orders of magnitude at pH 7. In this study, we confront X-ray absorption spectroscopy with Fourier transform infrared (FTIR) spectroscopy, time-resolved laser-induced fluorescence spectroscopy (TRLFS), and structural models obtained by molecular dynamics simulations to analyze the uranyl coordination in the native and phosphorylated calmodulin site I. For the native site I, extended X-ray absorption fine structure (EXAFS) data evidence a short U-Oeq distance, in addition to distances compatible with mono- and bidentate coordination by carboxylate groups. Further analysis of uranyl speciation by TRLFS and thorough investigation of the fluorescence decay kinetics strongly support the presence of a hydroxide uranyl ligand. For a phosphorylated site I, the EXAFS and FTIR data support a monodentate uranyl coordination by the phosphoryl group and strong interaction with mono- and bidentate carboxylate ligands. This study confirms the important role of a phosphoryl ligand in the stability of uranyl-protein interactions. By evidencing a hydroxide uranyl ligand in calmodulin site I, this study also highlights the possible role of less studied ligands as water or hydroxide ions in the stability of protein-uranyl complexes. PMID- 28869681 TI - Surgical treatment of a giant iliopsoas haemophilic pseudotumour with adjacent structure compressions: A case report. PMID- 28869682 TI - Individual fitness and the effects of a changing climate on the cessation and length of the breeding period using a 34-year study of a temperate songbird. AB - Studies of the phenological responses of animals to climate change typically emphasize the initiation of breeding although climatic effects on the cessation and length of the breeding period may be as or more influential of fitness. We quantified links between climate, the cessation and length of the breeding period, and individual survival and reproduction using a 34-year study of a resident song sparrow (Melospiza melodia) population subject to dramatic variation in climate. We show that the cessation and length of the breeding period varied strongly across years, and predicted female annual fecundity but not survival. Breeding period length was more influential of fecundity than initiation or cessation of breeding alone. Warmer annual temperature and drier winters and summers predicted an earlier cessation of breeding. Population density, the date breeding was initiated, a female's history of breeding success, and the number of breeding attempts initiated previously also predicted the cessation of breeding annually, indicating that climatic, population, and individual factors may interact to affect breeding phenology. Linking climate projections to our model results suggests that females will both initiate and cease breeding earlier in the future; this will have opposite effects on individual reproductive rate because breeding earlier is expected to increase fecundity, whereas ceasing breeding earlier should reduce it. Identifying factors affecting the cessation and length of the breeding period in multiparous species may be essential to predicting individual fitness and population demography. Given a rich history of studies on the initiation of breeding in free-living species, re-visiting those data to estimate climatic effects on the cessation and length of breeding should improve our ability to predict the impacts of climate change on multiparous species. PMID- 28869683 TI - RUNX1c Regulates Hematopoietic Differentiation of Human Pluripotent Stem Cells Possibly in Cooperation with Proinflammatory Signaling. AB - Runt-related transcription factor 1 (Runx1) is a master hematopoietic transcription factor essential for hematopoietic stem cell (HSC) emergence. Runx1 deficient mice die during early embryogenesis due to the inability to establish definitive hematopoiesis. Here, we have used human pluripotent stem cells (hPSCs) as model to study the role of RUNX1 in human embryonic hematopoiesis. Although the three RUNX1 isoforms a, b, and c were induced in CD45+ hematopoietic cells, RUNX1c was the only isoform induced in hematoendothelial progenitors (HEPs)/hemogenic endothelium. Constitutive expression of RUNX1c in human embryonic stem cells enhanced the appearance of HEPs, including hemogenic (CD43+) HEPs and promoted subsequent differentiation into blood cells. Conversely, specific deletion of RUNX1c dramatically reduced the generation of hematopoietic cells from HEPs, indicating that RUNX1c is a master regulator of human hematopoietic development. Gene expression profiling of HEPs revealed a RUNX1c induced proinflammatory molecular signature, supporting previous studies demonstrating proinflammatory signaling as a regulator of HSC emergence. Collectively, RUNX1c orchestrates hematopoietic specification of hPSCs, possibly in cooperation with proinflammatory signaling. Stem Cells 2017;35:2253-2266. PMID- 28869684 TI - Prevalence and associations of general practitioners' ordering of "non symptomatic" prostate-specific antigen tests: A cross-sectional analysis. AB - AIMS: Testing for asymptomatic prostate cancer with prostate specific antigen (PSA) is of uncertain benefit. Most relevant authorities recommend against screening, and for informed patient choice. We aimed to establish the prevalence and associations of "non-symptomatic" PSA-testing of men aged 40 or older by early-career general practitioners (GP registrars). METHODS: A cross-sectional analysis from the ReCEnT cohort study of registrars' consultations, 2010-2014 (analysed in 2016). Registrars record 60 consecutive consultations each 6-month training term. The outcome factor was ordering an "asymptomatic" PSA test (a PSA ordered for an indication that was not prostate-related symptoms or prostatic disease monitoring). Independent variables were patient, registrar, practice, consultation and educational factors. RESULTS: A total of 856 registrars contributed details of 21,372 individual consultations and 35,696 problems/diagnoses of males 40 or older. Asymptomatic PSAs were ordered for 1.8% (95%CI: 1.7-2.0%) of consultations and for 1.1% (95%CI: 1.0-1.2%) of problems/diagnoses. Multivariable associations of asymptomatic PSA testing (compared with problems/diagnoses for which a PSA was not ordered) included patient age (OR 2.32 [95%CI: 1.53-3.53] for 60-69 years compared with 40-49), patient ethnicity (OR 0.40 [95%CI: 0.19-0.86] for non-English speaking background), the patient being new to both the registrar and practice (ORs 1.46 [95%CI: 1.08-1.99] and 1.79 [95%CI: 1.03-3.10]), the number of problems/diagnoses addressed (OR 1.44 [95%CI: 1.25-1.66] for each extra problem) and more pathology tests being ordered (OR 1.88 [95%CI: 1.79-1.97] for each extra test). CONCLUSION: GP registrars frequently order "asymptomatic" PSA tests. Our findings suggest that non-compliance with current guidelines for PSA screening may be relatively common and that targeted education is warranted. PMID- 28869685 TI - Ratiometric Fluorescence Detection of Phosphorylated Amino Acids Through Excited State Proton Transfer by Using Molecularly Imprinted Polymer (MIP) Recognition Nanolayers. AB - A 2,3-diaminophenazine bis-urea fluorescent probe monomer (1) was developed. It responds to phenylphosphate and phosphorylated amino acids in a ratiometric fashion with enhanced fluorescence accompanied by the development of a redshifted emission band arising from an excited-state proton transfer (ESPT) process in the hydrogen-bonded probe/analyte complex. The two urea groups of 1 form a cleft-like binding pocket (Kb >1010 L2 mol-2 for 1:2 complex). Imprinting of 1 in presence of ethyl ester- and fluorenylmethyloxycarbonyl (Fmoc)-protected phosphorylated tyrosine (Fmoc-pTyr-OEt) as the template, methacrylamide as co-monomer, and ethyleneglycol dimethacrylate as cross-linker gave few-nanometer-thick molecularly imprinted polymer (MIP) shells on silica core microparticles with excellent selectivity for the template in a buffered biphasic assay. The supramolecular recognition features were established by spectroscopic and NMR studies. Rational screening of co-monomers and cross-linkers allowed to single out the best performing MIP components, giving significant imprinting factors (IF>3.5) while retaining ESPT emission and the ratiometric response in the thin polymer shell. Combination of the bead-based detection scheme with the phase transfer assay dramatically improved the IF to 15.9, allowing sensitive determination of the analyte directly in aqueous media. PMID- 28869687 TI - Ancestral acquisitions, gene flow and multiple evolutionary trajectories of the type three secretion system and effectors in Xanthomonas plant pathogens. AB - Deciphering the evolutionary history and transmission patterns of virulence determinants is necessary to understand the emergence of novel pathogens. The main virulence determinant of most pathogenic proteobacteria is the type three secretion system (T3SS). The Xanthomonas genus includes bacteria responsible for numerous epidemics in agroecosystems worldwide and represents a major threat to plant health. The main virulence factor of Xanthomonas is the Hrp2 family T3SS; however, this system is not conserved in all strains and it has not been previously determined whether the distribution of T3SS in this bacterial genus has resulted from losses or independent acquisitions. Based on comparative genomics of 82 genome sequences representing the diversity of the genus, we have inferred three ancestral acquisitions of the Hrp2 cluster during Xanthomonas evolution followed by subsequent losses in some commensal strains and re acquisition in some species. While mutation was the main force driving polymorphism at the gene level, interspecies homologous recombination of large fragments expanding through several genes shaped Hrp2 cluster polymorphism. Horizontal gene transfer of the entire Hrp2 cluster also occurred. A reduced core effectome composed of xopF1, xopM, avrBs2 and xopR was identified that may allow commensal strains overcoming plant basal immunity. In contrast, stepwise accumulation of numerous type 3 effector genes was shown in successful pathogens responsible for epidemics. Our data suggest that capacity to intimately interact with plants through T3SS would be an ancestral trait of xanthomonads. Since its acquisition, T3SS has experienced a highly dynamic evolutionary history characterized by intense gene flux between species that may reflect its role in host adaptation. PMID- 28869688 TI - Sequence Engineering to Control the Helix Handedness of Peptide Foldamers. AB - Peptide foldamers have been studied for over two decades and numerous sequence patterns have been shown to form well-defined three-dimensional arrangements in solution. In particular, helices of various geometries have been described. In this article, different concepts concerning the construction of helical foldameric peptides, for which the possibility of governing the sense of the formed helix was evidenced, are presented and discussed. PMID- 28869686 TI - Concise Review: Kidney Generation with Human Pluripotent Stem Cells. AB - Chronic kidney disease (CKD) is a worldwide health care problem, resulting in increased cardiovascular mortality and often leading to end-stage kidney disease, where patients require kidney replacement therapies such as hemodialysis or kidney transplantation. Loss of functional nephrons contributes to the progression of CKD, which can be attenuated but not reversed due to inability to generate new nephrons in human adult kidneys. Human pluripotent stem cells (hPSCs), by virtue of their unlimited self-renewal and ability to differentiate into cells of all three embryonic germ layers, are attractive sources for kidney regenerative therapies. Recent advances in stem cell biology have identified key signals necessary to maintain stemness of human nephron progenitor cells (NPCs) in vitro, and led to establishment of protocols to generate NPCs and nephron epithelial cells from human fetal kidneys and hPSCs. Effective production of large amounts of human NPCs and kidney organoids will facilitate elucidation of developmental and pathobiological pathways, kidney disease modeling and drug screening as well as kidney regenerative therapies. We summarize the recent studies to induce NPCs and kidney cells from hPSCs, studies of NPC expansion from mouse and human embryonic kidneys, and discuss possible approaches in vivo to regenerate kidneys with cell therapies and the development of bioengineered kidneys. Stem Cells 2017;35:2209-2217. PMID- 28869689 TI - Cooperative Adsorption by Porous Frameworks: Diffraction Experiment and Phenomenological Theory. AB - Materials science of metal open frameworks is a state-of-the-art field for numerous applications, such as gas storage, sensors, and medicine. Two nanoporous frameworks, gamma-Mg(BH4 )2 and MIL-91(Ti), with different levels of structural flexibility, were examined with in situ X-ray diffraction guest adsorption desorption experiments. Both frameworks exhibit a cooperative guest adsorption correlated with a lattice deformation. This cooperativity originates from the long-range interactions between guest molecules, mediated by elastic response of the host porous structure. The observed experimental scenarios are rationalized with a mean field Gorsky-Bragg-Williams (GBW) approach for the lattice-gas Ising model. The adjusted GBW model, in combination with in situ synchrotron powder diffraction, demonstrates an efficient experimental and phenomenological approach to characterize thermodynamics of the adsorption in MOFs not only for the total uptake but also for every specific guest site. PMID- 28869691 TI - Bone Morphogenetic Protein Promotes Lewis X Stage-Specific Embryonic Antigen 1 Expression Thereby Interfering with Neural Precursor and Stem Cell Proliferation. AB - The glycoprotein Prominin-1 and the carbohydrate Lewis X stage-specific embryonic antigen 1 (LeX-SSEA1) both have been extensively used as cell surface markers to purify neural stem cells (NSCs). While Prominin-1 labels a specialized membrane region in NSCs and ependymal cells, the specificity of LeX-SSEA1 expression and its biological significance are still unknown. To address these issues, we have here monitored the expression of the carbohydrate in neonatal and adult NSCs and in their progeny. Our results show that the percentage of immunopositive cells and the levels of LeX-SSEA1 immunoreactivity both increase with postnatal age across all stages of the neural lineage. This is associated with decreased proliferation in precursors including NSCs, which accumulate the carbohydrate at the cell surface while remaining quiescent. Exposure of precursors to bone morphogenetic protein (BMP) increases LEX-SSEA1 expression, which promotes cell cycle withdrawal by a mechanism involving LeX-SSEA1-mediated interaction at the cell surface. Conversely, interference with either BMP signaling or with LeX SSEA1 promotes proliferation to a similar degree. Thus, in the postnatal germinal niche, the expression of LeX-SSEA1 increases with age and exposure to BMP signaling, thereby downregulating the proliferation of subependymal zone precursors including NSCs. Stem Cells 2017;35:2417-2429. PMID- 28869690 TI - Highly Stretchable, Compliant, Polymeric Microelectrode Arrays for In Vivo Electrophysiological Interfacing. AB - Polymeric microelectrode arrays (MEAs) are emerging as a new generation of biointegrated microelectrodes to transduce original electrochemical signals in living tissues to external electrical circuits, and vice versa. So far, the challenge of stretchable polymeric MEAs lies in the competition between high stretchability and good electrode-substrate adhesion. The larger the stretchability, the easier the delamination of electrodes from the substrate due to the mismatch in their Young's modulus. In this work, polypyrrole (PPy) electrode materials are designed, with PPy nanowires integrated on the high conductive PPy electrode arrays. By utilizing this electrode material, for the first time, stretchable polymeric MEAs are fabricated with both high stretchability (~100%) and good electrode-substrate adhesion (1.9 MPa). In addition, low Young's modulus (450 kPa), excellent recycling stability (10 000 cycles of stretch), and high conductivity of the MEAs are also achieved. As a proof of concept, the as-prepared polymeric MEAs are successfully used for conformally recording the electrocorticograph signals from rats in normal and epileptic states, respectively. Further, these polymeric MEAs are also successful in stimulating the ischiadic nerve of the rat. This strategy provides a new perspective to the highly stretchable and mechanically stable polymeric MEAs, which are vital for compliant neural electrodes. PMID- 28869692 TI - The 1,6,7,12-Tetraazaperylene Bridging Ligand as an Electron Reservoir and Its Disulfonato Derivative as Redox Mediator in an Enzyme-Electrode Process. AB - The homodinuclear ruthenium(II) complex [{Ru(l-N4 Me2 )}2 (MU-tape)](PF6 )4 {[1](PF6 )4 } (l-N4 Me2 =N,N'-dimethyl-2,11-diaza[3.3](2,6)-pyridinophane, tape=1,6,7,12-tetraazaperylene) can store one or two electrons in the energetically low-lying pi* orbital of the bridging ligand tape. The corresponding singly and doubly reduced complexes [{Ru(l-N4 Me2 )}2 (MU-tape.- )](PF6 )3 {[2](PF6 )3 } and [{Ru(l-N4 Me2 )}2 (MU-tape2- )](PF6 )2 {[3](PF6 )2 }, respectively, were electrochemically generated, successfully isolated and fully characterized by single-crystal X-ray crystallography, spectroscopic methods and magnetic susceptibility measurements. The singly reduced complex [2](PF6 )3 contains the pi-radical tape.- and the doubly reduced [3](PF6 )2 the diamagnetic dianion tape2- as bridging ligand, respectively. Nucleophilic aromatic substitution at the bridging tape in [1]4+ by two sulfite units gave the complex [{Ru(l-N4 Me2 )}2 {MU-tape-(SO3 )2 }]2+ ([4]2+ ). Complex dication [4]2+ was exploited as a redox mediator between an anaerobic homogenous reaction solution of an enzyme system (sulfite/sulfite oxidase) and the electrode via participation of the low-energy pi*-orbital of the disulfonato-substituted bridging ligand tape (SO3 )22- (Ered1 =-0.1 V versus Ag/AgCl/1 m KCl in water). PMID- 28869693 TI - Diabetes prevalence and its impact on health-related quality of life in tuberculosis patients. AB - OBJECTIVE: To determine the prevalence of diabetes mellitus (DM), assess its influence on health-related quality of life (HRQoL) among patients with TB. METHODS: In this prospective study, eligible patients at three primary healthcare centres in urban slum region of south Delhi, India, underwent blood glucose screening at treatment initiation. HRQoL scores were determined by conducting face-to-face interviews using Dhingra and Rajpal (DR-12) scale at pre-treatment, end of intensive phase and end of the treatment. RESULTS: In 316 patients, the overall DM prevalence was 15.8%, of whom 9.5% were known to have diabetes, and 6.3% were diagnosed at TB treatment initiation. DM was more common among patients of older age (P < 0.001), with higher BMI (P < 0.001), with PTB (P = 0.02) and with poor psychological status. HRQoL was significantly poor in the socio psychological & exercise adaptation domain in patients with DM ?50 years of age at each visit. Older age, poor literacy, loss in workdays, alcohol use and socio economic status significantly predict poor HRQoL scores in patients with DM. Uncontrolled DM patients demonstrated poor HRQoL at the end of the intensive phase (P = 0.04) of treatment and at its completion (P = 0.03) compared to those with controlled DM. CONCLUSION: Addressing screening measures and glycaemic control along with social determinants such as literacy level and alcohol consumption could be an important means of improving the HRQoL of TB with DM patients. PMID- 28869694 TI - Strongyloides stercoralis infection increases the likelihood to detect Trypanosoma cruzi DNA in peripheral blood in Chagas disease patients. AB - OBJECTIVES: In a previous study performed by our group, Strongyloides stercoralis infection in patients with Chagas disease was associated with higher proportion of Trypanosoma cruzi DNA detection in peripheral blood. The aim of the study was to confirm this association in a larger cohort of patients. METHODS: Cross sectional study of all patients with Chagas disease diagnosed from 2005 to 2015 during blood donation at the Catalan Blood Bank. Demographic data and T. cruzi RT PCR were collected. S. stercoralis infection diagnosis was based on a serological test. RESULTS: Two hundred and two blood donors were included. T. cruzi RT-PCR was positive in 72 (35.6%) patients, and S. stercoralis serology was positive in 22 (10.9%) patients. Patients with positive S. stercoralis serology had higher proportion of positive T. cruzi RT-PCR than those with negative serology (54.5% vs. 33.3%, P = 0.050), and the difference increased when taking a serological index cut-off of 2.5, which increases the specificity of the test to detect a confirmed strongyloidiasis (60% vs. 33%, P = 0.017). CONCLUSIONS: Patients with Chagas disease with positive S. stercoralis serology had higher proportion of positive T. cruzi RT-PCR in peripheral blood than those with negative serology, which reflects the potential immunomodulatory effects of S. stercoralis in T. cruzi co-infected patients. PMID- 28869695 TI - Climate change alters stability and species potential interactions in a large marine ecosystem. AB - We have little empirical evidence of how large-scale overlaps between large numbers of marine species may have altered in response to human impacts. Here, we synthesized all available distribution data (>1 million records) since 1992 for 61 species of the East Australian marine ecosystem, a global hot spot of ocean warming and continuing fisheries exploitation. Using a novel approach, we constructed networks of the annual changes in geographical overlaps between species. Using indices of changes in species overlap, we quantified changes in the ecosystem stability, species robustness, species sensitivity and structural keystone species. We then compared the species overlap indices with environmental and fisheries data to identify potential factors leading to the changes in distributional overlaps between species. We found that the structure of the ecosystem has changed with a decrease in asymmetrical geographical overlaps between species. This suggests that the ecosystem has become less stable and potentially more susceptible to environmental perturbations. Most species have shown a decrease in overlaps with other species. The greatest decrease in species overlap robustness and sensitivity to the loss of other species has occurred in the pelagic community. Some demersal species have become more robust and less sensitive. Pelagic structural keystone species, predominately the tunas and billfish, have been replaced by demersal fish species. The changes in species overlap were strongly correlated with regional oceanographic changes, in particular increasing ocean warming and the southward transport of warmer and saltier water with the East Australian Current, but less correlated with fisheries catch. Our study illustrates how large-scale multispecies distribution changes can help identify structural changes in marine ecosystems associated with climate change. PMID- 28869696 TI - Comparison and functional characterisation of peripheral blood mononuclear cells isolated from filarial lymphoedema and endemic normals of a South Indian population. AB - OBJECTIVE: The underlying problem in lymphatic filariasis is irreversible swelling of the limbs (lymphoedema), which is a unique feature of lymphatic insufficiency. It is still unclear whether the natural ability of lymphatics to form functional lymphatic vasculature is achieved or attenuated in the lymphoedemal pathology. Clinical studies have clearly shown that circulating lymphatic progenitors (CLPs), a subset of bone marrow-derived mononuclear cells (PBMCs), contribute to post-natal lymph vasculogenesis. CLP-based revascularisation could be a promising strategy to bypass the endothelial disruption and damage incurred by the filarial parasites. Thus our aim was to compare and characterise the functional prowess of PBMCs in physiological and lymphoedemal pathology. METHODS: PBMCs were isolated from venous blood sample from drug-naive endemic normals (EN) and drug-deprived filarial lymphoedema (FL) individuals using density gradient centrifugation. Adhesion, transwell migration and in vitro matrigel assays were employed to characterise the lymphvasculogenic potential of PBMCs. CLPs were phenotypically characterised using flow cytometry; expression levels of lymphatic markers and inflammatory cytokines were quantified using qRT-PCR and ELISA, respectively. RESULTS: PBMCs from FL group display poor adherence to fibronectin (P = 0.040), reduced migration towards SDF-1alpha (P = 0.035), impaired tubular network (P = 0.004) and branching point (P = 0.048) formation. The PBMC mRNA expression of VEGFR3 (P = 0.039) and podoplanin (P = 0.050) was elevated, whereas integrin alpha9 (P = 0.046) was inhibited in FL individuals; additionally, the surface expression of CD34 (P = 0.048) was significantly reduced in the FL group compared to the EN group. CONCLUSION: PBMCs from filarial lymphoedema show defective and dysregulated lymphvasculogenic function compared to endemic normals. PMID- 28869697 TI - Comfort-Supporting Nursing Activities for End-of-Life Patients in an Institutionalized Environment. AB - PURPOSE: Comfort promotion plays a significant role in end-of-life patient care. The objective of this study was to determine the utilization rate of comfort supporting nursing activities in end-of-life patients in an institutionalized environment in the Czech Republic in relation to the age of the registered nurses (RNs), length of work experience, education level, and type of workplace. DESIGN: A cross-sectional, descriptive study was designed. A questionnaire with Likert scales included 31 activities of dying care and spiritual support interventions. The sample comprised 907 RNs working in 49 institutions in nine regions of the Czech Republic. The Kruskal-Wallis test, Mann-Whitney U post-hoc test with Bonferroni correction of significance, Spearman's correlation analysis, and logical regression model were used for statistical evaluation. FINDINGS: The least frequently implemented activity by RNs was "Show the patient's willingness to discuss death" and the most frequent activity was "Threat to the patient's dignity and respect." The highest utilization rate of nursing activities was reported in the physical dimension, while the lowest utilization rate of nursing activities was in the social dimension set. Significant predictors for the high utilization rate of physical dimension set activities were hospice care departments, long-term care facilities (LTCFs), and the age of RNs. Hospice departments were also a predictor of high utilization rate of activities in the psychological, spiritual, and social dimension set activities. CONCLUSIONS: With the exception of hospice departments, RNs used activities encouraging psychological, spiritual, and social comfort for end-of-life patients less frequently than the physical dimension. CLINICAL RELEVANCE: RNs in hospitals and LTCFs focus insufficiently on the spiritual and psychosocial comfort of end-of life patients. This study is of particular significance to educators who prepare the next generation of nurses. PMID- 28869698 TI - Biogeographic responses of the copepod Calanus glacialis to a changing Arctic marine environment. AB - Dramatic changes have occurred in the Arctic Ocean over the past few decades, especially in terms of sea ice loss and ocean warming. Those environmental changes may modify the planktonic ecosystem with changes from lower to upper trophic levels. This study aimed to understand how the biogeographic distribution of a crucial endemic copepod species, Calanus glacialis, may respond to both abiotic (ocean temperature) and biotic (phytoplankton prey) drivers. A copepod individual-based model coupled to an ice-ocean-biogeochemical model was utilized to simulate temperature- and food-dependent life cycle development of C. glacialis annually from 1980 to 2014. Over the 35-year study period, the northern boundaries of modeled diapausing C. glacialis expanded poleward and the annual success rates of C. glacialis individuals attaining diapause in a circumpolar transition zone increased substantially. Those patterns could be explained by a lengthening growth season (during which time food is ample) and shortening critical development time (the period from the first feeding stage N3 to the diapausing stage C4). The biogeographic changes were further linked to large scale oceanic processes, particularly diminishing sea ice cover, upper ocean warming, and increasing and prolonging food availability, which could have potential consequences to the entire Arctic shelf/slope marine ecosystems. PMID- 28869699 TI - Fourteen-day high-dose esomeprazole, amoxicillin and metronidazole as third-line treatment for Helicobacter pylori infection. AB - INTRODUCTION: The efficacy of currently recommended third-line therapies for Helicobacter pylori is suboptimal, even that of culture-guided treatments. Resistance to multiple antibiotics is the major factor related to treatment failure. The aim of this study was to evaluate the effectiveness and safety of a 14-day therapy using high-dose of amoxicillin, metronidazole and esomeprazole. MATERIAL AND METHODS: Multicenter open-label study as a register in routine clinical practice in patients with two previous failures of eradication therapy. A triple therapy with esomeprazole 40 mg b.d., amoxicillin 1 g t.d.s and metronidazole 500 mg t.d.s for 2 weeks was administered as a third-line therapy after a first treatment including clarithromycin and a second treatment including a quinolone. Helicobacter pylori status was determined by either histology or 13 C-UBT both before and after treatment. RESULTS: A total of 68 patients were included in this study. An interim analysis showed that only three out of eight patients who had received metronidazole in previous eradication regimens were cured (37%, 95% CI 8-75); as a result, after this interim analysis only metronidazole-naive patients were included. The ITT eradication rate in metronidazole-naive patients was 64% (95% CI 51-76). Adverse events occurred in 58% of patients, all of them mild-to-moderate. Two patients (3%) did not complete >90% of the treatment because of side effects. No severe adverse events occurred. CONCLUSION: Cure rates of this 14-day schedule using high-dose esomeprazole, amoxicillin and metronidazole as a third-line eradication regimen were suboptimal, especially in patients who had received metronidazole in previous failed eradication regimens. PMID- 28869700 TI - Efficacy of AMC/DCBA lozenges for sore throat: A systematic review and meta analysis. AB - BACKGROUND: Lozenges containing Amylmetacresol and 2,4-Dichlorobenzylalcohol (AMC/DCBA, eg Strepsils(r) ) are marketed as a remedy for acute sore throat. This over-the-counter formulation has antiseptic and local anaesthetic qualities. OBJECTIVES: The objective of this systematic review and meta-analysis is to evaluate the efficacy and safety of AMC/DCBA for the relief of pain associated with acute uncomplicated sore throat. METHODS: A systematic review of Literature was conducted using databases Medline, Embase and Cochrane to identify randomised controlled trials comparing AMC/DCBA against placebo or alternative local treatment options for acute uncomplicated sore throat. An additional hand search was performed. Two reviewers independently assessed citations for relevance, inclusion criteria and risk of bias. Meta-analysis was performed on included trials and standardised mean differences (SMD; dCohen ) with 95% confidence intervals (CIs) were calculated. RESULTS: The literature search yielded 77 citations, 3 of which met the inclusion criteria. AMC/DCBA lozenges (0.6 mg Amylmetacresol, 1.2 mg 2, 4-Dichlorobenzylalcohol) were compared with unflavoured, non-medicated lozenges. The AMC/DCBA formulation additionally contained lidocaine in one and flavouring additives in another trial. A total of 660 adults participated in the included trials. Primary outcome was reduction in pain intensity against baseline, 2 hours after intervention compared with placebo group. Fixed effects meta-analysis resulted in a standardised mean difference in pain intensity of -0.6 (-0.75; -0.45) on an 11-point ordinal rating scale, favouring the AMC/DCBA lozenges. Secondary outcomes were sore throat relief, difficulty swallowing and throat numbness. No serious side effects were reported, whereas mild side effects like headache, cough, nasal congestion and irritation of the oral cavity, were reported in up to 16% of subjects in both groups. All included trials were sponsored by a manufacturer of AMC/DCBA containing lozenges. CONCLUSIONS: Lozenges with AMC/DCBA can be a safe treatment option to relieve pain in patients with uncomplicated sore throat looking for local treatment options and valuing the modest additional effect compared with non-medicated lozenges. Registration: PROSPERO CRD42015008826. PMID- 28869702 TI - The prevalence and preventability of potentially relevant drug-drug interactions in patients admitted for cardiovascular diseases: A cross-sectional study. AB - AIM: The aim was to describe the type and prevalence of potentially relevant drug drug interactions (pDDIs) in a population of patients admitted for cardiovascular diseases (CVD), and management strategies for reducing the occurrence of pDDIs. METHODS: A retrospective cross-sectional study was performed on Cardiology ward of University Clinical Hospital Center in Belgrade, Serbia. A total of 527 patients, with more than one prescription during hospital stay, were enrolled in this study. Data were obtained from medical records. LexiInteract was used as the screening tool. RESULTS: At least one potentially relevant pDDI was identified in 83.9% of patients. Occurrence was significantly more prevalent in patients with higher number of drugs, multimorbidity, longer length of stay, arrhythmia, heart failure, infectious and respiratory disease. About 13% of pDDIs exposures were accompanied with concurrent renal or liver disease, as an additional risk for DDI manifestation. Among CVD, patients with a history of myocardial infarction possessed the highest additional risk. The most common potential clinical outcome was the effect on cardiovascular system 48.5%, renal function and/or potassium 22.3%, bleeding 9.5%, impaired glucose control 6.8% and digoxin toxicity 4.6%. Main management strategies to avoid X or D class included using paracetamol instead of NSAID or alternative NSAID (38%), alternative antibiotic or antifungal (20.4%), H2 receptor antagonist instead of PPI (8.3%), avoiding therapeutic duplication (7.3%), and alternative HMG-CoA reductase inhibitor (7%). Heart rate, blood pressure, electrolytes/potassium and blood glucose could have been employed in monitoring for potential consequence of 72.2% C class pDDIs. CONCLUSIONS: Use of drug interaction screening tools can be beneficial risk mitigation strategy for potentially relevant pDDIs in CVD patients. DDI screening software could be linked to the patient's laboratory results or clinical data regarding renal or liver function, as an approach to reinforce DDIs alert quality. PMID- 28869703 TI - Organocatalytic Intramolecular [4+2] Cycloaddition between In Situ Generated Vinylidene ortho-Quinone Methides and Benzofurans. AB - Described herein is the enantioselective construction of oxygen-containing [5-6 5] tricyclic heterocycles by an organocatalyzed asymmetric [4+2] cycloaddition of vinylidene ortho-quinone methides and benzofurans. According to this methodology, a series of oxygen-containing [5-6-5] tricyclic heterocycles with various functional groups were synthesized in excellent enantio- and diastereoselectivities (>99 % ee, >20:1 d.r.). Furthermore, the deuterium labeling experiments and high-resolution mass spectroscopy demonstrated that a vinylidene ortho-quinone methide intermediate was involved and possibly resulted from a prototropic rearrangement of 2-ethynylphenol. Remarkably, a catalyst loading as low as 0.1 mol %, and a gram-scale synthesis were achieved for this transformation. PMID- 28869701 TI - Nup42 and IP6 coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells. AB - The mRNA lifecycle is driven through spatiotemporal changes in the protein composition of mRNA particles (mRNPs) that are triggered by RNA-dependent DEAD box protein (Dbp) ATPases. As mRNPs exit the nuclear pore complex (NPC) in Saccharomyces cerevisiae, this remodeling occurs through activation of Dbp5 by inositol hexakisphosphate (IP6 )-bound Gle1. At the NPC, Gle1 also binds Nup42, but Nup42's molecular function is unclear. Here we employ the power of structure function analysis in S. cerevisiae and human (h) cells, and find that the high affinity Nup42-Gle1 interaction is integral to Dbp5 (hDDX19B) activation and efficient mRNA export. The Nup42 carboxy-terminal domain (CTD) binds Gle1/hGle1B at an interface distinct from the Gle1-Dbp5/hDDX19B interaction site. A nup42 CTD/gle1-CTD/Dbp5 trimeric complex forms in the presence of IP6 . Deletion of NUP42 abrogates Gle1-Dbp5 interaction, and disruption of the Nup42 or IP6 binding interfaces on Gle1/hGle1B leads to defective mRNA export in S. cerevisiae and human cells. In vitro, Nup42-CTD and IP6 stimulate Gle1/hGle1B activation of Dbp5 and DDX19B recombinant proteins in similar, nonadditive manners, demonstrating complete functional conservation between humans and S. cerevisiae. Together, a highly conserved mechanism governs spatial coordination of mRNP remodeling during export. This has implications for understanding human disease mutations that perturb the Nup42-hGle1B interaction. PMID- 28869704 TI - Eliminating glutaraldehyde from crosslinked collagen films using supercritical CO2. AB - Collagen has received considerable attention as a biomaterial for tissue engineering because of its low immunogenicity, controllable biodegradation, and ability to influence cell growth and proliferation. Frequently, collagen scaffolds require crosslinking to improve mechanical strength, requiring agents like glutaraldehyde that have high residual cytotoxicity. A novel method for extracting residual glutaraldehyde from crosslinked collagen films with supercritical carbon dioxide (CO2 ) is presented. CO2 is a nontoxic, nonflammable substance that is relatively inert and can be used to process biomaterials at mild pressures and physiologic temperatures. In this work, it was first determined that type I collagen is chemically compatible with both liquid and supercritical CO2 . Treated collagen showed minimal changes in physicochemical properties as determined by differential scanning calorimetry, gel electrophoresis, and circular dichroism. CO2 was subsequently used to extract residual glutaraldehyde from crosslinked collagen films. Glutaraldehyde concentration was reduced by over 95%, from over 20 ppm before treatment to about 1 ppm, in only 1 h. CO2 treatment caused negligible alteration of thermal stability but did significantly increase film stiffness and tensile strength. However, these changes were minor compared to heat-based removal of glutaraldehyde. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 86-94, 2018. PMID- 28869705 TI - Long-acting injectable antipsychotics for prevention and management of violent behaviour in psychotic patients. AB - BACKGROUND AND AIMS: It has been well established that long-term antipsychotic treatment prevents relapse, lowers number of rehospitalisations, and also effectively reduces violent behaviour. Although violent behaviour is not a typical manifestation of schizophrenia or other psychotic disorders, the diagnosis of psychosis increases the overall risk of violence. One of the few modifiable factors of violence risk is adherence with medication. In contrast, non-adherence with drug treatment and subsequent relapse increases risk of violent acts. Non-adherence can be addressed partially by long-acting injectable antipsychotics (LAI). The aim of our review was to examine the role of antipsychotic drugs, especially LAI, in prevention and management of violent behaviour in psychosis. METHODS: This is a non-systematic, narrative review of the data from open, naturalistic, retrospective, and population studies, case series, and post hoc analyses of randomised controlled trials. Search of electronic databases (PubMed, Embase) was performed to identify relevant papers. RESULTS: Nine published papers (3 cross-sectional chart reviews, 4 retrospective studies, 2 prospective, randomised trials) were found. The results indicated positive clinical and antiaggressive effects of LAI in psychotic patients with high risk of violent behaviour. DISCUSSION: Reviewed evidence suggests that secured drug treatment with LAI may have clinical benefit in schizophrenia patients with high risk of violent behaviour. LAI significantly reduced the severity of hostility, aggressivity, number of violent incidents, and criminal offences. These findings are supported further by the empirical evidence from clinical practice, high rates of prescribed LAI to schizophrenia patients in high security and forensic psychiatric facilities. CONCLUSIONS: Available data encourage the use of LAI in forensic psychiatry, especially during court-ordered commitment treatment. PMID- 28869706 TI - Early use of peripherally inserted central catheters is safe in Staphylococcus aureus bacteraemia. AB - BACKGROUND: Management of Staphylococcus aureus bacteraemia (SAB) includes prolonged intravenous antibiotics often administered through a peripherally inserted central catheter (PICC). Optimal timing of PICC insertion for SAB treatment is unknown. There are concerns that early insertion may increase the risk of subsequent line infection. AIMS: This retrospective audit aims to determine if early PICC insertion is safe. The outcomes considered included crude mortality, attributable mortality, PICC line infections, duration of bacteraemia and relapsed SAB. METHODS: Patients with SAB at our institution between March 2013 and September 2016 were identified. Early PICC line insertion was defined as occurring within 48 h of index positive blood culture. RESULTS: This retrospective audit identified 357 patients with SAB who subsequently received a PICC. This study did not show any significant differences between the early and late PICC insertion groups for attributable mortality (6.3% and 4.8%, P = 0.27), duration of bacteraemia (median 2 days for both groups, P = 0.48) and relapsed SAB (4.7% and 4.1%, P = 0.74). Importantly, no confirmed PICC infections were identified in either group. CONCLUSIONS: Early PICC insertion in SAB appears safe in this retrospective audit. If validated in prospective studies, this should allow for the early establishment of safe, reliable intraveous access in SAB patients. PMID- 28869708 TI - Optimization of spark plasma sintered titania for potential application as a keratoprosthesis skirt. AB - The manufacture of mechanically strong and biocompatible titania (TiO2 ) materials is of vital importance for their application as corneal implant skirts. This study was aimed at optimizing the selection of raw powder and sintering conditions for TiO2 ceramics. TiO2 compacts were synthesized from five raw powders, denoted as Altair, Inframat, Alfa, Materion, and Amperit, respectively, by spark plasma sintering using different sintering parameters. The XRD and Raman results confirmed that the anatase TiO2 phase in the Inframat powder had converted completely to rutile TiO2 phase after sintering at 900 degrees C and above. The nanoindentation results indicated that among the five types of TiO2 samples sintered at 1100 degrees C, the Inframat pellets possessed the highest Young's modulus and hardness. Additionally, when Materion samples were employed to study the effects of SPS parameters, a higher sintering temperature in the range of 1100-1300 degrees C decreased the mechanical properties of sintered pellets probably due to the generation of more structural defects. Culture of human corneal stromal fibroblasts on the sintered sample surfaces showed that comparably high cell viability and proliferation were observed on all TiO2 samples except Amperit compared to positive control. Furthermore, cells cultured on Inframat TiO2 sintered in the temperature range of 900-1300 degrees C exhibited viability and formation of focal adhesion complex similar to those on control, and those prepared at 1100 degrees C had significantly higher cell proliferation indices than control. In conclusion, Inframat TiO2 consolidated at 1100 degrees C by SPS was the best formulation for the preparation of mechanically strong and biocompatible Keratoprosthesis skirt. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3502-3513, 2017. PMID- 28869709 TI - In vitro basic fibroblast growth factor (bFGF) delivery using an antithrombogenic 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer coated with a micropatterned diamond-like carbon (DLC) film. AB - In this study, a newly designed drug-release platform composed of an antithrombogenic 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer was introduced, which was impregnated with basic fibroblast growth factor (bFGF) (bFGF/MPC polymer) to enhance the endothelial cell activation. The platform was also coated with an ultrathin micropatterned diamond-like carbon (DLC) film (DLC/bFGF/MPC polymer) to precisely control the drug release rate and the cell compatibility. The resulting DLC/bFGF/MPC polymer could effectively prolong the bFGF release rate by depositing the micropatterned DLC. The number of adherent platelets on the DLC/bFGF/MPC polymer was significantly lower (about 1/14) than that on a currently used stent made of stainless steel (SUS316L), indicating the enhanced antithrombogenicity in the DLC/bFGF/MPC polymer. The proliferation of endothelial cells on the DLC/bFGF/MPC polymer and the DLC/MPC polymer (without bFGF) were also examined. It was found that the optical density of HUVEC on the DLC/bFGF/MPC polymer determined by WST-8 assay was higher by 25%than that on the DLC/MPC polymer (without bFGF) measured after 72 h of incubation. Our results suggest that the released bFGF that contributes to the expression of other growth factors results in the early proliferation of the HUVEC on the DLC/bFGF/MPC polymer. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3384 3391, 2017. PMID- 28869707 TI - SPIO-Au core-shell nanoparticles for promoting osteogenic differentiation of MC3T3-E1 cells: Concentration-dependence study. AB - This work aims to explore the concentration-dependence of SPIO-Au core-shell nanoscale particles (NPs) (17.3 +/- 1.2 nm in diameter) on biocompatibility and osteogenic differentiation of preosteoblast MC3T3-E1 cells. The stability of NPs was first investigated by UV-vis absorption spectra and zeta potential measurement. Then concentration effects of NPs (1-80 MUg/mL) were evaluated on viability, morphology, proliferation, cellular uptake, and alkaline phosphate (ALP) activity levels. Results have shown strong stability and no acute toxicity (viability > 93%) or morphological difference at all concentration levels of NPs. The proliferation results indicated that the concentration of NPs below 40 MUg/mL does not affect the cell proliferation for 7 days of incubation. Transmission electron microscopy images revealed the successful internalization of NPs into MC3T3-E1 cells and the dose-dependent accumulation of NPs inside the cytoplasm. The ALP level of MC3T3-E1 cells was improved by 49% (of control) after treated with NPs at 10 MUg/mL for 10 days, indicating their positive effect on early osteogenic differentiation. This study confirmed the excellent biocompatibility of SPIO-Au NPs and their great potential for promoting osteogenic differentiation and promised the future application for these NPs in bone engineering including drug delivery, cell labeling, and activity tracking within scaffolds. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3350-3359, 2017. PMID- 28869710 TI - Influence of hydrodynamic pressure on the proliferation and osteogenic differentiation of bone mesenchymal stromal cells seeded on polyurethane scaffolds. AB - Hydraulic pressure has recently been introduced as an effective stimulation in the field of tissue engineering. In this study, a polymer scaffold consisting of polyurethane (PU)-based 1, 4-butanediisocyanate was fabricated. A self-designed bioreactor was employed to produce perfusion and hydrodynamic pressure stimulations. The viability, proliferation and osteogenic differentiation of the rat bone mesenchymal stromal cell (rBMSC) growing in the polymer scaffold were investigated after hydrodynamic pressure stimulation. Additionally, the mechanical properties of the cell-laden constructs were also evaluated. Our findings suggested that the perfusion rate (10 mL/min) and low hydrodynamic pressure stimulation (60 mmHg, 0.5 Hz) maintained the viability of rBMSC during 2 weeks cultivation. The cell proliferation was promoted by 60 mmHg stimulation in the first week. The synthesis of alkaline phosphates and osteocalcin was enhanced after 2 weeks stimulation. Meanwhile, the equilibrium modulus of scaffold was increased by 1.85-fold using 60 mmHg hydrodynamic pressure stimulation. Additionally, type I and III procollagen produced by rBMSC was increased 4.92- and 3.02-fold, respectively. However, no encouraging results were detected in 120 mmHg hydrodynamic pressure group. Our study suggests that the 60 mmHg hydrodynamic pressure is a promising approach to enhance the functional properties of the rBMSC-laden PU-based bone scaffold. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3445-3455, 2017. PMID- 28869711 TI - Might Sorafenib combined with radiotherapy be better option for treating hepatocellular carcinoma with portal vein tumour thrombosis? PMID- 28869712 TI - Acute oxygen therapy: an audit of prescribing and delivery practices in a tertiary hospital in Perth, Western Australia. AB - BACKGROUND: Oxygen is a widely used drug in the hospital setting. However, international audits suggest that oxygen administration practices are often not compliant with prescribed standards. This can place patients at risk and cause serious adverse events. AIM: To analyse data related to recent practices of oxygen prescription and administration at Royal Perth Hospital (RPH), Western Australia. The results of this audit aim to guide further research on possible interventional studies implementing key solutions. METHODS: All patients who received care in the Acute Medical Unit at RPH between 1 September and 14 September 2015 were included in this audit. Patients who were given supplemental oxygen during their admission were selected for further review of records. Appropriate medically indicated target oxygen saturations for each patient were judged under consultation with a respiratory specialist. RESULTS: A total of 65 patients received oxygen supplementation within the study period; 36 of these patients (55.4%) had target oxygen saturations prescribed by doctors, and 25% of the prescribed targets were judged to be inappropriate. In total, 49 patients (75.4%) were exposed to a potential risk from oxygen therapy due to prescription error and/or delivery error. A real risk was identified in 19 patients (29.2%) as they received oxygen at levels outside their appropriate medically indicated target range. CONCLUSION: The current practices of oxygen prescription and administration within RPH are suboptimal. Patients are placed at risk of oxygen toxicity due to deviation from oxygen prescription guidelines. PMID- 28869713 TI - Substrate Recognition by a Dual-Function P450 Monooxygenase GfsF Involved in FD 891 Biosynthesis. AB - GfsF is a multifunctional P450 monooxygenase that catalyzes epoxidation and subsequent hydroxylation in the biosynthesis of macrolide polyketide FD-891. Here, we describe the biochemical and structural analysis of GfsF. To obtain the structural basis of a dual-function reaction, we determined the crystal structure of ligand-free GfsF, which revealed GfsF to have a predominantly hydrophobic substrate binding pocket. The docking models, in conjunction with the results of the enzymatic assay with substrate analogues and site-directed mutagenesis suggested two distinct substrate binding modes for epoxidation and hydroxylation reactions, which explained how GfsF regulates the order of two oxidative reactions. These findings provide new insights into the reaction mechanism of multifunctional P450 monooxygenases. PMID- 28869714 TI - Ultrafast Vibrational Dynamics of Membrane-Bound Peptides at the Lipid Bilayer/Water Interface. AB - Vibrational energy transfer (VET) of proteins at cell membrane plays critical roles in controlling the protein functionalities, but its detection is very challenging. By using a surface-sensitive femtosecond time-resolved sum-frequency generation vibrational spectroscopy with infrared pump, the detection of the ultrafast VET in proteins at cell membrane has finally become possible. The vibrational relaxation time of the N-H groups is determined to be 1.70(+/-0.05) ps for the alpha-helix located in the hydrophobic core of the lipid bilayer and 0.9(+/-0.05) ps for the membrane-bound beta-sheet structure. The N-H groups with strong hydrogen bonding gain faster relaxation time. By pumping the amide A band and probing amide I band, the vibrational relaxation from N-H mode to C=O mode through two pathways (direct coupling and through intermediate states) is revealed. The ratio of the pathways depends on the NH???O=C hydrogen-bonding strength. Strong hydrogen bonding favors the coupling through intermediate states. PMID- 28869715 TI - Growth differentiation factor 15 as a predictor of adverse renal outcomes in patients with immunoglobulin A nephropathy. AB - BACKGROUND: Growth differentiation factor 15 (GDF 15) has recently been reported as a useful prognostic marker in patients with chronic inflammatory disease and heart disease. AIM: To evaluate the role of GDF 15 as a potential prognostic predictor of renal outcome in immunoglobulin A nephropathy (IgAN). METHODS: In total, 212 patients in the Chungnam National Hospital glomerulonephritis cohort, who were diagnosed as biopsy-proven IgAN between March 2010 and June 2014, were included. GDF Fifteen was analysed by the enzyme-linked immunosorbent assay. Cut off values of the GDF 15 and the hazard ratio of it resulting in haemodialysis within 2 years were analysed. RESULTS: The level of serum GDF 15 was negatively correlated with the initial eGFR. A serum GDF 15 level of more than 496.32 pg/mL showed 90% sensitivity and 72.9% specificity to predict the possibility of it resulting in haemodialysis within 2 years. In addition, a GDF 15 level higher than 490.4 pg/mL showed 63.64% sensitivity and 65% specificity to predict a decline in eGFR > 30 mL/min within 1 year of follow up. Moreover, initial serum GDF 15 level was associated with the development of interstitial fibrosis/tubular atrophy. CONCLUSIONS: Initial serum GDF 15 level showed an inverse correlation with serum eGFR and was associated with worse renal outcome. Our results suggested that GDF 15 may play a role as a potential prognosticator in IgAN. PMID- 28869716 TI - Identification of Chimeric alphabetagamma Diterpene Synthases Possessing both Type II Terpene Cyclase and Prenyltransferase Activities. AB - Two unusual diterpene synthases composed of three domains (alpha, beta, and gamma) were identified from fungal Penicillium species. They are the first enzymes found to possess both type II terpene cyclase (TC) and prenyltransferase (PT) activities. These enzymes were characterized by heterologous expression in Aspergillus oryzae and in vitro experiments with wild-type, mutated, and truncated enzymes. The results revealed that the alpha domain in the C-terminal region of these enzymes was responsible for the PT activity, whereas the betagamma domains in the N-terminal region composed the type II TC, and formed copalyl diphosphate (2). Additionally, between the alpha and betagamma domains, there is a characteristic linker region, in which minimal secondary structure is predicted. This linker does not exist in the characterized three-domain (alphabetagamma) terpene synthases known as monofunctional type I or type II TCs, or bifunctional type I and type II TC enzymes. Therefore, both the catalytic activities and protein architecture substantially differentiate these new enzymes from the previously characterized terpene synthases. PMID- 28869717 TI - Seasonal pattern of incidence and outcome of Acute Kidney Injury: A national study of Welsh AKI electronic alerts. AB - OBJECTIVES: To identify any seasonal variation in the occurrence of, and outcome following Acute Kidney Injury. METHODS: The study utilised the biochemistry based AKI electronic (e)-alert system established across the Welsh National Health Service to collect data on all AKI episodes to identify changes in incidence and outcome over one calendar year (1st October 2015 and the 30th September 2016). RESULTS: There were total of 48 457 incident AKI alerts. The highest proportion of AKI episodes was seen in the quarter of January to March (26.2%), and the lowest in the quarter of October to December (23.3%, P < .001). The same trend was seen for both community-acquired and hospital-acquired AKI sub-sets. Overall 90 day mortality for all AKI was 27.3%. In contrast with the seasonal trend in AKI occurrence, 90 day mortality after the incident AKI alert was significantly higher in the quarters of January to March and October to December compared with the quarters of April to June and July to September (P < .001) consistent with excess winter mortality reported for likely underlying diseases which precipitate AKI. CONCLUSIONS: In summary we report for the first time in a large national cohort, a seasonal variation in the incidence and outcomes of AKI. The results demonstrate distinct trends in the incidence and outcome of AKI. PMID- 28869719 TI - Phosphate Transfer in Activated Protein Complexes Reveals Interaction Sites. AB - For many proteins, phosphorylation regulates their interaction with other biomolecules. Herein, we describe an unexpected phenomenon whereby phosphate groups are transferred non-enzymatically from one interaction partner to the other within a binding interface upon activation in the gas phase. Providing that a high affinity exists between the donor and acceptor sites, this phosphate transfer is very efficient and the phosphate groups only ligate to sites in proximity to the binding region. Consequently, such phosphate-transfer reactions may define with high precision the binding site between a phosphoprotein and its binding partner, as well as reveal that the binding site in this system is retained in the phase transfer from solution to the gas phase. PMID- 28869718 TI - Prevalence and causes of preoperative anaemia in elective major surgery patients. AB - BACKGROUND: Preoperative anaemia is associated with increased morbidity and mortality in surgical patients. Recent national patient blood management guideline recommended screening surgical patients for anaemia, particularly iron deficiency anaemia, without reference to the prevalence of anaemia or iron deficiency anaemia in this patient population. AIMS: To establish the prevalence and cause of preoperative anaemia in elective major surgery patients. METHODS: Patients attending the anaesthetic pre-admission clinics from 1 July 2013 to 30 June 2014 prior to their major elective surgery in our institution were screened for anaemia and iron deficiency by measuring full blood count, iron studies and C reactive protein. Patients who were anaemic were either further assessed in the haematology clinic or had their medical records reviewed to ascertain the cause of the anaemia. RESULTS: Of 1494 patients, 208 (13.9%) were anaemic, with a male predominance (70.7%); 57 (27.4%) of them had iron deficiency anaemia. Other common causes of anaemia include underlying malignancy (18.3%), end-stage renal failure (11.5%) and other chronic diseases (7.2%). In 53 patients (25.5%), the cause was unknown. Anaemia was most commonly found in patients scheduled for gastrointestinal surgery. CONCLUSION: Preoperative anaemia affects 13.9% of patients undergoing elective major surgery. The most common causes are iron deficiency and chronic diseases. The cause was unexplained in 25.5% of patients with anaemia. The prevalence of anaemia in different surgical specialties may have implications on the approach to screening, particularly in resource-limited areas. PMID- 28869720 TI - Electrocatalytic Water Oxidation by MnOx /C: In Situ Catalyst Formation, Carbon Substrate Variations, and Direct O2 /CO2 Monitoring by Membrane-Inlet Mass Spectrometry. AB - Layers of amorphous manganese oxides were directly formed on the surfaces of different carbon materials by exposing the carbon to aqueous solutions of permanganate (MnO4- ) followed by sintering at 100-400 degrees C. During electrochemical measurements in neutral aqueous buffer, nearly all of the MnOx /C electrodes show significant oxidation currents at potentials relevant for the oxygen evolution reaction (OER). However, by combining electrolysis with product detection by using mass spectrometry, it was found that these currents were only strictly linked to water oxidation if MnOx was deposited on graphitic carbon materials (faradaic O2 yields >90 %). On the contrary, supports containing sp3 -C were found to be unsuitable as the OER is accompanied by carbon corrosion to CO2 . Thus, choosing the "right" carbon material is crucial for the preparation of stable and efficient MnOx /C anodes for water oxidation catalysis. For MnOx on graphitic substrates, current densities of >1 mA cm-2 at eta=540 mV could be maintained for at least 16 h of continuous operation at pH 7 (very good values for electrodes containing only abundant elements such as C, O, and Mn) and post operando measurements proved the integrity of both the catalyst coating and the underlying carbon at OER conditions. PMID- 28869721 TI - The utility and feasibility of assessing sleep disruption in a men's health clinic using a mobile health platform device: A pilot study. AB - INTRODUCTION: Evidence linking sleep disruption and sexual dysfunction in men is mounting; yet the characterisation of sleep patterns and complaints utilising a clinically feasible method within this patient population remain largely under reported. AIM: A pilot study aiming to demonstrate a clinically feasible method to characterise the sleep patterns and complaints in a representative sample of patients treated in a men's health clinic. METHODS: Male patients (n = 48) completed a battery of validated sleep questionnaires using an mHealth mobile platform, MySleepScript, at the Johns Hopkins Men's Health and Vitality Center. Metrics related to clinical feasibility such as completion time, ease of use, preference of electronic format, and patient satisfaction were also collected. MAIN OUTCOME MEASURES: Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Berlin Questionnaire, Patient Health Questionnaire (PHQ-9), and Primary Care PTSD Screen (PC-PTSD). RESULTS: Primary urological chief symptoms for this sample patient population were erectile dysfunction (ED; 80%), hypogonadism (40%), benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS; 40%) and Peyronie's disease (10%). Mean PSQI score was 7.8 [SD 4.2], with 67% of all patients falling within the "poor sleeper" range. At least mild symptoms of depression were noted in 40% and 43% were at risk for obstructive sleep apnea (OSA) on the Berlin Questionnaire. CONCLUSIONS: This pilot study demonstrated the feasibility and potential utility of an mHealth platform to assist clinicians, within a men's health clinic, in detecting sleep disturbances. Disrupted sleep was revealed in well over half of this sample of patients. As a result of the growing evidence linking poor sleep and sleep disorders (eg, OSA) to the conditions relevant to men's health (eg, erectile dysfunction, hypogonadism and BPH), further efforts beyond this pilot study are necessary to identify the aetiological processes underlying the association between specific disrupted sleep disorders and urological conditions. PMID- 28869723 TI - Answer to the Letter to the Editor of Dr. Clouatre and Dr. Preuss. PMID- 28869724 TI - The evidence of hydroxycitric acid (HCA) health risks to the testes points to manufacturing failings, not to properly made HCA salts. PMID- 28869722 TI - Pain relief of sore throat with a new anti-inflammatory throat lozenge, ibuprofen 25 mg: A randomised, double-blind, placebo-controlled, international phase III study. AB - OBJECTIVE: The aim of this study was to compare the efficacy and safety of a new oromucosal ibuprofen form, ibuprofen 25 mg lozenge, in single and repeat dosing for up to 4 days, to the matched placebo, in the treatment of acute sore throat pain in adults. METHODS: In this randomised, double-blind, placebo-controlled trial, adult patients with non-streptococcal sore throat and signs of moderate-to severe associated pain (>=5 on the objective Tonsillo-Pharyngitis Assessment 21 point scale and >=60 mm on the subjective 0-100 mm visual analogue Sore Throat Pain Intensity Scale [STPIS]) were assigned ibuprofen 25 mg (n=194) or matching placebo (n=191) lozenge treatment. Efficacy was assessed (at the investigating centre up to 2 hours after first dosing, then on an ambulatory basis) by parameters derived from patient's scores on scales of pain relief, pain intensity, and global efficacy assessment. The primary efficacy end-point was the time-weighted TOTal PAin Relief (TOTPAR) over 2 hours after first dosing using the Sore Throat Relief Scale (STRS). Safety and local tolerability were assessed. RESULTS: Ibuprofen 25 mg was superior to placebo on numerous pain relief parameters; TOTPAR was significantly higher with ibuprofen 25 mg over 2 hours after first dosing (P<.05), the effect being apparent from the first evaluation at 15 minutes (P<.05). The STPIS reduction in favour of ibuprofen 25 mg was not significant vs placebo. Mean STRS scores and patient's global efficacy assessment both reflected a higher efficacy of ibuprofen 25 mg over the 4-day treatment period with tests of statistical significance up to day 1 evening (P<.05), and, in patients with still clinically significant pain (n=128), after an average 4 days (P<.01). Ibuprofen 25 mg lozenge was well tolerated with a safety profile similar to placebo. CONCLUSION: Low-dose ibuprofen 25 mg lozenge in repeat dosing provides in adults more efficacious and rapid relief of sore throat pain and is as well tolerated as placebo. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01785862. PMID- 28869725 TI - [Advances in mass spectrometry-based approaches for neuropeptide analysis]. AB - Neuropeptides are an important class of endogenous bioactive substances involved in the function of the nervous system, and connect the brain and other neural and peripheral organs. Mass spectrometry-based neuropeptidomics are designed to study neuropeptides in a large-scale manner and obtain important molecular information to further understand the mechanism of nervous system regulation and the pathogenesis of neurological diseases. This review summarizes the basic strategies for the study of neuropeptides using mass spectrometry, including sample preparation and processing, qualitative and quantitative methods, and mass spectrometry imagining. PMID- 28869726 TI - [Direct reprogramming from fibroblasts into cardiamyocytes]. AB - Cardiac regenerative therapy has attracted much attention as a novel approach for heart diseases. Direct reprogramming of fibroblasts into cardiomyocytes without going through a pluripotent stem cell stage would provide a promising source of cells for cell transplantation in future. This review summarizes the research methods and problems of direct reprogramming of fibroblasts into cardiomyocytes in vitro and in vivo, and forecasts the future development of this new strategy. PMID- 28869727 TI - [Research progress in rotavirus VP4 subunit vaccine]. AB - Rotaviruses are leading causes of worldwide acute diarrhea in children younger than 5 years old, with severe consequence of social and economic burden. Vaccination is the most effective way to control rotavirus infection, however, the licensed rotavirus vaccines are ineffective in some low-income countries of Africa and Asia, where the mortality caused by rotavirus is higher than other areas. In addition, there are also safety concerns such as increased risk of intussusception. Therefore, it is urgent to improve the efficiency and safety of rotavirus vaccine to reduce the morbidity and mortality caused by rotavirus. Till now, many efforts are made to improve the effectiveness of rotavirus vaccines, and the inactive vaccine becomes the main trend in the research of rotavirus vaccine. The developments in recombinant rotavirus vaccines, especially in VP4 subunit vaccines are summarized in this review, and it could be helpful to develop effective recombinant rotavirus vaccines in further studies. PMID- 28869728 TI - [Application of nanobody in cancer treatment]. AB - Camelidae can produce a unique antibody that lacks light chain called variable heavy chain domain, also known as nanobodies. This antibody contains only one variable region, with high affinity, high stability, strong tissue penetration, efficient expression. Besides, their toxicity and immunogenicity are both low to be used for both therapeutic and diagnostic applications, as well as research tools. In this review, we discuss how nanobody has been explored as therapeutics in oncology, and provide ideas for the further development of nanobody. PMID- 28869729 TI - [Engineering and characterization of new intrinsic transcriptional terminators in Bacillus subtilis 168]. AB - Terminators as regulatory signals are typically placed behind the last coding sequence to block the transcription of DNA to RNA and release the transcript. In the present study, the hairpin and the U-rich sequence of the bacteriophage lambdato terminator were first modified to investigate their effects on termination efficiency and mRNA stability in Bacillus subtilis 168. Compared with the native lambdato terminator, the terminator variants M3, M11 and M12 showed higher termination efficiency values. Moreover, the variantsM3, M4 and M11 showed significant positive effects on the mRNA stability of the upstream gfp gene. Additionally, insertion of RNase site also increased the mRNA stability. The results of this study suggested that the composition of the hairpin loop is not required for effective intrinsic termination in B. subtilis. Our results also showed that the terminator could also be used as a potential tool for increasing mRNA stability and the corresponding enzyme production in B. subtilis. PMID- 28869730 TI - [Effect of sodium chloride on growth and lipid accumulation of Chlorella protothecoides CS-41]. AB - With basal medium, we studied the growth status, lipid droplet distribution, total lipid content of Chlorella protothecoides CS-41 treated with different concentrations of sodium chloride (0, 150, 300 and 600 mmol/L) by optical microscopy, electron microscopy, confocal laser focusing and Nile red staining. Results show that the addition of NaCl affected the growth of Chlorella protothecoides CS-41. With the increase of NaCl concentration, the growth rate of Chlorella was inhibited. Chlorella cell wall became thicker, and lipid droplets increased. At the early stage, the amount of lipid droplets in the 600 mmol/L NaCl culture was the highest, but at the late-log stage, the amount of lipid droplets increased with the increase of the biomass of culture in 150 and 300 mmol/L NaCl culture. At the stable stage, biomass (dry weight) in 300 mmol/L NaCl culture was 73.55% of that in the control, but the total lipid content was 2.22 times higher than that in the control. A certain concentration of sodium chloride treatment can significantly increase the lipid content of Chlorella protothecoides CS-41. PMID- 28869731 TI - [Prokaryotic expression, purification and characterization of arginine kinase of Bombyx mori]. AB - Arginine kinase (AK) is a key enzyme in energy metabolism of invertebrates and plays an important regulatory role in the life activities such as growth and development, nutrition utilization, immune resistance and stress response. Arginine kinase of Bombyx mori (BmAK) is related to the energy balance and anti NPV process, but there is little research on its molecular structure and enzymatic properties. We cloned the ORF sequence of BmAK gene, and analyzed chromosomal localization, genomic structure, mRNA structure, secondary and tertiary structure. Phylogenetic analysis indicated that AK was highly conserved in evolution. Soluble recombinant BmAK was obtained by prokaryotic expression, and purified by Ni-NTA affinity chromatography. The circular dichroism spectroscopy showed that BmAK contained alpha-helix structures, and its alpha helix structures were relatively stable in the pH range between 5 and 10. Enzyme activity analysis showed that the optimum temperature of BmAK was 30 C and the optimum pH of BmAK was 7.5. The optimal temperature of BmAK was 25 C. Between 15 C and 30 C, the structure and activity of BmAK was relatively stable. The structure of BmAK was relatively stable at pH 7.0. Our findings reveal the structure and function of BmAK to develop novel green safe and environmentally friendly insecticides. PMID- 28869732 TI - [Effect of calcium on sporulation of Taiwanofungus camphoratus in submerged fermentation]. AB - Taiwanofungus camphoratus is a valuable and rare medicinal mushroom with various bioactivities, such as liver protection and anti-cancer. T. camphoratus can produce many arthroconidia at the end of submerged fermentation, but molecular mechanism underlying this submerged conidiation remains unknown. In this study, we found that Ca2+ concentration in culture medium significantly affected the arthroconidium production of T. camphoratus. Then, we identified two proteins (CaM and HSP90) involved in Ca2+/calmodulin signaling pathway and one protein (AbaA) involved in FluG-mediated conidiation pathway by two-dimensional electrophoresis analyses. Furthermore, we proposed a Ca2+/calmodulin- and FluG mediated signaling pathway by bioinformatics analysis. By real-time quantitative PCR analyses of 23 key genes in the Ca2+/calmodulin- and FluG-mediated conidiation pathway, we found that expression levels of 7 genes (crz1, hsp90, flbB, brlA, abaA, wetA and fadA) showed significant responses to Ca2+ concentration in fermentation medium. Our research is beneficial for elucidating the underlying mechanism of submerged fermentation conidiation for T. camphoratus. PMID- 28869733 TI - [Effects of recombinant adenovirus Ad-miR-29b2c on HGC-27 cell proliferation and migration]. AB - We constructed recombinant adenoviruses expressing miR-29b2c (Ad-miR29b2c), and analyzed their effects on the proliferation and migration of HGC-27 and MGC-803 cells. miR-29b2c gene was amplified by PCR from genomic DNA and cloned into the pAdTrack-CMV vector to create the shuttle plasmid pAdT-29b2c. The recombinant plasmid was verified by restriction enzyme digestion and sequencing. The linearized shuttle vector was mixed with an adenoviral backbone plasmid (pAdEasy 1), followed by cotransformation into competent BJ5183 cells to generate the recombinant plasmid pAd-miR-29b2c. Finally, recombinant adenoviral vectors were generated by transfecting the recombinant plasmid into 293A packaging cell line. HGC-27 and MGC-803 cells were infected with the recombinant adenoviruses expressing pAd-miR-29b2c, then MTT and wound-healing assay were used to analyze the effects of pAd-miR-29b2c on the proliferation and migration of HGC-27 and MGC 803 cells. The miR-29b and miR-29c levels were significantly increased in HGC-27 cells after infected with pAd-miR-29b2c. MTT and wound-healing analysis also revealed a significant decrease in proliferation and migration of HGC-27 and MGC 803 cells compared to the control Ad-GFP-infected cells. Furthermore, western blotting results demonstrated that the protein expression level of delta-catenin was reduced in pAd-miR-29b2c transfected HGC-27 and MGC-803 cells. Taken together, the recombinant adenoviral vector was generated, and it can significantly inhibit the proliferation and migration of HGC-27 and MGC-803 cells. PMID- 28869734 TI - [Changes of urinary proteins in a bacterial meningitis rat model]. AB - Unlike cerebrospinal fluid or blood, urine accumulates metabolic changes of the body and has the potential to be a promising source of early biomarkers discovery. Bacterial meningitis is a major cause of illness among neonates and children worldwide. In this study, we used Escherichia coli-injected rat model to mimic meningitis and collected urine samples on day 1 and day 3. We used two different methods to digest proteins and analyzed peptides by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We identified 17 and 20 differential proteins by two methods respectively on day 1, and 5 differential proteins by filter-aided digestion method on day 3. Finding these differential proteins laid a foundation to further explore biomarkers of bacterial meningitis. PMID- 28869735 TI - [Effects of 1.8 mT sinusoidal electromagnetic fields of different frequencies on bone mineral density and bone histomorphometry of young rats]. AB - To study the effects of different frequency sinusoidal electromagnetic fields on the bone mineral density and bone histomorphometry of SD young rats, and to screen suitable electromagnetic field frequency. In total 32 female SD rats of 8 weeks old were randomly divided into 4 groups: control group, 15 Hz group, 30 Hz group and 45 Hz group. Except for the control group, rats in experimental groups were treated with corresponding frequency of 1.8 mT sinusoidal electromagnetic field 90 minutes every day. Rats were measured for bone mineral density after 8 weeks by dual energy X-ray absorptiometry. Rats' femur and vertebral bones were measured by analyzing the static and dynamic forms on the right tibia bone for morphometrics. Rat serum was measured to estimate the index of bone formation and bone resorption. Bone mineral density of rats from 15 Hz group and 45 Hz group was higher than that of the control group (P<0.05). Serum osteocalcin level of rats from 15 Hz group and 45 Hz group was higher than that of the control group (P<0.05). Double fluorescence spacing and static parameters of bone tissue in experimental group rat tibia were higher than that of the control group (P<0.05). Our findings imply that 15 Hz and 45 Hz sinusoidal electromagnetic fields can effectively increase bone mineral density in young rats for preventing osteoporosis. PMID- 28869736 TI - [Expression, purification, stability and transduction efficiency of full-length SOD2 recombinant proteins]. AB - Superoxide dismutase (SOD) family is necessary to protect cells from the toxicity of reactive oxygen species produced during normal metabolism. Among SODs, manganese-containing superoxide dismutase (Mn-SOD, SOD2) is the most important one. The DNA fragment containing the full nucleotide of full-length human SOD2 was synthesized and inserted into the prokaryotic expression vector pGEX-4T-1 with tag GST. DNA construct was then transformed into Escherichia coli BL21 (DE3) and expression was induced with IPTG at 25 C. The recombinant fusion protein GST SOD2 (46 kDa) was purified from the bacterial lysate by GST resin column affinity chromatography. GST tag was cleaved with thrombin, and a crude SOD2 recombinant protein (25 kDa) was obtained and further purified by heparin affinity chromatography. Activities of the two SOD2 proteins were 1 788 and 2 000 U/mg, respectively. Both SOD2 proteins were stable under physiological condition and cell-penetrating (P<0.05). Our findings open the possibility to study the structure and effects of two full-length recombinant SOD2 proteins. PMID- 28869737 TI - [A method to increase the production of insulin precursor in Pichia pastoris]. AB - To improve the yield of insulin precursor (PI), we constructed a recombinant expression vector pPIC9K-PI and transformed it into Pichia pastoris GS115 using electroporation. After screening, a mutant strain CL012 with 12 copies was obtained on the YPDS plate containing 4.0 mg/mL G418. Then, the components of SNAREs (Soluble N-ethylmaleimide-sensitive factor attachment receptor proteins), SNC2 and SNC2-SSO2, were expressed in the strain CL012 to explore the effect of SNAREs on the yield of PI. In shake flask culture, the strains expressing SNC2 and SNC2-SSO2 yielded PI of 1.89 mg/L and 2.21 mg/L after methanol induction for 96 h, which were improved by 23.53% and 44.44% compared to that of strain CL012 (1.53 mg/L), respectively. Further, in a 5-L bioreactor, the yield of PI with strain CL012 was 53 mg/L for high-density fermentation, after 96 h of methanol induction, which was 34.64-fold higher than that of shake culture. The strains expressing SNC2 and SNC2-SSO2 yielded the PI of 64 mg/L and 78 mg/L, which were respectively increased by 20.75% and 47.17%, compared to that of strain CL012. This work indicated that SNAREs components promoted the secretion of PI to improve its heterologous expression in P. pastoris. PMID- 28869738 TI - [Cloning short gene fragment and constructing recombinant plasmid based on restoration of antibiotic resistance]. AB - Molecular cloning is one of the most important and widely used technologies in molecular biology research. Generally, the target DNA fragment and the vector are separately digested by restriction enzyme, then purified and recovered, and then ligated with DNA-ligase. For some very short gene fragments (<300 bp), the recovery efficiency of the purified fragment is very low after digestion and cleavage, leading to the difficulty in its inserting into the expression vector. To address this issue, we developed a cloning method based on restoration of antibiotic resistance in constructing recombinant plasmid, which proved highly efficient in cloning very short gene fragments. PMID- 28869739 TI - [Mutation breeding of high 9alpha-hydroxy-androst-4-ene-3,17- dione transforming strains from phytosterols and their conversion process optimization]. AB - In order to improve transformation efficiency of phytosterols into 9alpha hydroxylation of 4-androstene-3,17-dione (9alpha-OH-AD) by Mycobacterium sp. LY 1, we studied the strains breeding using atmospheric and room temperature plasma (ARTP) technology and optimized their conversion process. A high production strain named C33 with a good genetic stability was selected and the product molar yield reached to 15.5%, 34.8% higher than that of original strain with 15 g/L phytosterols. Furthermore, the fermentation medium was optimized through the design of orthogonal experiment. Besides, oil-water bidirectional transformation system was set up to improve the 9alpha-OH-AD molar yield of mutant strain C33. With adding 12 mL soybean oil to each 1 g phytosterols, the molar yield of 9alpha OH-AD reached 47.0%, which increased twice than that of control (15.5%). PMID- 28869740 TI - 30 min of treadmill walking at self-selected speed does not increase gait variability in independent elderly. AB - Walking is one of the preferred exercises among elderly, but could a prolonged walking increase gait variability, a risk factor for a fall in the elderly? Here we determine whether 30 min of treadmill walking increases coefficient of variation of gait in elderly. Because gait responses to exercise depend on fitness level, we included 15 sedentary and 15 active elderly. Sedentary participants preferred a lower gait speed and made smaller steps than the actives. Step length coefficient of variation decreased ~16.9% by the end of the exercise in both the groups. Stride length coefficient of variation decreased ~9% after 10 minutes of walking, and sedentary elderly showed a slightly larger step width coefficient of variation (~2%) at 10 min than active elderly. Active elderly showed higher walk ratio (step length/cadence) than sedentary in all times of walking, but the times did not differ in both the groups. In conclusion, treadmill gait kinematics differ between sedentary and active elderly, but changes over time are similar in sedentary and active elderly. As a practical implication, 30 min of walking might be a good strategy of exercise for elderly, independently of the fitness level, because it did not increase variability in step and stride kinematics, which is considered a risk of fall in this population. PMID- 28869741 TI - Development of a quantitative multi-compound method for the detection of 14 nitrogen-rich adulterants by LC-MS/MS in food materials. AB - The increasing number of food frauds using exogenous nitrogen-rich adulterants to artificially raise the protein content for economically motivated adulteration has demonstrated the need for a robust analytical methodology. This method should be applicable for quality control in operations covering a wide range of analyte concentrations to be able to analyse high levels as usually found in adulteration, as well as low levels due to contamination. The paper describes a LC-MS/MS method covering 14 nitrogen-rich adulterants using a simple and fast sample preparation based on dilution and clean-up by dispersive SPE. Quantification is carried out by isotopic dilution reaching LOQs of 0.05-0.20 mg/kg in a broad range of food matrices (infant formula, liquid milk, dairy ingredient, high protein meal, cereal, infant cereal, and meat/fish powder). Validation of seven commodity groups was performed according to SANCO 12571/2013, giving satisfactory results demonstrating the method's fitness for purpose at the validated range at contamination level. Method ruggedness was further assessed by transferring the developed method into another laboratory devoted to routine testing for quality control. Next to the method description, emphasis is placed on challenges and problems appearing during method development as well as validation. They are discussed in detail and solutions are provided. PMID- 28869743 TI - Impact of agronomic and climatic factors on the mycotoxin content of harvested oats in the United Kingdom. AB - A survey was conducted to determine the concentration of Fusarium mycotoxins in UK oats over three seasons (2006-8). One hundred oat samples were collected each year at harvest, together with agronomic details, and analysed for 10 Fusarium mycotoxins. The incidence and concentration of most Fusarium mycotoxins, including deoxynivalenol and zearalenone, were relatively low in oats compared with values previously reported for wheat. HT-2 toxin (HT2) and T-2 toxin (T2) levels were relatively high with an overall combined (HT2+T2) mean of 450 MUg kg 1 for 2006-8. Data were combined with a previous dataset collected from 2002-5 to determine the effects of agronomic practices and climate. There was a negative relationship with late summer rainfall, indicating that drier conditions in July and August resulted in increased HT2 and T2 in UK oats. Agronomic factors that impacted upon HT2 and T2 in harvested oats were previous crop, cultivation, and variety. Analysis of the previous cropping history showed there was a stepwise increase in HT2+T2 as the cereal intensity of the rotation increased. Variety was an important factor, with higher levels and a wider range detected on winter versus spring varieties. Indicative levels for HT2 and T2 in cereals and cereal products were introduced by the EC in 2013. The indicative level for unprocessed oats for human consumption is a combined concentration (HT2+T2) of 1000 MUg kg-1. From 2002 to 2008, between 1% and 30% of samples exceeded 1000 MUg kg-1 HT2+T2 each year (overall mean, 16%). The introduction of European legislation on HT2 and T2 mycotoxins could have serious implications for UK oat production and oat processing industries based on the levels detected within these studies. PMID- 28869742 TI - Persistent organic pollutants in farmed European sea bass (Dicentrarchus labrax, Linnaeus, 1758) from Sicily (Italy). AB - Farmed European sea bass (Dicentrarchus labrax, Linnaeus, 1758) were collected during 2016 from one Sicilian fish farm that uses two different rearing systems - sea cage and concrete tank - for determination of polychlorinated biphenyls (PCB), organochlorine pesticides (OCP) and polycyclic aromatic hydrocarbons (PAH) residues by HRGC-MS/MS. Moreover, commercial feed was analysed. This study aimed to determine whether the different rearing systems affect the concentration of these compounds, and to assess the safety of cultured fish. PCBs represent the pollutants with the highest concentration; in particular, PCB138 and 153 have the highest concentration in almost all samples. Among OCPs, only 4,4'-DDE, 4,4'-DDD and 4,4'-DDT residues have been detected. Concerning PAHs, only fluorene and phenanthrene were detected, in both rearing systems. Although some residues of organic pollutants were found in the analysed samples, they were always below the MRLs, so the results suggest that farmed sea bass are safe for human consumption. PMID- 28869745 TI - Corrigendum. PMID- 28869744 TI - Impact of ion-pairs for the determination of multiclass antimicrobials residues in honey by LC-MS/MS. AB - This study examines the behaviour of volatile perfluorinated carboxylic acids used as ion-pairing reagents for the separation of multiclass antimicrobial residues in honey (tetracyclines, sulphonamides, macrolides, and aminoglycosides). Heptafluorobutanoic acid and pentafluoropentanoic acid were compared as mobile phase additives at concentrations of 0-20 mmol.L-1 using reversed-phase chromatography. Our objective was to find optimal conditions that enable the separation of antimicrobials with a minimum loss in sensitivity and efficiency. The influence of ion pairing on chromatographic performance was examined. Results showed that heptafluorobutanoic acid was able to separate aminoglycosides faster and more efficiently than pentafluoropentanoic acid, but at low concentrations of heptafluorobutanoic acid between 2.5 and 5 mM, tetracyclines showed poor chromatographic efficiency. A concentration of 10 mM was found to be optimal for all studied veterinary drugs. The method was then applied to determine multiclass antimicrobial residues in honey. Based on validation data, the mean recoveries of analytes ranged between 93% and 104%, and the intermediate precisions were <21%. The decision limit (CCalpha) and detection capability (CCbeta) were in the ranges of 5-25 and 7-33 MUg kg-1, respectively. The method was found to be suitable for use in analysis of veterinary drugs with a broader group of compounds found in food-producing animals. PMID- 28869746 TI - Physiological intensity profile, exercise load and performance predictors of a 65 km mountain ultra-marathon. AB - The aims of the study were to describe the physiological profile of a 65-km (4000 m cumulative elevation gain) running mountain ultra-marathon (MUM) and to identify predictors of MUM performance. Twenty-three amateur trail-runners performed anthropometric evaluations and an uphill graded exercise test (GXT) for VO2max, ventilatory thresholds (VTs), power outputs (PMax, PVTs) and heart rate response (HRmax, HR@VTs). Heart rate (HR) was monitored during the race and intensity was expressed as: Zone I (VT2) for exercise load calculation (training impulse, TRIMP). Mean race intensity was 77.1%+/-4.4% of HRmax distributed as: 85.7%+/-19.4% Zone I, 13.9%+/-18.6% Zone II, 0.4%+/-0.9% Zone III. Exercise load was 766+/-110 TRIMP units. Race time (11.8+/-1.6h) was negatively correlated with VO2max (r = -0.66, P <0.001) and PMax (r = -0.73, P <0.001), resulting these variables determinant in predicting MUM performance, whereas exercise thresholds did not improve performance prediction. Laboratory variables explained only 59% of race time variance, underlining the multi-factorial character of MUM performance. Our results support the idea that VT1 represents a boundary of tolerable intensity in this kind of events, where exercise load is extremely high. This information can be helpful in identifying optimal pacing strategies to complete such extremely demanding MUMs. PMID- 28869747 TI - Live imaging looks deeper. AB - Iodixanol provides an easy and affordable solution to a problem that has limited resolution and brightness when imaging living samples. PMID- 28869748 TI - Liver iron concentration is not raised in patients with dysmetabolic hyperferritinemia. AB - : Background & aims. Hyperferritinemia (HF) is frequently present in patients with metabolic syndrome (MS). MS associated with HF is named dysmetabolic hyperferritinemia (DH). There are some publications that propose that DH is associated with a raised liveriron concentration (LIC). We studied the LIC in patients referred for HF to a secondary hospital to determine if there are differences between patients with or without MS. MATERIAL AND METHODS: We conducted a prospective study of 132 consecutive patients with HF from January to December 2010. The MS was defined by the International Diabetes Federation criteria (2005). LIC was determined by Magnetic resonance imaging (MRI). RESULTS: The number of patients for which there was enough data to determine MS was 97, out of which 54 had MS and 43 had no MS (NMS). In 54/97 patients, MRI for LIC determination was performed. From the MS group, 44 were men (27 underwent MRI) and 10 women (9 MRI). The mean LIC was 27.83 +/- 20.90 ?mol/g for the MS group. In the NMS group, 36 were men (13 MRI), and 7 women (5 MRI). In 18 patients from the NMS group, LIC was determined by MRI. The mean LIC was 33.16 +/- 19.61 ?mol/g in the NMS group. We compared the mean values of LIC from both groups (MS vs. NMS) and no significant differences were found (p = 0.067). CONCLUSION: Patients with DH present a mean LIC within normal values and their values do not differ from those of patients with HF but without MS. PMID- 28869749 TI - Perspectives of female medical faculty in Ethiopia on a leadership fellowship program. AB - Objectives: This study aims to evaluate a leadership fellowship program through perspectives of Ethiopian women medical faculty participants. Methods: An intensive two-week leadership development fellowship was designed for women faculty from Ethiopian medical schools and conducted from 2011-2015 at the University of Wisconsin-School of Medicine and Public Health in Madison, Wisconsin. Nine Ethiopian women working in early- or mid-level academic positions were selected. Semi-structured interviews were conducted with the fellows. Transcripts were reviewed through qualitative analysis to assess the perceived impact of the training on their careers. Three male academic leaders were interviewed to solicit feedback on the program. Results: Eight of 9 fellows were interviewed. Themes describing the benefits of the fellowship included: increased awareness of gender inequities; enhanced motivation for career advancement; increased personal confidence; and improved leadership skills. Fellows provided suggestions for future training and scaling up efforts to promote gender equity. Male leaders described the benefits of men promoting gender equity within academic health centers. Conclusions: This paper provides evidence that targeted brief training programs can enhance women's motivation and skills to become effective leaders in academic medicine in Ethiopia. Promoting gender equity in academic medicine is an important strategy to address health workforce shortages and to provide professional role models for female students in the health professions. PMID- 28869750 TI - Thermoelectric performance and the role of anti-site disorder in the 24-electron Heusler TiFe2Sn. AB - Heusler compounds XY 2 Z with 24 valence electrons per formula unit are potential thermoelectric materials, given their thermal and chemical stability and their relatively earth-abundant constituent elements. We present results on the 24 electron compound TiFe2Sn here. First principles calculations on this compound suggest semiconducting behavior. A relatively flat conduction band that could be associated with a high Seebeck coefficient upon electron doping is found. A series of compounds have been prepared and characterized using a combination of synchrotron x-ray and neutron diffraction studies to understand the effects of site order/disorder phenomena and n-type doping. Samples fabricated by a three step processing approach were subjected to high temperature Seebeck and electrical resistivity measurements. Ti:Fe anti-site disorder is present in the stoichiometric compound and these defects are reduced when starting Ti-rich compositions are employed. Additionally, we investigate control of the Seebeck coefficient through the introduction of carriers through the substitution of Sb on the Sn site in these intrinsically p-type materials. PMID- 28869751 TI - Constructing hierarchical sulfur-doped nitrogenous carbon nanosheets for sodium ion storage. AB - Hierarchical sulfur-doped nitrogenous carbon (S/NC) and nitrogenous carbon (NC) nanosheets are successfully fabricated by carbonization of their corresponding precursor polymers which are synthesized through the polymerization reaction of dianhydride and multi-amine compounds. Hierarchical S/NC nanosheets deliver greatly enhanced reversible capacity, compared with hierarchical NC nanosheets, of 280 mAh g-1 at a current density of 100 mA g-1 after 300 cycles. It is found that the introduction of sulfur species in carbon skeleton results in increasing the turbostratic structures, rather than enlarging the interlayer distances, for boosting the specific capacity of sodium-ion storage. The turbostratic structures and sulfur dopant existed in the carbon can offer more active sites for the sodium-ion storage. Carbon-based materials doped with sulfur are capable of improving the sodium-ion storage property, which can broaden the horizon of designing a string of outstanding carbon materials for the future energy storage technologies. PMID- 28869752 TI - Spin-wave excitations in the spin-density wave state of doped iron pnictides. AB - We investigate spin-wave excitations in the spin-density wave state of doped iron pnictides within a five-orbital model. We find that the excitations along ([Formula: see text]) -> ([Formula: see text]) are very sensitive to dopings whereas they do not exhibit a similar sensitivity along ([Formula: see text]) -> ([Formula: see text]). Secondly, the ellipticity of the elliptical ring-like excitations around ([Formula: see text]) is also very much dependent on doping. Thirdly, the spin-wave spectral weight shifts towards the low-energy region as it moves away from zero doping. We find several features to be in qualitative agreement with the inelastic neutron-scattering measurements for the doped pnictides. PMID- 28869753 TI - Quantum plasmon model for the terahertz photoconductivity in intrinsic semiconductor nanowires. AB - A quantum plasmon model for the terahertz photoconductivity in intrinsic semiconductor nanowires is developed. The classical plasmon model assumes the excited electron in semiconductors feels a restoring force generated by a harmonic-oscillator potential. Although it is successfully applied to explain the terahertz photoconductivity in semiconductor nanowires, the classical treatment of the potential weakens accurate theoretical analysis. Here I treat the potential in a full quantum way and present an exact analytical formula for photoconductivity. The formula not only gives more reasonable photoconductivity, but also has the same conciseness when compared with that of the classical plasmon model. The validity of the quantum plasmon model is proved independently by numerical calculations in real space. PMID- 28869754 TI - The Irisin Hormone Profile and Expression in Human Bone Tissue in the Bone Healing Process in Patients. AB - BACKGROUND Whether or not there is a relationship between the newly-discovered irisin hormone and bone healing is not yet known. The aim of this study was to investigate what effect irisin hormone has on the bone healing process. MATERIAL AND METHODS The study included 21 adult patients with a diagnosed fracture of the lower extremity (femur or tibia). Informed consent was obtained from all the patients. A total of four venous blood samples were taken from the patients: before fracture stabilization, then postoperatively on days 1, 10, and 60. In patients with femoral neck fracture who had hip prosthesis applied, bone tissue samples were taken from the removed femur head and irisin was determined immunohistochemically in muscle biopsies taken from the same patients. RESULTS In analysis, it was revealed that the mean value of irisin 60 days after operation is significantly higher than the values of irisin before operation, 1 day after operation, and 15 day after operation (p<0.001, p<0.001, p<0.001, respectively). Intense staining was observed in compact bone tissue, muscle tissue, and in hypertrophic vascular endothelium within the Havers canal. CONCLUSIONS The level of irisin hormone increased in the bone union process and affects fracture healing due to irisin receptors in human bone tissue. PMID- 28869755 TI - Sampling strategies to capture single-cell heterogeneity. AB - Advances in single-cell technologies have highlighted the prevalence and biological significance of cellular heterogeneity. A critical question researchers face is how to design experiments that faithfully capture the true range of heterogeneity from samples of cellular populations. Here we develop a data-driven approach, illustrated in the context of image data, that estimates the sampling depth required for prospective investigations of single-cell heterogeneity from an existing collection of samples. PMID- 28869756 TI - Red-shifted luciferase-luciferin pairs for enhanced bioluminescence imaging. AB - Red-shifted bioluminescence reporters are desirable for biological imaging. We describe the development of red-shifted luciferins based on synthetic coelenterazine analogs and corresponding mutants of NanoLuc that enable bright bioluminescence. One pair in particular showed superior in vitro and in vivo sensitivity over commonly used bioluminescence reporters. We adapted this pair to develop a bioluminescence resonance-energy-based Antares reporter called Antares2, which offers improved signal from deep tissues. PMID- 28869758 TI - Internally ratiometric fluorescent sensors for evaluation of intracellular GTP levels and distribution. AB - GTP is a major regulator of multiple cellular processes, but tools for quantitative evaluation of GTP levels in live cells have not been available. We report the development and characterization of genetically encoded GTP sensors, which we constructed by inserting a circularly permuted yellow fluorescent protein (cpYFP) into a region of the bacterial G protein FeoB that undergoes a GTP-driven conformational change. GTP binding to these sensors results in a ratiometric change in their fluorescence, thereby providing an internally normalized response to changes in GTP levels while minimally perturbing those levels. Mutations introduced into FeoB to alter its affinity for GTP created a series of sensors with a wide dynamic range. Critically, in mammalian cells the sensors showed consistent changes in ratiometric signal upon depletion or restoration of GTP pools. We show that these GTP evaluators (GEVALs) are suitable for detection of spatiotemporal changes in GTP levels in living cells and for high-throughput screening of molecules that modulate GTP levels. PMID- 28869759 TI - p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (Abeta) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Abeta. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both Abeta and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of Abeta and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of Abeta and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. Cover Image for this Issue: doi. 10.1111/jnc.14163. PMID- 28869757 TI - A general method to fine-tune fluorophores for live-cell and in vivo imaging. AB - Pushing the frontier of fluorescence microscopy requires the design of enhanced fluorophores with finely tuned properties. We recently discovered that incorporation of four-membered azetidine rings into classic fluorophore structures elicits substantial increases in brightness and photostability, resulting in the Janelia Fluor (JF) series of dyes. We refined and extended this strategy, finding that incorporation of 3-substituted azetidine groups allows rational tuning of the spectral and chemical properties of rhodamine dyes with unprecedented precision. This strategy allowed us to establish principles for fine-tuning the properties of fluorophores and to develop a palette of new fluorescent and fluorogenic labels with excitation ranging from blue to the far red. Our results demonstrate the versatility of these new dyes in cells, tissues and animals. PMID- 28869760 TI - The Role of Parental Posttraumatic Stress, Marital Adjustment, and Dyadic Self Disclosure in Intergenerational Transmission of Trauma: A Family System Approach. AB - Research indicates that posttraumatic stress symptoms (PTSS) induced by war trauma may be transmitted to veterans' wives and offspring (secondary traumatic stress; STS). However, the interplay between family members' characteristics has not been accounted for in such processes. Taking a family systems perspective, we examine the contributions of fathers' PTSS, mothers' STS, marital adjustment, and self-disclosure of both parents to offspring's STS and test whether marital quality applies as a mechanism of parent-child transmission. Combat veterans and former prisoners of war (N = 123), their spouses, and adult offspring were investigated in a multiple-step mediation analysis. The results highlight the mother's crucial role in trauma transmission and suggest that strengthening the marital relationship may buffer the transmission of fathers' PTSS to offspring. PMID- 28869762 TI - Association of breast milk fatty acids with allergic disease outcomes-A systematic review. AB - INTRODUCTION: Dietary polyunsaturated fatty acids (PUFAs) have immunoregulatory properties. Breast milk is rich in PUFA, and it has been hypothesized that these PUFAs may be important in the aetiology of allergic diseases. Despite a growing body of evidence, the associations between breast milk PUFA and allergic disease have not previously been systematically reviewed. METHODS: The search was performed in PubMed and EMBASE databases using breastfeeding, fatty acid and allergic disease terms. Two authors were involved in selecting papers for review according to the inclusion criteria and extracting information on study characteristics and measures of association. Only studies that reported numeric associations between concentration of breast milk fatty acids and allergic disease outcomes were included. RESULTS: A total of 18 papers met the inclusion criteria, reporting results from 15 study populations. The majority were cohort studies (n=11), with data from only two case-control and two cross-sectional studies. Sample size varied between 30 and 352 participants, and follow-up time of the cohorts varied between 3 months and 14 years. Nine studies reported on eczema, seven reported on sensitization, and only five reported on asthma/wheeze. There was heterogeneity among studies in terms of presenting the association between PUFA and allergy; therefore, estimates could not be pooled. Only a few studies observed associations between n-3 and n-6 PUFAs and allergic disease, and the magnitude of this effect varied greatly. CONCLUSIONS: There is insufficient evidence to suggest that colostrum or breast milk polyunsaturated fatty acids influence the risk of childhood allergic diseases. PMID- 28869763 TI - Applying the Paradigm of Relational Ethics into Contextual Therapy. Analyzing the practice of Ivan Boszormenyi-Nagy. AB - Ivan Boszormenyi Nagy introduced with his contextual therapy a challenging theory into the world of family therapy. It is rooted in a relational ethical perspective on human relations and shifts the focus of therapy from pathology to evoking reciprocal care and a genuine dialogue, based on the conviction that inter-human relations are resources for individual growth and health. This article presents a research project on the practice of the founder himself, to describe how the principles of the contextual theory and therapy can be integrated into concrete therapeutic interventions. Using the Constant Comparison Method, the authors found six clusters of interventions representing methodical elements through which Ivan Boszormenyi-Nagy applies the paradigm of his approach. PMID- 28869764 TI - A comparative analysis of human plasma and serum proteins by combining native PAGE, whole-gel slicing and quantitative LC-MS/MS: Utilizing native MS electropherograms in proteomic analysis for discovering structure and interaction correlated differences. AB - MS identification has long been used for PAGE-separated protein bands, but global and systematic quantitation utilizing MS after PAGE has remained rare and not been reported for native PAGE. Here we reported on a new method combining native PAGE, whole-gel slicing and quantitative LC-MS/MS, aiming at comparative analysis on not only abundance, but also structures and interactions of proteins. A pair of human plasma and serum samples were used as test samples and separated on a native PAGE gel. Six lanes of each sample were cut, each lane was further sliced into thirty-five 1.1 mm * 1.1 mm squares and all the squares were subjected to standardized procedures of in-gel digestion and quantitative LC-MS/MS. The results comprised 958 data rows that each contained abundance values of a protein detected in one square in eleven gel lanes (one plasma lane excluded). The data were evaluated to have satisfactory reproducibility of assignment and quantitation. Totally 315 proteins were assigned, with each protein assigned in 1 28 squares. The abundance distributions in the plasma and serum gel lanes were reconstructed for each protein, named as "native MS-electropherograms". Comparison of the electropherograms revealed significant plasma-versus-serum differences on 33 proteins in 87 squares (fold difference > 2 or < 0.5, p < 0.05). Many of the differences matched with accumulated knowledge on protein interactions and proteolysis involved in blood coagulation, complement and wound healing processes. We expect this method would be useful to provide more comprehensive information in comparative proteomic analysis, on both quantities and structures/interactions. PMID- 28869765 TI - Family Subsystems Predicting Adolescents' Perceptions of Sibling Relationship Quality Over Time. AB - This study examined associations between parents' relationship conflict and parent-adolescent triangulation, and changes in adolescents' perceptions of sibling affection and hostility. The goal was to learn whether conflict in parents' relationships spills over to siblings' relationships, or whether siblings compensate by becoming less hostile and more affectionate. Using a subsample (N = 400) from the Flourishing Families Project (FFP), we found a trend for mother-adolescent triangulation predicting an increase in sibling hostility across 2 years. Fathers' reports of relationship conflict were related to increased levels of initial sibling hostility, but predicted a marginal decrease in hostility over time. Findings support increased understanding of parenting dynamics associated with changes in sibling relationship quality, and have the potential to inform clinical practice. PMID- 28869761 TI - Novel viral vectors in infectious diseases. AB - Since the development of vaccinia virus as a vaccine vector in 1984, the utility of numerous viruses in vaccination strategies has been explored. In recent years, key improvements to existing vectors such as those based on adenovirus have led to significant improvements in immunogenicity and efficacy. Furthermore, exciting new vectors that exploit viruses such as cytomegalovirus (CMV) and vesicular stomatitis virus (VSV) have emerged. Herein, we summarize these recent developments in viral vector technologies, focusing on novel vectors based on CMV, VSV, measles and modified adenovirus. We discuss the potential utility of these exciting approaches in eliciting protection against infectious diseases. PMID- 28869766 TI - Vaccination strategies in tauopathies and synucleinopathies. AB - Vaccination therapies constitute potential treatment options in neurodegenerative disorders such as Alzheimer disease or Parkinson disease. While a lot of research has been performed on vaccination against extracellular amyloid beta, the focus recently shifted toward vaccination against the intracellular proteins tau and alpha-synuclein, with promising results in terms of protein accumulation reduction. In this review, we briefly summarize lessons to be learned from clinical vaccination trials in Alzheimer disease that target amyloid beta. We then focus on tau and alpha-synuclein. For both proteins, we provide important data on protein immunogenicity, and put them into context with data available from both animals and human vaccination trials targeted at tau and alpha synuclein. Together, we give a comprehensive overview about current clinical data, and discuss associated problems. PMID- 28869768 TI - Recent advances in metal-organic frameworks and covalent organic frameworks for sample preparation and chromatographic analysis. AB - In the field of analytical chemistry, sample preparation and chromatographic separation are two core procedures. The means by which to improve the sensitivity, selectivity and detection limit of a method have become a topic of great interest. Recently, porous organic frameworks, such as metal-organic frameworks (MOFs) and covalent organic frameworks (COFs), have been widely used in this research area because of their special features, and different methods have been developed. This review summarizes the applications of MOFs and COFs in sample preparation and chromatographic stationary phases. The MOF- or COF-based solid-phase extraction (SPE), solid-phase microextraction (SPME), gas chromatography (GC), high-performance liquid chromatography (HPLC) and capillary electrochromatography (CEC) methods are described. The excellent properties of MOFs and COFs have resulted in intense interest in exploring their performance and mechanisms for sample preparation and chromatographic separation. PMID- 28869767 TI - Structural dissection of Shewanella oneidensis old yellow enzyme 4 bound to a Meisenheimer complex and (nitro)phenolic ligands. AB - Shewanella oneidensis, a Gram-negative gamma-proteobacterium with an extensive redox capacity, possesses four old yellow enzyme (OYE) homologs. Of these, Shewanella yellow enzyme 4 (SYE4) is implicated in resistance to oxidative stress. Here, we present a series of high-resolution crystal structures for SYE4 in the oxidized and reduced states, and in complex with phenolic ligands and the nitro-aromatic explosive picric acid. The structures unmask new features, including the identification of a binding platform for long-chain hydrophobic molecules. Furthermore, we present the first structural observation of a hydride Meisenheimer complex of picric acid with a flavoenzyme. Overall, our study exposes the binding promiscuity of SYE4 toward a variety of electrophilic substrates and is consistent with a general detoxification function for SYE4. PMID- 28869769 TI - Increased consumer density reduces the strength of neighborhood effects in a model system. AB - An individual's susceptibility to attack can be influenced by conspecific and heterospecifics neighbors. Predicting how these neighborhood effects contribute to population-level processes such as competition and evolution requires an understanding of how the strength of neighborhood effects is modified by changes in the abundances of both consumers and neighboring resource species. We show for the first time that consumer density can interact with the density and frequency of neighboring organisms to determine the magnitude of neighborhood effects. We used the bean beetle, Callosobruchus maculatus, and two of its host beans, Vigna unguiculata and V. radiata, to perform a response-surface experiment with a range of resource densities and three consumer densities. At low beetle density, damage to beans was reduced with increasing conspecific density (i.e., resource dilution) and damage to the less preferred host, V. unguiculata, was reduced with increasing V. radiata frequency (i.e., frequency-dependent associational resistance). As beetle density increased, however, neighborhood effects were reduced; at the highest beetle densities neither focal nor neighboring resource density nor frequency influenced damage. These findings illustrate the importance of consumer density in mediating indirect effects among resources, and suggest that accounting for consumer density may improve our ability to predict population-level outcomes of neighborhood effects and our use of them in applications such as mixed-crop pest management. PMID- 28869771 TI - Authors' Response. PMID- 28869772 TI - Transnational Intersectionality in Family Therapy With Resettled Refugees. AB - In this article, we discuss incorporating the transnational intersectionality framework in family therapy with resettled refugees. Transnational intersectionality is an extension of the framework of intersectionality which helps to better understand complexities of power and oppression across national contexts and their influence on refugees' lives. Adopting this framework alerts family therapists to: (a) develop critical awareness of refugee's transnational contexts; (b) understand differences in experiences of social identities across contexts; (c) acknowledge postmigration factors of oppression affecting resettlement; and (d) critically reflect upon therapist-interpreter-client intersectionalities. This shifts our conceptualization of therapy with refugees to actively consider transnational contexts which refugees uniquely occupy. We describe the framework and provide two case illustrations to highlight its usefulness. PMID- 28869774 TI - Compassion-focused self-help for skin conditions in individuals with insecure attachment: a pilot evaluation of acceptability and potential effectiveness. PMID- 28869775 TI - Internet-based interventions for smoking cessation. AB - BACKGROUND: Tobacco use is estimated to kill 7 million people a year. Nicotine is highly addictive, but surveys indicate that almost 70% of US and UK smokers would like to stop smoking. Although many smokers attempt to give up on their own, advice from a health professional increases the chances of quitting. As of 2016 there were 3.5 billion Internet users worldwide, making the Internet a potential platform to help people quit smoking. OBJECTIVES: To determine the effectiveness of Internet-based interventions for smoking cessation, whether intervention effectiveness is altered by tailoring or interactive features, and if there is a difference in effectiveness between adolescents, young adults, and adults. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register, which included searches of MEDLINE, Embase and PsycINFO (through OVID). There were no restrictions placed on language, publication status or publication date. The most recent search was conducted in August 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs). Participants were people who smoked, with no exclusions based on age, gender, ethnicity, language or health status. Any type of Internet intervention was eligible. The comparison condition could be a no-intervention control, a different Internet intervention, or a non Internet intervention. To be included, studies must have measured smoking cessation at four weeks or longer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed and extracted data. We extracted and, where appropriate, pooled smoking cessation outcomes of six-month follow-up or more, reporting short-term outcomes narratively where longer-term outcomes were not available. We reported study effects as a risk ratio (RR) with a 95% confidence interval (CI).We grouped studies according to whether they (1) compared an Internet intervention with a non-active control arm (e.g. printed self-help guides), (2) compared an Internet intervention with an active control arm (e.g. face-to-face counselling), (3) evaluated the addition of behavioural support to an Internet programme, or (4) compared one Internet intervention with another. Where appropriate we grouped studies by age. MAIN RESULTS: We identified 67 RCTs, including data from over 110,000 participants. We pooled data from 35,969 participants.There were only four RCTs conducted in adolescence or young adults that were eligible for meta-analysis.Results for trials in adults: Eight trials compared a tailored and interactive Internet intervention to a non-active control. Pooled results demonstrated an effect in favour of the intervention (RR 1.15, 95% CI 1.01 to 1.30, n = 6786). However, statistical heterogeneity was high (I2 = 58%) and was unexplained, and the overall quality of evidence was low according to GRADE. Five trials compared an Internet intervention to an active control. The pooled effect estimate favoured the control group, but crossed the null (RR 0.92, 95% CI 0.78 to 1.09, n = 3806, I2 = 0%); GRADE quality rating was moderate. Five studies evaluated an Internet programme plus behavioural support compared to a non-active control (n = 2334). Pooled, these studies indicated a positive effect of the intervention (RR 1.69, 95% CI 1.30 to 2.18). Although statistical heterogeneity was substantial (I2 = 60%) and was unexplained, the GRADE rating was moderate. Four studies evaluated the Internet plus behavioural support compared to active control. None of the studies detected a difference between trial arms (RR 1.00, 95% CI 0.84 to 1.18, n = 2769, I2 = 0%); GRADE rating was moderate. Seven studies compared an interactive or tailored Internet intervention, or both, to an Internet intervention that was not tailored/interactive. Pooled results favoured the interactive or tailored programme, but the estimate crossed the null (RR 1.10, 95% CI 0.99 to 1.22, n = 14,623, I2 = 0%); GRADE rating was moderate. Three studies compared tailored with non-tailored Internet-based messages, compared to non-tailored messages. The tailored messages produced higher cessation rates compared to control, but the estimate was not precise (RR 1.17, 95% CI 0.97 to 1.41, n = 4040), and there was evidence of unexplained substantial statistical heterogeneity (I2 = 57%); GRADE rating was low.Results should be interpreted with caution as we judged some of the included studies to be at high risk of bias. AUTHORS' CONCLUSIONS: The evidence from trials in adults suggests that interactive and tailored Internet based interventions with or without additional behavioural support are moderately more effective than non-active controls at six months or longer, but there was no evidence that these interventions were better than other active smoking treatments. However some of the studies were at high risk of bias, and there was evidence of substantial statistical heterogeneity. Treatment effectiveness in younger people is unknown. PMID- 28869776 TI - Cutaneous melanoma in Birt-Hogg-Dube syndrome: part of the clinical spectrum? PMID- 28869773 TI - Antioxidant Consumption is Associated with Decreased Odds of Congenital Limb Deficiencies. AB - BACKGROUND: Approximately 1 in 2000 infants is born with a limb deficiency in the US. Research has shown that women's periconceptional diet and use of vitamin supplements can affect risk of birth defects. We investigated whether maternal consumption of nutritional antioxidants was associated with occurrence of transverse limb deficiency (TLD) and longitudinal limb deficiencies (LLD). METHODS: We analysed case-control data from mothers and their singleton infants with TLD (n = 566), LLD (n = 339), or no malformation (controls; n = 9384) in the National Birth Defects Prevention Study (1997-2009). Using a modified food frequency, we estimated usual pre-pregnancy antioxidant consumption by total fruit and vegetable consumption (in grams) grouped into tertiles, and cumulative antioxidant score (ranging from 1 to 10) based on consumption of three antioxidants: beta-carotene, lycopene, and lutein. We estimated odds ratios (OR) adjusted for maternal age, race/ethnicity, education, smoking, alcohol use, body mass index, and total energy. RESULTS: Compared to women in the lowest tertile of fruit and vegetable consumption, women in the highest tertile were less likely to have infants with TLD (OR 0.74, 95% CI 0.57, 0.96) or LLD (OR 0.82, 95% CI 0.59, 1.13). Compared to the lowest antioxidant consumption score of 1, those with the highest score of 10 had ORs of 0.68 (95% CI 0.48, 0.95) for TLD and 0.77 (95% CI 0.50, 1.17) for LLD. CONCLUSIONS: Dietary intake of antioxidants was associated with reduced odds of limb deficiencies. These findings add further evidence for women's periconceptional diet reducing occurrence of some birth defects. PMID- 28869777 TI - Genetic variation of a foundation rockweed species affects associated communities. AB - Genetic variation in a foundation species may affect the composition of associated communities as well as modify ecosystem function. While the ecological consequences of genetic diversity of foundation species have been widely reported, the ability of individual genotypes to support dissimilar communities has been documented only in forest ecosystems. Here, for the first time in a marine ecosystem, we test whether the different genotypes of the rockweed Fucus vesiculosus harbor distinct community phenotypes and whether the genetic similarity of individual genotypes or their defensive compound content can explain the variation of the associated communities. We reared replicated genotypes in a common garden in the sea and analyzed their associated communities of periphytic algae and invertebrates as well as determined their contents of defense compounds, phlorotannins, and genetic distance based on neutral molecular markers. The periphytic community was abundant in mid-summer and its biovolume, diversity and community composition varied among the rockweed genotypes. The diversity of the periphytic community decreased with its increasing biovolume. In autumn, when grazers were abundant, periphytic community biomass was lower and less variable among rockweed genotypes, indicating different relative importance of bottom-up regulation through heritable variation of the foundation species and top-down regulation through grazing intensity. Similarly, composition of the invertebrate community varied among the rockweed genotypes. Although the genotype explained about 10-18% of the variation in associated communities, the variation was explained neither by the genetic distance nor the phlorotannin content. Thus, neither neutral genetic markers nor a single phenotypic trait could provide a mechanistic understanding of the genetic basis of community specificity. Therefore, a more comprehensive mapping of quantitative trait variation is needed to understand the underlying mechanisms. The community specificity implies that genetic variation within a foundation species is crucial for the biodiversity and assembly of associated organisms and, thus, for the functioning of associated communities. The result highlights the importance of ensuring the genetic variation of foundation species as a conservation target. PMID- 28869778 TI - A geographic cline in the ability to self-fertilize is unrelated to the pollination environment. AB - The reproductive assurance (RA) hypothesis predicts that the ability to autonomously self-fertilize should be favored in environments where a lack of mates or pollinators limits outcross reproduction. Because such limits to outcrossing are predicted to be most severe at range edges, elevated autonomy in peripheral populations is often attributed to RA. We test this hypothesis in 24 populations spanning the range of Campanula americana, including sampling at the range interior and three geographic range edges. We scored autonomous fruit set in a pollinator-free environment and detected clinal variation-autonomy increased linearly from the southern to the northern edge, and from the eastern to the western edge. We then address whether the cline reflects the contemporary pollination environment. We measured population size, plant density, pollinator visitation, outcross pollen limitation and RA in natural populations over two years. Most populations were pollen limited, and those that experienced higher visitation rates by bumblebees had reduced pollen limitation. Reproductive assurance, however, was generally low across populations and was unrelated to pollen limitation or autonomy. Neither pollen limitation nor RA displayed geographic clines. Finally, autonomy was not associated with pollinator visitation rates or mate availability. Thus, the data do not support the RA hypothesis; clinal variation in autonomy is unrelated to the current pollination environment. Therefore, geographic patterns of autonomy are likely the result of historical processes rather than contemporary natural selection for RA. PMID- 28869779 TI - Quality of life in people with vitiligo: a systematic review and meta-analysis. PMID- 28869780 TI - Deciphering the enigma of undetected species, phylogenetic, and functional diversity based on Good-Turing theory. AB - Estimating the species, phylogenetic, and functional diversity of a community is challenging because rare species are often undetected, even with intensive sampling. The Good-Turing frequency formula, originally developed for cryptography, estimates in an ecological context the true frequencies of rare species in a single assemblage based on an incomplete sample of individuals. Until now, this formula has never been used to estimate undetected species, phylogenetic, and functional diversity. Here, we first generalize the Good-Turing formula to incomplete sampling of two assemblages. The original formula and its two-assemblage generalization provide a novel and unified approach to notation, terminology, and estimation of undetected biological diversity. For species richness, the Good-Turing framework offers an intuitive way to derive the non parametric estimators of the undetected species richness in a single assemblage, and of the undetected species shared between two assemblages. For phylogenetic diversity, the unified approach leads to an estimator of the undetected Faith's phylogenetic diversity (PD, the total length of undetected branches of a phylogenetic tree connecting all species), as well as a new estimator of undetected PD shared between two phylogenetic trees. For functional diversity based on species traits, the unified approach yields a new estimator of undetected Walker et al.'s functional attribute diversity (FAD, the total species pairwise functional distance) in a single assemblage, as well as a new estimator of undetected FAD shared between two assemblages. Although some of the resulting estimators have been previously published (but derived with traditional mathematical inequalities), all taxonomic, phylogenetic, and functional diversity estimators are now derived under the same framework. All the derived estimators are theoretically lower bounds of the corresponding undetected diversities; our approach reveals the sufficient conditions under which the estimators are nearly unbiased, thus offering new insights. Simulation results are reported to numerically verify the performance of the derived estimators. We illustrate all estimators and assess their sampling uncertainty with an empirical dataset for Brazilian rain forest trees. These estimators should be widely applicable to many current problems in ecology, such as the effects of climate change on spatial and temporal beta diversity and the contribution of trait diversity to ecosystem multi-functionality. PMID- 28869781 TI - Plant diversity maintains long-term ecosystem productivity under frequent drought by increasing short-term variation. AB - Increasing frequency of extreme climatic events can disrupt ecosystem processes and destabilize ecosystem functioning. Biodiversity may dampen these negative effects of environmental perturbations to provide greater ecosystem stability. We assessed the effects of plant diversity on the resistance, recovery and stability of experimental grassland ecosystems in response to recurring summer drought over 7 yr. Plant biomass production was reduced during the summer drought treatment compared with control plots. However, the negative effect of drought was relatively less pronounced at high than at low plant diversity, demonstrating that biodiversity increased ecosystem resistance to environmental perturbation. Furthermore, more diverse plant communities compensated for the reduced productivity during drought by increasing spring productivity compared to control plots. The drought-induced compensatory recovery led to increased short-term variations in productivity across growing seasons in more diverse communities that stabilized the longer-term productivity across years. Our findings show that short-term variation between seasons in the face of environmental perturbation can lead to longer-term stability of annual productivity in diverse ecosystems compared to less diverse ecosystems. PMID- 28869782 TI - Olmutinib-induced palmoplantar keratoderma. PMID- 28869783 TI - High-performance liquid chromatography thermodynamic study of new potential antiepileptic compounds on a cholesterol column using isocratic elution with methanol/water and acetonitrile/water eluent systems. AB - Basic thermodynamic functions responsible for retention of new 1,2,4-triazole derivatives exhibiting varied antiepileptic activity on cholesterol-based stationary phase were determined. Evaluation of the Gibbs energy change, the change in enthalpy and the change in entropy was based on the van't Hoff relationship representing lnk versus 1/T. A detailed discussion of the van't Hoff equation, exploring the influence of the phase ratio on deviations from linearity in a van't Hoff plot is presented. We show chromatographic evidence to the question of how a varied mobile phase composition may cause different thermodynamic phase ratios. The analysis of data from a differential scanning calorimetry excluded any phase transitions of either the individual solutes or cholesterol stationary phase suspended in the mobile phase components within the studied temperature range. PMID- 28869784 TI - Selective C-H Bond Cleavage in Methane by Small Gold Clusters. AB - Methane represents the major constituent of natural gas. It is primarily used only as a source of energy by means of combustion, but could also serve as an abundant hydrocarbon feedstock for high quality chemicals. One of the major challenges in catalysis research nowadays is therefore the development of materials that selectively cleave one of the four C-H bonds of methane and thus make it amenable for further chemical conversion into valuable compounds. By employing infrared spectroscopy and first-principles calculations it is uncovered herein that the interaction of methane with small gold cluster cations leads to selective C-H bond dissociation and the formation of hydrido methyl complexes, H Aux+ -CH3 . The distinctive selectivity offered by these gold clusters originates from a fine interplay between the closed-shell nature of the d states and relativistic effects in gold. Such fine balance in fundamental interactions could prove to be a tunable feature in the rational design of a catalyst. PMID- 28869785 TI - OsASR2 regulates the expression of a defence-related gene, Os2H16, by targeting the GT-1 cis-element. AB - The GT-1 cis-element widely exists in many plant gene promoters. However, the molecular mechanism that underlies the response of the GT-1 cis-element to abiotic and biotic stresses remains elusive in rice. We previously isolated a rice short-chain peptide-encoding gene, Os2H16, and demonstrated that it plays important roles in both disease resistance and drought tolerance. Here, we conducted a promoter assay of Os2H16 and identified GT-1 as an important cis element that mediates Os2H16 expression in response to pathogen attack and osmotic stress. Using the repeated GT-1 as bait, we characterized an abscisic acid, stress and ripening 2 (ASR2) protein from yeast-one hybridization screening. Sequence alignments showed that the carboxy-terminal domain of OsASR2 containing residues 80-138 was the DNA-binding domain. Furthermore, we identified that OsASR2 was specifically bound to GT-1 and activated the expression of the target gene Os2H16, as well as GFP driven by the chimeric promoter of 2 * GT-1 35S mini construct. Additionally, the expression of OsASR2 was elevated by pathogens and osmotic stress challenges. Overexpression of OsASR2 enhanced the resistance against Xanthomonas oryzae pv. oryzae and Rhizoctonia solani, and tolerance to drought in rice. These results suggest that the interaction between OsASR2 and GT-1 plays an important role in the crosstalk of the response of rice to biotic and abiotic stresses. PMID- 28869786 TI - Population Pharmacokinetic/ Pharmacodynamic Modelling of Auditory-Evoked Event Related Potentials with Lorazepam. AB - Event-related potentials (ERPs) are commonly used in Neuroscience research, particularly the P3 waveform because it is associated with cognitive brain functions and is easily elicited by auditory or sensory inputs. ERPs are affected by drugs such as lorazepam, which increase the latency and decrease the amplitude of the P3 wave. In this study, auditory-evoked ERPs were generated in 13 older healthy volunteers using an oddball tone paradigm, after administration of single 0.5 and 2 mg doses of lorazepam. Population pharmacokinetics (PK)/pharmacodynamics (PD) models were developed using nonlinear mixed-effects methods in order to assess the effect of lorazepam on the latency and amplitude of the P3 waveforms. The PK/PD models showed that doses of 0.3 mg of lorazepam achieved approximately half of the maximum effect on the latency of the P3 waveform. For P3 amplitude, half the maximum effect was achieved with a dose of 1.2 mg of lorazepam. The PK/PD models also predicted an efficacious dose range of lorazepam, which was close to the recommended therapeutic range. The use of longitudinal P3 latency data allowed better predictions of the lorazepam efficacious dose range than P3 amplitude or aggregate exposure-response data, suggesting that latency could be a more sensitive parameter for drugs with similar mechanisms of action as lorazepam and that time course rather than single time-point ERP data should be collected. Overall, the results suggest that P3 ERP waveforms could be used as potential non-specific biomarkers for functional target engagement for drugs with brain activity, and PK/PD models can aid trial design and choice of doses for development of new drugs with ERP activity. PMID- 28869787 TI - The microbiology of oral lichen planus: Is microbial infection the cause of oral lichen planus? AB - Oral lichen planus (OLP) is a variant of lichen planus (LP), a common chronic mucocutaneous inflammatory disease. Cutaneous lesions of LP are self-limiting, but OLP lesions are non-remissive, alternating periods of exacerbation and quiescence, and only symptomatic treatments exist for OLP. The precise etiology and pathogenesis of OLP are hardly understood, which is a major obstacle to the development of new therapeutics for this disease. OLP is considered a T-cell mediated inflammatory disease. Although various antigens have been considered, what actually triggers the inflammatory response of T cells is unknown. Suggested predisposing factors include genetic factors, stress, trauma, and infection. The aim of this review was to determine whether microbial infection can cause OLP. We first reviewed the association between OLP and microbial factors, including viral, fungal, and bacterial infections. In addition, each microbial factor associated with OLP was assessed by modified guidelines of Fredricks and Relman to determine whether it establishes a causal relationship. In conclusion, no microbial factor yet fulfills the guidelines to establish the causality of OLP. By focusing on the unclarified issues, however, the potential roles of microbial factors in the pathogenesis of OLP will be soon elucidated. PMID- 28869788 TI - Biocatalytic Valorization of Furans: Opportunities for Inherently Unstable Substrates. AB - Biogenic furans (furfural and 5-hydroxymethylfurfural) are expected to become relevant building blocks based on their high degree of functionality and versatility. However, the inherent instability of furans poses considerable challenges for their synthetic modifications. Valorization routes of furans typically generate byproducts, impurities, wastes, and a cumbersome downstream processing, compromising their ecological footprint. Biocatalysis may become an alternative, given the high selectivity of enzymes, together with the mild reaction conditions applied. This Review critically discusses the options for enzymes in the upgrading of furans. Based on previous reports, a variety of biocatalytic transformations have been applied to furans, with successful cases both in aqueous and in water-free media. Options comprise the biodetoxification of toxic furans in hydrolysates, selective syntheses based on oxidation-reduction processes, solvent-free esterifications, or carboligations to afford C12 derivatives. Reported strategies show in general promising but still modest productivities (2-30 gproduct L-1 d-1 , depending on the example). There are opportunities with high potential and deserving of further development, scale-up, and technoeconomic assessment, to entirely validate them as realistic alternatives. PMID- 28869789 TI - Subtle changes in the active site architecture untangled overlapping substrate ranges and mechanistic differences of two reductive dehalogenases. AB - : Reductive dehalogenases (RDases) of organohalide-respiring bacteria are cobamide-containing iron-sulfur proteins that catalyze different reductive dehalogenation reactions. Here, we report a functional analysis of two recombinant RDases, the tetrachloroethene (PCE) reductive dehalogenase (PceA) of Desulfitobacterium hafniense Y51 and the 1,2-dichloroethane (1,2-DCA) reductive dehalogenase (DcaA) of Desulfitobacterium dichloroeliminans DCA1. Both enzymes share 88% protein sequence identity, but appeared to have divergent mechanisms. In this study, the heterologously produced DcaA converted 1,2-DCA and 1,1,2 trichloroethane (1,1,2-TCA) via dihaloelimination to ethene and vinyl chloride, respectively. In addition, halogen substitution at PCE, trichloroethene (TCE) and tribromoethene (TBE) was observed, but only at low rates. In contrast, recombinant PceA exclusively converted halogenated ethenes and showed no dihaloelimination activity. In silico structural analysis of both RDases revealed similar architectures of their active site cavities. Exchange of the highly conserved Tyr298 to Phe led to a complete loss of the PCE, TCE and TBE conversion by both RDases, strengthening the assumption that Tyr298 functions as proton donor in the course of halogen substitution. The exchange did not affect the ability of DcaA to convert 1,2-DCA and 1,1,2-TCA. This result makes the involvement of a proton transfer in the dihaloelimination reaction unlikely and allows for a clear differentiation between two mechanisms working in DcaA and PceA. The analysis of the role of the active site structure for RDase function was extended to the mutations W118F that had a negative effect on DcaA function and W432F or T294V that caused alterations in the substrate specificity of the enzyme. ENZYMES: Tetrachloroethene reductive dehalogenase (EC 1.21.99.5), DCA RDase. PMID- 28869790 TI - Evaluating the role of magnetic resonance imaging post-neoadjuvant therapy for breast cancer in the NEONAB trial. AB - BACKGROUND: Magnetic resonance imaging (MRI) accuracy after neoadjuvant systemic therapy (NST) for breast cancer varies according to hormone receptor (HR), human epidermal growth factor receptor type-2 (HER2) subtype and Ki-67 proliferation index. Whether MRI accuracy varies by genomic signatures is unknown. We examined the accuracy of MRI in the NEONAB trial (Clinicaltrials.gov #: NCT01830244). AIM: To examine the accuracy of MRI to predict pathological response to neoadjuvant therapy for breast cancer in the NEONAB trial. METHODS: Patients with stages II III breast cancer received sequential epirubicin, cyclophosphamide and nab paclitaxel and trastuzumab if they were HER2+. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated to assess the utility of preoperative MRI to predict pathological complete response (pCR). Bland-Altman plots were used to assess agreement between MRI and pathological assessment of residual disease. RESULTS: MRI correctly predicted pCR in 64.1% of the cohort. Sensitivity and specificity were 52% and 78%, respectively; PPV 73% and NPV 58%. MRI predicted pCR most accurately in HER2 positive patients; sensitivity 58%, specificity 100%, PPV 100% and NPV 38%. MRI had higher PPV and NPV in tumours with Ki-67 >= 15% than tumours with Ki-67 < 15%, 75% versus 50% and 57.5% versus 50%, respectively. In this study, MRI underestimated residual tumour size by 1.65 mm (limits of agreement: 43.07-39.77 mm). CONCLUSIONS: MRI appears more accurate for predicting pCR in HER2+ disease than other subtypes and in cancers with Ki-67 >= 15% compared to those with Ki-67 < 15%. Accuracy of MRI in our HR+, RS >= 25 cohort is comparable to previous reports of unselected HR+ disease. MRI post-NST should be interpreted in conjunction with HER2 status and Ki-67 index of the primary. PMID- 28869791 TI - Proteogenomic Insights into the Intestinal Parasite Blastocystis sp. Subtype 4 Isolate WR1. AB - Blastocystis sp. is known for years as a highly prevalent anaerobic eukaryotic parasite of humans and animals. Several monophyletic clades have been delineated based on molecular data, and the occurrence of each subtype in humans and/or animal hosts has been documented. The genome of several representatives has been sequenced revealing specific traits such as an intriguing 3'-end processing of primary transcripts. Here, a first high-throughput proteomics dataset acquired on this difficult-to-cultivate parasite is presented for the zoonotic subtype T4 isolate WR1. Amongst the 2766 detected proteins, we highlighted the role of a small ADP ribosylation factor GTP-binding protein involved in intracellular traffic as major regulator of vesicle biogenesis and a voltage-dependent anion selective channel protein because both were unexpectedly highly abundant. We show how these data may be used for gaining proteogenomics insights into Blastocystis sp. specific molecular mechanisms. We evidenced for the first time by proteogenomics a functional termination codon derived from transcript polyadenylation for seven different key cellular components. PMID- 28869792 TI - Comprehensive description of genomewide nucleotide and structural variation in short-season soya bean. AB - Next-generation sequencing (NGS) and bioinformatics tools have greatly facilitated the characterization of nucleotide variation; nonetheless, an exhaustive description of both SNP haplotype diversity and of structural variation remains elusive in most species. In this study, we sequenced a representative set of 102 short-season soya beans and achieved an extensive coverage of both nucleotide diversity and structural variation (SV). We called close to 5M sequence variants (SNPs, MNPs and indels) and noticed that the number of unique haplotypes had plateaued within this set of germplasm (1.7M tag SNPs). This data set proved highly accurate (98.6%) based on a comparison of called genotypes at loci shared with a SNP array. We used this catalogue of SNPs as a reference panel to impute missing genotypes at untyped loci in data sets derived from lower density genotyping tools (150 K GBS-derived SNPs/530 samples). After imputation, 96.4% of the missing genotypes imputed in this fashion proved to be accurate. Using a combination of three bioinformatics pipelines, we uncovered ~92 K SVs (deletions, insertions, inversions, duplications, CNVs and translocations) and estimated that over 90% of these were accurate. Finally, we noticed that the duplication of certain genomic regions explained much of the residual heterozygosity at SNP loci in otherwise highly inbred soya bean accessions. This is the first time that a comprehensive description of both SNP haplotype diversity and SV has been achieved within a regionally relevant subset of a major crop. PMID- 28869793 TI - The relationship between knowledge, health literacy, and adherence among patients taking oral anticoagulants for stroke thromboprophylaxis in atrial fibrillation. AB - BACKGROUND: Patients' knowledge regarding their oral anticoagulant (OAC) treatment for stroke prevention in atrial fibrillation (AF), their level of medication adherence, and health literacy are known to affect treatment outcomes. However, contemporary data regarding the relationships between these variables are lacking. OBJECTIVE: To investigate the relationships between anticoagulant knowledge, health literacy, and self-reported adherence in patients taking warfarin and the directly acting oral anticoagulants. METHODS: A cross-sectional survey was conducted in 48 patients with AF identified from general practices. The Anticoagulation Knowledge Tool (AKT) was used to assess anticoagulation knowledge; the Short Test of Functional Health Literacy in Adults (s-TOFHLA) for health literacy; and the 8-item Morisky Medication Adherence Scale (MMAS) for medication adherence. RESULTS: Participants had mean scores of 61.6 +/- 15.8, 7.2 +/- 1.1, and 24.7 +/- 9.5 for the AKT, MMAS-8 and s-TOFHLA, respectively. Significant correlations were observed between anticoagulation knowledge and health literacy with medication adherence (0.37, P < .01 and .30, P < .05, respectively). Participants with inadequate health literacy had a significantly lower mean knowledge score than those with adequate health literacy (55.8 +/- 15.9 vs 66.1 +/- 14.4, P < .05). Participants who self-reported adherence to their OAC had significantly higher knowledge scores than those who did not (67.5 +/- 13.3 vs 56.1 +/- 16.2, P < .05). CONCLUSION: Significant correlations between health literacy, OAC knowledge, and adherence were observed, and these relationships should to be considered by health professionals responsible for monitoring patients who are prescribed anticoagulants. We also observed serious gaps in OAC knowledge. Interventions designed to optimize the outcomes of anticoagulant treatment need to address these factors. PMID- 28869794 TI - Extensive genome heterogeneity leads to preferential allele expression and copy number-dependent expression in cultivated potato. AB - Relative to homozygous diploids, the presence of multiple homologs or homeologs in polyploids affords greater tolerance to mutations that can impact genome evolution. In this study, we describe sequence and structural variation in the genomes of six accessions of cultivated potato (Solanum tuberosum L.), a vegetatively propagated autotetraploid and their impact on the transcriptome. Sequence diversity was high with a mean single nucleotide polymorphisms (SNP) rate of approximately 1 per 50 bases suggestive of high levels of allelic diversity. Additive gene expression was observed in leaves (3605 genes) and tubers (6156 genes) that contrasted the preferential allele expression of between 2180 and 3502 and 3367 and 5270 genes in the leaf and tuber transcriptome, respectively. Preferential allele expression was significantly associated with evolutionarily conserved genes suggesting selection of specific alleles of genes responsible for biological processes common to angiosperms during the breeding selection process. Copy number variation was rampant with between 16 098 and 18 921 genes in each cultivar exhibiting duplication or deletion. Copy number variable genes tended to be evolutionarily recent, lowly expressed, and enriched in genes that show increased expression in response to biotic and abiotic stress treatments suggestive of a role in adaptation. Gene copy number impacts on gene expression were detected with 528 genes having correlations between copy number and gene expression. Collectively, these data suggest that in addition to allelic variation of coding sequence, the heterogenous nature of the tetraploid potato genome contributes to a highly dynamic transcriptome impacted by allele preferential and copy number-dependent expression effects. PMID- 28869795 TI - Maternal Smoking during Pregnancy and Offspring Weight Gain: a Consideration of Competing Explanations. PMID- 28869796 TI - Antitumor effects of eribulin depend on modulation of the tumor microenvironment by vascular remodeling in mouse models. AB - We previously reported that eribulin mesylate (eribulin), a tubulin-binding drug (TBD), could remodel tumor vasculature (i.e. increase tumor vessels and perfusion) in human breast cancer xenograft models. However, the role of this vascular remodeling in antitumor effects is not fully understood. Here, we investigated the effects of eribulin-induced vascular remodeling on antitumor activities in multiple human cancer xenograft models. Microvessel densities (MVD) were evaluated by immunohistochemistry (CD31 staining), and antitumor effects were examined in 10 human cancer xenograft models. Eribulin significantly increased MVD compared to the controls in six out of 10 models with a correlation between enhanced MVD levels and antitumor effects (R2 = 0.54). Because of increased MVD, we next used radiolabeled liposomes to examine whether eribulin treatment would result in increased tumoral accumulation levels of these macromolecules and, indeed, we found that eribulin, unlike vinorelbine (another TBD) enhanced them. As eribulin increased accumulation of radiolabeled liposomes, we postulated that this treatment might enhance the antitumor effect of Doxil (a liposomal anticancer agent) and facilitate recruitment of immune cells into the tumor. As expected, eribulin enhanced antitumor activity of Doxil in a post erlotinib treatment H1650 (PE-H1650) xenograft model. Furthermore, infiltrating CD11b-positive immune cells were significantly increased in multiple eribulin treated xenografted tumors, and natural killer (NK) cell depletion reduced the antitumor effects of eribulin. These findings suggest a contribution of the immune cells for antitumor activities of eribulin. Taken together, our results suggest that vascular remodeling induced by eribulin acts as a microenvironment modulator and, consequently, this alteration enhanced the antitumor effects of eribulin. PMID- 28869797 TI - Identification of the biosynthesis gene cluster for the novel lantibiotic paenilan from Paenibacillus polymyxa E681 and characterization of its product. AB - AIMS: To analyse the function of a putative lantibiotic gene cluster of Paenibacillus polymyxa E681 and to characterize its product, paenilan. METHODS AND RESULTS: Comparative analysis of the lantibiotic gene cluster of E681 revealed that the cluster, consisting of 11 open reading frames, is involved in the biosynthesis of a class I lantibiotic. The pnlA gene encoding the prepeptide PnlA was identified and P. polymyxa strain EPT14 producing only paenilan was constructed by knockout of the other five antibiotic biosynthetic gene clusters of E681. Paenilan was purified from EPT14 culture by solvent partitioning, ODS silica gel chromatography and reversed-phase preparative HPLC. The molecular mass (2510.10 Da) and structure of paenilan analysed by Nanoelectrospray ionization mass spectrometry (MS) and MS/MS showed that paenilan is a novel class I lantibiotic. Paenilan exhibited antimicrobial activity against Gram-positive bacteria such as Bacillus cereus, Micrococcus luteus and Paenibacillus durus. The paenilan gene is well-conserved in different Paenibacillus sp. isolated from globally distant places. CONCLUSIONS: The lantibiotic gene cluster of P. polymyxa E681 was analysed and its product, a novel and useful lantibiotic named paenilan that inhibits the growth of some Gram-positive bacteria, was characterized. SIGNIFICANCE AND IMPACT OF THE STUDY: Paenibacillus species are a good source of new lantibiotics, and the conservation of the paenilan gene among Paenibacillus sp. implies paenilan has an important function(s) for their survival. PMID- 28869798 TI - Antimicrobial activity of plant extracts against the honeybee pathogens, Paenibacillus larvae and Ascosphaera apis and their topical toxicity to Apis mellifera adults. AB - AIMS: To explore alternative nonchemical control measures against two honeybee pathogens, Paenibacillus larvae and Ascosphaera apis, 37 plant species were screened for antimicrobial activity. METHODS AND RESULTS: The activity of selected plant extracts was screened using an in vitro disc diffusion assay and the minimal inhibitory concentration (MIC) was determined by the broth microdilution method. The results showed that 36 plant extracts had some antibacterial activity on P. larvae by disc diffusion assay. Chromolaena odorata showed the greatest antibacterial activity against P. larvae (MIC 16-64 MUg ml-1 ). Of the 37 tested plants, only seven species, Amomum krervanh, Allium sativum, Cinnamomum sp., Piper betle, Piper ribesioides, Piper sarmentosum and Syzygium aromaticum had inhibitory effects on A. apis (MICs of 32-64 MUg ml-1 ). The results demonstrated that promising plant extracts were not toxic to adult bees at the concentrations used in this study. CONCLUSIONS: The results demonstrate the potential antimicrobial activity of natural products against honeybee diseases caused by P. larvae and A. apis. Chromolaena odorata in particular showed high bioactivity against P. larvae. Further study is recommended to develop these nonchemical treatments against American foulbrood and chalkbrood in honeybees. SIGNIFICANCE AND IMPACT OF THE STUDY: This work proposes new natural products for the control of American foulbrood and chalkbrood in honeybees. PMID- 28869799 TI - Trehalose 6-phosphate is involved in triggering axillary bud outgrowth in garden pea (Pisum sativum L.). AB - Trehalose 6-phosphate (Tre6P) is a signal of sucrose availability in plants, and has been implicated in the regulation of shoot branching by the abnormal branching phenotypes of Arabidopsis (Arabidopsis thaliana) and maize (Zea mays) mutants with altered Tre6P metabolism. Decapitation of garden pea (Pisum sativum) plants has been proposed to release the dormancy of axillary buds lower down the stem due to changes in sucrose supply, and we hypothesized that this response is mediated by Tre6P. Decapitation led to a rapid and sustained rise in Tre6P levels in axillary buds, coinciding with the onset of bud outgrowth. This response was suppressed by simultaneous defoliation that restricts the supply of sucrose to axillary buds in decapitated plants. Decapitation also led to a rise in amino acid levels in buds, but a fall in phosphoenolpyruvate and 2-oxoglutarate. Supplying sucrose to stem node explants in vitro triggered a concentration dependent increase in the Tre6P content of the buds that was highly correlated with their rate of outgrowth. These data show that changes in bud Tre6P levels are correlated with initiation of bud outgrowth following decapitation, suggesting that Tre6P is involved in the release of bud dormancy by sucrose. Tre6P might also be linked to a reconfiguration of carbon and nitrogen metabolism to support the subsequent growth of the bud into a new shoot. PMID- 28869800 TI - Self-Stigma Mediates the Impact of Insight on Current Suicide Ideation in Suicide Attempters with Schizophrenia: Results of a Moderated Mediation Approach. AB - This study examined the relationships among insight, self-stigma, self-esteem, hope, quality of life, and suicidal behavior in individuals diagnosed as having schizophrenia. Hypotheses concerning mediating and moderating effects were examined. A total of 170 community-dwelling patients with schizophrenia participated in the study. The results revealed a negative association between insight and suicide ideation, which was partially mediated by self-stigma. Moreover, this indirect link was stronger among patients with suicide attempts than among those without attempts. We discuss the implications of these results for preventing or reducing the considerable risks of suicide in this population. PMID- 28869802 TI - Deadly Experience: The Association Between Firing a Gun and Various Aspects of Suicide Risk. AB - Firearms account for half of all U.S. suicide deaths, but research on mechanisms through which firearms confer risk is limited. Although research has indicated firearm ownership and the unsafe storage of firearms are associated with an elevated risk of suicide, such research cannot provide insight into the extent to which a history of using a gun plays a role. We recruited a community sample (N = 100; 76% female; 44% Black) oversampled for prior suicidal behavior in a high gun ownership state (Mississippi). Consistent with hypotheses, a greater number of lifetime experiences of firing a gun were associated with elements of the capability for suicide (fearlessness about death, pain tolerance, pain persistence) and lifetime suicide attempts, but not with suicide ideation or simple pain detection. These findings indicate that guns may confer risk of suicide in part through increased comfort and aptitude with the weapon, a notion consistent with the construct of practical capability. Furthermore, these findings are consistent with research indicating that guns do not cause healthy individuals to become suicidal, but rather increase risk among already suicidal individuals. Overall, our findings highlight the importance of considering practical experience with guns as well as simple ownership and storage methods. PMID- 28869801 TI - Japanese genome-wide association study identifies a significant colorectal cancer susceptibility locus at chromosome 10p14. AB - Genome-wide association studies are a powerful tool for searching for disease susceptibility loci. Several studies identifying single nucleotide polymorphisms (SNP) connected intimately to the onset of colorectal cancer (CRC) have been published, but there are few reports of genome-wide association studies in Japan. To identify genetic variants that modify the risk of CRC oncogenesis, especially in the Japanese population, we performed a multi-stage genome-wide association study using a large number of samples: 1846 CRC cases and 2675 controls. We identified 4 SNP (rs7912831, rs4749812, rs7898455 and rs10905453) in chromosome region 10p14 associated with CRC; however, there are no coding or non-coding genes within this region of fairly extensive linkage disequilibrium (a 500-kb block) on 10p14. Our study revealed that the 10p14 locus is significantly correlated with susceptibility to CRC in the Japanese population, in accordance with the results of multiple studies in other races. PMID- 28869803 TI - Identification of alpha-tocopherol as a bioactive component of Dicranopteris linearis with disrupting property against preformed biofilm of Staphylococcus aureus. AB - AIMS: The potential of Dicranopteris linearis leaves' extract and its bioactive components were investigated for the first time for its disrupting ability against Staphylococcus aureus biofilms. METHODS AND RESULTS: The leaves of D. linearis were subjected to sonication-assisted extraction using hexane (HEX), dichloromethane, ethyl acetate and methanol (MeOH). It was found that only the MeOH fraction exhibited antimicrobial activity using broth microdilution assay; while all four fractions do not exhibit biofilm inhibition activity against S. aureusATCC 6538P, S. aureusATCC 43300, S. aureusATCC 33591 and S. aureusATCC 29213 using crystal violet assay. Among the four fractions tested, only the HEX fraction showed biofilm disrupting ability, with 60-90% disruption activity at 5 mg ml-1 against all four S. aureus strains tested. Bioassay-guided purification of the active fraction has led to the isolation of alpha-tocopherol. alpha Tocopherol does not affect the cells within the biofilms but instead affects the biofilm matrix in order to disrupt S. aureus biofilms. CONCLUSIONS: alpha Tocopherol was identified to be the bioactive component of D. linearis with disruption activity against S. aureus biofilm matrix. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of alpha-tocopherol as a biofilm disruptive agent might potentially be useful to treat biofilm-associated infections in the future. PMID- 28869804 TI - Erosive pustular dermatosis of the scalp and Kindler syndrome: a new association. PMID- 28869806 TI - Characterizing Viscoelastic Modulations in Biopolymer Hydrogels by Coherence Gated Light Scattering. AB - pH-responsive hydrogels are of great interest for the controlled release of drugs. However, the changes in the structural and mechanical properties of hydrogels during the pH-responsive swelling/contraction process remains largely unknown. In this article, we demonstrate that coherence-gated dynamic light scattering can be used to in situ characterize the structural dynamics of chitosan (CS) hydrogels at different pH values and show that the CS hydrogels undergo viscoelastic modulations during the swelling/contraction/recovery process induced by pH changes. The conditions for the CS hydrogels to undergo these modulations are found by continuously monitoring the nonequilibrium, long-term dynamical process. Our findings are in a close correspondence to the macroscopic observations made at time points where the CS hydrogels are at equilibrium. PMID- 28869805 TI - Pre-operative trans-catheter arterial chemo-embolization increases hepatic artery thrombosis after liver transplantation - a retrospective study. AB - Little is known about nonsurgical risk factors for hepatic artery thrombosis (HAT) after liver transplantation (LT). We determined risk factors for HAT occurring within 90 days post-LT and analysed the effect of HAT on graft and patient survival. Donor and recipient demographics, surgery-related data and outcome in transplants complicated by thrombosis (HAT+) and their matched controls (HAT-) were compared. Risk factors were assessed by univariate logistic regression. Median (IQR) is given. A total of 25 HAT occurred among 1035 adult LT (1/1997-12/2014) and 50 controls were manually matched. Donor and recipient demographics were similar. Pre-LT trans-catheter arterial chemo-embolization (TACE) was more frequent in HAT+ (HAT+ 20% vs. HAT- 4%, P = 0.037). HAT+ had longer implantation [HAT+ 88 min (76-108) vs. HAT- 77 min (66-93), P = 0.028] and surgery times [HAT+ 6.25 h (5.18-7.47) vs. HAT- 5.25 h (4.33-6.5), P = 0.001]. Early graft dysfunction and sepsis were more frequent in HAT+ and hospitalization longer. TACE had the greatest odds ratio in unadjusted analysis (OR: 6, 95% CI: 1.07-33.53, P = 0.03). All but seven grafts were lost after HAT (HAT+ 72% vs. HAT 36%, P = 0.003); however, patient survival was unaffected (HAT+ 79.8% vs. HAT- 76%, P = 0.75). LT candidates undergoing TACE are at risk of developing HAT early after transplant. PMID- 28869807 TI - Prolonged toilet training in children with Down syndrome: a case-control study. AB - OBJECTIVES: Children with Down syndrome have delayed psychomotor development, which is a factor that influences the level of difficulty in toilet training. The current study aims to estimate the age toilet training starts and completes in children with DS compared to children with normal psychomotor development and to evaluate the method and type of toilet training most frequently used, as well as its association with lower urinary tract symptoms and functional constipation. METHODS: A case-control study was carried out from 2010 to 2015. All parents completed a questionnaire designed to assess the toilet training process. Lower urinary tract symptoms were assessed through the application of the Dysfunctional Voiding Symptom Score. The presence of functional constipation was assessed according to the Rome III criteria. RESULTS: The study included 93 children with Down syndrome and 204 children with normal psychomotor development (control group [CG]). The mean age of toilet training onset was 22.8 months in those with DS and 17.5 months in the CG (p=0.001). In children with DS, the mean age when completing toilet training was 56.2 months and 27.1 months in the CG (p=0.001). Among children with DS, females completed toilet training earlier (p=0.02). The toilet training method used most often was child-oriented approach in both groups. No association was observed with the presence of lower urinary tract symptoms or functional constipation and the age of beginning and completing toilet training in both groups. CONCLUSION: Children with Down syndrome experienced prolonged toilet training time. Prospective longitudinal studies are essential to gain insight into the toilet training of these children. PMID- 28869808 TI - Pediatric emergency in Brazil: the consolidation of an area in the pediatric field. AB - OBJECTIVE: The aim of this study was to present a review on the evolution, development, and consolidation of the pediatric emergency abroad and in Brazil, as well as to discuss the residency program in this key area for pediatricians. DATA SOURCES: This was a narrative review, in which the authors used pre-selected documents utilized as the minimum requirements for the Residency Program in Pediatric Emergency Medicine and articles selected by interest for the theme development, at the SciELO and Medline databases, between 2000 and 2017. DATA SYNTHESIS: The historical antecedents and the initial evolution of pediatric emergency in Brazil, as well as several challenges were described, regarding the organization, the size, the training of professionals, and also the regulation of the professional practice in this new specialty. Additionally, a new pediatric emergency residency program to be implemented in Brazil is described. CONCLUSIONS: Pediatric emergency training will be a powerful stimulus to attract talented individuals, to establish them in this key area of medicine, where they can exercise their leadership by promoting care qualification, research, and teaching, as well as acting decisively in their management. PMID- 28869809 TI - Editorial Comment. PMID- 28869810 TI - Autophagy regulation in preeclampsia: Pros and cons. AB - Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis against stress. This process has two main functions: producing energy and quality control of intracellular proteins. During early pregnancy, extravillous trophoblasts (EVTs) invade the uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions. Autophagy activation is observed in EVTs under these conditions, suggesting that EVTs use autophagy for adjusting to such harsh conditions. On the other hand, soluble endoglin, which is increased in sera in preeclamptic cases, inhibits autophagy in vitro, resulting in suppression of EVT functions, invasion and vascular remodeling. In addition, p62/SQSTM1, a substrate degraded by autophagy, accumulates in EVTs in preeclamptic placental biopsy samples, exhibiting impaired autophagy in vivo. There are, however, some opposing reports in which autophagy activation, an increase of autophagy vacuoles or LC3 dots, was more frequently observed in preeclamptic or FGR placentas than in normal pregnancy. Thus, changes in autophagy status are seen in preeclamptic placentas, but the mechanism by which autophagy modulates biological changes in the placentas is still unknown. Recently, there is increasing evidence that autophagy is involved in maintaining pregnancy. This review introduces the role of autophagy for maintaining pregnancy and its correlation with preeclampsia. PMID- 28869811 TI - Hidden Markov model analysis reveals the advantage of analytic eye movement patterns in face recognition across cultures. AB - It remains controversial whether culture modulates eye movement behavior in face recognition. Inconsistent results have been reported regarding whether cultural differences in eye movement patterns exist, whether these differences affect recognition performance, and whether participants use similar eye movement patterns when viewing faces from different ethnicities. These inconsistencies may be due to substantial individual differences in eye movement patterns within a cultural group. Here we addressed this issue by conducting individual-level eye movement data analysis using hidden Markov models (HMMs). Each individual's eye movements were modeled with an HMM. We clustered the individual HMMs according to their similarities and discovered three common patterns in both Asian and Caucasian participants: holistic (looking mostly at the face center), left-eye biased analytic (looking mostly at the two individual eyes in addition to the face center with a slight bias to the left eye), and right-eye-based analytic (looking mostly at the right eye in addition to the face center). The frequency of participants adopting the three patterns did not differ significantly between Asians and Caucasians, suggesting little modulation from culture. Significantly more participants (75%) showed similar eye movement patterns when viewing own- and other-race faces than different patterns. Most importantly, participants with left-eye-biased analytic patterns performed significantly better than those using either holistic or right-eye-biased analytic patterns. These results suggest that active retrieval of facial feature information through an analytic eye movement pattern may be optimal for face recognition regardless of culture. PMID- 28869812 TI - The effects of prosthetic foot stiffness on transtibial amputee walking mechanics and balance control during turning. AB - BACKGROUND: Little evidence exists regarding how prosthesis design characteristics affect performance in tasks that challenge mediolateral balance such as turning. This study assesses the influence of prosthetic foot stiffness on amputee walking mechanics and balance control during a continuous turning task. METHODS: Three-dimensional kinematic and kinetic data were collected from eight unilateral transtibial amputees as they walked overground at self-selected speed clockwise and counterclockwise around a 1-meter circle and along a straight line. Subjects performed the walking tasks wearing three different ankle-foot prostheses that spanned a range of sagittal- and coronal-plane stiffness levels. FINDINGS: A decrease in stiffness increased residual ankle dorsiflexion (10-13 degrees ), caused smaller adaptations (<5 degrees ) in proximal joint angles, decreased residual and increased intact limb body support, increased residual limb propulsion and increased intact limb braking for all tasks. While changes in sagittal-plane joint work due to decreased stiffness were generally consistent across tasks, effects on coronal-plane hip work were task-dependent. When the residual limb was on the inside of the turn and during straight-line walking, coronal-plane hip work increased and coronal-plane peak-to-peak range of whole body angular momentum decreased with decreased stiffness. INTERPRETATION: Changes in sagittal-plane kinematics and kinetics were similar to those previously observed in straight-line walking. Mediolateral balance improved with decreased stiffness, but adaptations in coronal-plane angles, work and ground reaction force impulses were less systematic than those in sagittal-plane measures. Effects of stiffness varied with the residual limb inside versus outside the turn, which suggests that actively adjusting stiffness to turn direction may be beneficial. PMID- 28869814 TI - Multi-residue determination of 47 organic compounds in water, soil, sediment and fish-Turia River as case study. AB - A sensitive and reliable method based on solid-liquid extraction (SLE) using McIlvaine-Na2EDTA buffer (pH=4.5)-methanol and solid-phase extraction (SPE) clean up prior to ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was applied to determine 47 organic contaminants in fish, soil and sediments. The SPE procedure to clean-up the extracts was also used as extraction method to determine these compounds in water. Recoveries ranged from 38 to 104% for all matrices with RSDs<30%. Limits of Quantification for the target compounds were in the range of 10-50ng/g for soil, 2-40ng/g for sediment, 5-30ng/g for fish and 0.3-26ng/L for water. Furthermore, the proposed method was compared to QuEChERS (widely used for environmental matrices) that involves extraction with buffered acetonitrile (pH 5.5) and dispersive SPE clean up. The results obtained (recoveries>50% for 36 compounds in front of 9, matrix effect<20% for 31 compounds against 21, and LOQs <25ngg-1 for 38 compounds against 22) indicates that the proposed method is more efficient than QuEChERS, The method was applied to monitoring these compounds along the Turia River. In river waters, Paracetamol (175ngL-1), ibuprofen (153ngL-1) and bisphenol A (41ngL 1) were the compounds most frequently detected while in sediments were vildagliptin (7ngg-1) and metoprolol (31ngg-1) and in fish, bisphenol A (33ngg-1) or sulfamethoxazole (13ngg-1). PMID- 28869813 TI - Prevalence and predictors of depression and well-being after hysterectomy: An observational study. AB - OBJECTIVES: To assess risk and predictive factors for depression and well-being, 3 and 12 months after elective hysterectomy. Secondary objectives were to assess the incidence of depression, level of well-being, and feelings of femininity. STUDY DESIGN: A prospective multicenter cohort study was performed among 419 women, undergoing hysterectomy for benign indication. Data were collected in the week prior to surgery, and in the per- and postoperative period up to the fourth postoperative day and 3 and 12 months after surgery. Sociodemographic variables, baseline health status, psychosocial predictors, and surgery data were assessed. Outcome measures were Center for Epidemiological Studies-Depression scale (CES-D, range 0-60), the 12-item well-being questionnaire energy and positive well-being subscales (range 0-12), and feelings of femininity. Predictor analyses were performed using linear mixed model analyses. RESULTS: Levels of depression, energy, and positive well-being after hysterectomy were predicted by their corresponding baseline levels (estimate 0.62 p<0.001, 0.39 p<0.001, 0.37 p<0.001, respectively) and baseline pain (0.31 p=0.003, -0.09 p=0.026, -0.10 p=0.008). Postoperative infection reported at 12 months affected CES-D and energy level. Several other gynaecological, psychosocial, or perioperative factors were also predictive for one of the outcomes. Prevalence of depression at baseline, 3 and 12 months was 24%, 19%, and 21%, respectively. In general, well-being scores were slightly higher 3 and 12 months after hysterectomy than at baseline. Feelings of femininity were not negatively affected in 92% of the patients. CONCLUSIONS: Preoperative psychosocial status, perioperative pain, and postoperative infection were found as predictors of psychological outcome after hysterectomy. In the majority of patients we observed small but significant improvements with regard to postoperative depression and well-being, while feelings of femininity were unaffected. PMID- 28869815 TI - Separation of bioactive chamazulene from chamomile extract using metal-organic framework. AB - Isolation of bioactive compounds from extracts of pharmaceutical plant is very important. In this work, copper benzene-1,3,5-tricarboxylate metal organic framework (Cu-BTC MOF) has been synthesized. It is used in separating of chamazulene from chamomile extract. The Cu-BTC MOF not only shows good chamazulene adsorption but also maintains good desorption properties. However, the research on this field is still new and the maturation of novel MOFs or the enhancements of known ones are required.The chamomile extract obtained after each stage of the treatments was carefully characterized by thin-layer chromatography (TLC), Fourier-transform infrared spectroscopy (FTIR), UV-vis spectrometry and gas chromatography-mass spectrometry (GC-MS). The morphology and the crystallinity of Cu-BTC MOF were investigated using scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD), respectively. Breakthrough experiments in a column was investigated and the data was fitted with Bohart-Adams model. Monte Carlo simulation was conducted to investigate the preferential adsorption sites of Cu-BTC for chamazulene molecules. PMID- 28869817 TI - DNA hypermethylation of tumor suppressor genes RASSF6 and RASSF10 as independent prognostic factors in adult acute lymphoblastic leukemia. AB - BACKGROUND: The Hypermethylation of Ras association domain family (RASSF) often plays a key role in malignant progression of solid tumors; however, their impact on the prognosis and survival of adult ALL patients remain elusive. METHODS: The frequency of the promoter methylation pattern of RASSF6 and RASSF10 were analyzed in the peripheral blood (PB) samples taken at the time of diagnosis of 45 ALL patients. The methylation-specific PCR (MSP) assay was used to detect the DNA methylation patterns. RESULTS: RASSF6 was frequently hypermethylated in patients diagnosed with pre-B-ALL (90.9%) and B-ALL (87.5%), followed by T-ALL (66.7%); whereas, RASSF10 methylation was more confined to T-ALL (80%) as compared to B ALL (25%) and pre-B ALL (9.1%) patients. Moreover, hypermethylation of RASSF6 was significantly associated with a poor prognosis and shorter overall survival (OS) in patients with pre-B-ALL (log-rank test; P=0.041). CONCLUSION: RASSF6 and RASSF10 were frequently hypermethylated in the samples at the time of diagnosis of adult ALL patients. Our study represents the first report of methylation of RASSF6 at a high frequency in patients with pre-B ALL. Furthermore, hypermethylation of RASSF6 was significantly associated with inferior overall survival in pre-B ALL patients. It may suggest that the frequent epigenetic inactivation of RASSF6 plays an important role in the pathogenesis and progression of pre-B-ALL. PMID- 28869818 TI - Maximum entropy models as a tool for building precise neural controls. AB - Neural responses are highly structured, with population activity restricted to a small subset of the astronomical range of possible activity patterns. Characterizing these statistical regularities is important for understanding circuit computation, but challenging in practice. Here we review recent approaches based on the maximum entropy principle used for quantifying collective behavior in neural activity. We highlight recent models that capture population level statistics of neural data, yielding insights into the organization of the neural code and its biological substrate. Furthermore, the MaxEnt framework provides a general recipe for constructing surrogate ensembles that preserve aspects of the data, but are otherwise maximally unstructured. This idea can be used to generate a hierarchy of controls against which rigorous statistical tests are possible. PMID- 28869816 TI - Timed sequential therapy for acute myelogenous leukemia: Results of a retrospective study of 301 patients and review of the literature. AB - Timed sequential therapy (TST) aims to improve outcomes in acute myelogenous leukemia (AML) by harnessing drug-induced cell cycle kinetics of AML, where a second drug is timed to coincide with peak leukemia proliferation induced by the first drugs. We analyzed outcomes in 301 newly diagnosed AML patients treated from 2004-2013 with cytarabine, anthracycline, and etoposide TST induction. Median age was 52 (range 20-74) and complete remission rate 68%. With median follow-up 5.8 years, 5-year DFS and overall survival (OS) were 37% (95% CI 31 45%) and 32% (95% CI 27-38%), respectively. In multivariate analysis, older age, unfavorable cytogenetics, and WBC>=50*109/L resulted in worse OS. Among patients not undergoing blood and marrow transplant, a propensity score analysis, which reduces imbalance in baseline characteristics, showed consolidation with TST compared with 1 or more cycles high-dose cytarabine trended toward lower DFS and post-remission survival with hazard ratio (HR) 1.9 (95% CI 0.9-4.0), and 1.6 (95% CI 0.7-3.6), respectively. Our results demonstrate the efficacy and feasibility of TST induction for newly diagnosed patients with AML, with results comparable to that seen in clinical trials with other TST therapies and 7+3. PMID- 28869819 TI - Rational optimization of the mannoside building block for automated electrochemical assembly of the core trisaccharide of GPI anchor oligosaccharides. AB - We have developed a carbohydrate building block of mannosides based on DFT calculations, electrochemical analysis, and automated solution-phase synthesis. The optimized building block in hand was used to prepare the core trisaccharide of GPI anchor oligosaccharides. PMID- 28869820 TI - Graphene-based nanomaterials for drug and/or gene delivery, bioimaging, and tissue engineering. AB - Here, we discuss the biomedical applications of graphene-based nanomaterials (GBNs). We examine graphene and its various derivatives, including graphene, graphene oxides (GOs), reduced graphene oxides (rGOs), graphene quantum dots (GQDs), and graphene composites, and discuss their unique properties related to their biomedical applications. We also summarize the detailed biomedical applications of GBNs, including drug and/or gene delivery, bioimaging, and tissue engineering. We also highlight the toxicity of these nanomaterials. PMID- 28869821 TI - Composition and abundance of particles present on "powder-free" examination gloves. AB - Seven widely available brands of powder free nitrile gloves, commonly used in forensic laboratories during the handling of exhibits were examined. Samples were collected from the outer surfaces of the gloves and the particle types present were characterised using automated mineral analysis. Particles less than 10MUm in diameter are abundant on the surface of all of the gloves examined. Although the particles are dominated by common compounds/minerals (e.g. calcite, gypsum, NaCl, Fe oxides/carbonates, Al oxides, quartz, plagioclase, kaolinite) each glove brand analysed has a distinct population of particles present which allows the samples to be differentiated from each other. These particle types may be transferred from the gloves to exhibits during handling. In addition, these distinct populations of particles may be transferred to anyone wearing powder free nitrile gloves. PMID- 28869822 TI - Potential of GHB phase-II-metabolites to complement current approaches in GHB post administration detection. AB - Recently, phase-II-metabolites of gamma-hydroxybutyric acid (GHB), namely GHB beta-O-glucuronide and GHB-4-sulfate, were implemented in the scope of drug testing methods The clearance of GHB from the circulation is extremely fast due to its incorporation into the metabolic pathway of the citrate cycle. The elimination half-life of GHB from blood was reported to be dose dependent between 30 and 50min resulting in narrow detection windows of less than 12h after illicit administration or cases of drug facilitated sexual assault regardless of the biological matrix used. As sulfated metabolites tend to show prolonged half-lives and slower elimination kinetics compared to unmodified or glucuronidated drugs, the potential of GHB-4-sulfate in prolonging the detection of GHB administration was assessed. Its urinary concentrations were determined in n=100 samples from athletes and n=50 samples from sport students, and the resulting data were used to calculate a preliminary reference population-based threshold for urinary GHB sulfate concentration. The threshold was then compared to concentrations found in post-administration urine samples collected from 3 volunteers who administered GHB within the setting of a clinical trial. Due to the large inter-individual variability of concentrations found in the reference population, GHB-4-sulfate itself was not suitable to prolong the detection times for GHB applications, even when specific gravity-corrected values were used. Therefore, a metabolomics-based approach was applied to the reference population samples and evaluated regarding other urinary metabolites that potentially correlate with the urinary excretion of GHB-4-sulfate and GHB-beta-O-glucuronide in order to find a suitable marker to normalize urinary concentrations. The most promising candidate was found at a molecular mass of 321.0696 and was preliminarily identified as beta-citryl glutamic acid. PMID- 28869823 TI - Evidence of perceptive impairment in OSA patients investigated by means of a visual search task. AB - Obstructive Sleep Apnoea (OSA) is a common sleep disorder characterized by episodes of complete or partial obstruction of respiratory airways during sleep that leads to hypoxaemia and sleep fragmentation. One relevant daytime consequence of OSA is a negative impact on neurocognitive domain, ranging from psychomotor performance to executive function. In spite of a huge amount of evidence regarding cognitive impairment, little is known about perceptual processing in these patients. The aim of this research is to investigate the effects of OSA on visual mechanisms by employing a visual search paradigm. 19 OSA patients and 19 age-matched healthy controls (HC) participated in a case-control study. After a nocturnal cardiorespiratory monitoring, patients performed a visual search task in which they had to detect the presence/absence of a target (letter T) embedded in the 50% of trials into a set of distractors (letters Os, Xs, or Ls). Target's salience and distractors' numerosity were manipulated as independent variables, whereas accuracy and reaction times (RT) were recorded as dependent variables. HC, after the exclusion of any sleep disorder or sleepiness, performed the same experiments. Results generally confirmed the typical effects of visual search. OSA patients reported significantly slower RT in comparison with HC, indicating an overall perceptual deficit consisting in a harder extraction of relevant information from noise. Neither patients' age nor the objective clinical indices were associated with RT. This study indicates the presence of an impairment in OSA patients involving basic mechanisms of visual processing and likely ascribable to the disorder per se. PMID- 28869824 TI - Analysis of aerobic granules under the toxic effect of ampicillin in sequencing batch reactors: Performance and microbial community. AB - To study the change of the aerobic granules' microbial community in the present of antibiotics, ampicillin (AMP) was selected as a model component. With acetate as carbon source, different concentrations of AMP (5, 10 and 15 mg L-1) were applied to the inflow intermittently and the results showed that the stability of the aerobic granules was maintained below 10 mg L-1 AMP. Simultaneously, under exposure to 5 and 10 mg L-1 AMP, the COD removal efficiency in the batch reactors remained at 86% and AMP was degraded almost completely with a removal efficiency of 97%. However, the EPS concentration and dehydrogenase activity decreased constantly with increasing AMP dosage. High-throughput sequencing analysis revealed that Proteobacteria was the most prominent phylum in the whole experiment and contributed to the degradation of AMP. The percentages of Azoarcus and Mycoplana increased at 10 mg L-1 AMP. In addition, Hydrogenophaga and Enterococcus played a key role in the microbial metabolism. PMID- 28869825 TI - Patient learning of treatment contents in cognitive therapy. AB - BACKGROUND AND OBJECTIVES: Research has demonstrated that both memory and learning for treatment contents are poor, and that both are associated with worse treatment outcome. The Memory Support Intervention has been shown to improve memory for treatment, but it has not yet been established if this intervention can also improve learning of treatment contents. This study was designed to document the number of times participants exhibited each of the indices of learning, to examine the indices of learning and their relationship to recall of treatment points, and to investigate the association between the indices of learning and depression outcome. METHODS: Adults diagnosed with major depressive disorder (N = 48) were randomly assigned to 14 sessions of cognitive therapy-as usual (CT-as-usual) or cognitive therapy plus the Memory Support Intervention (CT + Memory Support). Measures of learning, memory, and depressive symptomatology were taken at mid-treatment, post-treatment, and at 6-month follow-up. RESULTS: Relative to the CT-as-usual group, participants in the CT + Memory Support group reported more accurate thoughts and applications of treatment points at mid treatment, post-treatment, and 6-month follow-up. Patient recall was significantly correlated with application and cognitive generalization. Thoughts and application at mid-treatment were associated with increased odds of treatment response at post-treatment. LIMITATIONS: The learning measure for this study has not yet been psychometrically validated. The results are based on a small sample. CONCLUSIONS: Learning during treatment is poor, but modifiable via the Memory Support Intervention. These results provide encouraging data that improving learning of treatment contents can reduce symptoms during and following treatment. PMID- 28869826 TI - Origins, evolution, domestication and diversity of Saccharomyces beer yeasts. AB - Yeasts have been used for food and beverage fermentations for thousands of years. Today, numerous different strains are available for each specific fermentation process. However, the nature and extent of the phenotypic and genetic diversity and specific adaptations to industrial niches have only begun to be elucidated recently. In Saccharomyces, domestication is most pronounced in beer strains, likely because they continuously live in their industrial niche, allowing only limited genetic admixture with wild stocks and minimal contact with natural environments. As a result, beer yeast genomes show complex patterns of domestication and divergence, making both ale (S. cerevisiae) and lager (S. pastorianus) producing strains ideal models to study domestication and, more generally, genetic mechanisms underlying swift adaptation to new niches. PMID- 28869828 TI - Is the biocompatibility of copper with polymerized natural coating dependent on the potential selected for the electropolymerization process? AB - With the intention of taking care of the environment and human health, the development of alternative eco-friendly methods to inhibit metal corrosion is intensively encouraged. In previous works we showed that some phytocompounds components of essential oils such as carvacrol (Carv) and thymol (TOH) are able to be electropolymerized on metals and they seem to be promissory for this purpose. The aim this paper is to investigate if the biocompatibility of copper covered by coatings formed by electropolymerization of Carv and TOH (polyCarv and polyTOH) is related with the potential selected for the electropolymerization process. Potentiostatic perturbations at different potentials, AFM images, ATR FTIR spectroscopy and measurements of copper ions release provided suitable information to make a detailed analysis of different stages of the electropolymerization process that leads to polyCarv and polyTOH layers on copper surface. The change of the characteristics of the coatings over time was evaluated after several polymerization periods and current transients were interpreted by using nucleation and growth models. Results showed interesting changes in the polymerization process with the electrochemical perturbation, nature of the isomer, and time of the treatment. The treatment that provides the most protective, transparent and homogeneous layer, that strongly increased the biocompatibility of Cu could be selected: electropolymerization of Carv at 0.4V. Results highlight the importance of the detailed study of the evolution of the electropolymerization processes to select the best ecofriendly condition due the high impact of potential perturbation and polarization time on the biocompatibility of the resulting polymeric layer-copper system. PMID- 28869827 TI - Effects of dexamethasone and nimesulide on bisphosphonate-related osteonecrosis of the jaw: An experimental study. AB - OBJECTIVE: To evaluate the effects of dexamethasone (DEX) and nimesulide (NIM) on Bisphosphonate-related Osteonecrosis of the Jaw (BRONJ) in rats. DESIGN: BRONJ was induced by zoledronic acid (ZA) infusion (0.2mg/kg) in Wistar rats (n=8), followed by extraction of the left lower first molar (BRONJ groups). Control groups (n=40) received saline (IV). For eight weeks, DEX (0.04, 0.4, 4mg/kg) or saline (SAL) were administered by gavage 24h before each infusion of ZA or saline (IV), or NIM (10.3mg/kg) was administered 24h and 12h before each infusion of ZA or saline (IV). The haematological analyses were conducted weekly. After euthanasia (day 70), the jaws were submitted to radiographic and microscopic analysis. Kidney, liver, spleen and stomach were analysed histopathologically. RESULTS: The BRONJ groups showed a higher radiolucent area compared with the control groups (p<0.05). Histomorphometric analysis revealed healing and new bone formation in the control groups, while the BRONJ groups exhibited devitalized bone with bacterial colonies and inflammatory infiltrate. The BRONJ-DEX 0.4 and 4mg/kg groups had a greater number of bacterial colonies (p<0.05) and an increased polymorphonuclear cell count compared to the saline-BRONJ group, while the BRONJ-NIM group had a lower polymorphonuclear count (p<0.05). The BRONJ groups had leucocytosis, which was reduced by DEX administration. Treatments with DEX with or without ZA caused white pulp atrophy. CONCLUSION: Thus, DEX or NIM therapy was not effective in preventing radiographic and histopathologic events associated with BRONJ. Treatment with DEX attenuated leucocytosis post-infusion with ZA. PMID- 28869829 TI - Strontium doping promotes bioactivity of rhBMP-2 upon calcium phosphate cement via elevated recognition and expression of BMPR-IA. AB - Preserving and improving osteogenic activity of bone morphogenetic protein-2 (BMP 2) upon implants remains one of the key limitations in bone regeneration. With calcium phosphate cement (CPC) as model, we have developed a series of strontium (Sr)-doped CPC (SCPC) to address this issue. The effects of fixed Sr on the bioactivity of recombinant human BMP-2 (rhBMP-2) as well as the underlying mechanism were investigated. The results suggested that the rhBMP-2-induced osteogenic activity was significantly promoted upon SCPCs, especially with a low amount of fixed Sr (SrCO3 content <10wt%). Further studies demonstrated that the Sr-induced enhancement of bioactivity of rhBMP-2 was related to an elevated recognition of bone morphogenetic protein receptor-IA (BMPR-IA) to rhBMP-2 and an increased expression of BMPR-IA in C2C12 model cells. As a result, the activations of BMP-induced signaling pathways were different in C2C12 cells incubated upon CPC/rhBMP-2 and SCPCs/rhBMP-2. These findings explicitly decipher the mechanism of SCPCs promoting osteogenic bioactivity of rhBMP-2 and signify the promising application of the SCPCs/rhBMP-2 matrix in bone regeneration implants. PMID- 28869830 TI - Modification of hysteresis behaviors of protein monolayer and the corresponding structures with the variation of protein surface charges. AB - Successive compression-decompression cycles of the surface pressure (pi) - specific molecular area (A) isotherms of protein (BSA) monolayers show that reversible hysteresis persists if the protein molecules contain effective positive or negative surface charges. However, for neutral condition, i.e., close to the isoelectric point of the protein, irreversibility in the hysteresis behaviour dominates. Out-of-plane structures obtained from the X-ray reflectivity analysis suggest that at lower surface pressure monomolecular layer of BSA is formed on the water surface. With increasing surface pressure, molecules start to lift-up from the water surface in such a way that semi-major axis makes an angle with the water surface. Depending on the surface pressure and surface charge of BSA, monomolecular or bimolecular layer of tilted BSA molecules is formed on the water surface, however, formation of bimolecular layer is observed when the pH is relatively closer to the BSA isoelectric point. After complete decompression, tilted monomolecular or bimolecular structures again transform into monomolecular layer as evidenced from the structural analysis of the films deposited at lower surface pressures in the second compression, however, structural hysteresis varies depending upon the subphase pH or protein surface charge. Structures obtained from the films deposited at first and second compressions at lower pressure implies that although structural dissimilarity is present but structural hysteresis is only present near the isoelectric point of BSA and becomes negligible below and above that pH. Competitive electrostatic and van der Waals interactions are responsible for such hysteresis behaviours and structural modifications. PMID- 28869831 TI - Characterisation of volatile organic compounds (VOCs) released by the composting of different waste matrices. AB - The complaints arising from the problem of odorants released by composting plants may impede the construction of new composting facilities, preclude the proper activity of existing facilities or even lead to their closure, with negative implications for waste management and local economy. Improving the knowledge on VOC emissions from composting processes is of particular importance since different VOCs imply different odour impacts. To this purpose, three different organic matrices were studied in this work: dewatered sewage sludge (M1), digested organic fraction of municipal solid waste (M2) and untreated food waste (M3). The three matrices were aerobically biodegraded in a bench-scale bioreactor simulating composting conditions. A homemade device sampled the process air from each treatment at defined time intervals. The samples were analysed for VOC detection. The information on the concentrations of the detected VOCs was combined with the VOC-specific odour thresholds to estimate the relative weight of each biodegraded matrix in terms of odour impact. When the odour formation was at its maximum, the waste gas from the composting of M3 showed a total odour concentration about 60 and 15,000 times higher than those resulting from the composting of M1 and M2, respectively. Ethyl isovalerate showed the highest contribution to the total odour concentration (>99%). Terpenes (alpha-pinene, beta-pinene, p-cymene and limonene) were abundantly present in M2 and M3, while sulphides (dimethyl sulphide and dimethyl disulphide) were the dominant components of M1. PMID- 28869832 TI - Sentinel lymph node biopsy in Chinese patients with large operable breast cancer (>=4 cm): A decade's experience from a single institution. AB - BACKGROUND: Performing sentinel lymph node biopsy (SLNB) in patients with large operable breast cancer is still controversial. Our aim is to find whether or not performing SLNB is feasible and safety in Chinese patients with large operable breast cancer. METHODS: We reviewed the data of patients in our center from 2003 to 2015, a series of 267 patients with large operable breast cancer (>=4 cm) who underwent SLNB were examined. All selected patients recieved preoperative axillary evaluation. RESULTS: The successful rate for localizing SLNs was 96.3% (257 of 267). 31.1% (78 of 257) patients were found to have positive sentinel lymph nodes (SLN). The median follow-up was 52 months. 2.2% (4 of 179) SLN negative patients developed axillary recurrence (AR) as first event. The 5-year axillary recurrence free survival in SLN-negative patients was 96.9% (95%CI, 93.8%-100%). Patients with suspicious nodes on ultrasonography (US) (P = 0.16) and undergoing breast conserving therapy (BCT) (P = 0.057) had a higher trend to be associated with AR. The 5-year recurrence free survival (RFS) was 86.1% (95%CI, 80.8%-93.0%) in SLN-negative patients and 76.3% (95%CI, 68.1%-90.1%) in SLN-positive patients (P = 0.246). CONCLUSIONS: SLNB is feasible and safety in patients with large operable breast cancer who underwent preoperative axillary evaluation. PMID- 28869833 TI - Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways. AB - Despite the increasingly important role of Hippo-Yap in hepatocellular carcinoma (HCC) development and progression, little insight is available at the time regarding the specifics interaction of Yap and cancer cells migration. Here, we identified the mechanism by which tumor-intrinsic Yap deletion resulted in HCC migratory inhibition. Yap was greatly upregulated in HCC and its expression promoted the cells migration. Functional studies found that knockdown of Yap induced JNK phosphorylation which closely bound to the Bnip3 promoter and contributed to Bnip3 expression. Higher Bnip3 employed excessive mitophagy leading to mitochondrial dysfunction and ATP shortage. The insufficient ATP inactivated SERCA and consequently triggered intracellular calcium overload. As the consequence of calcium oscillation, Ca/calmodulin-dependent protein kinases II (CaMKII) was signaled and subsequently inhibited cofilin activity via phosphorylated modification. The phosphorylated cofilin failed to manipulate F actin polymerization and lamellipodium formation, resulting into the impairment of lamellipodium-based migration. Collectively, our results identified Hippo-Yap as the tumor promoter in hepatocellular carcinoma that mediated via activation of cofilin/F-actin/lamellipodium axis by limiting JNK-Bnip3-SERCA-CaMKII pathways, with potential application to HCC therapy involving cancer metastasis. PMID- 28869835 TI - Inhibition of TRAF6-Ubc13 interaction in NFkB inflammatory pathway by analyzing the hotspot amino acid residues and protein-protein interactions using molecular docking simulations. AB - Protein-protein interactions (PPIs) are important in most of the biochemical processes. Hotspot amino acid residues in proteins are the most important contributors for proper protein-protein interactions. Hotspot amino acid residues have been looked down upon as important therapeutic targets in inhibiting PPIs. Interaction between TRAF6 and Ubc13 is a crucial point in the NFkB inflammatory pathway. Dysfunction of the NFkB pathway is associated with numerous human diseases including cancer and neurodenegeration disorders. Ubc13 also interacts specifically to TRAF6 and not with other proteins of the TRAF family and this makes the TRAF6-Ubc13 complex an important target for specific inhibition. Hence, interfering with the TRAF6-Ubc13 association may prove effective in suppressing the NFkB disease pathway. In the present study, we searched the TRAF6-Ubc13 interaction interface to analyze their binding hotspot amino acid residues using various computational techniques. Heterocyclic compounds are known for their medicinal properties. We screened for heterocyclic analogues to the known TRAF6 inhibitor PDTC, to predict a better inhibitor using in silico protein-ligand and protein-protein interaction studies. Our in silico prediction results suggest that tetrahydro-2-thiophenecarbothioamide (Chemspider ID 36027528) binds one of the major hot-spot residues of TRAF6-Ubc13 interface and can be a better alternative in suppressing TRA6-Ubc13 complex formation in chronic inflammation than PDTC. PMID- 28869836 TI - Toward a generalized computational workflow for exploiting transient pockets as new targets for small molecule stabilizers: Application to the homogentisate 1,2 dioxygenase mutants at the base of rare disease Alkaptonuria. AB - Alkaptonuria (AKU) is an inborn error of metabolism where mutation of homogentisate 1,2-dioxygenase (HGD) gene leads to a deleterious or misfolded product with subsequent loss of enzymatic degradation of homogentisic acid (HGA) whose accumulation in tissues causes ochronosis and degeneration. There is no licensed therapy for AKU. Many missense mutations have been individuated as responsible for quaternary structure disruption of the native hexameric HGD. A new approach to the treatment of AKU is here proposed aiming to totally or partially rescue enzyme activity by targeting of HGD with pharmacological chaperones, i.e. small molecules helping structural stability. Co-factor pockets from oligomeric proteins have already been successfully exploited as targets for such a strategy, but no similar sites are present at HGD surface; hence, transient pockets are here proposed as a target for pharmacological chaperones. Transient pockets are detected along the molecular dynamics trajectory of the protein and filtered down to a set of suitable sites for structural stabilization by mean of biochemical and pharmacological criteria. The result is a computational workflow relevant to other inborn errors of metabolism requiring rescue of oligomeric, misfolded enzymes. PMID- 28869834 TI - PKR activation causes inflammation and MMP-13 secretion in human degenerated articular chondrocytes. AB - Osteoarthritis (OA) is a degenerative joint disease affecting a large population of people. Although the elevated expression of PKR (double stranded RNA-dependent protein kinase) and MMP-13 (collagenase-3) have been indicated to play pivotal roles in the pathogenesis of OA, the exact mechanism underlying the regulation of MMP-13 by PKR following inflammatory stimulation was relatively unknown. The purpose of this study was to determine the signaling pathway involved in the PKR mediated induction of MMP-13 after TNF-alpha-stimulation. In this study, cartilages of knee joint were obtained from OA subjects who underwent arthroplastic knee surgery. Cartilages were used for tissue analysis or for chondrocytes isolation. In results, the upregulated expression of PKR was observed in damaged OA cartilages as well as in TNF-alpha-stimulated chondrocytes. Phosphorylation of PKC (protein kinase C) was found after TNF-alpha administration or PKR activation using poly(I:C), indicating PKC was regulated by PKR. The subsequent increased activity of NADPH oxidase led to oxidative stress accumulation and antioxidant capacity downregulation followed by an exaggerated inflammatory response with elevated levels of COX-2 and IL-8 via ERK/NF-kappaB pathway. Activated ERK pathway also impeded the inhibition of MMP-13 by PPAR gamma. These findings demonstrated that TNF-alpha-induced PKR activation triggered oxidative stress-mediated inflammation and MMP-13 in human chondrocytes. Unraveling these deregulated signaling cascades will deepen our knowledge of OA pathophysiology and provide aid in the development of novel therapies. PMID- 28869837 TI - Simultaneous sound velocity and thickness measurement by the ultrasonic pitch catch method for corrosion-layer-forming polymeric materials. AB - Since thermosetting resins have excellent resistance to chemicals, fiber reinforced plastics composed of such resins and reinforcement fibers are widely used as construction materials for equipment in chemical plants. Such equipment is usually used for several decades under severe corrosive conditions so that failure due to degradation may result. One of the degradation behaviors in thermosetting resins under chemical solutions is "corrosion-layer-forming" degradation. In this type of degradation, surface resins in contact with a solution corrode, and some of them remain asa corrosion layer on the pristine part. It is difficult to precisely measure the thickness of the pristine part of such degradation type materials by conventional pulse-echo ultrasonic testing, because the sound velocity depends on the degree of corrosion of the polymeric material. In addition, the ultrasonic reflection interface between the pristine part and the corrosion layer is obscure. Thus, we propose a pitch-catch method using a pair of normal and angle probes to measure four parameters: the thicknesses of the pristine part and the corrosion layer, and their respective sound velocities. The validity of the proposed method was confirmed by measuring a two-layer sample and a sample including corroded parts. The results demonstrate that the pitch-catch method can successfully measure the four parameters and evaluate the residual thickness of the pristine part in the corrosion-layer forming sample. PMID- 28869839 TI - Interventions aimed at closing the social class achievement gap: changing individuals, structures, and construals. AB - Understanding the sources of the social class achievement gap in education is an important step toward ensuring that education serves its purpose as an engine of social mobility. The goal of the current article is to provide a brief overview of the sources of the social class achievement gap as well as interventions aimed at closing this gap. We outline three major sources of the social class achievement gap-individual skills, structural conditions, and people's processes of meaning-making, or construals-and the interventions that target them. While all of these interventions can effect change, we propose that interventions will be most effective when tailored to fit the specific needs of students and the context in which they are delivered. PMID- 28869838 TI - FGFR2-Driven Signaling Counteracts Tamoxifen Effect on ERalpha-Positive Breast Cancer Cells. AB - Signaling mediated by growth factors receptors has long been suggested as one of the key factors responsible for failure of endocrine treatment in breast cancer (BCa). Herein we present that in the presence of tamoxifen, FGFs (Fibroblast Growth Factors) promote BCa cell growth with the strongest effect being produced by FGF7. FGFR2 was identified as a mediator of FGF7 action and the FGFR2-induced signaling was found to underlie cancer-associated fibroblasts-dependent resistance to tamoxifen. FGF7/FGFR2-triggered pathway was shown to induce ER phosphorylation, ubiquitination and subsequent ER proteasomal degradation which counteracted tamoxifen-promoted ER stabilization. We also identified activation of PI3K/AKT signaling targeting ER-Ser167 and regulation of Bcl-2 expression as a mediator of FGFR2-promoted resistance to tamoxifen. Analysis of tissue samples from patients with invasive ductal carcinoma revealed an inversed correlation between expression of FGFR2 and ER, thus supporting our in vitro data. These results unveil the complexity of ER regulation by FGFR2-mediated signaling likely to be associated with BCa resistance to endocrine therapy. PMID- 28869840 TI - The cognate facilitation effect in bilingual lexical decision is influenced by stimulus list composition. AB - Cognates share their form and meaning across languages: "winter" in English means the same as "winter" in Dutch. Research has shown that bilinguals process cognates more quickly than words that exist in one language only (e.g. "ant" in English). This finding is taken as strong evidence for the claim that bilinguals have one integrated lexicon and that lexical access is language non-selective. Two English lexical decision experiments with Dutch-English bilinguals investigated whether the cognate facilitation effect is influenced by stimulus list composition. In Experiment 1, the 'standard' version, which included only cognates, English control words and regular non-words, showed significant cognate facilitation (31ms). In contrast, the 'mixed' version, which also included interlingual homographs, pseudohomophones (instead of regular non-words) and Dutch-only words, showed a significantly different profile: a non-significant disadvantage for the cognates (8ms). Experiment 2 examined the specific impact of these three additional stimuli types and found that only the inclusion of Dutch words significantly reduced the cognate facilitation effect. Additional exploratory analyses revealed that, when the preceding trial was a Dutch word, cognates were recognised up to 50ms more slowly than English controls. We suggest that when participants must respond 'no' to non-target language words, competition arises between the 'yes'- and 'no'-responses associated with the two interpretations of a cognate, which (partially) cancels out the facilitation that is a result of the cognate's shared form and meaning. We conclude that the cognate facilitation effect is a real effect that originates in the lexicon, but that cognates can be subject to competition effects outside the lexicon. PMID- 28869841 TI - Effects of attention on the speech reception threshold and pupil response of people with impaired and normal hearing. AB - For people with hearing difficulties, following a conversation in a noisy environment requires substantial cognitive processing, which is often perceived as effortful. Recent studies with normal hearing (NH) listeners showed that the pupil dilation response, a measure of cognitive processing load, is affected by 'attention related' processes. How these processes affect the pupil dilation response for hearing impaired (HI) listeners remains unknown. Therefore, the current study investigated the effect of auditory attention on various pupil response parameters for 15 NH adults (median age 51 yrs.) and 15 adults with mild to moderate sensorineural hearing loss (median age 52 yrs.). Both groups listened to two different sentences presented simultaneously, one to each ear and partially masked by stationary noise. Participants had to repeat either both sentences or only one, for which they had to divide or focus attention, respectively. When repeating one sentence, the target sentence location (left or right) was either randomized or blocked across trials, which in the latter case allowed for a better spatial focus of attention. The speech-to-noise ratio was adjusted to yield about 50% sentences correct for each task and condition. NH participants had lower ('better') speech reception thresholds (SRT) than HI participants. The pupil measures showed no between-group effects, with the exception of a shorter peak latency for HI participants, which indicated a shorter processing time. Both groups showed higher SRTs and a larger pupil dilation response when two sentences were processed instead of one. Additionally, SRTs were higher and dilation responses were larger for both groups when the target location was randomized instead of fixed. We conclude that although HI participants could cope with less noise than the NH group, their ability to focus attention on a single talker, thereby improving SRTs and lowering cognitive processing load, was preserved. Shorter peak latencies could indicate that HI listeners adapt their listening strategy by not processing some information, which reduces processing time and thereby listening effort. PMID- 28869842 TI - Changes in intrinsic local connectivity after reading intervention in children with autism. AB - Most of the existing behavioral and cognitive intervention programs in autism spectrum disorders (ASD) have not been tested at the neurobiological level, thus falling short of finding quantifiable neurobiological changes underlying behavioral improvement. The current study takes a translational neuroimaging approach to test the impact of a structured visual imagery-based reading intervention on improving reading comprehension and assessing its underlying local neural circuitry. Behavioral and resting state functional MRI (rs-fMRI) data were collected from children with ASD who were randomly assigned to an Experimental group (ASD-EXP; n=14) and a Wait-list control group (ASD-WLC; n=14). Participants went through an established reading intervention training program (Visualizing and Verbalizing for language comprehension and thinking or V/V; 4-h per day, 10-weeks, 200h of face-to-face instruction). Local functional connectivity was examined using a connection density approach from graph theory focusing on brain areas considered part of the Reading Network. The main results are as follows: (I) the ASD-EXP group showed significant improvement, compared to the ASD-WLC group, in their reading comprehension ability evidenced from change in comprehension scores; (II) the ASD-EXP group showed increased local brain connectivity in Reading Network regions compared to the ASD-WLC group post intervention; (III) intervention-related changes in local brain connectivity were observed in the ASD-EXP from pre to post-intervention; and (IV) improvement in language comprehension significantly predicted changes in local connectivity. The findings of this study provide novel insights into brain plasticity in children with developmental disorders using targeted intervention programs. PMID- 28869843 TI - Flexing dual-systems models: How variable cognitive control in children informs our understanding of risk-taking across development. AB - Prevailing models of the development of decision-making propose that peak risk taking occurs in adolescence due to a neural imbalance between two processes: gradual, linearly developing cognitive control and rapid, non-linearly developing reward-processing. Though many studies have found neural evidence supporting this dual-systems imbalance model, its behavioral predictions have been surprisingly difficult to document. Most laboratory studies have not found adolescents to exhibit greater risk-taking than children, and public health data show everyday risk-taking to peak in late adolescence/early adulthood. Moreover, when adolescents are provided detailed information about decision options and consequences, they evince similar behavior to adults. Such findings point to a critical feature of the development of decision-making that is missed by imbalance models. Specifically, the engagement of cognitive control is context dependent, such that cognitive control and therefore advantageous decision-making increases when available information is high and decreases when available information is low. Furthermore, the context dependence of cognitive control varies across development, such that increased information availability benefits children more than adolescents, who benefit more than adults. This review advances a flexible dual-systems model that is only imbalanced under certain conditions; explains disparities between neural, behavioral, and public health findings; and provides testable hypotheses for future research. PMID- 28869844 TI - Blindness and social trust: The effect of early visual deprivation on judgments of trustworthiness. AB - Investigating the impact of early visual deprivation on evaluations related to social trust has received little attention to date. This is despite consistent evidence suggesting that early onset blindness may interfere with the normal development of social skills. In this study, we investigated whether early blindness affects judgments of trustworthiness regarding the actions of an agent, with trustworthiness representing the fundamental dimension in the social evaluation. Specifically, we compared performance between a group of early blind individuals with that of sighted controls in their evaluation of trustworthiness of an agent after hearing a pair of two positive or two negative social behaviors (impression formation). Participants then repeated the same evaluation following the presentation of a third (consistent or inconsistent) behavior regarding the same agent (impression updating). Overall, blind individuals tended to give similar evaluations compared to their sighted counterparts. However, they also valued positive behaviors significantly more than sighted controls when forming their impression of an agent's trustworthiness. Moreover, when inconsistent information was provided, blind individuals were more prone to revise their initial evaluation compared to controls. These results suggest that early visual deprivation may have a dramatic effect on the evaluation of social factors such as trustworthiness. PMID- 28869845 TI - A microdevice for rapid, monoplex and colorimetric detection of foodborne pathogens using a centrifugal microfluidic platform. AB - Outbreaks of foodborne diseases have become a global health concern; hence, many improvements and developments have been made to reduce the risk of food contamination. We developed a centrifugal microfluidic automatic wireless endpoint detection system integrated with loop mediated isothermal amplification (LAMP) for monoplex pathogen detection. Six identical sets were designed on the microfluidic compact disc (CD) to perform 30 genetic analyses of three different species of foodborne pathogens. The consecutive loading, mixing, and aliquoting of the LAMP primers/reagents and DNA sample solutions were accomplished using an optimized square-wave microchannel, metering chambers and revulsion per minute (RPM) control. We tested 24 strains of pathogenic bacteria (Escherichia coli, Salmonella spp and Vibrio cholerae), with 8 strains of each bacterium, and performed DNA amplification on the microfluidic CD for 60min. Then, the amplicons of the LAMP reaction were detected using the calcein colorimetric method and further analysed via the developed electronic system interfaced with Bluetooth wireless technology to transmit the results to a smartphone. The system showed a limit of detection (LOD) of 3 * 10-5ngMUL-1 DNA by analysing the colour change when tested with chicken meat spiked with the three pathogenic bacteria. Since the entire process was performed in a fully automated way and was easy to use, our microdevice is suitable for point-of-care (POC) testing with high simplicity, providing affordability and accessibility even to poor, resource-limited settings. PMID- 28869847 TI - Adaptive response under multiple stress exposure in fish: From the molecular to individual level. AB - Aquatic systems are subjected to various sources of stress due to global changes, such as increasing temperature and pollution. A major challenge for the next decade will be to evaluate the combined effects of these multiple stressors on organisms and ecosystems. For organisms submitted to chemical, biological or physical stressors, the capacity to set up an efficient adaptive response is a fundamental prerequisite for their long-term survival and performance. In this study, goldfish (Carassius auratus) were subjected to individual and combined pesticide mixtures and increased temperatures to evaluate their adaptive response in multistress conditions from the molecular to the individual level. Fish were exposed for 16 days to a mixture of pesticides at environmental relevant concentrations (S-metolachlor, isoproturon, linuron, atrazine-desethyl, aclonifen, pendimethalin and tebuconazole) and at two temperatures (22 degrees C and 32 degrees C). Three major physiological traits of the stress response were measured: the hormonal response (i.e. plasma cortisol), the metabolic balance from molecular to individuals' levels (metabolomics, cellular energy allocation, energy reserves and global condition indexes), and the cellular defense system induction (SOD, CAT and GST). Results show that (1) environmentally relevant concentrations of pesticides lead to significant responses in fish at all biological levels; (2) the metabolic response depends on the nature of stress (thermal vs. chemical); and (3) fish may be unable to set up an efficient adaptive response when chemical and thermal stresses were combined, with adverse outcomes at the individuals' level. PMID- 28869846 TI - A statistical framework for applying RNA profiling to chemical hazard detection. AB - Use of 'omics technologies in environmental science is expanding. However, application is mostly restricted to characterizing molecular steps leading from toxicant interaction with molecular receptors to apical endpoints in laboratory species. Use in environmental decision-making is limited, due to difficulty in elucidating mechanisms in sufficient detail to make quantitative outcome predictions in any single species or in extending predictions to aquatic communities. Here we introduce a mechanism-agnostic statistical approach, supplementing mechanistic investigation by allowing probabilistic outcome prediction even when understanding of molecular pathways is limited, and facilitating extrapolation from results in laboratory test species to predictions about aquatic communities. We use concepts familiar to environmental managers, supplemented with techniques employed for clinical interpretation of 'omics-based biomedical tests. We describe the framework in step-wise fashion, beginning with single test replicates of a single RNA variant, then extending to multi-gene RNA profiling, collections of test replicates, and integration of complementary data. In order to simplify the presentation, we focus on using RNA profiling for distinguishing presence versus absence of chemical hazards, but the principles discussed can be extended to other types of 'omics measurements, multi-class problems, and regression. We include a supplemental file demonstrating many of the concepts using the open source R statistical package. PMID- 28869848 TI - Discriminating modes of toxic action in mice using toxicity in BALB/c mouse fibroblast (3T3) cells. AB - The objective of this study was to determine whether toxicity in mouse fibroblast cells (3T3 cells) could predict toxicity in mice. Synthesized data on toxicity was subjected to regression analysis and it was observed that relationship of toxicities between mice and 3T3 cells was not strong (R2 = 0.41). Inclusion of molecular descriptors (e.g. ionization, pKa) improved the regression to R2 = 0.56, indicating that this relationship is influenced by kinetic processes of chemicals or specific toxic mechanisms associated to the compounds. However, to determine if we were able to discriminate modes of action (MOAs) in mice using the toxicities generated from 3T3 cells, compounds were first classified into "baseline" and "reactive" guided by the toxic ratio (TR) for each compound in mice. Sequence, binomial and recursive partitioning analyses provided strong predictions of MOAs in mice based upon toxicities in 3T3 cells. The correct classification of MOAs based on these methods was 86%. Nearly all the baseline compounds predicted from toxicities in 3T3 cells were identified as baseline compounds from the TR in mice. The incorrect assignment of MOAs for some compounds is hypothesized to be due to experimental uncertainty that exists in toxicity assays for both mice and 3T3 cells. Conversely, lack of assignment can also arise because some reactive compounds have MOAs that are different in mice compared to 3T3 cells. The methods developed here are novel and contribute to efforts to reduce animal numbers in toxicity tests that are used to evaluate risks associated with organic pollutants in the environment. PMID- 28869849 TI - Metabolic pathway and role of individual species in the bacterial consortium for biodegradation of azo dye: A biocalorimetric investigation. AB - In this study, an attempt was made to investigate the functional role and metabolic behaviour of the monoculture (Staphylococcus lentus (SL), Bacillus flexus (BF) and Pseudomonas aeruginosa (PA)) in the bacterial biocenosis for biotransformation of an azo dye. The power-time profile obtained from consortia depicted three distinct peaks, which correlated well with the individual bacterial growth (PA > SL > BF), indicating the synergistic relation and division of labour in the biocenosis. The heat release pattern was used to identify the sequential behaviour of microbial consortia in real time. Yield calculation based on total heat liberated to the complete substrate utilization Y (Q/S) for PA, SL, and BF were 15.99, 16.68, 7.32 kJ/L respectively. Similarly, the oxy calorific values Y (Q/O) for the above species are respectively 386, 375, 440 kJ/mol and indicates the aerobic nature of microorganism employed. Further, the metabolome produced during the biotransformation were identified using Gas Chromatography Mass Spectrometry (GC-MS), based on which a plausible pathway was predicted. The abundant metabolites were palmitic acid (m/z = 256) and diethyl phthalate (m/z = 222.2). The abundance of diethyl phthalate was much lesser in the consortia compared to the monoculture. Thus, the biocalorimetric heat yield calculation along with the stoichiometry and plausible pathway based biochemical elucidation provides a mechanistic basis for understanding the azo-dye biotransformation by the monocultures in consortia. PMID- 28869850 TI - The incidence and epidemiology of eldercide in the city of Johannesburg, South Africa. AB - The current study describes the incidence and epidemiological characteristics of eldercide (homicides among victims aged 60 years and older) in Johannesburg for the period 2001 to 2010. A retrospective population-based study was conducted on cases drawn from the National Injury Mortality Surveillance System. A total of 557 eldercides were recorded by NIMSS for the study period with an average annual rate of 23.1 per 100 000. The average annual rate for males was 42.4 per 100 000 and 8.9 per 100 000 for females. There was little variation in the rates by race. Eldercide victims were predominantly male (77.4%), black (48.3%) or white (43.2%), and were mainly killed by firearms (44.8%) or the use of blunt force (27.8%), in a private residence (66.0%), on a week day (53.8%) and during the day (56.1%). The study also found that the characteristics of eldercide varied across males and females, and across black and white race groups. The high incidence of eldercides points to the need for interventions that give special attention to the risk configurations and circumstances associated with these violent deaths. PMID- 28869852 TI - Association between intimate partner violence and mental health among Korean married women. AB - OBJECTIVES: Intimate partner violence (IPV) has only attracted limited attention in Korea despite numerous studies in Western countries that indicate IPV is associated with depressive symptoms. This study examined the association of IPV with depressive symptoms and suicidal ideation as moderated by the perceived gender roles of married women in South Korea. STUDY DESIGN: We analyzed a data set of 4659 married females from the 8th wave of the Korea Welfare Panel Study. Participants were categorized into three groups of non-IPV, non-physical IPV, and physical IPV. The presence of depressive symptoms and suicidal ideation was then used to predict mental health outcomes. METHODS: Logistic regression helped to investigate the association of IPV and mental health. Furthermore, an interactive regression of IPV and perceived gender roles was also done. RESULTS: Each type of IPV (non-physical and physical) was significantly associated with depressive symptoms (Odds ratios [ORs]: 1.65 and 4.34; 95% confidence interval [CIs]: 1.28 2.13 and 2.71-7.28, respectively) and suicidal ideation (ORs: 1.40 and 3.84; 95% CIs: 1.06-1.85 and 2.32-6.36, respectively) after adjusting for covariates. In addition, women who experienced IPV and reported having traditional gender roles were also more likely to report depressive symptoms (OR: 4.59; 95% CI: 2.90-7.28) and suicidal ideation (OR: 7.28; 95% CI: 3.56-14.87). CONCLUSIONS: Research findings indicate an increasingly marked pattern of work-family conflict in regard to the relationship between traditional gender roles and the effect of IPV on the mental health of women. Policy efforts are needed to reduce IPV as a mental health risk factor and address paternalistic traditions deeply rooted in Korean society that place women in an inferior family status. PMID- 28869851 TI - Repurposing ribosomes for synthetic biology. AB - The translation system is the cell's factory for protein biosynthesis, stitching together hundreds to thousands of amino acids into proteins, which are required for the structure, function, and regulation of living systems. The extraordinary synthetic capability of this system, which includes the ribosome and its associated factors required for polymerization, has driven extensive efforts to harness it for societal use in areas as diverse as energy, materials, and medicine. A powerful example is recombinant protein production, which has impacted the lives of patients through the synthesis of biopharmaceuticals such as insulin. In nature, however, only limited sets of monomers are utilized, thereby resulting in limited sets of biopolymers (i.e., proteins). Expanding nature's repertoire of ribosomal monomers could yield new classes of enzymes, therapeutics, materials, and chemicals with diverse, genetically encoded chemistry. Here, we discuss recent progress towards engineering ribosomes both in vivo and in vitro. These fundamental and technical breakthroughs open doors for advanced applications in biotechnology and synthetic biology. PMID- 28869853 TI - Association of smoking status with substance use and psychological distress in Serbia. PMID- 28869854 TI - Estimating the effect of finite depth of field in single-particle cryo-EM. AB - The extent to which the resolution varies within a three-dimensional (3-D) reconstruction, when the diameter of an object is large, is investigated computationally. Numerical simulation is used to model ideal three-dimensional point-spread functions at different radial positions within an object. It is shown that reconstructed density maps are affected less than might have been expected when particles are larger than the depth of field. This favorable outcome is attributed mainly to the fact that a point which lies outside the depth of field relative to the center, for some orientations of the object, will also lie within the depth of field for other orientations. We find, as a result, that the diameter of a particle can be as much as four times the depth of field (as defined by a 90 degrees phase-error criterion) before curvature of the Ewald sphere becomes a limiting factor in determining the resolution that can be achieved. PMID- 28869855 TI - Reactivity of 12-tungstophosphoric acid and its inhibitor potency toward Na+/K+ ATPase: A combined 31P NMR study, ab initio calculations and crystallographic analysis. AB - Influence of 12-tungstophosphoric acid (WPA) on conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) in the presence of Na+/K+ ATPase was monitored by 31P NMR spectroscopy. It was shown that WPA exhibits inhibitory effect on Na+/K+-ATPase activity. In order to study WPA reactivity and intermolecular interactions between WPA oxygen atoms and different proton donor types (D=O, N, C), we have considered data for WPA based compounds from the Cambridge Structural Database (CSD), the Crystallographic Open Database (COD) and the Inorganic Crystal Structure Database (ICSD). Binding properties of Keggin's anion in biological systems are illustrated using Protein Data Bank (PDB). This work constitutes the first determination of theoretical Bader charges on polyoxotungstate compound via the Atom In Molecule theory. An analysis of electrostatic potential maps at the molecular surface and charge of WPA, resulting from DFT calculations, suggests that the preferred protonation site corresponds to WPA bridging oxygen. These results enlightened WPA chemical reactivity and its potential biological applications such as the inhibition of the ATPase activity. PMID- 28869856 TI - Detection rates, trends in and factors affecting observed levels of selected volatile organic compounds in blood among US adolescents and adults. AB - Data from National Health and Nutrition Examination Survey were analyzed to evaluate detection rates, trend in and factors affecting the observed levels of 1,4-dichlorobenzene, benzene, ethylbenzene, o-xylene, styrene, toluene, and m/p xylene among US adolescents and adults over 2005-2012. Over 2005-20102, among adolescents, detection rates declined by more than 50% for benzene, ethylbenzene, and o-xylene, and among adults, detection rates declined by more than 50% for ethylbenzene and o-xylene and by a little less than 50% for benzene. Among adults, adjusted levels of 1, 4-dichlorobenzene, benzene, ethylbenzene, o-xylene, toluene, and m/p-xylene decreased by 13.7%, 17.1%, 20%, 17.7%, 23.2%, and 18.7% respectively for every two-year survey cycle. Among adolescents, percentage decline in the levels of 1, 4-dichlorobenzene, benzene, ethylbenzene, o-xylene, styrene, toluene, and m/p-xylene was 15.2%, 21.4%, 19.3%, 16.1%, 47.8%, and 17.7% respectively for every two year survey period. The ratio of adjusted geometric means for adult smokers as compared to adult nonsmokers was 10.7 for benzene, 3.5 for ethylbenzene, 2.0 for o-xylene, 3.4 for styrene, 3.5 for toluene, and 2.2 for m/p-xylene. Among adolescents, gender did not affect the adjusted levels of any of the seven VOCs, and the order in which adjusted levels for 1, 4 dichlorobenzene by race/ethnicity was observed was: non-Hispanic white (0.038ng/mL)90% were obtained using a citrate-buffered pH gradient method and the resulting immunoliposomes reached in vivo erythrocyte targeting and retention efficacies of >80%. In P. yoelii-infected mice, the immunoliposomized aminoquinoline succeeded in decreasing blood parasitemia from severe to uncomplicated malaria parasite densities (i.e. from >=25% to ca. 5%), whereas the same amount of drug encapsulated in non-targeted liposomes had no significant effect on parasite growth. Pharmacokinetic analysis indicated that this good performance was obtained with a rapid clearance of immunoliposomes from the circulation (blood half-life of ca. 2 h), suggesting a potential for improvement of the proposed model. PMID- 28869863 TI - Understanding molecular interactions between scavenger receptor A and its natural product inhibitors through molecular modeling studies. AB - Scavenger receptor A (SRA), as an immune regulator, has been shown to play important roles in lipid metabolism, cardiovascular diseases, and pathogen recognition. Several natural product inhibitors of SRA have been studied for their potential application in modulating SRA functions. To understand the binding mode of these inhibitors on SRA, we conducted systematic molecular modeling studies in order to identify putative binding domain(s) that may be responsible for their recognition to the receptor as well as their inhibitory activity. Treatment of SRA with one of the natural product inhibitors, rhein, led to significant dissociation of SRA oligomers to its trimer and dimer forms, which further supported our hypothesis on their putative mechanism of action. Such information is believed to shed light on design of more potent inhibitors for the receptor in order to develop potential therapeutics through immune system modulation. PMID- 28869865 TI - Visual in vivo degradation of injectable hydrogel by real-time and non-invasive tracking using carbon nanodots as fluorescent indicator. AB - Visual in vivo degradation of hydrogel by fluorescence-related tracking and monitoring is crucial for quantitatively depicting the degradation profile of hydrogel in a real-time and non-invasive manner. However, the commonly used fluorescent imaging usually encounters limitations, such as intrinsic photobleaching of organic fluorophores and uncertain perturbation of degradation induced by the change in molecular structure of hydrogel. To address these problems, we employed photoluminescent carbon nanodots (CNDs) with low photobleaching, red emission and good biocompatibility as fluorescent indicator for real-time and non-invasive visual in vitro/in vivo degradation of injectable hydrogels that are mixed with CNDs. The in vitro/in vivo toxicity results suggested that CNDs were nontoxic. The embedded CNDs in hydrogels did not diffuse outside in the absence of hydrogel degradation. We had acquired similar degradation kinetics (PBS-Enzyme) between gravimetric and visual determination, and established mathematical equation to quantitatively depict in vitro degradation profile of hydrogels for the predication of in vivo hydrogel degradation. Based on the in vitro data, we developed a visual platform that could quantitatively depict in vivo degradation behavior of new injectable biomaterials by real-time and non-invasive fluorescence tracking. This fluorescence-related visual imaging methodology could be applied to subcutaneous degradation of injectable hydrogel with down to 7 mm depth in small animal trials so far. This fluorescence-related visual imaging methodology holds great potentials for rational design and convenient in vivo screening of biocompatible and biodegradable injectable hydrogels in tissue engineering. PMID- 28869866 TI - Synergistic antitumor effect mediated by a paclitaxel-conjugated polymeric micelle-coated oncolytic adenovirus. AB - Combination treatment consisting of oncolytic adenovirus (Ad) and paclitaxel (PTX) is a promising strategy to achieve synergistic antitumor effect. However, a co-administration approach is subject to inherent limitations due to the poor solubility of PTX and chemoresistance of tumor cells. In order to overcome these limitations, an oncolytic Ad expressing a p53 variant (oAd-vp53) that is resistant to p53 inactivation in the tumor microenvironment was complexed with PEGylated and PTX-conjugated polymeric micelle (APP). This approach generated an oAd-vp53/APP complex (176.4 nm in diameter) that could concurrently deliver both oncolytic Ad and the nanoparticulate drug APP to tumors. APP-complexed replication-incompetent Ad (dAd/APP) exhibited 12-fold higher transduction efficiency than naked dAd in coxsackie adenovirus receptor (CAR)-negative cancer cells. This increased efficiency was attributed to more efficient cellular internalization mediated by charge interactions between APP and anionic cell membranes. Furthermore, oAd-vp53/APP elicited synergistically higher cancer cell killing than naked oAd-vp53, APP, or oAd-vp53 in combination with PTX (oAd-vp53 + PTX); this synergistic effect was shown to be due to superior induction of apoptosis and viral replication. Importantly, oAd-vp53/APP induced more potent and synergistic antitumor effect through both local and systemic administration by enhancing replication of oncolytic Ad and induction of apoptosis in tumor tissue. Further, the APP coating on the surface of Ad markedly attenuated the host immune response against Ad and decreased hepatic sequestration, resulting in minimal hepatotoxicity and a good safety profile. These attributes enabled oAd vp53/APP to elicit potent antitumor effect over multiple treatment cycles. Altogether, we demonstrate that concurrent delivery of oncolytic Ad and APP as a single nanocomplex is a promising strategy for achieving synergistic antitumor effect. PMID- 28869867 TI - Atopic dermatitis and psoriasis: two different immune diseases or one spectrum? AB - Psoriasis and atopic dermatitis (AD) are common T-cell mediated inflammatory diseases of the skin that can be treated by specific cytokine antagonists or more broad immunosuppressive drugs. The diseases are similar in that epidermal keratinocytes respond to T-cell derived cytokines by altering growth and differentiation responses, accounting for major parts of the overall disease phenotype. When studied across European-American populations, psoriasis and AD display differing T-cell polarity and different arrays of cytokines. Psoriasis is a disease largely driven by Th17 T-cells and associated IL-17 activation, while AD has a strong Th2 component associated with IL-4 and IL-13 over-production, and both diseases have activation of Th22 T-cells and Th1 pathways with increased IL 22 and IFNgamma production, respectively. AD is a disease frequently associated with increased IgE production and overt allergies or asthma, most likely due to increased Th2 activation, which is largely lacking in psoriasis. Hence, psoriasis and AD can be viewed as distinct diseases with differing clinical, tissue, and molecular disease phenotypes, but this view does not account for specific subtypes of AD, including Asian-origin, intrinsic, and pediatric AD, that have a prominent IL-17 component and also tissue patterning that overlaps with distinctive psoriasis histopathology. Hence, when considering the range of AD phenotypes, a case can be made that psoriasis and AD exist across a spectrum where polar T-cell axes can be variably present and create some overlapping disease characteristics. Today, ~90% of psoriasis patients have extremely controlled disease by targeting the IL-23/Th17 T-cell axis with IL-23 or IL-17 targeting antibodies. An outstanding question is whether targeting a single cytokine axis in AD, for example, Th2 axis, will lead to disease suppression in the majority of patients and across all subtypes, including those with higher IL 17 expression, or whether it is necessary to personalize therapies and target multiple T-cell axes to attain similar disease improvement to psoriasis. PMID- 28869868 TI - Patient and program costs, and outcomes, of including gender-sensitive services in intensive inpatient programs for substance use. AB - Gender-sensitive services (GSS) attempt to make substance use treatment better for women, but at what cost and with what results? We sought answers to these questions in a federally-funded study by measuring separately the patient and provider costs of adding GSS, outcomes, and cost-outcome relationships for 12 mixed-gender intensive inpatient programs (IIP) that varied in amounts and types of GSS. GSS costs to female inpatients included time devoted to GSS and expenses for care of dependents while in the IIP. GSS costs to providers included time spent with patients, indirect services, treatment facilities, equipment, and materials. Offering more GSS was expected to consume more patient and provider resources. Offering more GSS also was expected to enhance outcomes and cost outcome relationships. We found that average GSS costs to patients at the IIPs were $585 ($515-$656) per patient. Average GSS costs to providers at the IIPs were $344 ($42-$544) per patient. GSS costs to patients significantly exceeded GSS costs to providers. Contrary to previous research, offering more GSS services to patients did not result in significantly higher costs to patients or providers. IIPs offering more GSS may have delivered fewer traditional services, but this did not significantly affect outcomes, i.e., days until returning to another substance use treatment. In fact, median cost-outcome for these IIPs was a promising 35 treatment-free days, i.e., over a month, per $100 of GSS resources used by patients and providers. PMID- 28869869 TI - SYK protects cardiocytes against anoxia and hypoglycemia-induced injury in ischemic heart failure. AB - Spleen tyrosine kinase (SYK), a non-receptor protein tyrosine kinase, is reported to be related to cell survival after A/H (anoxia/hypoglycemia) insult. However, the role of SYK in cardiocyte survival under A/H injury remains unclear. In this study, we aimed to gain insight into the role and molecular mechanism of SYK in cardiocytes exposed to A/H stress. The mRNA and protein expressions of SYK in H9c2 cardiocytes exposed to A/H injury, separately detected by real-time quantitative PCR and Western blot, were both robustly up-regulated. Then we overexpressed SYK in H9c2 with A/H injury, and found that cell viability was significantly increased and LDH leakage was decreased. Moreover, apoptosis measured by annexin V-fluorescein isothiocyanate/propidium iodide and reactive oxygen species (ROS) identified by 2', 7'-dichlorofluorescin diacetate were markedly inhibited in H9c2 with A/H injury following SYK overexpression. Furthermore, we observed that SYK could induce HO-1 expression by regulating the Akt phosphorylation level in H9c2 with A/H injury, protecting H9c2 from the injury induced by A/H treatment. PMID- 28869870 TI - The hematological and biochemical changes in rats exposed to britholite mineral. AB - The present study was to investigate the alteration of biochemical and hematological parameters on the rats exposed to natural radiation caused by britholite mineral (REE, Ca, Na)5 [(Si,P)O4]3(OH,F) within 15 days. Britholite was collected from Kuluncak mining area, Malatya, bearing radioactive 232Th isotope (average 2.68% ThO2), which is rare earth elements found high amounts. Britholite is toxic for the living animal and human and emits the radiation to natural surroundings about 0.8R/h due to its radioactive 232Th properties. In this study, animals were divided to two groups, one groups exposed to 232Th, the other group was served as control group. All animals were fed with same food and water during the experimental study (15 days). After 15 days, the hematologic and biochemical parameters (Na, K, Ca, P, Cl, Mg, glucose, cholesterol, HDL, LDL, albumin, Uric acid, AST, ALT, total protein, Fe, urea and creatine level and hormonal parameters (TSH, T3 and T4)) were analyzed The levels of serum triglyceride in the ionizing radiation group generated by 232Th isotope (p < 0.05) statistically significantly increased compared with control group value. Lymphocytes, TSH, T3 and T4 decreased in the ionizing radiation group generated by 232Th isotope while neutrophils increased in the ionizing radiation group generated by 232Th isotope. The rats exposed to ionizing radiation generated by 232Th isotope caused significant changes in the hematological and biochemical parameters and the most significantly alteration was observed in the thyroid hormonal levels, which might be due to high radiation doses within short time. These results should be kept in mind to maintain healthy life in people who lives in britholite mineral vicinity. PMID- 28869871 TI - Biochemical characterization and homology modeling of polyamine oxidase from cyanobacterium Synechocystis sp. PCC 6803. AB - The intracellular polyamine contents are regulated not only by polyamine biosynthesis and transport but also by polyamine degradation catalyzed by copper dependent amine oxidase (DAO) and FAD-dependent polyamine oxidase (PAO). The genome sequence of Synechocystis sp. PCC 6803 reveals the presence of at least one putative polyamine oxidase gene, slr5093. The open reading frame of slr5093 encoding Synechocystis polyamine oxidase (SynPAO, E.C. 1.5.3.17) was expressed in Escherichia coli. The purified recombinant enzyme had the characteristic absorption spectrum of a flavoprotein with absorbance peaks at 380 and 450 nm. The optimum pH and temperature for the oxidation of both spermidine and spermine are 8.5 and 30 degrees C, respectively. The enzyme catalyzed the conversion of spermine and spermidine to spermidine and putrescine, respectively, with higher catalytic efficiency when spermine served as substrate. These results suggest that SynPAO is a polyamine oxidase involved in a polyamine back-conversion pathway. Based on the structural analysis, Gln94, Tyr403 and Thr440 in SynPAO are predicted to be important residues in the active site. PMID- 28869872 TI - Semi-preparative high-performance countercurrent chromatography method for the purification of chemically synthesized ATP analogue, ApppI. AB - An efficient high-performance countercurrent chromatography (HPCCC) based method has been developed for the purification of chemically synthesized 1-adenosin-5' yl 3-(3-methylbut-3-enyl)triphosphoric acid diester (ApppI). ApppI is an adenosine triphosphate (ATP) analogue with biological significance due to its varied actions in the body. ApppI was synthesized and purified as its tetrabutylammonium (TBA) salt and converted successfully into its more practical sodium salt form after purification. The amount of TBA hydroxide (2.0, 2.5 and 3.0 eq) used in the synthesis of ApppI was shown to exert an effect on the purification process with HPCCC and on the overall yield (8%, 16% and 22%, respectively). 1-Adenosin-5'-yl 3-(3-methylbut-3-enyl)diphosphoric acid diester (AppI) was also isolated as a side product. PMID- 28869873 TI - HPLC-MS/MS method for bioavailability study of bruceines D & E in rat plasma. AB - Bruceines D and E are quassinoids from seeds of Brucea javanica (L.) Merr. exhibiting hypoglycemia effect. The crude drug is used as a traditional medicine by diabetes patients. The aim of this study is to understand the bioavailability and pharmacokinetics of both the bruceines D & E. A rapid and sensitive HPLC MS/MS method was developed and validated for the quantification of both quassinoids, bruceines D & E in rat plasma. Both the bruceines D & E were separated with the Zorbax SBC-18 column with gradient elution and mobile phase system of acetonitrile and deionized water with 0.1% formic acid at a flow rate of 0.5mL/min. Analytes were detected in multiple reaction monitoring (MRM) mode with electrospray positive ionization. The quassinoids, namely bruceines D & E were detected with transitions of m/z 411.2->393.2 and m/z 395.2->377.2, respectively. Another quassinoid, eurycomanone was used as the internal standard with transition of m/z 409.2->391.2. The method was validated and conformed to the regulatory requirements. The validated method was applied to pharmacokinetic and bioavailability studies in rats. The pharmacokinetic study indicated both bruceine D and E were rapidly absorbed into the circulation system and reached its peak concentration at 0.54+/-0.34h and 0.66+/-0.30h, respectively. Bruceine E was eliminated slower than Bruceine D with t1/2 value almost increased two-fold compared to Bruceine D. In conclusion, a rapid, selective and sensitive HPLC MS/MS method was developed for the simultaneous determination of both the bruceines D and E in rat plasma. Both bruceines D and E displayed poor oral bioavailability. PMID- 28869874 TI - Effects of micro-structure on aerodynamics of Coccinella septempunctata elytra (ladybird) in forward flight as assessed via electron microscopy. AB - The effects of micro-structure on aerodynamics of Coccinella septempunctata (Coleoptera: Coccinellidae) elytra in forward flight were investigated. The micro structure was examined by a scanning electron microscope and a digital microscope. Based on the experimental results, five elytron models were constructed to separately investigate the effects of the camber and the local corrugation in both leading edge and trailing edge on aerodynamics. Computational fluid dynamic simulations of five elytron models were conducted by solving the Reynolds-Averaged Navier-Stokes equations with the Reynolds number of 245. The results show that camber and the local corrugation in the leading edge play significant roles in improving the aerodynamic performance, while the local corrugation in the trailing edge has little effect on aerodynamics. PMID- 28869875 TI - Ultrastructure and morphometric features of epididymal epithelium in Desmodus rotundus. AB - The blood-feeding behavior of Desmodus rotundus made this bat a potential vector of rabies virus and a public health issue. Consequently, the better understanding of its reproductive biology becomes valuable for the development of methods to control its population. In this study, we described morphological aspects of epithelial cells in D. rotundus' epididymis using light and transmission electron microscopy methods. The duct compartment was the main component of initial segment (83%), caput (90%), corpus (88%) and cauda (80%) regions. The epithelium lining the duct presented a progressive decrease in its height from initial segment to cauda regions. Moreover, the morphology of each cell type was the same along the entire duct. Similarly to rodents, columnar-shaped principal cells were the most abundant cell type throughout the epididymis, followed by basal and clear cells. Differently in rat and mice, the frequency of clear cells did not increase in the epididymis cauda, whereas the proportion of principal and basal cells was greater in this region. Furthermore, D. rotundus presented goblet shaped clear cells with the nucleus located in the apical portion of the epididymal epithelium. This cellular portion also presented electron-lucid vesicles of different sizes that may correspond to vesicles enriched with proteins related to proton secretion. In addition to the findings regarding clear cells' structural organization, basal cells presented scarce cytoplasm and no axiopodia. Taken these findings together, we suggest that the mechanism of luminal acidification may have other pathways in D. rotundus than those described in rodents. PMID- 28869877 TI - Solid-state NMR spectroscopic trends for supramolecular assemblies and protein aggregates. AB - Solid-state NMR is able to generate structural data on sample preparations that are explicitly non-crystalline. In particular, for amyloid fibril samples, which can comprise significant degrees of sample disorder, solid-state NMR has been used very successfully. But also solid-state NMR studies of other supramolecular assemblies that have resisted assessment by more standard methods are being performed with increasing ease and biological impact, many of which are briefly reviewed here. New technical trends with respect to structure calculation, protein dynamics and smaller sample amounts have reshaped the field of solid state NMR recently. In particular, proton-detected approaches based on fast Magic Angle Spinning (MAS) were demonstrated for crystalline systems initially. Currently, such approaches are being expanded to the above-mentioned non crystalline targets, the characterization of which can now be pursued with sample amounts on the order of a milligram. In this Trends article, I am giving a brief overview about achievements of the last years as well as the directions that the field has been heading into and delineate some satisfactory perspectives for solid-state NMR's future striving. PMID- 28869876 TI - Associations between internal exposure levels of persistent organic pollutants in adipose tissue and deep infiltrating endometriosis with or without concurrent ovarian endometrioma. AB - Endometriosis is a gynaecological disease characterized by the presence of ectopic endometrial tissue. Histologically, it appears as different sub-types, being peritoneal endometriosis, ovarian endometrioma (OvE) and deep infiltrating endometriosis (DIE), which are of major relevance due to their varying clinical presentations. A number of persistent organic pollutants (POPs) have been associated with the onset of endometriosis, yet the overall set of existing studies remains fairly divergent. In this preliminary case-control study we aimed to assess the potential associations between the internal exposure to POPs and the presence of DIE with or without concurrent OvE. Adipose tissue and serum samples were collected from surgically confirmed cases (n=55) and controls (n=44) enrolled during 2013 and 2015 in Pays de la Loire, France. Targeted pollutants (76 historical or more emerging POPs including dioxins, polychlorobiphenyls (PCB), polybrominated diphenyl ethers (PBDEs), polybrominated biphenyls (PBBs), hexabromocyclododecanes (HBCDs) and organochlorine pesticides (OCPs) were quantified by chromatography coupled to mass spectrometry. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated from unconditional logistic regression adjusted for known confounding variables. The results showed significant associations between DIE and adipose tissue levels of 1.2.3.7.8 - PeCDD, OCDF, PCB 105, 114, 118 and 123, PBDE 183, PBB 153, and several OCPs including trans-nonachlor, cis-heptachlor epoxide, dieldrin, beta hexachlorocyclohexane and hexachlorobenzene. The largest associations were observed for OCDF followed by cis-heptachlor epoxide, exhibiting adjusted ORs (95% CI) of 5.42 (2.73-12.85) and 5.36 (2.44-14.84) per 1-SD increase, respectively. The stratified analysis comparing both disease sub-types suggested that adipose tissue exposure markers may be more associated with DIE concurrent with OvE, however these results need to be confirmed in a larger population. PMID- 28869878 TI - From ecstasy to MDMA: Recreational drug use, symbolic boundaries, and drug trends. AB - BACKGROUND: Ecstasy pills with MDMA as the main ingredient were introduced in many European countries in the 1980s, and were often linked to the rave and club scenes. However, use gradually levelled off, in part as a response to increased concerns about possible mental health consequences and fatalities. Extensive use of MDMA now seems to be re-emerging in many countries. In this study, we investigated the cultural and social meaning associated with MDMA use in Oslo, Norway, with an emphasis on how users distinguish MDMA crystals and powder from "old ecstasy pills". METHODS: Qualitative in-depth interviews (n=31, 61,3% males) were conducted with young adult party-goers and recreational MDMA/ecstasy users (20-34 years old, mean age 26.2 years). RESULTS: Research participants emphasised three important perceived differences between the MDMA crystals and ecstasy pills: (i) The effects of MDMA were described as better than ecstasy; (ii) MDMA was regarded as a safer drug; (iii) Users of MDMA crystals were described as more distinct from and less anchored in out-of-fashion rave culture than those using ecstasy. These differences were an important part of the symbolic boundary work MDMA users engaged in when justifying their drug use. CONCLUSION: MDMA has re emerged as an important psychoactive substance in Oslo's club scene. One important reason for this re-emergence seems to be its perceived differentiation from ecstasy pills, even though the active ingredient in both drugs is MDMA. This perceived distinction between MDMA and ecstasy reveals the importance of social and symbolic meanings in relation to psychoactive substance use. Insights from this study can be important in terms of understanding how trends in drug use develop and how certain drugs gain or lose popularity. PMID- 28869879 TI - Hazardous child labor in Nepal: The case of brick kilns. AB - Hazardous child labor in Nepal is a serious concern, particularly in the brick kiln industry. Although a range of interventions have been implemented in Nepal to address hazardous child labor, there is a lack of research to both measure success and shape further development in interventions that integrate sound child protection practices to ensure the wellbeing of all children. This paper provides a review of the literature outlining interventions for children working in brick kilns in Nepal, and presents preliminary case study findings of one current intervention in the Kathmandu Valley. The paper highlights the strength of applying foundational child protection principles and advocates for the development and implementation of future programs underpinned by broad civil society principles within a child rights and protection framework. PMID- 28869880 TI - Psychometric properties of the Adverse Childhood Experiences Abuse Short Form (ACE-ASF) among Romanian high school students. AB - Child abuse is a major public health problem. In order to establish the prevalence of abuse exposure among children, measures need to be age-appropriate, sensitive, reliable and valid. This study aimed to investigate the psychometric properties of the Adverse Childhood Experiences Questionnaire Abuse Short Form (ACE-ASF). The ACE-ASF is an 8-item, retrospective self-report questionnaire measuring lifetime physical, emotional and sexual abuse. Data from a nationally representative sample of 15-year-old, school-going adolescents (n=1733, 55.5% female) from the Romanian Health Behavior in School-Based Children Study 2014 (HBSC) were analyzed. The factorial structure of the ACE-ASF was tested with Exploratory Factor Analysis (EFA) and confirmed using Confirmatory Factor Analysis (CFA). Measurement invariance was examined across sex, and internal reliability and concurrent criterion validity were established. Violence exposure was high: 39.7% physical, 32.2% emotional and 13.1% sexual abuse. EFA established a two-factor structure: physical/emotional abuse and sexual abuse. CFA confirmed this model fitted the data well [chi2(df)=60.526(19); RMSEA=0.036; CFI/TLI=0.990/0.986]. Metric invariance was supported across sexes. Internal consistency was good (0.83) for the sexual abuse scale and poor (0.57) for the physical/emotional abuse scale. Concurrent criterion validity confirmed hypothesized relationships between childhood abuse and health-related quality of life, life satisfaction, self-perceived health, bullying victimization and perpetration, externalizing and internalizing behaviors, and multiple health complaints. Results support the ACE-ASF as a valid measure of physical, emotional and sexual abuse in school-aged adolescents. However, the ACE-ASF combines spanking with other types of physical abuse when this should be assessed separately instead. Future research is needed to replicate findings in different youth populations and across age groups. PMID- 28869881 TI - The learner as co-creator: A new peer review and self-assessment feedback form created by student nurses. AB - BACKGROUND: Engagement with peer review and self-assessment is not always regarded by student nurses as an activity that results in a positive learning experience. Literature indicates that withdrawal from the learning process becomes attractive to individuals affected by a negative experience of peer review. Literature also provides examples of student nurses' feeling 'torn to shreds' during the process of peer review, resulting in loss of confidence and self-esteem. An influencing factor in such situations appears to be the absence of specific learner-driven criteria against which student nurses can assess peer and self-performance. The idea was thus ignited, that creation and utilisation of a learner-driven feedback form might potentially prevent, or at least minimise, the possibility of negative peer review experience. CONTEXT: Set within the context of a pre-registration nursing programme, within a Higher Education institution, student nurses (n=25), created a peer review/self-assessment feedback form. Its potential cross-discipline, global applicability is reasonably speculated. METHODS: Purposive sampling, followed by Stratified Random sampling, maximised participant variation. Data collection took place on 34 occasions, utilising focus group discussions using Nominal Group Technique, a practical task which was video recorded for mediating artefact purposes, and individual interviews. Analysis was concept and theme driven. FINDINGS: The study found that participants desired a new feedback form that specifically asks the evaluator to judge human qualities, such as 'compassion' and 'kindness', in addition to the skills and knowledge criteria that any peer review or self-assessment form used currently had incorporated. CONCLUSION: Providing the participants with the opportunity to develop criteria, against which performance could be measured, with emphasis being afforded to student inclusivity and resultant shift in power balance from the educator to the learner, embraces the idea of teaching and learning in the 21st Century. PMID- 28869882 TI - The utilization of waste by-products for removing silicate from mineral processing wastewater via chemical precipitation. AB - This study investigates an environmentally friendly technology that utilizes waste by-products (waste acid and waste alkali liquids) to treat mineral processing wastewater. Chemical precipitation is used to remove silicate from scheelite (CaWO4) cleaning flotation wastewater and the waste by-products are used as a substitute for calcium chloride (CaCl2). A series of laboratory experiments is conducted to explain the removal of silicate and the characterization and formation mechanism of calcium silicate. The results show that silicate removal reaches 90% when the Ca:Si molar ratio exceeds 1.0. The X ray diffraction (XRD) results confirm the characterization and formation of calcium silicate. The pH is the key factor for silicate removal, and the formation of polysilicic acid with a reduction of pH can effectively improve the silicate removal and reduce the usage of calcium. The economic analysis shows that the treatment costs with waste acid (0.63 $/m3) and waste alkali (1.54 $/m3) are lower than that of calcium chloride (2.38 $/m3). The efficient removal of silicate is confirmed by industrial testing at a plant. The results show that silicate removal reaches 85% in the recycled water from tailings dam. PMID- 28869883 TI - Degradation of sulfolane using activated persulfate with UV and UV-Ozone. AB - This study investigates the degradation of sulfolane in aqueous system by (NH4)2S2O8/UVC and (NH4)2S2O8/O3/UVC. While bubbling O3 significantly decreased the reaction time, the experimental results in both cases were consistent: firstly, the degradation of sulfolane followed pseudo-first order kinetic models, secondly, the reaction rates were affected by persulfate dosages, UV light intensity, initial pH and concentration of carbonate/bicarbonate present. Low concentration of chloride (less then 100 ppm) had no effect on the reaction rate. Application of (NH4)2S2O8/O3/UVA for degradation of sulfolane was also investigated. It was found that for higher sulfolane degradation kinetics, higher concentrations of persulfate was required under UVA irradiation. Finally, (NH4)2S2O8/UVC was evaluated for its applicability for degradation of sulfolane in groundwater samples. PMID- 28869884 TI - Serum C-peptide as a key contributor to lipid-related residual cardiovascular risk in the elderly. AB - OBJECTIVES: The serum levels of C-peptide, an important risk factor for cardiovascular disease (CVD), increase with age. This study aimed to investigate the association between serum C-peptide and increased risk for CVD with altered lipid metabolism in the elderly. METHODS: This was a population-based cross sectional study that included 3091 elderly participants aged >=65 years. Serum C peptide and lipid levels were measured according to standard protocols. Sampling weights were used to estimate the characteristics of study participants. Stratified analysis of covariance was used to evaluate the changes in the serum lipid levels according to quartiles of serum C-peptide levels, and the linear trend was assessed using a linear model. The logistic regression model was carried out to determine the association between the serum C-peptide levels and serum lipid levels. RESULTS: The results of the analysis of covariance stratified by sex and serum insulin level showed that the serum triglyceride (TG) and high density lipoprotein cholesterol (HDL-C) levels were significantly associated with changes in the serum C-peptide levels, independent of the serum insulin level. The logistic regression analyses indicated that the serum C-peptide levels were positively associated with the serum TG levels, and negatively associated with the serum HDL-C levels. A significant dose-response association was obtained in both men and women. CONCLUSIONS: Serum C-peptide levels were strongly associated with increased serum TG and reduced HDL-C levels in the elderly. Our results suggest that serum C-peptide increases the risk of CVD via a pathway that increases TG or decreases HDL-C levels. PMID- 28869885 TI - Development and validation of a prognostic index for 6- and 12-month mortality in hospitalized older adults. AB - BACKGROUND/AIM: Estimation of mortality in elderly patients is difficult yet very important when planning care. Previous tools are complicated or do no take into account some major determinants of mortality (i.e., frailty). We designed a simple, accurate, and non-disease-specific tool to predict individual mortality risk after hospital discharge in older adults. METHODS: Patients admitted to the Acute Geriatric Unit were assessed at adission and at discharge and contacted 6 and 12 months later. Determinants of mortality were obtained. Using multivariable analysis, beta coeffcicients were calculated to build 2 scores able to predict mortality at 6 and 12 months after discharge. The scores were tested on a sample comprising 75% of the patients, who were randomly selected; they were validated using the remaining 25%. Discrimination was assessed using ROC curves. Scores were calculated for each patient and divided into tertiles. Survival analysis was performed. RESULTS: Determinants of mortality at 6 months were dependent ambulation at baseline, full dependence at discharge, length of stay, pluripatology, pressure ulcers, low grip strength, malignacy, and male gender. At 12 months the determinants were: dependent amblation at baseline, full dependence at discharge, pluripatology, low BMI, low grip strength, heart failure, malignacy, and male gender. Discrimination and calibration were excellent. Survival analysis demonstrated different survival trajectories (p<0.001) for each tertile in both scores. CONCLUSIONS: Our incices provide accurate prognostic information in elderly patients after discharge. They can be calculated easily, quickly and do not require technical or laboratory support, thus endorsing their value in dalily clinical practice. PMID- 28869886 TI - Persistent organic pollutants in red-crowned cranes (Grus japonensis) from Hokkaido, Japan. AB - The red-crowned crane (Grus japonensis) from eastern Hokkaido is classified as a Special Natural Monument in Japan. In this study, we determined the concentrations of persistent organic pollutants (POPs) in red-crowned crane muscle tissues (n = 47). Polychlorinated biphenyls (PCBs) had the highest median concentration (240ng/g lipid weight), followed by dichlorodiphenyltrichloroethane and its metabolites (DDTs) (150ng/g lipid weight), chlordane-related compounds (CHLs) (36ng/g lipid weight), hexachlorobenzene (HCB) (16ng/g lipid weight), hexachlorocyclohexanes (HCHs) (4.4ng/g lipid weight), polybrominated diphenyl ethers (PBDEs) (1.8ng/g lipid weight), and finally, Mirex (1.5ng/g lipid weight). Additionally, a positive correlation was found among POP concentrations. No sex differences beyond body parameters were observed. Additionally, red-crowned cranes exhibited a high enantiomeric excess of (+)-alpha-HCH, with enantiomer fractions varying from 0.51 to 0.87 (average: 0.69). PMID- 28869887 TI - Chronic toxicity of 1,3,5-triazine herbicides in the postembryonic development of the western clawed frog Silurana tropicalis. AB - Seven 1,3,5- triazine (s-triazine) herbicides (ametryn, prometryn, dimethametryn, simazine, atrazine, propazine, and cyanazine) were tested using an amphibian (Silurana tropicalis) metamorphosis assay focusing on morphometric, gravimetric, and thyroid-histological endpoints. Premetamorphic tadpoles were exposed to each s-triazine at 2 concentrations between 1/1000 and 1/10 of the 96-h acute toxicity values, until all tadpoles in the control group reached either the late prometamorphosic stages or the initial stage of metamorphic climax. All s triazines tested induced significant retardation in growth and development at the higher concentrations (0.2-1.0mg/L), and some of them induced similar effects even at the lower concentrations (0.02-0.1mg/L) while each showing a linear dose response. Total size of the thyroid glands tended to be reduced corresponding to the delayed development, but without showing histomorphological lesions typical of anti-thyroid chemicals. These consistent results suggest that the s-triazines can act as a chemical stressor inhibiting tadpole growth and development, possibly without disrupting the thyroid axis. In addition, tadpoles exhibiting spinal curvatures appeared in either one or both of the lower and higher concentration groups for each s-triazine tested. The incidence rate in the s triazine exposure groups where tadpoles with scoliosis were observed ranged from 3.3% to 63.3%, some of which were significantly higher than that in the respective control groups (0-6.7%). It is speculated that the s-triazines may promote to occur axial malformations in developing tadpoles. PMID- 28869888 TI - Pancreatic ductal adenocarcinoma: State-of-the-art 2017 and new therapeutic strategies. AB - Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with an overall 5 year survival of 8% for all stages combined. The majority of patients present with stage IV disease at diagnosis and these patients have an overall 5-year survival of 3%. Currently, the standard of care for metastatic pancreas adenocarcinoma is combination cytotoxic therapy, namely FOLFIRINOX or gemcitabine plus nab-paclitaxel for good performance status patients. Given the challenges and the rising incidence of PDAC expected to become the second leading cause of cancer-related death by 2030, there is a major unmet need to develop more effective therapies. In this setting, the molecular and genomic characterization of PDAC have underpinned the use of targeted therapies. To date, the results from targeted agent evaluation have been disappointing with some exceptions. Novel promising strategies depend on biomarker identification and patient selection e.g. germline mutations in DNA repair or mismatch repair genes, where the addition of a platinum agent or checkpoint inhibitor can have a positive impact on survival. This article will review the state-of-the-art treatment of metastatic pancreatic cancer with an emphasis on novel promising therapeutic strategies and an overview on emerging biomarkers. PMID- 28869889 TI - IL-36 induces cytokine IL-6 and chemokine CXCL8 expression in human lung tissue cells: Implications for pulmonary inflammatory responses. AB - IL-36alpha, IL-36beta and IL-36gamma are cytokine members of IL-1 family. Although IL-36 expression was observed in human lung during pulmonary infections, it remains unknown whether IL-36 could act directly on lung tissue cells during pulmonary inflammatory responses. In this study, we showed that IL-36 receptor was expressed in human lung fibroblasts and bronchial epithelial cells. Correspondingly, IL-36alpha, IL-36beta or IL-36gamma up-regulated gene expression of cytokine IL-6 and chemokine CXCL8 in human lung fibroblasts and bronchial epithelial cells, and promoted IL-6 and CXCL8 release from human lung fibroblasts and bronchial epithelial cells. The production of IL-6 and CXCL8 in these lung tissues cells induced by IL-36alpha, IL-36beta or IL-36gamma was regulated by p38MAPK, ERK or Akt signaling pathways. Taken together, the above results suggest that IL-36-mediated IL-6 and CXCL8 production in human lung fibroblasts and bronchial epithelial cells may be involved in pulmonary inflammation especially caused by bacterial or viral infections. PMID- 28869890 TI - Development of anti-hepatitis B surface (HBs) antibodies after HBs antigen loss in HIV-hepatitis B virus co-infected patients. AB - BACKGROUND: Hepatitis B surface antigen (HBsAg)-seroconversion, or loss of HBsAg and acquisition of anti-hepatitis B surface (HBs) antibodies, defines functional cure of chronic hepatitis B virus (HBV) infection. After HBsAg-loss, little is known regarding the development of anti-HBs antibodies and even less so in individuals co-infected with HIV. OBJECTIVES: To determine anti-HBs antibody kinetics after HBsAg-loss and explore determinants of HBsAg-seroconversion in HIV HBV co-infected patients. STUDY DESIGN: Patients enrolled in the French HIV-HBV cohort were included if they had >1 study visit after HBsAg-loss. Individual patient kinetics of anti-HBs antibody levels were modeled over time using mixed effect non-linear regression, whereby maximum specific growth rate and maximal level of antibody production were estimated from a Gompertz growth equation. RESULTS: Fourteen (4.6%) of 308 co-infected patients followed in the cohort exhibited HBsAg-loss, all of whom were undergoing antiretroviral therapy. Nine (64.3%) of these patients achieved HBsAg-seroconversion during a median 3.0 years (IQR=1.1-5.1) after HBsAg-loss. Across individuals with HBsAg-seroconversion, the fastest rates of antibody growth ranged between 0.57-1.93year-1 (population maximum growth rate=1.02) and antibody production plateaued between 2.09-3.66 log10 mIU/mL at the end of follow-up (population maximal antibody levels=2.66). Patients with HBsAg-seroconversion had substantial decreases in HBV DNA viral loads (P=0.03) and proportion with elevated ALT levels (P=0.02) and HBeAg positive serology (P=0.08). No such differences were observed in those without HBsAg-seroconversion. CONCLUSIONS: Most co-infected patients with HBsAg seroconversion produced and maintained stable antibody levels, yet kinetics of anti-HBs production were much slower compared to those observed post-vaccination or after clearance of acute HBV-infection. PMID- 28869891 TI - Synthesis and biological effect of chrom-4-one derivatives as functional inhibitors of heat shock protein 27. AB - Heat Shock Protein 27 (HSP27) is a member of small heat shock proteins with a highly-conserved alpha-crystalline domain. It inhibits aggregation of damaged proteins through a complex structural systems of phosphorylation-dependent oligomerization and self-assembly. It has been demonstrated that HSP27 is involved in a variety of pathophysiological pathways with negative or positive protective activities. In this study, we synthesized six chromone analogs possessing thiiran-2-ylmethoxy or oxyran-2-ylmethoxy substituents and evaluated their biological activities against HSP27 protein. Compounds YK598-2, J4 and J2 induced significant abnormal HSP27 dimer formation in NCI-H460, a human lung cancer cell line. In synergistic anticancer activity test, the compounds effectively producing abnormal HSP27 cross-linking remarkably enhanced the antiproliferative activity of 17-AAG, a HSP90 inhibitor. Target specificity test using the HSP27-silenced cells (shHSP27) showed that compounds YK598-2, J4, and J2 significantly lost their cross-linking activity only under conditions when HSP27 was deprived of. In the evaluation of cancer cell sensitization with cisplatin, cisplatin-induced lung cancer cell growth inhibition was sensitized with statistical significance by J4 and J2 as compared to compound alone treatment. These results suggest that abnormal HSP27 dimerization can be an efficient control point for cancer cell proliferation and chromone compounds might have potential as anticancer agents that modulate abnormal HSP27 dimerization. PMID- 28869892 TI - Combination lung cancer chemotherapy: Design of a pH-sensitive transferrin-PEG-Hz lipid conjugate for the co-delivery of docetaxel and baicalin. AB - The aim of the present study is to design a novel dual-ligand lipid based nanoparticle system. It is conducted by a specific ligand and pH sensitive lipid conjugate. Docetaxel (DTX) and baicalein (BA) are co-delivered by this system for combination lung cancer chemotherapy. Firstly, transferrin (Tf)-polyethylene glycol (PEG)-hydrazone (hz)-glyceryl monostearate (GMS), Tf-PEG-hz-GMS, was synthesized. Tf decorated DTX and BA loaded solid lipid nanoparticles (Tf-D/B SLNs) were prepared by emulsification method. The capability of Tf-D/B-SLNs in suppressing lung cancer cells in vitro and in vivo was investigated. The results revealed the better antitumor efficiency of Tf-D/B-SLNs than the non-decorated SLNs and single drug loaded SLNs. Significant synergistic effects were observed in the dual drugs loaded systems. The best tumor inhibition ability and the lowest systemic toxicity also proved the pH-sensitive co-delivery nano-system could be a promising strategy for treatment of lung cancer. PMID- 28869893 TI - Antioxidant and glucose metabolizing potential of edible insect, Brachytrupes orientalis via modulating Nrf2/AMPK/GLUT4 signaling pathway. AB - Brachytrupes orientalis (Gryllidae) is a common edible insect species eaten by the different tribes of North East India. This study investigated the potentiality of Brachytrupes orientalis extracts in different solvent hydro alcoholic (AEBO), hexane (HEBO) and ethyl acetate (EEBO) on glucose utilization and cell viability in high glucose (HG) treated myotubes. It has been observed that AEBO supplementation significantly increased the glucose utilization against HG exposure; however, treatment HEBO and EEBO have no significant effect. AEBO also increased the intercellular glucose-6-phosphate level and the protein expression of both phospho-AMPK and GLUT4 in HG treated myotubes in a dose dependent manner. Furthermore, supplementation with AEBO decreased the intercellular ROS production, lipid peroxidation, and up-regulated the protein expression of Nrf2 and GST. Chromatography and Spectroscopic analyses of AEBO also suggest that Ursolic acid may be one of the bioactive principles with rich potassium, sodium, calcium and magnesium content. PMID- 28869894 TI - SPOCK1 promotes the growth of Osteosarcoma cells through mTOR-S6K signaling pathway. AB - SPOCK1 belongs to the SPARC family, which plays an important role in proliferation, invasion and migration of various tumour cells. However, the functions of SPOCK1 in osteosarcoma cell growth and proliferation have not been fully elucidated. In the present study, we found that SPOCK1 is significantly upregulated in osteosarcoma tissue. Moreover, overexpression of SPOCK1 was associated with tumour size, metastasis, Enneking stage and pathological degree. Furthermore, knockdown of SPOCK1 expression suppressed the growth of osteosarcoma cells in vitro and reduced tumourigenicity in nude mice in vivo. Additionally, our data suggest that inactivation of the mTOR-S6K signaling pathway participated in inhibition of SPOCK1-mediated suppression of osteosarcoma cell growth. These findings represent a novel pathogenetic mechanism of osteosarcoma development that provides a potential target for therapeutic strategies for osteosarcoma. PMID- 28869896 TI - Proteomic approaches for drug discovery against tegumentary leishmaniasis. AB - Tegumentary leishmaniases (TL) comprise various clinical forms, in which current therapeutic treatments lack in safety and efficacy. Recently the parasite is developing resistance mechanisms against anti leishmanial drugs startling the scientific community to recruit efforts to search for novel therapeutics. Proteomics hold promises for the treatment of leishmaniasis and investigation of parasite-host interaction since these set of methodological tools have provided a wealth of protein expression data on several Leishmania species. Firstly this review puts together the current treatment and challenges to fight tegumentary leishmaniasis. In addition, the 2 dimensional gel electrophoresis and mass spectrometry techniques in protein identification and characterization are described and discussed in the context of proteomics regarding Leishmania studies. In this review, we selected literature content on TL causative agents. Important proteomic findings related to differentiation proteome (promastigote and amastigote forms), Leishmania-macrophage interaction proteome and secreted and soluble proteins including molecules involved in parasite resistance and potential drug targets are examined and discussed. We also highlight open questions regarding drug research that can be addressed with proteomics approaches. PMID- 28869895 TI - The biochemical effects of nano tamoxifen and some bioactive components in experimental breast cancer. AB - The effect of nano tamoxifen and some bioactive components such as yeast, isoflavone, and silymarin on the level of resistance and prevention of breast cancer progression in experimental animals is the target of this study. Thirty female Sprague-Dawley rats received a single medication dosage of 7,12 dimethylbenz[a]anthracene (DMBA) intragastrically. After fourteen days of DMBA admission, the procedure protocol started out. Finally, all the experimental results evaluated, tabulated and statistically analyzed. The results demonstrated a highly significant elevation in the 8-OHdG level in group 1 (nano yeast) and 3 (nano silymarin) while the results demonstrated a highly significant reduction in group 2 (nano tamoxifen). The apoptosis results demonstrated a significant elevation in group 3 (nano silymarin) where appeared significant reduction in group 4 (nano isoflavone). ErbB-2 results demonstrated a significant elevation in group 2 (nano tamoxifen) and a significant reduction in each of group 3 (nano silymarin) and 4 (nano isoflavone). The lipid peroxide level demonstrated an extremely significant reduction in group 4 (nano isoflavone). And a significant reduction of total antioxidant was observed in group 3 (nano silymarin) in comparison to injected animals control. This may be considered a new vision and strategy to resist breast cancer disease or prevent progression. PMID- 28869897 TI - Thalidomide alleviates postoperative pain and spatial memory deficit in aged rats. AB - Pain is a major risk factor of post-operative cognitive dysfunction (POCD) in aged population. We investigated the effects of thalidomide, an anti-inflammatory and analgesic drug, on POCD in aged rats, and also explored the underlying mechanisms. Laparotomy was performed under anesthesia in aged rats (24-25 months) to establish POCD models. Thalidomide (5-50mg/kg) was intraperitoneally administered immediately after laparotomy. Within 12h after the operation, pain symptoms were assessed by rat grimace scale (RGS). Within postoperative day (POD) 3-14, spatial memory was evaluated using performance errors in a radial arm maze. Protein levels of inflammatory cytokines and N-methyl-D-aspartate (NMDA) receptors were measured on POD 14. POCD rats treated with thalidomide showed decreased RGS and performance errors, compared with saline-treated POCD rats. Single administration of thalidomide significantly reduced production of cytokines (tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta) in serum but not in the brain, and attenuated upregulation of NMDA receptor (NR) 2A/B subunits in the hippocampus at POD 14. MK-801 abolished thalidomide-induced attenuation of spatial memory deficits. Our results support that thalidomide could disrupt the development of post-operative memory deficit in aged rats through its long-term regulation of NMDA receptors (NRs) in the hippocampus. Therefore, thalidomide might provide a new means to prevent the development of POCD. PMID- 28869899 TI - A deep convolutional neural network model to classify heartbeats. AB - The electrocardiogram (ECG) is a standard test used to monitor the activity of the heart. Many cardiac abnormalities will be manifested in the ECG including arrhythmia which is a general term that refers to an abnormal heart rhythm. The basis of arrhythmia diagnosis is the identification of normal versus abnormal individual heart beats, and their correct classification into different diagnoses, based on ECG morphology. Heartbeats can be sub-divided into five categories namely non-ectopic, supraventricular ectopic, ventricular ectopic, fusion, and unknown beats. It is challenging and time-consuming to distinguish these heartbeats on ECG as these signals are typically corrupted by noise. We developed a 9-layer deep convolutional neural network (CNN) to automatically identify 5 different categories of heartbeats in ECG signals. Our experiment was conducted in original and noise attenuated sets of ECG signals derived from a publicly available database. This set was artificially augmented to even out the number of instances the 5 classes of heartbeats and filtered to remove high frequency noise. The CNN was trained using the augmented data and achieved an accuracy of 94.03% and 93.47% in the diagnostic classification of heartbeats in original and noise free ECGs, respectively. When the CNN was trained with highly imbalanced data (original dataset), the accuracy of the CNN reduced to 89.07%% and 89.3% in noisy and noise-free ECGs. When properly trained, the proposed CNN model can serve as a tool for screening of ECG to quickly identify different types and frequency of arrhythmic heartbeats. PMID- 28869898 TI - 3-O-Glucosylation of quercetin enhances inhibitory effects on the adipocyte differentiation and lipogenesis. AB - Glycosylation of natural flavonoids with various sugar moieties can affect their physicochemical and pharmacological properties. In this study, the plant flavonoids quercetin aglycon (Quer) and quercetin 3-O-glucoside (Q3G) were evaluated and compared for their potential anti-obesity effects. The Q3G dose dependently reduced the TG contents and lipid accumulation in 3T3-L1 adipocyte cells, by 52% and 60% at 20MUM, respectively, compared to differentiated control (100%), which were 1.6-fold and 2.4-fold higher reduction than Quer. The Q3G (20MUM) also more significantly reduced the expression of adipogenic markers such as C/EBP-beta, C/EBP-alpha, PPAR-gamma, and aP2 than Quer, indicating that the Q3G suppresses both adipocyte differentiation and lipogenesis more effectively than Quer in vitro. Comparing to those in the high-fat diet (HFD) fed mice control group for 10 weeks, both the body and liver weights and the size of adipocytes in epididymal adipose tissues were significantly reduced in HFD mice fed with Q3G for another 6 weeks (30mg/kg body weight by oral administration), accompanied by the reductions of TG, total cholesterol, and HDL-cholesterol in serum. The Q3G also reduced the levels of the lipid metabolism-associated proteins, PPAR-gamma, SREBP-1c, and FAS in the liver tissues. These results clearly demonstrated that Q3G exhibits a stronger anti-obesity effect than Quer and its anti-obesity effect is mediated via inhibition of adipocyte differentiation and lipogenesis, decreasing serum lipid levels by altering hepatic lipid metabolism, and reducing body weight gain. The results of this study suggest that the Q3G, but not Quer, can be a potent functional ingredient of beneficial health foods or a therapeutic agent to prevent or treat obesity. PMID- 28869900 TI - Integration of RNA-Seq and RPPA data for survival time prediction in cancer patients. AB - Integration of several types of patient data in a computational framework can accelerate the identification of more reliable biomarkers, especially for prognostic purposes. This study aims to identify biomarkers that can successfully predict the potential survival time of a cancer patient by integrating the transcriptomic (RNA-Seq), proteomic (RPPA), and protein-protein interaction (PPI) data. The proposed method -RPBioNet- employs a random walk-based algorithm that works on a PPI network to identify a limited number of protein biomarkers. Later, the method uses gene expression measurements of the selected biomarkers to train a classifier for the survival time prediction of patients. RPBioNet was applied to classify kidney renal clear cell carcinoma (KIRC), glioblastoma multiforme (GBM), and lung squamous cell carcinoma (LUSC) patients based on their survival time classes (long- or short-term). The RPBioNet method correctly identified the survival time classes of patients with between 66% and 78% average accuracy for three data sets. RPBioNet operates with only 20 to 50 biomarkers and can achieve on average 6% higher accuracy compared to the closest alternative method, which uses only RNA-Seq data in the biomarker selection. Further analysis of the most predictive biomarkers highlighted genes that are common for both cancer types, as they may be driver proteins responsible for cancer progression. The novelty of this study is the integration of a PPI network with mRNA and protein expression data to identify more accurate prognostic biomarkers that can be used for clinical purposes in the future. PMID- 28869901 TI - Transtibial Prosthetic Socket Shape in a Developing Country: A study to compare initial outcomes in Pressure Cast hydrostatic and Patella Tendon Bearing designs. AB - This study compared the physical function and comfort level of patients with unilateral transtibial amputation after being fitted with a hand-cast Patella Tendon Bearing (PTB) socket and a pressure-cast (PCAST) hydrocast socket. The latter technique aims to reduce the skill dependency currently required for socket manufacture and fit. The study was conducted at the Vietnamese Training Centre for Orthopaedic Technologies and involved seventeen Vietnamese participants with unilateral transtibial amputation, all of whom were long term users of prosthetics. All participants were fitted with two sockets manufactured using both hand-cast and PCAST techniques with International Committee of the Red Cross components. Walking tests (timed up and go test and six-minute-walk-test), spatio-temporal gait analyses and subjective comfort assessments were completed after a short acclimatisation period with each socket. The participant-preferred socket was also noted. No significant differences were found for the measures of mobility, functional capacity, spatio-temporal gait parameters, gait symmetry, perceived comfort or participant socket preference. The results show the initial patient outcomes are similar when participants are fitted with a hand-cast PTB socket and a PCAST hydrocast sockets. Future work should confirm these findings in a longer trial. PMID- 28869902 TI - Acute effects of anesthetic lumbar spine injections on temporal spatial parameters of gait in individuals with chronic low back pain: A pilot study. AB - This study examined whether epidural injection-induced anesthesia acutely and positively affected temporal spatial parameters of gait in patients with chronic low back pain (LBP) due to lumbar spinal stenosis. Twenty-five patients (61.7+/ 13.6years) who were obtaining lumbar epidural injections for stenosis-related LBP participated. Oswestry Disability Index (ODI) scores, Medical Outcomes Short Form (SF-36) scores, 11-point Numerical pain rating (NRSpain) scores, and temporal spatial parameters of walking gait were obtained prior to, and 11-point Numerical pain rating (NRSpain) scores, and temporal spatial parameters of walking gait were obtained after the injection. Gait parameters were measured using an instrumented gait mat. Patients received transforaminal epidural injections in the L1-S1 vertebral range (1% lidocaine, corticosteroid) under fluoroscopic guidance. Patients with post-injection NRSpain ratings of "0" or values greater than "0" were stratified into two groups: 1) full pain relief, or 2) partial pain relief, respectively. Post-injection, 48% (N=12) of patients reported full pain relief. ODI scores were higher in patients with full pain relief (55.3+/-21.4 versus 33.7 12.8; p=0.008). Post-injection, stride length and step length variability were significantly improved in the patients with full pain relief compared to those with partial pain relief. Effect sizes between full and partial pain relief for walking velocity, step length, swing time, stride and step length variability were medium to large (Cohen's d>0.50). Patients with LBP can gain immediate gait improvements from complete pain relief from transforaminal epidural anesthetic injections for LBP, which could translate to better stability and lower fall risk. PMID- 28869903 TI - Biomechanical differences between cases with suspected chronic exertional compartment syndrome and asymptomatic controls during running. AB - Chronic exertional compartment syndrome (CECS) has been hypothesised, following clinical observations, to be the result of abnormal biomechanics predominantly at the ankle. Treatment of CECS through running re-education to correct these abnormalities has been reported to improve symptoms. However no primary research has been carried out to investigate the movement patterns of those with CECS. This study aimed to compare the running kinematics and muscle activity of cases with CECS and asymptomatic controls. 20 men with bilateral symptoms of CECS of the anterior compartment and 20 asymptomatic controls participated. Barefoot and shod running 3D kinematics and muscle activity of the left and right legs; and anthropometry were compared. Cases displayed less anterior trunk lean and less anterior pelvic tilt throughout the whole gait cycle and a more upright shank inclination angle during late swing (peak mean difference 3.5 degrees , 4.1 degrees and 7.3 degrees respectively). Cases demonstrated greater step length and stance time, although this was not consistent across analyses. There were no consistent differences in Tibialis anterior or Gastrocnemius medialis muscle activity. Cases were heavier (mean difference 7.9kg, p=0.02) than controls with no differences in height (p>0.05) These differences only partially match the clinical observations previously described. However, no consistent differences were found at the ankle joint suggesting that current running re-education interventions which focus on adjusting ankle kinematics are not modifying pathological aspects of gait. The longer step length is a continuing theme in this population and as such may be a key component in the development of CECS. PMID- 28869904 TI - The impact of democracy and media freedom on under-5 mortality, 1961-2011. AB - Do democracies produce better health outcomes for children than autocracies? We argue that (1) democratic governments have an incentive to reduce child mortality among low-income families and (2) that media freedom enhances their ability to deliver mortality-reducing resources to the poorest. A panel of 167 countries for the years 1961-2011 is used to test those two theoretical claims. We find that level of democracy is negatively associated with under-5 mortality, and that that negative association is greater in the presence of media freedom. These results are robust to the inclusion of country and year fixed effects, time-varying control variables, and the multiple imputation of missing values. PMID- 28869905 TI - How acceptable are intoxicated behaviors? Discrepancy between personal versus perceived approval. AB - INTRODUCTION: College students report high rates of binge drinking yet they reliably endorse elevated perceptions of drinking by their peers. However, the drinking norms literature offers little insight into how college students think about behaviors exhibited while intoxicated. This study aims to determine (a) if the predicted self-other differences (SODs) are seen among college students with respect to approval of intoxicated behaviors and (b) whether gender and race/ethnicity moderate these differences. We hypothesized that students would perceive others as more approving of intoxicated behaviors than they were themselves, resulting in significant SODs. We also predicted that women would have larger SODs relative to their male counterparts, and minority students would have larger SODs relative to their white counterparts. METHODS: Participants (N=233, 63% female) were recruited from an introductory psychology course at a large public northeastern university. They completed online surveys that assessed demographics, and responded to a list of intoxicated behaviors with ratings of personal approval and perceived peer approval. RESULTS: Perceived others' approval ratings exceeded personal approval ratings for 42 of the 44 different intoxicated behaviors. Women had significantly higher SODs relative to men and differed on personal approval. Non-white students had significantly higher SODs relative to white students, and differed both on personal approval and perceptions of others' approval of intoxicated behaviors. CONCLUSIONS: Consistent SODs were observed in the approval of intoxicated behaviors. These findings may help to inform normative feedback interventions by revealing the potential for normative pressure, especially for non-white students. PMID- 28869906 TI - Association of childhood abuse and prescription opioid use in early adulthood. AB - INTRODUCTION: Previous research has examined the association of childhood abuse with opioid misuse and dependence in adulthood. However, little research has focused specifically on prescription opioids, and no studies have examined associations with prescription opioid use, a potential pathway to later opioid misuse and dependence. The aim of the present study was to examine the association of childhood emotional, physical, and sexual abuse with prescription opioid use in early adulthood. METHODS: We used data from Waves I (12-18years) and IV (24-32years) of the National Longitudinal Study of Adolescent to Adult Health. At Wave IV, respondents reported experiences of childhood abuse occurring prior to age 18years and prescription opioid use in the last four weeks. We conducted multivariable logistic regression to examine associations of childhood abuse with recent prescription opioid use. RESULTS: In multivariable models adjusted for respondent sex, race/ethnicity, age, and socioeconomic status, childhood emotional abuse (OR=1.57, 95% CI 1.29, 1.90), physical abuse (OR=1.46, 95% CI 1.14, 1.87), and any childhood abuse (OR=1.51, 95% CI 1.24, 1.82) were significantly associated with recent prescription opioid use. CONCLUSIONS: Given continued increases in prescription opioid use and opioid-related morbidity and mortality in the U.S., understanding upstream social and environmental factors associated with prescription opioid use is important to strengthening and expanding current prevention and intervention strategies. Future research is needed to examine factors potentially mediating the association between childhood abuse and prescription opioid use in order to provide additional insights for prevention and intervention efforts. PMID- 28869907 TI - Bone comparison identification method based on chest computed tomography imaging. AB - The aim of this study is to examine the usefulness of bone structure extracted data from chest computed tomography (CT) images for personal identification. Eighteen autopsied cases (12 male and 6 female) that had ante- and post-mortem (AM and PM) CT images were used in this study. The two-dimensional (2D) and three dimensional (3D) bone images were extracted from the chest CT images via thresholding technique. The similarity between two thoracic bone images (consisting of vertebrae, ribs, and sternum) acquired from AMCT and PMCT images was calculated in terms of the normalized cross-correlation value (NCCV) in both 2D and 3D matchings. An AM case with the highest NCCV corresponding to a given PM case among all of the AM cases studied was regarded as same person. The accuracy of identification of the same person using our method was 100% (18/18) in both 2D and 3D matchings. The NCCVs for the same person tended to be significantly higher than the average of NCCVs for different people in both 2D and 3D matchings. The computation times of image similarity between the two images were less than one second and approximately 10min in 2D and 3D matching, respectively. Therefore, 2D matching especially for thoracic bones seems more advantageous than 3D matching with regard to computation time. We conclude that our proposed personal identification method using bone structure would be useful in forensic cases. PMID- 28869908 TI - Bioactive ent-kaurane diterpenoids from Isodon rubescens. AB - Seven previously undescribed 7,20-epoxy-ent-kaurane diterpenoids, isojiangrubesins A-G, along with seventeen known ones, were isolated from the aerial parts of Isodon rubescens. Their structures were characterized on the basis of spectroscopic methods and signal-crystal X-ray diffraction. All of these compounds were evaluated for their in vitro cytotoxicity against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). Four isolates exhibited significant inhibitory ability against all cell lines, with IC50 values ranging from 0.5 to 6.5 MUM; They also strongly inhibited NO production in LPS-stimulated RAW264.7 cells. PMID- 28869909 TI - Dietary patterns and depressive symptoms during pregnancy in Japan: Baseline data from the Kyushu Okinawa Maternal and Child Health Study. AB - BACKGROUND: Only one Brazilian study has examined the association between dietary patterns and depressive symptoms during pregnancy. The current cross-sectional study examined this issue in Japan. METHODS: Study subjects were 1744 pregnant women. Between April 2007 and March 2008, information under study was obtained. Dietary patterns were derived from a factor analysis of 33 predefined food groups based on a self-administered diet history questionnaire. Depressive symptoms were defined as a Center for Epidemiological Studies Depression Scale score >= 16. Adjustment was made for age, gestation, region of residence, number of children, family structure, history of depression, family history of depression, smoking, secondhand smoke exposure, employment, household income, education, and body mass index. RESULTS: Three dietary patterns were identified: 'healthy', characterized by high intake of green and yellow vegetables, other vegetables, mushrooms, pulses, seaweed, potatoes, fish, sea products, miso soup, sugar, and shellfish; 'Japanese', characterized by high intake of rice and miso soup; and 'Western', characterized by high intake of beef and pork, processed meat, vegetable oil, chicken, eggs, shellfish, and salt-containing seasonings. The healthy and Japanese patterns were independently inversely associated with depressive symptoms during pregnancy: the adjusted prevalence ratios (95% confidence intervals, P for trend) between extreme quartiles were 0.56 (0.43-0.73, < 0.0001) and 0.72 (0.55-0.94, 0.008), respectively. No association was observed between the Western pattern and depressive symptoms during pregnancy. LIMITATIONS: Information was obtained between the 5th and 39th week of pregnancy. CONCLUSIONS: The healthy and Japanese dietary patterns may be inversely associated with depressive symptoms during pregnancy. PMID- 28869911 TI - Nanoporous PtCo/Co3O4 composites with high catalytic activities toward hydrolytic dehydrogenation of ammonia borane. AB - The design and fabrication of highly active and durable catalysts for the ammonia borane (AB) hydrolysis has been one of significant issues in the application of green and economic hydrogen energy. Nanoporous (NP) PtCo/Co3O4 composites are straightforwardly fabricated by selectively etching Al atoms followed by removing Co atoms from the PtCoAl precursor alloy. By controlling the second-step dealloying, the NP-PtCo/Co3O4 composites evolved into pure nanoporous structure with Co3O4 nanosheets on the surface gradually disappeared as well different Pt/Co ratios resulted. Compared with NP-Pt and pure Co3O4 catalysts, the NP PtCo/Co3O4 composites with different Pt/Co ratios exhibit markedly enhanced catalytic activity for the hydrolysis of AB. NP-Pt40Co60 composite with some Co3O4 nanosheets anchored on the surface shows the higher catalytic activity compared to other several samples with different Pt contents, exhibiting a high initial turnover frequency of 131mol H2 min-1 (mol Pt)-1. Meanwhile, the recyclability tests indicate that NP-Pt40Co60 composite retained 65% of the initial catalytic activity after the fifth run of hydrolysis. Therefore, the high catalytic activity and good durability render the as-made composite as a powerful catalyst candidate for the hydrolytic dehydrogenation of AB in the practical applications. PMID- 28869910 TI - Cognition in depression: Can we THINC-it better? AB - BACKGROUND: Cognitive compromise is a common experience for patients with depression and other mood disorders. Depressed patients sustain deficits in working memory and attentional distortions in emotional processing and negative attention biases, which may contribute to maintaining their depressive state. METHODS: The Mood Assessment and Classification (MAC) Committee comprised academic psychiatrists with clinical expertise in the management of mood disorders. The independently convened committee met to discuss contentious aspects of mood disorders diagnosis and assessment with the express aim of informing clinical practice and future research. RESULTS: The Committee specifically identified cognition as an important aspect for clinicians to consider in the context of depression and mood disorders. This article highlights some of the barriers to assessment and proposes tools that have the potential to be implemented in clinical practice. LIMITATIONS: The conclusions drawn within this article are based on expert opinion. We have noted the limitations of the literature that informs this opinion. CONCLUSIONS: As cognitive ability has been closely linked to patients' ability to achieve functional recovery, it is imperative that clinicians are able to identify patients with cognitive deficits and are equipped with tools to conduct effective cognitive assessments. Examining cognitive factors may generate a deeper understanding of the pathogenesis of depression and mood disorders which can ultimately be used to inform treatment. PMID- 28869912 TI - Well-organized migration of electrons for enhanced hydrogen evolution: Integration of 2D MoS2 nanosheets with plasmonic photocatalyst by a facile ultrasonic chemical method. AB - The construction of a plasmonic photocatalyst is an efficient way to suppress detrimental electrons-holes recombination and extend the spectral range of light absorption in semiconductors. However, the facilitation effect in the aspect of electrons-holes separation is great limited as the lack of a driving force compelled the electrons or holes migration to surface catalytic sites makes them flow randomly in semiconductors. In this work, we confirm that the integration of MoS2 nanosheets formed two dimensional (2D) layered heterojunction with C3N4 with Au-C3N4 plasmonic photocatalyst can further enhance electrons-holes separation through the formation of Au-C3N4-MoS2 nanostructure by a facile ultrasonic chemical method. The integrated MoS2 nanosheets extract the electrons not only from C3N4 due to a building up of 2D layered heterojunction but also from plasmonic Au via a "pipe" played by C3N4. The electrons "pump" role of the 2D MoS2 nanosheets makes electrons flow randomly turn into the well-organized migration direction, promoting the electrons-holes more efficient separation and lifetime prolongation. Meanwhile, MoS2 nanosheets also increase the light absorption of the photocatalyst owing to its inherent strength of the narrower band gap. Enabled by integration of 2D MoS2 nanosheets, the hydrogen production rate is 2.08 times higher than that of its counterpart Au-C3N4. This work highlights a new window to employ 2D layered heterojunction for enhanced photocatalytic hydrogen evolution performance. PMID- 28869913 TI - Modelling of immiscible liquid-liquid systems by Smoothed Particle Hydrodynamics. AB - Immiscible fluid systems are ubiquitous in industry, medicine and nature. Understanding the phase morphologies and intraphase fluid motion is often desirable in many of these situations; for example, this will aid improved design of microfluidic platforms for the production of medicinal formulations. In this paper, we detail a Smoothed Particle Hydrodynamics (SPH) approach that facilitates this understanding. The approach includes surface tension and enforces incompressibility. The approach also allows the consideration of an arbitrary number of immiscible phases of differing viscosities and densities. The nature of the phase morphologies can be arbitrary and change in time, including break-up (which is illustrated) and coalescence. The use of different fluid constitutive models, including non-Newtonian models, is also possible. The validity of the model is demonstrated by applying it to a range of model problems with known solutions, including the Young-Laplace problem, confined droplet deformation under a linear shear field, and a droplet falling under gravity through another quiescent liquid. Results are also presented to illustrate how the SPH model can be used to elucidate the behaviour of immiscible liquid systems. PMID- 28869914 TI - Synthesis of CdSe quantum dots decorated SnO2 nanotubes as anode for photo assisted electrochemical degradation of hydrochlorothiazide: Kinetic process. AB - Pharmaceutical residues have been increasingly detected in the aquatic environment and are considered important contaminants of emerging concern. This study examines the photo assisted electrochemical degradation of the Hydrochlorothiazide by using CdSe quantum dots decorated SnO2 nanotubes. The characteristic devices such as Scanning electron microscopy, X-ray diffraction, UV-vis diffuse reflectance Transmission electron Microscopy were used to analyze information structure of CdSe QDs/SnO2 nanotubes. All the experiments were perform with influence of the current density (10-60mAcm-2) and sodium chloride (0.02-0.10molL-1) in the supporting electrolyte composition was analyzed. The results showed that the Hydrochlorothiazide and TOC removal was achieved in the current density range used. As expected, the degradation kinetics presented a pseudo first order behavior. Comparison of the efficiencies of the photocatalytic, electrochemical (EC) and photo-assisted electrochemical (PAEC) techniques verified that the combined process showed a synergism for HCT and TOC removal. PMID- 28869915 TI - Organization and structure of mixed Langmuir films composed of polydiacetylene and hemicyanine. AB - Mixed Langmuir monolayers of 10,12-Pentacosadiynoic acid (DA) monomer and an amphiphilic Hemicyanine dye derivative have been formed at the air/water interface. Two derivatives of docosylpyridinium have been used, with either one included in the monolayer in 1:1molar ratio. The DA monomers within the mixed monolayers have been polymerized in situ at the air/water interface. The crystalline structure of the monolayer and the kinetics of polymerization have been probed by grazing incidence X-ray diffraction (GIXD). The polymerization of DA proceeds with no phase segregation, exclusively leading to the red polydiacetylene form. The kinetics of polymerization at the air/water interface has been monitored in situ by GIXD. The experimental results have been combined with Molecular Mechanics computer simulations, revealing that DA molecules are sequentially arranged with molecules of Hemicyanine dye in alternating rows. The hydrophobic chains of the dye molecules act as spacers between the DA monomers. Surprisingly, such molecular arrangement does not hinder the in situ photopolymerization of DA. The mechanism of polymerization of DA within the mixed Langmuir monolayers has been convincingly described in molecular detail. This approach for interfacial polymerization of DA holds great potential for optically active devices and nanostructures comprising self-assembled thin films based in polydiacetylene. PMID- 28869916 TI - Electrospun nylon 6,6 membrane as a reusable nano-adsorbent for bisphenol A removal: Adsorption performance and mechanism. AB - Bisphenol A (BPA) is highly considered as an emerging contaminants (ECs) due to their endocrine disrupting and reproductive toxicant nature. It has been detected in drinking water sources in many countries. This study deals with the adsorptive removal of BPA using nylon 6,6 nanofibrous membrane (NNM) fabricated by electrospinning technique. Langmuir and Freundlich isotherm models (R2=0.99) were obeyed for BPA adsorption, which indicates the monolayer adsorption of BPA and also surface heterogeneity of NNM. The adsorption kinetics of BPA was followed pseudo second order rate (R2=0.89-0.99), which suggests the occurrence of rapid adsorption rate through interaction of surface functional groups present in NNM. The maximum adsorption of BPA (91.3mgg-1) was attained at 30 degrees C. The hydroxyl groups of BPA form hydrogen bonding with carbonyl groups of NNM during the adsorptive removal process. Reusability study confirmed a much better stability of NNM in the recyclic application. Finally, this study suggests that NNM might be an outstanding nano-adsorbent for the emerging contaminants removal, including BPA from drinking water sources. PMID- 28869917 TI - Response of soil methane uptake to simulated nitrogen deposition and grazing management across three types of steppe in Inner Mongolia, China. AB - The response of soil methane (CH4) uptake to increased nitrogen (N) deposition and grazing management was studied in three types of steppe (i.e., meadow steppe, typical steppe, and desert steppe) in Inner Mongolia, China. The experiment was designed with four simulated N deposition rates such as 0, 50, 100, and 200kgNha 1, respectively, under grazed and fenced management treatments. Results showed that the investigated steppes were significant sinks for CH4, with an uptake flux of 1.12-3.36kgha-1 over the grass growing season and that the magnitude of CH4 uptake significantly (P<0.05) decreased with increasing N deposition rates. The soil CH4 uptake rates were highest in the desert steppe, moderate in the typical steppe, and lowest in the meadow steppe. Compared with grazed plots, fencing increased the CH4 uptake by 4.7-40.2% with a mean value of 20.2% across the three different steppe types. The responses of soil CH4 uptake to N deposition in the continental steppe varied depending on the N deposition rate, steppe type, and grazing management. A significantly positive correlation between CH4 uptake and soil temperature was found in this study, whereas no significant relationship between soil moisture and CH4 uptake occurred. Our results may contribute to the improvement of model parameterization for simulating biosphere-atmosphere CH4 exchange processes and for evaluating the climate change feedback on CH4 soil uptake. PMID- 28869918 TI - Circulating CD4+PD-1+ and CD8+PD-1+ T cells are profoundly decreased at the onset of fulminant type 1 diabetes and are restored by treatment, contrasting with CD4+CD25+FoxP3+ regulatory T cells. AB - Programed cell death protein-1 (PD-1) is an inhibitory receptor expressed by T cells that downregulates the activation and proliferation of these cells to maintain peripheral self-tolerance. Recent studies reported some cases of new onset type 1 diabetes (T1D) under anti-PD1 or PDL-1 antibodies. We demonstrated that circulating both CD4+PD-1+ and CD8+PD-1+ T cells were profoundly reduced at the onset of fulminant T1D and were restored by treatment in two patients with fulminant T1D. PMID- 28869919 TI - Cardiometabolic health in Asians with diabetes in the US. AB - AIMS: Asians develop diabetes at lower levels of adiposity than people of other race/ethnicities. However, there is limited data investigating the health of US Asians with diabetes. We compared cardiovascular risk factors in US Asians to other race/ethnicities stratified by diabetes status. METHODS: Among 4645 adults in the 2011-2014 National Health and Nutrition Examination Survey (NHANES), a cross-sectional survey of the US population, odds ratios were calculated for obesity, hypertension, and elevated low-density lipoprotein (LDL) cholesterol associated with race/ethnicity after adjustment for age, sex, income, education, smoking, alcohol consumption, and health insurance. RESULTS: Overall and stratified by diabetes status, non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans were significantly more likely to be obese compared to non Hispanic Asians after adjustment. Overall and stratified by diabetes status, adjusted levels of hypertension compared to non-Hispanic Asians was generally similar for non-Hispanic whites and Mexican-Americans and generally more common among non-Hispanic blacks; among those with diagnosed diabetes, the adjusted odds ratios (95% confidence interval) were 1.48 (0.79-2.77), 2.54 (1.49-4.30), and 1.38 (0.73-2.60) for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, respectively. Overall and stratified by diabetes status, elevated LDL cholesterol levels were generally similar between non-Hispanic Asians and other race/ethnicities; among those with diagnosed diabetes, the adjusted odds ratios (95% confidence interval) were 0.88 (0.32-2.43), 0.58 (0.24-1.42), and 1.15 (0.29 4.58) for non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans, respectively. CONCLUSIONS: Although non-Hispanic Asians had lower levels of adiposity compared to other race/ethnicities with diabetes, their adjusted levels of hypertension and LDL cholesterol were generally more comparable. PMID- 28869920 TI - Comparison of direct 13C and indirect 1H-[13C] MR detection methods for the study of dynamic metabolic turnover in the human brain. AB - A wide range of direct 13C and indirect 1H-[13C] MR detection methods exist to probe dynamic metabolic pathways in the human brain. Choosing an optimal detection method is difficult as sequence-specific features regarding spatial localization, broadband decoupling, spectral resolution, power requirements and sensitivity complicate a straightforward comparison. Here we combine density matrix simulations with experimentally determined values for intrinsic 1H and 13C sensitivity, T1 and T2 relaxation and transmit efficiency to allow selection of an optimal 13C MR detection method for a given application and magnetic field. The indirect proton-observed, carbon-edited (POCE) detection method provides the highest accuracy at reasonable RF power deposition both at 4T and 7T. The various polarization transfer methods all have comparable performances, but may become infeasible at 7T due to the high RF power deposition. 2D MR methods have limited value for the metabolites considered (primarily glutamate, glutamine and gamma amino butyric acid (GABA)), but may prove valuable when additional information can be extracted, such as isotopomers or lipid composition. While providing the lowest accuracy, the detection of non-protonated carbons is the simplest to implement with the lowest RF power deposition. The magnetic field homogeneity is one of the most important parameters affecting the detection accuracy for all metabolites and all acquisition methods. PMID- 28869921 TI - A 5-year descriptive study of electroconvulsive therapy at SCARF. PMID- 28869922 TI - A qualitative study of experience of parents of adolescents who received ECT. AB - AIM OF THIS STUDY: To evaluate the experience of parents of adolescents who received ECT for severe mental illness. METHODOLOGY: Using qualitative methods, 6 parents of 5 adolescents were interviewed by using a self-designed semi structured interview after the completion of ECT course. The clinicians involved in the ECT procedure, i.e., seeking informed consent and administration of ECT were not aware about the study. All the interviews were recorded and the content was analysed and themes were generated. RESULTS: Parents of all the 5 adolescents expressed that their children were considered for ECT only after the patient had not responded to medication and were unmanageable. Prior to ECT the treating doctors did explain to them about the ECT procedure, they were given information booklet and they were not coerced to consent for ECT. Some of the parents reported that they had dilemma prior to giving consent and were scared prior to the first ECT. However, as the clinical condition of their children improved, they felt that ECT was a good treatment. Majority of the parents felt that ECT was delayed for their children. When asked about restriction in use of ECT in children and adolescents, the parents expressed that it is important for law makers to understand the distress of the parents,when their children are acutely ill. They expressed that decision of administration of ECT must be left to the family and the treating clinicians. CONCLUSION: Parents of adolescents considered for ECT are generally satisfied with the treatment procedure. PMID- 28869923 TI - Infant, maternal, and familial predictors and correlates of regulatory problems in early infancy: The differential role of infant temperament and maternal anxiety and depression. AB - BACKGROUND: Excessive infant crying, feeding and sleeping problems are likely to emerge from the complex interplay of various factors. AIMS: To investigate the role of infant (e.g., temperament), maternal (e.g., anxiety and depressive disorders), and familial (e.g., social support) factors as potential precursors of infant regulatory problems. STUDY DESIGN: Prospective-longitudinal study. SUBJECTS: 286 mother-infant dyads were investigated from early pregnancy until 16 months postpartum via questionnaires and interviews. OUTCOME MEASURES: Regulatory problems at 2, 4 and 16 months postpartum assessed by standardized diagnostic interviews. RESULTS: Fussy infant temperament and maternal anxiety disorders were associated with excessive infant crying (OR=1.16, 95%CI:1.05-1.29, OR=3.28, 95%CI:1.16-9.26) and feeding problems (OR=1.05, 95%CI:1.01-1.11, OR=2.27, 95%CI:1.36-3.80) whereas maternal depressive disorders were associated with infant sleeping problems (OR=2.55, 95%CI:1.06-6.11). Moreover, high maternal age (OR=0.86, 95%CI:0.75-0.98) was associated with a lower risk for excessive crying and being a single mother (OR=0.16, 95%CI:0.03-0.73) and cognitive reappraisal to regulate emotions (OR: 0.59, 95%CI:0.36-0.96) was associated with a lower risk for sleeping problems. CONCLUSION: Excessive infant crying and feeding problems may be related to interactional deficits of anxious mothers who perceive their infants as "difficult" during soothing or feeding situations. Sleeping problems may be transmitted already during pregnancy by an altered sleep-wake-rhythm of mothers with a history of depression or by a genetic predisposition. Therapeutic interventions should focus on maternal anxiety and depression, behavior management techniques to cope with difficult situations with "fussy" infants and potential protective factors (e.g. favorable maternal emotion regulation) to address crying, feeding and sleeping problems. PMID- 28869924 TI - Methylisothiazolinone toxicity and inhibition of wound healing and regeneration in planaria. AB - Methylisothiazolinone (MIT) is a common biocide used in cosmetic and industrial settings. Studies have demonstrated that MIT is a human sensitizer, to the extent that in 2013 MIT was named allergen of the year. Recently, we showed that MIT exposure in Xenopus laevis (the African clawed frog) inhibits wound healing and tail regeneration. However, it is unknown whether MIT affects these processes in other animals. Here, we investigated the effects of MIT exposure in planaria-non parasitic freshwater flatworms able to regenerate all tissues after injury. Using a common research strain of Dugesia japonica, we determined that intact planarians exposed to 15MUM MIT displayed both neuromuscular and epithelial integrity defects. Furthermore, regenerating (head and tail) fragments exposed to 15MUM MIT failed to close wounds or had significantly delayed wound healing. Planarian wounds normally close within 1h after injury. However, most MIT-exposed animals retained open wounds at 24h and subsequently died, and those few animals that were able to undergo delayed wound healing without dying exhibited abnormal regeneration. For instance, head regeneration was severely delayed or inhibited, with anterior structures such as eyes failing to form in newly produced tissues. These data suggest that MIT directly affects both wound healing and regeneration in planarians. Next, we investigated the ability of thiol-containing antioxidants to rescue planarian wound closure during MIT exposure. The data reveal both n acetyl cysteine and glutathione were each able to fully rescue MIT inhibition of wound healing. Lastly, we established MIT toxicity levels by determining the LC50 of 5 different planarian species: D. japonica, Schmidtea mediterranea, Girardia tigrina, Girardia dorotocephala, and Phagocata gracilis. Our LC50 data revealed that concentrations as low as 39MUM (4.5ppm) are lethal to planarians, with concentrations of just 5MUM inhibiting wound healing, and suggest that phylogeny is predictive of species toxicity levels. Together these results indicate MIT may have broad wound healing effects on aquatic species in general and are not limited to X. laevis alone. Future studies should investigate the impact of MIT on wound healing in other organisms, including non-aquatic organisms and mammals. PMID- 28869925 TI - Cadmium stress assessment based on the electrocardiogram characteristics of zebra fish (Danio rerio): QRS complex could play an important role. AB - The electrocardiogram (ECG) of zebra fish (Danio rerio) expresses cardiac features that are similar to humans. Here we use sharp microelectrode measurements to obtain ECG characteristics in adult zebra fish and analyze the effects of cadmium chloride (CdCl2) on the heart. We observe the overall changes of ECG parameters in different treatments (0.1 TU, 0.5 TU and 1.0 TU CdCl2), including P wave, Q wave, R wave, S wave, T wave, PR interval (atrial contraction), QRS complex (ventricular depolarization), ST segment, and QT interval (ventricular repolarization). The trends of the ECG parameters showed some responses to the concentration and exposure time of CdCl2, but it was difficult to obtain more information about the useful indicators in water quality assessment depending on tendency analysis alone. A self-organizing map (SOM) showed that P values, R values, and T values were similar; R wave and T wave amplitude were similar; and most important, QRS value was similar to the CdCl2 stress according to the classified data patterns including CdCl2 stress (E) and ECG components based on the Ward linkage. It suggested that the duration of QRS complex was related to environmental stress E directly. The specification and evaluation of ECG parameters in Cd2+ pollution suggested that there is a markedly significant correlation between QRS complex and CdCl2 stress with the highest r (0.729) and the smallest p (0.002) among all ECG characteristics. In this case, it is concluded that QRS complex can be used as an indicator in the CdCl2 stress assessment due to the lowest AIC data abased on the linear regression model between the CdCl2 stress and ECG parameters. PMID- 28869926 TI - Outer, inner and planar polarity in the Arabidopsis root. AB - Plant roots control uptake of water and nutrients and cope with environmental challenges. The root epidermis provides the first selective interface for nutrient absorption, while the endodermis produces the main apoplastic diffusion barrier in the form of a structure called the Casparian strip. The positioning of root hairs on epidermal cells, and of the Casparian strip around endodermal cells, requires asymmetries along cellular axes (cell polarity). Cell polarity is termed planar polarity, when coordinated within the plane of a given tissue layer. Here, we review recent molecular advances towards understanding both the polar positioning of the proteo-lipid membrane domain instructing root hair initiation, and the cytoskeletal, trafficking and polar tethering requirements of proteins at outer or inner plasma membrane domains. Finally, we highlight progress towards understanding mechanisms of Casparian strip formation and underlying endodermal cell polarity. PMID- 28869927 TI - Improved Drug Adherence in Patients with Chronic Myeloid Leukemia in the Chronic Phase by Switching to Second-Generation Tyrosine Kinase Inhibitors. PMID- 28869929 TI - Editorial. PMID- 28869928 TI - Atypical Uterine Smooth Muscle Tumors: A Retrospective Evaluation of Clinical and Pathologic Features. AB - BACKGROUND: Clinical characteristics combined with new biomarkers help discriminate between atypical uterine smooth muscle tumors (AUSMT) and leiomyosarcomas (LMS). PATIENTS AND METHODS: We retrospectively collected a series of leiomyomas (LM), AUSMT, and LMS. Estrogen receptors (ER), progesterone receptors (PR), p16, Ki-67, and p53 expression were assessed by immunohistochemistry. For AUSMT patients, immunohistochemistry evaluations were performed at the time of diagnosis and at recurrences. RESULTS: A total of 27 cases of AUSMT, 22 LM, and 31 LMS were identified. The expression of ER and PR decreased from LM to LMS (ER+: LM 95.5%, AUSMT 88.9%, LMS 41.9%, p < 0.001; PR+: LM 100%, AUSMT 88.9%, LMS 38.2%, p = 0.002). By contrast, p16 and p53 expression increased (p16+: LM 4.5%, AUSMT 40.7%, LMS 45.2%, p = 0.004; p53: LM 9.1%, AUSMT 33.3%, LMS 58.1%, p = 0.001). At a median follow-up of 33.47 months, 40.7% of patients with AUSMT experienced recurrent disease, 6 patients relapsed as AUSMT and 5 as LMS. In univariate analysis was observed that ER status (p = 0.027) and p53 expression (p = 0.015) predicted risk of relapse. CONCLUSIONS: Treatment of AUSMT should be centralized in dedicated centers. International collaborations are needed to optimize research strategy, which may lead to the identification of new useful biomarkers and to improvement in the clinical management of this rare disease. PMID- 28869930 TI - Uremic Restless Legs Syndrome Pleads "Not Guilty". PMID- 28869931 TI - A Phase II Exploratory Study of PXD-101 (Belinostat) Followed by Zevalin in Patients with Relapsed Aggressive High-Risk Lymphoma. AB - OBJECTIVE: Aggressive lymphomas (aNHL) including diffuse large B-cell lymphoma (DLBCL) have poor outcomes in relapsed refractory patients. Prior studies have demonstrated that loss of major histocompatibility complex class II (MHCII) expression in DLBCL is associated with poor survival. The objective of this single-arm phase II study was to evaluate if PXD-101 would increase MHCII expression, synergize with Zevalin, and improve clinical outcomes. METHODS: This was a single-center open-label phase II trial (NCT01686165) geared toward heavily pretreated patients with CD20-positive aNHL. The primary endpoint was overall response rate (ORR) in aNHL patients treated with 2 cycles of PXD-101 followed by restaging CT and 1 cycle of Zevalin. RESULTS: Five patients were enrolled, and all were heavily pretreated. Therapy was well tolerated, with nausea and vomiting being the most frequent adverse events. All patients progressed after receiving therapy; the study did not achieve the required ORR to proceed to the next stage. CONCLUSION: The pleotropic effects of histone deacetylase inhibition and lack of clinical biomarkers have precluded a priori identification of responding patients. Thus, while we report a negative trial of PXD-101 in combination with Zevalin, this study highlights the importance of a clinically feasible biomarker. PMID- 28869932 TI - Pirfenidone in Idiopathic Pulmonary Fibrosis "RECAP-itulating Safety into the Real World". PMID- 28869933 TI - [Die therapeutische Wirksamkeit westlicher Atemtherapiemethoden: Ein systematischer Review]. PMID- 28869934 TI - Typical Hemodialysis in India: A Case Report. AB - We report here a typical case of a patient on hemodialysis (HD) for end-stage renal disease (ESRD) in India that highlights some of the management issues encountered in a country with an enormous burden of ESRD and major challenges of underdialysis and management of comorbidities. The patient, a 42-year-old multiparous woman with chronic kidney disease (CKD) stage V, type 2 diabetes mellitus, and hypertension is a homemaker from a middle-class family, living in a large city, with no family history of CKD. From May 2013 to December 2016, she has been receiving twice-weekly maintenance HD for 4 h (intermittent HD); access was via an internal jugular line initially and then via a left brachiocephalic arteriovenous fistula (AVF) from late June 2013. Medical problems in this patient included poor medication and dietary compliance, underdialysis, anemia, volume overload, congestive cardiac failure with recurrent pulmonary edema, and hypertensive crisis. In December 2016, she complained of pain in the fistula arm during dialysis, and in January 2017, she developed edema of the arm. Specific endovascular intervention with balloon angioplasty resulted in a resolution of the stenosis of the venous side of the AVF and the edema. Counselling for dietary compliance and drug adherence resulted in good blood pressure control. Unlike in most other dialysis units, we have been able to increase her HD to thrice weekly and institute several ancillary services, including skilled dietary counselling, cardiac care, and regular bioimpedance analysis with favorable outcomes. Thus, a multidisciplinary team approach offering such ancillary services would allow for better management and improved outcomes in patients with ESRD in resource-poor settings. PMID- 28869935 TI - Fetal Aneuploidy: A Comparison of Dichorionic Twins and Monochorionic Twins. AB - OBJECTIVE: To assess the clinical characteristics of fetal aneuploidy between dichorionic twins (DCT) and monochorionic twins (MCT) undergoing invasive prenatal diagnosis. METHODS: Twin fetuses undergoing invasive prenatal diagnosis were enrolled in this study. All twin fetuses were classified into 2 groups according to chorionicity. The rates of fetal aneuploidy in different groups were compared. RESULT: This study included 1,714 fetuses (857 sets of twin pairs); among them, 1,190 were DCT and 524 were MCT. Overall, the rate of aneuploidy was 4.7% (56/1,190) in DCT and 3.4% (18/524) in MCT. Sixty-four (86.5%, 64/74) fetal aneuploidies occurred in only one fetus of the twin pairs. In DCT, the most common aneuploidy was trisomy 21 (53.6%, 30/56), followed by trisomy 18 (21.4%, 12/56) and trisomy 13 (8.9%, 5/56), while in MCT, the most common aneuploidy was Turner syndrome (33.3%, 6/18), followed by trisomy 21 (27.7%, 5/18) and 47,XYY (11.0%, 2/18). CONCLUSION: Aneuploidy mostly occurred in only one fetus in the twin pairs. The most common aneuploidy was trisomy 21 in DCT and Turner syndrome in MCT. Dual amniocentesis should be performed when discordant monozygotic twins are suspected. PMID- 28869937 TI - Prospects for Vascular Access Education in Developing Countries: Current Situation in Cambodia. AB - We report our activities training doctors on vascular access procedures at International University (IU) Hospital in Cambodia through a program facilitated by Ubiquitous Blood Purification International, a nonprofit organization that provides medical support to developing countries in the field of dialysis medicine. Six doctors from Japan have been involved in the education of medical personnel at IU, and we have collectively visited Cambodia about 15 times from 2010 to 2016. In these visits, we have performed many operations, including 42 for arteriovenous fistula, 1 arteriovenous graft, and 1 percutaneous transluminal angioplasty. Stable development and management of vascular access is increasingly required in Cambodia due to increased use of dialysis therapy, and training of doctors in this technique is urgently required. However, we have encountered several difficulties that need to be addressed, including (1) the situation of personnel receiving this training, (2) problems with facilities, including medical equipment and drugs, (3) financial limitations, and (4) problems with management of vascular access. PMID- 28869936 TI - Synergistic Effect of Baicalin and Adriamycin in Resistant HL-60/ADM Leukaemia Cells. AB - BACKGROUND/AIMS: The present study was designed to investigate the expression of multidrug resistance (MDR)-related genes, verify the synergistic effects of baicalin and Adriamycin (ADM) and investigate the related mechanisms in ADM resistant leukaemic HL-60/ADM cells. METHODS: We used a HL-60/ADM cell line. Cytotoxicity and flow cytometry assays were employed to verify the cytotoxic effects of baicalin. Real-time polymerase chain reaction and Western blotting assays were used to assess the expression of MDR-related genes and the changes in gene expression (both MDR-related and PI3K/Akt pathway-related) induced by administration of baicalin. RESULTS: We found that only multidrug resistance protein 1 (MRP1), lung resistance-related protein (LRP) and Bcl-2 genes were expressed in both HL-60 and HL-60/ADM cells. HL-60/ADM cells exhibited significantly higher expression (p < 0.05). We also observed that low-dose baicalin (5 and 10 umol/L) can induce growth inhibition and apoptotic effects on HL-60/ADM cells by increasing the intracellular accumulation of ADM. The synergistic effect of baicalin and ADM was verified. Concerning the potential mechanisms involved in this process, we showed that baicalin down-regulated the expression of several MDR-related and PI3K/Akt pathway-related genes. CONCLUSIONS: We confirmed the increased expression of MRP1, LRP and Bcl-2 genes in HL-60/ADM cells compared to regular HL-60 cells, which are recommended for future investigation on MDR. The present study provided evidence of the synergistic effect of baicalin and ADM in HL-60/ADM cells. Therefore, baicalin may be considered as a potential therapeutic agent against resistant leukaemia. Suppression of the PI3K/Akt signalling pathway, followed by inhibition of the expression of MDR-related genes may be a common mechanism in combination treatments with ADM for the reduction of resistance to ADM. PMID- 28869938 TI - Mineral and Bone Disorder in Chronic Kidney Disease: A Case Report from Vietnam. AB - We report a case of calcium pyrophosphate dihydrate deposition disease (CPDD) involving a patient on maintenance hemodialysis (MHD). The 32-year-old man presented in August 2016 with a complaint of left shoulder swelling of 8 months' duration with no trauma or fever. He was diagnosed with nephrotic syndrome in 1998, which progressed to ESRD. He commenced MHD in 2012. Examination at our hospital revealed a soft nontender swelling of the left shoulder. Blood biochemistry showed elevated serum urate, phosphate, beta2 microglobulin, and parathyroid hormone. Imaging revealed joint effusion and dense heterogenous deposition. Aspirate analysis showed urate crystals 3+, and culture yielded no growth. Following rheumatology review, the working diagnosis was periarticular tissue tuberculosis, after excluding pseudogout and amyloidosis. Following 1 month of colchicine and allopurinol, synovial fluid microscopy showed CPDD crystals. Symptoms gradually resolved over the course of 6 months. In this rare case, a diagnosis of CPDD was made with a multidisciplinary approach that included imaging and biochemical investigations. PMID- 28869940 TI - Severe Secondary Hyperparathyroidism in a Hemodialysis Patient: A Case Report from Mongolia. AB - Secondary hyperparathyroidism (SHPT) occurs in patients with chronic renal failure complicated with renal bone disease and soft tissue/vascular calcification. In dialysis patients with severe SHPT, medical treatment may fail and parathyroidectomy (PTX) is indicated for definitive treatment. Severe hypocalcemia from hungry bone disease or postoperative hypoparathyroidism may occur during the postoperative period. We report here a case of severe SHPT in a hemodialysis patient treated with phosphate binders, calcitriol, and calcimimetics but who still required PTX. Severe hypocalcemia with muscle cramps occurred postoperatively. Around 1 year after PTX, anemia and features of SHPT have improved but the patient still has intermittent hypocalcemia with suspected postoperative hypoparathyroidism. Regular comprehensive assessment of calcium and phosphorus levels throughout all stages of chronic kidney disease is vital. The postoperative period of PTX in SHPT patients is critical, requiring monitoring to improve management. PMID- 28869939 TI - Survival of Dialysis Patients with Restless Legs Syndrome: A 15-Year Follow-Up Study. AB - BACKGROUND: Restless legs syndrome, also known as Willis/Ekbom disease (RLS/WED), is a sleep-related, sensorimotor disorder with a high prevalence among end-stage renal disease (ESRD) patients undergoing haemodialysis (HD) (about 15-40%). Whether RLS/WED in uremic patients influences cardiovascular morbidity and mortality remains a matter of controversy. The aim of this study was to evaluate the relationship of RLS/WED and mortality in a population of chronically dialyzed patients. METHOD: In 1996, we studied 128 patients with ESRD undergoing HD; 47 subjects (36.7%) complained RLS/WED symptoms. Fifteen years later we evaluated the mortality of this population. No clinical follow-up examination of the uremic population was made. The Kaplan-Maier curves in dialysis patients with or without RLS/WED (control group matched for age) were constructed for all-cause mortality and compared using log-rank test. RESULTS: The Kaplan-Maier curves disclosed a lower mortality rate in the uremic patients with RLS/WED than in those without RLS/WED (p = 0.04). In our analysis, the mortality rate was not influenced by RLS/WED severity (p = 0.11) or gender (p = 0.15). No difference among the causes of death was found in the 2 groups. CONCLUSIONS: Our study suggests that mortality in ESRD patients is not influenced by concomitant RLS/WED. After a 15 year follow-up, survival rates in our cohort were significantly longer in uremic subjects with RLS/WED than in those without RLS/WED. Finally, we found no relationship between RLS/WED severity and mortality. PMID- 28869941 TI - Identifying Attenuating Mutations: Tools for a New Vaccine Design against Flaviviruses. AB - Emerging Flaviviruses pose an increasing threat to global human health. To date, human vaccines against yellow fever virus (YFV), Japanese encephalitis virus (JEV), dengue virus (DV), and tick-borne encephalitis virus (TBEV) exist. However, there is no human vaccine against other Flaviviruses such as Zika virus (ZIKV) and West Nile virus (WNV). In order to restrict their spread and to protect populations against the diseases they induce, vaccines against these emerging viruses must be designed. Obtaining new live attenuated Flavivirus vaccines using molecular biology methods is now possible. Molecular infectious clones of the parental viruses are relatively easy to generate. Key mutations present in live attenuated vaccines or mutations known to have a key role in the Flavivirus life cycle and/or interactions with their hosts can be identified by sequencing, and are then inserted in infectious clones by site-directed mutagenesis. More recently, the use of chimeric viruses and large-scale reencoding and introduction of microRNA target sequences have also been tested. Indeed, a combination of these methods will help in designing new generations of vaccines against emerging and reemerging Flaviviruses. PMID- 28869942 TI - Pulmonary Cavities after Diagnostic Transbronchial Cryobiopsy in a Lung Transplantation Patient. PMID- 28869943 TI - Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells. AB - BACKGROUND/AIMS: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells. METHODS: We investigated the expression of Kv1.3 in different glioma cell lines by immunocytochemistry, western blotting and electron microscopy and analyzed the effect of newly synthesized, mitochondria-targeted, Kv1.3 inhibitors on the induction of cell death in these cells. Finally, we performed in vivo studies on glioma bearing mice. RESULTS: Here, we report that Kv1.3 is expressed in mitochondria of human and murine GL261, A172 and LN308 glioma cells. Treatment with the novel Kv1.3 inhibitors PAPTP or PCARBTP as well as with clofazimine induced massive cell death in glioma cells, while Psora-4 and PAP-1 were almost without effect. However, in vivo experiments revealed that the drugs had no effect on orthotopic brain tumors in vivo. CONCLUSION: These data serve as proof of principle that Kv1.3 inhibitors kills GBM cells, but drugs that act in vivo against glioblastoma must be developed to translate these findings in vivo. PMID- 28869945 TI - An Interview with the Guest Editors. PMID- 28869944 TI - Evidence for Concerted and Mosaic Brain Evolution in Dragon Lizards. AB - The brain plays a critical role in a wide variety of functions including behaviour, perception, motor control, and homeostatic maintenance. Each function can undergo different selective pressures over the course of evolution, and as selection acts on the outputs of brain function, it necessarily alters the structure of the brain. Two models have been proposed to explain the evolutionary patterns observed in brain morphology. The concerted brain evolution model posits that the brain evolves as a single unit and the evolution of different brain regions are coordinated. The mosaic brain evolution model posits that brain regions evolve independently of each other. It is now understood that both models are responsible for driving changes in brain morphology; however, which factors favour concerted or mosaic brain evolution is unclear. Here, we examined the volumes of the 6 major neural subdivisions across 14 species of the agamid lizard genus Ctenophorus (dragons). These species have diverged multiple times in behaviour, ecology, and body morphology, affording a unique opportunity to test neuroevolutionary models across species. We assigned each species to an ecomorph based on habitat use and refuge type, then used MRI to measure total and regional brain volume. We found evidence for both mosaic and concerted brain evolution in dragons: concerted brain evolution with respect to body size, and mosaic brain evolution with respect to ecomorph. Specifically, all brain subdivisions increase in volume relative to body size, yet the tectum and rhombencephalon also show opposite patterns of evolution with respect to ecomorph. Therefore, we find that both models of evolution are occurring simultaneously in the same structures in dragons, but are only detectable when examining particular drivers of selection. We show that the answer to the question of whether concerted or mosaic brain evolution is detected in a system can depend more on the type of selection measured than on the clade of animals studied. PMID- 28869946 TI - Stereotactic Radiosurgery for Intractable Tremor-Dominant Parkinson Disease: A Retrospective Analysis. AB - OBJECTIVE: The purpose of this study was to retrospectively analyze the outcomes of stereotactic radiosurgery for patients suffering from medically refractory Parkinson disease (PD) tremor. METHODS: We retrospectively studied the outcomes of 33 patients who were treated with gamma knife thalamotomy (GKT) over a 19-year period. Twelve patients were >=80 years. A median dose of 140 Gy (range, 130-150 Gy) was delivered to the nucleus ventralis intermedius through a single 4-mm isocenter. We used the Fahn-Tolosa-Marin clinical tremor rating scale to score tremor, handwriting, drawing, and ability to drink fluids. The median time to the last follow-up was 23 months (range, 9-144 months). RESULTS: After GKT, 31 patients (93.9%) experienced improvement in tremor. Twenty-three patients (70.0%) had complete or nearly complete tremor arrest. Nine patients (27.2%) noted tremor arrest and resolution of impairment in writing, drawing, and ability to drink fluids. One patient (3%) improved in bradykinesia, 3 patients (9%) improved in rigidity, and 3 patients (9%) decreased their dosage of dopa after GKT. Tremor relief was fully maintained in the last follow-up for 96.8% of responding patients. Two patients (6%) experienced temporary adverse radiation effects. CONCLUSIONS: GKT is a safe and effective treatment for medically refractory PD tremor, especially for the elderly or those not suitable for deep brain stimulation or thermal thalamotomy. PMID- 28869947 TI - The Protective Effects of Sika Deer Antler Protein on Cisplatin-Induced Nephrotoxicity. AB - BACKGROUND/AIMS: This study measured the effect of Sika deer (Cervus nippon Temminck) antler protein (SDAPR), glycoproteins (SDAG), and polysaccharides (SDAPO) on cisplatin-induced cytotoxicity in HEK 293 cells, and investigated the effect of SDAPR against cisplatin-induced nephrotoxicity in mice. METHODS: Cell viability was measured by MTT assay. ICR mice were randomly divided into five groups: control, cisplatin with vehicle, and cisplatin with SDAPR at three concentrations: 5, 10, or 20 mg/kg, p.o., 10 d. Cisplatin was injected on 7th day (25 mg/kg, i.p.). Renal function, oxidative stress, levels of inflammatory factors, and expression of apoptosis-related proteins were measured in vivo. Renal tissues were stained with TUNEL and H&E to observe renal cell apoptosis and pathological changes. RESULTS: Pretreatment with SDAPR (125-2000 ug/mL) significantly improved cell viability, with an EC50 of approximately 1000 ug/mL. SDAPR also ameliorated cisplatin-induced histopatholo- gic changes, and decreased blood urea nitrogen (BUN) and creatinine (Cr) (P < 0.05). Western blotting analysis showed SDAPR clearly decreased expression levels of cleaved-caspase-3 and Bax, and increased the expression level of Bcl-2 (P < 0.01). Additionally, SDAPR markedly regulated oxidative stress markers and inflammatory cytokines (P<0.05). TUNEL staining showed decreased apoptosis after SDAPR treatment (P < 0.01). CONCLUSIONS: These results indicate that SDAPR can be an effective dietary supplement, to relieve cisplatin-induced nephrotoxicity by improved antioxidase activity, suppressed inflammation, and inhibited apoptosis in vivo. PMID- 28869949 TI - Support for Dialysis Therapy in Vietnam, Cambodia, and Myanmar by Japanese Societies in the Field of Blood Purification. AB - With recent economic development in Southeast Asia, there have been improvements in medical services and healthcare provision. This has led to increased numbers of dialysis patients and increased numbers of dialysis facilities in the region. To assist economically developing countries in managing this change, support projects from Japan have been conducted in the region since around 2007. This article summarizes and discusses Japan's support activities, in which some of the authors were directly involved, in Vietnam, Cambodia, and Myanmar. Initial support was mainly organized by the non-governmental organization Ubiquitous Blood Purification International (NGO UBPI), and currently several organizations in the field of blood purification work together to offer ongoing support in the region. Many positive changes have resulted from these activities in Southeast Asia, but challenges remaining for the future are to establish an educational system for each dialysis specialty and develop dialysis techniques ensuring high treatment quality and safety. PMID- 28869948 TI - The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR). AB - BACKGROUNDS/AIMS: Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the progression of several tumors. The interaction between lncRNA and miRNA or miRNA's target genes is reported to play crucial roles in malignancy. In addition, Androgen receptor (AR) is considered to be involved in bladder cancer progression. In this study, we investigated the role of XIST in human bladder cancer and its interaction with miR-124 and AR. METHODS: XIST and AR expression was detected in bladder tumor samples and cell lines. Effects of XIST and AR on bladder cancer cells growth, invasion and migration were analyzed. Bioinformatic analysis and luciferase assays were used to identify the interaction among XIST, AR and miR-124. The correlations of miR-124 with XIST and AR in bladder cancer samples were statistically analyzed. RESULTS: XIST and AR were upregulated in bladder cancer tissues and positively correlated. Higher XIST and AR expression were related to poorer TNM stage of bladder cancer. XIST knockdown reduced bladder cancer cells' proliferation, invasion and migration. While this inhibitory effect could be partially restored by AR overexpression. XIST inhibited miR-124 expression by directly targeting. Moreover, miR-124 could bind to the 3'UTR of AR to regulate its expression. MiR-124 inhibition partially restored the XIST knockdown-induced reduction of AR, c-myc, p27, MMP13 and MMP9 expression. In bladder cancer tissues, miR-124 level was inversely correlated with the expression of XIST and AR, respectively. CONCLUSION: These findings indicated that XIST might be an oncogenic lncRNA that promoted the bladder cancer growth, invasion and migration via miR-124 dependent AR regulation. PMID- 28869950 TI - Interleukin-10 Gene-Modified Dendritic Cell-Induced Type 1 Regulatory T Cells Induce Transplant-Tolerance and Impede Graft Versus Host Disease After Allogeneic Stem Cell Transplantation. AB - BACKGROUND/AIMS: Tr1 cells can induce peripheral tolerance to self- and foreign antigens, and have been developed as a therapeutic tool for the induction of tolerance to transplanted tissue. We explored the feasibility of generating Tr1 cells by using IL-10 gene-modified recipient DCs (DCLV-IL-10) to stimulate donor naive CD4+ T cells. We also investigated some biological properties of Tr1 cells. METHODS: DCLV-IL-10 were generated through DCs transduced with a lentivirus vector carrying the IL-10 gene, and Tr1 cells were produced by using DCLV-IL-10 to stimulate naive CD4+ T cells. The effects of Tr1 cells on T-cell proliferation and the occurrence of graft versus host disease (GVHD) following allogeneic stem cell transplantation (allo-HSCT) were investigated. RESULTS: The DCLV-IL-10 induced Tr1 cells co-expressed LAG-3 and CD49b. Moreover, they also expressed CD4, CD25, and IL-10, but not Foxp3, and secreted significantly higher levels of IL-10 (1,729.36 +/- 185.79 pg/mL; P < 0.001) and INF-gamma (1,524.48 +/- 168.65 pg/mL; P < 0.01) than the control T cells upon the stimulation by allogeneic DCs. Tr1 cells markedly suppressed T-lymphocyte proliferation and the mixed lymphocytic response (MLR) in vitro. The mice used in the allo-HSCT model had longer survival times and lower clinical and pathological GVHD scores than the control mice. CONCLUSION: IL-10 gene-modified DC-induced Tr1 cells may be used as a potent cellular therapy for the prevention of GVHD after allo-HSCT. PMID- 28869951 TI - The "Dialysis Situation in Asian Countries" Symposium: Providing New Insights to Improve Dialysis in the Region. PMID- 28869952 TI - Risk Factors for Delirium in Older Medical Inpatients in Tanzania. AB - BACKGROUND: The risk factors for prevalent delirium in older hospitalised adults in Sub-Saharan Africa (SSA) remain poorly characterised. METHODS: A total of 510 consecutive admissions of adults aged >=60 years to acute medical wards of Kilimanjaro Christian Medical Centre in northern Tanzania were recruited. Patients were assessed within 24 h of admission with a risk factor questionnaire, physiological observations, neurocognitive assessment, and informant interview. Delirium and dementia diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM V) and DSM IV respectively, by an expert panel. RESULTS: Being male, current alcohol use, dementia, and physiological markers of illness severity were significant independent risk factors for delirium on multivariable analysis. CONCLUSIONS: The risk factors for prevalent delirium in older medical inpatients in SSA include pre-existing dementia, and are similar to those identified in high-income countries. Our data could help inform the development of a delirium risk stratification tool for older adults in SSA. PMID- 28869953 TI - Acute Kidney Injury following Ingestion of Henna Leaf Extract: A Case Report from Myanmar. AB - Alternative medicine is gaining popularity worldwide. In Asia, particularly Southeast Asia, herbal medicine plays an important role in healthcare. A 34-year old man from Yangon, Myanmar, was admitted to the medical ward of our hospital after ingesting a herbal remedy of boiled henna leaves (Dan Ywet in Burmese). He developed hemoglobinuria leading to acute kidney injury (AKI). The insult was severe, and he underwent 5 sessions of hemodialysis. His condition improved and within 7 weeks of injury, he made a full recovery. However, he was lost to follow up when renal function became normal. Our diagnosis was AKI from hemoglobinuria secondary to henna leaf extract nephrotoxicity in G6PD deficiency. This case highlights the steps required to achieve the International Society of Nephrology's goal of 0 preventable deaths from AKI by 2025 and the efforts needed to increase public knowledge about herbal remedies and AKI, medication adherence, and compliance with follow-up. PMID- 28869954 TI - Acute Kidney Injury due to Fish Gallbladder Ingestion: A Case Report from Cambodia. AB - We report the case of a 22-year-old woman with a 3-day history of watery stool, generalized abdominal pain, repeated vomiting, and decreased urine output following the consumption of fish gallbladder for self-treatment of acne. She was admitted and received empirical antiemetic, proton pump inhibitor, and intravenous saline treatment. Urine output reduced drastically with markedly elevated urea and creatinine, and she underwent urgent hemodialysis (HD). Based on thorough history taking and prompt biochemical investigations that showed extremely high urea and creatinine levels, we made a diagnosis of acute kidney injury (AKI) secondary to fish gallbladder poisoning. Renal function improved over a period of 5 weeks. Fish gallbladder poisoning is quite frequent in several developing countries in Asia. General physicians in these countries should note that various types of food poisoning can be involved in the etiology of AKI. The condition is commonly reversible, and therefore proper history taking is important and prompt biochemical investigations including blood urea and creatinine are needed to enable early diagnosis and fast institution of treatment, which may include HD. PMID- 28869956 TI - The Implications of Recent Recommendations for Managing Patients with Psoriasis Treated with Fumaric Acid Esters. AB - BACKGROUND/AIMS: Fumaric acid esters (FAEs) are a well-established efficacious systemic treatment for psoriasis. Recent recommendations from the European Medicines Agency suggest monitoring of full blood count every 4 weeks for the duration of therapy for psoriasis. The aim of our study was to assess the incidence of lymphopenia in patients taking FAEs and the impact of recent recommendations for our practice. METHODS: We reviewed 151 patients treated with FAEs for psoriasis between December 2013 and 2015. RESULTS: Lymphopenia <700 * 109/L was detected within the last 12 months in 36/151 (24%) and lymphopenia <500 * 109/L in 10/151 (7%). Of 39 patients no longer on treatment, 7 (18%) stopped because of persistent lymphopenia. CONCLUSION: The implementation of these recommendations would have significant resource implications and also likely influence the acceptability of FAEs to patients. Cessation of FAEs necessitates the need for alternative therapy, commonly biologic therapy. PMID- 28869957 TI - Diagnostic Value of Time-Constrained Naming Test in Mild Cognitive Impairment. AB - BACKGROUND: Naming difficulties have recently garnered more interest in elderly individuals with mild cognitive impairment (MCI). We anticipate that naming tests with the consideration of response time can provide more informative and distinct neuropsychological profiles of individuals with MCI. METHODS: Naming tests were administered to 76 elderly individuals with MCI and 149 healthy elderly (HE). We analyzed the impact of MCI on naming performance and occurrence of "delayed" response. We also validated the predictive power of naming tests with a time constrained scoring system. RESULTS: MCI participants performed poorer on the noun naming test than HE participants (p = 0.014). MCI was significantly associated with the occurrence of "delayed" response on the noun (odds ratio [OR] = 3.57; 95% confidence interval [CI] = 1.78-7.17) and verb naming tests (OR = 4.66; 95% CI = 2.07-10.46). The time-constrained naming scores were significantly better able to distinguish the MCI from the HE group than the conventional spontaneous naming score on both the noun (p < 0.001) and verb (p = 0.002) naming tests. CONCLUSIONS: Our findings broaden the knowledge related to the naming ability in individuals with MCI, with respect to the response time. We also confirmed the validity of the naming tests by applying the "delayed" responses as supplementary assessments in the diagnosis of MCI. PMID- 28869958 TI - Management of Nephrotic Syndrome: A Case Report from Lao PDR. AB - We report the case of a 23-year-old woman with a 2-week history of swelling around the eyes and both legs, and generalized body swelling. She had a history of chronic constipation and poor diet but no fever, recent illnesses, or hematuria. Examination revealed bilateral pedal edema and mild ascites. Laboratory investigations showed low hemoglobin 79 g/L, low mean corpuscular volume 53 fL, thrombocytosis 973 * 109/L, and marked hypochromia and microcytosis, with low iron and ferritin. She had hypoalbuminemia and reduced serum protein (albumin 1.9 g/dL, globulin 2.8 g/dL) with elevated triglycerides (454 mg/dL). Although kidney biopsy could not be performed due to a lack of facilities in the country, we made a diagnosis of idiopathic nephrotic syndrome (NS) with iron deficiency anemia secondary to poor diet based on clinical and laboratory findings. The patient was admitted and treated with intravenous methylprednisolone and iron supplements. Antiplatelet therapy was instituted with dipyridamole to prevent thromboembolism from the combination of nephrotic syndrome and thrombocytosis. She was later treated with albumin and furosemide due to elevated blood pressure and worsened edema. The edema resolved and her general condition improved. She was discharged to follow up and has remained stable, requiring no further treatment as of 18 months after admission. Kidney biopsy is important for diagnosis of NS. Diagnosis may be made from clinical and laboratory findings alone in some cases; however, biopsy is required to determine the type of NS and improve further management and treatment outcomes for patients. PMID- 28869959 TI - Screening of Cognitive Impairment in the Dialysis Population: A Scoping Review. AB - BACKGROUND: Cognitive impairment in end-stage kidney disease patients on dialysis is increasingly common. This study aimed to review the practice of screening and to evaluate the evidence on cognitive impairment prevalence in this population. METHODS: This scoping review of studies summarises the evidence on cognitive impairment in dialysis populations. The search included the Medline, CINAHL, Embase, PsycINFO, PubMed, and Cochrane Library databases for English-language articles published between 2000 and 2015. A total of 46 articles were reviewed. RESULTS: The studies were of prospective observational design, with the majority conducted in the haemodialysis population. The reported prevalence of cognitive impairment ranged from 6.6 to 51%. Three screening tools were consistently used. CONCLUSION: While cognitive impairment is recognised in the dialysis population, there is paucity of screening data. The design of prospective comparisons ideally includes established screening instruments, particularly the Montreal Cognitive Assessment, to determine the optimal results for this population. Translation of established screening tools to increase the inclusion of people from other cultural and language groups is required. Regular screening can enhance the timing to introduce home-based care support and advance care planning discussions. PMID- 28869960 TI - Syncytia Induction by Clinical Isolates of Human Respiratory Syncytial Virus A. AB - OBJECTIVE: Syncytia formation is the hallmark of the cytopathic effect caused by human respiratory syncytial virus (HRSV), which is the most important viral respiratory pathogen in children. This article reports methodological improvements in primary HRSV isolation and the importance of syncytia formation and mRNA levels of F protein for the progeny yield, using clinical isolates of HRSV. METHODS: The A and B strains of HRSV were isolated in HEp-2 cell cultures from fresh and frozen nasopharyngeal aspirates. The formation of syncytia was evaluated using 2 different assays. Levels of F protein mRNA were quantified by real-time PCR while HRSV progeny titration was done by plaque assay. RESULTS: HRSV was primarily isolated from 238 of 312 (90.7%) samples, and 13 of these (12 HRSV-A and 1 HRSV-B) were continuously passaged in vitro. The quantity and size of syncytia formed by 6 pure HRSV-A clinical isolates were different, as were the levels of F protein mRNA. CONCLUSION: There is a direct correlation of quantities of syncytia and inoculum size, but not with mRNA levels of HRSV-A F protein. Importantly, levels of F protein mRNA were directly related to progeny production. PMID- 28869961 TI - Contribution of Neuro-Imaging for Prediction of Functional Recovery after Ischemic Stroke. AB - Prediction measures of recovery and outcome after stroke perform with only modest levels of accuracy if based only on clinical data. Prediction scores can be improved by including morphologic imaging data, where size, location, and development of the ischemic lesion is best documented by magnetic resonance imaging. In addition to the primary lesion, the involvement of fiber tracts contributes to prognosis, and consequently the use of diffusion tensor imaging (DTI) to assess primary and secondary pathways improves the prediction of outcome and of therapeutic effects. The recovery of ischemic tissue and the progression of damage are dependent on the quality of blood supply. Therefore, the status of the supplying arteries and of the collateral flow is not only crucial for determining eligibility for acute interventions, but also has an impact on the potential to integrate areas surrounding the lesion that are not typically part of a functional network into the recovery process. The changes in these functional networks after a localized lesion are assessed by functional imaging methods, which additionally show altered pathways and activated secondary centers related to residual functions and demonstrate changes in activation patterns within these networks with improved performance. These strategies in some instances record activation in secondary centers of a network, for example, also in homolog contralateral areas, which might be inhibitory to the recovery of primary centers. Such findings might have therapeutic consequences, for example, image-guided inhibitory stimulation of these areas. In the future, a combination of morphological imaging including DTI of fiber tracts and activation studies during specific tasks might yield the best information on residual function, reserve capacity, and prospects for recovery after ischemic stroke. PMID- 28869962 TI - Mimicking biological stress-strain behaviour with synthetic elastomers. AB - Despite the versatility of synthetic chemistry, certain combinations of mechanical softness, strength, and toughness can be difficult to achieve in a single material. These combinations are, however, commonplace in biological tissues, and are therefore needed for applications such as medical implants, tissue engineering, soft robotics, and wearable electronics. Present materials synthesis strategies are predominantly Edisonian, involving the empirical mixing of assorted monomers, crosslinking schemes, and occluded swelling agents, but this approach yields limited property control. Here we present a general strategy for mimicking the mechanical behaviour of biological materials by precisely encoding their stress-strain curves in solvent-free brush- and comb-like polymer networks (elastomers). The code consists of three independent architectural parameters-network strand length, side-chain length and grafting density. Using prototypical poly(dimethylsiloxane) elastomers, we illustrate how this parametric triplet enables the replication of the strain-stiffening characteristics of jellyfish, lung, and arterial tissues. PMID- 28869963 TI - Cell biology: The persistence of memory. PMID- 28869964 TI - Biodiversity effects in the wild are common and as strong as key drivers of productivity. AB - More than 500 controlled experiments have collectively suggested that biodiversity loss reduces ecosystem productivity and stability. Yet the importance of biodiversity in sustaining the world's ecosystems remains controversial, largely because of the lack of validation in nature, where strong abiotic forcing and complex interactions are assumed to swamp biodiversity effects. Here we test this assumption by analysing 133 estimates reported in 67 field studies that statistically separated the effects of biodiversity on biomass production from those of abiotic forcing. Contrary to the prevailing opinion of the previous two decades that biodiversity would have rare or weak effects in nature, we show that biomass production increases with species richness in a wide range of wild taxa and ecosystems. In fact, after controlling for environmental covariates, increases in biomass with biodiversity are stronger in nature than has previously been documented in experiments and comparable to or stronger than the effects of other well-known drivers of productivity, including climate and nutrient availability. These results are consistent with the collective experimental evidence that species richness increases community biomass production, and suggest that the role of biodiversity in maintaining productive ecosystems should figure prominently in global change science and policy. PMID- 28869965 TI - The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. AB - The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have important roles in stimulating innate and adaptive immune responses that are required for resistance to helminth infection, promotion of allergic inflammation, metabolic homeostasis and tissue repair. Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses, how ILC2 responses are regulated by other stimuli remains poorly understood. Here we demonstrate that ILC2s in the mouse gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU). In contrast to other haematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation, and secretion of the type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and Galphaq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1-/- mice than in control mice. Furthermore, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU elicited type 2 cytokine responses. Together, these data indicate that the NMU NMUR1 neuronal signalling circuit provides a selective mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue protective type 2 responses at mucosal sites. PMID- 28869967 TI - A solvent- and vacuum-free route to large-area perovskite films for efficient solar modules. AB - Recent advances in the use of organic-inorganic hybrid perovskites for optoelectronics have been rapid, with reported power conversion efficiencies of up to 22 per cent for perovskite solar cells. Improvements in stability have also enabled testing over a timescale of thousands of hours. However, large-scale deployment of such cells will also require the ability to produce large-area, uniformly high-quality perovskite films. A key challenge is to overcome the substantial reduction in power conversion efficiency when a small device is scaled up: a reduction from over 20 per cent to about 10 per cent is found when a common aperture area of about 0.1 square centimetres is increased to more than 25 square centimetres. Here we report a new deposition route for methyl ammonium lead halide perovskite films that does not rely on use of a common solvent or vacuum: rather, it relies on the rapid conversion of amine complex precursors to perovskite films, followed by a pressure application step. The deposited perovskite films were free of pin-holes and highly uniform. Importantly, the new deposition approach can be performed in air at low temperatures, facilitating fabrication of large-area perovskite devices. We reached a certified power conversion efficiency of 12.1 per cent with an aperture area of 36.1 square centimetres for a mesoporous TiO2-based perovskite solar module architecture. PMID- 28869966 TI - Polycomb-like proteins link the PRC2 complex to CpG islands. AB - The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression and has essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like (PCL) proteins, such as PHF1, MTF2 and PHF19, are PRC2-associated factors that form sub complexes with PRC2 core components, and have been proposed to modulate the enzymatic activity of PRC2 or the recruitment of PRC2 to specific genomic loci. Mammalian PRC2-binding sites are enriched in CG content, which correlates with CpG islands that display a low level of DNA methylation. However, the mechanism of PRC2 recruitment to CpG islands is not fully understood. Here we solve the crystal structures of the N-terminal domains of PHF1 and MTF2 with bound CpG containing DNAs in the presence of H3K36me3-containing histone peptides. We show that the extended homologous regions of both proteins fold into a winged-helix structure, which specifically binds to the unmethylated CpG motif but in a completely different manner from the canonical winged-helix DNA recognition motif. We also show that the PCL extended homologous domains are required for efficient recruitment of PRC2 to CpG island-containing promoters in mouse embryonic stem cells. Our research provides the first, to our knowledge, direct evidence to demonstrate that PCL proteins are crucial for PRC2 recruitment to CpG islands, and further clarifies the roles of these proteins in transcriptional regulation in vivo. PMID- 28869968 TI - Structural basis of MsbA-mediated lipopolysaccharide transport. AB - Lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria is critical for the assembly of their cell envelopes. LPS synthesized in the cytoplasmic leaflet of the inner membrane is flipped to the periplasmic leaflet by MsbA, an ATP-binding cassette transporter. Despite substantial efforts, the structural mechanisms underlying MsbA-driven LPS flipping remain elusive. Here we use single-particle cryo-electron microscopy to elucidate the structures of lipid nanodisc-embedded MsbA in three functional states. The 4.2 A-resolution structure of the transmembrane domains of nucleotide-free MsbA reveals that LPS binds deep inside MsbA at the height of the periplasmic leaflet, establishing extensive hydrophilic and hydrophobic interactions with MsbA. Two sub-nanometre-resolution structures of MsbA with ADP-vanadate and ADP reveal an unprecedented closed and an inward-facing conformation, respectively. Our study uncovers the structural basis for LPS recognition, delineates the conformational transitions of MsbA to flip LPS, and paves the way for structural characterization of other lipid flippases. PMID- 28869969 TI - m6A modulates haematopoietic stem and progenitor cell specification. AB - N6-methyladenosine (m6A) has been identified as the most abundant modification on eukaryote messenger RNA (mRNA). Although the rapid development of high-throughput sequencing technologies has enabled insight into the biological functions of m6A modification, the function of m6A during vertebrate embryogenesis remains poorly understood. Here we show that m6A determines cell fate during the endothelial-to haematopoietic transition (EHT) to specify the earliest haematopoietic stem/progenitor cells (HSPCs) during zebrafish embryogenesis. m6A-specific methylated RNA immunoprecipitation combined with high-throughput sequencing (MeRIP-seq) and m6A individual-nucleotide-resolution cross-linking and immunoprecipitation with sequencing (miCLIP-seq) analyses reveal conserved features on zebrafish m6A methylome and preferential distribution of m6A peaks near the stop codon with a consensus RRACH motif. In mettl3-deficient embryos, levels of m6A are significantly decreased and emergence of HSPCs is blocked. Mechanistically, we identify that the delayed YTHDF2-mediated mRNA decay of the arterial endothelial genes notch1a and rhoca contributes to this deleterious effect. The continuous activation of Notch signalling in arterial endothelial cells of mettl3-deficient embryos blocks EHT, thereby repressing the generation of the earliest HSPCs. Furthermore, knockdown of Mettl3 in mice confers a similar phenotype. Collectively, our findings demonstrate the critical function of m6A modification in the fate determination of HSPCs during vertebrate embryogenesis. PMID- 28869971 TI - Leukaemia: Vitamin C regulates stem cells and cancer. PMID- 28869970 TI - Competing memories of mitogen and p53 signalling control cell-cycle entry. AB - Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state. Whether this choice between two cell cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals. Rather than erasing their signalling history at cell-cycle checkpoints before mitosis, mother cells transmit DNA damage-induced p53 protein and mitogen-induced cyclin D1 (CCND1) mRNA to newly born daughter cells. After mitosis, the transferred CCND1 mRNA and p53 protein induce variable expression of cyclin D1 and the CDK inhibitor p21 that almost exclusively determines cell-cycle commitment in daughter cells. We find that stoichiometric inhibition of cyclin D1 CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner. Thus, daughter cells control the proliferation-quiescence decision by converting the memories of variable mitogen and stress signals into a competition between cyclin D1 and p21 expression. We propose a cell-cycle control principle based on natural variation, memory and competition that maximizes the health of growing cell populations. PMID- 28869972 TI - Cell signalling: Red alert about lipid's role in skin cancer. PMID- 28869975 TI - Prostate Cancer Screening: Time to Question How to Optimize the Ratio of Benefits and Harms. PMID- 28869973 TI - Palmitoylation-dependent activation of MC1R prevents melanomagenesis. AB - The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation. Activation of MC1R in melanocytes by alpha melanocyte-stimulating hormone (alpha-MSH) stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation. Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma. However, how MC1R activity is modulated by ultraviolet irradiation, why individuals with red hair are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signalling, which triggers increased pigmentation, ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1re/eJ mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma. PMID- 28869974 TI - Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. AB - Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis, and are activated by host-derived cytokines and alarmins. Discrete subsets of immune cells integrate nervous system cues, but it remains unclear whether neuron-derived signals control ILC2s. Here we show that neuromedin U (NMU) in mice is a fast and potent regulator of type 2 innate immunity in the context of a functional neuron-ILC2 unit. We found that ILC2s selectively express neuromedin U receptor 1 (Nmur1), and mucosal neurons express NMU. Cell-autonomous activation of ILC2s with NMU resulted in immediate and strong NMUR1-dependent production of innate inflammatory and tissue repair cytokines. NMU controls ILC2s downstream of extracellular signal-regulated kinase and calcium-influx-dependent activation of both calcineurin and nuclear factor of activated T cells (NFAT). NMU treatment in vivo resulted in immediate protective type 2 responses. Accordingly, ILC2-autonomous ablation of Nmur1 led to impaired type 2 responses and poor control of worm infection. Notably, mucosal neurons were found adjacent to ILC2s, and these neurons directly sensed worm products and alarmins to induce NMU and to control innate type 2 cytokines. Our work reveals that neuron-ILC2 cell units confer immediate tissue protection through coordinated neuroimmune sensory responses. PMID- 28869976 TI - Proposed U.S. Funding Cuts Threaten Progress on Antimicrobial Resistance. PMID- 28869977 TI - Contemporary Influenza Diagnostics: Renewed Focus on Testing Patients. PMID- 28869978 TI - Web Exclusives. Annals Graphic Medicine - Dear Doctor I. PMID- 28869979 TI - Enhancing the Role of Internists in the Transition From Pediatric to Adult Health Care. PMID- 28869980 TI - Enhancing the Role of Internists in the Transition From Pediatric to Adult Health Care. PMID- 28869981 TI - Shared Humanity. PMID- 28869982 TI - Let me stop when it is done. PMID- 28869983 TI - connecting flight to Rochester, MN. PMID- 28869984 TI - Influenza. AB - Influenza is an acute viral respiratory disease that affects persons of all ages and is associated with millions of medical visits, hundreds of thousands of hospitalizations, and thousands of deaths during annual winter epidemics of variable severity in the United States. Elderly persons have the highest influenza-associated hospitalization and mortality rates. The primary method of prevention is annual vaccination. Early antiviral treatment has the greatest clinical benefit; otherwise, management includes adherence to recommended infection prevention and control measures as well as supportive care of complications. PMID- 28869986 TI - Diagnostic Accuracy of Novel and Traditional Rapid Tests for Influenza Infection Compared With Reverse Transcriptase Polymerase Chain Reaction: A Systematic Review and Meta-analysis. AB - Background: Rapid and accurate influenza diagnostics can improve patient care. Purpose: To summarize and compare accuracy of traditional rapid influenza diagnostic tests (RIDTs), digital immunoassays (DIAs), and rapid nucleic acid amplification tests (NAATs) in children and adults with suspected influenza. Data Sources: 6 databases from their inception through May 2017. Study Selection: Studies in English, French, or Spanish comparing commercialized rapid tests (that is, providing results in <30 minutes) with reverse transcriptase polymerase chain reaction reference standard for influenza diagnosis. Data Extraction: Data were extracted using a standardized form; quality was assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) criteria. Data Synthesis: 162 studies were included (130 of RIDTs, 19 of DIAs, and 13 of NAATs). Pooled sensitivities for detecting influenza A from Bayesian bivariate random-effects models were 54.4% (95% credible interval [CrI], 48.9% to 59.8%) for RIDTs, 80.0% (CrI, 73.4% to 85.6%) for DIAs, and 91.6% (CrI, 84.9% to 95.9%) for NAATs. Those for detecting influenza B were 53.2% (CrI, 41.7% to 64.4%) for RIDTs, 76.8% (CrI, 65.4% to 85.4%) for DIAs, and 95.4% (CrI, 87.3% to 98.7%) for NAATs. Pooled specificities were uniformly high (>98%). Forty-six influenza A and 24 influenza B studies presented pediatric-specific data; 35 influenza A and 16 influenza B studies presented adult-specific data. Pooled sensitivities were higher in children by 12.1 to 31.8 percentage points, except for influenza A by rapid NAATs (2.7 percentage points). Pooled sensitivities favored industry-sponsored studies by 6.2 to 34.0 percentage points. Incomplete reporting frequently led to unclear risk of bias. Limitations: Underreporting of clinical variables limited exploration of heterogeneity. Few NAAT studies reported adult-specific data, and none evaluated point-of-care testing. Many studies had unclear risk of bias. Conclusion: Novel DIAs and rapid NAATs had markedly higher sensitivities for influenza A and B in both children and adults than did traditional RIDTs, with equally high specificities. Primary Funding Source: Quebec Health Research Fund and BD Diagnostic Systems. PMID- 28869987 TI - Effects of Intensive Systolic Blood Pressure Control on Kidney and Cardiovascular Outcomes in Persons Without Kidney Disease: A Secondary Analysis of a Randomized Trial. AB - Background: The public health significance of the reported higher incidence of chronic kidney disease (CKD) with intensive systolic blood pressure (SBP) lowering is unclear. Objective: To examine the effects of intensive SBP lowering on kidney and cardiovascular outcomes and contrast its apparent beneficial and adverse effects. Design: Subgroup analyses of SPRINT (Systolic Blood Pressure Intervention Trial). (ClinicalTrials.gov: NCT01206062). Setting: Adults with high blood pressure and elevated cardiovascular risk. Participants: 6662 participants with a baseline estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m2. Intervention: Random assignment to an intensive or standard SBP goal (120 or 140 mm Hg, respectively). Measurements: Differences in mean eGFR during follow-up (estimated with a linear mixed-effects model), prespecified incident CKD (defined as a >30% decrease in eGFR to a value <60 mL/min/1.73 m2), and a composite of all-cause death or cardiovascular event, with surveillance every 3 months. Results: The difference in adjusted mean eGFR between the intensive and standard groups was -3.32 mL/min/1.73 m2 (95% CI, -3.90 to -2.74 mL/min/1.73 m2) at 6 months, was -4.50 mL/min/1.73 m2 (CI, -5.16 to -3.85 mL/min/1.73 m2) at 18 months, and remained relatively stable thereafter. An incident CKD event occurred in 3.7% of participants in the intensive group and 1.0% in the standard group at 3-year follow-up, with a hazard ratio of 3.54 (CI, 2.50 to 5.02). The corresponding percentages for the composite of death or cardiovascular event were 4.9% and 7.1% at 3-year follow-up, with a hazard ratio of 0.71 (CI, 0.59 to 0.86). Limitation: Long-term data were lacking. Conclusion: Intensive SBP lowering increased risk for incident CKD events, but this was outweighed by cardiovascular and all-cause mortality benefits. Primary Funding Source: National Institutes of Health. PMID- 28869988 TI - Survival After Fulminant Myocarditis Induced by Immune-Checkpoint Inhibitors. PMID- 28869991 TI - Robotic-Assisted Ivor Lewis Esophagectomy (RAMIE) with a Standardized Intrathoracic Circular End-to-side Stapled Anastomosis and a Team of Two (Surgeon and Assistant Only). AB - Robotic-assisted surgery is rapidly increasing, especially in general surgery. It has been shown for years that the minimal invasive esophagectomy (MIE) is possible using a robotic system, for example, da Vinci Xi, Intuitive Surgical. In the past, most robotic esophageal resections have been performed thoracoscopically, and the anastomosis was mostly sutured at the neck. Due to the increase of usable instruments and technical progress, it is possible to perform the total abdominothoracic esophagectomy with an intrathoracic sutured anastomosis robotically. In this article, we would like to present the standardized operation technique and tricks for the robotic-assisted (da Vinci Xi) Ivor Lewis MIE (RAMIE), especially the robotic technique in combination with a standardized intrathoracic circular end-to-side stapled esophagogastric anastomosis. PMID- 28869990 TI - Different Effects of Screening on Prostate Cancer Death in Two Trials. PMID- 28869989 TI - Reconciling the Effects of Screening on Prostate Cancer Mortality in the ERSPC and PLCO Trials. AB - Background: The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction. Objective: To evaluate whether effects of screening on prostate cancer mortality relative to no screening differed between the ERSPC and PLCO. Design: Cox regression of prostate cancer death in each trial group, adjusted for age and trial. Extended analyses accounted for increased incidence due to screening and diagnostic work-up in each group via mean lead times (MLTs), which were estimated empirically and using analytic or microsimulation models. Setting: Randomized controlled trials in Europe and the United States. Participants: Men aged 55 to 69 (ERSPC) or 55 to 74 (PLCO) years at randomization. Intervention: Prostate cancer screening. Measurements: Prostate cancer incidence and survival from randomization; prostate cancer incidence in the United States before screening began. Results: Estimated MLTs were similar in the ERSPC and PLCO intervention groups but were longer in the PLCO control group than the ERSPC control group. Extended analyses found no evidence that effects of screening differed between trials (P = 0.37 to 0.47 [range across MLT estimation approaches]) but strong evidence that benefit increased with MLT (P = 0.0027 to 0.0032). Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening. Limitation: The MLT is a simple metric of screening and diagnostic work-up. Conclusion: After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality. Primary Funding Source: National Cancer Institute. PMID- 28869992 TI - Transforaminal Epiduroscopic Laser Ablation of Sinuvertebral Nerve in Patients with Chronic Diskogenic Back Pain: Technical Note and Preliminary Result. PMID- 28869994 TI - [X-Ray Photographs from the First World War]. PMID- 28869995 TI - ? PMID- 28869993 TI - Early Dynamics of Interleukin-6 in Cerebrospinal Fluid after Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) is a severe condition associated with high mortality. Early brain injury (EBI) plays an important role in the pathophysiology of SAH, and inflammation is a major contributor to EBI. Inflammation is a widely studied topic in both experimental and clinical conditions; however, just a few clinical studies have focused primarily on the early inflammatory response after SAH, and detailed information about the association between the dynamics of early inflammatory response with main clinical characteristics is lacking. This study analyzes the early dynamics of inflammatory response after SAH and evaluates the possible associations between the markers of early inflammatory response and main clinical characteristics. PATIENTS AND METHODS: A total of 47 patients with a diagnosis of aneurysmal SAH within the last 24 hours were enrolled in the study. All treatments, including treatment of aneurysm (surgery/coiling) and implantation of a drainage system (external ventricular drainage/lumbar catheter), were conducted in the same way as in other patients with this diagnosis. Blood and cerebrospinal fluid (CSF) samples were collected three times a day for 4 days. The dynamics of proinflammatory cytokines were assessed, and associations between levels of the proinflammatory cytokines interleukin (IL)-6, IL-1beta, or tumor necrosis factor (TNF)alpha and main clinical characteristics were evaluated using linear mixed effect models. RESULTS: The CSF levels of IL-6 were massively increased initially after SAH (up to 72 hours) with an additional increase in later phases (after 72 hours), but there was high variability in IL-6 levels. A significant association was noted between the Glasgow Outcome Scale score and both overall levels of IL-6 (p = 0.0095) and their dynamics (p = 0.0208); the effect of the Hunt and Hess scale was borderline (p = 0.0887). No association was found between IL-6 levels and Fisher grade, modality of treatment (surgery, coiling, no treatment), and later development of cerebral vasospasm. Plasmatic levels of IL-6 increased slightly, but no significant association was found. The levels of IL 1beta and TNFalpha were within the physiologic range in both CSF and plasma. CONCLUSIONS: Early dynamics of IL-6 in CSF are associated with a patients outcome. But it is difficult to use IL-6 alone for outcome prediction due to its high variability. The question is whether the dynamics of IL-6 could be used in combination with other early markers associated with brain injury. More detailed research is required to answer this question. PMID- 28869996 TI - [Prevention of Head and Brain Injuries in Football: Is there a Need to Ban Headings?] AB - Football, the most popular sports worldwide, is associated with a high number of injuries. Head and brain injuries in football are less frequent, but may result in severe long-term damage. The mechanisms of these injuries in football are multifactorial, and the ball is rarely the main cause of a head injury. Short term, medium-term and long-term consequences of headings in football are insufficiently examined, and there are hardly any case reports about severe episodes. Heading has been banned in US junior football since November 2015, which is understandable considering the higher risk for head injuries in popular American sports such as ice hockey or American football and people's fear associated with this risk. However, the decision to ban heading in football is not based on scientific results, and different experiences have been made in European football. Therefore, this decision should not simply be transferred to Europe. In fact, other injury prevention strategies for head injuries in junior football are necessary, such as the adaptation of ball sizes, which has already been implemented. It is not necessary to change match rules in the form of a general ban on heading in football. Further scientific studies are needed for standardisation in football worldwide. PMID- 28869997 TI - [Surgical Refixation after Proximal Hamstring Tendon Avulsion Injuries: Does the Time of Surgery Influence Functional Outcomes?] AB - Background Proximal hamstring tendon avulsion injuries are rare. If they do occur, surgical treatment with tendon refixation is regarded as the method of choice. Surgical outcome measurements have been investigated heterogeneously and, therefore, are difficult to compare. Hence, the possibility for correlations between postoperative outcomes and surgical methods or time of surgery is limited. Objective Using the new, validated and injury-specific Perth Hamstring Assessment Tool (PHAT), we aimed to investigate a population of own patients in order to compare the results in relation to the time of surgery after trauma. Methods In this retrospective case control study, all patients who had undergone hamstring avulsion surgery between 1/2011 and 3/2016 with a follow-up period of at least six months were asked to document their subjective functional outcome using the PHAT. Depending on the time of surgery after trauma, patients and the results of their questionnaires were assigned either to an acute (< 4 weeks), a delayed (1 - 3 months) or a chronic (> 3 months) group. Results In the named period, 64 patients had a hamstring refixation surgery, 57 of them could be included in the study. 39 (68 %) returned the completed PHAT questionnaire. The mean PHAT score (0 - 100 pts.) was 72.4 (SD +/- 21.0). There was no significant difference between the acute and the delayed group (77.0 +/- 22.0 vs. 63.4 +/- 16.2; p: 0.0673), whereas a significant difference was detected between the acute and the chronic group (77.0 +/- 22.0 vs. 58.3 +/- 20.2; p: 0.0214). Conclusion The results of this study show that an early diagnosis and subsequent operation of a hamstring tendon avulsion injury leads to significant better functional outcomes compared with chronic procedures. PMID- 28869999 TI - Preparation of tritium-labeled PF-622, a novel fatty acid amide hydrolase inhibitor. AB - To make a detailed characterization of the mechanism of inhibition and selectivity of a novel fatty acid amide hydrolase inhibitor PF-622, 3 tritium isotopomers were prepared. [3 H]PF-622a labeled at the piperazine ring B and [3 H]PF-622b labeled at both the ring B and phenyl ring A were synthesized via catalytic H(hydrogen)-T(tritium) exchange, utilizing 1 equiv and excess of Crabtree's catalyst, respectively. The preparation of [3 H]PF-622c labeled only at the phenyl ring A was achieved via tritiodebromination of the bromide precursor, using Pd(PPh3 )4 as a catalyst. The observations from these tritiation reactions might open a new perspective in the labeling for the targets having a similar moiety. PMID- 28869998 TI - Changes in consumption of added sugars from age 13 to 30 years: a systematic review and meta-analysis of longitudinal studies. AB - Added sugar intake during adolescence has been associated with weight gain and cardiometabolic risk factors. Moreover, dietary habits may persist into adulthood, increasing chronic disease risk in later life. This systematic review investigated changes in intake of added sugars between the ages of 13 and 30 years. Literature databases were searched for longitudinal studies of diet during adolescence or early adulthood. Retrieved articles were screened for studies including multiple measures of intake of sugars or sugary foods from cohort participants between the ages of 13 and 30. Data were analysed using random effects meta-analysis, by the three main nutrient and food group categories identified (PROSPERO: CRD42015030126). Twenty-four papers reported longitudinal data on intake of added sugar or sucrose (n = 6), sugar-sweetened beverages (SSBs) (n = 20) and/or confectionery (n = 9). Meta-analysis showed a non significant per year of age decrease in added sugar or sucrose intake (-0.15% total energy intake (95%CI -0.41; 0.12)), a decrease in confectionery consumption (-0.20 servings/week (95%CI -0.41; -0.001)) and a non-significant decrease in SSB consumption (-0.15 servings/week (95%CI -0.32; 0.02)). Taken together, the overall decrease in added sugar intake observed from adolescence to early adulthood may suggest opportunities for intervention to further improve dietary choices within this age range. PMID- 28870000 TI - Effectiveness of the 'Hold me Tight' Relationship Enhancement Program in a Self referred and a Clinician-referred Sample: An Emotionally Focused Couples Therapy Based Approach. AB - While evidence-based couple therapies are available, only a minority of troubled couples seek help and they often do this too late. To reach more couples earlier, the couple relationship education (CRE) group program "Hold me Tight" (HmT) based on Emotionally Focused Couples Therapy (EFCT) was developed. This study is the first to examine the effectiveness of HmT. Using a three-wave (waiting period, treatment, and follow-up) within-subject design, HmT was delivered to 79 self referred couples and 50 clinician-referred couples. We applied a comprehensive outcome measure battery. Our main findings were that (1) self-referred couples significantly improved during HmT on all measures, that is relationship satisfaction, security of partner-bond, forgiveness, daily coordination, maintenance behavior, and psychological complaints, with a moderate-to-large mean effect size (d = .63), which was maintained (d = .57) during the 3.5 month follow up; (2) in clinician-referred couples, who were vulnerable in terms of insecure attachment status and psychopathology, the improvement during HmT was moderate (d = .42), but this was reduced during the 3.5-month follow-up to a small effect (d = .22); (3) emotional functioning (typical HmT target) as well as behavioral functioning (typical Behavioral Couples Therapy-based CRE target) improved during HmT; and (4) individual psychological complaints, although not specifically targeted, were reduced during HmT. These findings suggest that HmT is a promising intervention for enhancement of relationship functioning. Clinical implications are discussed. PMID- 28870001 TI - An efficient new method for the synthesis of 3-[18 F]fluoro-4-aminopyridine via Yamada-Curtius rearrangement. AB - 4-Aminopyridine is a clinically approved drug to improve motor symptoms in multiple sclerosis. A fluorine-18-labeled derivative of this drug, 3-[18 F]fluoro 4-aminopyridine, is currently under investigation for positron emission tomography (PET) imaging of demyelination. Herein, the Yamada-Curtius reaction has been successfully applied for the preparation of this PET radioligand with a better radiochemical yield and improved specific activity. The overall radiochemical yield was 5 to 15% (n = 12, uncorrected) with a specific activity of 37 to 148 GBq/MUmol (end of synthesis) in a 90 minute synthesis time. It is expected that this 1 pot Yamada-Curtius reaction can be used to prepare similar fluorine-18-labeled amino substituted heterocycles. PMID- 28870002 TI - Use of the RenalGuard system to prevent contrast-induced AKI: A meta-analysis. AB - BACKGROUND: Contrast-induced kidney injury (CI-AKI) following cardiovascular interventions results in increased morbidity and mortality. RenalGuard (RG) is a novel, closed loop system which balances volume administration with forced diuresis to maintain a high urine output. We performed a meta-analysis of the existing data comparing use of RG to conventional volume expansion. METHODS: Ten studies were found eligible, of which four were randomized controlled trials. Of an aggregate sample size (N) of 1585 patients, 698 were enrolled in the four RCTs and 887 belonged to the remaining registries included in this meta-analysis. Primary outcomes included CI-AKI incidence and relative risk. Mortality, dialysis, and major adverse cardiovascular events (MACCE) were secondary outcomes. A random effects model was used and data were evaluated for publication bias. RESULTS: RG was associated with significant risk reduction in CI-AKI compared to control (RR: 0.30, 95%CI: 0.18-0.50, P < 0.01). CI-AKI in RG was found to be 7.7% versus 23.6% in the control group (P < 0.01). Use of RG was associated with decreased mortality (RR: 0.43, 95%CI: 0.18-0.99, P = 0.05), dialysis (RR: 0.20, 95%CI: 0.06-0.61, P = 0.01), and MACCE (RR: 0.42, 95%CI: 0.27 0.65, P < 0.01) compared to control. CONCLUSIONS: RG significantly reduces rates of CI-AKI compared to standard volume expansion and is also associated with decreased rates of death, dialysis, and MACCE. PMID- 28870004 TI - Inverse Correlation between Extracellular DNase Activity and Biofilm Formation among Chicken-Derived Campylobacter Strains. AB - Campylobacter jejuni and Campylobacter coli are important foodborne pathogenic bacteria, particularly in poultry meat. In this study, the presence of extracellular DNase activity was investigated for biofilm-deficient Campylobacter strains versus biofilm-forming Campylobacter strains isolated from chickens, to understand the relationship between extracellular DNase activity and biofilm formation. A biofilm-forming reference strain, C. jejuni NCTC11168, was co incubated with biofilm non-forming strains isolated from raw chickens or their supernatants. The biofilm non-forming strains or supernatants significantly prohibited the biofilm formation of C. jejuni NCTC11168. In addition, the strains degraded pre-formed biofilms of C. jejuni NCTC11168. Degradation of C. jejuni NCTC11168 biofilm was confirmed after treatment with the supernatant of the biofilm non-forming strain 2-1 by confocal laser scanning microscopy. Quantitative analysis of the biofilm matrix revealed reduction of extracellular DNA (16%) and proteins (8.7%) after treatment. Whereas the biofilm-forming strains C. jejuni Y23-5 and C. coli 34-3 isolated from raw chickens and the C. jejuni NCTC11168 reference strain showed no extracellular DNase activity against their own genomic DNA, most biofilm non-forming strains tested, including C. jejuni 2-1, C. coli 34-1, and C. jejuni 63-1, exhibited obvious extracellular DNase activities against their own or 11168 genomic DNA, except for one biofilm non-former, C. jejuni 22-1. Our results suggest that extracellular DNase activity is a common feature suppressing biofilm formation among biofilm non-forming C. jejuni or C. coli strains of chicken origin. PMID- 28870003 TI - Outcomes of patients with severely calcified aorto-ostial coronary lesions who underwent orbital atherectomy. AB - OBJECTIVES: We assessed the feasibility and safety of orbital atherectomy in patients with severely calcified aorto-ostial coronary artery lesions. BACKGROUND: The treatment of calcified aorta-ostial coronary artery lesions is technically challenging. Orbital atherectomy can potentially damage the guiding catheter if it is not retracted sufficiently during treatment of ostial lesions. Orbital atherectomy can also excessively whip if the guiding catheter is not close enough to the ostium to provide sufficient support. Several techniques can be performed to successfully treat ostial lesions with orbital atherectomy. METHODS: Our retrospective multicenter registry included 548 real-world patients who underwent orbital atherectomy, 59 (10.8%) of whom underwent treatment for aorto-ostial coronary artery lesions (left main artery [n = 35] and right coronary artery [n = 24]). The primary endpoint was the rate of 30-day major adverse cardiac and cerebrovascular events (MACCE), defined as the occurrence of death, myocardial infarction, target vessel revascularization, and stroke. RESULTS: The primary endpoint was similar in patients with and without ostial lesions (3.4% vs 2.2%, P = 0.2), as were the 30-day rates of death (1.7% vs 1.4%, P = 0.7), myocardial infarction (1.7% vs 1.0%, P = 0.3), target vessel revascularization (0% vs 0%, P > 0.91), and stroke (0% vs 0.2%, P > 0.9). Angiographic complications and stent thrombosis did not occur in patients with ostial lesions. CONCLUSIONS: Despite its technical challenges, orbital atherectomy appears to be a feasible and safe treatment option for calcified aorto-ostial coronary lesions. PMID- 28870005 TI - In Vitro Effect of DFC-2 on Mycolic Acid Biosynthesis in Mycobacterium tuberculosis. AB - DFC-2, a methyl 5-[2-(dimethylamino)ethoxy]-7,12-dioxo-7,12-dihydrodinaphtho[1,2 b:2',3'-d]furan-6-carboxylate, is reported to have antitubercular effects against Mycobacterium tuberculosis. At concentrations ranging from 0.19 to 0.39 MUg/ml, DFC-2 inhibited both drug-susceptible and -resistant strains of M. tuberculosis. Microarray analyses were employed to gain insights into the molecular mechanisms of DFC-2's action in M. tuberculosis. The most affected functional gene category was "lipid biosynthesis," which is involved in mycolic acid synthesis. The decrease in transcription of genes related to mycolic acid synthesis was confirmed by RT-PCR. Furthermore, we found that DFC-2 triggered a reduction in mycolic acid levels, showing a similar pattern to that of mycolic acid synthesis inhibitor isoniazid. These results may explain how this compound kills mycobacteria efficiently by inhibiting mycolic acid synthesis. PMID- 28870006 TI - Downregulation of Hepatic De Novo Lipogenesis and Adipogenesis in Adipocytes by Pinus densiflora Bark Extract. AB - Korean red pine (Pinus densiflora) bark extract, PineXol (PX), was investigated for its potential antioxidant and anti-inflammation effects in vitro. It was hypothesized that PX treatment (25-150 MUg/ml) would reduce the lipid synthesis in HepG2 hepatocytes as well as lipid accumulation in 3T3-L1 adipocytes. Hepatocytes' intracellular triglycerides and cholesterol were decreased in the PX 150 MUg/ml treatment group compared with the control (p < 0.05). Consequently, de novo lipogenic proteins (acetyl-CoA carboxylase 1, stearoyl-CoA desaturase 1, elongase of very long chain fatty acids 6, glycerol-3-phosphate acyltransferase 1, and sterol regulatory element-binding protein 1) were significantly decreased in hepatocytes by PX 150 MUg/ml treatment compared with the control (p < 0.05). In differentiated 3T3-L1 adipocytes, the lipid accumulation was significantly attenuated by all PX treatments (p < 0.01). Regulators of adipogenesis, including CCAAT-enhancer-binding proteins alpha, peroxisome proliferator-activated receptor gamma, and perilipin, were decreased in PX 100 MUg/ml treatment compared with the control (p < 0.05). In conclusion, PX might have anti-obesity effects by blocking hepatic lipogenesis and by inhibiting adipogenesis in adipocytes. PMID- 28870007 TI - Glycosylation Enhances the Physicochemical Properties of Caffeic Acid Phenethyl Ester. AB - In this study, we synthesized a glycosylated derivative of caffeic acid phenethyl ester (CAPE) using the amylosucrase from Deinococcus geothermalis with sucrose as a substrate and examined its solubility, chemical stability, and anti inflammatory activity. Nuclear magnetic resonance spectroscopy showed that the resulting glycosylated CAPE (G-CAPE) was the new compound caffeic acid phenethyl ester-4-O-alpha-D-glucopyranoside. G-CAPE was 770 times more soluble than CAPE and highly stable in Dulbecco's modified Eagle's medium and buffered solutions, as estimated by its half-life. The glycosylation of CAPE did not significantly affect its anti-inflammatory activity, which was assessed by examining lipopolysaccharide-induced nitric oxide production and using a nuclear factor erythroid 2-related factor 2 reporter assay. Furthermore, a cellular uptake experiment using high-performance liquid chromatography analysis of the cell-free extracts of RAW 264.7 cells demonstrated that G-CAPE was gradually converted to CAPE within the cells. These results demonstrate that the glycosylation of CAPE increases its bioavailability by helping to protect this vital molecule from chemical or enzymatic oxidation, indicating that G-CAPE is a promising candidate for prodrug therapy. PMID- 28870008 TI - Oleaginous Yeast Rhodosporidium toruloides as a Tool for Rapid Evaluation of Anti Obesity Candidates: Inhibitory Effect of Persimmon Leaf Fermentate on Lipid Accumulation. AB - The aim of this study was to examine the efficiency of Rhodosporidium toruloides as a new tool to evaluate the triglyceride (TG) reduction effects of anti-obesity candidate materials. Unfermented and fermented persimmon leaf hot water extracts (UFPLE and FPLE) were used as anti-obesity agents. The content of TG in R. toruloides treated with FPLE was less than those with UFPLE by about 11% (p < 0.05) relative to the control (R. toruloides incubated in YPD medium without the agents). Fat reduction in 3T3-L1 cells achieved by FPLE was about 13% higher than that achieved by UFPLE. PMID- 28870009 TI - Comprehensive Analysis of Proteomic Differences between Escherichia coli K-12 and B Strains Using Multiplexed Isobaric Tandem Mass Tag (TMT) Labeling. AB - The Escherichia coli K-12 and B strains are among the most frequently used bacterial hosts for scientific research and biotechnological applications. However, omics analyses have revealed that E. coli K-12 and B exhibit notably different genotypic and phenotypic attributes, even though they were derived from the same ancestor. In a previous study, we identified a limited number of proteins from the two strains using two-dimensional gel electrophoresis and tandem mass spectrometry (MS/MS). In this study, an in-depth analysis of the physiological behavior of the E. coli K-12 and B strains at the proteomic level was performed using six-plex isobaric tandem mass tag-based quantitative MS. Additionally, the best lysis buffer for increasing the efficiency of protein extraction was selected from three tested buffers prior to the quantitative proteomic analysis. This study identifies the largest number of proteins in the two E. coli strains reported to date and is the first to show the dynamics of these proteins. Notable differences in proteins associated with key cellular properties, including some metabolic pathways, the biosynthesis and degradation of amino acids, membrane integrity, cellular tolerance, and motility, were found between the two representative strains. Compared with previous studies, these proteomic results provide a more holistic view of the overall state of E. coli cells based on a single proteomic study and reveal significant insights into why the two strains show distinct phenotypes. Additionally, the resulting data provide in-depth information that will help fine-tune processes in the future. PMID- 28870010 TI - Optimal Temperature and Light Intensity for Improved Mixotrophic Metabolism of Chlorella sorokiniana Treating Livestock Wastewater. AB - Mixotrophic microalgal growth gives a great premise for wastewater treatment based on photoautotrophic nutrient utilization and heterotrophic organic removal while producing renewable biomass. There remains a need for a control strategy to enrich them in a photobioreactor. This study performed a series of batch experiments using a mixotroph, Chlorella sorokiniana, to characterize optimal guidelines of mixotrophic growth based on a statistical design of the experiment. Using a central composite design, this study evaluated how temperature and light irradiance are associated with CO2 capture and organic carbon respiration through biomass production and ammonia removal kinetics. By conducting regressions on the experimental data, response surfaces were created to suggest proper ranges of temperature and light irradiance that mixotrophs can beneficially use as two types of energy sources. The results identified that efficient mixotrophic metabolism of Chlorella sorokiniana for organics and inorganics occurs at the temperature of 30-40 degrees C and diurnal light condition of 150-200 MUmol E.m2.s-1. The optimal specific growth rate and ammonia removal rate were recorded as 0.51/d and 0.56/h on average, respectively, and the confirmation test verified that the organic removal rate was 105 mg COD.l-1.d-1. These results support the development of a viable option for sustainable treatment and effluent quality management of problematic livestock wastewater. PMID- 28870011 TI - Inhibitory Effect of the Ethanol Extract of a Rice Bran Mixture Comprising Angelica gigas, Cnidium officinale, Artemisia princeps, and Camellia sinensis on Brucella abortus Uptake by Professional and Nonprofessional Phagocytes. AB - In this study, we evaluated the inhibitory effect of a rice bran mixture extract (RBE) on Brucella abortus pathogenesis in professional (RAW 264.7) and nonprofessional (HeLa) phagocytes. We fermented the rice bran mixture and then extracted it with 50% ethanol followed by gas chromatography-mass spectrometry to identify the components in RBE. Our results clearly showed that RBE caused a significant reduction in the adherence of B. abortus in both cell lines. Furthermore, analysis of phagocytic signaling proteins by western blot assay revealed that RBE pretreatment resulted in inhibition of phosphorylation of JNK, ERK, and p38, leading to decline of internalization compared with the controls. Additionally, the intensity of F-actin observed by fluorescence microscopy and FACS was remarkably reduced in RBE-pretreated cells compared with control cells. However, the intracellular replication of B. abortus within phagocytes was not affected by RBE. Taken together, these findings suggest that the phagocytic receptor blocking and suppressive effects of RBE on the MAPK-linked phagocytic signaling pathway could negatively affect the invasion of B. abortus into phagocytes. PMID- 28870012 TI - Lactoferrin Protects Human Mesenchymal Stem Cells from Oxidative Stress-Induced Senescence and Apoptosis. AB - Mesenchymal stem cells (MSCs) have been suggested as a primary candidate for cell therapy applications because they have self-renewal and differentiation capabilities. Although they can be expanded in ex vivo system, clinical application of these cells is still limited because they survive poorly and undergo senescence or apoptosis when transplanted and exposed to environmental factors such as oxidative stress. Thus, reducing oxidative stress is expected to improve the efficacy of MSC therapy. The milk protein lactoferrin is a multifunctional iron-binding glycoprotein that plays various roles, including reduction of oxidative stress. Thus, we explored the effect of lactoferrin on oxidative stress-induced senescence and apoptosis of human MSCs (hMSCs). Measurement of reactive oxygen species (ROS) revealed that lactoferrin inhibited the production of hydrogen peroxide-induced intracellular ROS, suggesting lactoferrin as a good candidate as an antioxidant in hMSCs. Pretreatment of lactoferrin suppressed hydrogen peroxide-induced senescence of hMSCs. In addition, lactoferrin reduced hydrogen peroxide-induced apoptosis via inhibition of caspase-3 and Akt activation. These results demonstrate that lactoferrin can be a promising factor to protect hMSCs from oxidative stress-induced senescence and apoptosis, thus increasing the efficacy of MSC therapy. PMID- 28870013 TI - Can documented coronary vasospasm be the smoking gun in settling the etiology of sudden cardiac death? PMID- 28870014 TI - Risk of hepatitis B virus-related hepatocellular carcinoma development is much higher in Koreans than in Taiwanese. PMID- 28870015 TI - Significance of duodenal mucosal lesions: can they be a clue to a systemic disease? PMID- 28870016 TI - Clinical features and treatment outcomes of blastic plasmacytoid dendritic cell neoplasm: a single-center experience in Korea. AB - BACKGROUND/AIMS: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that typically presents in the form of skin manifestations with or without lymph node and bone marrow involvement. Given its rarity and recent recognition as a distinct pathological entity, no standard of treatment exists for this aggressive disease and its prognosis is particularly dismal. METHODS: We retrospectively analyzed clinical features and treatment outcomes of patients who were diagnosed with BPDCN between 2000 and 2014. RESULTS: Ten patients had a median age at diagnosis of 41 years (range, 18 to 79), and seven patients were male. Sites of disease involvement were the skin (n = 7), lymph node (n = 5), bone marrow (n = 2), liver (n = 2), spleen (n = 2), and soft tissue (n = 1). Intensified chemotherapy regimens such as hyperCVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), and VPDL (vincristine, methylprednisolone, daunorubicin, L asparaginase) were used as a first-line treatment. Although all patients treated with intensified chemotherapy showed an objective response (five patients with complete response) with median progression-free survival of 11.2 months (range 6.2 to 19.4), complete remission was not sustained for more than 2 years in any case. The response was relatively long-lived compared with previously reported CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone)-like regimens, but the above regimens do not result in long-term remission. CONCLUSIONS: All patients treated with hyperCVAD or VPDL showed an objective response, but the duration of response was relatively short. Thus, the development of more effective induction as well as consolidation treatment strategy should be warranted to improve this rare disease entity. PMID- 28870018 TI - Exploring the pros and cons of mechanistic case diagrams for problem-based learning. AB - PURPOSE: Mechanistic case diagram (MCD) was recommended for increasing the depth of understanding of disease, but with few articles on its specific methods. We address the experience of making MCD in the fullest depth to identify the pros and cons of using MCDs in such ways. METHODS: During problem-based learning, we gave guidelines of MCD for its mechanistic exploration from subcellular processes to clinical features, being laid out in as much detail as possible. To understand the students' attitudes and depth of study using MCDs, we analyzed the results of a questionnaire in an open format about experiencing MCDs and examined the resulting products. RESULTS: Through the responses to questionnaire, we found several favorable outcomes, major of which was deeper insight and comprehensive understanding of disease facilitated by the process of making well-organized diagram. The main disadvantages of these guidelines were the feeling of too much workload and difficulty of finding mechanisms. Students gave suggestions to overcome these problems: cautious reading of comprehensive texts, additional guidance from staff about depth and focus of mechanisms, and cooperative group work. From the analysis of maps, we recognized there should be allowance of diversities in the appearance of maps and many hypothetical connections, which could be related to an insufficient understanding of mechanisms in nature. CONCLUSION: The more detailed an MCD task is, the better students can become acquainted with deep knowledges. However, this advantage should be balanced by the results that there are many ensuing difficulties for the work and deliberate help plans should be prepared. PMID- 28870017 TI - Research trends in studies of medical students' characteristics: a scoping review. AB - The purpose of this study is to investigate domestic and international research trends in studies of medical students' characteristics by using the scoping review methods. This study adopted the scoping review to assess papers on the characteristics of medical students. The procedure of research was carried out according to the five steps of the scoping review. The full texts of 100 papers are obtained and are read closely, after which suitable 88 papers are extracted by us for this research. The review is mapped by the year of the study, source, location, author, research design, research subject, objective, and key results. The frequency is analyzed by using Microsoft Excel and SPSS. We found 70 papers (79.5%) on a single medical school, 15 (17.0%) on multiple medical schools, and three (3.4%) on mixed schools, including medical and nonmedical schools. Sixty nine (79.5%) were cross-sectional studies and 18 (20.5%) were longitudinal studies. Eighty-two papers (93.2%) adopted questionnaire surveys. We summarized research trends of studies on medical students in Korea and overseas by topic, and mapped them into physical health, mental health, psychological characteristics, cognitive characteristics, social characteristics, and career. This study provides insights into the future directions of research for the characteristics of medical students. PMID- 28870019 TI - The mediating effect of calling on the relationship between medical school students' academic burnout and empathy. AB - PURPOSE: This study is aimed at identifying the relationships between medical school students' academic burnout, empathy, and calling, and determining whether their calling has a mediating effect on the relationship between academic burnout and empathy. METHODS: A mixed method study was conducted. One hundred twenty seven medical students completed a survey. Scales measuring academic burnout, medical students' empathy, and calling were utilized. For statistical analysis, correlation analysis, descriptive statistics analysis, and hierarchical multiple regression analyses were conducted. For qualitative approach, eight medical students participated in a focus group interview. RESULTS: The study found that empathy has a statistically significant, negative correlation with academic burnout, while having a significant, positive correlation with calling. Sense of calling proved to be an effective mediator of the relationship between academic burnout and empathy. CONCLUSION: This result demonstrates that calling is a key variable that mediates the relationship between medical students' academic burnout and empathy. As such, this study provides baseline data for an education that could improve medical students' empathy skills. PMID- 28870020 TI - Career exploration behavior of Korean medical students. AB - PURPOSE: This study is to analyze the effects of medical students' social support and career barriers on career exploration behavior mediated by career decision making self-efficacy. METHODS: We applied the t-test to investigate the difference among the variables based on gender and admission types. Also, we performed path analysis to verify the effect of perceived career barriers and social support on career exploration behavior with career decision efficacy as a mediator. RESULTS: First, we noted statistically significant gender and admission type difference in social support, career barriers and career exploration behaviors. Second, social support and career barriers were found to influence career exploration behavior as a mediating variable for career decision-making self-efficacy. CONCLUSION: Social support and career barriers as perceived by medical students influenced their career exploration behavior, with their decision-making self-efficacy serving as a full mediator. Therefore, this study has educational implications for career program development and educational training for career decision-making self-efficacy. PMID- 28870021 TI - Characteristics of medical teachers using student-centered teaching methods. AB - PURPOSE: This study investigated characteristics of medical teachers who have adopted student-centered teaching methods into their teaching. METHODS: A 24-item questionnaire consisted of respondent backgrounds, his or her use of student centered teaching methods, and awareness of the school's educational objectives and curricular principles was administered of faculty members at a private medical school in Korea. Descriptive statistics and chi-square analysis were conducted to compare faculty use of student-centered approaches across different backgrounds and awareness of curricular principles. RESULTS: Overall response rate was 70% (N=140/200), approximately 25% (n=34) of whom were using student centered teaching methods. Distributions in the faculty use of student-centered teaching methods were significantly higher among basic sciences faculty (versus clinical sciences faculty), with teaching experiences of over 10 years (versus less than 10 years), and who were aware of the school's educational objectives and curricular principles. CONCLUSION: Our study indicates differences in medical faculty's practice of student-centered teaching across disciplines, teaching experiences, and their understanding of the school's educational objectives curricular principles. These findings have implications for faculty development and institutional support to better promote faculty use of student-centered teaching approaches. PMID- 28870022 TI - Playing to our human strengths to prepare medical students for the future. AB - We are living in an age where artificial intelligence and astounding technological advances are bringing truly remarkable change to healthcare. Medical knowledge and skills which form the core responsibility of doctors such as making diagnoses may increasingly be delivered by robots. Machines are gradually acquiring human abilities such as deep learning and empathy. What, then is the role of doctors in future healthcare? And what direction should medical schools be taking to prepare their graduates? This article will give an overview of the evolving technological landscape of healthcare and examine the issues undergraduate medical education may have to address. The experience at The University of Hong Kong will serve as a case study featuring several curricular innovations that aim to empower medical graduates with the capabilities to thrive in the future. PMID- 28870023 TI - Medical education: addressing questions that require attention. PMID- 28870024 TI - Personal professional identity formation through interprofessional learning and early patient encounter during preclinical years. PMID- 28870026 TI - Optogenetics: Control of Brain Using Light AB - Neuronal cells communicate with each other by producing electrical signals or action potentials (APs). Different ion channels, including Na+, K+ and Ca2+ channels, are involved in generation of AP. Once an AP is generated in the soma, it travels down entire the axon length toward its terminal in a self-generating fashion that ultimately conveys information between neurons in the neural circuit. Depending on the neurotransmitter, each neuron inhibits or excites other neurons in a certain network. For instance, glutamate released from glutamatergic neurons, opens AMPA and NMDA channels permitting influx of Na+/Ca2+, which leads to postsynaptic depolarization. On the other hand, GABA released from GABAergic neurons results in Cl- influx and postsynaptic hyperpolarization. One of the major challenges in neuroscience is how actions of individual cells in the brain could underlie a certain behavior such as attention, food consumption, aggression, cognition, and movement... PMID- 28870025 TI - Clinical characteristics of patients with chronic hepatitis B who developed genotypic resistance to entecavir: Real-life experience. AB - BACKGROUND/AIMS: Clinical characteristics of patients with chronic hepatitis B (CHB) who developed genotypic resistance to entecavir (ETV) were compared to those without resistance. METHODS: Two hundred fifty eight CHB patients who underwent ETV treatment in our institution from July 2007 to May 2013 were included. RESULTS: Eight (3.1%) patients developed genotypic resistance to ETV during the follow-up period. The patterns of genotypic resistance to ETV were as follows: L180M + M204V + S202G (n=3); M204I + V173M (n=1); I169V + V173M (n=1); L180M + M204V + V173L (n=1); L180M + M204V + V173L + M250V (n=1); M204I + V214A + P237H (n=1). The cumulative occurrence rates of genotypic resistance to ETV were not significantly different between CHB patients with prior nucleos(t)tide analogues (NA) exposure (NA experienced, n=56) and NA naive patients (n=202, P=0.823 by log rank comparison). Older age, higher baseline log10hepatitis B virus-deoxynucleic acid (log10HBV-DNA), higher log10HBV-DNA at 3, 6, 12 and 24 months after baseline, and complete virologic response (CVR, undetectable serum HBV-DNA by polymerase chain reaction 6 months after ETV treatment) were significant contributors to the development of genotypic resistance to ETV. Multivariate analyses showed higher log10HBV-DNA 6 months after baseline and absence of CVR were independent and significant contributors to the development of ETV resistance. CONCLUSIONS: Clinical characteristics of patients who developed ETV resistance were higher log10HBV-DNA 6 months after baseline and absence of CVR during the ETV treatment. PMID- 28870028 TI - [Importance of rehabilitation in management of ankylosing spondylitis]. PMID- 28870027 TI - [Chronic disease management of rheumatic diseases, are you ready]. PMID- 28870029 TI - [Gitelman syndrome: early diagnosis and treatment]. PMID- 28870030 TI - [Physician professionalism, medicare reform, and reimbursement]. PMID- 28870031 TI - [The clinical characteristics of 346 patients with IgG4-related disease]. AB - Objective: To analyze the clinical characteristics of IgG4-related disease (IgG4 RD)so as to improve the understanding of IgG4-RD in China. Methods: IgG4-RD patients were recruited from Peking Union Medical College Hospital between January 2011 and January 2016. All patients were followed-up for more than 6 months. The demographic characteristics, symptoms, organ involvements, laboratory examinations and treatment efficacy were evaluated and analyzed. Results: A total of 346 patients were finally enrolled, including 230 males (66.5%) and 116 females (33.5%). The mean age of disease onset was (53.8+/-14.2) years old. The mostly common involved organs were lymph nodes (56.4%) and submandibular glands (52.6%). Other affected organs and manifestations included: swelling of the lacrimal glands (46.5%), autoimmune pancreatitis (38.4%), pulmonary involvement (28.0%), sclerosing cholangitis (25.4%), naso-sinusitis (23.4%), parotid gland swelling (21.7%), retroperitoneal fibrosis (19.9%), large arteries involvement (9.5%), kidney involvement (obstructive nephropathy caused by retroperitoneal fibrosis was excluded) (6.9%), skin lesions (6.4%). Rare features consisted of thyroid glands, pituitary glands, gastrointestinal tract, pachymeningitis, pericardium, sclerosing mediastinitis and orchitis. The majority of patients had multi-organ involvement, such as 74.3% patients with 3 and more, 18.2% and 7.5% patients with 2 and single organ involvement respectively. The average IgG4-RD responder index (IgG4-RD RI) was 13.21+/-5.70. History of allergy was found in 172 (49.7%) patients. As to the laboratory tests, elevated serum IgG4 levels were confirmed in 285 (94.1%) patients, which was positively correlated with IgG4-RD RI. There were 33.5% patients receiving monotherapy of glucocorticoid, 52.6% treated with glucocorticoids combined with immunosuppressive agents, 4.9% patients with immunosuppressant only, and 9.0% patients with mild disease not receiving medication. The majority (336, 97.1%) patients improved the above regimens. Conclusion: IgG4-RD is a systemic fibro-inflammatory disease with multiple organ involvement. The mostly common involved organs include lymph node, submandibular glands, and pancreas. Glucocorticoids and immunosuppressive agents were effective for IgG4-RD. PMID- 28870032 TI - [Neutrophil extracellular traps-induced endothelial cell damage in the pathogenesis of dermatomyositis-associated interstitial lung disease]. AB - Objective: To explore the role of neutrophil extracellular traps (NETs)-induced endothelial cell damage in the pathogenesis of dermatomyositis (DM)-associated interstitial lung disease(ILD). Methods: Serum free DNA and krebs von den lungen 6 (KL-6) level were tested in healthy controls, dermatomyositis patients with or without interstitial lung disease (DM-ILD and DM-NILD). Subjects' peripheral blood neutrophils were stimulated with phorbol 12-myristate 13-acetate (PMA), then human umbilical vein endothelial cells (HUVECs) were co-cultured with NETs. The cell morphology was observed by the inverted phase contrast microscope. Cell viability was detected by cell counting kit-8 (CCK8). Results: The concentration of serum free DNA in DM patients [(271.27+/- 76.53) MUg/L] was significantly higher than that in health control (HC)[(152.89+/-37.34) MUg/L, P<0.001]. Moreover, free DNA level in DM-ILD patients [(302.67+/-74.15) MUg/L] was higher than that in DM-NILD patients [(235.59+/-63.55 ) MUg/L, P<0.005]. The concentration of KL-6in DM patients [(3.08+/-2.07) MUg/L]was higher than that in HC[(0.87+/-0.51) MUg/L, P<0.001]. Similarly, KL-6 in DM-ILD patients [(4.00+/ 2.44) MUg/L ] was higher than that of DM-NILD patients [(2.03+/-0.61) MUg/L, P<0.005]. Free DNA and KL-6 were positively correlated (r=0.251, P<0.05). The survival of endothelial cells in DM group (53+/-11)% was lower than that of HC group [(70+/-5)%, P<0.001]. Not surprisingly, the survival of endothelial cells in DM-ILD group (44+/-4) % was lower than that in DM-NILD group [(61+/-8)%, P<0.01]. Conclusion: NETs could play an important role in the pathogenesis of dermatomyositis associated interstitial lung disease, suggesting that NETs may be the potential therapeutic target. PMID- 28870033 TI - [The expression and clinical significance of proprotein convertase subtilisin kexin 9 in rheumatoid arthritis]. AB - Objective: To assess the expression and significance of proprotein convertase subtilisin kexin 9 (PCSK9) in patients with rheumatoid arthritis (RA). Methods: Sixty-five RA patients and forty-seven healthy controls were recruited in this study. The body mass index (BMI) and serum total cholesterol(TC), triglyceride(TG), high density lipoprotein(HDL), lipoprotein a, low density lipoprotein(LDL), very low density lipoprotein(VLDL), apolipoprotein A(ApoA), apolipoprotein B(ApoB) and the ratio of LDL-C/HDL-C were tested. Other parameters included disease activity score 28(DAS28), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibody, erythrocyte sedimentation rate (ESR), c reactive protein (CRP). Serum PCSK9 level was measured by ELISA and compared between RA patients and healthy controls. Results: (1) The serum PCSK9 levels in RA patients were higher than those in healthy controls[(409.36+/-223.52) MUg/L vs (292.19+/-109.79) MUg/L, P<0.05]. (2) Compared with subgroup of moderate and low active disease and patients in remission, PCSK9 was significantly higher in patients with highly active disease (P<0.05). (3) The serum PCSK9 levels were positively correlated with RF, TC, TG, LDL, very low density lipoprotein (VLDL), ApoB, with r values as 0.303, 0.490, 0.320, 0.451, 0.319, 0.463, respectively (P<0.05). (4) Multiple stepwise regression analysis showed that DAS28, RF, TC and LDL-C/HDL-C were relevant factors for PCSK9 in RA patients. Conclusions: The serum PCSK9 level is elevated in RA patients, which is related to RF, disease activity, TC, TG, LDL, VLDL, ApoB. This suggests that PCSK9 is potentially linked to inflammatory reaction and lipid metabolism in rheumatoid arthritis. PMID- 28870034 TI - [The efficacy and safety of insulin degludec versus insulin glargine in insulin naive subjects with type 2 diabetes: results of a Chinese cohort from a multinational randomized controlled trial]. AB - Objective: To compare the safety and efficacy of insulin degludec (IDeg) with those of insulin glargine (IGlar) in insulin-naive subjects with type 2 diabetes (T2DM). Methods: This was a 26-week, randomized, open-label, parallel-group, treat-to-target trial in 560 Chinese subjects with T2DM (men/women: 274/263, mean age 56 years, mean diabetes duration 7 years) inadequately controlled on oral antidiabetic drugs (OADs). Subjects were randomized 2?1 to once-daily IDeg (373 subjects) or IGlar(187 subjects), both in combination with metformin. The primary endpoint was changes from baseline in glycosylated hemoglobin(HbA1c) after 26 weeks. Results: Mean HbA1c decreased from 8.2% in both groups to 6.9% in IDeg and 7.0% in IGlar, respectively. Estimated treatment difference (ETD) of IDeg-IGlar in change from baseline was -0.10% points (95%CI-0.25-0.05). The proportion of subjects achieving HbA1c<7.0% was 56.3%and 49.7% with IDeg and IGlar, respectively [estimated odds ratio of IDeg/IGlar: 1.26(95%CI 0.88-1.82)]. Numerically lower rateof overall confirmed hypoglycaemia and statistically significantly lower nocturnal confirmed hypoglycemia were associated with IDeg compared with IGlar, respectively [estimated rateratio of IDeg/IGlar 0.69(95%CI 0.46-1.03), and 0.43(95%CI 0.19-0.97)]. No differences in other safety parameters were found between the two groups. Conclusions: IDeg was non-inferior to IGlar in terms of glycaemic control, and was associated with a statistically significantly lower rate of nocturnal confirmed hypoglycaemia. IDeg is considered to be suitable for initiating insulin therapy in Chinese T2DM patients on OADs requiring intensified treatment. Clinical trail registration: Clinicaltrials.gov, NCT01849289. PMID- 28870035 TI - [Association of Crohn's disease with T cell immunoglobulin and mucin domain 3 gene polymorphisms in Chinese patients]. AB - Objective: To explore the association of Crohn's disease (CD) with T cell immunoglobulin and mucin domain 3 (Tim-3) gene polymorphisms in patients of Zhejiang Han population in China. Methods: A total of 308 CD patients and 573 age and sex-matched healthy controls were enrolled in our study. Two single nucleotide polymorphisms (SNPs) of Tim-3 (rs1036199 and rs10515746) were examined by the improved multiple ligase detection reaction technique (iMLDR). Analyses of linkage disequilibrium and haplotype were also performed by Haploview 4.2 software in all study subjects. Results: In general, the allele and genotype frequencies of Tim-3 (rs1036199 and rs10515746) were not statistically different between CD patients and the controls (all P>0.05). According to "the Montreal Classification" , CD patients were divided into different subgroups. The variant allele (C) and genotype (AC+ CC) of rs1036199 were more frequent in CD patients with penetrating diseases than in the controls (10.4% vs 1.7%, P=0.002; 20.8% vs 3.5%, P=0.023). Similar conclusions were also drawn for the variant allele (A) and genotype (CA+ AA) of rs10515746 in patients with penetrating diseases when compared with the controls (10.4% vs 2.2%, P=0.000; 20.8% vs 4.2%, P=0.033, respectively). The two SNPs of Tim-3 were in strong linkage disequilibrium (D'=1.0, r2=0.928). The haplotype (AC) formed by their wild-type alleles (A) and (C) was decreased in patients with penetrating CD compared with the controls (89.6% vs 98.3%, P=0.000). However, the haplotype (CA) formed by their variant alleles was more frequent in patients with penetrating CD than in the controls (10.4% vs 1.6%, P=0.000). Conclusions:Tim-3 (rs1036199 and rs10515746) variations might be correlated with the enhanced risk of penetrating diseases in CD patients. Furthermore, the haplotype (AC) and (CA) formed by the two SNPs might be a protective and a risky factor for penetrating CD respectively. PMID- 28870036 TI - [The correlation of brachial ankle pulse wave velocity with arterosclerosis at different estimated levels of glomerular filtration rate]. AB - To explore the relationship between brachial ankle artery pulse wave velocity of the (baPWV) in different estimation GFR (eGFR) groups and atherosclerosis.In 2010, 2012 and 2014, eGFR and baPWV were detected in 1 427 healthy persons.As eGFR level decreased, baPWV increased accordingly with higher proportion of baPWV >=1 400 cm/s.The percentage of eGFR lower than 60 ml.min-1.1.73 m-2 was similar in subgroups with different baPWV.However, the proportion of eGFR reduction>=30% decreased according to the elevation of baPWV.Multivariate logistic regression analysis indicated the lower the eGFR, the higher the risk of atherosclerosis.Low eGFR is an independent risk factor for atherosclerosis. PMID- 28870037 TI - [Clinical characteristics of a case of Gitelman syndrome and the gene detection analysis in family]. PMID- 28870038 TI - [Gene analysis in a family with adult onset Bartter syndrome type 2]. PMID- 28870040 TI - [A case report of IgA-kappa light chain multiple myeloma following essential thrombocythaemia]. PMID- 28870039 TI - [Four cases of gastritis cystica profunda]. PMID- 28870041 TI - [Gonadotropin-releasing hormone agonist to treat acute intermittent porphyria: a case report]. PMID- 28870043 TI - [Research of systemic sclerosis sine scleroderma]. PMID- 28870042 TI - [Building up holistic care in a patient with arthritis and lower limb edema]. PMID- 28870044 TI - [Advances in diagnosis and treatment of peripartum cardiomyopathy]. PMID- 28870045 TI - [Advances in eosinophilic disorders]. PMID- 28870046 TI - [The Chinese consensus for screening, diagnosis and management of Barrett's esophagus and early adenocarcinoma(2017, Wanning)]. AB - Patients with Barrett's esophagus (BE)/columnar lined esophagus (CLE) and adenocarcinoma are increasing, in whom 0.61% BE/CLE would develop to adenocarcinoma. The prognosis of esophageal cancer is related to the tumor stage at diagnosis. To standardize the screening, diagnosis and therapy of BE and adenocarcinoma in China, 31 digestive diseases and digestive endoscopy experts and digestive histologists drafted the consensus on the basis of clinical experience and references. The consensus defined BE as a complication of gastroesophageal reflux disease. The normal distal squamous epithelial lining is replaced by columnar epithelial. The squamous-columnar junction (SCJ) is above the gastroesophageal junction (GEJ) >=1 cm and proved by endoscopy and histology. Adenocarcinoma developing in BE mucosa is called BE adenocarcinoma. The early BE adenocarcinoma is divided into 4 stages: M1, M2, M3 and M4, according to the depth of tumor infiltration without expanding beyond mucosa. Because 90% esophageal cancers are esophageal squamous cell carcinoma (ESCC) in China, this consensus emphasizes the significance of screening BE and adenocarcinoma in esophageal cancers. The diagnosis of BE should meet the following criteria: under endoscopy, the normal distal squamous epithelial lining is replaced by columnar epithelial (SCJ is above the GEJ >=1cm), which is confirmed by histology. The lesion should be further assessed by electron staining endoscopy such as narrow band imaging (NBI), flexile spectral imaging color enhancement (FICE), i-scan, and endoscopic ultrasonography (EUS) to choose the optimal therapy. Endoscopic resection such as endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) is preferred. Radiofrequency ablation (RFA), photodynamic therapy (PDT), cryotherapy, Argon plasma coagulation (APC) are alternative therapeutic regimens yet should be administrated cautiously. The standardized histologic result is very important, which can be used to assess the response effect, further treatment and follow-up schedule. It is recommended that the follow-up would better be done with high resolution endoscope. Patients without intestinal metaplasia in the four quadrants of BE and the length <3 cm is recommended to be excluded from the follow-up. BE with intestinal metaplasia<3 cm is recommended only follow-up for 3-5 years. BE and metaplasia>=3 cm is recommended to be observed every 2-3 years. PMID- 28870047 TI - [Expert consensus for the diagnosis and treatment of patients with Gitelman syndrome]. AB - Gitelman syndrome (GS) is an autosomal recessive, salt-losing tubulopathy caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. GS is one of the most common inherited renal tubulopathy with a prevalence estimated at about one to ten per 40 000 people. The prevalence of GS is even higher in Asia than other countries. The majority of GS patients present mild and nonspecific symptoms during adolescence or adulthood. Common clinical manifestations are associated with electrolyte abnormalities, such as muscle weakness, salt craving and tetany. However, the phenotype of GS is highly variable and links to the quality of life. Diagnosis of GS is based on the clinical symptoms, biochemical abnormalities (normal/low blood pressure, metabolic alkalosis, hypomagnesemia, hypocalciuria and increased activity of renin-angiotensin- aldosterone system) and genetic test. Genetic diagnosis of GS is recommended for all patients and the diagnosis is confirmed when biallelic inactivating SLC12A3 mutations are identified. The differential diagnosis includes renal tubular acidosis, primary hyperaldosteronism, Bartter syndrome, Liddle syndrome and other diseases that cause hypokalemia. Among them Bartter syndrome (especially type III) is the most important genetic disorder to consider due to its similar manifestations with GS. All GS patients are encouraged to keep high-sodium diet. Magnesium and potassium supplements (oral or intravenous) are usually given to GS patients to improve clinical symptoms. Other medicines such as aldosterone receptor antagonists, angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) and prostaglandin synthetase inhibitors (PGSIs) are alternative choices of treating hypokalemia, but the side-effects of these medication should be well considered. Management of GS includes health education, complication evaluation and regular follow-up. Annual evaluation by a nephrologist is recommended. Extra evaluation and treatment depend on special conditions, such as pregnancy, perioperative or growth period. Antenatal diagnosis for GS is technically feasible but not recommend due to the benign prognosis in the majority of patients. In general, this expert consensus statement aims to establish an initial framework for the better diagnosis, treatment and management of Chinese patients with GS. PMID- 28870048 TI - [The treatment options of pancreatic neuroendocrine neoplasm with liver metastasis]. AB - Liver metastasis is the one of the main prognostic factors of pancreatic neuroendocrine neoplasm (PNEN). With the development of multidisciplinary collaboration among surgical oncology, medical oncology, and intervention treatment, the treatment of PNEN with liver metastasis gradually tends to become diversification. Surgery is still the only way for curing the patients with pancreatic neuroendocrine tumor with liver metastasis when the histological types are G1 and G2. Medical oncology and intervention treatment could be selected for those having PNEN with diffuse liver metastasis or those cannot tolerate surgery. Liver transplantation only suits for a small number of selected patients. The present article explored the relationship between histological classifications and the treatment options of PNEN with liver metastasis, and discussed the specific treatments from perspectives of surgical treatment, medical treatment and intervention treatment. PMID- 28870049 TI - [Clinical effect of terminal branches portal vein embolization combined with transcatheter arterial chemoembolization on liver neoplasms]. AB - Objective: To analyze the efficacy of branches portal vein embolization (TBPVE) combined with transcatheter arterial chemoembolization (TACE) on liver neoplasms. Methods: From August 2016 to May 2017, there were 13 patients including 11 males and 2 females with primary hepatocellular carcinoma who underwent TBPVE+ TACE , among whom there were 11 cases with a history of HBV infection.Average age of the 13 patients was (60.8+/-6.2)years. The live function of all patients were Child Pugh A classification.The CT or MRI images of each patient was reconstructed and the standard liver volume(SLV) before TBPVE+ TACE was (1 181.2+/-49.3)ml, estimated future liver remnant(FLR) was (326.1+/-72.1)ml and FLR/SLV was (27.6+/ 6.0)%.The puncture site for TBPVE was determined by the three-dimensional reconstruction of portal vein.CT scan or MRI, AFP and liver function test were repeated after one and two weeks after TBPVE+ TACE.FLR and FLR/SLV were calculated respectively.Hepatectomy would be performed if the patients agreed.The postoperative complications were analyzed. Results: On the 7thday after TBPVE+ TACE, the FLR/SLV was(42.6+/-8.0)% and the FLR increasement was(56.0+/-24.6)%.The level of AFP decreased from(87.9+/-81.8)MUg/L to (29.7+/-20.9)MUg/L.On the 14thday after TBPVE+ TACE, the FLR/SLV was(45.8+/-6.2)% and the FLR increasement was(71.8+/-29.0)%.Four patients underwent surgery which including 2 right hepatectomies and 2 right trisegmentectomies in 2 weeks after TBPVE+ TACE.Nine patients were performed with targeting intratumoral lactic acidosis TACE (TILA TACE). No severe complication occurred in all patients. Conclusions: TBPVE could induce a rapid growth of the liver remnant but still with the concern of inducing the growth of neoplasms at the same time.To combine TACE in TBPVE therapy not also can the growth of neoplasms be prevented but also inducing its shrinking.This method might be a new mode for the treatment of hepatocellular carcinoma. PMID- 28870050 TI - [Survey of current status of prevention of venous thromboembolism after thoracic surgery in China]. AB - Objective: To investigate the current status of prevention and treatment of venous thromboembolism (VTE) after thoracic surgery in China. Method: Chinese thoracic surgeons were investigated by the online questionnaire which was based on the Chinese version of International VTE questionnaire added with 6 extra questions with Chinese characteristics. Results: A total of 1 150 valid questionnaires were retrieved, accounting for about 20% of all the Chinese thoracic surgeons. The surgeons participating in this survey came from all over the country, most of whom were experienced professionals with high academic titles.For lung cancer patients, 66.96% (770/1 150) of the surgeons suggested that VTE prophylaxis should start 1 day after lung cancer resection, and 64.61% (743/1 150) of the surgeons suggested extending after discharge. For esophagestomy patients, and 48.35% (514/1 063) of the surgeons suggested that there was no need for patients to extend VTE prophylaxis after discharge. More than half of the surgeons participating in this survey made decision of the method and duration of VTE prophylaxis after lung cancer resection (53.91% (620/1 150)) or esophagectomy (52.49% (558/1 063)) depending on the clinical experience.Low molecular weight heparin was the common choice of most surgeons in VTE prophylaxis. More than half of the surgeons thought that previous history of VTE, advanced age, complicated with thrombophilia, obesity (body mass index>30 kg/m2), duration of surgery longer than 6 hours and family history of VTE were key risk factors of the occurrence of postoperative VTE. Conclusions: The results of this survey are highly credible and are a good reflection of the current status of VTE prevention and treatment after thoracic surgery in China. This survey will play an important role in promoting VTE prevention and treatment in Chinese thoracic surgery department, it will also provide data support for government setting new policies, hospital construction of VTE prevention and control as well as raising physicians' awareness. PMID- 28870051 TI - [Choices of methods in dividing the neck of pancreas in laparoscopic pancreaticoduodenectomy]. AB - Objective: To discuss the methods, skills and experiences of dividing the neck of pancreas in laparoscopic pancreaticoduodenectomy(LPD). Methods: The clinical data of 58 patients with periampullary tumors who received LPD at the Union Hospital of Fujian Medical University from December 2014 to January 2017 were retrospectively analyzed.There were 26 males and 32 females, ranged from 18 to 65 years, with a mean age of (46+/-12)years. Results: All of the 58 patients underwent operation smoothly.Three cases underwent open anastomosis via an auxiliary incision after the total resection of specimen laparoscopically, due to the early learning curve of LPD.Two cases transformed into open operation as a result of tumor vascular invasion to portal vein(PV) or superior mesenteric vein(SMV). Fifty-three cases underwent laparoscopic or laparoscopic combined with robotic pancreaticoduodenectomy completely.Forty-two cases ligated gastroduodenal artery(GDA), fully penetrated the interspace between rear of pancreatic neck and SMV, suspended the pancreas and then divided the neck of pancreas from inferior to superior. Thirteen cases fully dissected the interspace between rear of pancreatic neck and SMV, divided the neck of pancreas from inferior to superior and then ligated GDA.Three cases ligated GDA, dissected PV and SMV at the superior and inferior margin of the neck of pancreas separately, and then divided pancreas from anterior to posterior.Mean time of dividing pancreas was (34.9+/ 9.7)minutes, mean volume of blood loss while dividing pancreas was (30.1+/ 8.2)ml.The main postoperative complications included pancreatic fistula(7 cases, Biochemical leak 2 cases, B grade 3 cases, C grade 2 cases), biliary fistula(3 cases), gastric fistula(1 case), delayed gastric emptying(1 case, C grade), abdominal infection(5 cases), hepatic failure (1 case), intra-abdominal hemorrhage(2 cases), reoperation(2 cases). One case died at the perioperative period while others recovered.The mean duration of postoperative stay was (14.2+/ 5.1)days. Conclusions: Dividing the neck of pancreas is one of the most important steps in LPD, which deserved sufficient attention.At the meantime, a suitable method of dividing the neck of pancreas should be chosen according to intraoperative exploration and preoperative imageological examinations. PMID- 28870052 TI - [Clinical efficacy of enhanced recovery after surgery in atrial caval shunting for type II Budd-Chiari syndrome]. AB - Objective: To investigate the clinical efficacy of enhanced recovery after surgery(ERAS) in atrial caval shunting (ACS) for type II Budd-Chiari syndrome(BCS). Methods: The clinical data of patients underwent ACS for type II BCS in the Henan Province People's Hospital from January 2014 to June 2016 were prospectively analyzed.Randomized and single-blind, controlled study was performed among the patients, and all of them underwent ACS and were divided into control group (patients underwent traditional perioperative management) and ERAS group (patients underwent ERAS perioperative management) based on a random number table.Operational and postoperative data, levels of inflammatory cytokines, stress state evaluation and postoperative complications were observed.The comparison between the two groups was evaluated with an independent sample t test.The trend analyses for variables were done using repeated measures ANOVA.The count data were analyzed using the chi-square test or Fisher exact. Results: Eighty-two patients were screened for eligibility, and allocated into the control group (40 patients) and the ERAS group (42 patients). All patients underwent ACS successfully with no death.Comparison of intraoperative status: operation time, volume of intraoperative blood and number of patients receiving blood transfusion were (211.0+/-12.9) minutes vs. (207.7+/-10.7) minutes, (167.5+/-28.3) ml vs. (165.0+/-28.4) ml and 3 cases vs. 1 case between the control group and the ERAS group, respectively, showing no difference between the two groups (t=0.90, 0.29, chi2=0.32, all P>0.05). Comparison of postoperative status: time of gastric tube removal, time of catheter removal, time of chest tube, time to flatus, time of food intake, duration of postoperative infusion, duration of postoperative hospital stay and numeric rating scale were (3.7+/-0.5)days vs. (0.0+/-0.0)days, (2.3+/-0.7)days vs. (1.4+/-0.5)days, (3.7+/-0.7)days vs. (2.3+/-0.5)days, (75.2+/ 3.8)hours vs. (46.6+/-4.2)hours, (75.7+/-4.7)hours vs. (21.4+/-2.1)hours, (10.0+/ 1.0)days vs. (5.8+/-0.9)days, (11.4+/-1.0)days vs. (7.8+/-0.6)days, 2.9+/-0.4 vs. 1.9+/-0.6 between the control group and the ERAS group, respectively, with statistically differences (t=35.03, 4.36, 8.10, 22.89, 47.78, 14.75, 14.22, 6.13, all P<0.05). Stress state evaluation: the levels of IR were (2.7+/-0.1) vs.(2.7+/ 0.1), (8.8+/-0.7) vs. (5.2+/-0.3), (11.0+/-0.5) vs. (7.3+/-0.5), (4.9+/-0.2) vs. (3.9+/-0.1), and the levels of C-reaction protein were (14.6+/-1.3)mg/L vs.(14.6+/-1.1) mg/L, (101.2+/-13.6) mg/L vs. (89.5+/-6.9) mg/L, (62.7+/-8.6) mg/L vs. (56.4+/-8.4) mg/L, (46.4+/-6.7) mg/L vs. (40.0+/-5.6) mg/L from pre operation to postoperative day 1, 3 and 5 between the control group and the ERAS group, respectively, with statistically significant differences in changing trends(F=136.61, 4.97, both P<0.05). Comparisons of levels of inflammatory cytokines: the levels of IL-6 were (43.1+/-2.7) ng/L vs. (43.6+/-3.6) ng/L, (135.1+/-6.4) ng/L vs. (117.4+/-5.7) ng/L, (145.4+/-6.7) ng/L vs. (128.5+/-5.5) ng/L, (93.3+/-3.7) ng/L vs. (88.0+/-3.9) ng/L, and the levels of TNF-alpha were (10.4+/-0.3)mmol/L vs. (10.4+/-0.3) mmol/L, (14.4+/-0.4) mmol/L vs. (12.6+/-0.4) mmol/L, (15.6+/-0.4) mmol/L vs. (13.8+/-0.4) mmol/L, (12.3+/-0.7) mmol/L vs. (11.4+/-0.6) mmol/L from pre-operation to postoperative day 1, 3 and 5 between the control group and the ERAS group, respectively, with statistically significant differences in changing trends (F=15.15, 21.45, both P<0.05). Comparison of postoperative complications: incidence of complications was 30.0%(12/40) in the control group and 11.9%(5/42) in the ERAS group, and the numbers of patients with nausea and vomiting, respiratory complications and cardiovascular complications were 4, 3, 5 cases in the control group and 3, 1, 1 case in the ERAS group, respectively, showing statistically differences in the incidence of complications(chi2=4.08, P<0.05). All the 82 patients were followed up for 2 to 22 months (median time, 12 months), no patients received reoperation or re-admitted to the hospital duo to complications. Conclusion: ERAS management in the perioperative period of ACS for BCS is beneficial to postoperative recovery of patients, and can relieve postoperative stress state and inflammatory response, reduce the duration of hospital stay, and incidence of postoperative complications. PMID- 28870053 TI - [Domestic external fixator application in the treatment of limb deformities: 7 289 cases application report]. AB - Objective: To discuss the clinical application and effects of domestic external fixator in the treatment of patients with malformations of limbs. Methods: A total of 7 289 patients with malformation of limbs who had been operated in Qin Sihe orthopedic surgery team from January 1989 to June 2016 were retrospective analyzed. The patients were treated with domestic external fixator, including 4 033 males and 3 256 females, aging from 2 to 82 years with a mean age of 23.4 years. There were 2 732 patients using Ilizarov external fixator, 4 713 patients using hybrid external fixator, 57 patients using monobrachial external fixator, 232 patients using Ilizarov external fixator and hybrid external fixator. The Ilizarov, hybrid and monobrachial external fixator were used in 67, 65 and 0 patients on the upper limbs and in 2 665, 4 616 and 57 patients on the lower limbs. There were 3 028 patients operated on the left limbs, 3 260 patients operated on the right limbs and 1 001 patients operated on the bilateral limbs. The top three types of diseases were sequelae of poliomyelitis, cerebral palsy and post-traumatic stress disorder peromely. Deformity types inclued talipes equinovarus, knee flexion deformity, cavus foot and so on. Results: All the patients were followed up for a period of 2.5 months to 22.4 years, with an average follow-up time of 5.4 years. All of the external fixators were used for single once, and there was no substitute for external fixator quality problem. All the patients were completed surgery goal until removing external fixation except 1 patient gave up treatment and 1 removed the fixator because of metal allergy. The common complications included wire or pin infection and joint movement limitation and so on. Conclusions: The domestic external fixator developed and produced based on the characteristics of Chinese limb deformity disability. The domestic external fixator can be used to treat kinds of limb deformities with the advantages of practical, economical, adjustable, universal and portable. The domestic external fixator could meet the clinical demand for fixation of the osteotomy end of the limbs, the correction of the deformity, the repair of the defects and the limb lengthening. PMID- 28870054 TI - [Paracondylar-lateral cervical approach for resection of jugular foramen schwannomas: a retrospective analysis of 15 cases]. AB - Objective: To explore the effects of paracondylar-lateral cervical approach for resection of the jugular foramen schwannoma(JFS). Methods: A total of 15 patients with JFS operated via the paracondylar-lateral cervical approach between December 2011 and March 2016 at Department of Neurosurgery in Xiangya Hospital of Central South University were retrospectively analyzed. There were 7 males and 8 females, aging from 22 to 77 years with a mean age of (41.9+/-15.8) years.There were 12 patients who accepted primary surgery, 3 patients who accepted secondary surgery. There were 10 patients with tinnitus or hearing loss, 8 patients with dysphagia, 9 patients with hoarseness, 7 patients with tongue hemiparesis, 8 patients with ataxia, 1 patient with Pyramidal signs, 2 patients with facial hypesthesia or pain, 1 patient with facial paresis. According to Samii JFS grading system, 2 patients were type B, 4 were type C and 9 were type D. All patients were followed up through outpatient and telephone by MRI in 3, 9, 12 months postoperation. Results: Gross total removal of tumors were achieved in 14 patients and subtotal removal in 1 patient. Two patients had new hoarseness, 2 had new dysphagia and 3 had more serious dysphagia, 1 patient had more serious facial paresis after the operation. There were 2 patients with intracranial infection, 2 with pneumonia, 1 with subcutaneous effusion, 1 with cerebrospinal fluid rhinorrhea, 5 with gastric intubation during perioperative period. There were no death, intracranial hematoma and decreased hearing patients. All patients were followed up, the follow-up time were 3 to 33 months with a mean of (26.9+/-11.2) months. Till to the latest follow up, dysphagia improved in 2 cases, hoarseness and tongue hemiparesis improved in 3 cases, hearing loss and tinnitus improved in 9 cases, balance function improved in 7 cases, facial hypesthesia and pain improved in 2 cases, pyramidal signs disappeared in 1 case, facial nerve function improved to normal in 1 case. There was no recurrence and progressed case. Conclusion: Paracondylar-lateral cervical approach is an alternative approach for both intracranial and extracranial JFS. PMID- 28870055 TI - [Lymph node metastasis and prognostic factors for T1 esophageal cancer]. AB - Objective: To evaluate the lymph node metastasis (LNM) pattern and related prognostic factors for T1 esophageal cancer. Methods: Clinical data of 143 cases of pT1 esophageal cancer patients (120 male and 23 female patients with median age of 60 years) who underwent esophagectomy and lymph node resection during January 2011 and July 2016 at the Department of Esophageal Cancer of Tianjin Medical University Cancer Institute and Hospital were reviewed, including 50 cases of T1a patients and 93 cases of T1b patients. The LNM pattern was analyzed and the prognostic factors related to LNM were assessed by chi2 test and Logistic regression analysis. Results: Of 143 patients, 25 patients had LNM. The LNM rates were 17.5% for pT1 tumors, 16.0%(8/50) for pT1a tumors, and 22.6%(21/93) for T1b tumors. Of 25 patients with LNM, one patient had cervical metastasis, 15 patients with thoracic metastasis, and 17 patients with abdominal metastasis. The relatively highest LNM sites were laryngeal recurrent nerve (8 cases), left gastric artery (8 cases), right and left cardiac (6 cases) and thoracic paraesophageal (5 cases). Logistic regression analysis showed that the depth of tumor infiltration (OR=4.641, 95%CI: 1.279 to 16.836, P=0.020), tumor size (OR=5.301, 95%CI: 1.779 to 15.792, P=0.003), tumor location (OR=3.238, 95% CI: 1.248 to 8.401, P=0.016), and tumor differentiation (OR=5.301, 95%CI: 1.719 to 16.347, P=0.004) were independent prognostic factors related to LNM for T1 esophageal cancer. Tumor size (OR=4.117, 95% CI: 1.228 to 13.806, P=0.022) was an independent risk factor related to thoracic LNM, and the vessel invasion (OR=6.058, 95% CI: 1.228 to 29.876, P=0.027) and tumor location (OR=8.113, 95% CI: 1.785-36.872, P=0.007) were independent prognostic factors related to abdominal LNM. Conclusions: T1 esophageal cancer has a relatively high LNM rate, and the depth of tumor infiltration, tumor size, tumor location and tumor differentiation are correlated with LNM. The LNM risk and extent must be considered comprehensively in decision-making of a better surgical treatment and lymph node resection strategy. PMID- 28870056 TI - [Application of autologous fat grafting in breast reconstruction]. AB - Objective: To observe the outcome of breast reconstruction with autologous fat grafting in the patients following treatment for breast cancer. Methods: The clinical data of 22 patients after breast cancer modified radical mastectomy with fat grafting for breast reconstruction from January 2012 to March 2015 at Department of Body Contouring and Liposuction Center of Plastic Surgery, Hospital of Peking Union Medical College were analyzed retrospectively. The age of 22 patients (all female) was 28 to 54 years. Fifteen patients were performed breast modified radical mastectomy 5 to 16 year ago without radiotherapy, 7 patients were performed breast modified radical mastectomy following regular radiotherapy 2 years ago. Low negative pressure liposuction technical was applied to harvest fat tissue for 400 to 800 ml which was filtrated and purified by cotton pad method in low temperature environment. Fat grafting was performed with multi level and multi-tunnel and in multi-point injection ways. All patients were followed up by regular imaging evaluation with MRI or ultrasonography after operation every 3 months. Results: All breast reconstruction were successfully performed in 22 patients, no severe complications occurred. Among 15 patients without radiotherapy, 12 patients were performed with autologous fat grafting for breast reconstruction, 3 patients with prosthetic implantation for breast augmentation after autologous fat grafting. Among 7 patients with radiotherapy, 6 patients were performed with autologous fat grafting for breast reconstruction, 1 patient with prosthetic implantation for breast augmentation after autologous fat grafting. The volume of fat grafting was 104 to 380 ml. It took 2.5 hours to finish the operation including 1.0 to 1.5 hours for liposuction and 40 minutes for fat grafting. Next fat grafting were performed after 3 months. The fat of the breast were survived well detecting by MRI, only 1 patient had a cystic nodule which had been resected during nipple reconstruction. Ultrasonography screened several cystic nodules with the major axis of 0.1 to 0.2 cm in the breast, which couldn't be found by palpating in 18 patients. The patients were followed up for 18 to 36 months, the outcome were satisfactory. Conclusion: Autologous fat grafting for breast reconstruction simplifies the operation program with satisfied results and avoids the complications of breast reconstruction with skin flap. PMID- 28870057 TI - [Clinical analysis of 34 cases with sepsis and systemic capillary leak syndrome]. AB - Objective: To study the clinical characteristics of sepsis with systemic capillary leak syndrome(SCLS) and to evaluate the therapeutic effect and clinical significance of fluid therapy adjusted timely in these patients. Methods: The clinical data of 34 patients with sepsis and SCLS in the Department of Hepatobiliary Surgery ICU of General Hospital of People's Liberation Army General Hospital from July 2014 to January 2016 were retrospectively analyzed.There were 21 males and 13 females, aged from 21 to 74 years, with an average age of 56.3 years.Primary disease as follows: 18 cases with severe acute pancreatitis, 7 postoperative cases of subtotal hepatectomy, 5 postoperative cases of pancreatoduodenectomy, 4 postoperative cases of cholelithiasis.These patients were divided into survival group and death group according to their 28-day survival status.The clinical data including C-reactive protein(CRP), platelets (PLT), brain natriuretic peptide (BNP), the level of arterial blood lactic acid(LAC), oxygenation index(PaO2/FiO2, OI), net fluid balance(NFB) and norepinephrine dosage(NE) were collected and compared between two groups at three different intervals(day 1-3, day 4-6, day 7-9). The measurement data and numeration data were statistically analyzed with t test and chi2 test respectively to explore the inherent characteristics of the disease evolution and its clinical significance. Results: The survival group (n=23)and the death group(n=11)had no significant difference in the characteristics of basic clinical characters.The condition of the survival group and the death group were both in progress in 1-3 days period manifested as increased CRP(t=-0.473, P=0.640) and BNP levels(t=0.140, P=0.895), decreased PLT counts(t=-0.505, P=0.620) in the inflammatory response, decreased LAC(t=-1.008, P=0.320) and OI level (t=-2.379, P=0.020)in tissue perfusion index, and positive fluid balance(NFB: t=0.910, P=0.370), required NE(t=-0.853, P=0.400) to maintain effective perfusion pressure with systemic edema in both groups.There was no significant difference of all these clinical parameters between the two groups.The patients' condition of the survival group reached a plateau phase, whereas all relative indicators of the death group implied significant aggravation and deterioration of systemic infection(CRP: t=-3.438, P=0.000; PLT: t=1.649, P=0.110; BNP: t=-10.612, P=0.000), tissue perfusion (LAC: t=-11.305, P=0.000; OI: t=2.743, P=0.010)and tissue edema NFB(t=-4.257, P=0.000) and NE(t=-7.956, P=0.000) in 4-6 days period.In the last 7-9 days period the patients' condition of the survival group took a turn for improvement, yet the condition of the death group continued to deteriorate, refractory septic shock developed and multiple organ dysfunction syndrome followed afterwards inevitably(CRP: t=-10.036, P=0.000; PLT: t=6.061, P=0.000; BNP: t=-10.119, P=0.000; LAC: t=-24.466, P=0.000; OI: t=13.443, P=0.010; NFB: t=-8.345, P=0.000; NE: t=-7.121, P=0.000). Conclusions: The condition of patient with sepsis and SCLS would be improved markedly at the critical turning point around 7-9 days period since the effective systemic treatment began.If the infection does not be significantly constrolled and SCLS still remains in a sustained extravasation period in 7-9 days, the prognosis of these patients may be worse and the mortality may be higher than that of the patients mentioned before. PMID- 28870058 TI - Technologically-advanced assessment of upper-limb spasticity: a pilot study. AB - BACKGROUND: Spasticity is a muscle disorder associated with upper motor neuron syndrome occurring in neurological disorders, such as stroke, multiple sclerosis, spinal cord injury and others. It influences the patient's rehabilitation, interfering with function, limiting independence, causing pain and producing secondary impairments, such as contractures or other complications. Due to the heterogeneity of clinical signs of spasticity, there is no agreement on the most appropriate assessment and measurement modality for the evaluation of treatment outcomes. AIM: The aim of this article is to propose the use of new robotic devices for upper-limb spasticity assessment and describe the most relevant measures of spasticity which could be automatically assessed by using a technologically advanced device. DESIGN: Observational pilot study. SETTING: The treatment was provided in a Rehabilitation Centre where the device was located and the subjects were treated in an outpatients setting. POPULATION: Five post stroke patients, age range 19-79 years (mean age 61, standard deviation [SD]+/ 25) in their chronic phase. METHODS: A new robotic device able to automatically assess upper-limb spasticity during passive and active mobilization has been developed. The elbow spasticity of five post stroke patients has been assessed by using the new device and by means of the Modified Ashworth Scale (MAS). After the first assessment, subjects were treated with botulin toxin injections, and then underwent 10 sessions of robotic treatments. After the treatment, subjects spasticity was assessed by using the robotic device and the MAS Score. RESULTS: In four out of five patients, the botulin toxin injection and robotic treatment resulted in the improvement of the MAS Score; in three patients the robotic measures were able to detect the MAS changes. In one subject botulin toxin was not effective and the robotic device was able to detect the lack of effectiveness. CONCLUSIONS: By using the robotic device some spasticity parameters can be continuously recorded during the rehabilitation treatment in order to objectively measure the effectiveness of the interventions provided. CLINICAL REHABILITATION IMPACT: The standardized evaluation parameters recorded using robotic devices may provide several advantages: 1) the measures for spasticity assessment can be monitored during every rehabilitation session (even during each movement); 2) these measurements are able to highlight even small changes; 3) the recovery plateau can be detected early thus avoiding further rehabilitation sessions; and 4) these measurements can reduce the assessment bias in multicenter studies. PMID- 28870059 TI - Publication trends of study protocols in rehabilitation. AB - INTRODUCTION: Growing evidence points for the need to publish study protocols in the health field. The aim of this paper was to observe whether the growing interest in publishing study protocols in the broader health field has been translated into increased publications of rehabilitation study protocols. EVIDENCE ACQUISITION: PubMed was searched with appropriate combinations of Medical Subject Headings up to December 2014. The effective presence of study protocols was manually screened. Regression models analyzed the yearly growth of publications. Two-sample Z-tests analyzed whether the proportion of systematic reviews (SRs) and randomized controlled trials (RCTs) among study protocols differed from that of the same designs for the broader rehabilitation research. EVIDENCE SYNTHESIS: Up to December 2014, 746 publications of rehabilitation study protocols were identified, with an exponential growth since 2005 (r2=0.981; P<0.001). RCT protocols were the most common among rehabilitation study protocols (83%), while RCTs were significantly more prevalent among study protocols than among the broader rehabilitation research (83% vs. 35.8%; P<0.001). For SRs, the picture was reversed: significantly less common among study protocols (2.8% vs. 9.3%; P<0.001). Funding was more often reported by rehabilitation study protocols than the broader rehabilitation research (90% vs. 53.1%; P<0.001). Rehabilitation journals published a significantly lower share of rehabilitation study protocols than they did for the broader rehabilitation research (1.8% vs.16.7%; P<0.001). CONCLUSIONS: Identifying the reasons for these discrepancies and reverting unwarranted disparities (e.g. low rate of publication for rehabilitation SR protocols) are likely new avenues for rehabilitation research and its publication. SRs, particularly those aggregating RCT results, are considered the best standard of evidence to guide rehabilitation clinical practice; however, that standard can be improved in rigor and/or transparency if the publications of rehabilitation SRs protocols become more common. PMID- 28870060 TI - Sonographic features that can be used to differentiate between small triple negative breast cancer and fibroadenoma. AB - PURPOSE: Our study investigated whether any sonographic findings could be useful for differentiating between small triple-negative breast cancer (TNBC) and fibroadenoma. METHODS: This retrospective study was approved by our Institutional Review Board, which waived the requirement for patient consent. From January 2009 to December 2010, the sonographic features of 181 pathologically proven TNBC tumors and 172 fibroadenomas measuring less than or equal to 2 cm in the longest dimension were reviewed and analyzed according to the fifth edition of the Breast Imaging Reporting and Data System (BI-RADS) lexicon. Mean tumor roundness was also measured using in-house software. RESULTS: The median longest lesion dimension was 16 mm (range, 13 to 18 mm) in TNBCs and 13 mm (range, 10 to 16 mm) in fibroadenomas. In comparison to fibroadenomas, small TNBC tumors presented with a higher incidence of irregular shapes (66.9%), noncircumscribed margins (91.7%), hypoechoic echotexture (59.1%), posterior acoustic enhancement (65.2%), and associated features (24.4%). Most TNBCs were classified as BI-RADS category 4 (65.2%) or 5 (28.2%). The mean tumor roundness of small TNBCs was greater than that of fibroadenomas (60%+/-12% vs. 53%+/-13%). Multivariate analysis showed that older patient age, irregular shape, nonparallel orientation, posterior acoustic enhancement, associated features, a BI-RADS final assessment category of 4 or 5, and greater tumor roundness were significant independent factors indicative of TNBCs. CONCLUSION: TNBC tumors tend to demonstrate more suspicious sonographic features and greater tumor roundness than fibroadenomas. These features may have the potential to help differentiate between small TNBCs and fibroadenomas. PMID- 28870061 TI - Morphological alterations of the tendon and pulley on ultrasound after intrasynovial injection of betamethasone for trigger digit. AB - PURPOSE: The aim of this study was to elucidate whether intrasynovial corticosteroid injections for trigger digit reduced the volume of the tendon and pulley on high-resolution ultrasonography. METHODS: Twenty-three digits of 20 patients with trigger digit were included. Each affected finger was graded clinically according to the following classification: grade I for pre-triggering, grade II for active triggering, grade III for passive triggering, and grade IV for presence of contracture. Axial ultrasound examinations were performed before an intrasynovial corticosteroid injection and at an average of 31 days after the injection. The transverse diameter, thickness, and cross-sectional area of the tendon and the thickness of the pulley were measured by two independent, blinded researchers. RESULTS: At least 1 grade of improvement was achieved in this study group by the time of the second examination. The transverse diameter and cross sectional area of the tendon and the thickness of the pulley significantly decreased (P<0.05). CONCLUSION: The injection of a single dose of betamethasone improved clinical symptoms by reducing the volume of both the tendon and pulley, which may be related to the fact that tendon and pulley ruptures are delayed by corticosteroid injections. PMID- 28870063 TI - Validation of the Amsterdam Preoperative Anxiety and Information Scale among patients scheduled for cardiac surgery. PMID- 28870062 TI - Initial clinical and hemodynamic results of a regional pulmonary thromboendarterectomy program. AB - BACKGROUND: Pulmonary thromboendarterectomy (PTE) is the treatment of choice for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, access to CTEPH and PTE care is limited. There is a paucity of published data on PTE efficacy and outcomes from alternative, regional centers of excellence in CTEPH and PTE care in the USA, outside a single national and international referral center. METHODS: We performed a retrospective review of patients undergoing PTE at our institution from June 2013 to December 2016 (42 months), and collected clinical, echocardiographic and hemodynamic data on our patients pre- and post-PTE (N.=71). RESULTS: Patients age ranged between 20-83 years (mean+/-SD: 56+/-16), with 54% of patients female and 61% Caucasians. The predominant symptom was shortness of breath with a median duration of symptoms of 17 months. Following PTE, clinical improvements included a reduction in NYHA class from 3.1+/-1.1 to 2.2+/-1.2. There were major improvements in hemodynamics and echocardiographic parameters pre- versus post-PTE: mean pulmonary artery pressure (mmHg) 45+/-11 to 24+/-8, cardiac index (L/min/m2) 2.1+/-0.5 to 2.8+/ 0.5, pulmonary vascular resistance (mmHg/L/min) 8.9+/-4.5 to 2.8+/-1.8, ratio of right ventricle (RV): left ventricle (LV) 1.2+/-0.3 to 0.9+/-0.2, RV fractional area change (%) 23+/-14 to 44+/-13, reduction in the incidence of RV outflow tract Doppler notching and improved pulmonary artery acceleration time (96% to 30%, and 74+/-19 to 111+/-21). In-hospital mortality was 4.2% (3 patients). CONCLUSIONS: Herein, we report for the first time, the improvements in patient functionality, hemodynamics, right heart function and outcomes at a major regional PTE program. PMID- 28870064 TI - Amyloid beta Fibril Elongation by Monomers Involves Disorder at the Tip. AB - The growth of amyloid fibrils from Abeta1-42 peptide, one of the key pathogenic players in Alzheimer's disease, is believed to follow a nucleation-elongation mechanism. Fibril elongation is often described as a "dock-lock" procedure, where a disordered monomer adsorbs to an existing fibril in a relatively fast process (docking), followed by a slower conformational transition toward the ordered state of the template (locking). Here, we use molecular dynamics simulations of an ordered pentamer of Abeta42 at fully atomistic resolution, which includes solvent, to characterize the elongation process. We construct a Markov state model from an ensemble of short trajectories generated by an advanced sampling algorithm that efficiently diversifies a subset of the system without any bias forces. This subset corresponds to selected dihedral angles of the peptide chain at the fibril tip favored to be the fast growing one experimentally. From the network model, we extract distinct locking pathways covering time scales in the high microsecond regime. Slow steps are associated with the exchange of hydrophobic contacts, between nonnative and native intermolecular contacts as well as between intra- and intermolecular ones. The N-terminal segments, which are disordered in fibrils and typically considered inert, are able to shield the lateral interfaces of the pentamer. We conclude by discussing our findings in the context of a refined dock-lock model of Abeta fibril elongation, which involves structural disorder for more than one monomer at the growing tip. PMID- 28870066 TI - Simulation Studies on the Lipid Interaction and Conformation of Novel Drug Delivery Pseudopeptidic Polymers. AB - Pseudopeptides based on poly(l-lysine isophthalamide) backbone have emerged as promising drug delivery candidates due to their pH-activated membrane disruption ability. To gain molecular understanding on these novel polymeric species, we have constructed force-field parameters and simulated the behaviors of polymers with and without phenylalanine grafted as side chains under conditions compatible with different pHs. The free energy changes upon polymer permeation through membrane were calculated using the umbrella sampling technique. We show that both polymers with and without grafts interact better with the membrane under conditions compatible with lower pH. The conformational states of the polymers were investigated in water and at a water-membrane interface. On the basis of Markov state modeling results, we propose a possible advantage of the grafted polymer over the ungrafted polymer for membrane rupture because of its quicker conformational rearrangement kinetics. PMID- 28870065 TI - A Potential New Threat to Wild Life: Presence of UV Filters in Bird Eggs from a Preserved Area. AB - The present study uses bird eggs of seven wild species as a biomonitoring tool for sunscreens occurrence. Seven UV filters (UV-Fs), including 3 hydroxy metabolites of oxybenzone (benzophenone 3, BP3) were characterized in unhatched eggs from Donana Natural Space (Spain). High frequency of detection was observed for all UV-Fs, ranging from 95% to 100%. The oxybenzone metabolite 4 hydroxybenzophenone (4HB) was ubiquitous at concentrations in the range 12.0-3348 ng g-1 dry weight (dw). The parent compound, oxybenzone, was also present in all samples at lower concentrations (16.9-49.3 ng g-1 dw). Due to the three BP3's metabolites, benzophenone 1 (BP1), 4HB, and 4,4'-dihydroxybenzophenone (4DHB) presence in unhatched eggs, it can be inferred that parent compounds are absorbed into the bird through the upper gut and the OH-derivatives formed are transferred by the mother to the egg before the lying. White stork (Ciconia ciconia) and western marsh harrier (Circus aeruginosus) were the most contaminated species, with mean total UV-Fs concentrations of 834 and 985 ng g-1 dw, respectively. Results evidenced that biomagnification process across the bird species studied cannot be ruled out. PMID- 28870067 TI - Versatile Device Architectures for High-Performing Light-Soaking-Free Inverted Polymer Solar Cells. AB - Metal oxide charge transport layers have been widely employed to prepare inverted polymer solar cells with high efficiency and long lifetime. However, the intrinsic defects in the metal oxide layers, especially those prepared from low temperature routes, overshadow the high efficiency that can be achieved and also introduce "light-soaking" issues to these devices. In this work, we have employed polyethyleneimine (PEI) and poly(9,9-bis(6'-(N,N-diethylamino)propyl)-fluorene alt-9,9-bis-(3-ethyl(oxetane-3-ethyloxy)-hexyl)-fluorene] (PFN-OX) to modify our low-temperature-processed TiO2 electron transport layer (ETL) and demonstrated that the light-soaking issue can be effectively eliminated by PEI modifications because of the formation of abundant dipole moments, whereas PFN-OX was ineffective as a result of deficient dipole moments at the interface. Excitingly, PEI modifications enable versatile device architectures to obtain light-soaking free, inverted PTB7-Th:PC71BM solar cells with efficiencies of over 10%, by adding PEI either in the bulk or as an adjacent layer below or above the TiO2 ETL. PMID- 28870068 TI - Revealing the Effect of Irradiation on Cement Hydrates: Evidence of a Topological Self-Organization. AB - Despite the crucial role of concrete in the construction of nuclear power plants, the effects of radiation exposure (i.e., in the form of neutrons) on the calcium silicate-hydrate (C-S-H, i.e., the glue of concrete) remain largely unknown. Using molecular dynamics simulations, we systematically investigate the effects of irradiation on the structure of C-S-H across a range of compositions. Expectedly, although C-S-H is more resistant to irradiation than typical crystalline silicates, such as quartz, we observe that radiation exposure affects C-S-H's structural order, silicate mean chain length, and the amount of molecular water that is present in the atomic network. By topological analysis, we show that these "structural effects" arise from a self-organization of the atomic network of C-S-H upon irradiation. This topological self-organization is driven by the (initial) presence of atomic eigenstress in the C-S-H network and is facilitated by the presence of water in the network. Overall, we show that C-S-H exhibits an optimal resistance to radiation damage when its atomic network is isostatic (at Ca/Si = 1.5). Such an improved understanding of the response of C-S H to irradiation can pave the way to the design of durable concrete for radiation applications. PMID- 28870069 TI - Boosting Chemical Stability, Catalytic Activity, and Enantioselectivity of Metal Organic Frameworks for Batch and Flow Reactions. AB - A key challenge in heterogeneous catalysis is the design and synthesis of heterogeneous catalysts featuring high catalytic activity, selectivity, and recyclability. Here we demonstrate that high-performance heterogeneous asymmetric catalysts can be engineered from a metal-organic framework (MOF) platform by using a ligand design strategy. Three porous chiral MOFs with the framework formula [Mn2L(H2O)2] are prepared from enantiopure phosphono-carboxylate ligands of 1,1'-biphenol that are functionalized with 3,5-bis(trifluoromethyl)-, bismethyl-, and bisfluoro-phenyl substituents at the 3,3'-position. For the first time, we show that not only chemical stability but also catalytic activity and stereoselectivity of the MOFs can be tuned by modifying the ligand structures. Particularly, the MOF incorporated with -CF3 groups on the pore walls exhibits enhanced tolerance to water, weak acid, and base compared with the MOFs with -F and -Me groups. Under both batch and flow reaction systems, the CF3-containing MOF demonstrated excellent reactivity, selectivity, and recyclability, affording high yields and enantioselectivities for alkylations of indoles and pyrrole with a range of ketoesters or nitroalkenes. In contrast, the corresponding homogeneous catalysts gave low enantioselectivity in catalyzing the tested reactions. PMID- 28870070 TI - Engineering of Pore Geometry for Ultrahigh Capacity Methane Storage in Mesoporous Metal-Organic Frameworks. AB - Mesoporous Zn4O(-COO)6-based metal-organic frameworks (MOFs), including UMCM-1, MOF-205, MUF-7a, and the newly synthesized MOFs, termed ST-1, ST-2, ST-3, and ST 4 (ST = ShanghaiTech University), have been systematically investigated for ultrahigh capacity methane storage. Exceptionally, ST-2 was found to have the highest deliverable capacity of 289 cm3STP/cm3 (567 mg/g) at 298 K and 5-200 bar, which surpasses all previously reported records held by porous materials. We illustrate that the fine-tuned mesoporosity is critical in further improving the deliverable capacities at ultrahigh pressure. PMID- 28870071 TI - Orcein-Related Small Molecule O4 Destabilizes hIAPP Protofibrils by Interacting Mostly with the Amyloidogenic Core Region. AB - The accumulation of the human islet amyloid polypeptide (hIAPP) deposits in the pancreas is regarded as an important factor that leads to the depletion of islet beta-cells and islet transplantation failure. In recent experiments, it was reported that a small organic molecule O4 inhibits the formation of hIAPP1-37 oligomers and fibrils. However, the interaction between O4 molecules and hIAPP oligomers is largely unknown on the atomic level. In this work, we studied the influence of O4 molecules on fibril-like hIAPP pentamer and decamer by performing atomistic molecular dynamics simulations. Our results show that O4 molecules mostly bind to the amyloid core region spanning residues 22NFGAI26 for both hIAPP pentamer and decamer, which leads to the local disruption of interpeptide beta sheets. The calculation of contact probability and binding energy indicates that the binding of O4 molecules is mostly driven by aromatic stacking and hydrophobic interactions. Our work reveals the detailed disruption mechanism of full-length hIAPP protofibrils by O4 molecules and may be helpful to the design of more efficient inhibitors against hIAPP aggregation. PMID- 28870072 TI - Building Stable MMP2-Responsive Multifunctional Polymeric Micelles by an All-in One Polymer-Lipid Conjugate for Tumor-Targeted Intracellular Drug Delivery. AB - In this study, we described an "all-in-one" polymer-lipid conjugate (PEG2k-ppTAT PEG1k-PE) that could self-assemble to matrix metalloproteinase 2 (MMP2)-sensitive multifunctional micelles. The assembled micelles had several key features, including a protective long chain poly(ethylene glycol) (PEG2k) (the outer shell), an MMP2-sensitive peptide linker (pp) (the tumor-targeting middle layer), a trans-activating transcriptional activator (TAT) peptide (the cell-penetrating middle layer), and a stable PEG1k-PE micelle for drug loading (the inner core). In the absence of MMP2, the PEG2k-ppTAT-PEG1k-PE micelles were intact and showed low bioactivity due to the surface-anchored PEG2k, whereas in the presence of MMP2, the pp was cleaved, resulting in the PEG2k deshielding and exposure of the previously hidden TAT for enhanced intracellular drug delivery. Even if completely cleaved by MMP2, the remaining PEG1k-PE micelles were stable and the micelles' particle size and drug release were not significantly influenced. The paclitaxel (PTX)-loaded PEG2k-ppTAT-PEG1k-PE micelles showed significant MMP2 dependent cellular uptake, tumor penetration, and anticancer activity in various cancer cells and three-dimensional multicellular spheroids. Because of the enhanced intracellular drug accumulation, these multifunctional micelles were able to sensitize the drug-resistant cancer cells and their spheroids to PTX treatments. Furthermore, in vivo tumor uptake and retention data indicated that the PEG2k-ppTAT-PEG1k-PE micelles could dramatically increase the residence time of their payloads in the tumor. PMID- 28870073 TI - Enantioselective Total Synthesis of (-)-Pavidolide B. AB - The enantioselective synthesis of (-)-pavidolide B (1) was achieved in a linear sequence of 10 steps. The key steps are (a) an enantioselective organocatalytic cyclopropanation; (b) a radical-based cascade annulation for the regio- and diastereo-selective synthesis of the highly functionalized lactone 3 bearing the characteristic tricyclic core and seven contiguous stereocenters; PMID- 28870074 TI - Exhaled Volatile Organic Compounds of Infection: A Systematic Review. AB - With heightened global concern of microbial drug resistance, advanced methods for early and accurate diagnosis of infection are urgently needed. Analysis of exhaled breath volatile organic compounds (VOCs) toward detecting microbial infection potentially allows a highly informative and noninvasive alternative to current genomics and culture-based methods. We performed a systematic review of research literature reporting human and animal exhaled breath VOCs related to microbial infections. In this Review, we find that a wide range of breath sampling and analysis methods are used by researchers, which significantly affects interstudy method comparability. Studies either perform targeted analysis of known VOCs relating to an infection, or non-targeted analysis to obtain a global profile of volatile metabolites. In general, the field of breath analysis is still relatively immature, and there is much to be understood about the metabolic production of breath VOCs, particularly in a host where both commensal microflora as well as pathogenic microorganisms may be manifested in the airways. We anticipate that measures to standardize high throughput sampling and analysis, together with an increase in large scale collaborative international trials, will bring routine breath VOC analysis to improve diagnosis of infection closer to reality. PMID- 28870076 TI - In Situ Complementary Doping, Thermoelectric Improvements, and Strain-Induced Structure within Alternating PEDOT:PSS/PANI Layers. AB - Although the deposition of alternating layers from poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and polyaniline (PANI) salts has recently provided a breakthrough in the field of conductive polymers, the cause for the conductivity improvement has remained unclear. In this work, we report a cooperative doping effect between alternating PANI base and PEDOT:PSS layers, resulting in electrical conductivities of 50-100 S cm-1 and power factors of up to 3.0 +/- 0.5 MUW m-1 K-2, which surpass some of the recent values obtained for protonated PANI/PEDOT:PSS multilayers by a factor of 20. In this case, the simultaneous improvement in the electrical conductivity of both types of layers is caused by the in situ protonation of PANI, which corresponds to the removal of the excess acidic PSS chains from the PEDOT:PSS grains. The interplay between the functional groups' reactivity and the supramolecular chain reorganization leads to an array of preparation-dependent phenomena, including a stepwise increase in the film thickness, an alternation in the electrical conductivity, and the formation of a diverse surface landscape. The latter effect can be traced to a buildup of strain within the layers, which results in either the formation of folds or the shrinkage of the film. These results open new paths for designing nanostructured thin-film thermoelectrics. PMID- 28870075 TI - Cerium Dioxide-Mediated Signal "On-Off" by Resonance Energy Transfer on a Lab-On Paper Device for Ultrasensitive Detection of Lead Ions. AB - In this report, a 3D microfluidic lab-on-paper device for ultrasensitive detection of lead cation was designed using phoenix tree fruit-shaped CeO2 nanoparticles (PFCeO2 NPs) as the catalyst and 50 nm silver NPs (Ag NPs) as the quencher. First, snowflake-like Ag NPs were grown on the paper working electrode through an in situ growth method and used as a matrix for DNAzymes that were specific for lead ions (Pb2+). After the addition of Ag NP-labeled substrate strands, the Ag NPs restrained the electrochemiluminescence (ECL) intensity of luminol greatly through the resonance energy transfer from luminol to Ag NPs. However, under the existence of Pb2+, the substrate strands were separated, and then PFCeO2 NP-labeled signal strands were hybridized with the DNAzymes. The ECL signal was improved greatly under the fast catalytic reaction between PFCeO2 NPs and H2O2, which converted the response from signal off to signal on state, resulting in sensitive detection of Pb2+. Under the optimal conditions, the ECL signal response exhibited a good linear relationship with the logarithm of lead cation in a wide linear range of 0.05-2000 nM and an ultralow detection limit of 0.016 nM. Meanwhile, a sensor featured with good specificity, acceptable stability, reproducibility, and low cost provides a promising portable, simple, and effective strategy for Pb2+ detection. PMID- 28870077 TI - Interplay of Nanoscale, Hybrid P3HT/ZTO Interface on Optoelectronics and Photovoltaic Cells. AB - Photovoltaic effects in poly(3-hexylthiophene-2,5-diyl) (P3HT) have attracted much attention recently. Here, natively p-type doped P3HT nanofibers and n-type doped zinc tin oxide (ZTO) nanowires are used for making not only field-effect transistors (FETs) but also p-n nanoscale diodes. The hybrid P3HT/ZTO p-n heterojunction shows applications in many directions, and it also facilitates the investigation of photoelectrons and photovoltaic effects on the nanoscale. As for applications, the heterojunction device shows a simultaneously high on/off ratio of n- and p-type FETs, gatable p-n junction diodes, tristate buffer devices, gatable photodetectors, and gatable solar cells. On the other hand, P3HT nanofibers are taken as a photoactive layer and the role played by the p-n heterojunction in the photoelectric and photovoltaic effects is investigated. It is found that the hybrid P3HT/ZTO p-n heterojunction assists in increasing photocurrents and enhancing photovoltaic effects. Through the controllable gating of the heterojunction, we can discuss the background mechanisms of photocurrent generation and photovoltaic energy harvesting. PMID- 28870078 TI - In Situ Nanoreactor for Photosynthesizing H2 Gas To Mitigate Oxidative Stress in Tissue Inflammation. AB - Hydrogen gas can reduce cytotoxic reactive oxygen species (ROS) that are produced in inflamed tissues. Inspired by natural photosynthesis, this work proposes a multicomponent nanoreactor (NR) that comprises chlorophyll a, l-ascorbic acid, and gold nanoparticles that are encapsulated in a liposomal (Lip) system that can produce H2 gas in situ upon photon absorption to mitigate inflammatory responses. Unlike a bulk system that contains free reacting molecules, this Lip NR system provides an optimal reaction environment, facilitating rapid activation of the photosynthesis of H2 gas, locally providing a high therapeutic concentration thereof. The photodriven NR system reduces the degrees of overproduction of ROS and pro-inflammatory cytokines both in vitro in RAW264.7 cells and in vivo in mice with paw inflammation that is induced by lipopolysaccharide (LPS). Histological examinations of tissue sections confirm the ability of the NR system to reduce LPS-induced inflammation. Experimental results indicate that the Lip NR system that can photosynthesize H2 gas has great potential for mitigating oxidative stress in tissue inflammation. PMID- 28870079 TI - Characterizing Residue-Bilayer Interactions Using Gramicidin A as a Scaffold and Tryptophan Substitutions as Probes. AB - Previous experiments have shown that the lifetime of a gramicidin A dimer channel (which forms from two nonconducting monomers) in a lipid bilayer is modulated by mutations of the tryptophan (Trp) residues at the bilayer-water interface. We explore this further using extensive molecular dynamics simulations of various gA dimer and monomer mutants at the Trp positions in phosphatidylcholine bilayers with different tail lengths. gA interactions with the surrounding bilayer are strongly modulated by mutating these Trp residues. There are three principal effects: eliminating residue hydrogen bonding ability (i.e., reducing the channel monolayer coupling strength) reduces the extent of the bilayer deformation caused by the assembled dimeric channel; a residue's size and geometry affects its orientation, leading to different hydrogen bonding partners; and increasing a residue's hydrophobicity increases the depth of gA monomer insertion relative to the bilayer center, thereby increasing the lipid bending frustration. PMID- 28870081 TI - Bioavailability of Polyphenols and Flavonoids in the Era of Precision Medicine. PMID- 28870082 TI - Preface to the Surfaces and Interfaces for Molecular Monitoring Special Issue. PMID- 28870080 TI - Charge Shielding Prevents Aggregation of Supercharged GFP Variants at High Protein Concentration. AB - Understanding protein stability is central to combatting protein aggregation diseases and developing new protein therapeutics. At the high concentrations often present in biological systems, purified proteins can exhibit undesirable high solution viscosities and poor solubilities mediated by short-range electrostatic and hydrophobic protein-protein interactions. The interplay between protein amino acid sequence, protein structure, and solvent conditions to minimize protein-protein interactions is key to designing well-behaved pharmaceutical proteins. However, theoretical approaches have yet to yield a general framework to address these problems. Here, we analyzed the high concentration behavior of superfolder GFP (sfGFP) and two supercharged sfGFP variants engineered to have formal charges of -18 or +15. Under low cosolute conditions, sfGFP and the -18 variant formed a gel or phase separated at ~10 mg/mL. Under conditions that screen surface charges, including formulations with high histidine or high NaCl concentrations, all three variants attained concentrations up to 250 mg/mL with moderate viscosities. Moreover, all three variants exhibited very similar viscosity-concentration profiles over this range. This effect was not mimicked by high sugar concentrations that exert excluded volume effects without shielding charge. Collectively, these data demonstrate that charge shielding neutralizes not only long-range electrostatic interactions but also, surprisingly, short-range electrostatic effects due to surface charge anisotropy. This work shows that supercharged sfGFP behavior under high ionic strength is largely determined by particle geometry, a conclusion that is supported by colloid models and may be applicable to pharmaceutically relevant proteins. PMID- 28870083 TI - Socioeconomic disparities in head and neck cancer patients' access to cancer treatment centers. AB - INTRODUCTION: Both socioeconomic status and travel time to cancer treatment have been associated with treatment choice and patient outcomes. An improved understanding of the relationship between these two dimensions of access may enable cancer control experts to better target patients with poor access, particularly in isolated suburban and rural communities. METHODS: Using geographical information systems, head and neck cancer patients across British Columbia, Canada from 1981 to 2009, were mapped and their travel times to the nearest treatment center at their time of diagnosis were modelled. Patients' travel times were analysed by urban, suburban, and rural neighborhood types and an index of multiple socioeconomic deprivation was used to assess the role of socioeconomic status in patients' spatial access. RESULTS: Significant associations between socioeconomic deprivation and spatial access to treatment were identified, with the most deprived quintiles of patients experiencing nearly twice the travel time as the least deprived quintile. The sharpest disparities were observed among the most deprived patient populations in suburban and rural areas. However, the establishment of new treatment centers has decreased overall travel times by 28% in recent decades. CONCLUSIONS: Residence in a neighborhood with high socioeconomic deprivation is strongly associated with head and neck cancer patients' spatial access to cancer treatment centers. Patients residing in the most socioeconomically deprived neighborhoods consistently have longer travel times in urban, suburban, and rural communities in the study area. PMID- 28870084 TI - Comparison Between Thromboelastography and Conventional Coagulation Tests in Surgical Patients With Localized Prostate Cancer. AB - We aimed to examine hypercoagulable and hypocoagulable conditions in patients with prostate cancer using thromboelastography (TEG) and correlate TEG parameters with conventional coagulation test. The t test was used for comparing TEG parameters and routine coagulation results. Spearman rank-order correlation was used to describe the relationship of TEG and conventional tests. Sensitivity, specificity, positive predictive values, and negative predictive values were determined for bleeding and thrombosis. Totally, 20 patients had active bleeding postoperatively, 16 of whom showed hypocoagulation on TEG test and 9 of whom showed hypocoagulation by routine coagulation test ( P = .024). Overall, 60 patients did not have active bleeding postoperatively, 51 of whom showed hypercoagulation detected by TEG test and 42 of whom showed hypercoagulation found by routine coagulation test ( P = .040). Remarkably, patients had a little higher fibrinogen (FIB) compared to controls. There was no statistical difference in any of the conventional coagulation indexes between the groups. Correlation analysis showed that reaction time (R) and coagulation time (K) were positively correlated with the prothrombin time-international normalized ratio (PT-INR) and negatively correlated with FIB ( P < .001). Contrarily, alpha-angle and maximum amplitude (MA) were negatively correlated with PT-INR but positively correlated with FIB. Significantly, MA showed the strongest correlation with FIB and R exhibited the strongest correlation with PT-INR. Sensitivity and specificity for bleeding and thrombosis in TEG were higher than those in conventional coagulation test. Accordingly, TEG might be superior in evaluating hypercoagulation and detecting the risk of bleeding in patients with prostate cancer. PMID- 28870085 TI - A systematic review and critical appraisal of gene polymorphism association studies in medication-overuse headache. AB - Purpose of review Medication-overuse headache is a secondary chronic headache disorder, evolving from an episodic primary headache type, caused by the frequent and excessive use of headache symptomatic drugs. While gene polymorphisms have been deeply investigated as susceptibility factors for migraine, little attention has been paid to medication-overuse headache genetics. In the present study we conducted a systematic review to identify, appraise and summarize the current findings of gene polymorphism association studies in medication-overuse headache. Methods A comprehensive literature search was conducted on PubMed and Web of Knowledge databases of primary studies that met the diagnostic criteria for medication-overuse headache according to the temporally-relevant Classification of Headache Disorder of the International Headache Society. Results A total of 17 candidate gene association studies focusing on medication-overuse headache were finally included in the qualitative review. Among these, 12 studies investigated the role of common gene polymorphisms as risk factors for medication-overuse headache susceptibility, six studies focused on the relationship with clinical features of medication-overuse headache patients, and four studies evaluated their role as determinants of clinical outcomes in medication-overuse headache patients. Conclusion Results of single studies show a potential role of polymorphic variants of the dopaminergic gene system or of other genes related to drug-dependence pathways as susceptibility factors for disease or as determinants of monthly drug consumption, respectively. In this systematic review, we summarize the findings of gene polymorphism association studies in medication overuse headache and discuss the methodological issues that need to be addressed in the design of future studies. PMID- 28870087 TI - Impact on dose and image quality of a software-based scatter correction in mammography. AB - Background In 2014, Siemens developed a new software-based scatter correction (Progressive Reconstruction Intelligently Minimizing Exposure [PRIME]), enabling grid-less digital mammography. Purpose To compare doses and image quality between PRIME (grid-less) and standard (with anti-scatter grid) modes. Material and Methods Contrast-to-noise ratio (CNR) was measured for various polymethylmethacrylate (PMMA) thicknesses and dose values provided by the mammograph were recorded. CDMAM phantom images were acquired for various PMMA thicknesses and inverse Image Quality Figure (IQFinv) was calculated. Values of incident entrance surface air kerma (ESAK) and average glandular dose (AGD) were obtained from the DICOM header for a total of 1088 pairs of clinical cases. Two experienced radiologists compared subjectively the image quality of a total of 149 pairs of clinical cases. Results CNR values were higher and doses were lower in PRIME mode for all thicknesses. IQFinv values in PRIME mode were lower for all thicknesses except for 40 mm of PMMA equivalent, in which IQFinv was slightly greater in PRIME mode. A mean reduction of 10% in ESAK and 12% in AGD in PRIME mode with respect to standard mode was obtained. The clinical image quality in PRIME and standard acquisitions resulted to be similar in most of the cases (84% for the first radiologist and 67% for the second one). Conclusion The use of PRIME software reduces, in average, the dose of radiation to the breast without affecting image quality. This reduction is greater for thinner and denser breasts. PMID- 28870086 TI - Histogram analysis of apparent diffusion coefficient maps for the differentiation between lymphoma and metastatic lymph nodes of squamous cell carcinoma in head and neck region. AB - Background To clarify the nature of cervical malignant lymphadenopathy is highly important for the diagnosis and differential diagnosis of head and neck tumors. Purpose To investigate the role of first-order apparent diffusion coefficient (ADC) histogram analysis for differentiating lymphoma from metastatic lymph nodes of squamous cell carcinoma (SCC) in the head and neck region. Material and Methods Diffusion-weighted imaging (DWI) data of 67 patients (lymphoma, n = 20; SCC, n = 47) with malignant lymphadenopathy were retrospectively analyzed. The SCC group was divided into nasopharyngeal SCC and non-nasopharyngeal SCC groups. The ADC histogram features (ADC10, ADC25, ADCmean, ADCmedian, ADC75, ADC90, skewness, and kurtosis) were derived and then compared by independent-samples t test and one-way analysis of variance test, respectively. Receiver operating characteristic curve analyses were employed to investigate diagnostic performance of the significant parameters. Results Lymphoma showed significantly lower ADCmean, ADCmedian, ADC75, and ADC90 than SCC (all P < 0.05). Setting ADC90 = 0.719 * 10-3 mm2/s as the threshold value, optimal diagnostic performance was achieved (area under the curve [AUC] = 0.719, sensitivity = 95.7%, specificity = 50.0%). Subgroup analyses showed no significant difference between lymphoma and NPC (all P > 0.05). Lymphoma showed significantly lower ADC25, ADCmean, ADCmedian, ADC75, and ADC90 than non-nasopharyngeal SCC (all P < 0.05). Optimal diagnostic performance (AUC = 0.847, sensitivity = 86.7%, specificity = 80.0%) could be achieved when setting ADC90 = 0.943 * 10-3 mm2/s as the threshold value. Conclusion Given its limitations, our study has shown that first-order ADC histogram analysis is capable of differentiating lymphoma from metastatic lymph nodes of SCC, especially those of non-nasopharyngeal SCC. PMID- 28870088 TI - Transmitral thrombectomy to treat a patient with Takotsubo cardiomyopathy. AB - A 68-year-old woman with a history of bipolar disorder was admitted to another hospital with a gastric ulcer. On admission, Takotsubo cardiomyopathy was suspected because her electrocardiogram was abnormal and the characteristic left ventricular wall motion was apparent. On hospital day 11, echocardiography revealed a thrombus in the apex of the left ventricle. She was transferred to our hospital and heparin treatment was commenced. On follow-up echocardiography, the left ventricular wall motion had normalized but thrombus mobility had increased. Thrombectomy was performed via a transmitral approach with endoscopic assistance. Endoscopy allowed excellent visualization of the intracardiac structure. PMID- 28870090 TI - Efficiency of temporary storage of geothermal waters in a lake system: Monitoring the changes of water quality and bacterial community structures. AB - Disposal of used geothermal waters in Hungary often means temporary storage in reservoir lakes to reduce temperature and improve water quality. In this study, the physical and chemical properties and changes in the bacterial community structure of a reservoir lake system in southeast region of Hungary were monitored and compared through 2 years, respectively. The values of biological oxygen demand, concentrations of ammonium ion, total inorganic nitrogen, total phosphorous, and total phenol decreased, whereas oxygen saturation, total organic nitrogen, pH, and conductivity increased during the storage period. Bacterial community structure of water and sediment samples was compared by denaturing gradient gel electrophoresis (DGGE) following the amplification of the 16S rRNA gene. According to the DGGE patterns, greater seasonal than spatial differences of bacterial communities were revealed in both water and sediment of the lakes. Representatives of the genera Arthrospira and Anabaenopsis (cyanobacteria) were identified as permanent and dominant members of the bacterial communities. PMID- 28870091 TI - High prevalence of OXA-type carbapenemases among Acinetobacter baumannii strains in a teaching hospital of Tehran. AB - Nosocomial infection caused by carbapenem-resistant Acinetobacter baumannii (CRAB) has created a public health concern all around the world. In this study, 100 isolates of CRAB from hospitalized patients during 2015-2016 at Imam Khomeini Hospital were investigated to determine the rates of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains using Kirby-Bauer disk diffusion method. The minimum inhibitory concentrations (MICs) of six antibiotics were determined by broth microdilution method. Multiplex polymerase chain reaction (PCR) was performed to detect blaOXA-51 like and blaOXA-58 like, blaOXA-23 like, and blaOXA-24 like that are encoding resistance to carbapenems. All CRAB isolates were MDR and XDR and 2% of them were pandrug-resistant (PDR), whereas colistin, polymyxin B, and tigecycline were the most effective agents. All isolates were positive for blaOXA-51 like by PCR. The frequency of blaOXA-23 like and blaOXA-24 like was 81% and 22%, respectively. Findings of this study showed that very few therapeutic options remained for the treatment of CRAB infections and blaOXA-23 like is a dominant resistance gene in CRAB at this hospital. PMID- 28870092 TI - Emergence of armA and rmtB genes among VIM, NDM, and IMP metallo-beta-lactamase producing multidrug-resistant Gram-negative pathogens. AB - In the recent years, it has been noted that microorganisms with acquired resistance to almost all available potent antibiotics are increasing worldwide. Hence, the use of antibiotics in every clinical setup has to be organized to avoid irrational use of antibiotics. This study was aimed to establish the pattern of antibiotic sensitivity and relevance of antimicrobial resistance in aerobic Gram-negative bacilli. A total of 103 aerobic Gram-negative bacteria namely Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Citrobacter koserii, Proteus spp., and Pseudomonas aeruginosa were collected from tertiary care centers around Chennai. Kirby-Bauer Disk Diffusion test and study for genes of cephalosporin, carbapenem, and aminoglycoside resistance were done. A descriptive analysis of the data on altogether 103 clinical urine isolates was performed. All strains showed susceptibility to colistin. The frequency of genes encoding 16S rRNA methylases armA and rmtB were 7.8% and 6.8%, respectively. Among metallo-beta-lactamases, blaVIM, blaIMP, and blaNDM-1 were detected in 6.8%, 3.8%, and 3.8%, respectively. One E. coli strain harbored blaSIM-1 gene. Cumulative analysis of data suggested that 30% of the strains carried more than one resistance gene. The current research evidenced the increasing frequency of resistance mechanisms in India. Combined approach of antibiotic restriction, effective surveillance, and good infection control practices are essential to overcome antibiotic resistance. PMID- 28870089 TI - Mitogen- and Stress-Activated Protein Kinase 1 Regulates Status Epilepticus Evoked Cell Death in the Hippocampus. AB - Mitogen-activated protein kinase (MAPK) signaling has been implicated in a wide range of neuronal processes, including development, plasticity, and viability. One of the principal downstream targets of both the extracellular signal regulated kinase/MAPK pathway and the p38 MAPK pathway is Mitogen- and Stress activated protein Kinase 1 (MSK1). Here, we sought to understand the role that MSK1 plays in neuroprotection against excitotoxic stimulation in the hippocampus. To this end, we utilized immunohistochemical labeling, a MSK1 null mouse line, cell viability assays, and array-based profiling approaches. Initially, we show that MSK1 is broadly expressed within the major neuronal cell layers of the hippocampus and that status epilepticus drives acute induction of MSK1 activation. In response to the status epilepticus paradigm, MSK1 KO mice exhibited a striking increase in vulnerability to pilocarpine-evoked cell death within the CA1 and CA3 cell layers. Further, cultured MSK1 null neurons exhibited a heighted level of N-methyl-D-aspartate-evoked excitotoxicity relative to wild type neurons, as assessed using the lactate dehydrogenase assay. Given these findings, we examined the hippocampal transcriptional profile of MSK1 null mice. Affymetrix array profiling revealed that MSK1 deletion led to the significant (>1.25-fold) downregulation of 130 genes and an upregulation of 145 genes. Notably, functional analysis indicated that a subset of these genes contribute to neuroprotective signaling networks. Together, these data provide important new insights into the mechanism by which the MAPK/MSK1 signaling cassette confers neuroprotection against excitotoxic insults. Approaches designed to upregulate or mimic the functional effects of MSK1 may prove beneficial against an array of degenerative processes resulting from excitotoxic insults. PMID- 28870094 TI - Design, synthesis and biological activity of pyrazinamide derivatives for anti Mycobacterium tuberculosis. AB - A total of 11 pyrazinamide derivatives were designed and synthesised using pyrazinamide as the lead compound, which was optimised by structural modification with alkyl chains, six-membered rings, and bioisosterism, respectively. The target compounds were synthesised using pyrazinecarboxylic acid as the starting material by acylation, amidation, and alkylation, respectively. Their structures were confirmed by 1H NMR, 13C NMR, HRESIMS, and elemental analysis, respectively. The bioactivities of derivatives were assayed using bacteriostatic experiment and minimum inhibitory concentration experiment. It was showed that the derivatives had good inhibitory effect on Mycobacterium tuberculosis. The biological activity of derivative 1f was the best among all compounds, its antibacterial activity was 99.6%, and the minimum inhibitory concentration was 8.0 ug/mL. PMID- 28870093 TI - Novel series of 1,2,4-trioxane derivatives as antimalarial agents. AB - Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC50 values of 1.24 uM and 1.24 uM and 1.06 uM and 1.17 uM, against sensitive and resistant strains, respectively. Further, trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski's rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, 1,2,4-trioxane derivative(s) reported herein may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria. PMID- 28870095 TI - Efficacy of Traditional Chinese Medicine in Treatment and Prophylaxis of Radiation-Induced Oral Mucositis in Patients Receiving Radiotherapy: A Randomized Controlled Trial. AB - OBJECTIVE: To estimate the efficacy of traditional Chinese medicine (Chining decoction, CHIN) for radiation-induced oral mucositis in patients with head and neck cancer. METHODS: From May 2014 to December 2015, 70 consecutive patients were randomly assigned to receive CHIN (treatment group) or recombinant human epidermal growth factor (rhEGF) spray (control group) at a 1:1 ratio. CHIN was administered to treatment group from the first day of radiotherapy until the completion of radiotherapy. Simultaneously, the rhEGF spray was administered to control group on the oral mucosa of irradiated area. The clinical benefit was determined by gradation of mucositis (Common Terminology Criteria for Adverse Events v4.0), oral pain, and xerostomia (visual analysis scale) for each week during radiotherapy. Body mass index was evaluated before and after radiotherapy. RESULTS: Patients in the treatment group had prominent remission of oral pain and grade of mucositis on each observing point compared with those in control group ( P < .01). Xerostomia was decreased notably in treatment group compared with control group ( P < .01). Body mass index in the treatment group exhibited advantage over control group after radiotherapy, but there was no statistical significance (19.8 +/- 3.26 vs 18.8 +/- 2.5 kg/m2, P = .153, >.05). CONCLUSIONS: CHIN presented an obvious advantage in preventing radiation-induced oral mucositis compared with rhEGF spray. PMID- 28870096 TI - Major health service transformation and the public voice: conflict, challenge or complicity? AB - Objectives Calls for major reconfigurations of health services have been accompanied by recommendations that wide ranging stakeholders be involved. In particular, patients and the wider public are seen as critical contributors as both funders and beneficiaries of public health care. But public involvement is fraught with challenges, and little research has focused on involvement in the health service transformation initiatives. This paper examines the design and function of public involvement in reconfiguration of health services within the English NHS. Methods Qualitative data including interviews, observation and documents were collected in two health service 'transformation' programmes; interviews include involved public and professional participants. Data were analysed using parallel deductive and inductive approaches. Results Public involvement in the programmes was extensive but its terms of reference, and the individuals involved, were restricted by policy pressures and programme objectives. The degree to which participants descriptively or substantively represented the wider public was limited; participants sought to 'speak for' this public but their views on what was 'acceptable' and likely to influence decision making led them to constrain their contributions. Conclusions Public involvement in two major service reconfiguration programmes in England was seen as important and functional, and could not be characterized as tokenistic. Yet involvement in these programmes fell short of normative ideals, and could inadvertently reduce, rather than enlarge, public influence on health service reconfiguration decisions. PMID- 28870098 TI - Expectations and reality: perceptions of support among African American breast cancer survivors. AB - OBJECTIVE: The experience of an illness such as breast cancer is not a static event. Just as physiological needs change as a patient transitions through diagnosis, treatment, to long-term survivorship, so too will their needs for social support. We applied a transitions theory framework to explore how African American women with breast cancer conceptualized and experienced support along their breast cancer journey. DESIGN: We recruited 16 African American women with breast cancer from a regional cancer center in South Carolina to complete qualitative, semi-structured interviews. We iteratively examined verbatim transcripts using thematic analysis. RESULTS: Three core themes emerged: 'I guess she was supposed to': When support meets patient expectations; 'I wasn't expecting that and that just made me feel so good': When reality exceeds expectations; and 'Don't try to make an invalid out of me': When support given wasn't what was desired. Survivors shared how their family, friends and clergy met their needs for emotional (e.g. prayer, sharing affirmations about God) and instrumental support (e.g. cooking meals, house cleaning). They emphasized how receiving emotional support from their healthcare providers was a pleasant surprise. However, survivors also described unexpected disappointments when family members offered support that was un-needed or un-desired. CONCLUSIONS: Applying transitions theory, we found that social support is a process of bidirectional negotiation where African American women with breast cancer perceive support as helpful and acceptable depending on who offers support, what type of support is offered, and when it is offered. Members of their social support network (e.g. family, friends, providers) should periodically assess the survivor's evolving needs to ensure the social support harmonizes with the needs and expectations of the survivor. PMID- 28870097 TI - Glycosylation profiling to evaluate glycoprotein immunogens against HIV-1. AB - INTRODUCTION: Much of the efforts to develop a vaccine against the human immunodeficiency virus (HIV) have focused on the design of recombinant mimics of the viral attachment glycoprotein (Env). The leading immunogens exhibit native like antigenic properties and are being investigated for their ability to induce broadly neutralizing antibodies (bNAbs). Understanding the relative abundance of glycans at particular glycosylation sites on these immunogens is important as most bNAbs have evolved to recognize or evade the dense coat of glycans that masks much of the protein surface. Understanding the glycan structures on candidate immunogens enables triaging between native-like conformations and immunogens lacking key structural features as steric constraints limit glycan processing. The sensitivity of the processing state of a particular glycan to its structural environment has led to the need for quantitative glycan profiling and site-specific analysis to probe the structural integrity of immunogens. Areas covered: We review analytical methodologies for HIV immunogen evaluation and discuss how these studies have led to a greater understanding of the structural constraints that control the glycosylation state of the HIV attachment and fusion spike. Expert commentary: Total composition and site-specific glycosylation profiling are emerging as standard methods in the evaluation of Env-based immunogen candidates. PMID- 28870099 TI - Discrepant Views of Oncologists and Cancer Patients on Complementary and Alternative Medicine in a Chinese General Hospital. AB - PURPOSE: Complementary and alternative medicine (CAM) has been widely used by cancer patients but rarely discussed by oncologists. This study was designed to evaluate the communication gap between China's oncologists and cancer patients on CAM. METHODS: Two parallel cross-sectional studies assessed 83 oncologists and 402 cancer patients on CAM communication between patients and oncologists, and attitudes toward CAM use and clinical decisions about CAM. RESULTS: A majority (75.1%) of the cancer patients (302/402) were identified as CAM users within the most recent three months while 77.6% of the cancer patients (312/402) were identified as CAM users since diagnosis of cancer. Oncologists and patients responded differently ( P < .001) on CAM communications. Both oncologists and patients expected that CAM could improve the immune system. They both agreed that oncologists usually discouraged their patients from using CAM. Regarding the effectiveness of CAM, cancer patients were more likely to believe that CAM was effective while oncologists had more concerns about adverse effects of CAM use. CAM use by patients was predicted by disease duration (>=9 months) in the multivariable logistic regression model. CONCLUSION: China's oncologists and cancer patients may hold discrepant views on CAM. China's oncologists are encouraged to improve their knowledge on CAM and to initiate more discussions with their patients regarding effective and the safe use of CAM. PMID- 28870100 TI - Biologic drugs in adult onset Still's disease: a systematic review and meta analysis of observational studies. AB - BACKGROUND: Biological drugs, mainly interleukin (IL)-1 and IL-6 antagonists, but also tumor necrosis factor (TNF) inhibitors, have been used in the treatment of adult onset Still's disease patients (AOSD). METHODS: We summarised the available evidence for the effectiveness of biologic drugs in AOSD. A systematic review of the literature was performed in order to identify all the available data concerning the effectiveness of biologic drugs in AOSD. The proportion of patients achieving complete remission or any clinical response was calculated. The meta-analysis was thus performed using a random-effects model accounting for the expected high level of heterogeneity. RESULTS: Nineteen observational published studies were included in the meta-analysis. The pooled analysis under a random-effects model showed an overall rate of clinical response of 0.85 (95% CI: 0.77-0.91, p < 0.0001) and an overall rate of complete remission of 0.66 (95% CI: 0.54-0.77, p = 0.01). The heterogeneity across studies was high (Q = 59.82 with df = 19.0, p < 0.0001, I2 = 68.23%). CONCLUSIONS: Our meta-analysis suggests that AOSD patients may experience a clinical response and/or a complete remission when treated with biologic drugs. Specifically designed and powered studies are needed to fully investigate the role of such medications in the management of AOSD patients. PMID- 28870101 TI - Effects of non-medical switching on outcomes among patients prescribed tumor necrosis factor inhibitors. AB - OBJECTIVE: To evaluate health care use and outcomes among patients who experienced a non-medical switch of their prescribed anti-tumor-necrosis-factor biological agent (anti-TNF) for cost containment reasons. METHODS: Retrospective evaluation of Humedica electronic health records of patients >=18 years old with anti-TNF treatment for immune conditions. Using natural language processing, stable patients who experienced a non-medical switch (for cost reasons) of their anti-TNF between 2007 and 2013 were identified (NMS cohort, n = 158) and matched to patients who did not (control cohort, n = 4804). Rates of office visits, emergency department visits, and hospitalizations at 30, 90, and 365 days following were evaluated. Medication-related adverse events, defined as subsequent medication change due to a side effect and/or efficacy-related reason were also compared. RESULTS: Adjusted rates of office visits were higher among the NMS cohort than the control cohort at 30 (46.4% vs. 31.7%, p < .001), 90 (71.0% vs. 57.0%, p < .001), and 365 days (87.8% vs. 76.8%, p < .001). Rates of emergency department use and hospitalization were comparable between cohorts. The NMS cohort had higher adjusted rates of medication-related adverse consequences (both increased side effects and diminished efficacy) than the control cohort at 30 (13.8% vs. 4.0%, p = .003), 90 (31.6% vs 9.6%, p < .001), and 365 days (54.7% vs. 20.3%, p < .001). Compared with controls, the NMS cohort had higher adjusted rates of subsequent medication change within 1 year (27.82% vs. 13.9%, p = .001). CONCLUSION: Non-medical switching among patients prescribed anti-TNFs was associated with increased health care use, medication-related side effects, and reports of diminished efficacy. PMID- 28870102 TI - Therapeutic outcomes of the LHRH antagonists. AB - INTRODUCTION: Recently, LHRH antagonists have been established in the management of advanced prostate cancer, although the vast majority of Medical Oncologists and Urologists still prefer the LHRH agonists. Areas Covered: In this article we assess the therapeutic outcomes and the safety of the LHRH antagonists (mainly degarelix) compared to the LHRH agonists. Expert Commentary: Relevant studies demonstrated that LHRH antagonists are at least non-inferior to the LHRH agonists regarding therapeutic efficacy and safety, while there is potential benefit over the LHRH agonists in terms of cardiovascular morbidity and disease control. Disadvantages regarding formulation and frequency of administration are currently seem to be improving, as a 3-month depot of degarelix is evaluated and relugolix, an investigational orally administered is undergoing phase I studies, while the results of relative comparative studies are warranted. PMID- 28870103 TI - Racial/ethnic variation in the prevalence of vaccine-related human papillomavirus genotypes. AB - OBJECTIVE: There are currently three licensed human papillomavirus (HPV) vaccines that protect against cervical cancer. Here we compare the prevalence of bi-, quadri-, and nonavalent vaccine-related HPV genotypes in a multi-ethnic sample of non-Hispanic white, non-Hispanic black, Hispanic, and Asian women. DESIGN: Patients in this analysis (n = 419) represent a subset of women with a previous abnormal Pap test participating in a clinical trial. HPV genotyping was conducted using the Roche Linear Array. Prevalent HPV genotypes were grouped according to their inclusion in each of the vaccines: bivalent (16, 18), quadrivalent (16, 18, 6, 11), and nonavalent (16, 18, 31, 33, 45, 52, 58, 6, 11). RESULTS: The prevalence of HPV genotypes covered by the bi-/quadrivalent vaccines was lowest among non-Hispanic black (15%) and Hispanic women (20%), compared to non-Hispanic white (38%) and Asian women (38%). Across all racial/ethnic groups, a large proportion of infections (38%-49%) were with genotypes included in the nonavalent vaccine. However, the prevalence of HPV genotypes not covered by any vaccine was significantly higher among non-Hispanic black (36%) and Hispanic women (42%), compared to non-Hispanic white (24%) and Asian women (16%) (p < 0.001). Racial/ethnic differences in HPV genotype prevalence were observed when controlling for demographic and sexual behavior characteristics, as well as when restricting the analysis to women with CIN 2+. CONCLUSION: Our data suggest racial/ethnic differences in the prevalence of vaccine-related HPV genotypes. In particular, non-Hispanic black and Hispanic women had the lowest prevalence of HPV genotypes covered by the bi-/quadrivalent vaccines. While a large proportion of their infections were covered by the nonavalent vaccine, non-Hispanic black and Hispanic women also had the highest prevalence of HPV genotypes not covered by any vaccine. PMID- 28870104 TI - Type II transmembrane serine proteases as potential target for anti-influenza drug discovery. AB - INTRODUCTION: The outbreak of an influenza pandemic as well as the continued circulation of seasonal influenza highlights the need for effective antiviral therapies. The emergence of drug-resistant strains further necessitates the development of novel antivirals that target the host factors crucial for viral replication. Area covered: This review summarizes the current understanding of the structural and functional properties of type II transmembrane serine proteases (TTSPs) as a proteolytic activator of influenza virus infection and discusses their potential as antiviral targets. It also explores the experimental evidence accumulated for inhibitors of TTSPs as novel, broad-spectrum antivirals against various influenza virus subtypes. The review also provides an overview of the properties of small molecules, proteins, and peptides that efficiently inhibit the proteolytic activation of the influenza virus. Expert opinion: TTSPs activate a wide range of influenza virus subtypes including avian influenza viruses, both in vitro and in vivo, via proteolytic cleavage of influenza hemagglutinin (HA) into infection-competent fusogenic conformation. Other viruses such as SARS-, MERS-coronaviruses and human metapneumoviruses may use the same host cell proteases for activation, implying that TTSP inhibition might be a novel strategy for developing broad-spectrum antiviral agents for respiratory viral infections. PMID- 28870105 TI - Characterization of volatile compounds produced by Lactobacillus helveticus strains in a hard cheese model. AB - Starter cultures of Lactobacillus helveticus used in hard cooked cheeses play an important role in flavor development. In this work, we studied the capacity of three strains of L. helveticus, two autochthonous (Lh138 and Lh209) and one commercial (LhB02), to grow and to produce volatile compounds in a hard cheese extract. Bacterial counts, pH, profiles of organic acids, carbohydrates, and volatile compounds were analyzed during incubation of extracts for 14 days at 37 C. Lactobacilli populations were maintained at 106 CFU ml-1 for Lh138, while decreases of approx. 2 log orders were found for LhB02 and Lh209. Both Lh209 and LhB02 slightly increased the acetic acid content whereas mild increase in lactic acid was produced by Lh138. The patterns of volatiles were dependent on the strain which reflect their distinct enzymatic machineries: LhB02 and Lh209 produced a greater diversity of compounds, while Lh138 was the least producer strain. Extracts inoculated with LhB02 and Lh 209 were characterized by ketones, esters, alcohols, aldehydes, and acids, whereas in the extracts with Lh138 the main compounds belonged to aromatic, aldehydes, and ketones groups. Therefore, Lh209 and LhB02 could represent the best cheese starters to improve and intensify the flavor, and even a starter composed by combinations of LhB02 or Lh209 with Lh138 could also be a strategy to diversify cheese flavor. PMID- 28870106 TI - Expanded access to cancer treatments from conversion to neutropenia prophylaxis with biosimilar filgrastim-sndz. AB - AIM: Biosimilar medicines offer significant cost-savings potential over their reference products, which can be re-allocated to provide access to other cancer treatments on a budget-neutral basis. METHODS: Simulation study using cost data for the USA under consideration of several prophylaxis patterns. RESULTS: Potential savings from conversion from reference filgrastim to biosimilar filgrastim-sndz are significant. These savings expand budget-neutral access to novel immunotherapies (obinutuzumab; pembrolizumab) or supportive care (filgrastim-sndz). CONCLUSION: The combination of biosimilar savings and expanded access increases the value of cancer care as the same supportive care is provided at lower cost, additional cancer care is enabled at no additional cost, and more patients will have access to cancer care. PMID- 28870107 TI - Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study. AB - BACKGROUND: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study. METHODS: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained. RESULTS: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ? 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ? 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension. CONCLUSION: Cladribine tablets treatment for 2 years followed by 2 years' placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting. PMID- 28870108 TI - Positive and negative affectivity, stress, and well-being in African-Americans: Initial demonstration of a polynomial regression and response surface methodology approach. AB - OBJECTIVE: The extent to which positive (PA) and negative (NA) affect conjointly impact well-being is not yet well understood. Additionally, research investigating the role of affectivity in maintaining well-being among ethnic and racial minorities is scant. The current research demonstrates how polynomial regression and response surface methodology (PR and RSM) may be used to better understand how PA and NA jointly influence stress and well-being. DESIGN: In Study 1, 291 African-American undergraduates (Mage = 22.91, SD = 6.91; 67% female) completed measures of affectivity and psychological well-being. In Study 2, a community sample of 117 African-Americans (Mage = 31.87, SD = 13.83; 69% female) completed affectivity measures and a laboratory-based social stressor task to assess links between affectivity and salivary cortisol reactivity. MAIN OUTCOME MEASURES: Study 1 included life satisfaction, perceived stress and self reported depressive symptoms. Study 2 included salivary cortisol reactivity. RESULTS: Across both studies, PA ascendency (i.e. high PA combined with low NA) was associated with better well-being, while NA ascendancy (i.e. high NA combined with low PA) was associated with poorer outcomes. CONCLUSION: PR and RSM may provide new insight into the conjoint influence of PA and NA on health and well being. We discuss potential implications for affectivity research, including race related explorations. PMID- 28870109 TI - Usefulness of cardiometabolic index for the estimation of ischemic stroke risk among general population in rural China. AB - OBJECTIVES: Cardiometabolic index (CMI) has been recognized as a novel and practical marker for the assessment of cardiometabolic risk as it is independently related to diabetes and atherosclerotic progression. This study tested the hypothesis that CMI represents a risk of ischemic stroke in a general population of rural China. METHODS: From July 2012 to August 2013, we examined data from a large cross-sectional study of 11,345 participants (mean age 53.8 years; 60.8% females) who underwent biochemical determinations and anthropometric measurements in rural areas of northeast China. Ischemic stroke was documented as a history of cerebrovascular events and verified by medical record review. RESULTS: The prevalence of ischemic stroke was given to 3.1% of females and 3.2% of males. The cardio-metabolic profile was notably more adverse in ischemic stroke groups, irrespective of gender. A dose-response manner was detected for the prevalence of ischemic stroke, exhibiting a significant increase from the lowest to the highest quartiles of CMI (1.2% to 6.4% in females, P for trend<0.001; 2.3% to 4.3% in males, P for trend = 0.017). In multivariable analysis, for every 1 SD increment in CMI, the probability of ischemic stroke increased by 18% in females and 14% in males, respectively. The odds ratios for ischemic stroke comparing the top versus bottom quartiles of CMI were 2.047 (95%CI: 1.168-3.587) for females and 1.722 (95%CI: 1.019-2.910) for males. According to the area under receiver operating characteristic (AUC), the discrimination power of CMI in predicting ischemic stroke was relatively higher for females (AUC: 0.685) than males (AUC: 0.573). CONCLUSION: The strong and independent association of CMI with ischemic stroke in females, in comparison with the much lesser degree in males, provides further insight to better stratify by sex in investigations of ischemic stroke and solidly corroborates the potential role of ischemic stroke prevention targeted at CMI. PMID- 28870110 TI - Herbal Medicine for Xerostomia in Cancer Patients: A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: Xerostomia (dry mouth) causes many clinical problems, including oral infections, speech difficulties, and impaired chewing and swallowing of food. Many cancer patients have complained of xerostomia induced by cancer therapy. OBJECTIVE: The aim of this systematic review is to assess the efficacy of herbal medicine for the treatment of xerostomia in cancer patients. MATERIALS AND METHODS: Randomized controlled trials investigating the use of herbal medicines to treat xerostomia in cancer patients were included. We searched the following 12 databases without restrictions on time or language. The risk of bias was assessed using the Cochrane Risk of Bias Tool. RESULTS: Twenty-five randomized controlled trials involving 1586 patients met the inclusion criteria. A total of 24 formulas were examined in the included trials. Most of the included trials were insufficiently reported in the methodology section. Five formulas were shown to significantly improve the salivary flow rate compared to comparators. Regarding the grade of xerostomia, all formulas with the exception of a Dark Plum gargle solution with normal saline were significantly effective in reducing the severity of dry mouth. Adverse events were reported in 4 trials, and adverse effects of herbal medicine were reported in 3 trials. CONCLUSIONS: We found herbal medicines had potential benefits for improving salivary function and reducing the severity of dry mouth in cancer patients. However, methodological limitations and a relatively small sample size reduced the strength of the evidence. More high-quality trials reporting sufficient methodological data are warranted to enforce the strength of evidence regarding the effectiveness of herbal medicines. PMID- 28870111 TI - The anatomical variation of the circulus arteriosus cerebri in a cadaver cohort representing the population dynamics of the Western Cape. AB - The literature revealed a connection between the variations of the Circulus arteriosus cerebri (CAC) and cerebrovascular disease, ischemia, stroke, aneurysms and atherosclerosis. The diameters of the vessels forming the CAC have been classified into 22 types by previous authors. The aim of this study was to assess the variation of the CAC (diameter, length and anomalies) in a cadaver cohort representing the population of the Western Cape. Thirty-nine subjects (female n = 11, male n = 28) who had died of causes unrelated to brain trauma, were obtained from Stellenbosch University. Additionally, a pilot study was done on 20 specimens. The CAC were removed and fixed for three weeks in 10% buffered formaldehyde. Digital images were taken and the vessels were measured using Adobe Creative Suite 5: Extended edition (Photoshop). The normal diameter (type 1) was observed in 41% of specimens and type 4 (hypoplastic posterior communicating artery) was observed in 23.1%. One case (bilateral hypoplastic posterior communicating arteries and a hypoplastic right posterior cerebral artery) was classified as "other", since it could not be classified into the 22 types. Additional variations included duplication (17.9%) and one point fusion (15.4%) of the anterior communicating artery. Studies have shown that about half of a healthy population have a typical CAC (normal diameter and no anomalies). In the present study the prevalence of a typical CAC was only 15.4%. Studies can only be compared if the same definitions for variations are used. The knowledge of these variations is important in endarterectomy, stenting head and neck surgery and angiography. PMID- 28870112 TI - Engagement and Adherence With ezPARENT, an mHealth Parent-Training Program Promoting Child Well-Being. AB - Mobile health (mHealth) interventions use mobile technology (tablets and smartphones) delivery platforms for interventions to improve health outcomes. Despite growing acceptance, there is little understanding of how consumers engage with and adhere to mHealth interventions. This study analyzes usage data from the intervention arm ( n = 42) of a randomized clinical trial testing the efficacy of the ezPARENT program and provides recommendations for using engagement and adherence metrics. Engagement was measured by parent usage (duration, frequency, and activity) of ezPARENT and adherence using an adherence index (the sum of individual modules completed, number of visits to ezPARENT, and maximum time between visits). Parents spent M = 37.15 min per module and had M = 13.55 program visits in the 3-month intervention period. Parents visited the program over a period of M = 69.5 days and completed 82% of the modules. These data provide support that parents will use intervention programs delivered digitally; engagement and adherence metrics are useful in evaluating program uptake. PMID- 28870113 TI - Advances in quantifying apolipoproteins using LC-MS/MS technology: implications for the clinic. AB - INTRODUCTION: Apolipoproteins play a key role in pre-, pro-, and anti atherosclerotic processes and have become important circulating biomarkers for the prediction of cardiovascular disease (CVD) risk. Whereas currently clinical immunoassays are not available for most apolipoproteins and lack the capacity for multiplexing, liquid chromatography coupled to tandem mass spectrometry (LC MS/MS) allows simultaneous, highly-specific, and precise quantification of multiple apolipoproteins. Areas covered: We discuss LC-MS/MS methods for quantification of apolipoproteins reported in the literature and highlight key requirements for clinical use. Besides the advances in sample preparation and LC MS/MS technologies, this overview also discusses advances in proteoform analysis and applications of dried blood/plasma collection. Expert commentary: Standardized quantification using LC-MS/MS technology has been demonstrated for apolipoprotein A-I and B. However, for implementation in clinical CVD risk assessment, LC-MS/MS must bring significant added clinical value in comparison to fast, standardized, and straightforward clinical (immuno)assays. Ongoing advances in accuracy and multiplexing capacity of LC-MS/MS, nonetheless, bear potential to enable standardized and interpretable personalized profiling of a patient's CVD risk by simultaneous quantification of multiple apolipoproteins and -variants. We, moreover, anticipate further personalization of CVD risk assessment by the potential of LC-MS/MS to enable simultaneous genotyping and remote monitoring using dried blood/plasma collection devices. PMID- 28870115 TI - The Association Between Cognitive Impairment and Patterns of Activity Engagement Among Older Adults. AB - This study aims to assess the association between cognitive impairment and activity engagement patterns. Data from the 2012 Health and Retirement Study were used. A total of 3,943 participants aged 65 or older were included in analyses. Latent class analysis and multinomial logistic regression analysis were used. Four activity engagement profiles were identified: high activity (31.2%), active leisure (18.9%), passive leisure (28.2%), and low activity (21.7%). People in the high activity group engaged in all activities more than people in any other group, whereas people in the low activity group did not actively engage in most activities. Multinomial logistic regression analysis showed that cognitive impairment had an independent effect on the probability of being assigned to the low activity group compared to other groups. Cognitive impairment was associated with inactivity in a variety of activities. Future studies should examine supportive factors, which facilitate active patterns among people with cognitive impairment. PMID- 28870114 TI - Alleviating Mechanical Allodynia and Modulating Cellular Immunity Contribute to Electroacupuncture's Dual Effect on Bone Cancer Pain. AB - HYPOTHESIS: Electroacupuncture (EA) has been used as an alternative analgesic therapy for hundreds of years, yet its analgesic potency and therapeutic advantage against bone cancer pain (BCP) in comparison with morphine remains unclear. This study aimed to investigate the effects of EA on mechanical allodynia and cellular immunity of BCP rats, and to further explore the potential mechanism. METHODS: The BCP model was established by implanting Walker 256 mammary gland carcinoma cells into the left tibia of adult female Sprague-Dawley rats. EA (dilatational wave, 2/100 Hz, 0.5 mA-1mA-1.5 mA for 10 minutes each intensity) was applied bilaterally to Zusanli (ST 36) and Kunlun (BL 60) for 30 minutes. Both EA stimulation and morphine (10 mg/kg, intraperitoneally) was given once every other day. Naloxone (0.3 mg/kg, intraperitoneally) was injected at 30 minutes prior to EA. Mechanical allodynia were demonstrated by paw withdrawal thresholds (PWTs) which measured by dynamic plantar aesthesiometer. T cell proliferation, percentage of CD3+, CD4+ and CD8+ T lymphocytes in spleen as well as expression of interleukin-2 (IL-2) in plasma were detected by WST-8, flow cytometry, and enzyme-linked immunosorbent assay technique, respectively. RESULTS: An intratibial inoculation of Walker 256 mammary gland carcinoma cells significantly decreased PWTs to mechanical stimuli. EA stimulation alleviated mechanical allodynia in BCP rats, and the analgesic potency of EA was weaker than that of morphine. In contrast to morphine, EA stimulation of BCP rats increased splenic concanavalin A (Con A)-induced T cell proliferation and plasma IL-2 content, as well as increased the percentages of splenic CD3+CD4+ and CD3+CD8+ T cell subsets. Moreover, both the analgesic effect and the partial immunomodulation of EA were suppressed by an intraperitoneal injection of naloxone. CONCLUSION: EA could significantly alleviate BCP-induced mechanical allodynia. Although the analgesic effect of EA was weaker than that of morphine, EA had an immunomodulation effect on cellular immunity. Both analgesic and immunomodulatory effect of EA might share the same mechanism via the opioid mediated pathway, which needs further investigation. PMID- 28870116 TI - Beta-thalassemia in the paediatric cardiac surgery setting - a case report and literature review. AB - Beta (beta)-thalassemia is a blood disorder with an incidence of 1 in 100,000.1 This case report outlines a patient with beta-thalassemia requiring cardiopulmonary bypass (CPB) and the measures taken to ensure an uneventful procedure. PMID- 28870117 TI - Pseudotyped Lentiviral Vectors: One Vector, Many Guises. AB - Viruses have evolved specialized molecular mechanisms to transfer their genome efficiently into host cells. Viruses can be repurposed into viral vectors to achieve controlled gene transfer to desired cells. One of the most popular classes of vectors, lentiviral vectors (LVs), transduce mammalian cells efficiently. LVs are pseudotyped with various heterologous viral envelopes to alter their tropism. While the most common example is the envelope glycoprotein from vesicular stomatitis virus (VSVG), many other viral proteins have also been used. Pseudotyping LVs with a diverse set of naturally occurring or engineered viral envelopes has allowed targeted transduction of specific cell types. Many exciting studies are further uncovering new specificities and shortcomings of pseudotyped LVs. These studies will expand the toolbox to make LVs that cater to the specific requirements of transduction. This review provides a comprehensive overview of various viral envelope pseudotypes used with LVs, their specificities, advantages, and drawbacks. PMID- 28870118 TI - Suppression of chronic inflammation with engineered nanomaterials delivering nuclear factor kappaB transcription factor decoy oligodeoxynucleotides. AB - As a prototypical pro-inflammatory transcription factor, constitutive activation of NF-kappaB signaling pathway has been reported in several chronic inflammatory disorders including inflammatory bowel disease, cystic fibrosis, rheumatoid arthritis and cancer. Application of decoy oligodeoxynucleotides (ODNs) against NF-kappaB, as an effective molecular therapy approach, has brought about several promising outcomes in treatment of chronic inflammatory disorders. However, systematic administration of these genetic constructs is mostly hampered due to their instability, rapid degradation by nucleases and poor cellular uptake. Both chemical modification and application of delivery systems have shown to effectively overcome some of these limitations. Among different administered delivery systems, nanomaterials have gained much attention for delivering NF kappaB decoy ODNs owing to their high loading capacity, targeted delivery and ease of synthesis. In this review, we highlight some of the most recently developed nanomaterial-based delivery systems for overcoming limitations associated with clinical application of these genetic constructs. PMID- 28870119 TI - A history of concussions is associated with symptoms of common mental disorders in former male professional athletes across a range of sports. AB - OBJECTIVE: Recent reports suggest that exposure to repetitive concussions in sports is associated with an increased risk of symptoms of distress, anxiety and depression, sleep disturbance or substance abuse/dependence (typically referred as symptoms of common mental disorders[CMD]) and of later development of neurodegenerative disease, in particular chronic traumatic encephalopathy (CTE). The primary aim of this study was to explore the relationship between sports career-related concussions and the subsequent occurrence of symptoms of CMD among former male professional athletes retired from football (soccer), ice hockey and rugby (union). METHODS: Cross-sectional analyses were performed on baseline electronic questionnaires from three prospective cohort studies among former male professional athletes retired from football (soccer), ice hockey and rugby (union). The number of confirmed concussions was examined through a single question, while symptoms of distress, anxiety and depression, sleep disturbance and adverse alcohol use were assessed using validated questionnaires. RESULTS: From 1,957 former professional athletes contacted, a total of 576 (29%) completed the questionnaire. Of these, 23% had not incurred a concussion during their career, 34% had two or three, 18% four or five, and 11% six or more concussions. The number of sports career-related concussions was a predictor for all outcome measures (beta = 0.072-0.109; P <= 0.040). Specifically, former professional athletes who reported a history of four or five concussions were approximately 1.5 times more likely to report symptoms of CMD, rising to a two- to five-fold increase in those reporting a history of six or more sports career-related concussions. CONCLUSIONS: These data demonstrate an association between exposure to sports concussion and subsequent risk of symptoms of CMD in former professional athletes across a range of contact sports. Further work to explore the association between sports concussion and symptoms of CMD is required; in the meanwhile, strategies for effective risk reduction and improved management appear indicated. PMID- 28870120 TI - Virotherapy Research in Germany: From Engineering to Translation. AB - Virotherapy is a unique modality for the treatment of cancer with oncolytic viruses (OVs) that selectively infect and lyse tumor cells, spread within tumors, and activate anti-tumor immunity. Various viruses are being developed as OVs preclinically and clinically, several of them engineered to encode therapeutic proteins for tumor-targeted gene therapy. Scientists and clinicians in German academia have made significant contributions to OV research and development, which are highlighted in this review paper. Innovative strategies for "shielding," entry or postentry targeting, and "arming" of OVs have been established, focusing on adenovirus, measles virus, parvovirus, and vaccinia virus platforms. Thereby, new-generation virotherapeutics have been derived. Moreover, immunotherapeutic properties of OVs and combination therapies with pharmacotherapy, radiotherapy, and especially immunotherapy have been investigated and optimized. German investigators are increasingly assessing their OV innovations in investigator-initiated and sponsored clinical trials. As a prototype, parvovirus has been tested as an OV from preclinical proof-of-concept up to first-in-human clinical studies. The approval of the first OV in the Western world, T-VEC (Imlygic), has further spurred the involvement of investigators in Germany in international multicenter studies. With the encouraging developments in funding, commercialization, and regulatory procedures, more German engineering will be translated into OV clinical trials in the near future. PMID- 28870121 TI - Wide Awake and Ready to Move: 20 Years of Non-Viral Therapeutic Genome Engineering with the Sleeping Beauty Transposon System. AB - Gene therapies will only become a widespread tool in the clinical treatment of human diseases with the advent of gene transfer vectors that integrate genetic information stably, safely, effectively, and economically. Two decades after the discovery of the Sleeping Beauty (SB) transposon, it has been transformed into a vector system that is fulfilling these requirements. SB may well overcome some of the limitations associated with viral gene transfer vectors and transient non viral gene delivery approaches that are being used in the majority of ongoing clinical trials. The SB system has achieved a high level of stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, representing crucial steps that may permit its clinical use in the near future. This article reviews the most important aspects of SB as a tool for gene therapy, including aspects of its vectorization and genomic integration. As an illustration, the clinical development of the SB system toward gene therapy of age-related macular degeneration and cancer immunotherapy is highlighted. PMID- 28870122 TI - Diabetes fatalism and its emotional distress subscale are independent predictors of glycemic control among Lebanese patients with type 2 diabetes. AB - BACKGROUND: Achieving and sustaining optimal glycemic control in type 2 diabetes (T2DM) is difficult because of socio-cultural and psychosocial factors including diabetes fatalism. Diabetes fatalism is 'a complex psychological cycle characterized by perceptions of despair, hopelessness, and powerlessness'. PURPOSE: The purpose of this paper is to explore whether diabetes fatalism and other psychosocial and socio-cultural variables are correlates of glycemic control in Lebanese population with T2DM. METHODS: A convenience sample of 280 adult participants with T2DM were recruited from a major hospital in greater Beirut-Lebanon area and from the community. Diabetes fatalism was assessed using the Arabic version of 12-item Diabetes Fatalism Scale. Multiple linear regression models were used to assess the relationship between HbA1c and psychosocial and socio-cultural characteristics including diabetes fatalism. Four models were run to examine the independent association between HbA1c and diabetes fatalism and to identify which of the 3 subscales (emotional distress, spiritual coping and perceived self-efficacy) were associated with HbA1c. RESULTS: The mean age of the participants was 58.24(SD = 13.48) and the majority were females (53.76%), while 32.73% of the sample had diabetes for more than 10 years. Fully adjusted multiple linear regression models showed that higher scores on diabetes fatalism and the emotional distress subscale (P = 0.018) were significantly associated with higher HbA1c values. In addition, having diabetes for more than 11 years (P = 0.05) and a higher number of diabetes complications (P < 0.001) were associated with higher HbA1c levels. However, advanced age (P = 0.055), female gender (P = 0.003), and diabetes education (P = 0.011) were significantly associated with lower HbA1c levels. CONCLUSION: This is the first study in the Arab region that identifies diabetes fatalism as an independent predictor of glycemic control among Lebanese. Future studies should further investigate this construct to guide interventions that can address it for better diabetes outcomes. PMID- 28870123 TI - Bayesian treatment comparison using parametric mixture priors computed from elicited histograms. AB - A Bayesian methodology is proposed for constructing a parametric prior on two treatment effect parameters, based on graphical information elicited from a group of expert physicians. The motivating application is a 70-patient randomized trial to compare two treatments for idiopathic nephrotic syndrome in children. The methodology relies on histograms of the treatment parameters constructed manually by each physician, applying the method of Johnson et al. (2010). For each physician, a marginal prior for each treatment parameter characterized by location and precision hyperparameters is fit to the elicited histogram. A bivariate prior is obtained by averaging the marginals over a latent physician effect distribution. An overall prior is constructed as a mixture of the individual physicians' priors. A simulation study evaluating several versions of the methodology is presented. A framework is given for performing a sensitivity analysis of posterior inferences to prior location and precision and illustrated based on the idiopathic nephrotic syndrome trial. PMID- 28870124 TI - Reactive oxygen species trigger NF-kappaB-mediated NLRP3 inflammasome activation induced by zinc oxide nanoparticles in A549 cells. AB - Inhaled zinc oxide nanoparticles (ZnO-NPs) induce lung inflammation associated with oxidative stress. The NLRP3 inflammasome plays a pivotal role in the development of lung inflammation. However, the underlying effects of the NLRP3 inflammasome on ZnO-NPs-induced inflammation remain obscure. In the present study, reactive oxygen species (ROS) generation, expression of NLRP3, caspase-1 p10, and cytokines release of interleukin (IL)-1beta and IL-18 were determined after A549 cells were exposed to ZnO-NPs. The ROS scavenger N-acetyl-L-cysteine (NAC), nuclear factor kappa B (NF-kappaB inhibitor BAY11-7082, and NLRP3 inhibitor glibenclamide (GEL) were used to explore the mechanism of NLRP3 inflammasome activation-induced by ZnO-NPs. ZnO-NPs stimulation induced ROS generation and NF-kappaB p65 phosphorylation. Similarly, the expression of NLRP3 and caspase-1 p10 and the release of IL-1beta and IL-18 were significantly increased after ZnO-NPs treatment, which indicated that the NLRP3 inflammasome was activated by ZnO-NPs. Meanwhile, NAC pretreatment inhibited ZnO-NPs-induced activation of NF-kappaB and NLRP3 inflammasome. The NF-kappaB inhibitor BAY11 7082 did not affect ROS production but significantly reduced the NLRP3 inflammasome activation induced by ZnO-NPs. Furthermore, the ability of ZnO-NPs to increase the production of IL-1beta and IL-18 was significantly inhibited by GEL. The ZnO-NPs induced the activation of the NLRP3 inflammasome in A549 cells, which might be via a ROS-NF-kappaB-NLRP3 signaling pathway. PMID- 28870125 TI - Role of chest ultrasound in neonatal lung disease: a review of current evidences. AB - Among the common causes of neonatal admission to NICU, respiratory distress is one of the important causes. The neonatal respiratory distress is end result of various pulmonary and non-pulmonary causes. Differentiation of pulmonary causes of respiratory distress is important for the neonatologist as treatment differs with different etiologies. Conventionally, chest X-ray and sometimes CT scan have been used to identify the etiology of respiratory distress but these modalities have several limitations which make their use in NICU doubtful. In recent decades, there has been use of lung ultrasound (LUS) to identify and differentiate the etiologies of respiratory distress. The current available evidence show that LUS has good sensitivity and specificity to identify all the common causes of neonatal distress like respiratory distress syndrome, transient tachypnea of newborn, pneumothorax, and pneumonia. This review will cover the various uses of LUS in neonatal care with current available evidence. PMID- 28870126 TI - Innovative biomarkers in psychiatric disorders: a major clinical challenge in psychiatry. AB - INTRODUCTION: Currently, the diagnosis of psychiatric illnesses is based upon DSM 5 criteria. Although endophenotype-specificity for a particular disorder is discussed, the identification of objective biomarkers is ongoing for aiding diagnosis, prognosis, or clinical response to treatment. We need to improve the understanding of the biological abnormalities in psychiatric illnesses across conventional diagnostic boundaries. The present review investigates the innovative post-genomic knowledge used for psychiatric illness diagnostics and treatment response, with a particular focus on proteomics. Areas covered: This review underlines the contribution that psychiatric innovative biomarkers have reached in relation to diagnosis and theragnosis of psychiatric illnesses. Furthermore, it encompasses a reliable representation of their involvement in disease through proteomics, metabolomics/pharmacometabolomics and lipidomics techniques, including the possible role that gut microbiota and CYP2D6 polimorphisms may play in psychiatric illnesses. Expert opinion: Etiologic heterogeneity, variable expressivity, and epigenetics may impact clinical manifestations, making it difficult for a single measurement to be pathognomonic for multifaceted psychiatric disorders. Academic, industry, or government's partnerships may successfully identify and validate new biomarkers so that unfailing clinical tests can be developed. Proteomics, metabolomics, and lipidomics techniques are considered to be helpful tools beyond neuroimaging and neuropsychology for the phenotypic characterization of brain diseases. PMID- 28870127 TI - Major liver resection in pregnancy: three cases with different etiologies and review of the literature. AB - BACKGROUND: Major liver resection during pregnancy is extremely rare. When required, the associated physiologic and anatomic changes pose specific challenges and greater risk for both mother and fetus Materials and methods: Three cases of major liver resection during pregnancy due to different etiologies are presented. The relevant literature is reviewed and discussed. RESULTS: We present three cases of major liver resection due to giant liver hemangioma with Kasabach-Merrit syndrome, giant hydatid cyst, and intrahepatic cholangiocarcinoma, at gestational week (GW) 17, 19, and 30, respectively. All patients had an uneventful postoperative course, continued the pregnancy and gave birth at GW 38. CONCLUSION: Major liver resection can be performed safely during pregnancy. A multidisciplinary team of surgeons, anesthesiologists and gynecologists, in a highly experienced tertiary hepatobiliary center, should be involved. PMID- 28870128 TI - Relationship of surgically repaired ulnar collateral ligament injury of the thumb to the morphology of the metacarpophalangeal joint of the thumb. PMID- 28870129 TI - Intra-articular distal radius fractures in elderly patients: a randomized prospective study of casting versus volar plating. AB - : We compared outcomes in elderly patients with intra-articular distal radius fractures treated by closed reduction and plaster immobilization or open reduction and internal fixation with a volar plate. Ninety-seven patients older than 60 years were randomly allocated to conservative (47 patients) or surgical (50 patients) treatment. Over a 2-year period, we assessed patient-rated wrist evaluation score, DASH (disability arm, shoulder and hand) questionnaire, pain, wrist range of motion, grip strength, and radiological parameters. The functional outcomes and quality of life were significantly better after volar plating fixation compared with conservative treatment. We found that restoration of the articular surface, radial inclination, and ulnar variance affected the outcomes, but the articular step-off did not. Twenty-five per cent of the patients with conservative treatment had secondary loss of reduction. We conclude that surgical plating leads to better outcomes than conservative treatment for elderly patients with intra-articular distal radius fractures. LEVEL OF EVIDENCE: I. PMID- 28870131 TI - Re: Cluster analysis of the clinical histories of cattle affected with bovine anaemia associated with Theileria orientalis Ikeda type infection. PMID- 28870130 TI - Prevalence of the distal oblique bundle of the interosseous membrane of the forearm: an anatomical study. AB - A study was undertaken to examine the presence of the distal oblique bundle of the forearm in a large sample in order to describe its true prevalence. The study sample consisted of 200 cadaveric forearms. Fifteen were excluded due to defects in the distal interosseous membrane. In the remaining 185 specimens, the distal interosseous membrane was examined following removal of soft tissue, to determine whether a distal oblique bundle was present and whether there were connecting fibres to the distal radio-ulnar joint. The distal oblique bundle was observed in 53 specimens (29%). In 45 of these forearms (85%), one or more connecting fibres to the distal radio-ulnar joint were identified. The presence of a distal oblique bundle in 29% is less frequent than that reported in previous literature. The presence of the distal oblique bundle should be noted and may be of importance in the management of disorders of the distal radio-ulnar joint. PMID- 28870132 TI - Differential modes of photosensitisation in cancer cells by berberine and coralyne. AB - In this study, we demonstrated that the cytotoxicity of the protoberberine alkaloids such as coralyne, berberine and jatrorrhizine to several human cancer cell lines can be improved significantly in combination with UVA exposure. However, the phototoxic property of coralyne was much higher than that of the other two alkaloids. The combination of coralyne and UVA (designated as CUVA) induced oxygen-independent cytotoxicity in the human lung cancer A549 cells by producing more lethal DNA double-strand breaks, and the effect was mediated via the replication machinery. In comparison, the berberine-induced phototoxicity to the A549 cells was mediated by reactive oxygen species generation, mitochondrial membrane permeabilisation and caspase-9/caspase-3 activation. PMID- 28870133 TI - Treatment outcomes from forensic intellectual disability services: The perspectives of patients and their family/carers. AB - INTRODUCTION: Research investigating the treatment outcomes of forensic intellectual and developmental disability (FIDD) services has largely focused on the perspectives of clinicians and researchers. This study sought the perspectives of patients and family/carers on the outcomes important to them. METHODS: Semi-structured consultation groups were conducted with patients in FIDD services ( n = 21) and family carers ( n = 6). Interview data were content analysed, and outcomes identified fell into three main domains (effectiveness, safety and patient experience). RESULTS: The consultations identified outcome domains not considered in the published literature. Patients and carers also had differential perspectives on treatment outcomes commonly reported within literature. Illustrative quotes are used to evidence the domains. DISCUSSION: This study is the first to investigate the outcomes of relevance to patients and their families. These views have been incorporated into an outcomes framework which will form the foundation of future prospective outcome studies. PMID- 28870134 TI - Role of massage therapy on reduction of neonatal hyperbilirubinemia in term and preterm neonates: a review of clinical trials. AB - BACKGROUND: Neonatal hyperbilirubinemia (NNH) is one of the leading causes of admissions in nursery throughout the world. It affects approximately 2.4-15% of neonates during the first 2 weeks of life. AIMS: To evaluate the role of massage therapy for reduction of NNH in both term and preterm neonates. METHOD: The literature search was done for various randomized control trials (RCTs) by searching the Cochrane Library, PubMed, and EMBASE. RESULTS: This review included total of 10 RCTs (two in preterm neonates and eight in term neonates) that fulfilled inclusion criteria. In most of the trials, Field massage was given. Six out of eight trials reported reduction in bilirubin levels in term neonates. However, only one trial (out of two) reported significant reduction in bilirubin levels in preterm neonates. Both trials in preterm neonates and most of the trials in term neonates (five trials) reported increased stool frequencies. CONCLUSION: Role of massage therapy in the management of NNH is supported by the current evidence. However, due to limitations of the trials, current evidences are not sufficient to use massage therapy for the management of NNH in routine practice. PMID- 28870135 TI - Validation of an assessment tool for pre-operative EVAR planning. AB - INTRODUCTION: Current methods of teaching endovascular aortic aneurysm repair (EVAR) planning involve non-criteria-based observations that lack validity. The primary aim of this study was to validate an EVAR Planning Objective Structured Assessment of Skill (EpOSAS) tool for the assessment of pre-operative EVAR planning skills. METHODS: Content analysis was performed in order to inform the formulation of EpOSAS domains. Thirty-five participants planned two cases of infra-renal abdominal aortic aneurysm for EVAR, using the OsiriX 7 platform. EVAR planning measurements, with accompanying screenshots, were uploaded onto an electronic data collection sheet. Performance was assessed by three blinded assessors using the EpOSAS tool. Construct and concurrent validity were evaluated. RESULTS: Inter-observer reliability for the three assessors for total EpOSAS scores was high (Cronbach's alpha 0.89). There were statistically significant differences in total EpOSAS scores between the different experience groups, demonstrating construct validity (Novice (5.3, IQR 5-5.3), Intermediate (15.3, IQR 14.8-16.8) and Experts (17.5, IQR 17-17.7), p<0.001). A statistically significant correlation was found between total EpOSAS scores and percentage error in measurements, demonstrating concurrent validity (Spearman's rank correlation coefficient: R=-0.250, p<0.001). Receiver-operator characteristics analysis established a cut-off point of 16 out of 18 for determining competence. CONCLUSION: We have developed and validated a tool that can be used for the assessment of pre-operative EVAR planning skills. PMID- 28870136 TI - Ectonucleotidase inhibitors: a patent review (2011-2016). AB - INTRODUCTION: Ectonucleotidases are a broad family of metallo-ectoenzymes that are responsible for hydrolysing a variety of nucleotides to nucleosides, hence orchestrating the activation of P1 and P2 cell receptors via controlled release of nucleotides and nucleosides. Many disorders such as impaired calcification including aortic calcification, neurological and immunological disorders, platelet aggregation, cell proliferation and metastasis. are characterized by an increase in expression of these ectonucleotidases. Consequently, selective inhibitors of ectonucleotidases are required for therapeutic intervention. Area covered: Several classes of compounds such as purine, nucleotide derivatives (e.g., ARL67156) and monoclonal antibodies, have shown promising ectonucleotidase inhibitory potential. This review discusses chemistry and therapeutic applications of ectonucleotidase inhibitors patented from 2011 to 2016. Expert opinion: All eukaryotic cells express nucleotide and nucleoside receptors on their cell surface and are capable of releasing extracellular nucleotides. Ectonucleotidases are a broad family of metallo-ectoenzymes that hydrolyze a variety of nucleotides to nucleosides. These extracellular nucleotides and nucleosides are important cell signalling molecules and mediate a variety of (patho)physiological processes by acting upon their respective P1 and/or P2 receptors. Discovery of molecules that can selectively inhibit or activate ectonucleotidases is crucial from therapeutic point of view, since it allows human intervention into purinergic cell signalling, thereby allowing us to modulate related (patho)physiological processes as desired. PMID- 28870137 TI - The effect of supervised exercise on localized TMD pain and TMD pain associated with generalized pain. AB - OBJECTIVES: To evaluate the effect of a supervised exercise program in patients with localized/regional temporomandibular disorder (TMD) pain and with TMD associated with generalized pain. MATERIAL AND METHODS: Consecutively referred patients with localized/regional TMD pain (n = 56; 46 women and 10 men, mean age 44 years) and TMD associated with generalized pain (n = 21; 21 women, mean age 41 years) participated. Patients underwent a 10-session structured supervised exercise program over 10-20 weeks that included relaxation, and coordination and resistance training of the jaw and neck/shoulders. The outcomes were jaw pain intensity on the Numerical Rating Scale, endurance time for jaw opening and protrusion against resistance and chewing, and effect of pain on daily activities. RESULTS: After the exercise program, a reduction in jaw pain was reported by the local (p = .001) and general (p = .011) pain groups. There were no significant differences in jaw pain intensity between the groups, before (p = .062) or after treatment (p = .121). Endurance time increased for both groups for jaw opening/protrusion (both p < .001) and chewing (both p = .002). The effect of jaw pain on daily activities decreased after exercise compared to baseline for both the local (p < .001) and general (p = .008) pain groups. CONCLUSIONS: Supervised exercise can reduce TMD pain and increase capacity in patients with TMD. The results suggest that activation of the jaw motor system with exercise has a positive effect in patients with localized/regional TMD pain and TMD associated with generalized pain. PMID- 28870138 TI - A Plea for the Newborn Diagnosis of Hb S-Hereditary Persistence of Fetal Hemoglobin. AB - The gene for hereditary persistence of fetal hemoglobin (HPFH) in the Caribbean is much more common than previously estimated. To avoid labeling persons with the benign syndrome Hb S (HBB: c.20A>T)/HPFH as a disease and wasting scarce resources, parental studies are recommended when newborn screening reveals a pattern consistent with an SS phenotype. PMID- 28870139 TI - The role of segmental and durational cues in the processing of reduced words. AB - In natural conversations, words are generally shorter and they often lack segments. It is unclear to what extent such durational and segmental reductions affect word recognition. The present study investigates to what extent reduction in the initial syllable hinders word comprehension, which types of segments listeners mostly rely on, and whether listeners use word duration as a cue in word recognition. We conducted three experiments in Dutch, in which we adapted the gating paradigm to study the comprehension of spontaneously uttered conversational speech by aligning the gates with the edges of consonant clusters or vowels. Participants heard the context and some segmental and/or durational information from reduced target words with unstressed initial syllables. The initial syllable varied in its degree of reduction, and in half of the stimuli the vowel was not clearly present. Participants gave too short answers if they were only provided with durational information from the target words, which shows that listeners are unaware of the reductions that can occur in spontaneous speech. More importantly, listeners required fewer segments to recognize target words if the vowel in the initial syllable was absent. This result strongly suggests that this vowel hardly plays a role in word comprehension, and that its presence may even delay this process. More important are the consonants and the stressed vowel. PMID- 28870140 TI - Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccines in participants >/=3 years of age: a double-blind, randomized, parallel-controlled phase III clinical trial in China. AB - BACKGROUND: Viruses from two antigenically distinct influenza B strains have co circulated since the mid-1980s, yet inactivated trivalent influenza vaccines (TIVs) with either the Victoria or Yamagata lineage could only provide limited protection from influenza B strain. Quadrivalent influenza vaccine (QIV) including both influenza B lineages can improve protection against circulating influenza B viruses. METHODS: Participants >/ = 3 years of age were recruited, stratified by age, and then randomly allocated at a ratio of 2:1:1 to receive one injection of the experimental QIV, TIV-Victoria (Vic) or TIV-Yamagata (Yam). The primary objective of this study was to demonstrate that the hemagglutination inhibition (HI) antibodies induced by the QIV candidate are not inferior to the licensed TIVs. RESULTS: First, 3661 participants received the inoculation. The QIV was found to be non-inferior to TIVs in terms of the geometric mean titers (GMTs) and seroconversion rates (SCRs) of the HI antibodies against shared strains 28 days after completion of inoculation, and was superior to the TIVs against the alternate B strain, which is absent from the TIVs. The occurrences of adverse events (AEs) post-vaccination were similar across the treatment groups. CONCLUSION: The experimental QIV showed good immunogenicity and an acceptable safety profile. PMID- 28870141 TI - Physical and Psychosocial Characteristics of Current Child Dancers and Nondancers With Systemic Joint Hypermobility: A Descriptive Analysis. AB - Study Design Cross-sectional study. Background The effect of current participation in dance training on joint pain and instability, fatigue, and quality of life is unknown. Objectives To examine differences in joint pain, instability, gross motor skills, nonmusculoskeletal systemic manifestations, health-related quality of life (HRQoL), and fatigue between children with joint hypermobility syndrome/Ehlers-Danlos syndrome-hypermobility type (JHS/EDS-HT) who currently undertake formal dance training and those who do not. Methods Children with JHS/EDS-HT and 1 parent completed reports providing data on demographic variables, symptoms, organized activity participation, HRQoL, and fatigue. Physical and functional measures included extent of hypermobility, aerobic fitness, balance, and muscle endurance. Results Of the 102 participating children, 22 currently undertook dance classes, averaging 3.3 h/wk. While the dancers reported a number of painful joints similar to that reported by nondancers (mean +/- SD, 5.5 +/- 3.7 versus 6.4 +/- 3.9 joints, respectively; P = .36), they reported significantly lower pain levels on a 0-to-10 scale (3.8 +/- 3.3 versus 5.6 +/- 3.4, P = .04) and found pain to be less problematic, affecting less of their body. They reported fewer unstable joints (1.0 +/- 1.0 versus 2.0 +/- 1.8 joints, P = .001), despite being more hypermobile (Beighton score, 7.3 +/ 1.4 versus 6.6 +/- 1.6 on a 9-point scale, P = .047; Lower Limb Assessment Score, 9.2 +/- 2.0 versus 8.1 +/- 1.9 on a 12-point scale, P = .02). The dancers had significantly better HRQoL in the subdomain of school functioning (P = .004) and reported less fatigue (P = .024). Conclusion Children with JHS/EDS-HT who are currently undertaking formal dance training have fewer joint pain and instability symptoms, less fatigue, and better HRQoL; however, the cross-sectional nature of the study means that causation cannot be determined. Level of Evidence Therapy, level 2b. J Orthop Sports Phys Ther 2017;47(10):782-791. Epub 4 Sep 2017. doi:10.2519/jospt.2017.7331. PMID- 28870142 TI - Validation of the Standardized Universal Pain Evaluations for Rheumatology Providers for Children and Youth (SUPER-KIDZ). AB - Study Design Longitudinal observational clinimetric study with repeated measures. Background No validated multidimensional pain measure for children and youth with juvenile idiopathic arthritis exists. Objective To determine the test-retest reliability, construct validity, and responsiveness of English and French versions of the Standardized Universal Pain Evaluations for Rheumatology Providers for Children and Youth (SUPER-KIDZ). Methods Measurement properties of the SUPER-KIDZ (older child, younger child, and parent versions) were prospectively evaluated in patients (aged 4 to 18 years) with juvenile idiopathic arthritis at 2 centers. Internal consistency of the 3 subscales was measured using ordinal reliability alpha. Test-retest reliability for each subscale was evaluated with intraclass correlation coefficients (ICCs) from participants assumed to have stable pain (over a 1-week period with no change in treatment). Correlations of SUPER-KIDZ scores with validated measures determined construct validity. Responsiveness of SUPER-KIDZ subscales was evaluated in patients with improvement in pain, using standardized response mean and linear mixed-model regression. Results Seventy-one children aged 8 to 18 years and 29 parent-child dyads aged 4 to 7 years were included. Seventy-four percent of participants were female, with a median of 3 active joints (interquartile range, 1-5). Internal consistency was strong (alpha = .78-.96) for pain characteristics, interference, and emotional functioning SUPER-KIDZ subscales. Good test-retest reliability (ICC>=0.80) was found for the pain characteristics subscale in older- and younger child versions. Most other subscales had satisfactory reliability coefficients (ICC>=0.70). Correlations of 0.50 or greater were found between the older-child SUPER-KIDZ scores and the Childhood Health Assessment Questionnaire and Patient Reported Outcomes Measurement Information System depressive symptoms items, as well as the younger-child pain-intensity item and the Faces Pain Scale-Revised. Strong responsiveness was found for all subscales (standardized response mean, 0.63-1.54; significant linear mixed-model regression), except for the older-child emotional functioning subscale. Conclusion The SUPER-KIDZ has shown good internal consistency and responsiveness, and satisfactory test-retest reliability. Construct validity was moderate for the younger- and older-child versions, but weak for the parent version. J Orthop Sports Phys Ther 2017;47(10):731-740. Epub 4 Sep 2017. doi:10.2519/jospt.2017.7375. PMID- 28870143 TI - Characteristics and Outcome of Patellofemoral Pain in Adolescents: Do They Differ From Adults? AB - Study Design Case series with 1-year follow-up. Background Most of the recommendations for the diagnosis, treatment, and prognosis of patellofemoral pain (PFP) are based on research performed in adults. The literature suggests that there are potential differences between adolescents and adults with PFP. Objectives To investigate differences in characteristics, symptoms, and prognosis at 1-year follow-up between adolescents and adults with PFP. Methods Data from 64 patients with PFP, assessed at baseline and 1-year follow-up, were used. At baseline, data on demographics, symptoms, and coping strategies were obtained by questionnaire. Physical examination included strength and flexibility measurements of the quadriceps and hamstrings. At 1-year follow-up, a questionnaire was used to collect data on pain, function, and recovery. Differences between adolescents (14-18 years) and adults (18-40 years) were analyzed using regression techniques, adjusted for sex, body mass index, and the presence of bilateral pain. Results Of the 64 patients with PFP included at baseline, 78.1% were available for follow-up. At baseline, adolescents with PFP had a significantly lower body mass index (20.7 versus 24.9 kg/m2) and a greater percentage of bilateral pain (70% versus 43.2%) than adults with PFP. There were no differences in reported pain and symptoms between the 2 groups. In total, 25% of the adolescents regarded themselves as recovered after 1 year, compared to 22.7% of the adults (adjusted P = .725). Conclusion The sample size of the study, in relation to the number of statistical tests performed, urges caution in the interpretation of the results. In contrast to what has been suggested previously, only minor differences seem to exist between adolescents and adults with PFP. In both groups, PFP is clearly not a self-limiting disease, with nearly 75% of those in this study reporting persistent pain at 1-year follow-up. Level of Evidence Prognosis, level 4. J Orthop Sports Phys Ther 2017;47(10):801-805. Epub 4 Sep 2017. doi:10.2519/jospt.2017.7326. PMID- 28870144 TI - Higher survival rates in exercise-related out-of-hospital cardiac arrests, compared to non-exercise-related - a study from the Swedish Register of Cardiopulmonary Resuscitation. AB - Background Despite the positive effects of physical activity, the risk of sudden cardiac arrest is transiently increased during and immediately after exercise. The purpose of this study was to assess the incidence of exercise-related out-of hospital cardiac arrest in the general population and to compare characteristics and prognosis of these cardiac arrests with non-exercise-related out-of-hospital cardiac arrests. Methods Data from all cases of treated out-of-hospital cardiac arrest outside of home reported to the Swedish Register of Cardiopulmonary Resuscitation from 2011-2015 in three counties of Sweden were investigated (population 2.1 m). This registry captures almost 100% of all out-of-hospital cardiac arrests in Sweden. Results Of 1825 out-of hospital cardiac arrests, 137 (7.5%) were exercise-related, resulting in an incidence of 1.2 per 100,000 person years. The 30-day survival rate was significantly higher among exercise-related out-of hospital cardiac arrests compared to non-exercise-related out-of-hospital cardiac arrests (54.3 % vs 19.4%, p < 0.0001). Patients suffering an exercise related out-of-hospital cardiac arrest were on average 10 years younger than those who had a non-exercise-related out-of-hospital cardiac arrest, 56.4 years compared to 67.2 years. Exercise-related out-of-hospital cardiac arrests were more often witnessed (89.4% vs 78.6%, p = 0.002), had higher rates of bystander cardiopulmonary resuscitation (80.3% vs 61.0%, p < 0.0001) and were more frequently connected to an automated external defibrillator (20.4% vs 4.6%, p < 0.0001). Conclusions Cardiac arrests that occur in relation to exercise have a significantly better prognosis and outcome than non-exercise-related cardiac arrests. This may be explained by favourable circumstances but may also reflect that these persons experience a sudden cardiac arrest at a lower degree of coronary artery disease, due to their younger age and to exercise being a trigger. PMID- 28870145 TI - Real-world use and modeled impact of glucose-lowering therapies evaluated in recent cardiovascular outcomes trials: An NCDR(r) Research to Practice project. AB - Aims Recent trials (EMPA-REG OUTCOME and Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER]) have shown improved cardiovascular (CV) mortality with specific currently available glucose lowering medications (empagliflozin and liraglutide, respectively), but were limited to selected patient populations. We sought to evaluate the current use and potential real-world impact of empagliflozin (and other sodium-glucose co transporter 2 inhibitors [SGLT2is]) and liraglutide (and other glucagonlike peptide-1 receptor agonist [GLP-1 RAs]) among patients in the Diabetes Collaborative Registry (DCR). Methods and results We evaluated 182,525 patients from the DCR - a large, US-based outpatient registry of individuals with type 2 diabetes from 313 sites that included cardiology, endocrinology and primary care practices. Among these patients, 26.2% met major eligibility criteria for EMPA REG OUTCOME and 48.0% met major eligibility criteria for LEADER. Of these potentially eligible patients, only a small minority were actually prescribed these agents: 5.2% on an SGLT2i and 6.0% on a GLP-1 RA, respectively. Patients receiving these studied medications or medication classes, in general, had lower CV disease burden compared with those not on these agents. Assuming similar risk reductions as in the clinical trials, if all potentially trial-eligible patients in the DCR were treated for 1 year with empagliflozin (or other SGLT2is, assuming a class effect) or liraglutide (or other GLP-1 RAs, assuming a class effect), this may have prevented 354 CV deaths, 231 heart failure hospitalizations, 329 CV deaths and 247 myocardial infarctions, respectively. Conclusion In a large, US based outpatient registry, we found a significant number of patients would have been potentially eligible for glucose-lowering agents that demonstrated CV benefit in recent clinical trials. In view of these findings, a broader and better-targeted use of these medications in evidence-based patient populations should be considered. PMID- 28870146 TI - Effects of altering heel wedge properties on gait with the Intrepid Dynamic Exoskeletal Orthosis. AB - BACKGROUND: The Intrepid Dynamic Exoskeletal Orthosis is a custom-made dynamic response carbon fiber device. A heel wedge, which sits in the shoe, is an integral part of the orthosis-heel wedge-shoe system. Because the device restricts ankle movement, the system must compensate to simulate plantarflexion and allow smooth forward progression during gait. OBJECTIVES: To determine the influence of wedge height and durometer on the walking gait of individuals using the Intrepid Dynamic Exoskeletal Orthosis. STUDY DESIGN: Repeated measures. METHODS: Twelve individuals walked over level ground with their Intrepid Dynamic Exoskeletal Orthosis and six different heel wedges of soft or firm durometer and 1, 2, or 3 cm height. Center of pressure velocity, joint moments, and roll-over shape were calculated for each wedge. RESULTS: Height and durometer significantly affected time to peak center of pressure velocity, time to peak internal dorsiflexion and knee extension moments, time to ankle moment zero crossing, and roll-over shape center of curvature anterior-posterior position. Wedge height had a significant influence on peak center of pressure velocity, peak dorsiflexion moment, time to peak knee extension moment, and roll-over shape radius and vertical center of curvature. CONCLUSION: Changes in wedge height and durometer systematically affected foot loading. Participants preferred wedges which produced ankle moment zero crossing timing, peak internal knee extension moment timing, and roll-over shape center of curvature anterior-posterior position close to that of able-bodied individuals. Clinical relevance Adjusting the heel wedge is a simple, straightforward way to adjust the orthosis-heel wedge-shoe system. Changing wedge height and durometer significantly alters loading of the foot and has great potential to improve an individual's gait. PMID- 28870147 TI - Electronic cleansing in computed tomography colonography using AT layer identification with integration of gradient directional second derivative and material fraction model. AB - BACKGROUND: In computed tomography colonography images, electronic cleansing (EC) is applied to remove opacified residual materials, called fecal-tagging materials (FTM), using positive-contrast tagging agents and laxative to facilitate polyp detection. METHODS: The proposed EC, EC prop , integrates the gradient directional second derivative into material fraction model to preserve submerged soft tissue (ST) under FTM. Three-material fraction model is used to remove FTM and artifacts at air-tagging (AT) layers and T-junctions where air, ST, and FTM material meet simultaneously. Moreover, the proposed AT layer identification is used to distinguish AT layers from air-tissue-tagging (ATT) layers in order to preserve ATT layers during cleansing. The clinical evaluation on 467 3 Dimensional band view images was conducted by the abdominal radiologist using four grading levels of cleansing quality with five causes of low quality EC. The amount of the remaining artifacts at T-junctions was approximated from the results of EC prop . The results from EC prop were compared with the results from syngo.via Client 3.0 Software, EC syngo , and the fast three-material modeling, EC prev , using the preference of the radiologist. Two-tailed paired Wilcoxon signed rank test is used to indicate statistical significance. RESULTS: The average grade on cleansing quality is 2.89 out of 4. The artifacts at T-junctions from 86.94% of the test images can be removed, whereas artifacts at T-junctions from only 13.06% of the test images cannot be removed. For 13.06% of the test images, the results from EC prop are more preferable to the results from EC syngo (p<0.008). For all the test images, the results from EC prop are more preferable to the results from EC prev (p<0.001). Finally, the visual assessment shows that EC prop can preserve ATT layers, submerged polyps and folds while EC prev can preserve only submerged folds but fails to preserve ATT layers. CONCLUSION: From our implementation, EC prop can improve the performance of the existing EC, such that it can preserve ST, especially ATT layers and remove the artifacts at T junctions which have never been proposed by any other methods before. PMID- 28870148 TI - Accumulation of HIV-1 drug resistance in patients on a standard thymidine analogue-based first line antiretroviral therapy after virological failure: implications for the activity of next-line regimens from a longitudinal study in Mozambique. AB - BACKGROUND: We describe the accumulation of HIV-1 drug resistance and its effect on the activity of next-line components in patients with virological failure (HIV 1 RNA >1000 copies/mL) after 1 year (t1) of first-line antiretroviral therapy (ART) not switching to second-line drugs for one additional year (t2) in low middle income countries (LMIC). METHODS AND RESULTS: We selected 48 patients from the DREAM cohort (Maputo, Mozambique); their median pre-ART CD4+ cell count was 165 cells/MUl. At t1 patients were receiving ART since a median of 12.2 months (mainly zidovudine/lamivudine/nevirapine), their median HIV RNA was 3.8 log10 copies/mL, 43 (89.6%) presented at least one resistance-associated mutation (RAM), most frequently for lamivudine/emtricitabine, nevirapine and efavirenz. Resistance to tenofovir, was 10% at 1 year and higher than 20% at 2 years, while projection at 3 years was >30%. At t2, 42 (89.4%) had a predicted low-level or higher resistance to at least 1 s-line drug. At t1, the frequency of RAM in patients with a lower adherence to pharmacy appointments (<95%) was significantly lower (12/20, 60% for NRTI and 14/20, 70% for NNRTI) than in those with a better adherence (26/28, 92.8% for NRTI and 25/28, 89.3% for NNRTI) (OR 0.12, 95% CI 0.02-0.63, p = 0.012 and OR 0.28, 95% CI 0.06-1.29, p = 0.103, respectively). Overall thymidine analogue mutations (TAMs) accumulation rate was 0.32/year, 0.50/year in the subgroup with HIV RNA >10,000 copies/mL; NNRTI RAM accumulation rate was 0.15/year, 0.40/year in the subgroup with HIV RNA >10,000 copies/mL. CONCLUSIONS: While the activity of NNRTIs is compromised early during failure, tenofovir and zidovudine activity are reduced more frequently after 1 year of documented virological failure of thymidine analogue-based first-line ART, with RAMs accumulating faster in patients with higher viral loads. The present observation may help informing decisions on when to switch to a second line ART in patients on virological failure in LMIC. PMID- 28870149 TI - Development of novel InDel markers and genetic diversity in Chenopodium quinoa through whole-genome re-sequencing. AB - BACKGROUND: Quinoa (Chenopodium quinoa Willd.) is a balanced nutritional crop, but its breeding improvement has been limited by the lack of information on its genetics and genomics. Therefore, it is necessary to obtain knowledge on genomic variation, population structure, and genetic diversity and to develop novel Insertion/Deletion (InDel) markers for quinoa by whole-genome re-sequencing. RESULTS: We re-sequenced 11 quinoa accessions and obtained a coverage depth between approximately 7* to 23* the quinoa genome. Based on the 1453-megabase (Mb) assembly from the reference accession Riobamba, 8,441,022 filtered bi allelic single nucleotide polymorphisms (SNPs) and 842,783 filtered InDels were identified, with an estimated SNP and InDel density of 5.81 and 0.58 per kilobase (kb). From the genomic InDel variations, 85 dimorphic InDel markers were newly developed and validated. Together with the 62 simple sequence repeat (SSR) markers reported, a total of 147 markers were used for genotyping the 129 quinoa accessions. Molecular grouping analysis showed classification into two major groups, the Andean highland (composed of the northern and southern highland subgroups) and Chilean coastal, based on combined STRUCTURE, phylogenetic tree and PCA (Principle Component Analysis) analyses. Further analysis of the genetic diversity exhibited a decreasing tendency from the Chilean coast group to the Andean highland group, and the gene flow between subgroups was more frequent than that between the two subgroups and the Chilean coastal group. The majority of the variations (approximately 70%) were found through an analysis of molecular variation (AMOVA) due to the diversity between the groups. This was congruent with the observation of a highly significant FST value (0.705) between the groups, demonstrating significant genetic differentiation between the Andean highland type of quinoa and the Chilean coastal type. Moreover, a core set of 16 quinoa germplasms that capture all 362 alleles was selected using a simulated annealing method. CONCLUSIONS: The large number of SNPs and InDels identified in this study demonstrated that the quinoa genome is enriched with genomic variations. Genetic population structure, genetic core germplasms and dimorphic InDel markers are useful resources for genetic analysis and quinoa breeding. PMID- 28870150 TI - Hydrogen sulfide attenuates isoflurane-induced neuroapoptosis and cognitive impairment in the developing rat brain. AB - BACKGROUND: Isoflurane-induced neuroapoptosis and cognitive impairment has been previously reported. Hydrogen sulfide (H2S) has been shown to be a neuromodulator that is thought to have anti-apoptotic, anti-inflammatory, and anti-oxidative benefits. However, it is not known if H2S is protective against anesthesia induced apoptosis and cognitive defects. METHODS: In this study, postnatal day 7 (P7) Sprague-Dawley rats were randomly divided into four groups: control group (normal saline), H2S group (NaHS 28 MUM/kg), isoflurane group (normal saline +0.75% isoflurane) and H2S preconditioning group (NaHS 28 MUM/kg + 0.75% isoflurane). After exposure to isoflurane for 6 h, half the numbers of rats in each group were euthanized, and the hippocampus and cerebral cortex were dissected and examined for apoptosis by the terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL) technique and western blot. After 6 weeks, the remaining rats were subjected to a Morris water maze (MWM) test for behavioral assessment. RESULTS: The TUNEL assay and western blot showed that when rats were preconditioned with NaHS, neuroapoptosis decreased significantly both in hippocampus and cerebral cortex compering with the isofulrane group. The MWM showed that P7 rats administration of NaHS improved cognitive impairments induced by isoflurane. CONCLUSIONS: The current study demonstrates that H2S attenuates isoflurane-induced neuroapoptosis and improves cognitive impairments in the developing rat brain. PMID- 28870151 TI - Progression of arterial stiffness is associated with changes in bone mineral markers in advanced CKD. AB - BACKGROUND: Arterial stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with chronic kidney disease (CKD). There are limited prospective data however on progression of arterial stiffness in CKD, including evaluating associations with bone mineral markers such as fibroblast growth factor 23 (FGF23) and soluble alpha-klotho (sKl). METHODS: In this prospective, single-center, observational study, arterial stiffness [measured by pulse wave velocity (PWV)] and hormones influencing mineral homeostasis, including serum FGF23 and sKl, were compared between non-dialysis CKD stages 4/5 and healthy controls at baseline and 12 months (12 m). Abdominal aortic calcification (AAC) was quantitated using lateral lumbar radiography at baseline. RESULTS: Forty patients with CKD [mean estimated glomerular filtration rate (eGFR) 19.5 +/- 6.7 mL/min/1.73m2] and 42 controls (mean eGFR 88.6 +/- 12.9 mL/min/1.73m2) completed follow-up. There were no differences in age, gender and body mass index between groups. A significant increase in FGF23 [240.6 (141.9 1129.8) to 396.8 (160.3-997.7) pg/mL, p = 0.001] was observed in the CKD group but serum phosphate, corrected calcium, parathyroid hormone and sKl did not change significantly over 12 m. At baseline, CKD subjects had higher AAC prevalence [83.8% versus (vs.) 43.6%, p = 0.002] and higher aortic PWV [9.7(7.6 11.7) vs. 8.1 (7.2-9.7) m/s, p = 0.047] compared to controls. At 12 m, aortic PWV increased by 1.3 m/s (95% confidence interval, 0.56 to 2.08, p < 0.001) in the CKD cohort, with 30% of subjects showing progression from normal aortic elasticity to stiffening (PWV > 10 m/s). Serum FGF23 was associated with AAC, abnormal PWV and progression of PWV at 12 m. CONCLUSIONS: Arterial stiffness and serum FGF23, both of which are associated with increased cardiovascular risk, increased over one year in individuals with CKD. Additionally, a significant association was found between serum FGF23 and arterial calcification and stiffness. Larger clinical studies and further experimental work are warranted to delineate the temporal relationship as well as the pathological mechanisms linking FGF23 and vascular disease. PMID- 28870152 TI - Subjective patient-reported versus objective adherence to subcutaneous interferon beta-1a in multiple sclerosis using RebiSmart(r): the CORE study. AB - BACKGROUND: Patient adherence to treatment is key to preventing the worsening of neurological disability in multiple sclerosis (MS). The RebiSmart(r) autoinjector facilitates self-administration of subcutaneous interferon beta-1a (sc IFN beta 1a) and records objective adherence data. The CORE study was undertaken to evaluate the relationship between subjectively reported and objective adherence of MS patients using RebiSmart(r) in Switzerland and explore variables associated with objective adherence. METHODS: Patients with relapsing-remitting MS who were treated with sc IFN beta-1a 44 or 22 MUg three times weekly using RebiSmart(r) for at least 9 months participated in this phase IV non-interventional study. Neurologist questionnaires were used at month 0 to collect patient demographics, medical history and estimates of patients' adherence. Patient questionnaires were used to record subjective patient-reported adherence at month 0 and estimates of variables influencing adherence. Objective adherence data were obtained from the RebiSmart(r) log-files at months 0 and 6. RESULTS: Of 56 patients who completed the observation period, 53 had evaluable data. Objective adherence differed significantly between self-reported compliant (n = 33) and non-compliant groups (n = 20) (p = 0.00001). Older age, greater disability, patient's perception of the importance of ease of use and storage, being well informed about RebiSmart(r) features and neurologists' estimations of adherence were all positively associated with treatment adherence. CONCLUSIONS: We showed for the first time that subjective patient-reported adherence in MS was well in line with objective adherence, suggesting that the frequency of administration is reported accurately by patients to their neurologist. This observation may have implications for future treatment monitoring strategies and strategic medical decisions. Patients, particularly those who are younger and with lower levels of disability, may benefit from being better informed of the importance of being adherent to their treatments and receiving information about their medication and the device they are using. PMID- 28870153 TI - Myocardial infarction during anaphylaxis in a young healthy male with normal coronary arteries- is epinephrine the culprit? AB - BACKGROUND: Anaphylaxis is an acute, potentially fatal medical emergency. Myocardial injury or infarction in the setting of an anaphylaxis can be due the anaphylaxis itself, when it is known as Kounis syndrome or it can also be due to the effect of epinephrine treatment. Epinephrine is considered as the cornerstone in management of anaphylaxis. Myocardial infarction secondary to therapeutic doses of adrenaline is a rare occurrence and only a few cases have been reported in literature. The mechanism of myocardial injury was considered to be due to coronary vasospasm secondary to epinephrine as the coronary angiograms were normal on these occasions. CASE PRESENTATION: A 21-year- old previously healthy male got admitted to the local hospital with an urticarial rash and difficulty in breathing, one hour after ingestion of prawns for which he was known to be allergic. He was treated with 0.5 ml of intramuscular adrenaline (1:1000) which was administered to the lateral side of the thigh, following which he developed palpitations and tightening type central chest pain. Electrocardiogram showed ST segment depressions in leads III, aVF and V1 to V5 and he was transferred to a tertiary care hospital. The second electrocardiogram, done 2 h later, showed resolution of ST segment depressions but new T inversions in leads I and aVL. Troponin I was elevated with a titer of 2.15 ng/ml. He was treated with sublingual GTN in the emergency treatment unit and the symptoms resolved. Transthoracic 2D echocardiogram and stress testing with treadmill was normal and CT coronary angiogram revealed normal coronary arteries. CONCLUSION: Here we present a case of a young healthy adult with no significant risk factors for coronary artery disease who developed myocardial infarction following intramuscular administration of therapeutic dose of adrenalin for an anaphylactic reaction. The postulated mechanism is most likely an alpha receptor mediated coronary vascular spasm. However the use of adrenaline in the setting of life threatening anaphylaxis is life saving and the benefits far outweigh the risks of adverse effects. Therefore the purpose of reporting this case is not to discourage the use of adrenaline in anaphylaxis but to make aware of this potential adverse effect which can occur in the acute setting. PMID- 28870154 TI - Projecting prevalence, costs and evaluating simulated interventions for diabetic end stage renal disease in a Canadian population of aboriginal and non-aboriginal people: an agent based approach. AB - BACKGROUND: Diabetes-related end stage renal disease (DM-ESRD) is a devastating consequence of the type 2 diabetes epidemic, both of which disproportionately affect Indigenous peoples. Projecting case numbers and costs into future decades would help to predict resource requirements, and simulating hypothetical interventions could guide the choice of best practices to mitigate current trends. METHODS: An agent based model (ABM) was built to forecast First Nations and non-First Nations cases of DM-ESRD in Saskatchewan from 1980 to 2025 and to simulate two hypothetical interventions. The model was parameterized with data from the Canadian Institute for Health Information, Saskatchewan Health Administrative Databases, the Canadian Organ Replacement Register, published studies and expert judgement. Input parameters without data sources were estimated through model calibration. The model incorporated key patient characteristics, stages of diabetes and chronic kidney disease, renal replacement therapies, the kidney transplant assessment and waiting list processes, costs associated with treatment options, and death. We used this model to simulate two interventions: 1) No new cases of diabetes after 2005 and 2) Pre-emptive renal transplants carried out on all diabetic persons with new ESRD. RESULTS: There was a close match between empirical data and model output. Going forward, both incidence and prevalence cases of DM-ESRD approximately doubled from 2010 to 2025, with 250-300 new cases per year and almost 1300 people requiring RRT by 2025. Prevalent cases of First Nations people with DM-ESRD increased from 19% to 27% of total DM-ESRD numbers from 1990 to 2025. The trend in yearly costs paralleled the prevalent DM-ESRD case count. For Scenario 1, despite eliminating diabetes incident cases after 2005, prevalent cases of DM-ESRD continued to rise until 2019 before slowly declining. When all DM-ESRD incident cases received a pre-emptive renal transplant (scenario 2), a substantial increase in DM-ESRD prevalence occurred reflecting higher survival, but total costs decreased reflecting the economic advantage of renal transplantation. CONCLUSIONS: This ABM can forecast numbers and costs of DM-ESRD in Saskatchewan and be modified for application in other jurisdictions. This can aid in resource planning and be used by policy makers to evaluate different interventions in a safe and economical manner. PMID- 28870155 TI - Pessary or Progesterone to Prevent Preterm delivery in women with short cervical length: the Quadruple P randomised controlled trial. AB - BACKGROUND: Preterm birth is in quantity and in severity the most important topic in obstetric care in the developed world. Progestogens and cervical pessaries have been studied as potential preventive treatments with conflicting results. So far, no study has compared both treatments. METHODS/DESIGN: The Quadruple P study aims to compare the efficacy of vaginal progesterone and cervical pessary in the prevention of adverse perinatal outcome associated with preterm birth in asymptomatic women with a short cervix, in singleton and multiple pregnancies separately. It is a nationwide open-label multicentre randomized clinical trial (RCT) with a superiority design and will be accompanied by an economic analysis. Pregnant women undergoing the routine anomaly scan will be offered cervical length measurement between 18 and 22 weeks in a singleton and at 16-22 weeks in a multiple pregnancy. Women with a short cervix, defined as less than, or equal to 35 mm in a singleton and less than 38 mm in a multiple pregnancy, will be invited to participate in the study. Eligible women will be randomly allocated to receive either progesterone or a cervical pessary. Following randomization, the silicone cervical pessary will be placed during vaginal examination or 200 mg progesterone capsules will be daily self-administered vaginally. Both interventions will be continued until 36 weeks gestation or until delivery, whichever comes first. Primary outcome will be composite adverse perinatal outcome of perinatal mortality and perinatal morbidity including bronchopulmonary dysplasia, intraventricular haemorrhage grade III and IV, periventricular leukomalacia higher than grade I, necrotizing enterocolitis higher than stage I, Retinopathy of prematurity (ROP) or culture proven sepsis. These outcomes will be measured up until 10 weeks after the expected due date. Secondary outcomes will be, among others, time to delivery, preterm birth rate before 28, 32, 34 and 37 weeks, admission to neonatal intensive care unit, maternal morbidity, maternal admission days for threatened preterm labour and costs. DISCUSSION: This trial will provide evidence on whether vaginal progesterone or a cervical pessary is more effective in decreasing adverse perinatal outcome in both singletons and multiples. TRIAL REGISTRATION: Trial registration number: NTR 4414 . Date of registration January 29th 2014. PMID- 28870156 TI - Generation of expressed sequence tags for discovery of genes responsible for floral traits of Chrysanthemum morifolium by next-generation sequencing technology. AB - BACKGROUND: Chrysanthemum morifolium is one of the most economically valuable ornamental plants worldwide. Chrysanthemum is an allohexaploid plant with a large genome that is commercially propagated by vegetative reproduction. New cultivars with different floral traits, such as color, morphology, and scent, have been generated mainly by classical cross-breeding and mutation breeding. However, only limited genetic resources and their genome information are available for the generation of new floral traits. RESULTS: To obtain useful information about molecular bases for floral traits of chrysanthemums, we read expressed sequence tags (ESTs) of chrysanthemums by high-throughput sequencing using the 454 pyrosequencing technology. We constructed normalized cDNA libraries, consisting of full-length, 3'-UTR, and 5'-UTR cDNAs derived from various tissues of chrysanthemums. These libraries produced a total number of 3,772,677 high-quality reads, which were assembled into 213,204 contigs. By comparing the data obtained with those of full genome-sequenced species, we confirmed that our chrysanthemum contig set contained the majority of all expressed genes, which was sufficient for further molecular analysis in chrysanthemums. CONCLUSION: We confirmed that our chrysanthemum EST set (contigs) contained a number of contigs that encoded transcription factors and enzymes involved in pigment and aroma compound metabolism that was comparable to that of other species. This information can serve as an informative resource for identifying genes involved in various biological processes in chrysanthemums. Moreover, the findings of our study will contribute to a better understanding of the floral characteristics of chrysanthemums including the myriad cultivars at the molecular level. PMID- 28870158 TI - Erratum to: Lipid emulsion mitigates impaired pulmonary function induced by limb I/R in rats through attenuation of local cellular injury and the subsequent systemic inflammatory response/inflammation. PMID- 28870157 TI - Ten important articles on noninvasive ventilation in critically ill patients and insights for the future: A report of expert opinions. AB - BACKGROUND: Noninvasive ventilation is used worldwide in many settings. Its effectiveness has been proven for common clinical conditions in critical care such as cardiogenic pulmonary edema and chronic obstructive pulmonary disease exacerbations. Since the first pioneering studies of noninvasive ventilation in critical care in the late 1980s, thousands of studies and articles have been published on this topic. Interestingly, some aspects remain controversial (e.g. its use in de-novo hypoxemic respiratory failure, role of sedation, self-induced lung injury). Moreover, the role of NIV has recently been questioned and reconsidered in light of the recent reports of new techniques such as high-flow oxygen nasal therapy. METHODS: We conducted a survey among leading experts on NIV aiming to 1) identify a selection of 10 important articles on NIV in the critical care setting 2) summarize the reasons for the selection of each study 3) offer insights on the future for both clinical application and research on NIV. RESULTS: The experts selected articles over a span of 26 years, more clustered in the last 15 years. The most voted article studied the role of NIV in acute exacerbation chronic pulmonary disease. Concerning the future of clinical applications for and research on NIV, most of the experts forecast the development of innovative new interfaces more adaptable to patients characteristics, the need for good well-designed large randomized controlled trials of NIV in acute "de novo" hypoxemic respiratory failure (including its comparison with high-flow oxygen nasal therapy) and the development of software based NIV settings to enhance patient-ventilator synchrony. CONCLUSIONS: The selection made by the experts suggests that some applications of NIV in critical care are supported by solid data (e.g. COPD exacerbation) while others are still waiting for confirmation. Moreover, the identified insights for the future would lead to improved clinical effectiveness, new comparisons and evaluation of its role in still "lack of full evidence" clinical settings. PMID- 28870159 TI - Obstetric professionals' perceptions of non-invasive prenatal testing for Down syndrome: clinical usefulness compared with existing tests and ethical implications. AB - BACKGROUND: While non-invasive prenatal testing (NIPT) for fetal aneuploidy is commercially available in many countries, little is known about how obstetric professionals in non-Western populations perceive the clinical usefulness of NIPT in comparison with existing first-trimester combined screening (FTS) for Down syndrome (DS) or invasive prenatal diagnosis (IPD), or perceptions of their ethical concerns arising from the use of NIPT. METHODS: A cross-sectional survey among 327 obstetric professionals (237 midwives, 90 obstetricians) in Hong Kong. RESULTS: Compared to FTS, NIPT was believed to: provide more psychological benefits and enable earlier consideration of termination of pregnancy. Compared to IPD, NIPT was believed to: provide less psychological stress for high-risk women and more psychological assurance for low-risk women, and offer an advantage to detect chromosomal abnormalities earlier. Significant differences in perceived clinical usefulness were found by profession and healthcare sector: (1) obstetricians reported more certain views towards the usefulness of NIPT than midwives and (2) professionals in the public sector perceived less usefulness of NIPT than the private sector. Beliefs about earlier detection of DS using NIPT were associated with ethical concerns about increasing abortion. Participants believing that NIPT provided psychological assurance among low-risk women were less likely to be concerned about ethical issues relating to informed decision making and pre-test consultation for NIPT. CONCLUSIONS: Our findings suggest the need for political debate initially on how to ensure pregnant women accessing public services are informed about commercially available more advanced technology, but also on the potential implementation of NIPT within public services to improve access and equity to DS screening services. PMID- 28870160 TI - TREK-1 mediates isoflurane-induced cytotoxicity in astrocytes. AB - BACKGROUND: There are growing concerns that anaesthetic exposure can cause extensive apoptotic degeneration of neurons and the impairment of normal synaptic development and remodelling. However, little attention has been paid to exploring the possible cytotoxicity of inhalation anaesthetics, such as isoflurane, in astrocytes. In this research, we determined that prolonged exposure to an inhalation anaesthetic caused cytotoxicity in astrocytes, and we identified the underlying molecular mechanism responsible for this process. METHODS: Astrocytes were exposed to isoflurane, and astrocytic survival was then measured via LDH release assays, MTT assays, and TUNEL staining. TWIK-related potassium (K+) channel-1 (TREK-1) over-expression and knockdown models were also created using lentiviruses. The levels of TREK-1 and brain-derived neurotrophic factor (BDNF) were measured via Western blot and qRT-PCR. RESULTS: Prolonged exposure to isoflurane decreased primary astrocytic viability in a dose- and time-dependent manner. Moreover, with prolonged exposure to isoflurane, the TREK-1 level increased, and the BDNF level was reduced. TREK-1 knockdown promoted the survival of astrocytes and increased BDNF expression following isoflurane exposure. CONCLUSIONS: Overdoses of and prolonged exposure to isoflurane induce cytotoxicity in primary astrocytes. TREK-1 plays an important role in isoflurane induced cultured astrocytic cytotoxicity by down-regulating the expression of BDNF. PMID- 28870161 TI - Chronic dialysis, NAT2 polymorphisms, and the risk of isoniazid-induced encephalopathy - case report and literature review. AB - BACKGROUND: Isoniazid is the most widely used anti-tuberculosis agent, yet it may lead to life-threatening complications. CASE PRESENTATION: Here we report the case of a chronic hemodialysis patient who developed severe encephalopathy after the start of isoniazid. Blood levels of isoniazid were elevated, and acetyl isoniazid over isoniazid ratio was decreased 3 h after intake of the medication, suggesting that a slow acetylator phenotype may have contributed to drug toxicity, in addition to pyridoxal phosphate removal by dialysis. This hypothesis was confirmed by sequencing of NAT2, the gene responsible for isoniazid elimination, and identification of NAT2 polymorphisms compatible with a slow acetylator phenotype. Isoniazid withdrawal along with supplementation using high doses of pyridoxine successfully reversed the drug toxicity. Isoniazid toxicity occurs in populations at risk, including patients with chronic kidney failure or NAT2 polymorphisms, who have a disturbed metabolism of pyridoxine or isoniazid, respectively, and those on renal replacement therapies, in whom pyridoxal phosphate - the active metabolite of pyridoxine - is inadvertently removed by dialysis. CONCLUSIONS: Physicians should be aware of the increased risk of isoniazid toxicity in patients on dialysis and in those with a slow acetylator phenotype conferred by NAT2 polymorphisms. Adaptation of prescription - either with higher doses of pyridoxine or decreased doses of isoniazid, respectively - has been suggested to reduce the risk of potentially life-threatening toxicity of isoniazid. PMID- 28870162 TI - Estimation of utility weights for major liver diseases according to disease severity in Korea. AB - BACKGROUND: The global burden of liver diseases, such as hepatocellular carcinoma and liver cirrhosis, is substantial. In this study, we estimated utility weights of liver disease-related health states in the general population using a visual analogue scale (VAS) and the standard gamble (SG) method. METHODS: Depictions of standardized health states related to major liver diseases were developed based on patient education materials and previous publications. To fully reflect disease progression from diagnosis to prognosis, each health state comprised four parts: diagnosis, symptoms, treatment, and progression and prognosis. A total of 407 participants from the Korean general population evaluated the health states using the VAS and SG methods in computer-assisted personal interviews. After excluding illogical responses, mean utility weights were calculated for each health state. RESULTS: The utility weights for health states were significantly different according to the existence of inconsistency in general. According to the VAS results, the health state with the highest utility was 'Chronic hepatitis B virus infection' (0.64), whereas the health state with the lowest utility was 'Hepatocellular carcinoma that requires palliative therapy' (0.17). Similarly, the SG results revealed that the health state with the highest utility was 'Chronic hepatitis B virus infection' (0.85), and the health state with the lowest utility was 'Hepatocellular carcinoma that requires palliative therapy' (0.40). CONCLUSIONS: The estimated utility weights in this study will be useful to measure the burden of liver diseases and evaluate cost-utility of programs for reducing the burden of liver diseases. PMID- 28870163 TI - Comparison of the SupremeTM and ProSealTM laryngeal mask airways in infants: a prospective randomised clinical study. AB - BACKGROUND: The SupremeTM and ProSealTM laryngeal mask airways (LMAs) are widely used in paediatric anaesthesia; however, LMA use in infants is limited because many anaesthesiologists prefer to use tracheal intubation in infants. In this study, we compared the Supreme and ProSeal LMAs in infants by measuring their performance characteristics, including insertion features, ventilation parameters, induced changes in haemodynamics and rates of postoperative complications. METHODS: Infants of ASA physical status I scheduled for elective, minor, lower abdominal surgery were divided into two groups: the Supreme LMA group and the ProSeal LMA group. Times and ease of LMA insertion were noted. The percentages of tidal volume leakage as well as peak, mean and leakage pressures for all infants were measured. Heart rate (HR), oxygen saturation (SpO2) and end tidal carbon dioxide (EtCO2) values were recorded before and after LMA insertion and before and after extubation. After extubation, complications and adverse effects were noted. RESULTS: Demographic and surgical data were similar between the two groups. LMA insertion times were shorter for the ProSeal group than for the Supreme group (P < 0.002). The mean HR value for the ProSeal group was lower than for the Supreme group (P < 0.011). Both the peak pressure and the leakage percentage for the ProSeal group were statistically lower than for the Supreme group. The leakage pressure for the ProSeal group was statistically higher than for the Supreme group (P < 0.001). CONCLUSIONS: The ProSeal LMA is superior to the Supreme LMA for use in infants due to the ease of insertion, high oropharyngeal leakage pressure and fewer induced changes in haemodynamics. TRIAL REGISTRATION: ClinicalTrial.gov, NCT03251105 , retrospectively registered on 15 Aug 2017. PMID- 28870164 TI - Attention and motor deficits index non-specific background liabilities that predict autism recurrence in siblings. AB - BACKGROUND: Recent research has demonstrated that subclinical autistic traits of parents amplify the effects of deleterious mutations in the causation of autism spectrum disorder (ASD) in their offspring. Here, we examined the extent to which two neurodevelopmental traits that are non-specific to ASD inattention/hyperactivity and motor coordination-might contribute to ASD recurrence in siblings of ASD probands. METHODS: Data from a quantitative trait study of 114 ASD probands and their brothers, 26% of whom also had ASD, were analyzed. Autistic trait severity was ascertained using the Social Responsiveness Scale-2, attention/hyperactivity problems using the Achenbach System of Empirically Based Assessment, and motor coordination (in a subset of participants) using the Developmental Coordination Disorder Questionnaire. RESULTS: Among siblings (affected and unaffected), both categorical recurrence of ASD (Nagelkerke R 2 = 0.53) and quantitative ASD trait burden (R 2 = 0.55) were predicted by sibling ADHD and motor coordination impairment scores, even though these traits, on average, were not elevated among the unaffected siblings. CONCLUSIONS: These findings in a clinical family cohort confirm observations from general population studies that inattention/hyperactivity and motor impairment axes of behavioral development that are non-specific to ASD, and often appreciable before ASD is typically diagnosed-jointly account for over 50% of the variation in autistic impairment of siblings, whether ascertained quantitatively or categorically. This finding within a sibling design suggests that background ASD susceptibilities that are inherited but non-specific ("BASINS") may contribute to additive genetic liability in the same manner that ASD-specific susceptibilities (such as parental subclinical ASD traits and deleterious mutations) engender ASD risk. PMID- 28870165 TI - Myosin repertoire expansion coincides with eukaryotic diversification in the Mesoproterozoic era. AB - BACKGROUND: The last eukaryotic common ancestor already had an amazingly complex cell possessing genomic and cellular features such as spliceosomal introns, mitochondria, cilia-dependent motility, and a cytoskeleton together with several intracellular transport systems. In contrast to the microtubule-based dyneins and kinesins, the actin-filament associated myosins are considerably divergent in extant eukaryotes and a unifying picture of their evolution has not yet emerged. RESULTS: Here, we manually assembled and annotated 7852 myosins from 929 eukaryotes providing an unprecedented dense sequence and taxonomic sampling. For classification we complemented phylogenetic analyses with gene structure comparisons resulting in 79 distinct myosin classes. The intron pattern analysis and the taxonomic distribution of the classes suggest two myosins in the last eukaryotic common ancestor, a class-1 prototype and another myosin, which is most likely the ancestor of all other myosin classes. The sparse distribution of class 2 and class-4 myosins outside their major lineages contradicts their presence in the last eukaryotic common ancestor but instead strongly suggests early eukaryote eukaryote horizontal gene transfer. CONCLUSIONS: By correlating the evolution of myosin diversity with the history of Earth we found that myosin innovation occurred in independent major "burst" events in the major eukaryotic lineages. Most myosin inventions happened in the Mesoproterozoic era. In the late Neoproterozoic era, a process of extensive independent myosin loss began simultaneously with further eukaryotic diversification. Since the Cambrian explosion, myosin repertoire expansion is driven by lineage- and species-specific gene and genome duplications leading to subfunctionalization and fine-tuning of myosin functions. PMID- 28870166 TI - Injurious falls and subsequent adverse drug events among elderly - a Swedish population-based matched case-control study. AB - BACKGROUND: Fall injuries are stressful and painful and they have a range of serious consequences for older people. While there is some clinical evidence of unintentional poisoning by medication following a severe fall injuries, population-based studies on that association are lacking. This is investigated in the current study, in which attention is also paid to different clinical conditions of the injured patients. METHODS: We conducted a matched case-control study of Swedish residents 60 years and older from various Swedish population based registers. Cases defined as adverse drug events (ADE) by unintentional poisoning leading to hospitalization or death were extracted from the National Patient Register (NPR) and the Cause of Death Register from January 2006 to December 2009 (n = 4418). To each case, four controls were matched by sex, age and residential area. Information on injurious falls leading to hospitalization six months prior to the date of hospital admission or death from ADE by unintentional poisoning, and corresponding date for the controls, was extracted from the NPR. Data on clinical conditions, such as dispensed medications, comorbidity and previous fall injuries were also extracted from the Swedish Prescribed Drug Register (SPDR) and NPR. Effect estimates were calculated using conditional logistic regression and presented as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: We found a three-fold increased risk of unintentional poisoning by medication in the six-month period after an injurious fall (OR 3.03; 95% CI, 2.54-3.74), with the most pronounced increase 1-3 weeks immediately after (OR, 7.66; 95% CI, 4.86-12.1). In that time window, from among those hospitalized for a fall (n = 92), those who sustained an unintentional poisoning (n = 60) tended to be in poorer health condition and receive more prescribed medications than those who did not, although this was not statistically significant. Age stratified analyses revealed a higher risk of poisoning among the younger (aged 60-79 years) than older elderly (80+ years). CONCLUSION: Medication-related poisoning leading to hospitalization or death can be an ADE subsequent to an episode of hospitalization for a fall-related injury. Poisoning is more likely to occur closer to the injurious event and among the younger elderly. It cannot be ruled out that some of those falls are themselves ADE and early signs of greater vulnerability among certain patients. PMID- 28870167 TI - Identification of microRNAs controlling hepatic mRNA levels for metabolic genes during the metabolic transition from embryonic to posthatch development in the chicken. AB - BACKGROUND: The transition from embryonic to posthatch development in the chicken represents a massive metabolic switch from primarily lipolytic to primarily lipogenic metabolism. This metabolic switch is essential for the chick to successfully transition from the metabolism of stored egg yolk to the utilization of carbohydrate-based feed. However, regulation of this metabolic switch is not well understood. We hypothesized that microRNAs (miRNAs) play an important role in the metabolic switch that is essential to efficient growth of chickens. We used high-throughput RNA sequencing to characterize expression profiles of mRNA and miRNA in liver during late embryonic and early posthatch development of the chicken. This extensive data set was used to define the contributions of microRNAs to the metabolic switch during development that is critical to growth and nutrient utilization in chickens. RESULTS: We found that expression of over 800 mRNAs and 30 miRNAs was altered in the embryonic liver between embryonic day 18 and posthatch day 3, and many of these differentially expressed mRNAs and miRNAs are associated with metabolic processes. We confirmed the regulation of some of these mRNAs by miRNAs expressed in a reciprocal pattern using luciferase reporter assays. Finally, through the use of yeast one-hybrid screens, we identified several proteins that likely regulate expression of one of these important miRNAs. CONCLUSIONS: Integration of the upstream regulatory mechanisms governing miRNA expression along with monitoring the downstream effects of this expression will ultimately allow for the construction of complete miRNA regulatory networks associated with the hepatic metabolic switch in chickens. Our findings support a key role for miRNAs in controlling the metabolic switch that occurs between embryonic and posthatch development in the chicken. PMID- 28870168 TI - Dual RNA-seq reveals no plastic transcriptional response of the coccidian parasite Eimeria falciformis to host immune defenses. AB - BACKGROUND: Parasites can either respond to differences in immune defenses that exist between individual hosts plastically or, alternatively, follow a genetically canalized ("hard wired") program of infection. Assuming that large scale functional plasticity would be discernible in the parasite transcriptome we have performed a dual RNA-seq study of the lifecycle of Eimeria falciformis using infected mice with different immune status as models for coccidian infections. RESULTS: We compared parasite and host transcriptomes (dual transcriptome) between naive and challenge infected mice, as well as between immune competent and immune deficient ones. Mice with different immune competence show transcriptional differences as well as differences in parasite reproduction (oocyst shedding). Broad gene categories represented by differently abundant host genes indicate enrichments for immune reaction and tissue repair functions. More specifically, TGF-beta, EGF, TNF and IL-1 and IL-6 are examples of functional annotations represented differently depending on host immune status. Much in contrast, parasite transcriptomes were neither different between Coccidia isolated from immune competent and immune deficient mice, nor between those harvested from naive and challenge infected mice. Instead, parasite transcriptomes have distinct profiles early and late in infection, characterized largely by biosynthesis or motility associated functional gene groups, respectively. Extracellular sporozoite and oocyst stages showed distinct transcriptional profiles and sporozoite transcriptomes were found enriched for species specific genes and likely pathogenicity factors. CONCLUSION: We propose that the niche and host-specific parasite E. falciformis uses a genetically canalized program of infection. This program is likely fixed in an evolutionary process rather than employing phenotypic plasticity to interact with its host. This in turn might limit the potential of the parasite to adapt to new host species or niches, forcing it to coevolve with its host. PMID- 28870169 TI - Determinants of physical activity frequency and provider advice during pregnancy. AB - BACKGROUND: Our aims were to (1) describe the frequency of physical activity and prenatal healthcare provider advice about physical activity during pregnancy and (2) examine determinants and correlates of 3rd trimester physical activity and receipt of physical activity advice. METHODS: We analyzed data from the 2008 Pregnancy Risk Assessment Monitoring System. We studied 2669 women from North Carolina and Colorado with data on physical activity frequency in the 3 months prior to pregnancy and during the 3rd trimester and 1584 women from Oklahoma with data on provider advice regarding physical activity during pregnancy. Respondents reported physical activity, defined as 30 min or more of exercise/physical activity (excluding vocationally related activity), in in these categories: <1 day/week, 1-4 days/week, and >=5 days/week. We defined adherence to American College of Obstetrics & Gynecology (ACOG) criteria as physical activity >=5 days/week in the 3rd trimester. We performed logistic regression analyses weighted for sampling and adjusted for socio-demographic factors. RESULTS: Forty two percent of women in North Carolina and Colorado reported 3rd trimester physical activity <1 day/week, 42% 1-4 days/week, 9% >=5 days/week; 7% reported being told not to exercise. Seventy-two percent of women in Oklahoma reported receiving physical activity advice from a prenatal care provider. Low activity frequency (<1 day/week) prior to pregnancy was strongly associated with low likelihood of ACOG guideline adherence in the 3rd trimester (aOR 0.10, 95% CU 0.04, 0.30 vs. 1-4 days/week). Underweight women were more likely to adhere to ACOG guidelines than normal weight women (aOR 2.27, 95% CI 1.36, 3.79). Overweight women were more likely to receive physical activity advice (aOR 2.9, 95% CI 1.3, 6.3 vs. normal weight), but obese women were not (aOR 0.65, 95% CI 0.4, 1.2). CONCLUSIONS: Few women meet ACOG guideline criteria for physical activity during pregnancy. Improving physical activity and weight status prior to pregnancy may improve activity levels during pregnancy. Nearly one third did not receive advice about physical activity during prenatal care. Obese women were no more likely to receive advice than their normal weight counterparts, indicating the need for targeted physical activity counseling in this population. PMID- 28870170 TI - Analysis of the genome sequence of Phomopsis longicolla: a fungal pathogen causing Phomopsis seed decay in soybean. AB - BACKGROUND: Phomopsis longicolla T. W. Hobbs (syn. Diaporthe longicolla) is a seed-borne fungus causing Phomopsis seed decay in soybean. This disease is one of the most devastating diseases reducing soybean seed quality worldwide. To facilitate investigation of the genomic basis of pathogenicity and to understand the mechanism of the disease development, the genome of an isolate, MSPL10-6, from Mississippi, USA was sequenced, de novo assembled, and analyzed. RESULTS: The genome of MSPL 10-6 was estimated to be approximately 62 Mb in size with an overall G + C content of 48.6%. Of 16,597 predicted genes, 9866 genes (59.45%) had significant matches to genes in the NCBI nr database, while 18.01% of them did not link to any gene ontology classification, and 9.64% of genes did not significantly match any known genes. Analysis of the 1221 putative genes that encoded carbohydrate-activated enzymes (CAZys) indicated that 715 genes belong to three classes of CAZy that have a direct role in degrading plant cell walls. A novel fungal ulvan lyase (PL24; EC 4.2.2.-) was identified. Approximately 12.7% of the P. longicolla genome consists of repetitive elements. A total of 510 potentially horizontally transferred genes were identified. They appeared to originate from 22 other fungi, 26 eubacteria and 5 archaebacteria. CONCLUSIONS: The genome of the P. longicolla isolate MSPL10-6 represented the first reported genome sequence in the fungal Diaporthe-Phomopsis complex causing soybean diseases. The genome contained a number of Pfams not described previously. Information obtained from this study enhances our knowledge about this seed-borne pathogen and will facilitate further research on the genomic basis and pathogenicity mechanism of P. longicolla and aids in development of improved strategies for efficient management of Phomopsis seed decay in soybean. PMID- 28870171 TI - Evolution of mobile genetic element composition in an epidemic methicillin resistant Staphylococcus aureus: temporal changes correlated with frequent loss and gain events. AB - BACKGROUND: Horizontal transfer of mobile genetic elements (MGEs) that carry virulence and antimicrobial resistance genes mediates the evolution of methicillin-resistant Staphylococcus aureus, and the emergence of new MRSA clones. Most MRSA lineages show an association with specific MGEs and the evolution of MGE composition following clonal expansion has not been widely studied. RESULTS: We investigated the genomes of 1193 S. aureus bloodstream isolates, 1169 of which were MRSA, collected in the UK and the Republic of Ireland between 2001 and 2010. The majority of isolates belonged to clonal complex (CC)22 (n = 923), which contained diverse MGEs including elements that were found in other MRSA lineages. Several MGEs showed variable distribution across the CC22 phylogeny, including two antimicrobial resistance plasmids (pWBG751-like and SAP078A-like, carrying erythromycin and heavy metal resistance genes, respectively), a pathogenicity island carrying the enterotoxin C gene and two phage types Sa1int and Sa6int. Multiple gains and losses of these five MGEs were identified in the CC22 phylogeny using ancestral state reconstruction. Analysis of the temporal distribution of the five MGEs between 2001 and 2010 revealed an unexpected reduction in prevalence of the two plasmids and the pathogenicity island, and an increase in the two phage types. This occurred across the lineage and was not correlated with changes in the relative prevalence of CC22, or of any sub-lineages within in. CONCLUSIONS: Ancestral state reconstruction coupled with temporal trend analysis demonstrated that epidemic MRSA CC22 has an evolving MGE composition, and indicates that this important MRSA lineage has continued to adapt to changing selective pressure since its emergence. PMID- 28870172 TI - The lysin motif-containing proteins, Lyp1, Lyk7 and LysMe3, play important roles in chitin perception and defense against Verticillium dahliae in cotton. AB - BACKGROUND: Lysin motif (LysM)-containing proteins are important pattern recognition receptors (PRRs) in plants, which function in the perception of microbe-associated molecular patterns (MAMPs) and in the defense against pathogenic attack. To date, the LysM genes have not been systematically analyzed in cotton or effectively utilized for disease resistance. RESULTS: Here, we identified 29, 30, 60, and 56 LysM genes in the four sequenced cotton species, diploid Gossypium raimondii, diploid G. arboreum, tetraploid G. hirsutum acc. TM 1, and G. barbadense acc. 3-79, respectively. These LysM genes were classified into four groups with different structural characteristics and a variety of expression patterns in different organs and tissues when induced by chitin or Verticillium dahliae. We further characterized three genes, Lyp1, Lyk7 and LysMe3, which showed significant increase in expression in response to chitin signals, V. dahliae challenge and several stress-related signaling compounds. Lyp1, Lyk7 and LysMe3 proteins were localized to the plasma membrane, and silencing of their expression in cotton drastically impaired salicylic acid, jasmonic acid, and reactive oxygen species generation, impaired defense gene activation, and compromised resistance to V. dahliae. CONCLUSION: Our results indicate that Lyp1, Lyk7, and LysMe3 are important PRRs that function in the recognition of chitin signals to activate the downstream defense processes and induce cotton defense mechanisms against V. dahliae. PMID- 28870173 TI - Children with respiratory tract infections in Swedish primary care; prevalence of antibiotic resistance in common respiratory tract pathogens and relation to antibiotic consumption. AB - BACKGROUND: The majority of antibiotics consumed in developed countries are prescribed in primary care. However, little is known about resistance levels in the primary care population. METHOD: Nasopharyngeal cultures were obtained from children, 0-10 years of age, seeking care at their Primary Health Care Centre with symptoms of respiratory tract infection. Parental questionnaires were used to retrieve information about the child's previous antibiotic consumption. RESULT: Cultures from 340 children were gathered. The level of resistant Haemophilus influenzae was low and the prevalence of penicillin non-susceptible pneumococci (PNSP MIC >= 0.125 mg/L) was 6% compared to 10% (p = 0.31) in corresponding cultures from children diagnosed at the local clinical microbiology laboratory. Antibiotic treatment within the previous 4 weeks predisposed for resistant bacteria in the nasopharynx, OR: 3.08, CI 95% (1.13-8.42). CONCLUSION: Low prevalence of PNSP supports the use of phenoxymethylpenicillin as empirical treatment for childhood upper respiratory tract infections attending primary care in our setting. It is important that studies on resistance are performed in primary care populations to evaluate data from microbiological laboratories. Recent antibiotic treatment increases risk of bacterial resistance in children and continuous work to reduce unnecessary antibiotic prescribing should be prioritised. PMID- 28870174 TI - Local CD34-positive capillaries decrease in mouse models of kidney disease associating with the severity of glomerular and tubulointerstitial lesions. AB - BACKGROUND: The renal vasculature plays important roles in both homeostasis and pathology. In this study, we examined pathological changes in the renal microvascular in mouse models of kidney diseases. METHODS: Glomerular lesions (GLs) in autoimmune disease-prone male BXSB/MpJ-Yaa (Yaa) mice and tubulointerstitial lesions (TILs) in male C57BL/6 mice subjected to unilateral ureteral obstruction (UUO) for 7 days were studied. Collected kidneys were examined using histopathological techniques. A nonparametric Mann-Whitney U test (P < 0.05) was performed to compare healthy controls and the experimental mice. The Kruskal-Wallis test was used to compare three or more groups, and multiple comparisons were performed using Scheffe's method when significant differences were observed (P < 0.05). RESULTS: Yaa mice developed severe autoimmune glomerulonephritis, and the number of CD34+ glomerular capillaries decreased significantly in GLs compared to that in control mice. However, UUO-treated mice showed severe TILs only, and CD34+ tubulointerstitial capillaries were decreased significantly in TILs with the progression of tubulointerstitial fibrosis compared to those in untreated control kidneys. Infiltrations of B-cells, T cells, and macrophages increased significantly in the respective lesions of both disease models (P < 0.05). In observations of vascular corrosion casts by scanning electron microscopy and of microfil rubber-perfused thick kidney sections by fluorescence microscopy, segmental absences of capillaries were observed in the GLs and TILs of Yaa and UUO-treated mice, respectively. Further, transmission electron microscopy revealed capillary endothelial injury in the respective lesions of both models. The numbers of CD34+ glomerular and tubulointerstitial capillaries were negatively correlated with all examined parameters in GLs (P < 0.05) and TILs (P < 0.01), respectively. CONCLUSIONS: From the analysis of mouse models, we identified inverse pathological correlations between the number of local capillaries in GLs and TILs and the severity of kidney diseases. PMID- 28870175 TI - Treatment outcomes for isoniazid-resistant tuberculosis under program conditions in British Columbia, Canada. AB - BACKGROUND: Every year, over 1 million people develop isoniazid (INH) resistant tuberculosis (TB). Yet, the optimal treatment regimen remains unclear. Given increasing prevalence, the clinical efficacy of regimens used by physicians is of interest. This study aims to examine treatment outcomes of INH resistant TB patients, treated under programmatic conditions in British Columbia, Canada. METHODS: Medical charts were retrospectively reviewed for cases of culture confirmed INH mono-resistant TB reported to the BC Centre for Disease Control (BCCDC) from 2002 to 2014. Treatment regimens, patient and strain characteristics, and clinical outcomes were analysed. RESULTS: One hundred sixty five cases of INH mono-resistant TB were included in analysis and over 30 different treatment regimens were prescribed. Median treatment duration was 10.5 months (IQR 9-12 months) and treatment was extended beyond 12 months for 26 patients (15.8%). Fifty six patients (22.6%) experienced an adverse event that resulted in a drug regimen modification. Overall, 140 patients (84.8%) had a successful treatment outcome while 12 (7.2%) had an unsuccessful treatment outcome of failure (n = 2; 1.2%), relapse (n = 4; 2.4%) or all cause mortality (n = 6; 3.6%). CONCLUSION: Our treatment outcomes, while consistent with findings reported from other studies in high resource settings, raise concerns about current recommendations for INH resistant TB treatment. Only a small proportion of patients completed the recommended treatment regimens. High quality studies to confirm the effectiveness of standardized regimens are urgently needed, with special consideration given to trials utilizing fluoroquinolones. PMID- 28870176 TI - Toward a better judgment of item relevance in progress testing. AB - BACKGROUND: Items must be relevant to ensure item quality and test validity. Since "item relevance" has not been operationalized yet, we developed a rubric to define it. This study explores the influence of this rubric on the assessment of item relevance and on inter-rater agreement. METHODS: Members of the item review committee (RC) and students, teachers, and alumni (STA) reassessed the relevance of 50 previously used progress test (PT) items and decided about their inclusion using a 5-criteria rubric. Data were analyzed at item level using paired samples t-tests, Intraclass Correlation Coefficients (ICC), and linear regression analysis, and at rater level in a generalizability analysis per group. RESULTS: The proportion of items that the RC judged relevant enough to be included decreased substantially from 1.00 to 0.72 (p < 0.001). Agreement between the RC and STA was high, with an ICC of >0.7 across items. The relation between inclusion and relevance was strong (correlation = 0.89, p < 0.001), and did not differ between RC and STA. To achieve an acceptable inter-rater reliability for relevance and inclusion, 6 members must serve on the RC. CONCLUSIONS: Use of the rubric results in a stricter evaluation of items' appropriateness for inclusion in the PT and facilitates agreement between the RC and other stakeholders. Hence, it may help increase the acceptability and validity of the PT. PMID- 28870177 TI - Will Chinese external therapy with compound Tripterygium wilfordii hook F gel safely control disease activity in patients with rheumatoid arthritis: design of a double-blinded randomized controlled trial. AB - BACKGROUND: Chinese external therapy (CET) is a topical application with mainly Chinese herb medicine therapy with thousands of years of historical implications and is a clinical routine that is commonly used for relieving joint-related symptoms in patients with arthritis in Chinese hospitals. However, there is a paucity of modern medical evidence to support its effectiveness and safety. Thus, we propose to implement a randomized, double-blinded, placebo-controlled clinical trial in patients with rheumatoid arthritis (RA) using, as the experimental intervention, topical application of a hospital-compounded gel preparation of Tripterygium wilfordii Hook F (TwHF). METHODS: This study will be an 8-week double-blinded, randomized, placebo-controlled clinical trial conducted at Guang'anmen Hospital in Beijing, China, and 168 patients with moderately active RA will be randomly assigned with a 1:1 ratio to apply a topical gel preparation containing TwHF or placebo. The primary outcome variable will be the proportion of subjects, by study group, to achieve a 20% improvement in the American College of Rheumatology criteria (ACR20) by week 8. Secondary outcome measures to be assessed at weeks 4 or 8 will include: measurement of ACR20 response rate at week 4, ACR50 response rate, the changes in DAS28 score, and joint synovitis classification assessment monitored by musculoskeletal ultrasound. Safety evaluations conducted at weeks 4, 8 and 12 will be based on spontaneous complaints by the study subjects, but special emphasis will be focused on cutaneous allergy and alterations of menstruation in premenopausal female participants. Statistical analyses will be performed using the intention to treat analysis data set. DISCUSSION: This proposed clinical trail is designed to evaluate the efficacy and safety of CET based on a single topically-applied agent in a relatively large patient population with RA. This study protocol gives a detailed description of the usage and dosage of the topical compound TwHF gel and the methodology of this study. In addition, it is hoped that the outcomes of this study will be viewed as supporting the generalizability of CET in the setting of inflammatory rheumatic diseases. The results of this study are expected to have important public health implications for Asian RA patients that currently utilize CET as a complimentary treatment. TRIAL REGISTRATION: Clinical trial gov Identifier: NCT02818361 . Registrated on Jun. 15, 2016. PMID- 28870178 TI - Using total quality management approach to improve patient safety by preventing medication error incidences*. AB - BACKGROUND: Whereas one of the predominant causes of medication errors is a drug administration error, a previous study related to our investigations and reviews estimated that the incidences of medication errors constituted 6.7 out of 100 administrated medication doses. Therefore, we aimed by using six sigma approach to propose a way that reduces these errors to become less than 1 out of 100 administrated medication doses by improving healthcare professional education and clearer handwritten prescriptions. METHODS: The study was held in a General Government Hospital. First, we systematically studied the current medication use process. Second, we used six sigma approach by utilizing the five-step DMAIC process (Define, Measure, Analyze, Implement, Control) to find out the real reasons behind such errors. This was to figure out a useful solution to avoid medication error incidences in daily healthcare professional practice. Data sheet was used in Data tool and Pareto diagrams were used in Analyzing tool. RESULTS: In our investigation, we reached out the real cause behind administrated medication errors. As Pareto diagrams used in our study showed that the fault percentage in administrated phase was 24.8%, while the percentage of errors related to prescribing phase was 42.8%, 1.7 folds. This means that the mistakes in prescribing phase, especially because of the poor handwritten prescriptions whose percentage in this phase was 17.6%, are responsible for the consequent) mistakes in this treatment process later on. Therefore, we proposed in this study an effective low cost strategy based on the behavior of healthcare workers as Guideline Recommendations to be followed by the physicians. This method can be a prior caution to decrease errors in prescribing phase which may lead to decrease the administrated medication error incidences to less than 1%. CONCLUSION: This improvement way of behavior can be efficient to improve hand written prescriptions and decrease the consequent errors related to administrated medication doses to less than the global standard; as a result, it enhances patient safety. However, we hope other studies will be made later in hospitals to practically evaluate how much effective our proposed systematic strategy really is in comparison with other suggested remedies in this field. PMID- 28870181 TI - "Engaging with birth stories in pregnancy: a hermeneutic phenomenological study of women's experiences across two generations". AB - BACKGROUND: The birth story has been widely understood as a crucial source of knowledge about childbirth. What has not been reported is the effect that birth stories may have on primigravid women's understandings of birth. Findings are presented from a qualitative study exploring how two generations of women came to understand birth in the milieu of other's stories. The prior assumption was that birth stories must surely have a positive or negative influence on listeners, steering them towards either medical or midwifery-led models of care. METHODS: A Heideggerian hermeneutic phenomenological approach was used. Twenty UK participants were purposively selected and interviewed. Findings from the initial sample of 10 women who were pregnant in 2012 indicated that virtual media was a primary source of birth stories. This led to recruitment of a second sample of 10 women who gave birth in the 1970s-1980s, to determine whether they were more able to translate information into knowledge via stories told through personal contact and not through virtual technologies. RESULTS: Findings revealed the experience of 'being-in-the-world' of birth and of stories in that world. From a Heideggerian perspective, the birth story was constructed through 'idle talk' (the taken for granted assumptions of things, which come into being through language). Both oral stories and those told through technology were described as the 'modern birth story'. The first theme 'Stories are difficult like that', examines the birth story as problematic and considers how stories shape meaning. The second 'It's a generational thing', considers how women from two generations came to understand what their experience might be. The third 'Birth in the twilight of certainty,' examines women's experience of Being in a system of birth as constructed, portrayed and sustained in the stories being shared. CONCLUSIONS: The women pregnant in 2012 framed their expectations in the language of choice, whilst the women who birthed in the 1970s-1980s framed their experience in the language of safety. For both, however, the world of birth was the same; saturated with, and only legitimised by the birth of a healthy baby. Rather than creating meaningful understanding, the 'idle talk' of birth made both cohorts fearful of leaving the relative comfort of the 'system', and of claiming an alternative birth. PMID- 28870179 TI - The quality of systematic reviews about interventions for refractive error can be improved: a review of systematic reviews. AB - BACKGROUND: Systematic reviews should inform American Academy of Ophthalmology (AAO) Preferred Practice Pattern(r) (PPP) guidelines. The quality of systematic reviews related to the forthcoming Preferred Practice Pattern(r) guideline (PPP) Refractive Errors & Refractive Surgery is unknown. We sought to identify reliable systematic reviews to assist the AAO Refractive Errors & Refractive Surgery PPP. METHODS: Systematic reviews were eligible if they evaluated the effectiveness or safety of interventions included in the 2012 PPP Refractive Errors & Refractive Surgery. To identify potentially eligible systematic reviews, we searched the Cochrane Eyes and Vision United States Satellite database of systematic reviews. Two authors identified eligible reviews and abstracted information about the characteristics and quality of the reviews independently using the Systematic Review Data Repository. We classified systematic reviews as "reliable" when they (1) defined criteria for the selection of studies, (2) conducted comprehensive literature searches for eligible studies, (3) assessed the methodological quality (risk of bias) of the included studies, (4) used appropriate methods for meta analyses (which we assessed only when meta-analyses were reported), (5) presented conclusions that were supported by the evidence provided in the review. RESULTS: We identified 124 systematic reviews related to refractive error; 39 met our eligibility criteria, of which we classified 11 to be reliable. Systematic reviews classified as unreliable did not define the criteria for selecting studies (5; 13%), did not assess methodological rigor (10; 26%), did not conduct comprehensive searches (17; 44%), or used inappropriate quantitative methods (3; 8%). The 11 reliable reviews were published between 2002 and 2016. They included 0 to 23 studies (median = 9) and analyzed 0 to 4696 participants (median = 666). Seven reliable reviews (64%) assessed surgical interventions. CONCLUSIONS: Most systematic reviews of interventions for refractive error are low methodological quality. Following widely accepted guidance, such as Cochrane or Institute of Medicine standards for conducting systematic reviews, would contribute to improved patient care and inform future research. PMID- 28870180 TI - Awareness, attitudes and perceptions regarding HIV and PMTCT amongst pregnant women in Guinea-Bissau- a qualitative study. AB - BACKGROUND: The human immunodeficiency virus (HIV) continues to be a major cause of maternal and infant mortality and morbidity in sub-Saharan Africa. Prevention of mother-to-child transmission of HIV (PMTCT) strategies have proven effective in decreasing the number of children infected in utero, intrapartum and during the breastfeeding period. This qualitative study explores knowledge and perceptions of HIV amongst pregnant women, healthcare workers' experiences of the national PMTCT services, and barriers to PMTCT, during a period of programme scale-up in urban Guinea-Bissau (2010-11). METHODS: In-depth interviews were undertaken amongst 27 women and 19 key informants at local antenatal clinics and the national maternity ward in Bissau, Guinea-Bissau. RESULTS: Amongst women who had been tested for HIV, awareness and knowledge of HIV and PMTCT remained low. Testing without informed consent was reported in some cases, in particular when the test was performed around the time of delivery. Possible drivers of inadequate counselling included lack of confidentiality, suboptimal healthcare worker training, lack of time, and perceived occupational risk. Demand-side barriers to PMTCT included lack of HIV and PMTCT knowledge, customary and cultural beliefs associated with HIV and ill-health, HIV stigma and discrimination, and fear of partnership dissolution. CONCLUSIONS: Socio-cultural and operational challenges, including HIV testing without informed consent, present significant barriers to the scale-up of PMTCT services in Bissau. Strengthening local capacity for effective counselling and testing in the antenatal setting is paramount. Further research into local customary beliefs relating to HIV is warranted. PMID- 28870182 TI - Reviewing clinical guideline development tools: features and characteristics. AB - BACKGROUND: To improve consistency and streamline development and publication of clinical guidelines (GL), there is a need for appropriate software support. We have found few specific tools for the actual authoring and maintaining of GLs, and correspondingly few analyses or reviews of GL development tool functionality. In order to assist GL developers in selecting and evaluating tools, this study tries to address the perceived gap by pursuing four goals: 1) identifying available tools, 2) reviewing a representative group of tools and their supported functionalities, 3) uncovering themes of features that the studied tools support, and 4) compare the selected tools with respect to the themes. METHODS: We conducted a literature search using PubMed and Google Scholar in order to find GL development tools (GDT). We also explored tools and Content Management Systems (CMS) used in representative organisations and international communities that develop and maintain GLs. By reading a selected representative group of five GL tool manuals, exploring tools hands-on, we uncovered 8 themes of features. All found tools were compared according to these themes in order to identify the level of functionality they offer to support the GL development and publishing process. In order to limit the scope, tools for designing computer interpretable/executable GL are excluded. RESULTS: After finding 1552 published papers, contacting 7 organizations and international communities, we identified a total of 19 unique tools, of which 5 tools were selected as representative in this paper. We uncovered a total of 8 themes of features according to the identified functionalities that each tool provides. Four features were common among tools: Collaborative authoring process support, user access control, GL repository management, electronic publishing. We found that the GRADE methodology was supported by three of the reviewed tools, while only two tools support annotating GL with MeSH terms. We also identified that monitoring progress, reference management, Managing versions (version control), and Change control (tracking) were often the missing features. CONCLUSION: The results can promote sector discussion and eventual agreement on important tool functionality. It may aid tool and GL developers towards more efficient, and effective, GL authoring. PMID- 28870183 TI - Differences in drug use between men and women: an Italian cross sectional study. AB - BACKGROUND: Drugs are the most important treatment option for most diseases, and the majority of medical consultations result in a prescription. Women and men receive different drug prescriptions and differ in therapeutic response to pharmacological therapy. This disparity is due to biological factors (sex differences) or/and behavior, lifestyle and life experience (gender differences). Sex differences in drug use have been demonstrated in several therapeutic areas; however, there is a lack of overviews on sex and gender differences of drug use in an entire population. METHODS: We conducted a descriptive cross - sectional drug use study, involving the entire Italian population in 2012, aimed at showing and analyzing differences between men and women as regards their exposure to drugs. The data source was IMS LifeLink Treatment DynamicsTMLRx Database and it included all prescribed drugs reimbursed by the Italian National Healthcare System in 2012 and covered 90% of the entire Italian population. The information about the prescriptions was stratified by men and women and age. Drug consumption was expressed as DDD/ 1000 ab die. Exposure to drug prescriptions was expressed as period prevalence (the proportion of the population dispensed >=1 prescription in 2012 per 1000 inhabitants). Differences of prevalence between men and women were expressed as crude and age adjusted risk ratios with 95% CI. RESULTS: Our findings suggested that the largest differences in drug prescriptions regarded drugs affecting bone structure and mineralization (RR 15.9), calcium (RR 8.6) and thyroid therapy (RR 5.4), dispensed more to women than men. Otherwise ACE inhibitors were more commonly used in men. CONCLUSIONS: This is the first study exploring difference in drug use between men and women and carried out on the entire Italian population. Our findings showed substantial differences between men and women in term of prevalence of drug prescriptions. Some differences in drug use may be explained by sex differences (variations in disease prevalence and severity, pathophysiology, or by other biological differences), other differences need further investigation to explain the apparent lack of a rational medical explanation for some findings. The findings may subsequently be used to plan future studies to address differences suggesting inequity in treatment approaches. PMID- 28870184 TI - Agrimonia pilosa Ledeb. aqueous extract improves impaired glucose tolerance in high-fat diet-fed rats by decreasing the inflammatory response. AB - BACKGROUND: Agrimonia pilosa Ledeb. is a medicinal plant with physiological activities such as anti-cancer, antioxidant, anti-inflammatory activities and in vitro anti-diabetic activity. However, the effects of aqueous extracts from A. pilosa on insulin-resistant rats have not yet been examined. We investigated the effects of aqueous extract from A. pilosa on impaired glucose metabolism induced by a high-fat diet in rats. METHODS: Male Sprague-Dawley rats were assigned to the following groups: normal-fat diet (NF, n = 9); high-fat diet (HF, n = 9); high-fat diet with 0.1% A. pilosa aqueous extract (HFA, n = 10). Experimental diets were administered for 16 weeks. At the end of the treatment, liver and fat tissues were isolated, and serum was collected for biochemical analysis. RESULTS: The HF group rats had a significantly higher liver weight than the NF group rats did, and increased hepatic lipid accumulation (p < 0.05); however, supplementation with A. pilosa decreased liver weight. Blood glucose levels in the HFA group were lower than levels measured in the HF group 30, 60, and 120 min after glucose administration (p < 0.05). In addition, dietary A. pilosa supplementation decreased tumor necrosis factor alpha and interleukin 6 levels, while increasing serum adiponectin concentrations (p < 0.05 vs. the HF group). These effects were accompanied by reduced hepatic and adipose tissue expression of inflammation-related genes such as Tnf and Il1b (p < 0.05). CONCLUSIONS: Our findings indicate that A. pilosa aqueous extract can ameliorate insulin resistance in high-fat diet-fed rats by decreasing the inflammatory response. PMID- 28870185 TI - The contribution of female community health volunteers (FCHVs) to maternity care in Nepal: a qualitative study. AB - BACKGROUND: In resource-poor settings, the provision of basic maternity care within health centres is often a challenge. Despite the difficulties, Nepal reduced its maternal mortality ratio by 80% from 850 to an estimated 170 per 100,000 live births between 1991 and 2011 to achieve Millennium Development Goal Five. One group that has been credited for this is community health workers, known as Female Community Health Volunteers (FCHVs), who form an integral part of the government healthcare system. This qualitative study explores the role of FCHVs in maternal healthcare provision in two regions: the Hill and Terai. METHODS: Between May 2014 and September 2014, 20 FCHVs, 11 health workers and 26 service users were purposefully selected and interviewed using semi-structured topic guides. In addition, four focus group discussions were held with 19 FCHVs. Data were analysed using thematic analysis. RESULTS: All study participants acknowledged the contribution of FCHVs in maternity care. All FCHVs reported that they shared key health messages through regularly held mothers' group meetings and referred women for health checks. The main difference between the two study regions was the support available to FCHVs from the local health centres. With regular training and access to medical supplies, FCHVs in the hill villages reported activities such as assisting with childbirth, distributing medicines and administering pregnancy tests. They also reported use of innovative approaches to educate mothers. Such activities were not reported in Terai. In both regions, a lack of monetary incentives was reported as a major challenge for already overburdened volunteers followed by a lack of education for FCHVs. CONCLUSIONS: Our findings suggest that the role of FCHVs varies according to the context in which they work. FCHVs, supported by government health centres with emphasis on the use of local approaches, have the potential to deliver basic maternity care and promote health-seeking behaviour so that serious delays in receiving healthcare can be minimised. However, FCHVs need to be reimbursed and provided with educational training to ensure that they can work effectively. The study underlines the relevance of community health workers in resource-poor settings. PMID- 28870187 TI - Participation in a scientific pre-university program and medical students' interest in an academic career. AB - BACKGROUND: The proportion of medical doctors involved in research activities is declining. Undergraduate medical research programs are positively associated with medical students' research interest. Scientific pre-university programs (SPUPs) outside the medical domain are also positively associated with research interest, but have not been related to the shortage of clinician-scientists. This study examined the effect of an SPUP on medical students' research interest. METHODS: This study was conducted at a Dutch medical school. Medical students in all years who had participated in an SPUP and first-year master students who had not participated in an SPUP were invited to fill out an online survey on extracurricular activities and future career interests. SPUP participants were compared with three groups of non-participants: (i) an unmatched group, (ii) a group matched on gender and pre-university Grade Point Average (pu-GPA) and (iii) a group matched on gender and first-year GPA, one to five years after finishing the SPUP. Participants evaluated the SPUP through ratings of statements about the program. RESULTS: Two-hundred forty medical students, including 71 SPUP participants responded to the survey. SPUP participants participated significantly more often in the Honors class (i.e., extracurricular educational program for high-performing students), gained significantly more often extracurricular research experience, enrolled significantly more often in the Research master (i.e., research training program parallel to the clinical master program) and obtained significantly more often a scholarship than unmatched non SPUP participants. Using a non-SPUP group matched on gender and pu-GPA reduced the effect size of the significant differences in Honors class participation, Research master participation and scholarship obtainment. Using a non-SPUP group matched on gender and first-year GPA rendered the significant difference in Research master participation and scholarship obtainment insignificant. Significantly more SPUP participants than unmatched non-SPUP participants preferred a combination of clinical care and research in their future career. Using a non-SPUP group matched on gender and either pu-GPA or first-year GPA did not change the effect size of this significant difference. CONCLUSIONS: These findings demonstrate the potential value of an SPUP in increasing the number of medical students with research interest and as a policy measure to help to alleviate the shortage of clinician-scientists. PMID- 28870186 TI - Knowledge, attitude, and status of nitrite inhalant use among men who have sex with men in Tianjin, China. AB - BACKGROUND: Nitrite inhalants have become popular as recreational drugs among the homosexual population in some developed countries since the 1980s. These drugs, also called RUSH in China, have become attractive among Chinese men who have sex with men (MSM) in the past few years. The aim of this cross-sectional study was to understand the knowledge, attitude, and status of nitrite inhalant use among Chinese MSM. METHODS: The study participants were recruited from Tianjin, China between April and August 2012. Information, including demographics, sexual behavior, and RUSH use, was obtained through structured interviewer questionnaires. Blood samples were also collected to identify the status of HIV, HSV, and syphilis infections. RESULTS: A total of 500 participants were interviewed. Of the participants, 64.0% knew that RUSH could increase sexual pleasure and 38.6% of the participants had used RUSH at least once. The mean duration of RUSH use was 1.5 years. Among the participants who were familiar with RUSH, 60.0% had heard of RUSH for the first time after 2011, 55% received information about RUSH via the internet, and only 42.2% knew the side effects of RUSH. RUSH users were more likely to work in companies (Odds ratio [OR]: 2.61; 95% CI: 1.65-4.12), live with homosexual partners (OR: 1.88; 95% CI: 1.19-2.92), not live alone (OR: 2.26; 95% CI: 1.29-3.96), smoke cigarettes (OR: 1.49; 95% CI: 1.02-2.17), use alcohol (OR: 1.63; 95% CI: 1.12-2.39), and seek sexual partners on the internet (OR: 2.59; 95% CI: 1.50-4.50). CONCLUSIONS: The impact of RUSH abuse on the expanding HIV epidemic among MSM has been demonstrated in China. Our findings suggest that the communication and awareness of health hazard of recreational drugs should be reinforced in HIV prevention education, especially through new media. Future research is needed to further explore how integrative strategies should be used to reduce the substance abuse and risky sexual behaviors. PMID- 28870188 TI - Assessing the impact of the introduction of an electronic hospital discharge system on the completeness and timeliness of discharge communication: a before and after study. AB - BACKGROUND: Hospital discharge summaries are a key communication tool ensuring continuity of care between primary and secondary care. Incomplete or untimely communication of information increases risk of hospital readmission and associated complications. The aim of this study was to evaluate whether the introduction of a new electronic discharge system (NewEDS) was associated with improvements in the completeness and timeliness of discharge information, in Nottingham University Hospitals NHS Trust, England. METHODS: A before and after longitudinal study design was used. Data were collected using the gold standard auditing tool from the Royal College of Physicians (RCP). This tool contains a checklist of 57 items grouped into seven categories, 28 of which are classified as mandatory by RCP. Percentage completeness (out of the 28 mandatory items) was considered to be the primary outcome measure. Data from 773 patients discharged directly from the acute medical unit over eight-week long time periods (four before and four after the change to the NewEDS) from August 2010 to May 2012 were extracted and evaluated. Results were summarised by effect size on completeness before and after changeover to NewEDS respectively. The primary outcome variable was represented with percentage of completeness score and a non-parametric technique was used to compare pre-NewEDS and post-NewEDS scores. RESULTS: The changeover to the NewEDS resulted in an increased completeness of discharge summaries from 60.7% to 75.0% (p < 0.001) and the proportion of summaries created under 24 h from discharge increased significantly from 78.0% to 93.0% (p < 0.001). Furthermore, five of the seven grouped checklist categories also showed significant improvements in levels of completeness (p < 0.001), although there were reduced levels of completeness for three items (p < 0.001). CONCLUSION: The introduction of a NewEDS was associated with a significant improvement in the completeness and timeliness of hospital discharge communication. PMID- 28870189 TI - Can digital stories go where palliative care research has never gone before? A descriptive qualitative study exploring the application of an emerging public health research method in an indigenous palliative care context. AB - BACKGROUND: The World Health Organization (WHO) has called for global approaches to palliative care development. Yet it is questionable whether one-size-fits-all solutions can accommodate international disparities in palliative care need. More flexible research methods are called for in order to understand diverse priorities at local levels. This is especially imperative for Indigenous populations and other groups underrepresented in the palliative care evidence base. Digital storytelling (DST) offers the potential to be one such method. Digital stories are short first-person videos that tell a story of great significance to the creator. The method has already found a place within public health research and has been described as a useful, emergent method for community based participatory research. METHODS: The aim of this study was to explore Maori participants' views on DST's usefulness, from an Indigenous perspective, as a research method within the discipline of palliative care. The digital storytelling method was adapted to include Maori cultural protocols. Data capturing participant experience of the study were collected using participant observation and anonymous questionnaires. Eight participants, seven women and one man, took part. Field notes and questionnaire data were analysed using critical thematic analysis. RESULTS: Two main themes were identified during analyses: 1) issues that facilitated digital storytelling's usefulness as a research method for Maori reporting on end of life caregiving; and 2) issues that hindered this process. All subthemes identified: recruitment, the powhiri process, (Maori formal welcome of visitors) and technology, related to both main themes and are presented in this way. CONCLUSION: Digital storytelling is an emerging method useful for exploring Indigenous palliative care issues. In line with a Health Promoting Palliative Care approach that centres research in communities, it helps meet the need for diverse approaches to involve underrepresented groups. PMID- 28870190 TI - Monobloc implants in cementless total hip arthroplasty in patients with Legg Calve-Perthes disease: a long-term follow-up. AB - BACKGROUND: The purpose of this study was to evaluate 10-year outcomes in cementless monobloc total hip arthroplasty (THA) in a group of hips with Legg Calve-Perthes disease (LCPD). METHODS: We reviewed 71 patients (88 hips) who underwent cementless THA with a diagnosis of LCPD from 2003 to 2009. From the total of 71 patients, 34 men and 37 women with an average age of 49.94 years were included. The mean follow-up period was 10 years. RESULTS: The mean Harris Hip Score improved significantly from 46.42 to 89.70. Similarly, the postoperative range of motion, hip dysfunction and osteoarthritis outcome score and SF-12 score also significantly improved. The mean leg lengthening was 22.1 mm. During the follow-up, eight complications were noted, including two cases of intraoperative femoral fractures, two cases of sciatic nerve paralysis, two cases of heterotrophic ossifications, one case of thigh pain and one case of dislocation. One revision was conducted for a periprosthetic fracture, and the survivorship at 10 years was 98.3%. CONCLUSIONS: These data suggest that the monobloc stem can lead to satisfactory outcomes for clinical function, radiological evaluation, restoration of the normal limb lengths, complications, and survivorship among LCPD patients undergoing total hip arthroplasty. PMID- 28870191 TI - Effectiveness of a specific manual approach to the suboccipital region in patients with chronic mechanical neck pain and rotation deficit in the upper cervical spine: study protocol for a randomized controlled trial. AB - BACKGROUND: Mechanical neck pain is a highly prevalent problem in primary healthcare settings. Many of these patients have restricted mobility of the cervical spine. Several manual techniques have been recommended for restoring cervical mobility, but their effectiveness in these patients is unknown. The aim of the present study is to compare the effectiveness of two types of specific techniques of the upper neck region: the pressure maintained suboccipital inhibition technique (PMSIT) and the translatory dorsal glide mobilization (TDGM) C0-C1 technique, as adjuncts to a protocolized physiotherapy treatment of the neck region in subjects with chronic mechanical neck pain and rotation deficit in the upper cervical spine. METHODS: A randomized, prospective, double-blind (patient and evaluator) clinical trial. The participants (n = 78) will be randomly distributed into three groups. The Control Group will receive a protocolized treatment for 3 weeks, the Mobilization Group will receive the same protocolized treatment and 6 sessions (2 per week) of the TDGM C0-C1 technique, and the Pressure Group will receive the same protocolized treatment and 6 sessions (2 per week) of the PMSIT technique. The intensity of pain (VAS), neck disability (NDI), the cervical range of motion (CROM), headache intensity (HIT-6) and the rating of clinical change (GROC scale) will be measured. The measurements will be performed at baseline, post-treatment and 3 months after the end of treatment, by the same physiotherapist blinded to the group assigned to the subject. DISCUSSION: We believe that an approach including manual treatment to upper cervical dysfunction will be more effective in these patients. Furthermore, the PMSIT technique acts mostly on the musculature, while the TDGM technique acts on the joint. We expect to clarify which component is more effective in improving the upper cervical mobility. TRIAL REGISTRATION: ClinicalTrials.gov NCT02832232 . Registered on July 13th, 2016. PMID- 28870192 TI - Development of a framework for the co-production and prototyping of public health interventions. AB - BACKGROUND: Existing guidance for developing public health interventions does not provide information for researchers about how to work with intervention providers to co-produce and prototype the content and delivery of new interventions prior to evaluation. The ASSIST + Frank study aimed to adapt an existing effective peer led smoking prevention intervention (ASSIST), integrating new content from the UK drug education resource Talk to Frank ( www.talktofrank.com ) to co-produce two new school-based peer-led drug prevention interventions. A three-stage framework was tested to adapt and develop intervention content and delivery methods in collaboration with key stakeholders to facilitate implementation. METHODS: The three stages of the framework were: 1) Evidence review and stakeholder consultation; 2) Co-production; 3) Prototyping. During stage 1, six focus groups, 12 consultations, five interviews, and nine observations of intervention delivery were conducted with key stakeholders (e.g. Public Health Wales [PHW] ASSIST delivery team, teachers, school students, health professionals). During stage 2, an intervention development group consisting of members of the research team and the PHW ASSIST delivery team was established to adapt existing, and co-produce new, intervention activities. In stage 3, intervention training and content were iteratively prototyped using process data on fidelity and acceptability to key stakeholders. Stages 2 and 3 took the form of an action-research process involving a series of face-to-face meetings, email exchanges, observations, and training sessions. RESULTS: Utilising the three-stage framework, we co-produced and tested intervention content and delivery methods for the two interventions over a period of 18 months involving external partners. New and adapted intervention activities, as well as refinements in content, the format of delivery, timing and sequencing of activities, and training manuals resulted from this process. The involvement of intervention delivery staff, participants and teachers shaped the content and format of the interventions, as well as supporting rapid prototyping in context at the final stage. CONCLUSIONS: This three-stage framework extends current guidance on intervention development by providing step-by-step instructions for co-producing and prototyping an intervention's content and delivery processes prior to piloting and formal evaluation. This framework enhances existing guidance and could be transferred to co-produce and prototype other public health interventions. TRIAL REGISTRATION: ISRCTN14415936 , registered retrospectively on 05 November 2014. PMID- 28870193 TI - Mapping infectious disease hospital surge threats to lessons learnt in Singapore: a systems analysis and development of a framework to inform how to DECIDE on planning and response strategies. AB - BACKGROUND: Hospital usage and service demand during an Infectious Disease (ID) outbreak can tax the health system in different ways. Herein we conceptualize hospital surge elements, and lessons learnt from such events, to help build appropriately matched responses to future ID surge threats. METHODS: We used the Interpretive Descriptive qualitative approach. Interviews (n = 35) were conducted with governance and public health specialists; hospital based staff; and General Practitioners. Key policy literature in tandem with the interview data were used to iteratively generate a Hospital ID Surge framework. We anchored our narrative account within this framework, which is used to structure our analysis. RESULTS: A spectrum of surge threats from combinations of capacity (for crowding) and capability (for treatment complexity) demands were identified. Starting with the Pyramid scenario, or an influx of high screening rates flooding Emergency Departments, alongside fewer and manageable admissions; the Reverse-Pyramid occurs when few cases are screened and admitted but those that are, are complex; during a 'Black' scenario, the system is overburdened by both crowding and complexity. The Singapore hospital system is highly adapted to crowding, functioning remarkably well at constant near-full capacity in Peacetime and resilient to Endemic surges. We catalogue 26 strategies from lessons learnt relating to staffing, space, supplies and systems, crystalizing institutional memory. The DECIDE model advocates linking these strategies to types of surge threats and offers a step-by-step guide for coordinating outbreak planning and response. CONCLUSIONS: Lack of a shared definition and decision making of surge threats had rendered the procedures somewhat duplicative. This burden was paradoxically exacerbated by a health system that highly prizes planning and forward thinking, but worked largely in silo until an ID crisis hit. Many such lessons can be put into play to further strengthen our current hospital governance and adapted to more diverse settings. PMID- 28870195 TI - A qualitative study of Filipina immigrants' stress, distress and coping: the impact of their multiple, transnational roles as women. AB - BACKGROUND: Migration is associated with a number of stress factors which can affect mental health. Ethnicity, gender and socioeconomic status can intertwine with and influence the process of migration and mental health. Philippine migration to Europe has increased in recent years and has become more feminised. Knowing more about the factors that influence immigrants' mental health and coping can help aid health care delivery and policy planning. The purpose of this qualitative study was to explore the contextual factors that influence the mental health of Filipinas living in Norway and their coping strategies. METHOD: Individual in-depth interviews were conducted with fourteen Filipinas 24-49 years, living in Norway. The analysis was informed by the post-colonial feminist perspective in order to examine the process by which gender, ethnicity and socioeconomic status interact with contextual factors in these women's lives and influence their wellbeing. RESULTS: Data analysis revealed that all informants experienced some level of stress or distress. Two main factors: Sense of belonging and Securing a future contributed to the women's level of distress associated with living abroad as an immigrant woman. Distress was heighted by the women's multiple, transnational roles they occupied; roles as workers, breadwinners, daughters, wives and mothers. None of the women had sought professional help for their distress. Religion and informal support from friends and family appear to help these women cope with many of the challenges they face as immigrant women living and working abroad. CONCLUSIONS: Filipinas face a number of challenges related to their status as immigrant women and the juggling of their transnational lives. Understanding the context of these women's lives may aid the identification of mental health problems. Although the women show resilience and appear to cope successfully, some may benefit from professional help. PMID- 28870194 TI - A yeast fermentate improves gastrointestinal discomfort and constipation by modulation of the gut microbiome: results from a randomized double-blind placebo controlled pilot trial. AB - BACKGROUND: Constipation and symptoms of gastrointestinal discomfort such as bloating are common among otherwise healthy individuals, but with significant impact on quality of life. Despite the recognized contribution of the gut microbiome to this pathology, little is known about which group(s) of microorganism(s) are playing a role. A previous study performed in vitro suggests that EpiCor(r) fermentate has prebiotic-like properties, being able to favorably modulate the composition of the gut microbiome. Therefore, the aim of this study was to investigate the effects of EpiCor fermentate in a population with symptoms of gastrointestinal discomfort and reduced bowel movements and to evaluate its effect at the level of the gut microbiome. METHODS: This pilot study was performed according to a randomized, double-blind, placebo-controlled parallel design. Eighty subjects with symptoms of gastrointestinal discomfort and constipation were allocated to one of two trial arms (placebo or EpiCor fermentate). Randomization was done in a stratified manner according to symptom severity, resulting in two subgroups of patients: severe and moderate. Daily records of gastrointestinal symptoms were assessed on a 5-point scale, and also stool frequency and consistency were documented during a 2-week run-in and a 6 week intervention phases. Averages over two-week intervals were calculated. Constipation-associated quality of life and general perceived stress were assessed at baseline and after 3 and 6 weeks of intervention. Fecal samples were also collected at these same time points. RESULTS: EpiCor fermentate led to a significant improvement of symptoms such as bloating/distension (p = 0.033 and p = 0.024 after 2 and 4 weeks of intervention, respectively), feeling of fullness (p = 0.004 and p = 0.023 after 2 and 4 weeks of intervention, respectively) and general daily scores (p = 0.046 after 2 weeks of intervention) in the moderate subgroup. A significant improvement in stool consistency was observed for the total population (p = 0.023 after 2 weeks of intervention) as well as for the severe subgroup (p = 0.046 after 2 weeks of intervention), and a nearly significant increase in stool frequency was detected for the total cohort (p = 0.083 and p = 0.090 after 2 and 4 weeks of intervention, respectively). These effects were accompanied by an improvement in constipation-associated quality of life and general perceived stress, particularly in the moderate subgroup. Members of the families Bacteroidaceae and Prevotellaceae, two groups of bacteria that have been previously reported to be deficient in constipated patients, were found to increase with EpiCor fermentate in the severe subgroup. In the moderate subgroup, a significant increase in Akkermansia muciniphila was observed. CONCLUSIONS: Despite the relatively low dose administered (500 mg/day), particularly when comparing to the high recommended doses for prebiotic fibers, EpiCor fermentate was able to modulate the composition of the gut microbiome, resulting in improvement of constipation-associated symptoms. Conversely, the reported increase in bowel movements may have altered the gut microbial community by increasing those groups of bacteria that are better adapted to a faster gastrointestinal transit time. TRIAL REGISTRATION: NCT03051399 at ClinicalTrials.gov. Retrospectively registered. Registration date: 13 February 2017. PMID- 28870196 TI - EXPLICIT: a feasibility study of remote expert elicitation in health technology assessment. AB - BACKGROUND: Expert opinion is often sought to complement available information needed to inform model-based economic evaluations in health technology assessments. In this context, we define expert elicitation as the process of encoding expert opinion on a quantity of interest, together with associated uncertainty, as a probability distribution. When availability for face-to-face expert elicitation with a facilitator is limited, elicitation can be conducted remotely, overcoming challenges of finding an appropriate time to meet the expert and allowing access to experts situated too far away for practical face-to-face sessions. However, distance elicitation is associated with reduced response rates and limited assistance for the expert during the elicitation session. The aim of this study was to inform the development of a remote elicitation tool by exploring the influence of mode of elicitation on elicited beliefs. METHODS: An Excel-based tool (EXPLICIT) was developed to assist the elicitation session, including the preparation of the expert and recording of their responses. General practitioners (GPs) were invited to provide expert opinion about population alcohol consumption behaviours. They were randomised to complete the elicitation by either a face-to-face meeting or email. EXPLICIT was used in the elicitation sessions for both arms. RESULTS: Fifteen GPs completed the elicitation session. Those conducted by email were longer than the face-to-face sessions (13 min 30 s vs 10 min 26 s, p = 0.1) and the email-elicited estimates contained less uncertainty. However, the resulting aggregated distributions were comparable. CONCLUSIONS: EXPLICIT was useful in both facilitating the elicitation task and in obtaining expert opinion from experts via email. The findings support the opinion that remote, self-administered elicitation is a viable approach within the constraints of HTA to inform policy making, although poor response rates may be observed and additional time for individual sessions may be required. PMID- 28870197 TI - Polarity based characterization of biologically active extracts of Ajuga bracteosa Wall. ex Benth. and RP-HPLC analysis. AB - BACKGROUND: The concept of botanical therapeutics has revitalized due to wide importance of plant derived pharmaceuticals. Therefore, the ameliorative characteristics of Ajuga bracteosa were studied. METHODS: Total phenolic content, flavonoid content, antioxidant capacity, reducing power and free-radical scavenging activity were determined colorimetrically. Specific polyphenols were quantified by RP-HPLC analysis. Preliminary cytotoxicity was tested using brine shrimp lethality assay while antiproliferative activity against THP-1 and Hep-G2 cell lines was determined by MTT and SRB protocols respectively. Antileishmanial potential was assessed via MTT colorimetric method. To investigate antidiabetic prospect, alpha-amylase inhibition assay was adopted whereas disc diffusion method was used to detect likely protein kinase inhibitory, antibacterial and antifungal activities. RESULTS: Among fifteen different extracts, maximum total phenolic content (10.75 +/- 0.70 MUg GAE/mg DW), total reducing power (23.90 +/- 0.70 MUg AAE/mg DW) and total antioxidant capacity (11.30 +/- 0.80 MUg AAE/mg DW) were exhibited by methanol extract with superlative percent extract recovery (17.50 +/- 0.80% w/w). Chloroform-methanol extract demonstrated maximum flavonoid content (4.10 +/- 0.40 MUg QE/mg DW) and ethanol extract exhibited greatest radical scavenging activity (IC50 14.40 +/- 0.20 MUg/ml). RP-HPLC based quantification confirmed polyphenols such as pyrocatechol, gallic acid, resorcinol, catechin, chlorogenic acid, caffeic acid, syringic acid, p-coumaric acid, ferulic acid, vanillic acid, coumarin, sinapinic acid, trans-cinnamic acid, rutin, quercetin and kaempferol. The brine shrimp lethality assay ranked 78.60% extracts as cytotoxic (LC50 <= 250 MUg/ml) whereas significant THP-1 inhibition was shown by methanol-acetone extract (IC50 4.70 +/- 0.43 MUg/ml). The antiproliferative activity against Hep-G2 hepatoma cancer cell line was demonstrated by n-hexane, ethylacetate and methanol-distilled water (IC50 8.65 8.95 MUg/ml) extracts. Methanol extract displayed prominent protein kinase inhibitory activity (MIC 12.5 MUg/disc) while n-hexane extract revealed remarkable antileishmanial activity (IC50 4.69 +/- 0.01 MUg/ml). The antidiabetic potential was confirmed by n-hexane extract (44.70 +/- 0.30% alpha-amylase inhibition at 200 MUg/ml concentration) while a moderate antibacterial and antifungal activities were unveiled. CONCLUSION: The variation in biological spectrum resulted due to use of multiple solvent systems for extraction. We also deduce that the valuable information gathered can be utilized for discovery of anticancer, antileishmanial, antioxidant and antidiabetic bioactive lead candidates. PMID- 28870198 TI - Up-modulation of PLC-beta2 reduces the number and malignancy of triple-negative breast tumor cells with a CD133+/EpCAM+ phenotype: a promising target for preventing progression of TNBC. AB - BACKGROUND: The malignant potential of triple negative breast cancer (TNBC) is also dependent on a sub-population of cells with a stem-like phenotype. Among the cancer stem cell markers, CD133 and EpCAM strongly correlate with breast tumor aggressiveness, suggesting that simultaneous targeting of the two surface antigens may be beneficial in treatment of TNBC. Since in TNBC-derived cells we demonstrated that PLC-beta2 induces the conversion of CD133high to CD133low cells, here we explored its possible role in down-modulating the expression of both CD133 and EpCAM and, ultimately, in reducing the number of TNBC cells with a stem-like phenotype. METHODS: A magnetic step-by-step cell isolation with antibodies directed against CD133 and/or EpCAM was performed on the TNBC-derived MDA-MB-231 cell line. In the same cell model, PLC-beta2 was over-expressed or down-modulated and cell proliferation and invasion capability were evaluated by Real-time cell assays. The surface expression of CD133, EpCAM and CD44 in the different experimental conditions were measured by multi-color flow cytometry immunophenotyping. RESULTS: A CD133+/EpCAM+ sub-population with high proliferation rate and invasion capability is present in the MDA-MB-231 cell line. Over-expression of PLC-beta2 in CD133+/EpCAM+ cells reduced the surface expression of both CD133 and EpCAM, as well as proliferation and invasion capability of this cellular subset. On the other hand, the up-modulation of PLC beta2 in the whole MDA-MB-231 cell population reduced the number of cells with a CD44+/CD133+/EpCAM+ stem-like phenotype. CONCLUSIONS: Since selective targeting of the cells with the highest aggressive potential may have a great clinical importance for TNBC, the up-modulation of PLC-beta2, reducing the number of cells with a stem-like phenotype, may be a promising goal for novel therapies aimed to prevent the progression of aggressive breast tumors. PMID- 28870199 TI - Effects of dietary gelatin hydrolysates on bone mineral density in magnesium deficient rats. AB - BACKGROUND: The major types of commercially available gelatin hydrolysates are prepared from mammals or fish. Dietary gelatin hydrolysates from mammals were reported to improve bone mineral density (BMD) in some animal models. In contrast, there is limited study showing the effects of dietary gelatin hydrolysates from fish on BMD. The quantity and structure of peptides in the plasma after oral administration of gelatin hydrolysates depend on the gelatin source, which suggests that the biological activity of gelatin hydrolysates depend on the gelatin source. This study examined the effects of fish-derived gelatin hydrolysate (FGH) or porcine-derived gelatin hydrolysate (PGH) intake on BMD and intrinsic biomechanical properties in magnesium (Mg)-deficient rats as a model showing the decrease in both BMD and intrinsic biomechanical properties. METHODS: Four-week-old male Wistar rats were assigned into four groups: a normal group was fed a normal diet (48 mg Mg/100 g diet), a Mg-deficient (MgD) group was fed a MgD diet (7 mg Mg/100 g diet), a FGH group was fed a MgD + FGH diet (5% FGH), and a PGH group was fed a MgD + PGH diet (5% PGH) for 8 weeks. At the end of the study, BMD and intrinsic biomechanical properties of the femur were measured. RESULTS: The MgD group showed significantly lower Young's modulus, an intrinsic biomechanical property, and trabecular BMD of the femur than the normal group; however, the MgD diet did not affect cortical BMD and cortical thickness. Both the FGH and the PGH groups showed significantly higher cortical thickness and ultimate displacement of the femur than the normal group, but neither type of gelatin hydrolysate affected Young's modulus. Furthermore, the FGH group, but not the PGH group, showed significantly higher trabecular BMD than the MgD group. CONCLUSIONS: This study indicates that FGH and PGH increase cortical thickness but only FGH prevents the decrease in trabecular BMD seen in Mg-deficient rats, while neither type of gelatin hydrolysate affect intrinsic biomechanical properties. PMID- 28870200 TI - Anticancer activity of calyx of Diospyros kaki Thunb. through downregulation of cyclin D1 via inducing proteasomal degradation and transcriptional inhibition in human colorectal cancer cells. AB - BACKGROUND: Although it has been reported to contain high polyphenols, the pharmacological studies of the calyx of Diospyros kaki Thunb (DKC) have not been elucidated in detail. In this study, we elucidated anti-cancer activity and potential molecular mechanism of DKC against human colorectal cancer cells. METHODS: Anti-cell proliferative effect of 70% ethanol extracts from the calyx of Diospyros kaki (DKC-E70) was evaluated by MTT assay. The effect of DKC-E70 on the expression of cyclin D1 in the protein and mRNA level was evaluated by Western blot and RT-PCR, respectively. RESULTS: DKC-E70 suppressed the proliferation of human colorectal cancer cell lines such as HCT116, SW480, LoVo and HT-29. Although DKC-E70 decreased cyclin D1 expression in protein and mRNA level, decreased level of cyclin D1 protein by DKC-E70 occurred at the earlier time than that of cyclin D1 mRNA, which indicates that DKC-E70-mediated downregulation of cyclin D1 protein may be a consequence of the induction of degradation and transcriptional inhibition of cyclin D1. In cyclin D1 degradation, we found that cyclin D1 downregulation by DKC-E70 was attenuated in presence of MG132. In addition, DKC-E70 phosphorylated threonine-286 (T286) of cyclin D1 and T286A abolished cyclin D1 downregulation by DKC-E70. We also observed that DKC-E70 mediated T286 phosphorylation and subsequent cyclin D1 degradation was blocked in presence of the inhibitors of ERK1/2, p38 or GSK3beta. In cyclin D1 transcriptional inhibition, DKC-E70 inhibited the expression of beta-catenin and TCF4, and beta-catenin/TCF-dependent luciferase activity. CONCLUSIONS: Our results suggest that DKC-E70 may downregulate cyclin D1 as one of the potential anti-cancer targets through cyclin D1 degradation by T286 phosphorylation dependent on ERK1/2, p38 or GSK3beta, and cyclin D1 transcriptional inhibition through Wnt signaling. From these findings, DKC-E70 has potential to be a candidate for the development of chemoprevention or therapeutic agents for human colorectal cancer. PMID- 28870201 TI - Maternal cell phone use in early pregnancy and child's language, communication and motor skills at 3 and 5 years: the Norwegian mother and child cohort study (MoBa). AB - BACKGROUND: Cell phone use during pregnancy is a public health concern. We investigated the association between maternal cell phone use in pregnancy and child's language, communication and motor skills at 3 and 5 years. METHODS: This prospective study includes 45,389 mother-child pairs, participants of the MoBa, recruited at mid-pregnancy from 1999 to 2008. Maternal frequency of cell phone use in early pregnancy and child language, communication and motor skills at 3 and 5 years, were assessed by questionnaires. Logistic regression was used to estimate the associations. RESULTS: No cell phone use in early pregnancy was reported by 9.8% of women, while 39%, 46.9% and 4.3% of the women were categorized as low, medium and high cell phone users. Children of cell phone user mothers had 17% (OR = 0.83, 95% CI: 0.77, 0.89) lower adjusted risk of having low sentence complexity at 3 years, compared to children of non-users. The risk was 13%, 22% and 29% lower by low, medium and high maternal cell phone use. Additionally, children of cell phone users had lower risk of low motor skills score at 3 years, compared to children of non-users, but this association was not found at 5 years. We found no association between maternal cell phone use and low communication skills. CONCLUSIONS: We reported a decreased risk of low language and motor skills at three years in relation to prenatal cell phone use, which might be explained by enhanced maternal-child interaction among cell phone users. No evidence of adverse neurodevelopmental effects of prenatal cell phone use was reported. PMID- 28870202 TI - An assessment of healthcare professionals' knowledge about and attitude towards influenza vaccination in Freetown Sierra Leone: a cross-sectional study. AB - BACKGROUND: Vaccinating healthcare professionals against influenza is considered an effective infection control measure. However, there is a low uptake of influenza vaccine among healthcare professionals around the globe. Currently, it is unknown whether healthcare professionals in Sierra Leone are aware of, and have been vaccinated against influenza. Also, there is a paucity of research evidence on their level of knowledge and attitude toward influenza vaccination. This study assessed healthcare professionals' current influenza vaccine uptake rate, reasons for not getting vaccinated as well as their awareness, knowledge of, and attitude towards influenza vaccination in Freetown Sierra Leone. METHOD: A cross-sectional study was conducted between February and April 2016 among healthcare providers working in four public and two private health facilities in Freetown Sierra Leone. Linear regression analysis, one-way ANOVA and independent t-test were employed for data analysis. RESULTS: Among 706 respondents that participated in the study more than half were females 378 (53.6%), nurses 425 (60.4%), and the majority were between the age group of 20-39 years 600 (85.3%). Only 46 (6.5%) were vaccinated against influenza. Key reasons for not vaccinated against influenza were less awareness about influenza vaccination among HCPs 580 (82.73%) with (beta = 0.154; CI 0.058-0.163), the high cost of influenza vaccines and therefore not normally purchased 392 (55.92%) having (beta = 0.150; CI 0.063 0.186). More than half believed that HCPs are less susceptible to influenza infections than other people. Also, majority 585 (84.3%) of HCPs thought that influenza disease could be transmitted after symptoms appear. In addition, 579 (83.2%) of HCPs felt that symptoms usually appear 8-10 days after exposure. Close to half 321 (46.0%) of HCPs were not aware of the influenza immunisation guidelines published by the Advisory Committee on Immunization Practices and Centre for Disease Control. CONCLUSION: Influenza vaccine coverage among healthcare professionals in Freetown Sierra Leone was low. High cost, inadequate knowledge about influenza and its vaccine as well as the lack of awareness of vaccine availability were key barriers. Increasing access to influenza vaccine and the use of appropriate educational interventions to increase knowledge and awareness are required to improve influenza vaccination coverage among HCPs. PMID- 28870204 TI - Left atrial myxoma complicated with multi-system embolization. AB - BACKGROUND: Atrial myxoma accounts for approximately 50% of all cardiac tumors. The majority of myxomas are located in the left atrium and present variable clinical manifestation. CASE PRESENTATION: A young man was transferred to our hospital with sudden onset of resting pain, pallor and numb in right leg. An atrial mobile mass was detected by transthoracic echocardiography. Anticoagulant and antithrombotic therapy were administered, a timely surgery was performed and the mass was confirmed as a myxoma. The patient did not discharge any discomfort post-operation. CONCLUSION: For patients with atrial myxoma, early diagnosis is essential, anticoagulant or antithrombotic therapy and surgery have a great importance to prevent further embolism. PMID- 28870203 TI - The DLGAP family: neuronal expression, function and role in brain disorders. AB - The neurotransmitter glutamate facilitates neuronal signalling at excitatory synapses. Glutamate is released from the presynaptic membrane into the synaptic cleft. Across the synaptic cleft glutamate binds to both ion channels and metabotropic glutamate receptors at the postsynapse, which expedite downstream signalling in the neuron. The postsynaptic density, a highly specialized matrix, which is attached to the postsynaptic membrane, controls this downstream signalling. The postsynaptic density also resets the synapse after each synaptic firing. It is composed of numerous proteins including a family of Discs large associated protein 1, 2, 3 and 4 (DLGAP1-4) that act as scaffold proteins in the postsynaptic density. They link the glutamate receptors in the postsynaptic membrane to other glutamate receptors, to signalling proteins and to components of the cytoskeleton. With the central localisation in the postsynapse, the DLGAP family seems to play a vital role in synaptic scaling by regulating the turnover of both ionotropic and metabotropic glutamate receptors in response to synaptic activity. DLGAP family has been directly linked to a variety of psychological and neurological disorders. In this review we focus on the direct and indirect role of DLGAP family on schizophrenia as well as other brain diseases. PMID- 28870205 TI - Maintenance of stemness is associated with the interation of LRP6 and heparin binding protein CCN2 autocrined by hepatocellular carcinoma. AB - BACKGROUND: The overall response rate of hepatocellular carcinoma (HCC) to chemotherapy is poor. In our previous study, oxaliplatin-resistant HCC is found to exhibit an enhanced stemness, and increased levels of CCN2 and LRP6, while the role of CCN2 and LRP6 in the prognosis of HCC patients, and the interaction regulation mechanism between CCN2 and LRP6 are still unclear. METHODS: The expression levels of CCN2 and LRP6 were detected in large cohorts of HCCs, and functional analyses of CCN2 and LRP6 were performed both in vitro and in vivo. The roles of cell surface heparin sulfate proteoglycans (HSPGs) in the mutual regulatory between CCN2 and LRP6 were verified in HCC, and the interventions of low molecular weight heparin sodium (LMWH) were explored. RESULTS: CCN2 and LRP6 were overexpressed in HCCs, and the CCN2 and LRP6 levels were positively associated with the malignant phenotypes and poor prognosis of HCCs. LRP6 could significantly upregulate the expression of CCN2. Meanwhile, CCN2 was able to enhance malignant phenotype of HCC cells in a dose-dependent manner through binding with LRP6; and knock-down of LRP6 expression, perturbation of HSPGs, co incubation of CCN2 with LMWH could significantly block the adhesion of CCN2 to LRP6. LMWH enhanced the therapeutic effect of oxaliplatin on HCC with a high CCN2 expression. CONCLUSIONS: CCN2 plays a promoting role in HCC progression through activating LRP6 in a HSPGs-dependent manner. Heparin in combination with chemotherapy has a synergic effect and could be a treatment choice for HCCs with a high CCN2 expression. PMID- 28870206 TI - 3,6-Dihydroxyflavone regulates microRNA-34a through DNA methylation. AB - BACKGROUND: Breast cancer is the common cancer in China. In previous study, we determined that 3,6-dihydroxyflavone (3,6-DHF) increases miR-34a significantly in breast carcinogenesis, but the mechanism remains unclear. METHODS: We used qRT PCR to analyze miR-34a and ten-eleven translocation (TET)1, TET2, TET3 levels in breast cancer cells. With a cellular breast carcinogenesis model and an experimental model of carcinogenesis in rats, TET1 levels were evaluated by western blot analysis and immunofluorescence. TET1 and 5hmC (5 hydroxymethylcytosine) levels were evaluated by immunofluorescence in nude mouse xenografts of MDA-MB-231 cells. Chromatin immunoprecipitation(ChIP) assayed for TET1 on the TET1 promoter, and dot blot analysis of DNA 5hmC was performed in MDA MB-231 cells. We evaluated the mechanism of 3,6-DHF on the expression of tumor suppressor miR-34a by transfecting them with DNA methyltransferase (DNMT)1 plasmid and TET1 siRNA in breast cancer cells. Methylation-specific PCR detected methylation of the miR-34a promoter. RESULTS: First, we found that 3,6-DHF promotes the expression of TET1 during carcinogen-induced breast carcinogenesis in MCF10A cells and in rats. 3,6-DHF also increased TET1 and 5hmC levels in MDA MB-231 cells. Further study indicated that TET1 siRNA and pcDNA3/Myc-DNMT1 inhibited the 3,6-DHF reactivation effect on expression of miR-34a in breast cancer cells. Methylation-specific PCR assays indicated that TET1 siRNA and pcDNA3/Myc-DNMT1 inhibit the effect of 3,6-DHF on the demethylation of the miR 34a promoter. CONCLUSIONS: Our study showed that 3,6-DHF effectively increases TET1 expression by inhibiting DNMT1 and DNA hypermethylation, and consequently up regulates miR-34a in breast carcinogenesis. PMID- 28870207 TI - Effects of Trilostane on urinary Catecholamines and their metabolites in dogs with Hypercortisolism. AB - BACKGROUND: Glucocorticoids influence the synthesis and metabolism of catecholamines (epinephrine and norepinephrine) and metanephrines (metanephrine and normetanephrine). The aim of this study was to measure urinary catecholamines and metanephrines in dogs with hypercortisolism before and during trilostane therapy. Urine samples were collected during initial work up and during therapy with trilostane in 14 dogs with hypercortisolism and in 25 healthy dogs. Epinephrine, norepinephrine, metanephrine and normetanephrine were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. RESULTS: Untreated dogs with hypercortisolism had significantly higher epinephrine, norepinephrine, and normetanephrine:creatinine ratios compared to healthy dogs. During trilostane therapy, urinary catecholamines and their metabolites did not decrease significantly. However, dogs with low post ACTH cortisol concentrations during trilostane therapy had less increased epinephrine, norepinephrine and normetanephrine:creatinine ratios compared to healthy dogs. There was no correlation of urinary catecholamines and their metabolites with baseline or post-ACTH cortisol or endogenous ACTH concentrations during trilostane therapy. CONCLUSION: Influences between steroid hormones and catecholamines seem to occur, as dogs with hypercortisolism have significantly higher urinary epinephrine, norepinephrine, and normetanephrine:creatinine ratios. Once-daily trilostane therapy does not lead to a significant decrease in catecholamines and their metabolites. Trilostane-treated dogs still have increased urinary epinephrine, norepinephrine and normetanephrine:creatinine ratios during trilostane therapy. PMID- 28870208 TI - The role of self-regulatory skills and automaticity on the effectiveness of a brief weight loss habit-based intervention: secondary analysis of the 10 top tips randomised trial. AB - BACKGROUND: Habit-interventions are designed to promote the automaticity of healthy behaviours and may also enhance self-regulatory skills during the habit formation process. A recent trial of habit-based advice for weight loss (10 Top Tips; 10TT), found that patients allocated to 10TT lost significantly more weight over 3 months than those allocated to usual care, and reported greater increases in automaticity for the target behaviours. The current study aimed to test the hypothesis that i) 10TT increased self-regulatory skills more than usual care, and ii) that self-regulatory skills and automaticity changes mediated the effect of 10TT on weight loss. METHODS: 537 obese patients from 14 primary care practices in the UK were randomized to receive 10TT or usual care. Patients in the 10TT group received a leaflet containing tips for weight loss and healthy habits formation, a self-monitoring log book and a wallet-sized shopping guide on how to read food labels. Patients were weighed and completed validated questionnaires for self-regulation and automaticity at baseline and 3-month follow-up. Within-group and Between-group effects were explored using Paired T test and ANCOVA, respectively. Mediation was assessed using bootstrapping to estimate indirect effects and the sobel test. RESULTS: Over 3 months patients who were given 10TT reported greater increases in self-regulatory skills (Mean difference: .08; 95% CI .01; .15) than those who received usual care. Changes in self-regulatory skills and automaticity over 3 months mediated the effect of the intervention on weight loss (beta = .52, 95% Bias Corrected CI .17; .91). CONCLUSIONS: As hypothesised, 10TT enhanced self-regulatory skills and changes in self-regulatory skills and automaticity mediated the effect of the intervention on weight loss. This supports the proposition that self-regulatory training and habit formation are important features of weight loss interventions. TRIAL REGISTRATION: This study was prospectively registered with the International Standard Randomised Controlled Trials ( ISRCTN16347068 ) on 26 September 2011. PMID- 28870210 TI - Hemostatic bioactivity of novel Pollen Typhae Carbonisata-derived carbon quantum dots. AB - BACKGROUND: Pollen Typhae Carbonisata (PTC) is a type of calcined herb drug that has been used as a hemostatic medicine to promote hemostasis for thousands of years. In this study, we discovered and separated novel water-soluble carbon quantum dots (CQDs, named PTC-CQDs) from aqueous extracts of PTC. These PTC-CDs were characterized using transmission electron microscopy (TEM) and high resolution TEM, as well as Fourier transform infrared, ultraviolet-visible, and fluorescence spectroscopy. Then, we assessed the anti-hemorrhagic effects and related hemostatic mechanisms of the obtained PTC-CQDs. RESULTS: The PTC-CQDs separated from PTC are spherical, monodisperse, and have a narrow size distribution between 2 and 8 nm. In the pharmacology experiment, remarkable anti hemorrhage effects of PTC-CQDs were revealed. Additionally, the rats showed a profound decrease in activated partial thromboplastin time and increase in fibrinogen and PLT after PTC-CQDs treatment. CONCLUSIONS: These results indicated the explicit hemostasis effect of PTC-CQDs, which not only provided a new idea for the material research of PTC, but have also provided new insights into potential biomedical and healthcare applications of CQDs in the field of haemorrhage control and laid a solid foundation for future drug discovery. PMID- 28870211 TI - Re-irradiation for oligo-recurrence from esophageal cancer with radiotherapy history: a multi-institutional study. AB - BACKGROUND: Neoadjuvant chemoradiotherapy following surgery has recently become a standard therapy. The purpose of the present study was to determine the effectiveness and toxicity of re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy. METHODS: We reviewed retrospectively 248 patients treated with (chemo)radiotherapy for oligo-recurrence in lymph nodes from esophageal cancer in five Japanese high-volume centers between 2000 and 2015. Thirty-three patients in whom re-irradiation was performed were enrolled in this study, and the results for patients in whom re-irradiation was performed were compared with the results for other patients. RESULTS: Median maximum lymph node diameter was 22 mm. Median total radiation dose was 60 Gy. The median calculated biological effective dose using the LQ model with alpha/beta = 10 Gy (BED10) in patients in whom re-irradiation was performed was significantly lower than the median BED10 in others. There was no different factor except for BED10, histology and irradiation field between patients with a past irradiation history and patients without a past irradiation history. The median observation period in surviving patients in whom re-irradiation was performed was 21.7 months. The 3 year overall survival rate in the 33 patients with a past irradiation history was 17.9%, with a median survival period of 16.0 months. Overall survival rate and local control rate in patients with a past irradiation history were significantly worse than those in patients without a past irradiation history (log-rank test, p = 0.016 and p = 0.0007, respectively). One patient in whom re-irradiation was performed died from treatment-related gastric hemorrhage. CONCLUSIONS: Results in the present study suggested that re-irradiation for oligo-recurrence in lymph nodes from esophageal cancer treated by definitive radiotherapy or by surgery with additional radiotherapy might be acceptable but unsatisfactory. PMID- 28870213 TI - Test-and-treat approach to HIV/AIDS: a primer for mathematical modeling. AB - The public benefit of test-and-treat has induced a need to justify goodness for the public, and mathematical modeling studies have played a key role in designing and evaluating the test-and-treat strategy for controlling HIV/AIDS. Here we briefly and comprehensively review the essence of contemporary understanding of the test-and-treat policy through mathematical modeling approaches and identify key pitfalls that have been identified to date. While the decrease in HIV incidence is achieved with certain coverages of diagnosis, care and continued treatment, HIV prevalence is not necessarily decreased and sometimes the test-and treat is accompanied by increased long-term cost of antiretroviral therapy (ART). To confront with the complexity of assessment on this policy, the elimination threshold or the effective reproduction number has been proposed for its use in determining the overall success to anticipate the eventual elimination. Since the publication of original model in 2009, key issues of test-and-treat modeling studies have been identified, including theoretical problems surrounding the sexual partnership network, heterogeneities in the transmission dynamics, and realistic issues of achieving and maintaining high treatment coverage in the most hard-to-reach populations. To explicitly design country-specific control policy, quantitative modeling approaches to each single setting with differing epidemiological context would require multi-disciplinary collaborations among clinicians, public health practitioners, laboratory technologists, epidemiologists and mathematical modelers. PMID- 28870209 TI - Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations. AB - In recent years, evidence supporting a link between inflammation and neuropsychiatric disorders has been mounting. Autism spectrum disorders (ASD) and schizophrenia share some clinical similarities which we hypothesize might reflect the same biological basis, namely, in terms of inflammation. However, the diagnosis of ASD and schizophrenia relies solely on clinical symptoms, and to date, there is no clinically useful biomarker to diagnose or monitor the course of such illnesses.The focus of this review is the central role that inflammation plays in ASD and schizophrenia. It spans from pre-clinical animal models to clinical research and excludes in vitro studies. Four major areas are covered: (1) microglia, the inflammatory brain resident myeloid cells, (2) biomarkers, including circulating cytokines, oxidative stress markers, and microRNA players, known to influence cellular processes at brain and immune levels, (3) effect of anti-psychotics on biomarkers and other predictors of response, and (4) impact of gender on response to immune activation, biomarkers, and response to anti psychotic treatments. PMID- 28870212 TI - Chromosome contacts in activated T cells identify autoimmune disease candidate genes. AB - BACKGROUND: Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4+ T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. RESULTS: Within 4 h, activation of CD4+ T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases, we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach. CONCLUSIONS: Our systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes. PMID- 28870214 TI - Plasmodium vivax genetic diversity and heterozygosity in blood samples and resulting oocysts at the Thai-Myanmar border. AB - BACKGROUND: Polyclonal blood-stage infections of Plasmodium vivax are frequent even in low transmission settings, allowing meiotic recombination between heterologous parasites. Empirical data on meiotic products are however lacking. This study examined microsatellites in oocysts derived by membrane feeding of mosquitoes from blood-stage P. vivax infections at the Thai-Myanmar border. METHODS: Blood samples from patients presenting with vivax malaria were fed to Anopheles cracens by membrane feeding and individual oocysts from midguts were obtained by dissection after 7 days. DNA was extracted from oocysts and parental blood samples and tested by microsatellite analysis. RESULTS: A focused study of eight microsatellite markers was undertaken for nine blood stage infections from 2013, for which derived oocysts were studied in six cases. One or more alleles were successfully amplified for 131 oocysts, revealing high levels of allelic diversity in both blood and oocyst stages. Based on standard criteria for defining minor alleles, there was evidence of clear deviation from random mating (inbreeding) with relatively few heterozygous oocysts compared to variance across the entire oocyst population (FIT = 0.89). The main explanation appeared to be natural compartmentalisation at mosquito (FSC = 0.27) and human stages (FCT = 0.68). One single human case produced a total of 431 successfully amplified loci (across 70 oocysts) that were homozygous and identical to parental alleles at all markers, indicating clonal infection and transmission. Heterozygous oocyst alleles were found at 15/176 (8.5%) successfully amplified loci in the other five cases. There was apparently reduced oocyst heterozygosity in individual oocysts compared to diversity within individual mosquitoes (FIS = 0.55), but this may simply reflect the difficulty of detecting minor alleles in oocysts, given the high rate of amplification failure. Inclusion of minor allele peaks (irrespective of height) when matching peaks were found in related blood or oocyst samples, added 11 minor alleles for 9 oocysts, increasing the number of heterozygous loci to 26/176 (14.8%; p = 0.096). CONCLUSION: There was an apparently low level of heterozygous oocysts but this can be explained by a combination of factors: relatively low complexity of parental infection, natural compartmentalisation in humans and mosquitoes, and the methodological challenge of detecting minor alleles. PMID- 28870215 TI - The SPARK Tool to prioritise questions for systematic reviews in health policy and systems research: development and initial validation. AB - BACKGROUND: Groups or institutions funding or conducting systematic reviews in health policy and systems research (HPSR) should prioritise topics according to the needs of policymakers and stakeholders. The aim of this study was to develop and validate a tool to prioritise questions for systematic reviews in HPSR. METHODS: We developed the tool following a four-step approach consisting of (1) the definition of the purpose and scope of tool, (2) item generation and reduction, (3) testing for content and face validity, (4) and pilot testing of the tool. The research team involved international experts in HPSR, systematic review methodology and tool development, led by the Center for Systematic Reviews on Health Policy and Systems Research (SPARK). We followed an inclusive approach in determining the final selection of items to allow customisation to the user's needs. RESULTS: The purpose of the SPARK tool was to prioritise questions in HPSR in order to address them in systematic reviews. In the item generation and reduction phase, an extensive literature search yielded 40 relevant articles, which were reviewed by the research team to create a preliminary list of 19 candidate items for inclusion in the tool. As part of testing for content and face validity, input from international experts led to the refining, changing, merging and addition of new items, and to organisation of the tool into two modules. Following pilot testing, we finalised the tool, with 22 items organised in two modules - the first module including 13 items to be rated by policymakers and stakeholders, and the second including 9 items to be rated by systematic review teams. Users can customise the tool to their needs, by omitting items that may not be applicable to their settings. We also developed a user manual that provides guidance on how to use the SPARK tool, along with signaling questions. CONCLUSION: We have developed and conducted initial validation of the SPARK tool to prioritise questions for systematic reviews in HPSR, along with a user manual. By aligning systematic review production to policy priorities, the tool will help support evidence-informed policymaking and reduce research waste. We invite others to contribute with additional real-life implementation of the tool. PMID- 28870216 TI - Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination. AB - BACKGROUND: Resistance to adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM). Autophagy inhibitors have been shown to enhance the efficacy of radiotherapy for certain solid tumors. However, current inhibitors do not penetrate the blood-brain-barrier (BBB). Here, we assessed the radiosensitivity effects of the antipsychotic drug trifluoperazine (TFP) on GBM in vitro and in vivo. METHODS: U251 and U87 GBM cell lines as well as GBM cells from a primary human biopsy (P3), were used in vitro and in vivo to evaluate the efficacy of TFP treatment. Viability and cytotoxicity was evaluated by CCK-8 and clonogenic formation assays. Molecular studies using immunohistochemistry, western blots, immunofluorescence and qPCR were used to gain mechanistic insight into the biological activity of TFP. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models. RESULTS: IC50 values of U251, U87 and P3 cells treated with TFP were 16, 15 and 15.5 MUM, respectively. TFP increased the expression of LC3B-II and p62, indicating a potential disruption of autophagy flux. These results were further substantiated by a decreased Lysotracker Red uptake, indicating impaired acidification of the lysosomes. We show that TFP and radiation had an additive effect when combined. This effect was in part due to impaired TFP-induced homologous recombination. Mechanistically we show that down-regulation of cathepsin L might explain the radiosensitivity effect of TFP. Finally, combining TFP and radiation resulted in a significant antitumor effect in orthotopic GBM xenograft models. CONCLUSIONS: This study provides a strong rationale for further clinical studies exploring the combination therapy of TFP and radiation to treat GBM patients. PMID- 28870217 TI - Controlled ovulation of the dominant follicle using progestin in minimal stimulation in poor responders. AB - BACKGROUND: The use of progestin (P) during ovarian stimulation is effective in blocking the luteinizing hormone (LH) surge in women with normal ovarian reserve, however, its effects have not been determined in poor responders. This study aimed to explore the follicular dynamics in P-primed minimal stimulation in poor responders. METHODS: A total of 204 infertile women with diminished ovarian reserve were allocated into the medroxyprogesterone acetate (MPA) group or the natural-cycle control group in an alternating order. MPA (10 mg) was administered daily beginning from the early follicular phase and a low dose of hMG was added in the late follicular phase if the serum FSH level was lower than 8.0mIU/ml. When a dominant follicle reached maturity, triptorelin 100 MUg and hCG 1000 IU were used for trigger, and oocytes were retrieved 34-36 h later.All viable embryos were cryopreserved for subsequent frozen embryo transfer. Natural cycle IVF was used as controls. RESULTS: Compared with the natural cycle group, the MPA group exhibited a larger pre-ovulatory follicle (18.7 +/- 1.8 mm vs 17.2 +/- 2.2 mm), a longer follicular phase (13.6 +/- 3.6 days vs 12.3 +/- 3.2 days), and higher peak oestradiol values (403.88 +/- 167.16 vs 265.26 +/- 122.16 pg/ml), while maintaining lower LH values (P < 0.05). The incidences of spontaneous LH surge and premature ovulation decreased significantly (1.0% vs 50%; 2% vs. 10.8%, respectively; P < 0.05). A greater number of oocytes and viable embryos were harvested from the MPA group than from the natural cycle group (P < 0.05). Moreover,the clinical pregnancy rate was slightly higher in the MPA group than in the natural cycle controls, but the difference was not significant (11.8% vs 5.9%, P > 0.05). CONCLUSION: This study supported the hypothesis that P-primed minimal stimulation achieved ovulation control of the dominant follicle and did not adversely affect the quality of oocytes in poor responders. Therefore, P priming is a promising approach to overcome premature ovulation in minimal stimulation for poor responders. TRIAL REGISTRATION: ChiCTR-OCH-14004176 . Registered on January 8, 2014. PMID- 28870218 TI - Respiratory problems in children with esophageal atresia and tracheoesophageal fistula. AB - BACKGROUND: Children with congenital esophageal atresia (EA) and tracheoesophageal fistula (TEF) have chronic respiratory symptoms including recurrent pneumonia, wheezing and persistent cough. The aim of this study is to describe the clinical findings of a large group of children with EA and TEF surgically corrected and the instrumental investigation to which they have undergone in order to better understand the patient's needs and harmonize the care. METHODS: A retrospective data collection was performed on 105 children with EA and TEF followed at Department of Pediatric Medicine of Bambino Gesu Children's Hospital (Rome, Italy) between 2010 and 2015. RESULTS: 69/105 (66%) children reported lower respiratory symptoms with a mean age onset of 2.2 +/- 2.5 years and only 63/69 (91%) performed specialist assessment at Respiratory Unit. Recurrent pneumonia (33%) and wheezing (31%) were the most reported symptoms. The first respiratory evaluation was performed after surgically correction of gastroesophageal reflux (GER) at mean age of 3.9 +/- 4.2 years. Twenty nine patients have undergone to chest CT with contrast enhancement detecting localized atelectasis (41%), residual tracheal diverticulum (34%), bronchiectasis (31%), tracheal vascular compression (21%), tracheomalacia (17%) and esophageal diverticulum (14%). Fifty three patients have undergone to airways endoscopy detecting tracheomalacia (66%), residual tracheal diverticulum (26%), recurrent tracheoesophageal fistula (19%) and vocal cord paralysis (11%). CONCLUSIONS: Our study confirms that respiratory symptoms often complicate EA and TEF; their persistence despite medical and surgical treatment of GER means that other etiological hypothesis must be examined and that a complete respiratory diagnostic work up must be considered. PMID- 28870219 TI - Predictors of screen viewing time in young Singaporean children: the GUSTO cohort. AB - BACKGROUND: Higher screen viewing time (SVT) in childhood has been associated with adverse health outcomes, but the predictors of SVT in early childhood are poorly understood. We examined the sociodemographic and behavioral predictors of total and device-specific SVT in a Singaporean cohort. METHODS: At ages 2 and 3 years, SVT of 910 children was reported by their parents. Interviewer administered questionnaires assessed SVT on weekdays and weekends for television, computer, and hand-held devices. Multivariable linear mixed-effect models were used to examine the associations of total and device-specific SVT at ages 2 and 3 with predictors, including children's sex, ethnicity, birth order, family income, and parental age, education, BMI, and television viewing time. RESULTS: At age 2, children's total SVT averaged 2.4 +/- 2.2 (mean +/- SD) hours/day, including 1.6 +/- 1.6 and 0.7 +/- 1.0 h/day for television and hand-held devices, respectively. At age 3, hand-held device SVT was 0.3 (95% CI: 0.2, 0.4) hours/day higher, while no increases were observed for other devices. SVT tracked moderately from 2 to 3 years (r = 0.49, p < 0.0001). Compared to Chinese children, Malay and Indian children spent 1.04 (0.66, 1.41) and 0.54 (0.15, 0.94) more hours/day watching screens, respectively. Other predictors of longer SVT were younger maternal age, lower maternal education, and longer parental television time. CONCLUSIONS: In our cohort, the main predictors of longer children's SVT were Malay and Indian ethnicity, younger maternal age, lower education and longer parental television viewing time. Our study may help target populations for future interventions in Asia, but also in other technology-centered societies. TRIAL REGISTRATION: This ongoing study was first registered on July 1, 2010 on NCT01174875 as. Retrospectively registered. PMID- 28870221 TI - Isolation and characterization of the fall Chinook aquareovirus. AB - BACKGROUND: Salmon are paramount to the economy, ecology, and history of the Pacific Northwest. Viruses constitute one of the major threats to salmon health and well-being, with more than twenty known virus species that infect salmon. Here, we describe the isolation and characterization of the fall Chinook aquareovirus, a divergent member of the species Aquareovirus B within the family Reoviridae. METHODS: The virus was first found in 2014 as part of a routine adult broodstock screening program in which kidney and spleen tissue samples from healthy-appearing, adult fall Chinook salmon (Oncorhynchus tshawytscha) returning to a hatchery in Washington State produced cytopathic effects when inoculated onto a Chinook salmon embryo cell line (CHSE-214). The virus was not able to be confirmed by an RT-PCR assay using existing aquareovirus pan-species primers, and instead was identified by metagenomic next-generation sequencing. Metagenomic next-generation sequencing was used to recover the full genome and completed using 3' RACE. RESULTS: The genome of the fall Chinook aquareovirus contains 11 segments of double-stranded RNA totaling 23.3 kb, with each segment flanked by the canonical sequence termini found in the aquareoviruses. Sequence comparisons and a phylogenetic analysis revealed a nucleotide identity of 63.2% in the VP7 gene with the Green River Chinook virus, placing the new isolate in the species Aquareovirus B. A qRT-PCR assay was developed targeting the VP2, which showed rapid growth of the isolate during the initial 5 days in culture using CHSE-214 cells. CONCLUSIONS: This sequence represents the first complete genome of an Aquareovirus B species. Future studies will be required to understand the potential pathogenicity and epidemiology of the fall Chinook aquareovirus. PMID- 28870220 TI - The type VI adenylyl cyclase protects cardiomyocytes from beta-adrenergic stress by a PKA/STAT3-dependent pathway. AB - BACKGROUND: The type VI adenylyl cyclase (AC6) is a main contributor of cAMP production in the heart. The amino acid (aa) sequence of AC6 is highly homologous to that of another major cardiac adenylyl cyclase, AC5, except for its N-terminus (AC6-N, aa 1-86). Activation of AC6, rather than AC5, produces cardioprotective effects against heart failure, while the underlying mechanism remains to be unveiled. Using an AC6-null (AC6-/-) mouse and a knockin mouse with AC6-N deletion (AC6 DeltaN/DeltaN), we aimed to investigate the cardioprotective mechanism of AC6 in the heart. METHODS: Western blot analysis and immunofluorescence staining were performed to determine the intracellular distribution of AC6, AC6-DeltaN (a truncated AC6 lacking the first 86 amino acids), and STAT3 activation. Activities of AC6 and AC6-DeltaN in the heart were assessed by cAMP assay. Apoptosis of cardiomyocytes were evaluated by the TUNEL assay and a propidium iodine-based survival assay. Fibrosis was examined by collagen staining. RESULTS: Immunofluorescence staining revealed that cardiac AC6 was mainly anchored on the sarcolemmal membranes, while AC6-DeltaN was redistributed to the sarcoplasmic reticulum. AC6DeltaN/DeltaN and AC6-/- mice had more apoptotic myocytes and cardiac remodeling than WT mice in experimental models of isoproterenol (ISO)-induced myocardial injury. Adult cardiomyocytes isolated from AC6DeltaN/DeltaN or AC6-/- mice survived poorly after exposure to ISO, which produced no effect on WT cardiomyocytes under the condition tested. Importantly, ISO treatment induced cardiac STAT3 phosphorylation/activation in WT mice, but not in AC6DeltaN/DeltaN and AC6-/- mice. Pharmacological blockage of PKA-, Src-, or STAT3- pathway markedly reduced the survival of WT myocytes in the presence of ISO, but did not affect those of AC6DeltaN/DeltaN and AC6-/- myocytes, suggesting an important role of AC6 in mediating cardioprotective action through the activation of PKA-Src-STAT3-signaling. CONCLUSIONS: Collectively, AC6-N controls the anchorage of cardiac AC6 on the sarcolemmal membrane, which enables the coupling of AC6 with the pro-survival PKA-STAT3 pathway. Our findings may facilitate the development of novel therapies for heart failure. PMID- 28870222 TI - General anesthetics protects against cardiac arrest-induced brain injury by inhibiting calcium wave propagation in zebrafish. AB - Cardiac arrest is a leading cause of death and disability worldwide. Although many victims are initially resuscitated, they often suffer from serious brain injury, even leading to a "persistent vegetative state". Therefore, it is need to explore therapies which restore and protect brain function after cardiac arrest. In the present study, using Tg (HuC:GCaMP5) zebrafish as a model, we found the zebrafish brain generated a burst of Ca2+ wave after cardiac arrest by in vivo time-lapse confocal imaging. The Ca2+ wave was firstly initiated at hindbrain and then sequentially propagated to midbrain and telencephalon, the neuron displayed Ca2+ overload after Ca2+ wave propagation. Consistent with this, our study further demonstrated neuronal apoptosis was increased in cardiac arrest zebrafish by TUNEL staining. The cardiac arrest-induced Ca2+ wave propagation can be prevented by general anesthetics such as midazolam or ketamine pretreatment. Moreover, midazolam or ketamine pretreatment dramatically decreased the neuronal apoptosis and improved the survival rate in CA zebrafish. Taken together, these findings provide the first in vivo evidence that general anesthetics pretreatment protects against cardiac arrest-induced brain injury by inhibiting calcium wave propagation in zebrafish. PMID- 28870223 TI - Modified 'candy-plug' technique for chronic type B aortic dissection with aneurysmal dilatation: a case report. AB - BACKGROUND: The original 'candy-plug' technique has been reported to be beneficial for the treatment of residual perfused false lumen in patients with aortic dissection. However, this technique is also associated with several problems, such as narrowing of the true lumen and damage to the flap or vessel wall. Therefore, we modified the procedure to overcome these problems. Here we report a case in which the patient was successfully treated using the modified procedure. CASE PRESENTATION: A 59-year-old man presented with chronic type B aortic dissection with aneurysmal dilatation. The patient had undergone prosthetic graft replacement of the ascending aorta for acute type A aortic dissection 3 years previously and replacement of the descending aorta for residual type B aortic dissection with aneurysmal dilatation 1 year previously. After these procedures, the residual false lumen aneurysm of the distal descending aorta expanded to 57-mm in diameter. Endovascular stent grafting was successfully performed using the modified 'candy-plug' technique with relining of the true lumen and occlusion of the false lumen. The patient was discharged 10 days after the procedure. Follow-up imaging at 1 year showed a completely thrombosed false lumen aneurysm. CONCLUSION: The modified 'candy-plug' technique is useful for treatment of residual type B aortic dissection with aneurysmal dilatation. PMID- 28870224 TI - Psychoactive substances as a last resort-a qualitative study of self-treatment of migraine and cluster headaches. AB - BACKGROUND: Treatment resistant cluster headache and migraine patients are exploring alternative treatments online. The aim of this study was to improve comprehension regarding the use of non-established or alternative pharmacological treatments used by sufferers of cluster headaches and migraines. METHODS: A qualitative thematic analysis of the users' own accounts presented in online forum discussions were conducted. The forum boards https://shroomery.org/ , http://bluelight.org , and https://clusterbusters.org/ met the inclusion criteria and were used for the study. RESULTS: The analysis resulted in six themes: a desperate need for effective treatments; the role of the forum-finding alternative treatments and community support; alternative treatment substances; dosage and regimens; effects and treatment results; and adverse effects. The results provide an insight into why, how, and by which substances and methods sufferers seek relief from cluster headache and migraines. CONCLUSIONS: These patients are in a desperate and vulnerable situation, and illicit psychoactive substances are often considered a last resort. There appeared to be little or no interest in psychoactive effects per se as these were rather tolerated or avoided by using sub-psychoactive doses. Primarily, psilocybin, lysergic acid diethylamide, and related psychedelic tryptamines were reportedly effective for both prophylactic and acute treatment of cluster headache and migraines. Treatment results with cannabis were more unpredictable. No severe adverse events were reported, but it was observed how desperation sometimes spurred risky behavior when obtaining and testing various treatment alternatives. The forum discourse mainly revolved around maximizing treatment results and minimizing potential harms. PMID- 28870225 TI - Implementation framework for chronic disease intervention effectiveness in Maori and other indigenous communities. AB - BACKGROUND: About 40% of all health burden in New Zealand is due to cancer, cardiovascular disease, and type 2 diabetes/obesity. Outcomes for Maori (indigenous people) are significantly worse than non-Maori; these inequities mirror those found in indigenous communities elsewhere. Evidence-based interventions with established efficacy may not be effective in indigenous communities without addressing specific implementation challenges. We present an implementation framework for interventions to prevent and treat chronic conditions for Maori and other indigenous communities. THEORETICAL FRAMEWORK: The He Pikinga Waiora Implementation Framework has indigenous self-determination at its core and consists of four elements: cultural-centeredness, community engagement, systems thinking, and integrated knowledge translation. All elements have conceptual fit with Kaupapa Maori aspirations (i.e., indigenous knowledge creation, theorizing, and methodology) and all have demonstrated evidence of positive implementation outcomes. APPLYING THE FRAMEWORK: A coding scheme derived from the Framework was applied to 13 studies of diabetes prevention in indigenous communities in Australia, Canada, New Zealand, and the United States from a systematic review. Cross-tabulations demonstrated that culture-centeredness (p = .008) and community engagement (p = .009) explained differences in diabetes outcomes and community engagement (p = .098) explained difference in blood pressure outcomes. IMPLICATIONS AND CONCLUSIONS: The He Pikinga Waiora Implementation Framework appears to be well suited to advance implementation science for indigenous communities in general and Maori in particular. The framework has promise as a policy and planning tool to evaluate and design effective interventions for chronic disease prevention in indigenous communities. PMID- 28870226 TI - BayFish: Bayesian inference of transcription dynamics from population snapshots of single-molecule RNA FISH in single cells. AB - Single-molecule RNA fluorescence in situ hybridization (smFISH) provides unparalleled resolution in the measurement of the abundance and localization of nascent and mature RNA transcripts in fixed, single cells. We developed a computational pipeline (BayFish) to infer the kinetic parameters of gene expression from smFISH data at multiple time points after gene induction. Given an underlying model of gene expression, BayFish uses a Monte Carlo method to estimate the Bayesian posterior probability of the model parameters and quantify the parameter uncertainty given the observed smFISH data. We tested BayFish on synthetic data and smFISH measurements of the neuronal activity-inducible gene Npas4 in primary neurons. PMID- 28870227 TI - Cone-beam CT reconstruction for non-periodic organ motion using time-ordered chain graph model. AB - PURPOSE: The purpose of this study is to introduce the new concept of a four dimensional (4D) cone-beam computed tomography (CBCT) reconstruction approach for non-periodic organ motion in cooperation with the time-ordered chain graph model (TCGM) and to compare it with previously developed methods such as total variation-based compressed sensing (TVCS) and prior-image constrained compressed sensing (PICCS). MATERIALS AND METHODS: Our proposed reconstruction is based on a model including the constraint originating from the images of neighboring time phases. Namely, the reconstructed time-series images depend on each other in this TCGM scheme, and the time-ordered images are concurrently reconstructed in the iterative reconstruction approach. In this study, iterative reconstruction with the TCGM was carried out with 90 degrees projection ranges. The images reconstructed by the TCGM were compared with the images reconstructed by TVCS (200 degrees projection ranges) and PICCS (90 degrees projection ranges). Two kinds of projection data sets-an elliptic-cylindrical digital phantom and two clinical patients' data-were used. For the digital phantom, an air sphere was contained and virtually moved along the longitudinal axis by 3 cm/30 s and 3 cm/60 s; the temporal resolution was evaluated by measuring the penumbral width of the air sphere. The clinical feasibility of the non-periodic time-ordered 4D CBCT image reconstruction was examined with the patient data in the pelvic region. RESULTS: In the evaluation of the digital-phantom reconstruction, the penumbral widths of the TCGM yielded the narrowest result; the results obtained by PICCS and TCGM using 90 degrees projection ranges were 2.8% and 18.2% for 3 cm/30 s, and 5.0% and 23.1% for 3 cm/60 s narrower than that of TVCS using 200 degrees projection ranges. This suggests that the TCGM has a better temporal resolution, whereas PICCS seems similar to TVCS. These reconstruction methods were also compared using patients' projection data sets. Although all three reconstruction results showed motion related to rectal gas or stool, the result obtained by the TCGM was visibly clearer with less blurring. CONCLUSION: The TCGM is a feasible approach to visualize non-periodic organ motion. The digital phantom results demonstrated that the proposed method provides 4D image series with a better temporal resolution compared to TVCS and PICCS. The clinical patients' results also showed that the present method enables us to visualize motion related to rectal gas and flatus in the rectum. PMID- 28870228 TI - Changes in catastrophic health expenditure in post-conflict Sierra Leone: an Oaxaca-blinder decomposition analysis. AB - BACKGROUND: At the end of the eleven-year conflict in Sierra Leone, a wide range of policies were implemented to address both demand- and supply-side constraints within the healthcare system, which had collapsed during the conflict. This study examines the extent to which households' exposure to financial risks associated with seeking healthcare evolved in post-conflict Sierra Leone. METHOD: This study uses the 2003 and 2011 cross-sections of the Sierra Leone Integrated Household Survey to examine changes in catastrophic health expenditure between 2003 and 2011. An Oaxaca-Blinder decomposition approach is used to quantify the extent to which changes in catastrophic health expenditure are attributable to changes in the distribution of determinants (distributional effect) and to changes in the impact of these determinants on the probability of incurring catastrophic health expenditure (coefficient effect). RESULTS: The incidence of catastrophic health expenditure decreased significantly by 18% from approximately 50% in 2003 t0 32% in 2011. The decomposition analysis shows that this decrease represents net effects attributable to the distributional and coefficient effects of three determinants of catastrophic health expenditure - ill-health, the region in which households reside and the type of health facility used. A decrease in the incidence of ill-health and changes in the regional location of households contributed to a decrease in catastrophic health expenditure. The distributional effect of health facility types observed as an increase in the use of public health facilities, and a decrease in the use of services in facilities owned by non-governmental organizations (NGOs) also contributed to a decrease in the incidence of catastrophic health expenditure. However, the coefficient effect of public health facilities and NGO-owned facilities suggests that substantial exposure to financial risk remained for households utilizing both types of health facilities in 2011. CONCLUSION: The findings support the need to continue expanding current demand-side policies in Sierra Leone to reduce the financial risk of exposure to ill health. PMID- 28870229 TI - Potential factors associated with clinical stage of nasopharyngeal carcinoma at diagnosis: a case-control study. AB - BACKGROUND: In China, most patients with nasopharyngeal carcinoma (NPC) are diagnosed at a late stage and consequently have a poor prognosis. This study aimed to investigate potential factors associated with the clinical stage of NPC at diagnosis. METHODS: Data were obtained from 118 patients with early-stage NPC and 274 with late-stage NPC who were treated at Sun Yat-sen University Cancer Center between August 2014 and July 2015. Patients were individually matched by age, sex, and residence, and a conditional logistic regression model was applied to assess the associations of clinical stage at diagnosis with socioeconomic status indicators, knowledge of NPC, physical examinations, patient interval, and risk factors for NPC. RESULTS: Although knowledge of early NPC symptoms, smoking cessation, and patient interval were important factors, the number of cigarettes smoked per day, motorbike ownership, and physical examination exhibited the strongest associations with the clinical stage of NPC at diagnosis. Compared with smoking fewer than ten cigarettes a day, smoking 10-30 cigarettes [odds ratio (OR) 4.03; 95% confidence interval (CI) 1.11-14.68] or more than 30 cigarettes (OR 11.46; 95% CI 1.26-103.91) was associated with an increased risk of late diagnosis. Compared with not owning a motorbike, owning a motorbike (OR 0.38; 95% CI 0.23-0.64) was associated with early diagnosis. Subjects who underwent physical examinations were less likely to receive a late diagnosis than those who did not undergo examinations (OR 0.50; 95% CI 0.28-0.89). However, indicators of wealth were not significant factors. CONCLUSIONS: Initiatives to improve NPC patient prognosis should aim to promote knowledge about early symptoms and detection, health awareness, and accessibility to health facilities among all patients, regardless of socioeconomic status. PMID- 28870230 TI - Pre-pregnancy weight, gestational weight gain, and the gut microbiota of mothers and their infants. AB - BACKGROUND: Recent evidence supports that the maternal gut microbiota impacts the initial infant gut microbiota. Since the gut microbiota may play a causal role in the development of obesity, it is important to understand how pre-pregnancy weight and gestational weight gain (GWG) impact the gut microbiota of mothers at the time of delivery and their infants in early life. In this study, we performed 16S rRNA gene sequencing on gut microbiota samples from 169 women 4 days after delivery and from the 844 samples of their infants at six timepoints during the first 2 years of life. We categorized the women (1) according to pre-pregnancy body mass index into overweight/obese (OW/OB, BMI >= 25) or non-overweight/obese (BMI < 25) and (2) into excessive and non-excessive GWG in the subset of mothers of full-term singleton infants (N = 116). We compared alpha diversity and taxonomic composition of the maternal and infant samples by exposure groups. We also compared taxonomic similarity between maternal and infant gut microbiota. RESULTS: Maternal OW/OB was associated with lower maternal alpha diversity. Maternal pre-pregnancy OW/OB and excessive GWG were associated with taxonomic differences in the maternal gut microbiota, including taxa from the highly heritable family Christensenellaceae, the genera Lachnospira, Parabacteroides, Bifidobacterium, and Blautia. These maternal characteristics were not associated with overall differences in the infant gut microbiota over the first 2 years of life. However, the presence of specific OTUs in maternal gut microbiota at the time of delivery did significantly increase the odds of presence in the infant gut at age 4-10 days for many taxa, and these included some lean-associated taxa. CONCLUSIONS: Our results show differences in maternal gut microbiota composition at the time of delivery by pre-pregnancy weight and GWG, but these changes were only associated with limited compositional differences in the early life gut microbiota of their infants. Further work is needed to determine the degree to which these maternal microbiota differences at time of birth with OW/OB and GWG may affect the health of the infant over time and by what mechanism. PMID- 28870232 TI - HIV treatment cascade among female entertainment and sex workers in Cambodia: impact of amphetamine use and an HIV prevention program. AB - BACKGROUND: HIV prevalence remains high in Cambodia among female entertainment and sex workers (FESW), and amphetamine-type stimulant (ATS) use significantly increases risk of infection. A successful continuum of care (CoC) is key to effective clinical care and prevention. This study aimed to describe the HIV CoC in HIV-positive FESW. We examined CoC outcomes among HIV-positive FESW participating in the Cambodia Integrated HIV and Drug Prevention Implementation (CIPI) study, being implemented in ten provinces. CIPI is a trial aimed at reducing ATS use concomitant with the SMARTgirl HIV prevention program. METHODS: From 2013 to 2016, 1198 FESW >= 18 years old who reported multiple sex partners and/or transactional sex were recruited. We identified 88 HIV-positive women at baseline. We described linkage to care as 12-month retention and viral suppression (<1000 copies/mL). Logistic regression analyses were conducted to examine correlates of retention in care at 12 months, and viral suppression. RESULTS: Median age of the 88 HIV-positive women was 32 years [interquartile range (IQR) 28, 35]; 50% were working in entertainment venues and 50% as freelance sex workers; 70% reported SMARTgirl membership. In the past 3 months, women reported a median of 15 sex partners, 38% reported unprotected sex, and 55% reported using ATS. Overall, 88% were receiving HIV care, 83% were on antiretroviral therapy, 39% were retained in care at 12 months, and 23% were virally suppressed. SMARTgirl membership was independently associated with fourfold greater odds of 12-month retention in care (AOR = 4.16, 95% CI 1.38, 12.56). Those at high risk for an ATS use disorder had 91% lower odds of 12-month retention in care (AOR = 0.09, 95% CI 0.01, 0.72). Viral suppression was independently associated with SMARTgirl membership, older age, reporting of STI symptoms, worse symptoms of psychological distress, and greater numbers of sex partners. CONCLUSIONS: This is the first study to characterize the HIV CoC in Cambodian FESW. While most women were successfully linked to HIV care, retention and viral suppression were low. Tailored programs like SMARTgirl, targeting the broader population of HIV-positive FESW as well as interventions to reduce ATS use could optimize the clinical and population health benefits of HIV treatment. Trial registration This work reports data collected as part of a trial: NCT01835574. This work does not present trial results. PMID- 28870233 TI - Free fatty acids profile among lean, overweight and obese non-alcoholic fatty liver disease patients: a case - control study. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) given its association with obesity and diabetes may perhaps exert distinct free fatty acids (FFA) pattern, but the understanding of this phenomenon is limited. To this effect, we evaluated FFA profiles among healthy subjects and NAFLD patients stratified by body weight, to identify FFA valuable for early diagnosis of NAFLD. METHODS: Serum FFA profiles of healthy and NAFLD (lean, overweight and obese) subjects was determined using gas chromatography-mass spectrometry (GC-MS) and distinctions in FFA patterns were evaluated using one-way ANOVA while Receiver operating characteristics (ROC) and logistic regression models were used to explore FFA significant for diagnosing NAFLD. RESULTS: NAFLD patients presented significantly higher (P < 0.05) serum FFA profiles compared to healthy controls (HC). While total FFA profiles were insignificantly different between lean (2093.33 +/- 558.11 MUg/ml) and overweight (2420.81 +/- 555.18 MUg/ml) NAFLD patients, obese NAFLD (2739.01 +/- 810.35 MUg/ml) presented most significantly elevated (P < 0.05) total FFA profiles compared with HC. Of the four FFA; myristic acid (14:0), palmitoleic acid (16:1), gamma-linolenic acid (gamma-18:3) and cis-7,10,13,16,19 docosapentaenoic acid (22:5), selected in ROC analysis given their high Youden's index and AUC, only 14:0; 5.58(1.37, 22.76) and 16:1; 4.36(1.34, 14.13) had statistical significant odd ratios. CONCLUSION: Our findings suggest 14:0 and 16:1 are promising for early diagnosis of NAFLD. PMID- 28870231 TI - WNT signaling - lung cancer is no exception. AB - Since the initial discovery of the oncogenic activity of WNT ligands our understanding of the complex roles for WNT signaling pathways in lung cancers has increased substantially. In the current review, the various effects of activation and inhibition of the WNT signaling pathways are summarized in the context of lung carcinogenesis. Recent evidence regarding WNT ligand transport mechanisms, the role of WNT signaling in lung cancer angiogenesis and drug transporter regulation and the importance of microRNA and posttranscriptional regulation of WNT signaling are also reviewed. PMID- 28870235 TI - Soy isoflavones inducing overt hypothyroidism in a patient with chronic lymphocytic thyroiditis: a case report. AB - BACKGROUND: Many people have thyroid conditions that make them susceptible to hypothyroidism. If the foods they eat may interfere with the production of thyroid hormone, which can lead to development of serious hypothyroidism. The danger of health drinks should always be noted. CASE PRESENTATION: A 72-year-old Japanese woman was previously diagnosed with chronic lymphocytic thyroiditis caused by a goiter and had an elevated thyroid-stimulating hormone level (6.56 MUIU/ml), a high anti-thyroid peroxidase antibody level (>600 IU/ml), and a high antithyroglobulin level (> 4000 IU/ml) but normal levels of free triiodothyronine (3.08 pg/ml) and thyroxine (1.18 ng/ml). She presented to our hospital with sudden-onset general malaise, edema, and hoarseness with an elevated thyroid stimulating hormone (373.3 MUIU/ml) level and very low triiodothyronine (< 0.26 pg/ml) and thyroxine (0.10 ng/ml) levels. It was determined that for 6 months she had been consuming a processed, solved health drink ("barley young leaf") in amounts of 9 g/day, which included soybean and kale powder extract. Hypothyroidism might be affected by ingredients of health drinks. She discontinued consumption of the health drink immediately and began taking 12.5 MUg of levothyroxine. The amount of levothyroxine was gradually increased every 3 days up to 100 MUg. At day 61, her thyroid-stimulating hormone level had decreased (6.12 MUIU/ml), her free triiodothyronine (2.69 pg/ml) and thyroxine (1.56 ng/ml) levels had increased, and her general condition was improved. Among risky foods lowering thyroid function, some experimental studies have revealed that isoflavones reduce thyroid function. Therefore, we measured the presence of isoflavones in the patient's frozen serum with thin-layer chromatography. After she discontinued consumption of the health drink, two components quickly disappeared, and the other three components gradually decreased. On the basis of developing solvent composition and a positive ferric chloride reaction in thin layer chromatography experiment, the five ingredients that disappeared or decreased were highly suspected to be soy isoflavones. CONCLUSIONS: This case emphasizes that consuming health drinks that include soy isoflavone powder extracts can lead to severe hypothyroidism. PMID- 28870234 TI - Collection of non-meconium stool on fecal occult blood cards is an effective method for fecal microbiota studies in infants. AB - BACKGROUND: Effective methods are needed to collect fecal samples from children for large-scale microbiota studies. Stool collected on fecal occult blood test (FOBT) cards that can be mailed provides an effective solution; however, the quality of sequencing resulting from this method is unknown. The aim of this study is to compare microbiota metrics of 16S ribosomal RNA (rRNA) gene sequencing from stool and meconium collected on FOBT cards with stool collected in an Eppendorf tube (ET) under different conditions. METHODS: Eight stool samples from children in diapers aged 0 month-2 years and three meconium samples were collected and stored as follows: (1) <= 2 days at room temperature (RT) in an ET, (2) 7 days at - 80 degrees C in an ET, (3) 3-5 days at RT on a FOBT card, (4) 7 days at RT on a FOBT card, and (5) 7 days at - 80 degrees C on a FOBT card. Samples stored at - 80 degrees C were frozen immediately. Each specimen/condition underwent 16S rRNA gene sequencing with replicates on the Illumina MiSeq. Alpha and beta diversity measures and relative abundance of major phyla were compared between storage conditions and container (ET vs. FOBT card), with pairwise comparison between different storage conditions and the "standard" of 7 days at - 80 degrees C in an ET and fresh stool in an ET. RESULTS: Stool samples clustered mainly by individual diaper (P < 10-5, Adonis), rather than by storage condition (P = 0.42) or container (P = 0.16). However, meconium samples clustered more by container (P = 0.002) than by individual diaper (P = 0.009) and storage condition (P = 0.02). Additionally, there were no differences in alpha diversity measures and relative abundance of major phyla after Bonferroni correction between stool stored on a FOBT card at RT for 7 days with stool stored in an ET tube at - 80 degrees C; differences in alpha diversity were seen however when compared to fresh stool in an ET. Overall, based on the intraclass correlation coefficient (ICC), the different storage containers/conditions are reliable in preserving the microbial memberships and slightly less reliable in preserving the alpha diversity and relative microbial composition of infant stool. CONCLUSIONS: Acknowledging certain limitations, FOBT cards may be a useful tool in large-scale stool microbiota studies in children requiring outpatient follow-up where only small amounts of stool can be obtained, but should not be used when studying meconium. PMID- 28870236 TI - Acquired Hemophilia A in an advanced age patient of hispanic origin: a case report. AB - BACKGROUND: Acquired Hemophilia A (AHA) is a rare hematological disorder that exhibits an incidence of approximately 1.5 cases per million patients a year. It is characterized by the development of autoantibodies against circulating Factor VIII coagulation proteins which, in turn, which in turn lead to potentially life threatening hemorrhagic episodes. The incidence of AHA increases with age; with 80% of the affected patient population encompassing men and women that are 65 years or older. Some of the challenges that are highlighted in managing this disorder relate to the delayed diagnosis of this condition due to the rarity of the latter, the difficulty in establishing reliable hemostasis, and the secondary complications that are found when using immunosuppressive and hemostatic treatments in tandem with the elderly population afflicted with this disease. CASE PRESENTATION: A 90-year-old female of Hispanic origin presented with a 2 week history of generalized weakness, dizziness, shortness of breath and extensive purpuric formations that involved the left arm towards the lateral aspect of the thorax with the inclusion of a small right lateral neck hematoma formation. Upon initial laboratory screening, a hemoglobin level of 7.9, a hematocrit level of 21.9 and a PTT value of 70.9 were discovered. Despite conventional hemostatic treatment approaches, the patient did not show marked improvement of the laboratory values. Ongoing specialized laboratory reports, combined with the clinical presentation of the patient, led to the diagnosis of Acquired Hemophilia A. Treatment with recombinant porcine Factor VIII was initiated, which led to rapid improvement of clinical symptoms and laboratory values. The patient was discharged with current treatment plan and emergent follow/up with a hematologist was scheduled. CONCLUSION: Acquired Hemophilia A is an elusive bleeding disorder that has been seldom encountered in the demographics of Puerto Rico. The prompt detection of this diagnosis based on the clinical presentation alone is paramount to prevent the occurrence of grave hemorrhagic episodes. General knowledge and awareness of the treatment options available is key to ameliorate the prognosis of this ailment. PMID- 28870237 TI - The N- and C-terminal carbohydrate recognition domains of Haemonchus contortus galectin bind to distinct receptors of goat PBMC and contribute differently to its immunomodulatory functions in host-parasite interactions. AB - BACKGROUND: Hco-gal-m is a tandem-repeat galectin isolated from the adult worm of Haemonchus contortus. A growing body of studies have demonstrated that Hco-gal-m could exert its immunomodulatory effects on host peripheral blood mononuclear cells (PBMC) to facilitate the immune evasion. Our previous work revealed that C terminal and N-terminal carbohydrate recognition domains (CRD) of Hco-gal-m had different sugar binding abilities. However, whether different domains of Hco-gal m account differently for its multiple immunomodulatory functions in the host parasite interaction remains to be elucidated. RESULTS: We found that the N terminal CRD of Hco-gal-m (MNh) and the C-terminal CRD (MCh) could bind to goat peripheral blood mononuclear cells by distinct receptors: transmembrane protein 63A (TMEM63A) was a binding receptor of MNh, while transmembrane protein 147 (TMEM147) was a binding receptor of MCh. In addition, MCh was much more potent than MNh in inhibiting cell proliferation and inducing apoptosis, while MNh was much more effective in inhibiting NO production. Moreover, MNh could suppress the transcription of interferon-gamma (IFN-gamma), but MCh not. CONCLUSIONS: Our data suggested that these two CRDs of Hco-gal-m bind to distinct receptors and contributed differently to its ability to downregulate host immune response. These results will improve our understanding of galectins from parasitic nematodes contributing to the mechanism of parasitic immune evasion and continue to illustrate the diverse range of biological activities attributable to the galectin family. PMID- 28870239 TI - Evaluating somatic tumor mutation detection without matched normal samples. AB - BACKGROUND: Observations of recurrent somatic mutations in tumors have led to identification and definition of signaling and other pathways that are important for cancer progression and therapeutic targeting. As tumor cells contain both an individual's inherited genetic variants and somatic mutations, challenges arise in distinguishing these events in massively parallel sequencing datasets. Typically, both a tumor sample and a "normal" sample from the same individual are sequenced and compared; variants observed only in the tumor are considered to be somatic mutations. However, this approach requires two samples for each individual. RESULTS: We evaluate a method of detecting somatic mutations in tumor samples for which only a subset of normal samples are available. We describe tuning of the method for detection of mutations in tumors, filtering to remove inherited variants, and comparison of detected mutations to several matched tumor/normal analysis methods. Filtering steps include the use of population variation datasets to remove inherited variants as well a subset of normal samples to remove technical artifacts. We then directly compare mutation detection with tumor-only and tumor-normal approaches using the same sets of samples. Comparisons are performed using an internal targeted gene sequencing dataset (n = 3380) as well as whole exome sequencing data from The Cancer Genome Atlas project (n = 250). Tumor-only mutation detection shows similar recall (43 60%) but lesser precision (20-21%) to current matched tumor/normal approaches (recall 43-73%, precision 30-82%) when compared to a "gold-standard" tumor/normal approach. The inclusion of a small pool of normal samples improves precision, although many variants are still uniquely detected in the tumor-only analysis. CONCLUSIONS: A detailed method for somatic mutation detection without matched normal samples enables study of larger numbers of tumor samples, as well as tumor samples for which a matched normal is not available. As sensitivity/recall is similar to tumor/normal mutation detection but precision is lower, tumor-only detection is more appropriate for classification of samples based on known mutations. Although matched tumor-normal analysis is preferred due to higher precision, we demonstrate that mutation detection without matched normal samples is possible for certain applications. PMID- 28870238 TI - BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells. AB - BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD. METHODS: We screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures. RESULTS: Our screens identified several classes of molecules that include inhibitors of the bromodomain and extra-terminal (BET) family of proteins and agonists of the beta-2 adrenergic receptor. Further studies showed that compounds from these two classes suppress the expression of DUX4 messenger RNA (mRNA) by blocking the activity of bromodomain-containing protein 4 (BRD4) or by increasing cyclic adenosine monophosphate (cAMP) levels, respectively. CONCLUSIONS: These data uncover pathways involved in the regulation of DUX4 expression in somatic cells, provide potential candidate classes of compounds for FSHD therapeutic development, and create an important opportunity for mechanistic studies that may uncover additional therapeutic targets. PMID- 28870240 TI - Neuron-derived CCL2 contributes to microglia activation and neurological decline in hepatic encephalopathy. AB - BACKGROUND: CCL2 was up-regulated in neurons and involved in microglia activation and neurological decline in mice suffering from hepatic encephalopathy (HE). However, no data exist concerning the effect of neuron-derived CCL2 on microglia activation in vitro. METHODS: The rats were pretreated with CCL2 receptor inhibitors (INCB or C021, 1 mg/kg/day i.p.) for 3 days prior to thioacetamide (TAA) administration (300 mg/kg/day i.p.) for inducing HE model. At 8 h following the last injection (and every 4 h after), the grade of encephalopathy was assessed. Blood and whole brains were collected at coma for measuring CCL2 and Iba1 expression. In vitro, primary neurons were stimulated with TNF-alpha, and then the medium were collected for addition to microglia cultures with or without INCB or C021 pretreatment. The effect of the medium on microglia proliferation and activation was evaluated after 24 h. RESULTS: CCL2 expression and microglia activation were elevated in the cerebral cortex of rats received TAA alone. CCL2 receptors inhibition improved neurological score and reduced cortical microglia activation. In vitro, TNF-alpha treatment induced CCL2 release by neurons. Medium from TNF-alpha stimulated neurons caused microglia proliferation and M1 markers expression, including iNOS, COX2, IL-6 and IL-1beta, which could be suppressed by INCB or C021 pretreatment. The medium could also facilitate p65 nuclear translocation and IkappaBalpha phosphorylation, and NF-kappaB inhibition reduced the increased IL-6 and IL-1beta expression induced by the medium. CONCLUSION: Neuron-derived CCL2 contributed to microglia activation and neurological decline in HE. Blocking CCL2 or inhibiting microglia excessive activation may be potential strategies for HE. PMID- 28870241 TI - Intestinal helminthic infection and anemia among pregnant women attending ante natal care (ANC) in East Wollega, Oromia, Ethiopia. AB - BACKGROUND: Ethiopia is a developing country where intestinal helminthic infections are major public health problems. The burden of intestinal parasites, particularly the soil-transmitted helminths (STHs), is often very high in school children and pregnant women. Anemia, associated with STH, is a major factor in women's health, especially during pregnancy; it is an important contributor to maternal mortality. The aim of this study was to determine the prevalence of intestinal helminthic infection and anemia among pregnant women attending ANC in East Wollega Zone, Ethiopia. METHODS: A cross-sectional study was conducted in five health centers of East Wollega Zone of Oromia Region, Ethiopia between November 2015 and January 2016. The health centers were selected randomly and study participants were enrolled consecutively with proportions from all the health centers. Stool and blood specimens were processed using standard operating procedures in accordance with structured questionnaires. Logistic regression models were applied to assess the association between predictors and outcome variables. P values less than 0.05 were taken as significant levels. Results were presented in tables and figures. RESULTS: A total of 372 pregnant women were enrolled in this study with a median age of 25 years (range 17-40 years). The total prevalence of intestinal helminths was 24.7% (92/372) with the predominance of Hookworm (15.1%) followed by Ascaris lumbricoides (6.5%). Illiteracy [AOR, 95% CI 2.21 (1.3, 4.8), P = 0.042], absence of latrine [AOR, 95% CI 4.62 (1.7, 8.3), P = 0.013] and regular consumption of raw and/or unwashed fruit [AOR, 95% CI 3.30 (1.2, 6.3), P = 0.011] were significant predictors of intestinal helminthic infection. The overall prevalence of anemia was 17.5% (65/372) where mild anemia accounts for 80% of the total anemia. Anemia was significantly associated with the first trimester of gestation [AOR, 95% CI 2.82 (1.3, 6.2), P = 0.009], previous malaria infection [AOR, 95% CI 2.32 (1.3, 5.3), P = 0.003], failing to take iron supplements regularly [AOR, 95% CI 1.82 (1.1, 4.8), P = 0.022] and infection with intestinal helminths specifically with Hookworm (P = 0.001) and Ascaris lumbricoides (P = 0.022). CONCLUSION: The prevalence of intestinal helminths and anemia was significantly high in this study. Different socio demographic, lifestyle and obstetric factors were identified as significant contributors of intestinal helminthic infection and anemia among pregnant women. Therefore, public health measures and intensive antenatal care services are vital to promoting safe pregnancy. PMID- 28870242 TI - Intraoperative wound irrigation to prevent surgical site infection after laparotomy (IOWISI): study protocol for a randomized controlled trial. AB - BACKGROUND: Postoperative surgical site infection (SSI) is one of the most common hospital infections and contributes substantially to postoperative morbidity and mortality. In addition, SSIs dramatically increase the treatment cost and length of hospital stay. Following visceral surgery by laparotomy, SSI rates are especially high (14-25%). Therefore, measures to prevent SSI in this field are urgently needed. Prophylactic intraoperative wound irrigation (IOWI) of the subcutaneous soft tissue before skin closure hypothetically represents an easy and economical option to reduce SSI rates and is already frequently used in clinical practice. However, there are currently no definite recommendations on the use of IOWI since high-level evidence supporting its use is lacking. Consequently, clinical practice varies widely. Antiseptic polyhexanide (PHX) based solutions are approved for soft-tissue wound irrigation in surgery but have not been specifically evaluated in randomized clinical trials for the prevention of SSI following laparotomy for visceral surgery. METHODS/DESIGN: The IOWISI trial is a multicentre, randomized, observer- and patient-blinded clinical trial with three parallel treatment groups, comparing IOWI with a 0.04% PHX solution to no irrigation (test 1) or saline (test 2) before skin closure after laparotomy for visceral surgery (contamination level II-IV). The primary endpoint of the trial is the SSI rate within 30 days postoperatively. Statistical analysis of the primary endpoint measure will be based on the intention-to-treat population. The global level of significance is set at 2.5% for test 1 and 5% for test 2 and the sample size (n = 540) is determined to assure a power of 94% (test 1) and 85% (test 2). DISCUSSION: The IOWISI trial will provide high-level evidence as a basis for clinical recommendations regarding the use of IOWI with PHX or saline and will potentially impact on future clinical guidelines and practice. The pragmatic trial design guarantees high external validity. TRIAL REGISTRATION: Registered at the German Clinical Trials Register, DRKS00012251 . Registered on 3 July 2017. PMID- 28870243 TI - Human fascioliasis by Fasciola hepatica: the first case report in Nepal. AB - BACKGROUND: Fascioliasis is a zoonotic disease caused by Fasciola species. Patient may be asymptomatic or presents with jaundice and biliary colic or right hypochondriac pain due to bile duct obstruction with gastrointestinal symptoms. CASE PRESENTATION: We report a case of human fascioliasis in a 45 years old female presented to Tribhuvan University Teaching Hospital (TUTH), Kathmandu, Nepal on August, 2015 with fever, right hypochondriac pain, jaundice and occasional vomiting with anorexia for 4 months whose alkaline phosphatase was elevated and peripheral blood smear revealed eosinophilia. The patient also gives the history of consumption of water-cress. Endoscopic Retrograde Cholagiopancretography (ERCP) showed the presence of a flat worm resembling Fasciola hepatica and stool routine examination revealed ova of F. hepatica. The patient was treated with nitazoxanide by which she got improved. Repeat stool examination 2 weeks after treatment revealed no ova of F. hepatica. CONCLUSIONS: Patient with fascioliasis can be simply diagnosed with stool routine microscopy and treated with nitazoxanide. So patient with right hypochondriac pain, sign and symptoms of obstructive jaundice, eosinophilia and history of water-cress consumption should be suspected for fascioliasis and investigated and treated accordingly. PMID- 28870244 TI - Review of "Echinococcus and Echinococcosis, Part A." edited by R. C. Andrew Thompson, Alan J. Lymbery and Peter Deplazes. AB - BOOK DETAILS: Thompson RCA, Deplazes P, Lymbery AJ, Editors. Echinococcus and Echinococcosis, Part A. Volume 95, Advances in Parasitology 95. Academic Press; 2017. 525 pages, ISBN 978-0-12-8114711 (hardcover); 9780128114728 (eBook). PMID- 28870246 TI - Determinants of psychoactive substances use among Woldia University students in Northeastern Ethiopia. AB - BACKGROUND: Psychoactive substance use has become a major public health problem among students in Ethiopian universities. Hence, this study aimed to investigate the magnitude and determinants of psychoactive substances use (khat chewing, alcohol drinking and cigarette smoking) among undergraduate students of Woldia University, Ethiopia. METHODS: Institution based quantitative cross-sectional study was employed on Woldia University students in April 2015. 730 students were included in the study. Data were collected using self-administered questionnaires. EpiData version 3.02 was used to enter data. Then, data were exported to SPSS version 20 for analysis. RESULTS: The lifetime prevalence of alcohol drinking, khat chewing and cigarette smoking among the study students were 33.1, 13 and 7.9%, respectively. Likewise, the current prevalence of alcohol drinking, khat chewing and cigarette smoking was 27.9, 10.4 and 6.4%, respectively. More than half of the surveyed students (59.1%) were introduced to psychoactive substance use by peer pressure. About 66% of the study participants believed that psychoactive substances are important for relaxation, and 19% to relief from stress. Students who were Muslims [adjusted odds ratio (AOR) 3.74, 95% CI (1.57, 8.91)], Oromo ethnic group [AOR 2.63, 95% CI (1.19, 5.81)], ever drunk alcohol [AOR 6.32, 95% CI (2.96, 13.48)] and ever smoked cigarette [AOR: 9.16, 95% CI (4.33, 19.38)] were positively associated with khat chewing. Furthermore, pocket money and ever khat chewing were associated with alcohol drinking and cigarette smoking. CONCLUSION: This study showed that psychoactive substances use is somewhat prevalent among students in Woldia University. Hence, support of religious institutions in providing education aimed at preventing substance use, establishing and strengthening peer educators in the university are important interventions to tackle psychoactive substances use. PMID- 28870245 TI - Mice overexpressing growth hormone exhibit increased skeletal muscle myostatin and MuRF1 with attenuation of muscle mass. AB - BACKGROUND: In contrast to the acute effects of growth hormone (GH) on skeletal muscle protein synthesis, long-term GH treatment appears to have negligible effects on muscle mass. Despite this knowledge, little is known regarding the chronic effects of GH on skeletal muscle protein synthesis and atrophy signaling pathways. The purpose of this study was to determine if protein synthesis pathways are attenuated and/or muscle atrophy intracellular signaling pathways are altered in the skeletal muscle of transgenic bovine GH (bGH) mice. METHODS: The gastrocnemius and soleus from 5-month-old male bGH mice (n = 9) and wild type (WT) controls (n = 9) were harvested and analyzed for proteins involved in the protein synthesis (Akt/mTOR), growth and proliferation (MAPK), and muscle atrophy (MuRF1 and myostatin) pathways. RESULTS: Total body mass was significantly increased in bGH mice compared to WT controls (49%, P < 0.0001). When expressed relative to total body mass, the gastrocnemius (- 28%, P < 0.0001), but not the soleus, was significantly lower in mice overexpressing GH, compared to controls. Transgenic bGH mice had elevated phosphorylation levels of protein kinase b (Akt1), 4E-binding protein 1 (4E-BP1), p70 S6 kinase, p42/44, and p38 (P < 0.05) compared to WT littermates. Mature myostatin (26 kDa), premature myostatin (52 kDa), and activin receptor type IIB (AcvR2B) protein levels were increased in bGH mice (P < 0.05), along with elevated phosphorylation levels of mothers against decapentaplegic homolog (Smad2) (59%, P < 0.0001). Mice overexpressing GH had increased MuRF1 expression (30%, P < 0.05) and insulin receptor substrate 1 (IRS1) serine phosphorylation (44%, P < 0.05) in the gastrocnemius, but not the soleus, when compared to controls. CONCLUSIONS: These findings demonstrate that chronic elevations in circulating GH have a critical impact on signaling pathways involved in skeletal muscle protein synthesis and atrophy, and suggest that MuRF1, myostatin, and IRS1 serine phosphorylation may act to inhibit exaggerated glycolytic muscle growth, in environments of chronic GH/IGF-1 excess. PMID- 28870247 TI - Seropositivity for Trypanosoma cruzi in domestic dogs from Sonora, Mexico. AB - BACKGROUND: Chagas disease is an important health problem in Latin America due to its incapacitating effects and associated mortality. Studies on seropositivity for Trypanosoma cruzi in Mexican dogs have demonstrated a direct correlation between seropositivity in humans and dogs, which can act as sentinels for the disease in this region. The objective of this study was to determine the seropositivity for T.cruzi infection in dogs from Sonora, a northern borderstate of Mexico. METHODS: Responsible pet owners were selected at random from an urban area of Empalme municipality, Sonora, Mexico, and from there, 180 dog samples were collected. Anti-T. cruzi antibodies were determined using the enzyme-linked immunosorbent assay (ELISA) method. Reactive ELISA sera were processed by indirect immunofluorescence to confirm the presence of anti-T. cruzi antibodies. For the statistical analysis, chi-square tests were conducted. RESULTS: Dogs' sera showed a seropositivity rate of 4.44%. The rate of seropositivity was not associated with the dogs' age, sex, or socioeconomics pertaining to the geographical area. One sample (1/180, 0.55%) showed the acute state of the disease. CONCLUSIONS: The study found a presence of anti-T. cruzi antibodies in dogs in this area, which suggests vector transmission. There is a need for active surveillance programs throughout the state of Sonora and vector control strategies should also be implemented in endemic regions. PMID- 28870248 TI - Functional and quality of life outcomes after partial glossectomy: a multi institutional longitudinal study of the head and neck research network. AB - BACKGROUND: While aggressive treatment for oral cancer may optimize survival, decrements in speech and swallowing function and quality of life often result. This exploratory study investigated how patients recover their communicative function, swallowing ability, and quality of life after primary surgery [with or without adjuvant (chemo)radiation therapy] for tongue cancer over the course of the first year post-operation. METHODS: Patients treated for oral cancer at three institutions (University of Alberta Hospital, Mount Sinai Beth Israel Medical Center, and Turku University Hospital) were administered patient-reported outcomes assessing speech [Speech Handicap Index (SHI)], swallowing [(M.D. Anderson Dysphagia Inventory (MDADI)] and quality of life [European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module (EORTC-H&N35)]. Outcome measures were completed pre-operatively and at 1-, 6-, and 12-months post-operatively. RESULTS: One hundred and seventeen patients undergoing partial glossectomy with reconstruction participated in this study. Results indicated no significant differences in swallowing function (MDADI and EORTC-H&N35 subscales) between baseline and 6 months post-surgery and no significant differences in speech function (SHI subscales) between baseline and 1 year post-surgery. Most quality of life domains (EORTC-H&N35 subscales) returned to baseline levels by 1 year post-operation, while difficulties with dry mouth and sticky saliva persisted. A clear time trend of adjuvant (chemo)radiation therapy negatively affecting dry mouth scores over time was identified in this study, while negative independent effects of chemoradiation on MDADI swallowing, and EORTC-H&N35 swallowing, eating, and opening mouth subscales were found. CONCLUSIONS: Assessment time influenced patient-reported speech, swallowing, and quality of life outcomes, while treatment (by time) effects were found for only swallowing and quality of life outcomes. Results of the present study will help guide clinical care and will be useful for patient counseling on expected short and long-term functional and quality of life outcomes of surgical and adjuvant treatment for oral cavity cancer. PMID- 28870249 TI - Improving Emergency Department radiology transportation time: a successful implementation of lean methodology. AB - BACKGROUND: Emergency Department overcrowding has become a global problem and a growing safety and quality concern. Radiology and laboratory turnaround time, ED boarding and increased ED visits are some of the factors that contribute to ED overcrowding. Lean methods have been used in the ED to address multiple flow challenges from improving door-to-doctor time to reducing length of stay. The objective of this study is to determine the effectiveness of using Lean management methods on improving Emergency Department transportation times for plain radiography. METHODS: We performed a before and after study at an academic urban Emergency Department with 49,000 annual visits after implementing a Lean driven intervention. The primary outcome was mean radiology transportation turnaround time (TAT). Secondary outcomes included overall study turnaround time from order processing to preliminary report time as well as ED length of stay. All ED patients undergoing plain radiography 6 months pre-intervention were compared to all ED patients undergoing plain radiography 6 months post intervention after a 1 month washout period. RESULTS: Post intervention there was a statistically significant decrease in the mean transportation TAT (mean +/- SD: 9.87 min +/- 15.05 versus 22.89 min +/- 22.05, respectively, p-value <0.0001). In addition, it was found that 71.6% of patients in the post-intervention had transportation TAT <= 10 min, as compared to 32.3% in the pre-intervention period, p-value <0.0001, with narrower interquartile ranges in the post intervention period. Similarly, the "study processing to preliminary report time" and the length of stay were lower in the post-intervention as compared to the pre intervention, (52.50 min +/- 35.43 versus 54.04 min +/- 34.72, p-value = 0.02 and 3.65 h +/- 5.17 versus 4.57 h +/- 10.43, p < 0.0001, respectively), in spite of an increase in the time it took to elease a preliminary report in the post intervention period. CONCLUSION: Using Lean change management techniques can be effective in reducing transportation time to plain radiography in the Emergency Department as well as improving process reliability. PMID- 28870250 TI - Moon phases and moon signs do not influence morbidity, mortality and long-term survival, after living donor kidney transplantation. AB - BACKGROUND: Approximately 11% of the German population are convinced that certain moon phases and moon signs may impact their health and the onset and clinical course of diseases. Before elective surgery, a considerable number of patients look to optimize the timing of the procedure based on the lunar cycle. Especially patients awaiting living donor kidney transplantation (LDKT) commonly look for an adjustment of the date of transplantation according to the moon calendar. This study therefore investigated the perioperative and long-term outcome of LDKT dependent on moon phases and zodiac signs. METHODS: Patient data were prospectively collected in a continuously updated kidney transplant database. Two hundred and seventy-eight consecutive patients who underwent LDKT between 1994 and December 2009 were selected for the study and retrospectively assigned to the four moon phases (new-moon, waxing-moon, full-moon, and waning-moon) and the corresponding zodiac sign (moon sign Libra), based on the date of transplantation. Preexisting comorbidities, perioperative mortality, surgical outcome, and long-term survival data were analyzed. RESULTS: Of all LDKT procedures, 11.9, 39.9, 11.5, and 36.5% were performed during the new, waxing, full, and waning moon, respectively, and 6.2% during the moon sign Libra, which is believed to interfere with renal surgery. Survival rates at 1, 5, and 10 years after transplantation were 98.9, 92, and 88.7% (patient survival) and 97.4, 91.6, and 80.6% (graft survival) without any differences between all groups of lunar phases and moon signs. Overall perioperative complications and early graft loss occurred in 21.2 and 1.4%, without statistical difference (p > 0.05) between groups. CONCLUSION: Moon phases and the moon sign Libra had no impact on early and long-term outcome measures following LDKT in our study. Thus, concerns of patients awaiting LDKT regarding the ideal time of surgery can be allayed, and surgery may be scheduled independently of the lunar phases. PMID- 28870251 TI - HIV-1 tolerates changes in A-count in a small segment of the pol gene. AB - BACKGROUND: The HIV-1 RNA genome has a biased nucleotide composition with a surplus of As. Several hypotheses have been put forward to explain this striking phenomenon, but the A-count of the HIV-1 genome has thus far not been systematically manipulated. The reason for this reservation is the likelihood that known and unknown sequence motifs will be affected by such a massive mutational approach, thus resulting in replication-impaired virus mutants. We present the first attempt to increase and decrease the A-count in a relatively small polymerase (pol) gene segment of HIV-1 RNA. RESULTS: To minimize the mutational impact, a new mutational approach was developed that is inspired by natural sequence variation as present in HIV-1 isolates. This phylogeny instructed mutagenesis allowed us to create replication-competent HIV-1 mutants with a significantly increased or decreased local A-count. The local A-count of the wild-type (wt) virus (40.2%) was further increased to 46.9% or reduced to 31.7 and 26.3%. These HIV-1 variants replicate efficiently in vitro, despite the fact that the pol changes cause a quite profound move in HIV-SIV sequence space. CONCLUSIONS: Extrapolating these results to the complete 9 kb RNA genome, we may cautiously suggest that the A-rich signature does not have to be maintained. This survey also provided clues that silent codon changes, in particular from G-to-A, determine the subtype-specific sequence signatures. PMID- 28870252 TI - Change in serum level of vitamin D and associated factors at early phase of bone healing among fractured adult patients at University of Gondar teaching hospital, Northwest Ethiopia: a prospective follow up study. AB - INTRODUCTION: Currently, Vitamin D deficiency is a major public health problem and it affects more than one billion people worldwide. Vitamin D is crucial for bone mineralization and ossification. Patients with fractures need Vitamin D for the healing of their fractured bone. The current study was carried out to determine if there is change in the serum level of Vitamin-D associated with factors at early phase of fractured bone healing (ossification) process among adult fractured patients at University of Gondar teaching hospital, Northwest Ethiopia. METHODS: This facility-based prospective follow up study was conducted from March to June 2016. Data was collected by an interviewer, and pretested and structured questionnaires were used. Biological samples were collected to determine the serum level of vitamin-D in all subjects. In addition, X-Ray findings were used to determine the early phase of bone healing process. Data was entered into EPI INFO version 3.5.3 and analyzed using the Statistical Package for Social Sciences (SPSS) version 20. Both bivariate and multivariate logistic regression analysis was done to screen for factors associated with decreased serum levels of Vitamin-D. In the Multivariate regression analysis, those variables which had a P-value of <0.05 were considered as independently associated with change in serum level of Vitamin-D. RESULTS: A total of 118 adult patients with fractures participated in this study. The prevalence of patients' with decreased serum levels of vitamin-D at post-test was 63.6% [95% CI; (0.551 0.720)]. Inadequate intake of milk and milk products in the 1st week of fracture [AOR = 95%CI: 0.20 (0.05-0.90)], Poor Dietary Diversity Score [AOR = 95% CI: 29.1 (2.27-371.65)], and ossified bone [AOR =95% CI: 4.10 (1.12-14.95)] showed statistically significant association with decreased serum level of Vitamin-D. CONCLUSION AND RECOMMENDATIONS: Decreased serum level of Vitamin-D at early phase of fractured bone healing process was found in the majority of patients (>63%) raising concern for Vitamin D deficiency to be a significant public health problem in the study population. It was statistically associated with: poor dietary diversity score, in adequate intake of milk and milk products in the 1stone week of fracture and ossified (healed) bone. Introducing hospital based Vitamin-D supplementation and integrated with health and nutritional education is a vital intervention needed to improve serum levels of Vitamin-D. PMID- 28870254 TI - Understanding the factors affecting the attraction and retention of health professionals in rural and remote areas: a mixed-method study in Niger. AB - BACKGROUND: The critical shortage of human resources in health is a critical public health problem affecting most low- and middle-income countries, particularly in sub-Saharan Africa. In addition to the shortage of health professionals, attracting and retaining them in rural areas is a challenge. The objective of the study was to understand the factors that influence the attraction and retention of health professionals working in rural areas in Niger. METHODS: A mixed-method study was conducted in Tillabery region, Niger. A conceptual framework was used that included five dimensions. Three data collection methods were employed: in-depth interviews, documentary analysis, and concept mapping. In-depth interviews were conducted with three main actor groups: policy-makers and Ministry of Health officials (n = 15), health professionals (n = 102), and local health managers (n = 46). Concept mapping was conducted with midwifery students (n = 29). Multidimensional scaling and cluster analysis were performed to analyse the data from the concept mapping method. A content analysis was conducted for the qualitative data. RESULTS: The results of the study showed that the local environment, which includes living conditions (no electricity, lack of availability of schools), social factors (isolation, national and local insecurity), working conditions (workload), the lack of financial compensation, and individual factors (marital status, gender), influences the attraction and retention of health professionals to work in rural areas. Human resources policies do not adequately take into account the factors influencing the retention of rural health professionals. CONCLUSION: Intersectoral policies are needed to improve living conditions and public services in rural areas. The government should also take into account the feminization of the medical profession and the social and cultural norms related to marital status and population mobility when formulating human resources management policies. PMID- 28870253 TI - Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study. AB - BACKGROUND: Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. PATIENTS AND METHODS: We conducted a retrospective cohort study using data on 269 apatinib treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan-Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival. RESULTS: Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64-0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53-0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival. CONCLUSION: Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients. PMID- 28870255 TI - Detection and epidemic dynamic of ToCV and CCYV with Bemisia tabaci and weed in Hainan of China. AB - BACKGROUND: In recent years, two of the crinivirus, Tomato chlorosis virus (ToCV) and Cucurbit chlorotic yellows virus (CCYV) have gained increasing attention due to their rapid spread and devastating impacts on vegetable production worldwide. Both of these viruses are transmitted by the sweet potato whitefly, Bemisia tabaci (Gennadius), in a semi-persistent manner. Up to now, there is still lack of report in Hainan, the south of China. METHODS: We used observational and experimental methods to explore the prevalence and incidence dynamic of CCYV and ToCV transmitted by whiteflies in Hainan of China. RESULTS: In 2016, the chlorosis symptom was observed in the tomato and cucumber plants with a large number of B. tabaci on the infected leaves in Hainan, China, with the incidence rate of 69.8% and 62.6% on tomato and cucumber, respectively. Based on molecular identification, Q biotype was determined with a viruliferous rate of 65.0% and 55.0% on the tomato and cucumber plants, respectively. The weed, Alternanthera philoxeroides near the tomato and cucumber was co-infected by the two viruses. Furthermore, incidence dynamic of ToCV and CCYV showed a close relationship with the weed, Alternanthera philoxeroides, which is widely distributed in Hainan. CONCLUSION: Our results firstly reveal that the weed, A. philoxeroides is infected by both ToCV and CCYV. Besides, whiteflies showed a high viruliferous rate of ToCV and CCYV. Hainan is an extremely important vegetable production and seed breeding center in China. If the whitefly can carry these two viruses concurrently, co-infection in their mutual host plants can lead to devastating losses in the near future. PMID- 28870256 TI - Phylo_dCor: distance correlation as a novel metric for phylogenetic profiling. AB - BACKGROUND: Elaboration of powerful methods to predict functional and/or physical protein-protein interactions from genome sequence is one of the main tasks in the post-genomic era. Phylogenetic profiling allows the prediction of protein-protein interactions at a whole genome level in both Prokaryotes and Eukaryotes. For this reason it is considered one of the most promising methods. RESULTS: Here, we propose an improvement of phylogenetic profiling that enables handling of large genomic datasets and infer global protein-protein interactions. This method uses the distance correlation as a new measure of phylogenetic profile similarity. We constructed robust reference sets and developed Phylo-dCor, a parallelized version of the algorithm for calculating the distance correlation that makes it applicable to large genomic data. Using Saccharomyces cerevisiae and Escherichia coli genome datasets, we showed that Phylo-dCor outperforms phylogenetic profiling methods previously described based on the mutual information and Pearson's correlation as measures of profile similarity. CONCLUSIONS: In this work, we constructed and assessed robust reference sets and propose the distance correlation as a measure for comparing phylogenetic profiles. To make it applicable to large genomic data, we developed Phylo-dCor, a parallelized version of the algorithm for calculating the distance correlation. Two R scripts that can be run on a wide range of machines are available upon request. PMID- 28870257 TI - Enrichment of beneficial bacteria in the skin microbiota of bats persisting with white-nose syndrome. AB - BACKGROUND: Infectious diseases of wildlife are increasing worldwide with implications for conservation and human public health. The microbiota (i.e. microbial community living on or in a host) could influence wildlife disease resistance or tolerance. White-nose syndrome (WNS), caused by the fungus Pseudogymnoascus destructans (Pd), has killed millions of hibernating North American bats since 2007. We characterized the skin microbiota of naive, pre-WNS little brown bats (Myotis lucifugus) from three WNS-negative hibernation sites and persisting, previously exposed bats from three WNS-positive sites to test the hypothesis that the skin microbiota of bats shifts following WNS invasion. RESULTS: Using high-throughput 16S rRNA gene sequencing on 66 bats and 11 environmental samples, we found that hibernation site strongly influenced the composition and diversity of the skin microbiota. Bats from WNS-positive and WNS negative sites differed in alpha and beta diversity, as well as in microbiota composition. Alpha diversity was reduced in persisting, WNS-positive bats, and the microbiota profile was enriched with particular taxa such Janthinobacterium, Micrococcaceae, Pseudomonas, Ralstonia, and Rhodococcus. Some of these taxa are recognized for their antifungal activity, and specific strains of Rhodococcus and Pseudomonas are known to inhibit Pd growth. Composition of the microbial community in the hibernaculum environment and the community on bat skin was superficially similar but differed in relative abundance of some bacterial taxa. CONCLUSIONS: Our results are consistent with the hypothesis that Pd invasion leads to a shift in the skin microbiota of surviving bats and suggest the possibility that the microbiota plays a protective role for bats facing WNS. The detection of what appears to be enrichment of beneficial bacteria in the skin microbiota of persisting bats is a promising discovery for species re establishment. Our findings highlight not only the potential value of management actions that might encourage transmission, growth, and establishment of beneficial bacteria on bats, and within hibernacula, but also the potential risks of such management actions. PMID- 28870258 TI - Opportunities and challenges in rheumatology research in Central Europe. AB - The Central European Congress of Rheumatology (CECR) has been organized by seven Central European countries: Austria, Croatia, Czech Republic, Hungary, Poland, Slovakia, and Slovenia. These countries have lots of similarities, but also differences, with respect to rheumatology research. In this paper, based on questionnaires, we wish to demonstrate achievements and difficulties in rheumatology research performed in our region. PMID- 28870259 TI - RDFIO: extending Semantic MediaWiki for interoperable biomedical data management. AB - BACKGROUND: Biological sciences are characterised not only by an increasing amount but also the extreme complexity of its data. This stresses the need for efficient ways of integrating these data in a coherent description of biological systems. In many cases, biological data needs organization before integration. This is not seldom a collaborative effort, and it is thus important that tools for data integration support a collaborative way of working. Wiki systems with support for structured semantic data authoring, such as Semantic MediaWiki, provide a powerful solution for collaborative editing of data combined with machine-readability, so that data can be handled in an automated fashion in any downstream analyses. Semantic MediaWiki lacks a built-in data import function though, which hinders efficient round-tripping of data between interoperable Semantic Web formats such as RDF and the internal wiki format. RESULTS: To solve this deficiency, the RDFIO suite of tools is presented, which supports importing of RDF data into Semantic MediaWiki, with metadata needed to export it again in the same RDF format, or ontology. Additionally, the new functionality enables mash-ups of automated data imports combined with manually created data presentations. The application of the suite of tools is demonstrated by importing drug discovery related data about rare diseases from Orphanet and acid dissociation constants from Wikidata. The RDFIO suite of tools is freely available for download via pharmb.io/project/rdfio . CONCLUSIONS: Through a set of biomedical demonstrators, it is demonstrated how the new functionality enables a number of usage scenarios where the interoperability of SMW and the wider Semantic Web is leveraged for biomedical data sets, to create an easy to use and flexible platform for exploring and working with biomedical data. PMID- 28870260 TI - Programmed cell death ligand 1 cut-point is associated with reduced disease specific survival in resected pancreatic ductal adenocarcinoma. AB - BACKGROUND: Programmed cell death 1 (PD1) inhibitors have recently shown promising anti-cancer effects in a number of solid tumor types. A predictive biomarker to this class of drugs has not been clearly identified; however, overexpression of the PD1 ligand (PD-L1) has shown particular promise in lung adenocarcinoma. In this study, we explore the staining characteristics, prevalence, and clinico-molecular correlates of PD-L1 overexpression in pancreatic ductal adenocarcinoma (PDAC). METHODS: A tissue microarray (TMA) was constructed from cases of resected PDAC. PD-L1 immunohistochemistry (IHC) was performed using the SP142 primary antibody. Immunohistochemical assessment for deficient mismatch repair status (MMRd), CD3 and CD8 were performed. All biomarkers were assessed independently by two anatomical pathologists and consensus achieved on all cases. Survival analysis was performed using three thresholds (> = 1%, >5% and >10%) for tumor cell membrane staining. RESULTS: Two hundred fifty-two cases were included in the TMA and evaluable by IHC. Thirty-one (12%), 17 (7%), 12(5%) cases were positive at percentage cut offs of >0, >5, and >10% respectively. Increased PD-L1 expression was associated with inferior prognosis (p = 0.0367). No statistically significant association was identified between PD-L1 status and MMR status or tumor infiltrating lymphocytes. CONCLUSIONS: This data suggests that there is an inverse relationship between PD L1 expression and disease specific survival times in resected PDAC. Consequently, this association may represent a phenotype where increased PD-L1 expression has an effect on tumor biology and could therefore identify a subgroup where PD1 blockade could have enhanced effectiveness. PMID- 28870261 TI - Sustained-release study on Exenatide loaded into mesoporous silica nanoparticles: in vitro characterization and in vivo evaluation. AB - BACKGROUND: Exenatide (EXT), the first glucagon-like peptide-1 receptor agonist, has been approved as an adjunctive therapy for patients with type 2 diabetes. Due to EXT's short half-life, EXT must be administrated by continuous subcutaneous (s.c.) injection twice daily. In previous studies, many studies on EXT loaded into polymer materials carriers for sustained release had been reported. However, these carriers have some defects, such as hydrophobicity, low surface energy, low mechanical strength, and poor chemical stability. Therefore, this study aims to develop a novel drug delivery system, which is EXT loaded into well-ordered hexagonal mesoporous silica structures (EXT-SBA-15), to control the sustainability of EXT. METHODS: SBA-15 was prepared by hydrothermal method with uniform size. Morphology of SBA-15 was employed by transmission electron microscopy. The pore size of SBA-15 was characterized by N2 adsorption-desorption isotherms. The in vitro drug release behavior and pharmacokinetics of EXT-SBA-15 were investigated. Furthermore, the blood glucose levels of diabetic mice were monitored after subcutaneous injection of EXT-Sol and EXT-SBA-15 to evaluate further the stable hypoglycemic effect of EXT-SBA-15. RESULTS: EXT-SBA-15 showed a higher drug loading efficiency (15.2 +/- 2.0%) and sustained-release features in vitro. In addition, pharmacokinetic studies revealed that the EXT-SBA-15 treatment group extended the half-life t 1/2(beta) to 14.53 +/- 0.70 h compared with that of the EXT solution (EXT-Sol) treatment group (0.60 +/- 0.08 h) in vivo. Results of the pharmacodynamics study show that the EXT-SBA-15 treatment group had inhibited blood glucose levels below 20 mmol/L for 25 days, and the lowest blood glucose level was 13 mmol/L on the 10th day. CONCLUSIONS: This study demonstrates that the EXT-SBA-15 delivery system can control the sustainability of EXT and contribute to improve EXT clinical use. PMID- 28870262 TI - Virulence factors, antifungal susceptibility and molecular mechanisms of azole resistance among Candida parapsilosis complex isolates recovered from clinical specimens. AB - BACKGROUND: The aim of this study was to determine the biofilm formation, the extracellular enzymatic activities of 182 clinical isolates of the Candida parapsilosis complex. METHODS: Molecular identification of the C. parapsilosis species complex was performed using PCR RFLP of SADH gene and PCR sequencing of ITS region. The susceptibility of ours isolates to antifungal agents and molecular mechanisms underlying azole resistance were evaluated. RESULTS: 63.5% of C. parapsilosis were phospholipase positive with moderate activity for the majority of strains. None of the C. metapsilosis or C. orthopsilosis isolates was able to produce phospholipase. Higher caseinase activities were detected in C. parapsilosis (Pz = 0.5 +/- 0.18) and C. orthopsilosis (Pz = 0.49 +/- 0.07) than in C. metapsilosis isolates (Pz = 0.72 +/- 0.1). 96.5% of C. parapsilosis strains and all isolates of C. metapsilosis and C. orthopsilosis produced gelatinase. All the strains possessed the ability to show haemolysis on blood agar. C. metapsilosis exhibited the low haemolysin production with statistical significant differences compared to C. parapsilosis and C. orthopsilosis. The biofilm forming ability of C. parapsilosis was highly strain dependent with important heterogeneity, which was less evident with both C. orthopsilosis and C. metapsilosis. Some C. parapsilosis isolates met the criterion for susceptible dose dependent to fluconazole (10.91%), itraconazole (16.36%) and voriconazole (7.27%). Moreover, 5.45% and 1.82% of C. parapsilosis isolates were respectively resistant to fluconazole and voriconazole. All strains of C. metapsilosis and C. orthopsilosis were susceptible to azoles; and isolates of all three species exhibited 100% of susceptibility to caspofungin, amphotericin B and 5 flucytosine. CONCLUSIONS: A combination of molecular mechanisms, including the overexpression of ERG11, and genes encoding efflux pumps (CDR1, MDR1, and MRR1) were involved in azole resistance in C. parapsilosis. PMID- 28870263 TI - Effect of maternal vitamin D3 supplementation on maternal health, birth outcomes, and infant growth among HIV-infected Tanzanian pregnant women: study protocol for a randomized controlled trial. AB - BACKGROUND: Vitamin D has significant immunomodulatory effects on both adaptive and innate immune responses. Observational studies indicate that adults infected with HIV with low vitamin D status may be at increased risk of mortality, pulmonary tuberculosis, and HIV disease progression. Growing observational evidence also suggests that low vitamin D status in pregnancy may increase the risk of adverse birth and infant health outcomes. As a result, antiretroviral therapy (ART) adjunct vitamin D3 supplementation may improve the health of HIV infected pregnant women and their children. METHODS/DESIGN: The Trial of Vitamins 5 (ToV5) is an individually randomized, double-blind, placebo-controlled trial of maternal vitamin D3 (cholecalciferol) supplementation conducted among 2300 HIV infected pregnant women receiving triple-drug ART under Option B+ in Dar es Salaam, Tanzania. HIV-infected pregnant women of 12-27 weeks gestation are randomized to either: 1) 3000 IU vitamin D3 taken daily from randomization in pregnancy until trial discharge at 12 months postpartum; or 2) a matching placebo regimen. Maternal participants are followed-up at monthly clinic visits during pregnancy, at delivery, and then with their children at monthly postpartum clinic visits. The primary efficacy outcomes of the trial are: 1) maternal HIV disease progression or death; 2) risk of small-for-gestational age (SGA) births; and 3) risk of infant stunting at 1 year of age. The primary safety outcome of the trial is incident maternal hypercalcemia. Secondary outcomes include a range of clinical and biological maternal and child health outcomes. DISCUSSION: The ToV5 will provide causal evidence on the effect of vitamin D3 supplementation on HIV progression and death, SGA births, and infant stunting at 1 year of age. The results of the trial are likely generalizable to HIV-infected pregnant women and their children in similar resource-limited settings utilizing the Option B+ approach. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02305927 . Registered on 29 October 2014. PMID- 28870264 TI - Cryptosporidium infecting wild cricetid rodents from the subfamilies Arvicolinae and Neotominae. AB - We undertook a study on Cryptosporidium spp. in wild cricetid rodents. Fecal samples were collected from meadow voles (Microtus pennsylvanicus), southern red backed voles (Myodes gapperi), woodland voles (Microtus pinetorum), muskrats (Ondatra zibethicus) and Peromyscus spp. mice in North America, and from bank voles (Myodes glareolus) and common voles (Microtus arvalis) in Europe. Isolates were characterized by sequence and phylogenetic analyses of the small subunit ribosomal RNA (SSU) and actin genes. Overall, 33.2% (362/1089) of cricetids tested positive for Cryptosporidium, with a greater prevalence in cricetids from North America (50.7%; 302/596) than Europe (12.1%; 60/493). Principal Coordinate analysis separated SSU sequences into three major groups (G1-G3), each represented by sequences from North American and European cricetids. A maximum likelihood tree of SSU sequences had low bootstrap support and showed G1 to be more heterogeneous than G2 or G3. Actin and concatenated actin-SSU trees, which were better resolved and had higher bootstrap support than the SSU phylogeny, showed that closely related cricetid hosts in Europe and North America are infected with closely related Cryptosporidium genotypes. Cricetids were not major reservoirs of human pathogenic Cryptosporidium spp. PMID- 28870266 TI - Comparison of the lived experiences of family caregivers of patients with dementia and of patients with cancer in Indonesia. AB - : ABSTRACTBackground:Dementia, even more than cancer, demands long-term care. While in Indonesia cancer is accepted as a disease requiring caregiving, dementia is still considered "a normal condition." These differences might affect the experiences of caregivers, especially those relating to social health, the subject of our study. We aim to describe and compare the lived experiences of family caregivers of patients with cancer (PWC) with those of patients with dementia (PWD) in Yogyakarta, Indonesia, and to explore the role of their social health in these experiences. METHOD: A qualitative design was applied. In-depth face-to-face interviews were conducted with PWC and PWD caregivers in two outpatient clinics of a tertiary hospital. The constant comparative method was applied to analyze the data that were interpreted using the concept of social health to explore the experiences of the caregivers. We used Atlas.ti software. RESULTS: Three themes were identified: problems with caregiving, dealing with problems, and beliefs in caregiving. We found more similarities than differences in the experiences of caregivers in both groups. Half of the categories were related to social health: challenges, consequences, hiding, social support, and the caregiver's approach. The organization of dementia care is characterized by simplicity and direct ties between medical specialists, PWD, and caregivers, whereas cancer care encounters coordination problems. CONCLUSIONS: Family caregivers of both groups mostly had similar experiences of the caregiving process. Gaining a better understanding of the specific experiences of caregivers, and their social health, opens new avenues for interventions to improve their quality of life. PMID- 28870267 TI - Evil, terrorism, and psychiatry. PMID- 28870265 TI - Predicting Multidrug-Resistant Gram-Negative Bacterial Colonization and Associated Infection on Hospital Admission. AB - OBJECTIVE Isolation of multidrug-resistant gram-negative bacteria (MDR-GNB) from patients in the community has been increasingly observed. A prediction model for MDR-GNB colonization and infection risk stratification on hospital admission is needed to improve patient care. METHODS A 2-stage, prospective study was performed with 995 and 998 emergency department patients enrolled, respectively. MDR-GNB colonization was defined as isolates resistant to 3 or more classes of antibiotics, identified in either the surveillance or early (<=48 hours) clinical cultures. RESULTS A score-assigned MDR-GNB colonization prediction model was developed and validated using clinical and microbiological data from 995 patients enrolled in the first stage of the study; 122 of these patients (12.3%) were MDR GNB colonized. We identified 5 independent predictors: age>70 years (odds ratio [OR], 1.84 [95% confidence interval (CI), 1.06-3.17]; 1 point), assigned point value in the model), residence in a long-term-care facility (OR, 3.64 [95% CI, 1.57-8.43); 3 points), history of cerebrovascular accidents (OR, 2.23 [95% CI, 1.24-4.01]; 2 points), hospitalization within 1 month (OR, 2.63 [95% CI, 1.39 4.96]; 2 points), and recent antibiotic exposure (OR, 2.18 [95% CI, 1.16-4.11]; 2 points). The model displayed good discrimination in the derivation and validation sets (area under ROC curve, 0.75 and 0.80, respectively) with the best cutoffs of<4 and >=4 points for low- and high-risk MDR-GNB colonization, respectively. When applied to 998 patients in the second stage of the study, the model successfully stratified the risk of MDR-GNB infection during hospitalization between low- and high-risk groups (probability, 0.02 vs 0.12, respectively; log rank test, P<.001). CONCLUSION A model was developed to optimize both the decision to initiate antimicrobial therapy and the infection control interventions to mitigate threats from MDR-GNB. Infect Control Hosp Epidemiol 2017;38:1216-1225. PMID- 28870268 TI - Multi-level obstruction in obstructive sleep apnoea: prevalence, severity and predictive factors. AB - OBJECTIVES: To characterise multi-level obstruction in terms of prevalence, obstructive sleep apnoea severity and predictive factors, and to collect epidemiological data on upper airway morphology in obstructive sleep apnoea patients. METHODS: Retrospective review of 250 obstructive sleep apnoea patients. RESULTS: On clinical examination, 171 patients (68.4 per cent) had multi-level obstruction, 49 (19.6 per cent) had single-level obstruction and 30 (12 per cent) showed no obstruction. Within each category of obstructive sleep apnoea severity, multi-level obstruction was more prevalent. Multi-level obstruction was associated with severe obstructive sleep apnoea (more than 30 events per hour) (p = 0.001). Obstructive sleep apnoea severity increased with the number of obstruction sites (correlation coefficient = 0.303, p < 0.001). Multi-level obstruction was more likely in younger (p = 0.042), male (p = 0.045) patients, with high body mass index (more than 30 kg/m2) (p < 0.001). Palatal (p = 0.004), tongue (p = 0.026) and lateral pharyngeal wall obstructions (p = 0.006) were associated with severe obstructive sleep apnoea. CONCLUSION: Multi-level obstruction is more prevalent in obstructive sleep apnoea and is associated with increased severity. Obstruction at certain anatomical levels contributes more towards obstructive sleep apnoea severity. PMID- 28870270 TI - Resistance towards monensin is proposed to be acquired in a Toxoplasma gondii model by reduced invasion and egress activities, in addition to increased intracellular replication. AB - Monensin (Mon) is an anticoccidial polyether ionophore widely used to control coccidiosis. The extensive use of polyether ionophores on poultry farms resulted in widespread resistance, but the underlying resistance mechanisms are unknown in detail. For analysing the mode of action by which resistance against polyether ionophores is obtained, we induced in vitro Mon resistance in Toxoplasma gondii RH strain (MonR-RH) and compared it with the sensitive parental strain (Sen-RH). The proteome assessment of MonR-RH and Sen-RH strains was obtained after isotopic labelling using stable isotope labelling by amino acid in cell culture. Relative proteomic quantification between resistant and sensitive strains was performed using liquid chromatography-mass spectrometry/mass spectrometry. Overall, 1024 proteins were quantified and 52 proteins of them were regulated. The bioinformatic analysis revealed regulation of cytoskeletal and transmembrane proteins being involved in transport mechanisms, metal ion-binding and invasion. During invasion, actin and microneme protein 8 (MIC8) are seem to be important for conoid extrusion and forming moving junction with host cells, respectively. Actin was significantly upregulated, while MIC8 was downregulated, which indicate an invasion reduction in the resistant strain. Resistance against Mon is not a simple process but it involves reduced invasion and egress activity of T. gondii tachyzoites while intracellular replication is enhanced. PMID- 28870269 TI - Failure to Communicate: Transmission of Extensively Drug-Resistant bla OXA-237 Containing Acinetobacter baumannii-Multiple Facilities in Oregon, 2012-2014. AB - OBJECTIVE To determine the scope, source, and mode of transmission of a multifacility outbreak of extensively drug-resistant (XDR) Acinetobacter baumannii. DESIGN Outbreak investigation. SETTING AND PARTICIPANTS Residents and patients in skilled nursing facilities, long-term acute-care hospital, and acute care hospitals. METHODS A case was defined as the incident isolate from clinical or surveillance cultures of XDR Acinetobacter baumannii resistant to imipenem or meropenem and nonsusceptible to all but 1 or 2 antibiotic classes in a patient in an Oregon healthcare facility during January 2012-December 2014. We queried clinical laboratories, reviewed medical records, oversaw patient and environmental surveillance surveys at 2 facilities, and recommended interventions. Pulsed-field gel electrophoresis (PFGE) and molecular analysis were performed. RESULTS We identified 21 cases, highly related by PFGE or healthcare facility exposure. Overall, 17 patients (81%) were admitted to either long-term acute-care hospital A (n=8), or skilled nursing facility A (n=8), or both (n=1) prior to XDR A. baumannii isolation. Interfacility communication of patient or resident XDR status was not performed during transfer between facilities. The rare plasmid-encoded carbapenemase gene bla OXA-237 was present in 16 outbreak isolates. Contact precautions, chlorhexidine baths, enhanced environmental cleaning, and interfacility communication were implemented for cases to halt transmission. CONCLUSIONS Interfacility transmission of XDR A. baumannii carrying the rare blaOXA-237 was facilitated by transfer of affected patients without communication to receiving facilities. Infect Control Hosp Epidemiol 2017;38:1335-1341. PMID- 28870272 TI - In rats gestational iron deficiency does not change body fat or hepatic mitochondria in the aged offspring. AB - Mitochondrial dysfunction and resulting changes in adiposity have been observed in the offspring of animals fed a high fat (HF) diet. As iron is an important component of the mitochondria, we have studied the offspring of female rats fed complete (Con) or iron-deficient (FeD) rations for the duration of gestation to test for similar effects. The FeD offspring were ~12% smaller at weaning and remained so because of a persistent reduction in lean tissue mass. The offspring were fed a complete (stock) diet until 52 weeks of age after which some animals from each litter were fed a HF diet for a further 12 weeks. The HF diet increased body fat when compared with animals fed the stock diet, however, prenatal iron deficiency did not change the ratio of fat:lean in either the stock or HF diet groups. The HF diet caused triglyceride to accumulate in the liver, however, there was no effect of prenatal iron deficiency. The activity of the mitochondrial electron transport complexes was similar in all groups including those challenged with a HF diet. HF feeding increased the number of copies of mitochondrial DNA and the prevalence of the D-loop mutation, however, neither parameter was affected by prenatal iron deficiency. This study shows that the effects of prenatal iron deficiency differ from other models in that there is no persistent effect on hepatic mitochondria in aged animals exposed to an increased metabolic load. PMID- 28870271 TI - ICD-9-CM Coding for Multidrug Resistant Infection Correlates Poorly With Microbiologically Confirmed Multidrug Resistant Infection. PMID- 28870273 TI - Factors associated with delay in trauma team activation and impact on patient outcomes. AB - OBJECTIVE: Trauma code activation is initiated by emergency physicians using physiological and anatomical criteria, mechanism of injury, and patient demographic factors. Our objective was to identify factors associated with delayed trauma team activation. METHODS: We assessed consecutive cases from a regional trauma database from January 2008 to March 2014. We defined a delay in trauma code activation as a time greater than 30 minutes from the time of arrival. We conducted univariate analysis for factors potentially influencing trauma team activation, and we subsequently used multiple logistic regression analysis models for delayed activation in relation to mortality, length of stay, and time to operative management. RESULTS: Patients totalling 846 were included for our analysis; 4.1% (35/846) of trauma codes were activated after 30 minutes. Mean age was 40.8 years in the early group versus 49.2 in the delayed group (p=0.01). Patients were over age 70 years in 7.6% in the early activation group versus 17.1% in the delayed group (p=0.04). There was no significant difference in sex, type of injury, injury severity, or time from injury between the two groups. There was no significant difference in mortality, median length of stay, or median time to operative management. CONCLUSIONS: Delayed activation is linked with increasing age with no clear link to increased mortality. Given the severe injuries in the delayed cohort that required activation of the trauma team, further emphasis on the older trauma patient and interventions to recognize this vulnerable population should be made. PMID- 28870274 TI - Psychopharmacological options for adult patients with anorexia nervosa: the patients' and carers' perspectives. PMID- 28870275 TI - Identification of fall predictors in the active elderly population from the routine medical records of general practitioners. AB - : Aim To evaluate the possibility of determining predictors of falls in the active community-dwelling elderly from the routine medical records of the general practitioners (GPs). BACKGROUND: Time constraints and competing demands in the clinical encounters frequently undermine fall-risk evaluation. In the context of proactive primary healthcare, quick, and efficient tools for a preliminary fall risk assessment are needed in order to overcome these barriers. METHODS: The study included 1220 subjects of 65 years of age or older. Data were extracted from the GPs' patient records. For each subject, the following variables were considered: age, gender, diseases, and pharmacotherapy. Univariate and multivariable analyses have been conducted to identify the independent predictors of falls. Findings The mean age of the study population was 77.8+/-8.7 years for women and 74.9+/-7.3 years for men. Of the sample, 11.6% had experienced one or more falls in the previous year. The risk of falling was found to increase significantly (P<0.05) with age (OR=1.03; 95% CI=1.01-1.05), generalized osteoarthritis (OR=2.01; 95% CI=1.23-3.30), tinnitus (OR=4.14; 95% CI=1.25 13.74), cognitive impairment (OR=4.12; 95% CI=2.18-7.80), and two or more co existing diseases (OR=5.4; 95% CI=1.68-17.39). Results suggest that it is possible to identify patients at higher risk of falling by going through the current medical records, without adding extra workload on the health personnel. In the context of proactive primary healthcare, the analysis of fall predictors from routine medical records may allow the identification of which of the several known and hypothesized risk factors may be more relevant for developing quick and efficient tools for a preliminary fall-risk assessment. PMID- 28870276 TI - The developing world of DOHaD. AB - Since its debut in a ground-breaking report by Barker and Osmond in 1986, the concept of the Developmental Origins of Health and Disease (DOHaD) has been further developed in several aspects. Its methodology and conclusions relating to proposed origins and outcomes of early life events have been developing and spreading internationally. Indeed, the DOHaD concept now seems to have influenced many fields of research. This article aims to briefly review why the DOHaD concept is important in biomedical science, how it has developed, is currently developing, and how it should develop in future. PMID- 28870277 TI - Lessons Learned From Implementing an Incident Command System During a Local Multiagency Response to a Legionnaires' Disease Cluster in Sydney, NSW. AB - The incident command system (ICS) provides a common structure to control and coordinate an emergency response, regardless of scale or predicted impact. The lessons learned from the application of an ICS for large infectious disease outbreaks are documented. However, there is scant evidence on the application of an ICS to manage a local multiagency response to a disease cluster with environmental health risks. The Sydney Local Health District Public Health Unit (PHU) in New South Wales, Australia, was notified of 5 cases of Legionnaires' disease during 2 weeks in May 2016. This unusual incident triggered a multiagency investigation involving an ICS with staff from the PHU, 3 local councils, and the state health department to help prevent any further public health risk. The early and judicious use of ICS enabled a timely and effective response by supporting clear communication lines between the incident controller and field staff. The field team was key in preventing any ongoing public health risk through inspection, sampling, testing, and management of water systems identified to be at-risk for transmission of legionella. Good working relationships between partner agencies and trust in the technical proficiency of environmental health staff aided in the effective management of the response. (Disaster Med Public Health Preparedness. 2018;12:539-542). PMID- 28870278 TI - A CONSULTATION GUIDE FOR ASSESSING THE APPLICABILITY OF HEALTH TECHNOLOGIES:A CASE STUDY. AB - OBJECTIVES: The translation of research findings into policy and practice is crucially dependent on the applicability of such findings in a given decision making context. We explored in a case study whether a generic consultation guide to assess the applicability of a health technology could be rapidly deployed and deliver useful insights. METHODS: A consultation guide based on the context and implementation for complex interventions (CICI) framework was developed and piloted to assess the applicability of reinforced home-based palliative care in three European countries. Individual consultations in England and Germany and a panel discussion in Poland were completed. RESULTS: Various barriers may hinder successful implementation of reinforced home-based palliative care in the three countries. Whilst the experts across all countries emphasized the lack of funding along with organization and structure as major barriers, information varied by country for many of the other identified barriers and facilitators. Participants in the pilot study provided positive feedback in terms of understanding the topic and purpose of the consultation, and both individual and panel consultations could be easily implemented. CONCLUSIONS: In this case study, the consultation guide presented a pragmatic, ready-to-use tool to assess the applicability of a health technology. As shown here, it can be used in a generic manner without discrete empirical information on the technology in question or, ideally, makes use of specific information collected as part of a HTA. Further studies are needed to validate this guide and apply it to other types of health technologies and more diverse decision-making contexts. PMID- 28870279 TI - Graph-based impact analysis as a framework for incorporating practitioner knowledge in dairy herd health management. AB - Production diseases in dairy cows are multifactorial, which means they emerge from complex interactions between many different farm variables. Variables with a large impact on production diseases can be identified for groups of farms using statistical models, but these methods cannot be used to identify highly influential variables in individual farms. This, however, is necessary for herd health planning, because farm conditions and associated health problems vary largely between farms. The aim of this study was to rank variables according to their anticipated effect on production diseases on the farm level by applying a graph-based impact analysis on 192 European organic dairy farms. Direct impacts between 13 pre-defined variables were estimated for each farm during a round table discussion attended by practitioners, that is farmer, veterinarian and herd advisor. Indirect impacts were elaborated through graph analysis taking into account impact strengths. Across farms, factors supposedly exerting the most influence on production diseases were 'feeding', 'hygiene' and 'treatment' (direct impacts), as well as 'knowledge and skills' and 'herd health monitoring' (indirect impacts). Factors strongly influenced by production diseases were 'milk performance', 'financial resources' and 'labour capacity' (directly and indirectly). Ranking of variables on the farm level revealed considerable differences between farms in terms of their most influential and most influenced farm factors. Consequently, very different strategies may be required to reduce production diseases in these farms. The method is based on perceptions and estimations and thus prone to errors. From our point of view, however, this weakness is clearly outweighed by the ability to assess and to analyse farm specific relationships and thus to complement general knowledge with contextual knowledge. Therefore, we conclude that graph-based impact analysis represents a promising decision support tool for herd health planning. The next steps include testing the method using more specific and problem-oriented variables as well as evaluating its effectiveness. PMID- 28870280 TI - Glucose and cholesterol stabilization in patients with type 2 diabetes mellitus with depressive and anxiety symptoms by problem-solving therapy in primary care centers in Mexico City. AB - : Aim The aim of this study was to determine if the problem-solving therapy (PST) helps control metabolic variables in patients with type 2 diabetes mellitus (T2DM) who show depressive and anxiety symptoms. BACKGROUND: T2DM is a chronic degenerative multifactorial disease. It is considered one of the main public health problems in the world, and it represents an important social and economic burden. It is frequently associated with major depression and anxiety disorders, which are related with high glycated hemoglobin (HbA1c) concentrations and poor metabolic control. METHOD: We initially included 123 patients diagnosed with T2DM from five primary care centers (PCC) in Mexico City. HbA1c, central glucose, and lipid profile were measured in each patient. In addition, the Kessler psychological distress scale (K-10), the Beck Depression Inventory, and the Beck Anxiety Inventory were applied at the beginning and, to those who continued, at the end of the PST, as well as four months later. Findings In total, 36 patients completed the PST and the follow-up. There was a significant decrease in depressive and anxiety symptoms (P<0.001), as well as in total cholesterol (P=0.002), HbA1c (P=0.05), and low-density lipoprotein (LDL) (P=0.022). The PST helps reduce depressive and anxiety symptoms and may help stabilize glucose and cholesterol up to four months. Further studies on this area are recommended. If our findings are confirmed, the PST could help improve the quality of life of thousands of individuals with psychiatric-metabolic co-morbidity who only visit PCC. PMID- 28870281 TI - Workplace injuries in the Australian allied health workforce. AB - Objective This study aims to identify the number, costs and reported injury mechanisms of serious injury claims for allied health professionals.Methods Using Australian Workers' Compensation injury data, the number, mechanism, and costs of injury claims were calculated for eight groups of allied health professions (chiropractors and osteopaths, speech pathologists and audiologists, occupational therapists, physiotherapists, psychologists, podiatrists, social workers and prosthetists/orthotists) between the 2000-01 and 2013-14 financial years. Workforce injury rates were calculated using the 2011 Australian Census Workforce data (denominator) and 2011 Workers' Compensation Statistics claims data (numerator).Results Across the allied health professions, 7023 serious injuries (minimum 5 days absence from work) were recorded with an associated total compensation cost of A$201970000. Fewer than 1.5% of each allied health professional group had an injury claim, with the exception of prosthetists/orthotists who had a rate of 25.9% serious injury claims (95% confidence interval 21.9-30.4). The average cost per claim varied across the allied health professions, from the lowest cost of A$19091 per injury for occupational therapists to the highest of A$48466 per claim in chiropractic and osteopathy. Body stressing followed by mental stress were the most common mechanisms of injury.Conclusions Mechanism of injury, both physical and psychosocial, were identified. Prosthetists/orthotists are at the highest risk of workplace injury of all allied health professions. This suggests the need for further investigation and development of appropriately targeted injury prevention programs for each allied health profession.What is known about this topic? Retention of allied health professionals is a significant issue, with workplace injuries identified as one contributing factor to this problem. Healthcare workers are potentially at high risk of injury as they are exposed to a range of physical and psychosocial hazards in their workplace.What does this paper add? This paper is the first to report on serious injuries, minimum 5 days absence from work, from Australian Workers' Compensation data, across a range of allied health professions. Various allied health professions were examined to identify the number, mechanism and cost of serious workplace injuries finding there is an average of 500 serious claims per year at a cost of A$14million. Prosthetists/orthotists were identified as having the highest proportion of claims per workforce population.What are the implications for practitioners? These results suggest highly varied injury rates across allied health professions. Compensation data does not enable accurate identification of causal factors. Further work is required to identify relevant causal factors so that targeted risk reduction strategies can be developed to reduce workforce injuries. PMID- 28870282 TI - Transgender women and HIV-related health disparities: falling off the HIV treatment cascade. AB - : Background Transgender women living with HIV infection experience poorer health outcomes across the HIV continuum of care. While disparities are well established, their underlying mechanisms are not well understood. This study examined the HIV continuum of care (also known as the HIV treatment cascade), including linkage and engagement in care and health status among transgender women and cisgender women and cisgender men living with HIV. METHOD: Case-control matching was applied to a cohort of 1101 people living with HIV; 70 transgender women living with HIV were matched on years since testing HIV positive with cisgender women and cisgender men. Participants provided measures indicative of the HIV treatment cascade that included linkage and engagement in care, receiving and adhering to antiretroviral therapy (ART), and HIV viral suppression. Common correlates of HIV-related health status: depression symptoms, HIV-related stress, alcohol and drug use, healthcare conspiracy beliefs, medical mistrust, emotional social support and tangible social support, were also assessed. RESULTS: Transgender women were significantly less likely to receive ART, were less adherent to ART and had poorer HIV viral suppression than cisgender persons. Multivariable models demonstrated that health disparities were predicted by transgender women having poorer tangible social support over and above the other correlates of health outcomes. CONCLUSION: Tangible support is amenable by interventions such as building and strengthening supportive networks and paraprofessional services. Socially supportive interventions should be considered critical in efforts to decrease HIV health disparities among transgender women. PMID- 28870283 TI - Aging in Australia: country of birth and language preferences of residents in aged care facilities. AB - Objective There is a need to better understand the use of aged care services by people from culturally and linguistically diverse backgrounds. The aim of the present study was to describe the prevalence of people living in residential aged care facilities (RACFs) who were born in non-English-speaking countries and/or have a preferred language other than English and to describe service utilisation rates.Methods The present study consisted of a secondary analysis of data from the Australian Institute of Health and Welfare National Aged Care Data Clearinghouse. Data were analysed by country of birth, preferred language, state or territory and Aged Care Planning Regions within Victoria.Results Nationally, over 30000 (18.3%) RACF residents were born in a non-English-speaking country. In Victoria, almost one in four RACF residents (23.9%) was born in a non-English speaking country, and approximately one in eight (13.1%) has a preferred language other than English. Most Victorian RACFs (72.4%) have at least one resident with a preferred language other than English. Approximately one in four residents (26.1%) with a preferred language other than English are the sole speaker of the language in their facility.Conclusion All RACFs need to effectively address the needs and preferences of their residents, including those who were born in a non English-speaking country or prefer to speak a language other than English.What is known about the topic? The number of older people from a non-English-speaking background continues to increase, but little is known about the prevalence of this cohort living in RACFs and how aged care providers are responding to their needs and preferences.What does this paper add? The present study provides detailed, service- and policy-relevant information, demonstrating a substantial degree of diversity among people living in RACFs, with wide distribution across facilities and regions. The findings confirm the need for a systematic, sector wide approach to addressing linguistic diversity and developing inclusive practices.What are the implications for practitioners? All RACFs are required to develop policies and procedures in order to cater to the needs and preferences of residents who were born in non-English-speaking countries and/or who prefer to speak a language other than English. PMID- 28870285 TI - Rapid transporter regulation prevents substrate flow traffic jams in boron transport. AB - Nutrient uptake by roots often involves substrate-dependent regulated nutrient transporters. For robust uptake, the system requires a regulatory circuit within cells and a collective, coordinated behaviour across the tissue. A paradigm for such systems is boron uptake, known for its directional transport and homeostasis, as boron is essential for plant growth but toxic at high concentrations. In Arabidopsis thaliana, boron uptake occurs via diffusion facilitators (NIPs) and exporters (BORs), each presenting distinct polarity. Intriguingly, although boron soil concentrations are homogenous and stable, both transporters manifest strikingly swift boron-dependent regulation. Through mathematical modelling, we demonstrate that slower regulation of these transporters leads to physiologically detrimental oscillatory behaviour. Cells become periodically exposed to potentially cytotoxic boron levels, and nutrient throughput to the xylem becomes hampered. We conclude that, while maintaining homeostasis, swift transporter regulation within a polarised tissue context is critical to prevent intrinsic traffic-jam like behaviour of nutrient flow. PMID- 28870284 TI - Microsaccadic sampling of moving image information provides Drosophila hyperacute vision. AB - Small fly eyes should not see fine image details. Because flies exhibit saccadic visual behaviors and their compound eyes have relatively few ommatidia (sampling points), their photoreceptors would be expected to generate blurry and coarse retinal images of the world. Here we demonstrate that Drosophila see the world far better than predicted from the classic theories. By using electrophysiological, optical and behavioral assays, we found that R1-R6 photoreceptors' encoding capacity in time is maximized to fast high-contrast bursts, which resemble their light input during saccadic behaviors. Whilst over space, R1-R6s resolve moving objects at saccadic speeds beyond the predicted motion-blur-limit. Our results show how refractory phototransduction and rapid photomechanical photoreceptor contractions jointly sharpen retinal images of moving objects in space-time, enabling hyperacute vision, and explain how such microsaccadic information sampling exceeds the compound eyes' optical limits. These discoveries elucidate how acuity depends upon photoreceptor function and eye movements. PMID- 28870287 TI - Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis. AB - Intestinal regeneration and tumorigenesis are believed to be driven by intestinal stem cells (ISCs). Elucidating mechanisms underlying ISC activation during regeneration and tumorigenesis can help uncover the underlying principles of intestinal homeostasis and disease including colorectal cancer. Here we show that miR-31 drives ISC proliferation, and protects ISCs against apoptosis, both during homeostasis and regeneration in response to ionizing radiation injury. Furthermore, miR-31 has oncogenic properties, promoting intestinal tumorigenesis. Mechanistically, miR-31 acts to balance input from Wnt, BMP, TGFbeta signals to coordinate control of intestinal homeostasis, regeneration and tumorigenesis. We further find that miR-31 is regulated by the STAT3 signaling pathway in response to radiation injury. These findings identify miR-31 as a critical modulator of ISC biology, and a potential therapeutic target for a broad range of intestinal regenerative disorders and cancers. PMID- 28870289 TI - Ethanol production from chitosan by the nematophagous fungus Pochonia chlamydosporia and the entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana. AB - Chitin is the second most abundant biopolymer after cellulose and virtually unexplored as raw material for bioethanol production. In this paper, we investigate chitosan, the deacetylated form of chitin which is the main component of shellfish waste, as substrate for bioethanol production by fungi. Fungal parasites of invertebrates such as the nematophagous Pochonia chlamydosporia (Pc) or the entomopathogens Beauveria bassiana (Bb) and Metarhizium anisopliae (Ma) are biocontrol agents of plant parasitic nematodes (eg. Meloidogyne spp.) or insect pests such as the red palm weevil (Rhynchophorus ferrugineus). These fungi degrade chitin-rich barriers for host penetration. We have therefore tested the chitin/chitosanolytic capabilities of Pc, Bb and Ma for generating reducing sugars using chitosan as only nutrient. Among the microorganisms used in this study, Pc is the best chitosan degrader, even under anaerobic conditions. These fungi have alcohol dehydrogenase (ADH) and pyruvate decarboxylase (PDC) encoding genes in their genomes. We have therefore analyzed their ethanol production under anaerobic conditions using chitosan as raw material. P. chlamydosporia is the largest ethanol producer from chitosan. Our studies are a starting point to develop chitin-chitosan based biofuels. PMID- 28870288 TI - Influence of (p)ppGpp on biofilm regulation in Pseudomonas putida KT2440. AB - The global regulatory molecule (p)ppGpp is synthesized under limited nutrition conditions and involves in many cellular processes in bacteria. (p)ppGpp has been reported to affect biofilm formation in several bacterial species. Here, we found that deletion of (p)ppGpp synthase genes of Pseudomonas putida KT2440 led to enhanced biofilm formation in polystyrene microtitre plates. Besides, the pellicle of this mutant formed at the air-liquid interface lost the robust structure and became frail. The biofilm formation and its structure are mainly determined by exopolysaccharides (EPSs) and adhesins. Transcriptional analysis of four EPS operons designated as pea, peb, alg and bcs and two adhesin genes nominated as lapA and lapF showed that the deletion of (p)ppGpp synthase genes increased the expression of peb, bcs and lapA but repressed the expression of pea and lapF. Furthermore, expression of the regulation factor FleQ was significantly augmented in (p)ppGpp-synthase mutants while the expression of sigma factor RpoS was reduced. Since FleQ and RpoS play important roles in regulating expression of EPS and adhesin genes, (p)ppGpp may mediate the synthesis of biofilm matrix via influencing these regulators to control the biofilm formation and pellicle structure. PMID- 28870286 TI - Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age. AB - Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability. PMID- 28870290 TI - The yeast-like fungus Aureobasidium thailandense LB01 produces a new biosurfactant using olive oil mill wastewater as an inducer. AB - In this study, the biosurfactant production by an Aureobasidium thailandense LB01 was reported for the first time. Different agro-industrial by-products (corn steep liquor, sugarcane molasses, and olive oil mill wastewater) were evaluated as alternative low-cost substrates. The composition of the culture medium was optimized through response surface methodology. The highest biosurfactant production (139+/-16mg/L) was achieved using a culture medium containing yeast extract (2g/L); olive oil mill wastewater (1.5%, w/w); glucose (6g/L) and KH2PO4 (1g/L) after 48h of fermentation. The partially purified biosurfactant exhibited a critical micelle concentration of 550mg/L, reducing the surface tension of water up to 31.2mN/m. Its molecular structure was found to be similar to a lauric acid ester. The biosurfactant exhibited a better performance than the chemical surfactant sodium dodecyl sulfate (SDS) in oil dispersion assays, thus suggesting its potential application in bioremediation. PMID- 28870291 TI - Genomic characterization of an extensively-drug resistance Salmonella enterica serotype Indiana strain harboring blaNDM-1 gene isolated from a chicken carcass in China. AB - OBJECTIVES: The objective of this study was to genetically characterize the antimicrobial resistance mechanisms of Salmonella enterica serotype Indiana C629 isolated from a chicken carcass in China in 2014. METHODS: Antimicrobial susceptibility against a panel of 23 antimicrobial agents was carried out on Salmonella enterica serotype Indiana C629 and assessed according to CLSI standards. Whole-genome sequencing of this isolate was conducted to obtain the complete genome of S. Indiana. RESULTS: Salmonella Indiana C629 expressed an XDR phenotype being resistant to more than 20 antimicrobial agents, including imipenem and meropenem. From the analysis of the resistance mechanisms, two mutations were identified in subunit A of DNA gyrase within the quinolone resistance determining region, in addition to the acquisition of mobile efflux pumps encoding oqxA/B/R. Additionally, four beta-lactamases resistance genes (blaCTX-M-65, blaTEM-1, blaOXA-1, and blaNDM-1), five aminoglycosides resistance genes (aac(3)-IV, aac(6')-Ib-cr, aadA2, aadA5, and aph(4)-Ia), two phenicol resistance genes (catB3 and floR), and five trimethoprim/sulfamethoxazole resistance genes (sul1/2/3 and dfrA12/17) were also identified. A total of 191 virulence genes were identified. Among them, 57 belonged to type-three secretion system (T3SS) encoding genes, 55 belonged to fimbrial adherence encoding genes, and 39 belonged to flagella-encoding genes CONCLUSIONS: This study demonstrated that multi-resistance mechanisms consistent with an XDR-phenotype, along with various virulence encoding genes of a S. Indiana strain in China These findings highlight the importance of cooperation among different sectors in order to monitor the spread of resistant pathogens among food animal, foods of animal origin and human beings that might further take measures to protect consumers' health. PMID- 28870292 TI - Nutrients and host attributes modulate the abundance and functional traits of phyllosphere microbiome in rice. AB - The abundance of phyllosphere bacterial communities of seven genotypes of rice ADT- 38, ADT-43, CR-1009, PB-1, PS-5, P-44, and PB-1509 was investigated, in relation to nutrient dynamics of rhizosphere and leaves. P-44 genotype recorded highest pigment accumulation, while genotypes CR-1009 and P-44 exhibited most number of different bacterial morphotypes, Colony forming units in two media (Nutrient agar and R2A) varied significantly and ranged from 106-107 per g plant tissues. Among the selected 60 distinct morphotypes, IAA and siderophore producers were the dominant functional types. Biocontrol activity against Drechslera oryzae was shown by 38 isolates, while 17 and 9 isolates were potent against Rhizoctonia solani and Magnaporthe oryzae respectively. Principal Component Analysis (PCA) illustrated the significant effects of selected soil and leaf nutrients of seven rice varieties on the culturable phyllospheric population (log CFU), particularly in the R2A medium. Eigen values revealed that 83% of the variance observed could be assigned to Leaf-Fe, Leaf-Mn, chlorophyll b and soil organic carbon (OC). Quantitative PCR analyses of abundance of bacteria, cyanobacteria and archaebacteria revealed a host-specific response, with CR-1009 showing highest number of 16S rRNA copies of bacterial members, while both P-44 and PS-5 had higher cyanobacterial abundance, but lowest number of those belonging to archaebacteria. Nutritional aspects of leaf and soil influenced the abundance of bacteria and their functional attributes; this is of interest for enhancing the efficacy of foliar inoculants, thereby, improving plant growth and disease tolerance. PMID- 28870293 TI - Characterization of multifarious plant growth promoting traits of rhizobacterial strain AR6 under Chromium (VI) stress. AB - Plant growth promoting rhizobacteria (PGPR) can increase the host plant tolerance to cope up with heavy metal induced stress, which can be improve plant growth. Thus, the present study was designed to isolate Cr(VI) tolerant PGPR strain and evaluate its plant growth promoting (PGP) properties under Cr(VI) stress. Rhizobacterial strain AR6 was isolated from the rhizosphere of Phaseolus vulgaris L. and showed 99% homology with Cellulosimicrobium funkei (KM032184) in BLASTn analysis. Strain AR6 was specifically selected due to its high Cr(VI) tolerance (1200MUg/ml) and substantial production of PGP substances. Strain AR6 produced 36.75MUg/ml of indole acetic acid (IAA), 60.40MUg/ml of ammonia and 14.23MUg/ml of exopolysaccharide (EPS). Moreover, strain AR6 showed positive results for catalase, protease, amylase, lipase production and phosphate solubilization. A trend of Cr(VI) concentration dependent progressive decline for PGP traits of strain AR6 was observed excluding EPS which was regularly increased on increasing concentrations of Cr(VI). Among the four tested Cr(VI) concentrations, 250MUg/ml showed the maximum toxicity to PGP activities of strain AR6. Inoculation of rhizobacterial strain AR6 significantly increased the root length of test crops in the presence of Cr(VI) and produced a considerable number of colonizes on the root of versatile dicot and monocot plants. Moreover, strain AR6 exhibited strong antagonistic activity against phytopathogen Aspergillus niger. Thus, the present study suggests that metal tolerant and PGP activities of the rhizobacterial strain AR6 could be exploited for environmental and agricultural issues. PMID- 28870294 TI - Exploring the interaction network of the Bacillus subtilis outer coat and crust proteins. AB - Bacillus subtilis spores, representatives of an exceptionally resistant dormant cell type, are encircled by a thick proteinaceous layer called the spore coat. More than 80 proteins assemble into four distinct coat layers: a basement layer, an inner coat, an outer coat and a crust. As the spore develops inside the mother cell, spore coat proteins synthesized in the cytoplasm are gradually deposited onto the prespore surface. A small set of morphogenetic proteins necessary for spore coat morphogenesis are thought to form a scaffold to which the rest of the coat proteins are attached. Extensive localization and proteomic studies using wild type and mutant spores have revealed the arrangement of individual proteins within the spore coat layers. In this study we examined the interactions between the proteins localized to the outer coat and crust using a bacterial two hybrid system. These two layers are composed of at least 25 components. Self interactions were observed for most proteins and numerous novel interactions were identified. The most interesting contacts are those made with the morphogenetic proteins CotE, CotY and CotZ; these could serve as a basis for understanding the specific roles of particular proteins in spore coat morphogenesis. PMID- 28870296 TI - Targeting the Microbiome for Mental Health: Hype or Hope? PMID- 28870295 TI - Targets of ubiquitin like system in mycobacteria and related actinobacterial species. AB - Protein turnover and recycling is a prerequisite in all living organisms to maintain normal cellular physiology. Many bacteria are proteasome deficient but they possess typical protease enzymes for carrying out protein turnover. However, several groups of actinobacteria such as mycobacteria harbor both proteasome and proteases. In these bacteria, for cellular protein turnover the target proteins undergo post-translational modification referred as pupylation in which a small protein Pup (prokaryotic ubiquitin-like protein) is tagged to the specific lysine residues of the target proteins and after that those target proteins undergo proteasomal degradation. Thus, Pup serves as a degradation signal, helps in directing proteins toward the bacterial proteasome for a turnover. Although the Pup-proteasome system has a multifaceted role in environmental stresses, pathogenicity and regulation of cellular signaling, but the fate of all types of pupylation such as mono and polypupylation on the proteins is still not completely understood. In this review, we present the mechanisms involved in the activation and conjugation of Pup to the target proteins, describing the structural sketch of pupylation and fundamental differences between the eukaryotic ubiquitin-proteasome and bacterial Pup-proteasome systems. We are also presenting a concise classification and cataloging of the complete battery of experimentally identified Pup-substrates from various species of actinobacteria. PMID- 28870297 TI - Amygdalar-Prefrontal Connectivity Changes During Adolescence: Implications for Development of Mood Disorders. PMID- 28870298 TI - A Collaborative Psychopharmacology Research Agenda for Posttraumatic Stress Disorder. PMID- 28870299 TI - A New Perspective on the Mechanisms of Neglect. PMID- 28870300 TI - Enhancing Recovery After Total Knee Arthroplasty. AB - There have been multiple successful efforts to improve and shorten the recovery period after elective total joint arthroplasty. The development of rapid recovery protocols through a multidisciplinary approach has occurred in recent years to improve patient satisfaction as well as outcomes. Bundled care payment programs and the practice of outpatient total joint arthroplasty have provided additional pressure and incentives for surgeons to provide high-quality care with low cost and complications. In this review, the evidence for modern practices are reviewed regarding patient selection and education, anesthetic techniques, perioperative pain management, intraoperative factors, blood management, and postoperative rehabilitation. PMID- 28870301 TI - Perioperative Pain Management and Anesthesia: A Critical Component to Rapid Recovery Total Joint Arthroplasty. AB - Multimodal pain management has become the standard of care following total hip and knee replacement. The advantages include decreasing opioid consumption and its associated side effects, facilitating earlier mobilization, and faster return to function. An effective rapid recovery protocol includes the use of multiple different types of medications targeting each area of the pain pathway, preemptive analgesia, regional nerve blockade, and local infiltration analgesia. PMID- 28870302 TI - Perioperative Pain Management in Hip and Knee Arthroplasty. AB - Total hip and knee arthroplasty is associated with significant perioperative pain, which can adversely affect recovery by increasing risk of complications, length of stay, and cost. Historically, opioids were the mainstay of perioperative pain control. However, opioids are associated with significant downsides. Preemptive use of a multimodal pain management approach has become the standard of care to manage pain after hip and knee arthroplasty. Multimodal pain management uses oral medicines, peripheral nerve blocks, intra-articular injections, and other tools to reduce the need for opioids. Use of a multimodal approach promises to decrease complications, improve outcomes, and increase patient satisfaction after hip and knee arthroplasty. PMID- 28870303 TI - Patient Satisfaction After Total Knee Arthroplasty: A Realistic or Imaginary Goal? AB - This article summarizes the current literature regarding patient satisfaction after total knee arthroplasty. In 10% to 15% of cases, the operation has not met the patients' expectations. The causes of this dissatisfaction are multifactorial, and include patient-related factors, details related to the surgical procedure and prosthesis chosen, perioperative factors, and factors associated with nursing and general medical care. However, surgeons must bear the brunt of patients' dissatisfaction. This dissatisfaction erodes the doctor patient relationship, and may have implications in an emerging health care economy in which doctors and hospitals are reimbursed based on both clinical outcome and patient satisfaction. PMID- 28870304 TI - The Effect of Opioids, Alcohol, and Nonsteroidal Anti-inflammatory Drugs on Fracture Union. AB - The estimated rate of fracture nonunion is between 5% and 10%, adding significant cost to the health care system. The cause of fracture nonunion is multifactorial, including the severity of the injury, patient factors resulting in aberrancies in the biology of fracture, and the side effects of pain control modalities. Minimizing surgeon-controlled factors causing nonunion is important to reduce the cost of health care and improve patient outcomes. Opioids, alcohol, and nonsteroidal anti-inflammatory drugs have been implicated as risk factors for fracture nonunion. Current literature was reviewed to examine the effects of opioids, alcohol, and nonsteroidal anti-inflammatory drugs on fracture union. PMID- 28870305 TI - The Importance of Optimizing Acute Pain in the Orthopedic Trauma Patient. AB - Postoperative pain control is a highly studied topic because of its significant effect on costs, hospital course, and, most importantly, patient satisfaction. Opioid use has been the "status quo" of postoperative pain management but prolongs hospital stays and increases complications. Optimizing acute pain management in patients with orthopedic trauma is important and can translate into significant positive physiologic and financial outcomes. Although multiple viable examples of optimizing acute pain management in the literature demonstrate outcome improvements, implementation has not been widespread. Significant outcome success will depend more on systemwide implementation than a specific regimen for postoperative pain control. PMID- 28870306 TI - Pediatric Perioperative Pain Management. AB - Effective perioperative pain control in pediatric patients undergoing orthopedic surgery remains a challenge. Developing a successful pain control regimen begins preoperatively with assessment of the patient and discussion with the patient and family regarding expectations. Perioperative pain control regimens are customized based on the type of surgery, patient characteristics, and anticipated severity and duration of the postoperative pain. Recent study focuses on multimodal strategies and regional anesthesia options, allowing for decreased opioid use. This article provides an evidence-based overview of preoperative, intraoperative, and postoperative pain control for the pediatric orthopedic patient. PMID- 28870307 TI - Perioperative Pain Management in Pediatric Spine Surgery. AB - Pain management after spinal deformity correction surgery for scoliosis in the pediatric population can be difficult. Deformity correction with posterior spinal fusion causes significant tissue trauma. Historically, pain control has been achieved with intravenous opiates. Opiates provide excellent analgesic effect; however, they have serious consequences when used alone. In adult total joint arthroplasty, multimodal pain control has become an increasingly common method to achieve pain control without these sequelae. Recently, the same techniques have been studied in pediatric spinal deformity correction surgery. This article outlines the state of pain management in pediatric spine patients. PMID- 28870308 TI - Perioperative Pain Management for Upper Extremity Surgery. AB - Upper extremity surgeons are currently faced with a daunting array of anesthesia techniques, ranging from traditional general anesthesia to wide-awake surgery, during which patients can watch their surgeons operate in the morning and return to work as soon as that afternoon. This range of options means that surgeons must consider patient-related factors such as disease process and relevant comorbidities, as well as surgery-related factors such as anatomic location, complexity, length of procedure, and postoperative pain expectations. In general, the least invasive technique is favored, but each patient must be considered individually to ensure the best anesthesia choice. PMID- 28870309 TI - Multimodal Analgesia in Foot and Ankle Surgery. AB - Progress in surgical acute pain management has allowed most foot and ankle surgery to be performed in ambulatory outpatient surgical centers. Multimodal analgesia focuses on improving postoperative pain by combining pharmacologic and other modalities, addressing multiple pain mechanisms and receptor pathways while reducing adverse effects through lower doses of oral medications. Local anesthesia techniques provide excellent pain relief with few adverse events. Multimodal analgesia in foot and ankle surgery provides superior pain relief, and reduced opioid dependence and opioid-related side effects, improving patient satisfaction, safety, and timely return to function. PMID- 28870311 TI - Perioperative Pain Management. PMID- 28870310 TI - Peripheral Nerve Blocks in Foot and Ankle Surgery. AB - Postoperative pain is one of the most important factors in regard to patient outcomes. It has been linked with patient satisfaction, length of stay, and overall hospital costs. Peripheral nerve blocks have provided a safe, effective method to control early postoperative pain when symptoms are most severe. Peripheral nerve blocks, whether used intraoperatively or postoperatively, provide an alternative or adjunct to conventional pain management methods for patients who may not tolerate heavy narcotics or general anesthesia, in particular the elderly and those with cardiopulmonary disease. PMID- 28870313 TI - Long wavelength near-infrared transmission spectroscopy of barley seeds using a supercontinuum laser: Prediction of mixed-linkage beta-glucan content. AB - A supercontinuum laser was used to perform the first transmission measurements on intact seeds with long wavelength near-infrared spectroscopy. A total of 105 barley seeds from five different barley genotypes (Bomi, lys5.f, lys5.g, lys16 and lys95) were measured from 2275 to 2375 nm. The mixed-linkage (1->3,1->4)-beta D-glucan (BG) and protein content was measured with wet chemical analysis for each single seed. A partial least squares model correlated the BG % (w/w) with the spectral measurements with a R2CV and R2PRED of 0.83 and 0.90, respectively. The predictive model for BG could be improved by averaging spectra from the same seed and by replacing the individual seed BG content with the average BG of each barley genotype. PMID- 28870312 TI - Recent advances in microfluidic sample preparation and separation techniques for molecular biomarker analysis: A critical review. AB - Microfluidics is a vibrant and expanding field that has the potential for solving many analytical challenges. Microfluidics show promise to provide rapid, inexpensive, efficient, and portable diagnostic solutions that can be used in resource-limited settings. Researchers have recently reported various microfluidic platforms for biomarker analysis applications. Sample preparation processes like purification, preconcentration and labeling have been characterized on-chip. Additionally, improvements in microfluidic separation techniques have been reported for molecular biomarkers. This review critically evaluates microfluidic sample preparation platforms and separation methods for biomarker analysis reported in the last two years. Key advances in device operation and ability to process different sample matrices in a variety of device materials are highlighted. Finally, current needs and potential future directions for microfluidic device development to realize its full diagnostic potential are discussed. PMID- 28870314 TI - Visual and sensitive fluorescent sensing for ultratrace mercury ions by perovskite quantum dots. AB - Mercury ions sensing is an important issue for human health and environmental safety. A novel fluorescence nanosensor was designed for rapid visual detection of ultratrace mercury ions (Hg2+) by using CH3NH3PbBr3 perovskite quantum dots (QDs) based on the surface ion-exchange mechanism. The synthesized CH3NH3PbBr3 QDs can emitt intense green fluorescence with high quantum yield of 50.28%, and can be applied for Hg2+ sensing with the detection limit of 0.124 nM (24.87 ppt) in the range of 0 nM-100 nM. Furthermore, the interfering metal ions have no any influence on the fluorescence intensity of QDs, showing the perovskite QDs possess the high selectivity and sensitivity for Hg2+ detection. The sensing mechanism of perovskite QDs for Hg2+ is has also been investigated by XPS, EDX studies, showing Pb2+ on the surface of perovskite QDs has been partially replaced by Hg2+. Spot plate test shows that the perovskite QDs can also be used for visual detection of Hg2+. Our research indicated the perovskite QDs are promising candidates for the visual fluorescence detection of environmental micropollutants. PMID- 28870315 TI - Simultaneous fluorescent detection of multiple metal ions based on the DNAzymes and graphene oxide. AB - A novel fluorescent detection strategy for simultaneous detection of Cu2+, Pb2+ and Mg2+ based on DNAzyme branched junction structure with three kinds of DNAzymes and graphene oxide (GO) was presented. Three fluorophores labeled DNA sequences consisted with enzyme-strand (E-DNA) and substrate strand (S-DNA) were annealed to form DNAzyme branched junction structure. In the presence of target metal ion, the DNAzyme was activated to cleave the fluorophore labeled S-DNA. The S-DNA fragments were released and adsorbed onto GO surface to quench the fluorescent signal. The detection limit was calculated to be 1 nM for Cu2+, 200 nM for Mg2+, and 0.3 nM for Pb2+, respectively. This strategy was successfully used for simultaneous detection of Cu2+, Mg2+ and Pb2+ in human serum. Moreover, it had potential application for simultaneous detection of multiple metal ions in environmental and biological samples. PMID- 28870316 TI - Vacuum-assisted headspace solid-phase microextraction: A tutorial review. AB - Headspace solid-phase microextraction (HSSPME) sampling under vacuum conditions is a new and effective approach to accelerate the extraction kinetics of analytes with a low affinity for the headspace. Vacuum-assisted HSSPME (Vac-HSSPME) evolved from this approach and the resulting methods were always found to yield high extraction efficiencies and very good sensitivities within short sampling times and at mild temperatures. Vac-HSSPME preserves the simplicity of regular HSSPME and the only extra step required is that of air-evacuating the sample container before or after introducing the sample. Moreover, fast implementation of the technique is possible when using the latest, simplified and easy to construct sample container that can hold constant low-pressure conditions for extended sampling times. The main objective of the current tutorial is to provide a general strategy that can be applied towards the development of new Vac-HSSPME methods. The most important outcomes of past theoretical investigations are highlighted and a simple criterion for predicting the effect of vacuum on HSSPME sampling of water or water-containing samples is outlined. This theoretical discussion is then used as a background to elucidate the combined effects of low sampling pressure and several other experimental parameters on HSSPME sampling. Specific implications unique to Vac-HSSPME are also discussed, providing practical tips and a troubleshooting guide to new users. The great benefits of adopting the Vac-HSSPME approach are further demonstrated by reviewing all past applications reporting the quantitative and/or qualitative determination of compounds with a low tendency to escape to the headspace in a variety of samples. Vacuum is a new experimental parameter to control and exploit during HSSPME method optimization. The potential applications of Vac-HSSPME in areas like food, environmental and biological analysis are numerous and still remain to be explored. PMID- 28870317 TI - A universal SERS aptasensor based on DTNB labeled GNTs/Ag core-shell nanotriangle and CS-Fe3O4 magnetic-bead trace detection of Aflatoxin B1. AB - A novel universal Surface-enhanced Raman Spectroscopy (SERS) based aptasensor platform for the trace detection of Aflatoxin B1 (AFB1), a common food contaminating mycotoxin, has been constructed, with the aid of the specific interaction between AFB1 and aptamers. The amino-terminal aptamer conjugated magnetic-bead (CS-Fe3O4) and the gold nanotriangles (GNTs)-DTNB@Ag-DTNB nanotriangles (GDADNTs) were used as the capturer and the reporter of AFB1, respectively. Under the optimized assay condition, the platform shows a distinguished sensitivity with the LOD as low as 0.54 pg/mL and the linear range from 0.001 to 10 ng/mL, a high stability of the SERS substrate activity remained three months at least, a decent reproducibility with RSD of ca. 5%, and a good selectivity to the general coexisted interferences. The distinguished sensitivity and selectivity for trace AFB1 detection has been achieved mainly due to the strong Raman enhancement effect of GNTs as the kernel for GDADNTs from the double layer of the reporter molecules, the specificity of aptamer and superparamagnetic CS-Fe3O4 respectively. Furthermore, the proposed SERS aptasensor is universal to other trace molecules detection with the specific aptamers. PMID- 28870318 TI - Assay of DNA methyltransferase 1 activity based on uracil-specific excision reagent digestion induced G-quadruplex formation. AB - DNA methylation catalyzed by DNA methyltransferase plays an important role in many biological processes including gene transcription, genomic imprinting and cellular differentiation. Herein, a novel and effective electrochemical method for the assay of DNA methyltransferase 1(DNMT1) activity has been successfully developed by using uracil-specific excision reagent (USER) induced G-quadruplex formation. Briefly, double stranded DNA containing the recognition sequence of DNMT1 is immobilized on the electrode. Among them, one strand (DNA S1) contains G rich sequence and a cytosine base, while the supplement strand (DNA S2) cotains C rich sequence and a methylated cytosine. Through the activity of DNMT1, the hemimethylated CG recognition sequence of the double stranded DNA are methylated and DNA S2 strand is cleaved and removed after the subsequently treatment with EpiTect fast bisulfite conversion kits and USER, leaving the DNA S1 to form the G quadruplex-hemin DNAzyme for signal amplification. Under optimal-conditions, the method shows wide linear range of 0.1-40 U mL-1 with a detection limit of 0.06 U mL-1. Furthermore, the inhibition assay study demonstrates that SGI-1027 can inhibit the DNMT 1 activity with the IC50 values of 6 MUM in the presence of 160 MUM S-adenosylmethionine. Since this method can detect human DNMT1 activity effectively and has successfully been applied in complex biological samples, it may have great potential in the applications in DNA methylation related clinical practices and biochemical researches. PMID- 28870319 TI - Ultrasensitive electrochemical immunosensor for alpha fetoprotein detection based on platinum nanoparticles anchored on cobalt oxide/graphene nanosheets for signal amplification. AB - An ultrasensitive sandwich-type electrochemical immunosensor was developed for quantitative monitoring of Alpha fetoprotein (AFP). To achieve this objective, an incorporated signal amplification strategy of platinum nanoparticles anchored on cobalt oxide/graphene nanosheets (Pt NPs/Co3O4/graphene) was proposed by acting as the label of secondary antibodies. The prepared label not only empowered by advantages of each component but exhibited better electrochemical performance than single Pt NPs, Co3O4 and graphene, which has shown large specific surface area and good catalytic activity towards the reduction of H2O2. Meanwhile, the nanocomposite of gold nanoparticles adhered on 3-mercaptopropyltriethoxysilane functionalized graphene sheets (Au@MPTES-GS) was used as matrix to accelerate electron transfer and immobilize primary antibodies in this system. The signal amplification mechanism of the matrix and the label were explored successfully. Under optimal conditions, the electrochemical immunosensor exhibited a wide linear range from 0.1 pg mL-1 to 60 ng mL-1 with a low detection limit of 0.029 pg mL-1for AFP. The proposed immunosensor may have promising application in the clinical diagnosis of AFP and other tumor markers. PMID- 28870320 TI - A correlated information removing based interference suppression technique in electronic nose for detection of bacteria. AB - A sensor array with 30 gas sensors is used in the electronic nose (e-nose) for bacteria detection in wound infection. However, the interference is an urgent problem in e-nose, since it would impact on the detection of target due to the cross-sensitivity of gas sensors, especially the background interference caused by carrier gas. The related methods to suppress the background interference are independent component analysis and orthogonal signal correction algorithm which are unreasonable, because it is difficult to obtain the so-called reference vector in complex real-world scenario. Consider that the sampling process of pump suction is divided into three parts: baseline collecting, sample collecting and system purging. In the case of stabilized carrier gas, the information in baseline can be fully used to suppress the interference in sampling stage. Thus a novel and effective correlated information removing based interference suppression (CIRIS) method is proposed. Specifically, the principle of this method is to suppress the interference of the sampling stage by removing the information correlated with baseline samples. Experimental results show that the proposed method (CIRIS with principal component analysis used to calculate the projection matrix) is significantly effective for interference suppression in e nose. PMID- 28870321 TI - New stationary phases for gas chromatography based on polymers with intrinsic porosity. AB - Norbornene polymers with intrinsic porosity were investigated as candidates for polymeric stationary phases in capillary GC. Kinetic and thermodynamic characteristics of the stationary phases were evaluated and turned out that only polymer with vicinal distribution of trimethylsilyl groups (polymer II) provided properties making it potential candidate for application in capillary GC. Columns with stationary phase based on polymer II demonstrated unique selectivity, moderate thermostability and efficiency better than previously studied columns with stationary phase based on poly[(1-trimethylsilyl)-1-propine]. PMID- 28870322 TI - Highly selective enrichment of phosphorylated proteins by using Spore@Fe3+ microspheres. AB - The advantages of spore-based microspheres include high monodispersity, presence of different functional groups (carboxylic, amino, and hydroxyl groups), facile industrial-scale preparation by using cell cultures via fermentation in a potentially cost effective and environment friendly manner, and high uniformity. We developed a novel spore@Fe3+ microsphere for specific capture of phosphoproteins. Caseins (alpha-casein and beta-casein) as phosphoproteins were used to evaluate binding capacity and enrichment factor. The spore@Fe3+ microspheres demonstrate high binding capacity and selectivity for phosphoproteins (1983 and 1818 mg g-1 for alpha-casein and beta-casein, respectively). A mixture of bovine serum albumin and beta-casein at 100:1 ratio displayed an enrichment factor higher than 173-fold, which can nearly be considered "purification" of phosphoproteins. The proposed method is a promising technique in developing more selective, rapid, low cost, and high-throughput platforms for phosphoprotein enrichment, and it presents potential application in investigation of protein functions and in personalized diagnostic tests. PMID- 28870323 TI - Poly-l-cysteine/electrospun copper oxide nanofibers-zinc oxide nanoparticles nanocomposite as sensing element of an electrochemical sensor for simultaneous determination of adenine and guanine in biological samples and evaluation of damage to dsDNA and DNA purine bases by UV radiation. AB - A new nanocomposite film constructed of poly-l-cysteine/zinc oxide nanoparticles electrospun copper oxide nanofibers (PLC/ZnO-NPs-CuO-NFs) was prepared on the surface of the graphite electrode (GE). The novel electrode was successfully applied for the simultaneous determination of guanine (G) and adenine (A), two of the most important components of DNA and RNA. The PLC/ZnO-NPs-CuO-NFs/GE enhanced the anodic peak currents of the purine bases conspicuously and could determine them sensitively and separately in 0.1 M phosphate buffer solution at the physiological pH (7.0). The synthesized nanofibers, nanoparticles and nanocomposite were characterized by different methods such as Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), scanning electron microscopy (SEM), field emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and energy dispersive X ray analysis (EDS). Under the optimum operating conditions, linear calibration curves were obtained in the range of 0.05-6.78 and 0.01-3.87 MUM with a detection limit of 12.48 and 1.25 nM for G and A, respectively. The proposed method was applied to quantify A and G in three different DNA samples with satisfactory results. In addition, damage to human blood double-stranded DNA (dsDNA) and DNA purine bases (liberated in previously hydrolyzed human blood dsDNA) caused by UV C and UV-B were evaluated. The results demonstrated that the proposed biosensing platform not only provides a novel and sensitive approach to detecting DNA damage, but also can be used for simultaneous determination of purine bases and major products of DNA oxidative damage. PMID- 28870324 TI - Photoelectrochemical detection of copper ions by modulating the growth of CdS quantum dots. AB - We discovered that copper ions (Cu2+) catalyze the oxidation of cysteine (CSH) by oxygen (O2) to modulate the growth of CSH-capped cadmium sulfide (CdS) nanoparticles (NPs). This new chemical process was applied to sensitive fluorogenic and photoelectrochemical (PEC) detection of Cu2+ ions in real samples of mineral and tap water using the photocatalytic activity of the resulting NPs. Disposable screen-printed electrodes (SPCEs) modified with electroactive polyvinylpyridine bearing osmium complex (Os-PVP) by cyclic voltammetry (CV) were employed for PEC analytical system. CdS NPs formed during the assay photocatalyze oxidation of 1-thioglycerol (TG) upon application of 0.3 V vs. Ag/AgCl to SPCEs. Os-PVP complex mediated the electron transfer between the electrode surface and CdS NPs. We proved that our assays did not suffer from interference from other ions accompanying Cu2+ and the sensitivity of our assays covers the European Union standard limit of Cu2+ ions in drinking water. PMID- 28870325 TI - GC-MS based metabolomics of colon cancer cells using different extraction solvents. AB - The increasing incidence of colorectal cancer enforces the development of novel methodologies and protocols to deepen in the molecular mechanisms that govern disease pathophysiological events. The aim of this work is to deepen in the optimum metabolite extraction protocol from adherent mammalian cells of colon cancer for high throughput metabolomics using gas chromatography coupled to mass spectrometry (GC-MS). GC-MS results showed that metabolic information obtained from colon cancer cells was highly dependent on metabolite extraction selection, which at the same time is extremely influenced by the analytical platform. A further purpose of this investigation is to uncover an unexplored portion of HT 29 colon cancer cells metabolome, complementary to other already explored by CE MS and LC-MS methods. At this respect, a total of 150 metabolites were identified in HT-29 colon cancer cells by GC-MS. The extraction protocol with acetonitrile isopropanol-water was the most appropriate for fatty acids and related pathways analysis. Most of the metabolites involved in pathways of amino acids, glutathione, amino sugars and other polar metabolites were better extracted with acidified water, although water extraction showed the best overall reproducibility. Although pathways involving nitrogenous bases could be investigated using organic or aqueous extracts, a higher number of metabolites involved in these pathways were identified in the aqueous extracts. In addition, metabolite extraction protocol was observed to be crucial for the determination of potentially interesting clusters of metabolites. PMID- 28870326 TI - Molecularly imprinted polymers immobilized on 3D printed scaffolds as novel solid phase extraction sorbent for metergoline. AB - In the present work, a novel solid phase extraction (SPE) sorbent was developed based on molecularly imprinted polymers (MIPs) immobilized on 3D-printed scaffolds using polymer networks as MIP-immobilizing layer. MIPs were produced by precipitation polymerization in acetonitrile (ACN) using methacrylic acid (MAA) as functional monomer, trimethylolpropane trimethacrylate (TRIM) as crosslinker and metergoline as model template which allows final recognition of ergot alkaloid mycotoxins. Scanning electron microscopy (SEM) and dynamic light scattering (DLS) analyses showed an average MIP particle size of 457 +/- 145 nm. Functional MIP analysis revealed dissociation constants (KD) of 0.29 and 38.90 MUM for high and low affinity binding sites respectively. Subsequently, crosslinking of polymer network building blocks was applied as MIP immobilization method on poly-epsilon-caprolactone (PCL) which was selected as polymer model. Methodology optimization and subsequent evaluation were first realized on 2D PCL surfaces. Based on analyses such as optical evaluation of MIP availability after immobilization through SEM and depth profilometry, an optimal polymer network building block concentration of 7.5 w/w% was selected. In a final part, transfer of MIP immobilization to 3D PCL scaffolds was successfully realized. Functional analysis showed that the newly developed SPE sorbents were able to rebind 44.87 +/- 8.30% of a 1 MUM metergoline solution. In conclusion, a new type of SPE sorbent was developed for the detection of metergoline by the use of MIP functionalized polymer scaffolds. The applied technology opens up future possibilities for the extraction of a broad range of components such as other mycotoxins. PMID- 28870327 TI - The 5-azoniaspiro[4.4]nonyl group for improved MS peptide analysis: A novel non fragmenting ionization tag for mass spectrometric sensitive sequencing of peptides. AB - A novel class of ionization tags, based on 5-azoniaspiro[4.4]nonyl (ASN+) scaffold were designed for improved analysis of peptides by electrospray tandem mass spectrometry (ESI-MS/MS). A new labeling agent, 1-{[3-oxo-3 (pentafluorophenoxy)propyl]carbamoyl}-5-azoniaspiro[4.4]nonane, was developed to react with amine and/or thiol group-containing peptides. The ionization efficiency of peptides resulting from derivatization was enhanced 10-100 fold, depending on the peptide sequence and hydrophobicity of the ionization tag. The proposed tags are completely stable during collision-induced dissociation (CID) experiments: they do not undergo unwanted fragmentation via Hofmann elimination and, more importantly, they cannot be removed by intermolecular nucleophilic attack. Moreover, CID of the derivatized peptide ions generates a dominant series of y-type fragment ions with a high sequence coverage. The proposed procedure was successfully tested on digested model proteins: ubiquitin and bovine serum albumin. We also synthesized isotopically labeled analog of 5 azoniaspiro[4.4]nonyl tag to check its applicability for comparative quantitative LC-ESI-MS analysis. The obtained results indicate the general usefulness of the 5 azoniaspiro[4.4]nonyl quaternary ammonium ionization tag for LC-ESI-MS/MS sequencing and quantification of peptides, especially for those of low abundance. PMID- 28870328 TI - Sphingolipids in marine microalgae: Development and application of a mass spectrometric method for global structural characterization of ceramides and glycosphingolipids in three major phyla. AB - Sphingolipid compositions are crucial for the structural and physiological properties of microalgae membranes. In the present study, we developed a quadrupole time-of-flight (Q-TOF) mass spectrometric method based on MSE data collection for the identification of sphingolipids with high efficiency, selectivity, sensitivity and mass accuracy and applied this method for precise structural identification and quantitative profiling of ceramides and glycosphingolipids in total lipid extracts from 17 strains of microalgae, including 11 strains of diatom, 3 strains of dinoflagellate and 3 strains of haptophyta. Using this method, four species of sphingolipids including 27 ceramides, 13 monosaccharide ceramides, 18 disaccharide ceramides and 18 trisaccharide ceramides were identified. The compositions of sphingolipid included glycosyl moieties, long chain bases and N-acyl chains showed a significant difference among different microalgae categories. Some long chain bases including d19:2, d19:3 and d19:4, glycosyl moieties including disaccharide and trisaccharide, and N-acyl chains such as 14:0, 14:1, 24:0, 24:1, h18:1, h19:1 and h22:0-2 can be chosen as the molecular signature for microalgae from three major phyla. This methodology will be useful for a wide range of physiological and pathological studies of sphingolipids. Furthermore, the diversity of sphingolipid structure could provide a new criterion for microalgae chemotaxonomy. PMID- 28870329 TI - Molecular absorption measurements with an optical fibre coupled array of ultra violet light-emitting diodes. AB - A photometric detector based on eight different light-emitting diodes covering the ultraviolet range from 255 nm to 350 nm is described. These are coupled with fused silica optical fibres to a conventional cuvette with 1 cm optical path length or to a low volume flow through cell for detection in high-performance liquid chromatography. Photodiodes are employed for the measurement of the transmitted intensity as well as of a reference signal and the photocurrents are processed with a log-ratio amplifier to obtain a voltage proportional to absorbance values. The wavelength desired for the measurement at hand is selected by electronically switching on the requisite light-emitting diode. The detector was found to have a low noise level of 80 MUAU. In batch-wise measurements as well as in detection for high-performance liquid chromatography dynamic ranges of 2-3 orders of magnitude were possible. Reproducibilities in peak areas for the latter application were better than 1%. PMID- 28870330 TI - Evidence-based guidelines for being supportive of people who stutter in North America. AB - PURPOSE: While many resources, particularly those available on the Internet, provide suggestions for fluent speakers as they interact with people who stutter (PWS), little evidence exists to support these suggestions. Thus, the purpose of this study was to document the supportiveness of common public reactions, behaviors, or interventions to stuttering by PWS.Methods 148 PWS completed the Personal Appraisal of Support for Stuttering-Adults. Additionally, a comparison of the opinions of adults who stutter based on gender and their involvement in self-help/support groups was undertaken. Results Many of the Internet-based suggestions for interacting with PWS are aligned with the opinions of the participants of this study. Significant differences were found amongst people who stutter on the basis of gender and involvement in self-help groups.Conclusions Lists of "DOs and DON'Ts" that are readily available on the Internet are largely supported by the data in this study; however, the findings highlight the need for changing the emphasis from strict rules for interacting with people who stutter to more flexible principles that keep the needs of individual PWS in mind. PMID- 28870331 TI - Atypical non-verbal sensorimotor synchronization in adults who stutter may be modulated by auditory feedback. AB - PURPOSE: To investigate if non-verbal sensorimotor synchronization abilities in adult individuals who stutter (IWS) differ from non-stuttering controls (NS) under various performance conditions (tempo, auditory feedback, use of hands [single/both] and rhythm). METHODS: Participants were 11 IWS (5 males, 6 females, Mean age=25.8, SD=8.7) and 11 age- and gender-matched controls (Mean age=24.4, SD=8.4). During the experiment, participants were asked to prepare three melodies and subsequently perform them with a metronome at different rates and auditory feedback modalities (non-altered and suppressed). For each task/condition we tracked timing asynchrony related to the steady metronome beat. RESULTS AND CONCLUSIONS: Overall, IWS displayed significantly higher timing asynchrony. Of all conditions, auditory-feedback distinguished IWS from NS most strongly, a subgroup of IWS significantly benefitting from the absence of auditory feedback. In addition, IWS showed a non-significant trend of higher negative mean asynchrony (NMA) and were more affected by the slower rate and increased rhythmic complexity and occasionally suggested poorer beat perception. These results suggest aberrant timing of sensorimotor network interaction associated with the origin of developmental stuttering. PMID- 28870332 TI - Rethinking covert stuttering. AB - PURPOSE: The experience of passing as fluent, also called covert stuttering, has been uncritically framed as an inherently negative pursuit. Historically passing has been understood as a repression of one's true, authentic self in response to either psychological distress or social discrimination. The authors of this paper seek a more nuanced understanding of passing. We ask, how must a person relate to herself in order to pass as fluent? METHODOLOGY: This is a qualitative research study in which the authors utilized the ethical theories of philosopher Michel Foucault to contextualize data obtained from semi-structured interviews with nine participants who pass as fluent. RESULTS: Rather than a repression of an authentic self our data suggests passing is more usefully understood as a form of resistance by people who stutter to a hostile society. Participants learned from experiences of delegitimization that their stuttering had ethical ramifications. Consequently, they used a variety of self-forming practices to pass and thereby achieve the privileges that come with perceived able-bodiedness. CONCLUSION: Passing as fluent is not an inauthentic form of stuttering but a form of stuttering that is produced through the use of specific technologies of communication. These technologies of communication are constituted by the unique ethical relationship of the person who stutters with herself. Passing can be understood as an active form of resistance rather than a passive form of repression. By theorizing passing as fluent as an ethical relationship, we open up the possibility of changing the relationship and performing it differently. PMID- 28870333 TI - Stuttering generalization self-measure: Preliminary development of a self measuring tool. AB - INTRODUCTION: Generalization of treatment is considered a difficult task for clinicians and people who stutter (PWS), and can constitute a barrier to long term treatment success. To our knowledge, there are no standardized tests that collect measurement of the behavioral and cognitive aspects alongside the client's self-perception in real-life speaking situations. PURPOSE: This paper describes the preliminary development of a Stuttering Generalization Self-Measure (SGSM). The purpose of SGSM is to assess 1) stuttering severity and 2) speech anxiety level during real-life situations as perceived by PWS. Additionally, this measurement aims to 3) investigate correlations between stuttering severity and speech-anxiety level within the same real-life situation. METHOD: The SGSM initially reported includes nine speaking situations designed that are developed to cover a variety of frequent speaking scenario situations. However, two of these were less commonly encountered by participants and subsequently not included in the final analyses. Items were created according to five listener categories (family and close friends, acquaintances, strangers, persons of authority, and giving a short speech to small audience). Forty-three participants (22 PWS, and 21 control) aged 18 to 53 years were asked to complete the assessment in real-life situations. RESULTS: Analyses indicated that test-retest reliability was high for both groups. Discriminant validity was also achieved as the SGSM scores significantly differed between the controls and PWS two groups for stuttering and speech-anxiety. Convergent validity was confirmed by significant correlations between the SGSM and other speech-related anxiety measures. PMID- 28870334 TI - The Yin and Yang of It. PMID- 28870335 TI - Sisyphus. PMID- 28870336 TI - Unconscious Bias. PMID- 28870337 TI - Research advances on the multiple uses of Moringa oleifera: A sustainable alternative for socially neglected population. AB - Moringa oleifera Lam (Moringaceae) is a plant with high nutritional and medicinal value. Native to India, it is now widely distributed throughout tropical and subtropical regions of the world. Its different parts are sources of proteins, vitamins and minerals and present different pharmacological and biotechnological potential. Moreover, M. oleifera seeds are widely used in water and effluent treatment, for their coagulation, flocculation and sedimentation properties, their ability of improving water quality, by reducing organic matter and microbial load, with special applicability in intensive animal production systems, such as aquaculture. In addition, due to its high nutritional value and several medicinal properties, this tree may act as a nutritional and medical alternative for socially neglected populations. In this context, this review gathers information on M. oleifera, emphasizing its chemical constituents, nutritional, pharmacological and antimicrobial properties, applications in the treatment of water effluents, and ecological and social aspects. PMID- 28870338 TI - Alternate paradigms on Zika virus-related complications: An analytical review. AB - The proportion of the reported cases of Zika virus (ZIKV) infection reached the status of a pandemic. Numerous studies are being conducted on the isolation of ZIKV strains from various epidemics, diagnosis of the infections, various animal models and cell culture designs to study the pathogenesis of ZIKV in the attempts to find an effective ZIKV vaccine. This review focuses upon the 'Off-Spectrum' body of studies which analyses the epidemiology, pathogenesis and other attributes of ZIKV in the light of various dissident hypotheses. PMID- 28870339 TI - Birds and poultries toxoplasmosis in Iran: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the overall prevalence of Toxoplasma gondii infection among birds and poultries in Iran. METHODS: Data were systematically collected from 1983 to 2016 in Iran on the following electronic databases: PubMed, Google Scholar, Science Direct, Scopus, Web of Science, Magiran, Irandoc, IranMedex, and Scientific Information Database. Additionally, the abstracts of national scientific congresses and dissertations were included. RESULTS: A total of 20 articles in the field of birds and poultries toxoplasmosis, totally examining 4563 cases with 754 positive results reporting the overall prevalence of infection from all parts of Iran could fulfill our eligibility criteria. The overall estimated prevalence included in chicken 20% (95% CI: 3%-38%) in chicken, pigeons 8% (95% CI: -17%-33%) and in sparrows 15% (95% CI: -25%-54%). CONCLUSION: Although there is a lack in data about poultries and birds toxoplasmosis in Iran, our meta-analysis revealed that infection rate is high among birds and poultries in Iran. More studies are needed to manage controlling programs and prevention strategies among poultries in Iran. PMID- 28870340 TI - GC-MS analysis of volatile compounds of Perilla frutescens Britton var. Japonica accessions: Morphological and seasonal variability. AB - OBJECTIVE: To investigate the composition of volatile compounds in the different accessions of Perilla frutescens (P. frutescens) collected from various habitats of China and Japan. METHODS: In the present study, the essential oil from the leaves of P. frutescens cultivars from China and Japan was extracted by hydro distillation and the chemical composition and concentration of the volatile components present in the oils were determined by gas chromatography-mass spectrometry (GC-MS) analysis. RESULTS: Among the volatile components, the major proportion was of perilla ketone, which was followed by elemicin and beta caryophyllene in the Chinese Perilla cultivars. The main component in the oil extracted from the Japanese accessions was myristicin, which was followed by perilla ketone and beta-caryophyllene. We could distinguish seven chemotypes, namely the perilla ketone (PK) type, perilla ketone, myristicin (PM) type, perilla ketone, unknown (PU) type, perilla ketone, beta-caryophyllene, myristicine (PB) type, perilla ketone, myristicin, unknown (PMU) type, perilla ketone, elemicine, myristicin, beta-caryophyllene (PEMB) type, and the perilla ketone, limonene, beta-cryophyllene, myristicin (L) type. Most of the accessions possessed higher essential oil content before the flowering time than at the flowering stage. The average plant height, leaf length, leaf width of the Chinese accessions was higher than those of the Japanese accessions. CONCLUSION: The results revealed that the harvest time and geographical origin caused polymorphisms in the essential oil composition and morphological traits in the Perilla accessions originating from China and Japan. Therefore, these chemotypes with desirable characters might be useful for industrial exploitation and for determining the harvest time. PMID- 28870341 TI - Production, characterization and biological activities of acidic exopolysaccharide from marine Bacillus amyloliquefaciens 3MS 2017. AB - OBJECTIVE: To evaluate in-vitro antioxidant, anti-inflammatory and antitumor abilities against human breast adenocarcinoma (MCF7) and human prostate cancer (PC3) as well as the suppressor effect of bacterial exopolysaccharide (BAEPS) on Ehrlich ascites carcinoma (EAC). METHODS: In-vitro antioxidants characters of BAEPS were determined using various methods, while anti-inflammatory activity was estimated against cyclooxygenase (COX-1 and COX-2). In-vitro study, anticancer against MCF7 and PC3 were assessed by the mitochondrial dependent reduction of yellow MTT. In in-vivo study against EAC progression, mice were inoculated with EAC cells and then were orally administered BAEPS at 200 mg/kg after 24 h (equals to 0.10 of determined LD50)/10 d. RESULTS: BAEPS was acidic exopolysaccharide contained uronic acid (12.3%) and sulfate (22.8%) with constitution of glucose, galactose and glucuronic acid in a molar ratio 1.6:1.0:0.9, respectively, with a molecular mass of 3.76 * 104 g/mol. BAEPS appeared potent antioxidant characters as free radical scavenging, oxygen reactive species scavenging and metal chelation, while its reducing power was low. BAEPS showed selective anti inflammatory activity against COX-2 than COX-1, COX-2 selective. BAEPS exhibited potent and selective effect to breast cell cancer MCF7, the death percentage was 65.20% with IC50 = 70 MUg/mL and IC90 = 127.40 MUg/mL. BAEPS decreased counted viable EAC cells and induced non-viable cells. BAEPS improved all assessed hematological parameters. These improvements were reflected in the increasing median survival time and significant increment (P < 0.05) in life span. CONCLUSIONS: BAEPS has anti-tumor activity with a good margin of safety. The anti tumor activity of BAEPS may be due to its content from sulfated groups and uronic acids and they have antioxidant and anti-inflammatory properties. PMID- 28870342 TI - Chemical analysis and in vitro antimicrobial effects and mechanism of action of Trachyspermum copticum essential oil against Escherichia coli. AB - OBJECTIVE: To find a natural plant essential oil (EO) with excellent antimicrobial effects on food-borne bacteria and to explore the mechanism of its antimicrobial function against Escherichia coli (E. coli). METHODS: The antimicrobial activity of seven EOs against Gram-negative E. coli ATCC 8739 and Gram-positive Staphylococcus aureus ATCC 6538 was investigated using agar disk diffusion method, and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of each EO was determined using the broth dilution method. The chemical composition of the Trachyspermum copticum (T. copticum) EO was analyzed using gas chromatography-mass spectrometry (GC/MS). In order to explore the mechanism of the antimicrobial action, 1 MIC and 2 MIC of T. copticum EO was added to a suspension of E. coli, the growth curve and the scanning electron microscopy (SEM) analysis of E. coli, and the release of cell constituents and protein and potassium ions from the bacterial cell were measured. RESULTS: The T. copticum EO had the best antimicrobial activity against the test bacteria, and 10 compounds accounting for 94.57% of the total oil were identified, with the major components being thymol (46.22%), p-cymene (19.03%), and gamma-terpinene (22.41%). The addition of 1 MIC that T. copticum EO significantly inhibited the growth of E. coli and increased the release of cell constituents and protein and potassium ions from the bacterial cells. Scanning electron micrographs showed that T. copticum EO caused most of the E. coli cell membranes to collapse and rupture, leading to cell death. CONCLUSIONS: These results indicate that T. copticum EO is a good natural antimicrobial agent for food-borne pathogens. PMID- 28870343 TI - Solvent-solvent fractionations of Combretum erythrophyllum (Burch.) leave extract: Studies of their antibacterial, antifungal, antioxidant and cytotoxicity potentials. AB - OBJECTIVE: To evaluate the biological activities of Combretum erythrophyllum (C. erythrophyllum) leaf extracts against infectious diseases' pathogenesis and their cytotoxicity potentials. METHODS: Powdered leaf material (300 g) of C. erythrophyllum was extracted (1:10 w/v) using acetone to obtain the crude extract. Liquid-liquid fractionation was performed on the crude acetone extract (30 g) using solvents of different polarity. The bioautographic method was used to detect the inhibition of bacterial and fungal growth by active compounds present in the crude and fractions. The extracts were then tested on bacterial strains: Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa; fungal strains: Candida albicans (C. albicans), Cryptococcus neoformans, and Aspergillus fumigatus, by microtitre dilution method for MIC determination. RESULTS: The extracts MIC values ranged between 0.08 and 2.50 mg/mL against the tested pathogens. Water fraction had the highest activity against bacteria strains, while the fungal assay revealed crude acetone extract and ethyl acetate fraction to be active against C. albicans (1.25 mg/mL), dichloromethane extract against C. albicans and A. fumigatus (0.16 mg/mL). Extract fractions showed a good antioxidant activity via DPPH, ABTS and hydroxyl radical scavenging assays, in the order: ethyl acetate > water > acetone > dichloromethane > hexane. The toxicity level of crude extract and fractions evaluated in Vero monkey kidney cells ranged from 34 to 223 MUg/mL, while doxorubicin (IC50 = 7.19 MUg/mL) served as the positive control. CONCLUSIONS: It can be concluded that the extracts of C. erythrophyllum are safe for medicinal use in folk medicine for treating infectious and stress related diseases. PMID- 28870344 TI - Association between FGFR4 gene polymorphism and high-risk HPV infection cervical cancer. AB - OBJECTIVES: To discuss the association between FGFR4 gene polymorphism rs351855 (Glu388Aly) and the susceptibility and chemotherapeutic effect of cervical cancer infected by high-risk type HPV. METHODS: A total of 162 patients with high-risk HPV cervical cancer and 162 healthy women were collected and the genotypes of the FGFR4 rs351855 locus were detected. The genotype distributions in the two groups were compared. The cervical cancer patients were divided into four groups which namely good therapeutic effect group and bad therapeutic effect, recurrence or metastasis and no recurrence or metastasis group respectively, and the risks of different genotype on the curative effect and prognosis were analyzed by Logistic regression. The survival time of patients with different genotypes was compared. RESULTS: There was no statistic difference in FGFR4 rs351855 genotype distribution between the patients group and control group (P > 0.05), among which the risk of chemotherapy failure on GA + AA patients was 3.257 times as much as that of the GG patients, and the risk of recurrence or metastasis of GA + AA patients was 2.783 times as much as that of the GG patients. For AA patients, the risk of chemotherapy failure and the risk of relapse and metastasis are 3.833 and 3.406 times, respectively, as much as that of the GG patients. The overall survival of GA and AA patients was shorter than that of the GG patients, and significant difference was found (chi2 = 7.098, P = 0.029). The difference in overall survival between GA + AA patients and GG patients was almost statistically significant (chi2 = 3.634, P = 0.057). CONCLUSIONS: The FGFR4 rs351855 polymorphism is not associated with the susceptibility of high-risk HPV cervical cancer, but patients with gene A was at higher risk of unfavorable chemotherapy prognosis compared with patients with GG. PMID- 28870345 TI - Mechanism of antagonistic effects of Andrographis paniculata methanolic extract against Staphylococcus aureus. AB - OBJECTIVE: To investigate the effects of Andrographis paniculata (Burm.f.) Wall. Ex Nees (A. paniculata) on expressions and activities of catalase, superoxide dismutase and alkylhydroperoxide reductase C in Staphylococcus aureus (S. aureus) with respect to its survival in vitro. METHODS: Antioxidative property of methanolic leaves extract of A. paniculata (0.06 mg/mL). Minimum inhibitory concentration (MIC) was determined by its ability to reduce hydrogen peroxide (H2O2) toxicity against S. aureus ATCC 25923 [(3.8 * 108) cfu/mL]. Effects of the extract on expressions of katA (encoding catalase), sodA and sodM [encoding superoxide dismutases (SODs)], and ahpC [encoding alkylhydroperoxide reductase C (AhpC)] in S. aureus were determined by RT-qPCR and corresponding enzyme activity assays were performed. Nitroblue tetrazolium reduction (NBT) assay was performed to determine effects of the extract on intracellular and extracellular levels of O2- in S. aureus. RESULTS: Cells challenged with 7.5 mmol/L H2O2 showed 0% survival in 30 min whereas 25% survived after treatment with the extract and H2O2. Cells that were treated with the extract alone had 43% survival in the same exposure period. Expressions of sodA and sodM genes in extract-treated cells were lowered 0.8-fold and 0.7-fold, respectively with decrease in total SOD activity of 26.8 U compared to untreated cells, 32.4 U (P < 0.05). In contrast, extract treated S. aureus cells showed 3.3-fold increase in katA expression with corresponding increase in catalase activity of 1.828 U compared to untreated cells which was 1.248 U, (P < 0.05). More profoundly, ahpC expression was increased 61-fold in extract-treated cells, (P < 0.05) with corresponding increase in AhpC activity of 0.018 U compared to untreated cells, 0.012 U, (P < 0.05). Extract-treated cells had significantly lower intra- and extracellular O2- levels with absorbance readings (A575 nm) of 0.340 and 0.524 compared to untreated cells which were 0.516 and 0.928 (P < 0.05), respectively. CONCLUSIONS: Taken together these results suggest that the low MIC of A. paniculata methanolic leaves extract (0.06 mg/mL) reduce H2O2 toxicity and more importantly, was in itself effectively inhibitory against S. aureus. Further, our observations suggest that a probable mode of its inhibitory mechanism against S. aureus is by reducing total SOD activity through downregulation of sodA and sodM expressions. PMID- 28870346 TI - Effect of Taoren Quyu Decoction on human endometrial cells and its anti endometriosis activity in rats. AB - OBJECTIVE: To study the effect of Taoren Quyu Decoction (TQD) on endometrial cells in patients with endometriosis (EMs) and EMs in rats. METHODS: A total of 60 female Wistar rats were randomly divided into 4 groups, namely, normal group, model group, positive group and TQD group, each group having 15 rats. Except the normal group, EMs model was established in the other three groups by transplanting the rat autologous endometrium. After 4 weeks of intragastric administration, blood, eutopic and ectopic endometrial tissues of rats in each group were collected to detect the serum levels of estrogen (E2), cancer antigen 125 (CA125), endometrial antibody (EMAb), and expressions of microvessel density (MVD), vascular endothelial growth factor (VEGF) and angiopoietin (Ang-2). The volume of endometriosis cyst was determined simultaneously. For the in vitro culture of human endometrial cells, 4 groups, namely, normal group, model group, positive group and TQD group were used. The positive group and TQD group were treated with danazol and TQD respectively. Then 24 h after the treatment, the expressions of survivin and tumor suppressor gene (p53) of each group were detected. RESULTS: The volumes of the endometriosis cysts in the positive group and the TQD group were significantly reduced compared with the model group (P < 0.05). The serum levels of E2, CA125 and EMAb, and the expressions of MVD, VEGF and Ang-2 in the model group were significantly increased compared with the normal group (P < 0.05); while they were all significantly reduced in the positive group and TQD group (P < 0.05). Compared with the normal group, the expression of survivin in the model group was significantly up-regulated (P < 0.05), and expression of p53 was significantly reduced (P < 0.05); compared with the model group, the expressions of survivin in the positive and TQD groups were significantly decreased (P < 0.05), and expression of p53 was significantly up regulated (P < 0.05). The difference between positive group and TQD group was not statistically significant (P > 0.05). CONCLUSIONS: TQD has a significant anti-EMs effect, and its mechanism of action may be related to anti-angiogenesis and promoting apoptosis of ectopic endometrial cell. PMID- 28870347 TI - In vitro inhibitory analysis of consensus siRNAs against NS3 gene of hepatitis C virus 1a genotype. AB - OBJECTIVE: To explore inhibitory effects of genome-specific, chemically synthesized siRNAs (small interference RNA) against NS3 gene of hepatitis C virus (HCV) 1a genotype in stable Huh-7 (human hepatoma) cells as well as against viral replication in serum-inoculated Huh-7 cells. METHODS: Stable Huh-7 cells persistently expressing NS3 gene were produced under antibiotic gentamycin (G418) selection. The cell clones resistant to 1000 MUg antibiotic concentration (G418) were picked as stable cell clones. The NS3 gene expression in stable cell clone was confirmed by RT-PCR and Western blotting. siRNA cell cytotoxicity was determined by MTT cell proliferation assay. Stable cell lines were transfected with sequence specific siRNAs and their inhibitory effects were determined by RT PCR, real-time PCR and Western blotting. The viral replication inhibition by siRNAs in serum inoculated Huh-7 cells was determined by real-time PCR. RESULTS: RT-PCR and Western blot analysis confirmed NS3 gene and protein expression in stable cell lines on day 10, 20 and 30 post transfection. MTT cell proliferation assay revealed that at most concentrated dose tested (50 nmol/L), siRNA had no cytotoxic effects on Huh-7 cells and cell proliferation remained unaffected. As demonstrated by the siRNA time-dependent inhibitory analysis, siRNA NS3-is44 showed maximum inhibition of NS3 gene in stable Huh-7 cell clones at 24 (80%, P = 0.013) and 48 h (75%, P = 0.002) post transfection. The impact of siRNAs on virus replication in serum inoculated Huh-7 cells also demonstrated significant decrease in viral copy number, where siRNA NS3-is44 exhibited 70% (P < 0.05) viral RNA reduction as compared to NS3-is33, which showed a 64% (P < 0.05) decrease in viral copy number. siRNA synergism (NS3-is33 + NS3-is44) decreased viral load by 84% (P < 0.05) as compared to individual inhibition by each siRNA (i.e., 64%-70% (P < 0.05)) in serum-inoculated cells. Synthetic siRNAs mixture (NS5B-is88 + NS3-is33) targeting different region of HCV genome (NS5B and NS3) also decreased HCV viral load by 85% (P < 0.05) as compared to siRNA inhibitory effects alone (70% and 64% respectively, P < 0.05). CONCLUSIONS: siRNAs directed against NS3 gene significantly decreased mRNA and protein expression in stable cell clones. Viral replication was also vividly decreased in serum infected Huh-7 cells. Stable Huh-7 cells expressing NS3 gene is helpful to develop anti hepatitis C drug screening assays. siRNA therapeutic potential along with other anti-HCV agents can be considered against hepatitis C. PMID- 28870348 TI - Clinical study inpatient-reported outcomes after binocular implantation of aspheric intraocular lens of different negative spherical aberrations. AB - OBJECTIVE: To compare patient-reported outcomes after implantation of the ZA9003 intraocular lens (IOLs), or the MCX11 ASP IOLs or the spherical IOLs (HQ-201HEP). METHODS: Prospective nonrandomized controlled trial was used. A total of 105 patients (210 eyes) were divided into three groups according to the type of IOLs: ZA9003 (35 patients, 70 eyes), MCX11 ASP (35 patients, 70 eyes) or HQ-201HEP (35 patients, 70 eyes). The main outcome was scores of Catquest nine-item short-form questionnaire. Additional outcome was best corrected visual acuities, spherical aberration (SA) and total higher-order aberrations (HOAs). RESULTS: The global score was significantly lower in the spherical IOL group than the aspherical IOL group of -020 MUm SA (P < 0.05) and the aspherical IOL group of -027 MUm SA (P < 0.05), and no significant difference was found in the global score between the aspherical IOL group of -020 MUm SA than the aspherical IOL group of -027 MUm SA (P > 0.05). Significant differences were also found in question 2, question 5, question 6 and question 8 between the spherical IOLs and the aspherical IOLs. CONCLUSION: Implantation of an aspherical IOL could improve vision-related quality of life compared with a spherical IOL. However, there were no statistically significant differences in vision-related quality of life between aspheric IOLs with different negative spherical aberrations. PMID- 28870349 TI - Effect of axial vertical vibration on degeneration of lumbar intervertebral discs in modified bipedal rats: An in-vivo study. AB - OBJECTIVE: To assess the effects of axial vibrations on gene expression and lumbar intervertebral disc degeneration in vivo. METHODS: A modified bipedal rat model was established using a brachial plexus rhizotomy approach to imitate human upright posture. The experimental animals were randomly divided into three groups: control, vertical vibration, and whole-body vibration. Gene expression in degeneration of the intervertebral discs was assessed by reverse transcription quantitative polymerase chain reaction. RESULTS: The expression of aggrecan, Col1alpha1, Col2alpha1, and decorin were shown to be up-regulated in 14-week-old rats in the vertical vibration and whole-body vibration groups, whereas biglycan and versican expression was down-regulated in 14-week-old rats of the two experimental groups. Furthermore, biglycan and versican expression levels were shown to be lower in the whole-body vibration group than in the vertical vibration group (P < 0.05). CONCLUSIONS: This in-vivo study demonstrated that vibrations can influence the expression of anabolic genes. Furthermore, whole body vibrations seem to have a greater effect in this regard than vertical vibrations. A new method is expected to relieve the low back pain of the patients through our research. PMID- 28870350 TI - First report on molecular characterization of Leishmania species from cutaneous leishmaniasis patients in southern Khyber Pakhtunkhwa province of Pakistan. AB - OBJECTIVE: To report presence of Leishmania major in Khyber Pakhtunkhwa of Pakistan, where cutaneous leishmaniasis (CL) is endemic and was thought to be caused by Leishmania tropica only. METHODS: Biopsy samples from 432 CL suspected patients were collected from 3 southern districts of Khyber Pakhtunkhwa during years 2011-2016. Microscopy on Giemsa stained slides were done followed by amplification of the ribosomal internal transcribed spacer 1 gene. RESULTS: Leishmania amastigotes were detected by microscopy in 308 of 432 samples (71.3%) while 374 out of 432 samples (86.6%) were positive by ribosomal internal transcribed spacer 1 PCR. Subsequent restriction fragment length polymorphism confirmed L. tropica in 351 and L. major in 6 biopsy samples. CONCLUSIONS: This study is the first molecular characterization of Leishmania species in southern Khyber Pakhtunkhwa. It confirmed the previous assumptions that anthroponotic CL is the major CL form present in Khyber Pakhtunkhwa province. Furthermore, this is the first report of L. major from a classical anthroponotic CL endemic focus identified in rural areas of Kohat district in southern Khyber Pakhtunkhwa. PMID- 28870351 TI - Retraction notice to "Effect of phentolamine on myocardial extracellular matrix of cardiac remodeling in rats" [Asian Pac J Trop Med (2014) 645-649]. PMID- 28870352 TI - A Comment on Driving and Neurologic Impairment. PMID- 28870353 TI - Comparison of Unsafe Driving Across Medical Conditions. AB - OBJECTIVE: To compare risks of unsafe driving in patients with medical conditions. METHODS: This large population-based study included all patients who were referred for a fitness-to-drive evaluation at an official driving evaluation center in 2013 and 2014. Risks of unsafe driving included physician's fitness-to drive recommendation, comprehensive fitness-to-drive decision, motor vehicle crash history, and traffic violation history. RESULTS: A total of 6584 patients were included in the study. Risks of unsafe driving were significantly different across medical conditions (P<.001 for all outcome measures). Patients with neurological conditions comprised the majority of the database (4837; 74%), but were not at the highest risk for unsafe driving. Patients with psychiatric conditions or substance abuse did worse on most driving safety outcomes, despite their low representation in the total sample (359 [6%] and 46 [1%], respectively). CONCLUSION: The risk of unsafe driving varied greatly across medical conditions. Sensitization campaigns, education, and medical guidelines for physicians and driver licensing authorities are warranted to identify patients at risk, especially for those with psychiatric conditions and substance abuse problems. PMID- 28870354 TI - The Effect of Dogs on Human Sleep in the Home Sleep Environment. AB - OBJECTIVE: To objectively assess whether a dog in the bedroom or bed disturbs sleep. PARTICIPANTS AND METHODS: From August 1, 2015, through December 31, 2015, we evaluated the sleep of humans and dogs occupying the same bedroom to determine whether this arrangement was conducive to sleep. The study included 40 healthy adults without sleep disorders and their dogs (no dogs <6 months old). Each participant wore an accelerometer and their dog a validated dog accelerometer for 7 nights. RESULTS: The mean +/- SD age of the participants (88% women) was 44+/ 14 years and body mass index was 25+/-6. The mean +/- SD age of the dogs was 5+/ 3 years and weight was 15+/-13 kg. Mean +/- SD actigraphy data showed 475+/-101 minutes in bed, 404+/-99 minutes total sleep time, 81%+/-7% sleep efficiency, and 71+/-35 minutes wake time after sleep onset. The dogs' accelerometer activity during the corresponding human sleep period was characterized as mean +/- SD minutes at rest, active, and at play of 413+/-102, 62+/-43, and 2+/-4. The dogs had mean +/- SD 85%+/-15% sleep efficiency. Human sleep efficiency was lower if the dog was on the bed as opposed to simply in the room (P=.003). CONCLUSION: Humans with a single dog in their bedroom maintained good sleep efficiency; however, the dog's position on/off the bed made a difference. A dog's presence in the bedroom may not be disruptive to human sleep, as was previously suspected. PMID- 28870355 TI - Mechanical Ventilation: State of the Art. AB - Mechanical ventilation is the most used short-term life support technique worldwide and is applied daily for a diverse spectrum of indications, from scheduled surgical procedures to acute organ failure. This state-of-the-art review provides an update on the basic physiology of respiratory mechanics, the working principles, and the main ventilatory settings, as well as the potential complications of mechanical ventilation. Specific ventilatory approaches in particular situations such as acute respiratory distress syndrome and chronic obstructive pulmonary disease are detailed along with protective ventilation in patients with normal lungs. We also highlight recent data on patient-ventilator dyssynchrony, humidified high-flow oxygen through nasal cannula, extracorporeal life support, and the weaning phase. Finally, we discuss the future of mechanical ventilation, addressing avenues for improvement. PMID- 28870356 TI - The Childhood Roots of Cardiovascular Disease Disparities. AB - A recent national review of the social determinants of cardiovascular disease (CVD) underscored the growing recognition that poor socioeconomic conditions early in life place children at higher risk for CVD as adults. There is growing evidence that chronic elevation of allostatic load as a consequence of high levels of early childhood stress can trigger early atherosclerotic changes in children independently of behaviors. Elevated levels of circulating cortisol have been documented in children as young as 4 years who were raised in highly stressful circumstances. Chronic elevation of cortisol is associated with increased release of inflammatory proteins such as interleukin 6, which can lead to fibrosis and scarring in the vessel walls of the arterial circulation, resulting in increased intima-media thickness. Increased intima-media thickness of the carotid artery has been found in individuals with low socioeconomic status as early as age 18 years and has been associated with increased CVD risk throughout the adult years. The American Academy of Pediatrics has recommended that it is the task of pediatricians and other health care professionals to screen for toxic stress among children during their early years and to take steps known to reduce stress reactivity, thereby helping these children to reduce their risk of early atherosclerotic changes and increased CVD throughout the life course. PMID- 28870357 TI - Neurostimulation Devices for the Treatment of Neurologic Disorders. AB - Rapid advancements in neurostimulation technologies are providing relief to an unprecedented number of patients affected by debilitating neurologic and psychiatric disorders. Neurostimulation therapies include invasive and noninvasive approaches that involve the application of electrical stimulation to drive neural function within a circuit. This review focuses on established invasive electrical stimulation systems used clinically to induce therapeutic neuromodulation of dysfunctional neural circuitry. These implantable neurostimulation systems target specific deep subcortical, cortical, spinal, cranial, and peripheral nerve structures to modulate neuronal activity, providing therapeutic effects for a myriad of neuropsychiatric disorders. Recent advances in neurotechnologies and neuroimaging, along with an increased understanding of neurocircuitry, are factors contributing to the rapid rise in the use of neurostimulation therapies to treat an increasingly wide range of neurologic and psychiatric disorders. Electrical stimulation technologies are evolving after remaining fairly stagnant for the past 30 years, moving toward potential closed loop therapeutic control systems with the ability to deliver stimulation with higher spatial resolution to provide continuous customized neuromodulation for optimal clinical outcomes. Even so, there is still much to be learned about disease pathogenesis of these neurodegenerative and psychiatric disorders and the latent mechanisms of neurostimulation that provide therapeutic relief. This review provides an overview of the increasingly common stimulation systems, their clinical indications, and enabling technologies. PMID- 28870358 TI - In Reply-50 Shades of Brown: Going Beyond the Guidelines in Melanoma Screening With Partner Skin Examinations. PMID- 28870359 TI - 50 Shades of Brown: Going Beyond the Guidelines in Melanoma Screening With Partner Skin Examinations. PMID- 28870360 TI - Regarding "Emergencies in Hematology and Oncology"-I. PMID- 28870361 TI - Regarding "Emergencies in Hematology and Oncology"-II. PMID- 28870362 TI - In Reply-Regarding "Emergencies in Hematology and Oncology," I and II. PMID- 28870363 TI - Defining Physician Burnout, and Differentiating Between Burnout and Depression-I. PMID- 28870364 TI - Defining Physician Burnout, and Differentiating Between Burnout and Depression II. PMID- 28870366 TI - Correction. PMID- 28870365 TI - In Reply-Defining Physician Burnout, and Differentiating Between Burnout and Depression. PMID- 28870367 TI - Embolic Origin of Osler Nodes. PMID- 28870368 TI - Pancreatic Ductal Adenocarcinoma. PMID- 28870369 TI - Charles Fletcher, The Centaur Company, and Proprietary Medicine Revenue Stamps. PMID- 28870370 TI - Dos Quatro by Bill Barrett. AB - Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as interpreted by the author. PMID- 28870371 TI - Docosahexaenoic acid (DHA), a fundamental fatty acid for the brain: New dietary sources. AB - Docosahexaenoic acid (C22: 6n-3, DHA) is a long-chain polyunsaturated fatty acid of marine origin fundamental for the formation and function of the nervous system, particularly the brain and the retina of humans. It has been proposed a remarkable role of DHA during human evolution, mainly on the growth and development of the brain. Currently, DHA is considered a critical nutrient during pregnancy and breastfeeding due their active participation in the development of the nervous system in early life. DHA and specifically one of its derivatives known as neuroprotectin D-1 (NPD-1), has neuroprotective properties against brain aging, neurodegenerative diseases and injury caused after brain ischemia reperfusion episodes. This paper discusses the importance of DHA in the human brain given its relevance in the development of the tissue and as neuroprotective agent. It is also included a critical view about the ways to supply this noble fatty acid to the population. PMID- 28870372 TI - DHA and EPA in red blood cell membranes are associated with dietary intakes of omega-3-rich fish in healthy children. AB - Omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are important in child development. The primary objective of this study was to investigate the associations between dietary intakes of n-3 LCPUFA and red blood cell (RBC) n-3 LCPUFA in young children. Healthy children, (2-8y) underwent RBC fatty acid profiling. Dietary intakes were parent-reported over 6 mo using three 24h dietary intake assessments and three 30 d food frequency questionnaires (FFQ). Participants (n = 49, 5.6 +/- 1.9y), were 59% male, and had a body mass index (BMI) z-score of 0.65 +/- 0.84. Dietary n-3 LCPUFA intakes were not different over time. RBC docosahexaenoic acid (DHA) positively correlated with average DHA from the 24h recalls. RBC DHA and eicosapentaenoic acid (EPA) positively correlated with average n-3 LCPUFA-rich fish intake from the FFQ. RBC appear to reflect long-term stable intakes of n-3 LCPUFA during growth in healthy young children. PMID- 28870373 TI - New technologies in human factors and ergonomics research and practice. PMID- 28870374 TI - Potential roles of digital technologies in clinical trials. PMID- 28870375 TI - Dietary traits of the ungulates from the HWK EE site at Olduvai Gorge (Tanzania): Diachronic changes and seasonality. AB - The Oldowan site HWK EE (Olduvai Gorge, Tanzania) has yielded a large fossil and stone tool assemblage at the transition from Lower to Middle Bed II, ~1.7 Ma. Integrated tooth wear and stable isotope analyses were performed on the three most abundant ungulate taxa from HWK EE, namely Alcelaphini, cf. Antidorcas recki (Antilopini) and Equus oldowayensis (Equini), to infer dietary traits in each taxon. Some paleodietary changes were observed for cf. A. recki and E. oldowayensis based on tooth wear at the transition from the Lemuta to the Lower Augitic Sandstone (LAS) interval within the HWK EE sequence. Stable carbon and oxygen isotope data show no significant changes in bulk diet or hydroclimate between the Lemuta and LAS intervals. The combined tooth wear and stable isotope data suggest similar paleoecological conditions across the two HWK EE intervals, but that differences in vegetation consumed among ungulates may have resulted in changes in dietary niches. Integrating tooth wear and stable isotope analyses permits the characterization of ungulate diets and habitats at HWK EE where C4 dominated and minor mixed C3 and C4 habitats were present. Our results provide a better understanding of the paleoenvironmental conditions of the Lemuta and LAS intervals. The LAS assemblage was mostly accumulated during relatively dry periods at Olduvai Gorge when grasses were not as readily available and grazing animals may have been more nutritionally-stressed than during the formation of the Lemuta assemblage. This helps to contextualize variations in hominin and carnivore feeding behavior observed from the faunal assemblages produced during the two main occupations of the site. PMID- 28870376 TI - Associations of Body Mass Index and Body Fat With Markers of Inflammation and Nutrition Among Patients Receiving Hemodialysis. AB - BACKGROUND: Understanding the extent to which visceral and subcutaneous body fat are associated with markers of nutrition and inflammation in patients on dialysis therapy could shed light on the obesity paradox and the biology of subcutaneous fat. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 609 adults receiving hemodialysis who participated in the ACTIVE/ADIPOSE Study. PREDICTORS: Body mass index (BMI), waist circumference, and bioelectrical impedance spectroscopy derived estimates of percent body fat. OUTCOMES: C-Reactive protein (CRP), interleukin 6 (IL-6), prealbumin, albumin, leptin, and adiponectin concentrations. MEASUREMENTS: We performed linear regression analyses to examine the extent to which proxies of visceral and subcutaneous fat were associated with inflammation, nutrition, and adiposity-related hormones. RESULTS: BMI was directly associated with markers of inflammation (standardized estimate for ln[CRP in mg/L]: 0.30 [95% CI, 0.22-0.38] per 10kg/m2; for ln[IL-6 in pg/mL]: 0.10 [95% CI, 0.02-0.18] per 10kg/m2), but was not associated with markers of nutrition. BMI was also inversely associated with adiponectin and directly associated with leptin. With waist circumference and percent body fat (as a proxy of visceral and subcutaneous fat, respectively) modeled together, waist circumference was associated with markers of inflammation (standardized estimate for ln[CRP in mg/L]: 0.21 [95% CI, 0.09-0.34] per 10cm; for ln[IL-6 in pg/mL]: 0.18 [95% CI, 0.07-0.29] per 10cm), whereas percent body fat was not associated with CRP (standardized estimate for ln[CRP in mg/L]: 0.03 [95% CI, -0.10 to 0.15] per 1%) and was inversely associated with IL-6 (standardized estimate for ln[IL-6 in pg/mL]: -0.15 [95% CI, -0.27 to -0.02] per 1%). In addition, waist circumference was inversely associated with prealbumin and albumin (standardized estimates of -0.12 [95% CI, -0.23 to -0.02] mg/dL per 10cm and -0.17 [95% CI, 0.28 to -0.06] g/dL per 10cm, respectively), and percent body fat was directly associated with prealbumin and albumin (0.20 [95% CI, 0.07-0.32] mg/dL and 0.15 [95% CI, 0.02-0.28] g/dL per 1%, respectively). Higher waist circumference was associated indirectly with adiponectin and directly with leptin concentrations. LIMITATIONS: Although the observed associations implicate visceral fat as the cause of inflammation, it cannot be determined in this cross-sectional study. CONCLUSIONS: Proxies of visceral and subcutaneous fat appear to have opposing associations with biomarkers of inflammation and nutrition. Subcutaneous fat may be an indicator of nutritional status, and visceral fat, an indicator of inflammation. PMID- 28870377 TI - Cardiac Imaging in the Diagnosis of Coronary Artery Disease. AB - Coronary artery disease (CAD) continues to be a leading cause of morbidity and mortality worldwide. Although invasive coronary angiography has previously been the gold standard in establishing the diagnosis of CAD, there is a growing shift to more appropriately use the cardiac catheterization laboratory to perform interventional procedures once a diagnosis of CAD has been established by noninvasive imaging modalities rather than using it primarily as a diagnostic facility to confirm or refute CAD. With ongoing technological advancements, noninvasive imaging plays a pre-eminent role in not only diagnosing CAD but also informing the choice of appropriate therapies, establishing prognosis, all while containing costs and providing value-based care. Multiple imaging modalities are available to evaluate patients suspected of having coronary ischemia, such as stress electrocardiography, stress echocardiography, single-photon emission computed tomography myocardial perfusion imaging, positron emission tomography, coronary computed tomography (CT) angiography, and magnetic resonance imaging. These imaging modalities can variably provide functional and anatomical delineation of coronary stenoses and help guide appropriate therapy. This review will discuss their advantages and limitations and their usage in the diagnostic pathway for patients with CAD. We also discuss newer technologies such as CT fractional flow reserve, CT angiography with perfusion, whole-heart coronary magnetic resonance angiography with perfusion, which can provide both anatomical as well as functional information in the same test, thus obviating the need for multiple diagnostic tests to obtain a comprehensive assessment of both, plaque burden and downstream ischemia. Recognizing that clinicians have a multitude of tests to choose from, we provide an underpinning of the principles of ischemia detection by these various modalities, focusing on anatomy vs physiology, the database justifying their use, their prognostic capabilities and lastly, their appropriate and judicious use in this era of patient-centered, cost-effective imaging. PMID- 28870378 TI - "Think aloud" and "Near live" usability testing of two complex clinical decision support tools. AB - OBJECTIVES: Low provider adoption continues to be a significant barrier to realizing the potential of clinical decision support. "Think Aloud" and "Near Live" usability testing were conducted on two clinical decision support tools. Each was composed of an alert, a clinical prediction rule which estimated risk of either group A Streptococcus pharyngitis or pneumonia and an automatic order set based on risk. The objective of this study was to further understanding of the facilitators of usability and to evaluate the types of additional information gained from proceeding to "Near Live" testing after completing "Think Aloud". METHODS: This was a qualitative observational study conducted at a large academic health care system with 12 primary care providers. During "Think Aloud" testing, participants were provided with written clinical scenarios and asked to verbalize their thought process while interacting with the tool. During "Near Live" testing participants interacted with a mock patient. Morae usability software was used to record full screen capture and audio during every session. Participant comments were placed into coding categories and analyzed for generalizable themes. Themes were compared across usability methods. RESULTS: "Think Aloud" and "Near Live" usability testing generated similar themes under the coding categories visibility, workflow, content, understand-ability and navigation. However, they generated significantly different themes under the coding categories usability, practical usefulness and medical usefulness. During both types of testing participants found the tool easier to use when important text was distinct in its appearance, alerts were passive and appropriately timed, content was up to date, language was clear and simple, and each component of the tool included obvious indicators of next steps. Participant comments reflected higher expectations for usability and usefulness during "Near Live" testing. For example, visit aids, such as automatically generated order sets, were felt to be less useful during "Near-Live" testing because they would not be all inclusive for the visit. CONCLUSIONS: These complementary types of usability testing generated unique and generalizable insights. Feedback during "Think Aloud" testing primarily helped to improve the tools' ease of use. The additional feedback from "Near Live" testing, which mimics a real clinical encounter, was helpful for eliciting key barriers and facilitators to provider workflow and adoption. PMID- 28870379 TI - eSource for clinical trials: Implementation and evaluation of a standards-based approach in a real world trial. AB - OBJECTIVE: The Learning Health System (LHS) requires integration of research into routine practice. 'eSource' or embedding clinical trial functionalities into routine electronic health record (EHR) systems has long been put forward as a solution to the rising costs of research. We aimed to create and validate an eSource solution that would be readily extensible as part of a LHS. MATERIALS AND METHODS: The EU FP7 TRANSFoRm project's approach is based on dual modelling, using the Clinical Research Information Model (CRIM) and the Clinical Data Integration Model of meaning (CDIM) to bridge the gap between clinical and research data structures, using the CDISC Operational Data Model (ODM) standard. Validation against GCP requirements was conducted in a clinical site, and a cluster randomised evaluation by site nested into a live clinical trial. RESULTS: Using the form definition element of ODM, we linked precisely modelled data queries to data elements, constrained against CDIM concepts, to enable automated patient identification for specific protocols and pre-population of electronic case report forms (e-CRF). Both control and eSource sites recruited better than expected with no significant difference. Completeness of clinical forms was significantly improved by eSource, but Patient Related Outcome Measures (PROMs) were less well completed on smartphones than paper in this population. DISCUSSION: The TRANSFoRm approach provides an ontologically-based approach to eSource in a low-resource, heterogeneous, highly distributed environment, that allows precise prospective mapping of data elements in the EHR. CONCLUSION: Further studies using this approach to CDISC should optimise the delivery of PROMS, whilst building a sustainable infrastructure for eSource with research networks, trials units and EHR vendors. PMID- 28870380 TI - Active learning reduces annotation time for clinical concept extraction. AB - OBJECTIVE: To investigate: (1) the annotation time savings by various active learning query strategies compared to supervised learning and a random sampling baseline, and (2) the benefits of active learning-assisted pre-annotations in accelerating the manual annotation process compared to de novo annotation. MATERIALS AND METHODS: There are 73 and 120 discharge summary reports provided by Beth Israel institute in the train and test sets of the concept extraction task in the i2b2/VA 2010 challenge, respectively. The 73 reports were used in user study experiments for manual annotation. First, all sequences within the 73 reports were manually annotated from scratch. Next, active learning models were built to generate pre-annotations for the sequences selected by a query strategy. The annotation/reviewing time per sequence was recorded. The 120 test reports were used to measure the effectiveness of the active learning models. RESULTS: When annotating from scratch, active learning reduced the annotation time up to 35% and 28% compared to a fully supervised approach and a random sampling baseline, respectively. Reviewing active learning-assisted pre-annotations resulted in 20% further reduction of the annotation time when compared to de novo annotation. DISCUSSION: The number of concepts that require manual annotation is a good indicator of the annotation time for various active learning approaches as demonstrated by high correlation between time rate and concept annotation rate. CONCLUSION: Active learning has a key role in reducing the time required to manually annotate domain concepts from clinical free text, either when annotating from scratch or reviewing active learning-assisted pre-annotations. PMID- 28870381 TI - Impact of predicting health-guidance candidates using massive health check-up data: A data-driven analysis. AB - INTRODUCTION: Starting in 2008, specific health checkups and health guidance to prevent non-communicable diseases have been provided in Japan, which has the highest proportion of elderly citizens in the world. The attendance rate for health guidance appointments is 17.7%, which is far from the national goal of the system (45%). To improve the attendance rate, we present a model for predicting whether an examinee is a candidate for health guidance; this model was based on a machine learning method and a restricted but massive amount of health checkup information. MATERIALS AND METHODS: Using machine learning methods, we developed the following five prediction models for identifying health-guidance candidates: baseline: this model included sex and age; model 1: this model included variables that can be measured in person+information on whether the examinee was a candidate in the past year; model 2: model 1+systolic blood pressure+diastolic blood pressure; model 3: model 2+all health checkup results from the past year; and model 4: model 3 using the training dataset excluding cases with missing data. RESULTS: The performance levels of the five prediction models (the AUC values of the models for the test dataset) were as follows: 0.592 [95% CI: 0.586 0.596] for the baseline model, 0.855 [95% CI: 0.851-0.858] for model 1, 0.985 [95% CI: 0.984-0.985] for model 2, 0.993 [95% CI: 0.993-0.993] for model 3, and 0.943 [95% CI: 0.941-0.945] for model 4. CONCLUSIONS: We studied five models for identifying health-guidance candidates. The model that used all health checkup results from the past year had the highest predictive power. Application of the prediction model developed in the present study to the selection of health guidance candidates could reduce the cost of guidance. PMID- 28870382 TI - Simulation-based decision support framework for dynamic ambulance redeployment in Singapore. AB - OBJECTIVE: Dynamic ambulance redeployment policies tend to introduce much more flexibilities in improving ambulance resource allocation by capitalizing on the definite geospatial-temporal variations in ambulance demand patterns over the time-of-the-day and day-of-the-week effects. A novel modelling framework based on the Approximate Dynamic Programming (ADP) approach leveraging on a Discrete Events Simulation (DES) model for dynamic ambulance redeployment in Singapore is proposed in this paper. METHODS: The study was based on the Singapore's national Emergency Medical Services (EMS) system. Based on a dataset comprising 216,973 valid incidents over a continuous two-years study period from 1 January 2011-31 December 2012, a DES model for the EMS system was developed. An ADP model based on linear value function approximations was then evaluated using the DES model via the temporal difference (TD) learning family of algorithms. The objective of the ADP model is to derive approximate optimal dynamic redeployment policies based on the primary outcome of ambulance coverage. RESULTS: Considering an 8min response time threshold, an estimated 5% reduction in the proportion of calls that cannot be reached within the threshold (equivalent to approximately 8000 dispatches) was observed from the computational experiments. The study also revealed that the redeployment policies which are restricted within the same operational division could potentially result in a more promising response time performance. Furthermore, the best policy involved the combination of redeploying ambulances whenever they are released from service and that of relocating ambulances that are idle in bases. CONCLUSION: This study demonstrated the successful application of an approximate modelling framework based on ADP that leverages upon a detailed DES model of the Singapore's EMS system to generate approximate optimal dynamic redeployment plans. Various policies and scenarios relevant to the Singapore EMS system were evaluated. PMID- 28870384 TI - Top ten challenges when interfacing a laboratory information system to an electronic health record: Experience at a large academic medical center. AB - BACKGROUND: Recent U.S. government regulations incentivize implementation of an electronic health record (EHR) with computerized order entry and structured results display. Many institutions have also chosen to interface their EHR to their laboratory information system (LIS). Reported long-term benefits include increased efficiency and improved quality and safety. In order to successfully implement an interfaced EHR-LIS, institutions must plan years in advance and anticipate the impact of an integrated system. It can be challenging to fully understand the technical, workflow and resource aspects and adequately prepare for a potentially protracted system implementation and the subsequent stabilization. OBJECTIVES: We describe the top ten challenges that we encountered in our clinical laboratories following the implementation of an interfaced EHR LIS and offer suggestions on how to overcome these challenges. METHODS: This study was performed at a 777-bed, tertiary care center which recently implemented an interfaced EHR-LIS. Challenges were recorded during EHR-LIS implementation and stabilization and the authors describe the top ten. RESULTS: Our top ten challenges were selection and harmonization of test codes, detailed training for providers on test ordering, communication with EHR provider champions during the build process, fluid orders and collections, supporting specialized workflows, sufficient reports and metrics, increased volume of inpatient venipunctures, adequate resources during stabilization, unanticipated changes to laboratory workflow and ordering specimens for anatomic pathology. A few suggestions to overcome these challenges include regular meetings with clinical champions, advanced considerations of reports and metrics that will be needed, adequate training of laboratory staff on new workflows in the EHR and defining all tests including anatomic pathology in the LIS. CONCLUSION: EHR-LIS implementations have many challenges requiring institutions to adapt and develop new infrastructures. This article should be helpful to other institutions facing or undergoing a similar endeavor. PMID- 28870383 TI - Advancing Alzheimer's research: A review of big data promises. AB - OBJECTIVE: To review the current state of science using big data to advance Alzheimer's disease (AD) research and practice. In particular, we analyzed the types of research foci addressed, corresponding methods employed and study findings reported using big data in AD. METHOD: Systematic review was conducted for articles published in PubMed from January 1, 2010 through December 31, 2015. Keywords with AD and big data analytics were used for literature retrieval. Articles were reviewed and included if they met the eligibility criteria. RESULTS: Thirty-eight articles were included in this review. They can be categorized into seven research foci: diagnosing AD or mild cognitive impairment (MCI) (n=10), predicting MCI to AD conversion (n=13), stratifying risks for AD (n=5), mining the literature for knowledge discovery (n=4), predicting AD progression (n=2), describing clinical care for persons with AD (n=3), and understanding the relationship between cognition and AD (n=3). The most commonly used datasets are AD Neuroimaging Initiative (ADNI) (n=16), electronic health records (EHR) (n=11), MEDLINE (n=3), and other research datasets (n=8). Logistic regression (n=9) and support vector machine (n=8) are the most used methods for data analysis. CONCLUSION: Big data are increasingly used to address AD-related research questions. While existing research datasets are frequently used, other datasets such as EHR data provide a unique, yet under-utilized opportunity for advancing AD research. PMID- 28870385 TI - Interaction between visual and chemical cues in a Liolaemus lizard: a multimodal approach. AB - Multimodal communication involves the use of signals and cues across two or more sensory modalities. The genus Liolaemus (Iguania: Liolaemidae) offers a great potential for studies on the ecology and evolution of multimodal communication, including visual and chemical signals. In this study, we analyzed the response of male and female Liolaemus pacha to chemical, visual and combined (multimodal) stimuli. Using cue-isolation tests, we registered the number of tongue flicks and headbob displays from exposure to signals in each modality. Number of tongue flicks was greater when a chemical stimulus was presented alone than in the presence of visual or multimodal stimuli. In contrast, headbob displays were fewer in number with visual and chemical stimuli alone, but significantly higher in number when combined. Female signallers triggered significantly more tongue flicks than male signallers, suggesting that chemical cues are involved in sexual recognition. We did not find an inhibition between chemical and visual cues. On the contrary, we observed a dominance of the chemical modality, because when presented with visual stimuli, lizards also responded with more tongue flicks than headbob displays. The total response produced by multimodal stimuli was similar to that of the chemical stimuli alone, possibly suggesting non redundancy. We discuss whether the visual component of a multimodal signal could attract attention at a distance, increasing the effectiveness of transmission and reception of the information in chemical cues. PMID- 28870386 TI - [The antimicrobial activity of ephedrine and admixture of ephedrine and propofol: an in vitro study]. AB - INTRODUCTION: Propofol and Ephedrine are commonly used during anesthesia maintenance, the former as a hypnotic agent and the later as a vasopressor. The addition of propofol to ephedrine or administration of ephedrine before propofol injection is useful for decreasing or preventing propofol related hemodynamic changes and vascular pain. This in vitro study evaluated the antibacterial effect on common hospital-acquired infection pathogens of ephedrine alone or combined with propofol. MATERIAL AND METHOD: The study was performed in two stages. In the first, the Minimum Inhibitory Concentration of propofol and ephedrine alone and combined was calculated for Escherichia coli, Enterococcus faecium, Staphylococcus aureus, Pseudomonas aeruginosa, and a clinical isolate of Acinetobacter spp. at 0, 6, 12 and 24h, using the microdilution method. In the second stage, the same drugs and combination were used to determine their effect on bacterial growth. Bacterial solutions were prepared at 0.5MacFarland in sterile 0.9% physiological saline and diluted at 1/100 concentration. Colony numbers were measured as colony forming units.mL-1 at 0, 2, 4, 6, 8, 10 and 12th hours. RESULTS: Ephedrine either alone or combined with propofol did not have an antimicrobial effect on Escherichia coli, Enterococcus faecium or Pseudomonas aeruginosa and this was similar to propofol. However, ephedrine alone and combined with propofol was found to have an antimicrobial effect on Staphylococcus aureus and Acinetobacter species at 512mcg.mL-1 concentration and significantly decreased bacterial growth rate. CONCLUSION: Ephedrine has an antimicrobial activity on Staphylococcus aureus and Acinetobacter species which were frequently encountered pathogens as a cause of nosocomial infections. PMID- 28870387 TI - [Reply to the letter to the Editor]. PMID- 28870388 TI - The optimal timing of enteral nutrition and its effect on the prognosis of acute pancreatitis: A propensity score matched cohort study. AB - BACKGROUND: Early enteral nutrition (EN) can improve the prognosis of acute pancreatitis (AP), but the optimal initiation time is unknown. In this study, the optimal time of early EN was analyzed to disclose the application of early EN in AP. METHODS: Data of 104 patients with AP were prospectively collected. With secondary infection (infected pancreatic necrosis and extrapancreatic infection) as the primary outcome variable, receiver operating characteristic (ROC) curve was used to calculate the optimal cut-off time of early EN. Propensity score matching was used to adjust for covariates. Secondary outcomes include acute gastrointestinal injury (AGI) grades, serum albumin level, and EN-related complications. RESULTS: The ROC curve analysis showed that the third day after hospital admission was the best cut-off time of early EN (with the area under the curve of 0.744). After PS matching, the proportion of secondary infection in the early EN group was significantly lower than the late EN group (8.6% vs. 36.5%, P < 0.05). Regression analysis showed that early EN was a protective factor against secondary infection (OR 0.161, 95%CI 0.036-0.718, P < 0.05). The AGI grades and serum albumin levels were better improved in the early EN group (AGI F = 4.468, P < 0.05; serum albumin F = 3.794, P < 0.05).The proportion of EN-related abdominal distension in the early EN group was significantly lower (8.8% vs. 38.5%, P < 0.05). CONCLUSIONS: Early EN initiated within three days could reduce the risk of secondary infection and improve the nutritional status of patients with acute pancreatitis, with a better tolerance. PMID- 28870390 TI - How Do We Balance the Long-Term Health of a Patient With the Short-Term Risk to the Physician? AB - BACKGROUND: There is a wide variation in practice patterns among emergency medicine physicians; many factors weigh into the medical decision-making process including the health of the patient as well as short-term risk to the physician. OBJECTIVE: The objective of our discussion is to illustrate specific scenarios where medical decisions are focused on the physician's short-term risk, then to propose an approach to shifting the balance to the patient's long-term health. METHODS: Using recent data on the evaluation, disposition, and outcomes of patients with low-risk chest pain in the emergency department, we calculate the risk of outpatient evaluation compared to the common practice of admission or observation. RESULTS: Patients with low-risk chest pain and negative initial evaluation in the emergency department with 2 normal cardiac biomarkers, normal vital signs, and non-ischemic, interpretable ECGs, have an extremely low-risk of a short term clinically relevant adverse cardiac event. There is a suggestion of a higher patient risk from admission, prompting consideration that continued evaluation of the chest pain as an outpatient may be safer than admission or observation. CONCLUSION: A test/intervention should be done if the risk of a missed diagnosis or adverse outcome is greater that the risk of the test/intervention. Involving the patient in the decision-making process may help to shift the management balance from the physician's short-term concern of their own risk, to the patient's long-term health. PMID- 28870389 TI - Clinicopathologic and survival differences in younger patients with pancreatic ductal adenocarcinoma-A propensity score-matched comparative analysis. AB - BACKGROUND/OBJECTIVES: Early-onset pancreatic cancer (EOPC) is not optimally characterized because of its extremely low incidence. We investigated clinicopathologic differences between younger or older patients with pancreatic cancer, and compared their outcomes. METHODS: We enrolled 699 consecutive patients who were diagnosed with pancreatic ductal adenocarcinoma and admitted to our surgical department between 2000 and 2014. We compared demographics and clinical outcomes in patients who were younger and older than 45 years at diagnosis. We estimated 1:2 case propensity score matching (PSM) by a logistic regression model based on patients' ASA scores, postoperative AJCC stages, adjuvant chemotherapy and radiotherapy. RESULTS: At diagnosis 34 patients (4.9%) were younger than 45 years. After PSM, tested variables and median survival periods were not significantly different between two groups. Some 441 patients (63.1%) suffered postoperative recurrence, but did not significantly differ by age for local (14.7 vs. 18.5%, P = 0.658) or systemic recurrence (70.6 vs. 54.4%, P = 0.077). There was a significant difference of disease-free survival (DFS) after PSM (8.9 vs. 29.3%, P = 0.011). CONCLUSIONS: Five-year OS and recurrence patterns did not significantly differ between two groups. But five-year DFS was significantly worse after PSM and systemic recurrence tended to be more frequent in the younger group. PMID- 28870391 TI - Determinants of Adverse Outcomes After Systemic-To-Pulmonary Shunts in Biventricular Circulation. AB - BACKGROUND: Systemic-to-pulmonary shunts are useful palliative procedures, although many teams have been deterred by high mortality and morbidity. We aimed to identify predictors of adverse outcomes after shunts in biventricular lesions. METHODS: From 2004 to 2014, 173 children had shunt procedures. Morphologies included: tetralogy of Fallot, pulmonary atresia with ventricular septal defect (VSD) with and without major aortopulmonary collaterals (MAPCAs), transposition of great arteries with pulmonary stenosis, and double outlet right ventricle. Median age was 22 days (range, 3 to 3,438 days) and median weight 3.2 kg (range, 1.7 to 20 kg). Shunt sizes ranged from 3 to 5 mm with median shunt size/weight ratio 1.03 mm/kg (range, 0.3 to 2.5 mm/kg). RESULTS: In-hospital mortality was 5.2% for the initial shunt procedure. Inter-stage mortality was 3.6%. Overall, 86% of patients progressed to corrective surgery. Acute events were observed in 41 patients, leading to 6 deaths. Events included 30 emergency chest openings, 16 shunt thrombosis, and 17 pulmonary overcirculation. Independent predictors of acute events or in-hospital mortality were genetic or extracardiac anomalies (hazard ratio [HR] = 1.9, p = 0.04), and preoperative shock/acidosis (HR = 2.73, p = 0.003). Diagnosis of pulmonary atresia with VSD and MAPCAs was protective (HR = 0.23, p = 0.042). Weight, shunt size, and size/weight ratios were not significant risk factors. Shunt thrombosis occurred at a median 3 hours (range, 0 to 46 hours) postoperatively, leading to 33% of in-hospital deaths. Low postoperative oxygen saturation and higher platelet counts in intensive care were independent predictors of thrombosis (p = 0.022, p = 0.005 respectively). CONCLUSIONS: Early adverse events contribute to mortality and morbidity for the shunt procedure. Patients with lower oxygen saturation and higher platelet counts in the postoperative period are at higher risk of shunt thrombosis. PMID- 28870392 TI - How and when to refer patients diagnosed with secondary headache and other craniofacial pain in the Emergency Department and Primary Care: Recommendations of the Spanish Society of Neurology's Headache Study Group. AB - INTRODUCTION: When secondary headache is suspected and the patient is referred to the emergency department or to the outpatient neurology clinic, it is important to know which are the appropriate complementary examinations to perform and the suitable referral pathway for patients to follow. In order to establish recommendations on this matter, the Spanish Society of Neurology's Headache Study Group (GECSEN) has decided to issue a series of agreed recommendations constituting a referral protocol for patients with headache and/or craniofacial neuralgias. DEVELOPMENT: Young neurologists with an interest and experience in headache were invited to draft a series of practical guidelines in collaboration with GECSEN's Executive Committee. For practical reasons, the document was divided into 2 articles: the first focuses on primary headaches and craniofacial neuralgias and this second article on secondary headaches and other craniofacial pain. In order for the recommendations to be helpful for daily practice, they follow a practical approach, with tables summarising referral criteria, examinations to be performed, and referral to other specialists. CONCLUSIONS: We hope to offer a guide and tools to improve decision-making regarding patients with headache, identifying complementary tests to prioritise and referral pathways to be followed, in order to avoid duplicated consultations and delayed diagnosis and treatment. PMID- 28870393 TI - How and when to refer patients diagnosed with primary headache and craniofacial neuralgia in the Emergency department or Primary Care: Recommendations of the Spanish Society of Neurology's Headache Study Group. AB - INTRODUCTION: When a patient is diagnosed with primary headache or craniofacial neuralgia in the emergency department or in primary care, and is referred to a neurologist due to the complexity of the case, it is useful to know whether additional examination should be sought and the priority (urgent, preferential or normal) with which the patient should be seen. This will avoid unnecessary delays in patients with disabling headache and where organic causes are suspected. In order to issue recommendations on this matter, the Spanish Society of Neurology's Headache Study Group has decided to create a series of agreed recommendations constituting a referral protocol for patients with headache and/or craniofacial neuralgia. DEVELOPMENT: Young neurologists with an interest and experience in headache were invited to draft a series of practical guidelines in collaboration with Spanish Society of Neurology's Headache Study Group Executive Committee. For practical reasons, the document was divided into 2 articles: this first article focuses on primary headaches and craniofacial neuralgias and the second on secondary headaches. In order for the recommendations to be helpful for daily practice they follow a practical approach, with tables summarising referral criteria, examinations to be performed, and referral to other specialists. CONCLUSIONS: We hope to offer a guide and tools to improve decision-making regarding patients with headache, identifying complementary tests to prioritise and referral pathways to be followed, in order to avoid duplicated consultations and delayed diagnosis and treatment. PMID- 28870396 TI - Challenges in the study of adolescent and acculturative changes. AB - This article focuses on two recurrent themes in the study of acculturation in adolescence that challenge progress of the field. First, we often work with low dimensional, trait-like models of acculturation that cannot deal with modern types of acculturation that are often characterized by multidimensionality and domain specificity. Second, acculturative change in adolescence is undertheorized and there is a need to integrate developmental tasks and models of acculturation. It is argued that approaches that have been adopted in the study of identity (with their models that range from generalized traits to situated approaches and their adoption of both quantitative and qualitative methods) are highly suitable for the study of acculturation. A more contextualized approach would also facilitate the study of the interaction of contextual conditions and acculturative changes in adolescence. PMID- 28870394 TI - Variability in Interpretation of Cardiac Standstill Among Physician Sonographers. AB - STUDY OBJECTIVE: Cardiac standstill on point-of-care ultrasonography has been widely studied as a marker of prognosis in cardiac arrest. Return of spontaneous circulation has been reported in as few as 0% and as many as 45% of patients with cardiac standstill. When explicitly documented, the definition of cardiac activity in these studies varied from any slight change in echogenicity of the myocardium to any kinetic cardiac activity. We hypothesize that the variability in research definitions of cardiac activity may affect interpretation of video clips of patients in cardiac arrest. The goal of this study is to assess the variability in interpretation of standstill among physician sonographers. METHODS: We surveyed physician sonographers at 6 conferences held at 3 academic medical centers in the Greater New York area. Survey respondents were allotted 20 seconds per slide to determine whether each of 15 video clips of patients in cardiac arrest were standstill or not. Data were collected anonymously with radio frequency remotes. RESULTS: There were 127 total participants, including faculty, fellows, and resident physicians specializing in emergency medicine, critical care, and cardiology. There was only moderate interrater agreement among all participants (alpha=0.47). This lack of agreement persisted across specialties, self-reported training levels, and self-reported ultrasonographic expertise. CONCLUSION: According to the results of our study, there appears to be considerable variability in interpretation of cardiac standstill among physician sonographers. Consensus definitions of cardiac activity and standstill would improve the quality of cardiac arrest ultrasonographic research and standardize the use of this technology at the bedside. PMID- 28870395 TI - Synthesis and anti-enterovirus activity of new analogues of MDL-860. AB - A series of twelve novel compounds, analogues of antiviral agent MDL-860 were synthesized and their antiviral activity was evaluated in vitro against enteroviruses poliovirus 1 (PV1), Coxsackieviruses B1 (CVB1) and Coxsackieviruses B3 (CVB3). Compounds 14, 24 and 25 manifested strong antiviral effects against CVB1 and PV1 (SI values of 405 and 118 for CVB1 and PV1 respectively). In contrast to the wide anti-enteroviral activity of MDL-860, these three compounds were inactive against CVB3. Compounds 14, 24 and 25 along with MDL-860 were tested in vivo in mice infected with CVB1. Marked protective effects of compounds 14 and 24 were established, PI values of 50% and 33.3%, respectively. In addition, almost all of the tested compounds manifested very low toxicity. PMID- 28870397 TI - Eradicating hepatitis B virus: The critical role of preventing perinatal transmission. AB - Prevention of hepatitis B virus (HBV) transmission from infected mothers to their newborns is critical to HBV control and eventual eradication. Mother-to-child perinatal transmission causes the highest chronic carrier rate (>85%) with a high rate of subsequent chronic liver disease and hepatocellular carcinoma. This risk is reduced by 90% with HBV vaccine given along with hepatitis B immune globulin (HBIG) starting at birth. New analyses of our data from US trials of HBIG and HBV vaccine in high-risk infants revealed better efficacy with yeast-recombinant vaccine than plasma-derived vaccine, especially in preventing late onset infections, with evidence that vaccine prevented transmission of maternal HBV infection with the glycine to arginine mutation in surface antigen codon 145 (sG145R). Most late infections with sG145R were in vaccine non-responders, suggesting escape from HBIG rather than from vaccine-induced antibody. Our findings also help explain survey results from Taiwan following universal childhood immunization implemented in the mid-1980s. We conclude that current vaccines will remain effective against surface antigen mutants. Anti-viral drugs in high-risk pregnant women, in combination with newborn HBIG and vaccine, show promise for eliminating residual breakthrough neonatal infections, critical to meeting WHO 2030 goals and for eradicating HBV. PMID- 28870398 TI - Selective lobar exclusion by venous clamping during ex vivo lung perfusion. PMID- 28870399 TI - The risk of reoperative cardiac surgery in radiation-induced valvular disease. AB - OBJECTIVE: Mediastinal radiation therapy (MRT) increases the risk for adverse outcomes after cardiac surgery and is not incorporated in the Society of Thoracic Surgeons (STS) risk algorithm. We aimed to quantify the surgical risk conferred by MRT in patients undergoing primary and reoperative valvular operations. METHODS: A retrospective analysis of 261 consecutive patients with prior MRT who underwent valvular operations between January 2002 and May 2015. Short- and long term outcomes were compared for STS predicted risk of mortality, surgery type, gender, year of surgery, and age-matched patients stratified by reoperative status. RESULTS: Mean age was 62.6 +/- 12.1 years and 174 (67%) were women. The majority had received MRT for Hodgkin lymphoma (48.2%) and breast cancer (36%). Overall, 214 (82%) were primary and 47 (18%) were reoperative procedures. Reoperation carried a higher operative mortality than primary cases (17% vs 3.7%; P = .003). Compared with the 836 nonradiated matches, operative mortality and observed-to-expected STS mortality ratios were higher in primary (3.8% [1.4] vs 0.8% [0.32]; P = .004) and reoperative (17% [3.35] vs 2.3% [0.45]; P = .001) patients with prior MRT. Cox proportional hazard modeling revealed that in patients with previous MRT, primary (hazard ratio, 2.24; 95% confidence interval, 1.73-2.91) and reoperative status (hazard ratio, 3.19; 95% confidence interval, 1.95-5.21) adversely affected long-term survival compared with nonradiated matches. CONCLUSIONS: Surgery for radiation-induced valvular heart disease has a higher operative mortality than predicted by STS predicted risk of mortality. Reoperations are associated with increased morbidity and mortality compared with primary cases. Careful patient selection is paramount and expanded indications for transcatheter therapies should be considered, especially in reoperative patients. PMID- 28870400 TI - EGFR mutational status in lung adenocarcinoma: Staging implications or continuous evolution? PMID- 28870401 TI - Corrigendum to "Synchrotron Fourier transformed infrared mapping: A novel approach for membrane fouling characterization" [Water Res. 111 (2017) 375-381]. PMID- 28870402 TI - Corrigendum to 'Development of a model to simulate groundwater inundation induced by sea-level rise and high tides in Honolulu, Hawaii' [Water Research 114 (2017) 122-134]. PMID- 28870403 TI - High Antigen Processing Machinery component expression in Langerhans cells from melanoma patients' sentinel lymph nodes. AB - Langerhans cells (LCs) from melanoma patients sentinel lymph nodes (SLN) are poor T cell activators mostly due to an immature immunophenotype. However Antigen Presenting Machinery (APM) role is unknown. We investigated HLA-class I APM components (Delta, LMP-7/10, TAP-1, Calnexin, Tapasin, beta2-microglobulin and HLA-A,B,C) in LCs from healthy donors skin and melanoma patients SLN. APM component levels were low in immature epidermal LCs and significantly increased after maturation (p<0.05); their levels were significantly high in SLN LCs (p<0.01). APM component expression correlated with melanoma Breslow's thickness and SLN metastases: HLA-A,B,C level was significantly lower in SLN LCs from thick lesions patients compared with those from thin/intermediate lesions (p<0.05); beta2-microglobulin level was significantly higher in positive SLN LCs compared to negative ones (p<0.05). Functionally, SLN LCs did not phagocytose exogenous antigens. These findings extend LCs knowledge indicating that they are not fully impaired by melanoma, contributing to design new LCs-based therapeutic approaches. PMID- 28870404 TI - Interferon-gamma suppresses the proliferation and migration of human placenta derived mesenchmal stromal cells and enhances their ability to induce the generation of CD4+CXCR5+Foxp3+Treg subset. AB - We investigate the effects of interferon (IFN)-gamma on human placenta-derived mesenchymal stromal cells (hPMSCs), in particular, their adhesion, proliferation and migration and modulatory effects on the CD4+CXCR5+Foxp3+Treg subset. And we compared hPMSCs ability to induce the generation of different Treg subsets in response to treatment with IFN-gamma. We found that IFN-gamma suppressed the proliferation and migration for hPMSCs. The ability of hPMSCs to induce the generation of CD4+CXCR5+Foxp3+Treg subset was enhanced by IFN-gamma. And maximal effectiveness of IFN-gamma treated hPMSCs upon inducing the generation of Treg subsets was for CD4+CXCR5+Foxp3+Treg subset as compared with that of CD4+CD25+Foxp3+, CD8+CD25+Foxp3+, CD4+IL-10+ and CD8+IL-10+Treg subsets. These results have important implications for the development and application of hPMSCs in clinical use. PMID- 28870405 TI - Gut, microbiota-dependent trimethylamine-N-oxide is associated with long-term all cause mortality in patients with exacerbated chronic obstructive pulmonary disease. AB - OBJECTIVES: The gut, microflora-dependent metabolite trimethylamine-N-oxide (TMAO) has emerged as a dietary-associated risk factor for incident cardiovascular events. Chronic obstructive pulmonary disease (COPD) is a prevalent disease worldwide with a high associated risk for cardiovascular disease and death due to an infectious cause. AIMS: To study whether TMAO is predictive for adverse clinical outcomes in patients with exacerbated COPD. METHODS: A total of 189 patients with COPD exacerbation were prospectively followed for a median of 6.1 y. TMAO plasma levels at the time of emergency department admission were measured by liquid chromatography coupled with tandem mass spectrometry. Cox and linear regression models were used to investigate associations of TMAO with all-cause mortality and different comorbidities. RESULTS: All-cause mortality was 55.6% after 6 y. The deceased patients showed significantly higher median admission TMAO (MUmol/L) levels compared with survivors (3.9 [interquartile range: 2.3-7.1] versus 2.9 [interquartile range: 1.8-4.7]; P = 0.01), which resulted in an unadjusted hazard ratio of 1.8 ([95% confidence interval: 1.2-3.0], P = 0.01). This association was no longer significant after multivariate adjustment. Median TMAO levels were similar in nonpneumonic and pneumonic COPD exacerbation. Higher age, higher body mass index, diabetes mellitus, and chronic kidney disease were predictors for increased plasma TMAO levels in linear regression analysis. CONCLUSIONS: Increased circulating TMAO levels per se were associated with long-term all-cause mortality in patients with COPD independent of type of exacerbation. However, this association was largely explained by comorbidities and age. Whether TMAO levels can additionally be influenced by nutritional interventions should be addressed in future studies. PMID- 28870408 TI - Thyroid storm and warm autoimmune hemolytic anemia. AB - Graves' disease is often associated with other autoimmune disorders, including rare associations with autoimmune hemolytic anemia (AIHA). We describe a unique presentation of thyroid storm and warm AIHA diagnosed concurrently in a young female with hyperthyroidism. The patient presented with nausea, vomiting, diarrhea and altered mental status. Laboratory studies revealed hemoglobin 3.9g/dL, platelets 171*109L-1, haptoglobin <5mg/dL, reticulocytosis, and positive direct antiglobulin test (IgG, C3d, warm). Additional workup revealed serum thyroid stimulating hormone (TSH) <0.01MUIU/mL and serum free-T4 (FT4) level 7.8ng/dL. Our patient was diagnosed with concurrent thyroid storm and warm AIHA. She was started on glucocorticoids to treat both warm AIHA and thyroid storm, as well as antithyroid medications, propranolol and folic acid. Due to profound anemia and hemodynamic instability, the patient was transfused two units of uncrossmatched packed red blood cells slowly and tolerated this well. She was discharged on methimazole as well as a prolonged prednisone taper, and achieved complete resolution of the thyrotoxicosis and anemia at one month. Hyperthyroidism can affect all three blood cell lineages of the hematopoietic system. Anemia can be seen in 10-20% of patients with thyrotoxicosis. Several autoimmune processes can lead to anemia in Graves' disease, including pernicious anemia, celiac disease, and warm AIHA. This case illustrates a rarely described presentation of a patient with Graves' disease presenting with concurrent thyroid storm and warm AIHA. PMID- 28870409 TI - Frugal Biotech Applications of Low-Temperature Plasma. AB - Gas discharge low-temperature air plasma can be utilized for a variety of applications, including biomedical, at low cost. We term these applications 'frugal plasma' - an example of frugal innovation. We demonstrate how simple, robust, low-cost frugal plasma devices can be used to safely disinfect instruments, surfaces, and water. PMID- 28870406 TI - Probiotics and gastrointestinal conditions: An overview of evidence from the Cochrane Collaboration. AB - Alterations in the composition of the gut microbiota are associated with a number of gastrointestinal (GI) conditions, including diarrhea, inflammatory bowel diseases (IBD), and liver diseases. Probiotics, live microorganisms that may confer a health benefit to the host when consumed, are commonly used as a therapy for treating these GI conditions by means of modifying the composition or activity of the microbiota. The purpose of this review was to summarize the evidence on probiotics and GI conditions available from Cochrane, a nonprofit organization that produces rigorous and high-quality systematic reviews of health interventions. Findings from this review will help provide more precise guidance for clinical use of probiotics and to identify gaps in probiotic research related to GI conditions. PMID- 28870407 TI - Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: Implications for anhedonia, anxiety and treatment response. AB - Dopamine (DA) neurotransmission within the brain's reward circuit has been implicated in the pathophysiology of depression and in both, cognitive and pharmacological mechanisms of treatment response. Still, a direct relationship between measures of DA neurotransmission and reward-related deficits in patients with depression has not been demonstrated. To gain insight into the symptom specific alterations in the DA system in patients with depression, we used positron emission tomography (PET) and the D2/3 receptor-selective radiotracer [11C]raclopride in twenty-three non-smoking un-medicated Major Depressive Disorder (MDD) patients and sixteen healthy controls (HC). We investigated the relationship between D2/3 receptor availability and baseline measures of depression severity, anxiety, anhedonia, and cognitive and pharmacological mechanisms of treatment response. We found that, compared to controls, patients with depression showed greater D2/3 receptor availability in several striatal regions, including the bilateral ventral pallidum/nucleus accumbens (vPAL/NAc), and the right ventral caudate and putamen. In the depressed sample, D2/3 receptor availability in the caudal portion of the ventral striatum (NAc/vPAL) correlated with higher anxiety symptoms, whereas D2/3 receptor availability in the rostral area of the ventral striatum correlated negatively with the severity of motivational anhedonia. Finally, MDD non-remitters showed greater baseline anxiety, greater D2/3 availability in the NAc/vPAL, and greater placebo-induced DA release in the bilateral NAc. Our results demonstrate abnormally high D2/3 receptor availability in the ventral striatum of patients with MDD, which seem to be associated with comorbid anxiety symptoms and lack of response to antidepressants. PMID- 28870410 TI - Choosing Wisely: Mentors, Sponsors, and Your Kitchen Cabinet. PMID- 28870411 TI - Use of Value Stream Mapping to Reduce Outpatient CT Scan Wait Times. PMID- 28870412 TI - The Conventional Versus Alternative Agricultural Divide: A Response to Garibaldi et al. PMID- 28870413 TI - Esophageal baseline impedance levels allow the identification of esophageal involvement in patients with systemic sclerosis. AB - INTRODUCTION: Distal esophageal baseline impedance (BI) levels reflect the esophageal mucosal integrity in reflux disease. Systemic sclerosis (SSc) could potentially affect the integrity of esophageal mucosa and consequently impair distal and proximal BI levels, but data in this regard are lacking. AIM AND METHODS: We aimed to prospectively investigate and compare BI levels among non erosive reflux disease (NERD), SSc patients, and healthy controls (HCs). Consecutive patients with reflux symptoms and well-defined diagnosis of SSc underwent upper endoscopy and, in case of no lesions encountered, manometry and impedance-pH testing off-therapy. In addition to traditional impedance-pH parameters, BI values at 3, 5, 7, and 17cm above the lower esophageal sphincter were calculated. RESULTS: Fifty-two patients with NERD, 50 with SSc, and 50 HCs were enrolled. Nineteen (38%) SSc patients and 22 (42%) NERD patients had abnormal acid exposure. In patients with SSc, median BI values were significantly lower than in NERD patients and HCs (p < 0.0001) at 3, 5, and 7cm; there was no difference between HCs and NERD patients at 17cm in the proximal esophagus, whereas a significant difference was observed at 17cm between SSc and NERD as well as HCs (p < 0.01). CONCLUSION: Distal and proximal BI values in SSc patients were lower than in NERD and HCs, thus we speculated that these findings may be related to the deposition of collagen in the connective tissue. Measurement of BI may be used as an indirect, but simple and accurate marker of esophageal involvement in patients with SSc. PMID- 28870414 TI - Radioecological modelling of Polonium-210 and Caesium-137 in lichen-reindeer-man and top predators. AB - This work deals with analysis and modelling of the radionuclides 210Pb and210Po in the food-chain lichen-reindeer-man in addition to 210Po and 137Cs in top predators. By using the methods of Partial Least Square Regression (PLSR) the atmospheric deposition of 210Pb and 210Po is predicted at the sample locations. Dynamic modelling of the activity concentration with differential equations is fitted to the sample data. Reindeer lichen consumption, gastrointestinal absorption, organ distribution and elimination is derived from information in the literature. Dynamic modelling of transfer of 210Pb and 210Po to reindeer meat, liver and bone from lichen consumption, fitted well with data from Sweden and Finland from 1966 to 1971. The activity concentration of 210Pb in the skeleton in man is modelled by using the results of studying the kinetics of lead in skeleton and blood in lead-workers after end of occupational exposure. The result of modelling 210Pb and 210Po activity in skeleton matched well with concentrations of 210Pb and 210Po in teeth from reindeer-breeders and autopsy bone samples in Finland. The results of 210Po and 137Cs in different tissues of wolf, wolverine and lynx previously published, are analysed with multivariate data processing methods such as Principal Component Analysis PCA, and modelled with the method of Projection to Latent Structures, PLS, or Partial Least Square Regression PLSR. PMID- 28870415 TI - [Implementation of the tracer patient audit in a private radiation therapy centre]. AB - The "tracer patient" audit is an evaluation method introduced by the French health authority in the V2014 certification. This is not mandatory in private radiotherapy centres. In our continuous quality improvement approach and in order to improve the management of patient care, the management of our radiation therapy centre has decided to use this method to evaluate our medical practice and to engage healthcare professionals at the core of this approach. PMID- 28870416 TI - [Combination of radiotherapy and androgen deprivation therapy for localized prostate cancer]. AB - Combination of radiotherapy and androgen deprivation is now considered as the standard of care for patients with a localized prostate cancer but poor prognosis factors. Two groups of randomized trials have led to this recommendation: some have compared radiotherapy alone versus hormonal treatment and radiotherapy: these trials demonstrated, now with a long follow-up, an improvement in 10-year survival for the combined treatment. Three recent trials compared androgen deprivation alone or combined with radiotherapy; a benefit in survival was also demonstrated in favour of the combination. Some questions remained concerning the optimal duration of hormonal treatment, in view of its potential side effects. Patients in the intermediate prognostic groups could receive a short-term androgen deprivation, but those with a high Gleason score must be treated with a long-term hormonal treatment. Modalities of radiotherapy, regarding volumes and dose must also be precised in the next years. PMID- 28870417 TI - Characterization of an innovative intramedullary nail for diaphyseal fractures of long bones. AB - In this paper, an innovative design of nail for fractures occurring on long bones has been investigated. Its functioning is based essentially on sliding of conical surfaces, located in a spindle and in holding pins. Spindle and holding pins are connected together by a sleeve. The sliding transforms the rotational and translational motion of the spindle to a radial expansion of the holding pins, protruding inside the intramedullary canal. In order to evaluate mechanical behavior of the prosthesis different benchmarks and tests were numerically performed by an FE code. Results confirm good performances in terms of strength, under compression, bending and torque loading. Moreover, a complete model of the nail implanted on a tibia, has been developed and tested evaluating two loading configurations. Results confirmed a satisfactory behavior of the nail in terms of stress and strain shielding, comparable to the others traditional systems of prosthesis. In conclusion, this kind of nail appears to offer a good solution for elderly patients, which could not endure complications due to a complex surgery, as distal or medial screws are not necessary. PMID- 28870418 TI - Vibration-based fixation assessment of tibial knee implants: A combined in vitro and in silico feasibility study. AB - The preoperative diagnosis of loosening of cemented tibial knee implants is challenging. This feasibility study explored the basic potential of a vibration based method as an alternative diagnostic technique to assess the fixation state of a cemented tibia implant and establish the method's sensitivity limits. A combined in vitro and in silico approach was pursued. Several loosening cases were simulated. The largest changes in the vibrational behavior were obtained in the frequency range above 1500 Hz. The vibrational behavior was described with two features; the frequency response function and the power spectral density band power. Using both features, all experimentally simulated loosening cases could clearly be distinguished from the fully cemented cases. By complementing the experimental work with an in silico study, it was shown that loosening of approximately 14% of the implant surface on the lateral and medial side was detectable with a vibration-based method. Proximal lateral and medial locations on the tibia or locations toward the edge of the implant surface measured in the longitudinal direction were the most sensitive measurement and excitation locations to assess implant fixation. These results contribute to the development of vibration-based methods as an alternative follow-up method to detect loosened tibia implants. PMID- 28870419 TI - Healthy body, healthy mind: A mixed methods study of outcomes, barriers and supports for exercise by people who have chronic moderate-to-severe acquired brain injury. AB - BACKGROUND: Few people with chronic moderate-to-severe brain injury are following recommended physical activity guidelines. OBJECTIVE: Investigate effects of planned, systematic physical activity while cultivating social and emotional well being of people with chronic moderate-to-severe brain injury. HYPOTHESIS: Moderate-to-intensive physical activity would be associated with improvements in impairment and activity limitation measures (endurance, mobility, gait speed) immediately post-intervention and six weeks later (study week 12). METHODS: The intervention was a single group pre-/post-intervention study with 14 people with chronic moderate-to-severe brain injury who live in brain injury group homes and exercised 60-90 min, 3 days per week for 6 weeks at a maximum heart rate of 50 80%. Pre-post measures (administered weeks 0, 6 and 12) were the 6 Minute Walk Test, High-level Mobility Assessment Tool and 10 Meter Walk Test. The qualitative component used a brief survey and semi-structured interview guide with participants, family members, and staff. RESULTS: Following program completion, post-intervention group changes were noted on all outcome measures and greater than minimal detectable change for people with brain injury. Three transitioned from low to high ambulatory status and maintained this change at 12 weeks. During interviews, participants agreed the program was stimulating. More than eighty percent liked working out in a group and felt better being active. CONCLUSIONS: Program impact included physical, cognitive and social/emotional aspects. Social aspects (group format, trainers) were highly motivating and supported by residents, family, and staff. Investments in transportation and recruiting and training interns to assist participants are critical to program sustainability and expansion. PMID- 28870420 TI - Value of protein concentration in cerebrospinal fluid in paediatric patients with Guillain-Barre syndrome. AB - INTRODUCTION AND OBJECTIVE: The albumin-cytologic dissociation in cerebrospinal fluid (CSF) supports the diagnosis of Guillain-Barre syndrome (GBS) but does not support the prognosis, so the aim of this study is to determine the usefulness of protein numbers in the CSF to predict progression in paediatric patients. PATIENTS AND METHODS: A diagnostic test was performed in paediatric patients with GBS, analysing sociodemographic, clinical and protein variables in CSF as well as electromyography. The presence of dysautonomia was also documented. RESULTS: Data were analysed from 23 patients, predominantly males (87%), school age (43.5%) and history of digestive infection (73.9%). Using the ROC curve, an area under the curve of 0.966 with best CSF protein cut-off point of 87-92 proteins/mm was found for the presence of dysautonomias and to evaluate the poor response to treatment with 0.969 intravenous immunoglobulin with better cut-off point in 157 proteins/mm. CONCLUSION: The amount of proteins in the CSF can be used as a prognostic indicator and severity, such that proteins greater than 100 in CSF translate into a torpid evolution and with greater complications. PMID- 28870421 TI - State of the art of the telemedicine. Where are we and what is pending to be done? PMID- 28870423 TI - Diagnosis of infective endocarditis by 18F-FDG-PET/CT, presentation of a false negative result. PMID- 28870422 TI - Quantitative evaluation of capillaroscopic microvascular changes in patients with established coronary heart disease. AB - INTRODUCTION AND OBJECTIVES: Microcirculation disturbances have been associated to most of the cardiovascular risk factors as well as to multiple inflammatory diseases. However, whether these abnormalities are specifically augmented in patients with coronary heart disease is still unknown. We aimed to evaluate if there is a relationship between the presence of coronary heart disease and the existence of functional and structural capillary abnormalities evaluated in the cutaneous microcirculation by videocapillaroscopy. MATERIAL AND METHODS: Two matched samples of 30 participants with and without coronary heart disease but with similar clinical and anthropometric characteristics were evaluated by videocapillaroscopy at the dorsal skin of the third finger of the non-dominant hand. We calculated basal capillary density as well as capillary density after a period of arterial and venous occlusion in order to evaluate functionality and maximum capillary density. We also measured capillary recruitment. RESULTS: Microvascular capillary density at rest was significantly lower in patients suffering from coronary heart disease than in controls. This fact was also found after dynamic tests (arterial and venous occlusion), suggesting functional impairments. Capillary recruitment of the samples was not different in our sample. CONCLUSIONS: In our study, patients with coronary heart disease exhibit functional and structural microvascular disturbances. Although this is a very preliminary study, these findings open the door for further studying the microvascular functionality in coronary patients and how it relates to the response to treatment and/or the prognosis of the disease. PMID- 28870424 TI - Influence of atrial fibrillation on the mortality of patients with heart failure with preserved ejection fraction. AB - INTRODUCTION AND OBJECTIVES: The impact of atrial fibrillation (AF) on the prognosis of heart failure with preserved ejection fraction (HFpEF) is still the subject of debate. We analysed the influence of AF on the prognosis on mortality and readmission in patients with HFpEF. METHODS: Prospective observational study in 1,971 patients with HFpEF, who were admitted for acute heart failure. Patients were divided into 2 groups according to the presence or absence of AF. We analysed mortality, readmissions and combined mortality/readmissions at one year follow-up. RESULTS: A total of 1,177 (59%) patients had AF, mean age 80.3 (7.8) years and 1,233 (63%) were women. Patients with HFpEF and AF were older, female, greater valvular aetiology and lower comorbidity measured by the Charlson index. At the one year follow-up, 430 (22%) patients had died and 840 (43%) had been readmitted. In the 2 groups analysed, there was no difference in all-cause mortality (22 vs. 21%; P=.739, AF vs. no-AF, respectively) or cardiovascular causes (9.6 vs. 8.2%; P=.739, AF vs. no-AF, respectively). In the multivariable analysis, factors associated with higher mortality were: age, male, valvular aetiology, uric acid, and comorbidity. In the analysis of the subgroup with HFpEF with AF, the presence of chronic AF compared to de novo AF was associated with higher mortality (HR 1,716; 95% CI 1,099-2,681; P=.018). CONCLUSIONS: In patients with HFpEF, the presence of AF is frequent. During the one-year follow-up, the presence of AF does not influence mortality or readmissions in patients with HFpEF. PMID- 28870426 TI - Prognostic value of local relapse for patients with endometrial cancer. AB - BACKGROUND: The objective of our study was to determine survival and prognostic factors associated with isolated local recurrence of endometrial cancer. METHODS: Data of 1229 patients with endometrial carcinoma treated between 2000 and 2012 were extracted from maintained databases of nine French University Hospitals as well as from the Senti-Endo trial. Patients with isolated central pelvic and vaginal recurrence were selected for further analysis. RESULTS: Two hundreds and twenty five patients recurred during the inclusion period, 20 with isolated central pelvic recurrence and 23 with vaginal recurrence. Patients without recurrence had initially significantly less lymphovascular space invasion (p = 0.01), less advanced diseases (>stage II) (p < 0.001) and more often low or intermediate risk tumours than patients with local recurrence. Local recurrence was statistically associated with better overall survival than non-local recurrence (p = 0.028) but dramatically decreased overall survival when compared to patients without any recurrence (p < 0.001). The site of recurrence, i.e. vaginal or central pelvic, was significantly associated with overall survival (p = 0.015). Patients without brachytherapy at initial management were more likely to have local recurrence of their disease when compared to those without recurrence (p = 0.03). None of the prognostics factors for survival in patients with local recurrence was statistically significant in multivariate analysis. CONCLUSIONS: Local recurrence is a key event in endometrial cancer evolution severely impacting overall survival. Better understanding of the factors associated with prolonged survival is mandatory to improve our management of these patients. PMID- 28870425 TI - Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation. AB - The conserved, multifunctional Polymerase-Associated Factor 1 complex (Paf1C) regulates all stages of the RNA polymerase (Pol) II transcription cycle. In this review, we examine a diverse set of recent studies from various organisms that build on foundational studies in budding yeast. These studies identify new roles for Paf1C in the control of gene expression and the regulation of chromatin structure. In exploring these advances, we find that various functions of Paf1C, such as the regulation of promoter-proximal pausing and development in higher eukaryotes, are complex and context dependent. As more becomes known about the role of Paf1C in human disease, interest in the molecular mechanisms underpinning Paf1C function will continue to increase. PMID- 28870427 TI - [How to deal with a fetal head circumference lower than the third percentile?] AB - The prenatal finding of a head circumference (HC) below the 3rd percentile (p) remains, in the same way as short femur or increased nuchal translucency with normal karyotype, one the most difficult situations for the praticionner in the setting of prenatal diagnosis. Microcephaly is a gateway to possible cerebral pathologies, but the main objective is to identify serious prenatal situations. A standardized HC measurement, the use of adapted reference tools and charts, longitudinal following of cephalic biometrics in high-risk situations, and systematic central nervous system analysis can increase the diagnostic performance of ultrasound which is often disappointing for microcephaly. The early distinction between associated or isolated microcephaly makes it possible to quickly orient the prenatal management and counseling. Fetal MRI and genetic counseling are fundamental in this context, making it possible to specify at best the etiological diagnosis and to provide assistance to the neuropediatrician in the establishment of an often uncertain prognosis. The recent increase in cases of microcephaly concomitant with the epidemic of the ZIKA virus is an additional argument to improve our practices and the daily apprehension of HC<3rd p. PMID- 28870428 TI - Retro- and orthonasal olfactory function in relation to olfactory bulb volume in patients with hypogonadotrophic hypogonadism. AB - INTRODUCTION: Idiopathic hypogonadotrophic hypogonadism with an olfactory deficit is defined as Kallmann syndrome and is distinct from normosmic idiopathic hypogonadotrophic hypogonadism. OBJECTIVE: Because olfactory perception not only consists of orthonasally gained impressions but also involves retronasal olfactory function, in this study we decided to comprehensively evaluate both retronasal and orthonasal olfaction in patients with idiopathic hypogonadotrophic hypogonadism. METHODS: This case-control study included 31 controls and 45 idiopathic hypogonadotrophic hypogonadism patients. All participants whose olfactory and taste functions were evaluated with orthonasal olfaction (discrimination, identification and threshold), retronasal olfaction, taste function and olfactory bulb volume measurement. The patients were separated into three groups according to orthonasal olfaction: anosmic idiopathic hypogonadotrophic hypogonadism, hyposmic idiopathic hypogonadotrophic hypogonadism and normosmic idiopathic hypogonadotrophic hypogonadism. RESULTS: Discrimination, identification and threshold scores of patients with Kallmann syndrome were significantly lower than controls. Threshold scores of patients with normosmic idiopathic hypogonadotrophic hypogonadism. were significantly lower than those of controls, but discrimination and identification scores were not significantly different. Retronasal olfaction was reduced only in the anosmic idiopathic hypogonadotrophic hypogonadism group compared to controls. Identification of bitter, sweet, sour, and salty tastes was not significantly different when compared between the anosmic, hyposmic, and normosmic idiopathic hypogonadotrophic hypogonadism groups and controls. Olfactory bulb volume was lower bilaterally in all patient groups when compared with controls. The olfactory bulb volume of both sides was found to be significantly correlated with threshold, discrimination and identification scores in idiopathic hypogonadotrophic hypogonadism patients. CONCLUSION: 1) There were no significant differences in gustatory function between controls and idiopathic hypogonadotrophic hypogonadism patients; 2) retronasal olfaction was reduced only in anosmic patients but not in orthonasally hyposmic participants, possibly indicating presence of effective compensatory mechanisms; 3) olfactory bulb volumes were highly correlated with olfaction scores in the hypogonadotrophic hypogonadism group. The current results indicate a continuum from anosmia to normosmia in idiopathic hypogonadotrophic hypogonadism patients. PMID- 28870429 TI - Motor nerve to the masseter: A pediatric anatomic study and the "3:1 rule". PMID- 28870430 TI - Uncommon liver lesions with multimodality imaging and pathology correlation. AB - Uncommon liver lesions pose a diagnostic challenge because of unfamiliar imaging findings. For simplification, these lesions can be divided into four broad categories based on the dominant imaging feature in each: hypervascular, hypovascular, fat-containing, or cystic lesions. In this review, we profile the radiological features of uncommon liver lesions on multimodality imaging including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine. PMID- 28870431 TI - Could parenchymal enhancement on contrast-enhanced spectral mammography (CESM) represent a new breast cancer risk factor? Correlation with known radiology risk factors. AB - AIM: To compare background parenchymal enhancement (BPE) on contrast-enhanced (CE) spectral mammography (CESM) with CE magnetic resonance imaging (MRI), and evaluate how these relate to hormonal status, mammographic breast density (MBD) and MRI fibroglandular tissue volume (FGTV). METHODS AND MATERIALS: Between June 2012 to October 2015, participants in a cancer staging study underwent full-field digital mammography (FFDM), CEMRI, and CESM. Two readers independently rated FGTV, MBD, and BPE using the Breast Imaging-Reporting and Data System (BI-RADS) criteria. Inter-reader reliability was estimated using weighted kappa (k) and correlations between BPE, MBD, and FGTV calculated using Spearman's correlation coefficient. Associations with hormonal status were evaluated using multilevel ordinal regression analysis. RESULTS: Of the 96 eligible participants, 66 women (35-77 years) underwent CESM and CEMRI. Reasons for exclusion were declined or withdrawn consent (n=18), inadequate renal function (n=2), claustrophobia (n=2), previous reaction to contrast medium (n=2), mild reaction to contrast medium following CESM (n=2), lack of vascular access (n=1), neoadjuvant chemotherapy (n=1), CESM equipment failure (n=1), and unclear in one case. Inter-reader agreement was substantial (k=0.67) for CESM BPE, slight (k=0.19) for CEMRI BPE, moderate (k=0.57) for MRI FGTV and fair (k=0.35) for MBD. CESM BPE showed significant correlation with MBD (rho=0.36, p<0.0001), FGTV (rho=0.52, p<0.0001), and MRI BPE (rho=0.49, p<0.0001). BPE was significantly reduced in the post menopausal group for CEMRI and CESM (p<0.05). CESM BPE did not significantly fluctuate during the menstrual cycle. CONCLUSION: CESM BPE is correlated with MBD, FGTV, and CEMRI BPE, has better inter-reader reliability than CEMRI, and is not influenced by the menstrual cycle. Grading the degree of BPE on CESM could be a useful addition to breast cancer risk assessment tools. PMID- 28870432 TI - The "pseudo-CT myelogram sign": an aid to the diagnosis of underlying brain stem and spinal cord trauma in the presence of major craniocervical region injury on post-mortem CT. AB - AIM: To document the detection of underlying low-attenuation spinal cord or brain stem injuries in the presence of the "pseudo-CT myelogram sign" (PCMS) on post mortem computed tomography (PMCT). MATERIALS AND METHODS: The PCMS was identified on PMCT in 20 decedents (11 male, nine female; age 3-83 years, mean age 35.3 years) following fatal blunt trauma at a single forensic centre. Osseous and ligamentous craniocervical region injuries and brain stem or spinal cord trauma detectable on PMCT were recorded. PMCT findings were compared to conventional autopsy in all cases. RESULTS: PMCT-detected transection of the brain stem or high cervical cord in nine of 10 cases compared to autopsy (90% sensitivity). PMCT was 92.86% sensitive in detection of atlanto-occipital joint injuries (n=14), and 100% sensitive for atlanto-axial joint (n=8) injuries. PMCT detected more cervical spine and skull base fractures (n=22, and n=10, respectively) compared to autopsy (n=13, and n=5, respectively). CONCLUSION: The PCMS is a novel description of a diagnostic finding, which if present in fatal craniocervical region trauma, is very sensitive for underlying spinal cord and brain stem injuries not ordinarily visible on PMCT. Its presence may also predict major osseous and/or ligamentous injuries in this region when anatomical displacement is not evident on PMCT. PMID- 28870433 TI - Antibacterial activity of 3,3',4'-Trihydroxyflavone from Justicia wynaadensis against diabetic wound and urinary tract infection. AB - The present investigation was designed to study the effect of an active compound isolated from Justicia wynaadensis against multi drug resistant organisms (MDRO's) associated with diabetic patients. The drug resistant pathogens implicated in wound and urinary tract infection of diabetic patients were isolated and identified by molecular sequencing. Solvent-solvent fractionation of crude methanol extract produced hexane, chloroform, ethyl acetate and methanol water fraction, among which chloroform fraction was found to be potent when compared with other three fractions. Further, chloroform fraction was subjected to preparatory HPLC (High-Performance Liquid Chromatography), that produced four sub-fractions; chloroform HPLC fraction 1 (CHF1) through CHF4. Among the sub fractions, CHF1 inhibited the pathogens effectively in comparison to other three sub-fractions. The purity of CHF1 was found to be >95%. Therefore, CHF1 was further characterized by NMR and FTIR analysis and based on the structure elucidated, the compound was found to be 3,3',4'-Trihydroxyflavone. The effective dose of this bioactive compound ranged from 32MUg/mL to 1.2mg/mL. Thus, the present study shows that 3,3',4'-Trihydroxyflavone isolated from J. wynaadensis is an interesting biopharmaceutical agent and could be considered as a source of antimicrobial agent for the treatment of various infections and used as a template molecule for future drug development. PMID- 28870434 TI - Cerebral Infarctions Following Palliative Transarterial Chemoembolization with Embozene of a Vertebral Body Metastatic Tumor. AB - Preoperative transarterial chemoembolization has been widely used as an adjunct therapy for hypervascular metastatic spinal tumors. Several therapeutic iodized oil-based agents have been used in combination with anticancer drugs for injection into a feeding artery. Novel spherical agents with narrow-range particles and lower tendency to clump are preferred for the embolization of vascular malformations and hypervascular tumors. We describe the first case of cerebral embolization resulting in posterior circulation infarctions following transarterial embolization of a vascular vertebral body metastatic tumor with Embozene microspheres. PMID- 28870435 TI - Short progressive muscle relaxation or motor coordination training does not increase performance in a brain-computer interface based on sensorimotor rhythms (SMR). AB - Brain computer interfaces (BCIs) allow for controlling devices through modulation of sensorimotor rhythms (SMR), yet a profound number of users is unable to achieve sufficient accuracy. Here, we investigated if visuo-motor coordination (VMC) training or Jacobsen's progressive muscle relaxation (PMR) prior to BCI use would increase later performance compared to a control group who performed a reading task (CG). Running the study in two different BCI-labs, we achieved a joint sample size of N=154 naive participants. No significant effect of either intervention (VMC, PMR, control) was found on resulting BCI performance. Relaxation level and visuo-motor performance were associated with later BCI performance in one BCI-lab but not in the other. These mixed results do not indicate a strong potential of VMC or PMR for boosting performance. Yet further research with different training parameters or experimental designs is needed to complete the picture. PMID- 28870436 TI - How to Write a High Quality Multiple Choice Question (MCQ): A Guide for Clinicians. AB - Despite the variety of assessment tools available, multiple choice questions (MCQs) still play an integral part in examinations at both a national and speciality board level. MCQs have a number of methodological advantages yet their strength is related to the quality of the question posed. Specifically, there has been a move towards the MCQ testing a taxonomically higher order concept of integration-interpretation and problem solving. This paper focuses on question development and the potential pitfalls to avoid. PMID- 28870437 TI - Preliminary Interpretations of Transthoracic Echocardiograms by Cardiology Fellows. AB - BACKGROUND: Echocardiograms are often obtained after business hours on an urgent or emergent basis to assist in the care of patients with complex presentations. Considerable variation exists among academic medical centers with regard to who performs and interprets these studies, with different levels of cardiology fellow involvement in scanning and/or interpreting. On-call echocardiographic interpretation can be educationally valuable for cardiologists in training but may come at the expense of patient care. The aim of this study was to examine the agreement of preliminary fellows' interpretations of weekend on-call transthoracic echocardiograms with official attending cardiologists' interpretations. METHODS: Cardiology fellows perform preliminary interpretations of sonographer-obtained echocardiograms obtained on weekends, with final reports performed by attending cardiologists the following business day. In this study, 358 consecutive echocardiograms obtained on weekends over a 12-month period were reviewed. Discrepancies between the preliminary and final interpretations were categorized as either major (diagnoses with implications for urgent change in management) or minor (diagnoses without such implications). All discrepancies were also categorized as a missed diagnosis, an overcall (of severity), or an undercall. RESULTS: No preliminary interpretation was identified in 18.4% of the studies (66 of 358). Of the remaining on-call echocardiograms (n = 292), the overall discrepancy rate in interpretations between fellows and attending cardiologists was 16.8%. Out of these, the minor discrepancy rate was 14.4% (42 of 292), and the major discrepancy rate was 2.4% (seven of 292). Misses, overcalls, and undercalls accounted for 29%, 31%, and 40% of all discrepancies, respectively. CONCLUSIONS: The results indicate that although minor discrepancies between fellows' and attending cardiologists' interpretations were common (14.4%), major discrepancies were uncommon (2.4%) and similar to major discrepancy rates from the radiology literature. In general, discrepant interpretations were more likely to result from changes in severity, but misses accounted for almost all of the major discrepancies. Further research is needed to compare the clinical impact of different models of on-call echocardiographic services. PMID- 28870438 TI - Standardized Delineation of Endocardial Boundaries in Three-Dimensional Left Ventricular Echocardiograms. AB - BACKGROUND: Three-dimensional (3D) echocardiography is fundamental for left ventricular (LV) assessment. The aim of this study was to determine discrepancies in 3D LV endocardial tracings and suggest tracing guidance. METHODS: Forty-five 3D LV echocardiographic data sets were traced by three experienced operators, from different centers, according to predefined guidelines. The 3D meshes were compared with one another, and the endocardial areas of discrepancies were identified. A discussion and retracing protocol was used to reduce discrepancies. For each data set, an average 3D mesh was produced (reference mesh). Subsequently, four novice operators, divided into two groups, traced 20 of the data sets. Two operators followed the tracing protocol and two did not. RESULTS: The intraclass correlation coefficients among the three experienced operators for end-diastolic volume, end-systolic volume, and ejection fraction were 0.952, 0.955, and 0.932. The absolute distances between tracings were 1.11 +/- 0.45 mm. The highest tracing discrepancies were at the apical cap and anterior and anterolateral walls in end-diastole and end-systole and also at the basal anteroseptum in end-systole. Agreement with the reference meshes was better for the novice operators who followed the guidance (10.9 +/- 17.3 mL, 10.2 +/- 14.7 mL, and -2.2 +/- 4.1% for end-diastolic volume, end-systolic volume, and ejection fraction) compared with those who did not (16.3 +/- 16.4 mL, 17.0 +/- 16.0 mL, and -4.2 +/- 4.1%, respectively). CONCLUSIONS: Comparing 3D LV tracings, the endocardial areas that are the most difficult to delineate were identified. The suggested protocol for LV tracing resulted in very good agreement among operators. The reference 3D meshes are available for online testing and ranking of LV tracing algorithms. PMID- 28870439 TI - First insight into the heritable variation of the resistance to infection with the bacteria causing the withering syndrome disease in Haliotis rufescens abalone. AB - Withering syndrome disease has experienced worldwide spread in the last decade. This fatal disease for abalone is produced by a rickettsia-like organism (WS RLO), the bacterium "Candidatus Xenohaliotis californiensis". To evaluate the potential of the red abalone (Haliotis rufescens) to improve its resistance to infection by WS-RLO, the additive genetic component in the variation of this trait was estimated. For this, the variation in infection intensity with WS-RLOs and WS-RLOv (phage-infected RLOs) was analyzed in 56 families of full-sibs maintained for three years in a host-parasite cohabitation aquaculture system. A WS-RLO prevalence of 65% was observed in the analysed population; and from the total WS-RLO inclusions 60% were hyperparasited with the phage (WS-RLOv). The decrease in the food ingestion rate was the sole negative effect associated with increasing WS-RLO intensity of infection, suggesting that the high level of WS RLOv load may have diminished the symptoms of WS disease in the analyzed abalones. The estimated heritabilities were moderate to mid, but significant, varying from 0.21 to 0.23 and 0.36 for WS-RLO and WS-RLOv infections, respectively. This suggests that variation in resistance to infection with WS-RLO may respond to selection in the evaluated red abalone population. Estimated response to selection (G) for the level of infection by WS-RLO indicated that if the 10% of red abalone with the lowest infection level is selected as broodstock, a 90% reduction in the intensity of infection in the progeny can be expected, even with the lowest estimation of heritability (h2=0.21). This strong response would be also due to the large phenotypic variance of this trait. Strong positive correlations, both phenotypic and genotypic, were observed between infection intensities with WS-RLO and WS-RLOv, indicating that selection to increase resistance to one of the types of RLOs will affect resistance in the other in the same direction. This is the first study that demonstrates the existence of additive genetic variation for resistance to WS-RLO in abalone. Consequently, it is possible to increase the resistance to WS-RLO in H. rufescens by selective breeding, which can be an economically attractive and environmentally friendly manner to reduce mortalities and growth effects caused by WS in abalone farms. PMID- 28870440 TI - The noninvasive diagnosis of esophageal varices and its application in clinical practice. AB - Here, we review recent improvements made to different noninvasive tests used for the diagnosis of esophageal varices (EV) in the light of the recent Baveno VI recommendation and with an emphasis on clinical application. Like for fibrosis tests, these noninvasive EV tests can be classified as direct markers when they provide a visualization of EV (including all imaging procedures like endoscopy or radiology) and as indirect markers when they do not (blood markers or elastometry). Clinical descriptors expressed as percentages, especially the spared endoscopy rate and the missed high-risk esophageal varices (HREV) rate, are more eloquent in this setting than classical statistical descriptors like accuracy. Single biomarkers are insufficient, generally due to a missed HREV rate exceeding the acceptable limit of 5% indicated in the Baveno VI consensus. Thus, biomarker combinations are currently garnering the most interest. The Baveno VI recommendation states that in alcoholic and viral cirrhoses, screening endoscopy can be safely set aside for patients with liver stiffness<20kPa and platelets>150G/L. The Baveno rule's mean missed HREV rate is<5% but its spared endoscopy rate is<20%. New combinations or stepwise algorithms show promise but must be validated. Going forward, the Baveno rule provides a simple noninvasive method to rule out HREV in clinical practice but the need for further research continues. The noninvasive diagnosis of HREV will be significantly improved by new, simple and affordable combinations. PMID- 28870441 TI - Influences on decision-making for young women undergoing bilateral prophylactic mastectomy. AB - OBJECTIVE: The objective of this study was to explore the influences on decision making of younger women (<35) undergoing or considering bilateral prophylactic mastectomy (BPM). METHODS: Qualitative interviews guided by interpretative phenomenological analysis (IPA) were conducted with forty-six women who had a strong family history of breast cancer (BC) who had either undergone (n=26) or were considering (n=20) BPM. Participants were recruited from Australia and New Zealand (NZ) via hospitals, a genetics clinic, a research cohort, a registry and online. RESULTS: Four themes underpinning the influences on decision-making were identified: fear and anxiety, children, personal experiences with BC, health professional's influence. CONCLUSIONS: The decision to undergo BPM for younger women (<35) was multifaceted, however, it appeared that fear and anxiety were the main influence. Younger women appear more anxious than previous research with older women. There appears to be few differences between those with confirmed BRCA1/2 mutations and those with no known mutation and this is clinically significant. PRACTICE IMPLICATIONS: These findings have important practice implications, particularly improving communication of risk statistics, especially to those with no known mutation. Health professionals need to take into account the way younger women perceive information given to them when discussing risk. PMID- 28870442 TI - Mimicking non-verbal emotional expressions and empathy development in simulated consultations: An experimental feasibility study. AB - OBJECTIVE: To explore the feasibility of applying an experimental design to study the relationship between non-verbal emotions and empathy development in simulated consultations. METHOD: In video-recorded simulated consultations, twenty clinicians were randomly allocated to either an experimental group (instructed to mimic non-verbal emotions of a simulated patient, SP) or a control group (no such instruction). Baseline empathy scores were obtained before consultation, relational empathy was rated by SP after consultation. Multilevel logistic regression modelled the probability of mimicry occurrence, controlling for baseline empathy and clinical experience. ANCOVA compared group differences on relational empathy and consultation smoothness. RESULTS: Instructed mimicry lasted longer than spontaneous mimicry. Mimicry was marginally related to improved relational empathy. SP felt being treated more like a whole person during consultations with spontaneous mimicry. Clinicians who displayed spontaneous mimicry felt consultations went more smoothly. CONCLUSION: The experimental approach improved our understanding of how non-verbal emotional mimicry contributed to relational empathy development during consultations. Further work should ascertain the potential of instructed mimicry to enhance empathy development. PRACTICE IMPLICATIONS: Understanding how non-verbal emotional mimicry impacts on patients' perceived clinician empathy during consultations may inform training and intervention programme development. PMID- 28870444 TI - Pharmacists' satisfaction with their work: Analysis of an alumni survey. AB - BACKGROUND: The level of job satisfaction among practicing pharmacists is important because it has been found to affect job performance and employee turnover. The Swedish pharmacy market has undergone major changes in recent years, and little is known about pharmacists' job satisfaction. OBJECTIVES: The objective of this study was to investigate the level of job satisfaction and associated factors among graduates from the web-based pharmacy programs at Umea University. METHODS: Job satisfaction of pharmacists was measured as part of an alumni survey conducted with those who graduated from the pharmacy programmes between 2006 and 2014. Data analysis included descriptive statistics, and logistic regression was used to explore factors affecting job satisfaction. RESULTS: The total number of graduates who completed the survey was 222 (response rate 43%.) The majority of respondents were female (95%), and most were employed at a community pharmacy (85%). The mean age was 39.7 years. The majority of graduates (91%) were satisfied with their job "most of the time" or "all of the time", and 87% of the respondents would "definitely" or "maybe" choose the same career again. The multivariate analysis showed that increasing years in the current position (OR: 0.672 (0.519-0.871)) was associated with lower job satisfaction. Older age (OR: 1.123 (1.022-1.234)), the perception that the knowledge and skills acquired during university education is useful in the current job (OR: 4.643 (1.255-17.182)) and access to continuing professional development (OR: 9.472 (1.965-45.662)) were associated with higher job satisfaction. CONCLUSION: Most graduates from the web-based pharmacy programmes were satisfied with their current job. Access to continuing professional development seems to be important for the level of job satisfaction among pharmacists. PMID- 28870445 TI - Gene expression and molecular characterization of a novel C-type lectin, encapsulation promoting lectin (EPL), in the rice armyworm, Mythimna separata. AB - Insect cellular immune reactions differ depending on the target species. Phagocytosis is activated to scavenge microorganisms such as bacteria and fungi. On the other hand, larger invaders such as parasitoid wasps are eliminated by activation of encapsulation. In this study, we hypothesized that novel determinants regulate cellular immunities independent of surface molecular pattern recognition involving pattern recognition receptors (PRRs). Immune related genes differentially expressed depending on the treated material size were screened in larval hemocytes of the rice armyworm, Mythimna separata. Consequently, we identified a novel C-type lectin gene up-regulated by injection of large beads but not small beads of identical material. Examination of in vitro effect of the recombinant protein on the immune reactions clarified that the protein activated encapsulation reaction, while it suppressed phagocytosis. These results suggest that this novel C-type lectin designated "encapsulation promoting lectin (EPL)" regulates cellular immunity by a novel immune target size recognition mechanism. PMID- 28870443 TI - Light at night as an environmental endocrine disruptor. AB - Environmental endocrine disruptors (EEDs) are often consequences of human activity; however, the effects of EEDs are not limited to humans. A primary focus over the past ~30years has been on chemical EEDs, but the repercussions of non chemical EEDs, such as artificial light at night (LAN), are of increasing interest. The sensitivity of the circadian system to light and the influence of circadian organization on overall physiology and behavior make the system a target for disruption with widespread effects. Indeed, there is increasing evidence for a role of LAN in human health, including disruption of circadian regulation and melatonin signaling, metabolic dysregulation, cancer risk, and disruption of other hormonally-driven systems. These effects are not limited to humans; domesticated animals as well as wildlife are also exposed to LAN, and at risk for disrupted circadian rhythms. Here, we review data that support the role of LAN as an endocrine disruptor in humans to be considered in treatments and lifestyle suggestions. We also present the effects of LAN in other animals, and discuss the potential for ecosystem-wide effects of artificial LAN. This can inform decisions in agricultural practices and urban lighting decisions to avoid unintended outcomes. PMID- 28870446 TI - HEPACONTROL. A program that reduces early readmissions, mortality at 60 days, and healthcare costs in decompensated cirrhosis. AB - BACKGROUND & AIMS: Decompensated cirrhosis patients have an elevated incidence of early readmission, mortality and economic burden. The aims of HEPACONTROL were to reduce early readmission and to evaluate its impact on mortality and emergency department visits. PATIENTS AND METHODS: Quasi-experimental study with control group which compared two cohorts of patients discharged after being admitted for cirrhosis-related complications. A prospective cohort (n=80), who followed the HEPACONTROL program, which began with a follow-up examination seven days after discharge at the Hepatology Unit Day Hospital and a retrospective cohort of patients (n=112), who had been given a standard follow-up. Outcome variables that were compared between both groups were early readmission rates, the number of emergency department visits post-discharge, financial costs and mortality. RESULTS: The rate of early readmission was lower in the group with HEPACONTROL (11.3% vs 29.5%; P=.003). Also, the mean number of visits to the emergency department post-discharge (1.10+/-1.64 vs 1.71+/-2.36; P=.035), mortality at 60days (3.8% vs 14.3%; P=.016), and the cost of early readmission were all lower compared with the group with standard follow-up (P=.029). CONCLUSIONS: HEPACONTROL decreases the incidence of early readmission the rate of emergency department visits and mortality at 60days in patients with decompensated cirrhosis, and it is cost-effective. PMID- 28870450 TI - White blood cell profiles in amphibians help to explain disease susceptibility following temperature shifts. AB - Temperature variability, and in particular temperature decreases, can increase susceptibility of amphibians to infections by the fungus Batrachochytrium dendrobatidis (Bd). However, the effects of temperature shifts on the immune systems of Bd-infected amphibians are unresolved. We acclimated frogs to 16 degrees C and 26 degrees C (baseline), simultaneously transferred them to an intermediate temperature (21 degrees C) and inoculated them with Bd (treatment), and tracked their infection levels and white blood cell profiles over six weeks. Average weekly infection loads were consistently higher in 26 degrees C-history frogs, a group that experienced a 5 degrees C temperature decrease, than in 16 degrees C-history frogs, a group that experienced a 5 degrees C temperature increase, but this pattern only approached statistical significance. The 16 degrees C-acclimated frogs had high neutrophil:lymphocyte (N:L) ratios (suggestive of a hematopoietic stress response) at baseline, which were conserved post-treatment. In contrast, the 26 degrees C-acclimated frogs had low N:L ratios at baseline which reversed to high N:L ratios post-treatment (suggestive of immune system activation). Our results suggest that infections were less physiologically taxing for the 16 degrees C-history frogs than the 26 degrees C history frogs because they had already adjusted immune parameters in response to challenging conditions (cold). Our findings provide a possible mechanistic explanation for observations that amphibians are more susceptible to Bd infection following temperature decreases compared to increases and underscore the consensus that increased temperature variability associated with climate change may increase the impact of infectious diseases. PMID- 28870448 TI - Nasal interleukin 25 as a novel biomarker for patients with chronic rhinosinusitis with nasal polyps and airway hypersensitiveness: A pilot study. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the upper airway and is tightly linked with airway hyperresponsiveness (AHR) and asthma. However, the surrogate biomarkers for indicating AHR and asthma in patients with CRSwNP remain elusive. OBJECTIVE: To investigate the surrogate biomarkers for indicating AHR and asthma in patients with CRSwNP. METHODS: In this study, sinonasal tissues were collected from 42 patients with CRSwNP (asthma, n = 17; asymptomatic AHR, n = 11; non-AHR, n = 14), 11 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 13 controls. The protein and messenger RNA levels of interleukin (IL) 25 and other cytokines in nasal polyp (NP) and control sinonasal tissues were determined by quantitative real-time polymerase chain reaction and multiplex immunoassay, respectively. Multivariate logistic regression and receiver operating characteristic curve analysis were performed to assess the clinical relevance of IL-25. RESULTS: We found that the protein and messenger RNA levels of IL-25 were significantly increased in NP tissues compared with the control sinonasal tissues from patients with CRSwNP, patients with CRSsNP, and controls. Multivariate logistic regression revealed that the nasal IL-25 protein level and nasal and blood eosinophil counts were independent risk factors for AHR in patients with CRSwNP. According to receiver operating characteristic curve analysis, nasal tissue IL-25 had a sensitivity of 91.4% and a specificity of 62.8% (area under the curve, 0.845) at the cutoff level of 5 pg/MUL for indicating AHR in this CRSwNP cohort. CONCLUSION: Our findings indicated that IL-25 was significantly increased in NP tissues and may be considered as the molecular indicator for AHR in patients with CRSwNP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02110654. PMID- 28870449 TI - Assessing hypoxia risk during air travel after a severe asthma exacerbation in children. PMID- 28870451 TI - MicroRNA-based transcriptomic responses of Atlantic salmon during infection by the intracellular bacterium Piscirickettsia salmonis. AB - MicroRNAs (miRNAs) are small non-coding RNAs that have emerged as key regulators in diverse biological processes across taxa. However, despite the importance of these transcripts, little is known about their role during the immune response in salmonids. Because of this, we use deep sequencing technologies to explore the microRNA-based transcriptomic response of the Atlantic salmon (Salmo salar) to the intracellular bacteria Piscirickettsia salmonis, one of the main threats to salmon aquaculture in Chile. Hence, 594 different miRNAs were identified from head kidney and spleen transcriptomic data. Among them, miRNA families mir-181, mir-143 and mir-21 were the most abundant in control groups, while after infection with P. salmonis, mir-21, mir-181 and mir-30 were the most predominant families. Furthermore, transcriptional analysis revealed 84 and 25 differentially expressed miRNAs in head kidney and spleen respectively, with an overlapping response of 10 miRNAs between the analyzed tissues. Target prediction, coupled with GO enrichment analysis, revealed that the possible targets of the most regulated miRNAs were genes involved in the immune response, such as cortisol metabolism, chemokine-mediated signaling pathway and neutrophil chemotaxis genes. Among these, predicted putative target genes such as C-C motif chemokine 19-like, stromal cell-derived factor 1-like, myxovirus resistance protein 2 and hepcidin-1 were identified. Overall, our results suggest that miRNA expression in co modulation with transcription activity of target genes is related to putative roles of non-coding RNAs in the immune response of Atlantic salmon against intracellular bacterial pathogens. PMID- 28870447 TI - Psychosocial functioning and the cortisol awakening response: Meta-analysis, P curve analysis, and evaluation of the evidential value in existing studies. AB - Cortisol levels rise immediately after awakening and peak approximately 30-45min thereafter. Psychosocial functioning influences this cortisol awakening response (CAR), but there is considerable heterogeneity in the literature. The current study used p-curve and meta-analysis on 709 findings from 212 studies to test the evidential value and estimate effect sizes of four sets of findings: those associating worse psychosocial functioning with higher or lower cortisol increase relative to the waking period (CARi) and to the output of the waking period (AUCw). All four sets of findings demonstrated evidential value. Psychosocial predictors explained 1%-3.6% of variance in CARi and AUCw responses. Based on these effect sizes, cross-sectional studies assessing CAR would need a minimum sample size of 617-783 to detect true effects with 80% power. Depression was linked to higher AUCw and posttraumatic stress to lower AUCw, whereas inconclusive results were obtained for predictor-specific effects on CARi. Suggestions for future CAR research are discussed. PMID- 28870452 TI - Doxorubicin-loaded oligonucleotide conjugated gold nanoparticles: A promising in vivo drug delivery system for colorectal cancer therapy. AB - In this study, we propose doxorubicin (DOX) loaded oligonucleotides (ONTs) attached to gold nanoparticles (AuNPs) as a drug delivery system for cancer chemotherapy. DOX is one of the representative cancer chemotherapy agents and is widely used by many researchers as a chemotherapy agent in the drug delivery system. Due to the advantages of AuNPs such as simple steps in synthesis, high surface-area-to-volume ratio, and biocompatibility, we utilized AuNPs as drug delivery vehicle. AuNPs were synthesized by chemical reduction to be 13 nm diameter. The G-C rich oligonucleotides were used both for drug loading sites and AuNPs capping agents. 80% of DOX in solution could be bound to ONTs on AuNPs to became DOX-loaded AuNPs coated with ONTs (Doxorubicin-Oligomer-AuNP, DOA), and about 28% of loaded DOX was released from the as-prepared DOA. Confocal microscopy observation showed that DOA was well transported into cells, and finally the DOX was released into the cell nucleus. The drug's efficacies such as in vitro cytotoxicity and in vivo tumor growth inhibition were demonstrated with SW480 colon cancer cell line and a xenograft mouse model. MTT assay was performed to see the cytotoxicity effect on SW480 cells treated with DOA for 24 h, and the cell viability was determined to be 41.77% (p < 0.001). When DOA was administered regularly to a tumor bearing mouse, the tumor growth inhibition degree was examined by measuring the tumor size. The treatment-control (T/C) ratio was found to be 0.69. Thus, our results suggest the use of DOAs as promising drug delivery systems for colorectal cancer therapy. PMID- 28870454 TI - Introduction to flavoproteins: Beyond the classical paradigms. PMID- 28870453 TI - Spinal cord tumors in children: A review of 21 cases treated at the same institution. AB - INTRODUCTION: Spinal cord tumors in children (SCTC) are rare with a frequent diagnostic delay. Its management is multidisciplinary and challenging due to functional implications. The position of surgery is now better established but the role and timing of chemotherapy (CT) and radiotherapy (RT) still remains under debate. Adverse effects of treatments are important to be taken into account, in the follow-up of these children. The aim of this paper was to present a series of 21 cases of SCTC treated at the same institution, to briefly present clinical features, treatments and outcome, with a special focus on spinal deformities in children with this condition. MATERIAL AND METHODS: Twenty-one consecutive SCTC were referred to our institution from 1990 to 2014. Data regarding age, sex, diagnostic delay, clinical examination, MRI, surgery, pathology, other treatment (CT and RT), orthopedic issues and follow-up of these children were retrospectively recorded. RESULTS: Mean age was 8years (standard deviation: 5.2years) (range: 4 months-17years). Mean diagnosis delay was 5.5 months (standard deviation: 6.5 months) (range: 0 days-18 months). All children (10 girls, 11 boys) were operated on (10 partial removals, 7 subtotal and 4 gross total removals) as first-line treatment. Pathological results showed 12 juvenile pilocytic astrocytomas, 1 grade III astrocytoma, 1 grade IV astrocytoma, 3 oligodendrogliomas, 2 ependymomas, 1 glioblastoma and 1 rhabdoid tumor. Fourteen children (66.7%) received additional treatment: 12 CT and 7 RT. Ten children had postoperative spinal deformities. Mean follow-up (FU) was 71 months (5 months-180 months), with a median FU at 60 months, where 8 tumor progressions and 4 deaths were observed. Overall, survival (at 5years) was 81% and progression free survival (at 5years) was 67%. CONCLUSION: Surgery is the goal standard for SCTC and the only appropriate treatment in cases of a low-grade lesion with stable disease on MR follow-up. Additional treatment must be reserved for high-grade lesions or tumor progression not attainable by a second look surgery. Spinal deformities are a frequent complication. Overall, survival and event free survival primarily depends on the pathology. Studies involving more centers are obligatory with the aim of collecting more cases and drawing more definitive conclusions regarding the management of these tumors. PMID- 28870455 TI - Pharmacological evaluation of metformin and N-benzylbiguanide, a novel analogue of metformin, on the vasopressor responses to adrenergic system stimulation in pithed rats with fructose-induced insulin resistance. AB - Metformin has been associated with cardioprotection, vasorelaxation and normalization of endothelial function during type 2 Diabetes Mellitus. However, few studies have analysed its effects on vascular adrenergic system. Our study has evaluated the vasopressor responses induced by sympathetic stimulation or by i.v. bolus injections of the agonists noradrenaline (alpha1/2), methoxamine (alpha1) and UK 14,304 (alpha2) in rats with fructose-induced insulin resistance chronically pretreated with either metformin or EGL-6M (N-benzylbiguanide), a novel analogue of metformin. Rats were treated with fructose (15%) or tap water (control) during 16 weeks. Next, both groups were treated daily during 4 weeks with: (1) vehicle; (2) metformin (50mg/kg); or (3) EGL-6M (50mg/kg). Blood glucose and plasma insulin were determined before and after administration of glucose during oral glucose tolerance test. Animals treated with fructose showed hyperinsulinemia and insulin resistance, which were decreased by metformin and EGL-6M. In animals treated with fructose, the vasopressor responses induced by: (1) sympathetic stimulation were decreased; (2) noradrenaline were increased; and (3) methoxamine and UK 14,304 remained unaffected compared with control group. In control animals, metformin failed to modify the vasopressor responses analysed, while EGL-6M increased the vasopressor responses to sympathetic stimulation. In rats treated with fructose, metformin decreased vasopressor response to noradrenaline but did not modify the sympathetic stimulation responses. EGL-6M increased the vasopressor responses to sympathetic stimulation without modifying those to noradrenaline, methoxamine or UK 14,304. Collectively, these data suggest that EGL-6M is capable to increase insulin sensitivity and the vasopressor sympathetic outflow in rats. PMID- 28870456 TI - Pharmacological synergism of 2,2-dichloroacetophenone and EGFR-TKi to overcome TKi-induced resistance in NSCLC cells. AB - Combination treatment has been used as one of the therapeutic approaches for patients suffering from lung cancer, either to cope with the issue of acquired drug resistance due to prolong the use of a particular EGFR-TKi treatment, or to decrease the doses of each compound in order to reduce potential toxicity. 2,2 dichloroacetophenone (DAP) was reported as a PDK inhibitor recently, which is much more potent than dichloroacetate (DCA) in anti-cancer therapy. In this study, we applied DAP in combined with EGFR-TKis, erlotinib or gefitinib in NSCLC cell lines and NSCLC xenograft model. Synergistic anti-cancer effects in two NSCLC cell lines with EGFR mutation, NCI-H1975 and NCI-H1650, as well as in NCI H1975 xenograft model were observed. In comparison with either DAP or EGFR-TKi applied alone, the combination treatment not only further suppressed the EGFR signaling in vitro and in vivo, but also significantly promoted cell apoptosis. Interestingly, this synergistic anti-cancer effect was also observed in NCI-H1975 gefitinib induced-resistant cell line. Taken together, our results suggested that the combined use of DAP and EGFR-TKi exhibited anti-cancer synergy which may offer an additional treatment option for patients with EGFR-TKi induced resistance. PMID- 28870458 TI - Farm exposure in early childhood is associated with a lower risk of severe respiratory illnesses. PMID- 28870457 TI - A fluorogenic C. neoformans reporter strain with a robust expression of m-cherry expressed from a safe haven site in the genome. AB - C. neoformans is an encapsulated fungal pathogen with defined asexual and sexual life cycles. Due to the availability of genetic and molecular tools for its manipulation, it has become a model organism for studies of fungal pathogens, even though it lacks a reliable system for maintaining DNA fragments as extrachromosomal plasmids. To compensate for this deficiency, we identified a genomic gene-free intergenic region where heterologous DNA could be inserted by homologous recombination without adverse effects on the phenotype of the recipient strain. Since such a site in the C. neoformans genome at a different location has been named previously as "safe haven", we named this locus second safe haven site (SH2). Insertion of DNA into this site in the genome of the KN99 congenic strain pair caused minimal change in the growth of the engineered strain under a variety of in vitro and in vivo conditions. We exploited this 'safe' locus to create a genetically stable highly fluorescent strain expressing mCherry protein (KN99mCH); this strain closely resembled its wild-type parent (KN99alpha) in growth under a variety of in vitro stress conditions and in the expression of virulence traits. The efficiency of phagocytosis and the proliferation of KN99mCH inside human monocyte-derived macrophages were comparable to those of KN99alpha, and the engineered strain showed the expected organ dissemination after inoculation, although there was a slight reduction in virulence. The mCherry fluorescence allowed us to measure specific association of cryptococci with leukocytes in the lungs and mediastinal lymph nodes of infected animals and, for the first-time, to assess their live/dead status in vivo. These results highlight the utility of KN99mCH for elucidation of host-pathogen interactions in vivo. Finally, we generated drug-resistant KN99 strains of both mating types that are marked at the SH2 locus with a specific drug resistant gene cassette; these strains will facilitate the generation of mutant strains by mating. PMID- 28870459 TI - Long-term benefits of optimal asthma control in pregnancy. PMID- 28870460 TI - Increased IgE levels are linked to faster relapse in patients with omalizumab discontinued chronic spontaneous urticaria. PMID- 28870462 TI - Food diversity during the first year of life and allergic diseases until 15 years. PMID- 28870461 TI - Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab. AB - BACKGROUND: Atopy and viral respiratory tract infections synergistically promote asthma exacerbations. IgE cross-linking inhibits critical virus-induced IFN-alpha responses of plasmacytoid dendritic cells (pDCs), which can be deficient in patients with allergic asthma. OBJECTIVE: We sought to determine whether reducing IgE levels in vivo with omalizumab treatment increases pDC antiviral IFN-alpha responses in inner-city children with asthma. METHODS: PBMCs and pDCs isolated from children with exacerbation-prone asthma before and during omalizumab treatment were stimulated ex vivo with rhinovirus and influenza in the presence or absence of IgE cross-linking. IFN-alpha levels were measured in supernatants, and mRNA expression of IFN-alpha pathway genes was determined by using quantitative RT-PCR (qRT-PCR) in cell pellets. FcepsilonRIalpha protein levels and mRNA expression were measured in unstimulated cells by using flow cytometry and qRT-PCR, respectively. Changes in these outcomes and associations with clinical outcomes were analyzed, and statistical modeling was used to identify risk factors for asthma exacerbations. RESULTS: Omalizumab treatment increased rhinovirus- and influenza-induced PBMC and rhinovirus-induced pDC IFN-alpha responses in the presence of IgE cross-linking and reduced pDC surface FcepsilonRIalpha expression. Omalizumab-induced reductions in pDC FcepsilonRIalpha levels were significantly associated with a lower asthma exacerbation rate during the outcome period and correlated with increases in PBMC IFN-alpha responses. PBMC FcepsilonRIalpha mRNA expression measured on study entry significantly improved an existing model of exacerbation prediction. CONCLUSIONS: These findings indicate that omalizumab treatment augments pDC IFN alpha responses and attenuates pDC FcepsilonRIalpha protein expression and provide evidence that these effects are related. These results support a potential mechanism underlying clinical observations that allergic sensitization is associated with increased susceptibility to virus-induced asthma exacerbations. PMID- 28870463 TI - Efficacy and safety of 4 months of sublingual immunotherapy with recombinant Mal d 1 and Bet v 1 in patients with birch pollen-related apple allergy. AB - BACKGROUND: Birch pollen-related apple allergy is among the most prevalent food allergies in adolescent/adult subjects and mainly results from sensitization to the major birch pollen allergen Bet v 1 and subsequent cross-reaction with the apple protein Mal d 1. However, specific immunotherapy with birch pollen has inconsistent effects on apple allergy. OBJECTIVE: We sought to compare the safety and efficacy of sublingual immunotherapy (SLIT) with 2 formulations containing either rMal d 1 or rBet v 1 on birch pollen-related apple allergy. METHODS: Sixty participants with birch pollen-related apple allergy were randomized to daily sublingual application of placebo (n = 20) or 25 MUg of rMal d 1 (n = 20) or rBet v 1 (n = 20) for 16 weeks. Adverse events were regularly recorded. Sublingual challenges with standardized doses of rMal d 1, skin prick tests with recombinant allergens, and measurements of allergen-specific IgE and IgG4 antibodies were performed before and after treatment. RESULTS: Both formulations caused comparable, mainly local adverse events. No systemic reactions occurred. Compared with the placebo and rBet v 1-treated groups, SLIT with rMal d 1 reduced rMal d 1 induced oral symptoms (P = .001 and P = .038) accompanied by longitudinally reduced rMal d 1-specific cutaneous reactions (P = .022) and enhanced IgG4/IgE ratios (P = .012). SLIT with rBet v 1 neither improved the clinical reactivity to rMal d 1 nor enhanced rMal d 1-specific IgG4/IgE ratios. Participants receiving placebo showed no allergen-specific changes. CONCLUSION: Sublingual treatment with a recombinant food allergen was safe and clinically effective, as determined by using standardized challenges. We present a promising approach for the effective treatment of birch pollen-related apple allergy. PMID- 28870464 TI - Serum periostin, IgE, and SE-IgE can be used as biomarkers to identify moderate to severe chronic rhinosinusitis with nasal polyps. PMID- 28870465 TI - Inhibition of IL-17-committed T cells in a murine psoriasis model by a vitamin D analogue. AB - BACKGROUND: A better understanding of the means by which topical vitamin D analogues exert their therapeutic effect on psoriasis is of theoretical and practical importance. OBJECTIVE: We sought to clarify whether and how the topical vitamin D analogue calcipotriol (CAL) controls the IL-17A-mediated pathogenesis of murine psoriasis-like dermatitis in vivo. METHODS: Psoriasis-like dermatitis was induced by the topical application of an imiquimod (IMQ)-containing cream on the murine ear for 4 to 6 consecutive days. For topical CAL treatment, mice were treated daily with CAL solution on the ear before IMQ application. RESULTS: Mice treated topically with CAL exhibited much milder IMQ-induced psoriasis-like dermatitis compared with vehicle-treated mice, with impaired accumulation of IL 17A-committed T (T17) cells in the lesional skin. The IMQ-induced upregulation of Il12b and Il23a was marked in the epidermis and was abrogated by CAL application, suggesting CAL-mediated suppression of IL-23 expression. CAL inhibited Il12b and Il23a expression by Langerhans cells ex vivo stimulated with IMQ and CD40 cross linking. Topical CAL also inhibited T17 cell expansion in the draining lymph nodes of IMQ-treated skin, implying a possible effect on T17 cell-mediated dermatitis at distant sites. In fact, topical CAL application on the IMQ-treated left ear resulted in amelioration of T17 cell accumulation and psoriasis-like dermatitis in the right ear subsequently treated with IMQ. CONCLUSION: Topical CAL can exert its antipsoriatic effect on CAL-treated lesions and, concomitantly, distant lesions by attenuating the T17 cell accumulation in both CAL-treated lesions and draining lymph nodes. PMID- 28870466 TI - IL-12 and IL-7 synergize to control mucosal-associated invariant T-cell cytotoxic responses to bacterial infection. AB - BACKGROUND: Bacterial respiratory tract infections and exacerbations of chronic lung diseases are commonly caused by nontypeable Haemophilus influenzae (NTHi). Cell-mediated cytotoxicity might be key to controlling infection, but the responses of NTHi-specific T-cell populations are not well understood. Mucosal associated invariant T (MAIT) cells are a recently discovered, innate-like subset of T cells with cytotoxic function, the role of which in lung immunity is unclear. OBJECTIVE: The aim of this study was to determine the mechanisms behind conventional T-cell and MAIT cell cytotoxic responses to NTHi. METHODS: Human ex vivo lung explants were infected with a clinical strain of NTHi. Monocyte-derived macrophages were also infected with NTHi in vitro and cocultured with autologous T cells. Cytotoxic responses of T-cell subsets were measured by using flow cytometry. RESULTS: We found significant upregulation of the cytotoxic markers CD107a and granzyme B in lung CD4+, CD8+, and MAIT cell populations. We show that MAIT cell cytotoxic responses were upregulated by a combination of both time dependent antigen presentation and a novel mechanism through which IL-12 and IL-7 synergistically control granzyme B through upregulation of the IL-12 receptor. CONCLUSIONS: Overall, our data provide evidence for a cytotoxic role of MAIT cells in the lung and highlight important differences in the control of adaptive and innate-like T-cell responses. Understanding these mechanisms might lead to new therapeutic opportunities to modulate the antibacterial response and improve clinical outcome. PMID- 28870467 TI - Corrigendum to "Advanced breast cancer rates in the epoch of service screening: The 400,000 women cohort study from Italy" [Eur J Cancer 75 (April 2017) 109 116]. PMID- 28870468 TI - Corrigendum to "Accurate NMR determination of C-H or N-H distances for unlabeled molecules" [Solid State Nuclear Magnetic Resonance 73 (2016) 15-21]. PMID- 28870469 TI - First demonstration of equid gammaherpesviruses within the gastric mucosal epithelium of horses. AB - Horses commonly develop gastric mucosal ulcers, similar to humans, a condition known as equine gastric ulcer syndrome (EGUS) that can lead to poor performance and lost training time and care expenses. Unlike humans, however, an infectious bacterial cause of ulcers has not been conclusively identified. Herpesviruses, while well-established causative agents of diseases such as cold sores, genital lesions, and certain types of cancer, have also been implicated in the development of a subset of gastric ulcers in humans. The presence of equid herpesviruses in the gastrointestinal tract and their potential contribution to EGUS has not been evaluated. Here, we provide the first evidence of equid gammaherpesviruses 2 and 5 (EHV-2 and -5) within the epithelium of the gastric mucosa of horses. These viruses were initially detected by a nested PCR screen of gastric tissue samples obtained from client- and university-owned horses with and without ulcers; however, no association with EGUS was found in this limited sample set. We then validated a highly sensitive in situ hybridization (ISH) assay and used this assay to characterize the distribution of these viruses in necropsy gastric tissue samples from five racehorses. Analyses revealed frequent EHV-2 and EHV-5 co-infections within the gastric mucosal epithelium, regardless of the ulcer status. These results are the first to demonstrate the presence of equid gammaherpesviruses in the gastric mucosa of horses and warrants further investigation to determine the contribution of these viruses to the development of EGUS and/or other gastrointestinal diseases. PMID- 28870471 TI - Challenging Occam's Razor: An Unusual Combination of Sarcoidosis and Amyloidosis. The Value of Cardiac Magnetic Resonance Imaging in Infiltrative Cardiomyopathies. AB - We describe the case of a 66-year old woman with the extremely rare combination of sarcoidosis and amyloidosis (light chain) and the important role of cardiovascular magnetic resonance imaging to differentiate between these 2 infiltrative diseases. Myocardial characterization with T1 mapping can improve disease detection, especially in overlap cases, and possibly obviate the need for cardiac biopsy. PMID- 28870470 TI - Poliovirus Receptor: More than a simple viral receptor. AB - The human poliovirus receptor (PVR) is a cell surface protein with a multitude of functions in human biology. PVR was initially identified as the receptor for the human poliovirus and recent discoveries have given a greater insight into both its morphology and its function. Alternative splicing of the PVR gene results in a total of 4 alternatively spliced isoforms. Two of these isoforms lack a complete transmembrane domain and are considered soluble and block viral infection; the remaining two transmembrane isoforms differ only at their extreme C-terminal domains resulting in differential localization in epithelia and polarity of viral infection. In addition to its role as a receptor for the human poliovirus, several native biological functions have also been uncovered. PVR is an important cell adhesion protein and is involved in the transendothelial migration of leukocytes. Through its interactions with CD226 and TIGIT, transmembrane proteins found on leukocytes, PVR is a key regulator of the cell mediated immune response. As PVR is differentially regulated in a broad spectrum of cancers, it has a strong potential for clinical use as a biomarker. PVR is also a possible target for novel cancer therapies. Utilizing its natural tropism for PVR, a genetically modified form of the live attenuated poliovirus vaccine is currently being tested for its ability to locate and destroy certain tumors. These recent studies emphasize the importance of PVR in human biology and demonstrate its utility beyond being a viral receptor protein. PMID- 28870472 TI - Effects of high beta-glucan barley on visceral fat obesity in Japanese individuals: A randomized, double-blind study. AB - OBJECTIVE: The aim of this study was to investigate whether a diet in which high beta-glucan barley was substituted for rice would reduce visceral fat obesity in Japanese individuals. METHODS: A randomized, double-blind, placebo-controlled intervention study was conducted with 100 Japanese individuals with waist circumference (WC) >=85 cm for men or >=90 cm for women and body mass index (BMI) >=24 kg/m2. Participants were randomly assigned to consume a mixture of rice and either high beta-glucan barley (test group, 4.4 g/d) or beta-glucan-free barley (placebo group) for 12 wk. Blood samples and computed tomography scans were obtained before and after the trial. RESULTS: Both groups showed decreases in body weight and BMI, and these changes were significantly greater in the test group. WC and visceral fat area (VFA) significantly decreased in both groups (VFA: -10.7 cm2 in the test group; -6.8 cm2 in the placebo group). These changes did not differ significantly between the groups. However, a subgroup analysis of participants with VFA >=100 cm2 showed a significant decrease in the test group, and this decrease was significantly greater than in the placebo group. CONCLUSIONS: The intake of high beta-glucan barley led to significant and safe reductions in VFA, body weight, BMI, and WC in individuals with visceral fat obesity with VFA >=100 cm2. Barley high in beta-glucan may contribute to preventing visceral fat obesity. PMID- 28870473 TI - Short-term effects of a low glycemic index carob-containing snack on energy intake, satiety, and glycemic response in normal-weight, healthy adults: Results from two randomized trials. AB - OBJECTIVES: The potential positive health effects of carob-containing snacks are largely unknown. Therefore, the aims of these studies were to determine the glycemic index (GI) of a carob snack compared with chocolate cookie containing equal amounts of available carbohydrates and to compare the effects of a carob versus chocolate cookie preload consumed as snack before a meal on (a) short-term satiety response measured by subsequent ad libitum meal intake, (b) subjective satiety as assessed by visual analog scales and (c) postprandial glycemic response. METHODS: Ten healthy, normal-weight volunteers participated in GI investigation. Then, 50 healthy, normal-weight individuals consumed, crossover, in random order, the preloads as snack, with 1-wk washout period. Ad libitum meal (lunch and dessert) was offered. Capillary blood glucose samples were collected at baseline, 2 h after breakfast, just before preload consumption, 2 h after preload, 3 h after preload, just before meal (lunch and dessert), 1 h after meal, and 2 h after meal consumption. RESULTS: The carob snack was a low GI food, whereas the chocolate cookie was a high GI food (40 versus 78, respectively, on glucose scale). Consumption of the carob preload decreased the glycemic response to a following meal and to the individual's feelings of hunger, desire to eat, preoccupation with food, and thirst between snack and meal, as assessed with the use of visual analog scales. Subsequently, participants consumed less amounts of food (g) and had lower total energy intake at mealtimes. CONCLUSIONS: The carob snack led to increased satiety, lower energy intake at meal, and decreased postmeal glycemic response possibly due to its low GI value. Identifying foods that promote satiety and decrease glycemic response without increasing the overall energy intake may offer advantages to body weight and glycemic control. PMID- 28870474 TI - HMGB1 values and response to HBV vaccine in children with celiac disease. AB - OBJECTIVES: In addition to its wide clinical variability, celiac disease (CD) can also cause a lower response to the hepatitis B virus (HBV) than healthy individuals. The aim of this study was to examine high mobility group box 1 (HMGB1) as a new potential marker of an inadequate response to HBV vaccine in children with CD at diagnosis before starting a gluten-free diet. METHODS: We recruited 49 children with CD who were tested at admission for immunization against HBV. Serum HMGB1 levels were measured by an enzyme-linked immunosorbent assay test. RESULTS: Serum HMGB1 levels were significantly higher in nonresponders than in responders (P < 0.05). In the responders group in particular, with reference to the titer of vaccine response, we found a significantly higher serum HMGB1 level in the low responders (P < 0.001). We detected statistically significant higher values of HMGB1 in the typical form of disease presentation than in the atypical or silent form (P < 0.05). In the typical form, we showed even significantly higher HMGB1 values in low responders than in high responders (P < 0.001). With regard to the HLA haplotype and serum HMGB1 levels, any statistically significant difference was detected (P > 0.05). CONCLUSIONS: In patients with CD, HMGB1 could represent a new marker that is able to reflect the immune impairment that results in failure of the HBV vaccination. PMID- 28870475 TI - Taste-related factors and food neophobia: Are they associated with nutritional status and teenagers' food choices? AB - OBJECTIVE: The aim of this study was to evaluate the association of taste-related factors (craving for sweets, using food as a reward and pleasure) and food neophobia with nutritional status and food intake among teenagers. METHODS: This was a cross-sectional study with 132 teenagers 15 to 19 y of age. Food behavior, anthropometrics, body composition, and lifestyle measurements were obtained and analyzed. RESULTS: Craving for sweets was associated with overweight, adiposity, meal skipping, physical inactivity, and intake of sweets (P < 0.05). Reward was linked to adiposity, physical inactivity, lack of interest in information about food, and intake of sweets (P < 0.05). Pleasure was associated with physical inactivity, lack of interest in information about food, and intake of sweets and soft drinks (P < 0.05). Teenage girls had a higher craving for sweets (22.88 +/- 4.77) and higher pleasure scores (21.50 +/- 3.82), body fat (25.33 +/- 6.60), meal skipping (63.2%), and physical inactivity (64.7%) than their male counterparts (P < 0.05). There was no association among food neophobia, nutritional status, and food intake. CONCLUSION: The results of the present study indicated that, in contrast to food neophobia, taste-related factors can be associated with body fat and inadequate food choices in teenagers. However, this was a cross-sectional study and further cohort studies should be performed for in depth investigation of a causal relationship between the findings of this research. PMID- 28870476 TI - Branched-chain amino acid supplementation and exercise-induced muscle damage in exercise recovery: A meta-analysis of randomized clinical trials. AB - OBJECTIVE: Accumulating evidence suggests positive effects of branched-chain amino acids (BCAAs) on moderate muscle damage. However, findings vary substantially across studies. The aim of this review was to examine the effect of BCAAs on recovery following exercise-induced muscle damage. METHODS: Controlled trials were identified through a computerized literature search and tracking of citations performed up to November 2015. To pool data, either a fixed-effects or a random-effects model was used; for assessing heterogeneity, Cochran's Q and I2 tests were used. RESULTS: Eight trials met the inclusion criteria. Pooled data from the eight studies showed that BCAAs significantly reduced creatine kinase at two follow-up times (<24 and 24 h) in comparison with placebo recovery (<24 h: mean difference, -71.55 U/L, 95% confidence interval, -93.49 to -49.60, P < 0.000, n = 5 trials; 24 h: mean difference, -145.04 U/L, 95% confidence interval, -253.66 to -36.43, P = 0.009, n = 8 trials). In contrast, effects were not significant in any of the follow-up times for muscle soreness or lactate dehydrogenase. CONCLUSION: The current evidence-based information indicates that use of BCAAs is better than passive recovery or rest after various forms of exhaustive and damaging exercise. The advantages relate to a reduction in muscle soreness and ameliorated muscle function because of an attenuation of muscle strength and muscle power loss after exercise. PMID- 28870477 TI - A low-protein, high-carbohydrate diet increases browning in perirenal adipose tissue but not in inguinal adipose tissue. AB - OBJECTIVE: The aim of this study was to evaluate the browning and origin of fatty acids (FAs) in the maintenance of triacylglycerol (TG) storage and/or as fuel for thermogenesis in perirenal adipose tissue (periWAT) and inguinal adipose tissue (ingWAT) of rats fed a low-protein, high-carbohydrate (LPHC) diet. METHODS: LPHC (6% protein, 74% carbohydrate) or control (C; 17% protein, 63% carbohydrate) diets were administered to rats for 15 d. The tissues were stained with hematoxylin and eosin for histologic analysis. The content of uncoupling protein 1 (UCP1) was determined by immunofluorescence. Levels of T-box transcription factor (TBX1), PR domain containing 16 (PRDM16), adipose triacylglycerol lipase (ATGL), hormone-sensitive lipase, lipoprotein lipase (LPL), glycerokinase, phosphoenolpyruvate carboxykinase (PEPCK), glucose transporter 4, beta3 adrenergic receptor (AR), beta1-AR, protein kinase A (PKA), adenosine monophosphate-activated protein kinase (AMPK), and phospho-AMPK were determined by immunoblotting. Serum fibroblast growth factor 21 (FGF21) was measured using a commercial kit (Student's t tests, P < 0.05). RESULTS: The LPHC diet increased FGF21 levels by 150-fold. The presence of multilocular adipocytes, combined with the increased contents of UCP1, TBX1, and PRDM16 in periWAT of LPHC-fed rats, suggested the occurrence of browning. The contents of beta1-AR and LPL were increased in the periWAT. The ingWAT showed higher ATGL and PEPCK levels, phospho AMPK/AMPK ratio, and reduced beta3-AR and PKA levels. CONCLUSION: These findings suggest that browning occurred only in the periWAT and that higher utilization of FAs from blood lipoproteins acted as fuel for thermogenesis. Increased glycerol 3 phosphate generation by glyceroneogenesis increased FAs reesterification from lipolysis, explaining the increased TG storage in the ingWAT. PMID- 28870478 TI - Validity of equations using knee height to predict overall height among older people in Benin. AB - OBJECTIVES: Chumlea's formulas are a validated means of predicting overall height from knee height (KH) among people >60 y of age, but, to our knowledge, no formula is validated for use in African countries, including Benin. The aim of this study was to compare height provided by predictive formulas using KH to measured height in an elderly population in Benin. METHODS: Individuals >60 y of age in Benin underwent nutritional assessment with determination of weight, body mass index (BMI), height, and KH. A Bland-Altman analysis was carried out by sex and age. The percentage of predictions accurate to +/-5 cm compared with the measured height was calculated. The tested formulas were Chumlea's formulas for non-Hispanic Black people (CBP) and two formulas for use among Caucasians. RESULTS: Data from 396 individuals (81.1% male) were analyzed. The three formulas achieved 98% accuracy, but with 4.6% risk for error (+/-2 SD: -6 to +9 cm), which appeared to make them unfit for the whole population. Nevertheless, if a level of prediction +/-5 cm is considered acceptable in clinical practice, the CBP formula achieved 83.1% accuracy. Moreover, there was no significant difference in BMI calculated with the measured and the predicted height, and the nutritional status based on BMI did not differ. CONCLUSION: CBP formulas seem applicable in 83% of cases (+/-5 cm) to assess the height with KH of older people in Benin and do not overestimate the prevalence of malnutrition. PMID- 28870479 TI - North and South American countries food-based dietary guidelines: A comparison. AB - Food-based dietary guidelines (FBDGs) are regularly updated educational documents that provide scientific information on nutritional needs and food composition to the general population. The aim of this study was to review the FBDGs of countries in the Americas and compare them based on their pictorial representation, food grouping, and associated messages on healthy eating and behavior, considering intercultural differences. FBDGs from 30 countries in the Americas were collected, representing 97% of the entire North and South American population. Of these FBDGs, 93% (28 of 30) have adopted a food guide illustration shape that conveys local traditions and classifies foods into six or seven groups. The main food groups are vegetables, fruits, cereals, starchy vegetables and fruits, legumes, milk and dairy, protein-rich foods, oils and fats, and sugar and sweeteners. Some differences include single food classifications. Despite the dietary pattern resulting from geographic conditions and cultural heritages, the main nutritional keypoints are similar among the different American FBDGs as follows: (1) Consume large amounts of fruits, vegetables, and cereals; and (2) limit intake of fat, simple sugars, and salt. Although there is general agreement on the basic nutritional messages, FBDGs remain insufficient regarding food groups and the identification of subgroup population nutritional requirements, particularly in countries where both excess and deficit malnutrition are present. PMID- 28870480 TI - Propofol sedation substantially increases the caloric and lipid intake in critically ill patients. AB - OBJECTIVE: The amount of lipid delivered to patients varies considerably depending on the non-nutritional intake from sedation, and on the feeding solution. The aim of this study was to quantify the magnitude and proportion of lipids and energy provided from propofol sedation in intensive care unit (ICU) patients. METHODS: This was a retrospective analysis of prospectively collected data in consecutive patients admitted to the ICUs of two university hospitals. Inclusion criterion included an ICU stay >5 d. Data were collected for a maximum of 10 d. Propofol sedation using 1% or 2% propofol solutions was defined as >100 mg/d. Nutritional management was per protocol in both centers, recommending enteral feeding. Data are shown as means +/- standard deviation. RESULTS: In all, 701 admissions (687 patients, ages 59 +/- 16 y, SAPS II 51 +/- 17) and 6485 d, including 3484 propofol sedation days were analyzed. Energy targets were 1987 +/- 411 kcal/d; mean energy delivery was 1362 +/- 811 kcal/d (70% +/- 38% of prescription) including propofol and dextrose. Enteral feeding dominated (75% of days) and progressed similarly in both ICUs. Mean propofol sedation dose was 2045 +/- 1650 mg/d, resulting in 146 +/- 117 kcal/d. Fat from propofol constituted 17% of total energy (up to 100% during the first days). Fat delivery (40 +/- 23 g/d: maximum 310 g/d) was significantly increased by the combination of propofol sedation, the 1% solution, and high-fat-containing feeds. In survivors, high-fat proportion was associated with prolonged ventilation time (P < 0.0001). CONCLUSION: Propofol sedation resulted in large doses of lipids being delivered to patients, some receiving pure lipids during the first days. As the metabolic effects of high proportions of fat are unknown, further research is warranted. PMID- 28870481 TI - Inflammatory diet and risk for colorectal cancer: A population-based case-control study in Newfoundland, Canada. AB - OBJECTIVE: Chronic inflammation is implicated in causing cancer. Diet plays an important role in regulating chronic inflammation by altering circulating levels of inflammatory biomarkers. Effect of single food or nutrient on cancer often is inconclusive; perhaps due to dietary interactions and multicolinearity. The aim of this study was to determine prediagnostic inflammatory potential of overall diet in relation to risk for colorectal cancer (CRC). METHODS: In all, 547 patients with CRC from Newfoundland Familial Colorectal Cancer Registry and 685 controls from the general population were identified. Data on sociodemographic, medical history, lifestyle, and a 169-item food frequency questionnaire were collected retrospectively from both groups. Energy-adjusted Dietary Inflammatory Index (DII) score was calculated and used as both categorical and continuous variables for analysis. Odds ratio was estimated using multivariable logistic regression after adjusting potential confounders. A linear test for trend was performed using the median value in each quartile. RESULTS: Overall energy adjusted mean DII score was -0.81 (range -5.19 to 6.93). Cases (-0.73 +/- 1.5) had slightly higher DII scores than controls (-0.89 +/- 1.6; P = 0.04). After adjusting the potential confounders, a statistically significant association was found between DII score and CRC risk. Using DII as a continuous variable (odds ratio [OR]continuous 1.10, 95% confidence interval [CI] 1.01-1.20) and categorical variable (ORquartile 1 versus 4 1.65, 95% CI 1.13-2.42; Ptrend = 0.02). CONCLUSION: Our findings indicate that proinflammatory diets are associated with an increased risk for CRC in the Newfoundland population. PMID- 28870482 TI - Influence of chemotherapy on total energy expenditure in patients with gastrointestinal cancer: A pilot study. AB - OBJECTIVE: Resting energy expenditure (REE) and physical activity (PA) undergo variations during chemotherapy. The aim of this study was to use a metabolic Holter (SenseWear Armband [SWA]) to assess REE, total energy expenditure (TEE), and PA changes in patients undergoing chemotherapy to ensure the appropriate calorie intake. To our knowledge, this is the first study to do so. METHODS: Eight patients with gastrointestinal tumors and a Karnofsky performance status of >50 underwent evaluation of the body mass index; REE, TEE, metabolic equivalent, and sleep efficiency were evaluated by SWA. Fat-free mass and fat mass were measured by bioelectrical impedance analysis, muscle strength by handgrip, and dietary intake by food diary. All evaluations were performed before chemotherapy (T0), at mid-treatment (T1), and at the end of treatment (T2). A calorie equivalent diet to the TEE was recommended to all patients. RESULTS: At T0, a body weight loss of 15.1 +/- 7.2% in the previous 6 mo was observed in all patients. Two patients did not complete treatment. During chemotherapy, thanks to the nutritional counseling, the remaining patients increased their calorie intake (P = 0.006) and no significant change was observed in other parameters. The REE calculation measured by SWA was correlated to the Harris-Benedict formula (P <= 0.002). CONCLUSION: The present data excluded significant variations of REE and PA in the course of chemotherapy in patients who do not experience weight loss and who have a Karnofsky performance status of >50. Nutritional counseling based on SWA measurements is useful to support nutritional status in patients undergoing chemotherapy. PMID- 28870483 TI - Influence of an omega3-fatty acid-enriched enteral diet with and without added glutamine on the metabolic response to injury in a rat model of prolonged acute catabolism. AB - OBJECTIVE: In critically ill patients, acute injury alters gut function, causing greater risk for sepsis and malnutrition. Peptide-enriched diets may promote nitrogen absorption, whereas omega3-enriched diets reduce alterations in gut barrier function. The aim of this study was to assess the effectiveness of a peptide- and omega3-enriched diet on the metabolic response to injury and the gut barrier function in a model of prolonged catabolism in the rat. Given the intestinal trophic effect of glutamine, we tested for a synergistic effect of glutamine. METHODS: We randomized 40 male Sprague-Dawley rats (250 g) into four groups to enterally receive a standard high-protein diet (S), or a peptide- and omega3-enriched diet either alone (IMN) or supplemented with glutamine and alanine supplied as dipeptide (DIP) or as free amino acids (AAs) for 4 d. Metabolic response to injury was induced by turpentine injections on days 1 and 3. At sacrifice, nutritional and inflammatory biomarkers and intestinal and liver function were assessed. RESULTS: Weight gain (+45-62%) and nitrogen balance (+33 56%) were significantly higher in all groups than in the S group. In jejunal mucosa, total glutathione was significantly higher (+20-30%) and myeloperoxidase activity significantly lower in all groups compared with the S group. Hepatic triacylglycerol content was significantly lower in the AA (0.30 +/- 0.04 MUM/g) and DIP (0.43 +/- 0.08 MUM/g) groups than in the S group (0.71 +/- 0.08 MUM/g). CONCLUSIONS: In this model of prolonged catabolism, compared with a standard diet, a peptide- and omega3-enriched diet improved metabolic response to injury, with better nitrogen balance and weight recovery, and decreased intestinal myeloperoxidase activity. Only marginal additional effects of glutamine supplementation were observed with decreased hepatic fat content. PMID- 28870485 TI - Low skeletal muscle mass predicts early mortality in cirrhotic patients with acute variceal bleeding. AB - OBJECTIVES: Low skeletal muscle mass adversely affects outcomes in cirrhotic patients; however, its affect in patients with acute variceal bleeding remains unknown. The aim of this study was to evaluate the effects of low skeletal muscle mass on outcomes in patients with cirrhosis and acute variceal bleeding. METHODS: We evaluated 122 patients to identify factors associated with two outcomes: failure to control bleeding, defined as either rebleeding or death within 5 d, and 6-wk mortality. Skeletal muscle mass was estimated by calculating the psoas muscle area at the third lumbar vertebra on computed tomographic images. RESULTS: Forty-two patients had low skeletal muscle mass. Fifteen patients had failure to control bleeding and 32 patients died within 6 wk. Six of the patients with low skeletal muscle mass and nine without low skeletal muscle mass had failure to control bleeding; these proportions did not differ significantly (P = 0.628). Fifteen of the patients (35.7%) with low skeletal muscle mass died within 6 wk; this proportion was marginally higher than the 17 (21.3%) without low skeletal muscle mass who died within 6 wk (P = 0.084). On multivariate analysis, presence of low skeletal muscle mass (odds ratio [OR], 4.69; P = 0.024), nonalcoholic etiology (OR, 10.3; P = 0.024), higher international normalized ratio of prothrombin time (OR, 41.4; P < 0.001), and rebleeding within 6 wk (OR, 27; P < 0.001) were associated with 6-wk mortality. CONCLUSIONS: Low skeletal muscle mass is an independent predictor of 6-wk mortality in cirrhotic patients with acute variceal bleeding. PMID- 28870484 TI - Higher protein intake is associated with improved muscle strength in elite senior athletes. AB - OBJECTIVE: The optimal protein intake for elderly individuals who exercise regularly has not yet been clearly defined. The aim of this study was to test the hypothesis that protein intake level is associated with muscle strength in elderly elite athletes. METHODS: We evaluated 50 elite senior athletes (38 men and 12 women) participating in the European Master Games 2011 in an observational cross-sectional study. Participants were divided into two groups-lower (LPI) or higher (HPI) protein intake-according to the median value of their ratio of urinary urea nitrogen to urinary creatinine (i.e., 8.8 g/L), as a marker of protein intake. A dietary interview confirmed differences in protein consumption between the LPI and HPI groups. We also evaluated body composition (bioimpedance), muscle strength, and hematochemical indices. RESULTS: LPI and HPI groups were homogeneous for age (72 [68-74] and 71 [68-74] y, respectively), fat free mass index (18.4 [17-19.4] and 18.2 [17-19.1] kg/m2), body fat (18.3% [12.3 20.7%] and 16.6% [13.6-21.2%]), and glomerular filtration rate (57.7 [53.8-64.9] and 62.7 [56.1-69.3] mL/min/1.73 m2). The HPI group showed greater leg and trunk muscle strength (N) compared with the LPI group (left leg extension, 339 [238 369] versus 454 [273-561], respectively, P < 0.05; right leg extension, 319 [249 417] versus 432 [334-635], P <= 0.05; trunk extension, 435 [370-467] versus 464 [390-568], P <= 0.05). CONCLUSIONS: Higher protein intake in elite senior athletes is associated with a greater muscle strength. PMID- 28870486 TI - Effect of 1-y oral supplementation with vitaminized olive oil on platelets from healthy postmenopausal women. AB - OBJECTIVE: Olive oil is the main fat source in the Mediterranean diet and shows a protective role against aging and related diseases. Osteoporosis represents a serious health problem worldwide and is associated with an increased risk for fractures and mortality. Nutrition should be part of bone disease prevention strategies, especially in light of the aging population and the effect of diet on bone health. The aim of this study was to investigate whether oral supplementation with extra virgin olive oil (VOO) enriched with vitamins D3, K1, and B6 (VitVOO) is able to modify some physicochemical and functional plasma membrane properties and nitrosative stress markers status. METHODS: In this single-center, randomized placebo-controlled trial, 60 postmenopausal women were administered either VitVOO or placebo (PlaVOO). After 1 y of oral supplementation, platelet membrane fluidity changes, Na+/K+-ATPase activity, serum nitric oxide, and peroxynitrite levels were determined in participants. RESULTS: After 1 y (time 1), women taking VitVOO showed lower nitric oxide levels than those taking PlaVOO; the same trend was found for peroxynitrite levels. As far as membrane fluidity was concerned, a significant decrease in anisotropy of diphenylhexatriene and trimethylammonium-diphenylhexatriene at time 1 in VitVOO participants compared with PlaVOO was found. Finally, Na+/K+-ATPase activity showed a significant increase after VitVOO supplementation. CONCLUSION: The supplementation of VitVOO into the diet of postmenopausal women could represent a proper tool for platelet function and a useful strategy against nitrosative stress and related diseases, thus confirming the antioxidant role played by the added vitamins. PMID- 28870487 TI - Comparison of new adiposity indices for the prediction of body fat in hospitalized patients. AB - OBJECTIVE: To measure the accuracy of the body mass index (BMI), BMI adjusted for fat mass (BMIfat), body adiposity index (BAI), BAI for the Fels Longitudinal Study sample, Clinica Universidad de Navarra-Body Adiposity Estimator, and fat mass index and to compare the accuracy to that of bioelectrical impedance and dual-energy x-ray absorptiometry (DXA) in a sample of the Brazilian population. METHODS: A cross-sectional study conducted on 240 hospitalized patients, 43 (18%) male and 197 (83%) female. Mean patient ages were 53.0 +/- 13.3 y for males and 53.49 +/- 14.0 y for females. All subjects underwent anthropometric evaluation, bioelectrical impedance, and DXA, which permitted the calculation of the indices. The level of significance was set at P < 0.05 in the statistical analyses. RESULTS: Mean subject age (y), weight (kg), and height (cm) were 53.0 +/- 13.3 and 53.4 +/- 14.0; 72.8 +/- 14.9 and 67.6 +/- 14.0; and 171.0 +/- 8.0 and 157.0 +/- 7.0 for men and women, respectively. Excess weight was detected in 67.4% and 66% according to the BMI, in 30% and 69.5% according to the BMIfat, and in 51% and 38% according to the BAI for men and women, respectively. Pearson correlation revealed that BMIfat clearly showed a better correlation (r = 0.67) with DXA than the remaining tools. The Clinica Universidad de Navarra-Body Adiposity Estimator was the only body adiposity parameter that was significantly higher in men compared to women. CONCLUSION: The results suggest that BMIfat is the index best related to the prediction of body fat and that the BAI did not exceed the limits of the BMI. Further studies of this type are needed to strengthen the present findings. PMID- 28870488 TI - The Effect of Psychosocial Factors on Success Rates of Hepatitis C Treatment. AB - OBJECTIVE: Our study was to determine which psychosocial factors interfere with patients reaching sustained virologic response (SVR), a marker for hepatitis C virus eradication. METHODS: A retrospective chart review was performed between January 6, 2015 and February 24, 2016. The primary outcome was to assess which social and psychological factors may interfere with patients reaching SVR. SVR was defined as having an undetectable viral load 12 weeks after the completion of the treatment regimen. Bivariate analysis was followed by a multivariate logistic regression analysis to determine significant factors for SVR. Depression and generalized anxiety disorder were included. RESULTS: A total of 204 patients completed treatment within the designated time frame and were included in the final analysis. Social or home support was associated with SVR (odds ratio = 7.0, p = 0.02). Cocaine use was also a significant factor predicting SVR. Historical cocaine use compared with active cocaine use during treatment was associated with an odds ratio of SVR of 39.3 (p = 0.04). Interestingly, historical cocaine use vs no history of cocaine use did not influence SVR. No history of depression or generalized anxiety disorder was associated with a higher rate of SVR (odds ratio = 10.4, p = 0.05). No depression/generalized anxiety disorder compared with untreated depression/generalized anxiety disorder was associated with a 13.1 times greater rate of SVR (p = 0.04). CONCLUSION: It is important to recognize and address psychosocial factors related to mental illness and active cocaine addictions before hepatitis C virus treatment. Furthermore, patients without home or social support are at greater risk for failing treatment, thus strategies to provide support during treatment are necessary. PMID- 28870489 TI - Bisphenol A and immunotoxic potential: A commentary. AB - Bisphenol A (BPA) is used in the manufacture of polycarbonate and epoxy resin plastics. There has been interest in the possibility that BPA has immunotoxic properties, and a variety of investigations have explored this. Among the approaches taken have been human observational and cross-sectional studies, investigations using experimental animals, and in vitro studies, some of which have been reviewed previously by the European Food Safety Authority (EFSA). This commentary aims to provide a focused review of data regarding the ability of BPA to perturb the immune system, including the developing immune system, and to cause related adverse health effects. The objective is to complement the evaluations conducted by EFSA, with a focus on the ability of BPA to impair immune function, to promote respiratory allergy and airway inflammation, and to compromise immunological tolerance to dietary proteins. The conclusion drawn is that there is currently no persuasive evidence that BPA has significant immunotoxic potential. This is, in part, due to some of the data reviewed being apparently contradictory or inconsistent, and the investigations from which those data were derived having limitations with regard to experimental design. The conclusion drawn here is that presently there is no clear evidence that BPA has the potential to cause immunotoxicity resulting in adverse health effects. PMID- 28870490 TI - A study to support regulatory submission assessing effects of Tri(2-ethylhexyl) trimellitate (TEHTM) upon pre and post-natal development in the rat, with a comparative group receiving Di(2-ethyl hexyl) phthalate (DEHP) included. AB - Oral exposure of rodents to the plasticizer, Di(2-ethyl hexyl) phthalate (DEHP), elicits birth defects and effects upon the reproductive tract. There is currently limited published information regarding potential developmental effects in rodents of another phthalate ester, TEHTM. PMID- 28870491 TI - The effect of neonatal immune challenge on reproduction by altering intraovarian kisspeptin/GPR54 system in the rat. AB - Immune challenge in early life has been observed to influence the long-term reproductive dysfunction. On PNDs 3 and 5, female offsprings were administered with LPS (50MUg/kg, i.p.) or saline. Vaginal opening was recorded, and oestrous cyclicity was monitored immediately post puberty and again at 56-70 days. At 10 weeks of age, the ovaries were removed for immunostaining and RNA analysis. Neonatal exposure to LPS resulted in a significant delay puberty onset as well as destroyed expression of ovulation related genes. At PND 42 and 70, a significant increase in Kiss1 mRNA and Kisspeptin expression was detected at proestrus and oestrus in neo-LPS treated rats compared with the counterparts. Therefore, neonatal LPS exposure had a long-term effect on reproductive function and the up regulated expression of ovarian Kiss1 and kisspeptin during the ovulatory transition stage may contribute to ovulatory dysfunction induced by peripheral LPS administration in early life. PMID- 28870492 TI - Prenatal and postnatal exposure to low levels of permethrin exerts reproductive effects in male mice. AB - Permethrin, a pyrethroid chemical, is widely used as a pesticide because of its rapid insecticidal activity. Although permethrin is considered to exert very low toxicity on mammalian reproductive organs, the effects of early low-level and chronic exposure on adult spermatogenesis are unclear. We exposed mice to environmentally relevant concentrations of permethrin (0, 0.3, and 30ppm) in drinking water during prenatal and postnatal period and examined the effects on the testis in mice offspring when they reached maturity (12 weeks of age). Using methyl green-pyronin staining, we found an abnormal accumulation of RNA in the seminiferous epithelia of mice treated with permethrin; this accumulation may be derived from an enlargement of the residual body. Additionally, permethrin may cause a decline of Sertoli cell functions. Our findings demonstrate that low level and chronic permethrin exposure during prenatal and postnatal period has distinct effects on male reproductive system in mice. PMID- 28870493 TI - Incontinentia Pigmenti: A Summary Review of This Rare Ectodermal Dysplasia With Neurologic Manifestations, Including Treatment Protocols. AB - Incontinentia pigmenti is a rare neuroectodermal dysplasia caused by a defect in the IKBKG gene (formerly known as NEMO). There are 27.6 new cases per year worldwide; 65% to 75% are sporadic mutations, and 25% to 35% are familial. It is usually lethal in males, but females survive because of X-inactivation mosaicism. The disorder is typically identified by unique skin findings, a series of four stages that emerge throughout the first year of life. The central nervous system manifestations in the eye and in the brain cause the most disability. Defects of hair, nails, and teeth occur, and there can be other systemic involvement. Surveillance protocols for medical management have been established by the Incontinentia Pigmenti International Foundation. This article will summarize the existing knowledge of this condition and detail the protocols to help manage the care of the infant or child who presents with incontinentia pigmenti. PMID- 28870495 TI - Depression in the School-Aged Child With Type 1 Diabetes: Implications for Pediatric Primary Care Providers. AB - Depression is a common comorbid condition experienced by children with type 1 diabetes that, if undiagnosed, can lead to deterioration in glycemic control and other serious health complications. Although it is documented that children with type 1 diabetes experience high rates of depression, a comprehensive clinical guide does not exist to help direct the pediatric provider on how to best care for these children. The purpose of this article is to synthesize current evidence to aid the pediatric primary care provider in the detection and management of depression in the school-aged child with type 1 diabetes. PMID- 28870494 TI - Health-Related Quality of Life Outcomes of a Telehealth Care Coordination Intervention for Children With Medical Complexity: A Randomized Controlled Trial. AB - The purpose of this study was to explore health-related quality of life (HRQL) and family impact in the context of an advanced practice registered nurse delivered telehealth care coordination intervention for children with medical complexity (CMC). This was a secondary outcomes analysis of a randomized controlled trial with 163 families of CMC in an existing medical home. HRQL and family impact were measured using the PedsQL measurement model. Bivariate and analysis of covariance analyses were conducted to explore associations at baseline and the intervention effect over 2 years. Significant predictors of Year 2 child HRQL were baseline HRQL and the presence of both neurologic impairment and technology dependence. There was no significant intervention effect on child HRQL or family impact after 24 months. Care coordination interventions for CMC may need to incorporate family system interventions for optimal outcomes in a range of quality of life domains. PMID- 28870496 TI - Gut Protozoa: Friends or Foes of the Human Gut Microbiota? AB - The importance of the gut microbiota for human health has sparked a strong interest in the study of the factors that shape its composition and diversity. Despite the growing evidence suggesting that helminths and protozoa significantly interact with gut bacteria, gut microbiome studies remain mostly focused on prokaryotes and on populations living in industrialized countries that typically have a low parasite burden. We argue that protozoa, like helminths, represent an important factor to take into account when studying the gut microbiome, and that their presence - especially considering their long coevolutionary history with humans - may be beneficial. From this perspective, we examine the relationship between the protozoa and their hosts, as well as their relevance for public health. PMID- 28870497 TI - Parasites Lost: Neglecting a Crucial Element in De-Extinction. AB - Bringing back iconic and beloved extinct species is a hot and intensely debated current topic. Yet, the parasites of de-extinction candidate species have remained largely overlooked in this debate. Here we point out the potentially far reaching ecological impacts of bringing back extinct species without their parasites. PMID- 28870498 TI - Drug adherence in hypertension. AB - Blood pressure control remains unsatisfactory in all countries of the world with at best 60% of treated hypertensive patients reaching recommended therapeutic goals. Several factors have been identified which may explain why the rate of blood pressure control remains low. Among them, one can cite medical inertia and a poor adherence to drug therapies. In the absence of new drugs to control blood pressure, drug adherence has become a major issue in the management of hypertensive patients. Numerous studies have demonstrated that the major problem is the lack of persistence followed by a poor day to day execution of the prescribed regimens. Although there are multiple ways of assessing drug adherence, only very few of them are accurate and the most accurate ones are either difficult to implement in clinical practice or too expensive and hence not available outside reference centers. Therefore, physicians have no real capacity to establish a correct diagnosis of non persistence or poor adherence even in high risk patients such as those with resistant hypertension. Today a new approach is becoming increasingly used which consists in measuring urinary drug levels. Nevertheless, there is still an important need for simple and cheap techniques or devices helping physicians in their ability to tackle poor adherence to therapy and thereby improve blood pressure control in the population. PMID- 28870499 TI - The pleasures of drunken one-night stands: Assemblage theory and narrative environments. AB - BACKGROUND: In this study, we use assemblage theory to investigate the link between alcohol use and one-night stands. METHODS: The data come from qualitative interviews conducted with 104 young participants in the night-time economy. RESULTS: We show that: (i) alcohol-fuelled sexual explorations (e.g. erotic fantasizing, flirting and sex) are of paramount importance for young partygoers; (ii) sexualized territories (e.g. private parties, rural feasts and the backseat of cars) significantly shape the experience and performance of one-night stands; and (iii) contrary to previous research, one-night stands are to a large degree associated with pleasure-the immediate pleasure of having sex and the long-term pleasure of telling about it to others. CONCLUSION: We argue that drunken one night stands are part and parcel of a drinking culture that places high value on sexual encounters and personal sex stories. PMID- 28870500 TI - Home closure as a weapon in the Dutch war on drugs: Does judicial review function as a safety net? AB - BACKGROUND: A widespread sense of a failing criminal justice system and increased feelings of insecurity changed the response to crime into a culture of control, which is characterized by policies that punish and exclude. In the Netherlands, these influences can be witnessed in the war on drugs where local authorities use their administrative power to close homes involved in drug-related crime. Citizens can invoke judicial review over these administrative interferences by claiming that such closure results in an unfair balance between purposes, means and consequences. This paper assesses whether judicial review functions as a safety net against losing one's home due to drug-related crime. METHODS: We used doctrinal legal research methods to examine the "law in the books" and empirical legal research methods to analyse the "law in action". We used a survey to investigate how often the drug-related closure power was used in 2015, and we statistically analysed all published case law of Dutch lower courts between 2007 and 2016. RESULTS: The scope of the closure power broadened over the years and our data show that local authorities fiercely make use of this instrument. In 41.4% of the cases, citizens are successful in fighting the closure. While scholarly literature indicates that judicial courts function as safeguards by questioning the proportionality of administrative action, raising a proportionality defence does not necessarily result in a more favourable outcome for citizens. In fact, raising a proportionality defence makes it more likely to result in dismissal of the appeal. CONCLUSION: The stretched scope of the drug related closure power together with the relatively low success rate of citizens who fight the loss of their home and a seemingly meaningless proportionality check show no sign of a safety net against the loss of one's home at the suit of a local authority. PMID- 28870501 TI - [University and Health: Lights and shadows in Montreal (Canada)]. PMID- 28870502 TI - ? AB - OBJECTIVES: To analyse the efficiency of nurse prescription of the health products inherent to their care work, in Andalusia, Spain, between the years 2009 2015. To also analyse the discussions by the Medical Colleges Organisation and the Ministry of Health, Social Services and Equality, before the draft bill on nurse prescription and their outcome. DESIGN: Scoping review. DATA SOURCE: Main bibliographic databases of Latin-American, Spanish, and foreign languages were reviewed, including, Fundacion Index, Doyma, and Medline Library. Google Scholar was also used with the same search terms, adding to limit the search the term "Andalusia": "prescription nurse" AND "efficiency" OR "Andalusia". Another search was conducted in the grey literature using the same criteria in the Andalusian Health Service (SAS) web site. It was complemented with an interview with the care director of the SAS. DATA EXTRACTION: A total of 617 articles were found, of which 20 were selected. In the grey literature, 52 documents were found, of which 4 were used. RESULTS: Few studies were found on the efficiency in nurse prescription in Andalusia, although they are as strong as the data provided by the Andalusian Health Care Directorate on the health products inherent in their profession. After modification of Royal Decree 954/2015, and under pressure from the Medical Colleges Organisation, it leaves the competence of prescription nurse exclusively to the medical indication, who diagnoses and prescribes and eliminates it without argument scientifically endorsed. CONCLUSIONS: We corroborate the incorporation of efficiency in the Health System through the nurse prescription, and the rupture with the Royal Decree 954/2015. The allegations of the Medical Colleges Organisation are without argument. PMID- 28870503 TI - [Prospective study of the incidence of cardiovascular events in young adults and its relation to the metabolic syndrome]. PMID- 28870504 TI - The oxidized phospholipid POVPC impairs endothelial function and vasodilation via uncoupling endothelial nitric oxide synthase. AB - Endothelial dysfunction is an early stage of atherosclerosis. We recently have shown that 25-hydroxycholesterol found in atherosclerotic lesions could impair endothelial function and vasodilation by uncoupling and inhibiting endothelial nitric oxide synthase (eNOS). 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3 phosphocholine (POVPC), the oxidation product of oxidized low-density lipoprotein, is another proinflammatory lipid and has also been found in atherosclerotic lesions. However, whether POVPC promotes atherosclerosis like 25 hydroxycholesterol remains unclear. The purpose of this study was to explore the effects of POVPC on endothelial function and vasodilation. Human umbilical vein endothelial cells (HUVECs) were incubated with POVPC. Endothelial cell proliferation, migration and tube formation were measured. Nitric oxide (NO) production and superoxide anion generation (O2-) were determined. The expression and phosphorylation of endothelial nitric oxide synthase (eNOS), AKT, PKC-betaII and P70S6K as well as the association of eNOS and heat shock protein 90 (HSP90) were detected by immunoblotting and immunoprecipitation. Endothelial cell apoptosis was monitored by TUNEL staining. The expression of Bcl-2, Bax, and Cleaved Caspase 3 were detected by immunoblotting. Finally, aortic ring from C57BL6 mice were isolated and treated with POVPC and the endothelium-dependent vasodilation was evaluated. POVPC significantly inhibited HUVECs proliferation, migration, tube formation, decreased NO production but increased O2- generation. POVPC inhibited the phosphorylation of Akt and eNOS at Ser1177, increased activation of PKC-betaII, P70S6K and the phosphorylation of eNOS at Thr495, reduced the association of HSP90 with eNOS. Meanwhile, POVPC induced endothelial cell apoptosis by inhibiting Bcl-2 expression, increasing Bax and cleaved caspase 3 expressions as well as caspase-3 activity and impaired endothelium-dependent vasodilation. These data demonstrated that POVPC impaired endothelial function by uncoupling and inhibiting eNOS as well as by inducing endothelial cell apoptosis. Therefore, POVPC may play an important role in the development of atherosclerosis and may be considered as a potential therapeutic target for atherosclerosis. PMID- 28870506 TI - PCB in the environment: bio-based processes for soil decontamination and management of waste from the industrial production of Pleurotus ostreatus. AB - Polychlorinated biphenyls (PCBs) are hazardous soil contaminants for which a bio based technology for their recovery is essential. The objective of this study was to validate the exploitation of spent mushroom substrate (SMS), a low or null cost organic waste derived from the industrial production of P. ostreatus, as bulking agent in a dynamic biopile pilot plant. The SMS shows potential oxidative capacity towards recalcitrant compounds. The aim was consistent with the design of a process of oxidation of highly chlorinated PCBs, which is independent from their reductive dehalogenation. Feasibility was verified at a mesocosm scale and validated at pilot scale in a dynamic biopile pilot plant treating ten tons of a historically contaminated soil (9.28+/-0.08mg PCB/kg soil dry weight). Mixing of the SMS with the soil was required for the depletion of the contaminants. At the pilot scale, after eight months of incubation, 94.1% depletion was recorded. A positive correlation between Actinobacteria and Firmicutes active metabolism, soil laccase activity and PCB removal was observed. The SMS was found to be exploitable as a versatile low cost organic substrate capable of activating processes for the oxidation of highly chlorinated PCBs. Moreover, its exploitation as bulking agent in biopiles is a valuable management strategy for the re-utilisation of an organic waste deriving from the industrial cultivation of edible mushrooms. PMID- 28870507 TI - Can parallel ecological speciation be detected with phylogenetic analyses? AB - Distinguishing parallel divergence from vicariance scenarios is crucial to establish the determinism of natural selection in the formation of new species. It has been proposed that phylogenetic methods can be used to disentangle a single origin in allopatry and multiple origins in sympatry for ecological speciation. However, a key issue is to what extent introgression in a patchy environment may complicate the distinction between both origins through the analysis of variation at neutral markers. While divergence at environmentally based selected loci retains the initial correlation with ecological variables, such association may be lost at neutral loci unlinked to any selected locus. Thus, neutral divergence might reflect in the long-term the molecular fingerprint of isolation by distance regardless of the model of speciation considered, and a question arises as to whether phylogenetic analyses of neutral markers are able or not to retrieve the signals acquired in the ancestral populations. Here, we use computer simulations to show that the detection of the original signal using a phylogenetic method strongly depends on the migration rates among populations. Recombination accelerates the loss of the initial phylogenetic signal, but this effect is rather small compared with the effect of migration, and only substantial when recombination is very large. For model species with reduced gene flow between distant populations and between populations adapted to different habitats, the phylogenetic approach is able to distinguish a single origin in allopatry from multiple origins in sympatry. PMID- 28870505 TI - TGF-beta1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism. AB - The contractile property of the myocardium is maintained by cell-cell junctions enabling cardiomyocytes to work as a syncytium. Alterations in cell-cell junctions are observed in heart failure, a disease characterized by the activation of Transforming Growth Factor beta 1 (TGFbeta1). While TGFbeta1 has been implicated in diverse biologic responses, its molecular function in controlling cell-cell adhesion in the heart has never been investigated. Cardiac specific transgenic mice expressing active TGFbeta1 were generated to model the observed increase in activity in the failing heart. Activation of TGFbeta1 in the heart was sufficient to drive ventricular dysfunction. To begin to understand the function of this important molecule we undertook an extensive structural analysis of the myocardium by electron microscopy and immunostaining. This approach revealed that TGFbeta1 alters intercalated disc structures and cell-cell adhesion in ventricular myocytes. Mechanistically, we found that TGFbeta1 induces the expression of neural adhesion molecule 1 (NCAM1) in cardiomyocytes in a p38 dependent pathway, and that selective targeting of NCAM1 was sufficient to rescue the cell adhesion defect observed when cardiomyocytes were treated with TGFbeta1. Importantly, NCAM1 was upregulated in human heart samples from ischemic and non ischemic cardiomyopathy patients and NCAM1 protein levels correlated with the degree of TGFbeta1 activity in the human cardiac ventricle. Overall, we found that TGFbeta1 is deleterious to the heart by regulating the adhesion properties of cardiomyocytes in an NCAM1-dependent mechanism. Our results suggest that inhibiting NCAM1 would be cardioprotective, counteract the pathological action of TGFbeta1 and reduce heart failure severity. PMID- 28870508 TI - Inappropriate Dexamethasone Use by a Trekker in Nepal: A Case Report. AB - We present a case of inappropriate dexamethasone use in a trekker in the Everest region of Nepal. We aim to increase awareness among health professionals of the possible use of this medication by trekkers and promote knowledge of potential complications. In this case, a previously altitude-naive trekker was prescribed prophylactic dexamethasone by physicians in a Western travel clinic before high altitude trekking in Nepal. There were no indications for prophylactic medication nor for the use of dexamethasone. The trekker reported that no discussion regarding risks and benefits, alternatives, side effects, contraindications, or dose tapering on completion of the course had occurred before travel. Side effects were temporary, but serious complications may have ensued if it not for timely interventions by doctors at the International Porter Protection Group rescue post. The events leading to inappropriate dexamethasone use in this case cannot be known for certain. However, it is clear that the trekker lacked the knowledge to use the medication safely. Although the efficacy of dexamethasone in the prevention of acute mountain sickness is undisputed, associated side effects and other limitations make acetazolamide the prophylactic drug of choice. Inappropriate use of dexamethasone can lead to severe complications, and such a case has been reported from Mount Everest. Clinicians prescribing dexamethasone must understand the indications and risks, and health professionals at altitude should be aware of its use by trekkers and the potential complications. PMID- 28870509 TI - Avalanche Accident Resulting in Leg Amputation. PMID- 28870510 TI - Repeated transcranial direct current stimulation improves cognitive dysfunction and synaptic plasticity deficit in the prefrontal cortex of streptozotocin induced diabetic rats. AB - BACKGROUND: Cognitive dysfunction is commonly observed in diabetic patients. We have previously reported that anodal transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex can facilitate visuospatial working memory in diabetic patients with concomitant diabetic peripheral neuropathy and mild cognitive impairment, but the underlying mechanisms remain unclear. OBJECTIVE: We investigated the cellular mechanisms underlying the effect of tDCS on cognitive decline in streptozotocin (STZ)-induced diabetic rats. METHODS: STZ-induced diabetic rats were subjected to either repeated anodal tDCS or sham stimulation over the medial prefrontal cortex (mPFC). Spatial working memory performance in delayed nonmatch-to-place T maze task (DNMT), the induction of long-term potentiation (LTP) in the mPFC, and dendritic morphology of Golgi stained pyramidal neurons in the mPFC were assessed. RESULTS: Repeated applications of prefrontal anodal tDCS improved spatial working memory performance in DNMT and restored the impaired mPFC LTP of diabetic rats. The mPFC of tDCS-treated diabetic rats exhibited higher levels of brain-derived neurotrophic factor (BDNF) protein and N-Methyl-d-aspartate receptor (NMDAR) subunit mRNA and protein compared to sham stimulation group. Furthermore, anodal tDCS significantly increased dendritic spine density on the apical dendrites of mPFC layer V pyramidal cells in diabetic rats, whereas the complexity of basal and apical dendritic trees was unaltered. CONCLUSIONS: Our findings suggest that repeated anodal tDCS may improve spatial working memory performance in streptozotocin-induced diabetic rats through augmentation of synaptic plasticity that requires BDNF secretion and transcription/translation of NMDARs in the mPFC, and support the therapeutic potential of tDCS for cognitive decline in diabetes mellitus patients. PMID- 28870511 TI - Blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) during transcranial near-infrared laser irradiation. PMID- 28870512 TI - The use of cold cots following perinatal death. PMID- 28870513 TI - Transvaginal repair of a misunderstood large bowel evisceration six months after vaginal hysterectomy. PMID- 28870514 TI - Microstructure-informed slow diffusion tractography in humans enhances visualisation of fibre pathways. AB - Conventional fibre tractography methods based on diffusion tensor imaging exploit diffusion anisotropy and directionality in the range of low diffusion weightings (b-values). High b-value Biexponential Diffusion Tensor Analysis reported previously has demonstrated that fractional anisotropy of the slow diffusion component is essentially higher than that of conventional diffusion tensor imaging whereas popular compartment models associate this slow diffusion component with axonal water fraction. One of the primary aims of this study is to elucidate the feasibility and potential benefits of "microstructure-informed" whole-brain slow-diffusion fibre tracking (SDIFT) in humans. In vivo diffusion weighted images in humans were acquired in the extended range of diffusion weightings<=6000smm-2 at 3T. Fast and slow diffusion tensors were reconstructed using the bi-exponential tensor decomposition, and a detailed statistical analysis of the relevant whole-brain tensor metrics was performed. We visualised three-dimensional fibre tracts in in vivo human brains using deterministic streamlining via the major eigenvector of the slow diffusion tensor. In particular, we demonstrated that slow-diffusion fibre tracking provided considerably higher fibre counts of long association fibres and allowed one to reconstruct more short association fibres than conventional diffusion tensor imaging. SDIFT is suggested to be useful as a complimentary method capable to enhance reliability and visualisation of the evaluated fibre pathways. It is especially informative in precortical areas where the uncertainty of the mono exponential tensor evaluation becomes too high due to decreased anisotropy of low b-value diffusion in these areas. Benefits can be expected in assessment of the residual axonal integrity in tissues affected by various pathological conditions, in surgical planning, and in evaluation of cortical connectivity, in particular, between Brodmann's areas. PMID- 28870515 TI - MRI characteristics of the glia limitans externa: A 7T study. AB - PURPOSE: To perform a systematic analysis of the intrinsic contrast parameters of the FLAIR hyperintense rim (FHR), a thin layer of high intensity covering the entire surface of the cerebral cortex detected on fluid-attenuated inversion recovery (FLAIR) sequence T2 weighted imaging performed on a 7T system, in an attempt to identify its anatomical correlate. METHODS: Fast spin echo inversion recovery (FSE-IR) and cardiac-gated fast spin echo (FSE) images were obtained with defined parameters in eight normal volunteers on a 7 T MRI system to determine T2 and proton density, T1 characteristics. K-means clustering analysis of parameter sets was performed using MATLAB version R2015b for the purpose of identifying the cluster reflecting FHR. The results were subsequently confirmed by independent component analysis (ICA) based on T1 behavior on FSE-IR using a MATLAB script of FastICA algorithm. RESULTS: The structure giving rise to FHR was found to have a unique combination of intrinsic contrast parameters of low proton density, long T2, and disproportionally short T1. The findings are in strong agreement with the functional and structural specifics of the glia limitans externa (GLE), a structure composed of snuggled endfeet of astrocytes containing abundant aquaporin-4 (AQP-4), the main water channel of the brain. CONCLUSION: Intrinsic contrast parameters of FHR reflect structural and functional specifics of the GLE, and their values are highly dependent on the physiologic functionality of AQP-4. Microscopic imaging on a 7T system and analysis of GLE contrast parameters can be developed into a method for evaluating AQP-4 functionality. PMID- 28870516 TI - A docking model of dapsone bound to HLA-B*13:01 explains the risk of dapsone hypersensitivity syndrome. AB - BACKGROUND: Dapsone (4,4'-diaminodiphenylsulfone) has been widely used for the treatment of infections such as leprosy. Dapsone hypersensitivity syndrome (DHS) is a major side effect, developing in 0.5-3.6% of patients treated with dapsone, and its mortality rate is ~10%. Recently, human leukocyte antigen (HLA)-B*13:01 was identified as a marker of susceptibility to DHS. OBJECTIVES: To investigate why HLA-B*13:01 is responsible for DHS from a structural point of view. METHODS: First, we used homology modeling to derive the three-dimensional structures of HLA-B*13:01 (associated with DHS) and HLA-B*13:02 (not so associated despite strong sequence identity [99%] with HLA-B*13:01). Next, we used molecular docking, molecular dynamic simulations, and the molecular mechanics Poisson Boltzman surface area method, to investigate the interactions of dapsone with HLA B*13:01 and 13:02. RESULTS: We found a crucial structural difference between HLA B*13:01 and 13:02 in the F-pocket of the antigen-binding site. As Trp95 in the alpha-domain of HLA-B*13:02 is replaced with the less bulky Ile95 in HLA-B*13:01, we found an additional well-defined sub-pocket within the antigen-binding site of HLA-B*13:01. All three representative docking poses of dapsone against the antigen-binding site of HLA-B*13:01 used this unique sub-pocket, indicating its suitability for binding dapsone. However, HLA-B*13:02 does not seem to possess a binding pocket suitable for binding dapsone. Finally, a binding free energy calculation combined with a molecular dynamics simulation and the molecular mechanics Poisson-Boltzman surface area method indicated that the binding affinity of dapsone for HLA-B*13:01 would be much greater than that for HLA B*13:02. CONCLUSIONS: Our computational results suggest that dapsone would fit within the structure of the antigen-recognition site of HLA-B*13:01. This may change the self-peptides that bind to HLA-B*13:01, explaining why HLA-B*13:01 is a marker of DHS susceptibility. PMID- 28870517 TI - Phase 2 Trial of Capecitabine, Gemcitabine, and Bevacizumab in Sarcomatoid Renal Cell Carcinoma. AB - BACKGROUND: Patients with sarcomatoid renal-cell carcinomas (sRCC) have poor outcomes and limited treatment options. Preclinical and clinical data suggest susceptibility to cytotoxic agents and vascular endothelial growth factor targeted therapies. We designed a phase 2 trial to evaluate the efficacy and safety of capecitabine, gemcitabine, and bevacizumab in sRCC. PATIENTS AND METHODS: Patients with metastatic or unresectable sRCC were eligible for inclusion. Patients received oral capecitabine 800 mg/m2 twice daily on days 1 to 21 of a 28-day cycle, intravenous gemcitabine 900 mg/m2 on days 1 and 15, and intravenous bevacizumab 10 mg/kg on days 1 and 15. Primary end points were progression-free survival and time to treatment failure (TTF). Secondary end points were safety, objective response rate, and overall survival. RESULTS: Thirty-four patients were enrolled onto the trial. One patient was excluded from survival analysis and 4 from response analysis as a result of missing data. Median progression-free survival was 5.5 months (95% confidence interval [CI], 3.4-7.7), median TTF was 4.2 months (95% CI, 2.4-6.0), and median overall survival was 12 months (95% CI, 10.6-13.4). Objective response rate was 20% (5 partial responses, 1 complete response), and disease control rate was 73%. Thirty one (91%) of the 34 patients discontinued treatment. The most common reason for treatment discontinuation was progressive disease, which occurred in 24 patients (71%). The most common grade 3 toxicity was rash (including hand-foot syndrome) in 24% patients. CONCLUSION: The combination of capecitabine, gemcitabine, and bevacizumab is an option for patients with sRCC; however, response rates are low. Novel therapies are needed to improve outcomes in patients with sRCC. PMID- 28870518 TI - MultiTEP platform-based DNA vaccines for alpha-synucleinopathies: preclinical evaluation of immunogenicity and therapeutic potency. AB - We have previously demonstrated that anti-beta amyloid DNA vaccine (AV-1959D) based on our proprietary MultiTEP platform technology is extremely immunogenic in mice, rabbits, and monkeys. Importantly, MultiTEP platform enables development of vaccines targeting pathological molecules involved in various neurodegenerative disorders. Taking advantage of the universality of MultiTEP platform, we developed DNA vaccines targeting 3 B-cell epitopes (amino acids [aa]85-99, aa109 126, and aa126-140) of human alpha-synuclein (halpha-Syn) separately or all 3 epitopes simultaneously. All 4 DNA vaccines (1) generate high titers of anti halpha-Syn antibodies and (2) induce robust MultiTEP-specific T-helper cell responses without activation of potentially detrimental autoreactive anti-halpha Syn T-helper cells. Generated antibodies recognize misfolded halpha-Syn produced by neuroblastoma cells, halpha-Syn in the brain tissues of transgenic mouse strains and in the brain tissues of dementia with Lewy body cases. Based on these results, the most promising vaccine targeting 3 B-cell epitopes of halpha-Syn simultaneously (PV-1950D) has been chosen for ongoing preclinical assessment in mouse models of halpha-Syn with the aim to translate it to the human clinical trials. PMID- 28870519 TI - Sigma-1 receptor knockout increases alpha-synuclein aggregation and phosphorylation with loss of dopaminergic neurons in substantia nigra. AB - Sigma-1 receptor (sigma1R) is expressed in dopaminergic neurons of substantia nigra. Here, we show that sigma1R knockout (sigma1R-/-) mice, at age 6-12 months, appeared with age-related loss of dopaminergic neurons and decline of motor coordination. Levels of alpha-synuclein (alphaSyn) oligomers and fibrillar alphaSyn in substantia nigra of sigma1R-/- mice were age-dependently increased without the changes in alphaSyn monomers. The phosphorylation of alphaSyn monomers or oligomers in dopaminergic neurons was enhanced in sigma1R-/- mice. Levels of phosphorylated eIF2a and C/EBP homologous protein expression were elevated in sigma1R-/- mice with decline of proteasome activity. Inhibition of endoplasmic reticulum stress by salubrinal recovered the alphaSyn phosphorylation and proteasome activity and prevented early oligomerization of alphaSyn in sigma1R-/- mice. Rifampicin reduced the late increase of alphaSyn oligomers in sigma1R-/- mice. Rifampicin or salubrinal could reduce the loss of dopaminergic neurons in sigma1R-/- mice and improved their motor coordination. The results indicate that the sigma1R deficiency through enhanced aggregation and phosphorylation of alphaSyn causes the loss of dopaminergic neurons leading to the decline of motor coordination. PMID- 28870521 TI - Clinical aspects and biomarkers of Alzheimer's disease in Down syndrome. AB - Alzheimer's disease (AD) may affect in excess of 90% of individuals with Down syndrome (DS) after age 60, due to duplication of the APP gene in trisomy of chromosome 21, with neuropathology that is comparable to Sporadic AD and Familial AD (FAD). Previous literature suggested some unique features in clinical presentation of dementia in DS (DSd), which might be due to diagnostic difficulties, or represent a real difference compared to SAD or FAD. We review current knowledge on clinical diagnosis and presentation of dementia in DS in comparison with FAD due to APP mutations and APP duplication. We suggest that the clinical presentation in DS (prominent memory decline and behavioral symptoms, and early development of myoclonus and seizures) are similar to the clinical features associated with APP mutations that is known to have an increased Abeta42/ Abeta40 ratio, and highlight the relative lack of vascular complications associated with cerebral amyloid angiopathy in DS in comparison with those rare individuals with FAD due to duplication APP. We consider the biomarker evidence associated with DS and DSd with reference to Abeta peptide levels and oxidative stress, and suggest future directions for research to explore the potential mechanisms associated with the clinical presentation of DSd. PMID- 28870520 TI - Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung. AB - The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2flox/flox, and Nrf2Delta/Delta; SPC-Cre) were administered a thoracic dose of 12Gy and allowed to recover for 250 days. Whole slide digital and confocal microscopy imaging of H&E, Masson's trichrome and immunostaining were used to assess tissue remodeling, collagen deposition and cell renewal/mobilization during the regenerative process. Histological assessment of irradiated, fibrotic wild type lung revealed significant loss of alveolar type 2 cells 250 days after irradiation. Type 2 cell loss and the corresponding development of fibrosis were enhanced in the Nrf2 null mouse. Yet, conditional deletion of Nrf2 in alveolar type 2 cells in irradiated lung did not impair type 2 cell survival nor yield an increased fibrotic phenotype. Instead, radiation-induced DeltaNp63 stem/progenitor cell mobilization was inhibited in the Nrf2 null mouse while the propensity for radiation-induced myofibroblasts derived from alveolar type 2 cells was magnified. In summary, these results indicate that Nrf2 is an important regulator of irradiated lung's capacity to maintain alveolar type 2 cells, whose injury can initiate a fibrotic phenotype. Loss of Nrf2 inhibits DeltaNp63 stem/progenitor mobilization, a key event for reconstitution of injured lung, while promoting a myofibroblast phenotype that is central for fibrosis. PMID- 28870522 TI - Poly (I:C) impairs NO donor-induced relaxation by overexposure to NO via the NF kappa B/iNOS pathway in rat superior mesenteric arteries. AB - Recent studies have suggested a link between vascular dysfunction and innate immune activation including toll-like receptors (TLRs), but the detailed mechanism remains unclear. Here we investigated whether poly (I:C) [a synthetic double-strand RNA recognized by TLR3, melanoma differentiation-associated gene 5 (MDA5), and retinoic acid-inducible gene I (RIG-I)] affected nitric oxide (NO)/cGMP-related vascular relaxation, one of the major cascades of relaxation, in rat superior mesenteric arteries. Using organ-cultured arteries, we found that poly (I:C) (30MUg/mL for approximately 1 day) markedly reduced sodium nitroprusside (SNP)-induced relaxation (vs. vehicle); this was prevented by co treatment with a TLR3 inhibitor. Relaxation induced by 8-Br cGMP (a phosphodiesterase (PDE)-resistant cGMP analogue) and the expression of proteins related to NO/cGMP signaling did not differ between vehicle- and poly (I:C) treated groups. When PDEs were inhibited by IBMX (a nonselective PDE inhibitor), the SNP-induced relaxation was still greatly reduced in poly (I:C)-treated arteries (vs. vehicle). Poly (I:C) reduced SNP-stimulated cGMP production, but increased NO production and iNOS expression (vs. vehicle). The impairment of SNP induced relaxation by poly (I:C) was prevented by co-treatment with either iNOS or a nuclear factor-kappa B (NF-kappaB) inhibitor. This effect induced by poly (I:C) appeared to be independent of oxidative stress. The SNP-induced relaxation was reduced in freshly isolated arteries by pre-incubation with SNP in a concentration-dependent manner. Poly (I:C) did not alter protein levels of TLR3, TRIF/TICAM-1, or phospho-IRF3/IRF3, whereas RIG-I and MDA5 were significantly upregulated (vs. vehicle). These results suggest that poly (I:C) impairs NO donor induced relaxation in rat superior mesenteric arteries via overexposure to NO produced by the NF-kappaB/iNOS pathway. PMID- 28870524 TI - Folic acid supplement use and the risk of gestational hypertension and preeclampsia. AB - BACKGROUND: Hypertensive disorders of pregnancy are among the leading causes of maternal morbidity and mortality. Studies suggest that the use of folic acid may lower the risk of hypertensive disorders in pregnant women. AIM: The aim of this study was to assess the effects of timing and duration of folic acid-containing supplement use on the risk for gestational hypertension and preeclampsia. METHODS: Exposures and outcomes data were obtained through interviews and review of participant's medical records from the MotherToBaby cohort studies across the United States and Canada. Demographics, medical history, lifestyle factors, substance use, and fetal sex were assessed as potential confounders. Unadjusted and adjusted risks for gestational hypertension and preeclampsia were examined using odds ratios and 95% confidence intervals. FINDINGS: 3247 women were included in the study. Compared to non-supplement use, early and late supplement use were not significantly associated with the development of gestational hypertension or preeclampsia. The odds of developing gestational hypertension and preeclampsia were significantly reduced as the duration of folic acid-containing supplement use increased. CONCLUSION: Findings from this study suggest that the use of folic acid-containing supplements may mitigate the risk for gestational hypertension and preeclampsia. PMID- 28870523 TI - Antagonism of mGlu2/3 receptors in the nucleus accumbens prevents oxytocin from reducing cued methamphetamine seeking in male and female rats. AB - Methamphetamine (meth) addiction is a prevalent health concern worldwide, yet remains without approved pharmacological treatments. Preclinical evidence suggests that oxytocin may decrease relapse, but the neuronal underpinnings driving this effect remain unknown. Here we investigate whether oxytocin's effect is dependent on presynaptic glutamatergic regulation in the nucleus accumbens core (NAcore) by blocking metabotropic glutamate receptors 2/3 (mGluR2/3). Male and female Sprague-Dawley rats self-administered meth or sucrose on an escalating fixed ratio, followed by extinction and cue-induced reinstatement sessions. Reinstatement tests consisted of systemic (Experiment 1) or site-specific application of the drugs into the NAcore (Experiments 2 and 3). Before reinstatement sessions, rats received LY341495, an mGluR2/3 antagonist, or its vehicle followed by a second infusion/injection of oxytocin or saline. As expected, both males and females reinstated lever pressing to meth associated cues, and LY341495 alone did not impact this behavior. Oxytocin injected systemically or infused into the NAcore decreased cued meth seeking. Importantly, combined LY341495 and oxytocin administration restored meth cued reinstatement. Interestingly, neither oxytocin nor LY341495 impacted sucrose-cued reinstatement, suggesting distinct mechanisms between meth and sucrose. These findings were consistent between males and females. Overall, we report that oxytocin reduced responding to meth-associated cues and blocking presynaptic mGluR2/3 reversed this effect. Further, oxytocin's effects were specific to meth cues as NAcore oxytocin was without an effect on sucrose cued reinstatement. Results are discussed in terms of oxytocin receptor localization in the NAcore and modulation of presynaptic regulation of glutamate in response to drug associated cues. PMID- 28870525 TI - Rectal balloon use limits vaginal displacement, rectal dose, and rectal toxicity in patients receiving IMRT for postoperative gynecological malignancies. AB - Pelvic radiotherapy for gynecologic malignancies traditionally used a 4-field box technique. Later trials have shown the feasibility of using intensity-modulated radiotherapy (IMRT) instead. But vaginal movement between fractions is concerning when using IMRT due to greater conformality of the isodose curves to the target and the resulting possibility of missing the target while the vagina is displaced. In this study, we showed that the use of a rectal balloon during treatment can decrease vaginal displacement, limit rectal dose, and limit acute and late toxicities. Little is known regarding the use of a rectal balloon (RB) in treating patients with IMRT in the posthysterectomy setting. We hypothesize that the use of an RB during treatment can limit rectal dose and acute and long term toxicities, as well as decrease vaginal cuff displacement between fractions. We performed a retrospective review of patients with gynecological malignancies who received postoperative IMRT with the use of an RB from January 1, 2012 to January 1, 2015. Rectal dose constraint was examined as per Radiation Therapy Oncology Group (RTOG) 1203 and 0418. Daily cone beam computed tomography (CT) was performed, and the average (avg) displacement, avg magnitude, and avg magnitude of vector were calculated. Toxicity was reported according to RTOG acute radiation morbidity scoring criteria. Acute toxicity was defined as less than 90 days from the end of radiation treatment. Late toxicity was defined as at least 90 days after completing radiation. Twenty-eight patients with postoperative IMRT with the use of an RB were examined and 23 treatment plans were reviewed. The avg rectal V40 was 39.3% +/- 9.0%. V30 was65.1% +/- 10.0%. V50 was 0%. Separate cone beam computed tomography (CBCT) images (n = 663) were reviewed. The avg displacement was as follows: superior 0.4 + 2.99 mm, left 0.23 +/- 4.97 mm, and anterior 0.16 +/- 5.18 mm. The avg magnitude of displacement was superior/inferior 2.22 +/- 2.04 mm, laterally 3.41 +/- 3.62 mm, and anterior/posterior 3.86 +/- 3.45 mm. The avg vector magnitude was 6.60 +/- 4.14 mm. For acute gastrointestinal (GI) toxicities, 50% experienced grade 1 toxicities and 18% grade 2 GI toxicities. For acute genitourinary (GU) toxicities, 21% had grade 1 and 18% had grade 2 toxicities. For late GU toxicities, 7% had grade 1 and 4% had grade 2 toxicities. RB for gynecological patients receiving IMRT in the postoperative setting can limit V40 rectal dose and vaginal displacement. Although V30 constraints were not met, patients had limited acute and late toxicities. Further studies are needed to validate these findings. PMID- 28870526 TI - Drug repurposing strategy against Trypanosoma cruzi infection: In vitro and in vivo assessment of the activity of metronidazole in mono- and combined therapy. AB - Metronidazole (Mtz) is a commercial broad-spectrum nitroimidazolic derivative with relevant antimicrobial activity and relative safety profile. Therefore, it is fair to consider Mtz a candidate for drug repurposing for other neglected conditions such as Chagas disease (CD), a parasitic pathology caused by Trypanosoma cruzi. CD is treated only with benznidazole (Bz) and nifurtimox, both introduced in clinics decades ago despite important limitations, including low efficacy on the later disease stage (chronic form) and severe side effects. New cheap and fast alternative treatments for CD are needed, thus the repurposing of Mtz was assessed in vitro and in vivo in mono- and combined therapy. In vitro assays demonstrated EC50>200uM for Mtz, while for Bz the values ranged from 2.51uM (intracellular forms) to 11.5uM (bloodstream trypomastigotes). When both drugs were combined in fixed-ratio proportions, Mtz promoted Bz potency (lower EC50 values). In vivo toxicity assays for Mtz in mice showed no adverse effects neither histopathological alterations up to 2000mg/kg. Regarding experimental T. cruzi infection, Bz 100mg/kg suppressed parasitemia while Mtz (up to 1000mg/kg) in monotherapy did not, but prolonged animal survival at 250 and 500 regimen doses. The combination of both drugs (Bz 10+Mtz 250) prevented mortality (70%) besides protected against electric cardiac alterations triggered by the parasite infection. Although not able to reduce parasite load, the combination therapy prevented animal mortality; this was possibly due to a protection of the electric cardiac physiology that is normally altered in experimental infection of T. cruzi. It also suggested that the interaction with Mtz could have improved the pharmacokinetics of Bz. Our study emphasizes the importance of drug repurposing and combined therapy for CD to contribute to alternative therapies for this neglected and silent pathology. PMID- 28870527 TI - Identification and phenotyping of circulating autoreactive proteinase 3-specific B cells in patients with PR3-ANCA associated vasculitis and healthy controls. AB - OBJECTIVES: To develop a method to detect and phenotype circulating proteinase 3 (PR3)-specific B-cells in patients with PR3-ANCA associated vasculitis (AAV). METHODS: Recombinant human PR3 (rPR3) was tagged with FITC or biotin, and its binding characteristics were studied by flow cytometry using three hybridoma cell lines secreting antibodies (Ab) against human PR3, mouse PR3 (no cross-reactivity with human PR3), and human neutrophil elastase. We measured the proportion of PR3 specific B-cells and studied their surface phenotype in patients with PR3-AAV and healthy controls (HC). RESULTS: Labeled rPR3 efficiently and specifically bound to hybridoma cells producing anti-human-PR3-Ab but not anti-mouse-PR3-Ab or anti human-elastase-Ab. The proportion of rPR3-stained B cells was higher in patients with PR3-AAV compared to HCs: median (IQR) 1.11% (0.81-2.43) vs 0.45% (0.26-0.62) respectively, p < 0.001. There was a trend towards a higher proportion of PR3 specific B cells among patients with active disease compared to patients in remission: 2.91% (1.18-6.52) vs 0.99% (0.72-1.58), p = 0.09. In HCs, the proportion of PR3-specific B cells was highest among the transitional B-cell subset, and decreased with the maturation of B cells. Conversely, in patients, the proportion of PR3-specific B cells progressively increased with the maturation of B cells (median 1.90% of naive B cells, 2.30% of unswitched memory B cells, 2.37% of switched memory B cells, and 3.68% of plasmablasts). CONCLUSIONS: Circulating PR3-specific B cells can be detected in HC and patients with PR3-AAV. Their progressive enrichment during B-cell maturation suggests that they are actively selected and escape peripheral tolerance checkpoints in patients. PMID- 28870528 TI - Three-Dimensional Cross-Sectional Light-Sheet Microscopy Imaging of the Inflamed Mouse Gut. PMID- 28870529 TI - An Unusual Case of Abdominal Pain. PMID- 28870530 TI - Abnormal Responses to Local Esophageal Food Allergen Injections in Adult Patients With Eosinophilic Esophagitis. AB - Skin tests and measurement of serum levels of immunoglobulin E do not accurately identify foods for elimination from the diets of patients with eosinophilic esophagitis (EoE). We investigated whether an esophageal prick test, in which the esophageal mucosa is challenged by local injection of allergen extracts, could identify individuals with esophageal sensitization. During endoscopy, 6 allergens were injected in the esophagus of 8 patients with EoE and 3 patients without EoE (controls). A second endoscopy was performed after 24 hours to evaluate delayed responses. Five of the 8 patients with EoE had evidence for an acute response (luminal obstruction and mucosal blanching); 2 other patients had a delayed wheal or flare reaction. No responses were observed in controls. We conclude that esophageal mucosal food allergen injections induce acute and/or delayed responses in patients with EoE but not controls. The esophageal prick test deserves further exploration because it may guide elimination diets. PMID- 28870531 TI - The Perils of Competitive Speed Eating! PMID- 28870533 TI - Rituximab in refractory autoimmune hemolytic anemia in systemic lupus erythematosus. PMID- 28870532 TI - Progression of an Unusual Primary Liver Tumor. PMID- 28870534 TI - Assessing the insecticide susceptibility status of field population of Phlebotomus papatasi (Diptera: Psychodidae) in a hyperendemic area of zoonotic cutaneous leishmaniasis in Esfahan Province, Central Iran. AB - Leishmaniasis is a Neglected Tropical Disease (NTD) and emerging parasitic infection that affect mainly poor regions around the world. This study aimed to determine the baseline susceptibility of Phlebotomus papatasi to commonly used insecticides in a hyper endemic area using WHO standard procedure in central Iran. A total of 4-5 replicates containing 120-200 sand flies were used for each insecticide. Baseline susceptibility to DDT and pyrethroids was assessed on 5326 specimens collected from the study area. The LT50 and LT90 values were measured according to the World Health Organisation test using probit analysis and regression lines. The test results against males P. papatasi revealed that LT50 values to DDT 4%,Permethrin 0.75%, Deltamethrin 0.05%, Cyfluthrin 0.15% and Lambdacyhalothrin 0.05% were 564.07, 38.08, 1.95, 0.60 and 9.78s and the figures for females were 584.44, 110.10, 11.64, 1.53 and 16.91s, respectively. Our results indicated that P. papatasi as the main cutaneous leishmaniasis vector was susceptible to Cyfluthrin 0.15%, Lambdacyhalothrin 0.05%, Permethrin 0.75% and Deltamethrin 0.05% and tolerant to DDT 4%. This study was carried out in one out of many Leishmaniasis foci in Iran. We recommend that future studies incorporate other regions and use the same procedure for monitoring and evaluating sand fly resistance. Also, WHO can provide a specific guideline and create a test kit for sand fly resistance monitoring and for applying susceptibility test because the tubes prepared for mosquitoes are not actually fit for sand flies. PMID- 28870535 TI - Historical overview of infantile visceral leishmaniasis in El Agamy, Alexandria, Egypt. AB - Infantile visceral leishmaniasis (IVL) is considered a rare and neglected disease in Egypt. An outbreak of the disease in El Agamy, Alexandria occurred in 1982 although the disease was previously reported 80 years before. Epidemiological and entomological studies were conducted ever since the 1982 outbreak to identify human cases, the parasite, reservoir host and the sand fly vector. Leishmania infantum MON-98, a new and unique zymodeme, was responsible of the disease. Stray dogs acted as the reservoir host and Phlebotomus langeroni was the proven vector. The parasite isolates from human cases were identical to the parasite isolates from the reservoir host and the sand fly vector. The El Agamy focus in 1982 was basically a rural Bedouin setting of recently built cement houses surrounded by lime stone fences. The numbers of human cases of IVL in this area have been declining, with the last reported case in 2005. This coincides with the completion of irregular urbanization of El Agamy which resulted in the disappearance of P. langeroni. In this review, we characterize the old focus of IVL in El Agamy based on published literature to identify factors underlying the appearance and disappearance of the disease. PMID- 28870536 TI - Animal African Trypanosomiasis in Nigeria: A long way from elimination/eradication. AB - Animal African Trypanosomiasis (AAT) is a disease of livestock that directly hinders livestock production and therefore impedes the socio-economic development of sub-Saharan Africa. The establishment of the Pan-African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC) was to enhance the goal of elimination and eradication of tsetse flies and AAT from endemic countries in Africa. In order to achieve AAT eradication, a five-step progressive control pathway (PCP) model has been proposed. The data presented in this report demonstrates that Nigeria is highly endemic of AAT and that it is yet to comprehensively approach the process of eradication as it is at the infancy stage of data gathering and processing. This review is thus presented to serve as a wake-up call to all relevant stakeholders to intensify efforts in approaching the painstaking process of AAT eradication in Nigeria. PMID- 28870537 TI - Clinical characteristics of patients with ischemic stroke following the 2016 Kumamoto earthquake. AB - To investigate the clinical characteristics of patients with ischemic stroke following the 2016 Kumamoto earthquake. We retrospectively studied patients with ischemic stroke admitted to our hospital for 12weeks following the earthquake. We compared the clinical backgrounds and characteristics of the patients: before (the same period from the previous 3years) and after the earthquake; and the early (first 2weeks) and late (subsequent 10weeks) phases. A total of 194 patients with ischemic stroke were admitted to our hospital after the earthquake; 496 (165.3/year) patients were admitted before the earthquake. No differences between the two groups were noted for the clinical backgrounds, characteristics, or biomarkers. Past history of sleeping in a shelter or small vehicle was found in 13% and 28% of patients, respectively. Sleeping in a shelter (27% vs. 10%, p=0.013) was found more frequently in patients during the early phase than during the late phase after the earthquake. Admission of patients with ischemic stroke increased after the earthquake; however no differences between before and after the earthquake were noted for their clinical characteristics. To prevent ischemic stroke following earthquakes, mental stress and physical status of evacuees must be assessed. PMID- 28870538 TI - Long-term assessment of recruitment, early stages and population dynamics of the endangered Mediterranean fan mussel Pinna nobilis in the Columbretes Islands (NW Mediterranean). AB - A long-term experimental approach was undertaken to assess viability and resilience of the endangered Mediterranean fan mussel Pinna nobilis. Artificial and natural recruitment, mortality, population traits and juvenile growth were assessed in seasonal and annual surveys. In the Columbretes Islands, P. nobilis thrives in differing substrate types, from coarse sand to boulders, in Cymodocea nodosa meadows and among rhodoliths, and is always found sharing habitat with the less abundant sibling species P. rudis. In artificial collectors larval settlement occurred over a several months period, concentrating its peak in September and resulting from two separated spawning events. Recruitment in the collectors showed high inter-annual variability and was independent of depth, but positively correlated with seasonal water temperature increase in June. Natural recruitment of P. nobilis was low and showed little variability, evidencing the existence of intense post-settlement processes. Adult mortality was also low, thus leading to slow population dynamics and to the species' vulnerability to catastrophic events. Population size structure suggests the existence of a refuge size above 45 cm shell length. The fast growth during the first years of life would help shortening this vulnerability period. Altogether, essential information and tools for the species' conservation are provided, which will be critical in the current context of mass mortalities affecting P. nobilis. PMID- 28870539 TI - Mixed Reality Meets Pharmaceutical Development. AB - As science evolves, the need for more efficient and innovative knowledge transfer capabilities becomes evident. Advances in drug discovery and delivery sciences have directly impacted the pharmaceutical industry, though the added complexities have not shortened the development process. These added complexities also make it difficult for scientists to rapidly and effectively transfer knowledge to offset the lengthened drug development timelines. While webcams, camera phones, and iPads have been explored as potential new methods of real-time information sharing, the non-"hands-free" nature and lack of viewer and observer point-of view render them unsuitable for the R&D laboratory or manufacturing setting. As an alternative solution, the Microsoft HoloLens mixed-reality headset was evaluated as a more efficient, hands-free method of knowledge transfer and information sharing. After completing a traditional method transfer between 3 R&D sites (Rahway, NJ; West Point, PA and Schnachen, Switzerland), a retrospective analysis of efficiency gain was performed through the comparison of a mock method transfer between NJ and PA sites using the HoloLens. The results demonstrated a minimum 10-fold gain in efficiency, weighing in from a savings in time, cost, and the ability to have real-time data analysis and discussion. In addition, other use cases were evaluated involving vendor and contract research/manufacturing organizations. PMID- 28870540 TI - CON4EI: Slug Mucosal Irritation (SMI) test method for hazard identification and labelling of serious eye damaging and eye irritating chemicals. AB - Assessment of ocular irritancy is an international regulatory requirement in the safety evaluation of industrial and consumer products. Although many in vitro ocular irritation assays exist, alone they are incapable of fully categorizing chemicals. The objective of CEFIC-LRI-AIMT6-VITO CON4EI (CONsortium for in vitro Eye Irritation testing strategy) project was to develop tiered testing strategies for eye irritation assessment that can lead to complete replacement of the in vivo Draize rabbit eye test (OECD TG 405). A set of 80 reference chemicals was tested with seven test methods, one method was the Slug Mucosal Irritation (SMI) test method. The method measures the amount of mucus produced (MP) during a single 1-hour contact with a 1% and 10% dilution of the chemical. Based on the total MP, a classification (Cat 1, Cat 2, or No Cat) is predicted. The SMI test method correctly identified 65.8% of the Cat 1 chemicals with a specificity of 90.5% (low over-prediction rate for in vivo Cat 2 and No Cat chemicals). Mispredictions were predominantly unidirectional towards lower classifications with 26.7% of the liquids and 40% of the solids being underpredicted. In general, the performance was better for liquids than for solids with respectively 76.5% vs 57.1% (Cat 1), 61.5% vs 50% (Cat 2), and 87.5% vs 85.7% (No Cat) being identified correctly. PMID- 28870541 TI - Lay preferences for dentogingival esthetic parameters: A systematic review. AB - STATEMENT OF PROBLEM: An objective definition of the characteristics that render a smile esthetically acceptable in the eye of laypeople is lacking. PURPOSE: The purpose of this systematic review was to identify, appraise, and synthesize the available evidence on the opinion of laypeople regarding the dentogingival characteristics that render a smile esthetically acceptable. The evidence was collected by surveying with standardized digitally modified smile images. MATERIAL AND METHODS: Four databases were used to search English language studies published between January 1996 and December 2015. This was complemented by a manual search of 8 dental journals. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, 2 independent reviewers extracted the relevant characteristics of lay evaluators, the images evaluated, and the outcomes measure. Included studies were assessed in agreement with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. Outcomes were treated as a continuous variable, and when more than 1 article provided information on a parameter, the weighted arithmetic mean was calculated. RESULTS: After 8851 articles were screened, 20 studies were included. Those studies addressed 20 different dentogingival esthetic parameters. The total number of participants interviewed was 3107. According to the Olmos classification, 6 studies had a high level of quality, and 14 studies had a moderate level of quality. The 2 reviewers agreed on all the quality assessments. In the articles reviewed, central incisors clearly played a key role in smile esthetics. Almost all dental, gingival, and occlusal parameters are related to the proportion, shape, and position of central incisors and their relation to the adjacent dental structures. CONCLUSIONS: The present review provides the estimated thresholds of tolerability and ideal values of smile parameters determined by laypeople. This may guide clinicians in evidence-based diagnosis and the planning of dental esthetic treatments. PMID- 28870542 TI - Detailed qualitative analysis of honeybush tea (Cyclopia spp.) volatiles by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry and relation with sensory data. AB - The volatile composition of honeybush (Cyclopia) species was studied by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC*GC-TOF-MS). Headspace-solid phase micro-extraction (HS-SPME) was used to extract the volatile compounds from tea infusions prepared from the three species C. genistoides, C. maculata and C. subternata. A total of 287 compounds were identified, 101 of which were confirmed using reference standards, while the remainder were tentatively identified using mass spectral and retention index (RI) data. The identification power of TOF-MS enabled the tentative identification of 147 compounds for the first time in honeybush tea. The majority of the compounds identified were common to all three Cyclopia species, although there were differences in their relative abundances, and some compounds were unique to each of the species. In C. genistoides, C. maculata and C. subternata 265, 257 and 238 compounds were identified, respectively. Noteworthy was the tentative identification of cinnamaldehyde in particular C. maculata samples, which points to the likely contribution of this compound to their distinct sensory profiles. This study emphasises the complexity of honeybush tea volatile composition and confirms the power of GC*GC combined with TOF-MS for the analysis of such complex samples. PMID- 28870543 TI - Development and comprehensive comparison of two on-line capillary electrophoretic methods for beta-secretase inhibitor screening. AB - Alzheimer's disease is the most common cause of dementia, afflicting over 34 million patients worldwide. Since beta-secretase is a rate-limiting enzyme of the production of neurotoxic beta-amyloid peptide oligomers abnormally accumulated in the affected brain tissue, its specific inhibition appears to be a promising approach to slowing down or even stopping the progression of the disease. Hence two on-line capillary electrophoretic methods for studies of beta-secretase activity based on the principles of transverse diffusion of laminar flow profiles and electrophoretically mediated microanalysis were developed, both using a simple unlabeled peptide substrate and UV detection. The optimized procedures were thoroughly validated and applied for determining the enzyme's kinetic parameters and the inhibition characteristics of two potent probe inhibitors. The resulting values were found to be comparable to literature data obtained with other analytical techniques. The suitability of the employed methodologies for different experimental designs is discussed on the basis of a statistical evaluation of the experimental data. The presented methods constitute a miniaturized and fully automated tool, which should be suitable for kinetic and inhibition studies of beta-secretase as a target for Alzheimer's disease drug discovery in the early stages of the development of a new drug. PMID- 28870544 TI - Multi-analysis determination of tropane alkaloids in cereals and solanaceaes seeds by liquid chromatography coupled to single stage Exactive-Orbitrap. AB - Tropane alkaloids are a wide group of substances that comprises more than 200 compounds occurring especially in the Solanaceae family. The main aim of this study is the development of a method for the analysis of the principal tropane alkaloids as atropine, scopolamine, anisodamine, tropane, tropine, littorine, homatropine, apoatropine, aposcopolamine, scopoline, tropinone, physoperuvine, pseudotropine and cuscohygrine in cereals and related matrices. For that, a simple solid-liquid extraction was optimized and a liquid chromatographic method coupled to a single stage Exactive-Orbitrap was developed. The method was validated obtaining recoveries in the range of 60-109% (except for some compounds in soy), precision values (expressed as relative standard deviation) lower than 20% and detection and quantification limits equal to or lower than 2 and 3MUg/kg respectively. Finally, the method was applied to the analysis of different types of samples as buckwheat, linseed, soy and millet, obtaining positives for anisodamine, scopolamine, atropine, littorine and tropinone in a millet flour sample above the quantification limits, whereas atropine and scopolamine were detected in a buckwheat sample, below the quantification limit. Contaminated samples with Solanaceaes seeds (Datura Stramonium and Brugmansia Arborea) were also analysed, detecting concentrations up to 693MUg/kg (scopolamine) for contaminated samples with Brugmansia seeds and 1847MUg/kg (atropine) when samples were contaminated with Stramonium seeds. PMID- 28870545 TI - Arterial stiffness and cognitive impairment. AB - BACKGROUND: Arterial stiffness is one of the earliest indicators of changes in vascular wall structure and function and may be assessed using various indicators, such as pulse-wave velocity (PWV), the cardio-ankle vascular index (CAVI), the ankle-brachial index (ABI), pulse pressure (PP), the augmentation index (AI), flow-mediated dilation (FMD), carotid intima media thickness (IMT) and arterial stiffness index-beta. Arterial stiffness is generally considered an independent predictor of cardiovascular and cerebrovascular diseases. To date, a significant number of studies have focused on the relationship between arterial stiffness and cognitive impairment. OBJECTIVES AND METHODS: To investigate the relationships between specific arterial stiffness parameters and cognitive impairment, elucidate the pathophysiological mechanisms underlying the relationship between arterial stiffness and cognitive impairment and determine how to interfere with arterial stiffness to prevent cognitive impairment, we searched PUBMED for studies regarding the relationship between arterial stiffness and cognitive impairment that were published from 2000 to 2017. We used the following key words in our search: "arterial stiffness and cognitive impairment" and "arterial stiffness and cognitive impairment mechanism". Studies involving human subjects older than 30years were included in the review, while irrelevant studies (i.e., studies involving subjects with comorbid kidney disease, diabetes and cardiac disease) were excluded from the review. RESULTS: We determined that arterial stiffness severity was positively correlated with cognitive impairment. Of the markers used to assess arterial stiffness, a higher PWV, CAVI, AI, IMT and index-beta and a lower ABI and FMD were related to cognitive impairment. However, the relationship between PP and cognitive impairment remained controversial. The potential mechanisms linking arterial stiffness and cognitive impairment may be associated with arterial pulsatility, as greater arterial pulsatility damages the cerebral microcirculation, which causes various phenomena associated with cerebral small vessel diseases (CSVDs), such as white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and lacunar infarctions (LIs). The mechanisms underlying the relationship between arterial stiffness and cognitive impairment may also be associated with reductions in white matter and gray matter integrity, medial temporal lobe atrophy and Abeta protein deposition. Engaging in more frequent physical exercise; increasing flavonoid and long-chain n-3 polyunsaturated fatty acid consumption; increasing tea, nitrite, dietary calcium and vitamin D intake; losing weight and taking medications intended to improve insulin sensitivity; quitting smoking; and using antihypertensive drugs and statins are early interventions and lifestyle changes that may be effective in preventing arterial stiffness and thus preventing cognitive impairment. CONCLUSION: Arterial stiffness is a sensitive predictor of cognitive impairment, and arterial stiffness severity has the potential to serve as an indicator used to facilitate treatments designed to prevent or delay the onset and progression of dementia in elderly individuals. Early treatment of arterial stiffness is beneficial and recommended. PMID- 28870546 TI - Association of SAA gene polymorphism with ischemic stroke in northern Chinese Han population. AB - BACKGROUND: Serum amyloid A protein (SAA) is known as an inflammatory factor and an apolipoprotein that can replace apolipoprotein A-I/II components as the major apolipoprotein of high-density lipoprotein (HDL), which is related to atherosclerosis. The present study is aimed to evaluate whether the SAA gene polymorphism is involved in ischemic stroke in northern Chinese Han population. METHODS: In a case-control study, the participants included 396 patients (239 males, 157 females) with ischemic stroke and 360 healthy subjects (211 males, 149 females). The rs12218 polymorphism of the SAA gene was analyzed by polymerase chain reaction and restriction fragment length polymorphism, while the rs2468844 polymorphism of the SAA gene was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: The frequencies of the CC genotype and the C allele of rs12218 were higher in participants with ischemic stroke than in the control group (P=0.020 in males, P=0.001 in large artery atherosclerosis group, LAA). The frequencies of the AG genotype and the G allele of rs2468844 were higher in participants with ischemic stroke than in the control group (P=0.040 in males, P=0.011 in large-artery atherosclerosis group). Multiple logistic regression analysis revealed the significance of the rs12218 in males and in large-artery atherosclerosis group after adjustment for confounding factors. CONCLUSION: The rs12218 polymorphism of the SAA gene was associated with ischemic stroke in males and in patients with large-artery atherosclerosis group in northern Chinese Han population. PMID- 28870547 TI - Association of Ambulatory Blood Pressure Monitoring parameters with the Framingham Stroke Risk Profile. AB - The Framingham Stroke Risk Profile (FSRP) is a novel and reliable tool for estimating the 10-year probability for incident stroke in stroke-free individuals, while the predictive value of ambulatory blood pressure monitoring (ABPM) for first-ever and recurrent stroke has been well established. We sought to evaluate cross-sectionally the association of ABPM parameters with FSRP score in a large sample of 2343 consecutive stroke-free individuals (mean age: 56.0+/ 12.9, 49.1% male) who underwent 24-hour ABPM. True hypertensives showed significantly higher FSRP (11.2+/-5.0) compared to the normotensives (8.2+/-5.0, p<0.001), while subjects with white coat hypertension also had higher FSRP (10.2+/-4.7) than normotensives (8.2+/-5.0, p<0.001). Compared to dippers that exhibited the lowest FSRP, non-dippers and reverse-dippers exhibited significantly higher FSRP (9.8+/-4.8 for dippers vs 10.6+/-5.2 and 11.5+/-5.0 for non-dippers and reverse-dippers respectively, p<=0.001 for comparisons). In univariate analyses, the ABPM parameters that had the strongest correlation with FSRP were 24-hour (r=0.440, p<0.001), daytime (r=0.435, p<0.001) and night-time (r=0.423; p<0.001) pulse pressure (PP). The best fitting model for predicting FSRP (R2=24.6%) on multiple linear regression analyses after adjustment for vascular risk factors not included in FSRP comprised the following parameters in descending order: 24-hour PP (beta=0.349, p<0.001), daytime SBP variability (beta=0.124, p<0.001), 24-hour HR variability (beta=-0.091, p<0.001), mean 24 hour HR (beta=-0.107, p<0.001), BMI (beta=0.081, p<0.001) and dipping percentage (beta=-0.063, p=0.001). 24-hour PP and daytime SBP variability are the two ABPM parameters that were more strongly associated with FSRP-score. Reverse dippers had the highest FSRP among all dipping status profiles. PMID- 28870548 TI - Corticosteroid therapy and severity of vasogenic edema in posterior reversible encephalopathy syndrome. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a variable cerebrovascular syndrome associated with hypertension and autoregulatory failure. Steroids have been reported to both precipitate and treat PRES. We sought to determine the prevalence of steroid therapy at the time of PRES and to assess the relationship between steroid therapy and extent of vasogenic edema. METHODS: We performed a retrospective review of radiology reports between 2008 and 2014 from two academic medical centers to identify cases of PRES. Clinical and radiographic data were collected. Descriptive statistics were used to determine the prevalence of corticosteroid therapy at the time of PRES onset and the latency from steroid initiation to PRES onset. The association between steroid therapy and extent of vasogenic edema was assessed in multiple regression models. RESULTS: We identified 99 cases of PRES in 96 patients. The median age was 55years (IQR 30 65) and 74% were women. Steroid therapy at time of PRES onset was identified in 44 of 99 cases. Excluding patients on chronic therapy, the median duration of steroid exposure before PRES onset was 6 (IQR, 3-10) days. Steroid therapy was not associated with extent of vasogenic edema in unadjusted or linear and logistic regression models adjusted for age, sex, and maximum systolic blood pressure on day of onset. CONCLUSION: Corticosteroid therapy, often of brief duration, frequently preceded the onset of PRES and was not associated with severity of vasogenic edema. PMID- 28870549 TI - Altered expression of E-Cadherin-related transcription factors indicates partial epithelial-mesenchymal transition in aggressive meningiomas. AB - E-Cadherin has been suggested to be involved in meningioma progression but is also known as a key player of epithelial to mesenchymal transition (EMT). We wondered whether the adherens junction protein E-Cadherin, the tight junction protein Zo-1, and transcription factors suppressing E-Cadherin expression (Slug, Snail, Twist, Zeb-1) are differentially expressed between histopathological subtypes of meningioma, and if the expression of these factors is related to biological features of meningiomas. Analyzing 85 meningiomas of various histopathological subtypes and grades of malignancy by immunohistochemistry and 50 of them in addition by real-Time-PCR, we observed significantly reduced expression of Zeb-1, Twist and Slug, together with slightly increased expression levels for E-Cadherin and Zo- 1 in fibroblastic WHO-grade I tumors compared to meningothelial WHO grade I tumors, contradicting the hypothesis of EMT in the fibroblastic meningiomas characterized by mesenchymal appearance. However, comparing aggressive WHO grade II or III meningiomas with WHO-grade I tumors, we observed altered expression levels (loss of E-Cadherin and Zo-1, increased expression of Zeb-1 and Slug) indicating molecular features of EMT in aggressive meningiomas. This was supported by reduced E-Cadherin and increased Slug levels in recurrent compared to non-recurrent meningiomas. The expression levels of E cadherin and Zo-1 were positively correlated with expression of NF2 mRNA. In primary meningioma cultures and IOMM-Lee meningioma cells, EMT induction by TGF beta resulted in altered morphology and increased expression of EMT associated transcription factors. Meningioma cells with allelic losses of NF2 showed generally higher levels of various EMT relevant proteins, but were unresponsive to TGF-beta treatment. Our data indicate that aggressive meningiomas of WHO grade II/III are characterized by molecular alterations indicating partial EMT. This might contribute to the aggressive biology of these tumors. PMID- 28870550 TI - Reduced mitochondrial mRNA expression in dementia with Lewy bodies. PMID- 28870551 TI - Low IDL-B and high LDL-1 subfraction levels in serum of ALS patients. AB - INTRODUCTION: Converging evidence highlights that lipid metabolism plays a key role in ALS pathophysiology. Dyslipidemia has been described in ALS patients and may be protective but peripheral lipoprotein subclasses have never been studied. MATERIAL AND METHODS: We collected sera from 30 ALS patients and 30 gender and age-matched controls. We analyzed 11 distinct lipoprotein subclasses by linear polyacrylamide gel electrophoresis (Lipoprint, Quantimetrix Corporation, USA). We also measured lipoprotein (a), apolipoprotein B, and apolipoprotein E levels. RESULTS: ALS patients had significant higher total cholesterol, HDL-cholesterol, and LDL-cholesterol levels than controls (p<0.0001, p=0.0007, and p=0.0065, respectively). The LDL-1 subfraction concentration was higher (1.03+/-0.41 vs. 0.71+/-0.28mmol/L; p=0.0006) and the IDL-B subfraction lower (6.5+/-2% vs. 8.0+/ 2%; p=0.001) in ALS patients than controls. DISCUSSION: Our preliminary work confirmed the association between ALS and dyslipidemia. The low IDL-B levels may explain the hepatic steatosis frequently reported in ALS. The high levels of the cholesterol-rich LDL-1 subfraction is consistent with previously reported hypercholesterolemia. CONCLUSION: This study describes, for the first time, the distribution of serum lipoproteins in ALS patients, with low IDL-B and high LDL-1 subfraction level. PMID- 28870552 TI - High neutrophil to lymphocyte ratio is associated with white matter hyperintensity in a healthy population. AB - High neutrophil to lymphocyte ratio (NLR) is correlated with the occurrence, morbidity and mortality of cerebrovascular disease as a marker of systemic inflammation. However, its effect on cerebral white matter hyperintensity (WMH) is unclear. We investigated high NLR burden as a surrogate marker of WMH volume in a healthy population. Healthy subjects with voluntary health check-ups between January 2006 and December 2013, including brain MRI and laboratory examination, were collected. WMH volumes were rated quantitatively. A total of 2875 subjects were enrolled, and the mean volume of WMH was 2.63+/-6.26mL. In multivariate linear regression analysis, NLR [beta=0.191, 95% confidence interval (CI)=0.104 to 0.279, P<0.001] remained significant after adjusting for confounders. Age (beta=0.049, 95% CI=0.045 to 0.054, P<0.001), hypertension (beta=0.191, 95% CI=0.101 to 0.281, P<0.001), diabetes (beta=0.153, 95% CI=0.045 to 0.261, P=0.006), and extracranial atherosclerosis (beta=0.348, 95% CI=0.007 to 0.688, P=0.045) were also significant independently from NLR. Additionally, the high NLR group (NLR>=1.52) was related to male sex, hypertension, diabetes, current smoking, extracranial atherosclerosis, silent brain infarct, and high WMH volumes. In conclusion, high NLR is associated with larger WMH volumes in a healthy population. Assessment of NLR may be helpful in detecting cerebral WMH burdens in high risk groups. PMID- 28870553 TI - Is spasticity always the same? An observational study comparing the features of spastic equinus foot in patients with chronic stroke and multiple sclerosis. AB - Spasticity is common in stroke and multiple sclerosis. To treat spasticity we have a wide range of interventions, whose application may depend not only on the severity of spasticity but also on its etiology. Consequently, a better understanding of muscle spasticity in different neurological diseases may inform clinicians as to the more appropriate therapeutic approach. Our aim was to compare the clinical and ultrasonographic features of spastic equinus in patients with chronic stroke and multiple sclerosis. Thirty-eight patients with secondary progressive multiple sclerosis and 38 chronic stroke patients with spastic equinus were evaluated at the affected ankle according to the following outcomes: modified Ashworth scale, Tardieu scale, passive range of motion, spastic gastrocnemius muscle echo intensity and thickness. Affected calf muscles tone was significantly greater in patients with chronic stroke (modified Ashworth scale P=0.008; Tardieu scale angle P=0.004) as well as spastic gastrocnemius muscle echo intensity (P<0.001). Affected ankle range of motion was significantly greater in patients with multiple sclerosis (P<0.001) as well as spastic gastrocnemius muscle thickness (medialis: P=0.003; lateralis: P=0.004). Our findings evidenced that the same pattern of spasticity (equinus foot) has some different features according to its etiology. This may help the management of spasticity. PMID- 28870554 TI - Effectiveness of speech language therapy either alone or with add-on computer based language therapy software (Malayalam version) for early post stroke aphasia: A feasibility study. AB - CONTEXT AND AIMS: This study aimed to assess the feasibility of professional based conventional speech language therapy (SLT) either alone (Group A/less intensive) or assisted by novel computer based local language software (Group B/more intensive) for rehabilitation in early post stroke aphasia. SETTINGS AND DESIGN: Comprehensive Stroke Care Center of a tertiary health care institute situated in South India, with the study design being prospective open randomised controlled trial with blinded endpoint evaluation. MATERIAL AND METHODS: This study recruited 24 right handed first ever acute ischemic stroke patients above 15years of age affecting middle cerebral artery territory within 90days of stroke onset with baseline Western Aphasia Battery (WAB) Aphasia Quotient (AQ) score of <93.8 between September 2013 and January 2016.The recruited subjects were block randomised into either Group A/less intensive or Group B/more intensive therapy arms, in order to receive 12 therapy sessions of conventional professional based SLT of 1h each in both groups, with an additional 12h of computer based language therapy in Group B over 4weeks on a thrice weekly basis, with a follow up WAB performed at four and twelve weeks after baseline assessment. The trial was registered with Clinical trials registry India [2016/08/0120121]. STATISTICAL ANALYSIS: All the statistical analysis was carried out with IBM SPSS Statistics for Windows version 21. RESULTS: 20 subjects [14 (70%) Males; Mean age: 52.8years+/-SD12.04] completed the study (9 in the less intensive and 11 in the more intensive arm). The mean four weeks follow up AQ showed a significant improvement from the baseline in the total group (p value: 0.01). The rate of rise of AQ from the baseline to four weeks follow up (DeltaAQ %) showed a significantly greater value for the less intensive treatment group as against the more intensive treatment group [155% (SD: 150; 95% CI: 34-275) versus 52% (SD: 42%; 95% CI: 24-80) respectively: p value: 0.053]. CONCLUSIONS: Even though the more intensive treatment arm incorporating combined professional based SLT and computer software based training fared poorer than the less intensive therapy group, this study nevertheless reinforces the feasibility of SLT in augmenting recovery of early post stroke aphasia. PMID- 28870555 TI - Botulinum toxin alleviates dysphagia of patients with inclusion body myositis. AB - OBJECTIVES: Oropharyngeal dysphagia is a disabling and undertreated symptom that often occurs in patients with sporadic inclusion body myositis (s-IBM). In this study, we examined the effect of botulinum neurotoxin A (BoNT-A) injections to the cricopharyngeus muscle (CPM) of patients with s-IBM and dysphagia. PATIENTS, MATERIALS AND METHODS: A single-center retrospective study involving 40 biopsy proven s-IBM-patients treated in the District of Southwest Finland from 2000 to 2013. The incidence of dysphagia, rate of aspirations, rate of aspiration pneumonias and treatment results of dysphagia were analyzed. Patients treated for dysphagia were evaluated before and after surgery by video-fluoroscopy and/or using a questionnaire. RESULTS: Twenty-five of the 40 s-IBM patients (62.5%) experienced dysphagia. BoNT-A was injected a median of 2 times (range 1-7) in 12 patients with dysphagia. Before the injections 7 patients reported aspiration, none afterwards. The corresponding figures for aspiration pneumonia were 3 and 0. All of these patients had normal swallowing function 12months (median, range 2 60) after the last injection. CONCLUSION: BoNT-A injections to the CPM alleviate the dysphagia of s-IBM patients reversibly and appear to reduce the rate of aspiration effectively. PMID- 28870556 TI - The maid of the Bridal Room by Andrea Mantegna (1431-1506) shows evidence of hypopituitary dwarfism and neurofibromatosis type-1. PMID- 28870557 TI - Retroviral envelope proteins: Involvement in neuropathogenesis. AB - The primary disease caused by infection with the exogenous human retroviruses, human immunodeficiency virus 1 (HIV-1) or human T-cell lymphotropic virus 1 (HTLV 1), may overlay manifestations of additional autoimmune pathogenesis. Currently, a role for human endogenous retroviruses (HERVs) is also emerging in some autoimmune/immune-mediated diseases, particularly in multiple sclerosis (MS). Both exogenous and endogenous retroviruses have the potential to elicit the processes leading to autoimmune disease. The pathogenicity of the retroviral envelope protein (Env) is a key player with notable importance in neuroimmune diseases. An essential prerequisite of retroviral infection is the interactions between Env (the retroviral adhesion) proteins on the virion and specific surface receptors on the host cell. These interactions facilitate fusion of the viral envelope and cellular membranes. Additional fusiogenic activities mediated by Env may be beneficial (establishment of the syncytiotrophoblast induced by a HERV encoded Env) or detrimental to the host (syncytia formation, induction of apoptosis), and Envs are further implied in the direct induction of proinflammatory cytokines, the regulation of autophagy, and pathways of cell death. The pathogenic potential of retroviral Env is therefore not limited to the pathogenetics of infection but also comprise the pathogenic/toxic capacity of the Env protein itself. PMID- 28870558 TI - Video-EEG findings in acute bithalamic-midbrain ischemia. PMID- 28870559 TI - Intranasal deferoxamine affects memory loss, oxidation, and the insulin pathway in the streptozotocin rat model of Alzheimer's disease. AB - Accumulation of metal and the accompanying increase in oxidative stress and inflammation plays an important role in neurodegenerative disease. Deferoxamine (DFO) is a metal chelator found to be beneficial in several animal models of neurodegenerative disease and insult including Alzheimer's disease, Parkinson's disease, stroke, and subarachnoid hemorrhage. In this study, we determine whether intranasally (IN) administered DFO is beneficial in the intracerebroventricular streptozotocin (ICV STZ) rat model of sporadic Alzheimer's disease, which is different from previous models in that it exhibits dysregulation of insulin metabolism as well as oxidative stress and inflammation. Surgical induction of the model included ICV injections of either STZ or citrate buffer (sham in rats), which were treated IN with either saline or DFO (n=10-15/group). Treatment started either before or after injection of STZ to induce the model, and continued throughout the study. IN treatment continued three times per week for three weeks before behavior tests started followed by eventual euthanasia with tissue collection. Spatial memory tests with the Morris water maze showed that STZ rats treated with IN DFO both before and after model induction had significantly shorter escape latencies. Pre-treatment with IN DFO also significantly decreased footslips on the tapered balance beam test. Brain tissue analyses showed DFO treatment decreased oxidation as measured by oxyblot and increased insulin receptor expression. These results further support the potential of IN DFO for use as a treatment for Alzheimer's disease, and show benefit in a non-amyloid/tau rodent model. PMID- 28870560 TI - Cardioembolic stroke and cardiomyopathy: Rhythm is the key. PMID- 28870561 TI - MtDNA m.3472T>C could be classified as a primary mutation of Leber's hereditary optic neuropathy. PMID- 28870562 TI - Genetic variation in angiotensin converting-enzyme affects the white matter integrity and cognitive function of amnestic mild cognitive impairment patients. AB - Angiotensin-converting enzyme (ACE) gene has been implicated in amnestic mild cognitive impairment (aMCI). Most human genetic studies have focused on ACE insertion (I)/deletion (D) polymorphism and yielded conflicting results. In this work, we evaluated the relationships between cognitive function, serum ACE level, brain white matter (WM) integrity, and ACE I/D polymorphism in 48 patients with aMCI and 36 well matched control subjects from south China. In aMCI patients, D allele frequency was higher (D/I ratio=0.51:0.49) than that of the control subjects (D/I ratio=0.43:0.57); however, the difference was not statistically significant (p>0.05). The D carriers in aMCI subjects performed significantly poorer on auditory-verbal learning test (AVLT) -delayed recall than the I homozygous group (p=0.035). These carriers had higher serum ACE level than the I homozygous carriers of aMCI (p=0.037). In the aMCI group, D carriers showed significantly lower fractional anisotropy (FA) values in the left middle frontal gyrus, left anterior cingulate, right gyrus parahippocampalis, right inferior parietal lobule, and bilateral anterior central gyrus than the I homozygotes carriers. However, no significant difference was observed in FA values between I homozygotes and D carriers in the control subjects. The ACE D allele in aMCI patients may increase the risk of cognitive impairment. A high serum ACE level possibly plays an important role in the incidence of aMCI. PMID- 28870563 TI - Executive dysfunction, behavioral changes and quality of life in Chinese patients with progressive supranuclear palsy. AB - OBJECTIVES: To explore the prevalence and clinical correlates of executive impairment and behavioral changes, and the determinants of health-related quality of life (HRQoL) in Chinese patients with progressive supranuclear palsy (PSP). METHODS: This cross-sectional study included 52 patients with PSP. The frontal assessment battery (FAB) was used to assess executive function, while the frontal behavioral inventory (FBI) and Neuropsychiatry Inventory (NPI) were used to assess behavioral changes. The HRQoL of PSP patients was assessed using the Parkinson's disease questionnaire-39 (PDQ-39). The stepwise multiple regression model was use to explore their related factors. RESULTS: Executive deficits were detected in forty patients (76.9%), and fifty patients (96.2%) displayed varied degrees of frontal behavioral changes. FAB score was associated with Montreal Cognitive Assessment score (beta=0.620, P<0.001) and Unified Parkinson's disease Rating Scale (UPDRS) III score (beta=-0.238, P=0.025). FBI score was associated with FAB score (beta=-0.311, P=0.005) and UPDRS III score (beta=0.251, P=0.018). PDQ-39 score was associated with FAB score (beta=-0.324, P=0.005), UPDRS III score (beta=0.306, P=0.008), and Hamilton Depression Rating Scale score (beta=0.353, P=0.001). CONCLUSIONS: Executive deficits and behavioral changes are common in Chinese PSP patients. Executive functions are associated with disease severity. Patients with executive dysfunction and more severe disease disability are likely to exhibit frontal behavioral abnormalities. Executive dysfunction, disease severity and depression exert an impact on the HRQoL of PSP patients. PMID- 28870564 TI - Evaluation of polymerase chain reaction in nerve biopsy specimens of patients with Hansen's disease. AB - BACKGROUND: Pure neuritic variety of leprosy (PNL) presents as peripheral neuropathy with absent skin lesions and negative skin smears. Diagnosing PNL is an uphill task as most of these patients have nonspecific changes on nerve biopsy. In such circumstances, additional molecular diagnostic tools like polymerase chain reaction (PCR) has proven to be useful in diagnosing leprosy. The present study was planned to evaluate the role of PCR in nerve biopsy specimens of patients with PNL. METHODS: Patients attending the neuromuscular clinic from January 2013 to June 2014 with mononeuropathy multiplex underwent detailed diagnostic evaluation to ascertain the cause of neuropathy. Patients where this evaluation failed to establish an etiology underwent a nerve biopsy. RESULTS: Nerve biopsy was done in 52 patients, of which 35 were diagnosed as pure neuritic leprosy. Definite leprosy with positive wade fite staining for lepra bacilli was seen in 13 patients and 22 biopsies revealed a probable leprosy without lepra bacilli being identified. PCR for M. leprae was positive in 22 patients (62%). 12 of the 13 cases with definite leprosy on histopathology were PCR positive while in the AFB negative group, PCR was positive in 10 cases. PCR had a sensitivity of 92.3%, specificity of 54.5%. The positive and negative predictive value of PCR was 54.5% and 92.3% respectively. CONCLUSIONS: PCR helps in diagnosing PNL in doubtful cases. A positive PCR increases the sensitivity of detection of M. leprae especially in cases of probable PNL group where AFB cannot be demonstrated on histopathology. PMID- 28870565 TI - Corrigendum to "Is maraviroc useful in multiple sclerosis patients with natalizumab-related progressive multifocal leukoencephalopathy?" [J. Neurol. Sci. 378 (2017) 233-237]. PMID- 28870566 TI - Pre- and postganglionic vasomotor dysfunction causes distal limb coldness in multiple system atrophy. AB - BACKGROUND: The detailed pathophysiology of limb coldness in multiple system atrophy (MSA) is unknown. METHODS: We evaluated cutaneous vasomotor neural function in 18 MSA patients with or without limb coldness, and in 20 healthy volunteers as controls. We measured resting skin sympathetic nerve activity (SSNA) and spontaneous changes of the sympathetic skin response (SSR) and skin blood flow (skin vasomotor reflex: SVR), as well as SVR and reflex changes of SSNA after electrical stimulation. The parameters investigated were the SSNA frequency at rest, amplitude of SSNA reflex bursts, absolute decrease and percent reduction of SVR, recovery time, and skin blood flow velocity. RESULTS: Both the resting frequency of SSNA and the amplitude of SSNA reflex bursts were significantly lower in the MSA group than the control group (p<0.001 and p<0.05, respectively). There were no significant differences between the two groups with regard to the absolute decrease or percent reduction of SVR volume. The recovery time showed no significant difference between all MSA patients and control groups, but it was significantly prolonged in six MSA patients with limb coldness compared with that in the control group and that in MSA patients without limb coldness (p<0.01). The skin blood flow velocity was significantly slower in the MSA group than in the control group (p<0.001). CONCLUSION: In MSA patients, limb coldness might occur due to impairments of the peripheral circulation based on prolongation of vasoconstriction and a decrease of skin blood flow velocity secondary to combined pre- and postganglionic skin vasomotor dysfunction. PMID- 28870567 TI - Tele-neurology in sub-Saharan Africa: A systematic review of the literature. AB - BACKGROUND: The rapid advancement in telecommunications on the African continent has opened up avenues for improving medical care to underserved populations. Although the greatest burden of neurological disorders is borne by Low-and-Middle Income Countries (LMICs) including sub-Saharan Africa (SSA), there is a profound paucity of neurologists to serve the population. Telemedicine presents a promising avenue for effective mobilization and utilization of the few neurologists in Africa. OBJECTIVE: To systematically review the published literature on the use of telemedicine for improved care and outcomes for patients with neurological disorders in SSA. METHODS: We searched PubMed and Cochrane library from January 1, 1980 to April 30, 2017 using the following keywords: "Telemedicine neurology Africa", "Teleneurology Africa", "Telestroke Africa", "Telerehabilitation Africa", "Telemedicine for epilepsy", "Telemedicine for Parkinson's disease Africa", "Telemedicine for dementia Africa", "Telehealth neurology Africa". Our inclusion criteria were randomized controlled trials, or case series that reported the utilization of telemedicine for care/education of individuals with neurological disorders in sub-Saharan Africa. RESULTS: This search yielded 6 abstracts. By consensus between two investigators, 1 publication met the criteria for inclusion and further review. The one study identified utilized telemedicine for the purpose of improving education/knowledge of 16 doctors and 17 allied health professionals in Parkinson's disease (PD) in Cameroon. The study noted feasibility and satisfaction of participants with telemedicine as well as improved knowledge base of participants after the educational course but noted access to healthcare by patients did not change. No studies have evaluated the use of telemedicine for care of patients with neurological disorders. CONCLUSION: The indication is that teleneurology may be feasible in SSA and studies are needed to assess feasibility, acceptability, efficacy, cost-effectiveness of this promising discipline of neurology in these resource-limited settings. We propose the setting up of trans-continental, inter regional, intra-regional, and national networks of neurologists to utilize teleneurology platforms to improve the reach of neurology care in SSA. PMID- 28870568 TI - Herpes simplex encephalitis and Alzheimer's disease: Is there a link? PMID- 28870569 TI - Measurement of spontaneous blinks in patients with Parkinson's disease using a new high-speed blink analysis system. AB - INTRODUCTION: Parkinson's disease (PD) patients often have a blinking abnormality. In this study, we examined the kinematic features of spontaneous blinking in 65 PD patients and 62 healthy controls by a new research method utilizing an intelligent vision sensor camera prototype with a 1kHz sampling rate. METHODS: Spontaneous blinks were measured by use of a non-stress 'intelligent vision sensor' camera prototype. RESULTS: The mean spontaneous blink rate was 17.9 (blinks/min) in the PD patients and 15.6 in the controls (no correlation). However, there were extremely low and extremely high blink-rate groups among the PD patients. The amplitude of the closing and opening phase in the PD patients were significantly smaller than those in the controls. Small blink waves (100-200msec) prior to blink onset existed in 60% of the PD patients and in 18% of the controls. CONCLUSION: During spontaneous blinking the blink amplitude is decreased, and the pause between the closing and opening phase is prolonged in patients with PD. Small blink waves prior to blink onset were also characteristically found in the PD patients. PMID- 28870571 TI - Does fear of falling predict gait variability in multiple sclerosis? AB - BACKGROUND: Behavioural symptoms and gait disorders are very common in patients with multiple sclerosis. OBJECTIVE: To evaluate the association between fear of falling and gait instability at one year in patients with multiple sclerosis. METHODS: Thirty-five multiple sclerosis patients were included. Fear of falling was assessed by the Fall Efficacy Scale-International and gait variability with stride time variability under single and dual-task conditions at baseline and at one year. RESULTS: Baseline fear of falling score was associated with increased stride time variability at one year during dual-task condition even after adjustment on covariates. CONCLUSION: Fear of falling is associated with gait variability at one year, especially under dual-task condition. PMID- 28870570 TI - Effects of naftopidil on inhibitory transmission in substantia gelatinosa neurons of the rat spinal dorsal horn in vitro. AB - OBJECTIVE: Naftopidil is used clinically for the treatment of voiding disorders in benign prostatic hyperplasia. Previous in vivo experiments in which naftopidil was applied intrathecally abolished rhythmic bladder contraction, suggesting that naftopidil might inhibit a voiding reflex through interaction with spinal dorsal horn neurons. Here we aimed to clarify the mechanism of action of naftopidil on dorsal horn neurons. METHODS: Whole-cell patch-clamp recordings were performed using substantia gelatinosa neurons of adult rat spinal cord slices. Miniature or evoked inhibitor and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were analyzed. RESULTS: Bath-applied naftopidil increased the frequency but not the amplitude of miniature IPSCs (mIPSCs) in 38% of neurons tested; in contrast, the effect of naftopidil on miniature EPSCs (mEPSCs) were mild and observed in only 2 out of 19 neurons. Naftopidil enhanced the amplitude of both GABAergic and glycinergic evoked-IPSCs (eIPSCs) that were elicited by focal stimuli in the presence of either the non-NMDA receptor antagonist 6-cyano 7-nitroquinoxaline-2,3-dione (CNQX), or the NMDA receptor antagonist DL-2-amino-5 phosphonovaleric acid (APV). CONCLUSIONS: Although naftopidil was developed as an alpha-1 adrenoceptor antagonist, our previous spinal cord slice experiments showed that the activation of an alpha-1 adrenoceptor in substantia gelatinosa increases the frequency of mIPSCs. This result suggested that, under our conditions, naftopidil may interact with a receptor(s) other than an alpha-1 adrenoceptor in the spinal dorsal horn. The present results suggested that naftopidil enhances the release of GABA and glycine by activating inhibitory interneuron terminals in the spinal dorsal horn via a receptor other than an alpha-1 adrenoceptor, thereby modulating sensory transmission in the substantia gelatinosa. PMID- 28870572 TI - High angular resolution diffusion imaging abnormalities in the early stages of amyotrophic lateral sclerosis. AB - OBJECTIVE: Using magnetic resonance (MR) high angular resolution diffusion imaging (HARDI), we aimed at revealing possible microstructural alterations in the early stage of amyotrophic lateral sclerosis (ALS), still not completely elucidated. METHODS: We studied 22 patients with ALS, in stages 1 or 2 according to the King's staging system, compared to 18 healthy controls (HCs). Statistical mapping of HARDI-derived parameters and tractography measures were performed using the Q-ball imaging diffusion data model. RESULTS: When compared to HCs, the ALS group showed a highly significant decrease of generalized fractional anisotropy (GFA) and fiber length and density in the corticospinal tracts (CSTs) and in the corpus callosum (CC) (p<0.05, corrected level of significance). Moreover, stratifying the ALS population considering the disease phenotype, larger areas of decreased GFA were found in patients with bulbar phenotype compared to those with classic phenotype in several bilateral associative fiber tracts, such as superior and inferior longitudinal, inferior fronto-occipital and uncinate fasciculi. CONCLUSIONS: Our whole-brain HARDI results provided preliminary evidence of an early pattern of microstructural degeneration in ALS, mainly involving the CSTs and the CC, although divergent patterns of microstructural abnormalites could be related to different disease phenotypes. PMID- 28870574 TI - Argyrophilic grain disease in a 46-year-old male suicide victim. PMID- 28870573 TI - CXCL10 and CXCL13 chemokines in patients with relapsing remitting and primary progressive multiple sclerosis. AB - OBJECTIVES: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system characterized by a variable clinical course. Different pathogenic mechanisms responsible for relapsing remitting (RRMS) and primary progressive multiple sclerosis (PPMS) are modulated by immunological process with important role of chemokine network. CXCL10 and CXCL13 chemokines act as chemoattractants and modulators of proinflammatory reactions promoting process of demyelination. In the present study, we investigated the concentrations of CXCL10 and CXCL13 in serum and cerebrospinal fluid (CSF) of patients with RRMS and PPMS. MATERIALS AND METHODS: The study groups comprised 25 RRMS patients (39,5+/-12years), 24 PPMS patients (49,9+/-10,5years), 31 healthy individuals (36+/-10,4years) with tension headache without symptoms of inflammatory diseases. A quantitive test kit based on ELISA has been used for chemokines measurement. Correlations analysis between the levels of CXCL10, CXCL13 and patient age, duration of MS, EDSS and IgG index were done. RESULTS: The mean concentration of CXCL10 in the CSF was statistically significantly higher in RRMS in comparison with the control group. The mean concentration of CXCL13 in the CSF was significantly higher in RRMS and PPMS than in the control group. The results have shown that in the stable phase of MS without relapse, mean concentration of CXCL10 and CXCL13 in CSF did not differ significantly between RRMS and PPMS. In PPMS a positive correlation between IgG index and CSF CXCL10 level or CSF CXCL13 level was observed. In RRMS a positive correlation between IgG index and CSF CXCL13 level was observed. CONCLUSIONS: These data indicate involvement of CXCL10 and CXCL13 chemokines in immunopathogenetic mechanisms in MS. There was no significant difference between mean CXCL10 or CXCL13 concentrations in the CSF in both RRMS and PPMS patients. No significant correlations were found between patient age and chemokines levels in theCSF in all groups. It suggest that these chemokines play similar role in inflammatory process despite more pronounced neurodegenerative process in PPMS. PMID- 28870575 TI - Usefulness of platelet to lymphocyte and neutrophil to lymphocyte ratios in predicting the presence of cerebral venous sinus thrombosis and in-hospital major adverse cerebral events. AB - BACKGROUND: Platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) as recently emerging thrombo-inflammatory indicators were significantly associated with both major cerebrovascular/cardiovascular adverse events (MACE) and mortality. Therefore, we aimed to assess the effects of combinations of PLR and NLR in predicting the presence of CVST and in-hospital MACE. METHODS: A total of 277 participants comprising 80 patients with evidence of CVST and 197 controls with similar baseline characteristics were included in this retrospective study. Patients were classified into 3 groups based on the optimal cut-off values of PLR and NLR calculated with receiver operating characteristic (ROC) curve for in hospital MACE rates. RESULTS: PLR (148+/-61 vs 101+/-50, p<0.001) and NLR (3.12+/ 1.4 vs 1.94+/-1.1, p<0.001) were significantly higher in the CVST group. Furthermore, patients in the high risk group (a PLR of >=115.0 and an NLR of >=2.1) had the highest in-hospital MACE rates including seizure (p=0.012), papilledema (p=0.025) and diplopia or blurry vision (p=0.028). After multivariate logistic regression analysis MPV, PLR (1.052 [1.045-1.059], p=0.001) and NLR (1.442 [1.086-1.916], p=0.012) were found as independent predictors of CVST. CONCLUSION: These results suggest that PLR and NLR are easily available and cheap thrombo-inflammatory indicators, so that PLR and NLR could be used in prediction of CVST and in-hospital MACE. PMID- 28870577 TI - Serial changes of carotid wall thickening on ultrasound in Takayasu arteritis. PMID- 28870576 TI - Istradefylline improves daytime sleepiness in patients with Parkinson's disease: An open-label, 3-month study. AB - BACKGROUND: Istradefylline, a selective adenosine A2A receptor antagonist, has been reported to improve daily "off time" and motor symptoms in patients with Parkinson's disease (PD). However, the effect of istradefylline on sleep problems has not been thoroughly investigated. METHODS: We evaluated the effect of istradefylline on daytime sleepiness, sleep disturbances, and motor symptoms in 22 PD patients who were affected by the wearing off phenomenon in an open-label, 3-month study. Participants received 20-40mg/day istradefylline once daily (morning) over a 3-month period. The Epworth Sleepiness Scale (ESS), PD sleep scale (PDSS)-2 and PD Questionnaire (PDQ-8) were administered at baseline, 2weeks, 1month, 2months and 3months. At baseline and 3months, patients were evaluated on the Movement Disorder Society Revision of the Unified PD Rating Scale (MDS-UPDRS) parts III and IV. RESULTS: Twenty-one patients (95.5%) completed the study. At 3months, MDS-UPDRS part III (-5.3, p=0.0002) and part IV (-2.5, p=0.001) scores improved and off time decreased significantly (-50.1min, p=0.0004). PDQ-8 scores were unchanged at 3months. ESS scores decreased significantly at 2months and 3months (-2.4 and -3.3, respectively, p<0.0001), but the total PDSS-2 scores did not change. CONCLUSION: Istradefylline improved daytime sleepiness in PD patients, possibly through its effect on enhancing alertness. In addition, the lack of significant changes in the total PDSS-2 scores over the study period suggests istradefylline had no negative impact on sleep. PMID- 28870578 TI - Depression and fatigue in patients with multiple sclerosis. AB - BACKGROUND: Previous research has examined the components of depression and fatigue in multiple sclerosis (MS), but the findings have been inconsistent. The aim of this study was to explore the associations between overall and subscale scores of the Center for Epidemiologic Studies-Depression Scale (CES-D) and the Modified Fatigue Impact Scale (MFIS) as well as the longitudinal changes in scores in a large cohort of MS patients. METHODS: MS subjects who completed a battery of patient reported outcome (PRO) measures including the CES-D and MFIS (N=435) were included in our analysis. At the first available MFIS measurement, Pearson's correlation coefficient was used to estimate the association between the CES-D and MFIS in terms of both total scores and subscale scores. In addition, the longitudinal change in each total score and subscale score was estimated using a linear mixed model, and the association between the measures in terms of longitudinal change was estimated using Pearson's correlation coefficient and linear mixed models. RESULTS: At baseline, 15% of subjects were classified as high on both depression and fatigue scales, 16% were classified as high on the fatigue scale only, and 9% were classified as high on the depression scale only. There was a high correlation between CES-D and MFIS total scores (r=0.62). High correlations were also observed between the somatic and retarded activity subscales of the CES-D and each of the MFIS subscales (r>=0.60). In terms of longitudinal change, the change over the first year between the CES-D and MFIS total scores showed a moderate correlation (r=0.49). Subjects with high fatigue scores but low depression scores at baseline were more likely than subjects with low baseline fatigue and depression scores to develop high depression scores at follow-up. CONCLUSIONS: Our study demonstrated that depression and fatigue in MS share several features and have a similar longitudinal course. But using cut-off scores to define depression and fatigue, our study also found that non-depressed subjects with high fatigue may be at a greater risk for developing depression. PMID- 28870579 TI - Aberrant microRNA expression in patients with painful peripheral neuropathies. AB - Changes in the neuro-immune balance play a major role in the induction and maintenance of neuropathic pain. We recently reported pathophysiologically relevant alterations in skin and sural nerve cytokine expression in peripheral neuropathies of different etiologies. Immune processes and cytokine expression are under tight control of microRNAs (miRNAs). To identify potential master switches in the neuro-immune balance, we aimed at characterizing inflammation regulating miRNA profiles in patients with peripheral neuropathies. In an unselected patient cohort with polyneuropathies of different etiologies seen at our neuromuscular center between 2014 and 2015, we determined the systemic and local relative expression of miR-21-5p, miR-146a, and miR-155. In white blood cells we found higher miR-21 (p<0.001) and miR-146a (p<0.001) expression and lower miR-155 (p<0.001) expression when compared to healthy controls. In sural nerve, miR-21 (p<0.02) was increased in painful compared to painless neuropathies. In painful neuropathies, skin biopsies from the lower leg had reduced miR-146a (p<0.001) and miR-155 (p<0.001) expression compared to the thigh. Thus, peripheral neuropathies are associated with aberrant miRNA expression in white blood cells, sural nerve, and skin. These miRNA patterns may help to identify factors that determine the painfulness of peripheral neuropathies and lead to druggable targets. PMID- 28870580 TI - Management of glioblastoma in elderly patients. AB - Glioblastoma (GBM) is the most common primary malignant brain tumor in adults over 55years of age. The median age of diagnosis for patients with GBM is 64years old, with the incidence of patients between 75 and 85 increasing. The optimal treatment paradigm for elderly GBM patients continues to evolve due to the higher frequency of age-related and/or medical co-morbidities. Geriatric GBM patients have historically been excluded from larger, controlled clinical trials due to their presumed decreased likelihood of a sustained treatment response and/or a prolonged good outcome. Here, we highlight current treatment considerations of elderly GBM patients with respect to surgical, radiotherapeutic and systemic modalities, with considerations for improving future clinical outcomes for this patient population. PMID- 28870581 TI - Pharmacological treatments for fatigue in patients with multiple sclerosis: A systematic review and meta-analysis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disease. Fatigue is the most common symptom of MS patients, affecting >80% subjects. Medical treatment is an important method for managing fatigue. Currently, although many drugs have been tested in treatment of MS fatigue, the efficacy of these drugs remain largely unclear. METHODS: We researched available literatures in PubMed, Embase, Medline, Google Scholar, Cochrane Library (August 31, 2016). Search terms included multiple sclerosis, fatigue, medication treatments, amantadine, modafinil, aspirin, acetyl-l-carnitine, pemoline, 4 aminopyridine and randomized controlled trial (RCT). Two researchers were required to independently assess the quality of literatures, and finish data extraction. Meta-analysis was conducted using RevMan 5.3 software. FINDINGS: A total of 11 RCTs involving 723 patients were included. The therapeutic effects were quantified by different scales, such as Modified Fatigue Impact Scale (MFIS) or Fatigue Severity Scale (FSS). Here, meta-analysis suggested that amantadine, not modafinil, was effective for treating the fatigue in MS. Moreover, two studies implied that l-carnitine might have similar therapeutic effect with amantadine. However, the reliability of this finding was greatly weakened by the limited sample sizes. Additionally, current data could not answer whether treatment of MS fatigue using aspirin or 4-aminopyridine was beneficial. Finally, we found that all drugs except pemoline were relatively safe for treating MS fatigue. CONCLUSIONS: Current limited data suggest that amantadine may be the only drug that has relatively sufficient evidences in treatment of fatigue symptoms in MS. Further RCT studies recruiting larger samples sizes are required to validate the therapeutic effect of these candidate drugs. PMID- 28870582 TI - Linking Alzheimer's disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach. AB - BACKGROUND: Both type 2 diabetes (T2D) and Alzheimer's disease (AD) occur commonly in the aging populations and T2D has been considered as an important risk factor for AD. The heritability of both diseases is estimated to be over 50%. However, common pleiotropic single-nucleotide polymorphisms (SNPs)/loci have not been well-defined. The aim of this study is to analyze two large public accessible GWAS datasets to identify novel common genetic loci for T2D and/or AD. METHODS AND MATERIALS: The recently developed novel conditional false discovery rate (cFDR) approach was used to analyze the summary GWAS datasets from International Genomics of Alzheimer's Project (IGAP) and Diabetes Genetics Replication And Meta-analysis (DIAGRAM) to identify novel susceptibility genes for AD and T2D. RESULTS: We identified 78 SNPs (including 58 novel SNPs) that were associated with AD in Europeans conditional on T2D (cFDR<0.05). 66 T2D SNPs (including 40 novel SNPs) were identified by conditioning on SNPs association with AD (cFDR<0.05). A conjunction-cFDR (ccFDR) analysis detected 8 pleiotropic SNPs with a significance threshold of ccFDR<0.05 for both AD and T2D, of which 5 SNPs (rs6982393, rs4734295, rs7812465, rs10510109, rs2421016) were novel findings. Furthermore, among the 8 SNPs annotated at 6 different genes, 3 corresponding genes TP53INP1, TOMM40 and C8orf38 were related to mitochondrial dysfunction, critically involved in oxidative stress, which potentially contribute to the etiology of both AD and T2D. CONCLUSION: Our study provided evidence for shared genetic loci between T2D and AD in European subjects by using cFDR and ccFDR analyses. These results may provide novel insight into the etiology and potential therapeutic targets of T2D and/or AD. PMID- 28870583 TI - A new infectious encephalopathy syndrome, clinically mild encephalopathy associated with excitotoxicity (MEEX). AB - Acute infectious encephalopathy is often observed in children in East Asia including Japan. More than 40% of the patients remain unclassified into specific syndromes. To investigate the underlying pathomechanisms in those with unclassified encephalopathy, we evaluated brain metabolism by MR spectroscopy. Among seven patients with acute encephalopathy admitted to our hospital from June 2016 to May 2017, three were classified into acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). The other four showed consciousness disturbance lasting more than three days with no parenchymal lesion visible on MRI, which led to a diagnosis of unclassified encephalopathy. MR spectroscopy in these four patients, however, revealed an increase of glutamine with a normal N acetyl aspartate level on days 5 to 8, which had normalized by follow-up studies on days 11 to 16. The four patients clinically recovered completely. Among 27 patients with encephalopathy, including the present seven patients, admitted to our hospital from January 2015 to March 2017, seven (26%) were classified into this type, which we propose is a new encephalopathy syndrome, clinically mild encephalopathy associated with excitotoxicity (MEEX). MEEX is the second most common subtype, following AESD (30%). This study suggests that excitotoxicity may be a common underlying pathomechanism of acute infectious encephalopathy, and prompt astrocytic neuroprotection from excitotoxicity may prevent progression of MEEX into AESD. PMID- 28870584 TI - Relevance of CCM gene polymorphisms for clinical management of sporadic cerebral cavernous malformations. AB - Cerebral cavernous malformations (CCMs) are clusters of capillaries in the brain that may cause focal deficits or seizures in affected patients. They occur in both sporadic and inherited autosomal dominant form. Germline mutations in CCM1, CCM2 and CCM3 were identified in familial cases. Over the past 13years we performed sequencing and MLPA of the CCM genes in all sporadic and familial CCM cases coming from some hospital clinics of Neurology and Neurosurgery of Messina and other Italian cities. Our results showed that CCM sporadic patients, negative for previously reported CCM gene causative mutations, always carried known CCM polymorphisms. Previously, we reported polymorphisms in CCM2 gene associated with an increase in risk for CCM. Here, we undertook a case-control study to investigate the possible association of others polymorphisms (c.485+65 C/G, c.989+63 C/G, c.1980 A/G in CCM1 gene, c.472+127 C/T in CCM2 and c.150 G/A in CCM3) with CCMs. The five polymorphisms were characterized in 64 sporadic patients and in 90 healthy controls by ASO-PCR. Statistically significant differences in frequencies between patients and controls were found for c.485+65C/G, c.1980 A/G and c.472+127C/T polymorphisms. For c.485+65C/G polymorphism, a higher frequency of mutated allele (G) was found in patients group (9%) than in controls (2%) (p=0.0041); for c.1980 A/G polymorphism, we found a frequency of mutated allele (G) higher in the control group (25%) compared to that of patients (8%) (p=0.0396). Same trend was observed for c.472+127C/T polymorphism (T allele frequency=34% and 6% in control group and patients, respectively; p=0.0001). Polymorphisms c.485+65C/G, c.1980 A/G and c.472+127C/T were associated with an increased risk of CCM as indicated by odds ratio values. Furthermore, c.1980 A/G and c.472+127C/T polymorphisms were associated with less severe CCM symptomatology. Identification of these polymorphisms in CCM sporadic patient may represent a useful tool for clinicians to determine prognosis, scheduled periodic checks and appropriate treatment strategy. PMID- 28870585 TI - Medical decision-making capacity and its cognitive predictors in progressive MS: Preliminary evidence. AB - BACKGROUND: Medical decision-making capacity (MDC) refers to the ability to make informed decisions about treatment and declines in cognition are associated with declines in MDC across multiple disease entities. However, although it is well known that cognitive impairment is prevalent in multiple sclerosis (MS), little is known about MDC in the disease. METHODS: Data from 22 persons with progressive MS and 18 healthy controls were analyzed. All diagnoses were made by a board certified neurologist with experience in MS. All study participants were administered a vignette-based measure of MDC and also a neuropsychological battery. RESULTS: Performance on three MDC consent standards (i.e., Appreciation, Reasoning, Understanding) was significantly lower for people with progressive MS as compared to healthy controls. In the progressive MS group, verbal fluency was the primary cognitive predictor for both Reasoning and Understanding consent standards. Verbal learning and memory was the primary cognitive predictor for Appreciation. MS severity was not significantly correlated with any MDC variable. CONCLUSION: MDC is a complex and cognitively mediated functional ability that is impaired in many people with progressive MS. Verbal measures of fluency and memory are strongly associated with MDC performances in the current sample of people with MS and could potentially be utilized to quickly screen for MDC impairment in MS. PMID- 28870586 TI - Bacterial meningitis due to Streptococcus pneumoniae following untreated idiopathic hypertrophic pachymeningitis. PMID- 28870587 TI - The value of midbrain morphology in predicting prognosis in chronic disorders of consciousness: A preliminary ultrasound study. AB - Transcranial sonography (TCS) of the brainstem is currently used to support the clinical diagnosis of movement disorders. The aim of the study was to assess the usefulness of midbrain TCS in assessing outcome in patients with Chronic Disorders of Consciousness (DOC). Eleven patients with Minimally Conscious State (MCS) and Unresponsive Wakefulness Syndrome (UWS) were included in the study. We measured the area and echogenicity of the midbrain by encoding and digitally analyzing the corresponding images from the orbitomeatal plane, the morphology of brain parenchyma from the thalamic and cella media plane, and the intracranial circulation. All the patients showed an increase of pulsatility index and numerous morphological alterations on all the scan planes. In particular, we found a loss of the characteristic butterfly-shape of the midbrain, which appeared hypoechoic in the UWS but not in the MCS patients. After six months, the patients were clinically assessed by using Glasgow Outcome Scale Extended (GOSE). We found that a higher increase in GOSE scoring at follow-up was correlated with larger area and higher echogenicity of the midbrain at baseline. The present study suggests that TCS data of the midbrain may support clinical assessment of patients with chronic DOC to estimate their outcome. PMID- 28870588 TI - Suspected retroorbital inflammation resulting in bilateral occlusion of the internal carotid arteries. PMID- 28870589 TI - Subcutaneous "bolus" immunoglobulin dose in CIDP: A proof-of concept study. AB - BACKGROUND: Subcutaneous (SC) immunoglobulin (Ig) is an effective therapy for Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). However, optimal dosage and frequency of administration remain to be clarified. OBJECTIVES: We sought to assess the feasibility and tolerability of a novel regimen of SCIg administration, based on concentrated "bolus" doses delivered every other week, as compared to the "conventional" SCIg regimen, based on 1-3 administrations/week. MATERIALS AND METHODS: Consecutively consenting CIDP patients (6 men and 1 woman) were crossed-over from SCIg "conventional" to SCIg "bolus" and followed-up for 6months. The main endpoints were: tolerability, defined as the percentage of patients successfully completing the study, patient's perceived disability, as measured by the Rasch-built Overall Disability Scale (R-ODS), life quality index (LQI), and inflammatory neuropathy cause and treatment (INCAT) scale. RESULTS: SCIg "bolus" was well tolerated by all patients. The R-ODS score significantly improved (p=0.042), as well as the LQI sub-domains related to the interference of treatment in daily living activities (p=0.026), and therapy-related problems (p=0.039). No significant change was observed in the INCAT (p=0.317) score. There were no cases of drop-out and/or dose adjustment during follow-up. CONCLUSIONS: SCIg "bolus" seems to represent an effective and well-tolerated option for CIDP maintenance therapy. PMID- 28870590 TI - Micro-RNAs in ALS muscle: Differences in gender, age at onset and disease duration. AB - Few studies have explored the role of microRNAs (or miRNAs) in Amyotrophic Lateral Sclerosis (ALS) muscle, possibly because of the difficulty in obtaining samples and because this is a rare disease. We measured the expression levels of muscle-specific miRNAs (miRNA-1, miRNA-206, miRNA-133a, miRNA-133b, miRNA-27a) and inflammatory/angiogenic miRNAs (miRNA-155, miRNA-146a, miRNA-221, miRNA-149*) in the muscles of 13 ALS patients and controls. To highlight differences, patients were subdivided according to their gender, age at onset of symptoms, and disease duration. A significant over-expression of all miRNAs was observed in ALS patients versus controls, in male patients versus females, in patients with early onset versus patients with late onset, and in patients with long disease duration versus patients with short duration. A differential expression of miRNAs according to gender could be explained by the hormonal regulation which determines the body muscle mass. The course of the disease might reflect differential degree of muscle atrophy and signaling at miRNA levels. An evident role is also played by inflammatory/angiogenetic factors as shown by the observed miRNA changes. PMID- 28870592 TI - Computer-based assessment of upper-limb incoordination in autosomal recessive spastic ataxia of Charlevoix-Saguenay patients: A pilot study. AB - Ataxia refers to a group of neurological disorders characterized by a lack of coordination during voluntary movements. One of the most commonly used tests to assess upper-limb coordination is the Archimedes spiral test. The purpose of this research is to present an innovative computer-based Archimedes spiral test that can accurately assess coordination. Forty nine individuals (age: 25.2+/-7.1years) were recruited including thirteen patients diagnosed with Autosomal Recessive Spastic Ataxia of Charlevoix/Saguenay (ARSACS). Participants were instructed to trace a spiral on the touch-screen with the tip of their index finger at a self paced velocity by following an on-screen spiral template. Mean error and maximum error as well as frequency analysis were calculated to classify healthy and ARSACS participants. While mean and maximum errors provided good results, the highest classification success rate was obtained using frequency analysis, particularly between f=1.2Hz and f=1.7Hz. Interpretation of traditional paper drawn Archimedes spirals is limited, and several computerized versions have been reported. Herein, we present a custom-made tool that allows discrimination of measures assessing ataxia in ARSACS. This utilizes a proposed frequency method that may have the potential to track the evolution of upper-limb incoordination in patients and therefore help clinicians and scientists to better monitor their patients. PMID- 28870591 TI - Hemorrhage recurrence risk factors in cerebral amyloid angiopathy: Comparative analysis of the overall small vessel disease severity score versus individual neuroimaging markers. AB - INTRODUCTION: An MRI-based score of total small vessel disease burden (CAA-SVD Score) in cerebral amyloid angiopathy (CAA) has been demonstrated to correlate with severity of pathologic changes. Evidence suggests that CAA-related intracerebral hemorrhage (ICH) recurrence risk is associated with specific disease imaging manifestations rather than overall severity. We compared the correlation between the CAA-SVD-Score with the risk of recurrent CAA-related lobar ICH versus the predictive role of each of its components. METHODS: Consecutive patients with CAA-related ICH from a single-center prospective cohort were analyzed. Radiological markers of CAA related SVD damage were quantified and categorized according to the CAA-SVD-Score (0-6 points). Subjects were followed prospectively for recurrent symptomatic ICH. Adjusted Cox proportional hazards models were used to investigate associations between the CAA-SVD-Score as well as each of the individual MRI signatures of CAA and the risk of recurrent ICH. RESULTS: In 229 CAA patients with ICH, a total of 56 recurrent ICH events occurred during a median follow-up of 2.8years [IQR 0.9-5.4years, 781 person years). Higher CAA-SVD-Score (HR=1.26 per additional point, 95%CI [1.04-1.52], p=0.015) and older age were independently associated with higher ICH recurrence risk. Analysis of individual markers of CAA showed that CAA-SVD-Score findings were due to the independent effect of disseminated superficial siderosis (HR for disseminated cSS vs none: 2.89, 95%CI [1.47-5.5], p=0.002) and high degree of perivascular spaces enlargement (RR=3.50-95%CI [1.04-21], p=0.042). CONCLUSION: In lobar CAA-ICH patients, higher CAA-SVD-Score does predict recurrent ICH. Amongst individual elements of the score, superficial siderosis and dilated perivascular spaces are the only markers independently associated with ICH recurrence, contributing to the evidence for distinct CAA phenotypes singled out by neuro-imaging manifestations. PMID- 28870593 TI - Incidence and case-fatality from spontaneous intracerebral hemorrhage in a southern region of Portugal. AB - BACKGROUND: There is scarce information on incidence and case fatality of spontaneous intracerebral hemorrhage (SICH) in certain regions of the world, including in Europe. There is no community-based data on SICH in Southern Portugal. AIM: To determine the incidence and early case-fatality from SICH in Algarve, the southernmost region of Portugal. METHODS: The recommended criteria for stroke incidence studies was used to identify cases of incident first-ever SICH from January 1st to December 31st 2015 in a subregion with 280,081 inhabitants. Crude incidence rates per age group and gender; standardized rates to the European population; and age adjusted case fatality rates were calculated. RESULTS: Eighty-two first-ever cases of SICH (64.6% men) occurred. The mean age was 72.3 years (SD+/-12.1); women were 3 years older than men on average and had more frequently lobar SICH. The crude annual incidence rate was 29.2/100,000 (95% CI 23.4- 38.6; p<0.001); higher in men (39.7/100,000) than women (19.8/100,000). The standardized to the European population incidence was 15.1/100,000 (95% CI 3.6-18.9; p<0.05); 26.9 and 10.9/100,000 for men and women respectively. The 30 day case-fatality was 40 % (95% CI 29-51) and increased steeply with age CONCLUSION: The incidence of SICH in Southern Portugal was high, but within the figures found in some parts of Europe. However, a marked predominance of males was found and the case-fatality rate was amongst the highest reported in western countries. PMID- 28870594 TI - Rebound syndrome after teriflunomide cessation in a patient with multiple sclerosis. AB - We report a case of relapsing remitting multiple sclerosis (RRMS) with severe rebound syndrome 12weeks following discontinuation of teriflunomide therapy. The patient developed severe clinical relapses with significant increase in the number of brain and spine magnetic resonance imaging (MRI) lesions. She responded well to intravenous and oral steroids and was later maintained on rituximab. PMID- 28870595 TI - Evidence of small-fiber neuropathy (SFN) in two patients with unexplained genital sensory loss and sensory urinary cystopathy. PMID- 28870597 TI - Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability. AB - Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation. This study is to explore the novel SPAST splice site donor variant, c.1004+3A>C, in seven patients from two families, one from Italy and the other from Japan. Exon 6 is skipped out by the variant, leading to a premature termination of translation, p.Gly290Trpfs*5. Measurement of SPAST transcripts in lymphocytes demonstrated a reduction through nonsense-mediated mRNA decay (NMD). Intra- and inter-familial phenotypic variations were observed, including age-at-onset, severity of spasticity, and scoliosis. Our study demonstrated further evidence of allelic heterogeneity in SPG4, dosage effects through NMD, and broad clinical features of the SPAST mutation. PMID- 28870598 TI - Sensory-motor neuropathy in a case with SPG35: Expanding the phenotype. PMID- 28870596 TI - Common and specific risk factors for ischemic stroke in elderly: Differences based on type of ischemic stroke and aging. AB - BACKGROUND: The risk factors among the types of ischemic stroke (atherothrombotic cerebral infarction: ATI, cardio-embolic infarction: CEI, lacunar infarction: LI) in aged stroke patients have rarely been compared to each other. METHODS: We compared the clinical parameters of 300 elderly patients with ischemic stroke, age 65-98years, to 100 age-matched control patients. RESULTS: Comparison by parametric test and logistic regression analysis between all 300 and 100 control patients showed higher systolic and diastolic blood pressures (p<0.001, p=0.03), lower estimated glomerular filtration rate (eGFR) (p=0.01), larger cardiothoracic ratio (CTR) (p<0.001), smoking (p<0.01) and possibly poor adherence to anti hypertensive agents in the ischemic stroke patients (p<0.001). Comparisons among three types (n=100 for each) showed the highest atheromatous risk factors for ATI to be hemoglobin A1c (p=0.01) and low-density lipoprotein (p<0.001) and for CEI to be largest cardiac load, indicated by largest left atrial dimension (p<0.001), and CTR (p<0.001). Triglyceride level was found to be a borderline risk factor for LI (p=0.054). Comparison between those aged <74 versus >=75years (n=150 for each) showed a lower eGFR (p=0.02) and larger right atrial dimension (p<0.001) in patients >=75. CONCLUSION: The risk factors were quite different among the subtypes and aging. PMID- 28870599 TI - Hepatocyte nuclear factor 4A improves hepatic differentiation of immortalized adult human hepatocytes and improves liver function and survival. AB - Immortalized human hepatocytes (IHH) could provide an unlimited supply of hepatocytes, but insufficient differentiation and phenotypic instability restrict their clinical application. This study aimed to determine the role of hepatocyte nuclear factor 4A (HNF4A) in hepatic differentiation of IHH, and whether encapsulation of IHH overexpressing HNF4A could improve liver function and survival in rats with acute liver failure (ALF). Primary human hepatocytes were transduced with lentivirus-mediated catalytic subunit of human telomerase reverse transcriptase (hTERT) to establish IHH. Cells were analyzed for telomerase activity, proliferative capacity, hepatocyte markers, and tumorigenicity (c-myc) expression. Hepatocyte markers, hepatocellular functions, and morphology were studied in the HNF4A-overexpressing IHH. Hepatocyte markers and karyotype analysis were completed in the primary hepatocytes using shRNA knockdown of HNF4A. Nuclear translocation of beta-catenin was assessed. Rat models of ALF were treated with encapsulated IHH or HNF4A-overexpressing IHH. A HNF4A-positive IHH line was established, which was non-tumorigenic and conserved properties of primary hepatocytes. HNF4A overexpression significantly enhanced mRNA levels of genes related to hepatic differentiation in IHH. Urea levels were increased by the overexpression of HNF4A, as measured 24h after ammonium chloride addition, similar to that of primary hepatocytes. Chromosomal abnormalities were observed in primary hepatocytes transfected with HNF4A shRNA. HNF4alpha overexpression could significantly promote beta-catenin activation. Transplantation of HNF4A overexpressing IHH resulted in better liver function and survival of rats with ALF compared with IHH. HNF4A improved hepatic differentiation of IHH. Transplantation of HNF4A-overexpressing IHH could improve the liver function and survival in a rat model of ALF. PMID- 28870601 TI - Lung Alveolar Repair: Not All Cells Are Equal. AB - The lungs are capable of repair but the extent to which this occurs varies widely. Recent data indicate that, following injury, different progenitor cell populations can arise, depending on the molecular environment. In turn, these result in either normal or aberrant alveolar repair. Thus, a key question in lung regenerative medicine is how to maintain a 'Goldilocks zone' of repair. PMID- 28870600 TI - Interleukin 10 enhanced CD8+ T cell activity and reduced CD8+ T cell apoptosis in patients with diffuse large B cell lymphoma. AB - The pleiotropic cytokine interleukin (IL)-10 is best characterized by its ability to downregulate inflammation and promote peripheral tolerance. On the other hand, IL-10 was also found to maintain the effector response of CD8+ T cells and promote the expansion of tumor-resident CD8+ T cells. In diffuse large B cell lymphoma (DLBCL), the role of IL-10 has been characterized in tumor cells but not in CD8+ T cells. We found that CD8+ T cells in DLBCL presented robust interferon (IFN)-gamma expression early during TCR-activation but could not maintain this response later on, which was characterized by significantly lower CD8+ T cell degranulation and higher apoptosis. These observations were associated with higher PD-1 expression in DLBCL CD8+ T cells. Furthermore, the PD-1+ cells were strongly enriched in the IFN-gamma+, but not the IFN-gamma-, fraction. Interestingly, exogenous IL-10 significantly improved the survival of DLBCL CD8+ T cells, and resulted in significantly higher IFN-gamma, ganzyme A and granzyme B expression in the absence of CD19+ tumor cells, and significantly improved CD8+ T cell-mediated specific lysis of CD19+ tumor cells. IL-10 did not alter the expression of PD-1 in DLBCL CD8+ T cells, but curiously, IL-10-treated DLBCL CD8+ T cells were less susceptible to PD-L1-mediated apoptosis. We then demonstrated that IL-10 treatment significantly elevated the expression of pro-survival factor Bcl-2. Blocking IL-10 resulted in higher apoptosis, fewer IFN-gamma+ CD8+ T cells, and lower Bcl-2 expression. IL-10 also significantly increased STAT3, but not STAT1, phosphorylation in CD8+ T cells. Together, these results suggested that IL-10 could enhance CD8+ T cell inflammation in DLBCL patients. PMID- 28870602 TI - The Brazilian Back Complaints in the Elders (Brazilian BACE) study: characteristics of Brazilian older adults with a new episode of low back pain. AB - OBJECTIVE: Low back pain (LBP) is little explored in the aging population especially when considering age-relevant and culturally dependent outcomes. We aimed to describe socio-demographic and clinical characteristics of Brazilian older people with a new episode of LBP presenting to primary care. METHODS: We sourced baseline information on socio-demographic, pain-related and clinical characteristics from 602 older adults from the Brazilian Back Complaints in the Elders (Brazilian BACE) study. We analyzed differences in pain, disability, functional capacity and psychosocial factors between sub-groups based on age (i.e. participants aged 55-74 or >=75 years), education (i.e. those with four years or less of schooling or those with more than four years of schooling) and income (i.e. participants who reported earning two or less minimal wages or three and more). RESULTS: Participants presented severe LBP (7.18/10, SD: 2.59). Younger participants were slightly more disabled (mean difference 1.29 points, 95% confidence interval [CI]: 0.03/5.56), reporting poorer physical health, and less fall-related self-efficacy (mean difference of 2.41, 95% CI 0.35/4.46). Those less educated, and those with income equal or less than two minimum wages had more disability, pain catastrophizing and worse functional capacity. CONCLUSIONS: This was the first study showing that Brazilian older adults with LBP present high levels of functional disability and psychological distress, especially those with low socioeconomic status. PMID- 28870604 TI - Astrocytes in the spinal dorsal horn and chronic itch. AB - Chronic itch is a hallmark symptom of inflammatory skin conditions, such as atopic dermatitis. Existing treatment for chronic itch is largely ineffective. Despite recent progress in our understanding of the neuronal basis for itch sensation in the peripheral and central nervous systems, the mechanisms underlying how itch turns into a pathological chronic state remain poorly understood. Recent studies have uncovered the causal role of astrocytes in the spinal dorsal horn using mouse models of chronic itch, including atopic dermatitis. Understanding the key roles of astrocytes may provide us with exciting insights into the mechanisms for the chronicity of itch sensation and clues to develop novel therapeutic agents for treating chronic itch. PMID- 28870605 TI - The roles of cortical astrocytes in chronic pain and other brain pathologies. AB - Astrocytes are the most abundant cell type in the brain. Several decades ago, they were considered to be only support cells in the central nervous system. Recent studies using advanced technologies have clarified that astrocytes play more active roles in regulating neuronal function and remodeling synaptic structures by releasing molecules called gliotransmitters. In addition to various physiological functions, astrocytes are activated under disease conditions, such as chronic pain, releasing molecules that in turn cause reorganization of the central nervous system microstructure and disrupt behavior in pathological conditions. In the present review, we summarize cortical astrocyte function in chronic pain and other neurological disorders and discuss the role of astrocytes in brain pathologies. PMID- 28870603 TI - Hormonal correlates of development and natal dispersal in wild female owl monkeys (Aotus azarae) of Argentina. AB - Pair-living and socially monogamous primates typically do not reproduce before dispersing. It is currently unclear whether this reproductive suppression is due to endocrine or behavioral mechanisms. Cooperatively breeding taxa, like callitrichids, may forego reproduction in natal groups because they reap inclusive fitness benefits and/or they are avoiding inbreeding. However, neither of these benefits of delayed reproduction appear to adequately explain the lack of reproduction prior to leaving the natal group in pair-living monogamous species. In this study, we determined whether wild Azara's owl monkeys (Aotus azarae) in the Argentinean Chaco establish reproductive maturity prior to dispersing. We utilized 635 fecal extracts to characterize reproductive hormone profiles of 11 wild juvenile and subadult females using enzyme immunoassays. Subadult females showed hormone profiles indicative of ovulatory cycling and had mean PdG and E1G concentrations approximately five times higher than juveniles. Contrary to expectations from the inbreeding avoidance hypothesis, female owl monkeys do not delay puberty, but rather commence ovarian cycling while residing in their natal group. Still, subadults appear to have a period during which they experience irregular, non-conceptive cycles prior to reproducing. Commencing these irregular cycles in the natal group may allow them to develop a state of suspended readiness, which could be essential to securing a mate, while avoiding costs of ranging solitarily. Our results indicate that reproductive suppression in female owl monkeys is not due to endocrine suppression. We suggest that adults likely use behavioral mechanisms to prevent subadults from reproducing with unrelated adult males in their natal group. PMID- 28870606 TI - Supercritical fluid chromatography in traditional Chinese medicine analysis. AB - Traditional Chinese medicines (TCMs) are gaining increasing popularity throughout the world due to their long historical clinical practices. Highly efficient analytical separation tools are essential for investigating the mysterious properties of TCMs and their quality control. Supercritical fluid chromatography (SFC) showed a great potential in TCM analysis for both nonpolar and polar components. In this paper, an overview of the experimental conditions (i.e. detection mode, stationary phase, mobile phase composition, pressure and temperature) used in SFC for achiral separations of TCM components is presented and recent applications to the analysis of different classes of compounds extracted from TCMs, such as lipids, terpene and terpenoids, phenolic compounds, flavonoids, alkaloids, saponins and carbohydrates, will be briefly described. PMID- 28870607 TI - Circular dichroism in functional quality evaluation of medicines. AB - Circular dichroism (CD) is a non-destructive and powerful technique for providing structure and ligand interaction information of small molecules as well as biotechnological medicines. While CD is a well-established technique in biomedical research, and different types and variants of CD do exist, the focus of this review is on the pharmaceutical quality control (QC) aspects of the classic electronic CD (ECD). The basic principles of the CD technique are initially described, followed by a systematic literature research on pharmaceutical aspects encompassing chiral small molecules, bio-polymers (i.e. proteins, peptides and nucleic acids), medicine-biotarget interaction (i.e. small molecule-albumin interaction, protein-receptor interaction and peptide-biotarget interaction) and medicine changes (i.e. chemical modification, biosimilar/bio better with stability and aggregation). In addition, unstructured literature was also included covering the use of CD mainly in discovery and fundamental research, but which might shift towards the pharmaceutical QC field as well in the future. PMID- 28870608 TI - Associations Among Food Insecurity, Academic Performance, and Weight Status in Primary Schoolchildren in Tehran, Iran: A Cross-sectional Study. AB - OBJECTIVE: To examine the associations among household food insecurity (FI), academic performance, and weight status in urban primary schoolchildren. DESIGN: Cross-sectional study. SETTING: Primary schools in Tehran, Iran. PARTICIPANTS: A total of 803 students (419 boys and 384 girls), aged 10-12 years, were recruited from 43 primary schools. MAIN OUTCOME MEASURES: Levels of FI were measured using a locally validated, 18-item household food security survey module. Academic performance was assessed by 152 teachers through a specifically designed, 20 scale questionnaire. Standard anthropometric measurements were also taken. ANALYSIS: Linear and multinomial regressions were conducted. RESULTS: At the household level, FI was associated with poorer grades in all subjects studied (except for social science in FI without hunger) (P < .05). At the child level, a significant association was observed between low food security and poorer grades in all subjects studied, whereas for very low food security, this relationship was significant only for mathematics, reading, and science (P < .05). Food insecurity without hunger (odds ratio = 2.56; 95% confidence interval, 1.05-6.23) and low food security (odds ratio = 4.41; 95% confidence interval, 1.58-12.23) were associated with overweight only in girls. CONCLUSIONS AND IMPLICATIONS: The findings confirm the need for policies and programs to improve students' dietary quality and food security to improve their health as well as educational attainment. Future research is needed to explore further the association between food security and academic performance. PMID- 28870609 TI - Draw and Tell: Dietary Acculturation as Lived by Black Immigrant Children of African and Caribbean Descent Residing in Canada. AB - OBJECTIVE: Explore immigrant children's lived experience of dietary acculturation. DESIGN: Draw and tell qualitative research. PARTICIPANTS: A total of 167 school-aged children living in Ottawa, Canada, who had a mother born in sub-Saharan Africa or the Caribbean. METHODS: Children made 2 drawings about foods, 1 related to Canada and the other to their home country, and explained their drawings and what they meant to them. These discussions were recorded and transcribed. ANALYSIS: Foods were counted for each region (Canada/Africa/Caribbean). Thematic analysis was performed. RESULTS: Most children drew different foods for Canada and their home country. Apples were the most frequently mentioned food for Canada. Pizza, juice and sugar-sweetened beverages, fries/poutine, and hamburgers were among the 10 most frequently mentioned foods for Canada, whereas none of the top 10 foods for African and Caribbean countries were highly processed. Rice, chicken, meat, and leafy vegetables were in the top 10 foods mentioned for the 3 regions. Emerging themes were food availability and variety, mothers' lack of time and fatigue, and the school eating environment. CONCLUSION AND IMPLICATIONS: It seems that these black immigrant children experienced dietary acculturation and that changes in dietary habits have had mostly a negative impact on their diet. PMID- 28870610 TI - Tax on tobacco and sugary drinks in the United Arab Emirates. PMID- 28870612 TI - Discontinuation of melanoma combination immunotherapy. PMID- 28870611 TI - Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose escalation study. AB - BACKGROUND: TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16 based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma. METHODS: In this first in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged >=18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3 + 3 dose-escalation design in five dose cohorts. The dose escalation steps planned were 5 * 109, 7 * 109, and 9 * 109 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1 * 109 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651. FINDINGS: Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5 * 109 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5 * 109 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non cardiac pain in one patient who received 5 * 109 TargomiRs once weekly. We established that 5 * 109 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94-358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation. INTERPRETATION: The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors. FUNDING: Asbestos Diseases Research Foundation. PMID- 28870613 TI - Defeating anaemia in myelodysplastic syndromes: another step forward. PMID- 28870614 TI - Androgen deprivation therapy for prostate cancer. PMID- 28870616 TI - miR-16: expanding the range of molecular targets in mesothelioma. PMID- 28870617 TI - Spatial vs. non-spatial eco-evolutionary dynamics in a tumor growth model. AB - Metastatic prostate cancer is initially treated with androgen deprivation therapy (ADT). However, resistance typically develops in about 1 year - a clinical condition termed metastatic castrate-resistant prostate cancer (mCRPC). We develop and investigate a spatial game (agent based continuous space) of mCRPC that considers three distinct cancer cell types: (1) those dependent on exogenous testosterone (T+), (2) those with increased CYP17A expression that produce testosterone and provide it to the environment as a public good (TP), and (3) those independent of testosterone (T-). The interactions within and between cancer cell types can be represented by a 3 * 3 matrix. Based on the known biology of this cancer there are 22 potential matrices that give roughly three major outcomes depending upon the absence (good prognosis), near absence or high frequency (poor prognosis) of T- cells at the evolutionarily stable strategy (ESS). When just two cell types coexist the spatial game faithfully reproduces the ESS of the corresponding matrix game. With three cell types divergences occur, in some cases just two strategies coexist in the spatial game even as a non-spatial matrix game supports all three. Discrepancies between the spatial game and non-spatial ESS happen because different cell types become more or less clumped in the spatial game - leading to non-random assortative interactions between cell types. Three key spatial scales influence the distribution and abundance of cell types in the spatial game: i. Increasing the radius at which cells interact with each other can lead to higher clumping of each type, ii. Increasing the radius at which cells experience limits to population growth can cause densely packed tumor clusters in space, iii. Increasing the dispersal radius of daughter cells promotes increased mixing of cell types. To our knowledge the effects of these spatial scales on eco-evolutionary dynamics have not been explored in cancer models. The fact that cancer interactions are spatially explicit and that our spatial game of mCRPC provides in general different outcomes than the non-spatial game might suggest that non-spatial models are insufficient for capturing key elements of tumorigenesis. PMID- 28870615 TI - Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose finding study with long-term extension study. AB - BACKGROUND: Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF beta) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes. METHODS: In this phase 2, multicentre, open label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count <13 000/MUL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin <10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0.125 mg/kg to 1.75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1.0 mg/kg luspatercept; dose titration up to 1.75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E), defined as a haemoglobin concentration increase of 1.5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0.125-0.5 mg/kg vs 0.75-1.75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as >=4 vs <4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (<200 IU/L, 200-500 IU/L, and >500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383. FINDINGS: Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0.125-1.75 mg/kg) and 31 patients in the expansion cohort (1.0-1.75 mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose luspatercept concentrations (0.75-1.75 mg/kg) achieved HI-E versus two (22% [95% CI 3-60]) of nine receiving lower dose concentrations (0.125-0.5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration. INTERPRETATION: Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing. FUNDING: Acceleron Pharma. PMID- 28870618 TI - Revisiting the theoretical basis of the endosymbiotic origin of plastids in the original context of Lynn Margulis on the origin of mitosing, eukaryotic cells. AB - Fifty years ago, Lynn Margulis proposed a comprehensive hypothesis on the origin of eukaryotic cells with an emphasis on the origin of mitosis. This hypothesis postulated that the eukaryotic cell is a composite of different parts as a result of the symbiosis of various different bacteria. In this hypothesis, she integrated previously proposed ideas that mitochondria and chloroplasts were descendants of endosymbionts that originated from aerobic bacteria and blue-green algae (now cyanobacteria), respectively. However, the major part of her hypothesis, which she believed to be original, was the origin of mitosis. The core of her postulate involved a chromosome partition mechanism dependent on DNA microtubule binding, which originated from a hypothetical centriole-DNA complex, with an ability to replicate. Surprisingly, her complete lack of real experimental works in the cytoskeleton, cell motility, or paleontology did not prevent this 29-year-old junior scientist from assembling archival knowledge and constructing a narrative on the evolution of all organisms. Whether the centriole DNA complex originated from a spirochete or not was a minor anecdote in this initial postulate. Unfortunately, this hypothesis on the origin of mitosis, which she believed to be a holistic unity, testable by experiments, was entirely refuted. Despite falsification of her original narrative as a whole, her success as a founder of endosymbiotic theory on the origin of mitochondria and chloroplasts is undoubted. We will discuss the reasons for her success in terms of the historical situation in the latter half of the 20th century. PMID- 28870619 TI - A causal Bayesian network model of disease progression mechanisms in chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is a cancer of the hematopoietic system initiated by a single genetic mutation which results in the oncogenic fusion protein Bcr Abl. Untreated, patients pass through different phases of the disease beginning with the rather asymptomatic chronic phase and ultimately culminating into blast crisis, an acute leukemia resembling phase with a very high mortality. Although many processes underlying the chronic phase are well understood, the exact mechanisms of disease progression to blast crisis are not yet revealed. In this paper we develop a mathematical model of CML based on causal Bayesian networks in order to study possible disease progression mechanisms. Our results indicate that an increase of Bcr-Abl levels alone is not sufficient to explain the phenotype of blast crisis and that secondary changes such as additional mutations are necessary to explain disease progression and the poor therapy response of patients in blast crisis. PMID- 28870620 TI - Fixation probability of a nonmutator in a large population of asexual mutators. AB - In an adapted population of mutators in which most mutations are deleterious, a nonmutator that lowers the mutation rate is under indirect selection and can sweep to fixation. Using a multitype branching process, we calculate the fixation probability of a rare nonmutator in a large population of asexual mutators. We show that when beneficial mutations are absent, the fixation probability is a nonmonotonic function of the mutation rate of the mutator: it first increases sublinearly and then decreases exponentially. We also find that beneficial mutations can enhance the fixation probability of a nonmutator. Our analysis is relevant to an understanding of recent experiments in which a reduction in the mutation rates has been observed. PMID- 28870621 TI - Is weather related to the number of assaults seen at emergency departments? AB - BACKGROUND: It is often suggested that the weather can effect behaviour, increasing the likelihood of assaults and resulting in increased admissions to emergency departments (ED). Therefor a better understanding of the effect of climatic conditions could be useful to help EDs in capacity planning. Whilst other studies have looked at this, none have used data collected specifically to look at ED attendance for assaults or have taken account of potential behaviour modifiers. METHODS: We use data from our ED violence surveillance system, the Cardiff Model (CM), married to daily meteorological data to construct negative binomial regression models. The models are used to estimate changes in the assault rate with changes in temperature, adjusting for day of the week and alcohol consumption. RESULTS: We find that there is 1% increase in the assault rate for every degree increase in the maximum daily temperature (IRR=1.01, P value=0.033). Additionally, different patterns in alcohol consumption at weekends also provide a significant contribution. However, when we generalise this model to represent temperature in terms of factors of standard deviation from the mean temperature, the IRR relationship changes, plateauing at unusually high temperatures (+/-1.5 SD above the mean). CONCLUSIONS: The results presented here suggest that whilst temperature does increase the risk of assaults in Dorset, there may be a limit to its effect. This implies the 'curve-linear' relationship for temperature as suggested by others. PMID- 28870622 TI - How can we influence the incidence of secondary fragility fractures? A review on current approaches. AB - With the increasing number of elderly patients presenting with fragility fractures, their care has become a focus among trauma and orthopaedic surgeons. Protocols are ever evolving to improve the clinical pathways and treatment modalities targeting a more efficient and patient centred service. In this article, current approaches and their potential to reduce mortality and re fracture in these patients are discussed. PMID- 28870623 TI - Development of fracture liaison services: What have we learned? AB - Due to dramatic improvements in life expectancy we are seeing a rapidly growing population of older people. Increasing frailty and susceptibility to fragility fractures are becoming pressing issues for both the individuals that suffer them as well as society, through pressures on health and social care budgets. The success of fracture liaison services, co-ordinated programmes enhancing the management of the fracture, osteoporosis, frailty and falls risk, is undisputed. To achieve optimal outcomes, however, it is important to have a standardisation of design, scope and structure of the service. Experience has taught us that by delegating responsibility for the holistic care of the patient to a trained and adequately resourced professional/team (fracture prevention practitioner) with clear standards against which benchmarking occurs, is the optimal model of delivery. Future challenges include how best to measure the success of services in imparting a reduction in fractures at a local population level as well as how to detect those patients with unmet need who do not uniformly present to health care services, such as those with vertebral fractures. The implementation of fracture liaison services however, is a clear demonstration of how collaboration between health care, social care and charity organisations, among others, has materially improved the health and well-being of the population. PMID- 28870624 TI - Response to Letter to the Editor on "The outcome of unstable proximal femoral fracture treated with reverse LISS plates". PMID- 28870625 TI - Comparison of the moulding ability of Plaster of Paris and polyester cast material in the healthy adult forearm. AB - OBJECTIVES: To quantify the moulding ability of Plaster of Paris and polyester cast materials as assessed by the novel use of peripheral quantitative computed tomography. METHODS: A prospective crossover study was performed in 25 healthy volunteers aged 18-65 years. Participants' non-dominant wrist was immobilized using a synthetic polyester cast followed by a Plaster of Paris cast with three point moulding to simulate reduction of a dorsally angulated distal radius fracture. The novel use of peripheral quantitative computed tomography was used to measure the closeness of fit of each cast on an axial tomographic slice. RESULTS AND CONCLUSIONS: Plaster of Paris casts were able to achieve a closer mould than polyester when measured between the bone and the cast (p=0.002), as well as between the skin and the cast (p=0.001). There was no difference when stratified on BMI. Using pQCT assessment, a closely moulded fit was able to be more consistently achieved when using Plaster of Paris when compared to polyester casts of the distal radius. LEVEL OF EVIDENCE: III. PMID- 28870626 TI - Immunoreactivity of urate transporters, GLUT9 and URAT1, is located in epithelial cells of the choroid plexus of human brains. AB - It has been suggested that urate plays a protective role in neurons, while hyperuricemia is correlated with atherosclerosis and cardiovascular disease. However, whether there is a system that directly transports urate into the brain remains to be clarified. In this study, the localization of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), which are known to be representative reabsorptive urate transporters, was immunohistochemically examined in autopsied human brains. Immunoreactivity of GLUT9 was observed on the apical side of the cytoplasm of epithelial cells in the choroid plexus and in the cilia of ependymal cells of the human brain. Immunoreactivity of URAT1 was observed on the basolateral side of the cytoplasm of epithelial cells in the choroid plexus. In addition, immunoreactivity of GLUT9 and URAT1 was not observed in microvessels of the human brains. The choroid plexus and renal proximal tubule were similar in having a polarized distribution of these two transporters with the two transporters on opposite membranes, but the two transporters' distribution differs between the choroid plexus and the kidney in terms of which membrane (apical/basal) expresses which transporter. These findings support the hypothesis of the direct transport of intravascular urate into the central nervous system through the choroid plexus. PMID- 28870627 TI - Endurance exercise improves function in individuals with Parkinson's disease: A meta-analysis. AB - Current evidence has shown that exercise can reduce symptoms of Parkinson's disease (PD). However, previous studies indicated mixed results, possibly because of variability in terms of the nature of the exercise interventions. The purpose of this study was to perform a metaanalysis of current evidence from endurance exercise intervention studies for effects on the United Parkinson's Disease Rating Scale (UPDRS) in individuals with PD. A systematic literature search in six electronic databases was performed and two independent reviewers screened the title and abstract of 1106 records captured by the initial search. Inclusion criteria for full-text review were (A) peer-reviewed English-language publications, (B) randomized controlled trials that compared an endurance exercise intervention group to a non-exercising control group, and (C) an outcome measure which included the UPDRS total score or section III (motor) subscore. From the title/abstract screening, the same independent reviewers assessed 245 full-text articles for eligibility. Of the fulltext articles reviewed 7 articles were included in our meta-analysis, 238 were excluded for the following reasons: 147 did not meet endurance exercise criteria, 53 were review/systematic reviews, 34 were conference abstracts or posters, 2 were editorial or commentary, 1 was a study protocol, and 1 was unpublished. The d index was used to calculate the difference between means of different groups within individual studies, and a weighting factor or w was used to calculate the effect size across studies. Overall, d index was found to be -0.32 with 95% confidence interval, CI (-0.09, 0.56) found to be statistically significant indicating a positive effect of endurance exercise in UPDRS scores. In conclusion, this meta-analysis supports integrating endurance exercise training, as defined by ACSM, into treatment of PD. PMID- 28870628 TI - The role of anterior cruciate ligament in the control of posture; possible neural contribution. AB - The anterior cruciate ligament (ACL) is not only a mechanical structure for knee joint stability but is also a source of sensory information which could be used in the control of standing posture. It has been shown that the center of pressure (COP) time series during normal standing may be decomposed into two components which are hypothetically governed by different neural mechanisms, namely rambling and trembling. The aim of the present study was to investigate to what extent an injury to the ACL structure would affect these two control mechanisms. In this study the balance of a group of ACL deficient (ACLD) patients during double and single leg standing was examined and compared with that of a group of healthy individuals. We not only calculated the traditional measures of COP, but also decomposed this complex signal to investigate if ACL deficiency would affect the rambling and trembling components differently. The results showed that rambling was not significantly different between the two groups; however the trembling component was significantly greater for the ACLD group in both the single leg and the double leg condition. Further, there was also a component (rambling/trembling) by direction (anterior-posterior/mediolateral) interaction for both groups, indicating that the rambling component exhibited differences between directions of sway whereas the trembling component did not. This study provided evidence that the two components of postural control are differently affected by ACL deficiency, and that the rambling component is influenced by direction of sway. PMID- 28870629 TI - Microinjection of the dopamine D2-receptor antagonist Raclopride into the medial preoptic area reduces REM sleep in lactating rats. AB - The medial preoptic area (mPOA) is a brain structure classically related to both non-REM (NREM) sleep and maternal behavior. Although the dopaminergic system is known to play a role in the control of the states of sleep and wakefulness, its effects within the mPOA on sleep are still not clear. Microinjection of the dopamine D2 receptor antagonist Raclopride into the mPOA has been shown to promote nursing postures in lactating dams with no effects on active maternal behavior. We hypothesized that the facilitation of nursing postures may be also associated with the promotion of NREM sleep. In order to test the hypothesis, Raclopride was microinjected into the mPOA and maternal behavior and sleep were assessed in lactating rats. The changes observed included a reduction of the latency to start nursing and an increase of the time to reunite the entire litter. Contrary to our hypothesis, NREM sleep was not affected by Raclopride. On the other hand, REM sleep and its transitional stage from NREM sleep, were significantly reduced by this pharmacological agent. These data suggest that dopamine D2 receptors within the mPOA are involved in the transition from NREM to REM sleep. PMID- 28870630 TI - GLP-1 receptor agonists: An example of the challenge for animal models to predict plaque instability/rupture and cardiovascular outcomes. PMID- 28870632 TI - Are structural brain changes driven by aortic atherosclerosis? PMID- 28870631 TI - The sirtuin family members SIRT1, SIRT3 and SIRT6: Their role in vascular biology and atherogenesis. AB - The sirtuins, silent mating-type information regulation 2 (SIRTs), are a family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases with important roles in regulating energy metabolism and senescence. Activation of SIRTs appears to have beneficial effects on lipid metabolism and antioxidants, prompting investigation of the roles of these proteins in atherogenesis. Although clinical data are currently limited, the availability and safety of SIRT activators such as metformin and resveratrol provide an excellent opportunity to conduct research to better understand the role of SIRTs in human atherosclerosis. Encouraging observations from preclinical studies necessitate rigorous large, prospective, randomized clinical trials to determine the roles of SIRT activators on the progression of atherosclerosis and ultimately on cardiac outcomes, such as myocardial infarction and mortality. PMID- 28870633 TI - De novo assembly and annotation of the whole transcriptome of Oratosquilla oratoria. AB - As the representative species of Stomatopoda, Oratosquilla oratoria can tolerate the complex benthic environment. In this study, our goal was to develop the transcriptomic resource of O. oratoria that would support adaptation mechanism studies. We generated the whole transcriptome of O. oratoria from combined tissues (eyestalk, muscle, sexual and viscus) using Hiseq technology. A total of 51,305,284 high-quality clean reads were assembled to produce 59,054 non redundant transcripts with a mean length of 987nt using Trinity and CORSET software. Among the predictable unigenes, a total of 32,451 unigenes were annotated based on protein databases. Finally, we predicted the coding sequences of 31,822 unigenes and obtained 19,057 SSRs in the present study. The present study will provide an important resource and foundational understanding for future genomic research of O. oratoria. PMID- 28870634 TI - Dendritic spine actin cytoskeleton in autism spectrum disorder. AB - Dendritic spines are small actin-rich protrusions from neuronal dendrites that form the postsynaptic part of most excitatory synapses. Changes in the shape and size of dendritic spines correlate with the functional changes in excitatory synapses and are heavily dependent on the remodeling of the underlying actin cytoskeleton. Recent evidence implicates synapses at dendritic spines as important substrates of pathogenesis in neuropsychiatric disorders, including autism spectrum disorder (ASD). Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of the spine and synapse pathology may provide insight into their etiologies and could reveal new drug targets. In this review, we will discuss recent findings of defective actin regulation in dendritic spines associated with ASD. PMID- 28870635 TI - Cannabidiol inhibits priming-induced reinstatement of methamphetamine in REM sleep deprived rats. AB - Methamphetamine (METH) is a widely abused and a severely addictive psychostimulant. Relapse is the main cause of concern when treating addiction. It could manifest after a long period of abstinence. Previous studies showed that there is a strong connection between sleep impairment and relapse. Also, it has been reported that cannabidiol might be a potential treatment for drug craving and relapse. In this study, we used conditioned place preference (CPP) to investigate whether Cannabidiol (CBD), a phytocannabinoid, can prevent METH induced reinstatement in Rapid Eye Movement Sleep Deprived (RSD) rats. In order to induce CPP, the animals were given METH (1mg/kg; sc) for five days. The effective priming dose of METH (0.5mg/kg, sc) reinstated the extinguished METH induced CPP. In order to investigate the effect of RSD on METH-induced reinstatement, we used the inverted flowerpot technique to deprive the rats of REM sleep. We found that 24h-RSD could facilitate priming-induced reinstatement of METH. In addition to this, the ICV administration of CBD 10MUg/5MUl could suppress the METH-induced reinstatement even in RSD rats. In conclusion, the administration of CBD 10MUg/5MUl effectively prevents METH-induced CPP, even in a condition of stress. CBD can be considered an agent that reduces the risk of the relapse; however, this requires more investigation. PMID- 28870636 TI - De novo ERBB2 amplification causing intrinsic resistance to erlotinib in EGFR L858R mutated TKI-naive lung adenocarcinoma. PMID- 28870637 TI - A hierarchical Bayesian approach to calibrating the linear-quadratic model from clonogenic survival assay data. AB - We propose a Bayesian hierarchical model applicable to the calibration of the linear-quadratic model of radiation dose-response. Experimental data used in model calibration were taken from a clonogenic survival assay conducted on human breast cancer cells (MDA-MB-231) across a range of radiation doses (0-6Gy). Employing Markov-chain Monte Carlo methods, we calibrated the proposed Bayesian hierarchical model, computed posterior distributions for the model parameters and survival fraction dose-response probability densities. Key contributions include the proposal of a model that incorporates multiple sources of inter- and intra experiment variability commonly neglected in the standard frequentist approach and its subsequent application to in vitro experimental data. PMID- 28870638 TI - Exome sequencing for the differential diagnosis of ciliary chondrodysplasias: Example of a WDR35 mutation case and review of the literature. AB - Exome sequencing is becoming widely popular and affordable, making it one of the most desirable methods for the identification of rare genetic variants for clinical diagnosis. Here, we report the clinical application of whole exome sequencing for the ultimate diagnosis of a ciliary chondrodysplasia case presented with an initial clinical diagnosis of Asphyxiating Thoracic Dystrophy (ATD, Jeune Syndrome). We have identified a novel homozygous missense mutation in WDR35 (c.206G > A), a gene previously associated with Sensenbrenner Syndrome, Ellis-van Creveld syndrome and Short-rib polydactyly syndrome type V. The genetic findings in this family led to the re-evaluation of the initial diagnosis and a differential diagnosis of Sensenbrenner Syndrome was made after cautious re examination of the patient. Cell culture studies revealed normal subcellular localization of the mutant WDR35 protein in comparison to wildtype protein, pointing towards impaired protein-protein interaction and/or altered cell signaling pathways as a consequence of the mutated allele. This research study highlights the importance of including pathogenic variant identification in the diagnosis pipeline of ciliary chondrodysplasias, especially for clinically not fully defined phenotypes. PMID- 28870639 TI - Migratory properties of ex vivo expanded regulatory T cells: Influence of all trans retinoic acid and rapamycin. AB - Adoptively transferred regulatory T-cells represent a promising therapeutic approach for tolerance induction in autoimmunity and transplantation medicine. However, a major hurdle for clinical application is the manufacturing of sufficient Treg cell numbers with respect to the low frequency of naturally occurring Tregs in the peripheral blood. Therefore, ex vivo large-scale expansion is mandatory for most of the clinical conditions. Besides the Treg cell number other parameters of the cell product are of high relevance for safe and efficient clinical Treg cell application like Treg cell purity, suppressive capacity and genetic stability of the Treg cell phenotype. Moreover, migratory properties of ex vivo expanded Tregs should be defined very clearly in order to predict their migration to secondary lymphoid organs as sites of antigen-specific activation, in vivo proliferation and subsequent trafficking to affected target organs. Therefore, we studied different cell culture conditions for Treg large-cell expansion using all-trans retinoic acid (ATRA) and/or rapamycin (Rapa) with focus on their migratory properties. The tested culture conditions revealed comparable chemokine receptor expression profiles (CXCR3, CCR4, CCR6, CCR7) and functional migration capabilities (IP10 and CCL19) with respect to Th1 and Th2 inflammatory conditions. However, the most striking difference was detected for the expansion capacity, suppressive potency and genetic stability likely predisposing large scale expansion with ATRA and/or Rapa for therapeutic intervention in acute GvHD and without supplementation for chronic GvHD. PMID- 28870640 TI - IVUS Findings in Late and Very Late Stent Thrombosis. A Comparison Between Bare metal and Drug-eluting Stents. AB - INTRODUCTION AND OBJECTIVES: Stent thrombosis (ST) is a life-threatening complication after stent implantation. Intravascular ultrasound is able to discern most causes of ST. The aim of this study was to compare intravascular ultrasound findings between bare-metal stents (BMS) and drug-eluting stents (DES) in patients with late (31 days to 1 year) or very late ST (> 1 year). METHODS: Of 250 consecutive patients with late or very late ST in 7 Spanish institutions, 114 patients (45.5% BMS and 54.5% DES) were imaged with intravascular ultrasound. Off line intravascular ultrasound analysis was performed to assess malapposition, underexpansion, and neoatherosclerosis. RESULTS: The median time from stent implantation to ST was 4.0 years with BMS and 3.4 years with DES (P = .04). Isolated malapposition was similarly observed in both groups (36.5% vs 46.8%; P = .18) but was numerically lower with BMS (26.6% vs 48.0%; P = .07) in patients with very late ST. Isolated underexpansion was similarly observed in both groups (13.5% vs 11.3%; P = .47). Isolated neoatherosclerosis occurred only in patients with very late ST and was more prevalent with BMS (22.9%) than with DES (6.0%); P = .02. At 2.9 years' follow-up, there were 0% and 6.9% cardiac deaths, respectively (P = .06) and recurrent ST occurred in 4.0% and 5.2% of patients, respectively (P = .60). CONCLUSIONS: Malapposition was the most common finding in patients with late and very late ST and is more prevalent with DES in very late ST. In contrast, neoatherosclerosis was exclusively observed in patients with very late ST and mainly with BMS. PMID- 28870641 TI - Diagnosis and Treatment of Transthyretin Cardiac Amyloidosis. Progress and Hope. AB - Cardiac amyloidosis is an infiltrative disorder caused by extracellular protein deposition. Transthyretin is a proamyloidotic protein that produces one of the most frequent forms of cardiac amyloidosis, either through mutations or a wild type form (previously known as senile amyloidosis). Until very recently, diagnosis of transthyretin amyloidosis (ATTR) was very uncommon and histological confirmation was mandatory, making diagnosis of ATTR a real challenge in daily clinical practice. Moreover, the specific therapeutic options to alter the clinical course of the disease were very limited. However, advances in cardiac imaging and diagnostic strategies have improved recognition of ATTR. In addition, several compounds able to modify the natural history of the disease are in the final phases of research, with promising results. Given that effective therapies are on the horizon, cardiologists should be well-versed in this disease and be familiar with its diagnosis and treatment. This review describes the broad clinical spectrum of ATTR in detail, as well as recent advances in the diagnosis and treatment of this condition. PMID- 28870642 TI - High-dose Thiotepa, Busulfan, Cyclophosphamide, and Autologous Stem Cell Transplantation as Upfront Consolidation for Systemic Non-Hodgkin Lymphoma With Synchronous Central Nervous System Involvement. AB - INTRODUCTION: Synchronous involvement of the central nervous system (CNS) at the diagnosis of systemic non-Hodgkin lymphoma (NHL) is associated with an increased risk for relapse despite complete remission to initial therapy. High-dose chemotherapy with a CNS-directed conditioning regimen followed by autologous stem cell transplantation (ASCT) holds promise as a consolidative approach. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients with systemic B-cell NHL and synchronous CNS involvement who received upfront consolidation with high-dose chemotherapy with thiotepa, busulfan, cyclophosphamide, and ASCT while in first complete remission between July 2008 and June 2016 at 2 partner academic institutions. RESULTS: Twenty patients were identified through the transplant database. The median age at diagnosis was 53 years (range, 37-65 years). The majority had diffuse large B-cell lymphoma histology (n = 17; 85%). The sites of CNS involvement were parenchymal (n = 12; 60%) and leptomeningeal disease (n = 9; 45%). All patients received systemic and CNS-directed therapy prior to transplant, with the most common approaches being R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) (n = 13; 65%) and high-dose intravenous methotrexate (n = 16; 80%), respectively. With a median follow up of 4.4 years after ASCT (range, 2 months-8.5 years), the Kaplan-Meier estimates of 4-year progression-free and overall survival were 77% (95% confidence interval, 48%-91%) and 82% (95% confidence interval, 54%-94%), respectively. CONCLUSION: CNS-directed high-dose chemotherapy and ASCT provides durable remission for patients with synchronous aggressive lymphoma and should be strongly considered as consolidative therapy for eligible patients with systemic NHL with CNS involvement in first complete remission. PMID- 28870643 TI - Pegylated GCSF Can Be Used With First-Line da-EPOCH-R Without Compromising Dose Intensity, Safety, or Efficacy. AB - INTRODUCTION: Infusional da-EPOCH-R (dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab) is a dose intensified regimen with a potential role in treating high-risk subtypes of aggressive B-cell non-Hodgkin lymphoma (B-NHL). Studies of da-EPOCH-R use daily injections of granulocyte colony-stimulating factor (GCSF) to tailor chemotherapy dosing, and whether 1-time administration of pegylated GCSF (peg-GCSF) is as efficacious has not been addressed. PATIENTS AND METHODS: We reviewed aggressive B-NHL patients treated at our center with first-line da-EPOCH-R for clinician choice of growth factor, and analyzed dose level achieved, rate of unplanned hospitalizations, and patient outcomes. RESULTS: Among 73 patients, 44 received peg-GCSF. Overall, 11 patients (15%) patients achieved dose level 4. Baseline characteristics between peg-GCSF and GCSF groups were similar. The proportion of patients who achieved dose level 4 was comparable in the peg-GCSF group (5 of 44 [11%]) and daily GCSF (6 of 29 [21%]; P = .24). The rate of unplanned hospitalizations, and event-free and overall survival, were also similar between groups. CONCLUSION: We suggest routine use of peg-GCSF is an acceptable alternative to daily GCSF, for patients in whom da-EPOCH-R is selected as first line treatment for aggressive B-NHL. PMID- 28870644 TI - How unpredictable access to food increases the body fat of small passerines: A mechanistic approach. AB - Unpredictable rewards increase the vigor of responses in autoshaping (a Pavlovian conditioning procedure) and are preferred to predictable rewards in free-choice tasks involving fixed- versus variable-delay schedules. The significance those behavioral properties may have in field conditions is currently unknown. However, it is noticeable that when exposed to unpredictable food, small passerines - such as robins, titmice, and starlings - get fatter than when food is abundant. In functional terms, fattening is viewed as an evolutionary strategy acting against the risk of starvation when food is in short supply. But this functional view does not explain the causal mechanisms by which small passerines come to be fatter under food uncertainty. Here, it is suggested that one of these causal mechanisms is that involved in behavioral invigoration and preference for food uncertainty in the laboratory. Based on a psychological theory of motivational changes under food uncertainty, we developed an integrative computational model to test this idea. We show that, for functional (adaptive) reasons, the excitatory property of reward unpredictability can underlie the propensity of wild birds to forage longer and/or more intensively in an unpredictable environment, with the consequence that they can put on more fat reserves. PMID- 28870645 TI - Role of stressful life events and kindling in bipolar disorder: Converging evidence from a mania-predominant illness course. AB - Stressful life events can precipitate relapses and recurrences in bipolar disorder. Kindling in bipolar disorder has been linked to maladaptive psychological reactivity to minor stressful life events. Systematic studies on life events and kindling are rare in bipolar disorder with a manic predominant polarity. One hundred and forty-nine remitted patients with bipolar I disorder were recruited. The National Institute of Mental Health-Life Chart Methodology was used to depict the illness course retrospectively, and the Presumptive Stressful Life Events Scale-Lifetime version was used to record the stressful life events. The role of stressful life events and the probability of kindling were assessed using appropriate statistics. There was a mania-predominant course of bipolar disorder in the sample with 55.7% (n = 83) having only recurrent mania. Family conflict and altered sleep patterns were the commonly reported stressful life events. When controlled for the severity of the stressor, the stressful life events were often associated with the initial episodes rather than the latter ones. Kindling may occur in bipolar disorder with mania as the predominant polarity. However, retrospective recall bias and hospital-based sampling limit generalizability of such observations. PMID- 28870646 TI - Psychopathological dimensions and the clinician's subjective experience. AB - Classical psychopathology highly valued the interaction between clinician and patient, and recent findings have provided preliminary evidence of an association between categorical psychiatric diagnosis and the clinician's subjective experience during the first clinical assessment. To extend these findings, the present study examined the relationship between psychopathological dimensions and clinicians' subjective experiences. The study involved 45 clinicians and 783 patients in several psychiatric inpatient and outpatient units. When they saw a new patient, the clinicians completed the Assessment of Clinician's Subjective Experience questionnaire (ACSE) and the 24-item Brief Psychiatric Rating Scale (BPRS). Scores on five core psychopathological dimensions supported by meta analytic evidence (Affect, Positive Symptoms, Negative Symptoms, Activation, Disorganization) were derived from the BPRS. Multivariate analysis revealed that each psychopathological dimension was characterized by a distinct pattern of independent associations with certain aspects of Clinician's Subjective Experience, as measured by the ACSE. This study provided preliminary evidence of significant and theoretically consistent relationships between major psychopathological dimensions and the psychiatrist's subjective experience during the first clinical evaluation. Improving the understanding of intersubjective processes may have important implications for theory, practice, research, and training. PMID- 28870647 TI - Comparison between autogenous iliac bone and freeze-dried bone allograft for repair of alveolar clefts in the presence of plasma rich in growth factors: A randomized clinical trial. AB - PURPOSE: This study aimed to compare the effectiveness of alveolar cleft repair using iliac bone and freeze-dried bone allograft (FDBA) in the presence of plasma rich in growth factors (PRGF). MATERIALS AND METHODS: Patients with unilateral alveolar cleft (n = 32) were randomly allocated to either the iliac plus PRGF group or the FDBA plus PRGF group. CBCT images were obtained before and 6 months after the surgery to assess the regenerated bone volume. Paired t-tests and two way analysis of variance (ANOVA) were applied to analyze the data using SPSS 16.0 software. RESULTS: The patients' mean age was 15 +/- 5.7 years (range = 8-27). In the iliac plus PRGF group, the mean volume of cleft before the surgery and the mean regenerated bone volume 6 months after were 1.67 +/- 0.66 and 1.14 +/- 0.47 cm3, respectively. The corresponding values were 1.5 +/- 0.54 and 0.72 +/- 0.23 cm3 in the FDBA plus PRGF group. The remaining bone to cleft volume ratio was not associated with grafting time (secondary or tertiary) and the original cleft volume. Iliac bone reinforced with PRGF was more successful than FDBA plus PRGF in repairing alveolar cleft (p = 0.007). CONCLUSION: Due to the poor performance of the allograft, autografts should still be preferred in spite of possible donor site morbidity. PMID- 28870648 TI - Can electromagnetic-navigated maxillary positioning replace occlusional splints in orthognathic surgery? A clinical pilot study. AB - INTRODUCTION: Because of the inaccuracy of intermaxillary splints in orthognathic surgery, intraoperative guidance via a real time navigation system might represent a suitable method for enhancing the precision of maxillary positioning. Therefore, in this clinical trial, maxillary repositioning after Le Fort I osteotomy was guided splintless by an electromagnetic navigation system. MATERIALS AND METHODS: Conservatively planned maxillary reposition in each of 5 patients was transferred to a novel software module of the electromagnetic navigation system. Intraoperatively, after Le Fort I osteotomy, the software guided the maxilla to the targeted position. Accuracy was evaluated by pre- and postoperative cone beam computer tomography imaging (the vectorial distance of the incisal marker points was measured in three dimensions) and compared with that of a splint transposed control group. RESULTS: The repositioning of the maxilla guided by the electromagnetic navigation system was intuitive and simple to accomplish. The achieved maxillary position with a deviation of 0.7 mm on average to the planned position was equally accurate compared with that of the splint transposed control group of 0.5 mm (p > 0.05). DISCUSSION: The data of this clinical study display good accuracy for splintless electromagnetic navigated maxillary positioning. Nevertheless, this method does not surpass the splint-encoded gold standard with regard to accuracy. Future investigations will be necessary to show the full potential of electromagnetic navigation in orthognathic surgery. PMID- 28870650 TI - Adolescent Self-Screening for Mental Health Problems; Demonstration of an Internet-Based Approach. AB - OBJECTIVE: To examine the prevalence of positive screening scores, construct validity, and opportunities for follow-up in a large sample of adolescents who chose to fill out the Pediatric Symptom Checklist-Youth Form (PSC-Y) through the Mental Health America (MHA) Web site. METHODS: MHA sent researchers a deidentified data set of all PSC-Y data submitted to MHA from May 15, 2015 to May 14, 2016. The analytic data set contained 29,886 PSC-Y forms from youth aged 11 to 17 years who sought out the Web site and chose to fill out the PSC-Y anonymously and independently online. The prevalence of impairment on the PSC-Y was calculated overall and for various subgroups. Next steps reported by at-risk youth were also examined. RESULTS: Of all respondents, 77.4% of youth screened positive on the PSC-Y. Significant associations between positive screening and self-ratings of a need for help, previous history of mental health treatment, and low family income provided construct validation for the online PSC-Y. Almost two thirds of positively screened youth stated that they planned to get some kind of help in the future and 10% indicated that they planned to seek professional treatment. CONCLUSIONS: The large number of respondents suggested that many adolescents use the Internet to learn about mental health and that a very high percentage of them might be at risk. The availability of brief, free Internet based psychosocial screens might offer a viable way to identify at-risk youth and provide them with pathways to additional support and/or treatment. PMID- 28870649 TI - Lipopolysaccharide impairs permeability of pulmonary microvascular endothelial cells via Connexin40. AB - The endotoxin lipopolysaccharide (LPS)-induced pulmonary endothelial barrier disruption is a key pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the molecular mechanisms underlying LPS impaired permeability of pulmonary microvascular endothelial cells (PMVECs) are not fully understood. Gap junctions, particularly Connexin40 (Cx40), are necessary for the maintenance of normal vascular function. In this study, we for the first time investigated the role of Cx40 in LPS-impaired permeability of PMVECs and provided potential therapeutic approaches based on mechanistic findings of Cx40 regulation by LPS stimuli. Rat PMVECs were isolated, cultured and identified with cell morphology, specific markers, ultrastructural characteristics and functional tests. Western blot analysis demonstrated that Cx40 is the major connexin highly expressed in PMVECs. Furthermore, by inhibiting Cx40 in a time-dependent manner, LPS impaired gap junction function and induced permeability injury of PMVECs. The key role of Cx40 decline in mediating detrimental effects of LPS was further confirmed in rescue experiments through Cx40 overexpression. Mechanistically, LPS stress on PMVECs inhibited the protein kinase C (PKC) pathway, which may synergize with the inflammatory nuclear factor kappaB (NFkappaB) signaling activation in suppressing Cx40 expression level and phosphorylation. Moreover, through pharmacological PKC activation or NFkappaB inhibition, Cx40 activity in PMVECs could be restored, leading to maintained barrier function under LPS stress. Our findings uncover a previously unrecognized role of Cx40 and its regulatory mechanisms in impaired endothelial integrity under endotoxin and inflammation, shedding light on intervention approaches to improve pulmonary endothelial barrier function in ALI and ARDS. PMID- 28870651 TI - Bullying and Children's Academic Performance. PMID- 28870652 TI - Adolescent Health Risk Behaviors: Parental Concern and Concordance Between Parent and Adolescent Reports. AB - OBJECTIVE: We investigated which adolescent health risk behaviors are of concern to parents generally, according to adolescent age, gender, and in the context of perceived risk. We compared adolescent and parent reports of the presence of health-risk behaviors and factors predicting agreement. METHODS: Three hundred adolescents aged 13 to 18 years (mean, 14.5 years; 52% female) who presenting for well care completed an electronic screening tool used to assess health-risk behaviors. Parents completed parallel measures of their child's behavior and parental concern. Adolescent and parent reports were compared using McNemar test. Hierarchical linear regression was used to examine predictors of agreement. RESULTS: High parental concern was most commonly reported for screen time and diet. When parents identified their adolescent as at-risk, high parental concern was near universal for mental health but less commonly reported for substance use. There were no differences in parental concern according to adolescent gender. Parents of older adolescents expressed more concern regarding physical activity and alcohol. Compared with adolescents, parents were more likely to report risk regarding anxiety, fruit and vegetable consumption, and physical activity, and less likely to report risk regarding screen time, sleep, and marijuana use. Younger adolescent age and higher family relationship quality were predictive of stronger parent-adolescent agreement. CONCLUSIONS: Parents in well care visits commonly have concerns about adolescent lifestyle behaviors. Although parents are more likely to report concern when they know about a behavior, parental concern is not always aligned with parental awareness of risk, particularly for substance use. Parent report of higher prevalence of some risk behaviors suggests their input might assist in risk identification. PMID- 28870653 TI - The New RNA World: Growing Evidence for Long Noncoding RNA Functionality. AB - The past decade has seen a major increase in the study of noncoding RNAs (ncRNAs). However, there remains a great deal of confusion and debate over the levels of functionality and mechanisms of action of the majority of these new transcripts. This Opinion article addresses several of these issues, focusing particularly on long ncRNAs (lncRNAs). We reemphasize the unique abilities of RNAs to form myriad structures as well as to interact with other RNAs, DNA, and proteins, which provide them with unique and powerful abilities. One of these, the ability to interact sequence specifically with DNA, has been largely overlooked. Accumulating evidence suggests that evolution has taken advantage of RNA's properties via the rapid acquisition of new noncoding genes in testes, with subsequent gains of function in other tissues. This amplification process appears to be one of the major forces driving metazoan evolution and diversity. PMID- 28870654 TI - Molecular Dependency Impacts on the Compensating Ability of Paralogs: A Response to Veitia. PMID- 28870655 TI - Comparative health effects in mice of Libby amphibole asbestos and a fibrous amphibole from Arizona. AB - This project developed from studies demonstrating that Libby Amphibole Asbestos (LAA) causes a non-typical set of health outcomes not generally reported for asbestos, including systemic autoimmunity and an unusual and devastating lamellar pleural thickening that progresses to severe pulmonary dysfunction and death. Further, mineral fiber mixtures with some similarities to LAA have recently been discovered in southern Nevada and northwestern Arizona, where the material exists in extensive recreational areas and is present in yards, roads, parking lots and school yards. The objective was to compare the health outcomes in mice exposed to either LAA or the fibrous amphiboles collected in Arizona at the Lake Mead National Recreational Area at very low doses to represent environmental exposures. In this study, the fibrous amphibole asbestos sample from Arizona (AzA) is composed of winchite (69%), actinolite (22%), and non-amphibole minerals (9%) and has a mean aspect ratio of 16.7+/-0.9. Fibrous amphibole asbestos from Libby (LAA) is composed of winchite (70%), richterite (9%), tremolite (5%), and non-amphibole minerals (16%) with a mean aspect ratio of 8.4+/-0.7. C57BL/6 mice were exposed by oropharyngeal aspiration to fiber suspensions at a very low dose of 3MUg/mouse. After seven months, both LAA- and AzA-exposed mice had indices of chronic immune dysfunction related to a TH17 cytokine profile, with B cell activation, autoantibody production and proteinuria, suggesting kidney involvement. In addition, both exposures led to significant lung and pleural fibrosis. These data suggest that there is risk of pulmonary disease and autoimmune outcomes with environmental exposure to amphibole asbestos, and that this is not limited to Libby, Montana. PMID- 28870656 TI - A two-step model of TiO2 nanoparticle toxicity in human liver tissue. AB - We examine the toxicity of titanium dioxide (TiO2) nanoparticles on human liver through a two-step approach, including a physiologically-based pharmacokinetic (PBPK) model and a cell-response model. The PBPK model predicts the bio distribution of nanoparticles that remain in the human body after exposure, with special attention to their accumulation in liver tissue. The cell-response model predicts liver cell death as a consequence of the accumulated TiO2 nanoparticles by considering cell fate dynamics through the interplay between cellular uptake of the nanoparticles and their dilution due to cell division. The results suggest that tissue damage from a low nanoparticle dose is negligible due to renewal cell division, but for higher doses larger fractions of cells must participate in the cell cycle to recover the original tissue mass. By combining the two models, it becomes possible to explain the liver cell viability and cell death after TiO2 nanoparticle exposure. PMID- 28870658 TI - Cholelithiasis in a Patient With History of Cholecystectomy. PMID- 28870659 TI - Endoscopic Resolution of Black Esophagus With Treatment of Diabetic Ketoacidosis. PMID- 28870657 TI - Use of Biologic Therapy by Pregnant Women With Inflammatory Bowel Disease Does Not Affect Infant Response to Vaccines. AB - BACKGROUND & AIMS: In women with inflammatory bowel diseases (IBDs), exposure to immunomodulator or biologic therapy has not been associated with adverse events during pregnancy or outcomes of newborns. We investigated whether exposure of patients to these agents during pregnancy affects serologic responses to vaccines in newborns. METHODS: We collected data from the Pregnancy in IBD and Neonatal Outcomes registry, which records outcomes of pregnant women with diagnosis of IBD receiving care at multiple centers in the United States, from 2007 through 2016. Serum samples collected from infants at least 7 months old were analyzed for titers of antibodies to Haemophilus influenzae B (HiB) or tetanus toxin; mothers completed a survey of vaccine practices and outcomes from July 2013 through October 2016. Umbilical cord blood samples from 33 infants were assayed for concentration of biologic agents. Vaccination response was compared between infants born to mothers exposed to biologic therapy (infliximab, adalimumab, certolizumab pegol, golimumab, natalizumab, vedolizumab, or ustekinumab-either as a single agent or in combination with an immunomodulator, at any time between conception and delivery) and infants born to unexposed mothers. RESULTS: A total of 179 women completed the vaccine survey (26 biologic unexposed, 153 exposed to a biologic agent). We found no significant difference in proportions of infants with protective antibody titers against HiB born to exposed mothers (n = 42, 71%) vs unexposed mothers (n = 8, 50%) (P = .41). We also found no difference in the proportion of infants with protective antibody titers to tetanus toxoid born to exposed mothers (80%) vs unexposed mothers (75%) (P = .66). The median concentration of infliximab in cord blood did not differ significantly between infants with vs without protective antibody titers to HiB (P = .30) or tetanus toxoid (P = .93). Mild reactions were observed in 7/40 infants who received rotavirus vaccine and whose mothers had been exposed to biologic therapies. CONCLUSIONS: Vaccination of infants against HiB and tetanus toxin, based on antibody titers measured when infants were at least 7 months old, does not appear to be affected by in utero exposure to biologic therapy. PMID- 28870660 TI - Role of Age and Race in the Risk of Hepatocellular Carcinoma in Veterans With Hepatitis B Virus Infection. AB - BACKGROUND & AIMS: Hepatocellular (HCC) surveillance guidelines for patients with chronic hepatitis B virus (HBV) infection are based on race- and age-specific estimates of HCC risk, derived from studies conducted in areas in which HBV is endemic. METHODS: We conducted a retrospective cohort study using the national Veterans Administration data to identify patients with chronic HBV infection from 2001 through 2013. We examined the effect of race and age on HCC risk while adjusting for baseline clinical characteristics. RESULTS: The study cohort had 8329 patients; 3498 patients (42.0%) were white, 3248 (39%) were African Americans, and 659 (7.9%) were Asian Pacific Islanders. The annual HCC incidence was highest in Asian Pacific Islanders (0.65%), followed by whites (0.57%) and African Americans (0.40%). After adjusting for clinical and viral factors, the risk of HCC was significantly higher in Asian Pacific Islanders compared with whites (adjusted hazard ratio [HR] = 2.04; 95% CI, 1.31-3.17). There was no difference in HCC risk between African Americans and whites (adjusted HR, 0.77; 95% CI, 0.58-1.02). HCC risk increased with age: adjusted HR was 1.97 (95% CI, 0.99-3.87) for 40-49 years; adjusted HR was 3.00 (95% CI, 1.55-5.81) for 50-59 years; and adjusted HR was 4.02 (95% CI, 2.03-7.94) for more than 60 years vs less than 40 years. Patients with cirrhosis had higher risk of HCC than patients without cirrhosis (adjusted HR = 3.69; 95% CI, 2.82-4.83). However, even among patients without cirrhosis, the annual incidence of HCC was more than 0.2% for all patients older than 40 years with high levels of alanine aminotransferase regardless of race. CONCLUSIONS: In a sample of male veterans with chronic HBV infection, risk of HCC is highest among Asian Pacific Islanders, followed by whites and African Americans. Cirrhosis increased HCC risk. Among patients without cirrhosis, male patients who are older than 40 years and have increased levels of alanine aminotransferase might benefit from HCC surveillance, regardless of race. PMID- 28870661 TI - Risk of Colorectal Carcinoma in Siblings of Probands With Common Colorectal Carcinoma. PMID- 28870662 TI - Splenic Abscesses Caused by Salmonella D9. PMID- 28870663 TI - Videocapsule Endoscopy Identifies Small Bowel Lesions in Patients With Eosinophilic Enteritis. PMID- 28870664 TI - Gastric Mucosal Staining After Ethylene Vinyl Alcohol Embolization. PMID- 28870666 TI - Tenofovir alafenamide as a rescue therapy in a patient with HBV-cirrhosis with a history of Fanconi syndrome and multidrug resistance. AB - Tenofovir disoproxil fumarate (TDF) is a recommended first-line therapy for both naive and experienced patients with chronic hepatitis B (CHB), although reduced estimated glomerular filtration rate (eGFR), hypophosphatemia, hyperphosphaturia and Fanconi syndrome have been reported in some patients. Entecavir (ETV) could be considered as a rescue therapy for TDF-treated patients developing renal dysfunction, though patients with prior history of treatment with lamivudine (LAM) can develop ETV resistance strains, which can lead to potentially severe hepatitis flares. Tenofovir alafenamide (TAF), a new prodrug of tenofovir, has recently been developed to improve the renal and bone safety profile compared to TDF, while maintaining the same virologic efficacy. The recently published 48 week phase III TAF registration studies confirmed the superior safety profile. Here we describe a case of a 75-year-old woman with HBV mono-infection and compensated cirrhosis who developed ETV resistant strains and grade 3 chronic kidney disease after many years of LAM and adefovir (ADV) treatment and a TDF induced Fanconi syndrome. The administration of 25mg/day of TAF, granted as part of a compassionate use program, rapidly suppressed viral replication to undetectable levels without worsening renal function or side effects. PMID- 28870665 TI - Association of Paid Sick Leave Laws With Foodborne Illness Rates. AB - INTRODUCTION: Previous studies suggest an association between paid sick leave (PSL) and better population health, including fewer infectious and nosocomial gastrointestinal disease outbreaks. Yet few studies examine whether laws requiring employers to offer PSL demonstrate a similar association. This mixed methods study examined whether laws requiring employers to provide PSL are associated with decreased foodborne illness rates, particularly laws that are more supportive of employees taking leave. METHODS: The four earliest PSL laws were classified by whether they were more or less supportive of employees taking leave. Jurisdictions with PSL were matched to comparison jurisdictions by population size and density. Using difference-in-differences, monthly foodborne illness rates (2000-2014) in implementation and comparison jurisdictions before and after the laws were effective were compared, stratifying by how supportive the laws were of employees taking leave, and then by disease. The empirical analysis was conducted from 2015-2017. RESULTS: Foodborne illness rates declined after implementation of the PSL law in jurisdictions with laws more supportive of employees taking leave, but increased in jurisdictions with laws that are less supportive. In adjusted analyses, PSL laws that were more supportive of employees taking sick leave were associated with an adjusted 22% decrease in foodborne illness rates (p=0.005). These results are driven by campylobacteriosis. CONCLUSIONS: Although the results suggest an association between more supportive PSL laws and decreased foodborne illness rates, they should be interpreted cautiously because the trend is driven by campylobacteriosis, which has low person-to-person transmission. PMID- 28870667 TI - Reply to: "Is osteopontin a promising prognostic biomarker for cholangiocarcinoma?" PMID- 28870668 TI - Diagnostic and prognostic role of circulating microparticles in hepatocellular carcinoma. PMID- 28870669 TI - Reply to: "Risk factors of hepatocellular carcinoma after hepatitis B surface antigen seroclearance". PMID- 28870670 TI - IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF kappaB activation in hepatic macrophages. AB - BACKGROUND & AIM: Alcohol consumption increases intestinal permeability and causes damage to hepatocytes, leading to the release of pathogen- and damage associated molecular pattern molecules (PAMPs and DAMPs), stimulating hepatic macrophages and activating NF-kappaB. The resultant inflammation exacerbates alcoholic liver disease (ALD). However, much less is known about the mechanisms attenuating inflammation and preventing disease progression in most heavy drinkers. Interleukin (IL)-33 is a DAMP (alarmin) released from dead cells that acts through its receptor, IL-1 receptor like 1 (ST2). ST2 signaling has been reported to either stimulate or inhibit NF-kappaB activation. The role of IL 33/ST2 in ALD has not been studied. METHODS: Serum levels of IL-33 and its decoy receptor, soluble ST2 (sST2) were measured in ALD patients. Alcohol-induced liver injury, inflammation and hepatic macrophage activation were compared between wild type, IL-33-/- and ST2-/- mice in several models. RESULTS: Elevation of serum IL 33 and sST2 were only observed in patients with severe decompensated ALD. Consistently, in mice with mild ALD without significant cell death and IL-33 release, IL-33 deletion did not affect alcohol-induced liver damage. However, ST2 deletion exacerbated ALD, through enhancing NF-kappaB activation in liver macrophages. In contrast, when extracellular IL-33 was markedly elevated, liver injury and inflammation were attenuated in both IL-33-/- and ST2-/- mice compared to wild-type mice. CONCLUSION: Our data revealed a dichotomous role of IL-33/ST2 signaling during ALD development. At early and mild stages, ST2 restrains the inflammatory activation of hepatic macrophages, through inhibiting NF-kappaB, and plays a protective function in an IL-33-independent fashion. During severe liver injury, significant cell death and marked IL-33 release occur, which triggers IL 33/ST2 signaling and exacerbates tissue damage. LAY SUMMARY: In mild ALD, ST2 negatively regulates the inflammatory activation of hepatic macrophages, thereby protecting against alcohol-induced liver damage, whereas in the case of severe liver injury, the release of extracellular IL-33 may exacerbate tissue inflammation by triggering the canonical IL-33/ST2L signaling in hepatic macrophages. PMID- 28870672 TI - Risk factors of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. PMID- 28870671 TI - Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients. AB - BACKGROUND & AIMS: In diagnostics, serum hepatitis B virus (HBV)-RNA levels are valuable when the HBV-DNA load in circulation is effectively suppressed by nucleos(t)ide analogue (NUC) therapy. This study aimed to determine the intrahepatic viral replication activity reflected in serum HBV-RNA and whether HBV-RNA contributes to liver histological changes in patients treated with NUC. METHODS: A cross-sectional set of serum and liver biopsy samples was obtained from patients treated with entecavir, who had undetectable levels of serum HBV DNA. The correlations between serum HBV-RNA concentration and levels of peripheral and intrahepatic viral replicative forms, as well as histological scores, were analyzed. Quasispecies of serum HBV-RNA and intrahepatic viral replicative forms were examined by deep sequencing. HBV-RNA-positive hepatocytes were visualized by in situ hybridization. RESULTS: Serum HBV-RNA was detected in 35 of 47 patients (74.47%, 2.33-4.80log10copies/ml). These levels correlated not only with the intrahepatic HBV-RNA level and the ratio of intrahepatic HBV-RNA to covalently closed circular DNA (cccDNA), but also with the histological scores for grading and staging. Regarding quasispecies, serum HBV-RNA was dynamic and more genetically homogenous to simultaneously sampled intrahepatic HBV-RNA than to the cccDNA pool. In situ histology revealed that HBV-RNA-positive hepatocytes were clustered in foci, sporadically distributed across the lobules, and co localized with hepatitis B surface antigen. CONCLUSION: Serum HBV-RNA levels reflect intrahepatic viral transcriptional activity and are associated with liver histopathology in patients receiving NUC therapy. Our study sheds light on the nature of HBV-RNA in the pathogenesis of chronic HBV infection and has implications for the management of chronic hepatitis B during NUC therapy. LAY SUMMARY: Serum HBV-RNA levels are indicative of the intrahepatic transcriptional activity of covalently closed circular DNA and are associated with liver histological changes in patients with chronic B hepatitis who are receiving nucleos(t)ide analogue therapy. PMID- 28870673 TI - A fatty liver leads to decreased kidney function? PMID- 28870675 TI - Direct-acting antiviral therapy in patients with hepatocellular cancer: The timing of treatment is everything. PMID- 28870674 TI - Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: A cohort study. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has been associated with chronic kidney disease (CKD), but cohort studies are limited. We investigated the longitudinal association of NAFLD and its severity with the development of CKD. METHODS: We performed a retrospective cohort study of 41,430 adult men and women (average age, 48.9y) without CKD at baseline who underwent repeated health check-up examinations from January 1, 2003, through December 31, 2013. NAFLD status was assessed by ultrasonography, and NAFLD severity was assessed by the NAFLD fibrosis score (NFS). RESULTS: The outcome was an incident CKD, defined as an estimated glomerular filtration rate less than 60ml/min/1.73m2. During 200,790 person-years of follow-up (median follow-up of 4.15years), we identified 691 incident CKD cases. The multivariable-adjusted hazard ratio for CKD comparing participants with and without NAFLD was 1.22 (95% confidence interval [CI] 1.04-1.43). The risk of CKD increased progressively with increased NAFLD severity. The multivariable-adjusted hazard ratios for CKD comparing participants with NFS <-1.455 and those with NFS >=-1.455 to participants without NAFLD were 1.09 (95% CI 0.91-1.32) and 1.58 (95% CI 1.30 1.92), respectively. The association was consistent across clinically relevant subgroups. CONCLUSION: In a large cohort of adult men and women without CKD, NAFLD was associated with an increased risk of CKD development. NAFLD may adversely affect renal function and patients may need to be carefully monitored for an increased risk of CKD. LAY SUMMARY: The presence of fatty liver is associated with the future decline of renal function. Thus, fatty liver patients need to be monitored regularly for renal function. PMID- 28870676 TI - Hypothermic oxygenated perfusion (HOPE) for fatty liver grafts in rats and humans. AB - BACKGROUND & AIMS: Pretreatment of marginal organs by perfusion is a promising opportunity to make more organs available for transplantation. Protection of human donation after cardiac death (DCD) livers by a novel machine perfusion technique, hypothermic oxygenated perfusion (HOPE), was recently established. Herein, we tested whether HOPE is also useful for fatty liver grafts, using a rodent transplant model. METHODS: Rats were fed over three weeks with a special methionine-choline-deficient diet (MCDD) to induce severe hepatic macrosteatosis (>=60%). Afterwards, livers were transplanted with either minimal or 12h cold storage. Additional liver grafts were treated after 12h cold storage with 1h HOPE before transplantation. Graft injury after orthotopic liver transplantation (OLT) was assessed in terms of oxidative stress, damage-associated molecular patterns release, toll-like receptor-4 activation, cytokine release, endothelial activation, and the development of necrosis and fibrosis. RESULTS: Implantation of cold stored macrosteatotic liver grafts induced massive reperfusion injury after OLT, compared to controls (non-fatty livers). HOPE treatment after cold storage failed to change the degree of steatosis itself, but markedly decreased reperfusion injury after OLT, as detected by less oxidative stress, less nuclear injury, less Kupffer- and endothelial cell activation, as well as less fibrosis within one week after OLT. Protective effects were lost in the absence of oxygen in the HOPE perfusate. CONCLUSION: HOPE after cold storage of fatty livers prevents significant reperfusion injury and improves graft function, comparable to the effects of HOPE in DCD livers and DCD kidneys. HOPE treatment is easy and may become a universal concept to further expand the donor pool. LAY SUMMARY: An increasing number of donor livers contain fat. It is important to harness marginal livers, which may contain fat, as the stock of donor livers is limited. Hypothermic oxygenated perfusion (HOPE) prevents reperfusion injury and improves liver graft function. HOPE offers a simple and low-cost option for treating liver grafts in transplant centers, even after cold storage, instead of transporting machines to the place of procurement. HOPE could be used globally to expand the donor pool. PMID- 28870677 TI - Is osteopontin a promising prognostic biomarker for cholangiocarcinoma? PMID- 28870678 TI - Reply to: "Diagnostic and prognostic role of circulating microparticles in hepatocellular carcinoma". PMID- 28870679 TI - ACC/AATS/AHA/ASE/ASNC/HRS/SCAI/SCCT/SCMR/STS 2017 Appropriate Use Criteria for Multimodality Imaging in Valvular Heart Disease: A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. PMID- 28870680 TI - Correlation of MYC Gene and Protein Status With Breast Cancer Subtypes and Outcome of Patients Treated With Anthracycline-Based Adjuvant Chemotherapy. Pooled Analysis of 2 Hellenic Cooperative Group Phase III Trials. AB - BACKGROUND: The prognostic/predictive value of aberrant MYC gene copies and protein expression is not clear in breast cancer. PATIENTS AND METHODS: Early breast cancer patients were treated with anthracycline-containing chemotherapy within 2 randomized adjuvant trials. MYC gene and centromere-8 status, as well as Myc protein expression were investigated on 1060 paraffin tumors with fluorescence in situ hybridization and immunohistochemistry, respectively. RESULTS: MYC amplification was present in 45% and polysomy-8 in 23% of the tumors. Cytoplasmic staining was observed in 60% and nuclear staining in 26% of the tumors, strongly correlating with each other but not with MYC gene status. MYC gene amplification in the absence of polysomy-8 was associated with adverse disease-free survival (DFS) and overall survival (OS), and remained as an independent unfavorable prognostic factor in multivariate analysis (Wald P = .022 for DFS; P = .032 for OS), whereas patients with MYC amplification and polysomy 8, with polysomy-8 only, and with normal MYC without polysomy-8 performed significantly better compared with those with MYC gene amplification only. Nuclear Myc protein expression benefitted patients treated with paclitaxel (interaction P = .052 for DFS; P = .049 for OS). This interaction remained independently significant in multivariate analysis for OS (overall P = .028). CONCLUSION: The effect of MYC gene status on breast cancer patient outcome seems to depend on the underlying chromosomal instability and appears unfavorable for tumors with MYC amplification without polysomy. Nuclear Myc protein expression seems predictive for benefit from adjuvant paclitaxel. These data might aid in the interpretation of relevant findings from large clinical trials. PMID- 28870681 TI - The association of venous thromboembolism chemoprophylaxis timing on venous thromboembolism after major vascular surgery. AB - OBJECTIVE: Venous thromboembolism (VTE) is reported to occur in up to 33% of patients undergoing major vascular surgery. Despite this high incidence, patients inconsistently receive timely VTE chemoprophylaxis. The true incidence of VTE among patients receiving delayed VTE chemoprophylaxis is unknown. We sought to identify the association of VTE chemoprophylaxis timing on VTE risk, postoperative transfusion rates, and 30-day mortality and morbidity in patients undergoing major open vascular surgery. METHODS: Patients undergoing major open vascular surgery (open abdominal aortic aneurysm [oAAA] repair, aortofemoral bypass, and lower extremity infrainguinal bypass [LEB]) were identified using the Michigan Surgical Quality Collaborative (MSQC) between July 2012 and June 2015. The VTE rate was compared between patients receiving early versus delayed VTE chemoprophylaxis. VTE chemoprophylaxis delay was defined as therapy initiation more than 24 hours after surgery. The risk-adjusted association of the chemoprophylaxis timing and VTE development was determined using multivariable logistic regression. Blood transfusion rates, 30-day mortality, and postoperative complications were compared across groups. RESULTS: A total of 2421 patients underwent major open vascular surgery, including 196 oAAA repair, 259 aortofemoral bypass, and 1966 LEB. The overall incidence of 30-day VTE was 1.40%, ranging from 1.12% for LEB to 3.57% for oAAA repair. Among patients receiving early VTE chemoprophylaxis, the rate of VTE was 0.78% versus 2.26% among those with a delay in VTE chemoprophylaxis (P = .002). When accounting for the preoperative risk of VTE, delayed chemoprophylaxis was associated with a significantly higher risk of VTE (odds ratio, 2.38; 95% confidence interval, 1.12 5.06; P = .024). The early VTE chemoprophylaxis group was associated with a significantly decreased risk of bleeding compared with those with a delay (14.31% vs 18.90%; P = .002). Overall 30-day mortality and postoperative complications were similar with the exception of an associated higher rate of infectious complications in the delayed VTE chemoprophylaxis group, including superficial surgical site infection (6.00% vs 4.06%; P = .028), pneumonia (3.25% vs 1.85%; P = .028), urinary tract infection (2.95% vs 1.57%; P = .020), and severe sepsis (3.05% vs 1.71%; P = .029). CONCLUSIONS: Although patients undergoing major open vascular surgery have a low risk of VTE at baseline, there is a significantly greater risk of developing VTE among patients who have a delay in the administration of VTE chemoprophylaxis. Postoperative transfusion rates were significantly lower among patients receiving early chemoprophylaxis. There were no differences in the 30-day mortality and postoperative complications, except for infectious complications. Given these findings, surgeons should consider early chemoprophylaxis in the postoperative setting after major open vascular surgery without contraindication. PMID- 28870683 TI - Permethrin potentiates adipogenesis via intracellular calcium and endoplasmic reticulum stress-mediated mechanisms in 3T3-L1 adipocytes. AB - Permethrin, a pyrethroid insecticide, was previously reported to promote adipogenesis in vitro and weight gain in vivo. The mechanism by which permethrin promotes adipogenesis/obesity, however, has not been fully explored. Intracellular calcium and endoplasmic reticulum (ER) stress have been reported to be linked with adipogenesis and obesity. Because pyrethroid insecticides have been determined to influence intracellular calcium and ER stress in vitro, the purpose of this current study was to investigate whether permethrin potentiates adipogenesis via a change in intracellular calcium, leading to endoplasmic reticulum (ER) stress in 3T3-L1 adipocytes. 3T3-L1 cells were exposed to four different concentrations of permethrin (0.01, 0.1, 1 & 10 MUM) for 6 days during differentiation. Treatment of permethrin increased intracellular calcium level in a concentration-dependent manner. Similarly, permethrin treatment increased protein levels of ER stress markers in a concentration-dependent manner. These data suggest that intracellular calcium and ER stress may be involved in permethrin-induced adipogenesis of 3T3-L1 cells. PMID- 28870685 TI - Evaluation of the safety of a genetically modified DAS-444O6-6 soybean meal and hulls in a 90-day dietary toxicity study in rats. AB - A 90-day sub chronic toxicity study was conducted in rats to evaluate the safety of genetically modified DAS-444O6-6 soybeans expressing herbicide tolerant proteins when compared with its conventional comparators (non-transgenic near isoline control soybean and three commercially available non-transgenic line control soybeans). Rats were given diets formulated with either 10% or 20% w/w of soybean meal and 1% or 2% hulls of DAS-444O6-6 soybean with an equivalent amount of hulls from an isoline non-transgenic control soybean for at least 90 days. In addition, three separate 20% w/w non-transgenic commercially available soybean varieties were also given to groups of rats to serve as reference controls. Animals were evaluated by cage-side and hand-held detailed clinical observations, ophthalmic examinations, body weights/body weight gains, feed consumption, hematology, prothrombin time, urinalysis, clinical chemistry, selected organ weights, and gross and histopathologic examinations. Under the conditions of this study, the genetically modified DAS-444O6-6 diets did not cause any treatment related effects in rats following 90 days of dietary administration as compared with rats fed diets with soybean of isoline control or commercial reference controls and are considered equivalent to the diets prepared from conventional comparators. PMID- 28870682 TI - Association of arterial calcification with chronic limb ischemia in patients with peripheral artery disease. AB - OBJECTIVE: Arterial calcification is associated with an increased risk of limb events, including amputation. The association between calcification in lower extremity arteries and the severity of ischemia, however, has not been assessed. We thus sought to determine whether the extent of peripheral artery calcification (PAC) was correlated with Rutherford chronic ischemia categories and hypothesized that it could independently contribute to worsening limb status. METHODS: We retrospectively reviewed all patients presenting with symptomatic peripheral artery disease who underwent evaluation by contrast and noncontrast computed tomography scan of the lower extremities as part of their assessment. Demographic and cardiovascular risk factors were recorded. Rutherford ischemia categories were determined based on history, physical examination, and noninvasive testing. PAC scores and the extent of occlusive disease were measured on noncontrast and contrast computed tomography scans, respectively. Spearman's correlation testing was used to assess the relationship between occlusive disease and calcification scores. Multivariable logistic regression was used to identify factors associated with increasing Rutherford ischemia categories. RESULTS: There were 116 patients identified, including 75 with claudication and 41 with critical limb ischemia. In univariate regression, there was a significant association between increasing Rutherford ischemia category and age, diabetes duration, hypertension, the occlusion score, and PAC. There was a moderate correlation between the extent of occlusive disease and PAC scores (Spearman's R = 0.6). In multivariable analysis, only tobacco use (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.2-8.3), diabetes duration (OR, 1.04; 95% CI, 1.01-1.08), and the calcification score (OR, 2.1; 95% CI, 1.4-3.2) maintained an association with increasing ischemia categories after adjusting for relevant cardiovascular risk factors and the extent of occlusive disease. CONCLUSIONS: PAC is independently associated with increased ischemia categories in patients with peripheral artery disease. Further research aimed at understanding the relationship between arterial calcification and worsening limb ischemia is warranted. PMID- 28870684 TI - Isoliquiritigenin pretreatment attenuates cisplatin induced proximal tubular cells (LLC-PK1) death and enhances the toxicity induced by this drug in bladder cancer T24 cell line. AB - Cisplatin is an effective antineoplastic agent widely used in the treatment of solid tumors, however, it induces nephrotoxicity. Cisplatin-induced nephrotoxicity is associated with increased reactive oxygen species (ROS) production and decreased antioxidant system defense in kidney. Isoliquiritigenin (IsoLQ) is a chalcone, which is characterized by its antioxidant and antiinflammatory properties. Herein, we investigated the protective effect of IsoLQ on LLC-PK1 proximal tubular cells against cisplatin-induced death and its effect on the antineoplastic activity of cisplatin on bladder cancer T24 cell line. It was found that pretreatment with IsoLQ attenuates cisplatin-induced cell death, ROS production, and activation of caspase-3. IsoLQ also induced heme oxygenase-1 (HO-1) expression that may be associated with nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation. The protective effect of IsoLQ was abrogated by tin mesoporphyrin (SnMP), an HO inhibitor. Further, bilirubin and carbon monoxide releasing molecule-2 also showed a protective effect against cisplatin-induced cell death. In addition, IsoLQ induced in a dose dependent way, death of T24 cells and exacerbated cisplatin-induced cell death. These results suggest that IsoLQ has a protective effect on cisplatin-induced toxicity in LLC-PK1 cells, in part through induction of HO-1, without interfering with the antineoplastic activity of this agent in T24 cells. PMID- 28870686 TI - [Risk factors related to homicide in Moroccan patients with schizophrenia]. AB - BACKGROUND: Persons with schizophrenia are thought to be at increased risk of committing violent crime - 4 to 6 times the level of general population individuals without this disorder. The relationship between schizophrenia and homicide is complex and cannot be reduced to a simple causal link. OBJECTIVES: The objectives of this study were to describe the characteristics of homicide in Moroccan patients suffering from schizophrenia and to determine the correlated sociodemographic, clinical and toxic variables. METHODS: The study included two groups of patients with a DSM IV diagnosis of schizophrenia who attended the "Ibn Nafis" university psychiatric hospital of Marrakech in Morocco. The first group was composed of 30 patients hospitalized for homicide in the forensic unit between 1 January 2005 and 31 August 2015. The second group included 90 patients without any criminal record. These two groups have been matched according to age and gender. Demographic, clinical and therapeutic variables were analyzed and compared between the two groups. RESULTS: Data analysis has objectified the following results: the mean of age in the first group was 37.03 (+/-9.09) and in the second group was 31.4 (+/-8.76). No significant differences were found between the two groups regarding the different sociodemographic variables and the age of onset of disease. Significant differences were found between the two groups regarding: personal antecedents of attempt of homicide (P=0.003), personal antecedents of attempt of suicide (P<0.001), a history of previous violence (P=0.005), untreated psychosis before the act (P<0.001), poor medication compliance and a low familial support (P<0.001), antisocial behavior (P<0.001) and addictive behavior (P=0.005). DISCUSSION: Several studies identified some possible predictor factors for violent behavior: poor compliance, lack of insight impulsivity and paranoid-hallucinatory symptoms, systematized delusions and addictive behavior seem to considerably increase the risk of turning to violence. Demographic variables as suggested by other studies are less valuable predictors of homicide in patients with schizophrenia. CONCLUSION: Awareness of these factors will allow us to provide improved prevention of violence within schizophrenic subjects. Interventions for reducing such behavior should focus on clinical variables and integrate an early diagnosis of the disease and an improvement of medication compliance. PMID- 28870687 TI - [ACT in the treatment of sexual addiction: About a clinical case]. AB - While referring to the theoretical and practical model of R. Harris (2012), this article proposes the use of acceptance and commitment therapy (ACT) in the treatment of sexual addiction. While dependent behaviors begin and may be maintained by refusal of unpleasant emotional states (that is, addict individuals tend to fight or flee negative emotions by replacing eventually painful or otherwise unpleasant states by behaviors providing pleasure), the ACT framework appears as an ally in treatment of addictive behaviors, in that its goal is a fit between patients' behaviors and their values (instead avoidance of unpleasant states avoidance). Within a clinical case of a patient suffering from sexual addiction, we show that using ACT helps (i) to decrease the intensity of sexual addiction (as assessed through QMICA-Se in a pre-post design), (ii) to develop psychological flexibility (AAQ-II), and (iii) to decrease anxious and depressive symptoms of the patient (HADS). Moreover, the patient recognizes to feel himself in the here and now, and also to perform activities related to his own values. Acceptance of this limited form of sexuality now allows him to calmly consider the possibility of meeting a new person. ACT thus appears to provide clinical benefits in treatment of sexual addictions. PMID- 28870688 TI - [What do virtual reality tools bring to child and adolescent psychiatry?] AB - Virtual reality is a relatively new technology that enables individuals to immerse themselves in a virtual world. It offers several advantages including a more realistic, lifelike environment that may allow subjects to "forget" they are being assessed, allow a better participation and an increased generalization of learning. Moreover, the virtual reality system can provide multimodal stimuli, such as visual and auditory stimuli, and can also be used to evaluate the patient's multimodal integration and to aid rehabilitation of cognitive abilities. The use of virtual reality to treat various psychiatric disorders in adults (phobic anxiety disorders, post-traumatic stress disorder, eating disorders, addictions...) and its efficacy is supported by numerous studies. Similar research for children and adolescents is lagging behind. This may be particularly beneficial to children who often show great interest and considerable success on computer, console or videogame tasks. This article will expose the main studies that have used virtual reality with children and adolescents suffering from psychiatric disorders. The use of virtual reality to treat anxiety disorders in adults is gaining popularity and its efficacy is supported by various studies. Most of the studies attest to the significant efficacy of the virtual reality exposure therapy (or in virtuo exposure). In children, studies have covered arachnophobia social anxiety and school refusal phobia. Despite the limited number of studies, results are very encouraging for treatment in anxiety disorders. Several studies have reported the clinical use of virtual reality technology for children and adolescents with autistic spectrum disorders (ASD). Extensive research has proven the efficiency of technologies as support tools for therapy. Researches are found to be focused on communication and on learning and social imitation skills. Virtual reality is also well accepted by subjects with ASD. The virtual environment offers the opportunity to administer controlled tasks such as the typical neuropsychological tools, but in an environment much more like a standard classroom. The virtual reality classroom offers several advantages compared to classical tools such as more realistic and lifelike environment but also records various measures in standardized conditions. Most of the studies using a virtual classroom have found that children with Attention Deficit/Hyperactivity Disorder make significantly fewer correct hits and more commission errors compared with controls. The virtual classroom has proven to be a good clinical tool for evaluation of attention in ADHD. For eating disorders, cognitive behavioural therapy (CBT) program enhanced by a body image specific component using virtual reality techniques was shown to be more efficient than cognitive behavioural therapy alone. The body image specific component using virtual reality techniques boots efficiency and accelerates the CBT change process for eating disorders. Virtual reality is a relatively new technology and its application in child and adolescent psychiatry is recent. However, this technique is still in its infancy and much work is needed including controlled trials before it can be introduced in routine clinical use. Virtual reality interventions should also investigate how newly acquired skills are transferred to the real world. At present virtual reality can be considered a useful tool in evaluation and treatment for child and adolescent disorders. PMID- 28870689 TI - Tics and obsessive-compulsive disorder in relation to diet: Two case reports. PMID- 28870690 TI - Psychometric validation of the French version of the Connor-Davidson Resilience Scale. AB - OBJECTIVES: Resilience defines the ability to face adversity with positive outcomes. Different scales, including the 25-item Connor-Davidson Resilience Scale (CDRISC), have been elaborated in order to evaluate resilience among various populations. The evaluation of resilience in French populations was impossible until CDRISC was translated into French. In the present work, we aim to validate a French version of CDRISC (f-CDRISC). METHODS: The survey was conducted at Nantes University. Both dental and medical students were eligible. The factor structure of f-CDRISC was determined and its replicability was tested on two sub-samples by exploratory factor analysis (EFA) and parallel analysis (PA). A third student sample was used for confirmatory factorial analysis (CFA). RESULTS: We collected 1210 responses. Four items did not reach acceptance thresholds for reliability and were discarded from the f-CDRISC. EFA and PA of the remaining 21 items highlighted a replicable 3-factor structure that was further confirmed by CFA. Resilience factors included "tolerance to negative affects", "tenacity" and "self-confidence". All factors displayed acceptable to good internal consistency. They were characterized by positive medium to strong correlations with the overall f-CDRISC Scale. Significant positive correlations were also observed between the resilience factors. CONCLUSION: The present work constitutes the first study devoted to a French adaptation of the CDRISC questionnaire. We present evidence showing that the f-CDRISC is a reliable tool for resilience evaluation in French speaking populations. PMID- 28870691 TI - [Burnout in Tunisian medical residents: About 149 cases]. AB - BACKGROUND: Burnout is a professional psychological chronic stress-induced syndrome defined by three dimensions: emotional exhaustion, depersonalization, and low personal accomplishment. This syndrome concerns all professions but especially healthcare staff. Numerous studies have attempted to document the impact of work activities on the doctor's mental health. According to the literature, junior doctors are more vulnerable to develop this syndrome. AIMS: Are to determine the prevalence of severe burnout among residents of different specialties: anesthesiology, general surgery, emergency medicine, psychiatry, basic sciences. The secondary end points are to analyze risk factors, causes and consequences associated with burnout. METHODS: A cross-sectional study conducted among medical residents working in hospitals located in the governorates of Tunis. Three instruments were used: an anonymous self-administered questionnaire, Maslach Burnout Inventory (MBI) to assess burnout, and Abstract Beck Depression Inventory to evaluate the intensity of depression. Severe burnout was defined as a severely high level of both emotional exhaustion and depersonalization associated with a severely low level of personal accomplishment. RESULTS: A total of 149 participants (response rate=76.8%) participated in the survey. Among participants, 17.14% (n=26) had a severe burnout. The emergency medicine residents had the highest rate of emotional exhaustion and depersonalization and severe depression. Overall, resident respondents, 31% (n=46), had moderate to severe depression. Among stress factors, those significantly correlated to burnout were: lack of hobbies (P<0.001), bad job conditions (P=0.031), poor conditions of the workplace (P=0.046), relationship problems in workplace (P=0.01), work-family conflicts (P<0.001). The consequences of occupational stress associated with burnout were: Antecedents of specialty change (P=0.017) and desire for a specialty change (P<0.001). A significant correlation between depression and severe burnout was not found. CONCLUSION: Medical residents in all specialties are at risk of burnout. Nevertheless, this study revealed that some specialties are more exhausting, which is consistent with the results reported in the literature. Moreover, it is shown that several stress factors as well as many consequences are related to severe burnout, which is in agreement with numerous studies. However, results between different studies are disparate. PMID- 28870692 TI - Distinct Patterns of Acral Melanoma Based on Site and Relative Sun Exposure. AB - Acral melanoma is distinct from melanoma of other cutaneous sites, yet there is considerable variation within this category. To better define this variation, we assessed melanomas occurring on dorsal (n = 21), volar (n = 9), and subungual/interdigital (n = 13) acral skin as well as acral nevi (n = 24) for clinical, histologic, and molecular features. Melanomas on dorsal acral surfaces demonstrated clear differences compared with volar and subungual/interdigital melanomas. The latter two groups exhibited significantly less frequent BRAF mutations (P = 0.01), were significantly less likely to have the superficial spreading histologic subtype (P = 0.01), occurred in older patients (P = 0.05), and had more frequent involvement in non-Caucasians (P = 0.01). These differences can be explained by differing levels of UV exposure. Subungual/interdigital melanomas had the most diverse group of oncogenic mutations including PIK3CA (2/13), STK11 (2/13), EGFR (1/13), FGFR3 (1/13), and PTPN11 (1/13). In addition, subungual/interdigital melanomas had a significantly higher frequency of copy number aberrations (67%) than other subgroups (P = 0.02), particularly in CDK4 and cyclin D1, and were less likely to have BRAF mutations or a superficial spreading histologic subtype (P = 0.05) compared with volar acral melanomas. Although based on a limited sample size, differences between volar and subungual/interdigital melanomas in our study may be the result of differing levels of UV exposure. PMID- 28870694 TI - Embryonic Fate Mapping Uncovers the Critical Role of microRNAs in the Development of Epidermal gammadelta T Cells. PMID- 28870693 TI - Therapeutic Targeting of TAZ and YAP by Dimethyl Fumarate in Systemic Sclerosis Fibrosis. AB - Systemic sclerosis (scleroderma, SSc) is a devastating fibrotic disease with few treatment options. Fumaric acid esters, including dimethyl fumarate (DMF, Tecfidera; Biogen, Cambridge, MA), have shown therapeutic effects in several disease models, prompting us to determine whether DMF is effective as a treatment for SSc dermal fibrosis. We found that DMF blocks the profibrotic effects of transforming growth factor-beta (TGFbeta) in SSc skin fibroblasts. Mechanistically, we found that DMF treatment reduced nuclear localization of transcriptional coactivator with PDZ binding motif (TAZ) and Yes-associated protein (YAP) proteins via inhibition of the phosphatidylinositol 3 kinase/protein kinase B (Akt) pathway. In addition, DMF abrogated TGFbeta/Akt1 mediated inhibitory phosphorylation of glycogen kinase 3beta (GSK3beta) and a subsequent beta-transducin repeat-containing proteins (betaTRCP) mediated proteasomal degradation of TAZ, as well as a corresponding decrease of TAZ/YAP transcriptional targets. Depletion of TAZ/YAP recapitulated the antifibrotic effects of DMF. We also confirmed the increase of TAZ/YAP in skin biopsies from patients with diffuse SSc. We further showed that DMF significantly diminished nuclear TAZ/YAP localization in fibroblasts cultured on a stiff surface. Importantly, DMF prevented bleomycin-induced skin fibrosis in mice. Together, our work demonstrates a mechanism of the antifibrotic effect of DMF via inhibition of Akt1/GSK3beta/TAZ/YAP signaling and confirms a critical role of TAZ/YAP in mediating the profibrotic responses in dermal fibroblasts. This study supports the use of DMF as a treatment for SSc dermal fibrosis. PMID- 28870695 TI - Practical application of gene expression arrays in a clinical setting: The light at the end of a long tunnel. PMID- 28870696 TI - In vitro study of virulence potential of Acinetobacter baumannii outer membrane vesicles. AB - Acinetobacter baumannii has emerged as an important opportunistic pathogen mostly causing nosocomial infections. The virulence factors of this important pathogen are largely unknown. Outer membrane vesicles (OMV) are naturally secreted by many gram negative and gram positive bacteria. These vesicles contain outer membrane proteins, lipids, periplasmic proteins, DNA and RNA. Their role in intracellular and intercellular signaling, transfer of virulence factors and eliciting immune response in host cells has been established in many pathogens. In this study, we investigated OMVs from three multi-drug resistant (MDR) clinical isolates and a non-MDR reference strain of A. baumannii for virulence potential. A. baumannii OMVs showed phospholipase C, hemolytic and leukotoxic activities. We found large variations in virulence potential between OMVs of MDR clinical isolates and non MDR reference strain. These effector molecules were concentrated in OMVs than whole cell bacterial culture and cell-free supernatant. OMV-mediated phospholipase, hemolytic and leucotoxic activities may have a key role in pathogenicity of A. baumannii infection and may be future targets for therapeutic and preventive strategies. This is, to the best of our knowledge, the first report showing virulence potential of A. baumannii OMVs. PMID- 28870697 TI - A new pathogen, Myxobolus holzerae (Myxosporea: Myxozoa) causing severe gill disease in an Indian major carp Labeo rohita in a cold water wetland, Punjab (India). AB - The Indian major carp, Labeo rohita Hamilton, 1822 is a tropical freshwater cyprinid fish native to inland waters in Asia. Herein, we describe a novel myxozoan forming plasmodia in the gill lamellae of L. rohita from Ranjit Sagar Wetland in Punjab, India. Myxospores were consistent with the genus Myxobolus, round to elliptical in valvular view, lemon shaped in side view with a characteristic protrusion at the anterior end and a round posterior end; length 7.65 +/- 0.07 MUm, width 4.62 +/- 0.09 MUm. There were two polar capsules of equal length, pear shaped, length of polar capsule 2.54 +/- 0.05 MUm, width 1.60 +/- 0.02 MUm, with 5-6 turns of the polar filament. The 890 bp 18S rDNA sequence was up to 97% similar to M. catlae from other cyprinid fishes in India. In having, unique myxospore morphology and 18S rDNA sequence, we propose Myxobolus holzerae as new to science. PMID- 28870698 TI - Asbestos: insights from women. PMID- 28870699 TI - Enhancing recovery of recombinant hepatitis B surface antigen in lab-scale and large-scale anion-exchange chromatography by optimizing the conductivity of buffers. AB - In biopharmaceutical science, ion-exchange chromatography (IEC) is a well-known purification technique to separate the impurities such as host cell proteins from recombinant proteins. However, IEC is one of the limiting steps in the purification process of recombinant hepatitis B surface antigen (rHBsAg), due to its low recovery rate (<50%). In the current study, we hypothesized that ionic strengths of IEC buffers are easy-to-control parameters which can play a major role in optimizing the process and increasing the recovery. Thus, we investigated the effects of ionic strengths of buffers on rHBsAg recovery via adjusting Tris HCl and NaCl concentrations. Increasing the conductivity of equilibration (Eq.), washing (Wash.) and elution (Elut.) buffers from their initial values of 1.6 mS/cm, 1.6 mS/cm, and 7.0 mS/cm to 1.6 mS/cm, 7 mS/cm and 50 mS/cm, respectively yielded an average recovery rate of 82% in both lab-scale and large-scale weak anion-exchange chromatography without any harsh effect on the purity percentage of rHBsAg. The recovery enhancement via increasing the conductivity of Eq. and Wash. buffers can be explained by their roles in reducing the binding strength and aggregation of retained particles in the column. Moreover, further increase in the salt concentration of Elut. Buffer could substantially promote the ion exchange process and the elution of retained rHBsAg. PMID- 28870700 TI - Short inter-stimulus intervals can be used for olfactory electroencephalography in patients of varying olfactory function. AB - Use of chemosensory event-related potentials (ERPs) is limited by relatively poor signal-to-noise ratios (SNRs). We hypothesized that by reducing the standard inter-stimulus interval (ISI), the increased number of trial repetitions possible may increase SNR. In order to further investigate this, we performed the largest study to date assessing chemosensory ERP using short and long ISIs in 101 participants of varying olfactory function. Using rose odor (phenylethylalcohol, PEA) as a relatively selective olfactory stimulant, we found no significant difference in the proportion of individuals in whom ERPs were recorded using short or long ISIs. This was true in normosmic, hyposmic and functionally anosmic individuals. We also demonstrated significantly increased SNR using short PEA ISIs, in the normosmic and functionally anosmic groups. Comparing between groups of different olfactory function, hyposmic patients achieved faster onsets and greater amplitudes than normosmics under the PEA-10s protocol. This could be due to increased stimulus attendance, but requires confirmation with further research. PMID- 28870702 TI - Automatic Frequency-Shift Detection in the Auditory System: A Review of Psychophysical Findings. AB - The human brain has the task of binding successive sounds produced by the same acoustic source into a coherent perceptual stream, and binding must be selective when several sources are concurrently active. Binding appears to obey a principle of spectral proximity: pure tones close in frequency are more likely to be bound than pure tones with remote frequencies. It has been hypothesized that the binding process is realized by automatic "frequency-shift detectors" (FSDs), comparable to the detectors of spatial motion in the visual system. In 2005, this hypothesis was supported by a psychophysical study showing that human listeners are able to identify the direction of a frequency shift between two successive pure tones while the first of these tones is not audible individually due to informational masking by other tones presented synchronously. A number of variants of this study have been performed since 2005, in order to confirm the existence of FSDs, to characterize their properties, and to clarify as far as possible their neural underpinnings. The results obtained up to now suggest that the working of the FSDs exploits an implicit sensory memory which is powerful with respect to both capacity and retention time. Tones within chords can be perceptually enhanced by small frequency shifts, in a manner suggesting that the FSDs can serve in auditory scene analysis not only as binding tools but also, to a limited extent, as segregation tools. PMID- 28870701 TI - Hyper-oligodendrogenesis at the vascular niche and reduced blood-brain barrier integrity in the prefrontal cortex during protracted abstinence. AB - Alcoholism is a relapsing disorder with limited treatment options, in part due to our limited understanding of the disease etiology. We have recently shown that increased ethanol-seeking in a behavioral model of relapse in a rat model of alcoholism was associated with increased oligodendrogenesis which was positively correlated with platelet/endothelial cell adhesion molecule (PECAM-1) expression in the medial prefrontal cortex (mPFC). The current study investigated whether newly born oligodendrocytes form close physical associations with endothelial cells expressing PECAM-1 and whether these changes were accompanied by altered blood-brain barrier (BBB) integrity. Colableling and confocal analysis demonstrate that newly born oligodendroglia were always located in close physical proximity to PECAM-1 in the mPFC of rats that were ethanol dependent and demonstrated high propensity for relapse. Notably, the endothelial proximity of new oligodendrocytes was associated with reduced expression of endothelial barrier antigen (SMI-71), a marker for BBB integrity. Furthermore, voluntary wheel running during abstinence enhanced SMI-71 expression in endothelial cells, indicating protection against abstinence-induced reduction in BBB integrity. Taken together, these results suggest that ethanol experience and abstinence disrupts homeostasis in the oligo-vascular niche in the mPFC. Reversing these mechanisms may hold the key to reducing propensity for relapse in individuals with moderate to severe alcohol use disorder. PMID- 28870703 TI - A novel mutation at ANTXR1 in an Indian patient with growth retardation-alopecia pseudoanodontia-optic atrophy syndrome. AB - OBJECTIVE: Growth retardation-alopecia-pseudoanodontia-optic atrophy (GAPO) syndrome (Online Mendelian Inheritance in Man [OMIM] ID 230740) is one of the rarest autosomal recessive syndromes. It is characterized by many phenotypes, including wide anterior fontanel, frontal bossing of the face, depressed nasal bridge, along with the 4 classic phenotypes contained in the name of the syndrome. Recent reports identified nonsense, missense, and splicing mutations at different exons of ANTXR1 responsible for GAPO syndrome in patients from different ethnic populations. Here, we are reporting a mutation at ANTXR1 in an Indian patient with GAPO syndrome. STUDY DESIGN: We describe an inherited mutation at ANTXR1 in a 6-year-old Indian boy with GAPO syndrome. RESULTS: Genomic DNA from the patient with the GAPO syndrome and his family members were screened for previously reported mutations at ANTXR1 by sequencing. Novel homozygous and heterozygous mutations in exon-3 of ANTXR1 (c.265 G > A, p.Gly89 Arg) were identified in the patient and in other members of the family, respectively. However, no mutated allele was identified in genomic DNA from unrelated healthy individuals. Bioinformatic analysis by different tools predicted the deleterious, damaging, or aberrant splicing effect of mutation on the protein. CONCLUSIONS: Functional inefficiency of ANTXR1 as a result of mutation might have led to GAPO syndrome. PMID- 28870704 TI - The intricate connection between diet, microbiota, and cancer: A jigsaw puzzle. AB - The microbial community has a decisive role in determining our health and disease susceptibility. Presumably, this is closely associated with the complex community network of bacteria, fungi, archaea and viruses that reside our guts. This dynamic ecosystem exists in a symbiotic relationship with its host and plays a fundamental role in the hosts' physiological functions. The microbial community is highly personalized and therefore exhibits a high degree of inter-individual variability, which is dependent on host specifics such as genetic background, physiology and lifestyle. Although the gut microbiota is shaped early on during birth, there are several factors that affect the composition of microbiota during childhood and adulthood. Among them diet appears to be a consistent and prominent one. The metabolic activity of bacteria affects food digestion, absorption, energy production, and immunity. Thus, definition of the microbiota composition and functional profiles in response to a particular diet may lead to critical information on the direct and indirect role/use of the bacterial community during health and disease. In this review, I discuss gut microbiota and its potential link to cancer with specific emphasis on metabolism and diet. PMID- 28870705 TI - V. Aboyans et al. in response to the article by M. Helfre et al.: Usefulness of a systematic screening of carotid atherosclerosis in asymptomatic people with type 2 diabetes for cardiovascular risk reclassification. Ann Endocrinol (Paris). 2017;78:14-19. PMID- 28870706 TI - Bariatric surgery in adolescents with severe obesity: Review and state of the art in France. AB - Severe obesity (body mass index>120% of BMI IOTF-30 cut off) and morbid obesity (BMI>140% of BMI IOTF-30 cut off) affect 5 to 10% of obese adolescents in France. Organic complications can be found in about 50% of these patients, and depressive symptoms in one-third of them. Finally, over 70% will suffer from adult morbid obesity associated with a marked increase in morbidity and mortality. However, the reversion of obesity strongly decreases, and may even cancels, these risks. In controlled randomized studies, lifestyle interventions have limited effectiveness on BMI in children (and none in adolescents). Bariatric surgery has been shown to have short-term effectiveness in adolescents with severe and morbid obesity: the average BMI loss after gastric banding was 11.6kg/m2 (95% confidence interval from 9.8 to 13.4), 16.6kg/m2 (95% confidence interval from 13.4 to 19.8) after bypass, and 14.1kg/m2 (95% confidence interval 10.8 to 17.5) after sleeve gastrectomy. The resolution of comorbidities was the main aim, as well as the improvement of quality of life. This is not a simple surgical intervention, and minor side effects have been reported in approximately 10-15% of teenagers who underwent surgery (more common with the gastric band), and severe side effects in nearly 1-5% (mainly with bypass). In France, recommendations regarding indications, the care pathway, multidisciplinary meetings, reference management structures and postoperative care have been published by the French National Health Authority (HAS) in 2016 to provide a framework for bariatric surgery in underage patients. PMID- 28870707 TI - Interventions to improve beta-cell mass and function. AB - Diabetes mellitus (T2DM) has become an epidemiologically important disease worldwide and is also becoming a great matter of concern due to the effects associated with it like: high morbidity, elevated health care cost and shortened life span. T2DM is a chronic metabolic disease characterized by insulin resistance as well as beta-cell dysfunction. It is widely accepted that in the face of insulin resistance, euglycemia can be maintained by increase in pancreatic beta-cell mass and insulin secretion. This compensation is largely due to enhanced secretion of insulin by the beta-cell mass, which is present initially, and thereby subsequent increases in beta-cell mass provide additional insulin secretion. However, the mechanism by which beta-cell anatomical plasticity and functional plasticity for insulin secretion is coordinated and executed in different physiological and pathophysiological states is complex and has been poorly understood. As the incidence of T2DM continues to increase at an alarming rate, it is becoming imperative to shift the research focus towards the beta-cell physiology where identification of novel pathways that influence the beta-cell proliferation and/or contribute to increase insulin secretion has the potential to lead to new therapies for preventing or delaying onset of disease. PMID- 28870708 TI - Carbimazole embryopathy. PMID- 28870709 TI - Pheochromocytoma during pregnancy: Case report and review of recent literature. PMID- 28870710 TI - Communication Skills Training in Ophthalmology: Results of a Needs Assessment and Pilot Training Program. AB - OBJECTIVE: To conduct a needs assessment to identify gaps in communication skills training in ophthalmology residency programs and to use these results to pilot a communication workshop that prepares residents for difficult conversations. DESIGN: A mixed-methods design was used to perform the needs assessment. A pre and postsurvey was administered to workshop participants. SETTING: Mass Eye and Ear Infirmary, Harvard Medical School (HMS), Department of Ophthalmology. PARTICIPANTS: HMS ophthalmology residents from postgraduate years 2-4 participated in the needs assessment and the workshop. Ophthalmology residency program directors in the United States participated in national needs assessment. METHODS: Ophthalmology program directors across the United States were queried on their perception of resident communication skills training through an online survey. A targeted needs assessment in the form of a narrative exercise captured resident perspectives on communication in ophthalmology from HMS residents. A group of HMS residents participated in the pilot workshop and a pre- and postsurvey was administered to participants to assess its effectiveness. RESULTS: The survey of program directors yielded a response rate of 40%. Ninety percent of respondents agreed that the communication skills training in their programs could be improved. Fifteen of 24 residents (62%) completed the needs assessment. Qualitative analysis of the narrative material revealed four themes; (1) differing expectations, (2) work role and environment, (3) challenges specific to ophthalmology, and (4) successful strategies adopted. Nine residents participated in the workshop. There was a significant improvement post-workshop in resident reported scores on their ability to manage their emotions during difficult conversations (p = 0.03). CONCLUSIONS: There is an opportunity to improve communication skills training in ophthalmology residency through formalized curriculum. PMID- 28870711 TI - The Economics of Academic Advancement Within Surgery. AB - BACKGROUND: The success of an academic surgeon's career is often viewed as directly related to academic appointment; therefore, the sequence of promotion is a demanding, rigorous process. This paper seeks to define the financial implication of academic advancement across different surgical subspecialties. STUDY DESIGN: Data was collected from the Association of American Medical College's 2015 report of average annual salaries. Assumptions included 30 years of practice, 5 years as assistant professor, and 10 years as associate professor before advancement. The base formula used was: (average annual salary) * (years of practice [30 years - fellowship/research years]) + ($50,000 * years of fellowship/research) = total adjusted lifetime salary income. RESULTS: There was a significant increase in lifetime salary income with advancement from assistant to associate professor in all subspecialties when compared to an increase from associate to full professor. The greatest increase in income from assistant to associate professor was seen in transplant and cardiothoracic surgery (35% and 27%, respectively). Trauma surgery and surgical oncology had the smallest increases of 8% and 9%, respectively. With advancement to full professor, the increase in lifetime salary income was significantly less across all subspecialties, ranging from 1% in plastic surgery to 8% in pediatric surgery. CONCLUSION: When analyzing the economics of career advancement in academic surgery, there is a substantial financial benefit in lifetime income to becoming an associate professor in all fields; whereas, advancement to full professor is associated with a drastically reduced economic benefit. PMID- 28870712 TI - The Role of Simulation in Boosting the Learning Curve in EVAR Procedures. AB - OBJECTIVE: Simulation may be a useful tool for training in endovascular procedures. The aim of this study was to evaluate the effect of endovascular repair of abdominal aortic aneurysms (EVAR) simulation in boosting trainees' learning curve. DESIGN: Ten vascular surgery residents were recruited and divided in 2 groups (Trainee Group and Control group). At a first session (t0), each resident performed 2 simulated EVAR procedures using an endovascular simulator. After 2 weeks, each participant simulated other 2 EVAR procedures in a final session (t1). In the period between t0 and t1, each resident in the Trainee Group performed 6 simulated EVAR procedures, whereas the Control Group did not perform any other simulation. Both quantitative and qualitative performance evaluations were performed at t0 and t1. Quantitative evaluation from simulator metrics included total procedural time (TP), total fluoroscopy time (TF), time for contralateral gate cannulation (TG), and contrast medium volume (CM) injected. Qualitative evaluation was based on a Likert scale used to calculate a total performance score referred to skills involving major EVAR procedural steps. RESULTS: All residents in the Trainee Group significantly reduced TP (48 +/- 12 vs 32 +/- 8 minutes, t0 vs t1, p < 0.05), TF (18 +/- 7 vs 11 +/- 6 minutes, p < 0.05), and CM used over time (121 +/- 37 vs 85 +/- 26ml, p < 0.05), but not TG (5 +/- 5 vs 3 +/- 4 minutes, p = 0.284). In the Control Group metrics did not change significantly in any field (TP = 55 +/- 11 vs 46 +/- 10 minutes; TF = 25 +/- 9 vs 21 +/- 4 minutes; CM = 132 +/- 51 vs 102 +/- 42ml; TG = 6 +/- 4 vs 8 +/- 5 minutes, all p > 0.05). The average Trainee Group qualitative total performance score improved significantly (p < 0.05) after rehearsal sessions when compared with the Control Group. CONCLUSION: Simulation is an effective method to improve competence of vascular surgery residents with EVAR procedures. PMID- 28870714 TI - The dangers of unregulated stem-cell marketing. PMID- 28870713 TI - Dietary pomegranate extract and inulin affect gut microbiome differentially in mice fed an obesogenic diet. AB - Growing evidence suggests that dysbiosis of gut microbiota is associated with pathogenesis of a variety of human diseases. Using dietary intervention to shape the composition and metabolism of the gut microbiota is increasingly recognized. In the present study, we investigated the effects of polysaccharide inulin and polyphenol-rich pomegranate extract (PomX) alone or in combination on the cecal microbiota composition and function in a diet induced obesity mouse model. Male C57BL/6 mice were randomly divided into four experimental groups and consumed either high-fat/high-sucrose [HF/HS (32% energy from fat, 25% energy from sucrose, 17% energy from protein)] diet, HF/HS diet supplemented with PomX (0.25%), or inulin (9%) or PomX and inulin in combination for 4 weeks. In mice fed the PomX-diet the proportion of Turicibacteraceae and Ruminococcaceae was significantly increased compared to the control HF/HS diet. Supplementation with inulin alone and inulin + PomX combination significantly increased the proportion of Verrucomicrobiaceae (A. muciniphila) and decreased Clostridiaceae. Only mice fed the inulin diet experienced an increase in serum lipopolysaccharide (LPS) and monocyte chemoattractant protein 1 (MCP-1), which was reversed when feeding the inulin + PomX diet. Feeding the inulin + PomX diet was associated with a significant increase in Bifidobacteriaceae and Rikenellaceae, which may have contributed to the reduction of endotoxemia markers. Inulin supplementation showed lower species richness of gut microbiota compared to mice fed with HF/HS or HF/HS/PomX, and the reduction was reversed by the addition of PomX. Inulin alone and in combination with PomX had distinct microbial clusters determined by both weighted and unweighted UniFrac Beta-Diversity principle coordinate analysis. A total of 19 KEGG biological pathways were significantly regulated in the gut microbiota with PomX and inulin alone or combined treatment. Inulin significantly enhanced KEGG infectious disease-related pathway associated with increase of serum LPS and MCP-1. No changes in gene expression of ileal proinflammatory cytokine and tight junction genes were observed in mice treated with PomX and inulin. Our results demonstrated that the gut microbiota and their biological pathways were differentially effected by dietary PomX and inulin fed combined or alone. It is therefore very important to consider the interaction among bioactive components of food when evaluating potential prebiotic effects. PMID- 28870715 TI - Stretching the carotid sinus to treat resistant hypertension. PMID- 28870717 TI - Alleged acoustic attack on US diplomats puzzling experts. PMID- 28870716 TI - Endovascular baroreflex amplification for resistant hypertension: a safety and proof-of-principle clinical study. AB - BACKGROUND: Carotid baroreflex activation lowers blood pressure and might have potential application for the treatment of resistant hypertension. We did a proof of-principle trial with a novel endovascular baroreceptor amplification device, MobiusHD (Vascular Dynamics, Mountain View, CA, USA), in patients with resistant hypertension. METHODS: CALM-FIM_EUR was a prospective, first-in-human, open-label study done at six European centres. Eligible patients were adults with resistant hypertension (office systolic blood pressure >=160 mm Hg despite taking at least three antihypertensive agents, including a diuretic). MobiusHD devices were implanted unilaterally in the internal carotid artery. The primary endpoint was the incidence of serious adverse events at 6 months. Secondary endpoints included changes in office and 24 h ambulatory blood pressure. This trial is registered with ClinicalTrials.gov, number NCT01911897. FINDINGS: Between December, 2013, and February, 2016, 30 patients were enrolled and underwent successful implantation. Mean age was 52 years (SD 12), 15 patients (50%) were men, and mean antihypertensive use was 4.4 drugs (1.4). Mean office blood pressure was 184/109 mm Hg (18/14) at baseline and was reduced by 24/12 mm Hg (13-34/6-18) at 6 months (p=0.0003 for systolic and p=0.0001 diastolic blood pressure). Mean baseline 24 h ambulatory blood pressure was 166/100 mm Hg (17/14) at baseline and was reduced by 21/12 mm Hg (14-29/7-16) at 6 months (p<0.0001 for systolic and diastolic blood pressure). Five serious adverse events had occurred in four patients (13%) at 6 months: hypotension (n=2), worsening hypertension (n=1), intermittent claudication (n=1) and wound infection (n=1). INTERPRETATION: In patients with resistant hypertension, endovascular baroreceptor amplification with the MobiusHD device substantially lowered blood pressure with an acceptable safety profile. Randomised, double-blind, sham-controlled trials are warranted to investigate the use of this treatment further. FUNDING: Vascular Dynamics. PMID- 28870718 TI - Four-year experience of providing mobile extracorporeal life support to out-of center patients within a suprainstitutional network-Outcome of 160 consecutively treated patients. AB - AIM: Mobile extracorporeal life support (ECLS) may soon be on the verge to become a fundamental part of emergency medicine. Here, we report on our four-year experience of providing advanced mechanical circulatory support for out-of-center patients within the Dusseldorf ECLS Network (DELSN). METHODS: This retrospective cohort study analyses the outcome of 160 patients with refractory circulatory failure consecutively treated with mobile veno-arterial extracorporeal membrane oxygenation (vaECMO) between July 2011 and October 2015 within the DELSN. RESULTS: Out of the 160 patients (56+/-16years, vaECMO initiation under CPR 68%), 59 patients (36%) survived to primary discharge, with 50 patients (31%) still alive after a median follow-up of 1.74 years. Time-discrete mortality was highest during the first 24h. There was no difference between survivors and non-survivors regarding age, etiology of circulatory failure, presence of CPR during implantation or distance to implantation site. Incidence of kidney injury requiring dialysis (61% vs. 24%, p<0.0001), shock liver (27% vs. 12%, p=0.031) and visceral ischemia (19% vs. 3%, p=0.013) were the only complications increased in non-survivors. Subgroup analysis showed no significant outcome difference for ECPR vs. non-ECPR patients. Outcome was significantly impaired with initial neuron-specific enolase >=45.4MUg/L (AUC 0.75, p<0.0001) and lactate >=5.5mmol/L (AUC 0.70, p<0.0001). Program-year-dependent in-center mortality showed an increasing trend, while program-year-dependent follow-up mortality decreased over time. CONCLUSIONS: This study illustrates that regional mobile ECLS rescue therapy can be provided with encouraging outcomes, although patient selection criteria and early outcome parameters reflecting on therapy success or futility still need to be refined. PMID- 28870719 TI - Increased survival from out-of-hospital cardiac arrest when off duty medically educated personnel perform CPR compared with laymen. AB - BACKGROUND: Bystander cardiopulmonary resuscitation (CPR) has been proved to save lives; however, whether survival is affected by the training level of the bystander is not fully described. AIM: To describe if the training level of laymen and medically educated bystanders affect 30-day survival in out-of hospital cardiac arrests (OHCA). METHODS: This observational study included all witnessed and treated cases of bystander CPR reported to the Swedish Registry of Cardiopulmonary Resuscitation between 2010 and 2014. Bystander CPR was divided into two categories: (a) lay-byCPR (non-medically educated) and (b) med-byCPR (off duty medically educated personnel). RESULTS: During 2010-2014, 24,643 patients were reported to the OHCA registry, of which 6850 received lay-byCPR and 1444 med-byCPR; 16,349 crew-witnessed and non-witnessed cases and those with missing information were excluded from the analysis. The median interval from collapse to call for emergency medical services was 2min in both groups (p=0.97) and 2min from collapse to start of CPR for lay-byCPR versus 1min for med-byCPR (p<0.0001). There were no significant differences in CPR methods used; 64.3% (lay byCPR) and 65.7% (med-byCPR) applied compressions and ventilation, respectively (p=0.33). The 30-day survival was 14.7% for lay-byCPR and 17.2% for the med-byCPR group (p=0.02). The odds ratio adjusted for potential confounders regarding survival (med-byCPR versus lay-byCPR) was 1.34 (95% confidence interval, 1.11 1.62; p=0.002). CONCLUSIONS: In cases of OHCA, medically educated bystanders initiated CPR earlier and an increased 30-day survival was found compared with laymen bystanders. These results support the need to improve the education programme for laypeople. PMID- 28870721 TI - Factors Associated with Severity of Irritable Bowel Syndrome Symptoms in Patients with Endometriosis. AB - OBJECTIVE: This study sought to examine factors associated with severity of irritable bowel syndrome (IBS) by using the Birmingham IBS symptom scale in patients presenting with endometriosis to a tertiary referral centre. METHODS: A prospective research cohort of patients presenting to a tertiary referral centre for endometriosis was evaluated for the presence and severity of IBS between December 2013 and April 2015. Patients with endometriosis had a diagnosis of IBS by using the Rome III criteria and were evaluated for severity of IBS symptoms by using the Birmingham IBS symptom scale. Multifactorial variables, including stage of endometriosis at the time of previous surgery, clinical examination findings, mood disorder questionnaire scores, and lifestyle factors, were evaluated using the t test and Spearman rank correlation test. RESULTS: A total of 194 of 373 (52%) women with confirmed endometriosis had a diagnosis of IBS. Factors associated with severity of IBS symptoms in patients with endometriosis included lower-stage endometriosis (P = 0.004), presence of mood disorders (P <0.001), tenderness on physical examination (P <= 0.001), a history of sexual assault (P <= 0.02), and presence of sleep disturbance (P <= 0.01). Evaluation of the subscales of the Birmingham IBS symptom scale revealed a strong association between the previously identified factors and the pain subscale. CONCLUSION: Using the Birmingham IBS symptom scale, our study revealed more severe IBS symptoms in patients with lower-stage endometriosis and identified other variables highly associated with severity of IBS. Continued research is required to characterize further the clinical importance of IBS symptoms in patients with endometriosis-associated pelvic pain. PMID- 28870722 TI - Umbilical Cord Strangulation by Amniotic Bands. PMID- 28870720 TI - Post-resuscitation arterial oxygen and carbon dioxide and outcomes after out-of hospital cardiac arrest. AB - OBJECTIVE: To determine if arterial oxygen and carbon dioxide abnormalities in the first 24h after return of spontaneous circulation (ROSC) are associated with increased mortality in adult out-of-hospital cardiac arrest (OHCA). METHODS: We used data from the Resuscitation Outcomes Consortium (ROC), including adult OHCA with sustained ROSC >=1h after Emergency Department arrival and at least one arterial blood gas (ABG) measurement. Among ABGs measured during the first 24h of hospitalization, we identified the presence of hyperoxemia (PaO2>=300mmHg), hypoxemia (PaO2<60mmHg), hypercarbia (PaCO2>50mmHg) and hypocarbia (PaCO2<30mmHg). We evaluated the associations between oxygen and carbon dioxide abnormalities and hospital mortality, adjusting for confounders. RESULTS: Among 9186 OHCA included in the analysis, hospital mortality was 67.3%. Hyperoxemia, hypoxemia, hypercarbia, and hypocarbia occurred in 26.5%, 19.0%, 51.0% and 30.6%, respectively. Initial hyperoxemia only was not associated with hospital mortality (adjusted OR 1.10; 95% CI: 0.97-1.26). However, final and any hyperoxemia (1.25; 1.11-1.41) were associated with increased hospital mortality. Initial (1.58; 1.30 1.92), final (3.06; 2.42-3.86) and any (1.76; 1.54-2.02) hypoxemia (PaO2<60mmHg) were associated with increased hospital mortality. Initial (1.89; 1.70-2.10); final (2.57; 2.18-3.04) and any (1.85; 1.67-2.05) hypercarbia (PaCO2>50mmHg) were associated with increased hospital mortality. Initial (1.13; 0.90-1.41), final (1.19; 1.04-1.37) and any (1.01; 0.91-1.12) hypocarbia (PaCO2<30mmHg) were not associated with hospital mortality. CONCLUSIONS: In the first 24h after ROSC, abnormal post-arrest oxygen and carbon dioxide tensions are associated with increased out of-hospital cardiac arrest mortality. PMID- 28870723 TI - Managing Malnourishment in Pregnancy after Bariatric Surgery. AB - BACKGROUND: Little information exists to guide monitoring and treatment of malnourishment during pregnancy after bariatric surgery. Here we present a case with severe deficiencies and recommendations for testing and treatment. CASE: Our patient underwent a duodenal switch procedure resulting in significant weight loss and numerous deficiencies. She then experienced a neonatal demise with multiple congenital abnormalities, including diaphragmatic hernia, possibly related to severe vitamin A deficiency. After high doses of oral and parenteral replacement, pancreatic enzymes, and total parenteral nutrition, she delivered an anatomically normal but growth-restricted neonate in a subsequent pregnancy. CONCLUSION: Bariatric procedures may result in nutritional deficiencies that affect pregnancy outcome. Women with severe deficiencies require pre-pregnancy counselling, monitoring, aggressive treatment, and a multidisciplinary approach to care. PMID- 28870724 TI - Tubal Sterilization in Women Under 30: Case Series and Ethical Implications. AB - OBJECTIVE: According to the SOGC Contraception Consensus, it is recommended that permanent contraception be offered to women regardless of age or parity. Many women who desire sterilization at a young age experience barriers from physicians who decline to facilitate the request. METHODS: As part of a quality assurance project, we performed a review of cases where tubal sterilization was performed in women under 30 over a 42-month period (September 2013-March 2017). We also performed a literature review on the ethical and clinical considerations with respect to young women requesting permanent contraception. RESULTS: We identified 29 women under 30 who had consented for tubal sterilization; 27.5% of women were nulliparous, and 27.5% had a medical condition for which unintended pregnancy is associated with an increased risk of adverse event. As documented in the patients' records, many women expressed prior difficulty in obtaining the procedure. Despite being informed of the risk of regret, most women proceed with the surgical procedure. Three additional women had consented and subsequently cancelled their surgical procedure. CONCLUSION: Women who are well-informed and desire permanent contraception should be offered the procedure, regardless of age or parity. Declining such requests is a form of conscientious refusal and is not a clinical decision. PMID- 28870725 TI - Strangulation du cordon ombilical par des brides amniotiques. PMID- 28870726 TI - Analysis of the prophages carried by human infecting isolates provides new insight into the evolution of Group B Streptococcus species. AB - OBJECTIVES: Group B Streptococcus (GBS) emerged in the 1970s as a major cause of neonatal infections, and has been increasingly associated with infections in adults since the 1990s. Prophages have been suspected to have driven these epidemiological trends. We have characterized the prophages harboured by 275 human GBS isolates belonging to the major lineages. METHODS: We applied whole genome sequencing (WGS) to 14 isolates representative of the diversity within GBS species, located and identified their prophages. Using prediction tools, we searched for prophage elements potentially involved with the ability of GBS to infect humans. Using the data obtained by WGS, we designed a PCR-based tool and studied the prophage content of 275 isolates. RESULTS: WGS of the 14 isolates revealed 22 prophages (i) distributed into six groups (A-F), (ii) similar to phages and prophages from GBS and non-GBS streptococci recovered from livestock, and (iii) carrying genes encoding factors previously associated with host adaptation and virulence. PCR-based detection of prophages revealed the presence of at least one prophage in 72.4% of the 275 isolates and a significant association between neonatal infecting isolates and prophages C, and between adult infecting isolates and prophages A. CONCLUSIONS: Our results suggest that prophages (possibly animal-associated) have conditioned bacterial adaptation and ability to cause infections in neonates and adults, and support a role of lysogeny with the emergence of GBS as a pathogen in human. PMID- 28870727 TI - Selective digestive and oropharyngeal decontamination in medical and surgical ICU patients: individual patient data meta-analysis. AB - OBJECTIVES: Selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD) improved intensive care unit (ICU), hospital and 28-day survival in ICUs with low levels of antibiotic resistance. Yet it is unclear whether the effect differs between medical and surgical ICU patients. METHODS: In an individual patient data meta-analysis, we systematically searched PubMed and included all randomized controlled studies published since 2000. We performed a two-stage meta-analysis with separate logistic regression models per study and per outcome (hospital survival and ICU survival) and subsequent pooling of main and interaction effects. RESULTS: Six studies, all performed in countries with low levels of antibiotic resistance, yielded 16 528 hospital admissions and 17 884 ICU admissions for complete case analysis. Compared to standard care or placebo, the pooled adjusted odds ratios for hospital mortality was 0.82 (95% confidence interval (CI) 0.72-0.93) for SDD and 0.84 (95% CI 0.73-0.97) for SOD. Compared to SOD, the adjusted odds ratio for hospital mortality was 0.90 (95% CI 0.82-0.97) for SDD. The effects on hospital mortality were not modified by type of ICU admission (p values for interaction terms were 0.66 for SDD and control, 0.87 for SOD and control and 0.47 for SDD and SOD). Similar results were found for ICU mortality. CONCLUSIONS: In ICUs with low levels of antibiotic resistance, the effectiveness of SDD and SOD was not modified by type of ICU admission. SDD and SOD improved hospital and ICU survival compared to standard care in both patient populations, with SDD being more effective than SOD. PMID- 28870728 TI - Clinical use of fungal PCR from deep tissue samples in the diagnosis of invasive fungal diseases: a retrospective observational study. AB - OBJECTIVES: To assess the clinical use of panfungal PCR for diagnosis of invasive fungal diseases (IFDs). We focused on the deep tissue samples. METHODS: We first described the design of panfungal PCR, which is in clinical use at Helsinki University Hospital. Next we retrospectively evaluated the results of 307 fungal PCR tests performed from 2013 to 2015. Samples were taken from normally sterile tissues and fluids. The patient population was nonselected. We classified the likelihood of IFD according to the criteria of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG), comparing the fungal PCR results to the likelihood of IFD along with culture and microscopy results. RESULTS: There were 48 positive (16%) and 259 negative (84%) PCR results. The sensitivity and specificity of PCR for diagnosing IFDs were 60.5% and 91.7%, respectively, while the negative predictive value and positive predictive value were 93.4% and 54.2%, respectively. The concordance between the PCR and the culture results was 86% and 87% between PCR and microscopy, respectively. Of the 48 patients with positive PCR results, 23 had a proven or probable IFD. CONCLUSIONS: Fungal PCR can be useful for diagnosing IFDs in deep tissue samples. It is beneficial to combine fungal PCR with culture and microscopy. PMID- 28870730 TI - Comparing a single-day swabbing regimen with an established 3-day protocol for MRSA decolonization control. AB - OBJECTIVES: Success of methicillin-resistant Staphylococcus aureus (MRSA) decolonization procedures is usually verified by control swabs of the colonized body region. This prospective controlled study compared a single-day regimen with a well-established 3-day scheme for noninferiority and adherence to the testing scheme. METHODS: Two sampling schemes for screening MRSA patients of a single study cohort at a German tertiary-care hospital 2 days after decolonization were compared regarding their ability to identify MRSA colonization in throat or nose. In each patient, three nose and three throat swabs were taken at 3- to 4-hour intervals during screening day 1, and in the same patients once daily on days 1, 2 and 3. Swabs were analysed using chromogenic agar and broth enrichment. The study aimed to investigate whether the single-day swabbing scheme is not inferior to the 3-day scheme with a 15% noninferiority margin. RESULTS: One hundred sixty patients were included, comprising 105 and 101 patients with results on all three swabs for decolonization screening of the nose and throat, respectively. Noninferiority of the single-day swabbing scheme was confirmed for both pharyngeal and nasal swabs, with 91.8% and 89% agreement, respectively. The absolute difference of positivity rates between the swabbing regimens was 0.025 ( 0.082, 0.131) for the nose and 0.006 (-0.102, 0.114) (95% confidence interval) for the pharynx as calculated with McNemar's test for matched or paired data. Compliance with the single-day scheme was better, with 12% lacking second-day swabs and 27% lacking third-day swabs from the nostrils. CONCLUSIONS: The better adherence to the single-day screening scheme with noninferiority suggests its implementation as the new gold standard. PMID- 28870729 TI - Tigecycline-induced inhibition of mitochondrial DNA translation may cause lethal mitochondrial dysfunction in humans. AB - BACKGROUND: A 65-year-old patient developed an unexplained and ultimately lethal metabolic acidosis under prolonged treatment with tigecycline. Tigecycline is known to have a selective inhibitory effect on eukaryotic mitochondrial translation. The underlying molecular mechanisms of the metabolic acidosis in this patient were explored. METHODS: Oxidative phosphorylation system (OXPHOS) analysis, blue native polyacrylamide gel electrophoresis followed by in-gel activity staining in mitochondria, molecular analysis of mitochondrial DNA (mtDNA) for genomic rearrangements and sequencing of the rRNA genes was performed on the subject's skeletal muscle. RESULTS: OXPHOS analysis revealed a combined deficiency of the complexes I, III, IV and V, with a preserved function of complex II (encoded by nuclear DNA), thus demonstrating a defective mtDNA translation. There were no known underlying mitochondrial genetic defects. The patient had a (m.1391T>A) variant within the 12SrRNA gene in heteroplasmy (50 60%). CONCLUSIONS: This patient developed an ultimately lethal mitochondrial toxicity while receiving prolonged treatment with tigecycline, which was caused by a defective translation of the mtDNA. Tigecycline is known to suppress eukaryotic mitochondrial DNA translation, but until now this effect has been considered to be clinically insignificant. The observations in this patient suggest a clinically significant mitochondrial toxicity of tigecycline in this patient, and warrant further investigation. PMID- 28870732 TI - Processes and Outcomes of Congestive Heart Failure Care by Different Types of Primary Care Models. AB - BACKGROUND: Having nurse practitioners (NPs) as primary care providers for patients with congestive heart failure (CHF) is 1 way to address the growing shortage of primary care physicians (PCPs). METHODS AND RESULTS: We used inverse probability of treatment weighted with propensity score to examine the processes and outcomes of care for patients under 3 care models. Approximately 72.9%, 0.8%, and 26.3% of CHF patients received care under the PCP model, the NP model, and the shared care model, respectively. Patients under the NP or shared care models were more likely than those under the PCP model to be referred to cardiologists (odds ratio 1.35, 95% confidence interval 1.32-1.37; odds ratio 1.32, 95% confidence interval 1.30-1.35) and to get guideline-recommended medications. NPs and PCPs had similar rates of emergency room (ER) visits and Medicare spending after adjusting for processes of care. Patients under the shared care model had a higher burden of comorbidity and experienced a higher rate of ER visits and hospitalizations than those under the PCP model. CONCLUSION: The delivery of CHF care mirrors the severity of comorbidity in these patients. The high rate of hospitalization and ER visits in the shared care model underscores the need to design and implement more effective chronic disease management and integrated care programs. PMID- 28870731 TI - Chronic Neuregulin-1beta Treatment Mitigates the Progression of Postmyocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus by Suppressing Myocardial Apoptosis, Fibrosis, and Key Oxidant-Producing Enzymes. AB - BACKGROUND: Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher cardiovascular morbidity and mortality compared to their nondiabetic counterparts owing to the more frequent development of subsequent heart failure (HF). Neuregulin (NRG)-1beta is released from cardiac microvascular endothelial cells and acts as a paracrine factor via the ErbB family of tyrosine kinase receptors expressed in cardiac myocytes to regulate cardiac development and stress responses. Because myocardial NRG-1/ErbB signaling has been documented to be impaired during HF associated with type 1 DM, we examined whether enhancement of NRG-1beta signaling via exogenous administration of recombinant NRG-1beta could exert beneficial effects against post-MI HF in the type 1 diabetic heart. METHODS AND RESULTS: Type 1 DM was induced in male Sprague Dawley rats by a single injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, rats underwent left coronary artery ligation to induce MI. STZ-diabetic rats were treated with saline or NRG-1beta (100 ug/kg) twice per week for 7 weeks, starting 2 weeks before experimental MI. Residual left ventricular function was significantly greater in the NRG-1beta-treated STZ diabetic MI group compared with the vehicle-treated STZ-diabetic MI group 5 weeks after MI as assessed by high-resolution echocardiography. NRG-1beta treatment of STZ-diabetic MI rats was associated with reduced myocardial fibrosis and apoptosis as well as decreased gene expression of key oxidant-producing enzymes. CONCLUSIONS: These results suggest that recombinant NRG-1beta may be a promising therapeutic for HF post-MI in the setting of type 1 DM. PMID- 28870733 TI - Functionalized poly(3-hydroxybutyric acid) bodies as new in vitro biocatalysts. AB - Cytochromes P450 play a key role in the drug and steroid metabolism in the human body. This leads to a high interest in this class of proteins. Mammalian cytochromes P450 are rather delicate. Due to their localization in the mitochondrial or microsomal membrane, they tend to aggregate during expression and purification and to convert to an inactive form so that they have to be purified and stored in complex buffers. The complex buffers and low storage temperatures, however, limit the feasibility of fast, automated screening of the corresponding cytochrome P450-effector interactions, which are necessary to study substrate-protein and inhibitor-protein interactions. Here, we present the production and isolation of functionalized poly(3-hydroxybutyrate) granules (PHB bodies) from Bacillus megaterium MS941 strain. In contrast to the expression in Escherichia coli, where mammalian cytochromes P450 are associated to the cell membrane, when CYP11A1 is heterologously expressed in Bacillus megaterium, it is located on the PHB bodies. The surface of these particles provides a matrix for immobilization and stabilization of the CYP11A1 during the storage of the protein and substrate conversion. It was demonstrated that the PHB polymer basis is inert concerning the performed conversion. Immobilization of the CYP11A1 onto the PHB bodies allows freeze-drying of the complex without significant decrease of the CYP11A1 activity. This is the first lyophilization of a mammalian cytochrome P450, which allows storage over more than 18days at 4 degrees C instead of storage at -80 degrees C. In addition, we were able to immobilize the cytochrome P450 on the PHB bodies in vitro. In this case the expression of the protein is separated from the production of the immobilization matrix, which widens the application of this method. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. PMID- 28870734 TI - Curcusone C induces telomeric DNA-damage response in cancer cells through inhibition of telomeric repeat factor 2. AB - Telomeric repeat factor 2 (known as TRF2 or TERF2) is a key component of telomere protection protein complex named as Shelterin. TRF2 helps the folding of telomere to form T-loop structure and the suppression of ATM-dependent DNA damage response activation. TRF2 has been recognized as a potentially new therapeutic target for cancer treatment. In our routine screening of small molecule libraries, we found that Curcusone C had significant effect in disrupting the binding between TRF2 and telomeric DNA, with potent antitumor activity against cancer cells. Our result showed that Curcusone C could bind with TRF2 without binding interaction with TRF1 (telomeric repeat factor 1) although these two proteins share high sequence homology, indicating that their binding conformations and biological functions in telomere could be different. Our mechanistic studies showed that Curcusone C bound with TRF2 possibly through its DNA binding site causing blockage of its interaction with telomeric DNA. Further in cellular studies indicated that the interaction of TRF2 with Curcusone C could activate DNA-damage response, inhibit tumor cell proliferation, and cause cell cycle arrest, resulting in tumor cell apoptosis. Our studies showed that Curcusone C could become a promising lead compound for further development for cancer treatment. Here, TRF2 was firstly identified as a target of Curcusone C. It is likely that the anti-cancer activity of some other terpenes and terpenoids are related with their possible effect for telomere protection proteins. PMID- 28870735 TI - Percutaneous Osteotomies in Hallux Valgus: A Systematic Review. AB - Percutaneous and minimally invasive surgery is one of the greatest advances in the operating field of orthopedic since the late 1990s. The potential advantages include a shorter operative time, quicker recovery, and reduced hospital stay compared with traditional open surgery. However, scientific validation of the safety and efficacy of hallux valgus (HV) percutaneous surgery remains inconclusive. The objective of the present study was to systematically review the published data and clinical evidence for percutaneous HV surgery, evaluate the scientific method of the reports, and clarify the indications, safety, efficacy, and potential risks of these surgical techniques. Two reviewers independently identified the studies using a PubMed search, with the keywords "hallux valgus," "osteotomy," "minimally invasive," and "percutaneous." Quality assessment was performed using the Coleman methodology scale, and each study was assigned a level of evidence and grade of recommendation. Eighteen studies were included and reported a total of 1534 procedures for percutaneous HV surgery on 1397 patients. Of the 18 studies, 14 (77.8%) were level IV, 2 (11.1%) were level III, and 2 (11.1%) were level II. Overall, the average angle correction of the HV deformity improved postoperatively. Regarding the complications, although some investigators revealed no major complications, others described deformity recurrence in 7.8%, stiffness of the first metatarsophalangeal joint in 9.8%, malunion in 4% to 8.7%, and infection rates ranging from 1.9% to 14.3%. The main indication for percutaneous HV surgery is the correction of mild deformities. The complication rate was elevated even in experienced surgeons. In conclusion, future research in percutaneous techniques should include adequately sized randomized control trials, standardization of treatment protocols, and the use of validated tools for the measurement of clinical outcomes. PMID- 28870736 TI - Role of rifampin for the treatment of bacterial infections other than mycobacteriosis. AB - OBJECTIVES: Rifampin was initially approved for the treatment of tuberculosis. Because of its low toxicity, broad-spectrum activity, and good bioavailability, rifampin is now commonly administered as combination antimicrobial therapy for the treatment of various infections caused by organisms other than mycobacteria. This review summarizes the most recent clinical studies on the use of rifampin combinations for treating four common non-mycobacterial infections: acute bacterial meningitis, infective endocarditis and bacteraemia, pneumonia, and biofilm-related infections. METHODS: We performed a literature search of clinical studies published in English from January 2005 to June 2016 using the PubMed database with the search terms "rifampin" with "meningitis" or "infective endocarditis and bacteraemia" or "pneumonia" or "prosthetic joint infections. RESULTS: Current evidence to support a rifampin combination therapy as a treatment for non-mycobacterial infections was largely based on in vitro/in vivo studies and non-comparable retrospective case series. Additionally, controlled clinical trials that directly compared outcomes resulting from rifampin treatment versus treatment without rifampin were limited. CONCLUSIONS: Rifampin combination therapy appears promising for the treatment of non-mycobacterial infections. However, further definitive clinical trials are necessary to validate its use because the risk of adverse drug-drug interactions and of the emergence of rifampin resistance during treatment may outweigh the potential benefits. PMID- 28870738 TI - Errata. PMID- 28870737 TI - Chondrocyte primary cilium is mechanosensitive and responds to low-intensity ultrasound by altering its length and orientation. AB - The primary cilium has been implicated in mechanotransduction, however, its mechanosensory role in transducing signals under low-intensity ultrasound (LIUS) which has the potential to repair fractures and cartilage, remains uninvestigated. This study examined the impact of continuous-wave US, at the cell resonance frequency of 5.0MHz and pressure amplitude of either 14 or 60kPa, on the incidence, length and orientation of primary cilium in bovine articular chondrocytes. Visualization of primary cilium with acetylated alpha-tubulin staining demonstrated that the primary cilium was elongated, bent under US and these changes were reversible. Basal expression of phospho-ERK1/2 was lower in deciliated chondrocytes, thus implicating the role for the primary cilium in transducing signals via the MAPK/ERK pathway. This study demonstrates that the chondrocyte primary cilium is mechanosensitive and responds to US by altering its length and orientation. PMID- 28870740 TI - An extended framework for science. AB - We may be at the cusp of a next generation framework for science which can be facilitated by understanding current limitations in the context of a divergence of 'scientific' tradition from the Axial Age (800-200 BCE) to the present. A powerful advance may come from fusing certain elements from Western and Eastern traditions, synthesizing the framework with an apt understanding of the divergence. Key traits will include the ethopoetic nature of the scientist with attention to his/her experience of self. The framework will also 'access' knowledge through a state of mind less encumbered with paradoxes, duality, incompatibility and other aporias. Case studies in biology and physics illustrate possibilities. PMID- 28870741 TI - A neonatal death associated with Crimean-Congo hemorrhagic fever (Republic of Kalmykia, Russia, June 2016). PMID- 28870739 TI - Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia. AB - The biological and clinical behaviors of hematological malignancies can be influenced by the active crosstalk with an altered bone marrow (BM) microenvironment. In the present study, we provide a detailed picture of the BM vasculature in acute myeloid leukemia using intravital two-photon microscopy. We found several abnormalities in the vascular architecture and function in patient derived xenografts (PDX), such as vascular leakiness and increased hypoxia. Transcriptomic analysis in endothelial cells identified nitric oxide (NO) as major mediator of this phenotype in PDX and in patient-derived biopsies. Moreover, induction chemotherapy failing to restore normal vasculature was associated with a poor prognosis. Inhibition of NO production reduced vascular permeability, preserved normal hematopoietic stem cell function, and improved treatment response in PDX. PMID- 28870742 TI - The Effect of Smoking on Thirty-Day Postoperative Complications After Total Joint Arthroplasty: A Propensity Score-Matched Analysis. AB - BACKGROUND: Total joint arthroplasty (TJA) is a highly successful treatment, but is burdensome to the national healthcare budget. National quality initiatives seek to reduce costly complications. Smoking's role in perioperative complication after TJA is less well known. This study aims to identify smoking's independent contribution to the risk of short-term complication after TJA. METHODS: All patients undergoing primary TJA between 2011 and 2012 were selected from the American College of Surgeon's National Surgical Quality Improvement Program's database. Outcomes of interest included rates of readmission, reoperation, mortality, surgical complications, and medical complications. To eliminate confounders between smokers and nonsmokers, a propensity score was used to generate a 1:1 match between groups. RESULTS: A total of 1251 smokers undergoing TJA met inclusion criteria. Smokers in the combined total hip and knee arthroplasty cohort had higher 30-day readmission (4.8% vs 3.2%, P = .041), were more likely to have a surgical complication (odds ratio 1.84, 95% confidence interval 1.21-2.80), and had a higher rate of deep surgical site infection (SSI) (1.1% vs 0.2%, P = .007). Analysis of total hip arthroplasty only revealed that smokers had higher rates of deep SSI (1.3% vs 0.2%, P = .038) and higher readmission rate (4.3% vs 2.2%, P = .034). Analysis of total knee arthroplasty only revealed greater surgical complications (2.8% vs 1.2%, P = .048) and superficial SSI (1.8% vs 0.2%, P = .002) in smokers. CONCLUSION: Smoking in TJA is associated with higher rates of SSI, surgical complications, and readmission. PMID- 28870743 TI - Accuracy of Cup Positioning With the Computed Tomography-Based Two-dimensional to Three-Dimensional Matched Navigation System: A Prospective, Randomized Controlled Study. AB - BACKGROUND: The accuracy of various navigation systems used for total hip arthroplasty has been described, but no publications reported the accuracy of cup orientation in computed tomography (CT)-based 2D-3D (two-dimensional to three dimensional) matched navigation. METHODS: In a prospective, randomized controlled study, 80 hips including 44 with developmental dysplasia of the hips were divided into a CT-based 2D-3D matched navigation group (2D-3D group) and a paired-point matched navigation group (PPM group). The accuracy of cup orientation (absolute difference between the intraoperative record and the postoperative measurement) was compared between groups. Additionally, multiple logistic regression analysis was performed to evaluate patient factors affecting the accuracy of cup orientation in each navigation. RESULTS: The accuracy of cup inclination was 2.5 degrees +/- 2.2 degrees in the 2D-3D group and 4.6 degrees +/- 3.3 degrees in the PPM group (P = .0016). The accuracy of cup anteversion was 2.3 degrees +/- 1.7 degrees in the 2D-3D group and 4.4 degrees +/- 3.3 degrees in the PPM group (P = .0009). In the PPM group, the presence of roof osteophytes decreased the accuracy of cup inclination (odds ratio 8.27, P = .0140) and the absolute value of pelvic tilt had a negative influence on the accuracy of cup anteversion (odds ratio 1.27, P = .0222). In the 2D-3D group, patient factors had no effect on the accuracy of cup orientation. CONCLUSION: The accuracy of cup positioning in CT-based 2D-3D matched navigation was better than in paired-point matched navigation, and was not affected by patient factors. It is a useful system for even severely deformed pelvises such as developmental dysplasia of the hips. PMID- 28870744 TI - Total Joint Arthroplasty in Ambulatory Surgery Centers: Analysis of Disqualifying Conditions and the Frequency at Which They Occur. AB - BACKGROUND: The frequency of total joint arthroplasties (TJAs) performed in ambulatory surgery centers (ASCs) is increasing. However, not all TJA patients are healthy enough to safely undergo these procedures in an ambulatory setting. We examined the percentage of arthroplasty patients who would be eligible to have the procedure performed in a free-standing ASC and the distribution of comorbidities making patients ASC-ineligible. METHODS: We reviewed the charts of 3444 patients undergoing TJA and assigned ASC eligibility based on American Society of Anesthesiologists (ASA) status, a set of exclusion criteria, and any existing comorbidities. RESULTS: Overall, 70.03% of all patients undergoing TJA were eligible for ASC. Of the ASA class 3 patients who did not meet any exclusion criteria but had systemic disease (51.11% of all ASA class 3 patients), 53.69% were deemed ASC-eligible because of sufficiently low severity of comorbidities. The most frequent reasons for ineligibility were body mass index >40 kg/m2 (32.66% of ineligible patients), severity of comorbidities (28.00%), and untreated obstructive sleep apnea (25.19%). CONCLUSION: A large proportion of TJA patients were found to be eligible for surgery in an ASC, including over one third of ASA class 3 patients. ASC performed TJA provides an opportunity for increased patient satisfaction and decreased costs, selecting the right candidates for the ambulatory setting is critical to maintain patient safety and avoid postoperative complications. PMID- 28870745 TI - Failed Two-Stage Exchange: Factors Leading to Unachievable Endoprosthetic Reconstruction After Multiple Revision Surgeries. AB - BACKGROUND: Information about the outcome after failed 2-stage exchange is scarce. The aim of this study is to determine possible influencing factors leading to multiple revisions, resulting in a failed endoprosthetic joint reconstruction. METHODS: Medical records of patients (15 hip and 29 knee joints) who had undergone additional revision surgeries due to a failed 2-stage exchange were reviewed concerning infection parameters, number and type of procedure(s), current state of the revised joint, and whether failure of endoprosthetic reconstruction had occurred. RESULTS: Endoprosthetic reconstruction was achieved in 52.3% (n = 23) of the patients. About 36.4% (n = 16) of patients successfully reached the second stage of the initial 2-stage exchange. Half of the patients (n = 22) had to undergo spacer exchange in the initial interstage period. Five or more revision surgeries significantly increased the odds of failure of endoprosthetic reconstruction compared to patients with <5 revision surgeries (odds ratio 4.98, 95% confidence interval 1.34-18.4, P = .016). Patients with initial culture-negative revision surgery showed no significant differences in the odds of failure of endoprosthetic reconstruction (odds ratio 0.69, 95% confidence interval 0.20-2.43, P = .567). CONCLUSION: Patients undergoing re revision surgery due to a failed 2-stage exchange are very likely to ultimately experience a failed endoprosthetic reconstruction. The identification of the underlying pathogen does not influence the likelihood of a better outcome in terms of a successful endoprosthetic reconstruction. PMID- 28870746 TI - Incidence, Risk Factors, and Impact of Clostridium difficile Colitis Following Primary Total Hip and Knee Arthroplasty. AB - BACKGROUND: An improved understanding of Clostridium difficile is important as it is used as a measure of hospital quality and is associated with substantial morbidity. This study utilizes the National Surgical Quality Improvement Program to determine the incidence, timing, risk factors, and clinical implications of C difficile colitis in patients undergoing primary total hip or knee arthroplasty (THA or TKA). METHODS: Patients who underwent primary THA or TKA as part of the 2015 National Surgical Quality Improvement Program were identified. The primary outcome was a diagnosis of C difficile colitis within the 30-day postoperative period. Risk factors for the development of C difficile colitis were identified using Poisson multivariate regression. RESULTS: A total of 39,172 patients who underwent primary THA or TKA were identified. The incidence of C difficile colitis was 0.10% (95% confidence interval [CI] 0.07-0.13). Of the cases that developed C difficile colitis, 79% were diagnosed after discharge and 84% had not had a preceding infection diagnosed. Independent preoperative and procedural risk factors for the development of C difficile colitis were greater age (most notably >=80 years old, relative risk [RR] 5.28, 95% CI 1.65-16.92, P = .008), dependent functional status (RR 4.05, 95% CI 1.44-11.36, P = .008), preoperative anemia (RR 2.52, 95% CI 1.28-4.97, P = .007), hypertension (RR 2.51, 95% CI 1.06-5.98, P = .037), and THA (vs TKA; RR 2.25, 95% CI 1.16-4.36, P = .017). Postoperative infectious risk factors were urinary tract infection (RR 10.66, 95% CI 3.77 30.12, P < .001), sepsis (RR 17.80, 95% CI 3.77-84.00, P < .001), and "any infection" (RR 6.60, 95% CI 2.66-16.34, P < .001). CONCLUSION: High-risk patients identified in this study should be targeted with preventative interventions and have perioperative antibiotics judiciously managed. PMID- 28870747 TI - Development of a gallic acid-loaded chitosan and polyvinyl alcohol hydrogel composite: Release characteristics and antioxidant activity. AB - The physico-chemical properties of a chitosan and polyvinyl alcohol (CS/PVA) based hydrogel composite were investigated. Tetraethyl orthosilicate (TEOS) was employed as a crosslinking agent. The results indicated that the chitosan-based composite presented a thermal resistance up to 200 degrees C. The structural properties, which were evaluated using FTIR and DSC, showed good miscibility between chitosan and polyvinyl alcohol. SEM presented a compact and homogeneous structure. The release profile of the chitosan-based hydrogel composite was investigated using gallic acid (GA). It showed high antioxidant activities, which were monitored using DPPH radical scavenging. Diffusion of water into the chitosan-based hydrogel was assumed to be pseudo-Fickian in PBS solution. The CS/PVA-based hydrogel composite exhibited good properties as a drug delivery system. PMID- 28870748 TI - Sulfated polysaccharide of Sepiella Maindroni ink inhibits the migration, invasion and matrix metalloproteinase-2 expression through suppressing EGFR mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells. AB - Previous studies demonstrated that SIP-SII, a sulfated derivative of SIP that is isolated from the ink of Sepiella maindroni, showed significant inhibition of tumor growth and metastasis. In this study, the effects of SIP-SII on the migration, invasion and molecular mechanism in ovarian cancer cell line, SKOV-3 cells, were investigated. The flow cytometry, confocal microscope observation, western blot and RT-PCR results indicated that SIP-SII located on cell membrane and inhibited the expression and activation of epidermal growth factor receptor (EGFR). Moreover, the binding capacity of SIP-SII with EGFR was confirmed by surface plasmon resonance (SPR) analysis and co-localization of EGFR and SIP-SII. Accordingly, SIP-SII was proved to attenuate the EGF-induced EGFR phosphorylation and migration by western blot and wound healing assay, respectively. Additionally, SIP-SII inhibited p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells significantly. What is more, SIP-SII showed amplified inhibitory activity on migration, invasion, and MMP-2 expression in combination with p38 specific inhibitor, PI3K-specific inhibitor or mTOR-specific inhibitor in SKOV-3 cells. Therefore, the mechanism that SIP-SII suppressed EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways to inhibit migration and invasion of SKOV-3 cells was demonstrated. These findings suggested that SIP-SII might be used as a potential inhibitor against tumor metastasis. PMID- 28870749 TI - Bioprinting and its applications in tissue engineering and regenerative medicine. AB - Bioprinting of three-dimensional constructs mimicking natural-like extracellular matrix has revolutionized biomedical technology. Bioprinting technology circumvents various discrepancies associated with current tissue engineering strategies by providing an automated and advanced platform to fabricate various biomaterials through precise deposition of cells and polymers in a premeditated fashion. However, few obstacles associated with development of 3D scaffolds including varied properties of polymers used and viability, controlled distribution, and vascularization, etc. of cells hinder bioprinting of complex structures. Therefore, extensive efforts have been made to explore the potential of various natural polymers (e.g. cellulose, gelatin, alginate, and chitosan, etc.) and synthetic polymers in bioprinting by tuning their printability and cross-linking features, mechanical and thermal properties, biocompatibility, and biodegradability, etc. This review describes the potential of these polymers to support adhesion and proliferation of viable cells to bioprint cell laden constructs, bone, cartilage, skin, and neural tissues, and blood vessels, etc. for various applications in tissue engineering and regenerative medicines. Further, it describes various challenges associated with current bioprinting technology and suggests possible solutions. Although at early stage of development, the potential benefits of bioprinting technology are quite clear and expected to open new gateways in biomedical, pharmaceutics and several other fields in near future. PMID- 28870750 TI - Biosynthesis of Ag nanoparticles using isolated bacteria from contaminated sites and its application as an efficient catalyst for hydrazine electrooxidation. AB - In the present study, a bacterium resistance to heavy metals was isolated from contaminated areas. An eco-friendly and simple method was found to biosynthesis of silver nanoparticles (AgNPs) by reducing of aqueous Ag+ using the heavy metals resistance MKH1 bacterium. The biosynthesized AgNPs were characterized by UV-vis spectroscopy, scanning electron microscopy (SEM) and X-ray diffraction (XRD) techniques. A peak at about 420nm is related to absorption band of AgNPs which confirms by UV-vis spectroscopy. The SEM images showed that the biosynthesized AgNPs have mainly spherical shape with average diameters of 30-60nm. The electro catalytic properties of AgNPs with different Ag content were investigated by different electrochemical tests. Biosynthesized AgNPs using isolated MKH1 show high catalytic activity and stability towards the oxidation reaction of hydrazine. PMID- 28870751 TI - Molecular mechanism and characterization of self-assembly of feather keratin gelation. AB - Protein gels with controlled viscoelastic properties could find numerous material and biomedical applications. Feather keratin is naturally abundant protein while its gelation property has not been explored. In this study hydrogel from fully reduced feather keratin was prepared by dialysis. The objectives of this work were to study the molecular mechanism of self-assembly of feather keratin gel and to characterize the structural and viscoelastic properties of hydrogels prepared under various pHs (3-9) and temperatures (50-90 degrees C). Re-oxidation of free cysteine thiols and formation of hydrophobic interactions and hydrogen bond were determined as the main stabilizing forces in self-assembly of feather keratin gel. Adding thiol blocking agent of N-ethylmaleimide leads to reduced storage modulus of keratin gel; gelation was completely inhibited at 82% blockage of free thiols. Increasing temperature decreased storage modulus, while gelation at pH 3 resulted in stiffer gels compared to pHs of 5, 7 and 9. Feather keratin gels with tunable viscoelastic properties could find applications as engineered scaffolds for different tissues. PMID- 28870752 TI - Sarbohydrate binding module CBM28 of endoglucanase Cel5D from Caldicellulosiruptor bescii recognizes crystalline cellulose. AB - Optimal catalytic activity of endoglucanase Cel5D from the thermophilic anaerobic bacterium Caldicellulosiruptor bescii requires the presence of a carbohydrate binding module of family 28, CbCBM28. The binding properties of CbSVM28 with cello-, laminari-, xylo- and chito-oligosaccharides were studied by isothermal titration calorimetry. CbSVM28 bound only cello-oligosaccharides comprising at least four glucose residues with binding constants of 2.5.104 and 2.2.106M-1 for cellotetraose and cellohexaose, respectively. The interaction between CbSVM28 and amorphous cellulose is best described by a two-binding-site model with the binding constants of 1.5.105 and 1.9.105M-1. In a competitive binding assay in the presence of a 10-fold excess of cellohexaose the binding constant of CbSVM28 to amorphous cellulose was 1.9.105M-1. A two-binding-site model also better approximates the binding to Avicel with the binding constants of 8.3.105 and 3.2.104M-1; while in the presence of cellohexaose, the binding is described by a single-binding-site model with the binding constant of 2.3.104M-1. With CbSVM28 binding to bacterial crystalline cellulose with a constant of 7.4.104M-1, this is the first report of such a strong binding to crystalline cellulose for a module of family 28. PMID- 28870753 TI - Synthesis of Ag@Fe2O3 nanocomposite based on O-carboxymethylchitosan with antimicrobial activity. AB - In this paper, nano-hybrid particles of Ag@Fe2O3 based on O-carboxymethylchitosan were successfully synthesized using different reducing agents (NaBH4, sucrose) and without reducing agent. The smallest silver nanoparticles were those prepared without reducing agent (~5+/-3nm). The average size of silver particles prepared with NaBH4 is around 5-15nm, and for samples prepared with sucrose, the average particle size is 10-25nm. The magnetization curves are roughly reversible, indicating that gamma-Fe2O3 nanoparticles transit to a superparamagnetic state. Nanocomposites subjected to antimicrobial tests showed great antimicrobial activity against gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) bacteria, and good activity against the yeast Candida albicans and resistant strains of Staphylococcus aureus. The antibacterial behavior as a function of time was investigated in microbial growth kinetics, and the best nanocomposite was the one without reducing agent, which completely inhibited microbial growth for 48h. PMID- 28870754 TI - Clinical and non-clinical depression and anxiety in young people: A scoping review on heart rate variability. AB - BACKGROUND: Heart rate variability (HRV), a measure of cardiac autonomic nervous system functioning, has emerged as a physiological indicator for emotional regulation and psychological well-being. HRV is understudied in the context of depression and anxiety in young people (10-24years old). Main objectives: (1) describe the nature and breadth of reviewed studies; and (2) synthesize main findings in the context of clinical and non-clinical populations of young people with depression and/or anxiety. METHODS: The Arksey and O'Malley methodology was utilized for this scoping review. CINHAL, EMBASE, Medline, PsychInfo, Scopus, Web of Science, as well as grey literature, were searched. Two reviewers screened titles, abstracts and full papers for inclusion. A total of 20 citations were included in the final review (19 citations peer-reviewed journal articles, 1 journal abstract). Numerical and thematic analysis was used to summarize study findings. RESULTS: In clinical populations of either depression or anxiety, HRV was lower compared to controls. In non-clinical populations of either depression or anxiety, HRV was found to be lower in those who reported more depression or anxiety symptoms. LIMITATIONS: The quality of the reviewed articles was not assessed which limits the ability to generate conclusions regarding study findings. CONCLUSION: Changes in HRV were found across the spectrum of clinical and non-clinical populations of young people with depression or anxiety. Neurophysiological research on depression and anxiety in young people can act as a first step to understanding how physiological flexibility (i.e. HRV) is related to psychological flexibility (i.e. adaptive or maladaptive responses to life events). PMID- 28870755 TI - High seroprevalence of Toxoplasma gondii and probability of detecting tissue cysts in backyard laying hens compared with hens from large free-range farms. AB - Serological assays are commonly used to determine the prevalence of Toxoplasma gondii infection in livestock, but the predictive value of seropositivity with respect to the presence of infective tissue cysts is less clear. The present study aimed at the identification of seropositive and seronegative free-range laying hens from organic and backyard farms, and the relationship with the presence of viable tissue cysts. In addition, potential risk and protective factors on the selected farms were investigated. An in-house T. gondii surface antigen (TgSAG1, p30, SRS29B) ELISA was validated with sera from experimentally infected chickens and used to examine 470 serum samples collected from laying hens from large organic and small backyard farms at the end of their laying period. A total of 11.7% (55/470) of all chickens tested positive, and another 18.9% (89/470) of test results were inconclusive. The highest seroprevalences were observed on small backyard farms with 47.7% (41/86) of chickens being seropositive while another 20.9% (18/86) of test results were inconclusive. Twenty-nine seropositive, 20 seronegative and 12 laying hens which yielded inconclusive ELISA results, were selected for further examination. Hearts and limb muscles of these hens were examined for T. gondii tissue cysts in a bioassay with IFNgamma-knockout or IFNgamma-receptor-knockout mice. Viable T. gondii was isolated from 75.9% (22/29) of the seropositive, 25.0% (3/12) of the inconclusive, and 5.0% (1/20) of the seronegative chickens. All 26 chickens tested positive in heart samples, while drumstick muscles (i.e. limb muscles) tested positive only in three. Data on putative risk and protective factors were collected on the farms using a standard questionnaire. Generalised multilevel modelling revealed farm size, cat related factors ('cats on the premise', 'cats used for rodent control'), hen house/hall related factors ('size category of hen house/hall', 'frequency category of cleaning hen house/hall', 'service period') as significantly associated with seropositivity to T. gondii in hens. The final model, which included the age of the birds as an effect modifier and farm as a random effect variable, revealed that the use of cats for rodent control and an area available per hen in the chicken run of >=10sqm were statistically significant risk factors for T. gondii seropositivity. Overall this study showed that exposure to T. gondii is common in small backyard farms but is rare on large organic farms with a high density of free-range hens, even when cats were present on the premises. PMID- 28870756 TI - Stabilization of hyperforin dicyclohexylammonium salt with dissolved albumin and albumin nanoparticles for studying hyperforin effects on 2D cultivation of keratinocytes in vitro. AB - Due to the limited chemical stability of the natural hyperforin molecule, a more stable form of hyperforin, i.e., the hyperforin dicyclohexylammonium salt (HYP DCHA) has been used for ex vivo and in vitro experiments in recent years, but its actual stability under typical cell culture conditions has never been studied before. In this contribution the stability of HYP-DCHA was examined under typical cell culture conditions. Different cell culture media with and without fetal calf serum (FCS) supplementation were studied with regard to further stabilization of HYP-DCHA determined with HPLC analysis. Furthermore, albumin nanoparticles were examined as a stabilizing carrier system for HYP-DCHA. In this context, the interaction between HYP-DCHA and albumin nanoparticles (ANP) was examined with regard to size and loading with HYP . The effects of HYP-DCHA either supplied in cell culture medium or loaded on ANP on viability and cytotoxicity were studied in vitro on HaCaT monolayers (human keratinocyte cell line). HYP-DCHA supplied in FCS-containing medium was recovered completely after 24h of incubation. However, a lack of FCS caused a total loss of HYP-DCHA after less than 24h incubation time. Supplying HYP-DCHA loaded on ANP in an FCS-free medium resulted in a recovery of about 60% after 24h incubation. HYP-DCHA supplied in medium along with FCS showed a slow dose-dependent decrease in viability of HaCaT cells without any cytotoxic effects (antiproliferative effect). Treatment with HYP-DCHA with a lack of FCS resulted in a significantly faster decrease in viability which was mainly due to cytotoxicity. The latter was true for HYP-DHCA-loaded ANP where increased cytotoxicity was observed despite the presence of FCS. The results show that the stability of the widely used HYP-DCHA is rather limited under cell culture conditions. Especially a lack of FCS leads to degradation and/or oxidation of HYP-DCHA probably causing an increased cytotoxicity. In contrast, FCS supplementation fairly stabilizes HYP-DCHA under cell culture conditions while albumin nanoparticles may serve the same stabilization purpose despite increasing cytotoxic effects onto the cells themselves. PMID- 28870757 TI - Global effect of CsrA on gene expression in enterohemorrhagic Escherichia coli O157:H7. AB - The post-transcriptional regulator CsrA regulates multiple unrelated processes such as central carbon metabolism, motility, biofilm formation and bacterial virulence in different bacteria. However, regulation by CsrA in enterohemorrhagic Escherichia coli (EHEC) O157:H7 is still largely unknown. In this study, we performed a detailed analysis of gene expression differences between the EHEC O157:H7 wild-type strain and a corresponding csrA::kan mutant using RNA-seq technology. Genes whose expression was affected by CsrA were identified and grouped into different clusters of orthologous group categories. Genes located in the locus of enterocyte effacement (LEE) pathogenicity island were significantly upregulated, whereas expression of flagella-related genes was significantly reduced in the csrA::kan mutant. Subsequent bacterial adherence and motility assays showed that inactivation of CsrA in EHEC O157:H7 resulted in a significant increase in bacterial adherence to host epithelial cells, with a concomitant loss of swimming motility on semi-solid agar plates. Furthermore, we also found that CsrA regulates genes not previously identified in other bacterial species, including genes encoding cytochrome oxidases and those required for nitrogen metabolism. Our results provide essential insight into the regulatory function of CsrA. PMID- 28870758 TI - Posterior condylar offset influences the intraoperative soft tissue balance during posterior-stabilized total knee arthroplasty. AB - PURPOSE: This study aimed to clarify the influence of the posterior condylar offset (PCO) on intraoperative soft tissue balance including the joint component gap and varus ligament balance measured by an offset-type tensor during posterior stabilized (PS) total knee arthroplasty (TKA). METHODS: In this study, 35 patients with osteoarthritis of the knee underwent PS TKA. Intraoperative soft tissue balance including the joint component gap and varus/valgus ligament balance were assessed at 0 degrees , 10 degrees , 45 degrees , 90 degrees , and 135 degrees of flexion with an offset-type tensor that could be used with the femoral component placement and patellofemoral joint reduction. The correlations between the postoperative PCO and the intraoperative soft tissue balance parameters were assessed using simple regression analysis. RESULTS: The joint component gap at 0 degrees extension was inversely correlated with the PCO (R = 0.41, p < 0.05). The joint component gap of 10 degrees -0 degrees was positively correlated with the PCO (R = 0.35, p < 0.05). No other soft tissue balance parameters were correlated with the PCO. CONCLUSIONS: A larger PCO was confirmed to reduce joint component gap in extension but not always in flexion in PS TKA. PMID- 28870759 TI - Recurrent patellar dislocation with spontaneous valgus knee deformity treated by distal femoral osteotomy alone: A report of two cases. PMID- 28870760 TI - Endoscopic management of erosion after banded bariatric procedures. AB - BACKGROUND: Prosthetic materials wrapped around a portion of the stomach have been used to provide gastric restriction in bariatric surgery for many years. Intraluminal erosion of adjustable and nonadjustable gastric bands typically occurs many years after placement and results in various symptoms. Endoscopic management of gastric band erosion has been described and allows for optimal patient outcomes. OBJECTIVES: We will describe our methods and experience with endoscopic management of intraluminal gastric band erosions after bariatric procedures. SETTING: University hospital in the United States. METHODS: A retrospective review of our bariatric surgery database identified patients undergoing removal of gastric bands. A chart review was then undertaken to confirm erosion of prosthetic material into the gastrointestinal tract. Baseline characteristics, operative reports, and follow-up data were analyzed. RESULTS: Sixteen patients were identified with an eroded gastric band: 11 after banded gastric bypass, 3 after laparoscopic adjustable gastric band (LAGB), and 2 after vertical banded gastroplasty. All patients were successfully treated with endoscopic removal of the prosthetic materials using either endoscopic scissors or ligation of the banding material with off-label use of a mechanical lithotripter device. Complications included a postoperative gastrointestinal bleed requiring repeat endoscopy, 1 patient with asymptomatic pneumoperitoneum requiring observation, and 1 with seroma at the site of LAGB port removal. CONCLUSIONS: Endoscopic management of intraluminal prosthetic erosion after gastric banded bariatric procedures can be safe and effective and should be considered when treating this complication. Erosion of the prosthetic materials inside the gastric lumen allows for potential endoscopic removal without free intraabdominal perforation. Endoscopic devices designed for dividing eroded LAGBs may help standardize and increase utilization of this approach. PMID- 28870761 TI - An outbreak of acute respiratory illnesses in primary school children with low vaccine uptake, UK, 2016. PMID- 28870762 TI - Peripheral nerve and diclofenac sodium: Molecular and clinical approaches. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed medications worldwide. Diclofenac sodium (DS), one of these NSAIDs, has a high specificity for arachidonic acid-degrading cyclooxygenase (COX)-2 enzymes. This drug can be used to relieve neuropathic pain. In this review, we examine the relevant researches, including in vivo, animal, and clinical human studies, with the aim of understanding the effect of DS on the peripheral nerves. In injured nerves, COX-2 is potently upregulated around the injury site. When a nerve is damaged, both COX-1 and COX-2 expression is increased in macrophages and Schwann cells. In addition, COX inhibitors can promote axonal outgrowth in cultured neurons. Neuropathic pain occurs after injury and leads to dysfunction of the peripheral nervous system. NSAIDs can modulate the nociceptive and inflammatory pain pathways and control neuropathic pain. DS may accelerate nerve regeneration and its effects on healing, as well as causing deleterious effects in the developing nerves. DS teratogenicity disrupts myelin sheath thickness and axon structure. Understanding the possible benefits and limitations of DS and specific conditions such as prenatal use will be of benefit in clinical practice. PMID- 28870763 TI - Engineering PLGA nano-based systems through understanding the influence of nanoparticle properties and cell-penetrating peptides for cochlear drug delivery. AB - The properties of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and penetration enhancers play a deciding role in the inner ear drug delivery of NPs across the round window membrane (RWM). Thus, PLGA nano-based systems with a variety of particle sizes and surface chemistries and those combined with cell penetrating peptides (CPPs) as penetration enhancers were devised to explore their impact on the cochlear drug delivery in vivo. First, we demonstrated that the properties of NPs dictated the extent of NP cochlear entry by near-infrared fluorescence imaging. NPs with the sizes of 150 and 300nm had faster entry than that of 80nm NPs. At 0.5h, among the NPs unmodified and modified with chitosan (CS), poloxamer 407 (P407) and methoxy polyethylene glycol, CS-PLGA-NPs (positive surface charge) carried payload to the cochlea fastest, whereas P407-PLGA-NPs (surface hydrophilicity) showed the greatest distribution in the cochlea at 24h. Compared to other CPPs (TAT, penetratin and poly(arginine)8), low molecular weight protamine (LMWP) performed an outstanding enhanced NP cellular uptake in HEI-OC1 cells and cochlear entry. More importantly, NPs with optimized properties and CPPs may be combined to improve RWM penetration. For the first time, we confirmed that the combination of P407-PLGA-NPs (mean diameter: 100-200nm) and LMWP provided a synergistic enhancement in NP entry to the organ of Corti and stria vascularis without inducing pathological alteration of cochlear tissues and RWM. Taken together, we propose an effective PLGA nano-based strategy for enhanced drug delivery to the inner ear tissues that combines hydrophilic molecule-modified NPs and CPPs, ultimately opening an avenue for superior inner ear therapy. PMID- 28870764 TI - Supersaturating drug delivery systems: The potential of co-amorphous drug formulations. AB - Amorphous solid dispersions (ASDs) are probably the most common and important supersaturating drug delivery systems for the formulation of poorly water-soluble compounds. These delivery systems are able to achieve and maintain a sustained drug supersaturation which enables improvement of the bioavailability of poorly water-soluble drugs by increasing the driving force for drug absorption. However, ASDs often require a high weight percentage of carrier (usually a hydrophilic polymer) to ensure molecular mixing of the drug in the carrier and stabilization of the supersaturated state, often leading to high dosage volumes and thereby challenges in the formulation of the final dosage form. As a response to the shortcomings of the ASDs, the so-called co-amorphous formulations, which are amorphous combinations of two or more low molecular weight components, have emerged as an alternative formulation strategy for poorly-soluble drugs. While the current research on co-amorphous formulations is focused on preparation and characterization of these systems, more detailed research on their supersaturation and precipitation behavior and the effect of co-formers on nucleation and crystal growth inhibition is needed. The current status of this research is reviewed in this paper. Furthermore, the potential of novel preparation methods for co-amorphous systems with respect to the current preparation methods are discussed. PMID- 28870765 TI - A review of patient-specific gastrointestinal parameters as a platform for developing in vitro models for predicting the in vivo performance of oral dosage forms in patients with Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease that presents with visible motor symptoms, but that is accompanied by several additional symptoms, including gastrointestinal symptoms that may affect pharmacokinetics of oral medications. A detailed understanding of the nature of PD-specific gastrointestinal parameters and of how they may affect drug release of orally administered dosage forms seems to be essential information for developing better oral PD medications. The availability of bio-predictive drug release models simulating PD-specific gastrointestinal parameters would also be beneficial for this purpose. The focus of the present literature review was to determine PD specific gastrointestinal parameters that will allow for the development of a test methodology simulating the gastrointestinal passage of orally administered medications in PD patients. Whereas for some gastrointestinal segments there is quite a reasonable set of data available on fluid volumes, motility and passage times, for others there is still a big lack in information that would be required for simulating a detailed gastrointestinal passage in a PD patient. The latter is particularly true for potential disease-related changes in gastrointestinal fluid composition. However, with the availability of novel non-invasive diagnostic options there is a chance of obtaining more information in the near future. PMID- 28870766 TI - Mechanistic modeling of a capsule filling process. AB - Filling a dosator nozzle moving into a powder bed was investigated using the Discrete Element Method (DEM). Various particle diameters and contact properties were modeled. The simulations qualitatively showed the influence of powder properties on the amount of dosed powder. Two factors that influence the dosed mass were observed. First, the ratio between the particle and dosator diameters affects the packing of particles inside the dosator chamber. Second, the flow behavior of the powder significantly modifies its filling and compression behavior. Cohesive powders pack less densely inside the powder bed, which could lead to a lower amount of dosed powder. In contrast, cohesive powders are compressed more during dosing and the density inside the dosator chamber increases during the dosing process. Since the simulation of fine cohesive powders is numerically impossible due to a high number of particles and small simulation time steps, we applied a simple method for particle scaling to acquire a qualitative understanding of the filling behavior of coarse and fine powders. PMID- 28870767 TI - Broadening the spectrum of small-molecule antibacterials by metallic nanoparticles to overcome microbial resistance. AB - Now-a-days development of microbial resistancce have become one of the most important global public health concerns. It is estimated that about 2 million people are infected in USA with multidrug resistant bacteria and out of these, about 23,000 die per year. In Europe, the number of deaths associated with infection caused by MDR bacteria is about 25,000 per year, However, the situation in Asia and other devloping countries is more critical. Considering the increasing rate of antibiotic resistance in various pathogens, it is estimated that MDR organisms can kill about 10 million people every year by 2050. The use of antibiotics in excessive and irresponsible manner is the main reason towards its ineffectiveness. However, in this context, promising application of nanotechnology in our everyday life has generated a new avenue for the development of potent antimicrobial materials and compounds (nanoantimicrobials) capable of dealing with microbial resistance. The devlopement and safe incorporation of nanoantimicrobials will bring a new revolution in health sector. In this review, we have critically focused on current worldwide situation of antibiotic resistance. In addition, the role of various nanomaterials in the management of microbial resistance and the possible mechanisms for antibacterial action of nanoparticles alone and nanoparticle-antibiotics conjuagte are also discussed. PMID- 28870768 TI - Sponge like microparticles for drug delivery and cosmeto-textile use: Formulation and human skin penetration. AB - This unique work is targeted to achieve three main goals: i) to enhance the aqueous solubility of three specifically selected hydrophobic active agents, ii) to prepare such polymeric biodegradable microparticles which can encapsulate actives-cyclodextrin complexes and iii) to functionalize a polyamide base textile with active loaded microparticles and active-cyclodextrin loaded microparticles. To achieve this objective, biodegradable cationic microparticles were prepared via double emulsion solvent evaporation process and were loaded with hydroxypropyl-beta-cyclodextrin based complexes of Indomethacin, alpha tocopheroland Lauryl Isoquinolinium Bromide during the formulation process. Inclusion complex based particles were evaluated for their morphology, size distribution, zeta potential, skin penetration aptitude and adsorption onto a selected textile. It was observed that active-cyclodextrin complex encapsulation do not affect the morphology, size and zeta potential of the microparticles as well as adsorption of the microparticles onto textile remains unaltered. However such active-cyclodextrin complex encapsulated particles provided the enhancement in the aqueous solubility of hydrophobic agents and also provided prolonged release formulations. PMID- 28870769 TI - Progressing neurobiological strategies against proteostasis failure: Challenges in neurodegeneration. AB - Proteins are ordered useful cellular entities, required for normal health and organism's survival. The proteome is the absolute set of cellular expressed proteins, which regulates a wide range of physiological functions linked with all domains of life. In aging cells or under unfavorable cellular conditions, misfolding of proteins generates common pathological events linked with neurodegenerative diseases and aging. Current advances of proteome studies systematically generates some progress in our knowledge that how misfolding of proteins or their accumulation can contribute to the impairment or depletion of proteome functions. Still, the underlying causes of this unrecoverable loss are not clear that how such unsolved transitions give rise to multifactorial challengeable degenerative pathological conditions in neurodegeneration. In this review, we specifically focus and systematically summarize various molecular mechanisms of proteostasis maintenance, as well as discuss progressing neurobiological strategies, promising natural and pharmacological candidates, which can be useful to counteract the problem of proteopathies. Our article emphasizes an urgent need that now it is important for us to recognize the fundamentals of proteostasis to design a new molecular framework and fruitful strategies to uncover how the proteome defects are associated with aging and neurodegenerative diseases. A enhance understanding of progress link with proteome and neurobiological challenges may provide new basic concepts in the near future, based on pharmacological agents, linked with impaired proteostasis and neurodegenerative diseases. PMID- 28870770 TI - Mechanisms of the Improvement in Peak VO2 With Exercise Training in Heart Failure With Reduced or Preserved Ejection Fraction. AB - Heart failure (HF) is a major health care burden associated with high morbidity and mortality. Approximately 50% of HF patients have reduced ejection fraction (HFrEF) while the remainder of patients have preserved ejection fraction (HFpEF). A hallmark of both HF phenotypes is dyspnoea upon exertion and severe exercise intolerance secondary to impaired oxygen delivery and/or use by exercising skeletal muscle. Exercise training is a safe and effective intervention to improve peak oxygen uptake (VO2peak) and quality of life in clinically stable HF patients, however, evidence to date suggests that the mechanism of this improvement appears to be related to underlying HF phenotype. The purpose of this review is to discuss the role of exercise training to improve VO2peak, and how the central and peripheral adaptations that mediate the improvements in exercise tolerance may be similar or differ by HF phenotype (HFrEF or HFpEF). PMID- 28870771 TI - Identification and antimicrobial susceptibility of clinical Nocardia species in a tertiary hospital in China. AB - OBJECTIVES: There is a lack of information on the activities of antimicrobial agents against Nocardia clinical isolates of specific species in China. The aim of this study was to determine the antibiotic susceptibility of 28 clinical isolates of Nocardia spp. isolated from Beijing Chao-Yang Hospital (Beijing, China). METHODS: Molecular diagnosis of Nocardia spp. was performed using partial 16S rRNA and rpoB gene sequences. Antimicrobial susceptibility testing was performed by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) recommendations. RESULTS: The species distribution was as follows: Nocardia cyriacigeorgica (n=13); Nocardia farcinica (n=6); Nocardia beijingensis (n=3); Nocardia abscessus (n=2); Nocardia wallacei (n=2); Nocardia otitidiscaviarum (n=1); and Nocardia nova (n=1). The susceptibility rates to trimethoprim/sulfamethoxazole (SXT), linezolid, amikacin, imipenem, tobramycin, ceftriaxone and cefotaxime were 100.0%, 100.0%, 92.9%, 75.0%, 67.9%, 67.9% and 64.3%, respectively, whilst the resistance rate both to ciprofloxacin and clarithromycin was 71.4%. CONCLUSIONS: N. cyriacigeorgica was the most frequently isolated Nocardia spp. All clinical isolates showed low susceptibility to ciprofloxacin and clarithromycin and complete susceptibility both to SXT and linezolid, which can be considered the primary choice for the treatment of Nocardia infections in China. PMID- 28870772 TI - The dissolvable bead: A novel in vitro biofilm model for evaluating antimicrobial resistance. AB - In vitro biofilm assays are a vital first step in the assessment of therapeutic effectiveness. Current biofilm models have been found to be limited by throughput, reproducibility, and cost. We present a novel in vitro biofilm model, utilising a sodium alginate substratum for surface biofilm colony formation, which can be readily dissolved for accurate evaluation of viable organisms. The dissolving bead biofilm assay was evaluated using a range of clinically relevant strains. The reproducibility and responsiveness of the assay to an antimicrobial challenge was assessed using standardised methods. Cryo-scanning electron microscopy was used to image biofilm colonies. Biofilms were grown for 20h prior to testing. The model provides a reproducible and responsive assay to clinically relevant antimicrobial challenges, as defined by established guidelines. Moreover cryo-scanning electron microscopy demonstrates that biofilm formation is localised exclusively to the alginate bead surface. Our results suggest that this simple model provides a robust and adaptable assay for the investigation of bacterial biofilms. PMID- 28870774 TI - ETS transcription factor family member GABPA contributes to vitamin D receptor target gene regulation. AB - Binding motifs of the ETS-domain transcription factor GABPA are found with high significance below the summits of the vitamin D receptor (VDR) cistrome. VDR is the nuclear receptor for the biologically most active vitamin D metabolite 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). In this study, we determined the GABPA cistrome in THP-1 human monocytes and found that it is comprised of 3822 genomic loci, some 20% of which were modulated by 1,25(OH)2D3. The GABPA cistrome showed a high overlap rate with accessible chromatin and the pioneer transcription factor PU.1. Interestingly, 23 and 12% of persistent and transient VDR binding sites, respectively, co-localized with GABPA, which is clearly higher than the rate of secondary VDR loci (4%). Some 40% of GABPA binding sites were found at transcription start sites, nearly 100 of which are of 1,25(OH)2D3 target genes. On 593 genomic loci VDR and GABPA co-localized with PU.1, while only 175 VDR sites bound GABPA in the absence of PU.1. In total, VDR sites with GABPA co localization may control some 450 vitamin D target genes. Those genes that are co controlled by PU.1 preferentially participate in cellular and immune signaling processes, while the remaining genes are involved in cellular metabolism pathways. In conclusion, GABPA may contribute to differential VDR target gene regulation. PMID- 28870775 TI - Ethical Challenges in Hematopoietic Cell Transplantation for Sickle Cell Disease. AB - Hematopoietic cell transplantation (HCT) using an HLA-identical sibling donor offers a very high likelihood of cure with good outcomes for patients with sickle cell disease (SCD), and alternative donor HCT for SCD is an area of active clinical research. Thus, HCT is a potential option for a growing number of patients with SCD. This expanded use of HCT has raised several ethical questions. Who is eligible for HCT, in terms of both disease severity and psychosocial factors? Should affected children with matched sibling donors undergo HCT only when they have declared themselves as having significant symptomatology? Regarding donors, special ethical challenges include the use of preimplantation genetic diagnosis to conceive an HLA-identical sibling. In this review, we critically analyze various ethical challenges related to HCT for SCD, and offer recommendations to guide clinical care. PMID- 28870773 TI - Mitochondrial cytochrome c oxidase biogenesis: Recent developments. AB - Mitochondrial cytochrome c oxidase (COX) is the primary site of cellular oxygen consumption and is essential for aerobic energy generation in the form of ATP. Human COX is a copper-heme A hetero-multimeric complex formed by 3 catalytic core subunits encoded in the mitochondrial DNA and 11 subunits encoded in the nuclear genome. Investigations over the last 50 years have progressively shed light into the sophistication surrounding COX biogenesis and the regulation of this process, disclosing multiple assembly factors, several redox-regulated processes leading to metal co-factor insertion, regulatory mechanisms to couple synthesis of COX subunits to COX assembly, and the incorporation of COX into respiratory supercomplexes. Here, we will critically summarize recent progress and controversies in several key aspects of COX biogenesis: linear versus modular assembly, the coupling of mitochondrial translation to COX assembly and COX assembly into respiratory supercomplexes. PMID- 28870776 TI - Consensus Report by the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees on Supportive Care Guidelines for Management of Veno-Occlusive Disease in Children and Adolescents, Part 3: Focus on Cardiorespiratory Dysfunction, Infections, Liver Dysfunction, and Delirium. AB - Some patients with veno-occlusive disease (VOD) have multiorgan dysfunction, and multiple teams are involved in their daily care in the pediatric intensive care unit. Cardiorespiratory dysfunction is critical in these patients, requiring immediate action. The decision of whether to use a noninvasive or an invasive ventilation strategy may be difficult in the setting of mucositis or other comorbidities in patients with VOD. Similarly, monitoring of organ functions may be very challenging in these patients, who may have fulminant hepatic failure with or without hepatic encephalopathy complicated by delirium and/or infections. In this final guideline of our series on supportive care in patients with VOD, we address some of these questions and provide evidence-based recommendations on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees. PMID- 28870777 TI - Effects of Late Toxicities on Outcomes in Long-Term Survivors of Ex-Vivo CD34+ Selected Allogeneic Hematopoietic Cell Transplantation. AB - The late adverse events in long-term survivors after myeloablative-conditioned allogeneic hematopoietic cell transplantation (HCT) with ex vivo CD34+ cell selection are not well characterized. Using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0, we assessed all grade >=3 toxicities from the start of conditioning to the date of death, relapse, or last contact in 131 patients who survived >1 year post-HCT, identifying 285 individual toxicities among 17 organ-based toxicity groups. Pretransplantation absolute lymphocyte count >.5 K/uL and serum albumin >4.0 g/dL were associated with a reduced risk of toxicities, death, and nonrelapse mortality (NRM), whereas serum ferritin >1000 ng/mL was associated with an increased risk of toxicities and NRM after 1 year. An HCT Comorbidity Index (HCT CI) score >=3 was associated with an increased risk of all-cause death and NRM, but was not associated with a specific increased toxicity risk after 1 year. Patients who incurred more than the median number of toxicities (n = 7) among all patients within the first year subsequently had an increased risk of hematologic, infectious, and metabolic toxicities, as well as an increased risk of NRM and inferior 4-year overall survival (OS) (67% versus 86%; P = .003) after the 1-year landmark. The development of grade II-IV acute graft-versus-host disease (GVHD) within the first year was associated with incurring >7 toxicities within the first year (P = .016), and also with an increased risk of all-cause death and NRM after 1 year. In multivariate models, cardiovascular, hematologic, hepatic, infectious, metabolic, neurologic, and pulmonary toxicities incurred after 1 year were independently associated with increased risk of death and NRM when adjusting for both HCT-CI and grade II-IV acute GVHD within the first year. One-year survivors of ex vivo CD34+ selection had a favorable 4-year OS of 77%, although the development of grade >=3 toxicities after the first year was associated with poorer outcomes, emphasizing the fundamental importance of improving survivorship efforts that may improve long-term toxicity burden and outcome. PMID- 28870778 TI - Outcome Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia Treated with Total Body Irradiation-Free Allogeneic Hematopoietic Stem Cell Transplantation: Comparison of Patients with and Without Central Nervous System Involvement. AB - Hematopoietic stem cell transplantation (HSCT) with a non-total body irradiation (TBI) conditioning regimen has proven feasible for treating patients with acute lymphoblastic leukemia (ALL). However, it is commonly believed that for extramedullary involvement of ALL in sanctuary sites, such as the central nervous system (CNS), TBI shall not be abandoned. In this study, the outcomes of pediatric ALL patients with CNS involvement (CNS+) and without CNS involvement (CNS-) treated with TBI-free allogeneic HSCT were retrospectively compared. The patients received a TBI-free busulfan plus cyclophosphamide conditioning regimen. Comparing CNS+ (n = 27) and CNS- (n = 134) patients, the 5-year probabilities of relapse (44.4% versus 41.8%; P = .799), disease-free survival (DFS; 48.1% versus 43.3%; P = .642) and overall survival (OS; 51.9% versus 47.0%; P = .646) were not significantly different. Although transplantation-related mortality (TRM) was higher in the CNS- patients, the difference between the 2 groups was not significant (3.7% versus 12.7%; P = .177). In multivariate analysis, there were no significant between-group differences in OS (P = .502), DFS (P = .424), relapse rate (P = .226), or TRM (P = .117). These findings suggest that HSCT using a non-TBI-containing conditioning regimen can lead to similar outcomes in pediatric ALL patients with and without CNS involvement. TBI-free allogeneic HSCT might be feasible and effective for CNS+ ALL patients. PMID- 28870779 TI - Epitestosterone- and testosterone-replacement in immature castrated rats changes main testicular developmental characteristics. AB - Epitestosterone is the 17alpha-epimer of testosterone and has been described as an anti-androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the nuclear androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca2+ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells. PMID- 28870780 TI - Mutational analysis of rare subtypes of congenital adrenal hyperplasia in a highly inbred population. AB - CONTEXT: Apart from 21 Hydroxylase deficiency, other subtypes of congenital adrenal hyperplasia (CAH) are rare. We studied the clinical features and molecular genetics of a relatively large series of patients with CYP17A1, HSD3beta2 and StAR deficiencies. PATIENTS AND METHODS: We studied 21 patients including 7 patients with CYP17A1, 10 patients with HSD3beta2 and 4 patients with StAR deficiencies. For mutation detection, we isolated DNA from peripheral leucocytes, amplified genes of interest using polymerase chain reaction and directly sequenced the amplicons using Dideoxy Chain Termination method. RESULTS: Regardless of their karyotype, patients with CYP17A1 deficiency presented with normally looking external female genitalia and were raised as females. Hypertension and hypokalemia were prominent features in 4 of 7 patients. Two missense (p.R416H, p.R239Q) and 2 non-sense (p.Y329X, p.Y329X) mutations were found in these 7 cases. In 3 unrelated families with 10 affected siblings with HSD3beta2 mutations, two non-sense mutations were found (p.Q334X, p.R335X). 46XY patients with HSD3beta2 deficiency presented with ambiguous genitalia while 46XX patients presented with normal female external genitalia. Adrenal crisis was common in patients with both karyotypes. In the 4 patients with StAR deficiency, both genetic male and female patients presented with normally looking female external genitalia and adrenal crisis. One previously reported missense mutation (p.R182H) was found in 3 unrelated patients and a novel non-sense mutation (p.Q264X) in the fourth patient. CONCLUSIONS: These cases of rare subtypes of CAH illustrate the heterogeneous phenotypic and genetic features of these subtypes and add unique novel mutations to the previously known ones. PMID- 28870781 TI - Aberrant G protein-receptor expression is associated with DNA methylation in aldosterone-producing adenoma. AB - This study aimed to evaluate the methylation levels of G protein-coupled receptor (GPCR) related genes and the effects of methylation on mRNA expression levels in aldosterone-producing adenoma (APA). DNA methylation array and transcriptome analysis were applied in non-functioning adrenocortical adenoma (NFA) and APA. We investigated 192 GPCR-related genes and found hypo-methylation in the promoter region of 66 of these genes in APA. An integration study between microarray and methylation analysis revealed that HTR4, MC2R, TACR1, GRM3, and PTGER1 showed hypo-methylation and up-regulation of mRNA in APA. qPCR analysis showed that HTR4 and PTGER1 expression was 9.3-fold and 6.6-fold higher in APAs than in NFAs, respectively, whereas expression of the other genes was not different between the groups. Methylation of HTR4 and PTGER1 at positions -229 and -666 from the transcription start site, respectively, showed a significant inverse correlation with their mRNA levels. Methylation levels were not associated with KCNJ5 or ATP1A1 mutations in human adrenal samples. We demonstrated an increased incidence of CpG island demethylation of GPCR-related gene in APA. The expression of two receptors, HTR4 and PTGER1, showed a strong association with DNA methylation. PMID- 28870782 TI - The role of TET-mediated DNA hydroxymethylation in prostate cancer. AB - Ten-eleven translocation (TET) proteins are recently characterized dioxygenases that regulate demethylation by oxidizing 5-methylcytosine to 5 hydroxymethylcytosine and further derivatives. The recent finding that 5hmC is also a stable and independent epigenetic modification indicates that these proteins play an important role in diverse physiological and pathological processes such as neural and tumor development. Both the genomic distribution of (hydroxy)methylation and the expression and activity of TET proteins are dysregulated in a wide range of cancers including prostate cancer. Up to now it is still unknown how changes in TET and 5(h)mC profiles are related to the pathogenesis of prostate cancer. In this review, we explore recent advances in the current understanding of how TET expression and function are regulated in development and cancer. Furthermore, we look at the impact on 5hmC in prostate cancer and the potential underlying mechanisms. Finally, we tried to summarize the latest techniques for detecting and quantifying global and locus-specific 5hmC levels of genomic DNA. PMID- 28870783 TI - 19p13.3-GADD45B common variants and 19q13.3-PPP1R13L and 19q13.3-CD3EAP in lung cancer risk among Chinese. AB - Lung cancer is the most common cause of cancer-related mortality worldwide. The GADD45 gene family plays important roles in a variety of the responses to cell injury including cell cycle checkpoints, apoptosis, DNA repair and anti-tumor immunity. The 19p13.3-GADD45B encoded protein product is involved in apoptosis and inhibiting tumor growth. To evaluate the association of 19p13.3-GADD45B common variants and lung cancer risk, the present study containing 544 Chinese lung cancer cases and 550 cancer-free controls was conducted. Three htSNPs (haplotype-tagging single nucleotide polymorphism) (rs7354, rs14384, and rs3783501) covering 95% of the common haplotype diversity in 19p13.3-GADD45B and interaction of 19p13.3-GADD45B and 19q13.3-PPP1R13L and 19q13.3-CD3EAP variants and smoking-duration were explored. Genotype and allele frequencies and haplotype distributions of the 19p13.3-GADD45B 3 htSNPs were not associated with lung cancer risk after adjustment for smoking status. 19p13.3-GADD45B rs7354 was associated with lung cancer risk among <=20 (years) smokers [C/A-A/A versus CC, OR (95% CI) = 3.20 (1.11-9.20), P = 0.025] in a dominant model stratified by smoking duration. MDR (multifactor dimensionality reduction) analyses showed that smoking history as main effect and three-way models (smoking duration, 19p13.3 GADD45B rs3783501, 19q13.3-CD3EAP rs967591) (P = 0.001-0.002) indicated statistically significant association with lung cancer risk. The study identified evidence implicating DNA damage response genes on chromosome 19 in etiology of smoke-exposed lung cancer. In conclusion, our findings demonstrate that 19p13.3 GADD45B rs7354 variant and interaction between 19p13.3-GADD45B rs3783501 and 19q13.3-CD3EAP rs967591 may play a role in association with smoke-exposed lung cancer among Chinese. 19p13.3-GADD45B variants should be further evaluated in large prospective studies with molecular pathological annotations of lung cancer. PMID- 28870784 TI - Isotypes of autoantibodies against differentially expressed novel malondialdehyde modified peptide adducts in serum of Taiwanese women with rheumatoid arthritis. AB - : This study identified and validated four differentially expressed novel malondialdehyde (MDA)-modified peptide adducts and evaluated autoantibodies against native and MDA-modified peptides among Taiwanese women patients with rheumatoid arthritis (RA), osteoarthritis (OA) and healthy controls (HCs). Ig kappa chain C region76-99, alpha-1-antitrypsin284-298, alpha-2-macroglobulin824 841, and apolipoprotein B-1004022-4040 exhibiting 2-fold differences in relative modification ratios were identified by concanavalin A (Con A) affinity chromatography, 1D SDS-PAGE, in-gel digestion, nano-LC/MS/MS and nano-LC/MS using pooled serum-derived Con A-captured proteins from 9 RA and 9 age-matched HCs. Furthermore, the levels of proteins, serum MDA, and MDA-modified protein adducts were further validated against individual serum from 20 RA and 20 HCs, and autoantibodies against native and their MDA-modified peptides used 45 RA, 30 OA and 45 HCs. Levels of serum MDA and MDA-modified protein adducts were significantly higher in RA than HCs but protein levels were not significantly different. Serum Igs G and M against MDA-modified peptides showed better diagnostic performance in differentiating among patients with RA, OA and HCs, with an area under the receiver operating characteristic curve of 0.96-0.98, sensitivity of 88.9%-97.8%, and specificity of 88.9%-100%. Autoantibodies against MDA-modified epitopes become useful clinical biomarkers for RA. BIOLOGICAL SIGNIFICANCE: By using a label-free relative quantitative proteomic analysis of concanavalin A (Con A)-bound serum samples, the current study discovered and validated malondialdehyde (MDA)-modified peptide adducts as novel biomarkers for differentiating between rheumatoid arthritis (RA) patients and healthy controls (HCs). In addition, the serum levels of MDA, proteins, and MDA-modified protein adducts as well as the MDA modification of proteins were determined. Isotypes of autoantibodies against MDA-modified peptide adducts can be used as serological biomarkers for further discriminating among RA patients, osteoarthritis patients and HCs. This strategy can become the basis for identifying potential diagnostic and pathological biomarkers for RA. PMID- 28870785 TI - Concurrent Neoadjuvant Chemotherapy and Radiation Therapy in Locally Advanced Breast Cancer. AB - PURPOSE: To evaluate whether concurrent neoadjuvant radiation added to standard chemotherapy could increase the pathologic complete response (pCR) to treatment for locally advanced breast cancer (LABC). METHODS AND MATERIALS: This prospective phase 2 trial recruited 32 LABC patients from 2009 to 2011. Patients received neoadjuvant every-3-weekly 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) for 3 cycles, followed by weekly docetaxel (35 mg/m2) for 9 cycles. Regional radiation (45 Gy/25 plus 5.4 Gy/5) was delivered concurrently with docetaxel, then modified radical mastectomy. Patients were matched post hoc by a blinded statistician to a concurrent cohort treated with neoadjuvant chemotherapy, modified radical mastectomy, and adjuvant regional radiation. RESULTS: Thirty of 32 patients completed treatment. Twenty seven were successfully matched by propensity score to 81 control patients by age, stage, and molecular subtype. The concurrent chemoradiation produced a significant increase in pCR (14% vs 22%, P<.001) but no statistically significant difference in disease-free and overall survival at 3 years (respectively, 69% vs 81%, P=.186, hazard ratio 0.51; and 74% vs 89%, P=.162, hazard ratio 0.46). Toxicity included 25% of patients with grade 3 pneumonitis and 25% of patients with dermatitis, and 1 death. CONCLUSIONS: Concurrent neoadjuvant radiation added to radiosensitizing chemotherapy significantly improved pCR. A prospective randomized clinical trial is warranted to exploit the improved response seen with concurrent therapy but using another radio-sensitizing taxane, to better minimize treatment-related toxicity and determine its impact on overall survival. PMID- 28870786 TI - Online Adaptive Hyperthermia Treatment Planning During Locoregional Heating to Suppress Treatment-Limiting Hot Spots. AB - BACKGROUND: Adequate tumor temperatures during hyperthermia are essential for good clinical response, but excessive heating of normal tissue should be avoided. This makes locoregional heating using phased array systems technically challenging. Online application of hyperthermia treatment planning could help to improve the heating quality. The aim of this study was to evaluate the clinical benefit of online treatment planning during treatment of pelvic tumors heated with the AMC-8 locoregional hyperthermia system. METHODS: For online adaptive hyperthermia treatment planning, a graphical user interface was developed. Electric fields were calculated in a preprocessing step using our in-house developed finite-difference-based treatment planning system. This allows instant calculation of the temperature distribution for user-selected phase-amplitude settings during treatment and projection onto the patient's computed tomographic scan for online visualization. Online treatment planning was used for 14 treatment sessions in 8 patients to reduce the patients' reports of hot spots while maintaining the same level of tumor heating. The predicted decrease in hot spot temperature should be at least 0.5 degrees C, and the tumor temperature should decrease less than 0.2 degrees C. These predictions were compared with clinical data: patient feedback about the hot spot and temperature measurements in the tumor region. RESULTS: In total, 17 hot spot reports occurred during the 14 sessions, and the alternative settings predicted the hot spot temperature to decrease by at least 0.5 degrees C, which was confirmed by the disappearance of all 17 hot spot reports. At the same time, the average tumor temperature was predicted to change on average -0.01 degrees C (range, -0.19 degrees C to 0.34 degrees C). The measured tumor temperature change was on average only -0.02 degrees C (range, -0.26 degrees C to 0.31 degrees C). In only 2 cases the temperature decrease was slightly larger than 0.2 degrees C, but at most it was 0.26 degrees C. CONCLUSIONS: Online application of hyperthermia treatment planning is reliable and very useful to reduce hot spots without affecting tumor temperatures. PMID- 28870787 TI - Conditional Plasminogen Activator Inhibitor Type 1 Deletion in the Endothelial Compartment Has No Beneficial Effect on Radiation-Induced Whole-Lung Damage in Mice. AB - PURPOSE: To investigate whether the endothelial pool of plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of radiation-induced lung damage, as previously demonstrated in the intestine. METHODS AND MATERIALS: Human lung microvascular endothelial cells were exposed to 10 Gy irradiation so as to study their ability to acquire an "activated" phenotype. Mice in which the Cre-Lox strategy was used to produce PAI-1 deletion specifically in the endothelial compartment were exposed to 17 Gy whole-thorax irradiation and followed up for 2, 13, and 23 weeks after irradiation. RESULTS: Human lung microvascular endothelial cells had an activated phenotype after radiation exposure, overexpressed PAI-1, and underwent endothelial-to-mesenchymal transition. In mice, knockout of PAI-1 in the endothelium had no beneficial effect on radiation-induced lung damage and showed a tendency to worsen acute lesions. CONCLUSIONS: As opposed to the intestine, the endothelial pool of PAI-1 does not play a determinant role in the development of radiation-induced lung damage. The therapeutic value of PAI-1 inhibition in lung radiation injury may be associated with other types of cells. PMID- 28870788 TI - Effect of Brain Tumor Presence During Radiation on Tissue Toxicity: Transcriptomic and Metabolic Changes. AB - PURPOSE: Radiation therapy (RT) causes functional and transcriptomic changes in the brain; however, most studies have been carried out in normal rodent brains. Here, the long-term effect of irradiation and tumor presence during radiation was investigated. METHODS AND MATERIALS: Male Wistar rats ~7 weeks old were divided into 3 groups: sham implant, RT+sham implant, and RT+tumor implant (C6 glioma). Hypofractionated irradiation (8 or 6 Gy/day for 5 days) was localized to a 1-cm strip of cranium starting 5 days after implantation, resulting in complete tumor regression and prolonged survival. Biopsy of tissue was performed in the implant area 65 days after implantation. RNA was hybridized to GeneChip Rat Exon 1.0 ST array. Data were analyzed using significant analysis of microarrays and ingenuity pathway analysis. 1H magnetic resonance spectroscopy (1H-MRS) imaging was performed in the implantation site 65 to 70 days after implantation using a 9.4 T Biospec magnetic resonance imaging scanner with a quadrature rat brain array. Immunohistochemical staining for astrogliosis, HMG-CoA synthase 2, gamma aminobutyric acid (GABA) and taurine was performed at ~65 days after implantation. RESULTS: Eighty-four genes had a false discovery rate <3.5%. We compared RT+tumor implant with RT+sham implant animals. The tumor presence affected networks associated with cancer/cell morphology/tissue morphology. 1H MRS showed significant reduction in taurine levels (P<.04) at the implantation site in both groups. However, the RT+tumor group also showed significant increase in levels of neurotransmitter GABA (P=.02). Hippocampal taurine levels were only significantly reduced in the RT+tumor group (P=.03). HMG-CoA synthase 2, GABA and taurine levels were confirmed using staining. Glial fibrillary acidic protein staining demonstrated a significant increase in inflammation that was heightened in the RT+tumor group. CONCLUSIONS: Our data indicate that tumor presence during radiation significantly affects long-term functional transcriptomics landscape and neurotransmitter levels at the tumor implantation site/normal tissue, accompanied by increased inflammation (astrogliosis). PMID- 28870789 TI - Panitumumab in Combination With Preoperative Radiation Therapy in Patients With Locally Advanced RAS Wild-type Rectal Cancer: Results of the Multicenter Explorative Single-Arm Phase 2 Study NEORIT. AB - PURPOSE: Studies investigating combinations of anti-epidermal growth factor receptor monoclonal antibodies such as panitumumab or cetuximab with standard chemoradiation therapy protocols in rectal cancer have yielded disappointing results. Because of the supposed negative interaction of epidermal growth factor receptor inhibition and chemoradiation therapy, we conducted a phase 2 study using single-agent panitumumab in combination with radiation therapy in patients with RAS wild-type locally advanced rectal cancer. METHODS AND MATERIALS: Patients with RAS wild-type locally advanced (clinical stage II or III) rectal cancer localized 0 to 12 cm from the anus were eligible for study participation. The primary objective of the study was to determine pathologic complete response (pCR). Secondary objectives comprised assessing the safety, surgical morbidity, clinical response, tumor downstaging, and tumor regression grading according to Dworak. RESULTS: A total of 54 patients with a median age of 58 years were treated. In 3.7% of patients, pCR was achieved. Downstaging of the primary tumor or lymph nodes was seen in 65% of patients. No grade >=2 hematologic toxicity was seen. The most common grade >=3 nonhematologic toxicities were skin toxicity (24%) and diarrhea (10%). CONCLUSIONS: Panitumumab in combination with radiation therapy as neoadjuvant treatment for locally advanced rectal cancer showed a favorable toxicity profile but failed to meet the predefined pCR rate to justify further clinical trials. PMID- 28870790 TI - Adjuvant Intensity Modulated Whole-Abdominal Radiation Therapy for High-Risk Patients With Ovarian Cancer (International Federation of Gynecology and Obstetrics Stage III): First Results of a Prospective Phase 2 Study. AB - PURPOSE: To assess treatment tolerance and toxicity rates of consolidative whole abdominal radiation therapy (WART) following cytoreductive surgery and carboplatin/paclitaxel chemotherapy in high-risk patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III) using intensity modulated radiation therapy. METHODS AND MATERIALS: The OVAR-IMRT-02 study is a multicenter, single-arm, phase 2 trial. Twenty patients with optimally debulked ovarian cancer (International Federation of Gynecology and Obstetrics stage III) with complete remission after chemotherapy were treated with intensity modulated WART as a consolidation therapy. A total dose of 30 Gy in 20 fractions of 1.5 Gy was applied to the entire peritoneal cavity. The primary endpoint was treatment tolerability, defined as lack of any Common Terminology Criteria for Adverse Events grade 4 toxicity within 10 weeks after start of treatment; secondary objectives were acute and chronic toxicity, quality of life, rates of therapy disruption and abortion, and progression-free and overall survival. RESULTS: Intensity modulated WART resulted in excellent coverage of the whole peritoneal cavity, with effective sparing of all organs at risk. The primary analysis included all 20 enrolled patients, of whom 19 did not experience Common Terminology Criteria for Adverse Events grade 4 toxicity. Only 1 patient experienced acute grade 4 hematologic toxicity. Thus, the tolerability rate of intensity modulated WART was significantly higher than 70%. No gastrointestinal acute toxicities higher than grade 2 have been observed. During WART, mean global health status decreased by 18.1 points (95% confidence interval 7.1, 29.0). Six weeks after WART, global health status had already increased, with a mean score difference of 4.6 (95% confidence interval -11.1, 20.4) compared with baseline. Similar characteristics were observed for all function scale scores. CONCLUSION: Intensity modulated WART after aggressive surgery and carboplatin/paclitaxel chemotherapy is associated with an acceptable risk of acute toxicity and a treatment tolerability rate significantly higher than 70%. Together with our knowledge about clinical feasibility, meaning excellent coverage of the planning target volume and effective sparing of organs at risk, intensity modulated WART could offer a new therapeutic option for consolidation treatment of patients with advanced ovarian cancer. PMID- 28870791 TI - Performance of Knowledge-Based Radiation Therapy Planning for the Glioblastoma Disease Site. AB - PURPOSE: The presence of multiple serial organs at risk (OARs) in close proximity to the tumor makes treatment planning for glioblastoma (GBM) complex and time consuming. The present study aimed to create a knowledge-based (KB) radiation therapy model for GBM patients using RapidPlan. METHODS AND MATERIALS: An initial model was trained using 82 glioblastoma patients treated with 60 Gy in 30 fractions. Plans were created using either volumetric modulated arc therapy (VMAT) or intensity modulated radiation therapy (IMRT). To improve the goodness of-fit of the model, an intermediate model was generated by using the dose-volume histograms (DVHs) of best spared OARs of the initial model. Using the intermediate model and manual refinement, all 82 cases were replanned, resulting in the final model. The final model was validated on an independent set of 45 patients with GBM, astrocytoma, oligodendroglioma, and meningioma. RESULTS: The plans created by the final model exhibited superior planning target volume (PTV) dose metrics compared with manual clinical plans: DeltaD99%=-0.52 +/- 0.20 Gy, and DeltaD1%=0.80 +/- 0.13 Gy (differences are computed as clinical-model). OAR maximum doses were statistically similar, with improved optic apparatus sparing (DeltaDmax=2.78 +/- 0.82 Gy). Stated improvements correspond to P<.05. The KB planning time is typically 7 minutes for IMRT and 13 minutes for VMAT, compared with a typical 4 hours for manual planning. CONCLUSIONS: The KB approach results in significant improvement in planning efficiency and in superior PTV coverage and better normal tissue sparing irrespective of tumor size and location within the brain. PMID- 28870793 TI - Rare association of optic disk pits with myelinated retinal nerves. AB - We report the case of a 9-year-old girl who presented for a routine change of glasses. On slit-lamp examination, no abnormality was detected; however, dilated fundus examination revealed profuse myelination of the retinal nerves around the disk of the right eye along with an optic disk pit inferotemporally. The left eye fundus also had an optic disk pit inferotemporally but no associated myelination. Visual acuity was 6/9 in each eye, and the patient had no other ocular or systemic complaints. To our knowledge, cooccurrence of myelinated retinal nerves and optic disk pits in the same eye, has not been previously reported. PMID- 28870792 TI - Multicenter, Phase 1, Dose Escalation Study of Hypofractionated Stereotactic Radiation Therapy With Bevacizumab for Recurrent Glioblastoma and Anaplastic Astrocytoma. AB - PURPOSE: To establish the maximum tolerated dose of a 3-fraction hypofractionated stereotactic reirradiation schedule when delivered with concomitant bevacizumab to treat recurrent high-grade gliomas. METHODS AND MATERIALS: Patients with recurrent high-grade glioma with Karnofsky performance status >=60, history of standard fractionated initial radiation, tumor volume at recurrence <=40 cm3, and absence of brainstem or corpus callosum involvement were eligible. A standard 3+3 phase 1 dose escalation trial design was utilized, with dose-limiting toxicities defined as any grade 3 to 5 toxicities possibly, probably, or definitely related to radiation. Bevacizumab was given at a dose of 10 mg/kg every 2 weeks. Hypofractionated stereotactic reirradiation was initiated after 2 bevacizumab doses, delivered in 3 fractions every other day, starting at 9 Gy per fraction. RESULTS: A total of 3 patients were enrolled at the 9 Gy * 3 dose level cohort, 5 in the 10 Gy * 3 cohort, and 7 in the 11 Gy * 3 cohort. One dose-limiting toxicity of grade 3 fatigue and cognitive deterioration possibly related to hypofractionated stereotactic reirradiation was observed in the 11 Gy * 3 cohort, and this dose was declared the maximum tolerated dose in combination with bevacizumab. Although no symptomatic radionecrosis was observed, substantial treatment-related effects and necrosis were observed in resected specimens. The intent-to-treat median overall survival was 13 months. CONCLUSIONS: Reirradiation using a 3-fraction schedule with bevacizumab support is feasible and reasonably well tolerated. Dose-escalation was possible up to 11 Gy * 3, which achieves a near doubling in the delivered biological equivalent dose to normal brain, in comparison with our previous 6 Gy * 5 schedule. Promising overall survival warrants further investigation. PMID- 28870794 TI - Pediatric ophthalmology and childhood reading difficulties: Amblyopia and slow reading. AB - Reading is a major life activity, as recognized by the US Congress in the Americans with Disabilities Act Amendments Act of 2008, and the education code of most US states requires schools to evaluate reading and implement reading programs to addresses students' reading difficulties. Currently, such legislation is employed to identify accommodations needed for children with bilateral visual impairment and for children with dyslexia and/or related learning disabilities. Yet recent research has shown that children with the most common form of monocular visual impairment-amblyopia-read slowly. Slow reading can be detrimental to academic performance and learning, which in turn may affect self esteem. Parents and educators can work together to implement accommodations (eg, extra time) to help amblyopic students succeed in their daily school tasks, and improve their performance on the timed, standardized tests that are critical for promotion and admission to magnet schools, TAG programs, high schools, and colleges. Children with other visual disorders that cause visual impairment in one eye (eg, glaucoma, cataract, trauma, etc) should also be considered for academic accommodations. PMID- 28870796 TI - Forceps trauma in a newborn presenting as iris heterochromia. AB - Birth-associated ocular trauma is common and often minor, including subconjunctival and retinal haemorrhage and eyelid edema. Significant ocular trauma during birth, usually associated with forceps-assisted delivery, is rarer and can include Descemet's membrane rupture, lid lacerations, hyphema, Purtcher retinopathy, facial nerve palsy, corneal edema, and corneal laceration. We report the first case of ocular birth trauma from forceps presenting as isolated iris heterochromia and a pseudo rubeosis iridis, which completely resolved by 1 month of age with no known adverse ocular sequelae. PMID- 28870795 TI - Securing extraocular muscles in strabismus surgery: biomechanical analysis of muscle imbrication. AB - An experimental study was performed to quantitatively evaluate the tensile strength of extraocular muscle imbrication as it relates to the positioning of the imbricating suture. The study was conducted in a controlled fashion using fresh ex vivo pig eyes with extraocular muscles attached and a precision digital force gauge. The study provides clinically translatable data to inform surgical technique regarding secure muscle imbrication. Results suggest that imbrications performed 0.5 mm or less from the cut muscle edge or 0.5 mm or less from the lateral margin may be prone to tensile failure. PMID- 28870797 TI - Detailed characterisation of STC-1 cells and the pGIP/Neo sub-clone suggests the incretin hormones are translationally regulated. AB - STC-1 is a heterogeneous plurihormonal cell line producing several prominent gut peptide hormones. pGIP/Neo is a genetically selected sub-clone of STC-1 with augmented levels of glucose-dependent insulinotropic peptide (GIP). Morphometric parameters, hormone concentrations, mRNA transcripts, hormone immunocytochemistry and nutrient utilisation/production of these two cell lines were compared. Proglucagon-derived peptides (Glucagon-like peptide-1 (GLP-1) and - 2(GLP-2)) were lower in sub-clone cells than progenitor cells. High Content Analysis found altered intracellular GLP-1, GIP, cholecystokinin (CCK) and peptide YY (PYY) levels and differing hormone co-localisation. The proportion pGIP/Neo cells containing GIP immunoreactivity (82%) was greater than STC-1 (65%), as were the proportion with 'GIP only', 'GLP-1+GIP' or 'GIP+PYY' immunoreactivity. Most surprisingly mRNA transcripts of the proglucagon and GIP genes were inversely correlated to the levels of their translated peptides. This strongly suggests that proglucagon and GIP are encoded on 'translationally regulated genes' - a characteristic possessed by other endocrine hormones. Metabolomic profiling revealed differences in cellular nutrient utilisation/production and that under normal culture conditions both cell lines exhibit signs of overflow metabolism. These studies provide an insight into the metabolism and properties of these valuable cells, suggesting for the first time that incretin hormone genes are translationally regulated. PMID- 28870798 TI - Pattern of Mas expression in acute and post-acute stage of nerve injury in mice. AB - Angiotensin-(1-7) (Ang [1-7]) and its receptor Mas are involved in a number of physiological processes, including control of arterial pressure and modulation of nervous system actions. However, the involvement of the Ang-(1-7)/Mas axis in peripheral nerve injury has not been investigated. Using a model of sciatic nerve injury in mice, we demonstrated opposing changes in Mas receptor expression at days 2 and 14 post-injury. Mas receptor expression was more intense 2days after the nerve lesion, compared with the intensity of the intact nerve. At this time point, the sciatic nerve functional index was -20. At day 14 after the lesion, the intensity of the immunostaining labeling in longitudinal sections of the nerve was reduced (~30%) and the functional index increased +36 (gait improvement). In the axotomized group treated with A779 (a Mas receptor antagonist), the functional recovery index decreased in relation to the untreated axotomized group. The Mas receptor inhibitor also altered the intensity of labeling of S-100, GAP43, and IBA-1 (morphological features compatible with delayed axon growth). This study demonstrated that Ang-(1-7)/Mas axis activity was differentially modulated in the acute and post-acute stages of nerve injury. PMID- 28870799 TI - Cranial Electrotherapy Stimulation for the Management of Depression, Anxiety, Sleep Disturbance, and Pain in Patients With Advanced Cancer: A Preliminary Study. AB - CONTEXT: Cranial electrotherapy stimulation (CES) is a safe modulation of brain activity for treating depression, anxiety, insomnia, and pain. However, there are no published studies in patients with advanced cancer (ACPs). OBJECTIVES: The aim of the study was to determine the feasibility and preliminary efficacy of a four week CES intervention on depression, anxiety, sleep disturbance, and pain scores. Concurrent salivary biomarker studies were conducted. METHODS: In this one group open label pre- and post-intervention study with a four-week CES intervention, ACPs with one or more of four moderate intensity (>=3/10) Edmonton Symptom Assessment Scale (ESAS) symptoms (depression, anxiety, sleep disturbance, and pain) were eligible. Adherence (0%-100%), satisfaction rates (0-10), and safety were assessed. ESAS, Hospital Anxiety and Depression Scale (HADS), Pittsburgh Sleep Quality Index, Brief Pain Inventory, and salivary levels (cortisol, alpha amylase, C-reactive protein, and interleukin-1beta, and interleukin-6) were assessed from baseline to Week 4. RESULTS: Thirty-three of 36 patients (92%) completed the CES. Median (interquartile range) adherence CES use and satisfaction scores were 93% (89-100) and 10% (9-10), respectively, and the adherence criteria was met in the study. CES use was safe (no Grade 3 or higher adverse events). HADS anxiety (P < 0.001), HADS depression (P = 0.024), ESAS anxiety (P = 0.001), ESAS depression (P = 0.025), Brief Pain Inventory pain (P = 0.013), Pittsburgh Sleep Quality Index daytime dysfunction (P = 0.002), and medication use (P = 0.006) scores improved after four-week CES treatment. CONCLUSION: In this preliminary study, we found that the use of CES was safe and feasible in ACP. The use of CES was associated with significant improvement of depression, anxiety, pain, and sleep scores. These findings support further studies of CES in ACP for symptom control. PMID- 28870800 TI - Cancer Pain With a Neuropathic Component: A Cross-sectional Study of Its Clinical Characteristics, Associated Psychological Distress, Treatments, and Predictors at Referral to a Cancer Pain Clinic. AB - CONTEXT: In patients with cancer pain, identifying a neuropathic pain component (NPC) may inform the selection of subsequent therapeutic interventions. OBJECTIVES: The objective of this study was to determine the prevalence, clinical characteristics, associated psychological distress, pre-referral treatment, and predictors of cancer pain with an NPC in patients referred to a cancer pain clinic. METHODS: Participants had standard assessments and documentation: Brief Pain Inventory ratings, presence of an NPC, based on a Douleur Neuropathique 4 (DN4) (neuropathic pain screening scale) score >=4 combined with a physician's clinical assessment (blinded to DN4 result), the Hospital Anxiety Depression Scale, and Emotion Thermometer scores. Logistic regression analyses were used to determine predictors associated with an NPC. RESULTS: Of 371 study participants, 120 (32.3%) had a designated NPC. Overall, psychological distress indices were similar in the NPC and nociceptive pain groups, except for a Hospital Anxiety and Depression Scale >7 score that was proportionately higher (74% vs. 63%, P = 0.03) in the nociceptive group. The final multivariable logistic regression model generated the following NPC predictors and their respective odds ratios (95% CIs): recent chemotherapy, 2.93 (1.63-5.26); recent surgery, 3.65 (2.03-6.59); adjuvant analgesic use, 2.93 (1.66-5.17); episodic incident pain, 2.63 (1.44 4.84); episodic breakthrough pain, 3.67 (2.00-6.73); pain duration three or more months, 2.35 (1.36-4.06); higher pain intensity, 1.47 (1.24-1.74); and pelvic or perineal pain location, 2.75 (1.09-6.96). CONCLUSION: One in three patients with cancer have an NPC, which is independently associated with recent chemotherapy, surgery, adjuvant analgesic use, episodic incident and breakthrough pain, longer pain duration, higher pain intensity, and pelvic or perineal pain location. PMID- 28870801 TI - Design, synthesis and biological evaluation of 1,3 diphenylbenzo[f][1,7]naphthyrdines. AB - A novel series of twenty 1,3-diphenylbenzo[f][1,7]benzonaphthyrdine derivatives were designed and synthesized through intermolecular imino Diels-Alder reaction. Their in vitro cytotoxic activities were evaluated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Majority of synthesized compounds exhibited significant cytotoxic activities against all tested human cancer cell lines. Among them 4l, 4m, and 4o derivatives exhibited most promising cytotoxic activities. Furthermore these compounds were evaluated against human Topoisomerase IIalpha inhibition. Interestingly, the compound 4l exhibited 1.3 and 1.2 times more potent human Topoisomerase IIalpha inhibition than the reference drug etoposide in both 100uM and 20uM concentrations respectively. Molecular docking studies for the compound 4l have also been executed by Sybyl X-2.1 in which it reveals the binding site of the compound 4l with topo IIalpha DNA cleavage site where etoposide was situated. The benzo[f][1,7]naphthyridine ring was stacked between the DNA bases of the cleavage site. PMID- 28870802 TI - beta-Arrestin biased dopamine D2 receptor partial agonists: Synthesis and pharmacological evaluation. AB - beta-Arrestin biased G protein-coupled receptor ligands represent important molecular probes and may increase favorable drug action and safety as novel therapeutics. Starting from recently discovered hydroxy-substituted heterocyclic piperazine scaffolds, we have developed a series of dopamine D2 receptor ligands with a pyrazolo[1,5-a]pyridine as secondary pharmacophore that is functionalized in position 3 by a formyl or hydroxyiminomethyl substituent. The ligands, especially the benzoxazinone 9d, were found to stimulate substantial beta arrestin-2 recruitment, while being nearly devoid of activity in a GTPgammaS binding assay. Investigating a new series of truncated analogs lacking a secondary pharmacophore, considerable beta-arrestin-2 recruitment in the absence of G protein activation was found, when a 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H) one was combined with an N-propyl-substituted 1,4-diazepane (15c). Although 15c displayed reduced potency compared to 9d, the dose-response curves indicate that a hydroxy-substituted heterocyclic primary pharmacophore is sufficient for the functionally selective activation of D2R. PMID- 28870803 TI - Suppression of Wnt5a, but not Wnts, relieves chronic post-thoracotomy pain via anti-inflammatory modulation in rats. AB - With regard to post-surgical pain, the incidence of chronic post-thoracotomy pain (CPTP) is second only to that caused by amputation and the underlying mechanism remains elusive. The emerging role of Wnts has been confirmed in the pathogenesis of neuropathic and inflammatory pain, both of which are known components of CPTP. We investigated whether Wnt3a and Wnt5a were involved in the development of CPTP, concerning their regulation of inflammatory responses in a previously established rat model. We observed up regulated protein levels of Wnt3a, Wnt5a, beta-catenin, and TLR4, along with activated astrocytes and pro-inflammatory cytokines, in both dorsal root ganglia and the spinal cord dorsal horn. Furthermore, intrathecal inhibition of Wnt5a but not Wnts relieved mechanical hyperalgesia, down regulated expression of TLR4, and inactivated astrocytes and pro-inflammatory cytokines. These results suggest Wnt5a, but not Wnts, contributes to the development of CPTP, possibly by regulating the inflammatory response. PMID- 28870804 TI - High glucose instigates tubulointerstitial injury by stimulating hetero dimerization of adiponectin and angiotensin II receptors. AB - Abnormal expression and dysfunction of adiponectin and the cognate receptors are involved in diabetes and diabetic kidney disease (DKD), whereas angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) alleviate diabetic albuminuria and prevent development of DKD through upregulation of adiponectin expression. Here we report that high glucose stimulates expression of angiotensin II (AngII) receptors (AT1 and AT2) in renal proximal tubular epithelial cells (NRK-52E). These receptors underwent hetero dimerization with adiponectin receptor AdipoR1 and AdipoR2, respectively. High glucose inhibited the dimerization between AT1 and AT2. Interestingly, these hetero-dimers instigated tubulointerstitial injury by inhibiting the cytoprotective action of the adiponectin receptors. These modes of receptor receptor hetero-dimerization may contribute to high glucose-induced renal tubulointerstitial injury and could be potential therapeutic targets. PMID- 28870805 TI - RAI3 knockdown promotes adipogenic differentiation of human adipose-derived stem cells by decreasing beta-catenin levels. AB - Retinoic acid-induced protein 3 (RAI3) has been found to play significant roles in embryonic development, cellular proliferation and differentiation, but its role in adipogenesis has not been explored. In this study, we discovered RAI3 was downregulated during the adipogenic differentiation of human adipose derived stem cells (hASCs). Moreover, we demonstrated that knockdown of RAI3 promoted adipogenic differentiation of hASCs both in vitro and in vivo. Mechanistically, our findings showed that inhibition of RAI3 in hASCs reduced the expression of beta-catenin, and lithium chloride which can activate the beta-catenin pathway abolished the effect of RAI3 knockdown on the adipogenesis. These results suggest RAI3 plays an important role in adipogenesis of hASCs and may have a potential use in the future application. PMID- 28870806 TI - Structural insights into the functional role of GMP in modulating the YfiBNR system. AB - YfiBNR, a tripartite cyclic-di-GMP (c-di-GMP) signalling system, plays an important role in biofilm formation of the gram-negative bacterium P. aeruginosa, which regulates the cellular processes strongly associated with chronic lung infections and drug resistance. The outer-membrane lipoprotein YfiB can release the inhibition of the inner membrane protein YfiN by sequestering the periplasmatic protein YfiR, resulting in the activation of diguanylate cyclase activity of YfiN and the production of c-di-GMP. In contrast to the extensive studies on c-di-GMP, little is known about how GMP acts in the YfiBNR system. Here, we report the crystal structures of YfiR complexed with GMP and YfiBL43P YfiR complexed with GMP. In the YfiR-GMP complex, GMP is located in a hydrophilic pocket formed by R175/H177/R60, while in the YfiBL43P-YfiR-GMP complex, GMP is located in a slightly separated hydrophilic pocket, with GMP forming hydrogen bonds with both YfiB and YfiR. A binding affinity test and biofilm formation assay indicated that GMP may activate diguanylate cyclase activity to promote biofilm production by promoting the affinity of YfiB and YfiR. This finding thus provides a new perspective for preventing biofilm-related antibiotic resistance and chronic infections. PMID- 28870807 TI - A natural product toosendanin inhibits epithelial-mesenchymal transition and tumor growth in pancreatic cancer via deactivating Akt/mTOR signaling. AB - The pancreatic cancer is among the most aggressive malignancies with strong proclivity to metastasis. The malignancy during pancreatic cancer progression is largely ascribed to epithelial-mesenchymal transition (EMT). Here we showed that toosendanin (TSN), which is an active component in traditional Chinese medicine, can strongly attenuate pancreatic cancer progression. TSN suppressed the viability and grow of pancreatic cancer cells in a dose-dependent manner. The migration and invasion of pancreatic cancer cells were also consistently inhibited dose-dependently. TSN can reverse the TGF-beta induced EMT and morphological change in pancreatic cancer cells by increasing Ecadherin expression while reducing Vimentin, ZEB1 and SNAIL levels. Furthermore, TSN evidently repressed xenograft tumor growth in mouse pancreatic cancer models without significantly toxic side effects. Mechanistic studies suggested that TSN mediated pancreatic cancer inhibition by blocking Akt/mTOR signaling pathway. Our results showed that TSN inhibits pancreatic cancer progression via downregulating Akt/mTOR signaling. Since the concentrations of TSN used in current study is very low, our results demonstrated that TSN can inhibit pancreatic cancer progression thereby implying that TSN can be used as a potential pharmacological agent especially in treatment of pancreatic cancer. PMID- 28870808 TI - Hedgehog signaling inhibitor GANT61 induces endoplasmic reticulum stress-mediated protective autophagy in hepatic stellate cells. AB - Hedgehog (Hh) signaling plays an important role in the viability maintenance of hepatic stellate cells (HSC). HSCs have been identified as the major profibrogenic cells in the liver. The present study revealed that a novel Hh signaling antagonist GANT61 induced apoptosis in the activated human hepatic stellate cell line LX-2 cells, as it dose-dependently caused mitochondrial inner transmembrane potential (DeltaPsim) loss and caspase-3 cleavage. Autophagic flux was markedly increased after GANT61 treatment. Moreover, we found that autophagy was a pro-survival factor in GANT61-treated LX-2 cells because autophagic inhibitors 3-Methyladenine (3-MA) or Chloroquine (CQ) significantly aggravated GANT61-induced cytotoxicity. Furthermore, the endoplasmic reticulum (ER)-resident molecular chaperone BiP, a marker of ER stress, was markedly increased after incubation with GANT61. Meanwhile, the PERK-eIF2alpha-ATF4-CHOP pathway was observed to be activated by GANT61. Salubrinal, a selective inhibitor of ER stress, suppressed GANT61-induced LC3BII expression and enhanced poly (ADP ribose) polymerase (PARP) cleavage, indicating that ER stress is a trigger of autophagy and suppresses apoptosis in GANT61-treated LX-2 cells. Overall, these results demonstrate that simultaneous inhibition of Hh signaling and autophagy or ER stress could be a better way to reduce activated HSCs. PMID- 28870809 TI - Efficient potential of mean force calculation from multiscale simulations: Solute insertion in a lipid membrane. AB - The determination of potentials of mean force for solute insertion in a lipid membrane by means of all-atom molecular dynamics simulations is often hampered by sampling issues. Recently, a multiscale method has been proposed to leverage the conformational ensemble of a lower-resolution model as starting point for higher resolution simulations. In this work, we analyze the efficiency of this method by comparing its predictions for propanol insertion into a lipid membrane against conventional atomistic umbrella sampling simulation results. The multiscale approach is confirmed to provide accurate results with a gain of one order of magnitude in computational time. We then investigate the role of the coarse grained representation. We find that the accuracy of the results is tightly connected to the presence of a good configurational overlap between the coarse grained and atomistic models-a general requirement when developing multiscale simulation methods. PMID- 28870810 TI - Analysis of an acyl-CoA binding protein in Aspergillus oryzae that undergoes unconventional secretion. AB - Acyl-CoA binding protein (ACBP) plays important roles in the metabolism of lipids in eukaryotic cells. In the industrially important filamentous fungus Aspergillus oryzae, although we have previously demonstrated that the A. oryzae ACBP (AoACBP) localizes to punctate structures and exhibits long-range motility, which is dependent on autophagy-related proteins, the physiological role of AoACBP remains elusive. Here, we describe identification and characterization of another ACBP from A. oryzae; we named this ACBP as AoAcb2 and accordingly renamed AoACBP as AoAcb1. The deduced amino acid sequence of AoAcb2 lacked a signal peptide. Phylogenetic analysis classified AoAcb2 into a clade that was same as the ACBP Acb1 of the model yeast Saccharomyces cerevisiae, but was different from that of AoAcb1. In contrast to punctate localization of AoAcb1, AoAcb2 was found to be dispersedly distributed in the cytoplasm, as was previously observed for the S. cerevisiae Acb1. Since we could not generate an Aoacb2 disruptant, we created an Aoacb2 conditional mutant that exhibited less growth under Aoacb2-repressed condition, suggesting that Aoacb2 is an essential gene for growth. Moreover, we observed that A. oryzae AoAcb2, but not A. oryzae AoAcb1, was secreted under carbon-starved condition, suggesting that AoAcb2 might be secreted via the unconventional protein secretion (UPS) pathway, just like S. cerevisiae Acb1. We also demonstrated that the unconventional secretion of AoAcb2 was dependent on the t-SNARE AoSso1, but was independent of the autophagy-related protein AoAtg1, suggesting that the unconventional secretion of AoAcb2, unlike that of S. cerevisiae Acb1, via the UPS pathway, is not regulated by the autophagy machinery. Thus, the filamentous fungus A. oryzae harbors two types of ACBPs, one of which appears to be essential for growth and undergoes unconventional secretion. PMID- 28870811 TI - A hetero-micro-seeding strategy for readily crystallizing closely related protein variants. AB - Protein crystallization remains difficult to rationalize and screening for optimal crystallization conditions is a tedious and time consuming procedure. Here, we report a hetero-micro-seeding strategy for producing high resolution crystals of closely related protein variants, where micro crystals from a readily crystallized variant are used as seeds to develop crystals of other variants less amenable to crystallization. We applied this strategy to Bovine Pancreatic Trypsin Inhibitor (BPTI) variants, which would not crystallize using standard crystallization practice. Out of six variants in our analysis, only one called BPTI-[5,55]A14G formed well behaving crystals; and the remaining five (A14GA38G, A14GA38V, A14GA38L, A14GA38I, and A14GA38K) could be crystallized only using micro-seeds from the BPTI-[5,55]A14G crystal. All hetero-seeded crystals diffracted at high resolution with minimum mosaicity, retaining the same space group and cell dimension. Moreover, hetero-micro-seeding did not introduce any biases into the mutant's structure toward the seed structure, as demonstrated by A14GA38I structures solved using micro-seeds from A14GA38G, A14GA38L and A14GA38I. Though hetero-micro-seeding is a simple and almost naive strategy, this is the first direct demonstration of its workability. We believe that hetero micro-seeding, which is contrasting with the popular idea that crystallization requires highly purified proteins, could contribute a new tool for rapidly solving protein structures in mutational analysis studies. PMID- 28870812 TI - Thyroidectomy stimulates glucagon-like peptide-1 secretion and attenuates hepatic steatosis in high-fat fed rats. AB - Thyroid hormones (THs) as a therapeutic intervention to treat obesity has been tried but the effect of THs on body weight and the mechanistic details of which are far from clear. This study was designed to determine and elucidate the mechanistic details of metabolic action of THs in high-fat diet (HFD) fed Sprague Dawley (SD) rats. Rats were made surgically hypothyroid (thyroidectomy, Thx). Body weights and food and water intake profoundly decreased in HFD fed thyroidectomized group (HN Thx). Results showed that delayed insulin response, increased total cholesterol, high-density lipoprotein, and low-density lipoprotein in HN Thx. Unexpectedly, however, Thx reduced serum and hepatic triglyceride concentrations. Further studies revealed that Thx dramatically increased circulating GLP-1 as well as increased expressions of GLP-1 in small intestine. Diminished hepatic expressions of lipogenic genes, were observed in HN Thx group. Beta-catenin and glutamine synthetase, a known target of beta-catenin, were up-regulated in the liver of HN Thx group. The expressions of gluconeogenic genes G6P and PCK were reduced in the liver of HN Thx group. The results may suggest that surgery-induced hypothyroidism increases GLP-1, the actions of which may in part be responsible for the reduction in water intake, appetite and hepatic steatosis. PMID- 28870813 TI - ATP-independent inhibition of amyloid beta fibrillation by the endoplasmic reticulum resident molecular chaperone GRP78. AB - Neuronal cell death induced by an accumulation of amyloid beta (Abeta) peptides, which are pathogenic molecules for Alzheimer's disease, is closely related with endoplasmic reticulum (ER) stress. In the ER stress condition, part of the ER resident chaperones is known to be translocated to another cellular location, such as the cell surface. The ER chaperone 78-kDa glucose-regulated protein (GRP78), which shows ATP-dependent chaperone activity, also shows translocation to the cell surface. In this study, we examined the influence of GRP78 on Abeta fibrillation in the presence or absence of ATP. We revealed that a small amount of GRP78 effectively inhibited fibrillation of Abeta fragments. Intriguingly, the fibrillation inhibition by GRP78 was confirmed in the absence of ATP, suggesting GRP78 exhibited ATP-independent interaction with Abeta fragments. PMID- 28870815 TI - Activation of transient receptor potential melastatin 7 (TRPM7) channel increases basal autophagy and reduces amyloid beta-peptide. AB - Cerebral accumulation of amyloid beta-peptide (Abeta), which is produced from amyloid precursor protein (APP), is the primary cause of Alzheimer's disease (AD). Autophagy recycles cellular components and digests intracellular components including Abeta. The Ca2+- and Mg2+-permeable transient receptor potential melastatin 7 (TRPM7) channel underlies the constitutive Ca2+ influx in some cells. Since we already reported that TRPM7 channel-mediated Ca2+ influx regulates basal autophagy, we hypothesize that the activation of TRPM7 channel could increase basal autophagy and consequently decrease Abeta. In this study, we showed that naltriben (NTB), a specific TRPM7 channel activator, induced Ca2+ influx and activated autophagic signaling in neuroblastoma SH-SY5Y cells. NTB also promoted co-localization of LC3 and APP, and reduced Abeta. Furthermore, we found that an early-onset familial AD-associated presenilin1 DeltaE9 (PS1 DeltaE9) mutant cells had attenuated basal autophagy. NTB was able to recover autophagy and decrease Abeta in PS1 DeltaE9 cells. Our results show that the activating TRPM7 channel may prevent AD-related Abeta neuropathology via modulating Ca2+-regulated basal autophagy. PMID- 28870814 TI - Curcumin inhibits bladder cancer stem cells by suppressing Sonic Hedgehog pathway. AB - Cancer stem cells (CSCs) is responsible for the recurrence of human cancers. Thus, targeting CSCs is considered to be a valid way for human cancer treatment. Curcumin is a major component of phytochemicals that exerts potent anticancer activities. However, the effect of curcumin on bladder cancer stem cells (BCSCs) remains to be elucidated. In this study, we investigated the mechanism of curcumin suppressing bladder cancer stem cells. In this study, UM-UC-3 and EJ cells were cultured in serum-free medium (SFM) to form cell spheres that was characterized as BCSCs. Then cell spheres were separately treated with different concentrations of curcumin and purmorphamine. Cell cycle analysis were used to determine the percentage of cells in different phases. Western blot and quantitative real-time PCR analysis were used to detect the expression of relative molecules. Immunofluorescence staining analysis were also utilized to measure the protein level of CD44. We found that CSC markers, including CD44, CD133, ALDH1-A1, OCT-4 and Nanog, were obviously highly expressed in cell spheres. Moreover, we observed that curcumin reduced the cell spheres formation, decreased the expression of CSC markers, suppressed cell proliferation and induced cell apoptosis. We also found that curcumin inhibited the activation of Shh pathway, while the inhibitory effects of curcumin on BCSCs could be weakened by upregulation of Sonic Hedgehog (Shh) pathway. Altogether, these data suggested that curcumin inhibited the activities of BCSCs through suppressing Shh pathway, which might be an effective chemopreventive agent for bladder cancer intervention. PMID- 28870816 TI - [From TORCH to TORCHZ: Zika virus infection highlights infectious fetopathies]. PMID- 28870817 TI - [PRRT2 mutation and infantile convulsions]. AB - New genetic techniques have made it possible to better understand the implications of the PRRT2 gene (proline rich transmembrane protein 2) in various neurological disorders. Mutations within this gene are responsible for kinesigenic paroxysmal dyskinesias (PKD) as well as for benign familial infantile epilepsy (BFIE), a disease associating infantile convulsions and choreoathetosis (ICCA), a form of familial hemiplegic migraine (FHM type 4), paroxysmal benign torticollis of childhood, and episodic ataxia. We describe the case of an infant, carrying a mutation of the PRRT2 gene, with a classical presentation. Through her progression over time, we raise the question of systematic use of anti-epileptic drugs. PMID- 28870818 TI - [Fatal female genital mutilation in a 10-year-old girl]. AB - Female genital mutilation (FGM) comprises all procedures involving partial or total removal of the external genitalia and/or any other procedures affecting the female genitalia, for cultural or religious reasons or for nontherapeutic purposes in general. FGM is responsible for a number of short-, medium-, and long term complications that can engage the vital and functional prognosis, especially in African countries. We report on a case in a 10-year-old girl who underwent genital mutilation, a traditional type of total excision during the neonatal period. She was followed for urethral meatus stenosis, which then was complicated by obstructive chronic kidney failure and urinary sepsis, whose progression was fatal. PMID- 28870819 TI - [Type 1 neurofibromatosis: Onset of two tumors before the age of 5years]. AB - Neurofibromatosis type 1 (NF1) is a frequent autosomal dominant genetic disorder that predisposes to the development of benign and malignant tumors. Mutation of the NF1 gene affects the RAS-MAPK signaling pathway and leads to a dysfunction in cell proliferation and induces tumor development. Epidemiology of cancer in children with NF1 is very different from the general pediatric population, which requires regular and specific monitoring. Neurofibroma is the most frequent benign tumor. It can be very invalidating depending on the size and location of the tumor. Currently, there is no specific treatment for these tumors. The most frequent malignancies in children with NF1 are leukemias, rhabdomyosarcomas, malignant peripheral nerve sheath tumors and gliomas. The treatment of these tumors should consider the risk of second cancers induced by radio- and chemotherapy. We report on the case of a 5-year-old boy with NF1 developing two tumors. PMID- 28870820 TI - Is There a Place for the Posterior Approach in Cases of Acute Myelopathy on Thoracic Disc Hernia? AB - BACKGROUND: Acute myelopathy in cases of thoracic disc herniation (TDH) is an exceptional condition for which the treatment is not codified. Here we present the results of a standardized procedure in 10 patients who underwent surgery for acute myelopathy on TDH between December 2009 and December 2016. METHODS: Our approach began with a cautious laminectomy without resection of the hernia on the day of admission. On subsequent days, a complementary thoracoscopic procedure was performed according to the patient's neurologic recovery and the nature of the hernia (calcified or fibrous). Outcome was assessed by the Frankel score at the last consultation. RESULTS: All patients had acute myelopathy, with Frankel score of C or worse and a TDH detected on magnetic resonance imaging occupying an average of 62.5 +/- 18.4% of the canal. This lesion was calcified in 6 cases and soft in 4 cases. The laminectomy allowed stabilization in 1 case and a neurologic improvement in 9 cases. Complementary surgery via a thoracoscopic approach was performed in the 6 cases of calcified hernia. After an average follow-up of 44.55 +/- 26.44 months, 6 patients showed complete neurologic recovery and 4 had moderate sequelae (Frankel D). CONCLUSIONS: Laminectomy appears to allow stabilization of the neurologic situation in rare cases of acute myelopathy on TDH. The need for complementary resection of the hernia by an anterior approach should always be discussed secondarily. PMID- 28870821 TI - Self-Made, Cost-Reducing Hemostatic Agent for Use in Spine Surgery. AB - Operative bleeding complications can lead to patient morbidity and mortality as well as longer and increased hospitalization costs. Matrix hemostatic sealants are used commonly to shorten the time to hemostasis, operative times, and the need for blood transfusion. Commercially available hemostatic powders are used in spine surgery because of their ability to conform to wounds and decrease bleeding in difficult-to-access surgical sites. Hospital costs for these agents are variable and are dependent on negotiated institutional contracted prices. We present our technique for mixing and use of our own hemostatic agent that has been used by our senior spine surgeons for more than a decade. It uses supplies that are commonly found in the hospital for a fraction of the cost and at different concentrations of thrombin. We hope that this report serves to assist surgeons working in hospitals with limited resources and enriches their armamentarium of hemostatic agents. PMID- 28870822 TI - Radiologic Features and Surgical Strategy of Hemangioblastomas with Enhanced Cyst Wall. AB - OBJECTIVE: Hemangioblastomas with enhanced cyst walls represent a rare radiologic presentation of hemangioblastomas with poor understandings. We aimed to summarize the clinical and radiologic features, important differential diagnosis, surgical strategy, and clinical outcome of this rare entity. METHODS: From June 2008 to March 2017, 12 patients with cystic hemangioblastomas presenting with enhanced wall thickness on MRI were treated in our department. The clinical presentations, radiologic investigations, surgical treatment, neurologic outcome, and recurrence rate were evaluated. Important preoperative differential diagnosis and surgical strategy of this entity were discussed. RESULTS: Twelve patients with cystic hemangioblastomas presenting with an enhanced cyst wall on magnetic resonance imaging were analyzed retrospectively. There were 5 male and 7 female subjects, with a mean age of 41.4 years (range, 13-78 years) and an average duration of symptoms before diagnosis of 2.23 months (range, 0.5-8.0 months). Radiologically, enhancement of both tumoral nodule and cyst were observed in 8 patients, while pure ring-enhanced cyst without typical tumoral nodule was found in 4 patients. Histopathologic examination confirmed the diagnosis of hemangioblastomas, and the enhanced cyst wall and mural nodule shared the same histopathologic pattern. Postoperative complications occurred in only 1 patient with postoperative cerebellar hemorrhage. During follow-up, 8 patients achieved favorable neurologic outcomes (Karnofsky score: 100) without recurrence; however, 4 patients experienced local tumor recurrence after the initial surgery. CONCLUSIONS: Hemangioblastomas with enhanced cyst wall possess distinctive radiologic features, and they are frequently misdiagnosed preoperatively. Favorable tumor control can be achieved only when gross total resection of both the tumor nodule and cyst wall are performed. Close follow-up is necessary because of the high recurrence rate in this subset of hemangioblastomas. PMID- 28870824 TI - Spine Navigation Based on 3-Dimensional Robotic Fluoroscopy for Accurate Percutaneous Pedicle Screw Placement: A Prospective Study of 66 Consecutive Cases. AB - BACKGROUND: Minimally invasive spine surgery is associated with obstructed visibility of anatomic landmarks and increased radiation exposure, leading to higher incidence of pedicle screw mispositioning. To address these drawbacks, intraoperative 3-dimensional fluoroscopy (io3DF) and navigation are being increasingly used. We aimed to present our dedicated multifunctional hybrid operating room (HyOR) setup and evaluate the accuracy and safety of io3DF image guided spinal navigation in transforaminal lumbar interbody fusion with percutaneous pedicle screw (PPS) placement. METHODS: The HyOR includes a fixed 3D multiaxis robotic fluoroscopy arm that moves automatically to the preprogrammed position when needed. An initial io3DF assessment is performed to collect intraoperative images, which are automatically transferred into the navigation system. These data are used to calibrate the PPSs and insert them under computer assisted navigation. A second io3DF is performed for verifying PPS position. RESULTS: Between January 2014 and December 2016, 66 consecutive patients (age, 58.6 +/- 14.1 years) were treated for refractory lumbar degenerative pain. Seventy-three spinal levels were treated, and 276 screws were placed, with 4.2 +/ 0.76 screws per patient. There was no measurable radiation to the HyOR staff, whereas the mean radiation dose per patient was 378.3 MUGym2. The overall accuracy rate of PPS placement was 99.6%. There were no significant procedure related complications. CONCLUSIONS: Spine navigation based on io3DF images enabled us to avoid radiation exposure to the operating room team while delivering minimal but sufficient radiation doses to our patients. This approach achieved an accuracy rate of 99.6% for PPS placement in the safe zone, without significant complications. PMID- 28870823 TI - Occipital Artery to Middle Cerebral Artery Bypass: Operative Nuances. AB - BACKGROUND: Superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis is a common procedure for vascular neurosurgeons, and it is used in a variety of diseases. However, there are cases in which the STA is absent or is too hypoplastic to be used as a donor for revascularization. Occipital artery (OA)-MCA bypass may be a treatment option in these cases. METHODS: We encountered 4 cases of symptomatic cerebral ischemia in which the STA was absent or unavailable. These cases were treated by revascularization from the OA to the periphery of the MCA. RESULTS: By meticulous dissection of the OA to the level of the superior temporal line, the OA could reach the periphery of the angular artery and be anastomosed to it in the usual fashion. The patency of the donor artery was confirmed by magnetic resonance angiography soon after the operation and 3 years later. CONCLUSIONS: OA-MCA bypass may be a surgical option for cerebral revascularization when the STA is not available. PMID- 28870825 TI - Prolonged but non-permanent expression of a transgene in ependymal cells of adult rats using an adenovirus-mediated transposon gene transfer system. AB - Ependymal cells have been considered one of prime targets for gene therapy in the central nervous system as they can secrete proteins directly into the cerebrospinal fluid. In this study, we have explored the probability of permanent exogenous gene expression using a combined adenovirus/transposon system. To this end, we created three adenoviruses; adenovirus #1 containing a CAG promoter driven enhanced green fluorescent protein tagged with a palmitoylation site (palEGFP), whose DNA sequence was flanked by two different Tol2 ends, #2 containing a human FoxJ1 promoter-driven T2TP transposase, and #3 containing an EF-1 alpha promoter-driven T2TP transposase. We injected these adenoviruses into the lateral ventricles of adult rats to assess the duration of transgene expression, by which adenoviruses selectively infected to ependymal cells because they express the specific receptor. In animals injected with only adenovirus #1, we found palEGFP-expressing ependymal cells 1week after injection, but these cells had disappeared by 2weeks. In animals that received adenoviruses #1 and #2 in combination, despite detecting many palEGFP-expressing ependymal cells within the initial 2weeks, transgene expression in ependymal cells was almost disappeared 1month after injection. In contrast, many palEGFP-expressing astrocytes, oligodendrocytes, and neurons were found near the sites injected with adenoviruses #1 and #3, even 1month after injection. There was no prominent infiltration of immunological cells during the observation period. These findings indicate that an adenovirus-mediated transposon gene transfer system can lead to prolonged, but not permanent, expression of exogenous genes in ependymal cells of adult rats. PMID- 28870826 TI - Hyperforin protects against acute cerebral ischemic injury through inhibition of interleukin-17A-mediated microglial activation. AB - Hyperforin, a pharmacologically active component of the medicinal plant Hypericum perforatum (St. John's wort), has been shown to be neuroprotective against acute ischemic stroke. However, the underlying mechanisms are still unclear and need to be fully elucidated. C57BL/6 wildtype (WT) mice or interleukin (IL)-17A knock-out mice were subjected to middle cerebral artery occlusion (60min) followed by reperfusion for 72h. Hyperforin (0.5MUg) was injected slowly into the right ventricle of WT mice 1, 24 and 48h after middle cerebral artery occlusion (MCAO) onset. Here, we found that hyperforin treatment decreased the mRNA and protein expression of IL-17A at 72h after MCAO onset. Hyperforin reduced infarct volumes and increased neurologic scores accompanied by a decrease in microglial activation and a shift from M1 to M2 phenotypes in the peri-infarct striatum. Furthermore, we revealed that IL-17A was essential to the microglial activation in the acute phase of ischemic stroke. IL-17A knock-out (il-17a-/-) or anti-IL-17 A monoclonal antibody treatment markedly decreased the microglial activation and induced a shift from M1 to M2 phenotypes of activated microglia. In addition, treatment with recombinant mouse IL-17A abolished the protective effects of hyperforin on acute ischemic brain injury, attenuated the inhibitory effects of hyperforin on the microglial activation, and inhibited the enhanced shift from M1 to M2 phenotypes mediated by hyperforin. In conclusion, our results clearly showed that hyperforin could protect against acute cerebral ischemic injury through inhibition of interleukin-17A-mediated microglial activation and polarization of microglia to M2 phenotype. PMID- 28870827 TI - Distinguishing response to names in Rett and MECP2 Duplication syndrome: An ERP study of auditory social information processing. AB - Despite significant advances at the level of basic research, the characterization of higher-level processes in Rett and MECP2 Duplication syndrome remains understudied. In this pilot study, we assessed social-emotional information processing by testing whether children (ages 4-12years) with Rett (n=9) and MECP2 Duplication syndrome (n=7) distinguished their own spoken name from other names. We hypothesized that own and familiar names would elicit more positive parietal P300 responses than unknown names, and that the groups would have different neural responses to these stimuli. The MECP2 Duplication group partially mirrored the parietal responses to own name observed in typically developing participants, and better name discrimination correlated with more adaptive behaviors. Conversely, participants with RTT did not resemble the typical group, and showed greater responses to close other names at frontal/central regions. These results may reflect the different consequences of too much (MECP2 Duplication) vs. too little (RTT) MeCP2 protein. PMID- 28870829 TI - Chemiluminescence immunoassays for estradiol and ethinylestradiol based on new biotinylated estrogen derivatives. AB - New chemiluminescence-based immunoassays for sensitive detection of 17-beta estradiol (E2) and ethinylestradiol (EE2) are described on the basis of the use of biotinylated estrogen derivatives. Estrogen derivatives bearing a carboxylic group (E2-COOH and EE2-COOH) on C-3 position were synthesized, covalently bound to aminated biotin and subsequently immobilized on avidin-coated microtiter plates. The assay principle was based on competition between free and immobilized estrogens for their binding to primary antibodies, with subsequent revelation using horseradish peroxidase (HRP)-labeled secondary antibodies. Under optimized conditions, the chemiluminescence immunoassays showed a highly sensitive response to E2 and EE2, with respective detection limits of 0.5 and 1.2 ng L-1. The LOD achieved using biotinylated E2 was in the same order of magnitude as those obtained using commercially available E2-bovine serum albumin conjugate (E2-BSA). The developed devices were successfully applied to analysis wastewater treatment plants effluents (WWTP) with negligible matrix effect. PMID- 28870828 TI - A miniaturized assay for kinetic characterization of the Na+-translocating NADH:ubiquinone oxidoreductase from Vibrio cholerae. AB - We demonstrate the miniaturization of an enzymatic assay for the determination of NADH oxidation and quinone reduction by the Na+ -translocating NADH quinone oxidoreductase (NQR) in the 96-well plate format. The assay is based on the spectrophotometric detection of NADH consumption and quinol formation. We validated the new method with known inhibitors of the NQR and optimized conditions for high-throughput screening as demonstrated by excellent Z-factors well above the accepted threshold (>=0.5). Overall, the method allows the screening and identification of potential inhibitors of the NQR, and rapid characterization of NQR variants obtained by site-specific mutagenesis. PMID- 28870830 TI - An improved amperometric creatinine biosensor based on nanoparticles of creatininase, creatinase and sarcosine oxidase. AB - An improved amperometric biosensor for detection of creatinine was developed based on immobilization of nanoparticles (NPs) of creatininase (CA), creatinase (CI), and sarcosine oxidase (SOx) onto glassy carbon (GC) electrode. Transmission electron microscopy (TEM) and fourier transform infrared spectroscopy (FTIR) were employed for characterization of enzyme nanoparticles (ENPs). The GC electrode was characterized by scanning electron microscopy (SEM), cyclic voltammetry (CV) and electrochemical impedance spectra (EIS) at different stages of its amendment. The biosensor showed optimum response within 2s at pH 6.0 in 0.1 M sodium phosphate buffer and 25 degrees C, when operated at 1.0 V against Ag/AgCl. Biosensor exhibited wider linear range from 0.01 MUM to 12 MUM with a limit of detection (LOD) of 0.01 MUM. The analytical recoveries of added creatinine in sera were 97.97 +/- 0.1% for 0.1 mM and 98.76 +/- 0.2% for 0.15 mM, within and between batch coefficients of variation (CV) were 2.06% and 3.09% respectively. A good correlation (R2 = 0.99) was observed between sera creatinine values obtained by standard enzymic colorimetric method and the present biosensor. This biosensor measured creatinine level in sera of apparently healthy subjects and persons suffering from renal and muscular dysfunction. The ENPs electrode lost 10% of its initial activity within 240 days of its regular uses, when stored at 4 degrees C. PMID- 28870831 TI - The complex and instructive relationship between OSA and nocturnal cardiovascular death. PMID- 28870832 TI - Tuning polypeptide-based micellar carrier for efficient combination therapy of ErbB2-positive breast cancer. PMID- 28870833 TI - Multivalent interactions between streptavidin-based pretargeting fusion proteins and cell receptors impede efficient internalization of biotinylated nanoparticles. AB - : Pretargeting represents a promising strategy to enhance delivery of nanoparticles. The strategy involves first introducing bispecific antibodies or fusion proteins (BFP) that can bind specific epitopes on target cells with one arm, and use the other arm to capture subsequently administered effector molecules, such as radionuclides or drug-loaded nanoparticles. Nevertheless, it remains unclear whether BFP that bind slowly- or non-internalizing epitopes on target cells can facilitate efficient intracellular delivery. Here, we investigated the cellular uptake of biotin-functionalized nanoparticles with streptavidin-scFv against TAG-72, a membrane protein on Jurkat T-cell leukemia cells. Unlike conventional active-targeted nanoparticles, we found that pretargeting resulted in preferential retention of ~100nm nanoparticles at the plasma membrane rather than internalization into cells. We found no improvement in nanoparticle internalization by simply reducing nanoparticle concentration or surface biotin density. Interestingly, by adding both the BFP and a monoclonal antibody against TAG-72, we observed a twofold improvement in internalization of pretargeted nanoparticles. Our work illustrates that the cellular fate of pretargeted nanoparticles can be controlled by carefully tuning the interactions between pretargeting molecules and nanoparticles on the cell surface. STATEMENT OF SIGNIFICANCE: Pretargeting is a multi-step strategy that utilizes bispecific proteins that recognize both cellular epitopes and subsequently administered therapeutic molecules. This approach has been extensively studied for radiotherapy of blood cancers; however, pretargeting remains largely underexplored for nanoparticle targeting, including whether pretargeting can facilitate efficient intracellular delivery. Here, we found that high density of targeting proteins on the cell surface can effectively limit internalization of pretargeted nanoparticles. Our work underscores the need to carefully assess specific cell-pretargeting molecule pairs for applications requiring intracellular delivery, and the key design requirements for such bispecific pretargeting molecules. PMID- 28870834 TI - Prevalence of Preventive Cardiovascular Medication Use In Nursing Home Residents. Room for Deprescribing? The SHELTER Study. AB - INTRODUCTION: In nursing home (NH) residents with a very short life expectancy, the benefits of preventive cardiovascular medication maintenance are questionable. OBJECTIVE: To assess the prevalence of 4 classes of preventive cardiovascular medication (PCM) in NH residents, and to explore differences of prevalence across length of stay, mortality risk, cognitive impairment, functional disability, and across countries. METHODS: A 12-month prospective cohort study was conducted in 57 NHs in 8 countries (Czech Republic, England, Finland, France, Germany, Italy, The Netherlands, and Israel). We assessed the prevalence at first measurement of 4 classes of PCM: oral anticoagulants (OAC), platelet aggregation inhibitor (PAI), antihypertensive (AHT), and lipid-modifying agent (LMA), in older (60+ years) residents with valid medication assessments. The PCM prevalence was compared across the length of stay (short <60 days, mid, long >12 months), health instability as defined by Changes in Health, End-Stage Disease, Signs, and Symptoms Scale (CHESS) > 3, cognitive impairment by Cognitive Performance Scale (CPS) > 2, and functional disability was measured using the Activities of Daily Living Hierarchy Scale (ADLH) >=5. RESULTS: Of the 3759 eligible residents, 2175 (57.9%) used at least 1 PCM. The prevalence of the 4 groups of PCM: OAC, PAI, AHT and LMA were 5.6%, 34.9%, 35.7%, and 10.4%, respectively. PCM use was lower in long-stay residents versus mid-stay: 56.0% vs. 62.7%, in cognitively impaired residents (47.1% vs. 67%), in residents with a high mortality risk (47.4% vs. 58.6%), and in residents with a high ADLH score (48.6% vs 64.0%). CONCLUSION: Although the prevalence of PCM use was lower in long-stay, cognitively impaired residents, persons with a high mortality risk, and residents with more functional disabilities, there seems to be room for deprescribing. PMID- 28870835 TI - Feasibility and reliability of digital imaging for estimating food selection and consumption from students' packed lunches. AB - Although increasing attention is placed on the quality of foods in children's packed lunches, few studies have examined the capacity of observational methods to reliably determine both what is selected and consumed from these lunches. The objective of this project was to assess the feasibility and inter-rater reliability of digital imaging for determining selection and consumption from students' packed lunches, by adapting approaches previously applied to school lunches. Study 1 assessed feasibility and reliability of data collection among a sample of packed lunches (n = 155), while Study 2 further examined reliability in a larger sample of packed (n = 386) as well as school (n = 583) lunches. Based on the results from Study 1, it was feasible to collect and code most items in packed lunch images; missing data were most commonly attributed to packaging that limited visibility of contents. Across both studies, there was satisfactory reliability for determining food types selected, quantities selected, and quantities consumed in the eight food categories examined (weighted kappa coefficients 0.68-0.97 for packed lunches, 0.74-0.97 for school lunches), with lowest reliability for estimating condiments and meats/meat alternatives in packed lunches. In extending methods predominately applied to school lunches, these findings demonstrate the capacity of digital imaging for the objective estimation of selection and consumption from both school and packed lunches. PMID- 28870836 TI - Patients' experience with nonsurgical treatment for lumbar spinal stenosis: a qualitative study. AB - BACKGROUND CONTEXT: Lumbar spinal stenosis (LSS) is a highly prevalent disease in older adults that causes significant limitations in walking and other daily activities. Research into optimal nonsurgical treatment approaches for LSS is lacking. PURPOSE: The purpose of this qualitative study is to assess the opinions of participants in a randomized clinical trial of nonsurgical LSS treatments regarding the interventions they received, factors contributing to adherence to the interventions, and methods of outcomes assessment. STUDY DESIGN/SETTING: This study used a qualitative focus group design conducted at an academic research center. PATIENT SAMPLE: Individuals participating in a randomized clinical trial (RCT) for non-surgical LSS treatment were invited to discuss their study treatments and general experiences with LSS. The three treatment arms in the study were medical care, community-based group exercise, and clinic-based manual therapy and individual exercise. OUTCOME MEASURES: Following coding of qualitative data, kappa statistic was used to calculate agreement between observers. Themes were identified and agreed upon by both coders. METHODS: This study was funded by the Patient-Centered Outcomes Research Institute (PCORI). Fifty individuals (28 women, mean age 73+/-7.7 years) participated in a focus group. Two focus groups based on modified grounded theory were held for participants of each of the three treatment arms, for a total of six focus groups. Discussion topics included perceived effectiveness of the assigned treatment, suggestions for improvement, barriers and facilitators to completing treatment, and opinions of research outcome measures. RESULTS: Several themes were evident across all treatment groups. First, patients prefer individualized treatment that is tailored to their specific impairments and functional limitations. They also want to learn self-management strategies to rely less upon formal health care providers. Participants consistently stated that exercise improved their pain levels and physical function. However, they noted that these effects are temporary, so commitment to exercising long-term is important. Common barriers to completing the assigned LSS treatment included transportation issues and other comorbid health conditions. All three treatment groups cited perceived treatment benefit as a strong facilitator to continuing treatment. In addition, the ability of the health care provider to relate to the patient and listen to the patient's concerns was a common facilitator. Within the community-based group exercise treatment arm, most individuals continued group exercise after study completion, and social support was often mentioned as a facilitator to continuing treatment. Medical care was most often associated with minimal to no effect of treatment. CONCLUSIONS: Many individuals with LSS report barriers to accessing non-surgical treatment, but may also be willing to commit to a long-term treatment strategy that includes exercise. Social support from others with LSS and from health care providers with good communication skills may facilitate compliance with treatment recommendations. PMID- 28870837 TI - Post-tetanic transcranial motor evoked potentials augment the amplitude of compound muscle action potentials recorded from innervated and non-innervated muscles. AB - BACKGROUND CONTEXT: Transcranial electrical stimulation used to produce motor evoked potentials (TES-MEPs) and subsequent compound muscle action potential (CMAP) recording is widely used to monitor motor function during surgery when there is risk of damaging the spinal cord. Nonetheless, some muscles do not produce CMAP amplitudes sufficient for intraoperative monitoring. PURPOSE: This study aimed to investigate the utility of tetanic stimulation at single and multiple peripheral nerve sites for augmenting CMAP amplitudes recorded from innervated and non-innervated muscles. STUDY DESIGN/SETTING: A retrospective study was carried out. PATIENT SAMPLE: The study sample comprised 24 patients with cervical myelopathy who underwent decompression surgery at our department between November 2005 and March 2007. OUTCOME MEASURES: Compound muscle action potential amplitude was a physiological measure. METHODS: We used two patterns of tetanic peripheral nerve stimulation for each patient. The first pattern consisted of tetanic stimulation of the left tibial nerve only (Pattern 1), and the second pattern consisted of tetanic stimulation of the bilateral median nerves and left tibial nerve (Pattern 2). RESULTS: Compound muscle action potential amplitudes from all muscles were augmented by both tetanic stimulation patterns compared with conventional TES-MEP recording; however, Pattern 2 elicited the greatest augmentation of CMAP amplitudes, especially for CMAPs recorded from the bilateral abductor pollicis brevis muscles. CONCLUSIONS: Although tetanic stimulation of a single peripheral nerve increased CMAP amplitudes recorded from both innervated and non-innervated muscles, CMAP amplitudes were best augmented when the corresponding nerve received tetanic stimulation. Additionally, tetanic stimulation of multiple nerves rather than a single nerve appears to provide better augmentation. PMID- 28870838 TI - Comparison of S2-Alar and traditional iliac screw pelvic fixation for pediatric neuromuscular deformity. AB - BACKGROUND CONTEXT: Many pelvic fixation options exist for posterior spinal fusion of pediatric neuromuscular scoliosis, including standard iliac screws (SISs) or a more recently introduced S2-Alar (S2A) technique. However, little data exist comparing the clinical and radiographic outcomes of these techniques. PURPOSE: This study aimed to dentify differences in clinical and radiographic outcomes for pediatric neuromuscular scoliosis patients treated with SIS or S2A pelvic fixation. STUDY DESIGN/SETTING: This was a retrospective cohort study at a pediatric orthopedic clinic. PATIENT SAMPLE: Patients aged 8-19 years undergoing posterior spinal fusion to the pelvis for neuromuscular scoliosis using SIS or S2A technique, with Gross Motor Function Classification System (GMFCS) Level 4 or 5 were included. OUTCOMES MEASURES: Postoperative complication rates associated with pelvic fixation method were the outcome measures. METHODS: Charts and radiographs were reviewed for demographics, intra- and postoperative course, levels of instrumentation, operative correction, and implant failure (IF). Postoperative complications were classified according to the Accordion scale. RESULTS: We studied 50 patients (28 SIS, 22 S2A) aged 14.0+/-2.8 years and an average follow-up of 3.5+/-1.7 years. The average number of levels fused was 16.5+/-1.1 with an average curve correction of 48 degrees +/-21 degrees postoperatively. A significant difference in radiographic IF rates was noted between SIS and S2A groups (57% vs. 27%, p=.02). No difference was noted between groups for frequency or severity of postoperative complications, inclusive of wound infections. Subgroup analysis demonstrated equivalent IF rates when comparing the S2A group with the SIS group with cross-links. CONCLUSIONS: The S2A group generally demonstrated improved rates of radiographic IF compared with the SIS group, but the rates became equivalent when a cross-link was added to an SIS construct. Further, no difference in postoperative complication rates were identified between SIS and S2A groups. PMID- 28870839 TI - Long-term clinical results following Charite III lumbar total disc replacement. AB - BACKGROUND CONTEXT: Lumbar total disc replacement (TDR) operation represents an alternative to lumbar fusion for the treatment of symptomatic lumbar intervertebral disc degeneration and has gained increasing attention in recent years. PURPOSE: This study aimed to assess clinical outcomes in a cohort of patients with TDR and the long-term survival rate of the prostheses. STUDY DESIGN: This is a retrospective, single-center clinical study. PATIENT SAMPLE: The sample comprised 30 patients, giving a total of 35 prostheses after an average follow-up (FU) of 15.2 years following TDR, which was performed for the treatment of lumbar degenerative disc disease. OUTCOME MEASURES: Clinical evaluation included visual analog scale (VAS) and the Oswestry Disability Index (ODI). Radiological parameters of intervertebral disc height (IDH), range of motion (ROM), lumbar lordosis, lumbar scoliosis, and prosthesis position were evaluated in surgical and adjacent levels. Complications and re-operation rates were also assessed. METHODS: Clinical evaluation and radiological parameters were evaluated preoperatively and at final FU. All data were collected by members of our department, including research assistants and nurses who were not involved in the decision making of this study. RESULTS: Thirty of the 35 patients participated in the final FU. The cumulative survival rate of the prosthesis at a mean FU of 15.4 years was 100%. The clinical success rate was 93.3%. The VAS and ODI scores at final FU were significantly lower than preoperatively (p<.001). The average ROM of the operated and superior adjacent segment decreased significantly at the final FU, whereas the inferior adjacent segment was not affected. The IDH of all surgical and adjacent levels were well maintained at the final FU. Ten patients had a lumbar scoliosis >3 degrees and the mean angle was 8.5 degrees , of which 7 had left convex curvature. Three prostheses were offset more than 5 mm from the midline on the coronal plane. Four prostheses showed subsidence. Twenty six operative segments and five adjacent segments showed heterotopic ossification. Two patients of the total 35-patient cohort underwent a secondary operation. CONCLUSIONS: Satisfactory clinical results and good prosthesis survival can be achieved in the long term. Lumbar TDR surgeries also have the potential to reduce the incidence of adjacent segment disease. PMID- 28870840 TI - Surgical outcomes in the elderly with degenerative spondylolisthesis: comparative study between patients over 80 years of age and under 80 years-a gender-, diagnosis-, and surgical method-matched two-cohort analyses. AB - BACKGROUND: In Taiwan, the current life expectancy of an 80-year-old man is 88.4 years and that of an 80-year-old is woman is 89.8 years. Surgical candidates older than 80 years usually ask surgeons whether it would be safe for them to undergo surgery. PURPOSE: The objectives of this study were to report the surgical outcomes of patients with degenerative spondylolisthesis who were older than 80 years and underwent instrumented surgeries and to compare these data with the outcomes of patients aged 65-79 years. STUDY DESIGN/SETTING: This is a retrospective study. PATIENT SAMPLE: The study included 76 patients. OUTCOME MEASURES: The preoperative medical condition was reviewed using the weighted Charlson Comorbidity Index (CCI) and the American Society of Anesthesiologists (ASA) physical status classification. Clinical outcomes were evaluated according to the Oswestry Disability Index (ODI) and the visual analog scale (VAS) for leg and back pain. Plain radiographs were used to assess the fusion status, implant related complications, and the prevalence of osteoporotic compression fractures (OVFx). MATERIALS AND METHODS: The study comprised patients older than 80 years, and the control group comprised patients aged 65-79 years. The two cohorts were matched for gender, main diagnosis, and surgical method. RESULTS: In total, 76 patients were included in the study. The study group had 38 patients with a mean age of 82.4 years (80-93 years); the control group also had 38 patients with a mean age of 70.8 years (65-79 years). The study group had a significantly higher ASA classification (2.94 vs. 2.76, p=.040) and CCI score (1.84 vs. 1.13, p=.012). The study group had a higher prevalence of preoperative OVFx (10.5% vs. 2.6%, p=.116) and incidence of new-onset OVFx (13.2% vs. 2.6%, p=.089). The study group had longer operative times (204.6 vs. 179.1 minutes, p=.052) with more blood loss (606.5 vs. 525.8 mL, p=.512), but this finding was not statistically significant. The mean ODI and VAS scores were similar between the two groups. The bone union rate was superior in the control group (81.6% vs. 89.5%, p=.328). CONCLUSIONS: Patients older than 80 years have a higher osteoporotic status and comorbidities, which may lead to longer operative times and greater blood loss, with poorer radiographic outcomes. However, the clinical results were not affected. With appropriate patient selection, the age of >80 years is not a negative predictive factor for instrumented surgery for degenerative spondylolisthesis. PMID- 28870841 TI - An increase in the degree of olisthesis during axial loading reduces the dural sac size and worsens clinical symptoms in patients with degenerative spondylolisthesis. AB - BACKGROUND CONTEXT: Previous studies have shown that axial loading during magnetic resonance imaging (MRI) significantly reduces the size of the dural sac compared with conventional MRI in patients with degenerative lumbar disease. In our previous study, axial-loaded MRI showed a significantly larger degree of olisthesis than conventional MRI in patients with degenerative spondylolisthesis (DS). Furthermore, the degree of olisthesis on axial-loaded MRI correlated more strongly with that observed on X-ray in the upright position. However, no study has investigated whether or not the increase in the degree of olisthesis during axial loading correlates with the reduction in the dural sac size and affects the severity of clinical symptoms in patients with DS. PURPOSE: The objective of this study was to determine whether or not the increase in the degree of olisthesis correlates with the reduction of the dural sac cross-sectional area (DCSA) detected on axial-loaded MRI and worsens the severity of clinical symptoms in patients with DS. STUDY DESIGN/SETTING: This is an imaging cohort study. PATIENT SAMPLE: A total of 41 consecutive patients with DS were prospectively evaluated in this study. OUTCOME MEASURES: The outcome measures include the degree of olisthesis, the DCSA, the Pearson correlation coefficient, and the severity of clinical symptoms. MATERIALS AND METHODS: The differences in the degree of olisthesis and the DCSA between conventional and axial-loaded MRIs were determined. The Pearson correlation coefficient of the increase in the degree of olisthesis with the reduction in the DCSA during axial loading was calculated. The reduction in the DCSA and the severity of clinical symptoms in patients exhibiting a >=2-mm increase in the degree of olisthesis were compared with those in patients exhibiting a <2-mm increase. RESULTS: The increase in the degree of olisthesis was significantly correlated with the reduction in the DCSA during axial loading (Pearson correlation coefficient=0.63, p<.001). The reduction in the DCSA during axial loading in patients with a >=2-mm increase in the degree of olisthesis (26+/-3 mm2) was significantly greater than in those with a <2-mm increase (13+/-2 mm2) (p<.01). Clinical symptoms such as walking distance and activity of daily living evaluated using the Japanese Orthopaedic Association score were significantly worse in patients with a >=2-mm increase in the degree of olisthesis (117+/-19 m and 6.7+/-0.5 points, respectively) than in those with a <2-mm increase (236+/-36 m and 8.4+/-0.4 points, respectively) (p<.05). CONCLUSIONS: The present study demonstrated that the increase in the degree of olisthesis was significantly correlated with the reduction in the dural sac size detected on axial-loaded MRI and worsened the severity of clinical symptoms in patients with DS. These results suggest that axial-loaded MRI may be a useful imaging study for detecting dynamic changes in the degree of olisthesis during axial loading to the lumbar spine related to the narrowing of the spinal canal and the severity of clinical symptoms in the assessment of patients with DS. PMID- 28870842 TI - Bioinformatics solutions for big data analysis in life sciences presented by the German network for bioinformatics infrastructure. PMID- 28870843 TI - Phosphatidylserine: A cancer cell targeting biomarker. AB - Cancer is a leading cause of mortality and morbidity globally. Many prominent cancer-associated molecules have been identified over the recent years which include EGFR, CD44, TGFbRII, HER2, miR-497, NMP22, BTA, Fibrin/FDP etc. These biomarkers are often used for screening, detection, diagnosis, prognosis, prediction and monitoring of cancer development. Phosphatidylserine (PS) is an essential component in all human cells which is present on the inner leaflet of the cell membrane. The oxidative stress causes exposure of PS on the surface of the vascular endothelium in the cancer cells (lung, breast, pancreatic, bladder, skin, brain metastasis, rectal adenocarcinoma etc.) but not on the normal cells. The external PS is regulated by calcium-dependent flippase activity. Cancer cell lines with high surface PS have low flippase activity and high intracellular calcium content. Human Annexin-V, PS targeting antibodies (PGN635 and bavituximab and mch1N11), lysosomal protein, phospholipid Saposin C dioleoylphosphatidylserine (SapC-DOPS), peptide-peptoid hybrid PPS1, PS-binding 14-mer peptide (PSBP-6) and hexapeptide (E3) have been reported to target PS present on cancer cell surface. High expression of CD47 inhibits tumor cell phagocytosis by macrophages. The PS cancer biomarker has also been used to target the drugs to cancer cells specifically without affecting other healthy cells. Currently, the fusion protein (FP) consisting of L-methionase linked to human Annexin-V has been reported to target the cancer cells. The FP catalyzes the conversion of non-toxic prodrug selenomethionine into toxic methyl selenol which thus also prevents the methionine (essential amino acid) supplementation to the cancer cells. PMID- 28870845 TI - Gluten-Free Labeling: Are Growth Media Containing Wheat, Barley, and Rye Falling through the Cracks? PMID- 28870844 TI - Inhibitory synapse deficits caused by familial alpha1 GABAA receptor mutations in epilepsy. AB - Epilepsy is a spectrum of neurological disorders with many causal factors. The GABA type-A receptor (GABAAR) is a major genetic target for heritable human epilepsies. Here we examine the functional effects of three epilepsy-causing mutations to the alpha1 subunit (alpha1T10'I, alpha1D192N and alpha1A295D) on inhibitory postsynaptic currents (IPSCs) mediated by the major synaptic GABAAR isoform, alpha1beta2gamma2L. We employed a neuron - HEK293 cell heterosynapse preparation to record IPSCs mediated by mutant-containing GABAARs in isolation from other GABAAR isoforms. IPSCs were recorded in the presence of the anticonvulsant drugs, carbamazepine and midazolam, and at elevated temperatures (22, 37 and 40 degrees C) to gain insight into mechanisms of febrile seizures. The mutant subunits were also transfected into cultured cortical neurons to investigate changes in synapse formation and neuronal morphology using fluorescence microscopy. We found that IPSCs mediated by alpha1T10'Ibeta2gamma2L, alpha1D192Nbeta2gamma2L GABAARs decayed faster than those mediated by alpha1beta2gamma2L receptors. IPSCs mediated by alpha1D192Nbeta2gamma2L and alpha1A295Dbeta2gamma2L receptors also exhibited a heightened temperature sensitivity. In addition, the alpha1T10'Ibeta2gamma2L GABAARs were refractory to modulation by carbamazepine or midazolam. In agreement with previous studies, we found that alpha1A295Dbeta2gamma2L GABAARs were retained intracellularly in HEK293 cells and neurons. However, pre-incubation with 100nM suberanilohydroxamic acid (SAHA) induced alpha1A295Dbeta2gamma2L GABAARs to mediate IPSCs that were indistinguishable in magnitude and waveform from those mediated by alpha1beta2gamma2L receptors. Finally, mutation-specific changes to synaptic bouton size, synapse number and neurite branching were also observed. These results provide new insights into the mechanisms of epileptogenesis of alpha1 epilepsy mutations and suggest possible leads for improving treatments for patients harbouring these mutations. PMID- 28870846 TI - Retailer-Led Sugar-Sweetened Beverage Price Increase Reduces Purchases in a Hospital Convenience Store in Melbourne, Australia: A Mixed Methods Evaluation. AB - BACKGROUND: Limited evidence has been gathered on the real-world impact of sugar sweetened beverage price changes on purchasing behavior over time or in community retail settings. OBJECTIVE: Our aim was to determine changes in beverage purchases, business outcomes, and customer and retailer satisfaction associated with a retailer-led sugar-sweetened beverage price increase in a convenience store. We hypothesized that purchases of less-healthy beverages would decrease compared to predicted sales. DESIGN: A convergent parallel mixed methods design complemented sales data (122 weeks pre-intervention, 17 weeks during intervention) with stakeholder interviews and customer surveys. PARTICIPANTS/SETTING: Electronic beverage sales data were collected from a convenience store in Melbourne, Australia (August through November 2015). Convenience store staff completed semi-structured interviews (n=4) and adult customers exiting the store completed surveys (n=352). INTERVENTION: Beverages were classified using a state government framework. Prices of "red" beverages (eg, nondiet soft drinks, energy drinks) increased by 20%. Prices of "amber" (eg, diet soft drinks, small pure fruit juices) and "green" beverages (eg, water) were unchanged. MAIN OUTCOME MEASURES: Changes in beverage volume, item sales, and revenue during the intervention were compared with predicted sales. STATISTICAL ANALYSES: Sales data were analyzed using time series segmented regression while controlling for pre-intervention trends, autocorrelation in sales data, and seasonal fluctuations. RESULTS: Beverage volume sales of red (-27.6%; 95% CI 32.2 to -23.0) and amber (-26.7%; 95% CI -39.3 to -16.0) decreased, and volume of green beverages increased (+26.9%; 95% CI +14.1 to +39.7) in the 17th intervention week compared with predicted sales. Store manager and staff considered the intervention business-neutral, despite a small reduction in beverage revenue. Fifteen percent of customers noticed the price difference and 61% supported the intervention. CONCLUSIONS: A 20% sugar-sweetened beverage price increase was associated with a reduction in their purchases and an increase in purchases of healthier alternatives. Community retail settings present a bottom up approach to improving consumer beverage choices. PMID- 28870847 TI - Bundle of care for blunt chest trauma patients improves analgesia but increases rates of intensive care unit admission: A retrospective case-control study. AB - INTRODUCTION: This single-centre retrospective case-control study aimed to assess the effectiveness of a multidisciplinary clinical pathway for blunt chest trauma patients admitted in emergency department (ED). PATIENTS AND METHODS: All consecutive blunt chest trauma patients with more than 3 rib fractures and no indication of mechanical ventilation were compared to a retrospective cohort over two 24-month periods, before and after the introduction of the bundle of care. Improvement of analgesia was the main outcome investigated in this study. The secondary outcomes were the occurrence of secondary respiratory complications (pneumonia, indication for mechanical ventilation, secondary ICU admission for respiratory failure or death), the intensive care unit (ICU) and hospital length of stay (LOS). RESULTS: Sixty-nine pairs of patients were matched using a 1:1 nearest neighbour algorithm adjusted on age and indices of severity. Between the two periods, there was a significant reduction of the rate of uncontrolled analgesia (55 vs. 17%, P<0.001). A significant increase in the rate of primary ICU transfer during the post-protocol period (23 vs. 52%, P<0.001) was not associated with a reduction of secondary respiratory complications or a reduction of ICU or hospital LOS. Only the use of non-steroidal anti-inflammatory drugs appeared to be associated with a significant reduction of secondary respiratory complications (OR=0.3 [0.1-0.9], P=0.03). CONCLUSION: Implementation of a multidisciplinary clinical pathway significantly improves pain control after ED management, but increases the rate of primary ICU admission without significant reduction of secondary respiratory complications. PMID- 28870848 TI - Sevoflurane-induced cardioprotection in coronary artery bypass graft surgery: Randomised trial with clinical and ex-vivo endpoints. AB - BACKGROUND: Myocardial ischaemia reperfusion injury following cardiac surgery with cardiopulmonary bypass (CPB) increases postoperative mortality. Setting techniques to protect the heart during this critical period therefore represents a considerable challenge. METHOD: A randomised controlled study in Caen University Hospital Centre, investigated whether the clinical cardio protective effects of administration sevoflurane before cardiopulmonary bypass during coronary artery bypass graft surgery (CABG) could translate into protected atrial trabeculae contractility against hypoxia-reoxygenation in vitro. Patients undergoing elective on-pump CABG surgery were allocated to receive either sevoflurane (n=24) or no halogenated volatile anaesthetic (n=21). MAIN OUTCOME MEASURES: the relationship between sevoflurane exposure before CPB and the incidence of major adverse cardiac events, with primary endpoint: the postoperative troponin I peak level, and secondary endpoints: the inotropic support, and the duration of stay in intensive unit and in-hospital stay were chosen as study endpoints. The right atrial was collected at the beginning of bypass surgery for the in vitro experimentation. Isometrically contracting isolated human right atrial trabeculae obtained from the two groups were exposed to 30-min hypoxia followed by 60-min reoxygenation. RESULTS: The patients receiving sevoflurane prior to aortic clamping significantly exhibited less cardiac Troponin I (1.39 [0.34-2.97] vs. 2.80 [2.54-3.64] ng.mL-1 in Control; P=0.03) and required a reduced inotropic drug support (P<0.001). Isolated trabeculae from patients receiving sevoflurane enhanced the recovery of force after reoxygenation compared to the Control group (79+/-5% vs. 53+/-8% of baseline in Control; P<0.001). CONCLUSIONS: Administration of sevoflurane before CPB induced cardioprotection in patients undergoing CABG and preconditioned human myocardium against hypoxia-reoxygenation in vitro. PMID- 28870849 TI - Perioperative management of asplenic patients in France: A national survey among anaesthetists. PMID- 28870850 TI - Hypoprothrombinemia and severe perioperative haemorrhagic complications in cardiac surgery patients treated with high-dose cefazolin for infective endocarditis. AB - Endocarditis is a serious and common disease that requires prolonged antimicrobial therapy. The recent shortage of oxacillin has led to the use of other antimicrobial agents such as cefazolin to treat endocarditis due to methicillin-sensitive Staphylococcus aureus. We describe four cases of life threatening haemorrhagic complications (fatal in two cases) in patients treated with high-dose cefazolin. All of these patients with major bleeding presented with hypoprothrombinemia secondary to hypovitaminosis K. This adverse event may be due to inhibition of vitamin K epoxide reductase and/or gamma-glutamyl carboxylase by the 2-methyl-1,2,3-thiadiazol-5-thiol group of cefazolin. This inhibition may result in hypoprothrombinemia by altering the synthesis of vitamin K-dependent coagulation factors. The increasing use of cefazolin, especially at a high dose and for a prolonged period of time, should be accompanied by regular monitoring of coagulation, including prothrombin index, and vitamin K supplementation. PMID- 28870852 TI - Independent circuits in basal ganglia and cortex for the processing of reward and precision feedback. AB - In order to understand human decision making it is necessary to understand how the brain uses feedback to guide goal-directed behavior. The ventral striatum (VS) appears to be a key structure in this function, responding strongly to explicit reward feedback. However, recent results have also shown striatal activity following correct task performance even in the absence of feedback. This raises the possibility that, in addition to processing external feedback, the dopamine-centered "reward circuit" might regulate endogenous reinforcement signals, like those triggered by satisfaction in accurate task performance. Here we use functional magnetic resonance imaging (fMRI) to test this idea. Participants completed a simple task that garnered both reward feedback and feedback about the precision of performance. Importantly, the design was such that we could manipulate information about the precision of performance within different levels of reward magnitude. Using parametric modulation and functional connectivity analysis we identified brain regions sensitive to each of these signals. Our results show a double dissociation: frontal and posterior cingulate regions responded to explicit reward but were insensitive to task precision, whereas the dorsal striatum - and putamen in particular - was insensitive to reward but responded strongly to precision feedback in reward-present trials. Both types of feedback activated the VS, and sensitivity in this structure to precision feedback was predicted by personality traits related to approach behavior and reward responsiveness. Our findings shed new light on the role of specific brain regions in integrating different sources of feedback to guide goal directed behavior. PMID- 28870851 TI - New furostanol saponins with anti-inflammatory and cytotoxic activities from the rhizomes of Smilax davidiana. AB - Seven new furostanol saponins have been isolated from the rhizomes of Smilax davidiana. Their structures were established by 2D NMR spectroscopic techniques (1H,1H-COSY, NOESY, HSQC and HMBC), mass spectrometry and comparison with the literature. The isolated compounds were subjected to evaluate anti-inflammatory and cytotoxic activities in vitro. Compounds 3, 5 and 7 were found to have modest anti-inflammatory effects through suppression of IL-1beta production and promote the expression of IL-10 in LPS-stimulated RAW 264.7 cells. Davidianoside F (6) showed activity against MCF-7 and HELA cell lines at the concentration of 10.2uM and 4.3uM, respectively. PMID- 28870853 TI - Neural overlap of L1 and L2 semantic representations in speech: A decoding approach. AB - Although research has now converged towards a consensus that both languages of a bilingual are represented in at least partly shared systems for language comprehension, it remains unclear whether both languages are represented in the same neural populations for production. We investigated the neural overlap between L1 and L2 semantic representations of translation equivalents using a production task in which the participants had to name pictures in L1 and L2. Using a decoding approach, we tested whether brain activity during the production of individual nouns in one language allowed predicting the production of the same concepts in the other language. Because both languages only share the underlying semantic representation (sensory and lexical overlap was maximally avoided), this would offer very strong evidence for neural overlap in semantic representations of bilinguals. Based on the brain activation for the individual concepts in one language in the bilateral occipito-temporal cortex and the inferior and the middle temporal gyrus, we could accurately predict the equivalent individual concepts in the other language. This indicates that these regions share semantic representations across L1 and L2 word production. PMID- 28870854 TI - Opposite effects of binge drinking on consciously vs. subliminally induced cognitive conflicts. AB - Binge-drinking is very prevalent and potentially harmful, yet very little is known about the specificity of its effects on behavior and the underlying neurophysiologic mechanisms. While it is generally accepted that alcohol impairs top-down cognitive control and conflict monitoring, it has remained unclear whether this also applies to subliminally triggered conflicts, as alcohol may not impair automated processes to the same extent. To investigate this, we used a within-subjects design in a sample of n = 22 healthy young male subjects who performed a complex response conflict paradigm while an EEG was recorded. Behavioral data showed that a binge-like intoxication of 1.10/00 increased the response conflict induced by consciously perceived flankers, but paradoxically decreased the response conflict induced by subliminal primes. The latter was found to be reflected in decreased amplitude differences in the visual N1, which reflects attentional aspects of stimulus processing, and the N2 as well as a following central negativity, which are thought to reflect conflict monitoring and cognitive effort. On the neuroanatomical level, we found the decrease in subliminally induced response conflicts to be based on changes in fronto-parietal networks (including BA 7/the precuneus, BA 40/the postcentral gyrus, BA 23 & 24/the cingulate cortex and BA 13/the insular cortex) that subserve attention allocation, the processing of complex stimuli and cognitive conflict. It can be concluded that alcohol intoxication paradoxically reduces subliminally triggered response conflicts, which may be caused by decreased allocation of attention towards less salient/noticeable stimuli. PMID- 28870855 TI - Growth media in anaerobic fermentative processes: The underestimated potential of thermophilic fermentation and anaerobic digestion. AB - Fermentation and anaerobic digestion of organic waste and wastewater is broadly studied and applied. Despite widely available results and data for these processes, comparison of the generated results in literature is difficult. Not only due to the used variety of process conditions, but also because of the many different growth media that are used. Composition of growth media can influence biogas production (rates) and lead to process instability during anaerobic digestion. To be able to compare results of the different studies reported, and to ensure nutrient limitation is not influencing observations ascribed to process dynamics and/or reaction kinetics, a standard protocol for creating a defined growth medium for anaerobic digestion and mixed culture fermentation is proposed. This paper explains the role(s) of the different macro- and micronutrients, as well as the choices for a growth medium formulation strategy. In addition, the differences in nutrient requirements between mesophilic and thermophilic systems are discussed as well as the importance of specific trace metals regarding specific conversion routes and the possible supplementary requirement of vitamins. The paper will also give some insight into the bio-availability and toxicity of trace metals. A remarkable finding is that mesophilic and thermophilic enzymes are quite comparable at their optimum temperatures. This has consequences for the trace metal requirements of thermophiles under certain conditions. Under non-limiting conditions, the trace metal requirement of thermophilic systems is about 3 times higher than for mesophilic systems. PMID- 28870856 TI - Transcriptome analysis of hybrid tilapia (Oreochromis spp.) with Streptococcus agalactiae infection identifies Toll-like receptor pathway-mediated induction of NADPH oxidase complex and piscidins as primary immune-related responses. AB - Streptococcus agalactiae infection is one of the most significant bacterial diseases in tilapia aquaculture. Identification of immune-related genes associated with Streptococcus agalactiae infection may provide a basis for breeding selection or therapeutics to augment disease resistance. Therefore, we utilized transcriptome profiling to study the host response in tilapia following Streptococcus agalactiae infection. Based on GO and KEGG enrichment analyses, we found that differentially expressed genes are widely involved in immune-related pathways, including the induction of antimicrobial peptides. Moreover, the main components of two immune-related pathways (Toll-like receptor signaling and leukocyte transendothelial migration) and four environmental information processing pathways (TNF, PI3K-Akt, Jak-STAT and MAPK) were identified. Finally, a time-course expression profile for several of the identified transcripts including tilapia piscidin 3 (TP3), tilapia piscidin 4 (TP4), TLR2, TLR5, MyD88, TRAF6, p38, and interleukin components was performed by qRT-PCR. Collectively, these results provide a starting point to study molecular mechanisms of tilapia immune response to Streptococcus agalactiae infection and may be applied as a basis for developing disease resistant strains by breeding selection. PMID- 28870857 TI - Molecular characterization and expression analysis of interferon-gamma in black seabream Acanthopagrus schlegelii. AB - Interferon gamma (IFN-gamma) is a major component in immunological signaling and plays a key role in resisting viral infection. In this study, we identified and characterized an IFN-gamma gene (AsIFN-gamma) in the marine fish black seabream (Acanthopagrus schlegelii). We cloned AsIFN-gamma genomic sequence, which comprises four exons, three introns and an upstream promoter including several conserved regulatory elements. The complete cDNA of AsIFN-gamma was 816 bp in length and encoded a putative 194 amino acids (aa) protein with a 22 aa signal peptide, six alpha-helices and one nuclear localization signal (NLS). Multiple alignment showed that AsIFN-gamma protein shared 31-60% identity with IFN-gamma of other fish but low identity with fish IFN-gammarel and IFN-gamma of other vertebrates. AsIFN-gamma was constitutively expressed in all examined tissues with the highest expression level in immune organs, such as spleen, gill and kidney. In black seabream infected by red spotted nervous necrosis virus (RGNNV), the expression of AsIFN-gamma was significantly up-regulated in most tissues, and RGNNV infection in vitro also induced significant up-regulation of AsIFN-gamma, indicating that AsIFN-gamma was involved in immune response to RGNNV infection. Overexpression of AsIFN-gamma in cultured Acanthopagrus schlegelii brain (AsB) cells rapidly and transiently stimulated the expression of JAK-STAT signaling pathway related genes including STAT1, STAT2 and IRF9, as well as the downstream antiviral genes MX1 and ISG15. Furthermore, overexpression of AsIFN-gamma was able to significantly inhibit RGNNV replication and virus production in AsB cells. In summary, we identified a conserved IFN-gamma gene of black seabream, and demonstrated the rapid and strong antiviral activities of AsIFN-gamma against RGNNV in black seabream. PMID- 28870859 TI - Ocean acidification and pathogen exposure modulate the immune response of the edible mussel Mytilus chilensis. AB - Ocean acidification (OA) is one of the main consequences of increasing atmospheric carbon dioxide (CO2), impacting key biological processes of marine organisms such as development, growth and immune response. However, there are scarce studies on the influence of OA on marine invertebrates' ability to cope with pathogens. This study evaluated the single and combined effects of OA and bacterial infection on the transcription expression of genes related to antioxidant system, antimicrobial peptides and pattern recognition receptors in the edible mussel Mytilus chilensis. Individuals of M. chilensis were exposed during 60 days at two concentrations of pCO2 (550 and 1200 MUatm) representing respectively current and future scenario of OA and were then injected with the pathogenic bacterium Vibrio anguillarum. Results evidenced an immunomodulation following the OA exposure with an up-regulation of C-type Lectin and Mytilin B and a down-regulation of Myticin A and PGRP. This immunomodulation pattern is partially counteracted after challenge with V. anguillarum with a down-regulation of the C-type lectin and Mytilin B and the up-regulation of Myticin A. In turn, these results evidence that pCO2-driven OA scenarios might triggers specific immune-related genes at early stages of infection, promoting the transcription of antimicrobial peptides and patterns recognition receptors. This study provides new evidence of how the immune response of bivalves is modulated by higher CO2 conditions in the ocean, as well one factor for the resilience of marine population upon global change scenarios. PMID- 28870860 TI - Does Early Prostate Specific Antigen Doubling Time after Radical Prostatectomy, Calculated Prior to Prostate Specific Antigen Recurrence, Correlate with Prostate Cancer Outcomes? A Report from the SEARCH Database Group. AB - PURPOSE: Short prostate specific antigen doubling time following recurrence after radical prostatectomy portends a poor prognosis. Prostate specific antigen doubling time is traditionally calculated using prostate specific antigen values 0.2 ng/ml or greater. We determined whether early prostate specific antigen doubling time, calculated from the first detectable postoperative prostate specific antigen up to and including the first recurrence value, correlates with prostate cancer outcomes. MATERIALS AND METHODS: Cox models were used to examine the association between early prostate specific antigen doubling time and castration resistant prostate cancer, metastases, and all cause and prostate cancer specific mortality in 674 men who underwent radical prostatectomy between 1988 and 2014 and had a biochemical recurrence. Early prostate specific antigen doubling time was examined as a log transformed continuous and a categorical variable. RESULTS: After adjusting for multiple clinicopathological characteristics, log transformed early prostate specific antigen doubling time was not associated with any outcome. However, when early doubling time was categorized as 15 or greater, 9 to 14.9, 3 to 8.9 and less than 3 months, on multivariable analysis men with early doubling time less than 3 months were at increased risk for castration resistant prostate cancer (HR 6.20, p = 0.004), metastases (HR 5.26, p = 0.001), prostate cancer specific mortality (HR 5.06, p = 0.026) and all cause mortality (HR 1.63, p = 0.065) compared to those with an early doubling time of 15 months or greater. However, the association with all cause mortality was not significant. Those with an early prostate specific antigen doubling time of 3 to 8.9 months were at increased risk for castration resistant prostate cancer (HR 3.56, p = 0.015), all cause mortality (HR 1.67, p = 0.006) and prostate cancer specific mortality (HR 3.17, p = 0.044) but not metastases (p = 0.13). CONCLUSIONS: Early prostate specific antigen doubling time less than 9 months, calculated using prostate specific antigen values before and up to biochemical recurrence, is associated with an increased risk of castration resistant prostate cancer, metastases, and prostate cancer specific and all cause mortality among men with biochemical recurrence after radical prostatectomy. Early prostate specific antigen doubling time allows for risk stratification at biochemical recurrence and before prostate specific antigen doubling time is calculable, enabling these men to be referred for early aggressive secondary treatment and/or clinical trials. PMID- 28870858 TI - Molecular characterization and expression analysis of the large yellow croaker (Larimichthys crocea) chemokine receptors CXCR2, CXCR3, and CXCR4 after bacterial and poly I:C challenge. AB - The large yellow croaker (Larimichthys crocea) has a well-developed innate immune system. We studied a component of this system, chemokine receptor CXCR family. In this study, we report the full-length open reading frames, as well as the identification and characterization of the chemokine receptor genes CXCR2 (LycCXCR2), CXCR3 (LycCXCR3), and CXCR4 (LycCXCR4) of large yellow croaker. We report that LycCXCR3 and LycCXCR4 are evolving neutrally according to PAML analyses. Quantitative real-time PCR analysis revealed that CXCR transcripts were expressed in all examined tissues. The expression of chemokine receptors LycCXCR2, LycCXCR3, and LycCXCR4 was elevated in the kidney, spleen, and particularly the liver of the large yellow croaker after challenge with Vibrio anguillarum and polyinosinic:polycytidylic acid (poly I:C). These results suggest that LycCXCR2, LycCXCR3, and LycCXCR4 may be important immune-related genes, playing crucial roles in immune defence against bacterial infection. PMID- 28870861 TI - Sleep Problems are Associated with Development and Progression of Lower Urinary Tract Symptoms: Results from REDUCE. AB - PURPOSE: Although lower urinary tract symptoms and sleep problems often develop together, to our knowledge it is unknown whether sleep disturbances are linked to lower urinary tract symptoms development and progression. As measured by the 6 item MOS-Sleep (Medical Outcomes Study Sleep Scale) survey we examined the relationship between sleep problems, and the development and progression of lower urinary tract symptoms in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study. MATERIALS AND METHODS: REDUCE was a randomized trial testing prostate cancer chemoprevention with dutasteride in men with prostate specific antigen 2.5 to 10 ng/ml and a negative biopsy. At baseline men completed MOS Sleep and a scaled average was used to calculate the sleep score. Men were followed for 4 years and I-PSS (International Prostate Symptom Score) was completed at baseline and every 6 months. Asymptomatic men had I-PSS less than 8 while symptomatic men had I-PSS 8 or greater. In the placebo arm of 2,588 men not receiving alpha-blockers or 5alpha-reductase inhibitors at baseline we tested the association between sleep problems and lower urinary tract symptom development and progression using Cox models. RESULTS: During followup lower urinary tract symptoms developed in 209 of 1,452 asymptomatic men (14%) and 580 of 1,136 (51%) with lower urinary tract symptoms demonstrated progression. On multivariable analysis higher sleep scores were suggestively associated with increased lower urinary tract symptoms in asymptomatic men (quartile 4 vs 1 HR 1.41, 95% CI 0.92 2.17, p = 0.12) and with lower urinary tract symptom progression in symptomatic men (per 10 points of sleep score HR 1.06, 95% CI 1.01-1.12, p = 0.029). CONCLUSIONS: Among men with lower urinary tract symptoms worse sleep scores were associated with the progression of lower urinary tract symptoms and among asymptomatic men worse sleep scores were suggestively associated with the development of lower urinary tract symptoms. If confirmed, these data suggest that sleep problems may precede such symptoms. Whether treating sleep problems would improve lower urinary tract symptoms requires further testing. PMID- 28870862 TI - Incidence, Clinicopathological Risk Factors, Management and Outcomes of Nonmuscle Invasive Recurrence after Complete Response to Trimodality Therapy for Muscle Invasive Bladder Cancer. AB - PURPOSE: We describe the incidence, clinicopathological risk factors, management and outcomes of recurrent nonmuscle invasive bladder cancer after a complete response to trimodality therapy of muscle invasive bladder cancer. MATERIALS AND METHODS: We retrospectively reviewed the records of 342 patients with cT2-4aN0M0 muscle invasive bladder cancer and a complete response after trimodality therapy from 1986 to 2013. Using competing risks analyses we examined the association between baseline clinicopathological variables and nonmuscle invasive bladder cancer outcomes. Kaplan-Meier and the generalized Fleming-Harrington test were used to compare disease specific and overall survival. RESULTS: At a median followup of 9 years nonmuscle invasive bladder cancer recurred in 85 patients (25%) who had had a complete response. On Kaplan-Meier analysis baseline carcinoma in situ was associated with recurrent nonmuscle invasive bladder cancer (p = 0.02). However, on multivariate analysis carcinoma in situ and other baseline clinicopathological characteristics did not predict such recurrence. Patients with recurrent nonmuscle invasive bladder cancer had worse 10-year disease specific survival than those without recurrence (72.1% vs 78.4%, p = 0.002), although overall survival was similar (p = 0.66). Of the 39 patients (46%) who received adjuvant intravesical bacillus Calmette-Guerin 29 (74%) completed induction therapy and 19 (49%) reported bacillus Calmette-Guerin toxicity. Three-year recurrence-free and progression-free survival after induction bacillus Calmette-Guerin was 59% and 63%, respectively. CONCLUSIONS: After a complete response to trimodality therapy nonmuscle invasive bladder cancer recurred in 25% of patients, developing in some of them more than a decade after trimodality therapy. No baseline clinicopathological characteristics were associated with such recurrence after a complete response. Patients with nonmuscle invasive bladder cancer recurrence had worse disease specific survival than those without such recurrence but similar overall survival. Adjuvant intravesical bacillus Calmette-Guerin had a reasonable toxicity profile and efficacy in this population. Properly selected patients with recurrent nonmuscle invasive bladder cancer after a complete response may avoid immediate salvage cystectomy. PMID- 28870863 TI - Use of targeted sequence capture and high-throughput sequencing identifies a novel PKD1 mutation involved in adult polycystic kidney disease. AB - Polycystic kidney disease (PKD) is a common inherited disease that is characterized by a progressive development of renal cysts. Approximately 85% of PKD cases are due to mutations in the polycystin 1 (PKD1) gene. Here, we report a pedigree containing nine patients with autosomal dominant PKD (ADPKD). Using targeted exome sequencing of PKD1 and PKD2 genes, we identified a novel heterozygous frameshift mutation c.3976_3977insCT (p.F1326Sfs*21) in the PKD1 gene that segregated between affected and unaffected family members. This mutation is currently not present in the 1000 Genomes Project nor ExAC databases and is therefore a novel PKD1 mutation involved in ADPKD. These results provide a novel sequence variant for the genetic analysis of this disease. PMID- 28870865 TI - Changes in water manganese levels and longitudinal assessment of intellectual function in children exposed through drinking water. AB - BACKGROUND: Manganese is commonly found in water but potential neurotoxic effects from exposure through drinking water are poorly understood. We previously reported a cross-sectional study showing that drinking water Mn concentration was associated with lower IQ in children aged 6 to 13 years. OBJECTIVE: For this follow-up study, we aimed to re-assess the relation between exposure to Mn from drinking water and IQ at adolescence. In addition, we aimed to examine whether changes in drinking water Mn concentration was associated with changes in IQ scores. METHODS: From the 380 children enrolled in the baseline study, 287 participated to this follow-up study conducted in average 4.4 years after. Mn concentration was measured in home tap water and children's hair. The relationships between these Mn exposure indicators and IQ scores (Weschsler Abbreviated Scale of Intelligence) at follow-up were assessed with linear regression analysis, adjusting for potential confounders. Intra-individual differences in IQ scores between the two examinations were compared for children whose Mn concentration in water remained stable between examinations, increased or decreased. RESULTS: The mean age at follow-up was 13.7 years (range, 10.5 to 18.0 years). Geometric mean of Mn concentration in water at follow-up was 14.5MUg/L. Higher Mn concentration in water measured at follow-up was associated with lower Performance IQ in girls (beta for a 10-fold increase=-2.8, 95% confidence intervals [CI] -4.8 to -0.8) and higher Performance IQ in boys (beta=3.9, 95% CI 1.4 to 6.4). IQ scores were not significantly associated with Mn concentration in hair, although similar trends as for concentration in water were observed. For children whose Mn concentration in water increased between baseline and follow-up, Performance IQ scores decreased significantly (intra individual difference, -2.4 points). CONCLUSION: Higher levels of Mn in drinking water were associated with lower Performance IQ in girls, whereas the opposite was observed in boys. These findings suggest long-term exposure to Mn through drinking water is associated differently with cognition in boys and girls. PMID- 28870864 TI - Counter regulation of ECRG4 gene expression by hypermethylation-dependent inhibition and the Sp1 transcription factor-dependent stimulation of the c2orf40 promoter. AB - The human cytokine precursor ECRG4 has been associated with multiple physiological, developmental and pathophysiological processes involving cell proliferation, cell migration, innate immunity, inflammation, cancer progression and metastases. Although down-regulation of ECRG4 gene expression has been largely attributed to hypermethylation of CpG islands in the 5'untranslated region of the ECRG4 promoter, the mechanisms that underlie the dynamics of its regulation have never been systematically described. Here we show that the ECRG4 gene is widely expressed in human tissues and report that its core promoter lies between the -780 to +420 base pairs relative to the ATG start codon of the ECRG4 open reading frame. This sequence, which contains several CpG islands, also includes multiple overlapping Sp1 consensus binding sequences and a putative binding site for NF-kB activation. 5'RACE of mRNA derived from human leukocytes shows that ECRG4 transcription initiates from the guanidine at -11 from the initiation ATG of the ECRG4 open reading frame. While there is no canonical TATA- or CAAT-boxes proximal to this translational initiation site, there is a distal TATA-sequence in the 5'UTR. This region was identified as the sequence targeted by hypermethylation because in vitro methylation of plasmids encoding the ECRG4 promoter abolish promoter activity and the treatment of Jurkat cells (which naturally express ECRG4) with the methylation inhibitor 5-AzaC, increases endogenous ECRG4 expression. Because ChIP assays show that Sp1 binds the ECRG4 promoter, that forced Sp1 expression trans-activates the ECRG4 promoter and Sp1 inhibition with mithramycin inhibits ECRG4 expression, we conclude that the dynamic positive and negative regulatory elements controlling ECRG4 expression include a counter regulation between promoter methylation and Sp1 activation. PMID- 28870866 TI - Evaluation of the effect of an environmental management program on exposure to manganese in a mining zone in Mexico. AB - BACKGROUND: In the state of Hidalgo, Mexico, is found the largest second deposit of Manganese (Mn) in Latin America. Various studies on the sources of emission, exposure, and the effects on the health of children and adults have been conducted utilizing an ecosystem approach. Given the findings of Mn levels in air and the neurocognitive effects, an Environmental Management Program (EMP) was designed and implemented with the purpose of reducing exposure to Mn of the population, including various actions for reducing Mn emissions into the atmosphere. OBJECTIVE: To evaluate the impact of the EMP on the concentrations of Mn in air, as well as the modification of exposure to Mn in the blood and hair of adult residents of the communities intervened. METHODS: A quasi-experimental study was conducted in five rural communities, in which Mn concentrations were evaluated in air and in blood in the years 2002 and 2007, pre-intervention, and in 2013, postintervention. In 2003, the concentration of hair Mn among the communities was evaluated. Measurements were carried out of Particulate Matter (PM) of >10 and 2.5MUm (PM10 and PM2.5), and Mn in PM10 and PM2.5 were measured using proton-induced X-ray emissions (PIXE). The method of Difference in Differences (DID) was applied to estimate the impact of EMP on Mn concentrations in particulate matter via linear regression through multilevel models. To evaluate the effect of Mn concentrations in air over Mn concentrations in blood in both study periods in the mining communities per year (2002 and 2013), a linear regression model for each year was employed. RESULTS: We estimated that the EMP contributed to reducing the average daily concentrations of Mn in PM10 and PM2.5 by 92 and 85%, respectively. The adjusted model did not show an effect of Mn concentrations in air over Mn concentrations in blood in both study periods. CONCLUSIONS: The results suggest that the measures implemented to reduce Mn emissions in air exerted a significant impact on the reduction of inhaled exposure in adult population. PMID- 28870867 TI - Hematologic neoplasms: Dendritic cells vaccines in motion. AB - Dendritic cells (DCs) are bone-marrow-derived immune cells accounted for a key role in cancer vaccination as potent antigen-presenting cells within the immune system. Cancer microenvironment can modulate DCs maturation resulting in their accumulation into functional states associated with a reduced antitumor immune response. In this regard, a successful cancer vaccine needs to mount a potent antitumor immune response able to overcome the immunosuppressive tumor milieu. As a consequence, DCs-based approaches are a safe and promising strategy for improving the therapeutic efficacy in hematological malignancies, particularly in combinations with additional treatments. This review summarizes the most significant evidence about the immunotherapeutic strategies performed to target hematologic neoplasms including the tumoral associated antigens (TAA) pulsed on DCs, whole tumor cell vaccines or leukemia-derived DCs. PMID- 28870868 TI - Heme oxygenase-1 participates in the resolution of seawater drowning-induced acute respiratory distress syndrome. AB - The aim of the present study was to investigate whether heme oxygenase-1(HO-1) participated in the resolution of seawater drowning-induced acute respiratory distress syndrome (ARDS). In this study, gross and microscopic morphology of pulmonary tissue, computed tomography images and biochemical indexes were continuously observed from 15min to 15day after seawater drowning. The content and activity of HO-1 were determined by western-blot and spectrophotometric method, respectively. The morphological and biochemical indexes indicated that the seawater drowning could lead to the serious pulmonary hemorrhage and edema. However, 6h after drowning, these morphological and biochemical indexes gradually returned to basal level. Meanwhile, seawater drowning increased the HO-1 expression and activity while Zinc protoporphyrin (a HO-1 specific activity inhibitor) decreased the content of transforming growth factor beta-1 in lung tissue and hampered the repair process of seawater drowning-induced ARDS. Thus, HO-1 participates in the resolution of seawater drowning-induced ARDS. PMID- 28870869 TI - Dysfunctional breathing is more frequent in chronic obstructive pulmonary disease than in asthma and in health. AB - Involuntary adaptations of breathing patterns to counter breathlessness may lead to dysfunctional breathing in obstructive lung diseases. However, no studies examining dysfunctional breathing in Chronic Obstructive Pulmonary Disease (COPD) have been reported. Patients with verified COPD (n=34), asthma (n=37) and a healthy control group (n=41) were recruited. All participants completed the Nijmegen questionnaire for dysfunctional breathing as well as measures of disease activity. Comparisons between groups employed analysis of variance with post-hoc Bonferroni analyses and Pearson correlation for associations. Patients with COPD had significantly higher Nijmegen questionnaire scores than asthmatics (COPD: 23.4+/-10.6 versus 17.3+/-10.6, p=0.016) and healthy individuals (14.3+/-9.6, p=0.002). Significantly more patients with COPD had severe dysfunctional breathing with Nijmegen scores >23 (47%; 16/34) compared to asthma (27%; 10/37) and healthy controls (17%; 7/41) respectively (p=0.019). Dysfunctional breathing was detected in ~50% of patients with COPD, more so than in asthma or health. Strategies to reduce abnormal breathing behaviours may have important benefits for treatment of breathlessness in COPD. PMID- 28870870 TI - "Spirometric" lung age reference equations: A narrative review. AB - The aim of the present paper was to conduct a narrative review of the published norms of the "spirometric" lung-age (SLA). A literature search which covered the period 1970 to June 2017, was conducted using the Pubmed. The search strategy had used the following MeSH words: "Spirometry"[Majr]) AND "Aging"[Majr]. Six original studies have reported equations predicting SLA for adults aged 18-90 years [USA (n=2), Japan (n=2); Australia (n=1) and Tunisia (n=1)]. Their sample sizes varied from 125 to 15238, with a total of 32334 volunteers (11788 men). Several models of norms were developed. They included one (often, FEV1) or more spirometric data in addition to one (often, height) or more anthropometric data. All studies have validated their norms in additional one or more groups, with satisfactory results. Only three authors have proposed algorithms to interpret SLA. All studies presented several limitations concerning the sample size and/or representation, the age distribution, the use of old spirometric data and/or equipment, the application of old spirometric methods, and especially mathematical and statistical flaws. PMID- 28870871 TI - Controversy and debate on clinical genomics sequencing-paper 1: genomics is not exceptional: rigorous evaluations are necessary for clinical applications of genomic sequencing. AB - Next generation genomic sequencing (NGS) technologies-whole genome and whole exome sequencing-are now cheap enough to be within the grasp of many health care organizations. To many, NGS is symbolic of cutting edge health care, offering the promise of "precision" and "personalized" medicine. Historically, research and clinical application has been a two-way street in clinical genetics: research often driven directly by the desire to understand and try to solve immediate clinical problems affecting real, identifiable patients and families, accompanied by a low threshold of willingness to apply research-driven interventions without resort to formal empirical evaluations. However, NGS technologies are not simple substitutes for older technologies and need careful evaluation for use as screening, diagnostic, or prognostic tools. We have concerns across three areas. First, at the moment, analytic validity is unknown because technical platforms are not yet stable, laboratory quality assurance programs are in their infancy, and data interpretation capabilities are badly underdeveloped. Second, clinical validity of genomic findings for patient populations without pre-existing high genetic risk is doubtful, as most clinical experience with NGS technologies relates to patients with a high prior likelihood of a genetic etiology. Finally, we are concerned that proponents argue not only for clinically driven approaches to assessing a patient's genome, but also for seeking out variants associated with unrelated conditions or susceptibilities-so-called "secondary targets"-this is screening on a genomic scale. We argue that clinical uses of genomic sequencing should remain limited to specialist and research settings, that screening for secondary findings in clinical testing should be limited to the maximum extent possible, and that the benefits, harms, and economic implications of their routine use be systematically evaluated. All stakeholders have a responsibility to ensure that patients receive effective, safe health care, in an economically sustainable health care system. There should be no exception for genome-based interventions. PMID- 28870872 TI - Five indicators were developed to assess the quality of reviews on preventive interventions. AB - OBJECTIVES: The objective of the study was to develop quality indicators for preventive effectiveness and to evaluate their use with Cochrane Reviews of primary preventive interventions. STUDY DESIGN AND SETTING: Based on the quality of care framework, we searched the literature to develop a set of quality indicators. Two authors applied the quality indicators independently to a sample of Cochrane systematic reviews of primary prevention. RESULTS: Five quality indicators were developed: sample size, directness of evidence, adherence, harm, and costs. We applied the quality indicators to a random sample of 84 of a total of 264 Cochrane reviews of primary preventive interventions. Only 70% reviews (n = 59) complied with the indicator sample size, whereas 61% (n = 51) complied with directness of the outcome, 48% (n = 40) with adherence, 76% (n = 64) with harm, and 46% (n = 39) with the indicator cost. CONCLUSION: Applying the five quality indicators is feasible. The quality of evidence in reviews of primary prevention can be substantially improved. Trialists and review authors should provide more information especially on adherence, costs, and indirectness of the outcome. Methodological research is needed on how to incorporate cost information in systematic reviews and how to better deal with indirectness. PMID- 28870873 TI - The kinematic alignment technique for TKA reliably aligns the femoral component with the cylindrical axis. AB - INTRODUCTION: Kinematic alignment (KA) technique is an alternative technique for positioning a TKA, which aims a patient-specific implant positioning in order to reproduce the pre-arthritic knee anatomy. Because reliability in implant positioning is of interest to obtain reproducible good functional results, our study tests the hypothesis that the medial and lateral distal and posterior positions of the planned and surgically implanted kinematically aligned femoral component are similar. METHODS: Preoperative knee magnetic resonance imaging (MRI) and postoperative knee computed tomography (CT) of 13 patients implanted with a KA Persona(r) TKA (Zimmer, Warsaw, USA) using manual instrumentation (kinematically-aligned TKA procedure pack(r), Zimmer Biomet, Warsaw, USA) were segmented to create 3D femoral models. The kinematic alignment position of the femoral component was planned on the 3D model created from the preoperative MRI. Differences in the positions of the planned and surgically implanted kinematically-aligned femoral component were determined with in-house analysis software. RESULTS: The average differences between the medial and lateral distal and posterior positions of the planned and surgically implanted kinematically aligned femoral component were inferior to 1mm and no statistically significant. In terms of variability, 62% (8/13) of performed implants matched all four positions within 1.5mm, and the maximum difference was 3mm. CONCLUSION: In this small series, intraoperative kinematic positioning of the femoral component with the specific manual instrumentation closely matched the planned position, which suggests that this technique reliably aligned the flexion-extension axis of the femoral component to the cylindrical axis. LEVEL OF EVIDENCE: Level 3. PMID- 28870874 TI - Characteristics and outcome following transcatheter aortic valve replacement in patients with severe aortic stenosis with low flow. AB - AIMS: Only a few studies have examined the respective impact of low flow (LF), low gradient (LG) and low ejection fraction (LEF) on outcomes following transcatheter aortic valve replacement (TAVR). The purpose of this study was to assess the impact of preprocedural stroke volume index, aortic valve gradient, left ventricular ejection fraction (LVEF) and different flow/gradient/LVEF patterns on the clinical outcomes of patients with severe aortic stenosis (AS) who undergo TAVR. METHODS AND RESULTS: We analysed the clinical, echocardiographic, and outcome data collected in 770 patients with AS who underwent TAVR. Overall, 357 patients had normal flow (NF) AS and 413 had LF AS. Patients with NF had similar one-year mortality (12.0% vs. 15.0%, p=0.23) compared with those in the LF group. Overall, patients with NF and/or HG had lower one-year mortality rates (11.7 to 13%) compared to those with paradoxical LF-LG with NEF (19%) and those with classical LF-LG with LEF (27.3%). Low mean gradient was an independent predictor of all-cause mortality (hazard ratio: 1.14, per 10 mmHg decrease, p=0.02). Despite significant association in univariable analyses, LF and LEF were not found to be predictors of outcomes in multivariable analyses. CONCLUSIONS: Patients with HG and those with NF-LG have low one-year mortality rates following TAVR, whereas those with classical LF-LG and LEF and those with paradoxical LF-LG and NEF have high and intermediate risk of mortality, respectively. In contradiction to previous reports, LG but not LF or LEF is an independent predictor of late mortality in high-risk patients with severe AS undergoing TAVR. PMID- 28870875 TI - Which is the best antiaggregant or anticoagulant therapy after TAVI? A propensity matched analysis from the ITER registry. The management of DAPT after TAVI. AB - AIMS: The safety and efficacy of single vs. dual antiplatelet therapy (DAPT) in patients undergoing TAVI remain to be addressed. The aim of our study was to evaluate the usefulness of a DAPT compared to a single platelet therapy in patients undergoing TAVI with a balloon-expandable prosthesis. METHODS AND RESULTS: All consecutive patients enrolled in the ITER registry were included. Patients undergoing TAVI discharged with aspirin alone were compared to those taking DAPT before and after selection using propensity score with matching. Subgroup analysis was performed for those on OAT. Prosthetic heart valve dysfunction at follow-up was the primary endpoint, whereas all-cause death, cardiovascular death, bleedings, vascular complications and cerebrovascular accidents were the secondary ones. From 1,364 patients, after propensity score with matching, 605 were selected for each group (aspirin alone vs. DAPT). At 30 days, rates of VARC mortality were lower in patients with aspirin alone (1.5% vs. 4.1%, p=0.003), mainly driven by a reduction of major vascular complications (5.3% vs. 10.7%, p<0.001) and of major bleedings (6.6% vs. 11.5%, p<0.001), without a difference in prosthetic heart valve dysfunction after 45+/-14 months (2.8% vs. 3.0%, p=0.50). These results were confirmed on multivariable analysis. CONCLUSIONS: After TAVI with a balloon-expandable prosthesis, aspirin alone does not increase the risk of prosthetic valve dysfunction, and reduces the risk of periprocedural complications and of 30-day all-cause death. PMID- 28870876 TI - Prevalence and impact of critical limb ischaemia on in-hospital outcome in transcatheter aortic valve implantation in Germany. AB - AIMS: Peripheral artery disease (PAD) is common in patients with aortic valve stenosis (AS). This study sought to assess the prevalence of critical limb ischaemia (CLI) and its impact on in-hospital outcome in patients undergoing transcatheter aortic valve implantation (TAVI) for severe AS. METHODS AND RESULTS: All isolated TAVI procedures for AS in Germany between 2007 and 2013 were analysed regarding the stage-specific prevalence of PAD, comorbidities, in hospital complications and mortality using diagnostic and procedural codes. Among 32,044 patients with TAVI, 3,375 (10.5%) had PAD and 654 (2.0%) CLI. TAVI patients with PAD, particularly those with CLI, had a higher incidence of periprocedural stroke, bleeding and acute kidney injury (p<0.001). The overall in hospital mortality among TAVI without PAD, non-CLI PAD and CLI was 6.1%, 8.4% and 14.7%, respectively (p<0.001). In a multivariate logistic regression analysis, CLI was an independent predictor of in-hospital mortality (odds ratio 1.96, 95% confidence interval 1.56-2.47; p<0.001). CONCLUSIONS: In patients undergoing TAVI, the presence of PAD is associated with an increased risk of periprocedural complications, while only CLI independently predicts increased in-hospital mortality. Whether CLI represents a marker of general poor health status resulting in poor outcome or is a modifiable risk factor whose treatment prior to TAVI can improve the outcome requires prospective studies. PMID- 28870877 TI - Very low pacemaker rate following ACURATE neo transcatheter heart valve implantation. AB - AIMS: The aim of this study was to investigate whether minimising trauma to the aortic annulus and left ventricular outflow tract reduces the occurrence of new conduction disorders and the need for permanent pacemakers. METHODS AND RESULTS: A total of 175 patients (58% female, mean age 83+/-6 years) underwent transfemoral TAVI with the Boston Scientific ACURATE neo at three centres in Europe. Prosthesis size selection was based on perimeter-derived annular diameter. Predilatation was performed in all with a balloon 1.9+/-0.9 mm smaller than the perimeter-derived annular diameter. Post-dilatation was performed in 46 (26.3%) with a balloon 1.2+/-0.9 mm smaller than the perimeter-derived annular diameter. Eighteen patients (10.3%) developed a new left bundle branch block, 13 (7%) a new first-degree AV block, and four (2.3%) received a new permanent pacemaker. Paravalvular regurgitation was none/trace in 66 (37.7%), mild in 101 (57.7%) and moderate in eight (4.6%). At 30 days, the rate of any stroke was 1.7% (3/175), and one patient (0.6%) had died. CONCLUSIONS: With careful selection of the balloon and the ACURATE neo prosthesis size, very low rates of new conduction disorders and permanent pacemaker implantation may be achieved without increasing the amount of paravalvular regurgitation. PMID- 28870878 TI - Clinical outcomes after percutaneous coronary intervention with the COMBO stent versus Resolute Integrity and PROMUS Element stents: a propensity-matched analysis. AB - AIMS: The COMBO stent combines sirolimus elution with an endothelial progenitor cell-capturing layer to promote early endothelialisation. There has not been a head-to-head comparison of this novel device with any other currently used drug eluting stent (DES). We sought to compare clinical outcome at two years after COMBO stent placement with the Resolute Integrity or PROMUS Element stent in an all-comers cohort. METHODS AND RESULTS: Patients from the REMEDEE registry (COMBO, n=1,000) were matched with patients from the DUTCH PEERS trial (PROMUS Element/Resolute Integrity, n=1,811). Propensity score matching on 13 baseline characteristics was applied to create two balanced cohorts of patients treated with COMBO versus PROMUS Element/Resolute Integrity. Propensity score matching yielded 771 patient pairs, representing all-comers patients, with a median age of 65 years, 27% female and more than 50% of patients presenting with acute coronary syndrome. Target lesion failure (TLF), a composite of cardiac death, target vessel MI and any target lesion revascularisation, at two-year follow-up was 7.9% in COMBO and 6.4% in PROMUS Element/Resolute Integrity, HR 1.24 (95% CI: 0.85 1.81), p=0.26. Definite stent thrombosis (ST) was not significantly different between groups (0.8% vs. 0.9%, p=0.79). CONCLUSIONS: In a propensity-matched analysis, the COMBO stent showed similar rates of TLF and ST at two-year follow up compared to Resolute Integrity and PROMUS Element. PMID- 28870879 TI - Initial experience with the novel BioMime 60 mm-long sirolimus-eluting tapered stent system in long coronary lesions. PMID- 28870880 TI - Percutaneous closure of subannular rupture following transcatheter aortic valve implantation. PMID- 28870881 TI - Transcatheter edge-to-edge repair of lead-associated tricuspid regurgitation. PMID- 28870882 TI - Two-year outcome after biodegradable polymer sirolimus- and biolimus-eluting coronary stents (from the randomised SORT OUT VII trial). PMID- 28870883 TI - Percutaneous renal artery revascularization after prolonged ischemia secondary to blunt trauma: pooled cohort analysis. AB - PURPOSE: We aimed to identify factors related to technical and clinical success of percutaneous revascularization for blunt renal arterial trauma. METHODS: All cases of percutaneous revascularization for blunt renal arterial trauma were searched in the available literature. We included a case of iatrogenic renal artery occlusion at our institution treated by percutaneous stenting 20 hours after injury. A pooled cohort analysis of percutaneous revascularization for blunt renal artery injury was then performed to analyze factors related to technical and clinical success. Clinical failure was defined as development of new hypertension, serum creatinine rise, or significant asymmetry in split renal function. RESULTS: A total of 53 cases have been reported, and 54 cases were analyzed including our case. Median follow-up was 6 months. Technical success was 88.9% and clinical success was 75%. Of 12 treatment failures (25%), 66.7% occurred during the first postprocedure month. Time from injury to revascularization was not a predictor of clinical success (OR=1.00, P = 0.681). Renal artery occlusion was significantly associated with clinical failure (OR=7.50, P = 0.017) and postintervention antiplatelet therapy was significantly associated with treatment success (OR=0.16, P = 0.043). At 37-month follow-up, the stented renal artery in our case remained patent and the patient was normotensive with preserved glomerular filtration rate. CONCLUSION: Percutaneous revascularization for blunt renal arterial injury resulted in relatively high technical and clinical success. Time-to-revascularization was independent of successful outcomes. Clinical success was significantly associated with a patent renal artery at the time of intervention and with postprocedure antiplatelet therapy. PMID- 28870885 TI - Mesenteric panniculitis. AB - A 53-year-old black woman presented with a 3-day history of abdominal pain. Ultrasound of the abdomen showed a gall bladder packed with small stones. She gave a history of abdominal surgery for a gynaecological condition. She had a cholecystectomy done, but her symptoms continued after cholecystectomy. She then had anendoscopic retrograde cholangiopancreatogram (ERCP) and sphincterotomy done, again her symptoms remained the same. A CT scan of the abdomen was done, and mesenteric panniculitis was suspected. A laparoscopic biopsy of the mesentery was performed, and it confirmed mesenteric panniculitis. She was started on a 2 week course of steroids to which she responded very well. Three months after the initial presentation, she was still asymptomatic. PMID- 28870886 TI - What would a sustainable health and care system look like? PMID- 28870884 TI - A combined VBM and DTI study of schizophrenia: bilateral decreased insula volume and cerebral white matter disintegrity corresponding to subinsular white matter projections unlinked to clinical symptomatology. AB - PURPOSE: Grey matter and white matter changes within the brain are well defined in schizophrenia. However, most studies focused on either grey matter changes or white matter integrity separately; only in limited number of studies these changes were interpreted in the same frame. In addition, the relationship of these findings with clinical variables is not clearly established. Here, we aimed to investigate the grey matter and white matter changes in schizophrenia patients and exhibit the relation of these imaging findings with clinical variables. METHODS: A total of 20 schizophrenia patients and 16 matched healthy controls underwent magnetic resonance imaging to investigate the grey matter and white matter alterations that occur in schizophrenia patients using voxel-based morphometry (VBM) and whole brain voxel-wise analysis of diffusion tensor imaging (DTI) parameters with SPM8, respectively. While the preprocessing steps of VBM were performed with the default parameters of VBM8 toolbox, the preprocessing steps of DTI were carried out using FSL. Additionally, VBM results were correlated with clinical variables. RESULTS: Bilateral insula showed decreased grey matter volume in schizophrenia patients compared with healthy controls (P < 0.01). The opposite contrast did not show a significant difference. Psychiatric scores, duration of illness, and age were not correlated with the decreased grey matter volume of insula in schizophrenia patients. DTI analysis revealed a significant increase in mean, radial, and axial diffusivity, mainly of the fibers of bilateral anterior thalamic radiation and superior longitudinal fasciculus with left predominance, which intersected with bilateral subinsular white matter (P < 0.05). CONCLUSION: Our findings suggest that insula may be the main affected brain region in schizophrenia, which is also well supported by the literature. Our results were independent of disease duration and schizophrenia symptoms. White matter alterations were observed within bilateral anterior thalamic radiation and superior longitudinal fasciculus that intersects with subinsular white matter. Studies with larger sample sizes and more detailed clinical assessments are required to understand the function of insula in the neurobiology of schizophrenia. PMID- 28870887 TI - Appetite, food intake and gut hormone responses to intense aerobic exercise of different duration. AB - The purpose of the study is to investigate the effect of acute bouts of high intensity aerobic exercise of differing durations on subjective appetite, food intake and appetite-associated hormones in endurance-trained males. Twelve endurance-trained males (age = 21 +/- 2 years; BMI = 21.0 +/- 1.6 kg/m2; VO2max = 61.6 +/- 6.0 mL/kg/min) completed four trials, within a maximum 28 day period, in a counterbalanced order: resting (REST); 15 min exercise bout (15-min); 30 min exercise bout (30-min) and 45 min exercise bout (45-min). All exercise was completed on a cycle ergometer at an intensity of ~76% VO2max Sixty minutes post exercise, participants consumed an ad libitum meal. Measures of subjective appetite and blood samples were obtained throughout the morning, with plasma analyzed for acylated ghrelin, total polypeptide tyrosine-tyrosine (PYY) and total glucagon-like peptide 1 (GLP-1) concentrations. The following results were obtained: Neither subjective appetite nor absolute food intake differed between trials. Relative energy intake (intake - expenditure) was significantly greater after REST (2641 +/- 1616 kJ) compared with both 30-min (1039 +/- 1520 kJ) and 45 min (260 +/- 1731 kJ), and significantly greater after 15-min (2699 +/- 1239 kJ) compared with 45-min (condition main effect, P < 0.001). GLP-1 concentration increased immediately post exercise in 30-min and 45-min, respectively (condition * time interaction, P < 0.001). Acylated ghrelin was transiently suppressed in all exercise trials (condition * time interaction, P = 0.011); the greatest, most enduring suppression, was observed in 45-min. PYY concentration was unchanged with exercise. In conclusion, high-intensity aerobic cycling lasting up to 45 min did not suppress subjective appetite or affect absolute food intake, but did reduce relative energy intake, in well-trained endurance athletes. Findings question the role of appetite hormones in regulating subjective appetite in the acute post-exercise period. PMID- 28870888 TI - Cell-secreted vesicles containing microRNAs as regulators of gamete maturation. AB - Mammalian gamete maturation requires extensive signaling between germ cells and their surrounding somatic cells. In the ovary, theca cells, mural granulosa cells, cumulus cells and the oocyte all secrete factors throughout follicle growth and maturation that are critical for ovulation of a high-quality oocyte with the competence to develop into an embryo. Similarly, maturation of sperm occurs as it transits the epididymis during which epididymal epithelium and sperm exchange secretory factors that are required for sperm to gain motility and fertility. Recent studies in a variety of species have uncovered the presence of cell-secreted vesicles in follicular fluid (microvesicles and exosomes) and epididymal fluid (epididymosomes). Moreover, these cell-secreted vesicles contain small non-coding regulatory RNAs called microRNAs, which can be shuttled between maturing gametes and surrounding somatic cells. Although little is known about the exact mechanism of how microRNAs are loaded into these cell-secreted vesicles or are transferred and modulate gene expression and function in gametes, recent studies clearly suggest that cell-secreted vesicle microRNAs play a role in oocyte and sperm maturation. Moreover, a role for cell-secreted vesicular microRNAs in gamete maturation provides for novel opportunities to modulate and discover new diagnostic markers associated with male or female fertility. This manuscript provides an overview of cell-secreted vesicles in ovarian follicular fluid and epididymal fluid and microRNAs and discusses recent discoveries on the potential function of cell-secreted vesicles as carriers of microRNAs in oocyte and sperm maturation. PMID- 28870889 TI - miR-194 as predictive biomarker of responsiveness to neoadjuvant chemoradiotherapy in patients with locally advanced rectal adenocarcinoma. AB - AIMS: Curative surgery remains the primary form of treatment for locally advanced rectal cancer (LARC). Recent data support the use of preoperative chemoradiotherapy (pCRT) to improve the prognosis of LARC with a significant reduction of local relapse and an increase of overall survival. Unfortunately, only 20% of the patients with LARC present complete pathological response after pCRT, whereas in 20%-40%, the response is poor or absent. METHODS: We investigated the expression level of miR-194 in n=38 patients with LARC using our public microRNA (miRNA) expression dataset. miR-194 expression was further validated by real-time quantitative PCR (qRT-PCR) and in situ hybridisation (ISH). Protein-protein interaction network and pathway enrichment analysis were performed on miR-194 targets. RESULTS AND DISCUSSION: Using biopsy samples collected at diagnosis, mir-194 was significantly upregulated in patients responding to treatment (p value=0.016). The data was confirmed with qRT-PCR (p value=0.0587) and ISH (p value=0.026). Protein-protein interaction network and pathway enrichment analysis reveal a possible mechanism of susceptibility to pCRT involving Wnt pathway via its downstream mediator TRAF6. Finally, we interrogated the Comparative Toxicogenomics Database database in order to identify those chemical compounds able to mimic the biological effects of miR-194 as new possible therapeutic option in LARC treatment. The present study combining miRNA expression profiling with integrative computational biology identified miR-194 as predictive biomarker of response to pCRT. Using known and predicted drug mechanism of action, we then identified possible chemical compounds for further in vitro validation. PMID- 28870890 TI - Thrombocytosis Portends Adverse Prognosis in Colorectal Cancer: A Meta-Analysis of 5,619 Patients in 16 Individual Studies. AB - AIM: The current study aimed to determine the prognostic significance of thrombocytosis in patients with colorectal cancer (CRC) by a meta-analysis of the literature. PATIENTS AND METHODS: The meta-analysis followed the 2009 guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic literature review was conducted from PubMed and Web of Science for articles published up to May 15, 2015. Sixteen studies with a total of 5,619 patients met the inclusion criteria. Hazard ratios and 95% confidence intervals were retrieved from the original articles, calculated from the published Kaplan Meier survival curves, or the corresponding authors were contacted for additional information. Heterogeneity was assessed using the I2 statistic and Chi-square tests. Publication bias was assessed by Begg's funnel plot, Egger's linear regression test and trim-and-fill method. Sensitivity analysis was performed to validate the reliability. RESULTS: Thrombocytosis is associated with shorter overall, disease-free and cancer-specific survival. Overall survival is reduced in patients with thrombocytosis regardless of their clinical tumor stage, and ethnicity. Shortened disease-free survival is associated with elevated platelet count in the non-specific stage (I-IV), localized tumor (stage I-III), and in the Asian patient population. Thrombocytosis is further associated with reduced cancer-specific survival in the non-specific stage and in Asian patients. Finally, thrombocytosis is significantly related to female patients, colon tumor location, T3-4 stage, lymph node positivity, metastasis, undifferentiated histology and lymphatic involvement. CONCLUSION: Thrombocytosis portends adverse prognosis in CRC, and may serve as a clinically useful marker to facilitate risk stratification and guide postoperative management. PMID- 28870891 TI - Lidocaine Stimulates the Function of Natural Killer Cells in Different Experimental Settings. AB - BACKGROUND: One of the functions of natural killer (NK) cells is to eliminate cancer cells. The cytolytic activity of NK cells is tightly regulated by inhibitory and activation receptors located in the surface membrane. Lidocaine stimulates the function of NK cells at clinically relevant concentrations. It remains unknown whether this effect of lidocaine has an impact on the expression of surface receptors of NK cells, can uniformly stimulate across different cancer cell lines, and enhances the function of cells obtained during oncological surgery. MATERIALS AND METHODS: NK cells from healthy donors and 43 patients who had undergone surgery for cancer were isolated. The function of NK cells was measured by lactate dehydrogenase release assay. NK cells were incubated with clinically relevant concentrations of lidocaine. By flow cytometry, we determined the impact of lidocaine on the expression of galactosylgalactosylxylosylprotein3 beta-glucuronosytranferase 1, marker of cell maturation (CD57), killer cell lectin like receptor A, inhibitory (NKG2A) receptors and killer cell lectin like receptor D, activation (NKG2D) receptors of NK cells. Differences in expression at p<0.05 were considered statistically significant. RESULTS: Lidocaine increased the expression of NKG2D receptors and stimulated the function of NK cells against ovarian, pancreatic and ovarian cancer cell lines. Lidocaine also increased the cytolytic activity of NK cells from patients who underwent oncological surgery, except for those who had orthopedic procedures. CONCLUSION: Lidocaine showed an important stimulatory activity on NK cells. Our findings suggest that lidocaine might be used perioperatively to minimize the impact of surgery on NK cells. PMID- 28870893 TI - Deepening a Simple Question: Can MSCs Be Used to Treat Cancer? AB - In cancer, mesenchymal stem/stromal cells (MSCs) have been considered as vehicles for targeted delivery of drugs due to their inherent tropism toward primary and metastatic tumors. However, it is still unclear whether MSCs could be therapeutically explored without significant harm, since a great amound of evidence indicates that MSCs are able to exert both tumor-suppressive and pro oncogenic effects. Here, we discuss how MSCs might adopt a pro- or anti inflammatory profile in response to changes within the tumor microenvironment and how these features may lead to opposite outcomes in tumor development. Additionally, we address how differences in experimental design might impact interpretation and consistency of the current literature in this specific field. Finally, we point-out critical issues to be addressed at a pre-clinical stage, regarding safety and therapeutic effectiveness of MSCs application in cancer treatment. PMID- 28870892 TI - Physical Needs of Long-term Cancer Patients. AB - The enormous success in the therapeutic area of oncology has allowed achieving a number of long-term survival patients unthinkable until a few decades ago. The number of cancer survivors in the world has, in fact, almost tripled in the last decade alone. Anticancer therapies, including those of the latest generation, aimed at targeting also the chronicity of the disease, are not free from side effects, especially when used in the long term. This scenario should lead to development of follow-up programs with the purpose of assessing long-term effects related to cancer treatments, in addition to the early detection of any relapse or a second tumor. Oncologists who take care of cancer survivors cannot ignore these effects; it is, therefore, essential to start a program of prevention and treatment of these sequelae, to meet patients' health needs. PMID- 28870894 TI - Colorectal Carcinogenesis: Role of Oxidative Stress and Antioxidants. AB - One of the contributory causes of colon cancer is the negative effect of reactive oxygen species on DNA repair mechanisms. Currently, there is a growing support for the concept that oxidative stress may be an important etiological factor for carcinogenesis. The purpose of this review is to elucidate the role of oxidative stress in promoting colorectal carcinogenesis and to highlight the potential protective role of antioxidants. Several studies have documented the importance of antioxidants in countering oxidative stress and preventing colorectal carcinogenesis. However, there are conflicting data in the literature concerning its proper use in humans, since these studies did not yield definitive results and were performed mostly in vitro on cell populations, or in vivo in experimental animal models. PMID- 28870895 TI - Fluoride Induces Apoptosis in Mammalian Cells: In Vitro and In Vivo Studies. AB - Apoptosis is genetically programmed cell death, an irreversible process of cell senescence with characteristic features different from other cellular mechanisms of death such as necrosis. In the last years, apoptosis has been extensively studied in the scientific literature, because it has been established that apoptosis plays a crucial role following the time course of chronic degenerative diseases, such as cancer. Thus, several researchers have strugged to detect what chemical agents are able to inter fere with the apoptotic process. Thus, the purpose of this literature review is to assess if fluoride induces apoptosis in mammalian cells using in vivo and in vitro test systems. Certain mammalian cell types such as oral cells, blood and brain were exetensively investigated; the results showed that fluoride is able to induce apoptosis in both intrinsinc and extrinsic pathways. Moreover, other cells types have been poorly investigated such as bone, kidney and reproductive cells with conflicting results so far. Therefore, this area needs further investigation for the safety of human populations exposed to fluoride in a chronic way, as for example in developing countries. PMID- 28870896 TI - Gefitinib Enhances Mitochondrial Biological Functions in NSCLCs with EGFR Mutations at a High Cell Density. AB - BACKGROUND/AIM: Gefitinib is a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and has been approved for the treatment of non-small cell lung cancers (NSCLCs) with EGFR mutations. Here we demonstrated that gefitinib induced a significantly enhanced biological activity of succinate-tetrazolium reductase (STR) in mitochondria and mitochondrial membrane potential in HCC827 cells (EGFR mutation NSCLCs, sensitive to gefitinib) at a high cell density. MATERIALS AND METHODS: We assessed the biological activity (STR, mitochondrial membrane potential, expression level of Bcl-2 family proteins) of gefitinib on NSCLCs at different cell densities. RESULTS: The 3D cell culture experiments showed the enhanced mitochondrial biological activity in clustered cell culture treated with gefitinib. Interestingly, the expression levels of Bcl-xL and Bax, were affected by the cellular number and gefitinib treatment. We also found that gefitinib prevented additive anticancer activity in the combinational treatment with doxorubicin, which induces mitochondria-dependent apoptotic cell death. CONCLUSION: Our results indicate that gefitinib may work as a mitochondrial protector against combinational treatment with mitochondria-dependent anticancer agents in high-cell-density. PMID- 28870897 TI - Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells. AB - BACKGROUND: Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. MATERIALS AND METHODS: Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. RESULTS: Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. CONCLUSION: Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application. PMID- 28870898 TI - Inhibitory Activity of Iron Chelators ATA and DFO on MCF-7 Breast Cancer Cells and Phosphatases PTP1B and SHP2. AB - BACKGROUND: Rapidly-dividing cancer cells have higher requirement for iron compared to non-transformed cells, making iron chelating a potential anticancer strategy. In the present study we compared the anticancer activity of uncommon iron chelator aurintricarboxylic acid (ATA) with the known deferoxamine (DFO). MATERIALS AND METHODS: We investigated the impact of ATA and DFO on the viability and proliferation of MCF-7 cancer cells. Moreover we performed enzymatic activity assays and computational analysis of the ATA and DFO effects on pro-oncogenic phosphatases PTP1B and SHP2. RESULTS: ATA and DFO decrease the viability and proliferation of breast cancer cells, but only ATA considerably reduces the activity of PTP1B and SHP2 phosphatases. Our studies indicated that ATA strongly inactivates and binds in the PTP1B and SHP2 active site, interacting with arginine residue essential for enzyme activity. CONCLUSION: We confirmed that iron chelating can be considered as a potential strategy for the adjunctive treatment of breast cancer. PMID- 28870899 TI - Effective Metabolic Targeting of Human Osteosarcoma Cells In Vitro and in Orthotopic Nude-mouse Models with Recombinant Methioninase. AB - BACKGROUND: Methionine dependence may be the only known general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine alpha-deamino-gamma-mercaptomethane lyase [EC 4.4.1.11]) (recombinant methioninase [rMETase]), which was subsequently tested in mouse models of various types of human tumors. The present study aimed to investigate the efficacy of rMETase on human osteosarcoma cells in vitro and in vivo. MATERIALS AND METHODS: Human osteosarcoma cell lines 143B, HOS and SOSN2 were tested in vitro for survival during a 72-h exposure to rMETase using the WST 8 assay. Half-maximal inhibitory concentrations were calculated for in vitro efficacy experiments. 143B cells were orthotopically transplanted into the tibia of nude mice. Mouse models were randomized into the following groups 1 week after transplantation: Group 1, untreated control; Group 2, cisplatinum (CDDP) [intraperitoneal (i.p.) injection at 6 mg/kg weekly, for 3 weeks], positive control; Group 3, rMETase, 100 units/mouse i.p. daily, for 21 days. Tumor sizes and body weight were measured with calipers and a digital balance once per week, respectively. RESULTS: rMETase significantly inhibited osteosarcoma cell growth, in a dose-dependent manner, in vitro. Both CDDP and rMETase treatment significantly inhibited tumor volume compared to untreated control mice at 5 weeks after initiation. Tumor volumes were as follows: Group 1, untreated, control: 1808.2 +/- 344 mm3; Group 2, CDDP: 1102.2 +/- 316 mm3, p=0.0008 compared to untreated control; Group 3, rMETase: 884.8 +/- 361 mm3, p=0.0001 compared to untreated control. There were no animal deaths in any group. The body weight of mice was not significantly different between any group. CONCLUSION: rMETase showed promising efficacy against osteosarcoma, a recalcitrant tumor type. Future studies will investigate the efficacy of rMETase on patient-derived orthotopic xenograft (PDOX) models of osteosarcoma as a bridge to testing rMETase in the clinic. PMID- 28870900 TI - Probing the Molecular Mechanisms Governing the Oncolytic Activity of Paeonia suffruticosa on Triple-negative Breast Cancer Cells In Vitro. AB - BACKGROUND/AIM: Extracts of Paeonia suffruticosa are traditionally used in Chinese medicine to increase blood flow. Recently, this extract has been shown to possess anti-tumor and anti-inflammatory properties, though this mechanism remains unknown. In the current work, we prepared extracts of P. suffruticosa and analyzed their effects on MDA-MB-231 triple-negative breast cancer cells. MATERIALS AND METHODS: Varying concentrations of an aqueous extract of P. suffruticosa was administered to MDA-MB-231. An MTS assay was used to determine the cell viability. Cytokine production was investigated through enzyme-linked immunosorbent assay (ELISA). Caspase-Glo assays were performed to measure caspase 3/7, 8 and 9 to analyze anti-apoptotic effects. RESULTS: MTS assay for cell viability revealed that the extract increased viability at low concentrations (0.6 mg/ml) and decreased viability observed at concentrations >=2.5 mg/ml (p<0.01). ELISA for IL-6, IL-2, and TNF-alpha revealed a biphasic dose-response inversely related to viability (p<0.05). IL-24 expression also increased at 2.5 mg/ml and 4.0 mg/ml (p<0.05). Bax levels remained relatively constant while Bcl-2 decreased significantly in all concentrations (p<0.01). Small decreases in Fas ligand levels was observed in parallel with a lack of increase in caspase-8 activity. Most notable was that while 4mg/ml of P. suffruticosa extract reduced MDA-MB-231 viability by >60% (p<0.01), the same concentration reduced the viability of non-transformed HaCat cells by ~8% (p>0.05), suggesting a selective oncolytic effect. CONCLUSION: P. suffruticosa extract has the ability to modulate the production of several tumor suppressive cytokines, induce intrinsic apoptosis and has the capability of reducing cancer burden while sparing healthy tissue. PMID- 28870901 TI - Nicotinamide Phosphoribosyl Transferase a Reliable Marker of Progression in Cervical Dysplasia. AB - BACKGROUND/AIM: Nicotinamide phosphoribosyl transferase (Nampt) catalyses the rate-limiting step of the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway. Nampt is highly expressed in several epithelial and mesenchymal neoplasms, where is promotes cell-cycle progression ans chemotherapy resistance. To our knowledge, alterations in Nampt expression have not been examined in cervical intraepithelial neoplasia (CIN) or squamous cell carcinoma (SCC). MATERIALS AND METHODS: We performed immunohistochemical analysis for Nampt using tissue microarrays on 14 samples of benign cervical squamous epithelium and 15 CIN I, 15 CIN II, and 13 samples of CIN III. The SCCs included 5 low-grade, 67 intermediate-grade, and 81 high-grade tumors. RESULTS: Nampt levels increased with increased CIN grades were compared to benign cervical squamous epithelium. Similarly, Nampt levels increased with increasing SCC grade. CONCLUSION: Nampt expression is a reliable marker of progression in cervical dysplasia and SCC. PMID- 28870902 TI - Communicate or Die - A Model for HPV+ and HPV- CSCs and Their Interactions with SDF-1alpha. AB - BACKGROUND/AIM: Cancer stem cells (CSCs) are suspected of being a reason for limited therapy in head and neck squamous cell carcinoma (HNSCC). Stromal cell derived factor-1alpha (SDF-1alpha) plays a critical role in the communication between CSCs and their microenvironment. We investigated the influence of SDF 1alpha on HPV+/HPV- SCC cell lines to find an approach of explanation for the superior prognosis of HPV+ HNSCCs. MATERIALS AND METHODS: We evaluated the expression of CD44/CXCR4 on HPV+/HPV- SCC cell lines and monitored the influence of SDF-1alpha on proliferation, morphology and migration of HPV+/HPV- SCCs. RESULTS: HPV- SCCs showed a significant increase of podia formation and an intensified migration towards SDF-1alpha. HPV+ SCCs rested nearly unaffected by SDF-1alpha. CONCLUSION: Weakened reaction to SDF-1alpha in HPV+ SCC could lead to an impaired communication between CSCs and their niche, that would result in an increased exposure of CSCs to the harming influence of e.g. chemotherapeutic agents. PMID- 28870903 TI - Role of ARHGAP24 in ADP Ribosylation Factor 6 (ARF6)-dependent Pseudopod Formation in Human Breast Carcinoma Cells. AB - BACKGROUND/AIM: The small GTPase ADP ribosylation factor 6 (ARF6) promotes carcinoma cell invasion and metastasis through remodeling of actin cytoskeleton and formation of pseudopod that is regulated by RAC. RHO GTPase activating protein 24 (ARHGAP24), a RAC-specific GTPase activating protein, binds to activated ARF6 and is recruited to the plasma membrane. The aim of the present study was to demonstrate if ARHGAP24 is involved in the ARF6-mediated formation of pseudopods in breast carcinoma cells. MATERIALS AND METHODS: The formation of pseudopods induced by activated ARF6 was monitored using MDA-MB-231 human breast carcinoma cells. The effect of knockdown of endogenous ARHGAP24 by siRNA was examined. RESULTS: Knockdown of ARHGAP24 in MDA-MB-231 carcinoma cells increased the lifespan of pseudopods to retract, which resulted in increased length of pseudopods induced by activated ARF6. ARHGAP24 required a binding site of ARF6 to achieve ARF6-dependent actin remodeling. CONCLUSION: ARHGAP24 may regulate pseudopod formation downstream of activated ARF6 in MDA-MB-231 human breast carcinoma cells. PMID- 28870904 TI - Increased CXCL8 Expression Is Negatively Correlated with the Overall Survival of Patients with ER-Negative Breast Cancer. AB - BACKGROUND: C-X-C motif chemokine ligand 8 (CXCL8) is a multi-functional chemokine and has important roles during tumor formation and development. It was previously reported that increased CXCL8 protein levels occurred in certain patients. MATERIALS AND METHODS: In the present study, we examined levels of CXCL8 mRNA in breast cancer tissues and analyzed its levels in correlation to patients' clinical data and 10-year overall survival (OS). RESULTS: Our results clearly demonstrated that the level of CXCL8 mRNA was significantly higher in patients without estrogen receptor expression. The receiver operating characteristic curve indicated that the best cut-off value for CXCL8 expression was 3.095 for predicting patient's OS. CONCLUSION: The present study demonstrated that higher CXCL8 mRNA levels in breast cancer tissues together with estrogen receptor negativity was associated with significantly shorter OS, and could be applied as a negative risk factor for 10-year OS. PMID- 28870905 TI - Transforming Growth Factor-beta, Interleukin-10, and Serological Markers in EBV associated Gastric Carcinoma. AB - BACKGROUND/AIM: The association between Epstein-Barr virus (EBV) and gastric cancer (GC) has been reported by many researchers. Immunosuppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor beta (TGFbeta), play an important role in the tumor process. The aim of the present study was to detect antibodies against EBV and explore the levels of TGFbeta and IL-10 in Polish GC patients. PATIENTS AND METHODS: Fifty patients with GC and 50 hospitalized individuals without GC (control group) were enrolled in the study. Frozen tumor tissue fragments were tested using nested PCR assay for EBV DNA detection. ELISA test was used to detect the presence of anti-VCA IgG, anti-EBNA IgG, anti-EA IgG, TGFbeta and Il-10 in sera from all individuals. RESULTS: EBVCA was detected in 88.0%, EBNA in 90.0%, and EA in 72.0% of patients. Levels of TGFbeta and IL-10 were significantly higher in patients with high levels of anti EA antibodies (25.4 ng/ml; 7.8 pg/ml) compared to patients with low levels of anti-EA antibodies (12.61 ng/ml; 4.29 pg/ml). CONCLUSION: The significantly higher level of EA in patients' sera indicates EBV reactivation. TGFbeta level was significantly higher in GC than in the control group, especially in EA positive patients, indicating its possible role in gastric carcinogenesis. PMID- 28870906 TI - Discordance and Conversion Rates of Progesterone-, Estrogen-, and HER2/neu Receptor Status in Primary Breast Cancer and Brain Metastasis Mainly Triggered by Hormone Therapy. AB - BACKGROUND/AIM: Knowing the molecular footprint of tumors is a precondition for personalized medicine. For breast cancer, targeted therapies are frequently based on the molecular status of the tissue gained from the primary tumor operation. However, it is unclear whether metastases in different organs maintain the same status. PATIENTS AND METHODS: We compared the estrogen- (ER), progesterone- (PgR) and HER2/neu receptor status of the primary tumor with brain metastases in a series of 24 consecutive breast cancer patients. RESULTS: 62.5-75% of patients exhibited a constant receptor status between the primary tumor and the brain metastasis, whereas discordance rates of 25-37.5% were found, depending on the receptor. The rate of ER and PgR expression was each 41.6% in the primary tumors and decreased to 12.5% and 16.6% in the brain metastases. In contrast, the rate for Her2+ tumors increased from 41.6% in primary breast cancer to 65.2% in the respective brain metastases. The Ki-67 proliferation index increased significantly from a mean of 21% at the primary tumor site to 60% in brain metastases (p<0.001). All anti-estrogen treated breast tumors lost the estrogen receptor expression in the brain metastases, whereas no Her2/neu conversions occurred after treatment with trastuzumab. CONCLUSION: In summary, receptor conversion is frequent during disease progression. Therefore, the receptor status of the primary tumor is invalid for planning a therapy targeted against brain metastases, especially after hormone-therapy. In these cases, new tissue collection by biopsy or resection is mandatory for the selection of adequate therapeutic targets and accurate decision-making for systemic therapies. PMID- 28870907 TI - Circulating Levels of VEGF and CXCL1 Are Predictive of Metastatic Organotropismin in Patients with Colorectal Cancer. AB - Colorectal cancer is the most common cancer of the gastrointestinal system and has a marked preference to metastasize to distant organs. In this study, we investigated whether levels of circulating serum pro-angiogenic cytokine such as chemokine (C-X-C motif) ligand 1 (melanoma growth-stimulating activity, alpha; CXCL1) and vascular endothelial growth factor (VEGF) have a role in favoring the colonization of metastatic cells at preferential sites and determined their prognostic significance in a cohort of 103 patients with metastatic colorectal cancer. Importantly, we found that the presence of elevated circulating levels of VEGF and CXCL1 are predictive of liver and lung metastasis, respectively. Moreover, the presence of a high serum VEGF level represents a negative prognostic factor for patients with liver metastases, with a worse prognosis than patients with lung metastasis. This suggests an additional role for circulating cytokines as a predictive tool for cancer prognosis and diagnosis, as well as for assessment of tumor sensitivity to anticancer therapy. PMID- 28870908 TI - Bcl-2-like Protein 11 (BIM) Expression Is Associated with Favorable Prognosis for Patients with Cervical Cancer. AB - BACKGROUND/AIM: Bcl-2-like protein 11 (BIM) is a pro-apoptotic member of the Bcl 2 protein family. BIM elicits cell death by binding to pro-survival Bcl-2 proteins. Even though the association of BIM expression with cell death has been investigated, its clinical survival significance in cervical cancer has not. In the current study, the prognostic significance of BIM in cervical cancer was investigated. PATIENTS AND METHODS: The study included normal cervical tissues (n=254), cervical intraepithelial neoplasia (CIN) tissues (n=275), and invasive cervical cancer (n=164). In order to identify BIM expression, immunohistochemistry (IHC) was performed, and IHC scoring by quantitative digital image analysis was determined. Then, the association of BIM with prognostic factors was investigated. RESULTS: BIM expression was higher in cervical cancer than normal cervical tissues (p<0.001). Well and moderate differentiation indicated higher BIM expression than did poor differentiation (p=0.001). Also, BIM expression was high in radiation-sensitive cervical cancer relative to radiation-resistant cancer (p=0.049). High BIM expression showed better 5-year disease-free survival (DFS) and overall survival (OS) rates (p=0.049 and pi=0.030, respectively) than did low expression. In a multivariate analysis, BIM was shown to be an independent risk factor for DFS and OS in cervical cancer, with hazard ratios of 0.22 (p=0.006) and 0.46 (p=0.046), respectively. CONCLUSION: BIM is associated with favorable prognostic markers for prediction of DFS and OS in cervical cancer. High BIM expression is a potential prognostic marker as well as a chemotherapeutic target for cervical cancer. PMID- 28870909 TI - Expression of Cancer Stem Cell-associated DKK1 mRNA Serves as Prognostic Marker for Hepatocellular Carcinoma. AB - BACKGROUND/AIM: Cancer stem cells (CSCs) are associated with prognosis of hepatocellular carcinoma (HCC). In our previous study, we created cDNA microarray databases on the CSC population of human HuH7 cells. In the present study, we identified genes that might serve as prognostic markers of HCC by employing existing databases. MATERIALS AND METHODS: Expressions of glutathione S transferase pi 1 (GSTP1), lysozyme (LYZ), C-X-C motif chemokine ligand 5 (CXCL5), interleukin-8 (IL8) and dickkopf WNT signaling pathway inhibitor 1 (DKK1), the five most highly expressed genes in the CSC cDNA microarray databases, were examined in 99 patients with HCC by real-time polymerase chain reaction (qRT PCR), and their clinical significance was analyzed. RESULTS: The Kaplan-Meier analysis showed that both overall and cancer-specific survival were significantly longer in patients with low DKK1 expression than in those with high DKK1 expression. The multivariate analysis revealed that overall survival was negatively associated with albumin and positively associated with alkaline phosphatase (ALP), serosal invasion and stage, and cancer-specific survival was positively associated with ALP, portal vein invasion and DKK1 mRNA. CONCLUSION: Expression of CSC-associated DKK1 mRNA might be an unfavorable prognostic marker for patients with HCC. PMID- 28870910 TI - Induction and Analysis of Cytotoxic T-Lymphocytes that Recognize Autologous Oral Squamous Cell Carcinoma. AB - BACKGROUND: It is essential that cytotoxic T-lymphocytes (CTLs) recognize tumor associated antigens (TAAs) and exhibit antitumor effects in immunological responses for tumor rejection. However, only a few cases with oral squamous cell carcinoma (OSCC) have been studied for these antitumor mechanisms. We established a cancer cell line and autologous CTL pair for identifying TAAs in OSCC, despite difficulties in establishing such a pair. MATERIALS AND METHODS: A cell line (OTM) from a primary lesion and a CTL line (TcOTM) were derived from OSCC in a 64 year-old female patient. CTL clones were generated by repetitive limiting dilutions. Accurate characterization was performed by in vitro analysis. RESULTS: The TcOTM clone showed specific cytotoxic activity against OTM cells in an human leukocyte antigen (HLA)-A24-restricted manner. Furthermore, it exerted cytotoxicity against the allogenic HLA-A24 cell lines. CONCLUSION: These data indicated that the TcOTM clone recognized a TAA presented by HLA-A24 cells. This unique method will allow for identification of unknown TAAs for OSCC in the future. PMID- 28870911 TI - Sunitinib Inhibits Breast Cancer Cell Proliferation by Inducing Apoptosis, Cell cycle Arrest and DNA Repair While Inhibiting NF-kappaB Signaling Pathways. AB - The tyrosine kinase inhibitor sunitinib was recently approved for use against gastrointestinal stromal tumors and advanced renal cell carcinoma. Yet, the protective effect of sunitinib against breast cancer has been poorly investigated. In this study, we investigated the antiproliferative and apoptogenic effects of sunitinib and the possible mechanism involved against the MCF7 human breast cancer cell line. Treatment of MCF7 cells with sunitinib caused concentration-dependent cell growth suppression due to apoptosis. Apoptotic death induced by sunitinib in MCF7 cells was mediated by activation of caspase-3 and p53 mRNA and protein expression and an increase in the percentage of apoptotic cells (40%) as determined by flow cytometry. Apoptosis was associated with a significant inhibition of nuclear factor-kappa B mRNA and protein expression. Mechanistically, blocking of de novo RNA synthesis by actinomycin D significantly inhibited sunitinib-induced expression of p53 mRNA, but not that of caspase-3, indicating involvement of a transcriptional mechanism. This apoptosis-mediated inhibition of MCF7 cell growth was attributed to inhibition of cell cycle-related genes (cyclin D1 and cyclin E2) and arrest of MCF7 cells in the G2/M phase in the cell cycle, allowing up-regulation of expression of DNA repair genes such as x ray repair cross-complementing protein 1. In addition, sunitinib exhibited concentration-dependent induction of oxidative stress genes (heme oxygenase 1 and glutathione transferase A1) through the nuclear factor erythroid 2-related factor 2 pathway. These findings lead us to propose that sunitinib suppressed the proliferation of MCF7 cells via cell-cycle arrest and apoptotic- and oxidative stress-mediated pathways. PMID- 28870912 TI - Amentoflavone Inhibits Metastatic Potential Through Suppression of ERK/NF-kappaB Activation in Osteosarcoma U2OS Cells. AB - AIM: The study goal was to investigate effect of amentoflavone on nuclear factor kappaB (NF-kappaB)-modulated metastatic mechanism in osteosarcoma U2OS cells. U2OS cells were treated with amentoflavone, NF-kappaB inhibitor, protein kinase B (PKB or AKT) inhibitor or mitogen-activated protein kinase (MAPK) inhibitor. Change of cell viability, NF-kappaB activation, expression of metastasis associated proteins, signal transduction, and cell migration and invasion were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, NF-kappaB reporter gene assay, western blotting, and cell migration and invasion assays. The results demonstrated that inhibition of activation of extracellular signal-regulated kinases (ERK) was a key point for suppression of NF-kappaB-modulated metastatic mechanism. Amentoflavone significantly inhibited NF-kappaB activation, ERK phosphorylation, expression of metastasis-associated proteins, and cell migration and invasion. Our findings indicate that amentoflavone reduces metastatic potential through suppression of ERK and NF kappaB activation in osteosarcoma U2OS cells. PMID- 28870913 TI - Regorafenib Induces Apoptosis and Inhibits Metastatic Potential of Human Bladder Carcinoma Cells. AB - The aim of the present study was to verify the effects of regorafenib on apoptosis and metastatic potential in TSGH 8301 human bladder carcinoma cells in vitro. Cells were treated with different concentration of regorafenib for different periods of time. Effects of regorafenib on cell viability, apoptosis pathways, metastatic potential, and expression of metastatic and anti-apoptotic proteins were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium (MTT) assay, flow cytometry, cell migration and invasion assay, and western blotting. We found regorafenib significantly reduced cell viability, cell migration and invasion, and expression of metastatic and anti apoptotic proteins. In addition, regorafenib significantly induced accumulation of sub-G1 phase cells, loss of mitochondrial membrane potential, and expression of active caspase-3 and caspase-8. These results show that regorafenib not only induces apoptosis, but also inhibits metastatic potential in bladder cancer TSGH 8301 cells in vitro. PMID- 28870914 TI - An Adaptation System to Avoid Apoptosis via Autophagy Under Hypoxic Conditions in Pancreatic Cancer Cells. AB - BACKGROUND/AIM: Pancreatic cancer tissue is a hypoxic environment resistant to anticancer drugs. This study examined the role of autophagy as a response to hypoxic stress in pancreatic cancer. MATERIALS AND METHODS: Pancreatic cell lines (PANC-1, BxPC-3 and AsPC-1) were exposed to hypoxic conditions using cobalt chloride, a hypoxia-mimicking agent. Protein expression and cytotoxicity assays were performed to determine the effect of hypoxia on autophagy. RESULTS: When pancreatic cancer cells were exposed to hypoxia, autophagy was induced. The autophagy-inducing signal was dependent on the AMPK pathway. Inhibition of autophagy in a hypoxic state induced a remarkable cytotoxicity and enhanced apoptosis. When an AMPK inhibitor was added, cytotoxicity was observed in the hypoxic environment. CONCLUSION: The induced autophagy, dependent on the AMPK pathway, is a necessary survival strategy adopted by pancreatic cancer cells to adapt to hypoxic stress, and could be an attractive target for drug development. PMID- 28870915 TI - Critical Overview of HER2 Assessement in Bladder Cancer: What Is Missing for a Better Therapeutic Approach? AB - BACKGROUND/AIM: To assess the concordance between IHC and FISH and its influence on tumor type, grade and lympho-vascular invasion (LVI). MATERIALS AND METHODS: HER2 immunohistochemistry (IHC) to 45 cases of bladder carcinoma, followed by fluorescent in situ hybridization (FISH) were applied. RESULTS: 31.12% cases were IHC positive. Less than 35% of HER2-negative cases presented LVI and this percent increased to 54.54% for +1 HER2 cases. LVI increases up to 57.14% for +2 HER2 cases and slightly decreased for +3 HER2 cases to 42.85%. IHC/FISH concordance was found for 73.34% cases but 31.57% were previously negative and 36.36% scored as +1 by IHC had gene amplification as shown by FISH analysis. T3 was correlated with HER2-IHC (p=0.05) and HER2-FISH (p=0.01). CONCLUSION: Improved HER2 assessement is needed for urothelial carcinomas. HER2-IHC scored as 0-2 should be validated by and reclassified according to FISH analysis. PMID- 28870916 TI - GRP78 Regulates Apoptosis, Cell Survival and Proliferation in 5-Fluorouracil resistant SNUC5 Colon Cancer Cells. AB - 5-Fluorouracil (5-FU) is an effective anticancer drug. However, the development of drug resistance has limited its chemotherapeutic efficacy. To address this problem, we investigated the expression of glucose-regulated protein (GRP78, 78 kDa) in 5-FU-resistant colorectal cancer (CRC) cells (SNUC5/5FUR). GRP78 was highly expressed in the SNUC5/5FUR cells compared to wild-type SNUC5 cells. In the presence of 5-FU, GRP78 knockdown induced apoptosis via activation of caspase 3 and poly(ADP-ribose)-polymerase 1. GRP78 also inhibited the production of intracellular reactive oxygen species by regulating stress-associated signaling pathways. Furthermore, GRP78 enhanced cell survival and proliferation via activation of the phosphatidylinosito-3-kinase-AKT-mammalian target of rapamycin axis and cell cycle-associated proteins. These effects were blocked upon GRP78 knockdown, which indicates that GRP78 is involved in the development of 5-FU resistance in these CRC cells. Therefore, a combination of chemotherapy and GRP78 specific targeting may counteract 5-FU resistance in CRC cells. PMID- 28870917 TI - The Association Between HSP90/topoisomerase I Immunophenotype and the Clinical Features of Colorectal Cancers in Respect to KRAS Gene Status. AB - AIM: The aim of this study was to investigate heat shock protein 90 (HSP90) and topoisomerase I (Topo I) expression and the association between both proteins and clinicopathological parameters of colorectal cancer (CRC), in order to describe their role in tumor biology regarding to Kirsten Ras (KRAS) - positive/negative cases. MATERIALS AND METHODS: Expression of HSP90 and Topo I, and KRAS gene mutations were estimated in primary CRCs. RESULTS: HSP90/Topo I immunophenotype correlated with gender, Duke staging, tumor grade and lymph node metastasis (p<0.01). Positive correlation was found between KRAS mutation and HSP90 expression (p=0.02). HSP90, Topo I expression, and co-expression of HSP90/Topo I correlated with unfavorable parameters of CRCs in respect to KRAS gene status (p<0.001). CONCLUSION: Our results revealed that cooperation between HSP90 and Topo I expression exists in CRCs, independently of KRAS gene status, suggesting that co-expression of both proteins might be considered as a double target on individual tumor cells. PMID- 28870918 TI - The Diagnostic Significance of Serum Alcohol Dehydrogenase Isoenzymes and Aldehyde Dehydrogenase Activity in Prostate Cancer Patients. AB - BACKGROUND/AIM: The aim of this study was to investigate a potential role of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as tumor markers for prostate cancer (PCa). MATERIALS AND METHODS: Serum samples were obtained from 52 patients with PCa, 34 patients with benign prostatic hyperplasia (BPH) and 60 healthy subjects. Class III and IV of ADH and total ADH activity were measured by the photometric method. For measurement of class I and II ADH and ALDH activity, the fluorometric method was employed. RESULTS: Significantly higher total activity of ADH, ADH III and ADH IV were found in the sera of both, PCa and BPH patients compared with healthy individuals. The diagnostic sensitivity for ADH III activity was 94.2%, specificity 100%, PPV (positive predictive value) and NPV (negative predictive value) were 100% and 95.2% respectively. Area under receiver-operating characteristics (ROC) curve for ADH III activity was 0.993. CONCLUSION: The results suggest a potential role of ADH III activity as a parameter included in the panel of markers for PCa. PMID- 28870919 TI - The Impact of Environmental Light Intensity on Experimental Tumor Growth. AB - BACKGROUND/AIM: Cancer research requires for consistent models that minimize environmental variables. Within the typical laboratory animal housing facility, animals may be exposed to varying intensities of light as a result of cage type, cage position, light source, and other factors; however, studies evaluating the differential effect of light intensity during the light phase on tumor growth are lacking. MATERIALS AND METHODS: The effect of cage face light intensity, as determined by cage rack position was evaluated with two tumor models using the C57Bl/6NHsd mouse and transplantable B16F10 melanoma cells or Lewis lung carcinoma (LLC) cells. Animals were housed in individually-ventilated cages placed at the top, middle, or bottom of the rack in a diagonal pattern so that the top cage was closest to the ceiling light source, and cage face light intensity was measured. Following a two-week acclimation period at the assigned cage position, animals were subcutaneously administered either 1.3*106 B16F10 melanoma cells or 2.5*105 Lewis lung carcinoma cells. Weights of excised tumors were measured following euthanasia 18 days (melanoma) or 21 days (LCC) after tumor cell administration. RESULTS: Cage face light intensity was significantly different depending on the location of the cage, with cages closest to the light source have the greatest intensity. Mean tumor weights were significantly less (p<0.001 for melanoma; p<=0.01 for LCC) in middle light intensity mice compared to high and low light intensity mice. CONCLUSION: The environmental light intensity to which experimental animals are exposed may vary markedly with cage location and can significantly influence experimental tumor growth, thus supporting the idea that light intensity should be controlled as an experimental variable for animals used in cancer research. PMID- 28870920 TI - The Contribution of Matrix Metalloproteinase-7 Promoter Genotypes in Breast Cancer in Taiwan. AB - BACKGROUND/AIM: The matrix metalloproteinase (MMP) family of enzymes are in charge of degradation of various components of the extracellular matrix and their functional genetic polymorphisms may be associated with cancer susceptibility. The functional polymorphisms in the promoter region of MMP7 (A-181G and C-153T) have been reported to influence the binding capacity of nuclear proteins and may contribute to genetic susceptibility to cancer. In this study, we focused on investigating the contribution of the genotypes of MMP7 (A-181G and C-153T) to breast cancer in Taiwan. MATERIALS AND METHODS: These two polymorphisms were genotyped in 1,232 patients with breast cancer and 1,232 controls by polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The odds ratios (ORs) after adjusting for age, family history of cancer, smoking and alcohol drinking status for those carrying AG and GG genotypes at MMP7 promoter A 181G were 1.22 (95%CI=0.91-1.63, p=0.2235) and 2.84 (95%CI=1.64-7.48, p=0.0007) respectively, compared to those carrying the wild-type AA genotype. Supporting this finding, the adjusted OR for those carrying the G allele at MMP7 promoter A 181G was 1.57 (95%CI=1.29-1.93, p=0.0008), compared to those carrying the wild type A allele. There was no polymorphic genotype at MMP7 C-153T found among any of the investigated individuals. CONCLUSION: Our findings suggest that the MMP7 A 181G polymorphisms may play a role in determining personal cancer susceptibility and GG genotype at MMP7 A-181G may serve as a biomarker for early detection and prediction of breast cancer in Taiwanese. PMID- 28870921 TI - Significance of Circulating Galectin-3 in Patients with Pancreatobiliary Cancer. AB - BACKGROUND/AIM: Pancreatobiliary cancer is a disease associated with a dismal prognosis and limited treatment options. The aim of the present study was to clarify the usefulness of circulating galectin-3 in pancreatobiliary cancer. PATIENTS AND METHODS: We examined serum galectin-3 concentrations in 45 patients with pancreatobiliary cancer. Receiver operating characteristic curves were utilized to evaluate the accuracy of circulating galectin-3 to discriminate pancreatobiliary cancer patients from controls and predict the prognostic outcomes. RESULTS: Circulating galectin-3 had diagnostic value at the cut-off level of 6.2 ng/ml, and the patients' overall survival was predictable at the cut off level of 10.3 ng/ml. Furthermore, circulating galectin-3 >=10.3 ng/ml was an independent prognostic marker in pancreatobiliary cancer. Regarding biliary cancer, higher galectin-3 was associated with malnutrition. On the other hand, regarding pancreatic cancer, higher galectin-3 levels were associated with higher inflammatory parameters. CONCLUSION: Galectin-3 can be a useful biomarker in patients with pancreatobiliary cancer. PMID- 28870922 TI - Hedgehog Inhibition Upregulates TRK Expression to Antagonize Tumor Suppression in Small Cell Lung Cancer Cells. AB - BACKGROUND/AIM: Previously we have shown that tropomyosin-related kinase B (TRKB) and Hedgehog (Hh) signalling pathways induce malignant phenotypes in many cancer types. However, results from small cell lung cancer (SCLC) clinical trials using TRK and Hh inhibitors have been disappointing. One reason for this may be the existence of crosstalk between TRKB and Hh signalling pathways. In this study, we detected negative crosstalk between the TRKB and Hh-GLI1 signalling pathways. MATERIALS AND METHODS: The human small cell lung carcinoma cell line, SBC-5, was used. Using small interfering RNA to inhibit TRKB and Hh signalling, whether TRKB and Hh signaling contribute to proliferation and invasiveness in SBC-5 cells were investigated. RESULTS: TRKB expression in GLI1 siRNA-transfected SBC-5 cells was higher than that of control cells. GLI1-knockdown alone did not affect invasiveness of SBC-5 cells. However, combined knockdown of TRKB and GLI1 significantly decreased invasiveness. Moreover, combined TRKB and GLI1 knockdown inhibited proliferation and migration to a greater extent than when either was inhibited alone. CONCLUSION: These results suggest that Hh inhibition increases TrkB expression to counter tumor suppression in SBC-5 cells. The combined use of TRKB and Hh inhibitors may, therefore, be useful for the treatment of refractory SCLC. PMID- 28870923 TI - Magnetic Resonance Compatibility of a Transponder Aimed for Radiotherapy Positioning - A Phantom Study. AB - BACKGROUND/AIM: Electromagnetic Positioning Systems (EMP) is a new position-ing technique in four-dimensional radiotherapy. Patients with implanted transponders may be referred for magnetic resonance imaging (MRI) making it important to establish the MR safety. MATERIALS AND METHODS: Oranges were prepared with transponders and imaged on a 3T MR scanner with different sequences. Computed tomography (CT) was performed as comparison. MR artifacts were assessed. An estimation of the maximum transponder de-flection force and heating was made. RESULTS: The mean measured displacement of transponders was 0.1 mm (range=0.03 0.3 mm). Artifacts were observed adjacent to transponders using all sequences. The deflection force on the transponder in the gantry was less than 38 mN. No heating was observed. CONCLUSION: The absence of any substantial movement, the weak measured deflection force and absence of observed heating speaks for the safe use of MR imaging with transponder 3T. Local artefacts makes evaluation impossible adjacent to transponders. PMID- 28870924 TI - Role of Caspase-9 Gene Ex5+32 G>A (rs1052576) Variant in Susceptibility to Primary Brain Tumors. AB - BACKGROUND/AIM: This study is the first to evaluate the relationship of caspase-9 (CASP-9) gene polymorphism with the risk for primary brain tumor development. MATERIALS AND METHODS: The study group included 43 glioma and 27 meningioma patients and 76 healthy individuals. CASP-9 gene Ex5+32 G>A (rs1052576) polymorphism was analyzed by real-time polymerase chain reaction (RT-PCR). RESULTS: Individuals with the CASP-9 GG genotype had significantly decreased risk of developing a glioma brain tumor (p=0.024). Additionally, the GA genotype was significantly lower in patients with glioma than the control group (p=0.019). A significantly decreased risk of developing glioma was found in the A allele carrier group (p=0.024). However, there was no statistically significant relationship between CASP-9 polymorphism and brain meningioma (p=0.493). CONCLUSION: CASP-9 (rs1052576) mutant A allele seems to be a protective factor for glioma brain tumor. Future studies with a larger sample size will clarify the possible roles of CASP-9 gene in the etiology and progression of primary brain tumors. PMID- 28870926 TI - Hedgehog Stimulation Suppresses Clonogenicity and Activates NOTCH Signalling in T lymphoblastic Leukaemia Jurkat Cells. AB - BACKGROUND/AIM: Hedgehog (HH) and NOTCH pathways are involved in the regulation of cancer stem cells and haematopoietic malignancies. However, the effects of HH stimulation on cell growth and NOTCH signalling in acute T-lymphoblastic leukaemia (T-ALL) cells have not been elucidated. MATERIALS AND METHODS: Two T ALL cell lines, Jurkat and KOPT-K1 harbouring activating NOTCH1 mutations, were cultured with recombinant Sonic (S) HH and analysed for proliferation, colony formation, and expression of NOTCH-regulated genes and proteins. RESULTS: SHH stimulation did not affect cell growth but suppressed colony formation, increased the levels of cleaved NOTCH1 fragment characteristic for NOTCH1 activation, and upregulated mRNA expression of HES1, while decreasing that of MYC in Jurkat cells. However, no such effects were observed in KOPT-K1 cells. CONCLUSION: Our results indicate that SHH stimulation activates NOTCH signalling in Jurkat cells, thus disclosing a novel relationship between HH and NOTCH pathways. PMID- 28870925 TI - Usefulness of Flow Cytometry in Diagnosis of IgG4-Related Ophthalmic Disease and Extranodal Marginal Zone B-Cell Lymphoma of the Ocular Adnexa. AB - BACKGROUND/AIM: Although flow cytometry (FCM) is used to evaluate cell surface markers of various leucocyte populations quantitatively, little is known about the usefulness of FCM in lymphoproliferative disorders of the ocular adnexa. The aim of this study was to disclose results of FCM, which were compared among IgG4 related ophthalmic disease (IgG4-ROD), idiopathic orbital inflammation (IOI), and extranodal marginal zone B-cell lymphoma (EMZL). MATERIALS AND METHODS: This is a retrospective observational study. Sixty-nine tumors comprising of 16 IgG4-ROD, 24 IOI, and 29 EMZL were enrolled in the study. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM. In FCM, the percentage of T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8), B-cell markers (CD10, CD19, CD20, CD23), NK cell marker (CD56) and cell surface kappa/lambda was searched based on medical records. Ig light chain restriction was evaluated from results in kappa/lambda deviation by FCM. RESULTS: The percentage of CD2, CD3, CD4, CD7, and CD10 was significantly higher in IgG4-ROD/IOI than EMZL (p<0.05 in every factor). In contrast, CD19 and CD20 percentages were significantly greater in EMZL than IgG4-ROD/IOI (p<0.01). There was no significant difference in any marker between IgG4-ROD and IOI. Kappa positive cells were significantly greater in EMZL than IgG4-ROD/IOI (p<0.05). In kappa/lambda deviation, false-positive was noted in 3 (7.5%) benign IgG4-ROD/IOI and false-negative was observed in 10 (34.5%) EMZL cases. Sensitivity and specificity of Ig light chain restriction were 65.5 and 92.5%, respectively. CONCLUSION: Analyses of cell surface markers using FCM were useful in differentiating EMZL from IgG4-ROD/IOI. Sensitivity of Ig light chain restriction was relatively low in diagnosis of EMZL using FCM. PMID- 28870927 TI - Response of OVCAR-3 Cells to Cisplatin and Hyperthermia: Does Hyperthermia Really Matter? AB - BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) is proposed as a promising treatment method, but fundamental information about the contribution of hyperthermia to intraperitoneal chemotherapy is lacking. The purpose of this study was to investigate the cytotoxic effect of hyperthermia and cisplatin on OVCAR-3 cells in vitro. MATERIALS AND METHODS: Imitating the typical clinical conditions of HIPEC, OVCAR-3 cells were exposed to hyperthermia and cisplatin for 1 h. MTT viability test, flow cytometric analysis, and real-time cell and isobologram analysis were performed. RESULTS: Hyperthermia up to 42 degrees C did not significantly increase the effect of cisplatin regarding the viability and apoptosis of OVCAR-3 cells. Moreover, an antagonistic effect of hyperthermia and cisplatin was revealed. CONCLUSION: Our investigation of OVCAR-3 cells critically disputes the benefit of hyperthermia in ovarian cancer treatment. Further in vitro and in vivo research is essential for better understanding of the mechanisms of action of hyperthermia and its role in the treatment of epithelial ovarian cancer. PMID- 28870928 TI - Outcomes and Prognostic Factors of Resected Salivary Gland Malignancies: Examining a Single Institution's 12-year Experience. AB - BACKGROUND: Despite adjuvant radiotherapy, survival outcomes remain poor in patients with salivary gland malignancies who have multiple poor prognostic factors. This study aimed to determine which patients may benefit from treatment intensification. PATIENTS AND METHODS: Patients who underwent curative resection with or without adjuvant radiotherapy between 2002 and 2014 were identified and a retrospective chart review was performed. Overall survival (OS) and disease-free survival (DFS) were the main outcomes measured. RESULTS: A total of 95 patients met the inclusion criteria. The median follow-up was 46.8 months. The median age was 60 years. Radiotherapy was given to 78 patients. Multivariate analysis revealed that male sex and perineural invasion significantly reduced overall and disease-free survival. Distant metastases comprised of 67% of recurrences and 33% were locoregional. CONCLUSION: Adjuvant chemoradiotherapy should be considered for patients with tumors with perineural invasion, especially in males with high risk histopathology or high-grade, late-stage disease. To our knowledge, this is the first study to assess the impact of pack-year smoking history on survival outcomes. PMID- 28870929 TI - Diffusion-weighted MRI Provides a Useful Biomarker for Evaluation of Radiotherapy Efficacy in Patients with Prostate Cancer. AB - BACKGROUND: Diffusion-weighted imaging (DWI) with measurement of apparent diffusion coefficient (ADC) allows for assessment of tumor aggressiveness. The objective of this study was to evaluate the changes of ADC value in prostate cancer after volumetric-modulated arc radiotherapy (VMAT) and to identify magnetic resonance imaging (MRI) biomarkers for monitoring tissue changes after radiotherapy. PATIENTS AND METHODS: Thirty-seven patients with biopsy-proven prostate cancer treated with VMAT underwent serial MRI examinations including DWI before radiotherapy, and at 3 and 12 months after radiotherapy. ADC values of the tumor and healthy prostate tissue were measured and compared at these three time points. RESULTS: The tumor ADC value increased significantly 3 months after radiotherapy (p<0.0001). There was a further increase of tumor ADC from 3 to 12 months after radiotherapy (p<0.01). The ADC of healthy prostate tissue did not show any significant changes. CONCLUSION: The ADC value is a useful biomarker for evaluating the efficacy of radiotherapy in prostate cancer. PMID- 28870930 TI - Comparison of the Serum Tumor Markers S100 and Melanoma-inhibitory Activity (MIA) in the Monitoring of Patients with Metastatic Melanoma Receiving Vaccination Immunotherapy with Dendritic Cells. AB - BACKGROUND: In patients with melanoma, early dissemination via lymphatic and hematogenous routes is frequently seen. Thus, besides clinical follow-up examination and imaging, reliable melanoma-specific serological tumor markers are needed. PATIENTS AND METHODS: We retrospectively compared two serum markers for melanoma, S100 and melanoma-inhibitory activity (MIA), for monitoring of patients with metastatic melanoma under either adjuvant or therapeutic vaccination immunotherapy with dendritic cells (DC). Serum was obtained from a total of 100 patients (28 patients in stage III and 72 patients in stage IV, according to the American Joint Committee on Cancer 2002) at regular intervals during therapy, accompanied by follow-up imaging. RESULTS: When relapse was detected, both markers often remained within normal range. In contrast, in patients with metastatic measurable disease receiving therapeutic and not adjuvant DC vaccination, an increase of both markers was a strong indicator for disease progression. When comparing both markers in the whole study population, MIA showed a superior sensitivity to detect disease progression. CONCLUSION: S100 and MIA are highly sensitive tumor markers for monitoring of patients with melanoma with current metastases, but less sensitive for monitoring of tumor-free patients. In the current study, MIA had a slightly superior sensitivity to detect progressive disease compared to S100 and seems to be more useful in monitoring of patients with metastatic melanoma receiving immunotherapy. PMID- 28870931 TI - Long-term Clinical Results of Concurrent Chemoradiotherapy for Patients with Cervical Esophageal Squamous Cell Carcinoma. AB - BACKGROUND/AIM: We assessed the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) in patients with squamous cell carcinoma of the cervical esophagus. PATIENTS AND METHODS: We retrospectively analyzed 37 patients treated with definitive CCRT. The patients received radiotherapy at a fraction dose of 2 Gy (total; 60 or 70 Gy) and concurrent chemotherapy. Adjuvant chemotherapy consisted of 1 to 2 cycles of 5-fluorouracil plus cisplatin or nedaplatin. RESULTS: The median follow-up was 119.0 months, the 10-year overall survival, progression-free survival and laryngectomy-free survival rates were 35.6, 19.9 and 30.2% respectively. In the univariate analysis, T stage (T4 vs. T1-3) was the only prognostic factor for PFS. The most common acute toxicity was leukocytopenia (Grade 3; 27%). As for late toxicities, 4 patients (11%) developed Grade 2 or 3 esophageal strictures. CONCLUSION: The results of this study demonstrated that CCRT yielded satisfactory clinical outcomes with acceptable toxicities. PMID- 28870933 TI - Clinicopathological Features of Ductal Carcinoma In Situ from 18F-FDG-PET Findings. AB - AIM: The presence of ductal carcinoma in situ (DCIS) can increase the risk of developing an invasive ductal carcinoma (IDC), but it is difficult to predict what will occur if a DCIS is left untreated. We reported the usefulness of 18F fluorodeoxyglucose positron emission tomography (FDG-PET) for DCIS, and that the presence of FDG uptake in the tumor could be considered a predictor of invasive potential in patients with DCIS. In this study, we retrospectively evaluated the clinicopathological features of DCIS by using FDG-PET findings, and we evaluated the possibility of using FDG-PET in DCIS cases as a biomarker of which lesions will go on to become invasive. PATIENTS AND METHODS: We investigated the cases of 185 consecutive patients with primary breast cancer who were diagnosed as having DCIS or IDC and underwent FDG-PET preoperatively. RESULTS: We divided the cases into two groups on the basis of histology; DCIS vs. IDC (n=171). The DCIS cases were divided into two groups on the basis of FDG uptake in the primary tumor. Fourteen of the 185 patients (7.4%) were revealed to have a DCIS. The analysis revealed that the SUVmax and the number of cases not detected by FDG-PET were significantly different between the DICS and IDC groups. The extent of the primary tumor was not significantly different between the two groups. In six cases (42.9%) of the 14 DCIS cases, no FDG uptake was detected by FDG-PET. The extent of tumor did not significantly differ between the two groups. In addition, all six cases without FDG uptake were of the diffuse-spread type, without mass formation. All eight cases with mass formation had FDG uptake. CONCLUSION: Our present findings suggest that the FDG-PET uptake reflects tumor burden or tumor density, which should be considered to be associated with the presence of invasion. PMID- 28870932 TI - Clinical Significance of Salvage Esophagectomy for Patients with Esophageal Cancer and Factors of Influencing Long-term Survival. AB - BACKGROUND/AIM: Definitive chemoradiotherapy (CRT) without planned surgery has been recently widely used as a therapeutic option for locally advanced esophageal cancer. Salvage esophagectomy can offer the chance of prolonged survival for patients who have locoregional failure after definitive CRT, but many clinicians oppose the use of surgery due to the associated excessive morbidity and mortality. The aim of this study was to identify patients who are good candidates for salvage surgery by investigating factors influencing long-term survival. PATIENTS AND METHODS: A total of 40 patients underwent concurrent CRT or RT followed by esophagectomy for residual tumor or locoregional recurrence of esophageal squamous cell carcinoma without distant organ metastasis at the Department of General Surgical Science, Gunma University, Gunma, Japan, and were included in this study. As short-term outcomes after salvage esophagectomy, pulmonary and cardiovascular complications, anastomotic leakage, and chylothorax, and the length of postoperative stay were evaluated. Survival rates were calculated using the Kaplan-Meier method, and the Cox proportional hazards model was used for univariate and multivariate analyses of disease-specific survival. RESULTS: Postoperative complications were noted in 20 patients (50%), and pulmonary complications were the most common (25%), followed by anastomotic leakage (20%). There was also one case of in-hospital death, caused by multiple organ failure due to chylothorax. Univariate analysis revealed that sex, clinical residual tumor, CRT response, pathological tumor depth, and pathological residual tumor were significant factors affecting disease-specific survival (p=0.034, p=0.009, p=0.014, p=0.020, and p=0.026, respectively). Moreover, multivariate analysis demonstrated that clinical residual tumor was the only independent factor influencing disease-specific survival (p=0.036). Thirteen patients (32.5%) died from other illnesses after salvage surgery, 53.8% patients from pneumonia. CONCLUSION: Based on long-term survival, recurrence rather than residual tumor after definitive CRT was a favorable indicator for salvage esophagectomy. Not only management of postoperative morbidity and curative operation but, also long term rigorous outpatient management, including respiratory rehabilitation to reduce pneumonia, is necessary. PMID- 28870934 TI - Inflammatory Breast Cancer Outcomes in a Contemporary Series. AB - BACKGROUND: Evidence on the management of inflammatory breast cancer (IBC) is limited. This study investigated factors influencing IBC treatment outcomes such as event-free survival (EFS) and overall survival (OS). MATERIALS AND METHODS: Data were collected from 173 patients with stage III non-IBC and 17 patients with IBC diagnosed at the Keck Medical Center and Los Angeles County and University of Southern California (LAC+USC) Medical Center. Cox proportional hazard regression evaluated associations between variables significant for EFS and OS. RESULTS: On multivariate analysis, negative estrogen receptor (ER)status [hazard ratio (HR)=1.88, 95% confidence interval (CI)=1.11-3.18, p<0.06) and lack of postoperative radiation treatment (HR=2.07, 95% CI=1.03-4.15, p<0.04) were significant for poorer EFS. High Scarff-Bloom-Richardson (SBR) score (HR=2.24, 95% CI=0.79-6.36, p<0.13) and lack of postoperative radiation treatment to the breast (HR=4.39, 95% CI=0.39-49.55, p<0.23) were associated with lower rates of OS. CONCLUSION: The diagnosis of IBC has a significantly worse prognosis. Receipt of post-mastectomy radiation therapy was a significant predictor of better EFS and OS. PMID- 28870935 TI - Detection of Ductal Carcinoma In Situ by Ultrasound and Mammography: Size dependent Inaccuracy. AB - BACKGROUND: Retrospective analysis of breast cancer imaging methods is a common tool for evaluating the effectiveness of ultrasound and mammography regarding ductal carcinoma in situ (DCIS). No large number subpopulation of pure DCIS has been reported. It is however known that mammography and ultrasound underestimate tumor dimension with increasing tumor size. We aimed to quantify this discrepancy. MATERIALS AND METHODS: This retrospective analysis reviewed the ultrasound and mammography data from 173 patients with DCIS at the University of Cologne - Department of Gynecology and Obstetrics between the years 2007 and 2010. Of these 173 patients, 34 fulfilled the DCIS analysis requirements and were evaluated in this study. RESULTS: Overall, ultrasound underestimated tumor size 79.4% of the time, while overestimating only 20.6% of the time. Mammography underestimated tumor size in 50%, overestimated in 38.2%, correctly estimating in 11.8%. Over and underestimation distributions differed drastically above and a cut-off point of <=2 cm actual tumor size, with a significant shift toward severe underestimation by both methods above a tumor size of 2 cm. DCIS misestimation was defined as the absolute value of the difference between actual tumor size and pre-surgical measurement by an imaging method. Mean DCIS size misestimation (actual tumor size <=2 cm) was 3 mm for ultrasound and 6.2 mm for mammography. CONCLUSION: We support previous findings that ultrasound and mammography lose accuracy with increasing tumor size. Nonetheless, ultrasound may be more useful in estimation of DCIS size for tumors <=2 cm than previously expected. PMID- 28870936 TI - Subcellular Localization of Maspin Correlates with Histone Deacetylase 1 Expression in Human Breast Cancer. AB - BACKGROUND/AIM: Maspin is known to be a tumor suppressor protein. Its nuclear localization and endogenous inhibition of histone deacetylase 1 (HDAC1) are considered crucial for its tumor suppressor activity. However, it remains unclear whether subcellular localization of maspin correlates with HDAC1 expression level in human breast cancer. PATIENTS AND METHODS: Immunohistochemical analyses were performed on 164 resected specimens of invasive breast carcinoma using antibodies for maspin and HDAC1. Subcellular localization of maspin protein and HDAC1 mRNA expression level in two human breast cancer cell lines (MCF7, MDA-MB-231) and mammary epithelial cell line (MCF10) were analyzed by immunofluorescence and quantitative polymerase chain reaction, respectively. RESULTS: The frequency of cytoplasmic-only, pancellular (combined nuclear and cytoplasm) and no staining of maspin were 31%, 14.0% and 55%, respectively. The cytoplasmic-only subgroup showed significantly higher histological grade (p=0.004), negative progesterone receptor status (p=0.003) and shorter disease-free survival compared to the pancellular subgroup (p=0.043). High HDAC1 expression was observed in 60% of cases and was significantly correlated with cytoplasmic-only staining compared to pancellular (p<0.001) or no staining (p=0.004). Immunofluorescence analysis revealed that maspin protein was localized mainly in the cytoplasm in MCF7 and MDA-MB-231 cells, while in both the nucleus and cytoplasm in MCF10A cells. HDAC1 mRNA levels were significantly up-regulated in MCF7 and MDA-MB-231 cells compared to MCF10A cells (p<0.001). CONCLUSION: High HDAC1 expression may contribute to the aggressiveness of human breast cancer with cytoplasmic-only expression of maspin. PMID- 28870937 TI - MRI and Ultrasound Fusion Imaging for Cervical Cancer. AB - BACKGROUND: Evaluating locoregional extension of cervical cancer is a key step in patient management. This study evaluated the feasibility of fusion imaging - a combination of magnetic resonance imaging (MRI) with real-time high-resolution ultrasound (US) - to diagnose cervical cancer and its extension. PATIENTS AND METHODS: This prospective bi-center study included 13 women who underwent a 1.5-T MRI protocol including at least one T2-weighted plane. The results of imaging fusion were then compared with US and MRI results alone. RESULTS: Cervical cancer was detected as a hyperechogenic hypervascularized lesion. Parametrial extension was detected by exploration of the stromal ring and the use of color Doppler mode in fusion imaging, and characterized by visualization of a vascular bridge. CONCLUSION: Fusion imaging could be used as a complementary technique for MRI to enhance diagnostic performance for cervical cancer lesions. While MRI remains the reference, real-time fusion imaging could improve its characterization and detect parametrial infiltration. PMID- 28870938 TI - Identifying Rational Candidates for Immunotherapy Targeting PD-1/PD-L1 in Cervical Cancer. AB - BACKGROUND/AIM: To investigate the abundance of programmed death-ligand 1 (PD-L1) expression and identify rational candidates for anti-PD-1/PD-L1 immunotherapies in cervical cancer. PATIENTS AND METHODS: In 27 patients with FIGO stage IB1-IIA cervical cancer, paraffin-embedded tumors were immunohistochemically stained with PD-L1 antibody. The correlation of tumoral PD-L1 expression with clinicopathological factors and survival outcomes were evaluated. RESULTS: Overall, PD-L1 expression was primarily detected in 12 (44.4%) patients. All tumors with PD-L1 expression were squamous cell carcinomas (SqCC). In subgroup analysis of SqCC, higher PD-L1 expression was associated with low preoperative serum SqCC antigen level (p=0.030) and no parametrial invasion (p=0.048). The 5 year progression-free survival (83.3% vs. 50.0%. p=0.136) and overall survival rates (90.9% vs. 83.3%, p=0.615) were superior in patients with PD-L1 expression that in those without PD-L1 expression; however, neither was significant. CONCLUSION: Patients with SqCC and favorable clinicopathological factors could be candidates for anti-PD-1/PD-L1 immunotherapy in cervical cancer. PMID- 28870939 TI - Clinical and Oncological Outcomes of Laparoscopic Lateral Pelvic Lymph Node Dissection in Advanced Lower Rectal Cancer: Single-institution Experience. AB - AIM: The aim of this study was to compare the clinical outcomes of laparoscopic versus open surgery for total mesorectal excision (TME) with lateral pelvic lymph node dissection (LPLD) in advanced lower rectal cancer. PATIENTS AND METHODS: Forty-four patients who underwent TME with LPLD for lower rectal cancer (pStage II/III) between January 2008 and December 2014 were divided into two groups according to the type of surgical approach as follows: open LPLD group (OLD, n=17) and laparoscopic LPLD group (LLD, n=27). RESULTS: Operative time was comparable between the groups (p=0.15), whereas intraoperative blood loss and complication rates were significantly less in LLD than in OLD. Postoperative hospital stay was shorter in LLD than in OLD. Overall survival and local recurrence-free survival were similar in the two groups. Disease-free survival was better in LLD than in OLD, although the difference was not significant. CONCLUSION: Laparoscopic TME with LPLD is safe and feasible. PMID- 28870940 TI - Inconsistent Reporting Between Meta-analysis Protocol and Publication - A Cross Sectional Study. AB - BACKGROUND: Inconsistent reporting in published meta-analyses compared to registered protocol are poorly understood. The aim of the study was to assess inconsistencies between registered protocols and published reports among oncology drug meta-analyses. MATERIALS AND METHODS: A cross-sectional study was performed including oncology drug meta-analyses published between January 1st and November 14th 2016 with a published protocol. Two investigators extracted data on: selection criteria, outcome(s) and statistical plan in protocol and manuscript, plus self-acknowledgement of inconsistent reporting between protocol and publication. RESULTS: Protocol registration was present in 19% (23/119) of all oncology drug meta-analyses. In meta-analyses with protocol (n=23), 70% (16/23) had issues with inconsistent reporting between protocol and published report concerning; inclusion criteria, comparator group, intervention, outcome (PICO) or statistical analysis. Self-acknowledgement of changes between protocol and publication was found in 50% (8/16). CONCLUSION: In meta-analyses with protocol, discrepancies between registered protocols and publications are frequent. PMID- 28870941 TI - Metastatic Microcystic Adnexal Carcinoma with DNA Sequencing Results and Response to Systemic Antineoplastic Chemotherapy. AB - Microcystic adnexal carcinoma (MAC) is a rare cutaneous malignancy. Due to its rarity, the molecular characteristics and treatment for metastatic MAC remain undefined. Here we present, as far as we are aware, the first case of metastatic MAC with DNA sequencing results indicating a mutation in TP53 and chromosomal losses in cyclin dependent kinase inhibitor 2A (CDKN2A) and cyclin dependent kinase inhibitor 2B (CDKN2B). In addition, this is the first case of metastatic MAC with a documented objective response to systemic antineoplastic chemotherapy (carboplatin and paclitaxel) confirmed by positron emission tomography/computed tomography. Our case increases the very limited medical knowledge of this rare disease. PMID- 28870942 TI - Long-term Survival After Stereotactic Radiosurgery of Brain Metastases: A Case Series with 10-year Follow-up. AB - Patients with brain metastases (BRM) generally have a poor prognosis with infrequent long-term outcomes. Four patients treated by stereotactic radiosurgery (SRS) for BRM between 2000 and 2010 with a minimum follow-up of 10 years are described. The mean age was 43.5 years, and these individuals exhibited good performance status at the time of diagnosis of intracranial disease. BRM was solitary or multiple, and the primary malignant tumor originated from the thyroid gland, lung, mediastinum or large intestine. Progression of the original and secondary tumors subsequent to diagnosis and SRS was not observed. Radioimaging of the brain obtained 9 years later in one of the patients who was asymptomatic at follow-up revealed white matter changes; BRM in this individual was treated by tumor resection and cranial irradiation prior to SRS. We contend that extended longevity is not precluded when standard management of BRM is practiced in selected cases. PMID- 28870943 TI - Prospective Evaluation of Neuromediator Dynamics in Castration-Resistant Prostate Cancer Patients During Docetaxel. AB - AIM: Aim of the study was to detect small cell/neuroendocrine (SCNC) transformation in metastatic castration-resistant prostate cancer (mCRPC) that is a challenging procedure. We investigated the role of neuromediator dynamics as potential evidence of SCNC in patients undergoing docetaxel therapy. PATIENTS AND METHODS: A multi-institutional, prospective observational study was conducted. Patients undergoing docetaxel treatment were included. Chromogranin A (CGA), neuron-specific enolase (NSE), and pro-gastrin releasing peptide (Pro-GRP) were sequentially evaluated at predefined time points. Outcome measures were overall survival (OS), progression-free survival (PFS) and PSA nadir. RESULTS: Fifty-two patients were included. A general rise in CGA levels was observed. Patients with a high CGA rise (100%ULN: CGA >=98.1ng/ml) between the 1st and 3rd cycle trended towards a decreased OS (p=0.0649) and showed a decreased PFS (p=0.0369). In multivariate analysis, continuous CGA rise correlated with PFS (p=0.0553; HR 1.136), but was not an independent predictor of OS. CONCLUSION: Patients with an early high CGA rise may demonstrate a subgroup with poor outcome due to underlying SCNC transformation. Monitoring of CGA appears to be an option worth considering. PMID- 28870944 TI - Predictive Role of CYFRA21-1 and CEA for Subsequent Docetaxel in Non-small Cell Lung Cancer Patients. AB - BACKGROUND/AIM: The aim of the present study was to determine the clinical value of tumor marker levels for previously treated NSCLC patients. PATIENTS AND METHODS: We retrospectively screened 113 previously treated patients with advanced NSCLC who were treated with docetaxel monotherapy regarding the pretreatment serum level of cytokeratin 19 fragment (CYFRA21-1) and carcinoembryonic antigen (CEA). RESULTS: The thirty-two patients with normal CYFRA21-1 levels and high CEA levels had a significantly higher response rate than the other 81 patients (25% vs. 8.6%, p=0.031). The former group showed statistically longer progression-free survival (PFS) and overall survival (OS) than the latter group (median PFS, 180 vs. 59 days, p<0.001; median OS, 579 vs. 255 days, p=0.002). In multivariate analysis, tumor marker levels had a significant impact on PFS and OS. CONCLUSION: Combination of the two tumor markers is a predictive and prognostic marker of docetaxel monotherapy for previously treated NSCLC patients. PMID- 28870945 TI - Flattening Filter Free vs. Flattened Beams for Lung Stereotactic Body Radiation Therapy. AB - BACKGROUND/AIM: To assess the clinical impact of high dose rate stereotactic body radiation therapy (SBRT) in patients with lung neoplastic lesions. PATIENTS AND METHODS: From January 2014 to June 2016, a single-center retrospective analysis was performed including all patients treated by either flattening filter free (FFF) beams or flattening filter beams (FF) three-dimensional (3D) SBRT for lung neoplastic lesions. RESULTS: A total of 99 SBRT were performed on 75 patients. Among these, 29 SBRT were performed using a FFF technique while 70 other SBRT were done using a FF technique. Median follow-up time was 12.9 months. Overall, no difference between the two groups was found except for the mean beam on time which was reduced by 3.3 to 0.9 minutes in the FFF group (p<0.001). CONCLUSION: We report a low toxicity rate and a shortened beam on time in patients treated with 3D FFF SBRT for lung neoplastic lesions. PMID- 28870946 TI - Effects of an Alkaline Diet on EGFR-TKI Therapy in EGFR Mutation-positive NSCLC. AB - BACKGROUND: The acidic tumor microenvironment is associated with progression of cancers. The purpose of this study was to investigate the association between an alkaline diet and the effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Eleven advanced or recurrent NSCLC patients with EGFR mutations treated with EGFR-TKI after being instructed to follow an alkaline diet were retrospectively evaluated. RESULTS: The median progression-free survival (PFS) and overall survival (OS) were 19.5 (range=3.1-33.8) and 28.5 (range=15.4-46.6) months. The average dosage of EGFR-TKI was 56+/-22% of the standard dosage. Urine pH was significantly increased after the alkaline diet (6.00+/-0.38 vs. 6.95+/ 0.55; p<0.05). CONCLUSION: An alkaline diet may enhance the effect of EGFR-TKI treatment in NSCLC patients with EGFR mutations. PMID- 28870947 TI - Evaluation of Factors Affecting Metastasis for Renal Cell Carcinoma Based on Current Guidelines in Japan. AB - BACKGROUND/AIM: To analyze the suitability for metastasis evaluation of each pathologic item on the Fourth Edition of the General Rule for Clinical and Pathologic Studies on Renal Cell Carcinoma in Japan. PATIENTS AND METHODS: We retrospectively examined 457 cases of renal operation after 2011 using the current edition of the guidelines. RESULTS: The mean postoperative follow-up period was 25.3 months. Radical nephrectomy was performed in 264 cases, whereas partial nephrectomy was performed in 193 cases. Including the 33 cases discovered after operation, the overall number of metastatic cases was 68 (14.9%). Using the current edition of the guidelines, the items of histologic grade, morphology of tumor invasion, tumor pseudocapsule, and intrarenal metastasis were all correlated with distant metastasis. CONCLUSION: This is the first report showing that each item on the current Japanese guidelines for renal cell cancer was useful for predicting metastasis. PMID- 28870948 TI - Neoadjuvant Imatinib Therapy Followed by Intersphincteric Resection for Low Rectal Gastrointestinal Stromal Tumors. AB - BACKGROUND/AIM: Intersphincteric resection (ISR) aims to preserve anal function in patients with very low rectal tumors. Here, we analyzed patients who underwent neoadjuvant imatinib therapy followed by ISR for low rectal gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS: We retrospectively analyzed patients with low rectal GISTs who underwent neoadjuvant imatinib therapy and ISR between January 2013 and December 2015 at the University of Tokyo hospital. RESULTS: The study included 4 men and 1 woman, with a median age of 67 years (range=45-67). All patients received 400 mg of neoadjuvant imatinib once daily for the median duration of 4 months (range=3-12). Microscopically, R0 resection was performed in 4 patients, and R1, in 1 patient. There was 1 recurrence event during the median follow-up duration of 35 months. CONCLUSION: Neoadjuvant imatinib therapy and ISR for low rectal GISTs is a challenging, but promising, alternative to achieve complete resection margins and preserve anal function. PMID- 28870949 TI - Prognostic Significance of Serum CEA for Non-small Cell Lung Cancer Patients Receiving Stereotactic Body Radiotherapy. AB - BACKGROUND/AIM: To examine the prognostic significance of serum carcinoembryonic antigen (CEA) for stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). PATIENTS AND METHODS: In total, 129 stage I NSCLC patients were analyzed and divided into two groups: CEA-High (CEA>5 ng/ml) and CEA-Low (CEA<=5 ng/ml). RESULTS: Median follow-up time was 38 months. Overall survival was not significantly different between CEA-High (n=47) and CEA Low (n=82) patients (57% vs. 63% at 3 years; p=0.39), although progression-free survival (PFS) was significantly worse in CEA-High patients (31% vs. 51% at 3 years; p=0.01). Larger tumor size and high CEA level were independent prognostic factors for worse PFS. Failure pattern analysis showed that regional node or distant recurrence was more common in CEA-High patients (47%) than in CEA-Low patients (29%). CONCLUSION: Patients with CEA-High stage I NSCLC have a higher risk of regional or systemic relapse and should be followed-up carefully. PMID- 28870950 TI - A Scoring System to Predict the Development of Bone Metastasis After Radical Resection of Colorectal Cancer. AB - BACKGROUND/AIM: To develop a scoring system to predict bone metastasis after radical resection within 5 years. PATIENTS AND METHODS: We evaluated the patient records of 1,749 patients, of whom 50 patients developed bone metastasis. Treatment-related factors (age, gender, localization, histology, preoperative carbohydrate antigen 199 level, T-stage, lymph node metastasis (LN) and pulmonary metastasis (PM)) were analyzed. RESULTS: We found three independent risk factors, namely rectal cancer (p=0.038), LN (p=0.006) and metachronous PM (p<0.001). Scoring was conducted by adding zero or one point from each variable and resulted in four groups of 0, 1, 2 or 3 points. Three groups were formed, with 0-1 points vs. 2 points vs. 3 points (1.5% vs. 6.6% and 10.5%, p<0.001). CONCLUSION: This new score can help clinicians identify patients at risk for continuous monitoring and optimize surveillance to be able to detect and treat bone metastases very early in order to avoid skeletal complications. PMID- 28870951 TI - Comparison of Postoperative Outcomes Between Laparoscopic and Open Surgery for Colorectal Cancer. AB - BACKGROUND/AIM: To determine the superiority of the laparoscopic vs. open technique for colorectal cancer surgery. PATIENTS AND METHODS: We performed a retrospective analysis of consecutive patients who underwent curative surgery by laparoscopic colectomy (LC) or open colectomy (OC) for colon cancer. The patients were classified into two groups: as LC group and OC group. We retrospectively assessed clinical characteristics, intraoperative and postoperative outcomes and long-term outcomes between the two groups by univariate analysis. RESULTS: The LC group had significantly less intraoperative blood loss, complications, and shorter post-operative hospital stay than the OC group. The overall survival of Stage II in the LC group is significantly longer than the OC group. DFS of Stage III in the LC group was significantly longer than the OC group. CONCLUSION: LC showed more favorable results in both short-term and long-term outcomes than OC. PMID- 28870952 TI - Metallothionein Isoform Expression in Benign and Malignant Thyroid Lesions. AB - BACKGROUND: Metallothioneins (MTs) are involved in numerous cell processes such as binding and transport of zinc and copper ions, differentiation, proliferation and apoptosis, therefore contributing to carcinogenesis. Scarce data exist on their expression in benign and malignant lesions of the thyroid. MATERIALS AND METHODS: mRNA expression of functional isoforms of MT genes (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1X, MT2A, MT4) was studied in 17 nodular goiters (NG), 12 follicular adenomas (FA) and 26 papillary thyroid carcinomas (PTC). RESULTS: One way ANOVA revealed significant differences in mRNA expression levels of MT1A (p<0.05), MT1E (p<0.005), MT1F (p<0.0001), MT1G (p<0.005), MT1X (p<0.0005) and MT2A (p<0.005) in the analyzed samples. Post hoc analysis confirmed a significantly lower expression of MT1A mRNA in PTC compared to NG (p<0.05). Significant down-regulation was also noted for other MT isoforms in PTC in comparison to NG: MT1E (p<0.05), MT1F (p<0.0001), MT1G (p<0.005), MT1X (p<0.0005) and MT2A (p<0.05). In addition, significant down-regulation of MT1F and MT1G in FA compared to NG was observed (p<0.005 and p<0.05, respectively). CONCLUSION: Expression of functional MT isoforms may contribute to thyroid carcinogenesis and potentially serve as a diagnostic marker in distinguishing benign and malignant lesions. PMID- 28870953 TI - Role of Densitometric Criteria in Evaluation of Effectiveness of Antiangiogenic Therapies in Metastatic Colorectal Cancer: An Italian Clinical Experience. AB - BACKGROUND/AIM: To evaluate the role of densitometric criterion using the Choi Criteria in the assessment of the response to antiangiogenic treatments of metastatic colorectal cancer (mCRC) compared to the RECIST criteria. PATIENTS AND METHODS: Fifty-four patients (mean age=50.6 years) affected by advanced colorectal cancer and with hepatic and possibly peritoneal and pulmonary metastases, that can be treated with bevacizumab, were prospectively evaluated by computerized tomography (CT) scan. Metastases were also evaluated by CT in one dimensional form according to RECIST. RESULTS: Results show that in 58% of analyzed cases, stable disease according to RECIST coincided with stable disease according to the CHOI criteria, whereas in 42% of analyzed cases disease progression according to RECIST corresponded to stable disease or even partial response according to CHOI criteria. CONCLUSION: By using the densitometric criterion with CHOI criteria, the evaluation of the response to antiangiogenic treatment of mCRC is partially different compared to RECIST criteria. PMID- 28870954 TI - First-line Treatment of Advanced Biliary Ducts Carcinoma: A Randomized Phase II Study Evaluating 5-FU/LV Plus Oxaliplatin (Folfox 4) Versus 5-FU/LV (de Gramont Regimen). AB - BACKGROUND/AIM: Few clinical trials are available for advanced biliary tract carcinoma (BTC). We conducted this randomized phase II clinical trial to explore efficacy and safety of 5-fluorouracil/leucovorin (5-FU/LV - de Gramont) or the same regimen plus oxaliplatin (Folfox 4) as first-line treatment of advanced BTC. PATIENTS AND METHODS: Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), response and toxicity. RESULTS: A total of 48 patients were enrolled, 23 in de Gramont arm and 25 in the Folfox arm. Disease control rate was 56.5% for de Gramont vs. 72% for Folfox. RR was 21.7% for de Gramont arm and 28% for Folfox arm (p=0.12). PFS was in favor of Folfox (5.2 vs. 2.8 months; p=0.031). OS was 7.5 and 13.0 months for de Gramont and Folfox arm respectively (p=0.0010). Toxicity was generally mild in both arms. CONCLUSION: Folfox 4 could be considered a valid option as first-line treatment of BTC due to its efficacy and tolerability. PMID- 28870955 TI - Correlation of Radiation Pneumonitis History Before Nivolumab with Onset of Interstitial Lung Disease and Progression-free Survival of Patients with Pre treated Advanced Non-small Cell Lung Cancer. AB - BACKGROUND/AIM: Nivolumab has a promising efficacy for patients with non-small cell lung cancer (NSCLC) as second-line or later treatment, and after radiotherapy as abscopal effect. However, the effects of radiation pneumonitis history before nivolumab have not been clarified. Therefore, we retrospectively analyzed the correlation of a history of radiation pneumonitis before nivolumab with onset of interstitial lung disease (ILD) and progression-free survival (PFS) after nivolumab treatment in patients with previously treated NSCLC. PATIENTS AND METHODS: A total of 201 patients treated with nivolumab were retrospectively reviewed. We collected clinical data of patients at the time of starting nivolumab and we evaluated ILD incidence and PFS in relation to patient characteristics, including radiation pneumonitis history. RESULTS: The median age was 68 years; 135 patients were men, 157 had a smoking history, and 153 had performance status of 0 or 1. Thirty-four patients experienced radiation pneumonitis before nivolumab, and 50 patients received radiotherapy to the chest (31 patients received curative radiotherapy). The overall median PFS was 2.8 months and the overall ILD rate was 12.4%. Higher ILD incidence was observed in the group with a history of radiation pneumonitis (26.5%) compared to the group without radiation pneumonitis (9.6%). The median PFS was 3.6 and 2.3 months, respectively. On multivariate analysis, a history of radiation pneumonitis was also significantly correlated with good PFS (p=0.023). CONCLUSION: Although increasing the risk of ILD, a history of radiation pneumonitis before nivolumab also contributes to the prolongation of PFS after nivolumab. PMID- 28870957 TI - Comparing the Efficacy of DeVIC Therapy and High-dose Methotrexate Monotherapy with Whole-brain Radiation Therapy for Newly-diagnosed Primary Central Nervous System Lymphoma: A Single Institution Study. AB - BACKGROUND/AIM: In the current study, we aimed to compare DeVIC (dexamethasone, etoposide, ifosfamide and carboplatin) chemotherapy with high-dose methotrexate (HD-MTX) monotherapy plus whole-brain radiation therapy (WBRT) for newly diagnosed primary central nervous system lymphoma (PCNSL), in terms of their efficacies and tolerability. PATIENTS AND METHODS: A total of 21 consecutive patients with PCNSL were treated with DeVIC therapy and WBRT, between 2002 and 2010. From 2010 to 2014, 14 consecutive patients with PCNSL were treated with HD MTX followed by WBRT. RESULTS: Overall response rates of complete and partial response for initial chemotherapy were significantly better with DeVIC therapy (95.2%) than with HD-MTX monotherapy (50%). Furthermore, one-year and two-year progression-free survival (PFS) rates were better in the DeVIC cohort than in the HD-MTX cohort. DeVIC therapy yielded higher early response rates, longer PFS, and manageable adverse events, and may be potentially better for the treatment of cases that are refractory to MTX-based therapy. CONCLUSION: Our retrospective clinical study revealed that DeVIC therapy is comparable with that of HD-MTX monotherapy plus WBRT, for newly diagnosed PCNSL. PMID- 28870956 TI - Targeted Delivery of Cordycepin to Liver Cancer Cells Using Transferrin conjugated Liposomes. AB - BACKGROUND/AIM: Cordycepin is an endogenous nucleoside with significant anticancer biological activity. The objective of this study was to develop targeted liposomes to improve solubility and biological activity of cordycepin. MATERIALS AND METHODS: We established transferrin-conjugated liposomes to deliver cordycepin to liver cancer cells and evaluated the uptake and effect. RESULTS: The liposomes were loaded with cordycepin. Their average size was 125.3 nm, with drug encapsulation efficiency of 65.3%. The liposomes had good colloidal stability and released cordycepin slowly. Liposomal cordycepin was shown to increase reactive oxygen species production and cause depolarization of the mitochondrial transmembrane in liver cancer cells. Cellular uptake of liposomal cordycepin was enhanced by conjugation to transferrin, that facilitated receptor mediated endocytosis. CONCLUSION: Transferrin-conjugated liposomes are effective as nanocarriers for cordycepin delivery to liver cancer cells. PMID- 28870958 TI - Anti-proliferative, Cytotoxic and NF-KB Inhibitory Properties of Spiro(Lactone Cyclohexanone) Compounds in Human Leukemia. AB - BACKGROUND/AIM: NF-KB affects most aspects of cellular physiology. Deregulation of NF-KB signaling is associated with inflammatory diseases and cancer. In this study, we evaluated the cytotoxic and NF-KB inhibition potential of new spiro(lactone-cyclohexanone) compounds in two different human leukemia cell lines (U937 and K562). MATERIALS AND METHODS: The anti-proliferative effects of the spiro(lactone-cyclohexanone) compounds on human K562 and U937 cell lines was evaluated by trypan blue staining, as well as their involvement in NF-kB regulation were analyzed by luciferase reporter gene assay, Caspase-3/7 activities were evaluated to analyze apoptosis induction. RESULTS: Both spiro(coumarin-cyclohexanone) 4 and spiro(6- methyllactone-cyclohexanone) 9 down regulated cancer cell viability and proliferation. Compound 4 inhibited TNF-alpha induced NF-KB activation in a dose-dependent manner and induced caspase-dependent apoptosis in both leukemia cell lines. CONCLUSION: Results show that compound 4 and compound 9 have potential as anti-cancer agents. In addition, compound 4 exerted NF-kB inhibition activity in leukemia cancer cells. PMID- 28870959 TI - Differences in Urinary Renal Failure Biomarkers in Cancer Patients Initially Treated with Cisplatin. AB - BACKGROUND/AIM: We investigated whether measuring the excretion of each acute kidney injury (AKI) biomarker after cisplatin (CDDP) administration is useful for predicting AKI and evaluated the most appropriate AKI marker in patients treated with CDDP. PATIENTS AND METHODS: We measured NAG, Kim-1, and NGAL in urinary samples of 40 cancer patients treated with chemotherapy on day 1 (before chemotherapy), day 2, and day 5 after treatment; serum creatinine (sCr) was compared on days 7 and 28 after CDDP administration vs. baseline. RESULTS: NAG, Kim-1, and NGAL excretion (creatinine corrected) were not significantly elevated 5 days after receiving chemotherapy in the non-CDDP chemotherapy group. Conversely, all markers were significantly higher 5 days after receiving chemotherapy in the CDDP group when compared to baseline. CONCLUSION: Urinary NAG, Kim-1, and NGAL can detect renal injury more sensitively than sCr. PMID- 28870960 TI - Risk-reducing Salpingo-Oophorectomy in Women at Higher Risk of Ovarian and Breast Cancer: A Single Institution Prospective Series. AB - BACKGROUND/AIM: Occult cancers' reported rates vary from 2-12% and serous tubal intraepithelial carcinomas (STICs) have been identified in 3-12% of the prophylactically removed tubes of women carrying a BRCA mutation. The aim of this study was to evaluate the incidence of tubal minor epithelial atypia (STIL), STIC, and occult invasive cancer and to evaluate the cancer-specific mortality in a prospective series of women at higher risk of ovarian and breast cancer undergoing risk-reducing salpingo-oophorectomy (RRSO) n a tertiary cancer center. PATIENTS AND METHODS: A series of RRSO specimens (including endometrial biopsy) from women carrying a BRCA mutation, BRCA-unknown and BRCA-negative were collected between January 1998 and April 2016 at the Division of Gynecology at the European Institute of Oncology. Inclusion criteria were: asymptomatic women who had a negative gynecologic screening within 3 months prior to RRSO. Exclusion criteria were: women with ovarian/tubal cancer prior to RRSO. RESULTS: A total of 411 women underwent RRSO. Median age at RRSO was 47.0 years (range=32-70 years); 75.2% had a history of breast cancer. Fifteen women were diagnosed with an occult cancer (7 STIC, 4 invasive cancers, 2 breast cancers metastatic to the adnexa, 2 endometrial cancer) (3.6%). Sixteen showed a STIL (3.9%). When excluding cases with preoperative positive markers, the occult invasive cancer rate drops to 1.5%. CONCLUSION: Our study, covering an 18-year period, shows a substantial low risk of occult cancer among a high-risk population of women undergoing RRSO. Our data still support the indication for RRSO in higher-risk patients. An endometrial biopsy should also be routinely obtained as it raises the chances of detecting occult endometrial cancers that may be otherwise missed. PMID- 28870961 TI - The Local Recurrence of Breast Cancer with Squamous Metaplasia and Obvious Histological Heterogeneity. AB - CASE REPORT: We herein report a case of local recurrence of breast cancer with squamous metaplasia and obvious intratumoral and intertumoral heterogeneity. A 39 year-old female patient was diagnosed with T3N2M0 stage IIIB right breast cancer and underwent right total mastectomy and axillar lymph node dissection. At four years after surgery, she became aware of chest wall pain and diagnostic imaging revealed recurrence in the lung, right thoracic wall and sternum. The recurrent lesions remained stable for 18 months with endocrine therapy. Thereafter, the lesion in the right thoracic wall suddenly became enlarged. Moreover, liver metastasis was confirmed on FDG-PET/CT. She underwent right thoracic wall tumor resection. A biopsy was simultaneously performed to obtain a specimen from the site of liver metastasis. Postoperatively, the right chest wall mass showed obvious intratumoral heterogeneity; squamous differentiation with aggressive features and a papillotubular component similar to the primary tumor. The metastatic liver tumor showed similar pathological features to the primary tumor. CONCLUSION: Intratumoral and intertumoral heterogeneity within primary tumors and associated metastatic sites may contribute to treatment failure and drug resistance. PMID- 28870962 TI - Value of Additional Digital Breast Tomosynthesis for Preoperative Staging of Breast Cancer in Dense Breasts. AB - AIM: This retrospective study was initiated to determine the diagnostic value of additional preoperative breast tomosynthesis (DBT) for breast cancer staging in dense breasts. PATIENTS AND METHODS: Sixty-six patients (69 breasts) with findings of American College of Radiology category 3 or 4 with Breast Imaging Reporting and Data System 5, 6 or 0 were included. All patients underwent digital mammography and additional DBT. RESULTS: A total of 40/69 (58%) cancers were detected on both mammography and DBT, 23 (33.3%) were only seen on DBT (p=0.0001); 6/69 (8.7%) carcinomas were not detected by either method, of which three were invasive lobular carcinomas. Sensitivity for multifocal/multicentric disease was significantly higher on DBT (12/19, 63.2%) compared to mammography (4/19, 21.1%) (p=0.02), specificity was comparable (96.0% vs. 90.0%). Multifocal/multicentric disease was not detected on mammography nor DBT in 7/19 (36.8%) patients, including three invasive lobular carcinomas. CONCLUSION: DBT may significantly improve preoperative breast cancer staging in patients with dense breasts compared to conventional mammography alone. Nevertheless, limitations have to be expected in the case of invasive lobular carcinoma. PMID- 28870963 TI - Are Multiple Tumors of the Parotid Gland Uncommon or Underestimated? AB - BACKGROUND/AIM: Parotid gland tumors are mostly solitary tumors of the salivary gland tissue. There is limited evidence about multifocal tumor growth of the parotid gland. PATIENTS AND METHODS: We reviewed medical records of 796 consecutive parotidectomies in 758 patients over the last 40 years in our department, and investigated the incidence and histological type of synchronous and metachronous parotid tumors. Multifocal recurrent tumors and hybrid tumors were excluded. RESULTS: We identified 93 (13%) patients with multiple parotid lesions. Their mean age was 63 (range=15-93) years. Multiple parotid tumors were found unilaterally in 59% and bilaterally in 41% of cases. The contralateral tumor was diagnosed synchronously in 13 of 38 (34%) cases and in 25 of 38 (66%) cases metachronously. The time separating the diagnoses of both contralateral tumors ranged between one and eleven years. The same histological type was found in 95% of the tumors, and 96% of the parotid tumors had lymphatic origin. Warthin tumors (65%) were the most frequent histological type. CONCLUSION: Every sixth patient with a parotid tumor has multifocal tumor lesions. The majority of multifocal parotid tumors have a lymphoid element, while multifocal growth is uncommon in other histological types. PMID- 28870964 TI - Incidence and Oncological Implications of Previously Undetected Tumor Multicentricity Following Pancreaticoduodenectomy for Pancreatic Adenocarcinoma in Patients Undergoing Salvage Pancreatectomy. AB - BACKGROUND: The risk for multicentricity of pancreatic adenocarcinoma remains unclear and the question whether pancreaticoduodenectomy represents sufficient oncological treatment for patients with ductal adenocarcinoma of the head of the pancreas needs further investigation. PATIENTS AND METHODS: Clinicopathological data of patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma between 2005 and 2015 were assessed and the incidence of tumor multicentricity among patients who required salvage pancreatectomy within 90 postoperative days was evaluated. RESULTS: Pancreaticoduodenectomy was performed in 1,005 patients. Sixty-two patients (6%) suffered a major postoperative complication (pancreatic fistula/anastomotic leak/bleeding) after resection of the head of the pancreas, requiring salvage pancreatectomy. Histological examination of the pancreatic remnant in patients with ductal adenocarcinoma (n=19) revealed multicentric carcinoma in two patients, resulting in an incidence of 11% for tumor multicentricity. Preoperative cross-sectional imaging failed to identify tumor multicentricity in these patients. Additionally, two patients with pancreatic intraepithelial neoplasia and two with neuroendocrine tumor were identified. CONCLUSION: The incidence of previously undetected multicentric adenocarcinoma among patients undergoing salvage pancreatectomy in our study was surprisingly high. This finding suggests that the role of total pancreatectomy for pancreatic head cancer, as well as the current strategies for postoperative tumor surveillance, should be re-evaluated in order to provide the best oncological approach and prolonged survival for patients with ductal adenocarcinoma. PMID- 28870966 TI - Robot-assisted Extracranial Stereotactic Radiotherapy of Adrenal Metastases in Oligometastatic Non-small Cell Lung Cancer. AB - AIM: The aim of this study was to evaluate the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in the treatment of patients with adrenal metastases in oligometastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between November 2012 and May 2015, fifteen patients with oligometastatic non-small cell lung cancer and adrenal metastases were treated with the Cyberknife(r) system. The primary endpoint was local control. RESULTS: The 1-year and 2-year local control rates were 60% and 46.6%, respectively. The differences in local control for patients with metachronous and synchronous metastases reached statistical significance (p=0.00028). Two-year overall survival of 91.2% for patients with metachronous metastases was also more favourable compared to patients with synchronous adrenal metastases with 42.8%. CONCLUSION: Extracranial stereotactic radiotherapy with the Cyberknife(r) is a safe and non-invasive technique that extends the therapeutic spectrum in the treatment of patients with adrenal metastases in oligometastatic NSCLC. PMID- 28870965 TI - Surgical Strategy for T1 Duodenal or Ampullary Carcinoma According to the Depth of Tumor Invasion. AB - AIM: To investigate the utility of local resection (LR) for T1 duodenal carcinoma and T1 ampullary carcinoma. PATIENTS AND METHODS: Between June 2002 and November 2014, a total of 64 patients with pathological T1 (pT1) ampullary carcinoma (25 patients) and pT1 duodenal carcinoma (39 patients) were treated. Of these, 33 patients underwent local resection (LR group), while the other 31 patients underwent pancreatoduodenectomy (PD group). RESULTS: The LR group had 31 patients with pT1a and 2 patients with pT1b. PD group had 18 patients with pT1a and 13 patients with pT1b. One patient with pT1b duodenal carcinoma (20.0%) and one patient with pT1b ampullary carcinoma (10.0%) developed lymph node metastasis, while none of the patients with pT1a disease developed metastases. CONCLUSION: LR may be considered in the patients preoperatively diagnosed with T1a duodenal carcinoma and T1a ampullary carcinoma. PMID- 28870967 TI - Safety for Repeat Lumpectomy Without Radiotherapy for Ipsilateral Breast Tumor Recurrence. AB - BACKGROUND: There is little information on the local recurrence risk of patients who undergo repeat lumpectomy without radiotherapy after salvage surgery for ipsilateral breast tumor recurrence (IBTR). PATIENTS AND METHODS: Sixty-five patients who underwent repeat lumpectomy without radiotherapy after IBTR were retrospectively analyzed. The risk factors of second IBTR, including the breast cancer subtype of IBTR defined by the estrogen receptor (ER) and HER2 status, were assessed. RESULTS: The median follow-up period was 62 months. The 5-year second IBTR-free survival rate was 83%. Patients with the ER-positive/HER2 negative subtype of IBTR had a significantly better second IBTR-free survival rate than those with other subtypes of IBTR (88% vs. 75%, respectively, p=0.02). Multivariate analysis revealed that the breast cancer subtype of IBTR was a significantly independent predictive factor of second IBTR-free survival (p=0.003). A low-risk group for second IBTR, defined by the breast cancer subtype of IBTR and margin status of primary surgery, was detected (5-year second IBTR free survival rate: 100%). CONCLUSION: Patients in the low-risk group defined by the breast cancer subtype of IBTR and margin status of primary surgery could safely undergo repeat lumpectomy without radiotherapy for IBTR. PMID- 28870968 TI - Efficacy of Additional Surgical Resection After Endoscopic Submucosal Dissection for Superficial Esophageal Cancer. AB - BACKGROUND/AIM: This study aimed to investigate the efficacy of additional surgical resection (ASR) after endoscopic submucosal dissection (ESD) for superficial esophageal cancer (SEC). PATIENTS AND METHODS: Clinicopathological features and prognoses were analyzed in esophageal cancer (EC) cases with the indication for additional treatments (AT) after ESD (37 cases) and in cases that underwent primary resection (13 cases). RESULTS: Sixteen out of 37 cases underwent ASR. The remaining 21 cases underwent other treatments or observation. Although all ASR cases are alive without recurrence, recurrence developed in 2 non-ASR cases. Residual tumors were detected in 2 ASR cases. All 4 cases were T1b and positive for lymph vessel invasion (ly+). No significant difference was observed in surgical outcomes between ASR and primary surgical resection (PSR) cases. CONCLUSION: AT need to be considered for T1b and ly+ cases, and ASR is one of the effective AT. The safety of ASR was similar to PSR for SEC. PMID- 28870969 TI - Study on the Validity of Pancreaticoduodenectomy in the Elderly. AB - AIM: Pancreaticoduodenectomy (PD) is still the only curative treatment for periampullary cancer. Confirming the outcomes of PD in elderly patients is important as the aging population continues to grow. PATIENTS AND METHODS: We analyzed 340 patients with periampullary cancer who underwent PD, dividing them into three groups by age: group A: aged 64 years or younger, n=115; group B: 65 74 years, n=144; and group C: 75 years or older, n=81. RESULTS: Group C had a significantly higher 60-day mortality of 6.3% (p=0.04), the lowest 5-year overall survival rate of 9.9% (p=0.02), and there was no impact of staging of the Union for International Cancer Control classification on overall survival of patients with pancreatic cancer. Independent prognostic factors of group C in the multivariate analysis were pancreatic cancer and reoperation. CONCLUSION: For elderly patients aged 75 years or over, caution should be exercised in selecting PD for patients with pancreatic cancer. PMID- 28870970 TI - Errata. PMID- 28870972 TI - LDL cholesterol level in fifth-grade schoolchildren associates with stature. AB - Short stature is associated with increased LDL-cholesterol levels and coronary artery disease in adults. We investigated the relationship of stature to LDL levels in children in the West Virginia Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) Project to determine whether the genetically determined inverse relationship observed in adults would be evident in fifth graders. A cross-sectional survey of schoolchildren was assessed for cardiovascular risk factors. Data collected at school screenings over 18 years in WV schools were analyzed for 63,152 fifth-graders to determine relationship of LDL to stature with consideration of age, gender, and BMI. The first (shortest) quartile showed an LDL level of 93.6 mg/dl compared with an LDL level of 89.7 mg/dl for the fourth (tallest) quartile. Each incremental increase of 1 SD of height lowered LDL by 0.049 mg/dl (P < 0.0001). Multivariate analysis showed LDL to vary inversely as a function of the first (lowest) quartile of height after controlling for gender, median age, BMI percentile for age and gender, and year of screening. The odds ratio for LDL >= 130 mg/dl for shortest versus tallest quartile is 1.266 (95% CL 1.162-1.380). The odds ratio for LDL >= 160 mg/dl is 1.456 (95% CL 1.163-1.822). The relationship between short stature and LDL, noted in adults, is confirmed in childhood. PMID- 28870971 TI - Polygenic determinants in extremes of high-density lipoprotein cholesterol. AB - HDL cholesterol (HDL-C) remains a superior biochemical predictor of CVD risk, but its genetic basis is incompletely defined. In patients with extreme HDL-C concentrations, we concurrently evaluated the contributions of multiple large- and small-effect genetic variants. In a discovery cohort of 255 unrelated lipid clinic patients with extreme HDL-C levels, we used a targeted next-generation sequencing panel to evaluate rare variants in known HDL metabolism genes, simultaneously with common variants bundled into a polygenic trait score. Two additional cohorts were used for validation and included 1,746 individuals from the Montreal Heart Institute Biobank and 1,048 individuals from the University of Pennsylvania. Findings were consistent between cohorts: we found rare heterozygous large-effect variants in 18.7% and 10.9% of low- and high-HDL-C patients, respectively. We also found common variant accumulation, indicated by extreme polygenic trait scores, in an additional 12.8% and 19.3% of overall cases of low- and high-HDL-C extremes, respectively. Thus, the genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants. Multiple types of genetic variants should be considered as contributing factors in patients with extreme dyslipidemia. PMID- 28870973 TI - Primary hyperparathyroidism in young patients in Russia: high frequency of hyperparathyroidism-jaw tumor syndrome. AB - BACKGROUND: Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial. OBJECTIVE: To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age. DESIGN: We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome. METHODS: The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation dependent probe amplification was performed. RESULTS: NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8. CONCLUSIONS: Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with CDC73 mutations. PMID- 28870974 TI - Serum levels of polyamine synthesis enzymes increase in diabetic patients with breast cancer. AB - BACKGROUND: In this study, it was aimed to investigate the relationship between diabetes and breast cancer and the detection of enzymes and ornithine levels in polyamine synthesis pathway in diabetes, breast cancer and diabetic breast cancer patients. METHODS: Ornithine, arginine decarboxylase, ornithine decarboxylase and agmatinase levels have been measured in serum of all groups. Ornithine levels were measured spectrophotometrically. Arginine decarboxylase, ornithine decarboxylase and agmatinase levels were determined by ELISA kits. RESULTS: Except for the diabetic group, the levels of enzymes in the polyamine synthesis pathway were increased in all and statistically significant (P < 0.05). The increase in the levels of agmatinase was very important among the enzymes (P < 0.001). CONCLUSIONS: Decreased levels of polyamine synthase enzymes in diabetes mellitus were found to be increased patients with breast cancer. Whether and how diabetes-based breast cancer development relates to increase activity of enzymes responsible for polyamine synthesis requires further mechanistic and prospective monitoring studies in larger patient cohorts. PMID- 28870975 TI - Three cases of imported eyeworm infection in dogs: a new threat for the United Kingdom. AB - In July 2016 we described the first known case of canine ocular thelaziosis in the UK in a dog recently imported from Romania. Here we confirm our initial diagnosis using PCR followed by sequence analysis, and we report a further two clinical cases in dogs with recent history of travel to Italy and France. In view of the presence in the UK of the vector for Thelazia callipaeda, namely Phortica spp, we discuss the significance of these three cases in the context of the UK government's pet travel scheme, disease control and both animal and public health in the UK. PMID- 28870976 TI - Caregiver burden in owners of a sick companion animal: a cross-sectional observational study. AB - Much recent work has focused on occupational stress in veterinary medicine, although little is known about the possible contribution of client-based factors. Clients providing care for a companion animal with protracted illness are likely to experience 'caregiver burden' and reduced psychosocial functioning, which may ultimately lead to increased veterinarian stress. This cross-sectional observational study assessed caregiver burden and psychosocial function in 238 owners of a dog or cat, comparing owners of an animal with chronic or terminal diseases (n=119) with healthy controls blindly matched for owner age/sex and animal species (n=119). Results showed greater burden, stress and symptoms of depression/anxiety, as well as poorer quality of life, in owners of companion animals with chronic or terminal disease (p<0.001 for all). Higher burden was correlated with reduced psychosocial function (p<0.001 for all). Owners of a sick companion animal exhibit elevated caregiver burden, which is linked to poorer psychosocial functioning. This knowledge may help veterinarians understand and more effectively handle client distress in the context of managing the challenges of sick companion animal caregiving. Future work is needed to determine whether clients with this presentation impact veterinarian stress and how burden in this population might be reduced. PMID- 28870977 TI - Recommendations for Prevention and Control of Influenza in Children, 2017 - 2018. AB - This statement updates the recommendations for routine use of the seasonal influenza vaccine and antiviral medications for the prevention and treatment of influenza in children. The American Academy of Pediatrics recommends annual seasonal influenza immunization for everyone 6 months and older, including children and adolescents. Highlights for the upcoming 2017-2018 season include the following:1. Annual universal influenza immunization is indicated with either a trivalent or quadrivalent (no preference) inactivated vaccine;2. The 2017-2018 influenza A (H1N1) vaccine strain differs from that contained in the 2016-2017 seasonal vaccines. The 2017-2018 influenza A (H3N2) vaccine strain and influenza B vaccine strains included in the trivalent and quadrivalent vaccines are the same as those contained in the 2016-2017 seasonal vaccines: a. trivalent vaccine contains an A/Michigan/45/2015 (H1N1)pdm09-like virus, an A/Hong Kong/4801/2014 (H3N2)-like virus, and a B/Brisbane/60/2008-like virus (B/Victoria lineage); and b. quadrivalent vaccine contains an additional B virus (B/Phuket/3073/2013-like virus [B/Yamagata lineage]);3. Quadrivalent live attenuated influenza vaccine (LAIV4) is not recommended for use in any setting in the United States during the 2017-2018 influenza season. This interim recommendation, originally made in 2016, followed observational data from the US Influenza Vaccine Effectiveness Network revealing that LAIV4 performed poorly against influenza A (H1N1)pdm09 viruses in recent influenza seasons;4. All children with an egg allergy of any severity can receive an influenza vaccine without any additional precautions beyond those recommended for any vaccine;5. All health care personnel should receive an annual seasonal influenza vaccine, a crucial step in preventing influenza and reducing health care-associated influenza infections, because health care personnel often care for individuals at high risk for influenza-related complications; and6. Pediatricians should attempt to promptly identify children suspected of having influenza infection for timely initiation of antiviral treatment, when indicated, to reduce morbidity and mortality. Best results are seen when treated within 48 hours of symptom onset. PMID- 28870978 TI - 10,000 Steps Australia: a community-wide eHealth physical activity promotion programme. PMID- 28870979 TI - NHS needs extra L350m to cope this winter, service providers say. PMID- 28870980 TI - Former health secretary is still pushing for justice over contaminated blood scandal. PMID- 28870981 TI - Acquired cardiovascular disease in adult patients with congenital heart disease. PMID- 28870982 TI - Understanding the effect of corticosteroid pretreatment in brain-dead organ donors: new mechanistic insights for improvement of organ quality in liver transplantation. AB - Transplant surgeons are currently faced with the challenge to accept marginal liver transplants due to steatosis or old age. Improving organ quality by implementing a selective organ protective donor management could be the first step towards a graft of enhanced quality. However, the molecular mechanisms of such treatments are still poorly understood. Glucocorticoid medication in donor medicine has been carried out and discussed for a long time. In a recent study published in Clinical Science, Jimenez-Castro et al. [Clin. Sci. (2017) 131, 733 746] demonstrate how liver histology and transplant liver function can be improved by administration of glucocorticoids to brain-dead donor rats with steatotic livers. This work illustrates the need for further trials in order to selectively improve the quality of steatotic livers with a potential for liver transplantation. PMID- 28870983 TI - Ischaemia as a cause of LVOT gradient reversal in HCM. AB - : We present the case of a previously fit 84-year-old female with long-standing systemic hypertension and the echo phenotype of hypertrophic cardiomyopathy (HCM) - asymmetrical septal hypertrophy, significant resting left ventricular (LV) outflow obstruction and mitral regurgitation (MR) secondary to systolic anterior motion (SAM) of the mitral valve. Valsalva provocation caused an increase in LVOT dynamic gradient and MR severity. The patient presented with a progressive decrease in exercise capacity along with chest pain relieved by rest or sublingual GTN. Exercise stress echo demonstrated a paradoxical response with reduction of both LVOT gradient and severity of MR. There was evidence of inducible regional wall motion abnormalities associated with no change in LV cavity size. Coronary angiogram revealed significant triple vessel disease. LEARNING POINTS: 20% of adult HCM patients over the age of 45 years have been shown to have coexistent coronary artery disease (CAD) that is associated with a reduced overall survival. Diagnosis of CAD in patients with HCM is difficult to make based on clinical grounds because of the high incidence of angina in patients with HCM but no CAD.Reduction of LVOT gradient with stress in patients with HCM (in the absence of a vaso-vagal response) may indicate ischaemia due to significant multivessel epicardial CAD, including left mainstem stenosis. Hence, this finding during stress echocardiography suggests that further investigation of the coronaries should be considered.Exercise stress echocardiography has not been validated for the assessment of ischaemia secondary to epicardial coronary disease in patients with HCM because ischaemia in this group of patients is often caused by multiple mechanisms, including microvascular ischaemia and myocardial bridging.Comparative assessment of rest and peak exercise 2D strain may add incremental value in identifying regional wall motion abnormalities, which may be difficult to distinguish by eye in hypertrophied, dynamic myocardium.A paradoxical response to exercise with significant decrease in LVOT obstruction and MR has been reported in the literature. This is often associated with a trend toward increased exercise capacity and better prognostic outcomes. Our clinical case presents a significant decrease in LVOT obstruction and MR that was associated with a trend toward reduced exercise capacity and was caused by ischaemia. PMID- 28870984 TI - Optimal follow-up strategies for adrenal incidentalomas: reappraisal of the 2016 ESE-ENSAT guidelines in real clinical practice. AB - OBJECTIVE: Recently, the European Society of Endocrinology (ESE), in collaboration with the European Network for the Study of Adrenal Tumors (ENSAT), asserted that adrenal incidentalomas (AIs) <4 cm and <=10 Hounsfield units (HU) do not require further follow-up imaging. To validate the clinical application of the follow-up strategies suggested by the 2016 ESE-ENSAT guidelines, we explored the clinical characteristics and natural course of AIs in a single center over 13 years. DESIGN AND METHODS: This retrospective cohort study included a total of 1149 patients diagnosed with AIs between 2000 and 2013 in a single tertiary center. Hormonal examination and radiological evaluations were performed at the initial diagnosis of AI and during the follow-up according to the appropriate guidelines. RESULTS: The mean age at diagnosis was 54.2 years, and the majority of AIs (68.0%) were nonfunctional lesions. Receiver operating curve analysis was used to discriminate malignant from benign lesions; the optimal cut-off value for mass size was 3.4 cm (sensitivity: 100%; specificity: 95.0%), and that for the pre-contrast HU was 19.9 (sensitivity: 100%; specificity: 67.4%). The majority of nonfunctional lesions did not change in size during the 4-year follow-up period. Applying a cut-off value of 1.8 MUg/dL after a 1-mg overnight dexamethasone suppression test, 28.0% of all nonfunctional AIs progressed to autonomous cortisol secretion during the follow-up period. However, we observed no development of overt Cushing's syndrome in the study. CONCLUSIONS: We advocate that no follow-up imaging is required if the detected adrenal mass is <4 cm and has clear benign features. However, prospective studies with longer follow-up are needed to confirm the appropriate follow-up strategies. PMID- 28870986 TI - Factors affecting seizure outcome after epilepsy surgery: an observational series. AB - IMPORTANCE: Surgical treatment can bring seizure remission in people with focal epilepsy but requires careful selection of candidates. OBJECTIVES: To determine which preoperative factors are associated with postoperative seizure outcome. DESIGN: We audited seizure outcome of 693 adults who had resective epilepsy surgery between 1990 and 2010 and used survival analysis to detect preoperatively identifiable risk factors of poor seizure outcome. RESULTS: Seven factors were significantly associated with increased probability of recurrence of seizures with impaired awareness postsurgery: MRI findings (eg, HR adjusted for other variables in the model 2.5; 95% CI 1.6 to 3.8 for normal MRI compared with hippocampal sclerosis), a history of secondarily generalised convulsive seizures (2.3; 95% CI 1.7 to 3.0 for these seizures in the previous year vs never), psychiatric history (1.3; 95% CI 1.1 to 1.7), learning disability (1.8; 95% CI 1.2 to 2.6) and extratemporal (vs temporal) surgery (1.4; 95% CI 1.02, 2.04). People with an older onset of epilepsy had a higher probability of seizure recurrence (1.01; 95% CI 1.00, 1.02) as did those who had used more antiepileptic drugs (1.05; 95% CI 1.01 to 1.09). Combinations of variables associated with seizure recurrence gave overall low probabilities of 5-year seizure freedom (eg, a normal MRI and convulsive seizures in the previous year has a probability of seizure freedom at 5 years of approximately 0.19). CONCLUSIONS AND RELEVANCE: Readily identified clinical features and investigations are associated with reduced probability of good outcome and need consideration when planning presurgical evaluation. PMID- 28870985 TI - Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity. AB - BACKGROUND: GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. OBJECTIVE: To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. METHODS: We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. RESULTS: A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. CONCLUSIONS: Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres. PMID- 28870987 TI - Maternal Dead-end 1 promotes translation of nanos1 by binding the eIF3 complex. AB - In the developing embryo, primordial germ cells (PGCs) represent the exclusive progenitors of the gametes, and their loss results in adult infertility. During early development, PGCs are exposed to numerous signals that specify somatic cell fates. To prevent somatic differentiation, PGCs must transiently silence their genome, an early developmental process that requires Nanos activity. However, it is unclear how Nanos translation is regulated in developing embryos. We report here that translation of nanos1 after fertilization requires Dead-end 1 (Dnd1), a vertebrate-specific germline RNA-binding protein. We provide evidence that Dnd1 protein, expression of which is low in oocytes, but increases dramatically after fertilization, directly interacts with, and relieves the inhibitory function of eukaryotic initiation factor 3f, a repressive component in the 43S preinitiation complex. This work uncovers a novel translational regulatory mechanism that is fundamentally important for germline development. PMID- 28870988 TI - A fluorescent toolkit for spatiotemporal tracking of apoptotic cells in living Drosophila tissues. AB - Far from being passive, apoptotic cells influence their environment. For example, they promote tissue folding, myoblast fusion and modulate tumor growth. Understanding the role of apoptotic cells necessitates their efficient tracking within living tissues, a task that is currently challenging. In order to easily spot apoptotic cells in developing Drosophila tissues, we generated a series of fly lines expressing different fluorescent sensors of caspase activity. We show that three of these reporters (GFP-, Cerulean- and Venus-derived molecules) are detected specifically in apoptotic cells and throughout the whole process of programmed cell death. These reporters allow the specific visualization of apoptotic cells directly within living tissues, without any post-acquisition processing. They overcome the limitations of other apoptosis detection methods developed so far and, notably, they can be combined with any kind of fluorophore. PMID- 28870990 TI - Three-dimensional automated reporter quantification (3D-ARQ) technology enables quantitative screening in retinal organoids. AB - The advent of stem cell-derived retinal organoids has brought forth unprecedented opportunities for developmental and physiological studies, while presenting new therapeutic promise for retinal degenerative diseases. From a translational perspective, organoid systems provide exciting new prospects for drug discovery, offering the possibility to perform compound screening in a three-dimensional (3D) human tissue context that resembles the native histoarchitecture and to some extent recapitulates cellular interactions. However, inherent variability issues and a general lack of robust quantitative technologies for analyzing organoids on a large scale pose severe limitations for their use in translational applications. To address this need, we have developed a screening platform that enables accurate quantification of fluorescent reporters in complex human iPSC derived retinal organoids. This platform incorporates a fluorescence microplate reader that allows xyz-dimensional detection and fine-tuned wavelength selection. We have established optimal parameters for fluorescent reporter signal detection, devised methods to compensate for organoid size variability, evaluated performance and sensitivity parameters, and validated this technology for functional applications. PMID- 28870991 TI - The receptor protein tyrosine phosphatase PTPRB negatively regulates FGF2 dependent branching morphogenesis. AB - PTPRB is a transmembrane protein tyrosine phosphatase known to regulate blood vessel remodelling and angiogenesis. Here, we demonstrate that PTPRB negatively regulates branching morphogenesis in the mouse mammary epithelium. We show that Ptprb is highly expressed in adult mammary stem cells and also, although at lower levels, in oestrogen receptor-positive luminal cells. During mammary development, Ptprb expression is downregulated during puberty, a period of extensive ductal outgrowth and branching. In vivo shRNA knockdown of Ptprb in the cleared mammary fat pad transplant assay resulted in smaller epithelial outgrowths with an increased branching density and also increased branching in an in vitro organoid assay. Organoid branching was dependent on stimulation by FGF2, and Ptprb knockdown in mammary epithelial cells resulted in a higher level of fibroblast growth factor receptor (FGFR) activation and ERK1/2 phosphorylation, both at baseline and following FGF2 stimulation. Therefore, PTPRB regulates branching morphogenesis in the mammary epithelium by modulating the response of the FGFR signalling pathway to FGF stimulation. Considering the importance of branching morphogenesis in multiple taxa, our findings have general importance outside mammary developmental biology. PMID- 28870989 TI - A stepwise model of reaction-diffusion and positional information governs self organized human peri-gastrulation-like patterning. AB - How position-dependent cell fate acquisition occurs during embryogenesis is a central question in developmental biology. To study this process, we developed a defined, high-throughput assay to induce peri-gastrulation-associated patterning in geometrically confined human pluripotent stem cell (hPSC) colonies. We observed that, upon BMP4 treatment, phosphorylated SMAD1 (pSMAD1) activity in the colonies organized into a radial gradient. We developed a reaction-diffusion (RD) based computational model and observed that the self-organization of pSMAD1 signaling was consistent with the RD principle. Consequent fate acquisition occurred as a function of both pSMAD1 signaling strength and duration of induction, consistent with the positional-information (PI) paradigm. We propose that the self-organized peri-gastrulation-like fate patterning in BMP4-treated geometrically confined hPSC colonies arises via a stepwise model of RD followed by PI. This two-step model predicted experimental responses to perturbations of key parameters such as colony size and BMP4 dose. Furthermore, it also predicted experimental conditions that resulted in RD-like periodic patterning in large hPSC colonies, and rescued peri-gastrulation-like patterning in colony sizes previously thought to be reticent to this behavior. PMID- 28870992 TI - Cell migration, intercalation and growth regulate mammalian cochlear extension. AB - Developmental remodeling of the sensory epithelium of the cochlea is required for the formation of an elongated, tonotopically organized auditory organ, but the cellular processes that mediate these events are largely unknown. We used both morphological assessments of cellular rearrangements and time-lapse imaging to visualize cochlear remodeling in mouse. Analysis of cell redistribution showed that the cochlea extends through a combination of radial intercalation and cell growth. Live imaging demonstrated that concomitant cellular intercalation results in a brief period of epithelial convergence, although subsequent changes in cell size lead to medial-lateral spreading. Supporting cells, which retain contact with the basement membrane, exhibit biased protrusive activity and directed movement along the axis of extension. By contrast, hair cells lose contact with the basement membrane, but contribute to continued outgrowth through increased cell size. Regulation of cellular protrusions, movement and intercalation within the cochlea all require myosin II. These results establish, for the first time, many of the cellular processes that drive the distribution of sensory cells along the tonotopic axis of the cochlea. PMID- 28870993 TI - Klf5 maintains the balance of primitive endoderm versus epiblast specification during mouse embryonic development by suppression of Fgf4. AB - The inner cell mass of the mouse blastocyst gives rise to the pluripotent epiblast (EPI), which forms the embryo proper, and the primitive endoderm (PrE), which forms extra-embryonic yolk sac tissues. All inner cells coexpress lineage markers such as Nanog and Gata6 at embryonic day (E) 3.25, and the EPI and PrE precursor cells eventually segregate to exclusively express Nanog and Gata6, respectively. Fibroblast growth factor (FGF)-extracellular signal-regulated kinase (ERK) signalling is involved in segregation of the EPI and PrE lineages; however, the mechanism involved in Fgf4 regulation is poorly understood. Here, we identified Klf5 as an upstream repressor of Fgf4Fgf4 was markedly upregulated in Klf5 knockout (KO) embryos at E3.0, and was downregulated in embryos overexpressing Klf5 Furthermore, Klf5 KO and overexpressing blastocysts showed skewed lineage specification phenotypes, similar to FGF4-treated preimplantation embryos and Fgf4 KO embryos, respectively. Inhibitors of the FGF receptor (Fgfr) and ERK pathways reversed the skewed lineage specification of Klf5 KO blastocysts. These data demonstrate that Klf5 suppresses Fgf4-Fgfr-ERK signalling, thus preventing precocious activation of the PrE specification programme. PMID- 28870995 TI - One hundred years on: Ypres and ATLS. PMID- 28870994 TI - Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia. AB - Elongation factor, RNA polymerase II, 2 (ELL2) is an RNA Pol II elongation factor with functional properties similar to ELL that can interact with the prostate tumor suppressor EAF2. In the prostate, ELL2 is an androgen response gene that is upregulated in benign prostatic hyperplasia (BPH). We recently showed that ELL2 loss could enhance prostate cancer cell proliferation and migration, and that ELL2 gene expression was downregulated in high Gleason score prostate cancer specimens. Here, prostate-specific deletion of ELL2 in a mouse model revealed a potential role for ELL2 as a prostate tumor suppressor in vivoEll2-knockout mice exhibited prostatic defects including increased epithelial proliferation, vascularity and PIN lesions similar to the previously determined prostate phenotype in Eaf2-knockout mice. Microarray analysis of prostates from Ell2 knockout and wild-type mice on a C57BL/6J background at age 3 months and qPCR validation at 17 months of age revealed a number of differentially expressed genes associated with proliferation, cellular motility and epithelial and neural differentiation. OncoPrint analysis identified combined downregulation or deletion in prostate adenocarcinoma cases from the Cancer Genome Atlas (TCGA) data portal. These results suggest that ELL2 and its pathway genes likely play an important role in the development and progression of prostate cancer. PMID- 28870996 TI - Vestigial-like 3 is a novel Ets1 interacting partner and regulates trigeminal nerve formation and cranial neural crest migration. AB - Drosophila Vestigial is the founding member of a protein family containing a highly conserved domain, called Tondu, which mediates their interaction with members of the TEAD family of transcription factors (Scalloped in Drosophila). In Drosophila, the Vestigial/Scalloped complex controls wing development by regulating the expression of target genes through binding to MCAT sequences. In vertebrates, there are four Vestigial-like genes, the functions of which are still not well understood. Here, we describe the regulation and function of vestigial-like 3 (vgll3) during Xenopus early development. A combination of signals, including FGF8, Wnt8a, Hoxa2, Hoxb2 and retinoic acid, limits vgll3 expression to hindbrain rhombomere 2. We show that vgll3 regulates trigeminal placode and nerve formation and is required for normal neural crest development by affecting their migration and adhesion properties. At the molecular level, vgll3 is a potent activator of pax3, zic1, Wnt and FGF, which are important for brain patterning and neural crest cell formation. Vgll3 interacts in the embryo with Tead proteins but unexpectedly with Ets1, with which it is able to stimulate a MCAT driven luciferase reporter gene. Our findings highlight a critical function for vgll3 in vertebrate early development. PMID- 28870997 TI - The Evolution, Functions and Applications of the Breast Cancer Genes BRCA1 and BRCA2. AB - BRCA1 and BRCA2 are both tumor suppressors whose mutations are the cause of most hereditary breast cancers. Both genes are highly involved in ensuring genome stability. BRCA1 homologs are found in the plant and animal kingdoms while BRCA2 homologs are additionally found in the fungi kingdom. The initial origin of both genes remains unknown, however it is expected that the common ancestors originated around 1.6 billion years ago prior to the kingdoms diverging. There has been a great amount of divergence between homologs that is not observed in other tumor suppressors with only functionally important domains conserved. This divergence continues today with evidence of primate BRCA1/2 evolution. Cancer associated mutations have been found to occur at conserved sites, indicating that conserved sites are important for function. In this study, we present a review on the phylogenesis of BRCA1 and BRCA2. PMID- 28870999 TI - Chemical Proteomic Approaches Targeting Cancer Stem Cells: A Review of Current Literature. AB - Cancer stem cells (CSCs) have been proposed as central drivers of tumor initiation, progression, recurrence, and therapeutic resistance. Therefore, identifying stem-like cells within cancers and understanding their properties is crucial for the development of effective anticancer therapies. Recently, chemical proteomics has become a powerful tool to efficiently determine protein networks responsible for CSC pathophysiology and comprehensively elucidate molecular mechanisms of drug action against CSCs. This review provides an overview of major methodologies utilized in chemical proteomic approaches. In addition, recent successful chemical proteomic applications targeting CSCs are highlighted. Future direction of potential CSC research by integrating chemical genomic and proteomic data obtained from a single biological sample of CSCs are also suggested in this review. PMID- 28871000 TI - Low Levels of Microsatellite Instability at Simple Repeated Sequences Commonly Occur in Human Hepatocellular Carcinoma. AB - BACKGROUND/AIM: The aim of this study was to assess the incidence of MSI in a large series of human hepatocellular carcinomas (HCC) with various etiologies. MATERIALS AND METHODS: The MSI status was determined by polymerase chain reaction (PCR) using 5 mononucleotide and 13 CAn dinucleotide repeats. RESULTS: None of the 122 HCC samples displayed an MSI-High phenotype, as defined by the presence of alterations at more than 30% of the microsatellite markers analyzed. Yet, limited microsatellite instability consisting in the insertion or deletion of a few repeat motifs was detected in 32 tumor samples (26.2%), regardless of the etiology of the underlying liver disease. MSI tended to be higher in patients with cirrhosis (p=0.051), possibly reflecting an impact of the inflammatory context in this process. CONCLUSION: Based on a large series of HCC with various etiologies, our study allowed us to definitely conclude that MSI is not a hallmark of HCC. PMID- 28870998 TI - Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises. AB - Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 gene. It comprises approximately 15-20% of breast cancers (BCs). Unfortunately, TNBC's treatment continues to be a clinical problem because of its relatively poor prognosis, its aggressiveness and the lack of targeted therapies, leaving chemotherapy as the mainstay of treatment. It is essential to find new therapies against TNBC, in order to surpass the resistance and the invasiveness of already existing therapies. Given the fact that epigenetic processes control both the initiation and progression of TNBC, there is an increasing interest in the mechanisms, molecules and signaling pathways that participate at the epigenetic modulation of genes expressed in carcinogenesis. The acetylation of histone proteins provokes the transcription of genes involved in cell growth, and the expression of histone deacetylases (HDACs) is frequently up-regulated in many malignancies. Unfortunately, in the field of BC, HDAC inhibitors have shown limited effect as single agents. Nevertheless, their use in combination with kinase inhibitors, autophagy inhibitors, ionizing radiation, or two HDAC inhibitors together is currently being evaluated. HDAC inhibitors such as suberoylanilidehydroxamic acid (SAHA), sodium butyrate, mocetinostat, panobinostat, entinostat, YCW1 and N-(2-hydroxyphenyl)-2 propylpentanamide have shown promising therapeutic outcomes against TNBC, especially when they are used in combination with other anticancer agents. More studies concerning HDAC inhibitors in breast carcinomas along with a more accurate understanding of the TNBC's pathobiology are required for the possible identification of new therapeutic strategies. PMID- 28871001 TI - Colitic Cancer Develops Through Mutational Alteration Distinct from that in Sporadic Colorectal Cancer: A Comparative Analysis of Mutational Rates at Each Step. AB - BACKGROUND: Patients with ulcerative colitis (UC) are at risk of UC-associated colorectal cancer (CRC); however, little is known about genetic alterations occurring during UC carcinogenesis. We examined mutational changes in patients with colitic cancer and the features that differed between the carcinogenesis of UC and sporadic CRC. MATERIAL AND METHODS: Specimens were obtained from the non neoplastic mucosa and cancer cells of 12 patients with colitic cancer. The mutational rate of oncogenes in colitic cancer was analyzed and compared to that of oncogenes in sporadic CRC. RESULTS: We observed a lower mutation rate in adenomatous polyposis coli (APC) (16.7%(2/12) vs. 75.9%(161/212), respectively, p=0.0001) and KRAS (16.7%(2/12) vs. 42% (89/212), respectively, p=0.04) in colitic cancer than in sporadic CRC. With respect to cadherin 1 (CDH1) and fibroblast growth factor receptor 2 (FGFR2), the mutational rates for non neoplastic colorectal mucosa were similar to those in sporadic CRC. CONCLUSION: We demonstrated that mutational rates for APC and KRAS differ between colitic cancer and sporadic CRC. Furthermore, we revealed that CDH1 and FGFR2 become mutated at an earlier stage in colitic carcinogenesis than in sporadic CRC. PMID- 28871002 TI - Trichostatin A Sensitizes Hepatocellular Carcinoma Cells to Enhanced NK Cell mediated Killing by Regulating Immune-related Genes. AB - BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. The ability of HCC to avoid immune detection is considered one of the main factors making it difficult to cure. Abnormal histone deacetylation is thought to be one of the mechanisms for HCC immune escape, making histone deacetylases (HDACs) attractive targets for HCC treatment. Here, we investigated the effect of trichostatin A (TSA), a highly potent HDAC inhibitor, on HCC (HepG2) gene expression and function. MATERIALS AND METHODS: A genome wide-transcriptional microarray was used to identify genes regulated by TSA in HepG2 cells. Gene Ontology was used to identify pathways regulated by TSA, and these changes were confirmed by qPCR. The effect of TSA on natural killer (NK) cell-mediated killing of HCC cell lines were analyzed by both flow cytometry and LDH cytotoxicity assay. A study was also conducted in a Balb/c nude mice xenograft model to assess the anti-tumor activity of TSA. RESULTS: TSA regulated the transcription of numerous innate immunity & tumor antigen recognition associated genes, such as ULBP1 and RAET1G, in HCC cells. In vivo, TSA reduced tumor cell growth in an NK cell-dependent manner. In vitro, TSA treatment of HepG2 cells rendered them more susceptible to NK cell-mediated killing while increasing the expression of NKGD2 ligands, including ULBP1/2/3 and MICA/B. TSA also induced direct killing of HCC cells by stimulating apoptosis. CONCLUSION: TSA likely increases killing of HCC cells indirectly by increasing NK cell directed killing and directly by increasing apoptosis. PMID- 28871004 TI - miR18a and miR19a Recruit Specific Proteins for Splicing in Thyroid Cancer Cells. AB - BACKGROUND: Thyroid cancer is one of the most frequent types of endocrine cancers. In most cases, thyroid cancers are caused by deregulated miRNA expression, especially involving the miR17-92 cluster. miR17-92 transcription is altered in several different tumor types including lymphoma, leukemia, and of the breast and thyroid. As an intronic cluster, miR17-92 must be processed during splicing and therefore interaction between microprocessor and spliceosome machineries is of major importance in understanding its expression. MATERIALS AND METHODS: We investigated the protein composition of spliceosomes assembled on pre RNAs containing intronic miR18a and miR19a, components of the miR17-92 cluster, using mass spectrometry. RESULTS: Interestingly, we observed that proteins associated with intronic miR18a and miR19a are cell-specific, and are similar for both miRNAs analyzed. The only exception is the group of heterogeneous nuclear proteins that are commonly recruited by different cells. CONCLUSION: miRNA processing depends on cell-specific proteins and heterogeneous nuclear proteins have a general role in miRNA processing from introns. PMID- 28871003 TI - Association Between RASSF1A Promoter Methylation and Testicular Germ Cell Tumor: A Meta-analysis and a Cohort Study. AB - BACKGROUND: The RAS association domain family protein 1a (RASSF1A) is a prominent tumor suppressor gene showing altered promoter methylation in testicular germ cell tumors (TGCT). RASSF1A promoter hypermethylation might represent an early event in TGCT tumorigenesis. We investigated whether the RASSF1A promoter methylation in peripheral blood of TGCT patients can be associated with testicular cancer risk. MATERIALS AND METHODS: Following a meta-analysis, we performed a cohort study including 32 testicular cancer patients and 32 healthy controls. Promoter methylation of the RASSF1A and O6-methylguanine-DNA methyltransferase (MGMT) genes was analyzed using bisulfite pyrosequencing of DNA from peripheral blood. RESULTS: Meta-analysis showed an odds ratio (OR) of 7.69 for RASSF1A promoter methylation as a risk factor for TGCT. Cohort study found altered methylation of the RASSF1A promoter in blood of TGCT patients. Methylation was higher in TGCT patients before BEP chemotherapy. CONCLUSION: The meta-analysis indicates a role of the RASSF1A promoter hypermethylation from peripheral blood in TCGT. We confirmed that finding in our cohort study, which represents the first report of changed RASSF1A promoter methylation in peripheral blood TGCT. PMID- 28871005 TI - Evaluation of Podoplanin Expression in Hepatocellular Carcinoma Using RNAscope and Immunohistochemistry - A Preliminary Report. AB - BACKGROUND: Podoplanin (PDPN), a mucin-type transmembrane glycoprotein, is expressed in a variety of human cancer types, and contributes to tumor progression. Our goal was to evaluate PDPN expression in hepatocellular carcinoma (HCC) using both immunohistochemistry (IHC) and RNAscope in situ hybridization. MATERIALS AND METHODS: Twenty patients with HCC who underwent partial hepatectomy with curative intent were retrospectively analyzed. RESULTS: IHC gave positive results in 11 cases, while RNAscope assay for PDPN detected amplification in 16 cases. A significant association was noted between PDPN protein expression and histological tumor grade (p=0.036). Four cases that had negative PDPN results by RNAscope were also negative by IHC, while the remaining five cases with negative results by IHC were positive by RNAscope. A positive relationship was found between PDPN mRNA protein expression (p<0.001). CONCLUSION: Our preliminary results suggest that PDPN contributes to the malignant potential of HCC. RNAscope proved to be a more sensitive and reliable method than IHC in PDPN detection. PMID- 28871007 TI - Occurrence of depressive tendency and associated social factors among elderly persons forced by the Great East Japan Earthquake and nuclear disaster to live as long-term evacuees: a prospective cohort study. AB - PURPOSE: This study examined the incidence of depression and associated factors among elderly persons from Iitate village after the March 2011 earthquake. METHOD: This was a prospective cohort study. As a baseline survey, in May 2010 a self-assessment Basic Checklist (BCL) was distributed to 1611 elderly villagers, of which 1277 responded. Of these respondents, 885 without a tendency to depression (69.3%) were given a follow-up survey in May 2013. The BCL was used to assess depression tendency, instrumental activities of daily living (IADL), physical function, nutritional status, oral function, homeboundness, cognitive function and social activities. Univariate analysis was used to examine differences in risk between those with a presence of depression tendency (PDT) and those without (non-PDT) depending on demographic and BCL variables. Variables found to be significant were analysed by Poisson regression analysis. RESULTS: Of the 438 respondents in the second survey, 163 (37.2%) showed depression tendency. PDT risk was significantly increased by female gender, age, history of diabetes and cognitive disorder. It was significantly reduced by increased IADL. Engagement in social activities decreased PDT risk in rental accommodation. DISCUSSION: Renters faced a higher risk of PDT than persons evacuated in groups to purpose-built housing. The inclusion of social activities in the multivariate Poisson regression analysis weakened this effect. Female gender, a history of diabetes, reduced IADL and a tendency to cognitive disorder each independently affected PDT risk. These findings may inform future responses to earthquakes and the technical disasters that may accompany them. PMID- 28871006 TI - Post-transcriptional Regulation of MMP16 and TIMP2 Expression via miR-382, miR 410 and miR-200b in Endometrial Cancer. AB - BACKGROUND/AIM: The post-transcriptional regulation of matrix metalloproteinases (MMPs) via microRNAs (miRNAs) has been recently described in numerous human malignancies. However, the exact mechanisms of miRNA-mediated MMPs deregulation in endometrial cancer (EC) remain unclear. Herein, we aimed to analyze the expression of MMP2, MMP16 and TIMP2 and identify miRNAs that modulate their expression. MATERIALS AND METHODS: Protein expression was assessed by immunohistochemistry in formalin-fixed paraffin-embedded EC samples. Target prediction algorithms were applied to select miRNAs binding the 3'UTRs of MMP16 (miR-377, miR-382, miR-410, miR-200b) or TIMP2 (miR-200b), and their levels were measured by qPCR in laser capture-microdissected tissue fragments. Luciferase assays and western blotting were used to indicate individual miRNA- mRNA interactions. RESULTS: Overexpression of MMP2 and MMP16 in cancerous tissues corresponded to down-regulation of miR-377, miR-382 and miR-410, while decreased expression of TIMP2 was associated with miR-200b up-regulation. In vitro experiments confirmed direct regulation of MMP16 by miR-382 and miR-410, and TIMP2 by miR-200b in EC Ishikawa cells. CONCLUSION: We demonstrated novel mechanisms of miRNA-mediated regulation of MMPs activity in EC. PMID- 28871008 TI - Can health indicators and psychosocial characteristics predict attrition in youths with overweight and obesity seeking ambulatory treatment? Data from a retrospective longitudinal study in a paediatric clinic in Luxembourg. AB - OBJECTIVES: The current study aimed to identify factors that could predict attrition in youths starting ambulatory treatment to control or lose weight. DESIGN: Retrospective longitudinal study. SETTING: Paediatric clinic: ambulatory treatment programme. PATIENTS AND MEASURES: A youth sample (n=191; 89 boys; aged 7-17 years) completed measures of demographic characteristics, and health and psychosocial traits before starting an ambulatory weight management programme. Anthropometric and biological markers related to obesity were also obtained. Tests of mean differences and regression analyses were used to investigate the relationship between these variables and attrition after 1 year. RESULTS: The chi2and t test results showed both psychosocial and health indicators differentiated between participants who continued attending the treatment programme and those who dropped out. More specifically, youths that dropped out of treatment were significantly older, had higher body mass index z scores, higher levels of insulin, triglycerides and HOMA-IR, reported poorer health, had more conduct problems and were more dissatisfied with themselves and their bodies before starting treatment. Results of regression analyses revealed that weight status (anthropometric and biological markers), age and body dissatisfaction predicted attrition (overall prediction success 73%; prediction success for continued attendance 90/91%; prediction success for dropouts 42/44%). CONCLUSION: Attrition, but especially the continued attendance in treatment, can be successfully predicted by age, weight status and body dissatisfaction. For patients who present with one or more risk factors, careful consideration is needed to decide which (combination of) inpatient or outpatient programme may facilitate prolonged engagement of the patient and hence may be most effective in establishing weight loss. PMID- 28871009 TI - Guideline use behaviours and needs of primary care practitioners in China: a cross-sectional survey. AB - OBJECTIVES: Clinical guidelines have been recognised as an effective way to improve healthcare performance. However, little is known about the uptake and implementation of guidelines by general practitioners in China. The aim of this study was to investigate the guideline use behaviours and needs of practitioners in primary care settings in China. METHODS: We conducted a cross-sectional survey from December 2015 to May 2016 that included practitioners at 268 institutions in 15 provinces in China. Questionnaire development was informed by the execution of a literature review and consultation of experts. On-site surveys were implemented using a paper questionnaire to minimise missing responses. A multivariate logistic regression analysis was performed to identify factors associated with provider knowledge of and attitudes towards clinical guidelines. RESULTS: Of the respondents, 91.7% (1568/1708) were aware of clinical guidelines, but only 11.3% (177/1568) frequently used them. The main mechanism by which primary care practitioners accessed guidelines was public search engines (63.4%; 911/1438), and practitioners seldom reported using biomedical databases. The most frequently identified barriers to guideline use were lack of training (49.9%; 778/1560), lack of access (44.6%; 696/1560) and lack of awareness (38.0%; 592/1560). Less than one-quarter of respondents considered current guidelines 'entirely appropriate' for use in primary care (23.5%; 339/1442). Most participants (96.2%; 1509/1568) believed it was necessary to develop primary care guidelines. Provider attitudes towards current guidelines were associated with the location and level of the institution and professional title of the practitioner (p<0.05). CONCLUSION: Our survey revealed poor knowledge and uptake of clinical guidelines in primary care, and we identified a gap between the needs of practitioners and availability of clinical guidelines for use in primary care in China. In addition, lacking access to and training in guidelines also prevented primary healthcare practitioners from using guidelines in daily practice. PMID- 28871010 TI - Exploring the association between chorangioma and infantile haemangioma in singleton and multiple pregnancies: a case-control study in a Swedish tertiary centre. AB - OBJECTIVES: Placenta or placental chorangioma could be the origin site of infantile haemangioma since they share various histochemical and genetic characteristics with placental vascular tissue. The aim of the current study was to investigate the association between chorangiomas and infantile haemangiomas in singleton and multiple pregnancies. MATERIALS AND METHODS: An informative questionnaire enquiring about the presence or not of infantile haemangioma and including illustrative photos of haemangioma was sent to 469 (153 cases with chorangioma and 316 controls) mothers of 323 singleton (104 cases and 219 controls) and 146 multiple (49 cases and 97 controls) liveborn neonates registered in Sweden. Overall, 310 mothers (66.1%) from 216 singleton and 94 multiple pregnancies (96 cases and 214 controls) provided feedback and their consent to participate in the current case-control study. RESULTS: The incidence of infantile haemangioma showed no statistically significant differences between cases and controls (18.8% vs 18.2%) or between singleton and multiple pregnancies (18.9% vs 17.0%). The frequency of pre-eclampsia was significantly higher in cases with chorangioma compared with controls (41.7% vs 24.3%, OR=2.22, 95% CI 1.33 to 3.71, p=0.0022) and in singleton compared with multiple pregnancies (33.3% vs 21.3%, OR=1.85, 95% CI 1.04 to 3.26, p=0.034), whereas there were no significant differences in the incidence of infantile haemangioma in neonates of mothers with or without pre-eclampsia or in neonates of mothers with multiple compared with singleton pregnancies. CONCLUSION: There was no association between placental chorangiomas and infantile haemangiomas. Multiple pregnancies or pre eclampsia were not significantly related to higher incidence of infantile haemangioma. PMID- 28871011 TI - Economic impact of ulipristal acetate on surgical procedures for uterine fibroids in France. AB - OBJECTIVE: To assess the budget impact of using ulipristal acetate (UPA) 5 mg to treat women with uterine fibroids (UF) causing moderate to severe symptoms. DESIGN: We modelled trends in the number of surgical procedures for symptomatic UF, with and without the use of UPA for preoperative or intermittent treatment and assessed the budget impact of UPA use from the French national healthcare insurance system perspective. SETTING: A French national hospital database (PMSI) that records admissions and relative procedures to public and private hospitals. PARTICIPANTS: Women eligible for surgical procedures for uterine fibroids. MAIN OUTCOME MEASURES: Economic impact of UPA treatment. RESULTS: This study based on observational retrospective data shows that the current use of UPA in its preoperative indication was associated with 5645 fewer surgeries from 2013 to 2015. Extrapolation suggests 17 885 fewer surgeries from 2016 to 2019. Overall, preoperative use of UPA results in substantial cost savings for the French national healthcare insurance system, with a cumulated budget impact estimated at ?-5 million from 2013 to 2015 and ?-13.5 million from 2016 to 2019. In addition, treating women nearing the menopause (>=48 years old) with intermittent treatment from 2017 to 2019 could produce an incremental cost saving of ?19 million. CONCLUSIONS: This study shows that the use of UPA in women eligible for surgical procedures for UF is associated with considerable savings for the French national healthcare insurance system in both preoperative and intermittent indications by decreasing the need to perform surgeries. PMID- 28871012 TI - Performance of a postnatal metabolic gestational age algorithm: a retrospective validation study among ethnic subgroups in Canada. AB - OBJECTIVES: Biological modelling of routinely collected newborn screening data has emerged as a novel method for deriving postnatal gestational age estimates. Validation of published models has previously been limited to cohorts largely consisting of infants of white Caucasian ethnicity. In this study, we sought to determine the validity of a published gestational age estimation algorithm among recent immigrants to Canada, where maternal landed immigrant status was used as a surrogate measure of infant ethnicity. DESIGN: We conducted a retrospective validation study in infants born in Ontario between April 2009 and September 2011. SETTING: Provincial data from Ontario, Canada were obtained from the Institute for Clinical Evaluative Sciences. PARTICIPANTS: The dataset included 230 034 infants born to non-landed immigrants and 70 098 infants born to immigrant mothers. The five most common countries of maternal origin were India (n=10 038), China (n=7468), Pakistan (n=5824), The Philippines (n=5441) and Vietnam (n=1408). Maternal country of origin was obtained from Citizenship and Immigration Canada's Landed Immigrant Database. PRIMARY AND SECONDARY OUTCOME MEASURES: Performance of a postnatal gestational age algorithm was evaluated across non-immigrant and immigrant populations. RESULTS: Root mean squared error (RMSE) of 1.05 weeks was observed for infants born to non-immigrant mothers, whereas RMSE ranged from 0.98 to 1.15 weeks among infants born to immigrant mothers. Area under the receiver operating characteristic curve for distinguishing term versus preterm infants (>=37 vs <37 weeks gestational age or >34 vs <=34 weeks gestational age) was 0.958 and 0.986, respectively, in the non immigrant subgroup and ranged from 0.927 to 0.964 and 0.966 to 0.99 in the immigrant subgroups. CONCLUSIONS: Algorithms for postnatal determination of gestational age may be further refined by development and validation of region or ethnicity-specific models. However, our results provide reassurance that an algorithm developed from Ontario-born infant cohorts performs well across a range of ethnicities and maternal countries of origin without modification. PMID- 28871013 TI - Understanding symptom appraisal and help-seeking in people with symptoms suggestive of pancreatic cancer: a qualitative study. AB - OBJECTIVE: Pancreatic cancer has poor survival rates due to non-specific symptoms leading to later diagnosis. Understanding how patients interpret their symptoms could inform approaches to earlier diagnosis. This study sought to explore symptom appraisal and help-seeking among patients referred to secondary care for symptoms suggestive of pancreatic cancer. DESIGN: Qualitative analysis of semistructured in-depth interviews. Data were analysed iteratively and thematically, informed by the Model of Pathways to Treatment. PARTICIPANTS AND SETTING: Pancreatic cancer occurs rarely in younger adults, therefore patients aged >=40 years were recruited from nine hospitals after being referred to hospital with symptoms suggestive of pancreatic cancer; all were participants in a cohort study. Interviews were conducted soon after referral, and where possible, before diagnosis. RESULTS: Twenty-six interviews were conducted (cancer n=13 (pancreas n=9, other intra-abdominal n=4), non-cancer conditions n=13; age range 48-84 years; 14 women). Time from first symptoms to first presentation to healthcare ranged from 1 day to 270 days, median 21 days. We identified three main themes. Initial symptom appraisal usually began with intermittent, non specific symptoms such as tiredness or appetite changes, attributed to diet and lifestyle, existing gastrointestinal conditions or side effects of medication. Responses to initial symptom appraisal included changes in meal type or frequency, or self-medication. Symptom changes such as alterations in appetite and enjoyment of food or weight loss usually prompted further appraisal. Triggers to seek help included a change or worsening of symptoms, particularly pain, which was often a 'tipping point'. Help-seeking was often encouraged by others. We found no differences in symptom appraisal and help-seeking between people diagnosed with cancer and those with other conditions. CONCLUSIONS: Greater public and healthcare professional awareness of the combinations of subtle and intermittent symptoms, and their evolving nature, is needed to prompt timelier help-seeking and investigation among people with symptoms of pancreatic cancer. PMID- 28871014 TI - Prevalence of stroke and associated risk factors: a population based cross sectional study from northeast China. AB - OBJECTIVES: Epidemiological studies aimed at stroke and its risk factors can help identify persons at higher risk and therefore promote stroke prevention strategies. We aimed to explore the current prevalence of stroke and its associated risk factors in northeast China. DESIGN: Population based cross sectional study. SETTING: Data were collected using a structured precoded questionnaire designed by the Stroke Screening and Prevention Programme of the National Health and Family Planning Commission of China, between January and March 2016. PARTICIPANTS: 4100 permanent residents, aged 40 years or older, who had lived in Dehui City of Jilin Province for more than 6 months volunteered to participate in the survey, with a response rate of 92.2%. For the purpose of the present analysis, 48 subjects were excluded due to missing values, giving a total of 4052 people included in this analysis. MAIN OUTCOME MEASURE: The questionnaire included demographic characteristics, stroke related behavioural factors, personal and family medical history of stroke, physical examination and laboratory testing. RESULTS: The overall prevalence of stroke in Jilin Province was 7.2% (95% CI 6.3% to 8.2%). Of all stroke cases, 91.7% (95% CI 87.4% to 94.6%) were ischaemic stroke and 8.3% (95% CI 5.4% to 12.6%) were haemorrhagic stroke. The prevalence rates of dyslipidaemia, smoking and hypertension were ranked as the top three cerebrovascular risk factors and were 62.1%, 61.8% and 57.3%, respectively. We found that hypertension, dyslipidaemia and lack of exercise were associated with ischaemic stroke. However, only hypertension (OR=4.064, 95% CI 1.358 to 12.160) was significantly associated with haemorrhagic stroke. CONCLUSIONS: The prevalence of stroke, especially ischaemic stroke, and associated cerebrovascular risk factors among adults aged 40 years or older in northeast China were high. A higher regional prevalence of hypertension, dyslipidaemia and lack of exercise may be responsible. PMID- 28871015 TI - Impact of chronic obstructive pulmonary disease on patients with aortic aneurysms: a nationwide retrospective cohort study in Taiwan. AB - OBJECTIVES: Aortic aneurysm (AA) is a leading cause of death worldwide. Chronic obstructive pulmonary disease (COPD) is a risk factor for AA, and the prognoses of COPD patients with AA who underwent/did not undergo an operation warrant investigation. DESIGN: A nationwide retrospective cohort study. SETTING: We included patients with AA older than 18 years who received their first AA diagnosis between 2005 and 2011 in Taiwan. PARTICIPANTS: This study enrolled 3263 COPD patients with AA before propensity score matching and 2127 COPD patients with AA after propensity score matching. OUTCOME MEASURES: The main outcomes were all-cause mortality and rehospitalisation for AA or operation. The outcomes of COPD patients with AA and COPD patients without AA during an 8-year follow-up period were examined using Cox proportional hazards models. RESULTS: In the AA population, patients with COPD showed higher rates of mortality and rehospitalisation than patients without COPD with adjusted HRs of 1.12 (95% CI 1.03 to 1.22) and 1.11 (95% CI 1.01 to 1.23), respectively, after propensity score matching. Analysis of the patients who underwent an operation revealed that the rates of mortality of COPD and non-COPD patients were not significantly different. In contrast, among the patients who did not receive an operation, patients with COPD showed a higher mortality rate than patients without COPD with an adjusted HR of 1.11 (95% CI 1.0 to 1.22). CONCLUSIONS: The outcomes of COPD patients with AA undergoing an operation were improved, but the mortality rate of non-COPD patients with AA remained high. An effective treatment to reduce mortality in this group warrants further investigation. PMID- 28871016 TI - Health-related quality of life in residents aged 18 years and older with and without disease: findings from the First Provincial Health Services Survey of Hunan, China. AB - OBJECTIVE: Published research has not considered acute diseases and injuries in assessing the impact of varying disease counts on health-related quality of life (HRQoL). We used Chinese value sets of EQ-5D-3L to examine the relationship between the number of diseases individuals had (including chronic diseases, acute diseases and injuries) and their HRQoL. METHODS: A total of 19 387 individuals aged 18 years and older were included in the study. Using data from the First Provincial Health Services Survey of Hunan, China, HRQoL was assessed with the EQ 5D-3L scale, a standardized instrument developed by the EuroQoL group. The EQ-5D 3L utility score was calculated using the Chinese EQ-5D-3L value set. This survey coded disease using the list of 133 conditions that was defined by the First Provincial Health Services Survey of Hunan, China, based on the 10th International Classification of Diseases. 126 conditions were disease-related and were therefore included in data analysis. RESULTS: Of 15 245 respondents, urban residents and male constituted 53.0% and 48.2%, respectively. 19.3% of respondents had one disease and 5.0% had at least two diseases. Of the five dimensions of the EQ-5D-3L, the pain/discomfort dimension had the highest proportion of moderate or serious problems among the respondents (14.4%, 95% CI 10.5% to 18.2%). The average Visual Analogue Scale (VAS) score and utility score were 78.0 (95% CI 76.9 to 79.1) and 0.958 (95% CI 0.946 to 0.970), respectively. Residents with 1 and >=2 diseases had higher proportions of moderate or serious problems in five dimensions of the EQ-5D-3L scale during the previous 2 weeks than those without disease after controlling for location (urban/rural), sex, age, education level and household income, respectively (adjusted ORs: 3.1-3.7 and 4.4-6.6, respectively). The mean of the EQ VAS score was 8.4 and 13.6 points lower in respondents with 1 and >=2 diseases than in respondents without disease; the corresponding mean score difference was 0.048 and 0.086 in EQ-5D-3L utility score. Disease-specific analyses were not conducted due to the inadequacy of sample size. CONCLUSIONS: The HRQoL of residents aged 18 years and older declines distinctly as the number of diseases increases. Actions should be taken to improve the HRQoL of residents with multiple diseases in China (including acute diseases, chronic diseases and injuries). PMID- 28871017 TI - Scoping review protocol: education initiatives for medical psychiatry collaborative care. AB - INTRODUCTION: The collaborative care model is an approach providing care to those with mental health and addictions disorders in the primary care setting. There is a robust evidence base demonstrating its clinical and cost-effectiveness in comparison with usual care; however, the transitioning to this new paradigm of care has been difficult. While there are efforts to train and prepare healthcare professionals, not much is known about the current state of collaborative care training programmes. The objective of this scoping review is to understand how widespread these collaborative care education initiatives are, how they are implemented and their impacts. METHODS AND ANALYSIS: The scoping review methodology uses the established review methodology by Arksey and O'Malley. The search strategy was developed by a medical librarian and will be applied in eight different databases spanning multiple disciplines. A two-stage screening process consisting of a title and abstract scan and a full-text review will be used to determine the eligibility of articles. To be included, articles must report on an existing collaborative care education initiative for healthcare providers. All articles will be independently assessed for eligibility by pairs of reviewers, and all eligible articles will be abstracted and charted in duplicate using a standardised form. The extracted data will undergo a 'narrative review' or a descriptive analysis of the contextual or process-oriented data and simple quantitative analysis using descriptive statistics. ETHICS AND DISSEMINATION: Research ethics approval is not required for this scoping review. The results of this scoping review will inform the development of a collaborative care training initiative emerging from the Medical Psychiatry Alliance, a four-institution philanthropic partnership in Ontario, Canada. The results will also be presented at relevant national and international conferences and published in a peer reviewed journal. PMID- 28871018 TI - Early-life exposure to air pollutants and adverse pregnancy outcomes: protocol for a prospective cohort study in Beijing. AB - INTRODUCTION: The association between early exposure to ambient air pollution and adverse pregnancy outcomes in China is unclear. This study will assess the risk of early-life exposure to air pollutants in Beijing and explore the viability of 8-hydroxydeoxyguanosine (8-OHdG) as a biological indicator to assess oxidative stress induced by early-life exposure to air pollution. METHODS AND ANALYSIS: Here, 2500 women with singleton pregnancies and their infants will be recruited from the Beijing Obstetrics and Gynecology Hospital. We will collect nine types of biological samples, including maternal serum, urine, placental tissue, umbilical cord tissue and umbilical cord blood during all three trimesters. The air pollution data (particulate matter (PM)2.5, PM10 and similar factors) will be recorded at official fixed-site monitoring stations closest to where the pregnant women live. We plan to assess the effect of air pollutants on adverse pregnancy outcomes and infant respiratory and circulatory disease using Cox regression and competitive risk analysis and explore possible critical windows of exposure during pregnancy using daily pollutant concentrations averaged over various periods of pregnancy combined with individual activity and physiological parameters. Maternal and umbilical cord blood samples (1000 samples) will be randomly selected for 8-OHdG assays to assess the correlation between exposures to air pollutants and oxidative stress. We will determine whether air pollutant exposure or 8-OHdG levels are associated with adverse pregnancy outcomes. SPSS and SAS statistical software will be used for data analysis. Cox regression and competing risk analysis will be used to compute the HR and population attributable risk. ETHICS AND DISSEMINATION: This research protocol has already been approved by the Medical Ethics Committee of Beijing Obstetrics and Gynecology Hospital. Written informed consent will be obtained from all study participants prior to enrolment. The results will be published in peer-reviewed journals or disseminated through conference presentations. TRIAL REGISTRATION NUMBER: This study has been registered in WHO International Clinical Trial Register-Chinese Clinical Trial Registry under registrationnumber ChiCTR-ROC 16010181 (http :// www.chictr.org.cn / showproj.aspx ?proj=17328). PMID- 28871019 TI - Biopsychosocial factors associated with non-recovery after a minor transport related injury: protocol for a systematic review. AB - INTRODUCTION: Globally, road transport accidents contribute substantially to the number of deaths and also to the burden of disability. Up to 50 million people suffer a transport-related non-fatal injury each year, which often leads to long term disability. It has been shown that substantial number of people with minor injuries struggle to recover and the reasons are still not well explored.Despite the high prevalence, little is known about the factors hindering recovery following minor traffic-related injuries. The aim of this paper is to present a protocol for the systematic review aiming to understand biopsychosocial factors related to non-recovery and identify current gaps in the literature. METHODS AND ANALYSIS: The review will be conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol guidelines. A search of the electronic databases, MEDLINE, EMBASE, Cochrane Central Register of Controlled trials, will be undertaken, in addition to Google Scholar and grey literature to identify studies in period from 2006 to 2016. Quantitative and qualitative research articles describing and identifying biopsychosocial factors associated with non-recovery and health outcomes such as pain, disability, functional recovery, health-related quality of life, post-traumatic stress disorder, depression, anxiety and return to work will be included. A conceptual framework developed to identify biopsychosocial factors will be applied to assure defined criterion.At present, there is little anticipation for meta-analyses due to the heterogeneity of factors and outcomes assessed. Therefore, a narrative synthesis based on study findings will be conducted. ETHICS AND DISSEMINATION: Ethical approval is not required as primary data will not be collected. Review results will be published as a part of thesis, peer-reviewed journal and conferences. TRIALREGISTRATION NUMBER: PROSPEROregistration number: CRD42016052276. PMID- 28871020 TI - Intermittent catheter users' symptom identification, description and management of urinary tract infection: a qualitative study. AB - OBJECTIVES: To elucidate the views of intermittent catheter (IC) users regarding urinary tract infection (UTI) symptom presentation, terminology for describing signs and symptoms, the cause of UTI and management strategies. DESIGN: Qualitative study with semi-structured interviews. The transcribed text was analysed thematically. SETTING: 12 general practitioner (GP) surgeries in Hampshire and Dorset, UK. PARTICIPANTS: A convenience sample of 30 IC users, aged over 18, using IC for at least 3 months who had at least one self-reported UTI since starting IC. RESULTS: Participants reported a variety of signs and symptoms, such as urine cloudiness and smell, as indicators of UTI. The terms used often differed from those in the modified National Institute on Disability and Rehabilitation Research (NIDRR) symptom set. IC users had difficulty distinguishing possible UTI symptoms from those of their comorbidities. They expressed uncertainty about the cause of UTI, often attributing it to poor hygiene and lifestyle behaviours. Whereas some viewed UTI as an expected consequence of IC use that could be self-managed, others felt more concerned and were more reliant on their GP for support. A range of management strategies was described, including drinking more fluids, increased attention to personal hygiene and self-medicating with antibiotics. CONCLUSIONS: There is uncertainty among IC users about UTI signs and symptoms and when to seek help. Individual accounts of UTI fitted generally within the modified NIDRR descriptors but adopted less technical and more 'lay' language. IC users' descriptions of UTI signs and symptoms can lack precision, owing partly to the presence of underlying health conditions. This, together with differing levels of concern about the need to seek help and self-medication with antibiotics, presents challenges for the GP. This study provides the basis for developing a self-help tool which may aid identification of UTI and enhance communication with healthcare professionals. PMID- 28871022 TI - Perceived effects of the economic recession on population mental health, well being and provision of care by primary care users and professionals: a qualitative study protocol in Portugal. AB - INTRODUCTION: Economic recession periods can pose accentuated risks to population's mental health and well-being as well as additional threats to health systems. Users and health professionals are key stakeholders in care delivery; however, little attention has been given to their experiences of the crisis. This paper presents a qualitative study protocol to assess users' and health professionals' perceptions about the effects of the post-2008 economic recession on mental health and care delivery in the Lisbon Metropolitan Area, Portugal. METHODS AND ANALYSIS: The methodology to assess perceived effects of the economic recession by primary care users and professionals on population mental health, well-being and provision of care is presented. Focus groups with users and semistructured interviews with health professionals will be carried out in three primary healthcare units in Lisbon areas especially affected by the crisis. Thematic analysis of full-transcribed interviews will be conducted using an iterative and reflexive approach. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of NOVA Medical School, NOVA University of Lisbon. The findings will be useful for other researchers and policy-makers to develop and implement the assessment of prevailing experiences of users and health professionals on the effects of the economic recession on mental health and quality of care in primary health context, promoting their involvement and contribution to services responsiveness. PMID- 28871021 TI - Effectiveness of two psychological interventions for pain management, emotional regulation and promotion of quality of life among adult Portuguese men with haemophilia (PSY-HaEMOPEQ): study protocol for a single-centre prospective randomised controlled trial. AB - INTRODUCTION: Haemophilia is a bleeding disorder associated with significant pain, emotional distress, quality of life (QoL) impairment and considerable healthcare costs. Psychosocial health and effective pain management are considered essential end points for optimal haemophilia care, but there is a significant gap in evidence-based treatments targeting these outcomes in people with haemophilia (PWH). Psychological interventions are cost-effective in promoting emotional well-being, QoL and pain control, although these have been scarcely used in haemophilia field. This investigation aims to evaluate the effectiveness of two psychological interventions for pain management, emotional regulation and promotion of QoL in PWH. METHODS AND ANALYSIS: This is a single centre parallel randomised controlled trial conducted at a European Haemophilia Comprehensive Care Centre in Portugal, with five assessment points: baseline (T0), postintervention (T1), 3 (T2), 6 (T3) and 12 (T4) months follow-up. Eligible adult males, with moderate or severe haemophilia A or B will be randomised to experimental (EG) or control (CG) group. Intervention is either cognitive-behavioural therapy (EG1) or hypnosis (EG2), both consisting of four weekly sessions following standardised scripts delivered by trained psychologists. Randomisation will be computer generated, allocation concealment will be guaranteed and outcome assessors will be blind to EG/CG allocation. Main outcomes are pain and haemophilia-related QoL and secondary outcomes include clinical (clotting factor replacement consumption, joint bleeding episodes, analgesic intake) and psychological (pain coping strategies, anxiety, depression, illness perceptions) variables, functional assessment of the joints, inflammatory biomarkers (cytokines, high-sensitivity C reactive protein) and white blood cell count. ETHICS AND DISSEMINATION: This study was approved by the competent authorities and all procedures will comply with international ethical guidelines for clinical studies involving humans. Written informed consent will be obtained from all participants. The dissemination plan includes peer-reviewed scientific publications, conference participation and web and media coverage. TRIAL REGISTRATION NUMBER: NCT02870452. PMID- 28871023 TI - Effect of Baduanjin exercises on elevated blood lipid levels of middle-aged and elderly individuals: protocol for a systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To assess the safety and effect on elevated blood lipid levels of Baduanjin exercises in middle-aged and elderly individuals. METHODS: A systematic literature search for articles up to March 2017 will be conducted using seven databases: PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Science and Technology Periodicals Database, Chinese BioMedical Database and Wanfang Data. Inclusion criteria are randomised controlled trials of Baduanjin exercises that examine blood lipid levels in middle-aged and elderly individuals. The primary outcome measures will be total cholesterol, triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Stata V.13.0 software will be used for data synthesis, sensitivity analysis, metaregression, subgroup analysis and risk of bias assessment. A funnel plot will be developed to evaluate reporting bias and Begg and Egger tests will be used to assess funnel plot symmetries. We will use the Grading of Recommendations Assessment, Development and Evaluation system to assess the quality of evidence. ETHICS AND DISSEMINATION: This systematic review will be submitted to a peer-reviewed journal. Our findings will provide information about the safety of Baduanjin exercises for middle-aged and elderly individuals and their effect on elevated blood lipid levels. TRIAL REGISTRATION NUMBER: PROSPERO CRD 42017060613. PMID- 28871024 TI - Telemedicine-guided education on secondary stroke and fall prevention following inpatient rehabilitation for Texas patients with stroke and their caregivers: a feasibility pilot study. AB - INTRODUCTION: The aftermath of stroke leaves many consequences including cognitive deficits and falls due to imbalance. Stroke survivors and families struggle to navigate the complex healthcare system with little assistance posthospital discharge, often leading to early hospital readmission and worse stroke outcomes. Telemedicine Guided Education on Secondary Stroke and Fall Prevention Following Inpatient Rehabilitation feasibility study examines whether stroke survivors and their caregivers find value in telerehabilitation (TR) home visits that provide individualised care and education by a multidisciplinary team after discharge from inpatient rehabilitation. METHODS AND ANALYSIS: A prospective, single arm, pilot study is designed to evaluate the feasibility of weekly TR home visits initiated postdischarge from inpatient rehabilitation. Newly diagnosed patients with stroke are recruited from a Houston-based comprehensive stroke centre inpatient rehabilitation unit, loaned an iPad with data plan and trained to use information technology security-approved videoconferencing application. After hospital discharge, six weekly TR home visits are led by rotating specialists (pharmacist, physical/occupational therapist, speech therapist, rehabilitation physician, social worker, geriatrician specialised in fracture prevention) followed by satisfaction survey on week 7. Specialists visually assess patients in real time, educate them on secondary stroke and fall prevention and suggest ways to improve function including direct medical interventions when indicated. Primary outcomes are proportion of eligible patients consenting to the study, participation rate in all six TR home visits and satisfaction score. The study started 31 December 2015 with plan to enrol up to 50 patients over 24 months. Feasibility study results will inform us as to whether a randomised controlled trial is warranted to determine efficacy of TR home visit intervention in improving stroke outcomes. ETHICS AND DISSEMINATION: Ethics approval obtained by the Institutional Review Board (IRB), Committee for the Protection of Human Subjects, IRB number: HSC-MS 14-0994. Study results will be submitted for publication in a peer-reviewed journal. PMID- 28871025 TI - The economic impact of childhood acute gastroenteritis on Malawian families and the healthcare system. AB - OBJECTIVES: This prospective cohort study sought to estimate health system and household costs for episodes of diarrhoeal illness in Malawi. SETTING: Data were collected in two Malawian settings: a rural health centre in Chilumba and an urban tertiary care hospital in Blantyre. PARTICIPANTS: Children under 5 years of age presenting with diarrhoeal disease between 1 January 2013 and 21 November 2014 were eligible for inclusion. Illnesses attributed to other underlying causes were excluded, as were illnesses commencing more than 2 weeks prior to presentation. Complete data were collected on 514 cases at both the time of the initial visit to the participating healthcare facility and 6 weeks after discharge. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the total cost of an episode of illness. Costs to the health system were gathered from chart review (drugs and diagnostics) and actual hospital expenditure (staff and facility costs). Household costs, including lost income, were obtained by interview with the parents/guardians of patients. RESULTS: Total costs in 2014 US$ for rural inpatient, rural outpatient, urban inpatient and urban outpatient were $65.33, $8.89, $60.23 and $14.51, respectively (excluding lost income). Mean household contributions to these costs were 15.8%, 9.8%, 21.3% and 50.6%. CONCLUSION: This study found significant financial burden from childhood diarrhoeal disease to the healthcare system and to households. The latter face the risk of consequent impoverishment, as the study demonstrates how the costs of seeking treatment bring the income of the majority of families in all income strata below the national poverty line in the month of illness. PMID- 28871026 TI - Study protocol for a matter of heart: a qualitative study of patient factors driving overuse of cardiac catheterisation. AB - INTRODUCTION: Overuse of cardiac catheterisation (CC) for stable coronary artery disease (CAD) is documented in Germany and other regions, although percutaneous coronary interventions do not provide a benefit over medical therapy for stable patients. Various studies investigated health system, physician and patient factors driving non-adherence to guidelines which recommend a stepwise approach with invasive procedures only in case of signs of ischaemia in non-invasive testing. In a larger-scale project, we aim to better understand the patients' perspective in order to develop an intervention that enhances patient's acceptance of this stepwise diagnostic approach for stable CAD. As a first step, this qualitative study aims to identify patient factors that prevent and promote the described overuse. METHODS AND ANALYSIS: The exploratory qualitative interview study will include about 20 patients with stable CAD and a history of acute coronary syndrome from two German teaching practices. Narrative, structured interviews designed to last 30 to 90 min will be conducted. The interviews will be analysed using qualitative content analysis by Mayring. The analysis will address the following questions: (1) What are reasons for stable patients to undergo CC? (2) How do patients deal with their heart disease (secondary prevention)? (3) Which processes do patients describe regarding decision-making for non-invasive and invasive coronary procedures? (4) What information needs exist on behalf of patients to better understand the stepwise diagnostic approach outlined in guidelines and thereby avoid low-appropriate CCs? Based on these data, empirical typification will be conducted. ETHICS AND DISSEMINATION: Ethical approval for the study was obtained. All participants will provide written informed consent. Data will be pseudonymised for analysis. The findings will contribute to the development of an appropriate intervention. Results will be disseminated by conference presentations and journal publications. PMID- 28871028 TI - The role of pragmatism in explaining heterogeneity in meta-analyses of randomised trials: a protocol for a cross-sectional methodological review. AB - INTRODUCTION: There has been increasing interest in pragmatic trials methodology. As a result, tools such as the Pragmatic-Explanatory Continuum Indicator Summary 2 (PRECIS-2) are being used prospectively to help researchers design randomised controlled trials (RCTs) within the pragmatic-explanatory continuum. There may be value in applying the PRECIS-2 tool retrospectively in a systematic review setting as it could provide important information about how to pool data based on the degree of pragmatism. OBJECTIVES: To investigate the role of pragmatism as a source of heterogeneity in systematic reviews by (1) identifying systematic reviews with meta-analyses of RCTs that have moderate to high heterogeneity, (2) applying PRECIS-2 to RCTs of systematic reviews, (3) evaluating the inter-rater reliability of PRECIS-2, (4) determining how much of this heterogeneity may be explained by pragmatism. METHODS: A cross-sectional methodological review will be conducted on systematic reviews of RCTs published in the Cochrane Library from 1 January 2014 to 1 January 2017. Included systematic reviews will have a minimum of 10 RCTs in the meta-analysis of the primary outcome and moderate to substantial heterogeneity (I2>=50%). Of the eligible systematic reviews, a random selection of 10 will be included for quantitative evaluation. In each systematic review, RCTs will be scored using the PRECIS-2 tool, in duplicate. Agreement between raters will be measured using the intraclass correlation coefficient. Subgroup analyses and meta-regression will be used to evaluate how much variability in the primary outcome may be due to pragmatism. DISSEMINATION: This review will be among the first to evaluate the PRECIS-2 tool in a systematic review setting. Results from this research will provide inter-rater reliability information about PRECIS-2 and may be used to provide methodological guidance when dealing with pragmatism in systematic reviews and subgroup considerations. On completion, this review will be submitted to a peer-reviewed journal for publication. PMID- 28871027 TI - Case management in primary care among frequent users of healthcare services with chronic conditions: protocol of a realist synthesis. AB - INTRODUCTION: A common reason for frequent use of healthcare services is the complex healthcare needs of individuals suffering from multiple chronic conditions, especially in combination with mental health comorbidities and/or social vulnerability. Frequent users (FUs) of healthcare services are more at risk for disability, loss of quality of life and mortality. Case management (CM) is a promising intervention to improve care integration for FU and to reduce healthcare costs. This review aims to develop a middle-range theory explaining how CM in primary care improves outcomes among FU with chronic conditions, for what types of FU and in what circumstances. METHODS AND ANALYSIS: A realist synthesis (RS) will be conducted between March 2017 and March 2018 to explore the causal mechanisms that underlie CM and how contextual factors influence the link between these causal mechanisms and outcomes. According to RS methodology, five steps will be followed: (1) focusing the scope of the RS; (2) searching for the evidence; (3) appraising the quality of evidence; (4) extracting the data; and (5) synthesising the evidence. Patterns in context-mechanism-outcomes (CMOs) configurations will be identified, within and across identified studies. Analysis of CMO configurations will help confirm, refute, modify or add to the components of our initial rough theory and ultimately produce a refined theory explaining how and why CM interventions in primary care works, in which contexts and for which FU with chronic conditions. ETHICS AND DISSEMINATION: Research ethics is not required for this review, but publication guidelines on RS will be followed. Based on the review findings, we will develop and disseminate messages tailored to various relevant stakeholder groups. These messages will allow the development of material that provides guidance on the design and the implementation of CM in health organisations. TRIAL REGISTRATION NUMBER: Prospero CRD42017057753. PMID- 28871029 TI - Protocol for a qualitative study exploring perspectives on the INternational CLassification of Diseases (11th revision); Using lived experience to improve mental health Diagnosis in NHS England: INCLUDE study. AB - INTRODUCTION: Developed in dialogue with WHO, this research aims to incorporate lived experience and views in the refinement of the International Classification of Diseases Mental and Behavioural Disorders 11th Revision (ICD-11). The validity and clinical utility of psychiatric diagnostic systems has been questioned by both service users and clinicians, as not all aspects reflect their lived experience or are user friendly. This is critical as evidence suggests that diagnosis can impact service user experience, identity, service use and outcomes. Feedback and recommendations from service users and clinicians should help minimise the potential for unintended negative consequences and improve the accuracy, validity and clinical utility of the ICD-11. METHODS AND ANALYSIS: The name INCLUDE reflects the value of expertise by experience as all aspects of the proposed study are co-produced. Feedback on the planned criteria for the ICD-11 will be sought through focus groups with service users and clinicians. The data from these groups will be coded and inductively analysed using a thematic analysis approach. Findings from this will be used to form the basis of co produced recommendations for the ICD-11. Two service user focus groups will be conducted for each of these diagnoses: Personality Disorder, Bipolar I Disorder, Schizophrenia, Depressive Disorder and Generalised Anxiety Disorder. There will be four focus groups with clinicians (psychiatrists, general practitioners and clinical psychologists). ETHICS AND DISSEMINATION: This study has received ethical approval from the Coventry and Warwickshire HRA Research Ethics Committee (16/WM/0479). The output for the project will be recommendations that reflect the views and experiences of experts by experience (service users and clinicians). The findings will be disseminated via conferences and peer-reviewed publications. As the ICD is an international tool, the aim is for the methodology to be internationally disseminated for replication by other groups. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03131505. PMID- 28871031 TI - Angular Gyrus Involvement at Encoding and Retrieval Is Associated with Durable But Less Specific Memories. AB - After consolidation, information belonging to a mental schema is better remembered, but such memory can be less specific when it comes to details. A neuronal mechanism consistent with this behavioral pattern could result from a dynamic interaction that entails mediation by a specific cortical network with associated hippocampal disengagement. We now report that, in male and female adult human subjects, encoding and later consolidation of a series of objects embedded in a semantic schema was associated with a buildup of activity in the angular gyrus (AG) that predicted memory 24 h later. In parallel, the posterior hippocampus became less involved as schema objects were encoded successively. Hippocampal disengagement was related to an increase in falsely remembering objects that were not presented at encoding. During both encoding and retrieval, the AG and lateral occipital complex (LOC) became functionally connected and this interaction was beneficial for successful retrieval. Therefore, a network including the AG and LOC enhances the overnight retention of schema-related memories and their simultaneous detachment from the hippocampus reduces the specificity of the memory.SIGNIFICANCE STATEMENT This study provides the first empirical evidence on how the hippocampus and the neocortex interact dynamically when acquiring and then effectively retaining durable knowledge that is associated to preexisting knowledge, but they do so at the cost of memory specificity. This interaction is a fundamental mnemonic operation that has thus far been largely overlooked in memory research. PMID- 28871030 TI - Spatiochromatic Interactions between Individual Cone Photoreceptors in the Human Retina. AB - A remarkable feature of human vision is that the retina and brain have evolved circuitry to extract useful spatial and spectral information from signals originating in a photoreceptor mosaic with trichromatic constituents that vary widely in their relative numbers and local spatial configurations. A critical early transformation applied to cone signals is horizontal-cell-mediated lateral inhibition, which imparts a spatially antagonistic surround to individual cone receptive fields, a signature inherited by downstream neurons and implicated in color signaling. In the peripheral retina, the functional connectivity of cone inputs to the circuitry that mediates lateral inhibition is not cone-type specific, but whether these wiring schemes are maintained closer to the fovea remains unsettled, in part because central retinal anatomy is not easily amenable to direct physiological assessment. Here, we demonstrate how the precise topography of the long (L)-, middle (M)-, and short (S)-wavelength-sensitive cones in the human parafovea (1.5 degrees eccentricity) shapes perceptual sensitivity. We used adaptive optics microstimulation to measure psychophysical detection thresholds from individual cones with spectral types that had been classified independently by absorptance imaging. Measured against chromatic adapting backgrounds, the sensitivities of L and M cones were, on average, receptor-type specific, but individual cone thresholds varied systematically with the number of preferentially activated cones in the immediate neighborhood. The spatial and spectral patterns of these interactions suggest that interneurons mediating lateral inhibition in the central retina, likely horizontal cells, establish functional connections with L and M cones indiscriminately, implying that the cone-selective circuitry supporting red-green color vision emerges after the first retinal synapse.SIGNIFICANCE STATEMENT We present evidence for spatially antagonistic interactions between individual, spectrally typed cones in the central retina of human observers using adaptive optics. Using chromatic adapting fields to modulate the relative steady-state activity of long (L)- and middle (M)-wavelength-sensitive cones, we found that single-cone detection thresholds varied predictably with the spectral demographics of the surrounding cones. The spatial scale and spectral pattern of these photoreceptor interactions were consistent with lateral inhibition mediated by retinal horizontal cells that receive nonselective input from L and M cones. These results demonstrate a clear link between the neural architecture of the visual system inputs-cone photoreceptors-and visual perception and have implications for the neural locus of the cone-specific circuitry supporting color vision. PMID- 28871032 TI - KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS. AB - Neurons in the adult mammalian CNS decrease in intrinsic axon growth capacity during development in concert with changes in Kruppel-like transcription factors (KLFs). KLFs regulate axon growth in CNS neurons including retinal ganglion cells (RGCs). Here, we found that knock-down of KLF9, an axon growth suppressor that is normally upregulated 250-fold in RGC development, promotes long-distance optic nerve regeneration in adult rats of both sexes. We identified a novel binding partner, MAPK10/JNK3 kinase, and found that JNK3 (c-Jun N-terminal kinase 3) is critical for KLF9's axon-growth-suppressive activity. Interfering with a JNK3 binding domain or mutating two newly discovered serine phosphorylation acceptor sites, Ser106 and Ser110, effectively abolished KLF9's neurite growth suppression in vitro and promoted axon regeneration in vivo These findings demonstrate a novel, physiologic role for the interaction of KLF9 and JNK3 in regenerative failure in the optic nerve and suggest new therapeutic strategies to promote axon regeneration in the adult CNS.SIGNIFICANCE STATEMENT Injured CNS nerves fail to regenerate spontaneously. Promoting intrinsic axon growth capacity has been a major challenge in the field. Here, we demonstrate that knocking down Kruppel like transcription factor 9 (KLF9) via shRNA promotes long-distance axon regeneration after optic nerve injury and uncover a novel and important KLF9-JNK3 interaction that contributes to axon growth suppression in vitro and regenerative failure in vivo These studies suggest potential therapeutic approaches to promote axon regeneration in injury and other degenerative diseases in the adult CNS. PMID- 28871033 TI - Reticulospinal Contributions to Gross Hand Function after Human Spinal Cord Injury. AB - Multiple descending motor pathways likely contribute to the recovery of hand motor function following spinal cord injury (SCI). Reticulospinal neurons project to spinal motor neurons controlling hand muscles and extensively sprout into gray matter structures after SCI; therefore, it has been proposed that the reticulospinal tract is one of the descending motor pathways involved in recovery of hand function after injury. To test this hypothesis, we examined the StartReact response, an involuntary release of a planned movement via a startling stimulus that engages the reticulospinal tract, by measuring reaction times from electromyographic activity in an intrinsic finger muscle during three motor tasks requiring different degrees of hand dexterity: index finger abduction, a precision grip, and a power grip. Males and females with and without incomplete chronic cervical SCI were tested. We found that although SCI participants voluntarily responded to all tasks, reaction times were shorter during a startle cue while performing a power grip but not index finger abduction or precision grip. Control subjects had similarly shorter reaction times during a startle cue in all motor tasks. These results provide the first evidence for a contribution of the reticulospinal tract to hand control in humans with SCI during gross finger manipulations and suggest that this contribution is less pronounced during fine dexterous finger movements.SIGNIFICANCE STATEMENT It has been long proposed that brainstem pathways contribute to the recovery of hand function in humans with spinal cord injury (SCI). Here, we show that individuals with anatomically incomplete chronic cervical SCI responded to a startle stimulus, a test that engages the reticulospinal tract, while performing a power grip but not during index finger abduction or precision grip. Control subjects responded to a startle stimulus similarly across tasks. These observations suggest that reticulospinal outputs after SCI contribute to hand motor tasks involving gross finger movements. Interestingly, this contribution is less pronounced during fine dexterous finger movements. PMID- 28871036 TI - Sodium Channel beta2 Subunits Prevent Action Potential Propagation Failures at Axonal Branch Points. AB - Neurotransmitter release depends on voltage-gated Na+ channels (Navs) to propagate an action potential (AP) successfully from the axon hillock to a synaptic terminal. Unmyelinated sections of axon are very diverse structures encompassing branch points and numerous presynaptic terminals with undefined molecular partners of Na+ channels. Using optical recordings of Ca2+ and membrane voltage, we demonstrate here that Na+ channel beta2 subunits (Navbeta2s) are required to prevent AP propagation failures across the axonal arborization of cultured rat hippocampal neurons (mixed male and female). When Navbeta2 expression was reduced, we identified two specific phenotypes: (1) membrane excitability and AP-evoked Ca2+ entry were impaired at synapses and (2) AP propagation was severely compromised with >40% of axonal branches no longer responding to AP-stimulation. We went on to show that a great deal of electrical signaling heterogeneity exists in AP waveforms across the axonal arborization independent of axon morphology. Therefore, Navbeta2 is a critical regulator of axonal excitability and synaptic function in unmyelinated axons.SIGNIFICANCE STATEMENT Voltage-gated Ca2+ channels are fulcrums of neurotransmission that convert electrical inputs into chemical outputs in the form of vesicle fusion at synaptic terminals. However, the role of the electrical signal, the presynaptic action potential (AP), in modulating synaptic transmission is less clear. What is the fidelity of a propagating AP waveform in the axon and what molecules shape it throughout the axonal arborization? Our work identifies several new features of AP propagation in unmyelinated axons: (1) branches of a single axonal arborization have variable AP waveforms independent of morphology, (2) Na+ channel beta2 subunits modulate AP-evoked Ca2+-influx, and (3) beta2 subunits maintain successful AP propagation across the axonal arbor. These findings are relevant to understanding the flow of excitation in the brain. PMID- 28871035 TI - Odorant Receptor Sensitivity Modulation in Drosophila. AB - The ability to modulate sensitivity in sensory systems is essential for useful information to be extracted from fluctuating stimuli in a wide range of background conditions. The mechanisms underlying sensitivity regulation in insect primary olfactory neurons are poorly understood. Here we reveal that dephosphorylation of OrcoS289 that occurs upon prolonged odor exposure is a mechanism underlying reduction in odorant sensitivity in Drosophila primary olfactory neurons in both sexes. OrcoS289A mutants, unable to phosphorylate this position, have low intrinsic odorant sensitivity that is independent of altered expression or localization. A phosphomimetic allele, OrcoS289D , has enhanced odorant sensitivity compared with wild-type controls. To explore the functional ramifications of this phosphorylation in vivo, we generated phospho-specific antiserum to OrcoS289 and show that phosphorylation at this residue is dynamically regulated by odorant exposure with concomitant modulation of odorant sensitivity. OrcoS289 is phosphorylated in the sensitized state, and odorant exposure triggers dephosphorylation and desensitization without altering receptor localization. We further show that dephosphorylation of OrcoS289 is triggered by neuronal activity, and not conformational changes in the receptor occurring upon ligand binding. Mutant flies unable to regulate Orco function through phosphorylation at S289 are defective for odor-guided behavior. These findings provide insight into the mechanisms underlying regulation of insect odorant receptors in vivoSIGNIFICANCE STATEMENT We have uncovered a mechanism underlying olfactory receptor sensitivity regulation in Drosophila The phosphorylation state of Orco S289 is altered in an odorant-dependent manner and changes in phosphorylation affect receptor sensitivity without changing subcellular localization. We show that neuronal activity triggers the phosphorylation changes and that this phenomenon is important for odorant-guided behaviors in Drosophila This phosphorylation site is conserved in other insects, including mosquitoes, indicating this mechanism may be a target for manipulation of insect behaviors in the future. PMID- 28871037 TI - Identification of Protein Tyrosine Phosphatase Receptor Type O (PTPRO) as a Synaptic Adhesion Molecule that Promotes Synapse Formation. AB - The proper formation of synapses-specialized unitary structures formed between two neurons-is critical to mediating information flow in the brain. Synaptic cell adhesion molecules (CAMs) are thought to participate in the initiation of the synapse formation process. However, in vivo functional analysis demonstrates that most well known synaptic CAMs regulate synaptic maturation and plasticity rather than synapse formation, suggesting that either CAMs work synergistically in the process of forming synapses or more CAMs remain to be found. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters in co-cultures of human embryonic kidney 293 cells and hippocampal neurons cultured from newborn mice regardless of gender. PTPRO was enriched in the mouse brain and localized to postsynaptic sites at excitatory synapses. The overexpression of PTPRO in cultured hippocampal neurons increased the number of synapses and the frequency of miniature EPSCs (mEPSCs). The knock down (KD) of PTPRO expression in cultured neurons by short hairpin RNA (shRNA) reduced the number of synapses and the frequencies of the mEPSCs. The effects of shRNA KD were rescued by expressing either full-length PTPRO or a truncated PTPRO lacking the cytoplasmic domain. Consistent with these results, the N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in the co-culture assay. Our data show that PTPRO is a synaptic CAM that serves as a potent initiator of the formation of excitatory synapses.SIGNIFICANCE STATEMENT The formation of synapses is critical for the brain to execute its function and synaptic cell adhesion molecules (CAMs) play essential roles in initiating the formation of synapses. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters. Using loss-of function and gain-of-function approaches, we show that PTPRO promotes the formation of excitatory synapses. The N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in cultured hippocampal neurons and the co-culture assay. Together, our data show that PTPRO is a synaptic CAM that serves as a potent initiator of synapse formation. PMID- 28871038 TI - Accountable care systems and accountable care organisations. PMID- 28871034 TI - Domain-General Brain Regions Do Not Track Linguistic Input as Closely as Language Selective Regions. AB - Language comprehension engages a cortical network of left frontal and temporal regions. Activity in this network is language-selective, showing virtually no modulation by nonlinguistic tasks. In addition, language comprehension engages a second network consisting of bilateral frontal, parietal, cingulate, and insular regions. Activity in this "multiple demand" (MD) network scales with comprehension difficulty, but also with cognitive effort across a wide range of nonlinguistic tasks in a domain-general fashion. Given the functional dissociation between the language and MD networks, their respective contributions to comprehension are likely distinct, yet such differences remain elusive. Prior neuroimaging studies have suggested that activity in each network covaries with some linguistic features that, behaviorally, influence on-line processing and comprehension. This sensitivity of the language and MD networks to local input characteristics has often been interpreted, implicitly or explicitly, as evidence that both networks track linguistic input closely, and in a manner consistent across individuals. Here, we used fMRI to directly test this assumption by comparing the BOLD signal time courses in each network across different people (n = 45, men and women) listening to the same story. Language network activity showed fewer individual differences, indicative of closer input tracking, whereas MD network activity was more idiosyncratic and, moreover, showed lower reliability within an individual across repetitions of a story. These findings constrain cognitive models of language comprehension by suggesting a novel distinction between the processes implemented in the language and MD networks.SIGNIFICANCE STATEMENT Language comprehension recruits both language specific mechanisms and domain-general mechanisms that are engaged in many cognitive processes. In the human cortex, language-selective mechanisms are implemented in the left-lateralized "core language network", whereas domain general mechanisms are implemented in the bilateral "multiple demand" (MD) network. Here, we report the first direct comparison of the respective contributions of these networks to naturalistic story comprehension. Using a novel combination of neuroimaging approaches we find that MD regions track stories less closely than language regions. This finding constrains the possible contributions of the MD network to comprehension, contrasts with accounts positing that this network has continuous access to linguistic input, and suggests a new typology of comprehension processes based on their extent of input tracking. PMID- 28871040 TI - Ministers must act "without delay" to solve GP indemnity crisis, defence bodies warn. PMID- 28871039 TI - Human TorsinA can function in the yeast cytosol as a molecular chaperone. AB - TorsinA (TorA) is an AAA+ (ATPases associated with diverse cellular activities) ATPase linked to dystonia type 1 (DYT1), a neurological disorder that leads to uncontrollable muscular movements. Although DYT1 is linked to a 3 bp deletion in the C-terminus of TorA, the biological function of TorA remains to be established. Here, we use the yeast Saccharomyces cerevisiae as a tractable in vivo model to explore TorA function. We demonstrate that TorA can protect yeast cells against different forms of environmental stress and show that in the absence of the molecular disaggregase Hsp104, TorA can refold heat-denatured luciferase in vivo in an ATP-dependent manner. However, this activity requires TorA to be translocated to the cytoplasm from the endoplasmic reticulum in order to access and process cytoplasmic protein aggregates. Furthermore, mutational or chemical inactivation of the ATPase activity of TorA blocks this activity. We also find that TorA can inhibit the propagation of certain conformational variants of [PSI+], the aggregated prion form of the endogenous Sup35 protein. Finally, we show that while cellular localisation remains unchanged in the dystonia-linked TorA mutant DeltaE302-303, the ability of this mutant form of TorA to protect against cellular stress and to facilitate protein refolding is impaired, consistent with it being a loss-of-function mutation. PMID- 28871041 TI - Vena Cava Filter Retrieval Rates and Factors Associated With Retrieval in a Large US Cohort. AB - BACKGROUND: Retrieval of vena cava filters (VCFs) is important for safety as complications increase with longer dwell times. This study assessed VCF retrieval rates and factors associated with retrieval in a national cohort. METHODS AND RESULTS: VCFs were identified by procedural codes from an administrative claims database. Patients were identified who had a VCF placement during a hospitalization from a national commercial administrative claims database. Indications for VCF placement were identified as pulmonary embolism with or without deep vein thrombosis, deep vein thrombosis only, or prophylactic. Patient demographic and clinical characteristics were included in proportional hazard regression models to find associations with early (90-day) and 1-year VCF retrieval. Initiation of anticoagulation and the correlation between time-to retrieval and time-to-initiation of anticoagulation were observed. Of 54 766 patients receiving a VCF, 36.9% had pulmonary embolism, 43.9% had deep vein thrombosis only, and 19.2% had no apparent venous thromboembolism present. Over the 1 year of follow-up, the cumulative incidence of VCF retrieval was 18.4%. Retrieval increased over time from a low of 14.0% in 2010 up to ~24% in 2014. In adjusted time-to-event models, increasing age, differing regions, and some comorbidities were associated with poorer retrieval rates. Initiation of anticoagulation was poorly correlated with retrieval, with anticoagulation preceding retrieval by a median of 51 days while those without retrieval had a median of 278 days of exposure to anticoagulation. CONCLUSIONS: VCF retrieval increased over the study period but remained suboptimal and was weakly correlated with anticoagulation initiation. PMID- 28871042 TI - Trimethylamine-N-Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3-SOD2-mtROS Signaling Pathway. AB - BACKGROUND: Trimethylamine-N-oxide (TMAO) has recently been identified as a novel and independent risk factor for promoting atherosclerosis through inducing vascular inflammation. However, the exact mechanism is currently unclear. Studies have established a central role of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in the pathogenesis of vascular inflammation. Here, we examined the potential role of the NLRP3 inflammasome in TMAO-induced vascular inflammation in vitro and in vivo and the underlying mechanisms. METHODS AND RESULTS: Experiments using liquid chromatography-tandem mass spectrometry, Western blot, and fluorescent probes showed that TMAO-induced inflammation in human umbilical vein endothelial cells (HUVECs) and aortas from ApoE-/- mice. Moreover, TMAO promoted NLRP3 and activated caspase-1 p20 expression and caspase-1 activity in vitro and in vivo. Notably, a caspase-1 inhibitor (YVAD), an NLRP3 inhibitor (MCC950), as well as NLRP3 short interfering RNA attenuated TMAO-induced activation of the NLRP3 inflammasome, subsequently leading to suppression of inflammation in HUVECs. TMAO additionally stimulated reactive oxygen species (ROS) generation, in particular, mitochondrial ROS, while inhibiting manganese superoxide dismutase 2 (SOD2) activation and sirtuin 3 (SIRT3) expression in HUVECs and aortas from ApoE-/- mice. TMAO-induced endothelial NLRP3 inflammasome activation was ameliorated by the mitochondrial ROS scavenger Mito-TEMPO, or SIRT3 overexpression in HUVECs. Conversely, TMAO failed to further inhibit magnesium SOD2 and activate the NLRP3 inflammasome or induce inflammation in SIRT3 short interfering RNA-treated HUVECs and aortas from SIRT3-/- mice. CONCLUSIONS: TMAO promoted vascular inflammation by activating the NLRP3 inflammasome, and the NLRP3 inflammasome activation in part was mediated through inhibition of the SIRT3-SOD2-mitochondrial ROS signaling pathway. PMID- 28871043 TI - MMI-0100 Inhibits Cardiac Fibrosis in a Mouse Model Overexpressing Cardiac Myosin Binding Protein C. AB - BACKGROUND: Cardiac stress can trigger production of a 40-kDa peptide fragment derived from the amino terminus of the cardiac myosin-binding protein C. Cardiac stress, as well as cMyBP-C mutations, can trigger production of 1 such truncated protein fragment, a 40-kDa peptide fragment derived from the amino terminus of cMyBP-C. Genetic expression of this 40-kDa fragment in mouse cardiomyocytes (cMyBP-C40k) leads to cardiac disease, fibrosis, and death within the first year. Fibrosis can occur in many cardiovascular diseases, and mitogen-activated protein kinase--activated protein kinase-2 signaling has been implicated in a variety of fibrotic processes. Recent studies demonstrated that mitogen-activated protein kinase--activated protein kinase-2 inhibition using the cell-permeant peptide inhibitor MMI-0100 is protective in the setting of acute myocardial infarction. We hypothesized that MMI-0100 might also be protective in a chronic model of fibrosis, produced as a result of cMyBP-C40k cardiomyocyte expression. METHODS AND RESULTS: Nontransgenic and cMyBP-C40k inducible transgenic mice were given MMI-0100 or PBS daily for 30 weeks. In control groups, long-term MMI-0100 was benign, with no measurable effects on cardiac anatomy, function, cell viability, hypertrophy, or probability of survival. In the inducible transgenic group, MMI 0100 treatment reduced cardiac fibrosis, decreased cardiac hypertrophy, and prolonged survival. CONCLUSIONS: Pharmaceutical inhibition of mitogen-activated protein kinase--activated protein kinase-2 signaling via MMI-0100 treatment is beneficial in the context of fibrotic cMyBPC40k disease. PMID- 28871044 TI - LPP3 mediates self-generation of chemotactic LPA gradients by melanoma cells. AB - Melanoma cells steer out of tumours using self-generated lysophosphatidic acid (LPA) gradients. The cells break down LPA, which is present at high levels around the tumours, creating a dynamic gradient that is low in the tumour and high outside. They then migrate up this gradient, creating a complex and evolving outward chemotactic stimulus. Here, we introduce a new assay for self-generated chemotaxis, and show that raising LPA levels causes a delay in migration rather than loss of chemotactic efficiency. Knockdown of the lipid phosphatase LPP3 - but not of its homologues LPP1 or LPP2 - diminishes the cell's ability to break down LPA. This is specific for chemotactically active LPAs, such as the 18:1 and 20:4 species. Inhibition of autotaxin-mediated LPA production does not diminish outward chemotaxis, but loss of LPP3-mediated LPA breakdown blocks it. Similarly, in both 2D and 3D invasion assays, knockdown of LPP3 diminishes the ability of melanoma cells to invade. Our results demonstrate that LPP3 is the key enzyme in the breakdown of LPA by melanoma cells, and confirm the importance of attractant breakdown in LPA-mediated cell steering.This article has an associated First Person interview with the first author of the paper. PMID- 28871045 TI - Loss of Arabidopsis p24 function affects ERD2 trafficking and Golgi structure, and activates the unfolded protein response. AB - The p24 family of proteins (also known as the TMED family) are key regulators of protein trafficking along the secretory pathway, but very little is known about their functions in plants. A quadruple loss-of-function mutant affecting the p24 genes from the delta-1 subclass of the p24delta subfamily (p24delta3delta4delta5delta6) showed alterations in the Golgi, suggesting that these p24 proteins play a role in the organization of the compartments of the early secretory pathway in Arabidopsis Loss of p24delta-1 proteins also induced the accumulation of the K/HDEL receptor ERD2a (ER lumen protein-retaining receptor A) at the Golgi and increased secretion of BiP family proteins, ER chaperones containing an HDEL signal, probably due to an inhibition of COPI dependent Golgi-to-ER transport of ERD2a and thus retrieval of K/HDEL ligands. Although the p24delta3delta4delta5delta6 mutant showed enhanced sensitivity to salt stress, it did not show obvious phenotypic alterations under standard growth conditions. Interestingly, this mutant showed a constitutive activation of the unfolded protein response (UPR) and the transcriptional upregulation of the COPII subunit gene SEC31A, which may help the plant to cope with the transport defects seen in the absence of p24 proteins. PMID- 28871046 TI - Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome. AB - Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P2, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane is poorly understood. Here, we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in Ocrl-null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P2 in Lowe patient cells. Accumulation of sonic hedgehog protein in response to hedgehog agonist was decreased in MEFs derived from a Lowe syndrome mouse model. Together, our findings show for the first time an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome. PMID- 28871049 TI - Industrial hardware and software verification with ACL2. AB - The ACL2 theorem prover has seen sustained industrial use since the mid-1990s. Companies that have used ACL2 regularly include AMD, Centaur Technology, IBM, Intel, Kestrel Institute, Motorola/Freescale, Oracle and Rockwell Collins. This paper introduces ACL2 and focuses on how and why ACL2 is used in industry. ACL2 is well-suited to its industrial application to numerous software and hardware systems, because it is an integrated programming/proof environment supporting a subset of the ANSI standard Common Lisp programming language. As a programming language ACL2 permits the coding of efficient and robust programs; as a prover ACL2 can be fully automatic but provides many features permitting domain-specific human-supplied guidance at various levels of abstraction. ACL2 specifications and models often serve as efficient execution engines for the modelled artefacts while permitting formal analysis and proof of properties. Crucially, ACL2 also provides support for the development and verification of other formal analysis tools. However, ACL2 did not find its way into industrial use merely because of its technical features. The core ACL2 user/development community has a shared vision of making mechanized verification routine when appropriate and has been committed to this vision for the quarter century since the Computational Logic, Inc., Verified Stack. The community has focused on demonstrating the viability of the tool by taking on industrial projects (often at the expense of not being able to publish much).This article is part of the themed issue 'Verified trustworthy software systems'. PMID- 28871047 TI - Axonal localization of neuritin/CPG15 mRNA is limited by competition for HuD binding. AB - HuD protein (also known as ELAVL4) has been shown to stabilize mRNAs with AU-rich elements (ARE) in their 3' untranslated regions (UTRs), including Gap43, which has been linked to axon growth. HuD also binds to neuritin (Nrn1) mRNA, whose 3'UTR contains ARE sequences. Although the Nrn1 3'UTR has been shown to mediate its axonal localization in embryonic hippocampal neurons, it is not active in adult dorsal root ganglion (DRG) neurons. Here, we asked why the 3'UTR is not sufficient to mediate the axonal localization of Nrn1 mRNA in DRG neurons. HuD overexpression increases the ability of the Nrn1 3'UTR to mediate axonal localizing in DRG neurons. HuD binds directly to the Nrn1 ARE with about a two fold higher affinity than to the Gap43 ARE. Although the Nrn1 ARE can displace the Gap43 ARE from HuD binding, HuD binds to the full 3'UTR of Gap43 with higher affinity, such that higher levels of Nrn1 are needed to displace the Gap43 3'UTR. The Nrn1 3'UTR can mediate a higher level of axonal localization when endogenous Gap43 is depleted from DRG neurons. Taken together, our data indicate that endogenous Nrn1 and Gap43 mRNAs compete for binding to HuD for their axonal localization and activity of the Nrn1 3'UTR. PMID- 28871048 TI - An emerging case for membrane pore formation as a common mechanism for the unconventional secretion of FGF2 and IL-1beta. AB - Extracellular proteins with important signalling roles in processes, such as inflammation and angiogenesis, are known to employ unconventional routes of protein secretion. Although mechanisms of unconventional protein secretion are beginning to emerge, the precise molecular details have remained elusive for the majority of cargo proteins secreted by unconventional means. Recent findings suggest that for two examples of unconventionally secreted proteins, interleukin 1beta (IL-1beta) and fibroblast growth factor 2 (FGF2), the common molecular principle of pore formation may be shared. Under specific experimental conditions, secretion of IL-1beta and FGF2 is triggered by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]-dependent formation of pores across the plasma membrane. However, the underlying mechanisms are different, with FGF2 known to directly interact with PI(4,5)P2, whereas in the case of IL-1beta secretion, it is proposed that the N-terminal fragment of gasdermin D interacts with PI(4,5)P2 to form the pore. Thus, although implemented in different ways, these findings suggest that pore formation may be shared by the unconventional secretion mechanisms for FGF2 and IL-1beta in at least some cases. In this Opinion article, we discuss the unconventional mechanisms of FGF2 and IL-1beta release with a particular emphasis on recent discoveries suggesting the importance of pore formation on the plasma membrane. PMID- 28871050 TI - The HACMS program: using formal methods to eliminate exploitable bugs. AB - For decades, formal methods have offered the promise of verified software that does not have exploitable bugs. Until recently, however, it has not been possible to verify software of sufficient complexity to be useful. Recently, that situation has changed. SeL4 is an open-source operating system microkernel efficient enough to be used in a wide range of practical applications. Its designers proved it to be fully functionally correct, ensuring the absence of buffer overflows, null pointer exceptions, use-after-free errors, etc., and guaranteeing integrity and confidentiality. The CompCert Verifying C Compiler maps source C programs to provably equivalent assembly language, ensuring the absence of exploitable bugs in the compiler. A number of factors have enabled this revolution, including faster processors, increased automation, more extensive infrastructure, specialized logics and the decision to co-develop code and correctness proofs rather than verify existing artefacts. In this paper, we explore the promise and limitations of current formal-methods techniques. We discuss these issues in the context of DARPA's HACMS program, which had as its goal the creation of high-assurance software for vehicles, including quadcopters, helicopters and automobiles.This article is part of the themed issue 'Verified trustworthy software systems'. PMID- 28871051 TI - Formal verification: will the seedling ever flower? AB - In one sense, formal specification and verification have been highly successful: techniques have been developed in pioneering academic research, transferred to software companies through training and partnerships, and successfully deployed in systems with national significance. Altran UK has been in the vanguard of this movement. This paper summarizes some of our key deployments of formal techniques over the past 20 years, including both security- and safety-critical systems. The impact of formal techniques, however, remains within an industrial niche, and while government and suppliers across industry search for solutions to the problems of poor-quality software, the wider software industry remains resistant to adoption of this proven solution. We conclude by reflecting on some of the challenges we face as a community in ensuring that formal techniques achieve their true potential impact on society.This article is part of the themed issue 'Verified trustworthy software systems'. PMID- 28871052 TI - Program synthesis: challenges and opportunities. AB - Program synthesis is the mechanized construction of software, dubbed 'self writing code'. Synthesis tools relieve the programmer from thinking about how the problem is to be solved; instead, the programmer only provides a description of what is to be achieved. Given a specification of what the program should do, the synthesizer generates an implementation that provably satisfies this specification. From a logical point of view, a program synthesizer is a solver for second-order existential logic. Owing to the expressiveness of second-order logic, program synthesis has an extremely broad range of applications. We survey some of these applications as well as recent trends in the algorithms that solve the program synthesis problem. In particular, we focus on an approach that has raised the profile of program synthesis and ushered in a generation of new synthesis tools, namely counter-example-guided inductive synthesis (CEGIS). We provide a description of the CEGIS architecture, followed by recent algorithmic improvements. We conjecture that the capacity of program synthesis engines will see further step change, in a manner that is transparent to the applications, which will open up an even broader range of use-cases.This article is part of the themed issue 'Verified trustworthy software systems'. PMID- 28871053 TI - Provably trustworthy systems. AB - We present recent work on building and scaling trustworthy systems with formal, machine-checkable proof from the ground up, including the operating system kernel, at the level of binary machine code. We first give a brief overview of the seL4 microkernel verification and how it can be used to build verified systems. We then show two complementary techniques for scaling these methods to larger systems: proof engineering, to estimate verification effort; and code/proof co-generation, for scalable development of provably trustworthy applications.This article is part of the themed issue 'Verified trustworthy software systems'. PMID- 28871054 TI - Compositional relaxed concurrency. AB - There is a broad design space for concurrent computer processors: they can be optimized for low power, low latency or high throughput. This freedom to tune each processor design to its niche has led to an increasing diversity of machines, from powerful pocketable devices to those responsible for complex and critical tasks, such as car guidance systems. Given this context, academic concurrency research sounds notes of both caution and optimism. Caution because recent work has uncovered flaws in the way we explain the subtle memory behaviour of concurrent systems: specifications have been shown to be incorrect, leading to bugs throughout the many layers of the system. And optimism because our tools and methods for verifying the correctness of concurrent code-although built above an idealized model of concurrency-are becoming more mature. This paper looks at the way we specify the memory behaviour of concurrent systems and suggests a new direction. Currently, there is a siloed approach, with each processor and programming language specified separately in an incomparable way. But this does not match the structure of our programs, which may use multiple processors and languages together. Instead we propose a compositional approach, where program components carry with them a description of the sort of concurrency they rely on, and there is a mechanism for composing these. This will support not only components written for the multiple varied processors found in a modern system but also those that use idealized models of concurrency, providing a sound footing for mature verification techniques.This article is part of the themed issue 'Verified trustworthy software systems'. PMID- 28871055 TI - Verified trustworthy software systems. PMID- 28871056 TI - Position paper: the science of deep specification. AB - We introduce our efforts within the project 'The science of deep specification' to work out the key formal underpinnings of industrial-scale formal specifications of software and hardware components, anticipating a world where large verified systems are routinely built out of smaller verified components that are also used by many other projects. We identify an important class of specification that has already been used in a few experiments that connect strong component-correctness theorems across the work of different teams. To help popularize the unique advantages of that style, we dub it deep specification, and we say that it encompasses specifications that are rich, two-sided, formal and live (terms that we define in the article). Our core team is developing a proof of-concept system (based on the Coq proof assistant) whose specification and verification work is divided across largely decoupled subteams at our four institutions, encompassing hardware microarchitecture, compilers, operating systems and applications, along with cross-cutting principles and tools for effective specification. We also aim to catalyse interest in the approach, not just by basic researchers but also by users in industry.This article is part of the themed issue 'Verified trustworthy software systems'. PMID- 28871057 TI - KH-type splicing regulatory protein is a new component of chromatoid body. AB - The chromatoid body (CB) is a specific cloud-like structure in the cytoplasm of haploid spermatids. Recent findings indicate that CB is identified as a male germ cell-specific RNA storage and processing center, but its function has remained elusive for decades. In somatic cells, KH-type splicing regulatory protein (KSRP) is involved in regulating gene expression and maturation of select microRNAs (miRNAs). However, the function of KSRP in spermatogenesis remains unclear. In this study, we showed that KSRP partly localizes in CB, as a component of CB. KSRP interacts with proteins (mouse VASA homolog (MVH), polyadenylate-binding protein 1 (PABP1) and polyadenylate-binding protein 2 (PABP2)), mRNAs (Tnp2 and Odf1) and microRNAs (microRNA-182) in mouse CB. Moreover, KSRP may regulate the integrity of CB via DDX5-miRNA-182 pathway. In addition, we found abnormal expressions of CB component in testes of Ksrp-knockout mice and of patients with hypospermatogenesis. Thus, our results provide mechanistic insight into the role of KSRP in spermatogenesis. PMID- 28871059 TI - Chromosome structure dynamics during the cell cycle: a structure to fit every phase. PMID- 28871058 TI - The Hox proteins Ubx and AbdA collaborate with the transcription pausing factor M1BP to regulate gene transcription. AB - In metazoans, the pausing of RNA polymerase II at the promoter (paused Pol II) has emerged as a widespread and conserved mechanism in the regulation of gene transcription. While critical in recruiting Pol II to the promoter, the role transcription factors play in transitioning paused Pol II into productive Pol II is, however, little known. By studying how Drosophila Hox transcription factors control transcription, we uncovered a molecular mechanism that increases productive transcription. We found that the Hox proteins AbdA and Ubx target gene promoters previously bound by the transcription pausing factor M1BP, containing paused Pol II and enriched with promoter-proximal Polycomb Group (PcG) proteins, yet lacking the classical H3K27me3 PcG signature. We found that AbdA binding to M1BP-regulated genes results in reduction in PcG binding, the release of paused Pol II, increases in promoter H3K4me3 histone marks and increased gene transcription. Linking transcription factors, PcG proteins and paused Pol II states, these data identify a two-step mechanism of Hox-driven transcription, with M1BP binding leading to Pol II recruitment followed by AbdA targeting, which results in a change in the chromatin landscape and enhanced transcription. PMID- 28871060 TI - Hydroxysteroid dehydrogenase HSD1L is localised to the pituitary-gonadal axis of primates. AB - Steroid hormones play clinically important and specific regulatory roles in the development, growth, metabolism, reproduction and brain function in human. The type 1 and 2 11-beta hydroxysteroid dehydrogenase enzymes (11beta-HSD1 and 2) have key roles in the pre-receptor modification of glucocorticoids allowing aldosterone regulation of blood pressure, control of systemic fluid and electrolyte homeostasis and modulation of integrated metabolism and brain function. Although the activity and function of 11beta-HSDs is thought to be understood, there exists an open reading frame for a distinct 11betaHSD-like gene; HSD11B1L, which is present in human, non-human primate, sheep, pig and many other higher organisms, whereas an orthologue is absent in the genomes of mouse, rat and rabbit. We have now characterised this novel HSD11B1L gene as encoded by 9 exons and analysis of EST library transcripts indicated the use of two alternate ATG start sites in exons 2 and 3, and alternate splicing in exon 9. Relatively strong HSD11B1L gene expression was detected in human, non-human primate and sheep tissue samples from the brain, ovary and testis. Analysis in non-human primates and sheep by immunohistochemistry localised HSD11B1L protein to the cytoplasm of ovarian granulosa cells, testis Leydig cells, and gonadatroph cells in the anterior pituitary. Intracellular localisation analysis in transfected human HEK293 cells showed HSD1L protein within the endoplasmic reticulum and sequence analysis suggests that similar to 11betaHSD1 it is membrane bound. The endogenous substrate of this third HSD enzyme remains elusive with localisation and expression data suggesting a reproductive hormone as a likely substrate. PMID- 28871062 TI - A critique of phrenology in Moby-Dick. AB - Phrenology has a fascinating, although controversial, place in the history of localizationism of brain and mental functions. The 2 main proponents of phrenology were 2 German-speaking doctors, Joseph Gall (1758-1828) and Johann Spurzheim (1776-1832). According to their theory, a careful examination of skull morphology could disclose personality characters. Phrenology was initially restricted to medical circles and then diffused outside scientific societies, reaching nonscientific audiences in Europe and North America. Phrenology deeply penetrated popular culture in the 19th century and its tenets can be observed in British and American literature. Here we analyze the presence of phrenologic concepts in Moby-Dick; or, The Whale, by Herman Melville (1819-1891), one of the most prominent American writers. In his masterpiece, he demonstrates that he was familiarized with Gall and Spurzheim's writings, but referred to their theory as "semi-science" and "a passing fable." Of note, Melville's fine irony against phrenology is present in his attempt to perform a phrenologic and physiognomic examination of The Whale. Thus, Moby-Dick illustrates the diffusion of phrenology in Western culture, but may also reflect Melville's skepticism and criticism toward its main precepts. PMID- 28871063 TI - Intra-arterial milrinone may differentiate fulminant RCVS from vasculitis. PMID- 28871064 TI - Editors' Note. PMID- 28871065 TI - Letter re: A dedicated scholarly research program in an adult and pediatric neurology residency program. PMID- 28871066 TI - Author response: A dedicated scholarly research program in an adult and pediatric neurology residency program. PMID- 28871067 TI - Letter re: Hans Jacob and brain research on Hamburg "euthanasia" victims: "Awaiting further brains!" PMID- 28871061 TI - Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells. AB - Increasing peak bone mass is a promising strategy to prevent osteoporosis. A mouse model of global progesterone receptor (PR) ablation showed increased bone mass through a sex-dependent mechanism. Cre-Lox recombination was used to generate a mouse model of osteoprogenitor-specific PR inactivation, which recapitulated the high bone mass phenotype seen in the PR global knockout mouse mode. In this work, we employed RNA sequencing analysis to evaluate sex independent and sex-dependent differences in gene transcription of osteoprogenitors of wild-type and PR conditional knockout mice. PR deletion caused marked sex hormone-dependent changes in gene transcription in male mice as compared to wild-type controls. These transcriptional differences revealed dysregulation in pathways involving immunomodulation, osteoclasts, bone anabolism, extracellular matrix interaction and matrix interaction. These results identified many potential mechanisms that may explain our observed high bone mass phenotype with sex differences when PR was selectively deleted in the MSCs. PMID- 28871068 TI - Author response: Hans Jacob and brain research on Hamburg "euthanasia" victims: "Awaiting further brains!" PMID- 28871069 TI - Clinical Reasoning: A 27-year-old man with unsteady gait. PMID- 28871070 TI - Pearls & Oy-sters: Frontal lobe epilepsy presenting as complex stereotyped movements. PMID- 28871071 TI - Teaching NeuroImages: Central neurocytoma. PMID- 28871072 TI - Teaching Video NeuroImages: Bilateral abducens ocular neuromyotonia. PMID- 28871073 TI - Optical techniques for breath analysis: from single to multi-species detection. AB - Optical spectroscopy can be used for trace-level gas analysis in different applications, including exhaled breath research. A common approach is the targeted on-line, real-time analysis of small molecules (two to five atoms). Currently, the methodology is normally used for the detection of single analytes at trace levels, or two to three species at most at the same time. The main limitation preventing sensitive multi-species detection has been the limited fast scanning range of the lasers used as light sources. This limitation is currently being eliminated by the availability of optical frequency combs (OFC) which offer wide spectral bandwidths and the benefits of a laser-type light source. Recent advances in mid-infrared OFC technology allow measurements in the so-called molecular fingerprint region of the electromagnetic spectrum, where many molecules have strong fundamental vibrational transitions that enable sensitive detection. Several technical hurdles remain to be overcome, but if these problems can be solved laser absorption spectroscopy has the potential to challenge mass spectrometry in on-line multi-species trace gas analysis. PMID- 28871074 TI - Acoustics of snoring and automatic snore sound detection in children. AB - OBJECTIVE: Acoustic analyses of snoring sounds have been used to objectively assess snoring and applied in various clinical problems for adult patients. Such studies require highly automatized tools to analyze the sound recordings of the whole night's sleep, in order to extract clinically relevant snore- related statistics. The existing techniques and software used for adults are not efficiently applicable to snoring sounds in children, basically because of different acoustic signal properties. In this paper, we present a broad range of acoustic characteristics of snoring sounds in children (N = 38) in comparison to adult (N = 30) patients. APPROACH: Acoustic characteristics of the signals were calculated, including frequency domain representations, spectrogram-based characteristics, spectral envelope analysis, formant structures and loudness of the snoring sounds. MAIN RESULTS: We observed significant differences in spectral features, formant structures and loudness of the snoring signals of children compared to adults that may arise from the diversity of the upper airway anatomy as the principal determinant of the snore sound generation mechanism. Furthermore, based on the specific audio features of snoring children, we proposed a novel algorithm for the automatic detection of snoring sounds from ambient acoustic data specifically in a pediatric population. The respiratory sounds were recorded using a pair of microphones and a multi-channel data acquisition system simultaneously with full-night polysomnography during sleep. Brief sound chunks of 0.5 s were classified as either belonging to a snoring event or not with a multi-layer perceptron, which was trained in a supervised fashion using stochastic gradient descent on a large hand-labeled dataset using frequency domain features. SIGNIFICANCE: The method proposed here has been used to extract snore-related statistics that can be calculated from the detected snore episodes for the whole night's sleep, including number of snore episodes (total snoring time), ratio of snore to whole sleep time, variation of snoring rate, regularity of snoring episodes in time and amplitude and snore loudness. These statistics will ultimately serve as a clinical tool providing information for the objective evaluation of snoring for several clinical applications. PMID- 28871075 TI - Dose assessment from chronic exposure to industrial NORM in iron ore processing. AB - Radiological exposures due to naturally occurring radioactive material (NORM) can occur during a wide range of work-related activities in the mineral processing and chemical industries. However, evaluation of such exposures in industrial settings remains a difficult exercise owing inter alia to the large number of personnel, operations and plants affected; assumptions that often have to be made concerning the actual duration and frequency of exposures; the complex chemistry and radioactive disequilibria involved and typically, the paucity of historical data. In our study, the challenges associated with assessing chronic exposure to fugitive dust enriched in 210Pb and 210Po and the determination of the associated internal dose by inhalation and ingestion are described by reference to a case study undertaken at an iron ore sintering plant between June 2013 and July 2015. The applicability of default dose coefficients and biokinetic models provided by the International Commission for Radiological Protection (ICRP) was verified by combining air and dust monitoring with information on the characteristics of the aerosols and in-vitro solubility experiments. The disparity between particulate matter 100 microns or less in diameter (PM100), particulate matter 10 microns or less in diameter (PM10) and 210Pb/210Po activity concentrations observed over the different monitoring campaigns and sampling locations confirmed that use of positional short-term monitoring surveys to extrapolate intake over a year was not appropriate and could lead to unrealistic intake and dose figures. Personal air sampling is more appropriate for estimating the dose in such situations, though it is not always practical and may collect insufficient quantities of material for radiochemical analysis; this is an important constraint when dealing with low specific activity materials. PMID- 28871077 TI - Treatment of Hepatic Hydatid Cyst in a 7-Year-Old Boy Using a New Type of Radiofrequency Ablation Electrode. AB - BACKGROUND Radiofrequency ablation has been established as a treatment method for malignancies and some particular cystic lesions, especially in adults. Experience with radiofrequency ablation in the treatment of hydatid cysts, especially in children, is limited. CASE REPORT Although echinococcosis is rare, especially in children, we describe a 7-year-old boy with lung and liver cystic echinococcosis. Diagnosis was established by clinical history and imaging findings and confirmed by positive antiechinococcal antibodies. After 6 months of chemotherapy with albendazole, the liver lesion remained and a radiofrequency ablation under computed tomography guidance was obtained. The procedure was performed with a new type of ablation electrode in order to minimize handling and procedure duration and to achieve the best clinical result in only 1 session. This type of electrode provides the ability to simultaneously drain and ablate the cyst and the ability to monitor the desired ablation temperature in real time. CONCLUSIONS Our patient is the first pediatric case with hepatic hydatid cyst treated successfully with the use of a new type of radiofrequency ablation electrode under computed tomography guidance. PMID- 28871076 TI - Knockdown of MicroRNA-122 Protects H9c2 Cardiomyocytes from Hypoxia-Induced Apoptosis and Promotes Autophagy. AB - BACKGROUND Acute myocardial infarction (AMI) is a severe disease causing heart failure and sudden death. Studies indicate that microRNAs (miRNAs) are involved in the pathophysiology of AMI. In the present study, we carefully explored the effects of miR-122 on myocardial hypoxia injury and its possible underlying mechanism. MATERIAL AND METHODS miR-122 expression was analyzed in H9c2 cardiomyocytes after being transfected with miR-122 mimic, ASO-miR-122, or negative control. Cell viability and apoptosis were investigated by CCK-8 assays and flow cytometry analysis, respectively. Cell migration was analyzed using wound-healing assays. Western blotting was performed to analyze the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/phosphatidylinositol 3-hydroxy kinase (PI3K)/AKT and LC3-II/LC3-I. RESULTS Hypoxia exposure significantly inhibited H9c2 cell viability (P<0.01). miR-122 overexpression promoted the hypoxia-induced H9c2 cell proliferation and migration loss (P<0.05), and cell apoptosis was increased (P<0.05). miR-122 knockdown enhanced cell viability and decreased cell apoptosis (P<0.05). Knockdown of miR 122 enhanced PTEN/PI3K/AKT activation and cell autophagy. Overexpression of miR 122 inhibited the PTEN/PI3K/AKT pathway and cell autophagy pathway. CONCLUSIONS The expression of miR-122 is involved in hypoxia-induced H9c2 cardiomyocyte injury. Knockdown of miR-122 protects H9c2 cells from hypoxia-induced apoptosis and enhances cell viability. PMID- 28871078 TI - Impact of Forced Expiratory Volume in 1 Second (FEV1) and 6-Minute Walking Distance at 3, 6, and 12 Months and Annually on Survival and Occurrence of Bronchiolitis Obliterans Syndrome (BOS) After Lung Transplantation. AB - BACKGROUND Development of bronchiolitis obliterans syndrome (BOS) is a great limitation for patient survival in lung transplantation (LTx). A curative treatment for BOS is still missing, and in terminal stages re-transplantation (Re LTx) is the only salvation. It is possible to slow the progress of BOS if it is detected at an early stage. This might be possible by assessing pulmonary function pattern. MATERIAL AND METHODS Between 1990 and 2014, 278 patients underwent LTx at Skane University Hospital, Sweden. Pulmonary function was followed using spirometry (FEV1) and 6-minute walking test (6MWT) measured at 3, 6, and 12 months and annually. The endpoint used was freedom from BOS (BOS grade <=1), BOS (BOS grade >=2), and death or Re-LTx. RESULTS Double-lung transplantation (DLTx) showed a hazard ratio (HR) of 0.514 (p=0.001) versus recipients who underwent single-lung transplantation (SLTx). Regarding freedom from BOS, FEV1 showed an HR of 0.597 and 6MWT an HR of 0.982 (p<0.001). Regarding combined endpoint BOS >=2 and Re-LTx, FEV1 showed an HR of 0.618 and 6MWT an HR of 0.972 (p<0.001). CONCLUSIONS Recipients with higher FEV1 or 6MWT values had better chances of survival. Recipients with DLTx had a significant survival benefit and a protective effect against development of BOS. As the distance that the patient can walk in 6 minutes increases, risk for death or Re-LTx is significantly lower, as is incidence of developing BOS grade >=2. Understanding changes within pulmonary function are probably key to understanding patient prognosis. PMID- 28871079 TI - Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. AB - Podocyte injury is a major determinant of proteinuric kidney disease and the identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Here, we show that histone deacetylase Sirt6 protects against podocyte injury through epigenetic regulation of Notch signaling. Sirt6 is downregulated in renal biopsies from patients with podocytopathies and its expression correlates with glomerular filtration rate. Podocyte-specific deletion of Sirt6 exacerbates podocyte injury and proteinuria in two independent mouse models, diabetic nephropathy, and adriamycin-induced nephropathy. Sirt6 has pleiotropic protective actions in podocytes, including anti-inflammatory and anti apoptotic effects, is involved in actin cytoskeleton maintenance and promotes autophagy. Sirt6 also reduces urokinase plasminogen activator receptor expression, which is a key factor for podocyte foot process effacement and proteinuria. Mechanistically, Sirt6 inhibits Notch1 and Notch4 transcription by deacetylating histone H3K9. We propose Sirt6 as a potential therapeutic target for the treatment of proteinuric kidney disease.Podocytes are essential components of the renal glomerular filtration barrier and podocyte dysfunction leads to proteinuric kidney disease. Here Liu et al. show that Sirt6 protects podocytes from apoptosis and inflammation by increasing autophagic flux through inhibition of the Notch pathway. PMID- 28871080 TI - Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin. AB - A short half-life in the circulation limits the application of therapeutics such as single-domain antibodies (VHHs). We utilize red blood cells to prolong the circulatory half-life of VHHs. Here we present VHHs against botulinum neurotoxin A (BoNT/A) on the surface of red blood cells by expressing chimeric proteins of VHHs with Glycophorin A or Kell. Mice whose red blood cells carry the chimeric proteins exhibit resistance to 10,000 times the lethal dose (LD50) of BoNT/A, and transfusion of these red blood cells into naive mice affords protection for up to 28 days. We further utilize an improved CD34+ culture system to engineer human red blood cells that express these chimeric proteins. Mice transfused with these red blood cells are resistant to highly lethal doses of BoNT/A. We demonstrate that engineered red blood cells expressing VHHs can provide prolonged prophylactic protection against bacterial toxins without inducing inhibitory immune responses and illustrates the potentially broad translatability of our strategy for therapeutic applications.The therapeutic use of single-chain antibodies (VHHs) is limited by their short half-life in the circulation. Here the authors engineer mouse and human red blood cells to express VHHs against botulinum neurotoxin A (BoNT/A) on their surface and show that an infusion of these cells into mice confers long lasting protection against a high dose of BoNT/A. PMID- 28871081 TI - Dynamic plasticity in phototransduction regulates seasonal changes in color perception. AB - To cope with seasonal changes in the environment, organisms adapt their physiology and behavior. Although color perception varies among seasons, the underlying molecular basis and its physiological significance remain unclear. Here we show that dynamic plasticity in phototransduction regulates seasonal changes in color perception in medaka fish. Medaka are active and exhibit clear phototaxis in conditions simulating summer, but remain at the bottom of the tank and fail to exhibit phototaxis in conditions simulating winter. Mate preference tests using virtual fish created with computer graphics demonstrate that medaka are more attracted to orange-red-colored model fish in summer than in winter. Transcriptome analysis of the eye reveals dynamic seasonal changes in the expression of genes encoding photopigments and their downstream pathways. Behavioral analysis of photopigment-null fish shows significant differences from wild type, suggesting that plasticity in color perception is crucial for the emergence of seasonally regulated behaviors.Animal coloration and behavior can change seasonally, but it is unclear if visual sensitivity to color shifts as well. Here, Shimmura et al. show that medaka undergo seasonal behavioral change accompanied by altered expression of opsin genes, resulting in reduced visual sensitivity to mates during winter-like conditions. PMID- 28871083 TI - Interspecies quorum sensing in co-infections can manipulate trypanosome transmission potential. AB - Quorum sensing (QS) is commonly used in microbial communities and some unicellular parasites to coordinate group behaviours 1,2 . An example is Trypanosoma brucei, which causes human African trypanosomiasis, as well as the livestock disease, nagana. Trypanosomes are spread by tsetse flies, their transmission being enabled by cell-cycle arrested 'stumpy forms' that are generated in a density-dependent manner in mammalian blood. QS is mediated through a small (<500 Da), non-proteinaceous, stable but unidentified 'stumpy induction factor' 3 , whose signal response pathway has been identified. Although QS is characterized in T. brucei, co-infections with other trypanosome species (Trypanosoma congolense and Trypanosoma vivax) are common in animals, generating the potential for interspecies interactions. Here, we show that T. congolense exhibits density-dependent growth control in vivo and conserves QS regulatory genes, of which one can complement a T. brucei QS signal-blind mutant to restore stumpy formation. Thereafter, we demonstrate that T. congolense-conditioned culture medium promotes T. brucei stumpy formation in vitro, which is dependent on the integrity of the QS signalling pathway. Finally, we show that, in vivo, co infection with T. congolense accelerates differentiation to stumpy forms in T. brucei, which is also QS dependent. These cross-species interactions have important implications for trypanosome virulence, transmission, competition and evolution in the field. PMID- 28871082 TI - Stromal and epithelial transcriptional map of initiation progression and metastatic potential of human prostate cancer. AB - While progression from normal prostatic epithelium to invasive cancer is driven by molecular alterations, tumor cells and cells in the cancer microenvironment are co-dependent and co-evolve. Few human studies to date have focused on stroma. Here, we performed gene expression profiling of laser capture microdissected normal non-neoplastic prostate epithelial tissue and compared it to non transformed and neoplastic low-grade and high-grade prostate epithelial tissue from radical prostatectomies, each with its immediately surrounding stroma. Whereas benign epithelium in prostates with and without tumor were similar in gene expression space, stroma away from tumor was significantly different from that in prostates without cancer. A stromal gene signature reflecting bone remodeling and immune-related pathways was upregulated in high compared to low Gleason grade cases. In validation data, the signature discriminated cases that developed metastasis from those that did not. These data suggest that the microenvironment may influence prostate cancer initiation, maintenance, and metastatic progression.Stromal cells contribute to tumor development but the mechanisms regulating this process are still unclear. Here the authors analyze gene expression profiles in the prostate and show that stromal gene signature changes ahead of the epithelial gene signature as prostate cancer initiates and progresses. PMID- 28871084 TI - Engineering a riboswitch-based genetic platform for the self-directed evolution of acid-tolerant phenotypes. AB - Environmental pH is a fundamental signal continuously directing the metabolism and behavior of living cells. Programming the precise cellular response toward environmental pH is, therefore, crucial for engineering cells for increasingly sophisticated functions. Herein, we engineer a set of riboswitch-based pH-sensing genetic devices to enable the control of gene expression according to differential environmental pH. We next develop a digital pH-sensing system to utilize the analogue-sensing behavior of these devices for high-resolution recording of host cell exposure to discrete external pH levels. The application of this digital pH-sensing system is demonstrated in a genetic program that autonomously regulated the evolutionary engineering of host cells for improved tolerance to a broad spectrum of organic acids, a valuable phenotype for metabolic engineering and bioremediation applications.Cells are exposed to shifts in environmental pH, which direct their metabolism and behavior. Here the authors design pH-sensing riboswitches to create a gene expression program, digitalize the system to respond to a narrow pH range and apply it to evolve host cells with improved tolerance to a variety of organic acids. PMID- 28871085 TI - Probing the potential of mucus permeability to signify preterm birth risk. AB - Preterm birth is the leading cause of neonatal mortality, and is frequently associated with intra-amniotic infection hypothesized to arise from bacterial ascension across a dysfunctional cervical mucus plug. To study this dysfunction, we assessed the permeability of cervical mucus from non-pregnant ovulating (n = 20) and high- (n = 9) and low-risk (n = 16) pregnant women to probes of varying sizes and surface chemistries. We found that the motion of negatively charged, carboxylated microspheres in mucus from pregnant patients was significantly restricted compared to ovulating patients, but not significantly different between high- and low-risk pregnant women. In contrast, charged peptide probes small enough to avoid steric interactions, but sensitive to the biochemical modifications of mucus components exhibited significantly different transport profiles through mucus from high- and low-risk patients. Thus, although both microstructural rearrangements of the components of mucus as well as biochemical modifications to their adhesiveness may alter the overall permeability of the cervical mucus plug, our findings suggest that the latter mechanism plays a dominant role in the impairment of the function of this barrier during preterm birth. We expect that these probes may be readily adapted to study the mechanisms underlying disease progression on all mucosal epithelia, including those in the mouth, lungs, and gut. PMID- 28871086 TI - Identification of HSP90 inhibitors as a novel class of senolytics. AB - Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated beta-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1 -/- murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1 -/? mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs.The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice. PMID- 28871088 TI - Human Primary Bone Marrow Mesenchymal Stromal Cells and Their in vitro Progenies Display Distinct Transcriptional Profile Signatures. AB - Bone marrow mesenchymal stromal cells (BM-MSCs) are a rare population of cells that gives rise to skeletal tissues and the hematopoietic stroma in vivo. Recently, we have demonstrated that BM-MSCs fulfill stringent in vivo stem cell criteria when propagated as non-adherent mesenspheres but not as adherent cultured cells. Motivated by these profound functional differences, the current study aimed to identify potential important MSC regulators by investigating global gene expression profiles of adherent and non-adherent culture-derived BM MSCs in comparison with primary BM-MSCs. A substantial number of genes were differentially expressed between primary and culture-expanded cells already early upon culture, and numerous genes were found to be different when comparing adherent and non-adherent BM-MSCs. Cluster analysis identified 16 sets of genes of which two displayed comparable gene expression levels in primary and non adherent cultured cells, but not in adherent cultured cells. This pattern suggested that these clusters contained candidate regulators of BM-MSCs. Gene expression differences were confirmed for selected genes and BM-MSC transcription factors by protein analysis and RT-PCR, respectively. Taken together, these data demonstrated profound gene expression changes upon culture of primary BM-MSCs. Moreover, gene cluster differences provide the basis to uncover the regulatory mechanisms that control primary and cultured BM-MSCs. PMID- 28871087 TI - Ethnic differences in smoking intensity and COPD risk: an observational study in primary care. AB - Chronic obstructive pulmonary disease risk is lower in black and south Asian people than white people, when adjusting for age, sex, deprivation and smoking status. The role of smoking intensity was assessed for its contribution to ethnic differences in chronic obstructive pulmonary disease risk, a relationship not previously investigated. This cross-sectional study included routinely collected primary care data from four multi-ethnic London boroughs. Smoking intensity (estimated by cigarettes per day) was compared between ethnic groups. Chronic obstructive pulmonary disease risk was compared between ethnic groups using multiple logistic regression, controlling for age, sex, deprivation, asthma and both smoking status and smoking intensity, examined independently. In all, 1,000,388 adults were included. Smoking prevalence and intensity were significantly higher in the white British/Irish groups than other ethnic groups. Higher smoking intensity was associated with higher chronic obstructive pulmonary disease risk. Chronic obstructive pulmonary disease risk was significantly lower in all ethnic groups compared with white British/Irish after adjustment for either smoking status or smoking intensity, with lowest risk in black Africans (odds ratio 0.33; confidence interval 0.28-0.38). Ethnic differences in chronic obstructive pulmonary disease risk were not explained in this study by ethnic differences in smoking prevalence or smoking intensity. Other causes of ethnic differences in chronic obstructive pulmonary disease risk should be sought, including ethnic differences in smoking behaviour, environmental factors, repeated respiratory infections, immigrant status, metabolism and addictiveness of nicotine and differential susceptibility to the noxious effects of cigarette smoke.COPD: SMOKING INTENSITY NOT BEHIND ETHNIC DIFFERENCES IN DISEASE RISK: Lower smoking intensity among blacks and south Asians does not explain their lower risk for chronic obstructive pulmonary disease (COPD). A UK team led by Alexander Gilkes from Kings College London analysed primary care data from more than a million people living in four multi-ethnic boroughs of the British capital. The researchers found that smoking status and intensity (as measured by number of cigarettes smoked per day) were both significantly higher in white British or Irish groups than in other ethnic populations. Even after statistically adjusting for smoking status or smoking intensity, however, the researchers couldn't account for the fact that people of south Asian or African descent had much lower prevalence rates of COPD, a lung disease linked to smoking. The findings suggest that other explanations of ethnic differences are still needed. PMID- 28871089 TI - CD81 association with SAMHD1 enhances HIV-1 reverse transcription by increasing dNTP levels. AB - In this study, we report that the tetraspanin CD81 enhances human immunodeficiency virus (HIV)-1 reverse transcription in HIV-1-infected cells. This is enabled by the direct interaction of CD81 with the deoxynucleoside triphosphate phosphohydrolase SAMHD1. This interaction prevents endosomal accumulation and favours the proteasome-dependent degradation of SAMHD1. Consequently, CD81 depletion results in SAMHD1 increased expression, decreasing the availability of deoxynucleoside triphosphates (dNTP) and thus HIV-1 reverse transcription. Conversely, CD81 overexpression, but not the expression of a CD81 carboxy (C)-terminal deletion mutant, increases cellular dNTP content and HIV-1 reverse transcription. Our results demonstrate that the interaction of CD81 with SAMHD1 controls the metabolic rate of HIV-1 replication by tuning the availability of building blocks for reverse transcription, namely dNTPs. Together with its role in HIV-1 entry and budding into host cells, the data herein indicate that HIV-1 uses CD81 as a rheostat that controls different stages of the infection. PMID- 28871091 TI - Demonstration of sub-luminal propagation of single-cycle terahertz pulses for particle acceleration. AB - The sub-luminal phase velocity of electromagnetic waves in free space is generally unobtainable, being closely linked to forbidden faster than light group velocities. The requirement of sub-luminal phase-velocity in laser-driven particle acceleration schemes imposes a limit on the total acceleration achievable in free space, and necessitates the use of dispersive structures or waveguides for extending the field-particle interaction. We demonstrate a travelling source approach that overcomes the sub-luminal propagation limits. The approach exploits ultrafast optical sources with slow group velocity propagation, and a group-to-phase front conversion through nonlinear optical interaction. The concept is demonstrated with two terahertz generation processes, nonlinear optical rectification and current-surge rectification. We report measurements of longitudinally polarised single-cycle electric fields with phase and group velocity between 0.77c and 1.75c. The ability to scale to multi-megavolt-per metre field strengths is demonstrated. Our approach paves the way towards the realisation of cheap and compact particle accelerators with femtosecond scale control of particles.Controlled generation of terahertz radiation with subluminal phase velocities is a key issue in laser-driven particle acceleration. Here, the authors demonstrate a travelling-source approach utilizing the group-to-phase front conversion to overcome the sub-luminal propagation limit. PMID- 28871090 TI - TRIM23 mediates virus-induced autophagy via activation of TBK1. AB - Autophagy and interferon (IFN)-mediated innate immunity are critical antiviral defence mechanisms, and recent evidence indicated that tripartite motif (TRIM) proteins are important regulators of both processes. Although the role of TRIM proteins in modulating antiviral cytokine responses has been well established, much less is known about their involvement in autophagy in response to different viral pathogens. Through a targeted RNAi screen examining the relevance of selected TRIM proteins in autophagy induced by herpes simplex virus 1 (HSV-1), encephalomyocarditis virus (EMCV) and influenza A virus (IAV), we identified several TRIM proteins that regulate autophagy in a virus-species-specific manner, as well as a few TRIM proteins that were essential for autophagy triggered by all three viruses and rapamycin, among them TRIM23. TRIM23 was critical for autophagy mediated restriction of multiple viruses, and this activity was dependent on both its RING E3 ligase and ADP-ribosylation factor (ARF) GTPase activity. Mechanistic studies revealed that unconventional K27-linked auto-ubiquitination of the ARF domain is essential for the GTP hydrolysis activity of TRIM23 and activation of TANK-binding kinase 1 (TBK1) by facilitating its dimerization and ability to phosphorylate the selective autophagy receptor p62. Our work identifies the TRIM23-TBK1-p62 axis as a key component of selective autophagy and further reveals a role for K27-linked ubiquitination in GTPase-dependent TBK1 activation. PMID- 28871092 TI - Acupuncture and related therapies used as add-on or alternative to prokinetics for functional dyspepsia: overview of systematic reviews and network meta analysis. AB - Prokinetics for functional dyspepsia (FD) have relatively higher number needed to treat values. Acupuncture and related therapies could be used as add-on or alternative. An overview of systematic reviews (SRs) and network meta-analyses (NMA) were performed to evaluate the comparative effectiveness of different acupuncture and related therapies. We conducted a comprehensive literature search for SRs of randomized controlled trials (RCTs) in eight international and Chinese databases. Data from eligible RCTs were extracted for random effect pairwise meta analyses. NMA was used to explore the most effective treatment among acupuncture and related therapies used alone or as add-on to prokinetics, compared to prokinetics alone. From five SRs, 22 RCTs assessing various acupuncture and related therapies were included. No serious adverse events were reported. Two pairwise meta-analyses showed manual acupuncture has marginally stronger effect in alleviating global FD symptoms, compared to domperidone or itopride. Results from NMA showed combination of manual acupuncture and clebopride has the highest probability in alleviating patient reported global FD symptom. Combination of manual acupuncture and clebopride has the highest probability of being the most effective treatment for FD symptoms. Patients who are contraindicated for prokinetics may use manual acupuncture or moxibustion as alternative. Future confirmatory comparative effectiveness trials should compare clebopride add-on manual acupuncture with domperidone add-on manual acupuncture and moxibustion. PMID- 28871093 TI - Fatty Acid Concentration and Phase Transitions Modulate Abeta Aggregation Pathways. AB - Aggregation of amyloid beta (Abeta) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Abeta aggregates, especially the low molecular weight oligomers, are the primary toxic agents in AD and hence, there is increasing interest in understanding their formation and behavior. Aggregation is a nucleation-dependent process in which the pre-nucleation events are dominated by Abeta homotypic interactions. Dynamic flux and stochasticity during pre-nucleation renders the reactions susceptible to perturbations by other molecules. In this context, we investigate the heterotypic interactions between Abeta and fatty acids (FAs) by two independent tool-sets such as reduced order modelling (ROM) and ensemble kinetic simulation (EKS). We observe that FAs influence Abeta dynamics distinctively in three broadly-defined FA concentration regimes containing non-micellar, pseudo-micellar or micellar phases. While the non-micellar phase promotes on-pathway fibrils, pseudo-micellar and micellar phases promote predominantly off-pathway oligomers, albeit via subtly different mechanisms. Importantly off-pathway oligomers saturate within a limited molecular size, and likely with a different overall conformation than those formed along the on-pathway, suggesting the generation of distinct conformeric strains of Abeta, which may have profound phenotypic outcomes. Our results validate previous experimental observations and provide insights into potential influence of biological interfaces in modulating Abeta aggregation pathways. PMID- 28871095 TI - Stable reconstruction of the (110) surface and its role in pseudocapacitance of rutile-like RuO2. AB - Surfaces of rutile-like RuO2, especially the most stable (110) surface, are important for catalysis, sensing and charge storage applications. Structure, chemical composition, and properties of the surface depend on external conditions. Using the evolutionary prediction method USPEX, we found stable reconstructions of the (110) surface. Two stable reconstructions, RuO4-(2 * 1) and RuO2-(1 * 1), were found, and the surface phase diagram was determined. The new RuO4-(2 * 1) reconstruction is stable in a wide range of environmental conditions, its simulated STM image perfectly matches experimental data, it is more thermodynamically stable than previously proposed reconstructions, and explains well pseudocapacitance of RuO2 cathodes. PMID- 28871094 TI - The immunologic advantage of recurrent nasopharyngeal carcinoma from the viewpoint of Galectin-9/Tim-3-related changes in the tumour microenvironment. AB - Given salvage treatment for recurrent nasopharyngeal carcinoma (NPC) remains a clinical dilemma, immunotherapy targeting NPC-specific immunosuppression may bring new hope. We analyzed the expression of CD8, CD4, Foxp3 and Tim-3 in lymphocytes, and of Galectin-9 in tumour cells between paired primary and recurrent NPC from 95 patients and we noted that there was significant increase in the expression of Galectin-9+ tumour cells (p < 0.001) and Foxp3+ lymphocytes (p < 0.001) but a significant decrease in the expression of CD8+ lymphocytes (p = 0.01) between paired primary and recurrent NPC. Of all patients, 53 patients (55.79%) and 57 patients (60%) had increased percentages of Galectin-9+ tumour cells and of Foxp3+ lymphocytes, respectively. Conversely, 42 patients (44.21%) had decreased percentages of CD8+ lymphocytes. The patients with high Galectin-9 expression in recurrent NPC frequently also had high Tim-3 (p = 0.04) and Foxp3 (p = 0.01), and low CD8 (p = 0.04) expression in lymphocytes. After multivariate analyses, low CD8 expression in lymphocytes was an independent risk factor for relapse-free survival (p = 0.002) and overall survival (p = 0.02). Our data suggests that recurrent NPC may had more immunologic advantage than primary NPC, especially the Galectin-9/Tim-3 pathway. The immunotherapies targeting Galectin 9/Tim-3/Foxp3 interaction may serve as a potential salvage treatment for recurrent NPC. PMID- 28871096 TI - Near-source high-rate GPS, strong motion and InSAR observations to image the 2015 Lefkada (Greece) Earthquake rupture history. AB - The 2015/11/17 Lefkada (Greece) earthquake ruptured a segment of the Cephalonia Transform Fault (CTF) where probably the penultimate major event was in 1948. Using near-source strong motion and high sampling rate GPS data and Sentinel-1A SAR images on two tracks, we performed the inversion for the geometry, slip distribution and rupture history of the causative fault with a three-step self consistent procedure, in which every step provided input parameters for the next one. Our preferred model results in a ~70 degrees ESE-dipping and ~13 degrees N striking fault plane, with a strike-slip mechanism (rake ~169 degrees ) in agreement with the CTF tectonic regime. This model shows a bilateral propagation spanning ~9 s with the activation of three main slip patches, characterized by rise time and peak slip velocity in the ranges 2.5-3.5 s and 1.4-2.4 m/s, respectively, corresponding to 1.2-1.8 m of slip which is mainly concentrated in the shallower (<10 km) southern half of the causative fault. The inferred slip distribution and the resulting seismic moment (M0 = 1.05 * 1019 N m) suggest a magnitude of M w 6.6. Our best solution suggests that the occurrence of large (M w > 6) earthquakes to the northern and to the southern boundaries of the 2015 causative fault cannot be excluded. PMID- 28871098 TI - Anisotropic resonance modes emerging in an antiferromagnetic superconducting state. AB - Two strong arguments in favor of magnetically driven unconventional superconductivity arise from the coexistence and closeness of superconducting and magnetically ordered phases on the one hand, and from the emergence of magnetic spin-resonance modes at the superconducting transition on the other hand. Combining these two arguments one may ask about the nature of superconducting spin-resonance modes occurring in an antiferromagnetic state. This problem can be studied in underdoped BaFe2 As2, for which the local coexistence of large moment antiferromagnetism and superconductivity is well established by local probes. However, polarized neutron scattering experiments are required to identify the nature of the resonance modes. In the normal state of Co underdoped BaFe2 As2 the antiferromagnetic order results in broad magnetic gaps opening in all three spin directions that are reminiscent of the magnetic response in the parent compound. In the superconducting state two distinct anisotropic resonance excitations emerge, but in contrast to numerous studies on optimum and over-doped BaFe2 As2 there is no isotropic resonance excitation. The two anisotropic resonance modes appearing within the antiferromagnetic phase are attributed to a band selective superconducting state, in which longitudinal magnetic excitations are gapped by antiferromagnetic order with sizable moment. PMID- 28871097 TI - Miltefosine Resistant Field Isolate From Indian Kala-Azar Patient Shows Similar Phenotype in Experimental Infection. AB - Emergence of resistance to drugs used to treat the Indian Kala-azar patients makes control strategy shattered. In this bleak situation, Miltefosine (MIL) was introduced to treat mainly antimonial unresponsive cases. Within years, resistance to MIL has been reported. While checking the MIL sensitivity of the recent KA clinical isolates (n = 26), we came across one isolate which showed four times more EC50 for MIL than that of MIL-Sensitive (MIL-S) isolates and considered as putative MIL-Resistant (MIL-R). The expressions of LdMT and LdRos3 genes of this isolate were found down regulated. Th1/Th2 cytokines, ROS and NO, FACS dot plots and mitochondrial trans membrane potential measurement were performed. In vivo hamster model with this MIL-R isolate showed much lesser reduction in liver weight (17.5%) compared to average reduction in liver weight (40.2%) of the animals infected with MIL-S isolates. The splenic and hepatic stamps smears of MIL-R infected hamsters revealed the retention of parasite load of about 51.45%. The splenocytes of these animals failed to proliferate anti leishmanial T-cells and lack of cell mediated immunity hampered recovery. Thus, these phenotypic expressions of experimental model may be considered similar to that of the MIL unresponsive patients. This is first such kind of report. PMID- 28871099 TI - Vocal greeting during mother-infant reunions in a nocturnal primate, the gray mouse lemur (Microcebus murinus). AB - In human societies, ritualized greeting behavior includes gestural and vocal displays to signal the social acceptance of an encountering person. These displays are universal across cultures suggesting a pre-human origin. Vocal greeting displays are only reported for monkeys and apes with complex social systems, but none of these studies confirmed that greeting signals fulfill all criteria characterizing human greeting behavior. In this study, we analyzed for the first time whether vocal exchanges between mother and infants in a non-human primate fulfill the criteria of human greeting behavior and whether vocal greeting behavior is present in a basal primate with a less complex social system, the gray mouse lemur. By comparing spontaneous leave-takings and reunions, we found that vocal exchanges during mother-infant reunions fulfilled all six criteria characterizing human greeting behavior. Thus, predictable reciprocal vocal exchanges occurred at the start of the reunion (but not during leave-taking), when mother and infant had visual contact to each other. Thus, we argued that mother-infant vocal exchanges governing reunions are essential to establish social bonds and to ritualize the greeting function. Our findings suggest that ritualized vocal greeting has its origins deeply rooted in mammalian phylogeny and derives from vocal exchanges during parent-infant reunions. PMID- 28871100 TI - Exposure to arousal-inducing sounds facilitates visual search. AB - Exposure to affective stimuli could enhance perception and facilitate attention via increasing alertness, vigilance, and by decreasing attentional thresholds. However, evidence on the impact of affective sounds on perception and attention is scant. Here, a novel aspect of affective facilitation of attention is studied: whether arousal induced by task-irrelevant auditory stimuli could modulate attention in a visual search. In two experiments, participants performed a visual search task with and without auditory-cues that preceded the search. Participants were faster in locating high-salient targets compared to low-salient targets. Critically, search times and search slopes decreased with increasing auditory induced arousal while searching for low-salient targets. Taken together, these findings suggest that arousal induced by sounds can facilitate attention in a subsequent visual search. This novel finding provides support for the alerting function of the auditory system by showing an auditory-phasic alerting effect in visual attention. The results also indicate that stimulus arousal modulates the alerting effect. Attention and perception are our everyday tools to navigate our surrounding world and the current findings showing that affective sounds could influence visual attention provide evidence that we make use of affective information during perceptual processing. PMID- 28871101 TI - Retrospective Analysis of Structural Disease Progression in Retinitis Pigmentosa Utilizing Multimodal Imaging. AB - In this report, we assess the natural progression rate of retinitis pigmentosa (RP) over an average of three years using spectral-domain optical coherence tomography (SD-OCT) and short wavelength fundus autofluorescence (SW-AF). Measurement of the ellipsoid zone (EZ) line width and hyperautofluorescent ring diameters was performed in 81 patients with RP in a retrospective, longitudinal fashion. Rate of structural disease progression, symmetry between eyes, and test retest variability were quantified. We observed on average, EZ-line widths decreased by 140 um (5.2%, p < 0.001) per year, and average horizontal and vertical hyperautofluorescent ring diameters decreased by 149 um (3.6%, p < 0.001) and 120 um (3.9%, p < 0.001) per year, respectively. The 95th percentile of this cohort had differences in progression slopes between eyes that were less than 154 um, 118 um, and 132 um for EZ-line width and horizontal and vertical ring diameters, respectively. For all measures except horizontal ring diameter, progression rates were significantly slower at end-stage disease. From our data, we observed a statistically significant progression rate in EZ line width and SW AF ring diameters over time, verifying the utility of these measurements for disease monitoring purposes. Additionally, calculated differences in progression slopes between eyes may prove useful for investigators evaluating the efficacy of unilateral treatments for RP in clinical trials. PMID- 28871103 TI - Lipidomic dysregulation within the lung parenchyma following whole-thorax lung irradiation: Markers of injury, inflammation and fibrosis detected by MALDI-MSI. AB - Radiation-induced lung injury (RILI) is a delayed effect of acute radiation exposure that can limit curative cancer treatment therapies and cause lethality following high-dose whole-thorax lung irradiation (WTLI). To date, the exact mechanisms of injury development following insult remain ill-defined and there are no FDA approved pharmaceutical agents or medical countermeasures. Traditionally, RILI development is considered as three phases, the clinically latent period, the intermediate acute pneumonitis phase and the later fibrotic stage. Utilizing matrix-assisted laser desorption ionization mass spectrometry imaging, we identified a number of lipids that were reflective of disease state or injury. Lipids play central roles in metabolism and cell signaling, and thus reflect the phenotype of the tissue environment, making these molecules pivotal biomarkers in many disease processes. We detected decreases in specific surfactant lipids irrespective of the different pathologies that presented within each sample at 180 days post whole-thorax lung irradiation. We also detected regional increases in ether-linked phospholipids that are the precursors of PAF, and global decreases in lipids that were reflective of severe fibrosis. Taken together our results provide panels of lipids that can differentiate between naive and irradiated samples, as well as providing potential markers of inflammation and fibrosis. PMID- 28871102 TI - Angiotensin II affects inflammation mechanisms via AMPK-related signalling pathways in HL-1 atrial myocytes. AB - Inflammation is a common cause of cardiac arrhythmia. Angiotensin II (Ang II) is a major contributing factor in the pathogenesis of cardiac inflammation; however, its underlying molecular mechanism remains unclear. Here, we explored the effect of Ang II on inflammatory mechanisms and oxidative stress using HL-1 atrial myocytes. We showed that Ang II activated c-Jun N-terminal kinase (JNK) phosphorylation and other inflammatory markers, such as transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha). Ang II decreased oxygen consumption rate, which resulted in reactive oxygen species (ROS) generation and inhibition of ROS blocked Ang II-mediated JNK phosphorylation and TGF-beta1 induction. Ang II induced the expression of its specific receptor, AT1R. Ang II-induced intracellular calcium production associated with Ang II-mediated signalling pathways. In addition, the generated ROS and calcium stimulated AMPK phosphorylation. Inhibiting AMPK blocked Ang II mediated JNK and TGF-beta signalling pathways. Ang II concentration, along with TGF-beta1 and tumor necrosis factor-alpha levels, was slightly increased in plasma of patients with atrial fibrillation. Taken together, these results suggest that Ang II induces inflammation mechanisms through an AMPK-related signalling pathway. Our results provide new molecular targets for the development of therapeutics for inflammation-related conditions, such as atrial fibrillation. PMID- 28871104 TI - Aggregated mesoporous nanoparticles for high surface area light scattering layer TiO2 photoanodes in Dye-sensitized Solar Cells. AB - Hierarchically structured aggregates, consisting of TiO2 nanoparticles were produced via one-step solvothermal syntheses with a mixed solvent system containing both acetic acid and ethanol. Two of the resulting structures, one ~700 nm and the other ~300 nm in diameter, were found to be comprised of 8.5 nm and 10.5 nm anatase crystals, and possess specific surface areas of 138 and 106 m2 g-1 respectively. These particles were incorporated into Dye-sensitized Solar Cells (DSCs) as high surface area scattering layers, along with a layer of a transparent material. Solar-to-electric conversion efficiencies (PCE) of 9.1% and 8.2% were recorded using these aggregated particles as compared to those of commonly used large particles scattering layer 7.4%. PMID- 28871106 TI - 3D imaging of the brain morphology and connectivity defects in a model of psychiatric disorders: MAP6-KO mice. AB - In the central nervous system, microtubule-associated protein 6 (MAP6) is expressed at high levels and is crucial for cognitive abilities. The large spectrum of social and cognitive impairments observed in MAP6-KO mice are reminiscent of the symptoms observed in psychiatric diseases, such as schizophrenia, and respond positively to long-term treatment with antipsychotics. MAP6-KO mice have therefore been proposed to be a useful animal model for these diseases. Here, we explored the brain anatomy in MAP6-KO mice using high spatial resolution 3D MRI, including a volumetric T1w method to image brain structures, and Diffusion Tensor Imaging (DTI) for white matter fiber tractography. 3D DTI imaging of neuronal tracts was validated by comparing results to optical images of cleared brains. Changes to brain architecture included reduced volume of the cerebellum and the thalamus and altered size, integrity and spatial orientation of some neuronal tracks such as the anterior commissure, the mammillary tract, the corpus callosum, the corticospinal tract, the fasciculus retroflexus and the fornix. Our results provide information on the neuroanatomical defects behind the neurological phenotype displayed in the MAP6-KO mice model and especially highlight a severe damage of the corticospinal tract with defasciculation at the location of the pontine nuclei. PMID- 28871105 TI - Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer. AB - Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small cell lung cancer models. Moreover, phospho-Akt levels are increased in most clinical specimens obtained from EGFR-mutant non-small-cell lung cancer patients with acquired EGFR tyrosine kinase inhibitor resistance. Our findings provide a rationale for clinical trials testing Akt and EGFR inhibitor co-treatment in patients with elevated phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms.EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo. PMID- 28871107 TI - Concentration, source identification, and exposure risk assessment of PM2.5-bound parent PAHs and nitro-PAHs in atmosphere from typical Chinese cities. AB - Sixteen parent PAHs and twelve nitro-PAHs were measured in PM2.5 samples collected over one year (2013-2014) at nine urban sites in China. During the sampling period, concentrations of individual nitro-PAHs were one or two orders of magnitude lower than their parent PAHs. Typical seasonal variations in parent PAH concentrations, which increased 10- to 80- fold in winter compared to summer, were observed in this study. Conversely, the mean atmospheric concentrations of nitro-PAHs were similar in all four seasons, with the exception of 9 nitroanthracene (9n-Ant). Compared to other nitro-PAHs which were secondary formation products, 9n-Ant had a higher concentration and made up a larger proportion of total nitro-PAHs. Positive matrix factorization results indicated that 9n-Ant sources included biomass burning (20%), vehicle exhaust emissions (43%), and secondary formation (30%). Overall, the elevated concentrations of parent PAHs observed in winter correlated with the contribution from coal combustion at all sites, especially in north China (>80%). The contribution of secondary formation products to total nitro-PAHs was measured during the summer, and was especially high in the larger cities such as Shanghai (84%), Beijing (76%), Guangzhou (60%), and Chengdu (64%), largely due to the summer concentrations of parent PAHs were markedly lower than in winter. PMID- 28871108 TI - Allelic variation of the rice blast resistance gene Pid3 in cultivated rice worldwide. AB - In this study, the re-sequencing data from 3,000 rice genomes project (3 K RGP) was used to analyze the allelic variation at the rice blast resistance (R) Pid3 locus. A total of 40 haplotypes were identified based on 71 nucleotide polymorphic sites among 2621 Pid3 homozygous alleles in the 3k genomes. Pid3 alleles in most japonica rice accessions were pseudogenes due to premature stop mutations, while those in most indica rice accessions were identical to the functional haplotype Hap_6, which had a similar resistance spectrum as the previously reported Pid3 gene. By sequencing and CAPS marker analyzing the Pid3 alleles in widespread cultivars in China, we verified that Hap_6 had been widely deployed in indica rice breeding of China. Thus, we suggest that the priority for utilization of the Pid3 locus in rice breeding should be on introducing the functional Pid3 alleles into japonica rice cultivars and the functional alleles of non-Hap_6 haplotypes into indica rice cultivars for increasing genetic diversity. PMID- 28871109 TI - Two-color pump-probe interferometry of ultra-fast light-matter interaction. AB - Two-color side-view probing of light-matter interaction from minute focal volume of a tightly focused fs-laser pump pulse reveals charge dynamics with high 0.9 MUm optical resolution and approximately ~45fs temporal resolution defined by pulse duration. Use of two colors is advantageous for probing optically excited plasma regions with different density. Holographical digital focusing and spatial filtering were implemented to obtain the same resolution images for subsequent Fourier analysis. Fast plasma density decay with time constant ~150 fs was resolved and is consistent with self-trapping. Potential applications of an optical control over light-induced defects with deep-sub-wavelength resolution is discussed. PMID- 28871110 TI - A Deep Learning-Based Radiomics Model for Prediction of Survival in Glioblastoma Multiforme. AB - Traditional radiomics models mainly rely on explicitly-designed handcrafted features from medical images. This paper aimed to investigate if deep features extracted via transfer learning can generate radiomics signatures for prediction of overall survival (OS) in patients with Glioblastoma Multiforme (GBM). This study comprised a discovery data set of 75 patients and an independent validation data set of 37 patients. A total of 1403 handcrafted features and 98304 deep features were extracted from preoperative multi-modality MR images. After feature selection, a six-deep-feature signature was constructed by using the least absolute shrinkage and selection operator (LASSO) Cox regression model. A radiomics nomogram was further presented by combining the signature and clinical risk factors such as age and Karnofsky Performance Score. Compared with traditional risk factors, the proposed signature achieved better performance for prediction of OS (C-index = 0.710, 95% CI: 0.588, 0.932) and significant stratification of patients into prognostically distinct groups (P < 0.001, HR = 5.128, 95% CI: 2.029, 12.960). The combined model achieved improved predictive performance (C-index = 0.739). Our study demonstrates that transfer learning based deep features are able to generate prognostic imaging signature for OS prediction and patient stratification for GBM, indicating the potential of deep imaging feature-based biomarker in preoperative care of GBM patients. PMID- 28871111 TI - Monitoring the electron dynamics of the excited state via higher-order spectral minimum. AB - A pump-probe scheme for monitoring the electron dynamics of the excited state has been investigated by numerically solving the two-state time-dependent Schrodinger equation based on the non-Born-Oppenheimer approximation. By adjusting the delay time between a mid-infrared probe pulse and an ultra violet pump pulse, an obvious minimum can be seen in the higher-order harmonic region. With electron probability density distribution, ionization rate and classical simulation, the minimum can be ascribed to the electron localization around one nucleus at larger delay time and represents the electron dynamics of the excited state at the time of ionization. Moreover, the position of the minimum is much more sensitive to the nuclear motion. PMID- 28871112 TI - Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish. AB - Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Previously we have found that some stromal cells, including hepatic stellate cells (HSCs), neutrophils and macrophages, play crucial roles in promoting sex disparity in kras V12 -induced zebrafish HCC. The activation of HSCs is mediated by serotonin while activation of neutrophils and macrophages is mediated by cortisol. To ensure that these findings are also applicable to other oncogene induced tumors, stromal cell activation was compared between male and female fish during liver tumorigenesis initiated by xmrk or Myc oncogene. Consistently, we observed male biased liver tumorigenesis in the xmrk and Myc models. In both models, there was a higher rate of HSC activation accompanied with a higher level of serotonin in male liver tumors. For tumor-infiltrated neutrophils and macrophages, significantly higher densities in male liver tumors were observed in both xmrk and Myc models. However, the male-biased increase of cortisol was observed only in xmrk- but not apparently in Myc expressing liver tumors. Overall, these observations are consistent with the observations in the kras liver tumor model, indicating that the serotonin- and cortisol-mediated pathways also play roles in sex disparity of liver tumors caused by other molecular pathways. PMID- 28871114 TI - A comparative integrated gene-based linkage and locus ordering by linkage disequilibrium map for the Pacific white shrimp, Litopenaeus vannamei. AB - The Pacific whiteleg shrimp, Litopenaeus vannamei, is the most farmed aquaculture species worldwide with global production exceeding 3 million tonnes annually. Litopenaeus vannamei has been the focus of many selective breeding programs aiming to improve growth and disease resistance. However, these have been based primarily on phenotypic measurements and omit potential gains by integrating genetic selection into existing breeding programs. Such integration of genetic information has been hindered by the limited available genomic resources, background genetic parameters and knowledge on the genetic architecture of commercial traits for L. vannamei. This study describes the development of a comprehensive set of genomic gene-based resources including the identification and validation of 234,452 putative single nucleotide polymorphisms in-silico, of which 8,967 high value SNPs were incorporated into a commercially available Illumina Infinium ShrimpLD-24 v1.0 genotyping array. A framework genetic linkage map was constructed and combined with locus ordering by disequilibrium methodology to generate an integrated genetic map containing 4,817 SNPs, which spanned a total of 4552.5 cM and covered an estimated 98.12% of the genome. These gene-based genomic resources will not only be valuable for identifying regions underlying important L. vannamei traits, but also as a foundational resource in comparative and genome assembly activities. PMID- 28871113 TI - TRIB3 inhibits proliferation and promotes osteogenesis in hBMSCs by regulating the ERK1/2 signaling pathway. AB - Osteogenic differentiation in human bone marrow-derived mesenchymal stem cells (hBMSCs) is regulated by various factors, including bone morphogenetic proteins (BMPs), Notch, growth hormones and mitogen-activated protein kinases (MAPKs). Tribbles homolog 3 (TRIB3), a pseudokinase, plays an important role in cancer cells and adipocytes. However, TRIB3 function in osteogenic differentiation is unknown, although it is involved in regulating signaling pathways associated with osteogenic differentiation. Here, we found that TRIB3 was highly expressed during osteogenic differentiation in hBMSCs. Inhibition of focal adhesion kinase (FAK) or phosphatidylinositol 3-kinase (PI3K) resulted in a significant decrease in TRIB3 expression, and expression of TRIB3 was restored by increasing insulin-like growth factor-1 (IGF-1) via activating phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling. TRIB3 knock-down enhanced proliferation and decreased osteogenic differentiation at the middle stage of differentiation, and these effects were reversed by inhibiting the activation of extracellular signal regulated kinase (ERK)-1/2. In conclusion, TRIB3 plays an important role in proliferation and osteogenic differentiation by regulating ERK1/2 activity at the middle stage of differentiation, and expression of TRIB3 is regulated by FAK in a PI3K/AKT-dependent manner. PMID- 28871115 TI - In-situ visualization of multiple filament competition dynamic during nonlinear propagation of femtosecond laser. AB - In this work, multiple filamentation competition of femtosecond pulse in methanol is studied both experimentally and numerically. The visualization of multiple filamentation competition has been realized in the experiment performing the three-photon fluorescence of Coumarin 440. The random changes of multiple filamentation stemmed from the jitter of the peak laser intensity ratio of initial hot spots are first observed directly and visually, which can be well explained by a simplified (2D+1)-dimensional model. PMID- 28871116 TI - Controlling Directed Protein Interaction Networks in Cancer. AB - Control theory is a well-established approach in network science, with applications in bio-medicine and cancer research. We build on recent results for structural controllability of directed networks, which identifies a set of driver nodes able to control an a-priori defined part of the network. We develop a novel and efficient approach for the (targeted) structural controllability of cancer networks and demonstrate it for the analysis of breast, pancreatic, and ovarian cancer. We build in each case a protein-protein interaction network and focus on the survivability-essential proteins specific to each cancer type. We show that these essential proteins are efficiently controllable from a relatively small computable set of driver nodes. Moreover, we adjust the method to find the driver nodes among FDA-approved drug-target nodes. We find that, while many of the drugs acting on the driver nodes are part of known cancer therapies, some of them are not used for the cancer types analyzed here; some drug-target driver nodes identified by our algorithms are not known to be used in any cancer therapy. Overall we show that a better understanding of the control dynamics of cancer through computational modelling can pave the way for new efficient therapeutic approaches and personalized medicine. PMID- 28871118 TI - Durable and self-hydrating tungsten carbide-based composite polymer electrolyte membrane fuel cells. AB - Proton conductivity of the polymer electrolyte membranes in fuel cells dictates their performance and requires sufficient water management. Here, we report a simple, scalable method to produce well-dispersed transition metal carbide nanoparticles. We demonstrate that these, when added as an additive to the proton exchange Nafion membrane, provide significant enhancement in power density and durability over 100 hours, surpassing both the baseline Nafion and platinum containing recast Nafion membranes. Focused ion beam/scanning electron microscope tomography reveals the key membrane degradation mechanism. Density functional theory exposes that OH* and H* radicals adsorb more strongly from solution and reactions producing OH* are significantly more endergonic on tungsten carbide than on platinum. Consequently, tungsten carbide may be a promising catalyst in self-hydrating crossover gases while retarding desorption of and capturing free radicals formed at the cathode, resulting in enhanced membrane durability.The proton conductivity of polymer electrolyte membranes in fuel cells dictates their performance, but requires sufficient water management. Here, the authors report a simple method to produce well-dispersed transition metal carbide nanoparticles as additives to enhance the performance of Nafion membranes in fuel cells. PMID- 28871117 TI - Conjoint and dissociated structural and functional abnormalities in first-episode drug-naive patients with major depressive disorder: a multimodal meta-analysis. AB - Published MRI evidence of structural and resting-state functional brain abnormalities in MDD has been inconsistent. To eliminate interference by repeated disease episodes and antidepressant treatment, we conducted the first multimodal voxel-wise meta-analysis of studies of voxel-based morphometry (VBM) and the amplitude of low-frequency fluctuation (ALFF) in first-episode drug-naive MDD patients, using the Seed-based d Mapping method (SDM). Fifteen VBM data sets and 11 ALFF data sets were included. SDM-based multimodal meta-analysis was used to highlight brain regions with both structural and functional abnormalities. This identified conjoint structural and functional abnormalities in left lateral orbitofrontal cortex and right supplementary motor area, and also dissociated abnormalities of structure (decreased grey matter in right dorsolateral prefrontal cortex and right inferior temporal gyrus; increased grey matter in right insula, right putamen, left temporal pole, and bilateral thalamus) and function (increased brain activity in left supplementary motor area, left parahippocampal gyrus, and hippocampus; decreased brain activity in right lateral orbitofrontal cortex). This study reveals a complex pattern of conjoint and dissociated structural and functional abnormalities, supporting the involvement of basal ganglia-thalamocortical circuits, representing emotional, cognitive and psychomotor abnormalities, in the pathophysiology of early-stage MDD. Specifically, this study adds to Psychoradiology, an emerging subspecialty of radiology, which seems primed to play a major clinical role in guiding diagnostic and treatment planning decisions in patients with mental disorder. PMID- 28871119 TI - Magnetite nanoparticles enhance the performance of a combined bioelectrode-UASB reactor for reductive transformation of 2,4-dichloronitrobenzene. AB - Direct interspecies electron transfer (DIET) among the cometabolism microbes plays a key role in the anaerobic degradation of persistent organic pollutants and stability of anaerobic bioreactor. In this study, the COD removal efficiency increased to 99.0% during the start-up stage in the combined bioelectrode-UASB system (R1) with magnetite nanoparticles addition, which was higher than those in the coupled bioelectrode-UASB (R2; 83.2%) and regular UASB (R3; 71.0%). During the stable stage, the increase of 2,4-dichloronitrobenzene (2,4-DClNB) concentration from 25 mg L-1 to 200 mg L-1 did not affect the COD removal efficiencies in R1 and R2, whereas the performance of R3 was deteriorated obviously. Further intermediates analysis indicated that magnetite nanoparticles enhanced the reductive dechlorination of 2,4-DClNB. High-throughput sequencing results showed that the functional microbes like Syntrophobacter and Syntrophomonas which have been reported to favor the DIET, were predominant on the cathode surface of R1 reactor. It is speculated that the addition of magnetite nanoparticles favors the cooperative metabolism of dechlorinating microbes and electricigens during 2,4-DClNB degradation process in the combined bioelectrode-UASB reactor. This study may provide a new strategy to improve the performance of microbial electrolysis cells and enhance the pollutant removal efficiency. PMID- 28871120 TI - Development of a luciferase-based biosensor to assess enterovirus 71 3C protease activity in living cells. AB - Enterovirus 71 (EV71) is a major pathogen of hand, foot, and mouth disease (HFMD). To date, no antiviral drug has been approved to treat EV71 infection. Due to the essential role that EV71 3 C protease (3Cpro) plays in the viral life cycle, it is generally considered as a highly appealing target for antiviral drug development. In this study, we present a transgene-encoded biosensor that can accurately, sensitively and quantitatively report the proteolytic activity of EV71 3Cpro. This biosensor is based on the catalyzed activity of a pro interleukin (IL)-1beta-enterovirus 3Cpro cleavage site-Gaussia Luciferase (GLuc) fusion protein that we named i-3CS-GLuc. GLuc enzyme is inactive in the fusion protein because of aggregation caused by pro-IL-1beta. However, the 3Cpro of EV71 and other enteroviruses, such as coxsackievirus A9 (CVA9), coxsackievirus B3 (CVB3), and poliovirus can recognize and process the canonical enterovirus 3Cpro cleavage site between pro-IL-1beta and GLuc, thereby releasing and activating GLuc and resulting in increased luciferase activity. The high sensitivity, ease of use, and applicability as a transgene in cell-based assays of i-3CS-GLuc biosensor make it a powerful tool for studying viral protease proteolytic events in living cells and for achieving high-throughput screening of antiviral agents. PMID- 28871121 TI - Effects of cycloheximide on the interpretation of ribosome profiling experiments in Schizosaccharomyces pombe. AB - Stress conditions lead to global and gene-specific changes in RNA translation. Ribosome profiling experiments have identified genome-wide alterations in the distribution of ribosomes along mRNAs. However, it is contentious whether these changes reflect real responses, or whether they are artefacts caused by the use of inhibitors of translation (notably cycloheximide). To address this issue we performed ribosome profiling with the fission yeast Schizosaccharomyces pombe under conditions of exponential growth (unstressed) and nitrogen starvation (nutritional stress), and both in the presence and absence of cycloheximide. We examined several aspects of the translational response, including density of ribosomal footprints on coding sequences, 5' leader ribosomal densities, distribution of ribosomes along coding sequences, and ribosome codon occupancies. Cycloheximide had minor effects on overall ribosome density, which affected mostly mRNAs encoding ribosomal proteins. Nitrogen starvation caused an accumulation of ribosomes on 5' leaders in both cycloheximide-treated and untreated cells. By contrast, stress-induced ribosome accumulation on the 5' side of coding sequences was cycloheximide-dependent. Finally, codon occupancy showed strong positive correlations in cycloheximide-treated and untreated cells. Our results demonstrate that cycloheximide does influence some of the results of ribosome profiling experiments, although it is not clear if this effect is always artefactual. PMID- 28871122 TI - Effect of Correlations in Swarms on Collective Response. AB - Social interaction increases significantly the performance of a wide range of cooperative systems. However, evidence that natural swarms limit the number of interactions suggests potentially detrimental consequences of excessive interaction. Using a canonical model of collective motion, we find that the collective response to a dynamic localized perturbation-emulating a predator attack-is hindered when the number of interacting neighbors exceeds a certain threshold. Specifically, the effectiveness in avoiding the predator is enhanced by large integrated correlations, which are known to peak at a given level of interagent interaction. From the network-theoretic perspective, we uncover the same interplay between number of connections and effectiveness in group-level response for two distinct decision-making models of distributed consensus operating over a range of static networks. The effect of the number of connections on the collective response critically depends on the dynamics of the perturbation. While adding more connections improves the response to slow perturbations, the opposite is true for fast ones. These results have far reaching implications for the design of artificial swarms or interaction networks. PMID- 28871123 TI - The role of Hfq in regulation of lipA expression in Pseudomonas protegens Pf-5. AB - Pseudomonas lipase is a well-studied lipase. However, few studies have been conducted to examine the mechanisms underlying the regulation of the lipase expression. Hfq is a global regulatory protein that, among others, controls the expression of multiple genes, regulate bacterial peristalsis, and participates in the regulation of quorum-sensing (QS) system. In this study, the effects of Hfq on lipase expression were investigated by knocking out the hfq and rsmY genes or overexpressing of hfq and rsmY genes. We found that Hfq regulates the expression of lipA at both transcriptional and translational levels. The translational level was the main regulatory level of lipA. Hfq also regulates the expression and stability of rsmY. Additionally, using hfq/rsmY double gene knock-out, we showed that Hfq can directly bind to the rsmY to regulate lipA activity. In conclusion, our results indicate that Hfq regulates the expression of rsmY mainly at the translational level to influence the expression of lipA in Pseudomonas protegens Pf-5. PMID- 28871124 TI - Cell Division Cycle 42 plays a Cell type-Specific role in Lung Tumorigenesis. AB - Cell division cycle 42 (CDC42) plays important roles in polarity establishment and maintenance as well as cell cycle progression and cell division. Although disruption of cell polarity is a prerequisite in epithelial tumor initiation, the roles of CDC42 in tumorigenesis are still poorly understood. Here we find that Cdc42 deficiency inhibits the Kras G12D -induced lung alveoli tumor formation, while conversely promotes bronchiole tumor formation in mice. Bronchial Cdc42 loss destroys contact inhibition potentially through cell polarity disruption, and results in increased tumor formation. In contrast, deletion of Cdc42 in alveoli cells prevents Kras G12D -induced cell proliferation, which leads to reduced tumor formation. Further analyses of clinical specimens uncover a significant positive correlation between CDC42 and type II alveolar epithelial cells marker SP-A, indicating the potential importance of CDC42 in this specific subset of lung cancer. Collectively, we identify the lineage-specific function of CDC42 in lung tumorigenesis potentially through the regulation of cell polarity integrity. PMID- 28871125 TI - HIV-1 matrix protein p17 misfolding forms toxic amyloidogenic assemblies that induce neurocognitive disorders. AB - Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation that adversely affects a patient's quality of life. HIV-1 matrix protein p17 (p17) has been detected in autoptic brain tissue of HAND individuals who presented early with severe AIDS encephalopathy. We hypothesised that the ability of p17 to misfold may result in the generation of toxic assemblies in the brain and may be relevant for HAND pathogenesis. A multidisciplinary integrated approach has been applied to determine the ability of p17 to form soluble amyloidogenic assemblies in vitro. To provide new information into the potential pathogenic role of soluble p17 species in HAND, their toxicological capability was evaluated in vivo. In C. elegans, capable of recognising toxic assemblies of amyloidogenic proteins, p17 induces a specific toxic effect which can be counteracted by tetracyclines, drugs able to hinder the formation of large oligomers and consequently amyloid fibrils. The intrahippocampal injection of p17 in mice reduces their cognitive function and induces behavioral deficiencies. These findings offer a new way of thinking about the possible cause of neurodegeneration in HIV-1-seropositive patients, which engages the ability of p17 to form soluble toxic assemblies. PMID- 28871126 TI - MDM2 Contributes to High Glucose-Induced Glomerular Mesangial Cell Proliferation and Extracellular Matrix Accumulation via Notch1. AB - Murine double minute 2 (MDM2) is an E3-ubiquitin ligase critical for various biological functions. Previous data have revealed an indispensable role of MDM2 in kidney homeostasis. However, its role in glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) accumulation during hyperglycemia condition remains unclear. In our present study, we found that MDM2 protein level was significantly upregulated in high glucose-treated GMCs, while knocking down MDM2 by siRNA could attenuate high glucose-induced ECM accumulation and GMCs proliferation. Unexpectedly, Nutlin-3a, a MDM2-p53 interaction blocker, had no benefit in protecting diabetic mice from renal impairment in vivo and in alleviating high glucose-induced ECM accumulation in vitro. Intriguingly, we found that Notch1 signaling activation was obviously attenuated by MDM2 depletion in GMCs with high glucose exposure. However, Numb, a substrate of MDM2 which suppresses Notch1 signaling, was found not to be involved in the MDM2 and Notch1 association. Moreover, our findings demonstrated that MDM2 interacted with Notch1 intracellular domain (NICD1) independent of Numb and regulated the ubiquitination status of NICD1. Collectively, our data propose a pivotal role of MDM2 in high glucose-induced GMC proliferation and ECM accumulation, via modulating the activation of Notch1 signaling pathway in an ubiquitination-dependent way. PMID- 28871127 TI - Simultaneous multi-band valley-protected topological edge states of shear vertical wave in two-dimensional phononic crystals with veins. AB - The introduction of the concept of valley pseudospin to phononic crystals has made a remarkable topologically protected interface transport of sound, which opens a novel research area referred to as valley Hall topological insulators. Here, we demonstrate the simultaneous multi-band edge states of shear vertical waves in two-dimensional phononic crystals with veins. The multi-band edge states are topologically valley-protected and are obtained by simultaneously gapping multiple Dirac points at K (or K') under the inversion symmetry breaking. As the relative radius of the two adjacent steel columns varies, the band diagram undergoes a topological transition which can be characterized by topological charge distributions and opposite valley Chern numbers. Subsequently, the vortex chirality of the bulk valley modes is unveiled. With numerical simulations, simultaneous multi-band valley dependent edge states and the associated valley protected backscattering suppression around the curved waveguide are further demonstrated. Our work could become a promising platform for applications of multi-functional topological acoustic devices. PMID- 28871128 TI - Synergistic Effect of BDNF and FGF2 in Efficient Generation of Functional Dopaminergic Neurons from human Mesenchymal Stem Cells. AB - To understand the process of neurogenesis, generation of functional dopaminergic (DAergic) neurons from human mesenchymal stem cells (hMSCs) is important. BDNF has been reported to be responsible for inducing neuronal maturation and functionality. Previously, we have reported the efficient generation of neurons from human bone marrow derived MSCs using FGF2 alone. We hypothesize that hMSCs from various tissues [(bone marrow (BM), adipose tissue (AD) and dental pulp (DP)], if treated with BDNF on 9th day of induction, alongwith FGF2 will generate functional DAergic neurons. Hence, cells were characterized at morphometric, transcription and translational levels for various markers like MAP2, TH, NGN2, PITX3, DAT, synaptophysin, Kv4.2 and SCN5A. Functionality of in vitro generated neurons was studied by calcium ion imaging. Result analysis depicted that BDNF has effect on expression of dopaminergic neuronal markers at gene and protein levels and functionality of neurons. Among these hMSCs, DP-MSC showed significantly better neuronal characteristics in terms of morphology, expression of neuronal markers and foremost, functionality of neurons. From the present study, therefore, we concluded that i) BDNF has additive effect on neuronal characteristics and functionality ii) DP-MSC are better MSC candidate to study DAergic neurogenesis and perform future studies. PMID- 28871129 TI - A novel inducible mutagenesis screen enables to isolate and clone both embryonic and adult zebrafish mutants. AB - Conventional genetic screens for recessive mutants are inadequate for studying biological processes in the adult vertebrate due to embryonic lethality. Here, we report that a novel inducible mutagenesis system enables to study gene function in both embryonic and adult zebrafish. This system yields genetic mutants with conditional ectopic over- or under-expression of genes in F1 heterozygotes by utilizing inducible Tet-On transcriptional activation of sense or anti-sense transcripts from entrapped genes by Tol2 transposase-meditated transgenesis. Pilot screens identified 37 phenotypic mutants displaying embryonic defects (34 lines), adult fin regeneration defects (7 lines), or defects at both stages (4 lines). Combination of various techniques (such as: generating a new mutant allele, injecting gene specific morpholino or mRNA etc) confirms that Dox-induced embryonic abnormalities in 10 mutants are due to dysfunction of entrapped genes; and that Dox-induced under-expression of 6 genes causes abnormal adult fin regeneration. Together, this work presents a powerful mutagenesis system for genetic analysis from zebrafish embryos to adults in particular and other model organisms in general. PMID- 28871130 TI - Early weaning increases aggression and stereotypic behaviour in cats. AB - Behaviour problems are common in companion felines, and problematic behaviour may be a sign of chronic stress. In laboratory animals, early weaning increases the risk for aggression, anxiety, and stereotypic behaviour. However, very few studies have focused on early weaning in one of the world's most popular pets, the domestic cat, although weaning soon after the critical period of socialisation is common practice. To study the effects of early weaning (<12 weeks) on behaviour, a large data set (N = 5726, 40 breeds) was collected from home-living domestic cats through a questionnaire survey. The results show that weaning before 8 weeks of age increases the risk for aggression, but not fearful behaviour. Moreover, cats weaned after 14 weeks of age have a lower probability for aggression towards strangers than early weaned cats and a lower probability for stereotypic behaviour (excessive grooming) than cats weaned at 12 weeks. The effect of weaning age on stereotypic behaviour is partially explained by the effects on aggression. These findings indicate that early weaning has a detrimental effect on behaviour, and suggest delayed weaning as a simple and inexpensive approach to significantly improve the welfare of millions of domestic cats. PMID- 28871132 TI - An LC-MS Approach to Quantitative Measurement of Ammonia Isotopologues. AB - Ammonia is a fundamental aspect of metabolism spanning all of phylogeny. Metabolomics, including metabolic tracing studies, are an integral part of elucidating the role of ammonia in these systems. However, current methods for measurement of ammonia are spectrophotometric, and cannot distinguish isotopologues of ammonia, significantly limiting metabolic tracing studies. Here, we describe a novel LC-MS-based method that quantitatively assesses both 14N-and 15N-isotopologues of ammonia in polar metabolite extracts. This assay (1) quantitatively measures the concentration of ammonia in polar metabolite isolates used for metabolomic studies, and (2) accurately determines the percent isotope abundance of 15N-ammonia in a cell lysate for 15N-isotope tracing studies. We apply this assay to quantitatively measure glutamine-derived ammonia in lung cancer cell lines with differential expression of glutaminase. PMID- 28871131 TI - A novel quantitative PCR mediated by high-fidelity DNA polymerase. AB - The biggest challenge for accurate diagnosis of viral infectious disease is the high genetic variability of involved viruses, which affects amplification efficiency and results in low sensitivity and narrow spectrum. Here, we developed a new simple qPCR mediated by high-fidelity (HF) DNA polymerase. The new method utilizes an HFman probe and one primer. Fluorescent signal was generated from the 3'-5' hydrolysis of HFman probe by HF DNA polymerase before elongation initiation. Mismatches between probe/primer and template have less influence on the amplification efficiency of the new method. The new qPCR exhibited higher sensitivity and better adaptability to sequence variable templates than the conventional TaqMan probe based-qPCR in quantification of HIV-1 viral load. Further comparison with COBAS TaqMan HIV-1 Test (v2.0) showed a good correlation coefficient (R2 = 0.79) between both methods in quantification of HIV-1 viral load among 21 clinical samples. The characteristics of tolerance to variable templates and one probe-one primer system imply that the probe/primer design for the new method will be easier and more flexible than the conventional method for highly heterogeneous viruses. Therefore, the HF DNA polymerase-mediated qPCR method is a simple, sensitive and promising approach for the development of diagnostics for viral infectious diseases. PMID- 28871133 TI - Mixed invasive ductal and lobular carcinoma has distinct clinical features and predicts worse prognosis when stratified by estrogen receptor status. AB - In order to investigate clinicopathological characteristics and prognosis of mixed invasive ductal and lobular carcinoma (IDC-L), 209,109 primary breast cancer patients diagnosed with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) or IDC-L were included. It was found that IDC-L patients had lower tumor grade and higher hormone receptor positive proportions than IDC patients. Moreover, IDC-L patients were younger and had a similar hormone receptor status compared with ILC patients. Kaplan-Meier plots showed that the breast cancer-specific survival (BCSS) of IDC-L patients was significantly better than IDC patients (P < 0.001) and tended to be better than ILC patients (P = 0.166). However, after adjusting for clinicopathological factors, survival advantage of IDC-L disappeared. Subgroup analysis indicated that IDC-L had higher hazard ratios (HRs) than IDC in grade 1, grade 2, ER-positive and ER-negative subgroups. Survival analysis in ER-positive and ER-negative subgroups showed that IDC-L predicted a worse prognosis than IDC. In conclusion, IDC-L is a distinct histological subtype compared with IDC and ILC. Lower grade and higher ER positive proportions mainly contribute to its better prognosis. In both ER positive and ER-negative subgroups, IDC-L predicts worse prognosis than IDC, which suggested the inadequacy of IDC-based therapy and the need of escalated therapy. PMID- 28871134 TI - High-fat diet increases pain behaviors in rats with or without obesity. AB - Obesity is associated with increased risk for chronic pain. Basic mechanisms for this association are poorly understood. Using a milder version of a radicular pain model, local inflammation of the dorsal root ganglion (DRG), we observed marked increases in mechanical and cold allodynia in rats of both sexes that were maintained on a high-fat diet (HFD) for 6 weeks prior to DRG inflammation. Notably, this increase in pain-related behaviors occurred in both Long-Evans and Sprague-Dawley rats despite the fact that the 6-week HFD exposure induced obesity (e.g., increased insulin, leptin, weight, and percent body fat) in the Long Evans, but not Sprague-Dawley, strains. This suggested that HFD, rather than obesity per se, increased pain behaviors. Increased pain behaviors were observed even after a much shorter (1 week) exposure to the HFD but the effect was smaller. HFD also increased behavioral responses and paw swelling to paw injection of complete Freund's adjuvant, a model of peripheral inflammatory pain. No change was detected in plasma cytokine levels in HFD rats. However, increased macrophage infiltration of the DRG was observed in response to the HFD, absent any pain model. The results suggest that HFD can increase pain even when it does not cause obesity. PMID- 28871135 TI - Physico-chemical characterization of Antheraea mylitta silk mats for wound healing applications. AB - In the field of plastic reconstructive surgery, development of new innovative matrices for skin repair is in demand. The ideal biomaterial should promote attachment, proliferation and growth of cells. Additionally, it should degrade in an appropriate time period without releasing harmful substances, not exerting a pathological immune response. The materials used should display optimized mechanical properties to sustain cell growth and limit scaffold contraction. Wound healing is a biological process directed towards restoration of tissue that has suffered an injury. An important phase of wound healing is the generation of a basal epithelium wholly replacing the epidermis of the wound. Wild silk from Antheraea mylitta meets these demands to a large extent. To evaluate the effects of the treatment, Antheraea mylitta and Bombyx mori samples were characterized by SEM-EDX, FT-IR, XRD and TGA-DSC techniques. Preliminary cell growth behavior was carried out by culturing epidermal cells and proliferation was quantified via viability assay. Moreover, Antheraea mylitta possesses excellent cell-adhesive capability, effectively promoting cell attachment and proliferation. Antheraea mylitta serves as a delivery vehicle for cells. With all these unique features, it is expected that Antheraea mylitta mat will have wide utility in the areas of tissue engineering and regenerative medicine. PMID- 28871136 TI - Small molecule T63 suppresses osteoporosis by modulating osteoblast differentiation via BMP and WNT signaling pathways. AB - Osteoporosis results from the imbalance between bone resorption and bone formation, and restoring the normal balance of bone remodeling is highly desirable for identification of better treatment. In this study, using a cell based high-throughput screening model representing Runt-related transcription factor 2 (RUNX2) transcriptional activity, we identified a novel small-molecular weight compound, T63, as an efficient up-regulator of osteogenesis. T63 increased the alkaline phosphatase (ALPL) activity and mineralization as well as gene expression of Alpl and other osteogenic marker genes in mouse osteoblasts and mesenchymal stem cell-like cells. Upon induction of osteoblast differentiation, T63 inhibited adipogenic differentiation in the pluripotent mesenchymal cells. Consistently, T63 up-regulated RUNX2 mRNA and protein levels, and knockdown of RUNX2 reduced the osteogenic role of T63. Mechanistically, T63 activated both BMPs and WNT/beta-catenin signaling pathways. Inhibition of either signaling pathway with specific inhibitor suppressed T63-induced RUNX2 expression and the osteogenic phenotypes. Moreover, T63 markedly protected against bone mass loss in the ovariectomized and dexamethasone treated rat osteoporosis model. Collectively, our data demonstrate that T63 could be a promising drug candidate and deserves further development for potential therapeutics in osteoporosis. PMID- 28871137 TI - C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation. AB - Overexpression of the BRE (brain and reproductive organ-expressed) gene defines a distinct pediatric and adult acute myeloid leukemia (AML) subgroup. Here we identify a promoter enriched for active chromatin marks in BRE intron 4 causing strong biallelic expression of a previously unknown C-terminal BRE transcript. This transcript starts with BRE intron 4 sequences spliced to exon 5 and downstream sequences, and if translated might code for an N terminally truncated BRE protein. Remarkably, the new BRE transcript was highly expressed in over 50% of 11q23/KMT2A (lysine methyl transferase 2A)-rearranged and t(8;16)/KAT6A-CREBBP cases, while it was virtually absent from other AML subsets and normal tissues. In gene reporter assays, the leukemia-specific fusion protein KMT2A-MLLT3 transactivated the intragenic BRE promoter. Further epigenome analyses revealed 97 additional intragenic promoter marks frequently bound by KMT2A in AML with C terminal BRE expression. The corresponding genes may be part of a context dependent KMT2A-MLLT3-driven oncogenic program, because they were higher expressed in this AML subtype compared with other groups. C-terminal BRE might be an important contributor to this program because in a case with relapsed AML, we observed an ins(11;2) fusing CHORDC1 to BRE at the region where intragenic transcription starts in KMT2A-rearranged and KAT6A-CREBBP AML. PMID- 28871138 TI - Predicting irreversible electroporation-induced tissue damage by means of magnetic resonance electrical impedance tomography. AB - Irreversible electroporation (IRE) is gaining importance in routine clinical practice for nonthermal ablation of solid tumors. For its success, it is extremely important that the coverage and exposure time of the treated tumor to the electric field is within the specified range. Measurement of electric field distribution during the electroporation treatment can be achieved using magnetic resonance electrical impedance tomography (MREIT). Here, we show improved MREIT enabled electroporation monitoring of IRE-treated tumors by predicting IRE ablated tumor areas during IRE of mouse tumors in vivo. The in situ prediction is enabled by coupling MREIT with a corresponding Peleg-Fermi mathematical model to obtain more informative monitoring of IRE tissue ablation by providing cell death probability in the IRE-treated tumors. This technique can potentially be used in electroporation-based clinical applications, such as IRE tissue ablation and electrochemotherapy, to improve and assure the desired treatment outcome. PMID- 28871139 TI - A strategy for the identification of patterns in the biosynthesis of nonribosomal peptides by Betaproteobacteria species. AB - Nonribosomal peptides have an important pharmacological role due to their extensive biological properties. The singularities in the biosynthesis of these natural products allowed the development of genome-mining strategies which associate them to their original biosynthetic gene clusters. Generally, these compounds present complex architectures that make their identification difficult. Based on these evidences, genomes from species of the class Betaproteobacteria were studied with the purpose of finding biosynthetic similarities among them . These organisms were applied as templates due to their large number of biosynthetic gene clusters and the natural products isolated from them. The strategy for Rapid Identification of Nonribosomal Peptides Portions (RINPEP) proposed in this work was built by reorganizing the data obtained from antiSMASH and NCBI with a product-centered way. The verification steps of RINPEP comprehended the fragments of existent compounds and predictions obtained in silico with the purpose of finding common subunits expressed by different genomic sequences. The results of this strategy revealed patterns in a global overview of the biosynthesis of nonribosomal peptides by Betaproteobacteria. PMID- 28871140 TI - Increased incidence of cytomegalovirus coinfection in HCV-infected patients with late liver fibrosis is associated with dysregulation of JAK-STAT pathway. AB - Herein, we examined the association between cytomegalovirus (CMV) coinfection and the progression of liver fibrosis in hepatitis C virus (HCV) infection, and investigated the effect of CMV coinfection on JAK-STAT pathway. CMV DNAemia was detected by PCR in DNA from controls (n = 120), and HCV patients with early (F0 F1, n = 131) and late (F2-F4, n = 179) liver fibrosis. By quantitative real time PCR (qRT-PCR), we examined the profile of 8 JAK-STAT transcripts in PBMCs RNA from 90 HCV patients (39 CMV positive and 51 CMV negative), 4 CMV mono-infected patients, and 15 controls. Our results demonstrated higher incidence of CMV in F2 F4 group than in control (OR 5.479, 95% CI 3.033-9.895, p < 0.0001) or F0-F1 groups (OR 2, 95% CI 1.238-3.181, p = 0.005). qRT-PCR showed downregulation of STAT2 (p = 0.006) and IRF7 (p = 0.02) in CMV positive group compared to CMV negative one. The downregulation of STAT2 and IRF7 was mainly in CMV positive patients with late fibrosis compared to CMV negative patients (p = 0.0007 for IRF7 and p = 0.01 for STAT2). Our results are the first to report that CMV coinfection is a possible risk factor for the progression of HCV-induced liver fibrosis, and thereby CMV screening and treatment are important for HCV patients. PMID- 28871141 TI - Monolithic integration of AlGaInP-based red and InGaN-based green LEDs via adhesive bonding for multicolor emission. AB - In general, to realize full color, inorganic light-emitting diodes (LEDs) are diced from respective red-green-blue (RGB) wafers consisting of inorganic crystalline semiconductors. Although this conventional method can realize full color, it is limited when applied to microdisplays requiring high resolution. Designing a structure emitting various colors by integrating both AlGaInP-based and InGaN-based LEDs onto one substrate could be a solution to achieve full color with high resolution. Herein, we introduce adhesive bonding and a chemical wet etching process to monolithically integrate two materials with different bandgap energies for green and red light emission. We successfully transferred AlGaInP based red LED film onto InGaN-based green LEDs without any cracks or void areas and then separated the green and red subpixel LEDs in a lateral direction; the dual color LEDs integrated by the bonding technique were tunable from the green to red color regions (530-630 nm) as intended. In addition, we studied vertically stacked subpixel LEDs by deeply analyzing their light absorption and the interaction between the top and bottom pixels to achieve ultra-high resolution. PMID- 28871142 TI - Genetic and non-genetic determinants of thymic epithelial cell number and function. AB - The thymus is the site of T cell development in vertebrates. In general, the output of T cells is determined by the number of thymic epithelial cells (TECs) and their relative thymopoietic activity. Here, we show that the thymopoietic activity of TECs differs dramatically between individual mouse strains. Moreover, in males of some strains, TECs perform better on a per cell basis than their counterparts in females; in other strains, this situation is reversed. Genetic crosses indicate that TEC numbers and thymopoietic capacity are independently controlled. Long-term analysis of functional parameters of TECs after castration provides evidence that the number of Foxn1-expressing TECs directly correlates with thymopoietic activity. Our study highlights potential complications that can arise when comparing parameters of TEC biology across different genetic backgrounds; these could affect the interpretation of the outcomes of interventions aimed at modulating thymic activity in genetically diverse populations, such as humans. PMID- 28871143 TI - Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine. AB - Chronic constipation is a prevalent functional gastrointestinal disorder accompanied with intestinal dysbiosis. However, causal relationship between dysbiosis and constipation remains poorly understood. Serotonin transporter (SERT) is a transmembrane transport protein which re-uptakes excessive 5 hydroxytryptamine (5-HT) from effective location to terminate its physiological effects and involves in regulating gastrointestinal motility. In this study, fecal microbiota from patients with constipation and healthy controls were transplanted into the antibiotic depletion mice model. The mice which received fecal microbiota from patients with constipation presented a reducing in intestinal peristalsis and abnormal defecation parameters including the frequency of pellet expulsion, fecal weight and fecal water content. After fecal microbiota transplantation, the SERT expression in the colonic tissue was significantly upregulated, and the content of 5-HT was decreased which negatively correlated with the gastrointestinal transit time. Moverover, fecal microbiota from the mice which received fecal microbiota from patients with constipation also upregulated SERT in Caco-2 cells. Besides, this process accompanied with the decreased abundance of Clostridium, Lactobacillus, Desulfovibrio, and Methylobacterium and an increased tend of Bacteroides and Akkermansia, which also involved in the impairment of intestinal barrier after FMT. Taken together, intestinal dysbiosis may upregulate the SERT expression and contribute to the development of chronic constipation. PMID- 28871144 TI - Evolutionary morphology of the lizard chemosensory system. AB - Foraging mode plays a pivotal role in traditional reconstructions of squamate evolution. Transitions between modes are said to spark concerted changes in the morphology, physiology, behaviour, and life history of lizards. With respect to their sensory systems, species that adopt a sit-and-wait strategy are thought to rely on visual cues primarily, while actively hunting species would predominantly use chemical information. The morphology of the tongue and the vomeronasal-organs is believed to mirror this dichotomy. Still, support for this idea of concerted evolution of the morphology of the lizard sensory system merely originates from studies comparing only a few, distantly related taxa that differ in many aspects of their biology besides foraging mode. Hence, we compared vomeronasal-lingual morphology among closely related lizard species (Lacertidae). Our findings show considerable interspecific variation indicating that the chemosensory system of lacertids has undergone substantial change over a short evolutionary time. Although our results imply independent evolution of tongue and vomeronasal-organ form, we find evidence for co-variation between sampler and sensor, hinting towards an 'optimization' for efficient chemoreception. Furthermore, our findings suggest species' degree of investment in chemical signalling, and not foraging behaviour, as a leading factor driving the diversity in vomeronasal-lingual morphology among lacertid species. PMID- 28871145 TI - Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy. AB - Mitophagy orchestrates the autophagic degradation of dysfunctional mitochondria preventing their pathological accumulation and contributing to cellular homeostasis. We previously identified a novel chemical tool (hereafter referred to as PMI), which drives mitochondria into autophagy without collapsing their membrane potential (DeltaPsim). PMI is an inhibitor of the protein-protein interaction (PPI) between the transcription factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autophagy associated proteins, including p62/SQSTM1. Here we show that PMI promotes mitochondrial respiration, leading to a superoxide-dependent activation of mitophagy. Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover, while covalent Keap1 modifiers, including sulforaphane (SFN) and dimethyl fumarate (DMF), are unable to induce a similar response. Additionally, we demonstrate that SFN reverses the effects of PMI in co-treated cells by reducing the accumulation of p62 in mitochondria and subsequently limiting their autophagic degradation. This study highlights the unique features of Keap1-Nrf2 PPI inhibitors as inducers of mitophagy and their potential as pharmacological agents for the treatment of pathological conditions characterized by impaired mitochondrial quality control. PMID- 28871146 TI - Light rare earth element depletion during Deepwater Horizon blowout methanotrophy. AB - Rare earth elements have generally not been thought to have a biological role. However, recent work has demonstrated that the light REEs (LREEs: La, Ce, Pr, and Nd) are essential for at least some methanotrophs, being co-factors in the XoxF type of methanol dehydrogenase (MDH). We show here that dissolved LREEs were significantly removed in a submerged plume of methane-rich water during the Deepwater Horizon (DWH) well blowout. Furthermore, incubation experiments conducted with naturally methane-enriched waters from hydrocarbon seeps in the vicinity of the DWH wellhead also showed LREE removal concurrent with methane consumption. Metagenomic sequencing of incubation samples revealed that LREE containing MDHs were present. Our field and laboratory observations provide further insight into the biochemical pathways of methanotrophy during the DWH blowout. Additionally, our results are the first observations of direct biological alteration of REE distributions in oceanic systems. In view of the ubiquity of LREE-containing MDHs in oceanic systems, our results suggest that biological uptake of LREEs is an overlooked aspect of the oceanic geochemistry of this group of elements previously thought to be biologically inactive and an unresolved factor in the flux of methane, a potent greenhouse gas, from the ocean. PMID- 28871147 TI - Breast Cancer Spheroids Reveal a Differential Cancer Stem Cell Response to Chemotherapeutic Treatment. AB - An abnormal multicellular architecture is a defining characteristic of breast cancer and, yet, most in vitro tumor models fail to recapitulate this architecture or accurately predict in vivo cellular responses to therapeutics. The efficacy of two front-line chemotherapeutic agents (paclitaxel and cisplatin) are described within three distinct in vitro models employing the triple-negative basal breast cancer cell line MDA-MB-231 and the luminal breast cancer cell line MCF7: a) a 3D collagen embedded multicellular spheroid tumor model, which reflects the architecture and cellular heterogeneity of tumors in vivo; b) a 3D collagen model with a single cell-type diffusely embedded; and c) a 2D monolayer. The MDA-MB-231 embedded spheroid tumor model exhibited the most robust response to chemotherapeutic treatment, and possessed the greatest cancer stem cell (CSC) content. CSC-related genes are elevated across all MDA-MB-231 in vitro models following paclitaxel treatment, indicating that paclitaxel enrichment of chemoresistant CSCs is less dependent on microenvironmental tumor structure, while cisplatin showed a more context-dependent response. In the MCF7 cell models a context-dependent response is observed with paclitaxel treatment increasing the CSC related genes in the 2D monolayer and 3D diffuse models while cisplatin treatment afforded an increase in ALDH1A3 expression in all three models. PMID- 28871149 TI - Rapid LC-MS Based High-Throughput Screening Method, Affording No False Positives or False Negatives, Identifies a New Inhibitor for Carbonic Anhydrase. AB - Developing effective high-throughput screening (HTS) methods is of paramount importance in the early stage of drug discovery. While rugged and robust assays may be easily developed for certain enzymes, HTS assays designed to identify ligands that block protein binding are much more challenging to develop; attenuating the number of false positives and false negatives under high throughput screening conditions is particularly difficult. We describe an MS based HTS workflow that addresses these challenges. The assay mitigates false positives by selectively identifying positive hits exclusively when a ligand at the binding site of interest is displaced; it mitigates false negatives by detecting a reporter compound that ionizes well, not by detecting the ligand binder, which may not ionize. The method was validated by detecting known binders of three proteins, pepsin, maltose binding protein (MBP), and carbonic anhydrase (CA) in the presence of hundreds of non-binders. We also identified a novel CA binder, pifithrin-u, which could not have been identified by any other MS-based assay because of its poor ionization efficiency. This new method addresses many of the challenges that are currently encountered during high-throughput screening. PMID- 28871148 TI - Editing an alpha-globin enhancer in primary human hematopoietic stem cells as a treatment for beta-thalassemia. AB - beta-Thalassemia is one of the most common inherited anemias, with no effective cure for most patients. The pathophysiology reflects an imbalance between alpha- and beta-globin chains with an excess of free alpha-globin chains causing ineffective erythropoiesis and hemolysis. When alpha-thalassemia is co-inherited with beta-thalassemia, excess free alpha-globin chains are reduced significantly ameliorating the clinical severity. Here we demonstrate the use of CRISPR/Cas9 genome editing of primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes the MCS-R2 alpha-globin enhancer and causes alpha-thalassemia. When edited CD34+ cells are differentiated into erythroid cells, we observe the expected reduction in alpha-globin expression and a correction of the pathologic globin chain imbalance in cells from patients with beta-thalassemia. Xenograft assays show that a proportion of the edited CD34+ cells are long-term repopulating hematopoietic stem cells, demonstrating the potential of this approach for translation into a therapy for beta thalassemia.beta-thalassemia is characterised by the presence of an excess of alpha-globin chains, which contribute to erythrocyte pathology. Here the authors use CRISP/Cas9 to reduce alpha-globin expression in hematopoietic precursors, and show effectiveness in xenograft assays in mice. PMID- 28871150 TI - Intragastric balloon as an adjunct to lifestyle programme in severely obese adolescents: impact on biomedical outcomes and skeletal health. AB - Intragastric Balloons are a temporary, reversible and safer option compared to bariatric surgery to promote significant weight loss, leading to improved metabolic outcomes. However, due to subsequent weight regain, alternative procedures are now preferred in adults. In adolescents, more amenable to lifestyle change, balloons may be an alternative to less reversible procedures. Our aim was to assess the tolerability and efficacy of the intragastric balloon in severely obese adolescents and the impact of associated weight loss on biomedical outcomes (glucose metabolism, blood pressure, lipid profiles) and bone density. A 2-year cohort study of 12 adolescents (BMI >3.5 s.d., Tanner stage >4) following 6 months intragastric balloon placement was carried out. Subjects underwent anthropometry, oral glucose tolerance test, and DEXA scans at 0, 6 and 24 months. The results showed clinically relevant improvements in blood pressure, insulin: glucose metabolism, liver function and sleep apnoea at 6 months. Changes were not sustained at 2 years though some parameters (Diastolic BP, HBA1c, insulin AUC) demonstrated longer-term improvement despite weight regain. Despite weight loss, bone mass accrual showed age appropriate increases. In conclusion, the intragastric balloon was safe, well tolerated and effective in supporting short-term weight loss and clinically relevant improvement in obesity-related complications, which resolved in some individuals. Benefits were not sustained in the majority at 2 years. PMID- 28871151 TI - Time-Resolved Pharmacological Studies using Automated, On-line Monitoring of Five Parallel Suspension Cultures. AB - Early stage pharmacological studies rely on in vitro methodologies for screening and testing compounds. Conventional assays based on endpoint measurements provide limited information because the lack in temporal resolution may not determine the pharmacological effect at its maximum. We developed an on-line, automated system for near real-time monitoring of extracellular content from five parallel suspension cultures, combining cell density measurements with a high-resolution separations every 12 minutes for 4 days. Selector and switching valves provide the fluidic control required to sample from one culture during the analysis of the previous sample from another culture, a time-saving measure that is fundamental to the throughput of the presented system. The system was applied to study the metabolic effects of the drugs rotenone, beta-lapachone and clioquinol using lactate as metabolic indicator. For each drug, 96 assays were executed on the extracellular matrix at three concentrations with two controls in parallel, consuming only 5.78 mL of media from each culture over four days, less than 60 MUL per analysis. The automated system provides high sample throughput, good temporal resolution and low sample consumption combined with a rugged analytical method with adequate sensitivity, providing a promising new platform for pharmacological and biotechnological studies. PMID- 28871153 TI - Omni-resonant optical micro-cavity. AB - Optical cavities transmit light only at discrete resonant frequencies, which are well-separated in micro-structures. Despite attempts at the construction of planar 'white-light cavities', the benefits accrued upon optically interacting with a cavity - such as resonant field buildup - have remained confined to narrow linewidths. Here, we demonstrate achromatic optical transmission through a planar Fabry-Perot micro-cavity via angularly multiplexed phase-matching that exploits a bio-inspired grating configuration. By correlating each wavelength with an appropriate angle of incidence, a continuous spectrum resonates and the micro cavity is rendered transparent. The locus of a single-order 0.7-nm-wide resonance is de-slanted in spectral-angular space to become a 60-nm-wide achromatic resonance spanning multiple cavity free-spectral-ranges. The result is an 'omni resonant' planar micro-cavity in which light resonates continuously over a broad spectral span. This approach severs the link between the resonance bandwidth and the cavity-photon lifetime, thereby promising resonant enhancement of linear and nonlinear optical effects over broad bandwidths in ultrathin devices. PMID- 28871154 TI - Herbivores rescue diversity in warming tundra by modulating trait-dependent species losses and gains. AB - Climate warming is altering the diversity of plant communities but it remains unknown which species will be lost or gained under warming, especially considering interactions with other factors such as herbivory and nutrient availability. Here, we experimentally test effects of warming, mammalian herbivory and fertilization on tundra species richness and investigate how plant functional traits affect losses and gains. We show that herbivory reverses the impact of warming on diversity: in the presence of herbivores warming increases species richness through higher species gains and lower losses, while in the absence of herbivores warming causes higher species losses and thus decreases species richness. Herbivores promote gains of short-statured species under warming, while herbivore removal and fertilization increase losses of short statured and resource-conservative species through light limitation. Our results demonstrate that both rarity and traits forecast species losses and gains, and mammalian herbivores are essential for preventing trait-dependent extinctions and mitigate diversity loss under warming and eutrophication.Warming can reduce plant diversity but it is unclear which species will be lost or gained under interacting global changes. Kaarlejarvi et al. manipulate temperature, herbivory and nutrients in a tundra system and find that herbivory maintains diversity under warming by reducing species losses and promoting gains. PMID- 28871155 TI - Long-distance impact of Iceland plume on Norway's rifted margin. AB - Results of a 3D modeling study inspired by recent seismic tomography of the Northern Atlantic mantle suggest that a complex pattern of hot mantle distribution with long horizontal flows originating from the Iceland mantle plume has been the norm in the geological past. In the Northern Atlantic the Iceland plume has a strong long-distance impact on intraplate deformation affecting both onshore and offshore parts of Norway's rifted margin. As a result, this margin is characterized by large magnitude differential topography sustained over at least several tens of Myr. Here we use high-resolution 3D thermo-mechanical modeling to demonstrate that the long-distance plume impact can be explained by its fast lateral propagation controlled by pre-existing lithosphere structures. Numerical models show that these structures strongly affect the style of horizontal flow of plume head material. This results in long-distance propagation of hot material emplaced at the lithosphere-asthenosphere boundary causing long-wavelength anomalies in onshore topography of Norway's rifted margin. Short-wavelength offshore topographic domes are likely caused by joint occurrence of plume-related thermal perturbations and gravitational forces related to plate thickening (ridge push). Our 3D modeling brings together plume impingement, spreading ridge dynamics, and the formation of anomalous intraplate structures offshore Norway in one scenario. PMID- 28871152 TI - Genome-Wide Association Study of Blood Pressure Traits by Hispanic/Latino Background: the Hispanic Community Health Study/Study of Latinos. AB - Hypertension prevalence varies between ethnic groups, possibly due to differences in genetic, environmental, and cultural determinants. Hispanic/Latino Americans are a diverse and understudied population. We performed a genome-wide association study (GWAS) of blood pressure (BP) traits in 12,278 participants from the Hispanics Community Health Study/Study of Latinos (HCHS/SOL). In the discovery phase we identified eight previously unreported BP loci. In the replication stage, we tested these loci in the 1982 Pelotas Birth Cohort Study of admixed Southern Brazilians, the COGENT-BP study of African descent, women of European descent from the Women Health Initiative (WHI), and a sample of European descent from the UK Biobank. No loci met the Bonferroni-adjusted level of statistical significance (0.0024). Two loci had marginal evidence of replication: rs78701042 (NGF) with diastolic BP (P = 0.008 in the 1982 Pelotas Birth Cohort Study), and rs7315692 (SLC5A8) with systolic BP (P = 0.007 in European ancestry replication). We investigated whether previously reported loci associated with BP in studies of European, African, and Asian ancestry generalize to Hispanics/Latinos. Overall, 26% of the known associations in studies of individuals of European and Chinese ancestries generalized, while only a single association previously discovered in a people of African descent generalized. PMID- 28871156 TI - Late-onset hypersensitivity after a lesion in the ventral posterolateral nucleus of the thalamus: A macaque model of central post-stroke pain. AB - Central post-stroke pain (CPSP) can occur as a result of a cerebrovascular accident in the ventral posterolateral nucleus (VPL) of the thalamus. Developing therapeutic interventions for CPSP is difficult because its pathophysiology is unclear. Here we developed and characterized a macaque model of CPSP. The location of the VPL was determined by magnetic resonance imaging (MRI) and extracellular recording of neuronal activity during tactile stimulation, after which a hemorrhagic lesion was induced by injecting collagenase type IV. Histological analysis revealed that most of the lesion was localized within the VPL. Several weeks after the injection, the macaques displayed behavioral changes that were interpreted as reflecting the development of both mechanical allodynia and thermal hyperalgesia. Immunohistochemistry revealed that microglial and astrocytic activation in the perilesional areas lasted at least 3 months after injection. The present model reproduced the symptoms of patients suffering from CPSP, in which both mechanical allodynia and thermal hyperalgesia often develop several weeks after cerebrovascular accident. Further, the long-lasting glial activation revealed here may be characteristic of primate brains following injury. The present model will be useful not only for examining the neurological changes underlying CPSP, but also for testing therapeutic interventions for CPSP. PMID- 28871157 TI - GDP-D-mannose epimerase regulates male gametophyte development, plant growth and leaf senescence in Arabidopsis. AB - Plant GDP-D-mannose epimerase (GME) converts GDP-D-mannose to GDP-L-galactose, a precursor of both L-ascorbate (vitamin C) and cell wall polysaccharides. However, the genetic functions of GME in Arabidopsis are unclear. In this study, we found that mutations in Arabidopsis GME affect pollen germination, pollen tube elongation, and transmission and development of the male gametophyte through analysis of the heterozygous GME/gme plants and the homozygous gme plants. Arabidopsis gme mutants also exhibit severe growth defects and early leaf senescence. Surprisingly, the defects in male gametophyte in the gme plants are not restored by L-ascorbate, boric acid or GDP-L-galactose, though boric acid rescues the growth defects of the mutants, indicating that GME may regulate male gametophyte development independent of L-ascorbate and GDP-L-galactose. These results reveal key roles for Arabidopsis GME in reproductive development, vegetative growth and leaf senescence, and suggest that GME regulates plant growth and controls male gametophyte development in different manners. PMID- 28871158 TI - Hub-driven remote synchronization in brain networks. AB - The phenomenon of "remote synchronization" (RS), first observed in a star network of oscillators, involves synchronization of unconnected peripheral nodes through a hub that maintains independent dynamics. In the RS regime the central hub was thought to serve as a passive gate for information transfer between nodes. Here, we investigate the physical origin of this phenomenon. Surprisingly, we find that a hub node can drive remote synchronization of peripheral oscillators even in the presence of a repulsive mean field, thus actively governing network dynamics while remaining asynchronous. We study this novel phenomenon in complex networks endowed with multiple hub-nodes, a ubiquitous feature of many real-world systems, including brain connectivity networks. We show that a change in the natural frequency of a single hub can alone reshape synchronization patterns across the entire network, and switch from direct to remote synchronization, or to hub driven desynchronization. Hub-driven RS may provide a mechanism to account for the role of structural hubs in the organization of brain functional connectivity networks. PMID- 28871159 TI - Molecular characterization of 20 small supernumerary marker chromosome cases using array comparative genomic hybridization and fluorescence in situ hybridization. AB - The variability of a small supernumerary marker chromosome (sSMC)-related phenotype is determined by the molecular component, the size, and shape of the marker chromosome. As fluorescence in situ hybridization has limitations regarding the resolution, efficiency, and accuracy. Recently, array comparative genomic hybridization (aCGH) was used for sSMC characterization. In this study, twenty cases with sSMCs were characterized by aCGH and FISH. Chromosomal origin of the marker chromosomes were successfully identified in seventeen of them. For the three cases with negative aCGH results, two of them were more likely due to that the sSMCs only contained centromere heterochromatin, whereas the reason for the remaining case with negative aCGH finding was uncertain. In order to establish a stronger genotype-phenotype correlation for clinical service in the future and avoid miss characterization, more sSMC cases were needed to be detailed characterized. This will help to clarify the variable clinical characteristics of sSMCs and provide additional information to aid clinical service and future research. PMID- 28871161 TI - Developing cost-effective seismic mineral exploration methods using a landstreamer and a drophammer. AB - To be fully embraced into mineral exploration, seismic data require to be acquired fast, cheaper and with minimum environmental impacts addressing also the often brown-field highly noisy environment where these surveys are employed. Since 2013 and through a number of case studies, we have been testing a newly developed for urban environment, digital-based 240 m long, seismic landstreamer for mine planning and mineral exploration purposes. Here, we present a pilot study examining the potential of the streamer for deep targeting a known, down to approximately 850 m depth, iron-oxide mineralization in the Bergslagen mineral district of central Sweden. Combined streamer (100-3C-MEMS (micro electromechanical system), 2-4 m spacing) and 75 wireless recorders (mixed 10 Hz and MEMS, 10 m spacing) were used. A Bobcat-mounted drophammer, 500 kg, was used to generate the seismic signal. Within 4 days, approximately 3.5 km of seismic data using 2-10 m source and receiver spacing were acquired. Reflection data processing results clearly image the mineralization as a set of strong high amplitude reflections and likely slightly extending beyond the known 850 m depth. This is encouraging and suggests such a cost-effective exploration method can be used in the area and elsewhere to delineate similar depth range iron-oxide deposits. PMID- 28871160 TI - White light emission from a single organic molecule with dual phosphorescence at room temperature. AB - The development of single molecule white light emitters is extremely challenging for pure phosphorescent metal-free system at room temperature. Here we report a single pure organic phosphor, namely 4-chlorobenzoyldibenzothiophene, emitting white room temperature phosphorescence with Commission Internationale de l'Eclair age coordinates of (0.33, 0.35). Experimental and theoretical investigations reveal that the white light emission is emerged from dual phosphorescence, which emit from the first and second excited triplet states. We also demonstrate the validity of the strategy to achieve metal-free pure phosphorescent single molecule white light emitters by intrasystem mixing dual room temperature phosphorescence arising from the low- and high-lying triplet states.The development of single molecule white light-emitters is extremely challenging for pure phosphorescent metal-free systems at room temperature. Here the authors show a single pure organic room temperature phosphor, 4-chlorobenzoyldibenzothiophene, utilizing the emission from both T1 and T2 states. PMID- 28871162 TI - Cervical nodal volume for prognostication and risk stratification of patients with nasopharyngeal carcinoma, and implications on the TNM-staging system. AB - We aim to evaluate the quantitative parameters of 18F-FDG PET/CT (metabolic parameters) and MRI (morphologic parameters) for prognostication and risk stratification in nasopharyngeal carcinoma (NPC). 200 (147 males, aged 50 +/- 13 years-old, mean +/- S.D.) newly diagnosed patients with NPC (TxNxM0) were prospectively recruited. Primary tumor and nodal lesions were identified and segmented for both morphologic (volume, VOL) and metabolic (SUV and MTV) quantification. Independent predictive factors for recurrence free survival (RFS) and overall survival (OS) were morphologic nodal volume (VOL_N, p < 0.001), TNM stage (p = 0.022), N-Stage (p = 0.024) for RFS, and VOL_N (p = 0.014) for OS. Using Classification and Regression Tree (CART) analysis, three risk-layers were identified for RFS: Stage I/II with VOL_N < 18cc (HR = 1), stage III /IV with VOL_N < 18cc (HR = 2.93), VOL_N >= 18cc (HR = 7.84) regardless of disease stage (p < 0.001). For OS, two risk layers were identified: VOL_N < 18cc (HR = 1), VOL_N >= 18cc (HR = 4.23) (p = 0.001). The 18cc threshold for morphologic nodal volume was validated by an independent cohort (n = 105). Based on the above risk classification, 35 patients (17.5%) would have a higher risk than suggested by the TNM-staging system. Thus, morphologic nodal volume is an important factor in prognostication and risk stratification in NPC, and should be incorporated into the staging system, while PET parameters have no advantage for this purpose in our cohort. PMID- 28871163 TI - Increase of vitamin D assays prescriptions and associated factors: a population based cohort study. AB - A worldwide increase in the frequency of testing for serum 25-hydroxyvitamin D (25OHD) levels has been observed over the last years. Our aim was to measure the evolution in the number of vitamin D assays performed in France from 2008 to 2013 and to investigate some of the drivers that may explain this increase. Patients within the representative 1/97th sample of the French health insurance system reimbursement database (EGBS database) who had at least one 25OHD or 1-25(OH)2D assay between 2008 and 2013 were included. Trends over time in number of vitamin D assays were analysed globally and per year in a multivariable Poisson regression model with GEE. Among the 639,163 patients of the EGBS database, 118,509 (18.5%) had at least one vitamin D assay over the 6-year study period. Among the individuals tested, 52.1% had only one test. The number of vitamin D assays (25OHD or 1-25(OH)2D) increased 7.5-fold from 9,620 in 2008 to 81,641 in 2013. This study confirms the rapid and dramatic increase in vitamin D assays prescriptions and shows that this is mostly due to a global increase of the proportion of patients tested rather than an increase in repetition of tests in some individual patients. PMID- 28871164 TI - Tumor-infiltrating CD45RO+ Memory T Lymphocytes Predict Favorable Clinical Outcome in Solid Tumors. AB - The prognostic role of tumor-infiltrating CD45RO+ memory T lymphocytes (CD45RO+ T cells) in human solid tumors remains controversial. Herein, we conducted a meta analysis including 25 published studies with 4720 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor-infiltrating CD45RO+ T cells in human solid tumors. We found that CD45RO+ T cell infiltration was significantly associated with improved overall survival (OS) and disease-free survival (DFS) in all types of solid tumors. In stratified analyses, CD45RO+ T cell infiltration significantly improved 1-year, 3-year and 5-year OS in colorectal, gastric and esophageal cancer, but only 5-year OS in hepatocellular carcinoma. And these cells were positively associated with 1-year, 3-year and 5 year DFS in hepatocellular, colorectal and esophageal cancer. In addition, high density of intratumoral CD45RO+ T cells inversely correlated with TNM stage of solid tumor. In conclusion, CD45RO+ memory T lymphocyte infiltration leads to a favorable clinical outcome in solid tumors, implicating that it is a valuable biomarker for prognostic prediction for human solid malignances. PMID- 28871166 TI - The oceanic origin of path-independent carbon budgets. AB - Virtually all Earth system models (ESM) show a near proportional relationship between cumulative emissions of CO2 and change in global mean temperature, a relationship which is independent of the emissions pathway taken to reach a cumulative emissions total. The relationship, which has been named the Transient Climate Response to Cumulative CO2 Emissions (TCRE), gives rise to the concept of a 'carbon budget'. That is, a finite amount of carbon that can be burnt whilst remaining below some chosen global temperature change threshold, such as the 2.0 degrees C target set by the Paris Agreement. Here we show that the path independence of TCRE arises from the partitioning ratio of anthropogenic carbon between the ocean and the atmosphere being almost the same as the partitioning ratio of enhanced radiative forcing between the ocean and space. That these ratios are so close in value is a coincidence unique to CO2. The simple model used here is underlain by many assumptions and simplifications but does reproduce key aspects of the climate system relevant to the path-independence of carbon budgets. Our results place TCRE and carbon budgets on firm physical foundations and therefore help validate the use of these metrics for climate policy. PMID- 28871165 TI - Zoonotic intestinal helminths interact with the canine immune system by modulating T cell responses and preventing dendritic cell maturation. AB - Parasite co-evolution alongside the mammalian immune system gave rise to several modulatory strategies by which they prevent exaggerated pathology and facilitate a longer worm survival. As little is known about the immunoregulatory potential of the zoonotic canine parasites Ancylostoma caninum and Toxocara canis in the natural host, the present study aimed to investigate whether their larval excretory-secretory (ES) products can modulate the canine immune system. We demonstrated TcES to increase the frequency of CD4+ Foxp3high T cells, while both AcES and TcES were associated with elevated Helios expression in Foxp3high lymphocytes. ES products were further capable of inducing IL-10 production by lymphocytes, which was mainly attributed to CD8+ T cells. ES treatment of PBMCs prior to mitogen stimulation inhibited polyclonal proliferation of CD4+ and CD8+ T cells. Moreover, monocyte-derived ES-pulsed dendritic cells reduced upregulation of MHC-II and CD80 in response to lipopolysaccharide. The data showed that regulation of the canine immune system by A. caninum and T. canis larvae comprises the modification of antigen-specific and polyclonal T cell responses and dendritic cell maturation. PMID- 28871167 TI - Supported Cu0 nanoparticles catalyst for controlled radical polymerization reaction and block-copolymer synthesis. AB - The synthesis of Cu0 nanoparticles on different supports and their activity in controlled living radical polymerization processes is presented. The type of support influences the final size of the copper nanoparticles as well as their adhesion to the support. These aspects have a direct influence on the characteristics of the polymers obtained. The best results were obtained for SiO2 particles, which afforded a good molecular weight distribution (Mw/Mn = 1.25). The activity, recovery and recycling of the catalyst was explored for ultrafast polymerization reaction of butyl acrylate. Further, the terminal bromine reactivity was used for the synthesis of a block poly(n butyl acrylate-block styrene). The influence of ligand type on the control of the reaction was studied. Also, a straightforward polymerization procedure without any ligand afforded a polydispersity value of 1.38. PMID- 28871170 TI - Capturing PM2.5 Emissions from 3D Printing via Nanofiber-based Air Filter. AB - This study investigated the feasibility of using polycaprolactone (PCL) nanofiber based air filters to capture PM2.5 particles emitted from fused deposition modeling (FDM) 3D printing. Generation and aggregation of emitted particles were investigated under different testing environments. The results show that: (1) the PCL nanofiber membranes are capable of capturing particle emissions from 3D printing, (2) relative humidity plays a signification role in aggregation of the captured particles, (3) generation and aggregation of particles from 3D printing can be divided into four stages: the PM2.5 concentration and particles size increase slowly (first stage), small particles are continuously generated and their concentration increases rapidly (second stage), small particles aggregate into more large particles and the growth of concentration slows down (third stage), the PM2.5 concentration and particle aggregation sizes increase rapidly (fourth stage), and (4) the ultrafine particles denoted as "building unit" act as the fundamentals of the aggregated particles. This work has tremendous implications in providing measures for controlling the particle emissions from 3D printing, which would facilitate the extensive application of 3D printing. In addition, this study provides a potential application scenario for nanofiber based air filters other than laboratory theoretical investigation. PMID- 28871168 TI - Central Nervous System Responses of the Oriental migratory, Locusta migratoria manilensis, to Fungal Infection. AB - Responses of the central nervous system (CNS) to microbial challenge and the interplay between the CNS and the immune system are important for defending against pathogen attack. We have examined the CNS transcriptional response of Locusta migratoria manilensis to infection by the locust-specific fungal pathogen, Metarhizium acridum. CNS responses were examined during spore attachment, fungal germination and pre-penetration of the cuticle, and cuticle penetration/hemocoel ingress and proliferation. Effects were seen at the earliest time points (4 h post-infection) and the number of differentially expressed genes (DEGs) was highest during late mycosis (72 h post-infection). Significantly affected neurological pathways included genes involved in serotonergic, cholinergic, dopaminergic, GABAergic, and glutamergic synapse responses, as well as pathways responsible for synaptic vesicle cycle, long-term potentiation and depression, and neurotrophin and retrograde endocannabinoid signaling. In addition, a significant number of immune related DEGs were identified. These included components of the Toll, Imd and JAK/STAT pathways, consistent with interactions between the CNS and immune systems. The activation of immune response related CNS genes during early stage infection highlights the rapid detection of microbial pathogens and suggests an important role for the CNS in modulating immunity potentially via initiating behavioral adaptations along with innate immune responses. PMID- 28871169 TI - Ancestry & molecular evolutionary analyses of heat shock protein 47 kDa (HSP47/SERPINH1). AB - HSP47/SERPINH1 is key-regulator for collagen biosynthesis and its structural assembly. To date, there is no comprehensive study on the phylogenetic history of HSP47. Herein we illustrate the evolutionary history of HSP47/SERPINH1 along with sequence, structural and syntenic traits for HSP47/SERPINH1. We have identified ancestral HSP47/SERPINH1 locus in Japanese lamprey (Lethenteron japonicum). This gene remains on the same or similar locus for ~500 million years (MY), but chromosomal duplication was observed in ray-finned fishes, leading into three sets of three sets (I-III) of HSP47/SERPINH1. Two novel introns were inserted at the positions 36b and 102b in the first exon of only HSP47_1 gene from the selected ray-finned fishes. On the evolutionary time scale, the events of HSP47 duplications took placed between 416-360 MY ago (MYA) while intron insertion dates back to 231-190 MYA after early divergence of ray-finned fishes. PMID- 28871172 TI - The cytoplasmic nuclear receptor RARgamma controls RIP1 initiated cell death when cIAP activity is inhibited. AB - Tumor necrosis factor (TNF) has a critical role in diverse cellular events including inflammation, apoptosis and necroptosis through different signaling complexes. However, little is known about how the transition from inflammatory signaling to the engagement of death pathways is modulated. Here we report that the cytoplasmic retinoic acid receptor gamma (RARgamma) controls receptor interacting protein kinase 1 (RIP1)-initiated cell death when cellular inhibitor of apoptosis (cIAP) activity is blocked. Through screening a short hairpin RNA library, we found that RARgamma was essential for TNF-induced RIP1-initiated apoptosis and necroptosis. Our data suggests that RARgamma initiates the formation of death signaling complexes by mediating RIP1 dissociation from TNF receptor 1. We demonstrate that RARgamma is released from the nucleus to orchestrate the formation of the cytosolic death complexes. In addition, we demonstrate that RARgamma has a similar role in TNF-induced necroptosis in vivo. Thus, our study suggests that nuclear receptor RARgamma provides a key checkpoint for the transition from life to death.The molecular switch between how tumour necrosis factor (TNF) controls inflammation versus cell death is less well defined. Here, the authors show that the nuclear receptor retinoic acid receptor gamma is released from the nucleus to disrupt TNF initiated cell death complexes in the cytoplasm. PMID- 28871171 TI - Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities. AB - Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 +/- 0.7%, 86 +/- 0.7% and 85 +/- 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 +/- 0.1, 0.80 +/- 0.1 and 0.89 +/- 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis. PMID- 28871173 TI - Two loci single particle trajectories analysis: constructing a first passage time statistics of local chromatin exploration. AB - Stochastic single particle trajectories are used to explore the local chromatin organization. We present here a statistical analysis of the first contact time distributions between two tagged loci recorded experimentally. First, we extract the association and dissociation times from data for various genomic distances between loci, and we show that the looping time occurs in confined nanometer regions. Second, we characterize the looping time distribution for two loci in the presence of multiple DNA damages. Finally, we construct a polymer model, that accounts for the local chromatin organization before and after a double-stranded DNA break (DSB), to estimate the level of chromatin decompaction. This novel passage time statistics method allows extracting transient dynamic at scales varying from one to few hundreds of nanometers, it predicts the local changes in the number of binding molecules following DSB and can be used to characterize the local dynamic of the chromatin. PMID- 28871174 TI - Erythropoietin enhances Kupffer cell number and activity in the challenged liver. AB - Erythropoietin (EPO) is the main hormone driving mammalian erythropoiesis, with activity mediated via the surface receptor, EPO-R, on erythroid progenitor cells. Recombinant human EPO is currently used clinically for the treatment of anemia in patients with end-stage renal disease, and in certain cancer patients suffering from anemia induced either by the tumor itself or by chemotherapy. EPO-R expression is also detected in non-erythroid cells, including macrophages present in the peritoneum, spleen, and bone marrow (BM). Here we demonstrate that Kupffer cells (KCs) - the liver-resident macrophages - are EPO targets. We show that, in vitro, EPO initiated intracellular signalling and enhanced phagocytosis in a rat KC line (RKC-2) and in sorted KCs. Moreover, continuous EPO administration in mice, resulted in an increased number of KCs, up-regulation of liver EPO-R expression and elevated production of the monocyte chemoattractant CCL2, with corresponding egress of Ly6Chi monocytes from the BM. In a model of acute acetaminophen-induced liver injury, EPO administration increased the recruitment of Ly6Chi monocytes and neutrophils to the liver. Taken together, our results reveal a new role for EPO in stimulating KC proliferation and phagocytosis, and in recruiting Ly6Chi monocytes in response to liver injury. PMID- 28871175 TI - Fluorescent CRISPR Adaptation Reporter for rapid quantification of spacer acquisition. AB - CRISPR-Cas systems are adaptive prokaryotic immune systems protecting against horizontally transferred DNA or RNA such as viruses and other mobile genetic elements. Memory of past invaders is stored as spacers in CRISPR loci in a process called adaptation. Here we developed a novel assay where spacer integration results in fluorescence, enabling detection of memory formation in single cells and quantification of as few as 0.05% cells with expanded CRISPR arrays in a bacterial population. Using this fluorescent CRISPR Adaptation Reporter (f-CAR), we quantified adaptation of the two CRISPR arrays of the type I E CRISPR-Cas system in Escherichia coli, and confirmed that more integration events are targeted to CRISPR-II than to CRISPR-I. The f-CAR conveniently analyzes and compares many samples, allowing new insights into adaptation. For instance, we show that in an E. coli culture the majority of acquisition events occur in late exponential phase. PMID- 28871177 TI - Enhanced Low-temperature Electro-optical Kerr Effect of Stable Cubic Soft Superstructure Enabled by Fluorinated Polymer Stabilization. AB - An enhanced electro-optical Kerr effect of the stable self-organized cubic blue phase liquid crystal superstructure at a relatively low temperature down to -50 degrees C was achieved through a judiciously designed fluorinated polymer stabilization. The fluorinated sample exhibited not only a rather stable cubic structure, but the promoted electro-optical performances of low driving voltage, weak hysteresis and high contrast ratio at such a low-temperature, which were much distinct from the common non-fluorinated polymer stabilized blue phase liquid crystal without conspicuous low-temperature Kerr response behaviours. Kerr constant, which reflects the obviousness of Kerr effect, of the fluorinated sample at -50 degrees C indicated a spectacular enhancement of two orders of magnitude in contrast to the commonly material, thereby corroborating the high efficiency of polymer fluorination in enhancing low-temperature Kerr effect. Such an enhancement of Kerr effect was probably resulted from the decreasing of interfacial anchoring between liquid crystal and fluorinated polymer network. The fluorinated polymer stabilization not only ensures the stability of self organized cubic structure of blue phase, but overcomes the challenge and bottleneck problem of low-temperature inapplicability of common blue phase liquid crystal and paves a brilliant and broad way for relevant materials to abundant perspective applications at low temperature. PMID- 28871176 TI - Interleukin-17A is involved in mechanical hyperalgesia but not in the severity of murine antigen-induced arthritis. AB - Interleukin-17A (IL-17A) is considered an important pro-inflammatory cytokine but its importance in joint diseases such as rheumatoid arthritis (RA) is unclear. It has also been reported that IL-17A may induce pain but it is unclear whether pro inflammatory and pro-nociceptive effects are linked. Here we studied in wild type (WT) and IL-17A knockout (IL-17AKO) mice inflammation and hyperalgesia in antigen induced arthritis (AIA). We found that the severity and time course of AIA were indistinguishable in WT and IL-17AKO mice. Furthermore, the reduction of inflammation by sympathectomy, usually observed in WT mice, was preserved in IL 17AKO mice. Both findings suggest that IL-17A is redundant in AIA pathology. However, in the course of AIA IL-17AKO mice showed less mechanical hyperalgesia than WT mice indicating that IL-17A contributes to pain even if it is not crucial for arthritis pathology. In support for a role of IL-17A and other members of the IL-17 family in the generation of pain we found that sensory neurones in the dorsal root ganglia (DRG) express all IL-17 receptor subtypes. Furthermore, in isolated DRG neurones most IL-17 isoforms increased tetrodotoxin- (TTX-) resistant sodium currents which indicate a role of IL-17 members in inflammation evoked sensitization of sensory nociceptive neurones. PMID- 28871179 TI - Epigenetic analysis confirms no accelerated brain aging in schizophrenia. AB - Epigenetic aging is associated with several biological mechanisms and diseases. We assessed two brain data sets, one small (n = 48) and one large (n = 392), to test epigenetic aging in schizophrenia. DNA methylation age from frontal cortex was significantly correlated with chronological age but no significant differences in DNA methylation age acceleration between schizophrenia cases and controls were observed in both data sets. Our results were consistent with a previous study investigating schizophrenia and epigenetic aging in superior temporal gyrus. Future studies targeting different brain regions and defined cell types are warranted to further investigate accelerated brain aging in schizophrenia. PMID- 28871178 TI - A novel mathematical model of protein-bound uremic toxin kinetics during hemodialysis. AB - Protein-bound uremic toxins (PBUTs) are difficult to remove by conventional hemodialysis; a high degree of protein binding reduces the free fraction of toxins and decreases their diffusion across dialyzer membranes. Mechanistic understanding of PBUT kinetics can open new avenues to improve their dialytic removal. We developed a comprehensive model of PBUT kinetics that comprises: (1) a three-compartment patient model, (2) a dialyzer model. The model accounts for dynamic equilibrium between protein, toxin, and the protein-toxin complex. Calibrated and validated using clinical and experimental data from the literature, the model predicts key aspects of PBUT kinetics, including the free and bound concentration profiles for PBUTs and the effects of dialysate flow rate and dialyzer size on PBUT removal. Model simulations suggest that an increase in dialysate flow rate improves the reduction ratio (and removal) of strongly protein-bound toxins, namely, indoxyl sulfate and p-cresyl sulfate, while for weakly bound toxins, namely, indole-3-acetic acid and p-cresyl glucuronide, an increase in blood flow rate is advantageous. With improved dialyzer performance, removal of strongly bound PBUTs improves gradually, but marginally. The proposed model can be used for optimizing the dialysis regimen and for in silico testing of novel approaches to enhance removal of PBUTs. PMID- 28871181 TI - Inactivation of Staphylococcus aureus in water by pulsed spark discharge. AB - A pulsed spark plasma discharge system was developed and tested as an energy efficient water sterilization method. A 5 log10 reduction on Staphylococcus aureus concentration of 108 CFU/ml was obtained. Complete inactivation was achieved for concentration of 106 CFU/ml. Of the various factors generated by an underwater spark discharge, ultraviolet radiation plays a major role. The inactivation was completely suppressed by the addition of 30 mg/L of a soluble sunscreen, Benzophenone-9. Results obtained using the pulsed spark plasma discharge showed that this system has several advantages, such as high energy efficiency, absence of harmful by-products and portability, over the conventional sterilization methods. PMID- 28871180 TI - Phenotyping and susceptibility of established porcine cells lines to African Swine Fever Virus infection and viral production. AB - African swine fever virus (ASFV) is a highly pathogenic, double-stranded DNA virus with a marked tropism for cells of the monocyte-macrophage lineage, affecting swine species and provoking severe economic losses and health threats. In the present study, four established porcine cell lines, IPAM-WT, IPAM-CD163, C?2+ and WSL, were compared to porcine alveolar macrophage (PAM) in terms of surface marker phenotype, susceptibility to ASFV infection and virus production. The virulent ASFV Armenia/07, E70 or the naturally attenuated NHV/P68 strains were used as viral models. Cells expressed only low levels of specific receptors linked to the monocyte/macrophage lineage, with low levels of infection overall, with the exception of WSL, which showed more efficient production of strain NHV/P68 but not of strains E70 and Armenia/07. PMID- 28871182 TI - Mott Transition and Magnetism in Rare Earth Nickelates and its Fingerprint on the X-ray Scattering. AB - The metal-insulator transition (MIT) remains among the most thoroughly studied phenomena in solid state physics, but the complexity of the phenomena, which usually involves cooperation of many degrees of freedom including orbitals, fluctuating local moments, magnetism, and the crystal structure, have resisted predictive ab-initio treatment. Here we develop ab-initio theoretical method for correlated electron materials, based on Dynamical Mean Field Theory, which can predict the change of the crystal structure across the MIT at finite temperature. This allows us to study the coupling between electronic, magnetic and orbital degrees of freedom with the crystal structure across the MIT in rare-earth nickelates. We predict the electronic free energy profile of the competing states, and the theoretical magnetic ground state configuration, which is in agreement with neutron scattering data, but is different from the magnetic models proposed before. The resonant elastic X-ray response at the K-edge, which was argued to be a probe of the charge order, is theoretically modelled within the Dynamical Mean Field Theory, including the core-hole interaction. We show that the line-shape of the measured resonant elastic X-ray response can be explained with the "site-selective" Mott scenario without real charge order on Ni sites. PMID- 28871183 TI - Functional expression of the entire adhesiome of Salmonella enterica serotype Typhimurium. AB - Adhesins are crucial virulence factors of pathogenic bacteria involved in colonization, transmission and pathogenesis. Many bacterial genomes contain the information for a surprisingly large number of diverse adhesive structures. One prominent example is the invasive and facultative intracellular pathogen Salmonella enterica with an adhesiome of up to 20 adhesins. Such large repertoire of adhesins contributes to colonization of a broad range of host species and may allow adaptation to various environments within the host, as well as in non-host environments. For S. enterica, only few members of the adhesiome are functionally expressed under laboratory conditions, and accordingly the structural and functional understanding of the majority of adhesins is sparse. We have devised a simple and versatile approach to functionally express all adhesins of S. enterica serotype Typhimurium, either within Salmonella or within heterologous hosts such as Escherichia coli. We demonstrate the surface expression of various so far cryptic adhesins and show ultrastructural features using atomic force microscopy and transmission electron microscopy. In summary, we report for the first time the expression of the entire adhesiome of S. enterica serotype Typhimurium. PMID- 28871184 TI - Motion correction in optoacoustic mesoscopy. AB - Raster-scan optoacoustic mesoscopy (RSOM), also termed photoacoustic mesoscopy, offers novel insights into vascular morphology and pathophysiological biomarkers of skin inflammation in vivo at depths unattainable by other optical imaging methods. Using ultra-wideband detection and focused ultrasound transducers, RSOM can achieve axial resolution of 4 micron and lateral resolution of 20 micron to depths of several millimeters. However, motion effects may deteriorate performance and reduce the effective resolution. To provide high-quality optoacoustic images in clinical measurements, we developed a motion correction algorithm for RSOM. The algorithm is based on observing disruptions of the ultrasound wave front generated by the vertical movement of the melanin layer at the skin surface. From the disrupted skin surface, a smooth synthetic surface is generated, and the offset between the two surfaces is used to correct for the relative position of the ultrasound detector. We test the algorithm in measurements of healthy and psoriatic human skin and achieve effective resolution up to 5-fold higher than before correction. We discuss the performance of the correction algorithm and its implications in the context of multispectral mesoscopy. PMID- 28871185 TI - Evaluating the Sources of Graphene's Resistivity Using Differential Conductance. AB - We explore the contributions to the electrical resistance of monolayer and bilayer graphene, revealing transitions between different regimes of charge carrier scattering. In monolayer graphene at low densities, a nonmonotonic variation of the resistance is observed as a function of temperature. Such behaviour is consistent with the influence of scattering from screened Coulomb impurities. At higher densities, the resistance instead varies in a manner consistent with the influence of scattering from acoustic and optical phonons. The crossover from phonon-, to charged-impurity, limited conduction occurs once the concentration of gate-induced carriers is reduced below that of the residual carriers. In bilayer graphene, the resistance exhibits a monotonic decrease with increasing temperature for all densities, with the importance of short-range impurity scattering resulting in a "universal" density-independent (scaled) conductivity at high densities. At lower densities, the conductivity deviates from this universal curve, pointing to the importance of thermal activation of carriers out of charge puddles. These various assignments, in both systems, are made possible by an approach of "differential-conductance mapping", which allows us to suppress quantum corrections to reveal the underlying mechanisms governing the resistivity. PMID- 28871186 TI - Analysis of population-specific pharmacogenomic variants using next-generation sequencing data. AB - Functional rare variants in drug-related genes are believed to be highly differentiated between ethnic- or racial populations. However, knowledge of population differentiation (PD) of rare single-nucleotide variants (SNVs), remains widely lacking, with the highest fixation indices, (Fst values), from both rare and common variants annotated to specific genes, having only been marginally used to understand PD at the gene level. In this study, we suggest a new, gene-based PD method, PD of Rare and Common variants (PDRC), for analyzing rare variants, as inspired by Generalized Cochran-Mantel-Haenszel (GCMH) statistics, to identify highly population-differentiated drug response-related genes ("pharmacogenes"). Through simulation studies, we reveal that PDRC adequately summarizes rare and common variants, due to PD, over a specific gene. We also applied the proposed method to a real whole-exome sequencing dataset, consisting of 10,000 datasets, from the Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) initiative, and 3,000 datasets from the Genetics of Type 2 diabetes (Go-T2D) repository. Among the 48 genes annotated with Very Important Pharmacogenetic summaries (VIPgenes), in the PharmGKB database, our PD method successfully identified candidate genes with high PD, including ACE, CYP2B6, DPYD, F5, MTHFR, and SCN5A. PMID- 28871188 TI - Himalayan glaciers experienced significant mass loss during later phases of little ice age. AB - To date, there is a gap in the data about the state and mass balance of glaciers in the climate-sensitive subtropical regions during the Little Ice Age (LIA). Here, based on an unprecedented tree-ring sampling coverage, we present the longest reconstructed mass balance record for the Western Himalayan glaciers, dating to 1615. Our results confirm that the later phase of LIA was substantially briefer and weaker in the Himalaya than in the Arctic and subarctic regions. Furthermore, analysis of the time-series of the mass-balance against other time series shows clear evidence of the existence of (i) a significant glacial decay and a significantly weaker magnitude of glaciation during the latter half of the LIA; (ii) a weak regional mass balance dependence on either the El Nino-Southern Oscillation (ENSO) or the Total Solar Irradiance (TSI) taken in isolation, but a considerable combined influence of both of them during the LIA; and (iii) in addition to anthropogenic climate change, the strong effect from the increased yearly concurrence of extremely high TSI with El Nino over the past five decades, resulting in severe glacial mass loss. The generated mass balance time-series can serve as a source of reliable reconstructed data to the scientific community. PMID- 28871187 TI - Prolonged fasting elicits increased hepatic triglyceride accumulation in rats born to dexamethasone-treated mothers. AB - We investigated the effect of dexamethasone during the last week of pregnancy on glucose and lipid metabolism in male offspring. Twelve-week old offspring were evaluated after fasting for 12-hours (physiological) and 60-hours (prolonged). Physiological fasting resulted in glucose intolerance, decreased glucose clearance after pyruvate load and increased PEPCK expression in rats born to dexamethasone-treated mothers (DEX). Prolonged fasting resulted in increased glucose tolerance and increased glucose clearance after pyruvate load in DEX. These modulations were accompanied by accumulation of hepatic triglycerides (TG). Sixty-hour fasted DEX also showed increased citrate synthase (CS) activity, ATP citrate lyase (ACLY) content, and pyruvate kinase 2 (pkm2), glucose transporter 1 (slc2a1) and lactate dehydrogenase-a (ldha) expressions. Hepatic AKT2 was increased in 60-hour fasted DEX, in parallel with reduced miRNAs targeting the AKT2 gene. Altogether, we show that metabolic programming by prenatal dexamethasone is characterized by an unexpected hepatic TG accumulation during prolonged fasting. The underlying mechanism may depend on increased hepatic glycolytic flux due to increased pkm2 expression and consequent conversion of pyruvate to non-esterified fatty acid synthesis due to increased CS activity and ACLY levels. Upregulation of AKT2 due to reduced miRNAs may serve as a permanent mechanism leading to increased pkm2 expression. PMID- 28871189 TI - Expression and anti-inflammatory role of activin receptor-interacting protein 2 in lipopolysaccharide-activated macrophages. AB - The bacterial endotoxin lipopolysaccharide (LPS), a key pathogenic stimulator, can induce the activation of macrophages. Activin receptor-interacting protein 2 (ARIP2), an intracellular signaling protein, has a wide histological distribution, however, whether ARIP2 is involved in regulation of activation of macrophages was not well characterized. Here, by immunocytochemical staining, we found that ARIP2 protein existed in monocyte-macrophage cell line RAW264.7 cells and peritoneal macrophages of mouse, and ARIP2 expression in RAW264.7 cells was up-regulated by LPS. Furthermore, the results revealed that ARIP2 overexpression in the LPS-activated RAW264.7 cells inhibited the productions of IL-1beta and TNFalpha, phagocytic activities and CD14 expression, whereas did not alter expressions of MyD88, TLR2 and TLR4. Additionally, in vivo ARIP2 overexpression also reduced the productions of IL-1beta and TNFalpha from the LPS-stimulated peritoneal macrophages of mouse. These data suggest that ARIP2 may play an anti inflammatory role in macrophages via inhibiting CD14 expression. PMID- 28871190 TI - New insights about functional and cross-reactive properties of antibodies generated against recombinant TbpBs of Haemophilus parasuis. AB - Vaccines have become fundamental in the control and elimination of Glasser Disease, a systemic disease of pigs caused by Haemophilus parasuis. The classic vaccines available for prevention of this infection were developed without a robust knowledge about host immunological mechanisms. In this study, we demonstrated the presence of cross-reactive epitopes on both the N-lobe and C lobe of variants of transferrin binding protein B (TbpBs) expressed on the surface of 6 virulent serovars of H. parasuis. Antibodies against TbpB-derived antigens were capable of increasing the phagocytic capacity of neutrophils and were also capable of blocking porcine transferrin from binding to TbpB. Surprisingly, none of the pig or mice antisera from animals immunized with TbpB derived antigens mixed with Montanide IMS 2215 VG PR adjuvant were able to activate the classical complement pathway (CCP). In contrast, antisera from mice immunized with TbpB-derived antigens adjuvanted with Freund's adjuvants or Montanide Gel 01 were able to activate the CCP and kill H. parasuis. Our results demonstrate that the type of adjuvant can modulate the functional response induced by TbpB-derived antigens. Based on these results, we propose that a properly formulated TbpB-based vaccine may elicit a functional protective antibody response with broad cross-reactivity against heterologous strains of H. parasuis. PMID- 28871191 TI - Pharmacogenetics of methylphenidate in childhood attention-deficit/hyperactivity disorder: long-term effects. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in which a significant proportion of patients do not respond to treatment. The objective of this study was to examine the role of genetic risk variants in the response to treatment with methylphenidate (MPH). The effectiveness of MPH was evaluated based on variations in the CGI-S and CGAS scales over a 12-month treatment period using linear mixed effects models. A total of 208 ADHD patients and 34 polymorphisms were included in the analysis. For both scales, the response was associated with time, extended-release MPH/both formulations, and previous MPH treatment. For the CGI-S scale, response was associated with SLC6A3 rs2550948, DRD4 promoter duplication, SNAP25 rs3746544, and ADGRL3 rs1868790. Interactions between the response over time and SLC6A3 and DRD2 were found in the CGI-S and CGAS scales, respectively. The proportion of the variance explained by the models was 18% for the CGI-S and 22% for the CGAS. In this long-term study, the effects of SLC6A3, DRD4, SNAP25, and ADGRL3 on response to treatment reflect those observed in previous studies. In addition, 2 previously unreported interactions with response to treatment over a 12-month period were found (SLC6A3 and DRD2). PMID- 28871192 TI - Voice cues are used in a similar way by blind and sighted adults when assessing women's body size. AB - Humans' ability to gauge another person's body size from their voice alone may serve multiple functions ranging from threat assessment to speaker normalization. However, how this ability is acquired remains unknown. In two experiments we tested whether sighted, congenitally blind and late blind adults could accurately judge the relative heights of women from paired voice stimuli, and importantly, whether errors in size estimation varied with task difficulty across gr oups. Both blind (n = 56) and sighted (n = 61) listeners correctly judged women's relative heights on approximately 70% of low difficulty trials, corroborating previous findings for judging men's he ights. However, accuracy dropped to chance levels for intermediate difficulty trials and to 25% for high difficulty trials, regardless of the listener's sightedness, duration of vision loss, sex, or age. Thus, blind adults estimated women's height with the same degree of accuracy, but also the same pattern of errors, as did sighted controls. Our findings provide further evidence that visual experience is not necessary for accurate body size estimation. Rather, both blind and sighted listeners appear to follow a general rule, mapping low auditory frequencies to largeness across a range of contexts. This sound-size mapping emerges without visual experience, and is likely very important for humans. PMID- 28871193 TI - Estradiol Regulates Txnip and Prevents Intermittent Hypoxia-Induced Vascular Injury. AB - Chronic intermittent hypoxia (IH) contributes to obstructive sleep apnea (OSA) related cardiovascular diseases through increasing oxidative stress. It has been widely recognized that estradiol decreases the risk for cardiovascular disease, but the estrogen replacement therapy is limited for its side effects. Thioredoxin (Trx) and its endogenous inhibitor, thioredoxin-interacting protein (Txnip), are associated with the protective effect of estradiol in some conditions. In this study, we aimed to explore whether estradiol could protect against IH-induced vascular injury, and the possible effect of Trx-1/Txnip in this process. Forty eight adult female C57/BL6J mice were randomly divided into 4 groups, ovariectomy combined with IH group, sham operation combined with IH group, IH group and the control group. The mice treated with IH for 8 hrs/day, and 28 days. IH induced the injury of aorta, and ovariectomized mice were more prone to the IH-induced aortic injury, with higher level of oxidative stress. In vitro, estradiol increased Trx-1 level, but decreased the level of Txnip and oxidative stress in human umbilical vein endothelial cells (HUVECs) treated with IH for 16 hrs. Knock down of Txnip by specific siRNA rescued oxidative stress and apoptosis. In conclusion, estradiol protects against IH-induced vascular injury, partially through the regulation of Trx-1/Txnip pathway. PMID- 28871194 TI - Effect of amino acid mutations on the conformational dynamics of amyloidogenic immunoglobulin light-chains: A combined NMR and in silico study. AB - The conformational dynamics of a pathogenic kappa4 human immunoglobulin light chain variable domain, SMA, associated with AL amyloidosis, were investigated by 15N relaxation dispersion NMR spectroscopy. Compared to a homologous light-chain, LEN, which differs from SMA at eight positions but is non-amyloidogenic in vivo, we find that multiple residues in SMA clustered around the N-terminus and CDR loops experience considerable conformational exchange broadening caused by millisecond timescale protein motions, consistent with a destabilized dimer interface. To evaluate the contribution of each amino acid substitution to shaping the dynamic conformational landscape of SMA, NMR studies were performed for each SMA-like point mutant of LEN followed by in silico analysis for a subset of these proteins. These studies show that a combination of only three mutations located within or directly adjacent to CDR3 loop at the dimer interface, which remarkably include both destabilizing (Q89H and Y96Q) and stabilizing (T94H) mutations, largely accounts for the differences in conformational flexibility between LEN and SMA. Collectively, our studies indicate that a correct combination of stabilizing and destabilizing mutations is key for immunoglobulin light-chains populating unfolded intermediates that result in amyloid formation, and underscore the complex nature of correlations between light-chain conformational flexibility, thermodynamic stability and amyloidogenicity. PMID- 28871195 TI - Role of floral organ identity genes in the development of unisexual flowers of Quercus suber L. AB - Monoecious species provide an excellent system to study the specific determinants that underlie male and female flower development. Quercus suber is a monoecious species with unisexual flowers at inception. Despite the overall importance of this and other tree species with a similar reproductive habit, little is known regarding the mechanisms involved in the development of their male and female flowers. Here, we have characterised members of the ABCDE MADS-box gene family of Q. suber. The temporal expression of these genes was found to be sex-biased. The B-class genes, in particular, are predominantly, or exclusively (in the case of QsPISTILLATA), expressed in the male flowers. Functional analysis in Arabidopsis suggests that the B-class genes have their function conserved. The identification of sex-biased gene expression plus the identification of unusual protein-protein interactions suggest that the floral organ identity of Q. suber may be under control of specific changes in the dynamics of the ABCDE model. This study constitutes a major step towards the characterisation of the mechanisms involved in reproductive organ identity in a monoecious tree with a potential contribution towards the knowledge of conserved developmental mechanisms in other species with a similar sex habit. PMID- 28871196 TI - Magnetophoretic sorting of microdroplets with different microalgal cell densities for rapid isolation of fast growing strains. AB - Microalgae - unicellular photosynthetic organisms - have received increasing attention for their ability to biologically convert CO2 into valuable products. The commercial use of microalgae requires screening strains to improve the biomass productivity to achieve a high-throughput. Here, we developed a microfluidic method that uses a magnetic field to separate the microdroplets containing different concentrations of microalgal cells. The separation efficiency is maximized using the following parameters that influence the amount of lateral displacement of the microdroplets: magnetic nanoparticle concentration, flow rate of droplets, x- and y-axis location of the magnet, and diameter of the droplets. Consequently, 91.90% of empty, 87.12% of low-, and 90.66% of high-density droplets could be separated into different outlets through simple manipulation of the magnetic field in the microfluidic device. These results indicate that cell density-based separation of microdroplets using a magnetic force can provide a promising platform to isolate microalgal species with a high growth performance. PMID- 28871197 TI - Thermal conductivity and air-mediated losses in periodic porous silicon membranes at high temperatures. AB - Heat conduction in silicon can be effectively engineered by means of sub micrometre porous thin free-standing membranes. Tunable thermal properties make these structures good candidates for integrated heat management units such as waste heat recovery, rectification or efficient heat dissipation. However, possible applications require detailed thermal characterisation at high temperatures which, up to now, has been an experimental challenge. In this work we use the contactless two-laser Raman thermometry to study heat dissipation in periodic porous membranes at high temperatures via lattice conduction and air mediated losses. We find the reduction of the thermal conductivity and its temperature dependence closely correlated with the structure feature size. On the basis of two-phonon Raman spectra, we attribute this behaviour to diffuse (incoherent) phonon-boundary scattering. Furthermore, we investigate and quantify the heat dissipation via natural air-mediated cooling, which can be tuned by engineering the porosity.Nanostructuring of silicon allows acoustic phonon engineering, but the mechanism of related thermal transport in these structures is not fully understood. Here, the authors study the heat dissipation in silicon membranes with periodic nanoholes and show the importance of incoherent scattering. PMID- 28871198 TI - Modulation of action potentials using PEDOT:PSS conducting polymer microwires. AB - : We describe the use of PEDOT:PSS conducting polymer microwires to modulate action potentials in single cells. PEDOT: PSS conducting polymer microwires are electrochemically synthesized with diameters ranging from 860 nm to 4.5 MUm and conductivities of ~30 S/cm. The length of the microwires is controlled by the spacing of the electrodes used for the electrochemical polymerization. We demonstrate the use of these microwires to control the action potentials of cardiomyocytes, showing that the cellular contractions match the frequency of the applied voltage. Membrane integrity assays confirm that the voltage delivered by the wires does not damage cells. We expect the conducting polymer microwires will be useful as minimally invasive devices to control the electrical properties of cells with high spatial precision. PMID- 28871200 TI - Highly oxidising fluids generated during serpentinite breakdown in subduction zones. AB - Subduction zones facilitate chemical exchanges between Earth's deep interior and volcanism that affects habitability of the surface environment. Lavas erupted at subduction zones are oxidized and release volatile species. These features may reflect a modification of the oxidation state of the sub-arc mantle by hydrous, oxidizing sulfate and/or carbonate-bearing fluids derived from subducting slabs. But the reason that the fluids are oxidizing has been unclear. Here we use theoretical chemical mass transfer calculations to predict the redox state of fluids generated during serpentinite dehydration. Specifically, the breakdown of antigorite to olivine, enstatite, and chlorite generates fluids with high oxygen fugacities, close to the hematite-magnetite buffer, that can contain significant amounts of sulfate. The migration of these fluids from the slab to the mantle wedge could therefore provide the oxidized source for the genesis of primary arc magmas that release gases to the atmosphere during volcanism. Our results also show that the evolution of oxygen fugacity in serpentinite during subduction is sensitive to the amount of sulfides and potentially metal alloys in bulk rock, possibly producing redox heterogeneities in subducting slabs. PMID- 28871199 TI - Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide. AB - Opiates are potent analgesics but their clinical use is limited by side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). The Opiates produce analgesia and other adverse effects through activation of the mu opioid receptor (MOR) encoded by the Oprm1 gene. However, MOR and morphine metabolism involvement in OIH have been little explored. Hence, we examined MOR contribution to OIH by comparing morphine-induced hyperalgesia in wild type (WT) and MOR knockout (KO) mice. We found that repeated morphine administration led to analgesic tolerance and hyperalgesia in WT mice but not in MOR KO mice. The absence of OIH in MOR KO mice was found in both sexes, in two KO global mutant lines, and for mechanical, heat and cold pain modalities. In addition, the morphine metabolite morphine-3beta-D-glucuronide (M3G) elicited hyperalgesia in WT but not in MOR KO animals, as well as in both MOR flox and MOR-Nav1.8 sensory neuron conditional KO mice. M3G displayed significant binding to MOR and G protein activation when using membranes from MOR-transfected cells or WT mice but not from MOR KO mice. Collectively our results show that MOR is involved in hyperalgesia induced by chronic morphine and its metabolite M3G. PMID- 28871202 TI - Humans and climate change drove the Holocene decline of the brown bear. AB - The current debate about megafaunal extinctions during the Quaternary focuses on the extent to which they were driven by humans, climate change, or both. These two factors may have interacted in a complex and unexpected manner, leaving the exact pathways to prehistoric extinctions unresolved. Here we quantify, with unprecedented detail, the contribution of humans and climate change to the Holocene decline of the largest living terrestrial carnivore, the brown bear (Ursus arctos), on a continental scale. We inform a spatially explicit metapopulation model for the species by combining life-history data and an extensive archaeofaunal record from excavations across Europe with reconstructed climate and land-use data reaching back 12,000 years. The model reveals that, despite the broad climatic niche of the brown bear, increasing winter temperatures contributed substantially to its Holocene decline - both directly by reducing the species' reproductive rate and indirectly by facilitating human land use. The first local extinctions occurred during the Mid-Holocene warming period, but the rise of the Roman Empire 2,000 years ago marked the onset of large-scale extinctions, followed by increasingly rapid range loss and fragmentation. These findings strongly support the hypothesis that complex interactions between climate and humans may have accelerated megafaunal extinctions. PMID- 28871201 TI - Protective immunity differs between routes of administration of attenuated malaria parasites independent of parasite liver load. AB - In humans and murine models of malaria, intradermal immunization (ID-I) with genetically attenuated sporozoites that arrest in liver induces lower protective immunity than intravenous immunization (IV-I). It is unclear whether this difference is caused by fewer sporozoites migrating into the liver or by suboptimal hepatic and injection site-dependent immune responses. We therefore developed a Plasmodium yoelii immunization/boost/challenge model to examine parasite liver loads as well as hepatic and lymph node immune responses in protected and unprotected ID-I and IV-I animals. Despite introducing the same numbers of genetically attenuated parasites in the liver, ID-I resulted in lower sterile protection (53-68%) than IV-I (93-95%). Unprotected mice developed less sporozoite-specific CD8+ and CD4+ effector T-cell responses than protected mice. After immunization, ID-I mice showed more interleukin-10-producing B and T cells in livers and skin-draining lymph nodes, but fewer hepatic CD8 memory T cells and CD8+ dendritic cells compared to IV-I mice. Our results indicate that the lower protection efficacy obtained by intradermal sporozoite administration is not linked to low hepatic parasite numbers as presumed before, but correlates with a shift towards regulatory immune responses. Overcoming these immune suppressive responses is important not only for live-attenuated malaria vaccines but also for other live vaccines administered in the skin. PMID- 28871203 TI - Targeting transferrin receptors at the blood-brain barrier improves the uptake of immunoliposomes and subsequent cargo transport into the brain parenchyma. AB - Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain. PMID- 28871204 TI - Higher-order assembly of crystalline cylindrical micelles into membrane extendable colloidosomes. AB - Crystallization-driven self-assembly of diblock copolymers into cylindrical micelles of controlled length has emerged as a promising approach to the fabrication of functional nanoscale objects with high shape anisotropy. Here we show the preparation of a series of crystallizable diblock copolymers with appropriate wettability and chemical reactivity, and demonstrate their self assembly into size-specific cylindrical micelle building blocks for the hierarchical construction of mechanically robust colloidosomes with a range of membrane textures, surface chemistries and optical properties. The colloidosomes can be structurally elaborated post assembly by in situ epitaxial elongation of the membrane building blocks to produce microcapsules covered in a chemically distinct, dense network of hair-like outgrowths. Our approach provides a route to hierarchically ordered colloidosomes that retain the intrinsic growth activity of their constituent building blocks to permit biofunctionalization, and have potential applications in areas such as biomimetic encapsulation, drug delivery, catalysis and biosensing.Functional nanoscale objects can be prepared via crystallization-driven self-assembly of diblock copolymers. Here the authors show the self-assembly of crystalline block copolymers into size-specific cylindrical micelles for the hierarchical construction of mechanically robust colloidosomes with a range of membrane textures. PMID- 28871206 TI - Gold nanoparticles approach to detect chondroitin sulphate and hyaluronic acid urothelial coating. AB - This study investigated the location of hyaluronic acid (HA)- and chondroitin sulphate (CS)-coated gold nanoparticles in rabbit bladder and evaluated gene expression of CD44, RHAMM and ICAM-1 receptors involved in HA and CS transport into the cell. Gold nanoparticles were synthesised by reduction of gold salts with HA or CS to form HA-AuNPs and CS-AuNPs. Bladder samples were incubated with CS-AuNPs and HA-AuNPs or without glycosaminoglycans. Transmission electron microscopy, optic microscopy and scanning electron microscopy were used to determine the location of the synthesised AuNPs. Real-time PCR was used to analyse expression of urothelial cell receptors CD44, RHAMM, ICAM-1, after ex vivo administration of CS-AuNPs and HA-AuNPs. We showed that HA-AuNPs and CS AuNPs were located in the cytoplasm and tight junctions of urothelial umbrella cells; this appearance was absent in untreated bladders. There were no significant differences in gene expression levels for CD44, RHAMM and ICAM-1 receptors in treated versus control bladder tissues. In conclusion, we clearly showed the presence of exogenous GAGs in the bladder surface and the tight junctions between umbrella cells, which is important in the regeneration pathway of the urothelium. The GAGs-AuNPs offer a promising approach to understanding the biophysical properties and imaging of urothelial tissue. PMID- 28871205 TI - Siderophore cheating and cheating resistance shape competition for iron in soil and freshwater Pseudomonas communities. AB - All social organisms experience dilemmas between cooperators performing group beneficial actions and cheats selfishly exploiting these actions. Although bacteria have become model organisms to study social dilemmas in laboratory systems, we know little about their relevance in natural communities. Here, we show that social interactions mediated by a single shareable compound necessary for growth (the iron-scavenging pyoverdine) have important consequences for competitive dynamics in soil and pond communities of Pseudomonas bacteria. We find that pyoverdine non- and low-producers co-occur in many natural communities. While non-producers have genes coding for multiple pyoverdine receptors and are able to exploit compatible heterologous pyoverdines from other community members, producers differ in the pyoverdine types they secrete, offering protection against exploitation from non-producers with incompatible receptors. Our findings indicate that there is both selection for cheating and cheating resistance, which could drive antagonistic co-evolution and diversification in natural bacterial communities.Lab strains of Pseudomonas are model systems for the evolution of cooperation over public goods (iron-scavenging siderophores). Here, Butaite et al. add ecological and evolutionary insight into this system by showing that cheating and resistance to cheating both shape competition for iron in natural Pseudomonas communities. PMID- 28871207 TI - Optical-flow based non-invasive analysis of cardiomyocyte contractility. AB - Characterization of cardiomyocyte beat patterns is needed for quality control of cells intended for surgical injection as well as to establish phenotypes in disease modeling or toxicity studies. Optical-flow based analysis of videomicroscopic recordings offer a manipulation-free and efficient characterization of contractile cycles, an important characteristics of cardiomyocyte phenotype. We demonstrate that by appropriate computational analysis of optical flow data one can identify distinct contractile centers and distinguish active cell contractility from passive elastic tissue deformations. Our proposed convergence measure correlates with myosin IIa immuno-localization and is capable to resolve contractile waves and their synchronization within maturing, unlabeled induced pluripotent stem cell-derived cardiomyocyte cultures. PMID- 28871208 TI - Identify latent chromosomal aberrations relevant to myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) are a group of heterogeneous hematologic malignancies. This study aims to identify latent chromosomal abnormalities relevant to MDS, which may optimize the current diagnosis of MDS. Affymetrix CytoScan 750 K microarray platform was utilized to perform a genome-wide detection of chromosomal aberrations in the bone marrow cells of the patients. The findings were compared with the results from traditional karyotypic analysis and FISH to reveal latent chromosomal aberrations. Chromosomal gain, loss, and UPD, and complex karyotypes were identified in those samples. In addition to established cytogenetic aberrations detected by karyotypic analysis, CytoScan 750 K microarray also detected cryptic chromosomal lesions in MDS. Those latent defects underlying multiple gene mutations may construe the clinical variability of MDS. In Conclusion, Affymetrix CytoScan 750 K microarray is efficient in identifying latent chromosomal aberrations in MDS. PMID- 28871209 TI - HMGB1/Advanced Glycation End Products (RAGE) does not aggravate inflammation but promote endogenous neural stem cells differentiation in spinal cord injury. AB - Receptor for advanced glycation end products (RAGE) signaling is involved in a series of cell functions after spinal cord injury (SCI). Our study aimed to elucidate the effects of RAGE signaling on the neuronal recovery after SCI. In vivo, rats were subjected to SCI with or without anti-RAGE antibodies micro injected into the lesion epicenter. We detected Nestin/RAGE, SOX-2/RAGE and Nestin/MAP-2 after SCI by Western blot or immunofluorescence (IF). We found that neural stem cells (NSCs) co-expressed with RAGE were significantly activated after SCI, while stem cell markers Nestin and SOX-2 were reduced by RAGE blockade. We found that RAGE inhibition reduced nestin-positive NSCs expressing MAP-2, a mature neuron marker. RAGE blockade does not improve neurobehavior Basso, Beattie and Bresnahan (BBB) scores; however, it damaged survival of ventral neurons via Nissl staining. Through in vitro study, we found that recombinant HMGB1 administration does not lead to increased cytokines of TNF alpha and IL-1beta, while anti-RAGE treatment reduced cytokines of TNF-alpha and IL-1beta induced by LPS via ELISA. Meanwhile, HMGB1 increased MAP-2 expression, which was blocked after anti-RAGE treatment. Hence, HMGB1/RAGE does not exacerbate neuronal inflammation but plays a role in promoting NSCs differentiating into mature neurons in the pathological process of SCI. PMID- 28871210 TI - Disorder versus two transport lifetimes in a strongly correlated electron liquid. AB - We report on angle-dependent measurements of the sheet resistances and Hall coefficients of electron liquids in SmTiO3/SrTiO3/SmTiO3 quantum well structures, which were grown by molecular beam epitaxy on (001) DyScO3. We compare their transport properties with those of similar structures grown on LSAT [(La0.3Sr0.7)(Al0.65Ta0.35)O3]. On DyScO3, planar defects normal to the quantum wells lead to a strong in-plane anisotropy in the transport properties. This allows for quantifying the role of defects in transport. In particular, we investigate differences in the longitudinal and Hall scattering rates, which is a non-Fermi liquid phenomenon known as lifetime separation. The residuals in both the longitudinal resistance and Hall angle were found to depend on the relative orientations of the transport direction to the planar defects. The Hall angle exhibited a robust T 2 temperature dependence along all directions, whereas no simple power law could describe the temperature dependence of the longitudinal resistances. Remarkably, the degree of the carrier lifetime separation, as manifested in the distinctly different temperature dependences and diverging residuals near a critical quantum well thickness, was completely insensitive to disorder. The results allow for a clear distinction between disorder-induced contributions to the transport and intrinsic, non-Fermi liquid phenomena, which includes the lifetime separation. PMID- 28871212 TI - Evaluation of consumer monitors to measure particulate matter. AB - Recently, inexpensive (<$300) consumer aerosol monitors (CAMs) targeted for use in homes have become available. We evaluated the accuracy, bias, and precision of three CAMs (Foobot from Airoxlab, Speck from Carnegie Mellon University, and AirBeam from HabitatMap) for measuring mass concentrations in occupational settings. In a laboratory study, PM2.5 measured with the CAMs and a medium-cost aerosol photometer (personal DataRAM 1500, Thermo Scientific) were compared to that from reference instruments for three aerosols (salt, welding fume, and Arizona road dust, ARD) at concentrations up to 8500 MUg/m3. Three of each type of CAM were included to estimate precision. Compared to reference instruments, mass concentrations measured with the Foobot (r-value = 0.99) and medium-cost photometer (r-value = 0.99) show strong correlation, whereas those from the Speck (r-value range 0.88 - 0.99) and AirBeam (0.7 - 0.96) were less correlated. The Foobot bias was (-12%) for ARD and measurements were similar to the medium-cost instrument. Foobot bias was (< -46%) for salt and welding fume aerosols. Speck bias was at 18% salt for ARD and -86% for welding fume. AirBeam bias was (-36%) for salt and (-83%) for welding fume. All three photometers had a bias (< -82%) for welding fume. Precision was excellent for the Foobot (coefficient of variation range: 5% to 8%) and AirBeam (2% to 9%), but poorer for the Speck (8% to 25%). These findings suggest that the Foobot, with a linear response to different aerosol types and good precision, can provide reasonable estimates of PM2.5 in the workplace after site-specific calibration to account for particle size and composition. PMID- 28871213 TI - Evaluation of the Alphasense Optical Particle Counter (OPC-N2) and the Grimm Portable Aerosol Spectrometer (PAS-1.108). AB - We compared the performance of a low-cost (~$500), compact optical particle counter (OPC, OPC-N2, Alphasense) to another OPC (PAS-1.108, Grimm Technologies) and reference instruments. We measured the detection efficiency of the OPCs by size from 0.5 to 5 MUm for monodispersed, polystyrene latex (PSL) spheres. We then compared number and mass concentrations measured with the OPCs to those measured with reference instruments for three aerosols: salt, welding fume and Arizona road dust. The OPC-N2 detection efficiency for monodispersed was similar to the PAS-1.108 for particles larger than 0.8 MUm (minimum of 79% at 1 MUm and maximum of 101% at 3 MUm). For 0.5-MUm particles, the detection efficiency of OPCN2 was underestimated at 78%, whereas PAS-1.108 overestimated concentrations by 183%. The mass concentrations from the OPCs were linear (r >= 0.97) with those from the reference instruments for all aerosols, although the slope and intercept were different. The mass concentrations were overestimated for dust (OPC-N2, slope = 1.6; PAS-1.108, slope = 2.7) and underestimated for welding fume (OPC-N2, slope = 0.05; PAS-1.108, slope = 0.4). The coefficient of variation (CV, precision) for OPC-N2 for all experiments was between 4.2% and 16%. These findings suggest that, given site-specific calibrations, the OPC-N2 can provide number and mass concentrations similar to the PAS-1.108 for particles larger than 1 MUm. PMID- 28871214 TI - Rapid Analysis of the Size Distribution of Metal-Containing Aerosol. AB - Conventional methods to measure the metallic content of particles by size are time consuming and expensive, requiring collection of particles with a cascade impactor and subsequent metals analysis by inductively coupled plasma mass spectrometry (ICP-MS). In this work, we describe a rapid way to measure the size distribution of metal-containing particles from 10 nm to 20 MUm, using a nano micro-orifice uniform-deposit impactor (nano-MOUDI) to size-selective and collect particles that are then analyzed with a field portable X-ray fluorescence (FP XRF) to determine metal composition and concentration. The nano-MOUDI was used to sample a stainless-steel aerosol produced by a spark discharge system. The particle-laden substrates were then analyzed directly with FP-XRF and then with ICP-MS. Results from FP-XRF were linearly correlated with results from ICP-MS (R2 = 0.91 for Fe and R2 = 0.84 for Cr). Although the FP-XRF was unable to detect Fe particles at mass per substrate loadings less than 2.5 MUg effectively, it produced results similar to those using the ICP-MS at a mass per substrate loading greater than 2.5 MUg. PMID- 28871211 TI - Functional prediction of long non-coding RNAs in ovarian cancer-associated fibroblasts indicate a potential role in metastasis. AB - Cancer-associated fibroblasts (CAFs) contribute to the poor prognosis of ovarian cancer. Unlike in tumour cells, DNA mutations are rare in CAFs, raising the likelihood of other mechanisms that regulate gene expression such as long non coding RNAs (lncRNAs). We aimed to identify lncRNAs that contribute to the tumour promoting phenotype of CAFs. RNA expression from 67 ovarian CAF samples and 10 normal ovarian fibroblast (NOF) samples were analysed to identify differentially expressed lncRNAs and a functional network was constructed to predict those CAF specific lncRNAs involved in metastasis. Of the 1,970 lncRNAs available for analysis on the gene expression array used, 39 unique lncRNAs were identified as differentially expressed in CAFs versus NOFs. The predictive power of differentially expressed lncRNAs in distinguishing CAFs from NOFs were assessed using multiple multivariate models. Interrogation of known transcription factor lncRNA interactions, transcription factor-gene interactions and construction of a context-specific interaction network identified multiple lncRNAs predicted to play a role in metastasis. We have identified novel lncRNAs in ovarian cancer that are differentially expressed in CAFs compared to NOFs and are predicted to contribute to the metastasis-promoting phenotype of CAFs. PMID- 28871215 TI - Racial/Ethnic Patterns of Kindergarten School Enrollment in the United States. AB - Enrollment into unequal schools at the start of formal education is an important mechanism for the reproduction of racial/ethnic educational inequalities. We examine whether there are racial/ethnic differences in school enrollment options at kindergarten, the start of schooling. We use nationally representative data from the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B) to model whether parents seek information about their child's school before enrolling, whether parents move to a location so that a child can attend a certain school, or whether parents enroll their child in a school other than the assigned public school. Results indicate that enrollment patterns differ greatly across race/ethnicity. Whereas Black families are the most likely to seek information on a school's performance, White families are the most likely to use the elite option of choosing their residential location to access a particular school. These differences persist when controlling for socioeconomic status and sociogeographic location. Kindergarten enrollment patterns preserve the advantages of White families, perpetuating racial/ethnic disparities through multiple institutions and contributing to intergenerational processes of social stratification. Research should continue to examine specific educational consequences of housing inequities and residential segregation. PMID- 28871216 TI - Motivational Interviewing as an Adjunct to Cognitive Behavior Therapy for Anxiety Disorders: A Critical Review of the Literature. AB - Cognitive behavior therapy (CBT) is efficaciously and effectively used in the treatment of anxiety disorders; however, as CBT for anxiety routinely utilizes exposure components, clients often experience ambivalence about treatment and their clinicians often must deal with resistance. Motivational Interviewing (MI) is a therapeutic strategy that addresses ambivalence about change in clinical interventions. MI has been applied as an adjunct for treatments such as CBT in order to increase motivation for and commitment to the intervention, especially when components of the treatment may be challenging (e.g., exposure, cognitive restructuring). Though researchers have commented specifically on the use of MI as a supplement to CBT for anxiety disorders, no comprehensive review has systematically assessed the strengths and limitations of extant literature on the topic, nor across anxiety disorders. Findings are summarized from 6 case studies and uncontrolled trials and 11 randomized controlled trials published through March 2016. An integrated critique of this literature also is offered. Limitations and the preliminary nature of the work in this area notwithstanding, it appears that it is feasible to supplement or integrate CBT with MI and that doing so has the potential to improve treatment initiation and engagement, as well as clinical outcomes. A number of directions for future research are addressed, such as determining which MI approaches to implement, with whom, when, and in what contexts. PMID- 28871217 TI - Diagnosing Autism Spectrum Disorder from Brain Resting-State Functional Connectivity Patterns Using a Deep Neural Network with a Novel Feature Selection Method. AB - The whole-brain functional connectivity (FC) pattern obtained from resting-state functional magnetic resonance imaging data are commonly applied to study neuropsychiatric conditions such as autism spectrum disorder (ASD) by using different machine learning models. Recent studies indicate that both hyper- and hypo- aberrant ASD-associated FCs were widely distributed throughout the entire brain rather than only in some specific brain regions. Deep neural networks (DNN) with multiple hidden layers have shown the ability to systematically extract lower-to-higher level information from high dimensional data across a series of neural hidden layers, significantly improving classification accuracy for such data. In this study, a DNN with a novel feature selection method (DNN-FS) is developed for the high dimensional whole-brain resting-state FC pattern classification of ASD patients vs. typical development (TD) controls. The feature selection method is able to help the DNN generate low dimensional high-quality representations of the whole-brain FC patterns by selecting features with high discriminating power from multiple trained sparse auto-encoders. For the comparison, a DNN without the feature selection method (DNN-woFS) is developed, and both of them are tested with different architectures (i.e., with different numbers of hidden layers/nodes). Results show that the best classification accuracy of 86.36% is generated by the DNN-FS approach with 3 hidden layers and 150 hidden nodes (3/150). Remarkably, DNN-FS outperforms DNN-woFS for all architectures studied. The most significant accuracy improvement was 9.09% with the 3/150 architecture. The method also outperforms other feature selection methods, e.g., two sample t-test and elastic net. In addition to improving the classification accuracy, a Fisher's score-based biomarker identification method based on the DNN is also developed, and used to identify 32 FCs related to ASD. These FCs come from or cross different pre-defined brain networks including the default-mode, cingulo-opercular, frontal-parietal, and cerebellum. Thirteen of them are statically significant between ASD and TD groups (two sample t-test p < 0.05) while 19 of them are not. The relationship between the statically significant FCs and the corresponding ASD behavior symptoms is discussed based on the literature and clinician's expert knowledge. Meanwhile, the potential reason of obtaining 19 FCs which are not statistically significant is also provided. PMID- 28871218 TI - Mapping Sonification for Perception and Action in Motor Skill Learning. PMID- 28871219 TI - P2X7 Receptor Activation Modulates Autophagy in SOD1-G93A Mouse Microglia. AB - Autophagy and inflammation play determinant roles in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), an adult-onset neurodegenerative disease characterized by deterioration and final loss of upper and lower motor neurons (MN) priming microglia to sustain neuroinflammation and a vicious cycle of neurodegeneration. Given that extracellular ATP through P2X7 receptor constitutes a neuron-to-microglia alarm signal implicated in ALS, and that P2X7 affects autophagy in immune cells, we have investigated if autophagy can be directly triggered by P2X7 activation in primary microglia from superoxide dismutase 1 (SOD1)-G93A mice. We report that P2X7 enhances the expression of the autophagic marker microtubule-associated protein 1 light chain 3 (LC3)-II, via mTOR pathway and concomitantly with modulation of anti-inflammatory M2 microglia markers. We also demonstrate that the autophagic target SQSTM1/p62 is decreased in SOD1-G93A microglia after a short stimulation of P2X7, but increased after a sustained challenge. These effects are prevented by the P2X7 antagonist A-804598, and the autophagy/phosphoinositide-3-kinase inhibitor wortmannin (WM). Finally, a chronic in vivo treatment with A-804598 in SOD1-G93A mice decreases the expression of SQSTM1/p62 in lumbar spinal cord at end stage of disease. These data identify the modulation of the autophagic flux as a novel mechanism by which P2X7 activates ALS-microglia, to be considered for further investigations in ALS. PMID- 28871220 TI - The Vomeronasal Organ: A Neglected Organ. PMID- 28871221 TI - Commentary: Out-of-Body Experience during Awake Craniotomy. PMID- 28871223 TI - Effects of Enzymatically Depolymerized Low Molecular Weight Heparins on CCl4 Induced Liver Fibrosis. AB - With regard to identifying the effective components of LMWH drugs curing hepatic fibrosis disease, we carried out a comparative study on the efficacy of enzymatically depolymerized LMWHs on CCl4 induced mouse liver fibrosis. The results showed that the controlled enzymatic depolymerization conditions resulted in LMWHs with significantly different activities. The LMWH product depolymerized by Heparinase I (I-11) with a Mw of 7160, exhibited a significant advantage in reducing the liver inflammation by suppressing TNF-alpha and IL-1beta secretion, and minimizing hepatic fibrogenesis. The products prepared by only Heparinase II (II-11), and combined Heparinase III and II (III-II-5) showed limited positive effect on hepatic inflammation and fibrosis. On the contrary, the products by combined Heparinase III and I (III-I-9, III-I-5) showed no effect or stimulation effect on the hepatic fibrogenesis. Our results provided the basis for structure activity relationship insight for inhibition of liver fibrosis activities of LMWHs, which might have significant implications for generic anti-fibrosis disease drug development. PMID- 28871224 TI - NFIX as a Master Regulator for Lung Cancer Progression. AB - About 40% of lung cancer cases globally are diagnosed at the advanced stage. Lung cancer has a high mortality and overall survival in stage I disease is only 70%. This study was aimed at finding a candidate of transcription regulator that initiates the mechanism for metastasis by integrating computational and functional studies. The genes involved in lung cancer were retrieved using in silico software. 10 kb promoter sequences upstream were scanned for the master regulator. Transient transfection of shRNA NFIXs were conducted against A549 and NCI-H1299 cell lines. qRT-PCR and functional assays for cell proliferation, migration and invasion were carried out to validate the involvement of NFIX in metastasis. Genome-wide gene expression microarray using a HumanHT-12v4.0 Expression BeadChip Kit was performed to identify differentially expressed genes and construct a new regulatory network. The in silico analysis identified NFIX as a master regulator and is strongly associated with 17 genes involved in the migration and invasion pathways including IL6ST, TIMP1 and ITGB1. Silencing of NFIX showed reduced expression of IL6ST, TIMP1 and ITGB1 as well as the cellular proliferation, migration and invasion processes. The data was integrated with the in silico analyses to find the differentially expressed genes. Microarray analysis showed that 18 genes were expressed differentially in both cell lines after statistical analyses integration between t-test, LIMMA and ANOVA with Benjamini-Hochberg adjustment at p-value < 0.05. A transcriptional regulatory network was created using all 18 genes, the existing regulated genes including the new genes PTCH1, NFAT5 and GGCX that were found highly associated with NFIX, the master regulator of metastasis. This study suggests that NFIX is a promising target for therapeutic intervention that is expected to inhibit metastatic recurrence and improve survival rate. PMID- 28871222 TI - Reproducibility of Single-Pulse, Paired-Pulse, and Intermittent Theta-Burst TMS Measures in Healthy Aging, Type-2 Diabetes, and Alzheimer's Disease. AB - Background: Transcranial magnetic stimulation (TMS) can be used to assess neurophysiology and the mechanisms of cortical brain plasticity in humans in vivo. As the use of these measures in specific populations (e.g., Alzheimer's disease; AD) increases, it is critical to understand their reproducibility (i.e., test-retest reliability) in the populations of interest. Objective: Reproducibility of TMS measures was evaluated in older adults, including healthy, AD, and Type-2 diabetes mellitus (T2DM) groups. Methods: Participants received two identical neurophysiological assessments within a year including motor thresholds, baseline motor evoked potentials (MEPs), short- and long-interval intracortical inhibition (SICI, LICI) and intracortical facilitation (ICF), and MEP changes following intermittent theta-burst stimulation (iTBS). Cronbach's alpha coefficients were calculated to assess reproducibility. Multiple linear regression analyses were used to investigate factors related to intraindividual variability. Results: Reproducibility was highest for motor thresholds, followed by baseline MEPs, SICI and LICI, and was lowest for ICF and iTBS aftereffects. The AD group tended to show higher reproducibility than T2DM or controls. Intraindividual variability of baseline MEPs was related to age and variability of RMT, while the intraindividual variability in post-iTBS measures was related to baseline MEP variability, intervisit duration, and Brain-derived neurotrophic factor (BDNF) polymorphism. Conclusion: Increased reproducibility in AD may reflect pathophysiological declines in the efficacy of neuroplastic mechanisms. Reproducibility of iTBS aftereffects can be improved by keeping baseline MEPs consistent, controlling for BDNF genotype, and waiting at least a week between visits. Significance: These findings provide the first direct assessment of reproducibility of TMS measures in older clinical populations. Reproducibility coefficients may be used to adjust effect- and sample size calculations for future studies. PMID- 28871225 TI - Exposure Characteristics of the Analogous beta-Carboline Alkaloids Harmaline and Harmine Based on the Efflux Transporter of Multidrug Resistance Protein 2. AB - Harmaline and harmine occur naturally in plants and are distributed endogenously in human and animal tissues. The two beta-carboline alkaloids possess potential for treating Alzheimer's disease, Parkinson's disease, depression and other central nervous system diseases. However, studies have showed that the two compounds have similar structures but with quite different bioavailability. The aim of this study was to elucidate the exposure difference and characterize the in vitro transport, metabolism, and pharmacokinetic properties of harmaline and harmine. The results showed that the harmaline and harmine transport across the Caco-2 and MDCK cell monolayers was varied as the time, concentration, pH and temperature changed. The absorption of harmaline and harmine was significantly decreased when ES (OATPs inhibitor), TEA (OCTs/OCTNs substrate), NaN3 (adenosine triphosphate inhibitor), or sodium vanadate (ATPase Na+/K+-dependent inhibitor) was added. However, when given MK571 and probenecid (the typical MRP2 inhibitor), the PappAB of harmine was increased (1.62- and 1.27-folds), and the efflux ratio was decreased from 1.59 to 0.98 and from 1.59 to 1.19, respectively. In addition, the uptake ratio of harmine at 1 MUM was >2.65 in the membrane vesicles expressing human MRP2. Furthermore, harmine could slightly up-regulate the expression of MRP2, which implying harmine might be the substrate of MRP2. Particularly, the CLint -value for harmine was ~1.49-folds greater than that of harmaline in human liver microsomes. It was worth noting that the F-value of harmine was increased 1.96-folds after harmine co-administration with probenecid. To summarize, comprehensive analysis indicated that harmaline and harmine were absorbed by transcellular passive diffusion and a pH- and Na+-dependent mechanism might be mediated by OATPs and OCTs/OCTNs. MRP2 but MDR1 or BCRP might be involved in the transport of harmine. Furthermore, harmine was more unstable and easily metabolized than harmaline. All these findings suggested that harmine not only appears be an MRP2 substrate, but also possesses weak metabolic stability, and eventually leads to a low oral bioavailability. Taken together, the elucidated absorption, transport, metabolism as well as pharmacokinetic characteristics of harmaline and harmine provide useful information for designing delivery systems, pharmacological applications and avoiding drug-drug interactions. PMID- 28871226 TI - Pharmacokinetic and Pharmacodynamic Evaluation of Marbofloxacin and PK/PD Modeling against Escherichia coli in Pigs. AB - The aim of this study was to evaluate the activity of marbofloxacin and establish the optimal dose regimens for decreasing the development of fluoroquinolone resistance in pigs against Escherichia coli with ex vivo pharmacokinetic/pharmacodynamic (PK/PD) modeling. The recommended dose (2 mg/kg body weight) of marbofloxacin was orally administered in healthy pigs. The ileum content and plasma were both collected for the determination of marbofloxacin. The main parameters of Cmax, AUC0-24 h, AUC, Ke, t1/2ke, MRT and Clb were 11.28 MUg/g, 46.15, 77.81 MUg?h/g, 0.001 h-1, 69.97 h, 52.45 h, 0.026 kg/h in ileum content, and 0.55 MUg/ml, 8.15, 14.67 MUg?h/ml, 0.023 h-1, 30.67 h, 34.83 h, 0.14 L/h in plasma, respectively In total, 218 E. coli strains were isolated from most cities of China. The antibacterial activity in vitro and ex vivo of marbofloxacin against E. coli was determined following CLSI guidance. The MIC90 of sensitive strains (142) was calculated as 2 MUg/ml. The minimum inhibitory concentration (MIC) of HB197 was 2 and 4 MUg/ml in broth and ileum fluids, respectively. In vitro mutant prevention concentration, growth and killing-time in vitro and ex vivo of marbofloxacin against selected HB197 were assayed for pharmacodynamic studies. According to the inhibitory sigmoid Emax modeling, the value of AUC0-24 h/MIC produced in ileum content was achieved, and bacteriostatic, bactericidal activity, and elimination were calculated as 16.26, 23.54, and 27.18 h, respectively. Based on Monte Carlo simulations to obtain 90% target attainment rate, the optimal doses to achieve bacteriostatic, bactericidal, and elimination effects were 0.85, 1.22, and 1.41 mg/kg.bw for 50% target, respectively, and 0.92, 1.33, and 1.53 mg/kg.bw for 90% target, respectively, after oral administration. The results in this study provided a more optimized alternative for clinical use and demonstrated that the dosage 2 mg/kg of marbofloxacin by oral administration could have an effect on bactericidal activity against E. coli. PMID- 28871228 TI - Interplay of the Quality of Ciprofloxacin and Antibiotic Resistance in Developing Countries. AB - Ciprofloxacin, a second generation broad spectrum fluoroquinolone, is active against both Gram-positive and Gram-negative bacteria. Ciprofloxacin has a high oral bioavailability and a large volume of distribution. It is used for the treatment of a wide range of infections including urinary tract infections caused by susceptible bacteria. However, the availability and use of substandard and spurious quality of oral ciprofloxacin formulations in the developing countries has been thought to have contributed toward increased risk of treatment failure and bacterial resistance. Therefore, quality control and bioequivalence studies of the commercially available oral ciprofloxacin formulations should be monitored. Appropriate actions should be taken against offending manufacturers in order to prevent the sale of substandard and spurious quality of ciprofloxacin formulations. PMID- 28871227 TI - Comparative Proteomic Analysis Provides insight into the Key Proteins as Possible Targets Involved in Aspirin Inhibiting Biofilm Formation of Staphylococcus xylosus. AB - Staphylococcus xylosus is an opportunistic pathogen that causes infection in humans and cow mastitis. And S. xylosus possesses a strong ability to form biofilms in vitro. As biofilm formation facilitates resistance to antimicrobial agents, the discovery of new medicinal properties for classic drugs is highly desired. Aspirin, which is the most common active component of non-steroidal anti inflammatory compounds, affects the biofilm-forming capacity of various bacterial species. We have found that aspirin effectively inhibits biofilm formation of S. xylosus by Crystal violet (CV) staining and scanning electron microscopy analyses. The present study sought to elucidate possible targets of aspirin in suppressing S. xylosus biofilm formation. Based on an isobaric tag for relative and absolute quantitation (iTRAQ) fold-change of >1.2 or <0.8 (P-value < 0.05), 178 differentially expressed proteins, 111 down-regulated and 67 up-regulated, were identified after application of aspirin to cells at a 1/2 minimal inhibitory concentration. Gene ontology analysis indicated enrichment in metabolic processes for the majority of the differentially expressed proteins. We then used the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database to analyze a large number of differentially expressed proteins and identified genes involved in biosynthesis of amino acids pathway, carbon metabolism (pentose phosphate and glycolytic pathways, tricarboxylic acid cycle) and nitrogen metabolism (histidine metabolism). These novel proteins represent candidate targets in aspirin-mediated inhibition of S. xylosus biofilm formation at sub-MIC levels. The findings lay the foundation for further studies to identify potential aspirin targets. PMID- 28871229 TI - Gabapentin Modulates HCN4 Channel Voltage-Dependence. AB - Gabapentin (GBP) is widely used to treat epilepsy and neuropathic pain. There is evidence that GBP can act on hyperpolarization-activated cation (HCN) channel mediated Ih in brain slice experiments. However, evidence showing that GBP directly modulates HCN channels is lacking. The effect of GBP was tested using two-electrode voltage clamp recordings from human HCN1, HCN2, and HCN4 channels expressed in Xenopus oocytes. Whole-cell recordings were also made from mouse spinal cord slices targeting either parvalbumin positive (PV+) or calretinin positive (CR+) inhibitory neurons. The effect of GBP on Ih was measured in each inhibitory neuron population. HCN4 expression was assessed in the spinal cord using immunohistochemistry. When applied to HCN4 channels, GBP (100 MUM) caused a hyperpolarizing shift in the voltage of half activation (V1/2) thereby reducing the currents. Gabapentin had no impact on the V1/2 of HCN1 or HCN2 channels. There was a robust increase in the time to half activation for HCN4 channels with only a small increase noted for HCN1 channels. Gabapentin also caused a hyperpolarizing shift in the V1/2 of Ih measured from HCN4-expressing PV+ inhibitory neurons in the spinal dorsal horn. Gabapentin had minimal effect on Ih recorded from CR+ neurons. Consistent with this, immunohistochemical analysis revealed that the majority of CR+ inhibitory neurons do not express somatic HCN4 channels. In conclusion, GBP reduces HCN4 channel-mediated currents through a hyperpolarized shift in the V1/2. The HCN channel subtype selectivity of GBP provides a unique tool for investigating HCN4 channel function in the central nervous system. The HCN4 channel is a candidate molecular target for the acute analgesic and anticonvulsant actions of GBP. PMID- 28871230 TI - Comparative Analysis for Glycopatterns and Complex-Type N-Glycans of Glycoprotein in Sera from Chronic Hepatitis B- and C-Infected Patients. AB - Background: Chronic infection with HBV (CHB) or HCV (CHC) is the most common chronic viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma in humans, their infections have distinct pathogenic processes, however, little is known about the difference of glycoprotein glycopatterns in serum between hepatitis B virus (HBV)- and hepatitis C virus (HCV)-infected patients. Methods: A method combining the lectin microarrays, letin-mediated affinity capture glycoproteins, and MALDI-TOF/TOF-MS was employed to analyze serum protein glycopatterns and identify the glycan structures from patients with CHB (n = 54) or CHC(n = 47), and healthy volunteers (HV, n = 35). Lectin blotting was further utilized to validate and assess the expression levels of their serum glycopatterns. Finally, the differences of the glycoprotein glycopatterns were systematically compared between CHB and CHC patients. Conclusions: As a result, there were 11 lectins (e.g., HHL, GSL-II, and EEL) exhibited significantly increased expression levels, and three lectins (LCA, VVA, and ACA) exhibited significantly decreased expression levels of serum protein glycopatterns only in the CHB patients. However, DBA exhibited significantly decreased expression levels, and two lectins (WGA and SNA) exhibited significantly increased expression levels of serum glycopatterns only in the CHC patients. Furthermore, LEL and MAL-I showed a coincidentally increasing trend in both CHC and CHB patients compared with the HV. The individual analysis demonstrated that eight lectins (MPL, GSL-I, PTL-II, UEA-I, WGA, LEL, VVA, and MAL-I) exhibited a high degree of consistency with the pooled serum samples of HV, CHB, and CHC patients. Besides, a complex-type N-glycans binder PHA-E+L exhibited significantly decreased NFIs in the CHB compared with HV and CHC subjects (p < 0.01). The MALDI TOF/TOF-MS results of N-linked glycans from the serum glycoproteins isolated by PHA-E+L-magnetic particle conjugates showed that there was an overlap of 23 N glycan peaks (e.g., m/z 1419.743, 1663.734, and 1743.581) between CHB, and CHC patients, 5 glycan peaks (e.g., m/z 1850.878, 1866.661, and 2037.750) were presented in virus-infected hepatitis patients compared with HV, 3 glycan peaks (1460.659, 2069.740, and 2174.772) were observed only in CHC patients. Our data provide useful information to find new biomarkers for distinguishing CHB and CHC patients based on the precision alteration of their serum glycopatterns. PMID- 28871231 TI - Expression of the Fatty Acid Receptors GPR84 and GPR120 and Cytodifferentiation of Epithelial Cells in the Gastric Mucosa of Mouse Pups in the Course of Dietary Transition. AB - During weaning, the ingested food of mouse pups changes from exclusively milk to solid food. In contrast to the protein- and carbohydrate-rich solid food, high fat milk is characterized primarily by fatty acids of medium chain length particularly important for the suckling pups. Therefore, it seems conceivable that the stomach mucosa may be specialized for detecting these important nutrients during the suckling phase. Here, we analyzed the expression of the G protein coupled receptors GPR84 and GPR120 (FFAR4), which are considered to be receptors for medium and long chain fatty acids (LCFAs), respectively. We found that the mRNA levels for GPR84 and GPR120 were high during the suckling period and progressively decreased in the course of weaning. Visualization of the receptor-expressing cells in 2-week-old mice revealed a high number of labeled cells, which reside in the apical as well as in the basal region of the gastric glands. At the base of the gastric glands, all GPR84-immunoreactive cells and some of the GPR120-positive cells also expressed chromogranin A (CgA), suggesting that they are enteroendocrine cells. We demonstrate that the majority of the CgA/GPR84 cells are X/A-like ghrelin cells. The high degree of overlap between ghrelin and GPR84 decreased post-weaning, whereas the overlap between ghrelin and GPR120 increased. At the apical region of the glands the fatty acid receptors were mainly expressed in unique cell types. These contain lipid-filled vacuole- and vesicle-like structures and may have absorptive functions. We detected decreased immunoreactivity for GPR84 and no lipid droplets in surface cells post weaning. In conclusion, expression of GPR84 in ghrelin cells as well as in surface cells suggests an important role of medium chain fatty acids (MCFAs) in the developing gastric mucosa of suckling mice. PMID- 28871232 TI - Fear, Anger, and Risk Preference Reversals: An Experimental Study on a Chinese Sample. AB - Fear and anger are basic emotions of the same valence which differ in terms of their certainty and control dimensions according to the Appraisal Tendency Framework, a theory addressing the relationship between specific emotions, and judgments and choices. Past research based on the Appraisal Theory revealed contradictory results for risky choice decision-making. However, these conclusions were drawn from Western samples (e.g., North American). Considering potential cultural differences, the present study aims to investigate whether the Appraisal Tendency hypothesis yields the same results in a Chinese sample. Our first study explores how dispositional fear and anger influence risk preferences through a classic virtual "Asia Disease Problem" task and the second study investigates how induced fear and anger influence risk preferences through an incentive-compatible task. Consistent with previous research, our results reveal that induced fear and anger have differential effects on risky decisions: angry participants prefer the risk-seeking option, whereas fearful participants prefer a risk-averse option. However, we find no associations between dispositional fear (or anger) and risky decisions. PMID- 28871233 TI - Commentary: Primary Emotional Systems and Personality: An Evolutionary Perspective. PMID- 28871234 TI - Test Anxiety in Spanish Adolescents: Examining the Role of Emotional Attention, and Ruminative Self-focus and Regulation. AB - Emotional attention has been found as a key predictive dimension of stress. However, very few studies have investigated the relationship between emotional attention and test anxiety. The objective of the present study was to analyze the role of emotional attention, measured using the Trait Meta-Mood Scale (TMMS), on the level of test anxiety, and measured using the Test Anxiety Inventory (TAI). In addition, we examined the potential mediating role of Self-Rumination and Self Reflection, as measured through the Rumination-Reflection Questionnaire (RRQ), on the relationship between emotional attention and test anxiety. The sample included 385 Spanish adolescents between 14 and 19 years of age. Mediation analysis results are consistent with a model in which Self-Rumination, but no Self-Reflection, mediates the relationship between Emotional Attention and Test Anxiety. Finally, several potential implications of these findings to improve quality of life in adolescents are discussed. PMID- 28871235 TI - Increase of Reproductive Life Span Delays Age of Onset of Parkinson's Disease. AB - One striking observation in Parkinson's disease (PD) is the remarkable gender difference in incidence and prevalence of the disease. Data on gender differences with regard to disease onset, motor and non-motor symptoms, and dopaminergic medication are limited. Furthermore, whether estrogen status affects disease onset and progression of PD is controversially discussed. In this retrospective single center study, we extracted clinical data of 226 ambulatory PD patients and compared age of disease onset, disease stage, motor impairment, non-motor symptoms, and dopaminergic medication between genders. We applied a matched-pairs design to adjust for age and disease duration. To determine the effect of estrogen-related reproductive factors including number of children, age at menarche, and menopause on the age of onset, we applied a standardized questionnaire and performed a regression analysis. The male to female ratio in the present PD cohort was 1.9:1 (147 men vs. 79 women). Male patients showed increased motor impairment than female patients. The levodopa equivalent daily dose was increased by 18.9% in male patients compared to female patients. Matched pairs analysis confirmed the increased dose of dopaminergic medication in male patients. No differences were observed in age of onset, type of medication, and non-motor symptoms between both groups. Female reproductive factors including number of children, age at menarche, and age at menopause were positively associated with a delay of disease onset up to 30 months. The disease-modifying role of estrogen-related outcome measures warrants further clinical and experimental studies targeting gender differences, specifically hormone-dependent pathways in PD. PMID- 28871236 TI - Non-Visual Photopigments Effects of Constant Light-Emitting Diode Light Exposure on the Inner Retina of Wistar Rats. AB - The retina is part of the central nervous system specially adapted to capture light photons and transmit this information to the brain through photosensitive retinal cells involved in visual and non-visual activities. However, excessive light exposure may accelerate genetic retinal diseases or induce photoreceptor cell (PRC) death, finally leading to retinal degeneration (RD). Light pollution (LP) caused by the characteristic use of artificial light in modern day life may accelerate degenerative diseases or promote RD and circadian desynchrony. We have developed a working model to study RD mechanisms in a low light environment using light-emitting diode (LED) sources, at constant or long exposure times under LP conditions. The mechanism of PRC death is still not fully understood. Our main goal is to study the biochemical mechanisms of RD. We have previously demonstrated that constant light (LL) exposure to white LED produces a significant reduction in the outer nuclear layer (ONL) by classical PRC death after 7 days of LL exposure. The PRCs showed TUNEL-positive labeling and a caspase-3-independent mechanism of cell death. Here, we investigate whether constant LED exposure affects the inner-retinal organization and structure, cell survival and the expression of photopigments; in particular we look into whether constant LED exposure causes the death of retinal ganglion cells (RGCs), of intrinsically photosensitive RGCs (ipRGCs), or of other inner-retinal cells. Wistar rats exposed to 200 lx of LED for 2 to 8 days (LL 2 and LL 8) were processed for histological and protein. The results show no differences in the number of nucleus or TUNEL positive RGCs nor inner structural damage in any of LL groups studied, indicating that LL exposure affects ONL but does not produce RGC death. However, the photopigments melanopsin (OPN4) and neuropsin (OPN5) expressed in the inner retina were seen to modify their localization and expression during LL exposure. Our findings suggest that constant light during several days produces retinal remodeling and ONL cell death as well as significant changes in opsin expression in the inner nuclear layer. PMID- 28871237 TI - Characteristics and Outcomes of Young Patients with First-Ever Ischemic Stroke Compared to Older Patients: The National Acute Stroke ISraeli Registry. AB - BACKGROUND: Nationwide data on the clinical profile and outcomes of ischemic stroke in younger adults are still scarce. Our aim was to analyze clinical characteristics and outcomes of young patients with first-ever ischemic stroke compared to older patients. METHODS: The National Acute Stroke ISraeli registry is a nationwide prospective hospital-based study performed triennially. Younger adults, aged 50 years and younger, were compared with patients, aged 51-84 years regarding risk factors, clinical presentation, stroke severity, stroke etiology, and outcomes. A logistic model for stroke outcome was fitted for each age group. RESULTS: 336 first-ever ischemic strokes were identified among patients aged 50 years and younger and 3,243 among patients 51-84 years. Younger adults had lower rates of traditional vascular risk factors, but 82.7% had at least one of these risk factors. Younger adults were more likely to be male (62.8%), current smokers (47.3%), and to have a family history of stroke (7.4%). They tended to have less common stroke presentation such as sensory disturbances or headache and were more likely to arrive at the hospital independently by car. The majority of young adults (70%) had a favorable outcome (modified Ranking Scale; mRS <= 1) at discharge, but 11.7% had poor outcome (mRS > 3) and 18.2% had an in-hospital complication. According to a multivariable regression model, in young adults, only baseline stroke severity (National Institute of Health Stroke Scale > 5) was associated with poor outcome at discharge (p < 0.001), whereas in older adults, stroke severity (p < 0.001), female gender (OR = 1.35, CI 95% 1.03-1.76), older age (OR = 1.08, CI 95% 1.01-1.16), atrial fibrillation (OR = 1.62, CI 95% 1.16 2.26), and anterior circulation territory (OR = 2.10, CI 95% 1.50-2.94) were all significantly associated with poor outcome. CONCLUSION: Our findings, in this nationwide registry, demonstrate the relatively high rate of smoking and family history of stroke, and the lower rate of hospital arrival by ambulance among young adults. This calls for increasing awareness to the possibility of stroke among young adults and for better prevention, especially smoking cessation. PMID- 28871238 TI - Overcoming Therapeutic Inertia in Multiple Sclerosis Care: A Pilot Randomized Trial Applying the Traffic Light System in Medical Education. AB - BACKGROUND: Physicians often do not initiate or intensify treatments when clearly warranted, a phenomenon known as therapeutic inertia (TI). Limited information is available on educational interventions to ameliorate knowledge-to-action gaps in TI. OBJECTIVES: To evaluate the feasibility and efficacy of an educational intervention compared to usual care among practicing neurologists caring for patients with multiple sclerosis (MS). METHODS: We conducted a pilot double blind, parallel-group, randomized clinical trial. Inclusion criteria included neurologists who are actively involved in managing MS patients. Participants were exposed to 20 simulated case-scenarios (10 cases at baseline, and 10 cases post randomization to usual care vs. educational intervention) of relapsing-remitting MS with moderate or high risk of disease progression. The educational intervention employed a traffic light system (TLS) to facilitate decisions, allowing participants to easily recognize high-risk scenarios requiring treatment escalation. We also measured differences between blocks to invoke decision fatigue. The control group responded as they would do in their usual clinical practice not exposed to the educational intervention. The primary feasibility outcome was the proportion of participants who completed the study and the proportion of participants who correctly identified a high-risk case-scenario with the "red traffic light." Secondary outcomes included decision fatigue (defined as an increment of TI in the second block of case-scenarios compared to the first block) and the efficacy of the educational intervention measured as a reduction in TI for MS treatment. RESULTS: Of 30 neurologists invited to be part of the study, the participation rate was 83.3% (n = 25). Of the 25 participants, 14 were randomly assigned to the control group and 11 to the intervention group. TI was present in 72.0% of participants in at least one case scenario. For the primary feasibility outcome, the completion rate of the study was 100% (25/25 participants). Overall, 77.4% of participants correctly identified the "red traffic light" for clinical-scenarios with high risk of disease progression. Similarly, 86.4% of participants correctly identified the "yellow traffic light" for cases that would require a reassessment within 6-12 months. For the secondary fatigue outcome, within-group analysis showed a significant increased prevalence of TI in the second block of case-scenarios (decision fatigue) among participants randomized to the control group (TI pre-intervention 57.1% vs. TI post intervention 71.4%; p = 0.015), but not in the active group (TI pre-intervention 54.6% vs. TI post-intervention 63.6%; p = 0.14). For the efficacy outcome, we found a non-significant reduction in TI for the targeted intervention compared to controls (22.6 vs. 33.9% post-intervention; OR 0.57; 95% CI 0.26-1.22). CONCLUSION: An educational intervention applying the TLS is feasible and shows some promising results in the identification of high-risk scenarios to reduce decision fatigue and TI. Larger studies are needed to determine the efficacy of the proposed educational intervention. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT03134794. PMID- 28871239 TI - Arginine Vasopressin Effects on Subjective Judgments and Neural Responses to Same and Other-Sex Faces in Men and Women. AB - Arginine vasopressin (AVP) influences social and emotional behaviors across a wide range of species. In humans, intranasal AVP has been previously shown to alter physiological responses to and subjective judgments of same-sex faces in both men and women. The present study attempted to elucidate the neural mechanism for these effects by randomizing 40 healthy men and 40 healthy women to treatment with either 40 IU intranasal AVP or a saline placebo approximately 30 min before imaging their brain function with fMRI as they viewed same and other-sex faces. All subjects were also scanned a second time several days later with no treatment to evaluate the persistence of AVP effects over time. AVP acutely increased positive ratings of same-sex faces in women, with some evidence that these effects persisted until the second scan. While AVP had no acute effects on same sex ratings in men, AVP increased positive ratings of same-sex faces several days later. On the other hand, AVP had no effect on other-sex face judgments in either sex. AVP modulation of brain function was focused on the nucleus accumbens (NAc) and the lateral septum, two reward processing areas involved in the formation of social bonds. AVP provoked acute increases in right NAc and bilateral lateral septum responses to female faces among men, with left lateral septum responses persisting over time while right NAc responses reversed over time. Finally, AVP modulated hypothalamic activation to faces in both men and women. The present study therefore indicates that intranasal AVP affects subjective ratings and neural responses to same and other-sex faces in men and women, with some effects persisting and others emerging over time. Future studies should investigate whether AVP effects are modulated by individual variables such as genotype, personality, or attachment style as previously reported for other nonapeptides. PMID- 28871240 TI - In Vivo and In Vitro Analysis in Coronary Artery Disease Related to Type 2 Diabetes. AB - AIM: The leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (DM) is coronary artery disease (CAD), a condition often asymptomatic but severe in these patients. Although glucose metabolism impairment and oxidative stress are known actors in the endothelial dysfunction/remodeling that occurs in diabetic patients, the relationship between cardiovascular disorders and DM is not fully understood. We have performed both an in vivo imaging and in vitro molecular analysis to investigate diabetic-specific CAD alterations. METHODS: Computed tomography coronary angiography (CTCA) was performed in a group of 20 diabetic patients with CAD (DM+CAD+), 20 non-diabetic with CAD (DM-CAD+), 10 diabetic non-CAD patients (DM+CAD-), and 20 non-diabetic healthy subjects (HS). Imaging quantitative parameters such as calcium score (Cascore), calcified plaque volume (CPV), non-calcified plaque volume (NCPV), total plaque volume (TPV), remodeling index (RI), and plaque burden were extracted for each CAD subject. Moreover, the expression levels of superoxide dismutase 2 (SOD2) and liver X receptor alpha (LXRalpha) genes were analyzed in the peripheral blood mononuclear cells, whereas hyaluronan (HA) concentrations were evaluated in the plasma of each subject. RESULTS: Imaging parameters, such as Cascore, CPV, RI, and plaque burden, were significantly higher in DM+CAD+ group, compared to DM-CAD+ (P = 0.019; P = 0.014; P < 0.001, P < 0.001, respectively). SOD2 mRNA was downregulated, while LXRalpha gene expression was upregulated in DM+CAD-, DM+CAD+, and DM-CAD+ groups compared to HS (P = 0.001, P = 0.03, and P = 0.001 for SOD2 and P = 0.006, P = 0.008, and P < 0.001 for LXRalpha, respectively). Plasmatic levels of HA were higher in DM-CAD+, DM+CAD-, and DM+CAD+ groups, compared to HS (P = 0.001 for the three groups). When compared to DM-CAD+, HA concentration was higher in DM+CAD- (P = 0.008) and DM+CAD+ (P < 0.001) with a significant difference between the two diabetic groups (P = 0.003). Moreover, HA showed a significant association with diabetes (P = 0.01) in the study population, and the correlation between HA levels and glycemia was statistically significant (rho = 0.73, P < 0.001). CONCLUSION: In our population, imaging parameters highlight a greater severity of CAD in diabetic patients. Among molecular parameters, HA is modulated by diabetic CAD-related alterations while SOD2 and LXRalpha are found to be more associated with CAD but do not discriminate between diabetic and non-diabetic subgroups. PMID- 28871241 TI - Inhibition of Fungal Pathogens across Genotypes and Temperatures by Amphibian Skin Bacteria. AB - Symbiotic bacteria may dampen the impacts of infectious diseases on hosts by inhibiting pathogen growth. However, our understanding of the generality of pathogen inhibition by different bacterial taxa across pathogen genotypes and environmental conditions is limited. Bacterial inhibitory properties are of particular interest for the amphibian-killing fungal pathogens (Batrachochytrium dendrobatidis and Batrachochytrium salamandrivorans), for which probiotic applications as conservation strategies have been proposed. We quantified the inhibition strength of five putatively B. dendrobatidis-inhibitory bacteria isolated from woodland salamander skin against six Batrachochytrium genotypes at two temperatures (12 and 18 degrees C). We selected six genotypes from across the Batrachochytrium phylogeny: B. salamandrivorans, B. dendrobatidis-Brazil and four genotypes of the B. dendrobatidis Global Panzootic Lineage (GPL1: JEL647, JEL404; GPL2: SRS810, JEL423). We performed 96-well plate challenge assays in a full factorial design. We detected a Batrachochytrium genotype by temperature interaction on bacterial inhibition score for all bacteria, indicating that bacteria vary in ability to inhibit Batrachochytrium depending on pathogen genotype and temperature. Acinetobacter rhizosphaerae moderately inhibited B. salamandrivorans at both temperatures (MU = 46-53%), but not any B. dendrobatidis genotypes. Chryseobacterium sp. inhibited three Batrachochytrium genotypes at both temperatures (MU = 5-71%). Pseudomonas sp. strain 1 inhibited all Batrachochytrium genotypes at 12 degrees C and four Batrachochytrium genotypes at 18 degrees C (MU = 5-100%). Pseudomonas sp. strain 2 and Stenotrophomonas sp. moderately to strongly inhibited all six Batrachochytrium genotypes at both temperatures (MU = 57-100%). All bacteria consistently inhibited B. salamandrivorans. Using cluster analysis of inhibition scores, we found that more closely related Batrachochytrium genotypes grouped together, suggesting that bacterial inhibition strength may be predictable based on Batrachochytrium relatedness. We conclude that bacterial inhibition capabilities change among bacterial strains, Batrachochytrium genotypes and temperatures. A comprehensive understanding of bacterial inhibitory function, across pathogen genotypes and temperatures, is needed to better predict the role of bacterial symbionts in amphibian disease ecology. For targeted conservation applications, we recommend using bacterial strains identified as strongly inhibitory as they are most likely to produce broad-spectrum antimicrobial agents at a range of temperatures. PMID- 28871242 TI - Concurrent Detection of Human Norovirus and Bacterial Pathogens in Water Samples from an Agricultural Region in Central California Coast. AB - Bacterial pathogens and human norovirus (HuNoV) are major cause for acute gastroenteritis caused by contaminated food and water. Public waterways can become contaminated from a variety of sources and flood after heavy rain events, leading to pathogen contamination of produce fields. We initiated a survey of several public watersheds in a major leafy green produce production region of the Central California Coast to determine the prevalence of HuNoV as well as bacterial pathogens. Moore swabs were used to collect environmental samples bi monthly at over 30 sampling sites in the region. High prevalence of HuNoV and bacterial pathogens were detected in environmental water samples in the region. The overall detection rates of HuNoV, O157 Shiga toxin-producing Escherichia coli (STEC), non-O157 STEC, Salmonella, and Listeria were 25.58, 7.91, 9.42, 59.65, and 44.30%, respectively. The detection rates of Salmonella and L. monocytogenes were significantly higher in the spring. Fall and spring had elevated detection rates of O157 STEC. The overall detection rates of non-O157 STEC in the fall were lower than the other seasons but not significant. The overall detection rates of HuNoV were highest in fall, followed by spring and winter, with summer being lowest and significantly lower than other seasons. This study presented the first study of evaluating the correlation between the detection rate of HuNoV and the detection rates of four bacterial pathogens from environmental water. Overall, there was no significant difference in HuNoV detection rates between samples testing positive or negative for the four bacterial pathogens tested. Pathogens in animal-impacted and human-impacted areas were investigated. There were significant higher detection rates in animal-impacted areas than that of human impacted areas for bacterial pathogens. However, there was no difference in HuNoV detection rates between these two areas. The overall detection levels of generic E. coli and detection rate of HuNoV showed no correlation. PMID- 28871243 TI - First Molecular Detection of Babesia gibsoni in Dogs from Wuhan, China. AB - Canine piroplasmosis is a significant disease in dogs caused by Babesia and Theileria parasites. The clinical manifestations range from mild illness to serious disease depending on the parasite species and the physical condition of the infected dog. Canine piroplasmosis has been reported to be prevalent in China. However, no molecular evidence of the disease has been reported in pet dogs from Wuhan. In this study, 118 blood samples were randomly collected from pet dogs in veterinary clinics. The blood samples were subjected to both microscopic examination and reverse line blot (RLB) hybridization assays to detect piroplasm infection. Parasites were observed in 10 blood samples via microscopic examination, whereas there were 14 Babesia gibsoni-positive RLB tests. Phylogenetic analysis was performed after the 18S rRNA and ITS gene sequences from the 14 positive samples were cloned and sequenced. The results confirmed the existence of B. gibsoni in this area. This is the first molecular report of canine babesiosis in pet dogs from Wuhan, China. Pet dogs are companion animals, and the prevalence of babesiosis will be of concern in daily life. This study will help veterinarians better understand the prevalence of canine babesiosis and provide a guide for disease control in pet dogs. PMID- 28871244 TI - Microbial Diversity in Sulfate-Reducing Marine Sediment Enrichment Cultures Associated with Anaerobic Biotransformation of Coastal Stockpiled Phosphogypsum (Sfax, Tunisia). AB - Anaerobic biotechnology using sulfate-reducing bacteria (SRB) is a promising alternative for reducing long-term stockpiling of phosphogypsum (PG), an acidic (pH ~3) by-product of the phosphate fertilizer industries containing high amounts of sulfate. The main objective of this study was to evaluate, for the first time, the diversity and ability of anaerobic marine microorganisms to convert sulfate from PG into sulfide, in order to look for marine SRB of biotechnological interest. A series of sulfate-reducing enrichment cultures were performed using different electron donors (i.e., acetate, formate, or lactate) and sulfate sources (i.e., sodium sulfate or PG) as electron acceptors. Significant sulfide production was observed from enrichment cultures inoculated with marine sediments, collected near the effluent discharge point of a Tunisian fertilizer industry (Sfax, Tunisia). Sulfate sources impacted sulfide production rates from marine sediments as well as the diversity of SRB species belonging to Deltaproteobacteria. When PG was used as sulfate source, Desulfovibrio species dominated microbial communities of marine sediments, while Desulfobacter species were mainly detected using sodium sulfate. Sulfide production was also affected depending on the electron donor used, with the highest production obtained using formate. In contrast, low sulfide production (acetate-containing cultures) was associated with an increase in the population of Firmicutes. These results suggested that marine Desulfovibrio species, to be further isolated, are potential candidates for bioremediation of PG by immobilizing metals and metalloids thanks to sulfide production by these SRB. PMID- 28871245 TI - Comparative Genomic Analysis of Neutrophilic Iron(II) Oxidizer Genomes for Candidate Genes in Extracellular Electron Transfer. AB - Extracellular electron transfer (EET) is recognized as a key biochemical process in circumneutral pH Fe(II)-oxidizing bacteria (FeOB). In this study, we searched for candidate EET genes in 73 neutrophilic FeOB genomes, among which 43 genomes are complete or close-to-complete and the rest have estimated genome completeness ranging from 5 to 91%. These neutrophilic FeOB span members of the microaerophilic, anaerobic phototrophic, and anaerobic nitrate-reducing FeOB groups. We found that many microaerophilic and several anaerobic FeOB possess homologs of Cyc2, an outer membrane cytochrome c originally identified in Acidithiobacillus ferrooxidans. The "porin-cytochrome c complex" (PCC) gene clusters homologous to MtoAB/PioAB are present in eight FeOB, accounting for 19% of complete and close-to-complete genomes examined, whereas PCC genes homologous to OmbB-OmaB-OmcB in Geobacter sulfurreducens are absent. Further, we discovered gene clusters that may potentially encode two novel PCC types. First, a cluster (tentatively named "PCC3") encodes a porin, an extracellular and a periplasmic cytochrome c with remarkably large numbers of heme-binding motifs. Second, a cluster (tentatively named "PCC4") encodes a porin and three periplasmic multiheme cytochromes c. A conserved inner membrane protein (IMP) encoded in PCC3 and PCC4 gene clusters might be responsible for translocating electrons across the inner membrane. Other bacteria possessing PCC3 and PCC4 are mostly Proteobacteria isolated from environments with a potential niche for Fe(II) oxidation. In addition to cytochrome c, multicopper oxidase (MCO) genes potentially involved in Fe(II) oxidation were also identified. Notably, candidate EET genes were not found in some FeOB, especially the anaerobic ones, probably suggesting EET genes or Fe(II) oxidation mechanisms are different from the searched models. Overall, based on current EET models, the search extends our understanding of bacterial EET and provides candidate genes for future research. PMID- 28871246 TI - Succession and Fermentation Products of Grass Carp (Ctenopharyngodon idellus) Hindgut Microbiota in Response to an Extreme Dietary Shift. AB - Dietary intake affects the structure and function of microbes in host intestine. However, the succession of gut microbiota in response to changes in macronutrient levels during a long period of time remains insufficiently studied. Here, we determined the succession and metabolic products of intestinal microbiota in grass carp (Ctenopharyngodon idellus) undergoing an abrupt and extreme diet change, from fish meal to Sudan grass (Sorghum sudanense). Grass carp hindgut microbiota responded rapidly to the diet shift, reaching a new equilibrium approximately within 11 days. In comparison to animal-diet samples, Bacteroides, Lachnospiraceae and Erysipelotrichaceae increased significantly while Cetobacterium decreased significantly in plant-diet samples. Cetobacterium was negatively correlated with Bacteroides, Lachnospiraceae and Erysipelotrichaceae, while Bacteroides was positively correlated with Lachnospiraceae. Predicted glycoside hydrolase and polysaccharide lyase genes in Bacteroides and Lachnospiraceae from the Carbohydrate-Active enZymes (CAZy) database might be involved in degradation of the plant cell wall polysaccharides. However, none of these enzymes was detected in the grass carp genome searched against dbCAN database. Additionally, a significant decrease of short chain fatty acids levels in plant-based samples was observed. Generally, our results suggest a rapid adaption of grass carp intestinal microbiota to dietary shift, and that microbiota are likely to play an indispensable role in nutrient turnover and fermentation. PMID- 28871247 TI - Archaeal Persisters: Persister Cell Formation as a Stress Response in Haloferax volcanii. AB - Persister cells are phenotypic variants within a microbial population, which are dormant and transiently tolerant to stress. Persistence has been studied extensively in bacteria, and in eukaryotes to a limited extent, however, it has never been observed in archaea. Using the model haloarchaeon, Haloferax volcanii DS2, we demonstrated persister cell formation in this domain, with time-kill curves exhibiting a characteristic biphasic pattern following starvation or exposure to lethal concentrations of various biocidal compounds. Repeated challenges of surviving cells showed that, as with bacteria, persister formation in H. volcanii was not heritable. Additionally, as previously shown with bacteria, persister formation in H. volcanii was suppressed by exogenous indole. The addition of spent culture media to assays conducted on planktonic cells showed that H. volcanii-conditioned media stimulated persistence, whereas conditioned media of other haloarchaea or halophilic bacteria did not, suggesting the involvement of a species-specific signal. Using a TLC overlay assay, the quorum sensing bioreporter Agrobacterium tumefaciens ATCC BAA-2240 detected the presence of C4 and C6 acyl homoserine lactone-like signal molecules in a H. volcanii culture extract. While synthetic bacterial AHLs did not induce persistence, this is potentially due to structural differences between bacterial and archaeal signals, and does not discount a quorum sensing component in haloarchaeal persister formation. The observation of persister cell formation by this haloarchaeon may provide some insights into the survival of these organisms in stressful or dynamic environments. PMID- 28871248 TI - Identification and Functional Characterization of Small Alarmone Synthetases in Corynebacterium glutamicum. AB - The hyperphosphorylated guanosine derivatives ppGpp and pppGpp represent global regulators of the bacterial stress response, as they act as central elements of the stringent response system. Although it was assumed that both, (p)ppGpp synthesis and hydrolysis, are catalyzed by one bifunctional RSH-protein in the actinobacterial model organism Corynebacterium glutamicum ATCC 13032, two putative short alarmone synthetases (SASs) were identified by bioinformatic analyses. The predicted sequences of both enzymes, designated as RelP*Cg and RelSCg, exhibit high similarities to the conserved (p)ppGpp synthetase catalytic domain. In the context of sequence analysis, significant differences were found between the RelP variants of different C. glutamicum isolates. In contrast to the bifunctional RelA/SpoT homolog (RSH) protein RelCg, whose gene deletion results in a reduced growth rate, no change in growth characteristics were observed for deletion mutants of the putative SAS proteins under standard growth conditions. The growth deficit of the Deltarel strain could be restored by the additional deletion of the gene encoding RelSCg, which clearly indicates a functional relationship between both enzymes. The predicted pyrophosphokinase activity of RelSCg was demonstrated by means of genetic complementation of an Escherichia coli DeltarelADeltaspoT strain. For the expression of RelP*Cg , as well as the slightly differing variant RelPCg from C. glutamicum AS1.542, no complementation was observed, concluding that both RelP versions possess no significant pyrophosphokinase activity in vivo. The results were confirmed by in vitro characterization of the corresponding proteins. In the course of this investigation, the additional conversion of GMP to pGpp was determined for the enzyme RelSCg. Since the SAS species analyzed extend both the network of stringent response related enzymes and the number of substances involved, the study of this class of enzymes is an important component in understanding the bacterial stress response. In addition to the comprehension of important biological processes, such as growth rate regulation and the survival of pathogenic species in the host organism, SAS enzymes can be used to produce novel hyperphosphorylated nucleotide species, such as pGpp. PMID- 28871249 TI - Neutralization of Human Interleukin 23 by Multivalent Nanobodies Explained by the Structure of Cytokine-Nanobody Complex. AB - The heterodimeric cytokine interleukin (IL) 23 comprises the IL12-shared p40 subunit and an IL23-specific subunit, p19. Together with IL12 and IL27, IL23 sits at the apex of the regulatory mechanisms shaping adaptive immune responses. IL23, together with IL17, plays an important role in the development of chronic inflammation and autoimmune inflammatory diseases. In this context, we generated monovalent antihuman IL23 variable heavy chain domain of llama heavy chain antibody (VHH) domains (Nanobodies(r)) with low nanomolar affinity for human interleukin (hIL) 23. The crystal structure of a quaternary complex assembling hIL23 and several nanobodies against p19 and p40 subunits allowed identification of distinct epitopes and enabled rational design of a multivalent IL23-specific blocking nanobody. Taking advantage of the ease of nanobody formatting, multivalent IL23 nanobodies were assembled with properly designed linkers flanking an antihuman serum albumin nanobody, with improved hIL23 neutralization capacity in vitro and in vivo, as compared to the monovalent nanobodies. These constructs with long exposure time are excellent candidates for further developments targeting Crohn's disease, rheumatoid arthritis, and psoriasis. PMID- 28871250 TI - MicroRNA-21: A Positive Regulator for Optimal Production of Type I and Type III Interferon by Plasmacytoid Dendritic Cells. AB - Plasmacytoid dendritic cells (pDCs) are the major producers of type I and type III interferons (IFNs) that play essential roles in host antiviral immunity. MicroRNAs (miRs) are small, noncoding RNAs that can modulate many immune processes. Although molecular regulation of type I IFN production by pDCs has been studied extensively, the regulation of type III IFN production has not been studied thoroughly, particularly at posttranscriptional level. We show here that miR-21 is an essential positive regulator for the production of both IFN-alpha and IFN-lambda by pDCs and for promoting host defense against viral infection. miR-21 was markedly upregulated in toll-like receptor (TLR)-activated pDCs and was crucial for TLR7/9 ligand- or herpesvirus-induced production of IFN-alpha and IFN-lambda by pDCs. miR-21-deficient pDCs produced significantly lower levels of IFN-alpha and IFN-lambda on activation than those by wild-type pDCs. Impaired antiviral immune responses were also observed in miR-21-deficient mice. Mechanistically, we identified phosphatase and tensin homolog (PTEN) as the major target of miR-21 in pDCs, and miR-21 deficiency resulted in increased expression of PTEN that suppressed TLR-mediated activation of PI3K-Akt-mTOR signaling in pDCs. Hence, our findings provide evidence that miR-21 positively regulates both IFN-alpha and IFN-lambda production and identify an important role for miR-21 in regulating the function of pDCs and in host antiviral immunity. PMID- 28871251 TI - Th17-Inducing Cytokines IL-6 and IL-23 Are Crucial for Granuloma Formation during Experimental Paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM), a chronic granulomatous disease caused by the thermally dimorphic fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii, has the highest mortality rate among systemic mycosis. The T helper 1 mediated immunity is primarily responsible for acquired resistance during P. brasiliensis infection, while susceptibility is associated with Th2 occurrence. Th17 is a population of T CD4+ cells that, among several chemokines and cytokines, produces IL-17A and requires the presence of IL-1, IL-6, and TGF-beta for differentiation in mice and IL-23 for its maintenance. Th17 has been described as an arm of the immune system that enhances host protection against several bacterial and fungal infections, as Pneumocystis carinii and Candida albicans. In this study, we aimed to evaluate the Th17 immune response and the role of Th17-associated cytokines (IL-6, IL-23, and IL-17A) during experimental PCM. First, we observed that P. brasiliensis infection [virulent yeast strain 18 of P. brasiliensis (Pb18)] increased the IL-17A production in vitro and all the evaluated Th17-associated cytokines in the lung tissue from C57BL/6 wild-type mice. In addition, the deficiency of IL-6, IL-23, or IL-17 receptor A (IL-17RA) impaired the compact granuloma formation and conferred susceptibility during infection, associated with reduced tumor necrosis factor-alpha, IFN-gamma, and inducible nitric oxide synthase enzyme expression. Our data suggest that IL-6 production by bone marrow-derived macrophages (BMDMs) is important to promote the Th17 differentiation during Pb18 infection. In accordance, the adoptive transfer of BMDMs from C57BL/6 to infected IL-6-/- or IL-17RA-/- mice reduced the fungal burden in the lungs compared to nontransferred mice and reestablished the pulmonary granuloma formation. Taken together, these results suggest that Th17 associated cytokines are involved in the modulation of immune response and granuloma formation during experimental PCM. PMID- 28871252 TI - Development and Characterization of a Camelid Single Domain Antibody-Urease Conjugate That Targets Vascular Endothelial Growth Factor Receptor 2. AB - Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor, which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFRs). In this study, we describe the development and characterization of V21-DOS47, an immunoconjugate that targets VEGFR2. V21-DOS47 is composed of a camelid single domain anti-VEGFR2 antibody (V21) and the enzyme urease. The conjugate specifically binds to VEGFR2 and urease converts endogenous urea into ammonia, which is toxic to tumor cells. Previously, we developed a similar antibody-urease conjugate, L-DOS47, which is currently in clinical trials for non-small cell lung cancer. Although V21-DOS47 was designed from parameters learned from the generation of L-DOS47, additional optimization was required to produce V21-DOS47. In this study, we describe the expression and purification of two versions of the V21 antibody: V21H1 and V21H4. Each was conjugated to urease using a different chemical cross-linker. The conjugates were characterized by a panel of analytical techniques, including SDS PAGE, size exclusion chromatography, Western blotting, and LC-MSE peptide mapping. Binding characteristics were determined by ELISA and flow cytometry assays. To improve the stability of the conjugates at physiologic pH, the pIs of the V21 antibodies were adjusted by adding several amino acid residues to the C terminus. For V21H4, a terminal cysteine was also added for use in the conjugation chemistry. The modified V21 antibodies were expressed in the E. coli BL21 (DE3) pT7 system. V21H1 was conjugated to urease using the heterobifunctional cross-linker succinimidyl-[(N-maleimidopropionamido) diethyleneglycol] ester (SM(PEG)2), which targets lysine resides in the antibody. V21H4 was conjugated to urease using the homobifunctional cross-linker, 1,8 bis(maleimido)diethylene glycol (BM(PEG)2), which targets the cysteine added to the antibody C-terminus. V21H4-DOS47 was determined to be the superior conjugate as the antibody is easily produced and purified at high levels, and the conjugate can be efficiently generated and purified using methods easily transferrable for cGMP production. In addition, V21H4-DOS47 retains higher binding activity than V21H1-DOS47, as the native lysine residues are unmodified. PMID- 28871253 TI - Severe Tuberculosis in Humans Correlates Best with Neutrophil Abundance and Lymphocyte Deficiency and Does Not Correlate with Antigen-Specific CD4 T-Cell Response. AB - It is generally thought that Mycobacterium tuberculosis (Mtb)-specific CD4+ Th1 cells producing IFN-gamma are essential for protection against tuberculosis (TB). In some studies, protection has recently been associated with polyfunctional subpopulation of Mtb-specific Th1 cells, i.e., with cells able to simultaneously secrete several type 1 cytokines. However, the role for Mtb-specific Th1 cells and their polyfunctional subpopulations during established TB disease is not fully defined. Pulmonary TB is characterized by a great variability of disease manifestations. To address the role for Mtb-specific Th1 responses during TB, we investigated how Th1 and other immune cells correlated with particular TB manifestations, such as the degree of pulmonary destruction, TB extent, the level of bacteria excretion, clinical disease severity, clinical TB forms, and "Timika X-ray score," an integrative parameter of pulmonary TB pathology. In comparison with healthy Mtb-exposed controls, TB patients (TBP) did not exhibit deficiency in Mtb-specific cytokine-producing CD4+ cells circulating in the blood and differed by a polyfunctional profile of these cells, which was biased toward the accumulation of bifunctional TNF-alpha+IFN-gamma+IL-2- lymphocytes. Importantly, however, severity of different TB manifestations was not associated with Mtb specific cytokine-producing cells or their polyfunctional profile. In contrast, several TB manifestations were strongly correlated with leukocyte numbers, the percent or the absolute number of lymphocytes, segmented or band neutrophils. In multiple alternative statistical analyses, band neutrophils appeared as the strongest positive correlate of pulmonary destruction, bacteria excretion, and "Timika X-ray score." In contrast, clinical TB severity was primarily and inversely correlated with the number of lymphocytes in the blood. The results suggest that: (i) different TB manifestations may be driven by distinct mechanisms; (ii) quantitative parameters and polyfunctional profile of circulating Mtb-specific CD4+ cells play a minor role in determining TB severity; and (iii) general shifts in production/removal of granulocytic and lymphocytic lineages represent an important factor of TB pathogenesis. Mechanisms leading to these shifts and their specific role during TB are yet to be determined but are likely to involve changes in human hematopoietic system. PMID- 28871255 TI - Signaling to the Epigenome: New Insights into the Roles of Nuclear Signaling Kinases in the Context of the Immune System and Cancer. PMID- 28871254 TI - Single-Domain Antibodies As Versatile Affinity Reagents for Analytical and Diagnostic Applications. AB - With just three CDRs in their variable domains, the antigen-binding site of camelid heavy-chain-only antibodies (HcAbs) has a more limited structural diversity than that of conventional antibodies. Even so, this does not seem to limit their specificity and high affinity as HcAbs against a broad range of structurally diverse antigens have been reported. The recombinant form of their variable domain [nanobody (Nb)] has outstanding properties that make Nbs, not just an alternative option to conventional antibodies, but in many cases, these properties allow them to reach analytical or diagnostic performances that cannot be accomplished with conventional antibodies. These attributes include comprehensive representation of the immune specificity in display libraries, easy adaptation to high-throughput screening, exceptional stability, minimal size, and versatility as affinity building block. Here, we critically reviewed each of these properties and highlight their relevance with regard to recent developments in different fields of immunosensing applications. PMID- 28871256 TI - Human Leukocyte Antigen (HLA)-DRB1*15:01 and HLA-DRB5*01:01 Present Complementary Peptide Repertoires. AB - Human leukocyte antigen (HLA)-DR15 is a haplotype associated with multiple sclerosis. It contains the two DRB* genes DRB1*1501 (DR2b) and DRB5*0101 (DR2a). The reported anchor motif of the corresponding HLA-DR molecules was determined in 1994 based on a small number of peptide ligands and binding assays. DR2a could display a set of peptides complementary to that presented by DR2b or, alternatively, a similar peptide repertoire but recognized in a different manner by T cells. It is known that DR2a and DR2b share some peptide ligands, although the degree of similarity of their associated peptidomes remains unclear. In addition, the contribution of each molecule to the global peptide repertoire presented by the HLA-DR15 haplotype has not been evaluated. We used mass spectrometry to analyze the peptide pools bound to DR2a and DR2b, identifying 169 and 555 unique peptide ligands of DR2a and DR2b, respectively. The analysis of these sets of peptides allowed the refinement of the corresponding binding motifs revealing novel anchor residues that had been overlooked in previous analyses. Moreover, the number of shared ligands between both molecules was low, indicating that DR2a and DR2b present complementary peptide repertoires to T cells. Finally, our analysis suggests that, quantitatively, both molecules contribute to the peptide repertoire presented by cells expressing the HLA-DR15 haplotype. PMID- 28871257 TI - Reactivation of Intestinal Inflammation Is Suppressed by Catestatin in a Murine Model of Colitis via M1 Macrophages and Not the Gut Microbiota. AB - While there is growing awareness of a relationship between chromogranin-A (CHGA) and susceptibility to inflammatory conditions, the role of human catestatin [(hCTS); CHGA352-67] in the natural history of established inflammatory bowel disease is not known. Recently, using two different experimental models, we demonstrated that hCTS-treated mice develop less severe acute colitis. We have also shown the implication of the macrophages in this effect. The aims of this study were to determine (1) whether hCTS treatment could attenuate the reactivation of inflammation in adult mice with previously established chronic colitis; (2) whether this effect is mediated through macrophages or the gut microbiota. Quiescent colitis was induced in 7-8-week-old C57BL6 mice using four cycles (2-4%) of dextran sulfate sodium. hCTS (1.5 mg/kg/day) treatment or vehicle started 2 days before the last induction of colitis and continuing for 7 days. At sacrifice, macro- and microscopic scores were determined. Colonic pro inflammatory cytokines [interleukin (IL)-6, IL-1beta, and TNF- alpha], anti inflammatory cytokines (IL-10, TGF- beta), classically activated (M1) (iNOS, Mcp1), and alternatively activated (M2) (Ym1, Arg1) macrophages markers were studied using ELISA and/or RT-qPCR. In vitro, peritoneal macrophages isolated from naive mice and treated with hCTS (10-5 M, 12 h) were exposed to either lipopolysaccharide (100 ng/ml, 12 h) to polarize M1 macrophages or to IL-4/IL-13 (20 ng/ml) to polarize M2 macrophages. M1/M2 macrophage markers along with cytokine gene expression were determined using RT-qPCR. Feces and mucosa associated microbiota (MAM) samples were collected, and the V4 region of 16 s rRNA was sequenced. Micro- and macroscopic scores, colonic IL-6, IL-1beta, TNF- alpha, and M1 macrophages markers were significantly decreased in the hCTS treated group. Treatment did not have any effect on colonic IL-10, TGF-beta, and M2 markers nor modified the bacterial richness, diversity, or the major phyla in colitic fecal and MAM samples. In vitro, pro-inflammatory cytokines levels, as well as their gene expression, were significantly reduced in hCTS-treated M1 macrophages. hCTS treatment did not affect M2 macrophage markers. These findings suggest that hCTS treatment attenuates the severity of inflammatory relapse through the modulation of the M1 macrophages and the release of pro-inflammatory cytokines. PMID- 28871258 TI - Distinctive Surface Glycosylation Patterns Associated With Mouse and Human CD4+ Regulatory T Cells and Their Suppressive Function. AB - Regulatory T-cells (Treg) are essential for maintaining immune homeostasis and tolerance. Surface glycosylation is ubiquitous on mammalian cells and regulates diverse biological processes. While it is currently well accepted that surface glycan expression influences multiple aspects of T-cell function, little is known about the relevance of glycosylation to Treg biology. This study aimed to profile the surface glycosylation characteristics of Treg in various lymphoid compartments of mouse and in human peripheral blood with comparison to non regulatory, conventional CD4+ T-cells (Tconv). It also sought to determine the relationship between the surface glycosylation characteristics and suppressive potency of Treg. Lectin-based flow cytometric profiling demonstrated that Treg surface glycosylation differs significantly from that of Tconv in the resting state and is further modified by activation stimuli. In mouse, the surface glycosylation profiles of FoxP3+ Treg from spleen and lymph nodes were closely comparable but greater variability was observed for Treg in thymus, bone marrow, and blood. Surface levels of tri/tetra-antennary N-glycans correlated with expression of proteins known to be involved in Treg suppressive functions, including GITR, PD-1, PD-L1, CD73, CTLA-4, and ICOS. In coculture experiments involving purified Treg subpopulations and CD4+ or CD8+ Tconv, higher surface tri/tetra-antennary N-glycans was associated with greater Treg suppressive potency. Enzymatic manipulation of mouse Treg surface glycosylation resulting in a temporary reduction of surface N-glycans significantly reduced Treg capacity to suppress Tconv activation through contact-dependent mechanisms. Overall, these findings demonstrate that Treg have distinctive surface glycan characteristics that show variability across anatomical locations and are modulated by activation events. They also provide evidence of an important role for surface glycosylation in determining Treg phenotype and suppressive potency. These insights may prove relevant to the analysis of Treg in disease settings and to the further development of Treg-based immunotherapies. PMID- 28871259 TI - Syphilis Infection Differentially Regulates the Phenotype and Function of gammadelta T Cells in HIV-1-Infected Patients Depends on the HIV-1 Disease Stage. AB - A rapidly escalating outbreak of syphilis infection has been affected men who have sex with men, particularly those with HIV-1 infection. gammadelta T cells are unconventional immune cells with two main subsets, Vdelta1 T cells and Vdelta2 T cells, which possess a combination of innate and adaptive immune features allowing them against HIV-1. However, whether syphilis infection affects the phenotype and function of gammadelta T cells in HIV-1-infected patients remains unclear, especially in acute HIV-1 infection (AHI). In this study, we enrolled 57 HIV-1-infected patients (24 with HIV-1 infection only and 33 coinfected with syphilis) from an acute HIV-1-infected cohort in Beijing (PRIMO). A comprehensive analysis of gammadelta T-cell phenotype and function was performed by flow cytometry. We found syphilis coinfection could reverse the imbalance of Vdelta1/Vdelta2 ratio in AHI. Syphilis infection results in decreased gammadelta T-cell activation in AHI, but increased gammadelta T-cell activation in chronic HIV-1 infection (CHI). Moreover, patients with CHI had larger numbers of IL-17-producing gammadelta T cells than those with AHI, regardless of syphilis status. Thus, syphilis affected the gammadelta T-cell immune response differently in patients depending on the stages of HIV-1 disease. In addition, the percentage of IL-17-producing gammadelta T cells was positively correlated with the percentage of neutrophils. These results suggest that the gammadelta T-cell/IL-17/neutrophil axis is involved in HIV-1 pathogenesis and disease progression. Taken together, our observations provide new insight into the roles of gammadelta T cells in immunopathogenesis of syphilis and HIV-1 coinfection, particularly during AHI, and our findings may be helpful for the prevention of syphilis and other sexually transmitted infections and highlight the great significance on the remedy of patients coinfected with HIV-1. PMID- 28871260 TI - Dermatomyositis and Immune-Mediated Necrotizing Myopathies: A Window on Autoimmunity and Cancer. AB - Autoimmune myopathies (myositides) are strongly associated with malignancy. The link between myositis and cancer, originally noticed by Bohan and Peter in their classification in 1975 (1), has been evidenced by large population-based cohort studies and a recent meta-analysis. The numerous reports of cases in which the clinical course of myositis reflects that of cancer and the short delay between myositis and cancer onset support the notion that myositis may be an authentic paraneoplastic disorder. Thus, cancer-associated myositis raises the question of cancer as a cause rather than a consequence of autoimmunity. Among myositides, dermatomyositis and more recently, although to a lesser extent, immune-mediated necrotizing myopathies are the most documented forms associated with cancer. Interestingly, the current diagnostic approach for myositis is based on the identification of specific antibodies where each antibody determines specific clinical features and outcomes. Recent findings have shown that the autoantibodies anti-TIF1gamma, anti-NXP2 and anti-HMGCR are associated with cancers in the course of myositis. Herein, we highlight the fact that the targets of these three autoantibodies involve cellular pathways that intervene in tumor promotion and we discuss the role of cancer mutations as autoimmunity triggers in adult myositis. PMID- 28871261 TI - The Chronic Stages of Bovine Fasciola hepatica Are Dominated by CD4 T-Cell Exhaustion. AB - Fasciola hepatica infection of ruminants leads to non-resolving chronic infection, as patency develops, there is switching to a TGF-beta and IL-10 led response. Here, we explore the responses of CD4 T-cells within the major draining lymph nodes. We found minimal expression of Foxp3 within CD4 cells but elevated levels within the gammadelta (WC1+) population. There is a strong T-cell intrinsic exhaustion phenotype within the hepatic lymph node (HLN) characterized by a lack of antigen-specific proliferation and cytokine secretion. CD4 T-cells recovered from the HLN had high levels of PD-1 expression and low levels of IL-2 secretion. Exogenous IL-2 partially rescued this defect; when combined with neutralization of IL-10 and TGF-beta, full restoration of proliferation, and cytokine production was achieved. Moreover, there is a clear uncoupling of the mechanisms that facilitate this regulation with parasite-specific proliferation and cytokine secretion being governed by independent means. These data would suggest that there is a CD4 T-cell-intrinsic regulation in place early in chronic infection, potentially leading to failure in resistance to reinfection. PMID- 28871263 TI - The Activity of the Neutral Sphingomyelinase Is Important in T Cell Recruitment and Directional Migration. AB - Breakdown of sphingomyelin as catalyzed by the activity of sphingomyelinases profoundly affects biophysical properties of cellular membranes which is particularly important with regard to compartmentalization of surface receptors and their signaling relay. As it is activated both upon TCR ligation and co stimulation in a spatiotemporally controlled manner, the neutral sphingomyelinase (NSM) has proven to be important in T cell activation, where it appears to play a particularly important role in cytoskeletal reorganization and cell polarization. Because these are important parameters in directional T cell migration and motility in tissues, we analyzed the role of the NSM in these processes. Pharmacological inhibition of NSM interfered with early lymph node homing of T cells in vivo indicating that the enzyme impacts on endothelial adhesion, transendothelial migration, sensing of chemokine gradients or, at a cellular level, acquisition of a polarized phenotype. NSM inhibition reduced adhesion of T cells to TNF-alpha/IFN-gamma activated, but not resting endothelial cells, most likely via inhibiting high-affinity LFA-1 clustering. NSM activity proved to be highly important in directional T cell motility in response to SDF1-alpha, indicating that their ability to sense and translate chemokine gradients might be NSM dependent. In fact, pharmacological or genetic NSM ablation interfered with T cell polarization both at an overall morphological level and redistribution of CXCR4 and pERM proteins on endothelial cells or fibronectin, as well as with F actin polymerization in response to SDF1-alpha stimulation, indicating that efficient directional perception and signaling relay depend on NSM activity. Altogether, these data support a central role of the NSM in T cell recruitment and migration both under homeostatic and inflamed conditions by regulating polarized redistribution of receptors and their coupling to the cytoskeleton. PMID- 28871262 TI - Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons (MNs) comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining MNs in ALS patients and animal models of the disease. PMID- 28871265 TI - Expression of a Chimeric Gene Encoding Insecticidal Crystal Protein Cry1Aabc of Bacillus thuringiensis in Chickpea (Cicer arietinum L.) Confers Resistance to Gram Pod Borer (Helicoverpa armigera Hubner.). AB - Domain swapping and generation of chimeric insecticidal crystal protein is an emerging area of insect pest management. The lepidopteran insect pest, gram pod borer (Helicoverpa armigera H.) wreaks havoc to chickpea crop affecting production. Lepidopteran insects were reported to be controlled by Bt (cryI) genes. We designed a plant codon optimized chimeric Bt gene (cry1Aabc) using three domains from three different cry1A genes (domains I, II, and III from cry1Aa, cry1Ab, and cry1Ac, respectively) and expressed it under the control of a constitutive promoter in chickpea (cv. DCP92-3) to assess its effect on gram pod borer. A total of six transgenic chickpea shoots were established by grafting into mature fertile plants. The in vitro regenerated (organogenetic) shoots were selected based on antibiotic kanamycin monosulfate (100 mg/L) with transformation efficiency of 0.076%. Three transgenic events were extensively studied based on gene expression pattern and insect mortality across generations. Protein expression in pod walls, immature seeds and leaves (pre- and post-flowering) were estimated and expression in pre-flowering stage was found higher than that of post-flowering. Analysis for the stable integration, expression and insect mortality (detached leaf and whole plant bioassay) led to identification of efficacious transgenic chickpea lines. The chimeric cry1Aabc expressed in chickpea is effective against gram pod borer and generated events can be utilized in transgenic breeding program. PMID- 28871264 TI - Neuroinflammation, Bone Marrow Stem Cells, and Chronic Pain. AB - Current treatments for chronic pain, such as inflammatory pain, neuropathic pain, and cancer pain are insufficient and cause severe side effects. Mounting evidence suggests that neuroinflammation in the peripheral and central nervous system (PNS and CNS) plays a pivotal role in the genesis and maintenance of chronic pain. Characteristic features of neuroinflammation in chronic pain conditions include infiltration of immune cells into the PNS [e.g., the sciatic nerve and dorsal root ganglion (DRG)], activation of glial cells such as microglia and astrocytes in the CNS (spinal cord and brain), and production and secretion of pro inflammatory cytokines and chemokines [TNF, interleukin (IL)-1beta, IL-6, CCL2, and CXCL1]. Recent studies suggest that bone marrow stem cells or bone marrow stromal cells (BMSCs) produce powerful analgesic effects in animal models of inflammatory pain, neuropathic pain, and cancer pain. We recently demonstrated that intrathecal injection of BMSCs resulted in a long-term relief of neuropathic pain for several weeks after peripheral nerve injury. Strikingly, this analgesic effect is mediated by the anti-inflammatory cytokine transforming growth factor beta secreted from BMSCs. Additionally, BMSCs exhibit potent modulation of neuroinflammation, by inhibiting monocyte infiltration, glial activation, and cytokine/chemokine production in the DRG and spinal cord. Thus, BMSCs control chronic pain by regulation of neuroinflammation in the PNS and CNS via paracrine signaling. In this review, we discuss the similar results from different laboratories of remarkable anti-nociceptive efficacy of BMSCs in animal and clinical studies. We also discuss the mechanisms by which BMSCs control neuroinflammation and chronic pain and how these cells specifically migrate to damaged tissues. PMID- 28871266 TI - Molecular Mapping of QTLs Associated with Lodging Resistance in Dry Direct-Seeded Rice (Oryza sativa L.). AB - Dry direct-seeded rice (DSR) is an alternative crop establishment method with less water and labor requirement through mechanization. It provides better opportunities for a second crop during the cropping season and therefore, a feasible alternative system to transplanted lowland rice. However, lodging is one of the major constraints in attaining high yield in DSR. Identification of QTLs for lodging resistance and their subsequent use in improving varieties under DSR will be an efficient breeding strategy to address the problem. In order to map the QTLs associated with lodging resistance, a set of 253 BC3F4 lines derived from a backcross between Swarna and Moroberekan were evaluated in two consecutive years. A total of 12 QTLs associated with lodging resistance traits [culm length (qCL), culm diameter (qCD), and culm strength (qCS)] were mapped on chromosomes 1, 2, 6, and 7 using 193 polymorphic SNP markers. Two major and consistent effect QTLs, namely qCD1.1 (with R2 of 10%) and qCS1.1 (with R2 of 14%) on chromosome 1 with id1003559 being the peak SNP marker (flanking markers; id1001973-id1006772) were identified as a common genomic region associated with important lodging resistance traits. In silico analysis revealed the presence of Gibberellic Acid 3 beta-hydroxylase along with 34 other putative candidate genes in the marker interval region of id1001973-id1006772. The positive alleles for culm length, culm diameter, and culm strength were contributed by the upland adaptive parent Moroberekan. Our results identified significant positive correlation between lodging related traits (culm length diameter and strength) and grain yield under DSR, indicating the role of lodging resistant traits in grain yield improvement under DSR. Deployment of the identified alleles influencing the culm strength and culm diameter in marker assisted introgression program may facilitate the lodging resistance under DSR. PMID- 28871268 TI - Xylem Vessel Diameter Affects the Compartmentalization of the Vascular Pathogen Phaeomoniella chlamydospora in Grapevine. AB - Fungal wilt diseases are a threat to global food safety. Previous studies in perennial crops showed that xylem vessel diameter affects disease susceptibility. We tested the hypothesis that xylem vessel diameter impacts occlusion processes and pathogen compartmentalization in Vitis vinifera L. We studied the interaction between four grape commercial cultivars with the vascular wilt pathogen Phaeomoniella chlamydospora. We used qPCR and wood necrotic lesion length to measure fungal colonization coupled with histological studies to assess differences in xylem morphology, pathogen compartmentalization, and fungal colonization strategy. We provided evidence that grape cultivar with wide xylem vessel diameter showed increased susceptibility to P. chlamydospora. The host response to pathogen included vessel occlusion with tyloses and gels, deposition of non-structural phenolic compounds and suberin in vessel walls and depletion of starch in parenchyma cells. Pathogen compartmentalization was less efficient in wide xylem vessels than in narrow diameter vessels. Large vessels displayed higher number of tyloses and gel pockets, which provided substrate for P. chlamydospora growth and routes to escape occluded vessels. We discuss in which capacity xylem vessel diameter is a key determinant of the compartmentalization process and in turn grape cultivar resistance to disease caused by P. chlamydospora. PMID- 28871267 TI - How the Depletion in Mineral Major Elements Affects Grapevine (Vitis vinifera L.) Primary Cell Wall. AB - The noteworthy fine remodeling that plant cell walls (CWs) undergo to adapt to developmental, physiological and environmental cues and the observation that its composition and dynamics differ between species represents an opportunity to couple crop species agronomic studies with research on CW modifications. Vitis vinifera is one of the most important crops from an economic point-of-view due to the high value of the fruit, predominantly for winemaking. The availability of some information related to this species' CWs allows researching its responses to imposed conditions that affect the plant's development. Mineral deficiency, in particular nitrogen, phosphorus, potassium and sulfur, strongly affects plant metabolism, reducing both growth and crop yield. Despite the importance of mineral nutrition in development, its influence on CW synthesis and modifications is still insufficiently documented. Addressing this knowledge gap, V. vinifera experimental models were used to study CW responses to imposed mineral depletion in unorganized (callus) and organized (shoots) tissues. The discussion of the obtained results is the main focus of this review. Callus and shoots submitted to mineral restriction are impaired in specific CW components, predominantly cellulose. Reorganization on structure and deposition of several other polymers, in particular the degree and pattern of pectin methyl-esterification and the amount of xyloglucan (XyG), arabinan and extensin, is also observed. In view of recently proposed CW models that consider biomechanical hotspots and direct linkages between pectins and XyG/cellulose, the outcome of these modifications in explaining maintenance of CW integrity through compensatory stiffening can be debated. Nutrient stresses do not affect evenly all tissues with undifferentiated callus tissues showing more pronounced responses, followed by shoot mature internodes, and then newly formed internodes. The impact of nitrogen depletion leads to more noticeable responses, supporting this nutrient's primary role in plant development and metabolism. The consequential compensatory mechanisms highlight the pivotal role of CW in rearranging under environmental stresses. PMID- 28871269 TI - A Chemical-Induced, Seed-Soaking Activation Procedure for Regulated Gene Expression in Rice. AB - Inducible gene expression has emerged as a powerful tool for plant functional genomics. The estrogen receptor-based, chemical-inducible system XVE has been used in many plant species, but the limited systemic movement of inducer beta estradiol in transgenic rice plants has prohibited a wide use of the XVE system in this important food crop. Here, we constructed an improved chemical-regulated, site-specific recombination system by employing the XVE transactivator in combination with a Cre/loxP-FRT system, and optimized a seed-soaking procedure for XVE induction in rice. By using a gus gene and an hpRNAi cassette targeted for OsPDS as reporters, we demonstrated that soaking transgenic seeds with estradiol solution could induce highly efficient site-specific recombination in germinating embryos, resulting in constitutive and high-level expression of target gene or RNAi cassette in intact rice plants from induced seeds. The strategy reported here thereby provides a useful gene activation approach for effectively regulating gene expression in rice. PMID- 28871270 TI - In vivo Assembly in Escherichia coli of Transformation Vectors for Plastid Genome Engineering. AB - Plastid transformation for the expression of recombinant proteins and entire metabolic pathways has become a promising tool for plant biotechnology. However, large-scale application of this technology has been hindered by some technical bottlenecks, including lack of routine transformation protocols for agronomically important crop plants like rice or maize. Currently, there are no standard or commercial plastid transformation vectors available for the scientific community. Construction of a plastid transformation vector usually requires tedious and time consuming cloning steps. In this study, we describe the adoption of an in vivo Escherichia coli cloning (iVEC) technology to quickly assemble a plastid transformation vector. The method enables simple and seamless build-up of a complete plastid transformation vector from five DNA fragments in a single step. The vector assembled for demonstration purposes contains an enhanced green fluorescent protein (GFP) expression cassette, in which the gfp transgene is driven by the tobacco plastid ribosomal RNA operon promoter fused to the 5' untranslated region (UTR) from gene10 of bacteriophage T7 and the transcript stabilizing 3'UTR from the E. coli ribosomal RNA operon rrnB. Successful transformation of the tobacco plastid genome was verified by Southern blot analysis and seed assays. High-level expression of the GFP reporter in the transplastomic plants was visualized by confocal microscopy and Coomassie staining, and GFP accumulation was ~9% of the total soluble protein. The iVEC method represents a simple and efficient approach for construction of plastid transformation vector, and offers great potential for the assembly of increasingly complex vectors for synthetic biology applications in plastids. PMID- 28871272 TI - Scalable Convex Multiple Sequence Alignment via Entropy-Regularized Dual Decomposition. AB - Multiple Sequence Alignment (MSA) is one of the fundamental tasks in biological sequence analysis that underlies applications such as phylogenetic trees, profiles, and structure prediction. The task, however, is NP-hard, and the current practice resorts to heuristic and local-search methods. Recently, a convex optimization approach for MSA was proposed based on the concept of atomic norm [23], which demonstrates significant improvement over existing methods in the quality of alignments. However, the convex program is challenging to solve due to the constraint given by the intersection of two atomic-norm balls, for which the existing algorithm can only handle sequences of length up to 50, with an iteration complexity subject to constants of unknown relation to the natural parameters of MSA. In this work, we propose an accelerated dual decomposition algorithm that exploits entropy regularization to induce closed-form solutions for each atomic-norm-constrained subproblem, giving a single-loop algorithm of iteration complexity linear to the problem size (total length of all sequences). The proposed algorithm gives significantly better alignments than existing methods on sequences of length up to hundreds, where the existing convex programming method fails to converge in one day. PMID- 28871271 TI - Somatic Embryogenesis in Coffee: The Evolution of Biotechnology and the Integration of Omics Technologies Offer Great Opportunities. AB - One of the most important crops cultivated around the world is coffee. There are two main cultivated species, Coffea arabica and C. canephora. Both species are difficult to improve through conventional breeding, taking at least 20 years to produce a new cultivar. Biotechnological tools such as genetic transformation, micropropagation and somatic embryogenesis (SE) have been extensively studied in order to provide practical results for coffee improvement. While genetic transformation got many attention in the past and is booming with the CRISPR technology, micropropagation and SE are still the major bottle neck and urgently need more attention. The methodologies to induce SE and the further development of the embryos are genotype-dependent, what leads to an almost empirical development of specific protocols for each cultivar or clone. This is a serious limitation and excludes a general comprehensive understanding of the process as a whole. The aim of this review is to provide an overview of which achievements and molecular insights have been gained in (coffee) somatic embryogenesis and encourage researchers to invest further in the in vitro technology and combine it with the latest omics techniques (genomics, transcriptomics, proteomics, metabolomics, and phenomics). We conclude that the evolution of biotechnology and the integration of omics technologies offer great opportunities to (i) optimize the production process of SE and the subsequent conversion into rooted plantlets and (ii) to screen for possible somaclonal variation. However, currently the usage of the latest biotechnology did not pass the stage beyond proof of potential and needs to further improve. PMID- 28871273 TI - Greedy Direction Method of Multiplier for MAP Inference of Large Output Domain. AB - Maximum-a-Posteriori (MAP) inference lies at the heart of Graphical Models and Structured Prediction. Despite the intractability of exact MAP inference, approximate methods based on LP relaxations have exhibited superior performance across a wide range of applications. Yet for problems involving large output domains (i.e., the state space for each variable is large), standard LP relaxations can easily give rise to a large number of variables and constraints which are beyond the limit of existing optimization algorithms. In this paper, we introduce an effective MAP inference method for problems with large output domains. The method builds upon alternating minimization of an Augmented Lagrangian that exploits the sparsity of messages through greedy optimization techniques. A key feature of our greedy approach is to introduce variables in an on-demand manner with a pre-built data structure over local factors. This results in a single-loop algorithm of sublinear cost per iteration and O(log(1/epsilon)) type iteration complexity to achieve epsilon sub-optimality. In addition, we introduce a variant of GDMM for binary MAP inference problems with a large number of factors. Empirically, the proposed algorithms demonstrate orders of magnitude speedup over state-of-the-art MAP inference techniques on MAP inference problems including Segmentation, Protein Folding, Graph Matching, and Multilabel prediction with pairwise interaction. PMID- 28871274 TI - Paired Expression Analysis of Tumor Cell Surface Antigens. AB - Adoptive immunotherapy with antibody-based therapy or with T cells transduced to express chimeric antigen receptors (CARs) is useful to the extent that the cell surface membrane protein being targeted is not expressed on normal tissues. The most successful CAR-based (anti-CD19) or antibody-based therapy (anti-CD20) in hematologic malignancies has the side effect of eliminating the normal B cell compartment. Targeting solid tumors may not provide a similar expendable marker. Beyond antibody to Her2/NEU and EGFR, very few antibody-based and no CAR-based therapies have seen broad clinical application for solid tumors. To expand the way in which the surfaceome of solid tumors can be analyzed, we created an algorithm that defines the pairwise relative overexpression of surface antigens. This enables the development of specific immunotherapies that require the expression of two discrete antigens on the surface of the tumor target. This dyad analysis was facilitated by employing the Hotelling's T-squared test (Hotelling Lawley multivariate analysis of variance) for two independent variables in comparison to a third constant entity (i.e., gene expression levels in normal tissues). We also present a unique consensus scoring mechanism for identifying transcripts that encode cell surface proteins. The unique application of our bioinformatics processing pipeline and statistical tools allowed us to compare the expression of two membrane protein targets as a pair, and to propose a new strategy based on implementing immunotherapies that require both antigens to be expressed on the tumor cell surface to trigger therapeutic effector mechanisms. Specifically, we found that, for MYCN amplified neuroblastoma, pairwise expression of ACVR2B or anaplastic lymphoma kinase (ALK) with GFRA3, GFRA2, Cadherin 24, or with one another provided the strongest hits. For MYCN, non amplified stage 4 neuroblastoma, neurotrophic tyrosine kinase 1, or ALK paired with GFRA2, GFRA3, SSK1, GPR173, or with one another provided the most promising paired-hits. We propose that targeting these markers together would increase the specificity and thereby the safety of CAR-based therapy for neuroblastoma. PMID- 28871275 TI - Radiation Treatment in Women with Ovarian Cancer: Past, Present, and Future. AB - Ovarian cancer is the most lethal of the gynecologic cancers, with 5-year survival rates less than 50%. Most women present with advanced stage disease as the pattern of spread is typically with dissemination of malignancy throughout the peritoneal cavity prior to development of any symptoms. Prior to the advent of platinum-based chemotherapy, radiotherapy was used as adjuvant therapy to sterilize micrometastatic disease. The evolution of radiotherapy is detailed in this review, which establishes radiotherapy as an effective therapy for women with micrometastatic disease in the peritoneal cavity after surgery, ovarian clear cell carcinoma, focal metastatic disease, and for palliation of advanced disease. However, with older techniques, the toxicity of whole abdominal radiotherapy and the advancement of systemic therapies have limited the use of radiotherapy in this disease. With newer radiotherapy techniques, including intensity-modulated radiotherapy (IMRT), stereotactic body radiotherapy (SBRT), and low-dose hyperfractionation in combination with targeted agents, radiotherapy could be reconsidered as part of the standard management for this deadly disease. PMID- 28871276 TI - Fear of Massive Deportations in the United States: Social Implications on Deprived Pediatric Communities. PMID- 28871278 TI - Community Mobilization for Slum Upgrading through Sanitation in Roma Informal Settlements in the Paris Region. AB - BACKGROUND: Community-based processes addressing environment, housing, and health issues may decrease health inequities by addressing social, economic, and political health determinants more effectively. Yet little analysis of their effectiveness has been undertaken and their potential transfer to marginalized groups in rich country settings. In Europe, stark health inequalities are seen among the Roma, Europe's most impoverished community who often reside in informal settlements suffering from illiteracy, inadequate housing, and lack of water and sanitation. This paper assesses a dry sanitation project in a Roma informal settlement in the Paris region to improve their living conditions. METHODS: Between 2014 and 2017, multiple stakeholders were involved in a participatory process of design, construction, and maintenance of toilets. Interviews, mapping, model construction, and facilitated discussion were used to identify design features and follow-up indicators. Field notes, videos, questionnaires, and observation provided data for monitoring and evaluation. For questionnaires delivered to women in the community, a cross section time series was conducted to due to migration. RESULTS: Despite issues related to maintenance, the overall quality of life of women improved after toilet construction. This included indicators for comfort, cleanliness, practicality, privacy, security, and menstrual hygiene management. Furthermore, fewer women restrained themselves from relieving themselves or from drinking less water to avoid urinating. Odors continued to be an issue. Self-reporting of illnesses, such as diarrhea and urinary tract infections, were not reliable due to the vague description of these illnesses and the potential recall bias. Appropriate sanitation in informal settlements is a necessity as shown by feedback from Roma women and the literature. However, a more sustainable toilet project would have required an adequate budget, good quality materials, accountability, and buy in from all inhabitants as well as good relationships between the chief and all stakeholders in the settlement. Furthermore, provision should have been made for vulnerable and less autonomous inhabitants to ensure proper follow-up and maintenance. CONCLUSION/RECOMMENDATIONS: Safe water and sanitation is essential to decrease health inequities. Formative research, identifying natural leaders, sanitation committee formation, outcome indicator and baseline questionnaire development, appropriate messages and toilet design and placement, long-term follow-up, and political support are elements for effective interventions with the Roma. Potential attrition and reporting bias should be considered in monitoring and evaluation. PMID- 28871279 TI - Longitudinal Changes in AbsoluteVO2peak, Physical Activity Level, Body Mass Index, and Overweightedness among Adolescents in Vocational and Non-Vocational Studies. AB - The purpose of the study was to examine differences in physical activity level, physical fitness, body mass index, and overweight among adolescents in vocational and non-vocational studies, at the age of 14, 16, and 19, using a 5-year longitudinal design. Students in sport studies had the highest absoluteVO2peak and higher physical activity levels, than students in vocational subjects and students with a specialization in general studies. However, there were no significant differences between students in vocational subjects and students with a specialization in general studies according to absoluteVO2peak and physical activity levels. Students in vocational subjects were significantly more overweight/obese at 19 years of age, compared with the other students. Our findings support previous research pointing to overweightedness as being more widespread among adolescents in vocational programs than in non-vocational programs. However, differences in the physical activity level and physical fitness do not seem to explain these differences. PMID- 28871277 TI - The Centenary of Immune Thrombocytopenia-Part 2: Revising Diagnostic and Therapeutic Approach. AB - Primary immune thrombocytopenia (ITP) is the most common cause of thrombocytopenia in children and adolescents and can be considered as a paradigmatic model of autoimmune disease. This second part of our review describes the clinical presentation of ITP, the diagnostic approach and overviews the current therapeutic strategies. Interestingly, it suggests an algorithm useful for differential diagnosis, a crucial process to exclude secondary forms of immune thrombocytopenia (IT) and non-immune thrombocytopenia (non-IT), which require a different therapeutic management. Advances in understanding the pathogenesis led to new therapeutic targets, as thrombopoietin receptor agonists, whose role in treatment of ITP will be discussed in this work. PMID- 28871280 TI - Impacting Binational Health through Leadership Development: A Program Evaluation of the Leaders across Borders Program, 2010-2014. AB - BACKGROUND: Workforce and leadership development is imperative for the advancement of public health along the U.S./Mexico border. The Leaders across borders (LaB) program aims to train the public health and health-care workforce of the border region. The LaB is a 6-month intensive leadership development program, which offers training in various areas of public health. Program curriculum topics include: leadership, border health epidemiology, health diplomacy, border public policies, and conflict resolution. METHODS: This article describes the LaB program evaluation outcomes across four LaB cohort graduates between 2010 and 2014. LaB graduates received an invitation to participate via email in an online questionnaire. Eighty-five percent (n = 34) of evaluation participants indicated an improvement in the level of binationality since participating in the LaB program. Identified themes in the evaluation results included increased binational collaborations and partnerships across multidisciplinary organizations that work towards improving the health status of border communities. Approximately 93% (n = 37) of the LaB samples were interested in participating in future binational projects while 80% (n = 32) indicated interest in the proposal of other binational initiatives. Participants expressed feelings of gratitude from employers who supported their participation and successful completion of LaB. DISCUSSION: Programs such as LaB are important in providing professional development and education to a health-care workforce along the U.S./Mexico border that is dedicated to positively impacting the health outcomes of vulnerable populations residing in this region. PMID- 28871282 TI - Commentary: How Cells Can Control Their Size by Pumping Ions. PMID- 28871281 TI - Live-cell Microscopy and Fluorescence-based Measurement of Luminal pH in Intracellular Organelles. AB - Luminal pH is an important functional feature of intracellular organelles. Acidification of the lumen of organelles such as endosomes, lysosomes, and the Golgi apparatus plays a critical role in fundamental cellular processes. As such, measurement of the luminal pH of these organelles has relevance to both basic research and translational research. At the same time, accurate measurement of intraorganellar pH in living cells can be challenging and may be a limiting hurdle for research in some areas. Here, we describe three powerful methods to measure rigorously the luminal pH of different intracellular organelles, focusing on endosomes, lysosomes, and the Golgi apparatus. The described methods are based on live imaging of pH-sensitive fluorescent probes and include: (1) A protocol based on quantitative, ratiometric measurement of endocytosis of pH-sensitive and pH-insensitive fluorescent conjugates of transferrin; (2) A protocol for the use of proteins tagged with a ratiometric variant of the pH-sensitive intrinsically fluorescent protein pHluorin; and (3) A protocol using the fluorescent dye LysoSensorTM. We describe necessary reagents, key procedures, and methods and equipment for data acquisition and analysis. Examples of implementation of the protocols are provided for cultured cells derived from a cancer cell line and for primary cultures of mouse hippocampal neurons. In addition, we present strengths and weaknesses of the different described intraorganellar pH measurement methods. These protocols are likely to be of benefit to many researchers, from basic scientists to those conducting translational research with a focus on diseases in patient-derived cells. PMID- 28871283 TI - GPla Polymorphisms Are Associated with Outcomes in Patients at High Cardiovascular Risk. AB - BACKGROUND: Platelet membrane glycoprotein receptors mediate thrombus formation. GP Ia/IIa is an essential platelet integrin receptor. Single-nucleotide polymorphisms (SNPs) of the GP Ia/IIa gene alter GP Ia/IIa expression; however, their influence on cardiovascular disease remains unclear. This study aimed to investigate the effect of the GP Ia/IIa SNPs rs1126643 and rs1062535 on clinical outcomes in a large collective including high-risk patients with cardiovascular disease. METHODS AND RESULTS: GP Ia SNP analysis was performed in 943 patients with symptomatic coronary artery disease. All patients were tracked for all-cause death, myocardial infarction, and ischemic stroke for 360 days. Homozygous carriers of the minor allele showed significantly worse event-free survival when compared with major allele carriers in the complete collective as well as in the subset of high-risk patients (carrying all of the following three risk factors: diabetes type II, hypertension, and hyperlipidemia). There was no significant difference in the subset of low-risk patients (carrying none of the three risk factors). CONCLUSIONS: GPla SNPs are associated with cardiovascular prognosis especially in high-risk patients. Identification of GPIa SNPs is of importance to tailor therapies in patients at already high cardiovascular risk. PMID- 28871285 TI - Immortalization and Characterization of Porcine Macrophages That Had Been Transduced with Lentiviral Vectors Encoding the SV40 Large T Antigen and Porcine Telomerase Reverse Transcriptase. AB - The domestic pig is an important agricultural animal, and thus, infectious diseases that affect pigs can cause severe economic losses in the global swine industry. Various porcine pathogens target macrophages, which are classical innate immune cells. Although macrophages basically protect the host from pathogens, they also seem to contribute to infectious processes. Therefore, cultured macrophages can be used to develop in vitro models for studying not only genes associated with porcine innate immunity but also the infectious processes of porcine pathogens. However, the availability of porcine macrophage cell lines is limited. In this study, we describe a novel immortalized porcine kidney derived macrophage (IPKM) cell line, which was generated by transferring the SV40 large T antigen (SV40LT) and porcine telomerase reverse transcriptase (pTERT) genes into primary porcine kidney-derived macrophages using lentiviral vectors. The IPKM displayed a typical macrophage morphology and was routinely passaged (doubling time: about 4 days). These cells were immunostained for macrophage markers. In addition, they exhibited substantial phagocytosis of polystyrene microbeads and released inflammatory cytokines upon lipopolysaccharide (LPS) stimulation. Furthermore, the maturation and secretion of interleukin-1beta were observed after nigericin-induced inflammasome activation in LPS-primed IPKM. These findings suggest that IPKM exhibit the typical inflammatory characteristics of macrophages. By transferring the SV40LT and pTERT genes using lentiviral vectors, we also successfully immortalized macrophages derived from the peripheral blood of a low-density lipoprotein receptor-deficient pig. These results suggest that the co-expression of SV40LT and pTERT is an effective way of immortalizing porcine macrophages. PMID- 28871286 TI - Editorial: Foot-and-Mouth Disease in Swine. PMID- 28871284 TI - Hops (Humulus lupulus L.) Bitter Acids: Modulation of Rumen Fermentation and Potential As an Alternative Growth Promoter. AB - Antibiotics can improve ruminant growth and efficiency by altering rumen fermentation via selective inhibition of microorganisms. However, antibiotic use is increasingly restricted due to concerns about the spread of antibiotic resistance. Plant-based antimicrobials are alternatives to antibiotics in animal production. The hops plant (Humulus lupulus L.) produces a range of bioactive secondary metabolites, including antimicrobial prenylated phloroglucinols, which are commonly called alpha- and beta-acids. These latter compounds can be considered phyto-ionophores, phytochemicals with a similar antimicrobial mechanism of action to ionophore antibiotics (e.g., monensin, lasalocid). Like ionophores, the hop beta-acids inhibit rumen bacteria possessing a classical Gram positive cell envelope. This selective inhibition causes several effects on rumen fermentation that are beneficial to finishing cattle, such as decreased proteolysis, ammonia production, acetate: propionate ratio, and methane production. This article reviews the effects of hops and hop secondary metabolites on rumen fermentation, including the physiological mechanisms on specific rumen microorganisms, and consequences for the ruminant host and ruminant production. Further, we propose that hop beta-acids are useful model natural products for ruminants because of (1) the ionophore-like mechanism of action and spectrum of activity and (2) the literature available on the plant due to its use in brewing. PMID- 28871288 TI - Error-Specific Cognitive Control Alterations in Generalized Anxiety Disorder. AB - BACKGROUND: Trait anxiety is reliably associated with enhanced neural responses following errors: meta analyses have described how the electrophysiological response to errors known as the Error-Related Negativity (ERN) is increased in anxious individuals, particularly in relation to worry. The ERN has been related to a broader class of control signals, particularly via a common theta band denominator, but it is unknown whether worry relates to these alternative medial frontal metrics. Moreover, it is unclear if increased ERN in anxiety relates to altered cognitive control. METHODS: In this report we examine EEG activities in Generalized Anxiety Disorder (GAD, N=39) and control (CTL: N=52) participants during an executive control task. We leveraged a previously defined theta-band network to examine if an altered control signal in GAD underlies a differential implementation of cognitive control. RESULTS: GAD and CTL groups were reliably dissociated by both error- and conflict- related neural activity, in both the time and frequency (i.e. theta band) domains. Moreover, we demonstrate that ERN, error-related theta power, and the single trial correlation between theta and response time were unique predictors of GAD status. Overall, we were able to account for nearly 1/4 of the group variance and successfully classify GAD from control participants with 2/3 accuracy. CONCLUSIONS: Collectively, these findings suggest that multiple neural metrics of error processing may uniquely distinguish clinical anxiety from healthy individuals, and that mechanisms of control also differ in GAD; finally, these error-related neural measures have the potential to be sensitive and specific bio-signatures of anxiety. PMID- 28871289 TI - Probing charges on solid-liquid interfaces with the resistive-pulse technique. AB - Our manuscript addresses the issue of probing an effective surface charge that any surface can acquire at the solid/liquid interface. Even if a particle is predicted to be neutral based on its chemical structure, the particle can carry finite surface charges when placed in a solution. We present tools to probe the presence of surface charge densities of meso-particles, characterized with zeta potentials below 10 mV. The tools are based on the resistive-pulse technique, which uses single pores to probe properties of individual objects including molecules, particles, and cells. The presented experiments were performed with particles 280 and 400 nm in diameter and single pores with opening diameter tuned between ~ 200 nm and one micron. Surface charge properties were probed in two modes: (i) the passage of the particles through pores of diameters larger than the particles, as well as (ii) an approach curve of a particle to a pore that is smaller than the particle diameter. The curve in the latter mode has a biphasic character starting with a low-amplitude current decrease, followed by a current enhancement reaching an amplitude of ~10% of the baseline current. The current increase was long-lasting and stable, and shown to strongly depend on the particle surface charge density. The results are explained via voltage-modulation of ionic concentrations in the pore. PMID- 28871287 TI - Bayesian Analysis of the Association between Family-Level Factors and Siblings' Dental Caries. AB - We conducted a Bayesian analysis of the association between family-level socioeconomic status and smoking and the prevalence of dental caries among siblings (children from infant to 14 y) among children living in rural and urban Northern Appalachia using data from the Center for Oral Health Research in Appalachia (COHRA). The observed proportion of siblings sharing caries was significantly different from predicted assuming siblings' caries status was independent. Using a Bayesian hierarchical model, we found the inclusion of a household factor significantly improved the goodness of fit. Other findings showed an inverse association between parental education and siblings' caries and a positive association between households with smokers and siblings' caries. Our study strengthens existing evidence suggesting that increased parental education and decreased parental cigarette smoking are associated with reduced childhood caries in the household. Our results also demonstrate the value of a Bayesian approach, which allows us to include household as a random effect, thereby providing more accurate estimates than obtained using generalized linear mixed models. PMID- 28871290 TI - Image-based feedback and analysis system for digital microfluidics. AB - Digital microfluidics (DMF) is a technology that provides a means of manipulating nL-MUL volumes of liquids on an array of electrodes. By applying an electric potential to an electrode, these discrete droplets can be controlled in parallel which can be transported, mixed, reacted, and analyzed. Typically, an automation system is interfaced with a DMF device that uses a standard set of basic instructions written by the user to execute droplet operations. Here, we present the first feedback method for DMF that relies on imaging techniques that will allow online detection of droplets without the need to reactivate all destination electrodes. Our system consists of integrating open-source electronics with a CMOS camera and a zoom lens for acquisition of the images that will be used to detect droplets on the device. We also created an algorithm that uses a Hough transform to detect a variety of droplet sizes and to detect singular droplet dispensing and movement failures on the device. As a first test, we applied this feedback system to test droplet movement for a variety of liquids used in cell based assays and to optimize different feedback actuation schemes to improve droplet movement fidelity. We also applied our system to a colorimetric enzymatic assay to show that our system is capable of biological analysis. Overall, we believe that using our approach of integrating imaging and feedback for DMF can provide a platform for automating biological assays with analysis. PMID- 28871291 TI - Visible-light-induced tandem cyclization of 2-alkynylanilines with disulfides: a convenient method for accessing benzothiophenes under transition-metal-free and photocatalyst-free conditions. AB - A simple and efficient strategy for the preparation of benzothiophenes via visible-light-induced cyclization of 2-alkynylanilines with disulfides was developed. The reaction afforded the desired products in good yields at room temperature under transition-metal-free and photocatalyst-free conditions. PMID- 28871292 TI - Emerging investigator series: As(v) in magnetite: incorporation and redistribution. AB - Exposure to As in groundwater negatively impacts millions of people around the globe, and As mobility in groundwater is often controlled by Fe mineral dissolution and precipitation. Additionally, trace elements can be released from and incorporated into the structure of Fe oxides in the presence of dissolved Fe(ii). The potential for As to redistribute between sorbed on the magnetite surface and incorporated in the magnetite structure, however, remains unclear. In this study, we use selective chemical extraction and X-ray absorption spectroscopy (XAS) to distinguish magnetite-sorbed and incorporated As(v) and to provide evidence for As(v) incorporation during magnetite precipitation. While As in the As-magnetite coprecipitates did not redistribute between sorbed and incorporated over a 4 month period, a small, but measurable increase in incorporated As(v) of up to 13% was observed for sorbed As(v). We suggest that Fe(ii)-catalyzed recrystallization of magnetite did not significantly influence the redistribution of sorbed As(v) because the extent of Fe atom exchange was small (~10%). In addition, the extent of As redistribution was the same in the absence and presence of added aqueous Fe(ii), suggesting that aqueous Fe(ii) had, overall, a minor effect on As redistribution for both coprecipitated and sorbed As(v). Our results suggest that coprecipitation of As(v) with magnetite and redistribution of As(v) sorbed on magnetite are potential pathways for irreversible As(v) uptake and sequestration. These pathways are likely to play a significant role in controlling As mobility in natural systems, during human induced redox cycling of groundwater such as aquifer storage and recovery, as well as in iron oxide-based As removal systems. PMID- 28871294 TI - Structure of nanoscale-pitch helical phases: blue phase and twist-bend nematic phase resolved by resonant soft X-ray scattering. AB - Periodic structures of phases with orientational order of molecules but homogenous electron density distribution: a short pitch cholesteric phase, blue phase and twist-bend nematic phase, were probed by resonant soft X-ray scattering (RSoXS) at the carbon K-edge. The theoretical model shows that in the case of a simple heliconical nematic structure, two resonant signals corresponding to the full and half pitch band should be present, while only the full pitch band is observed experimentally. This suggests that the twist-bend nematic phase has a complex structure with a double-helix built of two interlocked, shifted helices. We confirm that the helical pitch in the twist-bend nematic phase is in a 10 nm range for both the chiral and achiral materials. We also show that the symmetry of the blue phase can be unambiguously determined through a resonant enhancement of the X-ray diffraction signals, by including polarization effects, which are found to be an important indicator in phase structure determination. PMID- 28871293 TI - Modular total syntheses of mycolactone A/B and its [2H]-isotopologue. AB - A modular total synthesis of mycolactone A/B, the exotoxin produced by Mycobacterium ulcerans, has been achieved through the orchestration of several Pd catalyzed key steps. While this route leads to a mixture of the natural product and its C12 epimer (4 : 1 ratio), this was inconsequential from the biological activity standpoint. Compared to the previously reported routes, this synthetic blueprint allows the late-stage modification of the toxin, as exemplified by the preparation of [22,22,22-2H3]-mycolactone A/B. PMID- 28871295 TI - Synthesis of the fungus metabolite cladosin C. AB - Cladosin C is one of the few known enaminotetramic acids, isolated from extracts of the deep sea fungus Cladosporium sphaerospermum. It was synthesised in ten steps and 14% overall yield by a late-stage amination of the corresponding 3 acyltetramic acid. This was obtained by a Dieckmann condensation of an N-beta ketoacylaminoester derived from dehydrovalinate and the thioester-terminated side chain containing the stereogenic centre which stemmed from poly-(R)-3 hydroxybutyrate. PMID- 28871296 TI - Two solvent-induced porous hydrogen-bonded organic frameworks: solvent effects on structures and functionalities. AB - Two solvent-induced porous hydrogen-bonded organic frameworks have been obtained, and their synthesis, crystal structures, gas sorption behaviours and fluorescence sensing applications have been systematically investigated to elucidate the solvent effects on the structures and functionalities of HOFs. PMID- 28871297 TI - The influence of nearest-neighbour interactions and assembly dynamics on the transport properties of porphyrin supramolecular assemblies on Au(111). AB - Here we report on the effect of local molecular organization or "tertiary structure" on the charge transport properties of thiol-tethered tetraphenylporphyrin (ZnTPPF4-SC5SH) nanoscale clusters of ca. 5 nm in lateral dimension embedded within a dodecanethiol (C12) monolayer on Au(111). The structure of the clusters in the mixed monolayers and their resulting transport properties were monitored by Atomic Force Microscopy (AFM), Scanning Tunneling Microscopy (STM) and Spectroscopy (STS). The mixed films were deposited on Au(111) for a period of one to five days, during which the lateral dimensions of the ZnTPPF4-SC5SH islands that were formed after one day reduced by nearly 35% on average by five days, accompanied by a noticeable depletion of the surrounding C12 monolayer. These subtle changes in mixed monolayer morphology were accompanied by drastic differences in conductance. The ZnTPPF4-SC5SH clusters assembled for one day exhibited highly reproducible I-V spectra with simple tunneling behavior. By three days, this evolved into bias-induced switching of conductance, with a ~100-1000 fold increase. Furthermore, current fluctuations started to become significant, and then dominated transport across the ZnTPPF4 SC5SH clusters assembled over five days. Our data suggests that this evolution can be understood by slow surface diffusion, enabling the ZnTPPF4-SC5SH molecules to overcome initial steric hindrance in the early stages of island formation in the C12 monolayer (at day one), to reach a more energetically-favored, close packed organization, as noted by the decrease in island size (by day three). However, when desorption of the supporting matrix of C12 became pronounced (by day five), the ZnTPPF4-SC5SH clusters began to lose stabilization, and stochastic switching was then observed to dominate transport in the clusters, illustrating the critical nature of the local organization on these transport properties. PMID- 28871298 TI - Selective synthesis of three product classes from imine and carboxylic acid precursors via direct imine acylation. AB - Three divergent Direct Imine Acylation (DIA) procedures are reported that allow the selective generation of delta-lactams, beta-lactams and tetrahydropyrimidinones (via a novel three-component coupling) from imine and carboxylic acid precursors. All operate via initial N-acyliminium ion formation and diverge depending on the reaction conditions and nature of the substrates. PMID- 28871299 TI - Phosphine-catalyzed [3 + 2] annulation reaction: highly regio- and diastereoselective synthesis of 2-azaspiro[4.4]nonene-1,3-diones. AB - A novel phosphine-catalyzed [3 + 2] annulation of gamma-substituted allenoates with succinimides was developed, which was successfully applied to the synthesis of 2-azaspiro[4.4]nonene-1,3-dione derivatives. The reaction afforded the desired products in moderate to high yields (up to 96%) with excellent regioselectivities and diastereoselectivities (up to >99 : 1 dr). A plausible reaction mechanism has also been proposed based on previous literature. PMID- 28871300 TI - Polymer-immobilized, hybrid multi-catalyst architecture for enhanced electrochemical oxidation of glycerol. AB - The development of a hybrid, tri-catalytic architecture is demonstrated by immobilizing MWCNTs, TEMPO-modified linear poly(ethylenimine) and oxalate decarboxylase on an electrode to enable enhanced electrochemical oxidation of glycerol. This immobilized, hybrid catalytic motif results in a synergistic 3.3 fold enhancement of glycerol oxidation and collects up to 14 electrons per molecule of glycerol. PMID- 28871301 TI - Synthesis and characterisation of new tripodal lanthanide complexes and investigation of their optical and magnetic properties. AB - This paper presents the synthesis of a tripodal ligand (H3L) via the Schiff base condensation of N,N-diethylsalicylaldehyde and tris(2-aminoethyl)amine. The neutral complexes of type [EuL], [GdL] and [DyL] were synthesized and characterized by FT-IR, SEM-EDS, PXRD, single crystal X-ray diffraction, CHN analysis and high resolution ESI-MS. X-ray crystallographic studies demonstrated that the heptadentate ligand incorporating a cavity pre-organized by hydrogen bonding binds the Ln(iii) ions to yield a face capped octahedral coordination geometry with three-fold symmetry. Photoluminescence studies show a typical Ln(iii) absorption character for the three complexes, with [EuL] demonstrating considerably stronger lanthanide-based luminescence peaks, and a Eu(iii) centered luminescence lifetime of 0.144 +/- 0.01 ms. Temperature/field-dependent DC and temperature/frequency-dependent AC magnetic measurements carried out for the Dy(iii) complex indicated obvious magnetic anisotropy and suggested slow relaxation behaviour with considerable quantum tunnelling of the magnetization contribution. PMID- 28871302 TI - Copper-catalysed difluoroalkylation of aromatic aldehydes via a decarboxylation/aldol reaction. AB - A copper-catalysed tandem decarboxylation/aldol reaction of simple aromatic aldehydes with 2,2-difluoro-3-oxo-3-arylpropanoic acid has been developed under mild conditions. This method provides a new route for the direct one-pot synthesis of difluorinated aldols in moderate to good yields from simple substrates. PMID- 28871303 TI - Polymeric mannosides prevent DC-SIGN-mediated cell-infection by cytomegalovirus. AB - Human cytomegalovirus (HCMV) is a beta-herpesvirus with a high prevalence in the population. HCMV is asymptomatic for immunocompetent adults but is a leading cause of morbidity for new born and immunocompromised patients. It was recently shown that the envelope glycoprotein B (gB) of HCMV interacts with the Dendritic Cell-Specific ICAM-3 Grabbing Non integrin (DC-SIGN) to infect the host. In this work we developed a set of DC-SIGN blockers based on mono-, di-, tetra and polyvalent mannosides. The multivalent mannosides were designed to interact with the carbohydrate recognition domains of DC-SIGN in a chelate or bind and recapture process, and represent the first chemical antiadhesives of HCMV reported so far. Polymeric dextrans coated with triazolylheptylmannoside (THM) ligands were highly potent, blocking the gB and DC-SIGN interaction at nanomolar concentrations. The compounds were further assessed for their ability to prevent the DC-SIGN mediated HCMV infection of dendritic cells. A dextran polymer coated with an average of 902 THM ligands showed an outstanding effect in blocking the HCMV trans-infection with IC50 values down to the picomolar range (nanomolar when expressed in THM concentration). Each THM moiety on the polymer surpassed the antiadhesive effect of the methylmannoside reference by more than four orders of magnitude. The compound proved non-cytotoxic at the high concentration of 2 mM and therefore represents an interesting antiadhesive candidate against HCMV and potentially against other virus hijacking dendritic cells to infect the host. PMID- 28871304 TI - An electrochemiluminescence cloth-based biosensor with smartphone-based imaging for detection of lactate in saliva. AB - Cloth fabrics and smartphones have become the two things people are most familiar with. Particularly, smartphones are used as portable personal computers, revolutionizing communication and lifestyle. Here, screen-printing technology is applied to fabricate carbon electrodes and electrochemical chambers on a single hydrophilic cloth, while the cloth-based electrochemiluminescence (ECL) signals are read out by using an inexpensive smartphone. Therefore, the ECL detection is available in both low-cost disposable sensors and a portable format, which may be very suitable to be used as a non-invasive monitoring tool for medical diagnostics. As a proof-of-principle, lactate oxidase is immobilized onto the working electrode for the lactate measurement. Under optimized conditions, the lactate levels can be quantified over the range of 0.05-2.5 mM, with a detection limit of 0.035 mM and the relative standard deviations of 4.7%, 5.2% and 5.0% for 0.05, 0.5 and 2.5 mM lactate (n = 5). In addition, the proposed biosensor has an acceptable stability and selectivity. Finally, the ECL biosensor is successfully applied for the determination of lactate in human saliva. These results show that the presented ECL platform has the potential to be applied to non-invasively detect a variety of analytes of medical interest. PMID- 28871305 TI - Skeletal muscle-on-a-chip: an in vitro model to evaluate tissue formation and injury. AB - Engineered skeletal muscle tissues can be used for in vitro studies that require physiologically relevant models of native tissues. Herein, we describe the development of a three-dimensional (3D) skeletal muscle tissue that recapitulates the architectural and structural complexities of muscle within a microfluidic device. Using a 3D photo-patterning approach, we spatially confined a cell-laden gelatin network around two bio-inert hydrogel pillars, which induce uniaxial alignment of the cells and serve as anchoring sites for the encapsulated cells and muscle tissues as they form and mature. We have characterized the tissue morphology and strain profile during differentiation of the cells and skeletal muscle tissue formation by using a combination of fluorescence microscopy and computational tools. The time-dependent strain profile suggests the existence of individual cells within the gelatin matrix, which differentiated to form a multinucleated skeletal muscle tissue bundle as a function of culture time. We have also developed a method to calculate the passive tension generated by the engineered muscle tissue bundles suspended between two pillars. Finally, as a proof-of-concept we have examined the applicability of the skeletal muscle-on chip system as a screening platform and in vitro muscle injury model. We studied the dose-dependent effect of cardiotoxin on the engineered muscle tissue architecture and its subsequent effect on the passive tension. This simple yet effective tool can be appealing for studies that necessitate the analysis of skeletal muscle structure and function, including preclinical drug discovery and development. PMID- 28871306 TI - Introduction to Sigma Proteins: Evolution of the Concept of Sigma Receptors. AB - For over 40 years, scientists have endeavored to understand the so-called sigma receptors. During this time, the concept of sigma receptors has continuously and significantly evolved. With thousands of publications on the subject, these proteins have been implicated in various diseases, disorders, and physiological processes. Nevertheless, we are just beginning to understand what sigma proteins do and how they work. Two subtypes have been identified, Sigma1 and Sigma2. Whereas Sigma1 (also known as sigma-1 receptor, Sig1R, sigma1 receptor, and several other names) was cloned over 20 years ago, Sigma2 (sigma-2 receptor, sigma2 receptor) was cloned very recently and had remained a pharmacologically defined entity. In this volume, we will focus primarily on Sigma1. We will highlight several key subject areas in which Sigma1 has been well characterized as well as (re)emerging areas of interest. Despite the large number of publications regarding Sigma1, several fundamental questions remain unanswered or only partially answered. Most of what we know about Sigma1 comes from pharmacological studies; however, a clearly defined molecular mechanism of action remains elusive. One concept has become clear; Sigma1 is not a traditional receptor. Sigma1 is now considered a unique pharmacologically regulated integral membrane chaperone or scaffolding protein. A number of landmark discoveries over the past decade have begun to reshape the concept of sigma receptors. With the rapid emergence of new information, development of new tools, and changing conceptual frameworks, the field is poised for a period of accelerated progress. PMID- 28871307 TI - Combined rupture of left ventricular free wall and pericardium. PMID- 28871308 TI - [Laparoscopic lavage for perforated sigmoid diverticulitis : One-year results of the SCANDIV trial]. PMID- 28871309 TI - Erratum to: Ultrasound-guided interscalene brachial plexus block in a child with acute upper respiratory infection. PMID- 28871311 TI - [Multiprofessional outpatient psychosocial treatment for elderly patients with mental disorders]. AB - Mental disorders contribute substantially to the loss of quality of life and life expectancy in old age. Life expectancy is reduced especially by the bidirectional interaction with heart diseases, diabetes mellitus as well as the depression specific risk of suicide. Depression in old age is a strong risk factor for nursing home placement, which is usually an undesired outcome for older people. Utilization of mental health services is hindered by self-stigmatization and prejudice; however, according to recent surveys older people increasingly value psychotherapeutic services. Shortcomings in the diagnostics and therapy in the primary treatment of old age depression have stimulated research in low-threshold options in primary care and collaborative multiprofessional outpatient interventions in many countries. The core features of collaborative care approaches are improved diagnostics, stepped-care protocols, continuous disease monitoring, and access to psychiatric and psychotherapeutic supervision or services. Collaborative multiprofessional outpatient approaches have been shown to be superior for the treatment of old age depression compared to treatment as usual. PMID- 28871310 TI - Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential. AB - Diabetic kidney disease, a leading cause of end-stage renal disease, has become a serious public health problem worldwide and lacks effective therapies. Autophagy is a highly conserved lysosomal degradation pathway that removes protein aggregates and damaged organelles to maintain cellular homeostasis. As important stress-responsive machinery, autophagy is involved in the pathogenesis of various diseases. Emerging evidence has suggested that dysregulated autophagy may contribute to both glomerular and tubulointerstitial pathologies in kidneys under diabetic conditions. This review summarizes the recent findings regarding the role of autophagy in the pathogenesis of diabetic kidney disease and highlights the regulation of autophagy by the nutrient-sensing pathways and intracellular stress signaling in this disease. The advances in our understanding of autophagy in diabetic kidney disease will facilitate the discovery of a new therapeutic target for the prevention and treatment of this life-threatening diabetes complication. PMID- 28871314 TI - [Psychotherapy with mild cognitive impairment and dementia]. AB - BACKGROUND: Despite evidence for psychotherapy (PT) in elderly patients, it is not standard care in patients with mild cognitive impairment and dementia. Although neuropsychiatric symptoms are frequent in these patients, there is a lack of studies investigating the importance and efficiency of PT. OBJECTIVE: Can patients with mild cognitive impairment and dementia benefit from PT? If so, which modifications of therapeutic strategies are necessary for treating elderly patients with mild cognitive impairments? MATERIAL AND METHODS: Evaluation of empirical evidence on the efficiency of PT for patients with mild cognitive impairment and dementia. Presentation of interventions and modifications of therapeutic strategies. RESULTS: Empirical evidence points towards beneficial effects of PT on depressive symptoms and quality of life. The treatment of anxiety disorders has so far been broadly neglected. Modifications of therapeutic strategies include simplification of content, repetitions, implementation of external memory aids and inclusion of caregivers into therapeutic process. CONCLUSION: Psychotherapy can be effective in patients with mild cognitive impairment and early stages of dementia. When practicing PT, an adaptation of therapeutic strategies is necessary. Nevertheless, there is a need for further studies investigating the benefits and implementation of PT into standard care, especially as pharmacological interventions are very limited in their efficiency and tolerability in this patient population. PMID- 28871315 TI - Laboratory Investigation of Mineralization of Refractory Nitrogen from Sewage Treatment Plants. AB - Laboratory studies were conducted and modeled to evaluate whether refractory organic nitrogen in tertiary-treated wastewater effluent could become bioavailable by conversion to mineral forms. Multiday incubations of effluent collected from the Branford and New Haven, Connecticut, waste water treatment plants (WWTP) revealed low but steady conversion of organic nitrogen to nitrate (NO3-). In Branford, the principal form of organic nitrogen was dissolved, and in New Haven it was particulate. Modeling suggested that in both the cases conversion to NO3- from organic forms occurred at several per cent per day, and appeared to happen via the intermediary NH4+. The results suggest that organic nitrogen may be an important source of bioavailable N, contributing to the problem of hypoxia in Long Island Sound and other estuaries. PMID- 28871316 TI - [Red, scaly baby: a pediatric dermatological emergency : Clinical and differential diagnoses of neonatal erythroderma]. AB - Neonatal, ichthyosiform erythroderma is rare and may be associated with primarily cutaneous disorders as well as with a broad spectrum of potentially severe underlying diseases. Neonatal erythroderma represents a pediatric dermatological emergency requiring a swift diagnosis and effective, interdisciplinary management. This review summarizes both primary skin diseases and systemic illnesses that are known to elicit erythroderma in neonates and young infants. PMID- 28871317 TI - [Drug therapy safety at the transition from hospital to community medicine]. AB - OBJECTIVE: We evaluated the qualitative and quantitative changes of medications during the stay on a geriatric-psychiatric ward where the medication was optimized by a clinical pharmacist, and after discharge. The goal of the study was to analyze the continuity of the medication at the transfer from hospital to ambulatory care. METHODS: We interviewed 41 patients on the phone about their drug regimen 4 and 12 weeks after discharge. Medications were compared to their discharge medication. The number of medications from the PRISCUS list of inappropriate medications for the elderly as well as the number of drug interactions was documented. The drug interaction database MediQ was used to identify and classify the drug-drug interactions. RESULTS: During the hospitalization of the patients, 101 interventions of the clinical pharmacist were recommended and accepted. In cooperation with the physicians, the number of drug interactions decreased by 44% and the number of PRISCUS list medications by 42%. Only 4 weeks after discharge, 54 drugs for 27 patients (66%) had already been changed. During the following 8 weeks, another 44 medications were changed in 14 patients (35%). The total number of drugs after discharge did not change. The number of moderate drug interactions (p = 0.17) of medications from the PRISCUS list increased (p = 0.77), but not significantly. CONCLUSION: While the interventions of a clinical pharmacist can lead to a reduction in drug interactions and inappropriate medication for the elderly during the hospitalization, the medication was changed after discharge in numerous cases. In a detailed analysis it was found that some of the changes increased the number of drug interactions as well as the number of potentially inappropriate medications for the elderly. A drug interaction check after discharge could prevent drug interactions and medication errors. Also the nationwide medication plan can help to prevent medication errors by the prescribing physician as well as by the patient. PMID- 28871318 TI - [Psychotherapy with older caregivers]. AB - Nursing and caring for a relative can be regarded as an important developmental task, which mainly affects elderly people who provide care for their very old parents or their (spouse) partners. Being responsible for the care of someone can be associated with a severe caregiver burden and experienced as a crisis. Possible psychological consequences are pronounced depressive symptoms or maladaptive stress reactions. For these caregivers, psychotherapeutic counselling can be sensible and helpful in addition to other resources of caregiver support. This applies in particular to improving coping with problematic everyday situations, stressful emotions, and strengthening resources. Multimodal interventions that address methods of cognitive behavioral therapy and acceptance as well as commitment therapy could show good evidence for this target group but have so far received little attention in healthcare programs. Because it is often difficult for caregivers to organize regular visits to the psychotherapist's practice, psychotherapeutic offers would be desirable in more flexible settings (e. g. by telephone or internet-based). The extent to which such supplementary interventions can be embedded and financed in the context of chronic care models is still unclear. PMID- 28871312 TI - ALK1 signaling in development and disease: new paradigms. AB - Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels. In this review, we present an updated view of the mechanism of ALK1 signaling, put forth a unified hypothesis to explain the cellular missteps that lead to AVMs associated with ALK1 deficiency, and discuss emerging roles for ALK1 signaling in diseases beyond HHT. PMID- 28871319 TI - Onset ages of hepatopulmonary syndrome and pulmonary hypertension in patients with biliary atresia. AB - PURPOSE: Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) are extrahepatic complications of biliary atresia (BA). Their detection is sometimes delayed, which may result in missed opportunities for liver transplantation. The aim of this study was to determine the onset ages of HPS and PoPH in BA patients. METHODS: BA patients followed at our institution were identified. Patients visited our clinic for routine blood work, as well as regular electrocardiography, chest X-rays, and arterial blood gas tests. Lung perfusion scintigraphy and cardiac ultrasound were performed to diagnose HPS. Cardiac catheterization was conducted to diagnose PoPH. RESULTS: The study population consisted of 88 BA patients. The median follow-up duration was 11.6 years (range 0.8-26.0 years). Six patients (6.8%) developed HPS and three patients (3.4%) developed PoPH. The median age of onset of HPS was significantly younger than that of PoPH (HPS: 4 years, PoPH: 15 years, P < 0.019). Two patients (66%) with PoPH died, while all patients with HPS survivied. CONCLUSION: The onset of HPS was significantly earlier than that of PoPH. The mortality rate was high in patients with PoPH. Teenagers with BA should receive routine cardiac echocardiograms to detect PH in its early stages. PMID- 28871320 TI - Excess risk of venous thromboembolism in hip fracture patients and the prognostic impact of comorbidity. AB - : Hip fracture patients were at increased excess risk of venous thromboembolism (VTE) up to 1 year following hip fracture. During the first year, interaction between hip fracture and comorbidity was observed among patients with severe and very severe comorbidity. INTRODUCTION: We compared the risk of VTE in hip fracture patients with that in the general population. We also examined whether and to what extent the association between hip fracture and VTE varied by comorbidity level. METHODS: Nationwide cohort study based on Danish health registries, 1995-2015. We identified hip fracture patients (n = 110,563) and sampled a comparison cohort without hip fracture from the general population (n = 552,774). Comorbidity was assessed using the Charlson comorbidity index. We calculated attributable fraction, as the proportion of the VTE rate, among persons exposed to both hip fracture and comorbidity, attributed to exposure interaction. RESULTS: The cumulative incidences of VTE were 0.73% within 30 days and 0.83% within 31-365 days among hip fracture patients, and 0.05 and 0.43% in the general population. Adjusted hazard ratios (HRs) of VTE among hip fracture patients were 17.29 [95% confidence interval (CI) 14.74-20.28] during the first 30 days and 2.13 (95% CI 1.95-2.32) during 31-365 days following hip fracture. The relative risks of VTE were 1.03 (95% CI 0.96-1.11) and 1.11 (95% CI 1.00 1.23) after 1-5 years and 6-10 years. During the first 30 days and 31-365 days, 14%/28% of VTE rates and 5%/4% of VTE rates were attributable to the interaction between hip fracture and severe/very severe comorbidity, respectively. Mortality risks within 30 days of VTE were 29.4% in hip fracture and 11.0% in general population cohorts. CONCLUSIONS: Hip fracture patients were at increased excess risk of VTE up to 1 year following their fracture. During the first year, interaction between hip fracture and comorbidity was observed among patients with severe and very severe comorbidity. PMID- 28871321 TI - Revealing Adaptive Management of Environmental Flows. AB - Managers of land, water, and biodiversity are working with increasingly complex social ecological systems with high uncertainty. Adaptive management (learning from doing) is an ideal approach for working with this complexity. The competing social and environmental demands for water have prompted interest in freshwater adaptive management, but its success and uptake appear to be slow. Some of the perceived "failure" of adaptive management may reflect the way success is conceived and measured; learning, rarely used as an indicator of success, is narrowly defined when it is. In this paper, we document the process of adaptive flow management in the Edward-Wakool system in the southern Murray-Darling Basin, Australia. Data are from interviews with environmental water managers, document review, and the authors' structured reflection on their experiences of adaptive management and environmental flows. Substantial learning occurred in relation to the management of environmental flows in the Edward-Wakool system, with evidence found in planning documents, water-use reports, technical reports, stakeholder committee minutes, and refereed papers, while other evidence was anecdotal. Based on this case, we suggest it may be difficult for external observers to perceive the success of large adaptive management projects because evidence of learning is dispersed across multiple documents, and learning is not necessarily considered a measure of success. We suggest that documentation and sharing of new insights, and of the processes of learning, should be resourced to facilitate social learning within the water management sector, and to help demonstrate the successes of adaptive management. PMID- 28871323 TI - [Orthopedic surgery in Dhulikhel, Nepal]. AB - Nepal is one of the 20 poorest countries in the world. Thus, medical care in Nepal is dependent on significant medical and financial commitment from within and outside the country. Dhulikhel Hospital - Kathmandu University Hospital (DH KUH) was founded in 1996 by Prof. Dr. Ram and colleagues. Collaboration and support of many people and institutions are, in contrast to the experience in other hospitals of the third world, characterized by an extraordinary sustainability. The reason for this is the spirit lived according to the motto "best service for the poor". The structures in DH-KUH are influenced by a very close cooperation with a number of international (university) hospitals. Most of the DH-KUH departments have an amazingly high technical standard. Assuming this development and progress can be continued, a splendid future for DH-KUH can be predicted. PMID- 28871322 TI - Frequency and characteristics of pulmonary nodules in children at computed tomography. AB - BACKGROUND: Normative data on pulmonary nodules in children without malignancy are limited. Knowledge of the frequency and characteristics of pulmonary nodules in healthy children can influence care decisions in children with malignant disease. OBJECTIVE: To provide normative data concerning the frequency and characteristics of pulmonary nodules on computed tomography (CT) in young children. MATERIALS AND METHODS: All children ages 1 year-12 years who underwent chest CT after high-energy trauma were retrospectively investigated. Exclusion criteria were a history of malignancy, thick image slices, motion artefacts and extensive post-traumatic pulmonary changes. Two radiologists were asked to independently identify all nodules and to characterize each nodule with respect to location, size, perifissural location and calcification. Discrepancies were adjudicated by a third reader, who set the reference standard in this study. Interobserver agreement in detection and characterization was assessed using the kappa coefficient (kappa). RESULTS: Identified were 120 patients, of whom 72 (75% male; median age: 8.0 years [interquartile range: 4-11]) were included. A total of 59 pulmonary nodules were present in 27 patients (38%; 95% confidence interval: 26-49%; range: 1-5 nodules per patient, with a mean diameter of 3.2 mm [standard deviation: 0.9 mm]). For nodule detection, the per-patient interobserver agreement was substantial (kappa=0.78) and per-lobe agreement was moderate (kappa=0.40). For characterization, there was fair to substantial agreement (kappa=0.36-0.74). CONCLUSION: Small pulmonary nodules on chest CT are a common finding in otherwise healthy children, but detection and characterization have only moderate interobserver agreement. PMID- 28871324 TI - Visual and auditory temporal integration in healthy younger and older adults. AB - As people age, they tend to integrate successive visual stimuli over longer intervals than younger adults. It may be expected that temporal integration is affected similarly in other modalities, possibly due to general, age-related cognitive slowing of the brain. However, the previous literature does not provide convincing evidence that this is the case in audition. One hypothesis is that the primacy of time in audition attenuates the degree to which temporal integration in that modality extends over time as a function of age. We sought to settle this issue by comparing visual and auditory temporal integration in younger and older adults directly, achieved by minimizing task differences between modalities. Participants were presented with a visual or an auditory rapid serial presentation task, at 40-100 ms/item. In both tasks, two subsequent targets were to be identified. Critically, these could be perceptually integrated and reported by the participants as such, providing a direct measure of temporal integration. In both tasks, older participants integrated more than younger adults, especially when stimuli were presented across longer time intervals. This difference was more pronounced in vision and only marginally significant in audition. We conclude that temporal integration increases with age in both modalities, but that this change might be slightly less pronounced in audition. PMID- 28871325 TI - High level of soluble interleukin-2 receptor in serum predicts treatment resistance and poor progression-free survival in multiple myeloma. AB - The IL-2/IL-2 receptor (IL-2R) system plays a central role in maintaining normal T cell immunity, and its disturbance is associated with several hematologic disorders. Studies have found in several types of lymphoma that abnormal amounts of soluble IL-2R (sIL-2R) may result in imbalance of the IL-2/IL-2R system and hence of the T cell immunoregulation. Whether the level of sIL-2R in blood could predict treatment outcomes or not needs to be investigated in multiple myeloma (MM) patients. The level of sIL-2R in serum was measured using enzyme-linked immunosorbent assay (ELISA) in 81 patients with newly diagnosed MM. Twenty-six patients (32.1%) were treated with bortezomib-based regimens and 55patients (67.9%) received old drugs-based regimens. The mean concentration of sIL-2R for myeloma patients was 8.51 ng/ml, significantly higher than that of healthy controls (0.56 ng/ml, p < 0.0001). The best cutoff value for sIL-2R in predicting high risk for disease progression is 6.049 ng/ml with an area under curve (AUC) of 0.665 (p = 0.013). Thirty-six patients (44.4%) were classified as higher sIL 2R level group (> 6.049 ng/ml), and 45 patients (55.6%) as lower group (<= 6.049 ng/ml). The overall response rate (ORR) was 60.0% in lower sIL-2R level group, and 41.7% in higher level group (p = 0.156). The median progression-free survival (PFS) and overall survival (OS) was 12 months (range, 2.0-65 months) and 20 months (range, 2.0-118 months), respectively. In a multivariate survival analysis, including Eastern Cooperative Oncology Group performance status score, treatment response, and sIL-2R level, it was found that all these three parameters were significantly independent prognostic factors for PFS (p = 0.032, 0.016, and 0.043, respectively), but none factors maintained their value in predicting OS. Subgroup analysis revealed that high level of sIL-2R is correlated with significantly inferior PFS in patients treated with bortezomib-based regimens (p = 0.004). Serum sIL-2R level is an independent prognostic factor for PFS, indicating novel drugs targeting the imbalance of IL-2/IL-2R system may be a promising strategy in MM. PMID- 28871326 TI - Mortality and Morbidity After Hartmann's Procedure Versus Primary Anastomosis Without a Diverting Stoma for Colorectal Perforation: A Nationwide Observational Study. AB - BACKGROUND: The benefit of primary anastomosis (PA) without a diverting stoma over Hartmann's procedure (HP) for colorectal perforation remains controversial. We compared postoperative mortality and morbidity between HP and PA without a diverting stoma for colorectal perforation of various etiologies. METHODS: Using the Japanese Diagnosis Procedure Combination database, we extracted data on patients who underwent emergency open laparotomy for colorectal perforation of various etiologies from July 1, 2010 to March 31, 2014. We compared 30-day mortality, postoperative complication rates, and postoperative critical care interventions between HP and PA groups using propensity score matching, inverse probability of treatment weighting, and instrumental variable analyses to adjust for measured and unmeasured confounding factors. RESULTS: We identified 8500 eligible patients (5455 HP and 3045 PA). In the propensity score-matched model, a significant difference between the HP and PA groups was detected in 30-day mortality (7.7% vs. 9.6%; risk difference, 1.9%; 95% confidence interval [CI], 0.5-3.4). The inverse probability of treatment weighting showed similar results (8.8% vs. 10.7%; risk difference, 1.9%; 95% CI, 1.0-2.8). In the instrumental variable analysis, the point estimate suggested similar direction to that of the propensity score analyses (risk difference, 4.4%; 95% CI, -3.3 to 12.1). The PA group had significantly higher rates of secondary surgery for complications (4.6% vs. 8.4%; risk difference, 3.8%; 95% CI, 2.5-4.1) and slightly longer duration of postoperative critical care interventions. CONCLUSIONS: This study revealed a significant difference in 30-day mortality between HP and PA without a diverting stoma. PMID- 28871328 TI - Selective determination of mandelic acid in urine using molecularly imprinted polymer in microextraction by packed sorbent. AB - Mandelic acid (MA) is a major metabolite of ethylbenzene and styrene. For the first time, a selective, fast, and easy-to-use procedure was developed for the determination of MA in urine samples. The new procedure is based on MIMEPS, the combination of a molecularly imprinted polymer (MIP) and microextraction by packed sorbent (MEPS). High-performance liquid chromatography with ultraviolet detection (HPLC-UV) was used for the separation and determination of MA. The bulk polymerization method was used to synthesize the MIP, and the MIP and non imprinted polymer (NIP) were characterized by Fourier transform infrared spectroscopy. The selectivity of the MIP was investigated in the presence of interferents. In addition, we investigated the various parameters that affect the performance of the MEPS, including the pH of the sample, the number of extraction cycles, sample volume, and the types and volumes of the washing and elution solvents. A six-point calibration curve was obtained in the range of 0.2-20 ug/mL (R 2 = 0.9994). The extraction recovery was more than 88.8%. The limit of detection and the limit of quantitation were 0.06 and 0.2 ug/mL, respectively. The intra- and inter-day precisions were in the range of 3.6-4.7% and 3.8-5.1%, respectively. The accuracy was -8.4 to -11.1%. The optimized procedure was selective, sensitive, and rapid, and it was both user friendly and environmentally friendly. The sample preparation process took only about 5 min, so the MIMEPS-HPLC-UV procedure is recommended as an alternative for the biomonitoring of workers exposed to ethylbenzene and/or styrene. PMID- 28871327 TI - Micronutrient intake adequacy and depression risk in the SUN cohort study. AB - PURPOSE: The aim of the study was to prospectively assess the association between micronutrient intake adequacy and risk of depression. METHODS: This dynamic cohort study involves Spanish university graduates (SUN Project). Dietary intake was assessed at baseline and after 10 years of follow-up with a semi-quantitative food frequency questionnaire. Micronutrient intake adequacy for vitamins B1, B2, B3, B6, B12, C, A, D, E, folic acid, zinc, iodine, selenium, iron, calcium, potassium, phosphorus, magnesium and chrome was estimated. Inadequate intake for each nutrient was defined when the intake of the nutrient was below the estimated average requirements (EAR) if available or the adequate intake levels, if EARs were not available. We compared participants with inadequate intake for >=4 nutrients vs. those with one nutrient. Participants were classified as having incident depression if they had no previous history of depression or antidepressants use at baseline, but they reported during follow-up a new clinical diagnosis of depression by a physician, use of antidepressant drugs, or both. Time-dependent multivariable Cox regression models were fitted. RESULTS: After a median follow-up of 8.5 years, 953 new cases of depression were observed among 13,983 participants. Participants with inadequate intake for >=4 nutrients showed a significantly higher risk of depression [multivariable hazard ratio (HR) = 1.37; 95% confidence interval (CI) 1.01-1.85]. When the analyses were updated with repeated assessments of intakes, the association was attenuated and it was no longer statistically significant (Multivariable HR = 1.11; 95% CI 0.82-1.51). CONCLUSIONS: Micronutrient inadequacy in four or more micronutrients could exert a moderate role in the development of depression. PMID- 28871329 TI - Transforming growth factor-beta-mediated CD44/STAT3 signaling contributes to the development of atrial fibrosis and fibrillation. AB - Atrial fibrillation (AF) is associated with atrial fibrosis. Inhibition of atrial fibrosis might be a plausible approach for AF prevention and therapy. This study is designed to evaluate the potential role of CD44, a membrane receptor known to regulate fibrosis, and its related signaling in the pathogenesis of atrial fibrosis and AF. Treatment of cultured rat atrial fibroblasts with transforming growth factor-beta (TGF-beta, a key mediator of atrial fibrosis) led to a higher expression of hyaluronan (HA), CD44, STAT3, and collagen (a principal marker of fibrosis) than that of ventricular fibroblasts. In vivo, TGF-beta transgenic mice and AF patients exhibited a greater expression of HA, CD44, STAT3, and collagen in their atria than wild-type mice and sinus rhythm subjects, respectively. Treating TGF-beta transgenic mice with an anti-CD44 blocking antibody resulted in a lower expression of STAT3 and collagen in their atria than those with control IgG antibody. Programmed stimulation triggered less AF episodes in TGF-beta transgenic mice treated with anti-CD44 blocking antibody than in those with control IgG. Blocking CD44 signaling with anti-CD44 antibody and mutated CD44 plasmids attenuated TGF-beta-induced STAT3 activation and collagen expression in cultured atrial fibroblasts. Deletion and mutational analysis of the collagen promoter along with chromatin immunoprecipitation demonstrated that STAT3 served as a vital transcription factor in collagen expression. TGF-beta-mediated HA/CD44/STAT3 pathway plays a crucial role in the development of atrial fibrosis and AF. Blocking CD44-dependent signaling may be a feasible way for AF management. PMID- 28871330 TI - Forensic features and phylogenetic analyses of Sichuan Han population via 23 autosomal STR loci included in the Huaxia Platinum System. AB - Short tandem repeats (STRs) are DNA regions with a variable number of repeated units (2-6 bp) and attractive to genetic application like forensic, population genetics, and anthropological studies. The Huaxia Platinum System allows the multiplex amplification of 23 autosomal STR loci and two gender determination loci. In the present study, genetic polymorphisms of these 23 autosomal STR loci were first obtained from 309 Sichuan Han individuals, southwest China. No evidence of deviation from the Hardy-Weinberg equilibrium (HWE) was identified. The combined match probability (CMP), combined power of discrimination (CPD), and combined power of exclusion (CPE) are 1.087 * 10-27, 0.999999999999999999999999999, and 0.9999999996 in the Sichuan Han Chinese population, respectively. The inter-population differentiation, PCA, MDS, and phylogenetic analysis revealed that Sichuan Han had a closer genetic relationship with neighboring Han Chinese populations. Our findings indicated that the 23 autosomal STR loci are polymorphic and informative in studied southwestern Chinese Han population and can be utilized as a powerful tool for forensic applications. In addition, population comparisons demonstrated that the genetic similarities widely existed among Han Chinese populations distributed in different administrative divisions, and genetic differences had existed between minorities (most prominently for Uyghur and Kazakh) and Han groups. PMID- 28871331 TI - Exploring the repetition bias in voluntary task switching. AB - In the voluntary task-switching paradigm, participants are required to randomly select tasks. We reasoned that the consistent finding of a repetition bias (i.e., participants repeat tasks more often than expected by chance) reflects reasonable adaptive task selection behavior to balance the goal of random task selection with the goals to minimize the time and effort for task performance. We conducted two experiments in which participants were provided with variable amount of preview for the non-chosen task stimuli (i.e., potential switch stimuli). We assumed that switch stimuli would initiate some pre-processing resulting in improved performance in switch trials. Results showed that reduced switch costs due to extra-preview in advance of each trial were accompanied by more task switches. This finding is in line with the characteristics of rational adaptive behavior. However, participants were not biased to switch tasks more often than chance despite large switch benefits. We suggest that participants might avoid effortful additional control processes that modulate the effects of preview on task performance and task choice. PMID- 28871333 TI - [Thermal injuries : Clinical and acute management in pediatric practice]. AB - BACKGROUND: Each year 30,000 children suffer from burn injuries in Germany and 2000 of these children must be treated in special pediatric burn centers. Approximately two thirds of these children are less than 4 years old, 70% of thermal injuries are due to scalding with hot liquids. OBJECTIVES: The aim of this article is to give an overview of the characteristics of pediatric burn trauma with recommendations for initial treatment, surgical therapy as well as follow-up treatment. CONCLUSION: Physicians are especially challenged by pediatric burn injuries which can cause lifelong stigma by scarring and other physical defects. The treatment of pediatric thermal injuries should be performed in clinics with expertise in treating pediatric burns to achieve optimal results. PMID- 28871332 TI - REM sleep behavior disorder, autonomic dysfunction and synuclein-related neurodegeneration: where do we stand? AB - INTRODUCTION: From newfound parasomnia to a marker of future synucleinopathy, since its first description in 1986, REM sleep behavior disorder (RBD) has been systematically tackled from virtually many viewpoints in basic, translational, and clinical studies. The time delay between RBD and synucleinopathy onset offers an exceptional window for observation and design of neuroprotective trials. In the last few years, research has focused on characterizing possible differences within RBD patients in order to draw potential profiles more or less susceptible to further neurodegeneration. Attention has been drawn towards autonomic dysfunction in RBD as one of such variables. OVERVIEW: In this review, REM sleep physiology and relevant brain anatomy is briefly mentioned and integrated with neuroanatomical and physiological concepts regarding the central autonomic network. A detailed summary of works showing the presence of autonomic dysfunction in RBD is provided, and clinical and electrophysiological features of RBD in synucleinopathies are discussed. A short overview of RBD in other neurodegenerative diseases is also provided. PMID- 28871334 TI - Role of percutaneous veno-arterial extracorporeal membrane oxygenation as bridge to left ventricular assist device. AB - Percutaneous veno-arterial extracorporeal membrane oxygenation (VA-ECMO) provides emergency circulatory support for cardiogenic shock patients and is used as a bridge to a left ventricular assist device (LVAD). The purpose of this study was to determine risk factors for LVAD implantation in patients who required percutaneous VA-ECMO as a bridge to long-term LVAD. We retrospectively investigated 32 consecutive LVAD patients who required percutaneous VA-ECMO as a bridge to long-term LVAD. Twenty-nine patients (91%) were intubated, and their serum creatinine and total bilirubin levels before LVAD implantation were 2.1 +/- 2.0 and 3.7 +/- 3.7 mg/dl, respectively. Patients were supported by LVAD for 495 +/- 393 days, during which 15 died, 6 recovered native cardiac functions and LVAD was explanted, and 11 underwent heart transplantation. Multivariate logistic regression analysis revealed that a preoperative left ventricular end-diastolic diameter (LVDd) <=54 mm was a significant predictor of 90-day mortality after LVAD implantation (OR 13.64; 95% CI 1.081-172.0; p = 0.0433) and freedom from death during LVAD support was significantly worse in patients with an LVDd <=54 mm. Furthermore, preoperative LVDd was positively correlated with postoperative right ventricular stroke work index (r = 0.739, p < 0.0001) and patients with an LVDd <=54 mm had significantly worse postoperative right ventricular, renal, and hepatic functions. We demonstrated that percutaneous VA-ECMO could be utilized as a bridge to long-term LVAD in selected patients. Our results suggest that preoperative LVDd is a useful predictor of mortality and right ventricular function after LVAD implantation in patients requiring VA-ECMO, in whom assessment of right ventricular function is challenging. PMID- 28871335 TI - Biodegradation of gaseous toluene with mixed microbial consortium in a biofilter: steady state and transient operation. AB - Petroleum oil refineries are massive emitters of risky volatile organic compounds (VOCs). Among the VOCs, toluene is taken into account as a significant pollutant. In the present study, a compost biofilter is used to treat the toluene vapor. However, an elimination capacity and removal efficiency of the biofilter was investigated for a wide range of toluene concentrations (0.29-3.8 g m-3) and operated for 54 days effectively. Elimination capacity of 93 g m-3 h-1 was recorded as maximum value at a toluene inlet concentration of 114 g m-3 h-1. An elimination capacity was perpetually better at the lower section of the biofilter, and therefore, the value was around 40-60 g m-3 h-1. The high removal efficiency of 97% was obtained at inlet toluene load of 60.55 g m-3 h-1. Hence, the biofilm was quite sensitive to handling transient loading conditions. The pressure drop had no vital impact on the biofilter performance. An Ottengraf model was applied to all phase of biofilter operation in each of the diffusion limiting region and reaction limiting region. The parameters of the model K 1 (75.95 g1/2 m-3/2 h-1) and K 0 (90.51 g m-3 h-1) were obtained from diffusion and reaction limiting region severally. However, K 1 was used to calculate the theoretical elimination capacities, and therefore, K 0 was used to discover the biofilm thickness. By the way, the average biofilm thickness was found to be 0.98 mm from reaction limiting region. PMID- 28871336 TI - Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. AB - Zoledronate is a bisphosphonate that is widely used in the treatment of metabolic bone diseases. However, zoledronate induces significant nephrotoxicity associated with acute tubular necrosis and renal fibrosis when administered intravenously. There is speculation that zoledronate-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway but the molecular mechanisms are not fully understood. In this report, human proximal tubular HK-2 cells and mouse models were combined to dissect the molecular pathways underlying nephropathy caused by zoledronate treatments. Metabolomic and proteomic assays revealed that multiple cellular processes were significantly disrupted, including the TGFbeta pathway, fatty acid metabolism and small GTPase signaling in zoledronate-treated HK-2 cells (50 MUM) as compared with those in controls. Zoledronate treatments in cells (50 MUM) and mice (3 mg/kg) increased TGFbeta/Smad3 pathway activation to induce fibrosis and kidney injury, and specifically elevated lipid accumulation and expression of fibrotic proteins. Conversely, fatty acid transport protein Slc27a2 deficiency or co-administration of PPARA agonist fenofibrate (20 mg/kg) prevented zoledronate-induced lipid accumulation and kidney fibrosis in mice, indicating that over-expression of fatty acid transporter SLC27A2 and defective fatty acid beta-oxidation following zoledronate treatments were significant factors contributing to its nephrotoxicity. These pharmacological and genetic studies provide an important mechanistic insight into zoledronate-associated kidney toxicity that will aid in development of therapeutic prevention and treatment options for this nephropathy. PMID- 28871337 TI - Clinical Course of Partial Virologic Response with Prolonged Tenofovir Therapy in Nuclos(t)ides-Naive Patients with Chronic Hepatitis B. AB - BACKGROUND/AIMS: The clinical course of chronic hepatitis B (CHB) patients with partial virologic response (PVR) during tenofovir disoproxil fumarate (TDF) therapy remains unclear. METHODS: We retrospectively investigated the long-term clinical outcomes of TDF treatment in nucleos(t)ides-naive CHB patients, particularly in those with PVR. RESULTS: A total of 391 patients treated with TDF therapy for more than 12 months were included. Virologic response (VR) was achieved in 341 patients (87.2%). PVR was evident in 127 (45.3%) of the 391 patients. Multivariate logistic regression analysis using selected baseline factors identified absolute HBV DNA levels at baseline (OR 0.496; 95% CI 1.369 1.969) and HBeAg positivity (OR 0.622; 95% CI 1.096-3.167) as factors significantly associated with PVR. During continuous prolonged TDF therapy, 127 (71.8%) of 177 patients with PVR achieved VR. The cumulative rates of VR in patients with PVR at 12, 24, and 36 months were 42.4, 79.7, and 90.2%, respectively. Serum HBV DNA level at week 24 was significantly associated with VR in patients with PVR. CONCLUSIONS: The vast majority of CHB patients with PVR achieved VR through prolonged TDF therapy, although the time to achieve VR was delayed in those with PVR. This suggests that adjustment of TDF therapy in patients with PVR is unnecessary. PMID- 28871338 TI - Comparison of the effectiveness on intra-articular and subcutaneous TNF inhibitor in rheumatoid arthritis patients. AB - The objective of this study is to evaluate the efficacy of single intra-articular (IA) injection of tumor necrosis factor alpha (TNFalpha) inhibitor in knee joints comparing with subcutaneous injection in rheumatoid arthritis (RA) patients. Forty-eight RA patients with 73 knee arthritis were divided into three groups, group A: received a single injection of TNF inhibitor into knee joints; group B: received regular subcutaneous injection; and group C: received both of the regimen as groups A and B. Ultrasound, erythrocyte sedimentation rate, C-reactive protein (CRP), patients' global visual analogue scale (VAS), and 28-joint Disease Activity Score (DAS28) were collected pre- and post-therapy 4 weeks. The results of the study are as follows: (1) CRP, VAS, and DAS28 of all groups improved significantly post-therapy (p < 0.05); (2) After therapy, synovial hypertrophy (SH) decreased significantly from 4.40 +/- 1.86 mm to 2.74 +/- 1.88 mm (p < 0.05) and power Doppler (PD) signal decreased significantly from 2.63 +/- 0.75 to 1.50 +/- 0.93 (p < 0.01) in group A. Synovial effusion (SE), SH, and PD showed no significant improvement in group B. SE decreased significantly from 9.84 +/- 4.70 mm to 5.89 +/- 4.47 mm (p < 0.05), SH decreased significantly from 4.52 +/- 1.97 mm to 2.49 +/- 1.73 mm (p < 0.01), and PD decreased significantly from 2.46 +/- 0.66 to 1.38 +/- 1.04 (p < 0.01) in group C; and (3) The improvement rate of SH and PD in both groups A and C was obviously higher than that of group B (p < 0.05). Single IA injection of TNFalpha inhibitor was an effective treatment in improvement of SH and PD of knee joints than subcutaneous injection in RA patients. PMID- 28871339 TI - Recruitment strategies in efferent sympathetic nerve activity. AB - In 1968, the first reported microneurographic recordings of muscle sympathetic nerve activity (MSNA) in humans revealed the bursty behavior of efferent sympathetic nerve activity. The timing of bursts could be explained by baroreflex physiology, but the variability in size of each burst was left unexplained. On the basis of shorter latencies of larger bursts, Wallin's group [53] proposed the existence of variable supraspinal synaptic delays and/or options for recruitment of faster-conducting sympathetic neurons when bursts become stronger. These options represent features of recruitable neural systems. Based on the highly variable latencies of single axons whose firing patterns could not explain reflexive increases in burst size, the concept of a latent subpopulation of sympathetic axons was speculated to exist. Using evidence from experimental preparations in anesthetized smaller animals, to recent signal processing of multi-fiber recordings in humans, this brief review will discuss the attempts to discover and understand recruitment strategies within the peripheral sympathetic nervous system. The review focuses on new information from human recordings supporting the idea that rate coding, population coding (recruitment), and temporal coding are options available within the peripheral sympathetic nervous system to adjust efferent sympathetic outflow. Although data are limited, possible clinical applications are discussed. PMID- 28871340 TI - PhzA, the shunt switch of phenazine-1,6-dicarboxylic acid biosynthesis in Pseudomonas chlororaphis HT66. AB - Natural phenazines are versatile secondary metabolites that are mainly produced by Pseudomonas and Streptomyces. All phenazine-type metabolites originate from two precursors: phenazine-1-carboxylic acid (PCA) in Pseudomonas or phenazine-1,6 dicarboxylic acid (PDC) in Streptomyces and other bacteria. Although the biosynthesis of PCA in Pseudomonas has been extensively studied, the origin of PDC still remains unclear. Comparing the phenazine biosynthesis operons of different species, we found that the phzA gene was restricted to Pseudomonas in which PCA is produced. By generating phzA-inactivated mutant, we found a new compound obviously accumulated; it was then isolated and identified as PDC. Protein sequence alignment showed that PhzA proteins from Pseudomonas form a separate group that is recognized by H73L and S77L mutations. Generating mutations of L73 into H73 and L77 into S77 resulted in a significant increase in PDC production. These findings suggest that phzA may act as a shunt switch of PDC biosynthesis in Pseudomonas and distinguish the pathway producing only PCA from the pathway forming PCA plus PDC. Using real-time PCR analysis, we suggested that the phzA, phzB, and phzG genes either directly or indirectly regulate the production of PDC, and phzA plays the most significant regulatory role. This is the first description of phzA in the biosynthesis of PDC, and the first-time substantial PDC was obtained in Pseudomonas. Therefore, this study not only provides valuable clues to better understand the biosynthesis of PCA and PDC in Pseudomonas but also introduces a method to produce PDC derivatives by genetically engineered strains. PMID- 28871341 TI - [Initial management of traumatic ventral shoulder dislocation]. AB - BACKGROUND: In the current literature a consensus on the specific management of primary anterior traumatic shoulder instability has not been reached. While the steps of the initial diagnostic and therapeutic procedures are mostly well defined, a variety of factors need to be considered for the planning of further treatment. OBJECTIVE: This article aims at giving an overview of the essential aspects of the initial management in the rescue center, clinical and radiological diagnostic procedures and the subsequent treatment options. MATERIAL AND METHODS: The content of this article is based on our own clinical experiences in combination with a systematic literature search for relevant clinical and baseline studies. RESULTS: Besides a detailed anamnesis and clinical examination, X-rays in two planes are important for the diagnosis. Potential nerve injuries or fractures need to be borne in mind before and after reduction of the joint and documented accordingly. The Matsen's maneuver can be recommended as it enables a careful repositioning. In rare cases of an irreducible shoulder dislocation due to soft tissue or bony articular interpositions, an open reduction might be necessary. Further therapeutic concepts should be adapted to patient age, activity level and accompanying pathologies, which determine the risk of a recurrent dislocation. A surgical approach for stabilization of the shoulder is highly recommended in cases of concomitant bony defects as well as in young and physically active patients. CONCLUSION: A well-structured treatment plan is essential for the initial management of primary anterior traumatic shoulder instability. A generally applicable algorithm for further management is not yet established. The treatment should therefore be individually planned based on patient-specific characteristics. PMID- 28871343 TI - Three steps and a join: a simple guide to right- and left-sided medial to lateral laparoscopic colorectal surgery. AB - BACKGROUND: To provide a standardised 'medial to lateral' approach to laparoscopic colorectal surgery. METHODS: Both right- and left- sided laparoscopic colorectal procedures were simplified into three well-defined steps and a join. An instructional video and procedural guide provides the important pearls and pitfalls in performing laparoscopic colorectal surgery. RESULTS: During a 10-year period (2006-2016) at a single institution, 20 senior colorectal trainee surgeons and 20 general surgery registrars were trained in the 'three steps and a join' technique. Five hundred and sixty-eight laparoscopic anterior resections using this technique were performed. There were 5 (0.9%) leaks. Five hundred and forty-three laparoscopic right-sided resections were performed. There were 3 (0.6%) anastomotic leaks requiring reoperation and loop ileostomy. CONCLUSIONS: This step-by-step instructional video and procedural guide provides a simple and standardised approach which may be incorporated into a training pathway for laparoscopic right- and left-sided colorectal surgery. PMID- 28871342 TI - A systematic review of publications on charged particle therapy for hepatocellular carcinoma. AB - Charged particle therapy (proton beam therapy and carbon ion therapy) is a form of radiotherapy which has the unique characteristic of superior depth dose distribution, and has been used for the treatment of hepatocellular carcinoma (HCC) in a limited number of patients, especially in Japan. We undertook a systematic review to define the clinical utility of charged particle therapy for patients with HCC. We searched the MEDLINE database from 1983 to June 2016 to identify clinical studies on charged particle therapy for HCC. Primary outcomes of interest were local control, overall survival, and late radiation morbidities. A total of 13 cohorts from 11 papers were selected from an initial dataset of 78 papers. They included a randomized controlled trial comparing proton beam therapy with transarterial chemoembolization, 9 phase I or II trials and 2 retrospective studies. The reported actuarial local control rates ranged from 71.4-95% at 3 years, and the overall survival rates ranged from 25-42.3% at 5 years. Late severe radiation morbidities were uncommon, and a total of 18 patients with grade >=3 late adverse events were reported among the 787 patients included in this analysis. Charged particle therapy for HCC was associated with good local control with limited probability of severe morbidities. The cost-effectiveness and the distinctive clinical advantages of charged particle therapies should be clarified in order to become a socially accepted treatment modality for HCC. PMID- 28871344 TI - Tubal ligation and ovarian cancer risk in African American women. AB - PURPOSE: Tubal ligation has been associated with reduced risk of epithelial ovarian cancer (EOC) in studies of primarily white women, but less is known about the association in African American (AA) women. We sought to evaluate the associations among 597 invasive ovarian cancer cases and 742 controls of AA descent recruited from the African American Cancer Epidemiology Study, a population-based case-control study in 11 geographical areas in the US. METHODS: Multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potentially confounding factors. RESULTS: An inverse association between tubal ligation and EOC was observed that was not statistically significant (OR 0.88, 95% CI 0.68-1.14). However, an inverse association with EOC risk was observed among women who had a tubal ligation at age 35 years or older (OR 0.64; 95% CI 0.41-0.98), but not among those who had a tubal ligation before age 35 (OR 0.98; 95% CI 0.74-1.29) (p for interaction = 0.08). The association also varied considerably by tumor subtype. A strong inverse association was observed for endometrioid tumors (OR 0.31, 95% CI 0.14-0.70), whereas associations with mucinous (OR 0.87, 95% CI 0.36-2.12) and serous (OR 0.94, 95% CI 0.71-1.24) tumors were weaker and not statistically significant. A statistically non-significant positive association for clear cell tumors (OR 1.84, 95% CI 0.58-5.82) was based on a low number of cases. CONCLUSIONS: Our findings show that tubal ligation may confer a reduced risk for EOC among AA women that is comparable to the associations that have been previously observed in primarily white populations. PMID- 28871345 TI - Expose: Different Faces of a Bleeding Giant Duodenal Ulcer. PMID- 28871346 TI - [Differential diagnosis of dissociative seizures]. AB - Patient history taking and semiology provide seminal clues to the diagnosis of dissociative seizures. Openness and alertness of the treating physician are essential. Video-electroencephalogram(EEG)-based analyses of the events are crucial to establish the correct diagnosis, particularly in complex cases. The patient-doctor relationship is of particular importance in order to successfully motivate the patient for psychotherapeutic treatment. Coexisting psychiatric morbidity as well as other functional somatic symptoms must be actively explored. Current changes in the established diagnostic manuals, including ICD-11, reflect the ongoing vivid interest and controversial discussions in the field of dissociative disorders. PMID- 28871347 TI - [Meta-analysis of adjuvant therapy for periampullary adenocarcinoma]. PMID- 28871349 TI - Recent Insights into Pharmacologic Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus. AB - Diabetes mellitus (DM) affects nearly 30 million Americans and carries an increased risk of macrovascular complications of myocardial infarction, stroke, and cardiovascular death. While aggressive cardiovascular risk factor reduction has long been advocated in patients with diabetes, clinical trials have only recently demonstrated that such reductions result in improved outcomes. This review discusses recent evidence for risk reduction strategies and therapies with a focus on the management of glycemia, dyslipidemia, and hypertension. Although the degree to which aggressive glycated hemoglobin reduction decreases the risk of macrovascular outcomes remains unclear, the use of specific agents, such as the newer sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, may reduce cardiovascular events in patients with diabetes, irrespective of glycated hemoglobin reduction. Statins have been the mainstay of dyslipidemia management, with recent guidelines recommending statin use in all patients aged 40-75 years with diabetes. There is an emerging role for the recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in diabetes, as these agents further reduce serum cholesterol and clinical cardiovascular events beyond the maximum tolerated statin therapy. Lastly, most evidence suggests that aggressive blood pressure lowering in diabetic patients with hypertension reduces macrovascular events. Recent studies have re-affirmed a goal blood pressure of 140/90, and a lower pressure is likely prudent in most patients with diabetes. Specifically, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may reduce cardiovascular risk in patients with diabetes beyond their blood pressure lowering effect. In conclusion, there is a growing literature which shows that the risk of cardiovascular outcomes can be reduced in most patients with diabetes, as outlined in this review. PMID- 28871348 TI - Characterization of complex flow patterns in the ascending aorta in patients with aortic regurgitation using conventional phase-contrast velocity MRI. AB - Ascending aorta (AA) flow displacement (FD) is a surrogate for increased wall shear stress. We prospectively studied the flow profile in the AA in patients with aortic regurgitation (AR), to identify predictors of FD and investigate whether magnetic resonance imaging (MRI) phase-contrast flow rate curves (PC-FRC) contain quantitative information related to FD. Forty patients with chronic moderate (n = 14) or severe (n = 26) AR (21 (53%) with bicuspid aortic valve) and 22 controls were investigated. FD was determined from phase-contrast velocity profiles and defined as the distance between the center of the lumen and the "center of velocity" of the peak systolic forward flow or the peak diastolic negative flow, normalized to the lumen radius. Forward and backward volume flow was determined separately for systole and diastole. Seventy percent had systolic backward flow and 45% had diastolic forward flow in large areas of the vessel. AA dimension was an independent predictor of systolic FD while AA dimension and regurgitant volume were independent predictors of diastolic FD. Valve phenotype was not an independent predictor of systolic or diastolic FD. The linear relationships between systolic backward flow and systolic FD and diastolic forward flow and diastolic FD were strong (R = 0.77 and R = 0.76 respectively). Systolic backward flow and diastolic forward flow identified marked systolic and diastolic FD (>=0.35) with a positive likelihood ratio of 6.0 and 10.8, respectively. In conclusion, conventional PC-FRC data can detect and quantify FD in patients with AR suggesting the curves as a research and screening tool in larger patient populations. PMID- 28871350 TI - [Approach to liver, spleen and pancreatic injuries including damage control surgery of terrorist attacks]. AB - BACKGROUND: Terrorist attacks have outreached to Europe with more and more attacks on civilians. Derived from war surgery experience and from lessons learned from major incidents, it seems mandatory for every surgeon to improve understanding of the special circumstances of trauma following a terrorist attack and its' management. METHOD: A short literature review is followed by outlining the damage control surgery (DCS) principle for each organ system with practical comments from the perspective of a specialized hepatobiliary (HPB) surgery unit. CONCLUSION: Every surgeon has to become familiar with the new entities of blast injuries and terrorist attack trauma. This concerns not only the medical treatment but also tailoring surgical treatment with a view to a lack of critical resources under these circumstances. For liver and pancreatic trauma, simple treatment strategies are a key to success. PMID- 28871351 TI - Beyond colour: consistent variation in near infrared and solar reflectivity in sunbirds (Nectariniidae). AB - The visible spectrum represents a fraction of the sun's radiation, a large portion of which is within the near infrared (NIR). However, wavelengths outside of the visible spectrum that are reflected by coloured tissues have rarely been considered, despite their potential significance to thermal effects. Here, we report the reflectivity from 300 to 2100 nm of differently coloured feathers. We measured reflectivity across the UV-Vis-NIR spectra of different (a) body parts, (b) colour-producing mechanisms and (c) sexes for 252 individuals of 68 sunbird (family: Nectariniidae) species. Breast plumage was the most reflective and cap plumage the least. Female plumage had greater reflectivity than males. Carotenoid based colours had the greatest reflectivity, followed by non-iridescent and iridescent melanin-based colours. As ordered arrays of melanin-filled organelles (melanosomes) produce iridescent colours, this suggests that nanostructuring may affect reflectance across the spectrum. Our results indicate that differently coloured feathers consistently vary in their thermal, as well as obvious visual, properties. PMID- 28871353 TI - Study of polyamide thin film characteristics impact on permeability/selectivity performance and fouling behavior of forward osmosis membrane. AB - In recent years, forward osmosis (FO) has received considerable attention due to its huge potentials in water desalination. The thin film composite (TFC) membrane used in the FO desalination consists of a bottom support layer covered by an active layer on top. Polyamide (PA) is commonly employed as an active layer forming via interfacial polymerization between m-phenylenediamine (MPD) and trimesoyl chloride (TMC) monomers. In this study, the effects that the MPD and TMC concentrations could have on the performance and anti-fouling behavior of the obtained FO membrane have been investigated. Results showed that there is a trade off relationship between the water flux and salt rejection, which by increasing MPD concentration, the water flux was reduced? while the salt rejection was enhanced. Also, by increasing the TMC concentration, an opposite trend was observed. Using 0.20 wt.% of TMC monomer, the highest water fluxes of 21.6 LMH and 29.3 LMH were achieved in two different membrane configurations. Furthermore, higher TMC concentration caused better anti-fouling property, when PA active layer of the membrane was in a high fouling potential environment. PMID- 28871352 TI - Co-operative intra-protein structural response due to protein-protein complexation revealed through thermodynamic quantification: study of MDM2-p53 binding. AB - The p53 protein activation protects the organism from propagation of cells with damaged DNA having oncogenic mutations. In normal cells, activity of p53 is controlled by interaction with MDM2. The well understood p53-MDM2 interaction facilitates design of ligands that could potentially disrupt or prevent the complexation owing to its emergence as an important objective for cancer therapy. However, thermodynamic quantification of the p53-peptide induced structural changes of the MDM2-protein remains an area to be explored. This study attempts to understand the conformational free energy and entropy costs due to this complex formation from the histograms of dihedral angles generated from molecular dynamics simulations. Residue-specific quantification illustrates that, hydrophobic residues of the protein contribute maximum to the conformational thermodynamic changes. Thermodynamic quantification of structural changes of the protein unfold the fact that, p53 binding provides a source of inter-element cooperativity among the protein secondary structural elements, where the highest affected structural elements (alpha2 and alpha4) found at the binding site of the protein affects faraway structural elements (beta1 and Loop1) of the protein. The communication perhaps involves water mediated hydrogen bonded network formation. Further, we infer that in inhibitory F19A mutation of P53, though Phe19 is important in the recognition process, it has less prominent contribution in the stability of the complex. Collectively, this study provides vivid microscopic understanding of the interaction within the protein complex along with exploring mutation sites, which will contribute further to engineer the protein function and binding affinity. PMID- 28871354 TI - Putting POP-Q to the test: does C - D = cervical length? AB - INTRODUCTION AND HYPOTHESIS: We investigated the correlation between calculated cervical length (CCL) and gross specimen cervical length (GCL) after total vaginal hysterectomy (TVH) at the time of surgery for pelvic organ prolapse (POP). METHODS: This was a retrospective chart review of patients who had undergone TVH with reconstructive surgery for POP between 2013 and 2015. Patients without an intact specimen or documented cervical length in the pathology report were excluded. CCL was defined as the absolute difference between Pelvic Organ Prolapse Quantification (POP-Q) points C and D. GCL was obtained from the pathology report as the distance from the external to the internal os. The Bland Altman method was used to assess the accuracy of POP-Q measurements with a priori ranges. Symptom severity was evaluated using the PFDI-20 questionnaire. Analysis of variance was used to model both GCL and CCL as a function of prolapse stage and the leading compartment. RESULTS: The final analysis included 202 subjects. Of the CCL measurements, 56.93% were within +/-2 cm of GCL, while 36.14% were within +/-1 cm. POP stage was significantly associated with GCL (P < 0.0024). CCL was significantly longer in patients with stage 4 POP (3.57 cm, 95% CI 3.13-4.00) than in those with stage 2 POP (P < 0.0017; mean 2.68 cm, 95% CI 2.45-2.92) and stage 3 POP (P < 0.0300; mean 2.94 cm, 95% CI 2.73-3.15). There were no significant correlations between PFDI scores and CCL or GCL. CONCLUSIONS: The agreement between POP-Q CCL (|C - D|) and GCL decreases with increasing POP-Q stage. There was no correlation between POP symptom severity and GCL or CCL. GCL significantly increased with increasing POP stage. PMID- 28871355 TI - Negative Mood States or Dysfunctional Cognitions: Their Independent and Interactional Effects in Influencing Severity of Gambling Among Chinese Problem Gamblers in Hong Kong. AB - Gambling-related cognitions and negative psychological states have been proposed as major factors in the initiation and maintenance of problem gambling (PG). While there are a substantial number of studies supporting the role of cognitive dysfunctions in the initiation and maintenance of PG, very few empirical studies have explored the specific role of negative psychological states in influencing PG behaviours. In addition, very few studies have examined the interaction effects of cognitive dysfunctions and negative psychological states in exerting influence on PG behaviours. Therefore, the present study aims to examine the main and interaction effects of gambling-related cognitions and psychological states on the gambling severity among a group of problem gamblers in Hong Kong. A cross sectional research design was adopted. A purposive sample of 177 problem gamblers who sought treatment from a social service organization in Hong Kong completed a battery of standardised questionnaires. While gambling-related cognitions were found to exert significant effects on gambling severity, negative psychological states (i.e. stress) significantly moderated the relationship between gambling cognitions and gambling severity. In essence, those participants who reported a higher level of stress had more stable and serious gambling problems than those who reported a lower level of stress irrespective of the level of gambling related cognitions. The findings of the moderating role of negative emotions in the relationship between cognitive distortions and severity of gambling provide insight towards developing an integrated intervention model which includes both cognitive-behavioural and emotion regulation strategies in helping people with PG. PMID- 28871356 TI - The importance of a full thickness vaginal wall dissection. Comment on "Transvaginal mesh: a historical review and update of the current state of affairs in the United States". PMID- 28871357 TI - [Immunotherapy as modern tumor treatment]. AB - BACKGROUND: The specific immune system is capable of preventing the development of tumor diseases and stimulation of cytotoxic T-lymphocytes can repress existing tumors. The activation of T-lymphocytes is influenced by a new class of antibody based medication, the immune checkpoint inhibitors. METHODS: Review of the scientific background and the published clinical trials on the activity and approval of immune checkpoint inhibitors for various tumor diseases. RESULTS: Immune checkpoint inhibitors function by activating T-lymphocytes during the priming (CTLA4) or effector phase (PDL1/PD1). Activated tumor-specific T lymphocytes in turn can attack the tumor. For malignant melanoma, a combination of both checkpoint inhibitors is approved and achieves response rates of 60%. The PD1 inhibitors are active against non-small cell lung cancer achieving a progression-free survival (PFS) of 12 months and a survival rate of 60% at 24 months. For renal cell cancer and bladder cancer response rates to PD-1 inhibitors of approximately 25% and an improvement in overall survival (OS) up to 4 months compared to previous standard therapies have been reported. CONCLUSION: Immune checkpoint inhibitors are active against a number of tumors. In some cases, such as malignant melanoma and non-small cell lung cancer, the response rates are impressive and exceed those achieved with conventional chemotherapies. Future combinations with other treatment modalities, such as chemotherapy and radiotherapy may further improve the response rates. PMID- 28871358 TI - Chemotherapy-induced nausea and vomiting (CINV) and adherence to antiemetic guidelines: results of a survey of oncology nurses. AB - PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) can be prevented in most patients with use of guideline-recommended antiemetic regimens. However, studies have suggested that adherence to antiemetic guidelines is suboptimal. Oncology nurses, as part of a multidisciplinary team, can help promote appropriate antiemetic prophylaxis. Therefore, nurses were surveyed to assess antiemetic guideline awareness and practice patterns of antiemetic use, determine adherence to guideline recommendations, and query barriers to adherence. METHODS: In September 2015, 531 US-based oncology nurses participated in an online survey administered and analyzed by ONS:Edge. RESULTS: Nurses were most familiar with National Comprehensive Cancer Network (73%) and American Society of Clinical Oncology (48%) antiemetic guidelines. While most (77%) felt that antiemetics prescribed were consistent with guideline recommendations, practice patterns of antiemetic use revealed low adherence to those guidelines, particularly during the delayed (25-120 h) phase following highly emetogenic chemotherapy, where only 25% of nurses reported administration of guideline-recommended agents. Overutilization of phenothiazines and benzodiazepines was common. Only 17% of respondents reported that most (> 75%) of their patients have CINV optimally controlled; 39% reported between 6 and 20% of patients have an alteration in their chemotherapy due to CINV, and reports of emergency department/hospital visits due to poorly controlled CINV were high. The predominant barrier interfering guideline-recommended antiemetic prophylaxis was reported as physician preference (71%). CONCLUSIONS: This survey revealed an opportunity to increase awareness of antiemetic guidelines and a critical need to address barriers interfering with utilization of guideline-recommended antiemetic agents in order to optimize CINV control for patients undergoing emetogenic chemotherapy. PMID- 28871359 TI - [Indications and strategies in mechanical circulatory support : Rise of the machines?] AB - Terminal heart failure is an emerging problem with a continuously growing number of diseased patients worldwide. Because of the limited number of donor hearts, mechanical circulatory support is increasingly becoming an integral part of surgical treatment for end-stage heart failure, especially in patients deemed for destination therapy. Accurate patient selection, appropriate indication, and the optimal implantation time point guarantee a good outcome for these patients. This review article gives a systematic overview of the possible indication settings and treatment strategies for various patient groups in need of mechanical circulatory support. PMID- 28871360 TI - The AES total ankle arthroplasty analysis of failures and survivorship at ten years. AB - BACKGROUND: AES mobile-bearing total ankle replacement was developed from the Buechel Pappas model. It was withdrawn in 2009, after identification of a higher than expected complication rate. The purpose of the current study was to analyse clinical outcomes, failures and survival of the initial series of 50 AES published in 2009. METHODS: In this single-centre continuous prospective study (2003-2006), 50 AES prostheses were included. Pre-operative osteoarthritis was mainly post-traumatic (50%) and secondary to instability (36%). All patients were assessed with clinical and radiographic follow-up at six months, one year, two years and every two to three years thereafter. A CT-scan was systematically performed before procedure, and at two years, five years and ten years. At last follow-up, all patients with TAR had a functional (SF 36, AOFAS) and clinical assessment. All complications or surgical events were analysed. RESULTS: The mean follow-up was ten +/- two years (range, 9-13). The mean AOFAS score was 75 points (range, 26-100). The mean SF 36 score was 69 points (range, 35-97). There was a significant deterioration in AOFAS score at five years and at last follow-up (p < 0.05). Fifteen TARs underwent reoperation for cyst curettage-graft because of development of periprosthetic lesions. Six of them ended up with prosthesis removal-arthrodesis. At the last follow-up, 14 TARs were removed for arthrodesis. Of the 30 prostheses seen at last follow-up, four are awaiting prosthesis removal arthrodesis and one for cyst curettage-graft. The ten year survivorships free of any prosthesis removal or arthrodesis and free of any reoperation were 68% (95% CI, 55-85) and 57% (95% CI, 44-74), respectively. CONCLUSION: Our data suggested a high rate of reoperation. Overall ten year survival was lower than with other designs, particularly due to cyst lesions. LEVEL OF EVIDENCE: Level IV, prospective case series. PMID- 28871361 TI - Are Negative Peer Influences Domain Specific? Examining the Influence of Peers and Parents on Externalizing and Drug Use Behaviors. AB - Most studies tend to characterize peer influences as either positive or negative. In a sample of 1815 youth from 14 different schools in Caracas, Venezuela, we explored how two types of peer affiliations (i.e., deviant and drug-using peers) differentially mediated the paths from positive parenting to youth's externalizing behavior and licit and illicit drug use. We used Zero Inflated Poisson models to test the probability of use and the extent of use during the past 12 months. Results suggested that peer influences are domain specific among Venezuelan youth. That is, deviant peer affiliations mediated the path from positive parenting to youth externalizing behaviors, and peer drug-using affiliations mediated the paths to the drug use outcomes. Mediation effects were partial, suggesting that parenting explained unique variance in the outcomes after accounting for both peer variables, gender, and age. We discuss implications for the development of screening tools and for prevention interventions targeting adolescents from different cultures. PMID- 28871362 TI - Electrocardiographic Markers of Appropriate Implantable Cardioverter Defibrillator Therapy in Young People with Congenital Heart Diseases. AB - Implantable cardioverter-defibrillators (ICDs) are increasingly utilized in patients with congenital heart disease (CHD). Prediction of the occurrence of shocks is important if improved patient selection is desired. The electrocardiogram (ECG) has been the first-line tool predicting the risk of sudden death, but data in CHD patients are lacking. We aim to evaluate the predictive value of electrocardiographic markers of appropriate therapy of ICD in young people with CHD. We conducted a prospective, longitudinal study, in twenty six CHD patients (mean age 24.7 +/- 5.3 years) who underwent first ICD implantation. Forty-two age- and diagnosis-matched controls were recruited. Twelve-lead ECG and 24 h Holter analysis were performed during a mean follow-up of 38.9 months. Data included heart rate, heart rate variability, QRS duration (QRSd), QTc interval and its dispersion, Tpeak-Tend (Tp-Te) interval and its dispersion, presence of fragmented QRS (fQRS), T wave alternans, atrial arrhythmias, and non-sustained ventricular tachycardia. Implant indication was primary prevention in ten cases (38.5%) and secondary prevention in 16 (61.5%). Overall, 17 subjects (65.3%) received at least one appropriate and effective ICD discharge. fQRS was present in 64.7% of cases with ICD therapy compared with patients without events or controls (p < 0.0001). Tp-e and Tp-e dispersion were significantly prolonged in patients with recurrences (113.5 and 37.2 ms) versus patients without ICD discharge (89.6 and 24.1 ms) or controls (72.4 and 19.3 ms) (p < 0.0001 and p < 0.0001, respectively). On univariate Cox regression analysis QRSd (hazard ratio: 1.19 per ms, p = 0.003), QTc dispersion (hazard ratio: 1.57 per ms, p = 0.002), fQRS (hazard ratio: 3.58 p < 0.0001), Tp-e (hazard ratio: 2.27 per ms, p < 0.0001), and Tp-e dispersion (hazard ratio: 4.15 per ms, p < 0.0001), emerged as strong predictors of outcome. On multivariate Cox analysis fQRS, Tp-e and Tp-e dispersion remained in the model. The presence of fQRS, and both Tp-e and Tp-e dispersion are useful ECG tools in daily clinical practice to identify CHD patients at risk for appropriate ICD therapy. PMID- 28871363 TI - A joint model of cancer incidence, metastasis, and mortality. AB - Many diseases, especially cancer, are not static, but rather can be summarized by a series of events or stages (e.g. diagnosis, remission, recurrence, metastasis, death). Most available methods to analyze multi-stage data ignore intermediate events and focus on the terminal event or consider (time to) multiple events as independent. Competing-risk or semi-competing-risk models are often deficient in describing the complex relationship between disease progression events which are driven by a shared progression stochastic process. A multi-stage model can only examine two stages at a time and thus fails to capture the effect of one stage on the time spent between other stages. Moreover, most models do not account for latent stages. We propose a semi-parametric joint model of diagnosis, latent metastasis, and cancer death and use nonparametric maximum likelihood to estimate covariate effects on the risks of intermediate events and death and the dependence between them. We illustrate the model with Monte Carlo simulations and analysis of real data on prostate cancer from the SEER database. PMID- 28871364 TI - Combined dexamethasone and desmopressin test in the differential diagnosis of ACTH-dependent Cushing's syndrome and pseudo-cushing's states. PMID- 28871365 TI - Immune profiling of melanoma tumors reflecting aggressiveness in a preclinical model. AB - Melanoma, like most solid tumors, is highly heterogeneous in terms of invasive, proliferative, and tumor-initiating potential. This heterogeneity is the outcome of differential gene expression resulting from conditions in the tumor microenvironment and the selective pressure of the immune system. To investigate possible signatures combining immune-related gene expression and lymphocyte infiltration, we established a preclinical model using B16.F1-derived clones, in the context of melanoma aggressiveness. Combinatorial analyses revealed that tumors concomitantly expressing low levels of Tnf-a, Pd-1, Il-10, Il-1ra, Ccl5, Ido, high Il-9, and with low infiltration by CD45+, CD3+, CD4+ and CD8+ cells and a high CD4+:CD8+ T cell ratio exhibited the most aggressive growth characteristics. Overall, these results support the notion that the intratumoral immunologic network molds aggressive melanoma phenotypes. PMID- 28871366 TI - Predictors of Mortality in Children with Pulmonary Atresia with Intact Ventricular Septum. AB - Pulmonary atresia with intact ventricular septum (PA/IVS) is a rare cardiac congenital lesion characterized by imperforate pulmonary valve, intact ventricular septum, and atrial level shunt. Although different management strategies to establish a source of non-ductal dependent pulmonary blood flow have been described, studies have not assessed the relationship between the therapeutic approach, patient characteristics, and outcomes. The purpose of this study was to identify predictors of mortality for patients with PA/IVS. Neonates and children with PA/IVS were identified through analysis of the 2012 Kids' Inpatient Database of the Healthcare Cost and Utilization Project. Hospital admissions that included a cardiac catheterization and/or surgical procedure were analyzed to identify demographics, co-morbidities, and outcomes. We identified 508 patients with PA/IVS with hospital admissions that included cardiac catheterization (n = 165), surgical procedures (n = 273), or both (n = 70). The incidence of mortality in this cohort was 6.69% (34/508). Univariable analysis demonstrated that age less than 12 months (p < 0.001), non-elective admission (p < 0.001), AKI (p = 0.001), sepsis (p = 0.002), and the use of ECMO (p < 0.001) were associated with an increased risk of mortality, while no difference was observed for the type of therapeutic approach (p = 0.498). These variables were used in a multivariable logistic regression analysis to develop the predictive model for mortality. Age less than 12 months, non-elective admission, and the use of ECMO in children with PA/IVS were predictors for mortality. Interestingly, the type of therapeutic approach did not influence mortality, which suggests that patient characteristics other than the method chosen to provide pulmonary blood flow determine mortality. PMID- 28871367 TI - Comment on "No superior treatment for primary osteochondral defects of the talus. Dahmen J, et al. KSSTA 2017 Jun 27 PMID:28656457". PMID- 28871368 TI - Infected multilocular hydrocephalus treated by rigid and flexible endoscopes with electromagnetic-guided neuronavigation: a case report. AB - BACKGROUND: Endoscopic surgery assisted by a navigation system has greatly aided treatment of infected multilocular hydrocephalus, especially in children. CASE REPORT: We describe a 2-year-old boy with multilocular hydrocephalus caused by repeated shunt infection, presenting with fever and vomiting. Magnetic resonance images (MRI) showed extraventricular cysts and severe ventricular deformity. There were three ventriculoperitoneal shunts and one residual ventricular catheter. With a flexible endoscope, we fenestrated the wall of extraventricular cysts and removed the residual catheter. We then used a rigid endoscope to fenestrate ventricular components. Both procedures were guided by electromagnetic (EM) navigation, and hydrocephalus was controlled with one ventricular catheter. CONCLUSION: We have successfully treated a case suffered from infected multilocular hydrocephalus in infants using rigid and flexible endoscopes combined with EM navigation. PMID- 28871369 TI - Self-inflicted explosive death by intra-oral detonation of a firecracker: a case report. AB - Self-inflicted explosive deaths due to detonation of fireworks are rare. In this case report, a peculiar case of an elderly male who discharged a firecracker inside his mouth, resulting in fatal blast induced craniofacial injuries, is described. There is paucity of published data describing fireworks-related suicidal and/or non-suicidal deaths. Even scantier data is present specifically describing fireworks-related blast induced neurotrauma and the mechanism(s) of injury involved in such cases. This case report emphasizes the severe damage that a commercially available explosive, the so-called "Gorilla Bomb", can cause, and raises questions about the relative ease of its acquisition. PMID- 28871370 TI - [Palmar dislocation of the proximal interphalangeal joint and traumatic boutonniere deformity]. AB - Injury to the central slip of the extensor tendon may occur with open and also with closed injuries, such as volar dislocation of the proximal interphalangeal (PIP) joint. For adequate treatment, it is necessary to identify all injured structures. Without appropriate primary management, the patient is likely to develop a subacute to chronic posttraumatic boutonniere deformity. A fixed boutonniere deformity requires recovery of joint mobility. Once joint mobility is achieved, secondary surgical reconstruction of the central slip can be performed with a tendon transfer or a tendon transplant. PMID- 28871372 TI - [Psychotherapy with older adults]. PMID- 28871371 TI - Management of skin and subcutaneous tissue in complex open abdominal wall reconstruction. AB - PURPOSE: Open abdominal wall reconstruction is often a complex endeavor, usually performed on patients with multiple risk factors and co-morbidities. METHODS: In this article, we review soft tissue management techniques that can optimize the skin and subcutaneous tissue, with the goal of reducing surgical-site occurrences. RESULTS: Regardless of the hernia repair technique used, outcomes can be highly dependent on the appropriate management of the skin and subcutaneous tissue. Indeed, dehiscence and surgical-site infection can jeopardize the entire reconstruction, especially in cases where synthetic mesh might become exposed and/or infected, setting up a "vicious cycle" (Holihan et al. in J Am Coll Surg 221:478-485, 2015). CONCLUSION: Multidisciplinary cooperation between the general and plastic surgeon is useful in cases of tenuous blood supply to the abdominal skin, in cases of redundant, marginal or excessive skin, and in cases of deficient skin. PMID- 28871373 TI - [Acute and chronic heart failure]. AB - The initial therapy of chronic heart failure is still based on diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and in specific cases mineralocorticoid receptor antagonists. The new European Society of Cardiology (ESC) guidelines published in 2016 introduced angiotensin-receptor neprilysin inhibitors, such as sacubitril/valsartan (LCZ 696) as new therapeutic agents in patients with chronic and progressive heart failure. New subgroup analyses for LCZ 696 have been published showing a beneficial effect in the context of various comorbidities, such as renal insufficiency, diabetes and hypotension. Furthermore, new data are available on intravenous iron substitution in chronic heart failure and on the indications for implantable converter defibrillators, cardiac resynchronization therapy and other cardiac devices. Medicinal therapy of acute heart failure is still limited. For patients who cannot be treated with medicinal therapy, mechanical circulatory support, such as extracorporeal membrane oxygenation (ECMO) should be recommended. PMID- 28871374 TI - Clinical outcomes and radiosurgical considerations for pediatric arteriovenous malformation: influence of clinical features on obliteration rate. AB - PURPOSE: Gamma knife radiosurgery (GKRS) is an established treatment modality for brain arteriovenous malformation (AVM), but there have been few published studies examining the relationship between clinical features of AVM and successful obliteration with GKRS in pediatric patients. In the current study, we investigate the outcomes of GKRS for pediatric patients with brain AVM and analyze the variables that influence obliteration. METHODS: We analyzed 68 pediatric patients (<= 18 years) with a mean follow-up period of 61.9 months (range 6-215 months). The following parameters were analyzed to determine their influence on obliteration of AVM treated by GKRS: age, sex, target volume, irradiation dose, prior treatment, location of AVM, nidus structure, velocity of AVM, location of venous drainage, number of feeding arteries, and initial presenting symptoms. Also, we estimated clinical factors which should be considered during the follow-up period. RESULTS: Of the 68 patients, complete obliteration was confirmed in 26 (38.2%) by cerebral angiography. The response rate of AVM for GKRS was 92.6%. No significant association was observed between any of the parameters investigated and the obliteration of AVM, with the exception of number of feeding arteries, which exhibited a statistically significant difference by univariate analysis (p = 0.003). However, on multivariate analysis, nidus structure (p = 0.007), velocity of the main arterial phase (p = 0.013), velocity of the feeding artery phase (p = 0.004), and the number of feeding arteries (p = 0.018) showed statistical significance. CONCLUSION: GKRS yielded good long-term clinical outcomes in most pediatric patients. Multiple arterial feeding vessels, diffuse nidus structure, and fast flow of AVM were specific factors associated with a low rate of obliteration in pediatric AVMs. PMID- 28871375 TI - Walter E. Dandy: his contributions to pituitary surgery in the context of the overall Johns Hopkins Hospital experience. AB - BACKGROUND: Walter E. Dandy (1886-1946) was an outstanding neurosurgeon who spent his entire career at the Johns Hopkins Hospital. After graduating from medical school in 1910, he completed a research fellowship in the Hunterian laboratory with Harvey Cushing and then joined the Department of Surgery as resident, rising to the rank professor in 1931. Dandy made several contributions that helped building the neurosurgical specialty, most famously the introduction of pneumo ventriculography to image brain lesions for which he received a Nobel prize nomination. He also performed many pituitary surgeries, although his role in this area is less known and overshadowed by that of Cushing's. PURPOSE: This retrospective cohort study was designed to unveil Dandy's pituitary work and place it in the context of the overall pituitary surgeries performed at the Johns Hopkins Hospital. METHODS: Pituitary surgery data were obtained by screening the paper and electronic surgical pathology records of the Department of Pathology, as well as the general operating room log books of the Johns Hopkins Hospital housed in the Chesney Medical Archives. RESULTS: A total of 3211 pituitary surgeries associated with a pathological specimen were performed between February 1902 and July 2017 in 2847 patients. Most of the surgeries (2875 of 3211 89%) were done by 21 neurosurgeons. Dandy ranks 4th as number of surgeries, with 287 pituitary operations in 35 years of activity. He averaged 8 pituitary surgeries per year, a rate that positions him 6th among all Hopkins neurosurgeons. With the exception of his first operation done in July 1912 while Cushing was still at Hopkins, Dandy approached the pituitary gland transcranially, rather than transphenoidally. The majority of Dandy's pituitary patients had a pathological diagnosis of pituitary adenomas, followed by craniopharyngiomas and sellar cysts. In the decades Dandy operated, pituitary surgeries represented 0.56% of the total Johns Hopkins surgeries, a percentage significantly greater (p < 0.001) than the 0.1% observed in modern days. Dandy's pituitary clinical work was matched by important experimental studies done in the early stages of his career. CONCLUSIONS: This study highlights the role of Dandy as an important contributor to advance our understanding of pathophysiology and treatment of pituitary diseases. PMID- 28871376 TI - [Branch duct intraductal papillary mucinous neoplasm - contra resection]. AB - Due to improvements in imaging modalities the diagnosis of branch duct intraductal papillary mucinous neoplasms (BD-IPMN) has been significantly increased in recent years. A BD-IPMN is frequently diagnosed as an incidental finding in asymptomatic patients. The optimal management of BD-IPMN is the subject of controversial discussions. Numerous studies have shown that an individualized therapeutic strategy with a follow-up observation of most BD-IPMNs is feasible and safe, considering age, comorbidities and patient preference. An accurate evaluation of BD-IPMN with a detailed anamnesis, high-resolution imaging techniques and endoscopic ultrasound is necessary. Symptomatic patients as well as patients with so-called high-risk stigmata should undergo resection. Asymptomatic patients with so-called worrisome features can either undergo surveillance or surgical resection, taking age and comorbidities into account. For BD-IPMN patients without high-risk stigmata and worrisome features and showing no symptoms, surveillance of the pancreatic lesion is the preferred approach. The high prevalence of BD-IPMN, limitations in differential diagnostics, an overestimation of the risk of malignancy due to an overrepresentation of symptomatic and suspected BD-IPMN in resected cohorts, an overestimated role of BD-IPMN as precursor lesions for pancreatic carcinoma and evidence of the safety of follow-up surveillance, underline the enormous importance of surveillance. Based on this and considering the background of a notable mortality and morbidity of pancreatic surgery, aggressive management with prophylactic surgical resection is not justified for all BD-IPMN, in particular for low-risk lesions. PMID- 28871378 TI - [The usage of protective gloves for routine disinfection of patient contact areas : An anonymous survey of work doctors and hygienists (infection control nurses, link nurses and physicians)]. AB - BACKGROUND: Disinfection, routinely carried out in healthcare facilities and known as "ongoing disinfection" or "untargeted disinfection", covers areas that are suspected of being contaminated with pathogen-containing material without being recognizable or visible in individual cases. The use of chemical resistant protective gloves is indispensable for surface disinfection. However, it is unclear if healthcare facilities set specific requirements regarding the selection and application of gloves. METHOD: The usage of protective gloves for routine disinfection of patient contact areas was assessed in an anonymous cross sectional study. Work doctors and hygienists (infection control nurses, link nurses and physicians) were queried by questionnaire. RESULTS: Disposable gloves were predominantly used, in most cases largely in accordance with EN 374. The most common glove material was nitrile. Glove change was mostly reported between rooms. Reprocessing of reusable gloves is inconsistent. Several professions are responsible for selecting protective gloves. CONCLUSIONS: Procedures for glove selection and application for disinfection of contact surfaces vary between the surveyed institutions. Therefore, more attention has to be paid to these three aspects in the future and these must be included in the hygiene plans. PMID- 28871377 TI - The maize CorA/MRS2/MGT-type Mg transporter, ZmMGT10, responses to magnesium deficiency and confers low magnesium tolerance in transgenic Arabidopsis. AB - KEY MESSAGE: ZmMGT10 was specifically expressed in maize roots and induced by a deficiency of magnesium. Overexpression of ZmMGT10 restored growth deficiency of the Salmonella typhimurium MM281 strain and enhanced the tolerance in Arabidopsis to stress induced by low magnesium levels by increasing uptake of Mg2+ via roots. CorA/MRS2/MGT-type Mg2+ transporters play a significant role in maintaining magnesium (Mg) homeostasis in plants. Although the maize CorA/MRS2/MGT family comprises of 12 members, currently no member has been functionally characterized. Here, we report the isolation and functional characterization of ZmMGT10 from the maize MRS2/MGT gene family. ZmMGT10 has a typical structure feature which includes two conserved TMs near the C-terminal end and an altered AMN tripeptide motif. The high sequence similarity and close phylogenetic relationship indicates that ZmMGT10 is probably the counterpart of Arabidopsis AtMGT6. The complementation of the Salmonella typhimurium mutated MM281 strain indicates that ZmMGT10 possesses the ability to transport Mg2+. ZmMGT10 was specifically expressed in the plant roots and it can be stimulated by a deficiency of Mg. Transgenic Arabidopsis plants which overexpressed ZmMGT10 grew more vigorously than wild-type plants under low Mg conditions, exhibited by longer root length, higher plant fresh weight and chlorophyll content, suggesting ZmMGT10 was essential for plant growth and development under low Mg conditions. Further investigations found that high accumulation of Mg2+ occurred in transgenic plants attributed to improved Mg2+ uptake and thereby enhanced tolerance to Mg deficiency. Results from this investigation illustrate that ZmMGT10 is a Mg transporter of maize which can enhance the tolerance to Mg deficient conditions by improving Mg2+ uptake in the transgenic plants of Arabidopsis. PMID- 28871380 TI - MRI of anal canal: common anal and perianal disorders beyond fistulas: Part 2. AB - A broad spectrum of disease, from benign processes to life-threatening pathologies, can cause anal pain. MR imaging (MRI) has become increasingly widely used method over the past two decades for the evaluation of individuals with anorectal symptoms. Although imaging is rarely necessary to determine the etiology of the majority of cases, MRI is particularly useful as a noninvasive method of excluding severe neoplastic conditions. In this article, MRI findings of a number of pathologies such as anal and perianal neoplasms, hemorrhoidal disease, arteriovenous malformation of the perianal region, and anal sphincter lesions (defects, scarring, atrophy) which may lead to fecal incontinence are presented. PMID- 28871379 TI - Discrepancy between subjective and objective measures of cognitive impairment in patients with rheumatoid arthritis. AB - This study explored the discrepancy between perceived cognitive dysfunction and computerized neuropsychological test performance in Korean patients with RA. Individuals with RA were recruited by their rheumatologists during follow-up visits at one hospital in Korea. After getting signed consents, a trained research nurse assessed participants with a range of physical, psychosocial, and biological metrics. Subjective cognitive dysfunction was assessed using the Perceived Deficits Questionnaire (PDQ; range 0-20). Objective cognitive impairment was assessed using a set of 6 computerized neurocognitive tests yielding 12 indices covering a range of cognitive domains. Subjects were classified as 'impaired' if they performed 1 SD below age-based population norms on each test. A total cognitive function score was calculated by summing the transformed scores (range 0-12). Multiple linear regression analyses determined the relationship of total cognitive function score with PDQ score, controlling for disease activity, functional limitations, and psychological factors. Forty subjects (mean +/- SD age: 63.1 +/- 11.4 years) were included. Mean +/- SD scores of total cognitive function and PDQ were 7.3 +/- 2.7 (2-12) and 11.8 +/- 5.1 (5 25), respectively. In multivariate analysis, there was no significant relationship between total cognitive function score and PDQ score. However, depression and sleep quality (beta = 0.37, p = 0.025; beta = 0.17, p = 0.034) were significantly associated with PDQ score. The findings emphasize the gap between subjective and objective measures of cognitive impairment and the importance of considering psychological factors within the context of cognitive complaints in clinical settings. PMID- 28871381 TI - N-Acetyl-L-cysteine protects thyroid cells against DNA damage induced by external and internal irradiation. AB - We evaluated the effect of the antioxidant N-acetyl-L-cysteine (NAC) on the levels of reactive oxygen species (ROS), DNA double strand breaks (DSB) and micronuclei (MN) induced by internal and external irradiation using a rat thyroid cell line PCCL3. In internal irradiation experiments, ROS and DSB levels increased immediately after 131I addition and then gradually declined, resulting in very high levels of MN at 24 and 48 h. NAC administration both pre- and also post-131I addition suppressed ROS, DSB and MN. In external irradiation experiments with a low dose (0.5 Gy), ROS and DSB increased shortly and could be prevented by NAC administration pre-, but not post-irradiation. In contrast, external irradiation with a high dose (5 Gy) increased ROS and DSB in a bimodal way: ROS and DSB levels increased immediately after irradiation, quickly returned to the basal levels and gradually rose again after >24 h. The second phase was in parallel with an increase in 4-hydroxy-2-nonenal. The number of MN induced by the second wave of ROS/DSB elevations was much higher than that by the first peak. In this situation, NAC administered pre- and post-irradiation comparably suppressed MN induced by a delayed ROS elevation. In conclusion, a prolonged ROS increase during internal irradiation and a delayed ROS increase after external irradiation with a high dose caused serious DNA damage, which were efficiently prevented by NAC. Thus, NAC administration even both after internal or external irradiation prevents ROS increase and eventual DNA damage. PMID- 28871382 TI - Beyond stroke-uncommon causes of diffusion restriction in the basal ganglia. AB - In the emergency setting, a regional area of restricted diffusion involving the basal ganglia typically represents an acute infarct due to small vessel occlusion. However, it is important to consider additional differentials, specifically systemic causes. This article will review anatomy of the basal ganglia and pertinent associated vasculature, followed by other entities that can be a cause of restricted diffusion. These include hemolytic uremic syndrome, hypereosinophilic syndrome, fat embolism, meningitis, and hypoxic-ischemic injury. It is important to recognize presenting findings in these conditions, as the radiologist may be the first to give an accurate diagnosis or prompt additional testing. PMID- 28871383 TI - Non-clostridial gas gangrene in a patient with poorly controlled type 2 diabetes mellitus on hemodialysis. PMID- 28871384 TI - "Back to the future": a historical perspective on the role of extra-articular reconstruction. PMID- 28871385 TI - Dynamic 3T pelvic floor magnetic resonance imaging in women progressing from the nulligravid to the primiparous state. AB - INTRODUCTION AND HYPOTHESIS: The objective was to prospectively characterize dynamic pelvic 3-Tesla magnetic resonance imaging (dp3T MRI) findings in nulligravida women and characterize changes 6 months after delivery in the same woman. METHODS: In this prospective study, nulligravida women seeking assisted reproductive technology for pregnancy were recruited. After physical examination by Pelvic Organ Prolapse Quantification (POP-Q), Brink assessment and measures including the Pelvic Floor Distress Inventory-20 and Pelvic Floor Impact Questionnaire-7, pre-pregnancy dp3T MRI at rest, with strain, and evacuation were performed. Assessments were repeated >=6 months postpartum. Analysis included Welch and paired t tests for continuous variables, Fisher's exact test for differences in categorical outcomes, and paired t tests for postpartum symptoms. RESULTS: Nineteen subjects (mean +/- SD age, 31 +/- 5 years) completed baseline clinical and dp3T MRI studies, 15 delivered and 10 (30.5 +/- 3 years) completed pre-pregnancy and post-delivery clinical and dp3T MRI assessments. There were no significant changes in scores of validated questionnaires (all p > 0.05) or on POP-Q measures post-delivery. Two (20%) subjects without pre-pregnancy levator tears had tears on MRI post-delivery. MRI measures of pelvic organ descent were increased post-delivery. Seventeen pelvic soft-tissue parameters increased by greater than 10% post-delivery, including 5 out of 70 (7.1%), 17 out of 110 (15.5%), and 50 out of 110 (45.5%) values exceeding thresholds at rest, strain, and evacuation respectively. CONCLUSIONS: Dynamic pelvic 3T MRI detected levator tears and increased pelvic organ descent, which can be directly attributed to pregnancy and delivery. PMID- 28871386 TI - PMCT images of a motorcycle helmet-associated fracture. PMID- 28871387 TI - Lethal hypothermia - a sometimes elusive diagnosis. PMID- 28871388 TI - Long-term micturition problems of asymptomatic postpartum urinary retention: a prospective case-control study. AB - INTRODUCTION AND HYPOTHESIS: Covert (asymptomatic) postpartum urinary retention (PUR) is defined as post-void residual volume (PVRV) >=150 mL. Although often supposed to be a common and harmless phenomenon, no data are available on the potential long-term micturition problems of increased PVRV after vaginal delivery. METHODS: After the first spontaneous void post-vaginal delivery, PVRV was measured using a portable scanning device. Micturition symptoms were compared using validated questionnaires between women with PVRV < 150 mL and those with PVRV >=150 mL until 1 year after delivery. Women with PVRV >= 150 mL were followed until complete bladder emptying was achieved. RESULTS: Data of 105 patients with PVRV < 150 mL and 119 with PVRV >= 150 mL were available for analysis. 75% of all patients included had PVRV >= 250 mL. More primiparous patients had PVRV >= 150 mL (p < 0.02). 92% of women with PVRV >= 150 mL after delivery were able to adequately empty their bladder within 4 days. One year after delivery, no statistically significant differences were found. CONCLUSIONS: Covert PUR according to the definition of PVRV >= 150 mL, is a common and transient phenomenon that does not result in more lower urinary tract symptoms 1 year after delivery. Although the current definition is not useful in identifying postpartum women with a pathological condition, we suggest that the definition of covert PUR should be change to: "PVRV>=500 mL after the first spontaneous void after (vaginal) delivery." This cut-off value is the value at which some women do need more time to normalise emptying of the bladder. The exact clinical implications of covert PUR need to be further studied in this subcategory of women. PMID- 28871390 TI - Exploring sets of molecules from patents and relationships to other active compounds in chemical space networks. AB - Patents from medicinal chemistry represent a rich source of novel compounds and activity data that appear only infrequently in the scientific literature. Moreover, patent information provides a primary focal point for drug discovery. Accordingly, text mining and image extraction approaches have become hot topics in patent analysis and repositories of patent data are being established. In this work, we have generated network representations using alternative similarity measures to systematically compare molecules from patents with other bioactive compounds, visualize similarity relationships, explore the chemical neighbourhood of patent molecules, and identify closely related compounds with different activities. The design of network representations that combine patent molecules and other bioactive compounds and view patent information in the context of current bioactive chemical space aids in the analysis of patents and further extends the use of molecular networks to explore structure-activity relationships. PMID- 28871389 TI - Boron neutron capture therapy (BNCT) translational studies in the hamster cheek pouch model of oral cancer at the new "B2" configuration of the RA-6 nuclear reactor. AB - Boron neutron capture therapy (BNCT) is based on selective accumulation of B-10 carriers in tumor followed by neutron irradiation. We demonstrated, in 2001, the therapeutic effect of BNCT mediated by BPA (boronophenylalanine) in the hamster cheek pouch model of oral cancer, at the RA-6 nuclear reactor. Between 2007 and 2011, the RA-6 was upgraded, leading to an improvement in the performance of the BNCT beam (B2 configuration). Our aim was to evaluate BPA-BNCT radiotoxicity and tumor control in the hamster cheek pouch model of oral cancer at the new "B2" configuration. We also evaluated, for the first time in the oral cancer model, the radioprotective effect of histamine against mucositis in precancerous tissue as the dose-limiting tissue. Cancerized pouches were exposed to: BPA-BNCT; BPA BNCT + histamine; BO: Beam only; BO + histamine; CONTROL: cancerized, no treatment. BNCT induced severe mucositis, with an incidence that was slightly higher than in "B1" experiments (86 vs 67%, respectively). BO induced low/moderate mucositis. Histamine slightly reduced the incidence of severe mucositis induced by BPA-BNCT (75 vs 86%) and prevented mucositis altogether in BO animals. Tumor overall response was significantly higher in BNCT (94-96%) than in control (16%) and BO groups (9-38%), and did not differ significantly from the "B1" results (91%). Histamine did not compromise BNCT therapeutic efficacy. BNCT radiotoxicity and therapeutic effect at the B1 and B2 configurations of RA-6 were consistent. Histamine slightly reduced mucositis in precancerous tissue even in this overly aggressive oral cancer model, without compromising tumor control. PMID- 28871391 TI - Hemofiltration induces generation of leukocyte-derived CD31+/CD41- microvesicles in sepsis. AB - BACKGROUND: Microvesicles (MV) are extracellular vesicles known to be associated with cellular activation and inflammation. Hemofiltration is an effective blood purification technique for patients with renal failure and possibly also eliminates inflammatory mediators in the setting of sepsis. On the other hand, proinflammatory stimuli are induced by blood contacting the artificial membrane during extracorporeal blood purification. In chronic dialysis patients a systemic increase in MV has been described. The aim of the study was to investigate whether hemofilter passage of blood in continuous veno-venous hemofiltration (CVVH) alters MV composition and levels in critically ill patients with sepsis. METHODS: Pre- and postfilter bloods as well as ultrafiltrate samples from intensive care unit patients with severe sepsis were obtained during CVVH with regional citrate anticoagulation. MV subtypes in blood were analyzed by high sensitivity flow cytometry. Additionally, tissue factor (TF) levels and MV associated TF activities as well as MV activities were quantified. All parameters were corrected for hemoconcentration applied during CVVH. RESULTS: Twelve patients were analyzed. A significant increase in presumably mostly leukocyte derived CD31+/CD41- MV (1.32 (1.09-1.93)-fold [median (25th-75th quartiles)], p = 0.021) was observed post- to prefilter, whereas platelet-derived MV as well as AnnexinV-binding MV were unaltered. Increments of AnnexinV+, CD42b+ and CD31+/CD41- MV post- to prefilter correlated with filtration fraction (FF) (all p < 0.05). Significant reductions in MV activity [0.72 (0.62-0.84)-fold, p = 0.002] and TF level [0.95 (0.87-0.99)-fold, p = 0.0093] were detected postfilter compared to prefilter. No MV activity was measurable in ultrafiltrate samples. CONCLUSIONS: Despite clearing a fraction of small PS-exposing MV CVVH does not eliminate larger MV. Concurrently, CVVH induces the release of CD31+/CD4- MV that indicate leukocyte activation during hemofilter passage in septic patients. Increments of several MV subtypes within the hemofilter correlate with FF, which supports common recommendations to keep FF low. A fraction of TF is being cleared by CVVH via ultrafiltration. PMID- 28871392 TI - Response to Comment by Ting et al.: The importance of a full-thickness vaginal wall dissection. PMID- 28871393 TI - T1 vs. T2 weighted magnetic resonance imaging to assess total kidney volume in patients with autosomal dominant polycystic kidney disease. AB - PURPOSE: In ADPKD patients total kidney volume (TKV) measurement using MRI is performed to predict rate of disease progression. Historically T1 weighted images (T1) were used, but the methodology of T2 weighted imaging (T2) has evolved. We compared the performance of both sequences. METHODS: 40 ADPKD patients underwent an abdominal MRI at baseline and follow-up. TKV was measured by manual tracing with Analyze Direct 11.0 software. Three readers established intra- and interreader coefficients of variation (CV). T1 and T2 measured kidney volumes and growth rates were compared with ICC and Bland-Altman analyses. RESULTS: Participants were 49.7 +/- 7.0 years of age, 55.0% female, with estimated GFR of 50.1 +/- 11.5 mL/min/1.73 m2. CVs were low and comparable for T2 and T1 (intrareader: 0.83% [0.48-1.79] vs. 1.15% [0.34-1.77], P = 0.9, interreader: 2.18% [1.59-2.61] vs. 1.69% [1.07-3.87], P = 0.9). TKV was clinically similar, but statistically significantly different between T2 and T1: 1867 [1172-2721] vs. 1932 [1180-2551] mL, respectively (P = 0.006), with a bias of only 0.8% and high agreement (ICC 0.997). Percentage kidney growth during 2.2 +/- 0.3 years was similar for T2 and T1 (9.3 +/- 10.6% vs. 7.8 +/- 9.9%, P = 0.1, respectively), with a bias of 1.5% and high agreement (ICC 0.843). T2 was more often of sufficient quality for volume measurement (86.7% vs. 71.1%, P < 0.001). CONCLUSIONS: In patients with ADPKD, measurement of kidney volume and growth rate performs similarly when using T2 compared to T1 weighted images, although T2 performs better on secondary outcome parameters; they are more often of sufficient quality for volume measurement and result in slightly lower intra- and interreader variability. PMID- 28871394 TI - The effects of hydraulic retention time (HRT) on chromium(VI) reduction using autotrophic cultivation of Chlorella vulgaris. AB - Chromium is an acutely toxic heavy metal that is known to be a carcinogen. Of the two predominant forms of chromium, Cr(III) and Cr(VI), Cr(III) has only about one thousandth the toxicity of Cr(VI). Using microalgal biomass is one way to remove Cr(VI) from the environment. Four days of hydraulic retention time (HRT) was required to completely reduce 10 mg/L of Cr(VI) in the influent. Microalgal biomass is conventionally regarded as an adsorbent in most Cr(VI) reduction studies. However, this study found that Chlorella vulgaris had the potential to convert Cr(VI) to Cr(III) through the enzymatic route of chromium reductase although the measured chromium reductase activity of C. vulgaris was less than that reported values obtained in bacteria. X-ray absorption near-edge spectroscopy (XANES) analysis further showed the absorption edge of Cr(III) in Cr(VI)-treated C. vulgaris, supporting the assumption of Cr(VI) potentially being converted to less-toxic Cr(III). PMID- 28871396 TI - Retrospective comparison of direct in-bore magnetic resonance imaging (MRI) guided biopsy and fusion-guided biopsy in patients with MRI lesions which are likely or highly likely to be clinically significant prostate cancer. AB - PURPOSE: To compare clinically significant prostate cancer (csPCa) detection rates between magnetic resonance imaging (MRI)-transrectal ultrasound (TRUS) fusion-guided prostate biopsy (FGB) and direct in-bore MRI-guided biopsy (MRGB). METHODS: We performed a comparison of csPCa detection rates between FGB and MRGB. Included patients had (1) at least one prior negative TRUS biopsy; (2) a Prostate Imaging Reporting and Data System (PI-RADS) 4 or 5 lesion and (3) a lesion size of >=8 mm measured in at least one direction. We considered a Gleason score >=7 being csPCa. Descriptive statistics with 95% confidence intervals (CI) were used to determine any differences. RESULTS: We included 51 patients with FGB (59 PI RADS 4 and 41% PI-RADS 5) and 227 patients with MRGB (34 PI-RADS 4 and 66% PI RADS 5). Included patients had a median age of 69 years (IQR, 65-72) and a median PSA level of 11.0 ng/ml (IQR, 7.4-15.1) and a median age of 67 years (IQR, 61 70), the median PSA 12.8 ng/ml (IQR, 9.1-19.0) within the FGB and the MRGB group, respectively. Detection rates of csPCA did not differ significantly between FGB and MRGB, 49 vs. 61%, respectively. CONCLUSION: We did not detect significant differences between FGB and MRGB in the detection of csPCa. The differences in detection ratios between both biopsy techniques are narrow with an increasing lesion size. This study warrants further studies to optimize selection of best biopsy modality. PMID- 28871395 TI - Interactome analysis of transcriptional coactivator multiprotein bridging factor 1 unveils a yeast AP-1-like transcription factor involved in oxidation tolerance of mycopathogen Beauveria bassiana. AB - Oxidation tolerance is an important determinant to predict the virulence and biocontrol potential of Beauveria bassiana, a well-known entomopathogenic fungus. As a transcriptional coactivator, multiprotein bridging factor 1 mediates the activity of transcription factor in diverse physiological processes, and its homolog in B. bassiana (BbMBF1) contributes to fungal oxidation tolerance. In this study, the BbMBF1-interactomes under oxidative stress and normal growth condition were deciphered by mass spectrometry integrated with the immunoprecipitation. BbMBF1p factor has a broad interaction with proteins that are involved in various cellular processes, and this interaction is dynamically regulated by oxidative stress. Importantly, a B. bassiana homolog of yeast AP-1 like transcription factor (BbAP-1) was specifically associated with the BbMBF1 interactome under oxidation and significantly contributed to fungal oxidation tolerance. In addition, qPCR analysis revealed that several antioxidant genes are jointly controlled by BbAP-1 and BbMBF1. Conclusively, it is proposed that BbMBF1p protein mediates BbAP-1p factor to transcribe the downstream antioxidant genes in B. bassiana under oxidative stress. This study demonstrates for the first time a proteomic view of the MBF1-interactome in fungi, and presents an initial framework to probe the transcriptional mechanism involved in fungal response to oxidation, which will provide a new strategy to improve the biocontrol efficacy of B. bassiana. PMID- 28871397 TI - Vertical distribution of archaeal communities associated with anaerobic degradation of pentabromodiphenyl ether (BDE-99) in river-based groundwater recharge with reclaimed water. AB - When groundwater is recharged with reclaimed water, the presence of trace amounts of biorefractory pentabromodiphenyl ether (PBDE, specifically BDE-99) might cause potential groundwater pollution. A laboratory-scale column was designed to investigate the distribution of the community of archaea in this scenario and the associated anaerobic degradation of BDE-99. The concentration of BDE-99 decreased significantly as soil depth increased, and fluorescence in situ hybridization (FISH) analysis suggested that archaea exerted significant effects on the biodegradation of PBDE. Through 454 pyrosequencing of 16s rRNA genes, we found that the distribution and structure of the archaeal community associated with anaerobic degradation of BDE-99 in the river-based aquifer media changed significantly between different soil depths. The primary debrominated metabolites varied with changes in the vertically distributed archaeal community. The archaea in the surface layer were dominated by Methanomethylovorans, and the middle layer was mainly composed of Nitrososphaera. Nitrosopumilus and Nitrososphaera were equally abundant in the bottom layer. In addition, Methanomethylovorans abundance depended on the depth of soil, and the relative abundance of Nitrosopumilus increased with increasing depth, which was associated with the oxidation reduction potential and the content of intermediate metabolites. We propose that Nitrososphaera and Nitrosopumilus might be the key archaeal taxa mediating the biodegradation of BDE-99. PMID- 28871398 TI - Effect of Pulsed Electric Fields (PEF) on Accumulation of Magnesium in Lactobacillus rhamnosus B 442 Cells. AB - The aim of this study was to determine the effect of pulsed electric fields (PEF) on accumulation of magnesium ions in Lactobacillus rhamnosus B 442 cells. Under optimized conditions, this is, on 15 min exposure of the 20 h grown culture to PEF of the 2.0 kV/cm and 20 us pulse width at concentration 400 MUg Mg2+/mL medium, accumulation of magnesium in the biomass reached maximum 4.28 mg/g d.m. Optimization of PEF parameters caused an increase of magnesium concentration in the cells by 220% in comparison to the control not treated with PEF. Bacterial cell biomass enriched with Mg2+ may be an alternative for pharmacological supplementation applied in deficiency of this cation. PMID- 28871399 TI - Understanding therapeutic emergencies in acute hemolysis. PMID- 28871400 TI - Phosphorus and nitrogen resorption from different chemical fractions in senescing leaves of tropical tree species on Mount Kinabalu, Borneo. AB - Nutrient resorption, a process by which plants degrade organic compounds and resorb their nutrients from senescing tissues, is a crucial plant function to increase growth and fitness in nutrient-poor environments. Tropical trees on phosphorus (P)-poor soils are particularly known to have high P-resorption efficiency (PRE, the percentage of P resorbed from senescing leaves before abscission per total P in green leaves). However, the biochemical mechanisms underlying this greater PRE remain unclear. In this study, we determined the P concentration in easily soluble, nucleic acid, lipid and residual fractions for green and senescent leaves of 22 tree species from three sites, which differed in P availability, on the lower flanks of Mt. Kinabalu, Borneo. PRE varied from 24 to 93% and was higher in species from the P-poor site. P-resorption rate was greatest from the lipid fraction, the nucleic acid fraction, and lowest in the easily soluble fraction and the residual fraction when all the species were pooled. For species with higher PRE, P-resorption rate of the residual fraction was relatively high and was comparable in magnitude to that of the other labile fractions. This suggests that tree species inhabiting P-poor environments increased PRE by improving the degradation of recalcitrant compounds. This study suggests that plants selectively degrade organic compounds depending on environmental conditions, which is a key mechanism underlying the variation of PRE. PMID- 28871401 TI - A febrile eruption after delivery. PMID- 28871402 TI - A smartphone colorimetric reader integrated with an ambient light sensor and a 3D printed attachment for on-site detection of zearalenone. AB - Smartphone biosensors could be cost-effective, portable instruments to be used for the readout of liquid colorimetric assays. However, current reported smartphone colorimetric readers have relied on photos of liquid assays captured using a camera, and then analyzed using software programs. This approach results in a relatively low accuracy and low generality. In this work, we reported a novel smartphone colorimetric reader that has been integrated with an ambient light sensor and a 3D printed attachment for the readout of liquid colorimetric assays. The portable and low-cost ($0.15) reader utilized a simplified electronic and light path design. Furthermore, our reported smartphone colorimetric reader can be compatible with different smartphones. As a proof of principle, the utility of this device was demonstrated using it in conjunction with an enzyme linked immunosorbent assay to detect zearalenone. Results were consistent with those obtained using a professional microplate reader. The developed smartphone colorimetric reader was capable of providing scalable, cost-effective, and accurate results for liquid colorimetric assays that related to clinical diagnoses, environment pollution, and food testing. Graphical abstract A novel smartphone colorimetric reader that has been integrated with an ambient light sensor and a 3D printed attachment for the readout of liquid colorimetric assays. PMID- 28871403 TI - Comment to: Rectus abdominis atrophy after ventral abdominal incisions: midline versus chevron by Vigneswaran et al. PMID- 28871404 TI - Assessment of bioavailable B vitamin content in food using in vitro digestibility assay and LC-MS SIDA. AB - Standardized analytical methods, where each B vitamin is extracted from a given sample individually using separate procedures, typically ensure that the extraction conditions provide the maximum recovery of each vitamin. However, in the human gastrointestinal tract (GIT), the extraction conditions are the same for all vitamins. Here, we present an analytically feasible extraction protocol that simulates conditions in the GIT and provides a measure of the content of bioavailable vitamins using LC-MS stable isotope dilution assay. The results show that the activities of both human gastric and duodenal juices were insufficient to liberate absorbable vitamers (AV) from pure cofactors. The use of an intestinal brush border membrane (IBBM) fraction derived from the mucosal tissue of porcine small intestine ensured at least 70% AV recovery. The rate of AV liberation, however, was strongly dependent on the cofactor, e.g., in the case of NADH, it was magnitudes higher than in the case of thiamine diphosphate. For some vitamins in some food matrices, the use of the IBBM fraction assay resulted in lower values for the content of AV than conventional vitamin determination methods. Conventional methods likely overestimate the actual bioavailability of some vitamins in these cases. Graphical abstract Assessment of bioavailable B vitamin content in food. PMID- 28871405 TI - [Survival after radical completion dissection or observation for sentinel node metastasis in melanoma]. PMID- 28871406 TI - Heavy Metal Contamination in Fish (Callinectis amnicola) From an Estuarine Creek in the Niger Delta, Nigeria and Health Risk Evaluation. AB - Heavy metal bioconcentration in crabs from an estuarine creek in the Niger Delta was examined using atomic absorption spectrophotometry. Health risk via human exposure to metal toxicity was evaluated. Mean metal levels (ug/g) were Cr 2.32 +/- 0.71, Ni 2.76 +/- 0.48, Cu 12.94 +/- 3.53, Pb 5.67 +/- 1.03, Ag 1.83 +/- 0.71 and Cd 0.73 +/- 0.14 with significant difference (p < 0.001) between periods. Ni, Pb and Cd had values above FAO/WHO recommended limits. Estimated daily intake values were below the reference oral doses and the target hazard quotient was <1 for each metal examined while hazard index for all metals was also <1. The target carcinogenic risk value for Ni was 3.4 * 10-3. Based on the evaluations, the study concluded that consumers of crabs from the study area had minimal/moderate metal toxicity exposures of no significant health concern but recommended continuous monitoring to detect anomalies. PMID- 28871408 TI - Evaluation of the relationship between the topographical anatomy in the axillary region of the brachial plexus and the body mass index. AB - To investigate the topographic anatomy of the median, musculocutaneous, radial and ulnar nerves with respect to the axillary artery and to seek whether these configurations are associated with baseline descriptive data including age, gender, and body-mass index. This cross-sectional trial was carried out on 199 patients (85 women, 114 men; average age: 46.78 +/- 15.45 years) in the department of anaesthesiology and reanimation of a tertiary care center. Topographic anatomy of the median, musculocutaneous, radial and ulnar nerves was assessed with ultrasonography. Localization of these nerves with respect to the axillary artery was marked on the map demonstrating 16 zones around the axillary artery. Frequencies of localizations of every nerve in these zones were recorded, and the correlation of these locations with descriptive data including age, gender and BMI was investigated. There was no difference between women and men for the distribution of the median (p = 0.74), ulnar (p = 0.35) and radial (p = 0.64) nerves. However, the musculocutaneous nerve was more commonly located in Zone A13 in men compared to women (p = 0.02). The localization of the median (p = 0.85), ulnar (p = 0.27) and radial (p = 0.88) nerves did not differ remarkably between patients with BMI < 25 kg/m2 and patients with BMI >= 25 kg/m2. Notably, the musculocutaneous nerve was more often determined in Zone A10 in cases with BMI >= 25 kg/m2 (p = 0.001). Our results imply that the alignment of the musculocutaneous nerve may vary in men and overweight people. This fact must be considered by the anaesthetist before planning the axillary block of brachial plexus. All these informations may enlighten the planning stages of the brachial plexus blockade. PMID- 28871407 TI - In vitro antimicrobial susceptibility testing methods: agar dilution to 3D tissue engineered models. AB - In the field of orthopaedic surgery, bacterial invasion of implants and the resulting periprosthetic infections are a common and unresolved problem. Antimicrobial susceptibility testing methods help to define the optimal treatment and identify antimicrobial resistance. This review discusses proven gold-standard techniques and recently developed models for antimicrobial susceptibility testing, while also providing a future outlook. Conventional, gold-standard methods, such as broth microdilution, are still widely applied in clinical settings. Although recently developed methods based on microfluidics and microdroplets have shown advantages over conventional methods in terms of testing speed, safety and the potential to provide a deeper insight into resistance mechanisms, extensive validation is required to translate this research to clinical practice. Recent optical and mechanical methods are complex and expensive and, therefore, not immediately clinically applicable. Novel osteoblast infection and tissue models best resemble infections in vivo. However, the integration of biomaterials into these models remains challenging and they require a long tissue culture, making their rapid clinical implementation unlikely. A method applicable for both clinical and research environments is difficult to realise. With a continuous increase in antimicrobial resistance, there is an urgent need for methods that analyse recurrent infections to identify the optimal treatment approaches. Graphical abstract Timeline of published and partly applied antimicrobial susceptibility testing methods, listed according to their underlying mechanism, complexity and application in research or clinics. PMID- 28871409 TI - Retrospective analysis of treatments with recombinant FSH and recombinant LH versus human menopausal gonadotropin in women with reduced ovarian reserve. AB - PURPOSES: The aim of this study is to determine whether a clinical advantage is gained with use of LH in combination with FSH or as a component of human menopausal gonadotropin (hMG) to achieve optimal ovarian stimulation. METHODS: In this study, we compared retrospectively two regimens, r-FSH/r-LH and hMG, for the treatment of women with reduced ovarian reserve, identified as subjects with antral follicle count (AFC) < 11 and AMH <= 1.1 ng/ml. RESULTS: Overall, the clinical pregnancy per started cycle was higher in the r-FSH/r-LH group (12.5 vs. 8.1%, P < 0.02), while implantation (11.1 vs. 9.5%) and miscarriage rates (29.9 vs. 35.9%) were comparable. Data were further analysed performing separate comparisons in subpopulations with different ranges of AFC, i.e. < 4, 4-6 and 7 10. Major differences between the two regimens were observed in women with AFC < 4. In this subpopulation, not only was the clinical pregnancies per started cycle higher in the r-FSH/r-LH group (10.2 vs. 1.5%, P < 0.01), but also implantation was significantly higher (13.0 vs. 2.8%, P < 0.02). CONCLUSIONS: A r-FSH/r-LH regimen appears to be beneficial for the treatment of women with extremely poor ovarian reserve. It should be considered however that, being retrospective, this study is affected by obvious limitations, such as post-treatment patient selection criteria and absence of randomisation. PMID- 28871410 TI - Early results of a safety and feasibility clinical trial of a novel single-port flexible robot for transoral robotic surgery. AB - The aim of this study was to describe the early results of a phase 1 safety and feasibility clinical trial of the first clinical use of a novel robot for transoral robotic surgery (TORS)-the da Vinci SP (Intuitive Surgical Inc., Sunnyvale, CA, USA). Study design of this study is prospective clinical trial. The methods used in this study are prospective innovation, development, exploration, assessment, and long-term study phase 1 clinical trial. Early results of six patients underwent TORS with the da Vinci SP (Intuitive Surgical Inc., Sunnyvale, CA, USA) demonstrate access the nasopharynx, oropharynx, larynx, and hypopharynx. There were no conversions of the robotic surgical system. There were no serious adverse events or adverse events related to the use of the robot at 30-day follow-up for all six patients. The early results of this safety and feasibility trial of the da Vinci SP (Intuitive Surgical Inc., Sunnyvale, CA, USA) clearly demonstrate that the device is safe and that it is feasible in performing TORS to access the nasopharynx, oropharynx, larynx, and hypopharynx. PMID- 28871411 TI - Histodifferentiation of oil palm somatic embryo development at low auxin concentration. AB - Large-scale propagation of oil palm (Elaeis guineensis, Jacq.) is difficult due to its single apical meristem. Thus, obtaining plants is mainly through seed germination, and a long growing period is required before oil production is possible. An alternative to large-scale seedling production is indirect somatic embryogenesis. The aim of this study was to analyze the somatic embryogenesis process in oil palm (E. guineensis Jacq.) with amino acids and low concentrations of auxins. The Tenera hybrid was analyzed by cytochemical and ultrastructural methods and was used to regenerate oil palm plants. First, calli were induced in MS culture media supplemented with 2,4-D and picloram. Two types of calli were obtained, characterized by beige or translucent color. Beige calli had embryogenic characteristics, such as large nuclei with prominent nucleoli, and they were multiplied for 8 months in MM culture (half strength MS, 1 mg L-1 2,4 D, 2 mg L-1 2iP, 1 mg L-1 IBA, 250 mg L-1 citric acid, 10 mg L-1 cysteine, 100 mg L-1 inositol, 1 mg L-1 thiamine, 1 mg L-1 pyridoxine, 1 mg L-1 nicotinic acid, 1 mg L-1 glycine, 200 mg L-1 malt extract, and 100 mg L-1 casein hydrolysate). After multiplication, the MCB culture medium (half strength MS, supplemented with 0.25 mg L-1 NAA, 2 mg L-1 BAP, MM vitamins and 200 mg L-1 malt extract, and 100 mg L-1 casein hydrolysate) was the most efficient for embryo formation, showing meristematic centers with totipotent cells in histochemical analyses. The somatic embryos were developed and germinated in MG medium (half strength MS, 0.45 mg L-1 IAA, 0.25 mg L-1 BAP, and MM vitamins), transplanted into polyethylene tubes containing pine bark substrates, and acclimatized in a greenhouse, achieving a 97% survival rate. The use of picloram for callus induction and somatic embryogenesis is advantageous and multiplication in MM medium is an important step for increasing cell mass. The calli with light beige color and nodular structures have meristematic cells with dense cytoplasm and totipotential features that later give rise to protoderm, procambium, and ground meristem during the globular, cordiform, and torpedo embryogenesis phases. In MCB medium, the concentration of vitamins and amino acids are crucial for somatic embryogenesis. PMID- 28871413 TI - [Regionalization of federal health reporting using the example of diabetes surveillance : Aims and results of the discussion between the Robert Koch Institute and the federal states]. AB - Insufficiently treated diabetes mellitus can lead to severe comorbidities. National and international analyses show a continuous increase in diabetes prevalence over the last decades. Currently, an indicator-based national diabetes surveillance system is implemented at the Robert Koch Institute (RKI) to monitor and report on diabetes development on the basis of available primary and secondary data. The aim of the meeting was to go into deeper discussions and to integrate expectations and expertise of the federal states into the design of the national surveillance system. A close collaboration between the RKI and the federal states is intended. PMID- 28871412 TI - RAGE-NF-kappaB-PPARgamma Signaling is Involved in AGEs-Induced Upregulation of Amyloid-beta Influx Transport in an In Vitro BBB Model. AB - The receptor for advanced glycation end products (RAGE) at the blood-brain barrier (BBB) is critical for regulation of amyloid-beta (Abeta) homeostasis in the diabetic brain. In this study, we used an in vitro BBB model consisting of mouse brain capillary endothelial cells (MBCECs) to investigate whether advanced glycation end products (AGEs) increase Abeta influx transport across the BBB and the underlying mechanisms. We found that AGEs induced Abeta influx transport across the BBB in concentration- and time-dependent manner, accompanied by increased RAGE expression and nuclear factor-kappa B p65 (NF-kappaB p65), and decreased nuclear peroxisome proliferator-activated receptor gamma (PPARgamma). Blockade of RAGE with its antibody and inhibition of NF-kappaB signaling with PDTC as well as activation of PPARgamma with rosiglitazone significantly decreased Abeta transport across the BBB from the periphery to the brain. These treatments also pronouncedly suppressed AGEs-induced increases in RAGE expression and nuclear NF-kappaB p65 and reversed the decrease in nuclear PPARgamma. These results suggest that RAGE-NF-kappaB-PPARgamma signaling is involved in regulation of AGEs-induced influx transport of Abeta across the BBB and targeting the signaling pathway could serve as a novel strategy to modify such Abeta transport. PMID- 28871414 TI - Postoperative urinary retention after inguinal hernia repair: a single institution experience. AB - PURPOSE: Inguinal hernia repair is a common general surgery procedure with low morbidity. However, postoperative urinary retention (PUR) occurs in up to 22% of patients, resulting in further extraneous treatments.This single institution series investigates whether patient comorbidities, surgical approaches, and anesthesia methods are associated with developing PUR after inguinal hernia repairs. METHODS: This is a single institution retrospective review of inguinal hernia from 2012 to 2015. PUR was defined as patients without a postoperative urinary catheter who subsequently required bladder decompression due to an inability to void. Univariate and multivariate logistic regressions were performed to quantify the associations between patient, surgical, and anesthetic factors with PUR. Stratification analysis was conducted at age of 50 years. RESULTS: 445 patients were included (42.9% laparoscopic and 57.1% open). Overall rate of PUR was 11.2% (12% laparoscopic, 10.6% open, and p = 0.64). In univariate analysis, PUR was significantly associated with patient age >50 and history of benign prostatic hyperplasia (BPH). Risk stratification for age >50 revealed in this cohort a 2.49 times increased PUR risk with lack of intraoperative bladder decompression (p = 0.013). CONCLUSIONS: At our institution, we found that patient age, history of BPH, and bilateral repair were associated with PUR after inguinal hernia repair. No association was found with PUR and laparoscopic vs open approach. Older males may be at higher risk without intraoperative bladder decompression, and therefore, catheter placement should be considered in this population, regardless of surgical approach. PMID- 28871415 TI - Response to Improving Adherence to Treatment and Reducing Economic Costs of Hypertension: The Role of Olmesartan-Based Treatment. PMID- 28871416 TI - Robotic ventral mesh rectopexy for rectal prolapse: a single-institution experience. AB - BACKGROUND: Robotic ventral mesh rectopexy (RVMR) is an appealing approach for the treatment of rectal prolapse and other conditions. The aim of this study was to evaluate the outcomes of RVMR for rectal prolapse. METHODS: We performed a retrospective chart review for patients who underwent RVMR for rectal prolapse at our institution between July 2012 and May 2016. Any patient who underwent RVMR during this time frame was included in our analysis. Any cases involving colorectal resection or other rectopexy techniques were excluded. RESULTS: Of the 24 patients who underwent RVMR, 95.8% of patients were female. Median age was 67.5 years old (IQR 51.5-73.3), and 79.2% of patients were American Society of Anesthesiologists class III or IV. Median operative time was 191 min (IQR 164.3 242.5), and median length of stay was 3 days (IQR 2-3). There were no conversions, RVMR-related complications or mortality. Patients were followed for a median of 3.8 (IQR 1.2-15.9) months. Full-thickness recurrence occurred in 3 (12.4%) patients. Rates of fecal incontinence improved after surgery (62.5 vs. 41.5%, respectively) as did constipation (45.8 vs. 33.3%, respectively). No patients reported worsening symptoms postoperatively. Only one (4.2%) patient reported de novo constipation postoperatively. CONCLUSIONS: RVMR is a feasible, safe and effective option for the treatment of rectal prolapse, with low short term morbidity and mortality. Multicenter and long-term studies are needed to better assess the benefits of this procedure. PMID- 28871417 TI - Review of enhanced recovery programs in benign gynecologic surgery. AB - INTRODUCTION AND HYPOTHESIS: Enhanced recovery programs (ERPs) are evidence-based protocols designed to improve functional rehabilitation after surgery. ERPs have gained widespread acceptance in many surgical disciplines, and their use leads to significant improvements in patient outcomes while reducing hospital length of stay (LOS). There remains a paucity of data on the use of ERPs in benign gynecologic surgery. The purpose of this review was to evaluate current literature on the use of ERP concepts in benign gynecologic surgery. METHODS: A systematic search of PubMed, CINAHL, Web of Science, and the Cochrane databases was conducted, cross-referencing search terms related to gynecologic surgery and ERP concepts. The search was limited to publications available in English. Studies published prior to 2000, and those involving gynecologic oncology, nonadult patients, and outpatient surgery were excluded. RESULTS: Nine studies were included in the analysis. Due to heterogeneity of the included studies, no statistical pooling was possible and comparison between studies was limited to their respective themes. Primary study outcomes included LOS, postoperative nausea and vomiting (PONV), pain management, patient satisfaction, and hospital costs. Five studies investigated ERPs, two evaluated measures to improve PONV, and four focused on unique aspects of pain management. Across the studies, ERPs that focused on the patients' basic symptoms and recovery were found to have equal, if not better, outcomes than standard practice. CONCLUSIONS: This integrative review supports the implementation of ERPs in benign gynecologic surgery. The results showed that the use of ERPs decreased LOS, improved pain scores, and reduced hospital costs, without increasing perioperative complications. We suggest additional randomized controlled trials of ERP concepts in benign gynecologic surgery to support their more widespread use and application. PMID- 28871418 TI - Time spent with impaired autoregulation is linked with outcome in severe infant/paediatric traumatic brain injury. AB - BACKGROUND: It could be shown in traumatic brain injury (TBI) in adults that the functional status of cerebrovascular autoregulation (AR), determined by the pressure reactivity index (PRx), correlates to and even predicts outcome. We investigated PRx, cerebral perfusion pressure (CPP) and intracranial pressure (ICP) and their correlation to outcome in severe infant and paediatric TBI. METHODS: Seventeen patients (range, 1 day to 14 years) with severe TBI (median GCS at presentation, 4) underwent long-term computerised ICP and mean arterial pressure (MAP) monitoring using dedicated software to determine CPP and PRx and optimal CPP (CPP level where PRx shows best autoregulation) continuously. Outcome was determined at discharge and at follow-up using the Glasgow Outcome Scale. RESULTS: Favourable outcome was reached in eight patients, unfavourable outcome in seven patients. Two patients died. Nine patients underwent decompressive craniectomy to control ICP during Intensive Care Unit treatment. When dichotomised to outcome, no significant difference was found for overall ICP, CPP and PRx. The time with severely impaired AR (PRx >0.2) was significantly longer for patients with unfavourable outcome (64 h vs 6 h, p = 0.001). Continuously impaired AR of >=24 h and age <1 year was associated to unfavourable outcome. Children with favourable outcome spent the entire monitoring time at or above the optimal CPP. CONCLUSIONS: Integrity of AR has a similar role for outcome after TBI in the paediatric population as in adults. The amount of time spent with deranged AR seems to be associated with outcome; a factor especially critical for infant patients. The results of this preliminary study need to be validated in the future. PMID- 28871419 TI - Thalamic and basal ganglia regions are involved in attentional processing of behaviorally significant events: evidence from simultaneous depth and scalp EEG. AB - Extensive descriptions exist on cortical responses to change in the acoustic environment. However, the involvement of subcortical regions is not well understood. Here we present simultaneous recordings of cortical and subcortical event-related potentials (ERPs) to different pure tones in patients undergoing surgery for deep brain stimulation (DBS). These patients had externalized electrodes in the subthalamic nucleus (STN), the ventrolateral posterior thalamus (VLp) or the globus pallidus internus (GPi). Subcortical and cortical ERPs were analyzed upon presentation of one frequent non-target stimulus and two infrequent stimuli, either being a target or a distractor stimulus. The results revealed that amplitudes of scalp-recorded P3 and subcortical late attention-modulated responses (AMR) were largest upon presentation of target stimuli compared with distractor stimuli. This suggests that thalamic and basal ganglia regions are sensitive to behaviorally relevant auditory events. Comparison of the subcortical structures showed that responses in VLp have shorter latency than in GPi and STN. Further, the subcortical responses in VLp and STN emerged significantly prior to the cortical P3 response. Our findings point to higher-order cognitive functions already at a subcortical level. Auditory events are categorized as behaviorally relevant in subcortical loops involving basal ganglia and thalamic regions. This label is then distributed to cortical regions by ascending projections. PMID- 28871420 TI - Weber's law in 2D and 3D grasping. AB - Visually guided grasping movements directed to real, 3D objects are characterized by a distinguishable trajectory pattern that evades the influence of Weber's law, a basic principle of perception. Conversely, grasping trajectories directed to 2D line drawings of objects adhere to Weber's law. It can be argued, therefore, that during 2D grasping, the visuomotor system fails at operating in analytic mode and is intruded by irrelevant perceptual information. Here, we explored the visual and tactile cues that enable such analytic processing during grasping. In Experiment 1, we compared grasping directed to 3D objects with grasping directed to 2D object photos. Grasping directed to photos adhered to Weber's law, suggesting that richness in visual detail does not contribute to analytic processing. In Experiment 2, we tested whether the visual presentation of 3D objects could support analytic processing even when only partial object-specific tactile information is provided. Surprisingly, grasping could be performed in an analytic fashion, violating Weber's law. In Experiment 3, participants were denied of any haptic feedback at the end of the movement and grasping trajectories again showed adherence to Weber's law. Taken together, the findings suggest that the presentation of real objects combined with indirect haptic information at the end of the movement is sufficient to allow analytic processing during grasp. PMID- 28871421 TI - Biosimilar uptake by British local formularies: a cross sectional study. AB - Background Biological medicines are starting to lose their patent protection, so similar, inexact copies (biosimilars) are being developed and licensed. The high acquisition costs of biologics for healthcare providers could be reduced by switching to biosimilars, thus alleviating budgetary pressures and increasing patient access. Therefore, the acceptance of biosimilars by prescribers in Great Britain (GB; England, Scotland, Wales) needs to be described and understood. Objective To determine uptake of the first wave of biosimilars (somatropin, epoetin, filgrastim) by local formularies (lists of preferred medicines for prescribing in local healthcare settings). Settings This study targeted local formularies in GB. Method In November 2014, local formularies (medicines formularies of Acute Trusts and Health Boards in GB) were screened for their approach to listing of biologics and their biosimilars as well as recommendations on usage of these pharmaceuticals. Main Outcomes Measures Listing frequencies of biosimilars. Results One hundred and forty-six British local formularies were screened. Amongst the 80% of formularies in which brand names were specified, biosimilar filgrastim was the most frequently listed when compared to the other targeted biosimilars. Biosimilars were listed in preference to reference biologic medicine in 49% of local formularies for filgrastim, 11% for somatropin and in only 6% for epoetin. Conclusion Although the market for biosimilars can act in parallel to the generic market, their uptake measured using local British formularies was less than what is expected given that the British market for medicines has a strong focus on generics. Finally, geographical variability within GB requires further investigation. PMID- 28871422 TI - The role of angiogenic markers in adverse perinatal outcomes: fresh versus frozen embryo transfers. AB - PURPOSE: We aimed to investigate the angiogenic balance in fresh compared to frozen embryo transfers, and among neonates with adverse perinatal outcomes. METHODS: This was a retrospective cohort study. All IVF cycles resulting in a singleton live birth at a university academic fertility center from January 1, 2011, to December 31, 2013, were examined. Concentrations of sFLT-1 and PlGF were measured in previously frozen serum specimens collected during early gestation at approximately 5 weeks gestation. Patients completed an electronic survey to detail perinatal outcome. RESULTS: We identified 152 singleton live births (103 fresh, 49 frozen). Demographic characteristics were similar between the two groups. Ratios of sFlt-1:PlGF were not different between fresh and frozen transfers. Neonates from fresh cycles had a mean birth weight 202 g lighter (p = 0.01) than frozen cycles, after adjusting for gestational age. Among babies born with poor perinatal outcomes, there was a difference in sFlt-1:PlGF ratios after adjusting for race. In non-Asians, infants born small for gestational age (SGA) (< 10th percentile) had significantly higher sFLT-1:PLGF ratio, median ratio (0.21 vs 0.12, p = 0.016). CONCLUSIONS: Fresh transfers were associated with lower birth weight infants compared to frozen transfers. While there was no difference in sFlt-1:PlGF ratios between fresh and frozen transfers, these ratios were significantly lower in SGA infants, suggesting an imbalance in angiogenic markers during placentation. PMID- 28871423 TI - An application study of low-dose computed tomography perfusion imaging for evaluation of the efficacy of neoadjuvant chemotherapy for advanced gastric adenocarcinoma. AB - BACKGROUND: This study used low-dose computed tomography (CT) perfusion imaging technology to evaluate the efficacy of neoadjuvant chemotherapy in patients with advanced gastric adenocarcinoma and to determine whether any of the perfusion parameters could predict tumor response to chemotherapy. METHODS: Forty patients with gastric adenocarcinoma (T3-4NxM0) received three cycles of neoadjuvant chemotherapy and low-dose spiral CT perfusion imaging prior to and after the first and third series of chemotherapy. We calculated tissue blood flow (BF) and blood volume (BV) using commercial software. One-way analysis of variance (ANOVA) was used to detect any significant variation of the tested parameters between different times of scanning. Spearman's test was used to evaluate the correlation among perfusion parameters, tumor size and pathological efficacy grade, and clinical response after chemotherapy, respectively. A receiver-operating characteristic analysis was used to determine the optimal diagnostic cutoff value for changes in perfusion parameters and tumor size. RESULTS: One-way ANOVA showed significant differences in BF and BV values between those before and after chemotherapy (p < 0.01). The BF, BV and size reduction rate after three series of chemotherapy were significantly correlated with pathological efficacy grade. BF and BV values after the first and third series of chemotherapy were also significantly correlated with clinical response (p < 0.01, respectively). The diagnostic sensitivity and specificity of the BV reduction rate were higher than those of size reduction rate. CONCLUSIONS: Low-dose CT perfusion imaging is a valuable tool that permits microcirculation evaluation and therefore can evaluate the efficacy of neoadjuvant chemotherapy in patients with advanced gastric adenocarcinoma. PMID- 28871424 TI - New species of Eimeria (Apicomplexa: Eimeriidae) from Thrichomys fosteri and Clyomys laticeps (Rodentia: Echimyidae) of the Brazilian Pantanal. AB - The echimyid rodents Thrichomys fosteri and Clyomys laticeps are among the most commonly recorded small mammals in the Pantanal wetland of Brazil. These species play important ecological roles since they are the basis of the food chain of some predators and are parasitized by some pathogens. Knowledge of the eimerians that parasitize echimyid rodents in Brazil is absent, and only one report is available for South America. We therefore investigated parasitism by coccidians in the echimyids T. fosteri and C. laticeps in the Pantanal. Using morphological and morphometric features and associated statistical analyses, we describe five new eimerian species parasitizing T. fosteri (Eimeria nhecolandensis n. sp., Eimeria jansenae n. sp., and Eimeria fosteri n. sp.) and C. laticeps (E. nhecolandensis n. sp., Eimeria corumbaensis n. sp., and Eimeria laticeps n. sp.) in different types of infection associations. We document the developmental forms in the tissues, and describe lesions in the enteric tract of some infected animals. We also discuss some approaches regarding epidemiological and ecological data. Our results demonstrate that echimyid rodents in the Brazilian Pantanal are important hosts for the maintenance of enteric coccidia. Moreover, in some circumstances, this parasitism may threaten the health of the hosts. PMID- 28871425 TI - miR-33a inhibits cell proliferation and invasion by targeting CAND1 in lung cancer. AB - BACKGROUND: Lung cancer continues to be one of the top five causes of cancer related mortality. This study aims to identify down- and upregulated miRNAs and mRNA which can be used as potential biomarkers and/or therapeutic targets for lung cancer. METHODS: Integrated analysis of differential expression profiles of miRNA and mRNA in lung cancer was performed by searching Gene Expression Omnibus datasets. Based on miRNA expression profiles, direct mRNA targets of miRNAs with experimental support were identified through miRTarBase. The levels of representative miRNAs and mRNAs were confirmed through qualitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: The miR-33a was decreased in non-small cell lung cancer (NSCLC) tissues compared with the para-carcinoma tissues, whereas its target mRNA of cullin-associated NEDD8 dissociated protein 1 (CAND1) was increased in NSCLC tissues. Further research has shown that miR-33a can inhibit lung cancer cell proliferation, cell cycle progression, and migration by targeting CAND1. Moreover, the CAND1 knockout lung cancer cells showed similar results as cells transfected with miR-33a mimic. CONCLUSIONS: These results suggested that the data mining based on online databases was an effective method in finding novel target in cancer research, and the miR-33a and CAND1 played an important role in lung cancer proliferation and cell migration. PMID- 28871426 TI - Assessment of overactive bladder symptoms among women with successful pessary placement. AB - INTRODUCTION AND HYPOTHESIS: The causal association between pelvic organ prolapse (POP) and overactive bladder (OAB) symptoms is supported by several theories. The aim of this study is to assess any changes in OAB symptoms among women with POP and OAB after successful pessary placement. METHODS: During the study period, all women with symptomatic POP stage II or greater and OAB symptoms were offered the solution of either a ring or a Gellhorn pessary. All patients were asked to complete a 3-day micturition/incontinence diary. Objective evaluation endpoints at baseline and at 6 weeks included: change in the mean number of micturitions/24 h, change in the mean volume voided per micturition/24 h, and change in the number of urinary incontinence episodes. Subjective evaluation of the urgency, frequency, and nocturia symptoms was carried out using the score change of the questions 3, 5, and 2 of the International Consultation on Incontinence Questionnaire for Evaluating Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) respectively. RESULTS: Seventy-four women were included in the study. A statistically significant decrease (-28.3%; p < 0.001) of the mean number of micturitions/24 h with a significant increase (37%; p < 0.001) in the mean voided volume per micturition/24 h was observed. The total urine volume/24 h remained unchanged. The number of urinary incontinence episodes was significantly increased 6 weeks after pessary placement (p < 0.001). De novo stress urinary incontinence (SUI) was reported by 16.7% of the initially stress continent women. CONCLUSIONS: Women with coexisting POP and OAB symptoms may experience a significant improvement in micturition frequency and in urgency and frequency symptoms after successful pessary fitting. PMID- 28871428 TI - A prospective randomized trial of transanal hemorrhoidal dearterialization with mucopexy versus ultrasonic scalpel hemorrhoidectomy for grade III hemorrhoids. AB - BACKGROUND: The aim of the present study was to compare short- and medium-term results of transanal Doppler-guided hemorrhoidal dearterialization with mucopexy (DM) versus hemorrhoidectomy using an ultrasonic scalpel (US) for third-degree hemorrhoids. METHODS: Forty-four patients were randomly assigned to undergo either DM or US. The patients were followed up at 1, 2, 3 months at our clinic, and by telephone interview when the study was completed in May 2017. The primary endpoint was postoperative pain with quality of life, length of stay, return to normal activities, and incontinence among secondary endpoints. RESULTS: Postoperative pain was less intense in the DM group than in the US group during week 1 (p < 0.05), but no difference was seen after 2 weeks. More DM patients returned to normal daily activities within 3 days (p < 0.05). There were no between-group differences in quality of life. One patient in each group developed postoperative hemorrhage requiring readmission. No differences were found between the groups in postoperative incontinence, obstructed defecation scores, or SF-36. During a median 33-month follow-up (range 12-46 months), two patients in the DM group and one patient in the US group underwent further surgery for residual hemorrhoid related problems. Two patients in the DM group required further rubber band ligation. CONCLUSIONS: Medium-term results demonstrated that DM and US have similar effects on quality of life in the treatment of third-degree hemorrhoids. However, DM was associated with less early postoperative pain than US and a faster return to normal activities. PMID- 28871427 TI - Measuring Pain Catastrophizing and Pain-Related Self-Efficacy: Expert Panels, Focus Groups, and Cognitive Interviews. AB - PURPOSE: Pain-related self-efficacy and pain catastrophizing are important psychosocial determinants of pain and can be therapeutic targets for chronic pain management. Advances in psychometric science have made shorter or dynamically administered instruments possible. The aim of this study was to generate and test candidate items for two new patient-reported outcome measures of pain-related self-efficacy and pain catastrophizing. METHODS: An expert panel of pain clinicians and researchers was convened to establish construct definitions of pain-related self-efficacy and pain catastrophizing and guide item development. Two patient advisors provided guidance throughout the project. Nineteen people with chronic pain participated in focus groups about their perspectives and experiences related to pain-related self-efficacy and pain catastrophizing. Twenty-two people with chronic pain participated in cognitive interviews to test proposed candidate items. RESULTS: Saturation was reached after three focus groups with no new subdomains identified by participants in the third focus group. Following cognitive interviews, five of the 48 initial pain-related self efficacy candidate items were dropped and seven required substantial revision resulting in 43 pain-related self-efficacy candidate items. After two rounds of cognitive interviews, ten items were eliminated and ten substantially revised, resulting in a set of 30 from the initial 43 pain catastrophizing candidate items. CONCLUSION: This article summarizes results of the qualitative phase of the development of new measures of pain-related self-efficacy and pain catastrophizing. Candidate items will be field tested with a large sample of people with chronic pain and the data will be used to calibrate items to an item response theory model. Resulting item banks and short forms will be made publicly available to researchers and clinicians. PMID- 28871429 TI - Elucidating the rapid action of 2-(2-chlorophenyl)ethylbiguanide on HT-29 cells under a serum- and glucose-deprived condition. AB - We recently demonstrated the cytotoxic action of a novel phenformin derivative, 2 (2-chlorophenyl)ethylbiguanide (2-Cl-Phen), on HT-29 cells under a serum- and glucose-deprived condition. In that study, we showed that the ATF6 arm of the ER stress pathway and c-Myc expression were downregulated 12 h after the treatment with 2-Cl-Phen. Through characterization of intracellular events at the early phase of the 2-Cl-Phen treatment before noticeable morphological changes, we found rapid fluctuations in the c-Myc and ATF4 proteins but not in their mRNAs in 2-Cl-Phen-treated HT-29 cells under the serum- and glucose-deprived condition. The 2-Cl-Phen-mediated downregulation of ATF4 protein was not paralleled by the phosphorylation status of PERK and eIF2alpha. Reduction of c-Myc expression by 2 Cl-Phen was more profound than that of ATF4 expression, and phosphorylated c-Myc was downregulated within 2 h. Pharmacological studies on the expression of c-Myc and ATF4 proteins showed that this decrease was mediated through proteasomal degradation but not by autophagy. Interestingly, treatment with lithium chloride, which is a well-known inhibitor of GSK3beta, partially recovered the expression of ATF4 protein, but its effect on the level of total c-Myc protein was negligible. Treatment with 2-Cl-Phen increased the expression of phosphorylated AMPK, but Compound C, an AMPK inhibitor, did not influence the expression of c Myc protein in HT-29 cells. Finally, we observed that 2-Cl-Phen partially attenuated the gene expression of integrin subunit alpha1 (ITGA1), a downstream target of c-Myc. Taken together, these results show that 2-Cl-Phen rapidly downregulated the expression of c-Myc in addition to ER stress responses in a post-translational manner. Further elucidation and improvement of this multi target-directed compound will provide new insights for developing therapeutic strategies against cancer. PMID- 28871430 TI - [Electronic Shiazo waterpipes: a new source of indoor air pollutants]. AB - BACKGROUND: For some time, a new form of waterpipe smoking has been advertised, where steam stones moistened with aroma fluids (Shiazo) are heated electronically. Since there is no combustion of tobacco, it is often assumed that the produced vapor is not harmful to health. To clarify this issue, we performed a comprehensive inner and outer exposure assessment during the use of an electronic Shiazo waterpipe. METHODS: Three volunteers smoked an electronic waterpipe operated with nicotine-free Shiazo stones in a thoroughly ventilated room for 2 h. In three smoking sessions, three fluids with different flavorings were vaporized. In parallel, emissions of particles, volatile organic compounds, polycyclic aromatic hydrocarbons (PAH), and metals were measured in indoor air. Within a biomonitoring study, urinary metabolite profiles of air pollutants were checked. For comparison, the components of the Shiazo fluids were also analyzed. RESULTS: During the smoking sessions, concentrations of formaldehyde, acetaldehyde, glycerine, and propylene glycol rose significantly in the indoor environment. The content of putative carcinogenic PAH in indoor air increased by 42% to 174 ng/m3. Particle number concentrations ranged from 39,968 to 65,610 particles/cm3 (median), with peaks at diameters from 25 to 31 nm. 3-HPMA, the mercapturic acid metabolite of the pyrolysis product acrolein, was strongly elevated in urine samples of the smokers. All fluids contained high amounts of contact allergens. CONCLUSIONS: Electronic Shiazo waterpipes release various harmful substances that considerably impact indoor air quality. Compared to conventional waterpipes, the release of pollutants is lower. Nevertheless, smoking with Shiazo waterpipes is a source of health risks for both users and bystanders. PMID- 28871431 TI - Involvement of NAC transcription factor SiNAC1 in a positive feedback loop via ABA biosynthesis and leaf senescence in foxtail millet. AB - MAIN CONCLUSION: The foxtail millet NAC transcription factor NAC1, an ortholog of Arabidopsis NAP, is induced by ABA and senescence and accelerates leaf senescence by promoting ABA biosynthesis. Leaf senescence, a unique developmental stage involving macromolecule degradation and nutrient remobilization, is finely tuned and tightly controlled by different gene families. NO APICAL MERISTEM, ARABIDOPSIS ATAF1, and CUP-SHAPED COTYLEDON (NAC) transcription factors have been demonstrated to be involved in the modulation of leaf senescence in many land plant species. Foxtail millet (Setaria italica L.), an important food and fodder crop, has been studied for its strong stress tolerance and potential to be a biofuel model plant. However, the functional roles of senescence-associated NACs in foxtail millet are still unknown. In this study, we characterized a nuclear localized NAC transcription factor, SiNAC1, which is induced by senescence and concentrated in senescent leaves in foxtail millet. SiNAC1 also positively responds to abscisic acid (ABA) treatment in foxtail millet. Moreover, SiNAC1 promotes the natural and dark-induced leaf senescence by an ABA-dependent manner in Arabidopsis thaliana. NCED2 and NCED3 are elevated by SiNAC1 overexpression, which subsequently promotes ABA biosynthesis in Arabidopsis. Finally, as a homolog of AtNAP, SiNAC1 can partially rescue the delayed leaf senescence phenotype in atnap mutants. Overall, our results demonstrate that SiNAC1 functions as a positive regulator of leaf senescence and is involved in a positive feedback loop via ABA biosynthesis and leaf senescence. PMID- 28871432 TI - Comparative physiological and proteomic analyses reveal different adaptive strategies by Cymbidium sinense and C. tracyanum to drought. AB - MAIN CONCLUSION: A terrestrial orchid, Cymbidium sinense appears to utilizes "remedy strategy", while an epiphytic orchid, C. tracyanum , employs a "precaution strategy" to drought stress based on morphological, physiological and proteomic analysis. Drought condition influences plant growth and productivity. Although the mechanism by which plants adapt to this abiotic stress has been studied extensively, the water-adaptive strategies of epiphytes grown in water limited habitats remain undefined. Here, root and leaf anatomies, dynamic changes in physiological and proteomic responses during periods of drought stress and recovery studied in an epiphytic orchid (Cymbidium tracyanum) and a terrestrial orchid (C. sinense) to investigate their strategies for coping with drought. Compared with C. sinense, C. tracyanum showed stronger drought-resistant adaptive characteristics to drought because its leaves had more negative water potential at turgor loss point and roots had higher proportion of velamen radicum thickness. Although both species demonstrated quick recovery of photosynthesis after stress treatment, they differed in physiological and proteomic responses. We detected and functionally characterized 103 differentially expressed proteins in C. sinense and 104 proteins in C. tracyanum. These proteins were mainly involved in carbon and energy metabolism, photosynthesis, and defense responses. The up-regulated expression of plastid fibrillin may have contributed to the marked accumulation of jasmonates only in stressed C. sinense, while ferredoxin NADP reductase up-regulation was only found in C. tracyanum which possibly related to the stimulation of cyclic electron flow that is linked with photoprotection. These physiological and proteomic performances suggest distinct adaptive strategies to drought stress between C. sinense (remedy strategy) and C. tracyanum (precaution strategy). Our findings may help improve our understanding about the ecological adaptation of epiphytic orchids. PMID- 28871433 TI - Identification of an oleosin-like gene in seagrass seeds. AB - OBJECTIVE: To investigate the oil body protein and function in seeds of mature seagrass, Thalassia hemprichii. RESULTS: Seeds of mature seagrass T. hemprichii when stained with a fluorescent probe BODIPY showed the presence of oil bodies in intracellular cells. Triacylglycerol was the major lipid class in the seeds. Protein extracted from seagrass seeds was subjected to immunological cross recognition with land plant seed oil body proteins, such as oleosin and caleosin, resulting in no cross-reactivity. An oleosin-like gene was found in seagrass seeds. Next generation sequencing and sequence alignment indicated that the deduced seagrass seed oleosin-like protein has a central hydrophobic domain responsible for their anchoring onto the surface of oil bodies. Phylogenetic analysis showed that the oleosin-like protein was evolutionarily closer to pollen oleosin than to seed oleosins. CONCLUSION: Oil body protein found in seagrass seeds represent a distinct class of land seed oil body proteins. PMID- 28871435 TI - Comparison of the bacterial community composition in the granular and the suspended phase of sequencing batch reactors. AB - Granulation of activated sludge is an increasingly important area within the field of wastewater treatment. Granulation is usually achieved by high hydraulic selection pressure, which results in the wash-out of slow settling particles. The effect of the harsh wash-out conditions on the granular sludge ecosystem is not yet fully understood, but different bacterial groups may be affected to varying degrees. In this study, we used high-throughput amplicon sequencing to follow the community composition in granular sludge reactors for 12 weeks, both in the granular phase and the suspended phase (effluent). The microbiome of the washed out biomass was similar but not identical to the microbiome of the granular biomass. Certain taxa (e.g. Flavobacterium spp. and Bdellovibrio spp.) had significantly (p < 0.05) higher relative abundance in the granules compared to the effluent. Fluorescence in situ hybridization images indicated that these taxa were mainly located in the interior of granules and therefore protected from erosion. Other taxa (e.g. Meganema sp. and Zooglea sp.) had significantly lower relative abundance in the granules compared to the effluent, and appeared to be mainly located on the surface of granules and therefore subject to erosion. Despite being washed out, these taxa were among the most abundant members of the granular sludge communities and were likely growing fast in the reactors. The ratio between relative abundance in the granular biomass and in the effluent did not predict temporal variation of the taxa in the reactors, but it did appear to predict the spatial location of the taxa in the granules. PMID- 28871434 TI - Cutaneous and Mucosal Manifestations of Sjogren's Syndrome. AB - Sjogren's syndrome is currently considered an "autoimmune epithelitis," as exocrine glands, especially salivary and lacrimal, are progressively destructed by an immune-mediated process associated with specific serum autoantibodies and local lymphocyte infiltrate. Xerostomia remains a key complain in patients with Sjogren's syndrome but should be evaluated also for other causes such as xerogenic medications, followed by radiation and chemotherapy for head and neck cancers, hormone disorders, infections, or other connective tissue diseases. Further, xerophtalmia (also known as dry eye) frequently associated with keratoconjunctivitis sicca cumulatively affects approximately 10-30% of the general population with increasing incidence with age and is more frequently secondary to non-autoimmune diseases. On the other hand, numerous patients with Sjogren's syndrome manifest signs of systemic dryness involving the nose, the trachea, the vagina, and the skin, suggesting that other glands are also affected beyond the exocrine epithelia. Skin involvement in Sjogren's syndrome is relatively common, and various manifestations may be present, in particular xeroderma, eyelid dermatitis, annular erythema, and cutaneous vasculitis. Additional skin non-vasculitic manifestations include livedo reticularis which may occur in the absence of vasculitis, and localized nodular cutaneous amyloidosis possibly representing lymphoproliferative diseases related to Sjogren's syndrome. The treatment of skin and mucosal manifestations in Sjogren's syndrome is similar regardless of the cause, starting from patient education to avoid alcohol and tobacco smoking and to pursue dental hygiene. In conclusion, a strict collaboration between the dermatologist and the rheumatologist is essential in the adequate management of Sjogren's syndrome skin and mucosal manifestations. PMID- 28871436 TI - The prevalence of medication-related adverse events in inpatients-a systematic review and meta-analysis. AB - PURPOSE: Adverse drug events (ADEs) have been internationally recognized as a major threat to patient safety. The purpose of this study was to conduct a meta analysis focusing on inpatient ADEs in the Western World to provide better estimate of the current state of medication safety in these countries. METHODS: The studies for meta-analysis were identified through electronic search in Cochrane, Scopus, Medline, and Web of science databases. Included articles focused on adult inpatient ADEs, had commonly accepted definition for ADE, and were conducted between 2000 and 2016. Disease or ADE-specific studies were excluded. Meta-analysis was conducted on the prevalence of inpatient ADEs and fatal adverse drug reactions (FADRs). RESULTS: The pooled estimate of the prevalence of inpatient ADEs was formed by 46,626 patient records included in 9 articles. Inpatient ADE prevalence was 19 and 32.3% of these ADEs were assessed preventable (MD 28.6%, SD 22.6%). Three articles including 3385 patients focused on inpatient FADRs, but the pooled estimate of this was disregarded due to low number and high heterogeneity of the included studies. CONCLUSIONS: ADEs are estimated to affect 19% of inpatients during hospitalization. Most of the ADEs are moderate in severity causing no permanent harm to the patient. Only a small amount of ADEs cause inpatient deaths, but in this meta-analysis, however, we were unable to give direct estimate of the prevalence. PMID- 28871437 TI - Free radical studies of components of the extracellular matrix: contributions to protection of biomolecules and biomaterials from sterilising doses of ionising radiation. AB - The purpose of the current review is show how the principles and techniques of radiation chemistry have enabled the direct reactions of free radicals with biomolecules and biomaterials to be investigated at the molecular level. In particular, the review focusses on the free radical-induced fragmentation of glycosaminoglycans. Glycosaminoglycans are large linear polysaccharides consisting of repeating disaccharide units and are important components of the extracellular matrix (ECM) either in free form (hyaluronan) or as a component of proteoglycans. Oxidative damage of the extracellular matrix components by either enzymatic or non-enzymatic pathways may have implications for the initiation and progression of a range of human diseases. These include arthritis, kidney disease, cardiovascular disease, lung disease, periodontal disease and chronic inflammation. Oxidative damage to hyaluronan by reactive oxidative species and thus the potential mechanism of damage to the ECM and its role in human pathologies is reviewed with particular focus on damage initiated by potential in vivo free radicals such as superoxide, carbonate and hydroxyl radicals. Such knowledge has also allowed radiation protecting systems to be developed so that sterilising doses of radiation can be delivered to sensitive biomolecules such as proteins and glycosaminoglycans, and also to sensitive biomaterials such as tissue allografts. PMID- 28871438 TI - The structure, splicing, synteny and expression of lamprey COE genes and the evolution of the COE gene family in chordates. AB - COE genes encode transcription factors that have been found in all metazoans examined to date. They possess a distinctive domain structure that includes a DNA binding domain (DBD), an IPT/TIG domain and a helix-loop-helix (HLH) domain. An intriguing feature of the COE HLH domain is that in jawed vertebrates it is composed of three helices, compared to two in invertebrates. We report the isolation and expression of two COE genes from the brook lamprey Lampetra planeri and compare these to COE genes from the lampreys Lethenteron japonicum and Petromyzon marinus. Molecular phylogenetic analyses do not resolve the relationship of lamprey COE genes to jawed vertebrate paralogues, though synteny mapping shows that they all derive from duplication of a common ancestral genomic region. All lamprey genes encode conserved DBD, IPT/TIG and HLH domains; however, the HLH domain of lamprey COE-A genes encodes only two helices while COE-B encodes three helices. We also identified COE-B splice variants encoding either two or three helices in the HLH domain, along with other COE-A and COE-B splice variants affecting the DBD and C-terminal transactivation regions. In situ hybridisation revealed expression in the lamprey nervous system including the brain, spinal cord and cranial sensory ganglia. We also detected expression of both genes in mesenchyme in the pharyngeal arches and underlying the notochord. This allows us to establish the primitive vertebrate expression pattern for COE genes and compare this to that of invertebrate chordates and other animals to develop a model for COE gene evolution in chordates. PMID- 28871439 TI - One normal void and residual following MUS surgery is all that is necessary in most patients. AB - INTRODUCTION AND HYPOTHESIS: There is considerable variation worldwide on how the assessment of voiding function is performed following midurethral sling (MUS) surgery. There is potentially a financial cost, and reduction in efficiency when patient discharge is delayed. Using our current practice of two normal void and residual (V&R) readings before discharge, the aim of this retrospective study was to evaluate the likelihood of an abnormal second V&R test if the first V&R test was normal in order to determine if a policy of discharge after only one satisfactory V&R test is reasonable. METHODS: Data from 400 patients who had had MUS surgery with or without other procedures were collected. Our unit protocol included two consecutive voids of greater than 200 ml with residuals less than 150 ml before discharge. The patients were divided into the following groups: MUS only, MUS plus anterior colporrhaphy (AR) plus any other procedures (MUS/AR), and MUS with any non-AR procedures (MUS+). RESULTS: Complete datasets were available for 335 patients. Once inadequate tests (low volume voids <200 ml) had been excluded (28% overall), the likelihood of an abnormal second V&R test if the first test was normal was 7.1% overall, but 3.6% for MUS, 11.5% for MUS/AR and 8.6% for MUS+. CONCLUSION: The findings in the MUS-only group indicate that it is probably safe to discharge patients after one satisfactory V&R test, as long as safety measures such as 'open access' are available so that patients have unhindered readmission if problems arise. PMID- 28871440 TI - Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial. AB - BACKGROUND: Observational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium-chain triglyceride (MCT) treatment of long-chain fatty acid oxidation disorders (LC-FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven-carbon fatty acid triglyceride, to trioctanoin (C8), an eight carbon fatty acid triglyceride, in patients with LC-FAODs. METHODS: A double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long-chain acylCoA dehydrogenase, trifunctional protein or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis. RESULTS: Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% (p = 0.046) while experiencing a 20% (p = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups. CONCLUSIONS: C7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC-FAODs. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01379625. PMID- 28871442 TI - Nocturnal herbivore-induced plant volatiles attract the generalist predatory earwig Doru luteipes Scudder. AB - Numerous studies have demonstrated that entomophagous arthropods use herbivore induced plant volatile (HIPV) blends to search for their prey or host. However, no study has yet focused on the response of nocturnal predators to volatile blends emitted by prey damaged plants. We investigated the olfactory behavioral responses of the night-active generalist predatory earwig Doru luteipes Scudder (Dermaptera: Forficulidae) to diurnal and nocturnal volatile blends emitted by maize plants (Zea mays) attacked by either a stem borer (Diatraea saccharalis) or a leaf-chewing caterpillar (Spodoptera frugiperda), both suitable lepidopteran prey. Additionally, we examined whether the earwig preferred odors emitted from short- or long-term damaged maize. We first determined the earwig diel foraging rhythm and confirmed that D. luteipes is a nocturnal predator. Olfactometer assays showed that during the day, although the earwigs were walking actively, they did not discriminate the volatiles of undamaged maize plants from those of herbivore damaged maize plants. In contrast, at night, earwigs preferred volatiles emitted by maize plants attacked by D. saccharalis or S. frugiperda over undamaged plants and short- over long-term damaged maize. Our GC-MS analysis revealed that short-term damaged nocturnal plant volatile blends were comprised mainly of fatty acid derivatives (i.e., green leaf volatiles), while the long term damaged plant volatile blend contained mostly terpenoids. We also observed distinct volatile blend composition emitted by maize damaged by the different caterpillars. Our results showed that D. luteipes innately uses nocturnal herbivore-induced plant volatiles to search for prey. Moreover, the attraction of the earwig to short-term damaged plants is likely mediated by fatty acid derivatives. PMID- 28871441 TI - International registry on the use of the CytoSorb(r) adsorber in ICU patients : Study protocol and preliminary results. AB - INTRODUCTION: The aim of this clinical registry is to record the use of CytoSorb(r) adsorber device in critically ill patients under real-life conditions. METHODS: The registry records all relevant information in the course of product use, e. g., diagnosis, comorbidities, course of the condition, treatment, concomitant medication, clinical laboratory parameters, and outcome (ClinicalTrials.gov Identifier: NCT02312024). Primary endpoint is in-hospital mortality as compared to the mortality predicted by the APACHE II and SAPS II score, respectively. RESULTS: As of January 30, 2017, 130 centers from 22 countries were participating. Data available from the start of the registry on May 18, 2015 to November 24, 2016 (122 centers; 22 countries) were analyzed, of whom 20 centers from four countries provided data for a total of 198 patients (mean age 60.3 +/- 15.1 years, 135 men [68.2%]). In all, 192 (97.0%) had 1 to 5 Cytosorb(r) adsorber applications. Sepsis was the most common indication for CytoSorb(r) treatment (135 patients). Mean APACHE II score in this group was 33.1 +/- 8.4 [range 15-52] with a predicted risk of death of 78%, whereas the observed mortality was 65%. There were no significant decreases in the SOFA scores after treatment (17.2 +/- 4.8 [3-24]). However interleukin-6 levels were markedly reduced after treatment (median 5000 pg/ml before and 289 pg/ml after treatment, respectively). CONCLUSIONS: This third interim report demonstrates the feasibility of the registry with excellent data quality and completeness from 20 study centers. The results must be interpreted with caution, since the numbers are still small; however the disease severity is remarkably high and suggests that adsorber treatment might be used as an ultimate treatment in life threatening situations. There were no device-associated side effects. PMID- 28871443 TI - MMP-7 cleaves amyloid beta fragment peptides and copper ion inhibits the degradation. AB - The extracellular deposition of amyloid beta (Abeta) is known to be the fundamental cause of Alzheimer's disease (AD). Abeta1-42, generated by beta secretases from the amyloid precursor protein (APP), is the main component of neuritic plaque, and the aggregation of this protein is shown to be dependent to an extent on metal ions such as copper and zinc. However, the mechanism by which Cu2+ affects the physicochemical properties of Abeta1-42 or the central nervous system is still under debate. A recent series of studies have demonstrated that both the soluble-type matrix metalloproteinases (MMP-2 and MMP-9) and the membrane-type matrix metalloproteinase (MT1-MMP) are capable of degrading Abeta peptides. MMP-7, one of the soluble-type matrix metalloproteinases, is expressed in hippocampal tissue; however, less information is available concerning the pathophysiological roles of this enzyme in the process and/or progress of Alzheimer's disease. In this study, we examined the degradation activity of MMP-7 against various Abeta1-42's fragment peptides and the effect of Cu2+. Although Abeta22-40 was degraded by MMP-7 regardless of Cu2+, Cu2+ inhibited the degradation of Abeta1-19, Abeta11-20, and Abeta11-29 by MMP-7. These results indicate that MMP-7 is capable of degrading Abeta1-42, and that Abeta1-42 acquired resistance against MMP-7 cleavage through Cu2+-binding and structure changes. Our results demonstrate that MMP-7 may play an important role in the defensive mechanism against the aggregation of Abeta1-42, which gives rise to the pathology of AD. PMID- 28871444 TI - Kondoa gutianensis f.a. sp. nov., a novel ballistoconidium-forming yeast species isolated from plant leaves. AB - Two strains, GT-165T and GT-261, isolated from plant leaves collected from Gutian Mountain in Zhejiang province in China were identified as a novel species of the genus Kondoa by the sequence analysis of the internal transcribed spacer (ITS) region, the D1/D2 domains of the large subunit of rRNA (LSU rRNA) and the RNA polymerase II second largest subunit (RPB2), complemented by physiological tests. Phylogenetic analysis based on the concatenated sequences of ITS, D1/D2 and RPB2 showed that the closest known relatives of the new species are three undescribed Kondoa species and Kondoa thailandica. The ITS and D1/D2 sequences of the new species differ from the closely related species by 11-22% and 2-9%, respectively. The name Kondoa gutianensis f.a. sp. nov. (MB 820648, holotype = CGMCC 2.5703T; isotype: CBS 14811T = CGMCC 2.5703T) is proposed to accommodate the new taxon. PMID- 28871445 TI - Lateralized pointing does not cause a cognitive bias. AB - Lateralized pointing has been shown to cause not only a shift in visuo-motor midline, but also a shift in non-lateralized spatial attention. Non-lateralized cognitive consequences of lateralized pointing have been reported for local and global visuospatial processing. Here, we evaluate these findings and examine this effect for categorical and coordinate spatial relation processing, for which the attentional processes are thought to be highly similar to local and global visuospatial processing, respectively. Participants performed a commonly used working memory task to assess categorical and coordinate spatial relation processing. Lateralized pointing with either the left or the right hand, to either the left or the right side was introduced as a manipulation, as well as a new control condition without any pointing. Performance on the spatial relation task was measured before and after pointing. The results suggest that non lateralized consequences of lateralized pointing cannot be generalized to other cognitive tasks relying on attentional processing. Further examination of lateralized pointing is recommended before drawing further conclusions concerning its impact on non-lateralized cognition. PMID- 28871447 TI - Determination of endogenous inflammation-related lipid mediators in ischemic stroke rats using background subtracting calibration curves by liquid chromatography-tandem mass spectrometry. AB - Accurate and reliable quantification of endogenous lipid mediators in complex biological samples is a daunting challenge. In this study, a robust and direct endogenous quantitative method using background subtracting calibration curves by liquid chromatography-tandem mass spectrometry was first developed for the determination of endogenous lipid mediators in ischemic stroke rats. Absolute quantification without surrogate matrix could be achieved by using background subtracting calibration curves, which were corrected and verified from standard curves constructed on original matrix. The recoveries of this method were in the range of 50.3-98.3%, the precision with the relative standard deviation was less than 13.8%, and the accuracy with the relative error was within +/- 15.0%. In addition, background subtracting calibration curves were further verified by validation factors ranging from 90.3 to 110.9%. This validated method has been successfully applied to the analysis of seven endogenous inflammation-related lipid mediators in the brain tissues of ischemic stroke rats. The results indicated that prostaglandins as inflammatory factors and some lipid mediators with neuroprotective effects increased apparently (p < 0.05) in the stroke groups compared with the normal rats. Besides, the two drugs (isosteviol sodium and edaravone) could significantly reduce (p < 0.05) the levels of prostaglandin E2 and prostaglandin F2alpha of stroke rats to inhibit inflammation. Based on the results, it is strongly believed that this approach can be readily generalized as a new reference for the quantification of endogenous compounds in the complex biological samples. Graphical abstract The analysis procedure of determining endogenous inflammation-related lipid mediators using BSCC by LC-MS/MS. PMID- 28871448 TI - Pitfalls in MR imaging of acute anterior cruciate ligament injuries. PMID- 28871446 TI - Mechanisms and clinical implications of tumor heterogeneity and convergence on recurrent phenotypes. AB - Tumor heterogeneity has been identified at various -omic levels. The tumor genome, transcriptome, proteome, and phenome can vary widely across cells in patient tumors and are influenced by tumor cell interactions with heterogeneous physical conditions and cellular components of the tumor microenvironment. Here, we explore the concept that while variation exists at multiple -omic levels, changes at each of these levels converge on the same pathways and lead to convergent phenotypes in tumors that can provide common drug targets. These phenotypes include cellular growth and proliferation, sustained oncogenic signaling, and immune avoidance, among others. Tumor heterogeneity complicates treatment of patient cancers as it leads to varied response to therapies. Identification of convergent cellular phenotypes arising in patient cancers and targeted therapies that reverse them has the potential to transform the way clinicians treat these cancers and to improve patient outcome. PMID- 28871449 TI - ARHGEF39 promotes gastric cancer cell proliferation and migration via Akt signaling pathway. AB - Dbl-family guanine nucleotide exchange factors (GEFs) can activate RhoGTPases by facilitating the exchange of GDP for GTP, the aberrant expression of which has been implicated in tumorigenicity and metastasis of human cancers. ARHGEF39, as a member of Dbl-family GEFs, was reported to be a potential oncogene in human hepatocellular carcinoma previously. However, the role of ARHGEF39 in gastric cancer (GC) remains unclear so far. In the current study, we demonstrated that ARHGEF39 expression was significantly upregulated in GC tissues compared with paired adjacent normal tissues by quantitative real-time PCR analysis. Functional analyses revealed that ARHGEF39 overexpression could promote proliferation, colony formation, and migration of GC cells in vitro, whereas ARHGEF39 knockdown markedly suppressed these phenotypes. Moreover, ARHGEF39 enhanced tumorigenicity and lung metastasis potential of GC cells in nude mice model. Mechanistically, we found that overexpressed ARHGEF39 significantly increased the phosphorylation level of Akt (p-Akt), and its effect on cell proliferation was attenuated by PI3K inhibitor LY294002. Thus, our findings suggest that ARHGEF39 may contribute to cell proliferation and migration in GC via a possible mechanism involving Akt signaling. PMID- 28871450 TI - Cup detachment during vacuum-assisted vaginal delivery and birth outcome. AB - OBJECTIVE: To determine the perinatal outcome associated with cup detachment during vacuum-assisted vaginal delivery (VAVD). METHODS: A retrospective cohort study of all women attempting VAVD in a tertiary hospital (2012-2014). Singleton term pregnancies were included. Antepartum fetal death and major fetal structural or chromosomal abnormalities were excluded. Primary outcome was neonatal birth trauma (subgaleal hematoma, subarachnoid hematoma, subdural hematoma, skull fracture, and/or erb's palsy). Secondary outcomes were maternal complications or other neonatal morbidities. Outcomes were compared between women after >=1 cup detachment (study group) and the rest (control group). Logistic regression analysis was utilized to adjust results to potential confounders. RESULTS: Overall, 1779 women attempted VAVD during study period. Of them, in 146 (8.2%), the cup detached prior to delivery; 130/146 (89%) had a single detachment. After detachment, 4 (2.7%) delivered by cesarean section, 77 (52.7%) delivered after cup reapplication, and 65 (44.6%) delivered spontaneously. Women in the study group were more likely to undergo VAVD due to prolonged second stage, and were characterized by lower rates of metal cup use. Neonates in the detachment group had higher rates of subarachnoid hematoma and composite neonatal birth trauma (2.7 vs. 0.1% and 4.8 vs. 1.8%, respectively, p < 0.05). This remained significant after adjustment to potential confounders (subarachnoid hematoma aOR = 45.44, 95% CI 6.42-321.62 and neonatal birth trauma aOR = 2.62, 95% CI 1.1 6.22, p < 0.05 for all). Other neonatal and maternal morbidities were similar between groups. CONCLUSION: Cup detachment is associated with a higher rate of adverse neonatal outcome. Cup reapplication should be considered carefully. PMID- 28871451 TI - Methylation status of IGF2 DMR and LINE1 in leukocyte DNA provides distinct clinicopathological features of gastric cancer patients. AB - DNA methylation of leukocyte DNA has been proposed to be a biomarker for cancer that can be used to target patients for appropriate clinical implementation. We investigated IGF2 DMR and LINE1 methylation in the leukocyte DNA and their association with clinicopathological features and prognosis of gastric cancer (GC) patients. Methylation status of IGF2 DMR and LINE1 in the leukocyte DNA was quantified using bisulfite pyrosequencing in 207 GC patients. Methylation of both IGF2 DMR and the LINE1 was significantly higher in the undifferentiated histologic type compared to the differentiated histologic type (both P = 0.0002). Hypermethylation of both the IGF2 DMR and the LINE1 was associated with more aggressive features of GC such as advanced stage (IGF2 DMR, P = 0.0002; LINE1, P < 0.0001), lymphatic invasion positive (IGF2 DMR, P = 0.004; LINE1, P = 0.002), venous invasion positive (IGF2 DMR, LINE1, both P = 0.03), lymph node metastasis positive (IGF2 DMR, P = 0.01; LINE1, P = 0.001), peritoneal dissemination positive (IGF2 DMR, P = 0.04; LINE1, P = 0.002), liver metastasis positive (IGF2 DMR, P = 0.008; LINE1, P = 0.001), and other distant metastasis positive (IGF2 DMR, P = 0.04). Our data suggest that high LINE1 and IGF2 DMR methylation status would be a phenomenon that is observed with the progression of GC, supporting their potential utility as a biomarker in GC patients. PMID- 28871452 TI - Click chemistry-mediated cyclic cleavage of metal ion-dependent DNAzymes for amplified and colorimetric detection of human serum copper (II). AB - The determination of the level of Cu2+ plays important roles in disease diagnosis and environmental monitoring. By coupling Cu+-catalyzed click chemistry and metal ion-dependent DNAzyme cyclic amplification, we have developed a convenient and sensitive colorimetric sensing method for the detection of Cu2+ in human serums. The target Cu2+ can be reduced by ascorbate to form Cu+, which catalyzes the azide-alkyne cycloaddition between the azide- and alkyne-modified DNAs to form Mg2+-dependent DNAzymes. Subsequently, the Mg2+ ions catalyze the cleavage of the hairpin DNA substrate sequences of the DNAzymes and trigger cyclic generation of a large number of free G-quadruplex sequences, which bind hemin to form the G quadruplex/hemin artificial peroxidase to cause significant color transition of the sensing solution for sensitive colorimetric detection of Cu2+. This method shows a dynamic range of 5 to 500 nM and a detection limit of 2 nM for Cu2+ detection. Besides, the level of Cu2+ in human serums can also be determined by using this sensing approach. With the advantages of simplicity and high sensitivity, such sensing method thus holds great potential for on-site determination of Cu2+ in different samples. Graphical abstract Sensitive colorimetric detection of copper (II) by coupling click chemistry with metal ion dependentDNAzymes. PMID- 28871453 TI - Hypertension in patients with CKD in China: clinical characteristics and management. PMID- 28871455 TI - Clinical characteristics and outcomes of biopsy-proven diabetic nephropathy. AB - Kidney damage is common in patients with diabetes mellitus (DM). However, whether the type of kidney damage can be reliably diagnosed using clinical data alone remains unclear. Predictive factors for diabetic nephropathy (DN) outcomes are also poorly understood. In this study, the clinical manifestations of 111 cases of biopsy-proven DN were described, and the clinical and pathological parameters of patients with different DN outcomes were compared. Results showed that long DM duration ( > 10 years in 32.4% of patients), severe proteinuria (62.2%), and renal dysfunction (estimated glomerular filtration rate [eGFR] < 60 mL/(min$1.73 m2)) (52.3%) did not accurately indicate whether the condition of these patients progressed to DN. Hematuria (48.6%) failed to specify either DN or nondiabetic renal disease. Diabetic retinopathy (78.4%) was a crucial complication in patients with DN. Kaplan-Meier analysis revealed that the renal survival of 53 patients who were diagnosed with DN and were followed up was not significantly associated with glomerular classification (P > 0.05). Cox's regression analysis demonstrated that renal survival time was significantly influenced by sex (beta = 1.394, P = 0.038), hematuria (beta = 0.036, P = 0.029), and eGFR (beta =-0.039, P = 0.002) but was not significantly affected by age, 24 h urinary protein excretion, or glomerular classification (P > 0.05). In conclusion, the clinical characteristics of DN vary, and renal biopsy is necessary to determine renal damage patterns. Sex, hematuria, and the eGFR may affect DN outcomes, whereas the glomerular classification may not. PMID- 28871456 TI - Queueing theoretic analysis of labor and delivery : Understanding management styles and C-section rates. AB - Childbirth is a complex clinical service requiring the coordinated support of highly trained healthcare professionals as well as management of a finite set of critical resources (such as staff and beds) to provide safe care. The mode of delivery (vaginal delivery or cesarean section) has a significant effect on labor and delivery resource needs. Further, resource management decisions may impact the amount of time a physician or nurse is able to spend with any given patient. In this work, we employ queueing theory to model one year of transactional patient information at a tertiary care center in Boston, Massachusetts. First, we observe that the M/G/infinity model effectively predicts patient flow in an obstetrics department. This model captures the dynamics of labor and delivery where patients arrive randomly during the day, the duration of their stay is based on their individual acuity, and their labor progresses at some rate irrespective of whether they are given a bed. Second, using our queueing theoretic model, we show that reducing the rate of cesarean section - a current quality improvement goal in American obstetrics - may have important consequences with regard to the resource needs of a hospital. We also estimate the potential financial impact of these resource needs from the hospital perspective. Third, we report that application of our model to an analysis of potential patient coverage strategies supports the adoption of team-based care, in which attending physicians share responsibilities for patients. PMID- 28871454 TI - Non-genetic mechanisms of diabetic nephropathy. AB - Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetes mellitus patients and is characterized by thickened glomerular basement membrane, increased extracellular matrix formation, and podocyte loss. These phenomena lead to proteinuria and altered glomerular filtration rate, that is, the rate initially increases but progressively decreases. DN has become the leading cause of end-stage renal disease. Its prevalence shows a rapid growth trend and causes heavy social and economic burden in many countries. However, this disease is multifactorial, and its mechanism is poorly understood due to the complex pathogenesis of DN. In this review, we highlight the new molecular insights about the pathogenesis of DN from the aspects of immune inflammation response, epithelial-mesenchymal transition, apoptosis and mitochondrial damage, epigenetics, and podocyte-endothelial communication. This work offers groundwork for understanding the initiation and progression of DN, as well as provides ideas for developing new prevention and treatment measures. PMID- 28871457 TI - Protective Effect of 1,25-Dihydroxy Vitamin D3 on Pepsin-Trypsin-Resistant Gliadin-Induced Tight Junction Injuries. AB - BACKGROUND: Tight junction (TJ) injuries induced by pepsin-trypsin-resistant gliadin (PT-G) play an important role in the pathogenesis of celiac disease. Previously, 1,25-dihydroxy vitamin D3 (VD3) was reported to be a TJ regulator that attenuates lipopolysaccharide- and alcohol-induced TJ injuries. However, whether VD3 can attenuate PT-G-induced TJ injuries is unknown. AIM: The aim of this study was to evaluate the effects of VD3 on PT-G-induced TJ injuries. METHODS: Caco-2 monolayers were used as in vitro models. After being cultured for 21 days, the monolayers were treated with PT-G plus different concentrations of VD3. Then, the changes in trans-epithelial electrical resistance and FITC-dextran 4000 (FD-4) flux were determined to evaluate the monolayer barrier function. TJ protein levels were measured to assess TJ injury severity, and myeloid differentiation factor 88 (MyD88) expression and zonulin release levels were determined to estimate zonulin release signaling pathway activity. Additionally, a gluten-sensitized mouse model was established as an in vivo model. After the mice were treated with VD3 for 7 days, we measured serum FD-4 concentrations, TJ protein levels, MyD88 expression, and zonulin release levels to confirm the effect of VD3. RESULTS: Both in vitro and in vivo, VD3 significantly attenuated the TJ injury-related increase in intestinal mucosa barrier permeability. Moreover, VD3 treatment up-regulated TJ protein expression levels and significantly decreased MyD88 expression and zonulin release levels. CONCLUSIONS: VD3 has protective effects against PT-G-induced TJ injuries both in vitro and in vivo, which may correlate with the disturbance of the MyD88-dependent zonulin release signaling pathway. PMID- 28871458 TI - Percutaneous irreversible electroporation combined with allogeneic natural killer cell immunotherapy for patients with unresectable (stage III/IV) pancreatic cancer: a promising treatment. AB - PURPOSE: This study was attempted to investigate the safety and clinical efficacy of percutaneous irreversible electroporation combined with allogeneic natural killer cell therapy for treating stage III/IV pancreatic cancer, evaluate median progression-free survival (PFS), and overall survival (OS). METHODS: Between March 2016 and February 2017, we enrolled 67 patients who met the enrollment criteria. According to the latest NCCN Guidelines, the patients were divided into stage III (35 patients, 16 patients received only irreversible electroporation (IRE) and 19 patients received IRE-NK: 8 patients underwent one course NK and 11 patients underwent >=3 courses) and stage IV (32 patients, 14 patients received only IRE and 18 patients received IRE-NK: 8 patients underwent one course NK and 10 patients underwent >=3 courses). The safety and short-term effects were evaluated first, then the median PFS, median OS, response rate (RR) and disease control rate (DCR) were assessed. RESULTS: Adverse events of all patients were limited to grades A and B, included local (mainly cough 12.7%, nausea and emesis 6.8%, pain of puncture point 25.3% and duodenum and gastric retention 5.9%) and systemic (mainly fatigue 21.5, fever 33.5%, and blood pressure intraoperative transient reduction 27.4% and white cell count reduction 22.6%) reactions, fever was most frequent. The serum amylase level at 24 h and 7 d after IRE was not significantly changed compared to those before IRE (P > 0.05). CA19-9 value was lower in IRE-NK group than in IRE at 1 month after treatment (P < 0.05). After a median follow-up of 7.9 months (3.8-12.1 months): in stage III group, median PFS was higher in IRE-NK group (9.1 months) than in IRE group (7.9 months, P = 0.0432), median OS was higher in IRE-NK (13.6 months) than in IRE (12.2 months; P = 0.0327), and median PFS was higher in who received multiple NK than single NK (9.9 vs. 8.2 months; P = 0.0387, respectively), median OS who received multiple NK was higher than single NK (13.7 vs. 12.1 months; P = 0.0451, respectively), the RR in IRE-NK (63.2%) was higher than in IRE (50.0%; P < 0.05); in stage IV group, median OS was higher in IRE-NK (10.2 months) than in IRE (9.1 months; P = 0.0367), the DCR in IRE-NK (66.7%) was higher than in IRE (42.9%; P < 0.05). CONCLUSION: Percutaneous irreversible electroporation combined with allogeneic natural killer cell immunotherapy significantly increased median PFS and median OS in stage III pancreatic cancer and extended the median OS of stage IV pancreatic cancer. Multiple allogeneic natural killer cells infusion was associated with better prognosis to stage III pancreatic cancer. PMID- 28871459 TI - Facultative CAM photosynthesis (crassulacean acid metabolism) in four species of Calandrinia, ephemeral succulents of arid Australia. AB - Crassulacean acid metabolism (CAM) was demonstrated in four small endemic Australian terrestrial succulents from the genus Calandrinia (Montiaceae) viz. C. creethiae, C. pentavalvis, C. quadrivalvis and C. reticulata. CAM was substantiated by measurements of CO2 gas-exchange and nocturnal acidification. In all species, the expression of CAM was overwhelmingly facultative in that nocturnal H+ accumulation was greatest in droughted plants and zero, or close to zero, in plants that were well-watered, including plants that had been droughted and were subsequently rewatered, i.e. the inducible component was proven to be reversible. Gas-exchange measurements complemented the determinations of acidity. In all species, net CO2 uptake was restricted to the light in well-watered plants, and cessation of watering was followed by a progressive reduction of CO2 uptake in the light and a reduction in nocturnal CO2 efflux. In C. creethiae, C. pentavalvis and C. reticulata net CO2 assimilation was eventually observed in the dark, whereas in C. quadrivalvis nocturnal CO2 exchange approached the compensation point but did not transition to net CO2 gain. Following rewatering, all species returned to their original well-watered CO2 exchange pattern of net CO2 uptake restricted solely to the light. In addition to facultative CAM, C. quadrivalvis and C. reticulata exhibited an extremely small constitutive CAM component as demonstrated by the nocturnal accumulation in well-watered plants of small amounts of acidity and by the curved pattern of the nocturnal course of CO2 efflux. It is suggested that low-level CAM and facultative CAM are more common within the Australian succulent flora, and perhaps the world succulent flora, than has been previously assumed. PMID- 28871460 TI - Opposing effects of memory-driven and stimulus-driven attention on distractor perception. AB - It is well known that a match between working memory contents and a visual stimulus creates attentional bias toward the memory-matching stimulus. The present study investigated whether this memory-driven attentional bias exerts similar effects with conventional, spatial attention driven by a cue stimulus. Specifically, we examined how the effect of a distracting, task-irrelevant stimulus is modulated when attention was oriented toward the distractor in memory and stimulus-driven manners. The results showed that significant interference by a distractor decreased when attention was allocated to the distractor in a memory driven manner, whereas the distracter captured attention in a stimulus-driven manner exerted increased interference. By contrast, memory-driven attention brought an unattended stimulus into attentional focus, while stimulus-driven attention failed to do so. These results provide evidence that the mechanisms underlying working memory-driven and stimulus-driven attention are separable, pointing to the dynamic and flexible relationship between working memory and attention. PMID- 28871462 TI - Response to the letter "Reviewers should have known better" by Mahir Gachabayov. PMID- 28871461 TI - Relationship Satisfaction and Dyadic Coping in Couples with a Child with Autism Spectrum Disorder. AB - Dyadic coping strategies may play a pivotal role in relationship satisfaction and explain why some couples adapt positively to the challenges associated with raising a child with ASD and others do not. Survey data from 127 caregivers of a child with ASD were used in generalized estimating equation analyses to investigate the factors associated with relationship satisfaction, including socio-demographics, parenting stress and dyadic coping. Results showed that over two-thirds of the sample reported satisfaction, which was associated with low parenting stress, increased use of positive and decreased use of negative dyadic coping strategies. Positive dyadic coping was found to have a greater influence than negative dyadic coping, supporting a strengths-based approach to interventions promoting family resilience. PMID- 28871463 TI - Specific effects of prenatal DEHP exposure on neuroendocrine gene expression in the developing hypothalamus of male rats. AB - Endocrine disrupting chemicals may disrupt developing neuroendocrine systems, especially when the exposure occurs during a critical period. This study aimed to investigate whether prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a major component of plasticizers used worldwide, disrupted the development of a network of genes important for neuroendocrine function in male rats. Pregnant rats were treated with corn oil (vehicle control), 2, 10 or 50 mg/kg DEHP by gavage from gestational day 14 to 19. The neuroendocrine gene expressions were quantified using a 48-gene Taqman qPCR array in the whole hypothalamus of neonatal rats (postnatal day 1) and in the anteroventral periventricular nucleus (AVPV), medial preoptic nucleus (MPN) and arcuate nucleus (ARC) of adult rats (postnatal day 70). Immunofluorescent signals of ERalpha and CYP19 were detected using the confocal microscopy in adult AVPV, MPN and ARC. The results showed that prenatal DEHP exposure perturbed somatic and reproductive development of offspring. Eleven genes were down-regulated in neonatal hypothalamus and showed non-monotonic dose-response relationships, that the 10 mg/kg DEHP dosage was associated with the greatest number of gene expression changes. Different from this, 14 genes were altered in adult AVPV, MPN and ARC and most of alterations were found in the 50 mg/kg DEHP group. Also, 50 mg/kg DEHP reduced ERalpha expression in the ARC, but no alterations were observed in CYP19 expression. These results indicated that prenatal DEHP exposure may perturb hypothalamic gene programming and the influences are permanent. The effects showed dependence on developmental stages and nuclei region. PMID- 28871465 TI - The crossing duct sign. AB - Pancreas divisum is a common variation in pancreatic ductal anatomy present in up to 10% of the population with variable clinical importance. The crossing duct sign refers to the appearance of dominant dorsal duct crossing the intrapancreatic common bile duct to empty into the minor papilla, best illustrated on maximum intensity projection images from MRCP. PMID- 28871464 TI - Treatment Response and Outcome with Two Different Prednisolone Regimens in Autoimmune Hepatitis. AB - BACKGROUND: Beyond available guidelines, therapy of autoimmune hepatitis (AIH) shows wide variation among physicians. We compared two regimens for treatment naive AIH: one recommended protocol with an initial prednisolone dose of 30 mg/day and our own 40 mg/day prednisolone with a slow dose tapering protocol. We analyzed the safety, response rates, and outcomes for two groups of treated patients. PATIENTS AND METHODS: We retrospectively evaluated data of 71 AIH patients including, group I (n = 32, prednisone 30 mg/day) and group II (n = 39, prednisone 40 mg/day). All patients also received azathioprine. RESULTS: The frequency of complete biochemical response was significantly higher in group II than in group I (69.2 vs. 43.8%, p = 0.031) after 3 months of therapy, but not after 6 and 12 months (79.5 vs. 59.4%, p = 0.065 and 89.5 vs. 80.6%, p = 0.30). In patients with severe interface hepatitis, the complete response rates were significantly higher in group II than in group I after 3 (63.6 vs. 23.1%, p = 0.02) and 6 months (72.7 vs. 38.5%, p = 0.046), but not after 12 months of therapy (86.4 vs. 69.2%, p = 0.221). Relapses were observed in 50% of group I and in 35.9% of group II during maintenance therapy (p = 0.23). Overall survival was significantly better in group II than in group I (100 vs. 87.5%, log-rank, p = 0.048). No severe steroid-related side effects were observed in either group. CONCLUSIONS: Our real-world experience suggests that an initial prednisolone dose of 40 mg/day with a slower tapering protocol induces earlier biochemical response, tends to result in less relapses during maintenance, and is associated with a better disease outcome. PMID- 28871466 TI - Salting-out-enhanced ionic liquid microextraction with a dual-role solvent for simultaneous determination of trace pollutants with a wide polarity range in aqueous samples. AB - In real aquatic environments, many occupational pollutants with a wide range of polarities coexist at nanogram to milligram per liter levels. Most reported microextraction methods focus on extracting compounds with similar properties (e.g., polarity or specific functional groups). Herein, we developed a salting out-enhanced ionic liquid microextraction based on a dual-role solvent (SILM-DS) for simultaneous detection of tetracycline, doxycycline, bisphenol A, triclosan, and methyltriclosan, with log K ow ranging from -1.32 to 5.40 in complex milk and environmental water matrices. The disperser in the ionic-liquid-based dispersive liquid-liquid microextraction was converted to the extraction solvent in the subsequent salting-out-assisted microextraction procedures, and thus a single solvent performed a dual role as both extractant and disperser in the SILM-DS process. Acetonitrile was selected as the dual-role solvent because of its strong affinity for both ionic liquids and water, as well as the extractant in the salting-out step. Optimized experimental conditions were 115 MUL [C8MIM][PF6] as extractor, 1200 MUL acetonitrile as dual-role solvent, pH 2.0, 5.0 min ultrasound extraction time, 3.0 g Na2SO4, and 3.0 min vortex extraction time. Under optimized conditions, the recoveries of the five pollutants ranged from 74.5 to 106.9%, and their LODs were 0.12-0.75 MUg kg-1 in milk samples and 0.11-0.79 MUg L-1 in environmental waters. Experimental precision based on relative standard deviation was 1.4-6.4% for intraday and 2.3-6.5% for interday analyses. Compared with previous methods, the prominent advantages of the newly developed method are simultaneous determination of pollutants with a wide range of polarities and a substantially reduced workload for ordinary environmental monitoring and food tests. Therefore, the new method has great application potential for simultaneous determination of trace pollutants with strongly contrasting polarities in several analytical fields. Graphical Abstract A salting-out-enhanced ionic liquid microextraction based on a dual-role solvent (SILM-DS) was developed for simultaneous detection of tetracycline, doxycycline, bisphenol A, triclosan and methyltriclosan, with log K ow ranging from -1.32 to 5.40. The novelty of SILM-DS method lies in (1) simultaneous quantification of pollutants with contrasting polarity; (2) microextraction based on a dual-role solvent (as a disperser and extractant); (3) giving high recoveries for analytes with a wide range of polarities; and (4) reducing workload for ordinary environmental monitoring and food tests. PMID- 28871467 TI - Epigallocatechin gallate protects against homocysteine-induced vascular smooth muscle cell proliferation. AB - Epigallocatechin gallate (EGCG), a bioactive ingredient of green tea, plays a protective role in the cardiovascular system. Homocysteine (Hcy) is a major risk factor for chronic kidney disease and cardiovascular disease. The present study aimed to investigate the role of EGCG in Hcy-induced proliferation of vascular smooth muscle cells (VSMCs) and its underlying mechanism. We also explored the roles of rennin-angiotensin system (RAS), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) in this process. Human aortic smooth muscle cells (HASMCs) were treated with different drugs for different periods. The proliferation rate of HASMCs was detected using the CCK-8 and BrdU labeling assays. The Western blot assay was used to determine the expression levels of angiotensin II type 1 receptor (AT-1R), ERK1/2, and p38 MAPK. Compared with the control group, the HASMCs treated with Hcy at different doses (100, 200, 500, and 1000 uM) showed significantly increased proliferation. Hcy increased the expression of AT-1R, whereas EGCG decreased the protein expression of AT-1R. Furthermore, we found that Hcy-induced expression of p ERK1/2 and p-p38MAPK was dependent on AT-1R. Compared with Hcy (500 uM)-treated cells, EGCG (20 uM)-treated cells showed decreased proliferation as well as expression of AT-1R, p-ERK1/2, and p-p38MAPK. In addition, HASMC proliferation was suppressed by the addition of an AT-1R blocker (olmesartan), an ERK1/2 inhibitor (PD98059), and a p38MAPK inhibitor (SB202190). EGCG can inhibit AT-1R and affect ERK1/2 and p38MAPK signaling pathways, resulting in the decrease of VSMC proliferation induced by Hcy. PMID- 28871468 TI - MicroRNA Expression in the Locus Coeruleus, Entorhinal Cortex, and Hippocampus at Early and Middle Stages of Braak Neurofibrillary Tangle Pathology. AB - The present study analyzes by RT-qPCR the expression of microRNA (miRNA)-27a-3p, miRNA-124-3p, miRNA-132-3p, and miRNA-143-3p in the locus coeruleus (LC), entorhinal cortex (EC), CA1 region of the hippocampus (CA1), and dentate gyrus (DG) of middle-aged (MA) individuals with no brain lesions and of cases at Braak and Braak stages I-II and II-IV of neurofibrillary tangle (NFT) pathology. The most affected region is the LC in which miRNA-27a-3p, miRNA-124-3p, and miRNA-143 3p show a trend to increase at stages I-II and are significantly up-regulated at stages III-IV when compared with MA. Only miRNA-143-3p is up-regulated in the EC at stages III-IV when compared with MA and with stages I-II. No modifications in the expression levels of miRNA-27a-3p, miRNA-124-3p, miRNA-132-3p, and miRNA-143 3p are found in CA1 at any stage, whereas miRNA-124-3p is significantly down regulated in DG at stages I-II. Accompanying in situ hybridization reveals miRNA 27a-3p, miRNA-124-3p, and miRNA-143-3 localization in neurons, indicating that changes in miRNA expression are not a direct effect of changes in the numbers of neurons and glial cells. Present observations show for the first time important miRNA de-regulation in the LC at the first stages of NFT. Since the LC is the main noradrenergic input to the cerebral cortex, key regulator of mood and depression, and one of the first nuclei affected in aging and Alzheimer's disease (AD), these findings provide insights for additional study of the LC in aging and AD. PMID- 28871470 TI - Lifestyle and bladder cancer prevention: no consistent evidence from cohort studies. PMID- 28871469 TI - Imaging correlates for the 2016 update on WHO classification of grade II/III gliomas: implications for IDH, 1p/19q and ATRX status. AB - The 2016 World Health Organization Classification of Tumors of the Central Nervous System incorporates the use of molecular information into the classification of brain tumors, including grade II and III gliomas, providing new prognostic information that cannot be delineated based on histopathology alone. We hypothesized that these genomic subgroups may also have distinct imaging features. A retrospective single institution study was performed on 40 patients with pathologically proven infiltrating WHO grade II/III gliomas with a pre treatment MRI and molecular data on IDH, chromosomes 1p/19q and ATRX status. Two blinded Neuroradiologists qualitatively assessed MR features. The relationship between each parameter and molecular subgroup (IDH-wildtype; IDH-mutant-1p/19q codeleted-ATRX intact; IDH-mutant-1p/19q intact-ATRX loss) was evaluated with Fisher's exact test. Progression free survival (PFS) was also analyzed. A border that could not be defined on FLAIR was most characteristic of IDH-wildtype tumors, whereas IDH-mutant tumors demonstrated either well-defined or slightly ill-defined borders (p = 0.019). Degree of contrast enhancement and presence of restricted diffusion did not distinguish molecular subgroups. Frontal lobe predominance was associated with IDH-mutant tumors (p = 0.006). The IDH-wildtype subgroup had significantly shorter PFS than the IDH-mutant groups (p < 0.001). No differences in PFS were present when separating by tumor grade. FLAIR border patterns and tumor location were associated with distinct molecular subgroups of grade II/III gliomas. These imaging features may provide fundamental prognostic and predictive information at time of initial diagnostic imaging. PMID- 28871471 TI - Impact of maternal nutrition in hepatitis E infection in pregnancy. AB - BACKGROUND AND AIM: The basis of host response in hepatitis E virus (HEV)-related liver disease during pregnancy-is still unclear. The study aims to evaluate anthropometric parameters and biochemical nutritional parameters in hepatitis E infection during pregnancy and correlate it with severity of the disease. METHODS: A total of consecutive 267 pregnant women with jaundice were recruited. The jaundiced patients were classified as acute viral hepatitis (AVH) or acute liver failure (ALF). The study group included 144 pregnant women with HEV infection and 144 healthy asymptomatic age and gestational age-matched pregnant women as controls. Nutritional factors were evaluated on basis of anthropometric parameters and biochemical factors. Serum prealbumin and folate were assayed by ELISA kit. RESULTS: All nutritional parameters were significantly lower in pregnant women with HEV infection as compared with healthy pregnant controls. Some of the nutritional parameters significantly lower in ALF pregnant patients compared to AVH pregnant patients in HEV group. Linear regression analysis of the AVH group showed that serum total protein and mid-upper arm circumference (MUAC) were significant predictors for bilirubin, body mass index (BMI) could significantly predict viral load level, and total protein, prealbumin, folate, and tricep skin fold thickness (TSFT) could significantly predict prothrombin time. In ALF group, serum prealbumin could significantly predict bilirubin levels and MUAC could significantly predict prothrombin time. CONCLUSION: Malnutrition might confer a higher predisposition for HEV infection during pregnancy and is associated with increased severity of disease in terms of occurrence of ALF. PMID- 28871474 TI - Does your discussion realize its potential? PMID- 28871472 TI - Cytochrome P450 2D6 and Parkinson's Disease: Polymorphism, Metabolic Role, Risk and Protection. AB - Cytochrome P450 (CYP) 2D6 is one of the most highly active, oxidative and polymorphic enzymes known to metabolize Parkinsonian toxins and clinically established anti-Parkinson's disease (PD) drugs. Albeit CYP2D6 gene is not present in rodents, its orthologs perform almost the similar function with imprecise substrate and inhibitor specificity. CYP2D6 expression and catalytic activity are found to be regulated at every stage of the central dogma except replication as well as at the epigenetic level. CYP2D6 gene codes for a set of alternate splice variants that give rise to a range of enzymes possessing variable catalytic activity. Case-control studies, meta-analysis and systemic reviews covering CYP2D6 polymorphism and PD risk have demonstrated that poor metabolizer phenotype possesses a considerable genetic susceptibility. Besides, ultra-rapid metabolizer offers protection against the risk in some populations while lack of positive or inverse association is also reported in other inhabitants. CYP2D6 polymorphisms resulting into deviant protein products with differing catalytic activity could lead to inter-individual variations, which could be explained to certain extent on the basis of sample size, life style factors, food habits, ethnicity and tools used for statistical analysis across various studies. Current article describes the role played by polymorphic CYP2D6 in the metabolism of anti-PD drugs/Parkinsonian toxins and how polymorphisms determine PD risk or protection. Moreover, CYP2D6 orthologs and their roles in rodent models of Parkinsonism have also been mentioned. Finally, a perspective on inconsistency in the findings and futuristic relevance of CYP2D6 polymorphisms in disease diagnosis and treatment has also been highlighted. PMID- 28871473 TI - Role of Peroxiredoxin 2 in the Protection Against Ferrous Sulfate-Induced Oxidative and Inflammatory Injury in PC12 Cells. AB - Peroxiredoxin 2 (Prdx2) is a ubiquitous antioxidant enzyme in mammalian brain. Although a protective role of Prdx2 has been established in cerebral ischemia and several neurodegenerative diseases, its contribution against iron-induced neurocytotoxicity still remains to be determined. Accordingly, in this study, we aimed to investigate the effects of Prdx2 on iron-induced cytotoxicity using an in vitro model in which PC12 cells are exposed to ferrous sulfate (FS). The FS treatment increased Prdx2 expression, and promoted lactate dehydrogenase (LDH) release and cell apoptosis in PC12 cells, accompanied by the increase in the Bax/Bcl2 ratio, cytochrome c release, and caspase-3 cleavage. FS exposure also increased the malondialdehyde content (lipid peroxidation), 3'-nitrotyrosine expression (protein nitration), gamma-H2A.X formation (DNA oxidation), and promoted nuclear factor kappa B nuclear translocation, cyclooxygenase-2 expression, and release of tumor necrosis factor-alpha and interleukin-1beta. Lentivirus-mediated Prdx2 knockdown intensified the FS-induced LDH release and cell apoptosis by aggravating the oxidative and inflammatory damage. In conclusion, our findings demonstrated that Prdx2 played a vital role in the protection against iron-induced cytotoxicity in PC12 cells. PMID- 28871475 TI - Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with or without Ribavirin for Treatment of Hepatitis C Virus Genotype 1: A Systematic Review and Meta-analysis. AB - BACKGROUND AND OBJECTIVE: Interferon-free regimens are rapidly evolving for patients with chronic hepatitis C virus (HCV) infection. We performed this meta analysis to investigate the safety and efficacy of a combination regimen (ombitasvir [OBV]/paritaprevir [PTV]/ritonavir [r] +/- dasabuvir [DSV]) for the treatment of patients with HCV genotype 1 infection. METHODS: A computerized literature search for relevant clinical trials was conducted during May 2017. Data on sustained virological response (SVR), virological relapse, and safety outcomes were extracted and calculated as pooled proportion (PP) or risk ratio (RR) with their 95% confidence interval (CI), using StatsDirect and RevMan software. RESULTS: The final analysis included 13 studies for HCV genotype 1 (3115 patients). The pooled effect estimate showed that 12-week treatment of genotype 1 patients with the OBV/PTV/r regimen achieved a high SVR rate (PP = 94%, 95% CI 92-96) that increased to (PP = 97%, 95% CI 96-98) upon the addition of DSV. These results were consistent when independent subgroup analyses were conducted based on viral subgenotypes, the presence of cirrhosis, or former treatment failure. Adding ribavirin (RBV) to this regimen was not associated with increased SVR rates (risk ratio = 1, 95% CI 0.98-1.02), while it increased the risk of serious adverse events (p = 0.02), insomnia (p = 0.001), and pruritus (p < 0.001). CONCLUSION: The current meta-analysis showed a high efficacy for the OBV/PTV/r regimen in the treatment of HCV genotype 1 (with DSV) infection, regardless of the presence of cirrhosis or former treatment failure. Adding RBV to this regimen slightly decreased the relapse rate. Future studies with larger sample sizes are required to investigate the efficacy of this regimen in other HCV genotypes and to establish the evidence about the effect of adding RBV to OBV/PTV/r + DSV. PMID- 28871476 TI - Peritoneal perforation is less a complication than an expected event during transanal endoscopic microsurgery: experience from 194 consecutive cases. AB - BACKGROUND: Indications for transanal endoscopic microsurgery (TEM) have been extended to technically challenging tumors, which may be associated with an increased risk of peritoneal perforation (PP). The aim of the present study was to investigate the occurrence, management and outcome of PP in patients having TEM. METHODS: All the patients who had TEM for rectal adenoma or adenocarcinoma in our unit were included. Patients in whom PP occurred (Group A) were compared to those without PP (Group B). RESULTS: From 2007 to 2015, 194 TEM (116 men, median age 66 [range 21-100] years) were divided into Groups A (n = 28, 14%) and B (n = 166). The latter group included four patients, in whom a laparoscopy did not confirm suspicion of PP made during TEM. In 2 of 28 patients (7%), the diagnosis of PP was made postoperatively during reoperation for peritonitis. For the 26 other patients (93%), routine exploratory laparoscopy was performed with suture of the peritoneal defect on the pouch of Douglas in 24 cases and a rectal suture alone in 2 cases. Independent predictive factors for PP were: distance from the anal verge >10 cm (OR = 3.6), circumferential tumor (OR = 3.0) and anterior location (OR = 2.7). Hospital stay was significantly longer in Group A (7.5 [3-31] days) than in Group B (4 [1-38] days; p < 0.0001), whereas there was no significant difference regarding postoperative morbidity and recurrence rate. CONCLUSIONS: Our results suggested that PP is not a very rare event during TEM, especially in anterior, circumferential and/or high rectal tumors. Laparoscopic treatment of PP is feasible and safe. The occurrence of PP is not associated with poor oncologic results. PMID- 28871477 TI - [Diagnostics and management of herpes zoster ophthalmicus]. AB - Herpes zoster (HZ, shingles) represents the secondary manifestation of an infection with varicellazoster virus (VZV). A reactivation of dormant VZV in the ophthalmic branch of the fifth cranial nerve leads to ophthalmic HZ (HZO). The predominantly older and immune compromised patients often present with eye involvement (approximately 50%) as well as characteristic skin changes. Clinical manifestations include the cornea and conjunctiva but anterior uveitis and (rarely) acute retinal necrosis may also occur. Associated sensory symptoms that range from paresthesia to severe pain may severely affect the quality of life. Particularly in immunocompromised and/or elderly patients, HZO is associated with complicated courses. Systemic antiviral treatment and an adequate pain medication are the mainstay of the recommended management. The present article provides an overview of the contents of the current consensus-based European guidelines on the management of HZ with a specific focus on HZO. PMID- 28871479 TI - In Vitro Evaluation and Statistical Optimization of Antimicrobial Activity of Prunus cerasoides Stem Bark. AB - Nature is a generous source of compounds with the potential for prevention of infections. Antimicrobial screening of aqueous extract from bark of wild Himalayan cherry (Prunus cerasoides) was carried out against various pathogenic microorganisms with inhibition zone ranging from 19 to 24 mm. An optimization strategy, which included classical method and statistical method (RSM), was applied to optimize the effect of process variables. Fifteen percent plant material extracted at 40 degrees C for 60 min and at its natural pH (4.5) exhibited best antimicrobial activity with an average zone of inhibition ranging from 19 to 29 mm. Statistical optimization using RSM further enhanced the activity by 1.09-1.24 folds. Minimum inhibitory concentration of the aqueous extract against different microorganism ranged from 1 to 10 mg/ml. The aqueous extract was found to be reasonably thermostable at boiling temperature for 1 h. Viable cell count (VCC) studies of the extract showed it to be bactericidal in nature. Further, the aqueous extract was found to be neither cytotoxic nor mutagenic, when evaluated by MTT assay and Ames mutagenicity test. The results suggest that the aqueous extract of P. cerasoides could be a potential source to obtain new antimicrobials and effective herbal medicines to combat the problem of ever emerging microbial resistance. PMID- 28871478 TI - The iron-chelate transporter OsYSL9 plays a role in iron distribution in developing rice grains. AB - KEY MESSAGE: Rice OsYSL9 is a novel transporter for Fe(II)-nicotianamine and Fe(III)-deoxymugineic acid that is responsible for internal iron transport, especially from endosperm to embryo in developing seeds. Metal chelators are essential for safe and efficient metal translocation in plants. Graminaceous plants utilize specific ferric iron chelators, mugineic acid family phytosiderophores, to take up sparingly soluble iron from the soil. Yellow Stripe 1-Like (YSL) family transporters are responsible for transport of metal phytosiderophores and structurally similar metal-nicotianamine complexes. Among the rice YSL family members (OsYSL) whose functions have not yet been clarified, OsYSL9 belongs to an uncharacterized subgroup containing highly conserved homologs in graminaceous species. In the present report, we showed that OsYSL9 localizes mainly to the plasma membrane and transports both iron(II) nicotianamine and iron(III)-deoxymugineic acid into the cell. Expression of OsYSL9 was induced in the roots but repressed in the nonjuvenile leaves in response to iron deficiency. In iron-deficient roots, OsYSL9 was induced in the vascular cylinder but not in epidermal cells. Although OsYSL9-knockdown plants did not show a growth defect under iron-sufficient conditions, these plants were more sensitive to iron deficiency in the nonjuvenile stage compared with non transgenic plants. At the grain-filling stage, OsYSL9 expression was strongly and transiently induced in the scutellum of the embryo and in endosperm cells surrounding the embryo. The iron concentration was decreased in embryos of OsYSL9 knockdown plants but was increased in residual parts of brown seeds. These results suggested that OsYSL9 is involved in iron translocation within plant parts and particularly iron translocation from endosperm to embryo in developing seeds. PMID- 28871480 TI - Evaluation of disordered eating tendencies in young adults. AB - PURPOSE: It was aimed to determine the prevalence of high disordered eating tendencies and its relationship with food addiction, emotional eating and self esteem in participants at 18 and 33 years age group. METHODS: This study was planned as a cross-sectional study and conducted with 1359 young adult volunteers (M = 386, F = 973) with an average age of 22.4 +/- 2.84 years. Eating Attitudes Test-26 (EAT-26), Yale Food Addiction Scale (YFAS), Emotional Appetite Questionnaire (EMAQ) and Rosenberg Self-Esteem Scale (RSES) were used. EAT-26 score above 20 was considered as eating disorders risk cutoff. RESULTS: Participants with disordered eating tendencies have higher rates (22.4%) of food addiction compared to participants without high disordered eating tendencies (7.2%). There is no difference for EMAQ and YFAS scores; however, there is a significant difference for RSES and EAT-26 scores according to gender. A positive association of EAT-26 with YFAS and EMAQ-negative scores and a negative association of EAT-26 with RSES and EMAQ-positive were found. DISCUSSION: There is association among EAT-26, YFAS, and Rosenberg Self-Esteem Scale, and Emotional Appetite Questionnaire scores. This study provides information for future studies about high disordered eating tendencies, food addiction and mood that are thought to be important in young adults. LEVEL OF EVIDENCE: Level V (cross-sectional descriptive study). PMID- 28871482 TI - Global sagittal alignment. PMID- 28871483 TI - A comprehensive dose assessment of irradiated hand by iridium-192 source in industrial radiography. AB - Among the various incidents in industrial radiography, inadvertent handling of sources by hands is one of the most frequent incidents in which some parts of the hands may be locally exposed to high doses. An accurate assessment of extremity dose assists medical doctors in selecting appropriate treatments, preventing the injury expansion in the region. In this study, a phantom was designed to simulate a fisted hand of a radiographer when the worker holds a radioactive source in their hands. The local doses were measured using implanted TLDs in the phantom at different distances from a source. Furthermore, skin dose distribution was measured by Gaf-chromic films in the palm region of the phantom. The reliability of the measurements has been studied via analytical as well as Monte-Carlo simulation methods. The results showed that the new phantom design can be used reliably in extremity dose assessments, particularly at the points next to the source. PMID- 28871481 TI - Vascular Manifestations in Antiphospholipid Syndrome (APS): Is APS a Thrombophilia or a Vasculopathy? AB - PURPOSE OF REVIEW: Antiphospholipid antibody syndrome (APS) is characterized primarily by thrombosis and pregnancy morbidity. Chronic vascular lesions can also occur. While the underlying mechanisms of these vascular lesions are not entirely known, there have been multiple theories describing the potential process of vasculopathy in APS and the various clinical manifestations associated with it. RECENT FINDINGS: Recently, it has been demonstrated that endothelial proliferation in kidneys can be explained by the activation of the mammalian target of rapamycin complex (mTORC) pathway by antiphospholipid antibodies (aPL). These data support the existence of an APS-related vasculopathy in different locations which can explain-in part-the different manifestations of APS. This review focuses on the various manifestations of APS as a result of APS-related vasculopathy, as well as pathophysiology, current screening, and treatment options for clinicians to be aware of. PMID- 28871484 TI - EPR Oximetry Sensor-Developing a TAM Derivative for In Vivo Studies. AB - Oxygenation is one of the most important physiological parameters of biological systems. Low oxygen concentration (hypoxia) is associated with various pathophysiological processes in different organs. Hypoxia is of special importance in tumor therapy, causing poor response to treatment. Triaryl methyl (TAM) derivative radicals are commonly used in electron paramagnetic resonance (EPR) as sensors for quantitative spatial tissue oxygen mapping. They are also known as magnetic resonance imaging (MRI) contrast agents and fluorescence imaging compounds. We report the properties of the TAM radical tris(2,3,5,6 tetrachloro-4-carboxy-phenyl)methyl, (PTMTC), a potential multimodal (EPR/fluorescence) marker. PTMTC was spectrally analyzed using EPR and characterized by estimation of its sensitivity to the oxygen in liquid environment suitable for intravenous injection (1 mM PBS, pH = 7.4). Further, fluorescent emission of the radical was measured using the same solvent and its quantum yield was estimated. An in vitro cytotoxicity examination was conducted in two cancer cell lines, HT-29 (colorectal adenocarcinoma) and FaDu (squamous cell carcinoma) and followed by uptake studies. The stability of the radical in different solutions (PBS pH = 7.4, cell media used for HT-29 and FaDu cells culturing and cytotoxicity procedure, full rat blood and blood plasma) was determined. Finally, a primary toxicity test of PTMTC was carried out in mice. Results of spectral studies confirmed the multimodal properties of PTMTC. PTMTC was demonstrated to be not absorbed by cancer cells and did not interfere with luciferin-luciferase based assays. Also in vitro and in vivo tests showed that it was non-toxic and can be freely administrated till doses of 250 mg/kg BW via both i.v. and i.p. injections. This work illustrated that PTMTC is a perfect candidate for multimodal (EPR/fluorescence) contrast agent in preclinical studies. PMID- 28871485 TI - Inflammatory Response Occurs in Veins of Broiler Chickens Treated with a Selenium Deficiency Diet. AB - Selenium (Se) has been indicated to prevent chronic diseases including cancer, cardiovascular disease, and type 2 diabetes. However, a few studies have indicated that Se deficiency can induce vascular diseases. Thus, in the present study, we investigated the effect of Se deficiency on vascular pathology. A total of 60 male broiler chickens were randomly divided into 2 groups (n = 30). The control group (C group) was fed a basic diet, and the Se-deficient group (L group) was fed a Se-deficient, corn-soy-based diet. Changes in messenger RNA (mRNA) and protein levels of inflammatory factors and inflammation-related cytokines were examined by both RT-PCR and Western blot analysis. Our results indicate that the mRNA and protein levels of inflammatory factors and inflammation-related cytokines in the L group were significantly changed in the vein. In addition, principal component analysis (PCA) was used to define the most important parameters that could be used as key factors. The in vitro experiments also demonstrated that Se can enhance the anti-inflammatory ability of vein endothelial cells. In conclusion, Se deficiency induces an inflammatory response by modulating inflammatory factors and inflammation-related cytokines. PMID- 28871486 TI - Erratum to: TERT Promoter Mutation and Telomere Length in Salivary Gland Tumors. PMID- 28871487 TI - Fabry disease in children: a federal screening programme in Russia. AB - : Our objective was to examine the prevalence of Fabry disease in Russian children with chronic pain in the distal limbs. This non-interventional, multi centre study included children 2-18 years of age with chronic recurrent unilateral or bilateral pain, burning, or acroparesthesia in the hands or feet. The presence of Fabry disease was defined by abnormal alpha-galactosidase A activity in males or alpha-galactosidase gene (GLA) mutation in females. Among 214 patients (110 males), 84.1% had bilateral limb pain and 31.8% had unilateral limb pain recorded at some time point; 61 (28.5%) patients had a positive family history possibly associated with Fabry disease. Alpha-galactosidase A activity was within the normal range in all 109 of the male patients tested. One female patient had a GLA mutation (C937G > T) and alpha-galactosidase A activity within the normal range. CONCLUSION: We did not find definitive evidence of Fabry disease in these children with a history of chronic recurrent unilateral or bilateral limb pain or acroparesthesia. The presence of chronic limb pain does not appear to be highly predictive of a diagnosis of Fabry disease in Russian children and adolescents, suggesting that key early signs and symptoms of Fabry disease are not specific to the disease. What is Known: * Signs and symptoms of Fabry disease are seen in children < 10 years of age; pain in the distal limbs is a common early symptom. What is New: * Fabry disease was not diagnosed in this population of Russian children with a history of chronic limb pain. * The presence of acroparesthesia or chronic limb pain does not appear to be highly predictive of a diagnosis of Fabry disease in Russian children and adolescents, suggesting that these early symptoms of Fabry disease are not specific to the disease. PMID- 28871488 TI - Radio-Protective Effects of Melatonin on Subventricular Zone in Irradiated Rat: Decrease in Apoptosis and Upregulation of Nestin. AB - Neural stem cells are self-renewing, multipotent cells that can be found in subventricular (SVZ) and subgranular (SGZ) zones of the brain. These zones are susceptible to irradiation-induced apoptosis and oxidative stress. Melatonin (MLT) is a natural protector of neural cells against toxicity. The aim of this study was to evaluate the effects of MLT as a radio-protective material effective in reducing tissue lesions in the SVZ of the brain and changing local apoptotic potential in rats. Twenty-five Gray irradiation was applied on adult rat brain for this study. One hour before irradiation, 100 mg/kg/IP MLT was injected, and 6 h later, the animals were sacrificed. The antioxidant enzymes and MDA activity levels were measured post-sacrifice. Also, the expression level of Nestin and caspase 3 were studied by immunohistochemistry. Spectrophotometric analysis showed significant increases in the amount of malondialdehyde (MDA) levels in the irradiation-exposed (RAD) group compared to that of the control (Co) group (P < 0.05). Pre-treatment with MLT (100 mg/kg) ameliorates the harmful effects of the aforementioned 25 Gy irradiation by increasing antioxidant enzyme activity and decreasing MDA levels. A significant reduction in apoptotic cells was observed in rats treated with MLT 1 h before exposure (P < 0.001). Nestin-positive cells were also reduced in the RAD group (P < 0.001). Our results confirm the anti-apoptotic and antioxidant role of MLT. The MLT concentration used may serve as a threshold for significant protection against 25 Gy gamma irradiations on neural stem cells in SVZ. PMID- 28871489 TI - What Role for Parental Attributions in Parenting Interventions for Child Conduct Problems? Advances from Research into Practice. AB - The role of parental attributions in parenting interventions has been the subject of intense interest from clinicians and researchers attempting to optimise outcomes in treatments for children with conduct problems. Despite research articulating the many ways parental attributions can influence behavioural parent training (BPT) outcomes, and recognition that addressing parental attributions in treatment is one of the great challenges faced by BPT practitioners, parenting interventions generally do not provide components that explicitly target or focus on changing problematic parental attributions. In this paper, we ask 'Should parental attributions be included into best practice interventions? If so, how can this be done in a way that improves outcomes without cluttering and complicating the parent training model?' We review the theoretical and empirical status of our understanding of the role of parental attributions in BPT with reference to three questions: 'do pre-treatment parental attributions uniquely predict treatment outcomes'; 'do changes in parental attributions uniquely predict treatment outcomes'; and 'does targeting parental attributions in BPT affect treatment outcomes'. Our review indicates that existing research supports the importance of focussing on parental attributions for some families in order to maximise treatment outcomes. However, clinical processes for doing this are yet to be identified and specified in a way that would allow for manualised replication and scrutiny in research designs. We finish with a discussion of how these clinical and research challenges could be approached. PMID- 28871490 TI - A comparison of the responsiveness of EQ-5D-5L and the QOLIE-31P and mapping of QOLIE-31P to EQ-5D-5L in epilepsy. AB - OBJECTIVE: To investigate the responsiveness of and correlation between the EQ-5D 5L and the QOLIE-31P in patients with epilepsy, and develop a mapping function to predict EQ-5D-5L values based on the QOLIE-31P for use in economic evaluations. METHODS: The dataset was derived from two clinical trials, the ZMILE study in the Netherlands and the SMILE study in the UK. In both studies, patients' quality of life using the EQ-5D-5L and QOLIE-31P was measured at baseline and 12 months follow-up. Spearman's correlations, effect sizes (EF) and standardized response means (SRM) were calculated for both the EQ-5D-5L and QOLIE-31P domains and sub scores. Mapping functions were derived using ordinary least square (OLS) and censored least absolute deviations models. RESULTS: A total of 509 patients were included in this study. Low to moderately strong significant correlations were found between both instruments. The EQ-5D-5L showed high ceiling effects and small EFs and SRMs, whereas the QOLIE-31P did not show ceiling effects and also showed small to moderate EFs and SRMs. Results of the different mapping functions indicate that the highest adjusted R 2 we were able to regress was 0.265 using an OLS model with squared terms, leading to a mean absolute error of 0.103. CONCLUSIONS: Results presented in this study emphasize the shortcomings of the EQ 5D-5L in epilepsy and the importance of the development of condition-specific preference-based instruments which can be used within the QALY framework. In addition, the usefulness of the constructed mapping function in economic evaluations is questionable. PMID- 28871491 TI - Robust age, but limited sex, differences in mu-opioid receptors in the rat brain: relevance for reward and drug-seeking behaviors in juveniles. AB - In the brain, the u-opioid receptor (MOR) is involved in reward-seeking behaviors and plays a pivotal role in the mediation of opioid use disorders. Furthermore, reward-seeking behaviors and susceptibility to opioid addiction are particularly evident during the juvenile period, with a higher incidence of opioid use in males and higher sensitivity to opioids in females. Despite these age and sex differences in MOR-mediated behaviors, little is known regarding potential age and sex differences in the expression of MORs in the brain. Here, we used receptor autoradiography to compare MOR binding densities between juvenile and adult male and female rats. Age differences were found in MOR binding density in 12 out of 33 brain regions analyzed, with 11 regions showing higher MOR binding density in juveniles than in adults. These include the lateral septum, as well as sub-regions of the bed nucleus of the stria terminalis, hippocampus, and thalamus. Sex differences in MOR binding density were observed in only two brain regions, namely, the lateral septum (higher in males) and the posterior cortical nucleus of the amygdala (higher in females). Overall, these findings provide an important foundation for the generation of hypotheses regarding differential functional roles of MOR activation in juveniles versus adults. Specifically, we discuss the possibility that higher MOR binding densities in juveniles may allow for higher MOR activation, which could facilitate behaviors that are heightened during the juvenile period, such as reward and drug-seeking behaviors. PMID- 28871492 TI - Frequency of Antibiotic-Associated Diarrhea and Related Complications in Pediatric Patients Who Underwent Hypospadias Repair: a Comparative Study Using Probiotics vs Placebo. AB - This study aimed to evaluate the effectiveness of probiotics (Lactobacillus rhamnosus GG), as a preventive measure of antibiotic-associated diarrhea (AAD) in children who underwent hypospadias repair and its clinical consequences on postoperative outcome, comparing the group treated with probiotics + antibiotics with two control groups (only antibiotics and antibiotics + placebo). We performed a prospective, randomized, placebo-controlled study with three groups of patients (30 boys for each group) who underwent hypospadias repair in our unit from March 2016 to December 2016. G1 received antibiotics + probiotics (L. rhamnosus GG), while G2 and G3 respectively received only antibiotics or antibiotics + placebo (glucose solution at 5%) for the same period. The patients were evaluated in regard to the number of evacuations/day, stool consistency, and the number of dressings/day. The overall incidence of postoperative AAD was 33.3% (30/90), and it was statistically lower in G1 patients compared to G2 and G3 ones (p = 0.002). The duration of AAD was significantly longer in G2 and G3 compared to G1 (p = 0.001). In G1, the frequency of dressing change was significantly lower compared to G2 and G3 (p = 0.001).The incidence of postoperative complications (fistula and dehiscence) was significantly higher in G2 and G3 compared to G1 (p = 0.001). Our study confirmed that the use of probiotic L. rhamnosus GG associated with antibiotics significantly reduced the incidence and the duration of postoperative AAD. In addition, the use of probiotics LGG reduced the frequency of dressing changes and the incidence of postoperative complications, such as urethral fistula and foreskin dehiscence. PMID- 28871494 TI - Delignification and detoxification of peanut shell bio-waste using an extremely halophilic laccase from an Aquisalibacillus elongatus isolate. AB - Lignocellulose bioconversion is a harsh process requiring the use of surfactants and organic solvents. Consequently, the incorporation of laccases in this bioconversion requires the bioprospecting of enzymes that can remain stable under extreme conditions. An extracellular, highly stable laccase was produced by the halophilic isolate Aquisalibacillus elongatus in submerged liquid culture fermentation. Statistical and non-statistical strategies gave the highest enzymatic activity (8.02 U mL-1) following addition of glucose (1.7 g L-1), copper sulfate (0.8 g L-1), urea (15 g L-1), and CaCl2 (0.8 g L-1). The enzyme, after purification using a synthetic affinity support, delignified a peanut shell substrate by 45%. A pH of 8.0 and a temperature of 35 degrees C were optimal for delignification of this bio-waste material. Addition of [Bmim][PF6], 1,4-dioxane, acetone, and HBT promoted this bio-waste delignification. Bio-treatment in the presence of 50% [Bmim][PF6] gave a maximal lignin removal of 87%. The surfactants tested had no significant effects on the delignification yield. The laccase also detoxified the toxic phenols found in peanut shell waste. The high catalytic efficiency of this enzyme against a lignocellulosic sample under extreme conditions suggests the suitability of this laccase for industrial applications. PMID- 28871495 TI - Responding to Other People's Direct Gaze: Alterations in Gaze Behavior in Infants at Risk for Autism Occur on Very Short Timescales. AB - Atypical gaze processing has been reported in children with autism spectrum disorders (ASD). Here we explored how infants at risk for ASD respond behaviorally to others' direct gaze. We assessed 10-month-olds with a sibling with ASD (high risk group; n = 61) and a control group (n = 18) during interaction with an adult. Eye-tracking revealed less looking at the adult in the high risk group during 300-1000 ms after the adult initiated direct gaze: a short alteration that is likely to go unnoticed by the naked eye. Data aggregated over longer segments (the traditional eye-tracking approach) showed no group differences. Although findings are limited by lack of outcome data, they are in line with theories linking atypical eye processing to the emergence of ASD. PMID- 28871496 TI - Factors influencing As(V) stabilization in the mine soils amended with iron-rich materials. AB - Chemical stability of As(V) in amended mine-impacted soils was assessed according to functions of incubation period (0, 1, 2, 4, and 6 months), amendment dose (2.5 and 5%), and application timing (0 and 3rd month). Six soils contaminated with 26 209 mg kg-1 of As(V) were collected from two abandoned mine sites and were treated with two alkaline iron-rich materials (mine discharge sludge (MS) and steel-making slag (SS)). Seventeen to 23% of As(V) in soils was labile. After each designated time, As(V) stability was assessed by the labile fractions determined with sequential extraction procedures (F1-F5). Over 6 months, a reduction (26.9-70.4%) of the two labile fractions (F1 and F2) and a quantitative increase (7.4-29.9%) of As(V) in F3 were observed (r 2 = 0.956). Two recalcitrant fractions (F4 and F5) remained unchanged. Temporal change of As(V) stability in a sample was well described by the two-domain model (k fast, k slow, and Ffast). The stabilization (%) correlated well with the fast-stabilizing domain (Ffast), clay content (%), and Fe oxide content (mg kg-1), but correlated poorly with kinetic rate constants (k fast and k slow). Until the 3rd month, the 2.5%-MS amended sample resulted in lower As(V) stabilization (25-40%) compared to the 5% sample (50-60%). However, the second 2.5% MS addition on the 2.5% sample upon the lapse of the 3rd month led to a substantial reduction (up to 38%) of labile As(V) fraction in the following 4th and 6th months. As a result, an additional 15-25% of As(V) stability was obtained when splitting the amendment dose into 3-month intervals. In conclusion, the As(V) stabilization by Fe-rich amendment is time dependent and its efficacy can be improved by optimizing the amendment dose and its timing. PMID- 28871493 TI - Plant and animal aquaporins crosstalk: what can be revealed from distinct perspectives. AB - Aquaporins (AQPs) can be revisited from a distinct and complementary perspective: the outcome from analyzing them from both plant and animal studies. (1) The approach in the study. Diversity found in both kingdoms contrasts with the limited number of crystal structures determined within each group. While the structure of almost half of mammal AQPs was resolved, only a few were resolved in plants. Strikingly, the animal structures resolved are mainly derived from the AQP2-lineage, due to their important roles in water homeostasis regulation in humans. The difference could be attributed to the approach: relevance in animal research is emphasized on pathology and in consequence drug screening that can lead to potential inhibitors, enhancers and/or regulators. By contrast, studies on plants have been mainly focused on the physiological role that AQPs play in growth, development and stress tolerance. (2) The transport capacity. Besides the well-described AQPs with high water transport capacity, large amount of evidence confirms that certain plant AQPs can carry a large list of small solutes. So far, animal AQP list is more restricted. In both kingdoms, there is a great amount of evidence on gas transport, although there is still an unsolved controversy around gas translocation as well as the role of the central pore of the tetramer. (3) More roles than expected. We found it remarkable that the view of AQPs as specific channels has evolved first toward simple transporters to molecules that can experience conformational changes triggered by biochemical and/or mechanical signals, turning them also into signaling components and/or behave as osmosensor molecules. PMID- 28871497 TI - Safety and Efficacy of a New Swallowable Intragastric Balloon Not Needing Endoscopy: Early Italian Experience. AB - PURPOSE: The aim of this study was to evaluate the safety and efficacy of a new intragastric balloon (ElipseTM Balloon, Allurion Technologies, Natick, MA USA) not needing endoscopy. MATERIALS AND METHODS: The balloon was swallowed under fluoroscopy in 38 consecutive patients (F/M 28/10, mean age 46.4 +/- 10.6 years, mean weight 109.7 +/- 21.9 kg, and mean body mass index (BMI) 38.6 +/- 6.7 kg/m2). After 4 months, the balloon spontaneously emptied and it was excreted through the digestive tract without upper endoscopy. RESULTS: There were no complications during balloon passage. After 16 weeks, the mean weight loss was 12.7 kg, mean percent excess weight loss was 26%, and mean BMI reduction was 4.2 kg/m2. Total body weight loss was 11.6%. There was a significant reduction in major co-morbidities related to metabolic syndrome: blood pressure (p < 0.02), waist circumference (p < 0.002), triglycerides (p < 0.0001), blood glucose (p < 0.001), and HOMA-IR index (p < 0.001). At the end of the treatment, 37 balloons were naturally excreted in the stool, and one balloon was endoscopically removed. CONCLUSIONS: The results of this study on 38 consecutive patients demonstrate that the ElipseTM Balloon is safe, effective, and very well accepted by patients. PMID- 28871498 TI - Tangeretin ameliorates renal failure via regulating oxidative stress, NF-kappaB TNF-alpha/iNOS signalling and improves memory and cognitive deficits in 5/6 nephrectomized rats. AB - Chronic kidney disease (CKD) is a significant global health concern with limited treatment options. Oxidative stress and inflammatory responses have been implicated in the pathology of CKD. Patients with CKD are frequently affected with neurological complications that affect both the central and peripheral nervous system. Identification of effective treatment strategies are of much clinical value in the therapy of CKD. Tangeretin, a plant-derived flavonoid has been described to retain extensive pharmacological properties. In the present study, we explored whether tangeretin exerted protective effects in 5/6 nephrectomized rats. CKD was induced in Sprague-Dawley rats by 5/6 nephrectomy (Nx). Separate groups of 5/6 Nx rats were treated with tangeretin (50, 100 or 200 mg/kg b.wt.) or enalapril for 30 days (starting 5 days after surgery for 35 days). Control animals were not subjected to Nx nor were treated with tangeretin or enalapril. Renal dysfunction, as evinced by raised serum urea, serum creatinine, proteinuria, and histological alterations were significantly reduced by tangeretin and enalapril treatment. 5/6 Nx animals exhibited raised levels of malondialdehyde (MDA) and reactive oxygen species. Elevated TNF-alpha, nitric oxide (NO) and cytokines-IL-6 and IL-1beta with upregulated NF-kappaB/TNF alpha/iNOS signalling pathways were effectively down-regulated by tangeretin. Cognitive disturbances and memory impairments observed in Nx rats were substantially improved by tangeretin. Collectively, the experimental data indicate that the anti-oxidant and anti-inflammatory effects of tangeretin effectively improved renal function and reduced the cognitive and memory impairments in CKD-induced animals. PMID- 28871499 TI - A Prospective Evaluation of Ileocecal Valve Dysfunction and Intestinal Motility Derangements in Small Intestinal Bacterial Overgrowth. AB - BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is an increasingly recognized clinical syndrome; however, its etiophathogenesis is poorly understood. We hypothesized that loss of gastric acid, a delayed intestinal transit, and ileocecal valve dysfunction may contribute to the genesis of this syndrome. AIMS: Our primary aim was to assess these parameters using wireless motility capsule (WMC) testing and to correlate them with the presence or absence of SIBO. METHODS: We prospectively evaluated 30 consecutive patients at a tertiary care center with suspected SIBO, diagnosed by lactulose hydrogen breath testing (LBT), and small bowel aspirate microbiology. Patients underwent WMC testing to assess ileocecal junction pressure (ICJP), small bowel transit time (SBTT), and regional gastrointestinal pH. RESULTS: Thirty patients completed testing; 15 had a positive LBT, and 11 had a positive aspirate culture. As compared with LBT-negative patients, ICJP was lower (27.8 vs. 72.7 mmHg, p = 0.027), SBTT was longer (10.0 vs. 1.1 h, p = 0.004), gastric pH was higher (3.63 vs. 2.42, p < 0.01), and small bowel pH was higher (6.96 vs. 6.61, p = 0.05). A hypotensive ICJP (<46.61 mmHg) was more prevalent in LBT-positive patients as compared with LBT-negative patients (73.3 vs. 14.29%, p = 0.003). Logistic regression models were used to assess the magnitude of each measured WMC parameter and the presence of SIBO. p values <=0.05 were considered statistically significant. CONCLUSIONS: Patients with SIBO have significantly lower ICJP, prolonged SBTT, and a higher gastrointestinal pH as compared to those without SIBO. These abnormalities may play different roles in the pathogenesis of SIBO, facilitating more targeted treatment to prevent recurrences of SIBO. PMID- 28871501 TI - Body mass index is an independent predictive factor for kidney function evaluated by glomerular filtration rate in a community-dwelling population. AB - BACKGROUND: The effects of overweight and obesity on kidney function have since been identified and become a subject of increased study and concern. But the association between body mass index (BMI) and estimated glomerular filtration rate (eGFR) is not well characterized. The aim of this study was to determine the relationship between BMI and eGFR. METHODS: To better understand the relationship between BMI and kidney function, we investigated the association between BMI and eGFR using both the baseline BMI level and the follow-up eGFR level and investigated the relationship between the change in BMI and the change in eGFR in 1447 patients from a 4.8-year prospective study in Beijing, People's Republic of China. RESULTS: In multiple linear regression analysis, age, antihypertensive treatment, and BMI were negatively associated with the follow-up eGFR levels in all participants (R = -0.622, -0.926, and -0.266, respectively; P < 0.05), or in the elderly (R = -0.883, -1.035, and -0.630, respectively; P < 0.05); sex was found to be associated with the follow-up eGFR levels independently not only in all participants (R = 6.783; P < 0.001), but also in the elderly (R = 3.518; P < 0.05). In addition, the change in eGFR levels was positively related to age, the change in LDL-C, the change in TC, and the change in SBP, but negatively related to the change in BMI and the change in HDL-C (all P < 0.05). CONCLUSIONS: The present study clearly indicated that BMI is an independent predictive factor for kidney function evaluated by the eGFR level during a median 4.8 years of follow up in Chinese population. LEVEL OF EVIDENCE: Level III, prospective cohort study. PMID- 28871502 TI - Science and Sentiment: Grinnell's Fact-Based Philosophy of Biodiversity Conservation. AB - At the beginning of the twentieth century, the biologist Joseph Grinnell made a distinction between science and sentiment for producing fact-based generalizations on how to conserve biodiversity. We are inspired by Grinnellian science, which successfully produced a century-long impact on studying and conserving biodiversity that runs orthogonal to some familiar philosophical distinctions such as fact versus value, emotion versus reason and basic versus applied science. According to Grinnell, unlike sentiment-based generalizations, a fact-based generalization traces its diverse commitments and thus becomes tractable for its audience. We argue that foregrounding tractability better explains Grinnell's practice in the context of his time as well as in the context of current discourse among scientists over the political "biases" of biodiversity research and its problem of "reproducibility." PMID- 28871500 TI - Computational neuroanatomy of human stratum proprium of interparietal sulcus. AB - Recent advances in diffusion-weighted MRI (dMRI) and tractography have enabled identification of major long-range white matter tracts in the human brain. Yet, our understanding of shorter tracts, such as those within the parietal lobe, remains limited. Over a century ago, a tract connecting the superior and inferior parts of the parietal cortex was identified in a post-mortem study: stratum proprium of interparietal sulcus (SIPS; Sachs, Das hemispharenmark des menschlichen grosshirns. Verlag von georg thieme, Leipzig, 1892). The tract has since been replicated in another fibre dissection study (Vergani et al., Cortex 56:145-156, 2014), however, it has not been fully investigated in the living human brain and its precise anatomical properties are yet to be described. We used dMRI and tractography to identify and characterise SIPS in vivo, and explored its spatial proximity to the cortical areas associated with optic-flow processing using fMRI. SIPS was identified bilaterally in all subjects, and its anatomical position and trajectory are consistent with previous post-mortem studies. Subsequent evaluation of the tractography results using the linear fascicle evaluation and virtual lesion analysis yielded strong statistical evidence for SIPS. We also found that the SIPS endpoints are adjacent to the optic-flow selective areas. In sum, we show that SIPS is a short-range tract connecting the superior and inferior parts of the parietal cortex, wrapping around the intraparietal sulcus, and that it may be a crucial anatomy underlying optic-flow processing. In vivo identification and characterisation of SIPS will facilitate further research on SIPS in relation to cortical functions, their development, and diseases that affect them. PMID- 28871503 TI - Optimization and in line potentiometric monitoring of enhanced photocatalytic degradation kinetics of gemifloxacin using TiO2 nanoparticles/H2O2. AB - Gemifloxacin (GEM) is a broad-spectrum quinolone antibiotic. The presence of GEM residuals in industrial and hospital wastewater has been associated with genotoxicity and antibiotic resistance. In this contribution, the photodegradation of GEM using titanium dioxide nanoparticles (TiO2NPs)/H2O2 as a catalyst was optimized to eliminate residual drug and its photodegradates with antibacterial activity. A half-factorial design was implemented, investigating the effects of pH, initial concentration, H2O2 concentration, TiO2NP loading, and irradiation time. Owing to the time-dependent, multi-transformation of GEM into a wide range of structurally related photodegradation products, the monitoring of GEM throughout the experiments was achieved using both HPLC and potentiometric ion-selective electrodes (ISE). The sensor enabled in-line tracking of residual GEM in the presence of its photodegradates in real time. Results indicated that the pH, irradiation time, and GEM initial concentration were the most significant factors. At the optimum set of experimental conditions, the reaction followed first-order reaction kinetics with a mean percentage degradation of ~ 95% in less than 30 min of irradiation time and almost complete loss of antibacterial activity against Escherichia coli. The promising results demonstrated the efficiency of UV/TiO2NP/H2O2 as a photocatalyst for the breakdown of the pharmacophore of fluoroquinolones from water samples. The high selectivity, minimal solvent consumption, and lack of harmful waste generation confirmed the superiority of in-line monitoring using ISE. Optimization and in-line monitoring protocol should be applicable also at the pharmaceutical industry scale to eliminate the risk of antibiotic resistance. PMID- 28871504 TI - Using EEG Frontal Asymmetry to Predict IT User's Perceptions Regarding Usefulness, Ease of Use and Playfulness. AB - Information systems (IS) community is increasingly interested in employing neuroscience tools and methods in order to develop new theories concerning Human computer interaction (HCI) and further understand IS acceptance models. The new field of NeuroIS has been introduced to address these issues. NeuroIS researchers have proposed encephalography (EEG), among other neuroscience instruments, as a valuable usability metric, when used effectively in appropriately designed experiments. Moreover, numerous researchers have suggested that EEG frontal asymmetry may serve as an important metric of user experience. Based on the aforementioned evidence, this study aims to integrate frontal asymmetry with Technology acceptance model (TAM). Particularly, we assumed that frontal asymmetry might predict users' perceptions regarding Usefulness and Ease of Use. Furthermore, we hypothesized that frontal asymmetry might also affect (influence) users' Perceived Playfulness. Specifically, 82 (43 females and 39 males) undergraduate students were chosen to use a Computer-Based Assessment (while being connected to the EEG) in the context of an introductory informatics course. Results confirmed our hypothesis as well as points of theory about Information technology (IT) acceptance variables. This is one of the first studies to suggest that frontal asymmetry could serve as a valuable tool for examining IT acceptance constructs and better understanding HCI. PMID- 28871505 TI - Changing etiology and management patterns for spontaneous renal hemorrhage: a systematic review of contemporary series. AB - OBJECTIVE: To conduct a systematic literature review on spontaneous renal hemorrhage (SRH) in a contemporary cohort describing patterns in etiology and treatment. METHODS: A systematic search of MEDLINE and CENTRAL databases was conducted to include articles, including case reports and case series on SRH published from 2000 to 2016. Full-text manuscripts were reviewed for clinical parameters which were collated and analyzed with univariate methods. RESULTS: Seventy-nine publications met inclusion criteria, reporting on 102 cases. Renal neoplasms (56.9%) and polyarteritis nodosa (PAN) (11.8%) remained as the most common overall and vascular causes of SRH, respectively. Angiomyolipoma (AML) was the most common causative renal neoplasm (74.1%), and patients were more likely to be female and present with macroscopic hematuria than those with vasculitis, while malignant neoplasms were more common in men. Proportions of SRH due to malignant neoplasms (specifically renal cell carcinoma, RCC) were reported less than PAN. Among this contemporary series, transarterial embolization (TAE) was most commonly used for acute SRH (42.2%). CONCLUSIONS: Renal neoplasms remain as the most common cause of SRH, of which AML predominates, while PAN is currently the second most common etiology in acute SRH, replacing RCC. Minimally invasive approaches, such as TAE and conservative/medical management, were preferred to initial surgery. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42017069222. PMID- 28871506 TI - Evaluation of Project RISE, an HIV Prevention Intervention for Black Bisexual Men Using an Ecosystems Approach. AB - Black men who have sex with men and women (MSMW) are among the populations at highest risk for HIV infection. We describe the evaluation of Project RISE, a six session individual-level intervention developed for black MSMW using an ecosystems approach. A randomized controlled trial was used to test the effect of the intervention on sexual risk outcomes. Eligibility criteria included having both male and female sex partners in the past 12 months. Complete data at 5-month follow-up were collected from 86.7% of the 165 participants. In analyses controlling for HIV status, age, and baseline risk, intervention participants were found to have significantly greater reductions in number of female partners (p < 0.05) and total male and female partners (p < 0.05) at follow-up, compared to the control group. Intervention participants also were significantly more likely to report a reduction in number of sex episodes without a condom with female partners (p < 0.05) and with all partners (p < 0.02) at follow-up, compared to the control group. PMID- 28871507 TI - Delayed post-operative tension pneumocephalus and pneumorrhachis. AB - INTRODUCTION: The incidence of pneumocephalus and pneumorrhachis after spinal surgery is unknown, with a paucity of literature on this complication. MATERIALS AND METHODS: We present the first published case of delayed onset tension pneumocephalus and pneumorrhachis associated with spinal surgery. RESULTS: This complication occurred from a cerebro-spinal fluid (CSF) leak after posterior instrumentation removal and was successfully treated with emergent wound debridement and the formation of a CSF fistula. CONCLUSIONS: This case illustrates that delayed post-operative tension pneumocephalus and pneumorrhachis can occur after spinal surgery in a patient with a CSF leak. It also illustrates that pneumocephalus and pneumorrhachis can be easily diagnosed with cross sectional CT imaging. Furthermore, in a patient with rapid deterioration emergent surgical debridement may be necessary. Lastly, if the dural tear cannot be identified intra-operatively, the formalization of a CSF fistula should be considered. PMID- 28871509 TI - Atypical purging behaviors in a patient with anorexia nervosa: consumption of raw red kidney beans as an emetic. PMID- 28871508 TI - A Novel Role of a Chemotherapeutic Agent in a Rat Model of Endotoxemia: Modulation of the STAT-3 Signaling Pathway. AB - Sepsis caused by lipopolysaccharide (LPS) is a life-threatening disease accompanied by multiple organ failure. This study investigated the curative effects of imatinib (IMA) against hepatic, renal, and pulmonary responses caused by a single administration of LPS (10 mg/kg, i.p.) in rats. Treatment with IMA (15 mg/kg, i.p.) 30 min after LPS antagonized the LPS-induced boost of liver enzymes (ALT, AST), kidney functions (BUN, sCr) as well as the elevated pulmonary vascular permeability and edema. IMA declined tissue contents of NF-kappaB, STAT 3, P38-MAPK, TNF-alpha, IL-1beta, and iNOS. It also amplified the anti inflammatory cytokine IL-10 as well as the Bcl-2/Bax ratio, a cardinal indicator of the anti-apoptotic effect. Meanwhile, the rats exhibited marked reduction of the broncho-alveolar lavage fluid (BALF) contents of TNF-alpha, IL-1beta, IFN gamma, and neutrophil count; however, they revealed prominent augmentation of the BALF content IL-10. In conclusion, these findings suggest that IMA is endowed with anti-inflammatory, anti-oxidant, and anti-apoptotic properties and hence may provide a novel agent for the management of sepsis. PMID- 28871511 TI - Nurses' work with interruptions: an objective model for testing interventions. AB - Interruptions experienced by nurses may lead to errors as their focus and attention to multiple patient needs are disrupted. As quantitative models to understand the dynamics of interruptions are lacking, the objective of this study is a model of a nurse's work with interruptions, generating insights into the onset of interruptions and evaluating suggested interventions. We observed nurses in a US Level I trauma center for 47.3 h, including 259 interruptions (9.1% of total time) across 580 nursing activities. A stochastic, non-stationary, model of a nurse's work was developed considering source and activity-dependent interruptions, with parameters clustered across similar periods of day. Two interventions emulating 'do not disturb' strategies were evaluated, along with a more focused intervention from suggestions that nurses' phone calls be 'triaged'. Modeled outcomes included the increase in interruptions in other activities due to deferment and changes to the beneficial/detrimental interruption (B/D) ratio. Across-the-board sequestering of nurses by deferring interruptions during medication increased the B/D ratio 17% (1.35 vs. 1.58), but resulted in an unforeseen 73% (1.04/h vs. 1.80/h) increase in interruptions during direct care. In contrast, the focused intervention (deferring only those interruptions arriving via cell phone during medication and direct care), netted a 31% improvement in the B/D ratio (1.29 vs. 1.69) and with moderated (< 0.13/h) impact on interruptions during other activities. Modeling the dynamics of the onset of interruptions reveals the potentially negative impact of across-the-board interventions, and the advantage of focused interventions anticipating unmet needs before they present as interruptions. PMID- 28871510 TI - Cyto-histology in NET: what is necessary today and what is the future? AB - The carcinoid as originally described is part of the relatively large family of neuroendocrine neoplasia found in almost every organ. Historical reasons back their current definitions. Neuroendocrine cancer is most frequently observed in the lung and the digestive tract. In the lung is defined as carcinoid (typical and atypical) for well differentiated, low to intermediate grade, and small cell and large cell neuroendocrine carcinoma for poorly differentiated, high grade. In the digestive system are respectively defined as neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC) of small and large cell types. Grading and staging are developed for their clinical classification by the World Health Organization (WHO) and the American Joint Committee on Cancer (AJCC). In both anatomical sites the morphological features are overlapping, with bland histology for carcinoid and NET, and aggressive features with extensive necrosis, severe atypia and abundant, atypical mitoses for high grade cancer types. Such features are also essential diagnostic clues in cytological preparations. The confirmation of the neuroendocrine signature by immunohistochemistry is mandatory for the diagnosis; a minimum panel comprising chromogranin A and synaptophysin is recommended in the digestive system. In addition, the application of grading requires the mitotic count and or spotty necrosis assessment for lung, or the mitotic count and the Ki67 assessment in the digestive system. PMID- 28871512 TI - Decision Making and Priority Setting: The Evolving Path Towards Universal Health Coverage. AB - Health technology assessment (HTA) is widely viewed as an essential component in good universal health coverage (UHC) decision-making in any country. Various HTA tools and metrics have been developed and refined over the years, including systematic literature reviews (Cochrane), economic modelling, and cost effectiveness ratios and acceptability curves. However, while the cost effectiveness ratio is faithfully reported in most full economic evaluations, it is viewed by many as an insufficient basis for reimbursement decisions. Emotional debates about the reimbursement of cancer drugs, orphan drugs, and end-of-life treatments have revealed fundamental disagreements about what should and should not be considered in reimbursement decisions. Part of this disagreement seems related to the equity-efficiency tradeoff, which reflects fundamental differences in priorities. All in all, it is clear that countries aiming to improve UHC policies will have to go beyond the capacity building needed to utilize the available HTA toolbox. Multi-criteria decision analysis (MCDA) offers a more comprehensive tool for reimbursement decisions where different weights of different factors/attributes can give policymakers important insights to consider. Sooner or later, every country will have to develop their own way to carefully combine the results of those tools with their own priorities. In the end, all policymaking is based on a mix of facts and values. PMID- 28871514 TI - A Scoping Review of Economic Evaluations Alongside Randomised Controlled Trials of Home Monitoring in Chronic Disease Management. AB - Many countries have considered telemedicine and home monitoring of patients as a solution to the demographic challenges that health-care systems face. However, reviews of economic evaluations of telemedicine have identified methodological problems in many studies as they do not comply with guidelines. The aim of this study was to examine economic evaluations alongside randomised controlled trials of home monitoring in chronic disease management and hereby to explore the resources included in the programme costs, the types of health-care utilisation that change as a result of home monitoring and discuss the value of economic evaluation alongside randomised controlled trials of home monitoring on the basis of the studies identified. A scoping review of economic evaluations of home monitoring of patients with chronic disease based on randomised controlled trials and including information on the programme costs and the costs of equipment was carried out based on a Medline (PubMed) search. Nine studies met the inclusion criteria. All studies include both costs of equipment and use of staff, but there is large variation in the types of equipment and types of tasks for the staff included in the costs. Equipment costs constituted 16-73% of the total programme costs. In six of the nine studies, home monitoring resulted in a reduction in primary care or emergency contacts. However, in total, home monitoring resulted in increased average costs per patient in six studies and reduced costs in three of the nine studies. The review is limited by the small number of studies found and the restriction to randomised controlled trials, which can be problematic in this area due to lack of blinding of patients and healthcare professionals and the difficulty of implementing organisational changes in hospital departments for the limited period of a trial. Furthermore, our results may be based on assessments of older telemedicine interventions. PMID- 28871515 TI - A thermostable pyrimidine nucleoside phosphorylase from Brevibacillus borstelensis LK01 for synthesizing halogenated nucleosides. AB - OBJECTIVE: To isolate a thermostable pyrimidine nucleoside phosphorylase (PyNP) from mesophilic bacteria by gene mining. RESULTS: BbPyNP from Brevibacillus borstelensis LK01 was isolated by gene mining. BbPyNP had a highest 60% identity with that of reported PyNPs. BbPyNP could catalyze the phosphorolysis of thymidine, 2'-deoxyuridine, uridine and 5-methyuridine. BbPyNP had good thermostability and retained 73% of its original activity after 2 h incubation at 50 degrees C. BbPyNP had the highest activity at an optimum alkaline pH of 8.5. BbPyNP was stable from pH 7 to 9.8. Under preliminary optimized conditions, the biosynthesis of various 5-halogenated pyrimidine nucleosides by BbPyNP reached the yield of 61-84%. CONCLUSION: An efficient approach was estimated in isolating thermostable PyNP from mesophilic bacteria. PMID- 28871516 TI - Stability and Change in In-Group Mate Preferences among Young People in Ethiopia Are Predicted by Food Security and Gender Attitudes, but Not by Expected Pathogen Exposures. AB - There is broad anthropological interest in understanding how people define "insiders" and "outsiders" and how this shapes their attitudes and behaviors toward others. As such, a suite of hypotheses has been proposed to account for the varying degrees of in-group preference between individuals and societies. We test three hypotheses related to material insecurity, pathogen stress, and views of gender equality among cross-sectional (n = 1896) and longitudinal (n = 1002) samples of young people in Ethiopia (aged 13-17 years at baseline) to explore stability and change in their preferences for coethnic spouses. We show that food insecurity is associated with a greater likelihood of intolerant mate preferences. We also find that young people who hold more gender equitable attitudes tended to hold more tolerant mate preferences. Finally, we find no support for the hypothesis that expected pathogen exposure is associated with intolerant mate preferences. Our results most strongly support a material insecurity hypothesis of in-group bias, which assumes that uncertainty over meeting basic needs leads people to favor those in their in-group. As such, our findings join a small but growing group of studies that highlight the importance of material insecurity for understanding tolerance, xenophobia, in-group bias, and favoritism. PMID- 28871517 TI - Evaluation of the content of Zn, Cu, Ni and Pb as well as the enzymatic activity of forest soils exposed to the effect of road traffic pollution. AB - The paper evaluates the contents of total forms of selected heavy metals (Zn, Cu, Ni and Pb) as well as the activity of catalase (CAT), dehydrogenases (DEH), alkaline phosphatase (AlP) and acid phosphatase (AcP) in mineral surface horizons of forest soils exposed to the effect of road traffic pollutions. The sampling locations (n = 24) were determined in the area covered by the Szubin Forest along the exit road from Bydgoszcz to Poznan (provincial road no. 223). Soil was sampled 25 m away from the traffic lane, from two depths, 5-20 cm (humus horizons) and 20-50 cm (eluvial horizons). The contents of the heavy metals analysed were in the order of Pb > Zn > Cu > Ni. Despite intensive road traffic, with the Integrated Pollution Index (IPI) calculated, there was found a low pollution with nickel, average with zinc and copper and high with lead only. However, under the Regulation of the Minister of Environment, heavy metal values recorded allow for classifying the soils analysed as soils unpolluted with those metals. In the soil samples analysed, there were found significant positive dependencies between the content of clay fraction and zinc (r = 0.455; P < 0.05) and copper (r = 0.430; P < 0.05). With the enzyme activity results, values of the soil resistance index (RS) were calculated. The enzymes analysed were classified in the following decreasing order in terms of their resistance to traffic pollution: catalase > acid phosphatase > alkaline phosphatase > dehydrogenases (humus horizons) and catalase > dehydrogenases > alkaline phosphatase > acid phosphatase (eluvial horizons). Organic carbon showed a significant positive correlation with the activities of alkaline (r = 0.668; P < 0.05) and acid phosphatase (r = 0.668; P < 0.05) however not with catalase and dehydrogenases. PMID- 28871518 TI - Temporal integration of soil N2O fluxes: validation of IPNOA station automatic chamber prototype. AB - The assessment of nitrous oxide (N2O) fluxes from agricultural soil surfaces still poses a major challenge to the scientific community. The evaluations of integrated soil fluxes of N2O are difficult owing to their lower emissions when compared with CO2. These emissions are also sporadic as environmental conditions act as a limiting factor. A station prototype was developed to integrate annual N2O and CO2 emissions using an automatic chamber technique and infrared spectrometers within the LIFE project (IPNOA: LIFE11 ENV/IT/00032). It was installed from June 2014 to October 2015 in an experimental maize field in Tuscany. The detection limits for the fluxes were evaluated up to 1.6 ng N-N2O m2 s-1 and 0.3 MUg C-CO2 m2 s-1. A cross-comparison carried out in September 2015 with the "mobile IPNOA prototype"; a high-sensibility transportable instrument already validated provided evidence of very similar values and highlighted flux assessment limitations according to the gas analyzers used. The permanent monitoring device showed that temporal distribution of N2O fluxes can be very large and discontinuous over short periods of less than 10 days and that N2O fluxes were below the detection limit of the instrumentation during approximately 70% of the measurement time. The N2O emission factors were estimated to 1.9% in 2014 and 1.7% in 2015, within the range of IPCC assessments. PMID- 28871520 TI - Visceral Adiposity and Sarcopenic Visceral Obesity are Associated with Poor Prognosis After Resection of Pancreatic Cancer. AB - BACKGROUND: Visceral fat accumulation and muscle depletion have been identified as poor prognostic factors for various cancers. However, the significance of visceral adiposity and sarcopenic visceral obesity on outcomes after resection of pancreatic cancer remains unclear. METHODS: A retrospective analysis of 301 patients who underwent resection for localized pancreatic cancer between 2004 and 2015 was performed. The extent of visceral adiposity [visceral to subcutaneous adipose tissue area ratio (VSR)] and visceral obesity [visceral fat area (VFA)] were measured on preoperative computed tomography images, together with skeletal muscle index (SMI) and muscle attenuation (MA). The impacts of these body composition parameters on outcomes after pancreatic resection were investigated. RESULTS: The overall survival (OS) and recurrence-free survival (RFS) rates in patients with high VSR were significantly lower than those in patients with low VSR (P = 0.001, P = 0.007, respectively). There were no differences in OS and RFS between high VFA and low VFA group; however, when analyzed together with sarcopenic factors, OS and RFS rates of the patients with sarcopenic visceral obesity were significantly lower compared with those of the others. Multivariate analyses revealed that high VSR was an independent risk factor for mortality (hazard ratio (HR) 1.58, P = 0.009) and recurrence (HR 1.41, P = 0.026) together with low SMI, low MA, high CA19-9, microvascular invasion, and nodal metastasis. CONCLUSIONS: Visceral adiposity and sarcopenic visceral obesity, as well as low muscle mass and quality, were closely associated with mortality and recurrence after resection of pancreatic cancer. PMID- 28871519 TI - A Meta-Analysis of GLP-1 After Roux-En-Y Gastric Bypass: Impact of Surgical Technique and Measurement Strategy. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is an effective treatment for diabetes. Glucagon-like peptide-1 (GLP-1) is a gut hormone that is important to glucose homeostasis. OBJECTIVE: This study aimed to assess GLP-1 level and its predictors after RYGB. METHODS: The study design was a meta-analysis. The data sources were MEDLINE, EMBASE, Web of Science, and the Cochrane Databases. The study selection composed of studies with pre- and post-RYGB levels. The main outcomes were as follows: Primary outcome was the change in postprandial GLP-1 levels after RYGB. Secondary outcomes included the changes in fasting glucose, fasting insulin, and fasting GLP-1 levels after RYGB. Meta-regression to determine predictors of changes in GLP-1 levels was performed. Outcomes were reported using Hedge's g. RESULTS: Twenty-four studies with 368 patients were included. Postprandial GLP-1 levels increased after RYGB (Hedge's g = 1.29, p < 0.0001), while fasting GLP-1 did not change (p = 0.23). Peak postprandial GLP-1 levels gave the most consistent results (I 2 = 9.11). Fasting glucose and insulin levels decreased after RYGB (p < 0.0001). Roux limb length was a significant predictor for amount of GLP-1 increase (beta = - 0.01, p = 0.02). Diabetes status, amount of weight loss, length of biliopancreatic limb, and time of measurement were not significant predictors (p > 0.05). CONCLUSION: Postprandial GLP-1 levels increase after RYGB, while fasting levels remain unchanged. Shorter Roux limb length is associated with greater increase in postprandial GLP-1, which may lead to better glycemic control in this population. PMID- 28871521 TI - Astragaloside-IV prevents acute kidney injury and inflammation by normalizing muscular mitochondrial function associated with a nitric oxide protective mechanism in crush syndrome rats. AB - BACKGROUND: Crush syndrome (CS) is a serious medical condition characterized by muscle cell damage resulting from decompression after compression (i.e., ischemia/reperfusion injury). A large number of CS patients develop cardiac failure, kidney dysfunction, and systemic inflammation, even when fluid therapy is administered. We evaluated whether the administration of astragaloside-IV (AS) containing fluid improved survival by preventing kidney and muscular mitochondrial dysfunction in a rat model of CS. RESULTS: The CS model was generated by subjecting anesthetized rats to bilateral hind limb compression with a rubber tourniquet for 5 h. Rats were then randomly divided into four groups: (1) sham; (2) CS with no treatment; (3) CS with normal saline treatment; and (4) CS with normal saline + 10 mg/kg AS. AS-containing fluid improved kidney function by improving shock and metabolic acidosis in CS rats. In addition, there was a reduction in oxidative damage. The attenuation of hyperkalemia was significantly related to improving muscle injury via preventing mitochondrial dysfunction. Moreover, this mitochondria protection mechanism was related to the nitric oxide (NO) generated by activation of endothelial nitric oxide synthase, which provided an anti-oxidative and anti-inflammatory effect. CONCLUSIONS: Treatment with AS containing fluid led to a dramatic improvement in survival following CS because of direct and indirect anti-oxidative effects in the kidney, and improvements in mitochondrial dysfunction and inflammation owing to AS acting as an NO donor in injured muscle. PMID- 28871522 TI - The acute toxicity of bisphenol A and lignin-derived bisphenol in algae, daphnids, and Japanese medaka. AB - Risk assessing newly synthesized chemicals prior to their applications is extremely important, if we want to ensure substitution of risky chemicals with more benign ones. During the past two decades, many analogs of bisphenol A (BPA) have been manufactured, while their toxicity remains less studied. The aim of this study was to compare the acute toxicity of a synthesized lignin-derived BPA (LD-BP) with that of BPA in representative aquatic organisms including two algal species (Chlorella pyrenoidosa and Scenedesmus obliquus), a cladoceran species (Daphnia magna), and the Japanese medaka (Oryzias latipes). The results revealed that the two algal species showed different responses to the two chemicals. For C. pyrenoidosa, both BPA and LD-BP stimulated growth within 48 h of exposure, except for the 50 mg L-1 of LD-BP treatment. After 96 and 144 h of exposures, BPA stimulated the growth of C. pyrenoidosa at low-exposure concentrations but inhibited its growth at high concentrations, while LD-BP caused a concentration dependent response in C. pyrenoidosa. S. obliquus exhibited a monotonic concentration-response curve for both BPA and LD-BP exposures. For both D. magna and O. latipes, concentration-responses were monotonic with 96 h-LC50 of BPA and LD-BP of 11.7 and 5.0 mg L-1 and 9.4 and 4.1 mg L-1, respectively. Our results demonstrate that LD-BP is more toxic than BPA in the representative aquatic organisms, and it can pose higher ecological risk to the aquatic ecosystem than BPA. PMID- 28871523 TI - A Personalized Diagnostic and Treatment Approach for Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Adults. AB - OBJECTIVE: We assessed the clinical features and outcomes based on therapeutic options adopted during hospital stay for adult patients with macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis (MAS/sHLH). METHODS: We conducted a retrospective chart review of all adult patients (age >= 18 years) diagnosed with MAS/sHLH at our center between 2010 and 2015. Inclusion criteria for patients were diagnosis of MAS/sHLH during admission and patients meeting at least 5 out of 8 of Henter's criteria or at least 4 out of 6 of the criteria that were tested. RESULTS: Nineteen adult patients with MAS/sHLH met the inclusion criteria from January 2010 to October 2015 (median age 48 years; female 68.4%). Treatment had been personalized, depending on the clinical presentation and course of disease. Majority of the patients received anakinra, cyclosporine, intravenous immunoglobulins (IVIG), and steroids. Fourteen (74%) patients survived, with clinical improvement by the time of discharge. After excluding the three patients with underlying leukemia/lymphoma who opted for palliative care and subsequently died, the survival rate was 88%. CONCLUSION: A modified diagnostic and treatment protocol for adult patients with MAS/sHLH that incorporated graded introduction of medications based on clinical presentation and cytokine profile resulted in the best adult survival rate reported in literature. PMID- 28871524 TI - Comparison of three different methods of internal sinus lifting for elevation heights of 7 mm: an ex vivo study. AB - BACKGROUND: Various techniques are available for elevating the sinus membrane. The aim of this study is to evaluate three methods of indirect sinus floor elevation regarding elevation heights of 7 mm on the outcomes of membrane perforation, length of perforation, and time required to perform the procedure. METHODS: Three different methods for indirect sinus lifting, bone added osteotome sinus floor elevation (BAOSFE), sinus floor elevation with an inflatable balloon, and crestal approach system (CAS kit) from OSSTEM, were assessed for their ability to lift the sinus without causing laceration of the Schneiderian membrane. The study was performed on 18 freshly slaughtered sheep heads (36 sinus lifts were done, 12 for each method). CBCT images of the heads were taken to assess the best location for the sinus lift. Then, the heads were bisected and the membrane was exposed from the medial aspect. After that, each method was performed. The intended elevation height was 7 mm. If the 7 mm were not reached, the maximum height of elevation was measured. RESULTS: The method used was significantly associated with the occurrence of perforation (p value = 0.014) where BAOSFE was associated with the largest number of perforations (58.4%, n = 7) compared to 8.3% and 8.3% for the balloon and CAS kit methods, respectively. The odds ratio for perforation occurrence from BAOSFE compared to the CAS kit was significant (OR = 0.091, p = .022). No significant odds ratio was found for the balloon method compared to CAS kit. Additionally, the method used was significantly associated with time of operation and with the length of perforation (p value < 0.001) where CAS kit required the longest time and BAOSFE caused the biggest perforations. CONCLUSIONS: The study shows that both the balloon and the CAS kit were superior to the BAOSFE in terms of safety in elevating the sinus membrane. Further, in vivo studies have to prove these findings. PMID- 28871525 TI - Modelling studies for photocatalytic degradation of organic dyes using TiO2 nanofibers. AB - In this work, modelling of the photocatalytic degradation of para-nitrophenol (PNP) using synthesized electrospun TiO2 nanofibers under UV light illumination is reported. A dynamic model was developed in order to understand the behaviour of operating parameters, i.e. light intensity and catalyst loading on the photocatalytic activity. This model was simulated and analysed for both TiO2 solid nanofibers and TiO2 hollow nanofibers, applied as photocatalysts in the Langmuir-Hinshelwood kinetic framework. The entire photocatalytic degradation rate follows pseudo-first-order kinetics. The simulated results obtained from the developed model are in good agreement with the experimental results. At a catalyst loading of 1.0 mg mL-1, better respective degradation rates were achieved at UV light irradiance of 4 mW cm-2, for both the TiO2 solid and hollow nanofibers. However, it was also observed that TiO2 hollow nanofibers have a higher adsorption rate than that of TiO2 solid nanofibers resulting in a higher photocatalytic degradation rate of PNP. PMID- 28871527 TI - Rapid Eating is Linked to Emotional Eating in Obese Women Relieving from Bariatric Surgery. AB - BACKGROUND AND AIMS: Eating rate is associated with BMI and weight gain in various populations, and is a factor modulating the risk of complications after bariatric surgery. The aim of the present study is to determine whether common difficulties to change eating rate in subjects with obesity candidate to bariatric surgery, could be due to more extensive abnormalities in eating behavior. METHODS: A self-administered questionnaire was distributed to 116 consecutive female patients attending a nutrition consultation for obesity in a specialized center in France. This questionnaire explored eating rate (on an analog 10-point analog scale; a score >= 7 defines rapid eating), degree of chewing, signs of prandial overeating and scores of emotionality, externality, and restrained eating. RESULTS: Average age of the study population was 38.4 +/- 12.7 years. Mean BMI was 45.5 +/- 6.7, and eating rate was 6.3 +/- 1.8. Rapid eating was present in 50.0% of the population. There was an inverse relationship between eating rate and degree of chewing (r = -0.59, p < 0.0001). The proportion of "rapid eating" patients was significantly higher among those who responded "all the time", "very often" or "often" (63.1%), as compared to "sometimes" or "never" (25.0%) to the question "Do you feel like you eat too much?" (p < 0.0001). There was a significant positive correlation between eating rate and emotional eating score (r = 0.30, p = 0.001) and external eating score (r = 0.30, p = 0.001), but not with restrained eating score. CONCLUSION: These data show that rapid eating, by being potentially associated to emotional eating, must be considered as an important issue in bariatric surgery. PMID- 28871526 TI - Feasibility and acceptability of a prevention program for eating disorders (Me, You and Us) adapted for young adolescents in Korea. AB - PURPOSE: The aim of this study was to assess the adaptability and acceptability of a prevention program. METHODS: A total of 169 Korean students (83 boys and 86 girls) with a mean age of 12.3 years from a 6th grade class at an elementary school participated in the study. Mental health social workers delivered Me, You and Us, a school-based body image intervention program originally developed in the UK, through a set of six sessions. The participants were assessed in terms of their body satisfaction and self-esteem before the program, after the program, and at 1-month follow-up. They were also surveyed about their satisfaction and acceptability levels after the program. RESULTS: At baseline, girls had lower body satisfaction and self-esteem than boys, and their body satisfaction and self esteem improved after the program. The improved body satisfaction was maintained at the 1-month follow-up. The efficacy of the program on body satisfaction was positively correlated with the frequency of their baseline level of "fat talk." The program was more effective in girls with possible symptoms of an eating disorder at baseline. 93.7% of boys and 77.4% of girls responded that they enjoyed the program. CONCLUSIONS: The program Me, You and Us was well-accepted by early adolescents in Korea and it can play a role in increasing body satisfaction and self-esteem by reducing "fat talk" in 6th grade students. LEVEL OF EVIDENCE: Level III, cohort study with intervention. PMID- 28871528 TI - Co-production of Fructooligosaccharides and Levan by Levansucrase from Bacillus subtilis natto with Potential Application in the Food Industry. AB - Fructooligosaccharides and levan have a wide range of applications in the food industry due to their physiological and functional properties. The enzymatic synthesis of these molecules exhibits great advantages when compared with microbial fermentation. In this study, the production of levansucrase from Bacillus subtilis natto and its utilization in fructooligosaccharides and levan syntheses using different reaction conditions were described. The best condition for levansucrase production was 420.7 g L-1 of sucrose at pH 7.0, which reached 23.9 U ml-1 of transfructosylation activity. In a bioreactor, the highest production of fructooligosaccharides was 41.3 g L-1 using a medium containing 350 g L-1 sucrose at 35 degrees C for 36 h. The enzymatic synthesis of levan resulted in 86.9 g L-1 when conditions similar to those used for fructooligosaccharides synthesis were applied. These results indicate that the levansucrase from B. subtilis natto could be applied for the co-production of fructooligosaccharides and levan, which are biomolecules that have health benefits and are used successfully in the food industry. PMID- 28871529 TI - Assessing Metabolic Flux in Plants with Radiorespirometry. AB - Carbohydrates are the dominant respiratory substrate in many plant cells. However, the route of carbohydrate oxidation varies depending on the relative cellular demands for energy, reductant, and precursors for biosynthesis. During these processes individual substrate carbon atoms are differentially released as carbon dioxide by specific reactions in the network, and this can be measured by monitoring the release of 14CO2 from a range of positionally labeled forms of [14C]glucose. Although the relative amounts of carbon dioxide produced from different carbon positions do not allow precise determination of fluxes, they are indicative of the route of carbohydrate utilization. Such information can be used to determine whether a comprehensive metabolic flux analysis is merited, and also to facilitate independent verification of flux maps generated by other techniques. This chapter describes an approach to determine and interpret the pattern of oxidation of carbohydrates by monitoring 14CO2 release during metabolism of exogenously supplied [1-14C]-, [2-14C]-, [3,4-14C]-, and [6 14C]glucose. The method is exemplified by studies on Arabidopsis cell suspension cultures, but the protocol can be easily adapted for the investigation of other plant materials. PMID- 28871530 TI - Coupling Radiotracer Experiments with Chemical Fractionation for the Estimation of Respiratory Fluxes. AB - Carbohydrates catabolized via respiratory processes are not only used for energy production but also for biosynthesis of cellular components including soluble molecules (sugars, amino acids, organic acids, and their derivatives) and insoluble macromolecules (proteins, starch, and cell wall). Radiotracer experiments using 14C-labeled glucose provide a global picture of the fate of respired carbon in the metabolic network. This method is based on a chemical fractionation of biomolecules in 14C-glucose fed plant materials and the subsequent determination of radioactivity in each fraction. Metabolic flux into each fraction can be estimated from the specific activity of the hexose phosphate pool. Here, we describe the procedure for glucose metabolism in potato tuber but similar protocols can be adopted for various plant organs and substrates. PMID- 28871531 TI - A Method for Imaging Oxygen Distribution and Respiration at a Microscopic Level of Resolution. AB - Conventional oxygen (micro-) sensors assess oxygen concentration within a particular region or across a transect of tissue, but provide no information regarding its bidimensional distribution. Here, a novel imaging technology is presented, in which an optical sensor foil (i.e., the planar optode) is attached to the surface of the sample. The sensor converts a fluorescent signal into an oxygen value. Since each single image captures an entire area of the sample surface, the system is able to deduce the distribution of oxygen at a resolution level of few micrometers. It can be deployed to dynamically monitor oxygen consumption, thereby providing a detailed respiration map at close to cellular resolution. Here, we demonstrate the application of the imaging tool to developing plant seeds; the protocol is explained step by step and some potential pitfalls are discussed. PMID- 28871532 TI - VisiSens Technique to Measure Internal Oxygen and Respiration in Barley Roots. AB - Respiration is vital for production of energy in plants where oxygen is essential for conducting respiration. Internal oxygen levels in plants depend on respiratory rates. Tissues such as underground roots experience hypoxia due to their isolation from atmospheric oxygen and their internal oxygen depends on tissue size and local oxygen in soil and rhizosphere. Here, we used the ViSisens imaging technique, in which an optical sensor foil (i.e., the planar optode) is attached surface of root. This sensor measures oxygen values from fluorescence. Visisens microscope captures an entire area root surface and gives profile of internal oxygen. Interestingly, this system is also able to measure respiratory rate by measuring oxygen levels in a vial that contains root tissue. PMID- 28871533 TI - MultiSense: A Multimodal Sensor Tool Enabling the High-Throughput Analysis of Respiration. AB - The high-throughput analysis of respiratory activity has become an important component of many biological investigations. Here, a technological platform, denoted the "MultiSense tool," is described. The tool enables the parallel monitoring of respiration in 100 samples over an extended time period, by dynamically tracking the concentrations of oxygen (O2) and/or carbon dioxide (CO2) and/or pH within an airtight vial. Its flexible design supports the quantification of respiration based on either oxygen consumption or carbon dioxide release, thereby allowing for the determination of the physiologically significant respiratory quotient (the ratio between the quantities of CO2 released and the O2 consumed). It requires an LED light source to be mounted above the sample, together with a CCD camera system, adjusted to enable the capture of analyte-specific wavelengths, and fluorescent sensor spots inserted into the sample vial. Here, a demonstration is given of the use of the MultiSense tool to quantify respiration in imbibing plant seeds, for which an appropriate step-by-step protocol is provided. The technology can be easily adapted for a wide range of applications, including the monitoring of gas exchange in any kind of liquid culture system (algae, embryo and tissue culture, cell suspensions, microbial cultures). PMID- 28871534 TI - Measurement of Respiration and Internal Oxygen in Germinating Cicer arietinum L. Seeds Using Optic Microsensor. AB - Internal oxygen concentrations vary in different tissues depending on tissue size, developmental stage, and their location. Respiratory rate of tissue also determines internal oxygen levels. For studying various signaling pathways it is essential to establish a correlation between respiration and internal oxygen. Seed germination is associated with increase in respiration which can dictate the internal oxygen and subsequent production of reactive oxygen species. Using optic oxygen microsensor we made an attempt to measure respiratory rate and internal oxygen. We found that microsensor is able to sense internal oxygen and it is also possible to measure oxygen levels in a close vial that contains seeds. Step-by step protocol is described here along with illustration. PMID- 28871535 TI - Using an Oxygen Microsensor to Measure Oxygen Dynamics in Tomato Plants in Response to Pseudomonas syringae Infection. AB - Pathogen infection leads to induction of defense responses which includes modulation of gene expression and changes in metabolism plants. Despite of extensive research little is information known about the role of respiration and photosynthesis during pathogen infection in plants. Limited methods are available to measure oxygen dynamics in response to pathogen infection. Here by using an oxygen microsensor we measured oxygen changes in tomato plants infected with avirulent Pseudomonas syringae pv. tomato DC3000. In this method plant is placed in a closed chamber and change in oxygen levels can be measured by an oxygen sensor. PMID- 28871536 TI - Measurement of Oxygen Status in Arabidopsis Leaves Undergoing the Hypersensitive Response During Pseudomonas Infection. AB - When plants are infected with pathogens they defend themselves via various processes. Once such process is the development of the hypersensitive response (HR), a kind of programmed cell death (PCD), in which localized cell death takes place in order to prevent pathogen spread to other part of tissue. The Arabidopsis and Pseudomonas syringae system is one of the best known examples to study the HR. Here we used the VisiSensTM oxygen-imaging system to investigate oxygen distributions in Arabidopsis leaves infected with an avirulent strain of P. syringae and undergoing the hypersensitive response. Using this method we observed a change in oxygen status at 6 h post-infection and a drop in oxygen levels at 24 h after infection. PMID- 28871537 TI - Isolation of Physiologically Active and Intact Mitochondria from Chickpea. AB - Chickpea is an important leguminous crop that belongs to Fabaceae family, highly valued for its nutritious seeds. Seeds contain reserve food for the developing embryos. Mitochondria are crucial organelle for generation of chemical energy in the form of ATP which is required for achieving metabolically active state; therefore, investigating mitochondrial function and respiration rate is crucial for exploring various metabolic and physio-biochemical changes that occur during seed germination. Here we describe a method for isolation of mitochondria from germinating seeds of two chickpea varieties, i.e., Desi and Kabuli. Structure of Mitotracker-stained isolated mitochondria was observed by confocal microscopy and respiration rate was measured using an oxygen microsensor. PMID- 28871538 TI - Isolation and Structural Studies of Mitochondria from Pea Roots. AB - For structural and respiratory studies, isolation of intact and active mitochondria is essential. Here, we describe an isolation method which gave good yield and intact mitochondria from 2-week-old pea (Pisum sativum) roots grown hydroponically under standard growth conditions. We used Percoll gradient centrifugation for this isolation procedure. The yield of purified mitochondria was 50 MUg/g FW. Isolated mitochondria maintained their structure which was observed by using MitoTracker green in confocal microscope and scanning electron microscopy (SEM). Intact mitochondria are clearly visible in SCM images. Taken together this isolation method can be used for physiological and microscopic studies on mitochondria. PMID- 28871539 TI - Mitochondrial Respiration and Oxygen Tension. AB - Measurements of respiration and oxygen tension in plant organs allow a precise understanding of mitochondrial capacity and function within the context of cellular oxygen metabolism. Here we describe methods that can be routinely used for the isolation of intact mitochondria, and the determination of respiratory electron transport, together with techniques for in vivo determination of oxygen tension and measurement of respiration by both CO2 production and O2 consumption that enables calculation of the respiratory quotient [CO2]/[O2]. PMID- 28871540 TI - Isolation of Mitochondria from Model and Crop Plants. AB - The ability to isolate intact and functional mitochondria has greatly deepened our understanding of mitochondrial structure and function. With the advancement of molecular biology techniques and progression into omics-based research over recent decades, mitochondrial research has shifted from crop species such as wheat, pea, and potato to genetically sequenced models such as Arabidopsis thaliana and rice. Although there are many attributes that make model species particularly appealing for plant research, they are often less than ideal for conducting biochemical investigations and as such, considerable modification to mitochondrial isolation methods has been made.As the cost of genome sequencing continues to decrease however, an increasing number of crop species are now being sequenced and with these new resources it appears that the research community is turning back toward crop research. In this chapter we present mitochondrial isolation methods using density gradient centrifugation for both model species such as Arabidopsis thaliana, rice, and Medicago and crop species including wheat, potato, and pea. In addition, we present a number of marker enzyme assays to confirm mitochondrial purity as well as respiratory assays to determine outer membrane integrity and respiratory function of isolated mitochondria. PMID- 28871541 TI - Procedures of Mitochondria Purification and Gene Expression to Study Alternative Respiratory and Uncoupling Pathways in Fruits. AB - We describe detailed procedures to get intact and well-coupled mitochondria from a variety of fruit species such as papaya (Carica papaya), guava (Psidium guajava), tomato (Solanum lycopersicum), and strawberry (Fragaria x ananassa) as well as the protocols to assess the capacities of AOX and UCP pathways in intact fruit mitochondria. The procedures presented here were tested for the species mentioned above; their use with other types of fruits must be tested for yield of intact and active mitochondria. This is possible from individual adjustments. Strict care during extraction, including the use of osmotic protectants (i.e., mannitol/sucrose) and antioxidants (i.e., cysteine, ascorbate) at defined concentrations, are critical factors to ensure mitochondrial integrity and to obtain higher yields. The mitochondria purified using the discontinuous Percoll gradients described here can be used for the analysis of the capacity of alternative respiration and uncoupling pathways in fruits. In addition, protocols for quantitative and semiquantitative PCR applicable for the analysis of AOX and UCP gene expression in fruits are shown. Microarray and RNA-seq data from public databases are also valuable for the analysis of AOX and UCP genes. In both cases having the sequences of genes or cDNAs to be used in primer design or probe identification is necessary. PMID- 28871542 TI - Measurement of Tricarboxylic Acid Cycle Enzyme Activities in Plants. AB - Mitochondria are vital cytoplasmic organelle of eukaryotic cells responsible for oxidative energy metabolism and the synthesis of intermediates utilized in various other metabolic pathways. The functions of mitochondrion are the oxidation of organic acids by the tricarboxylic acid (TCA) cycle and the synthesis of ATP by the oxidative phosphorylation in the mitochondrial electron transport chain. The TCA cycle is composed by a set of enzymes that are essential for optimal functioning of the primary carbon metabolism in plants. The activity of each TCA cycle enzyme in plants may vary according to cell type, plant tissue, stage of plant development, and the environment. Here, we describe current methods used for the determination of the TCA cycle enzyme activities in different plant tissues. PMID- 28871543 TI - Respiration Traits as Novel Markers for Plant Robustness Under the Threat of Climate Change: A Protocol for Validation. AB - Respiration traits allow calculating temperature-dependent carbon use efficiency and prediction of growth rates. This protocol aims (1) to enable validation of respiration traits as non-DNA biomarkers for breeding on robust plants in support of sustainable and healthy plant production; (2) to provide an efficient, novel way to identify and predict functionality of DNA-based markers (genes, polymorphisms, edited genes, transgenes, genomes, and hologenomes), and (3) to directly help farmers select robust material appropriate for a specified region. The protocol is based on applying isothermal calorespirometry and consists of four steps: plant tissue preparation, calorespirometry measurements, data processing, and final validation through massive field-based data.The methodology can serve selection and improvement for a wide range of crops. Several of them are currently being tested in the author's lab. Among them are important cereals, such as wheat, barley, and rye, and diverse vegetables. However, it is critical that the protocol for measuring respiration traits be well adjusted to the plant species by considering deep knowledge on the specific physiology and functional cell biology behind the final target trait for production. Here, Daucus carota L. is chosen as an advanced example to demonstrate critical species-specific steps for protocol development. Carrot is an important global vegetable that is grown worldwide and in all climate regions (moderate, subtropical, and tropical). Recently, this species is also used in my lab as a model for studies on alternative oxidase (AOX) gene diversity and evolutionary dynamics in interaction with endophytes. PMID- 28871544 TI - Calorespirometry: A Novel Tool in Functional Hologenomics to Select "Green" Holobionts for Biomass Production. AB - Endophytes can diversify temperature response and biomass production in plants and microalgae. Natural and inoculated endophytes that modify growth performance are increasingly considered in research and practical initiatives for sustainable agriculture. However, efficient, novel tools are required that are able to support identification of differential effects of native endophyte populations and for pre-selection of inocula.This protocol gives instructions for applying calorespirometry as a rapid means for identifying differential effects of endophytes on temperature response and predicted biomass productivity in microalgae and plant holobionts. The protocol can help discriminating hologenomes, genes, and molecular neutral or functional markers for microalgae strain and plant improvement. Here, we focus on the microalga Chlorella vulgaris and associated microorganisms as an example for highlighting the methodology for its integration in research and application. PMID- 28871545 TI - Measurements of Electron Partitioning Between Cytochrome and Alternative Oxidase Pathways in Plant Tissues. AB - Plant respiration is characterized by the existence of the alternative oxidase pathway (AOP) that competes with cytochrome oxidase pathway (COP) for the electrons of the ubiquinone pool of the mitochondrial electron transport chain, thus reducing ATP synthesis. The oxygen (O2) isotope fractionation technique is the only available to determine the electron partitioning between the two pathways and their in vivo activities in plant tissues. In this chapter, the basis of the O2 isotope fractionation technique and its derived calculations are carefully explained together with a detailed description of the dual-inlet isotope ratio mass spectrometry (DI-IRMS) system and the protocol developed at the University of Balearic Islands. The key advantages of the DI-IRMS over other systems are highlighted as well as the potential problems of this technique. Among these problems, those associated with leakage, diffusion, and inhibitor treatments are noted and solutions to prevent, detect, and repair these problems are detailed. PMID- 28871546 TI - A Driving Bioinformatics Approach to Explore Co-regulation of AOX Gene Family Members During Growth and Development. AB - The alternative oxidase (AOX) gene family is a hot candidate for functional marker development that could help plant breeding on yield stability through more robust plants based on multi-stress tolerance. However, there is missing knowledge on the interplay between gene family members that might interfere with the efficiency of marker development. It is common view that AOX1 and AOX2 have different physiological roles. Nevertheless, both family member groups act in terms of molecular-biochemical function as "typical" alternative oxidases and co regulation of AOX1 and AOX2 had been reported. Although conserved sequence differences had been identified, the basis for differential effects on physiology regulation is not sufficiently explored.This protocol gives instructions for a bioinformatics approach that supports discovering potential interaction of AOX family members in regulating growth and development. It further provides a strategy to elucidate the relevance of gene sequence diversity and copy number variation for final functionality in target tissues and finally the whole plant. Thus, overall this protocol provides the means for efficiently identifying plant AOX variants as functional marker candidates related to growth and development. PMID- 28871547 TI - A Step-by-Step Protocol for Classifying AOX Proteins in Flowering Plants. AB - The potential of alternative oxidase (AOX) genes to develop functional markers for plant breeding programs has been emphasized. In this sense, it is essential to have a reliable classification system, which could aid in the selection of candidate AOX genes from different species. In the case of angiosperms AOX, a robust classification system is required because this enzyme is encoded by variable gene numbers (1-6 genes) with variable AOX subfamilies and subtypes. Thus, in this protocol, we present a detailed guideline to application of a classification scheme of AOX based on specific amino acids and phylogeny. We believe that this classification protocol provides an easier and practical way of classifying new angiosperm AOX genes besides that it can help to standardize AOX gene names used in AOX research community. PMID- 28871548 TI - Studying Individual Plant AOX Gene Functionality in Early Growth Regulation: A New Approach. AB - AOX1 and AOX2 genes are thought to play different physiological roles. Whereas AOX1 is typically expected to associate to stress and growth responses, AOX2 was more often found to be linked to development and housekeeping functions. However, this view is questioned by several adverse observations. For example, co regulated expression for DcAOX1 and DcAOX2a genes was recently reported during growth induction in carrot (Daucus carota L.). Early expression peaks for both genes during the lag phase of growth coincided with a critical time point for biomass prediction, a result achieved by applying calorespirometry. The effect of both AOX family member genes cannot easily be separated. However, separate functional analysis is required in order to identify important gene-specific polymorphisms or patterns of polymorphisms for functional marker development and its use in breeding. Specifically, a methodology is missing that enables studying functional effects of individual genes or polymorphisms/polymorphic patterns on early growth regulation.This protocol aims to provide the means for identifying plant alternative oxidase (AOX) gene variants as functional markers for early growth regulation. Prerequisite for applying this protocol is available Schizosaccharomyces pombe strains that were transformed with individual AOX genes following published protocols from Anthony Moore's group (Albury et al., J Biol Chem 271:17062-17066, 1996; Affourtit et al., J Biol Chem 274:6212-6218, 1999). The novelty of the present protocol comes by modifying yeast cell densities in a way that allows studying critical qualitative and quantitative effects of AOX gene variants (isoenzymes or polymorphic genes) during the early phase of growth. Calorimetry is used as a novel tool to confirm differences obtained by optical density measurements in early growth regulation by metabolic phenotyping (released heat rates). This protocol enables discriminating between AOX genes that inhibit growth and AOX genes that enhance growth under comparable conditions. It also allows studying dependency of AOX gene effects on gene copy number. The protocol can also be combined with laser microdissection of individual cells from target tissues for specified breeding traits. PMID- 28871549 TI - Laser Capture Microdissection for Amplification of Alternative Oxidase (AOX) Genes in Target Tissues in Daucus carota L. AB - Laser microdissection provides a useful method for isolating specific cell types from complex biological samples for downstream applications. In contrast to the texture of mammalian cells, most plant tissues exhibit a cell organization with hard, cellulose-containing cell walls, large vacuoles, and air spaces, thus complicating tissue preparation and extraction of macromolecules such as DNA. In this study, we report a method that allows tissue-specific gene amplification. An improved perception of genetic identity of the entire plant can contribute to improved functional marker strategies. Alternative oxidase (AOX) has crucial position for stress-induced responses/adaptation. Daucus carota sequence polymorphisms in AOX were identified, however, never at tissue/cell level. This technology will support studying AOX gene sequences in carrot organs/tissues/cells and specifically exploring differential polymorphisms in root meristem that might be associated to adaptive growth upon all kind of stresses. Details on aspects of tissue preparation, including fixation and embedding procedures, laser capture microdissection, DNA extraction, and amplification, are provided. A combination of laser microdissection and polymerase chain reaction amplification provides a powerful tool for the analysis of AOX gene amplification in methacarn-fixed paraffin-embedded tissues. PMID- 28871550 TI - Measurement of Mitochondrial Respiration in Isolated Protoplasts: Cytochrome and Alternative Pathways. AB - The electron partitioning between COX and AOX pathways of mitochondria and their coordination is necessary to meet the energy demands as well as to maintain optimized redox status in plants under varying environmental conditions. The relative contribution of these two pathways to total respiration is an important measure during a given stress condition. We describe in detail the procedure that allows the measurement of the parameters of COX and AOX pathway of respiration in mesophyll protoplasts using Clark-type O2 electrode. This chapter also lists the steps for rapid isolation procedure for mesophyll protoplasts from pea leaves. The advantages and limitations of the use of metabolic inhibitors and the protoplasts for measuring the respiration are also briefly discussed. PMID- 28871551 TI - Measuring Spatial and Temporal Oxygen Flux Near Plant Tissues Using a Self Referencing Optrode. AB - Self-referencing optrodic microsensing is a noninvasive method for measuring oxygen transport into/from tissues. The sensing mechanism is based on fluorescence quenching by molecular oxygen at the tip of a fiber-optic probe, and facilitates microscale spatial mapping and continuous monitoring at 100-350 mHz sampling frequency. Over the last decade, this technique has been applied for plant tissues, including roots, seeds, leaves, and flowers in both liquid and air. Here, we describe the operating principle of self-referencing optrodic microsensing for the study of plant tissues with a specific focus on juvenile roots. PMID- 28871553 TI - Treatment with granulocyte colony-stimulating factor in the refeeding phase of anorexia nervosa complicated with severe neutropenia and sepsis: a case report. AB - Leukopenia is frequently observed in patients with anorexia nervosa (AN). However, serious infectious diseases are infrequent in patients with AN. We present the case of a 13-year-old girl with AN complicated with severe neutropenia and sepsis upon refeeding. Her body mass index was 11 kg/m2 and her absolute neutrophil count (ANC) was 1555/uL on admission. After the initiation of refeeding, her ANC gradually declined to 346/uL. High fever occurred and a blood culture tested positive for Enterobacter cloacae. Although fever subsided with administration of antibiotics, human recombinant granulocyte colony-stimulating factor (G-CSF) was administered to improve her severe neutropenia. After administration of G-CSF, initially for 5 days and again for 3 days, her ANC became normal and stable. The combination of neutropenia and low body mass index may contribute to severe bacterial infection. Usually, hematological abnormalities such as neutropenia improve spontaneously with the recovery of nutritional status in AN patients. Therefore, it is difficult to determine the indication for treatment with G-SCF. Although a careful consideration is required, treatment with G-CSF is effective in AN patients with sepsis caused by severe neutropenia. PMID- 28871552 TI - Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease. AB - Tarantula's leg muscle thick filament is the ideal model for the study of the structure and function of skeletal muscle thick filaments. Its analysis has given rise to a series of structural and functional studies, leading, among other things, to the discovery of the myosin interacting-heads motif (IHM). Further electron microscopy (EM) studies have shown the presence of IHM in frozen hydrated and negatively stained thick filaments of striated, cardiac, and smooth muscle of bilaterians, most showing the IHM parallel to the filament axis. EM studies on negatively stained heavy meromyosin of different species have shown the presence of IHM on sponges, animals that lack muscle, extending the presence of IHM to metazoans. The IHM evolved about 800 MY ago in the ancestor of Metazoa, and independently with functional differences in the lineage leading to the slime mold Dictyostelium discoideum (Mycetozoa). This motif conveys important functional advantages, such as Ca2+ regulation and ATP energy-saving mechanisms. Recent interest has focused on human IHM structure in order to understand the structural basis underlying various conditions and situations of scientific and medical interest: the hypertrophic and dilated cardiomyopathies, overfeeding control, aging and hormone deprival muscle weakness, drug design for schistosomiasis control, and conditioning exercise physiology for the training of power athletes. PMID- 28871554 TI - The Impact of Histologic Phenotype in the Treatment of Sinonasal Cancer. AB - The management of sinonasal cancer is a challenge due to its low occurrence and anatomical and significant diversity of histological types. The therapeutic modality used should be tailored individually according to the histology, tumour stage, molecular profile and previous treatments. The clinical management of sinonasal cancer has improved greatly owing to developments in endoscopic surgery and precision radiotherapy. Complete surgical resection is the mainstay of sinonasal malignancies' management but multimodality therapy is associated with improved outcomes in certain histologies. The recognition of various histological types with biological behaviours more suitable for non-surgical modalities has allowed treatment protocols to become more tailored to the disease. In this review we aim to describe and to summarise the current data guiding the management of sinonasal cancer with emphasis on phenotypic variation. PMID- 28871555 TI - Prediction of membrane fouling using artificial neural networks for wastewater treated by membrane bioreactor technologies: bottlenecks and possibilities. AB - Membrane fouling is a major concern for the optimization of membrane bioreactor (MBR) technologies. Numerous studies have been led in the field of membrane fouling control in order to assess with precision the fouling mechanisms which affect membrane resistance to filtration, such as the wastewater characteristics, the mixed liquor constituents, or the operational conditions, for example. Worldwide applications of MBRs in wastewater treatment plants treating all kinds of influents require new methods to predict membrane fouling and thus optimize operating MBRs. That is why new models capable of simulating membrane fouling phenomenon were progressively developed, using mainly a mathematical or numerical approach. Faced with the limits of such models, artificial neural networks (ANNs) were progressively considered to predict membrane fouling in MBRs and showed great potential. This review summarizes fouling control methods used in MBRs and models built in order to predict membrane fouling. A critical study of the application of ANNs in the prediction of membrane fouling in MBRs was carried out with the aim of presenting the bottlenecks associated with this method and the possibilities for further investigation on the subject. PMID- 28871557 TI - Anatomy of the Transverse Mesocolon Based on Embryology for Laparoscopic Complete Mesocolic Excision of Right-Sided Colon Cancer. AB - BACKGROUND: To treat colon cancer via complete mesocolic excision (CME) with central vascular ligation (CVL), dissection along the embryologic fusion planes is required. However, this surgery is difficult, especially for right-sided colon cancer, because the anatomy and embryology of the transverse mesocolon are not familiar to gastrointestinal surgeons. METHODS: In this video article, the anatomic details of the transverse mesocolon based on embryology are illustrated with a focus on the venous anatomy. Dissection of the transverse mesocolon along the embryologic planes using a cranial approach during laparoscopic right hemicolectomy also is presented. RESULTS: During the development of the primitive gastrointestinal tract, the transverse mesocolon locates between the terminal portion of the midgut and the beginning of the hindgut. After 270 degrees counterclockwise rotation of the primary intestinal loop, the transverse mesocolon fuses with the frontal surface of the duodenum and pancreas. Simultaneously, the greater omentum hangs down from the greater curvature of the stomach in front of the transverse colon and fuses with the transverse mesocolon. Moreover, the drainage vein of the right colon sometimes joins the right gastroepiploic vein, and the gastrocolic trunk is formed. Anatomic complexity of the transverse mesocolon is caused by rotation and fusion of the gastrointestinal tract during embryologic development. CONCLUSIONS: Knowledge concerning these embryologic peculiarities of the transverse mesocolon should be useful in the performance of laparoscopic CME with CVL for right-sided colon cancer. PMID- 28871556 TI - Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function. AB - The tarantula skeletal muscle X-ray diffraction pattern suggested that the myosin heads were helically arranged on the thick filaments. Electron microscopy (EM) of negatively stained relaxed tarantula thick filaments revealed four helices of heads allowing a helical 3D reconstruction. Due to its low resolution (5.0 nm), the unambiguous interpretation of densities of both heads was not possible. A resolution increase up to 2.5 nm, achieved by cryo-EM of frozen-hydrated relaxed thick filaments and an iterative helical real space reconstruction, allowed the resolving of both heads. The two heads, "free" and "blocked", formed an asymmetric structure named the "interacting-heads motif" (IHM) which explained relaxation by self-inhibition of both heads ATPases. This finding made tarantula an exemplar system for thick filament structure and function studies. Heads were shown to be released and disordered by Ca2+-activation through myosin regulatory light chain phosphorylation, leading to EM, small angle X-ray diffraction and scattering, and spectroscopic and biochemical studies of the IHM structure and function. The results from these studies have consequent implications for understanding and explaining myosin super-relaxed state and thick filament activation and regulation. A cooperative phosphorylation mechanism for activation in tarantula skeletal muscle, involving swaying constitutively Ser35 mono phosphorylated free heads, explains super-relaxation, force potentiation and post tetanic potentiation through Ser45 mono-phosphorylated blocked heads. Based on this mechanism, we propose a swaying-swinging, tilting crossbridge-sliding filament for tarantula muscle contraction. PMID- 28871558 TI - Examining the accessibility of high-quality physical activity behaviour change support freely available online for men with prostate cancer. AB - BACKGROUND: While the internet is considered a promising avenue for providing physical activity support to prostate cancer survivors, little is known about the accessibility of quality websites in the real world. PURPOSE: This work aimed to explore what websites prostate cancer survivors are likely to find when seeking physical activity support online and to evaluate their quality using evidenced based criteria. METHOD: A search strategy was developed in consultation with prostate cancer survivors (n = 44) to reflect the most common ways they are likely to search the internet. The search was then conducted by a single reviewer, and identified websites were assessed for quality by two reviewers using an evidence-based quality assessment tool developed for this study. Discrepancies were resolved by a third reviewer. RESULTS: Of the 45 identified websites, 13 (29%) received a high quality rating, 22 (49%) received a moderate rating and 10 (22%) received a low quality rating. Higher-quality websites tended to have a .org or .gov domain and tended to be located using searches specific to prostate cancer or prostate cancer and exercise. Very few websites contained complete information regarding the physical activity guidelines for cancer survivors, and no websites provided comprehensive behaviour change support. CONCLUSION: There are some good-quality physical activity websites accessible to men with prostate cancer. However, they may be difficult to find and/or require updating to include complete recommendations and more behaviour change support. IMPLICATIONS FOR CANCER SURVIVORS: Efforts to improve physical activity information online and strategies to direct prostate cancer survivors to higher quality websites and support services are needed to ensure safety and efficacy. PMID- 28871559 TI - Optical and Electronic Properties of Femtosecond Laser-Induced Sulfur-Hyperdoped Silicon N+/P Photodiodes. AB - Impurity-mediated near-infrared (NIR) photoresponse in silicon is of great interest for photovoltaics and photodetectors. In this paper, we have fabricated a series of n+/p photodetectors with hyperdoped silicon prepared by ion implantation and femtosecond pulsed laser. These devices showed a remarkable enhancement on absorption and photoresponse at NIR wavelengths. The device fabricated with implantation dose of 1014 ions/cm2 has exhibited the best performance. The proposed method offers an approach to fabricate low-cost broadband silicon-based photodetectors. PMID- 28871560 TI - Oesophageal coins invisible on chest radiography: a case report. AB - BACKGROUND: Coins are made of metal, which is generally radiopaque, and so physicians often have the misconception that all coins are detectable by radiography. Here, we report a case of intentionally swallowed coins in the oesophagus of an adult; the coins could not be detected on chest radiography but were detected using computed tomography (CT). CASE PRESENTATION: A 46-year-old woman with a history of depression presented to the emergency department after an intentional medication overdose and ingestion of two Japanese 1-yen coins. She complained of persistent retrosternal discomfort. In order to confirm whether the coins were in the oesophagus or trachea, an anteroposterior chest radiograph was obtained; however, no coins were detected. Owing to her persistent symptoms, a chest CT was performed. On the initial CT scan, two 1-yen coins were observed in the oesophagus: one in the middle oesophagus and the other in the lower oesophagus. After the scanning, the patient drank water with permission, but vomited. No coins were found in her vomit, and the symptoms of retrosternal discomfort had completely disappeared. A subsequent CT scan revealed that the two 1-yen coins were in the patient's stomach. CONCLUSIONS: Japanese 1-yen coins are made of 100% aluminium, which is less radiopaque than the metals that make up coins (nickel, bronze, and lead), and so, they were not visible via chest radiography in our case. Detecting very small or thin radiolucent foreign bodies is not possible using a chest radiograph or contrast oesophagram, but is possible via CT. CT is both increasingly convenient and non-invasive, unlike endoscopy or bronchoscopy, and so, the use of CT scans should be considered in cases of possible radiolucent foreign body ingestion. PMID- 28871561 TI - Erratum to: Contribution of clinical and socioeconomic factors to differences in breast cancer subtype and mortality between Hispanic and non-Hispanic white women. PMID- 28871562 TI - Teledermatology: A Review and Update. AB - Telemedicine is slowly transforming the way in which healthcare is delivered and has the potential to improve access to subspecialty expertise, reduce healthcare costs, and improve the overall quality of care. While many subspecialty fields within medicine today have either experimented with or begun to implement telemedicine platforms to enable remote consultation and care, dermatology is particularly suited for this care system as skin disorders are uniquely visible to the human eye. Through teledermatology, diagnostic images of skin disorders with accompanying clinical histories can be remotely reviewed by teledermatologists by any number of modalities, such as photographic clinical images or live video teleconferencing. Diagnoses and treatment recommendations can then be rendered and implemented remotely. The evidence to date supports both its diagnostic and treatment accuracy and its cost effectiveness. Administrative, regulatory, privacy, and reimbursement policies surrounding this dynamic field continue to evolve. In this review, we examine the history, evidence, and administrative landscape surrounding teledermatology and discuss current practice guidelines and ongoing controversies. PMID- 28871563 TI - Prognostic Value of the Age-Adjusted Charlson Comorbidity Index (ACCI) on Short- and Long-Term Outcome in Patients with Advanced Primary Epithelial Ovarian Cancer. AB - BACKGROUND: We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center. PATIENTS AND METHODS: Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB-IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0-1), intermediate (2-3), and high (>=4), and postoperative surgical complications were graded according to the Clavien-Dindo classification (CDC). The Fisher's exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS. RESULTS: Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3-5; odds ratio 3.27, 95% confidence interval 1.97-5.43, p < 0.001). Median OS for patients with a low, intermediate, or high ACCI was 50, 40, and 23 months, respectively (p < 0.001), and the ACCI remained a significant prognostic factor for OS in multivariate analysis (p = 0.001). The same impact was observed in a sensitivity analysis including only those patients with complete tumor resection. CONCLUSION: The ACCI is associated with perioperative morbidity in patients undergoing PDS for EOC, and also has a prognostic impact on OS. The potential role of the ACCI as a selection criteria for different therapy strategies is currently under investigation in the ongoing, prospective, multicenter AGO-OVAR 19 trial. PMID- 28871564 TI - Redefining the Positive Margin in Pancreatic Cancer: Impact on Patterns of Failure, Long-Term Survival and Adjuvant Therapy. AB - PURPOSE: There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA. METHODS: We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5-1, >1-2, or >2 mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS). RESULTS: Among all margins, PM clearance up to 2 mm was prognostic of DFS (p = 0.01) and OS (p = 0.01). Dichotomizing the PM at 2 mm revealed it to be an independent predictor of local recurrence-free survival [hazard ratio HR] 0.20, 95% confidence interval [CI] 0.048-0.881, p = 0.033), DFS (HR 0.46, 95% CI 0.22-0.96, p = 0.03), and OS (HR 0.31, 95% CI 0.14-0.74, p = 0.008). A margin status of >2 mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11-0.89, p = 0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10-1.58, p = 0.19). CONCLUSION: These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2 mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2 mm. PMID- 28871565 TI - Cost-Effectiveness Analysis of Sensor-Augmented Insulin Pump Therapy with Automated Insulin Suspension Versus Standard Insulin Pump Therapy in Patients with Type 1 Diabetes in Sweden. AB - INTRODUCTION: In Sweden an estimated 10,000 people with type 1 diabetes use continuous subcutaneous insulin infusion (CSII). Sensor-augmented pump therapy (SAP) is associated with higher acquisition costs but provides additional clinical benefits (e.g. reduced rate of hypoglycemic events) over and above that of CSII alone. The aim of the analysis was to assess the cost-effectiveness of SAP with automated insulin suspension relative to CSII alone in two different groups of patients with type 1 diabetes in Sweden. METHODS: Cost-effectiveness analyses were performed using the QuintilesIMS CORE Diabetes Model, with clinical and economic input data derived from published literature. Separate analyses were performed for patients at increased risk of hypoglycemia and for patients with uncontrolled glycated hemoglobin (HbA1c) at baseline. Analyses were performed from a societal perspective over a lifetime time horizon. Future costs and clinical outcomes were discounted at 3% per annum. RESULTS: SAP with automated insulin suspension was associated with an incremental gain in quality-adjusted life expectancy versus the CSII of 1.88 quality-adjusted life years (QALYs) in patients at high risk of hypoglycemia and of 1.07 QALYs in patients with uncontrolled HbA1c at baseline. Higher lifetime costs for SAP with automated insulin suspension resulted in projected incremental cost-effectiveness ratios for the SAP with automated insulin suspension versus CSII of Swedish Krona (SEK) 139,795 [euros (EUR) 14,648] per QALY gained for patients at increased risk for hypoglycemia and SEK 251,896 (EUR 26,395) per QALY gained for patients with uncontrolled HbA1c. In both groups, SAP with automated insulin suspension also reduced the incidence of diabetes-related complications relative to CSII. CONCLUSIONS: In Sweden, SAP with automated insulin suspension likely represents a cost-effective treatment option relative to CSII for the management of patients with type 1 diabetes with a history of severe hypoglycemic events or patients who struggle to achieve good glycemic control despite the use of CSII. FUNDING: Medtronic International Trading Sarl. PMID- 28871566 TI - Natural killer cells and tumor metastasis. AB - Natural killer (NK) cells are cytotoxic lymphocytes that recognize tumor cells or stressed cells through 'missing-self' signals, such as altered or absent expression of MHC class I molecules. The function of NK cells is regulated by the activation or inhibition of receptors present on their surface. The activation of NK cells results in cytotoxic activity on target cells through release of toxic granules and inflammatory cytokines. However, NK cells infiltrating tumors have been frequently shown to exhibit a skewed phenotype that includes decreased antitumor activity and enhanced protumor activities, such as angiogenesis and metastasis. In fact, many studies have reported that tumor microenvironments induce a protumor phenotype in NK cells. Here, we review the biological properties of NK cells in the context of tumorigenesis and tumor progression, with a specific focus on the interactions between NK cells and critical tumor microenvironments, such as epithelial-to-mesenchymal transition, matrix metalloproteinases, and tumor-associated chronic inflammation in tumor metastasis. PMID- 28871567 TI - A case of biliary atresia with pancreaticobiliary maljunction. AB - BACKGROUND: The pathogenesis of biliary atresia (BA) is still unknown. There are several reports on the etiology of BA, including pancreaticobiliary maljunction (PBM). We experienced a case of Kasai type IIIa BA with PBM, in which we found elevation of pancreatic enzymes in the gallbladder. We evaluated whether PBM is related to the pathogenesis of BA based on our findings. CASE PRESENTATION: The patient was born at 40 weeks of gestation. His body weight at birth was 2850 g. At the age of 4 days, he had an acholic stool and was referred to our hospital. Abdominal ultrasonography showed that triangular cord sign was negative. The gallbladder was isolated with a diameter of 19 mm, and it contracted in response to oral feeding. His ultrasonographic findings were atypical for BA, but his jaundice did not improve. Therefore, we performed an operation at the age of 56 days. Intraoperative cholangiography showed a common bile duct and pancreatic duct and a common channel patent, while the common hepatic duct or intrahepatic duct was not visualized. Bile in the gallbladder contained colorless fluid, which showed elevated lipase level (34,100 IU/L). We performed Kasai portoenterostomy under the diagnosis of Kasai type IIIa BA with PBM. The patient's postoperative course was uneventful, and he was discharged on day 30 after the operation. Histopathological evaluation showed that the lumens of the common bile duct and cystic duct were patent. However, the common hepatic duct was closed, and only bile ductules with diameters of less than 50 MUm were isolated. Infiltration of lymphocytes was detected in the porta hepatis. No apparent inflammation was observed around the cystic duct, which was constantly exposed to pancreatic juice because of reflux through PBM. CONCLUSIONS: Reflux of pancreatic juice through PBM might not be an etiological factor for BA, but might be associated with patency of the common and cystic bile ducts in Kasai type IIIa BA. PMID- 28871568 TI - A mini-overview of single muscle fibre mechanics: the effects of age, inactivity and exercise in animals and humans. AB - Many basic movements of living organisms are dependent on muscle function. Muscle function allows for the coordination and harmonious integrity of movement that is necessary for various biological processes. Gross and fine motor skills are both regulated at the micro-level (single muscle fibre level), controlled by neuronal regulation, and it is therefore important to understand muscle function at both micro- and macro-levels to understand the overall movement of living organisms. Single muscle mechanics and the cellular environment of muscles fundamentally allow for the harmonious movement of our bodies. Indeed, a clear understanding of the functionality of muscle at the micro-level is indispensable for explaining muscular function at the macro-(whole gross muscle) level. By investigating single muscle fibre mechanics, we can also learn how other factors such Ca2+ kinetics, enzyme activity and contractile proteins can contribute to muscle mechanics at the micro- and macro-levels. Further, we can also describe how aging affects the capacity of skeletal muscle cells, as well as how exercise can prevent aging-based sarcopenia and frailty. The purpose of this review is to introduce and summarise the current knowledge of single muscle fibre mechanics in light of aging and inactivity. We then describe how exercise mitigates negative muscle adaptations that occur under those circumstances. In addition, single muscle fibre mechanics in both animal and human models are discussed. PMID- 28871569 TI - Treatment strategies and outcome of surgery for synchronous colorectal liver metastases. AB - OBJECTIVES: To report survival following different operative strategies and perioperative chemotherapy in patients with synchronous colorectal liver metastases in a tertiary academic referral centre. METHODS: We performed a retrospective analysis, based on a prospective database, of patients who presented with synchronous colorectal liver metastases. Follow-up data were obtained from medical records, letters or telephone contacts. The main endpoint was overall survival. An additional event of interest was postoperative mortality according to treatment strategy. Predefined variables were analysed to identify associated risk factors. RESULTS: Overall, 109 patients undergoing liver resection for synchronous colorectal liver metastases between 2000 and 2010 were identified. The majority of patients had resection of the primary tumour first (n = 82), the classic approach; notably fewer were treated according to a combined (n = 20) or a reverse "liver first" strategy (n = 7). Most patients (92%) received preoperative, interval and/or postoperative chemotherapy. Median overall survival of the entire population was 33.6 months (interquartile range [IQR] 11 92.7 months). Patients undergoing classic surgery had a median overall survival of 40.3 months (IQR 14.9-96.6 months). The 3-year survival rates of the three patient groups were 53% in the classic, 47% in the combined and 58% in the reverse group. The lowest rate of 180-day mortality (9%) was after the classic surgical approach. On a multivariate Cox proportional hazards regression analysis, patient age >60 years (hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.1-3.9; p = 0.018), R2-status (HR 2.08, 95% CI 1.03-4.2; p = 0.040), and >4 liver metastases (HR 2.4, 95% CI 1.2-4.6; p = 0.011) were associated significantly with worse overall survival. CONCLUSIONS: In patients undergoing surgical resection for synchronous colorectal liver metastases, promising survival rates could be achieved, irrespective of the chosen surgical strategy. The presence of five or more liver metastases, patient age over 60 years and R2 status were found to be adverse risk factors. PMID- 28871570 TI - Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the SVGO/ASCO. AB - Antiosteoporotic drugs are recommended in patients with fragility fractures and in patients considered to be at high fracture risk on the basis of clinical risk factors and/or low bone mineral density. As first-line treatment most patients are started with an antiresorptive treatment, i.e. drugs that inhibit osteoclast development and/or function (bisphosphonates, denosumab, oestrogens or selective oestrogen receptor modulators). In the balance between benefits and risks of antiresorptive treatment, uncertainties remain regarding the optimal treatment duration and the management of patients after drug discontinuation. Based on the available evidence, this position statement will focus on the long-term management of osteoporosis therapy, formulating decision criteria for clinical practice. PMID- 28871571 TI - Acute aortic dissection: pathogenesis, risk factors and diagnosis. AB - Acute aortic dissection is a rare but life-threatening condition with a lethality rate of 1 to 2% per hour after onset of symptoms in untreated patients. Therefore, its prompt and proper diagnosis is vital to increase a patient's chance of survival and to prevent grievous complications. Typical symptoms of acute aortic dissection include severe chest pain, hypotension or syncope and, hence, mimic acute myocardial infarction or pulmonary embolism. Advanced age, male gender, long-term history of arterial hypertension and the presence of aortic aneurysm confer the greatest population attributable risk. However, patients with genetic connective tissue disorders such as Marfan, Loeys Dietz or Ehlers Danlos syndrome, and patients with bicuspid aortic valves are at the increased risk of aortic dissection at a much younger age. Imaging provides a robust foundation for diagnosing acute aortic dissection, as well as for monitoring of patients at increased risk of aortic disease. As yet, easily accessible blood tests play only a small role but have the potential to make diagnosis and monitoring of patients simpler and more cost-effective. PMID- 28871572 TI - Early complications after living donor nephrectomy: analysis of the Swiss Organ Living Donor Health Registry. AB - BACKGROUND: We evaluated the prospectively collected data about the incidence of early peri- and postoperative complications, and potential risk factors for adverse outcomes after living kidney donation in Switzerland. METHODS: Peri- and postoperative events were prospectively recorded on a questionnaire by the local transplant teams of all Swiss transplant centres and evaluated by the Swiss Organ Living Donor Health Registry. Complications were classified according to the Clavien grading system. A total of 1649 consecutive donors between 1998 and 2015 were included in the analysis. RESULTS: There was no perioperative mortality observed. The overall complication rate was 13.5%. Major complications defined as Clavien >=3 occurred in 2.1% of donors. Obesity was not associated with any complications. Donor age >70years was associated with major complications (odds ratio [OR] 3.99) and genitourinary complications (urinary tract infection OR 5.85; urinary retention OR 6.61). There were more major complications observed in donors with laparoscopic surgery versus open surgery (p = 0.048), but an equal overall complication rate (p = 0.094). CONCLUSION: We found a low rate of major and minor complications, independent of surgical technique, after living donor nephrectomy. There was no elevated complication rate in obese donors. In contrast, elderly donors >70 years had an elevated risk for perioperative complications. PMID- 28871573 TI - More practice - better results: applicable even in visceral surgery. PMID- 28871574 TI - The role of pharmacotherapy in the management of chronic subdural haematoma. PMID- 28871575 TI - Inert gas washout: background and application in various lung diseases. AB - Multiple breath inert gas washout (MBW) is a lung function technique to measure ventilation inhomogeneity. The technique was developed more than 60 years ago, but not much used for many decades. Technical improvements, easy protocols and higher sensitivity compared with standard lung function tests in some disease groups have led to a recent renaissance of MBW. The lung clearance index (LCI) is a common measure derived from MBW tests, and offers information on lung pathology complementary to that from conventional lung function tests such as spirometry. The LCI measures the overall degree of pulmonary ventilation inhomogeneity. There are other MBW-derived parameters, which describe more regional airway ventilation and enable specific information on conductive or acinar ventilation inhomogeneity. How this specific ventilation distribution is exactly related to different disease processes has not entirely been examined yet. MBW measurements are performed during tidal breathing, making this technique attractive for children, even young children and infants. These benefits and the additional physiological information on ventilation inhomogeneity early in the course of lung diseases have led to increasing research activities and clinical application of MBW, especially in paediatric lung diseases such as cystic fibrosis (CF). In these patients, LCI detects early airway damage and enables monitoring of disease progression and treatment response. Guidelines for the standardisation of the MBW technique were recently published. These guidelines will, hopefully, increase comparability of LCI data obtained in different centres or intervention trials in children and adults. In this non-systematic review article, we provide an overview of recent developments in MBW, with a special focus on children. We first explain the physiological and technical background to this technique with a short explanation of several methodological aspects that are important for understanding the principle behind the technique and enable high quality measurements. We then provide examples of MBW application in different lung diseases of children and adults, with regards to both clinical application and research activities. Lastly, we report on ongoing clinical trials using MBW as outcome and give an outlook on possible future developments. PMID- 28871576 TI - First trimester combined screening for preeclampsia and small for gestational age - a single centre experience and validation of the FMF screening algorithm. AB - AIM OF THE STUDY: Preeclampsia (PE) is associated with severe maternal and fetal morbidity in the acute presentation and there is increasing evidence that it is also an important risk factor for cardiovascular disease later in life. Therefore, preventive strategies are of utmost importance. The Fetal Medicine Foundation (FMF) London recently developed a first trimester screening algorithm for placenta-related pregnancy complications, in particular early onset preeclampsia (eoPE) requiring delivery before 34 weeks, and preterm small for gestational age (pSGA), with a birth weight <5th percentile and delivery before 37 weeks of gestation, based on maternal history and characteristics, and biochemical and biophysical parameters. The aim of this study was to test the performance of this algorithm in our setting and to perform an external validation of the screening algorithm. MATERIAL AND METHODS: Between September 2013 and April 2016, all consecutive women with singleton pregnancies who agreed to this screening were included in the study. The proposed cut-offs of >=1:200 for eoPE, and >=1:150 for pSGA were applied. Risk calculations were performed with Viewpoint(r) program (GE, Mountainview, CA, USA) and statistical analysis with GraphPad version 5.0 for Windows. RESULTS: 1372 women agreed to PE screening; the 1129 with complete data and a live birth were included in this study. Nineteen (1.68%) developed PE: 14 (1.24%) at term (tPE) and 5 (0.44%) preterm (pPE, <37 weeks), including 2 (0.18%) with eoPE. Overall, 97/1129 (8.6%) screened positive for eoPE, including both pregnancies that resulted in eoPE and 4/5 (80%) that resulted in pPE. Forty-nine of 1110 (4.41%) pregnancies without PE resulted in SGA, 3 (0.27%) of them in pSGA. A total of 210/1110 (18.9%) non-PE pregnancies screened positive for pSGA, including 2/3 (66.7%) of the pSGA deliveries and 18/46 (39.1%) of term SGA infants. CONCLUSION: Our results show that first trimester PE screening in our population performs well and according to expectations, whereas screening for SGA is associated with a high false positive rate. PMID- 28871577 TI - Right retroperitoneoscopic living donor nephrectomy does not increase surgical complications in the recipient and leads to excellent long-term outcome. AB - BACKGROUND: Right-sided retroperitoneoscopic living donor nephrectomy (LDN) has been shown to be safe for the donor but it is unknown whether the short renal vein is associated with complications or an impaired long-term outcome in the recipient. METHODS: In this retrospective cohort study, consecutive transplant recipients after retroperitoneoscopic LDN were enrolled. Complications occurring within 1 year were classified according to the Clavien-Dindo Classification for Surgical Complications and analysed using multivariable logistic regression. Predictors of 1-year creatinine clearance were analysed with multivariable linear regression. Cox proportional hazard models were used to analyse graft survival. RESULTS: Of the 251 recipients, 193 (77%) received a left kidney and 58 (23%) a right kidney. Surgical complications of Clavien-Dindo grade 3 or higher were comparable in recipients of right and left kidneys (33% vs 29%, odds ratio 0.98, 95% confidence interval [CI] 0.50, 1.94). The occurrence of a surgical complication had a significant impact on creatinine clearance at 1 year (decrease of 6 ml/min/m2, p = 0.016). Vascular complications in right kidneys were more common but were all corrected without impact on graft survival. One-year graft survival was similar in recipients of right (98.3%) and left (96.9%) kidneys, as was creatinine clearance one year after transplantation (mean difference 3.3 ml/min/m2, 95% CI -1.5, 8.1; p = 0.175). After a median follow-up of 5 years, neither the side (hazard ratio 1.56, 95% CI 0.67, 3.63) nor surgical complications (hazard ratio 1.44, 95% CI 0.65, 3.19) were associated with graft failure. CONCLUSION: Right retroperitoneoscopic LDN does not compromise the outcome of transplantation. Surgical complications, long-term graft function and graft survival were comparable in right and left kidneys. PMID- 28871578 TI - Secondary Adrenal Insufficiency Following Nivolumab Therapy in a Patient with Metastatic Renal Cell Carcinoma. AB - Currently, nivolumab (an anti-programmed cell death-1 receptor monoclonal antibody) is available for many types of advanced cancers in Japan. However, there have been few detailed case reports about endocrine-related adverse events of this therapy. Here, we report a patient with metastatic renal cell carcinoma who presented with secondary adrenal insufficiency following nivolumab therapy. Endocrinological assessment by rapid adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) tests revealed that the patient's disorder was a secondary adrenal insufficiency due to pituitary dysfunction. Moreover, the results of the thyrotropin-releasing hormone (TRH), luteinizing hormone-releasing hormone (LH-RH) and growth hormone-releasing peptide-2 (GHRP-2) tests showed that only the ACTH function was destroyed (isolated ACTH deficiency). The magnetic resonance imaging (MRI) findings of hypophysitis, which is the major cause of isolated ACTH deficiency, usually demonstrate enlargement of the pituitary gland. However, the MRI findings of our case showed no abnormalities of the pituitary gland and stalk. Therefore, not only oncologists, but also other specialists, including doctors in emergency units, should have knowledge of this specific feature. Our clinical observation could be useful to avoid a delay in diagnosis and to treat life-threatening adverse effects of nivolumab therapy, such as secondary adrenal insufficiency. PMID- 28871579 TI - A Case of Pedunculated Esophageal Leiomyoma Successfully Treated by Endoscopic Mucosal Resection. AB - Leiomyoma is one of the most commonly observed esophageal submucosal tumors, often appearing as a smooth-surfaced and semicircular protruded lesion. It sometimes grows toward the esophageal lumen and may be pedunculated in rare cases. We encountered a case of a pedunculated esophageal submucosal tumor diagnosed before treatment as a leiomyoma originating in the muscularis mucosae of a 68-year-old man. As the tumor arose in the muscularis mucosae, it could be safely resected via an endoscopic procedure. Only one case of pedunculated leiomyoma has been reported to date, and we herein report the second case, which was successfully treated by a minimally invasive endoscopic technique. PMID- 28871580 TI - Successful Treatment of Blunt Musculophrenic Artery Injury by Transcatheter Arterial Embolization: A Case Report. AB - An 86-year-old woman was transported by ambulance after jumping from the second floor of a building. Upon arrival, the blood pressure was stable; however, computed tomography indicated the presence of an anterior mediastinal hematoma. Eight hours after arrival, the patient exhibited shock. The blood pressure increased with rapid infusion. Emergency angiography was performed. Extravasation from the musculophrenic artery, which branches off from the left internal mammary artery, was observed. Transcatheter arterial embolization was performed and bleeding was controlled. This is the first report of musculophrenic artery injury caused by blunt trauma to the best of our knowledge. Findings suggested that if an anterior mediastinal hematoma develops, bleeding must be rapidly controlled. If the patient responds to rapid infusion and injury of the internal mammary artery or one of its branches is suspected, transcatheter arterial embolization is considered appropriate. PMID- 28871581 TI - A Case of Overwhelming Postsplenectomy Infection Caused by Streptococcus pneumoniae with Fulminant Purpura. AB - Severe infection in patients who have lost splenic function is called overwhelming postsplenectomy infection (OPSI). Untimely treatment of patients with OPSI results in critical conditions with mortality rates as high as 50 %-70 %. For patients who undergo a splenectomy, vaccination is recommended for the prevention of OPSI. However, in Japan, the vaccination utilization rates are low. Herein, we report a case of OPSI caused by Streptococcus pneumoniae with a fulminant purpura resulting in multi-organ failure, which could be reversed by intensive care. PMID- 28871582 TI - Pyoderma Gangrenosum after Breast Mastectomy and Primary Rectus Abdominis Flap Reconstruction. AB - Pyoderma gangrenosum is an intractable disease of unknown cause involving recurrent ulcerative lesions on the skin, and may accompany ulcerative colitis, rheumatoid arthritis, leukemia, systemic lupus erythematosus, and other conditions. Here, we report a rare case of pyoderma gangrenosum in the thoracic abdomen following post-mastectomy reconstructive surgery. A 39-year-old presented at the hospital with a complaint of left papilla erosion. Skin biopsy at the site revealed invasive skin cancer, with Paget-like progression in the cancerous nipple and suspected malignancy of skin appendages. After partial mastectomy including the areola, invasive ductal breast carcinoma was diagnosed. The patient underwent a subsequent full mastectomy with simultaneous sentinel lymph node biopsy and primary breast reconstructive surgery using a rectus abdominis myocutaneous flap. Two weeks post-surgery, healing of the abdominal surgical wound was found to be delayed, and suture abscess was suspected. Despite localized treatment, an ulcerative lesion developed in the thoracic region, and pyoderma gangrenosum was diagnosed following skin biopsy. After the introduction of steroid pulse therapy, no progression of the lesion was observed. This report describes the disease characteristics, diagnosis, and treatment of post-surgical pyoderma gangrenosum and discusses the case in the context of previous literature. PMID- 28871583 TI - Efficacy of Tape Feedback Therapy on Synkinesis Following Severe Peripheral Facial Nerve Palsy. AB - BACKGROUND: Mirror feedback rehabilitation is effective in preventing the development of oro-ocular synkinesis following severe facial palsy. However, we do not have effective maneuvers to prevent the deterioration of oculo-oral synkinesis. We developed a new method of biofeedback rehabilitation using tape for the prevention of oculo-oral synkinesis. OBJECTIVE: The aim of the present study was to investigate the efficacy of taping feedback rehabilitation. METHODS: Twelve consecutive patients with peripheral facial nerve palsy who developed synkinesis were divided into 2 groups. Six patients were treated with the new training method, and the remaining 6 patients were treated with conventional therapy as controls. In the experiment group, tape was placed around the mouth, and the patient was instructed to close the eyes so that no movements of the mouth would be perceived from sensations of the taped skin. After 4 weeks of training, facial movements were recorded and movie images were graded for mouth synkinesis using the revised Sunnybrook facial grading system by examiners blinded to patient grouping. RESULTS: Mouth corner contraction during eye closure was significantly weaker in the experimental group than in the control group. CONCLUSIONS: Our new feedback method could help prevent the deterioration of oculo-oral synkinesis. PMID- 28871584 TI - Selected aspects of medical care for patients with asthma and chronic obstructive pulmonary disease (COPD) in Poland. AB - INTRODUCTION: Noncompliance with healthcare undoubtedly has a strong influence on the high prevalence of uncontrolled obstructive diseases. The aim of our study was to evaluate the quality of medical conduct in patients with asthma or chronic obstructive lung diseases (COPD), with encompassed two-levelled system of health care. MATERIAL AND METHODS: A survey of general practitioners (GP), allergists and pulmonologists practicing in Poland was performed between September and December 2016. The basic survey included the data concerning the number of treated patients, the course of the visits, treatment regimens and whether the patients follow the instructions of the physician. The specialist survey recorded the details of the specialist visits, their frequency and character, an evaluation of the pharmacological and non-pharmacological therapies and an evaluation of the GP's actions. RESULTS: The basic questionnaire was completed by 807 doctors with an average of 21 +/- 9.85 years of medical experience. Most of the interviewed individuals were GPs (56%), followed by pulmonologists (28%) and allergists (16%). The GP reported 47 cases/month with obstructive pulmonary conditions, including 48.94% asthma and 51.06% COPD patients. They diagnosed three new asthma and COPD patients per month. The allergists treated patients with asthma (105 patients/ month), with 19 newly-diagnosed patients/month. The pulmonologists treated fewer asthma cases than COPD: 71 and 98 patients respectively. They reported 14 patients/month of newly-diagnosed COPD cases. The patients took inhaled glucocorticoids and long-acting b adrenoceptor agonists in separate inhalers. The most frequently-used device was a disc. In opinion of the specialists, half of the therapies initiated recently by GPs for patients with asthma and COPD required modifications. CONCLUSIONS: There is a disparity between the true state of medical care of asthma and COPD patients and globally-accepted standards. PMID- 28871585 TI - Exhaled nitric oxide atopy, and spirometry in asthma and rhinitis patients in India. AB - INTRODUCTION: Asthma is a chronic airway inflammatory disorder. Nitric oxide (NO) is non-invasively measured in exhaled breath (FeNO). The aim of the study was to investigate the anthropometric and physiologic factors that influence FeNO measurements. Also, to evaluate FeNO correlation with spirometry and inflammatory markers in asthma and rhinitis. MATERIAL AND METHODS: The study was a prospective analysis of asthma (BA) and rhinitis (AR) in patients enrolled from outpatient clinics between 2011 and 2015. Healthy controls (HC) were enrolled from the community. All subjects underwent baseline spirometry with reversibility, FeNO measurements, skin prick tests, and blood sampling for absolute eosinophil counts and serum total IgE levels. RESULTS: Of 528 enrolled participants, 215 were BA, 248 were BA-AR and 65 were HC. The mean FeNO was higher in atopic versus nonatopic subjects (34.14 vs. 25.99; p < 0.001); asthmatics versus non-asthmatics (30.46 vs. 12.91; p < 0.001), and in participants with BA-AR, compared to those without BA-AR (32.56 vs. 30.46; p < 0.001). The odds ratio for FeNO in the study population showed a significant positive association with male gender, absolute eosinophil count (AEC), breathlessness, duration of symptoms, family history and atopy. In examining the diagnostic accuracy of FeNO for asthma, the AUC for FeNO value is 0.833 (95% confidence interval [CI], 0.717-0.901), with cut-off levels to screen for asthma being 19.45 at 71.2% sensitivity and 81.8% specificity (p < 0.001). The Positive Predictive Value 96.84% (95% CI: 94.43-98.23) and Negative Predictive Value 30% (95% CI: 23.78-37.05) for asthma prediction with FeNO. CONCLUSION: The study highlights the importance of estimation of anthropometric parameters and dyspnea assessment in the evaluation of FeNO levels. Also, the presence of atopy may influence the results in the interpretation of FeNO readings. Moreover, the study have demonstrated that spirometry and FeNO have no significant correlation, which further lays emphasis on them as being different physiological parameters of asthma.  . PMID- 28871586 TI - Using a CD45dim/CD123bright/HLA-DRneg phenotyping protocol to gate basophils in FC for airway allergy. CD123 does not decrease. AB - Physicians in the field of respiratory medicine are particularly concerned about the availability of a reliable diagnostic tool to investigate respiratory allergy. Usually, basophils are easy to obtain from peripheral blood and therefore they represent a reproducible model to assess allergy in individuals. Cell assays called basophil activation tests (BATs) are widespread tools for allergy diagnosis and are easily available in most of the medical labs. The strategy by which basophils are captured in a flow cytometry protocol has met many suggestions, recommendations and experimental novelties in recent years, yet the debate needs to be further expanded. Concerns still remain about the suitability of the many approaches to make the basophil activation test (BAT) an excellent and practical tool to diagnose allergy, while improving its analytical performance. This technical report describes the methodological aspects of the use of the protocol adopting the panel CD45dim/CD123bright/HLA-DRneg to gate basophils in flow cytometry, trying to highlight the main biases related to an incorrect use of this protocol. PMID- 28871587 TI - Primary pulmonary MALT lymphoma presenting as non-resolving pneumonia. AB - Primary lung lymphoma (PLL) is a rare unilateral or bilateral lung disorder that is challenging to diagnose solely based on clinical and radiological presentation. PLL may be misdiagnosed as pneumonia or a lung tumor due to non specific findings. PLL is most frequently a mucosa-associated lymphoid tissue (MALT) lymphoma, a type of extranodal low-grade B-cell lymphoma most commonly discovered in the gastrointestinal tract. PLL should be considered in the differential diagnosis of non-resolving pneumonias. Herein we present a case of an 84-year-old patient discovered to have a primary pulmonary MALT lymphoma presenting as a non-resolving pneumonia causing a clinical challenge. PMID- 28871588 TI - Primary pleuropulmonary synovial sarcoma with brain metastases in a paediatric patient: an unusual presentation. AB - Primary lung neoplasms are rare in children. The most common primary lung malignancies in children are pleuropulmonary blastoma and carcinoid tumour. Synovial sarcoma (SS) accounts for approximately 1% of all childhood malignancies. In absolute terms, the SS of the lungs and pleura are extremely rare and pose a diagnostic difficulty. Soft tissue sarcomas usually have a high potential for metastases, however, metastasis to the brain is rare, even in widely disseminated disease, and it has been described only in 3 case reports previously. Primary pleuropulmonary SS with brain metastases is even rarer. Here we present a case of an 11-year-old boy who presented with respiratory complaints, viz. fever and cough for 20 days. Initial impression was lung abscess, however, on histopathological, immunohistochemical and molecular study, the disorder was diagnosed as synovial sarcoma. After a week from the first consult, the child developed neurological symptoms, viz., an episode of convulsion and gradually worsening power of the lower limb. Computed tomography scan and Magnetic Resonance Spectroscopy was suggestive of brain metastases. Given the rarity of primary lung neoplasms in children, clinical detection remains a challenge. Delayed diagnoses are common as respiratory symptoms may be attributed to inflammatory or infective processes. Primary pleuropulmonary synovial sarcoma is a rare tumour and it is not known to commonly metastasise to the brain. Though rare, primary pleuropulmonary SS should be considered an important differential among peadiatric primary lung neoplasms due to its potential for curability if detected early, and more aggressive metastatic pattern, e.g. brain metastases making early detection imperative. PMID- 28871589 TI - Metastasising leiomyoma of the uterus with pulmonary involvement - case report. AB - Benign metastasising leiomyoma (BML) is characterised by extrauterine smooth muscle tumours in women after surgical treatment for uterine leiomyoma. Usually manifested as solitary or multiple focal lesions in various organs, it imposes a scrutinous diagnostic work-up to exclude a malignant disease and requires confirmation in microscopic examination of the extrauterine focus. The authors present a case of a 56-year-old woman with BML manifesting as bilateral multiple pulmonary nodules, with a tentative diagnosis of a disseminated malignant disease of mesenchymal origin. The patient underwent multiple diagnostic tests, which excluded malignancy. The definite diagnosis was established after the microscopic reevaluation of an excised pulmonary nodule. The patient is monitored with chest magnetic resonance. BML should be considered in the differential diagnosis of multiple pulmonary nodules in asymptomatic women. Patients with BML require long term monitoring, therefore the selected imaging method should not carry the risk of cumulative side effects. PMID- 28871590 TI - Pulmonary hypertension in diffuse parenchymal lung diseases - is there any benefit of PAH-specific therapy? AB - Pulmonary hypertension (PH) is diagnosed in 40-50% of the patients with end-stage diffuse parenchymal lung diseases (DPLD), and it is associated with significant worsening of life expectancy. Latest ERS/ESC guidelines recommend best available treatment of DPLD, and long-term oxygen therapy in the patients with PaO2 less than 60 mm Hg. Pulmonary arterial hypertension (PAH)-targeted drugs are not recommended in PH-DPLD patients, due to the risk of increasing the ventilation perfusion mismatch, and consequently worsening of hypoxaemia. Nevertheless, PAH oriented treatment may be beneficial to selected groups of patients. The authors try to find the answer to several important questions: is there any benefit of PAH-specific therapy in PH-DPLD, who should be the candidate for PAH-specific therapy, what class of drugs is most promising, and what outcome measures should be employed? PMID- 28871591 TI - Network of breathing. Multifunctional role of the diaphragm: a review. AB - The diaphragm is the primary muscle involved in active inspiration and serves also as an important anatomical landmark that separates the thoracic and abdominal cavity. However, the diaphragm muscle like other structures and organs in the human body has more than one function, and displays many anatomic links throughout the body, thereby forming a 'network of breathing'. Besides respiratory function, it is important for postural control as it stabilises the lumbar spine during loading tasks. It also plays a vital role in the vascular and lymphatic systems, as well as, is greatly involved in gastroesophageal functions such as swallowing, vomiting, and contributing to the gastroesophageal reflux barrier. In this paper we set out in detail the anatomy and embryology of the diaphragm and attempt to show it serves as both: an important exchange point of information, originating in different areas of the body, and a source of information in itself. The study also discusses all of its functions related to breathing. PMID- 28871592 TI - Bangladeshi school-age children's experiences and perceptions on child maltreatment: A qualitative interview study. AB - BACKGROUND: Child maltreatment (CM) is a public health problem and is recognized as a huge barrier for child development. Most of the research and definitions on CM are from the perspective of high-income western countries. Because no major studies have been conducted on CM in Bangladesh, the aim of the current study was to explore the experiences of and perceptions on CM in school-age children in rural and urban Bangladesh in order to understand maltreatment in a local context and from a child perspective. METHODS: Semistructured individual interviews with 24 children (13 boys and 11 girls), between the ages of 9 and 13 years of which 11 were schoolgoing and 13 non-schoolgoing, were conducted during July 2013 and analysed according to qualitative content analysis. RESULTS: CM was a common and painful experience with serious physical and emotional consequences but highly accepted by the society. Vulnerable groups were especially young children, girls, and poor children. The children's voices were not heard due to their low status and low position in their families, schools, and working places. The main theme that emerged in the analysis was children's subordination, which permeated the five categories: (a) perception of children's situation in society, (b) understanding children's development and needs, (c) CM associated to school achievement, (d) negative impact of CM, and (e) emotional responses. CONCLUSIONS: Different kinds of abuse are obviously common in Bangladesh, and the schools do not follow the law from 2011 prohibiting corporal punishment at school. The society has to take further steps to live up to the UN Convention on the Rights of the Child, which was ratified already in 1990, to protect the Bangladeshi children from CM. PMID- 28871593 TI - Comment on Vitamin D serum levels are cross-sectionally but not prospectively associated with late-life depression. PMID- 28871594 TI - Do different probing depths exhibit striking differences in microbial profiles? AB - AIM: To perform a thorough characterization of the subgingival microbiota of shallow, moderate and deep sites in subjects with chronic periodontitis (ChP). MATERIAL AND METHODS: Subgingival samples were collected from subjects with ChP (n = 3/category of probing depth: <=3, 4-6 and >=7 mm) and periodontal health (PH). Individual samples were submitted to 16S rDNA high- throughput sequencing and the analysis was made using mothur and R packages. RESULTS: Nine subjects with ChP and seven with PH were included and 101 samples were evaluated. Thirteen phyla, 118 genera and 211 OTUs were detected. Taxa from Chloroflexi and Spirochaetes phyla were associated with initial stages of disease. Fretibacterium, Eubacterium[XI][G-6], Desulfobulbus, Peptostreptococcaceae[XI][G 1] and [G-3], Bacteroidetes[G-3], Bacteroidaceae[G-1] genera and Filifactor alocis, Fretibacterium fastidiosum, Johnsonella spHOT166, Peptostreptococcaceae[XIII][G-1]HOT113, Porphyromonas endodontalis and Treponema sp. HOT258, which are not conventionally associated with disease, increased with the deepening of the pockets and/or were elevated in ChP; while Streptococcus, Corynebacterium and Bergeyella genera were associated with PH (p < .05). CONCLUSION: Striking differences were observed between the microbiota of shallow and moderate/deep sites, but not between moderate and deep sites in ChP subjects. Differences between shallow sites in PH and ChP were also observed. The characterized microbiota included known oral microorganisms and newly identified periodontal taxa, some of them not-yet-cultured. PMID- 28871595 TI - Role of immune microenvironment in gastrointestinal stromal tumours. AB - AIMS: The immune microenvironment is a prognostic factor for various malignancies. The significance of key players of this immune microenvironment, including tumour-infiltrating lymphocytes (TILs) and expression of programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase (WARS) in gastrointestinal stromal tumours (GISTs) is largely unknown. METHODS AND RESULTS: Tissue microarrays were constructed from pathology files, 1996-2016. Immunohistochemistry for PD-L1, IDO and WARS was correlated with tumour size, mitoses and outcomes. TILs expressing CD3, CD4, CD8, FoxP3 and GBP5 were counted. A total of 129 GISTs were analysed. Mean patient age was 62.5 years; 52.0% were male. Tumour location included 89 stomach (69.0%), 33 small bowel (25.6%) and seven other (5.4%). Mean tumour size was 5.6 cm; mean mitoses were 7.2 per 50 high-power field. Nineteen patients (15.0%) developed disease progression, to abdominal wall (n = 8), liver (n = 6) and elsewhere (n = 5). Median progression-free survival was 56.6 months; five patients died of disease. PD-L1 was positive in 88 of 127 tumour samples (69.0%), 114 of 127 tumours were IDO-positive (89.8%) and 60 of 127 were positive for WARS (47.2%). PD-L1 was associated with increased size (P = 0.01), necrosis (P = 0.018) and mitoses (P = 0.006). Disease progression was not associated with PD-L1 (P = 0.44), IDO (P = 0.14) or WARS (P = 0.36) expression. PD-L1-positive GISTs with CD8+ or CD3+ TILs were significantly smaller than tumours with CD8+ or CD3+ TILs. CONCLUSIONS: PD L1 expression was associated with increased size and mitoses. High CD8+ or CD3+ TIL counts were associated with decreased PD-L1/IDO+ GIST size. PD-L1 and IDO could be significant in GIST tumour biology, which invites consideration of immunotherapy as a potential treatment option. PMID- 28871596 TI - Introduction of a prediction model to assigning periodontal prognosis based on survival time. AB - AIMS: To develop a prediction model for tooth loss due to periodontal disease (TLPD) in patients following periodontal maintenance (PM), and assess its performance using a multicentre approach. MATERIAL AND METHODS: A multilevel analysis of eleven predictors of TLPD in 500 patients following PM was carried out to calculate the probability of TLPD. This algorithm was applied to three different TLPD samples (369 teeth) gathered retrospectively by nine periodontist, associating several intervals of probability with the corresponding survival time, based on significant differences in the mean survival time. The reproducibility of these associations was assessed in each sample (One-way ANOVA and pairwise comparison with Bonferroni corrections). RESULTS: The model presented high specificity and moderate sensitivity, with optimal calibration and discrimination measurements. Seven intervals of probability were associated with seven survival time and these associations contained close to 80% of the cases: the probability predicted the survival time at this percentage. The model performed well in the three samples, as the mean survival time of each association were significantly different within each sample, while no significant differences between the samples were found in pairwise comparisons of means. CONCLUSIONS: This model might be useful for predicting survival time in different TLPD samples. PMID- 28871597 TI - Activation of the mitochondrial apoptotic pathway contributes to methotrexate induced small intestinal injury in rats. AB - The efficacy of methotrexate (MTX), a commonly used chemotherapeutic drug, is limited by intestinal injury. As the mechanism of MTX-induced small intestinal injury is not clear, there is no definitive treatment for MTX-induced gastrointestinal injury. The present study investigates the role of mitochondrial apoptotic pathway in MTX-induced small intestinal injury and examines whether aminoguanidine is effective in preventing the damage. Eight Wistar rats were administered 3 consecutive i.p. injections of 7 mg/kg body wt. MTX. Some rats were pretreated with 30 mg or 50 mg/kg body wt. of aminoguanidine (n = 6 in each group). Protein expressions of cytochrome c, caspases 3 and 9, and PARP-1 were determined in the small intestines by immunohistochemistry and western blot. Mitochondrial pathway of apoptosis was activated in the small intestines of MTX treated rats as evidenced by intense immunostaining for cyt c, caspases 9 and 3, and PARP-1 and mitochondrial release of cyt c, activation of caspases, and PARP-1 cleavage by Western blot. Immunofluorescence revealed increased nuclear localization of PARP-1. Aminoguanidine pretreatment ameliorated MTX-induced small intestinal injury in dose-dependent manner and inactivated the mitochondrial apoptotic pathway. Aminoguanidine may possess beneficial intestinal protective effects as an adjuvant co-drug against MTX intestinal toxicity during cancer chemotherapy. As the mechanism of MTX-induced small intestinal injury is not clear, there is no definitive treatment for MTX-induced gastrointestinal injury. The results of the present study show that the mitochondrial pathway of apoptosis plays a role in MTX-induced small intestinal injury as evidenced by cytochrome c release, activation of caspases 9 and 3, PARP-1 cleavage, and DNA fragmentation. Aminoguanidine (AG) pretreatment attenuates the severity of small-intestinal injury induced in rats by MTX treatment. The mechanisms of action of AG involve inhibition of iNOS, and mitochondrial pathway of apoptosis. It is suggested that aminoguanidine may possess beneficial intestinal protective effects as an adjuvant co-drug against MTX intestinal toxicity during cancer chemotherapy. PMID- 28871598 TI - Introducing universal ultrasound screening for developmental dysplasia of the hip doubled the treatment rate. AB - AIM: There is no evidence on the effect of universal ultrasound screening on developmental dysplasia of the hip. We examined the impact of adding an ultrasound examination to a one examiner clinical screening strategy on treatment, follow-up rates and the number of cases detected late in a low prevalence population. METHODS: All eligible babies born at Kongsberg Hospital, Norway, from 1998 to 2006 (n = 4245) underwent both clinical and ultrasound hip examinations within three days of life. Indications for immediate treatment were positive Barlow or Ortolani manoeuvres and, or, sonographic dysplasia. Sonographic immature hips were followed until normalisation. Treatment rates and rates from the 1989 to 1997 prestudy period (n = 3594), including late diagnoses, were collected from hospital records. RESULTS: Treatment was initiated in 90 (2.1%) infants (74 girls), 63 (70%) from birth, compared to 33 (0.9%) during the prestudy period. The follow-up rate did not change (11%). There were two (0.5/1000) and four (1.0/1000) cases detected late, respectively. No one underwent surgery during the first year of life and no avascular necrosis was seen. CONCLUSION: Adding universal ultrasound to clinical screening performed by the same, experienced paediatrician doubled the treatment rate, without influencing the already low numbers of late cases. PMID- 28871599 TI - Shaken baby syndrome and the risk of losing scientific scrutiny. AB - : A systematic review of shaken baby syndrome by the Swedish Agency for Health Technology Assessment and Assessment of Social Services generated numerous reactions from professional organisations, even before the review was published. There was also a lively debate after a paper summarising its findings were published in Acta Paediatrica The various responses are worth debating further, as they raise several important issues with regard to research ethics, having an open debate and publishing scientific findings. CONCLUSION: The responses to the shaken baby syndrome report indicate that scientific scrutiny risks being lost when researchers and organisations are not open to challenging established ideas. PMID- 28871600 TI - Effect of ghrelin on total antioxidant capacity, lipid peroxidation, sperm parameters and fertility in mice against oxidative damage caused by cyclophosphamide. AB - Cyclophosphamide is a drug used for chemotherapy and as an immune-suppressive in the organ transplantation. Despite its many clinical implications in the treatment of cancers, this drug has toxic effects on the reproductive system. This study aimed to evaluate the effect of ghrelin against the damages caused by cyclophosphamide. In this experimental study, 40 male mice were randomly divided into four groups: (i) control; (ii) cyclophosphamide; (iii) cyclophosphamide + ghrelin; and (iv) ghrelin. Cyclophosphamide (100 mg/kg body weight), once a week, and ghrelin (80 MUg/kg body weight), daily, were administered intraperitoneally for 5 weeks. After 5 weeks, the epididymides were removed and the lipid peroxidation, total antioxidant capacity and sperm parameters were examined. The fertility rate was evaluated by performance in vitro fertilisation. In the mice exposed to cyclophosphamide, the number of spermatozoa and viability, as well as total antioxidant capacity, decreased significantly (p < .05). The increase in the abnormal sperm and MDA levels was observed (p < .05). In addition, the fertility rate decreased in this group, while the use of ghrelin significantly improved the above disorders in the treatment group (p < .05). The findings of this study showed that ghrelin attenuates negative effects caused by cyclophosphamide in the sperm parameters and enhances the fertility. PMID- 28871601 TI - Comparison of donor and general population demographics over time: a BEST Collaborative group study. AB - BACKGROUND: We compared donor and general population demographics over time to provide insight into current donation patterns and the future adequacy of the blood supply. STUDY DESIGN AND METHODS: Seventeen blood center members of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative from 12 countries provided the number of donors and people in the general population by demographic category for 2001 and 2011, changes in age criteria, and percentage of first-time donors. We calculated the median age of donors and the general population and determined the percentage of each group in age and sex cohorts. RESULTS: Age criteria vary, with upper limits recently liberalized in several countries. In 2011, the percentage of first-time donors ranged from 10% to 41%. The median age of the donor and general population increased from 2001 to 2011 in most countries, as did the percentage of the general population over 60. The youngest donor cohort is overrepresented to a variable degree; this tendency increased over time. Although still underrepresented, older donors contributed more in 2011. A large middle-aged cohort is aging at a rate exceeding the progression of time, while 25- to 45-year-olds are relatively underrepresented. CONCLUSIONS: All participating countries are experiencing aging of their general population. Donor demographics differ substantially between countries; this can be only partly explained by population demographics and age criteria. Many countries have an aging middle-aged donor and population cohort and are increasingly relying on their youngest donors to contribute disproportionately to the blood supply. PMID- 28871602 TI - Elective transfers of preterm neonates to regional centres on non-invasive respiratory support is cost effective and increases tertiary care bed capacity. AB - AIM: Managing capacity at regional facilities caring for sick neonates is increasingly challenging. This study estimated the clinical and economic impact of the elective transfer of stable infants requiring nasal continuous positive airway pressure (NCPAP) from level three to level two neonatal intensive care units (NICUs) within an established clinical network of five NICUs. METHODS: We retrospectively analysed the records of 99 stable infants transferred on NCPAP between two level three NICUs and three level two NICUs in Calgary, Canada, between June 2014 and May 2016. RESULTS: The median gestational age and weight at birth were 28 weeks and 955 g, and the median corrected gestational age and weight at transfer were 33 weeks and 1597 g, respectively. This resulted in cost savings of $2.65 million Canadian dollars during the two-year study period, and 848 level three NICU days were freed up for potentially sick neonates. There were no adverse events associated with the transfers. CONCLUSION: The elective transfer of stable neonates on NCPAP from level three to level two NICUs within an established clinical network led to substantial cost savings, was safe and increased the bed capacity at the two level three NICUs. PMID- 28871603 TI - Targeting histone-acetyltransferase Tat-interactive protein 60 inhibits intestinal allergy. AB - BACKGROUND: The overproduction of IgE plays a critical role in the pathogenesis of allergy; the mechanism is unclear. Histone-acetyltransferase (HAT) activities are required in gene transcription of a large number of molecules in the immune system of the body. OBJECTIVES: This study tests a hypothesis that HAT Tat interactive protein 60 (Tip60) plays an important role in the initiation of IgE mediated allergy. METHODS: The effects of Tip60 on regulating IgE expression were assessed with B cells. An intestinal allergy mouse model was developed to assess the role of Tip60 in the induction of IgE-mediated allergic inflammation. RESULTS: High levels of Tip60 were observed in the peripheral B cells of patients with FA. Tat-interactive protein 60 (Tip60) was required in the expression of IgE and IgG1 in B cells by inducing the chromatin remolding at the gene locus, in which histone acetylation, signal transducer and activator of transcription 6 (STAT6), and nuclear factor-kappaB at the locus of Iepsilon promoter were markedly increased. Blocking Tip60 significantly attenuated the allergic inflammation in the mouse intestinal mucosa. CONCLUSIONS: Tat-interactive protein 60 (Tip60) plays an important role in the induction of IgE in B cells. Blocking Tip60 inhibits the allergic inflammation in the intestine, suggesting Tip60 inhibitor may be a potential anti-allergy drug. PMID- 28871604 TI - Rethinking contact lens aftercare. AB - The evolution of contact lens technology and clinical practice over the past three decades has been remarkable, with dramatic improvements in material biocompatibility, better lens designs and care systems, and more flexible and convenient modalities of wear. However, our approach to the aftercare examination has remained conservative, with the general modus operandi having not fully evolved from the difficult, early years of fitting non-regular replacement rigid and low water content hydrogel lenses. In this paper, we review current aftercare practice and in particular, the preferred frequency that lens wearers should return for routine visits and the appropriateness of regulations governing contact lens prescription expiry. Four key clinical reasons for conducting a routine aftercare visit are identified: preserving ocular health, maintaining good vision, optimising comfort and ensuring satisfactory lens fitting performance. Commercial reasons for conducting aftercare visits are also considered. A decision matrix is presented to help practitioners decide on an appropriate time interval between routine aftercare visits. The first aftercare visit should always take place within one to two weeks of lens dispensing. After this, the following time intervals between routine aftercare visits are advised as a general guideline: soft daily disposable, 24 months; soft daily reusable and rigid daily wear, 12 months; soft and rigid extended wear, six months. These aftercare visit frequencies may need to be adjusted when rapid rates of refractive change are anticipated, such as every six months during child/teenager myopic progression and every 12 months during the advancement of presbyopia. Numerous clinical caveats for varying these recommended aftercare frequencies are also discussed. Those new to lens wear should be seen within the first two months of lens dispensing. Regulatory authorities charged with the responsibility of stipulating the validity of a contact lens prescription should continue to allow optometrists to set an expiry date relevant to the circumstances of individual lens wearers. PMID- 28871605 TI - Detection of climate change-driven trends in phytoplankton phenology. AB - The timing of the annual phytoplankton spring bloom is likely to be altered in response to climate change. Quantifying that response has, however, been limited by the typically coarse temporal resolution (monthly) of global climate models. Here, we use higher resolution model output (maximum 5 days) to investigate how phytoplankton bloom timing changes in response to projected 21st century climate change, and how the temporal resolution of data influences the detection of long term trends. We find that bloom timing generally shifts later at mid-latitudes and earlier at high and low latitudes by ~5 days per decade to 2100. The spatial patterns of bloom timing are similar in both low (monthly) and high (5 day) resolution data, although initiation dates are later at low resolution. The magnitude of the trends in bloom timing from 2006 to 2100 is very similar at high and low resolution, with the result that the number of years of data needed to detect a trend in phytoplankton phenology is relatively insensitive to data temporal resolution. We also investigate the influence of spatial scales on bloom timing and find that trends are generally more rapidly detectable after spatial averaging of data. Our results suggest that, if pinpointing the start date of the spring bloom is the priority, the highest possible temporal resolution data should be used. However, if the priority is detecting long-term trends in bloom timing, data at a temporal resolution of 20 days are likely to be sufficient. Furthermore, our results suggest that data sources which allow for spatial averaging will promote more rapid trend detection. PMID- 28871606 TI - Risk and outcomes of pulmonary fungal infection after pediatric lung transplantation. AB - BACKGROUND: Prospective studies to determine associated risk factors and related outcomes for pulmonary fungal infection (PFI) after pediatric lung transplant (PLT) are lacking. METHODS: NIH-sponsored Clinical Trials in Organ Transplantation in Children enrolled PLT candidates, collecting data prospectively for 2 years post-transplant. Demographics, signs/symptoms, radiology, pathology and microbiology were collected. Analyses evaluated for PFI related risks and outcomes. RESULTS: In 59 PLT, pre-transplant fungal colonization occurred in 6 donors and 15 recipients. Cystic fibrosis (CF) was associated with pre-transplant colonization (P < .01). Twenty-five (42%) PLT had 26 post-transplant colonizations (median = 67 days, range = 0-750 days) with Candida (13), Aspergillus (4), mold (6) or yeast (3). Post-PLT colonization was not associated with CF, age, or pre-PLT colonization. Thirteen PFIs occurred in 10 (17%) patients, 3 proven (Candida species) and 10 probable (Candida [3], Aspergillus [3], Penicillium [3], and mold [1]). Pulmonary fungal infection was preceded by post-PLT colonization with the same organism in 4 of 13 PFI, but post PLT colonization did not predict subsequent PFI (P = .87). Older age at transplant was a risk for PFI (P < .01). No mortality was attributed to PFI. Prophylaxis use was not associated with decreased post-PLT colonization (P = .60) or PFI (P = .48). CONCLUSION: In PLT, PFI and fungal colonization are common but without associated mortality. Post-PLT colonization did not predict PFI. Optimal prevention strategies require additional study. PMID- 28871608 TI - Paediatric invasive Haemophilus influenzae in Queensland, Australia, 2002-2011: Young Indigenous children remain at highest risk. AB - AIM: Haemophilus influenzae continues to cause invasive disease in children despite widespread Hib immunisation. The significance of non-B serotypes continues to be investigated, with evidence of increased invasive non-typeable H. influenzae (NTHi) world-wide. The aim of this study was to examine the current epidemiological and clinical features of invasive H. influenzae disease in children in Queensland, Australia. METHODS: A retrospective review was performed of all cases of invasive H. influenzae disease in children <18 years of age in Queensland between January 2002 and December 2011. Cases were identified from pathology records and data requested from treating hospitals. RESULTS: Laboratory data were obtained for 144 cases and clinical/demographic data for 123 cases. The majority (72%) of cases were children <5 years of age. Annual incidence rate for all children <5 years was 7.4/100 000, and for Aboriginal and Torres Strait Islander children <5 years was 10.2/100 000. Serotype was reported for 132 isolates, 69 NTHi and 63 encapsulated strains. The most common clinical diagnoses were pneumonia, meningitis and bacteraemia without clinical focus. Of the patients, 5 patients died, and 12 had significant morbidity at hospital discharge. CONCLUSIONS: While rates of invasive H. influenzae disease have decreased dramatically following the introduction of Hib vaccination, H. influenzae remains a cause of significant morbidity and mortality, and Aboriginal and Torres Strait Islander children remain particularly vulnerable. PMID- 28871607 TI - Characterization of ectonucleoside triphosphate diphosphohydrolase (E-NTPDase; EC 3.6.1.5) activity in mouse peritoneal cavity cells. AB - This study aimed to characterize the activity of ectonucleoside triphosphate diphosphohydrolase (E-NTPDase; EC 3.6.1.5) in peritoneal cavity cells from BALB/c mice. E-NTPDase was activated in the presence of both calcium (1.5mM) and magnesium (1.5mM) ions. However, the activity was higher in the presence of Ca2+ . A pH of 8.5 and temperature of 37 degrees C were the optimum conditions for catalysis. The apparent Km values were 0.51mM and 0.66mM for the hydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate (ADP), respectively. The Vmax values were 136.4 and 120.8 nmol Pi/min/mg of protein for ATPase and ADPase activity, respectively. Nucleotide hydrolysis was inhibited in the presence of sodium azide (20mM, ATP: P < .05; ADP: P < .001), sodium fluoride (20mM; ATP and ADP: P < .001), and suramin (0.3mM; ATP: P < .01; ADP: P < .05), which is a known profile for NTPDase inhibition. Although all of the diphosphate and triphosphate nucleotides that were tested were hydrolyzed, enzyme activity was increased when adenine nucleotides were used as substrates. Finally, we stress that knowledge of the E-NTPDase catalytic biochemical properties in mouse peritoneal cavity cells is indispensable for properly determining its activity, as well as to fully understand the immune response profile in both healthy and sick cells. PMID- 28871609 TI - The origin of soil organic matter controls its composition and bioreactivity across a mesic boreal forest latitudinal gradient. AB - Warmer climates have been associated with reduced bioreactivity of soil organic matter (SOM) typically attributed to increased diagenesis; the combined biological and physiochemical transformation of SOM. In addition, cross-site studies have indicated that ecosystem regime shifts, associated with long-term climate warming, can affect SOM properties through changes in vegetation and plant litter production thereby altering the composition of soil inputs. The relative importance of these two controls, diagenesis and inputs, on SOM properties as ecosystems experience climate warming, however, remains poorly understood. To address this issue we characterized the elemental, chemical (nuclear magnetic resonance spectroscopy and total hydrolysable amino acids analysis), and isotopic composition of plant litter and SOM across a well constrained mesic boreal forest latitudinal transect in Atlantic Canada. Results across forest sites within each of three climate regions indicated that (1) climate history and diagenesis affect distinct parameters of SOM chemistry, (2) increases in SOM bioreactivity with latitude were associated with elevated proportions of carbohydrates relative to plant waxes and lignin, and (3) despite the common forest type across regions, differences in SOM chemistry by climate region were associated with chemically distinct litter inputs and not different degrees of diagenesis. The observed climate effects on vascular plant litter chemistry, however, explained only part of the regional differences in SOM chemistry, most notably the higher protein content of SOM from warmer regions. Greater proportions of lignin and aliphatic compounds and smaller proportions of carbohydrates in warmer sites' soils were explained by the higher proportion of vascular plant relative to moss litter in the warmer relative to cooler forests. These results indicate that climate change induced decreases in the proportion of moss inputs not only impacts SOM chemistry but also increases the resistance of SOM to decomposition, thus significantly altering SOM cycling in these boreal forest soils. PMID- 28871610 TI - What mediates tree mortality during drought in the southern Sierra Nevada? AB - Severe drought has the potential to cause selective mortality within a forest, thereby inducing shifts in forest species composition. The southern Sierra Nevada foothills and mountains of California have experienced extensive forest dieback due to drought stress and insect outbreak. We used high-fidelity imaging spectroscopy (HiFIS) and light detection and ranging (LiDAR) from the Carnegie Airborne Observatory (CAO) to estimate the effect of forest dieback on species composition in response to drought stress in Sequoia National Park. Our aims were (1) to quantify site-specific conditions that mediate tree mortality along an elevation gradient in the southern Sierra Nevada Mountains, (2) to assess where mortality events have a greater probability of occurring, and (3) to estimate which tree species have a greater likelihood of mortality along the elevation gradient. A series of statistical models were generated to classify species composition and identify tree mortality, and the influences of different environmental factors were spatially quantified and analyzed to assess where mortality events have a greater likelihood of occurring. A higher probability of mortality was observed in the lower portion of the elevation gradient, on southwest- and west-facing slopes, in areas with shallow soils, on shallower slopes, and at greater distances from water. All of these factors are related to site water balance throughout the landscape. Our results also suggest that mortality is species-specific along the elevation gradient, mainly affecting Pinus ponderosa and Pinus lambertiana at lower elevations. Selective mortality within the forest may drive long-term shifts in community composition along the elevation gradient. PMID- 28871611 TI - Long-term trajectories of patients with neck pain and low back pain presenting to chiropractic care: A latent class growth analysis. AB - BACKGROUND: Information on the course of neck pain (NP) and low back pain (LBP) typically relies on data collected at few time intervals during a period of up to 1 year. METHODS: In this prospective, multicentre practice-based cohort study, patients consulting a chiropractor responded weekly for 52 weeks to text messages on their cell phones. Data from 448 patients (153 NP, 295 LBP) who had returned at least one set of answers in the first 26 weeks were used. Outcome measures were pain intensity (VAS) and functional outcome, assessed using four different questions: pain intensity, limitation in activities of daily living (ADL), number of days with pain in the previous week and number of days limited in ADL. Distinct patterns of pain were analysed with quadratic latent class growth analysis. RESULTS: The final model was a 4-class model for NP and LBP. The 'recovering from mild baseline pain' is most common (76.3% of NP patients/58.3% of LBP patients) followed by the 'recovering from severe baseline pain' class (16.3% NP/29.8% LBP). They follow similar trajectories when considered over a period of 6 months. Pain at baseline, duration of complaints, functional status, limitations in ADL and the score on psychosocial scales were the variables that most contributed to distinguish between groups. CONCLUSIONS: Most patients with NP or LBP presenting in chiropractic care show a trajectory of symptoms characterized by persistent or fluctuating pain of low or medium intensity. Only a minority either experience a rapid complete recovery or develop chronic severe pain. SIGNIFICANCE: Ninety percentage of patients with neck pain or low back pain presenting to chiropractors have a 30% improvement within 6 weeks and then show a trajectory of symptoms characterized by persistent or fluctuating pain of low or medium intensity. Only a minority either experience a rapid complete recovery or develop chronic severe pain. PMID- 28871612 TI - Short-cut diagnostic tool in cystinosis: Bone marrow aspiration. AB - BACKGROUND: Cystinosis is a rare metabolic genetic disorder caused by a mutation in cystinosin lysosomal cystine transporter (CTNS). The diagnosis of nephropathic cystinosis (NC) is made by observing corneal cystine crystals and/or measuring the cystine content of leukocytes. CTNS mutation analysis confirms the diagnosis of cystinosis, but leukocyte cystine measurement and CTNS analysis have not been widely available, and cystine crystals in the cornea may not be apparent in the first months of life. Cystine crystal deposition can be seen in the bone marrow earlier than corneal deposition, in patients with NC. METHODS: Ten patients with cystinosis diagnosis were enrolled in the study. Medical records were reviewed retrospectively to collect demographic and clinical data such as age at diagnosis, disease presentation, parental consanguinity, family history, corneal cystine deposition, leukocyte cystine level, bone marrow cystine deposition, presence of renal failure, follow-up time and prognosis. RESULTS: Cystine crystals were seen in all of the patients' fresh bone marrow aspiration samples. Eight patients had corneal cystine deposition. Leukocyte cystine measurement could have been performed in four patients who had come from another center. Complications such as pulmonary hypertension and idiopathic intracranial hypertension (IIH) were observed in two patients. CONCLUSIONS: Bone marrow aspiration might be an easy and short-cut diagnostic tool for NC especially when it is not possible to measure fibroblast cystine content. Additionally some rare complications such as pulmonary hypertension and IIH can be encountered during the course of NC. PMID- 28871613 TI - Quality-assured long-term satellite-based leaf area index product. PMID- 28871614 TI - A Decision Instrument to Identify Isolated Traumatic Subdural Hematomas at Low Risk of Neurologic Deterioration, Surgical Intervention, or Radiographic Worsening. AB - OBJECTIVES: Subdural hematoma (SDH) is the most common form of traumatic intracranial hemorrhage. Severity of disease in patients with SDH varies widely. It was hypothesized that a decision rule could identify patients with SDH who are at very low risk for neurologic decline, neurosurgical intervention, or radiographic worsening. METHODS: Retrospective chart review of consecutive patients age >= 16 with Glasgow Coma Score (GCS) >= 13 and computed tomography (CT)-documented isolated SDH presenting to a university-affiliated, urban, 100,000-annual-visit ED from 2009 to 2015. Demographic, historical, and physical examination variables were collected. Primary outcome was a composite of neurosurgical intervention, worsening repeat CT, and neurologic decline. Univariate analysis was performed and statistically important variables were utilized to create a logistic regression model. RESULTS: A total of 644 patients with isolated SDH were reviewed, 340 in the derivation group and 304 in the validation set. Mortality was 2.2%. A total 15.5% of patients required neurosurgery. A decision instrument was created: patients were low risk if they had none of the following factors-SDH thickness >= 5mm, warfarin use, clopidogrel use, GCS < 14, and presence of midline shift. This model had a sensitivity of 98.6% for the composite endpoint, specificity of 37.1%, and a negative likelihood ratio of 0.037. In the validation cohort, sensitivity was 96.3%, specificity was 31.5%, and negative likelihood ratio was 0.127. CONCLUSION: Subdural hematomas are amenable to risk stratification analysis. With prospective validation, this decision instrument may aid in triaging these patients, including reducing the need for transfer to tertiary centers. PMID- 28871615 TI - Controlled oxygenated rewarming up to normothermia for pretransplant reconditioning of liver grafts. AB - Controlled oxygenated rewarming (COR) up to 20 degrees C during ex vivo machine perfusion limits reperfusion-induced tissue injury upon graft implantation. Rewarming up to normothermia might add further benefits and provide better prediction of post-transplantation organ function. The effect of 90 minutes of oxygenated machine perfusion with Aqix RS-I after cold storage combined with gentle rewarming up to 20 degrees C (COR20) or 35 degrees C (COR35) was studied in rat livers and compared with cold storage alone (CS, n = 6, resp). Postpreservation recovery was evaluated upon warm reperfusion using an established in vitro system. COR generally resulted in significantly improved energetic recovery, increased bile flow, less activities alanine aminotransferase (ALT) release, and improved histopathology upon reperfusion as compared to only cold-stored livers, without significant differences between COR20 and COR35. Parameters obtained during COR, especially during COR35, also allowed for prediction of hepatic recovery upon reperfusion. For instance, ulterior bile production upon reperfusion was found closely correlated to bile flow observed already during COR35 (R2 = 0.91). COR significantly improved liver quality after static cold storage. Elevation of machine perfusion temperature up to 35 degrees C may prove promising to refine ex vivo evaluation of the graft prior to transplantation. PMID- 28871616 TI - Rangifer management controls a climate-sensitive tundra state transition. AB - Rangifer (caribou/reindeer) management has been suggested to mitigate the temperature-driven transition of Arctic tundra into a shrubland state, yet how this happens is uncertain. Here we study this much focused ecosystem state transition in riparian areas, where palatable willows (Salix) are dominant tall shrubs and highly responsive to climate change. For the state transition to take place, small life stages must become tall and abundant. Therefore we predicted that the performance of small life stages (potential recruits) of the tall shrubs were instrumental to the focal transition, where Rangifer managed at high population density would keep the small-stage shrubs in a "browse trap" independent of summer temperature. We used a large-scale quasi-experimental study design that included real management units that spanned a wide range of Rangifer population densities and summer temperatures in order to assess the relative importance of these two driving variables. Ground surveys provided data on density and height of the small shrub life stages, while the distributional limit (shrubline) of established shrublands (the tall shrub life stage) was derived from aerial photographs. Where Rangifer densities were above a threshold of approximately 5 animals/km2 , we found, in accordance with the expectation of a "browse trap," that the small life stages of shrubs in grasslands were at low height and low abundance. At Rangifer densities below this threshold, the small life stages of shrubs were taller and more abundant indicating Rangifer were no longer in control of the grassland state. For the established shrubland state, we found that the shrubline was at a 100-m lower elevation in the management units where Rangifer had been browsing in summer as opposed to the migratory ranges with no browsing in summer. In both seasonal ranges, the shrubline increased 100 m per 1 degrees C increment in temperature. Our study supports the proposal that Rangifer management within a sustainable range of animal densities can mitigate the much-focused transition from grassland to shrubland in a warming Arctic. PMID- 28871617 TI - What is expected in lung function after lung transplantation due to end-stage pulmonary silicosis? AB - In this study, we aimed to determine the impact of lung transplantation (LTx) on pulmonary function tests (PFTs) and survival among patients with end-stage silicosis. We included patients with end-stage silicosis on the wait list for LTx, between January 1989 and July 2015 (N = 26). Sixteen of these patients received LTx; 10 were eligible, but did not undergo LTx (non-LTx) during the study period. Retrospective information on PFTs (spirometry [volumes and flows], 6-minute walking test [6MWT], and DLCO) was retrieved from patients' medical charts, including baseline information for all patients and follow-up information for the LTx. At baseline, most patients presented with spirometric and 6MWT values that were suggestive of severe disease (FEV1 /FVC 76.5 +/- 29.7; 6MWT 267.4 +/- 104.5 m). Significant increases in these values were observed at follow up in the LTx (P = .036 and .151, respectively). The overall median survival of patients in the LTx and non-LTx was 3.35 years (95% CI: 0.16-14.38) and 0.78 years (95% confidence interval [CI]: 0.12-3.65) (P = 0.002), respectively. For patients with end-stage silicosis, LTx offers significant benefits regarding pulmonary function and survival when compared to non-LTx, and is a reliable tool to help this critical population of patients, whose only treatment option is LTx. PMID- 28871618 TI - Abdominal emergencies after liver transplantation: Presentation and surgical management. AB - With an increasing number of liver transplantation (LT) and an enhanced overall survival, LT recipients are more likely to be admitted in emergency departments of general hospitals. Yet, in LT recipients, common but also benign symptoms may reveal a LT-related (or not) severe condition. To improve management of LT recipients by emergency physicians and general surgeons and potentially improve long-term outcomes, a clinical review was performed. Overall, CT scan and blood tests should be systematically performed. Immunosuppressive side effects should be excluded using blood tests. LT-related complications are more likely to occur during the first three months after LT, including mainly bile leak, arterial aneurysm, and pseudoaneurysm. Patients should be referred in emergency to tertiary centers. Non-LT-related complications and common abdominal conditions may also be diagnosed in LT recipients. Except in case of diffuse peritonitis or in hemodynamically unstable patients when surgical procedure should be performed, most conditions should be reassessed regarding the immunosuppressive treatment and the adhesive abdominal cavity. PMID- 28871619 TI - From cytokines to pragmatic designs: changing paradigms. AB - Emily Cooley was a well-respected medical technologist and morphologist with a remarkable skill set. She was highly regarded both professionally and personally. The "Emily Cooley Lectureship and Award" was established to honor her in particular and medical technologists in general. This article first reviews how a medical laboratory technologist was inspired to become a clinical researcher, then goes on to describe research that led to the discovery of cytokines as the cause of febrile nonhemolytic transfusion and the use of a pragmatic randomized controlled trial design to address evidence of harm when stored red blood cells were transfused. Important lessons for performing quality, meaningful research are highlighted. PMID- 28871620 TI - Oropharyngeal surfactant can improve initial stabilisation and reduce rescue intubation in infants born below 25 weeks of gestation. AB - AIM: Minimally aggressive and easily performed techniques that facilitate spontaneous respiratory stabilisation are required to reduce rescue intubation in extremely premature infants. This study evaluated the feasibility and safety of administering surfactant into the pharynx of infants born at <25 weeks immediately after birth. METHODS: This study of 19 infants was conducted from January 2013 to June 2014 in a tertiary perinatal centre in Prague. We administered 1.5 mL of Curosurf as a bolus into the pharynx and simultaneously performed a sustained inflation manoeuvre (SIM). The extent of the interventions, death and severe neonatal morbidity in the study group were compared with 20 controls born before the study period and 20 born after it. RESULTS: All infants received oropharyngeal surfactant within the median (interquartile range) time of 40 seconds (25-75) after cord camping. The surfactant had to be suctioned in one infant because of upper airway obstruction. Although more subsequent surfactant was administered in the study group, significantly fewer study period infants required intubation than the before and after controls (16% versus 75% and 58%, respectively, p < 0.01). CONCLUSION: Oropharyngeal surfactant with simultaneous SIM was feasible and safe and reduced the need for delivery room intubation in these fragile infants. PMID- 28871621 TI - Systolic blood pressure reduction during the first 24 h in acute heart failure admission: friend or foe? AB - AIMS: Changes in systolic blood pressure (SBP) during an admission for acute heart failure (AHF), especially those leading to hypotension, have been suggested to increase the risk for adverse outcomes. METHODS AND RESULTS: We analysed associations of SBP decrease during the first 24 h from randomization with serum creatinine changes at the last time-point available (72 h), using linear regression, and with 30- and 180-day outcomes, using Cox regression, in 1257 patients in the VERITAS study. After multivariable adjustment for baseline SBP, greater SBP decrease at 24 h from randomization was associated with greater creatinine increase at 72 h and greater risk for 30-day all-cause death, worsening heart failure (HF) or HF readmission. The hazard ratio (HR) for each 1 mmHg decrease in SBP at 24 h for 30-day death, worsening HF or HF rehospitalization was 1.01 [95% confidence interval (CI) 1.00-1.02; P = 0.021]. Similarly, the HR for each 1 mmHg decrease in SBP at 24 h for 180-day all-cause mortality was 1.01 (95% CI 1.00-1.03; P = 0.038). The associations between SBP decrease and outcomes did not differ by tezosentan treatment group, although tezosentan treatment was associated with a greater SBP decrease at 24 h. CONCLUSIONS: In the current post hoc analysis, SBP decrease during the first 24 h was associated with increased renal impairment and adverse outcomes at 30 and 180 days. Caution, with special attention to blood pressure monitoring, should be exercised when vasodilating agents are given to AHF patients. PMID- 28871622 TI - 'heartfailurematters.org', an educational website for patients and carers from the Heart Failure Association of the European Society of Cardiology: objectives, use and future directions. AB - AIMS: In 2007, the Heart Failure Association of the European Society of Cardiology (ESC) launched the information website heartfailurematters.org (HFM site) with the aim of creating a practical tool through which to provide advice and guidelines for living with heart failure to patients, their carers, health care professionals and the general public worldwide. The website is managed by the ESC at the European Heart House and is currently available in nine languages. The aim of this study is to describe the background, objectives, use, lessons learned and future directions of the HFM site. METHODS AND RESULTS: Data on the number of visitor sessions on the site as measured by Google Analytics were used to explore use of the HFM site from 2010 to 2015. Worldwide, the annual number of sessions increased from 416 345 in 2010 to 1 636 368 in 2015. Most users (72-75%) found the site by using a search engine. Desktops and, more recently, smartphones were used to visit the website, accounting for 50% and 38%, respectively, of visits to the site in 2015. CONCLUSIONS: Although its use has increased, the HFM site has not yet reached its full potential: fewer than 2 million users have visited the website, whereas the number of people living with heart failure worldwide is estimated to be 23 million. Uptake and use could be further improved by a continuous process of qualitative assessment of users' preferences, and the provision of professional helpdesk facilities, comprehensive information technology, and promotional support. PMID- 28871623 TI - Clinical course of patients with symptomatic isolated superficial vein thrombosis: the ICARO follow-up study. AB - : Essentials Late sequelae of isolated superficial vein thrombosis (iSVT) have rarely been investigated. We studied 411 consecutive outpatients with acute iSVT with a median follow-up of three years. Male sex and cancer are risk factors for future deep vein thrombosis or pulmonary embolism. Patients without cancer appear to be at a negligible risk for death. SUMMARY: Background Studies of long-term thromboembolic complications and death following acute isolated superficial vein thrombosis (iSVT) of the lower extremities are scarce. Objectives To investigate the course of iSVT in the setting of an observational multicenter study. Methods We collected longitudinal data of 411 consecutive outpatients with acute, symptomatic, objectively diagnosed iSVT who were previously included in the cross sectional ICARO study. Four patients followed for < 30 days and 79 with concomitant deep vein thrombosis (DVT) or pulmonary embolism (PE) were excluded from the present analysis. The primary outcome was symptomatic DVT or PE. The safety outcomes were major bleeding and all-cause death. Results The median follow-up time was 1026 days (interquartile range 610-1796). Symptomatic DVT/PE occurred in 52 (12.9%) patients, giving annualized rates of 1.3% (95% confidence interval [CI] 0.3-3.9%) on anticoagulant treatment and 4.4% (95% CI 3.2-5.8%) off anticoagulant treatment. Male sex (adjusted hazard ratio [HR] 2.03 [95% CI 1.16 3.54]) and active solid cancer (adjusted HR 3.14 [95% CI 1.11-8.93]) were associated with future DVT/PE, whereas prior DVT/PE failed to show significance, most likely because of bias resulting from prolonged anticoagulant treatment. Three major bleeding events occurred on treatment, giving an annualized rate of 1.4% (95 CI 0.3-4.0%). Death was recorded in 16 patients (annualized rate: 1.1% [95% CI 0.6-1.7%]), and was attributable to cancer (n = 8), PE (n = 1), cardiovascular events (n = 3), or other causes (n = 4). Conclusions The long-term risk of DVT/PE after anticoagulant discontinuation for acute iSVT is clinically relevant, especially in males and in the presence of active cancer. The risk of death appears to be negligible in patients without cancer. PMID- 28871624 TI - Low skeletal muscle mass is associated with increased hospital costs in patients with cirrhosis listed for liver transplantation-a retrospective study. AB - Low skeletal muscle mass (sarcopenia) is associated with increased morbidity and mortality in liver transplant candidates. We investigated the association between sarcopenia and hospital costs in patients listed for liver transplantation. Consecutive patients with cirrhosis listed for liver transplantation between 2007 and 2014 in a Eurotransplant centre were identified. The skeletal muscle index (SMI, cm2 /m2 ) was measured on CT performed within 90 days from waiting list placement. The lowest sex-spe cific quartile represented patients with sarcopenia. In total, 224 patients were included. Median time on the waiting list was 170 (IQR 47-306) days, and median MELD score was 16 (IQR 11-20). The median total hospital costs in patients with sarcopenia were ?11 294 (IQR 3570-46 469) compared with ?6878 (IQR 1305-20 683) in patients without sarcopenia (P = 0.008). In multivariable regression analysis, an incremental increase in SMI was significantly associated with a decrease in total costs (?455 per incremental SMI, 95% CI 11-900, P = 0.045), independent of the total time on the waiting list. In conclusion, sarcopenia is independently associated with increased health related costs for patients on the waiting list for liver transplantation. Optimizing skeletal muscle mass may therefore lead to a decrease in hospital expenditure, in addition to greater health benefit for the transplant candidate. PMID- 28871625 TI - Rare finding of a giant ischioanal lipoma. PMID- 28871626 TI - The muscle hypothesis revisited. PMID- 28871627 TI - Important Aspects of Pharmacist-led Medication Reviews in an Acute Medical Ward. AB - In some hospitals, clinical pharmacists review the medication to find drug related problems (DRPs) in acutely admitted patients. We aimed to identify the nature of identified DRPs and investigate factors of potential importance for the clinical implementation of pharmacist suggestions. In 100 randomly selected medication review (MR) notes, we retrospectively evaluated the clinical implementation and classified (1) timing and communication of the review; (2) DRPs and related suggestions for the physician; and (3) DRPs' potential clinical relevance to patients as 'beneficial', 'somewhat beneficial', 'no relevance' or 'other relevance'. Of 327 DRPs (0-13 DRPs per patient), 42% were implemented. The clinical implementation was higher if the MR note was made prior to (instead of after) the physician's admission, and even higher if the suggestions were communicated verbally (instead of only in writing) to the physicians (44% versus 79%, p < 0.05). The clinical relevance of the DRPs was either 'beneficial' (16%), 'somewhat beneficial' (43%), 'no relevance' (22%) or 'other relevance' (19%). The 'beneficial' DRPs had a higher clinical implementation (53%) than 'no relevance' (34%) (p < 0.05). The most frequently implemented suggestions were based on DRPs concerning 'indication for drug treatment not noticed', 'inappropriate drug form' and 'drug dose too low', with implementation rates of 83%, 67% and 63%, respectively. In our sample, the pharmacist's MR suggestions were only implemented by physicians in 42% of the cases, but review prior to physician contact and verbal communication of the suggestions, higher clinical relevance and specific types of DRPs were associated with a higher implementation rate. PMID- 28871628 TI - Response to: stated conclusion about industry funding is opposite to what the paper's data show: letter regarding "Selective outcome reporting in obesity clinical trials: a cross-sectional review". PMID- 28871629 TI - Nonpublication and discontinuation of randomised controlled trials in newborns. AB - AIM: To determine the rate of nonpublication and discontinuation of randomised controlled trials (RCTs) in newborns. METHODS: This was a retrospective, cross sectional study of RCTs registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) between 2008 and 2012. RESULTS: Fifty trials were identified, of which 23 (46%) were retrospectively registered. Thirty trials (60%) were published. After a median follow-up of 8.0 (range 4.6-17.4) years from Research Ethics Committee approval, 15 of 41 completed trials (37%) remained unpublished, representing 5422 neonatal trial participants. Nine trials (18%) were discontinued, including four that were published. The most frequent reason for discontinuation was poor recruitment (n = 4). Sample size discrepancies between registration and publication were found in 17 (65%) of the 26 completed, published trials. In nine (35%) of these trials, the calculated sample size in the method section of the published article differed from the planned sample size in the trial registry (relative difference -20% to +33%). CONCLUSION: Nonpublication and discontinuation of RCTs conducted in newborns is common. Additional efforts are needed to minimise the number of neonatal trial participants that are exposed to interventions without subsequent publication. PMID- 28871630 TI - Changes in psychosocial health during a 7-week paediatric weight management program. AB - Youth with obesity are at increased risk of psychosocial symptoms; however, little is known regarding the impact of paediatric weight management (PWM) on psychosocial health. The aim of the study was to investigate changes in psychosocial health among children who completed a 7-week PWM program. Participants aged 5 to 16 years with a BMI >=85th percentile completed a 7-week, family-centred PWM program focused on health behaviour education, exercise and mentored goal setting. The Paediatric Symptom Checklist (PSC) was assessed via parent report to evaluate psychosocial symptoms before and after the program, and subscales were calculated for internalizing (PSC-IS), externalizing (PSC-ES) and attention symptoms (PSC-AS). At baseline, positive screen rates for psychosocial symptoms among the 317 patients included 16.1% for PSC, 14.1% for PSC-ES, 18.6% for PSC-IS and 12.3% for PSC-AS. Among program completers, total PSC scores improved in those with normal (p = 0.010) and elevated p < .001 psychosocial symptoms at baseline. Youth with positive screens for elevated PSC subscales improved their subscale scores, on average, and the majority reduced scores to below elevated levels for PSC (54.2%), PSC-ES (64.7%), PSC-IS (78.3%) and PSC-AS (64.7%). Improvements in PSC remained significant after adjusting for BMI changes during treatment, but BMI differed across PSC-change groups, including BMI increases among participants with PSC deterioration (0.33 +/- 0.64 kg m-2 ) (P = 0.035) and BMI decreases among patients with no reliable PSC change (-0.26 +/- 1.04 kg m-2 ) (P = 0.038) or reliable PSC improvement (-0.22 +/- 0.74 kg m-2 ) (P = 0.025). Youth with positive screens for psychosocial symptoms can improve emotional and behavioural functioning during short-term PWM. Future research is needed to elucidate mechanisms and long-term outcome durability. PMID- 28871632 TI - Specific and Direct Amplified Detection of MicroRNA with MicroRNA:Argonaute-2 Cleavage (miRACle) Beacons. AB - MicroRNA detection is a valuable method for determining cell identity. Molecular beacons are elegant sensors that can transform intracellular microRNA concentration into a fluorescence intensity. While target binding enhances beacon fluorescence, the degree of enhancement is insufficient for demanding applications. The addition of specialty nucleases can enable target recycling and signal amplification, but this process complicates the assay. We have developed and characterized a class of beacons that are susceptible to the endogenous nuclease Argonaute-2 (Ago2). After purification of the complex by co immunoprecipitation, microRNA:Ago2 cleavage (miRACle) beacons undergo site- and sequence-specific cleavage, and show a 13-fold fluorescence enhancement over traditional beacons. The system can be adapted to any microRNA sequence, and can cleave nuclease-resistant, non-RNA bases, potentially allowing miRACle beacons to be designed for cells without interference from non-specific nucleases. PMID- 28871631 TI - Characteristics and outcomes among patients with need for early dialysis after lung transplantation surgery. AB - BACKGROUND: With the introduction of lung allocation score (LAS), increasingly sicker patients are undergoing lung transplantation (LT). This study was conducted to determine the time trends in need for dialysis after LT, identify variables independently associated with need for dialysis, and evaluate its association with 1- and 5-year mortality. METHODS: We queried the United Network of Organ Sharing database for adult patients undergoing LT between 1994 and 2014. We excluded patients with simultaneous dual organ transplantation and where data regarding the need for dialysis were not available. RESULTS: Time trends in the yearly incidence of the need for dialysis showed a gradual increase (P = .012). In the post-LAS era, ethnicity, underlying diagnosis, estimated GFR <90 mL/min/1.73 m2 and mean pulmonary pressures>35 mm Hg, ventilator or extracorporeal membrane oxygenation support at LT, and >20% increase in serum creatinine between listing and match were independently associated with the need for dialysis. Patients with need for dialysis had significantly increased hazard of 1-year (n = 13 849; adjusted hazard ratio, 95% CI:7.23, 6.2-8.4, P < .001) and 5-year mortality (n = 7287; adjusted hazard ratio, 95% CI:3.96, 3.43-4.56, P < .001). CONCLUSIONS: There is a gradual increase in the incidence of the need for early dialysis after LT, and these patients have significantly worse early and late survival. Several pre-transplant recipient characteristics are independently associated with the need for dialysis. PMID- 28871633 TI - Evaluation of Aintree LOSS, a community-based, multidisciplinary weight management service: outcomes and predictors of engagement. AB - Aintree LOSS is a community-based, multidisciplinary weight management programme for patients with severe and complex obesity, focusing on a flexible and individualized service with follow-up for up to 2 years. We evaluated all 2472 patients referred to the service between October 2009 and 2013. Demographic data were recorded at baseline, with the Index of Multiple Deprivation (IMD) used to measure socioeconomic deprivation. Weight was recorded at each visit. Mean body mass index at baseline was 45.6 (standard deviation 6.8), and 58.9% of patients lived in areas in the most deprived decile nationally. Of 2315 appropriate referrals, 1249 (55.1%) attended >2 visits; mean final weight loss was 3.50 +/- 8.55 kg, and 24.1% achieved >=5% weight loss. Of the patients, 754 (33.3%) attended for over 6 months; mean final weight loss was 4.94 +/- 10 kg, and 34% achieved 5% weight loss. Multivariate logistic regression analysis showed increasing age, residence in a less deprived area and sleep apnoea to be independently associated with attendance for >6 months, and there was a linear relationship between 6-month attendance and deprivation quintile. Year-on-year analyses showed improvement in engagement over time, coinciding with efforts to improve access to the service. This work shows a multidisciplinary, community based weight loss programme prioritizing a fully flexible and individualized approach functioning effectively in real-world practice. Maintaining engagement remains a challenge in weight loss programmes, and our results suggest younger patients living in areas with greater deprivation should be a target for efforts to improve engagement. PMID- 28871634 TI - Assembly and analysis of a qingke reference genome demonstrate its close genetic relation to modern cultivated barley. AB - Qingke, the local name of hulless barley in the Tibetan Plateau, is a staple food for Tibetans. The availability of its reference genome sequences could be useful for studies on breeding and molecular evolution. Taking advantage of the third generation sequencer (PacBio), we de novo assembled a 4.84-Gb genome sequence of qingke, cv. Zangqing320 and anchored a 4.59-Gb sequence to seven chromosomes. Of the 46,787 annotated 'high-confidence' genes, 31 564 were validated by RNA sequencing data of 39 wild and cultivated barley genotypes with wide genetic diversity, and the results were also confirmed by nonredundant protein database from NCBI. As some gaps in the reference genome of Morex were covered in the reference genome of Zangqing320 by PacBio reads, we believe that the Zangqing320 genome provides the useful supplements for the Morex genome. Using the qingke genome as a reference, we conducted a genome comparison, revealing a close genetic relationship between a hulled barley (cv. Morex) and a hulless barley (cv. Zangqing320), which is strongly supported by the low-diversity regions in the two genomes. Considering the origin of Morex from its breeding pedigree, we then demonstrated a close genomic relationship between modern cultivated barley and qingke. Given this genomic relationship and the large genetic diversity between qingke and modern cultivated barley, we propose that qingke could provide elite genes for barley improvement. PMID- 28871635 TI - Fatty acid synthase as a potential therapeutic target in feline oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is an aggressive and treatment-resistant malignancy in both feline and human patients. Recent work has demonstrated aberrant expression of fatty acid synthase (FASN) and an increased capacity for lipogenesis in human OSCC and other cancers. In human OSCC, inhibition of FASN decreased cell viability and growth in vitro, and diminished tumour growth and metastasis in murine preclinical models. This study aimed to characterize FASN as a therapeutic target in feline OSCC. Immunohistochemistry revealed high FASN expression in primary feline OSCC tumours, and FASN expression was detected in OSCC cell lines (3 feline and 3 human) by immunoblotting and quantitative real time-polymerase chain reaction (qRT-PCR). Orlistat, a FASN inhibitor, substantially reduced cell viability in both feline and human OSCC lines, although feline cell lines consistently displayed higher sensitivity to the drug. FASN mRNA expression among cell lines mirrored sensitivity to orlistat, with feline cell lines expressing higher levels of FASN. Consistent with this observation, diminished sensitivity to orlistat treatment and decreased FASN mRNA expression were observed in feline OSCC cells following incubation under hypoxic conditions. Treatment with orlistat did not potentiate sensitivity to carboplatin in the cell lines investigated; instead, combinations of the 2 drugs resulted in additive to antagonistic effects. Our results suggest that FASN inhibition is a viable therapeutic target for feline OSCC. Furthermore, cats may serve as a spontaneous large animal model for human oral cancer, although differences in the regulation of lipogenesis between these 2 species require further investigation. PMID- 28871636 TI - Age-specific infectious period shapes dynamics of pneumonia in bighorn sheep. AB - Superspreading, the phenomenon where a small proportion of individuals contribute disproportionately to new infections, has profound effects on disease dynamics. Superspreading can arise through variation in contacts, infectiousness or infectious periods. The latter has received little attention, yet it drives the dynamics of many diseases of critical public health, livestock health and conservation concern. Here, we present rare evidence of variation in infectious periods underlying a superspreading phenomenon in a free-ranging wildlife system. We detected persistent infections of Mycoplasma ovipneumoniae, the primary causative agent of pneumonia in bighorn sheep (Ovis canadensis), in a small number of older individuals that were homozygous at an immunologically relevant genetic locus. Interactions among age-structure, genetic composition and infectious periods may drive feedbacks in disease dynamics that determine the magnitude of population response to infection. Accordingly, variation in initial conditions may explain divergent population responses to infection that range from recovery to catastrophic decline and extirpation. PMID- 28871638 TI - Correction. PMID- 28871637 TI - Deaths and end-of-life decisions differed between neonatal and paediatric intensive care units at the same children's hospital. AB - AIM: We compared neonatal deaths and end-of-life decisions in a neonatal intensive care unit (NICU) and paediatric intensive care unit (PICU) in a Dutch tertiary children's hospital. SUBJECTS: All 235 full-term infants who died within 28 days of life between 2003 and 2013 in the NICU (n = 199) and PICU (n = 36) were retrospectively studied. RESULTS: The median length of stay was three days in the NICU and seven days in the PICU (p = 0.003). The main reasons for NICU stays were asphyxia (52.8%) and congenital malformations (42.2%), and in the PICU, they were congenital malformations (97.2%) and primarily cardiac problems (83.3%, p < 0.001). The median age of death was three days in the NICU and eight days in the PICU (p < 0.001), and mortality despite full intensive care treatment was 4.0% and 25.0%, respectively. Intensive treatment was discontinued because of poor survival chances in 25.1% of NICU and 52.8% of PICU cases (p < 0.001), and care was redirected because of expected poor quality of life in 70.9% and 22.2%, respectively. CONCLUSION: Differences between the age at death and end-of-life decisions were found between full-term infants in the NICU and PICU in the same children's hospital. Underlying disorders and doctors' attitudes may have played a role. PMID- 28871639 TI - Letters to the Editor. PMID- 28871640 TI - A novel approach to monitoring adherence to preventive therapy for tuberculosis in adolescence. AB - OBJECTIVES: To evaluate the usefulness of a microelectronic tablet-dispenser for monitoring adherence to preventive therapy for tuberculosis infection in adolescents. METHODOLOGY: Twenty-one patients with positive Mantoux tests were treated with isoniazid (INH), dispensed in a microelectronic tablet-dispenser that recorded the date, time and duration that the container was opened. Other measures of adherence included attendance at clinic, patient self-report, tablet count, and measurement of urinary INH metabolites. RESULTS: The mean adherence rates were: 83% using attendance at clinic, 91% using tablet counts, 79% using urine assays, and 66% using the electronic tablet-dispenser. Self-reporting appeared to over-estimate adherence. CONCLUSIONS: Adherence to 6 months of INH calculated using different measures is higher in this study than in previous reports. Microelectronic tablet-dispensers are an effective method to objectively measure adherence on a daily basis. Other measures are less helpful. PMID- 28871641 TI - Varicella vaccine in non-immune household contacts of children with cancer or leukaemia. AB - OBJECTIVE: To assess the immunogenicity and reactogenicity of a new formulation of live attenuated varicella vaccine (Oka strain) in non-immune household contacts of children with cancer or leukaemia. METHODOLOGY: This was an open study with one group. Healthy varicella-susceptible adults and children living in the same household as children with cancer or leukaemia were vaccinated with a new live attenuated varicella vaccine (Oka strain) which is stable when stored at 2-8 degrees C (refrigerator temperature) for at least 24 months (Varilrix). Children less than 13 years of age received one dose (0.5 mL containing at least 103.3 plaque forming units) by subcutaneous injection and those aged over 13 years received two doses 8 weeks apart. Adverse reactions following vaccination were recorded daily by the vaccinees. Post-vaccination antibody estimation was determined using indirect immunofluorescence 6 weeks after vaccination. RESULTS: Thirty-five seronegative subjects (28 children and 7 adults and adolescents) were vaccinated. All subjects tested (34) had seroconverted after vaccination. Local injection site reactions were experienced by 15/35. Other adverse reactions were uncommon (rash 2/35, fever (>= 37.5 degrees C) 3/35). No cases of clinical varicella occurred amongst the high-risk household contacts of the vaccine. CONCLUSION: This is the first study of this formulation of varicella vaccine in household contacts of children with cancer or leukaemia. The vaccine was found to be safe and immunogenic, but further follow-up is needed to document duration of immunity. PMID- 28871642 TI - Papilloedema secondary to acute purulent sinusitis. AB - Upper respiratory tract infections and sinusitis are common, but intracranial complications of sinusitis are rare in children and are often clinically unremarkable. Papilloedema secondary to purulent sinusitis is a complication previously not reported. We report two cases to highlight atypical manifestations of sinusitis in children. PMID- 28871643 TI - Post-extubation prophylactic nasal continuous positive airway pressure in preterm infants: Systematic review and meta-analysis. AB - OBJECTIVES: To determine whether management with nasal continuous positive airway pressure (NCPAP) in preterm infants having their endotracheal tube removed following a period of intermittent positive pressure ventilation (IPPV), leads to an increased proportion remaining free of additional ventilatory support, compared to extubation directly to headbox oxygen. METHODOLOGY: Search Strategy- Searches were made of the Oxford Database of Perinatal Trials, Medline, abstracts of conferences and symposia proceedings, expert informants, journal hand searching mainly in the English language and expert informant searches in the Japanese language. Selection criteria- All trials utilising random or quasi random patient allocation, in which NCPAP (delivered by any method) was compared with headbox oxygen for postextubation care were included. Methodological quality was assessed independently by the two authors. Data collection and analysis- Data were extracted independently by the two authors. Meta-analysis using event rate ratios (ERRs) and event rate differences (ERDs) was performed using Revman 3.0 statistical software. Prespecified subgroup analysis to determine the impact of different levels of NCPAP and use of aminophylline were also performed using the same package. Similar analysis to investigate the effect of postnatal age on outcomes of interest was also undertaken. RESULTS: Nasal CPAP, when applied to preterm infants being extubated following IPPV, reduces the incidence of adverse clinical events (apnoea, respiratory acidosis and increased oxygen requirements) indicating the need for additional ventilatory support. This result is both statistically significant and clinically important; ERR, 0.62 (0.49, 0.79) and ERD, - 0.175 (- 0.256, - 0.095). A trend towards reduction in the incidence of oxygen dependency at 28 days of age is also seen in the group extubated to NCPAP; ERR, 0.86 (0.67, 1.10) and ERD, - 0.069 (- 0.177, 0.039). CONCLUSIONS: Nasal CPAP is effective in preventing failure of extubation in preterm infants following a period of endotracheal intubation and IPPV. Further definition of the patient gestational age and weight groups to whom these results apply is required. Optimal levels of NCPAP as well as methods of administration remain to be determined. PMID- 28871645 TI - Letters to the Editor. PMID- 28871644 TI - Retinopathy of prematurity in infants < 32 weeks' gestation at birth in New South Wales in 1993 and 1994. AB - OBJECTIVE: To study the incidence and severity of retinopathy of prematurity (ROP) in infants < 32 weeks' gestation. DESIGN: Review of the records maintained in the New South Wales Neonatal Intensive Care Unit Study (NICUS) database on infants admitted to the neonatal intensive care units (NICU) in NSW from 1 January 1993 to 31 December 1994. RESULTS: In the more premature infants, 23-26 weeks' gestation, 65% developed ROP (102 of 157 examined for ROP). Forty-four infants (28%) developed severe ROP (Stage >= 3 ROP), 19 infants (12.1%) required cryo/laser therapy and one infant (0.6%) in this group had a retinal detachment. One hundred and fifty-seven of 159 surviving infants (98.7%) were examined for ROP. In the infants 27-28 weeks' gestation, 38.3% developed ROP (103 of 269 examined for ROP). Fifteen infants (5.6%) developed severe ROP, seven infants (2.6%) required cryo/laser therapy for threshold ROP and three infants (1.1%) in this group had a retinal detachment. Two hundred and sixty-nine of 299 surviving infants (90%) were examined for ROP. In the infants 29-31 weeks' gestation, 10.8% developed ROP (48 of 443 examined for ROP). Six infants (1.4%) developed severe ROP, one infant (0.2%) required cryo/laser therapy for threshold ROP and no infant in this group had a retinal detachment. However, only 443 of 681 surviving infants (65.1%) in this group were examined for ROP. Of the four infants with detached retinas, one was a 25 week gestation infant weighing 840 g, two were 27 weeks' gestation weighing 960 and 980 g and one infant was a 28 week gestation infant weighing 620 g. No infant developed Stage 5 ROP. CONCLUSION: In the more mature infants 29-31 weeks' gestation, the rate of ROP is low, although severe ROP still occurs. However, only 65.1% of these infants were examined for ROP and we should be diligent in screening for ROP in the sicker infants in this group. The incidence of severe ROP as well as the rate of cryo/laser therapy in premature infants 23-26 weeks' in NSW has not changed since the increases seen in the early 1990s. Retinal detachment also occurs in the infants 27-28 weeks' gestation and it is important that all these infants are screened for ROP. PMID- 28871646 TI - Effect of nappy liners on temperature stability in very preterm infants. AB - OBJECTIVE: To determine whether absorbent liners used in posturally supportive cloth nappies influence temperature stability in infants < 31 weeks gestation. METHODOLOGY: Randomized cross-over trial conducted at King Edward Memorial Hospital for Women, Perth, Western Australia. Twenty-three infants nursed in incubators on Infant Servo Control were randomly assigned to wear cloth postural support nappies alternately with or without absorbent liners for 24-h periods over 4 days. Measurements of skin and incubator temperatures were recorded hourly. Times of all nappy changes and infant handling procedures were also recorded. RESULTS: There was no change in any temperature measurement over time, between days, or between day/night periods. Infants nursed with the liner demonstrated a higher skin temperature (0.04 degrees C), and a lower incubator temperature (1.05 degrees C). A drop in skin temperature of 0.02 degrees C and an increase in incubator temperature of 0.28 degrees C occurred following handling of infants. There was no effect due to sex, gestational age, or actual age of the infants. CONCLUSION: Use of an absorbent liner within a cloth postural support nappy promotes better temperature regulation in infants < 31 weeks gestation, by reducing incubator temperature and increasing skin temperature. PMID- 28871647 TI - Galactosaemia in Chinese. PMID- 28871648 TI - Subglottic haemangioma: Controversies in management. AB - OBJECTIVE: To discuss treatment modalities for subglottic haemangioma (SGH). METHODOLOGY: Case report of two children definitively managed by different modalities. RESULTS: Management by CO2 laser vaporization in one child, and laser followed by interferon 2-alpha in the second child were both successful in controlling the SGH without the need for tracheostomy. CONCLUSIONS: The stepped care approach at John Hunter Children's Hospital, Newcastle, New South Wales, is presented. Both laser surgery and interferon can help control SGH. Careful surveillance and interdisciplinary cooperation are essential to achieve a good outcome. PMID- 28871649 TI - Letters to the Editor. PMID- 28871650 TI - Classical galactosaemia in Chinese: A case report and review of disease incidence. AB - We report a case of galactose-1-phosphate uridyl transferase (GALT) deficiency in a full-term Chinese neonate, who presented with atypical biochemical features of hyperammonaemia in addition to the classical presenting features of jaundice and lethargy after feeding. Red cell GALT activity was virtually absent in the patient while 50% of normal activity was found in parents and a sibling. Mutation screening excluded both Q188R and N314D as the causative mutation in GALT gene, which suggested a possible genetic segregation among ethnic groups. Data from a Taiwan screening program suggested that the incidence of the disease was approximately 1 in 400 000 in the Chinese population which was a sixth of that in Caucasian populations. PMID- 28871652 TI - Antibiotic therapy for Salmonella enteritis. PMID- 28871651 TI - Letters to the Editor. PMID- 28871653 TI - Stress experienced by mothers of Malaysian children with mental retardation. AB - OBJECTIVE: To compare parenting stress among Malaysian mothers of children with mental retardation and a control group, and to determine factors associated with stress. METHODOLOGY: Seventy-five mothers of children with mental retardation aged 4-12 years and 75 controls (those without disabilities who attended the walk in paediatric clinic) participated in the Parenting Stress Index (PSI). Intelligence quotient (IQ) and Child Behaviour Checklist (CBCL) scores, together with sociodemographic data, were entered into a multiple stepwise regression analysis, using the PSI as the criterion. RESULTS: Mothers of children with mental retardation scored significantly higher than control subjects in both the child-related domain (difference between means 26.1, 95% confidence interval 19.6 32.5) and parent-related domain (difference between means 15.0, 95% confidence interval 7.9-22.1) of the PSI. The total child behaviour scores from the CBCL (P < 0.01), IQ scores (P < 0.01) and sibship size (P < 0.01) were associated with child-related domain scores. For the parent-related domain, CBCL (P < 0.01) and IQ scores (P = 0.01) remained important factors but Chinese ethnicity (P < 0.01) and maternal unemployment (P < 0.01) were also significant predictors of stress. CONCLUSION: A large proportion of mothers of children with mental retardation experienced substantial parenting stress, especially Chinese and unemployed mothers, and this warrants appropriate intervention. PMID- 28871654 TI - Transverse cerebellar diameter on cranial ultrasound scan in preterm neonates in an Australian population. AB - OBJECTIVE: Fetal measurement of transverse cerebellar diameter (TCD) has been shown to correlate well with gestational age (GA), even in the presence of growth retardation. The aim of this study was to define the normal range of TCD in preterm neonates in an Australian population between 23 and 32 weeks GA. METHODOLOGY: Infants admitted to the Royal Women's Hospital, Melbourne, having routine cranial ultrasound scans (< 1500 g and/or of gestational age <= 32 weeks at birth) had their TCD measured on a cranial scan performed during the first 3 days of life. The posterior fossa was examined through the asterion using a General Electric LOGIQ 500 scanner (GE Medical Systems, Waukesha, USA) and TCD measurement was taken in the coronal plane. RESULTS: 106 infants < 1500 g and/or of GA <= 32 weeks at birth had their TCD measured between 1 January 1997 and 30 November 1997. Transverse cerebellar diameter and associated 95% confidence intervals are described for infants between 23 and 32 weeks GA. The linear regression equation relating TCD and GA was: TCD (mm) = -12.9 + 1.61 * GA (weeks). R2 = 0.80, P < 0.001. CONCLUSION: This is the only study of TCD measurement using cranial ultrasound in a group of preterm newborns, and forms the basis for nomograms of TCD which can be used as a tool to assist in the assessment of GA, even in growth-retarded preterm newborns, and in the diagnosis of cerebellar hypoplasia. PMID- 28871655 TI - Predictive mapping of the biotic condition of conterminous U.S. rivers and streams. AB - Understanding and mapping the spatial variation in stream biological condition could provide an important tool for conservation, assessment, and restoration of stream ecosystems. The USEPA's 2008-2009 National Rivers and Streams Assessment (NRSA) summarizes the percentage of stream lengths within the conterminous United States that are in good, fair, or poor biological condition based on a multimetric index of benthic invertebrate assemblages. However, condition is usually summarized at regional or national scales, and these assessments do not provide substantial insight into the spatial distribution of conditions at unsampled locations. We used random forests to model and predict the probable condition of several million kilometers of streams across the conterminous United States based on nearby and upstream landscape features, including human-related alterations to watersheds. To do so, we linked NRSA sample sites to the USEPA's StreamCat Dataset; a database of several hundred landscape metrics for all 1:100,000-scale streams and their associated watersheds within the conterminous United States. The StreamCat data provided geospatial indicators of nearby and upstream land use, land cover, climate, and other landscape features for modeling. Nationally, the model correctly predicted the biological condition class of 75% of NRSA sites. Although model evaluations suggested good discrimination among condition classes, we present maps as predicted probabilities of good condition, given upstream and nearby landscape settings. Inversely, the maps can be interpreted as the probability of a stream being in poor condition, given human-related watershed alterations. These predictions are available for download from the USEPA's StreamCat website. Finally, we illustrate how these predictions could be used to prioritize streams for conservation or restoration. PMID- 28871656 TI - Fabrication of a biomimetic ZeinPDA nanofibrous scaffold impregnated with BMP-2 peptide conjugated TiO2 nanoparticle for bone tissue engineering. AB - A biomimetic Zein polydopamine based nanofiber scaffold was fabricated to deliver bone morphogenic protein-2 (BMP-2) peptide conjugated titanium dioxide nanoparticles in a sustained manner for investigating its osteogenic differentiation potential. To prolong its retention time at the target site, BMP 2 peptide has been conjugated to titanium dioxide nanoparticles owing to its high surface to volume ratio. The effect of biochemical cues from BMP-2 peptide and nanotopographical stimulation of electrospun Zein polydopamine nanofiber were examined for its enhanced osteogenic expression of human fetal osteoblast cells. The sustained delivery of bioactive signals, improved cell adhesion, mineralization, and differentiation could be attributed to its highly interconnected nanofibrous matrix with unique material composition. Further, the expression of osteogenic markers revealed that the fabricated nanofibrous scaffold possess better cell-biomaterial interactions. These promising results demonstrate the potential of the composite nanofibrous scaffold as an effective biomaterial substrate for bone regeneration. PMID- 28871657 TI - Seasonality of mortality and graft failure among kidney transplant recipients in the US - a retrospective study. AB - Mortality in the general population and in patients on chronic hemodialysis is significantly higher in winter than summer. It is unknown whether such a seasonal difference exists for mortality or graft failure among kidney transplant recipients. We analyzed United Network for Organ Sharing (UNOS) data to assess whether the annual distribution of deaths and graft failures differed significantly from expected. There was significant annual variation in both deaths (n = 52 523) and graft failures (n = 50 301; both P < 0.001). The number of observed deaths exceeded the number expected by 8.9% in winter (P < 0.001), whereas the number of deaths was 4.8% lower than expected in summer (P < 0.01). The pattern was strongest for deaths attributable to cardiovascular disease (n = 11 509; 21.9%). Similarly, there was an excess of graft failures in winter (3.6%; P < 0.01) and a deficit in other seasons (all P <= 0.02). This pattern was observed for graft failures due to chronic rejection (P < 0.001) and other causes (P < 0.001), but not for acute rejection (P = 0.28) or recurrent disease (P = 0.27). Potential explanations for this variation include changes in physiologic parameters, changes in medication adherence and other behaviors, or changes in insurance coverage or clinical care. Further studies are necessary to identify specific mechanisms. PMID- 28871658 TI - Minimal factor XIII activity level to prevent major spontaneous bleeds: comment. PMID- 28871659 TI - Overexpression of HER-2 via immunohistochemistry in canine urinary bladder transitional cell carcinoma - A marker of malignancy and possible therapeutic target. AB - Transitional cell carcinoma (TCC) is the most commonly diagnosed neoplasm in the urinary bladder. Distant metastases to the regional lymph nodes, lungs, abdominal organs or bones are noted in up to 50% of dogs at time of death. Surgical excision is often not practical as TCC typically involve the trigone of the bladder and/or occurs multifocally throughout the bladder with field cancerization. Therapeutic approaches are very challenging and the requirement to evaluate alternative therapeutic protocols that may prolong survival times in dogs bearing these tumours is compelling. We assessed the immunohistochemical expression of HER-2 in 23 cases of canine TCCs of the urinary bladder and compare it with non-neoplastic urothelium in order to evaluate a rationale for targeted therapies and gene-based vaccines. HER-2 positivity was recorded in 13/23 (56%) neoplastic lesions. The receptor was significantly overexpressed in neoplastic than in non-neoplastic samples (P = .015). According to our preliminary results, it would be of interest to further evaluate the role of HER-2 in canine TCCs as a marker of malignancy and a therapeutic target for cancer vaccine and antibodies. Moreover, the significantly different overexpression of HER-2 in TCCs than in non neoplastic urothelium further supports to investigate its role in the progression toward malignancy of non-neoplastic lesions. PMID- 28871660 TI - Clinical, echocardiographic, and therapeutic aspects of congenital heart diseases of children at Douala General Hospital: A cross-sectional study in sub-Saharan Africa. AB - INTRODUCTION: Cardiovascular diseases in pediatric pathologies have emerged in the recent years in sub-Saharan Africa (SSA), with congenital heart diseases (CHDs) being the most frequent. Unfortunately, their diagnosis is usually delayed, thereby increasing childhood morbidity and mortality. OBJECTIVES: Describe the clinical, echocardiographic, and therapeutic aspects of CHDs of children at Douala General Hospital. METHODS: We carried out a cross-sectional descriptive study over a 10-year period, from January 2006 to December 2015. Files and reports of cardiac ultrasounds of patients aged <= 15 years were reviewed. RESULTS: We reviewed the medical records of 1616 children, of which 370 (22.9%) had CHD. The age range was 1 day to 15 years, with a mean of 26 months. Heart murmur was the most frequent clinical sign, seen in 72.3% of the cases. CHD with left-to-right shunt was seen in 61.8%, with ventricular septal defect being the most common (29.8% of all cases). The second most common CHDs were those due to obstruction (20.4%), mainly pulmonary stenosis (19.6% of all cases). Cyanogenic CHDs accounted for 17.8% of cases, dominated by tetralogy of Fallot (7.4% of all cases). Indications for surgical treatment was found in 171 (46.2%) patients, but due to financial constraints, only 48 (28.1%) patients were operated. Among those who underwent surgery, 66.7% were operated abroad, and Humanitarian organizations financed the surgical management of 58.3% of those operated. CONCLUSIONS: CHDs are seen in one out of five children seen in the pediatric cardiology unit of our Hospital for suspected heart disease. Most cases are diagnosed late in life as toddlers. The rate of surgical correction remains low due to financial constraints, with most cases operated abroad with the assistance of Humanitarian organizations. PMID- 28871662 TI - Tropical Medicine & International Health. PMID- 28871664 TI - Correction to "Rehospitalization in a National Population of Home Health Care Patients with Heart Failure". PMID- 28871661 TI - Update on Aire and thymic negative selection. AB - Twenty years ago, the autoimmune regulator (Aire) gene was associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and was cloned and sequenced. Its importance goes beyond its abstract link with human autoimmune disease. Aire identification opened new perspectives to better understand the molecular basis of central tolerance and self-non-self distinction, the main properties of the immune system. Since 1997, a growing number of immunologists and molecular geneticists have made important discoveries about the function of Aire, which is essentially a pleiotropic gene. Aire is one of the functional markers in medullary thymic epithelial cells (mTECs), controlling their differentiation and expression of peripheral tissue antigens (PTAs), mTEC thymocyte adhesion and the expression of microRNAs, among other functions. With Aire, the immunological tolerance became even more apparent from the molecular genetics point of view. Currently, mTECs represent the most unusual cells because they express almost the entire functional genome but still maintain their identity. Due to the enormous diversity of PTAs, this uncommon gene expression pattern was termed promiscuous gene expression, the interpretation of which is essentially immunological - i.e. it is related to self-representation in the thymus. Therefore, this knowledge is strongly linked to the negative selection of autoreactive thymocytes. In this update, we focus on the most relevant results of Aire as a transcriptional and post-transcriptional controller of PTAs in mTECs, its mechanism of action, and its influence on the negative selection of autoreactive thymocytes as the bases of the induction of central tolerance and prevention of autoimmune diseases. PMID- 28871663 TI - Kidney retransplantation from HLA-incompatible living donors: A single-center study of 3rd/4th transplants. AB - BACKGROUND: The demand for kidney retransplantation following graft failure is rising. Repeat transplantation is often associated with poorer outcomes due to both immunological and surgical challenges. The aim of this study was to compare surgical and functional outcomes of kidney retransplantation in recipients that had previously had at least two kidney transplants with a focus on those with antibody incompatibility. METHODS: We analyzed 66 patients who underwent renal transplantation at a single center between 2003 and 2011. Consecutive patients receiving their 3rd or 4th kidney were case-matched with an equal number of 1st and 2nd transplants. RESULTS: Twenty-two 3rd and 4th kidney transplants were matched with 22 first and 22 seconds transplants. Operative times and length of stay were equivalent between the subgroups. Surgical complication rates were similar in all groups (22.7% in 1st and 2nd transplants, and 27.2% in 3rd/4th transplants). There was no significant difference in patient or graft survival over 5 years. Graft function was similar between transplant groups at 1, 3, and 5 years. CONCLUSIONS: Third and fourth kidney transplants can be performed safely with similar outcomes to 1st and 2nd transplants. Kidney retransplantation from antibody-incompatible donors may be appropriate for highly sensitized patients. PMID- 28871665 TI - The Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation. AB - Evaluation methods, such as scoring systems for predicting complications in advance, are necessary for determining the adaptation of allogeneic hematopoietic cell transplantation (HCT) and selecting appropriate conditioning regimens. The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), which is based on functions of main organs, is a useful tool for pre-transplant risk assessments and has been widely applied in determining treatment strategies for patients with hematological diseases. However, as allogeneic HCT is performed on patients with diverse backgrounds, another factor, which reinforces the HCT-CI, is required to evaluate pre-transplant risk assessments. The Glasgow Prognostic Score (GPS), which assesses the combined C-reactive protein and albumin, was reported to predict survival of patients with solid-organ malignancies independently of receiving chemo/radiotherapy and stages of cancer. In this study, we applied the GPS for pre-transplant risk assessments for allogeneic HCT. The GPS successfully stratified the patients into three risk groups of overall survival (OS) and non-relapse mortality (NRM). Moreover, the GPS could predict outcomes independently of the HCT-CI for OS and NRM in multivariate analysis. The GPS is considered to be a useful tool and reinforces the HCT-CI for determining adaptation of allogeneic HCT for patients with hematopoietic neoplasms. PMID- 28871666 TI - Transperineal rectocele repair: a systematic review. AB - BACKGROUND: Transperineal rectocele repairs, either as isolated fascial repair or in combination with mesh augmentation, are hypothesized to reduce the risk of complications compared with alternative techniques. AIM: The aim of this study was to ascertain long-term success and complication rates following transperineal rectocele repairs. METHOD: A literature search of PubMed and Embase was performed using the terms 'transperineal rectocele', 'rectocele', 'transperineal' and 'repair'. Prospective studies, case series and retrospective case note analyses from 1 January 1994 to 1 December 2016 were included. Those that detailed outcomes of the transperineal approach or compared it to transanal/transvaginal approaches were included. The main outcome measures were reported complications and functional outcome scores. RESULTS: A total of 14 studies were included. Of 566 patients, 333 (58.8%) underwent a transperineal rectocele repair and 220 (41.2%) a transanal repair. Complications were identified in 27 (12.3%) of the 220 transanal repairs and in 41 (12.3%) of the 333 transperineal repairs. A significant complication following transperineal repair was noted in eight studies. There are not enough data to make a reliable comparison between mesh and non-mesh transperineal repairs or to compare biological and synthetic mesh use. LIMITATIONS: Outcome reporting differed between studies, precluding a full meta analysis. CONCLUSION: Transperineal rectocele repair offers an effective method of symptom improvement and appears to have a similar complication rate as transanal rectocele repair. Concomitant use of synthetic and biological mesh augmentation is becoming more common; however, high-quality comparative data are lacking, so a direct comparison between surgical approaches is not yet possible. PMID- 28871667 TI - Visualizing the Adenylation Activities and Protein-Protein Interactions of Aryl Acid Adenylating Enzymes. AB - Structural and activity studies have revealed the dynamic and transient actions of carrier protein (CP) activity in primary and secondary metabolic pathways. CP mediated interactions play a central role in nonribosomal peptide biosynthesis, as they serve as covalent tethers for amino acid and aryl acid substrates and enable the growth of peptide intermediates. Strategies are therefore required to study protein-protein interactions efficiently. Herein, we describe activity based probes used to demonstrate the protein-protein interactions between aryl CP (ArCP) and aryl acid adenylation (A) domains as well as the substrate specificities of the aryl acid A domains. If coupled with in-gel fluorescence imaging, this strategy allows visualization of the protein-protein interactions required to recognize and transfer the substrate to the partner ArCP. This technique has potential for the analysis of protein-protein interactions within these biosynthetic enzymes at the molecular level and for use in the combinatorial biosynthesis of new nonribosomal peptides. PMID- 28871671 TI - [Advances of species identification and quality control for Tibetan medicines]. AB - Species identification and quality control of Tibetan medicines are an important part of its modernization studies, and they have important significance for ensuring the safety and effectiveness of Tibetan medicines in clinical application. In order to provide a reference for the modernization research of Tibetan medicines, this paper summarized the research progress of species identification, quality standards and quality evaluation of Tibetan medicines in the past 10 years. It also introduces the application examples of some new technologies and methods, such as DNA barcoding, infrared spectroscopy and 1H NMR based metabolomics. PMID- 28871672 TI - [Research progress on resources and quality evaluation of Tibetan medicine in Qinghai-Tibet Plateau]. AB - With the development of Tibetan medicine industry, the demands for Tibetan medicine were rising sharply. In addition, with the eco-environment vulnerability of Qinghai-Tibet Plateau region and the phenomenon of synonymies and homonymies in Tibetan medicine, there were a lack of resources and varieties in the clinical application of Tibetan medicine. At present, the shortage of Tibetan medicine and the inadequacy of its quality standard have become the two major problems that seriously restricted the sustainable development of Tibetan medicine industry. Therefore, it is important to develop the resources investigation and quality evaluation for Tibetan medicine, which were contribute to its resources protection and sustainable utilization. In this paper, current status of resources investigation, quality standardization, artificial breeding and germplasm resources of Tibetan medicine were presented by the integrated application of the new technologies, such as DNA barcoding and 1H-NMR, which provided a reference information for resources protection, sustainable utilization, variety identification and quality standardization of Tibetan medicine resources in Qinghai-Tibet Plateau. PMID- 28871673 TI - [Identification of Tibetan medicine "Dida" of Gentianaceae using DNA barcoding]. AB - The ITS2 barcode was used toidentify Tibetan medicine "Dida", and tosecure its quality and safety in medication. A total of 13 species, 151 experimental samples for the study from the Tibetan Plateau, including Gentianaceae Swertia, Halenia, Gentianopsis, Comastoma, Lomatogonium ITS2 sequences were amplified, and purified PCR products were sequenced. Sequence assembly and consensus sequence generation were performed using the CodonCode Aligner V3.7.1. The Kimura 2-Parameter (K2P) distances were calculated using MEGA 6.0. The neighbor-joining (NJ) phylogenetic trees were constructed. There are 31 haplotypes among 231 bp after alignment of all ITS2 sequence haplotypes, and the average G+/-C content of 61.40%. The NJ tree strongly supported that every species clustered into their own clade and high identification success rate, except that Swertia bifolia and Swertia wolfangiana could not be distinguished from each other based on the sequence divergences. DNA barcoding could be used as a fast and accurate identification method to distinguish Tibetan medicine "Dida" to ensure its safe use. PMID- 28871674 TI - [Study on genetic-chemical relation of Pterocephali Herba based on DNA barcode and UFLC]. AB - DNA barcoding technique in combination with UFLC analysis technology was used to evaluate the quality of Tibetan medicine Pterocephalus hookeri from species identification and chemical qualitative and other aspects. Hybrid identification was established by DNA barcoding; UFLC-PDA was adopted to analyse fingerprint of different parts of Pterocephali Herba, and SPSS and Grey relation software were used for data analysis. The result showed that DNA barcoding is an accurate and reliable method in origin identification of Pterocephalus hookeri. The compounds in overground is more than underground by analysis of the different part fingerprint by UFLC. The genetic gene may be involved in the secondary metabolites of iridoid glycosides. Pertinence between gene and chemical component, as a new model established, could be suited for quality evaluation and resources protection. PMID- 28871675 TI - [Genetic and chemical discrimination of traditional Tibetan medicine seabuckthorn based on DNA barcode and 1H-NMR metabolic method]. AB - To differentiate three medicinal Hippopahe species of seabuckthorn, a combined genetic and chemical identification method was established in this study. ITS2 and psbA-trnH were tested for identification of 3 species of seabuckthorn. Detection of the kimura 2-parameter (K2P) distance, the neighbor-joining (NJ) tree and the barcoding gap were used to assess the identification efficiency. 1H NMR based metabolic method was applied to acquire the profile of metabolites. PCA was used to analysis the metabolite data. The results indicated that DNA barcode combined 1H-NMR based metabolic method is a powerful tool for the identification of 3 medicinal Hippopahe species of seabuckthorn. The finding demonstrated that different genetic variation and chemical constituents existed among 3 medicinal Hippopahe species of seabuckthorn. The combined identification method will improve the reliability of species discrimination and could be applicable to much other ethnic medicine which has various origins in China. PMID- 28871676 TI - [Study on HPLC fingerprint and quantitative analysis of 3 components of Tibetan medicine Gyantse Seabuckthorn]. AB - This study is to establish an HPLC fingerprint and quantitative analysis of 3 components of Gyantse Seabuckthorn from different producing areas.The separation was developed on Shimadzu InertSustain C18column (4.6 mm * 250 mm,5 MUm) by gradient elution with acetonitrile and 0.2% phosphoric acid water as mobile phase at a flow rate of 1.0 mL*min -1; the detection wavelength was set at 360 nm and column temperature was set at 30 C. The data calculation was performed with similarity evaluation system for chromatographic fingerprint of traditional Chinese medicine(Version 2004A).The fingerprints of 10 batches of Gyantse Seabuckthorn were carried out by similarity comparison, and 12 chromatographic peaks were extracted as the common peaks of fingerprint, of which three main active ingredients were successfully determined. This is the first established fingerprint and multi-component quantitative determination of Gyantse Seabuckthorn by using HPLC. This method has good precision stability and repeatability that could provide basis for quality control and evaluation of Gyantse Seabuckthorn. PMID- 28871677 TI - [Study on quality standard of Berberidis Cortex]. AB - In order to establish the quality standard of Berberidis Cortex and improve its quality control level, water, total ash, acid-insoluble ash and alcohol-soluble extract were determined according to procedures recorded in the Chinese Pharmacopoeia (2010 edition). The qualitative and quantitative analyses were performed by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) methods. The results showed that TLC identification had a good resolution with clear spots. The water content was 8.39%-12.23%; total ash was 4.50%-9.96%; acid-insoluble ash was 0.10%-0.69%, and the alcohol-soluble extraction was 20.62%-37.13%. The average contents of magnoflorine, jatrorrhizine, palmatine, and berberine in Berberidis Cortex were 5.98%, 0.63%, 0.30%, 2.50%, respectively. It was concluded that the developed method was accurate and good in specificity, which can be used for quality control of Berberidis Cortex in the future. PMID- 28871678 TI - [Studies on dosage-efficacy/toxicity relationship of anti-hypoxia effects and quality standard of Tibetan medicine Brassicea Radix extract]. AB - To evaluate the efficacy and safety associated with anti-hypoxia effect and establish the quality standard for Brassicea Radix extract, the investigations of acute toxicity and subacute toxicity were carried out to preliminarily appraise the toxicity, and the models of normal pressure hypoxia, acute cerebral ischemia and sodium nitrite poisoning in mice were used to evaluate the effect of enhancing anoxia endurance. Then according to the methods described in the Appendix of Chinese Pharmacopoeia (2010 edition), the sulfuric acid-phenol method was applied to determine the content of polysaccharide, and the water, ash and insoluble matter in water inspections were carried out and the control medicinal herb was identified with the samples by qualitative TLC. The results indicated that 1 the toxic effects (LD50) of mice was 56.73 g*kg-1 by oral administration of Brassicea Radix extract, while Dm and Dn were respective 86.80 g*kg*d-1 and 35.55 g*kg*d-1;2the determined effective dosage of Brassicea Radix extract which could enhance anoxia endurance was 0.388 g*kg-1*d-1; 3 the methods of TLC and the content of polysaccharide were established. The method of quality control has been recorded in Sichuan Province Standard for Tibetan Medicine, which is reliable, accurate and simple, with good reproducibility. Meanwhile, given the prominent effect on anti-hypoxia and good safety, it provided important basis for clinic safe and effective usage and the development of health products. PMID- 28871679 TI - [Effects of traditional Tibetan drug Liu Tea on proliferation and chemotherapeutic sensitivity of drug-resistant human gastric cancer cell BGC823/5 FU]. AB - To investigate the effects of Liu Tea extracts(LTE) on proliferation, apoptosis and drug sensitivity of drug-resistant gastric cancer cell BGC823/5-FU. MTT assay was used to analyze effect of LTE on cell growth and sensitivity chemotherapeutic drugs, and synergistic effect of the combination of LTE with 5-FU on BGC823/5-FU cells. Combination index (CI) was calculated by CompuSyn. Cell apoptosis was measured by flow cytometry (FCM). Protein expressions of P-gp, Bcl-2, Bax and Caspase-3 (17KD) were detected by Western blot at different concentrations of LTE in BGC823/5-FU cells (100, 200, 400 mg*L-1). The results showed that LTE had an inhibitory effect on growth of BGC823/5-FU cell in a dose-time-dependent manner and significantly reduced IC50 of 5-FU, CDDP, PTX and ADM to BGC823/5-FU cells(P<0.05), indicating it could reverse tolerance of drug resistant cells to chemotherapeutic drugs, with reversion multiples of 2.35, 1.68, 1.96, 0.52. The combination of LTE with 5-FU had positive synergistic effect on the BGC-823 cell line. FCM assay suggested that LTE could induce BGC823/5-FU apoptosis. The apoptosis rate was up to 46.2% when the cells were treated with 800 mg*L-1 LTE after 24 h(P<0.01). According to the protein detection results, with the increase in concentration of LTE, the protein expression of Bcl-2 was gradually decreased(P<0.01), the expression of Bax and Caspase-3 were extremely increased(P<0.01), with statistical significance in difference(P<0.01) but no difference in the expression of P-gp between experiment group and control group. LTE can inhibit the growth of drug-resistant human gastric cancer cell BGC823/5 FU and reverse its chemotherapeutic tolerance to some extent. Inhibition of antiapoptotic proteins, activation of proapoptotic proteins and induction of apoptosis of resistant cells may be its main mechanisms. PMID- 28871680 TI - [Research on origin, property and efficacy of Tibetan medicine "Dida"]. AB - Tibetan medicine "Dida" isoccasionally misused due to its complex origins, which ultimately affects its clinical efficacy. The accurate name, origin, property, and efficacy of "Dida"are highly important for its further research and development. In the present study, by viewing the classic Tibetan medicine and modern literature, and combining the clinical practice of Tibetan medicine, the origins, properties and the clinic effects of "Dida" were defined. "Dida" originated from multiple plant species of Swertia, Gentianopsis, Halenia, Lomatogonium, Comastoma(Gentianaceae), Hedyotis (Saxifragaceae) and Erysimum (Cruciferae). The medicinal properties of "Dida" is mainly bitter and cold. It has been commonly used to treat febrile diseases and hepatic and gall diseases. This study suggested that the relevant herbalogical study, species identification and pharmacological effects of "Dida" should be taken based on the Tibetan medicine theories and clinical practice. Thus the medicine can be better used and ensure its safety and quality simultaneously. PMID- 28871681 TI - [Research progress on biological activities of Olea europaea leaf extract]. AB - Olea europaea oil is one of the most important part of the "Mediterranean dietary pattern", and a lot of epidemiological evidences showed that people with the Mediterranean diet having a lower morbidity of the cardiovascular system diseases, skin cancer and colon cancer. The health benefits of a Mediterranean diet not only attributed to monounsaturated fatty acids and vitamins and other nutrients in O. europaea oil, but also the phenolic compounds named as antioxidant effect. Studies have shown that O. europaea leaf contains much more antioxidant activity composition than the fruit, and oleuropein, flavonoids such polyphenols are the main active ingredients in O. europaea leaf. A small amount of O. europaea was introduced into China in 1956, after widely cultivated in Fujian, Guangdong, Taiwan, Sichuan, Shaanxi, Yunnan, and Longnan in Gansu province is the biggest O. europaea planting area in the country. In every winter pruning O. europaea will produce a large number of the leaves, which could be a high added value products (phenolic compounds) of rich source. This article through consulting the literature at home and abroad, classified and summarized the biological activity research status of O. europaea leaf extract and the possible mechanisms, including antimicrobial, antitumor, antioxidation, and on the function of brain, cardiovascular system, anti-diabetes, anti-inflammatory and analgesia and so on. At the same time looked ahead to its development prospects of O. europaea leaf extract, it has variety and high content of active ingredients, and antioxidant synergy, which provide a theoretical basis for the further development and utilization of O. europaea leaf. And O. europaea leaf extract has a rich cheap source and good bioavailability, which provided a broad space in the application of medical and health care. PMID- 28871682 TI - [Pharmacological activity of Terminalia chebula]. AB - Terminalia chebula Retz, known as the "king" of Mongolian and Tibetan medicines, is a drug for a wide range of diseases. The main chemical components of myrobalan include triterpene acid, galloyl glucose, anthraquinonoid. The modern pharmacological studies show that myrobalan has multiple biological activities, including antimicrobial, anti-inflammatory, antioxidation as well as anti-tumor. Based on domestic and foreign literatures in recent years, this paper gave a review on the advance of studies for pharmacological activity of T. chebula. and its active components, so as to provide a reference for the in-depth studies on the pharmacological action of myrobalan, and the further development and utilization of myrobalan. PMID- 28871683 TI - [Optimum harvest time of Tulipa edulis based on comparison of biomass accumulation and medicinal quality evaluation]. AB - The optimum harvest time of Tulipa edulis was explored based on biomass accumulation and medicinal quality evaluation. Samples were taken from bud stage (Feb 13th) to dormancy stage (May 14th) and the growth indexes, organs biomasses, drying rate, contents of water-soluble extract and polysaccharides were determined. The results showed that biomass distribution of T. edulis varied with growth center and the bulb gained maximum biomass allocation in the whole growth period. The total biomass accumulation and bulb biomass accumulation increased in the whole growth period and peaked in fructescence stage. No differences were observed in bulb biomass among fructescence stage, withering stage and dormancy stage. The correlation between bulb biomass allocation and other morphological indexes varied with the harvest time. Bulb dry weight biomass had negative correlation with some morphological indexes of aerial part of T. edulis at bud stage, flower stage and fructescence and had significant positive (P<0.05) or extremely significant positive correlation(P<0.01)with other morphological indexes except for root at bearing fruits stage. The drying rate of bulb of T. edulis increased with the extension of harvest time and peaked in dormancy stage. The water-soluble extract of T. edulis bulb was the highest in pre-growing-stage. The tendency of polysaccharides contents showed a W-shape variation during the harvesting period. The polysaccharides content was the lowest in fructescence stage and was the highest in dormancy stage. Considering the yield and medicinal quality of T. edulis bulb, the optimum harvest time of T. edulis is in the withering stage or early stage of dormancy. PMID- 28871684 TI - [Identification and bactericidal activity of a novel Cathelicidin family member from skin of Bufu bufo gargarizans]. AB - The skin transcriptome of Bufu bufo gargarizans was determined by conventional methods. A novel full length cDNA coding for a Cathelicidin precursor was identified by transcriptomic data assembling, annotation and blast search of corresponding data banks. According to the known processing methods of Cathelicidin family members, present reported novel Cathelicidin precursor of B. bufo gargarizans might be cleaved at 2 possible sites of the same precursor and generate both BG-CATH25 and BG-CATH29 as mature molecules. The deduced BG-CATH25 and BG-CATH29 were synthesized with purity>95% to evaluate the properties and bactericidal activities. The secondary structural characteristics of both BG CATH25 and BG-CATH29 in different solutions were determined by Circular Dichroism (CD) Analysis. CD results indicated that random coil conformation were the main structural elements for both BG-CATH25 and BG-CATH29 in different buffer systems. Antimicrobial activities against tested bacterial strains were carried out by plating method. Both BG-CATH25 and BG-CATH29 showed strong antibacterial activities against Aeromonas hydrophila, with MIC values of 1.25, 10 mg*L-1, respectively. However, both of them showed weak bactericidal activities against human pathogenic bacteria, like Escherichia coli (ATCC25922),Staphylococcus aureus (ATCC25923)and Pseudomonas aeruginosa (ATCC 27853). PMID- 28871685 TI - [Cloning and tissue expression of mevalonate disphosphate decarboxylase genes from Andrographis paniculata]. AB - Andrographolide is a main bioactive substance in Andrographis paniculata, and extensively used in anti-inflammatory drugs. In order to increase andrographolide production in plant, three 1260 bp ORFs encoding mevalonate disphosphate decarboxylases with 419 amino acids were cloned from A. paniculata by RACE method and analyzed by bioinformatic software. Their tissue expression patterns were predicted by real time PCR. Eleven conserved amino acid residues determining specificity and activity of these MVDs were predicted in these amino acid sequences, but no plastid targeted signal peptides were detected. These MVDs have high similarities with the MVD protein (GenBank number: AEZ55675.1) from Salvia miltiorrhiza. In stems and leaves, expression levels of these MVD genes were constant, and reached the highest level at bud stage and the beginning of flowering. The MVD genes we have cloned from A. paniculata could be used in genetic engineering of andrographolide biosynthsis pathway in future. PMID- 28871686 TI - [Expression of key enzyme genes and content of saikosaponin in saikosaponin biosynthesis under drought stress in Bupleurum chinense]. AB - To research the expression of key enzymes in saikosaponin biosynthesis and the content of saikosaponin under the drought stress, the study focused on the gene level and the end product responses to environmental change. Taking the five months of Bupleurum chinense as research materials, the contents of saikosaponin A and saikosaponin D under different stress levels were measured by HPLC. The drought was simulated by poly ethylene glycol. The real-time fluorescence quantitative PCR was used to analyze the expression of four key enzymes genes HMGR, IPPI, FPS, beta-AS and the expression of beta-tubulin was set as a reference gene. The results showed that drought stress significantly improved the content of saikosaponin. The contents of SSa and SSd were highest researching 0.648% and 0.781%, respectively when the concentration of PEG was 10%. Meanwhile, the results reflected that the expression of four key enzymes had risen differently and FPS, beta-AS raised significantly(P<0.01). In addition, the results of correlation analysis showed that there was a significant positive correlation between the expression of the four key enzymes genes and the content of saikosaponin. In a word, the contents of secondary metabolites were regulated by the expression of key enzymes genes under the drought stress in B. chinense. PMID- 28871687 TI - [Screening target genes for bimolecular marking methods of Magnolia quality]. AB - The study used use bimolecular marking methods to evaluate the lignans of Magnolia officinalis and M. officinalis var. biloba. First, we compare the chemical constituents between M. officinalis and M. officinalis var.biloba. There were significant differences in concentration of magnolignan I between leaves of these two varieties. Then we further select the p-hydroxyphenyl lignin to mining the key enzyme genes of biosynthesis from Magnolia transcriptome, and screened an encoding cinnamyl alcohol dehydrogease gene as the candidate marker of bimolecular marking methods of Magnolia quality by comparing of the expression level and structure variation in homologous gene between M. officinalis and M. officinalis var.biloba. The established method provides the technical support for bimolecular marking methods of Magnolia quality evaluation. PMID- 28871688 TI - [Application of molecular biotechnology in Pharmacognosy]. AB - Using the methods of informetrics analysis, articles retrieved from the database of CNKI were statistically analyzed on development course and knowledge system, so as to reflect the overall situation of pharmacognostical studies by molecular biotechnology. The result shows that the research on pharmacognosy by molecular biotechnology is an inter-disciplinary research area, the major research fields can be divided into 7 categories, including molecular identification of Chinese medicinal materials, molecular systematics and genetic diversity analysis of Chinese medicinal materials, biosynthesis and bioregulation of secondary metabolites in medicinal plants, molecular mechanism and genetic basis of Dao-di Herbs, and tissue culture and molecular breeding in medicinal plants. The research on pharmacognosy by molecular have achieved remarkable progress in recent 20 years, and have broad development prospects. PMID- 28871689 TI - [Preparation and characterization of salvianolic acids-tanshinones composite powder for inhalation via co-micronized method]. AB - Salvianolic acids and tanshinones are main hydrophilic and lipophilic extracts from Salvia Miltiorrhiza with significant anti-pulmonary fibrosis effects. The aim of this study was to prepare a co-micronized salvianolic acids-tanshinones composite powder for inhalation using a planetary ball mill. The micronization process parameters were optimized by central composite design (CCD) and response surface methodology (RSM). Treatment time, rotation speed and the ball/sample weight ratio were selected as the independent variables, and the volume fraction of particle size in 1-5 MUm was taken as the dependent variable. The powder properties were evaluated by scanning electron microscopy (SEM), laser diffraction and X-ray powder diffraction (XRPD). The powder flow and hygroscopicity were determined with repose angle, compressibility index and critical relative humidity(CRH). According to the results, the salvianolic acids tanshinones composite powder produced in optimal conditions had a narrow and unimodal particle size distribution and a smaller D50 of 2.33 MUm. The volume fraction of particle size in 1-5 MUm was 80.82%. The repose angle was (50.60+/ 1.13) degrees , and the critical relative humidity is about 77%. After being micronized, the particle size significantly reduced, and the number of amorphous substances slightly increased, with no significant changes in powder flow and hygroscopicity. These findings indicate that the grinding method with a planetary ball mill can be used to co-micronize various components with different properties and prepare composite drug powders for dry powder inhalation. PMID- 28871690 TI - [Effects of baicalin, matrine, glycyrrhetinic acid and emodin in three kinds of emulsifier cream system on transdermal absorption in vitro]. AB - To study effects of APG, Span-Tween and A6/25 emulsifier cream system on transdermal absorption in vitro of baicalin, matrine, glycyrrhetinic acid and emodin in emulsifier. Permeations studies were carried out in vitro with excised mice skin by improved Franz diffusion cells. The cumulative penetration amounts and the retention amounts of Chinese herbal medicinal ingredients in three kinds of emulsifier cream systems were determined by HPLC. The effects of different Chinese herbal medicinal ingredients in the same emulsifier system and the same herbal medicinal ingredients in different emulsifier systems on cumulative permeation amount, skin retention amount and permeation rate were investigated. According to the results, the order of different Chinese herbal medicinal ingredients in same kinds of emulsifier system by the cumulative permeation amount and the permeation rate were matrine>baicalin>glycyrrhetinic acid>emodin. With respect to the effect of different emulsifier systems on cumulative permeation amount and permeation rate of the same herbal medicinal ingredients, glycyrrhetinic acid and emodin showed no significant difference, Span-Tween emulsifier cream system had higher cumulative permeation amount and permeation rate. The cumulative permeation amount and the permeation rate of Chinese herbal medicinal ingredients in the three kinds of emulsifier cream systems had an identical regularity. However, the cumulative permeation amount, the skin retension amount and the permeation rate of the same herbal medicinal ingredients in different emulsifier systems had no regularity. PMID- 28871691 TI - [Comparisons on chemical constituents of crude and wine-processed Dipsacus asper by using UPLC-Q-TOF/MS]. AB - To compare the quality control indexes and chemical constituents of crude and wine-processed Dipsacus asper. According to Chinese Pharmacopoeia 2015 edition, water content, total ash, acid-insoluble ash and water soluble extract of different processed products were detected. UPLC-Q-TOF/MS approach was established to compare the contents of major constituents in crude and wine processed D. asper. Moreover, the linearity, precision, stability, repeatability and recoveries of the approach were well studied. The results of water content, total ash, acid-insoluble ash and water-soluble extract of crude and wine processed D. asper were all in line with the requirements of the Chinese Pharmacopoeia 2015 edition. Meanwhile, 20 main chemical constituents were identified by using UPLC-Q-TOF/MS. After wine-processing, the contents of asperosaponin VI, acetylate analogues and caffeic acid were significantly increased, while the contents of other phenolic components such as dicaffeoylquinic acid were decreased significantly, which may be which may be the main reason for different clinical efficacy of crude and wine-processed D. asper. PMID- 28871692 TI - [Fast measurement method based on near infrared spectroscopy in extraction process of Tianshu capsules]. AB - Based on the near infrared spectroscopy, partial least square (PLS) method was used to respectively develop the quantitative calibration models to fast measure the contents of the total solid and ferulic acid in extraction process of Tianshu capsule extracts. The results showed that in the quantitative model of solid content, the correlation coefficients (R2) of calibration set and cross validation set were 0.967 301 and 0.947 726. The root-mean square error of calibration set (RMSEC) was 0.054 7 and root-mean square error of cross validation set (RMSECV) was 0.069 8. Besides, in the quantitative model of ferulic acid, the correlation coefficients (R2) of calibration set and cross validation set were 0.986 879 and 0.962 243. RMSEC was 1.402 6 and RMSECV was 2.400 2. When the established models were applied to on-line monitoring, the correlation coefficients of predicted results and measured values for total solid content and ferulic acid were 0.993 3 and 0.991 6; root-mean square error of predicted value (RMSEP) was 0.039 3 and 1.669 3 respectively; mean relative deviation of predicted value (RSEP) was 3.49% and 3.58%. The results indicated that the established models can be used to fast measure the contents of the total solid and ferulic acid in extraction process of Tianshu capsule extracts. PMID- 28871693 TI - [Optimization of ultrasonic extraction process for Xiaoqinglong granules by Box Behnken in condition of medium scale]. AB - This paper is to investigate the optimization conditions of ultrasonic technique for extraction process of Xiaoqinglong granules in medium scale. First of all, single factor experiment was used to determine the overall impact tendency and range of each factor; secondly, Box-Behnken method was used for optimization and detecting the content of paeoniflorin, ephedrine hydrochloride, glycyrrhizic acid of the liquid medicine. Their respective extraction rate was calculated and the comprehensive evaluation was carried out. The results were used as the evaluation basis for the efficacy of Xiaoqinglong granules ultrasonic extraction. The test results showed that the optimum extraction process of Xiaoqinglong granules by ultrasonic extraction was under the following conditions: ultrasonic power 600 W, liquid-solid ratio 10?1, extraction for 31 min. Under this condition, the predicted value of extraction rate for Xiaoqinglong granules was 85.90%, and the test value was 85.87%. The mathematical model(P<0.01) established in this paper was significant, and can be used for the analysis and prediction of the ultrasonic extraction process of Xiaoqinglong granules. PMID- 28871694 TI - [Chemical structure and bioactivity of cis-5'-oxopropylnicotine]. AB - In this paper, the chemical constituents and bioactivities of leaves of Nicotiana tabacum were investigated. Six compounds were isolated by means of various chromatographic techniques (silica gel, Sephadex LH-20, MCI GEL CHP-20P and HPLC), and their structures were elucidated as cis-5'-(2-oxopropyl)-nicotine (1), 3-O-(9, 12, 15-octadecatrienoyl)-glyceryl-beta-D-galactppyranoside (2), (l'R, 2R, 5S, 10R)-2-(1', 2'-dihydroxy-l'-methylethyl)-6, 10-dimethylspiro [4, 5] dec-6-en 8-one (3), (l'S, 2R, 5S, l0R)-2-(1', 2'-dihydroxy-l'-methylethyl)-6, 10 dimethylspiro [4, 5] dec-6-en-8-one (4),2, 3-dihydroxypropyl-beta-D-galactoside (5) and phenylethyl beta-D-glucopyranoside (6) by extensive spectroscopic analyses (UV, IR, MS, 1D- and 2D-NMR). Among them, compound 1 is a new alkaloid, and compounds 2-6 are isolated for the first time from N. tabacum. Compounds 1 and 2 were assayed for agitating activities on transient receptor potential vanilloid 1 (TRPV1), melatonin receptor 1 and 2 (MT1 and MT2), 1 showed agitating rate of 55.41% (1.53mmol*L-1) on MT2 and 2 possessed agitating rate of 128.11% (0.59 mmol*L-1) and 52.00% (0.73mmol*L-1) on TRPV1 and MT1, respectively. PMID- 28871695 TI - [Icaritin promotes chondrogenic differentiation of BMSCs by Wnt/beta-catenin signaling pathway]. AB - To investigate the effect of icaritin (ICT) combined with GDF-5 on chondrogenic differentiation of bone marrow stromal cells (BMSCs), and discuss the action of Wnt signaling pathway, full bone marrow adherent method was used to isolate and culture SD rats BMSCs, and the cells at P3 generation were taken and divided into 6 groups: BMSCs group, ICT group, GDF-5 group, GDF-5+ICT group, GDF 5+ICT+SB216763 group, and GDF-5+ICT+ XAV-939 group. The cells were induced and cultured for 14 days. The morphology change was observed by inverted microscope. Alcian blue staining method was used to detect the changes of proteoglycans. RT PCR was used to detect the mRNA expressions of aggrecan, Col2, Sox9, Dvl1, Gsk3beta, and beta-catenin. The protein expressions of collagen 2 (COL2) and beta catenin were detected by Western blot. The results indicated that, compared with the BMSCs group, gradual increase was present in proteoglycan Alcian blue staining; mRNA expressions of cartilage differentiation marker genes aggrecan, COL2, Sox9 and the protein expression of COL2, as well as mRNA and protein expressions of Wnt signaling pathway-related gene beta-catenin, but with gradual decrease in Gsk3beta mRNA expressions in GDF-5 group, GDF-5+ICT group and GDF 5+ICT+SB216763 group. On the contrary, compared with GDF-5+ICT group, there was a decrease in expressions of Dvl1, and beta-catenin related to chondrogenic differentiation and Wnt signaling pathway, a increase in Gsk3beta mRNA expression, and also a decrease in protein expressions of COL2 and beta-catenin in GDF-5+ICT+XAV-939 group, with statistically significant difference between two groups. GDF-5 in combination with icaritin can induce chondrogenic differentiation of BMSCs in rats, and icaritin (ICT) can promote the chondrogenic differentiation. ICT can promote the chondrogenic differentiation of BMSCs in vitro probably by activating the Wnt/beta-catenin signaling pathway. PMID- 28871696 TI - [Ginsenoside Rh2-induced inhibition of histone deacetylase 6 promotes K562 cells autophagy and apoptosis in vivo]. AB - To study the in vivo inhibition effect of ginsenoside Rh2 on humanleukemia cells, and explore its mechanism from autophagy and apoptosis aspects, human leukemia K562 cells allograft tumor models were applied, and after administration of ginsenosides Rh2 by gavage, the tumor diameter, volume and inhibitory rate were measured, and the anti-tumor activity of ginsenosides Rh2 was observed. The levels of HAT and HDAC in tumor tissues were detected by chemical colorimetry assay, and expressions of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5 and HDAC6 were detected by Western blotting assay. The expression levels of vital genes closely associated with autophagy and mRNA expressions of HDAC6 and Hsp90 were detected by Real time-PCR. HE staining was used to observe apoptosis, and immunohistochemistry was used to detect the protein expressions of HDAC6, Hsp90 and activated caspases 3. The results showed that ginsenoside Rh2 could inhibit the growth of k562 cells allograft tumor, with a tumor inhibition rate up to 53.10%. Ginsenoside Rh2 could significantly decrease HDAC activity and decrease the expressions of HDAC1, HDAC2 and HDAC6, and inhibit the expressions of HDAC6 and HSP90, increase the expressions of vital autophagy genes (beclin-1, LC3A and LC3B). Histopathological results showed that ginsenosides Rh2 could significantly increase the tumor apoptosis. Therefore, ginsenoside Rh2 had good anti-tumor effect in vivo, and the mechanism maybe associated with regulating autophagy and apoptosis through HDAC6 and Hsp90 pathways and inhibiting the in vivo proliferation of tumor cells. PMID- 28871697 TI - [Comparison of anti-inflammatory activity between crude Atractylodes lancea and their processed products by stir-baking with bran in rat models of gastric ulcer]. AB - To compare the anti-inflammatory activity of the crude Atractylodes lancea (AL) and AL processed products by stir-baking with bran in rat models of gastric ulcer, and preliminarily explore the anti-ulcer mechanisms of AL, the model of gastric ulcer was imitated by local acetic acid injection into gastric mucosa in rats by surgery according to the modified Okabe method. All rats were randomly divided into the following 10 groups: sham-operation group, model group, omeprazole group, Sanjiu Weitai granule group, crude AL low dose group, crude AL middle dose group, crude AL high dose group, processed AL low dose group, processed AL middle dose group, and processed AL high dose group. Rats were administered via intragastric (ig) two times each day, for 10 consecutive days. Blood was collected from the abdominal aorta, serum was separated, and the ulcer tissues were taken. The levels of inflammatory factors interleukin 6, 8 (IL-6, 8), tumor necrosis factor-alpha (TNF-alpha), and prostaglandin E2 (PGE2) in serum and gastric tissues were determined by enzyme-linked immunosorbent assay (ELISA), and the mRNA expressions of TNF-alpha and IL-8 in gastric tissues were detected by quantitative real-time reverse transcription polymerase chain reaction (RT PCR). The protein expressions of TNF-alpha and IL-8 in gastric tissues were detected by immunohistochemistry. Compared with sham-operation group, the levels of TNF-alpha, IL-8, IL-6, PGE2 as well as the mRNA expressions and protein expressions of TNF-alpha, IL-8 in gastric tissues were significantly higher in model group. The above levels were reduced in different degrees in all treatment groups. Compared with the crude AL, same dose of processed AL was more effective in decreasing the levels of TNF-alpha, IL-8, IL-6, PGE2 in serum and gastric tissues and down-regulating the mRNA expressions of TNF-alpha and IL-8 in gastric tissues, with significant difference in middle dose groups and high dose groups. The results showed that AL had potent anti-inflammatory effects in rat models of gastric ulcer induced by acetic acid, and the processed AL had more obvious effect. The anti-ulcer action of AL could be attributed partly to down-regulating the levels of TNF-alpha, IL-8, IL-6 and PGE2. PMID- 28871698 TI - [Effect of total flavones of hawthorn leafonon expression of COX-2/Nrf2 in liver of rats with nonalcoholic steatohepatitis]. AB - To explore the effect of total flavones from hawthorn leaf on (THFL) on the expression of COX-2/Nrf2 in the liver tissues of rats with nonalcoholic steatohepatitis (NASH), and discuss its anti-NASH mechanism, thirty-two SD rats were randomly divided into the normal group, model group, THFL high dose group and low dose group, 8 in each group. High fat diet was given to the rats for 12 weeks to establish the NASH models, and the high and low dose groups were administered with TFHL at the dosage of 250, 125 mg*kg-1*d-1 respectively. Steatosis and the inflammatory changes of the liver tissues in rats were observed by HE staining; T-AOC level was detected by colorimetry; the level of 8-OHdG and the protein expressions of COX-2, Nrf2 and HO-1 in the liver tissues were determined by immunohistochemistry; and the mRNA expressions of COX-2, Nrf2 and HO-1 in liver tissues were detected by Real time-PCR. Compared with the normal group, the liver steatosis, ballooning degeneration for inflammatory degree and NAFLD activity scores (NAS) were significantly increased in model group, while total antioxidant capacity (T-AOC) was decreased, DNA damage marker 8-OHdG level was increased, and the mRNA and protein expressions of COX-2, Nrf2 and HO-1 were significantly increased. After the administration of high and low dose of TFHL, the inflammation degree of the liver tissues and NAS were significantly decreased, 8-OHdG level and COX-2mRNA and protein expressions were decreased, and the mRNA and protein expressions of Nrf2 and HO-1 were significantly increased when compared with the model group. COX-2/Nrf2 pathway was involved in the development and progression of NASH induced by high fat diet. TFHL could prevent the development of NASH by promoting the expression Nrf2/HO-1, regulating and inhibiting the over expression of COX-2, and further attenuating the cell injury and hepatic inflammation caused by oxidation reaction. PMID- 28871699 TI - [Effect of different fractions of Taohong Siwu decoction on ADP-induced platelet aggregation and thrombin activity]. AB - To evaluate the effect of different fractions of Taohong Siwu decoction on ADP induced platelet aggregation and thrombin activity, and to exploit the bioactive constituents, ADP-induced platelet aggregation rate in rabbits was determined by using the method of turbidity method. A bioassay called thrombin time was developed for determining anti-thrombin activities. UHPLC-Q-TOF-MS method was used to qualitatively analyze the chemical constituents of different parts. Alcohol precipitation deposition fraction, alcohol precipitation supernatant fraction and 20% to 30% alcohol elution fraction could significantly inhibit ADP induced platelet aggregation. Alcohol precipitation supernatant fraction, water insoluble fraction and 40% to 70% alcohol elution fraction could significantly inhibit thrombin activity. The main components of alcohol precipitation deposition fraction, alcohol precipitation supernatant fraction and 20% to 40% alcohol elution fraction were analyzed and identified as aromatic acids, glycosides and phthalides. The bioactive constituents of Taohong Siwu decoction for inhibiting ADP-induced platelet aggregation and thrombin activity include aromatic acids, glycosides and phthalides. This experiment provides scientific basis to further explore the bioactive constituents and mechanism of Taohong Siwu decoction in treating blood stasis syndrome. PMID- 28871700 TI - [Protective effect and mechanism of compound Ginkgo biloba granules on oxidative stress injury of HUVEC]. AB - To reveal the protective and anti-apoptosis effect of compound Ginkgo biloba granules on oxidative stress injury of human umbilical vein endothelial cells (HUVEC). Negative control group, H2O2 model group and 4 drug pretreatment groups (80, 160, 320, 640 mg* L-1) were established. The cell proliferation, morphological changes in each group after oxidative stress injury was detected by MTT assay and through microscope observation respectively. The content of LDH, MDA, SOD and NO and SOD activity in supernatant were detected to judge the protection effect of the drugs on endothelial cells. The protective effect on HUVEC apoptosis was analyzed by Caspase-3 activity test and Annexin V-FITC/PI staining. Western blot was used to observe the expression of apoptosis-related proteins Bcl-2 and Bax. Results showed that 1 200 MUmol* L-1 H2O2 can induce oxidative stress injury in endothelial cells and reduce the cell survival rate; cell proliferation inhibition degree is positively correlated with the effect time of H2O2. Besides, 80, 160, 320 640 mg*L-1 compound Ginkgo biloba granules can protect HUVEC from oxidative stress injury, recover the normal proliferation level of cells, improve their state, prohibit cell apoptosis, and can up-regulate and down-regulate the expression level of Bcl-2 and Bax respectively. In conclusion, compound G. biloba granules can protect HUVEC from the oxidative stress injury induced by H2O2, its mechanism may be correlated with inhibition of the mitochondrial apoptotic pathway in HUVEC. PMID- 28871701 TI - [Effect of Yupingfeng granule on cytokines of allergic rhinitis induced by OVA in rats]. AB - To investigate the effects of Yupingfeng granule (YPF) on immune factors of the rats with allergic rhinitis (AR) induced by ovalbumin(OVA). OVA 0.3 mg, Al(OH)3 30 mg and saline 1 mL were mixed and intraperitoneally injected for the initial immunization, 4% OVA 200 MUg (50 MUL) was given to the nose on the 15th day for the second immunization to establish the allergic rhinitis model. Sixty male SD rats were randomly divided into allergic rhinitis(AR) model group, Yupingfeng granule three dose (2.7,1.35,0.68 g*kg-1) groups, control drug Biyankang (0.4 g*kg-1) and normal control group. After 14 days, efforts were made to collect blood from abdominal aorta, and take nasopharynx tissues and fasten them into 10% formaldehyde for a pathological examination. The levels of HIS, IgE, IL-4 and TNF alpha in serum were examined by radioimmunoassay, and nasal mucosa tissues were examined by HE staining. According to the results, the levels of HIS, IgE, IL-4 and TNF-alpha in serum of Yupingfeng granule groups were significantly lower than that of AR model group (P<0.05, P<0.01). Nasal mucosa tissues showed slight morphological changes and inflammatory cell infiltration, with unobvious necrosis. Yupingfeng granule can improve the pathological changes of nasal mucosa tissues, and reduce the production and release of immune factors during allergic rhinitis (AR) process in vivo by OVA, which may be the important curative mechanism of allergic rhinitis. PMID- 28871702 TI - [iTRAQ technology combined with 2D-LC-MS/MS to analyze effect of Coptidis Rhizoma on cytochrome P450 isoenzyme expression]. AB - Coptidis Rhizoma is commonly used in clinical medicine. It has been widely used in traditional Chinese medicine (TCM), with the functions of clearing heat, drying dampness, purging intense heat relieve toxins. However, the herb contains complex ingredients, and CYP450 isoenzyme is the main metabolic enzyme of the drug, so it is of important clinical significance to study the effect of Coptidis Rhizoma on cytochrome P450 enzymes. In the experiment, liver tissues of rats were selected and liver microsomes were separated by differential centrifugation. Bicinchoninic acid (BCA) Protein quantitation was done by enzyme linked immunosorbent assay, and iTRAQ (isobaric tags for relative and absolute quantification) was combined with the 2D-LC-MS/MS analysis method for identification of CYP450 proteins. With Coptidis Rhizoma, 30 CYP450 isoenzymes were identified, with 7 proteins significantly increased and 8 decreased in response to Coptidis Rhizoma, while the rest 15 had no change. iTRAQ technology combined with 2D-LC-MS/MS method could be used to comprehensively study CYP450 enzyme, but it is necessary to further evaluate in vitro levels of Coptidis Rhizoma and avoid any potential clinical drug-drug interaction. PMID- 28871703 TI - [Pharmacokinetics of Tongmai granule in acute myocardialischemic model beagles]. AB - Tongmai granule (TM) is composed of Puerariae Lobatae Radix (Gegen), Salviae Miltiorrhizae Radix et Rhizoma(Danshen) and Chuanxiong Rhizoma(Chuanxiong). It has been used to treat ischemic cardio-cerebrovascular diseases for decades. For the purpose of elucidating its pharmacodynamic material foundation, the absorption and pharmacokinetic property of TM were investigated in acute myocardial ischemic model beagles. All serum samples were extracted before analysis with ethyl acetate after being acidified by hydrochloric acid. Under negative ESI detection mode, the chromatographic separation was carried out with monolithic C18 column for gradient elution. A simultaneous quantitative analysis was made on 15 polyphenols, including 8 from Gegen, 5 from Danshen and 2 from Chuanxiong, in 8.5 min. The validation result demonstrated the specificity, accuracy and precision of the method in line with the bioanalysis requirements. After TM solution was administrated to acute myocardial ischemic model beagles through duodenum injection, serum samples were collected after 6 h. The quantitative detection proved the prompt absorption of TM, all of the components were detectable in the blood samples 5 min later, and reached peak respectively at 0.18-3.83 h after administration. The components presented large variabilities. The most components were exposed in serum with puerarin and salvianic acid A, followed by 3'-methoxypuerarin, mirificin, and 3' hydroxypuerarin. The study proves puerarin and salvianic acid A are dominating active components of TM in acute myocardial ischemic model beagles. PMID- 28871704 TI - [Analysis of clinical use of post-marketing hospital centralized monitoring of Xiyanping injection]. AB - To assess the clinical use and occurrence of adverse reactions of Xiyanping injection, and to provide reference for rational drug use in the clinic. Based on hospital central monitoring method, the clinical data of Xiyanping injection in our hospital in 2014 was tracked and analyzed. A total of 848 inpatients were enrolled in this study. Among them, 39.9% were not in accordance with the medication purpose. In practice, the dose more than the limits prescribed by the instructions of child and adult were accounted for 1.72% and 6.62%, respectively; improper choice of solvent, accounting for 3.18%; both the choice of versus intravenous drip and aerosol inhalati administration route were reasonable; mixed with other drug, accounting for 2.24%. The incidence of ADR of Xiyanping injection was 0.12%, which showed good safety. Irrational use of Xiyanping injection existed in clinics, and the use should be strengthened and regulated. The manufacturer should improve the drug instruction of usage and dosage. PMID- 28871705 TI - [Rationality analysis of clinical application of Danhong injection in affiliated hospital of Nanjing university of Chinese medicine from 2013 to 2014]. AB - It is necessary to investigate the influence of the rationality of clinical drug use on the benefit and risk factors of traditional Chinese medicine injections. The retrospective survey was based on the medical records and information of 4 950 patients who used Danhong injection in the HIS database of the first affiliated hospital of Nanjing University of Chinese Medicine from 2013 to 2014. The basic statistical methods and associated rules analysis were utilized to analyze the HIS information of these patients, including the basic information, the diagnosis, the department, the dosage, the usage of medication, the drug combination and the adverse reactions. And the rationality analysis of the clinical application of Danhong injection was carried out to investigate relevant factors of the adverse reactions. The results showed that most cases came from the department of cardiology (51.95%) and encephalopathy center (20.67%). In the statistical period, the patients aged above 40 years old accounted for 96.65%. And the two western medicine diagnosis items with the highest confidence level were coronary heart disease and angina pectoris (97.15%), while the three items were coronary heart disease, angina pectoris and hypertension (97.02%). The irrational indications were mainly hypertension (12.93%) and diabetes (4.55%). All of them were diagnosed as blood stasis syndrome by the traditional Chinese medicine. About 98.93% of the single dosage was within the range stipulated on package insert, the duration mainly ranged between 1 and 21 days, and 97.64% of the menstrua contained 0.9% NS and 5% GS. According to the medication records,99.26% were the use of combined drugs, with 8.41 drugs on average. Antiplatelet drugs (72.04%) were the most frequently combined with western medicine, followed by the cholesterol-regulating drugs (64.86%) and the cerebrovascular drugs (60.26%). When used in the combination with antibiotics for the infection, cephalosporin antibiotics were the most frequently applied (8.81%). When used with traditional Chinese medicines, traditional Chinese medicines for activating blood circulation and removing blood stasis or monomer traditional Chinese medicine injections (28.93%) were the dominance, in which Gastrodin injection was the most frequently applied (16.23%). And 12 cases of adverse reactions were reported, with the ADR rate of 0.24%. The indications, solvent compatibility and irrational drug combination may be the potential risk factors for ADRs induced by Danhong injection. Further experiments are required to evaluate the benefits and risks in these three aspects. PMID- 28871706 TI - [Common household traditional Chinese medicines]. AB - With the enhancement in the awareness of self-diagnosis among residents, it's very common for each family to prepare common medicines for unexpected needs. Meanwhile, with the popularization of the traditional Chinese medicine knowledge, the proportion of common traditional Chinese medicines prepared at residents' families is increasingly higher than western medicines year by year. To make it clear, both pre-research and closed questionnaire research were adopted for residents in Chaoyang District, Beijing, excluding residents with a medical background. Based on the results of data, a analysis was made to define the role and influence on the quality of life of residents and give suggestions for relevant departments to improve the traditional Chinese medicine popularization and promote the traditional Chinese medicine market. PMID- 28871707 TI - Search for relevant indications for selenium supplementation in thyroid diseases. AB - Selenium plays a significant role in the thyroid function and its deficiency is considered by some authors to be a cause of thyroid disorders. The potential therapeutic influence of selenium supplementation in thyroid disease was investigated in several studies and some results were encouraging, however results were inconsistent and did not allow conclusion to be drawn. For that reason, we have performed a review study on relevance of selenium supplementation in thyroid disease. Till now, there is no strong evidence that selenium supplementation leads to clinical improvement in the course of autoimmune thyroiditis, nodular goitre or thyroid cancer. On the other hand, there is some evidence that selenium is effective in the treatment of orbitopathy; thus, the European Group on Graves' Orbitopathy (EUGOGO) recommends selenium administration in mild active orbitopathy. PMID- 28871708 TI - Pituitary hyperplasia mimicking macroadenoma associated with primary hypothyroidism in a patient with selective L-thyroxine malabsorption. AB - We present the case of a 29-year-old woman who developed a severe hypothyroidism induced by a thyroxine malabsorption and a secondary pituitary hyperplasia. We performed thyroxine absorption tests to diagnose the malabsorption and to evaluate the best therapeutic intervention. Once assessed a correct therapy lowering TSH, we observed the regression of pituitary mass confirming our diagnosis of secondary pituitary hyperplasia. We suggest to evaluate any possible reason for thyroxine malabsorption and to consider the hypothesis of pituitary hyperplasia in the presence of pituitary mass together with overt hypothyroidism. PMID- 28871710 TI - Importance of education in the prevention of diabetic foot syndrome. AB - To the Editor, Diabetic foot syndrome (DFS) is defined by the WHO as ulceration or destruction of foot tissue in diabetic patients associated with neuropathy, with different degrees of the disease existing and frequently also with infection. The statistics are frightening: more than million amputations are annually carried out worldwide due to diabetic foot (Foster and Lauver 2014) and these amputations represent as far as 70% of all non-traumatic amputations. In 2013, 861 647 patients were treated for diabetes mellitus in Czech Republic, including 44 657 patients with diabetic foot syndrome and 11 168 patients had to experience the amputation of lower limb due to this condition. Up to 80% of ulcerations results from external trauma, most frequently due to poor footwear (Zvolsky 2013). Diabetic foot syndrome possesses serious medical, social and economic consequences with the length of the therapy and high risk of the amputation. Patients with diabetic foot syndrome become marginalised and vulnerable after amputations, mainly due to the dependence on family and society, whether on the level of self-care or economic. PMID- 28871709 TI - Unusual presentations of Carney Complex in patient with a novel PRKAR1A mutation. AB - Carney Complex (CNC) is a multiple neoplasia syndrome characterized by skin tumors and pigmented lesions, myxomas, and various endocrine tumors. The aim of this case report was to describe a case of CNC with a novel PRKAR1A mutation. A man aged 46 years with a medical history of surgery for cardiac myxomas at the age of 39 was admitted to our hospital because of four newly-developed heart masses. The histologic examination confirmed cardiac myxomas. He had many presentations of CNC such as growth hormone (GH) and prolactin (PRL)-secreting mixed pituitary adenoma, benign thyroid nodule, large-cell calcifying Sertoli cell tumor (LCCST), and superficial angiomyxoma. A bilateral adrenalectomy was performed because the laboratory findings suggested primary pigmented nodular adrenocortical disease (PPNAD). The pathologic examination revealed a focal unilateral PPNAD, unilateral nonpigmented adrenocortical nodule, and bilateral adrenal medullary hyperplasia. Two years after the second cardiac operation, an interatrial septum-derived tumor was detected. An atrial myxoma was confirmed with histologic studies. Based on these findings, the patient was confirmed to have CNC. A novel insertion mutation in the type 1A regulatory subunit of the cAMP-dependent protein kinase A gene (PRKAR1A) in exon 2 was detected in our patient through genetic analysis. The presence of multiple myxomas and endocrine abnormalities should be an indication to physicians to further investigate for CNC. Herein, we described a case of CNC with a novel mutation in exon 2 of the PRKAR1A gene with typical and atypical clinical features. PMID- 28871712 TI - Some quantitative EEG features in default mode resting state network under general anaesthesia. AB - OBJECTIVES: The default mode resting state network (DMRSN) constitutes a circuit which is active in conditions when the subject is at rest. We tested the hypothesis that its function will be altered during unconsciousness. METHODS: Changes in the mean squared coherences in five conventional frequency bands (delta to gamma) in DMRSN during general anaesthesia (GA) were investigated in 39 patients. They were compared with the normal EEG of 86 alert subjects, severely abnormal EEG of 112 patients with dementia and/or encephalopathy, and the mathematical model of brain death. RESULTS: Anaesthetised patients showed significant decrease in the gamma coherence in the posterior area of the DMRSN compared to both the control group and the patients with dementia and/or encephalopathy. Among the anaesthetized patients 21 had a clear burst suppression pattern with prolonged epochs of suppression in EEG. In suppressed EEG segment the differences between the connections of the anterior to posterior parts and connections between the posterior parts of the DMRSN were almost lost. However, they still showed highly significant differences in most items when compared with coherences in the mathematical model of brain death. CONCLUSION: The functional connectivity in the DMRSN could be a reliable and robust method for assessing the depth of anaesthesia and maybe also disorders of consciousness in general. The mean squared coherences in the gamma frequency band indicated the highest sensitivity for the depth of unconsciousness. The measure is not dependent on the diffused slowing in dementia or encephalopathy patients as long as they remain in a full consciousness. PMID- 28871711 TI - Analysis of the rs13306560 functional variant in the promoter region of the MTHFR gene in sporadic Parkinson's disease. AB - OBJECTIVE: Among susceptibility genes for Sporadic Parkinson's Disease (SPD), the MTHFR gene has been suggested as candidate. The A allele of the functional variant rs13306560 in its promoter region has been liked to decreased transactivation capacity. Therefore, we sought to determine a possible association of the rs13306560 and SPD. METHODS: In total, 237 individuals were genotyped, 113 patients with SPD diagnosed according to the Queen Square Brain Bank criteria and 124 neurologically healthy controls. Genotyping was performed using TaqMan probes for the rs13306560 and real-time PCR. RESULTS: The A allelle was associated to protection in SPD, under the dominant model, (OR=0.22, C.I.=[0.048-1.080], p=0.04), nevertheless, after logistic regression analysis with adjustment for gender, resulted only in a trend (Exp (beta)=0.211, [I.C. 95.0%, 0.042-1.057], p=0.058). CONCLUSION: Although further studies are needed, our data suggest an important role of the MTHFR gene variants in the fine-tuning regulation of one-carbon metabolism in the brain. PMID- 28871713 TI - Cognitive functions and serum cortisol concentration in perimenopausal and postmenopausal women working non-manually. AB - OBJECTIVES: To asses a possible relationship between serum cortisol concentration and cognitive function in peri- and postmenopausal women engaging in non-manual work. METHODS: The Montreal Cognitive Assessment (MoCA) was used to screen women for the study and the Computerized Neurocognitive-assessment Software (CNS) Vital Signs to diagnose cognitive functions. RESULTS: Cognitive functions and serum cortisol concentration did not differ between women in early and late perimenopause and postmenopause. The women in the study obtained lower reaction time compared to other cognitive functions studied. Cognitive functions correlated negatively with age and educational level, but not BMI. Serum cortisol concentration correlated negatively to NCI, motor speed, psychomotor speed and reaction time in postmenopausal women, but positively to complex memory in early perimenopausal women and to processing speed in early and late perimenopasal women. CONCLUSION: Higher serum cortisol concentration may negatively effect cognitive functions in women post menopause. PMID- 28871714 TI - Borderline personality disorder and unmet needs. AB - BACKGROUND: Borderline personality disorder (BPD) is a disabling psychiatric condition with a chronic and challenging course. BPD is reflected as a disorder of self-regulation" and is associated with both psychological vulnerabilities and social relations that fail to support basic emotional needs. The objective of the paper is to provide the up-to-date data on the unmet needs of BPD patients and their families. METHOD: A computerized search of the literature printed between January 1990 and May 2017 was conducted in PubMed, and additional papers were extracted using keywords "borderline personality disorder,"needs," "pharmacotherapy," "psychotherapy," "CBT," and "family" in various combinations. According to the eligibility criteria, 57 articles were chosen. Secondary articles from the reference lists of primarily identified papers have been selected for the eligibility and added to the first list (N=151). RESULTS: The results were divided into three categories: the needs connected with (1) the symptom control; (2) the treatment; (3) the quality of life. The needs connected with symptoms were described issues such as emotional needs, social interactions, self-harm, parasuicide, suicidality, comorbidity, mentalization, identity disturbance, moreover, barriers to treatment. The needs connected with the treatment described are focused on needs for early diagnosis, early intervention, holding environment, therapeutic relation, assertive community treatment, destigmatization, hospitalization, and primary care. The needs connected with the quality of life involve family needs, physical health, spiritual needs, advocacy needs, and needs for the separation-individuation. The part focused on implications for the treatment presented several treatment approaches, focusing mostly on the their basics and efficacy. CONCLUSION: Observing the patients' needs may be essential to the treatment of the individuals suffering from BPD. However, many needs remain unmet in the areas linked to medical, personal, and social factors. A bigger focus on the patients' needs could be beneficial and should be targeted in the treatment. PMID- 28871715 TI - Personality as significant predictor of post-stroke anxiety. AB - OBJECTIVES: Anxiety in stroke patients is very frequent. It negatively influences the whole recovery process. The study objective is to study personality traits, age, gender, and type of stroke as predictors of anxiety in stroke patients. METHODS: Research presents a prospective cross-sectional descriptive study. The sample consisted of 74 hospitalized stroke patients. The data collection methods were the HADS for anxiety measurement and the Mini IPIP for evaluation of five personality factors. Hierarchical multiple regression analysis was used to study the relationship between anxiety and personality variables, gender, age, and type of stroke. RESULTS: We found three statistically significant predictors of anxiety in stroke patients. Neuroticism and low Agreeableness explain 50% of the variability of anxiety. Another statistically significant predictor was age; higher-level anxiety relates to lower age. Other personality traits (Extraversion, Openness to experience, and Conscientiousness), gender, and type of stroke do not appear as significant predictors of post-stroke anxiety. CONCLUSION: Anxiety in stroke patients is predicted mostly by the personality traits and young age of patients. Knowing these predictors can result in early detection and management of emotional consequences of disease, and thus influence the whole recovery process. PMID- 28871716 TI - The influence of Eruca sativa (Arugula) on pharmacokinetics of Sildenafil in rats. AB - OBJECTIVES: A drug like Sildenafil is commonly used for the treatment of erectile dysfunction. Eruca sativa is known as a garden plant used in folk medicine to enhance the sexual desire in males. Nevertheless, the interaction of Sildenafil and Eruca sativa was not studied. In the current study, we aimed to examine the influence of Eruca sativa on Sildenafil pharmacokinetics in rats. STUDY DESIGN: A crossover experiment with washout period of two weeks was conducted. To one group of animals, Eruca sativa was given as food and a drinking solution to rats for 12 hours before the day of the experiment. On the day of the experiment, the same group received 5 ml (50 mg/ml) orally and a half an hour later animals received 1 ml Sildenafil citrate (2.85 mg/kg) oral administrated to the study group. The other group of rats only received Sildenafil. Two-weeks later a cross-over design on the same animals was conducted. Blood samples were collected from optical vein on different time intervals, samples were analyzed using validated (HPLC-UV) method. RESULTS AND CONCLUSION: Pre-administration of Eruca sativa has increased Sildenafil Cmax from 226.72 to 345.25 ng/ml, (p<0.05). In addition, the AUC of Sildenafil has significantly increased when it was pre-administered with Eruca sativa (550.59 vs. 916.48 ng/ml*hr). Our findings suggest that co-administration of Eruca sativa with Sildenafil enhances the pharmacokinetics of Sildenafil in rats plasma. PMID- 28871718 TI - Clostridium difficile infection a current therapeutic and epidemiological problem AB - Clostridium difficile (CD) is the most common etiologic agent of antibiotic associated diarrhea. The number of infections has increased dramatically in the last decade. Although the diseases caused by CD are mostly related to health care and antibiotic therapy, some are community-acquired cases. This article explains the pathogenesis of this microorganism, pointing to depletion of intestinal microflora diversity and the inadequate response of the immune system as an important factor predisposing the development of CD infection. Previous published studies have demonstrated an increased incidence of hipervirulent ribotype 027 in Poland and Europe and also the emergence of other ribotypes in various parts of Europe with increased potential for pathogenicity. A high percentage of CD strains, which were isolated in Poland demonstrated resistance to ciprofloxacin, imipenem, erythromycin and moxifloxacin and multidrug resistance. In addition, there was observed a trend to increase in the value of MIC for vancomycin and metronidazole. Factors that may affect the reduction of effectiveness in drug therapy include the sublethal doses achieved in the intestinal lumen, heterogenicity of resistance to metronidazole, the ability to form the biofilms, presence of protein, which repair damaged DNA, transformation of an antibiotic to inactive form and mutations leading to changes to the binding sites of vancomycin. PMID- 28871717 TI - Acromegaly determination using discriminant analysis of the three-dimensional facial classification in Taiwanese. AB - OBJECTIVES: The aim of this study was to assess the size, angles and positional characteristics of facial anthropometry between "acromegalic" patients and control subjects. We also identify possible facial soft tissue measurements for generating discriminant functions toward acromegaly determination in males and females for acromegaly early self-awareness. MATERIAL AND METHODS: This is a cross-sectional study. Subjects participating in this study included 70 patients diagnosed with acromegaly (35 females and 35 males) and 140 gender-matched control individuals. Three-dimensional facial images were collected via a camera system. Thirteen landmarks were selected. Eleven measurements from the three categories were selected and applied, including five frontal widths, three lateral depths and three lateral angular measurements. Descriptive analyses were conducted using means and standard deviations for each measurement. Univariate and multivariate discriminant function analyses were applied in order to calculate the accuracy of acromegaly detection. RESULTS: Patients with acromegaly exhibit soft-tissue facial enlargement and hypertrophy. Frontal widths as well as lateral depth and angle of facial changes were evident. The average accuracies of all functions for female patient detection ranged from 80.0-91.40%. The average accuracies of all functions for male patient detection were from 81.0-94.30%. The greatest anomaly observed was evidenced in the lateral angles, with greater enlargement of "nasofrontal" angles for females and greater "mentolabial" angles for males. Additionally, shapes of the lateral angles showed changes. The majority of the facial measurements proved dynamic for acromegaly patients; however, it is problematic to detect the disease with progressive body anthropometric changes. CONCLUSION: The discriminant functions of detection developed in this study could help patients, their families, medical practitioners and others to identify and track progressive facial change patterns before the possible patients go to the hospital, especially the lateral "angles" which can be calculated by relative point-to-point changes derived from 2D lateral imagery without the 3D anthropometric measurements. This study tries to provide a novel and easy method to detect acromegaly when the patients start to have awareness of abnormal appearance because of facial measurement changes, and it also suggests that undiagnosed patients be urged to go to the hospital as soon as possible for acromegaly early diagnosis. PMID- 28871719 TI - A steady course in health policy. PMID- 28871720 TI - ? PMID- 28871721 TI - [An inconvenient truth]. PMID- 28871722 TI - [Eternal life as a medical goal]. PMID- 28871723 TI - [Expectations on our next minister of health]. PMID- 28871724 TI - [Norway's health is global health, but do we include everyone?]. PMID- 28871725 TI - [Do not use the health care finances for political gain!]. PMID- 28871726 TI - [A 50-year-old man with proximal pareses and heart disease]. PMID- 28871727 TI - [From social state to minimal state]. PMID- 28871728 TI - [The expert rule]. PMID- 28871729 TI - ? PMID- 28871730 TI - ? PMID- 28871731 TI - ? PMID- 28871732 TI - ? PMID- 28871733 TI - [E-health and ill health]. PMID- 28871734 TI - [Hysterectomy at St. Olavs Hospital 1989-2014]. PMID- 28871735 TI - ? PMID- 28871736 TI - [Worthless health policy]. PMID- 28871737 TI - Decentralised health services. PMID- 28871738 TI - New guidelines for the prevention of cardiovascular disease. PMID- 28871739 TI - [Prescription for a better health service?]. PMID- 28871740 TI - [The family physicians - useful idiots?]. PMID- 28871741 TI - [The family physician system needs to hurry]. PMID- 28871742 TI - [Clinical practice for the future of health care]. PMID- 28871743 TI - [Give us politics back in health policy!]. PMID- 28871744 TI - ? PMID- 28871745 TI - [Four things the election campaign could have been about]. PMID- 28871746 TI - ? PMID- 28871747 TI - ? PMID- 28871748 TI - ? PMID- 28871749 TI - ? PMID- 28871750 TI - [Cancer patient in his 50's with troublesome palpitations]. PMID- 28871751 TI - [Racing thoughts - a psychiatric term without meaning?]. PMID- 28871752 TI - ? PMID- 28871753 TI - ? PMID- 28871755 TI - ? PMID- 28871754 TI - ? PMID- 28871756 TI - ? PMID- 28871757 TI - ? PMID- 28871759 TI - ? PMID- 28871758 TI - ? PMID- 28871760 TI - [Self-reported sources for distribution of cigarettes, snus and e-cigarettes]. PMID- 28871761 TI - General practice consultations and use of prescription drugs after changes to school absence policy. AB - BACKGROUND: New rules for absence with stricter requirements for documentation were introduced in upper secondary schools in the autumn of 2016. We investigated the use of general practice services and dispensing of prescription drugs among 16 - 18-year-olds in the autumn of 2016 and compared this with equivalent figures for the period 2013 - 15. MATERIAL AND METHOD: We retrieved information on consultations in general practice (GP) and dispensing of prescription drugs to 15 - 18-year-olds in the period 2013 - 16 from the Directorate of Health's system for control and payment of health reimbursements (KUHR) and the Norwegian Prescription Database respectively. The number of consultations and dispensing of drugs were compared to previous years using Poisson regression (reference year 2015). The incidence rate ratio (IRR) was used as an outcome measure. RESULTS: The number of GP consultations for 16 - 18-year-olds was 30 % higher in the autumn of 2016 than in the autumn of 2015 (IRR 1.30, 95 % confidence interval (CI) 1.29 - 1.31). In the same period, the dispensing of drugs to this age group increased by 8 % (IRR 1.08, 95 % CI 1.08 - 1.09). Among the diagnosis groups, respiratory tract infections had the largest increase (IRR 2.21, 95 % CI 2.17 - 2.25). The largest increase in drug dispensing was found for remedies for coughs and colds (IRR 1.73, 95 % CI 1.65 - 1.80). INTERPRETATION: The increase in consultations in general practice and dispensing of drugs to 16 - 18-year-olds coincided in time with the introduction of new rules for absence from school. We hold it to be highly likely that the changes were caused by the stricter rules for documentation of absence from school. PMID- 28871762 TI - [Not Available]. PMID- 28871764 TI - Useful textbook on diabetes. PMID- 28871765 TI - ? PMID- 28871763 TI - Dietary therapy for epilepsy. AB - Children with pharmacoresistant epilepsy should be offered ketogenic dietary therapy. The diet, which is rich in fat and low in carbohydrate, has a beneficial effect in reducing seizures in this patient group. It may also have a beneficial effect in adults, but there is less evidence than in children. Dietary treatment of epilepsy is a specialist therapy, and in order to adhere to the diet, strong motivation of the patient and relatives as well as close follow-up from the specialist health service are necessary. PMID- 28871766 TI - ? PMID- 28871768 TI - ? PMID- 28871767 TI - ? PMID- 28871769 TI - ? PMID- 28871770 TI - ? PMID- 28871771 TI - ? PMID- 28871772 TI - ? PMID- 28871773 TI - Internal abdominal hernia. PMID- 28871774 TI - [When should you choose a non-parametric method?]. PMID- 28871776 TI - Atmospheric Pressure Plasma Jet Treatment of Poly-epsilon-caprolactone Polymer Solutions To Improve Electrospinning. AB - An atmospheric pressure plasma jet (APPJ) specifically designed for liquid treatment has been used in this work to improve the electrospinnability of a 5 w/v % solution of poly-epsilon-caprolactone (PCL) in a mixture of chloroform and N,N-dimethylformamide. Untreated PCL solutions were found to result in nonuniform fibers containing a large number of beads, whereas plasma-treated solutions (exposure time of 2-5 min) enabled the generation of beadless, uniform nanofibers with an average diameter of 450 nm. This enhanced electrospinnability was found to be mainly due to the highly increased conductivity of the plasma-modified PCL solutions. Consequently, more stretching of the polymer jet occurred during electrospinning, leading to the generation of bead-free fibers. Plasma treatment also results in an increased viscosity and decreased pH values. To explain these observed changes, optical emission spectroscopy (OES) has been used to examine the excited species present in the APPJ in contact with the PCL solution. This study revealed that the peaks attributed to H, CH, CH2, and C2 species could be responsible for the degradation of solvent molecules and/or PCL structures during the plasma treatment. Size exclusion chromatography and X-ray photoelectron spectroscopy results showed that the molecular weight and the chemical composition of PCL were not significantly affected by the APPJ treatment. Plasma exposure mainly results in the degradation of the solvent molecules instead of modifying the PCL macromolecules, preserving the original polymer as much as possible. A hypothesis for the observed macroscopic changes in viscosity and pH values could be the generation of new chemical species such as HCl and/or HNO3. These species are characterized by their high conductivity, low pH values, and strong polarity and could enhance the solvent quality for PCL, leading to the expansion of the polymer coil, which could in turn explain the observed enhanced viscosity after plasma modification. PMID- 28871775 TI - Functionalized 2D-MoS2-Incorporated Polymer Ternary Solar Cells: Role of Nanosheet-Induced Long-Range Ordering of Polymer Chains on Charge Transport. AB - In this paper, we demonstrated the enhancement in power conversion efficiency (PCE) of solar cells based on poly(3-hexylthiophene-2,5-diyl) (P3HT)/[6,6]-phenyl C71 butyric acid methyl ester (PC71BM) by incorporation of functionalized 2D-MoS2 nanosheets (NSs) as an additional charge-transporting material. The enhancement in PCE of ternary solar cells arises due to the synergic enhancement in exciton dissociation and the improvement in mobility of both electrons and holes through the active layer of the solar cells. The improved hole mobility is attributed to the formation of the long-range ordered nanofibrillar structure of polymer phases and improved crystallinity in the presence of 2D-MoS2 NSs. The improved electron mobility arises due to the highly conducting 2D network of MoS2 NSs which provides additional electron transport channels within the active layer. The nanosheet-incorporated ternary blend solar cells exhibit 32% enhancement in PCE relative to the binary blend P3HT/PC71BM. PMID- 28871777 TI - Developing an Inositol-Phosphate-Actuated Nanochannel System by Mimicking Biological Calcium Ion Channels. AB - In eukaryotic cells, ion channels, which ubiquitously present as polypeptides or proteins, usually regulate the ion transport across biological membranes by conformational switching of the channel proteins in response to the binding of diverse signaling molecules (e.g., inositol phosphate, abbreviated to InsP). To mimic the gating behaviors of natural Ca2+ channels manipulated by InsPs, a smart poly[(N-isopropylacrylamide-co-4-(3-acryloylthioureido) benzoic acid)0.2] (denoted as PNI-co-ATBA0.2) was integrated onto a porous anodic alumina (PAA) membrane, building an InsP-actuated nanochannel system. Driven by the intensive hydrogen bonding complexation of ATBA monomer with InsP, the copolymer chains displayed a remarkable and reversible conformational transition from a contracted state to a swollen one, accompanied with significant changes in surface morphology, wettability, and viscoelasticity. Benefiting from these features, dynamic gating behaviors of the nanochannels located on the copolymer-modified PAA membrane could be precisely manipulated by InsPs, reflected as a satisfactory linear relationship between real-time variation in transmembrane ionic current and the InsP concentration over a wide range from 1 nmol L-1 to 10 MUmol L-1, as well as a clear discrimination among InsP2, InsP3, and InsP6. This study indicates the great potential of biomolecule-responsive polymers in the fabrication of biomimetic ion nanochannels and other nanoscale biodevices. PMID- 28871778 TI - Graphitized Porous Carbon for Rapid Screening of Angiotensin-Converting Enzyme Inhibitory Peptide GAMVVH from Silkworm Pupa Protein and Molecular Insight into Inhibition Mechanism. AB - A novel hydrophobic hexapeptide with high angiotensin-converting enzyme (ACE) inhibitory activity was screened from silkworm pupa protein (SPP) hydrolysate via graphitized porous carbon and reverse-phase high-performance liquid chromatography methods. Graphitized porous carbon derived from dopamine, possessing high surface area and high graphitic carbon, was used to rapidly screen and enrich hydrophobic peptides from SPP hydrolysate. The ACE inhibition pattern and mechanism of the purified peptide were also systematically studied by the classic Lineweaver-Burk model and by molecular docking/dynamic simulation. The novel hydrophobic hexapeptide was identified as Gly-Ala-Met-Val-Val-His (GAMVVH, IC50 = 19.39 +/- 0.21 MUM) with good thermal/antidigestive stabilities. Lineweaver-Burk plots revealed that GAMVVH behaved as a competitive ACE inhibitor. It formed hydrogen bonds with S1 and S2 pockets of ACE and established competitive coordination with Zn(II) of ACE. The synergy of hydrogen bonds with active pockets and Zn(II) coordination efficiently changed the three-dimensional structure of ACE and thus inhibited bioactivity of ACE. PMID- 28871779 TI - Excimer Emission-Based Fluorescent Probe Targeting Caspase-3. AB - A fluorescent probe based on an excimer-forming benzothiazolyl-cyanovinylene (CV) dye was developed to target the apoptotic protease caspase-3. Upon the action of caspase-3, the water-soluble fluorescent probe Ac-DEVD-NH-CV, which is weakly green emissive in aqueous solution, is converted to hydrophobic CV-NH2, which spontaneously aggregates. Aggregation of CV-NH2 promotes excimer emission of the CV dye, which allows for the study of caspase-3 activity in vitro and for imaging the activity of the enzyme in living cells because of the large red shift and enhanced fluorescence signal of the probe. PMID- 28871780 TI - Learning from Natural Nacre: Constructing Layered Polymer Composites with High Thermal Conductivity. AB - Inspired by the microstructures of naturally layered and highly oriented materials, such as natural nacre, we report a thermally conductive polymer composite that consists of epoxy resin and Al2O3 platelets deposited with silver nanoparticles (AgNPs). Owing to their unique two-dimensional structure, Al2O3 platelets are stacked together via a hot-pressing technique, resulting in a brick and-mortar structure, which is similar to the one of natural nacre. Moreover, the AgNPs deposited on the surfaces of the Al2O3 platelets act as bridges that link the adjacent Al2O3 platelets due to the reduced melting point of the AgNPs. As a result, the polymer composite with 50 wt % filler achieves a maximum thermal conductivity of 6.71 W m-1 K-1. In addition, the small addition of AgNPs (0.6 wt %) minimally affects the electrical insulation of the composites. Our bioinspired approach will find uses in the design and fabrication of thermally conductive materials for thermal management in modern electronics. PMID- 28871781 TI - Structural and Dynamic Heterogeneity of Capillary Wave Fronts at Aqueous Interfaces. AB - Using a unique combination of slab-layering analyses and identification of truly interfacial molecules, this work examines water/vapor and water/n-hexane interfaces, specifically the structural and dynamic perturbations of the interfacial water molecules at different locations within the surface capillary waves. From both the structural and dynamic properties analyzed, it is found that these interfacial water molecules dominate the perturbations within the interfacial region, which can extend deep into the water phase relative to the Gibbs dividing surface. Of more importance is the demonstration of structural and dynamic heterogeneity of the interfacial water molecules at the capillary wave front, as indicated by the dipole orientation and the structural and dynamic behavior of hydrogen bonds and their networks. PMID- 28871783 TI - Temperature-Dependent NO2 Sensing Mechanisms over Indium Oxide. AB - The surface species responsible for NO2 gas sensing over indium oxide was studied by operando DRIFTS coupled to a multivariate spectral analysis. It revealed the important roles of surface nitrites on the temperature-dependent gas sensing mechanism and the interaction of such nitrites with surface hydroxyls. A highly hydroxylated surface with high concentration of surface adsorbed H2O is beneficial to enhance the concentration of adsorbed NO2, present as nitrites, thus explaining superior sensing response at lower operating temperatures. PMID- 28871782 TI - Antibiotic Treatment Preventing Necrotising Enterocolitis Alters Urinary and Plasma Metabolomes in Preterm Pigs. AB - Necrotising enterocolitis (NEC) is a serious gut inflammatory condition in premature neonates, onset and development of which depend on the gut microbiome. Attenuation of the gut microbiome by antibiotics can reduce NEC incidence and severity. However, how the antibiotics-suppressed gut microbiome affects the whole-body metabolism in NEC-sensitive premature neonates is unknown. In formula fed preterm pigs, used as a model for preterm infants, plasma and urinary metabolomes were investigated by LC-MS and 1H NMR, with and without antibiotic treatment immediately after birth. While it reduced the gut microbiome density and NEC lesions as previously reported, the antibiotic treatment employed in the current study affected the abundance of 44 metabolites in different metabolic pathways. In antibiotics-treated pigs, tryptophan metabolism favored the kynurenine pathway, relative to the serotonin pathway, as shown by specific metabolites. Metabolites associated with the gut microbiome, including 3 phenyllactic acid, 4-hydroxyphenylacetic acid, and phenylacetylglycine, all from phenylalanine, and three bile acids showed lower levels in the antibiotics treated pigs where the gut microbiome was extensively attenuated. Findings in the current study warrant further investigation of metabolic and developmental consequences of antibiotic treatment in preterm neonates. PMID- 28871784 TI - Graphene- and Phosphorene-like Boron Layers with Contrasting Activities in Highly Active Mo2B4 for Hydrogen Evolution. AB - Two different boron layers, flat (graphene-like) and puckered (phosphorene-like), found in the crystal structure of Mo2B4 show drastically different activities for hydrogen evolution, according to Gibbs free energy calculations of H-adsorption on Mo2B4. The graphene-like B layer is highly active, whereas the phosphorene like B layer performs very poorly for hydrogen evolution. A new Sn-flux synthesis permits the rapid single-phase synthesis of Mo2B4, and electrochemical analyses show that it is one of the best hydrogen evolution reaction active bulk materials with good long-term cycle stability under acidic conditions. Mo2B4 compensates its smaller density of active sites if compared with highly active bulk MoB2 (which contains only the more active graphene-like boron layers) by a 5-times increase of its surface area. PMID- 28871785 TI - Adsorption of Methyl Ester Sulfonate at the Air-Water Interface: Can Limitations in the Application of the Gibbs Equation be Overcome by Computer Purification? AB - We describe a new laboratory synthesis of the alpha-methyl ester sulfonates based on direct sulfonation of the methyl ester by SO3 introduced from the vapor phase. This was used to synthesize a chain deuterated sample of alphaC14MES, which was then used to measure the surface excess of alphaC14MES directly at the air/water interface over a wide range of concentration using neutron reflection. The adsorption isotherm could be fitted to an empirical equation close to a Langmuir isotherm and gave a limiting surface excess of (3.4 +/- 0.1) * 10-6 mol m-2 in the absence of added electrolyte. The neutron-measured surface excesses were combined with the integrated Gibbs equation to fit the variation in surface tension with concentration (sigma-ln C curve). The fit was exact provided that we used a prefactor consistent with the counterion at the surface being an impurity divalent ion, as has previously been found for sodium diethylhexylsulfosuccinate (aerosol OT or AOT) and various perfluorooctanoates. The critical micelle concentration (CMC) was determined from this fit to be 2.4 +/- 0.3 mM in the absence of electrolyte. In the presence of 100 mM NaCl, this contamination was suppressed and the sigma-ln C curve could be fitted using the integrated Gibbs equation with the expected prefactor of 1. The new data were used to reinterpret measurements by Danov et al. on an unpurified sample of alphaC14MES for which computer refinement was used to try to eliminate the effects of the impurities. PMID- 28871786 TI - Fast, Background-Free DNA-PAINT Imaging Using FRET-Based Probes. AB - DNA point accumulation in nanoscale topography (DNA-PAINT) enables super resolution microscopy by harnessing the predictable, transient hybridization between short dye-labeled "imager" and complementary target-bound "docking" strands. DNA-PAINT microscopy allows sub-5 nm spatial resolution, spectrally unlimited multiplexing, and quantitative image analysis. However, these abilities come at the cost of nonfluorogenic imager strands, also emitting fluorescence when not bound to their docking strands. This has thus far prevented rapid image acquisition with DNA-PAINT, as the blinking rate of probes is limited by an upper bound of imager strand concentrations, which in turn is dictated by the necessity to facilitate the detection of single-molecule binding events over the background of unbound, freely diffusing probes. To overcome this limitation and enable fast, background-free DNA-PAINT microscopy, we here introduce FRET-based imaging probes, alleviating the concentration-limit of imager strands and speeding up image acquisition by several orders of magnitude. We assay two approaches for FRET-based DNA-PAINT (or FRET-PAINT) using either fixed or transient acceptor dyes in combination with transiently binding donor-labeled DNA strands and achieve high-quality super-resolution imaging on DNA origami structures in a few tens of seconds. Finally, we also demonstrate the applicability of FRET-PAINT in a cellular environment by performing super-resolution imaging of microtubules in under 30 s. FRET-PAINT combines the advantages of conventional DNA-PAINT with fast image acquisition times, facilitating the potential study of dynamic processes. PMID- 28871787 TI - NMR Spectroscopy-based Metabolomics of Drosophila Model of Huntington's Disease Suggests Altered Cell Energetics. AB - Huntington's disease (HD) is a neurodegenerative disorder induced by aggregation of the pathological form of Huntingtin protein that has expanded polyglutamine (polyQ) repeats. In the Drosophila model, for instance, expression of transgenes with polyQ repeats induces HD-like pathologies, progressively correlating with the increasing lengths of these repeats. Previous studies on both animal models and clinical samples have revealed metabolite imbalances during HD progression. To further explore the physiological processes linked to metabolite imbalances during HD, we have investigated the 1D 1H NMR spectroscopy-based metabolomics profile of Drosophila HD model. Using multivariate analysis (PCA and PLS-DA) of metabolites obtained from methanolic extracts of fly heads displaying retinal deformations due to polyQ overexpression, we show that the metabolite imbalance during HD is likely to affect cell energetics. Six out of the 35 metabolites analyzed, namely, nicotinamide adenine dinucleotide (NAD), lactate, pyruvate, succinate, sarcosine, and acetoin, displayed segregation with progressive severity of HD. Specifically, HD progression was seen to be associated with reduction in NAD and increase in lactate-to-pyruvate ratio. Furthermore, comparative analysis of fly HD metabolome with those of mouse HD model and HD human patients revealed comparable metabolite imbalances, suggesting altered cellular energy homeostasis. These findings thus raise the possibility of therapeutic interventions for HD via modulation of cellular energetics. PMID- 28871788 TI - Antifungal Effect of Arabidopsis SGT1 Proteins via Mitochondrial Reactive Oxygen Species. AB - The highly conserved SGT1 (suppressor of the G2 alleles of skp1) proteins from Arabidopsis are known to contribute to plant resistance to pathogens. While SGT1 proteins respond to fungal pathogens, their antifungal activity is not reported and the mechanism for this inhibition is not well understood. Therefore, recombinant Arabidopsis SGT1 proteins were cloned, expressed, and purified to evaluate their antifungal activity, resulting in their potent inhibition of pathogen growth. Dye-labeled proteins are localized to the cytosol of Candida albicans cells without the disruption of the cell membrane. Moreover, we showed that entry of the proteins into C. albicans cells resulted in the accumulation of reactive oxygen species (ROS) and cell death via altered mitochondrial potential. Morphological changes of C. albicans cells in the presence of proteins were visualized by scanning electron microscopy. Our data suggest that AtSGT1 proteins play a critical role in plant resistance to pathogenic fungal infection and they can be classified to a new plant antifungal protein. PMID- 28871789 TI - Production and Purification of the Native Saccharomyces cerevisiae Hsp12 in Escherichia coli. AB - Hsp12 is a small heat shock protein produced in many organisms, including the yeast Saccharomyces cerevisiae. It has been described as an indicator of yeast stress rate and has also been linked to the sweetness sensation of wine. To obtain a sufficient amount of protein, we produced and purified Hsp12 without tag in Escherichia coli. A simple fast two-step process was developed using a microplate approach and a design of experiments. A capture step on an anion exchange salt-tolerant resin was followed by size exclusion chromatography for polishing, leading to a purity of 97%. Thereafter, specific anti-Hsp12 antibodies were obtained by rabbit immunization. An ELISA was developed to quantify Hsp12 in various strains of Saccharomyces cerevisiae. The antibodies showed high specificity and allowed the quantitation of Hsp12 in the yeast. The quantities of Hsp12 measured in the strains differed in direct proportion to the level of expression found in previous studies. PMID- 28871790 TI - Mesoporous Iron Sulfide for Highly Efficient Electrocatalytic Hydrogen Evolution. AB - We report a facile synthetic protocol to prepare mesoporous FeS2 without the aid of hard template as an electrocatalyst for the hydrogen evolution reaction (HER). The mesoporous FeS2 materials with high surface area were successfully prepared by a sol-gel method following a sulfurization treatment in an H2S atmosphere. A remarkable HER catalytic performance was achieved with a low overpotential of 96 mV at a current density of 10 mA.cm-2 and a Tafel slope of 78 mV per decade under alkaline conditions (pH 13). The theoretical calculations indicate that the excellent catalytic activity of mesoporous FeS2 is attributed to the exposed (210) facets. The mesoporous FeS2 material might be a promising alternative to the Pt-based electrocatalysts for water splitting. PMID- 28871791 TI - Real-Time Bioimpedance Sensing of Antifibrotic Drug Action in Primary Human Cells. AB - Fibrotic diseases are among the most serious health issues with severe burdens due to their chronic nature and a large number of patients suffering from the debilitating effects and long-term sequelae. Collagenase treatment is a nonsurgical option but has limited results. To date, there is no potent noninvasive solution for fibrosis. Part of the reason for this is the lack of appropriate in vitro live cell screening tools to assess the efficacy of new therapeutical agents. Here, we demonstrate the utility of a cell-based electrochemical impedance biosensor platform to screen the efficacy of potential antifibrotic compounds. The platform employs a label-free and noninvasive strategy to detect the progression of fibrosis and the potency of the antifibrotic molecules in real-time. The fundamental principle that governs this novel system is that dynamic changes in cell shape and adhesion during fibrosis can be measured accurately by monitoring the changes in the impedance. This is achieved by growing the cells on a transparent interdigitated indium tin oxide (ITO) electrodes. It was demonstrated by monitoring the efficacy of a model antifibrotic compound, PXS64, on cells collected from patients with Dupuytren's contracture. We confirmed the validity of the developed biochemical impedance biosensor as an tool for in vitro screening of antifibrotic compounds and provided quantitative information on subcellular influences of the examined chemical molecules using correlative microscopy analyses that monitor the average cell area, cell morphology, and the amount and directionality of the deposited extracellular matrix protein collagen and measurement of cytosolic Ca2+ changes. PMID- 28871792 TI - One-Pot Synthesis of Nickel-Modified Carbon Nitride Layers Toward Efficient Photoelectrochemical Cells. AB - A new method to significantly enhance the photoelectrochemical properties of phenyl-modified carbon nitride layers via the insertion of nickel ions into carbon nitride layers is reported. The nickel ions are embedded within the carbon nitride layers by manipulating the interaction of Ni ions and molten organic molecules at elevated temperature prior to their condensation. A detailed analysis of the chemical and photophysical properties suggests that the nickel ions dissolve in the molten molecules, leading to the homogeneous distribution of nickel atoms within the carbon nitride layers. We found that the nickel atoms can alter the growth mechanism of carbon nitride layers, resulting in extended light absorption, charge transfer properties, and the total photoelectrochemical performance. For the most photoactive electrode, the Ni ions have an oxidation state of 2.8, as confirmed by soft X-ray absorption spectroscopy. Furthermore, important parameters such as absorption coefficient, exciton lifetime, and diffusion length were studied in depth, providing substantial progress in our understanding of the photoelectrochemical properties of carbon nitride films. This work opens new opportunities for the growth of carbon nitride layers and similar materials on different surfaces and provides important progress in our understanding of the photophysical and photoelectrochemical properties of carbon nitride layers toward their implantation in photoelectronic and other devices. PMID- 28871793 TI - Utility of Montreal Cognitive Assessment in Differentiating Dementia With Lewy Bodies From Alzheimer's Dementia. AB - Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the 2 most common neurodegenerative dementias. Identification of patients with DLB is necessary to guide appropriate clinical management and medication trials. Patients with DLB are reported to perform poorly on tasks of visuospatial and executive function, compared to patients with AD who perform poorly on memory tasks. Using the Montreal Cognitive Assessment, we found that patients with DLB (n = 73) had statistically significant lower performance in clock drawing (visuospatial and executive function) and higher performance in delayed recall (memory) subscores compared to patients with AD (n = 57). This score pattern should raise suspicion for a DLB diagnosis at initial evaluation of patients with dementia. PMID- 28871794 TI - Differentiating Between Apathy and Depression in Patients With Parkinson Disease Dementia. AB - In Parkinson disease (PD), apathy and depression often overlap, making it difficult to differentiate between them. This study sought to analyze apathy and depression in patients with PD dementia (PDD). Forty patients were diagnosed with PDD using the Movement Disorder Society criteria. A statistically significant correlation was identified between worsening dementia and an improvement in depression ( r = .3695; r2 = .1365, 95% confidence interval [CI]: 0.0985 to 05.894, P = .0044) and between worsening dementia and worsening apathy ( r = .2578, r2 = .0664, 95% CI: -0.5025 to .0251, P = .036). Depression had a greater correlation with advanced motor symptoms ( r = .4988, r2 = .2438, 95% CI: 0.2218 0.7013, P = .0005]. In conclusion, depression was associated with less advanced PDD and more intense motor features, while apathy was associated with more advanced cognitive impairment. PMID- 28871795 TI - Increasing Burden of Complex Multimorbidity Across Gradients of Cognitive Impairment. AB - INTRODUCTION: This study evaluates the burden of multimorbidity (MM) across gradients of cognitive impairment (CI). METHODS: Using data from the 2010 Health and Retirement Study, we identified individuals with no CI, mild CI, and moderate/severe CI. In addition, we adopted an expansive definition of complex MM by accounting for the occurrence and co-occurrence of chronic conditions, functional limitations, and geriatric syndromes. RESULTS: In a sample of 18 913 participants (weighted n = 87.5 million), 1.93% and 1.84% presented with mild and moderate/severe CI, respectively. The prevalence of most conditions constituting complex MM increased markedly across the spectrum of CI. Further, the percentage of individuals presenting with 10 or more conditions was 19.9%, 39.3%, and 71.3% among those with no CI, mild CI, and moderate/severe CI, respectively. DISCUSSION: Greater CI is strongly associated with increased burden of complex MM. Detailed characterization of MM across CI gradients will help identify opportunities for health care improvement. PMID- 28871796 TI - Alzheimers' disease and caregiving: a meta-analytic review comparing the mental health of primary carers to controls. AB - OBJECTIVES: To quantitatively review the literature comparing depressed mood, anxiety and psychological distress in caregivers (CGs) of older adults with Alzheimer's disease (AD) with non-caregivers (NCGs) Methods: Eighteen independent studies comparing AD CGs (N = 2378) with NCGs (N = 70,035) were evaluated in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Standardised mean differences (Hedges' g) with associated 95% confidence intervals and p-values were calculated using a random effects model. RESULTS: Studies generally conformed to STROBE criteria in terms of their methodological and procedural detail, although data management issues that may contribute to methodological bias were identified. Pooled effect estimates revealed medium to large group differences in depression (gw = 1.01 [CI: 0.73, 1.29] p < 0.01) and anxiety (gw = 0.64 [CI: 0.39, 0.89] p < 0.01): AD caregivers reported higher symptom severity. Gender was a significant moderator: female caregivers experienced poor self-reported mood (gw = 1.58 [CI: 1.11, 2.05], p < 0.01), although this analysis was limited in power given the small number of contributing studies. DISCUSSION: Caregivers of patients with AD experience poor mental health in comparison to the general population, with female caregivers being disproportionately affected. Further exploration of the psychosocial variables that contribute to these group differences is needed to inform effective support services and, in turn, help caregivers manage the emotional demands of AD. PMID- 28871797 TI - Qualitative Analysis of Dairy and Powder Milk Using Laser-Induced Breakdown Spectroscopy (LIBS). AB - Laser-induced breakdown spectroscopy (LIBS) technique was used to compare various types of commercial milk products. Laser-induced breakdown spectroscopy spectra were investigated for the determination of the elemental composition of soy and rice milk powder, dairy milk, and lactose-free dairy milk. The analysis was performed using radiative transitions. Atomic emissions from Ca, K, Na, and Mg lines observed in LIBS spectra of dairy milk were compared. In addition, proteins and fat level in milks can be determined using molecular emissions such as CN bands. Ca concentrations were calculated to be 2.165 +/- 0.203 g/L in 1% of dairy milk fat samples and 2.809 +/- 0.172 g/L in 2% of dairy milk fat samples using the standard addition method (SAM) with LIBS spectra. Univariate and multivariate statistical analysis methods showed that the contents of major mineral elements were higher in lactose-free dairy milk than those in dairy milk. The principal component analysis (PCA) method was used to discriminate four milk samples depending on their mineral elements concentration. In addition, proteins and fat level in dairy milks were determined using molecular emissions such as CN band. We applied partial least squares regression (PLSR) and simple linear regression (SLR) models to predict levels of milk fat in dairy milk samples. The PLSR model was successfully used to predict levels of milk fat in dairy milk sample with the relative accuracy (RA%) less than 6.62% using CN (0,0) band. PMID- 28871799 TI - Costs and benefits of different methods of esophagectomy for esophageal cancer. AB - Background A minimally invasive approach to esophagectomy is being used increasingly, but concerns remain regarding the feasibility, safety, cost, and outcomes. We performed an analysis of the costs and benefits of minimally invasive, hybrid, and open esophagectomy approaches for esophageal cancer surgery. Methods The data of 83 consecutive patients who underwent a McKeown's esophagectomy at Prince of Songkla University Hospital between January 2008 and December 2014 were analyzed. Open esophagectomy was performed in 54 patients, minimally invasive esophagectomy in 13, and hybrid esophagectomy in 16. There were no differences in patient characteristics among the 3 groups Minimally invasive esophagectomy was undertaken via a thoracoscopic-laparoscopic approach, hybrid esophagectomy via a thoracoscopic-laparotomy approach, and open esophagectomy by a thoracotomy-laparotomy approach. Results Minimally invasive esophagectomy required a longer operative time than hybrid or open esophagectomy ( p = 0.02), but these patients reported less postoperative pain ( p = 0.01). There were no significant differences in blood loss, intensive care unit stay, hospital stay, or postoperative complications among the 3 groups. Minimally invasive esophagectomy incurred higher operative and surgical material costs than hybrid or open esophagectomy ( p = 0.01), but there were no significant differences in inpatient care and total hospital costs. Conclusion Minimally invasive esophagectomy resulted in the least postoperative pain but the greatest operative cost and longest operative time. Open esophagectomy was associated with the lowest operative cost and shortest operative time but the most postoperative pain. Hybrid esophagectomy had a shorter learning curve while sharing the advantages of minimally invasive esophagectomy. PMID- 28871800 TI - Clinicopathologic features of minute pulmonary meningothelial-like nodules. AB - Purpose Minute pulmonary meningothelial-like nodules are incidentally discovered in lung specimens. We analyzed the clinicopathologic features of 14 cases identified in surgically resected lungs. Methods Among patients who underwent lung resection in our hospital from October 2007 to March 2016, 14 were found to have minute pulmonary meningothelial-like nodules. The clinical parameters, radiologic findings, and pathologic features of these patients were retrospectively reviewed using the medical records. Results The patients included 4 men and 10 women, with a mean age of 69 years (range 53-82 years). The coexisting main disease was adenocarcinoma in 8 patients, squamous cell carcinoma in 1, atypical adenomatous hyperplasia in 1, and metastatic pulmonary tumor in 3. In one patient, the minute pulmonary meningothelial-like nodules presented as multiple lung nodules on chest computed tomography. The median size of the nodules was 1.4 mm (range 0.3-6.0 mm). Similar to meningioma, one case had immunoreactivity to progesterone receptor and epithelial membrane antigen, although the minute pulmonary meningothelial-like nodules were not associated with a meningioma. Conclusions The relationship between minute pulmonary meningothelial-like nodules and meningioma should be investigated. If minute pulmonary meningothelial-like nodules are found on preoperative computed tomography, thoracoscopic lung biopsy is helpful for differential diagnosis. PMID- 28871805 TI - Acoustic Radiation Force Impulse Elastography in Determining the Effects of Type 1 Diabetes on Pancreas and Kidney Elasticity in Children. AB - OBJECTIVE: The aim of this study is to determine the effects of type 1 diabetes on pancreas and kidney elasticity in children, using acoustic radiation force impulse ultrasound elastography. SUBJECTS AND METHODS: Sixty autoantibody positive patients with type 1 diabetes (45% girls; mean [+/- SD] age, 11.7 +/- 4.4 years; range, 1.9-19.3 years) admitted to the pediatric endocrinology outpatient clinic and 32 healthy children (50% girls; mean age, 10.2 +/- 3.8 years; range, 2.1-17.3 years) were included in the study. Acoustic radiation force impulse elastography measurements were performed of the kidneys and pancreas in both groups. Body mass index, duration of diabetes, HbA1c levels, and insulin dosage of patients with type 1 diabetes were recorded. RESULTS: The mean shear-wave velocities of the pancreas were 0.99 +/- 0.25 m/s in patients with type 1 diabetes and 1.09 +/- 0.22 m/s in healthy control subjects; the difference was not significant (p = 0.08). The median shear-wave velocities of the right and left kidneys in patients with type 1 diabetes were 2.43 +/- 0.29 and 2.47 +/- 0.25 m/s, respectively. There were no significant differences in the shear-wave velocities of the right and left kidneys between the patients with type 1 diabetes and the healthy control subjects (p = 0.91 and p = 0.73, respectively). Correlation analysis showed no correlation between the shear-wave velocities of the pancreas and kidney versus HbA1c level, duration of diabetes, insulin dosage, height, weight, and body mass index of the patients with type 1 diabetes. CONCLUSION: The current study showed no significant difference in the shear-wave velocity of kidneys in children with type 1 diabetes with normoalbuminuria compared with the healthy control subjects. We also observed that the shear-wave velocity of the pancreas in children with type 1 diabetes and healthy control subjects did not differ significantly. PMID- 28871806 TI - Effectiveness of a Mobile Mammography Program. AB - OBJECTIVE: Mobile mammography units have increasingly been used to address patient health care disparities; however, there are limited data comparing mobile units to stationary sites. This study aims to evaluate the characteristics of women who underwent mammography screening in a mobile unit versus those who underwent mammography screening at a cancer center. MATERIALS AND METHODS: In this retrospective study, we analyzed all screening mammography examinations performed in a mobile unit in 2014 (n = 1433 examinations). For comparison, we randomized and reviewed an equivalent number of screening mammography examinations performed at our cancer center in 2014 (n = 1434 examinations). BI RADS assessment, adherence to follow-up, biopsies performed, cancer detection rate, and sociodemographic variables were recorded. An independent-samples t test was conducted to identify potential differences in age between cancer center patients and mobile unit patients. Chi-square analyses were used to test for associations between location and factors such as health insurance, race, marital status, geographic area, adherence to screening guidelines, recall rate, adherence to follow-up, and cancer detection rates. RESULTS: Patients visiting our cancer center (mean = 57.74 years; SD = 10.55) were significantly older than those visiting the mobile unit (mean = 52.58 years; SD = 8.19; p < 0.001). There was a significant association between location and health insurance status (chi2 = 610.92; p < 0.001) with more uninsured patients undergoing screening in the mobile van (cancer center = 3.70%, mobile unit = 38.73%). There was a significant association between screening location and patient race (chi2 = 118.75, p < 0.001), with more white patients being screened at the cancer center (cancer center = 47.28%, mobile unit = 33.30%), more black patients being screened in the mobile van (cancer center = 49.30%, mobile unit = 54.15%), and more Hispanic patients being screened in the mobile van (cancer center = 1.05%, mobile unit = 6.77%). There was a significant association between location and patient marital status (chi2 = 135.61, p < 0.001), with more married patients screened at the cancer center (cancer center = 49.16%, mobile unit = 38.31%), more single patients screened in the mobile van (cancer center = 25.17%, mobile unit = 34.47%), and more widowed patients being screened at the cancer center (cancer center = 8.09%, mobile unit = 4.47%). There was a significant association between location and geographic area (chi2 = 33.33, p < 0.001), with both locations reaching more urban than rural patients (cancer center = 79.99%, mobile unit = 70.62%). There was a significant association between location and adherence to screening guidelines (chi2 = 179.60, p < 0.001), with patients screened at the cancer center being more compliant (cancer center = 56.90%, mobile unit = 34.47%). Finally, there was a significant association between location and recall rate (chi2 = 4.06, p < 0.001). The cancer center had a lower recall rate (13.32%) than the mobile van (15.98%). Of those patients with BI-RADS 0, there was a significant association between location and adherence to follow-up (chi2 = 22.75, p < 0.001) with patients using the mobile unit less likely to return for additional imaging (cancer center = 2.65%, mobile unit = 17.03%). CONCLUSION: Significant differences were found among patients visiting the cancer center versus the mobile mammography van. The cancer center's population is older and more adherent to guidelines, whereas the mobile mammography population exhibited greater racial and marital diversity, higher recall rate, and lack of adherence to follow-up recommendations. By identifying these characteristics, we can develop programs and materials that meet these populations' needs and behaviors, ultimately increasing mammography screening and follow-up rates among underserved populations. PMID- 28871807 TI - Visualizing Carotid Bodies With Doppler Ultrasound Versus CT Angiography: Preliminary Study. AB - OBJECTIVE: The purpose of this article is to evaluate the utility of ultrasound in identifying carotid bodies (CBs) in patients with drug-resistant arterial hypertension. SUBJECTS AND METHODS: We enrolled 13 patients with drug-resistant hypertension into a trial for surgical CB excision. CT angiography (CTA) and Doppler ultrasound (DUS) of the cervical arteries were performed before surgery. CBs were identified in a blind manner at both CTA and DUS. CBs were defined at CTA as ovoid avidly enhancing structures at the inferomedial aspect of the carotid bifurcation. At DUS, CBs were defined as ovoid solid structures in the inferomedial aspect of the bifurcation. RESULTS: CBs were identified in 12 of 13 patients (23/26 sides) using CTA and in 11 of 13 patients (18/26 sides) using DUS. Identification of CB with DUS and CTA correlated in 17 of 18 cases; in one instance, CB was identified with DUS but not CTA. There was no statistically significant difference in size and volume of CB measured by both methods. CONCLUSION: Noncarcinogenic CBs can be visualized using DUS, with good correlation of size and location compared with CTA. The findings show that DUS can be reliably used to further examine the role of CBs in cardiovascular disorders and can be used in conjunction with therapies that target CBs. PMID- 28871808 TI - Sex Differences in Radiologist Salary in U.S. Public Medical Schools. AB - OBJECTIVE: The purpose of this study was to evaluate salary differences between male and female academic radiologists at U.S. medical schools. MATERIALS AND METHODS: Laws in several U.S. states mandate public release of government records, including salary information of state employees. From online salary data published by 12 states, we extracted the salaries of all academic radiologists at 24 public medical schools during 2011-2013 (n = 573 radiologists). In this institutional review board-approved cross-sectional study, we linked these data to a physician database with information on physician sex, age, faculty rank, years since residency, clinical trial involvement, National Institutes of Health (NIH) funding, scientific publications, and clinical volume measured by 2013 Medicare payments. Sex difference in salary, the primary outcome, was estimated using a multilevel logistic regression adjusting for these factors. RESULTS: Among 573 academic radiologists, 171 (29.8%) were women. Female radiologists were younger (48.5 vs 51.6 years, p = 0.001) and more likely to be assistant professors (50.9% [87/171] vs 40.8% [164/402], p = 0.026). Salaries between men and women were similar in unadjusted analyses ($290,660 vs $289,797; absolute difference, $863; 95% CI, -$18,363 to $20,090), and remained so after adjusting for age, faculty rank, years since residency, clinical trial involvement, publications, total Medicare payments, NIH funding, and graduation from a highly ranked medical school. CONCLUSION: Among academic radiologists employed at 24 U.S. public medical schools, male and female radiologists had similar annual salaries both before and after adjusting for several variables known to influence salary among academic physicians. PMID- 28871809 TI - Iodine Concentration in Spectral CT: Assessment of Prognostic Determinants in Patients With Gastric Adenocarcinoma. AB - OBJECTIVE: The purpose of this study was to use virtual monochromatic spectral CT to investigate the usefulness of iodine concentration (IC) and its correlation with clinicopathologically determined prognostic factors in gastric adenocarcinoma. SUBJECTS AND METHODS: From June 2012 to March 2015, 34 patients with gastric adenocarcinoma underwent arterial and portal venous phase spectral CT. The ICs in the arterial and portal venous phases were calculated and then normalized with the aorta as normalized IC (NIC). The surgical specimen was evaluated with CD34 staining to determine microvessel density (MVD). The correlation between imaging results and clinicopathologic findings was investigated for histologic grading, lymph node metastasis, serosal involvement, distant metastasis, pathologic TNM stage, and MVD. RESULTS: The mean arterial phase NIC value of tumors was 0.12 +/- 0.03, portal venous phase NIC value was 0.39 +/- 0.06, and MVD was 26.94 +/- 7.87 vessels per high-power field (*400). Both arterial phase and portal venous phase NIC values were significantly higher in poorly differentiated gastric adenocarcinomas (p = 0.005) than in moderately differentiated tumors (p = 0.013). There was no significant correlation between NIC and serosal involvement or distant metastasis. There was significant correlation between the NIC and MVD in gastric adenocarcinoma (arterial phase NIC, p = 0.013; portal venous phase NIC, p = 0.001). However, neither the arterial nor the portal venous phase NIC of gastric adenocarcinoma had a significant relation to lymphatic metastasis or pathologic TNM stage. There was a significant difference between the high and low MVD groups with respect to portal venous phase NIC (p = 0.045). CONCLUSION: NIC can serve as a useful predictor of angiogenesis and degree of differentiation of moderately and poorly differentiated gastric adenocarcinomas. PMID- 28871810 TI - Mammography Positioning Standards in the Digital Era: Is the Status Quo Acceptable? AB - OBJECTIVE: The objective of our study was to evaluate positioning of full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) compared with film-screen (FS) mammography positioning standards. MATERIALS AND METHODS: A retrospective study was conducted of consecutive patients who underwent screening FFDM in 2010-2012 and DBT in 2012-2013 at an academic institution. Examinations were performed by five experienced technologists who underwent updated standardized positioning training. Positioning criteria were assessed by consensus reads among three breast radiologists and compared with FS mammography data from a 1993 study by Bassett and colleagues. RESULTS: One hundred seventy patients (n = 340 examinations) were analyzed, showing significant differences between FFDM and DBT examinations (p < 0.05) for medial or inferior skin folds (FFDM vs DBT: craniocaudal [CC] view, 16% [n = 56] vs 23% [n = 77]; mediolateral oblique [MLO] view, 35% [n = 118] vs 45% [n = 154]), inclusion of lateral glandular tissue on CC view (FFDM vs DBT, 73% [n = 247] vs 81% [n = 274]), and concave pectoralis muscle shape (FFDM vs DBT, 36% [n = 121] vs 28% [n = 95]). In comparison with Bassett et al. data, all positioning criteria for both FFDM and DBT examinations were significantly different (p < 0.05). The largest differences were found in visualization of the pectoralis muscle on CC views and the inframammary fold on MLO views, inclusion of posterior or lateral glandular tissue, and inclusion of skin folds, with DBT and FFDM more frequently exhibiting all criteria than originally reported Bassett et al. FINDINGS: CONCLUSION: DBT and FFDM mammograms more frequently include posterior or lateral tissue, the inframammary fold on MLO views, the pectoralis muscle on CC views, and skin folds than FS mammograms. Inclusion of more breast tissue with newer technologies suggests traditional positioning standards, in conjunction with updated standardized positioning training, are still applicable at the expense of including more skin folds. PMID- 28871811 TI - Imaging of Uncommon Causes of Large-Bowel Obstruction. AB - OBJECTIVE: The most common causes of large-bowel obstruction (LBO) are colon carcinoma and volvulus. Nevertheless, the increased frequency of the condition and widespread use of diagnostic imaging have revealed uncommon causes of LBO. We review the imaging features of the unusual causes of LBO on several imaging modalities, with particular emphasis on CT, along with the current literature. CONCLUSION: We propose an algorithmic approach to the radiologic evaluation of the uncommon causes of LBO. PMID- 28871812 TI - 'This is killing me inside': The impact of having a parent with young-onset dementia. AB - This study explored the experience of young adults having a parent with young onset dementia. In-depth interviews were undertaken with five participants aged between 23 and 36 years of age and these were analysed using interpretative phenomenological analysis. Participants were found to experience a number of stresses in relation to their parent's illness, many of which were linked to loss and guilt. Five main themes were identified related to relationship changes, shifts in roles and responsibilities, support for the non-affected parent, support for self and the impact of living with their own potential risk of dementia. These findings are discussed in relation to the existing literature and suggest that individuals with a parent with young-onset dementia have needs which service providers should consider in the wider context of young-onset dementia care. PMID- 28871813 TI - Unspecified intestinal malabsorption in patients treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers: a retrospective analysis in primary care settings. AB - OBJECTIVE: To investigate the possible relationship between the use of Angiotensin II Receptor Blockers (ARBs) or Angiotensin-Converting-Enzyme Inhibitors (ACE-i) and unspecified intestinal malabsorption (IM) within the Italian and German real-life context. RESEARCH DESIGN AND METHODS: a retrospective cohort of patients with a new unspecified IM diagnosis during the period 1 January 2010-31 December 2013 was extracted from Italian IMS Health Longitudinal Patient Database and German IMS Disease Analyzer. Only patients with at least one prescription of ARB or ACE-i medication during the 6 months preceding the IM diagnosis were included and then followed up for 12 months to assess treatment exposure. RESULTS: After stratification by year and molecule, the proportion of patients experiencing an unspecified IM diagnosis on total patients receiving ARBs or ACE-i ranged from 0% to 0.14%, showing no relevant differences between molecules and no time trends. CONCLUSIONS: this study indicates that ACE-i or ARBs were rarely associated to an unspecified IM diagnosis. No relevant difference between each specific ACE-i and ARB was highlighted. PMID- 28871814 TI - Osseous changes in patients with medication-related osteonecrosis of the jaws. AB - OBJECTIVES: Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive agents. The aim of this study was to investigate the osseous changes in patients with MRONJ. METHODS: Cone beam CT (CBCT) images of 25 patients with MRONJ and controls were retrospectively evaluated. Buccal, lingual, apical cortical bone thicknesses; buccal, lingual, apical intracortical and cancellous bone density; diameter of mental foramen and incisive canal, and width of mental foramen were measured. RESULTS: Buccal and apical cortical bone thicknesses were increased; however intracortical radiodensity values decreased in the Study Group when compared with the Control Group (p = 0.007, p = 0.001). Narrowing of incisive canal was observed in patients with MRONJ (p = 0.000). CONCLUSIONS: Clinician should have awareness about narrowing of incisive canal, apical and buccal cortical bone thickening, decreasing in cancellous bone radiodensity, and the lingual cortex destruction in patients with MRONJ. PMID- 28871815 TI - Pharmacogenetics of aldo-keto reductase 1C (AKR1C) enzymes. AB - INTRODUCTION: Genetic variation in metabolizing enzymes contributes to variable drug response and disease risk. Aldo-keto reductase type 1C (AKR1C) comprises a sub-family of reductase enzymes that play critical roles in the biotransformation of various drug substrates and endogenous compounds such as steroids. Several single nucleotide polymorphisms have been reported among AKR1C encoding genes, which may affect the functional expression of the enzymes. Areas covered: This review highlights and comprehensively discusses previous pharmacogenetic reports that have examined genetic variations in AKR1C and their association with disease development, drug disposition, and therapeutic outcomes. The article also provides information about the effect of AKR1C genetic variants on enzyme function in vitro. Expert opinion: The current evidence that links the effect of AKR1C gene polymorphisms to disease progression and development is inconsistent and needs further validation, despite of the tremendous knowledge available. Information about association of AKR1C genetic variants and drug efficacy, safety, and pharmacokinetics is limited, thus, future studies that advance our understanding about these relationships and their clinical relevance are needed. It is imperative to achieve consistent findings before the potential translation and adoption of AKR1C genetic variants in clinical practice. PMID- 28871816 TI - Comparative pharmacokinetics study of five alkaloids in rat plasma and related compound-herb interactions mechanism after oral administration of Shuanghua Baihe tablets. AB - Shuanghua Baihe tablet is a traditional Chinese patent medicine which showed special advantages in the treatment of recurrent aphthous stomatitis. Scientists have improved and implemented the LC-MS/MS method, which is specific and sensitive, for comparative pharmacokinetics study of five alkaloids, including palmatine, berberine, epiberberine, jatrorrhizine and coptisine in rat plasma after oral administration of Rhizoma Coptidis extract and Shuanghua Baihe tablets. The results showed that Shuanghua Baihe tablets could promote the absorption of these five alkaloids and improved their bioavailability compared with R. Coptidis extract. To further investigate the related mechanism, everted intestinal sac model in vitro was used to indicate that alteration of in vivo pharmacokinetics of five alkaloids could be attributed to, at least in part, the absorption changes by coadministration of other herbs. These discoveries served as a theoretical basis for clinical use of Shuanghua Baihe tables. PMID- 28871817 TI - Cytotoxicity, In vitro anti-Leishmanial and fingerprint HPLC- photodiode array analysis of the roots of Trillium govanianum. AB - Trillium govanianum Wall. ex D. Don (Melanthiaceae alt. Trilliaceae), commonly known as 'nagchhatry' or 'teen patra', distributed from Pakistan to Bhutan about 2500-3800 m altitude is indigenous to Himalayas region. In folk medicine the plant has been reported for the treatment of wound healing, sepsis and in various sexual disorders. This paper reports, for the first time, to evaluate the cytotoxicity, in vitro anti-leishmanial (promastigotes) and fingerprint HPLC photodiode array analysis of the MeOH extract of the roots of T. govanianum and its solid phase extraction fractions. Reverse phase HPLC-PDA based quantification revealed the presence of significant amount of quercetin, myrecetin and kaemferol ranging from 0.221to 0.528 MUg/mg DW. MeOH extract revealed distinguishable protein kinase inhibitory activity against Streptomyces 85E strain with 18 mm bald phenotype. The remarkable toxicity profile against brine shrimps and leishmanial was manifested by MeOH extract with LC50 10 and 38.5 MUg/mL, respectively. PMID- 28871818 TI - Optimisation of extraction conditions for total saponins from Cynanchum wallichii using response surface methodology and its anti-tumour effects. AB - Cynanchum wallichii Wight, is a traditional Chinese medicine herb, which is rich in saponins and has varieties of pharmacological activities. In this study, a standardized C. wallichii extract was established and the anti-tumor activity of the total saponins was evaluated by MTT assay. The extraction conditions of the standardized extract was optimized using response surface methodology. The experimental value was in good agreement (the yield 4.28%) with predicted values. The total saponins of the extract showed significant anti-tumor activity against three human tumor cell lines (A549, HepG2 and MCF-7), especially for MCF-7 (IC50. 67.63 MUg/mL) cells in vitro. PMID- 28871819 TI - Cyanide poisoning in Thailand before and after establishment of the National Antidote Project. AB - CONTEXT: Antidote shortage is a global problem. In Thailand, the National Antidote Project (NAP) has operated since November 2010 to manage the national antidote stockpile, educate the healthcare providers on appropriate antidote use, and evaluate antidote usage. OBJECTIVE: To evaluate the effect of NAP implementation on mortality rate and antidote use in cyanide poisoning cases arising from ingestion of cyanide or cyanogenic glycoside. METHODS: This is a retrospective cohort of poisoning cases involving cyanide or cyanogenic glycoside ingestion reported to Ramathibodi Poison Center from 1 January 2007 to 31 December 2015. Mortality rate, antidote use, and appropriateness of antidote use (defined as correct indication, proper dosing regimen, and administration within 90 min) before and after NAP implementation were compared. Association between parameters and fatal outcomes was analyzed. RESULTS: A total of 343 cases involving cyanide or cyanogenic glycoside ingestion were reported to Ramathibodi Poison Center. There were 213 cases (62.1%) during NAP (Project group) and 130 cases (37.9%) pre-NAP implementation (Before group). Implementation of NAP led to increased antidote use (39.9% in Project group versus 24.6% in Before group) and a higher rate of appropriate antidote use (74.1% in Project group versus 50.0% in Before group). All 30 deaths were presented with initial severe symptoms. Cyanide chemical source and self-harm intent were associated with death (OR: 12.919, 95% CI: 4.863-39.761 and OR: 10.747, 95% CI: 3.884-28.514, respectively). No difference in overall mortality rate (13 [10.0%] deaths before versus 17 [8.0%] deaths after NAP) was found. In subgroup analysis of 80 cases with initial severe symptoms, NAP and appropriate antidote use reduced mortality (OR: 0.327, 95% CI: 0.106-0.997 and OR: 0.024, 95% CI: 0.004-0.122, respectively). In the multivariate analysis of the cases with initial severe symptoms, presence of the NAP and appropriate antidote use independently reduced the risk of death (OR: 0.122, 95% CI: 0.023-0.633 and OR: 0.034, 95% CI: 0.007-0.167, respectively), adjusted for intent of exposure, cyanide source, age, and sex. CONCLUSIONS: After NAP implementation, both antidote use and appropriate antidote use increased. In cases presenting with severe symptoms, presence of the NAP and appropriate antidote use independently reduced the risk of mortality. PMID- 28871821 TI - Centruroides sculpturatus envenomation in three adult patients requiring treatment with antivenom. AB - CONTEXT: Envenomation by Centruroides sculpturatus can manifest with cranial nerve dysfunction and neuromuscular hyperactivity. While these symptoms are most commonly seen in young children, they may also be seen in adults. CASE DETAILS: Three cases of adult patients are presented with grades III & IV scorpion envenomation. They reported symptoms including disconjugate, roving eye movements, and motor involvement. Also reported were hyposmia, difficulty with fine motor movements, and dysgeusia. All were first treated with benzodiazepines with little to no effect. They then received a three vial antivenom bolus with resolution of severe symptoms within 30-60 min. DISCUSSION: Severe Centruroides envenomation can occur in adults as well as children. These three cases demonstrate the usefulness, safety, and effectiveness of antivenom therapy to quickly relieve symptoms in adult patients with grades III & IV envenomations. PMID- 28871820 TI - Acute heart failure presentations and outcomes during the fasting month of Ramadan: an observational report from seven Middle Eastern countries. AB - BACKGROUND: Fasting during the month of Ramadan is practiced by over 1.5 billion Muslims worldwide. It remains unclear, however, how this change in lifestyle affects heart failure, a condition that has reached epidemic dimensions. This study examined the effects of fasting in patients with acute heart failure (AHF) using data from a large multi-center heart failure registry. METHODS AND RESULTS: Data were derived from Gulf CARE (Gulf aCute heArt failuRe rEgistry), a prospective multi-center study of consecutive patients hospitalized with AHF during February-November 2012. The study included 4,157 patients, of which 306 (7.4%) were hospitalized with AHF in the fasting month of Ramadan, while 3,851 patients (92.6%) were hospitalized in other days. Clinical characteristics, precipitating factors, management, and outcome were compared among the two groups. Patients admitted during Ramadan had significantly lower prevalence of symptoms and signs of volume overload compared to patients hospitalized in other months. Atrial arrhythmias were significantly less frequent and cholesterol levels were significantly lower in Ramadan. Hospitalization in Ramadan was not independently associated with increased immediate or 1-year mortality. CONCLUSIONS: The current study represents the largest evaluation of the effects of fasting on AHF. It reports an improved volume status in fasting patients. There were also favorable effects on atrial arrhythmia and total cholesterol and no effects on immediate or long-term outcomes. PMID- 28871824 TI - Abstracts for the 11th International Neural Transplantation and Repair Meeting Held in Conjunction with the 18th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28871823 TI - Characterization of polysaccharides purified from Lacquer tree seed cakes and its antioxidant activity. AB - Three polysaccharides, LTPS-1, LTPS-21 and LTPS-31 were isolated and purified from the seed cakes of lacquer tree using DEAE-52 cellulose and Sephadex G-200 column chromatography. The total sugar contents of LTPS-1, LTPS-21 and LTPS-31 were 931.8, 958.2 and 895.1 g kg-1, respectively. LTPS-1 (3.48 kDa) was mainly composed of rhamnose, arabinose, glucose and galactose in a ratio of 35.36:5.06:1:2. LTPS-21 (11.4 kDa) was mainly composed of rhamnose, arabinose, mannose and galactose in a ratio of 41.93:21.8:1.01:9.24. LTPS-31 (19.49 kDa) was mainly composed of rhamnose, arabinose and mannose in a ratio of 38.31:16.44:1.1. IR analysis suggested they contained lower sulphuric acids, the LTPS-21 and LTPS 31 belonged to beta-type polysaccharide. Among the three polysaccharides, LTPS-21 exhibited the strongest reducing power, scavenging activity on ABTS and hydroxyl radicals. These findings suggested that polysaccharides from the seed cakes could be potentially developed as natural functional ingredients in the food and cosmetic industry. PMID- 28871825 TI - The effects of ex vivo ozone treatment on human erythrocyte carbonic anhydrase enzyme. AB - Ozone autohemotherapy is used in the treatment of some diseases. Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes and play a role in homeostatic mechanisms. The aim of this study was to investigate the effects of ozone on human red blood cell CA (hCA) enzyme activity. Blood samples were treated with different doses of ozone (10, 20, 30 ug/ml) and the erythrocyte total CA activities were determined. Also, purified hCAI and hCAII isozymes were treated with the same doses of ozone and the enzyme activities were measured. About 30 ug/ml ozone treatment decreased the purified hCAI and hCAII activity and increased the total CA activity compared to the control. Because the implication of CAs on many physiological and biochemical processes is linked to pathologies, it can be suggested that the ozone at a concentration of 30 ug/ml is safely used by autohaemotherapy in a well-designed clinical trial. PMID- 28871826 TI - Baicalin induces apoptosis in human osteosarcoma cell through ROS-mediated mitochondrial pathway. AB - Baicalin is extracted from a traditional Chinese herb, Scutellaria baicalensis. In this study, the anticancer activity and underlying mechanisms of baicalin towards human osteosarcoma cell (HOS) were investigated. Baicalin could inhibit HOS cell proliferation in a concentration-dependent manner. Mitochondrial membrane potential decreased obviously after treated with different concentration of baicalin by flow cytometry assay and revealed that baicalin triggered a significant generation of reactive oxygen species (ROS). Western blotting assay further revealed that baicalin-induced cell apoptosis by suppressing Bcl-2 level, then activating caspase-9 and caspase-3. In vivo experiment, baicalin significantly suppressed tumour growth in female BALB/C nude mice bearing HOS tumours. In addition, baicalin did show toxicity to treated animal by comparing the body weight increase and mortality. In general, the present results demonstrated that baicalin-induced apoptosis in human osteosarcoma cell via a ROS mediated mitochondrial pathway. The paper indicated that baicalin is a promising candidate for the treatment of HOS. PMID- 28871827 TI - Synthesis and evaluation of antitumour activity in vitro and in vivo of chrysin salicylate derivatives. AB - A series of chrysin salicylate derivatives as potential antitumour agents were synthesised and evaluated their antitumour activities in vitro and in vivo. Most of the compounds exhibited moderate to good activities against MCF-7 cells, HepG2 cells, MGC-803cells and MFC cells. Among them, compound 3f showed the most potent activity against MGC-803 cells and MFC cells with IC50 values of 23.83 +/- 3.68 and 27.34 +/- 5.21 MUM, respectively. The flow cytometry assay reconfirmed that compound 3f promoted the occurrence of tumour cells' G1/S block under the inhibiting effect of compound 3f. Compound 3f possessed higher antitumour efficacy in tumour-bearing mice, compared with the positive control 5-Fu and the blank control saline. PMID- 28871828 TI - Eating behaviors and emotional distress are predicted by treatment and adverse outcome in patients with type 2 diabetes. AB - Depression and anxiety are hightly prevalent among patients with Type 2 Diabetes (T2D), however not commonly related to outcomes, treatment and comorbidities. Eating behaviors could also have an implication. To evaluate the relation between mood and eating behaviors with demographic, physical, treatment, biochemical profiles and chronic comorbidities in T2D we conducted this exploratory cross sectional study in a population from Mexico. Hospital Anxiety and Depression Scale and the Three Factor Eating Questionnaire Revised 21 (TFEQ-R21) were correlated with age, gender, blood pressure, treatment and comorbidities (nephropathy, neuropathy, retinopathy and cardiopathy). Multi-linear regression models and 2k factorial analyses were conducted. Sixty-one patients (31 male) 55 years old (SD 13) with at least 5 years of T2D were included. Anxiety correlated with depression (r = 0.25, p < 0.05). Gender (women) (std B 0.026, p < 0.001), insulin therapy (std B 0.3, p = 0.11), systolic blood pressure (std B 0.263, p = 0.02) and cardiovascular disease (std B 0.232, p = 0.035) predicted depression. Insulin therapy had a positive effect in cognitive restraint. (std B 0.32, p = 0.001). Age (std B 0.37, p = 0.003) and systolic blood pressure (std B 0.237, p = 0.048) predicted positively emotional eating (not previously published). 2k factorial analyses proved additive interaction between complications and insulin therapy with depression. This study supports the relation between mood disorders and eating behaviors with demographic, physical, treatment, biochemical profiles and chronic comorbidities in T2D and the additive interaction between factors and mood disorders. PMID- 28871829 TI - Effects of high hydrostatic pressure on the functional and rheological properties of the protein fraction extracted from pine nuts. AB - High hydrostatic pressure treatments could increase the protein solubility (200 MPa), water holding capacity (400 MPa), and oil holding capacity (400 MPa) of pine nuts protein fractions, respectively. The exposed sufhydryl content for albumin was highest at 100 MPa while for other fractions it was 400 MPa, contrary for total sufhydryl content-generally it was at 100 MPa, except glutelin (400 MPa). Pine nuts protein fractions demonstrated the typical behavior of weak gels (G' > G"). After the treatments of high hydrostatic pressure the specific surface area of pine nuts protein particle was increased upon pressure, and the surface of protein became rough which increased the particle size. The functional groups of protein were found to be unchanged, but the characteristic peaks of pine nuts protein moved to a low-band displacement and the value of peaks was amplified accordingly to the pressure. The high hydrostatic pressure treatments were found to improve the functional properties of pine nuts protein isolates by enhancing the heat-induced gel strength of pine nuts protein isolates which make proteins more stretchable. These results suggest that high hydrostatic pressure treatments can increase the functional properties and alter the rheological properties of pine nuts protein fractions which will broaden its applications in food industry. PMID- 28871831 TI - Identification of some novel xanthine-based derivatives with bronchodilator activity. AB - AIM: The discovery of new bronchodilators with higher efficacy than theophylline is an important issue for asthmatic patients. MATERIALS & METHODS: Theophylline 2, 8-bromotheophylline 4 and theobromine 6 were reacted with different 2/3-chloro N-phenylacetamides 1a-d or their propanamide analogs 1e-g to obtain 3a-g, 5a-g and 7a-g, respectively. The target compounds were screened for their in vitro bronchodilator activity using isolated guinea pig tracheal rings precontracted with histamine and compared with their precursors. RESULTS: Many compounds exhibited promising activity especially 3d, 3f, 5d, 7d and 7e. 2D-QSAR study resulted in a significant model (N = 24, n = 5, R 2 = 0.848, R 2cvOO = 0.748, R 2cvMO = 0.745, F = 21.215, s 2 = 0.0002) using CODESSA-Pro software. CONCLUSION: These compounds can be considered as promising hits for potent bronchodilators that may be useful for further investigations. [Formula: see text]. PMID- 28871830 TI - Comparison of panoramic radiography and cone beam CT in the assessment of juxta apical radiolucency. AB - OBJECTIVES: To compare the performance of panoramic radiography (PAN) and cone beam CT (CBCT) in the detection of juxta-apical radiolucency (JAR), as well as to investigate, in CBCT images, if there are factors associated with the detection of JAR on PAN. METHODS: Two oral radiologists assessed the presence of JAR in PAN and CBCT images of 175 individuals (308 mandibular third molars). The cortical plates involvement and the JAR size and location were assessed on CBCT to evaluate if these factors were related to JAR detection on PAN. McNemar's test and multiple logistic regression were performed. RESULTS: PAN and CBCT differed significantly in the detection of JAR (p = 0.001). On PAN, JAR was identified on 24% of the patients while on CBCT its detection increased to 32.6%. JAR was detected only on CBCT and only on PAN in 26 and 7 cases, respectively. Distal/mesial surfaces of dental roots were where JAR was mostly located (84.5%), cortical thinning was found in 59.2% of cases and the mean (SD) of JAR size was 5.03 (+/-1.8) mm. However, these factors were not associated with JAR detection on PAN (p > 0.05). On the other hand, the location of the cortical involvement (if buccal or lingual) was associated with JAR detection on PAN, which was more detectable when the thinning was on buccal cortical. CONCLUSIONS: Juxta-apical radiolucency is more often detected on CBCT than on PAN. JAR detection on PAN was improved when it was related to the buccal cortical plate of the mandible. PMID- 28871833 TI - Facing Death in Medical Training: A View From Students in Mexico. AB - This study explores how medical students feel about caring for terminally ill patients as well as how their medical courses prepare them for addressing end-of life (EOL) issues with patients. Four hundred and five Mexican medical students were surveyed through the Student Views on Death questionnaire. The vast majority of students (94%) felt that physicians should inform patients of their impending death. Most students said they felt comfortable talking with (61%) or examining (76%) terminally ill patients. However, only half the students actually talked with patients about death. Participants in our study were interested in learning about EOL medical attention, yet most considered themselves poorly prepared to offer this type of care to terminally ill patients. The study provides objective data on a topic that has scarcely been explored in Mexico, data that will be useful in designing educational activities to improve EOL medical training. PMID- 28871832 TI - Adding Fish Oil to Whey Protein, Leucine, and Carbohydrate Over a Six-Week Supplementation Period Attenuates Muscle Soreness Following Eccentric Exercise in Competitive Soccer Players. AB - Soccer players often experience eccentric exercise-induced muscle damage given the physical demands of soccer match-play. Since long chain n-3 polyunsaturated fatty acids (n-3PUFA) enhance muscle sensitivity to protein supplementation, dietary supplementation with a combination of fish oil-derived n-3PUFA, protein, and carbohydrate may promote exercise recovery. This study examined the influence of adding n-3PUFA to a whey protein, leucine, and carbohydrate containing beverage over a six-week supplementation period on physiological markers of recovery measured over three days following eccentric exercise. Competitive soccer players were assigned to one of three conditions (2 * 200 mL): a fish oil supplement beverage (FO; n = 10) that contained n-3PUFA (1100 mg DHA/EPA approximately 550 mg DHA, 550 mg EPA), whey protein (15 g), leucine (1.8 g), and carbohydrate (20 g); a protein supplement beverage (PRO; n = 10) that contained whey protein (15 g), leucine (1.8 g), and carbohydrate (20 g); and a carbohydrate supplement beverage (CHO; n = 10) that contained carbohydrate (24 g). Eccentric exercise consisted of unilateral knee extension/flexion contractions on both legs separately. Maximal force production was impaired by 22% during the 72-hour recovery period following eccentric exercise (p < 0.05). Muscle soreness, expressed as area under the curve (AUC) during 72-hour recovery, was less in FO (1948 +/- 1091 mm * 72 h) than PRO (4640 +/- 2654 mm * 72 h, p < 0.05) and CHO (4495 +/- 1853 mm * 72 h, p = 0.10). Blood concentrations of creatine kinase, expressed as AUC, were ~60% lower in FO compared to CHO (p < 0.05) and tended to be lower (~39%, p = 0.07) than PRO. No differences in muscle function, soccer performance, or blood c-reactive protein concentrations were observed between groups. In conclusion, the addition of n-3PUFA to a beverage containing whey protein, leucine, and carbohydrate ameliorates the increase in muscle soreness and blood concentrations of creatine kinase following eccentric exercise in competitive soccer players. PMID- 28871834 TI - Changing Attitudes Toward Euthanasia and Suicide for Terminally Ill Persons, 1977 to 2016: An Age-Period-Cohort Analysis. AB - Several longitudinal studies show that over time the American public has become more approving of euthanasia and suicide for terminally ill persons. Yet, these previous findings are limited because they derive from biased estimates of disaggregated hierarchical data. Using insights from life course sociological theory and cross-classified logistic regression models, I better account for this liberalization process by disentangling the age, period, and cohort effects that contribute to longitudinal changes in these attitudes. The results of the analysis point toward a continued liberalization of both attitudes over time, although the magnitude of change was greater for suicide compared with euthanasia. More fluctuation in the probability of supporting both measures was exhibited for the age and period effects over the cohort effects. In addition, age-based differences in supporting both measures were found between men and women and various religious affiliations. PMID- 28871835 TI - Peer Support Services for Bereaved Survivors: A Systematic Review. AB - This systematic literature review assesses the evidence regarding benefits of peer support services for bereaved survivors of sudden or unexpected death. Reports were included that addressed peer support services for adults who experienced death of a family member, close friend, or coworker. Of the 32 studies meeting all inclusion criteria, most showed evidence that peer support was helpful to bereaved survivors, reducing grief symptoms and increasing well being and personal growth. Studies also showed benefits to providers of peer support, including increased personal growth and positive meaning in life. Several studies addressed the growing trend of Internet-based peer support programs, finding that these are beneficial in part due to their easy accessibility. Peer support appears to be especially valuable for survivors of suicide loss, a result that may be related to stigma and lack of support from family and friends experienced by many suicide survivors. The reviewed studies provide consistent evidence that peer support is beneficial to bereaved survivors. PMID- 28871836 TI - Vocal Fold Immobility due to Birth Trauma: A Systematic Review and Pooled Analysis. AB - Objectives To describe the present understanding of birth trauma-related vocal fold immobility and quantitatively compare it with idiopathic congenital vocal fold immobility to explore whether it is a discrete entity. Data Sources PubMed, Ovid, and Cochrane databases. Review Methods English-language, observational, or experimental studies involving infants with idiopathic congenital or birth trauma related vocal fold immobility were included. Data from these studies were pooled with our institution's vocal fold immobility database, with the resultant idiopathic congenital and birth trauma cohorts compared regarding patterns and outcomes of immobility. Results The search returned 288 articles, with 24 meeting inclusion criteria. Of studies reviewing all-cause immobility, 8 of 9 (88.9%) identified birth trauma as an etiology, although birth trauma definitions and proposed mechanisms of immobility varied. The study subjects, combined with our institution's database, yielded 188 idiopathic congenital and 113 birth trauma cases. Compared with idiopathic congenital cases, birth trauma cases had a higher proportion of unilateral immobility (72 of 113 [63.7%] vs 52 of 188 [27.7%], P < .001) and rate of resolution (41 of 51 [80.4%] vs 91 of 159 [57.2%], P = .003). Resolution occurred in 24 of 26 (91.3%) unilateral and 17 of 25 (68.0%) bilateral birth trauma cases and in 30 of 40 (75.0%) unilateral and 59 of 109 (54.1%) bilateral idiopathic congenital cases ( P = .11 and .20, respectively). Conclusion While the definition and mechanism of birth trauma-related vocal fold immobility warrant further investigation, these findings suggest that it is distinct from idiopathic congenital vocal fold immobility, with a unique presentation and potentially more favorable outcomes. This can inform counseling and management for infants with otherwise unexplained immobility but known birth trauma. PMID- 28871837 TI - Sweat Sodium Concentration: Inter-Unit Variability of a Low Cost, Portable, and Battery Operated Sodium Analyzer. AB - The B-722 Laqua Twin is a low cost, portable, and battery operated sodium analyzer, which can be used for the assessment of sweat sodium concentration. The Laqua Twin is reliable and provides a degree of accuracy similar to more expensive analyzers; however, its interunit measurement error remains unknown. The purpose of this study was to compare the sodium concentration values of 70 sweat samples measured using three different Laqua Twin units. Mean absolute errors, random errors and constant errors among the different Laqua Twins ranged respectively between 1.7 mmol/L to 3.5 mmol/L, 2.5 mmol/L to 3.7 mmol/L and -0.6 mmol/L to 3.9 mmol/L. Proportional errors among Laqua Twins were all < 2%. Based on a within-subject biological variability in sweat sodium concentration of +/- 12%, the maximal allowable imprecision among instruments was considered to be L 6%. In that respect, the within (2.9%), between (4.5%), and total (5.4%) measurement error coefficient of variations were all < 6%. For a given sweat sodium concentration value, the largest observed difference in mean and lower and upper bound error of measurements among instruments were, respectively, 4.7 mmol/L, 2.3 mmol/L, and 7.0 mmol/L. In conclusion, our findings show that the interunit measurement error of the B-722 Laqua Twin is low and methodologically acceptable. PMID- 28871838 TI - Availability of Health-Related Programs in Private and Public Prisons. AB - Little is known about the resources available to protect inmates' health in private prisons compared to their public counterparts. This is the first national level study that exclusively examined the availability of health-related programs in private and public prisons in the United States. We applied propensity score weighting and doubly robust estimation to compare private prisons to comparable public prisons. Data were self-reported by prison administrators as part of the 2005 Census of State and Federal Adult Correctional Facilities. We found that private prisons offered fewer substance dependency, psychological/psychiatric, and HIV/AIDS-related programs. But the differences were progressively reduced when the comparison was limited to public prisons most similar on a variety of facility-level characteristics. The extent to which the two types of prisons differ is closely tied to the characteristics of the facilities that are compared. PMID- 28871839 TI - Association between Asthma and Chronic Rhinosinusitis Severity in the Context of Asthma Control. AB - Objective Comorbid asthma is associated with decreased quality of life (QOL) in chronic rhinosinusitis (CRS). It is unclear whether this association is independent of the patients' clinical asthma status. We therefore sought to determine if asthma is associated with lower QOL in CRS, independent of asthma control. Study Design Cross-sectional cohort study of 350 patients with CRS. Setting Tertiary academic rhinology clinic. Subjects and Methods In total, 350 participants with CRS were recruited and 28.3% were asthmatic. CRS-specific QOL was measured using the 22-item Sinonasal Outcome Test (SNOT-22). Asthma control was assessed with the Asthma Control Test (ACT). General health-related QOL was assessed with the EuroQoL 5-dimensional general health-related quality of life survey visual analog scale (EQ-5D VAS). Associations were sought between SNOT-22 and EQ-5D VAS (dependent variables) and asthma (independent variable), while controlling for ACT. ACT score for patients with CRS without asthma was set at 25 (indicating completely controlled, asymptomatic asthma). Results Comorbid asthma was associated with SNOT-22 (beta = 11.8; 95% confidence interval [CI], 6.2-17.3; P < .001) and EQ-5D VAS (beta = -6.2; 95% CI, -11.2 to -1.3; P = .014). After controlling for ACT, asthma was no longer associated with SNOT-22 ( P = .147) or EQ-5D VAS ( P = .994). Instead, ACT score was associated with SNOT-22 (beta = 2.1; 95% CI, -3.2 to -1.1; P < .001) and EQ-5D VAS (beta = 2.1; 95% CI, 1.1 to 3.0; P < .001). ACT score completely drove the association between asthma and worse QOL. Conclusion Comorbid asthma is not necessarily reflective of decreased QOL in CRS. The association of comorbid asthma with lower QOL in CRS is related to the clinical status (eg, control) of asthma. PMID- 28871840 TI - Lingual Tonsillectomy for Pediatric Persistent Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. AB - Objective To determine the role of lingual tonsillectomy (LT) in pediatric patients with persistent obstructive sleep apnea (OSA) after tonsillectomy and adenoidectomy (T&A). Data Sources PubMed, OVID-MEDLINE, and Cochrane Central from 2006 to 2017. Review Methods Inclusion criteria included English-language studies containing original data on LT in pediatric patients with persistent OSA. Exclusion criteria included case reports and studies without outcome measures. Two investigators independently reviewed all manuscripts and performed quality assessment using validated tools. Meta-analysis was performed. Results Of the 866 abstracts identified, 5 studies met inclusion criteria. All studies were case series (level of evidence 4). Outcome measures included apnea-hypopnea index (AHI), minimum oxygen saturation (minSaO2), comorbidity status, and adverse events. Qualitatively, all studies demonstrated reduction in AHI and increase in minSaO2 after LT. Comorbidities may not affect the success of LT for lingual tonsil hypertrophy (LTH). LT had similar adverse event rates as T&A. Meta analysis was performed on 4 studies. LT showed a mean change in reduction of AHI and increase of minSaO2 of -6.64 (95% CI, -8.63 to -4.65) and 4.17 (95% CI, 1.25 7.08), respectively. The overall success rate, defined as postoperative AHI <5, was 52%. Conclusion LT for LTH can be a safe and effective adjunct surgery for persistent OSA in patients after T&A. LT may reduce AHI and increase minSaO2, though complete resolution of OSA is rare. Given the limited number of patients studied, no formal recommendations can be made for the routine use of LT for LTH in persistent pediatric OSA. PMID- 28871841 TI - Men and suicide prevention: a scoping review. AB - BACKGROUND: Male suicide rates are higher than their female counterparts in almost every country around the world. Several developed countries have attempted to implement suicide prevention programmes, but few have specifically targeted men. AIMS: To identify what is currently known about suicide prevention strategies, programmes, and interventions of relevance to men. METHOD: A scoping review guided by Arksey and O'Malley's five-stage framework. RESULTS: Twenty-two studies were included. Thematic analysis identified three categories: (i) male suicide prevention interventions; (ii) factors or coping strategies that interrupt the suicidal process in men; (iii) men's perspectives on service provision. Interventions included awareness campaigns; training of community "gatekeepers"; psychological support; and educational initiatives targeted to either GPs or depressed or suicidal men. Men emphasised the need to receive support from a trusted and respected individual, preferably in an informal setting. Connecting with others, reframing help-seeking as masculine, and the use of emotional regulation techniques were all identified as factors with potential to interrupt the suicidal process. CONCLUSIONS: This review demonstrates the need for further research examining the perspectives of suicidal middle-aged men and their close family and friends. PMID- 28871842 TI - Retraction of Complaints Among Female Victims of Intimate Partner Violence Living in Poverty in Nicaragua. AB - Retraction among female victims of intimate partner violence (IPV) who report their abuser is a major problem in all societies. This article describes a study of 136 female victims of physical IPV living in poverty in Nicaragua, one of the countries with the lowest levels of development in Central America. This article analyses the aspects that differentiate women living in poverty who retracted after reporting IPV from those who did not. The results show that retraction is widespread among female victims of IPV living in poverty in Leon (Nicaragua). Although it is difficult to predict the retraction behaviour of the respondents, some differences between the women who retracted their complaint and those who did not were observed. A combination of five variables (including personal circumstances and beliefs about the intimate partner relationship and family) was the best alternative for discriminating between women who had retracted and those who had not. PMID- 28871843 TI - Immunotherapies for advanced melanoma: as promising as they are expensive? PMID- 28871844 TI - Management of Bleeding in Exclusive Endoscopic Ear Surgery: Pilot Clinical Experience. AB - Objective Transcanal exclusive endoscopic ear surgery requires the management of the endoscope and the surgical instruments in the external auditory canal. Bleeding in this narrow space is one of the most challenging issues, especially for novice endoscopic ear surgeons. We aim to assess the severity and occurrence of bleeding and describe strategies to control the bleeding during endoscopic ear surgery. We hypothesize that bleeding is reasonably controllable in endoscopic ear surgery. Study Design Case series with chart review. Setting Tertiary referral center. Subjects and Methods We retrospectively assessed 104 consecutive cases of exclusive endoscopic ear surgery at the University Hospital of Modena, Italy. The surgical videos and the patient charts were carefully investigated and analyzed. Results Hemostatic agents included injection of diluted epinephrine (1:200,000, 2% mepivacaine), cottonoids soaked with epinephrine (1:1000), mono- or bipolar cautery, washing with hydrogen peroxide, and self-suctioning instruments. The localization of bleeding in the external auditory canal was most frequently the posterior superior part, and inside of the middle ear, it was the pathology itself. Statistical analysis revealed significant differences comparing the mean arterial pressure and the type of intervention among bleeding scores. Conclusion The management of bleeding in endoscopic ear surgery is feasible through widely available hemostatic agents in reasonable frequency. This study gives an instructive overview on how to manage the bleeding in the exclusive endoscopic technique. Even the highest bleeding scores could be managed in an exclusively endoscopic technique. PMID- 28871845 TI - Accuracy of Parental Perception of Nighttime Breathing in Children with Down Syndrome. AB - Objective In 2011, the American Academy of Pediatrics published a guideline for children with Down syndrome (DS), recommending a polysomnogram (PSG) by age 4 years regardless of symptoms. Their rationale was based on 2 publications with small cohorts, where at least 50% of the children had no obstructive sleep apnea (OSA) symptoms but their PSG results were abnormal. The American Academy of Otolaryngology-Head and Neck Surgery Foundation published a clinical practice guideline recommending PSG prior to adenotonsillectomy for these children. This study aimed to assess parents' accuracy of their children's breathing patterns as compared with PSGs in a larger cohort of children with DS. Study Design Case series with chart review. Setting Tertiary care academic pediatric hospital. Subjects and Methods Sleep intake forms assessing frequency of parent-observed apnea, snoring, and restless sleep were analyzed. None of the children had a previous tonsillectomy. Two groups were analyzed according to symptoms: infrequent (<3 nights per week on all questions answered) and frequent (>=6 nights per week on at least 1 question). OSA severity was categorized as follows: normal, <2 events per hour; mild, 2 to 4.9; moderate, 5 to 9.9; and severe, >=10. Results A total of 113 children met inclusion criteria: 34% (n = 38) had infrequent symptoms, and 66% (n = 75) had frequent symptoms. Parents were unable to predict the presence or absence of OSA by nighttime symptoms ( P = .60). The risk of OSA for children with frequent symptoms versus those with infrequent symptoms was 1.04 (95% CI, 0.89-1.3). Conclusion Parents of DS children are unable to predict the presence or absence of OSA by nighttime symptoms, nor are they able to determine its severity. PMID- 28871846 TI - Traits of vulnerability in repetitive sexual assaults of mentally disabled people. AB - The issue of sexual abuse, assault, rape and unwanted pregnancies among mentally disabled women is largely under-reported for many reasons. Several myths prevail including that mentally disabled women offer little interest to sexual predators, together with a negative public attitude and this contributes to the problem. We report the case of a single centre in Albania, where repetitive sexual assaults were perpetrated against three mentally disabled women. Three unwanted pregnancies followed. The issue gained public attention after three criminal abortions were performed secretly with the aim of covering up the story. Charges were raised against the director of the centre and an employee from the nursing staff. Proceedings are still ongoing. We discuss some details from the forensic investigation and consider several systemic weaknesses that have exposed this vulnerable target group to the risk of being severely and repetitively abused. We believe greater staff awareness, and a better medical and legal framework, are indispensable to deter further offences especially where facilities are under resourced as here. PMID- 28871847 TI - Single Nucleotide Polymorphisms in Carnosinase Genes (CNDP1 and CNDP2) are Associated With Power Athletic Status. AB - Carnosine (beta-alanyl-L-histidine), abundantly found in skeletal muscle, plays an important role during exercise, especially for high-intensity contractions. Variability in muscle carnosine content between individuals exists and may also be explained by different genetic bases, although no study has addressed the association of polymorphisms in genes related to carnosine metabolism in athletes. This study aimed to investigate the frequency of single nucleotide polymorphisms (SNPs) in the carnosinase genes (CNDP1 and CNDP2) in a large Brazilian cohort of athletes and nonathletes. Eight SNPs were compared between a representative cohort of elite athletes from Brazil (n = 908) and a paired group of nonathletes (n = 967). The athletes were stratified into three groups: endurance (n = 328), power (n = 415), and combat (n = 165). The CNDP2 rs6566810 (A/A genotype) is overrepresented in endurance athletes, but only in international-level endurance athletes. Three SNPs (CNDP2 rs3764509, CNDP2-CNDP1 rs2346061, and CNDP1 rs2887) were overrepresented in power athletes compared with nonathletes. Carriers of the minor allele had an increased odds ratio of being a power athlete. For the rs2346061, no significant difference was observed in genotype frequencies between power and combat sports athletes, but for rs2887 the power and combat groups showed an inverse genotype distribution. In conclusion, we found that minor alleles carriers for CNDP2 rs3764509 (G-allele), CNDP2-CNDP1 rs2346061 (C-allele), and CNDP1 rs2887 (A-allele) are more likely to be a power athlete. These polymorphisms may be novel genetic markers for power athletes. Furthermore, these results are suggestive of a distinct CNDP genotype for sporting development. PMID- 28871848 TI - Personality characteristics and individual factors associated with PTSD in firefighters one month after extended wildfires. AB - BACKGROUND: Firefighters participate in activities with intense physical and psychological stress and are constantly at risk to develop various psychopathological reactions. AIMS: To investigate psychological reactions in firefighters one month after devastating wildfires in Greece, during August 2007, which lead to the devastation of large areas and the death of 43 people among whom three were firefighters. METHODS: One month after the wildfires, a joint task force of mental health clinicians was organized in order to provide psychological support and to investigate the psychological consequences of wildfires to firefighters. One hundred and two firefighters, living within the fire-devastated area, who were on duty for the whole period of wildfires were interviewed and assessed with the use of several questionnaires and inventories. RESULTS: Post-traumatic stress disorder (PTSD) was detected in 18.6% of firefighters. Multiple logistic regression found that existence of fear of dying during firefighting, insomnia and increased scores in neuroticism, as well as in depression subscale of the SCL-90, were significantly associated with greater likelihood for having PTSD. Additionally those firefighters who worked permanently had 70% lower probability of having PTSD vs. those seasonally employed. CONCLUSIONS: Insomnia, depressive symptoms, as well as personality characteristics as neuroticism and the perception of fear of imminent death during firefighting operations may precipitate the development of PTSD in firefighters. Within this context, mental health clinicians should be aware that the early detection of these predisposing factors may facilitate the prevention and mitigation of PTSD in firefighters particularly those who are seasonally employed. PMID- 28871849 TI - Resistance Training Combined With Diet Decreases Body Fat While Preserving Lean Mass Independent of Resting Metabolic Rate: A Randomized Trial. AB - The purpose of this study was to determine the effects of resistance training only (RT; n = 10), dietary intervention only (DIET; n = 10), resistance training plus diet (RT+DIET; n = 10), and control (CON; n = 10) on body composition and resting metabolic rate (RMR) in a cohort of 40 premenopausal female volunteers. Subjects in DIET and RT+DIET were provided with daily macronutrient and calorie goals based on DXA and RMR tests, with protein maintained at 3.1 g/kg/day. Subjects in the RT and RT+DIET groups performed a supervised progressive RT program consisting of exercises for all the major muscle groups of the body. Results showed a significant month-by-group interaction for change in fat mass with no significant linear trend for control. The three treatment groups all showed significant linear decreases in fat mass, but the slope of the decrease became progressively steeper from the RT, to DIET, to RT+DIET. A significant linear increase for lean mass was seen for resistance training only. There was a nonsignificant increase in RMR in all groups from Month 0 to Month 4 but no significant month by group interaction. In conclusion, significant reductions in fat mass were achieved by all experimental groups, but results were maximized by RT+DIET. Only the RT group showed significant increases in lean mass. PMID- 28871850 TI - Succinoglycan Production Contributes to Acidic pH Tolerance in Sinorhizobium meliloti Rm1021. AB - In this work, the hypothesis that exopolysaccharide plays a role in the survival of Sinorhizobium meliloti at low pH levels is addressed. When S. meliloti was grown at pH 5.75, synthesis of succinoglycan increased, whereas synthesis of galactoglucan decreased. Succinoglycan that was isolated from cultures grown at low pH had a lower degree of polymerization relative to that which was isolated from cultures grown at neutral pH, suggesting that low-molecular weight (LMW) succinoglycan might play a role in adaptation to low pH. Mutants unable to produce succinoglycan or only able to produce high-molecular weight polysaccharide were found to be sensitive to low pH. However, strains unable to produce LMW polysaccharide were 10-fold more sensitive. In response to low pH, transcription of genes encoding proteins for succinoglycan, glycogen, and cyclic beta(1-2) glucans biosynthesis increased, while those encoding proteins necessary for the biosynthesis of galactoglucan decreased. While changes in pH did not affect the production of glycogen or cyclic beta(1-2) glucan, it was found that the inability to produce cyclic beta(1-2) glucan did contribute to pH tolerance in the absence of succinoglycan. Finally, in addition to being sensitive to low pH, a strain carrying mutations in exoK and exsH, which encode the glycanases responsible for the cleavage of succinoglycan to LMW succinoglycan, exhibited a delay in nodulation and was uncompetitive for nodule occupancy. Taken together, the data suggest that the role for LMW succinoglycan in nodule development may be to enhance survival in the colonized curled root hair. PMID- 28871851 TI - Reliability and Precision of the Nana Protocol to Assess Body Composition Using Dual Energy X-Ray Absorptiometry. AB - The Nana positioning protocol is widely used to position participants to minimize technical error when undertaking body composition scanning and analysis with a Dual energy X-Ray absorptiometry (DXA) machine. Once biological and technical errors are accounted for, the only variation in test-retest results is from statistical fluctuation or machine error. Therefore, the aim of this study is to assess the test-retest reliability of the Nana positioning protocol and establish the smallest real difference percentage (SRD%). A gender-balanced group of 30 participants (15 males, 15 females) underwent two scans in succession using the Nana positioning protocol, with repositioning between scans. Percentage change in mean with typical error, Intraclass Correlation Coefficients (ICC), and standard error measurement percentage (SEM%) were used to identify the test-retest reliability and error rate of these protocols. Additionally, SRD% was calculated to assess the point at which clinically important changes occurred in a participant. The reliabilities of the whole body and regional scans were excellent. Percentage change in mean ranged between 0.00% and 0.23%. High reproducibility of the Nana positioning protocol was evident through an ICC ranging between 0.966-1.000. Additionally, typical error, SEM%, and SRD% were all low. Interestingly, fat mass was associated with the largest fluctuations observed to be associated with any of the parameters assessed. When all sources of biological and technical errors have been accounted for, the Nana positioning protocol has excellent test-retest reliability and produces low SEM% and SRD%. PMID- 28871852 TI - Recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin infusion in primary immunodeficiency diseases. AB - Most primary immunodeficiency diseases (PIDDs) resulting in antibody deficiency require intravenous or subcutaneous immunoglobulin G (SCIG) replacement therapy. The flow and distribution of SCIG to the vasculature is impeded by the glycosaminoglycan hyaluronan in the extracellular matrix, which limits the infusion rate and volume per site, necessitating frequent infusions and multiple infusion sites. Hyaluronidase depolymerizes hyaluronan and is a spreading factor for injectable biologics. Recombinant human hyaluronidase (rHuPH20) increases SCIG absorption and dispersion. In patients with PIDD, SCIG facilitated with rHuPH20 (IGHy) has been shown to prevent infections, be well-tolerated and reduce infusion frequency and number of infusion sites as compared with conventional SCIG. This article reviews IGHy clinical studies and real-world practice data in patients with PIDD. PMID- 28871855 TI - Additional Abstracts for the 13th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28871854 TI - Repairing the Nervous System: A Special Issue Based on the 12th Annual American Society for Neural Therapy and Repair (ASNTR) Meeting. PMID- 28871853 TI - Effect of a participatory multisectoral maternal and newborn intervention on maternal health service utilization and newborn care practices: a quasi experimental study in three rural Ugandan districts. AB - BACKGROUND: The MANIFEST study in eastern Uganda employed a participatory multisectoral approach to reduce barriers to access to maternal and newborn care services. OBJECTIVES: This study analyses the effect of the intervention on the utilization of maternal and newborn services and care practices. METHODS: The quasi-experimental pre- and post-comparison design had two main components: community mobilization and empowerment, and health provider capacity building. The primary outcomes were utilization of antenatal care (ANC), delivery and postnatal care, and newborn care practices. Baseline (n = 2237) and endline (n = 1946) data were collected from women of reproductive age. The data was analysed using difference in differences (DiD) analysis and logistic regression. RESULTS: The DiD results revealed an 8% difference in early ANC attendance (p < 0.01) and facility delivery (p < 0.01). Facility delivery increased from 66% to 73% in the intervention area, but remained unchanged in the comparison area (64% vs 63%, p < 0.01). The DiD results also demonstrated a 20% difference in clean cord care (p < 0.001) and an 8% difference in delayed bathing (p < 0.001). The intervention elements that predicted facility delivery were attending ANC four times [adjusted odds ratio (aOR) 1.42, 95% confidence interval (CI) 1.17-1.74] and saving for maternal health (aOR 2.11, 95% CI 1.39-3.21). Facility delivery and village health team (VHT) home visits were key predictors for clean cord care and skin-to skin care. CONCLUSIONS: The multisectoral approach had positive effects on early ANC attendance, facility deliveries and newborn care practices. Community resources such as VHTs and savings are crucial to maternal and newborn outcomes and should be supported. VHT-led health education should incorporate practical measures that enable families to save and access transport services to enhance adequate preparation for birth. PMID- 28871856 TI - Prolonged Allogeneic Islet Graft Survival by Protoporphyrins. AB - Transplantation of islets of Langerhans in patients with type 1 diabetes allows for improved metabolic control and insulin independence. The need for chronic immunosuppression limits this procedure to selected patients with brittle diabetes. Definition of therapeutic strategies allowing permanent engraftment without the need for chronic immunosuppression could overcome such limitations. We tested the effect of the use of protoporphyrins (CoPP and FePP), powerful inducers of the cytoprotective protein hemeoxygenase 1 (HO-1), on allogeneic islet graft survival. Chemically induced diabetic C57BL/6 mice received DBA/2 islets. Treatment consisted in peritransplant administration of CoPP or saline. Islets were either cultured in the presence of FePP or vehicle before implant. Short-course administration of CoPP led to long-term islet allograft survival in a sizable proportion of recipients. Long-term graft-bearing animals rejected third-party islets while accepting a second set donor-specific graft permanently, without additional treatment. Preconditioning of islets with FePP by itself led to improved graft survival in untreated recipients, and provided additional advantage in CoPP-treated recipients, resulting in an increased proportion of long-term surviving grafts. Preconditioning of the graft with protoporphyrins prior to implant resulted in reduction of class II expression. Administration of protoporphyrins to the recipients of allogeneic islets also resulted in transient powerful immunosuppression with reduced lymphocyte proliferative responses, increased proportion of regulatory cells (CD4+CD25+), decreased mononuclear cell infiltrating the graft, paralleled by a systemic upregulation of HO-1 expression. All these mechanisms may have contributed to the induction of donor-specific hyporesponsiveness in a proportion of the protoporphyrintreated animals. PMID- 28871857 TI - Encapsulation of Islets in Rough Surface, Hydroxymethylated Polysulfone Capillaries Stimulates VEGF Release and Promotes Vascularization after Transplantation. AB - The transplantation of encapsulated islets of Langerhans is one approach to treat type 1 diabetes without the need of lifelong immunosuppression. Capillaries have been used for macroencapsulation because they have a favorable surface-to-volume ratio and because they can be refilled. It is unclear at present whether the outer surface of such capillaries should be smooth to prevent, or rough to promote, cell adhesions. In this study we tested a new capillary made of modified polysulfone (MWCO: 50 kDa) with a rough, open-porous outer surface for islet transplantation. Compared with free-floating islets, encapsulation of freshly isolated rat islets affected neither the kinetics nor the efficiency of glucose induced insulin release in perifusion experiments. Free-floating islets maintained insulin secretion during cell culture but encapsulated islets gradually lost their glucose responsiveness and released VEGF. This indicated hypoxia in the capillary lumen. Transplantation of encapsulated rat islets into diabetic rats significantly reduced blood glucose concentrations from the first week of implantation. This hypoglycaemic effect persisted until explantation 4 weeks later. Transplantation of encapsulated porcine islets into diabetic rats reduced blood glucose concentrations depending on the islet purity. With semipurified islets a transient reduction of blood glucose concentrations was observed (2, 8, 18, 18 days) whereas with highly purified islets a sustained normoglycaemia was achieved (more than 28 days). Explanted capillaries containing rat islets were covered with blood vessels. Vascularization was also observed on capillaries containing porcine islets that were explanted from normoglycaemic rats. In contrast, on capillaries containing porcine islets that were explanted from hyperglycemic rats a fibrous capsule and lymphocyte accumulations were observed. No vascularization on the surface of transplanted capillaries was observed in the absence of islets. In conclusion, encapsulated islets can release VEGF, which appears to be an important signal for the vascularization of the capillary material. The rough, open-porous outer surface of the polysulfone capillary provides a site well suited for vascular tissue formation and may allow a prolonged islet function after transplantation. PMID- 28871858 TI - Evaluating the Effect of Serine Proteases on Collagenase Activity during Human Islet Isolation. AB - Inconsistencies in human islet yields after collagenase digestion have been attributed to the activation of endogenous enzymes of the donor pancreas. It has been suggested that pancreatic serine proteases contribute to the proteolysis of collagenase. This study defined the effects of endogenous enzymes within the pancreas on pancreas dissociation during collagenase digestion. Levels of collagenase activity from samples taken throughout several steps in islet isolation procedures, both with and without the addition of the serine protease inhibitor Pefabloc, were determined by a spectrophotometric assay using N-[3-(2 furyl)acryloyl]-Leu-Gly-Pro-Ala as the substrate. Results clearly demonstrated that the level of collagenase activity remains stable throughout the isolation procedure despite differences in the donor factors from several cadaveric donor pancreases. This was further demonstrated by observing no difference in activity levels after incubating commercial collagenase preparations with serine proteases and analyzing by means of collagenase activity and SDS-PAGE. These data show that the presence of serine proteases does not affect the level of collagenase activity; however, they likely damage the islet cells upon prolonged digestion of the pancreatic tissue. Further efforts at examining exogenous and endogenous enzyme levels may result in the development of an enzyme cocktail that is both stable and effective for digesting the human pancreas while preserving islet function and viability. PMID- 28871859 TI - Development of a Novel Cytomedical Treatment that can Protect Entrapped Cells from Host Humoral Immunity. AB - Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed "cytomedicine, " which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-l-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic beta-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy. PMID- 28871860 TI - Effects of variable power on tissue ablation dynamics during magnetic resonance guided laser-induced thermal therapy with the Visualase system. AB - PURPOSE: Magnetic resonance-guided laser-induced thermal therapy (MRgLITT) is a minimally invasive procedure used to treat various intracranial pathologies. This study investigated the effects of variable power on maximal estimated thermal damage during ablation and duration required to reach maximal ablation. MATERIALS/METHODS: All ablations were performed using the Visualase Thermal Therapy System (Medtronic Inc., Minneapolis, Minnesota), which uses a 980 nm diffusing tip diode laser. Cases were stratified into low, medium and high power. Maximal thermal damage estimate (TDEmax) achieved in a single plane and time to reach maximal damage (ttdemax) were measured and compared between groups using a 2*3 Fixed Factor Analysis of Covariance. Ablation area change for cases in which an initial thermal dose was followed by a subsequent dose, with increased power, was also assessed. RESULTS: We used real-time ablation data from 93 patients across various intracranial pathologies. ttdemax (mean +/- SEM) decreased linearly as power increased (low: 139.2 +/- 10.4 s, medium: 127.5 +/- 4.3 s, high: 103.7 +/- 5.8 s). In cases where a second thermal dose was delivered at higher power, the TDE expanded an average of 51.4 mm2 beyond the initial TDE generated by the first ablation, with the second ablation approaching TDEmax at a higher rate than the initial ablation. CONCLUSION: Increased power results in a larger TDEmax and an increased ablation rate. In cases where an initial thermal dose does not fully ablate the target lesion, a second ablation at higher power can increase the area of ablation with an increased ablation rate. PMID- 28871861 TI - Reduction of Aspergillus spp. and aflatoxins in peanut sauce processing by oil less frying of chilli powder and retort processing. AB - Among the many roles played by small and medium enterprises (SMEs) in the food industry is the production of heritage foods such as peanut sauce. Unfortunately, the safety of peanut sauce is not always assured as the processing line is not controlled. Peanut sauce is usually made of peanuts and chilli, and these commodities are normally contaminated with Aspergillus spp. and aflatoxins (AFs). Hence, the objective of this study was to evaluate the practices related to reduction of AF hazard and the effect of interventions in peanut sauce processing. Peanut samples were collected from each step of peanut sauce processing from a small peanut sauce company according to four designs: (1) control; (2) oil-less frying of chilli powder; (3) addition of retort processing; and (4) combination of oil-less frying of chilli powder and retort processing. Oil-less frying of chilli powder (Design 2) reduced total AFs by 33-41%, retort processing (Design 3) reduced total AFs by 49%, while combination of these two thermal processes (Design 4) significantly reduced total AFs, by 57%. The present work demonstrated that Design 4 yielded the highest reduction of total AFs and is therefore recommended to be employed by SME companies. PMID- 28871862 TI - Research and analysis of biogas produced from sewage sludge using a batch bioreactor. AB - The examined equipment is a batch bioreactor intended to produce biogas from sewage sludge, vegetal and other organic wastes. The maintenance of an optimal temperature and oxygen concentration inside the devise, as well as the intensity of mixing a substrate, result in methane CH4 actively generated by methanogenic bacterial colonies. Manufacturing biotechnologies and biogas deal with environmental protection, energy and economic problems. For research purposes, considering organic loading (hereinafter, VS/L), four different types of the packing material of sewage sludge, including VS/L = 3.5 g L-1, VS/L = 5.0 g L-1, VS/L = 10.0 g L-1 and VS/L = 15.0 g L-1, were used. The highest concentration of CH4 (75.1%) and yield of biogas (36.78 L d-1) were found using a packing material, the organic loading of which made 15.0 g L-1. Throughout the experiment, the temperature of the mesophilic process reached 35-37 degrees C, and the concentration of oxygen was 0.0-0.1%. The research carried out has disclosed the dependencies of the components of biogas on the number of the days of the performed experiment. With reference to experimental research conducted at the laboratory, a small-sized batch bioreactor can be designed and successfully used in a small farm. PMID- 28871863 TI - The HIV aspartyl protease inhibitor ritonavir impairs planktonic growth, biofilm formation and proteolytic activity in Trichosporon spp. AB - This study evaluated the effect of the protease inhibitor ritonavir (RIT) on Trichosporon asahii and Trichosporon inkin. Susceptibility to RIT was assessed by the broth microdilution assay and the effect of RIT on protease activity was evaluated using azoalbumin as substrate. RIT was tested for its anti-biofilm properties and RIT-treated biofilms were assessed regarding protease activity, ultrastructure and matrix composition. In addition, antifungal susceptibility, surface hydrophobicity and biofilm formation were evaluated after pre-incubation of planktonic cells with RIT for 15 days. RIT (200 MUg ml-1) inhibited Trichosporon growth. RIT (100 MUg ml-1) also reduced protease activity of planktonic and biofilm cells, decreased cell adhesion and biofilm formation, and altered the structure of the biofilm and the protein composition of the biofilm matrix. Pre-incubation with RIT (100 MUg ml-1) increased the susceptibility to amphotericin B, and reduced surface hydrophobicity and cell adhesion. These results highlight the importance of proteases as promising therapeutic targets and reinforce the antifungal potential of protease inhibitors. PMID- 28871864 TI - Quantifying the combined effects of pronase and benzalkonium chloride in removing late-stage Listeria monocytogenes-Escherichia coli dual-species biofilms. AB - This work presents the assessment of the effectivity of a pronase (PRN) benzalkonium chloride (BAC) sequential treatment in removing Listeria monocytogenes-Escherichia coli dual-species biofilms grown on stainless steel (SS) using fluorescence microscopy and plate count assays. The effects of PRN-BAC on the occupied area (OA) by undamaged cells in 168 h dual-species samples were determined using a first-order factorial design. Empirical equations significantly (r2 = 0.927) described a negative individual effect of BAC and a negative interactive effect of PRN-BAC achieving OA reductions up to 46%. After treatment, high numbers of remaining attached and released viable and cultivable E. coli cells were detected in PRN-BAC combinations when low BAC concentrations were used. Therefore, at appropriate BAC doses, in addition to biofilm removal, sequential application of PRN and BAC represents an appealing strategy for pathogen control on SS surfaces while hindering the dispersion of live cells into the environment. PMID- 28871865 TI - Proteomic analysis of silica hybrid sol-gel coatings: a potential tool for predicting the biocompatibility of implants in vivo. AB - The interactions of implanted biomaterials with the host organism determine the success or failure of an implantation. Normally, their biocompatibility is assessed using in vitro tests. Unfortunately, in vitro and in vivo results are not always concordant; new, effective methods of biomaterial characterisation are urgently needed to predict the in vivo outcome. As the first layer of proteins adsorbed onto the biomaterial surfaces might condition the host response, mass spectrometry analysis was performed to characterise these proteins. Four distinct hybrid sol-gel biomaterials were tested. The in vitro results were similar for all the materials examined here. However, in vivo, the materials behaved differently. Six of the 171 adsorbed proteins were significantly more abundant on the materials with weak biocompatibility; these proteins are associated with the complement pathway. Thus, protein analysis might be a suitable tool to predict the in vivo outcomes of implantations using newly formulated biomaterials. PMID- 28871866 TI - Ectopic Ossification in the Scar Tissue of Rats with Myocardial Infarction. AB - We describe the occurrence of bone-like formations in the left ventricular wall of infarcted rats treated or not with bone marrow cells injected systemically or locally into the myocardium. The incidence of ectopic calcification in hearts has been reported in rare cases in children with infarcts without previous coronary artery disease. Recently, ventricular calcification has been correlated with unselected bone marrow cell transplantation into infarcted rat hearts. Echocardiographic analysis of large infarction in rats frequently reveals the presence of echogenic structures in the left ventricular wall, sometimes projecting to the lumen of the chamber. The histological examination of these echogenic structures exhibited bone, cartilage, and marrowlike formations extending from the collagen-rich matrix of the ventricle wall. Microanalytical techniques verified the presence of hydroxyapatite in the mineral phase. Ossification was found in 25 out of 30 hearts evaluated 90 days postinfarct, being observed in 14 out of 17 animals submitted to cell therapy and in 11 out of 13 infarcted rats not submitted to cell therapy. Our study indicates that chondro osteogenic differentiation can take place in the pathological rat heart independent of animal treatment with marrow cells. PMID- 28871867 TI - Assessment of in Vitro Applicability of Reversibly Immortalized NKNT-3 Cells and Clonal Derivatives. AB - In vitro applications of human hepatocytes, such as bioartificial livers and toxicity assays, require thoroughly testing of human cell lines prior to using them as alternative cell sources. The reversibly immortalized NKNT-3 cell line was reported to show clear in vivo functionality. Here, NKNT-3 cells were tested for their in vitro applicability. Low-passage (P2) and high-passage (P28) NKNT-3 cells and clonal derivatives were characterized for reversion of immortalization, heterogeneity, and hepatic functionality. Reversion with reduced expression of immortalizing agent could be established. However, during culturing the cells lost the capacity to be selected for completed reversion. The phenotypic instability is probably associated with heterogeneity in the culture, as clonal derivatives of P2 cells varied in morphology, growth, and reversion characteristics. The mRNA levels of genes related with hepatic differentiation increased 4-20-fold after reversion. However, the levels never exceeded 0.1% of that detected in liver and no urea production nor ammonia elimination was detected. Additionally, activities of different cytochrome P450s were limited. In conclusion, the NKNT-3 culture is heterogeneous and unstable and the in vitro functionality is relatively low. These findings emphasize that in vivo testing of hepatic cell lines is little informative for predicting their value for in vitro applications. PMID- 28871868 TI - Suppression of Human T-Cell Responses to beta-Cells by Activation of B7-H4 Pathway. AB - B7-H4, a recently described member of the B7 family of cosignal molecules, is thought to be involved in the regulation of cellular and humoral immune responses through receptors on activated T and B cells. Human islet cells express positive B7-H4 mRNA in RT-PCR assays, but not B7-H4 protein on cell surface in flow cytometric analyses. To investigate the regulatory effects of activation of the B7-H4 pathway on the function of activated T cells of patients with type 1 diabetes (T1D), we have used our in vitro human experimental system, including human beta-cell antigen-specific T-cell clones and human beta-cell lines CM and HP62, as well as primary islet cells. B7-H4.Ig protein was purified from the culture supernatant of 293T cells transfected by a B7-H4.Ig plasmid (pMIgV, containing a human B7-H4 cDNA and a mouse IgG2a Fc cDNA). Our preliminary studies showed that immobilized fusion protein human B7-H4.Ig (coated with 5 MUg/ml for 2 h at 37 degrees C), but not control Ig, clearly inhibited the proliferation of activated CD4+ and CD8+ T cells of patients induced by anti-CD3 antibody in CFSE assays. B7-H4.Ig also arrested cell cycle progression of T cells in G0/G1 phase and induced T-cell apoptosis as measured by BrdU-7-AAD flow cytometric analysis. To determine the cytoprotective effects of B7-H4, we developed transfectants of human beta-cell lines CM and HP62 and islet cells transfected with the B7-H4.Ig plasmid, using empty vector transfectants as controls. The results demonstrate that cell-associated B7-H4.Ig expressed on human beta-cells clearly inhibits the cytotoxicity of the T-cell clones to targeted human beta-cells in 51Cr release cytotoxicity assays. Activation of the B7-H4 pathway may represent a novel immunotherapeutic approach to inhibit T-cell responses for the prevention of beta cell destruction in T1D. PMID- 28871872 TI - Comparative Study of 2D and 3D Optical Imaging Systems: Laparoendoscopic Single Site Surgery in an Ex Vivo Model. AB - BACKGROUND: Usually laparoscopy is performed by means of a 2-dimensional (2D) image system and multiport approach. To overcome the lack of depth perception, new 3-dimensional (3D) systems are arising with the added advantage of providing stereoscopic vision. To further reduce surgery-related trauma, there are new minimally invasive surgical techniques being developed, such as LESS (laparoendoscopic single-site) surgery. The aim of this study was to compare 2D and 3D laparoscopic systems in LESS surgical procedures. MATERIALS AND METHODS: All participants were selected from different levels of experience in laparoscopic surgery-10 novices, 7 intermediates, and 10 experts were included. None of the participants had had previous experience in LESS surgery. Participants were chosen randomly to begin their experience with either the 2D or 3D laparoscopic system. The exercise consisted of performing an ex vivo pork cholecystectomy through a SILS port with the assistance of a fixed distance laparoscope. Errors, time, and participants' preference were recorded. Statistical analysis of time and errors between groups was conducted with a Student's t test (using independent samples) and the Mann-Whitney test. RESULTS: In all 3 groups, the average time with the 2D system was significantly reduced after having used the 3D system ( P < .05). In the postexercise questionnaire, two thirds of participants showed a preference for using the 3D system. CONCLUSION: This study suggests that the 3D system may improve the learning curve and that learning from the 3D system is transferable to the 2D environment. Additionally, the majority of participants prefer 3D equipment. PMID- 28871876 TI - Genetic Modification of Hepatocytes towards Hepatocyte Transplantation and Liver Tissue Engineering. AB - Cell-based therapies, including liver tissue engineering following hepatocyte transplantation, have therapeutic potential for several types of liver diseases. Modifications in the methodology to manipulate the donor hepatocytes in a more simple and timely manner prior to transplantation would enhance the therapeutic efficacy of this procedure. Conventional approach for vector-mediated gene transduction to the isolated hepatocytes has been performed under primary culture conditions that routinely require several days to complete. In our study, we have established a clinically feasible approach that requires only 1 h of infection time with an adenoviral vector system that results in an extremely efficient transduction efficiency (>80%). To optimize transduction efficiency and sustain normal cellular function, we determined that the isolated hepatocytes should be maintained in UW solution as a suspension medium and infected with adenoviral vectors (Ad) for no more than 1 h at a MOI of 1. To establish if the isolated hepatocytes could be used as a source for cell-based therapies, we transplanted the Ad-transduced hepatocytes into the liver or under the kidney capsule. When the cells were transplanted into the liver, Ad-transduced hepatocytes cultured in suspension conditions were found to have a significantly higher survival rate (p < 0.01) than Ad-transduced hepatocytes cultured under standard conditions. We also confirmed that these Ad-transduced hepatocytes have ability to survive long term and were able to engineer a biologically active hepatic tissue under the kidney capsule. Finally, we obtained high level of transduction into canine, porcine, and human isolated hepatocytes in a suspension solution mixed with Ad. In conclusion, the present studies demonstrate that isolated hepatocytes could be genetically modified using Ad when kept in a suspension solution. For this reason, this cell-modified technique could be used for the treatment of liver targeted diseases and/or disorders. PMID- 28871877 TI - Silicone Oil-Induced Nasal Polyposis: A Case Report. PMID- 28871878 TI - Premature Identical Twin Neonates With Sleep Apnea. PMID- 28871879 TI - Screen Time Engagement Is Increased in Urban Children With Asthma. AB - Physical activity in children has been shown to play a role in its relationship to asthma, both in terms of prevalence and incidence. One measure of physical activity in children is sedentary behavior, which might be measured by the degree of engagement with media electronic screens. We found that children with asthma, as compared with children without asthma, engage in significantly more hours of screen time (median 35 vs 26 h/wk, P = .004). In this birth cohort, those who developed a diagnosis of asthma at 8 years of age were significantly more engaged in electronic screen time than their peers. No other clinical or lifestyle behaviors were significantly associated with a diagnosis of asthma. Further study will be needed to determine directionality of this finding. PMID- 28871881 TI - A Child With Right Ear Pain and a Gaze Palsy. PMID- 28871880 TI - Clinical Factors Associated With Chest Imaging Findings in Hospitalized Infants With Bronchiolitis. AB - Despite recommendations against routine imaging, chest radiography (CXR) is frequently performed on infants hospitalized for bronchiolitis. We conducted a review of 811 infants hospitalized for bronchiolitis to identify clinical factors associated with imaging findings. CXR was performed on 553 (68%) infants either on presentation or during hospitalization; 466 readings (84%) were normal or consistent with viral illness. Clinical factors significantly associated with normal/viral imaging were normal temperature (odds ratio = 1.66; 95% CI = 1.03 2.67) and normal oxygen saturation (odds ratio = 1.77; 95% CI = 1.1-2.83) on presentation. Afebrile patients with normal oxygen saturations were nearly 3 times as likely to have a normal/viral CXR as patients with both fever and hypoxia. Our findings support the limited role of radiography in the evaluation of hospitalized infants with bronchiolitis, especially patients without fever or hypoxia. PMID- 28871882 TI - Cultural Differences in Shame and Guilt as Understandable Reasons for Suicide. AB - According to the World Health Organization, a major barrier to suicide prevention work is the social stigma surrounding suicide. Since clinical research has long shown that shame and guilt are often involved in suicide and suicide ideation, the present two studies explore the extent to which individuals associate shame and guilt with suicide ideation and behavior according to their cultural background. Using a scenario approach, 1,147 Americans in two separate studies read about a traumatic situation in which the target person experienced intense shame or intense guilt. A mini meta-analysis of these studies showed that all participants were more likely to link the experience of shame to suicidality than guilt. Additionally, participants from U.S. dignity states were more likely to report suicide ideation when the target experienced guilt as opposed to shame. Our findings support the notion that the centrality of the emotions of shame and guilt varies relative to the social context, which has implications on how others perceive suicide. PMID- 28871887 TI - Residual Cholesteatoma during Second-Look Procedures following Primary Pediatric Endoscopic Ear Surgery. AB - Objectives To determine the rate of residual cholesteatoma during planned second look procedures in pediatric patients following primary cholesteatoma resection using endoscopic and microscopic operative approaches. Study Design Case series with chart review. Setting Tertiary care center. Subjects and Methods Outcomes from pediatric patients undergoing cholesteatoma surgery from January 2011 through August 2015 were analyzed. Cholesteatoma extent at initial resection was staged, and comparison among endoscopic dissection and microscopic or endoscopic inspection groups was made. Presence of disease at time of planned second look was quantified. Descriptive analysis was performed. Results Fifty-five patients (56 ears) with planned second-look procedures were included and underwent a total of 120 procedures. Median age was 11 years (6.7-13 years). Endoscopes were used for inspection in 25 (39%) primary resections and for dissection in 39 (61%) primary resections. Extent of disease at the time of primary resection was similar among groups (chi2, P = .72). Cases where the endoscope was used for inspection only or not at all during primary resection had a 24% rate of residual cholesteatoma at the time of second look compared with a 23% rate for cases with endoscopic dissection (chi2, P = .93). Rate of mastoidectomy significantly decreased from 63% to 33% over the study period ( P = .04) with similar disease extent ( P = .99). Conclusions Residual cholesteatoma rates during planned second look procedures were similar between the study groups. Use of the endoscope led to a lower rate of mastoidectomy for cases with similar disease extent. PMID- 28871888 TI - Subproteomic signature comparison of in vitro selected fluoroquinolone resistance and ciprofloxacin stress in Salmonella Typhimurium DT104B. AB - BACKGROUND: Fluoroquinolone resistance in nontyphoidal Salmonella is a situation of serious and international concern, particularly in S. Typhimurium DT104B multiresistant strains. Although known to be multifactorial, fluoroquinolone resistance is still far from a complete understanding. METHODS: Subproteome changes between an experimentally selected fluoroquinolone-resistant strain (Se6 M) and its parent strain (Se6), and also in Se6-M under ciprofloxacin (CIP) stress, were evaluated in order to give new insights into the mechanisms involved. Proteomes were compared at the intracellular and membrane levels by a 2 DE~LC-MS/MS and a shotgun LC-MS/MS approach, respectively. RESULTS: In total, 35 differentially abundant proteins were identified when comparing Se6 with Se6-M (25 more abundant in Se6 and 10 more abundant in Se6-M) and 82 were identified between Se6-M and Se6-M+CIP (51 more abundant in Se6-M and 31 more abundant under ciprofloxacin stress). CONCLUSION: Several proteins with known and possible roles in quinolone resistance were identified which provide important information about mechanism-related differential protein expression, supporting the current knowledge and also leading to new testable hypotheses on the mechanism of action of fluoroquinolone drugs. PMID- 28871889 TI - Adverse maternal and neonatal outcomes in women with preeclampsia in Iran. AB - BACKGROUND: Preeclampsia is relatively a common complication in pregnancy and is characterized by high blood pressure and protein in urine during pregnancy. Consistent with the adverse outcomes followed by preeclampsia, this study designed to investigate the how preeclampsia is associated with preterm, low birth weight (LBW), cesarean section, and weigh gain during pregnancy. METHODS: In this population-based cross-sectional study, 5166 deliveries from 103 hospitals in Tehran (Capital of Iran) were included in the analysis in 2015. The independent variable was preeclampsia during pregnancy and weight gain during pregnancy, preterm birth, cesarean section, and LBW were considered as interested outcomes. The data were analyzed by statistical Stata software (version 13, Stata Inc., College Station, TX). RESULTS: Adjusted results showed that the mean of weight gain in women with preeclampsia was significantly higher than women without preeclampsia (mean difference: 1.77 kg, 95%CI: 0.76-12.78, p = .001). The adjusted odds ratio for preterm birth, cesarean section, and LBW were 4.19 (95%CI: 2.71-6.48, p = .001), 1.92 (95%CI: 1.24-2.98, p = .003), and 1.19 (95%CI: 0.61-2.31, p = .599), respectively. CONCLUSION: Weight gain in women with preeclampsia was higher than women without preeclampsia and also the odds of preterm birth, cesarean section and LBW in women with preeclampsia was higher than women without preeclampsia. PMID- 28871890 TI - Association Between Periodontitis With Blood Lipid Levels in Korean Population. AB - BACKGROUND: Hyperlipidemia is a known risk factor for cardiovascular diseases. A common biological mechanism between systemic diseases like cardiovascular diseases and periodontal diseases has been suggested. We aimed to examine the association between blood lipid profile and periodontitis. METHODS: The study included 6,905 Korean adults, aged >=20 years. Individuals with incomplete data on blood lipid levels, those who lacked results of periodontitis examination by using the Community Periodontal Index system in the Fifth Korean National Health and Nutrition Examination Survey for 2010 and 2012, and those diagnosed with diabetes mellitus, hypertension and hyperlipidemia were excluded from the study. All analyses involved complex sampling design. The association was assessed using multiple logistic regression analysis adjusted for covariates. RESULTS: Women with low HDL cholesterol levels showed significantly higher risk of periodontitis (odds ratio [OR] 95% confidence interval [CI]): 1.65 for the lowest group), and those with high LDL cholesterol levels showed higher risk of the disease (OR (95% CI): 2.38 (1.01-5.60) for the highest group), than those with high HDL and low LDL levels. There was significant dose-response relationships between the disease risk and levels of HDL and LDL (p-trend of 0.001 and 0.039, respectively). There was no significant difference in the risk between pre- and post-menopausal women. Men did not show any significant association between blood lipid levels and periodontitis. CONCLUSION: There was a significant association between periodontitis and low HDL and high LDL cholesterol levels in women. PMID- 28871891 TI - Inhibition of 5-Lipoxygenase (5-Lo) Attenuates Inflammation and Bone Resorption in Lipopolysaccharide (Lps)-Induced Periodontal Disease. AB - BACKGROUND: Arachidonate-5-lipoxygenase (5-LO) activity and increased leukotriene B4 (LTB4) production have been implicated in various inflammatory conditions. Increased production of leukotrienes has been associated with periodontal diseases; however their relative contribution to the tissue destruction is unknown. We used an orally-active specific 5-LO inhibitor to assess its role in inflammation and bone resorption in a murine model of lipopolysaccharide (LPS) induced periodontal disease. METHODS: Periodontal disease was induced in Balb/c mice by direct injections of LPS into the palatal gingival tissues adjacent to the upper first molars 3 times/week for four weeks. Animals were treated with the biochemical inhibitor (2 mg/Kg/day) or the same volume of the vehicle by oral gavage. uCT analysis was used to assess bone resorption. EIA determined leukotriene B4, and ELISAs quantified TNF, IL-12 and IL-10 in the gingival tissues. Histological sections were used for the morphometric analysis (number neutrophils and mononuclear cells). Osteoclasts were counted in TRAP-stained sections. RESULTS: Administration of 5-LO inhibitor effectively reduced the production of LTB4 (23.7% decrease) and significantly reduced TNF and IL-12 levels in the gingival tissues. Moreover, reduction of LTB4 levels in the gingival tissues was associated with a significant decrease in bone resorption and a marked reduction in the number of osteoclasts and inflammatory cells. CONCLUSION: 5-LO activity plays a relevant role in inflammation and bone resorption associated with the LPS model of experimental periodontal disease. PMID- 28871892 TI - Association between asthma and periodontal disease: A systematic review and meta analysis. AB - BACKGROUND: The aim of this systematic review (SR) is to evaluate the association between asthma and periodontal disease. METHODS: An electronic search without date or language restrictions was carried out in PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, and LILACS until May 2016. In addition, manual searches and searches of the gray literature were conducted. The search process, data analysis, and quality assessment were performed by two independent reviewing authors. Eligibility criteria included prospective and retrospective cohort studies, case-controls, and randomized clinical trials. RESULTS: The search and selection process yielded 21 studies, published between 1979 and 2017. The meta-analysis showed a statistically significant difference for the parameters of gingival bleeding, plaque index, and gingival index for participants with asthma (P < 0.001). CONCLUSION: Data from this SR strongly suggest the association of asthma with periodontal disease. PMID- 28871893 TI - Metabolism and Whole-Body Fat Oxidation Following Postexercise Carbohydrate or Protein Intake. AB - PURPOSE: This study investigated how postexercise intake of placebo (PLA), protein (PRO), or carbohydrate (CHO) affected fat oxidation (FO) and metabolic parameters during recovery and subsequent exercise. METHODS: In a cross-over design, 12 moderately trained women (VO2max 45 +/- 6 ml.min-1.kg-1) performed three days of testing. A 23-min control (CON) incremental FO bike test (30-80% VO2max) was followed by 60 min exercise at 75% VO2max. Immediately postexercise, subjects ingested PLA, 20 g PRO, or 40 g CHO followed by a second FO bike test 2 h later. RESULTS: Maximal fat oxidation (MFO) and the intensity at which MFO occurs (Fatmax) increased at the second FO test compared to the first following all three postexercise drinks (MFO for CON = 0.28 +/- 0.08, PLA = 0.57 +/- 0.13, PRO = 0.52 +/- 0.08, CHO = 0.44 +/- 0.12 g fat.min-1; Fatmax for CON = 41 +/- 7, PLA = 54 +/- 4, PRO = 55 +/- 6, CHO = 50 +/- 8 %VO2max, p < 0.01 for all values compared to CON). Resting FO, MFO, and Fatmax were not significantly different between PLA and PRO, but lower for CHO. PRO and CHO increased insulin levels at 1 h postexercise, though both glucose and insulin were equal with PLA at 2 h postexercise. Increased postexercise ketone levels only occurred with PLA. CONCLUSION: Protein supplementation immediately postexercise did not affect the doubling in whole body fat oxidation seen during a subsequent exercise trial 2 h later. Neither did it affect resting fat oxidation during the postexercise period despite increased insulin levels and attenuated ketosis. Carbohydrate intake dampened the increase in fat oxidation during the second test, though a significant increase was still observed compared to the first test. PMID- 28871895 TI - Allocating a scarce mental health treatment to the underweight and overweight. AB - BACKGROUND: This is one of a number of programmatic studies on the allocation of scarce medical resources. AIMS: This study investigated whether certain characteristics about patients influence the priority they are assigned for a scarce mental health treatment. Similar studies for physical treatments have found that young, poor, and mentally healthy patients are given the highest priority. METHOD: Each participant completed one questionnaire where they ranked a list of eight hypothetical patients in order of priority for treatment for anorexia or obesity. The patients varied on three dimensions: age, social class and mental health history. This involved a ranking of prioritisation for treatment. RESULTS: Participants gave the young patients, from a low social class background, who had a mental health history the highest priority for treatment. This is in contrast to previous studies indicating that the mentally unwell are discriminated against. CONCLUSIONS: Participants seemed to be using social class as a proxy measure of ability to pay which they weighted very highly. PMID- 28871894 TI - Surgeon-Performed Ultrasound for Chronic Obstructive Sialadenitis Helps Predict Sialendoscopic Findings and Outcomes. AB - Objective To determine the accuracy of surgeon-performed ultrasound (SP-US) features for predicting intraoperative sialendoscopic findings and to correlate ultrasound features with short-term symptomatic outcomes following sialendoscopy assisted salivary duct surgery (SASDS). Study Design Case series with chart review. Setting The practices of 2 academic sialendoscopy surgeons. Subjects and Methods Between February 2014 and September 2015, 82 patients with 105 symptomatic glands underwent SASDS, of whom 56 patients (75 glands) met inclusion criteria. SP-US and sialendoscopic findings were reviewed for patients with chronic obstructive sialadenitis who underwent SASDS and who had been prospectively evaluated with the University of California-San Francisco Chronic Obstructive Sialadenitis Symptoms (COSS) questionnaire (scored 0-100) administered preoperatively and 3 months postoperatively. Results The positive predictive value (PPV) and negative predictive value (NPV) of SP-US for identifying sialoliths intraoperatively were 94% (33/35) and 91% (39/43), respectively. Of glands with sialoliths on SP-US, 97% (34/35) had complete symptom resolution (COSS <=10) after SASDS. The PPV and NPV of salivary duct dilation on SP-US for finding a corresponding stenosis on sialendoscopy were 93% (14/15) and 50% (14/28), respectively. Nonsialolith SP-US features with the highest PPV for complete or partial symptom resolution (COSS <=25) following SASDS included distal duct dilation of all glands (86%; 6/7) and dilation of both distal and proximal parotid ducts (75%; 6/8). Conclusion SP-US has high accuracy for ruling in and ruling out sialoliths, as well as for ruling in but not for necessarily ruling out stenosis presence and location. Ultrasound is helpful in estimating degree of short-term symptom response following SASDS. PMID- 28871896 TI - Adherence predictors in an Internet-based Intervention program for depression. AB - Internet-delivered psychotherapy has been demonstrated to be effective in the treatment of depression. Nevertheless, the study of the adherence in this type of the treatment reported divergent results. The main objective of this study is to analyze predictors of adherence in a primary care Internet-based intervention for depression in Spain. A multi-center, three arm, parallel, randomized controlled trial was conducted with 194 depressive patients, who were allocated in self guided or supported-guided intervention. Sociodemographic and clinical characteristics were gathered using a case report form. The Mini international neuropsychiatric interview diagnoses major depression. Beck Depression Inventory was used to assess depression severity. The visual analogic scale assesses the respondent's self-rated health and Short Form Health Survey was used to measure the health-related quality of life. Age results a predictor variable for both intervention groups (with and without therapist support). Perceived health is a negative predictor of adherence for the self-guided intervention when change in depression severity was included in the model. Change in depression severity results a predictor of adherence in the support-guided intervention. Our findings demonstrate that in our sample, there are differences in sociodemographic and clinical variables between active and dropout participants and we provide adherence predictors in each intervention condition of this Internet-based program for depression (self-guided and support-guided). It is important to point that further research in this area is essential to improve tailored interventions and to know specific patients groups can benefit from these interventions. PMID- 28871897 TI - Dissipation kinetics and safety evaluation of tebuconazole and trifloxystrobin in tea under tropical field conditions. AB - Dissipation kinetics of tebuconazole, trifloxystrobin and its acid metabolite residues were studied in tea under tropical field conditions using GC-MS (SIM). The average recoveries ranged from 80.7% to 105.8%, with a RSD of <9.3%. Dissipation rate for both doses applied followed first-order kinetics, with half lives in green leaves in the range of 2.8-3.3 and 2.9-3.3 days; ranges in processed tea were 2.7-3.6 days for trifloxystrobin and 3.0-3.1 days for tebuconazole. The trifloxystrobin residues were not transferred into the tea infusion during the infusion process; tebuconazole did transfer, in the range of 14.3-18.9%. As the theoretical maximum residue contributions on tea from initial deposits were found to be less than the maximum permissible intake values, at the recommended application dose a withdrawal period of 23 days before consumption should be applied to reduce risk. PMID- 28871899 TI - Psychological Risk Factors and Outcomes of Dance Injury: A Systematic Review. AB - Historically, dance medicine and science has focused on the physical aspects rather than the psychological aspects of dance injury. Psychological variables, however, have been shown to influence the occurrence of injury and post-injury outcomes. The purpose of this review was to examine the dance psychology literature and determine the specific psychological factors reported to be associated with the incidence, frequency, and outcome of dance injuries. A systematic literature search was conducted using SPORTDiscus, MEDLINE, CINAHL, and PsycINFO. All retrieved articles were screened based on criteria developed a priori, and selected articles were subsequently assessed for quality. Thirteen studies met the inclusion and quality assessment criteria. Psychological factors associated with both risk and outcome of dance injury included the following: stress, psychological distress, disordered eating, and coping. Factors associated only with risk of injury were sleep, personality, and social support. The results suggest that psychological variables can affect both the incidence and outcome of dance injury among dancers. Therefore, it is critical to gain a well-rounded, thorough understanding of all the factors, including psychological, that have a negative impact on dancers with respect to dance injury. The findings are discussed in terms of the utility of including psychological assessment and intervention, such as cognitive behavioral therapy, when implementing preventative and treatment measures in dance schools and companies. PMID- 28871898 TI - COST-EFFECTIVENESS IMPACTS CANCER CARE FUNDING DECISIONS IN BRITISH COLUMBIA, CANADA, EVIDENCE FROM 1998 TO 2008. AB - OBJECTIVES: The Priorities and Evaluation Committee (PEC) funding recommendations for new cancer drugs in British Columbia, Canada have been based on both clinical and economic evidence. The British Columbia Ministry of Health makes funding decisions. We assessed the association between cost-effectiveness of cancer drugs considered from 1998 to 2008 and the subsequent funding decisions. METHODS: All proposals submitted to the PEC between 1998 and 2008 were reviewed, and the association between cost-effectiveness and funding decisions was examined by (i) using logistic regression to test the hypothesis that interventions with higher incremental cost-effectiveness ratios (ICERs) have a lower probability of receiving a positive funding decision and (ii) using parametric and nonparametric tests to determine if a statistically significant difference exists between the mean cost-effectiveness of funded versus not funded proposals. A sub-analysis was conducted to determine if the findings varied across different outcome measures. RESULTS: Of the 149 proposals reviewed, 78 reported cost-effectiveness using various outcome measures. In the proposals that used life-years gained as the outcome (n = 22), a statistically significant difference of nearly $115,000 was observed between the mean ICERs for funded proposals ($42,006) and for unfunded proposals ($156,967). An odds ratio indicating higher ICERs have a lower probability of being funded was also found to be statistically significant (p < .05). CONCLUSIONS: Economic evidence appears to play a role in British Columbia cancer funding decisions from 1998 to 2008; other decision-making criteria may also have an important role in recommendations and subsequent funding decisions. PMID- 28871900 TI - Effects of a Modified Ballet Class on Strength and Jumping Ability in College Ballet Dancers. AB - The ability to jump high with precision is an important component of the ballet dancer's technique. The aim of this study was to evaluate the effect of a modified ballet class on strength and jumping ability in high level female dancers. Seventeen female ballet students were divided into two groups, experimental and control, and tested before and after an 8-week, 2 times/week intervention for peak torque of knee extensors and flexors at 60 degrees and 180 degrees , and jumping ability (squat jump, countermovement jump, countermovement with arm swing jump, saute in first position, and saute in first position with port de bras). Statistical analysis was performed using Analysis of Variance (Anova 2x2) with repeated measure of factor time (pre and post). T-test with Bonferroni adjustment was used to assess any differences between groups. The experimental group showed improvement in height (7.7%), takeoff velocity (4.0%), and power (5.1%) of the squat jump. In addition, increases were revealed in peak (60 degrees , 11.9%; 180 degrees , 7.8%) and relative peak torque (60 degrees , 13.2%; 180 degrees , 9.2%) of the right knee flexors. Moreover, enhancements of the knee flexor-extensor strength ratio in both angular velocities were found (60 degrees , 10.4%; 180 degrees , 9.7%). These outcomes suggest that the proposed program could help ballet dancers improve the height of their vertical jumps and leg strength. PMID- 28871901 TI - Associations Between Sedentary Behaviors, Sleep Patterns, and BMI in Young Dancers Attending a Summer Intensive Dance Training Program. AB - The purpose of this study was to investigate associations between sedentary behaviors, sleep hours, and body mass index (BMI) in 12- to 17-year-old dancers. This was a cross sectional survey in which bivariate correlation and simple linear regression were used to determine associations between self-reported components. One hundred fifteen dancers were queried, 91.3% of whom were female. The mean BMI was 19.6 +/- 2.3 kg/m2. Two-thirds of dancers fell below the 50th percentile for age-adjusted BMI, and 30.4% fell below the 25th percentile. Better than 12% of dancers reported a history of anxiety, and 2.6% reported depression. Mean hours of sleep per night was 7.8 +/- 0.9, with 58% of the dancers getting less than 8 hours of sleep per night. The mean total screen time for dancers was 3.4 +/- 2.1 hours/day, which consisted of tablet and computer usage: 1.6 +/- 1.1 hours/day; texting: 0.5 +/- 1.1 hours/day; watching television: 1.2 +/- 1.1 hours/day; and playing video games 1.2 +/- 1.1 hours/ day. Total screen time was independently associated positively with BMI, explaining nearly 10% of the variability in BMI. Age, hours dancing per day, and hours of sleep per night were not independently associated with BMI. To summarize: screen time was associated with increased BMI in this young dancer cohort; the majority of dancers slept less than 8 hours per night; anticipatory guidance addressing media use and sleep hygiene in the adolescent dancer population is needed. PMID- 28871902 TI - Height of the Medial Longitudinal Arch During Classical Ballet Steps. AB - The purpose of this study was to evaluate the midfoot longitudinal arch height and correlate it with active hip external rotation (ER) in dancers during static postures and technical steps of classical ballet (i.e., first position, demi plie, battement fondu a la seconde, pas jete a la seconde, and grand jete a la seconde). A 3D motion analysis system was used for kinematic analysis. The arch height was significantly reduced during the battement fondu a la seconde, pas jete a la seconde, and grand jete a la seconde when compared to standing (p = 0.000 for all comparisons), first position (p = 0.000, p = 0.000, and p = 0.001, respectively) and demi-plie (p = 0.015, p = 0.003, and p = 0.006, respectively). No significant correlation was found between arch height and active hip external rotation (p > 0.05). Hence, active hip external rotation does not seem to be related to midfoot pronation in this sample. Other factors, such as intrinsic and extrinsic foot muscle strength, may be related to the midfoot arch height. These findings contribute to a better understanding of ballet steps, but future studies are required to clarify this topic completely. PMID- 28871903 TI - Perfectionism, Burnout, and Motivation in Dance: A Replication and Test of the 2*2 Model of Perfectionism. AB - The relationships between multidimensional perfectionism, burnout, and motivation were examined. In so doing, this study aimed to replicate and extend the study by Cumming and Duda (2012). Ninety-one ballet dancers completed questionnaires assessing the target constructs. Using cluster analysis, four profiles emerged that replicated Cumming and Duda's findings and generally supported Gaudrau and Thompson's 2x2 model of perfectionism. As such, these profiles represented pure personal standards perfectionism, mixed perfectionism, pure evaluative concerns perfectionism, and non-perfectionism. Extending previous literature, the four profiles were then compared on a range of burnout symptoms and motivational regulations. It was found that the four clusters differed significantly on these constructs, in a manner partly supportive of the hypotheses associated with the 2x2 model of perfectionism. In particular, our results reflect and extend those of Cumming and Duda, in that mixed perfectionism and pure evaluative concerns perfectionism did not differ on any of the measures. Thus, the higher personal standards of dancers exhibiting mixed perfectionism did not appear to be associated with better functioning than that experienced by dancers with pure evaluative concerns perfectionism. Altogether, the study extends our current understanding of perfectionism in dance and its potential effects, including those on burnout and motivation. PMID- 28871904 TI - The Biomechanics and Motor Control of Tap Dancing. AB - Although tap dancing is a popular dance genre, little is known about the biomechanics and motor control of this complex motor skill. We conducted a detailed 3D kinematic analysis of movement timing, amplitude, and symmetry in three experienced female tap dancers. Kinematic analyzes of three basic tap dance steps (nerve beats, brush brush stamps, and heel ball walks) were undertaken. A 10-camera Vicon motion analysis system was used to collect the data. The results showed the feet and knees to play a major role in movement execution. Each step required at least 10 degrees of ankle motion (range: 10 degrees to 66.8 degrees ). Knee range of motion varied from 1.3 degrees to 147.4 degrees . For each of the dance steps the hips showed the smallest amplitude of movement, which was not greater than 21 degrees in two out of the three dance steps. Analyzes of movement timing showed that each of the dance steps was fast, accurate, and well synchronized. The nerve beats took on average 0.50 seconds, the brush brush stamps 1.36 seconds, and the heel ball walks 4.03 seconds. A high degree of symmetry in total movement amplitude was evident at the ankles,knees, and hips for the nerve beats and heel ball walks. There was a mild degree of asymmetry at the hip for the brush brush stamp steps (symmetry index 90%). The results showed that experienced dancers had very high levels of proficiency in controlling movement amplitude, timing, and inter-limb coordination across the ankles, knees, and hips. This resulted in skilled, fast, and well executed dance steps. PMID- 28871922 TI - Development and Significance of the E-surveillance System for Contact Allergies in Slovenia. AB - This paper describes the development and significance of online systems for the collection and analysis of medical data (patch test results) with a web application. Modern digital tools greatly aid in collecting, combining, and preserving the data in a way that is friendly, undemanding and time-efficient for the dermatologist. Creating a central database for the results of patch testing provides a better picture of contact sensitivity and characteristics of allergic contact dermatitis in Slovenia. An electronic database and connected network was started in Slovenia in 2010. Data from skin allergy units since 2000 has also been included retrospectively. At present (Oct 2016), the database contains the data of 19,772 patch tests performed by seven skin allergy units. Creating a central database of the results of patch testing provides a larger and therefore more credible collection of data. Immediate integration and data processing enable a current overview of contact sensitivity for each participating center as well as at the national level. Data can be easily transferred to other databases or edited with other software tools. This on-line register has worked flawlessly for more than five years. We have contributed data to the European Surveillance System on Contact Allergies (ESSCA) network database since 2012, which, along with the Deutsche Kontaktallergie-Gruppe system of collecting patch test data for German-speaking countries, represents the only multicenter surveillance system of patch test results in Europe. PMID- 28871923 TI - Predictive Value of Intraoperative Sentinel Lymph Node Imprint Cytology Analysis for Metastasis in Patients with Melanoma. AB - Since there are no standardized protocols regarding the detection of microscopic melanoma deposits in sentinel lymph nodes (SLN), the aim of this study was to present our experience with intraoperative cytological evaluation of SLN in patients with melanoma. The study included 475 SLN biopsies (SLNB) from 201 patients with primary cutaneous melanoma of intermediate thickness. Each lymph node was cut in half; touch imprint cytology (TIC) preparations of all cut surfaces were performed and stained according to a modified May-Grunwald-Giemsa method. The results were compared to definitive postoperative histology. Twenty of 25 SLNB positive on TIC proved to be metastatic when compared to definitive histology. Most of 32 SLN that were suspicious but not diagnostic on TIC were proven negative (23/32, 71.8%), while 7 nodes had metastases (one micrometastasis and one with isolated tumor cells only). The majority (94%) of SLNBs negative on TIC remained negative on final histology, while 6% or 25 nodes were positive, mostly with micrometastases or isolated tumor cells (17/25). In frozen sections performed in cases of suspicious or positive SLN cytology, metastasis was confirmed in 80% of positive and in 21.9% of suspicious TIC. Altogether, 49% (27/55) of positive SLNB were identified intraoperatively in 57% (24/42) of patients, and in those cases a complete regional lymph node dissection was performed in the first step. TIC assessment of SLNB with 99% specificity and 57% sensitivity for intraoperative identification of metastasis is useful and beneficial for avoiding a second operative procedure. PMID- 28871924 TI - Comparison of Doxycycline and Benzathine Penicillin G for the Treatment of Early Syphilis. AB - Doxycycline is the preferred recommended second-line treatment for the treatment of early syphilis. Recent reports showed a declining efficacy trend of doxycycline in treatment of early syphilis. The aim of our study was to assess the serological response to the treatment for early syphilis with doxycycline compared with benzathine penicillin G and evaluate whether doxycycline is still an effective agent for the treatment of early syphilis. A record-based retrospective study was conducted. Patients were diagnosed with early syphilis in an sexually transmitted disease (STD) clinic from January 1, 2008 to December 31, 2014. They were treated with a single dose of benzathine penicillin G 2.4MU or oral doxycycline 100 mg twice daily for 14 days. Pearson's chi-squared test was used for data analysis. 601 cases were included in the final study sample: 105 (17.5%) patients received a 14-day course of doxycycline (doxycycline group), and 496 (82.5%) patients received single-dose benzathine penicillin G (BPG group). The serological responses at 6 months and 12 months after treatment were compared. No statistically significant differences were found between the two groups at 6 months (69.52% vs. 75.00%, P=0.245), and at 12 months (92.38% vs. 96.17%, P=0.115). Doxycycline is still an effective agent for the treatment of early syphilis. PMID- 28871925 TI - Mast Cell Disorders, Melanoma and Pancreatic Carcinoma: From a Clinical Observation to a Brief Review of the Literature. AB - Mastocytosis can be associated with other clonal or non-clonal hematologic diseases as well as a variety of non-hematologic malignancies. A 75-year-old Caucasian male patient was referred to us with a 5-month history of neutrophilic leukocytosis and mild splenomegaly. He had developed a cutaneous melanoma sixteen years ago. According to the clinical and pathological features, a final diagnosis of systemic mastocytosis was established. The patient started treatment with interferon-alpha at a dose of 3 MIU/day, combined with low doses of prednisone. We observed a rapid disappearance of symptoms. Unfortunately, after 3 months a diagnosis of pancreatic adenocarcinoma was established. A review of the literature suggests that mastocytes could have a pivotal role in several malignancies. Different chemokines, mitogenic factors, chemical mediators of inflammation, and specific gene mutations could explain the association between mastocytosis and other hematologic and non-hematologic disorders. PMID- 28871926 TI - Translation and Validation of the Serbian Version of the Skindex-29 Instrument for Measuring Impact of Skin Disease on Quality of Life. AB - The Skindex-29 instrument, which is intended for measuring the influence of skin diseases on quality of life, was developed and validated in several languages. However, a Serbian translation of the instrument is not available. The aim of this study was to translate the Skindex-29 from English to Serbian, to make necessary cultural adaptations, and to test its psychometric properties in a sample of outpatients with various skin diseases. The Skindex-29 was translated and adapted according to internationally accepted guidelines and then tested on a sample of Serbian outpatients with various skin diseases. Internal consistency was checked through calculation of Cronbach's alpha and Interclass Correlation Coefficient for the instrument's domains. The criterion validity of the translation was tested by correlating scores of domains with scores on the Serbian version of Dermatological Life Quality Index (DLQI).Validity of the construct was tested through comparison of the domains scores in groups of patients with different skin diseases. Fifty-three patients (18.6%) suffered from acne vulgaris, 48 (16.8%) from verrucae vulgares, 40 (14.0%) from psoriasis, 34 (11.9%) from an undetermined type of mild dermatitis, 20 (7.0%) from venous ulcers, 19 (6.7%) from eczema, and 71 (24.9%) from other skin diseases. The Serbian translation of Skindex-29 showed good internal consistency: Cronbach's alpha for Emotional, Symptoms, and Functioning domains was 0.885, 0.752, and 0.901, respectively. Validity of the instrument in all aspects (criterion, content, and construct validity) was satisfactory, yet the Symptoms domain could not discriminate well between more and less severe skin diseases. The Serbian translation of Skindex-29 appears to be a reliable and valid specific instrument for measuring the adverse influence of skin diseases on quality of life. PMID- 28871927 TI - Sociodemographic, Sexual Behavior, and Microbiological Profiles of Men Attending Public Health Laboratories for Testing for Sexually Transmitted Diseases. AB - In order to identify the groups at risk of sexually transmitted diseases (STDs), we assessed the sociodemographic profiles of men testing for STD, their sexual habits, and the results of microbiological analysis. During a three-year period, a total of 700 men older than 18 years of age completed the questionnaire regarding sociodemographic and sexual behavior. Urethral swabs were taken for microbiological analysis. Thirty-three percent of respondents reported not using condoms. Those that do not use condoms were predominantly less educated, unmarried but in steady relationships, employed, with children, and smokers. Alcohol or drug usage before sexual intercourse was disclosed by 21.4% of respondents, and 10.3% respondents reported sexual intercourses with commercial sex workers. Finally, 24.0% respondents reported sexual relations abroad. In 28.1% of subjects, one or more pathogens were observed in urethral swabs. The most commonly diagnosed microorganism was Ureaplasma urealyticum, followed by Chlamydia trachomatis, Mycoplasma hominis, Trichomonas vaginalis, and Neisseria gonorrhoeae. This study identified several factors that may contribute to the general risk of STD transmission, which will serve to better understand the transmission dynamics and implementation of adequate prevention programs. PMID- 28871928 TI - The Impact of Pyschological Stress on Acne. AB - Acne is one of the most common skin disorders. It is a multifactorial and complex disease, originating in the pilosebaceous follicle where a hereditary background, androgens, skin lipids, disorders of keratinization, inflammatory signaling, and regulatory neuropeptides seem to be mainly involved. Even though emotional stress has long been suspected to trigger or exacerbate acne, its influence on acne severity has been mostly underestimated until recently when studies have brought new data about the different mechanisms and possible factors involved in this interaction. A point to note is that there have been relatively few studies examining stress as a possible cause of acne or acne exacerbation; more studies have focused on stress and mental health problems occurring as a result of acne. In this review, we have tried to identify the underlying mechanisms that link stress to acne according to the latest scientific findings, and we summarize this perplexing connection. The basis for the association between emotional stress and the onset or exacerbation of acne is in several cutaneous neurogenic factors which interact with a pathogenic cascade in acne. This bidirectional intimate relationship of the skin and the mind emphasizes the importance of a holistic and interdisciplinary approach to caring for patients with acne that involves not only dermatologists but also psychologists and psychiatrists. PMID- 28871929 TI - Association of Generalized Psoriasis and Mixed Glomerulonephritis in a 10-year old Girl. AB - Generalized psoriasis and renal function disorder were previously described in sporadic adult cases, revealing a new entity - psoriatic nephropathy. So far there have been only two cases describing this association in children. We present and discuss a case of 10-year-old girl with the unique biopsy findings of double glomerulonephritis associated with the simultaneous onset of generalized psoriasis. PMID- 28871930 TI - Can Hematologic Parameters be an Indicator of Metabolic Disorders Accompanying Rosacea? AB - Recently, diverse hematologic parameters have been used as an indicator of the presence or severity of inflammatory and cardiovascular diseases. Our aim was to investigate the ratios of neutrophils to lymphocytes (NL), monocytes to high density lipoprotein (HDL) cholesterol (MHC), and platelets to lymphocytes (PL) in patients with rosacea in comparison with the control group and determine whether there was a correlation between these ratios and metabolic disorders in patients with rosacea. We conducted a case-control study on 61 patients with rosacea and 60 healthy controls between January 2015 and January 2016 at the Dermatology Outpatient Clinic, Mugla, Turkey. Demographic data, biochemical parameters, hematologic parameters and ratios, the presence of metabolic syndrome (MS), and the presence of insulin resistance (IR) in the participants were recorded. Sixty one patients with rosacea (16 men, 45 women) and 60 controls (13 men, 47 women) were included in the study. The NL ratio, mean levels of low-density lipoprotein (LDL) and total cholesterol, triglyceride, C-reactive protein (CRP), systolic and diastolic blood pressures, and the presence of IR were significantly higher in patients with rosacea than in controls. In the rosacea group, the MHC ratio was significantly higher in patients with rosacea with IR and MS. Moreover, only the MHC ratio was an independent predictor of MS according to univariate logistic regression analysis. The cutoff value of MHC on admission for predicting MS in patients with rosacea was 0.013.The higher levels of NL ratio and IR in the rosacea group corroborate the previous studies demonstrating a high level of cardiovascular risk factors in patients with rosacea. The MHC ratio may be used as a simple and inexpensive method to predict metabolic disorders in patients with rosacea. PMID- 28871931 TI - Kerion Celsi due to Microsporum canis with a Dermatophytid Reaction. AB - Microsporum (M.) canis is the most common fungus to cause tinea capitis in Europe, especially in the Mediterranean region and South and Central Europe. Fungal scalp infections caused by M. canis tend to be non-inflammatory. Recently, a growing number of cases of tinea capitis characterized by inflammatory infection caused by M. canis and M. gypseum have been registered. We present a case of highly inflammatory tinea capitis, also known as kerion celsi, caused by M. canis in a 6-year-old-patient. Scalp infections due to M. canis are a growing problem in dermatological practice. Changes in epidemiology, etiology, and clinical patterns of fungal infections due to M. canis are significant. Greater awareness of this problem is needed in order to establish proper diagnosis and successful treatment strategy for these patients. PMID- 28871933 TI - Prognostic Predictors of Thin Melanoma in Clinico-Pathological Practice. AB - The latest reviews on thin melanoma (TM) continue to consider it a melanoma within 1 mm in thickness, but no consensus exists as to which patients with TM are at risk for lymph node metastases (1). Numerous studies have evaluated the impact of various predictors (Breslow thickness, Clark level, ulceration, regression, vascular invasion, mitotic activity, location, sex) for nodal disease in melanoma, but the conclusions have not been homogenous (2,3). For this reason, we read the paper by Homolak et al. with great interest, where the authors examine the sentinel lymph node biopsies (SLNB) of 184 patients affected by melanoma of thickness less than 1.5 mm, defined as thin (4). SLNB was positive in 22 patients (12%), and 30 patients (7.65%) developed metastatic disease. The group of thinnest tumors (<0.50 mm) had the highest proportion of positive nodes (33%); the group of thickest tumors (1.26-1.50 mm) had the highest proportion of patients with metastatic disease (23%). The authors divided TM into 5 groups: 1) <0.50 mm (15 patients, 5 with positive SLNB); 2) 0.50-0.75 mm (18 patients, 3 with positive SLNB); 3) 0.76-1.00 mm (67 patients, 7 with positive SLNB); 4) 1.01 1.25 mm (45 patients, 4 with positive SLNB); 5) 1.26-1.50 mm (36 patients, 3 with positive SLNB). The current staging system of the American Joint Committee on Cancer (AJCC) uses Breslow thickness as the primary attribute, and up to 1 mm thick melanoma is defined as 'thin' because it shows a good prognosis after surgical excision, with a 10-year survival rate of 85-90% in case of a tumor-free margin of at least 1 cm (5). Based on our experience, this limit should be maintained at 1 mm because TM includes four main histological subtypes, which reflect specific biological attitudes: the intra-epidermal (in situ) radial growth phase (RGP), the non-tumorigenic micro-invasive radial growth phase without regression, the micro-invasive radial growth phase with regression (>75%) of uncertain tumorigenic potential, and the tumorigenic early (<=1 mm) invasive vertical growth phase (VGP) (6-10). This proposed sub-typing fits better with the AJCC staging system, as elucidated below and in Table 1: intra-epidermal radial growth phase (pTis), micro-invasive radial growth phase without regression (pT1), micro-invasive radial growth phase with regression (pT1), early invasive vertical growth phase (pT1), invasive vertical growth phase >1 mm, <=2 mm (pT2), invasive vertical growth phase >2 mm, <=4 mm (pT3), invasive vertical growth phase >4 mm (pT4). The in situ RGP and micro-invasive RGP without regression are biologically indolent if completely removed, and SLNB is not necessary in these cases (6). In micro-invasive RGP with regression, performing SLNB is prudent, in particular if accompanied by high mitotic rates, while it is mandatory in early invasive VGP (7). Therefore, the prognostic predictors of nodal and distant metastases require further research in the four above-mentioned histological subtypes of thin melanoma. PMID- 28871932 TI - A 12-year-old Girl with Severe Plaque Psoriasis and Down Syndrome Treated Successfully with Etanercept. AB - The association between Down syndrome and psoriasis is unclear. Immunological abnormalities that present in individuals with Down syndrome result in mild immune debilitation, thus the risk of infectious complications during immunosuppressive therapy might be higher in this group of patients. We present a case of 12-year-old girl with severe plaque psoriasis and Down syndrome, who was initially treated with cyclosporine with good response. However, the drug was withdrawn due to massive viral warts development and loss of efficacy. Afterwards, the girl was treated with etanercept in short 10 week and long 24 week courses with excellent response. The presented case is the first report of a child with Down syndrome and concomitant severe plaque psoriasis treated successfully with etanercept. PMID- 28871934 TI - Diffuse Palmoplantar Keratoderma, Onychodystrophy, universal Hypotrichosis and Cysts. AB - Dear Editor, Clouston syndrome, also called hidrotic ectodermal dysplasia (HED), is an autosomal dominant ectodermal dysplasia characterized by a clinical triad of onychodystrophy, generalized hypotrichosis, and palmoplantar keratoderma (1). Herein we report the case of a 24-year-old male with the distinctive clinical triad associated with multiple epidermoid cysts, which probably reflects the phenotype of Clouston syndrome. A 24-year-old male presented to our Department with diffuse thickening of the skin of his palms and soles since infancy. He also complained of sparsity to near absence of body hair and also reported thickening of the nails and multiple swellings involving the genitals and head since childhood. There was no history of consanguinity or of recurrent painful paronychia or abnormality in sweating. The patient denied any history of deafness, diminution of vision, redness, or watering of the eyes. On examination, diffuse hyperkeratosis of the palms and soles was observed (Figure 1 a, b) However, there was no extension of this hyperkeratosis to the dorsal aspects of the hands and feet or any proximal extension to the forearms or legs. Extensor aspects of the elbows and knees did not reveal any hyperkeratotic skin lesions. The nails were yellowish-brown, thickened, and hyperconvex, which was more pronounced in the finger nails than the toe nails (Figure 1 c, d). There was no associated paronychia. The scalp hair was very sparse, fine, and pale in color, reaching just a length of 3-4 mm in some places while totally absent in other places. The hair from the beard, eyebrows, eyelashes, moustaches, and pubic and axillary regions was very sparse to nearly absent (Figure 2 a, b, c). General body hair was also absent. In the left pre-auricular area there was a 3*2.5 cm swelling, soft to firm in consistency, non-tender, and non-pulsatile with no sinus or scar over it (Figure 2c). Multiple similar swellings of variable size measuring 0.6 to 1.3 cm were present over the scrotum (Figure 2 d). Systemic examination including oro-dental and ophthalmological examination was unremarkable. Physical tests for hearing were normal. Nail clippings for KOH examination did not reveal any fungal components. Fine needle aspiration from the pre-auricular swelling was consistent with epidermoid cyst. The classical triad of onychodystrophy, universal hypotrichosis, and palmoplantar hyperkeratosis with normal sweating and teeth indicated a diagnosis of Clouston syndrome. Hidrotic ectodermal dysplasia was first described in a French-Canadian kindred (2). However, it has subsequently been described in other ethnic and geographical areas. There is a mutation in the beta gap junction protein gene which codes for the protein connexin 30 (Cx30) (3). This condition primarily affects the hair, nails, and skin, while sparing the teeth and sweat glands. The hair is sparse and pale, and the alopecia can be patchy or total. Hair loss may lead to total alopecia by puberty. The eyelashes are short and sparse, and the eyebrows as well as axillary and pubic hair are also sparse or absent (1), as in our case. During infancy, the nails are typically milky white, gradually thickening throughout childhood. The nail plate is short, thick, slow-growing, and discolored, which was consistent with our patient's nail changes. Diffuse palmoplantar hyperkeratosis is a characteristic sign which may extend to the dorsum of the hands and feet (4). However, our case had no transgradient component. There are other less common abnormalities reported in Clouston syndrome, which include conjunctivitis, strabismus, congenital cataract, oral leucoplakia, diffuse eccrine poromatosis, sensorineural hearing loss, thickened skull bones, and tufting of the terminal phalanges (2,5-8). However, to the best of our knowledge, the presence of epidermoid cysts in Clouston syndrome has not been previously reported, making our case a unique clinical presentation. Pachyonychia congenita is a very close differential diagnosis for this entity. However, universal hypotrichosis and the lack of oral leukokeratosis were the differentiating features in our case. Additionally, palmoplantar keratoderma in pachyonychia congenita is mainly focal rather than diffuse, as in our case. However, genetic studies are needed to establish such a diagnosis. PMID- 28871935 TI - Topical Imiquimod is an Effective and Safe Drug for Molluscum Contagiosum in Children. AB - Dear Editor, Molluscum contagiosum (MC) is a very common skin infection caused by a molluscipox virus gene of the poxvirus family. It usually occurs in young children, sexually active adults, and immunocompromised individuals. The typical clinical picture of this infection is characterized by asymptomatic flesh colored, single or multiple papules, measuring 2-6 mm in diameter with a central umbilication that occur on the skin and the mucous membranes. In adults, the skin lesions are predominantly located in the genital region, whereas in children they are found on the trunk, the extremities, and the face. MC is generally regarded as a self-limited disease; however, its treatment is usually advisable considering its potentially protracted course and the risk of superinfection, scarring, autoinoculation, and transmission to other members of the community. A large number of approaches to the treatment of MC have been used so far (none of them approved by the Food and Drug Administration (FDA)) including ablative regimens (curettage, electrodessication, cryotherapy, laser therapy) and topical or systemic pharmacologic agents (tretinoin, cantharidin, trichloroacetic and salicylic acid, potassium hydroxide, interferon-alfa, and cimetidine). Imiquimod is a topically applicable Toll-like receptor (TLR)-7/8 agonist, which is capable of stimulating the innate cutaneous immunity and the cellular arm of the adaptive immune response and of exerting potent anti-viral, anti-tumor and immunoregulatory effects (1). Originally approved for the treatment of external genital and perianal warts in adults, imiquimod was later approved for the therapy of basal cell carcinomas and actinic keratoses and has also been used in the management of several off-label indications including cutaneous infections and neoplasms. Our group has successfully used topical imiquimod in the treatment of a variety of dermatoses including granuloma annulare, pyogenic granuloma, herpes labialis, and lichen striatus (2-6). Moreover, we have examined the topical application of imiquimod over the last twelve years in the treatment of 23 children with MC, the demographic data and the therapeutic response of which are summarized in Table 1. Seventeen out of 23 children (73.91%) treated with topical imiquimod once daily under occlusion (including two cases with disseminated lesions) showed a complete remission within 3 to 8 weeks of treatment. Furthermore, 6 other children who switched to other forms of treatment showed a partial remission (55.55%-84.61%) after 10 to 12 weeks of therapy. The only cutaneous adverse reaction to topical imiquimod was a mild to moderate irritation in the application area that was observed in all treated children, whereas no systemic side effects could be seen. Our findings are compatible with those of other groups, who also demonstrated the therapeutic efficacy and safety of topical imiquimod in MC. Interestingly, in two very similar subsequent papers Katz and Swetman (7) and Katz (8,9) expressed the view that "imiquimod is neither efficacious nor safe in the treatment of MC in children". This view was not the result of the author's clinical experience but was exclusively based on the findings of two randomized clinical trials (RCTs). These were carried out in 2006 upon request of the FDA from the drug's original manufacturer (3M) and "definitely showed that imiquimod does not effectively treat MC in children". Surprisingly, today, 10 years after their completion, these RCTs still remain unpublished, whereas the corresponding FDA site provides no information with regard to the researchers, the centers in which these trials were conducted, their research protocol, and the demographic data of the enrolled patients. In a very recent review on childhood skin infections, Rush and Dinulos (10), exclusively based on Dr. Katz's paper, fully adopted this view and stated that "imiquimod is neither efficacious nor safe in the treatment of MC", although they admit that the RCTs cited by the latter still remain unpublished. In contrast to these authors, we reject Dr Katz's inexplicable request to the medical community to fully ignore all articles published in peer-reviewed journals that demonstrate the efficacy and safety of imiquimod in MC. We do not claim that imiquimod is a panacea. However, based on our clinical experience and that of other groups, we are convinced that this compound represents a very useful and painless tool in the dermatologic arsenal for the treatment of MC, an otherwise difficult to manage dermatosis, particularly in children. PMID- 28871936 TI - Xanthoma-like Skin Changes in an Elderly Woman with a Normal Lipid Profile. AB - Dear Editor, An 83-year-old woman developed yellow-brownish infiltrates, nodules, and tumors mimicking xanthomas, mostly involving the periorbital and chest area within three months (Figure 1). She had no abnormalities in serum cholesterol or triglycerides levels. A detailed laboratory analysis revealed the presence of mild monoclonal gammopathy with a presence of immunoglobulin G (IgG) kappa light chains; however, according to hematologist consultation, it did not require medical intervention. Imaging assessment and ultrasound examination did not show any specific involvement of internal organs. The skin biopsy demonstrated necrobiotic areas alternated with foci of xanthogranulomatous infiltration throughout the reticular dermis with extension into subcutaneous tissue. The granulomatous infiltrate was composed of epithelioid, foamy histiocytes in addition to conspicuous giant cells of the Touton type and foreign body type, as well as variable numbers of lymphocytes, plasma cells, and neutrophiles. Lipid vacuoles were seen within the foci of necrobiosis and xanthogranulomatous infiltration (Figure 2). Two months after first admission to our department, the first signs of necrosis within the lesions were noted, and massive necrosis of skin lesions occurred after the following 5 months (Figure 1). Based on the clinical manifestation and histological and laboratory findings, the diagnosis of necrobiotic xanthogranuloma (NXG) was established. In our patient, the extremely late onset of the disease, its very aggressive course, and the absence of malignant hematological disorder were remarkable. The general condition improved after local treatment and a low dose of prednisone. However, patient anamnesis revealed myocardial infarction in the past, congestive heart failure, and atrial fibrillation. Eventually, the patient died due to acute heart failure before alkylating agents could be administered; we consider the patient's death to have been unrelated to NXG. NXG is a rare, chronic granulomatous disorder which was first described in 1980 by Kossard and Winkelmann (1). Currently, less than one hundred fifty cases of this syndrome have been reported in the literature worldwide (2,3). The disease occurs during adulthood, slightly more frequently in women, and usually after the age of 60 years, although the youngest reported patient was 17 years old (3). The disease initially manifests as xanthoma-like eruptions of yellowish or red-orange papules and nodules that coalesce into indurated plaques (4). The size of the lesions typically increases over time or with the next recurrences. In comparison to hyperlipemic and normolipemic xanthomas, the lesions are firmer, more prominent, and more polymorphic (3) with superficial telangiectasias, sometimes erythematous and/or violaceous borders, and atrophy (5). Ulcerations of the lesions were observed in about 50% of patients and tended to be extensive and progressive (4). Skin lesions of NXG can occur anywhere on the body. However, about two-thirds of patients had periorbital involvement, particularly on the upper and/or lower eyelids or elsewhere on the face. The second most commonly affected site was the trunk, predominantly the chest (3-6). However, many skin lesions first appear on the trunk or extremities and subsequently involve the periorbital area (4). More than one body area was affected in about 90% of the published cases (3,4). In individual cases, the occurrence of NXG was noted within scars, after trauma, or in a previously X-ray irradiated area (5). Lesions may be asymptomatic; however, over half of patients asked reported various symptoms, predominantly itching but also burning, tenderness, and even pain (4,5). Periorbital skin lesions are often accompanied by ophthalmic manifestations, mainly scleritis, choroiditis, or conjunctivitis (3), and with complications such as blepharoptosis, restricted ocular motility, and proptosis (4,5). Extracutaneous lesions are most commonly seen in the respiratory tract, including the lungs and larynx, followed by the myocardium, oral cavity, skeletal muscles, kidneys, ovaries, intestine, and other sites (5,6). Extracutaneous involvement was reported in less than 20% of cases (3), but its frequency seems to have increased in recent years (5). Regarding laboratory abnormalities, the majority of patients with NXG (70% and up to 90% depending on the studied population) have a monoclonal gammopathy (more often IgG-kappa than IgG-lambda). Elevated erythrocyte sedimentation rate, anemia, leukopenia, low C1 and C4 levels, and cryoglobulinemia are also frequently present (3-6). Incisional biopsy is recommended to confirm the diagnosis of NXG, but correlations between the clinical presentation and specific histopathologic findings have been poorly characterized so far. The histopathology shows an inflammatory infiltrate composed of macrophages, foam cells, plasma cells, and other inflammatory cells as well as Touton and foreign body-type giant cells in the dermis and subcutaneous tissue. Necrobiosis is usually present, and nodular lymphoid aggregates are common. Cholesterol clefts or asteroid bodies are rare or absent. The epidermis may be atrophic or normal. Special stains are not helpful in establishing the diagnosis of NXG, but immunohistochemistry for CD68 is positive while it is always for CD1a and PS100 negative, like in non-X histiocytosis (4,5). In patients without a known myeloproliferative disorder, bone marrow biopsy may reveal atypical or increased plasma cells and, very rarely, true multiple myeloma (5). As mentioned above, NXG can be a manifestation of multiple myeloma. However, chronic lymphocyte leukemia, B-cell lymphoma, and other lymphoproliferative diseases have also been reported in patients with NXG (3). Remarkably, hematological disorders may emerge many years before or after the onset of skin lesions (even up to 11 years) (4). According to available literature data, the course of the disease is usually chronic and slowly progressive, and the prognosis is relatively good in the absence of co-occurrence of malignant hematological disorders ([5-7). Aside from hyperlipemic and normolipemic xanthomas, the differential diagnosis of NXG includes multifocal necrobiosis lipoidica, granuloma annulare, foreign-body granuloma, juvenile xanthogranuloma, rheumatoid nodules, and amyloidosis (4). In 5 cases from the literature, xanthoma and NXG were present at the same time (3). Despite several hypotheses, the etiopathogenesis of NXG remains unknown (3,4,8). For that reason and due to the rarity of the disease, the optimal therapy has not been not defined. Frequently, chlorambucil or melphalan have been used alone or in combination with prednisone (4). Treatment may result in remission of symptoms on the skin, but it does not provide a permanent cure (8). There are also single reports of the successful use of thalidomide, lenalidomide, cyclophosphamide, dexamethasone, interferon 2a and 2b, plasmapheresis and hydroxychloroquine, azathioprine, infliximab, and autologous bone marrow transplantation (3). Methotrexate seems to be ineffective (9). Local therapy, including local steroids, laser CO2, or radiotherapy, results in partial improvement (3,4). Skin lesions which relapsed or were unresponsive to treatment could be excised surgically and the defects resurfaced with skin grafts. [2]. PMID- 28871937 TI - [Pleurotus ferulae polysaccharide adjuvant enhances the immune infertility of CZP3DNA vaccine]. AB - Objective To investigate the effect of Pleurotus ferulae polysaccharide (PFP) as an adjuvant on the infertility induced by canine zona pellucida 3 (CZP3) DNA vaccine (pcDNA3-CZP3). Methods Female mice were intramuscularly immunized with pcDNA3-CZP3 alone or co-immunized with pcDNA3-CZP3 and aluminum adjuvant or PFP for three times. CZP3-specific antibody titers of antiserum were determined by ELISA. The maturation of dendritic cells (DCs) and the proliferation of T lymphocytes were detected by flow cytometry. The litter of the immunized mice were counted. Results Compared with pcDNA3-CZP3 alone, pcDNA3-CZP3 combined with aluminum or PFP significantly increased the CZP3-specific antibody titers. Moreover, PFP as an adjuvant significantly up-regulated the expressions of CD86 and MHCII on DCs, enhanced the proliferation of T cells, and decreased the fertility rate and mean litter. Conclusion PFP can enhance the infertility efficacy of CZP3 DNA vaccine through increasing the humoral and cellular immune responses, promoting DC maturation and T cell proliferation. PMID- 28871938 TI - [Shendi granules regulates the balance of T cell subsets and down-regulates podocalyxin in rats with mesangial proliferative glomerulonephritis]. AB - Objective To observe the effect of Shendi granules on T cell subsets and podocyte marker protein in rats with mesangial proliferative glomerulonephritis (MsPGN), and study possible mechanism. Methods Totally 40 SD rats were randomly divided into the model group, valsartan group, Shendi granule group and normal group. The Shendi granule group were given 4 g/(kg.d) of Shendi granule by gavage; the valsartan group were given 10.3 mg/(kg.d) of valsartan by gavage; the model group and normal group were given the same amount of saline per day by gavage. The treatments lasted 12 weeks. Routine biochemical method was used to quantify 24 hour urine protein; the numbers of CD4+ and CD8+ T cells were detected by flow cytometry; the serum levels of interleukin 2 (IL-2), IL-4 and IL-17, the levels of urinary podocalyxin (PCX) and B7-1, the renal calcineurin (CaN) content were determined by ELISA. Results Compared with the normal group, the levels of 24 hour urine protein, CD8+ T cells, serum IL-2 and IL-17, urinary PCX and B7-1, CaN in the model group were higher. The above indexes in the valsartan group and control group were lower than those in the model group, they were lower in the Shendi granule group than in the valsartan group. The whole blood CD4+ T cell number and serum IL-4 level in the model group were lower than those in the normal group, they were higher in the valsartan group and control group than in the model group. Compared with the valsartan group, the Shendi granule group had a better improvement. Conclusion Shendi granule could reduce 24-hour urine protein effectively. The mechanism may be related to the regulation of CD4+ T and CD8+ T cell numbers, the down-regulated expressions of serum IL-2, IL-17, the decreased levels of PCX and B7-1 in urine, CaN in kidney tissue, and the up regulated level of serum IL-4. PMID- 28871939 TI - [Astragalus polysaccharide alleviates lipopolysaccharide-induced lung injury in rats by inhibiting neutrophil activation]. AB - Objective To study the effects of Astragalus polysaccharide (APS) on rat lung injury induced by lipopolysaccharide (LPS). Methods A total of 36 adult SD rats were randomly divided into control group, LPS model group and APS administration group. Acute lung injury was induced by a single intratracheal injection of LPS. Lung injury in rats was observed by HE staining. The changes of proinflammatory factors such as tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL 1beta) were detected by ELISA. The numbers of white blood cells (WBCs) and neutrophils in bronchoalveolar lavage fluid (BALF) were determined by cell counting. The activity of myeloperoxidase (MPO) and reactive oxygen species (ROS) were tested by the respective kits. Results Compared with the control group, the LPS-induced model group showed pulmonary edema and increased vascular permeability, upregulated levels of TNF-alpha and IL-1beta in BALF, significantly ascended numbers of WBCs and neutrophils, enhanced MPO activity and increased ROS level. However, administration of APS suppressed LPS-induced vascular permeability, tissue injury and inflammation in the rat lung. APS also suppressed LPS-induced neutrophilic inflammation in BALF. MPO activity and ROS level decreased significantly as well. Conclusion Administration of APS suppresses LPS induced lung injury via inhibiting of neutrophil activation in rats. PMID- 28871940 TI - [The level of IL-2 and IL-6 in stimulated peripheral lymphocyte supernatants of kidney transplant recipients can predict acute renal allograft rejection]. AB - Objective To detect the expressions of interleukin 2 (IL-2) and IL-6 using in vitro lymphocyte stimulation and flow cytometric microcarrier assay, and explore the feasibility of the method for predicting the acute rejection in kidney transplant recipients. Methods Using phorbol myfismte acetate (PMA)/ionomycin, we stimulated the peripheral blood lymphocytes in vitro from 52 kidney transplant recipients, including 22 ones with acute rejection (AR) and 30 with stable allograft function (STA). Eight hours later, we detected the expressions of IL-2 and IL-6 in cell culture supernatant by flow cytometric microcarrier assay. IL-2 and IL-6 expressions were compared between in the stimulated cell culture supernatant and in the unstimulated plasma, as well as between the two groups to evaluate the ability of the method predicting the acute rejection. Results The expressions of IL-2 and IL-6 in the AR group were significantly higher than those in the STA group after the peripheral blood lymphocytes were stimulated. In both of the groups, the expressions of IL-2 and IL-6 in stimulated lymphocyte culture supernatants were significantly higher than those in the unstimulated plasma. The sensitivity and specificity of combined IL-2 and IL-6 detection in stimulated lymphocyte culture supernatants for predicting the acute rejection were 81.8% and 90%, respectively, which were higher than the individual sensitivity and specificity. Conclusion The method of detecting both IL-2 and IL-6 expressions in stimulated peripheral lymphocyte culture supernatants by flow microsphere carrier assay had good sensitivity and specificity for predicting the acute renal allograft rejection in kidney transplant recipients. PMID- 28871941 TI - [Elevated expression of endothelin 2 in lung tissues of asthmatic rats after exposed to cigarette smoke and its mechanism]. AB - Objective To study the effect of cigarette smoke exposure on the expression of endothelin 2 (ET-2) in bronchial epithelium of asthmatic rats. Methods Asthma models were established through intraperitoneal injection of 1 mL chicken ovalbumin (OVA)/Al(OH)3 mixture (asthma model group, n=6); based on the asthma models, exposure to smoking gas lasted four weeks with 10 cigarettes per day (smoke-exposed asthma group, n=6); based on the smoke-exposed asthma models, the rats were treated with intraperitoneal injection of dexamethasone 2 mg/(kg.d), intragastric administration of ET receptor inhibitor bosentan 100 mg/(kg.d) and combined use, respectively named dexamethasone treated group, bosentan treated group, and dexamethasone-bosentan treated group, 6 rats in every group. What's more, other 6 rats were only subjected to intraperitoneal injection of 1 mL normal saline as normal controls; in addition to the injection of saline, cigarette smoke control group (n=6) was set up by the exposure to smoking gas for four weeks with 10 cigarettes per day. Bronchoalveolar lavage fluid (BALF) was collected from the upper lobe of the left lung for cell counting and classification. Pathological changes of the right upper lung lobe tissues were observed by HE staining. In other lung tissues, the expression of JNK1/2 was detected by Western blotting; ET-2 was tested by Western blotting and immunohistochemistry; thiobarbituric acid reactive substances (TBARS) assay and trace enzyme standard method were used to measure malondialdehyde (MDA) and glutathione (GSH), respectively. Results Compared with normal control group, the number of airway inflammation cells increased in the BALF, and the expressions of ET-2, JNK1/2, MDA and GSH increased in the lung tissues of cigarette smoke control group, asthma model group and cigarette smoke-exposed asthma group. Compared with cigarette smoke-exposed asthma group, the number of airway inflammation cells decreased in the BALF, and the expressions of ET-2, JNK1/2, MDA and GSH decreased in the lung tissues of the dexamethasone treated group, bosentan treated group, and dexamethasone-bosentan treated group. Airway inflammation was attenuated and the staining intensity of ET-2 in the lung tissue was reduced in the dexamethasone treated group, bosentan treated group, and dexamethasone-bosentan treated group, which were more obvious in the dexamethasone-bosentan treated group. Conclusion Cigarette smoke exposure obviously aggravates airway inflammation in asthmatic rats, and bosentan can effectively alleviate the airway inflammation. The mechanism of the inflammation may be related to ET-2 and JNK1/2 signaling pathway. PMID- 28871942 TI - [gamma-secretase inhibitor MW167 reduces the level of GATA3 in peripheral blood mononuclear cells in children with respiratory syncytial virus bronchiolitis]. AB - Objective To study the changes of GATA3 in peripheral blood mononuclear cells (PBMCs) of children with respiratory syncytial virus (RSV) bronchiolitis after gamma-secretase inhibitor (GSI) MW167 blocks Notch signaling. Methods The study enrolled 30 patients with RSV bronchiolitis and 25 normal controls. PBMCs were separated and divided into normal control group, RSV group, and MW167 treated group. The level of interleukin-4 (IL-4) in supernatant was detected by ELISA; level of GATA3 mRNA was determined by real-time fluorescent quantitative PCR; and the expressions of Notch1 intracellular domain (NICD) and GATA3 proteins were examined by Western blotting. Results Compared with RSV group, the levels of IL-4 decreased, and the levels of GATA3 mRNA, NICD and GATA3 proteins also significantly decreased in MW167 treated group. Conclusion GSI can block the Notch signaling pathway and decrease the level of GATA3. PMID- 28871943 TI - [Immunization with Bifidobacterium bifidum-vectored OprI vaccine of Pseudomonas aeruginosa enhances inhibitory effect on P. aeruginosa in mice]. AB - Objective To study the pulmonary bacterial loads, splenocyte proliferation, distributions of T cell subsets and cell apoptosis in mice immunized with Bifidobacterium bifidum-vectored OprI (Bb-OprI) vaccine of Pseudomonas aeruginosa and challenged with P. aeruginosa PA01 strain. Methods BALB/c mice were immunized with 5*109 CFUs of vaccine by intragastric administration, 3 times a week for 3 weeks, and challenged intranasally with 5*106 CFUs of PA01 strain at the fourth week after the first immunization. At the second week after the challenge, all mice were sacrificed to separate their lungs and spleens, and the pulmonary bacterial loads were counted. The proliferation of the splenocytes was determined by MTT assay. The splenic CD4+, CD8+ T cell subsets and the apoptotic rate of splenocytes were detected by flow cytometry. Results The number of pulmonary bacterial colonies in the mice immunized with the vaccine and challenged with PA01 strain decreased, while the proliferation of splenocytes and the proportion of CD4+ T cells markedly increased, and the apoptosis of splenocytes was notably reduced. Conclusion The intragastric vaccination of recombinant Bb-OprI vaccine can increase the proportion of CD4+ T cells and enhance the inhibitory effect on P. aeruginosa. PMID- 28871944 TI - [Effect of Kruppel-like factor 2 (KLF2) over-expression on activities of chicken PPARgamma and C/EBPalpha promoters]. AB - Objective To examine the effect of Kruppel-like factor 2 (KLF2) over-expression on the activities of chicken peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha) promoters. Methods Luciferase reporter assay was used to investigate the effect of KLF2 over expression on reporter activities of 6 kinds of chicken PPARgamma promoter construct and 5 kinds of chicken C/EBPalpha promoter construct in DF1 cells. Results KLF2 over-expression significantly inhibited the reporter activities of 4 kinds of chicken PPARgamma promoter construct (-1978/-82, -1513/-82, -1254/-82 and -1019/-82), but had no significant effect on the reporter activities of 2 kinds of PPARgamma promoter construct (-513/-82 and -320/-82). In addition, the effect of KLF2 over-expression on the reporter activities of 2 kinds of PPARgamma promoter construct (-1513/-82 and -1254/-82) was significantly greater than that on the other 2 kinds of PPARgamma promoter construct (-1978/-82 and -1019/-82). Additionally, KLF2 over-expression inhibited the reporter activity of one kind of C/EBPalpha promoter construct (-1863/+332), and enhanced the reporter activities of 4 kinds of C/EBPalpha promoter construct (-1318/+332, -891/+332, -538/+332 and -123/+332). There was no significant difference in the promoting effect of KLF2 over-expression among the 4 kinds of C/EBPalpha promoter construct (-1318/+332, 891/+332, -538/+332 and -123/+332). Conclusion The effect of KLF2 over-expression on the activities of chicken PPARgamma and C/EBPalpha promoters are different among the constructs containing various lengths. PMID- 28871945 TI - [Over-expression of miR-497 promotes the proliferation of U87 glioma cells by targeting neuregulin receptor degradation protein 1]. AB - Objective To investigate the effect of miR-497 over-expression on the proliferation of U87 human glioma cells. Methods We packaged both pGLV3/H1-NC lentivirus as a negative control group and pGLV3/H1-miR-497 lentivirus as an experimental group, and then constructed U87-NC and U87-miR-497 cell lines, respectively. The relationship between miR-497 and neuregulin receptor degradation protein 1 (Nrdp1) was analyzed by luciferase reporter assay in U87 cells; cell colony formation assay was used to detect cell proliferation and flow cytometry to detect cell cycle; the expressions of Nrdp1, AKT and phosphorylated AKT (p-AKT) were determined by Western blotting. Results We successfully packaged pGLV3/H1-NC and pGLV3/H1-miR-497 lentivirus, and obtained stable U87-NC and U87 miR-497 cell lines. When miR-497 was over-expressed in U87 cells, the cell colony formation ability was enhanced compared with the control group U87-NC. The luciferase reporter assay confirmed that miR-497 targeted Nrdp1 in U87 cells. In the stable infected cells, the level of Nrdp1 protein decreased and p-AKT protein increased, while the AKT protein did not change significantly after over expression of miR-497. Conclusion Over-expression of miR-497 promotes the proliferation of glioma cells U87 by targeting Nrdp1. PMID- 28871946 TI - [Mechanism for the inhibition of proliferation and promotion of apoptosis in Huh7.5 cells by iron overload]. AB - Objective To investigate the effect of iron overload on biological activity and apoptosis in Huh7.5 cells. Methods Huh7.5 cells were cultured in the medium supplemented with 50, 100, 200 MUmol/L ferric ammonium citrate (FAC). Fluorescence microscopy was employed to determine cell iron load labeled by Phen Green FL; proliferation activity of Huh7.5 cells was evaluated by MTT assay; protein and mRNA levels of transferrin receptor (TfR1), TfR2, divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1) in Huh7.5 cells were detected by Western blotting and real-time PCR, respectively; cell reactive oxygen species (ROS) labeled by dichlorofluorescin diacetate (DCFH-DA) and cell apoptosis labeled by annexinV-FITC/PI were analyzed by flow cytometry. Results FAC treatment increased intracellular iron load in a dose-dependent manner. Compared with control group, mRNA and protein expressions of TfR1, TfR2 and DMT1 were down regulated, while mRNA and protein expression of FPN1 was significantly up regulated in FAC treated groups. With the increasing dose of FAC, intracellular ROS level increased significantly and cell proliferation activity decreased significantly. The cell apoptosis rate in FAC treated groups were remarkably higher than that in control group, but after antioxidant N-acetylcysteine (NAC) was added, the cell apoptosis in FAC treated group was inhibited obviously. Conclusion Iron overload can inhibit the proliferation and promote the apoptosis of Huh7.5 cells through oxidative stress. PMID- 28871947 TI - [Knock-down of KHDRBS3 gene inhibits proliferation of human ovarian cancer CAOV-3 cells]. AB - Objective To investigate the effect of KH RNA binding domain-containing, signal transduction-associated 3 (KHDRBS3) gene on the proliferation of human ovarian cancer CAOV-3 cells in vitro. Methods The logarithmic growth phase cells were divided into non-transfection group, unrelated small interfering RNA (siRNA) sequence transfection group and KHDRBS3-siRNA transfection group. Reverse transcription PCR and Western blotting were used to verify the result of KHDRBS3 gene silencing. The proliferation of CAOV-3 cells in different groups was compared by MTT assay. The cell cycle distribution of CAOV-3 cells in different treatment groups was detected by flow cytometry. Results KHDRBS3-siRNA transfection significantly decreased the mRNA and protein levels of KHDRBS3 gene in CAOV-3 cells. After the knock-down of KHDRBS3 gene in CAOV-3 cells, the proliferation of the cells markedly decreased, the percentage of G0/G1 phase cells increased, and the percentage of S phase cells decreased, while the percentage of G2/M phase cells did not change significantly. Conclusion Down regulating the KHDRBS3 gene can cause G0/G1 phase arrest and inhibit cell proliferation in CAOV-3 cells. PMID- 28871948 TI - [Over-expressed HER2 enhances proliferation, migration and invasion of melanoma B16 cells]. AB - Objective To establish a melanoma B16 cell line stably over-expressing the HER2 (ErbB2) gene and study its effect on the proliferation, migration and invasion of melanoma cells. Methods The recombinant plasmid pCMV3-ErbB2 was transfected into B16 melanoma cell line by cationic liposome. The positive clones were screened with hygromycin B. Real-time quantitative PCR (qRT-PCR) was utilized to determine the expression of ErbB2 mRNA. Immunofluorescence was used to evaluate the expression of ErbB2 protein. MTT assay was applied to detect the cell proliferation ability. The cell migration ability was examined by a scratch assay. TranswellTM assay was performed to determine the effect of HER2 over expression on the capability of B16s invasion. Results The cell line over expressing HER2 was successfully established as showed by qRT-PCR. Over expression of HER2 remarkably enhanced the proliferation, invasion and migration of B16 cells. Conclusion Over-expression of HER2 can enhance the growth and invasion of B16 cells. PMID- 28871949 TI - [Knock-down of ZEB1 inhibits the proliferation, invasion and migration of gastric cancer cells]. AB - Objective To down-regulate the expression of zinc-finger E-box binding homeobox 1 (ZEB1) gene by shRNA, and investigate its effect on invasion, migration and proliferation, as well as the related gene expressions of lncRNA HOTAIR and E cadherin in human gastric cancer BGC823 cells. Methods RNA interfering (RNAi) was used to knock down ZEB1 in gastric cancer BGC823 cells. The recombinant plasmid shZEB1 was constructed and transfected into the gastric cancer BGC823 cells by LipofectamineTM 2000, and the stably transfected cells were isolated by G418 selection and limited dilution. The expression of ZEB1 mRNA and protein was detected by real-time quantitative PCR and Western blot analysis. Cell proliferation was determined by MTT assay, and the invasion and migration abilities of BGC823 cells were monitored by TranswellTM invasion assay and wound healing assay, respectively. The expressions of lncRNA HOTAIR and E-cadherin mRNA were detected by real-time quantitative PCR. Results After ZEB1 expression was successfully down-regulated in BGC823 cells by siRNA, the proliferation, invasion and migration rates in shZEB1 transfection group were significantly lower than those in control group; meanwhile, the expression of lncRNA HOTAIR was reduced and E-cadherin expression was enhanced. Conclusion Knock-down of ZEB1 expression by RNA interference can decease lncRNA HOTAIR expression and restrain cell proliferation, invasion and migration in gastric cancer BGC823 cells. PMID- 28871950 TI - [Effect of microRNA-155 on inflammatory response and lipid uptake of macrophages and its mechanism]. AB - Objective To investigate the effect of microRNA-155 on inflammatory response and lipid uptake of macrophages after the cells are stimulated by ox-LDL and its potential mechanism. Methods Macrophage RAW264.7 cells were treated with 0, 25, 50 and 100 MUg/mL ox-LDL for 24 hours or with 50 MUg/mL ox-LDL for 0, 6, 12, 24 hours. The level of miR-155 was evaluated in all above samples through real-time quantitative PCR. In our research, RAW264.7 cells were divided into six groups: control group, ox-LDL group, ox-LDL/negative control group, ox-LDL/anti-miR-155 group, ox-LDL/shRNA negative control group and ox-LDL/PPARgamma-shRNA group. Oil red O staining was used to observe lipid uptake in the cells. Filipin staining was used to evaluate the cellular uptake of ox-LDL. Cholesterol testing was performed to examine the levels of total cholesterol (TC) and free cholesterol (FC). Real-time quantitative PCR was done to detect the expressions of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and IL-6 mRNAs. According to study purpose, we explored the potential mechanisms of miR-155 inhibitor (including control group, ox-LDL group, ox-LDL/negative control group and ox-LDL/miR-155 inhibitor group), miR-155 mimic (including negative control group and miR-155 mimic group), and PPARgamma shRNA (including control group, ox LDL group, ox-LDL/shRNA negative control group and ox-LDL/PPARgamma shRNA group) in ox-LDL-treated RAW264.7 cells through evaluating the expressions of p-STAT3, PPARgamma, CD36 and NF-kappaBp65 using Western blotting. Results Ox-LDL stimulation increased the relative expression of miR-155 in a dose- and time dependent manner. Through oil red O staining, Filipin staining, cholesterol testing and real-time PCR experiment, we found the relative absorbance, levels of TC and FC, filipin fluorescence intensity, and levels of TNF-alpha, IL-1beta and IL-6 mRNAs were significantly lower in ox-LDL/anti-miR-155 group than in ox-LDL and ox-LDL/negative control group. Similarly, the relative absorbance, levels of TC and FC, filipin fluorescence intensity and levels of TNF-alpha, IL-1beta and IL-6 mRNAs were significantly lower in ox-LDL/ PPARgamma shRNA group than in ox LDL group and ox-LDL/shRNA negative control group. The expressions of p-STAT3, PPARgamma, CD36 and NF-kappaBp65 proteins were suppressed in ox-LDL/anti-miR-155 group as compared with ox-LDL group and ox-LDL/negative control group. Similarly, p-STAT3, PPARgamma, CD36 and NF-kappaBp65 protein levels decreased in ox LDL/PPARgamma shRNA as compared with ox-LDL/vector group. Moreover, p-STAT3, PPARgamma, CD36 and NF-kappaBp65 protein levels were higher in miR-155 mimic group than in negative control group. Conclusion Mediated by PPARgamma, miR-155 induced inflammation response and lipid uptake of macrophages via STAT3/NF-kappaB signal pathway and CD36. PMID- 28871951 TI - [Inhibition of miR-18a increases expression of estrogen receptor 1 and promotes apoptosis in human HTR8 trophoblasts]. AB - Objective To investigate the role of pre-eclampsia related miR-18a in regulating estrogen receptor 1 (ER1) expression, cell cycle and apoptosis in HTR8 human trophoblasts. Methods HTR8 cells were transfected with synthesized negative control (NC) miRNA, miR-18a and miR-18a inhibitor, respectively. The mRNA expressions of miR-18a and ER1 were determined by reverse transcription PCR (RT PCR). The protein expression level of ER1 was examined by Western blotting. The cell cycle and apoptosis were evaluated by flow cytometry. Results The mRNA level of miR-18a was significantly up-regulated in miR-18a-transfected group, while down-regulated in miR-18a inhibitor group as compared with the NC group in HTR8 cells. Compared with the NC group, both mRNA and protein expression levels of ER1 were significantly higher in the miR-18a inhibitor group. Cell cycle analysis showed that no significant difference was observed among the three groups. The apoptosis rate was significantly higher in the miR-18a inhibitor group as compared with the other two groups. Conclusion Inhibition of miR-18a increases the expression of ER1 and promotes apoptosis in HTR8 human trophoblasts. PMID- 28871952 TI - [Up-regulated expression of NK1R in eosinophil-enriched blood cells from patients with chronic spontaneous urticaria]. AB - Objective To investigate the expressions of substance P (SP) and neurokinin-1 receptor (NK1R) in eosinophil-enriched blood cells from patients with chronic spontaneous urticaria (CSU). Methods Peripheral venous blood samples were collected from patients with CSU and healthy controls (HCs), and then stimulated with crude extracts of Artemisia pollen, dust mite, and Platanus pollen (all at concentrations of 0.1 and 1.0 MUg/mL). The expressions of SP and NK1R in eosinophil-enriched blood cells were detected by flow cytometry. Results Compared with HCs, eosinophil proportion in peripheral blood of CSU patients increased 1.2 fold. Percentage of NK1R+ eosinophils in the patients with CSU was elevated up to 66% compared with HCs when cultured in the medium only. However, the level of SP decreased by 40% in the CSU patients. In eosinophil-enriched blood cells from the CSU patients, the crude extract of dust mite at 0.1 MUg/mL induced approximately 1.11-fold increase of NK1R expression. Conclusion Expression of NK1R increases in the eosinophils of CSU patients. Blockers of NK1R might be used for CSU treatment. PMID- 28871953 TI - [Detection and analysis of serum level of anti-Candida enolase IgG antibody in patients with autoimmune diseases]. AB - Objective To detect IgG antibody against Candida enolase in the sera of patients with autoimmune diseases. Methods Using purified recombinant Candida enolase as the coating antigen, an ELISA was established for enolase IgG antibody detection and the reactive conditions were optimized. The enolase IgG antibody in the sera from patients with autoimmune diseases and healthy controls were detected by ELISA. The specificity of the positive sera was confirmed by Western blotting. Results The study collected 70 serum samples from the patients with autoimmune diseases and 44 from the healthy individuals. ELISA showed anti-Candida enolase IgG antibody in 19 cases of the autoimmune disease group and and 3 cases of the healthy control group, the positive rates of which were 27.14% (19/70) and 6.82% (3/44), respectively. In the autoimmune disease group, the positive rate of anti Candida enolase IgG antibody in the systemic lupus erythematosus patients was 45.8% (11/24), significant higher than that in the rheumatoid arthritis patients (11.8%, 2/17). Western blotting validated the specificity of the positive sera. Conclusion The positive rate of anti-Candida enolase IgG antibody in patients with autoimmune disease is high, which would be an interference factor in the application of IgG antibody detection for the diagnosis of invasive candidiasis. PMID- 28871954 TI - [Elevated serum IL-25 levels in rheumatoid arthritis patients with bone erosion and interstitial lung disease]. AB - Objective To detect the serum levels of IL-25 and IL-17 in rheumatoid arthritis (RA) patients and investigate the potential relationship with bone erosion and concomitant interstitial lung disease (ILD). Methods The study enrolled a total of 117 RA patients and 56 healthy subjects as controls. The serum levels of IL-25 and IL-17 were determined by ELISA, and rheumatoid factor (RF) was detected by turbidimetric immunoassay, anticyclic citrullinated peptide (anti-CCP) antibody as well as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were also tested. ILD was identified on high-resolution computed tomography (HR-CT), the degree of bone erosion was inspected by musculoskeletal ultrasonography, and radiographic grade was graded by Sharp-van der Heijde Score (SHS). Disease activity in RA was scored with the DAS28 and visual analogue scale (VAS). Correlation analysis was used to evaluate the correlations of IL-25 and IL-17 in different groups. Results Compared with healthy control group, the serum levels of IL-25 and IL-17 increased significantly in the patients with RA. Compared with bone erosion negative group, the serum level of IL-25 was higher significantly in bone erosion group. The level of IL-25 was higher in the ILD group of RA patients than the non-ILD group. In addition, there were positive correlations between the serum level of IL-25 and RF-IgG (r=0.285), RF-IgA (r=0.314), RF-IgM (r=0.380). Meanwhile, the serum level of IL-17 had the positive correlations with RF-IgG (r=0.198) and RF-IgM (r=0.273). Both of them had no correlations with anti-CCP antibody. Conclusion The serum level of IL-25 is raised in RA patients with bone erosion and ILD. PMID- 28871955 TI - [The polymorphisms of IL-13 rs848G/T and rs1295686A/G in Guangxi population of China and comparative analysis]. AB - Objective To investigate the distribution characteristics of polymorphisms of rs848G/T and rs1295686A/G in the interleukin 13 (IL-13) gene in Guangxi normal people and compare them with those of Europeans, Beijing peoples, Japanese and Africans published in HapMap. Methods The rs848G/T and rs1295686A/G of IL-13 gene in 275 cases of Guangxi people were genotyped by SNaPshot and DNA sequencing. The differences between groups were analyzed statistically. Results Three genotypes, namely GG, GT and TT, were found in rs848G/T with frequency distributions of 38.2%, 47.3% and 14.5%, respectively. There was no significant difference in each genotype and allele frequency between different genders in Guangxi people. However, there were significant differences in the genotype frequency of rs848G/T in Guangxi people compared with those of Europeans, Japanese and Africans published in HapMap. The allele frequency of rs848G/T between Guangxi people and the other four groups was statistically different. Three genotypes, namely AA, AG and GG, were found in rs1295686A/G with frequency distributions of 11.6%, 46.2% and 42.2%, respectively. There was no significant difference in the genotypes and allele frequency in rs1295686A/G between different genders in Guangxi people, while they were statistically different from those of Europeans and Africans published in HapMap. Conclusion There are different degrees of variance in the polymorphisms of rs848G/T and rs1295686A/G of IL-13 gene in different regions. PMID- 28871956 TI - [Screening of specific IgE-binding epitopes of dust mite allergens using short peptide array]. AB - Objective To screen the possible linear epitopes of major and mid-potency allergens in Dermatophagoides farinae (Der f1, Der f2, Der f4, Der f5 and Der f7). Methods Short peptides were synthesized on the basis of the amino acid sequences in active fraction of Der f1, Der f2, Der f4, Der f5 and Der f7. Each peptide had eight amino acids in length and seven of them were overlapped with each other. Put these peptides to the chip to build microarrays that would have immunoreaction with human serum IgE. Then the chips were scanned to analyze the data. Results A total of 1128 short peptides from the above five groups of allergens were synthesized, and the microarray chips were constructed. Six serum samples from children who were allergic to Dermatophagoides farinae were mixed and added to the microarray chips. The chips were scanned and analyzed, and the results showed that Der f1 had four epitopes (46-53aa, 71-78aa, 99-110aa and 179 186aa), that Der f2 had three epitopes (15-22aa, 80-89aa and 106-113aa), that Der f 4 had six epitopes (69-82aa, 107-116aa, 225-232aa, 261-268aa, 355-365aa and 483 496aa), that Der f5 had one epitope (102-109aa), and Der f7 had three epitopes (32-39aa, 52-64aa and 100-107aa). Conclusion We identified the linear epitopes of Der f1, Der f2, Der f4, Der f5 and Der f7. PMID- 28871957 TI - [Expression of BRCA2 in tumor tissues in patients with laryngeal squamous cell carcinoma and its clinical significance]. AB - Objective To determine the role of breast cancer susceptibility gene 2 (BRCA2) in laryngeal squamous cell carcinoma and investigate its clinical implication. Methods The expression of BRCA2 was examined by immunohistochemistry in 62 tissues of pathologically identified laryngeal squamous cell carcinoma and 23 tissues of vocal fold polyp. The relationships between BRCA2 expression and clinicopathological characteristics were further analyzed. The expression of BRCA2 mRNA and protein were detected by real-time quantitative PCR (qRT-PCR) and Western blot analysis in pathologically identified laryngeal squamous cell carcinoma tissues and corresponding normal tissues. Results The immunohistochemistry showed that the expression rate of BRCA2 in laryngeal carcinoma tissues and vocal fold polyp tissues were 29.03%(18/62) and 69.56%(16/23), respectively. The expression of BRCA2 was not significantly related with patients' gender, age, smoking, differentiation degree, cervical lymph node metastasis, and clinical stage. There was a negative correlation between BRCA2 expression and T stage. The qRT-PCR and Western blotting showed that BRCA2 mRNA and protein expression in the laryngeal squamous carcinoma tissues was lower than that in the corresponding normal tissues. Conclusion The expression of BRCA2 is low in laryngeal squamous cell carcinoma, and it is negatively correlated with T stage. PMID- 28871958 TI - Control of AMPA receptor activity by the extracellular loops of auxiliary proteins. AB - At synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs gamma2 and gamma8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of gamma2 and gamma8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of gamma2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate. PMID- 28871959 TI - Dipolar extracellular potentials generated by axonal projections. AB - Extracellular field potentials (EFPs) are an important source of information in neuroscience, but their physiological basis is in many cases still a matter of debate. Axonal sources are typically discounted in modeling and data analysis because their contributions are assumed to be negligible. Here, we established experimentally and theoretically that contributions of axons to EFPs can be significant. Modeling action potentials propagating along axons, we showed that EFPs were prominent in the presence of terminal zones where axons branch and terminate in close succession, as found in many brain regions. Our models predicted a dipolar far field and a polarity reversal at the center of the terminal zone. We confirmed these predictions using EFPs from the barn owl auditory brainstem where we recorded in nucleus laminaris using a multielectrode array. These results demonstrate that axonal terminal zones can produce EFPs with considerable amplitude and spatial reach. PMID- 28871960 TI - Striatal fast-spiking interneurons selectively modulate circuit output and are required for habitual behavior. AB - Habit formation is a behavioral adaptation that automates routine actions. Habitual behavior correlates with broad reconfigurations of dorsolateral striatal (DLS) circuit properties that increase gain and shift pathway timing. The mechanism(s) for these circuit adaptations are unknown and could be responsible for habitual behavior. Here we find that a single class of interneuron, fast spiking interneurons (FSIs), modulates all of these habit-predictive properties. Consistent with a role in habits, FSIs are more excitable in habitual mice compared to goal-directed and acute chemogenetic inhibition of FSIs in DLS prevents the expression of habitual lever pressing. In vivo recordings further reveal a previously unappreciated selective modulation of SPNs based on their firing patterns; FSIs inhibit most SPNs but paradoxically promote the activity of a subset displaying high fractions of gamma-frequency spiking. These results establish a microcircuit mechanism for habits and provide a new example of how interneurons mediate experience-dependent behavior. PMID- 28871961 TI - Genetic epidemiology of dengue viruses in phase III trials of the CYD tetravalent dengue vaccine and implications for efficacy. AB - This study defined the genetic epidemiology of dengue viruses (DENV) in two pivotal phase III trials of the tetravalent dengue vaccine, CYD-TDV, and thereby enabled virus genotype-specific estimates of vaccine efficacy (VE). Envelope gene sequences (n = 661) from 11 DENV genotypes in 10 endemic countries provided a contemporaneous global snapshot of DENV population genetics and revealed high amino acid identity between the E genes of vaccine strains and wild-type viruses from trial participants, including at epitope sites targeted by virus neutralising human monoclonal antibodies. Post-hoc analysis of all CYD14/15 trial participants revealed a statistically significant genotype-level VE association within DENV-4, where efficacy was lowest against genotype I. In subgroup analysis of trial participants age 9-16 years, VE estimates appeared more balanced within each serotype, suggesting that genotype-level heterogeneity may be limited in older children. Post-licensure surveillance is needed to monitor vaccine performance against the backdrop of DENV sequence diversity and evolution. PMID- 28871962 TI - Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. AB - A sudden aversive event produces escape behaviors, an innate response essential for survival in virtually all-animal species. Nuclei including the lateral habenula (LHb), the lateral hypothalamus (LH), and the midbrain are not only reciprocally connected, but also respond to negative events contributing to goal directed behaviors. However, whether aversion encoding requires these neural circuits to ultimately prompt escape behaviors remains unclear. We observe that aversive stimuli, including foot-shocks, excite LHb neurons and promote escape behaviors in mice. The foot-shock-driven excitation within the LHb requires glutamatergic signaling from the LH, but not from the midbrain. This hypothalamic excitatory projection predominates over LHb neurons monosynaptically innervating aversion-encoding midbrain GABA cells. Finally, the selective chemogenetic silencing of the LH-to-LHb pathway impairs aversion-driven escape behaviors. These findings unveil a habenular neurocircuitry devoted to encode external threats and the consequent escape; a process that, if disrupted, may compromise the animal's survival. PMID- 28871964 TI - Ethics in Radiation Oncology and the American Society for Radiation Oncology's Role. PMID- 28871963 TI - Species-specific modulation of food-search behavior by respiration and chemosensation in Drosophila larvae. AB - Animals explore their environment to encounter suitable food resources. Despite its vital importance, this behavior puts individuals at risk by consuming limited internal energy during locomotion. We have developed a novel assay to investigate how food-search behavior is organized in Drosophila melanogaster larvae dwelling in hydrogels mimicking their natural habitat. We define three main behavioral modes: resting at the gel's surface, digging while feeding near the surface, and apneic dives. In unstimulated conditions, larvae spend most of their time digging. By contrast, deep and long exploratory dives are promoted by olfactory stimulations. Hypoxia and chemical repellents impair diving. We report remarkable differences in the dig-and-dive behavior of D. melanogaster and the fruit-pest D. suzukii. The present paradigm offers an opportunity to study how sensory and physiological cues are integrated to balance the limitations of dwelling in imperfect environmental conditions and the risks associated with searching for potentially more favorable conditions. PMID- 28871965 TI - Ethics in Clinical Care. PMID- 28871966 TI - Are We for Sale? Awareness of Industry-Related Financial Conflicts of Interest in Radiation Oncology. PMID- 28871967 TI - Clinical Research Ethics: Considerations for the Radiation Oncologist. AB - Consideration of clinical research ethics in radiation oncology is underexplored relative to other areas of oncology. A number of ethical challenges related to informed consent, randomization, conflicts of interest, and scientific validity and social value are shared with other areas of medicine, although their exact inflections are specific to radiation oncology. In addition, there are unique concerns in radiation oncology arising from the rapid evolution and uneven distribution of radiation technologies; the greater unfamiliarity of the general public and research oversight committees in regard to radiation oncology clinical practice; and the high complexity of managing most radiation oncology research, much of which is carried out in high-acuity multidisciplinary oncologic settings. To produce the best research, adherence to the highest ethical standards should be pursued as an integral component of all radiation oncology research. PMID- 28871968 TI - Ethics in the Legal and Business Practices of Radiation Oncology. AB - Ethical issues arise when a professional endeavor such as medicine, which seeks to place the well-being of others over the self-interest of the practitioner, meets granular business and legal decisions involved in making a livelihood out of a professional calling. The use of restrictive covenants, involvement in self referral patterns, and maintaining appropriate comity among physicians while engaged in the marketplace are common challenges in radiation oncology practice. A paradigm of analysis is presented to help navigate these management challenges. PMID- 28871969 TI - The Ethical Imperative and Evidence-Based Strategies to Ensure Equity and Diversity in Radiation Oncology. PMID- 28871970 TI - The Ethics of Scientific Publishing: Black, White, and "Fifty Shades of Gray". PMID- 28871971 TI - Financial Relationships With Industry of Editorial Board Members of the Three Journals of the American Society for Radiation Oncology. AB - PURPOSE: To quantitate financial conflicts of interest (FCOIs) among radiation oncology peer-reviewers, specifically editorial board members of the 3 American Society for Radiation Oncology journals. METHODS AND MATERIALS: The public Centers for Medicare and Medicaid Services Open Payments database delineates payments in 3 categories (general payments, research funding, and company ownership). After excluding non-US and non-MDs, names of board members were searched. Values of each FCOI were extracted for 2013 to 2015 and compiled. RESULTS: Of 85 board members, 65 (76%) received any form of payment during the overall period. The majority of delivered payments were general payments: 59 (69%) received at least 1 general payment during these 3 years. In each year, 9 board members (11%) received research funding, and 3 board members (4%) reported company ownership. Over the studied period, all board members received a sum total of $5,387,985; this was composed of $665,801 (12%) in general payments, $3,758,968 (70%) in research funding, and $963,216 (18%) in company ownership. The mean general payment and research funding amounts (all members) were $2,621 and $14,741, respectively. Median (interquartile range) general payments and research funding only in board members receiving payments were $419 ($91-$5072) and $56,250 ($13,345-$200,000), respectively. When assessing general payments according to amount, the vast majority of editorial board members received lower quantity or no such payments, along with a smaller proportion that received higher-volume payments. The most frequent sources of general payments were Varian, Elekta, and Bristol-Myers Squibb. Merck and Varian were the most frequent funding sources for research payments. CONCLUSIONS: In this population, the majority of FCOIs were general payments, but research funding comprised the highest monetary sums. Large-volume FCOIs do not apply to the vast majority of editorial board members, implying that the maintained integrity of academic peer review is likely not influenced to a large extent by FCOIs. PMID- 28871972 TI - Retroperitoneal Sarcoma: Setting the Stage for Treatment Strategies Tailored to Histologic Subtype and Other Patient and Tumor Factors. PMID- 28871973 TI - A Pancreatic Predicament. PMID- 28871974 TI - SBRT for Unresectable Pancreatic Cancer Can Improve Local Control With Minimal Toxicity. PMID- 28871975 TI - Consolidation Chemoradiation Improves Local Control in Unresectable Pancreatic Cancer. PMID- 28871976 TI - Chemoradiation for Unresectable Pancreatic Cancer Can Improve Quality of Life and Does Not Exclude Potential Resection. PMID- 28871977 TI - After Neoadjuvant Therapy, Imaging No Longer Provides a Clear Answer. PMID- 28871978 TI - Hypofractionated Radiation Therapy With BED >100 Gy May Rival Surgical Outcomes. PMID- 28871979 TI - Reducing Bias in Oncology Research: The End of the Radiation Variable in the Surveillance, Epidemiology, and End Results (SEER) Program. PMID- 28871981 TI - Inversed-Planned Respiratory Phase Gating in Lung Conformal Radiation Therapy. AB - PURPOSE: To assess whether the optimal gating window for each beam during lung radiation therapy with respiratory gating will be dependent on a variety of patient-specific factors, such as tumor size and location and the extent of relative tumor and organ motion. METHODS AND MATERIALS: To create optimal gating treatment plans, we started from an optimized clinical plan, created a plan per respiratory phase using the same beam arrangements, and used an inverse planning optimization approach to determine the optimal gating window for each beam and optimal beam weights (ie, monitor units). Two pieces of information were used for optimization: (1) the state of the anatomy at each phase, extracted from 4 dimensional computed tomography scans; and (2) the time spent in each state, estimated from a 2-minute monitoring of the patient's breathing motion. We retrospectively studied 15 lung cancer patients clinically treated by hypofractionated conformal radiation therapy, for whom 45 to 60 Gy was administered over 3 to 15 fractions using 7 to 13 beams. Mean gross tumor volume and respiratory-induced tumor motion were 82.5 cm3 and 1.0 cm, respectively. RESULTS: Although patients spent most of their respiratory cycle in end exhalation (EE), our optimal gating plans used EE for only 34% of the beams. Using optimal gating, maximum and mean doses to the esophagus, heart, and spinal cord were reduced by an average of 15% to 26%, and the beam-on times were reduced by an average of 23% compared with equivalent single-phase EE gated plans (P<.034, paired 2-tailed t test). CONCLUSIONS: We introduce a personalized respiratory-gating technique in which inverse planning optimization is used to determine patient- and beam-specific gating phases toward enhancing dosimetric quality of radiation therapy treatment plans. PMID- 28871982 TI - Evaluating the Toxicity Reduction With Computed Tomographic Ventilation Functional Avoidance Radiation Therapy. AB - PURPOSE: Computed tomographic (CT) ventilation imaging is a new modality that uses 4-dimensional (4D) CT information to calculate lung ventilation. Although retrospective studies have reported on the reduction in dose to functional lung, no work to our knowledge has been published in which the dosimetric improvements have been translated to a reduction in the probability of pulmonary toxicity. Our work estimates the reduction in toxicity for CT ventilation-based functional avoidance planning. METHODS AND MATERIALS: Seventy previously treated lung cancer patients who underwent 4DCT imaging were used for the study. CT ventilation maps were calculated with 4DCT deformable image registration and a density change based algorithm. Pneumonitis was graded on the basis of imaging and clinical presentation. Maximum likelihood methods were used to generate normal tissue complication probability (NTCP) models predicting grade 2 or higher (2+) and grade 3+ pneumonitis as a function of dose (V5 Gy, V10 Gy, V20 Gy, V30 Gy, and mean dose) to functional lung. For 30 patients a functional plan was generated with the goal of reducing dose to the functional lung while meeting Radiation Therapy Oncology Group 0617 constraints. The NTCP models were applied to the functional plans and the clinically used plans to calculate toxicity reduction. RESULTS: By the use of functional avoidance planning, absolute reductions in grade 2+ NTCP of 6.3%, 7.8%, and 4.8% were achieved based on the mean fV20 Gy, fV30 Gy, and mean dose to functional lung metrics, respectively. Absolute grade 3+ NTCP reductions of 3.6%, 4.8%, and 2.4% were achieved with fV20 Gy, fV30 Gy, and mean dose to functional lung. Maximum absolute reductions of 52.3% and 16.4% were seen for grade 2+ and grade 3+ pneumonitis for individual patients. CONCLUSION: Our study quantifies the possible toxicity reduction from CT ventilation-based functional avoidance planning. Reductions in grades 2+ and 3+ pneumonitis were 7.1% and 4.7% based on mean dose-function metrics, with reductions as high as 52.3% for individual patients. Our work provides seminal data for determining the potential toxicity benefit from incorporating CT ventilation into thoracic treatment planning. PMID- 28871980 TI - Empowering Intensity Modulated Proton Therapy Through Physics and Technology: An Overview. AB - Considering the clinical potential of protons attributable to their physical characteristics, interest in proton therapy has increased greatly in this century, as has the number of proton therapy installations. Until recently, passively scattered proton therapy was used almost entirely. Notably, the overall clinical results to date have not shown a convincing benefit of protons over photons. A rapid transition is now occurring with the implementation of the most advanced form of proton therapy, intensity modulated proton therapy (IMPT). IMPT is superior to passively scattered proton therapy and intensity modulated radiation therapy (IMRT) dosimetrically. However, numerous limitations exist in the present IMPT methods. In particular, compared with IMRT, IMPT is highly vulnerable to various uncertainties. In this overview we identify three major areas of current limitations of IMPT: treatment planning, treatment delivery, and motion management, and discuss current and future efforts for improvement. For treatment planning, we need to reduce uncertainties in proton range and in computed dose distributions, improve robust planning and optimization, enhance adaptive treatment planning and delivery, and consider how to exploit the variability in the relative biological effectiveness of protons for clinical benefit. The quality of proton therapy also depends on the characteristics of the IMPT delivery systems and image guidance. Efforts are needed to optimize the beamlet spot size for both improved dose conformality and faster delivery. For the latter, faster energy switching time and increased dose rate are also needed. Real-time in-room volumetric imaging for guiding IMPT is in its early stages with cone beam computed tomography (CT) and CT-on-rails, and continued improvements are anticipated. In addition, imaging of the proton beams themselves, using, for instance, prompt gamma emissions, is being developed to determine the proton range and to reduce range uncertainty. With the realization of the advances described above, we posit that IMPT, thus empowered, will lead to substantially improved clinical results. PMID- 28871983 TI - Phase 1-2 Study of Dual-Energy Computed Tomography for Assessment of Pulmonary Function in Radiation Therapy Planning. AB - PURPOSE: To quantify lung function according to a dual-energy computed tomography (DECT)-derived iodine map in patients treated with radiation therapy for lung cancer, and to assess the dosimetric impact of its integration in radiation therapy planning. METHODS AND MATERIALS: Patients treated with stereotactic ablative radiation therapy for early-stage or intensity modulated radiation therapy for locally advanced lung cancer were prospectively enrolled in this study. A DECT in treatment position was obtained at time of treatment planning. The relative contribution of each voxel to the total lung function was based on iodine distribution. The composition of each voxel was determined on the basis of a 2-material decomposition. The DECT-derived lobar function was compared with single photon emission computed tomography/computed tomography (SPECT/CT). A functional map was integrated in the treatment planning system using 6 subvolumes of increasing iodine distribution levels. Percent lung volume receiving 5 Gy (V5), V20, and mean dose (MLD) to whole lungs (anatomic) versus functional lungs were compared. RESULTS: Twenty-five patients with lung cancer, including 18 patients treated with stereotactic ablative radiation therapy and 7 patients with intensity modulated radiation therapy (locally advanced), were included. Eighty four percent had chronic obstructive pulmonary disease. Median (range) forced expiratory volume in 1 second was 62% of predicted (29%-113%), and median diffusing capacity of the lung for carbon monoxide was 56% (39%-91%). There was a strong linear correlation between DECT- and SPECT/CT-derived lobar function (Pearson coefficient correlation r=0.89, P<.00001). Mean (range) differences in V5, V20, and MLD between anatomic and functional lung volumes were 16% (0%-48%, P=.03), 5% (1%-15%, P=.12), and 15% (1%-43%, P=.047), respectively. CONCLUSIONS: Lobar function derived from a DECT iodine map correlates well with SPECT/CT, and its integration in lung treatment planning is associated with significant differences in V5 and MLD to functional lungs. Future work will involve integration of the weighted functional volume in the treatment planning system, along with integration of an iodine map for functional lung-sparing IMRT. PMID- 28871986 TI - Quality of Life After Radiation Therapy for Prostate Cancer With a Hydrogel Spacer: 5-Year Results. AB - PURPOSE: To evaluate quality of life changes up to 5 years after prostate cancer radiation therapy (RT) with a hydrogel spacer. METHODS AND MATERIALS: In the years 2010 to 2011, 114 patients received external beam radiation therapy to the prostate; 54 patients were selected for a hydrogel injection before the beginning of RT. Treatment was performed applying fractions of 2 Gy up to a total dose of 76 Gy (n=96) or 78 Gy (n=18, all with hydrogel). Patients were surveyed before RT; at the last day of RT; and a median time of 2 months, 17 months, and 63 months after RT using a validated questionnaire (Expanded Prostate Cancer Index Composite). A mean score change of >5 points was defined as clinically relevant. RESULTS: For patients treated with a hydrogel spacer, mean bowel function and bother score changes of >5 points in comparison with baseline levels were found only at the end of RT (10-15 points; P<.01). No spacer patient reported moderate or big problems with his bowel habits overall. Mean bother score changes of 21 points at the end of RT, 8 points at 2 months, 7 points at 17 months, and 6 points at 63 months after RT were found for patients treated without a spacer. A bowel bother score change >10 points was found in 6% versus 32% (P<.01) at 17 months and in 5% versus 14% (P=.2) at 63 months with versus without a spacer. CONCLUSIONS: The first 5-year quality of life results in a group of prostate cancer patients treated with a hydrogel spacer demonstrate excellent treatment tolerability, in particular regarding bowel problems. Further studies with dose escalated or re-irradiation concepts can be encouraged. PMID- 28871984 TI - Developing and Validating a Survival Prediction Model for NSCLC Patients Through Distributed Learning Across 3 Countries. AB - PURPOSE: Tools for survival prediction for non-small cell lung cancer (NSCLC) patients treated with chemoradiation or radiation therapy are of limited quality. In this work, we developed a predictive model of survival at 2 years. The model is based on a large volume of historical patient data and serves as a proof of concept to demonstrate the distributed learning approach. METHODS AND MATERIALS: Clinical data from 698 lung cancer patients, treated with curative intent with chemoradiation or radiation therapy alone, were collected and stored at 2 different cancer institutes (559 patients at Maastro clinic (Netherlands) and 139 at Michigan university [United States]). The model was further validated on 196 patients originating from The Christie (United Kingdon). A Bayesian network model was adapted for distributed learning (the animation can be viewed at https://www.youtube.com/watch?v=ZDJFOxpwqEA). Two-year posttreatment survival was chosen as the endpoint. The Maastro clinic cohort data are publicly available at https://www.cancerdata.org/publication/developing-and-validating-survival prediction-model-nsclc-patients-through-distributed, and the developed models can be found at www.predictcancer.org. RESULTS: Variables included in the final model were T and N category, age, performance status, and total tumor dose. The model has an area under the curve (AUC) of 0.66 on the external validation set and an AUC of 0.62 on a 5-fold cross validation. A model based on the T and N category performed with an AUC of 0.47 on the validation set, significantly worse than our model (P<.001). Learning the model in a centralized or distributed fashion yields a minor difference on the probabilities of the conditional probability tables (0.6%); the discriminative performance of the models on the validation set is similar (P=.26). CONCLUSIONS: Distributed learning from federated databases allows learning of predictive models on data originating from multiple institutions while avoiding many of the data-sharing barriers. We believe that distributed learning is the future of sharing data in health care. PMID- 28871987 TI - Low-dose-rate Brachytherapy for Prostate Cancer in Low-resource Settings. AB - PURPOSE: In areas with limited health care, it is important to identify and implement effective treatment methods and to optimize available resources. We investigated the implementation of a low-dose-rate (LDR) brachytherapy program for the treatment of prostate cancer (PCa) in a low-resource setting such as Puerto Rico (PR), where PCa is the main cause of cancer-associated death. METHODS AND MATERIALS: After institutional approval, the medical records of patients with nonmetastatic PCa undergoing LDR brachytherapy from 2008 to 2013 were reviewed from PR. The factors analyzed included adequate D90 (radiation dose delivered to 90% of the target volume) coverage (>=140 Gy), early and late toxicity (Common Terminology Criteria for Adverse Events grade >2), and prostate-specific antigen failure. Freedom from biochemical failure was evaluated using Kaplan-Meier analysis. RESULTS: The barriers to implementation of LDR brachytherapy in a country with limited resources were identified. These included lack of access to funding for startup costs, specific referral patterns, lack of trained support staff, such as dosimetrists and physicists, and initial opposition from insurance companies for reimbursement. The initial results from 191 patients were included in the present study with a median follow-up period of 26 months. Prostate specific antigen failure occurred in 6 patients (3%). No early or late gastrointestinal toxicity (grade >2) developed. Only 3 (2%) and 2 (1%) patients experienced early and late genitourinary toxicity (grade >2), respectively. The 2 and 3-year freedom from biochemical failure in this population was 97% and 95.9%, respectively. CONCLUSIONS: At present, limited data are available delineating the barriers faced by low-resource settings in the implementation of LDR brachytherapy. Our data highlight the issues unique to this environment and support the use of LDR brachytherapy as a reliable and effective treatment modality for patients with PCa in low-resource settings. PMID- 28871988 TI - Bladder-Preserving Therapy Patterns of Care: A Survey of US Radiation Oncologists. AB - PURPOSE: Clinical trials have demonstrated the efficacy of bladder-preserving chemoradiation therapy (BPT) in muscle-invasive bladder cancer but have differed in the radiation therapy dose/fractionations, radiation therapy targets, and concurrent chemotherapy regimens used. No data exist on the technical and practical approaches actually used in clinical practice throughout the United States when delivering BPT. We performed a survey to explore radiation oncologists' practice patterns. METHODS AND MATERIALS: We conducted an electronic survey of US radiation oncologists regarding the management of patients with cT2 3N0M0 transitional cell muscle-invasive bladder cancer. The instrument included questions regarding the types of patients treated with BPT, as well as several aspects of treatment delivery. Descriptive statistics were reported for all responses. Pearson chi2 tests were used for univariate analysis. RESULTS: In total, 277 physicians completed our survey. Most respondents (58%) stated that they only treated 1 to 3 patients in the prior year. Seventy-four percent of respondents primarily treated patients deemed unfit for cystectomy, while only 28% saw patients prior to cystectomy for consultation to discuss BPT. The majority of radiation oncologists used conventional fractionation (91%) instead of hypofractionation (7.6%), but more variability existed for radiation therapy targets. Sixty percent used a small pelvis field, 29% used a whole-pelvis field, and 12% treated the bladder only. There was increased use of hypofractionation (29%) and bladder-only radiation therapy (34%) in patients who were not candidates for cystectomy or chemotherapy (P<.001). Cisplatin-based concurrent chemotherapy was most commonly preferred (89%). In non-cisplatin candidates, most respondents preferred 5-fluorouracil plus mitomycin C (32%) or carboplatin (32%). Intensity modulated radiation therapy use and midtreatment cystoscopic re evaluation were variable, while hyperfractionation use was low. CONCLUSIONS: Our study describes radiation oncologists' practice patterns for patients undergoing BPT. Although there are areas of consistency, variability exists in many technical and practical aspects of treatment delivery. Further research and education are needed to determine the optimal radiation therapy target, dose/fractionation, and concurrent chemotherapy regimen. PMID- 28871985 TI - Stimulating Innate Immunity to Enhance Radiation Therapy-Induced Tumor Control. AB - Novel ligands that target Toll-like receptors and other innate recognition pathways represent a potent strategy for modulating innate immunity to generate antitumor immunity. Although many of the current clinically successful immunotherapies target adaptive T-cell responses, both preclinical and clinical studies suggest that adjuvants have the potential to enhance the scope and efficacy of cancer immunotherapy. Radiation may be a particularly good partner to combine with innate immune therapies, because it is a highly efficient means to kill cancer cells but may fail to send the appropriate inflammatory signals needed to act as an efficient endogenous vaccine. This may explain why although radiation therapy is a highly used cancer treatment, true abscopal effects regression of disease outside the field without additional systemic therapy-are extremely rare. This review focuses on efforts to combine innate immune stimuli as adjuvants with radiation, creating a distinct and complementary approach from T cell-targeted therapies to enhance antitumor immunity. PMID- 28871989 TI - Long-Term Outcomes of Phase 1 and 2 Studies of SBRT for Hepatic Colorectal Metastases. AB - PURPOSE: To report mature outcomes of prospective phase 1 and 2 studies of stereotactic body radiation therapy (SBRT) for the treatment of colorectal liver metastases (CLMs). METHODS AND MATERIALS: Patients with histologically confirmed CLMs unsuitable for resection or standard therapies were eligible for sequential phase 1 and 2 studies conducted from 2003 to 2012. RESULTS: Of 60 patients treated, 82% had received previous chemotherapy, 23% had undergone previous focal liver treatment, and 38% had extrahepatic disease at the time of SBRT. The median number of gross tumor volume (GTV) targets per patient was 1 (range, 1-6), with a median total target volume of 117.7 cm3 (range, 6.7-3115.4 cm3). The median minimum dose to the GTV was 37.6 Gy (range, 22.7-62.1 Gy) in 6 fractions over a period of 2 weeks. Other than 1 case of grade 3 nausea, there were no acute toxicities greater than grade 2. With a median follow-up period of 28.1 months for survivors, no gastrointestinal bleed or biliary or liver toxicity was seen. The local control rate per lesion at 1 and 4 years was 49.8% and 26.2%, respectively. Increasing minimum dose to the GTV was associated with improved local control (P=.003). Median overall survival was 16.0 months (95% confidence interval, 11.9-20.5 months). On multivariate analysis, improved survival was associated with smaller total GTV (P=.017), performance status of 0 or 1 (P=.007), no extrahepatic disease at the time of treatment (P=.005), and local control of targeted liver disease (P=.001). Two long-term survivors remain disease free at 49 and 125 months. CONCLUSIONS: Six-fraction SBRT for CLM is safe and may be associated with long-term cure. Local control was significantly associated with delivered dose and was lower than seen in other studies using a higher SBRT dose. Survival was associated with smaller tumor volume, absence of extrahepatic disease, performance status of 0 or 1, and local control of treated liver lesions. PMID- 28871990 TI - Transarterial Radioembolization Versus Concurrent Chemoradiation Therapy for Locally Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis. AB - PURPOSE: It is unclear whether the efficacy and safety of concurrent chemoradiation therapy (CCRT) and transarterial radioembolization (TARE) with 90Y are comparable in patients with locally advanced hepatocellular carcinoma. METHODS AND MATERIALS: In total, 209 treatment-naive patients with stage B or C cancer according to the Barcelona Clinic Liver Cancer classification who were treated with TARE or CCRT were analyzed. Propensity scores were calculated and matched at a 1:1 ratio for TARE versus CCRT using age, tumor size, tumor number, portal vein thrombosis, and Barcelona Clinic Liver Cancer staging. In the CCRT group, concurrent hepatic arterial infusion chemotherapy with 5-fluorouracil was delivered at a dosage of 500 mg/d during the first and last 5 days of radiation therapy (median, 45 Gy). Overall survival, freedom from progression, tumor response, and complication rate were compared between the TARE and CCRT groups. RESULTS: Among 209 patients, 124 (62 undergoing TARE and 62 undergoing CCRT) were selected after propensity score matching. Overall survival (TARE vs CCRT, 14.0 months vs 13.2 months, P=.435) and freedom from progression (6.9 months vs 7.8 months, P=.437) were comparable between the 2 groups. Objective response rates at 1 month after treatment were higher for CCRT than for TARE (46.8% vs 16.1%, P<.001), while objective response rates at 3 months were significantly higher for TARE than for CCRT (39.3% vs 21.4%, P=.04). There was no significant difference in long-term response rates (at 6 months and 1 year) between the 2 groups. The CCRT group experienced a higher rate of curative resection or liver transplantation after treatment than the TARE group, although the statistical significance was marginal (24.2% vs 11.3%, P=.060). Treatment-related complications were less frequent after TARE than after CCRT. CONCLUSIONS: Both treatments yielded comparable survival rates and long-term response rates in patients with intermediate- or advanced-stage hepatocellular carcinoma. The role of these modalities as a bridge to curative therapy requires further investigation. PMID- 28871991 TI - Recursive Partitioning Analysis Identifies Pretreatment Risk Groups for the Utility of Induction Chemotherapy Before Definitive Chemoradiation Therapy in Esophageal Cancer. AB - PURPOSE: To assess the contribution of induction chemotherapy (IC) before definitive chemoradiation therapy (dCRT) in patients with esophageal cancer (EC) based on recursive partitioning analysis (RPA). METHODS AND MATERIALS: A total of 496 eligible patients with EC staged by positron emission tomography (PET) who received dCRT from 1998 to 2015 were included, 162 (32.7%) of whom underwent IC before dCRT. RPA was used to risk-stratify patients on the basis of independent prognostic factors to predict progression-free survival (PFS). Outcomes were compared between treatment groups. RESULTS: The median follow-up time was 49.1 months (range, 7.0-155.9 months) for survivors. Compared with the non-IC group, the IC group had a comparable 5-year PFS rate (21.0% vs 23.4%; P=.726) in the whole cohort. Multivariate analysis identified age, performance status, primary tumor length, baseline PET maximum standard uptake value (SUVmax), and maximum lymph node diameter as independent prognostic factors for PFS. RPA segregated patients into 3 prognostic groups: low-risk group (PET SUVmax <9.7 and tumor length <=5 cm), intermediate-risk group (PET SUVmax >=9.7 and age >=67), and high risk group (PET SUVmax <9.7 and tumor length >5 cm, or PET SUVmax >=9.7 and age <67). Significant improvements in PFS (P=.006) and locoregional failure-free survival (P=.028) in the IC group in comparison with the non-IC group were observed in high-risk patients, whereas no differences in survival were found between the 2 treatment groups in low-risk or intermediate-risk patients. After propensity score matching, the high-risk group still demonstrated a significantly improved PFS with IC (P=.009). CONCLUSIONS: The RPA prognostic grouping provides a useful method of selecting high-risk EC patients who may benefit from IC before receiving dCRT. Prospective validation is warranted. PMID- 28871992 TI - Improved Metastasis- and Disease-Free Survival With Preoperative Sequential Short Course Radiation Therapy and FOLFOX Chemotherapy for Rectal Cancer Compared With Neoadjuvant Long-Course Chemoradiotherapy: Results of a Matched Pair Analysis. AB - PURPOSE: To compare treatment and toxicity outcomes between a phase 2 institutional trial of near total neoadjuvant therapy (nTNT) for locally advanced rectal cancer and a similar historical control cohort treated at Washington University in St. Louis with the current US standard of care, defined as neoadjuvant chemoradiotherapy (NCRT), total mesorectal excision (TME), and adjuvant FOLFOX chemotherapy; to expand the comparison to an additional institution, patients treated with similar NCRT at Stanford University were included. METHODS AND MATERIALS: Sixty-nine patients with cT3-4N0-2M0 rectal adenocarcinoma enrolled on the Washington University in St. Louis phase 2 study of nTNT were included for analysis. Patients treated at the same institution with conventional NCRT and adjuvant FOLFOX were matched for exact cTNM stage. Forty one patients treated with NCRT at Stanford University were included in a second analysis. Kaplan-Meier analysis with log-rank test was used to compare local control, distant metastasis-free survival, disease-free survival, and overall survival. RESULTS: Median follow-up was 49 and 54 months for nTNT and NCRT, respectively. Pathologic complete response and T-downstaging rates were 28% versus 16% (P=.21) and 75% versus 41% (P<.001) in the nTNT and NCRT cohorts, respectively. Three-year disease-free survival (85% vs 68%, P=.032) was significantly better in the nTNT group. Actuarial 3-year local control (92% vs 96%, P=.36) and overall survival (96% vs 88%, P=.67) were similar. The Stanford cohort had significantly lower clinical stage. After controlling for clinical stage, age, tumor location, institution, and number of chemotherapy cycles, nTNT treatment remained significantly associated with lower risk of recurrence (P=.006). CONCLUSIONS: Patients treated with nTNT had higher T-downstaging and superior distant metastasis-free survival and disease-free survival compared with conventional NCRT when matched for tumor location and exact cTNM stage. Near total neoadjuvant therapy remained a significant multivariate predictor for improved outcome when including patients treated with NCRT at another institution. PMID- 28871993 TI - Predicted Rate of Secondary Malignancies Following Adjuvant Proton Versus Photon Radiation Therapy for Thymoma. AB - PURPOSE: Thymic malignancies are the most common tumors of the anterior mediastinum. The benefit of adjuvant radiation therapy for stage II disease remains controversial, and patients treated with adjuvant radiation therapy are at risk of late complications, including radiation-induced secondary malignant neoplasms (SMNs), that may reduce the overall benefit of treatment. We assess the risk of predicted SMNs following adjuvant proton radiation therapy compared with photon radiation therapy after resection of stage II thymic malignancies to determine whether proton therapy improves the risk-benefit ratio. METHODS AND MATERIALS: Ten consecutive patients treated with double-scattered proton beam radiation therapy (DS-PBT) were prospectively enrolled in an institutional review board-approved proton registry study. All patients were treated with DS-PBT. Intensity modulated radiation therapy (IMRT) plans for comparison were generated. SMN risk was calculated based on organ equivalent dose. RESULTS: Patients had a median age of 65 years (range, 25-77 years), and 60% were men. All patients had stage II disease, and many had close or positive margins (60%). The median dose was 50.4 Gy (range, 50.4-54.0 Gy) in 1.8-Gy relative biological effectiveness daily fractions. No differences in target coverage were seen with DS-PBT compared with IMRT plans. Significant reductions were seen in mean and volumetric lung, heart, and esophageal doses with DS-PBT compared with IMRT plans (all P<=.01). Significant reductions in SMNs in the lung, breast, esophagus, skin, and stomach were seen with DS-PBT compared with IMRT. For patients with thymoma diagnosed at the median national age, 5 excess secondary malignancies per 100 patients would be avoided by treating them with protons instead of photons. CONCLUSIONS: Treatment with proton therapy can achieve comparable target coverage but significantly reduced doses to critical normal structures, which can lead to fewer predicted SMNs compared with IMRT. By decreasing expected late complications, proton therapy may improve the therapeutic ratio of adjuvant radiation therapy for patients with stage II thymic malignancies. PMID- 28871994 TI - Inclusion of Incidental Radiation Dose to the Cardiac Atria and Ventricles Does Not Improve the Prediction of Radiation Pneumonitis in Advanced-Stage Non-Small Cell Lung Cancer Patients Treated With Intensity Modulated Radiation Therapy. AB - PURPOSE: To evaluate whether inclusion of incidental radiation dose to the cardiac atria and ventricles improves the prediction of grade >=3 radiation pneumonitis (RP) in advanced-stage non-small cell lung cancer (AS-NSCLC) patients treated with intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). METHODS AND MATERIALS: Using a bootstrap modeling approach, clinical parameters and dose-volume histogram (DVH) parameters of lungs and heart (assessing atria and ventricles separately and combined) were evaluated for RP prediction in 188 AS-NSCLC patients. RESULTS: After a median follow-up of 18.4 months, 26 patients (13.8%) developed RP. Only the median mean lung dose (MLD) differed between groups (15.3 Gy vs 13.7 Gy for the RP and non-RP group, respectively; P=.004). The MLD showed the highest Spearman correlation coefficient (Rs) for RP (Rs = 0.21; P<.01). Most Rs of the lung DVH parameters exceeded those of the heart DVH parameters. After predictive modeling using a bootstrap procedure, the MLD was always included in the predictive model for grade >=3 RP, whereas the heart DVH parameters were seldom included in the model. CONCLUSION: Incidental dose to the cardiac atria and ventricles did not improve RP risk prediction in our cohort of 188 AS-NSCLC patients treated with IMRT or VMAT. PMID- 28871995 TI - A Multicenter Study of Carbon-Ion Radiation Therapy for Head and Neck Adenocarcinoma. AB - PURPOSE: Head and neck (HN) adenocarcinoma is rare, and to date, there have been no reports of prospective studies. We retrospectively evaluated the efficacy and safety of carbon-ion radiation therapy (C-ion RT) for HN adenocarcinoma in institutions in Japan. METHODS AND MATERIALS: HN adenocarcinoma patients with N0M0 or N1M0 disease who were treated with C-ion RT at institutions in Japan between November 2003 and December 2014 were analyzed retrospectively. We enrolled 47 patients (30 male and 17 female patients; median age, 60 years) with HN adenocarcinoma. RESULTS: Primary sites included the nasal and paranasal sinus in 21 patients, orbit in 11, salivary grand in 7, oral cavity and pharynx in 6, and acoustic organ in 2. Thirty-two patients had T4 tumors, 6 had T3, and 6 had T2. Forty-five patients received a diagnosis of N0 disease, whereas 2 had N1 disease. The median total dose of C-ion RT and the number of fractions were 64.0 Gy (relative biological effectiveness) and 16 fractions, respectively. The median follow-up period was 51 months (range, 6-118 months). The 2- and 5-year overall survival rates were 87.9% and 60.4%, respectively, and the 2- and 5-year local control rates were 83.3% and 79.3%, respectively. Multivariate analysis showed that operability (patients with operable tumors) (P=.045) and fractionation (16 fractions) (P=.010) were significant independent prognostic factors for better overall survival. No grade 5 late morbidities were observed. Grade 4 late morbidities were observed in 4 patients, and all of these grade 4 morbidities were visual impairments. All 4 patients with grade 4 visual impairment had T4 tumors in the nasopharynx or paranasal sinuses, which implied inoperable tumors with orbital or brain invasion. CONCLUSIONS: C-ion RT resulted in excellent local control. C-ion RT could become a curative treatment option for HN adenocarcinoma with acceptable toxicities. PMID- 28871996 TI - Prognostic Relevance of Treatment Failure Patterns in Pediatric High-Grade Glioma: Is There a Role for a Revised Failure Classification System? AB - PURPOSE: We sought to investigate the pattern of treatment failure with respect to anatomic extent, radiation dose, and criteria for failure according to the Response Assessment in Neuro-Oncology (RANO). We evaluated the corresponding prognostic significance of these factors in patients with pediatric high-grade glioma (pHGG). METHODS AND MATERIALS: Fifty-six patients with pHGG were enrolled in an institutional phase 1 to 2 prospective trial that included maximal safe resection and radiation therapy with concurrent and adjuvant erlotinib. The radiation therapy dose administered was 54 to 59.4 Gy at 1.8 Gy/d. Tumor progression was defined according to clinical symptoms and imaging features and was classified in relation to the original extent of the tumor, radiation prescription target volume coverage, and RANO criteria (RANOc). RESULTS: With a median follow-up period of 90 months (range, 70-124 months), progression occurred in 48 patients (85.7%) while 8 (14.3%) were without progression. Central failure represented 42.6% of the total cohort, while in-field, marginal, and distant failures occurred in 7.4%, 9.3%, and 22.2%, respectively. Patients with biopsy or subtotal resection had increased rates of central failure and represented 14.81% and 16.67% of the total cohort, respectively. Tumor progression was classified as local, local plus distant, or distant. Among patients with local failure as a component of failure, 5 were considered to have marginal failure. Patients with frontal, temporal, and parietal disease had the highest rates of multifocal failure. A comparison between responses defined by RANOc demonstrated varied time to death (TTD) from progression. CONCLUSIONS: Pediatric high-grade glioma was shown to have high rates of central failure, particularly in cases with limited resection. Patients with central failure had a trend toward more prolonged TTD from failure relative to other failure patterns. The low marginal failure rates seen in this group suggest that less conservative radiation target margins may be possible. TTD from failure varied according to RANO type, suggesting that adult RANOc require modification before being applied to pHGG. PMID- 28871997 TI - Single-Fraction Stereotactic Radiosurgery (SRS) Alone Versus Surgical Resection and SRS for Large Brain Metastases: A Multi-institutional Analysis. AB - PURPOSE: Stereotactic radiosurgery (SRS) dose is limited by brain metastasis (BM) size. The study goal was to retrospectively determine whether there is a benefit for intracranial outcomes and overall survival (OS) for gross total resection with single-fraction SRS versus SRS alone for patients with large BMs. METHODS AND MATERIALS: A large BM was defined as >=4 cm3 (2 cm in diameter) prior to the study. We reviewed the records of consecutive patients treated with single fraction SRS alone or surgery with preoperative or postoperative SRS between 2005 and 2013 from 2 institutions. RESULTS: Overall, 213 patients with 223 treated large BMs were included; 66 BMs (30%) were treated with SRS alone and 157 (70%) with surgery and SRS (63 preoperatively and 94 postoperatively). The groups (SRS vs surgery and SRS) were well balanced except regarding lesion volume (median, 5.9 cm3 vs 9.6 cm3; P<.001), median number of BMs (1.5 vs 1, P=.002), median SRS dose (18 Gy vs 15 Gy, P<.001), and prior whole-brain radiation therapy (33% vs 5%, P<.001). The local recurrence (LR) rate was significantly lower with surgery and SRS (1-year LR rate, 36.7% vs 20.5%; P=.007). There was no difference in radiation necrosis (RN) by resection status, but there was a significantly increased RN rate with postoperative SRS versus with preoperative SRS and with SRS alone (1-year RN rate, 22.6% vs 5% and 12.3%, respectively; P<.001). OS was significantly higher with surgery and SRS (2-year OS rate, 38.9% vs 19.8%; P=.01). Both multivariate adjusted analyses and propensity score-matched analyses demonstrated similar results. CONCLUSIONS: In this retrospective study, gross total resection with SRS was associated with significantly reduced LR compared with SRS alone for patients with large BMs. Postoperative SRS was associated with the highest rate of RN. Surgical resection with SRS may improve outcomes in patients with a limited number of large BMs compared with SRS alone. Further studies are warranted. PMID- 28871998 TI - Peripheral Blood Biomarkers Associated With Toxicity and Treatment Characteristics After 131I- Metaiodobenzylguanidine Therapy in Patients With Neuroblastoma. AB - PURPOSE: Few tools exist to predict clinical outcomes after radiopharmaceutical therapy. Our goal was to identify associations between blood-based biomarkers of radiation effect and clinical outcomes after 131I-metaiodobenzylguanidine (131I MIBG) therapy in patients with neuroblastoma. METHODS AND MATERIALS: We conducted a prospective, single-center cohort study in children with advanced neuroblastoma treated with 131I-MIBG as monotherapy or in combination with systemic putative radiation sensitizers. We collected serial peripheral blood samples after 131I MIBG infusions and quantified a panel of protein and messenger RNA markers. We plotted relative change from baseline to assess degree of modulation over time and then evaluated association of marker modulation with toxicity and response endpoints. RESULTS: The cohort included 40 patients (30 male/10 female; median age 7 years). We observed significant modulation of the majority of markers between baseline and hour 72 after 131I-MIBG. Greater fold increase of plasma FLT3 ligand was associated with subsequent grade 4 neutropenia (P=.039). Modulation of peripheral blood BCLXL and DDB2 was associated with grade 3+ nonhematologic toxicity (P=.043 and .048, respectively). No markers were associated with tumor response. Greater plasma FLT3 ligand, BCLXL, and BCL2 modulation was observed in patients receiving 131I-MIBG in combination with radiation sensitizers. Among 9 patients who received 2 courses, the degree of modulation in serum amylase was significantly lower after the second course (P=.012). CONCLUSIONS: Peripheral blood biomarkers relevant to radiation exposure are significantly modulated during the acute period after 131I-MIBG. The degree of modulation of a subset of these markers is associated with toxicity and receipt of concomitant radiation sensitizers. PMID- 28871999 TI - Multimodal Magnetic Resonance Imaging of Treatment-Induced Changes to Diffuse Infiltrating Pontine Gliomas in Children and Correlation to Patient Progression Free Survival. AB - PURPOSE: To use multimodal magnetic resonance imaging (MRI) to quantify treatment induced changes in the whole volume of diffuse infiltrating pontine gliomas and correlate them with progression-free survival (PFS). METHODS AND MATERIALS: This prospective study included 22 children aged 3.3 to 14.7 years (median, 5.9 years). Multimodal MRI was performed at 3 distinct time points: before treatment, the first week following radiation therapy (RT), and 2 months after RT. The imaging protocol included morphologic, multi b-value diffusion; arterial spin labeling; and dynamic susceptibility contrast-enhanced perfusion. Morphologic and multimodal data-lesion volume, diffusion coefficients, relative cerebral blood flow, and relative cerebral blood volume (rCBV)-were recorded at the 3 aforementioned time points. The Wilcoxon test was used to compare each individual parameter variation between time points, and its correlation with PFS was assessed by the Spearman test. RESULTS: Following RT, the tumors' solid component volume decreased by 40% (P<.001). Their median diffusion coefficients decreased by 20% to 40% (P<.001), while median relative cerebral blood flow increased by 60% to 80% (P<.001) and median rCBV increased by 70% (P<.001). PFS was positively correlated with rCBV measured immediately after RT (P=.003), and in patients whose rCBV was above the cutoff value of 2.46, the median PFS was 4.6 months longer (P=.001). These indexes tended to return to baseline 2 months after RT. Lesion volume before or after RT was not correlated with survival. CONCLUSIONS: Multimodal MRI provides useful information about diffuse infiltrating pontine gliomas' response to treatment; rCBV increases following RT, and higher values are correlated with better PFS. High rCBV values following RT should not be mistaken for progression and could be an indicator of response to therapy. PMID- 28872000 TI - Renal Function Outcomes of High-risk Neuroblastoma Patients Undergoing Radiation Therapy. AB - PURPOSE: To analyze the renal function outcomes in patients undergoing radiation therapy for neuroblastoma. METHODS AND MATERIALS: The clinical metrics of renal function were analyzed in patients undergoing radiation therapy for high-risk neuroblastoma from 2000 to 2015. The blood urea nitrogen (BUN) and creatinine values before radiation therapy were compared with last available follow-up values and analyzed with the clinical circumstances, including follow-up length, age at primary irradiation, nephrectomy, and radiation technique. The creatinine clearance was estimated using the Shull method. RESULTS: With a median follow-up period of 3.5 years, none of the 266 patients studied developed a chronic renal insufficiency. For all patients, the creatinine level increased from 0.44 to 0.51 mg/dL and the BUN increased from 10.53 to 15.52 mg/dL. Three patients required antihypertensive medication. The patients who underwent intensity modulated radiation therapy did not experience increased creatinine levels during the follow-up period; however, they had a reduced median follow-up length compared with patients treated with anteroposterior/posteroanterior beams (4.7 vs 3.3 years). A longer follow-up length was associated with an increased creatinine level. The preradiation therapy creatinine level increased with patient age, similar to that of the last follow-up creatinine level, suggesting that the changes in creatinine could likely be explained by physiologic increases associated with aging rather than radiation-induced renal damage. The creatinine clearance did not decrease in any circumstance. CONCLUSIONS: The present cohort had excellent renal outcomes after radiation therapy for neuroblastoma. No patient developed chronic renal insufficiency, and the small increases in BUN and creatinine we observed correlated, as expected, with increases in patient age. The results of the present study revealed a possible advantage for intensity modulated radiation therapy in preserving renal function; however, the follow-up length is a recognized confounding variable. The kidneys are vital structures to consider when planning radiation therapy for neuroblastoma patients, and we have found encouraging evidence that modern techniques to spare them in the setting of multiple treatment-related insults have been successful. PMID- 28872001 TI - Pulmonary Toxicity Following Proton Therapy for Thoracic Lymphoma. PMID- 28872002 TI - In Regard to Rahimi et al. PMID- 28872003 TI - In Reply to Gerber et al. PMID- 28872004 TI - In Regard to Parikh et al. PMID- 28872005 TI - In Reply to Zhang. PMID- 28872006 TI - Letter to the Editor. PMID- 28872007 TI - In Reply to Tokuuye. PMID- 28872008 TI - Department of Error. PMID- 28872009 TI - Department of Error. PMID- 28872010 TI - Department of Error. PMID- 28872011 TI - January 4-10, 2014. PMID- 28872013 TI - June 14-20, 2014. PMID- 28872012 TI - Department of Error. PMID- 28872015 TI - Problem gambling is a public health concern. PMID- 28872016 TI - Supporting the need for nation-building in Afghanistan. PMID- 28872017 TI - Palliative care in chronic obstructive pulmonary disease. PMID- 28872014 TI - The empress of subterfuge: cancer of the fallopian tube presenting with malapropism. PMID- 28872018 TI - Classification of maternal deaths: where does the chain of events start? PMID- 28872019 TI - Offline: Terrorism and Syria-"a crisis of the world". PMID- 28872020 TI - Over 60 children die in a hospital in north India. PMID- 28872021 TI - Alvar Agusti: bringing systems biology to COPD. PMID- 28872022 TI - Lung cancer. PMID- 28872023 TI - Addressing racism: a new approach to promotion of positive policies is needed. PMID- 28872024 TI - Public health must confront racism and xenophobia. PMID- 28872025 TI - Intertwining migration, ethnicity, racism, and health. PMID- 28872026 TI - Anchors aweigh. PMID- 28872027 TI - What can Japan learn from tobacco control in the UK? PMID- 28872028 TI - Naming of the victims of Nazi medicine. PMID- 28872030 TI - What does endotyping mean for treatment in chronic obstructive pulmonary disease? AB - Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease, both at the clinical and biological level. However, COPD is still diagnosed and treated according to simple clinical measures (level of airflow limitation, symptoms, and frequency of previous exacerbations). To address this clinical and biological complexity and to move towards precision medicine in COPD, we need to integrate (bioinformatics) and interpret (clinical science) the vast amount of high-throughput information that existing technology provides (systems biology and network medicine) so diagnosis, stratification, and treatment of patients with COPD can occur on the basis of their pathobiological mechanism (ie, endotypes). Therefore, this Series paper discusses a possible new taxonomy of COPD, the role of endotypes and associated biomarkers and phenotypes, the gaps (and opportunities) in existing knowledge of COPD pathobiology, how systems biology and network medicine can improve understanding of the disease and help to identify relevant endotypes and their specific biomarkers, and how endotypes and their biomarkers can improve the precision, effectiveness, and safety of the treatment of patients with COPD. PMID- 28872029 TI - Prevention of hearing loss in patients with multidrug-resistant tuberculosis. PMID- 28872031 TI - Palliative care and management of troublesome symptoms for people with chronic obstructive pulmonary disease. AB - People with advanced chronic obstructive pulmonary disease (COPD) have distressing physical and psychological symptoms, often have limited understanding of their disease, and infrequently discuss end-of-life issues in routine clinical care. These are strong indicators for expert multidisciplinary palliative care, which incorporates assessment and management of symptoms and concerns, patient and caregiver education, and sensitive communication to elicit preferences for care towards the end of life. The unpredictable course of COPD and the difficulty of predicting survival are barriers to timely referral and receipt of palliative care. Early integration of palliative care with respiratory, primary care, and rehabilitation services, with referral on the basis of the complexity of symptoms and concerns, rather than prognosis, can improve patient and caregiver outcomes. Models of integrated working in COPD could include: services triggered by troublesome symptoms such as refractory breathlessness; short-term palliative care; and, in settings with limited access to palliative care, consultation only in specific circumstances or for the most complex patients. PMID- 28872032 TI - Atlas of Electroencephalography, 3rd Edition. AB - Electroencephalography (EEG) is the recording of the electrical activity of the brain. EEG is a reliable test to assess cerebral function. It aids in diagnosis, classification, and management of patients with epilepsy. It also has practical uses in conditions other than epilepsy. Moreover, it is harmless and inexpensive. EEG is an important tool for evaluating patients with epilepsy. It may help classify the syndrome, identify the likely source of focal seizures, and confirm a diagnosis of status epilepticus. EEG is therefore helpful when selecting appropriate antiepileptic drugs for patients with epilepsy, is valuable for diagnosis and management of status epilepticus as well as predicting the prognosis in epilepsy syndromes, and, is finally useful when localizing an area for resection in surgery candidates. In addition, despite advances in neuroimaging, EEG remains a valuable tool in the evaluation of stuporous and comatose patients. A systematic approach is essential for EEG interpretation, and when combined with good clinical judgment, it will improve diagnostic sensitivity and specificity and may improve therapeutic outcomes. This EEG atlas is designed as a practical guide for neurology residents, neurologists, and epileptologists, so that they may appropriately identify normal and abnormal findings, while reading an EEG. By reading and reviewing the relevant chapter of this well organized atlas, that includes many EEG images, the reader will also learn how to report an EEG finding. We hope that this atlas fills an unmet need, and leads to improved patient care. PMID- 28872033 TI - Nursing home in question. PMID- 28872034 TI - Interest of a medical surgical geriatric unit in a district hospital: a retrospective study. AB - BACKGROUND: Orthogeriatric units have shown through several studies their effectiveness on reducing the morbidity and mortality after hip fracture. What about other emergency surgeries at the elderly? We evaluated the results of a small medical surgical geriatric unit (UMCG) for all the not sheduled surgeries. METHODS: A retrospective sudy has been done, analyzing management of patients over 75 years after an emergency surgery, between 1st January 2013 and 15 February 2014 for the surgical unit, and between 15 February 2014 and 15 April 2014 for the UMCG. 3-month mortality, 6-month mortality and the main early complications were compared between the two groups, by a multivariated analysis fitting on the data on patient characteristics. RESULTS: 3-month mortality was significantly lower in the UMCG group (odds ratio 0.07 [95%IC: 0.004-0.48]; p=0.02), while the patients in this unit were more likely with dementia, with fall antecedent and with more comorbidity. 6-month mortality as well was lower in the UMCG group (0.10 [0.02-0.36]; p=0.001). CONCLUSION: Management of not sheduled surgeries at the elderly in specific surgical geriatric unit is associated in a statistically significant reduction of 3-month mortality and 6 month mortality. PMID- 28872035 TI - Prevalence and severity of peripheral arterial disease among patient with heel pressure ulcer: a retrospective study of 42 patients. AB - Heel pressure ulcer is a major complication in elderly hospitalized patients. The association with peripheral arterial disease (PAD) which is also a frequent disease in this population is poorly known. The aim of this study was to assess the prevalence of PAD and critical limb ischemia (CLI) in patients with heel pressure ulcer. Patients referred to the vascular medicine department for heel pressure ulcer from October 2014 to June 2015 were included in the study. The assessment of peripheral arterial disease was made with the results of ankle brachial index and/or doppler ultra sound of lower limb arteries. Toe systolic pressure and transcutaneous pressure (TcPO2) were also recorded, and the diagnosis of critical limb ischemia was made according to the TASC 2 criteria. The population was composed with 42 patients (women 43%, men 57%). The mean age was 81+/-11 years. Heel pressures ulcers were diagnosed in the following situations: lower limb fracture (31%), acute medical illness (21%), multiple chronic conditions (28%) and critical care unit hospitalization (7%). A peripheral arterial disease was present in 31 patients (73%), and a critical limb ischemia in 7 patients. For 18 patients, PAD was not known in their past medical history, and this was the case of 5 patients among those with critical limb ischemia. A revascularization was performed in 12 patients, and 5 patients undergo a lower limb amputation. 12 patients were died at 3 months. PAD is frequent among patients with heel pressure ulcer, and is often unknown. The functional and vital prognostic are poor, and the results of our study emphasize the importance of screening PAD in the evaluation of heel pressure ulcer risk. PMID- 28872036 TI - Decision-making for gastrostomy after 70 years old: a prospective study about 26 patients. AB - Management of undernutrition is based on young adults analysis. However, enteral nutrition is mainly discussed in the elderly. The aim of this study was to analyse factors related to laying gastrostomy, in geriatrics. A prospective, descriptive study, was conducted in the Loire department, from 2014 to 2016, in geriatric and palliative units. All patients over 70 years who had a theorical indication of gastrostomy were included. Decision-making process was analyzed from data affecting the reflection. Patients were followed for three months. Twenty-six patients were included with an average of 81 years old. They were frailty with a low mean serum albumin (29.2 g/L), an undernutrition (85%), an extended bedridden (73%), a medical history of aspiration pneumonia (46%) and with pressure ulcers (27%). The main diagnoses were strokes (38%) and dementia (23%). After a singular decision-making, only 15% received a gastrostomy. At three months, 69.2% of patients had died. Patients over 70 years old, with a vital prognosis at short term, are not good candidates for gastrostomy. In geriatrics, decision-making for gastrostomy laying is complex because managed by contradictory recommendations. It requires a global assessment to identify risk situations. The early detection of undernutrition is the key to successful management, for patients requiring gastrostomy. PMID- 28872037 TI - Executive dysfunctions as a good predictor of misuse of respiratory inhalers among hospitalized patients: a prospective survey. AB - The objectives of the study are to determine the prevalence and potential risk factors of misuse of respiratory inhalers among hospitalized patients admitted at the CHU UcL Namur, site Godinne. Using a cross-sectional design, patients using respiratory inhalers since more than 7 days were recruited from a database established by the hospital pharmacy. Inhaler technique was assessed using a standardised check-list and graded misuse as major or minor errors using previously published criteria. Demographic and clinical data were prospectively collected using standardised tools. Among the 100 consecutive patients selected for the study (median of age: 68 years), the prevalence of misuse was 40%. According to univariate analysis, main risk factors of misuse were age, executive dysfunction, a low grip strength, a low level of manual dexterity and the type of inhaler used. The best predictor of misuse according to multivariate analysis was executive dysfunction as assessed by the BREF scale (batterie rapide d'efficience frontale) (adjusted odds ratio: 1.35 [CI95%: 1.11-1.64]; p: 0.002). A BREF score <= 12/18 was associated with a six-fold increase of respiratory inhaler misuse risk. We conclude that executive dysfunction is associated with a higher risk of respiratory inhalers misuse. A short screening of executive function, using the BREF scale, before starting respiratory inhaler may improve the selection of inhaler devices and therefore the compliance to treatment. PMID- 28872038 TI - High rate of errors in pillbox filling by cognitively healthy elderly people. AB - An appropriate medication management depends on executive system integrity, which can be affected by aging. Previous studies showed that seniors commit frequent errors when having to fill in a pillbox. Nevertheless, to the best of our knowledge, no study has really considered the absence of cognitive disorders in the studied sample. The present study aimed to investigate pillbox filling in cognitively healthy elderly (specially focusing on executive system preservation) for whom no cognitive deterioration neither any depressive episode had occurred during a one year period. The filling task has been completed using a weekly pillbox and eight fictitious drugs. The selection of the 27 seniors aged from 71 to 90 years has been based on their results to neuropsychological tests (Trail making test, Stroop Victoria, Tower of London, Montreal cognitive assessment) and a depression assessment scale (Short geriatric depression scale). Results showed that 67% of the participants committed at least one error when filling the pillbox and 56% at least 3. The maximal number of errors was 38. Further, the errors analysis showed that 85% of the errors had been repeated (e.g. reproduced on several days). Finally, the more complex the drug prescriptions are, the higher the error rate is. No other variable (age, gender, level education, habit of filling a pillbox) had any effect on the number of errors. So, the pillbox filing task can be considered as a complex task associated with a high risk of errors. Moreover, the absence of cognitive disorders is not a success factor to the task. A prospect for the future should be to try to limit the error rate by developing, for instance, an external support helping to the filling of the pillbox and a learning process for the use of this support. PMID- 28872039 TI - Editorial. PMID- 28872041 TI - Lev Semenovich Vygotsky (1896-1924): an introduction to the historico-cultural psychology and the development of the higher psychological processes. AB - In the 1930's LS Vygotsky developed an original conception of the psychology and the development of the higher psychological processes, which stands up the current theories in Russia and the West. He layed the bases for the study of the higher mental processes and their relationship with the brain functioning, which will be later on developped by AR Luria. After a brief historical notice, this paper will specify the relationships between Vygoski and Marx's and Engels's philosophy, the Soviet power and the works of Freud and Piaget. PMID- 28872042 TI - Retrieval of memories with the help of music in Alzheimer's disease. AB - This study focuses on music as a mediator facilitating access to autobiographical memory in Alzheimer's disease (AD). Studies on this topic are rare, but available data have shown a beneficial effect of music on autobiographical performance in AD patients. Based on the "index word" method, we developed the "index music" method for the evaluation of autobiographical memory. The subjects had to tell a memory of their choice from the words or music presented to them. The task was proposed to 54 patients with diagnosis of AD according to DSM IV and NINCDS-ADRDA criteria. All of them had a significant cognitive decline on the MMSE (mean score: 14.5). Patients were matched by age, sex and level of education with 48 control subjects without cognitive impairment (mean score on the MMSE: 28). Results showed that autobiographical memory quantity scores of AD patients were significantly lower than those of healthy control in both methods. However, autobiographical memory quality scores of AD patients increased with "index music" whereas autobiographical memory quality scores of healthy control decreased. Also, the autobiographical performance of patients with AD in condition index music was not correlated with cognitive performance in contrast to the autobiographical performances in index word. These results confirm that music improves access to personal memories in patients with AD. Personal memories could be preserved in patients with AD and music could constitute an interesting way to stimulate recollection. PMID- 28872040 TI - Structural magnetic resonance imaging in frontotemporal lobar dementia. AB - Frontotemporal lobar dementia (FTLD) is a heterogeneous group of neurodegenerative diseases. FTLD encompass: 1) behavioral forms, sometimes associated with amyotrophic lateral sclerosis; 2) linguistic forms (semantic and non-fluent primary progressive aphasia); 3) atypical parkinsonian syndromes (progressive supranuclear palsy and corticobasal syndrome). Standard brain MRI allows for strengthening the clinical suspicion of FTLD, by showing a pattern of atrophy in relation with the patient's clinical symptoms: frontotemporal anterior atrophy in behavioral forms; temporopolar or inferior left frontal atrophy in the linguistic forms; mesencephalic or corticosubcortical hemispheric atrophy in forms with atypical pakinsonism. MRI is now part of the diagnostic criteria of some FTLD (behavioral FTLD, primary progressive aphasia). Genetic forms are common in FTLD, especially in behavioral FTLD. The three main mutations (C9ORF72, GRN and MAPT) are associated with different imaging patterns, which can thus orient the clinician towards a particular mutation in a patient with a familial form of FTLD. PMID- 28872043 TI - Representations of their own sexuality and aging body by old people: phenomenological and psychodynamic approach. AB - The sexuality of the elderly is rarely mentioned in general medicine although it holds an important place in many old people's life, and sexual well-being is a part of the global well-being according to the World Health Organization. To explore the representations of their own sexuality and aging body by the elderly. Qualitative study using semi-structured interviews in 15 healthy elderly people over 65 years of age, living at home. In-depth interviews were transcribed and submitted to qualitative content using a phenomenological and a psychodynamic analysis. The phenomenological approach allows to explore the meaning and significance of the sexuality of older people (their representations and individual experience). The psychodynamic approach allows an analysis of defense mechanisms in verbal and nonverbal behavior. Some elderly maintain a view of their sexuality in accordance with the societal standards existing before the sexual liberalization following the events of May 68 in France. For these people, sexuality is tabooed and only linked to procreation, no longer part of the aging body, and perceived as degraded, then difficult to be approached by general practitioners in relation with defense mechanisms. Other elderly people have managed to free themselves from those previous societal standards. The notion of pleasure is still present in these people and their aging body is perceived as an altered body, difficult to be accepted on account of the pressure for conformity due to actual societal standards. These standards reserve sexuality to young people and convey a picture of a sexuality that would be improper for the elderly. Understanding the representations of their sexuality by the elderly allows GPs a better approach for helping older patients to improve their sexual well-being. PMID- 28872044 TI - Insular cognitive impairment at the early stage of dementia with Lewy bodies: a preliminary study. AB - BACKGROUND: The anterior part of the insula appears atrophied in the early stage of dementia with Lewy bodies (DLB) whereas it is not the case in early Alzheimer's disease (AD). OBJECTIVE: The objective of this study was to develop neuropsychological markers supposed to reflect insular dysfunction, which would facilitate early diagnosis of DLB, namely in comparison to AD. METHODS: Twelve patients with DLB, 12 patients with AD, all at the stage of Mild cognitive impairment (MCI) or mild dementia, as well as 10 Controls subjects (CS) participated in the study. Cognitive functions supposedly related to the insula were evaluated with a battery of tests: a facial expression recognition test, a test assessing the feeling of disgust with images, a test evaluating idioms' comprehension, an empathy questionnaire and a questionnaire screening for disgusting behaviors. RESULTS: Compared to AD patients and CS, DLB patients experienced less disgust when they were shown disgusting images, whereas their ability to recognize emotional expression of disgust appeared to be preserved. Furthermore, DLB patients seemed less empathetic than AD patients. Finally, compared to CS, DLB patients were less effective to provide an intuitive decision about idioms' signification since they needed significantly more time to answer. CONCLUSION: This preliminary study suggests the existence of a potential " insular cognitive impairment " profile in DLB at the early stage. These results provide interesting leads to develop tools facilitating the differential diagnosis of DLB and AD. PMID- 28872047 TI - Doing More About Health Care Disparities: Moving Past Description to Action. PMID- 28872048 TI - Human-brain ferritin studied by muon spin rotation: a pilot study. AB - Muon spin rotation is employed to investigate the spin dynamics of ferritin proteins isolated from the brain of an Alzheimer's disease (AD) patient and of a healthy control, using a sample of horse-spleen ferritin as a reference. A model based on the Neel theory of superparamagnetism is developed in order to interpret the spin relaxation rate of the muons stopped by the core of the protein. Using this model, our preliminary observations show that ferritins from the healthy control are filled with a mineral compatible with ferrihydrite, while ferritins from the AD patient contain a crystalline phase with a larger magnetocrystalline anisotropy, possibly compatible with magnetite or maghemite. PMID- 28872046 TI - Racial and Ethnic Differences in Antibiotic Use for Viral Illness in Emergency Departments. AB - BACKGROUND AND OBJECTIVES: In the primary care setting, there are racial and ethnic differences in antibiotic prescribing for acute respiratory tract infections (ARTIs). Viral ARTIs are commonly diagnosed in the pediatric emergency department (PED), in which racial and ethnic differences in antibiotic prescribing have not been previously reported. We sought to investigate whether patient race and ethnicity was associated with differences in antibiotic prescribing for viral ARTIs in the PED. METHODS: This is a retrospective cohort study of encounters at 7 PEDs in 2013, in which we used electronic health data from the Pediatric Emergency Care Applied Research Network Registry. Multivariable logistic regression was used to examine the association between patient race and ethnicity and antibiotics administered or prescribed among children discharged from the hospital with viral ARTI. Children with bacterial codiagnoses, chronic disease, or who were immunocompromised were excluded. Covariates included age, sex, insurance, triage level, provider type, emergency department type, and emergency department site. RESULTS: Of 39 445 PED encounters for viral ARTIs that met inclusion criteria, 2.6% (95% confidence interval [CI] 2.4%-2.8%) received antibiotics, including 4.3% of non-Hispanic (NH) white, 1.9% of NH black, 2.6% of Hispanic, and 2.9% of other NH children. In multivariable analyses, NH black (adjusted odds ratio [aOR] 0.44; CI 0.36-0.53), Hispanic (aOR 0.65; CI 0.53-0.81), and other NH (aOR 0.68; CI 0.52-0.87) children remained less likely to receive antibiotics for viral ARTIs. CONCLUSIONS: Compared with NH white children, NH black and Hispanic children were less likely to receive antibiotics for viral ARTIs in the PED. Future research should seek to understand why racial and ethnic differences in overprescribing exist, including parental expectations, provider perceptions of parental expectations, and implicit provider bias. PMID- 28872049 TI - Development of ultralight, super-elastic, hierarchical metallic meta-structures with i3DP technology. AB - Lightweight and mechanically robust materials show promising applications in thermal insulation, energy absorption, and battery catalyst supports. This study demonstrates an effective method for creation of ultralight metallic structures based on initiator-integrated 3D printing technology (i3DP), which provides a possible platform to design the materials with the best geometric parameters and desired mechanical performance. In this study, ultralight Ni foams with 3D interconnected hollow tubes were fabricated, consisting of hierarchical features spanning three scale orders ranging from submicron to centimeter. The resultant materials can achieve an ultralight density of as low as 5.1 mg cm-3 and nearly recover after significant compression up to 50%. Due to a high compression ratio, the hierarchical structure exhibits superior properties in terms of energy absorption and mechanical efficiency. The relationship of structural parameters and mechanical response was established. The ability of achieving ultralight density <10 mg cm-3 and the stable [Formula: see text] scaling through all range of relative density, indicates an advantage over the previous stochastic metal foams. Overall, this initiator-integrated 3D printing approach provides metallic structures with substantial benefits from the hierarchical design and fabrication flexibility to ultralight applications. PMID- 28872050 TI - Super-resolution reconstruction of 4D-CT lung data via patch-based low-rank matrix reconstruction. AB - Lung 4D computed tomography (4D-CT), which is a time-resolved CT data acquisition, performs an important role in explicitly including respiratory motion in treatment planning and delivery. However, the radiation dose is usually reduced at the expense of inter-slice spatial resolution to minimize radiation related health risk. Therefore, resolution enhancement along the superior inferior direction is necessary. In this paper, a super-resolution (SR) reconstruction method based on a patch low-rank matrix reconstruction is proposed to improve the resolution of lung 4D-CT images. Specifically, a low-rank matrix related to every patch is constructed by using a patch searching strategy. Thereafter, the singular value shrinkage is employed to recover the high resolution patch under the constraints of the image degradation model. The output high-resolution patches are finally assembled to output the entire image. This method is extensively evaluated using two public data sets. Quantitative analysis shows that the proposed algorithm decreases the root mean square error by 9.7% 33.4% and the edge width by 11.4%-24.3%, relative to linear interpolation, back projection (BP) and Zhang et al's algorithm. A new algorithm has been developed to improve the resolution of 4D-CT. In all experiments, the proposed method outperforms various interpolation methods, as well as BP and Zhang et al's method, thus indicating the effectivity and competitiveness of the proposed algorithm. PMID- 28872051 TI - Optimization of sampling parameters for standardized exhaled breath sampling. AB - The lack of standardization of breath sampling is a major contributing factor to the poor repeatability of results and hence represents a barrier to the adoption of breath tests in clinical practice. On-line and bag breath sampling have advantages but do not suit multicentre clinical studies whereas storage and robust transport are essential for the conduct of wide-scale studies. Several devices have been developed to control sampling parameters and to concentrate volatile organic compounds (VOCs) onto thermal desorption (TD) tubes and subsequently transport those tubes for laboratory analysis. We conducted three experiments to investigate (i) the fraction of breath sampled (whole vs. lower expiratory exhaled breath); (ii) breath sample volume (125, 250, 500 and 1000ml) and (iii) breath sample flow rate (400, 200, 100 and 50 ml/min). The target VOCs were acetone and potential volatile biomarkers for oesophago-gastric cancer belonging to the aldehyde, fatty acids and phenol chemical classes. We also examined the collection execution time and the impact of environmental contamination. The experiments showed that the use of exhaled breath sampling devices requires the selection of optimum sampling parameters. The increase in sample volume has improved the levels of VOCs detected. However, the influence of the fraction of exhaled breath and the flow rate depends on the target VOCs measured. The concentration of potential volatile biomarkers for oesophago-gastric cancer was not significantly different between the whole and lower airway exhaled breath. While the recovery of phenols and acetone from TD tubes was lower when breath sampling was performed at a higher flow rate, other VOCs were not affected. A dedicated 'clean air supply' overcomes the contamination from ambient air, but the breath collection device itself can be a source of contaminants. In clinical studies using VOCs to diagnose gastro oesophageal cancer, the optimum parameters are 500mls sample volume of whole breath with a flow rate of 200ml/min. . PMID- 28872052 TI - Harmonic phase angles used for nanoparticle sensing. AB - A series of techniques have been developed to use magnetic nanoparticles as biosensors to characterize their local microenvironment. Two approaches have been used to obtain quantitative information: model based approaches and scaling based approaches. We have favored scaling based approaches, because approximations made in models can lead to limitations in the accuracy. Currently all the scaling approaches use harmonic ratios to retrieve physical parameters like temperature, viscosity and relaxation time. In this work, we showed that the phase angle of the signal at a single harmonic frequency is an alternative to the ratio. The phase angle is nanoparticle density-independent, and can be used to improve sensitivity, enabling us to measure smaller biomedical effects. With the phase angle as an example, we showed that scaling methods are general and do not depend on specific approximations. We showed that the same scaling techniques can be used with both the phase angle and harmonic ratio because they both depend on the same combinations of physical parameters. Using the phase angle improves the precision and using the combination of phase angles and harmonic ratio provides the best precision. PMID- 28872053 TI - Ambient pressure phase transitions over Ir(1 1 1): at the onset of CO oxidation. AB - In this study we report on the adsorbate structures on an Ir(1 1 1) surface during the phase transition from the inactive to the active state during CO oxidation. The CO oxidation over Pt(1 1 1) is used as a reference case. Where Pt(1 1 1) either is inactive and CO covered or active and O covered, Ir(1 1 1) exhibits a transition state with co-existing chemisorbed O and CO. The observed structural differences are explained in terms of DFT-calculated adsorption energies. For Pt(1 1 1) the repulsive CO-O interaction makes co-existing chemisorbed CO and O unfavourable, while for Ir(1 1 1) the stronger O and CO adsorption allows for overcoming the repulsive interaction. At the onset of CO oxidation over Ir(1 1 1), a CO structure containing defects forms, which enables O2 to dissociatively adsorb on the Ir(1 1 1) surface, thus enabling the CO oxidation reaction. At the mass transfer limit, the Ir(1 1 1) surface is covered by a chemisorbed O structure with defects; hence, the active surface is predominately chemisorbed O covered at a total pressure of 0.5 mbar and no oxide formation is observed. PMID- 28872055 TI - The magnetic properties and structure of the quasi-two-dimensional antiferromagnet CoPS3. AB - The magnetic properties and magnetic structure are presented for CoPS3, a quasi two-dimensional antiferromagnet on a honeycomb lattice with a Neel temperature of [Formula: see text] K. The compound is shown to have XY-like anisotropy in its susceptibility, and the anisotropy is analysed to extract crystal field parameters. For temperatures between 2 K and 300 K, no phase transitions were observed in the field-dependent magnetization up to 10 Tesla. Single-crystal neutron diffraction shows that the magnetic propagation vector is k = [Formula: see text] with the moments mostly along the [Formula: see text] axis and with a small component along the [Formula: see text] axis, which largely verifies the previously-published magnetic structure for this compound. The magnetic Bragg peak intensity decreases with increasing temperature as a power law with exponent [Formula: see text] for [Formula: see text]. PMID- 28872054 TI - Enhancement of multimodality texture-based prediction models via optimization of PET and MR image acquisition protocols: a proof of concept. AB - Texture-based radiomic models constructed from medical images have the potential to support cancer treatment management via personalized assessment of tumour aggressiveness. While the identification of stable texture features under varying imaging settings is crucial for the translation of radiomics analysis into routine clinical practice, we hypothesize in this work that a complementary optimization of image acquisition parameters prior to texture feature extraction could enhance the predictive performance of texture-based radiomic models. As a proof of concept, we evaluated the possibility of enhancing a model constructed for the early prediction of lung metastases in soft-tissue sarcomas by optimizing PET and MR image acquisition protocols via computerized simulations of image acquisitions with varying parameters. Simulated PET images from 30 STS patients were acquired by varying the extent of axial data combined per slice ('span'). Simulated T 1-weighted and T 2-weighted MR images were acquired by varying the repetition time and echo time in a spin-echo pulse sequence, respectively. We analyzed the impact of the variations of PET and MR image acquisition parameters on individual textures, and we investigated how these variations could enhance the global response and the predictive properties of a texture-based model. Our results suggest that it is feasible to identify an optimal set of image acquisition parameters to improve prediction performance. The model constructed with textures extracted from simulated images acquired with a standard clinical set of acquisition parameters reached an average AUC of [Formula: see text] in bootstrap testing experiments. In comparison, the model performance significantly increased using an optimal set of image acquisition parameters ([Formula: see text]), with an average AUC of [Formula: see text]. Ultimately, specific acquisition protocols optimized to generate superior radiomics measurements for a given clinical problem could be developed and standardized via dedicated computer simulations and thereafter validated using clinical scanners. PMID- 28872056 TI - New understanding of nano-scale interstitial dislocation loops in BCC iron. AB - Complex states of nanoscale interstitial dislocation loop can be described by its habit plane and Burgers vector. Using atomistic simulations, we provide direct evidences on the change of the habit plane of a 1/2<1 1 1> loop from {1 1 1} to {1 1 0} and {2 1 1}, in agreement with TEM observations. A new {1 0 0} habit plane of this loop is also predicted by simulations. The non-conservation of the Burgers vector is approved theoretically for: (1) dislocation reactions between loops with different Burgers vectors and (2) the transition between <1 0 0> loops and 1/2<1 1 1> loops. The rotation from a 1/2<1 1 1> to a <1 0 0> loop has also been explored, which occurs at 570 K for time on the order of 10 s. The dislocation-precipitate phase duality and change of habit plane are then proposed as new features for nano-scale dislocation loops. PMID- 28872057 TI - Simulation study on exchange interaction and unique magnetization near ferromagnetic morphotropic phase boundary. AB - Extensive efforts have been made in searching enhanced functionalities near the so-called morphotropic phase boundaries (MPBs) in both ferroelectric and ferromagnetic materials. Due to the exchange anti-symmetry of the wave function of fermions, it is widely recognized that the exchange interaction plays a critical role in ferromagnetism. As a quantum effect, the exchange interaction is magnitudes larger than electric interaction, leading to a fundamental difference between ferroelectricity and ferromagnetism. In this paper, we establish an energetic model capturing the interplay among the anisotropy energy, magnetostatic energy and the exchange energy to investigate systematically the effects of the exchange energy on the behavior of the ferromagnetic MPB. For the first time, it is found that the exchange energy can narrow the width of MPB region in the composition temperature phase diagram for ferromagnetic MPB systems. As temperature increases, MPB region becomes wider because of the weakening of the exchange interaction. Our simulation results suggest that the exchange energy play a critical role on the unique behavior of ferromagnetic MPB, which is in contrast different from that of ferroelectric MPB. PMID- 28872059 TI - Seventy years of publications. PMID- 28872058 TI - Nanoparticles target early-stage breast cancer metastasis in vivo. AB - Despite advances in cancer therapy, treating cancer after it has metastasized remains an unmet clinical challenge. In this study we demonstrate that 100 nm liposomes target triple-negative murine breast-cancer metastases post intravenous administration. Metastatic breast cancer was induced in BALB/c mice either experimentally, by a tail vein injection of 4T1 cells, or spontaneously, after implanting a primary tumor xenograft. To track their biodistribution in vivo the liposomes were labeled with multi-modal diagnostic agents, including indocyanine green and rhodamine for whole-animal fluorescent imaging, gadolinium for magnetic resonance imaging (MRI), and europium for a quantitative biodistribution analysis. The accumulation of liposomes in the metastases peaked at 24 h post the intravenous administration, similar to the time they peaked in the primary tumor. The efficiency of liposomal targeting to the metastatic tissue exceeded that of a non-liposomal agent by 4.5-fold. Liposomes were detected at very early stages in the metastatic progression, including metastatic lesions smaller than 2 mm in diameter. Surprisingly, while nanoparticles target breast cancer metastasis, they may also be found in elevated levels in the pre-metastatic niche, several days before metastases are visualized by MRI or histologically in the tissue. This study highlights the promise of diagnostic and therapeutic nanoparticles for treating metastatic cancer, possibly even for preventing the onset of the metastatic dissemination by targeting the pre-metastatic niche. PMID- 28872060 TI - Invariom-model refinement and Hirshfeld surface analysis of well-ordered solvent free dibenzo-21-crown-7. AB - Crown ethers and their supramolecular derivatives are well-known chelators and scavengers for a variety of cations, most notably heavier alkali and alkaline earth ions. Although they are widely used in synthetic chemistry, available crystal structures of uncoordinated and solvent-free crown ethers regularly suffer from disorder. In this study, we present the X-ray crystal structure analysis of well-ordered solvent-free crystals of dibenzo-21-crown-7 (systematic name: dibenzo[b,k]-1,4,7,10,13,16,19-heptaoxacycloheneicosa-2,11-diene, C22H28O7). Because of the quality of the crystal and diffraction data, we have chosen invarioms, in addition to standard independent spherical atoms, for modelling and briefly discuss the different refinement results. The electrostatic potential, which is directly deducible from the invariom model, and the Hirshfeld surface are analysed and complemented with interaction-energy computations to characterize intermolecular contacts. The boat-like molecules stack along the a axis and are arranged as dimers of chains, which assemble as rows to form a three dimensional structure. Dispersive C-H...H-C and C-H...pi interactions dominate, but nonclassical hydrogen bonds are present and reflect the overall rather weak electrostatic influence. A fingerprint plot of the Hirshfeld surface summarizes and visualizes the intermolecular interactions. The insight gained into the crystal structure of dibenzo-21-crown-7 not only demonstrates the power of invariom refinement, Hirshfeld surface analysis and interaction-energy computation, but also hints at favourable conditions for crystallizing solvent free crown ethers. PMID- 28872061 TI - Computational, 1H NMR, and X-ray structural studies on 1-arylurazole tetrazane dimers. AB - Nitrogen-centered urazole radicals exist in equilibrium with tetrazane dimers in solution. The equilibrium established typically favors the free-radical form. However, 1-arylurazole radicals bearing substituents at the ortho position favor the dimeric form. We were able to determine the structure of one of the dimers (substituted at both ortho positions with methyl groups), namely 1,2-(2,4 dimethylphenyl)-2-[2-(2,4-dimethylphenyl)-4-methyl-3,5-dioxo-1,2,4-triazolidin-1 yl]-4-methyl-1,2,4-triazolidine-3,5-dione, C24H28N6O4, via X-ray crystallography. The experimentally determined structure agreed well with the computationally obtained geometry at the B3LYP/6-311G(d,p) level of theory. The preferred syn conformation of these 1-arylurazole dimers results in the two aromatic rings being proximate and nearly parallel, which leads to some interesting shielding effects of certain signals in the 1H NMR spectrum. Armed with this information, we were able to decipher the more complicated 1H NMR spectrum obtained from a dimer that was monosubstituted at the ortho position with a methyl group. PMID- 28872062 TI - Polymorphism of a widely used building block for halogen-bonded assemblies: 1,3,5 trifluoro-2,4,6-triiodobenzene. AB - After reporting the structure of a new polymorph of 1,3,5-trifluoro-2,4,6 triiodobenzene (denoted BzF3I3), C6F3I3, (I), which crystallized in the space group P21/c, we perform a comparative analysis with the already reported P21/n polymorph, (II) [Reddy et al. (2006). Chem. Eur. J. 12, 2222-2234]. In polymorph (II), type-II I...I halogen bonds and I...pi interactions connect molecules in such a way that a three-dimensional structure is formed; however, the way in which molecules are connected in polymorph (I), through type-II I...I halogen bonds and pi-pi interactions, gives rise to an exfoldable lamellar structure, which looks less tightly bound than that of (II). In agreement with this structural observation, both the melting point and the melting enthalpy of (I) are lower than those of (II). PMID- 28872063 TI - Three zinc(II) and cadmium(II) complexes containing 4-amino-3,5-bis(pyridin-2-yl) 1,2,4-triazole and polynitrile ligands: synthesis, molecular and supramolecular structures, and photoluminescence properties. AB - Three photoluminescent complexes containing either ZnII or CdII have been synthesized and their structures determined. Bis[4-amino-3,5-bis(pyridin-2-yl) 1,2,4-triazole-kappa2N1,N5]bis(dicyanamido-kappaN1)zinc(II), [Zn(C12H10N6)2(C2N3)2], (I), bis[4-amino-3,5-bis(pyridin-2-yl)-1,2,4-triazole kappa2N1,N5]bis(dicyanamido-kappaN1)cadmium(II), [Cd(C12H10N6)2(C2N3)2], (II), and bis[4-amino-3,5-bis(pyridin-2-yl)-1,2,4-triazole kappa2N1,N5]bis(tricyanomethanido-kappaN1)cadmium(II), [Cd(C12H10N6)2(C4N3)2], (III), all crystallize in the space group P-1, with the metal centres lying on centres of inversion, but neither analogues (I) and (II) nor CdII complexes (II) and (III) are isomorphous. A combination of N-H...N and C-H...N hydrogen bonds and pi-pi stacking interactions generates three-dimensional framework structures in (I) and (II), and a sheet structure in (III). The photoluminescence spectra of (I)-(III) indicate that the energies of the pi-pi* transitions in the coordinated triazole ligand are modified by minor changes of the ligand geometry associated with coordination to the metal centres. PMID- 28872064 TI - Weak hydrogen and halogen bonding in 4-[(2,2-difluoroethoxy)methyl]pyridinium iodide and 4-[(3-chloro-2,2,3,3-tetrafluoropropoxy)methyl]pyridinium iodide. AB - To enable a comparison between a C-H...X hydrogen bond and a halogen bond, the structures of two fluorous-substituted pyridinium iodide salts have been determined. 4-[(2,2-Difluoroethoxy)methyl]pyridinium iodide, C8H10F2NO+.I-, (1), has a -CH2OCH2CF2H substituent at the para position of the pyridinium ring and 4 [(3-chloro-2,2,3,3-tetrafluoropropoxy)methyl]pyridinium iodide, C9H9ClF4NO+.I-, (2), has a -CH2OCH2CF2CF2Cl substituent at the para position of the pyridinium ring. In salt (1), the iodide anion is involved in one N-H...I and three C-H...I hydrogen bonds, which, together with C-H...F hydrogen bonds, link the cations and anions into a three-dimensional network. For salt (2), the iodide anion is involved in one N-H...I hydrogen bond, two C-H...I hydrogen bonds and one C Cl...I halogen bond; additional C-H...F and C-F...F interactions link the cations and anions into a three-dimensional arrangement. PMID- 28872065 TI - Synthesis and characterization of (cryptand-222)potassium (2 methylimidazolato)(meso-tetraphenylporphinato)ferrate(II)-2-methylimidazole tetrahydrofuran (1/1/2). AB - Metalloporphyrin complexes containing an additional imidazole ligand can provide information about the effect of deprotonation or hydrogen bonding on the axial histidine unit in heme proteins. The title high-spin five-coordinate imidazolate ligated iron(II) porphyrinate, [K(C18H36N2O6)][Fe(C4H5N2)(C44H28N4)].C4H6N2.2C4H8O, has been synthesized and investigated. The solvated salt crystallizes with one 2-methylimidazole molecule, two tetrahydrofuran solvent molecules and a potassium cation chelated inside a cryptand-222 (4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane) molecule. The imidazolate ligand is ordered. The average Fe-Np (Np is a porphyrin N atom) bond length is 2.113 (11) A and the axial Fe-NIm (NIm is an imidazolate N atom) is 2.0739 (13) A. The out-of-plane displacement of the FeII atom from the 24-atom mean plane is 0.6098 (5) A, indicating an apparent doming of the porphyrin core. PMID- 28872066 TI - Crystal structures and new perspectives on Y3Au4 and Y14Au51. AB - Y3Au4 (triyttrium tetragold) and Y14Au51 (tetradecayttrium henpentacontagold), two binary representatives of Au-rich rare earth (R) systems crystallize with the space groups R-3 and P6/m, adopting the Pu3Pd4 and Gd14Ag51 structure types, respectively (Pearson symbols hR42 and hP65). A variety of binary R-Au compounds have been reported, although only a few have been investigated thoroughly. Many reports lack information or misinterpret known compounds reported elsewhere. The Pu3Pd4 type is fairly common for group 10 elements Ni, Pd, and Pt, while Au representatives are restricted to just five examples, i.e. Ca3Au4, Pr3Au4, Nd3Au4, Gd3Au4, and Th3Au4. Sm6Au7 is suspected to be Sm3Au4 due to identical symmetry and close unit-cell parameters. The Pu3Pd4 structure type allows for full substitution of the position of the rare earth atom by more electronegative and smaller elements, i.e. Ti and Zr. The Gd14Ag51 type instead is more common for the group 11 metals, while rare representatives of group 12 are known. Y3Au4 can be represented as a tunnel structure with encapsulated cations and anionic chains. Though tunnels are present in Y14Au51, this structure is more complex and is best described in terms of polyhedral 'pinwheels' around the tunnel forming polyhedra along the c axis. PMID- 28872067 TI - A luminescent bis(pyridyl)-substituted benzimidazole platinum(II) complex exhibiting an intermolecular anagostic interaction. AB - The photophysical properties of transition metal complexes of the 5,6-dimethyl-2 (pyridin-2-yl)-1-(pyridin-2-ylmethyl)-1H-benzimidazole ligand are of interest. Dichlorido[5,6-dimethyl-2-(pyridin-2-yl)-1-(pyridin-2-ylmethyl)-1H-benzimidazole kappa2N2,N3]platinum(II), [PtCl2(C20H18N4)], is luminescent in the solid state at room temperature. The compound displays a distorted square-planar coordination geometry. The Pt-N(imidazole) bond length is shorter than the Pt-N(pyridine) bond length. The extended structure reveals that symmetry-related molecules display weak C-H...N, C-H...Cl, and C-H...Pt hydrogen-bonding interactions that are clearly discernable in the Hirshfeld surface and fingerprint plots. The intermolecular C-H...Pt and C-H...N interactions have been explored using density functional theory. The result of an analysis of the distance dependence of C H...Pt yields a value consistent with that observed in the solid-state structure. The energy of interaction for the C-H...Pt interaction is found to be about -11 kJ mol-1. PMID- 28872068 TI - A bipyridine-ligated zinc(II) complex with bridging flavonolate ligation: synthesis, characterization, and visible-light-induced CO release reactivity. AB - Metal-flavonolate compounds are of significant current interest as synthetic models for quercetinase enzymes and as bioactive compounds of importance to human health. Zinc-3-hydroxyflavonolate compounds, including those of quercetin, kampferol, and morin, generally exhibit bidentate coordination to a single ZnII center. The bipyridine-ligated zinc-flavonolate compound reported herein, namely bis(MU-4-oxo-2-phenyl-4H-chromen-3-olato)-kappa3O3:O3,O4;kappa3O3,O4:O3-bis[(2,2' bipyridine-kappa2N,N')zinc(II)] bis(perchlorate), {[Zn2(C15H9O3)2(C10H8N2)2](ClO4)2}n, (1), provides an unusual example of bridging 3-hydroxyflavonolate ligation in a dinuclear metal complex. The symmetry-related ZnII centers of (1) exhibit a distorted octahedral geometry, with weak coordination of a perchlorate anion trans to the bridging deprotonated O atom of the flavonolate ligand. Variable-concentration conductivity measurements provide evidence that, when (1) is dissolved in CH3CN, the complex dissociates into monomers. 1H NMR resonances for (1) dissolved in d6-DMSO were assigned via HMQC to the H atoms of the flavonolate and bipyridine ligands. In CH3CN, (1) undergoes quantitative visible-light-induced CO release with a quantum yield [0.004 (1)] similar to that exhibited by other mononuclear zinc-3-hydroxyflavonolate complexes. Mass spectroscopic identification of the [(bpy)2Zn(O benzoylsalicylate)]+ ion provides evidence of CO release from the flavonol and of ligand exchange at the ZnII center. PMID- 28872069 TI - A fluorophore-labelled copper complex: crystal structure, hybrid cyclic water perchlorate cluster and biological properties. AB - A fluorophore-labelled copper(II) complex, aquabis(dimethylformamide kappaO)(perchlorato-kappaO)[2-(quinolin-2-yl)-1,3-oxazolo[4,5 f][1,10]phenanthroline]copper(II) perchlorate monohydrate, [Cu(ClO4)(C22H12N4O)(C3H7NO)2(H2O)]ClO4.H2O, has been synthesized and characterized. A cyclic hydrogen-bonded water-perchlorate anionic cluster, i.e. [(ClO4)2(H2O)2]2-, has been identified within the structure. Each cyclic anionic cluster unit is interconnected by hydrogen bonding to the cation. The cations join into an infinite hydrogen-bonded chain running in the [010] direction. Furthermore, interaction of the complex with calf-thymus DNA (CT-DNA) and cellular localization within the cells was explored. Spectroscopic studies indicate that the compound has a good affinity for DNA and stains the nucleus of the cells. PMID- 28872070 TI - Hydrogen-bonded structures and interaction energies in two forms of the SGLT-2 inhibitor sotagliflozin. AB - The sotagliflozin molecule exhibits two fundamentally different molecular conformations in form 1 {systematic name: (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4 ethoxybenzyl)phenyl]-6-(methylsulfanyl)tetrahydro-2H-pyran-3,4,5-triol, C21H25ClO5S, (I)} and the monohydrate [C21H25ClO5S.H2O, (II)]. Both crystals display hydrogen-bonded layers formed by intermolecular interactions which involve the three -OH groups of the xyloside fragment of the molecule. The layer architectures of (I) and (II) contain a non-hydrogen-bonded molecule-molecule interaction along the short crystallographic axis (a axis) whose total PIXEL energy exceeds that of each hydrogen-bonded molecule-molecule pair. The hydrogen bonded layer of (I) has the topology of the 4-connected sql net and that formed by the water and sotagliflozin molecules of (II) has the topology of a 3,7 connected net. PMID- 28872071 TI - 3-(Pyridin-4-yl)acetylacetone: CdII and HgII compete for nitrogen coordination. AB - 3-(Pyridin-4-yl)acetylacetone (HacacPy) acts as a pyridine-type ligand towards CdII and HgII halides. With CdBr2, the one-dimensional polymer [Cd(MU Br)2(HacacPy)Cd(MU-Br)2(HacacPy)2]infinity is obtained in which five- and six coordinated CdII cations alternate in the chain direction. Reaction of HacacPy with HgBr2 results in [Hg(MU-Br)Br(HacacPy)]infinity, a polymer in which each HgII centre is tetracoordinated. In both compounds, each metal(II) cation is N coordinated by at least one HacacPy ligand. Equimolar reaction between these CdII and HgII derivatives, either conducted in ethanol as solvent or via grinding in the solid state, leads to ligand redistribution and the formation of the well ordered bimetallic polymer catena-poly[[bromidomercury(II)]-MU-bromido-[aquabis[4 hydroxy-3-(pyridin-4-yl)pent-3-en-2-one]cadmium(II)]-di-MU-bromido], [CdHgBr4(C10H11NO2)2(H2O)]n or [{HgBr}(MU-Br){(HacacPy)2Cd(H2O)}(MU Br)2]infinity. HgII and CdII cations alternate in the [100] direction. The HacacPy ligands do not bind to the HgII cations, which are tetracoordinated by three bridging and one terminal bromide ligand. The CdII centres adopt an only slightly distorted octahedral coordination. Three bromide ligands link them in a (2 + 1) pattern to neighbouring HgII atoms; two HacacPy ligands in a cis configuration, acting as N-atom donors, and a terminal aqua ligand complete the coordination sphere. Classical O-H...Br hydrogen bonds stabilize the polymeric chain. O-H...O hydrogen bonds between aqua H atoms and the uncoordinated carbonyl group of an HacacPy ligand in a neighbouring strand in the c direction link the chains into layers in the (010) plane. PMID- 28872073 TI - Supramolecular architectures in the salt trimethoprimium ferrocene-1-carboxylate and the cocrystal 4-amino-5-chloro-2,6-dimethylpyrimidine-ferrocene-1-carboxylic acid (1/1). AB - In the salt trimethoprimium ferrocenecarboxylate [systematic name: 2,4-diamino-5 (3,4,5-trimethoxybenzyl)pyrimidin-1-ium ferrocene-1-carboxylate], (C14H19N4O3)[Fe(C5H5)(C6H4O2)], (I), of the antibacterial compound trimethoprim, the carboxylate group interacts with the protonated aminopyrimidine group of trimethoprim via two N-H...O hydrogen bonds, generating a robust R22(8) ring motif (heterosynthon). However, in the cocrystal 4-amino-5-chloro-2,6 dimethylpyrimidine-ferrocene-1-carboxylic acid (1/1), [Fe(C5H5)(C6H5O2)].C6H8ClN3, (II), the carboxyl-aminopyrimidine interaction [R22(8) motif] is absent. The carboxyl group interacts with the pyrimidine ring via a single O-H...N hydrogen bond. The pyrimidine rings, however, form base pairs via a pair of N-H...N hydrogen bonds, generating an R22(8) supramolecular homosynthon. In salt (I), the unsubstituted cyclopentadienyl ring is disordered over two positions, with a refined site-occupation ratio of 0.573 (10):0.427 (10). In this study, the two five-membered cyclopentadienyl (Cp) rings of ferrocene are in a staggered conformation, as is evident from the C...Cg...Cg...C pseudo-torsion angles, which are in the range 36.13-37.53 degrees for (I) and 22.58-23.46 degrees for (II). Regarding the Cp ring of the minor component in salt (I), the geometry of the ferrocene ring is in an eclipsed conformation, as is evident from the C...Cg...Cg...C pseudo-torsion angles, which are in the range 79.26-80.94 degrees . Both crystal structures are further stabilized by weak pi pi interactions. PMID- 28872074 TI - A three-dimensional cadmium coordination polymer based on 1,4-bis(1,2,4-triazol-1 yl)but-2-ene and benzene-1,3,5-tricarboxylic acid. AB - The CdII three-dimensional coordination poly[[[MU4-1,4-bis(1,2,4-triazol-1-yl)but 2-ene]bis(MU3-5-carboxybenzene-1,3-dicarboxylato)dicadmium(II)] dihydrate], {[Cd2(C9H4O6)2(C8H10N6)].2H2O}n, (I), has been synthesized by the hydrothermal reaction of Cd(NO3)2.4H2O, benzene-1,3,5-tricarboxylic acid (1,3,5-H3BTC) and 1,4 bis(1,2,4-triazol-1-yl)but-2-ene (1,4-btbe). The IR spectrum suggests the presence of protonated carboxylic acid, deprotonated carboxylate and triazolyl groups. The purity of the bulk sample was confirmed by elemental analysis and X ray powder diffraction. Single-crystal X-ray diffraction analysis reveals that the CdII ions adopt a five-coordinated distorted trigonal-bipyramidal geometry, coordinated by three O atoms from three different 1,3,5-HBTC2- ligands and two N atoms from two different 1,4-btbe ligands; the latter are situated on centres of inversion. The CdII centres are bridged by 1,3,5-HBTC2- and 1,4-btbe ligands into an overall three-dimensional framework. When the CdII centres and the tetradentate 1,4-btbe ligands are regarded as nodes, the three-dimensional topology can be simplified as a binodal 4,6-connected network. Thermogravimetric analysis confirms the presence of lattice water in (I). Photoluminescence studies imply that the emission of (I) may be ascribed to intraligand fluorescence. PMID- 28872072 TI - A phase transition caught in mid-course: independent and concomitant analyses of the monoclinic and triclinic structures of (nBu4N)[Co(orotate)2(bipy)].3H2O. AB - The preparation and characterization of the nBu4N+ salts of two bis-orotate(2-) complexes of cobalt, namely bis(tetra-n-butylammonium) diaquabis(2,4-dioxo 1,2,3,4-tetrahydropyrimidin-1-ide-6-carboxylato-kappa2N1,O6)cobalt(II) 1.8 hydrate, (C16H36N)2[Co(C5H2N2O4)2(H2O)2].1.8H2O, (1), and tetra-n-butylammonium (2,2'-bipyridine-kappa2N,N')bis(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ide-6 carboxylato-kappa2N1,O6)cobalt(III) trihydrate, (C16H36N)[Co(C5H2N2O4)2(C10H8N2)].3H2O, (2), are reported. The CoIII complex, (2), which is monoclinic at room temperature, presents a conservative single crystal-to-single-crystal phase transition below 200 K, producing a triclinic twin. The transition, which involves a conformational change in one of the nBu groups of the cation, is reversible and can be cycled. Both end phases have been characterized structurally and the system was also characterized structurally in a two-phase intermediate state, using single-crystal diffraction techniques, with both the monoclinic and triclinic phases present. Thermal analysis allows a rough estimate of the small energy content, viz. 0.25 kJ mol-1, for both the monoclinic to-triclinic transformation and the reverse transition, in agreement with the nature of the structural changes involving only the nBu4N+ cation. PMID- 28872075 TI - A halide-free pyridinium-substituted eta3-cycloheptatrienide-Pd complex. AB - We report the synthesis and characterization of a novel 4 (dimethylamino)pyridinium-substituted eta3-cycloheptatrienide-Pd complex which is free of halide ligands. Diacetonitrile{eta3-[4-(dimethylamino)pyridinium-1 yl]cycloheptatrienido}palladium(II) bis(tetrafluoroborate), [Pd(C2H3N)2(C14H16N2)](BF4)2, was prepared by the exchange of two bromide ligands for noncoordinating anions, which results in the empty coordination sites being occupied by acetonitrile ligands. As described previously, exchange of only one bromide leads to a dimeric complex, di-MU-bromido-bis({eta3-[4 (dimethylamino)pyridinium-1-yl]cycloheptatrienido}palladium(II)) bis(tetrafluoroborate) acetonitrile disolvate, [Pd2Br2(C14H16N2)2](BF4)2.2CH3CN, with bridging bromide ligands, and the crystal structure of this compound is also reported here. The structures of the cycloheptatrienide ligands of both complexes are analogous to the dibromide derivative, showing the allyl bond in the beta position with respect to the pyridinium substituent. This indicates that, unlike a previous interpretation, the main reason for the formation of the beta-isomer cannot be internal hydrogen bonding between the cationic substituents and bromide ligands. PMID- 28872076 TI - [Inhibitory effect of BEZ235 on human prostate carcinoma in vitro]. AB - OBJECTIVE: To determine effects of BEZ235, an inhibitor of phosphoionsitol-3 kinase (PI3K)/mTOR, on the cell proliferation and migration in human prostate carcinoma lines including RWPE-1, PC3, and DU145 cells.? Methods: Viability of RWPE-1, PC3, and DU145 cells was detected by 3-(4,5-dimethylthiazol- 2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay, while cell migration was analyzed by wound healing assay. Western blot and immunofluorescence were used to examine the changes of relevant protein expression. ? Results: The proliferation of PC3 and DU145 cells was effectively inhibited by BEZ235 (P<0.01), whereas RWPE-1 was not obviously inhibited. Invasion and migration of PC3 and DU145 cells were attenuated by BEZ235 via EMT pathway.? Conclusion: The PI3K/mTOR dual inhibitor BEZ235 shows substantial anti-tumor activity in human prostate carcinoma lines of PC3 and DU145 cells, which may be involved in the EMT pathway. PMID- 28872077 TI - [Role of PpIX-based photodynamic therapy in promoting the damage and apoptosis of colorectal cancer cell and its mechanisms]. AB - OBJECTIVE: To explore the effects of protoporphyrin IX (PpIX)-mediated photodynamic therapy (PDT) on induction of apoptosis and death in colon cancer cell and the underlying mechanisms.? Methods: The cell killing effect of PDT on HCT116 cell was determined by cell counting kit (CCK). The cells were divided into a control group, a single light group, a single PpIX group, and a PDT group. Hoechst 33342 and flow cytometry was used to assess the cell apoptosis. Western blot was employed to analyze the expressions of bcl-2, bax, and caspase-3. Reactive oxygen species (ROS) was detected by flow cytometry.? Results: The viability of HCT116 cell was decreased gradually with the increase of irradiation dose (P<0.05). Compared to the other 3 groups, ROS production, the number of apoptotic cells and the protein expressions of bax and caspase-3 in PDT group increased, while bcl-2 expression was decreased (P<0.05).? Conclusion: PpIX mediated PDT can enhance the apoptosis in HCT116 cell, which may be related to mitochondrial apoptosis pathway. PMID- 28872078 TI - [Correlations between the p-Akt-mTOR-p70S6K pathway and clinicopathological features or chemoresistance of ovarian cancer]. AB - OBJECTIVE: To study the relationship between alpha seine/threonine-protein kinase (p-Akt)-serine/threonine-protein kinase (mTOR)-ribosomal protein S6 kinase (p70S6K) signaling pathway and clinicopathological features or chemoresistance of ovarian cancer.? Methods: We checked the p-Akt, mTOR and p70S6K protein levels in 18 tissues with chemoresistance or 25 with chemosensitivity of ovarian cancer by immunohistochemistry technique, and analyzed the relationship between those proteins and clinicopathological features or chemoresistance of ovarian cancer.? Results: The levels of p-Akt protein in ovarian serous carcinoma, mucinous carcinoma and endometrioid carcinoma were 77.14%, 50.00% and 66.67%, respectively, with no significant difference (P>0.05). The levels of these proteins in well-middle differentiated carcinoma and low differentiated carcinoma were 73.33% and 75.00%, respectively, with no significant difference (P>0.05). The levels of these proteins in I-II stage carcinoma, and III-IV stage carcinoma were 18.18% and 93.75%, respectively, with significant difference (P<0.05). The levels of mTOR protein in ovarian serous carcinoma, mucinous carcinoma and endometrioid carcinoma were 77.14%, 100.00% and 83.33%, respectively, with no significant difference (P>0.05). The levels of this protein in well-middle differentiated carcinoma and low differentiated carcinoma were 80.00% and 78.57%, respectively, with no significant difference (P>0.05). The levels of this protein in I-II stage carcinoma, and III-IV stage carcinoma were 27.27% and 96.88%, respectively, with significant difference (P<0.05). The levels of p70S6K protein in ovarian serous carcinoma, mucinous carcinoma and endometrioid carcinoma were 80.00%, 100.00% and 100.00%, respectively, with no significant difference (P>0.05). The levels of this protein in well-middle differentiated carcinoma and low differentiated carcinoma were 93.33% and 78.57%, respectively, with no significant difference (P>0.05). The levels of this protein in I-II stage carcinoma, and III-IV stage carcinoma were 45.45% and 96.88%, respectively, with significant difference (P<0.05). The levels of p-Akt protein in tissue of chemoresistance and chemosensitivity of ovarian cancer were 88.89% and 64.00%, respectively, with significant difference (P<0.05). The levels of mTOR protein in tissue of chemoresistance and chemosensitivity of ovarian cancer were 94.44% and 68.00%, respectively, with significant difference (P<0.05). The levels of p70S6K protein in tissue of chemoresistance and chemosensitivity of ovarian cancer were 100.00% and 72.00%, respectively, with significant difference (P<0.05).? Conclusion: The p-Akt-mTOR-p70S6K signaling pathway may take part in invasion and metastasis of ovarian cancer. The up-regulation of these proteins may be associated with the chemoresistance of ovarian cancer, and these proteins may have potential to be the prognostic markers for the chemoresistance of ovarian cancer. PMID- 28872079 TI - [Mechanisms for the regulatory effect of prostaglandin E2/prostaglandin E receptor 4 on high mobility group box-1 protein in lipopolysaccharide-induced sepsis in mouse peritoneal macrophage]. AB - OBJECTIVE: To explore the effect of prostaglandin E2 (PGE2) on the expression of high mobility group box-1 protein (HMGB1) in peritoneal macrophages of septic mice and its possible mechanisms.? Methods: The mouse peritoneal macrophages were isolated and cultured by conventional methods.The model of inflammation was established by using lipopolysaccharide (LPS) to incubate with mouse peritoneal macrophages. The PGE2, prostaglandin E receptor (EP) 4 agonist, EP4 RNAi, and DN.CREB inhibitory plasmid were used to interfere with the LPS-treated mouse peritoneal macrophage. The levels of HMGB1 was determined by Western blot.? Results: Compared with LPS alone treatment, the expression of HMGB1 in peritoneal macrophages was increased obviously after 24 h by treatment with PGE2 and LPS, and it was also increased after the combined treatment of EP4 receptor agonist with LPS for 24 h (both P<0.05); compared with the PGE2+LPS treatment, the level of HMGB1 was decreased after knockdown of EP4 receptor expression (P<0.05); compared with EP4 receptor agonist +LPS treatment, there was no difference in HMGB1 levels in mice after the treatment with DN.CREB plasmid to suppress CREB function (P>0.05); compared with LPS alone treatment, the combined treatment of EP4 receptor agonist with LPS for 24 h could up-regulate the phosphorylation of epidermal growth factor receptor (EGFR) and protein kinase B (Akt) thr308 (P<0.05), which were blocked by EGFR inhibitor. Once Akt specific inhibitor was used before EP4 and LPS treatment, the expression of HMGB1 was declined (P<0.05).? Conclusion: PGE2 can up-regulate the expression of HMGB1 in sepsis of peritoneal macrophages through EP4 receptor, which may be related to the activation of EGFR/PI3K/Akt signaling pathway. PMID- 28872080 TI - [Role of autophagy in ameliorating sepsis-induced acute lung injury by allicinin in mice]. AB - OBJECTIVE: To investigate roles of autophagy in ameliorating sepsis-induced acute lung injury by allicinin in mice.? Methods: A total of 152 male Balb/c mice (8 week old) were randomly divided into a sham group, a septic model group, an allicin treatment group, and an autophagy inhibition group. Septic mouse model was established by cecal ligation and puncture (CLP). Mice in the allicin treatment group were given allicin (30 mg/kg, intra-peritoneal injection) at 6 and 12 h, while those in the autophagy inhibition group were given autophagy inhibitor 3-MA (15 mg/kg, intra-peritoneal injection) at half an hour after allicin administration. Mice in the model and sham group were administered with the same amount of saline. Twenty mice in each group were randomly chosen to observe the 7 d survival rate. The other 12 mice were killed at 24 h, and the bronchoalveolar lavage fluid (BALF) (n=6) and lung tissues (n=6) were collected. ELISA was used to detect the tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the BALF. Hematoxylin-eosin staining was preformed to show the morphological changes in the lung tissues. Malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) in the lung tissues were examined. The expression of LC3B and Beclin-1 was determined by immunohistochemical analysis.? Results: Compared with the sham group, the 7 d survival rate and lung SOD activity were decreased in the CLP group (P<0.05); the lung morphological damage score, the levels of TNF-alpha and IL-6 in the BALF, MDA content in the lung, and expression of LC3B and Beclin-1 were increased greatly in the CLP group (P<0.05). Compared with the CLP group, the 7 d survival rate, lung SOD activity and the expressions of LC3B and Beclin-1 were increased significantly in the allicin treatment group (P<0.05); the lung morphological damage scores, the levels of TNF-alpha and IL-6 in the BALF and MDA content in the lung were decreased obviously in the allicin treatment group (P<0.05). Compared with the allicin treatment group, the 7 d survival rate, lung SOD activity, and the expressions of LC3B and Beclin-1 were decreased in the 3-MA group (P<0.05); the lung morphological damage scores, the levels of TNF-alpha and IL-6 in the BALF, and MDA content in the lung were increased significantly in the 3-MA group (P<0.05).? Conclusion: Allicin may ameliorate sepsis-induced acute lung injury in mice by enhancing the level of autophagy. PMID- 28872081 TI - [Effect of Shexiang Baoxin Pills on isoprenaline-induced myocardial cell hypertrophy and Cx43 expression]. AB - OBJECTIVE: To observe the effects of Shexiang Baoxin Pill (SBP) on isoprenaline (Iso)-induced changes in myocardial cell volume, shape, and connexin 43 (Cx43) expression.? Methods: H9C2 myocardial cells were randomly divided into a control group, a Iso group and a Iso+SBP group. After 72 h of culture, the average surface area of H9C2 cells was measured under phase contrast microscope. Bicinchoninic acid (BCA) protein assay was carried out to determine the concentration of proteins. The survival rate of myocardial cells was measured by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, and the Cx43 expression was detected by Western blot.? Results: The mean surface area and Cx43 concentration in Iso-treated myocardial cells were increased under the phase contrast microscope (P<0.05). Compared with the Iso group, the mean surface area was decreased, and the Cx43 concentration was reduced in the Iso+SBP group (both P<0.05). Compared with the control group, the Cx43 expression was obviously down regulated in the H9C2 cells of the Iso group (P<0.05); while compared with the Iso group, the Cx43 expression was obviously up-regulated in the Iso+SBP group (P<0.05).? Conclusion: Shexiang Baoxin Pills can prevent Iso-induced myocardial hypertrophy and down-regulate Cx43 expression. PMID- 28872082 TI - [Relationship between the methylation status of STAT3 promoter DNA in peripheral blood CD4+ T cells from patients after allo-HSCT and aGVHD]. AB - OBJECTIVE: To study the relationship between acute graft versus host disease (aGVHD) and the methylation status of the STAT3 promoter in peripheral blood CD4+ T cells from patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).? Methods: We collected 40 patients who underwent allo-HSCT from HLA identical sibling donors. Serum IL-10, TGF-beta1, IL-17A and IL-17F levels were detected by ELISA. Foxp3 cytotoxic T-lymphocyte-associated protein 4 (CTLA4), IL 10, TGF-beta1, RORgammat, IL-17A and IL-17F mRNA levels in CD4+ T cells were measured by real-time PCR. STAT3 expression levels were detected by real-time PCR and Western blot, and promoter DNA methylation was analyzed by bisulfite sequencing PCR (BSP).? Results: IL-10 and TGF-beta1 levels were significantly down-regulated, while IL-17A and IL-17F levels were significantly up-regulated in patients with aGVHD compared with patients without aGVHD. Foxp3, CTLA4, IL-10, TGF-beta1 mRNA levels were significantly down-regulated, while RORgammat, IL-17A, IL-17F mRNA levels were significantly up-regulated in patients with aGVHD compared with patients without aGVHD. STAT3 expression was increased, while STAT3 promoter DNA was hypomethylated in patients with aGVHD compared with those without aGVHD. The STAT3 mRNA level was negatively correlated with STAT3 promoter DNA methylation.? Conclusion: The imbalance of Treg/Th17 in CD4+ T cells from patients after allo-HSCT is a key factor for triggering aGVHD, and the DNA hypomethylation of STAT3 promoter could promote its expression in CD4+ T cells and contribute to the imbalance. PMID- 28872083 TI - [Repair of articular cartilage defects by autologous bone mesenchymal stem cells and allogeneic costal chondrocytes in the knee of Wuzhishan miniature pigs]. AB - OBJECTIVE: To investigate the feasibility of construction of tissue engineered cartilage by co-culture of bone marrow mesenchymal stem cells (BMSCs) and costal chondrocytes (CCs), and to provide theoretical basis and experimental basis for clinical repair of articular cartilage defects by Wuzhishan miniature pig knee cartilage defects with co-cultured cells.? Methods: Density gradient centrifugation method was used to isolate BMSCs from Wuzhishan miniature pig. The double enzyme digestion method was used to isolate CCs. The passage 3 generation of BMSCs and passage 2 generation of CCs were randomly divided into 3 groups: a co-culture group of BMSCs:CCs for 1:2 (Group A), a simple CCs (Group B), and a simple BMSCs (Group C). The cell growth curve was drawn, and the content of glycosaminoglycan (GAG) of external separation in chondrocytes was determined. The 12 Wuzhishan miniature pigs were randomly divided into a co-culture cells/collagen membrane experimental group, a collagen membrane control group and the blank group. In the co-culture cells/collagen membrane experimental group, the co-cultured cells/collagen membrane were implanted into the cartilage defects of the mandibular condyle; in the collagen membrane control group, only collagen membrane was implanted; while in the blank group, nothing was implanted. Six animals were sacrificed at 8 and 16 weeks after surgery respectively (2 animals in each group). General observation, cartilage histological score and histopathological examination were carried out.? Results: The BMSCs and co culture cells grew well. The biological activity of CCs was good. After 16 weeks of operation, the repair tissues in the co-cultured cells/collagen membrane experimental group showed hyaline cartilage features: smooth, flat, and integrated well with the surrounding cartilage and subchondral bone. The collagen membrane in the collagen membrane control group was fibrously repaired. Repair tissue gross score in the co-culture cells/collagen membrane experimental group was significantly better than that in the collagen membrane control group and the blank group (both P<0.05), but there was no significant difference between the collagen membrane control group and the blank group (P>0.05).? Conclusion: BMSCs, CCs and co-cultured cells can function as the seed cells for cartilage tissue engineering, and the co-culture cells (BMSCs:CCs=1:2) possess more advantages; the short-term effect of co-culture cells with collagen membrane on repairing cartilage defects is satisfied. PMID- 28872084 TI - Mortality trend of inpatients with connective tissue diseases: 2005-2014. AB - OBJECTIVE: To analyze the trend relevant factors leading to death and their patterns over a 10-year period in inpatients with connective tissue diseases (CTDs).? Methods: All clinical data about death in inpatients with CTDs were retrospectively reviewed between 2005 and 2014 at the Department of Rheumatology and Immunology in Xiangya Hospital of Central South University.? Results: In the 10-year time period, the overall hospital mortality was 15.680/00. The disease itself accounted for 44.71% of the total causes of death, infection accounted for 42.94%, and comorbidities accounted for 12.35%. The constituent ratio of deaths and the average hospital mortality caused by the disease itself declined gradually year by year, and the constituent ratio of deaths caused by infection and comorbidities increased gradually year by year (P<0.05). In 2013-2014, infection was the leading cause of death, which accounted for 51.06%. The survival time for CTDs inpatients with interstitial lung disease (ILD) was shorter than that of CTDs inpatients without ILD, and even the risk of death was 1.722 times of the latter. The proportion of deaths caused by the disease itself was the highest in systemic sclerosis and systemic lupus erythematosus, that by infection was the highest in idiopathic inflammatory myopathy (IIM), and that by comorbidities was the highest in rheumatoid arthritis.? Conclusion: The proportion of deaths and the hospital mortality in CTDs inpatients caused by the disease itself show a declining trend, while the proportion of deaths caused by infection and comorbidities increase. CTDs patients with ILD have shorter survival time and an increase in risk of death. PMID- 28872085 TI - [Manifestations of the connective tissue associated interstitial lung disease under high resolution computed tomography]. AB - OBJECTIVE: To analyze the features of the connective tissue associated interstitial lung disease (CTD-ILD) by high resolution computed tomography (HRCT).? Methods: A total of 127 patients with CTD-ILD, who were diagnosed by clinic laboratory examination and pathology in Xiangya Hospital of Central South University form September 2013 to September 2015, were enrolled for this study. Their lung features of HRCT imaging were retrospectively analyzed.? Results: The classifications for 127 patients were as follows: 36 cases of rheumatoid arthritis (28.3%), 34 cases of dermatomyositis and polymyositis (26.8%), 31 cases of systemic sclerosis (24.4%), 18 cases of Sjogren syndrome (14.2%), 7 cases of mixed connective tissue disease (5.5%), and 1 cases of systemic lupus erythematosus (0.8%). According to the features of HRCT imaging, the patients were divided as follows: 77 cases (60.6%) of nonspecific interstitial pneumonia (NSIP), 46 cases (36.2%) of usual interstitial pneumonia (UIP), 2 cases (1.6%) of lymphocytic interstitial pneumonia (LIP), 1 case (0.8%) of cryptogenic interstitial pneumonia (COP), and 1 case (0.8%) of acute interstitial pneumonia (AIP). The HRCT findings for 36 cases of rheumatoid arthritis associated interstitial lung disease were UIP (24 cases, 66.7%) and NSIP (12 cases, 33.3%); the HRCT findings for 34 cases of dermatomyositis and polymyositis associated interstitial lung disease were NSIP (32 cases, 94.1%), UIP (1 case, 2.9%) and COP (1 case, 2.9%); the HRCT findings for 31 cases of systemic sclerosis associated interstitial lung disease were NSIP (21 cases, 67.8%), UIP (9 cases, 29%), LIP(1 case, 3.2%); the HRCT findings for 18 cases of Sjogren syndrome associated interstitial lung disease were NSIP (9 cases, 50.0%), UIP (8 cases, 44.4%), LIP (1 case, 5.6%); the HRCT findings for 7 cases of mixed connective tissue disease associated interstitial lung disease were UIP (4 cases, 57.1%), NSIP (3 cases, 42.9%). SLE-ILD was rare, with only 1 case of AIP.? Conclusion: Different types of CTD-ILD patients display relatively unique manifestation of HRCT. PMID- 28872086 TI - [Subclinical hypothyroidism and endocrine metabolic characteristics in women with polycystic ovary syndrome]. AB - OBJECTIVE: To explore associations of subclinical hypothyroidism (SCH) with endocrine metabolic characteristics in women with polycystic ovary syndrome (PCOS).? Methods: A total of 321 women who were newly diagnosed as PCOS were recruited from two endocrine outpatient clinics. The diagnosis of PCOS was established according to the 2003 Rotterdam consensus criteria. Thyroid function was examined by chemiluminescent immunoassay. Patients who had normal free thyroxine (FT4) were divided into different SCH subgroups according to two thyroid stimulating hormone (TSH) cutoff points (4.2 and 2.5 mU/L). Endocrine metabolic characteristics in different subgroups were compared and analyzed.? Results: In PCOS women with normal FT4, the patients with TSH>=4.2 mU/L had higher prolactin (PRL), luteinizing hormone-to-follicle stimulating hormone ratio, and visceral adipose index (all P<0.05). There were trends toward an increase in triglyceride (P=0.085) and a decrease in high-density lipoprotein cholesterol (HDL-C) (P=0.060) in the patients with TSH>=4.2 mU/L compared with that in the patients with TSH<4.2 mU/L. Also in PCOS women with normal FT4, the patients with TSH>=2.5 mU/L had higher body mass index, PRL, triglyceride, visceral adipose index and lower HDL-C in comparison of that in the patients with TSH<2.5 mU/L (all P<0.05).? Conclusion: SCH is associated with more severe endocrine abnormality, dyslipidemia, and visceral obesity in PCOS women. PCOS women with normal FT4 and endocrine metabolic characteristics are more prone to be different between the SCH group and the euthyroid group when setting 2.5 mU/L as a TSH cutoff for SCH, indicating that 2.5 mU/L is a good TSH cutoff for SCH in PCOS women. PMID- 28872087 TI - [Serum level of chemerin and bone mineral density in patients with Graves disease]. AB - OBJECTIVE: To investigate relationships between serum chemerin and bone mineral density (BMD) in patients with newly diagnosed Graves disease (GD).? Methods: A total of 120 newly diagnosed GD patients with a course more than 3 months were enrolled from the Department of Endocrinology between June 2013 and June 2015. Sixty age- and sex-matched healthy people served as a normal control. Serum levels of chemerin, beta-crosslaps (beta-CTX), and N-MID-osteocalcin (N-MID-OT) were measured by ELISA. Fat mass and BMD were evaluated by dual energy X-ray absorptiometry (DEXA).? Results: Compared with the normal control, the fat mass, lean weight, fat mass index (FMI) and body mass index (BMI) in the GD group were decreased, and BMD in all skeletal sites was decreased. There was a positive correlation between them (all P<0.05). Serum level of chemerin was increased and it was positively correlated with beta-CTX or N-MID-OT level and negatively correlated with fat mass, FMI or BMI in the GD group. There was a negative correlation between chemerin level and BMD in femoral neck, total hip, lumbar or right forearm distal 1/3 (rs=-0.352, -0.279, -0.379, -0.289, -0.394; P<0.05). After adjusting for age, fat mass or BMI, the correlation of chemerin with total hip or bone mineral density remained significant (rs=-0.273, -0.378; P<0.05). Multiple linear regression analysis revealed that chemerin or BMI was correlated with BMD (P<0.05).? Conclusion: The decrease of bone mineral density in patients with GD is not only related to the direct or indirect effect of excessive thyroid hormones on systemic and osteoblastic cells, but it is also related to the negative regulation of bone metabolism due to the elevated chemerin level. PMID- 28872088 TI - [Clinical characteristics and prognosis for 126 patients with severe drug eruption]. AB - OBJECTIVE: To explore the clinical characteristics of various types of severe drug eruption and common sensitized drugs, and to provide clinical references for reducing the incidence of severe drug eruption.? Methods: The clinical data regarding 126 cases of severe drug eruption were analyzed retrospectively from June 2009 to May 2017 in Xiangya Hospital, Central South University.? Results: In the 126 cases of severe drug eruption, the distribution of men and women ratio was 1:1.38. The length of stay was (12.7+/-9.8) d. The most common type was Steven-Johnson syndrome; the most dangerous type was drug-induced bullosa epidermolysis. The most common sensitized drug category in these patients was antibiotics; the most common single sensitizing drug was carbamazepine, following by allopurinol.? Conclusion: Severe drug eruption occurs mostly in young and middle-aged people. Steven-Johnson syndrome is the most common type; drug hypersensitive syndrome has the longest length of hospital course. Mortality rate of drug-induced bullosa epidermolysis is the highest. Timely stop using of allergens, early using glucocorticoids, and timely combination of non glucocorticoids treatment (such as intravenous immunogloblin, plasma exchange and hemodialysis), can improve the efficacy and reduce the complications and mortality. ?. PMID- 28872089 TI - [Personal characteristics of paradoxical insomnia: A case-control study]. AB - OBJECTIVE: To compare the personal characteristics between the patients with paradoxical insomnia and the patients with primary insomnia or the normal sleepers.? Methods: A case-control study with the proportion at 1:1:1 was carried out. The patients with paradoxical insomnia were diagnosed in Sleep Medicine Center of West China Hospital of Sichuan University between March 2013 and December 2013. A case of paradoxical insomnia was matched with two controls: a primary insomnia patient and a normal sleeper. A total of 63 matched cases were collected. A face-to-face survey was conducted by using the following scales: General Data Scale and Eysenck Personality Questionnaire (EPQ).? Results: The average scores of psychoticism, extraversion, and neuroticism for paradoxical insomnia cases were (52.1+/-10.2), (49.6+/-9.8), and (56.0+/-12.0), respectively. In general, 31.7% of paradoxical insomnia patients had psychoticism or psychoticism tendency in their personality, which were more obvious than those in primary insomnia patients (7.9%) (chi2=11.228, P<0.0125) and normal sleepers (0) (chi2=23.774, P<0.0125). Moreover, 19.0% of paradoxical insomnia patients had extroversion or extroversion tendency in their personality, which were more significant than those in primary insomnia patients (3.2%) (Z=-4.047, P<0.0125) but less obvious than those in normal sleepers (60.3%) (Z=-4.754, P<0.0125). Also, 46.0% of paradoxical insomnia patients had neuroticism or neuroticism tendency in their personality, which were more significant than those in normal sleepers (0) (chi2=37.670, P<0.0125) but similar to those in primary insomnia patients (52.4%) (chi2=0.508, P>0.0125).? Conclusion: The personal characteristics for paradoxical insomnia patients did not reached obviously abnormal level. However, their psychoticism tendency, extroversion tendency and neuroticism tendency needed to be paid attention. PMID- 28872090 TI - [Therapeutic effect of one-day outpatient on gestational diabetes mellitus patients]. AB - OBJECTIVE: To study the effect of one-day outpatient intervention on gestational diabetes mellitus (GDM) patients, and to explore the pregnancy outcome relevant to GDM patients and their fetus.? Methods: The GDM patients were divided into two groups according to their own intention to the one-day outpatient. According to systematic sampling method, we chose 200 GDM patients from the above 2 groups, respectively. The 200 GDM patients in the control group were matched the observation group with the age and gestational age, then the pregnancy outcome was tracked.? Results: The control level and success rate for the two hours blood sugar after breakfast and hemoglobin A1c (HbA1c) in the observation group were better than those in the control group (P<0.001). The maternal complication rate (46.50%) and neonatal complication rate (21.50%) in the observation group were lower than those in the control group (71.50%, 41.50%; P<0.001). The maternal complications rate of fetal distress, premature and the neonatal complications rate of fetal macrosomia, neonatal respiratory distress syndrome (NRDS), low weight, congenital heart disease, neonatal pneumonia, and rate in neonatal NICU were significantly lower than those in the control group (P<0.05).? Conclusion: One-day outpatient intervention could control blood sugar effectively, reduce the maternal and neonatal complications. It is worth promoting. PMID- 28872091 TI - [Demands for cardiac rehabilitation information in patients with coronary atherosclerotic heart disease and influential factors]. AB - OBJECTIVE: To investigate the demands for cardiac rehabilitation information in patients with coronary atherosclerotic heart disease (CHD) and influential factors. ? Methods: Information demands for cardiac rehabilitation in CHD patients were surveyed by questionnaire and the influential factors were analyzed by one-way ANOVA and multi-factor analysis of variance.? Results: The score of demands for cardiac rehabilitation information in CHD patients was 3.86+/-0.53. Among them, the most urgent top 5 items were: drug knowledge, diagnosis and treatment, basic knowledge of the heart, emergency and safety and nutrition knowledge. The top 3-demand modes were: communication with medical workers, movies or videos to take home, and lectures. The score of demands for cardiac rehabilitation information was different in different age groups. The highest score was in the patients with age less than 60. There were different demands in different characteristic groups.? Conclusion: The most urgent need and mode are drug knowledge and communication with medical workers, respectively. With the age increase, the demands for patients' cardiac rehabilitation information decrease. An individualized health education strategy should be developed according to the characteristics of CHD patients. PMID- 28872092 TI - [Vitamin D/vitamin D receptor, autophagy and inflammation relevant diseases]. AB - The biological effects mediated by vitamin D and vitamin D receptor (VDR) are involved in the regulation of multiple pathophysiologic processes, including calcium phosphorus metabolism, immune regulation, anti-inflammation, anti infection and cancer prevention, etc. Autophagy is a eukaryotic cell lysosome mediated catabolic pathway, which is classified into 3 different types: macroautophagy, microautophagy, and chaperone-mediated autophagy. Since autophagy is vital to maintain energy and metabolism in cells, autophagy dysfunction is closely associated with various pathological processes such as inflammation, infection and tumor. Studies have shown that vitamin D/VDR can affect the different stages of autophagy and regulate inflammation in autophagy. Moreover, vitamin D/VDR and autophagy play an important role in autoimmune disease, diabetes, cardiovascular disease, cancer and other inflammatory diseases. PMID- 28872093 TI - [Research progress of trimethylamine-N-oxide in the pathogenesis of atherosclerosis]. AB - Trimethylamine-N-oxide (TMAO), metabolites of the intestinal microflora, is a newly discovered risk factor for cardiovascular disease. The intestinal flora converted choline and L-carnitine into trimethylamine in the food. Trimethylamine is oxidized to TMAO in liver enzymes. Lowering TMA can stimulate macrophages to reverse cholesterol transport and inhibit atherogenesis. TMAO poietin monooxygenase 3 (FMO3) is a tool for cholesterol metabolism and reverse cholesterol transpor, lowering FMO3 can slow the gallbladder's secretion of bile, delay intestinal absorption of cholesterol, and limit the synthesis of oxidized cholesterol and cholesterol esters. TMAO in the blood can up regulate scavenger receptors in macrophages, and promote accumulation of cholesterol and formation of foam cells in macrophages, thereby promoting vascular plaque formation and promote the inflammatory response by MAPK and nuclear factor kappa B pathway. TMAO concentrates on affecting cholesterol metabolism, increasing insulin resistance, promoting platelet aggregation, increasing thrombosis, promoting vascular inflammatory response and directly leading to the formation of atherosclerotic plaques. Lowering TMAO levels can potentially prevent or treat atherosclerotic related diseases and reduce the incidence of cardiovascular and cerebrovascular diseases. PMID- 28872094 TI - [Transcatheter aortic valve implantation: Present and development trend]. AB - Currently, although surgical aortic valve replacement (SAVR) is still the golden standard in treatment of severe aortic stenosis according to the guideline, transcatheter aortic valve implantation (TAVI) is gradually becoming a common treatment for patients who are prohibitive or in high risk for SAVR. Recently, the valve manufacturers, including medical companies in China, are making their utmost to develop valve device, leading remarkable results achieved by TAVI. With the complications being controlled, TAVI displays promising future. It is likely that TAVI is expected to become a substitute for SAVR to treat patients with aortic stenosis or even aortic regurgitation. PMID- 28872095 TI - Laparoscopic excision of the choledochal cyst in adult patients: An experience. AB - BACKGROUND: Laparoscopic choledochal cyst excision (LCCE) in adult patients is not common. AIMS: The aim is to report our experience of LCCE in adult patients. PATIENTS AND METHODS: This study includes a retrospective review of twenty adult patients (age >18 years) with choledochal cyst (CC) who underwent LCCE by a single surgical team from February 2011 to April 2016. RESULTS: The mean age was 45.5 years. Nineteen (95%) patients had Type-I CC, and one patient (5%) had Type IV CC (Todani's classification). Fifteen patients (75%) presented with pain in the abdomen, and five patients (25%) presented with jaundice and/or cholangitis. LCCE was successful in 16 (80%) patients, whereas four patients (20%) required conversion to open method. The reason for conversion was technical difficulty due to the initial learning curve, adhesion and inflammation. The mean blood loss, operation time and post-operative stay were 117.5 ml, 299.5 min and 8.15 days, respectively. Bilioenteric anastomosis leak and formation of pseudoaneurysm occurred in one patient (5%); this patient later died due to uncontrolled intra abdominal haemorrhage. There were no remote complications during a mean follow-up of 17.2 months. CONCLUSION: LCCE in adult patients is safe and feasible, but bilioenteric anastomosis leak may have fatal consequences. PMID- 28872096 TI - Clinical reappraisal of vasculobiliary anatomy relevant to laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) has many advantages as compared to open cholecystectomy. However, vasculobiliary injuries still continue to be a matter of concern despite advances in laparoscopic techniques. Misidentification and misperception of vasculobiliary structures is considered to be a pivotal factor leading to injuries. Although many studies since time immemorial have stressed on the importance of anatomy, an insight into laparoscopic anatomy is what essentially constitutes the need of the hour. OBJECTIVE: To assess the frequency and the relevance of anatomical variations of extrahepatic biliary system in patients undergoing LC. MATERIALS AND METHODS: The present study is an observational study performed for a period of 2 years from August 2014 to August 2016. It included all diagnosed patients of cholelithiasis undergoing routine LC performed by a single surgeon by achieving a critical view of safety. During dissection, vascular and ductal anomalies were noted and assessed for their relevance in LC. RESULTS: Seven hundred forty cases of cholelithiasis, irrespective of pathology, comprising 280 (37.83%) men and 460 (62.16%) females with a mean age of 39.85 +/- 18.82 years were included in the study. Photodocumentation and operative recordings were available in 93% of cases. Operative findings revealed 197 (26.62%) vascular anomalies and 90 (12.16%) ductal anomalies. A single cystic artery was seen in 340 cases, and a normal cystic duct was seen in 650 cases. Variations in ductal anatomy were fewer than variations in vascular anatomy. CONCLUSION: Extra-biliary anatomy relevant to LC is unpredictable and varies from patient to patient. Vascular anomalies are more frequent than the ductal anomalies, and surgeon should be alert regarding their presence. PMID- 28872097 TI - Robot-assisted thyroidectomy using a gasless, transaxillary approach for the management of thyroid lesions: Indian experience. AB - AIM: Since last decades, more and more thyroidectomies have been performed by the minimally invasive method. Compared to conventional thyroidectomy, minimally invasive thyroidectomy has a superior cosmetic result. However, the outcome depends, in a large extent, on the skill of the operator and the learning curve is relatively long. Robotic thyroidectomy (RT) is a relatively new approach in treating thyroid lesions with improved ergonomics and surgical outcomes. PURPOSE: We performed a prospective study of robotic-assisted transaxillary approach for thyroidectomy in Indian patients to examine the feasibility of the procedure. MATERIALS AND METHODS: A total of 35 patients underwent RT. Demographics, surgical indications, operative findings, postoperative functional outcome, local complications and pathological outcomes were recorded and analyzed. RESULTS: The median age of the cohort was 28.6 years and 31 of the patients were women. The median size of the largest nodule was 3.2 cm (range, 1.0-4.5 cm). The median size of the largest nodule was 3.2 cm (range, 1.0-4.5 cm). Eighteen patients underwent less than total thyroidectomy and 17 patients underwent total thyroidectomy, with no conversion. The mean console time standard deviation was 115 min initially, and with experience, it reduced to 106 min for subsequent cases. The mean blood loss was 13 ml. Post-operative outcome was good with no serious complication noted in our series. CONCLUSION: Robotic-assisted thyroidectomy using a gasless transaxillary approach is a feasible, safe and noninferior surgical alternative for selected patients. We believe with time RT will be widened and it will be performed more often. PMID- 28872098 TI - Is a diagnostic video-assisted thoracoscopic thymectomy an acceptable first-line approach to the suspicious anterior mediastinal mass? AB - INTRODUCTION: The incidental early-stage thymic mass presents a diagnostic challenge. Video-assisted thoracoscopic (VAT) thymectomy is an attractive but potentially morbid solution. The aim was to show it can be safely applied as a first-line modality in those with undiagnosed thymic enlargement with acceptable long-term results. METHODS: A total of 45 patients were identified (24 male, median age 52 interquartile range [IQR]: 41-66 years) in a 14-year experience who had CT evidence of an enlarged, possibly malignant thymic mass, but no tissue diagnosis before undertaking VAT thymectomy. The clinical outcomes of both benign and malignant diagnoses were compared. RESULTS: Myasthenic symptoms were present in 20 patients (44%), whereas 15 (33%) were asymptomatic. Benign lesions were resected in 27 patients (60%): thymic hyperplasia (56%), thymic cyst (33%), lipoma (7%) and xanthogranulomatous inflammation (4%). Of the 18 malignant patients, 82% had thymoma (three had Masaoka Stage I, 11 Stage II and one Stage III), 6% thymic carcinoma, 6% teratoma and 6% seminoma. Seven patients required radiotherapy for R1 resection. There was no difference in median hospital stay in either group: Benign group: 4 versus 5 days (P = 0.07). One patient in both groups required conversion to open. Two patients in the malignant group had significant morbidity (one myocardial infarction and one pulmonary embolism). There were no cases of tumour recurrence or mortality at a median follow-up of 6.6 years (IQR: 4.4-9.5 years). CONCLUSION: Right-sided diagnostic VAT thymectomy is a safe and effective first-line approach to suspected malignant thymic enlargement. At 5-year follow-up, there were no cases of recurrence in the malignant group. PMID- 28872099 TI - Impact of bariatric surgery on obstructive sleep apnoea-hypopnea syndrome in morbidly obese patients. AB - BACKGROUND: Obstructive sleep apnea (OSA) is commonly associated with morbid obesity. Weight loss following bariatric surgery results in resolution or improvement of OSA. However, few studies have done objective assessment of the impact of bariatric surgery on OSA. OBJECTIVE: The aim of this study was to assess the outcome of bariatric surgery on OSA. SETTING: The study was conducted in the teaching institution of a tertiary care centre. METHODS: Twenty-seven morbidly obese patients seeking bariatric surgery were administered Epworth Sleepiness Scale (ESS) health questionnaire and subjected to overnight polysomnography. Repeat assessment using ESS and polysomnography was done at 3-6 months after surgery. RESULTS: Mean age was 42.4 +/- 10.5 years, and majority (77.8%) were female. The mean pre-operative weight and body mass index (BMI) were 126.4 +/- 24.9 kg and 48.4 +/- 8.2 kg/m2, respectively. Nearly 29.6% patients had symptoms of excessive daytime somnolence based on ESS score and overnight polysomnography detected the presence of OSA in 96.3% patients, of which 51.9% had severe OSA. At mean follow-up of 5.2 +/- 2.5 months after surgery, mean weight and BMI decreased to 107.4 +/- 24.5 kg and 41.2 +/- 8.2 kg/m2, respectively. Mean ESS score and mean apnoea-hypopnea index declined from 8.9 +/- 3.2 to 4.03 +/- 2.15 (P < 0.001) and from 31.8 +/- 20.4 to 20.2 +/- 23.1 (P = 0.007), respectively. Number of patients requiring continuous positive airway pressure (CPAP) therapy declined from 15 to 3 and average CPAP requirement came down from 11.3 cm of H2O to 6 cm of H2O. CONCLUSION: OSA was present in a significant proportion of patients undergoing bariatric surgery. Bariatric surgery resulted in significant improvement in both subjective and objective parameters of OSA. PMID- 28872100 TI - Comparison of mid-term clinical outcomes of laparoscopic partial cystectomy versus conventional partial cystectomy for the treatment of hepatic hydatid cyst. AB - BACKGROUND: The aim of this study was to compare the mid-term outcomes of open and laparoscopic partial cystectomy (LPC). METHODS: The medical records of patients who underwent conventional partial cystectomy (CPC) and LPC for liver hydatid cyst from May 2010 to February 2015 were retrospectively reviewed. Operative time, blood loss, length of hospital stay, post-operative morbidity, mortality and mid-term follow-up outcomes were evaluated. RESULTS: Amongst 130 patients, 38 patients were underwent LPC and 92 underwent CPC. Blood loss and post-operative complications were similar in both groups. The mean operative time in the LPC and the CPC groups was, respectively, 95.4 +/- 13.1 and 63.5 +/- 15.6 min, which showed a significant difference between the both groups. The mean length of hospital stay in CPC group was significantly longer when compared the LPC group. The mean diameter of cyst in LPC group was 6.1 +/- 1.1 cm and 7.8 +/- 2.1 cm in CPC group with a significant difference. The overall complication rates were 13.1% in LPC group and 17.3% in CPC group without significant difference. The most common complication was biliary leakage and surgical site infection. CONCLUSION: LPC for the surgical treatment of liver hydatid cyst appears to be safe and effective method with low morbidity rates in selected patients. PMID- 28872101 TI - Laparoscopic excision of rare case of recurrent presacral teratoma. AB - Tumours of the presacral space are rare to present. Most of them are benign masses, very rarely malignant. Surgery is the mainstay of treatment as it establishes the diagnosis and prevents the adverse consequences associated with malignant degeneration and secondary bacterial infection. Their surgical excision is often difficult because of their anatomic location. Very few cases have been reported so far concerning a laparoscopic management of presacral tumour. We hereby present a young girl with recurrent presacral teratoma. She underwent laparoscopic successful excision of tumour with uneventful post-operative recovery. Here, we are highlighting the importance of laparoscopic approach for this scenario in terms additional advantages of minimally invasive approach such as better visualisation of the deep structures in the narrow presacral space, precise dissection in a limited space between the tumour and neighbouring structures with avoiding injury to neurovascular structure. PMID- 28872102 TI - Single-incision laparoscopic excision of symptomatic accessory spleen in the pelvis: An initial report. AB - An accessory spleen (AS) is commonly located near the spleen's hilum and/or in the pancreas tail. However, a symptomatic AS is rarely found in the pelvis. We present a resected case with lower abdominal pain whose final diagnosis was symptomatic AS caused by torsion in the pelvis. An 18-year-old man was presented to our hospital with lower abdominal pain. Enhanced abdominal computed tomography showed an inflammatory mass with a cord-like band in the pelvic space. We finally diagnosed pelvic neoplasm and performed single-incision laparoscopic surgery (SILS) using an access platform. SILS of these tumours located on a pelvic lesion has never been reported; this is the first report of torsion of a pelvic AS. SILS for AS is a safe, feasible procedure, even when the AS lays in the pelvic space. PMID- 28872103 TI - Mini gastric bypass: Un-answered questions. PMID- 28872104 TI - Are objections to one anastomosis/mini gastric bypass scientific? PMID- 28872105 TI - Using a Split-belt Treadmill to Evaluate Generalization of Human Locomotor Adaptation. AB - Understanding the mechanisms underlying locomotor learning helps researchers and clinicians optimize gait retraining as part of motor rehabilitation. However, studying human locomotor learning can be challenging. During infancy and childhood, the neuromuscular system is quite immature, and it is unlikely that locomotor learning during early stages of development is governed by the same mechanisms as in adulthood. By the time humans reach maturity, they are so proficient at walking that it is difficult to come up with a sufficiently novel task to study de novo locomotor learning. The split-belt treadmill, which has two belts that can drive each leg at a different speed, enables the study of both short- (i.e., immediate) and long-term (i.e., over minutes-days; a form of motor learning) gait modifications in response to a novel change in the walking environment. Individuals can easily be screened for previous exposure to the split-belt treadmill, thus ensuring that all experimental participants have no (or equivalent) prior experience. This paper describes a typical split-belt treadmill adaptation protocol that incorporates testing methods to quantify locomotor learning and generalization of this learning to other walking contexts. A discussion of important considerations for designing split-belt treadmill experiments follows, including factors like treadmill belt speeds, rest breaks, and distractors. Additionally, potential but understudied confounding variables (e.g., arm movements, prior experience) are considered in the discussion. PMID- 28872107 TI - Soft Lithographic Procedure for Producing Plastic Microfluidic Devices with View ports Transparent to Visible and Infrared Light. AB - Infrared (IR) spectro-microscopy of living biological samples is hampered by the absorption of water in the mid-IR range and by the lack of suitable microfluidic devices. Here, a protocol for the fabrication of plastic microfluidic devices is demonstrated, where soft lithographic techniques are used to embed transparent Calcium Fluoride (CaF2) view-ports in connection with observation chamber(s). The method is based on a replica casting approach, where a polydimethylsiloxane (PDMS) mold is produced through standard lithographic procedures and then used as the template to produce a plastic device. The plastic device features ultraviolet/visible/infrared (UV/Vis/IR) -transparent windows made of CaF2 to allow for direct observation with visible and IR light. The advantages of the proposed method include: a reduced need for accessing a clean room micro fabrication facility, multiple view-ports, an easy and versatile connection to an external pumping system through the plastic body, flexibility of the design, e.g., open/closed channels configuration, and the possibility to add sophisticated features such as nanoporous membranes. PMID- 28872106 TI - An In Vitro Model for Studying Cellular Transformation by Kaposi Sarcoma Herpesvirus. AB - Kaposi sarcoma (KS) is an unusual tumor composed of proliferating spindle cells that is initiated by infection of endothelial cells (EC) with KSHV, and develops most often in the setting of immunosuppression. Despite decades of research, optimal treatment of KS remains poorly defined and clinical outcomes are especially unfavorable in resource-limited settings. KS lesions are driven by pathological angiogenesis, chronic inflammation, and oncogenesis, and various in vitro cell culture models have been developed to study these processes. KS arises from KSHV-infected cells of endothelial origin, so EC-lineage cells provide the most appropriate in vitro surrogates of the spindle cell precursor. However, because EC have a limited in vitro lifespan, and as the oncogenic mechanisms employed by KSHV are less efficient than those of other tumorigenic viruses, it has been difficult to assess the processes of transformation in primary or telomerase-immortalized EC. Therefore, a novel EC-based culture model was developed that readily supports transformation following infection with KSHV. Ectopic expression of the E6 and E7 genes of human papillomavirus type 16 allows for extended culture of age- and passage-matched mock- and KSHV-infected EC and supports the development of a truly transformed (i.e., tumorigenic) phenotype in infected cell cultures. This tractable and highly reproducible model of KS has facilitated the discovery of several essential signaling pathways with high potential for translation into clinical settings. PMID- 28872108 TI - Induction of Paralysis and Visual System Injury in Mice by T Cells Specific for Neuromyelitis Optica Autoantigen Aquaporin-4. AB - While it is recognized that aquaporin-4 (AQP4)-specific T cells and antibodies participate in the pathogenesis of neuromyelitis optica (NMO), a human central nervous system (CNS) autoimmune demyelinating disease, creation of an AQP4 targeted model with both clinical and histologic manifestations of CNS autoimmunity has proven challenging. Immunization of wild-type (WT) mice with AQP4 peptides elicited T cell proliferation, although those T cells could not transfer disease to naive recipient mice. Recently, two novel AQP4 T cell epitopes, peptide (p) 135-153 and p201-220, were identified when studying immune responses to AQP4 in AQP4-deficient (AQP4-/-) mice, suggesting T cell reactivity to these epitopes is normally controlled by thymic negative selection. AQP4-/- Th17 polarized T cells primed to either p135-153 or p201-220 induced paralysis in recipient WT mice, that was associated with predominantly leptomeningeal inflammation of the spinal cord and optic nerves. Inflammation surrounding optic nerves and involvement of the inner retinal layers (IRL) were manifested by changes in serial optical coherence tomography (OCT). Here, we illustrate the approaches used to create this new in vivo model of AQP4-targeted CNS autoimmunity (ATCA), which can now be employed to study mechanisms that permit development of pathogenic AQP4-specific T cells and how they may cooperate with B cells in NMO pathogenesis. PMID- 28872109 TI - Measurements of Soil Carbon by Neutron-Gamma Analysis in Static and Scanning Modes. AB - The herein described application of the inelastic neutron scattering (INS) method for soil carbon analysis is based on the registration and analysis of gamma rays created when neutrons interact with soil elements. The main parts of the INS system are a pulsed neutron generator, NaI(Tl) gamma detectors, split electronics to separate gamma spectra due to INS and thermo-neutron capture (TNC) processes, and software for gamma spectra acquisition and data processing. This method has several advantages over other methods in that it is a non-destructive in situ method that measures the average carbon content in large soil volumes, is negligibly impacted by local sharp changes in soil carbon, and can be used in stationary or scanning modes. The result of the INS method is the carbon content from a site with a footprint of ~2.5 - 3 m2 in the stationary regime, or the average carbon content of the traversed area in the scanning regime. The measurement range of the current INS system is >1.5 carbon weight % (standard deviation +/- 0.3 w%) in the upper 10 cm soil layer for a 1 hmeasurement. PMID- 28872110 TI - A Protocol for the Administration of Real-Time fMRI Neurofeedback Training. AB - Neurologic disorders are characterized by abnormal cellular-, molecular-, and circuit-level functions in the brain. New methods to induce and control neuroplastic processes and correct abnormal function, or even shift functions from damaged tissue to physiologically healthy brain regions, hold the potential to dramatically improve overall health. Of the current neuroplastic interventions in development, neurofeedback training (NFT) from functional Magnetic Resonance Imaging (fMRI) has the advantages of being completely non-invasive, non pharmacologic, and spatially localized to target brain regions, as well as having no known side effects. Furthermore, NFT techniques, initially developed using fMRI, can often be translated to exercises that can be performed outside of the scanner without the aid of medical professionals or sophisticated medical equipment. In fMRI NFT, the fMRI signal is measured from specific regions of the brain, processed, and presented to the participant in real-time. Through training, self-directed mental processing techniques, that regulate this signal and its underlying neurophysiologic correlates, are developed. FMRI NFT has been used to train volitional control over a wide range of brain regions with implications for several different cognitive, behavioral, and motor systems. Additionally, fMRI NFT has shown promise in a broad range of applications such as the treatment of neurologic disorders and the augmentation of baseline human performance. In this article, we present an fMRI NFT protocol developed at our institution for modulation of both healthy and abnormal brain function, as well as examples of using the method to target both cognitive and auditory regions of the brain. PMID- 28872111 TI - Method and Instrumented Fixture for Femoral Fracture Testing in a Sideways Fall on-the-Hip Position. AB - Mechanical testing of femora brings valuable insights into understanding the contribution of clinically-measureable variables such as bone mineral density distribution and geometry on the femoral mechanical properties. Currently, there is no standard protocol for mechanical testing of such geometrically complex bones to measure strength, and stiffness. To address this gap we have developed a protocol to test cadaveric femora to fracture and to measure their biomechanical parameters. This protocol describes a set of adaptable fixtures to accommodate the various load magnitudes and directions accounting for possible bone orientations in a fall on the hip configuration, test speed, bone size, and left leg-right leg variations. The femora were prepared for testing by cleaning, cutting, scanning, and potting the distal end and greater trochanter contact surfaces in poly(methyl methacrylate) (PMMA) as presented in a different protocol. The prepared specimens were placed in the testing fixture in a position mimicking a sideways fall on the hip and loaded to fracture. During testing, two load cells measured vertical forces applied to the femoral head and greater trochanter, a six-axis load cell measured forces and moments at the distal femoral shaft, and a displacement sensor measured differential displacement between the femoral head and trochanter contact supports. High speed video cameras were used to synchronously record the sequence of fracture events during testing. The reduction of this data allowed us to characterize the strength, stiffness, and fracture energy for nearly 200 osteoporotic, osteopenic, and normal cadaveric femora for further development of engineering-based diagnostic tools for osteoporosis research. PMID- 28872112 TI - Fat Body Organ Culture System in Aedes Aegypti, a Vector of Zika Virus. AB - The insect fat body plays a central role in insect metabolism and nutrient storage, mirroring functions of the liver and fat tissue in vertebrates. Insect fat body tissue is usually distributed throughout the insect body. However, it is often concentrated in the abdomen and attached to the abdominal body wall. The mosquito fat body is the sole source of yolk proteins, which are critical for egg production. Therefore, the in vitro culture of mosquito fat body tissues represents an important system for the study of mosquito physiology, metabolism, and, ultimately, egg production. The fat body culture process begins with the preparation of solutions and reagents, including amino acid stock solutions, Aedes physiological saline salt stock solution (APS), calcium stock solution, and fat body culture medium. The process continues with fat body dissection, followed by an experimental treatment. After treatment, a variety of different analyses can be performed, including RNA sequencing (RNA-Seq), qPCR, Western blots, proteomics, and metabolomics. In our example experiment, we demonstrate the protocol through the excision and culture of fat bodies from the yellow fever mosquito, Aedes aegypti, a principal vector of arboviruses including dengue, chikungunya, and Zika. RNA from fat bodies cultured under a physiological condition known to upregulate yolk proteins versus the control were subject to RNA-Seq analysis to demonstrate the potential utility of this procedure for investigations of gene expression. PMID- 28872113 TI - Organotypic Hippocampal Slice Cultures As a Model to Study Neuroprotection and Invasiveness of Tumor Cells. AB - In organotypic hippocampal slice cultures (OHSC), the morphological and functional characteristics of both neurons and glial cells are well preserved. This model is suitable for addressing different research questions that involve studies on neuroprotection, electrophysiological experiments on neurons, neuronal networks or tumor invasion. The hippocampal architecture and neuronal activity in multisynaptic circuits are well conserved in OHSC, even though the slicing procedure itself initially lesions and leads to formation of a glial scar. The scar formation alters presumably the mechanical properties and diffusive behavior of small molecules, etc. Slices allow the monitoring of time dependent processes after brain injury without animal surgery, and studies on interactions between various brain-derived cell types, namely astrocytes, microglia and neurons under both physiological and pathological conditions. An ambivalent aspect of this model is the absence of blood flow and immune blood cells. During the progression of the neuronal injury, migrating immune cells from the blood play an important role. As those cells are missing in slices, the intrinsic processes in the culture may be observed without external interference. Moreover, in OHSC the composition of the medium-external environment is precisely controlled. A further advantage of this method is the lower number of sacrificed animals compared to standard preparations. Several OHSC can be obtained from one animal making simultaneous studies with multiple treatments in one animal possible. For these reasons, OHSC are well suited to analyze the effects of new protective therapeutics after tissue damage or during tumor invasion. The protocol presented here describes a preparation method of OHSC that allows generating highly reproducible, well preserved slices that can be used for a variety of experimental research, like neuroprotection or tumor invasion studies. PMID- 28872114 TI - Quantification of Information Encoded by Gene Expression Levels During Lifespan Modulation Under Broad-range Dietary Restriction in C. elegans. AB - Sensory systems allow animals to detect, process, and respond to their environment. Food abundance is an environmental cue that has profound effects on animal physiology and behavior. Recently, we showed that modulation of longevity in the nematode Caenorhabditis elegans by food abundance is more complex than previously recognized. The responsiveness of the lifespan to changes in food level is determined by specific genes that act by controlling information processing within a neural circuit. Our framework combines genetic analysis, high throughput quantitative imaging and information theory. Here, we describe how these techniques can be used to characterize any gene that has a physiological relevance to broad-range dietary restriction. Specifically, this workflow is designed to reveal how a gene of interest regulates lifespan under broad-range dietary restriction; then to establish how the expression of the gene varies with food level; and finally, to provide an unbiased quantification of the amount of information conveyed by gene expression about food abundance in the environment. When several genes are examined simultaneously under the context of a neural circuit, this workflow can uncover the coding strategy employed by the circuit. PMID- 28872115 TI - Quantitative Immunofluorescence to Measure Global Localized Translation. AB - The mechanisms regulating mRNA translation are involved in various biological processes, such as germ line development, cell differentiation, and organogenesis, as well as in multiple diseases. Numerous publications have convincingly shown that specific mechanisms tightly regulate mRNA translation. Increased interest in the translation-induced regulation of protein expression has led to the development of novel methods to study and follow de novo protein synthesis in cellulo. However, most of these methods are complex, making them costly and often limiting the number of mRNA targets that can be studied. This manuscript proposes a method that requires only basic reagents and a confocal fluorescence imaging system to measure and visualize the changes in mRNA translation that occur in any cell line under various conditions. This method was recently used to show localized translation in the subcellular structures of adherent cells over a short period of time, thus offering the possibility of visualizing de novo translation for a short period during a variety of biological processes or of validating changes in translational activity in response to specific stimuli. PMID- 28872116 TI - Chromatin Immunoprecipitation (ChIP) Protocol for Low-abundance Embryonic Samples. AB - Chromatin immunoprecipitation (ChIP) is a widely-used technique for mapping the localization of post-translationally modified histones, histone variants, transcription factors, or chromatin-modifying enzymes at a given locus or on a genome-wide scale. The combination of ChIP assays with next-generation sequencing (i.e., ChIP-Seq) is a powerful approach to globally uncover gene regulatory networks and to improve the functional annotation of genomes, especially of non coding regulatory sequences. ChIP protocols normally require large amounts of cellular material, thus precluding the applicability of this method to investigating rare cell types or small tissue biopsies. In order to make the ChIP assay compatible with the amount of biological material that can typically be obtained in vivo during early vertebrate embryogenesis, we describe here a simplified ChIP protocol in which the number of steps required to complete the assay were reduced to minimize sample loss. This ChIP protocol has been successfully used to investigate different histone modifications in various embryonic chicken and adult mouse tissues using low to medium cell numbers (5 x 104 - 5 x 105 cells). Importantly, this protocol is compatible with ChIP-seq technology using standard library preparation methods, thus providing global epigenomic maps in highly relevant embryonic tissues. PMID- 28872117 TI - Electroencephalographic, Heart Rate, and Galvanic Skin Response Assessment for an Advertising Perception Study: Application to Antismoking Public Service Announcements. AB - The evaluation of advertising, products, and packaging is traditionally performed through methods based on self-reports and focus groups, but these approaches often appear poorly accurate in scientific terms. Neuroscience is increasingly applied to the investigation of the neurophysiological bases of the perception of and reaction to commercial stimuli to support traditional marketing methods. In this context, a particular sector or marketing is represented by public service announcements (PSAs). The objective of this protocol is to apply electroencephalography (EEG) and autonomic signal analysis to study responses to selected antismoking PSAs. Two EEG indices were employed: the frontal alpha band EEG asymmetry (the Approach Withdrawal (AW) index) and the frontal theta (effort index). Furthermore, the autonomic Emotional Index (EI) was calculated, as derived from the Galvanic Skin Response (GSR) and Heart Rate (HR) signals. The present protocol describes a series of operational and computational steps required to properly estimate, through the aforementioned indices, the emotional and cerebral reaction of a group of subjects towards a selected number of antismoking PSAs. In particular, a campaign characterized by a symbolic communication style (classified as "awarded" on the basis of the prizes received by specialized committees) obtained the highest approach values, as estimated by the AW index. A spot and an image belonging to the same PSA campaign based on the "fear arousing appeal" and with a narrative/experiential communication style (classified as "effective" on the basis of the economical/health-related improvements promoted) reported the lowest and highest effort values, respectively. This is probably due to the complexity of the storytelling (spot) and to the immediateness of the image (a lady who underwent a tracheotomy). Finally, the same "effective" campaign showed the highest EI values, possibly because of the empathy induced by the testimonial and the explicitness of the message. PMID- 28872118 TI - Quantification of the Abundance and Charging Levels of Transfer RNAs in Escherichia coli. AB - Transfer RNA (tRNA) is an essential part of the translational machinery in any organism. tRNAs bind and transfer amino acids to the translating ribosome. The relative levels of different tRNAs, and the ratio of aminoacylated tRNA to total tRNA, known as the charging level, are important factors in determining the accuracy and speed of translation. Therefore, the abundance and charging levels of tRNAs are important variables to measure when studying protein synthesis, for example under various stress conditions. Here, we describe a method for harvesting tRNA and directly measuring both the relative abundance and the absolute charging level of specific tRNA species in Escherichia coli. The tRNA is harvested in such a way that the labile bond between the tRNA and its amino acid is preserved. The RNA is then subjected to gel electrophoresis and Northern blotting, which results in separation of the charged and uncharged tRNAs. The levels of specific tRNAs in different samples can be compared due to the addition of spike-in cells for normalization. Prior to RNA purification, we add 5% of E. coli cells that overproduce the rare tRNAselC to each sample. The amount of the tRNA species of interest in a sample is then normalized to the amount of tRNAselC in the same sample. Addition of spike-in cells prior to RNA purification has the advantage over addition of purified spike-in RNAs that it also accounts for any differences in cell lysis efficiency between samples. PMID- 28872119 TI - Intravital Microscopy of Monocyte Homing and Tumor-Related Angiogenesis in a Murine Model of Peripheral Arterial Disease. AB - The therapeutic goal for peripheral arterial disease and ischemic heart disease is to increase blood flow to ischemic areas caused by hemodynamic stenosis. Vascular surgery is a viable option in selected cases, but for patients without indications for surgery such as progression to rest pain, critical limb ischemia, or major disruptions to life or work, there are few possibilities for mitigating their disease. Cell therapy via monocyte-enhanced perfusion through the stimulation of collateral formation is one of a few non-invasive options. Our group examines arteriogenesis after monocyte transplantation into mice using the hindlimb ischemia model. Previously, we have demonstrated improvement in hindlimb perfusion using tetanus-stimulated syngeneic monocyte transplantation. In addition to the effects on the collateral formation, tumor growth could be affected by this therapy as well. To investigate these effects, we use a basement membrane-like matrix mouse model by injecting the extracellular matrix of the Engelbreth-Holm-Swarm sarcoma into the flank of the mouse, after occlusion of the femoral artery. After the artificial tumor studies, we use intravital microscopy to study in vivo tumor-angiogenesis and monocyte homing within collateral arteries. Previous studies have described the histological examination of animal models, which presupposes subsequent analysis to post-mortem artifacts. Our approach visualizes monocyte homing to areas of collateralization in real time sequences, is easy to perform, and investigates the process of arteriogenesis and tumor angiogenesis in vivo. PMID- 28872120 TI - Dissection of the Mouse Pancreas for Histological Analysis and Metabolic Profiling. AB - We have been investigating the pancreas specific transcription factor, 1a cre recombinase; lox-stop-lox- Kristen rat sarcoma, glycine to aspartic acid at the 12 codon (Ptf1acre/+;LSL-KrasG12D/+) mouse strain as a model of human pancreatic cancer. The goal of our current studies is to identify novel metabolic biomarkers of pancreatic cancer progression. We have performed metabolic profiling of urine, feces, blood, and pancreas tissue extracts, as well as histological analyses of the pancreas to stage the cancer progression. The mouse pancreas is not a well defined solid organ like in humans, but rather is a diffusely distributed soft tissue that is not easily identified by individuals unfamiliar with mouse internal anatomy or by individuals that have little or no experience performing mouse organ dissections. The purpose of this article is to provide a detailed step-wise visual demonstration to guide novices in the removal of the mouse pancreas by dissection. This article should be especially valuable to students and investigators new to research that requires harvesting of the mouse pancreas by dissection for metabolic profiling or histological analyses. PMID- 28872121 TI - Minimally Invasive Muscle Embedding (MIME) - A Novel Experimental Technique to Facilitate Donor-Cell-Mediated Myogenesis. AB - Skeletal muscle possesses regenerative capacity due to tissue-resident, muscle fiber-generating (myogenic) satellite cells (SCs), which can form new muscle fibers under the right conditions. Although SCs can be harvested from muscle tissue and cultured in vitro, the resulting myoblast cells are not very effective in promoting myogenesis when transplanted into host muscle. Surgically exposing the host muscle and grafting segments of donor muscle tissue, or the isolated muscle fibers with their SCs onto host muscle, promotes better myogenesis compared to myoblast transplantation. We have developed a novel technique that we call Minimally Invasive Muscle Embedding (MIME). MIME involves passing a surgical needle through the host muscle, drawing a piece of donor muscle tissue through the needle track, and then leaving the donor tissue embedded in the host muscle so that it may act as a source of SCs for the host muscle. Here we describe in detail the steps involved in performing MIME in an immunodeficient mouse model that expresses a green fluorescent protein (GFP) in all of its cells. Immunodeficiency in the host mouse reduces the risk of immune rejection of the donor tissue, and GFP expression enables easy identification of the host muscle fibers (GFP+) and donor-cell-derived muscle fibers (GFP-). Our pilot data suggest that MIME can be used to implant an extensor digitorum longus (EDL) muscle from a donor mouse into the tibialis anterior (TA) muscle of a host mouse. Our data also suggest that when a myotoxin (barium chloride, BaCl2) is injected into the host muscle after MIME, there is evidence of donor-cell-derived myogenesis in the host muscle, with approximately 5%, 26%, 26% and 43% of the fibers in a single host TA muscle showing no host contribution, minimal host contribution, moderate host contribution, and maximal host contribution, respectively. PMID- 28872122 TI - Ammonia Synthesis at Low Pressure. AB - Ammonia can be synthesized at low pressure by the use of an ammonia selective absorbent. The process can be driven with wind energy, available locally in areas requiring ammonia for synthetic fertilizer. Such wind energy is often called "stranded," because it is only available far from population centers where it can be directly used. In the proposed low pressure process, nitrogen is made from air using pressure swing absorption, and hydrogen is produced by electrolysis of water. While these gases can react at approximately 400 degrees C in the presence of a promoted conventional catalyst, the conversion is often limited by the reverse reaction, which makes this reaction only feasible at high pressures. This limitation can be removed by absorption on an ammine-like calcium or magnesium chloride. Such alkaline metal halides can effectively remove ammonia, thus suppressing the equilibrium constraints of the reaction. In the proposed absorption-enhanced ammonia synthesis process, the rate of reaction may then be controlled not by the chemical kinetics nor the absorption rates, but by the rate of the recycle of unreacted gases. The results compare favorably with ammonia made from a conventional small scale Haber-Bosch process. PMID- 28872123 TI - Ileectomy-induced Bile Overaccumulation in Mouse Intestine. AB - Intestinal resection is a common therapeutic approach for human diseases such as obesity, inflammatory bowel disease, Crohn's disease, and colon cancer that often results in severe short bowel syndrome-like adverse effects including bile acid diarrhea, dehydration, electrolyte disturbances, and nutrient malabsorption. Here we introduce a murine ileal resection model, termed ileectomy, to evaluate tissue communication and the maintenance of systemic homeostasis. After ileal resection, circulating blood is permanently devoid of the ileum-specific endocrine hormone fibroblast growth factor 15 (FGF15), which releases its endocrinal inhibition of bile acid synthesis in the liver. In combination with the increased production and abolished reabsorption of bile acids after removing the ileum, mice that underwent surgery suffer from bile salt overaccumulation in the intestine and associated diarrhea, morbidity, and mortality. Novel usage of the surgery model introduced in this study may provide mechanistic and functional insights into ileal control of systemic metabolic regulation in physiology and disease. PMID- 28872124 TI - In Vitro Polymerization of F-actin on Early Endosomes. AB - Many early endosome functions, particularly cargo protein sorting and membrane deformation, depend on patches of short F-actin filaments nucleated onto the endosomal membrane. We have established a microscopy-based in vitro assay that reconstitutes the nucleation and polymerization of F-actin on early endosomal membranes in test tubes, thus rendering this complex series of reactions amenable to genetic and biochemical manipulations. Endosomal fractions are prepared by floatation in sucrose gradients from cells expressing the early endosomal protein GFP-RAB5. Cytosolic fractions are prepared from separate batches of cells. Both endosomal and cytosolic fractions can be stored frozen in liquid nitrogen, if needed. In the assay, the endosomal and cytosolic fractions are mixed, and the mixture is incubated at 37 degrees C under appropriate conditions (e.g., ionic strength, reducing environment). At the desired time, the reaction mixture is fixed, and the F-actin is revealed with phalloidin. Actin nucleation and polymerization are then analyzed by fluorescence microscopy. Here, we report that this assay can be used to investigate the role of factors that are involved either in actin nucleation on the membrane, or in the subsequent elongation, branching, or crosslinking of F-actin filaments. PMID- 28872125 TI - Measurements of Long-range Electronic Correlations During Femtosecond Diffraction Experiments Performed on Nanocrystals of Buckminsterfullerene. AB - The precise details of the interaction of intense X-ray pulses with matter are a topic of intense interest to researchers attempting to interpret the results of femtosecond X-ray free electron laser (XFEL) experiments. An increasing number of experimental observations have shown that although nuclear motion can be negligible, given a short enough incident pulse duration, electronic motion cannot be ignored. The current and widely accepted models assume that although electrons undergo dynamics driven by interaction with the pulse, their motion could largely be considered 'random'. This would then allow the supposedly incoherent contribution from the electronic motion to be treated as a continuous background signal and thus ignored. The original aim of our experiment was to precisely measure the change in intensity of individual Bragg peaks, due to X-ray induced electronic damage in a model system, crystalline C60. Contrary to this expectation, we observed that at the highest X-ray intensities, the electron dynamics in C60 were in fact highly correlated, and over sufficiently long distances that the positions of the Bragg reflections are significantly altered. This paper describes in detail the methods and protocols used for these experiments, which were conducted both at the Linac Coherent Light Source (LCLS) and the Australian Synchrotron (AS) as well as the crystallographic approaches used to analyse the data. PMID- 28872126 TI - Application and Methodology of the Non-destructive 19F Time-domain NMR Technique to Measure the Content in Fluorine-containing Drug Products. AB - Here, we describe a protocol developed by our group that uses low-field fluorine 19 (19F) time-domain (TD) nuclear magnetic resonance (NMR) to measure the average content of fluorinated drugs in their formulated drug product forms: tablets or capsules. This method is specific to fluorinated drugs because it detects only the content of fluorine, avoiding interference from the excipients that lack fluorine. The advantages of measuring the active content of fluorinated drugs using low-field 19F TD-NMR versus high-field 19F solid-state (SS) NMR are the simplicity of the method; the low cost; and the non-destructive nature of the technique, with all samples recoverable in intact forms (e.g., powders, tablets, and capsules), making this technique affordable for any laboratory. We have tested the method with three fluorinated drug products available on the market - cinacalcet, lansoprazole, and ciprofloxacin - with doses ranging from 15 to 500 mg. The results of the analyses, measured by low-field 19F TD-NMR, supported the reported label claims for the average drug content. Based on the simplicity and reproducibility of the analysis, we envision this methodology being implemented in any laboratory, including manufacturing plants, as a process analytical technology (PAT) tool in the pharmaceutical industry. PMID- 28872127 TI - Detection of Rare Mutations in CtDNA Using Next Generation Sequencing. AB - The analysis of circulating tumor DNA (ctDNA) using next-generation sequencing (NGS) has become a valuable tool for the development of clinical oncology. However, the application of this method is challenging due to its low sensitivity in analyzing the trace amount of ctDNA in the blood. Furthermore, the method may generate false positive and negative results from this sequencing and subsequent analysis. To improve the feasibility and reliability of ctDNA detection in the clinic, here we present a technique which enriches rare mutations for sequencing, Enrich Rare Mutation Sequencing (ER-Seq). ER-Seq can distinguish a single mutation out of 1 x 107 wild-type nucleotides, which makes it a promising tool to detect extremely low frequency genetic alterations and thus will be very useful in studying disease heterogenicity. By virtue of the unique sequencing adapter's ligation, this method enables an efficient recovery of ctDNA molecules, while at the same time correcting for errors bidirectionally (sense and antisense). Our selection of 1021 kb probes enriches the measurement of target regions that cover over 95% of the tumor-related driver mutations in 12 tumors. This cost-effective and universal method enables a uniquely successful accumulation of genetic data. After efficiently filtering out background error, ER-seq can precisely detect rare mutations. Using a case study, we present a detailed protocol demonstrating probe design, library construction, and target DNA capture methodologies, while also including the data analysis workflow. The process to carry out this method typically takes 1-2 days. PMID- 28872128 TI - Fabrication of Ultra-thin Color Films with Highly Absorbing Media Using Oblique Angle Deposition. AB - Ultra-thin film structures have been studied extensively for use as optical coatings, but performance and fabrication challenges remain. We present an advanced method for fabricating ultra-thin color films with improved characteristics. The proposed process addresses several fabrication issues, including large area processing. Specifically, the protocol describes a process for fabricating ultra-thin color films using an electron beam evaporator for oblique angle deposition of germanium (Ge) and gold (Au) on silicon (Si) substrates. Film porosity produced by the oblique angle deposition induces color changes in the ultra-thin film. The degree of color change depends on factors such as deposition angle and film thickness. Fabricated samples of the ultra-thin color films showed improved color tunability and color purity. In addition, the measured reflectance of the fabricated samples was converted into chromatic values and analyzed in terms of color. Our ultra-thin film fabricating method is expected to be used for various ultra-thin film applications such as flexible color electrodes, thin film solar cells, and optical filters. Also, the process developed here for analyzing the color of the fabricated samples is broadly useful for studying various color structures. PMID- 28872129 TI - Bottlenose Dolphin (Tursiops truncatus) Spermatozoa: Collection, Cryopreservation, and Heterologous In Vitro Fertilization. AB - The use of cryopreserved dolphin spermatozoa facilitates the exchange of genetic material between aquatic parks and makes spermatozoa accessible to laboratories for studies to further our understanding of marine mammal reproduction. Heterologous IVF, a replacement for homologous IVF, could provide a means to test the sperm fertility potential; to study gamete physiology and early embryo development; and to avoid the use of valuable dolphin oocytes, which are difficult to obtain. Here, we present protocols that have been successfully used to collect and cryopreserve dolphin spermatozoa. The collection of semen is performed by manual stimulation on trained dolphins. Cryopreservation is accomplished using a TRIS egg-yolk based extender with glycerol. In addition, we present a protocol that describes heterologous IVF using dolphin spermatozoa and bovine oocytes and that verifies the hybrid nature of the resulting embryo using PCR. Heterologous fertilization raises questions on fertilization and can be used as a tool to study gamete physiology and early embryo development. In addition, the success of heterologous IVF demonstrates the potential of this technique to test dolphin sperm fertilizing capacity, which is worth further examination. PMID- 28872130 TI - A Protocol for Using Gene Set Enrichment Analysis to Identify the Appropriate Animal Model for Translational Research. AB - Recent studies that compared transcriptomic datasets of human diseases with datasets from mouse models using traditional gene-to-gene comparison techniques resulted in contradictory conclusions regarding the relevance of animal models for translational research. A major reason for the discrepancies between different gene expression analyses is the arbitrary filtering of differentially expressed genes. Furthermore, the comparison of single genes between different species and platforms often is limited by technical variance, leading to misinterpretation of the con/discordance between data from human and animal models. Thus, standardized approaches for systematic data analysis are needed. To overcome subjective gene filtering and ineffective gene-to-gene comparisons, we recently demonstrated that gene set enrichment analysis (GSEA) has the potential to avoid these problems. Therefore, we developed a standardized protocol for the use of GSEA to distinguish between appropriate and inappropriate animal models for translational research. This protocol is not suitable to predict how to design new model systems a-priori, as it requires existing experimental omics data. However, the protocol describes how to interpret existing data in a standardized manner in order to select the most suitable animal model, thus avoiding unnecessary animal experiments and misleading translational studies. PMID- 28872131 TI - A Standard Methodology to Examine On-site Mutagenicity As a Function of Point Mutation Repair Catalyzed by CRISPR/Cas9 and SsODN in Human Cells. AB - Combinatorial gene editing using CRISPR/Cas9 and single-stranded oligonucleotides is an effective strategy for the correction of single-base point mutations, which often are responsible for a variety of human inherited disorders. Using a well established cell-based model system, the point mutation of a single-copy mutant eGFP gene integrated into HCT116 cells has been repaired using this combinatorial approach. The analysis of corrected and uncorrected cells reveals both the precision of gene editing and the development of genetic lesions, when indels are created in uncorrected cells in the DNA sequence surrounding the target site. Here, the specific methodology used to analyze this combinatorial approach to the gene editing of a point mutation, coupled with a detailed experimental strategy to measuring indel formation at the target site, is outlined. This protocol outlines a foundational approach and workflow for investigations aimed at developing CRISPR/Cas9-based gene editing for human therapy. The conclusion of this work is that on-site mutagenesis takes place as a result of CRISPR/Cas9 activity during the process of point mutation repair. This work puts in place a standardized methodology to identify the degree of mutagenesis, which should be an important and critical aspect of any approach destined for clinical implementation. PMID- 28872132 TI - Aqueous Droplets Used as Enzymatic Microreactors and Their Electromagnetic Actuation. AB - For the successful implementation of microfluidic reaction systems, such as PCR and electrophoresis, the movement of small liquid volumes is essential. In conventional lab-on-a-chip-platforms, solvents and samples are passed through defined microfluidic channels with complex flow control installations. The droplet actuation platform presented here is a promising alternative. With it, it is possible to move a liquid drop (microreactor) on a planar surface of a reaction platform (lab-in-a-drop). The actuation of microreactors on the hydrophobic surface of the platform is based on the use of magnetic forces acting on the outer shell of the liquid drops which is made of a thin layer of superhydrophobic magnetite particles. The hydrophobic surface of the platform is needed to avoid any contact between the liquid core and the surface to allow a smooth movement of the microreactor. On the platform, one or more microreactors with volumes of 10 uL can be positioned and moved simultaneously. The platform itself consists of a 3 x 3 matrix of electrical double coils which accommodate either neodymium or iron cores. The magnetic field gradients are automatically controlled. By variation of the magnetic field gradients, the microreactors' magnetic hydrophobic shell can be manipulated automatically to move the microreactor or open the shell reversibly. Reactions of substrates and corresponding enzymes can be initiated by merging the microreactors or bringing them into contact with surface immobilized catalysts. PMID- 28872133 TI - Peptide and Protein Quantification Using Automated Immuno-MALDI (iMALDI). AB - Mass spectrometry (MS) is one of the most commonly used technologies for quantifying proteins in complex samples, with excellent assay specificity as a result of the direct detection of the mass-to-charge ratio of each target molecule. However, MS-based proteomics, like most other analytical techniques, has a bias towards measuring high-abundance analytes, so it is challenging to achieve detection limits of low ng/mL or pg/mL in complex samples, and this is the concentration range for many disease-relevant proteins in biofluids such as human plasma. To assist in the detection of low-abundance analytes, immuno enrichment has been integrated into the assay to concentrate and purify the analyte before MS measurement, significantly improving assay sensitivity. In this work, the immuno- Matrix-Assisted Laser Desorption/Ionization (iMALDI) technology is presented for the quantification of proteins and peptides in biofluids, based on immuno-enrichment on beads, followed by MALDI-MS measurement without prior elution. The anti-peptide antibodies are functionalized on magnetic beads, and incubated with samples. After washing, the beads are directly transferred onto a MALDI target plate, and the signals are measured by a MALDI-Time of Flight (MALDI TOF) instrument after the matrix solution has been applied to the beads. The sample preparation procedure is simplified compared to other immuno-MS assays, and the MALDI measurement is fast. The whole sample preparation is automated with a liquid handling system, with improved assay reproducibility and higher throughput. In this article, the iMALDI assay is used for determining the peptide angiotensin I (Ang I) concentration in plasma, which is used clinically as readout of plasma renin activity for the screening of primary aldosteronism (PA). PMID- 28872134 TI - Coulomb Explosion Imaging as a Tool to Distinguish Between Stereoisomers. AB - This article shows how the COLTRIMS (Cold Target Recoil Ion Momentum Spectroscopy) or the "reaction microscope" technique can be used to distinguish between enantiomers (stereoisomers) of simple chiral species on the level of individual molecules. In this approach, a gaseous molecular jet of the sample expands into a vacuum chamber and intersects with femtosecond (fs) laser pulses. The high intensity of the pulses leads to fast multiple ionization, igniting a so called Coulomb Explosion that produces several cationic (positively charged) fragments. An electrostatic field guides these cations onto time- and position sensitive detectors. Similar to a time-of-flight mass spectrometer, the arrival time of each ion yields information on its mass. As a surplus, the electrostatic field is adjusted in a way that the emission direction and the kinetic energy after fragmentation lead to variations in the time-of-flight and in the impact position on the detector. Each ion impact creates an electronic signal in the detector; this signal is treated by high-frequency electronics and recorded event by event by a computer. The registered data correspond to the impact times and positions. With these data, the energy and the emission direction of each fragment can be calculated. These values are related to structural properties of the molecule under investigation, i.e. to the bond lengths and relative positions of the atoms, allowing to determine molecule by molecule the handedness of simple chiral species and other isomeric features. PMID- 28872135 TI - Methods and Tips for Intravenous Administration of Adeno-associated Virus to Rats and Evaluation of Central Nervous System Transduction. AB - Adeno-associated virus (AAV) vectors are a key reagent in the neurosciences for clustered regularly interspaced short palindromic repeats (CRISPR), optogenetics, cre-lox targeting, etc. The purpose of this manuscript is to aid the investigator attempting expansive central nervous system (CNS) gene transfer in the rat via tail vein injection of AAV. Wide-scale expression is relevant for conditions with widespread pathology, and a rat model is significant due to its greater size and physiologic similarities to humans compared to mice. In this example application, a wide-scale neuronal transduction is used to mimic a neurodegenerative disease that affects the entire spinal cord, amyotrophic lateral sclerosis (ALS). The efficient wide-scale CNS transduction can also be used to deliver therapeutic protein factors in pre-clinical studies. After a post-injection expression interval of several weeks, the effects of the transduction are evaluated. For a green fluorescent protein (GFP) control vector, the amount of GFP in the cerebellum is estimated quickly and reliably by a basic imaging program. For motor disease phenotypes that are induced by the ALS related protein transactive response DNA-binding protein of 43 kDa (TDP-43), the deficits are scored by escape reflex and rotarod. Beyond disease modeling and gene therapy, there are diverse potential applications for the wide-scale gene targeting described here. The expanded use of this method will aid in expediting hypothesis testing in the neurosciences and neurogenetics. PMID- 28872136 TI - Generation of Escape Variants of Neutralizing Influenza Virus Monoclonal Antibodies. AB - Influenza viruses exhibit a remarkable ability to adapt and evade the host immune response. One way is through antigenic changes that occur on the surface glycoproteins of the virus. The generation of escape variants is a powerful method in elucidating how viruses escape immune detection and in identifying critical residues required for antibody binding. Here, we describe a protocol on how to generate influenza A virus escape variants by utilizing human or murine monoclonal antibodies (mAbs) directed against the viral hemagglutinin (HA). With the use of our technique, we previously characterized critical residues required for the binding of antibodies targeting either the head or stalk of the novel avian H7N9 HA. The protocol can be easily adapted for other virus systems. Analyses of escape variants are important for modeling antigenic drift, determining single nucleotide polymorphisms (SNPs) conferring resistance and virus fitness, and in the designing of vaccines and/or therapeutics. PMID- 28872137 TI - Experimental Methods for Trapping Ions Using Microfabricated Surface Ion Traps. AB - Ions trapped in a quadrupole Paul trap have been considered one of the strong physical candidates to implement quantum information processing. This is due to their long coherence time and their capability to manipulate and detect individual quantum bits (qubits). In more recent years, microfabricated surface ion traps have received more attention for large-scale integrated qubit platforms. This paper presents a microfabrication methodology for ion traps using micro-electro-mechanical system (MEMS) technology, including the fabrication method for a 14 um-thick dielectric layer and metal overhang structures atop the dielectric layer. In addition, an experimental procedure for trapping ytterbium (Yb) ions of isotope 174 (174Yb+) using 369.5 nm, 399 nm, and 935 nm diode lasers is described. These methodologies and procedures involve many scientific and engineering disciplines, and this paper first presents the detailed experimental procedures. The methods discussed in this paper can easily be extended to the trapping of Yb ions of isotope 171 (171Yb+) and to the manipulation of qubits. PMID- 28872138 TI - Nitrogen Cavitation and Differential Centrifugation Allows for Monitoring the Distribution of Peripheral Membrane Proteins in Cultured Cells. AB - Cultured cells are useful for studying the subcellular distribution of proteins, including peripheral membrane proteins. Genetically encoded fluorescently tagged proteins have revolutionized the study of subcellular protein distribution. However, it is difficult to quantify the distribution with fluorescent microscopy, especially when proteins are partially cytosolic. Moreover, it is often important to study endogenous proteins. Biochemical assays such as immunoblots remain the gold standard for quantification of protein distribution after subcellular fractionation. Although there are commercial kits that aim to isolate cytosolic or certain membrane fractions, most of these kits are based on extraction with detergents, which may be unsuitable for studying peripheral membrane proteins that are easily extracted from membranes. Here we present a detergent-free protocol for cellular homogenization by nitrogen cavitation and subsequent separation of cytosolic and membrane-bound proteins by ultracentrifugation. We confirm the separation of subcellular organelles in soluble and pellet fractions across different cell types, and compare protein extraction among several common non-detergent-based mechanical homogenization methods. Among several advantages of nitrogen cavitation is the superior efficiency of cellular disruption with minimal physical and chemical damage to delicate organelles. Combined with ultracentrifugation, nitrogen cavitation is an excellent method to examine the shift of peripheral membrane proteins between cytosolic and membrane fractions. PMID- 28872139 TI - In Situ Characterization of Shewanella oneidensis MR1 Biofilms by SALVI and ToF SIMS. AB - Bacterial biofilms are surface-associated communities that are vastly studied to understand their self-produced extracellular polymeric substances (EPS) and their roles in environmental microbiology. This study outlines a method to cultivate biofilm attachment to the System for Analysis at the Liquid Vacuum Interface (SALVI) and achieve in situ chemical mapping of a living biofilm by time-of flight secondary ion mass spectrometry (ToF-SIMS). This is done through the culturing of bacteria both outside and within the SALVI channel with our specialized setup, as well as through optical imaging techniques to detect the biofilm presence and thickness before ToF-SIMS analysis. Our results show the characteristic peaks of the Shewanella biofilm in its natural hydrated state, highlighting upon its localized water cluster environment, as well as EPS fragments, which are drastically different from the same biofilm's dehydrated state. These results demonstrate the breakthrough capability of SALVI that allows for in situ biofilm imaging with a vacuum-based chemical imaging instrument. PMID- 28872140 TI - Purification of the Membrane Compartment for Endoplasmic Reticulum-associated Degradation of Exogenous Antigens in Cross-presentation. AB - Dendritic cells (DCs) are highly capable of processing and presenting internalized exogenous antigens upon major histocompatibility class (MHC) I molecules also known as cross-presentation (CP). CP plays an important role not only in the stimulation of naive CD8+ T cells and memory CD8+ T cells for infectious and tumor immunity but also in the inactivation of self-acting naive T cells by T cell anergy or T cell deletion. Although the critical molecular mechanism of CP remains to be elucidated, accumulating evidence indicates that exogenous antigens are processed through endoplasmic reticulum-associated degradation (ERAD) after export from non-classical endocytic compartments. Until recently, characterizations of these endocytic compartments were limited because there were no specific molecular markers other than exogenous antigens. The method described here is a new vesicle isolation protocol, which allows for the purification of these endocytic compartments. Using this purified microsome, we reconstituted the ERAD-like transport, ubiquitination, and processing of the exogenous antigen in vitro, suggesting that the ubiquitin-proteasome system processed the exogenous antigen after export from this cellular compartment. This protocol can be further applied to other cell types to clarify the molecular mechanism of CP. PMID- 28872141 TI - Derivation of Stem Cell Lines from Mouse Preimplantation Embryos. AB - Mouse embryonic stem cell (mESC) derivation is the process by which pluripotent cell lines are established from preimplantation embryos. These lines retain the ability to either self-renew or differentiate under specific conditions. Due to these properties, mESC are a useful tool in regenerative medicine, disease modeling, and tissue engineering studies. This article describes a simple protocol to obtain mESC lines with high derivation efficiencies (60-80%) by culturing blastocysts from permissive mouse strains on feeder cells in defined medium supplemented with leukemia inhibitory factor. The protocol can also be applied to efficiently derive mESC lines from non-permissive mouse strains, by the simple addition of a cocktail of two small-molecule inhibitors to the derivation medium (2i medium). Detailed procedures on the preparation and culture of feeder cells, collection and culture of mouse embryos, and derivation and culture of mESC lines are provided. This protocol does not require specialized equipment and can be carried out in any laboratory with basic mammalian cell culture expertise. PMID- 28872142 TI - Preparation and Metabolic Assay of 3-dimensional Spheroid Co-cultures of Pancreatic Cancer Cells and Fibroblasts. AB - Many cancer types, including pancreatic cancer, have a dense fibrotic stroma that plays an important role in tumor progression and invasion. Activated cancer associated fibroblasts are a key component of the tumor stroma that interact with cancer cells and support their growth and survival. Models that recapitulate the interaction of cancer cells and activated fibroblasts are important tools for studying the stromal biology and for development of antitumor agents. Here, a method is described for the rapid generation of robust 3-dimensional (3D) spheroid co-culture of pancreatic cancer cells and activated pancreatic fibroblasts that can be used for subsequent biological studies. Additionally, described is the use of 3D spheroids in carrying out functional metabolic assays to probe cellular bioenergetics pathways using an extracellular flux analyzer paired with a spheroid microplate. Pancreatic cancer cells (Patu8902) and activated pancreatic fibroblast cells (PS1) were co-cultured and magnetized using a biocompatible nanoparticle assembly. Magnetized cells were rapidly bioprinted using magnetic drives in a 96 well format, in growth media to generate spheroids with a diameter ranging between 400-600 um within 5-7 days of culture. Functional metabolic assays using Patu8902-PS1 spheroids were then carried out using the extracellular flux technology to probe cellular energetic pathways. The method herein is simple, allows consistent generation of cancer cell-fibroblast spheroid co-cultures and can be potentially adapted to other cancer cell types upon optimization of the current described methodology. PMID- 28872143 TI - Creating and Applying a Reference to Facilitate the Discussion and Classification of Proteins in a Diverse Group. AB - Related proteins that have been studied in different labs using varying organisms may lack a uniform system of nomenclature and classification, making it difficult to discuss the group as a whole and to place new sequences into the appropriate context. Developing a reference that prioritizes important sequence features related to structure and/or activity can be used in addition to established names to add some coherency to a diverse group of proteins. This paper uses the cysteine-stabilized alpha-helix (CS-alphabeta) superfamily as an example to show how a reference generated in spreadsheet software can clarify relationships between existing proteins in the superfamily, as well as facilitate the addition of new sequences. It also shows how the reference can help to refine sequence alignments generated in commonly used software, which impacts the validity of phylogenetic analyses. The use of a reference will likely be most helpful for protein groups that include highly divergent sequences from a broad spectrum of taxa, with features that are not adequately captured by molecular analyses. PMID- 28872144 TI - Volume Segmentation and Analysis of Biological Materials Using SuRVoS (Super region Volume Segmentation) Workbench. AB - Segmentation is the process of isolating specific regions or objects within an imaged volume, so that further study can be undertaken on these areas of interest. When considering the analysis of complex biological systems, the segmentation of three-dimensional image data is a time consuming and labor intensive step. With the increased availability of many imaging modalities and with automated data collection schemes, this poses an increased challenge for the modern experimental biologist to move from data to knowledge. This publication describes the use of SuRVoS Workbench, a program designed to address these issues by providing methods to semi-automatically segment complex biological volumetric data. Three datasets of differing magnification and imaging modalities are presented here, each highlighting different strategies of segmenting with SuRVoS. Phase contrast X-ray tomography (microCT) of the fruiting body of a plant is used to demonstrate segmentation using model training, cryo electron tomography (cryoET) of human platelets is used to demonstrate segmentation using super- and megavoxels, and cryo soft X-ray tomography (cryoSXT) of a mammalian cell line is used to demonstrate the label splitting tools. Strategies and parameters for each datatype are also presented. By blending a selection of semi-automatic processes into a single interactive tool, SuRVoS provides several benefits. Overall time to segment volumetric data is reduced by a factor of five when compared to manual segmentation, a mainstay in many image processing fields. This is a significant savings when full manual segmentation can take weeks of effort. Additionally, subjectivity is addressed through the use of computationally identified boundaries, and splitting complex collections of objects by their calculated properties rather than on a case-by-case basis. PMID- 28872145 TI - Synthesis of Infectious Bacteriophages in an E. coli-based Cell-free Expression System. AB - A new generation of cell-free transcription-translation (TXTL) systems, engineered to have a greater versatility and modularity, provide novel capabilities to perform basic and applied sciences in test tube reactions. Over the past decade, cell-free TXTL has become a powerful technique for a broad range of novel multidisciplinary research areas related to quantitative and synthetic biology. The new TXTL platforms are particularly useful to construct and interrogate biochemical systems through the execution of synthetic or natural gene circuits. In vitro TXTL has proven convenient to rapidly prototype regulatory elements and biological networks as well as to recapitulate molecular self-assembly mechanisms found in living systems. In this article, we describe how infectious bacteriophages, such as MS2 (RNA), PhiChi174 (ssDNA), and T7 (dsDNA), are entirely synthesized from their genome in one-pot reactions using an all Escherichia coli, cell-free TXTL system. Synthesis of the three coliphages is quantified using the plaque assay. We show how the yield of synthesized phage depends on the biochemical settings of the reactions. Molecular crowding, emulated through a controlled concentration of PEG 8000, affects the amount of synthesized phages by orders of magnitudes. We also describe how to amplify the phages and how to purify their genomes. The set of protocols and results presented in this work should be of interest to multidisciplinary researchers involved in cell-free synthetic biology and bioengineering. PMID- 28872146 TI - Characterizing Cell Migration Within Three-dimensional In Vitro Wound Environments. AB - Currently, most in vitro models of wound healing, such as well-established scratch assays, involve studying cell migration and wound closure on two dimensional surfaces. However, the physiological environment in which in vivo wound healing takes place is three-dimensional rather than two-dimensional. It is becoming increasingly clear that cell behavior differs greatly in two-dimensional vs. three-dimensional environments; therefore, there is a need for more physiologically relevant in vitro models for studying cell migration behaviors in wound closure. The method described herein allows for the study of cell migration in a three-dimensional model that better reflects physiological conditions than previously established two-dimensional scratch assays. The purpose of this model is to evaluate cell outgrowth via the examination of cell migration away from a spheroid body embedded within a fibrin matrix in the presence of pro- or anti migratory factors. Using this method, cell outgrowth from the spheroid body in a three-dimensional matrix can be observed and is easily quantifiable over time via brightfield microscopy and analysis of spheroid body area. The effect of pro migratory and/or inhibitory factors on cell migration can also be evaluated in this system. This method provides researchers with a simple method of analyzing cell migration in three-dimensional wound associated matrices in vitro, thus increasing the relevance of in vitro cell studies prior to the use of in vivo animal models. PMID- 28872147 TI - Generation of a Chronic Obstructive Pulmonary Disease Model in Mice by Repeated Ozone Exposure. AB - Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung parenchymal destruction. It has a very high incidence in aging populations. The current conventional therapies for COPD focus mainly on symptom-modifying drugs; thus, the development of new therapies is urgently needed. Qualified animal models of COPD could help to characterize the underlying mechanisms and can be used for new drug screening. Current COPD models, such as lipopolysaccharide (LPS) or the porcine pancreatic elastase (PPE)-induced emphysema model, generate COPD-like lesions in the lungs and airways but do not otherwise resemble the pathogenesis of human COPD. A cigarette smoke (CS)-induced model remains one of the most popular because it not only simulates COPD-like lesions in the respiratory system, but it is also based on one of the main hazardous materials that causes COPD in humans. However, the time-consuming and labor-intensive aspects of the CS-induced model dramatically limit its application in new drug screening. In this study, we successfully generated a new COPD model by exposing mice to high levels of ozone. This model demonstrated the following: 1) decreased forced expiratory volume 25, 50, and 75/forced vital capacity (FEV25/FVC, FEV50/FVC, and FEV75/FVC), indicating the deterioration of lung function; 2) enlarged lung alveoli, with lung parenchymal destruction; 3) reduced fatigue time and distance; and 4) increased inflammation. Taken together, these data demonstrate that the ozone exposure (OE) model is a reliable animal model that is similar to humans because ozone overexposure is one of the etiological factors of COPD. Additionally, it only took 6 - 8 weeks, based on our previous work, to create an OE model, whereas it requires 3 - 12 months to induce the cigarette smoke model, indicating that the OE model might be a good choice for COPD research. PMID- 28872148 TI - Incidence of traumatic spinal cord injury in Italy during 2013-2014: a population based study. AB - STUDY DESIGN: Observational prospective population-based incidence study. OBJECTIVES: The main objective of this study was to assess the incidence of traumatic spinal cord injuries (TSCIs) and incidence rates, in order to provide estimates by age, gender, characteristics and cause. SETTING: This study was conducted at acute-care spinal cord injury (SCI) hospitals and SCI centers from 11 Italian regions, between 1 October 2013 and 30 September 2014. METHODS: Data of all consecutive patients with acute TSCI who met the inclusion criteria were obtained through case reporting by clinicians. The data were collected into a web database. Incidence rates and incidence rate ratios were calculated and stratified by age, gender, cause, level and completeness. RESULTS: From 50% of the entire population of Italy, 445 new cases of TSCI were included. The crude incidence rate of TSCI was 14.7 cases per million per year (95% CI: 13.4-16.4); the overall male to female ratio was 4:1 and the mean age was 54. Complete information was available in 85% of the sample and revealed tetraplegia in 58% and incomplete lesion in 67% of cases. The leading cause of TSCI was falls (40.9%) followed by road traffic accidents (33.5%). The leading cause was falls for patients over 55 and road traffic accidents for patients under 55. CONCLUSION: The changing trend of TSCI epidemiology concerns the increase in the average age of TSCI people and the increase of both cervical and incomplete lesions. The etiology shows the primacy of falls over road traffic accidents and suggests the need for a change in prevention policies. PMID- 28872149 TI - Correlation between diffusion tensor imaging parameters and clinical assessments in patients with cervical spondylotic myelopathy with and without high signal intensity. AB - STUDY DESIGN: A cross-sectional observational study. OBJECTIVES: The aim of this study is to compare the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) between patients with cervical spondylotic myelopathy (CSM) with and without high T2-weighted signal intensity, and to correlate each parameter with clinical assessments. SETTING: CSM is a common cause of spinal cord dysfunction. The significance of T2 high signal intensity in the prognosis of CSM remains controversial. METHODS: Diffusion tensor imaging was performed at the cervical spinal cord in 40 patients with CSM and 42 healthy subjects. Patients with high signal intensity were separated from those without high signal intensity. ADC and FA values were compared among different groups, and the correlation between each parameter and the modified Japanese Orthopedic Association (mJOA) score was examined. RESULTS: The ADC and FA values of C2/3 differed significantly from those of C5/6 and C6/7 in healthy subjects. Patients with CSM had a higher ADC but a lower FA value than did healthy subjects. In all patients with CSM, there was a negative linear correlation between ADC and mJOA score, but FA value correlated positively with mJOA score. Secondary analysis suggested that FA value in patients with high signal intensity was lower than that in patients without high signal intensity. FA value showed a positive linear correlation with mJOA score in the patients with high signal intensity but not in the patients without high signal intensity. CONCLUSIONS: Patients with high signal intensity may have more severe spinal cord injury than patients without high signal intensity, and FA may be a useful indicator of functional status in patients with CSM with high signal intensity. PMID- 28872150 TI - Clinical Characteristics and Outcome of Hepatic Sarcoidosis: A Population-Based Study 1976-2013. AB - OBJECTIVES: Data on clinical manifestations and outcome of hepatic sarcoidosis are scarce. This study aimed to use a population-based cohort of patients with incident sarcoidosis to better describe the characteristics of hepatic sarcoidosis. METHODS: A cohort of incident cases of sarcoidosis in Olmsted County, MN, USA, from 1976 to 2013 was identified from the database. Diagnosis was verified by individual medical record review. Confirmed cases of sarcoidosis were then reviewed for liver involvement. Data on clinical manifestations, imaging study, liver biochemical tests, treatment, and outcome were collected. Cumulative incidence of cirrhosis adjusted for the competing risk of death was estimated. RESULTS: A total of 345 cases of incident sarcoidosis were identified. Of these, 19 cases (6%) had liver involvement (mean age 46.1 years, 53% female and 79% Caucasian). Most patients had asymptomatic liver disease and were discovered in pursuit of abnormal biochemical tests and imaging studies. Alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were elevated in the majority of patients (88 and 90%, respectively). Elevated transaminases were less common and less severe. About half of patients had abnormal imaging study with hypodense nodular lesions being the most common abnormality (six patients) followed by hepatomegaly (three patients). Liver biopsy revealed non-caseating granuloma in 88% (14 of 16 patients). A total of four patients developed cirrhosis. CONCLUSIONS: Involvement of the liver by sarcoidosis was seen in 6% of patients with sarcoidosis. The majority of patients were asymptomatic. Elevated ALP and GGT were the most common abnormal biochemical tests. Liver biopsy revealed non-caseating granuloma in almost all cases. Cirrhosis was seen in a significant number of patients. Generalizability of the observations to other populations may be limited, as the studied population was predominantly Caucasian. The prevalence of liver disease may be higher in more diverse populations. PMID- 28872152 TI - From Patient to Patient-Entrepreneur: Development of an Ostomy Bag Sensor. PMID- 28872151 TI - Living on Liquids: Surviving and Thriving on Exclusive Enteral Nutrition. PMID- 28872153 TI - Breast cancer: Short-term NAT reveals resistance. PMID- 28872154 TI - Ethnicity and ERG frequency in prostate cancer. AB - Emerging observations emphasize a distinct biology of prostate cancer among men of different ethnicities and races, as demonstrated by remarkable differences in the frequency of ERG oncogenic activation, one of the most common and widely studied prostate cancer driver genes. Worldwide assessment of ERG alterations frequencies show consistent trends, with men of European ancestry having the highest rates of alteration and men of African or Asian ancestries having considerably lower alteration rates. However, data must be interpreted cautiously, owing to variations in assay platforms and specimen types, as well as ethnic and geographical classifications. Many opportunities and challenges remain in assessing cancer-associated molecular alterations at a global level, and these need to be addressed in order to realize the true potential of precision medicine for all cancer patients. PMID- 28872155 TI - The rising incidence of parotid metastases: our experience from four decades of parotid gland surgery. AB - Secondary neoplasia in the parotid gland is increasingly frequent. We examined outcomes from 40 years of parotid surgery to analyse patterns for metastasis, review the staging procedure and discuss management. We retrospectively examined 772 consecutive cases of parotid surgery in a university hospital between 1975 and 2015 and assessed changes in incidence and management over four decades. In all, 71% percent of patients were male and 29% were female, with a mean age of 68 years, aged between 23 and 93 years. We diagnosed 683 parotid tumours of which 15.8% (n = 108) were malignant; 44% (n = 48) of all malignant lesions were metastases. The incidence of malignant tumours rose from 8% in the first decade, 14% in the second, 17% in the third to 21% in the fourth. The incidence increased even further from 10% in the first to 57% in the final decade. Most frequent tumours were metastases of squamous cell carcinoma (79%), and the majority of these lesions (87%) arose from above the clavicle, with 30 primary tumours in the skin. In most cases, the skin tumour had been excised between 6 and 24 months prior to parotid metastasis. Management consisted of surgery with neck dissection. 48 patients (67%) received adjuvant therapy, but despite aggressive multimodal treatment, disease progressed in the majority of cases, in 57% squamous cell carcinoma of the skin primaries, 67% of mucosal primaries above the clavicle and 83% of infraclavicular primaries. Parotid malignant tumours are increasing in incidence, mostly due to a rise in metastatic malignant tumours within the parotid gland, most of which are metastases of skin tumours, commonly squamous cell carcinoma. Despite multimodal therapy, their recurrence and progression rate remains high. We propose inclusion in head and neck follow-up in all cases of head and neck skin cancers. PMID- 28872156 TI - Indications of cone beam CT in head and neck imaging in children. AB - For imaging of bony structures, especially for the anterior and lateral skull base in ORL medicine, cone beam computed tomography (CBCT) is an increasingly used alternative to CT, with a lower exposition to plain radiography that makes its use for imaging, particularly in children, very interesting. The aim of this study was to analyse possible indications and settings for CBCT in children and compare them to those of adults. A total of 554 patients (age range 0-18 years, mean age 10.36 years), who underwent CBCT between 01/2004-06/2013 in the ENT department at the university clinic of Marburg were enrolled in this retrospective analysis to evaluate technical parameters and indications. Data on CBCT of all children were compared with previously published data collected from 1730 adults who were diagnosed with the help of CBCT in the ENT department at the university clinic of Marburg, during the years 2012-2013. The most frequent indications of CBCT in children vs. adults were in the anterior skull base region: mid-facial trauma (60.4%) vs. chronic rhinosinusitis (54.8%), disturbed nasal breathing (13.9% vs. 13.0%) and chronic rhinosinusitis (12%) vs. mid-facial trauma (10.8%). For the lateral skull base the main indications were cholesteatoma (20.3%) vs. position control of cochlear implant (CI) electrode (31.2%), chronic otorrhoea (17.5%) vs. cholesteatoma (20.9%), and position control of CI electrode (11.8%) vs. chronic otitis media mesotympanalis (6.8%). CBCT is a suitable imaging modality for bony structures in adults and children. Settings mainly depend on the region of interest. One aim should also be to reduce exposure to radiation in both adults and children. PMID- 28872157 TI - Laryngectomy: what is the impact of the type of surgery on life quality and sexual function? AB - The purpose of this study is to compare total and partial larygectomy on private life functions and sexuality in patients with laryngeal cancer. The study included 31 partial laryngectomy patients (Group 1) and 51 total laryngectomy patients (Group 2) who were operated for laryngeal cancer. European Organization for Research and Treatment of Cancer (EORTC) head and neck cancer module (QLQ H&N35) and Arizona Sexual Experiences Scale (ASEX) forms were filled in by interviewing face to face with patients. HNSW (swallowing), HNSE (senses), HNSP (speech), HNSO (social eating), HNSX (sexuality), HNTE (problems with teeth), HNOM (problems with opening mouth) and HNCO (coughing) scores of EORTC QLQ-H&N35 were significantly higher in group 2 than in group 1. However, according to Arizona test results, there were no significant difference between the two groups. PMID- 28872158 TI - Stabilometric findings in patients affected by organic dysphonia before and after phonomicrosurgery. AB - The purpose of this study is to understand if there is any alteration in the posture of patients affected by organic dysphonia and describe possible postural modifications after phonomicrosurgery on the vocal folds. Forty subjects (22 males, 18 females; mean age 32.6 +/- 7.5 years) suffering from organic dysphonia (15 cases of polyps, 11 submucosal retention cysts, 10 bilateral fibrous vocal fold nodules and 4 bilateral Reinke's oedema) were examined by open-eye and closed-eye posturography while breathing spontaneously before surgery, 24 hours after surgery and after 6 months. The variables taken into account were: the coordinates of the centre of pressure on both frontal and sagittal planes, length and surface of the track, mean velocity of the oscillations and relative standard deviations, spectral analysis of oscillation frequency, statokinesigram and stabilogram values. No characteristic pathological pattern was seen in basal stabilometry in any of the subgroups (polyps, cysts, Reinke's oedema). Only the subgroup of patients with fibrous vocal fold nodules (8/10; 80%) showed a slight forward shift from the centre of gravity when analysed in both open-eye and closed-eye posturography. A comparison performed within the same subgroup using open-eye and closed-eye posturography before and after surgery revealed no significant difference in any of the parameters being studied. The use of static stabilometry in this study demonstrates the absence of characteristic postural alterations in patients affected by organic dysphonia and also excludes that simple removal of the vocal fold lesion can change posture. PMID- 28872159 TI - Cerebrospinal fluid rhinorrhoea following transsphenoidal surgery for pituitary adenoma: experience in a Chinese centre. AB - The aim of this study was to elucidate the risk factors for cerebrospinal fluid (CSF) rhinorrhoea following transsphenoidal surgery and discuss its prevention and treatments. We retrospectively reviewed 474 consecutive cases of pituitary adenoma treated with 485 transsphenoidal surgical procedures from January 2008 to December 2011 in our department. We analysed the incidence of intra- and post operative CSF leakage and outcomes of various repair strategies. Intra-operative CSF leakage was encountered in 85 cases (17.9%), and post-operative CSF rhinorrhoea in 13 cases (2.7%). Seven of the 13 patients with post-operative CSF rhinorrhoea did not experience intra-operative CSF leakage; three of these patients had adrenocorticotropic hormone-secreting adenomas. Of the remaining 6 patients with both intra- and post-operative CSF leakage, 2 were treated for giant invasive prolactinomas, and 2 had previously undergone transsphenoidal surgery. In eight patients, the leak was resolved by lumbar puncture, lumbar external drainage, resting in a semi-reclining position, or other conservative treatment. Two CSF leaks were repaired with gelatine foam and fibrin glue using a transsphenoidal approach, and two with autologous fat graft and sellar floor reconstruction using a transnasal endoscopic approach. After undergoing two transnasal endoscopic repairs, one patient with post-operative CSF rhinorrhoea was successfully treated by further lumbar subarachnoid drainage. In conclusion, procedures using gelatine foam, fibrin glue and autologous fat graft are common and effective techniques for the management of CSF rhinorrhoea after transsphenoidal surgery. When a CSF leak is detected during transsphenoidal surgery, thorough sellar reconstruction and long-term follow-up are necessary. PMID- 28872160 TI - A mild phenotype of sensorineural hearing loss and palmoplantar keratoderma caused by a novel GJB2 dominant mutation. AB - Dominant GJB2 mutations are known to cause a syndromic form of sensorineural hearing loss associated with palmo-plantar skin manifestations. We present the genotype/phenotype correlations of a new GJB2 mutation identified in three generations of an Italian family (proband, mother and grandfather) whose members are affected by sensorineural hearing impairment associated with adult-onset palmoplantar keratoderma. In all affected members we identified a new heterozygous GJB2 mutation (c.66G > T, p.Lys22Asn) whose segregation, population frequency and in silico prediction analysis have suggested a pathogenic role. The p.Lys22Asn GJB2 mutation causes a dominant form of hearing loss associated with variable expression of palmoplantar keratoderma, representing a model of full penetrance, with an age-dependent effect on the phenotype. PMID- 28872161 TI - Temporal changes in impedance of implanted adults for various cochlear segments. AB - Electrode impedance (EI) is the first objective assessment carried out during the surgical procedure and follow-up of cochlear implanted patients. This measure provides information on the integrity of electrodes and on the surrounding environment. It is one of the main factors responsible for energy consumption of the cochlear implant (CI). The aim of our study is to investigate changes over time in EI in adult recipients implanted with the perimodiolar array by comparing differences in various cochlear segments. In addition, we explore the relationship between these objective measures and subjective measures such as T level and C-level. We studied 28 adult patients. Impedance values (IVs) were calculated in "common-ground" (CG) and in monopolar (M1+2) mode for electrode groups in basal middle and apical segments. We found significant decreases in IVs between activation and 1 month. We obtained higher values for basal impedance, whereas lower IVs were found for apical electrodes at all observation times. Statistical pairing over time between impedance and T/C values showed significant correlation for both global impedance (GI) and T-C levels at CG and M1+2 mode up to 6 months. Segregated statistical analysis also showed a significant and prolonged correlation of basal IVs and fitting parameters. The higher basal impedance over time can be explained by the higher proportion of newly formed tissue in this region. The linear correlation of impedances with the fitting parameters become not significant after 3/6 months for the apical and middle segments and remained significant only for the basal region over time. This behaviour underlines the importance of persistence in intra-cochlear factors in influencing fitting parameters in the basal segment. PMID- 28872162 TI - Conservative treatment of vestibular schwannoma: growth and Penn Acoustic Neuroma Quality of Life scale in French language. AB - The aim of this study was to determine the natural history of growth and quality of life (QoL) outcomes for vestibular schwannoma (VS) managed conservatively, and to validate the disease-specific Penn Acoustic Neuroma Quality-of-Life (PANQOL) scale in French language. We retrospectively studied 26 patients with VS managed conservatively. Patient characteristics and radiological findings were collected. Two scales were used to measure QoL: the Short Form-36 Health Survey (SF-36) and the PANQOL scale translated into French. Internal consistency and scores were compared with previous studies. The mean follow-up was 25 months (range 6-72). We observed tumour growth in 14 patients (53.8%), no growth in 12 patients (46.2%) and no case of tumour shrinkage. The mean tumour growth was 2.22 mm/year. No predictive factor of growth was found. Patients with vertigo or dizziness experienced a poorer QoL according to the SF-36 (Social Functioning and Emotional Role Limitation dimensions) and to the PANQOL scale (Balance and Energy dimensions). Our results were comparable with the literature using the SF-36. With the PANQOL scale, our scores were not statistically different with those from Dutch and North American studies except in the field of hearing (p = 0.019). Quality of life becomes essential in the management of VS. According to these results, we support a non-conservative strategy associated with vestibular rehabilitation for patients with dizziness or vertigo. The PANQOL is a validated specific scale for VS, which can be useful in French. PMID- 28872164 TI - RhIII-Catalyzed site-selective amidation with nitrone as a traceless directing group: an approach to functionalized arylaldehydes. AB - An efficient Rh-catalyzed site-selective amidation of nitrones with 1,4,2 dioxazol-5-ones has been developed. The reaction can tolerate a number of groups and generates functionalized aldehydes in good yields. The significance of the amidation is highlighted by the late-stage transformation of the formed aldehydes. PMID- 28872163 TI - Italian survey on benign paroxysmal positional vertigo. AB - Benign paroxysmal positional vertigo (BPPV) is the most common type of peripheral vertigo. BPPV often relapses after the first episode, with a recurrence rate between 15% and 50%. To date both the aetiopathogenetic processes that lead to otoconia detachment and the factors that make BPPV a relapsing disease are still unclear, but recent epidemiological studies have shown a possible association with cardiovascular risk factors. The aim of the present study (Sesto Senso Survey) was to evaluate in the Italian population through an observational survey, the main demographic and clinical characteristics of patients with BPPV (first episode or recurrent) with particular focus on the potential cardiovascular risk factors. The survey was conducted in 158 vestibology centres across Italy on 2,682 patients (mean age 59.3 +/- 15.0 years; 39.1% males and 60.9% females) suffering from BPPV, from January 2013 to December 2014. The results showed a high prevalence of cardiovascular risk factors such as high blood pressure (55.8%), hypercholesterolaemia (38.6%) and diabetes (17.7%), as well as a family history of cardiovascular disease (49.4%). A high percentage of patients also had hearing loss (42.9%), tinnitus (41.2%), or both (26.8%). The presence of hypertension, dyslipidaemia and pre-existing cardiovascular comorbidities were significantly related to recurrent BPPV episodes (OR range between 1.84 and 2.31). In addition, the association with diabetes and thyroid/autoimmune disease (OR range between 1.73 and 1.89) was relevant. The survey results confirm the significant association between cardiovascular comorbidities and recurrent BPPV and identify them as a potential important risk factor for recurrence of BPPV in the Italian population, paving the way for the evaluation of new therapeutic strategies in the treatment of this disease. PMID- 28872165 TI - On-slide detection of enzymatic activities in selected single cells. AB - With increasing recognition of the importance in addressing cell-to-cell heterogeneity for the understanding of complex biological systems, there is a growing need for assays capable of single cell analyses. In the current study, we describe the measurement of human topoisomerase I activity in single CD44 positive Caco2 cells specifically captured from a mixed population on glass slides, which were dual functionalized with anti-CD44-antibodies and specific DNA primers. On-slide lysis of captured CD44 positive cells, resulted in the release of human topoisomerase I, allowing the enzyme to circularize a specific linear DNA substrate added to the slides. The generated circles hybridized to the anchored DNA primers and acted as templates for a solid support rolling circle amplification reaction leading to the generation of long tandem repeat products that were detected at the single molecule level in a fluorescent microscope upon hybridization of fluorescent labelled probes. The on-slide detection system was demonstrated to be directly quantitative and specific towards CD44 positive cells. Moreover, it allowed reproducible detection of human topoisomerase I activity in single cells. PMID- 28872166 TI - A luminescent heterometallic metal-organic framework for the naked-eye discrimination of nitroaromatic explosives. AB - A luminescent heterometallic MOF with an interrupted cap topology was synthesized and characterized. This compound exhibits a strong blue-light emission and shows naked-eye selective detection toward trinitrobenzene (TNB) even in the presence of other nitro explosives. Furthermore, the compound is also capable of selectively sensing nitroaromatic picric acid (PA) based on the fluorescence quenching mechanism. PMID- 28872167 TI - Metal-free, direct conversion of alpha-amino acids into alpha-keto gamma-amino esters for the synthesis of alpha,gamma-peptides. AB - An efficient, metal-free synthesis of unusual alpha-keto gamma-amino esters from alpha-amino acids is achieved by a radical scission-oxidation-addition of silyloxy acrylates procedure, where no purification of the reaction intermediates is needed. This protocol can be applied to the selective modification of the C terminal position in peptides to give alpha,gamma-hybrids. PMID- 28872168 TI - Amidinoquinoxaline N-oxides: spin trapping of O- and C-centered radicals. AB - Amidinoquinoxaline N-oxides represent a novel family of heterocyclic spin traps. In this work, their ability to trap O- and C-centered radicals was tested using selected derivatives with different structural modifications. All the studied nitrones were able to trap radicals forming persistent spin adducts, also in the case of OH and OOH radicals which are of wide biological interest as examples of ROS. The stability of the adducts was mainly attributed to the wide delocalization of the unpaired electron over the whole quinoxaline moiety. The nitroxide spectral parameters (hfccs and g-factors) were analyzed and the results were supported by DFT calculations. The N-19 hfccs and g-factors were characteristic of each aminoxyl and could aid in the identification of the trapped radical. The enhanced stability of the OH adducts under the employed reaction conditions could be ascribed to their possible stabilization by IHBs with two different acceptors: the N-O moiety or the amidine functionality. DFT calculations indicate that the preferred IHB is strongly conditioned by the amidine ring size. While five membered homologues show a clear preference for the IHB with the N-O group, in six membered derivatives this stabilizing interaction is preferentially established with the amidine nitrogen as an IHB acceptor. PMID- 28872169 TI - Volatiles from the fungal microbiome of the marine sponge Callyspongia cf. flammea. AB - The volatiles emitted by five fungal strains previously isolated from the marine sponge Callyspongia cf. flammea were captured with a closed-loop stripping apparatus (CLSA) and analyzed by GC-MS. Besides several widespread compounds, a series of metabolites with interesting bioactivities were found, including the quorum sensing inhibitor protoanemonin, the fungal phytotoxin 3,4-dimethylpentan 4-olide, and the insect attractant 1,2,4-trimethoxybenzene. In addition, the aromatic polyketides isotorquatone and chartabomone that are both known from Eucalyptus and a new O-desmethyl derivative were identified. The biosynthesis of isotorquatone was studied by feeding experiments with isotopically labeled precursors and its absolute configuration was determined by enantioselective synthesis of a reference compound. Bioactivity testings showed algicidal activity for some of the identified compounds, suggesting a potential ecological function in sponge defence. PMID- 28872170 TI - Intermediate scattering function of an anisotropic Brownian circle swimmer. AB - Microswimmers exhibit noisy circular motion due to asymmetric propulsion mechanisms, their chiral body shape, or by hydrodynamic couplings in the vicinity of surfaces. Here, we employ the Brownian circle swimmer model and characterize theoretically the dynamics in terms of the directly measurable intermediate scattering function. We derive the associated Fokker-Planck equation for the conditional probabilities and provide an exact solution in terms of generalizations of the Mathieu functions. Different spatiotemporal regimes are identified reflecting the bare translational diffusion at large wavenumbers, the persistent circular motion at intermediate wavenumbers and an enhanced effective diffusion at small wavenumbers. In particular, the circular motion of the particle manifests itself in characteristic oscillations at a plateau of the intermediate scattering function for wavenumbers probing the radius. PMID- 28872171 TI - Regioselective oxidative cross-coupling of benzo[d]imidazo[2,1-b]thiazoles with styrenes: a novel route to C3-dicarbonylation. AB - A novel I2 promoted, highly efficient metal-free and peroxide-free greener domino protocol for the C3-dicarbonylation of benzo[d]imidazo[2,1-b]thiazoles (IBTs) with styrenes has been developed via oxidative cleavage of the C(sp2)-H bond, followed by C3-nucleophilic attack of IBT and oxidation. Interestingly, under these conditions 2-(benzo[d]imidazo[2,1-b]thiazol-2-yl)aniline gave the benzo[4',5']thiazolo[2',3':2,3]imidazo[4,5-c]quinoline derivative via oxidative cleavage of the C(sp2)-H bond, followed by Pictet-Spengler cyclization and aromatization. This method offers the advantages of broad substrate scope, ecofriendly feature and high atom economy apart from higher yields. PMID- 28872172 TI - A luminescent and colorimetric probe based on the functionalization of gold nanoparticles by ruthenium(ii) complexes for heparin detection. AB - A sensitive assay was demonstrated for the colorimetric and luminescent detection of heparin. Positively charged [Ru(phen)2np]2+ (np: naphtho[2,3 f][1,10]phenanthroline) can interact with negatively charged AuNPs through electrostatic interaction, leading to the luminescence quenching of [Ru(phen)2np]2+via energy transfer as well as the aggregation of AuNPs together with a color change in solution from red to blue. Upon the addition of negatively charged heparin to gold nanoparticles functionalized by ruthenium(ii) complexes, the emission of [Ru(phen)2np]2+ recovered due to the competitive adsorption of [Ru(phen)2np]2+ to heparin and AuNPs. A linear calibration curve was obtained in the 0.4 MUM to 100 MUM range and 0.1 MUM to 6 MUM with a low detection limit of 0.22 MUM and 0.024 MUM based on 3sigma/s for heparin quantification in buffer solution and in 1% fetal bovine serum (FBS), respectively. Interestingly, the naked eye alone can judge the presence of 0.02 MUM heparin without the aid of any advanced instruments by color change. Thus a convenient and visual method to detect heparin was established. PMID- 28872176 TI - A general route to coat poly(cyclotriphosphazene-co-4,4'-sulfonyldiphenol) on various substrates and the derived N, P, S-doped hollow carbon shells for catalysis. AB - The construction of core-shell structures through surface coating, and then making use of the synergistic effects between the core and shell to design and synthesize heterogeneous catalysts is a hot topic in the heterogeneous catalysis field. Developing a general coating route with functional shell materials is further highly desirable. Here we found that a poly(cyclotriphosphazene-co-4,4' sulfonyldiphenol) (PZS) layer can be generally coated on various substrates with different components and morphologies, including metal oxides, noble metal nanoparticles, carbon materials and metal-organic frameworks (MOFs). In addition, the coating thickness could be well controlled through simply adjusting the amount of monomers. Taking advantage of the heteroatoms in the PZS layer and the synergistic effect between the core and shell, new methods for fabrication of co doped hollow carbon shell catalysts and transition metal phosphide nanoparticles were developed. As a proof-of-concept application, the N, P, S-doped hollow carbon shells prepared by calcination of a ZnCo-ZIFs@PZS core-shell structure could act as a good carbo-catalyst for selective oxidation of C-H bonds in water. PMID- 28872178 TI - Unique structural micro-adjustments in a new benzothiadiazole-derived Zn(ii) metal organic framework via simple photochemical decarboxylation. AB - The first example of micro-adjustments of a metal organic framework (MOF) structure was observed in a new Zn(ii) MOF (Zn-BTDC-M1) derived from a benzothiadiazole-4,7-dicarboxylic acid (H2BTDC) ligand using a light-driven decarboxylation process. Interestingly, such decarboxylation occurs at the non chelated wing of the ligand, which induced a change in the capability of the MOF for physical N2 adsorption and chemical NH3 gas adsorption. PMID- 28872179 TI - Observation of magnetic interactions between localized 4f- and itinerant pi electrons in a single crystal of cationic bisphthalocyanine complexes containing diluted spin centres. AB - Magnetic f-pi interactions between localized 4f-electrons and itinerant pi electrons have been observed in a single crystal of bisphthalocyaninato yttrium(iii)/terbium(iii) tetrafluoroborate ([Pc2Y0.95Tb0.05][BF4]) by measuring electrical conductivity of the crystal in the presence of an external magnetic field. PMID- 28872180 TI - Rhodium(iii)-catalyzed regio- and stereoselective benzylic alpha fluoroalkenylation with gem-difluorostyrenes. AB - Rhodium(iii)-catalyzed mild benzylic alpha-fluoroalkenylation of 8 methylquinolines with gem-difluorostyrenes has been developed. This reaction occurred via C-H activation and C-F cleavage and is applicable to a wide range of substrates, leading to the synthesis of Z-alkenyl fluorides under mild and redox neutral conditions with high regio- and stereoselectivity. PMID- 28872181 TI - InP-InxGa1-xAs core-multi-shell nanowire quantum wells with tunable emission in the 1.3-1.55 MUm wavelength range. AB - The usability and tunability of the essential InP-InGaAs material combination in nanowire-based quantum wells (QWs) are assessed. The wurtzite phase core-multi shell InP-InGaAs-InP nanowire QWs are characterised using cross-section transmission electron microscopy and photoluminescence measurements. The InP InGaAs direct interface is found to be sharp while the InGaAs-InP inverted interface is more diffused, in agreement with their planar counterpart. Bright emission is observed from the single nanowires containing the QWs at room temperature, with no emission from the InP core or outer barrier. The tunability of the QW emission wavelength in the 1.3-1.55 MUm communication wavelength range is demonstrated by varying the QW thickness and in the 1.3 MUm range by varying the composition. The experiments are supported by simulation of the emission wavelength of the wurtzite phase InP-InGaAs QWs in the thickness range considered. The radial heterostructure is further extended to design multiple QWs with bright emission, therefore establishing the capability of this material system for nanowire based optical devices for communication applications. PMID- 28872182 TI - Quantum dots in photocatalytic applications: efficiently enhancing visible light photocatalytic activity by integrating CdO quantum dots as sensitizers. AB - The amalgamation of a wide optical band gap photocatalyst with visible-light active CdO quantum dots (QDs) as sensitizers is one of the most efficient ways to improve photocatalytic performance under visible light irradiation. The photocatalytic performance of cadmium benzoate ((Cd(C7H5O2)2)3(CH3CN)1) is comprehensively investigated. The estimated optical band gap of cadmium benzoate is 2.64 eV and the EPc and EPv are about -0.09 V (vs. NHE) and +2.55 V (vs. NHE), respectively, which implies that cadmium benzoate possesses a high negative reduction potential of excited electrons due to its higher conduction band position, and hence, the locations of the conduction band minimum and the valence band maximum meet the redox capacity. Thus, this composite photocatalyst exhibits superior activity in visible-light-driven photocatalytic H2 evolution. We found that introducing the QDs enhance the photocatalytic performance towards the visible light region. The electronic band structure shows high k-dispersion bands around the Fermi level, which implies low effective masses, and hence, the high mobility carriers favor the enhancement of the charge transfer process. The mobility of the photogenerated carriers significantly influences the photocatalytic efficiency and the higher photogenerated carriers' mobility enhances the photocatalytic performance. Moreover, the result shows a great effective mass difference between electrons (e-) and holes (h+), which can facilitate the e- and h+ migration and separation, and finally improve the photocatalytic performance. The large mobility difference is useful for the separation of e- and h+, the reduction of the e- and h+ recombination rate, and the improvement of the photocatalytic activity. Thus, cadmium benzoate exhibits rapid generation of e--h+ pairs with photoexcitation and a high negative reduction potential of excited electrons due to its higher CB position. Based on these results one can conclude that cadmium benzoate satisfied all requirements to be an efficient photocatalyst. This will greatly improve the search efficiency and greatly help experimentalists in saving resources in the exploration of new photocatalysts with good photocatalytic performance. PMID- 28872183 TI - Ex vivo 3D human corneal stroma model for Schnyder corneal dystrophy - role of autophagy in its pathogenesis and resolution. AB - INTRODUCTION: Multilamellar bodies (MLBs) are concentric cytoplasmic membranes which form through an autophagy-dependent mechanism. In the cornea, the presence of MLBs is associated with Schnyder corneal dystrophy (SCD). Ex vivo 3D modelling of the corneal stroma and SCD can help study pathogenesis and resolution of the disorder. METHODS: Corneal stroma explants were isolated from cadavers and cultivated long-term for more than 3 months to achieve spontaneous 3D outgrowth of corneal stroma-derived mesenchymal stem-like cells (CSMSCs). The 3D tissues were then examined by transmission electron microscopy (TEM) for presence of MLBs, and by immunofluorescent labelling against markers for autophagy (p62, LC3). Autophagy was induced by classical serum starvation or rapamycin (RAP) treatment (50 nM), and inhibited by the autophagy inhibitor 3-methyladenine (3 MA, 10 mM) for 24 hours. RESULTS: CSMSCs can form spontaneously 3D outgrowths over a 3-4 weeks period, depositing their own extracellular matrix containing collagen I. TEM confirmed the presence of MLBs in the long-term (>3 months) 3D cultures, which became more abundant under starvation and RAP treatment, and decreased in number under autophagy inhibition with 3-MA. The presence of autophagy and its disappearance could be confirmed by an inversely related increase and decrease in the expression of LC3 and p62, respectively. CONCLUSIONS: MLB formation in long-standing CSMSC cultures could serve as a potential ex vivo model for studying corneal stroma diseases, including SCD. Inhibition of autophagy can decrease the formation of MLBs, which may lead to a novel treatment of the disease in the future. PMID- 28872185 TI - Cognitive diagnosis modelling incorporating item response times. AB - To provide more refined diagnostic feedback with collateral information in item response times (RTs), this study proposed joint modelling of attributes and response speed using item responses and RTs simultaneously for cognitive diagnosis. For illustration, an extended deterministic input, noisy 'and' gate (DINA) model was proposed for joint modelling of responses and RTs. Model parameter estimation was explored using the Bayesian Markov chain Monte Carlo (MCMC) method. The PISA 2012 computer-based mathematics data were analysed first. These real data estimates were treated as true values in a subsequent simulation study. A follow-up simulation study with ideal testing conditions was conducted as well to further evaluate model parameter recovery. The results indicated that model parameters could be well recovered using the MCMC approach. Further, incorporating RTs into the DINA model would improve attribute and profile correct classification rates and result in more accurate and precise estimation of the model parameters. PMID- 28872186 TI - Asymptotic confidence intervals for the Pearson correlation via skewness and kurtosis. AB - When bivariate normality is violated, the default confidence interval of the Pearson correlation can be inaccurate. Two new methods were developed based on the asymptotic sampling distribution of Fisher's z' under the general case where bivariate normality need not be assumed. In Monte Carlo simulations, the most successful of these methods relied on the (Vale & Maurelli, 1983, Psychometrika, 48, 465) family to approximate a distribution via the marginal skewness and kurtosis of the sample data. In Simulation 1, this method provided more accurate confidence intervals of the correlation in non-normal data, at least as compared to no adjustment of the Fisher z' interval, or to adjustment via the sample joint moments. In Simulation 2, this approximate distribution method performed favourably relative to common non-parametric bootstrap methods, but its performance was mixed relative to an observed imposed bootstrap and two other robust methods (PM1 and HC4). No method was completely satisfactory. An advantage of the approximate distribution method, though, is that it can be implemented even without access to raw data if sample skewness and kurtosis are reported, making the method particularly useful for meta-analysis. Supporting information includes R code. PMID- 28872184 TI - Role of toll-like receptor 2 in inflammation and alveolar bone loss in experimental peri-implantitis versus periodontitis. AB - BACKGROUND AND OBJECTIVE: Peri-implantitis and periodontitis are different entities in immune characteristics even though they share similar features in clinical and radiologic signs. Toll-like receptor 2 (TLR-2), one of the key pathogen-recognition receptors in the innate immune system, plays an important role in the progression of periodontitis. However, the role of TLR-2 in peri implantitis remains unclear. The objective of this study was to investigate the role of TLR-2 in inflammation and alveolar bone loss in a murine model of ligature-induced peri-implantitis and to compare it with ligature-induced periodontitis. MATERIAL AND METHODS: Smooth-surface titanium implants were placed in the alveolar bone of the left maxillary molars of wild-type (WT) and Tlr2 knockout (Tlr2-KO) mice 6 weeks after tooth extraction. Silk ligatures were applied to the left implant fixtures and the right maxillary second molars to induce peri-implantitis and periodontitis 4 weeks after implant placement. Two weeks after ligation, bone loss around the implants and maxillary second molars was analysed by micro-computed tomography (micro-CT), and inflammation around the implants and maxillary second molars was assessed at the same time point using histology and TRAP staining, respectively. Expression of mRNA for proinflammatory cytokines (interleukin-1beta [Il1beta], tumor necrosis factor-alpha [Tnfalpha]), an anti-inflammatory cytokine (interleukin-10 [Il10]) and osteoclastogenesis related cytokines (Rankl, osteoprotegerin [Opg]) were evaluated, in gingival tissue, using real-time quantitative PCR (RT-qPCR). RESULTS: The success rate of implant osseointegration was significantly higher in Tlr2-KO mice (85.71%) compared with WT mice (53.66%) (P = .0125). Micro-CT revealed significantly decreased bone loss in Tlr2-KO mice compared with WT mice (P = .0094) in peri implantitis. The levels of mRNA for Il1beta (P = .0055), Tnfalpha (P = .01) and Il10 (P = .0019) in gingiva were significantly elevated in the peri-implantitis tissues of WT mice, but not in Tlr2-KO mice, compared with controls. However, the gingival mRNA ratios of Rankl/Opg in peri-implant tissues were significantly upregulated in both WT (P = .0488) and Tlr2-KO (P = .0314) mice. Ligature-induced periodontitis exhibited similar patterns of bone loss and inflammatory cytokine profile in both groups of mice, except that the level of Il10 was elevated (P = .0114) whereas the Rankl/Opg ratio was not elevated (P = .9755) in Tlr2-KO mice compared with control mice. Histological findings showed increased numbers of TRAP-positive cells and infiltrated inflammatory cells in ligature-induced peri implantitis in both WT (P < .01) and Tlr2-KO mice (P < .05), and the numbers of both types of cell were significantly higher in WT mice than in Tlr2-KO mice (P < .01). CONCLUSION: This study suggests that TLR-2 mediates bone loss in both peri implantitis and periodontitis. However, different molecular features may exist in the pathogenesis of the two diseases. PMID- 28872187 TI - The Attachment Imperative: Parental Experiences of Relation-making in a Danish Neonatal Intensive Care Unit. AB - In this article, we explore how parents establish relations with extremely premature infants whose lives and futures are uncertain. Drawing on ethnographic fieldwork in a Danish Neonatal Intensive Care Unit (NICU), we engage recent discussions of the limits of conventional anthropological thinking on social relations and point to the productive aspects of practices of distance and detachment. We show that while the NICU upholds an imperative of attachment independently of the infant's chances of survival, for parents, attachment is contingent on certain hesitations in relation to their infant. We argue that there are nuances in practices of relationmaking in need of more attention (i.e., the nexus of attachment and detachment). Refraining from touching, holding, and feeding their infants during critical periods, the parents enact detachment as integral to their practices of attachment. Such "cuts" in parent-infant relations become steps on the way to securing the infant's survival and making kin(ship). We conclude that although infants may be articulated as "maybe-lives" by staff, in the NICU as well as in Danish society, the ideal of attachment appears to leave little room for "maybe-parents." PMID- 28872188 TI - Does the adjunctive use of statins provide additional benefits to nonsurgical periodontal treatment? A systematic review and meta-analysis. AB - Adjunctive therapeutic agents may be used to improve the response to nonsurgical periodontal therapy. Local delivery of statins (simvastatin, artovastatin and rosuvastatin) is a promising adjunct to scaling and root planing (SRP). Thus, the aim of this review is to evaluate if adjunctive local delivery of statins is more effective than SRP alone. Randomized clinical trials that presented a test group evaluating local delivery of statins as adjuncts in healthy, diabetic and smoking patients were included. Medline and the Cochrane library database were searched up to November 2016. Random effects meta-analyses were conducted for pocket depth change and clinical attachment gain. One hundred and twenty-five studies potentially related to the aim of this review were screened, but only 10 were included. The majority of the trials reported additional clinical benefits in the groups that were treated with adjunctive local delivery of statins. Pooled calculations showed that local delivery of statins resulted in additional reduction of pocket depth and clinical attachment gain in healthy people, smokers and diabetic patients. Local statins may offer additional clinical benefits to SRP, even in smokers and diabetics. PMID- 28872189 TI - Vascular, inflammatory, and metabolic factors associated with cognition in aging persons with chronic epilepsy. AB - We examined cognition in aging persons with chronic epilepsy; characterized targeted vascular, inflammatory, and metabolic risk factors associated with abnormal cognitive aging in the general population; and examined associations between cognition and vascular, inflammatory, and metabolic health. Participants included 40 persons with chronic localization-related epilepsy and 152 controls, aged 54.6 and 55.3, respectively. Participants underwent neuropsychological assessment, clinical examination, and fasting blood evaluation for quantification of vascular status (systolic and diastolic blood pressure, obesity/body mass index [BMI], total and high-density lipoprotein [HDL] cholesterol level, and homocysteine), inflammatory markers (high sensitivity C-reactive protein [hs CRP], and interleukin-6 [IL-6]), and metabolic status (insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], glucose). Epilepsy participants exhibited impairment across all cognitive factor scores (all p's < 0.0001); abnormalities in BMI (p = 0.049), hs-CRP (p = 0.046), HOMA-IR (p = 0.0040), and fasting glucose (p = 0.03), with significant relationships between higher HOMA-IR with poorer Immediate Memory (p = 0.03) and Visuospatial Ability (0.03); elevated hs-CRP with poorer Visuospatial (p = 0.035) and Verbal Ability (p = 0.06); elevated BMI with poorer Speed/Flexibility (p = 0.04), Visuospatial (p = 0.001) and Verbal Ability (p = 0.02); and lower HDL with poorer Verbal Learning/Delayed Memory (p = 0.01), Speed/Flexibility (p = 0.043), and Working Memory (p = 0.008). Aging persons with chronic epilepsy exhibit multiple abnormalities in metabolic, inflammatory, and vascular health that are associated with poorer cognitive function. PMID- 28872191 TI - Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sezary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with biologic response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients. PMID- 28872194 TI - Association of polymorphisms in the 5' regulatory region of LEPR gene with meat quality traits in Berkshire pigs. PMID- 28872195 TI - Goat domestication and breeding: a jigsaw of historical, biological and molecular data with missing pieces. AB - Domestic goats (Capra hircus) are spread across the five continents with a census of 1 billion individuals. The worldwide population of goats descends from a limited number of bezoars (Capra aegagrus) domesticated 10 000 YBP (years before the present) in the Fertile Crescent. The extraordinary adaptability and hardiness of goats favoured their rapid spread over the Old World, reaching the Iberian Peninsula and Southern Africa 7000 YBP and 2000 YBP respectively. Molecular studies have revealed one major mitochondrial haplogroup A and five less frequent haplogroups B, C, D, F and G. Moreover, the analysis of autosomal and Y-chromosome markers has evidenced an appreciable geographic differentiation. The implementation of new molecular technologies, such as whole-genome sequencing and genome-wide genotyping, allows for the exploration of caprine diversity at an unprecedented scale, thus providing new insights into the evolutionary history of goats. In spite of a number of pitfalls, the characterization of the functional elements of the goat genome is expected to play a key role in understanding the genetic determination of economically relevant traits. Genomic selection and genome editing also hold great potential, particularly for improving traits that cannot be modified easily by traditional selection. PMID- 28872196 TI - Critical Time Intervention for Homeless People Making the Transition to Community Living: A Randomized Controlled Trial. AB - To help create an evidence base in Europe for effective interventions that improve the well-being of homeless people, we tested whether critical time intervention (CTI), a time-limited intervention developed to support vulnerable people during times of transition, is effective outside the United States. For this multicenter, parallel-group randomized controlled trial, 183 adults who were moving from shelters in the Netherlands to supported or independent housing were allocated to CTI or care-as-usual. The primary outcome was number of days rehoused, which was assessed by interviewing participants four times during a 9 month follow-up. Outcomes were analyzed with three-level mixed-effects models. The primary outcome did not differ between groups. CTI had a significant effect on family support and, for people experiencing less social support, psychological distress. Groups did not differ significantly on social support, fulfillment of care needs, quality of life, self-esteem, excessive alcohol use, or cannabis use. Because few participants were homeless at 9 months, more research is needed to establish whether CTI can prevent long-term recurrent homelessness. Given recent emphasis on informal support in public services and positive effects of CTI on family support and psychological distress, CTI is a fitting intervention for Dutch shelter services. PMID- 28872197 TI - Contact allergy to methyldibromo glutaronitrile is still of clinical relevance. PMID- 28872198 TI - Allergic contact urticaria secondary to hair dye use. PMID- 28872199 TI - Care of pets entails the risk of allergic contact dermatitis caused by plants. PMID- 28872200 TI - A first case of erythema multiforme-like contact dermatitis caused by propolis. PMID- 28872201 TI - Confocal microscopy in the diagnosis of fibreglass dermatitis. PMID- 28872202 TI - Fixed drug eruption induced by ciprofloxacin and cross-reactivity to other quinolones. PMID- 28872203 TI - Contact urticaria caused by the ultraviolet absorber octocrylene in sunscreens. PMID- 28872204 TI - Allergic contact stomatitis caused by camphorquinone in a light cure periodontal dressing. PMID- 28872206 TI - Generalized systemic allergic dermatitis caused by Cinnamomum zeylanicum in a herbal tea. PMID- 28872209 TI - International Endodontic Journal 50th Anniversary Editorial. PMID- 28872207 TI - Protein contact dermatitis caused by chicken meat in bird-egg syndrome. PMID- 28872210 TI - Community health workers' experiences of using video teaching tools during home visits-A pilot study. AB - Innovations in health, such as the use of tablet computers, show promise in broadening the scope of work of community health workers (CHWs), and play an important role in keeping CHWs and their clients up to date with advancements in health. While the use of mobile phones and tablets is innovative, the applicability of these technologies in different contexts remains poorly understood. Furthermore, little is known about the acceptability and feasibility of the use of video teaching tools on such devices across diverse contexts. In this study, we aimed to explore the acceptability and feasibility of using tablets with teaching videos (about HIV, alcohol, nutrition and breastfeeding) to support the health promotion efforts of 24 CHWs who work with pregnant mothers and mothers of young children in an urban township in South Africa. Between November 2015 and May 2016, we conducted focus groups and identified four key themes (with several sub-themes) that demonstrated factors related to the acceptability and feasibility of these devices and their content. Focus group transcripts were analysed thematically using qualitative data analysis software. The findings indicated that while the devices contained several supportive features (such as lightening the workload, and stimulating interest in their work), they also contained several restrictive features (safety and confidentiality). CHWs considered the video content an important tool to engage not only their clients but also family members and the community at large. Issues surrounding safety, privacy and confidentiality of using these devices require careful consideration prior to implementation in large-scale studies. Furthermore, stigma associated with household visits by CHWs and the nature of their work also need to be addressed by researchers and programme implementers. Overall, CHWs deemed the devices and the video content an acceptable and feasible means with which to provide health promotion and education among their clients. PMID- 28872211 TI - Genomic signatures of evolution in Nautilus-An endangered living fossil. AB - Living fossils are survivors of previously more diverse lineages that originated millions of years ago and persisted with little morphological change. Therefore, living fossils are model organisms to study both long-term and ongoing adaptation and speciation processes. However, many aspects of living fossil evolution and their persistence in the modern world remain unclear. Here, we investigate three major aspects of the evolutionary history of living fossils: cryptic speciation, population genetics and effective population sizes, using members of the genera Nautilus and Allonautilus as classic examples of true living fossils. For this, we analysed genomewide ddRAD-Seq data for all six currently recognized nautiloid species throughout their distribution range. Our analyses identified three major allopatric Nautilus clades: a South Pacific clade, subdivided into three subclades with no signs of admixture between them; a Coral Sea clade, consisting of two genetically distinct populations with significant admixture; and a widespread Indo-Pacific clade, devoid of significant genetic substructure. Within these major clades, we detected five Nautilus groups, which likely correspond to five distinct species. With the exception of Nautilus macromphalus, all previously described species are at odds with genomewide data, testifying to the prevalence of cryptic species among living fossils. Detailed FST analyses further revealed significant genome-wide and locus-specific signatures of selection between species and differentiated populations, which is demonstrated here for the first time in a living fossil. Finally, approximate Bayesian computation (ABC) simulations suggest large effective population sizes, which may explain the low levels of population differentiation commonly observed in living fossils. PMID- 28872213 TI - Handovers in primary healthcare in Norway: A qualitative study of general practitioners' collaborative experiences. AB - Worldwide demographic development increases the pressure on healthcare services. In Norway, municipal acute wards (MAWs) have been established as a 24-hr acute healthcare service as a primary healthcare alternative to hospitalisation. General practitioners (GPs) are key holders of referrals to different healthcare service levels, yet studies of GPs' experiences with these wards are sparse. Suboptimal handovers could lead to hospital readmissions, avoidable morbidity and even mortality. The aim of this study was to explore GPs' experiences with patient handovers to MAWs as well as to hospitals. A qualitative study including semi-structured interviews with 23 GPs in a county in south-eastern Norway was conducted. Data were analysed using thematic analysis. The results show that GPs preferred to collaborate with others in their own profession for patient handovers. The GPs had positive collaborative experiences with MAW doctors, while collaboration with doctors in hospitals was viewed more negatively, particularly as GPs had the impression that hospital doctors felt they had superior medical competence. After patient transfer, GPs felt uncertainty related to their own responsibilities for the patient. This study contributes new knowledge about GPs' experiences with collaboration and distribution of responsibility between primary and tertiary healthcare services. This information is essential when developing acceptable alternatives to general hospitals. PMID- 28872212 TI - Galectin-3 and risk of ischaemic stroke: Reasons for Geographic and Racial Differences in Stroke cohort. AB - BACKGROUND AND PURPOSE: Galectin-3 is a biomarker of atherosclerotic and cardiovascular disease, and may be a useful marker for ischaemic stroke risk. METHODS: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled and examined 30 239 US participants between 2003 and 2007 (41% black, 59% white and 55% in the southeastern stroke belt). Baseline galectin-3 was measured in 526 subjects with incident ischaemic stroke over 5.4 years and in a cohort random sample (CRS) of 947 participants. Cox proportional hazards models were used to calculate hazard ratios (HRs) of ischaemic stroke by quartiles of galectin-3. RESULTS: In the CRS, galectin-3 was significantly higher with older age, black race, female sex, body mass index, hypertension, diabetes mellitus and kidney disease, and also in those who developed incident stroke. Participants with galectin-3 levels in the fourth versus first quartile had a 2.3-fold increased stroke risk [95% confidence interval (CI) 1.6, 3.4] in an unadjusted model. An interaction with age was found (P = 0.06), and therefore age-stratified analyses were performed. Amongst those younger than age 64, baseline galectin-3 in the second-fourth quartiles was associated with increased stroke risk (HR 3.0, 95% CI 1.6, 5.5) compared to the first quartile in an age-, race- and sex adjusted model. The HR was 2.0 (95% CI 1.0, 4.0) with multivariable adjustment. There was no association amongst older participants. CONCLUSIONS: Galectin-3 was associated with incident ischaemic stroke in younger but not older individuals. Confirmation of this finding, and elucidation of its implications for stroke pathophysiology and prevention, is needed. PMID- 28872214 TI - Quality of life after thyroidectomy in patients with nontoxic nodular goiter: A prospective cohort study. AB - BACKGROUND: Using the thoroughly validated Thyroid-Related Quality-of-Life Patient-Reported Outcome (ThyPRO) questionnaire, the purpose of this study was to investigate changes in disease-specific quality of life (QOL) after surgical treatment in patients with benign nontoxic multinodular goiters. METHOD: Patients with goiters scheduled for thyroid surgery (n = 106) and individuals from the general population (n = 739) were studied. The ThyPRO data before, 3 months, and 6 months after surgery were compared with normative scores from the general population using a linear mixed model and t tests. RESULTS: Before surgery, patients with goiters experienced poorer scores on all scales compared to the general population. After surgery, moderate to large improvements were seen in goiter symptoms, tiredness, anxiety, and overall QOL. After surgery, all scales returned to values equal to the general population. The degree of anxiety was, in fact, lower than in the general population. CONCLUSION: Thyroid surgery leads to significant benefit among patients with benign nontoxic goiters by restoring QOL equal to that in the general population. PMID- 28872215 TI - Alzheimer's disease. AB - Alzheimer's disease, the commonest cause of dementia, is a growing global health concern with huge implications for individuals and society. In this review, current understanding of the epidemiology, genetics, pathology and pathogenesis of Alzheimer's disease is outlined, before its clinical presentation and current treatment strategies are discussed. Finally, the review discusses how our enhanced understanding of Alzheimer pathogenesis, including the recognition of a protracted preclinical phase, is informing new therapeutic strategies with the aim of moving from treatment to prevention. PMID- 28872216 TI - Perilesional and contralateral white matter evolution and integrity in patients with periventricular nodular heterotopia and epilepsy: a longitudinal diffusion tensor imaging study. AB - BACKGROUND AND PURPOSE: This study aimed to assess the evolution of perinodular and contralateral white matter abnormalities in patients with periventricular nodular heterotopia (PNH) and epilepsy. METHODS: Diffusion tensor imaging (DTI) (64 directions) and 3 T structural magnetic resonance imaging were performed in 29 PNH patients (mean age 27.3 years), and 16 patients underwent a second scan (average time between the two scans 1.1 years). Fractional anisotropy and mean diffusivity were measured within the perilesional and contralateral white matter. RESULTS: Longitudinal analysis showed that white matter located 10 mm from the focal nodule displayed characteristics intermediate to tissue 5 mm away, and normal-appearing white matter (NAWM) also established evolution profiles of perinodular white matter in different cortical lobes. Compared to 29 age- and sex matched healthy controls, significant decreased fractional anisotropy and elevated mean diffusivity values were observed in regions 5 and 10 mm from nodules (P < 0.01), whilst DTI metrics of the remaining NAWM did not differ significantly from controls. Additionally, normal DTI metrics were shown in the contralateral region in patients with unilateral PNH. CONCLUSIONS: Periventricular nodular heterotopia is associated with microstructural abnormalities within the perilesional white matter and the extent decreases with increasing distance from the nodule. In the homologous contralateral region, white matter diffusion metrics were unchanged in unilateral PNH. These findings have clinical implications with respect to the medical and surgical interventions of PNH-related epilepsy. PMID- 28872217 TI - Adverse effects produced by different drugs used in the treatment of Parkinson's disease: A mixed treatment comparison. AB - OBJECTIVE: This mixed treatment comparison is used to compare the adverse effects of eleven different drugs used to treat Parkinson's disease (PD). The drugs that we compare include the following: ropinirole, rasagiline, rotigotine, entacapone, apomorphine, pramipexole, sumanirole, bromocriptine, piribedil, pergolide, and levodopa. METHODS: PubMed, EMBASE, and Cochrane Library were searched from the inception to December 2015. Our analysis combines the evidences of direct comparison and indirect comparison between various literatures. We evaluated the merging odds ratios (OR) value and surface under the cumulative ranking curves (SUCRA) of each of the drugs and used this as a mode of comparison. RESULTS: Twenty-four randomized controlled trials (RCTs) were included in this study. Our results demonstrated that the incidence of adverse reactions of ropinirole, rotigotine, entacapone, and sumanirole were obviously higher in terms of nausea compared to the placebo. Ropinirole produced the highest incidence rates of dyskinesia side effects, whereas pramipexole was significantly higher in terms of patients' hallucination. In addition, the SUCRA values of all the drugs showed that the incidence of adverse reaction of pergolide was relatively high (nausea: 83.5%; hallucination: 79.8%); for dyskinesia and somnolence, the incidence of ropinirole was higher (dyskinesia: 80.5%; somnolence: 69.4%); the incidence of adverse reaction of piribedil was higher on PD in terms of dizziness (67.0%); and the incidence of bromocriptine was relatively high in terms of constipation (62.3%). CONCLUSIONS: This mixed treatment comparison showed that the drugs ropinirole, bromocriptine, and piribedil produced the highest incidence rates of nausea, dyskinesia, hallucination, dizziness, constipation, and somnolence symptoms. Thus, we conclude that as these three drugs produced the most frequent symptoms, they are not recommended for the treatment of patients with Parkinson's disease. PMID- 28872218 TI - Adolescents' self-perceived and actual weight: Which plays a dominant role in weight loss behaviour in Lebanon? AB - BACKGROUND: The decision to lose weight among adolescents is complex and is guided by a number of body-related factors. This study examined the extent of agreement between actual weight, measured as body mass index, and self-perceived weight and assessed their relative importance in weight loss behaviour among Lebanese adolescents. METHODS: Data on 278 adolescents aged 13-17 years were drawn from the nationwide Nutrition and Non-Communicable Disease Risk Factor Survey (Lebanon, 2009). Binary multivariable logistic regressions were conducted to test associations with "effort to lose weight" as the outcome variable, controlling for a number of potential confounders. RESULTS: Close to 36% reported trying to lose weight. Around 21% and 13% were overweight and obese, respectively, and 40% and 10% perceived their weight as slightly high and very high, respectively. Inaccurate perceivers, those underestimating or overestimating their weight, constituted 39%, with overall percent agreement between actual and self-perceived weight being 60.8% (kappa statistic = 0.319, 95% CI [0.242, 0.396]). About a third of the overweight adolescents (30.5%) and more than half of the obese (56.8%) underestimated their weight. In the multivariable analysis, self-perceived weight was statistically significant and a stronger predictor of weight loss effort than body mass index (adjusted odds ratios = 14.42 and 6.42 for slightly high and very high perceived weight, respectively, compared to odds ratios = 1.47 and 2.31 for overweight and obese adolescents, respectively). CONCLUSION: Health professionals need to consider self-perceived weight in conjunction with actual weight in their pursuit of weight management goals and in planning prevention programmes that guide weight loss behaviours for adolescents. PMID- 28872220 TI - A REPORT FROM AUSTRALIA: WHEN A HUMAN LIFE HAS NOT YET BEGUN - ACCORDING TO THE LAW. PMID- 28872221 TI - FROM THE EDITORS. PMID- 28872219 TI - Characterization of sediment bacterial communities in plain lakes with different trophic statuses. AB - Sediment microbial communities play an important role in lake trophic status. This study determined millions of Illumina reads (16S rRNA gene amplicons) to compare the bacterial communities in moderately eutrophic, lightly eutrophic, and moderately trophic regions using a technically consistent approach. The results indicated that the sediments from moderately eutrophic and trophic lake had the higher bacterial diversity than lightly eutrophic lake. Proteobacteria was the most abundant phylum (22.7%-86.2%) across samples from three regions. The sediments from moderately eutrophic region were enriched with Chloroflexi and Nitrospirae. Alphaproteobacteria, Gammaproteobacteria, and Bacteroidetes were enriched in the sediments from lightly eutrophic lake. The sediments from moderately trophic lake contained a high abundance of Acidobacteria and Deltaproteobacteria because of the low pH of the sediments in this lake. In moderately eutrophic region, Nitrospira held an absolute predominance, while Lysobacter and Flavobacterium were the most predominant genera in lightly eutrophic region. Temperature was the main factor influencing the bacterial community in the three lakes. The bacterial communities in the sediment samples obtained from moderately eutrophic lake were associated with nutrient concentration, whereas organic matter and total nitrogen contents mainly influenced the bacterial communities in sediments obtained from lightly eutrophic lake and moderately trophic lake, respectively. PMID- 28872222 TI - PRINCIPAL/AGENT THEORY AND DECISIONMAKING IN HEALTH CARE. PMID- 28872223 TI - 'FROM THE MOMENT OF CONCEPTION...': THE VATICAN INSTRUCTION ON ARTIFICIAL PROCREATION TECHNIQUES. PMID- 28872224 TI - Birth weight, early life weight gain and age at menarche: a systematic review of longitudinal studies. AB - BACKGROUND AND OBJECTIVE: Adiposity in pre- and postnatal life may influence menarcheal age. Existing evidence is primarily cross-sectional, failing to address temporality, for which the role of adiposity in early life remains unclear. The current study sought to systematically review longitudinal studies evaluating the associations between birth weight and infant/childhood weight status/weight gain in relation to menarcheal age. METHODS: PubMed, EMBASE, Web of Science, Global Health (Ovid) and CINAHL were systematically searched. Selected studies were limited to English-language articles presenting multi-variable analyses. Seventeen studies reporting risk estimates for birth weight (n = 3), infant/childhood weight gain/weight status (n = 4) or both (n = 10), in relation to menarcheal age were included. RESULTS: Lower vs. higher birth weight was associated with earlier menarche in nine studies and later menarche in one study, while three studies reported a null association. Greater BMI or weight gain over time and greater childhood weight were significantly associated with earlier menarche in nine of nine and six of seven studies, respectively. CONCLUSIONS: Studies suggested that lower birth weight and higher body weight and weight gain in infancy and childhood may increase the risk of early menarche. The pre- and postnatal period may thus be an opportune time for weight control interventions to prevent early menarche, and its subsequent consequences. PMID- 28872225 TI - Left ventricular ejection time is an independent predictor of incident heart failure in a community-based cohort. AB - AIMS: Systolic time intervals change in the progress of cardiac dysfunction. The usefulness of left ventricular ejection time (LVET) to predict cardiovascular morbidity, however, is unknown. METHODS AND RESULTS: We studied middle-aged African-Americans from one of four cohorts of the Atherosclerosis Risk in Communities study (Jackson cohort, n=1980) who underwent echocardiography between 1993 and 1995. Left ventricular ejection time was measured by pulsed-wave Doppler of the left ventricular outflow tract and related to outcomes. A shorter LVET was associated with younger age, male sex, higher diastolic blood pressure, higher proportion of diabetes, higher heart rate, higher blood glucose levels and worse fractional shortening. During a median follow-up of 17.6 years, 384 (19%) had incident heart failure (HF), 158 (8%) had a myocardial infarction, and 587 (30%) died. In univariable analysis, a lower LVET was significantly associated with increased risk of all events (P<0.05 for all). However, after multivariable adjustment for age, sex, hypertension, diabetes, body mass index, heart rate, systolic and diastolic blood pressure, fractional shortening and left atrial diameter, LVET remained an independent predictor only of incident HF [hazard ratio 1.07 (1.02-1.14), P=0.010 per 10 ms decrease]. In addition, LVET provided incremental prognostic information to the known risk factors included in the Framingham risk score, in regard to predicting all outcomes except for myocardial infarction. CONCLUSION: Left ventricular ejection time is an independent predictor of incident HF in a community-based cohort and provides incremental prognostic information on the risk of future HF and death when added to known risk prediction models. PMID- 28872226 TI - Prebiopsy multiparametric MRI-based risk score for predicting prostate cancer in biopsy-naive men with prostate-specific antigen between 4-10 ng/mL. AB - BACKGROUND: Risk calculators have traditionally utilized serum prostate-specific antigen (PSA) values in addition to clinical variables to predict the likelihood of prostate cancer (PCa). PURPOSE: To develop a prebiopsy multiparametric MRI (mpMRI)-based risk score (RS) and a statistical equation for predicting the risk of PCa in biopsy-naive men with serum PSA between 4-10 ng/mL that may help reduce unnecessary biopsies. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: In all, 137 consecutive men with PSA between 4-10 ng/mL underwent prebiopsy mpMRI (diffusion-weighted [DW]-MRI and MR spectroscopic imaging [MRSI]) during 2009 2015 were recruited for this study. FIELD STRENGTH/SEQUENCE: 1.5T (Avanto, Siemens Health Care, Erlangen, Germany); T1 -weighted, T2 -weighted, DW-MRI, and MRSI sequences were used. ASSESSMENT: All eligible patients underwent mpMRI directed, cognitive-fusion transrectal ultrasound (TRUS)-guided biopsies. STATISTICAL TESTS: An equation model and an RS were developed using receiver operating characteristic (ROC) curve analysis and a multivariable logistic regression approach. A 10-fold crossvalidation and simulation analyses were performed to assess diagnostic performance of various combinations of mpMRI parameters. RESULTS: Of 137 patients, 32 were diagnosed with PCa on biopsy. Multivariable analysis, adjusted with positive pathology, showed apparent diffusion coefficient (ADC), metabolite ratio, and PSA as significant predictors of PCa (P < 0.05). A statistical equation was derived using these predictors. A simple 6-point mpMRI-based RS was derived for calculating the risk of PCa and it showed that it is highly predictive for PCa (odds ratio = 3.74, 95% confidence interval [CI]: 2.24-6.27, area under the curve [AUC] = 0.87). Both models (equation and RS) yielded high predictive performance (AUC >=0.85) on validation analysis. DATA CONCLUSION: A statistical equation and a simple 6-point mpMRI based RS can be used as a point-of-care tool to potentially help limit the number of negative biopsies in men with PSA between 4 and 10 ng/mL. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1227-1236. PMID- 28872227 TI - Elementspezifische Analyse einer Hyperpigmentierung infolge Levofloxacin Therapie. PMID- 28872228 TI - Pembrolizumab-induced hepatitis: diagnosis and treatment. PMID- 28872229 TI - Multiple Papeln und Tumoren an Kopf und Gesicht. PMID- 28872231 TI - Jahrestagung der Society for Dermatology in the Tropics e. V. in Dresden am 1. und 2. April 2017. PMID- 28872230 TI - Deutsches "Nationales Krebshilfe-Monitoring" 2015-2019 - Studienprotokoll und erste Ergebnisse. AB - HINTERGRUND UND ZIELE: Das Projekt "Nationales Krebshilfe-Monitoring zur Solariennutzung" (National Cancer Aid Monitoring of Tanning Bed Use, NCAM) ist eine deutsche Grobetastudie mit dem Ziel, die wichtigsten Risikofaktoren fur Hautkrebs zu beobachten: naturliches Sonnenlicht und kunstliche UV-Strahlung. TEILNEHMER UND METHODEN: NCAM ist eine bundesweite Querschnittstudie mit zunachst vier Runden der Datenerfassung (sogenannten Wellen) zwischen 2015 und 2018. Jedes Jahr wird eine bundesweit reprasentative Stichprobe aus 3.000 Personen im Alter von 14 bis 45 Jahren befragt. Die Querschnittsbefragung wird durch eine Kohorte von n = 450 aktuellen Solariennutzern erganzt. ERGEBNISSE: Die erste Welle im Jahr 2015 ergab eine Gesamtpravalenz der Solariennutzung von 29,5 %. Elf Prozent aller Teilnehmer hatten in den vergangenen zwolf Monaten ein Solarium genutzt. Zu den Determinanten der aktuellen Solariennutzung gehorten jungeres Alter, weibliches Geschlecht und Vollzeit-/Teilzeitbeschaftigung. Die hauptsachlichen Beweggrunde, die fur die Nutzung eines Solariums genannt wurden, waren Entspannung und Attraktivitatssteigerung. SCHLUSSFOLGERUNGEN: NCAM ist weltweit die erste Studie zur Uberwachung der Risikofaktoren fur Hautkrebs in jahrlichen Intervallen anhand einer grobetaen, landesweit reprasentativen Stichprobe. Erste Ergebnisse deuten darauf hin, dass Millionen Deutsche trotz Warnungen der WHO Solarien nutzen, und dass viele dieser Nutzer Jugendliche sind - trotz gesetzlicher Beschrankungen, die das Ziel haben, die Nutzung von Solarien durch Minderjahrige zu verhindern. PMID- 28872232 TI - Prognose der erworbenen idiopathischen generalisierten Anhidrose. PMID- 28872235 TI - Ausschreibung Forschungspreis Alopecia areata. PMID- 28872234 TI - Element-specific analysis of a hyperpigmentation caused by levofloxacin therapy. PMID- 28872233 TI - Update on the clinical use of kinase inhibitors in melanoma. AB - The identification of targetable molecules in cellular signaling pathways represents a milestone in the treatment of melanoma. Selective inhibitors of these molecules, known as phosphokinases, allow for individual signaling pathways to be "switched off". This is of particular importance for tumors in which these pathways are constitutively activated by mutations in genes encoding said molecules. Especially patients with BRAF-mutated melanomas significantly benefit from kinase inhibitor therapies, with the current standard of combined BRAF and MEK inhibition providing very good long-term disease control. Such regimens have been shown to achieve a progression-free survival of more than ten months and an overall survival of more than two years, along with good quality of life. Given that the majority of patients develop secondary resistance during long-term kinase inhibitor therapy, current clinical trials are geared towards finding suitable drug combinations including inhibitors of other signaling pathways as well as immune checkpoint inhibitors. The present review highlights targeted therapies for melanoma currently available as well as potential future options presently under clinical investigation. PMID- 28872237 TI - Anagener Haarverlust, Anti-Desmoglein 1 und Pemphigus Disease Area Index: Ein signifikanter Zusammenhang? PMID- 28872238 TI - 1 * 1 der Dermatohistologie. Teil 2 - Tumoren der Haut. AB - In diesem CME-Artikel werden histopathologische Grundkenntnisse der haufigsten Hauttumoren (epidermal, adnexiell, melanozytar, mesenchymal), deren labortechnische Aufarbeitung sowie der Stellenwert immunhistochemischer und molekularer Zusatzuntersuchungen zusammengefasst. Dies soll dem erfahrenen Kliniker bei der Wahl der richtigen Entnahmetechnik und der Interpretation der histopathologischen Befundberichte behilflich sein und in dermatologischer Weiterbildung befindlichen Arzten ein besseres Verstandnis der Dermatohistologie vermitteln. Ahnlich wie bei den entzundlichen Dermatosen sind auch in der Diagnostik von Hauttumoren Kliniker und Dermatohistopathologen aufeinander angewiesen und konnen die Qualitat der Diagnostik und der daraus resultierenden therapeutischen Verstandnisbasis deutlich verbessern. PMID- 28872239 TI - Kongresskalender 2017. PMID- 28872240 TI - Spiny keratoderma of the palms and soles - once seen, never forgotten. PMID- 28872241 TI - Anagen hair loss, anti-desmoglein 1, and pemphigus disease area index: a significant relationship? PMID- 28872242 TI - Kutane kollagene Vaskulopathie - Remission der perivaskularen Depositionen nach Farbstofflasertherapie. PMID- 28872243 TI - Pyogenes CD30-positives grobetazelliges anaplastisches T-Zell-Lymphom: Spontane Remission bei einem jungen Erwachsenen. PMID- 28872244 TI - Durch Pembrolizumab verursachte Hepatitis: Diagnose und Behandlung. PMID- 28872245 TI - Symmetrische entzundliche, erosive Plaques und Blasen bei einem Saugling. PMID- 28872246 TI - Juckende erythematose Papeln und braunliche Maculae an Rumpf und Beinen. PMID- 28872248 TI - Hereditare Hauterkrankungen - Klinisch und genetisch heterogen. PMID- 28872247 TI - Update zum klinischen Einsatz von Inhibitoren mutierter Phosphokinasen beim Melanom. AB - Die Behandlungsstrategie beim metastasierten Melanom hat sich mit der Identifizierung therapeutisch angreifbarer molekularer Zielstrukturen innerhalb zellularer Signalwege radikal geandert. Durch die Zulassung von Substanzen, die gezielt an den zentralen Schaltmolekulen, den Phosphokinasen, angreifen, konnen diese Signalwege selektiv abgeschaltet werden. Dies ist insbesondere bei denjenigen Tumoren von Interesse, deren Signalwege durch aktivierende Mutationen der fur die Schaltmolekule kodierenden Gene konstitutiv aktiviert sind. Aktuell ist diese therapeutische Strategie insbesondere fur Patienten bedeutsam, deren Melanome eine Mutation im BRAF-Gen aufweisen. Diese Patienten konnen durch eine Kombinationstherapie aus Inhibitoren der Phosphokinasen BRAF und MEK langfristig mit sehr guter Krankheitskontrolle behandelt werden. Unter dieser Kombinationstherapie wird aktuell ein progressionsfreies Uberleben von uber zehn Monaten und ein Gesamtuberleben von mehr als zwei Jahren bei guter Lebensqualitat erzielt. Da unter langerfristiger Therapie mit Kinaseinhibitoren jedoch bei einem Grobetateil der Patienten eine Resistenzbildung auftritt, sind aktuelle klinische Therapiestudien auf die Suche nach geeigneten Kombinationspartnern unter Blockierung anderer Signalwege oder unter Aktivierung der T-Zell-vermittelten Immunantwort ausgerichtet. Der vorliegende Ubersichtsartikel stellt sowohl die aktuell verfugbaren als auch die in der klinischen Testung befindlichen zukunftigen Optionen der zielgerichteten Therapie des Melanoms dar. PMID- 28872249 TI - Spiny Keratoderma der Hand- und Fubetaflachen - einmal gesehen, nie wieder vergessen. PMID- 28872250 TI - Forschungspreis zur Forderung der experimentellen Dermatologie - Deutsche Dermatologische Gesellschaft verleiht Oscar-Gans-Preis. PMID- 28872251 TI - Room temperature synthesis and binding studies of solution-processable histamine imprinted microspheres. AB - Accurate quantification of histamine levels in food and in biological samples is important for monitoring the quality of food products and for the detection of pathophysiological conditions. In this study, solution processable histamine imprinted microspheres were synthesized at 30 degrees C via dilute free radical phototochemical polymerization technique using ethylene glycol dimethacrylate (EGDMA) as the crosslinker and methacrylic acid (MAA) as the monomer. The processability of the resulting polymer is dictated by the monomer feed concentration (eg, 4 wt% 80:20 EGDMA:MAA formulation) and solvent (acetonitrile). Whereas, the particle size is influenced by the monomer feed concentration, the presence of template molecule, and independent of the crosslinker content. Evaluation of the binding performance of the photochemically imprinted polymers (PCP) with different crosslinker content (80 and 90 wt%) indicated that the selective binding capacity was notably higher in PCP-80 (N= 16.0 MUmol/g) compared to PCP-90 (N= 10.1 MUmol/g) when analyzed via frontal analysis capillary electrophoresis (FACE) using Freundlich isotherm. In addition, PCP-80 microspheres are more selective toward histamine than conventional thermal polymers (CTP-80) prepared at 60 degrees C in the presence of structural analogs such as histidine, imidazole, and tryptamine under cross-rebinding and competitive conditions. These results demonstrated that histamine-selective imprinted polymers can be obtained readily using room temperature photochemical polymerization where these materials can be subsequently used as recognition element for optical-based histamine sensing. PMID- 28872252 TI - Nursing leadership challenges and opportunities. PMID- 28872253 TI - Genome-wide scans between two honeybee populations reveal putative signatures of human-mediated selection. AB - Human-mediated selection has left signatures in the genomes of many domesticated animals, including the European dark honeybee, Apis mellifera mellifera, which has been selected by apiculturists for centuries. Using whole-genome sequence information, we investigated selection signatures in spatially separated honeybee subpopulations (Switzerland, n = 39 and France, n = 17). Three different test statistics were calculated in windows of 2 kb (fixation index, cross-population extended haplotype homozygosity and cross-population composite likelihood ratio) and combined into a recently developed composite selection score. Applying a stringent false discovery rate of 0.01, we identified six significant selective sweeps distributed across five chromosomes covering eight genes. These genes are associated with multiple molecular and biological functions, including regulation of transcription, receptor binding and signal transduction. Of particular interest is a selection signature on chromosome 1, which corresponds to the WNT4 gene, the family of which is conserved across the animal kingdom with a variety of functions. In Drosophila melanogaster, WNT4 alleles have been associated with differential wing, cross vein and abdominal phenotypes. Defining phenotypic characteristics of different Apis mellifera ssp., which are typically used as selection criteria, include colour and wing venation pattern. This signal is therefore likely to be a good candidate for human mediated-selection arising from different applied breeding practices in the two managed populations. PMID- 28872254 TI - Prevalence odds ratio versus prevalence ratio: choice comes with consequences. PMID- 28872255 TI - A multiple imputation strategy for sequential multiple assignment randomized trials. PMID- 28872256 TI - Deformation strain is the main physical driver for skeletal precursors to undergo osteogenesis in earlier stages of osteogenic cell maturation. AB - Mesenchymal stem cells play a major role during bone remodelling and are thus of high interest for tissue engineering and regenerative medicine applications. Mechanical stimuli, that is, deformation strain and interstitial fluid-flow induced shear stress, promote osteogenic lineage commitment. However, the predominant physical stimulus that drives early osteogenic cell maturation is not clearly identified. The evaluation of each stimulus is challenging, as deformation and fluid-flow-induced shear stress interdepend. In this study, we developed a bioreactor that was used to culture mesenchymal stem cells harbouring a strain-responsive AP-1 luciferase reporter construct, on porous scaffolds. In addition to the reporter, mineralization and vitality of the cells was investigated by alizarin red staining and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide. Quantification of the expression of genes associated to bone regeneration and bone remodelling was used to confirm alizarin red measurements. Controlled perfusion and deformation of the 3-dimensional scaffold facilitated the alteration of the expression of osteogenic markers, luciferase activity, and calcification. To isolate the specific impact of scaffold deformation, a computational model was developed to derive a perfusion flow profile that results in dynamic shear stress conditions present in periodically loaded scaffolds. In comparison to actually deformed scaffolds, a lower expression of all measured readout parameters indicated that deformation strain is the predominant stimulus for skeletal precursors to undergo osteogenesis in earlier stages of osteogenic cell maturation. PMID- 28872257 TI - Acellular dermal matrix scaffolds coated with connective tissue growth factor accelerate diabetic wound healing by increasing fibronectin through PKC signalling pathway. AB - The regional injection of connective tissue growth factor (CTGF) for diabetic wound healing requires multiple components and results in a substantial loss of its biological activity. Acellular dermal matrix (ADM) scaffolds are optimal candidates for delivering these factors to local ischaemic environments. In this study, we explored whether CTGF loaded on ADM scaffolds can enhance fibronectin (FN) expression to accelerate diabetic wound healing via the protein kinase C (PKC) signalling pathway. The performance of CTGF and CTGF + PKC inhibitor, which were loaded on ADM scaffolds to treat dorsal skin wounds in streptozotocin induced diabetic mice, was evaluated with naked ADM as a control. Wound closure showed that ADM scaffolds loaded with CTGF induced greater diabetic wound healing in the early stage of the wound in diabetic mice. Moreover, ADM scaffolds loaded with CTGF obviously increased the expression of FN both at the mRNA and protein levels, whereas the expression of FN was significantly reduced in the inhibitor group. Furthermore, the ADM + CTGF group, which produce FN, obviously promoted alpha-smooth muscle actin and transforming growth factor-beta expression and enhanced neovasculature and collagen synthesis at the wound sites. ADM scaffolds loaded with CTGF + PKC inhibitor delayed diabetic wound healing, indicating that FN expression was mediated by the PKC signalling pathway. Our findings offer new perspectives for the treatment of diabetic wound healing and suggest a rationale for the clinical evaluation of CTGF use in diabetic wound healing. PMID- 28872258 TI - Conidia of Penicillium rubens formed at low water activities can attract more water. AB - To address the problem of indoor fungal growth, understanding the influence of moisture conditions on the fungal colonization process is crucial. This paper explores the influence of past moisture conditions on current processes. Specifically, it studies the growth and water sorption of conidia of Penicillium rubens formed at lower water activities (ranging from 0.86 to 0.99). For the first time, dynamic vapor sorption (DVS) is applied as a tool to quantify the water sorption of conidia as a function of the water activity at conidiation. Furthermore, growth experiments on agar and gypsum substrates are reported that relate hyphal growth rates of the mycelium from pretreated conidia to the water activity at conidiation. No effect of the conidiation water activity on mycelial growth rates is found on either gypsum or agar. It is found, however, that conidia formed at lower activities have a higher dry weight and attract more water from humid air. It is shown that both phenomena can be explained by conidia from lower activities carrying higher amounts of compatible solutes, glycerol in particular. The enhanced sorption observed in this study might constitute a mechanism through which solute reserves contribute to survival during the early steps of fungal colonization. PMID- 28872263 TI - ESCP President's Report. PMID- 28872259 TI - Prevalence and prognostic importance of precipitating factors leading to heart failure hospitalization: recurrent hospitalizations and mortality. AB - AIMS: Hospitalizations for heart failure (HF) are common and are associated with significant morbidity, mortality and cost. However, precipitating factors leading to HF hospitalization and their importance with respect to subsequent outcomes are not well understood. METHODS AND RESULTS: The symptoms and signs present at admission and investigator-identified factors thought to have contributed to the first adjudicated HF hospitalization in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) programme were prospectively collected and stratified by ejection fraction (EF). Potential precipitants were collected using a specifically designed case report form and categorized according to the presence of cardiovascular (CV), non-CV and unknown factors. Associations between these factors and subsequent rehospitalization and mortality rates were examined. Of 1668 patients who experienced HF hospitalization, 1152 had reduced EF (<=40%, HFrEF) and 516 had preserved EF (HFpEF). Overall, 54% had CV, 32% had non-CV and 14% had unknown factors thought to have precipitated HF, with similar proportions in the HFrEF and HFpEF groups. The most common precipitants were arrhythmia (15%), other non-CV factors (11%) and respiratory infection (10%). Subsequent CV readmission rates were highest in those whose initial HF hospitalization was precipitated by CV factors. However, mortality rates were similar among patients with any of the three categories of precipitating factors. Results were similar in HFrEF and HFpEF. CONCLUSIONS: Among chronic HF patients hospitalized for decompensation, the investigator reported precipitating factor was not associated with the subsequent mortality rate, but was associated with type of readmission: readmissions for CV reasons were more likely when the index precipitant was CV. PMID- 28872265 TI - Universal testing of colorectal cancer for deficient mismatch repair - a new era has arrived. PMID- 28872266 TI - Corrigendum: Biosynthetic Gene Cluster for Surugamide A Encompasses an Unrelated Decapeptide, Surugamide F. PMID- 28872267 TI - Psychological Pain in Suicidality: A Meta-Analysis. AB - OBJECTIVE: Perform a meta-analysis to quantify the association between psychological pain and current or lifetime history of suicidal ideation or suicide attempt. DATA SOURCES: Search MEDLINE, Web of Science, and PsycINFO from 1965 to 2015 for (psychache OR mental pain OR psychological pain) AND (suicid*). STUDY SELECTION: Observational case-control studies addressing the difference in psychological pain between individuals with and without current or lifetime history of suicidal ideation or suicide attempt. DATA EXTRACTION: Data were independently extracted into a standard electronic form. All authors were contacted for unpublished data related to current or lifetime history of suicide ideation or attempt. DATA SYNTHESIS: Twenty studies were included. Comparisons concerned 760 subjects with versus 8,803 subjects without lifetime history of suicide attempt; 344 subjects with versus 357 patients without current suicide attempt; 262 patients with versus 64 patients without lifetime history of suicidal ideation; and 551 subjects with versus 7,383 subjects without current suicidal ideation. The intensity of psychological pain was higher (1) in both subjects with lifetime history of suicide attempts and subjects with current suicide attempts versus without (effect sizes = 0.72, P < 10-2 and 0.66, P < 10 2, respectively) and (2) in both subjects with lifetime history of suicide ideation and subjects with current suicidal ideation versus without (effect sizes = 1.49, P = .01 and 1.15, P < 10-2, respectively). Association between psychological pain and suicidality remained significant even when depression levels were not different between subjects. CONCLUSIONS: Higher psychological pain levels are associated with suicidal ideation and acts. Considering psychological pain to be at the core of suicidality is important for daily clinical practice and for the promotion of innovative therapeutic strategies for suicide prevention. PMID- 28872268 TI - Risk of Suicide Attempts Among Adolescents and Young Adults With Autism Spectrum Disorder: A Nationwide Longitudinal Follow-Up Study. AB - BACKGROUND: Previous studies reported a high prevalence of depression among patients with autism spectrum disorder (ASD) and suggested a relationship between ASD and suicidality. However, whether ASD independently increases the risk of attempted suicide regardless of depression has not been determined. METHODS: Using the Taiwan National Health Insurance Research Database, 5,618 adolescents aged 12-17 years and young adults aged 18-29 years with ASD (ICD-9-CM code: 299) and 22,472 age- and sex-matched controls were enrolled between 2001 and 2009 and followed to the end of 2011. Any suicide attempt was identified during the follow up period. RESULTS: Patients with ASD had a higher incidence of suicide attempts (3.9% vs 0.7%, P < .001) than did those without ASD. Both adolescents (HR = 5.79; 95% CI, 3.98-8.41) and young adults (HR = 5.38; 95% CI, 3.58-8.06) with ASD were more likely to attempt suicide in later life after adjusting for demographic data and psychiatric comorbidities. Sensitivity analyses after excluding the first year (HR = 4.52; 95% CI, 3.39-6.03) or first 3 years (HR = 3.36; 95% CI, 2.40 4.70) of observation showed consistent findings. CONCLUSIONS: Patients with ASD had an increased risk of suicide attempts compared with those without ASD. ASD was an independent risk factor of attempted suicide. Further studies are needed to clarify the underlying pathophysiology between ASD and suicidality and to elucidate whether prompt intervention for ASD may reduce this risk. PMID- 28872269 TI - Clinical outcomes in children and adolescents initiating antiretroviral therapy in decentralized healthcare settings in Zimbabwe. AB - INTRODUCTION: Decentralized HIV care for adults does not appear to compromise clinical outcomes. HIV care for children poses additional clinical and social complexities. We conducted a prospective cohort study to investigate clinical outcomes in children aged 6-15 years who registered for HIV care at seven primary healthcare clinics (PHCs) in Harare, Zimbabwe. METHODS: Participants were recruited between January 2013 and December 2014 and followed for 18 months. Rates of and reasons for mortality, hospitalization and unscheduled PHC attendances were ascertained. Cox proportional modelling was used to determine the hazard of death, unscheduled attendances and hospitalization. RESULTS: We recruited 385 participants, median age 11 years (IQR: 9-13) and 52% were female. The median CD4 count was 375 cells/mm3 (IQR: 215-599) and 77% commenced ART over the study period, with 64% of those who had viral load measured achieving an HIV viral load <400 copies/ml. At 18 months, 4% of those who started ART vs. 24% of those who remained ART-naive were lost-to-follow-up (p < 0.001). Hospitalization and mortality rates were low (8.14/100 person-years (pyrs) and 2.86/100 pyrs, respectively). There was a high rate of unscheduled PHC attendances (34.94/100 pyrs), but only 7% resulted in hospitalization. Respiratory disease was the major cause of hospitalization, unscheduled attendances and death. CD4 count <350cells/mm3 was a risk factor for hospitalization (aHR 3.6 (95%CI 1.6-8.2)). CONCLUSIONS: Despite only 64% of participants achieving virological suppression, clinical outcomes were good and high rates of retention in care were observed. This demonstrates that in an era moving towards differentiated care in addition to implementation of universal treatment, decentralized HIV care for children is achievable. Interventions to improve adherence in this age-group are urgently needed. PMID- 28872270 TI - A public health approach to addressing and preventing misdiagnosis in the scale up of HIV rapid testing programmes. PMID- 28872271 TI - To err is human, to correct is public health: a systematic review examining poor quality testing and misdiagnosis of HIV status. AB - INTRODUCTION: In accordance with global testing and treatment targets, many countries are seeking ways to reach the "90-90-90" goals, starting with diagnosing 90% of all people with HIV. Quality HIV testing services are needed to enable people with HIV to be diagnosed and linked to treatment as early as possible. It is essential that opportunities to reach people with undiagnosed HIV are not missed, diagnoses are correct and HIV-negative individuals are not inadvertently initiated on life-long treatment. We conducted this systematic review to assess the magnitude of misdiagnosis and to describe poor HIV testing practices using rapid diagnostic tests. METHODS: We systematically searched peer reviewed articles, abstracts and grey literature published from 1 January 1990 to 19 April 2017. Studies were included if they used at least two rapid diagnostic tests and reported on HIV misdiagnosis, factors related to potential misdiagnosis or described quality issues and errors related to HIV testing. RESULTS: Sixty four studies were included in this review. A small proportion of false positive (median 3.1%, interquartile range (IQR): 0.4-5.2%) and false negative (median: 0.4%, IQR: 0-3.9%) diagnoses were identified. Suboptimal testing strategies were the most common factor in studies reporting misdiagnoses, particularly false positive diagnoses due to using a "tiebreaker" test to resolve discrepant test results. A substantial proportion of false negative diagnoses were related to retesting among people on antiretroviral therapy. Conclusions HIV testing errors and poor practices, particularly those resulting in false positive or false negative diagnoses, do occur but are preventable. Efforts to accelerate HIV diagnosis and linkage to treatment should be complemented by efforts to improve the quality of HIV testing services and strengthen the quality management systems, particularly the use of validated testing algorithms and strategies, retesting people diagnosed with HIV before initiating treatment and providing clear messages to people with HIV on treatment on the risk of a "false negative" test result. PMID- 28872272 TI - Understanding low sensitivity of community-based HIV rapid testing: experiences from the HPTN 071 (PopART) trial in Zambia and South Africa. AB - INTRODUCTION: Population-wide HIV testing services (HTS) must be delivered in order to achieve universal antiretroviral treatment (ART) coverage. To accurately deliver HTS at such scale, non-facility-based HIV point-of-care testing (HIV POCT) is necessary but requires rigorous quality assurance (QA). This study assessed the performance of community-wide HTS in Zambia and South Africa (SA) as part of the HPTN 071 (PopART) study and explores the impact of quality improvement interventions on HTS performance. METHODS: Between 2014 and 2016, HIV POCT was undertaken within households both as part of the randomly selected HPTN 071 research cohort (Population Cohort [PC]) and as part of the intervention provided by community HIV-care providers. HIV-POCT followed national algorithms in both countries. Consenting PC participants provided a venous blood sample in addition to being offered HIV-POCT. We compared results obtained in the PC using a laboratory-based gold standard (GS) testing algorithm and HIV-POCT. Comprehensive QA mechanisms were put in place to support the community-wide testing. Participants who were identified as having a false negative or false positive HIV rapid test were revisited and offered retesting. RESULTS: We initially observed poor sensitivity (45-54%, 95% confidence interval [CI] 31-69) of HIV-POCT in the PC in SA compared to sensitivity in Zambia for the same time period of 95.8% (95% CI 93-98). In both countries, specificity of HIV-POCT was >98%. With enhanced QA interventions and adoption of the same HIV-POCT algorithm, sensitivity in SA improved to a similar level as in Zambia. CONCLUSIONS: This is one of the first reports of HIV-POCT performance during wide-scale delivery of HTS compared to a GS laboratory algorithm. HIV-POCT in a real-world setting had a lower sensitivity than anticipated. Appropriate choice of HIV-POCT algorithms, intensive training and supervision, and robust QA mechanisms are necessary to optimize HIV-POCT test performance when testing is delivered at a community level. HIV-POCT in clients who did not disclose that they were on ART may have contributed to false negative HIV-POCT results and should be the topic of future research. PMID- 28872273 TI - Identification of misdiagnosed HIV clients in an Early Access to ART for All implementation study in Swaziland. AB - INTRODUCTION: Rapid diagnostic testing has made HIV diagnosis and subsequent treatment more accessible. However, multiple factors, including improper implementation of testing strategies and clerical errors, have been reported to lead to HIV misdiagnosis. The World Health Organization has recommended HIV retesting prior to antiretroviral therapy (ART) initiation which has become pertinent with scaling up of Early Access to ART for All (EAAA). In this analysis, misdiagnosed clients are identified from a subgroup of clients enrolled in EAAA implementation study in Swaziland. METHODS: The subgroup to assess misdiagnosis was identified from enrolled EAAA study clients, who had an undetectable viral load prior to ART initiation between September 1, 2014 and May 31, 2016. One hundred and five of 2533 (4%) clients had an undetectable viral load prior to initiation to ART (pre-ART). The HIV status of clients was confirmed using the Determine HIV 1/2 and Uni-Gold HIV 1/2 rapid tests performed serially as recommended by the national testing algorithm. The status of clients on ART was additionally confirmed by fourth-generation HIV Ag/Ab combo tests, Architect and Genscreen Ultra. RESULTS: Fourteen of the 105 (13%) clients were false positive (HIV negative) on confirmation testing, of whom five (36%) were still in pre-ART care, while nine (64%) were in ART care. Overall, proportion of false positive was 0.6% (14/2533). The false-positive clients had a median CD4 of 791 cells/ml (interquartile range (IQR): 628, 967) compared to 549 cells/ml (IQR: 387, 791) for true positives (HIV positive) (p = 0.0081) and were nearly 20 years older (p = 0.0008). CONCLUSIONS: Overall 0.6% of all enrolled EAAA clients were misdiagnosed, and 64% of misdiagnosed clients were initiated on ART. With adoption of EAAA guidelines by national governments, ART initiation regardless of immunological criteria, strengthening of proficiency testing and adoption of retesting prior to ART initiation would allow identification of misdiagnosed clients and further reduce potential of initiating misdiagnosed clients on ART. PMID- 28872274 TI - Misdiagnosis of HIV infection during a South African community-based survey: implications for rapid HIV testing. AB - INTRODUCTION: We describe the overall accuracy and performance of a serial rapid HIV testing algorithm used in community-based HIV testing in the context of a population-based household survey conducted in two sub-districts of uMgungundlovu district, KwaZulu-Natal, South Africa, against reference fourth-generation HIV 1/2 antibody and p24 antigen combination immunoassays. We discuss implications of the findings on rapid HIV testing programmes. METHODS: Cross-sectional design: Following enrolment into the survey, questionnaires were administered to eligible and consenting participants in order to obtain demographic and HIV-related data. Peripheral blood samples were collected for HIV-related testing. Participants were offered community-based HIV testing in the home by trained field workers using a serial algorithm with two rapid diagnostic tests (RDTs) in series. In the laboratory, reference HIV testing was conducted using two fourth-generation immunoassays with all positives in the confirmatory test considered true positives. Accuracy, sensitivity, specificity, positive predictive value, negative predictive value and false-positive and false-negative rates were determined. RESULTS: Of 10,236 individuals enrolled in the survey, 3740 were tested in the home (median age 24 years (interquartile range 19-31 years), 42.1% males and HIV positivity on RDT algorithm 8.0%). From those tested, 3729 (99.7%) had a definitive RDT result as well as a laboratory immunoassay result. The overall accuracy of the RDT when compared to the fourth-generation immunoassays was 98.8% (95% confidence interval (CI) 98.5-99.2). The sensitivity, specificity, positive predictive value and negative predictive value were 91.1% (95% CI 87.5 93.7), 99.9% (95% CI 99.8-100), 99.3% (95% CI 97.4-99.8) and 99.1% (95% CI 98.8 99.4) respectively. The false-positive and false-negative rates were 0.06% (95% CI 0.01-0.24) and 8.9% (95% CI 6.3-12.53). Compared to true positives, false negatives were more likely to be recently infected on limited antigen avidity assay and to report antiretroviral therapy (ART) use. CONCLUSIONS: The overall accuracy of the RDT algorithm was high. However, there were few false positives, and the sensitivity was lower than expected with high false negatives, despite implementation of quality assurance measures. False negatives were associated with recent (early) infection and ART exposure. The RDT algorithm was able to correctly identify the majority of HIV infections in community-based HIV testing. Messaging on the potential for false positives and false negatives should be included in these programmes. PMID- 28872275 TI - False-negative HIV tests using oral fluid tests in children taking antiretroviral therapy from Harare, Zimbabwe. AB - INTRODUCTION: Rapid diagnostic tests (RDT) for HIV infection have high sensitivity and specificity, but in the setting of longstanding antiretroviral therapy (ART), can give false results that can lead to misinterpretation, confusion and inadequate management. The objective of this study was to evaluate the proportion of falsely negative results of a RDT performed on oral fluid in HIV-infected children on longstanding ART. METHODS: One hundred and twenty-nine children with known HIV infection and receiving ART were recruited from the HIV Clinic at the Harare Central Hospital, Zimbabwe. HIV testing was performed on oral fluid and on finger-stick blood. RESULTS AND DISCUSSION: Children included in the study had a median age of 12 years (IQR 10-14) and 67 (51.9%) were female. Median age at HIV diagnosis was 5 years (IQR 3-6) and the median time on ART was 6.3 years (IQR 4.3-8.1). The oral fluid test was negative in 11 (8.5%) patients and indeterminate in 2 (1.6%). Finger-stick blood test was negative in 1 patient. Patients with a negative oral fluid test had a higher CD4 cell count (967 vs. 723 cells/mm3, p = 0.016) and a longer time on ART (8.5 vs. 6 years, p = 0.016). CONCLUSIONS: This study found that a substantial proportion of false-negative HIV test results in children on longstanding ART when using an oral fluid test. This could lead to misinterpretation of HIV test results and in the false perception of cure or delayed diagnosis. PMID- 28872276 TI - Prevalence and outcomes of HIV-1 diagnostic challenges during universal birth testing - an urban South African observational cohort. AB - INTRODUCTION: HIV-1 polymerase chain reaction (PCR) testing at birth aims to facilitate earlier initiation of antiretroviral therapy (ART) for HIV-infected neonates. Data from two years of universal birth testing implementation in a high burden South African urban setting are presented to demonstrate the prevalence and outcomes of diagnostic challenges in this context. METHODS: HIV-exposed neonates born at Rahima Moosa Mother and Child Hospital between 5 June 2014 and 31 August 2016 were routinely screened at birth for HIV-1 on whole blood samples using the COBAS(r) AmpliPrep/COBAS(r) TaqMan (CAP/CTM) HIV-1 Qualitative Test, version 2.0 (Roche Molecular Systems, Inc., Branchburg, NJ, USA). Virological results were interpreted according to standard operating procedures with the South African National Health Laboratory Service. All neonates with non-negative results were actively followed-up and categorized according to HIV infection status as positive, negative, uncertain and lost to follow-up (LTFU). RESULTS: 104 (1.8%) of 5743 HIV-exposed neonates received a non-negative birth PCR result, for which laboratory data were available for 102 (98%) cases - 78 (76%) tested positive and 24 (24%) indeterminate. HIV infection status was confirmed positive in 83 (81%) infants, negative in 8 (8%), uncertain in 5 (5%) and LTFU in 6 (6%) cases. The positive predictive value (excluding cases of uncertain diagnosis and inadequate testing) following a non-negative HIV-1 PCR screening test at birth was 0.91 (83/91; 95% confidence interval: 0.85-0.96). Neonates testing positive at birth had significantly higher viral load (VL) results than those testing indeterminate at birth of 4.5 and 3.0 log copies/ml (p = 0.0007), respectively. Similarly, mothers of neonates with positive as compared to indeterminate birth test results had higher VLs of 4.5 and 2.7 log copies/ml (p = 0.0013), respectively. Half of neonates with an indeterminate birth test were shown to be HIV-infected on subsequent confirmatory testing, with time to final diagnosis 30 days longer for these neonates (p < 0.0001). CONCLUSION: Indeterminate HIV-1 PCR results accounted for a quarter of non-negative results at birth and were associated with a high risk of infection in comparison to the risk of in utero transmission. Indeterminate birth results with positive HIV PCR results on repeat testing were associated with later final diagnosis. The HIV-1 status remains uncertain in a minority of cases because of repeatedly indeterminate results, highlighting the need for more sensitive and specific virological tests. PMID- 28872278 TI - HIV misdiagnosis in paediatrics: unpacking the complexity. PMID- 28872277 TI - Misdiagnosed HIV infection in pregnant women initiating universal ART in South Africa. AB - INTRODUCTION: Rapid diagnostic tests (RDTs) are the primary diagnostic tools for HIV used in resource-constrained settings. Without a proper confirmation algorithm, there is concern that false-positive (FP) RDTs could result in misdiagnosis of HIV infection and inappropriate antiretroviral treatment (ART) initiation, but programmatic data on FP are few. METHODS: We examined the accuracy of RDT diagnosis among HIV-infected pregnant women attending public sector antenatal services in Cape Town, South Africa. We describe the proportion of women found to have started on ART erroneously due to FP RDT results based on pre-ART viral load (VL) testing and enzyme-linked immunosorbent assay (ELISA). RESULTS: We analysed 952 consecutively enrolled pregnant women diagnosed as HIV infected based on two RDTs per local guideline and found 4.5% (43/952) of pre-ART VL results to be <50 copies/ml. After excluding 6 women who had detectable virus on subsequent VL measurements, ELISA was performed on the 37 remaining women. Of these, 3/952 (0.3%) HIV RDT diagnoses were found to be FP. We estimate that using ELISA to confirm all positive RDTs would cost $1110 (uncertainty interval $381 $5382) to identify one patient erroneously initiated on ART, while it costs $3912 for a lifetime of antiretrovirals with VL monitoring for one person. CONCLUSIONS: Compared to the cost of confirming the RDT-based diagnoses, the cost of HIV misdiagnosis is high. While testing programmes based on RDT should strive for constant quality improvement, where resources permit, laboratory confirmation algorithms can play an important role in strengthening the quality of HIV diagnosis in the era of universal ART. PMID- 28872279 TI - HIV point of care diagnosis: preventing misdiagnosis experience from a pilot of rapid test algorithm implementation in selected communes in Vietnam. AB - INTRODUCTION: In Vietnam, HIV testing services had been available only at provincial and district health facilities, but not at the primary health facilities. Consequently, access to HIV testing services had been limited especially in rural areas. In 2012, Vietnam piloted decentralization and integration of HIV services at commune health stations (CHSs). As a part of this pilot, a three-rapid test algorithm was introduced at CHSs. The objective of this study was to assess the performance of a three-rapid test algorithm and the implementation of quality assurance measures to prevent misdiagnosis, at primary health facilities. METHODS: The three-rapid test algorithm (Determine HIV-1/2, followed by ACON HIV 1/2 and DoubleCheckGold HIV 1&2 in parallel) was piloted at CHSs from August 2012 to December 2013. Commune health staff were trained to perform HIV testing. Specimens from CHSs were sent to the provincial confirmatory laboratory (PCL) for confirmatory and validation testing. Quality assurance measures were undertaken including training, competency assessment, field technical assistance, supervision and monitoring and external quality assessment (EQA). Data on HIV testing were collected from the testing logbooks at commune and provincial facilities. Descriptive analysis was conducted. Sensitivity and specificity of the rapid testing algorithm were calculated. RESULTS: A total of 1,373 people received HIV testing and counselling (HTC) at CHSs. Eighty people were diagnosed with HIV infection (5.8%). The 755/1244 specimens reported as HIV negative at the CHS were sent to PCL and confirmed as negative, and all 80 specimens reported as HIV positive at CHS were confirmed as positive at the PCL. Forty-nine specimens that were reactive with Determine but negative with ACON and DoubleCheckGold at the CHSs were confirmed negative at the PCL. The results show this rapid test algorithm to be 100% sensitive and 100% specific. Of 21 CHSs that received two rounds of EQA panels, 20 CHSs submitted accurate results. CONCLUSIONS: Decentralization of HIV confirmatory testing to CHS is feasible in Vietnam. The results obtained from this pilot provided strong evidence of the feasibility of HIV testing at primary health facilities. Quality assurance measures including training, competency assessment, regular monitoring and supervision and an EQA scheme are essential for prevention of misdiagnosis. PMID- 28872282 TI - Changes in bacterial flora and antibiotic resistance in clinical samples isolated from patients hospitalized in the Military Institute of Medicine in Warsaw, Poland, between 2005-2012 AB - BACKGROUND: Hospital infections have become an important problem. Knowledge of microbiological situations both helps in ensuring that the optimal choice of antibacterial treatment is made, and in improving the results of the selected therapy. OBJECTIVE: In this paper, both the changes in the bacterial flora of patients hospitalized in the Military Institute of Medicine, and the bacterial resistance to antimicrobials were analyzed. MATERIAL AND METHODS: Data were collected between 2005 and 2012. The identification and testing of pathogens, susceptibility tests, and analysis of bacterial resistance mechanisms to antibiotics were performed according to current guidelines. RESULTS: A total number of 28,066 bacterial strains were isolated. The most frequently isolated pathogens were Gram-negative bacteria (n=18,021; 64% of all isolated bacteria), including Enterobacteriaceae (71%) and non-Enterobacteriaceae (29%). The total number of isolated Gram-positive bacteria (n=10,045; 36% of all isolates) included Staphylococcus spp. (65%) and Enterococcus spp. (35%). The highest increase in the number of infections was caused by Enterobacteriaceae. The number of Staphylococcus aureus and coagulase negative Staphylococcus resistant to methicillin decreased. Analyzed alert pathogens with resistance phenotypes were highly susceptible to a single type of antibiotic. All multidrug resistant Gram negative bacteria (except those naturally resistant to colistin) were susceptible to colistin. All methicillin resistant S. aureus and methicillin resistant coagulase negative Staphylococci were susceptible to vancomycin and linezolid. All MSSA strains were susceptible to cloxacillin, all Enterococcus faecium strains to ampicillin, and all VRE strains were susceptible to linezolid and tigecycline. PMID- 28872281 TI - Transitioning young adults from paediatric to adult care and the HIV care continuum in Atlanta, Georgia, USA: a retrospective cohort study. AB - INTRODUCTION: The transition from paediatric to adult HIV care is a particularly high-risk time for disengagement among young adults; however, empirical data are lacking. METHODS: We reviewed medical records of 72 youth seen in both the paediatric and the adult clinics of the Grady Infectious Disease Program in Atlanta, Georgia, USA, from 2004 to 2014. We abstracted clinical data on linkage, retention and virologic suppression from the last two years in the paediatric clinic through the first two years in the adult clinic. RESULTS: Of patients with at least one visit scheduled in adult clinic, 97% were eventually seen by an adult provider (median time between last paediatric and first adult clinic visit = 10 months, interquartile range 2-18 months). Half of the patients were enrolled in paediatric care immediately prior to transition, while the other half experienced a gap in paediatric care and re-enrolled in the clinic as adults. A total of 89% of patients were retained (at least two visits at least three months apart) in the first year and 56% in the second year after transition. Patients who were seen in adult clinic within three months of their last paediatric visit were more likely to be virologically suppressed after transition than those who took longer (Relative risk (RR): 1.76; 95% confidence interval (CI): 1.07-2.9; p = 0.03). Patients with virologic suppression (HIV-1 RNA below the level of detection of the assay) at the last paediatric visit were also more likely to be suppressed at the most recent adult visit (RR: 2.3; 95% CI: 1.34-3.9; p = 0.002). CONCLUSIONS: Retention rates once in adult care, though high initially, declined significantly by the second year after transition. Pre-transition viral suppression and shorter linkage time between paediatric and adult clinic were associated with better outcomes post-transition. Optimizing transition will require intensive transition support for patients who are not virologically controlled, as well as support for youth beyond the first year in the adult setting. PMID- 28872284 TI - HBV or HCV and pregnancy AB - Despite effective anti-HBV prophylaxis, cases of acute and chronic inflammation are still occurring, including among pregnant women. Studies in Asia suggest considering antiviral treatment among pregnant women with viremia above 10 log6 copies / ml. Current guidelines exclude the use of caesarean section as a method to reduce the likelihood of neonatal infection. At the same time, there are no grounds to ban the breastfeeding of a baby born to an HBV-infected mother.HCV infection can adversely affect the course of pregnancy. As with HBV infection, caesarean section does not reduce the risk of infection. Also breastfeeding among these patients is not contraindicated. The inability to use appropriate prophylaxis in newborns is one of the reasons for the targeted treatment of HCV infected women at the procreation age in the first place. PMID- 28872283 TI - Impact of selected predictive factors on sustained virologic response in HCV genotype 4 infected patients treated with pegylated interferon alpha and ribavirin AB - BACKGROUND: Dual therapy (PegIFN and ribavirin) (DT) had been the standard of care in patients infected with HCV genotype 4 (HCV-4) until 2014. Thereafter, new treatment options were available including IFNbased and other IFN-free regimens. Objectives: The aim was to assess the efficacy (SVR24) of DT and a selection of predictive factors of SVR in HCV-4 infected patients. METHODS: 112 patients (62 men) of median age 23 years were treated with DT for 48/72 weeks (107/5). Most of them were treatment naive (80.4%) and with fibrosis F<=2(83.1%). Individuals with prior hepatitis B virus (HBV) infection, i.e. positive antibodies to the hepatitis B core antigen (anti-HBc), negative hepatitis B surface antigen and undetectable serum HBV DNA were included into the analysis. RESULTS: SVR24 was achieved in 46/112(41.1%) patients. Null response (NR) was recognized in 24.1%, partial response in 13.4%, relapse in 10.7% and breakthrough in 6.2% of patients. SVR24 was associated with lack of previous treatment experience, younger age (<40 years), pretreatment viral load <2x105 IU/ml, less advanced fibrosis (F<=2) and >10% loss of baseline weight. Anti-HBc was detected in 25(22.3%) patients out of which four (16%) achieved SVR24 in comparison to 42(48.8%) patients with anti-HBc negative (p<0.005); NR was observed in 10(40%) individuals vs 17(19.8%) in anti HBc negative patients. CONCLUSIONS: SVR24 was low. The age <40 years, less advanced fibrosis, pretreatment viral load <2x105 IU/ml, lack of previous treatment experience, loss of body weight were the positive predictive factors of SVR24. Prior HBV infection correlated with poorer SVR24 and NR. PMID- 28872285 TI - Outbreaks of nosocomial infections in Poland in the years 2011-2015 AB - INTRODUCTION: In hospitals outbreaks of nosocomial infections are recorded i.e. the occurrence of at least two clearly related cases of infections. In these outbreaks not only patients but also hospital staff are getting infected. Due to the fact, that nosocomial infections are inseparably related to the hospitalisation of the patients, there is a need to build a culture of active surveillance of emerging infections and their reporting to the authorities of the State Sanitary Inspection. MATERIAL AND METHODS: This article was developed on the basis of the information gathered in the report about the occurrence of outbreaks in entities carrying out the medical activities. This report is the result of the analysis of the preliminary reports submitted by the hospitals in the cases where there was a suspicion of or an epidemic outbreak and the final reports of the epidemic outbreak suppressions. RESULTS: In the years 2011-2015 in all hospitals in Poland a total number of 1 912 outbreaks of nosocomial infections was reported; in those outbreaks 15 282 patients and 1 226 medical personnel were infected. The biggest numbers of outbreaks of nosocomial infections were reported in the voivodeships: Masovia and Silesia. The most frequently etiological factor was Clostridium difficile; it caused 519 hospital outbreaks. Out of the viral factors, most of the outbreaks were due to the rotavirus - 359 of such instances. In addition to the numerous bacterial and viral factors, the outbreaks of nosocomial infections were also caused by fungi and parasites. PMID- 28872286 TI - Looking for the new preparations for antibacterial therapy. V. New antimicrobial agents from the oxazolidinones groups in clinical trials AB - This paper is the fifth part of the series concerning the search for new preparations for antibacterial therapy and discussing new compounds belonging to the oxazolidinone class of antibacterial chemotherapeutics. This article presents five new substances that are currently at the stage of clinical trials (radezolid, sutezolid, posizolid, LCB01-0371 and MRX-I). The intensive search for new antibiotics and antibacterial chemotherapeutics with effective antibacterial activity is aimed at overcoming the existing resistance mechanisms in order to effectively fight against multidrug-resistant bacteria, which pose a real threat to public health. The crisis of antibiotic resistance can be overcome by the proper use of these drugs, based on bacteriological and pharmacological knowledge. Oxazolidinones, with their unique mechanism of action and favorable pharmacokinetic and pharmacodynamic parameters, represent an alternative way to effectively treat serious infections caused by Gram-positive microorganisms. PMID- 28872287 TI - Monitoring adherence to cold chain storage of vaccines in 2014 in the Malopolska province AB - BACKGROUND AND AIM OF THE STUDY: The principles of "cold chain" have been developed for the safe transport and storage of vaccines because of their sensitivity to temperature and are guidelines for use in all countries. Available information on adherence to the principles of the "cold chain" by healthcare providers in Poland is insufficient. The aim of the study was to assess compliance with these rules in storing vaccines by vaccination centers implementing an immunization program in 2014 in the Malopolska province MATERIAL AND METHODS: The study was conducted in 111 vaccination centers in 19 districts of Malopolska, which represents 12% of all vaccination centers in the Malopolska province in 2014. The selection of vaccination centers for the study was not random. During a routine inspection of vaccination centers, an employee of the District Sanitary-Epidemiological Station conducted a study using a specially prepared questionnaire. Inspections in vaccination centers which qualified for the study were conducted from March to September 2015. RESULTS: Among the analyzed vaccinations centers 90% had a refrigerator or refrigerator-freezer, and 10% a pharmaceutical refrigerator. 3.6% of refrigerators were produced before 2000. A 24-hour recording of the temperature was conducted in 67.6% vaccination centers. 40.5% of vaccination centers had a 24-hour system of recording and notification when temperature parameters had been exceeded in refrigeration devices. 22.5% of vaccination centers had emergency power supply. 13.5% of vaccination centers a power failure occurred in refrigerators, including 40% of the vaccination centers which had a text message notification system.. Total cost of destroyed vaccines amounted to over 20 thousand zl. SUMMARY: Correct storage conditions are needed for vaccines to maintain their full effectiveness, which is why it is necessary to intensify efforts to ensure compliance with the principles of the cold chain in the storage of vaccines by healthcare providers. PMID- 28872288 TI - Determinants of vaccine hesitancy AB - Vaccine hesitancy is a worrying phenomenon due to its range and health-related consequences. Secondary epidemiological data on the current situation of vaccination in Poland were analyzed. The source of the analyzed data were obtained from the reports of the National Sanitary Inspection and the National Institute of Public Health-National Institute of Hygiene in Warsaw. Legal basis on vaccination and the responsibilities of physicians related to these regulations were also discussed. Considering the opinions of ECDC experts, factors influencing vaccine hesitancy were identified. Attention was paid to the activities of the anti-vaccination movements, their range of activity and a strategy of action. PMID- 28872289 TI - Chronic obstructive pulmonary disease (COPD) - epidemiology in Silesian voivodeship AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a problem requiring constant surveillance, both clinical and epidemiological. AIM: The aim of study was to analyze territorial and temporal variability of COPD hospitalization and incidence, as far as expenses incurred by the National Health Fund (NHF) due to medical treatment of disease in the Silesian Voivodeship based on secondary epidemiological data. MATERIAL AND METHODS: The epidemiological situation was presented on the basis of available health benefits data registered in adult patients with COPD treated from the NHF budget in the Silesian Voivodeship. The dynamics of incidence rates in 2006-2010, prevalence rates of hospitalization in 2000-2011 and costs of treatment of the disease were investigated. We also present variability of incidence and prevalence in particular districts of study region. RESULTS: The standardized incidence rate of COPD in the Silesian Voivodeship is still high, although it slowly decreased from the value of 656.93/100,000 in 2007 to 470.7/100,000 in 2010. We observed a significant decrease of hospitalization from 217.0/100,000 in 2005 to 117.7/100,000 in 2011. Higher values of both rates refer to men, besides, we observed their spatial variability in particular districts. The average annual cost of new cases of COPD treatment in Silesian Voivodeship was approximately 5 million EUR (20 million PLN), while the annual cost of all hospital admissions decreased substantially from the value of approx.10 million EUR (40 million PLN) in 2003 to approx. 5 million EUR (20 million PLN) in 2011. CONCLUSIONS: We observed temporal and spatial variability of COPD incidence and prevalence in Silesian Voivodeship. Asignificant reduction of COPD hospitalization rate implies serious reduction of expenses incurred by National Health Found. PMID- 28872290 TI - Trends in the incidence of dental caries in 18-year-olds in Lodzkie voivodeship in 1995-2014 AB - OBJECTIVE: The objective of this paper was to assess the dentition status of 18 year-olds living in Lodzkie voivodeship based on the epidemiological studies conducted in 1995-2014. MATERIAL AND METHODS: Study was carried out in 2014. Study group was composed of 302 adolescents aged 18 years old living in Lodzki and Brzezinski districts, including urban and rural areas selected using three stage cluster sampling method. Examinations were conducted pursuant to the WHO recommendations. The prevalence of caries, intensity of caries as well as the components (D,M,F) of caries intensity, treatment index and the SIC index were calculated. Furthermore, the changes in the intensity of caries were assessed, beginning from 1995. Statistical analysis was carried out. RESULTS: Dental caries was reported in 91.7% of adolescents. The intensity of caries, the SIC index and treatment index were estimated to be 5.5, 8.9 and 0.8, respectively. CONCLUSIONS: Having analysed the data as of 1995-2014, it may be stated that there is a systematic improvement of the dentition status in 18-year-olds living in Lodzkie voivodeship. PMID- 28872291 TI - Prevention programmes in primary health care - 8 aspects of their effective implementation AB - INTRODUCTION: Primary health care (PHC) is an optimal setting for the purpose of primary and secondary prevention. Health education, vaccinations, screening may be successfully introduced to the PHC settings. Consequently, it would ensure better access to services and their accessibility for all social groups. OBJECTIVE: The purpose of this paper was to determine factors which have an impact on the implementation of prevention programmes in the PHC settings as well as actions which improve the effectiveness of such programmes in Europe and worldwide with a special attention paid to the prevention programmes concerning chronic infectious diseases. MATERIAL AND METHODS: A review of literature was conducted in PubMed using the following key words: primary care/general practice, prevention, screening, implementation. A total of 540 articles published in 1976 2016 were subject to analysis. RESULTS: Having developed prevention programmes in the PHC settings, it should not be forgotten that it would be an additional task for medical personnel. It would be of importance to allocate adequate funds which would allow for an optimal execution of the programme - adequate time for visit, adequate number of visits, time for education of patients, follow-up visits, monitoring of the execution of the programme and care over diagnosed patients. Prevention programme must be accompanied by education (especially education of medical personnel). Effective execution of the prevention programmes is favoured by the following factors: simple inclusion criteria, less invasive diagnostic tests, support programmes and the presence of workers which are appointed for such a purpose. FINDINGS: Execution of preventive programmes in the PHC settings is feasible. Furthermore, there is an evidence which suggests that they may be effectively executed there. PMID- 28872293 TI - Review of English version of the monograph The Project KIK/35 "Prevention of Hepatitis C Virus (HCV) Infections" as an Example of Integrated Public Health Interventions to Reduce Blood-Borne Infections in Poland PMID- 28872292 TI - Jerzy Piatkowski (1929-1992) - laboratory technician inscribed in history of the Department of Epidemiology - in twenty fifth anniversary of death PMID- 28872294 TI - Review of "The Project KIK/35 "Prevention of Hepatitis C Virus (HCV) Infections" as an Example of Integrated Public Health Interventions to reduce Blood-Borne Infections in Poland PMID- 28872295 TI - M13 Virus-Incorporated Biotemplates on Electrode Surfaces To Nucleate Metal Nanostructures by Electrodeposition. AB - We report a virus-incorporated biological template (biotemplate) on electrode surfaces and its use in electrochemical nucleation of metal nanocomposites as an electrocatalytic material for energy applications. The biotemplate was developed with M13 virus (M13) incorporated in a silicate sol-gel matrix as a scaffold to nucleate Au-Pt alloy nanostructures by electrodeposition, together with reduced graphene oxide (rGO). The phage when engineered with Y3E peptides could nucleate Au-Pt alloy nanostructures, which ensured adequate packing density, simultaneous stabilization of rGO, and a significantly increased electrochemically active surface area. Investigation of the electrocatalytic activity of the resulting sol gel composite catalyst toward methanol oxidation in an alkaline medium showed that this catalyst had mass activity greater than that of the biotemplate containing wild-type M13 and that of monometallic Pt and other Au-Pt nanostructures with different compositions and supports. M13 in the nanocomposite materials provided a close contact between the Au-Pt alloy nanostructures and rGO. In addition, it facilitated the availability of an OH--rich environment to the catalyst. As a result, efficient electron transfer and a synergistic catalytic effect of the Au and Pt in the alloy nanostructures toward methanol oxidation were observed. Our nanocomposite synthesis on the novel biotemplate and its application might be useful for developing novel clean and green energy generating and energy-storage materials. PMID- 28872296 TI - Development of Selective Peptide Catalysts with Secondary Structural Frameworks. AB - Enzymes are biogenic catalysts that enable the vital activity of organisms. Enzymes promote reactions in a selective manner with a high level of substrate recognition ability. The development of such a sophisticated catalyst has been one of the goals for chemists. A synthetic peptide is the prime candidate to realize an enzyme-like catalyst. Considering that the catalytic function of enzymes derives from their molecular structures, the key for the creation of a peptide catalyst might be the introduction of a specific three-dimensional structure. Our motivation was to find a peptide catalyst with a versatile secondary structural framework and apply the peptide to a variety of selective reactions. Although helical-peptide-catalyzed asymmetric epoxidation of enones is popular, no other highly enantioselective reaction with a helical peptide has been reported. It was found that resin-supported alpha-helical polyleucine promoted asymmetric conjugate addition of a carbon nucleophile to enones via the formation of an iminium intermediate at the N-terminal amino group. By changing the helical chain to a repetitive Leu-Leu-Aib (Aib = alpha-aminoisobutyric acid) sequence and introducing a few amino acids to the N-terminus, a highly enantioselective peptide catalyst was obtained. The helical peptide catalyst was applicable for a tandem enamine/iminium-mediated reaction and asymmetric epoxidation of enones. Although the extension of the helical peptide to conjugate addition of a nucleophile to an enal was not successful simply by attaching proline to the N-terminus of the helix, the incorporation of a beta-turn motif was effective to improve the catalytic performance. In the sequence of such a turn-helix-type peptide, the helical part was seemingly distant from the N terminal amino group; however, the hydrophobicity, structure, and chirality of the helix largely affected the reaction. The turn-helix-type peptide promoted a wide range of asymmetric reactions: conjugated additions of hydride and carbon nucleophiles to enals via the iminium activation and alpha-oxyamination of aldehydes via the enamine activation. The peptides with turn-helix and helix frameworks were also employed for several reactions that were difficult to achieve with low-molecular-weight catalysts: enzyme-cocatalyzed asymmetric oxidation in water, diastereo- and enantioselective cyclopropanation, regioselective reduction of dienals, kinetic resolution of planar-chiral compounds, and desymmetrization to induce planar chirality. To explore other types of peptide catalysts, a combinatorial library screening was performed. On the way, it was revealed that a histidyl residue assisted to accelerate a reaction via reversible addition to an iminium intermediate. Through the screening of random peptide libraries, novel peptide sequences for efficient and enantioselective conjugate addition were discovered. Although we have no information about the molecular structure of the newly found peptides, they can be an entry point for establishing a versatile framework of peptide catalysts. PMID- 28872297 TI - Poly(2,5-benzimidazole)-Grafted Graphene Oxide as an Effective Proton Conductor for Construction of Nanocomposite Proton Exchange Membrane. AB - To improve proton conduction properties of conventional sulfonated poly(ether ether ketone) (SPEEK), poly(2,5-benzimidazole)-grafted graphene oxide (ABPBI-GO) was prepared to fabricate nanocomposite membranes, which then were further doped with phosphoric acid (PA). The ABPBI-GO was synthesized through the reaction of 3,4-diaminobenzoic acid with the carboxyl acid groups present on the GO surface. The simultaneous incorporation of ABPBI-GO and PA into SPEEK did not only improve the physicochemical performance of the membranes in terms of thermal stability, water uptake, dimensional stability, proton conductivity, and methanol permeation resistance but also relieve PA leaching from the membranes though acid-base interactions. The resulting composite membranes exhibited enhanced proton conductivities in extended humidity ranges thanks to the hygroscopic character of PA and the increased water uptake. Moreover, the unique self-ionization, self dehydration, and nonvolatile properties of PA improved the high-temperature proton conductivities (sigma) of PA-doped membranes. The PA-doped SPEEK/ABPBI-GO 3.0 delivered a sigma of 7.5 mS cm-1 at 140 degrees C/0% RH. This value was fourfold higher than that of pristine SPEEK membranes. The PA-doped SPEEK/ABPBI GO-3.0 based fuel cell membranes delivered power densities of 831.06 and 72.25 mW cm-2 at 80 degrees C/95% RH and 120 degrees C/0% RH, respectively. By contrast, the PA-doped SPEEK membrane generated only 655.63 and 44.58 mW cm-2 under the same testing conditions. PMID- 28872298 TI - Selective and Efficient RNA Analysis by Solid-Phase Microextraction. AB - In this study, a solid-phase microextraction (SPME) method was developed for the purification of mRNA (mRNA) from complex biological samples using a real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay for quantification. The chemical composition of the polymeric ionic liquid (PIL) and a polyacrylate (PA) SPME sorbent coating was optimized to enhance the extraction performance. Of the studied SPME sorbent coatings, the PIL containing carboxylic acid moieties in the monomer and halide-based anions extracted the highest amount of mRNA from aqueous solutions, whereas the native PA fiber showed the lowest extraction efficiency. On the basis of RT-qPCR data, electrostatic interactions and an ion-exchange mechanism between the negatively charged phosphate backbone of RNA and the PIL cation framework were the major driving forces for mRNA extraction. The optimized PIL-based SPME method purified a high quantity of mRNA from crude yeast cell lysate compared to a phenol/chloroform extraction method. The reusability and robustness of PIL-based SPME for RNA analysis represents a significant advantage over conventional silica-based solid-phase RNA extraction kits. The selectivity of the SPME method toward mRNA was enhanced by functionalizing the PA sorbent with oligo dT20 using carbodiimide-based amide linker chemistry. The oligo dT20-modified PA sorbent coating demonstrated superior extraction performance than the native PA sorbent coating with quantification cycle (Cq) values 33.74 +/- 0.24 and 39, respectively. The modified PA sorbent extracted sufficient mRNA from total RNA at concentrations as low as 5 ng MUL-1 in aqueous solutions without the use of organic solvents and time-consuming multiple centrifugation steps that are required in traditional RNA extraction methods. PMID- 28872299 TI - Comparison of alpha-Synuclein Fibril Inhibition by Four Different Amyloid Inhibitors. AB - Aggregation of alpha-synuclein (alpha-Syn) into toxic oligomers and fibrils leads to Parkinson's disease (PD) pathogenesis. Molecules that can inhibit the fibrillization and oligomerization of alpha-Syn have potential therapeutic value. Here, we studied four selective amyloid inhibitors: dopamine (Dopa), amphotericin B (Amph), epigallocatechingallate (EGCG), and quinacrinedihydrochloride (Quin) for their effect on oligomerization, fibrillization, and preformed fibrils of alpha-Syn. The aggregation kinetics of alpha-Syn using ThT fluorescence and conformational transition by circular dichroism (CD) in the presence and absence of these four compounds suggest that, except Quin, the remaining three molecules inhibit alpha-Syn aggregation in a concentration dependent manner. Consistent with the aggregation kinetics data, the morphological study of aggregates formed in the presence of these compounds showed corresponding decrease in fibrillar size. The analysis of cell viability using MTT assay showed reduction in toxicity of alpha-Syn aggregates formed in the presence of these compounds, which also correlates with reduction of exposed hydrophobic surface as studied by ANS binding. Additionally, these inhibitors, except Quin, demonstrated reduction in size as well as the toxicity of oligomeric/fibrillar aggregates of alpha-Syn. The residue specific interaction to low molecular weight (LMW) species of alpha-Syn by 2D NMR study revealed that, the region and extent of binding are different for all these molecules. Furthermore, fibril-binding data using SPR suggested that there is no direct relationship between the binding affinity and fibril inhibition by these compounds. The present study suggests that sequence based interaction of small molecules with soluble alpha-Syn might dictate their inhibition or modulation capacity, which might be helpful in designing modulators of alpha-Syn aggregation. PMID- 28872300 TI - Ultrasensitive MicroRNA Assay via Surface Plasmon Resonance Responses of Au@Ag Nanorods Etching. AB - Quantification of trace serum circulate microRNAs is extremely important in clinical diagnosis but remains a great challenge. Herein we developed an ultrasensitive platform for microRNA 141 (miR-141) detection based on a silver coated gold nanorods (Au@Ag NRs) etching process accompanied by surface plasmon resonance (SPR) shift. Both SPR absorption and scattering responses were monitored. Combined amplification cascades of catalyzed hairpin assembly (CHA) and hybridization chain reaction (HCR) with the sensitive SPR responses of plasmonic Au@Ag NRs, the proposed bioassay exhibited ultrahigh sensitivity toward miRNA-141 with dynamic range from 5.0 * 10-17 M to 1.0 * 10-11 M. With target concentration higher than 1.0 * 10-13 M, the color of the solution changed obviously that could be observed with naked eyes. Under dark-field microscopy observation of individual particle, a limit of detection down to 50 aM could be achieved. Owing to the superior sensitivity and selectivity, the proposed method was applied to detecting trace microRNA in serum. Similar SPR assays could be developed simply by redesigning the switching aptamer for the detections of other microRNAs or targets such as small molecule, DNA, or protein. Considering the convenient operation, good performance and simple observation modes of this method, it may have great potential in trace bioanalysis for clinical applications. PMID- 28872301 TI - Undecaprenyl Phosphate Phosphatase Activity of Undecaprenol Kinase Regulates the Lipid Pool in Gram-Positive Bacteria. AB - Bacteria cell walls contain many repeating glycan structures, such as peptidoglycans, lipopolysaccharides, teichoic acids, and capsular polysaccharides. Their synthesis starts in the cytosol, and they are constructed from a glycan lipid carrier, undecaprenyl phosphate (C55P), which is essential for cell growth and survival. The lipid derivative undecaprenol (C55OH) is predominant in many Gram-positive bacteria but has not been detected in Gram negative bacteria; its origin and role have thus remained unknown. Recently, a homologue of diacylglycerol kinase (DgkA) in Escherichia coli (E. coli) was demonstrated to be an undecaprenol kinase (UK) in the Gram-positive bacterium Streptococcus mutans (S. mutans). In this study, we found that S. mutans UK was not only an undecaprenol kinase but also a Mg-ADP-dependent undecaprenyl phosphate phosphatase (UpP), catalyzing the hydrolysis of C55P to C55OH and a free inorganic phosphate. Furthermore, the naturally undetectable C55OH was observed in E. coli cells expressing S. mutans dgkA, supporting the phosphatase activity of UK/UpP in vivo. These two activities were indispensable to each other and utilized identical essential residues binding to their substrates, suggesting that both activities share the same active site and might involve a direct phosphoryl transfer mechanism. This study revealed a unique membrane enzyme displaying bifunctional activities determined by substrate binding and C55OH production. The reciprocal conversion of C55P and the undecaprenol pool efficiently regulate cell wall synthesis, especially in Gram-positive bacteria. PMID- 28872302 TI - High-Affinity Interactions of Beryllium(2+) with Phosphatidylserine Result in a Cross-Linking Effect Reducing Surface Recognition of the Lipid. AB - Beryllium has multiple industrial applications, but its manufacture is associated with a serious occupational risk of developing chronic inflammation in the lungs known as berylliosis, or chronic beryllium disease. Although the Be2+-induced abnormal immune responses have recently been linked to a specific MHC-II allele, the nature of long-lasting granulomas is not fully understood. Here we show that Be2+ binds with a micromolar affinity to phosphatidylserine (PS), the major surface marker of apoptotic cells. Isothermal titration calorimetry indicates that, like that of Ca2+, binding of Be2+ to PS liposomes is largely entropically driven, likely by massive desolvation. Be2+ exerts a compacting effect on PS monolayers, suggesting cross-linking through coordination by both phosphates and carboxyls in multiple configurations, which were visualized in molecular dynamics simulations. Electrostatic modification of PS membranes by Be2+ includes complete neutralization of surface charges at ~30 MUM, accompanied by an increase in the boundary dipole potential. The data suggest that Be2+ can displace Ca2+ from the surface of PS, and being coordinated in a tight shell of four oxygens, it can mask headgroups from Ca2+-mediated recognition by PS receptors. Indeed, 48 MUM Be2+ added to IC-21 cultured macrophages specifically suppresses binding and engulfment of PS-coated silica beads or aged erythrocytes. We propose that Be2+ adsorption at the surface of apoptotic cells may potentially prevent normal phagocytosis, thus causing accumulation of secondary necrotic foci and the resulting chronic inflammation. PMID- 28872303 TI - Hexameric Silver(I) Pyrazolate: Synthesis, Structure, and Isomerization. AB - The first binary hexameric silver(I) pyrazolate (Ag6pz6) has been prepared, and X ray analysis demonstrated that it takes a rare figure-eight shape (pz- = deprotonated tert-butyl 3,5-diphenyl-1H-pyrazole-4-carboxylate). The hexamer can be easily converted to its tetrameric isomer (Ag4pz4) by recrystallization from ether. On the basis of the 1H NMR and mass spectrometry measurements, it is conjectured that the hexamer, after dissolving in CHCl3, quickly achieves equilibrium with Ag4pz4 and Ag3pz3, with the equilibrium lying far to the side of smaller rings. PMID- 28872304 TI - Development of an Azo-Based Photosensitizer Activated under Mild Hypoxia for Photodynamic Therapy. AB - Photodynamic therapy (PDT) utilizes photoirradiation in the presence of photosensitizers to ablate cancer cells via generation of singlet oxygen (1O2), but it is important to minimize concomitant injury to normal tissues. One approach for achieving this is to use activatable photosensitizers that can generate 1O2 only under specific conditions. Here, we report a novel photosensitizer that is selectively activated under hypoxia, a common condition in solid tumors. We found that introducing an azo moiety into the conjugated system of a seleno-rosamine dye effectively hinders the intersystem crossing process that leads to 1O2 generation. We show that the azo group is reductively cleaved in cells under hypoxia, enabling production of 1O2 to occur. In PDT in vitro, cells under mild hypoxia, within the range typically found in solid tumors (up to about 5% O2), were selectively ablated, leaving adjacent normoxic cells intact. This simple and practical azo-based strategy should be widely applicable to design a range of activatable photosensitizers. PMID- 28872305 TI - Increasing the Open-Circuit Voltage of Dye-Sensitized Solar Cells via Metal-Ion Coordination. AB - Considerable efforts are dedicated to increasing the open-circuit voltage (Voc) of dye-sensitized solar cells (DSSCs) by slowing charge recombination dynamics using atomic layer deposition, alkyl-substituted dyes, coadsorbents, and other strategies. In this report, we introduce metal-ion coordination to a metal oxide bound dye as an alternative means of increasing Voc. Metal-ion coordination has minimal influence on the photophysical and electrochemical properties of the N3 dye, but presumably because of increased steric hindrance at the interface, it slows charge recombination kinetics and increases Voc by upwards of 130 mV relative to the parent N3 DSSC. With respect to the nature of the metal ion, the trend in decreasing short-circuit current (Jsc) and increasing Voc correlates with the charge of the coordinated metal ion (MIV -> MIII -> MII). We attribute this trend to electrostatic interactions between the metal cation and I- or I3-, with the more highly charged cations maintaining a higher concentration of mediator anions in proximity to the surface and, as a result, increasing the regeneration and recombination rates. PMID- 28872306 TI - Modulating Supramolecular Peptide Hydrogel Viscoelasticity Using Biomolecular Recognition. AB - Self-assembled peptide-based hydrogels are emerging materials that have been exploited for wound healing, drug delivery, tissue engineering, and other applications. In comparison to synthetic polymer hydrogels, supramolecular peptide-based gels have advantages in biocompatibility, biodegradability, and ease of synthesis and modification. Modification of the emergent viscoelasticity of peptide hydrogels in a stimulus responsive fashion is a longstanding goal in the development of next-generation materials. In an effort to selectively modulate hydrogel viscoelasticity, we report herein a method to enhance the elasticity of beta-sheet peptide hydrogels using specific molecular recognition events between functionalized hydrogel fibrils and biomolecules. Two distinct biomolecular recognition strategies are demonstrated: oligonucleotide Watson Crick duplex formation between peptide nucleic acid (PNA) modified fibrils with a bridging oligonucleotide and protein-ligand recognition between mannose modified fibrils with concanavalin A. These methods to modulate hydrogel elasticity should be broadly adaptable in the context of these materials to a wide variety of molecular recognition partners. PMID- 28872307 TI - Gold Corroles as Near-IR Phosphors for Oxygen Sensing. AB - The triplet state of gold(III) corroles is exploited for optical oxygen sensing. We report intense phosphorescence for gold(III) corroles in the near-IR, an optical window that is ideal for tissue transparency. Moreover, the triplet excited-state emission exhibits significant changes in intensity and lifetime over the 0-160 Torr O2 pressure range. This renders these compounds sensitive at biologically relevant pressures and overcomes the spectral limitations of palladium and platinum porphyrins for oxygen sensing in biology. PMID- 28872308 TI - Copper-Catalyzed Dehydrogenative C(sp2)-N Bond Formation via Direct Oxidative Activation of an Anilidic N-H Bond: Synthesis of Benzoimidazo[1,2-a]indoles. AB - A dehydrogenative C(sp2)-N bond-forming strategy via copper-catalyzed intramolecular C-H/N-H coupling has been developed, which systematically unraveled the feasibility and practicality for benzoimdazo[1,2-a]indole formations through oxidative anilidic N-H activation. The merit of this strategy is illustrated by the broad tolerance of functionalities, as well as the utilization of extremely cheap copper catalysis to realize potentially useful indole-fused tetracycles in a step- and atom-economical manner. PMID- 28872309 TI - Recent Progress in Heterogeneous Asymmetric Hydrogenation of C?O and C?C Bonds on Supported Noble Metal Catalysts. AB - The ease of separation, simple regeneration, and the usually high stability of solid catalysts facilitating continuous production processes have stimulated the development of heterogeneous asymmetric hydrogenation catalysis. The simplest and so far most promising strategy to induce enantioselectivity to solid metal catalysts is their modification by chiral organic compounds, as most prominently represented by the cinchona-modified Pt and Pd catalysts for the asymmetric hydrogenation of activated C?O and C?C bonds. In this Review, we provide a systematic account of the research accomplished in the past decade on noble metal based heterogeneous asymmetric hydrogenation of prochiral C?O and C?C bonds, including all important facets of these catalytic systems. The advances made are critically analyzed, and future research challenges are identified. PMID- 28872310 TI - Mapping the Binding Modes of Hemilabile Pincer-Crown Ether Ligands in Solution Using Diamagnetic Anisotropic Effects on NMR Chemical Shift. AB - A protocol for identifying ligand binding modes in a series of iridium pincer complexes bearing hemilabile aza-crown ether ligands has been developed using readily accessible NMR methods. The approach was tested on a collection of 13 structurally diverse pincer-crown ether complexes that include several newly characterized species. New synthetic routes enable facile interconversion of coordination modes and supporting ligands. Detailed structural assignments of five complexes reveal that the difference in chemical shift (Deltadelta) between geminal protons in the crown ether is influenced by diamagnetic anisotropy arising from halides and other ligands in the primary coordination sphere. The average difference in chemical shift between diastereotopic geminal protons in the crown ether macrocycle (Deltadeltaavg), as determined through a single 1H-13C HSQC experiment, provides information on the pincer ligand binding mode by establishing whether the macrocycle is in close proximity to the metal center. The Deltadeltaavg values for binding modes that involve chelating ether(s) bound to iridium are roughly 2-fold larger than those for tridentate complexes with no Ir-O bonds. PMID- 28872311 TI - Debye Process and beta-Relaxation in 1-Propanol Probed by Dielectric Spectroscopy and Depolarized Dynamic Light Scattering. AB - We revisit the reorientational dynamics of 1-propanol as a prototype of a monohydroxy alcohol and H-bonding system by dielectric spectroscopy (DS) and depolarized dynamic light scattering (DDLS). In particular, we address the question of whether the Debye relaxation, which is seen as a dominant process in DS, is visible in light scattering and discuss how the Johari-Goldstein (JG) beta process, which is also a prominent feature of the dielectric spectrum, appears in photon correlation spectroscopy. For that purpose we performed depolarized photon correlation experiments with an improved setup and performed additional time domain dielectric experiments which gives us the possibility to compare dielectric and light scattering data in a broad temperature range. It turns out that the improved setup allows to unambiguously identify the JG beta-process, which shows almost identical properties in DDLS as in the dielectric spectra, but a Debye relaxation is not present in the DDLS data and can be excluded down to a level of 2.5% of the alpha-process amplitude. PMID- 28872312 TI - Light Adaptation in Phycobilisome Antennas: Influence on the Rod Length and Structural Arrangement. AB - Phycobilisomes, the light-harvesting antennas of cyanobacteria, can adapt to a wide range of environments thanks to a composition and function response to stress conditions. We study how structural changes influence excitation transfer in these supercomplexes. Specifically, we show the influence of the rod length on the photon absorption and subsequent excitation transport to the core. Despite the fact that the efficiency of individual disks on the rod decreases with increasing rod length, we find an optimal length for which the average rod efficiency is maximal. Combining this study with experimental structural measurements, we propose models for the arrangement of the phycobiliproteins inside the thylakoid membranes, evaluate the importance of rod length, and predict the corresponding transport properties for different cyanobacterial species. This analysis, which links the functional and structural properties of full phycobilisome complexes, thus provides further rationales to help resolve their exact structure. PMID- 28872313 TI - An Electrochemical Method for Carboxylic Ester Synthesis from N-Alkoxyamides. AB - An electrochemical method for the synthesis of carboxylic as well as hindered esters from N-alkoxyamides has been reported. The electrochemical reaction proceeds through constant current electrolysis (CCE) by taking advantage of the dual role of n-Bu4NI (TBAI) as the redox catalyst as well as the supporting electrolyte. Besides providing mild reaction conditions, the present protocol is free from external oxidants and conducting salts, thereby generating nitrogen as the nonhazardous side product. Additionally, the developed procedure is highly advantageous due to its short reaction time, wide substrate scope, and gram-scale synthesis. PMID- 28872314 TI - KuQuinones Equilibria Assessment for Biomedical Applications. AB - A small library of pentacyclic quinoid compounds, called KuQuinones (KuQs), has been prepared through a one-pot reaction. KuQuinones complex structure is made up by two naphthoquinone units connected by a five-membered ring. Due to KuQs structural features, keto-enol tautomerization in solution likely occurs, leading to the generation of four different species, i.e., the enol, the enolate, the external enol and the diquinoid species. The interchange among KuQ tautomers leads to substantial spectral variations of the dye depending on the experimental conditions used. The comprehension of tautomeric equilibria of this new class of quinoid compounds is strongly required in order to explain their behavior in solution and in biological environment. UV-vis, 1H NMR spectroscopies, and DFT calculations resulted appropriate tools to understand the nature of the prevalent KuQuinone species in solution. Moreover, due to the structural similarity of KuQuinones with camptothecin (CPT), a largely used anticancer agent, KuQs have been tested against Cisplatin-resistant SKOV3 and SW480 cancer cell lines. Results highlighted that KuQs are highly active toward the analyzed cell lines and almost nontoxic for healthy cell, indicating a high specific activity. PMID- 28872315 TI - Universal Equations for the Coalescence Probability and Long-Term Size Stability of Phospholipid-Coated Monodisperse Microbubbles Formed by Flow Focusing. AB - Resonantly driven monodisperse phospholipid-coated microbubbles are expected to substantially increase the sensitivity and efficiency in contrast-enhanced ultrasound imaging and therapy. They can be produced in a microfluidic flow focusing device, but questions remain as to the role of the device geometry, the liquid and gas flow, and the phospholipid formulation on bubble stability. Here, we develop a model based on simple continuum mechanics equations that reveals the scaling of the coalescence probability with the key physical parameters. It is used to characterize short-term coalescence behavior and long-term size stability as a function of flow-focusing geometry, bulk viscosity, lipid cosolvent mass fraction, lipid concentration, lipopolymer molecular weight, and lipopolymer molar fraction. All collected data collapse on two master curves given by universal equations for the coalescence probability and the long-term size stability. This work is therefore a route to a more fundamental understanding of the physicochemical monolayer properties of microfluidically formed bubbles and their coalescence behavior in a flow-focusing device. PMID- 28872316 TI - Directionality of Cation/Molecule Bonding in Lewis Bases Containing the Carbonyl Group. AB - Relationship between the C?O-X+ (X = H, Li, Na, K, Al, Cu) angle and covalent characteristic of the X+-M (M = CH2O, CH3CHO, acetone, imidazol-2-one (C2H2N2O), cytosine, gamma-butyrolactone) was investigated, theoretically. The calculated electron densities rho at the bond critical points revealed that the covalency of the M-X+ interaction depended on the nature of the cation and varied as H+ > Cu+ > Al+ > Li+ > Na+ > K+. The alkali cations tended to participate in electrostatic interactions and aligned with the direction of the molecule dipole or local dipole of C?O group to form linear C?O-X geometries. Because of overlapping with lone-pair electrons of the sp2 carbonyl oxygen, the H+ and Cu+ formed a bent C?O X angle. Al+ displayed an intermediate behavior; the C?O-Al angle was 180 degrees in [CH2O/Al]+ (mainly electrostatic), but when the angle was bent (146 degrees ) under the effect of local dipole of an adjacent imine group in cytosine, the covalency of the CO-Al+ interaction increased. The C?O-X angles in M/X+ adduct ions were scanned in different O-X bond lengths. It was found that the most favorable C?O-X angle depended on the O-X bond length. This dependency was attributed to variation of covalent and electrostatic contributions with O-X distance. In addition, the structures of [CH2S/X]+ and [CH2Se/X]+ were studied, and only bent C?S-X and C?Se-X angles were obtained for all cations, although the dipole vectors of CH2S and CH2Se coincide with the C?S and C?Se bonds. The bending of the C?S-X and C?Se-X angles was attributed to the covalent characteristic of S-X and Se-X interactions due to high polarizability of S and Se atoms. PMID- 28872317 TI - Building Complex Kondo Impurities by Manipulating Entangled Spin Chains. AB - The creation of molecule-like structures in which magnetic atoms interact controllably is full of potential for the study of complex or strongly correlated systems. Here, we create spin chains in which a strongly correlated Kondo state emerges from magnetic coupling of transition-metal atoms. We build chains up to ten atoms in length by placing Fe and Mn atoms on a Cu2N surface with a scanning tunneling microscope. The atoms couple antiferromagnetically via superexchange interaction through the nitrogen atom network of the surface. The emergent Kondo resonance is spatially distributed along the chain. Its strength can be controlled by mixing atoms of different transition metal elements and manipulating their spatial distribution. We show that the Kondo screening of the full chain by the electrons of the nonmagnetic substrate depends on the interatomic entanglement of the spins in the chain, demonstrating the prerequisites to build and probe spatially extended strongly correlated nanostructures. PMID- 28872318 TI - Topological Defects in Hexagonal Manganites: Inner Structure and Emergent Electrostatics. AB - Diverse topological defects arise in hexagonal manganites, such as ferroelectric vortices, as well as neutral and charged domain walls. The topological defects are intriguing because their low symmetry enables unusual couplings between structural, charge, and spin degrees of freedom, holding great potential for novel types of functional 2D and 1D systems. Despite the considerable advances in analyzing the different topological defects in hexagonal manganites, the understanding of their key intrinsic properties is still rather limited and disconnected. In particular, a rapidly increasing number of structural variants is reported without clarifying their relation, leading to a zoo of seemingly unrelated topological textures. Here, we combine picometer-precise scanning transmission-electron microscopy with Landau theory modeling to clarify the inner structure of topological defects in Er1-xZrxMnO3. By performing a comprehensive parametrization of the inner atomic defect structure, we demonstrate that one primary length scale drives the morphology of both vortices and domain walls. Our findings lead to a unifying general picture of this type of structural topological defects. We further derive novel fundamental and universal properties, such as unusual bound-charge distributions and electrostatics at the ferroelectric vortex cores with emergent U(1) symmetry. PMID- 28872319 TI - In Situ Dual Cross-Linking of Neat Biogel with Controlled Mechanical and Delivery Properties. AB - Injectable biomaterials play a critical role in many biomedical applications. These materials, however, often have limitations in mechanical and drug-eluting properties attributed to their high water content and the weak secondary forces holding them together. Here we describe a new injectable material based on two complementary water-free, prepolymers modified with succinimidyl carbonate (SC) or with NH2 end groups that form a stiff matrix upon mixing. Cross-linking involves an immediate reaction between PEG4-SC and PEG4-NH2 that forms carbamate bonds and a delayed reaction of PEG4-SC with hydroxyl functional groups that forms carbonate bonds. The mechanical properties, swelling, and erosion kinetics of this biomaterial can be fine-tuned by varying the ratio between the two prepolymers. Bovine serum albumin and poorly water-soluble free base doxorubicin were readily loaded into this system, resulting in a high drug loading content attributed to the absence of water in the formulation. Controlled release over a period of 1 to 30 days was observed, depending on mixture composition and drug properties. The injectable nature of the formulation, its tailored mechanical properties, the fact that it can be cross-linked by two separate mechanisms, and its ability to incorporate and release hydrophilic and hydrophobic drugs make it very attractive as a drug delivery system. PMID- 28872320 TI - Reassessing Graphene Absorption and Emission Spectroscopy. AB - We present a new paradigm for understanding optical absorption and hot electron dynamics experiments in graphene. Our analysis pivots on assigning proper importance to phonon-assisted indirect processes and bleaching of direct processes. We show indirect processes figure in the excess absorption in the UV region. Experiments which were thought to indicate ultrafast relaxation of electrons and holes, reaching a thermal distribution from an extremely nonthermal one in under 5-10 fs, instead are explained by the nascent electron and hole distributions produced by indirect transitions. These need no relaxation or ad hoc energy removal to agree with the observed emission spectra and fast pulsed absorption spectra. The fast emission following pulsed absorption is dominated by phonon-assisted processes, which vastly outnumber direct ones and are always available, connecting any electron with any hole any time. Calculations are given, including explicitly calculating the magnitude of indirect processes, supporting these views. PMID- 28872321 TI - OleB from Bacterial Hydrocarbon Biosynthesis Is a beta-Lactone Decarboxylase That Shares Key Features with Haloalkane Dehalogenases. AB - OleB is an alpha/beta-hydrolase found in bacteria that biosynthesize long-chain olefinic hydrocarbons, but its function has remained obscure. We report that OleB from the Gram-negative bacterium Xanthomonas campestris performs an unprecedented beta-lactone decarboxylation reaction, to complete cis-olefin biosynthesis. OleB reactions monitored by 1H nuclear magnetic resonance spectroscopy revealed a selectivity for decarboxylating cis-beta-lactones and no discernible activity with trans-beta-lactones, consistent with the known configuration of pathway intermediates. Protein sequence analyses showed OleB proteins were most related to haloalkane dehalogenases (HLDs) and retained the canonical Asp-His-Asp catalytic triad of HLDs. Unexpectedly, it was determined that an understudied subfamily, denoted as HLD-III, is comprised mostly of OleB proteins encoded within oleABCD gene clusters, suggesting a misannotation. OleB from X. campestris showed very low dehalogenase activity only against haloalkane substrates with long alkyl chains. A haloalkane substrate mimic alkylated wild-type X. campestris OleB but not OleBD114A, implicating this residue as the active site nucleophile as in HLDs. A sequence-divergent OleB, found as part of a natural OleBC fusion and classified as an HLD-III, from the Gram-positive bacterium Micrococcus luteus was demonstrated to have the same activity, stereochemical preference, and dependence on the proposed Asp nucleophile. H218O studies with M. luteus OleBC suggested that the canonical alkyl-enzyme intermediate of HLDs is hydrolyzed differently by OleB enzymes, as 18O is not incorporated into the nucleophilic aspartic acid. This work defines a previously unrecognized reaction in nature, functionally identifies some HLD-III enzymes as beta-lactone decarboxylases, and posits an enzymatic mechanism of beta-lactone decarboxylation. PMID- 28872322 TI - Local vs Nonlocal States in FeTiO3 Probed with 1s2pRIXS: Implications for Photochemistry. AB - Metal-metal charge transfer (MMCT) is expected to be the main mechanism that enables the harvesting of solar light by iron-titanium oxides for photocatalysis. We have studied FeTiO3 as a model compound for MMCT with 1s2pRIXS at the Fe K edge. The high-energy resolution XANES enables distinguishing five pre-edge features. The three first well distinct RIXS features are assigned to electric quadrupole transitions to the localized Fe* 3d states, shifted to lower energy by the 1s core-hole. Crystal field multiplet calculations confirm the speciation of divalent iron. The contribution of electric dipole absorption due to local p-d mixing allowed by the trigonal distortion of the cation site is supported by DFT and CFM calculations. The two other nonlocal features are assigned to electric dipole transitions to excited Fe* 4p states mixed with the neighboring Ti 3d states. The comparison with DFT calculations demonstrates that MMCT in ilmenite is favored by the hybridization between the Fe 4p and delocalized Ti 3d orbitals via the O 2p orbitals. PMID- 28872323 TI - Insight of Transmembrane Processes of Self-Assembling Nanotubes Based on a Cyclic Peptide Using Coarse Grained Molecular Dynamics Simulation. AB - Transmembrane self-assembling cyclic peptide (SCP) nanotubes are promising candidates for delivering specific molecules through cell membranes. The detailed mechanisms behind the transmembrane processes, as well as stabilization factors of transmembrane structures, are difficult to elucidate through experiments. In this study, the effects of peptide sequence and oligomeric state on the transmembrane capabilities of SCP nanotubes and the perturbation of embedded SCP nanotubes acting on the membrane were investigated based on coarse grained molecular dynamics simulation. The simulation results reveal that hydrophilic SCP oligomers result in the elevation of the energy barrier while the oligomerization of hydrophobic SCPs causes the reduction of the energy barrier, further leading to membrane insertion. Once SCP nanotubes are embedded, membrane properties such as density, thickness, ordering state and lateral mobility are adjusted along the radial direction. This study provides insight into the transmembrane strategy of SCP nanotubes and sheds light on designing novel transport systems. PMID- 28872324 TI - Molecular Mechanisms Underlying Solute Retention at Heterogeneous Interfaces. AB - Despite considerable effort, a molecular-level understanding of the mechanisms governing adsorption/desorption in reversed-phase liquid chromatography is still lacking. This impedes rational design of columns and the development of reliable, computationally more efficient approaches to predict the selectivity of a particular column design. Using state-of-the art, validated force fields and free energy simulations, the adsorption thermodynamics of benzene derivatives is investigated in atomistic detail and provides a quantitative microscopic understanding of retention when compared with experimental data. It is found that pure partitioning or pure adsorption is rather the exception than the rule. Typically, a pronounced ~1 kcal/mol stabilization on the surface is accompanied by a broad trough indicative of partitioning before the probe molecule incorporates into the mobile phase. The present findings provide a quantitative and rational basis to develop improved effective, coarse-grained computational models and to design columns for specific applications. PMID- 28872325 TI - Scale Effect on the Interface Reaction between PDMS-E Emulsion Droplets and Gelatin. AB - In this study, the scale effect on the interface reaction between PDMS-E emulsion droplets and gelatin was studied systematically. The monodisperse alpha-[3-(2,3 epoxy-propoxy)propyl]-omega-butyl-polydimethylsiloxane (PDMS-E) emulsion droplets on different scales were prepared using a Shirasu porous glass (SPG) membrane with a 0.5 MUm pore size. The zeta potential results showed that the surface charge density of PDMS-E droplets decreased with the droplet scale, and the variation went through three stages, which corresponded to the diameter ranges of 100-450, 450-680, and 670-800 nm, respectively. The results of Raman spectra indicated that the distribution concentration of head groups in surfactants decreased but the polar epoxy groups tend to be exposed on the interface with the increase in the droplet scale. This was conducive to the nucleophilic attack of amino groups in gelatin on the epoxy group. Thus, the conversion of amino groups was related to the scale of the PDMS-E droplet. This study might provide a proper way to control the rate of interfacial reaction between immiscible macromolecule monomers. PMID- 28872326 TI - Was it race or merit?: The cognitive costs of observing the attributionally ambiguous hiring of a racial minority. AB - OBJECTIVES: This study investigated individual and situational factors that may make observing positive treatment of an ingroup member attributionally ambiguous and cognitively taxing for ethnic minority perceivers. METHOD: 163 Latino/a participants who varied in the perception that Whites are externally motivated to behave positively toward minorities (Perceived External Motivation Scale; PEMS) observed a Latino candidate selected over 2 White candidates by a White Human Resources officer. The selected candidate was or was not the most qualified and a diversity rationale was or was not provided. Participants subsequently performed a test of cognitive interference. RESULTS: When a less-qualified minority candidate was selected, the presence (vs. absence) of a diversity rationale increased cognitive interference among low PEMS participants, but decreased cognitive interference among high PEMS participants. Results suggest that a diversity rationale made the selection of a less qualified minority more ambiguous for low PEMS but less ambiguous for high PEMS participants. CONCLUSIONS: The present study informs our understanding of when and for whom Whites' positive behavior is perceived as attributionally ambiguous. (PsycINFO Database Record PMID- 28872328 TI - Equal but different: Effects of equality/inclusion and cultural pluralism on intergroup outcomes in multiethnic classrooms. AB - OBJECTIVES: Integrating research on intergroup contact and intercultural relations, we investigated effects of 2 types of cultural diversity norms (equality/inclusion and cultural pluralism) on outgroup orientation and perceived discrimination among students of immigrant and nonimmigrant background. METHOD: Our sample comprised 1,975 6th graders (Mage = 11.53, SDage = 0.69, 47% female) in Germany, of whom 1,213 (61%) were of immigrant background, defined as having at least 1 parent born in a different country. A total of 83 countries of origin were represented. We applied a multilevel framework to assess the impact of individual-level and class-level predictors on intergroup outcomes, controlling for the classroom ethnic composition, school track, and individual-level covariates. Immigrant background was treated as a moderator. RESULTS: The 2 types of cultural diversity norms were generally associated with more positive intergroup outcomes. Some of the associations differed in strength between students of immigrant and nonimmigrant background. There were stronger associations of equality/inclusion with higher outgroup orientation among students of nonimmigrant background and with lower perceived discrimination among students of immigrant background. Ethnic composition, as well as the classroom aggregated diversity norms (diversity climate) showed weaker relations with the outcome variables. CONCLUSIONS: Equality/inclusion norms and cultural pluralism norms can make complementary contributions to positive relations between students of immigrant and nonimmigrant background. Equality/inclusion norms foster positive contact and equal treatment, while cultural pluralism norms emphasize that it is also important to value diversity.1 (PsycINFO Database Record PMID- 28872327 TI - Cultural socialization attitudes and behaviors: Examining mothers' centrality, discrimination experiences, and children's effortful control as moderators. AB - OBJECTIVES: The current study examined whether mothers' cultural socialization attitudes predicted cultural socialization behaviors. In addition, we tested whether this association was moderated by children's effortful control, mothers' ethnic-racial centrality, and mothers' experiences of ethnic discrimination. METHOD: Mexican-origin young mothers (N = 181; Mage = 20.97 years) completed the Cultural Socialization Attitudes Measure, a revised version of the Multidimensional Inventory of Black Identity, the Child Behavior Questionnaire Very Short Form, and the Perceived Discrimination Scale during an interview and then completed the Cultural Socialization Behaviors Measure a year later. RESULTS: Findings indicated that mothers' cultural socialization attitudes when their children were 4 years of age positively predicted their cultural socialization behaviors 1 year later. Furthermore, experiencing higher ethnic discrimination strengthened the association between mothers' cultural socialization attitudes and behaviors. In addition, mothers' ethnic-racial centrality and children's effortful control were positively associated with mothers' cultural socialization behaviors. CONCLUSIONS: These findings contribute to the literature by underscoring the role of individual characteristics and context in cultural socialization efforts with young children over time. (PsycINFO Database Record PMID- 28872329 TI - Sequential effects modulate spatial biases. AB - Healthy individuals usually display a bias toward the left side of space. This effect can be measured in a line bisection task or, alternatively, in a landmark task where prebisected lines are presented to participants. Several factors have been shown to influence pseudoneglect, that is, to vary the magnitude of the left side bias. We performed 2 landmark experiments: 1 online (n = 801) and a 2nd in the laboratory (n = 20). Our results demonstrate that pseudoneglect is strongly modulated by the sequence of trials in a landmark task. Of particular relevance is the fact that, for some histories of responses, pseudoneglect is inverted such that apparently there is a preference for the right side. In addition, we show that the way in which the point of subjective equality depends on the previous sequence of trials is well approximated by an exponential filter, well known from the literature of sequential effects to be related to motor control. In other words, the type of sequential effects we encountered in the landmark task is consistent with a purely motor contribution, further deepening our understanding of the way motor control influences pseudoneglect. (PsycINFO Database Record PMID- 28872330 TI - The effects of verbal descriptions on performance in lineups and showups. AB - Verbally describing a face has been found to impair subsequent recognition of that face from a photo lineup, a phenomenon known as the verbal overshadowing effect (Schooler & Engstler-Schooler, 1990). Recently, a large direct replication study successfully reproduced that original finding (Alogna et al., 2014). However, in both the original study and the replication studies, memory was tested using only target-present lineups (i.e., lineups containing the previously seen target face), making it possible to compute the correct identification rate (correct ID rate; i.e., the hit rate) but not the false identification rate (false ID rate; i.e., the false alarm rate). Thus, the lower correct ID rate for the verbal condition could reflect either reduced discriminability or a conservative criterion shift relative to the control condition. In four verbal overshadowing experiments reported here, we measured both correct ID rates and false ID rates using photo lineups (Experiments 1 and 2) or single-photo showups (Experiments 3 and 4). The experimental manipulation (verbally describing the face or not) occurred either immediately after encoding (Experiments 1 and 3) or 20-min after encoding (Experiments 2 and 4). In the immediate condition, discriminability did not differ between groups, but in the delayed condition, discriminability was lower in the verbal description group (i.e., a verbal overshadowing effect was observed). A fifth experiment found that the effect of the immediate-versus-delayed manipulation may be attributable to a change in the content of verbal descriptions, with the ratio of diagnostic to generic facial features in the descriptions decreasing as delay increases. (PsycINFO Database Record PMID- 28872331 TI - How do people think about interdependence? A multidimensional model of subjective outcome interdependence. AB - Interdependence is a fundamental characteristic of social interactions. Interdependence Theory states that 6 dimensions describe differences between social situations. Here we examine if these 6 dimensions describe how people think about their interdependence with others in a situation. We find that people (in situ and ex situ) can reliably differentiate situations according to 5, but not 6, dimensions of interdependence: (a) mutual dependence, (b) power, (c) conflict, (d) future interdependence, and (e) information certainty. This model offers a unique framework for understanding how people think about social situations compared to another recent model of situation construal (DIAMONDS). Furthermore, we examine factors that are theorized to shape perceptions of interdependence, such as situational cues (e.g., nonverbal behavior) and personality (e.g., HEXACO and Social Value Orientation). We also study the implications of subjective interdependence for emotions and cooperative behavior during social interactions. This model of subjective interdependence explains substantial variation in the emotions people experience in situations (i.e., happiness, sadness, anger, and disgust), and explains 24% of the variance in cooperation, above and beyond the DIAMONDS model. Throughout these studies, we develop and validate a multidimensional measure of subjective outcome interdependence that can be used in diverse situations and relationships-the Situational Interdependence Scale (SIS). We discuss how this model of interdependence can be used to better understand how people think about social situations encountered in close relationships, organizations, and society. (PsycINFO Database Record PMID- 28872332 TI - The road to extremism: Field and experimental evidence that significance loss induced need for closure fosters radicalization. AB - The present studies examined the hypothesis that loss of personal significance fuels extremism via the need for cognitive closure. Situations of significance loss-those that make one feel ashamed, humiliated, or demeaned-are inconsistent with the desire for a positive self-image, and instill a sense of uncertainty about the self. Consequently, individuals become motivated to seek certainty and closure that affords the restoration of personal significance. Extremist ideologies should thus increase in appeal, because they promise clear-cut strategies for such restoration. These notions were supported in a series of studies ranging from field surveys of political extremists imprisoned in the Philippines (Study 1) and Sri Lanka (Study 2) to experiments conducted with American samples (Studies 3-4). Implications of these findings are considered for the psychology of extremism, and for approaches to counterradicalization, and deradicalization. (PsycINFO Database Record PMID- 28872333 TI - Examining Wellness Programs Over Time: Predicting Participation and Workplace Outcomes. AB - The return on investment of employer wellness programs has been heavily debated in recent years, yet existing research has failed to adequately assess the psychological factors that motivate program participation and how participation relates to organizationally relevant employee attitudes and behaviors. Using data over a 3-year period, we found beliefs about the value of employee wellness programs and perceived organizational support (POS) for wellness to be linked to wellness program participation through the mediation of intention to participate in the wellness program. Those with greater wellness participation were found to have higher performance ratings, higher job satisfaction, higher intention to stay, and lower turnover. However, the effects for job satisfaction and intention to stay disappeared when controlling for prior levels of satisfaction and intention to stay in cross-lagged models. Implications for scholars and practitioners are discussed. (PsycINFO Database Record PMID- 28872334 TI - Disgust sensitivity is primarily associated with purity-based moral judgments. AB - Individual differences in disgust sensitivity are associated with a range of judgments and attitudes related to the moral domain. Some perspectives suggest that the association between disgust sensitivity and moral judgments will be equally strong across all moral domains (i.e., purity, authority, loyalty, care, fairness, and liberty). Other perspectives predict that disgust sensitivity is primarily associated with judgments of specific moral domains (e.g., primarily purity). However, no study has systematically tested if disgust sensitivity is associated with moral judgments of the purity domain specifically, more generally to moral judgments of the binding moral domains, or to moral judgments of all of the moral domains equally. Across 5 studies (total N = 1,104), we find consistent evidence for the notion that disgust sensitivity relates more strongly to moral condemnation of purity-based transgressions (meta-analytic r = .40) than to moral condemnation of transgressions of any of the other domains (range meta-analytic rs: .07-.27). Our findings are in line with predictions from Moral Foundations Theory, which predicts that personality characteristics like disgust sensitivity make people more sensitive to a certain set of moral issues. (PsycINFO Database Record PMID- 28872335 TI - Do emotional control beliefs lead people to approach positive or negative situations? Two competing effects of control beliefs on emotional situation selection. AB - Control beliefs are widely acknowledged to play a critical role in self regulation and well-being, but their impact on decisions to approach or avoid situations that vary in emotional valence remains unclear. We propose that two contradictory, yet equally intuitive, predictions can be made about the impact of control beliefs on emotional situation selection. On the one hand, control beliefs might encourage individuals to initiate proactive emotion regulatory efforts, helping people select positive situations. On the other hand, control beliefs might promote a sense of confidence in one's ability to manage emotions once they arise, helping people select negative situations. We propose that both effects occur via different mechanisms and suppress one another: control beliefs facilitate (1) positivity engagement by enhancing awareness of opportunities to regulate emotions, and (2) negativity engagement by enhancing confidence in one's ability to handle negative situations. We found support for this framework in four studies. Consistent with our hypotheses, control beliefs (measured in Studies 1-3 and manipulated in Study 4) exerted two simultaneous and competing effects on emotional situation selection (assessed via self-report measures in Studies 1 and 2 and behaviorally in Studies 3 and 4) via the proposed mechanisms, and evidence of suppression was found. New opportunities for research on control beliefs, emotion regulation, and motivation are discussed. (PsycINFO Database Record PMID- 28872336 TI - Differential effects of rejection and acceptance on feeling shocked, numb, and neutral. AB - According to the numbness hypothesis, rejection may not result in negative affect, but rather create several "nonvalenced" feelings, including feeling shocked, neutral, and numb. These feelings are hypothesized to lessen the extent to which people respond emotionally to various situations (emotional responsiveness). This project investigates (a) whether rejection produces these rarely assessed "nonvalenced" states, (b) to what extent these states are similar to one another and not negative, and (c) whether these states account for rejected individuals' lack of emotional responsiveness. In 3 experiments, participants experienced 3 different rejection manipulations. Participants reported their positive, negative, and "nonvalenced" feelings (Experiments 1, 2, and 3), and completed measures of emotional responsiveness (Experiments 2 and 3). A meta-analysis across the 3 experiments indicated that rejection increased negative affectivity, anger, hurt feelings, sadness, shock, and numbness, and decreased happiness, but did not significantly alter neutrality, positive affectivity, nor anxiety. In line with the view that these nonvalenced states are discriminable from each other, but in contrast with the numbness hypothesis, shock and numbness were positively correlated with negative affective states; whereas neutrality displayed weaker to null associations with them. Lastly, neither shock, neutrality, nor numbness mediated the link between rejection and emotional responding. In fact, increased negative and positive affect mediated the association between rejection and enhanced emotional responding. Overall, the data are inconsistent with the numbness hypothesis; albeit rejection produces shock and numbness, these 2 states are highly associated with increased negative affect and did not dampen emotional responsiveness. (PsycINFO Database Record PMID- 28872337 TI - The short-term stability of life satisfaction judgments. AB - Life satisfaction judgments are thought to reflect people's overall evaluation of the quality of their lives as a whole. Because the circumstances of these lives typically do not change very quickly, life satisfaction judgments should be relatively stable over time. However, some evidence suggests that these judgments can be easily manipulated, which leads to low stability even over very short intervals. The current study uses a unique data set that includes multiple assessments of life satisfaction over both long (up to 4 years) and short (over the course of a single interview) intervals to assess whether information that is made salient during the course of an interview affects life satisfaction judgments at the end of the interview. Results suggest that this intervening information has only small effects on the final judgment and that placement within an interview has little influence on the judgment that people provide. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28872338 TI - Perceptions of valence and arousal uniquely contribute to perceptions of ambiguous group membership from faces. AB - Although previous research has considered the role of emotional valence in the perception and communication of group membership, the influence of perceived emotional arousal remains relatively unexplored. Here, we examined how valence and arousal simultaneously contribute to perceptions of sexual orientation and political affiliation at 3 distinct levels of analysis: within perceivers, between perceivers, and between targets. We found that valence distinguished targets best, reflecting socioemotional stereotypes, whereas arousal largely accounted for individual differences among perceivers, suggesting that perceptions of group membership partly depend on how each perceiver evaluates targets' level of arousal. Valence and arousal therefore provide distinct information during social categorization, highlighting the importance of considering different levels of analysis to achieve a more complete understanding of person perception. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28872339 TI - Beyond personality traits: Which facial expressions imply dominance in two-person interaction scenes? AB - The ability to perceive a person's dominance plays an important role in survival and pro-social behavior. Perceived dominance has been investigated via assessments of facial expressions in 1-on-1 interaction situations, with expressions of anger and disgust judged to be more dominant. Given that human social interactions are complex, and multiple individuals interact at the same time, we investigated perceptions of trait dominance (an individual's competence and tendency to engage in dominant behavior) and relative dominance (an individual's social dominance within a social group). Participants were asked to rate the trait dominance of individuals depicted in pictorial stimuli. Results indicated that participants judged individuals expressing anger and disgust higher on trait dominance than individuals expressing happiness. Interestingly, when participants judged which of 2 individuals were more dominant in a confrontation scene, they judged individuals with happy expressions to be more dominant. These perceptions were consistent independent of the overall context. These results suggest that humans perceive social dominance without comparing personality trait dominance, and that criteria for evaluating social and personality trait dominance differ. (PsycINFO Database Record PMID- 28872341 TI - Smelling the space around us: Odor pleasantness shifts visuospatial attention in humans. AB - The prompt recognition of pleasant and unpleasant odors is a crucial regulatory and adaptive need of humans. Reactive answers to unpleasant odors ensure survival in many threatening situations. Notably, although humans typically react to certain odors by modulating their distance from the olfactory source, the effect of odor pleasantness over the orienting of visuospatial attention is still unknown. To address this issue, we first trained participants to associate visual shapes with pleasant and unpleasant odors, and then we assessed the impact of this association on a visuospatial task. Results showed that the use of trained shapes as flankers modulates performance in a line bisection task. Specifically, it was found that the estimated midpoint was shifted away from the visual shape associated with the unpleasant odor, whereas it was moved toward the shape associated with the pleasant odor. This finding demonstrates that odor pleasantness selectively shifts human attention in the surrounding space. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28872340 TI - Relations of emotion-related temperamental characteristics to attentional biases and social functioning. AB - The current study examined whether an important temperamental characteristic, effortful control (EC), moderates the associations between dispositional anger and sadness, attention biases, and social functioning in a group of preschool aged children (N = 77). Preschoolers' attentional biases toward angry and sad facial expressions were assessed using eye-tracking, and we obtained teachers' reports of children's temperament and social functioning. Associations of dispositional anger and sadness with time looking at relevant negative emotional stimuli were moderated by children's EC, but relations between time looking at emotional faces and indicators of social functioning, for the most part, were direct and not moderated by EC. In particular, time looking at angry faces (and low EC) predicted high levels of aggressive behaviors, whereas longer time looking at sad faces (and high EC) predicted higher social competence. Finally, latency to detect angry faces predicted aggressive behavior under conditions of average and low levels of EC. Findings are discussed in terms of the importance of differentiating between components of attention biases toward distinct negative emotions, and implications for attention training. (PsycINFO Database Record PMID- 28872342 TI - Proactive deprioritization of emotional distractors enhances target perception. AB - There are many situations in which it is important to focus on a task in the face of emotional distraction. Yet, emotional distractors can impair our ability to report items that appear soon after them, an effect known as emotion-induced blindness (EIB). To what degree does it help to know about emotional distractors ahead of time? Can we deprioritize emotional distractors when forewarned that they will appear? To address this question, we tested whether participants could overcome EIB when forewarned about the nature of an emotional distractor. On each trial, participants searched for 1 target (a rotated picture) presented within a rapid serial visual stream of upright images. An aversive, erotic, or neutral distractor could precede the target by either 200 or 400 ms. At the start of some trials, participants were informed which kind of distractor would appear on that trial, but in other trials they received no advance information. Results revealed that the provision of distractor information significantly improved target perception as early as 200 ms following both aversive and erotic distractors. These results suggest that people can "brace themselves" in the service of an attentional task by proactively deprioritizing emotional distractors. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28872343 TI - In the spirit of full disclosure: Maternal distress, emotion validation, and adolescent disclosure of distressing experiences. AB - The purpose of the current study was to investigate the dynamic process of disclosure within the adolescent-mother relationship by examining how maternal personal distress and validation of adolescent negative affect would be related to adolescent disclosure of a distressing experience for the first time. A community sample of 66 mothers and their adolescent children (M = 14.31 years, 58% female) participated. The adolescents disclosed an emotionally distressing experience to their mothers for the first time. Mothers' validating behaviors and personal distress in response to their adolescents' expressions of negative emotion were predictive of adolescent disclosure. Adolescents made less detailed or substantive disclosures to their mothers when adolescents perceived their mothers as less validating of their negative emotions and when mothers were more likely to become distressed themselves. Neither adolescent-perceived maternal invalidation nor observed maternal validating or invalidating behaviors were related to adolescent disclosure. Maternal personal distress was further indirectly associated with less substantive disclosures through less maternal validation of negative emotion. These findings provide the foundation for future research evaluating clinical interventions targeted at increasing mothers' emotion regulation skills and validation of children's negative emotions. Such interventions may provide an effective way to promote better mother-adolescent communication, especially in regard to distressing experiences. (PsycINFO Database Record PMID- 28872344 TI - Quality of return to work in patients with mild traumatic brain injury: a prospective investigation of associations among post-concussion symptoms, neuropsychological functions, working status and stability. AB - PRIMARY OBJECTIVE: Although 'return to work' (RTW) has been always emphasized for patients with mild traumatic brain injury (MTBI), methodological drawbacks weakened its representativeness. This study thus aims to evaluate the 'work quality' (WQ) which originated from 'working status' and 'working stability' simultaneously, and to further explore the associations among post-concussion symptoms (PCS), neuropsychological functions and WQ. METHODS AND PROCEDURES: A total of 179 participants, which included 132 patients with MTBI and 47 healthy participants, were prospectively recruited. The work quality index (WQI) was developed to evaluate WQ. All patients were evaluated for their PCS, neuropsychological functions and WQ at two weeks post-injury (T1), while PCS and WQ were recorded by one month post-injury (T2). RESULTS: More than half of the patients were not able to retain their pre-injury jobs at T1, while 26% of the patients still failed to regain previous works at T2. Interestingly, WQ was significantly associated with educational levels and physical PCS, such as headache and dizziness. CONCLUSIONS: Simultaneously considering working status and stability to reveal the quality of RTW is merited. A higher educational level might be a protective factor for successful RTW, and ameliorating physical symptoms is also necessary to get favourable WQ by one month after MTBI. PMID- 28872345 TI - Intra-cerebral cannabidiol infusion-induced neuroprotection is partly associated with the TNF-alpha/TNFR1/NF-kB pathway in transient focal cerebral ischaemia. AB - BACKGROUND: Stroke is a neurological disease, which, in addition to high mortality, imposes many financial and mental burdens on families and the society. The main objective of this study was to investigate the effect of cannabidiol (CBD) on one of the major inflammatory pathways in cerebral ischaemia. METHOD: Using stereotaxic surgery, the cannula was implanted into the right lateral ventricle of rats. CBD (50, 100, and 200 ng/rat; i.c.v.) was administrated for five consecutive days. After pretreatment, the rats were subjected to 60 min of right middle cerebral artery occlusion (MCAO). After 24 h, neurological deficits score, infarct volume, brain oedema, and blood-brain barrier (BBB) permeability in total, core, and penumbra areas were assessed. The expression of tumour necrosis factor alfa (TNF-alpha), tumour necrosis factor receptor 1 (TNFR1), and nuclear factor-kappa B (NF-kB) in the mentioned regions was also studied. RESULTS: Administration of CBD (100 and 200 ng/rat) caused a significant reduction in infarction, brain oedema, and BBB permeability compared with the vehicle-received group. Down-regulation of TNF-alpha, TNFR1, and NF-kB expression was also observed by CBD. CONCLUSION: The results achieved in this study support the idea that CBD has a cerebroprotective effect (partly through suppression of TNF-alpha, TNFR1, and NF-kB) on ischaemic injury. ABBREVIATIONS: CBD, cannabidiol; ANOVA, analysis of variance; PVDF, polyvinylidene difluoride; SDS PAGE, sodium dodecyl sulphate polyacrylamide gel electrophoresis; SEM, standard error of mean. PMID- 28872346 TI - Seasonal Variations in Meeting Physical Activity Recommendations and Development of Overweight during Adolescence. AB - BACKGROUND: Few longitudinal studies have examined seasonal variation in meeting physical activity (PA) recommendations in association with incident overweight among adolescents. METHODS: We assessed self-reported, season-specific PA among 12,949 adolescents in two US cohorts (Growing Up Today Studies 1 and 2). We examined the relationship between the number of seasons per year that adolescents met the recommended amount of moderate-to-vigorous physical activity (MVPA) and vigorous physical activity (VPA), respectively, and the development of incident overweight at the next survey period. The sex-specific analyses controlled for follow-up time, survey month, age, race/ethnicity, sexual maturation, television viewing, region of the country, and intakes of sugar-sweetened beverages and fried foods away from home. RESULTS: About one-third (34%) of adolescents met the MVPA recommendation of 60 minutes/day, and one-quarter (24%) the VPA recommendation of 3 hours/week, for four seasons of the baseline year. The risk of becoming overweight was 23% (95% confidence interval [CI]: 5%-45%) higher for girls who met the MVPA recommendation for 2 (vs. 4) seasons/year. The risk was similar for girls who met the recommendation for 1 (vs. 4) season/year (odds ratio = 1.23, 95% CI: 1.05-1.44). The number of seasons each year boys met the MVPA recommendation, or girls or boys met the VPA recommendation, was not associated with an increased risk of incident overweight. CONCLUSIONS: Meeting the MVPA recommendation for 1 or 2 (vs. 4) seasons/year is related to higher risk of becoming overweight among adolescent girls but not boys. Interventions to increase PA levels each season may contribute to overweight prevention efforts among girls. PMID- 28872347 TI - Central aortic systolic blood pressure can predict prolonged QTc duration better than brachial artery systolic blood pressure in rural community residents. AB - OBJECTIVES: Previous studies have suggested that prolonged electrocardiogram QTc duration was independent risk factor for both increased cardiovascular and all cause mortality, but there was no dating about the relationship between central aortic systolic blood pressure (CASP) and QTc duration. The aim of this study was to analyze the relationship between CASP and QTc duration, and assess whether CASP can predict prolonged QTc duration more than BSBP. METHODS: A total of 500 patients were enrolled in this study, central and brachial aortic blood pressure and electrocardiogram QTc duration were measured. Pearson correlation was assessed for determining the associations of QTc duration with clinical conditions. Multivariate logistic regression analyses were performed to determine the independent predictor of prolonged QTc duration. Receiver operating characteristic (ROC) curve was used to evaluate the utility of blood pressure for prolonged QTc duration. RESULTS: We found QTc durations were significantly positive with CASP (r = 0.308, p < 0.001), BSBP (r = 0.227, p < 0.001), and age (r = 0.154, p = 0.010), but negatively related to heart rate (r = -440, p < 0.001). A multiple logistic regression analysis demonstrated that the CASP was an independent determinant of prolonged QTc (OR = 1.648; 95%CI: 1.032, 2.101; p < 0.001). CASP had a better predictive value for prolonged QTc duration than (AUC: 0.771 vs. 0.646, p < 0.001) BSBP. CONCLUSION: Our results suggested that the non invasive CASP is independently correlated with QTc duration, and CASP can predict prolonged QTc duration more than BSBP. PMID- 28872348 TI - Marijuana and Breastfeeding: Applicability of the Current Literature to Clinical Practice. AB - With recent legalization of marijuana in numerous U.S. states, the risk of marijuana exposure via breast milk is a rising concern. This review analyzes the available human and animal literature regarding maternal use of marijuana during lactation. The findings can be categorized into four areas of analysis: effects of marijuana on the mother, transfer into milk, transfer to the offspring, and effects on the offspring. Human and animal data have reported decreased prolactin levels as well as potential maternal psychological changes. Animal and human studies have reported transfer into milk; levels were detected in animal offspring, and metabolites were excreted by both human and animal offspring. Further, animal data have predominately displayed motor, neurobehavioral, and developmental effects, whereas human data suggested possible psychomotor outcomes; however, some studies reported no effect. Despite these results, many human studies were marred by limitations, including small sample sizes and confounding variables. Also, the applicability of animal data to the human population is questionable and the true risk of adverse effects is not entirely known. There are large gaps in the literature that need to be addressed; in particular, studies need to focus on evaluating the short- and long-term consequences of maternal marijuana use for the infant and the potential for different risks based on the frequency of maternal use. Until further evidence becomes available, practitioners need to weigh the benefits of breastfeeding for mother and child, with the potential influence of marijuana on infant development when determining the infant's most suitable form of nutrition. PMID- 28872349 TI - Urinary liver-type fatty acid-binding protein is associated with subendocardial viability ratio in middle- and older-aged adults. AB - BACKGROUND: To identify one of the physiological underlying mechanisms of the predictive effects of urinary liver-type fatty acid-binding protein (L-FABP) for the onset of cardiovascular disease (CVD), we investigated the relationship between urinary L-FABP levels and subendocardial viability ratio (SEVR), a marker of myocardial perfusion, in middle- and older-aged adults. METHODS: This was a cross-sectional study of 249 middle- and older-aged adults (aged 46-83 years). We measured urinary L-FABP levels and central hemodynamic parameters, including SEVR, calculated by pulse wave analysis using an applanation tonometry. RESULTS: In the participants stratified in accordance with the tertiles of urinary L-FABP levels, SEVR decreased in a stepwise fashion with increasing tertiles (p < 0.001). Furthermore, this association remains significant after the consideration of various confounders. On the contrary, urinary albumin levels were not independently related with SEVR. CONCLUSION: Our results demonstrated that urinary L-FABP levels were independently associated with the SEVR of the middle- and older-aged adults. This result suggests that the increase in urinary L-FABP levels even within the normal range might be related to the decrease in myocardial perfusion (SEVR). PMID- 28872350 TI - Strategies towards rapid generation of forefoot model incorporating realistic geometry of metatarsals encapsulated into lumped soft tissues for personalized finite element analysis. AB - Use of finite element (FE) foot model as a clinical diagnostics tool is likely to improve the specificity of foot injury predictions in the diabetic population. Here we proposed a novel workflow for rapid construction of foot FE model incorporating realistic geometry of metatarsals encapsulated into lumped forefoot's soft tissues. Custom algorithms were implemented to perform unsupervised segmentation and mesh generation to directly convert CT data into a usable FE model. The automatically generated model provided higher efficiency and comparable numerical accuracy when compared to the model constructed using a traditional solid-based mesh process. The entire procedure uses MATLAB as the main platform, and makes the present approach attractive for creating personalized foot models to be used in clinical studies. PMID- 28872351 TI - Neuropsychological outcome of children with traumatic brain injury and its association with late magnetic resonance imaging findings: A cohort study. AB - OBJECTIVES: To evaluate neuropsychological outcome after traumatic brain injury (TBI) and its association with trauma severity and late magnetic resonance imaging (MRI) findings. METHODS: Prospective cohort study of patients with TBI admitted to the paediatric intensive care unit over 5 years. Trauma severity was determined by Glasgow Coma Scale (GCS), neurological outcome by King's Outcome Scale for Childhood Head Injury (KOSCHI) and neuropsychological outcome by Wechsler Intelligence Scale for Children - Fourth Edition. RESULTS: Twenty-five children (median age 6 years at trauma) were included. Patients were divided into Disability (DIS)(n = 10) and Good Recovery (GR)(n = 15) groups. Initial GCS score was not significantly different in both groups (median 6 vs. 10; p = 0.34). DIS group had lower values of working memory index (WMI)(median 74 vs. 94; p = 0.004), perceptual reasoning index (PRI)(75 vs. 96; p = 0.03), verbal comprehension index (VCI)(65 vs. 84; p = 0.02), processing speed index (PSI)(74 vs. 97; p = 0.01) and full-scale intelligence quotient (FSIQ)(65 vs. 87; p = 0.008). In the GR group, 60% of patients had normal or minimally altered MRI versus 10% of patients in the DIS group (p = 0.018). Fractional anisotropy positively correlated with WMI(r = 0.65; p = 0.005), PRI(r = 0.52; p = 0.03) and FSIQ(r = 0.50; p = 0.04). CONCLUSIONS: Neuropsychological impairment was observed in 40% of children who suffered a TBI and was associated with late MRI abnormalities. PMID- 28872352 TI - Patient movement characteristics and the impact on CBCT image quality and interpretability. AB - OBJECTIVES: To assess the impact of patient movement characteristics and metal/radiopaque materials in the field-of-view (FOV) on CBCT image quality and interpretability. METHODS: 162 CBCT examinations were performed in 134 consecutive (i.e. prospective data collection) patients (age average: 27.2 years; range: 9-73). An accelerometer-gyroscope system registered patient's head position during examination. The threshold for movement definition was set at >=0.5-mm movement distance based on accelerometer-gyroscope recording. Movement complexity was defined as uniplanar/multiplanar. Three observers scored independently: presence of stripe (i.e. streak) artefacts (absent/"enamel stripes"/"metal stripes"/"movement stripes"), overall unsharpness (absent/present) and image interpretability (interpretable/not interpretable). Kappa statistics assessed interobserver agreement. chi2 tests analysed whether movement distance, movement complexity and metal/radiopaque material in the FOV affected image quality and image interpretability. Relevant risk factors (p <= 0.20) were entered into a multivariate logistic regression analysis with "not interpretable" as the outcome. RESULTS: Interobserver agreement for image interpretability was good (average = 0.65). Movement distance and presence of metal/radiopaque materials significantly affected image quality and interpretability. There were 22-28 cases, in which the observers stated the image was not interpretable. Small movements (i.e. <3 mm) did not significantly affect image interpretability. For movements >= 3 mm, the risk that a case was scored as "not interpretable" was significantly (p <= 0.05) increased [OR 3.2-11.3; 95% CI (0.70-65.47)]. Metal/radiopaque material was also a significant (p <= 0.05) risk factor (OR 3.61-5.05). CONCLUSIONS: Patient movement >=3 mm and metal/radiopaque material in the FOV significantly affected CBCT image quality and interpretability. PMID- 28872354 TI - Video and clinical screening of national rugby league players suspected of sustaining concussion. AB - PRIMARY OBJECTIVE: This study reviewed the available sideline Sport Concussion Assessment Tool-Third Edition (SCAT3) performance of players who were removed from play using the 'concussion interchange rule' (CIR), the available video footage of these incidences, and associated return to play and concussion diagnosis decisions. RESEARCH DESIGN: Descriptive, observational case series. METHODS AND PROCEDURES: Data were collected from all NRL players who used the CIR during the 2014 season. MAIN OUTCOMES AND RESULTS: Complete SCAT3 and video analysis data were available for 38 (23%) of 167 uses of the concussion interchange rule, of which 20 (52.6%) players were medically diagnosed with concussion. Those with video evidence of unresponsiveness performed more poorly on the modified Balance Error Scoring System (M-BESS; p = .04; Cohen's d = .69) and reported greater symptoms (p = .03; d = .51). Similarly, players with a vacant stare reported greater symptoms (p = .05; d = .78). Those who demonstrated three signs (unresponsiveness, vacant stare and gait ataxia) performed more poorly on the M-BESS (p = .03; d = 1.4) and reported greater symptoms than those with no observable signs (p = .03; d = 1.4). CONCLUSIONS: The SCAT3 is sensitive to the acute effects of concussion in professional athletes; however, a minority of injured athletes might go undetected by this test. PMID- 28872353 TI - Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant. AB - RATIONALE: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. OBJECTIVES: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. METHODS: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. MEASUREMENTS AND MAIN RESULTS: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. CONCLUSIONS: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination. PMID- 28872355 TI - The role of stump pressure and cerebral oximetry in predicting ischaemic brain damage during carotid endarterectomy. AB - Objective is to compare the predictive value of stump pressure (SP) and cerebral oximetry (rSO2) levels in the evaluation of ischaemic injury of the cerebrum during clamping of the carotid artery (CCA) without temporary shunt (TS). Methods We included 84 patients with an asymptomatic stenosis (>70%) of the internal carotid artery (ICA) who underwent carotid endarterectomy (CEA) under GA. Cerebral ischaemic tolerance (CIT) was determined on the basis of SP, rSO2 and ?rSO2 (?rSO2 from baseline) during CCA. The levels of S100 protein (S100) and neuron-specific enolase (NSE) were measured on each stage of the study. MRI was performed for all patients. Results There were no perioperative strokes and myocardial infarctions during the study. Temporary shutdown of blood flow in CAs during CEA is accompanied by a significant elevation of S100, NSE concentration with their subsequent restoration (three days after surgery). ROC analysis showed that none of the methods for CIT assessment (SP, rSO2 and ?rSO2) was a valuable predictor of cerebral damage during CEA. Conclusion SP with a threshold value of <=40 mmHg has an average quality of prediction (AUC = 63). ?rSO2 of >=20% and a threshold value of rSO2 <= 40% have an unsatisfactory quality of prediction (AUC < 60). PMID- 28872356 TI - Vitamin B6 prevents isocarbophos-induced vascular dementia in rats through N methyl-D-aspartate receptor signaling. AB - BACKGROUND: We have previously reported that the long-term exposure of organophosphorus induces vascular dementia (VD) in rats. As a coenzyme, vitamin B6 is mainly involved in the regulation of metabolisms. Whether vitamin B6 improves VD remains unknown. METHODS: The model of VD was induced by feeding rats with isocarbophos (0.5 mg/kg per two day, 12 weeks). The blood flow of the posterior cerebral artery (PCA) in rat was assessed by transcranial Doppler (TCD). The learning and memory were evaluated by the Morris Water Maze (MWM) test. RESULTS: Administration of vitamin B6 increased the blood flow in the right and left posterior cerebral arteries and improved the functions of learning and memory in isocarbophos-treated rats. Vitamin B6 increased the protein levels of N methyl-D-aspartate receptor (NMDAR) 2B, postsynaptic densities (PSDs) protein 95, and calmodulin-dependent protein kinase II (CaMK-II) in the hippocampus, which were decreased by isocarbophos in rats. Morphological analysis by light microscope and electronic microscope indicated disruptions of the hippocampus caused by isocarbophos were normalized by vitamin B6. Importantly, the antagonist of NMDAR signaling by eliprodil abolished these beneficial effects produced by vitamin B6 on PCA blood flow, learning, memory, and hippocampus structure in rats, as well as the protein expression of NMDAR 2B, PSDs protein 95, and CaMK-II in the hippocampus. CONCLUSION: Vitamin B6 activates NMDAR signaling to prevent isocarbophos-induced VD in rats. PMID- 28872357 TI - ACMT and AACT position statement: preventing occupational fentanyl and fentanyl analog exposure to emergency responders. PMID- 28872358 TI - Nocturnal diastolic blood pressure decline is associated with higher 25 hydroxyvitamin D level and standing plasma renin activity in a hypertensive population. AB - Patients with nondipper hypertension are known to carry a high risk of cardiovascular complications. Vitamin D deficiency is associated with hypertension. Because vitamin D deficiency activates the renin-angiotensin aldosterone system (RAAS), we hypothesized that this vitamin would interact with the RAAS to influence blood pressure (BP) in nondipper hypertensive patients. We performed a cross-sectional analysis of 1,007 outpatients with hypertension (HTN). Dipper and nondipper patterns were detected, and the two groups were matched for clinical, laboratory, 25-hydroxyvitamin D (25OHD) levels, and ambulatory blood pressure recording. Plasma renin activity (PRA), angiotensin II, and plasma aldosterone concentration (PAC) were assessed in 174 patients treated with calcium channel blockers or no medication. The mean 25OHD concentration in the entire study population was 12.3ng/dL, and the prevalence of vitamin D deficiency was 87.0%. Dipper and nondipper HTN were noted in 187 patients (24.6%) and 573 patients (75.4%). 25OHD levels were similar between nondipper and dipper HTN groups. Forward stepwise logistic regression analysis showed that BMI and age were independent predictors of nondipper HTN. Neither 25OHD levels nor RAAS components were included in the model. In correlation analyses, nocturnal decline of diastolic BP was positively associated with 25OHD levels and standing PRA (r = 0.152 p = 0.045, r = 0.165 p = 0.038, respectively). The present study showed that vitamin D deficiency was astonishingly prevalent in hypertensive subjects residing in Xinjiang, China. There may be a weakly association of nocturnal DBP decline with 25OHD levels and standing PRA levels. We found no association between vitamin D deficiency and nondipper HTN. PMID- 28872359 TI - Ambulatory blood pressure results and heart rate variability in patients with premature ventricular contractions. AB - BACKGROUND: The presence of premature ventricular contractions (PVCs) is a sign of arrhythmia and typically trigerred by over stimulation of the sympathetic nervous system. This study examined the relationships among PVCs, heart rate variability (HRV), and 24-hour ambulatory blood pressure (ABP) results. METHODS: This observational clinical study evaluated a cohort of 100 consecutive patients (58 women and 42 men) with PVCs. The individuals were split into occasional (n = 50) and frequent (n = 50) PVCs groups. All Holter recordings were performed during a working day. RESULTS: Daytime low-frequency power (LFP), daytime low frequency/high frequency (LF/HF), nighttime LFP, and nighttime LF/HF and 24-hour systolic blood pressure (SBP) were slightly higher in the frequent PVCs group (p = 0.046, p = 0.027, p = 0.038, p = 0.032, and p < 0.001, respectively). Hypertension, LF, LF/HF, 24-hour SBP were positively correlated with PVCs (r = 0.305, p = 0.002; r = 0.269, p = 0.007; r = 0.403, p < 0.001, respectively). CONCLUSION: Frequent PVCs reflect dominance of the sympathetic system according to the results of Holter recordings. This study showed that PVC had a significant association with high blood pressure values. Assessment of ABP and HRV in patients with PVCs is part of a comprehensive approach to the assessment of cardiovascular regulation. PMID- 28872360 TI - Cardiorespiratory fitness and walking endurance improvements after 12 months of an individualised home and community-based exercise programme for people after stroke. AB - OBJECTIVE: To evaluate the immediate and longer-term effects of an individually tailored, home- and community-based exercise programme with ongoing remote support in people with stroke on cardiorespiratory fitness (CRF), ambulation and health-related quality of life (HRQoL). METHODS: Twenty people 5.3 +/- 3.5 months post stroke completed the 12-week HowFITSS? exercise programme aimed at increasing CRF and daily physical activity. Support was provided by phone and email, which decreased in frequency over time. Participants were assessed at baseline, then at 3, 6 and 12 months after initiation of the intervention. CRF (VO2peak) was evaluated using a portable metabolic system during the 6-minute walk test (6MWT), the Shuttle Walk Test (SWT) and the cycle graded exercise test (cGXT). Walking speed, balance, body composition, fatigue, depression and HRQoL were also measured. RESULTS: CRF improved significantly from pre-intervention to 12-month follow-up on the 6MWT (Effect Size, ES = 0.87; p = 0.002) and cGXT (ES = 0.60; p < 0.001), with more modest improvements on the SWT (ES = 0.52; p = 0.251). From baseline to 12 months, significant within-participant improvements were found for self-selected walking speed, balance and HRQoL. Performances on the remaining tests were maintained over the post-intervention period. CONCLUSION: There may be health benefits of providing people with stroke an exercise intervention with long-term support that encourages increased regular physical activity. PMID- 28872361 TI - Prevalence of sleep apnea and cardiovascular risk factors in patients with hypertension in a day hospital model. AB - INTRODUCTION: To identify patients at risk for obstructive sleep apnea (OSA) syndrome at a specialized hypertension center, we administered questionnaires and used respiratory polygraphy (RP). RESULTS: We studied 168 patients (64.8% men and 35.2% women). Patients' body mass index (BMI) was 34.7 +/- 6.79 and Epworth Sleepiness Scale (ESS) scores were 8.01 for male and 8.92 for women (p = 0.69). RP recordings revealed AHI (Apnea-Hypopnea Index) of 18.03 +/- 15.7, an ODI (Oxygen Desaturation Index) of 18.6 +/- 15.2, and a time oxygen saturation <90% (%) of 20.8 +/- 24.3. Around 44% of patients had an AHI of >15 events/h, and continuous positive airway pressure (CPAP) was recommended to 69 patients (41.07%). Pulse wave velocity (PWV) showed high values in AHI > 15/h (p = 0.050), and carotid intima-media thickness (IMT) did not correlate with AHI > 15; right IMT: 0.83 +/- 1.3 versus 0.78 +/- 0.13 mm (p = 0.41) and 0.82 +/- 0.16 versus 0.78 +/- 0.19 mm (p = 0.40). However, we find correlation with carotid plaque (p = 0.046). The ACC/AHA calculator revealed a gradual increase in the risk of cardiovascular events: 8.7% with AHI < 5/h, and 30.3% in severe OSA. CONCLUSIONS: In hypertension (HT) patients, RP revealed a high prevalence of OSA associated with carotid artery disease, high PWV, and increased cardiovascular risk. PMID- 28872362 TI - Ferulic acid but not alpha-lipoic acid effectively protects THP-1-derived macrophages from oxidant and pro-inflammatory response to LPS. AB - OBJECTIVE: The diet supplementation with antioxidants-rich products is a way to protect people from free radical-induced diseases. In this study, we compare the anti-inflammatory/antioxidant activity of two compounds available as supplements: alpha lipoic acid (ALA) and ferulic acid (FA). MATERIALS AND METHODS: The free radical scavenging capacity of ALA and FA in the cell free system was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Anti-inflammatory activity of both compounds was determined, in vitro, on THP-1 derived macrophages model, both resting (not stimulated) and inflammatory (lipopolysaccharide- or tumor-necrosis factor alpha-stimulated). RESULTS: We have found that FA exhibits much higher radical scavenging activity than ALA, in cell free system. The functional assays demonstrated that although both ALA and FA limited the reactive oxygen species (ROS) formation in the presence of inflammatory macrophages, the latter acid was significantly more effective. Only FA reduced the release of pro-inflammatory interleukin 1beta and interleukin 6 by lipopolysaccharide-treated macrophages. Neither FA nor ALA affected the viability of macrophages. CONCLUSION: Among those two compounds only FA has significant free radical scavenging activity in cell free system and acts as anti-inflammatory and antioxidant agent on macrophages. It can be assumed that application of FA in a diet can protect the host from the development and/or progression of inflammation. PMID- 28872363 TI - Docosahexaenoic acid (DHA) at the sn-2 position of triacylglycerols increases DHA incorporation in brown, but not in white adipose tissue, of hamsters. AB - We hypothesised that the incorporation of docosahexaenoic acid (DHA) across adipose tissues will be higher when it is ingested as triacylglycerols (TAG) structured at the sn-2 position. Ten-week old male hamsters were allocated to 4 dietary treatments (n = 10): linseed oil (LSO-control group), fish oil (FO), fish oil ethyl esters (FO-EE) and structured DHA at the sn-2 position of TAG (DHA-SL) during 12 weeks. In opposition to the large variations found for fatty acid composition in retroperitoneal white adipose tissue (WAT), brown adipose tissue (BAT) was less responsive to diets. DHA was not found in subcutaneous and retroperitoneal WAT depots but it was successfully incorporated in BAT reaching the highest percentage in DHA-SL. The PCA on plasma hormones (insulin, leptin, adiponectin) and fatty acids discriminated BAT from WATs pointing towards an individual signature on fatty acid deposition, but did not allow for full discrimination of dietary treatments within each adipose tissue. PMID- 28872364 TI - Can Cyberloafing and Internet Addiction Affect Organizational Information Security? AB - Researchers have noted potential links between Internet addiction, the use of work computers for nonwork purposes and an increased risk of threat to the organization from breaches in cybersecurity. However, much of this research appears conjectural in nature and lacks clear empirical evidence to support such claims. To fill this knowledge gap, a questionnaire-based study explored the link between cyberloafing, Internet addiction, and information security awareness (ISA). A total of 338 participants completed an online questionnaire, which comprised of the Online Cognition Scale, Cyberloafing Scale, and the Human Aspects of Information Security Questionnaire. Participants who reported higher Internet addiction and cyberloafing tendencies had lower ISA, and Internet addiction and cyberloafing predicted a significant 45 percent of the variance in ISA. Serious cyberloafing, such as the propensity to visit adult websites and online gambling, was shown to be the significant predictor for poorer ISA. Implications for organizations and recommendations to reduce or manage inappropriate Internet use are discussed. PMID- 28872365 TI - Recovery progression and symptom resolution in sport-related mild traumatic brain injury. AB - OBJECTIVE: To characterize the recovery progression of a group of athletes who participated in a concussion management program based on (1) group analysis and (2) individual analysis. SETTING: Concussion management clinic. PARTICIPANTS: Thirty athletes (22 males, 8 females; baseline age = 16.23 +/- 2.40 years) who had undergone four assessments: one baseline and three post-injury assessments at 3, 8, 15 days post-injury. DESIGN: Retrospective clinical. MAIN MEASURES: Four neurocognitive scores of the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) including verbal memory, visual memory, speed of processing and reaction time and also a total symptom score. RESULTS: Group-analysis showed a clear decline in verbal memory (F(3, 87) = 7.36, p < 0.000) and an increase in self-reported symptoms (chi2(3, N = 30) = 48.703, p < 0.000), 3 days post-injury. By day 8, athletes had returned to their baseline levels for verbal memory and were not experiencing symptoms. When athletes' scores were examined individually, at 3 days post-injury, 60% of the athletes showed deficits on two or more of the ImPACT variables. This rate dropped to 23% at 8 days post-injury and remained the same (23%) 15 days post-injury. CONCLUSIONS: In concussion recovery, variability is the rule, rather than the exception, with regard to both impaired neurocognitive functions and recovery duration. PMID- 28872366 TI - Breast Cancer Patients' Depression Prediction by Machine Learning Approach. AB - One of the most common cancer in females is breasts cancer. This cancer can has high impact on the women including health and social dimensions. One of the most common social dimension is depression caused by breast cancer. Depression can impairs life quality. Depression is one of the symptom among the breast cancer patients. One of the solution is to eliminate the depression in breast cancer patients is by treatments but these treatments can has different unpredictable impacts on the patients. Therefore it is suitable to develop algorithm in order to predict the depression range. PMID- 28872367 TI - Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer. AB - Vascular targeted therapies (VTTs) are agents that target tumor vasculature and can be classified into two categories: those that inhibit angiogenesis and those that directly interfere with established tumor vasculature. Although both the anti-angiogenic agents (AAs) and the vascular disrupting agents (VDAs) target tumor vasculature, they differ in their mechanism of action and therapeutic application. Combining these two agents may realize the full potential of VTT and produce an effective therapeutic regimen. Here, we review AAs and VDAs (monotherapy and in combination with conventional therapies). We also discuss the rationale of combined VTT and its potential to treat cancer. PMID- 28872368 TI - Cryotherapy Reinvented: Application of Phase Change Material for Recovery in Elite Soccer. AB - PURPOSE: To examine whether donning lower-body garments fitted with cooled phase change material (PCM) would enhance recovery after a soccer match. METHODS: In a randomized, crossover design, 11 elite soccer players from the reserve squad of a team in the second-highest league in England wore PCM cooled to 15 degrees C (PCMcold) or left at ambient temperature (PCMamb; sham control) for 3 h after a soccer match. To assess recovery, countermovement jump height, maximal isometric voluntary contraction (MIVC), muscle soreness, and the adapted Brief Assessment of Mood Questionnaire (BAM+) were measured before 12, 36, and 60 h after each match. A belief questionnaire was completed preintervention and postintervention to determine the perceived effectiveness of each garment. RESULTS: Results are comparisons between the 2 conditions at each time point postmatch. MIVC at 36 h postmatch was greater with PCMcold versus PCMwarm (P = .01; ES = 1.59; 95% CI, 3.9-17.1%). MIVC also tended to be higher at 60 h postmatch (P = .05; ES = 0.85; 95% CI, -0.4% to 11.1%). Muscle soreness was 26.5% lower in PCMcold versus PCMwarm at 36 h (P = .02; ES = 1.7; 95% CI, -50.4 to -16.1 mm) and 24.3% lower at 60 h (P = .04; ES = 1.1; 95% CI, -26.9 to -0.874 mm). There were no between conditions differences in postmatch countermovement jump height or BAM+ (P > .05). The belief questionnaire revealed that players felt the PCMcold was more effective than the PCMamb after the intervention (P = .004). CONCLUSIONS: PCM cooling garments provide a practical means of delivering prolonged postexercise cooling and thereby accelerate recovery in elite soccer players. PMID- 28872369 TI - Pacing Strategy and Tactical Positioning During Cyclo-Cross Races. AB - PURPOSE: To describe pacing strategy and competitive behavior in elite-level cyclo-cross races. METHODS: Data from 329 men and women competing in 5 editions (2012-2016) of Union Cycliste Internationale Cyclo-Cross World Championships were compiled. Individual mean racing speeds from each lap were normalized to the mean speeds of the whole race. Lap and overall rankings were also explored. Pacing strategy was compared between sexes and between top- and bottom-placed cyclists. RESULTS: A significant main effect of laps was found in 8 out of 10 races (4 positive, 3 variable, 2 even, and 1 negative pacing strategies), and an interaction effect of ranking-based groups was found in 2 (2016, male and female races). Kendall tau-b correlations revealed an increasingly positive relationship between intermediate and overall rankings throughout the races. The number of overtakes during races decreased from start to finish, as suggested by significant Friedman tests. In the first lap, normalized cycling speeds were different in 3 out of 5 editions-men were faster in 1 and slower in 2 editions. In the last lap, however, normalized cycling speeds of men were lower than those of women in 4 editions. CONCLUSIONS: Elite cyclo-cross competitors adopt slightly distinct pacing strategies in each race, but positive pacing strategies are highly probable in most events, with more changes in rankings during the first laps. Sporadically, top- and bottom-placed groups might adopt different pacing strategies during either men's or women's races. Men and women seem to distribute their efforts differently, but this effect is of small magnitude. PMID- 28872370 TI - Neuromuscular Responses to Conditioned Soccer Sessions Assessed via GPS-Embedded Accelerometers: Insights Into Tactical Periodization. AB - PURPOSE: To examine the reliability of field-based running-specific measures of neuromuscular function assessed using global positioning system (GPS)-embedded accelerometers and their responses to 3 typical conditioned sessions (ie, strength, endurance, and speed) in elite soccer players. METHODS: Before and immediately after each session, vertical jump (countermovement jump [CMJ]) and adductor squeeze strength (groin) performances were recorded. Players also performed a 4-min run at 12 km/h followed by four ~60-m runs (run = 12 s, r = 33 s). GPS (5 Hz) and accelerometer (100 Hz) data collected during the 4 runs and the recovery periods, excluding the last recovery period, were used to derive vertical stiffness (K), peak loading force (peak force over all the foot strikes [Fpeak]), and propulsion efficiency (ie, the ratio between velocity and force loads [Vl/Fl]). RESULTS: Typical errors were small (CMJ, groin, K, and Vl/Fl) and moderate (Fpeak), with moderate (Fpeak), high (K and Vl/Fl), and very high ICCs (CMJ and groin). After all sessions, there were small decreases in groin and increases in K, but changes in F were all unclear. By contrast, the CMJ and Vl/Fl ratio responses were session dependent. There was a small increase in CMJ after speed and endurance, but unclear changes after strength; the Vl/Fl ratio increased substantially after strength, but there were a small and a moderate decrease after endurance and speed, respectively. CONCLUSIONS: Running-specific measures of neuromuscular function assessed in the field via GPS-embedded accelerometers show acceptable levels of reliability. Although the 3 sessions examined may be associated with limited neuromuscular fatigue, changes in neuromuscular performance and propulsion efficiency are likely session-objective dependent. PMID- 28872371 TI - Reliability of Wearable Inertial Measurement Units to Measure Physical Activity in Team Handball. AB - PURPOSE: To assess the reliability and sensitivity of commercially available inertial measurement units to measure physical activity in team handball. METHOD: Twenty-two handball players were instrumented with 2 inertial measurement units (OptimEye S5; Catapult Sports, Melbourne, Australia) taped together. They participated in either a laboratory assessment (n = 10) consisting of 7 team handball-specific tasks or field assessment (n = 12) conducted in 12 training sessions. Variables, including PlayerLoadTM and inertial movement analysis (IMA) magnitude and counts, were extracted from the manufacturers' software. IMA counts were divided into intensity bands of low (1.5-2.5 m.s-1), medium (2.5-3.5 m.s-1), high (>3.5 m.s-1), medium/high (>2.5 m.s-1), and total (>1.5 m.s-1). Reliability between devices and sensitivity was established using coefficient of variation (CV) and smallest worthwhile difference (SWD). RESULTS: Laboratory assessment: IMA magnitude showed a good reliability (CV = 3.1%) in well-controlled tasks. CV increased (4.4-6.7%) in more-complex tasks. Field assessment: Total IMA counts (CV = 1.8% and SWD = 2.5%), PlayerLoad (CV = 0.9% and SWD = 2.1%), and their associated variables (CV = 0.4-1.7%) showed a good reliability, well below the SWD. However, the CV of IMA increased when categorized into intensity bands (2.9 5.6%). CONCLUSION: The reliability of IMA counts was good when data were displayed as total, high, or medium/high counts. A good reliability for PlayerLoad and associated variables was evident. The CV of the previously mentioned variables was well below the SWD, suggesting that OptimEye's inertial measurement unit and its software are sensitive for use in team handball. PMID- 28872372 TI - The Specificity of Rugby Union Training Sessions in Preparation for Match Demands. AB - PURPOSE: Investigations into the specificity of rugby union training practices in preparation for competitive demands have predominantly focused on physical and physiological demands. The evaluation of the contextual variance in perceptual strain or skill requirements between training and matches in rugby union is unclear, yet holistic understanding may assist to optimize training design. This study evaluated the specificity of physical, physiological, perceptual, and skill demands of training sessions compared with competitive match play in preprofessional, elite club rugby union. METHODS: Global positioning system devices, video capture, heart rate, and session ratings of perceived exertion were used to assess movement patterns, skill completions, physiologic, and perceptual responses, respectively. Data were collected across a season (training sessions n = 29; matches n = 14). Participants (n = 32) were grouped in playing positions as: outside backs, centers, halves, loose forwards, lock forwards, and front row forwards. RESULTS: Greater total distance, low-intensity activity, maximal speed, and meters per minute were apparent in matches compared with training in all positions (P < .02; d > 0.90). Similarly, match heart rate and session ratings of perceived exertion responses were higher than those recorded in training (P < .05; d > 0.8). Key skill completions for forwards (ie, scrums, rucks, and lineouts) and backs (ie, kicks) were greater under match conditions than in training (P < .001; d > 1.50). CONCLUSION: Considerable disparities exist between the perceptual, physiological, and key skill demands of competitive matches versus training sessions in preprofessional rugby union players. Practitioners should consider the specificity of training tasks for preprofessional rugby players to ensure the best preparation for match demands. PMID- 28872374 TI - Changes in Choice Reaction Time During and After 8 Days Exhaustive Cycling Are Not Related to Changes in Physical Performance. AB - PURPOSE: Reaction time has been proposed as a training monitoring tool, but to date, results are equivocal. Therefore, it was investigated whether reaction time can be used as a monitoring tool to establish overreaching. METHODS: The study included 30 subjects (11 females and 19 males, age: 40.8 [10.8] years, VO2max: 51.8 [6.3] mL/kg/min) who participated in an 8-day cycling event. The external exercise load increased approximately 900% compared with the preparation period. Performance was measured before and after the event using a maximal incremental cycling test. Subjects with decreased performance after the event were classified as functionally overreached (FOR) and others as acutely fatigued (AF). A choice reaction time test was performed 2 weeks before (pre), 1 week after (post), and 5 weeks after (follow-up), as well as at the start and end of the event. RESULTS: A total of 14 subjects were classified as AF and 14 as FOR (2 subjects were excluded). During the event, reaction time at the end was 68 ms (95% confidence interval, 46-89) faster than at the start. Reaction time post event was 41 ms (95% confidence interval, 12-71) faster than pre event and follow-up was 55 ms faster (95% confidence interval, 26-83). The time by class interaction was not significant during (P = .26) and after (P = .43) the event. Correlations between physical performance and reaction time were not significant (all Ps > .30). CONCLUSIONS: No differences in choice reaction time between AF and FOR subjects were observed. It is suggested that choice reaction time is not valid for early detection of overreaching in the field. PMID- 28872373 TI - Anticarcinogenic activity of Muntingia calabura leaves methanol extract against the azoxymethane-induced colon cancer in rats involved modulation of the colonic antioxidant system partly by flavonoids. AB - CONTEXT: Leaves of Muntingia calabura (Elaeocarpaceae) are widely used in traditional medical practice; scientific findings show various pharmacological activities. However, its anticancer effect has not been investigated thoroughly yet. OBJECTIVE: The objective of this study is to study the chemoprevention effects of MEMCL against azoxymethane (AOM)-induced colon cancer and to examine the involvement of endogenous antioxidants Materials and methods: Male Sprague Dawley rats, divided into five groups (n = 7), were injected intraperitoneally once weekly for 2 weeks with 15 mg/kg AOM, except for the normal group (received saline). The animals were then administered orally for 8 weeks with 8% Tween-80 (vehicle; normal group), 8% Tween-80 (vehicle; cancer group) or, 50, 250 or 500 mg/kg MEMC. After treatments, colon samples were collected from each rat for the histopathological analysis, quantification of aberrant crypt foci formed and determination of colon antioxidant levels. MEMC was also subjected to HPLC analysis. RESULTS: The extract exerted significant (p < 0.05): (i) anti carcinogenesis activity, indicated by a decrease in the total aberrant crypt formation; (ii) antioxidant activity by increasing the colon tissue antioxidant markers [i.e., superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH)] and reducing the oxidant marker (i.e., malonaldehyde (MDA) levels in comparison with the cancer group. HPLC analysis demonstrated the presence of rutin. DISCUSSION AND CONCLUSIONS: Muntingia calabura leaves exert anticancer effect against AOM-induced colon cancer possibly via the action of flavonoids on the colon tissue antioxidant activity. PMID- 28872375 TI - DNA sequence database as a tool to identify decapod crustaceans on the Sao Paulo coastline. AB - DNA barcoding has emerged as an efficient tool for taxonomy and other biodiversity fields. The vast and speciose group of decapod crustaceans is not an exception in the current scenario and comparing short DNA fragments has enabled researchers to overcome some taxonomic impediments to help broadening knowledge on the diversity of this group of crustaceans. Brazil is considered as an important area in terms of global marine biodiversity and some regions stand out in terms of decapod fauna, such as the Sao Paulo coastline. Thus, the aim of this study is to obtain sequences of the mitochondrial markers (COI and 16S) for decapod crustaceans distributed at the Sao Paulo coastline and to test the accuracy of these markers for species identification from this region by comparing our sequences to those already present in the GenBank database. We sampled along almost the 300 km of the Sao Paulo coastline from estuaries to offshore islands during the development of a multidisciplinary research project that took place for 5 years. All the species were processed to obtain the DNA sequences. The diversity of the decapod fauna on the Sao Paulo coastline comprises at least 404 species. We were able to collect 256 of those species and sequence of at least one of the target genes from 221. By testing the accuracy of these two DNA markers as a tool for identification, we were able to check our own identifications, including new records in GenBank, spot potential mistakes in GenBank, and detect potential new species. PMID- 28872376 TI - Caffeine and Physiological Responses to Submaximal Exercise: A Meta-Analysis. AB - The aim of this study was to carry out a systematic review and meta-analysis of the effects of caffeine supplementation on physiological responses to submaximal exercise. A total of 26 studies met the inclusion criteria of adopting double blind, randomized crossover designs that included a sustained (5-30 min) fixed intensity bout of submaximal exercise (constrained to 60-85% maximal rate of oxygen consumption) using a standard caffeine dose of 3-6 mg.kg-1 administered 30 90 min prior to exercise. Meta-analyses were completed using a random-effects model, and data are presented as raw mean difference (D) with associated 95% confidence limits (CLs). Relative to placebo, caffeine led to significant increases in submaximal measures of minute ventilation (D = 3.36 L.min-1; 95% CL, 1.63-5.08; P = .0001; n = 73), blood lactate (D = 0.69 mmol.L-1; 95% CL, 0.46 0.93; P < .00001; n = 208), and blood glucose (D = 0.42 mmol.L-1; 95% CL, 0.29 0.55; P < .00001; n = 129). In contrast, caffeine had a suppressive effect on ratings of perceived exertion (D = -0.8; 95% CL, -1.1 to -0.6; P < .00001; n = 147). Caffeine had no effect on measures of heart rate (P = .99; n = 207), respiratory exchange ratio (P = .18; n = 181), or oxygen consumption (P = .92; n = 203). The positive effects of caffeine supplementation on sustained high intensity exercise performance are widely accepted, although the mechanisms to explain that response are currently unresolved. This meta-analysis has revealed clear effects of caffeine on various physiological responses during submaximal exercise, which may help explain its ergogenic action. PMID- 28872377 TI - The Influence of Rotations on Match Running Performance in Female Australian Football Midfielders. AB - PURPOSE: With female Australian football (AF) gaining popularity, understanding match demands is becoming increasingly important. The aim of this study was to compare running performances of rotated and whole-quarter state-level female AF players during match quarters. METHODS: Twenty-two state-level female AF midfielders wore Global Positioning System units during 14 games to evaluate activity profiles. The Yo-Yo Intermittent Recovery Test Level 1 (Yo-Yo IR1) was used as a measure of high-intensity running ability. Data were categorized into whole quarter, rotation bout 1, and rotation bout 2 before being further divided into quartiles. Players were separated into high- or low-Yo-Yo IR1 groups using a median split based on their Yo-Yo IR1 performance. Short (4-6 min), moderate (6 12 min), and long (12-18 min) on-field bout activity profiles were compared with whole-quarter players. RESULTS: High Yo-Yo IR1 performance allowed players to cover greater relative distances (ES = 0.57-0.88) and high-speed distances (ES = 0.57-0.86) during rotations. No differences were reported between Yo-Yo IR1 groups when players were required to play whole quarters (ES <= 0.26, likelihood <=64%). Players who were on field for short to moderate durations exhibited greater activity profiles than whole-quarter players. CONCLUSIONS: Superior high speed running ability results in a greater activity profile than for players who possess lower high-speed running ability. The findings also highlight the importance of short to moderate (4-12 min) rotation periods and may be used to increase high-intensity running performance within quarters in female AF players. PMID- 28872378 TI - Intralesional corticosteroid injections as treatment for non-infectious orbital inflammation. AB - A retrospective single-center chart review identified 19 patients treated with intralesional corticosteroid injection between 2007 and 2015 for orbital inflammatory disease. Patients were treated in the office, or intraoperatively at the time of orbital exploration and biopsy, with 5-40 mg of triamcinolone acetonide. Average follow up time was 2.44 years. Information recorded included visual acuity and eyelid position measurements, pre-injection treatment, post injection treatment, complications, and exam findings. Nine of the identified patients received intraoperative injections, 9 in the office setting, and one received an injection in each. Eight patients (42.1%) were on oral corticosteroids prior to the injection. All patients showed initial clinical improvement after 1-2 injections and no more than a 1-2 line difference in visual acuity. Overall, six patients (31.6%) required repeat injections due to recurrence of inflammation, and seven (36.8%) required additional oral corticosteroids beyond the initial taper. Patients pre-treated with oral corticosteroids were more likely to need repeat injections (83.3% vs 16.7% respectively, p = 0.04). Compared to injections performed in the office setting, intraoperative injections were associated with fewer repeat injections (0% vs. 60.0% respectively, p = 0.01) and less need for post-injection oral steroids (0% vs. 58.3% respectively, p < 0.01). There were no systemic or permanent side effects observed from the injections. Two patients (10.5%) had transient post injection intraocular pressure elevation, which resolved. Intralesional orbital corticosteroid injection is an effective first-line and adjunctive treatment for localized and diffuse non-infectious orbital inflammation. PMID- 28872379 TI - Influence of Different Inertial Loads on Basic Training Variables During the Flywheel Squat Exercise. AB - PURPOSE: To analyze the effects of different inertial loads on power production and power maintenance, as well as the number of sessions required for proper familiarization during the flywheel quarter-squat. METHODS: Twenty-four high level handball players attended 4 testing sessions consisting of 4 sets of 10 repetitions using 4 different inertial loads (0.025, 0.050, 0.075, and 0.100 kg.m2). In addition, a 5th set of 15 repetitions was performed. Both concentric and eccentric peak power and the eccentric:concentric ratio were recorded. RESULTS: The results showed the need to perform 3 sessions for a proper familiarization (ie, outcomes stabilization). The inertial load of 0.025 kg.m2 led to greater concentric peak power compared with the other inertial loads (from likely to most likely greater values). Both 0.025 and 0.050 kg.m2 inertial loads entailed greater eccentric peak power compared with 0.075 and 0.100 kg.m2 (most likely greater). Conversely, the 0.025-kg.m2 inertial load showed a lower eccentric:concentric ratio, presenting negative effects (most likely lower values) compared with the inertial loads of 0.050, 0.075, and 0.100 kg.m2. Participants were able to perform 5-12 repetitions per set without significant peak power output decrements. CONCLUSIONS: This study highlights the importance of performing at least 3 sessions to obtain a stable measure during flywheel squat exercise. Lower inertial loads (0.025 kg.m2) are the better option for eliciting high concentric peak power output values. In contrast, medium to high inertial loads are more appropriate to achieve greater eccentric overload values. PMID- 28872380 TI - Optimizing Heat Acclimation for Endurance Athletes: High- Versus Low-Intensity Training. AB - PURPOSE: To determine the effect of high- versus low-intensity training in the heat and ensuing taper period in the heat on endurance performance. METHODS: In total, 19 well-trained triathletes undertook 5 days of normal training and a 1-wk taper including either low- (heat acclimation [HA-L], n = 10) or high-intensity (HA-H, n = 9) training sessions in the heat (30 degrees C, 50% relative humidity). A control group (n = 10) reproduced their usual training in thermoneutral conditions. Indoor 20-km cycling time trials (35 degrees C, 50% relative humidity) were performed before (Pre) and after the main heat exposure (Mid) and after the taper (Post). RESULTS: Power output remained stable in the control group from Pre to Mid (effect size: -0.10 [0.26]) and increased from Mid to Post (0.18 [0.22]). The HA-L group demonstrated a progressive increase in performance from Pre to Mid (0.62 [0.33]) and from Mid to Post (0.53 [0.30]), alongside typical physiological signs of HA (reduced core temperature and heart rate and increased body-mass loss). While the HA-H group presented similar adaptations, increased perceived fatigue and decreased performance at Mid (-0.35 [0.26]) were evidenced and reversed at Post (0.50 [0.20]). No difference in power output was reported at Post between the HA-H and control groups. CONCLUSION: HA-H can quickly induce functional overreaching in nonacclimatized endurance athletes. As it was associated with a weak subsequent performance supercompensation, coaches and athletes should pay particular attention to training monitoring during a final preparation in the heat and reduce training intensity when early signs of functional overreaching are identified. PMID- 28872381 TI - Pneumatic Compression Fails to Improve Performance Recovery in Trained Cyclists. AB - PURPOSE: To examine the efficacy of intermittent sequential pneumatic compression (ISPC) on exercise recovery and subsequent performance, when implemented between a 20-min cycling bout (simulated scratch race) and a 4-min cycling test (simulated individual pursuit), as experienced during an Omnium track cycling competition. METHODS: Twenty-one (13 male and 8 female, mean [SD]: age = 36 [14] y) trained cyclists completed a familiarization trial followed by 2 experimental trials in a counterbalanced, cross-over design. Participants performed a fixed intensity 20-min cycling bout on a Wattbike cycle ergometer, followed by a 30-min recovery period where ISPC recovery boots or passive recovery was implemented. At the conclusion of the recovery period, participants performed a 4-min maximal cycling bout (4-min time trial [TT]). Average power (watts) for the 4-min TT, blood lactate concentration, and perceived total quality recovery (TQR) during the recovery period were used to examine the influence of ISPC. RESULTS: There were no significant differences between trials for the 4-min TT (P = .08), with the effect deemed to be trivial (d = -0.08). There was an unclear effect (d [+/ 90% confidence interval] = 0.26 [+/-0.78], P = .57) for ISPC vs passive recovery in the clearance of blood lactate during the recovery period. There was a small but not significant difference for perceived TQR in favor of ISPC (d [+/-90% confidence interval] = 0.27 [+/-0.27], P = .07). CONCLUSION: There was little additional benefit associated with the use of ISPC to enhance recovery and subsequent performance when used during the recovery period between 2 events in a simulated Omnium track cycling competition. PMID- 28872382 TI - Higher DNA insert fragment sizes improve mitogenomic assemblies from metagenomic pyrosequencing datasets: an example using Limenitidinae butterflies (Lepidoptera, Nymphalidae). AB - A large number of diverse mitogenomic sequences can be obtained more easily and affordably via mitochondrial metagenomics, which generates high-throughput sequences directly from sheared DNA extractions and assembles mitogenomic sequences using a few bioinformatic processing steps. However, following de novo assembly analysis, the optimal DNA fragment insert size is unclear. In this study, four extracted Limenitidinae butterfly DNA samples were sonically fragmented, and two fragment size ranges (200-400 and 400-600 bp) of each sample were tagged with different barcodes, producing pyrosequencing datasets. The results show that the datasets generated from longer DNA insert fragments result in better coverage and more complete mitogenomic sequences, and the phylogenetic analysis shows high support at nodes, revealing that Athyma butterflies do not represent a monophyletic group. Therefore, we recommend using longer insert DNA fragment sizes to generate high-throughput datasets for obtaining complete mitogenomic sequences which can improve phylogenetic studies. PMID- 28872383 TI - Weight Management Practices of Australian Olympic Combat Sport Athletes. AB - PURPOSE: Combat sport athletes undertake chronic and rapid weight loss (RWL) practices to qualify for weight divisions lower than their training weight. Variation between sports in the prevalence, methods, and magnitude of weight loss as well as recovery practices may be influenced by factors including competition level and culture. Differences in methodologies of previous research in combat sports make direct comparisons difficult; thus, this study aimed to examine weight loss practices among all Olympic combat sports in Australia, using standardized methodology. METHODS: High-caliber competitors in wrestling, boxing, judo, and taekwondo (n = 260) at Australian competitions were surveyed using a validated tool that provides quantification of how extreme an athlete's weight loss practices are: the rapid weight loss score (RWLS). Additional qualitative and quantitative survey data were also collected. RESULTS: Neither sport, sex, nor weight division group had an effect on RWLS; however, a significant effect of athlete caliber was detected (F2,215 = 4.953, mean square error = 4.757, P = .00792). Differences between sports were also evident for most weight ever lost in order to compete (H = 19.92, P = .0002), age at which weight cutting began (H = 16.34, P = .001), and selected methods/patterns of RWL (P < .001). Weight cycling between competitions was common among all sports as were influences on athlete's behaviors. CONCLUSIONS: Although many similarities in weight loss practices and experiences exist between combat sports, specific differences were evident. Nuanced, context/culturally specific guidelines should be devised to assist fighters' in optimizing performance while minimizing health implications. PMID- 28872384 TI - Feasibility of the 2-Point Method for Determining the 1-Repetition Maximum in the Bench Press Exercise. AB - PURPOSE: This study compared the concurrent validity and reliability of previously proposed generalized group equations for estimating the bench press (BP) 1-repetition maximum (1RM) with the individualized load-velocity relationship modeled with a 2-point method. METHODS: Thirty men (BP 1RM relative to body mass: 1.08 [0.18] kg.kg-1) performed 2 incremental loading tests in the concentric-only BP exercise and another 2 in the eccentric-concentric BP exercise to assess their actual 1RM and load-velocity relationships. A high velocity (~1 m.s-1) and a low velocity (~0.5 m.s-1) were selected from their load-velocity relationships to estimate the 1RM from generalized group equations and through an individual linear model obtained from the 2 velocities. RESULTS: The directly measured 1RM was highly correlated with all predicted 1RMs (r = .847-.977). The generalized group equations systematically underestimated the actual 1RM when predicted from the concentric-only BP (P < .001; effect size = 0.15-0.94) but overestimated it when predicted from the eccentric-concentric BP (P < .001; effect size = 0.36-0.98). Conversely, a low systematic bias (range: -2.3 to 0.5 kg) and random errors (range: 3.0-3.8 kg), no heteroscedasticity of errors (r2 = .053-.082), and trivial effect size (range: -0.17 to 0.04) were observed when the prediction was based on the 2-point method. Although all examined methods reported the 1RM with high reliability (coefficient of variation <= 5.1%; intraclass correlation coefficient >= .89), the direct method was the most reliable (coefficient of variation < 2.0%; intraclass correlation coefficient >= .98). CONCLUSIONS: The quick, fatigue-free, and practical 2-point method was able to predict the BP 1RM with high reliability and practically perfect validity, and therefore, the authors recommend its use over generalized group equations. PMID- 28872385 TI - New Records in Human Power. AB - Maximal aerobic and anaerobic power are crucial performance determinants in most sport disciplines. Numerous studies have published power data from elite athletes over the years, particularly in runners, cyclists, rowers, and cross-country (XC) skiers. This invited review defines the current "world records" in human upper limits of aerobic and anaerobic power. Currently, [Formula: see text]max values of ~7.5 and 7.0 L.min-1 in male XC skiers and rowers, respectively, and/or ~90 mL.kg-1.min-1 in XC skiers, cyclists, and runners can be described as upper human limits for aerobic power. Corresponding values for women are slightly below 5.0 L.min-1 in rowers and XC skiers and ~80 mL.kg-1.min-1 in XC skiers and runners. Extremely powerful male athletes may reach ~85 W.kg-1 in countermovement jump (peak vertical power) and ~36 W.kg-1 in sprint running (peak horizontal power), cycling (instantaneous power during force-velocity testing from a standing position), and rowing (instantaneous power). Similarly, their female counterparts may reach ~70 W.kg-1 in countermovement jump and ~30 W.kg-1 in sprint running, cycling, and rowing. The presented values can serve as reference values for practitioners and scientists working with elite athletes. However, several methodological considerations should be taken into account when interpreting the results. For example, calibrated apparatus and strict procedures are required to ensure high measurement validity and reliability, and the sampling rate for anaerobic power assessments must be strictly predetermined and carefully measured. Doping is also a potential confounding factor when interpreting the human upper limits of aerobic and anaerobic power. PMID- 28872386 TI - On the Importance of "Front-Side Mechanics" in Athletics Sprinting. AB - Practitioners have, for many years, argued that athletic sprinters should optimize front-side mechanics (leg motions occurring in front of the extended line through the torso) and minimize back-side mechanics. This study aimed to investigate if variables related to front- and back-side mechanics can be distinguished from other previously highlighted kinematic variables (spatiotemporal variables and variables related to segment configuration and velocities at touchdown) in how they statistically predict performance. A total of 24 competitive sprinters (age: 23.1 [3.4] y, height: 1.81 [0.06] m, body mass: 75.7 [5.6] kg, and 100-m personal best: 10.86 [0.22] s) performed two 20-m starts from block and 2 to 3 flying sprints over 20 m. Kinematics were recorded in 3D using a motion tracking system with 21 cameras at a 250 Hz sampling rate. Several front- and back-side variables, including thigh (r = .64) and knee angle (r = .51) at lift-off and maximal thigh extension (r = .66), were largely correlated (P < .05) with accelerated running performance, and these variables displayed significantly higher correlations (P < .05) to accelerated running performance than nearly all the other analyzed variables. However, the relationship directions for most front- and back-side variables during accelerated running were opposite in comparison to how the theoretical concept has been described. Horizontal ankle velocity, contact time, and step rate displayed significantly higher correlation values to maximal velocity sprinting than the other variables (P < .05), and neither of the included front- and back-side variables were significantly associated with maximal velocity sprinting. Overall, the present findings did not support that front-side mechanics were crucial for sprint performance among the investigated sprinters. PMID- 28872387 TI - Correction to: Nesaratnam, Emeriewen, Smith, David, Wawrzynski, Sharma, and Saleh, Scaling the punctum and canaliculus in patients undergoing punctoplasty surgery: A prospective cohort study. PMID- 28872388 TI - Reasons, Motivational Factors, and Perceived Personal Barriers to Engagement in Physical Activity During Pregnancy Vary Within the BMI Classes: The Prenatal Prevention Project Germany. AB - BACKGROUND: International data indicate that approximately only 20.0% of pregnant women reach physical activity recommendations (>=150 min/wk). To find ways for increasing physical activity, the reasons for exercising, motivational factors, and barriers need to be determined. The aim of this pilot study was to identify these factors in respect to body mass index classification in German pregnant women. METHODS: A total of 61 women [age: 32.7 (4.8) y; 13.3 (3.4) wk of gestation] participated in this study. Before pregnancy, 10.0% of women were underweight, 58.3% were normal weight, 18.3% were overweight, and 13.4% were obese. Standardized questionnaires were used to evaluate the abovementioned factors. RESULTS: "Fun" was one of the main reasons for being active in underweight/normal weight compared with overweight/obese women (53.7% vs 10.5%; P = .002), whereas "burning fat" was more important in overweight/obese women (9.8% vs 36.8%; P = .027). According to motivational factors, differences occurred in "calorie burning" (7.3% underweight/normal weight vs 31.6% overweight/obese; P = .025) and "fat burning" (7.3% underweight/normal weight vs 47.4% overweight/obese; P = .001). Regarding barriers for being active, "tiredness" was more often a barrier in overweight/obese (63.2%) compared with normal weight/underweight women (31.7%; P = .022). CONCLUSION: Pregnant women should be given tailored advice/motivation according to prepregnancy body mass index. However, larger studies are necessary to evaluate these factors on pregnant women's physical activity level. PMID- 28872389 TI - Training-Related Changes in Force-Power Profiles: Implications for the Skeleton Start. AB - PURPOSE: Athletes' force-power characteristics influence sled velocity during the skeleton start, which is a crucial determinant of performance. This study characterized force-power profile changes across an 18-month period and investigated the associations between these changes and start performance. METHODS: Seven elite- and 5 talent-squad skeleton athletes' (representing 80% of registered athletes in the country) force-power profiles and dry-land push-track performances were assessed at multiple time points over two 6-month training periods and one 5-month competition season. Force-power profiles were evaluated using an incremental leg-press test (Keiser A420), and 15-m sled velocity was recorded using photocells. RESULTS: Across the initial maximum strength development phases, increases in maximum force (Fmax) and decreases in maximum velocity (Vmax) were typically observed. These changes were greater for talent (23.6% and -12.5%, respectively) compared with elite (6.1% and -7.6%, respectively) athletes. Conversely, decreases in Fmax (elite -6.7% and talent 10.3%) and increases in Vmax (elite 8.1% and talent 7.7%) were observed across the winter period, regardless of whether athletes were competing (elite) or accumulating sliding experience (talent). When the training emphasis shifted toward higher-velocity, sprint-based exercises in the second training season, force-power profiles seemed to become more velocity oriented (higher Vmax and more negative force-velocity gradient), which was associated with greater improvements in sled velocity (r = .42 and -.45, respectively). CONCLUSIONS: These unique findings demonstrate the scope to influence force-power-generating capabilities in well-trained skeleton athletes across different training phases. To enhance start performance, it seems important to place particular emphasis on increasing maximum muscle-contraction velocity. PMID- 28872390 TI - Classroom-Based Physical Activity: Minimizing Disparities in School-Day Physical Activity Among Elementary School Students. AB - BACKGROUND: Evidence of the positive effects of school physical activity (PA) interventions, including classroom-based PA (CBPA), is rapidly growing. However, few studies examine how variations in scheduled PA opportunities and teacher implemented CBPA affect students' PA outcomes. METHODS: Teachers at 5 elementary schools attended training on how to implement CBPA. Data on school-day PA opportunities [physical education (PE), recess, and CBPA] were obtained via calendar and teacher-recorded CBPA logs. Daily step counts were measured via accelerometry in 1346 students across 65 classrooms in first through fifth grades. RESULTS: PE, recess, and CBPA contributed significantly to students' daily steps. Males accrued more steps than females over the school day, during PE, and during recess. No gender disparity was seen in the amount of additional steps accrued during CBPA. Overall step counts were lower among fifth-grade students versus first-grade students, but CBPA attenuated this difference such that grade-level differences were not significant in fifth-grade students who received CBPA. CONCLUSIONS: Gender disparities in step totals were present on PE and recess days, but not on CBPA days. CBPA appears to provide equal PA benefits for both genders and to potentially minimize the decline in PA among older students. PMID- 28872391 TI - Health for Older Adults: The Role of Social Capital and Leisure-Time Physical Activity by Living Arrangements. AB - BACKGROUND: The purposes of this study were to (1) explore the influence of social capital and leisure-time physical activity on older adults' physical and mental health and (2) test whether these relationships varied by living arrangement. METHODS: This cross-sectional study used national data from the 2013 National Health Interview Study. The subjects included 7714 adults aged 65 years or older. Logistic regressions were used to predict the probability of subjects being overweight or obese. Ordinary linear regressions were performed to predict mental health outcomes. RESULTS: Older adults living alone were more likely to report feeling sad (alone: 1.5; with others: 1.36), hopeless (alone: 1.25; with others: 1.18), and worthless (alone: 1.22; with others: 1.15). They were also more likely to experience lower levels of social support (alone: 3.24; with others: 3.30), trust (alone: 3.34; with others: 3.44), cohesion (alone: 2.95; with others: 2.98), and enjoy less leisure-time physical activity (alone: 49.85 min; with others: 64.64 min) than those living with others. Hispanic and divorced/separated older adults who lived alone were prioritized for health intervention. CONCLUSIONS: Older adults living alone had poorer mental health, less social capital, and engaged in less frequent leisure-time physical activity. Promoting social capital could improve mental health in older adults living alone. PMID- 28872392 TI - The Relation of Physical Activity, Sedentary Behaviors, and Academic Achievement Is Mediated by Fitness and Bedtime. AB - BACKGROUND: This study investigated the associations of subjectively and objectively measured physical activity (PA) and sedentary behavior with academic achievement. We further examined whether aerobic fitness, obesity, and bedtime mediate these associations. METHODS: This study included 970 children aged 9-15 years (52.3% girls) from 9 schools throughout Finland. Register-based academic achievement [grade point average (GPA)] as well as self-reported and accelerometer-measured PA/sedentary behavior were assessed during spring 2013. Aerobic fitness (assessed via a maximal shuttle run test), body composition (assessed via bioimpedance analysis), and self-reported bedtime were collected. Structural equation modeling was applied to examine the associations. Standardized regression coefficients are presented. RESULTS: Self-reported PA had a direct positive [beta = 0.084; 95% confidence interval (CI), 0.023 to 0.145] and an indirect positive association with GPA through higher aerobic fitness (beta = 0.061; 95% CI, 0.033 to -0.087). Accelerometer-based PA was not associated with GPA. Self-reported screen time had an indirect negative association with GPA through later bedtime (beta = -0.071; 95% CI, -0.096 to 0.035) and lower aerobic fitness (beta = -0.039; 95% CI, -0.059 to 0.019). Nonscreen sedentary time had a direct positive (beta = 0.193; 95% CI, 0.101 to 0.289) and an indirect negative association with GPA through lower aerobic fitness (beta = -0.040; 95% CI, -0.063 to -0.016). CONCLUSIONS: Participating in PA, avoiding excessive screen time, and going to bed earlier may benefit academic achievement. PMID- 28872393 TI - The Influence of Source and Type of Support on College Students' Physical Activity Behavior. AB - BACKGROUND: College is a place where students develop health behaviors that persist throughout adulthood, yet a large percentage of students are not engaging in adequate physical activity. Social support is associated with physical activity; however, the effects of source (ie, family and friend) and type (ie, companionship, esteem, and informational) are not fully understood. The current study examined the effects of different sources and types of social support on college students' physical activity behaviors. METHODS: An online survey tool collected data from 733 college students enrolled at a Mid-Atlantic university. Structural equation models and a repeated-measures analysis of variance were conducted. RESULTS: Support from family and friends was associated with physical activity behaviors; however, support from friends exerted a stronger effect. Students received different types of support from their network, which differentially influenced physical activity behaviors. Students received higher levels of companionship support from their friends and higher levels of esteem support from their family, which was positively associated with physical activity behaviors. Students received higher levels of informational support from their families, which was negatively associated with physical activity behaviors. CONCLUSIONS: This study highlights the importance of examining the independent effects of source and type of support on college students' physical activity. PMID- 28872394 TI - Abdominal Circumference Versus Body Mass Index as Predictors of Lower Extremity Overuse Injury Risk. AB - BACKGROUND: Abdominal circumference (AC) is superior to body mass index (BMI) as a measure of risk for various health outcomes. Our objective was to compare AC and BMI as predictors of lower extremity overuse injury (LEOI) risk. METHODS: Retrospective review of electronic medical records of 79,868 US Air Force personnel over a 7-year period (2005-2011) for incidence of new LEOI. Subjects were stratified by BMI and AC. Injury risk for BMI/AC subgroups was calculated using Kaplan-Meier curves and Cox proportional-hazards regression. Receiver operating characteristic curves with area under the curve were used to compare each model's predictive value. RESULTS: Cox proportional-hazards regression showed significant risk association between elevated BMI, AC, and all injury types, with hazard ratios ranging 1.230-3.415 for obese versus normal BMI and 1.665-3.893 for high-risk versus low-risk AC (P < .05 for all measures). Receiver operating characteristic curves with area under the curve showed equivalent performance between BMI and AC for predicting all injury types. However, the combined model (AC and BMI) showed improved predictive ability over either model alone for joint injury, overall LEOI, and most strongly for osteoarthritis. CONCLUSIONS: Although AC and BMI alone performed similarly well, a combined approach using BMI and AC together improved risk estimation for LEOI. PMID- 28872395 TI - Palliation of Bladder Spasms #337. PMID- 28872396 TI - Whole-Body Vibration on Performance of Quadriceps After ACL Reconstruction: A Blinded Randomized Controlled Trial. AB - CONTEXT: Whole-body vibration (WBV) has been widely used in clinical and sport practice. These devices produce constant vibrations, originating symmetrical waves that move along the vertical axis. It is suggested that mechanical stimuli produced by high vibration can be an alternative to improve neuromuscular performance and balance in different populations. However, there is still a lack of consensus in the literature regarding neurophysiological responses in the skeletal muscle immediately after the use of WBV, specifically in individuals subjected to anterior cruciate ligament reconstruction. OBJECTIVE: To investigate the immediate effects of WBV on neuromuscular performance of the quadriceps femoris and postural oscillation of individuals subjected to anterior cruciate ligament reconstruction. DESIGN: This is a blinded randomized controlled trial. SETTING: University laboratory. PARTICIPANTS: Forty-four men. INTERVENTION: Participants were randomized into 2 groups: control group (n = 22, exercise protocol on the vibrating platform turned off) and WBV group (n = 22, exercises on the vibrating platform turned on, at a frequency of 50 Hz and amplitude of 4 mm). MAIN OUTCOME MEASURES: The volunteers underwent a dynamometric evaluation of the quadriceps femoris and electromyographic activity of vastus lateralis and vastus medialis muscles, in addition to oscillation of the center of pressure at 2 different moments: before and immediately after the intervention protocol. RESULTS: The intragroup comparison evidenced differences between preassessments and postassessments for the variables of laterolateral amplitude, peak torque, and total work. However, no significant difference was observed in the intergroup comparison after WBV protocol. CONCLUSION: The use of WBV did not immediately alter the performance of the quadriceps femoris and the electromyographic activity of vastus lateralis and vastus medialis muscles. In addition, it also did not interfere with pressure center oscillation of individuals subjected to anterior cruciate ligament reconstruction. PMID- 28872397 TI - Cancer-Specific Mortality Relative to Engagement in Muscle-Strengthening Activities and Lower Extremity Strength. AB - BACKGROUND: Skeletal muscle strength and engagement in muscle-strengthening activities are each inversely associated with all-cause mortality; however, less is known on their relationship with cancer-specific mortality. METHODS: Data from the 1999-2002 National Health and Nutrition Examination Survey were used assessing 2773 individuals aged 50 years or older. Individuals being dichotomized at the 75th percentile for knee extensor strength, and engagement in muscle strengthening activities was acquired through self-report with >=2 sessions per week were classified as meeting guidelines. RESULTS: With respect to cancer specific mortality, individuals in the upper quartile for muscle strength were at a 50% reduced risk (hazard ratio = 0.50; 95% confidence interval, 0.29-0.85; P = .01) and those meeting muscle-strengthening activities were at a nonsignificant 8% reduced risk (hazard ratio = 0.92; 95% confidence interval, 0.45-1.86, P = .81) of cancer-specific mortality after adjusting for covariates. CONCLUSIONS: Clinicians should routinely assess lower extremity strength and promote engagement in muscle-strengthening activities aimed at increasing muscle strength. PMID- 28872398 TI - Physical Activity and Sedentary Time Patterns in Children and Adolescents With Cystic Fibrosis and Age- and Sex-Matched Healthy Controls. AB - BACKGROUND: Regular physical activity (PA) is increasingly recognized as important in the care of patients with cystic fibrosis (CF), but there is a dearth of evidence regarding physical activity levels or how these are accrued in those with CF. METHODS: PA was measured by a hip-worn accelerometer for 7 consecutive days in 18 children [10 boys; 12.4 (2.8) y] with mild to moderate CF and 18 age- and sex-matched controls [10 boys; 12.5 (2.7) y]. RESULTS: Both children with CF and healthy children demonstrated similar physical activity levels and patterns of accumulation across the intensity spectrum, with higher levels of PA during weekdays in both groups. Forced expiratory volume in 1 second was predicted by high light PA in children with CF compared with low light PA in healthy children. CONCLUSION: These findings highlight weekends and light PA as areas warranting further research for the development of effective intervention strategies to increase PA in the youth CF population. PMID- 28872399 TI - Meteorologic and Geographic Barriers to Physical Activity in a Workplace Wellness Program. AB - BACKGROUND: Inclement weather and home environment can act as barriers to physical activity. However, it is unclear if they reduce the activity of persons participating in activity-promoting programs. METHODS: Data from a 6-month workplace financial incentives program were used to establish the association between meteorologic (temperature, rain, snow, and wind) and geographic factors (urban/nonurban home location and distance between home and work) and moderate to vigorous physical activity (MVPA). Multivariable models were built to estimate mean weekly minutes of MVPA adjusting for demographic factors, clinical factors, and impulsivity. RESULTS: The 292 participants had a mean age of 38 (SD = 11) years. Eighty-three percent were female and 62% were white. Twenty-nine percent lived within 3 miles of work, and 35% lived in urban areas. Participants who lived more than 3 miles from work averaged 75 [95% confidence interval (CI), 65 84] minutes of weekly MVPA compared with 105 (95% CI, 88-122) minutes for those who lived within 3 miles of work. Urban participants averaged 70 (95% CI, 57-83) minutes of MVPA compared with 91 (95% CI, 80-102) minutes for nonurban participants. Colder temperatures were associated with decreased MVPA, and impulsivity modified the effect. CONCLUSIONS: Colder temperatures, greater distance from work, and an urban residence are associated with fewer minutes of MVPA. PMID- 28872400 TI - What Is the Most Effective Training Approach for Preventing Noncontact ACL Injuries in High School-Aged Female Athletes? AB - Clinical Scenario: A variety of training approaches have been adopted in anterior cruciate ligament (ACL) prevention programs, including neuromuscular control training, core stability training, balance training, and plyometric exercise. This review was conducted to determine if current evidence supports one of these training approaches over the others for reducing noncontact ACL injuries in adolescent female athletes. Focused Clinical Question: What is the most effective training approach for preventing noncontact ACL injuries in adolescent and/or high school-aged female athletes? Summary of Key Findings: A literature search generated 2 level 1b randomized control trials and 1 level 2b cohort study. Plyometric training resulted in decreased knee valgus during landing in 3 studies and increased knee flexion at landing in 2 studies. Balance training or neuromuscular training led to decreased knee valgus and increased knee-flexion angles with landing in 2 studies. Core stability training had conflicting effects on knee valgus and knee-flexion angles at landing, with 1 study reporting no effect and another reporting an undesirable decrease in knee joint flexion angle at landing. Clinical Bottom Line: Based on this review, plyometric training, balance training, and neuromuscular training approaches appear sensible to include in ACL prevention programs for female athletes to help decrease knee valgus and knee flexion during landing. Core stability training may be somewhat beneficial for decreasing knee valgus angles at landing, although may have nominal or even deleterious effects on knee-flexion angle at landing, and thus should be implemented with caution. Strength of Recommendation: Our recommendations were derived from the results of 2 level 1b randomized control trials and 1 level 2b cohort study. PMID- 28872401 TI - Substituting Sedentary Time With Light and Moderate to Vigorous Physical Activity is Associated With Better Cardiometabolic Health. AB - BACKGROUND: The purpose of the current study was to apply a more novel approach to systematically examine (1) associations of clustered cardiometabolic risk and cardiometabolic risk factors and (2) theoretical substitution of sedentary time with either sleep, light physical activity (LPA), or moderate to vigorous physical activity (MVPA) and substituting LPA with MVPA. METHODS: Physical activity and sleep were objectively measured in 410 Flemish adults [55.5 (9.6) y, 64% men] with a SenseWear Pro 3 Armband. Cardiometabolic risk factors (obesity, hyperglycemia, dyslipidemia, and hypertension) and cardiorespiratory fitness were objectively measured. Isotemporal substitution analyses were performed to assess the associations between substituting time from a potentially negative behavior into another potentially positive behavior. RESULTS: Theoretical substitution of sedentary time with MVPA was associated with decreased clustered cardiometabolic risk, b = -0.06 (-0.08 to -0.04), and substituting LPA with MVPA was associated with a decrease in clustered cardiometabolic risk, b = -0.08 (-0.11 to -0.04). Substituting sedentary time with LPA or sleep improved high-density lipoprotein cholesterol, systolic and diastolic blood pressures, and waist circumference. CONCLUSION: Theoretical replacement of sedentary time with either sleep, LPA, or MVPA was positively associated with improved cardiometabolic risk factor status. Interventions for increasing cardiometabolic health can focus on replacing sedentary time with either sleep, LPA, or MVPA depending on the risk parameters that need to be targeted. PMID- 28872402 TI - Overall and Leisure-Time Physical Activity Among Brazilian Adults: National Survey Based on the Global Physical Activity Questionnaire. AB - BACKGROUND: To describe overall physical activity prevalence measured by the Global Physical Activity Questionnaire as well as inequalities in leisure-time physical activity among Brazilian adults (15 y and older). METHODS: Data from the Brazilian Survey on Medicine Access, Utilization, and Rational Use of Medicines were analyzed. The study was carried out between September 2013 and February 2014. Physical activity was measured through Global Physical Activity Questionnaire and classified according to the recommendations of the World Health Organization. Additional analysis determined the contribution of each physical activity domain to the total amount of physical activity. Inequalities in terms of sex, age, and socioeconomic position were explored. RESULTS: About one-third of the participants (37.1%; 95% confidence interval, 35.5-38.8) were physically inactive. Work-based activities were responsible for 75.7% of the overall physical activity. The prevalence of participants achieving physical activity guidelines considering only leisure-time activities was 17.8% (95% confidence interval, 16.7-19.2). Females and older participants were less active than their counterparts for both overall and leisure-time physical activity; socioeconomic status was positively associated to leisure-time physical activity. CONCLUSIONS: Major overall physical activity is attributed to work-related physical activity. Leisure-time physical activity, a key domain for public health, presents important gender and socioeconomic inequalities. PMID- 28872403 TI - Reliability of a Squat Movement Competency Screen in Individuals With a Previous Knee Injury. AB - CONTEXT: Movement screens are a common method of assessing movement efficiency either against a specific criterion of segments/joint(s) motion (segmental method) or a summary label of general quality of the whole movement (overall method). While not as commonly utilized within clinical practice as the segmental method, the overall method is less time consuming to perform and more reliable. OBJECTIVES: The aim of this study was to assess the reliability of the "overall" method approach during a squat in individuals with a previous knee joint injury. DESIGN: Cross-sectional, clinical measurement. PARTICIPANTS: Two-dimensional video recordings of 5 squat trials were recorded for 16 participants with a history of a major knee joint injury(s) and were visually rated by 3 novice and 3 expert raters. MAIN OUTCOME MEASURES: Weighted quadratic Kappa was used to determine the intra- and inter-rater reliability of the squat movement competency screen. RESULTS: Good inter-rater reliability for the expert and novice groups was observed. Intra-rater reliability was very good between analysis sessions for 1 expert rater. CONCLUSIONS: The overall method is a reliable method that enables allied health professionals of different levels of clinical experience to utilize a framework to assess movement quality during a squat in patients with a previous knee joint injury. PMID- 28872405 TI - Physical Activity Opportunities Within the Schedule of Early Care and Education Centers. AB - BACKGROUND: Physical activity has many benefits for young children's health and overall development, but few studies have investigated how early care and education centers allot time for physical activity, along with measured individual physical activity levels for indoor/outdoor activities during a typical day. METHODS: Fifty early care and education centers in central North Carolina participated in 4 full-day observations, and 559 children aged 3-5 years within centers wore accelerometers assessing physical activity during observation days. Observation and physical activity data were linked and analyzed for associations between child activity and type of classroom activity. RESULTS: Children averaged 51 (13) minutes per day of moderate to vigorous physical activity and 99 (18) minutes per day of light physical activity while in child care. Children averaged 6 (10) and 10 (13) minutes per day of observed outdoor and indoor daily teacher-led physical activity, respectively. Outdoor time averaged 67 (49) minutes per day, and physical activity levels were higher during outdoor time than during common indoor activities (center time, circle time, and TV time). CONCLUSIONS: Physical activity levels varied between indoor and outdoor class activities. Policy and program-related efforts to increase physical activity in preschoolers should consider these patterns to leverage opportunities to optimize physical activity within early care and education centers. PMID- 28872404 TI - Operative Versus Nonoperative Treatment After Acute Patellar Dislocation: Which Is More Effective at Reducing Recurrence in Adolescents? AB - Clinical Scenario: Acute patellar dislocations during adolescence often lead to future patellar instability. Two common treatment options include nonoperative treatment or operative repair of injured structures. Focused Clinical Question: In adolescents with acute patellar dislocation, how does operative stabilization compare with nonoperative treatment for reducing dislocation recurrence? Summary of Key Findings: Three studies were included: 2 randomized controlled trials and 1 nonrandomized study. All studies compared operative and nonoperative treatment outcomes in adolescents who experienced an acute patellar dislocation. Each study included nonoperative treatment such as patellar bracing and quadriceps strengthening. The operative treatments utilized in each study included lateral retinacular release and medial retinacular repair. All 3 of the studies included a follow-up of at least 6 years. Two of the studies concluded there to be no significant difference between treatment groups regarding redislocation rate, pain, and function. The third study reported a lower redislocation rate following operative treatment. Clinical Bottom Line: Reviewed evidence suggests that outcomes are similar when comparing operative and nonoperative treatment approaches with little agreement as to which is the optimal plan of action. Strength of Recommendation: One level II randomized controlled trial and a level III nonrandomized study suggest that patellar dislocation recurrence rates are similar among operative and nonoperative treatment approaches, while another level II randomized controlled trial suggests that an operative approach is superior. PMID- 28872406 TI - The Levels and Predictors of Physical Activity Engagement Within the Treatment Seeking Transgender Population: A Matched Control Study. AB - BACKGROUND: Physical activity has been found to alleviate mental health problems and could be beneficial for at-risk populations, such as transgender people. This study had 3 aims. First, to explore the amount of physical activity that treatment-seeking transgender people engage in and to compare this to matched cisgender people. Second, to determine whether there was a difference in physical activity depending on cross-sex hormone use. Third, to determine factors that predict physical activity among treatment-seeking transgender people. METHODS: Transgender (n = 360) and cisgender people (n = 314) were recruited from the United Kingdom. Participants were asked to complete questionnaires about physical activity, symptoms of anxiety and depression, self-esteem, body satisfaction, and transphobia. RESULTS: Transgender people engaged in less physical activity than cisgender people. Transgender people who were on cross-sex hormone treatment engaged in more physical activity than transgender people who were not. In transgender people on cross-sex hormones, high body satisfaction was the best statistical predictor of physical activity, whereas high self-esteem was the best statistical predictor in people who were not. CONCLUSION: Transgender people are less active than cisgender people. Cross-sex hormone treatment appears to be able to indirectly increase physical activity within this population, which may be beneficial for mental well-being. PMID- 28872407 TI - Relationship Between Physical Activity, Adiposity, and Attentional Inhibition. AB - BACKGROUND: Physical inactivity and excess adiposity are thought to be detrimental to physical and cognitive health. However, implications of these interrelated health factors are rarely examined together; consequently, little is known regarding the concomitant contribution of physical activity and adiposity to cognition. METHODS: Bivariate correlations and hierarchical linear regressions were conducted among a sample of adults between 25 and 45 years (N = 65). Attentional inhibition was assessed using an Eriksen Flanker task. Whole-body percent body fat (%Fat) was assessed using dual-energy X-ray absorptiometry. Daily percent time spent in moderate to vigorous physical activity (%MVPA) was monitored using an accelerometer (7 d). RESULTS: After adjusting for significant covariates, %MVPA was a positive predictor of accuracy in the incongruent task (beta = 0.31, P = .03). Individuals who engaged in greater %MVPA exhibited superior attentional inhibition. Additionally, there was an interaction effect of %Fat and %MVPA on attentional inhibition (beta = 0.45, P = .04). CONCLUSION: The positive influence of MVPA on cognitive control persists following the adjustment of significant covariates and adiposity. Additionally, interactive effects between %Fat and %MVPA suggest that individuals with lower activity and greater adiposity exhibited poorer attentional inhibition. These findings have relevance for public health given the elevated rates of physical inactivity and obesity. PMID- 28872408 TI - Healing Response of a Structural Hamstring Injury: Perfusion Imaging 8-Week Follow-Up. AB - CONTEXT: Hamstring injuries are frequently observed in various sports disciplines both in elite and recreational sport. OBJECTIVE: To quantify intramuscular tissue perfusion via contrast-enhanced ultrasound in the acute phase and during the healing of a structural muscle injury confirmed by high-resolution magnetic resonance imaging. DESIGN: Case study. SETTING: Laboratory environment. PATIENT: A 32-year-old wakeboarder (height = 176 cm, body weight = 76 kg, and body mass index = 24.5 kg/m2) with an acute indirect muscle injury of the semimembranosus muscle. MAIN OUTCOME MEASURES: Average values of quantifiable contrast-enhanced ultrasound, represented as peak enhancement and wash-in area under the curve, as well as conventional ultrasound, 1.5T magnetic resonance imaging were assessed at 48-hour, 3-week, and 8-week postinjury. RESULTS: Average values of the quantitative perfusion analysis at 48-hour and 8-week postinjury revealed an approximate 5-fold increase in peak enhancement, and the wash-in area under the curve increased more than 3-fold in the center of the lesion. Magnetic resonance imaging, performed 48 hours after the injury to gather reference data as gold standard, revealed a grade III structural muscle tear. CONCLUSIONS: The authors are able to demonstrate significant changes in intramuscular tissue perfusion in the center of the structural lesion as well as in the adjacent tissue. Quantifiable contrast-enhanced ultrasound seems to be able to gather relevant data for the assessment and monitoring of muscle injuries and could be established as a valuable tool for further studies focusing on healing processes or therapeutic interventions. PMID- 28872409 TI - Considerations for pediatric trial designs and analyses. AB - There are challenges in designing pediatric trials arising from special ethical issues and the relatively small accessible patient population. The application of conventional phase 3 trial designs to pediatrics is not realistic in some therapeutic areas. To address this issue, we propose various approaches for designing pediatric trials that incorporate data available from adult studies using James-Stein shrinkage estimation, empirical shrinkage estimation, and Bayesian methods. We also apply the concept of consistency used in multi-regional trials to pediatric trials. The performance of these methods is assessed through representative scenarios and an example using actual Type 2 diabetes mellitus (T2DM) trials. PMID- 28872410 TI - Epoprostenol for the treatment of increasing oxygenator pressure drop during cardiopulmonary bypass. A case report. AB - A change of oxygenator during cardiopulmonary bypass is a technically high-risk procedure with potential for a serious adverse event for the patient. This case report describes a case of increased pressure drop and pre-oxygenator blood pressure during cardiopulmonary bypass successfully treated with pre-oxygenator administered epoprostenol. PMID- 28872411 TI - Smartphone photography utilized to measure wrist range of motion. AB - : The purpose was to determine if smartphone photography is a reliable tool in measuring wrist movement. Smartphones were used to take digital photos of both wrists in 32 normal participants (64 wrists) at extremes of wrist motion. The smartphone measurements were compared with clinical goniometry measurements. There was a very high correlation between the clinical goniometry and smartphone measurements, as the concordance coefficients were high for radial deviation, ulnar deviation, wrist extension and wrist flexion. The Pearson coefficients also demonstrated the high precision of the smartphone measurements. The Bland-Altman plots demonstrated 29-31 of 32 smartphone measurements were within the 95% confidence interval of the clinical measurements for all positions of the wrists. There was high reliability between the photography taken by the volunteer and researcher, as well as high inter-observer reliability. Smartphone digital photography is a reliable and accurate tool for measuring wrist range of motion. LEVEL OF EVIDENCE: II. PMID- 28872412 TI - The effectiveness of splinting and surgery on sleep disturbance in carpal tunnel syndrome. AB - : This controlled prospective study assessed the effectiveness of night splinting compared with non-splinting and surgery for severity of insomnia in patients with carpal tunnel syndrome. Sleep characteristics were observed for several days without a brace, with a brace and after surgery. The sleep measurements included the use of an actigraph worn on the wrist during night, a 'sleep log' that conveyed subjective impressions as to how the patient had slept and a short insomnia instrument, the Insomnia Severity Index. The Insomnia Severity Index scores showed that a night splint significantly improved insomnia symptoms compared with no splinting, and surgery significantly improved insomnia symptoms compared with splinting. The sleep log scores showed that the sleep quality and the number of awakenings when a splint was not worn were significantly different from the scores with the splint and the scores after surgery but showed no differences between splint and surgery. The actigraph did not show any significant differences between the treatment methods. LEVEL OF EVIDENCE: III. PMID- 28872413 TI - Restoration of active pick-up function in patients with total brachial plexus avulsion injuries. AB - : We designed multiple nerve transfers in one surgery to restore active pick-up function in patients with total brachial plexus avulsion injuries. Forty patients with total brachial plexus avulsion injuries first underwent multiple nerve transfers. These included transfer of the accessory nerve onto the suprascapular nerve to recover shoulder abduction, contralateral C7 nerve onto the lower trunk via the modified prespinal route with direct coaptation to restore lower trunk function and onto the musculocutaneous nerve with interpositional bridging by medial antebrachial cutaneous nerve arising from lower trunk to restore elbow flexion, and the phrenic nerve onto the posterior division of lower trunk to recover elbow and finger extension. At least three years after surgery, the patients who had a meaningful recovery were selected to perform secondary reconstruction to restore active pick-up function. Active pick-up function was successfully restored in ten patients after they underwent multiple nerve transfers combined with additional secondary functional hand reconstructions. LEVEL OF EVIDENCE: IV. PMID- 28872414 TI - Suprascapular Nerve and Volleyball: A Potentially Dangerous "Sport Match". PMID- 28872415 TI - Auditory Statistical Learning During Concurrent Physical Exercise and the Tolerance for Pitch, Tempo, and Rhythm Changes. AB - Previous studies suggest that statistical learning is preserved when acoustic changes are made to auditory sequences. However, statistical learning effects can vary with and without concurrent exercise. The present study examined how concurrent physical exercise influences auditory statistical learning when acoustical and temporal changes are made to auditory sequences. Participants were presented with the 500-tone sequences based on a Markov chain while cycling or resting in ignored and attended conditions. Learning effects were evaluated using a familiarity test with four types of short tone series: tone series in which stimuli were same as 500-tone sequence and three tone series in which frequencies, tempo, or rhythm was changed. We suggested that, regardless of attention, concurrent exercise interferes with tolerance in statistical learning for rhythm, rather than tempo changes. There may be specific relationships among statistical learning, rhythm perception, and motor system underlying physical exercise. PMID- 28872416 TI - Retraction. AB - Since the following case report was found not to meet the ethical standards of Juntendo University, as previously stated by the authors, the article has been retracted from Regenerative Medicine: Kantake M, Hirano A, Sano M, Urushihata N, Tanemura H, Oki K, Suzaki E. Transplantation of allogeneic adipose-derived mesenchymal stem cells in a cerebral palsy patient. Regenerative Medicine doi:10.2217/rme-2017-0043 (2017) (Epub ahead of print). The authors and editors of Regenerative Medicine regret any negative consequences this publication might have caused in the scientific and medical communities. PMID- 28872417 TI - How Does the Relationship Between Motor Skill Performance and Body Mass Index Impact Physical Activity in Preschool Children? AB - PURPOSE: To determine if weight status modifies the relationship between motor skill (MS) performance and physical activity (PA) in preschoolers. METHODS: Preschoolers (N = 227, age 3-5 y) were recruited from 22 preschools. Preschoolers' MS (locomotor, object control, and total MS) were assessed with the Children's Activity and Movement in Preschool Study MS protocol. PA was measured by accelerometry. Mixed linear models were used to examine the relationship of MS performance and body mass index (BMI) z score to PA. Models were adjusted for age, race, sex, and parent education, with preschool as a random effect. RESULTS: There was a significant correlation between MS performance and PA (r = .14-.17, P < .05). A significant interaction was observed between BMI z score and object control, and between BMI z score and total MS score on PA (P = .03). Preschoolers with higher BMI z scores and high object control scores engaged in significantly (P = .03) more PA than preschoolers with lower BMI z scores and high object control scores (PA = 15.04 min/h and 13.54 min/h, respectively). Similarly, preschoolers with higher BMI z scores and high total MS scores spent significantly (P = .01) more time in PA compared with those with lower BMI z scores and high total MS scores (PA = 15.65 min/h and 13.91 min/h, respectively). CONCLUSION: Preschool children's MS performance is positively correlated with PA, and BMI z score modified the relationship between MS performance and PA. PMID- 28872418 TI - Pregnancy planning preferences among people and couples affected by human immunodeficiency virus: Piloting a discrete choice experiment. AB - Decision-making related to pregnancy planning is complex and human immunodeficiency virus (HIV) may further complicate the process. With increasing rates of pregnancy among individuals affected by HIV, the need to understand decision-making is imperative. The primary objectives of this pilot study were to confirm the feasibility of using discrete choice experimentation (DCE) to elicit an understanding of this process and to determine the acceptability of the choice factors that were included in two novel DCEs, while gathering a preliminary understanding of preference. The choice attributes were risk of vertical HIV transmission, risk of horizontal HIV transmission, cost, probability of conception, method of conception, and travel time. Thirteen respondents completed a DCE for serodiscordant couples in which the female partner was HIV-positive, and 12 respondents completed a DCE for seroconcordant couples. All respondents' utility for an increased chance of a successful pregnancy was positive and statistically significant. In the serodiscordant dyads, the attributes of risk of horizontal transmission, risk of vertical transmission, a 5-h travel time to clinic, and cost were significantly associated with decreased utility. In the seroconcordant dyads, only the attributes of chance of risk of vertical transmission and cost were significantly associated with decreased utility. The serodiscordant dyads preferred home insemination with a syringe and the seroconcordant couples preferred conception methods within fertility clinics, over condomless sex with timed ovulation. On average, participants were willing to pay more for greater chance of conception and less willing to pay for increased risk of transmission. Couples affected by HIV are willing to participate in a DCE and the attributes that were included all seem relevant except risk of vertical transmission. There are various real-life trade-offs that are made during pregnancy planning with HIV and better understanding of these can be useful for clinicians during preconception counseling. PMID- 28872419 TI - Impact of Scoliosis Severity on Functional Capacity in Patients With Adolescent Idiopathic Scoliosis. AB - PURPOSE: The aim of this study is to evaluate the walked distance and physiological responses during incremental shuttle walk test in patients with different degrees of adolescent idiopathic scoliosis (AIS). METHODS: We evaluated 20 healthy teenagers and 46 patients with AIS; they were divided into 2 groups: AIS > 45 degrees and AIS < 45 degrees . The volunteers performed an incremental shuttle walk test, and the following physiological responses were quantified: oxygen consumption, tidal volume, ventilation, and the incremental shuttle walked distance. Respiratory muscle strength was quantified, pulmonary function test was performed, and the forced vital capacity and expiratory volume in the first second were obtained. RESULTS: Patients with AIS > 45 degrees presented significant reduced incremental shuttle walked distance compared with the AIS < 45 degrees and control group [447 (85), 487 (95), and 603 (85), respectively]. Patients with AIS also showed reduced forced vital capacity (P = .001) and expiratory volume in the first second (P = .005) compared with control group. Moderate correlations between forced vital capacity (r = -.506) and tidal volume (r = -.476) with scoliosis angles were found. CONCLUSIONS: The incremental shuttle walk test was capable of identifying reduced functional capacity in patients with different degrees of AIS. Moreover, the severity of spinal curvature may exert influence on ventilatory and metabolic variables. PMID- 28872420 TI - Laterality of Motor Control and Induced Gamma-Band Activity During Voluntary Movement: A Clinical Perspective of an Inexpensive Paper-and-Pencil Bimanual Simultaneous Drawing Test. PMID- 28872421 TI - Response to: "On the Nature of Clinical Evaluations With Low Sensitivity for Concussion-Related Balance Deficits". PMID- 28872422 TI - Bone Turnover Markers and Lean Mass in Pubescent Boys: Comparison Between Elite Soccer Players and Controls. AB - The aim of this study was to examine the relationship between bone mass and bone turnover markers with lean mass (LM) in pubescent soccer players. Two groups participated in this study, which included 65 elite young soccer players who trained for 6-8 hours per week and 60 controls. Bone mineral density; bone mineral content in the whole body, lower limbs, lumbar spine, and femoral neck; biochemical markers of osteocalcin; bone-specific alkaline phosphatase; C telopeptide type I collagen; and total LM were assessed. Young soccer players showed higher bone mineral density and bone mineral content in the whole body and weight-bearing sites (P < .001). Indeed, the total LM correlated with whole-body bone mineral density and bone mineral content (P < .001). There were significant differences within the bone formation markers and osteocalcin (formation)/C telopeptide type I collagen (resorption) ratio between young soccer players compared with the control group, but no significant difference in C-telopeptide type I collagen was observed between the 2 groups. This study showed a significant positive correlation among bone-specific alkaline phosphatase, osteocalcin, and total LM (r = .29; r = .31; P < .05) only for the young soccer players. Findings of this study highlight the importance of soccer practice for bone mineral parameters and bone turnover markers during the puberty stage. PMID- 28872423 TI - The Use of Relative Speed Zones in Australian Football: Are We Really Measuring What We Think We Are? AB - OBJECTIVES: To examine the difference between absolute and relative workloads, injury likelihood, and the acute:chronic workload ratio (ACWR) in elite Australian football. DESIGN: Single-cohort, observational study. METHODS: Forty five elite Australian football players from 1 club participated. Running workloads of players were tracked using Global Positioning System technology and were categorized using either (1) absolute, predefined speed thresholds or (2) relative, individualized speed thresholds. Players were divided into 3 equal groups based on maximum velocity: (1) faster, (2) moderate, or (3) slower. One- and 4-wk workloads were calculated, along with the ACWR. Injuries were recorded if they were noncontact in nature and resulted in "time loss." RESULTS: Faster players demonstrated a significant overestimation of very high-speed running (HSR) when compared with their relative thresholds (P = .01; effect size = 0.73). Similarly, slower players demonstrated an underestimation of high-(P = .06; effect size = 0.55) and very-high-speed (P = .01; effect size = 1.16) running when compared with their relative thresholds. For slower players, (1) greater amounts of relative very HSR had a greater risk of injury than less (relative risk [RR] = 8.30; P = .04) and (2) greater absolute high-speed chronic workloads demonstrated an increase in injury likelihood (RR = 2.28; P = .16), whereas greater relative high-speed chronic workloads offered a decrease in injury likelihood (RR = 0.33; P = .11). Faster players with a very-high-speed ACWR of >2.0 had a greater risk of injury than those between 0.49 and 0.99 for both absolute (RR = 10.31; P = .09) and relative (RR = 4.28; P = .13) workloads. CONCLUSIONS: The individualization of velocity thresholds significantly alters the amount of very HSR performed and should be considered in the prescription of training load. PMID- 28872425 TI - Babies, Borders and Big Business. PMID- 28872424 TI - Intensified Training Period Increases Salivary IgA Responses But Does Not Affect the Severity of Upper Respiratory Tract Infection Symptoms in Prepuberal Rhythmic Gymnasts. AB - This study examined the effect of a 4-week intensified training (IT) period, followed by a 2-week tapering period (TP), on salivary immunoglobulin A (SIgA), salivary cortisol, and the severity of upper respiratory tract infection symptoms in 23 rhythmic gymnasts [12.1 (2.6) y; 143.9 (13.7) cm; 37.2 (9.4) kg]. Saliva sampling was conducted at pre- and post-IT, and post-TP (analyzed using enzyme linked immunosorbent assay). The Wisconsin Upper Respiratory Symptom Survey (WURSS-21) questionnaire was completed daily to analyze the severity of upper respiratory tract infection symptoms. The session rating of the perceived exertion was used to determine the internal training load and the acute:chronic workload ratio. A higher SIgA concentration [SIgAabs (MUg/mL); F = 7.6; P = .001] for post-IT [234 (104)] versus pre-IT [173 (91)], and post-TP [182 (70)], and a higher SIgA secretion rate [SIgArate (MUg/min); F = 3.4; P = .04] for post-IT [69 (28)] versus pre-IT [55 (27)], and post-TP [58 (22)] were observed. No significant change was observed for cortisol (F = 0.81; P = .45) or for the severity of upper respiratory tract infection symptoms (chi2 = 2.81; P = .24). Internal training load was higher during IT (vs TP; effect size = 2.37). The acute:chronic workload for the IT weeks varied from 1.2 (0.3) to 1.4 (0.3). These results suggest that a 4-week IT may temporarily augment the oral mucosal immunity, and an acute:chronic workload of 1.2-1.4 seems to be a safe approach to periodized training loads in youth rhythmic gymnasts. PMID- 28872426 TI - Enhancing quality practice for prevention and diagnosis of urinary tract infection during inpatient spinal cord rehabilitation. AB - OBJECTIVES: To reduce the incidence of Urinary Tract Infection (UTI) in subacute SCI individuals admitted for tertiary inpatient rehabilitation. DESIGN: A quality improvement team was assembled to improve UTI prevention/diagnosis. To plan data collection, UTI-related factors were mapped in an Ishikawa (fishbone) driver diagram. Data including patient demographics, presence and frequency of signs and/or symptoms of UTI and antibiotic initiation from August to December 2015 were recorded. Sensitivity, Specificity, Positive and Negative Predictive Values (PPV, NPV), and Likelihood Ratios (LR) were calculated for each sign and symptom. SETTING: Tertiary SCI Rehabilitation Results: Among 55 inpatients with subacute SCI who had signs/symptoms prompting urine culture and sensitivity (C&S), 32 (58.18%) were diagnosed with a UTI. The most frequent symptoms were foul smelling urine (41%), change in urine color (31%), and incontinence (25%), and the most common sign was fever (34%). Most UTIs (81%) occurred among individuals using Clean Intermittent Catheterization (CIC), with 46% of catheterizations performed by nurses. Foul smelling urine had the highest sensitivity (0.50, 95% CI: 0.31 0.69), and new incontinence had the highest specificity (0.88, 95% CI: 0.69-0.97) for UTI diagnosis. The highest PPV belonged to the cloudy urine (0.71, 95% CI: 0.42-0.92). The combination of cloudy and foul smelling urine increased the PPV to 78% (95% CI: (0.40-0.97). CONCLUSIONS: The concurrent presence of cloudy and foul smelling urine is predicted of UTI diagnosis inpatients tertiary setting. SCI inpatients are susceptible to UTI when learning CIC technique from nurses. PMID- 28872427 TI - Long-Term Dietary Supplementation with Yerba Mate Ameliorates Diet-Induced Obesity and Metabolic Disorders in Mice by Regulating Energy Expenditure and Lipid Metabolism. AB - This study evaluated whether long-term supplementation with dietary yerba mate has beneficial effects on adiposity and its related metabolic dysfunctions in diet-induced obese mice. C57BL/6J mice were randomly divided into two groups and fed their respective experimental diets for 16 weeks as follows: (1) control group fed with high-fat diet (HFD) and (2) mate group fed with HFD plus yerba mate. Dietary yerba mate increased energy expenditure and thermogenic gene mRNA expression in white adipose tissue (WAT) and decreased fatty acid synthase (FAS) mRNA expression in WAT, which may be linked to observed decreases in body weight, WAT weight, epididymal adipocyte size, and plasma leptin level. Yerba mate also decreased levels of plasma lipids (free fatty acids, triglycerides, and total cholesterol) and liver aminotransferase enzymes, as well as the accumulation of hepatic lipid droplets and lipid content by inhibiting the activities of hepatic lipogenic enzymes, such as FAS and phosphatidate phosphohydrolase, and increasing fecal lipid excretion. Moreover, yerba mate decreased the levels of plasma insulin as well as the homeostasis model assessment of insulin resistance, and improved glucose tolerance. Circulating levels of gastric inhibitory polypeptide and resistin were also decreased in the mate group. These findings suggest that long-term supplementation of dietary yerba mate may be beneficial for improving diet-induced adiposity, insulin resistance, dyslipidemia, and hepatic steatosis. PMID- 28872429 TI - The Non-Profit Sector: Leveraging Resources and Strengths to Promote More Physically Active Lifestyles. AB - BACKGROUND: Many Americans do not meet current minimum physical activity recommendations. Although the choice to be physically active is made by individuals, that choice is affected by the social and physical environments in which people live, work, play and learn. Creating environments that are more supportive of physical activity will require policies, practices and programs that individuals may not be able to influence on their own; such changes will require comprehensive, coordinated and collaborative action by a variety of organizational sectors at national, state and local levels. Because of their core and frequently unique-competencies, many non-profit organizations are poised to be active players in promoting important changes in policy and community environments that can facilitate lifelong physical activity for all Americans. METHODS: Review of mission statements and strategic plans of a variety of non profit organizations reveal key characteristics and competencies that can be leveraged, frequently across multiple levels and sectors, to promote physical activity. KEY RECOMMENDATIONS: Nonprofit organizations should leverage their unique capabilities, particularly in the areas of advocacy, strategic collaborations and outreach to their membership, volunteer and/or constituent bases to promote policy and environmental changes in support of physical activity. PMID- 28872428 TI - Community-based physical activity and wheelchair mobility programs for individuals with spinal cord injury in Canada: Current reflections and future directions. AB - RATIONALE: A clear need has been identified to find strategies and opportunities, beyond services provided during rehabilitation, to enhance community-based mobility and leisure-time physical activity (LTPA) participation among members of the spinal cord injury (SCI) population. METHOD: This review of existing mobility and LTPA programs that are available for individuals with SCI in Canada reflects the authors' current knowledge of existing evidence-based and community-based programs. The authors aim to highlight the gaps between existing programs and future needs. RESULTS: The major gaps identified in this brief clinical report include the need for: community-based mobility training programs, patient reported outcomes, assessment of long-term impact of programs, identifying the best approaches for program delivery, and developing researcher-stakeholder partnerships. CONCLUSION: Evidence-based mobility programs and community-based LTPA do exist, and the available research shows their promise. Despite the growing research for LTPA and mobility programs among adults with SCI, many gaps remain. Additional partnerships, community engagement practices, service program funding and health policy changes are needed to address the highlighted gaps to optimize community-based programs and enhance the lives of adults with SCI. PMID- 28872430 TI - A National Physical Activity Plan for the United States. PMID- 28872431 TI - National Plan for Physical Activity: Education Sector. AB - BACKGROUND: Schools must play a central role in combating the prevalence of overweight and obesity among children and youths. This cannot be achieved without more robust policy and funding programs at both federal and state levels. METHODS: Reviews of meta-analyses were used to assess the efficacy of improving PA/MVPA through interventions in school physical education programs. Individual research studies were reviewed to assess the efficacy of improving PA/MVPA in preschool settings, recess, and classroom activity breaks. Legislation at the federal and state levels was reviewed along with surveillance and accountability mechanisms at the state level. RESULTS: Physical education interventions produce improvements in PA/MVPA if protocols relating to use of time are followed. PA/MVPA in recess can be increased through careful planning for attractive activity opportunities on carefully designed playgrounds. Classroom activity breaks provide important PA/MVPA daily and improve student on-task behavior. CONCLUSIONS: Federal legislation is needed to provide guidelines and financial support for states to improve the quantity and quality of PA in school programs. States need to develop clear expectations for quantity and quality of PA programs in schools, surveillance systems to monitor district compliance in meeting those expectations, and an accountability system aimed at ensuring that state expectations are being met with assistance for districts that do not meet expectations. PMID- 28872432 TI - A Review of the National Physical Activity Plans of Six Countries. AB - BACKGROUND: Architects of the United States national physical activity plan can benefit from a thorough understanding of national physical activity plans from other nations. The purpose of this paper was to search for and analyze comprehensive national physical activity plan documents that can best inform the development of the U.S. plan. METHODS: Electronic databases were searched for national physical activity plan documents, yielding 252 documents from 56 countries. After eliminating documents that were not written in English, did not address physical activity primarily, and did not meet our definition of a national physical activity plan, we were left with physical activity plans from 6 countries-Australia, United Kingdom, Scotland, Sweden, Northern Ireland, and Norway. KEY RECOMMENDATIONS: Architects of the U.S. plan can learn as much from what was present in many documents as from what was absent. Examples of recommended components of national plans have been identified and highlighted for each of the 6 countries. Missing from all but 1 national plan document was a detailed process for accountability. Providing a clear path and detailed process of accountability will assist greatly in measuring short- and long-term success of the U.S. plan. PMID- 28872433 TI - The Healthcare Sector's Role in the U.S. National Physical Activity Plan. AB - BACKGROUND: Healthcare professionals are influential sources of health information and guidance for people of all ages. However healthcare providers do not routinely address physical activity (PA). Engaging health professionals in a national plan for physical activity will depend upon whether proven strategies can be found to promote PA within clinical settings. METHODS: The literature on promoting PA in healthcare settings was reviewed, as were recommendations from healthcare organizations and evidence-gathering entities about whether and how PA should be promoted in healthcare. KEY RECOMMENDATIONS: Evidence is mixed about whether interventions based in healthcare settings and offered by healthcare providers can improve PA behaviors in patients. Brief stand-alone counseling by physicians has not been shown to be efficacious, but office-based screening and advice to be active, followed by telephone or community support for PA has proven effective in creating lasting PA behavior improvement. Healthcare delivery models that optimize the organization of services across clinical and community resources may be very compatible with PA promotion in health care. Because of the importance of PA to health, healthcare providers are encouraged to consider adding PA as a vital sign for each medical visit for individuals aged 6 years and older. PMID- 28872434 TI - Park, Recreation, Fitness, and Sport Sector Recommendations for a More Physically Active America: A White Paper for the United States National Physical Activity Plan. AB - BACKGROUND: The United States' first National Physical Activity Plan is now under development. This plan follows the release of new physical activity guidelines and seeks to address the nation's ongoing physical inactivity and obesity crisis. For this plan to be successful, all facets of American culture need to unify behind its recommendations and action steps. Guidance for this plan involves active participation from a variety of sectors, including the park, recreation, fitness, and sport (PRFS) sector. PURPOSE: In this white paper, we discuss the potential of the PRFS sector in addressing America's physical inactivity. Specifically, we provide a brief description, history, and scope of the PRFS sector; present evidence concerning linkages between this sector and physical activity; and discuss existing challenges and emerging opportunities for promoting physical activity. We conclude by suggesting PRFS recommendations to promote physical activity based on anticipated effectiveness, reach, scope, and sustainability. METHODS: Academic articles, professional reports, and physical activity plans were reviewed to summarize the evidence concerning PRFS sector strategies for increasing physical activity. RECOMMENDATIONS: Based on our review, we propose several sector-specific proximity, place, program, partnership, promotion, people, policy, and performance indicator recommendations for improving physical activity in the United States. PMID- 28872435 TI - The Role of the Public Health Sector in Promoting Physical Activity: National, State, and Local Applications. AB - BACKGROUND: Regular physical activity has been demonstrated to protect against coronary heart disease, Type 2 diabetes mellitus, selected cancers, hypertension, obesity, and other chronic conditions. Therefore, the public health significance of promoting physical activity and preventing inactivity has become a well established agenda for public health agencies at all levels. METHODS: A secondary search of the literature, focusing on existing evidence reviews, was conducted to identify effective or promising public health physical activity interventions. Further examination of published evidence-based programs also was carried out to supplement the known evidence base. Intervention strategies were selected using criteria prescribed by each of the systematic reviews to yield categories of intervention effectiveness. KEY RECOMMENDATIONS: The selected physical activity interventions conformed to the domains identified by The Guide to Community Preventive Services. Recommended evidenced-based strategies from within the domain of informational approaches include 2 exemplary community-wide campaigns; mass media campaigns, represented by VERB; and an emerging practice of delivery of short physical activity messages at key community sites. Exemplary representative behavioral/social interventions include social support through organized walking clubs/partners within communities. Exemplary environmental/policy approaches include creating/enhancing access to places for physical activity with informational outreach activities and the emerging strategy of community-wide policies and planning. PMID- 28872436 TI - A National Plan for Physical Activity: The Enabling Role of the Built Environment. AB - BACKGROUND: Evidence shows significant relationships between aspects of the built environment and physical activity. Land use and transportation investments are needed to create environments that support and promote physical activity. METHODS: The policy relevance of recent evidence on the built environment and physical activity is discussed, along with an assessment of near, medium, and longer term pricing and regulatory actions that could be considered to promote physical activity. These actions are evaluated based on their consistency with the current evidence on what would support and promote physical activity. RESULTS: A wide range of pricing and regulatory strategies are presented that would promote physical activity. There is an unmet demand for activity friendly, walkable environments. Creating more walkable places is an essential component of a national plan to increase physical activity levels of Americans. CONCLUSIONS: The built environment is an enabler or disabler of physical activity. Creating more walkable environments is an essential step in averting what is currently a market failure where the supply and demand for walkable environments is misaligned. The desire to be more physically active would be supported through investments in walking, biking, and transit. Concentration of development within existing urban areas supported by transit and implementing pricing strategies can support physical activity. PMID- 28872437 TI - The Role of Media in Promoting Physical Activity. AB - BACKGROUND: This paper reviewed a) mass media campaigns and b) 'new media' interventions to promote physical activity. They are different kinds of interventions, with campaigns being mass-reach communications efforts to increase population awareness of physical activity. 'New media' interventions assess the impact of web-based, internet, other 'new media' and e-mail-delivered interventions to increase physical activity. METHODS: Previous reviews of mass media campaigns and 'new media' interventions were assessed, and more recent peer reviewed publications identified using routine electronic databases. For each area, a framework for interventions was described, and evidence for the effectiveness of these interventions, the main outcomes of interest, and methodological strengths and weaknesses were identified. KEY RECOMMENDATIONS: For mass media campaigns, key recommendations were to use consistent and well-branded messages, and for campaigns to be integrated across local, State and national levels, with sufficient resources to purchase sufficient media. Mass media campaigns should be subject to rigorous formative, process and impact evaluation. For 'new media' interventions, there is clear evidence of effectiveness, but efforts should be made to increase the reach and generalizability of these interventions. They should be provided as a low cost component of integrated communitywide physical activity programs. PMID- 28872438 TI - Physical Activity Promotion in Business and Industry: Evidence, Context, and Recommendations for a National Plan. AB - BACKGROUND: The contemporary workplace setting is in need of interventions that effectively promote higher levels of occupational and habitual physical activity. It is the purpose of this paper to outline an evidence-based approach to promote physical activity in the business and industry sector in support of a National Physical Activity Plan. METHODS: Comprehensive literature searches identified systematic reviews, comprehensive reviews, and consensus documents on the impact of physical activity interventions in the business and industry sector. A framework for action and priority recommendations for practice and research were generated. KEY RECOMMENDATIONS: Comprehensive, multicomponent worksite programs that include physical activity components generate significant improvements in health, reduce absenteeism and sick leave, and can generate a positive financial return. Specific evidence-based physical activity interventions are presented. Recommendations for practice include implementing comprehensive, multicomponent programs that make physical activity interventions possible, simple, rewarding and relevant in the context of a social-ecological model. The business and industry sector has significant opportunities to improve physical activity among employees, their dependents, and the community at-large and to reap important benefits related to worker health and business performance. PMID- 28872439 TI - Do Exercisers With Musculoskeletal Injuries Report Symptoms of Depression and Stress? AB - CONTEXT: Sports injuries in athletes can lead to negative emotional responses in terms of anger, anxiety, confusion, and sadness. Severe injuries can be understood as a stressful life event with increased levels of psychological distress, but injury assessment and rehabilitation typically focus on somatic symptoms. OBJECTIVE: The primary aim of this study was to estimate the prevalence of depression and emotional stress and to measure self-rated health in regular exercisers presenting to a sports medicine clinic with musculoskeletal injury. The secondary aim was to identify psychosocial factors associated with depression in injured exercisers and the potential need for psychological counseling. DESIGN: A cross-sectional survey study. SETTING: A sports medicine clinic for injuries of the foot, knee, or shoulder. PARTICIPANTS: Regular exercisers with present injuries (N = 694) and exercisers without injuries (N = 494). Regular exercisers were defined as those undertaking moderate exercise at least once a week. INTERVENTION: A questionnaire survey completed on paper by patients in a sports medicine clinic and a web-based version completed by online sports communities. MAIN OUTCOME MEASURES: Participants completed the Major Depression Inventory, Perceived Stress Scale, health-related quality of life, and questions on sociodemographics, exercise habits, and injury history. RESULTS: Symptoms of depression were reported by 12% of injured exercisers and 5% of noninjured controls (P < .001). Clinical stress was found in 30% of injured exercisers and 22% of controls (P = .002), and the EQ-5D-5L Visual Analog Scale score was lower for injured (69 [SD = 19]) than noninjured exercisers (87 [SD = 13], P < .001). Injured exercisers with symptoms of depression reported high stress levels and impaired daily functioning, were younger, and were more likely to have over 10 days injury-related work absence. CONCLUSIONS: The authors recommend psychological assessment of exercisers attending a sports medicine clinic for musculoskeletal injury and a supplemental clinical psychological interview for suspected depression or stress-related psychopathology. PMID- 28872440 TI - Erratum. PMID- 28872441 TI - Negotiating sexual safety in the era of biomedical HIV prevention: relationship dynamics among male couples using pre-exposure prophylaxis. AB - Up to two-thirds of new cases of HIV transmission between gay, bisexual and other men who have sex with men in the USA are attributed to primary relationships. Understanding the relationship dynamics and sexual agreements of male-male couples can provide insight into HIV transmission patterns and prevention needs in this population. The daily use of antiretroviral pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV, but its negotiation and use within social and intimate relationship contexts remain understudied. We conducted semi structured qualitative interviews with 20 male couples (n = 40 men) in which at least one partner was either using or in the process of initiating PrEP. Congruent with a theoretical focus on social theories of relationships and negotiated risk, couples were interviewed about relationship dynamics, trust, communication and sexual health practices, including their perception and use of PrEP. Overall, we found that couples showed heightened trust and communication when establishing open, sexual agreements and demonstrated high awareness of sexual risks and health practices in the context of PrEP use. This study demonstrates how understanding relationship dynamics can better inform HIV prevention and sexual health promotion efforts for male couples at risk of HIV. PMID- 28872443 TI - PACER Performance of Children Aged 11-14 With Attention-Deficit Hyperactive Disorder. AB - PURPOSE: The purposes of this study were to examine the performance on the progressive aerobic cardiovascular endurance run (PACER) test in children with and without attention-deficit hyperactive disorder (ADHD) over the course of a school year, and also to investigate the possible influence of age, sex, school sport participation, and body mass index on results. METHODS: Utilizing a repeated measures design, 892 middle school children aged 11-14 years (mean = 12.25, SD = 0.94) including 55 children with ADHD participated. While controlling for age, sex, sports participation, and body mass index, children were tested on the PACER 3 times during the school year. Procedures specified in the FITNESSGRAM test manual were explicitly followed. Hierarchical linear modeling was applied to analyze the data. RESULTS: Children with ADHD performed 8.6 fewer laps at intercept (baseline), than did healthy children without ADHD (t878 = -6.20, P < .001). However, no significant differences emerged for time (slope). In addition, no significant interactions were found for ADHD with age, sex, sports participation, or body mass index. CONCLUSION: A diagnosis of ADHD, independent of selected predictor variables, explained lower PACER performance. PMID- 28872442 TI - Added Value of Computer-aided CT Image Features for Early Lung Cancer Diagnosis with Small Pulmonary Nodules: A Matched Case-Control Study. AB - Purpose To test whether computer-aided diagnosis (CAD) approaches can increase the positive predictive value (PPV) and reduce the false-positive rate in lung cancer screening for small nodules compared with human reading by thoracic radiologists. Materials and Methods A matched case-control sample of low-dose computed tomography (CT) studies in 186 participants with 4-20-mm noncalcified lung nodules who underwent biopsy in the National Lung Screening Trial (NLST) was selected. Variables used for matching were age, sex, smoking status, chronic obstructive pulmonary disease status, body mass index, study year of the positive screening test, and screening results. Studies before lung biopsy were randomly split into a training set (70 cancers plus 70 benign controls) and a validation set (20 cancers plus 26 benign controls). Image features from within and outside dominant nodules were extracted. A CAD algorithm developed from the training set and a random forest classifier were applied to the validation set to predict biopsy outcomes. Receiver operating characteristic analysis was used to compare the prediction accuracy of CAD with the NLST investigator's diagnosis and readings from three experienced and board-certified thoracic radiologists who used contemporary clinical practice guidelines. Results In the validation cohort, the area under the receiver operating characteristic curve for CAD was 0.9154. By default, the sensitivity, specificity, and PPV of the NLST investigators were 1.00, 0.00, and 0.43, respectively. The sensitivity, specificity, PPV, and negative predictive value of CAD and the three radiologists' combined reading were 0.95, 0.88, 0.86, and 0.96 and 0.70, 0.69, 0.64, and 0.75, respectively. Conclusion CAD could increase PPV and reduce the false-positive rate in the early diagnosis of lung cancer. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28872444 TI - The Effect of Elevation on Intramuscular Tissue Temperatures. AB - CONTEXT: Ice, compression, and elevation, or ICE, is a widely used treatment for acute musculoskeletal injuries. The effects of ice and compression on tissue temperatures have been established, but whether elevation during cryotherapy affects temperature change has not. Elevation has potential to alter local perfusion and thereby alter the balance of heat loss/heat gain, potentially impacting tissue cooling during cryotherapy. OBJECTIVE: To measure the effect and interaction of ice, compression, and elevation on intramuscular temperatures. We hypothesized that elevation would not have an effect on intramuscular tissue temperature. DESIGN: Randomized crossover study design. SETTING: University athletic training facility. PATIENTS OR OTHER PARTICIPANTS: A total of 15 healthy volunteers (age 20.93 [1.67] y) provided informed consent and participated. INTERVENTIONS: Participants completed 8 treatment conditions: no treatment (control), ice only (I), compression only (C), elevation only (E), ice and compression (IC), ice and elevation (IE), compression and elevation (CE), or ice, compression, and elevation (ICE). All conditions were tested on each participant with a minimum of 48 hours between each condition. Intramuscular temperatures were recorded every 30 seconds during a 1-minute preapplication, 30-minute treatment, and 20-minute postapplication period. MAIN OUTCOME MEASURES: The temperature difference between the mean treatment temperature and the mean preapplication temperature was compared across each measurement depth and treatment condition. RESULTS: Non-ice treatments (control, C, E, and CE; means 33.4, 34.5, 33.7, and 34.6, respectively) had warmer intramuscular temperatures than any treatment that included ice (I, IC, IE, and ICE; means 28.4, 19.8, 28.0, and 19.3, respectively). There were no differences between IC and ICE (means 19.8 and 19.3, respectively). Ice alone was different from everything (Control, C, E, IC, CE, and ICE) except IE Conclusions: Elevation does not appear to play a role in temperature changes during cryotherapy treatments. PMID- 28872445 TI - Parks and Health: Differences in Constraints and Negotiation Strategies for Park Based Leisure Time Physical Activity by Stage of Change. AB - BACKGROUND: Public parks are increasingly recognized as important places that facilitate physical activity. Despite the presence of parks, constraints to recreation and physical activity at parks exist. As the health benefits identified with physical activity require long-term and regular activity, it is important to examine factors pertaining to physical activity participation beyond initiation. This study explored differences in reported constraints to park based physical activity and negotiation strategies by physical activity stage of change. METHODS: Data were collected among visitors to one Minnesota state park via onsite and follow-up questionnaires. RESULTS: The average visitor had a healthier weight than the average U.S. and Minnesota adult and the majority of visitors were meeting the physical activity recommendations (86.4%). Respondents in the inactive/insufficient stages were more constrained and used fewer negotiation strategies than respondents in the maintenance stage. CONCLUSIONS: Results both support and expand on previous research findings. Specifically, this study supports research which indicates the adoption and maintenance of physical activity are influenced by different individual, social and environmental factors, and expands the research base by examining constraints and negotiation at different physical activity stages in a park setting. Implications of these findings provide directions for future stage-based intervention efforts. PMID- 28872446 TI - Formative Research to Develop the IDEFICS Physical Activity Intervention Component: Findings from Focus Groups with Children and Parents. AB - BACKGROUND: The current study aimed at describing influencing factors for physical activity among young children to determine the best approaches for developing the IDEFICS community based intervention. METHODS: In 8 European sites a trained moderator conducted a minimum of 4 focus groups using standardized questioning guides. A total of 56 focus groups were conducted including 36 focus groups with parents and 20 focus groups with children, of which 74 were boys and 81 girls. Key findings were identified through independent reviews of focus group summary reports using content analysis methods. FINDINGS: Findings were generally consistent across countries. The greatest emphasis was on environmental physical (eg, seasonal influences, availability of facilities and safety), institutional (eg, length of breaks at school), and social factors (eg, role modeling of parents). Most cited personal factors by parents were age, social economical status, and perceived barriers. Both children and parents mentioned the importance of children's preferences. CONCLUSIONS: To increase physical activity levels of young children the intervention should aim at creating an environment (physical, institutional, social) supportive of physical activity. On the other hand strategies should take into account personal factors like age and social economical status and should consider personal barriers too. PMID- 28872447 TI - Measuring Physical Activity Change in Broad-Reach Intervention Trials. AB - BACKGROUND: We compared the responsiveness to change (prepost intervention) of 3 commonly-used self-report measures of physical activity. METHODS: In a cluster randomized trial of a telephone-delivered intervention with primary care patients, physical activity was assessed at baseline and 4 months (n = 381) using the 31-item CHAMPS questionnaire; the 6-item Active Australia Questionnaire (AAQ); and, 2 walking for exercise items from the US National Health Interview Survey (USNHIS). Responsiveness to change was calculated for frequency (sessions/week) and duration (MET.minutes/week) of walking and moderate-to vigorous intensity physical activity. RESULTS: The greatest responsiveness for walking frequency was found with the USNHIS (0.45, 95% CI: 0.19, 0.72) and AAQ (0.43, 95% CI: 0.19, 0.67), and for walking duration with the USNHIS (0.27, 95%CI 0.13, 0.41) and CHAMPS (0.24, 95% CI: 0.12, 0.36). For moderate-to-vigorous activity, responsiveness for frequency was slightly higher for the AAQ (0.50, 95% CI: 0.30, 0.69); for duration it was slightly higher for CHAMPS (0.32, 95% CI: 0.17, 0.47). CONCLUSIONS: In broad-reach trials, brief self-report measures (USNHIS and AAQ) are useful for their comparability to population physical activity estimates and low respondent burden. These measures can be used without a loss in responsiveness to change relative to a more detailed self-report measure (CHAMPS). PMID- 28872448 TI - Blood pressure variability and leukoaraiosis in acute ischemic stroke. AB - Higher blood pressure, blood pressure variability, and leukoaraiosis are risk factors for early adverse events and poor functional outcome after ischemic stroke, but prior studies differed on whether leukoaraiosis was associated with blood pressure variability, including in ischemic stroke. In the Third International Stroke Trial, blood pressure was measured in the acute phase of ischemic stroke immediately prior to randomization, and at 0.5, 1, and 24 h after randomization. Masked neuroradiologists rated index infarct, leukoaraiosis, and atrophy on CT using validated methods. We characterized blood pressure variation by coefficient of variance and three other standard methods. We measured associations between blood pressure, blood pressure variability, and leukoaraiosis using generalized estimating equations, adjusting for age, and a number of covariates related to treatment and stroke type/severity. Among 3017 patients, mean (+/-SD) systolic and diastolic blood pressure decreased from 155(+/-24)/82(+/-15) mmHg pre-randomization to 146(+/-23)/78(+/-14) mmHg 24 h later ( P < 0.005). Mean within-subject coefficient of variance was 0.09 +/- 0.05 for systolic and 0.11 +/- 0.06 for diastolic blood pressure. Patients with most leukoaraiosis were older and had higher blood pressure than those with least ( P < 0.0001). Although statistically significant in simple pairwise comparisons, no measures of blood pressure variability were associated with leukoaraiosis when adjusting for confounding variables ( P > 0.05), e.g. age. Our results suggest that blood pressure variability is not a potential mechanism to explain the association between leukoaraiosis and poor outcome after acute stroke. PMID- 28872449 TI - The PRE-hospital Stroke Treatment Organization. AB - Background The PRE-hospital Stroke Treatment Organization was formed in 2016 as an international consortium of medical practitioners involved in pre-hospital treatment of patients with acute stroke. Aims PRE-hospital Stroke Treatment Organization's mission is to improve stroke outcomes by supporting research and advocacy for pre-hospital stroke treatment in Mobile Stroke Units. PRE-hospital Stroke Treatment Organization will provide a platform to enhance collaborative research across the spectrum of acute stroke management in the pre-hospital setting. PRE-hospital Stroke Treatment Organization will also facilitate the appropriate proliferation and distribution of Mobile Stroke Units by providing a forum for professional communication, resource for public education, and stimulus for government, industry, and philanthropic support. Summary of review In this "white paper", we describe the evidence supporting pre-hospital stroke treatment, progress to date, practical issues such as application in various environments and staffing, planned research initiatives, and organizational structure. Conclusions PRE-hospital Stroke Treatment Organization is not-for-profit, with membership open to anyone involved (or hoping to become involved) in pre-hospital stroke care. PRE-hospital Stroke Treatment Organization has a Steering Committee comprised of members from Europe, U.S., Canada, Australia, and other regions having a Mobile Stroke Unit in operation. PRE-hospital Stroke Treatment Organization convenes satellite meetings for membership at the International Stroke Conference and European Stroke Congress each year to address the PRE hospital Stroke Treatment Organization mission. The first research collaborations agreed upon are to: (1) develop a list of common data elements to be collected by all Mobile Stroke Unit programs and entered into a common research database, and (2) develop a protocol for investigating the natural history of hyper-acute Intracerebral Hemorrhage. PMID- 28872450 TI - The association between aortic regurgitation and undetermined embolic infarction with aortic complex plaque. AB - Background Retrograde embolism from the descending thoracic aorta is one possible cause of undetermined ischemic stroke. Significant aortic regurgitation can increase the amount of reversed flow in the thoracic aorta and thus is associated with an increased incidence of stroke. Aims This study aimed to examine the association between significant aortic regurgitation and undetermined embolic infarction with aortic complex plaques. Methods This study included 380 patients with undetermined embolic stroke who did not have abnormal flow such as atrial septal defect, patent foramen ovale determined by agitated saline bubble test, intracardiac thrombi on transesophageal echocardiography, atrial fibrillation, or small vessel stroke, cerebral artery, and carotid stenosis on the brain magnetic resonance imaging. The patients were divided into the complex aortic plaques group (n = 63), which was defined as having plaque with >4 mm in thickness, ulceration, or high mobility, and the no complex aortic plaques group (n = 317). Results Transesophageal echocardiography with a bubble study, brain MRI, and laboratory tests were performed for all subjects. Significant aortic regurgitation was more prevalent in patients with undetermined embolic stroke and complex aortic plaques than in patients without complex aortic plaques (adjusted OR = 4.981; 95% CI = 1.323-18.876, P = 0.028). In addition, the distribution of complex aortic plaques according to the severity of aortic regurgitation in patients with undetermined embolic stroke had a tendency toward the ascending thoracic aorta and proximal aortic arch. Conclusions Significant aortic regurgitation may affect undetermined embolic stroke in patients with complex aortic plaques. PMID- 28872451 TI - Incidence of seizure in stroke patients treated with recombinant tissue plasminogen activator: A systematic review and meta-analysis. AB - Background Recombinant tissue plasminogen activator is the only FDA-approved thrombolytic agent for acute stroke treatment. However, there are concerns that recombinant tissue plasminogen activator may increase the risk of seizures (including early and late seizures). Aims We performed a systematic review to assess the incidence of seizures and the association of recombinant tissue plasminogen activator with seizure occurrence. Summary of review We searched major databases for articles published between 1995 and February 2016. The pooled incidence of post-stroke seizure, early seizure, late seizure, and seizures sub types was estimated overall and by status for recombinant tissue plasminogen activator treatment, and unadjusted odds ratio used to quantify the effects of recombinant tissue plasminogen activator on post-stroke seizure occurrence. In all, 4362 stroke participants were included with 49-63% being male and median age ranging from 68 to 71 years. A total of 792 received recombinant tissue plasminogen activator. The incidence of post-stroke seizure per 1000 participants (95% CI) was 95 (31-196) overall, 113 (49-202) in recombinant tissue plasminogen activator and 169 (6-326) in non-recombinant tissue plasminogen activator-treated (all heterogeneity- p<0.0001). Incidence of early seizure per 1000 (95% CI) was 35 (27-45) overall; 34 (22-50) among recombinant tissue plasminogen activator treated patients, and 36 (25-48) among recombinant tissue plasminogen activator naive participants (all heterogeneity- p > 0.826). The pool incidence rate per 1000 (95% CI) of late seizure was 84 (4-263), 46 (2-145), and 212 (184-241), respectively, in the overall, the recombinant tissue plasminogen activator treated group and non-recombinant tissue plasminogen activator-treated group (heterogeneity for overall and recombinant tissue plasminogen activator-treated group < 0.0001, non-recombinant tissue plasminogen activator naive = 0.999). The pooled odds ratio for post-stroke seizure (recombinant tissue plasminogen activator vs. no recombinant tissue plasminogen activator) was 0.94 (95% CI: 0. 17-5.26, heterogeneity- p < 0.0001). The pooled incidence per 1000 participants (95% CI) was 30 (0-144), 17 (2-49), 16 (2-44), and 9 (0-50), respectively, for focal seizure without impairment of consciousness, focal seizure with impairment of consciousness, generalized convulsive seizure, and status epilepticus; all heterogeneity- p < 0.0003. Accompanying pooled odds ratio (recombinant tissue plasminogen activator vs. no recombinant tissue plasminogen activator) based on one study was always in favor of non-significantly lower risk in recombinant tissue plasminogen activator-treated patients (all heterogeneity- p = 1). There were insufficient data to compute pooled odds ratio for early and late seizure. Conclusions Seizures affect nearly 1 out of every 10 stroke patients with inconclusive suggestion that rates are similar in recombinant tissue plasminogen activator-treated and recombinant tissue plasminogen activator naive patients. Large prospective studies are needed to better understand the relationship between recombinant tissue plasminogen activator and post-stroke seizure occurrence. PMID- 28872453 TI - Allium Stents: A Novel Solution for the Management of Upper and Lower Urinary Tract Strictures. AB - Stents are widely use in endoscopic urological procedures. One of the most important indications is the treatment of urinary tract strictures. AlliumTM Medical has introduced several types of stents for the treatment of different types of urinary tract strictures, based on anatomic location. All the stents are made of nitinol and coated with a co-polymer that reduces encrustations. These stents are self-expandable and have a large caliber and a high radial force. They have different shapes, designed especially for the treatment of each type of stricture. One of the most important features of Allium-manufactured stents is the ease of removal, due to their special unraveling feature. The company has introduced the Bulbar Urethral Stent (BUS) for treatment of bulbar urethral strictures; a rounded stent available in different lengths. Initial data on 64 patients with bulbar urethral stricture treated with the BUS showed a significant improvement in symptoms, with minimal complications and few adverse events. For treatment of prostate obstruction in patients unfit for surgery or unwilling to undergo a classical prostatic surgery, the Triangular Prostatic Stent (TPS) was introduced, which has a triangular shape that fits in the prostatic urethra. Its body has a high radial force attached to an anchor (which prevents migration) through a trans-sphincteric wire (which reduces incontinence rate). Initial data on 51 patients showed significant improvement in symptoms and in urinary peak flow rate, with a relatively small number of complications. The Round Posterior Stent (RPS) was designed for treatment of post radical prostatectomy bladder neck contracture. This short, round stent has an anchor, which is placed in the bladder neck. This stent being relatively new, the clinical data are still limited. Ureteral strictures can be treated with the Ureteral Stent (URS), which is round-shaped, available in different lengths, and has an anchor option (for very distal or very proximal strictures). We have previously published data on 107 URSs inserted in patients with ureteral stricture due to several etiologies, including patients who failed previous treatment. All patients were asymptomatic for a long period of follow-up after stent removal, with only one case of re stenosis. In this paper, we review the urological "covered" stents produced by Allium Medical with the relevant clinical data available at the present time. PMID- 28872454 TI - Review of the Clinical Approaches to the Use of Urine-based Tumor Markers in Bladder Cancer. AB - Bladder cancer is a common disease with a stable incidence for the past few decades despite advancements in molecular and genetic determinants of cancer development and progression. Cystoscopy remains the standard for detection and surveillance of bladder cancer, but it is an invasive and potentially costly procedure. With the knowledge of molecular alterations associated with bladder cancer numerous urine-based tumor markers have become commercially available. These urine markers have been evaluated in all clinical scenarios for the detection of bladder cancer including screening, hematuria, atypical cytology evaluation, and surveillance, but given the relative lack of impactful trials they are not routinely utilized. The efforts to develop markers with increased sensitivity to replace cystoscopy for the detection of bladder cancer have thus far been unsuccessful as well. This review addresses role of urine markers for screening, detection, and surveillance of bladder cancer. PMID- 28872456 TI - Graphene oxide wrapped ZnMn2O4 as high performance lithium ion battery anode. AB - Cation distribution between tetrahedral and octahedral sites within the ZnMn2O4 spinel lattice, along with microstructural features, is affected greatly by the temperature of heat treatment. Inversion parameter can easily be tuned, from 5 to 19%, depending on the annealing temperature. The upper limit of inversion is found for T= 400 degrees C as confirmed by X-ray powder diffraction and Raman spectroscopy. Excellent battery behavior is found for samples annealed at lower temperatures; after 500 cycles the specific capacities for as-prepared ZnMn2O4 is 909 mAh/g, while ZnMn2O4 heat-treated at 300 degrees C shows 1179 mAh/g which amounts to 101 % of its initial capacity. Despite excellent performance of sample processed at 300 degrees C at lower charge/discharge rates (100 mAh/g), a drop in the specific capacity is observed with rate increase. This issue is solved by graphene oxide wrapping; specific capacity obtained after 400th cycle for graphene oxide wrapped ZnMn2O4 heat-treated at 300 degrees C is 799 mAh/g at charge/discharge rate 0.5 A/g, which is higher by factor 6 compared to sample without graphene oxide wrapping. PMID- 28872458 TI - Piezotronic Effect tuned AlGaN/GaN High Electron Mobility Transistor. AB - The piezotronic effect is about utilizing strain-induced piezoelectric polarization charges to tune the carrier transportation across the interface/junction. We fabricated a high performance AlGaN/GaN High Electron Mobility Transistor (HEMT), and the transport property was proven to be enhanced by applying an external stress for the first time. The enhanced source-drain current was also observed at any gate voltage and the maximum enhancement of the saturation current was up to 21 % with 15 N applied stress (0.18 GPa at center) at -1 V gate voltage. The physical mechanism of HEMT with/without external compressive stress conditions was carefully illustrated and further confirmed by a self-consistent solution of the Schrodinger-Poisson equations. This study proves the cause-and-effect relationship between the piezoelectric polarization effect and two-dimensional electron gas formation, which provides a tunable solution to enhance the device performance. The strain tuned HEMT has potential applications in human-machine interface and the security control of the power system. PMID- 28872455 TI - Magnetic eye tracking in mice. AB - Eye movements provide insights about a wide range of brain functions, from sensorimotor integration to cognition; hence, the measurement of eye movements is an important tool in neuroscience research. We describe a method, based on magnetic sensing, for measuring eye movements in head-fixed and freely moving mice. A small magnet was surgically implanted on the eye, and changes in the magnet angle as the eye rotated were detected by a magnetic field sensor. Systematic testing demonstrated high resolution measurements of eye position of <0.1 degrees . Magnetic eye tracking offers several advantages over the well established eye coil and video-oculography methods. Most notably, it provides the first method for reliable, high-resolution measurement of eye movements in freely moving mice, revealing increased eye movements and altered binocular coordination compared to head-fixed mice. Overall, magnetic eye tracking provides a lightweight, inexpensive, easily implemented, and high-resolution method suitable for a wide range of applications. PMID- 28872459 TI - miR-146a modulates autoreactive Th17 cell differentiation and regulates organ specific autoimmunity. AB - Autoreactive CD4 T cells that differentiate into pathogenic Th17 cells can trigger autoimmune diseases. Therefore, investigating the regulatory network that modulates Th17 differentiation may yield important therapeutic insights. miR-146a has emerged as a critical modulator of immune reactions, but its role in regulating autoreactive Th17 cells and organ-specific autoimmunity remains largely unknown. Here, we have reported that miR-146a-deficient mice developed more severe experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS). We bred miR-146a-deficient mice with 2D2 T cell receptor-Tg mice to generate 2D2 CD4 T cells that are deficient in miR-146a and specific for myelin oligodendrocyte glycoprotein (MOG), an autoantigen in the EAE model. miR-146a-deficient 2D2 T cells induced more severe EAE and were more prone to differentiate into Th17 cells. Microarray analysis revealed enhancements in IL 6- and IL-21-induced Th17 differentiation pathways in these T cells. Further study showed that miR-146a inhibited the production of autocrine IL-6 and IL-21 in 2D2 T cells, which in turn reduced their Th17 differentiation. Thus, our study identifies miR-146a as an important molecular brake that blocks the autocrine IL 6- and IL-21-induced Th17 differentiation pathways in autoreactive CD4 T cells, highlighting its potential as a therapeutic target for treating autoimmune diseases. PMID- 28872460 TI - Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice. AB - Maintenance of muscle structure and function depends on the precise organization of contractile proteins into sarcomeres and coupling of the contractile apparatus to the sarcoplasmic reticulum (SR), which serves as the reservoir for calcium required for contraction. Several members of the Kelch superfamily of proteins, which modulate protein stability as substrate-specific adaptors for ubiquitination, have been implicated in sarcomere formation. The Kelch protein Klhl31 is expressed in a muscle-specific manner under control of the transcription factor MEF2. To explore its functions in vivo, we created a mouse model of Klhl31 loss of function using the CRISPR-Cas9 system. Mice lacking Klhl31 exhibited stunted postnatal skeletal muscle growth, centronuclear myopathy, central cores, Z-disc streaming, and SR dilation. We used proteomics to identify several candidate Klhl31 substrates, including Filamin-C (FlnC). In the Klhl31-knockout mice, FlnC protein levels were highly upregulated with no change in transcription, and we further demonstrated that Klhl31 targets FlnC for ubiquitination and degradation. These findings highlight a role for Klhl31 in the maintenance of skeletal muscle structure and provide insight into the mechanisms underlying congenital myopathies. PMID- 28872461 TI - Fibroblast-specific inhibition of TGF-beta1 signaling attenuates lung and tumor fibrosis. AB - TGF-beta1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-beta1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-beta1-induced epithelial-mesenchymal transition without immediate TGF-beta1 receptor (TbetaR) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-beta1 responses (IC50 ~50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TbetaRI kinase. Combined inhibition of LOXL2 and TbetaRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TbetaRI kinase in LOXL2-expressing cells. PMID- 28872462 TI - Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies. AB - The gene that encodes de novo DNA methyltransferase 3A (DNMT3A) is frequently mutated in acute myeloid leukemia genomes. Point mutations at position R882 have been shown to cause a dominant negative loss of DNMT3A methylation activity, but 15% of DNMT3A mutations are predicted to produce truncated proteins that could either have dominant negative activities or cause loss of function and haploinsufficiency. Here, we demonstrate that 3 of these mutants produce truncated, inactive proteins that do not dimerize with WT DNMT3A, strongly supporting the haploinsufficiency hypothesis. We therefore evaluated hematopoiesis in mice heterozygous for a constitutive null Dnmt3a mutation. With no other manipulations, Dnmt3a+/- mice developed myeloid skewing over time, and their hematopoietic stem/progenitor cells exhibited a long-term competitive transplantation advantage. Dnmt3a+/- mice also spontaneously developed transplantable myeloid malignancies after a long latent period, and 3 of 12 tumors tested had cooperating mutations in the Ras/MAPK pathway. The residual Dnmt3a allele was neither mutated nor downregulated in these tumors. The bone marrow cells of Dnmt3a+/- mice had a subtle but statistically significant DNA hypomethylation phenotype that was not associated with gene dysregulation. These data demonstrate that haploinsufficiency for Dnmt3a alters hematopoiesis and predisposes mice (and probably humans) to myeloid malignancies by a mechanism that is not yet clear. PMID- 28872466 TI - If Moses Had an Exoskeleton.... PMID- 28872465 TI - Increased Reliability of Quantitative Ultrasound Measures of the Supraspinatus Tendon Using Multiple Image Analysts and Analysis Runs. AB - Quantitative ultrasound (QUS) is an inexpensive and promising tool for sensitive measurement of tendon pathology. However, few studies have reported the psychometric properties of measurements obtained using this technique for assessments of the supraspinatus tendon. The present study was undertaken to determine the variance contributed by several sources of error (participant, ultrasound operator, image analyst, analysis session) to QUS measures of the supraspinatus tendon. Transverse images of the supraspinatus tendon were captured from eleven subjects (22 shoulders) by two ultrasonographers, and each image was analyzed by two image analysts who each completed two analysis runs. Generalizability theory and intraclass correlations were used to assess the reliability of seven QUS metrics. Measures of tendon/cartilage thickness demonstrated the greatest degree of overall dependability (phi = 0.84), followed by echogenicity (phi = 0.56), variance (phi = 0.55), and entropy (phi = 0.47), suggesting that these measures of the supraspinatus tendon may be promising metrics for assessing differences in tendon health. Interrater reliability between ultrasound operators ranged from low to moderate for different QUS metrics, but using more than one image analyst and performing repeated measurement analysis runs on each image help increase reliability of QUS measures for the supraspinatus tendon. PMID- 28872463 TI - mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. AB - The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance-associated gene (UVRAG), reducing the activity of the associated Beclin 1-Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1-Vps34-UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs. PMID- 28872467 TI - Irritable bowel syndrome and diet: where are we in 2018? AB - PURPOSE OF REVIEW: The aim is to review the most recent advances in the evidence supporting the use of various dietary interventions for the management of irritable bowel syndrome (IBS). RECENT FINDINGS: There is insufficient evidence of the effect of fibres other than psyllium in IBS, whereas the recent studies on prebiotics suggest a limited effect in IBS. Recent probiotic trials continue to provide varying results, with some probiotic strains exhibiting beneficial effects, whereas others show no effect. Recent trials have also confirmed the clinical effectiveness of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (i.e. low FODMAP diet) in IBS. Although gluten sensitivity has also been recently investigated, its presence cannot be confirmed yet because of the presence of other potential contributing compounds in wheat. Studies also suggest a potential beneficial effect of peppermint oil, which warrants further research. SUMMARY: It is clear that a low FODMAP diet has a beneficial effect in a majority of patients with IBS. Probiotics also have great potential in the management of IBS; however, it is still unclear which strains and doses are the most beneficial. Further research is needed on the effect of different fibres, or combinations of fibres, in IBS. PMID- 28872468 TI - Sexual disorders beyond DSM-5: the unfinished affaire. AB - PURPOSE OF REVIEW: To provide an overview of post-The Diagnostic and Statistical Manual of Mental Disorders, 5th ed. classifications related to human sexuality. After reviewing the literature on classification and clinical practice of sexual disorders, some of the most important contributions on main sexological classifications and frameworks were selected, especially from January 2016 till June 2017. RECENT FINDINGS: New relevant contributions on psychiatric and sexological classifications and frameworks have been proposed, such as the international classification of diseases 11th revision (ICD-11), research domain criteria, the third edition of the Diagnostic Manual in Sexology and the person centered psychiatry perspective. SUMMARY: ICD-11 proposals regarding conditions related to sexual health including sexual dysfunctions and gender incongruence as well as vaginismus, such as sexual pain disorder, paraphilic disorders as mental Disorders. The disorders associated with sexual development and orientation, are proposed for deletion. The other perspectives aforementioned are also presented. PMID- 28872464 TI - CNS inflammation and neurodegeneration. AB - There is an increasing recognition that inflammation plays a critical role in neurodegenerative diseases of the CNS, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and the prototypic neuroinflammatory disease multiple sclerosis (MS). Differential immune responses involving the adaptive versus the innate immune system are observed at various stages of neurodegenerative diseases, and may not only drive disease processes but could serve as therapeutic targets. Ongoing investigations into the specific inflammatory mechanisms that play roles in disease causation and progression have revealed lessons about inflammation-driven neurodegeneration that can be applied to other neurodegenerative diseases. An increasing number of immunotherapeutic strategies that have been successful in MS are now being applied to other neurodegenerative diseases. Some approaches suppress CNS immune mechanisms, while others harness the immune system to clear deleterious products and cells. This Review focuses on the mechanisms by which inflammation, mediated either by the peripheral immune response or by endogenous CNS immune mechanisms, can affect CNS neurodegeneration. PMID- 28872469 TI - Extending indication of cyclin-dependent kinase 4/6 inhibitors in the adjuvant and neoadjuvant setting. AB - PURPOSE OF REVIEW: A burst of recent activity has surrounded the study of cyclin dependent kinase 4/6 (CDK 4/6) inhibitors for the treatment of metastatic breast cancer. The success of these drugs in the metastatic setting has pushed the evaluation of these agents in early-stage disease. The use of CDK 4/6 inhibitors as neoadjuvant and adjuvant therapy is a hot topic and several studies are underway. RECENT FINDINGS: Ongoing studies are exploring the addition of CDK 4/6 inhibitors to endocrine therapy in early breast cancer. SUMMARY: Identification of the optimal treatment combinations is the goal of current research. Finding biomarkers for patients' selection will be the goal of future research. PMID- 28872471 TI - Lung xenotransplantation. AB - PURPOSE OF REVIEW: This review describes the most recent progress in xeno lung transplantation (XLTx) to date. It describes the potential mechanisms of early xeno lung graft loss, as well as the latest therapeutic strategies to overcome them. RECENT FINDINGS: Using ex-vivo perfusion models of porcine lungs with human blood, the use of genetically modified pig lungs along with novel pharmaceutical approaches has recently been studied. Strategies that have demonstrated improved lung survival include the knockout of known xenoantigens (GalTKO and N glycolylneuraminic acid-KO), genes that regulate complement activation (hCD46 and hCD55), as well as the inflammation/coagulation cascade (human leukocyte antigen E, human thrombomodulin, human endothelial protein C receptor, hCD47, hCD39, hCD73 and heme oxygenase-1). Furthermore, pharmacologic interventions including the depletion of pulmonary intravascular macrophages or von Willebrand factor, inhibition of thromboxane synthase and blockade of histamine receptors have also demonstrated protective effects on xeno lung grafts. Using in-vivo pig to nonhuman primate lung transplant models, these approaches have been shown to extend pulmonary xenograft survival to 5 days. SUMMARY: The development of new multitransgenic GalTKO pigs has demonstrated prolongation of porcine xenograft survival; however, advancement in XLTx has remained frustratingly limited. Further intensive and innovative strategies including genetic manipulation of donors, as well as inflammation/coagulation dysregulation, are required to make XLTx a clinical possibility. PMID- 28872473 TI - Capsaicin 8% Patch Repeat Treatment in Nondiabetic Peripheral Neuropathic Pain: A 52-Week, Open-Label, Single-Arm, Safety Study. AB - OBJECTIVES: To investigate the long-term safety and tolerability of capsaicin 8% patch repeat treatment in nondiabetic patients with peripheral neuropathic pain. METHODS: A prospective, open-label, observational study in patients with postherpetic neuralgia, posttraumatic or postsurgical nerve injury, HIV associated distal sensory polyneuropathy, or other peripheral neuropathic pain, and average daily pain score >=4, who received <=6 capsaicin 8% patch treatments over 52 weeks according to clinical need (retreatment at 9 to 12 wk intervals). Sensory testing and analgesic effectiveness were assessed using "bedside tests" and Brief Pain Inventory (question 5). RESULTS: Overall, 306 patients received treatment. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were reported by 252 (82.4%) and 207 (67.6%) patients. Application site pain was the most common drug-related TEAE (n=112, 36.6%); no drug-related serious TEAEs were reported. Sensory category shift analyses from baseline to end of study (EoS) in patients attending at least 2 sensory visits (n=278 for all tests except warm, n=277) found sensory deterioration/loss in at least 1 modality in 50.4% (n=140); deterioration/loss in 1, 2, 3, 4, or 5 modalities occurred in 26.6% (n=74), 14.0% (n=39), 5.8% (n=16), 2.5% (n=7), and 1.4% (n=4) cases. Newly emergent hyperesthesia or allodynia was apparent in 1.1% to 3.6% of the cases (depending on modality) by EoS. Between 25.2% and 32.0% of patients reported improvement in a sensory modality by EoS. Average daily pain was 6.6 and 4.7 at baseline and month 12. CONCLUSIONS: Generally, capsaicin 8% patch repeat treatment over 52 weeks was well tolerated, with variable alteration in sensory function and minimal chance of complete sensory loss. PMID- 28872470 TI - Stop and go: hematopoietic cell transplantation in the era of chimeric antigen receptor T cells and checkpoint inhibitors. AB - PURPOSE OF REVIEW: For several decades, hematopoietic cell transplantation (HCT) has been considered the standard curative therapy for many patients with hematological malignancies. In addition to the cytotoxic effects of the chemotherapy and radiation used in the conditioning regimen, the benefits of HCT are derived from a reset of the immune system and harnessing the ability of donor T cells to eliminate malignant cells. With the dawn of the era of immunotherapies in the form of checkpoint inhibitors and chimeric antigen receptor (CAR) T cells, the role of HCT has evolved. RECENT FINDINGS: Immunotherapy with checkpoint inhibitors is increasingly being used for relapsed Hodgkin and non-Hodgkin lymphoma after autologous HCT. Checkpoint inhibitors are also being tested after allogeneic HCT with observable benefits in treating hematological malignancies, but with a potential risk of increased graft versus host disease and transplant related mortality. Immunotherapy with Cluster of differentiation 19 CAR T cells are powerful options with aggressive B-cell malignancies both for therapy and as induction leading to allogeneic HCT. SUMMARY: Although immunotherapies with checkpoint inhibition and CAR T cells are increasingly being used to treat hematological malignancies, HCT remains a standard of care for most of the diseases with the best chance of cure. Combination of these therapies with HCT has the potential to more effectively treat hematological malignancies. PMID- 28872474 TI - Acupuncture for the Treatment of Chronic Pain in the Military Population: Factors Associated With Treatment Outcomes. AB - OBJECTIVES: Acupuncture is characterized as an alternative or complementary medicine with a low complication rate and minimal side effects. There is a lack of robust evidence that shows acupuncture is an effective treatment for chronic pain. The purpose of this study was to determine which (if any) characteristics can predict successful response to acupuncture in chronic pain patients treated at military treatment facilities. METHODS: Data from 222 patients who received treatment for a chronic pain condition were collected from 2 medical centers. The patients underwent at least 4 acupuncture treatments and had an average pain score of 4 or higher on a 0- to 10-point numerical rating scale or visual analog scale in the week before treatment initiation. A successful outcome was defined to be a 2-point or greater reduction on the numerical rating scale or visual analog scale 12 weeks postinitial treatment. RESULTS: The overall treatment success rate was 42.3%. Multivariate logistic regression found a higher baseline pain rating and the use of stimulation needles to be associated with a positive outcome (odds ratio [OR]=1.26; 95% confidence interval [CI], 1.03-1.55; P=0.02 and OR=2.73; 95% CI, 1.39-5.32; P=0.03, respectively). Only the presence of one or more psychological comorbidities was found to be associated with treatment failure (OR=0.67; 95% CI, 0.49-0.92; P=0.01). DISCUSSION: The use of electrical stimulation and higher baseline pain score were associated with a positive treatment outcome, while the presence of a psychological comorbidity diminished the likelihood of treatment success. Practitioners should consider using electrical stimulation more frequently, and addressing psychopathology before or concurrent to treatment, when initiating acupuncture. PMID- 28872476 TI - Do User-Applied Safety Labels on Medication Syringes Reduce the Incidence of Medication Errors During Rapid Medical Response Intervention for Deteriorating Patients on Wards? A Systematic Search and Review. AB - INTRODUCTION: Intravenous medication errors (MEs) occur during medical emergency situations. An initiative, not yet in common practice, that could address these errors is safety labeling. The aim of this review was to identify and appraise research evidence related to the impact of user-applied medication safety labeling on reducing the incidence of MEs during rapid medical response intervention for patient deterioration in the ward setting. METHOD: A systematic search and review framework was used to conduct the review. A comprehensive database search was conducted of BioMed Central, Clinical Trials, Cumulative Index to Nursing and Allied Health Literature, Expanded Academic ASAP, Joanna Briggs Institute, MEDLINE, OVID, ProQuest Central, PubMed, Wiley Online Library, and World Health Organization Library. The Young and Solomon (2009) critical appraisal tool was used to critically appraise the identified research articles. Each article was then analyzed using a thematic network strategy to identify commonality. RESULTS: Four primary themes were identified; they were as follows: MEs occur during medical emergency responses (MERs); MEs occur throughout the medication administration process; MERs are stressful and are associated with MEs; and role of medication labeling in reducing MEs during MERs. DISCUSSION: Greater vigilance is required by health professionals during the medication administration process. The implementation of specific medication safety labeling into the MER could be beneficial in reducing the overall incidence of MEs. Further research is required to validate the merits of a MER medication safety labeling system. PMID- 28872477 TI - Thyroid Metastasis as First Manifestation of a Colon Adenocarcinoma With KRAS Mutation: Usefulness of 18F-FDG PET/CT. AB - The synchronous diagnosis of a thyroid metastasis and of the primary colon adenocarcinoma that produces it is very rare, with only 5 cases reported to date, all of them treated with thyroid surgery showing a mean survival of 7 months. An 18F-FDG PET/CT in an asymptomatic 74-year-old woman with a thyroid cytology suggestive of malignancy but uncertain about the origin of the tumor revealed an stage IV colon adenocarcinoma with KRAS mutation and multiple metastasis (thyroid, lung, and liver). A prompt therapeutic planning with chemotherapy allowed 21 months of survival. PMID- 28872478 TI - Response to the letter to the editor: "Understanding the impact of preservation methods on the integrity and functionality of placental allografts". PMID- 28872479 TI - Letter to the Editor. PMID- 28872480 TI - A Random-allocation Graded Dose-Response Study of Norepinephrine and Phenylephrine for Treating Hypotension during Spinal Anesthesia for Cesarean Delivery. AB - BACKGROUND: Norepinephrine has been investigated as a potential alterative to phenylephrine for maintaining blood pressure during spinal anesthesia for cesarean delivery with the advantage of less depression of maternal heart rate and cardiac output. However, the relative potencies of these two vasopressors have not been fully determined in this context. METHODS: In a random-allocation, graded dose-response study, 180 healthy patients undergoing spinal anesthesia for elective cesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 ug or phenylephrine in one of six different doses ranging from 60 to 200 ug to treat the first episode of hypotension. The magnitude of response was measured as the percentage of full restoration of systolic blood pressure to the baseline value. Dose-response analysis was performed using nonlinear regression to derive four-parameter logistic dose-response curves, which were compared to determine relative potency. RESULTS: Data were analyzed for 180 patients. The estimated ED50 values (dose giving a 50% response) were norepinephrine 10 ug (95% CI, 6 to 17 ug) and phenylephrine 137 ug (95% CI, 79 to 236 ug). The estimated relative potency ratio for the two drugs was 13.1 ug (95% CI, 10.4 to 15.8 ug). CONCLUSIONS: Comparative dose-response analysis was completed for norepinephrine and phenylephrine given as a bolus to treat the first episode of hypotension in patients undergoing spinal anesthesia for cesarean delivery. The estimated dose equivalent to phenylephrine 100 ug was norepinephrine 8 ug (95% CI, 6 to 10 ug). These results may be useful to inform the design of future comparative studies. PMID- 28872481 TI - Xenon and Cardioprotection: Is This the Light at the End of the Tunnel? PMID- 28872482 TI - Stem Cell-based Therapies for Sepsis. AB - Sepsis is a life-threatening syndrome resulting in shock and organ dysfunction stemming from a microbial infection. Sepsis has a mortality of 40% and is implicated in half of all in-hospital deaths. The host immune response to microbial infection is critical, with early-phase sepsis characterized by a hyperinflammatory immune response, whereas the later phase of sepsis is often complicated by suppression. Sepsis has no treatment, and management remains supportive.Stem cells constitute exciting potential therapeutic agents for sepsis. In this review, we examine the rationale for stem cells in sepsis, focusing on mesenchymal stem/stromal cells, which currently demonstrate the greatest therapeutic promise. We examine the preclinical evidence base and evaluate potential mechanisms of action of these cells that are important in the setting of sepsis. We discuss early-phase clinical trials and critically appraise translational barriers to the use of mesenchymal stem/stromal cells in patients with sepsis. PMID- 28872483 TI - "Golf Ball" in the Left Ventricular Outflow Tract? PMID- 28872485 TI - What is the Value of a National Football League Draft Pick? An Analysis Based on Changes Made in the Collective Bargaining Agreement. AB - Kraeutler, MJ, Carver, TJ, Belk, JW, and McCarty, EC. What is the value of a National Football League draft pick? An analysis based on changes made in the collective bargaining agreement. J Strength Cond Res 32(6): 1656-1661, 2018-The purpose of this study was to analyze and compare the value of players drafted in early rounds of the National Football League (NFL) Draft since the new collective bargaining agreement began in 2011. The NFL's player statistics database and database of player contract details were searched for players drafted in the first 3 rounds of the 2011 to 2013 NFL Drafts. Performance outcomes specific to each position were divided by each player's salary to calculate a value statistic. Various demographics, NFL Combine results, and total number of games missed because of injury were also recorded for each player. These statistics were compared within each position between players selected in the first round of the NFL Draft (group A) vs. those drafted in the second or third round (group B). A total of 147 players were included (group A 35, group B 112). Overall, players in group A were significantly taller (p <= 0.01) and heavier (p = 0.037) than players in group B. Group B demonstrated significantly greater value statistics than group A for quarterbacks (p = 0.028), wide receivers (p <= 0.001), defensive tackles (p = 0.019), and cornerbacks (p <= 0.001). No significant differences were found between groups with regard to number of games missed because of injury. Players drafted in the second or third rounds of the NFL Draft often carry more value than those drafted in the first round. NFL teams may wish to more frequently trade down in the Draft rather than trading up. PMID- 28872484 TI - Effect of Xenon Anesthesia Compared to Sevoflurane and Total Intravenous Anesthesia for Coronary Artery Bypass Graft Surgery on Postoperative Cardiac Troponin Release: An International, Multicenter, Phase 3, Single-blinded, Randomized Noninferiority Trial. AB - BACKGROUND: Ischemic myocardial damage accompanying coronary artery bypass graft surgery remains a clinical challenge. We investigated whether xenon anesthesia could limit myocardial damage in coronary artery bypass graft surgery patients, as has been reported for animal ischemia models. METHODS: In 17 university hospitals in France, Germany, Italy, and The Netherlands, low-risk elective, on pump coronary artery bypass graft surgery patients were randomized to receive xenon, sevoflurane, or propofol-based total intravenous anesthesia for anesthesia maintenance. The primary outcome was the cardiac troponin I concentration in the blood 24 h postsurgery. The noninferiority margin for the mean difference in cardiac troponin I release between the xenon and sevoflurane groups was less than 0.15 ng/ml. Secondary outcomes were the safety and feasibility of xenon anesthesia. RESULTS: The first patient included at each center received xenon anesthesia for practical reasons. For all other patients, anesthesia maintenance was randomized (intention-to-treat: n = 492; per-protocol/without major protocol deviation: n = 446). Median 24-h postoperative cardiac troponin I concentrations (ng/ml [interquartile range]) were 1.14 [0.76 to 2.10] with xenon, 1.30 [0.78 to 2.67] with sevoflurane, and 1.48 [0.94 to 2.78] with total intravenous anesthesia [per-protocol]). The mean difference in cardiac troponin I release between xenon and sevoflurane was -0.09 ng/ml (95% CI, -0.30 to 0.11; per-protocol: P = 0.02). Postoperative cardiac troponin I release was significantly less with xenon than with total intravenous anesthesia (intention-to-treat: P = 0.05; per-protocol: P = 0.02). Perioperative variables and postoperative outcomes were comparable across all groups, with no safety concerns. CONCLUSIONS: In postoperative cardiac troponin I release, xenon was noninferior to sevoflurane in low-risk, on-pump coronary artery bypass graft surgery patients. Only with xenon was cardiac troponin I release less than with total intravenous anesthesia. Xenon anesthesia appeared safe and feasible. PMID- 28872486 TI - Comparison of Different Iron Preparations in the Prophylaxis of Iron-deficiency Anemia. AB - We compared the efficacy of ferrous sulfate (divalent) and ferric polymaltose (trivalent) compounds for the prophylaxis of iron-deficiency anemia (IDA). Study infants included exclusively breast milk-fed term infants. Subjects were divided randomly into 2 groups at 4 months of age and group 1 (n=56) received divalent and group 2 (n=56) received trivalent iron (Fe) preparation at a dose of 2 mg/kg/d for 5 months. At 9 months of age, after a 5-month prophylaxis, a significant increase was observed in hemoglobin (Hb), hematocrit, serum Fe levels, and transferrin saturation in both groups. However, group 1 had significantly higher Hb, hematocrit, mean corpuscular volume, Fe, and transferrin saturation than group 2 (11.7+/-0.6 g/dL, 34.6%+/-1.7%, 76.2+/-2.9 fL, 55.5+/-1.8 mcg, 20.8+/-3.9 g/L, respectively in group 1 vs. 11.3+/-0.5 g/dL, 33.5%+/-1.5%, 74.7+/-3.2 fL, 42.5+/-1.8 mcg, 14.1+/-7.5 g/L, respectively in group 2). No significant difference was found in ferritin values between the groups. Fe deficiency was found in 17 (30.3%) of the subjects in group 1, and 23 (41%) of subjects in group 2 whereas 5 (8.9%) subjects had IDA in group 1 and 12 (12%) in group 2 which were insignificant between groups. No significant difference was found with regard to side effects between 2 Fe preparations. Although divalent Fe therapy led to a higher Hb and serum Fe level, both ferrous and ferric Fe preparations were effective for prophylactic use in the prevention of Fe deficiency and IDA with comparable side effects. PMID- 28872488 TI - Acute motor and sensory axonal neuropathy related to treatment with MEK inhibitors in a patient with advanced melanoma. AB - Approximately one-half of advanced cutaneous melanomas have a V600 mutation in the BRAF gene that activates the mitogen-activated protein kinase pathway. The combination of BRAF plus MEK inhibitors is one of the most effective treatments for these patients. Severe neurological toxicities have been reported in the literature. However, these toxicities are very rare. Here, we present one patient with acute motor and sensory axonal neuropathy, which is a subtype of Guillain Barre syndrome, secondary to treatment with MEK inhibitors. This side effect had never been described as related to these agents. However, the mitogen-activated protein kinase pathway can be involved in Guillain-Barre syndrome, and awareness of early neurological injury signs is important in patients treated with MEK inhibitors. PMID- 28872489 TI - A case of pure red cell aplasia during nivolumab therapy for cardiac metastatic melanoma. AB - Nivolumab is an antibody against programmed cell death 1 and functions as an immune checkpoint inhibitor for various malignancies, including unresectable melanomas. Nivolumab causes several immune-related adverse events, which typically include skin rash, pneumonitis, thyroid dysfunction, hepatitis, and colitis; in rare cases, anemia may be present. There are several reports of autoimmune hemolytic anemia that has developed in response to nivolumab; however, there are few reports of pure red cell aplasia (PRCA). We describe a patient who developed PRCA during nivolumab administration. A 70-year-old Japanese woman received nivolumab for cardiac metastasis from malignant melanoma from an unknown site. Twenty-one months after nivolumab administration (31 courses), treatment was discontinued because she developed severe anemia. Blood test results indicated normocytic, normochromic anemia, and reticulocytopenia, but all other components were normal. Bone marrow aspiration showed increased megakaryocytes and decreased erythroblasts; these findings were consistent with PRCA. Anemia improved without recurrence after treatment with corticosteroids and blood transfusions. The steroid dosage was reduced gradually, and to date, the patient has not experienced recurrence of anemia. The tumor decreased in size and the patient has shown a continued response to treatment with decrease in disease for 3 years. Although it is unclear how nivolumab causes PRCA, hematological toxicities have been reported in patients treated with immunotherapy drugs. PRCA might be an unrecognized immune-mediated adverse event that did not manifest during the clinical trial phase. PMID- 28872490 TI - Menopausal hormone therapy for primary prevention: why the USPSTF is wrong. PMID- 28872491 TI - Please don't give hormone therapy a D recommendation or state that "harms far outweigh benefits for prevention of chronic disease". PMID- 28872492 TI - An update on ocular complications of Ebola virus disease. AB - PURPOSE OF REVIEW: This review provides a summary of our current understanding of the ophthalmic manifestations of Ebola virus disease (EVD), pathogenesis, treatment options and directions for future study. The individual, public health and global health implications of eye disease in EVD survivors are discussed. RECENT FINDINGS: The West Africa EVD outbreak was of unprecedented magnitude, leading to the largest survivor cohort since the first documented EVD outbreak in 1976. Because of the magnitude of the recent outbreak, thousands of survivors are at-risk of systemic and ophthalmic sequelae termed the 'post Ebola virus disease syndrome'. Uveitis is the most common finding during EVD convalescence and may lead to severe vision impairment or blindness in 40% of affected individuals. Ocular complications leading to vision loss include cataract, retinal scarring, optic neuropathy, hypotony and phthisis bulbi. The pathogenesis of eye disease in EVD survivors likely involves Ebola virus persistence, severe inflammation and tissue edema, which present as acute, rapidly progressive disease or chronic, smoldering disease. Further studies into disease pathogenesis including mechanisms of viral persistence may provide guidance into therapies for uveitis secondary to EVD. SUMMARY: Uveitis is the most common ophthalmic finding in EVD survivors and can lead to vision loss. Further studies into the clinical manifestations and mechanisms of disease are needed to improve therapies for EVD survivors who often have limited access to ophthalmic medical and surgical care. PMID- 28872495 TI - Dislocated Dental Prothesis Sitting at the Larynx in an Aphasic Patient: Potentially Fatal Situation. AB - INTRODUCTION: Foreign body in respiration tract is a life-threatening emergency and requires urgent treatment. The diagnosis and treatment requires awareness and suspicion of signs and symptoms of foreign body aspiration. CASE: A unique case of total dental prothesis aspiration of a 44-year-old aphasic patient is presented. The prothesis is completely removed from the larynx. DISCUSSION: Foreign-body aspiration is frequently suspected in children, it is rarely thought about in adults with subacute or chronic respiratory symptoms unless an evident history of an aspiration event is obtained. Facial trauma, dental procedures, central nervous system dysfunction due to stroke, mental retardation, metabolic encephalopathy, seizures, and alcoholism are precipitating factors in adults. Careful clinical history and physical examination is mandatory. Foreign bodies located in the laryngeal region are almost always treated with surgery. CONCLUSION: Loose dentures must be avoided especially in mental retarded, aphasic patients, and patients with central nervous system dysfunction. PMID- 28872494 TI - The genetics of congenital heart disease... understanding and improving long-term outcomes in congenital heart disease: a review for the general cardiologist and primary care physician. AB - PURPOSE OF REVIEW: This review has two purposes: to provide an updated review of the genetic causes of congenital heart disease (CHD) and the clinical implications of these genetic mutations, and to provide a clinical algorithm for clinicians considering a genetics evaluation of a CHD patient. RECENT FINDINGS: A large portion of congenital heart disease is thought to have a significant genetic contribution, and at this time a genetic cause can be identified in approximately 35% of patients. Through the advances made possible by next generation sequencing, many of the comorbidities that are frequently seen in patients with genetic congenital heart disease patients can be attributed to the genetic mutation that caused the congenital heart disease. These comorbidities are both cardiac and noncardiac and include: neurodevelopmental disability, pulmonary disease, heart failure, renal dysfunction, arrhythmia and an increased risk of malignancy. Identification of the genetic cause of congenital heart disease helps reduce patient morbidity and mortality by improving preventive and early intervention therapies to address these comorbidities. SUMMARY: Through an understanding of the clinical implications of the genetic underpinning of congenital heart disease, clinicians can provide care tailored to an individual patient and continue to improve the outcomes of congenital heart disease patients. PMID- 28872496 TI - Advantages of a Beveled Osteotomy on the Zygomatic Arch During Reduction Malarplasty. AB - During a conventional reduction malarplasty procedure, a dual approach including intraoral incisions and preauricular incisions is made to reduce both the zygomatic body and arch. As the preauricular approach is performed to cut the zygomatic arch, there are several remarkable advantages that can be achieved by simply beveling the osteotomy anteriorly on the zygomatic arch. This has the benefits of enhancing bone union by the increase in cross-sectional area for bone contact, decreasing palpability on the osteotomy site, placing the osteotomy more posteriorly, preventing depression in the anterior malar region, and reducing the need for metal fixtures. PMID- 28872497 TI - Myoepithelioma of the Nasal Septum. AB - Myoepithelioma is defined as myoepithelial cells composed of tumor with solid, myxoid, and reticular growth pattern by the World Health Organization. It is a rare neoplasm that arises in the major salivary gland or minor salivary gland comprising approximately 1% of all salivary gland tumor. This neoplasm occurs in the parotid gland and soft palate mostly, which can be found in other organs. However, up to now, myoepithelioma of nasal septum has not been reported in English medical literature. Histologically, it is grouped as spindle, epitheliod, reticular, and clear cell types. Spindle cell type is the most common. In this case, a 40-year-old woman presented with complaining of nasal stuffiness and accidentally found right nasal cavity mass. Endoscopic surgery for excision of the mass was performed under local anesthesia, which was confirmed as myoepithelioma. After surgery, the patient's symptom was disappeared and there has not been sign of recurrence for 6 months. We present a rare patient of myoepithelioma of the nasal septum with review of relevant literature. PMID- 28872498 TI - Diagnosis and Management of Cerebrospinal Fluid Leak in a Panfacial Fracture. AB - Cerebrospinal fluid fistula caused by head trauma is a potentially dangerous problem and precise localization and radical treatment are necessary. We present a case of a patient with Panfacial fracture caused by a motorcycle accident, resulting in a cerebrospinal fluid leakage. The correct diagnosis was realized by computed tomography and auxiliary tests. The successful treatment can be confirmed with the support of radionuclide cisternography examination. PMID- 28872499 TI - Mean Platelet Volume, Red Cell Distribution Width, and Neutrophil-to-Lymphocyte Ratio Before and After Surgery in Patients With Carotid Body Tumors. AB - OBJECTIVE: Carotid body tumors (CBTs) are rare hypervascular benign tumors that originate from the paraganglia at the carotid bifurcation. The red cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), and mean platelet volume (MPV) may serve as markers in inflammatory, cardiovascular, and neoplastic diseases. However, their prognostic value in CBTs is unknown. The purpose of this study was to assess the leukocyte count, MPV, RDW, and NLR before and after surgery in patients with CBTs. METHODS: This retrospective trial included data from 80 patients with CBTs and 65 age-matched healthy controls. The leukocyte, neutrophil, lymphocyte and platelet counts, RDW, and MPV were extracted and NLR was calculated from the complete blood count results of participants. RESULTS: The leukocyte and neutrophil counts as well as RDW levels were significantly increased in patients with CBTs compared with healthy controls (P = 0.005, P = 0.003, and P = 0.026; respectively). Patients with CBTs had lower lymphocytes counts (P = 0.241) and higher NLRs (P = 0.054); however, the difference was statistically insignificant. Moreover, no statistically significant difference was detected between groups in terms of platelet counts and MPV levels. Furthermore, the leukocyte count, platelet numbers, MPV, RDW, and NLR levels in patients with CBTs were not statistically significant after surgery (all; P > 0.05). CONCLUSION: This is the first study that documents the increased RDW levels and leukocyte count in patients with CBTs. The combined use of RDW and the leukocyte count along with other clinical assessments can be used as a biomarker for CBTs. Further clinical trials with larger cases series are required to determine the actual predictive roles of these systemic biomarkers. PMID- 28872500 TI - Simple Septocutaneous Free Flap Design for One-Stage Reconstruction of Pharyngocutaneous and Orocutaneous Fistulae. AB - Reconstruction of pharyngocutaneous fistula (PCF) or orocutaneous fistula is always a challenging task. It has many causes and is especially related to radiation therapy after resection of head and neck cancers. There are many reports of surgical procedures for fistula repair. For example, 2-stage methods, methods of combining multiple flaps, and methods of using chimeric flaps have been reported. However, there is no established simple method as a treatment of choice. The authors describe 5 patients of head and neck fistulas and recommend a useful 1-stage reconstruction method using a double skin paddle free flap.The authors modified the free flaps simply with a double skin paddle sharing 1 pedicle. The skin paddle of the flap was split into 2 parts, one skin island for inner mucosal coverage, and the other for outer skin resurfacing. The bridge between the 2 skin paddles was deepithelialized and then folded. To prevent leakage, a water-tight closure was ensured.The double skin paddle free flap method was used in 5 patients. Two patients had orocutaneous fistula, and the other 3 patients had PCF due to irradiation. Flap losses did not occur, but wound dehiscence was noted in the 3 PCF patients. Repeat wound revision procedures were performed in these patients, and the end result was good.Conventional methods are complex and require multiple flaps or repeat surgery. However, the double skin paddle free flap method allows for simple and effective 1-stage reconstruction using 1 flap, 1 pedicle, and 1 microanastomosis even for patients who received preoperative radiotherapy. PMID- 28872501 TI - Effects of Different Tissue Adhesives in Treating Calvarial Bone Defects. AB - The purpose of this study is to investigate the potential of the 2 different tissue adhesive materials as a barrier for guided bone regeneration and to compare them with resorbable collogen membrane on autogenous grafted critical sized cortical bone defects. Twenty-four rats were divided into 3 groups: Group M, Group G, and Group B. A 5-mm diameter critical-size defect was created in the calvarium of each animal. All defects were filled by autogenous graft harvested from tibia. In group M, resorbable collogen membrane was applied to defect area. In groups G and B, defects were closed by Glubran2 and Bioglue. All animals were euthanized at 28 days postoperative. Stereologic analyses were performed. New bone area and connective tissue volumes were measured. Mean new bone volumes were 0.97 +/- 0.28, 0.59 +/- 0.2, and 0.8 +/- 0.32 mm in groups M, G, and B, respectively. The differences between groups were not statistically significant (P > 0.05). In group M, mean connective tissue volumes were 4.25 +/- 0.7 mm, in groups G and B, 2.9 +/- 1.82 and 4.54 +/- 0.64 mm. Connective tissue volume differences were not statistically significant between groups. Glubran2 and Bioglue may play a role as a barrier for guided bone regeneration in treatment of critical size defects. PMID- 28872502 TI - Lingual Short Split: A Bilateral Sagittal Split Osteotomy Technique Modification. AB - The technique of sagittal split osteotomy of the mandibular ramus is an established technique that has been evolving over the years, with significant improvements regarding stability, better bone contact between the segments, and possibilities of osteosynthesis. However, paresthesia is common in the postoperatory, sometimes permanent, and undesirable fractures in the subcondylar region can occur leading to longer operative time and extraoral scars. The short lingual split technique is an easy technique that simplifies the horizontal osteotomy of the ramus and decreases the risk of undesirable fractures with a neurosensitive recovery of patients in a much shorter time because of minor trauma and nerve manipulation during the execution. PMID- 28872503 TI - Postoperative Orthognathic Surgery Edema Assessment With and Without Manual Lymphatic Drainage. AB - OBJECTIVE: To evaluate the effects of manual lymphatic drainage (MLD) on facial edema and pain in patients who underwent orthognathic surgery from patient and professional perspectives and clinical measures. METHODS: It is a randomized double-blind clinical trial, where 30 patients who underwent bimaxillary orthognathic surgery were divided into 2 groups (treatment and placebo). One group (treatment) received MLD from 2nd postoperative day, besides cryotherapy and postoperative medications. The other group (placebo) received cryotherapy, medications, and manual superficial sliding movements as placebo. For edema evaluation, facial measurements with tape and photographs were used. To evaluate patients' perception, visual analog scale for pain and edema was used. In statistical analysis, quantitative data were analyzed using Student t test for normally distributed variables and Mann-Whitney test for non-normal to find differences between groups; 5% significance level was adopted. RESULTS: No difference was found between groups in the amount of maximum developed edema (P = 0.290) nor on what day the edema peak occurred (P = 0.091). However, it was found that treatment group showed faster and greater regression of swelling compared with placebo (P < 0.001). Manual lymphatic drainage was not effective in relieving pain in these patients and nor in edema perception (P = 0.784 and P = 0.946, respectively). CONCLUSION: Manual lymphatic drainage was effective in reducing facial measurements in orthognathic surgery postoperatory. When considering patient's pain and swelling perception, no difference was found between groups. PMID- 28872504 TI - Chondrocutaneous Preauricular Free Flap for Reconstruction of Nasal Defects Aided by Interposition Vascular Graft. AB - INTRODUCTION: Reconstruction of a nose deformity with a full-thickness defect is not an easy procedure because the nose is highly noticeable, being located at the center of the face, and plays an important role in breathing. Esthetics and functionality are equally important. Local flap reconstruction is an option but it has limitations for reconstruction of large defects because of the following the scar and the deformity at the recipient site. Chondrocutaneous preauricular free flaps can be used to provide grafts with satisfactory esthetics. Since the chondrocutaneous preauricular free flap has a short pedicle for anastomosis with the facial artery and vein, in some patients there is a need for extra vessel grafts. The authors have had several successful results using chondrocutaneous free flaps aided by interposition vascular grafts with the descending branch of the lateral circumflex femoral artery and the accompanying vein. PATIENTS AND METHODS: A total of 6 patients with full thickness defects of the nose participated in chondrocutaneous preauricular free flap operations from 2011 to 2015. Operations were performed under general anesthesia. After dissection around the tissue and scar removal, the flap was designed to be a few centimeters size wide to include cartilage from the helical loop and preauricular skin. After finding the superficial temporal vein by dissection, the incision was extended to the proximal part of the flap and dissection was done below the superficial temporal vessels. To elongate the pedicle of the flap, the descending branch of the lateral circumflex femoral artery, used as a pedicle for the anterolateral femoral flap, and the accompanying vein were harvested together. The harvested descending branch of the lateral circumflex femoral artery and the accompanying vein were placed on the subcutaneous tunnel. End-to-end anastomosis between the pedicle of the flap and the vessel graft as well as between the vessel graft and the facial vessels was done. During flap inset, even though remnant parts were trimmed, sufficient tissue should be left cautiously, and the donor site was closed primarily. RESULTS: All 6 operations were successful. Despite the different etiologies in each patient, the nose defects were not different and the operations were not different either. The operative time varied from 3.5 to 6 hours. No major complications were reported. After the operation, necrosis and donor site complications did not occur, and scarring and deformity of the donor site were minimal. The patients were mostly satisfied with the results. CONCLUSION: Use of the chondrocutaneous preauricular free flap is not only effective for large defects of the nose, but also makes a good donor if the 3 floor structure and subunit structures of the nose are taken into consideration. Since the pedicle of the flap was short, the authors recruited the descending branch of the lateral circumflex femoral artery and the accompanying vein as a vessel graft. A year after surgery, all of the patients were satisfied with the results. PMID- 28872505 TI - Efficacy of Facilitated Capacity Building in Providing Cleft Lip and Palate Care in Low- and Middle-Income Countries. AB - Providing surgical repair for congenital anomalies such as cleft lip and palate (CLP) can be challenging in low- and middle-income countries. One nonprofit organization seeks to address this need through a partnership model. This model provides long-term aid on multiple levels: surgeon and healthcare provider education, community outreach, and funding. The authors examined the effectiveness of this partnership model in providing CLP care and increasing cleft care capacity over time. This organization maintains data on each partner and procedure and collected data on hospital and patient characteristics through voluntary partner surveys from 2010 to 2014. Effectiveness of care provision outcomes included number of surgeries/partner hospital and patient demographics. Cleft surgical system strengthening was measured by the complexity of repair, waitlist length, and patient follow-up. From 2001 to 2014, the number of procedures/hospital/year grew from 15 to 109, and frequency of alveolar bone grafts increased from 1% to 3.4%. In addition, 97.9% of partners reported that half to most patients come from rural areas. Waitlists decreased, with 9.2% of partners reporting a waitlist of >=50 in 2011 versus 2.7% in 2014 (P < 0.001). Patient follow-up also improved: 35% of partners in 2011 estimated a follow-up rate of >=75%, compared with 51% of partners in 2014 (P < 0.001). The increased number of procedures/hospital/year supports the partnership model's effectiveness in providing CLP care. In addition, data supports cleft surgical system strengthening-more repairs use alveolar bone grafts, waitlists decreased, and follow-up improved. These findings demonstrate that the partnership model may be effective in providing cleft care and increasing cleft surgical capacity. PMID- 28872506 TI - An Aneurysmal Bone Cyst in the Skull Base. AB - An aneurysmal bone cyst (ABC) is believed to be attributable to intraosseous circulatory disturbance. An ABC is a vascular tumor of the bone caused by bony expansion after partial vascular occlusion and congestion. Most ABCs are found in adolescents (approximately 75% of ABCs are observed in patients under 20 years of age). The most common ABC sites are the long bones of the limbs, the vertebrae, and the cranial bone. Aneurysmal bone cysts in the skull base or ethmoid sinus have been but rarely reported worldwide. The authors report on a patient with a very large ABC in the skull base and the ethmoid sinus; this was successfully managed by a neurosurgeon. PMID- 28872507 TI - Protection of the Temporomandibular Joint During Syndromic Mandibular Distraction With a Novel Condylar Offloading Device. AB - Mandibular distraction for severe micrognathia in syndromic patients often leads to temporomandibular joint (TMJ) ankylosis, which requires further interventions to regain joint motion. The increased incidence of postdistraction ankylosis is likely related to increased prevalence of preoperative joint pathology in syndromic micrognathic patients. Previous studies have demonstrated that offloading the pressure on the condyle during the distraction process can prevent such TMJ pathology. In this article, the authors describe a successful new method for offloading the condyle to prevent postdistraction ankylosis using an external TMJ offloading device. PMID- 28872508 TI - A Rare Cause of Dyspnea: Cervicothoracic Cystic Lymphangioma. AB - I read with great interest the article reported by Efe et al in Journal of Cranofacial Surgery (2016;27:1802-1803), presenting the excellent result obtained by the use of sclerotherapy with single-dose OK-432 in a growing cervical lymphangioma. Cervicothoracic lymphangioma is a rare congenital anomaly that is mostly asymptomatic. We would like to share our experience of a rare cause of dyspnea by lymphangioma. In our case, the patient presented with dyspnea and paroxysmal cough caused by cervicothoracic lymphangioma and sclerotherapy alleviated tracheal compression and relieved the dyspneic symptoms. PMID- 28872509 TI - Mandibular Condylar Fractures in Children: Morphofunctional Results After Treatment With External Fixation. AB - Best treatment for paediatric patients with mandibular condylar fractures is still debated, and many approaches have been proposed. Closed treatment is the most used, but there is evidence showing long-term problems in patients with dislocated fractures. On the other hand, there are concerns on surgical treatment with open reduction internal fixation, particularly on the implanted hardware during growth. The aim of this study is to evaluate the long-term outcomes of paediatric patients treated surgically with external fixation. A total of 21 paediatric patients were treated. Diagnostic procedures included clinical and radiographic examinations. Of those 21 patients, 16 presented monocondylar fractures, 5 bicondylar fractures. They were treated surgically with open reduction and external fixation. Patients showed good recovery in maximal mouth opening, maximal lateral excursion and in vertical height of ramus, and all returned to preinjury occlusion. No patient presented permanent facial nerve palsy, and none referred pain or stiffness in the operated area. Minimal scars were visible. Just 1 patient referred clicking in the operated temporo-mandibular joint. Surgical approach using external fixation could be considered an option for treatment of mandibular condylar fractures in paediatric patient. Vertical height recovery, early mobilization, and good occlusion can be achieved, minimizing the risk of facial asymmetry. PMID- 28872510 TI - Massive Intradural Dermoid Cyst Without Sinus Tract. AB - Dermoid cysts can present as a rare, benign, congenital intracranial tumor of neuroectoderm origin trapped during embryogenesis. Past clinical reports have reported lesions in the posterior fossa, at the midline, and in the intradural region all in conjunction with a superficial sinus tract. The authors present a unique patient of a completely intracranial, intradural, dermoid tumor of the midline cerebellum devoid of any evidence of sinus tract. The histological characteristics, radiological features, and management of this unusual patient are described. PMID- 28872511 TI - An Innovative Intracystic Negative Pressure System to Treat Odontogenic Cysts. PMID- 28872512 TI - The Effects of Adipose-Derived Stem Cells Differentiated Into Endothelial Cells and Osteoblasts on Healing of Critical Size Calvarial Defects. AB - Delayed vascularization and resultant resorption limits the clinical use of tissue engineered bony constructs. The objective of this study is to develop a strategy to accelerate the neovascularization of tissue-engineered bony constructs using endothelial differentiated adipose-derived stem cells (ASC). The authors harvested ASC from inguinal fat pads of male Lewis rats (n = 5) and induced toward endothelial and osteoblastic lineages. The authors created critical size calvarial defects on male Lewis rats (n = 30) and randomized the animals into 4 groups. For the repair of the defects the authors used hydroxyapatite/poly(lactide-co-glycolide) [HA-PLG] scaffolds in group I, HA-PLG scaffolds seeded with ASC in group II, HA-PLG scaffolds seeded with ASC-derived endothelial cells in group III, and HA-PLG scaffolds seeded with ASC-derived osteoblasts in group IV. The authors evaluated the bone healing histologically and with micro-computed tomography (CT) scans 8 weeks later. Adipose-derived stem cells exhibited the characteristics of endothelial and osteogenic lineages, and attached on HA-PLG scaffolds after differentiation. Micro-CT analysis revealed that highest bone mineral density was in group IV (1.46 +/- 0.01 g/cm) followed by groups III (1.43 +/- 0.05 g/cm), I (1.42 +/- 0.05 g/cm), and II (1.3 +/- 0.1 g/cm). Hematoxylin-Eosin and Masson Trichrome staining revealed similar results with the highest bone regeneration in group IV followed by groups II, III, and I. Regenerated bone in group IV also had the highest vascular density, but none of these differences achieved statistical significance (P > 0.05). The ASC-derived endothelial cells and osteoblasts provide a limited increase in calvarial bone healing when combined with HA-PLG scaffolds. PMID- 28872513 TI - Reconstruction of Orbital Floor With Auricular Concha. AB - Orbital floor fractures of varying sizes commonly occur after orbital injuries and remain a serious challenge. Serious complications of such fractures include enopthalmos, restriction of extraocular movement, and diplopia. There is a dearth of literature that can be applied widely, easily, and successfully in all such situations, and therefore there is no consensus on the treatment protocol of this pathology yet. Autogenous grafts and alloplastic and allogenic materials with a wide variety of advantages and disadvantages have been discussed. The value of preoperative and postoperative ophthalmological examination should be standard of care in all orbital fracture patients. An ideal reconstructed orbital floor fracture should accelerate the restoration of orbital function with acceptable cosmetic results. Management parameters of orbital fractures such as timing of surgery, incision type, and implant materials, though widely discussed, remain controversial. In this study, 55 patients with orbital floor fractures surgically reconstructed with conchal cartilage grafts between 2008 and 2014 were retrospectively evaluated. Complications and long-time follow-up visit results have been reported with clinical and radiographic findings. The aim of this study was to present the authors' clinical experiences of reconstruction of blow-out fractures with auricular conchal graft and to evaluate the other materials available for use. PMID- 28872514 TI - Stimuli-Responsive Biomaterials: Next Wave. PMID- 28872516 TI - Corneal Densitometry in Healthy Corneas and Its Correlation With Endothelial Morphometry. AB - PURPOSE: To evaluate the correlations between corneal endothelial cell properties and corneal densitometry values and to investigate whether corneal densitometry may be used as an indicator of the health of corneal endothelium. METHODS: Two hundred fifty-three eyes were analyzed in this prospective cross-sectional study. Corneal densitometry was measured with densitometry software of Pentacam HR Scheimpflug corneal topography over a 12-mm diameter of the cornea. Furthermore, corneal endothelial cell properties including cell density (CD), average cell area, SD of the cell area, coefficient of variation (CV) of the cell area, maximum cell area, minimum cell area, and percentage of hexagonal cells (HEX) were measured by a specular microscope. The correlations were calculated using Pearson correlation tests. RESULTS: The average cell area, SD, maximum cell area, and minimum cell area values were not statistically significantly correlated with the corneal densitometry values in any layer or concentric annulus. CD, CV, and HEX were statistically significantly correlated with the corneal densitometry values in all layers and concentric annuli (P < 0.05 for each one). Moreover, CD and HEX were inversely and moderately correlated with total corneal densitometry (r = -0.403, P < 0.001, and r = -0.327, P < 0.001, respectively), whereas the CV was positively and moderately correlated with total corneal densitometry (r = 0.349, P < 0.001). CONCLUSIONS: Corneal densitometry might have potential to be used as an indicator of the health of corneal endothelium in the future. PMID- 28872517 TI - Favorable Outcome in Coccidioides Endophthalmitis-A Combined Medical and Surgical Treatment Approach. AB - PURPOSE: To describe a case of Coccidioides endophthalmitis that resulted in a favorable visual outcome after a combined medical and surgical approach. METHODS: A 33-year-old previously healthy woman was referred for evaluation of dyspnea and left-sided vision loss, which began 3 months before, after a trip to Nevada. She was found to have a pulmonary cavitary lesion and fluffy white material in the anterior chamber. An aqueous and vitreous paracentesis grew Coccidioides species. She was managed medically with a total of 7 weekly intravitreal injections of amphotericin B and intravenous liposomal amphotericin B followed by transition to oral posaconazole. Seven months after presentation, to ensure ocular sterilization and to clear the visual axis, she underwent temporary keratoprosthesis implantation, anterior segment reconstruction, removal of a cyclitic membrane and the crystalline lens, pars plana vitrectomy, placement of a pars plana Ahmed drainage device, and penetrating keratoplasty. RESULTS: After surgical intervention and with maintenance posaconazole therapy, the patient had resolution of her dyspnea and improved uncorrected (aphakic) vision with a clear corneal graft, quiet anterior chamber, and normal optic nerve and retina. CONCLUSIONS: A combined medical and surgical approach resulted in a favorable visual outcome and avoided the need for enucleation. PMID- 28872518 TI - Tear Osmolarity and Correlation With Ocular Surface Parameters in Patients With Dry Eye. AB - PURPOSE: To analyze the distribution of tear film osmolarity in patients with dry eye and its association with other ocular surface parameters. METHODS: Tear osmolarity and other quantitative dry eye parameters were obtained from patients with 1) clinically significant dry eye (significant symptoms and ocular surface staining, n = 131), 2) symptoms-only dry eye (significant symptoms but no significant ocular surface staining, n = 52), and 3) controls (no significant symptoms or staining, n = 42). RESULTS: Tear osmolarity varied significantly across groups (P = 0.01), with patients with clinically significant dry eye having the highest tear osmolarity (312.0 +/- 16.9 mOsm/L), control patients having the lowest tear osmolarity (305.6 +/- 9.7 mOsm/L), and patients with symptoms-only dry eye falling in between (307.4 +/- 5.6 mOsm/L). Patients with clinically significant dry eye also tended to have a greater intereye difference in osmolarity (12.0 +/- 13.4) than did the individuals with symptoms-only dry eye (9.1 +/- 12.4) and controls (9.0 +/- 7.4) (P = 0.06). In multivariable regression models, higher tear osmolarity was associated with higher Ocular Surface Disease Index, discomfort subscore (P = 0.02), and higher corneal and conjunctival staining scores (P < 0.01 for both). Worse eye tear osmolarity was not correlated with the corresponding tear film breakup time or Schirmer test (P > 0.05 for both). CONCLUSIONS: Individuals with symptomatic dry eye that is not yet clinically significant seem to have higher and more variable osmolarity measurements than controls, potentially indicating that changes in osmolarity precede clinical findings. PMID- 28872519 TI - Changes in Corneal Density After Accelerated Corneal Collagen Cross-linking With Different Irradiation Intensities and Energy Exposures: 1-Year Follow-up. AB - PURPOSE: To determine and compare the changes in corneal density after 2 different protocols of accelerated corneal collagen cross-linking (A-CXL) in patients with progressive keratoconus. METHODS: Two groups of eyes received A-CXL treatment; 20 eyes received A-CXL using continuous UVA light exposure at 9 mW/cm for 10 minutes with a total energy dose of 5.4 J/cm, and 24 eyes received A-CXL using continuous UVA light exposure at 30 mW/cm for 4 minutes with a total energy dose of 7.2 J/cm. Corneal density was measured with Scheimpflug tomography at 1, 3, 6, and 12 months of follow-up. RESULTS: Densitometry peaked at 1 month (mean: 16.34 +/- 3.80, P = 0.006, 9-mW/cm A-CXL; mean: 20.90 +/- 2.81, P < 0.0001, 30 mw/cm A-CXL) in both groups, and it decreased over time in 30-mW/cm A-CXL. However, in 9-mW/cm A-CXL, increased corneal densitometry plateaued until 6 months postoperatively and started to decrease thereafter. Densitometry completely returned to baseline after 12 months in both groups. The mean change in density at 1- and 3-month follow-up was higher in the 30-mW A-CXL group than in the 9-mW A-CXL group (P = 0.003, P = 0.044; respectively). CONCLUSIONS: High energy exposure tends to induce more haze in the early posttreatment period, but it is reversible. PMID- 28872520 TI - Descemet Membrane Endothelial Keratoplasty Patch for Persistent Corneal Hydrops. AB - PURPOSE: To report successful management of a case of persistent keratoconus related hydrops with a Descemet membrane endothelial keratoplasty (DMEK) patch graft. METHODS: A case of corneal hydrops persisting for 7 months treated with DMEK was identified. The following information was collected: demographic data, surgical indications, clinical course, diagnostic tests, and clinical outcome. RESULTS: A 55-year-old patient with an established diagnosis of keratoconus was followed for 7 months without improvement in his acute corneal hydrops. Because of excellent vision and central corneal clarity, the patient was treated with a 5 mm DMEK covering the Descemet membrane tear, developing cataract secondary to the procedure, but with resolution of his corneal hydrops. An uncorrected visual acuity of 20/25 was achieved after uncomplicated cataract extraction. CONCLUSIONS: DMEK, although technically challenging, can be considered for patients with persistent hydrops with preservation of corneal clarity and contour in areas of the uninvolved cornea. PMID- 28872521 TI - Knowledge and Attitude Toward Corneal Donation Among High School Children in Northern India. PMID- 28872522 TI - Diagnostic Utility of Repetitive Nerve Stimulation in a Large Cohort of Patients With Myasthenia Gravis. AB - PURPOSE: Optimizing the diagnostic utility of repetitive nerve stimulation in myasthenia gravis (MG) may include tailoring the examination to clinical phenotype. Therefore, we analyzed all available repetitive nerve stimulation parameters in a large cohort of patients with confirmed MG diagnosis. METHODS: All repetitive nerve stimulation examinations at the Uppsala University Hospital rendering an MG diagnosis during 1996 to 2014 were analyzed. The deltoid, trapezius, anconeus, nasalis, abductor digiti quinti, and frontalis muscles were examined. RESULTS: Two hundred one patients with MG were diagnosed. Abnormal amplitude decrement was found in 54% of patients with ocular MG, 77% of patients with predominantly bulbar fatigue, and in 83% of patients with predominantly limb fatigue. The deltoid muscle had the highest sensitivity in all MG subtypes, with a mean of 77% sensitivity in all clinical subtypes, and the most pronounced decrement for amplitude (P = 0.0002) and area (P < 0.0001). Technical issues were rare. CONCLUSIONS: These data contribute to further optimization of repetitive nerve stimulation strategies regarding muscle selection and technical performance in the electrodiagnostic workup of MG. PMID- 28872523 TI - Serum D-Dimer Test Is Promising for the Diagnosis of Periprosthetic Joint Infection and Timing of Reimplantation. AB - BACKGROUND: Despite the availability of a battery of tests, the diagnosis of periprosthetic joint infection (PJI) continues to be challenging. Serum D-dimer assessment is a widely available test that detects fibrinolytic activities that occur during infection. We hypothesized that patients with PJI may have a high level of circulating D-dimer and that the presence of a high level of serum D dimer may be a sign of persistent infection in patients awaiting reimplantation. METHODS: This prospective study was initiated to enroll patients undergoing primary and revision arthroplasty. Our cohort consisted of 245 patients undergoing primary arthroplasty (n = 23), revision for aseptic failure (n = 86), revision for PJI (n = 57), or reimplantation (n = 29) or who had infection in a site other than a joint (n = 50). PJI was defined using the Musculoskeletal Infection Society criteria. In all patients, serum D-dimer level, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level were measured preoperatively. RESULTS: The median D-dimer level was significantly higher (p < 0.0001) for the patients with PJI (1,110 ng/mL [range, 243 to 8,487 ng/mL]) than for the patients with aseptic failure (299 ng/mL [range, 106 to 2,571 ng/mL). Using the Youden index, 850 ng/mL was determined as the optimal threshold value for serum D-dimer for the diagnosis of PJI. Serum D-dimer outperformed both ESR and serum CRP, with a sensitivity of 89% and a specificity of 93%. ESR and CRP had a sensitivity of 73% and 79% and a specificity of 78% and 80%, respectively. The sensitivity and specificity of ESR and CRP combined was 84% (95% confidence interval [CI], 76% to 90%) and 47% (95% CI, 36% to 58%), respectively. CONCLUSIONS: It appears that serum D-dimer is a promising marker for the diagnosis of PJI. This test may also have a great utility for determining the optimal timing of reimplantation. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 28872524 TI - The Influence of Arthritis in Other Major Joints and the Spine on the One-Year Outcome of Total Hip Replacement: A Prospective, Multicenter Cohort Study (EUROHIP) Measuring the Influence of Musculoskeletal Morbidity. AB - BACKGROUND: Although arthritis in other affected major joints and back pain are known to lead to worse outcomes following total hip replacement, to our knowledge, these risk factors have not previously been operationalized as a musculoskeletal morbidity profile. The aim of this study was to measure the influence of other major joints and the spine (as grades of musculoskeletal morbidity) on the 1-year outcome of primary total hip replacement. METHODS: The EUROHIP study consists of 1,327 patients undergoing primary total hip replacement for arthritis across 20 European orthopaedic centers. The primary outcome was the responder rate at 12 months calculated with the relative effect per patient for total hip replacement using the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. The primary predictor of interest was different combinations of arthritis of major joints and the spine grouped into 4 musculoskeletal morbidity grades: 1 (single major joint), 2 (multiple major joints), 3 (single major joint and spine), and 4 (multiple major joints and spine). The confounders adjusted for were age, sex, body mass index, living situation, years of hip pain, American Society of Anesthesiologists (ASA) class, anxiety or depression, and preoperative WOMAC subscales. RESULTS: For this analysis, 845 patients were included with complete 12-month follow-up WOMAC scores. The mean patient age was 65.7 years, and 55.2% of patients were female. CONCLUSIONS: The involvement of other major joints and the spine assessed as 1 of 4 musculoskeletal morbidity grades had a strong influence on the 1-year outcome after total hip replacement. The effect size was large compared with other risk factors. Even so, the majority of patients in musculoskeletal morbidity grade 4 had favorable outcomes from the surgical procedure (>74% response to surgical procedures). LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28872525 TI - Thumb Ossification Composite Index (TOCI) for Predicting Peripubertal Skeletal Maturity and Peak Height Velocity in Idiopathic Scoliosis: A Validation Study of Premenarchal Girls with Adolescent Idiopathic Scoliosis Followed Longitudinally Until Skeletal Maturity. AB - BACKGROUND: Accurate skeletal maturity assessment is important to guide clinical evaluation of idiopathic scoliosis, but commonly used methods are inadequate or too complex for rapid clinical use. The objective of the study was to propose a new simplified staging method, called the thumb ossification composite index (TOCI), based on the ossification pattern of the 2 thumb epiphyses and the adductor sesamoid bone; to determine its accuracy in predicting skeletal maturation when compared with the Sanders simplified skeletal maturity system (SSMS); and to validate its interrater and intrarater reliability. METHODS: Hand radiographs of 125 girls, acquired when they were newly diagnosed with idiopathic scoliosis prior to menarche and during longitudinal follow-up until skeletal maturity (a minimum of 4 years), were scored with the TOCI and SSMS. These scores were compared with digital skeletal age (DSA) and radius, ulna, and small hand bones (RUS) scores; anthropometric data; peak height velocity; and growth remaining profiles. Correlations were analyzed with the chi-square test, Spearman and Cramer V correlation methods, and receiver operating characteristic curve analysis. Reliability analysis using the intraclass correlation (ICC) was conducted. RESULTS: Six hundred and forty-five hand radiographs (average, 5 of each girl) were scored. The TOCI staging system was highly correlated with the DSA and RUS scores (r = 0.93 and 0.92, p < 0.01). The mean peak height velocity (and standard deviation) was 7.43 +/- 1.45 cm/yr and occurred at a mean age of 11.9 +/- 0.86 years, with 70.1% and 51.4% of the subjects attaining their peak height velocity at TOCI stage 5 and SSMS stage 3, respectively. The 2 systems predicted peak height velocity with comparable accuracy, with a strong Cramer V association (0.526 and 0.466, respectively; p < 0.01) and similar sensitivity and specificity on receiver operating characteristic curve analysis. The mean age at menarche was 12.57 +/- 1.12 years, with menarche occurring over several stages in both the TOCI and the SSMS. The growth remaining predicted by TOCI stage 8 matched well with that predicted by SSMS stage 7, with a mean of <2 cm/yr of growth potential over a mean of <1.7 years at these stages. The TOCI also demonstrated excellent reliability, with an overall ICC of >0.97. CONCLUSIONS: The new proposed TOCI could provide a simplified staging system for the assessment of skeletal maturity of subjects with idiopathic scoliosis. The index needs to be subjected to further multicenter validation in different ethnic groups. PMID- 28872526 TI - Wear of Vitamin E-Infused Highly Cross-Linked Polyethylene at Five Years. AB - BACKGROUND: In an earlier study with a 2-year follow-up of uncemented cups, we had reported low femoral-head penetration of vitamin E-infused highly cross linked polyethylene liners (E1) compared with highly cross-linked liners without vitamin E (ArComXL). We studied the penetration rate of E1 compared with that of ArComXL, with a focus on changes occurring between 2 and 5 years after total hip arthroplasty. METHODS: In this randomized controlled study, we performed radiostereometric analysis of the penetration rate up to 5 years in 63 hips. RESULTS: During the total period of observation, the median proximal penetration for E1, 0.13 mm (mean, 0.11 mm [95% confidence interval (CI), 0.08 to 0.14 mm]), was lower than that for ArComXL, 0.20 mm (mean, 0.22 mm [95% CI, 0.17 to 0.26 mm]). The median proximal penetration rate between 2 and 5 years was 0.02 mm/yr (mean, 0.01 mm/yr [95% CI, 0.01 to 0.02 mm/yr]) for E1 and 0.04 mm/yr (mean, 0.04 mm/yr [95% CI, 0.03 to 0.05 mm/yr) for ArComXL. The corresponding median total (i.e., 3-dimensional resultant) penetration rates were 0.04 mm/yr (mean, 0.04 mm/yr [95% CI, 0.03 to 0.05 mm/yr]) for E1 and 0.07 mm/yr (mean, 0.08 mm/yr [95% CI, 0.06 to 0.10 mm/yr]) for ArComXL. CONCLUSIONS: From years 2 to 5, we observed increased penetration in both groups. The penetration rate was higher for ArComXL, resulting in more proximal and total penetration at 5 years than for E1. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28872528 TI - Quantitative Measurement of Osseous Pathology in Advanced Glenohumeral Osteoarthritis. AB - BACKGROUND: Osteoarthritis of the glenohumeral joint has typical patterns of deformity as described by Walch et al. However, more severe glenoid pathology may be difficult to classify. The purpose of this study was to use 3-dimensional computed tomography (3-D CT) imaging analysis to define common pathologic subtypes that can be differentiated from the current Walch classification. METHODS: We performed quantitative measurements of premorbid and pathologic anatomy using preoperative 3-D CT scans from 155 cases of advanced glenohumeral osteoarthritis that underwent anatomic or reverse total shoulder arthroplasty. We defined premorbid glenohumeral anatomy on the basis of previously validated methods using 3-D glenoid vault and humeral best-fit circle models including the premorbid glenoid version, joint-line medialization, and humeral-glenoid alignment (HGA). We determined the anatomic features that differentiate new glenoid morphologic subtypes from the existing Walch classification both qualitatively and quantitatively. RESULTS: We defined 2 new glenoid subtypes (B3 and C2) for which the glenoid pathology and humeral alignment were not defined in the original Walch classification. The B3 glenoid has high pathologic retroversion, normal premorbid version, and acquired central and posterior bone loss that, on average, is greater than that of the B2 glenoid. The C2 glenoid is dysplastic with high pathologic retroversion, high premorbid version, and acquired posterior bone loss, giving it the appearance of a biconcave glenoid with posterior translation of the humeral head. This C2 glenoid can be confused with the B2 glenoid. CONCLUSIONS: The B3 and C2 patterns have qualitative and quantitative differences that may result in different clinical outcomes than classic B2 or C types; therefore, our findings suggest that these new subtypes should be included in a new or modified classification system. PMID- 28872527 TI - Muscle Microvascular Blood Flow, Oxygenation, pH, and Perfusion Pressure Decrease in Simulated Acute Compartment Syndrome. AB - BACKGROUND: The current gold standard for diagnosing acute compartment syndrome (ACS) is an assessment of clinical signs, invasive measurement of intramuscular pressure (IMP), and measurement of local perfusion pressure. However, IMP measurements have several shortcomings, including pain, risk of infection, risk of technique error, plugging of the catheter tip, lack of consensus on the diagnostic pressure threshold, and lack of specificity and sensitivity. The objective of this study was to evaluate muscle hemodynamics, oxygenation, and pH as diagnostic parameters in a human model of ACS. We hypothesized that as IMP increases, muscle microvascular blood flow, oxygenation, and pH decrease in the anterior compartment of a leg at heart level and that they decrease significantly more when the leg is elevated further. METHODS: An external pneumatic leg pressure chamber, combined with a venous stasis thigh cuff, was used to increase IMP and simulate ACS. Eight healthy subjects (5 males and 3 females; mean age, 26 years) had photoplethysmography and near-infrared spectroscopy-pH sensors placed over the middle aspect of the tibialis anterior muscle of the right (experimental) and left (control) legs. Leg chamber pressure conditions (40, 50, and 60 mm Hg) were applied in a randomized order after baseline measurements were taken. Data were collected continuously for each 11-minute pressure condition, with an 11-minute recovery period after each condition, and the average of the last 6 minutes was used for data analyses. The same protocol was repeated with each subject's legs elevated 12 cm above heart level. Data were analyzed using repeated-measures analysis of variance (ANOVA). RESULTS: As IMP increased, muscle microvascular blood flow (p = 0.01), oxygenation (p < 0.001), and pH (p < 0.001) all decreased significantly in the experimental leg compared with the control leg. At all IMP levels, leg elevation significantly decreased muscle oxygenation (p = 0.013) and perfusion pressure (p = 0.03) compared with the control leg at heart level. CONCLUSIONS: These results indicate that muscle microvascular blood flow, oxygenation, pH, and perfusion pressure decrease significantly as IMP increases in a human model of ACS. CLINICAL RELEVANCE: This study identifies hemodynamic and metabolic parameters as potential noninvasive diagnostic tools for ACS. PMID- 28872529 TI - In-Hospital Complications Following Ankle Arthrodesis Versus Ankle Arthroplasty: A Matched Cohort Study. AB - BACKGROUND: Ankle arthrodesis has been the traditional surgical treatment for end stage hindfoot arthritis. However, utilization of total ankle arthroplasty (TAA) is increasing as surgical techniques and implants have substantially improved. The purpose of this study was to compare the U.S. national rates of perioperative (in-hospital) complications between a statistically matched cohort of patients who underwent either an ankle arthrodesis or a TAA. METHODS: Data from the 2002 to 2013 Nationwide Inpatient Sample releases were analyzed. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) procedure codes were used to identify 4,192 patients treated with TAA (ICD 81.56) and 16,278 treated with ankle arthrodesis (ICD 81.11). ICD-9-CM diagnosis codes were utilized to identify major and minor in-hospital complications, and mortality was determined using the Uniform Bill patient disposition. The arthrodesis and TAA groups were matched with regard to age, sex, race, surgery year, hospital type, comorbidities, adjunctive procedures, and surgical indication. Unadjusted and adjusted in-hospital complication risks were compared between groups using the Fisher exact test and multiple logistic regression analysis. RESULTS: We were able to statistically match 1,574 patients who underwent a TAA (37.5%) with a patient who underwent arthrodesis. A major in hospital complication occurred in 8.5% (134) of the 1,574 patients in the ankle arthrodesis group compared with 5.3% (84) of the 1,574 in the TAA group (p < 0.001) whereas a minor complication was found in 4.7% (74) in the ankle arthrodesis group compared with 5.9% (93) in the TAA group (p = 0.14). There were no deaths in either group. After adjusting for case mix, we found that ankle arthrodesis was 1.8 times more likely to be followed by a major complication (odds ratio [OR] = 1.78, 95% confidence interval [CI] = 1.32 to 2.39) whereas the minor complication rate was 29% lower in that group (OR = 0.71, 95% CI = 0.45 to 1.13). CONCLUSIONS: In a matched cohort of 3,148 patients treated with either TAA or ankle arthrodesis, ankle arthrodesis was associated with a 1.8 times higher risk of a major complication but a 29% lower risk of a minor complication. Our findings are consistent with other studies that have shown TAA to be a safe procedure in the inpatient environment. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28872530 TI - Modified En Bloc Spondylectomy for Tumors of the Thoracic and Lumbar Spine: Surgical Technique and Outcomes. AB - BACKGROUND: Total en bloc spondylectomy (TES) for the treatment of spinal tumors decreases local recurrence and improves survival compared with intralesional resection. TES approaches vary in both the number of stages to complete the procedure and instruments with which osteotomies are performed. METHODS: We describe a 2-stage technique that employs the use of threadwire saws. We performed a retrospective review of cases of primary tumors and solitary metastases involving the thoracic or lumbar spine treated with use of our modified technique at our institution between 2010 and 2016, identifying eligible patients by searching for specific phrases in operative reports found in our oncologic database. Clinical notes, operative notes, imaging reports, and pathology reports were reviewed for all patients. RESULTS: Thirty-three patients underwent our modified technique, in which we pass a threadwire saw between the vertebral body and the thecal sac. The most common tumor type was chordoma (64%), and tumors were most commonly located in the lumbar spine (61%). There were no intraoperative injuries to the spinal cord or great vessels. One patient experienced a dural tear secondary to the passage of a saw. Seventeen (52%) of the patients had perioperative complications, with 1 death. Seven (22%) of the patients had complications occurring within 90 days after discharge, and 8 (25%) had complications occurring >90 days after discharge. Instrumentation failure was observed in 8 cases (25%). Negative margins were obtained in 94% of the cases. Local recurrence was observed in 2 cases (6%). The majority of patients had normal motor function at the time of the most recent follow-up. CONCLUSIONS: Our modified en bloc spondylectomy represents an effective technique for the resection of spinal tumors in selected patients, allowing for visualization of vessels anterior to the spine and the avoidance of spinal cord injury. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28872532 TI - Trunnionosis in Total Hip Arthroplasty. PMID- 28872531 TI - Flexion-Type Supracondylar Humeral Fractures: Ulnar Nerve Injury Increases Risk of Open Reduction. AB - BACKGROUND: The vast majority of displaced pediatric supracondylar humeral fractures can be treated successfully with closed reduction and percutaneous pinning. The need for open reduction is difficult to determine a priori and is typically due to the failure of closed reduction attempts or persistent limb ischemia. The aims of this study were to determine the prevalence of flexion-type supracondylar humeral fractures, the rate of open reduction for flexion-type fractures, and the predictive impact of ulnar nerve injury on the need for open reduction for flexion-type supracondylar humeral fractures. METHODS: We developed a database of consecutive pediatric supracondylar humeral fractures treated operatively at a tertiary care pediatric trauma center from 2000 to 2015. Data recorded included age, mechanism of injury, fracture type (open or closed), fracture pattern (flexion-type or extension-type), concomitant skeletal injury, neurovascular injury, treatment, and surgeon. Radiographs of all flexion-type supracondylar humeral fractures were reviewed in order to confirm the classification of the injury pattern. The rate of open reduction for fractures with a flexion-type injury pattern and for such fractures with and without ulnar nerve injury at presentation was assessed. RESULTS: Of 2,783 consecutive pediatric supracondylar humeral fractures treated by surgeons at our center, 95 (3.4%) were flexion-type fractures. Ulnar nerve injury was noted for 10 (10.5%) of the 95 flexion-type fractures. Open injuries were identified at presentation in 3 (3.2%) of the 95 cases. Among closed fractures, 21 (22.8%) of 92 flexion type fractures required open reduction compared with 50 (1.9%) of 2,647 extension type fractures (odds ratio [OR] = 15.4; 95% confidence interval [CI] = 8.8 to 27.0; p < 0.001). Among closed flexion-type fractures, open reduction was performed in 6 (60%) of 10 fractures with associated ulnar nerve injury and in 15 (18.3%) of 82 fractures without ulnar nerve injury (OR = 6.7; 95% CI = 1.7 to 26.7; p = 0.003). CONCLUSIONS: Among closed supracondylar humeral fractures, the flexion-type injury pattern was associated with a 15.4-fold increase in the odds of open reduction. The presence of an ulnar nerve injury at presentation resulted in an additional 6.7-fold higher risk of open reduction among flexion-type supracondylar humeral fractures. Patients and families should be counseled regarding the high rate of open reduction for flexion-type supracondylar humeral fractures, particularly those with an associated ulnar nerve injury. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28872533 TI - What's Important: Honesty and Humility. PMID- 28872534 TI - Morphological Analysis of True Acetabulum in Hip Dysplasia (Crowe Classes I-IV) Via 3-D Implantation Simulation. AB - BACKGROUND: The purpose of this study was to investigate the 3-dimensional (3D) morphological features of the true acetabulum in patients with developmental dysplasia of the hip (DDH). METHODS: Seventy-nine hips-53 in patients with developmental dysplasia of the hip (DDH) and 36 normal hips-were included in the present study. According to the Crowe classification, 26 hips were graded as Class I, 31 were Class II or III, and 22 were Class IV. The anterior pelvic plane was defined to standardize the measurements in the study. A selected virtual cup component was implanted into the true acetabulum of a 3D pelvic model of each hip. The acetabular anteversion angle, effective center-edge (CE) angle, effective Sharp angle, and thickness of the medial wall were measured to provide morphological indices of the true acetabulum. Acetabular sector angles and the component coverage ratio were measured to provide coverage indices. RESULTS: The acetabular anteversion angle increased with the severity of the DDH. Crowe-II/III hips had the smallest effective CE angle and the largest effective Sharp angle. The mean medial wall thickness was greatest in the Crowe-II/III hips (8.72 mm; 95% confidence interval [CI] = 7.52 to 9.92 mm), intermediate in the Crowe-I hips (7.17 mm; 95% CI = 6.24 to 8.11 mm), and smallest in the Crowe-IV hips (6.05 mm; 95% CI = 4.78 to 7.32 mm). The integrated coverage ratio of the Crowe-II/III hips was significantly less than that of the Crowe-I and IV hips. CONCLUSIONS: The morphological features of the true acetabulum in patients with DDH can be evaluated comprehensively by using 3D implantation simulation. Segmental bone deficiency was prevalent in the dysplastic hips, especially those in the Crowe II/III group. Both the severity and the individual morphology of the acetabular dysplasia should be carefully considered in preoperative planning. PMID- 28872535 TI - The Opportunity Awaits to Lead Orthopaedic Telehealth Innovation: AOA Critical Issues. AB - Telehealth is a way to provide health-care services to a patient from a provider who is at another location. The most common methods include a live interactive visit with the patient, interpretation of imaging, and monitoring of patient progress. Principally, telehealth is a way of providing a service rather than a type of service. It is about patient care, not data care.Examples of orthopaedic applications include conducting patient examinations, interpreting imaging studies, and providing postoperative care. Teleconsultation has been shown to be cost-effective. Other examples in orthopaedic research include the application of telemedicine when measuring patient-reported outcomes. Especially in cases when the patient lives far away from the provider, telehealth reduces time, produces good patient satisfaction, and costs less than hands-on care. As in everyday life, consumers have learned to demand convenience, ease of use, choice, control, and direct access. The ubiquity of telecommunications, combined with consumer technology savviness, drives the demand for telehealth. Unfortunately, the nation's largest payer for health services is one of the most restrictive for telehealth coverage. Medicare's restrictions are mostly the work of the U.S. Congress under Part B law. Video visits are very narrowly covered. Another major policy barrier is that interstate telehealth requires multiple state licenses for the physician, who must be licensed in the jurisdiction of each patient as well as the provider's physical locations. As Medicare shifts toward capitated payment and other value-based methods, there are opportunities to remove such restrictions.Despite these challenges, some states have been proactive in implementing telehealth systems. Arkansas is one of these states, and being a rural state with 2 main population centers, specialty care is relatively sparse. Implemented in 2014, the hand trauma program has been a partnership between the University of Arkansas for Medical Sciences (UAMS) and the Arkansas Trauma Communications Center (ATCC). This program has been very successful in decreasing the rate of hand trauma transfer, allowing patients to be treated closer to home while having coordinated access to fellowship-trained hand surgeons when necessary.More widespread innovation of orthopaedic applications for telehealth requires physician buy-in and health-systems partnerships. The regulatory environment will need streamlining. Ultimately, consumer demand will drive the implementation of technology to make care more accessible, convenient, and cost effective. PMID- 28872536 TI - Improved Safety and Cost Savings from Reductions in Cast-Saw Burns After Simulation-Based Education for Orthopaedic Surgery Residents. AB - BACKGROUND: The purpose of this investigation was to characterize the clinical efficacy and cost-effectiveness of simulation training aimed at reducing cast-saw injuries. METHODS: Third-year orthopaedic residents underwent simulation-based instruction on distal radial fracture reduction, casting, and cast removal using an oscillating saw. The analysis compared incidences of cast-saw injuries and associated costs before and after the implementation of the simulation curriculum. Actual and potential costs associated with cast-saw injuries included wound care, extra clinical visits, and potential total payment (indemnity and expense payments). Curriculum costs were calculated through time-derived, activity-based accounting methods. The researchers compared the costs of cast-saw injuries and the simulation curriculum to determine overall savings and return on investment. RESULTS: In the 2.5 years prior to simulation, cast-saw injuries occurred in approximately 4.3 per 100 casts cut by orthopaedic residents. For the 2.5-year period post-simulation, the injury rate decreased significantly to approximately 0.7 per 100 casts cut (p = 0.002). The total cost to implement the casting simulation was $2,465.31 per 6-month resident rotation. On the basis of historical data related to cast-saw burns (n = 6), total payments ranged from $2,995 to $25,000 per claim. The anticipated savings from averted cast-saw injuries and associated medicolegal payments in the 2.5 years post-simulation was $27,131, representing an 11-to-1 return on investment. CONCLUSIONS: Simulation based training for orthopaedic surgical residents was effective in reducing cast saw injuries and had a high theoretical return on investment. These results support further investment in simulation-based training as cost-effective means of improving patient safety and clinical outcomes. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28872537 TI - In Treating Arthritis of the Knee, Beware the Ipsilateral Hip: Commentary on an article by Joerg Huber, MD, et al.: "The Influence of Arthritis in Other Major Joints and the Spine on the One-Year Outcome of Total Hip Replacement. A Prospective, Multicenter Cohort Study (EUROHIP) Measuring the Influence of Musculoskeletal Morbidity". PMID- 28872539 TI - Moving from "See One, Do One": Simulation Training Can Save Money: Commentary on an article by Donald S. Bae, MD, et al.: "Improved Safety and Cost Savings from Reductions in Cast-Saw Burns After Simulation-Based Education for Orthopaedic Surgery Residents". PMID- 28872538 TI - Making the Unfamiliar More Familiar: Good for Patients and Hospitals Alike: Commentary on an article by Kelly Flynn et al.: "Flexion-Type Supracondylar Humeral Fractures. Ulnar Nerve Injury Increases Risk of Open Reduction". PMID- 28872540 TI - Effects on Pulmonary Vascular Mechanics of Two Different Lung-Protective Ventilation Strategies in an Experimental Model of Acute Respiratory Distress Syndrome. AB - OBJECTIVES: To compare the effects of two lung-protective ventilation strategies on pulmonary vascular mechanics in early acute respiratory distress syndrome. DESIGN: Experimental study. SETTING: University animal research laboratory. SUBJECTS: Twelve pigs (30.8 +/- 2.5 kg). INTERVENTIONS: Acute respiratory distress syndrome was induced by repeated lung lavages and injurious mechanical ventilation. Thereafter, animals were randomized to 4 hours ventilation according to the Acute Respiratory Distress Syndrome Network protocol or to an open lung approach strategy. Pressure and flow sensors placed at the pulmonary artery trunk allowed continuous assessment of pulmonary artery resistance, effective elastance, compliance, and reflected pressure waves. Respiratory mechanics and gas exchange data were collected. MEASUREMENTS AND MAIN RESULTS: Acute respiratory distress syndrome led to pulmonary vascular mechanics deterioration. Four hours after randomization, pulmonary vascular mechanics was similar in Acute Respiratory Distress Syndrome Network and open lung approach: resistance (578 +/- 252 vs 626 +/- 153 dyn.s/cm; p = 0.714), effective elastance, (0.63 +/- 0.22 vs 0.58 +/- 0.17 mm Hg/mL; p = 0.710), compliance (1.19 +/- 0.8 vs 1.50 +/- 0.27 mL/mm Hg; p = 0.437), and reflection index (0.36 +/- 0.04 vs 0.34 +/- 0.09; p = 0.680). Open lung approach as compared to Acute Respiratory Distress Syndrome Network was associated with improved dynamic respiratory compliance (17.3 +/- 2.6 vs 10.5 +/- 1.3 mL/cm H2O; p < 0.001), driving pressure (9.6 +/- 1.3 vs 19.3 +/- 2.7 cm H2O; p < 0.001), and venous admixture (0.05 +/- 0.01 vs 0.22 +/- 0.03, p < 0.001) and lower mean pulmonary artery pressure (26 +/- 3 vs 34 +/- 7 mm Hg; p = 0.045) despite of using a higher positive end-expiratory pressure (17.4 +/- 0.7 vs 9.5 +/- 2.4 cm H2O; p < 0.001). Cardiac index, however, was lower in open lung approach (1.42 +/- 0.16 vs 2.27 +/- 0.48 L/min; p = 0.005). CONCLUSIONS: In this experimental model, Acute Respiratory Distress Syndrome Network and open lung approach affected pulmonary vascular mechanics similarly. The use of higher positive end-expiratory pressures in the open lung approach strategy did not worsen pulmonary vascular mechanics, improved lung mechanics, and gas exchange but at the expense of a lower cardiac index. PMID- 28872541 TI - We're So Excited ... We Just Can't Hide It! PMID- 28872542 TI - Editor's Note: This article was previously published in issue 29.1 Reply. PMID- 28872544 TI - Soft Tissue Response on 18F-Fluorocholine PET/CT in Metastatic Castrate-Resistant Prostate Cancer Treated With 223Ra-Dichloride: A Possible Abscopal Effect? AB - Two patients with castrate-resistant prostate cancer and symptomatic skeletal metastases underwent F-fluorocholine PET/CT prior to treatment with Ra-dichloride to reveal additional active lesions in the prostate gland and lymph nodes. Subsequent scans performed at the midpoint and end of Ra-dichloride therapy showed resolution of this soft tissue activity alongside declining bone lesion activity. Concomitant increases in plasma interleukin 6 were detected, suggesting that immune system activation may have mediated the soft tissue response. Abscopal effects usually encountered with external beam radiotherapy may also be occurring with Ra-dichloride therapy. PMID- 28872545 TI - Concomitant 177Lu-DOTATATE and Capecitabine Therapy in Patients With Advanced Neuroendocrine Tumors: A Long-term-Outcome, Toxicity, Survival, and Quality-of Life Study. AB - PURPOSE: The purpose of this study was to evaluate the outcome, toxicity, survival, and quality of life in patients with advanced neuroendocrine tumors. METHODS: One hundred sixty-seven patients were enrolled in the study. All patients underwent baseline Ga-DOTANOC PET/CT scans. Lu-DOTATATE therapy was administered quarterly along with oral capecitabine therapy in group 1 patients (n = 88), whereas group 2 patients (n = 79) were treated only with Lu-DOTATATE. Hematologic, kidney function, liver function tests and chromogranin A levels were recorded before and after therapy at 2-week, 4-week, and 3-month intervals. Biochemical and morphological responses were assessed with the trend in chromogranin A levels and Response Evaluation Criteria in Solid Tumors 1.1 criteria, respectively. RESULTS: There was no significant difference in the hemoglobin levels after Lu-DOTATATE therapy (P = 0.4892). In most patients, there was a decrease in the platelet levels; however, all the patients had platelet counts greater than 100,000/MUL with no platelet toxicity. There was no toxicity related to leukocytes. Two patients showed renal insufficiencies. No hepatotoxicity was observed in any of the patients. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months. Ki-67 tumor proliferation index was significantly associated with increased risk of disease progression. CONCLUSIONS: Addition of capecitabine therapy with Lu DOTATATE therapy lengthens the OS and PFS. Patients with aggressive disease may benefit from this synergetic therapeutic approach. PMID- 28872546 TI - 68Ga-DOTA-TATE PET/CT for Molecular Imaging of Somatostatin Receptor Expression in Metastasizing Epithelioid Hemangioendothelioma: Comparison With 18F-FDG. AB - Epithelioid hemangioendothelioma (EHE) is a rare tumor originating from vascular endothelial or pre-endothelial cells. It has the potential to metastasize. We present the case of a 51-year-old woman with metastasizing EHE who underwent both F-FDG and Ga-DOTA-TATE PET/CT for staging of disease and for evaluation of targeted radionuclide therapy potential. On Ga-DOTA-TATE PET scans, intense tracer accumulation was observed in metastases. Besides the increased glucose metabolism in EHE, this case highlights the potential of Ga-DOTA-TATE PET/CT for restaging of EHE and the option of targeted radionuclide therapy in this entity. PMID- 28872547 TI - FDG PET/CT in 2 Cases of Renal Metastasis From Esophageal Squamous Cell Carcinoma. AB - Clinically, renal metastasis from esophageal squamous cell carcinoma is uncommon. We present 2 cases of renal metastasis from esophageal squamous cell carcinoma with enhanced CT and FDG PET/CT findings. In the first case, right kidney and right renal hilum were the only known metastatic sites. In the second case, bilateral kidneys were the only known metastatic sites. All the renal metastatic tumors appeared as hypovascular and hypoattenuating masses involving both the renal cortex and medulla on enhanced CT and intense FDG uptake on FDG PET/CT. PMID- 28872548 TI - Quality and Safety in Health Care, Part XXXII: Additional Outcome Predictors for Transcatheter Aortic Valve Replacement. AB - Mortality 12 months after a transcatheter aortic valve replacement (TAVR) is partly due to a number of reasons in addition to the usual preprocedural medical patient risk factors. In patients who need a permanent pacemaker placed after the procedure, the mortality risk goes up. The death rate following a TAVR varies considerably at different institutions, and the past death rate of TAVR patients at an institution is predictive of the mortality rate of new patients having this procedure. In addition, the quality of life of the individual before the procedure is predictive of the 12-month mortality outcome after the TAVR is done. PMID- 28872549 TI - 89Zr-Trastuzumab PET/CT for Detection of Human Epidermal Growth Factor Receptor 2 Positive Metastases in Patients With Human Epidermal Growth Factor Receptor 2 Negative Primary Breast Cancer. AB - PURPOSE: The aim of this study was to determine if imaging with Zr-trastuzumab, a human epidermal growth factor receptor 2 (HER2)-targeting PET tracer, can detect HER2-positive metastases in patients with HER2-negative primary breast cancer. METHODS: As part of an institutional review board-approved, prospective clinical trial of Zr-trastuzumab PET/CT (ClinicalTrials.gov identifier NCT02286843), a second group of 11 patients with HER2-negative primary breast cancer and known metastatic disease were recruited. Patients with confirmed HER2-negative primary breast cancer underwent Zr-trastuzumab PET/CT to screen for Zr-trastuzumab-avid lesions suggestive of unsuspected HER2-positive metastases. Zr-trastuzumab-avid lesions on PET/CT were biopsied and pathologically examined to determine HER2 status. RESULTS: All 11 patients had confirmed HER2-negative primary breast cancer. Four patients demonstrated suspicious foci on Zr-trastuzumab PET/CT. Of these 4 patients, 1 patient had biopsy-proven HER2-positive metastases. The other 3 patients with suspicious Zr-trastuzumab-avid foci had biopsy demonstrating a metastasis that was HER2-negative and were considered false-positive Zr trastuzumab PET foci. Combined with a published report of the first 9 patients, there have been a total of 20 HER2-negative primary breast cancer patients, with 3 patients (15%) having pathologically confirmed HER2-positive distant metastases and 6 (30%) with suspicious Zr-trastuzumab-avid foci that were HER2-negative on pathology, which were thus considered false-positive Zr-trastuzumab findings. CONCLUSIONS: This second group of patients confirms the proof of concept that Zr trastuzumab PET/CT detects unsuspected HER2-positive metastases in a subset of patients with HER2-negtive primary breast cancer. False-positive Zr-trastuzumab avid foci present a challenge to using this tracer. PMID- 28872550 TI - Methionine PET Might Be Reliable for the Detection of Low M-Protein-Producing Myelomas. AB - C-methionine (MET) positron emission tomography (PET) is more sensitive than F fluorodeoxyglucose (FDG)-PET for detecting myeloma lesion. Many clinical studies support this evidence mainly for multiple myeloma cases of IgG or IgA subtypes. However, this is not confirmed for low monoclonal protein-producing myelomas, such as IgD, IgE, and nonsecretory type. We encountered a 71-year-old man with IgD lambda-type myeloma. In this patient, FDG-PET did not reveal any abnormal uptake lesions, whereas MET-PET revealed diffuse bone marrow uptake that relieved after initial chemotherapy. We speculate that the determinants for high serological activity of protein metabolism are transporter system activity or proliferation index. PMID- 28872551 TI - Diagnostic Challenge of Staging Metastatic Bone Disease in the Morbidly Obese Patients: A Primary Study Evaluating the Usefulness of 18F-Sodium Fluoride (NaF) PET-CT. AB - PURPOSE: Optimizing diagnostic imaging may be challenging in obese patients. The quality of conventional bone scintigraphy can be poor in the morbidly obese due to a combination of factors including high background soft tissue activity. In comparison, sodium fluoride (F-NaF PET-CT) has a better target-to-background ratio attributed to rapid single-pass extraction and fast clearance from the soft tissues. The aim of the present study is to assess the diagnostic efficacy of F NaF PET-CT in the evaluation of bone metastases in obese cancer patients. PATIENTS AND METHODS: Two hundred twelve morbidly obese patients (body mass index, 45 +/- 5.1 kg/m; mean age, 57 years; range, 32-81 years) with body mass index greater than 40 kg/m referred for NaF PET-CT for osseous staging of malignancy were retrospectively analyzed. All patients underwent PET-CT scan by injecting 2.2 MBq/kg (0.06 mCi/kg) of F-NaF. RESULTS: F-NaF PET-CT was definitely benign in 145, possibly benign in 3, equivocal in 4, possibly malignant in 13, and definitely malignant in 47 patients. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of F-NaF PET-CT were 93.1%, 96.1%, 90%, 97.3%, and 95.2%, respectively (95% confidence interval). CONCLUSIONS: The results of the present study indicate that F-NaF PET-CT retains its high diagnostic accuracy in morbidly obese patients and, by inference, can be a preferred functional modality in these patients. PMID- 28872552 TI - Pancreatoblastoma With Metastatic Retroperitoneal Lymph Node and PET/CT. AB - A previously healthy 4-year-old girl presented with petechial rash and low platelet count. There were no other symptoms. On abdominal ultrasound, a 4.7-cm heterogeneous mass was demonstrated anterior to the left kidney. An abdominal MRI subsequently performed demonstrated a heterogeneously enhancing mass at the same location extending to the pancreas and spleen. A surgical biopsy of the mass was obtained. Pathology reported a malignant epithelioid neoplasm consistent with pancreatoblastoma. The mass demonstrated intense FDG uptake on PET and an FDG avid retrocaval lymph node. PMID- 28872553 TI - Hybrid SPECT/CT Helps Characterization and Localization of a Dual Thyroid Ectopia. AB - The presence of ectopic thyroid tissue in 2 or more different sites is rare. A 12 year-old girl presented with midline anterior neck swelling in the infrahyoid region with subclinical hypothyroidism. Thyroid scanning with Tc-pertechnetate was performed, and SPECT/CT was ordered for further evaluation. Two hyperdense lesions demonstrating intense radiotracer uptake were seen in the midline at the base of the tongue and infrahyoid neck. We emphasis the role of hybrid SPECT/CT for characterization and localization of suspected ectopic thyroid tissue. PMID- 28872554 TI - Detection of Non-FDG-Avid Residual Sinonasal Malignant Melanoma in the Skull Base With 11C-Choline PET and Contrast-Enhanced MRI. AB - Primary sinonasal melanoma is a rare disease. We present a case of melanoma in sinuses without abnormal F-FDG activity anywhere in the scanned portion of the body. In further assessment, C-choline PET/CT revealed high activity in the paranasal sinuses, skull base, and adjacent brain, in agreement with the high signal on contrast-enhanced T1-weighted MRI scan, which suggested the residual tumor. PMID- 28872555 TI - 18F-FDG PET/CT Imaging of Tracheal Mucoepidermoid Carcinoma. AB - A 54-year-old woman presented with dry cough for 3 months. An FDG PET/CT was performed to evaluate a tracheal nodule, which was revealed by chest CT. The PET/CT images showed increased FDG uptake with SUVmax of 3.3 in the known tracheal lesion. The results of pathological examination from the specimen of bronchoscopy were consistent with tracheal mucoepidermoid carcinoma. PMID- 28872556 TI - Early and Delayed 99mTc-MDP SPECT/CT Findings in Rheumatoid Arthritis and Osteoarthritis. AB - We report the case of a 74-year-old man with seropositive rheumatoid arthritis (RA) and radiographic osteoarthritis (OA) who underwent dual-phase high resolution Tc-MDP SPECT/CT. Early radiotracer enhancement was noted in 2 RA joints of the right hand, both presenting with a ring-like uptake pattern around the joint, consistent with synovitis. Insignificant early enhancement was noted at the first carpometacarpal joint, despite presentation of CT features of OA. The delayed-phase enhancement patterns were distinct, showing asymmetry in RA joints, but a symmetric, joint-centered pattern for the OA joint. PMID- 28872557 TI - Sodium Thiosulfate in the Treatment of Lung and Breast Calciphylaxis: CT and Bone Scintigraphy Findings. AB - A 19-year-old woman, with normal kidney function, was diagnosed as having visceral calciphylaxis, especially diffuse breast and lung calcification. The calcification findings were clearly shown on CT, and bone scintigraphy revealed diffuse uptake in the thoracic area. Although there was no standard therapeutic approach for this clinical setting, the patient received empiric therapy with sodium thiosulfate. After 5 months of consecutive therapy, the calcification condition had a striking regression. PMID- 28872558 TI - Treatment of Focal Hyperhidrosis With Needleless Injections of Botulinum Toxin Into Sites Other than the Axilla, Palm, and Sole. PMID- 28872559 TI - Primary Cutaneous Cribriform Carcinoma Treated With Mohs Micrographic Surgery. PMID- 28872560 TI - Use of Hypochlorous Acid as a Preoperative Antiseptic Before Placement of Dermal Fillers: An Alternative to the Standard Options. PMID- 28872561 TI - Topical Imiquimod for Melanoma In Situ? A Word of Caveat. PMID- 28872562 TI - GPX1 Pro198Leu polymorphism and GSTP1 Ile105Val polymorphisms are not associated with the risk of schizophrenia in the Chinese Han population. AB - Increasing lines of evidence show that oxidative stress plays a role in the pathophysiological mechanisms of schizophrenia (SCZ). Polymorphic variants of oxidative stress-related candidate genes GPX1 and GST1 can affect the antioxidant activities of their encoded enzymes. Therefore, this study aimed to explore the association between the single nucleotide polymorphisms (SNPs) of GPX1 and GSTP1 and susceptibility to schizophrenia in the Chinese Han population. DNA from 323 healthy controls and 210 schizophrenic patients was genotyped for SNPs rs1050450 in GPX1 and rs1695 in GSTP1 using a predesigned TaqMan SNP genotyping assay. Differences in genetic distributions between cases and controls were compared using the chi-test. No significant differences in allelic or genotypic frequencies of GPX1 rs1050450 or GSTP1 rs1695 were detected between cases and controls (GPX1 rs1050450: chi=0.370, P=0.831 by genotype, chi=0.377, P=0.539, odds ratio=1.145, 95% confidence interval=0.743-1.766 by allele; GSTP1 rs1695: chi=1.537, P=0.464 by genotype, chi=1.623, P=0.203, odds ratio=0.813, 95% confidence interval=0.592-1.118 by allele). Our results suggest that GPX1 rs1050450 and GSTP1 rs1695 SNPs are unlikely to play a major role in the pathogenesis of schizophrenia in the Chinese Han population. However, these results should be validated by replication in larger and independent samples. PMID- 28872563 TI - Jejunal atresia, periodic fevers and psoriatic arthropathy in Baraitser-Winter malformation syndrome. PMID- 28872564 TI - A novel COL1A1 mutation causing a variant of osteogenesis imperfecta. PMID- 28872565 TI - Sinus pericranii in achondroplasia: a case report and review of the literature. AB - In the field of dysmorphology, achondroplasia is a well-known disorder. Sinus pericranii (SP), however, is not. The latter condition is a rare vascular malformation characterized by abnormal connections between the intracranial and the extracranial venous drainage pathways. The etiology of SP remains unclear, and yet, these defects can be present at birth, develop spontaneously later, or evolve following head trauma. Here, we report on a 2-year-old male with achondroplasia, SP, and craniocervical junction stenosis. The latter two defects required surgical correction. SP is an underappreciated malformation that we propose may be induced by increased intracranial pressure. This case appears to be the first report of this condition in achondroplasia. PMID- 28872568 TI - A Teenager With Seizures and Cardiac Arrest After Drug Overdose: Are We Numb to the Danger? PMID- 28872566 TI - Pediatric Mild Traumatic Brain Injury in the Acute Setting. AB - Pediatric mild traumatic brain injuries, most of which are concussions, are an increasingly common reason for presentation to emergency departments. The diagnosis of concussion has increased dramatically over the past decade, necessitating the acute care provider to have up-to-date knowledge of the definition, pathophysiology, signs and symptoms, physical examination findings, and acute management of pediatric concussion. This article also addresses populations most vulnerable to prolonged recovery from pediatric concussion and referral recommendations. PMID- 28872569 TI - ECGs in the ED. PMID- 28872570 TI - When Fever, Leukocytosis, and Right Lower Quadrant Pain Is Not Appendicitis. AB - Mesenteric cystic lymphangioma (MCL) is an uncommon, benign, slow-growing abdominal tumor that is derived from the lymphatic vessels (World J Gastroenterol. 2012;18:6328-6332, Radiographics. 1994;14:729-737). It is most often diagnosed in the head and neck of affected children. Rarely, a lymphangioma can develop within the small bowel (Pan Afr Med J. 2012;12:7). The clinical presentation of patients with an abdominal MCL can range from asymptomatic to acute abdominal pain (J Korean Surg Soc. 2012;83:102-106). We report a case of small bowel volvulus caused by an MCL in a 3-year-old child who presented to the pediatric emergency department with right lower quadrant pain. The child was thought to have a perforated appendicitis and was taken to the operating room where an MCL was identified and resected. This case illustrates the need to consider MCL when a patient presents to the emergency department with right lower quadrant pain. PMID- 28872571 TI - Glenohumeral Mismatch in Anatomic Total Shoulder Arthroplasty. PMID- 28872572 TI - Tandem Spinal Stenosis: A Systematic Review. AB - BACKGROUND: Tandem spinal stenosis refers to spinal canal diameter narrowing in at least 2 distinct regions of the spine, most commonly the lumbar and cervical regions. This entity can be an asymptomatic radiographic finding, or it can present with severe myelopathy and lower-extremity symptoms. Tandem spinal stenosis may impact surgeon decision-making when planning either cervical or lumbar spine surgery, and there is currently no consensus in the literature regarding the treatment algorithm for operative intervention. METHODS: A MEDLINE literature search was performed using PubMed, the Cochrane Database of Systematic Reviews, and Embase from January 1980 to February 2015 using Medical Subject Heading queries for the terms "tandem spinal stenosis," "cervical stenosis AND lumbar stenosis," and "concomitant spinal stenosis." We included studies involving adult patients, tandem spinal stenosis of the cervical and lumbar regions, and a minimum of 5 patients. Articles that did not discuss spinal disorders or only explored disorders at a single spinal region were excluded. RESULTS: The initial database review resulted in 234 articles. After abstracts were reviewed, only 17 articles that met inclusion criteria were identified: 2 cadaveric studies, 5 clinical studies of patients with radiographic tandem spinal stenosis, and 10 clinical studies of patients with symptomatic tandem spinal stenosis. CONCLUSIONS: Tandem spinal stenosis is a common condition present in up to 60% of patients with spinal stenosis. This disorder, however, is often overlooked, which can lead to serious complications. Identification of tandem spinal stenosis is paramount as a first step in management and, although there is still no preferred intervention, both staged and simultaneous procedures have been shown to be effective. Surgeons may utilize a single, staged, or combined approach to decompression, always addressing cervical myelopathy as a priority. PMID- 28872573 TI - The Association of Posttraumatic Stress Disorder With Clinic and Ambulatory Blood Pressure in Healthy Adults. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with incident cardiovascular risk. We tested the association of PTSD with clinic and ambulatory blood pressure (ABP) in a sample of healthy participants and tested ABP reactivity to anxiety as a mechanism by which PTSD may influence blood pressure (BP). METHODS: Participants were originally enrolled during workplace BP screenings at three sites; approximately 6 years (standard deviation = 1.0) later, they completed nine clinic BP assessments within three visits, 1 week apart. Before the third visit, participants were screened for PTSD (>=33 on the PTSD Checklist-Civilian) and depression (Beck Depression Inventory) and then completed 24-hour ABP monitoring with electronic diary assessment of anxiety (0 100) at each awake reading. RESULTS: Of 440 participants, 92 (21%) screened positive for PTSD. In regression models adjusted for depression and demographic and clinical variables, PTSD was associated with greater mean systolic BP (3.8 mm Hg clinic [95% confidence interval {CI}] = 1.1-6.5, p = .006), 3.0 mm Hg awake ABP [95% CI = 0.1-5.9, p = .04], and a nonsignificant 2.1 mm Hg ABP during sleep [95% CI = -1.0 to 5.1, p = .18]). PTSD was associated with greater 24-hour median anxiety (p < .001), and changes in anxiety were positively associated with concurrent systolic ABP (p < .001). ABP reactivity to anxiety was greater in participants with PTSD, which partially explained the association of PTSD with ABP. CONCLUSIONS: PTSD is associated with greater systolic BP, partly because of greater anxiety, and systolic BP reactivity to anxiety throughout the day. Daily anxiety and related BP reactivity may be targets for interventions to reduce the cardiovascular risk associated with PTSD. PMID- 28872574 TI - Past, Present, and Future of Psychosomatic Movements in an Ever-Changing World: Presidential Address. AB - OBJECTIVE: The American Psychosomatic Society was founded in 1942 and is celebrating its 75th anniversary in 2017. In recognizing the society's anniversary, this article provides a historical perspective on its history, the field of psychosomatic medicine in general, and anticipated future directions. METHODS: Essay and narrative review of the literature on the historic development of psychosomatic concepts and their impact on medicine over time. RESULTS: Mind body associations have been described in the medical literature for more than 3500 years. Early concepts of mind-body dualism and attempts to overcome them are found in classical Greek medicine. Psychosomatic thinking can be observed ever since, but only in the 20th century, a "psychosomatic movement" emerged in Europe and North America, aiming at humanizing medicine by introducing a holistic understanding of man into what was considered a widely reductionistic practice of medicine. This movement led to the inauguration of the American Psychosomatic Society during World War II and of national and international societies of psychosomatic medicine and its subspecializations thereafter. CONCLUSIONS: Psychosomatic medicine has its roots in the beginnings of medicine. During the past 75 years, it has made substantial contributions to the science and practice of medicine. The field has also changed in response to developments in medicine, technology, and society and is facing new challenges and opportunities that may require further adaptation of its concepts and practice. PMID- 28872575 TI - Partner Loss in Monogamous Rodents: Modulation of Pain and Emotional Behavior in Male Prairie Voles. AB - OBJECTIVE: Pain is modulated by psychosocial factors, and social stress-induced hyperalgesia is a common clinical symptom in pain disorders. To provide a new animal model for studying social modulation of pain, we examined pain behaviors in monogamous prairie voles experiencing partner loss. METHODS: After cohabitation with novel females, males (n = 79) were divided into two groups on the basis of preference test scores. Half of the males of each group were separated from their partner (loss group), whereas the other half remained paired (paired group). Thus, males from both groups experienced social isolation. Open field tests, plantar tests, and formalin tests were then conducted on males to assess anxiety and pain-related behaviors. RESULTS: Loss males showing partner preferences (n = 20) displayed a significant increase in anxiety-related behavior in the open-field test (central area/total distance: 13.65% [1.58%] for paired versus 6.45% [0.87%] for loss; p < .001), a low threshold of thermal stimulus in the plantar test (withdrawal latencies: 9.69 [0.98] seconds for paired versus 6.15 [0.75] seconds for loss; p = .037), and exacerbated pain behaviors in the formalin test (total number of lifts: 40.33 [4.46] for paired versus 54.42 [1.91] for loss; p = .042) as compared with paired males (n = 20). Thermal thresholds in the plantar test significantly correlated with anxiety-related behavior in the open-field test (r = 0.64). No such differences were observed in the males that did not display partner preferences (r = 0.15). CONCLUSIONS: Results indicate that social bonds and their disruption, but not social housing without bonding followed by isolation, modulate pain and emotion in male prairie voles. The prairie vole is a useful model for exploring the neural mechanisms by which social relationships contribute to pain and nociceptive processing in humans. PMID- 28872576 TI - The renoprotective properties of xenon and argon in kidney transplantation. PMID- 28872577 TI - Acute and chronic neuropathic pain after surgery: Still a lot to learn. PMID- 28872578 TI - Comparison of polyvinyl chloride and tin stylets for postoperative sore throat and hoarseness: A randomised trial. PMID- 28872579 TI - Transcutaneous monitoring of partial pressure of carbon dioxide during bronchoscopic procedures performed with jet ventilation: Role of the perfusion index. PMID- 28872580 TI - Effect of intravenous dextrose administration on postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy: A randomised controlled trial. PMID- 28872581 TI - EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients. AB - Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome. PMID- 28872582 TI - Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients. AB - Targeting of alphaVbeta3 and alphaVbeta5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial in HNSCC (ADVANTAGE) investigated cisplatin, 5-fluorouracil, and cetuximab (PFE) without or with once (PFE+CIL1W) or twice weekly cilengitide (PFE+CIL2W) in recurrent/metastatic HNSCC. ADVANTAGE showed good tolerability of the cilengitide arms and even lower adverse events (AEs) compared to PFE but not the benefit in overall survival expected based on preclinical data. As we found in the FLAVINO assay, a short-time ex vivo assay for prediction of chemosensitivity, only a subgroup of HNSCC had an increased suppressive effect of cilengitide containing combination therapies on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines, whereas other HNSCC failed to respond. Response to alphaVbeta3 and alphaVbeta5 integrin targeting by cilengitide classifies HNSCC regarding outcome. We present FLAVINO data arguing for further development of cilengitide plus cetuximab in treatment of a subgroup of HNSCC potentially identified by the FLAVINO assay using a set of biomarkers for response evaluation. PMID- 28872583 TI - Design of a Sensor System for On-Line Monitoring of Contact Pressure in Chalcographic Printing. AB - Chalcographic printer is the name given to a specific type of press which is used to transfer the printing of a metal-based engraved plate onto paper. The printing system consists of two rollers for pressing and carrying a metal plate onto which an engraved inked plate is placed. When the driving mechanism is operated, the pressure exerted by the rollers, also called contact pressure, allows the engraved image to be transferred into paper, thereby obtaining the final image. With the aim of ensuring the quality of the result, in terms of good and even transfer of ink, the contact pressure must be uniform. Nowadays, the strategies utilized to measure the pressure are implemented off-line, i.e., when the press machines are shut down for maintenance, which poses limitations. This paper proposes a novel sensor system aimed at monitoring the pressure exerted by the rollers on the engraved plate while chalcographic printer is operating, i.e., on line. The purpose is two-fold: firstly, real-time monitoring reduces the number of breakdown repairs required, reduces machine downtime and reduces the number of low-quality engravings, which increases productivity and revenues; and secondly, the on-line monitoring and register of the process parameters allows the printing process to be reproducible even with changes in the environmental conditions or other factors such as the wear of the parts that constitute the mechanical system and a change in the dimensions of the printing materials. The proposed system consists of a strain gauge-based load cell and conditioning electronics to sense and treat the signals. PMID- 28872585 TI - To Nutraceuticals and Back: Rethinking a Concept. AB - The concept of nutraceuticals as pharma-foods comes fromfar. This termismade fromthe two words "nutrient" and "pharmaceutical", was coined by Stephen DeFelice, and is defined as "a food or part of a food that provide medical or health benefits, including the prevention and/or treatment of a disease" [...]. PMID- 28872586 TI - Examining the Relationship between Free Sugars and Calorie Contents in Canadian Prepacked Foods and Beverages. AB - To align with broader public health initiatives, reformulation of products to be lower in sugars requires interventions that also aim to reduce calorie contents. Currently available foods and beverages with a range of nutrient levels can be used to project successful reformulation opportunities. The objective of this study was to examine the relationship between free sugars and calorie levels in Canadian prepackaged foods and beverages. This study was a cross-sectional analysis of the University of Toronto's 2013 Food Label Database, limited to major sources of total sugar intake in Canada (n = 6755). Penalized B-spline regression modelling was used to examine the relationship between free sugar levels (g/100 g or 100 mL) and caloric density (kcal/100 g or 10mL), by subcategory. Significant relationships were observed for only 3 of 5 beverage subcategories and for 14 of 32 food subcategories. Most subcategories demonstrated a positive trend with varying magnitude, however, results were not consistent across related subcategories (e.g., dairy-based products). Findings highlight potential areas of concern for reformulation, and the need for innovative solutions to ensure free sugars are reduced in products within the context of improving overall nutritional quality of the diet. PMID- 28872584 TI - Sample Size Estimation for Detection of Splicing Events in Transcriptome Sequencing Data. AB - Merging data from multiple samples is required to detect low expressed transcripts or splicing events that might be present only in a subset of samples. However, the exact number of required replicates enabling the detection of such rare events often remains a mystery but can be approached through probability theory. Here, we describe a probabilistic model, relating the number of observed events in a batch of samples with observation probabilities. Therein, samples appear as a heterogeneous collection of events, which are observed with some probability. The model is evaluated in a batch of 54 transcriptomes of human dermal fibroblast samples. The majority of putative splice-sites (alignment gap sites) are detected in (almost) all samples or only sporadically, resulting in an U-shaped pattern for observation probabilities. The probabilistic model systematically underestimates event numbers due to a bias resulting from finite sampling. However, using an additional assumption, the probabilistic model can predict observed event numbers within a <10% deviation from the median. Single samples contain a considerable amount of uniquely observed putative splicing events (mean 7122 in alignments from TopHat alignments and 86,215 in alignments from STAR). We conclude that the probabilistic model provides an adequate description for observation of gap-sites in transcriptome data. Thus, the calculation of required sample sizes can be done by application of a simple binomial model to sporadically observed random events. Due to the large number of uniquely observed putative splice-sites and the known stochastic noise in the splicing machinery, it appears advisable to include observation of rare splicing events into analysis objectives. Therefore, it is beneficial to take scores for the validation of gap-sites into account. PMID- 28872587 TI - Quantification of Pseudouridine Levels in Cellular RNA Pools with a Modified HPLC UV Assay. AB - Pseudouridine (Psi) is the most abundant post-transcriptionally modified ribonucleoside. Different Psi modifications correlate with stress responses and are postulated to coordinate the distinct biological responses to a diverse panel of cellular stresses. With the help of different guide RNAs, the dyskerin complex pseudouridylates ribosomal RNA, small nuclear RNA and selective messenger RNAs. To monitor Psi levels quantitatively, a previously reported high performance liquid chromatography method coupled with ultraviolet detection (HPLC-UV) was modified to determine total Psi levels in different cellular RNA fractions. Our method was validated to be accurate and precise within the linear range of 0.06 15.36 pmol/MUL and to have absolute Psi quantification levels as low as 3.07 pmol. Using our optimized HPLC assay, we found that 1.20% and 1.94% of all ribonucleosides in nuclear-enriched RNA and small non-coding RNA pools from the HEK293 cell line, and 1.77% and 0.98% of ribonucleosides in 18S and 28S rRNA isolated from the HeLa cell line, were pseudouridylated. Upon knockdown of dyskerin expression, a consistent and significant reduction in total Psi levels in nuclear-enriched RNA pools was observed. Our assay provides a fast and accurate quantification method to measure changes in Psi levels of different RNA pools without sample derivatization. PMID- 28872588 TI - Ultrastructural Characterization of Membrane Rearrangements Induced by Porcine Epidemic Diarrhea Virus Infection. AB - The porcine epidemic diarrhea virus (PEDV) is a coronavirus (CoV) belonging to the alpha-CoV genus and it causes high mortality in infected sucking piglets, resulting in substantial losses in the farming industry. CoV trigger a drastic reorganization of host cell membranes to promote their replication and egression, but a detailed description of the intracellular remodeling induced by PEDV is still missing. In this study, we examined qualitatively and quantitatively, using electron microscopy, the intracellular membrane reorganization induced by PEDV over the course of an infection. With our ultrastructural approach, we reveal that, as most of CoV, PEDV initially forms double-membrane vesicles (DMVs) and convoluted membranes (CMs), which probably serve as replication/transcription platforms. Interestingly, we also found that viral particles start to form almost simultaneously in both the endoplasmic reticulum and the large virion-containing vacuoles (LVCVs), which are compartments originating from the Golgi, confirming that alpha-CoV assemble indistinguishably in two different organelles of the secretory pathway. Moreover, PEDV virons appear to have an immature and a mature form, similar to another alpha-CoV the transmissible gastroenteritis coronavirus (TGEV). Altogether, our study underlies the similarities and differences between the lifecycle of alpha-CoV and that of viruses belonging to other CoV subfamilies. PMID- 28872589 TI - Improved Range Estimation Model for Three-Dimensional (3D) Range Gated Reconstruction. AB - Accuracy is an important measure of system performance and remains a challenge in 3D range gated reconstruction despite the advancement in laser and sensor technology. The weighted average model that is commonly used for range estimation is heavily influenced by the intensity variation due to various factors. Accuracy improvement in term of range estimation is therefore important to fully optimise the system performance. In this paper, a 3D range gated reconstruction model is derived based on the operating principles of range gated imaging and time slicing reconstruction, fundamental of radiant energy, Laser Detection And Ranging (LADAR), and Bidirectional Reflection Distribution Function (BRDF). Accordingly, a new range estimation model is proposed to alleviate the effects induced by distance, target reflection, and range distortion. From the experimental results, the proposed model outperforms the conventional weighted average model to improve the range estimation for better 3D reconstruction. The outcome demonstrated is of interest to various laser ranging applications and can be a reference for future works. PMID- 28872590 TI - Synthesis of Nitric Oxide Donors Derived from Piloty's Acid and Study of Their Effects on Dopamine Secretion from PC12 Cells. AB - This study investigated the mechanisms and kinetics of nitric oxide (NO) generation by derivatives of Piloty's acid (NO-donors) under physiological conditions. In order to qualitatively and quantitatively measure NO release, electron paramagnetic resonance (EPR) was carried out with NO spin trapping. In addition, voltammetric techniques, including cyclic voltammetry and constant potential amperometry, were used to confirm NO release from Piloty's acid and its derivatives. The resulting data showed that Piloty's acid derivatives are able to release NO under physiological conditions. In particular, electron-withdrawing substituents favoured NO generation, while electron-donor groups reduced NO generation. In vitro microdialysis, performed on PC12 cell cultures, was used to evaluate the dynamical secretion of dopamine induced by the Piloty's acid derivatives. Although all the studied molecules were able to induce DA secretion from PC12, only those with a slow release of NO have not determined an autoxidation of DA itself. These results confirm that the time-course of NO donors decomposition and the amount of NO released play a key role in dopamine secretion and auto-oxidation. This information could drive the synthesis or the selection of compounds to use as potential drugs for the therapy of Parkinson's disease (PD). PMID- 28872592 TI - Application of a Surimi-Based Coating to Improve the Quality Attributes of Shrimp during Refrigerated Storage. AB - Shrimp is a popular seafood throughout the world. However, shrimp is highly perishable due to biochemical, microbiological, or physical changes during postmortem storage. In this study, the effect of a surimi-based coating with and without montmorillonite (MMT) nanoclay on shrimp quality was evaluated during eight days of refrigerator storage. Use of a surimi-based coating resulted in reductions of aerobic plate counts (APC) up to 2 log units. The combined effect of the MMT and coating was observed. Surimi-based coating with MMT resulted in lower APC (p < 0.05) toward the end of storage. The application of surimi-based coating with MMT to the shrimp samples improved sensory quality and delayed lipid oxidation and color deterioration during storage time. In general, better texture was observed when coating was applied either with or without MMT. This study suggests that surimi-based coating may improve the quality of shrimp during refrigerated storage. PMID- 28872591 TI - The Development of a Chinese Healthy Eating Index and Its Application in the General Population. AB - The objective of this study was to develop a Chinese Healthy Eating Index (CHEI) based on the updated Dietary Guidelines for Chinese (DGC-2016) and to apply it in the 2011 China Health and Nutrition Survey (CHNS-2011) to assess diet quality and its association with typical sociodemographic/economic factors. Data from 14,584 participants (>=2 years) from the CHNS-2011, including three 24-h dietary recalls and additional variables, were used to develop the CHEI. The standard portion size was applied to quantify food consumption. The CHEI was designed as a continuous scoring system, comprising 17 components; the maximum total score is 100. The mean, 1st and 99th percentiles of the CHEI score were 52.4, 27.6 and 78.3, respectively. Young and middle-aged adults scored better than the elderly. Diet insufficiency was chiefly manifested in fruits, dairy, whole grains and poultry; diet excess was mainly reflected in red meat, cooking oils and sodium. The CHEI was positively associated with education and urbanization levels; current smokers and unmarried people obtained relative low CHEI scores. Occupation and body mass index (BMI) were also related to the CHEI. Our findings indicate that the CHEI is capable of recognizing differences in diet quality among the Chinese, and it is sensitive to typical sociodemographic/economic factors. PMID- 28872593 TI - Effect of Different Activated Carbon as Carrier on the Photocatalytic Activity of Ag-N-ZnO Photocatalyst for Methyl Orange Degradation under Visible Light Irradiation. AB - In order to enhance the photodegradation of methyl orange (MO) by ZnO under visible light irradiation, ZnO nanoparticles co-doped with Ag and N and supported on activated carbon (AC) with different properties were synthesized through the sol-gel method. The prepared photocatalysts were characterized in terms of the structure and properties through X-ray diffraction, N2 adsorption-desorption, ultraviolet-visible (UV-vis), diffuse reflectance spectroscopy, X-ray photoelectron spectroscopy, photoluminescence, and electron spin resonance. The photocatalytic activities of these photocatalysts followed the order: Ag-N ZnO/ACs > Ag-N-ZnO > N, or Ag single-doped ZnO > commercial ZnO. This result was attributed to the small particle size, large surface area, narrow band gap, and high charge separation of Ag-N-ZnO/ACs. The Ag-N-ZnO/coconut husk activated carbon (Ag-N-ZnO/CHAC) exhibited the highest degradation efficiency of 98.82% for MO under visible light irradiation. This outcome was due to the abundant pore structure of Ag-N-ZnO/CHAC, resulting in stronger adsorption than that of other Ag-N-ZnO/ACs. Moreover, the degradation of MO on photocatalysis followed first order kinetics. The reactive species .OH and .O2- played more important roles in the photocatalytic degradation of MO over composite photocatalyst. Ag-N-ZnO/CHAC photocatalyst exhibited higher photocatalytic activity than unsupported Ag-N-ZnO after five recycling runs. PMID- 28872594 TI - Zebrafish Xenograft: An Evolutionary Experiment in Tumour Biology. AB - Though the cancer research community has used mouse xenografts for decades more than zebrafish xenografts, zebrafish have much to offer: they are cheap, easy to work with, and the embryonic model is relatively easy to use in high-throughput assays. Zebrafish can be imaged live, allowing us to observe cellular and molecular processes in vivo in real time. Opponents dismiss the zebrafish model due to the evolutionary distance between zebrafish and humans, as compared to mice, but proponents argue for the zebrafish xenograft's superiority to cell culture systems and its advantages in imaging. This review places the zebrafish xenograft in the context of current views on cancer and gives an overview of how several aspects of this evolutionary disease can be addressed in the zebrafish model. Zebrafish are missing homologs of some human proteins and (of particular interest) several members of the matrix metalloproteinase (MMP) family of proteases, which are known for their importance in tumour biology. This review draws attention to the implicit evolutionary experiment taking place when the molecular ecology of the xenograft host is significantly different than that of the donor. PMID- 28872595 TI - Active Transportation on a Complete Street: Perceived and Audited Walkability Correlates. AB - Few studies of walkability include both perceived and audited walkability measures. We examined perceived walkability (Neighborhood Environment Walkability Scale-Abbreviated, NEWS-A) and audited walkability (Irvine-Minnesota Inventory, IMI) measures for residents living within 2 km of a "complete street"-one renovated with light rail, bike lanes, and sidewalks. For perceived walkability, we found some differences but substantial similarity between our final scales and those in a prior published confirmatory factor analysis. Perceived walkability, in interaction with distance, was related to complete street active transportation. Residents were likely to have active transportation on the street when they lived nearby and perceived good aesthetics, crime safety, and traffic safety. Audited walkability, analyzed with decision trees, showed three general clusters of walkability areas, with 12 specific subtypes. A subset of walkability items (n = 11), including sidewalks, zebra-striped crosswalks, decorative sidewalks, pedestrian signals, and blank walls combined to cluster street segments. The 12 subtypes yielded 81% correct classification of residents' active transportation. Both perceived and audited walkability were important predictors of active transportation. For audited walkability, we recommend more exploration of decision tree approaches, given their predictive utility and ease of translation into walkability interventions. PMID- 28872596 TI - Survey of Veterinarians Using a Novel Physical Compression Squeeze Procedure in the Management of Neonatal Maladjustment Syndrome in Foals. AB - Horses are a precocious species that must accomplish several milestones that are critical to survival in the immediate post-birth period for their survival. One essential milestone is the successful transition from the intrauterine unconsciousness to an extrauterine state of consciousness or awareness. This transition involves a complex withdrawal of consciousness inhibitors and an increase in neuroactivating factors that support awareness. This process involves neuroactive hormones as well as inputs related to factors such as cold, visual, olfactory, and auditory stimuli. One factor not previously considered in this birth transition is a yet unreported direct neural reflex response to labor induced physical compression of the fetus in the birth canal (squeezing). Neonatal maladjustment syndrome (NMS) is a disorder of the newborn foal characterized by altered behavior, low affinity for the mare, poor awareness of the environment, failure to bond to the mother, abnormal sucking, and other neurologically-based abnormalities. This syndrome has been associated with altered events during birth, and was believed to be caused exclusively by hypoxia and ischemia. However, recent findings revealed an association of the NMS syndrome with the persistence of high concentrations of in utero neuromodulating hormones (neurosteroids) in the postnatal period. Anecdotal evidence demonstrated that a novel physical compression (squeeze) method that applies 20 min of sustained pressure to the thorax of some neonatal foals with this syndrome might rapidly hasten recovery. This survey provides information about outcomes and time frames to recovery comparing neonatal foals that were given this squeeze treatment to foals treated with routine medical therapy alone. Results revealed that the squeeze procedure, when applied for 20 min, resulted in a faster full recovery of some foals diagnosed with NMS. The adjunctive use of a non-invasive squeeze method may improve animal welfare by hastening recovery and foal-mare interactions that minimize health problems. This would also avoid or reduce costs arising from hospitalization associated with veterinary and nursing care that sometimes leads owners to elect for euthanasia. PMID- 28872597 TI - Changes in Daily Steps and Body Mass Index and Waist to Height Ratio during Four Year Follow-Up in Adults: Cardiovascular Risk in Young Finns Study. AB - Aims: Over the study years, there was a significant increase in body mass index (BMI) and waist-to-height ratio (WtHR) in middle aged Finnish adults. Methods: Data were obtained from 1033 Finnish adults from the Cardiovascular Risk in Young Finns Study in 2007 and 2011. Cohort study participants wore an Omron Walking Style One (HJ-152R-E) pedometer for five days and were grouped into those who increased, maintained and decreased their steps between 2007 and 2011. Paired samples t-test was used to compare body mass index (BMI) and waist-to-height ratio (WtHR) change values between the change groups in study years. Results: Among study population BMI and WtHR increase between study years was statistically significant (p < 0.001). Only those, who increased their total steps for at least 2000 steps, maintained their BMI in the same level, while people who decreased or maintained their total steps in the same level, BMI and WtHR increased during four years follow-up. Conclusions: This data suggests that increasing steps in middle age is associated with maintaining BMI at the same level. PMID- 28872599 TI - Perfluorinated Compounds as Test Media for Porous Membranes. AB - We suggest a failure-free method of porous membranes characterization that gives the researcher the opportunity to compare and characterize properties of any porous membrane. This proposal is supported by an investigation of eight membranes made of different organic and inorganic materials, with nine different perfluorinated compounds. It was found that aromatic compounds, perfluorobenzene, and perfluorotoluene, used in the current study show properties different from other perfluorinated aliphatics. They demonstrate extreme deviation from the general sequence indicating the existence of pi-pi-interaction on the pore wall. The divergence of the flow for cyclic compounds from ideal e.g., linear compounds can be an indication of the pore dimension. PMID- 28872601 TI - Erratum: History of U.S. Iodine Fortification and Supplementation; Nutrients 2012, 4, 1740-1746. PMID- 28872600 TI - Effects of Visual Stimulation with Bonsai Trees on Adult Male Patients with Spinal Cord Injury. AB - Nature therapy has been demonstrated to induce physiological relaxation. The psychophysiological effects of nature therapy (stimulation with bonsai trees) on adult male patients with spinal cord injury (SCI) were examined. Oxyhemoglobin concentration changes in the prefrontal cortex were measured using near-infrared spectroscopy, and heart rate variability was analyzed. Psychological responses were evaluated using the modified semantic differential method and Profile of Mood States (POMS) subscale scores. Visual stimulation of adult male patients with SCI elicited significantly decreased left prefrontal cortex activity, increased parasympathetic nervous activity, decreased sympathetic nervous activity, increased positive feelings, and resulted in lower negative POMS subscale scores. Nature therapy can lead to a state of physiological and psychological relaxation in patients with SCI. PMID- 28872602 TI - An IMM-Aided ZUPT Methodology for an INS/DVL Integrated Navigation System. AB - Inertial navigation system (INS)/Doppler velocity log (DVL) integration is the most common navigation solution for underwater vehicles. Due to the complex underwater environment, the velocity information provided by DVL always contains some errors. To improve navigation accuracy, zero velocity update (ZUPT) technology is considered, which is an effective algorithm for land vehicles to mitigate the navigation error during the pure INS mode. However, in contrast to ground vehicles, the ZUPT solution cannot be used directly for underwater vehicles because of the existence of the water current. In order to leverage the strengths of the ZUPT method and the INS/DVL solution, an interactive multiple model (IMM)-aided ZUPT methodology for the INS/DVL-integrated underwater navigation system is proposed. Both the INS/DVL and INS/ZUPT models are constructed and operated in parallel, with weights calculated according to their innovations and innovation covariance matrices. Simulations are conducted to evaluate the proposed algorithm. The results indicate that the IMM-aided ZUPT solution outperforms both the INS/DVL solution and the INS/ZUPT solution in the underwater environment, which can properly distinguish between the ZUPT and non ZUPT conditions. In addition, during DVL outage, the effectiveness of the proposed algorithm is also verified. PMID- 28872604 TI - Deep Eutectic Solvents as Convenient Media for Synthesis of Novel Coumarinyl Schiff Bases and Their QSAR Studies. AB - Deep eutectic solvents, as green and environmentally friendly media, were utilized in the synthesis of novel coumarinyl Schiff bases. Novel derivatives were synthesized from 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide and corresponding aldehyde in choline chloride:malonic acid (1:1) based deep eutectic solvent. In these reactions, deep eutectic solvent acted as a solvent and catalyst as well. Novel Schiff bases were synthesized in high yields (65-75%) with no need for further purification, and their structures were confirmed by mass spectra, 1H and 13C NMR. Furthermore, their antioxidant activity was determined and compared to antioxidant activity of previously synthesized derivatives, thus investigating their structure-activity relationship utilizing quantitative structure-activity relationship QSAR studies. Calculation of molecular descriptors has been performed by DRAGON software. The best QSAR model (Rtr = 0.636; Rext = 0.709) obtained with three descriptors (MATS3m, Mor22u, Hy) implies that the pairs of atoms higher mass at the path length 3, three dimensional arrangement of atoms at scattering parameter s = 21 A-1, and higher number of hydrophilic groups (-OH, -NH) enhanced antioxidant activity. Electrostatic potential surface of the most active compounds showed possible regions for donation of electrons to 1,1-diphenyl-2-picryhydrazyl (DPPH) radicals. PMID- 28872603 TI - Ginger Phytochemicals Inhibit Cell Growth and Modulate Drug Resistance Factors in Docetaxel Resistant Prostate Cancer Cell. AB - Ginger has many bioactive compounds with pharmacological activities. However, few studies are known about these bioactive compounds activity in chemoresistant cells. The aim of the present study was to investigate the anticancer properties of ginger phytochemicals in docetaxel-resistant human prostate cancer cells in vitro. In this study, we isolated 6-gingerol, 10-gingerol, 4-shogaol, 6-shogaol, 10-shogaol, and 6-dehydrogingerdione from ginger. Further, the antiproliferation activity of these compounds was examined in docetaxel-resistant (PC3R) and sensitive (PC3) human prostate cancer cell lines. 6-gingerol, 10-gingerol, 6 shogaol, and 10-shogaol at the concentration of 100 MUM significantly inhibited the proliferation in PC3R but 6-gingerol, 6-shogaol, and 10-shogaol displayed similar activity in PC3. The protein expression of multidrug resistance associated protein 1 (MRP1) and glutathione-S-transferase (GSTpi) is higher in PC3R than in PC3. In summary, we isolated the bioactive compounds from ginger. Our results showed that 6-gingerol, 10-gingerol, 6-shogaol, and 10-shogaol inhibit the proliferation of PC3R cells through the downregulation of MRP1 and GSTpi protein expression. PMID- 28872606 TI - Hypophosphite/Graphitic Carbon Nitride Hybrids: Preparation and Flame-Retardant Application in Thermoplastic Polyurethane. AB - A series of aluminum hypophosphite (AHPi)/graphite-like carbon nitride (g-C3N4) (designated as CAHPi) hybrids were prepared, followed by incorporation into thermoplastic polyurethane (TPU). The introduction of CAHPi hybrids into TPU led to a marked reduction in the peak of the heat release rate (pHRR), total heat release, weight loss rate, smoke production rate and total smoke production (TSP). For instance, pHRR and TSP decreased by 40% and 50% for TPU/CAHPi20. Furthermore, the increasing fire growth index and decreasing fire performance index were obtained for TPU/CAHPi systems, suggesting reduced fire hazards. It was found that improved fire safety of TPU nanocomposites was contributed by condensed phase and gas phase mechanisms. On one hand, g-C3N4 accelerated the thermal decomposition of AHPi for the formation of more char layers. On the other hand, g-C3N4 induced AHPi to generate more free radical capture agents when exposed to flame, besides protecting AHPi against thermal oxidation. PMID- 28872598 TI - The TORC2-Dependent Signaling Network in the Yeast Saccharomyces cerevisiae. AB - To grow, eukaryotic cells must expand by inserting glycerolipids, sphingolipids, sterols, and proteins into their plasma membrane, and maintain the proper levels and bilayer distribution. A fungal cell must coordinate growth with enlargement of its cell wall. In Saccharomyces cerevisiae, a plasma membrane-localized protein kinase complex, Target of Rapamicin (TOR) complex-2 (TORC2) (mammalian ortholog is mTORC2), serves as a sensor and masterregulator of these plasma membrane- and cell wall-associated events by directly phosphorylating and thereby stimulating the activity of two types of effector protein kinases: Ypk1 (mammalian ortholog is SGK1), along with a paralog (Ypk2); and, Pkc1 (mammalian ortholog is PKN2/PRK2). Ypk1 is a central regulator of pathways and processes required for plasma membrane lipid and protein homeostasis, and requires phosphorylation on its T-loop by eisosome-associated protein kinase Pkh1 (mammalian ortholog is PDK1) and a paralog (Pkh2). For cell survival under various stresses, Ypk1 function requires TORC2-mediated phosphorylation at multiple sites near its C terminus. Pkc1 controls diverse processes, especially cell wall synthesis and integrity. Pkc1 is also regulated by Pkh1- and TORC2 dependent phosphorylation, but, in addition, by interaction with Rho1-GTP and lipids phosphatidylserine (PtdSer) and diacylglycerol (DAG). We also describe here what is currently known about the downstream substrates modulated by Ypk1 mediated and Pkc1-mediated phosphorylation. PMID- 28872605 TI - Vegetable Oils as Alternative Solvents for Green Oleo-Extraction, Purification and Formulation of Food and Natural Products. AB - Since solvents of petroleum origin are now strictly regulated worldwide, there is a growing demand for using greener, bio-based and renewable solvents for extraction, purification and formulation of natural and food products. The ideal alternative solvents are non-volatile organic compounds (VOCs) that have high dissolving power and flash point, together with low toxicity and less environmental impact. They should be obtained from renewable resources at a reasonable price and be easy to recycle. Based on the principles of Green Chemistry and Green Engineering, vegetable oils could become an ideal alternative solvent to extract compounds for purification, enrichment, or even pollution remediation. This review presents an overview of vegetable oils as solvents enriched with various bioactive compounds from natural resources, as well as the relationship between dissolving power of non-polar and polar bioactive components with the function of fatty acids and/or lipid classes in vegetable oils, and other minor components. A focus on simulation of solvent-solute interactions and a discussion of polar paradox theory propose a mechanism explaining the phenomena of dissolving polar and non-polar bioactive components in vegetable oils as green solvents with variable polarity. PMID- 28872607 TI - Design and Antiproliferative Evaluation of Novel Sulfanilamide Derivatives as Potential Tubulin Polymerization Inhibitors. AB - A series of sulfanilamide-1,2,3-triazole hybrids were designed by a molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, MCF-7 and PC-3). The detailed structure activity relationships for these sulfanilamide-1,2,3-triazole hybrids were investigated. All these sulfanilamide-1,2,3-triazole hybrids exhibited moderate to potent activity against all cell lines. In particular 4-methyl-N-((1-(3 phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (11f) showed the most potent inhibitory effect against PC-3 cells, with an IC50 value of 4.08 MUM. Furthermore, the tubulin polymerization inhibitory activity in vitro of compound 11f was 2.41 MUM. These sulfanilamide hybrids might serve as bioactive fragments for developing more potent antiproliferative agents. PMID- 28872608 TI - Study on the Fluorescent Activity of N2-Indolyl-1,2,3-triazole. AB - A new type of blue emitter, N2-Indolyl-1,2,3-triazoles (NITs), with the lambdamax ranging from 420-480 nm and the Stokes shift from 89-143 nm, were synthesized through the coupling reaction of indoles with triazole derivatives. The influence of different substitution patterns on the optical properties (efficiency, excitation, and emission wavelengths) of the NITs was investigated. In addition, one palladium complex were synthesized by using NITs as the ligands, which, however, exhibited no fluorescent activity, but did show the enhanced co planarity. Lastly, two bio-active molecule derivatives were explored for the potential use of these novel dyes in related chemical and biological applications. PMID- 28872609 TI - Evaluation of VIIRS Land Aerosol Model Selection with AERONET Measurements. AB - The Visible Infrared Imaging Radiometer Suite (VIIRS) is a next-generation polar orbiting operational environmental sensor with a capability for global aerosol observations. Identifying land aerosol types is important because aerosol types are a basic input in retrieving aerosol optical properties for VIIRS. The VIIRS algorithm can automatically select the optimal land aerosol model by minimizing the residual between the derived and expected spectral surface reflectance. In this study, these selected VIIRS aerosol types are evaluated using collocated aerosol types obtained from the Aerosol Robotic Network (AERONET) level 1.5 from 23 January 2013 to 28 February 2017. The spatial distribution of VIIRS aerosol types and the aerosol optical depth bias (VIIRS minus AERONET) demonstrate that misidentifying VIIRS aerosol types may lead to VIIRS retrieval being overestimated over the Eastern United States and the developed regions of East Asia, as well as underestimated over Southern Africa, India, and Northeastern China. Approximately 22.33% of VIIRS aerosol types are coincident with that of AERONET. The agreements between VIIRS and AERONET for fine non-absorbing and absorbing aerosol types are approximately 36% and 57%, respectively. However, the agreement between VIIRS and AERONET is extremely low (only 3.51%). The low agreement for coarse absorbing dust may contribute to the poor performance of VIIRS retrieval under the aerosol model (R = 0.61). Results also show that an appropriate aerosol model can improve the retrieval performance of VIIRS over land, particularly for dust type (R increases from 0.61 to 0.72). PMID- 28872610 TI - Evaluation of Polyethylene Glycol Diacrylate-Polycaprolactone Scaffolds for Tissue Engineering Applications. AB - Polyethylene Glycol Diacrylate (PEGDA) tissue scaffolds having a thickness higher than 1 mm and without the presence of nutrient conduit networks were shown to have limited applications in tissue engineering due to the inability of cells to adhere and migrate within the scaffold. The PEGDA scaffold has been coated with polycaprolactone (PCL) electrospun nanofiber (ENF) membrane on both sides to overcome these limitations, thereby creating a functional PEGDA-PCL scaffold. This study examined the physical, mechanical, and biological properties of the PEGDA and PEGDA-PCL scaffolds to determine the effect of PCL coating on PEGDA. The physical characterization of PEGDA-PCL samples demonstrated the effectiveness of combining PCL with a PEGDA scaffold to expand its applications in tissue engineering. This study also found a significant improvement of elasticity of PEGDA due to the addition of PCL layers. This study shows that PEGDA-PCL scaffolds absorb nutrients with time and can provide an ideal environment for the survival of cells. Furthermore, cell viability tests indicate that the cell adhered, proliferated, and migrated in the PEGDA-PCL scaffold. Therefore, PCL ENF coating has a positive influence on PEGDA scaffold. PMID- 28872611 TI - Clinical and Physiological Perspectives of beta-Glucans: The Past, Present, and Future. AB - beta-Glucans are a group of biologically-active fibers or polysaccharides from natural sources with proven medical significance. beta-Glucans are known to have antitumor, anti-inflammatory, anti-obesity, anti-allergic, anti-osteoporotic, and immunomodulating activities. beta-Glucans are natural bioactive compounds and can be taken orally, as a food supplement, or as part of a daily diet, and are considered safe to use. The medical significance and efficiency of beta-glucans are confirmed in vitro, as well as using animal- and human-based clinical studies. However, systematic study on the clinical and physiological significance of beta-glucans is scarce. In this review, we not only discuss the clinical and physiological importance of beta-glucans, we also compare their biological activities through the existing in vitro and animal-based in vivo studies. This review provides extensive data on the clinical study of beta-glucans. PMID- 28872612 TI - Fructus Ligustri Lucidi in Osteoporosis: A Review of its Pharmacology, Phytochemistry, Pharmacokinetics and Safety. AB - Background: Fructus Ligustri Lucidi (FLL) has now attracted increasing attention as an alternative medicine in the prevention and treatment of osteoporosis. This study aimed to provide a general review of traditional interpretation of the actions of FLL in osteoporosis, main phytochemical constituents, pharmacokinetics, pharmacology in bone improving effect, and safety. Materials and Methods: Several databases, including PubMed, China National Knowledge Infrastructure, National Science and Technology Library, China Science and Technology Journal Database, and Web of Science were consulted to locate publications pertaining to FLL. The initial inquiry was conducted for the presence of the following keywords combinations in the abstracts: Fructus Ligustri Lucidi, osteoporosis, phytochemistry, pharmacokinetics, pharmacology, osteoblasts, osteoclasts, salidroside. About 150 research papers and reviews were consulted. Results: FLL is assumed to exhibit anti-osteoporotic effects by improving liver and kidney deficiencies and reducing lower back soreness in Traditional Chinese Medicine (TCM). The data from animal and cell experiments demonstrate that FLL is able to improve bone metabolism and bone quality in ovariectomized, growing, aged and diabetic rats through the regulation of PTH/FGF 23/1,25-(OH)2D3/CaSR, Nox4/ROS/NF-kappaB, and OPG/RANKL/cathepsin K signaling pathways. More than 100 individual compounds have been isolated from this plant. Oleanolic acid, ursolic acid, salidroside, and nuzhenide have been reported to exhibit the anti-osteoporosis effect. The pharmacokinetics data reveals that salidroside is one of the active constituents, and that tyrosol is hard to detect under physiological conditions. Acute and subacute toxicity studies show that FLL is well tolerated and presents no safety concerns. Conclusions: FLL provides a new option for the prevention and treatment of osteoporosis, which attracts rising interests in identifying potential anti-osteoporotic compounds and fractions from this plant. Further scientific evidences are expected from well designed clinical trials on its bone protective effects and safety. PMID- 28872613 TI - Roles of Long Noncoding RNAs in Recurrence and Metastasis of Radiotherapy Resistant Cancer Stem Cells. AB - Radiotherapy is a well-established therapeutic regimen applied to treat at least half of all cancer patients worldwide. Radioresistance of cancers or failure to treat certain tumor types with radiation is associated with enhanced local invasion, metastasis and poor prognosis. Elucidation of the biological characteristics underlying radioresistance is therefore critical to ensure the development of effective strategies to resolve this issue, which remains an urgent medical problem. Cancer stem cells (CSCs) comprise a small population of tumor cells that constitute the origin of most cancer cell types. CSCs are virtually resistant to radiotherapy, and consequently contribute to recurrence and disease progression. Metastasis is an increasing problem in resistance to cancer radiotherapy and closely associated with the morbidity and mortality rates of several cancer types. Accumulating evidence has demonstrated that radiation induces epithelial-mesenchymal transition (EMT) accompanied by increased cancer recurrence, metastasis and CSC generation. CSCs are believed to serve as the basis of metastasis. Previous studies indicate that CSCs contribute to the generation of metastasis, either in a direct or indirect manner. Moreover, the heterogeneity of CSCs may be responsible for organ specificity and considerable complexity of metastases. Long noncoding RNAs (lncRNAs) are a class of noncoding molecules over 200 nucleotides in length involved in the initiation and progression of several cancer types. Recently, lncRNAs have attracted considerable attention as novel critical regulators of cancer progression and metastasis. In the current review, we have discussed lncRNA-mediated regulation of CSCs following radiotherapy, their association with tumor metastasis and significance in radioresistance of cancer. PMID- 28872615 TI - Listeriolysin O Regulates the Expression of Optineurin, an Autophagy Adaptor That Inhibits the Growth of Listeria monocytogenes. AB - Autophagy, a well-established defense mechanism, enables the elimination of intracellular pathogens including Listeria monocytogenes. Host cell recognition results in ubiquitination of L. monocytogenes and interaction with autophagy adaptors p62/SQSTM1 and NDP52, which target bacteria to autophagosomes by binding to microtubule-associated protein 1 light chain 3 (LC3). Although studies have indicated that L. monocytogenes induces autophagy, the significance of this process in the infectious cycle and the mechanisms involved remain poorly understood. Here, we examined the role of the autophagy adaptor optineurin (OPTN), the phosphorylation of which by the TANK binding kinase 1 (TBK1) enhances its affinity for LC3 and promotes autophagosomal degradation, during L. monocytogenes infection. In LC3- and OPTN-depleted host cells, intracellular replicating L. monocytogenes increased, an effect not seen with a mutant lacking the pore-forming toxin listeriolysin O (LLO). LLO induced the production of OPTN. In host cells expressing an inactive TBK1, bacterial replication was also inhibited. Our studies have uncovered an OPTN-dependent pathway in which L. monocytogenes uses LLO to restrict bacterial growth. Hence, manipulation of autophagy by L. monocytogenes, either through induction or evasion, represents a key event in its intracellular life style and could lead to either cytosolic growth or persistence in intracellular vacuolar structures. PMID- 28872617 TI - A Piezoresponse Force Microscopy Study of CaxBa1-xNb2O6 Single Crystals. AB - Polar structures of CaxBa1-xNb2O6 (CBN100x) single crystals were investigated using piezoresponse force microscopy. Increasing Ca content results in decreasing domain size and enhancement of the polar disorder. For the composition with x = 0.32 the characteristic domain size is similar to that reported for relaxor Sr0.61Ba0.39Nb2O6 (SBN61). However, decay of an artificial macroscopic domain in CBN32 takes place below the macroscopic transition temperature, contrary to SBN61, where random fields stabilize it above the transition temperature. We can conclude that CBN with 0.26 <= x <= 0.32 does not display classical relaxor behavior and might be considered as a disordered ferroelectric. PMID- 28872618 TI - Magnetic Force Microscopy of Nanostructured Co/Pt Multilayer Films with Perpendicular Magnetization. AB - We present the results of magnetic force microscopy investigations of domain structures in multilayer [Co (0.5 nm)/Pt (1 nm)]5 thin film structures (denoted hereafter as Co/Pt) modified by additional Co capping layers and by ion irradiation. It is demonstrated that a Co capping layer essentially changes the domain structure and decreases the threshold of magnetization reversal, due to the formation of noncollinear magnetization in Co/Pt. It is shown that local irradiation with a focused He+ ion beam enables the formation of regions with decreased easy-axis anisotropy (magnetic bubbles) that have the inverse magnetization direction in the demagnetized state of Co/Pt. The experimental results demonstrate that the magnetic bubbles can be switched using a probe of a magnetic force microscope. The possible application of these effects for the development of magnetic logic and data storage systems is discussed. PMID- 28872616 TI - Use of a Yeast tRNase Killer Toxin to Diagnose Kti12 Motifs Required for tRNA Modification by Elongator. AB - Saccharomyces cerevisiae cells are killed by zymocin, a tRNase ribotoxin complex from Kluyveromyces lactis, which cleaves anticodons and inhibits protein synthesis. Zymocin's action requires specific chemical modification of uridine bases in the anticodon wobble position (U34) by the Elongator complex (Elp1 Elp6). Hence, loss of anticodon modification in mutants lacking Elongator or related KTI (K. lactis Toxin Insensitive) genes protects against tRNA cleavage and confers resistance to the toxin. Here, we show that zymocin can be used as a tool to genetically analyse KTI12, a gene previously shown to code for an Elongator partner protein. From a kti12 mutant pool of zymocin survivors, we identify motifs in Kti12 that are functionally directly coupled to Elongator activity. In addition, shared requirement of U34 modifications for nonsense and missense tRNA suppression (SUP4; SOE1) strongly suggests that Kti12 and Elongator cooperate to assure proper tRNA functioning. We show that the Kti12 motifs are conserved in plant ortholog DRL1/ELO4 from Arabidopsis thaliana and seem to be involved in binding of cofactors (e.g., nucleotides, calmodulin). Elongator interaction defects triggered by mutations in these motifs correlate with phenotypes typical for loss of U34 modification. Thus, tRNA modification by Elongator appears to require physical contact with Kti12, and our preliminary data suggest that metabolic signals may affect proper communication between them. PMID- 28872619 TI - Preparation of Humidity-Sensitive Poly(Ethylene Glycol) Inverse Opal Micropatterns Using Colloidal Lithography. AB - Humidity-sensitive poly(ethylene glycol) (PEG) inverse opals with micropatterns of 2 MUm wide anti-swell-broken grooves were prepared using polystyrene (PS) colloidal crystals as templates and colloidal lithography. Monodisperse PS colloids were deposited in an ordered manner onto glass slides using a double substrate vertical deposition method to form colloidal crystal templates. Poly(ethylene glycol) diacrylate (PEGDA) with photoinitiator was infiltrated into the interspaces of the colloidal crystals and photo-crosslinked by UV irradiation through a photomask. After removal the PS templates and unexposed PEGDA by tetrahydrofuran (THF), PEG hydrogel micropatterns with three-dimensional ordered porous structures were obtained. The band gaps of the PS colloidal crystals and corresponding PEG hydrogel inverse opals were measured by UV-VIS reflection spectrometer, calculated by Bragg law and simulated by Band SOLVE. The obtained PEG hydrogel inverse opal micropatterns can be used as sensors for humidity sensing due to absorption and desorption of moisture in the band gap structures. The sensor had a very reliable performance after repeated humidity sensing, and could be mass produced facilely with very low cost. The photopatterned anti-swell broken grooves play an important role in the reliability of the sensors. PMID- 28872620 TI - Electron Beam Welding of IN792 DS: Effects of Pass Speed and PWHT on Microstructure and Hardness. AB - Electron Beam (EB) welding has been used to realize seams on 2 mm-thick plates of directionally solidified (DS) IN792 superalloy. The first part of this work evidenced the importance of pre-heating the workpiece to avoid the formation of long cracks in the seam. The comparison of different pre-heating temperatures (PHT) and pass speeds (v) allowed the identification of optimal process parameters, namely PHT = 300 degrees C and v = 2.5 m/min. The microstructural features of the melted zone (MZ); the heat affected zone (HAZ), and base material (BM) were investigated by optical microscopy (OM), scanning electron microscopy (SEM), energy dispersion spectroscopy (EDS), electron back-scattered diffraction (EBSD), X-ray diffraction (XRD), and micro-hardness tests. In the as-welded condition; the structure of directionally oriented grains was completely lost in MZ. The gamma' phase in MZ consisted of small (20-40 nm) round shaped particles and its total amount depended on both PHT and welding pass speed, whereas in HAZ, it was the same BM. Even if the amount of gamma' phase in MZ was lower than that of the as-received material, the nanometric size of the particles induced an increase in hardness. EDS examinations did not show relevant composition changes in the gamma' and gamma phases. Post-welding heat treatments (PWHT) at 700 and 750 degrees C for two hours were performed on the best samples. After PWHTs, the amount of the ordered phase increased, and the effect was more pronounced at 750 degrees C, while the size of gamma' particles in MZ remained almost the same. The hardness profiles measured across the joints showed an upward shift, but peak valley height was a little lower, indicating more homogeneous features in the different zones. PMID- 28872614 TI - Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therapy. PMID- 28872621 TI - Metamaterial Waveguide Devices for Integrated Optics. AB - We show the feasibility of controlling the magnetic permeability of optical semiconductor devices on InP-based photonic integration platforms. We have achieved the permeability control of GaInAsP/InP semiconductor waveguides by combining the waveguide with a metamaterial consisting of gate-controlled split ring resonators. The split-ring resonators interact magnetically with light travelling in the waveguide and move the effective relative permeability of the waveguide away from 1 at optical frequencies. The variation in permeability can be controlled with the gate voltage. Using this variable-permeability waveguide, we have built an optical modulator consisting of a GaInAsP/InP Mach-Zehnder interferometer for use at an optical communication wavelength of 1.55 MUm. The device changes the permeability of its waveguide arm with controlling gate voltage, thereby varying the refractive index of the arm to modulate the intensity of light. For the study of variable-permeability waveguide devices, we also propose a method of extracting separately the permittivity and permeability values of devices from the experimental data of light transmission. Adjusting the permeability of optical semiconductors to the needs of device designers will open the promising field of 'permeability engineering'. Permeability engineering will facilitate the manipulation of light and the management of photons, thereby contributing to the development of novel devices with sophisticated functions for photonic integration. PMID- 28872623 TI - Compression Fracture of CFRP Laminates Containing Stress Intensifications. AB - For brittle fracture behaviour of carbon fibre reinforced plastics (CFRP) under compression, several approaches exist, which describe different mechanisms during failure, especially at stress intensifications. The failure process is not only initiated by the buckling fibres, but a shear driven fibre compressive failure beneficiaries or initiates the formation of fibres into a kink-band. Starting from this kink-band further damage can be detected, which leads to the final failure. The subject of this work is an experimental investigation on the influence of ply thickness and stacking sequence in quasi-isotropic CFRP laminates containing stress intensifications under compression loading. Different effects that influence the compression failure and the role the stacking sequence has on damage development and the resulting compressive strength are identified and discussed. The influence of stress intensifications is investigated in detail at a hole in open hole compression (OHC) tests. A proposed interrupted test approach allows identifying the mechanisms of damage initiation and propagation from the free edge of the hole by causing a distinct damage state and examine it at a precise instant of time during fracture process. Compression after impact (CAI) tests are executed in order to compare the OHC results to a different type of stress intensifications. Unnotched compression tests are carried out for comparison as a reference. With this approach, a more detailed description of the failure mechanisms during the sudden compression failure of CFRP is achieved. By microscopic examination of single plies from various specimens, the different effects that influence the compression failure are identified. First damage of fibres occurs always in 0 degrees -ply. Fibre shear failure leads to local microbuckling and the formation and growth of a kink-band as final failure mechanisms. The formation of a kink-band and finally steady state kinking is shifted to higher compressive strains with decreasing ply thickness. Final failure mode in laminates with stress intensification depends on ply thickness. In thick or inner plies, damage initiates as shear failure and fibre buckling into the drilled hole. The kink-band orientation angle is changing with increasing strain. In outer or thin plies shear failure of single fibres is observed as first damage and the kink-band orientation angle is constant until final failure. Decreasing ply thickness increases the unnotched compressive strength. When stress intensifications are present, the position of the 0 degrees -layer is critical for stability under compression and is thus more important than the ply thickness. Central 0 degrees -layers show best results for OHC and CAI strength due to higher bending stiffness and better supporting effect of the adjacent layers. PMID- 28872622 TI - Metabolic Profiling in Association with Vascular Endothelial Cell Dysfunction Following Non-Toxic Cadmium Exposure. AB - This study aimed to determine the metabolic profile of non-toxic cadmium (Cd) induced dysfunctional endothelial cells using human umbilical vein endothelial cells (HUVECs). HUVECs (n = 6 per group) were treated with 0, 1, 5, or 10 MUM cadmium chloride (CdCl2) for 48 h. Cell phenotypes, including nitric oxide (NO) production, the inflammatory response, and oxidative stress, were evaluated in Cd exposed and control HUVECs. Cd-exposed and control HUVECs were analysed using gas chromatography time-of-flight/mass spectrometry. Compared to control HUVECs, Cd exposed HUVECs were dysfunctional, exhibiting decreased NO production, a proinflammatory state, and non-significant oxidative stress. Further metabolic profiling revealed 24 significantly-altered metabolites in the dysfunctional endothelial cells. The significantly-altered metabolites were involved in the impaired tricarboxylic acid (TCA) cycle, activated pyruvate metabolism, up regulated glucogenic amino acid metabolism, and increased pyrimidine metabolism. The current metabolic findings further suggest that the metabolic changes linked to TCA cycle dysfunction, glycosylation of the hexosamine biosynthesis pathway (HBP), and compensatory responses to genomic instability and energy deficiency may be generally associated with dysfunctional phenotypes, characterized by decreased NO production, a proinflammatory state, and non-significant oxidative stress, in endothelial cells following non-toxic Cd exposure. PMID- 28872624 TI - Effect of Silane Coupling Agent on Tribological Properties of Hemp Fiber Reinforced Plant-Derived Polyamide 1010 Biomass Composites. AB - We have studied the effects of silane coupling agents used for the surface treatment of fiber on the tribological properties of hemp fiber (HF) reinforced plant-derived polyamide 1010 (PA1010) biomass composites. Hemp fibers were surface-treated by two surface treatment methods: (a) alkali treatment by sodium hydroxide solution and (b) surface treatment by silane coupling agents. Three types of silane coupling agents, namely aminosilane, epoxysilane and ureidosilane were used. These HF/PA1010 biomass composites were extruded using a twin extruder, and injection-molded. The mechanical and tribological properties were evaluated by the ring-on-plate type sliding wear test. It was found that tribological properties of HF/PA1010 biomass composites improved with the surface treatment by the silane coupling agent. This may be attributed to the change in the mode of friction and wear mechanism by the interfacial adhesion between fiber and matrix polymer according to the type of silane coupling agent used. In particular, the ureidosilane coupling agent showed the best improvement effect for the tribological properties of these biomass composites in this study. PMID- 28872625 TI - Salivary Gland Derived BDNF Overexpression in Mice Exerts an Anxiolytic Effect. AB - Brain-derived neurotrophic factor (BDNF) is abundant in the hippocampus and plays critical roles in memory and synapse formation, as well as exerting antidepressant-like effects in psychiatric disorders. We previously reported that BDNF is expressed in salivary glands and affects blood BDNF content. However, the function of salivary BDNF remains unclear. The aim of this study was to generate transgenic mice overexpressing BDNF in the salivary glands. Hence, we used the Lama construct (hemagglutinin (HA)-tagged mouse Bdnf cDNA) to specifically express BDNF in mouse salivary glands. Compared with control mice, Bdnf-HA transgenic mice showed increased blood BDNF and expressed salivary BDNF-HA. Molecular analysis revealed enhanced hippocampal BDNF levels and activation of the BDNF receptor, tyrosine kinase B (TrkB), in transgenic mice. In both the open field and elevated-plus maze tests, transgenic mice showed anxiolytic-like behavioral effects compared with control or sialoadenectomized mice. Among downstream components of the BDNF-TrkB signaling pathway, metabolic activation of the gamma-aminobutyric acid (GABA) synthetic pathway was found, including higher levels of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1). Thus, we have established a transgenic mouse expressing BDNF in the parotid gland that may be useful to examine the hippocampal effects of salivary BDNF. PMID- 28872626 TI - Anti-Melanogenic Effects of Flavonoid Glycosides from Limonium tetragonum (Thunb.) Bullock via Inhibition of Tyrosinase and Tyrosinase-Related Proteins. AB - Overproduction and stimulation of tyrosinase result in increased melanogenesis of which several skin disorders such as freckles, spots, and hyperpigmentation appear as complications. Limonium tetragonum is a halophyte well-known for its antioxidative properties. This study investigated the anti-melanogenic effects of solvent-partitioned L. tetragonum extracts (LTEs) and its bioactive constituents, two isolated flavonoid glycosides. Current study followed a set of experiments on B16-F10 mouse melanoma cell model with a focus on tyrosinase activity and production. The anti-melanogenic capacity of LTEs was confirmed by their tyrosinase inhibitory effects, prevention of DOPA oxidation, and suppression of melanin production. The inhibition of tyrosinase and DOPA oxidation by LTEs was suggested to be related with the downregulation of microphthalmia-associated transcription factor, tyrosinase, tyrosinase-related protein-1, and tyrosinase related protein-2, verified with mRNA and protein expression levels. Among all tested LTEs, 85% aq. MeOH and n-BuOH were found to be the most active fractions which later yielded the two known compounds, myricetin 3-galactoside and quercetin 3-O-beta-galactopyronaside. The anti-melanogenic potential of the compounds were confirmed by their tyrosinase inhibitory effects. These results suggested that L. tetragonum may serve as a potential source of bioactive substances with effective anti-melanogenesis properties. PMID- 28872627 TI - EPuL: An Enhanced Positive-Unlabeled Learning Algorithm for the Prediction of Pupylation Sites. AB - Protein pupylation is a type of post-translation modification, which plays a crucial role in cellular function of bacterial organisms in prokaryotes. To have a better insight of the mechanisms underlying pupylation an initial, but important, step is to identify pupylation sites. To date, several computational methods have been established for the prediction of pupylation sites which usually artificially design the negative samples using the verified pupylation proteins to train the classifiers. However, if this process is not properly done it can affect the performance of the final predictor dramatically. In this work, different from previous computational methods, we proposed an enhanced positive unlabeled learning algorithm (EPuL) to the pupylation site prediction problem, which uses only positive and unlabeled samples. Firstly, we separate the training dataset into the positive dataset and the unlabeled dataset which contains the remaining non-annotated lysine residues. Then, the EPuL algorithm is utilized to select the reliably negative initial dataset and then iteratively pick out the non-pupylation sites. The performance of the proposed method was measured with an accuracy of 90.24%, an Area Under Curve (AUC) of 0.93 and an MCC of 0.81 by 10 fold cross-validation. A user-friendly web server for predicting pupylation sites was developed and was freely available at http://59.73.198.144:8080/EPuL. PMID- 28872629 TI - An Adaptive Low-Cost INS/GNSS Tightly-Coupled Integration Architecture Based on Redundant Measurement Noise Covariance Estimation. AB - The main objective of the introduced study is to design an adaptive Inertial Navigation System/Global Navigation Satellite System (INS/GNSS) tightly-coupled integration system that can provide more reliable navigation solutions by making full use of an adaptive Kalman filter (AKF) and satellite selection algorithm. To achieve this goal, we develop a novel redundant measurement noise covariance estimation (RMNCE) theorem, which adaptively estimates measurement noise properties by analyzing the difference sequences of system measurements. The proposed RMNCE approach is then applied to design both a modified weighted satellite selection algorithm and a type of adaptive unscented Kalman filter (UKF) to improve the performance of the tightly-coupled integration system. In addition, an adaptive measurement noise covariance expanding algorithm is developed to mitigate outliers when facing heavy multipath and other harsh situations. Both semi-physical simulation and field experiments were conducted to evaluate the performance of the proposed architecture and were compared with state-of-the-art algorithms. The results validate that the RMNCE provides a significant improvement in the measurement noise covariance estimation and the proposed architecture can improve the accuracy and reliability of the INS/GNSS tightly-coupled systems. The proposed architecture can effectively limit positioning errors under conditions of poor GNSS measurement quality and outperforms all the compared schemes. PMID- 28872628 TI - Copper Corrosion and Biocorrosion Events in Premise Plumbing. AB - Corrosion of copper pipes may release high amounts of copper into the water, exceeding the maximum concentration of copper for drinking water standards. Typically, the events with the highest release of copper into drinking water are related to the presence of biofilms. This article reviews this phenomenon, focusing on copper ingestion and its health impacts, the physicochemical mechanisms and the microbial involvement on copper release, the techniques used to describe and understand this phenomenon, and the hydrodynamic effects. A conceptual model is proposed and the mathematical models are reviewed. PMID- 28872630 TI - If these data could talk. AB - In the last few decades, data-driven methods have come to dominate many fields of scientific inquiry. Open data and open-source software have enabled the rapid implementation of novel methods to manage and analyze the growing flood of data. However, it has become apparent that many scientific fields exhibit distressingly low rates of reproducibility. Although there are many dimensions to this issue, we believe that there is a lack of formalism used when describing end-to-end published results, from the data source to the analysis to the final published results. Even when authors do their best to make their research and data accessible, this lack of formalism reduces the clarity and efficiency of reporting, which contributes to issues of reproducibility. Data provenance aids both reproducibility through systematic and formal records of the relationships among data sources, processes, datasets, publications and researchers. PMID- 28872631 TI - Electrically conductive pili from pilin genes of phylogenetically diverse microorganisms. AB - The possibility that bacteria other than Geobacter species might contain genes for electrically conductive pili (e-pili) was investigated by heterologously expressing pilin genes of interest in Geobacter sulfurreducens. Strains of G. sulfurreducens producing high current densities, which are only possible with e pili, were obtained with pilin genes from Flexistipes sinusarabici, Calditerrivibrio nitroreducens and Desulfurivibrio alkaliphilus. The conductance of pili from these strains was comparable to native G. sulfurreducens e-pili. The e-pili derived from C. nitroreducens, and D. alkaliphilus pilin genes are the first examples of relatively long (>100 amino acids) pilin monomers assembling into e-pili. The pilin gene from Candidatus Desulfofervidus auxilii did not yield e-pili, suggesting that the hypothesis that this sulfate reducer wires itself with e-pili to methane-oxidizing archaea to enable anaerobic methane oxidation should be reevaluated. A high density of aromatic amino acids and a lack of substantial aromatic-free gaps along the length of long pilins may be important characteristics leading to e-pili. This study demonstrates a simple method to screen pilin genes from difficult-to-culture microorganisms for their potential to yield e-pili; reveals new sources for biologically based electronic materials; and suggests that a wide phylogenetic diversity of microorganisms may use e-pili for extracellular electron exchange. PMID- 28872632 TI - AmphiBIO, a global database for amphibian ecological traits. AB - Current ecological and evolutionary research are increasingly moving from species to trait-based approaches because traits provide a stronger link to organism's function and fitness. Trait databases covering a large number of species are becoming available, but such data remains scarce for certain groups. Amphibians are among the most diverse vertebrate groups on Earth, and constitute an abundant component of major terrestrial and freshwater ecosystems. They are also facing rapid population declines worldwide, which is likely to affect trait composition in local communities, thereby impacting ecosystem processes and services. In this context, we introduce AmphiBIO, a comprehensive database of natural history traits for amphibians worldwide. The database releases information on 17 traits related to ecology, morphology and reproduction features of amphibians. We compiled data from more than 1,500 literature sources, and for more than 6,500 species of all orders (Anura, Caudata and Gymnophiona), 61 families and 531 genera. This database has the potential to allow unprecedented large-scale analyses in ecology, evolution, and conservation of amphibians. PMID- 28872633 TI - The role of policy in red blood cell storage and transfusion in children. PMID- 28872634 TI - Advancing The Cancer Genome Atlas glioma MRI collections with expert segmentation labels and radiomic features. AB - Gliomas belong to a group of central nervous system tumors, and consist of various sub-regions. Gold standard labeling of these sub-regions in radiographic imaging is essential for both clinical and computational studies, including radiomic and radiogenomic analyses. Towards this end, we release segmentation labels and radiomic features for all pre-operative multimodal magnetic resonance imaging (MRI) (n=243) of the multi-institutional glioma collections of The Cancer Genome Atlas (TCGA), publicly available in The Cancer Imaging Archive (TCIA). Pre operative scans were identified in both glioblastoma (TCGA-GBM, n=135) and low grade-glioma (TCGA-LGG, n=108) collections via radiological assessment. The glioma sub-region labels were produced by an automated state-of-the-art method and manually revised by an expert board-certified neuroradiologist. An extensive panel of radiomic features was extracted based on the manually-revised labels. This set of labels and features should enable i) direct utilization of the TCGA/TCIA glioma collections towards repeatable, reproducible and comparative quantitative studies leading to new predictive, prognostic, and diagnostic assessments, as well as ii) performance evaluation of computer-aided segmentation methods, and comparison to our state-of-the-art method. PMID- 28872635 TI - Comprehensive analyses of somatic TP53 mutation in tumors with variable mutant allele frequency. AB - Somatic mutation of the tumor suppressor gene TP53 is reported in at least 50% of human malignancies. Most high-grade serous ovarian cancers (HGSC) have a mutant TP53 allele. Accurate detection of these mutants in heterogeneous tumor tissue is paramount as therapies emerge to target mutant p53. We used a Fluidigm Access ArrayTM System with Massively Parallel Sequencing (MPS) to analyze DNA extracted from 76 serous ovarian tumors. This dataset has been made available to researchers through the European Genome-phenome Archive (EGA; EGAS00001002200). Herein, we present analyses of this dataset using HaplotypeCaller and MuTect2 through the Broad Institute's Genome Analysis Toolkit (GATK). We anticipate that this TP53 mutation dataset will be useful to researchers developing and testing new software to accurately determine high and low frequency variant alleles in heterogeneous aneuploid tumor tissue. Furthermore, the analysis pipeline we present provides a valuable framework for determining somatic variants more broadly in tumor tissue. PMID- 28872636 TI - High resolution multibeam and hydrodynamic datasets of tidal channels and inlets of the Venice Lagoon. AB - Tidal channels are crucial for the functioning of wetlands, though their morphological properties, which are relevant for seafloor habitats and flow, have been understudied so far. Here, we release a dataset composed of Digital Terrain Models (DTMs) extracted from a total of 2,500 linear kilometres of high resolution multibeam echosounder (MBES) data collected in 2013 covering the entire network of tidal channels and inlets of the Venice Lagoon, Italy. The dataset comprises also the backscatter (BS) data, which reflect the acoustic properties of the seafloor, and the tidal current fields simulated by means of a high-resolution three-dimensional unstructured hydrodynamic model. The DTMs and the current fields help define how morphological and benthic properties of tidal channels are affected by the action of currents. These data are of potential broad interest not only to geomorphologists, oceanographers and ecologists studying the morphology, hydrodynamics, sediment transport and benthic habitats of tidal environments, but also to coastal engineers and stakeholders for cost effective monitoring and sustainable management of this peculiar shallow coastal system. PMID- 28872637 TI - Mechanisms of cognitive-behavioral therapy for obsessive-compulsive disorder involve robust and extensive increases in brain network connectivity. AB - Cognitive-behavioral therapy (CBT) is effective for obsessive compulsive disorder (OCD); however, little is understood about its mechanisms related to brain network connectivity. We examined connectivity changes from resting-state functional magnetic resonance imaging data pre-to-post-CBT in 43 OCD participants, randomized to receive either 4 weeks of intensive CBT or 4 weeks waitlist followed by 4 weeks of CBT, and 24 healthy controls before and after 4 weeks of no treatment. Network-based-statistic analysis revealed large-magnitude increases in OCD connectivity in eight networks. Strongest increases involved connectivity between the cerebellum and caudate/putamen, and between the cerebellum and dorsolateral/ventrolateral prefrontal cortices. Connectivity increases were associated with increased resistance to compulsions. Mechanisms of CBT may involve enhanced cross-network integration, both within and outside of classical cortico-striatal-thalamo-cortical regions; those involving cerebellar to striatal and prefrontal regions may reflect acquisition of new non-compulsive goal-directed behaviors and thought patterns. Our findings have implications for identifying targets for enhancing treatment efficacy and monitoring treatment progress. PMID- 28872638 TI - Modulation of defensive reactivity by GLRB allelic variation: converging evidence from an intermediate phenotype approach. AB - Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain's evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders. PMID- 28872639 TI - Gene expression associated with suicide attempts in US veterans. AB - According to a recent report from the Office of Suicide Prevention in the US Department of Veterans Affairs, veterans represent 8.5% of the US population, but account for 18% of all deaths from suicide. The aim of this study of psychiatric patients (n=39; 87% male) was to compare blood gene expression data from veterans with a history of one or more suicide attempts to veterans who had never attempted suicide. The attempter and non-attempter groups were matched for age and race/ethnicity, and both groups included veterans with a diverse psychiatric history that included posttraumatic stress disorder (PTSD) and substance-use disorders. Veterans were interviewed for lifetime psychiatric history, including a detailed assessment of prior suicide attempts and provided a blood sample. Results of Ingenuity Pathway Analysis (IPA) identified several pathways associated with suicide attempts, including the mammalian target of rapamycin (mTOR) and WNT signaling pathways. These pathways are of particular interest, given their role in explaining pharmacological treatments for suicidal behavior, including the use of ketamine and lithium. These results suggest that findings observed in civilians are also relevant for veterans and provide a context for interpreting results observed in post-mortem samples. In conclusion, an emerging body of work that shows consistency in findings across blood and brain samples suggests that it might be possible to identify molecular predictors of suicide attempts. PMID- 28872640 TI - Nectin-3 modulates the structural plasticity of dentate granule cells and long term memory. AB - Nectin-3, a cell adhesion molecule enriched in hippocampal neurons, has been implicated in stress-related cognitive disorders. Nectin-3 is expressed by granule cells in the dentate gyrus (DG), but it remains unclear whether nectin-3 in DG modulates the structural plasticity of dentate granule cells and hippocampus-dependent memory. In this study, we found that DG nectin-3 expression levels were developmentally regulated and reduced by early postnatal stress exposure in adult mice. Most importantly, knockdown of nectin-3 levels in all DG neuron populations by adeno-associated virus (AAV) mimicked the cognitive effects of early-life stress, and impaired long-term spatial memory and temporal order memory. Moreover, AAV-mediated DG nectin-3 knockdown increased the density of doublecortin-immunoreactive differentiating cells under proliferation and calretinin-immunoreactive immature neurons, but markedly decreased calbindin immunoreactivity, indicating that nectin-3 modulates the differentiation and maturation of adult-born DG granule cells. Using retrovirus to target newly generated DG neurons, we found that selective nectin-3 knockdown in new DG neurons also impaired long-term spatial memory. In addition, suppressing nectin-3 expression in new DG neurons evoked a reduction of dendritic spines, especially thin spines. Our data indicate that nectin-3 expressed in DG neurons may modulate adult neurogenesis, dendritic spine plasticity and the cognitive effects of early life stress. PMID- 28872642 TI - Climatologies at high resolution for the earth's land surface areas. AB - High-resolution information on climatic conditions is essential to many applications in environmental and ecological sciences. Here we present the CHELSA (Climatologies at high resolution for the earth's land surface areas) data of downscaled model output temperature and precipitation estimates of the ERA Interim climatic reanalysis to a high resolution of 30 arc sec. The temperature algorithm is based on statistical downscaling of atmospheric temperatures. The precipitation algorithm incorporates orographic predictors including wind fields, valley exposition, and boundary layer height, with a subsequent bias correction. The resulting data consist of a monthly temperature and precipitation climatology for the years 1979-2013. We compare the data derived from the CHELSA algorithm with other standard gridded products and station data from the Global Historical Climate Network. We compare the performance of the new climatologies in species distribution modelling and show that we can increase the accuracy of species range predictions. We further show that CHELSA climatological data has a similar accuracy as other products for temperature, but that its predictions of precipitation patterns are better. PMID- 28872644 TI - Self-assembly behaviour of hetero-nuclear Janus dumbbells. AB - We investigate the fluid structure and self-assembly of a system of Janus dumbbells by means of aggregation-volume-bias Monte Carlo simulations and Simulated Annealing techniques. In our approach, Janus dumbbells model asymmetric colloidal particles constituted by two tangent (touching) spheres (labelled as h and s) of different sizes and interaction properties: specifically, the h spheres interact with all other spheres belonging to different dumbbells via hard-sphere potentials, whereas two s spheres interact via a square-well potential. By introducing a parameter alpha ? [0,2] that controls the size ratio between the h and s spheres, we are able to investigate the overall phase behaviour of Janus dumbbells as a function of alpha. In a previous paper (O'Toole et al., Soft Matter, 2017, 13, 803) we focused on the region where the s sphere is larger than the h sphere (alpha > 1), documenting the presence of a variety of phase behaviours. Here we investigate a different regime of size ratios, predominantly where the hard sphere is larger than (or comparable to) the attractive one. Under these conditions, we observe the onset of many different self-assembled super structures. Depending on the specific value of alpha we document the presence of spherical clusters (micelles) progressively evolving into more exotic structures including platelets, filaments, networks and percolating fluids, sponge structures and lamellar phases. We find no evidence of a gas-liquid phase separation for alpha <= 1.1, since under these conditions it is pre-empted by the development of self-assembled phases. PMID- 28872641 TI - Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes. AB - The risk of schizophrenia is increased in offspring whose mothers experience malnutrition during pregnancy. Polyunsaturated fatty acids (PUFAs) are dietary components that are crucial for the structural and functional integrity of neural cells, and PUFA deficiency has been shown to be a risk factor for schizophrenia. Here, we show that gestational and early postnatal dietary deprivation of two PUFAs-arachidonic acid (AA) and docosahexaenoic acid (DHA)-elicited schizophrenia like phenotypes in mouse offspring at adulthood. In the PUFA-deprived mouse group, we observed lower motivation and higher sensitivity to a hallucinogenic drug resembling the prodromal symptoms in schizophrenia. Furthermore, a working memory task-evoked hyper-neuronal activity in the medial prefrontal cortex was also observed, along with the downregulation of genes in the prefrontal cortex involved in oligodendrocyte integrity and the gamma-aminobutyric acid (GABA) ergic system. Regulation of these genes was mediated by the nuclear receptor genes Rxr and Ppar, whose promoters were hyper-methylated by the deprivation of dietary AA and DHA. In addition, the RXR agonist bexarotene upregulated oligodendrocyte- and GABA-related gene expression and suppressed the sensitivity of mice to the hallucinogenic drug. Notably, the expression of these nuclear receptor genes were also downregulated in hair-follicle cells from schizophrenia patients. These results suggest that PUFA deficiency during the early neurodevelopmental period in mice could model the prodromal state of schizophrenia through changes in the epigenetic regulation of nuclear receptor genes. PMID- 28872643 TI - Tropism of engineered and evolved recombinant AAV serotypes in the rd1 mouse and ex vivo primate retina. AB - There is much debate on the adeno-associated virus (AAV) serotype that best targets specific retinal cell types and the route of surgical delivery intravitreal or subretinal. This study compared three of the most efficacious AAV vectors known to date in a mouse model of retinal degeneration (rd1 mouse) and macaque and human retinal explants. Green fluorescent protein (GFP) driven by a ubiquitous promoter was packaged into three AAV capsids: AAV2/8(Y733F), AAV2/2(quad Y-F) and AAV2/2(7m8). Overall, AAV2/2(7m8) transduced the largest area of retina and resulted in the highest level of GFP expression, followed by AAV2/2(quad Y-F) and AAV2/8(Y733F). AAV2/2(7m8) and AAV2/2(quad Y-F) both resulted in similar patterns of transduction whether they were injected intravitreally or subretinally. AAV2/8(Y733F) transduced a significantly smaller area of retina when injected intravitreally compared with subretinally. Retinal ganglion cells, horizontal cells and retinal pigment epithelium expressed relatively high levels of GFP in the mouse retina, whereas amacrine cells expressed low levels of GFP and bipolar cells were infrequently transduced. Cone cells were the most frequently transduced cell type in macaque retina explants, whereas Muller cells were the predominant transduced cell type in human retinal explants. Of the AAV serotypes tested, AAV2/2(7m8) was the most effective at transducing a range of cell types in degenerate mouse retina and macaque and human retinal explants. PMID- 28872645 TI - Water-stable Eu-MOF fluorescent sensors for trivalent metal ions and nitrobenzene. AB - Two novel Eu metal-organic frameworks (MOFs), namely {[Eu2(pdba)3(H2O)3].2H2O}n (1) and {[Eu3(pdba)4(H2O)4].5H2O}n (2), were prepared with 4'-(1H-pyrazol-3-yl) [1,1'-biphenyl]-3,5-dicarboxylic acid (H2pdba) under hydrothermal conditions. MOF 1 exhibits a 3D supramolecular structure assembled from the pipi interactions between the benzene rings of the ligands, whereas 2 comprises a 3D structure through coordination connection between nitrogen atom and Eu3+. It is worth noting that the two MOFs showed good luminescence performance and high sensitivity fluorescence quenching behavior toward Fe3+ (Cr3+) and nitrobenzene. Furthermore, the experimental results for stability in water and cycle test show that these two MOFs can be used as potential fluorescent probes. PMID- 28872646 TI - The impact of ionic liquids on the coordination of anions with solvatochromic copper complexes. AB - Solvatochromic transition metal (TM)-complexes with weakly associating counter anions are often used to evaluate traditional neutral solvent and anion coordination ability. However, when employed in ionic liquids (IL) many of the common assumptions made are no longer reliable. This study investigates the coordinating ability of weakly coordinating IL anions in traditional solvents and within IL solvents employing a range of solvatochromic copper complexes. Complexes of the form [Cu(acac)(tmen)][X] (acac = acetylacetonate, tmen = tetramethylethylenediamine) where [X]- = [ClO4]-, Cl-, [NO3]-, [SCN]-, [OTf]-, [NTf2]- and [PF6]- have been synthesised and characterised both experimentally and computationally. ILs based on these anions and imidazolium and pyrrolidinium cations, some of which are functionalised with hydroxyl and nitrile groups, have been examined. IL-anion coordination has been investigated and compared to typical weakly coordinating anions. We have found there is potential for competition at the Cu-centre and cases of anions traditionally assigned as weakly associating that demonstrate a stronger than expected level of coordinating ability within ILs. [Cu(acac)(tmen)][PF6] is shown to contain the least coordinating anion and is established as the most sensitive probe studied here. Using this probe, the donor numbers (DNs) of ILs have been determined. Relative donor ability is further confirmed based on the UV-Vis of a neutral complex, [Cu(sacsac)2] (sacsac = dithioacetylacetone), and DNs evaluated via23Na NMR spectroscopy. We demonstrate that ILs can span a wide donor range, similar in breadth to conventional solvents. PMID- 28872647 TI - Rapid and high-efficiency discrimination of different sialic acid species using dipeptide-based fluorescent sensors. AB - A series of dipeptide-based fluorescent sensors were developed that exhibit sensitive and distinct responses to six typical sialic acid (SA) species despite the interference of 300-fold d-glucose or other saccharides, thus contributing to a novel fluorescence sensing matrix allowing the rapid and high-efficiency discrimination of different SA species. PMID- 28872648 TI - MicroRNAs regulate the main events in rice drought stress response by manipulating the water supply to shoots. AB - MicroRNAs (miRNAs) are small endogenous regulatory RNAs that are involved in a variety of biological processes related to proliferation, development, and response to biotic and abiotic stresses. miRNA profiles of rice (Oryza sativa L. cv. IR64.) leaves in a partial root zone drying (PRD) system were analysed using a high-throughput sequencing approach to identify miRNAs associated with drought signalling. The treatments performed in this study were as follows: well-watered ("wet" roots, WW), wherein both halves of the pot were watered daily; drought ("dry" roots, DD), wherein water was withheld from both halves of the pot; and well-watered/drought ("wet" and "dry" roots, WD), wherein one half of each pot was watered daily, the same as in WW, and water was withheld from the other part, the same as in DD. High-throughput sequencing enabled us to detect novel miRNAs and study the differential expression of known miRNAs. A total of 209 novel miRNAs were detected in this study. Differential miRNA profiling of the DD, WD and WW conditions showed differential expression of 159 miRNAs, among which 83, 44 and 32 miRNAs showed differential expression under both DD and WD conditions. The detection of putative targets of the differentially expressed miRNAs and investigation of their functions showed that most of these genes encode transcription factors involved in growth and development, leaf morphology, regulation of hormonal homeostasis, and stress response. The most important differences between the DD and WD conditions involved regulation of the levels of hormones such as auxin, cytokinin, abscisic acid, and jasmonic acid and also regulation of phosphor homeostasis. Overall, differentially expressed miRNAs under WD conditions were found to differ from those under DD conditions, with such differences playing a role in adaptation and inducing the normal condition. The mechanisms involved in regulating hormonal homeostasis and involved in energy production and consumption were found to be the most important regulatory pathways distinguishing the DD and WD conditions. PMID- 28872649 TI - Effect of alloying on thermal conductivity and thermoelectric properties of CoAsS and CoSbS. AB - The effect of alloying on the thermoelectric properties of cobaltite, CoAsS, and paracostibite, CoSbS, has been investigated in this study. Density functional theory and the Boltzmann transport equation have been applied to explore the role of phonon-phonon scattering and atomistic scattering due to alloying in phonon transport. An almost 44% reduction in thermal conductivity of CoAs0.8Sb0.2S alloy compared to pure CoAsS and an ~15% reduction in thermal conductivity of CoAs0.2Sb0.8S compared to pure CoSbS were found. Simultaneously, the thermoelectric (TE) figure of merit (ZT) increased by ~11% in p-type CoAs0.8Sb0.2S alloy and ~8% in n-type CoAs0.2Sb0.8S alloy as compared to their base pure materials at 800 K. We found that by tuning the composition of CoAsxSb(1-x)S alloy, very similar ZT values for both p-type and n-type can be achieved in a large temperature range. We also calculated the TE properties of CoAsSe(1-x)Sx and CoSbS(1-x)Sex alloys. This study will help in designing CoAsxSb(1-x)S based alloys for efficient thermoelectric devices. PMID- 28872650 TI - ? AB - Prenatal first trimester fetal diagnosis in Sweden today and in the future The combined first trimester test for detection of trisomy 21 has been available in Sweden the last 10 years but the uptake among pregnant women is still less than 50% and varies largely between different regions. The non-invasive prenatal test (NIPT) has been introduced and is currently recommended to be used as a secondary test only in those women who have an increased risk following the combined test. With falling costs for NIPT and a general offer of this test as a primary screening tool to all women there is concern that the first trimester ultrasound scan will be abandoned. There are however many arguments for retaining the scan and use this examination to clarify unclear NIPT results, detect major structural malformations, date pregnancies, determine chorionicity in twins and predict and treat preeclampsia already in the first trimester. PMID- 28872651 TI - ? AB - Organisation of health care for families with young children with autism in a multiethnic community in Gothenburg, Sweden In a project in a multiethnic district in Gothenburg a local collaborative model with a multiprofessional team for families with young children with autism has been running for three years. The model allows assessments and intervention planning close to the family's local environment. The project has revealed that the time from identification of problems to assessment and intervention has been considerably shortened compared to the situation before the local collaborative model was started. PMID- 28872652 TI - ? AB - Routine pregnancy ultrasound scans can detect malformations. Multidisciplinary care of both the foetus and parent is required following diagnosed malformations In Sweden, all women are invited to at least one ultrasound examination during pregnancy. The "Routine ultrasound screening" is usually performed by a midwife around 18 weeks of gestation. There are several aims of the examination: to check viability, to detect multiple fetuses, to determine the location of the placenta, to check the amount of amniotic fluid, to estimate the date of delivery (if this had not been done earlier) and to detect structural fetal malformations. It is important to offer an adequate education for all providers and assure the quality of the examinations. Nationwide courses are offered once or twice a year, and as a goal, all providers should have a "certificate of competence" for this kind of examination. When a fetal malformation is suspected, confirmed after further investigations and the prospective parents decide to continue the pregnancy, multidisciplinary care is offered in cooperation with or at a university hospital. PMID- 28872653 TI - ? PMID- 28872654 TI - ? AB - Floorball - a common cause of sport related eye injury The aim of this study was to survey the incidence and type of sport related to eye injuries with special interest in floorball. A prospective study was conducted December 1st 2013 through November 30th 2014 at the Department of Ophthalmology, Orebro University Hospital. All patients presenting with an acute sports related eye injury were offered to be included. Information was collected from a self-administered questionnaire and from medical journals. During the study period, 49 patients sought care for sports related eye injuries, and 26 (53%) of those were related to floorball. The number of patients who agreed to take part in the study was 38, of which 25 had injuries related to floorball. Among the floorball players, there were two patients where the injury caused permanent vision impairment. None of the floorball players wore eye protection at the time of injury. According to this study, protective eyewear should be recommended when playing floorball, regardless of age or setting. PMID- 28872655 TI - ? AB - Fetal Cardiology. Experiences from a tertiary referral centre in Stockholm, Sweden This review provides a brief overview of the current position and clinical experiences of fetal cardiology at a tertiary referral centre in Stockholm, Sweden. In Stockholm, more than 60% of congenital cardiac defects requiring surgery or catheter intervention before one year of age are detected before birth. This not only results in termination of pregnancy in the majority of cases carrying a poor prognosis, but also conveys a better postnatal care and prognosis in cases of continued pregnancy. Almost all mechanisms generating fetal arrhythmias are elucidated using Doppler techniques, and arrhythmia treatment is preferably given in utero. Prenatal fetal echocardiography also provides the diagnostic tool necessary to detect and follow treatment of extracardiac conditions associated with fetal heart failure. PMID- 28872656 TI - Comparison of hand use and forelimb posture during vertical climbing in mountain gorillas (Gorilla beringei beringei) and chimpanzees (Pan troglodytes). AB - OBJECTIVES: Studies on grasping and limb posture during arboreal locomotion in great apes in their natural environment are scarce and thus, attempts to correlate behavioral and habitat differences with variation in morphology are limited. The aim of this study is to compare hand use and forelimb posture during vertical climbing in wild, habituated mountain gorillas (Gorilla beringei beringei) and semi-free-ranging chimpanzees (Pan troglodytes) to assess differences in the climbing styles that may relate to variation in hand or forelimb morphology and body size. MATERIALS AND METHODS: We investigated hand use and forelimb posture during both ascent and descent vertical climbing in 15 wild mountain gorillas and eight semi-free-ranging chimpanzees, using video records obtained ad libitum. RESULTS: In both apes, forelimb posture was correlated with substrate size during both ascent and descent climbing. While climbing, both apes used power grips and diagonal power grips, including three different thumb postures. Mountain gorillas showed greater ulnar deviation of the wrist during vertical descent than chimpanzees, and the thumb played an important supportive role when gorillas vertically descended lianas. DISCUSSION: We found that both apes generally had the same grip preferences and used similar forelimb postures on supports of a similar size, which is consistent with their overall similarity in hard and soft tissue morphology of the hand and forelimb. However, some species-specific differences in morphology appear to elicit slightly different grasping strategies during vertical climbing between mountain gorillas and chimpanzees. PMID- 28872657 TI - How intention and monitoring your thoughts influence characteristics of autobiographical memories. AB - Involuntary autobiographical memories come to mind effortlessly and unintended, but the mechanisms of their retrieval are not fully understood. We hypothesize that involuntary retrieval depends on memories that are highly accessible (e.g., intense, unusual, recent, rehearsed), while the elaborate search that characterizes voluntary retrieval also produces memories that are mundane, repeated or distant - memories with low accessibility. Previous research provides some evidence for this 'threshold hypothesis'. However, in almost every prior study, participants have been instructed to report only memories while ignoring other thoughts. It is possible that such an instruction can modify the phenomenological characteristics of involuntary memories. This study aimed to investigate the effects of retrieval intentionality (i.e., wanting to retrieve a memory) and selective monitoring (i.e., instructions to report only memories) on the phenomenology of autobiographical memories. Participants were instructed to (1) intentionally retrieve autobiographical memories, (2) intentionally retrieve any type of thought (3) wait for an autobiographical memory to spontaneously appear, or (4) wait for any type of thought to spontaneously appear. They rated the mental content on a number of phenomenological characteristics both during retrieval and retrospectively following retrieval. The results support the prediction that highly accessible memories mostly enter awareness unintended and without selective monitoring, while memories with low accessibility rely on intention and selective monitoring. We discuss the implications of these effects. PMID- 28872659 TI - It is ethical to recommend against assisted reproductive treatment for women with a high body mass index. PMID- 28872658 TI - Evidence of hysteresis in propofol pharmacodynamics. AB - It is commonly assumed that loss of responsiveness and recovery of responsiveness occur at similar concentrations of propofol. However, the 'conscious' and 'anaesthetised' conditions produced by general anaesthetics may behave as two bistable states. We hypothesised that loss of responsiveness and recovery of responsiveness occur at different propofol concentrations. Propofol was administered to 19 healthy volunteers by effect-site target-controlled infusion using increasing and decreasing stable concentration steps of 7 min. Propofol serum concentrations were measured from venous blood samples at the end of each 7 min step. A long step of 14 min was performed at loss of responsiveness. At this step, propofol concentrations were measured at 7 and 14 min. Propofol concentrations measured at loss of responsiveness and recovery of responsiveness were 2.6 (1.2-4.7) MUg.ml-1 and 1.6 (0.6-3.3) MUg.ml-1 , respectively (p < 0.001). Propofol plasma concentration and the corresponding bispectral index values measured at minute 7 and minute 14 of the long step performed at loss of responsiveness were 2.6 (1.2-4.7) vs. 2.6 (1.3-4.3) at recovery of responsiveness, (p = 0.96) and 61.2 (49.0-77.0) vs. 58.4 (45.0-74.0), (p = 0.058), respectively. Loss of responsiveness and recovery of responsiveness appear to occur at different propofol concentrations. However, it is possible that, if equilibration was not achieved between plasma and effect-sites at the end of each 7-min step, the higher concentrations found at loss of responsiveness compared with those observed during recovery of responsiveness could be explained by a possible bias in estimations of the effect-site concentrations of propofol by the Schnider model, rather than neural inertia. PMID- 28872660 TI - Fabricating PLGA microparticles with high loads of the small molecule antioxidant N-acetylcysteine that rescue oligodendrocyte progenitor cells from oxidative stress. AB - Reactive oxygen species (ROS), encompassing all oxygen radical or non-radical oxidizing agents, play key roles in disease progression. Controlled delivery of antioxidants is therapeutically relevant in such oxidant-stressed environments. Encapsulating small hydrophilic molecules into hydrophobic polymer microparticles via traditional emulsion methods has long been a challenge due to rapid mass transport of small molecules out of particle pores. We have developed a simple alteration to the existing water-in-oil-in-water (W/O/W) drug encapsulation method that dramatically improves loading efficiency: doping external water phases with drug to mitigate drug diffusion out of the particle during fabrication. PLGA microparticles with diameters ranging from 0.6 to 0.9 micrometers were fabricated, encapsulating high loads of 0.6-0.9 um diameter PLGA microparticles were fabricated, encapsulating high loads of the antioxidant N acetylcysteine (NAC), and released active, ROS-scavenging NAC for up to 5 weeks. Encapsulation efficiencies, normalized to the theoretical load of traditional encapsulation without doping, ranged from 96% to 400%, indicating that NAC-loaded external water phases not only prevented drug loss due to diffusion, but also doped the particles with additional drug. Antioxidant-doped particles positively affected the metabolism of oligodendrocyte progenitor cells (OPCs) under H2 O2 mediated oxidative stress when administered both before (protection) or after (rescue) injury. Antioxidant doped particles improved outcomes of OPCs experiencing multiple doses of H2 O2 by increasing the intracellular glutathione content and preserving cellular viability relative to the injury control. Furthermore, antioxidant-doped particles preserve cell number, number of process extensions, cytoskeletal morphology, and nuclear size of H2 O2 -stressed OPCs relative to the injury control. These NAC-doped particles have the potential to provide temporally-controlled antioxidant therapy in neurodegenerative disorders such as multiple sclerosis (MS) that are characterized by continuous oxidative stress. PMID- 28872661 TI - The Kent Face Matching Test. AB - This study presents the Kent Face Matching Test (KFMT), which comprises 200 same identity and 20 different-identity pairs of unfamiliar faces. Each face pair consists of a photograph from a student ID card and a high-quality portrait that was taken at least three months later. The test is designed to complement existing resources for face-matching research, by providing a more ecologically valid stimulus set that captures the natural variability that can arise in a person's appearance over time. Two experiments are presented to demonstrate that the KFMT provides a challenging measure of face matching but correlates with established tests. Experiment 1 compares a short version of this test with the optimized Glasgow Face Matching Test (GFMT). In Experiment 2, a longer version of the KFMT, with infrequent identity mismatches, is correlated with performance on the Cambridge Face Memory Test (CFMT) and the Cambridge Face Perception Test (CFPT). The KFMT is freely available for use in face-matching research. PMID- 28872662 TI - Current options in aerosolised drug therapy for children receiving respiratory support. AB - Inhalation of aerosolised medications are the mainstay of treatment for a number of chronic lung diseases and have several advantages over systemically administered medications. These include more rapid onset of action for drugs such as beta-adrenergic agonists when compared with oral medication, high luminal doses for inhaled antibiotics when used to treat endobronchial infection, and an improved therapeutic index compared with systemic delivery for these and other classes of drugs such as corticosteroids. The use of aerosolised drugs to treat patients whose tracheas are intubated is less well established, in part because systemic delivery via the intravenous route can be a simpler alternative for many drugs. Consequently, research in this area is largely limited to a number of in vitro studies and very few clinical trials. Unfortunately, a lack of focus in this area has resulted in a number of practices which at best are ineffective, and at worst dangerous for the patient. Although there have been some attempts to re-invigorate research in order to improve delivery systems, current devices are, to a great extent, based on long-standing technology developed more than 50 years ago. In this review, we explore current knowledge and provide guidance as to when and how the inhaled route may be of value when treating patients whose tracheas are intubated, and we set out the challenges facing those attempting to advance the topic. We conclude by reviewing current areas of interest that may lead to more effective and widespread use of aerosols in the treatment of intubated patients. PMID- 28872663 TI - Quality of life in patients with vitiligo using the Short Form-36. PMID- 28872664 TI - Middle cerebral artery Doppler reference centile charts for the prediction of fetal anemia in a population from India. AB - OBJECTIVE: To construct reference charts for the fetal middle cerebral artery (MCA) peak systolic velocity (PSV,) and the corresponding cord blood hemoglobin values at 24-40 weeks of pregnancy for the identification of fetal anemia. METHODS: In a cross-sectional study, 300 women with a pregnancy duration of 24-40 weeks planned for delivery within 72 hours underwent a Doppler study of the MCA and cord blood hemoglobin estimation at delivery. Regression analysis was used to construct reference charts. The validity of the charts was assessed in 40 fetuses from Rhesus-isoimmunized pregnancies. RESULTS: The MCA PSV and hemoglobin values increased with advancing gestational age. Multiples of the median (MOM) were calculated and reference charts were constructed for mild anemia (MCA PSV 1.29 MOM; hemoglobin 0.8 MOM), moderate anemia (MCA PSV 1.50 MOM; hemoglobin 0.6 MOM), and severe anemia (MCA PSV 1.55 MOM; hemoglobin 0.5 MOM). In the validation sample, the hemoglobin value estimated on the basis of the MCA PSV corresponded with the actual hemoglobin range in 90% of the fetuses. The sensitivity was 92% and the specificity was 95%. CONCLUSION: The constructed charts are suitable for the evaluation of fetal anemia in the regional population. PMID- 28872665 TI - Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease. AB - Cathelicidin peptide LL-37 plays an important role in the early host response against invading pathogens via its broad-spectrum anti-microbial activity. In this study, we investigated LL-37 expression in the inflamed mucosa of inflammatory bowel disease (IBD) patients. Furthermore, the regulatory mechanism of LL-37 induction was investigated in human colonic subepithelial myofibroblasts (SEMFs). LL-37 mRNA expression and protein secretion were analysed using real time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Intracellular signalling pathways were analysed using immunoblotting and specific small interference RNA (siRNA). The expression of LL 37 mRNA was increased significantly in the inflamed mucosa of ulcerative colitis and Crohn's disease. The Toll-like receptor (TLR)-3 ligand, polyinosinic polycytidylic acid (poly(I:C), induced LL-37 mRNA expression and stimulated LL-37 secretion in colonic SEMFs. The transfection of siRNAs specific for intracellular signalling proteins [Toll/IL-1R domain-containing adaptor-inducing interferon (IFN) (TRIF), tumour necrosis factor receptor-associated factor (TRAF)6, transforming growth factor beta-activated kinase (TAK)1] suppressed the poly(I:C) induced LL-37 mRNA expression significantly. Poly(I:C)-induced phosphorylation of mitogen-activated protein kinases (MAPKs) and activated nuclear factor kappa B (NF-kappaB) and activating factor protein (AP)-1. siRNAs specific for NF-kappaB and c-Jun inhibited poly(I:C)-induced LL-37 mRNA expression. LL-37 suppressed lipopolysaccharide (LPS)-induced interleukin (IL)-6 and IL-8 expression significantly in colonic SEMFs. The expression of LL-37 was up-regulated in the inflamed mucosa of IBD patients. LL-37 was induced by TLR-3 stimulation and exhibited an anti-microbial effect via interaction with lipopolysaccharide (LPS). PMID- 28872666 TI - Active dissemination of cellular antigens by DCs facilitates CD8+ T-cell priming in lymph nodes. AB - Antigen (Ag) specific activation of naive T cells by migrating dendritic cells (DCs) is a highly efficient process, although the chances for their colocalization in lymph nodes (LNs) appear low. Ag presentation may be delegated from Ag-donor DCs to the abundant resident DCs, but the routes of Ag transfer and how it facilitates T-cell activation remain unclear. We visualized CD8+ T cell-DC interactions to study the sites, routes, and cells mediating Ag transfer in mice. In vitro, Ag transfer from isolated ovalbumin (OVA)+ bone marrow (BM) DCs triggered widespread arrest, Ca2+ flux, and CD69 upregulation in OT-I T cells contacting recipient DCs. Intravital two-photon imaging revealed that survival of Ag-donor DCs in LNs was required for Ag dissemination among resident CD11c+ DCs. Upon interaction with recipient DCs, CD8+ T cells clustered, upregulated CD69, proliferated and differentiated into effectors. Few DCs sufficed for activation, and for efficient Ag dissemination lymphocyte function associated antigen 1 (LFA 1) expression on recipient DCs was essential. Similar findings characterized DCs infected with a replication-deficient OVA-expressing Vaccinia virus known to downregulate MHC-I. Overall, active Ag dissemination from live incoming DCs helped activate CD8+ T cells by increasing the number of effective presenting cells and salvaged T-cell priming when Ag-donor DCs could not present Ag. PMID- 28872667 TI - Cognitive and neuroimaging findings in developmental coordination disorder: new insights from a systematic review of recent research. AB - AIM: To better understand the neural and performance factors that may underlie developmental coordination disorder (DCD), and implications for a multi-component account. METHOD: A systematic review of the experimental literature published between June 2011 and September 2016 was conducted using a modified PICOS (population, intervention, comparison, outcomes, and study type) framework. A total of 106 studies were included. RESULTS: Behavioural data from 91 studies showed a broad cluster of deficits in the anticipatory control of movement, basic processes of motor learning, and cognitive control. Importantly, however, performance issues in DCD were often shown to be moderated by task type and difficulty. As well, we saw new evidence of compensatory processes and strategies in several studies. Neuroimaging data (15 studies, including electroencephalography) showed reduced cortical thickness in the right medial orbitofrontal cortex and altered brain activation patterns across functional networks involving prefrontal, parietal, and cerebellar regions in children with DCD than those in comparison groups. Data from diffusion-weighted magnetic resonance imaging suggested reduced white matter organization involving sensorimotor structures and altered structural connectivity across the whole brain network. INTERPRETATION: Taken together, results support the hypothesis that children with DCD show differences in brain structure and function compared with typically developing children. Behaviourally, these differences may affect anticipatory planning and reduce automatization of movement skill, prompting greater reliance on slower feedback-based control and compensatory strategies. Implications for future research, theory development, and clinical practice are discussed. PMID- 28872668 TI - Efficacy of oral pharmacological treatments in dyskinetic cerebral palsy: a systematic review. AB - AIM: To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP). METHOD: A systematic review was performed according to the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Articles were searched for in PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, Database of Reviews of Effectiveness, OTSeeker, Physiotherapy Evidence Database, REHABDATA, and ClinicalTrials.gov. RESULTS: Sixteen articles met the eligibility criteria. Eight studies on trihexyphenidyl and two on levodopa showed contradictory results. Low efficacy was reported for diazepam, dantrolene sodium, perphenazine, and etybenzatropine. Tetrabenazine, gabapentin and levetiracetam should be studied in more detail. The updated available evidence does not support any therapeutic algorithm for the management of dyskinetic CP. INTERPRETATION: This lack of evidence is partially owing to the inconsistency of classifications of patients and of outcome measures used in the reviewed studies. Further randomized, double blind, placebo-controlled pharmacological trials, optimized for different age groups, based on valid, reliable, and disease-specific rating scales are strongly needed. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health. WHAT THIS PAPER ADDS: Evidence to prove (or disprove) the efficacy of oral drugs in dyskinetic cerebral palsy is low. The most investigated drugs, trihexyphenidyl and levodopa, show contradictory results. Tetrabenazine, levetiracetam, and gabapentin efficacy should be studied in more detail. Lack of evidence is partially due to the inconsistency of classifications and outcome measures used. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health in next clinical trials. PMID- 28872669 TI - GPCR signalling from within the cell. AB - : Traditionally, signal transduction from GPCRs is thought to emanate from the cell surface where receptor interactions with external stimuli can be transformed into a broad range of cellular responses. However, emergent data show that numerous GPCRs are also associated with various intracellular membranes where they may couple to different signalling systems, display unique desensitization patterns and/or exhibit distinct patterns of subcellular distribution. Although many GPCRs can be activated at the cell surface and subsequently endocytosed and transported to a unique intracellular site, other intracellular GPCRs can be activated in situ either via de novo ligand synthesis, diffusion of permeable ligands or active transport of nonpermeable ligands. Current findings reinforce the notion that intracellular GPCRs play a dynamic role in various biological functions including learning and memory, contractility and angiogenesis. As new intracellular GPCR roles are defined, the need to selectively tailor agonists and/or antagonists to both intracellular and cell surface receptors may lead to the development of more effective therapeutic tools. LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc. PMID- 28872670 TI - TCR-pMHC encounter differentially regulates transcriptomes of tissue-resident CD8 T cells. AB - To investigate the role of TCR-pMHC interaction in regulating lung CD8 tissue resident T cell (TR ) differentiation, polyclonal responses were compared against NP366-374 /Db and PA224-233 /Db , two immunodominant epitopes that arise during influenza A infection in mice. Memory niches distinct from iBALTs develop within the lamina propria, supporting CD103+ and CD103- CD8 TR generation and intraepithelial translocation. Gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis (WGCNA) identify dominant TCR, adherens junction, RIG-I-like and NOD-like pattern recognition receptor as well as TGF beta signaling pathways and memory signatures among PA224-233 /Db T cells consistent with T resident memory (TRM ) status. In contrast, NP366-374 /Db T cells exhibit enrichment of effector signatures, upregulating pro-inflammatory mediators even among TRM . While NP366-374 /Db T cells manifest transcripts linked to canonical exhaustion pathways, PA224-233 /Db T cells exploit P2rx7 purinoreceptor attenuation. The NP366-374 /Db CD103+ subset expresses the antimicrobial lactotransferrin whereas PA224-233 /Db CD103+ utilizes pore-forming mpeg-1, with <22% of genes correspondingly upregulated in CD103+ (or CD103- ) subsets of both specificities. Thus, TCR-pMHC interactions among TR and antigen presenting cells in a tissue milieu strongly impact CD8 T cell biology. PMID- 28872672 TI - The Longitudinal Effects of Early Language Intervention on Children's Problem Behaviors. AB - Researchers examined whether a parent-implemented language intervention improved problem behaviors 1 year after intervention. Ninety-seven children with language delays (mean age at 12-month follow-up = 48.22 months) were randomized to receive Enhanced Milieu Teaching (EMT) language intervention or business as usual treatment. Twelve months after the intervention ended, children in the EMT intervention condition displayed lower rates of parent-reported externalizing, internalizing, and total problem behaviors. A mediation analysis revealed that the relation between EMT and problem behaviors was partially mediated by child rate of communication for both internalizing and total problem behaviors. A developmental framework is proposed to explain the impact of EMT on problem behaviors, and future lines of research are discussed. PMID- 28872673 TI - Direction of dependence in measurement error models. AB - Methods to determine the direction of a regression line, that is, to determine the direction of dependence in reversible linear regression models (e.g., x->y vs. y->x), have experienced rapid development within the last decade. However, previous research largely rested on the assumption that the true predictor is measured without measurement error. The present paper extends the direction dependence principle to measurement error models. First, we discuss asymmetric representations of the reliability coefficient in terms of higher moments of variables and the attenuation of skewness and excess kurtosis due to measurement error. Second, we identify conditions where direction dependence decisions are biased due to measurement error and suggest method of moments (MOM) estimation as a remedy. Third, we address data situations in which the true outcome exhibits both regression and measurement error, and propose a sensitivity analysis approach to determining the robustness of direction dependence decisions against unreliably measured outcomes. Monte Carlo simulations were performed to assess the performance of MOM-based direction dependence measures and their robustness to violated measurement error assumptions (i.e., non-independence and non normality). An empirical example from subjective well-being research is presented. The plausibility of model assumptions and links to modern causal inference methods for observational data are discussed. PMID- 28872671 TI - Wnt7a induces a unique phenotype of monocyte-derived macrophages with lower phagocytic capacity and differential expression of pro- and anti-inflammatory cytokines. AB - The variation of macrophage functions suggests the involvement of multiple signalling pathways in fine tuning their differentiation. Macrophages that originate from monocytes in the blood migrate to tissue in response to homeostatic or 'danger' signals and undergo substantial morphological and functional modifications to meet the needs of the dominant signals in the microenvironment. Wnts are secreted glycoproteins that play a significant role in organ and cell differentiation, yet their impact on monocyte differentiation is not clear. In this study, we assessed the role of Wnt1 and Wnt7a on the differentiation of monocytes and the subsequent phenotype and function of monocyte-derived macrophages (MDMs). We show that Wnt7a decreased the expression of CD14, CD11b, CD163 and CD206, whereas Wnt1 had no effect. The Wnt7a effect on CD11b was also observed in the brain and spleen of Wnt7a-/- adult brain mouse tissue and in embryonic Wnt7a-/- tissue. Wnt7a reduced the phagocytic capacity of M-MDMs, decreased interleukin-10 (IL-10) and IL-12 secretion and increased IL-6 secretion. Collectively, these findings demonstrate that Wnt7a generates an MDM phenotype with both pro-inflammatory and alternative MDM cytokine profiles and reduced phagocytic capacity. As such, Wnt7a can have a significant impact on macrophage responses in health and disease. PMID- 28872674 TI - The methylazoxymethanol acetate rat model: molecular and epigenetic effect in the developing prefrontal cortex: An Editorial Highlight for 'Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia' on page 320. AB - This Editorial highlights an article by Gulchina and colleagues in the current issue of the Journal of Neurochemistry, in which the authors describe molecular and epigenetic changes in the developing prefrontal cortex of the rats exposed to methylazoxymethanol acetate (MAM). They found an NMDAR hypofunction present in the prefrontal cortex of juvenile MAM rats which was associated with abnormal epigenetic regulation of the Grin2b gene. These changes may be related to early cognitive impairments observed in MAM rats and schizophrenia patients. PMID- 28872675 TI - Language and reading comprehension in middle childhood predicts emotional and behaviour difficulties in adolescence for those with permanent childhood hearing loss. AB - BACKGROUND: Permanent childhood hearing loss (PCHL) is associated with an elevated level of emotional and behaviour difficulties (EBD). In children and adolescents with PCHL, EBD has been found to be linked to language ability in children with PCHL. The present study was designed to test whether childhood language and/or reading comprehension abilities of children with PCHL predict subsequent EBD in adolescence. METHODS: Language comprehension (LC) and reading comprehension (RC) were measured at ages 6-10 years (Time 1) and 13-20 years (Time 2) in participants with PCHL who preferred to communicate using spoken language (n = 57) and a hearing comparison group (n = 38). EBD was measured at both time points by parent and by teacher ratings on the Strengths and Difficulties Questionnaire. RESULTS: Within the PCHL group there were negative correlations between EBD scores and concurrent LC and RC scores at Time 1 and at Time 2. Cross-lagged latent variable models fitted to the longitudinal data indicated that the associations between LC, RC and teacher-rated EBD were more likely to arise from the impact of LC and RC on behaviour rather than the other way around. CONCLUSIONS: In those with PCHL, poor language and reading comprehension in middle childhood increased the risk of emotional and behaviour difficulties at school in the teenage years. The results suggest that effective language and literacy interventions for children with hearing loss may also bring benefits to their mental health. PMID- 28872676 TI - Beliefs About Stress Attenuate the Relation Among Adverse Life Events, Perceived Distress, and Self-Control. AB - Prior research has shown that adverse events in the lives of adolescents precipitate psychological distress, which in turn impairs self-control. This study (N = 1,343) examined the protective effects of stress mindsets-beliefs about the extent to which stress might be beneficial or strictly detrimental. The results confirmed that increasing the number of adverse life events across the school year predicted rank order increases in perceived distress, which in turn predicted rank order decreases in self-control. Adolescents who believed in the potential benefits of stress were less prone to feeling stressed in the wake of adverse life events. These findings suggest that changing the way adolescents think about stress may help protect them from acting impulsively when confronted with adversity. PMID- 28872677 TI - Immunogenicity assessment during the development of protein therapeutics. AB - OBJECTIVE: Here we provide a critical review of the state of the art with respect to non-clinical assessments of immunogenicity for therapeutic proteins. KEY FINDINGS: The number of studies on immunogenicity published annually has more than doubled in the last 5 years. The science and technology, which have reached a critical mass, provide multiple of non-clinical approaches (computational, in vitro, ex vivo and animal models) to first predict and then to modify or eliminate T-cell or B-cell epitopes via de-immunization strategies. We discuss how these may be used in the context of drug development in assigning the immunogenicity risk of new and marketed therapeutic proteins. SUMMARY: Protein therapeutics represents a large share of the pharma market and provide medical interventions for some of the most complex and intractable diseases. Immunogenicity (the development of antibodies to therapeutic proteins) is an important concern for both the safety and efficacy of protein therapeutics as immune responses may neutralize the activity of life-saving and highly effective protein therapeutics and induce hypersensitivity responses including anaphylaxis. The non-clinical computational tools and experimental technologies that offer a comprehensive and increasingly accurate estimation of immunogenic potential are surveyed here. This critical review also discusses technologies which are promising but are not as yet ready for routine use. PMID- 28872678 TI - Characterization and pharmacokinetic study of itraconazole solid dispersions prepared by solvent-controlled precipitation and spray-dry methods. AB - OBJECTIVES: Solid dispersion formulations have attracted attention to improve solubility and bioavailability of water-insoluble drugs. In this study, the variation of solubility and bioavailability by different preparation methods were studied using itraconazole (ITZ) solid dispersions. METHODS: Itraconazole solid dispersions were prepared by a solvent-controlled precipitation method (SCPM) using HPMCAS-LF, HCl antisolvent or a spray-drying method (SDM) for comparison. Dissolution tests by pH transition and pharmacokinetic study using male Sprague Dawley rats were conducted. KEY FINDINGS: Itraconazole solid dispersion dissolution tests by pH transition exhibited better dissolution compared to naive ITZ, limited dissolution in acidic conditions and a burst release at neutral pH. The ITZ solid dispersions by SCPM indicated a smaller-sized particle dispersion, limited dissolution at acidic pH and a higher release at neutral pH compared to those by SDM, suggesting that the increased protonation of anionic polymers and HPMCAS-LF by acidic antisolvent could form a tighter hydrophobic aggregation with ITZ in solid dispersions. ITZ solid dispersion prepared by SCPM also showed improved ITZ absorption in male Sprague Dawley rats compared to SDM and naive ITZ. CONCLUSIONS: This study suggests that the SCPM method can be widely used for solid dispersion preparations due to improved dissolution and PK profile. PMID- 28872679 TI - Potential use of multispectral imaging technology to identify moisture content and water-holding capacity in cooked pork sausages. AB - BACKGROUND: The traditional detection methods for moisture content (MC) and water holding capacity (WHC) in cooked pork sausages (CPS) are destructive, time consuming, require skilled personnel and are not suitable for online industry applications. The goal of this work was to explore the potential of multispectral imaging (MSI) in combination with multivariate analysis for the identification of MC and WHC in CPS. RESULTS: Spectra and textures of 156 CPS treated by six salt concentrations (0-2.5%) were analyzed using different calibration models to find the most optimal results of predicting MC and WHC in CPS. By using the fused data of spectra and textures, partial least squares regression models performed well for determining the MC and WHC, with a correlation coefficient (r) of 0.949 and 0.832, respectively. Additionally, their spatial distribution in CPS could be visualized via applying prediction equations to transfer each pixel in the image. CONCLUSION: Results of satisfactory detection and visualization of the MC and WHC showed that MSI has the potential to serve as a rapid and non-destructive method for use in sausage industry. (c) 2017 Society of Chemical Industry. PMID- 28872681 TI - Development of a direct contact astrocyte-human cerebral microvessel endothelial cells blood-brain barrier coculture model. AB - OBJECTIVES: In conventional in-vitro blood-brain barrier (BBB) models, primary and immortalized brain microvessel endothelial cell (BMEC) lines are often cultured in a monolayer or indirect coculture or triculture configurations with astrocytes or pericytes, for screening permeation of therapeutic or potentially neurotoxic compounds. In each of these cases, the physiological relevancy associated with the direct contact between the BMECs, pericytes and astrocytes that form the BBB and resulting synergistic interactions are lost. We look to overcome this limitation with a direct contact coculture model. METHODS: We established and optimized a direct interaction coculture system where primary human astrocytes are cultured on the apical surface of a Transwell(r) filter support and then human cerebral microvessel endothelial cells (hCMEC/D3) seeded directly on the astrocyte lawn. KEY FINDINGS: The studies suggest the direct coculture model may provide a more restrictive and physiologically relevant model through a significant reduction in paracellular transport of model compounds in comparison with monoculture and indirect coculture. In comparison with existing methods, the indirect coculture and monoculture models utilized may limit cell cell signaling between human astrocytes and BMECs that are possible with direct configurations. CONCLUSIONS: Paracellular permeability reductions with the direct coculture system may enhance therapeutic agent and potential neurotoxicant screening for BBB permeability better than the currently available monoculture and indirect coculture in-vitro models. PMID- 28872680 TI - Current and novel anti-inflammatory drug targets for inhibition of cytokines and leucocyte recruitment in rheumatic diseases. AB - OBJECTIVES: Many studies of disease state mechanisms reveal that unbridled inflammation is to blame for many of the symptoms associated with autoimmune diseases such as Crohn's and Rheumatoid Arthritis (RA). While therapies aimed at decreasing levels of pro-inflammatory cytokines exist, some have failed clinically or have extensive adverse effects. The aim of this review is to discuss common drug targets for anti-inflammatory therapies as well as explore potential mechanisms of action for new therapies. Various studies done on novel mechanisms targeting pro-inflammatory cytokine release as well as leukocyte chemotaxis have been researched for discussion here. Both of these contribute to tissue injury and patient symptoms in inflammatory and autoimmune disease states. KEY FINDINGS: While many current drug targets suppress inflammation via the receptor, research aimed at identifying new compounds and signaling mechanisms is ongoing to identify new targets within pro-inflammatory signaling pathways, or specific immune cell types. CONCLUSIONS: While glucocorticoids and monoclonal antibodies have shown to be efficacious, some patients have encountered mixed results. Biologic therapies also come with a high price tag Thus, novel compounds with new immune drug targets are ideal for patients whose therapies have not been successful. PMID- 28872682 TI - beta-2-himachalen-6-ol protects against skin cancer development in vitro and in vivo. AB - BACKGROUND: Previous studies in our laboratory showed that Daucus carota oil extract (DCOE) possesses remarkable in-vitro anticancer activity and antitumour promoting effect against DMBA/TPA skin carcinogenesis in mice. Chemical analysis of DCOE led to the isolation of the beta-2-himachalen-6-ol (HC), major sesquiterpene with a potent anticancer activity against various colon, breast, brain and skin cancer cells. This study investigated the anticancer activity of HC against invasive epidermal squamous cell carcinoma cells and evaluated its effect in a DMBA/TPA skin carcinogenesis Balb/c murine model. METHODS: HaCaT-ras II-4 epidermal squamous cells were treated with HC (1, 5, 10, 25 and 50 MUg/ml), and cell viability was evaluated with WST 1 assay kit. Cell cycle analysis was carried out by flow cytometry, and pro/anti-apoptotic proteins were measured using Western blot. The effect of topical and intraperitoneal (IP) treatment with HC in mice was assessed using the DMBA/TPA skin carcinogenesis model. Cisplatin (2.5 mg/kg; IP) was used as a positive control. Papilloma incidence, yield and volume were monitored, and isolated papillomas were assessed for their pro/anti apoptotic proteins and morphology. RESULTS: beta-2-himachalen-6-ol showed a dose dependent decrease in cell survival with an IC50 and IC90 of 8 and 30 MUg/ml, respectively. Flow cytometry analysis revealed that treatment with 10 MUg/ml HC significantly increased the number of cells undergoing late apoptosis (28%), while 25 MUg/ml caused a larger cell shift towards late apoptosis (46.6%) and necrosis (39%). A significant decrease in protein levels of p53 and Bcl-2 and a significant increase in p21 and Bax were observed. Also, there was a significant decrease in p-Erk and p-Akt protein levels. The treatment of mice (IP and topical) with HC caused a significant decrease in papilloma yield, incidence and volume. Similar effects were observed with cisplatin treatment, but HC-treated groups exhibited twofold to threefold increase in survival rates. Similar patterns in the pro- and anti-apoptotic proteins were observed in mice treated with HC, except for a significant increase in p53 protein. CONCLUSIONS: In conclusion, HC treatment induced cell cycle arrest (low dose) and promoted apoptosis partly via inhibition of the MAPK/ERK and PI3K/AKT pathways with no significant toxicity to laboratory mice. PMID- 28872683 TI - Phytochemistry and pharmacological potential of Cassia absus - a review. AB - OBJECTIVES: Cassia absus is a plant of the family fabaceae with Ayurvedic ethnomedical records. It is used in traditional medicine for the treatment of bronchitis, asthma, cough, conjunctivitis, leucoderma, renal and hepatic diseases, constipation, tumors, venereal ulcer, headache, hemorrhoids and wound healing. Preliminary in vitro and in vivo studies have provided valuable scientific evidence for its use. This review aims to summarize reported pharmacognosy, traditional uses, phytochemistry and pharmacological potential of C. absus while identifying potential areas of further research of plant. KEY FINDINGS: The review comprises literature pertaining to the evidence base therapeutic potential, pharmacognosy and phytochemistry of C. absus spanning from 1935 to 2016 using published articles in peer-reviewed journals, ethno botanical text books, and worldwide accepted scientific databases via electronic search (Elsevier, Google Scholar, PubMed, Scopus, Springer, Web of Science, Wiley online library). Kew Botanical Garden databases and the Plant List were used to authenticate the scientific names. Different pharmacological experiments in many in-vitro and in-vivo models have proved the potential of C. absus with antihypertensive, antifertility, antifungal, anti-inflammatory, anti hyperglycemic, anti-glycation, antibacterial activity, alpha- amylase inhibitory activity, antioxidant and reducing activitity etc. chaksine, iso-chaksine, saturated and unsaturated fatty acids, chrysophanol, aloe-emodin and a wide range of chemical compounds have also been reported. Toxicity studies reveal the nontoxic nature of C. absus at a dose of 2000 mg/kg, however, plant possess reproductive toxicity and can be used as birth control or abortifacient. SUMMARY: Reported activities suggest that there is sufficient pharmacological potential for developing C. absus as a drug for hypertension, infections, diabetes and its complications. However, heterogeneity in study protocol and conflicting results mask the ability to replicate these studies. So, future studies should be replicated in line with best practices. More toxicological studies would aid the progress to clinical trial studies. Various ethno medical uses of C. absus have not been evaluated yet. PMID- 28872684 TI - New perspectives on the development of extrahepatic portosystemic shunts. AB - In this essay we use clinical evidence and knowledge of anatomy to examine the relationship between blood flow and formation of congenital extrahepatic portosystemic shunts in dogs and cats. First we report on the clinical findings in a series of 50 dogs and 10 cats and then systematically review peer-reviewed data on the detailed anatomy of shunts in dogs and cats. In dogs four types of shunt: spleno-caval, left gastro-phrenic, left gastro-azygos and those involving the right gastric vein account for 94% of extrahepatic shunts. Cats also exhibit four types of shunt: spleno-caval, left gastrophrenic, left gastro-caval and left gastro-azygos, and the first three of these account for 92% shunts in this species. Our findings lead us to propose that preferential blood flow influences the subsequent formation of one of a number of defined and consistent congenital extrahepatic portosystemic shunts in dogs and cats. PMID- 28872685 TI - Inactivation of Babesia microti in red blood cells and platelet concentrates. AB - BACKGROUND: With an increasing number of recognized transfusion-transmitted (TT) babesiosis cases, Babesia microti is the most frequently TT parasite in the United States. We evaluated the inactivation of B. microti in red blood cells (RBCs) prepared in Optisol (AS-5) using amustaline and glutathione (GSH) and in platelet components (PCs) in 100% plasma using amotosalen and low-energy ultraviolet A (UVA) light. STUDY DESIGN AND METHODS: Individual RBCs and apheresis PCs were spiked with B. microti-infected hamster RBCs (iRBCs) to a final concentration of 106 iRBCs/mL and treated with the respective inactivation systems according to the manufacturer's instruction. Samples were collected before (control) and after (test) each treatment. Dilutions of the control samples to 10-6 were inoculated into hamsters, while the test samples were inoculated neat or at 10-1 dilution. At 3 and 5 weeks postinoculation, hamsters were evaluated for B. microti infection by microscopic observation of blood smears and 50% infectivity titers (ID50 ) were determined. Log reduction was calculated as control log ID50 minus test log ID50 . RESULTS: Parasitemia was detected in hamsters injected with as low as 100,000-fold diluted control samples, while no parasites were detectable in the blood smears of any hamsters receiving neat test samples. Mean log reduction was more than 5 log/mL by amustaline/GSH for RBCs and more than 4.5 log/mL by amotosalen/UVA for PCs. CONCLUSION: B. microti was inactivated to the limit of detection in RBCs and PCs after the respective inactivation treatment. Complete inactivation of B. microti was achieved in this animal infectivity model, and pathogen reduction treatment inhibited transmission of infection. PMID- 28872686 TI - Weak bones in diabetes mellitus - an update on pharmaceutical treatment options. AB - OBJECTIVES: Diabetes mellitus is often associated with a number of complications such as nephropathy, neuropathy, retinopathy and foot ulcers. However, weak bone is a diabetic complication that is often overlooked. Although the exact mechanism for weak bones within diabetes mellitus is unclear, studies have shown that the mechanism does differ in both type I (T1DM) and type II diabetes (T2DM). This review, however, investigates the application of mesenchymal stem cells, recombinant human bone morphogenetic protein-2, teriparatide, insulin administration and the effectiveness of a peroxisome proliferator-activated receptor-Upsilon modulator, netoglitazone in the context of diabetic weak bones. KEY FINDINGS: In T1DM, weak bones may be the result of defective osteoblast activity, the absence of insulin's anabolic effects on bone, the deregulation of the bone-pancreas negative feedback loop and advanced glycation end product (AGE) aggregation within the bone matrix as a result of hyperglycaemia. Interestingly, T2DM patients placed on insulin administration, thiazolidinediones, SGLT2 inhibitors and sulfonylureas have an associated increased fracture risk. T2DM patients are also observed to have high sclerostin levels that impair osteoblast gene transcription, AGE aggregation within bone, which compromises bone strength and a decrease in esRAGE concentration resulting in a negative association with vertebral fractures. SUMMARY: Effective treatment options for weak bones in the context of diabetes are currently lacking. There is certainly scope for discovery and development of novel agents that could alleviate this complication in diabetes patients. PMID- 28872687 TI - Development of extended-release solid dispersion granules of tacrolimus: evaluation of release mechanism and human oral bioavailability. AB - OBJECTIVES: We aimed to prepare a once-daily modified-release oral formulation of tacrolimus by utilizing an extended-release granules (ERG). METHODS: Extended release granules were prepared using ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC) and lactose via a solvent evaporation method with ethanol. Physicochemical and biopharmaceutical studies were performed to determine the formulation with optimum release profile of tacrolimus from ERG. KEY FINDINGS: Tacrolimus existed in an amorphous state in ERG. Tacrolimus release from ERG was attenuated by EC and facilitated by lactose, suggesting that drug release kinetics could adequately be regulated by these components. Those release profiles were consistent with Higuchi's equation, suggesting a diffusion-type release mechanism. Smooth surface of ERG changed to the structure with pores after the release test, likely derived from the dissolution of HPMC and lactose. But ERG structure formed by EC was still maintained after the release test, leading to the longer maintenance of diffusion-type release. Two ERG formulations selected by blood concentration simulation successfully provided long-term retention of tacrolimus in blood in a human absorption study. CONCLUSIONS: We successfully developed the formulation exhibiting a significant reduction in Cmax , the longer mean residence time and AUC close to that of an immediate-release tacrolimus formulation, being preferred from the viewpoint of safe and effective immunosuppressant pharmacotherapy. PMID- 28872688 TI - Liposomal alpha-galactosylceramide is taken up by gut-associated lymphoid tissue and stimulates local and systemic immune responses. AB - OBJECTIVES: alpha-Galactosylceramide (alpha-GalCer), a synthetic glycosphingolipid that exhibits potent immunostimulatory effects through activation of natural killer T (NKT) cells, can be used to treat conditions such as atopy, cancer, infection and autoimmunity. Administration of therapeutics through the oral route has advantages such as patient convenience, safety and reduced cost; however, there has been little research to investigate whether oral delivery of alpha-GalCer is possible. The aim of this study was therefore to determine whether alpha-GalCer formulated in either DMSO/Tween 80 or in liposomes, could access lymphoid tissue and stimulate immune activation following oral administration. METHODS: Fluorescently labelled cationic liposomes incorporating alpha-GalCer were prepared, characterized and administered by oral gavage to fasted mice. KEY FINDINGS: Liposomes were detected inside the Peyer's patches (PPs), in the subepithelial dome just under the follicle-associated epithelium. CD11b+ cells and CD11c+ were shown to have taken up the formulation in a higher proportion compared to the total cell proportion in the PPs, suggesting that cells with these markers may be the prominent antigen-presenting cells involved in selective uptake. Finally, the liposomal formulation demonstrated a higher degree of immune stimulation compared to the DMSO/Tween 80 solubilized alpha-GalCer in the PPs, mesenteric lymph nodes and spleen as shown by the increased expression of IL-4 mRNA expression and increased proportion of NKT cells at 6 h and 3 days after administration. CONCLUSIONS: These results show that oral delivery of a liposomal alpha-GalCer can stimulate local and systemic immune responses to a different degree compared to the non-liposomal form. PMID- 28872689 TI - Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. AB - OBJECTIVES: Excessive exposure to acetaminophen (APAP, paracetamol) can cause liver injury through formation of a reactive metabolite that depletes hepatic glutathione and causes hepatocellular oxidative stress and damage. Generation of this metabolite is mediated by Cytochrome-P450 (CYP) isoforms, mainly CYP2E1. A number of naturally occurring flavonoids can mitigate APAP-induced hepatotoxicity in experimental animal models. Our objective was to determine the mechanism of these protective effects and to evaluate possible human applicability. METHODS: Two flavonoids, luteolin and quercetin, were evaluated as potential inhibitors of eight human CYP isoforms, of six UDP-glucuronosyltransferase (UGT) isoforms and of APAP glucuronidation and sulfation. The experimental model was based on in vitro metabolism by human liver microsomes, using isoform-specific substrates. KEY FINDINGS: Luteolin and quercetin inhibited human CYP isoforms to varying degrees, with greatest potency towards CYP1A2 and CYP2C8. However, 50% inhibitory concentrations (IC50 values) were generally in the micromolar range. UGT isoforms were minimally inhibited. Both luteolin and quercetin inhibited APAP sulfation but not glucuronidation. CONCLUSIONS: Inhibition of human CYP activity by luteolin and quercetin occurred with IC50 values exceeding customary in-vivo human exposure with tolerable supplemental doses of these compounds. The findings indicate that luteolin and quercetin are not likely to be of clinical value for preventing or treating APAP-induced hepatotoxicity. PMID- 28872690 TI - Parametric multistate survival models: Flexible modelling allowing transition specific distributions with application to estimating clinically useful measures of effect differences. AB - Multistate models are increasingly being used to model complex disease profiles. By modelling transitions between disease states, accounting for competing events at each transition, we can gain a much richer understanding of patient trajectories and how risk factors impact over the entire disease pathway. In this article, we concentrate on parametric multistate models, both Markov and semi Markov, and develop a flexible framework where each transition can be specified by a variety of parametric models including exponential, Weibull, Gompertz, Royston-Parmar proportional hazards models or log-logistic, log-normal, generalised gamma accelerated failure time models, possibly sharing parameters across transitions. We also extend the framework to allow time-dependent effects. We then use an efficient and generalisable simulation method to calculate transition probabilities from any fitted multistate model, and show how it facilitates the simple calculation of clinically useful measures, such as expected length of stay in each state, and differences and ratios of proportion within each state as a function of time, for specific covariate patterns. We illustrate our methods using a dataset of patients with primary breast cancer. User-friendly Stata software is provided. PMID- 28872691 TI - Reduce procedure time for cavotricuspid flutter ablation: What is the optimal catheter? PMID- 28872692 TI - Coomassie staining provides routine (sub)femtomole in-gel detection of intact proteoforms: Expanding opportunities for genuine Top-down Proteomics. AB - Modified colloidal Coomassie Brilliant Blue (cCBB) staining utilising a novel destain protocol and near-infrared fluorescence detection (nIRFD) rivals the in gel protein detection sensitivity (DS) of SYPRO Ruby. However, established DS estimates are likely inaccurate in terms of 2DE-resolved proteoform 'spots' since DS is routinely measured from comparatively diffuse protein 'bands' following wide-well 1DE. Here, cCBB DS for 2DE-based proteomics was more accurately determined using narrow-well 1DE. As precise estimates of protein standard monomer concentrations are essential for accurate quantitation, coupling UV absorbance with gel-based purity assessments is described. Further, as cCBB is compatible with both nIRFD and densitometry, the impacts of imaging method (and image resolution) on DS were assessed. Narrow-well 1DE enabled more accurate quantitation of cCBB DS for 2DE, achieving (sub)femtomole DS with either nIRFD or densitometry. While densitometry offers comparative simplicity and affordability, nIRFD has the unique potential for enhanced DS with Deep Imaging. Higher resolution nIRFD also improved analysis of a 2DE-resolved proteome, surpassing the DS of standard nIRFD and densitometry, with nIRFD Deep Imaging further maximising proteome coverage. cCBB DS for intact proteins rivals that of mass spectrometry (MS) for peptides in complex mixtures, reaffirming that 2DE-MS currently provides the most routine, broadly applicable, robust, and information rich Top-down approach to Discovery Proteomics. PMID- 28872693 TI - Modeling continuous response variables using ordinal regression. AB - We study the application of a widely used ordinal regression model, the cumulative probability model (CPM), for continuous outcomes. Such models are attractive for the analysis of continuous response variables because they are invariant to any monotonic transformation of the outcome and because they directly model the cumulative distribution function from which summaries such as expectations and quantiles can easily be derived. Such models can also readily handle mixed type distributions. We describe the motivation, estimation, inference, model assumptions, and diagnostics. We demonstrate that CPMs applied to continuous outcomes are semiparametric transformation models. Extensive simulations are performed to investigate the finite sample performance of these models. We find that properly specified CPMs generally have good finite sample performance with moderate sample sizes, but that bias may occur when the sample size is small. Cumulative probability models are fairly robust to minor or moderate link function misspecification in our simulations. For certain purposes, the CPMs are more efficient than other models. We illustrate their application, with model diagnostics, in a study of the treatment of HIV. CD4 cell count and viral load 6 months after the initiation of antiretroviral therapy are modeled using CPMs; both variables typically require transformations, and viral load has a large proportion of measurements below a detection limit. PMID- 28872694 TI - Alkaline extractive crude polysaccharide from Russula senecis possesses antioxidant potential and stimulates innate immunity response. AB - OBJECTIVES: Over past decades, investigation on bioactive polysaccharides extracted from mushroom by heated water reflux has been an emerging field of biomedicine especially in the area of immune stimulation. While studies with macromolecules isolated from remainder residue of aqueous extraction are scarce. In this context, crude polysaccharide from a traditionally edible macrofungus, Russula senecis, was prepared (RuseCap) by alkaline solvent using leftover residue of that conventional process and its structural along with therapeutic properties were evaluated. KEY FINDINGS: Investigation by FT-IR, HPTLC, GC-MS and spectrophotometry showed that the fraction was mainly consisted of carbohydrate with backbone of xylose, rhamnose, mannose and glucose (mostly beta-glucan). Besides, RuseCap exhibited strong antioxidant activity evident by radical scavenging (superoxide, hydroxyl, DPPH, ABTS), chelating ability and reduction power where EC50 values ranged from 257 to 4068 MUg/ml concentration. In addition, it also exhibited immune-boosting potentiality as the treatment effectively induced proliferation, phagocytosis, nitric oxide production, intracellular reactive oxygen species generation, morphological changes and increased transcription level of iNOS, COX-2, TNF-alpha, IL-6 genes in macrophage cells. CONCLUSIONS: Overall, the study provided blueprint for extended utilization of R. senecis basidiocarps beyond hot water process and defined use of RuseCap as potent therapeutic agent against free radicals as well as deprived immunity. PMID- 28872695 TI - Penalized estimation for proportional hazards models with current status data. AB - We provide a simple and practical, yet flexible, penalized estimation method for a Cox proportional hazards model with current status data. We approximate the baseline cumulative hazard function by monotone B-splines and use a hybrid approach based on the Fisher-scoring algorithm and the isotonic regression to compute the penalized estimates. We show that the penalized estimator of the nonparametric component achieves the optimal rate of convergence under some smooth conditions and that the estimators of the regression parameters are asymptotically normal and efficient. Moreover, a simple variance estimation method is considered for inference on the regression parameters. We perform 2 extensive Monte Carlo studies to evaluate the finite-sample performance of the penalized approach and compare it with the 3 competing R packages: C1.coxph, intcox, and ICsurv. A goodness-of-fit test and model diagnostics are also discussed. The methodology is illustrated with 2 real applications. PMID- 28872696 TI - The light cycle controls the hatching rhythm in Bombyx mori via negative feedback loop of the circadian oscillator. AB - Hatching behavior is a key target in silkworm (Bombyx mori) rearing, especially for the control of Lepidoptera pests. According to previous research, hatching rhythms appear to be controlled by a clock mechanism that restricts or "gates" hatching to a particular time. However, the underlying mechanism remains elusive. Under 12-h light:12-h dark photoperiod (LD) conditions, the transcriptional levels of the chitinase5 (Cht5) and hatching enzyme-like (Hel) genes, as well as the enzymatic activities of their gene products, oscillated in time with ambient light cycles, as did the transcriptional levels of the cryptochrome 1, cryptochrome 2, period (per), and timeless genes, which are key components of the negative feedback loop of the circadian rhythm. These changes were related to the expression profile of the ecdysteroid receptor gene and the hatching behavior of B. mori eggs. However, under continuous light or dark conditions, the hatching behavior, the expression levels of Cht5 and Hel, as well as the enzymatic activities of their gene products, were not synchronized unlike under LD conditions. In addition, immunohistochemistry experiments showed that light promoted the translocation of PER from the cytoplasm to the nucleus. In conclusion, LD cycles regulate the hatching rhythm of B. mori via negative feedback loop of the circadian oscillator. PMID- 28872697 TI - Perceived Barriers and Facilitators to Providing Methadone Maintenance Treatment Among Rural Community Pharmacists in Southwestern Ontario. AB - PURPOSE: Misuse of opioids has become a public health concern across North America. Rural patients have limited access to methadone maintenance treatment (MMT), an opioid addiction-treatment service that could be offered by community pharmacists. The aim of this study was to identify rural community pharmacists' perceived barriers, motivations, and solutions to offering MMT to their patients. METHODS: One-on-one, semistructured interviews were conducted with 11 community pharmacists who practice in rural southwestern Ontario. Interview transcripts were analyzed using inductive qualitative content analysis. FINDINGS: Increased workload, extended operating hours, and concerns about safety, theft, burglary, community resistance, and availability of methadone training courses were identified as pharmacist-related barriers to providing MMT services. Professional satisfaction and community service were primary motivations for offering the service. Limited pharmacy staff availability exacerbated concerns about increased workload and security. Slower rural emergency-response times were cited among safety concerns. Participating pharmacists felt that rural regions had fewer MMT prescribers and that rural community members had greater apprehension about addiction-treatment services than those in urban communities. Pharmacists proposed that coordinating MMT service provision across multiple community pharmacies in the region could help improve access to treatment among their patients. CONCLUSION: Rural community pharmacy practice has unique barriers to implementing and providing MMT services. A coordinated, multipharmacy approach may be an option to provide and expand MMT services in rural regions. PMID- 28872698 TI - A multivariate distance-based analytic framework for microbial interdependence association test in longitudinal study. AB - Human microbiome is the collection of microbes living in and on the various parts of our body. The microbes living on our body in nature do not live alone. They act as integrated microbial community with massive competing and cooperating and contribute to our human health in a very important way. Most current analyses focus on examining microbial differences at a single time point, which do not adequately capture the dynamic nature of the microbiome data. With the advent of high-throughput sequencing and analytical tools, we are able to probe the interdependent relationship among microbial species through longitudinal study. Here, we propose a multivariate distance-based test to evaluate the association between key phenotypic variables and microbial interdependence utilizing the repeatedly measured microbiome data. Extensive simulations were performed to evaluate the validity and efficiency of the proposed method. We also demonstrate the utility of the proposed test using a well-designed longitudinal murine experiment and a longitudinal human study. The proposed methodology has been implemented in the freely distributed open-source R package and Python code. PMID- 28872699 TI - Psychosocial Correlates of Ever Having a Pap Test and Abnormal Pap Results in a Sample of Rural Appalachian Women. AB - BACKGROUND: Despite known prevention and screening efforts, there are higher invasive cervical cancer rates in Appalachia than in other areas of the United States and higher mortality rates in the Appalachian region of Kentucky compared to Appalachian regions of other states. PURPOSE: The primary purpose of this study was to investigate the association of psychosocial factors relevant to cervical cancer and the outcome of ever having a Pap test in a rural sample of women. The secondary purpose was to determine whether any of the same psychosocial factors were also associated with ever having an abnormal Pap test result among women with a self-reported history of having one or more Pap tests in their lifetime. METHODS: Data were collected in fall of 2013 from 393 women in 8 economically distressed counties of rural Appalachian Kentucky. Women completed an interviewer-administered survey assessing sociodemographic and health information as well as beliefs about cervical cancer. FINDINGS: Multivariate logistic regression results indicated that low income and greater perceived local fatalism were significant predictors of never having a Pap test. Lack of personal control over prevention, and peer and family influences were significant predictors of ever having an abnormal Pap test result. CONCLUSIONS: Educational efforts targeted in rural Appalachia would be supported by encouraging the benefits of early and consistent screening, altering the established norms of community fatalism and lack of personal control over prevention, and creating targeted messages through public campaigns that convince rural Appalachian women that cervical cancer is highly preventable and screenable. PMID- 28872700 TI - Optimal procedural sequence for same-day bidirectional endoscopy with moderate sedation: A prospective randomized study. AB - BACKGROUND AND AIM: Same-day bidirectional endoscopy (BDE) is a commonly performed procedure, but the optimal sequence for the procedure with moderate conscious sedation is not well established. This study investigated the optimal sequence for same-day BDE under moderate conscious sedation and carbon dioxide insufflation in terms of sedation doses, patient discomfort, and colonoscopy performance. METHODS: A prospective randomized controlled study of 120 patients who were scheduled for BDE examination was performed. Colonoscopy followed by esophagogastroduodenoscopy (EGD) examination was performed in 60 patients (colonoscopy-EGD group), and EGD followed by colonoscopy examination was performed in another 60 patients (EGD-colonoscopy group). Endoscopists and patients completed a questionnaire to assess objective and subjective discomfort. RESULTS: Baseline demographics, procedure indications, bowel preparation quality, cecal intubation rate/time, colonoscopy withdrawal time, endoscopic interventions, BDE procedure time, colon polyp/adenoma detection rates, patient discomfort, and adverse events were similar between the two study groups. The total doses of fentanyl and midazolam were significantly higher for the colonoscopy-EGD group than for the EGD-colonoscopy group (83.4 +/- 17.7 vs 68.7 +/- 18.6 MUg and 6.3 +/- 1.4 vs 5.2 +/- 1.3 mg, P < 0.0001 and P < 0.0001, respectively). The recovery time to discharge was significantly longer for the colonoscopy-EGD group than for the EGD-colonoscopy group (43.5 +/- 16.2 vs 34.5 +/- 8.9 min, P = 0.0003). CONCLUSIONS: Esophagogastroduodenoscopy followed by colonoscopy is the optimal sequence for same-day BDE under moderate conscious sedation and carbon dioxide insufflation. Following this order allows for a reduction of sedation doses and for shorter recovery times. PMID- 28872701 TI - Natural history of pancreatic cystic lesions: A multicenter prospective observational study for evaluating the risk of pancreatic cancer. AB - BACKGROUND AND AIM: The aim of this study is to elucidate the natural history of pancreatic cystic lesions (PCLs), including branch duct-type intraductal papillary mucinous neoplasm (BD-IPMN), via midterm follow-up analysis of a multicenter prospective observational study (NSPINAL study). METHODS: From July 2011 to October 2016, 881 patients with PCLs were enrolled in NSPINAL study, and 664 patients with > 12 months of follow up were analyzed. Every patient was asymptomatic, and endoscopic ultrasound was performed at the initial diagnosis to exclude high-risk individuals. Follow up included endoscopic ultrasound, computed tomography, or magnetic resonance imaging at least once a year. Serial morphological changes and the pancreatic cancer (PC) incidence, including malignant progression of PCLs, were evaluated. RESULTS: The 664 patients (358 men) were followed for a median of 33.5 months (interquartile range 29). The cyst and main pancreatic duct sizes were 16.6 +/- 9.3 and 2.3 +/- 1.0 mm, respectively. Morphologically, 518 cases were multilocular, 137 were unilocular, and 9 had a honeycomb pattern; 269 cases involved multifocal lesions. Ninety-six patients (14.5%) showed worsening progression on imaging. There were two resectable and four unresectable cases of pancreatic ductal adenocarcinoma and three cases of malignant BD-IPMN. The 3-year risk of developing PC was 1.2%. The standardized incidence ratio for PC among PCLs was 10.0 (95% confidence interval 3.5-16.5), and the standardized incidence ratio among BD-IPMN was 16.6 (95% confidence interval 5.1-28.1). Multivariate analysis showed that development of symptoms and worsening progression were significant predictors of PC. CONCLUSIONS: Malignant progression of PCLs, including PC development, is not uncommon. Patients with PCLs should be carefully monitored to detect pancreatic ductal adenocarcinoma at early stages. PMID- 28872702 TI - Enhancement of l-phenylalanine production in Escherichia coli by heterologous expression of Vitreoscilla hemoglobin. AB - l-Phenylalanine is an important amino acid that is widely used in the production of food flavors and pharmaceuticals. Generally, l-phenylalanine production by engineered Escherichia coli requires a high rate of oxygen supply. However, the coexpression of Vitreoscilla hemoglobin gene (vgb), driven bya tac promoter, with the genes encoding 3-deoxy-d-arabinoheptulosonate-7-phosphate synthetase (aroF) and feedback-resistant chorismate mutase/prephenate dehydratase (pheAfbr ), led to increased productivity and decreased demand for aeration by E. coli CICC10245. Shake-flask studies showed that vgb-expressing strains displayed higher rates of oxygen uptake, and l-phenylalanine production under standard aeration conditions was increased. In the aerobic fermentation process, cell growth, l-phenylalanine production, and glucose consumption by the recombinant E. coli strain PAPV, which harbored aroF, pheAfbr , and tac-vgb genes, were increased compared to that in the strain harboring only aroF and pheAfbr (E. coli strain PAP), especially under oxygen-limited conditions. The vgb-expressing strain PAPV produced 21.9% more biomass and 16.6% more l-phenylalanine, while consuming only approximately 5% more glucose after 48 H of fermentation. This study demonstrates a method to enhance the l-phenylalanine production by E. coli using less intensive and thus more economical aeration conditions. PMID- 28872703 TI - Evaluation of beta-Aminocarboxylic Acid Derivatives in Hippocampal Excitatory Synaptic Transmission. AB - beta-Aminocarboxylic acid derivatives (LINS04 series) were screened with the aim to explore their potential functional role in excitatory synaptic transmission in the central nervous system. We used field recordings in rat hippocampal slices to investigate the effects of the LINS04 series on the synaptic transmission at hippocampal CA1 synapses. We found that LINS04008 and LINS04009 increase the size of the evoked field excitatory postsynaptic potential (EPSP) in a dose-dependent manner. The concentration-response curve shows that the efficacy of LINS04008 is highest in the series (EC50 = 91.32 uM; maximum fEPSP 44.97%). The esters LINS04006 and LINS04005 did not affect the synaptic evoked activity. These data provide the first evidence of synaptic activity enhancement by these compounds and the importance of the acidic group to the activity. This set of data may provide direction for a strategic procedure to restore the glutamate synaptic transmission; however, further studies are needed to establish a more complete picture of how these molecules act on the glutamate transmission, which are in our mind for the next steps. PMID- 28872704 TI - Design, Synthesis, and Biological Evaluation of New Peptide Analogues as Selective COX-2 Inhibitors. AB - A new class of peptide derivatives possessing SO2 Me and N3 pharmacophores at the para position of a phenyl ring bound to different aromatic amino acids were synthesized based on solid-phase synthesis methodology, and evaluated as selective cyclooxygenase-2 (COX-2) inhibitors. One of the analogues, i.e., compound 2a as the representative of this series, was recognized as the highest selective COX-2 inhibitor with a COX-2 selectivity index of >500. The structure activity relationships (SARs) acquired indicated that compound 2a containing a 4 (methylsulfonyl)benzoyl group as a pharmacophore and tyrosine as a ring bearing amino acid in the second position and glutamic acid as the C-terminal amino acid can give the essential geometry to provide selective COX-2 inhibitory activity. Antiproliferative activity of the synthesized peptides (1a-7b) was also determined against four different human cancer cell lines, including MCF-7, HepG2, A549, and HeLa. According to our results, A549, HepG2, and MCF7 seemed to be more sensitive cell lines than HeLa cells encountering these compounds, which gave inhibitory action with IC50 values from 4.8 to 64.4 uM. In this regard, compounds 3a and 2b displayed the best inhibitory activity against the cell lines. Moreover, a good correlation was observed between the antiproliferative potency and the COX-2 inhibitory activity of compounds 1a, 2a, 2b, and 5b. Such findings suggest that one of the mechanism of anticancer activity of these peptides may be through the COX-2 inhibitory action. PMID- 28872705 TI - Heat stress hardening of oriental armyworms is induced by a transient elevation of reactive oxygen species during sublethal stress. AB - Pre-exposure to mild heat stress enhances the thermotolerance of insects. Stress hardening is a beneficial physiological plasticity, but the mechanism underlying it remains elusive. Here we report that reactive oxygen species (ROS) concentrations were quickly and transiently elevated in the armyworms, Mythimna separata, by exposing them to 40 degrees C, but not other tested temperatures. Larvae exposed to 40 degrees C had subsequently elevated antioxidant activity and the highest survival of all tested heating conditions. The elevation of ROS after lethal heating at 44 degrees C for 1 h was approximately twofold compared to heating at 40 degrees C. Injection of an optimal amount of hydrogen peroxide (H2 O2 ) similarly caused sequential elevation of ROS and antioxidant activity in the test larval hemolymph, which led to significantly enhanced survival after lethal heat stress. The H2 O2 -induced thermotolerance was abolished by coinjection of potent antioxidants such as ascorbic acid or N-acetylcysteine. Both preheating at 40 degrees C and H2 O2 injection enhanced expression of genes encoding superoxide dismutase 1, catalase, and heat shock protein 70 in the fat body of test larvae, indicating the adequate heat stress induced a transient elevation of ROS, followed by upregulation of antioxidant activity. We infer that thermal stress hardening is induced by a small timely ROS elevation that triggers a reduction oxidation signaling mechanism. PMID- 28872707 TI - Changing diagnosis codes for lower respiratory tract infections can confound longitudinal studies. PMID- 28872706 TI - Candida bloodstream infections in Serbia: First multicentre report of a national prospective observational survey in intensive care units. AB - Candida bloodstream infections (BSI) are a significant cause of mortality in intensive care units (ICU), hereof the prospective 12-months (2014-2015) hospital and laboratory-based survey was performed at the Serbian National Reference Medical Mycology Laboratory (NRMML). Candida identification was done by a matrix assisted laser desorption/ionisation time-of-flight mass spectrometry and a susceptibility test, according to the Clinical and Laboratory Standards Institute methodology. Among nine centres (265 beds; 10 820 patient admissions), four neonatal/paediatric (NICU/PICUs) and five adult centres (ICUs) participated, representing 89 beds and 3446 patient admissions, 166 beds and 7347 patient admissions respectively. The NRMML received 43 isolates, 17 from NICU/PICUs and 26 from adult ICUs. C. albicans dominated highly in NICU/PICUs (~71%), whereas C. albicans and C. parapsilosis were equally distributed within adults (46%, each), both accounting for ~90% of received isolates. The resistance to itraconazole and flucytosine were 25% and 2.4% respectively. In addition, the 2 C. albicans were azole cross-resistant (4.6%). The overall incidence of CandidaBSI was ~3.97 cases/1000 patient admissions (4.93 in NICU/PICU and 3.53 in adult ICU). The 30 day mortality was ~37%, most associated with C. tropicalis and C. glabrataBSI. Data from this national survey may contribute to improving the Balkan and Mediterranean region epidemiology of CandidaBSI within ICUs. PMID- 28872708 TI - Validation of an automated immune turbidimetric assay for serum gelsolin and its possible clinical utility in sepsis. AB - BACKGROUND: Studies showing the potential predictive value of the actin-binding protein gelsolin, in critically ill patients are scarce. Moreover, even up to now a rapid automated measurement of gelsolin has still remained a challenge. Therefore, we developed and validated an automated serum gelsolin immune turbidimetric assay for possible clinical use. METHODS: Validation of serum gelsolin assay was performed on a Cobas 8000/c502 analyzer (Roche) according to the second edition of Eurachem guidelines. Furthermore, we also studied the diagnostic value of serum gelsolin in sepsis when investigating sera of septic (n = 25), systemic inflammatory response syndrome (SIRS; n = 8) and control patients (n = 14). We compared our previously published Western blot data with those of the new turbidimetric assay. RESULTS: The sample volume was 7 MUL and the assay time was 10 minutes. The detection limit was 0.72 mg/L, intra- and inter-assay imprecision remained in most cases less than 5% expressed as CV. Recovery was found to be 84.56%-93.52% and linearity study gave an appropriate correlation coefficient by linear regression analysis (r2 = .998). Septic patients exhibited lower (P = .015) first-day serum gelsolin levels than SIRS patients, which confirmed our previous Western blot results. The determined cut-off point for serum gelsolin was 14.05 mg/L (sensitivity: 75%; specificity: 60%) when investigating its diagnostic value in sepsis. CONCLUSION: Based on the results, our immune turbidimetric measurement offers a rapid and accurate quantitation of gelsolin in human serum samples. Serum gelsolin seems a promising additional diagnostic marker of sepsis which has to be further investigated. PMID- 28872709 TI - Implementing higher oxygen saturation targets reduced the impact of poor weight gain as a predictor for retinopathy of prematurity. AB - AIM: This study evaluated poor weight gain as a risk factor for infants who required treatment for retinopathy of prematurity (ROP), by comparing those born before and after the implementation of higher oxygen saturation (SpO2 ) targets at the Queen Silvia Children's Hospital, Gothenburg, Sweden. METHODS: We compared infants born at less than 31 weeks, who were screened and, or, treated for ROP: 127 in 2011-2012 when SpO2 targets were 88-92% and 142 in 2015-2016 when they were 91-95%. The subjects were reviewed for birth characteristics, weekly weight and ROP treatment. Data were analysed using the weight, insulin-like growth factor 1, neonatal, ROP (WINROP) prediction tool. RESULTS: The 2011-2012 infants who needed ROP treatment (12.6%) had significantly poorer postnatal weight gain than those who did not, but this was not seen in the treated (17.6%) and nontreated ROP groups in 2015-2016. WINROP sensitivity decreased from 87.5% in 2011-12 to 48% in 2015-2016. CONCLUSION: After the SpO2 target range was increased from 88-92% to 91-95%, postnatal weight gain was no longer a significant risk factor and WINROP lost its ability to predict ROP requiring treatment. Risk factors clearly change as neonatal care develops. PMID- 28872710 TI - Perceptions of dental treatment need in Australian-born and migrant populations. AB - The objective of this study was to investigate differences in self-perceived and dentist-determined treatment need in Australian-born and migrant residents of Australia. Participants in the National Survey of Adult Oral Health 2004-06 were categorized into six groups according to country of birth. Interview and examination data were used to analyze differences between self-perceived and the 'gold standard' examiner-determined treatment need, and to compare the accuracy of self-reporting according to country of birth. Self-reported treatment needs, defined as the need for a restoration and/or extraction, were cross-tabulated with clinically observed conditions and compared using a multivariable logistic regression model. Concordance between self-reported and clinically-determined treatment need differed significantly for migrants from Europe and the UK and Australian-born individuals. In the logistic regression model, stratification according to examiner-determined treatment need revealed significantly greater reporting of treatment need by Asian-born migrants than by the Australian-born reference group. The results of this study demonstrate that self-perceived treatment need was less than the examiner-determined findings in European and UK migrant groups and Australian-born individuals. Additionally, Asian migrants were more likely than Australian-born individuals to over-report treatment need for a filling and/or extraction. PMID- 28872711 TI - Candida-reactive T cells for the diagnosis of invasive Candida infection of the lumbar vertebral spine. AB - Invasive Candida infection is the fourth most common bloodstream infection. Blood cultures are the current gold standard diagnostic method, however, false negatives remain a clinical challenge. We developed a new technique measuring Candida-reactive T cells as diagnostic read-out for invasive Candida infection. In a pilot study, we followed the treatment course of a patient with an invasive Candida infection of the lumbar vertebral spine. We present the case of a 56-year old patient with HIV-associated Burkitt lymphoma who developed septic shock during chemotherapy-induced neutropenia. For the first time, we provide flow cytometry-based diagnostics with Candida-reactive T cells for invasive candidiasis with comprehensive MRI imaging. The Candida-reactive T cell assay has potential to complement current diagnostic assays for invasive Candida infection and thus to support targeted treatment. PMID- 28872712 TI - Regulation of hypothalamic corticotropin-releasing hormone neurone excitability by oxytocin. AB - Oxytocin (OT) is a neuropeptide that exerts multiple actions throughout the brain and periphery. Within the brain, OT regulates diverse neural populations, including neural networks controlling responses to stress. Local release of OT within the paraventricular nucleus (PVN) of the hypothalamus has been suggested to regulate stress responses by modulating the excitability of neighbouring corticotropin-releasing hormone (CRH) neurones. However, the mechanisms by which OT regulates CRH neurone excitability are unclear. In the present study, we investigated the morphological relationship between OT and CRH neurones and determined the effects of OT on CRH neurone excitability. Morphological analysis revealed that the processes of OT and CRH neurones were highly intermingled within the PVN, possibly allowing for local cell-to-cell cross-talk. Whole-cell patch-clamp recordings from CRH neurones were used to study the impact of OT on postsynaptic excitability and synaptic innervation. Bath-applied OT did not alter CRH neurone holding current, spiking output or any action potential parameters. Recordings of evoked excitatory and inhibitory postsynaptic currents (EPSCs/IPSCs) revealed no net effect of OT on current amplitude; however, subgroups of CRH neurones appeared to respond differentially to OT. Analysis of spontaneous EPSC events uncovered a significant reduction in spontaneous EPSC frequency but no change in spontaneous EPSC amplitude in response to OT. Together, these data demonstrate that OT exerts a subtle modulation of synaptic transmission onto CRH neurones providing one potential mechanism by which OT could suppress CRH neurone excitability and stress axis activity. PMID- 28872713 TI - Ultrahigh-Efficiency Green PHOLEDs with a Voltage under 3 V and a Power Efficiency of Nearly 110 lm W-1 at Luminance of 10 000 cd m-2. AB - Maintaining high power efficiency (PE) under high brightness is still a pressing problem for the practical application of organic light-emitting diodes (OLEDs). Here, ultrahigh-efficiency green phosphorescent OLEDs (PHOLEDs) with a record-low voltage at luminance above 5000 cd m-2 are fabricated, by developing a novel anthracene/pyridine derivative as the electron-transporting material (ETM) combined with a material displaying thermally activated delayed fluorescence as the host. The pyridine units of the ETM not only facilitate charge injection, but also enhance the electron-transporting mobility, profiting from the closely packed molecules caused by the intermolecular H-bonding. The optimized green PHOLEDs show record-low driving voltages of 2.76 and 2.92 V, with EQEs/PEs of 28.0%/102 lm W-1 and 27.9%/97 lm W-1 at 5000 and 10 000 cd m-2 , respectively. Furthermore, device optimization exhibits an unprecedented high PE of 109 lm W-1 at 10 000 cd m-2 with voltage under 3 V. Those values are the state-of-the-art among all reported green OLEDs so far, paving their way toward practical applications. PMID- 28872714 TI - Microbial epidemiology of candidaemia in neonatal and paediatric intensive care units at the Children's Medical Center, Tehran. AB - Invasive candidiasis is a major cause of morbidity and mortality in children. However, limited data are available on the epidemiology of this infection in paediatric settings in Iran. The aim of this study was to determine the prevalence, microbial epidemiology, risk factors and clinical outcomes associated with candidaemia in intensive care units at the Children's Medical Center, Tehran, Iran. All blood and other normally sterile specimen cultures positive for Candida species were included. Isolates were identified by morphological and molecular methods. Unidentified/doubtful yeast isolates were subjected to ITS sequencing. A total of 156 episodes of invasive candidiasis, with an overall incidence of 15.2 per 1000 ICU admissions, was recorded. Risk factors included presence of central venous lines (89.1%), mechanical ventilation (55.8%) and parenteral nutrition (51.3%). Candida albicans (57.1%) and Candida parapsilosis (24.4%) were the most commonly isolated species. Candida orthopsilosis, Candida glabrata, Candida dubliniensis, Candida lusitaniae, Candida kefyr and Candida intermedia accounted for about 11% of the cases. The overall mortality rate was 42.5%. Non-albicans Candida species accounted for nearly half of the cases of paediatric candidaemia. This is the first prospective study of candidaemia in paediatric settings in Iran and serves to inform necessary interventions for the prevention of candidaemia. PMID- 28872715 TI - Nanohybrids of Two-Dimensional Transition-Metal Dichalcogenides and Titanium Dioxide for Photocatalytic Applications. AB - The ever increasing need for renewable and clean energy resources as well as environmental concerns are considered as two serious challenges of today's society. Photocatalysis has proved to be a reliable and effective technology to overcome these issues. However, to bring the full potential of this approach into reality, two main hurdles of fast charge recombination and the limited visible light absorption should be tackled. To address these obstacles, nanocomposites based on titanium dioxide nanostructures and semiconducting two-dimensional transition-metal dichalcogenides have been developed and proven to be excellent photocatalysts. In this review, we will overview the recent developments on the fabrication and rational design of these nanocomposites both for hydrogen production and photocatalytic degradation of pollutants with emphasis on those appealing structures. PMID- 28872716 TI - Parent Thioketene S-Oxide H2 CCSO: Gas-Phase Generation, Structure, and Bonding Analysis. AB - The parent thioketene S-oxide H2 CCSO has been generated in the gas phase through flash vacuum pyrolysis (ca. 1000 K) of vinyl sulfoxide H2 CC(Br)-S(O)CF3 via the intermediacy of a novel vinyl sulfinyl radical H2 C=C(Br)-SO (syn and anti conformers). Upon irradiation at 266 nm, H2 CCSO decomposes into HCCH/SO and H2 CS/CO in cryogenic Ar matrix. Whereas, visible-light irradiations result in syn< >anti conformational interconversion in H2 C=C(Br)-SO. The molecular structures of H2 CCSO and isomers are computationally studied at the CCSD(T)-F12/VTZ-F12 level of theory, and the bonding properties of H2 CCSO are analyzed with the EDA NOCV method at the M06-2X/TZ2P level. PMID- 28872717 TI - Role of the Bridging Group in Bis-Pyridyl Ligands: Enhancing Both the Photo- and Electroluminescent Features of Cationic (IPr)CuI Complexes. AB - We report on the benefits of changing the bridging group X of bis-pyridyl ligands, that is, Py-X-Py where X is NH, CH2 , C(CH3 )2 , or PPh, on the photo- and electroluminescent properties of a new family of luminescent cationic H heterocyclic carbene (NHC) copper(I) complexes. A joint experimental and theoretical study demonstrates that the bridging group affects the molecular conformation from a planar-like structure (X is NH and CH2 ) to a boat-like structure (X is C(CH3 )2 and PPh), leading to i) four-fold enhancement of the photoluminescence quantum yield (phiem ) without affecting the thermally activated delayed fluorescence mechanism, and ii) one order of magnitude reduction of the ionic conductivity (sigma) of thin films. This leads to an overall enhancement of the device efficacy and luminance owing to the increased phiem and the use of low applied driving currents. PMID- 28872718 TI - Stereoselective Arene-Forming Aldol Condensation: Catalyst-Controlled Synthesis of Axially Chiral Compounds. AB - The fundamental role that aldol chemistry adopts in various disciplines, such as stereoselective catalysis or the biosynthesis of aromatic polyketides, illustrates its exceptional versatility. On the one hand, numerous aldol addition reactions reliably transfer the stereochemical information from catalysts into various valuable products. On the other hand, countless aromatic polyketide natural products are produced by an ingenious biosynthetic machinery based on arene-forming aldol condensations. With the aim of complementing aldol methodology that controls stereocenter configuration, we recently combined these two tenets by investigating small-molecule-catalyzed aldol condensation reactions that stereoselectively form diverse axially chiral compounds through the construction of a new aromatic ring. PMID- 28872719 TI - Oral herbal medicines marketed in Brazil for the treatment of osteoarthritis: A systematic review and meta-analysis. AB - Herbal medications are commonly used to manage symptoms associated with osteoarthritis (OA). This systematic review evaluated the effectiveness and safety of oral medications used in Brazil for the treatment of OA. Randomized clinical trials involving adults with OA treated by a herbal medicine or a control group were eligible. The primary outcomes measured were pain, physical function, swelling, stiffness and quality of life; and the secondary outcomes were adverse events, activity limitations and treatment satisfaction. Sixteen studies were included (n = 1,741 patients) in the systematic review and nine studies in the meta-analysis, representing 6 of the 13 herbal medicines studied: Boswellia serrata (n = 2), Curcuma longa (n = 3), Harpagophytum procumbens (n = 1), Salix daphnoides (n = 3), Uncaria guianensis (n = 2) and Zingiber officinale (n = 5). B. serrata was more effective than both placebo and valdecoxib for improvement of pain and physical function. No difference was observed for H. procumbens, C. longa and U. guianensis compared with control. Z. officinale showed improvement of pain over placebo. The evidence was insufficient to support the effective and safe use of these herbal medicines, because the quality of evidence of studies was low. This study guides managers of the Brazilian public health system and prescribers in decision-making regarding the use of these herbal medicines for OA. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28872720 TI - Laboratory-Based Investigation of Denture Sonication Method in Patients with Candida-Associated Denture Stomatitis. AB - PURPOSE: Denture stomatitis (DS) is a disease characterized by inflammation and erythema of the oral mucosa areas covered by the denture. Multifactorial etiological factors contribute to DS, but it seems that Candida plays the key role. The aim of the study was to evaluate the denture sonication method to: (i) increase the possibility of diagnosing patients with Candida-associated DS; (ii) detect and identify the mixed Candida spp., and (iii) determine the Candida colony forming units (CFU) and its possible relationship with DS severity, based on Newton's classification. MATERIALS AND METHODS: The cross-sectional study conducted at the Clinic for Dental Prosthetics, Belgrade (Serbia) from June 2013 to December 2014 enrolled edentulous patients with dentures (n = 250). Patients without DS (n = 20) were the control group (CG). The patients' data were collected, and patients with DS (study group/SG) were selected and divided into SG Candida+ and SG Candida-. Based on severity of DS, the SG patients were classified in 3 groups (Newton's classification). Four sampling methods were applied to detect patients with Candida-associated DS: mucosa swab, denture swab, oral rinse, and denture sonication method. The sensitivity and specificity of denture sonication method were shown using the receiver operating characteristic (ROC) curve and the area under the curve (AUC). RESULTS: In 97 (38.8%), out of 250 clinically examined patients, DS was diagnosed. In 82 (84.5%), out of 97 mycologically examined patients, Candida-associated DS was detected when denture sonication method was applied. Additionally, using the denture sonication method we observed: (i) the largest number of Candida positive patients compared to other sampling methods (p < 0.0001); (ii) the highest number of Candida CFU/ml (105 ), and (iii) the possibility to detect mixed Candida cultures. The largest number of patients with Candida-associated DS showed type II (60%) DS, followed by type I (21%), and type III (19%) DS. CONCLUSION: The denture sonication method is easy, accurate, and sensitive, and increases the possibility of diagnosing patients with Candida-associated DS. Additionally, yeast quantification, mixed Candida spp., and non-albicans Candida were detectable when cultivation on Candida CHROMagar was performed. It was not possible using conventional methods, such as swab or oral rinse. PMID- 28872721 TI - On risk in addiction science, policy and debate. PMID- 28872722 TI - Impact of Intentional Overload on Joint Stability of Internal Implant-Abutment Connection System with Different Diameter. AB - PURPOSE: To evaluate the axial displacement of the implant-abutment assembly of different implant diameter after static and cyclic loading of overload condition. MATERIALS AND METHODS: An internal conical connection system with three diameters (O 4.0, 4.5, and 5.0) applying identical abutment dimension and the same abutment screw was evaluated. Axial displacement of abutment and reverse torque loss of abutment screw were evaluated under static and cyclic loading conditions. Static loading test groups were subjected to vertical static loading of 250, 400, 500, 600, 700, and 800 N consecutively. Cyclic loading test groups were subjected to 500 N cyclic loading to evaluate the effect of excessive masticatory loading. After abutment screw tightening for 30 Ncm, axial displacement was measured upon 1, 3, 10, and 1,000,000 cyclic loadings of 500 N. Repeated-measure ANOVA and 2 way ANOVA were used for statistical analysis (alpha = 0.05). RESULTS: The increasing magnitude of vertical load and thinner wall thickness of implant increased axial displacement of abutment and reverse torque loss of abutment screw (p < 0.05). Implants in the O 5.0 diameter group demonstrated significantly low axial displacement, and reverse torque loss after static loading than O 4.0 and O 4.5 diameter groups (p < 0.05). In the cyclic loading test, all diameter groups of implant showed significant axial displacement after 1 cycle of loading of 500 N (p < 0.05). There was no significant axial displacement after 3, 10, or 1,000,000 cycles of loading (p = 0.603). CONCLUSIONS: Implants with O 5.0 diameter demonstrated significantly low axial displacement and reverse torque loss after the cyclic and static loading of overload condition. PMID- 28872723 TI - Working atmosphere, job satisfaction and individual characteristics of community mental health professionals in integrated care. AB - Working requirements of community mental healthcare professionals in integrated care are complex. There is a lack of research concerning the relation of job satisfaction, working atmosphere and individual characteristics. For the current study, a survey evaluating job satisfaction and working atmosphere of mental healthcare professionals in integrated care was performed. About 321 community mental healthcare professionals were included in the survey; the response rate was 59.5%. The professional background of community mental healthcare professionals included nursing, social work and psychology. Community mental healthcare professionals reported the highest satisfaction with colleagues and the lowest satisfaction with income. Moreover, it could be shown that more responsibility, more recognition and more variety in job tasks lead to an increase of overall job satisfaction. Healthcare for mentally ill patients in the community setting is complex and requires well-structured care with appropriate responsibilities within the team. A co-operative relationship among colleagues as well as clearly defined responsibilities seem to be the key for the job satisfaction of community mental healthcare professionals in integrated care. PMID- 28872724 TI - Successful treatment of bilateral endogenous Fusarium solani endophthalmitis in a patient with acute lymphocytic leukaemia. AB - Fusarium spp. are an uncommon cause of fungaemia in immunocompromised and neutropenic patients that may hematogenously disseminate to the eyes. Herein, we describe a patient with acute lymphoblastic leukaemia and a prior history of extensive corticosteroid exposure who developed disseminated Fusarium solani infection following chemotherapy despite posaconazole prophylaxis. She was successfully treated with combination liposomal amphotericin B and voriconazole, intraocular injections of voriconazole, topical amphotericin B and bilateral vitrectomy. We also review published literature describing the management of endogenous Fusarium endophthalmitis in immunocompromised hosts. PMID- 28872726 TI - Bond Strength of Resin Cement and Glass Ionomer to Nd:YAG Laser-Treated Zirconia Ceramics. AB - PURPOSE: To investigate the effect of neodymium-doped yttrium aluminum garnet (Nd:YAG) laser irradiation on the surface properties and bond strength of zirconia ceramics. MATERIALS AND METHODS: Forty-eight zirconia ceramic pieces (4 * 4 * 1 mm3 ) were divided into four groups according to surface treatment as follows: two control groups (no treatment) for resin bonding (CRC) and glass ionomer (GI) bonding (CGC); two laser treatment groups (Nd:YAG irradiation, 3 W, 200 MJ, 10 Hz, 180 MUs) for resin bonding (LRC) and GI bonding (LGC). The ceramics in the control groups and the laser groups were distinguished by the application of different cements (resin cement and GI). Following surface treatments, the specimens were cemented to human dentin with resin cement and GI. After bonding, the shear bond strength (SBS) of the ceramic to dentin was measured, and the failure mode of each specimen was analyzed using a stereomicroscope. A one-way ANOVA compared the average bond strength of the four groups. Pairwise comparisons among the groups were performed using the Games Howell test. The level of significance was set at 0.05. RESULTS: The means (+/- standard deviation) of SBS values in the CRC, CGC, LRC, and LGC groups were 3.98 +/- 1.10, 1.66 +/- 0.59, 10.24 +/- 2.46, and 2.21 +/- 0.38 MPa, respectively. Data showed that the application of the Nd:YAG laser resulted in a significantly greater SBS of the resin cement to the zirconia ceramics (p < 0.001). The highest bond strength was recorded in the LRC group. In the CRC group, 75% of the failures were of the adhesive type, compared with 66.7% and 83.3% in the LRC and LGC groups, respectively. In the CGC group, all failures were adhesive. CONCLUSIONS: Pretreatment of zirconia ceramic via Nd:YAG laser improves the bond strength of the resin cement to the zirconia ceramic. GI cement does not provide sufficient bond strength of zirconia ceramics to dentin. PMID- 28872725 TI - Dorsal Root Ganglion Field Stimulation Prevents Inflammation and Joint Damage in a Rat Model of Rheumatoid Arthritis. AB - OBJECTIVES: Electrical stimulation of the dorsal root ganglion (DRG), referred to here as ganglionic field stimulation (GFS), is effective in reducing clinical pain, probably by interrupting transmission of afferent impulse trains on sensory neurons as they pass through the DRG. We therefore tested whether efferent impulse trains conveyed by sensory neurons, which contribute to neurogenic inflammation, may also be interrupted by GFS. MATERIALS AND METHODS: Collagen induced arthritis, a model of clinical rheumatoid arthritis, was initiated in rats concurrently with the insertion of an electrode for GFS at the fourth lumbar DRG. Continuous GFS (20 Hz pulse rate, current at 80% of the motor threshold) was initiated 6 days later and continued for 14 days. Plantar pain sensitivity, ankle arthritis score, and dimensions of the foot and ankle were determined one hour after termination of GFS. RESULTS: The foot/ankle contralateral to GFS developed hypersensitivity to threshold and noxious mechanical stimulation, swelling, and high arthritis score, all of which were normalized in the foot/ankle ipsilateral with GFS. Histology showed GFS limited joint destruction. Electrophysiological recording showed GFS can block efferent impulse trains. CONCLUSIONS: Our findings show that GFS can reduce neurogenic inflammation and the resulting joint damage in a model of rheumatoid arthritis, probably by blocking the transit of impulse trains through the DRG. GFS may have clinical utility in limiting joint destruction in inflammatory arthritis such as rheumatoid arthritis. PMID- 28872727 TI - Hollow-Structured Graphene-Silicone-Composite-Based Piezoresistive Sensors: Decoupled Property Tuning and Bending Reliability. AB - A versatile flexible piezoresistive sensor should maintain high sensitivity in a wide linear range, and provide a stable and repeatable pressure reading under bending. These properties are often difficult to achieve simultaneously with conventional filler-matrix composite active materials, as tuning of one material component often results in change of multiple sensor properties. Here, a material strategy is developed to realize a 3D graphene-poly(dimethylsiloxane) hollow structure, where the electrical conductivity and mechanical elasticity of the composite can be tuned separately by varying the graphene layer number and the poly(dimethylsiloxane) composition ratio, respectively. As a result, the sensor sensitivity and linear range can be easily improved through a decoupled tuning process, reaching a sensitivity of 15.9 kPa-1 in a 60 kPa linear region, and the sensor also exhibits fast response (1.2 ms rising time) and high stability. Furthermore, by optimizing the density of the graphene percolation network and thickness of the composite, the stability and repeatability of the sensor output under bending are improved, achieving a measurement error below 6% under bending radius variations from -25 to +25 mm. Finally, the potential applications of these sensors in wearable medical devices and robotic vision are explored. PMID- 28872728 TI - Changes to Glazed Dental Ceramic Shade, Roughness, and Microhardness after Bleaching and Simulated Brushing. AB - PURPOSE: To evaluate shade stability, surface roughness, microhardness, and compressive strength of a glazed feldspathic ceramic subjected to bleaching and simulated brushing. MATERIALS AND METHODS: Eighty-eight glazed feldspathic ceramic specimens were made from microparticulate leucite and divided into eight groups (n = 10). The whitening products used were: Opalescence Treswhite Supreme (Ultradent), Opalescence(r)? PF 15% (Ultradent), and Oral-B 3D White Whitestrips. All substances for whitening were used for 4 hours/day for a period of 14 days; the control group was not bleached. Next, half of the specimens were individually brushed. Microhardness and surface roughness data were subjected to three-way ANOVA and Tukey test. The diametrical tensile strength data were subjected to two way ANOVA. The shade change data were analyzed using Kruskal-Wallis, Mann Whitney, and the Student-Newman-Keuls test. The significance level was set at 5%. RESULTS: Glazed feldspathic ceramic surface microhardness was significantly affected by bleaching agents (p = 0.007). Initially, glazed ceramic microhardness was significantly higher than that observed after contact with the bleaching agents, whether or not brushing was performed. The specimens submitted to bleaching in preloaded trays presented lower surface roughness values after brushing (p = 0.037). The surface roughness was significantly lower in the brushed specimens (p = 0.044). The diametrical tensile strength was not significantly affected by the application of bleaching agents (p = 0.563) or by brushing (p = 0.477). When the specimens were brushed, however, shade change was significantly influenced by the bleaching agent used (p = 0.041). CONCLUSIONS: Bleaching agents associated with brushing cycles can alter surface properties and shade stability of glazed feldspathic ceramics, though such findings may not reflect the performance of unglazed feldspathic ceramics. PMID- 28872729 TI - A Retrospective Cohort Study of the Cumulative Survival Rate of Obturator Prostheses for Marsupialization. AB - PURPOSE: After marsupialization of benign tumors and jawbone cysts, insertion of an obturator prosthesis maintains the surgical opening and improves hygiene. To date, there have been no reports clarifying the relationship between the obturator design and treatment outcomes. The purpose of this study was to examine the survival rate of three types of obturator, and to investigate the factors that expedite the removal of the obturator. MATERIALS AND METHODS: The subject group comprised 100 patients who had an obturator inserted after marsupialization at Kagoshima University Hospital between May 31, 2012 and March 31, 2015; 73 patients with lesions in the mandible were eligible. Three types of mandibular obturator were designed and inserted, considering the teeth missing, the anteroposterior position of the lesion, and the buccolingual direction of marsupialization. The endpoint of this study was defined as the removal of the obturator. The analyzed predictor values for the endpoint were age, gender, remaining teeth, nature of primary disease, anteroposterior location of primary disease, buccolingual direction of marsupialization, type of obturator, and dates of insertion and removal. RESULTS: No significant differences were found in the cumulative survival rate among the three types of obturator. Early obturator removal was more frequent in patients with cysts, anterior lesions, and/or marsupialization from the occlusal direction CONCLUSIONS: Because obturator design had minimal effect on the ability of the appliance to maintain the surgical opening, it is preferable to use the least invasive design. Our findings also suggest that the follow-up examination should account for the type of primary disease, the anteroposterior location of the lesion, and the buccolingual direction of marsupialization. PMID- 28872730 TI - Volumetric Evaluation of Void/Gap Formation and Microleakage Cementing Fiber Posts on Extracted Teeth with Three Different Cements. AB - PURPOSE: To evaluate microleakage in roots restored with fiber posts cemented using three different luting cements, to measure the volume of voids/gaps within the obturated/postcemented root canals, and to examine whether microleakage and the volume of voids/gaps were correlated. MATERIALS AND METHODS: Thirty-six extracted human mandibular incisors were decoronated, and the root canals were obturated using gutta-percha and sealer in the experimental groups (n = 30). Six roots were used as controls. A standard post space was prepared, and an identically sized fiber post was cemented in each experimental specimen using one of three luting cements (Panavia F2.0, Bifix SE, GC FujiCEM; n = 10 each). The specimens were scanned using micro-computed tomography, and the volume of voids/gaps was determined. The specimens were then subjected to a fluid filtration assay to evaluate microleakage. RESULTS: The volume of voids/gaps was significantly lower in the GC FujiCEM group, and significantly less microleakage occurred in the Bifix SE group compared with other groups (both p < 0.001). A significant correlation between the volume of voids/gaps and leakage was found only in the Panavia F2.0 group (p = 0.003; r = 0.830). No such correlation was found in the analysis of all groups combined. CONCLUSIONS: The group with the greatest volume of voids/gaps (Bifix SE) showed the least microleakage, and the group with the smallest volume of voids/gaps (GC FujiCEM) showed the most microleakage. Panavia F2.0 ranked between and exhibited significant correlation. PMID- 28872731 TI - Urbanization reduces and homogenizes trait diversity in stream macroinvertebrate communities. AB - More than one-half of the world's population lives in urban areas, so quantifying the effects of urbanization on ecological communities is important for understanding whether anthropogenic stressors homogenize communities across environmental and climatic gradients. We examined the relationship of impervious surface coverage (a marker of urbanization) and the structure of stream macroinvertebrate communities across the state of Maryland and within each of Maryland's three ecoregions: Coastal Plain, Piedmont, and Appalachian, which differ in stream geomorphology and community composition. We considered three levels of trait organization: individual traits, unique combinations of traits, and community metrics (functional richness, functional evenness, and functional divergence) and three levels of impervious surface coverage (low [<2.5%], medium [2.5% to 10%], and high [>10%]). The prevalence of an individual trait differed very little between low impervious surface and high impervious surface sites. The arrangement of trait combinations in community trait space for each ecoregion differed when impervious surface coverage was low, but the arrangement became more similar among ecoregions as impervious surface coverage increased. Furthermore, trait combinations that occurred only at low or medium impervious surface coverage were clustered in a subset of the community trait space, indicating that impervious surface affected the presence of only a subset of trait combinations. Functional richness declined with increasing impervious surface, providing evidence for environmental filtering. Community metrics that include abundance were also sensitive to increasing impervious surface coverage: functional divergence decreased while functional evenness increased. These changes demonstrate that increasing impervious surface coverage homogenizes the trait diversity of macroinvertebrate communities in streams, despite differences in initial community composition and stream geomorphology among ecoregions. Community metrics were also more sensitive to changes in the abundance rather than the gain or loss of trait combinations, showing the potential for trait based approaches to serve as early warning indicators of environmental stress for monitoring and biological assessment programs. PMID- 28872732 TI - Preferences Related to the Use of Mobile Apps as Dental Patient Educational Aids: A Pilot Study. AB - PURPOSE: Numerous patient education apps have been developed to explain dental treatment. The purpose of this study was to assess perceptions and preferences regarding the use of apps in dental settings. MATERIALS AND METHODS: Four patient education apps describing fixed partial dentures were demonstrated to participants (N = 25). Questions about each app were asked using a semi structured interview format to assess participants' opinions about each app's content, images, features, and use. Sessions were analyzed via note-based methods for thematic coding. RESULTS: Participants believed that apps should be used in conjunction with a dentist's explanation about a procedure. They desired an app that could be tailored for scope of content. Participants favored esthetic images of teeth that did not show structural anatomy, such as tooth roots, and preferred interactive features. CONCLUSIONS: Patient education apps may be a valuable tool to enhance patient-provider communication in dental settings. Participants exhibited varying preferences for different features among the apps and expressed the desire for an app that could be personalized to each patient. Additional research is needed to assess whether the use of apps improves oral health literacy and informed consent among patients. PMID- 28872733 TI - Cafeteria diet induces neuroplastic modifications in the nucleus accumbens mediated by microglia activation. AB - High-palatable and caloric foods are widely overconsumed due to hedonic mechanisms that prevail over caloric necessities leading to overeating and overweight. The nucleus accumbens (NAc) is a key brain area modulating the reinforcing effects of palatable foods and is crucially involved in the development of eating disorders. We describe that prolonged exposure to high caloric chocolate cafeteria diet leads to overeating and overweight in mice. NAc functionality was altered in these mice, presenting structural plasticity modifications in medium spiny neurons, increased expression of neuroinflammatory factors and activated microglia, and abnormal responses after amphetamine-induced hyperlocomotion. Chronic inactivation of microglia normalized these neurobiological and behavioural alterations exclusively in mice exposed to cafeteria diet. Our data suggest that prolonged exposure to cafeteria diet produces neuroplastic and functional changes in the NAc that can modify feeding behaviour. Microglia activation and neuroinflammation play an important role in the development of these neurobiological alterations. PMID- 28872734 TI - Xenon as an adjuvant to sevoflurane anesthesia in children younger than 4 years of age, undergoing interventional or diagnostic cardiac catheterization: A randomized controlled clinical trial. AB - BACKGROUND: Xenon has repeatedly been demonstrated to have only minimal hemodynamic side effects when compared to other anesthetics. Moreover, in experimental models, xenon was found to be neuroprotective and devoid of developmental neurotoxicity. These properties could render xenon attractive for the anesthesia in neonates and infants with congenital heart disease. However, experience with xenon anesthesia in children is scarce. AIMS: We hypothesized that in children undergoing cardiac catheterization, general anesthesia with a combination of sevoflurane with xenon results in superior hemodynamic stability, compared to sevoflurane alone. METHODS: In this prospective, randomized, single blinded, controlled clinical trial, children with a median age of 12 [IQR 3-36] months undergoing diagnostic/interventional cardiac catheterization were randomized to either general anesthesia with 50-65vol% xenon plus sevoflurane or sevoflurane alone. The primary outcome was the incidence of intraprocedural hemodynamic instability, defined as the occurrence of: (i) a heart rate change >20% from baseline; or (ii) a change in mean arterial blood pressure >20% from baseline; or (iii) the requirement of vasopressors, inotropes, chronotropes, or fluid boluses. Secondary endpoints included recovery characteristics, feasibility criteria, and safety (incidence of emergence agitation and postoperative vomiting. RESULTS: After inclusion of 40 children, the trial was stopped as an a priori planned blinded interim analysis revealed that the overall rate of hemodynamic instability did not differ between groups [100% in both the xenon sevoflurane and the sevoflurane group. However, the adjuvant administration of xenon decreased vasopressor requirements, preserved better cerebral oxygen saturation, and resulted in a faster recovery. Xenon anesthesia was feasible (with no differences in the need for rescue anesthetics in both groups). CONCLUSION: Our observations suggest that combining xenon with sevoflurane in preschool children is safe, feasible, and facilitates hemodynamic management. Larger and adequately powered clinical trials are warranted to investigate the impact of xenon on short- and long-term outcomes in pediatric anesthesia. PMID- 28872735 TI - In vitro efficacy of disinfectants utilised for skin decolonisation and environmental decontamination during a hospital outbreak with Candida auris. AB - Candida auris has caused nosocomial infections and transmissions within hospital settings. As little is known about the efficacy of skin and environmental decontamination products to kill C. auris, this study investigated the in vitro activity of chlorine, chlorhexidine, iodine povidone and vaporised hydrogen peroxide products against C. auris. H2 O2 vapour showed 96.6%-100% effective killing of C. auris. All isolates were inhibited by chlorhexidine gluconate concentrations at 0.125%-1.5% and for iodinated povidone at 0.07%-1.25%. Other species of Candida were also killed at 1000 ppm chlorine except C. parapsilosis which failed to be killed at 3 minutes contact time. We conclude that chlorhexidine gluconate, iodinated povidone, chlorine and H2 O2 vapour demonstrate effective killing activity against C. auris at concentrations used in clinical practice. PMID- 28872736 TI - Progression of prodromal motor and non-motor symptoms in the premotor phase study - 2-year follow-up data. AB - BACKGROUND AND PURPOSE: The neuropathological process starts years before the diagnosis of Parkinson's disease (PD). Assessment of prodromal features in healthy individuals may help to define those with high risk for future PD. Our aim was to evaluate the presence and progression of prodromal markers in individuals with low risk [healthy controls (HC), n = 14] and high risk for PD (HR-PD, n = 34) and early PD (n = 14) patients. METHODS: Several risk or prodromal markers were combined to define HR-PD. Other prodromal markers were followed in 6-month intervals for 2 years. As recommended by the Movement Disorder Society Task Force, likelihood ratios (LRs) of markers, motor scores and PD probability scores were calculated and compared. RESULTS: The baseline LR for non-motor prodromal markers was significantly higher in PD and HR-PD compared to HC. Within 2 years, changes in these LRs did not significantly differ between the groups. Motor worsening was significant only in the PD group (50% of the patients) against HR-PD (15%) and HC (7%). Change in the non-motor prodromal LR did not significantly correlate with motor worsening, but higher baseline non motor LRs were associated with Unified Parkinson's Disease Rating Scale III values at 2 years of follow-up. CONCLUSIONS: Our study shows that the frequency of non-motor prodromal markers is higher in the HR-PD group but does not increase within 2 years. The progression of motor and non-motor markers seems to be independent, but higher baseline non-motor burden is associated with the motor status after 2 years. Moreover, our data argue for a high impact of motor markers in the risk estimation for future PD. PMID- 28872737 TI - Chronic hepatitis caused by hepatitis C virus showing a discrepancy between serogroup and genotype because of intergenotypic 2b/1b recombination: A pitfall in antiviral therapy with direct-acting antivirals. AB - A 40-year-old male patient with virologic relapse after daclatasvir plus asunaprevir therapy for a serogroup 1 hepatitis C virus (HCV) infection visited our hospital for retreatment. Virologic examinations revealed that a genotype 2b HCV strain carrying both NS3-S122N / D168A and NA5A-R30Q / L31M / Q54H / Y93H mutations had relapsed. The patient received sofosbuvir plus ribavirin therapy, but virologic relapse occurred once again. Sequencing of the HCV genome clarified an intergenotypic recombination of 2b and 1b with an estimated crossover point between nucleotides 3114 and 3115, corresponding to the N-terminal end of the NS3 region (DDBJ/EMBL/GenBank databases accession no. LC273304). The NS5B-S282T mutation was not detected in the HCV strain, and resistance-association substitutions in the NS3 and NS5A regions were similar to those at baseline. Direct sequencing of the core and NS4A regions corresponding to the targeting sites of genotyping and serogrouping, respectively, is useful to determine the combination of direct-acting antivirals when a discrepancy is observed between the serogroup and genotype of HCV strains. PMID- 28872738 TI - Chronic post-stroke oropharyngeal dysphagia is associated with impaired cortical activation to pharyngeal sensory inputs. AB - BACKGROUND AND PURPOSE: The role of afferent sensory pathways in the pathophysiology of post-stroke oropharyngeal dysphagia is not known. We hypothesized that patients with chronic post-stroke dysphagia (PSD) would show impaired sensory cortical activation in the ipsilesional hemisphere. METHODS: We studied 28 chronic unilateral post-stroke patients [17 PSD and 11 post-stroke non dysphagic patients (PSnD)] and 11 age-matched healthy volunteers. Event-related sensory-evoked potentials to pharyngeal stimulation (pSEP) and sensory thresholds were assessed. We analyzed pSEP peak latency and amplitude (N1, P1, N2 and P2), and neurotopographic stroke characteristics from brain magnetic resonance imaging. RESULTS: Healthy volunteers presented a highly symmetric bihemispheric cortical pattern of brain activation at centroparietal areas (N1-P1 and N2-P2) to pharyngeal stimuli. In contrast, an asymmetric pattern of reduced ipsilesional activation was found in PSD (N2-P2; P = 0.026) but not in PSnD. PSD presented impaired safety of swallow (penetration-aspiration score: 4.3 +/- 1.6), delayed laryngeal vestibule closure (360.0 +/- 70.0 ms) and higher National Institute of Health Stroke Scale (7.0 +/- 6.2 vs. 1.9 +/- 1.4, P = 0.001) and Fazekas scores (3.0 +/- 1.4 vs. 2.0 +/- 1.1; P < 0.05) than PSnD. pSEP showed a unilateral delay at stroke site exclusively for PSD (peak-latency interhemispheric difference vs. PSnD: N1, 6.5 +/- 6.7 vs. 1.1 +/- 1.0 ms; N2, 32.0 +/- 15.8 vs. 4.5 +/- 4.9 ms; P < 0.05). CONCLUSIONS: Chronic post-stroke oropharyngeal dysphagia is associated with stroke severity and degree of leukoaraoisis. Impaired conduction and cortical integration of pharyngeal sensory inputs at stroke site are key features of chronic PSD. These findings highlight the role of sensory pathways in the pathophysiology of post-stroke oropharyngeal dysphagia and offer a potential target for future treatments. PMID- 28872739 TI - Enantioselective Catalysis Coupled with Stereodivergent Cyclization Strategies Enables Rapid Syntheses of (+)-Limaspermidine and (+)-Kopsihainanine A. AB - Enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates were used to construct the C20-quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet-Spengler and Bischler-Napieralski cyclization/reduction cascades furnish the cis- and trans fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en route to highly efficient syntheses of (+)-limaspermidine and (+)-kopsihainanine A. PMID- 28872740 TI - Enantioselective Direct Mannich-Type Reactions Catalyzed by Frustrated Lewis Acid/Bronsted Base Complexes. AB - An enantioselective direct Mannich-type reaction catalyzed by a sterically frustrated Lewis acid/Bronsted base complex is disclosed. Cooperative functioning of the chiral Lewis acid and achiral Bronsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond-activated aldimines delivers beta-aminocarbonyl compounds with high enantiomeric purity. PMID- 28872741 TI - Response to 'Expression of Concern' (Richardson et al, Psycho-Oncology, 2017, 26, 724-737). PMID- 28872742 TI - Association between social support, functional status, and change in health related quality of life and changes in anxiety and depression in colorectal cancer patients. AB - OBJECTIVE: The aim of this study was to explore the association between baseline social support, functional status, and change in health-related quality of life (HRQoL) in colorectal cancer patients and change in anxiety and depression measured by Hospital Anxiety and Depression Scale (HADS) at 1 year after surgery. METHODS: Consecutive patients who were due to undergo therapeutic surgery for the first time for colon or rectal cancer in 9 hospitals in Spain were eligible for the study. Patients completed the following questionnaires before surgery and 12 months afterward: 1 HRQoL instrument, the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire; a social support questionnaire, the Duke-UNC Functional Social Support Questionnaire; the Barthel Index, to assess functional status; the HADS, to assess anxiety and depression; and questions about sociodemographic information. General linear models were built to explore the association between social support, functional status, and change in HRQoL and changes in anxiety and depression 12 months after surgery. RESULTS: A total of 947 colorectal cancer patients took part in the study. Patients' functional status, social support, and change in HRQoL were associated with changes in anxiety and depression. Greater social support and improvements in physical, cognitive, and social functioning and in insomnia resulted in improvements in anxiety and depression. No functionally independent patients were associated with lesser improvements in anxiety and depression. CONCLUSIONS: Colorectal cancer patients who have more social support, are functionally independent and have higher improvements in HRQoL may have better results in anxiety and depression at 1 year after surgery, adjusting for age, gender, location, occupation, and baseline HADS scores. PMID- 28872743 TI - Expression of concern-inadequate review of the literature (Richardson et al, Psycho-Oncology, 2017, 26, 724-737). PMID- 28872744 TI - Combining Orthogonal Chain-End Deprotections and Thiol-Maleimide Michael Coupling: Engineering Discrete Oligomers by an Iterative Growth Strategy. AB - Orthogonal maleimide and thiol deprotections were combined with thiol-maleimide coupling to synthesize discrete oligomers/macromolecules on a gram scale with molecular weights up to 27.4 kDa (128mer, 7.9 g) using an iterative exponential growth strategy with a degree of polymerization (DP) of 2n -1. Using the same chemistry, a "readable" sequence-defined oligomer and a discrete cyclic topology were also created. Furthermore, uniform dendrons were fabricated using sequential growth (DP=2n -1) or double exponential dendrimer growth approaches (DP=22n -1) with significantly accelerated growth rates. A versatile, efficient, and metal free method for construction of discrete oligomers with tailored structures and a high growth rate would greatly facilitate research into the structure-property relationships of sophisticated polymeric materials. PMID- 28872746 TI - 'We are the eyes and ears of researchers and community': understanding the role of community advisory groups in representing researchers and communities in Malawi. AB - Community engagement to protect and empower participating individuals and communities is an ethical requirement in research. There is however limited evidence on effectiveness or relevance of some of the approaches used to improve ethical practice. We conducted a study to understand the rationale, relevance and benefits of community engagement in health research. This paper draws from this wider study and focuses on factors that shaped Community Advisory Group (CAG) members' selection processes and functions in Malawi. A qualitative research design was used; two participatory workshops were conducted with CAG members to understand their roles in research. Workshop findings were triangulated with insights from ethnographic field notes, key informant interviews with stakeholders, focus group discussions with community members and document reviews. Data were coded manually and thematic content analysis was used to identify main issues. Results have shown that democratic selection of CAG members presented challenges in both urban and rural settings. We also noted that CAG members perceived their role as a form of employment which potentially led to ineffective representation of community interests. We conclude that democratic voting is not enough to ensure effective representation of community's interests of ethical relevance. CAG members' abilities to understand research ethics, identify potential harms to community and communicate feedback to researchers is critical to optimise engagement of lay community and avoid tokenistic engagement. PMID- 28872745 TI - Neural mechanisms of extinguishing drug and pleasant cue associations in human addiction: role of the VMPFC. AB - The neurobiological mechanisms that underlie the resistance of drug cue associations to extinction in addiction remain unknown. Fear extinction critically depends on the ventromedial prefrontal cortex (VMPFC). Here, we tested if this same region plays a role in extinction of non-fear, drug and pleasant cue associations. Eighteen chronic cocaine users and 15 matched controls completed three functional MRI scans. Participants first learned to associate an abstract cue (the conditioned stimulus, CS) with a drug-related (CSD+ ) or pleasant (CSP+ ) image. Extinction immediately followed where each CS was repeatedly presented without the corresponding image. Participants underwent a second identical session 24 hours later to assess retention of extinction learning. Results showed that like fear extinction, non-fear-based extinction relies on the VMPFC. However, extinction-related changes in the VMPFC differed by cue valence and diagnosis. In controls, VMPFC activation to the CSD+ (which was unpleasant for participants) gradually increased as in fear extinction, while it decreased to the CSP+ , consistent with a more general role of the VMPFC in flexible value updating. Supporting a specific role in extinction retention, we further observed a cross-day association between VMPFC activation and skin conductance, a classic index of conditioned responses. Finally, cocaine users showed VMPFC abnormalities for both CSs, which, in the case of the CSD+ , correlated with craving. These data suggest a global deficit in extinction learning in this group that may hinder extinction-based treatment efforts. More broadly, these data show that the VMPFC, when functionally intact, supports extinction learning in diverse contexts in humans. PMID- 28872747 TI - Formation of Stable Tin Perovskites Co-crystallized with Three Halides for Carbon Based Mesoscopic Lead-Free Perovskite Solar Cells. AB - We synthesized and characterized methylammonium (MA) mixed tri-halide tin perovskites (MASnIBr2-x Clx ) for carbon-based mesoscopic solar cells free of lead and hole-transporting layers. Varied SnCl2 /SnBr2 ratios yielded tin perovskites with three halides (I, Br, and Cl) co-crystallized inside the tin perovskite. When the SnCl2 proportion was >=50 % (x>=1), phase separation occurred to give MASnI3-y Bry and MASnCl3-z Brz in the stoichiometric proportions of their precursors, confirmed by XRD. A device with MASnIBr1.8 Cl0.2 (SnCl2 =10 %) showed the best photovoltaic performance: JSC =14.0 mA cm-2 , VOC =380 mV, FF=0.573, and PCE=3.1 %, and long-term stability. Electrochemical impedance spectra (EIS) show superior charge recombination and dielectric relaxation properties for the MASnIBr1.8 Cl0.2 cell. Transient PL decays showed the intrinsic problem of tin-based perovskites with average lifetimes less than 100 ps. PMID- 28872748 TI - Thirty-day mortality after systemic anticancer treatment as a real-world, quality of-care indicator: the Northland experience. AB - BACKGROUND: Systemic anticancer treatment (SACT) at the end of life is considered poor practice due to its futility and associated toxicities. Consequently, 30-day mortality after SACT is increasingly recognised as a potential real-world quality of-care indicator in medical oncology. AIMS: Whangarei Base Hospital (WBH) provides outpatient SACT treatment to all patients living in the Northland region of New Zealand. The goal of this study was to report our 30-day mortality after SACT and to contribute to the experience of its use in Australasia. METHODS: In this retrospective study, the WBH electronic database was searched to identify all patients who had received SACT in WBH from 1 January 2012 to 31 December 2016. Patients who died within 30 days of their last treatment were shortlisted. Records were reviewed identifying key demographic, disease, treatment and mortality data. Composite 30-day mortality index and that of each tumour stream were calculated. Key findings were described using descriptive statistics. RESULTS: Over 5 years, 1103 patients received SACT in WBH, with 57 patients dying within 30 days of treatment, resulting in a composite 30-day mortality rate of 5.17%. One patient died receiving curative intent SACT. More deaths occurred in SACT-naive patients and during the first two cycles of therapy. Of the deaths, 28% was attributed to SACT, while 59.7% was attributed to cancer progression. CONCLUSION: Thirty-day mortality rates were comparable to studies from larger institutions. We demonstrated the feasibility of this index for auditing practice in smaller oncology units over a longer timeframe. PMID- 28872749 TI - Outstanding contribution to pediatric anesthesiology: An interview with Dr. Robert H. Friesen. AB - Dr. Robert H. Friesen, (1946-) Professor of Anesthesiology, Children's Hospital Colorado, University of Colorado, Anschutz Medical Campus, has played a pivotal and pioneering role in the development of pediatric and congenital cardiac anesthesiology. His transformative research included the study of the hemodynamic effects of inhalational and intravenous anesthetic agents in the newborn and the effects of anesthetic agents on pulmonary vascular resistance in patients with pulmonary hypertension. As a model clinician-scientist, educator, and administrator, he changed the practice of pediatric anesthesia and shaped the careers of hundreds of physicians-in-training, imbuing them with his core values of honesty, integrity, and responsibility. Based on a series of interviews with Dr. Friesen, this article reviews a career that advanced pediatric and congenital cardiac anesthesia during the formative years of the specialties. PMID- 28872750 TI - Multi-centre, prospective evaluation of the Seldinger technique for difficult male urethral catheter insertions by non-urology trained doctors. AB - OBJECTIVE: To evaluate the safety and effectiveness of the Seldinger technique by non-urology trained (NUT) doctors for difficult male indwelling urinary catheter (IDC) insertions. PATIENTS AND METHODS: In all, 115 patients and 57 participating NUT doctors were recruited by the urologist or urology registrar, when contacted in regards to failed IDC insertion. The successful passage of an IDC by the NUT doctors using the Seldinger technique with a straight, hydrophilic guidewire was assessed in our prospective, multicentre evaluation. Instruction of this technique was via bedside teaching by the urology registrar or via video media. RESULTS: The 115 patients, involving 57 NUT doctors, were prospectively evaluated across four sites; 93% (107/115) of cases had successful placement of an IDC with the Seldinger technique by a NUT doctor. No complications with the Seldinger technique were recorded. In 80 patients (69.6%), the technique was successfully performed by a NUT doctor without attendance by a urologist or urology registrar, with instruction provided from video media or prior bedside teaching by the urology registrar. CONCLUSIONS: Our study is the first to validate the safety and effectiveness of the Seldinger technique for difficult male IDC insertion performed by NUT doctors. This technique can be taught via video education and thus has important implications for health services where urological support is not readily available. PMID- 28872751 TI - Transport Matters: Boosting CO2 Electroreduction in Mixtures of [BMIm][BF4 ]/Water by Enhanced Diffusion. AB - Room-temperature ionic liquids (RTILs) are promising new electrolytes for efficient carbon dioxide reduction. However, due to their high viscosity, the mass transport of CO2 in RTILs is typically slow, at least one order of magnitude slower than in aqueous systems. One possibility to improve mass transport in RTILs is to decrease their viscosity through dilution with water. Herein, defined amounts of water are added to 1-butyl-3methylimidazolium tetrafluoroborate ([BMIm][BF4 ]), which is a hydrophilic RTIL. Electrochemical measurements on quiescent and hydrodynamic systems both indicate enhanced CO2 electroreduction. This enhancement has its origin in thermodynamic/kinetic effects (the addition of water increases the availability of H+ , which is a reaction partner of CO2 electroreduction) and in an increased rate of transport due to lower viscosity. Electrochemically determined diffusion coefficients for CO2 in [BMIm][BF4 ]/water systems agree well with values determined by NMR spectroscopy. PMID- 28872753 TI - African tick-bite fever - a tantalizing souvenir from South Africa. PMID- 28872752 TI - Time on androgen deprivation therapy and adaptations to exercise: secondary analysis from a 12-month randomized controlled trial in men with prostate cancer. AB - OBJECTIVES: To explore if duration of previous exposure to androgen deprivation therapy (ADT) in men with prostate cancer (PCa) undertaking a year-long exercise programme moderates the exercise response with regard to body composition and muscle performance, and also to explore the moderator effects of baseline testosterone, time since ADT, and baseline value of the outcome. PATIENTS AND METHODS: In a multicentre randomized controlled trial, 100 men who had previously undergone either 6 months (short-term) or 18 months (long-term) of ADT in combination with radiotherapy, as part of the TROG 03.04 RADAR trial, were randomized to 6 months supervised exercise, followed by a 6-month home-based maintenance programme, or to printed physical activity educational material for 12 months across 13 university-affiliated exercise clinics in Australia and New Zealand. The participants were long-term survivors of PCa with a mean age of 71.7 +/- 6.4 years, and were assessed for lower extremity performance (repeated chair rise), with a subset of men (n = 57) undergoing additional measures for upper and lower body muscle strength and body composition (lean mass, fat mass, appendicular skeletal muscle [ASM]) by dual X-ray absorptiometry. Data were analysed using generalized estimating equations. RESULTS: Time on ADT significantly moderated the exercise effects on chair rise (betainteraction = 1.3 s, 95% confidence interval [CI] -2.6 to 0.0), whole-body lean mass (betainteraction = 1194 g, 95% CI 234 to 2153) and ASM mass (betainteraction = 562 g, 95% CI 49 to 1075), and approached significance for fat mass (betainteraction = -1107 g, 95% CI -2346 to 132), with greater benefits for men previously on long-term ADT. At 6 months, the intervention effects on chair rise time -1.5 s (95% CI -2.5 to -0.5), whole-body lean mass 824 g (95% CI 8 to 1640), ASM mass 709 g (95% CI 260 to 1158), and fat mass -1377 g (95% CI -2156 to -598) were significant for men previously on long-term ADT, but not for men on short term ADT. At 12 months, the intervention effects for men on long-term ADT remained significant for the chair rise, with improved performance (-2.0 s, 95% CI -3.0 to -1.0) and increased ASM (537 g, 95% CI 153 to 921). Time on ADT did not moderate the exercise effects on muscle strength, nor did time since ADT cessation moderate any intervention effects. Similarly, testosterone and baseline values of the outcome had negligible moderator effects. CONCLUSIONS: Men with PCa previously treated long-term with ADT respond more favourably to exercise in terms of lower body muscle performance and body composition (lean and fat mass, and ASM) than those with short-term ADT exposure. As a result, men who were formerly on long-term androgen suppression regimens should be especially prescribed exercise medicine interventions to alleviate residual treatment related adverse effects. PMID- 28872754 TI - Contribution of virtual biopsy to the screening of microvascular invasion in hepatocellular carcinoma: A pilot study. AB - BACKGROUND & AIMS: Microvascular invasion (mVI) is a major prognostic factor in hepatocellular carcinoma (HCC) that cannot be detected before surgery. Predictive biomarkers of mVI are thus urgently needed. We have developed an original approach of virtual biopsy to assess the performance of an immunohistochemical panel comprising three biomarkers of mVI (H4K16ac, H4K20me2, PIVKA-II) for the prediction of mVI in HCC core needle biopsies (CNB). METHODS: A test set of HCC surgical specimens (n = 64) and an independent validation set of HCC CNB (n = 42) were retrospectively constituted. Immunostainings were first quantified in the test set on the whole tissue section, to determine optimal cut-off values for each marker. From the digitised image of the whole section, three virtual biopsies were provided. Immunostainings and accuracy of the panel for the prediction of mVI were further assessed in virtual biopsies and in the validation set of CNB. RESULTS: In virtual biopsies, PIVKA-II/H4K16ac had the best performance for prediction of mVI, with sensitivity, specificity, predictive positive value (PPV), and predictive negative value (PNV) of 30%, 97%, 91%, 56%, respectively. In CNB, PIVKA-II/H4K20me2 showed the best accuracy for prediction of mVI, with sensitivity, specificity, PPV, and NPV of 43%, 95%, 90%, and 62%, respectively. The two panels were independent predictive factors of mVI (PIVKA II/H4K16ac, P = .037; PIVKA-II/H4K20me2, P = .026). CONCLUSION: This study shows that a panel of two markers is able to predict mVI in HCC CNB, and pave the way for the future development of prognostic biomarkers in HCC that could guide the therapeutic strategy. PMID- 28872755 TI - African communal basis for autonomy and life choices. AB - I argue that the metaphysical capacity of autonomy is not intrinsically valuable; it is valuable only when used in relation to a community's values and instrumentally for making the proper choices that will promote one's own and the community's well-being. I use the example of the choice to take one's life by suicide to illuminate this view. I articulate a plausible African conception of personhood as a basis for the idea of relational autonomy. I argue that this conception is better understood as a social-moral thesis, and not a metaphysical thesis. A metaphysical thesis gives an account of the abstract nature of an atomic individual, his agency, and rational choice. The social-moral thesis indicates that personhood and autonomy are positive and relational to the life plans, well-being, material conditions, and the best means for achieving them that are made available and possible by harmonious living in a community. This idea of autonomy is not just having the capacity of freewill; it also involves how such freewill is used, in terms of how an individual's choices are guided by internalized communal values. PMID- 28872756 TI - Electrochemical CO2 Reduction: A Classification Problem. AB - In this work, we propose four non-coupled binding energies of intermediates as descriptors, or "genes", for predicting the product distribution in CO2 electroreduction. Simple reactions can be understood by the Sabatier principle (catalytic activity vs. one descriptor), while more complex reactions tend to give multiple very different products and consequently the product selectivity is a more complex property to understand. We approach this, as a logistical classification problem, by grouping metals according to their major experimental product from CO2 electroreduction: H2 , CO, formic acid and beyond CO* (hydrocarbons or alcohols). We compare the groups in terms of multiple binding energies of intermediates calculated by density functional theory. Here, we find three descriptors to explain the grouping: the adsorption energies of H*, COOH*, and CO*. To further classify products beyond CO*, we carry out formaldehyde experiments on Cu, Ag, and Au and combine these results with the literature to group and differentiate alcohol or hydrocarbon products. We find that the oxygen binding (adsorption energy of CH3 O*) is an additional descriptor to explain the alcohol formation in reduction processes. Finally, the adsorption energy of the four intermediates, H*, COOH*, CO*, and CH3 O*, can be used to differentiate, group, and explain products in electrochemical reduction processes involving CO2 , CO, and carbon-oxygen compounds. PMID- 28872757 TI - PROCAL: A Set of 40 Peptide Standards for Retention Time Indexing, Column Performance Monitoring, and Collision Energy Calibration. AB - Beyond specific applications, such as the relative or absolute quantification of peptides in targeted proteomic experiments, synthetic spike-in peptides are not yet systematically used as internal standards in bottom-up proteomics. A number of retention time standards have been reported that enable chromatographic aligning of multiple LC-MS/MS experiments. However, only few peptides are typically included in such sets limiting the analytical parameters that can be monitored. Here, we describe PROCAL (ProteomeTools Calibration Standard), a set of 40 synthetic peptides that span the entire hydrophobicity range of tryptic digests, enabling not only accurate determination of retention time indices but also monitoring of chromatographic separation performance over time. The fragmentation characteristics of the peptides can also be used to calibrate and compare collision energies between mass spectrometers. The sequences of all selected peptides do not occur in any natural protein, thus eliminating the need for stable isotope labeling. We anticipate that this set of peptides will be useful for multiple purposes in individual laboratories but also aiding the transfer of data acquisition and analysis methods between laboratories, notably the use of spectral libraries. PMID- 28872758 TI - A systematic review of Clostridium difficile infection following reversal of ileostomy. AB - AIM: The incidence of Clostridium difficile infection (CDI) has been reported to be as high as 4% following ileostomy reversal. CDI can be associated with significant morbidity. A systematic review on this subject has not been previously reported; our aim was to review the literature to establish incidence and to evaluate the factors that may contribute to an increased risk of CDI following ileostomy reversal. METHOD: A systematic review of Ovid, Embase and Medline was undertaken. Search terms included C. difficile, reversal of ileostomy and ileostomy closure. Articles were included where at least one case of C. difficile-associated diarrhoea following reversal of defunctioning ileostomy was reported. Data extraction for articles was performed by two authors, using predefined data fields. The primary outcome measure was incidence of CDI amongst patients undergoing ileostomy reversal. Secondary outcomes were defunctioning time, antibiotic regime, acid suppression, time to onset of symptoms and study conclusions including colectomy and mortality rate. RESULTS: Eleven articles were included (five case reports and six cohort studies). The overall incidence of CDI was 1.8% (242/13 728). The mean defunctioning time was 8.7 months (range 6-12). A variety of antibiotic regimes were described. Mean time to onset of symptoms was 6 days (range 3-14). Use of acid suppression, colectomy or mortality rate were frequently not reported. CONCLUSION: CDI should be recognized as a potentially life-threatening complication of ileostomy closure. Careful consideration should be given to peri-operative antibiotic regime, acid suppression, timing of reversal and appropriate preoperative counselling of patients. PMID- 28872759 TI - Hijacking of the nucleolar protein fibrillarin by TGB1 is required for cell-to cell movement of Barley stripe mosaic virus. AB - Barley stripe mosaic virus (BSMV) Triple Gene Block1 (TGB1) is a multifunctional movement protein with RNA-binding, ATPase and helicase activities which mainly localizes to the plasmodesmata (PD) in infected cells. Here, we show that TGB1 localizes to the nucleus and the nucleolus, as well as the cytoplasm, and that TGB1 nuclear-cytoplasmic trafficking is required for BSMV cell-to-cell movement. Prediction analyses and laser scanning confocal microscopy (LSCM) experiments verified that TGB1 possesses a nucleolar localization signal (NoLS) (amino acids 95-104) and a nuclear localization signal (NLS) (amino acids 227-238). NoLS mutations reduced BSMV cell-to-cell movement significantly, whereas NLS mutations almost completely abolished movement. Furthermore, neither the NoLS nor NLS mutant viruses could infect Nicotiana benthamiana systemically, although the NoLS mutant virus was able to establish systemic infections of barley. Protein interaction experiments demonstrated that TGB1 interacts directly with the glycine-arginine-rich (GAR) domain of the nucleolar protein fibrillarin (Fib2). Moreover, in BSMV-infected cells, Fib2 accumulation increased by about 60%-70% and co-localized with TGB1 in the plasmodesmata. In addition, BSMV cell-to-cell movement in fib2 knockdown transgenic plants was reduced to less than one-third of that of non-transgenic plants. Fib2 also co-localized with both TGB1 and BSMV RNA, which are the main components of the ribonucleoprotein (RNP) movement complex. Collectively, these results show that TGB1-Fib2 interactions play a direct role in cell-to-cell movement, and we propose that Fib2 is hijacked by BSMV TGB1 to form a BSMV RNP which functions in cell-to-cell movement. PMID- 28872761 TI - Granulomatous slack skin with vascular involvement. PMID- 28872762 TI - Communicating risk with aneuploidy screening: things are never as simple as they appear to be. PMID- 28872760 TI - Relating gastric scintigraphy and symptoms to motility capsule transit and pressure findings in suspected gastroparesis. AB - BACKGROUND: Wireless motility capsule (WMC) findings are incompletely defined in suspected gastroparesis. We aimed to characterize regional WMC transit and contractility in relation to scintigraphy, etiology, and symptoms in patients undergoing gastric emptying testing. METHODS: A total of 209 patients with gastroparesis symptoms at NIDDK Gastroparesis Consortium centers underwent gastric scintigraphy and WMCs on separate days to measure regional transit and contractility. Validated questionnaires quantified symptoms. KEY RESULTS: Solid scintigraphy and liquid scintigraphy were delayed in 68.8% and 34.8% of patients; WMC gastric emptying times (GET) were delayed in 40.3% and showed 52.8% agreement with scintigraphy; 15.5% and 33.5% had delayed small bowel (SBTT) and colon transit (CTT) times. Transit was delayed in >=2 regions in 23.3%. Rapid transit was rarely observed. Diabetics had slower GET but more rapid SBTT versus idiopathics (P <= .02). GET delays related to greater scintigraphic retention, slower SBTT, and fewer gastric contractions (P <= .04). Overall gastroparesis symptoms and nausea/vomiting, early satiety/fullness, bloating/distention, and upper abdominal pain subscores showed no relation to WMC transit. Upper and lower abdominal pain scores (P <= .03) were greater with increased colon contractions. Constipation correlated with slower CTT and higher colon contractions (P = .03). Diarrhea scores were higher with delayed SBTT and CTT (P <= .04). CONCLUSIONS & INFERENCES: Wireless motility capsules define gastric emptying delays similar but not identical to scintigraphy that are more severe in diabetics and relate to reduced gastric contractility. Extragastric transit delays occur in >40% with suspected gastroparesis. Gastroparesis symptoms show little association with WMC profiles, although lower symptoms relate to small bowel or colon abnormalities. PMID- 28872764 TI - Association between metabolic syndrome and intravesical prostatic protrusion in patients with benign prostatic enlargement and lower urinary tract symptoms (MIPS Study). AB - OBJECTIVE: To investigate the association between metabolic syndrome (MetS) and morphological features of benign prostatic enlargement (BPE), including total prostate volume (TPV), transitional zone volume (TZV) and intravesical prostatic protrusion (IPP). PATIENTS AND METHODS: Between January 2015 and January 2017, 224 consecutive men aged >50 years presenting with lower urinary tract symptoms (LUTS) suggestive of BPE were recruited to this multicentre cross-sectional study. MetS was defined according to International Diabetes Federation criteria. Multivariate linear and logistic regression models were performed to verify factors associated with IPP, TZV and TPV. RESULTS: Patients with MetS were observed to have a significant increase in IPP (P < 0.01), TPV (P < 0.01) and TZV (P = 0.02). On linear regression analysis, adjusted for age and metabolic factors of MetS, we found that high-density lipoprotein (HDL) cholesterol was negatively associated with IPP (r = -0.17), TPV (r = -0.19) and TZV (r = -0.17), while hypertension was positively associated with IPP (r = 0.16), TPV (r = 0.19) and TZV (r = 0.16). On multivariate logistic regression analysis adjusted for age and factors of MetS, hypertension (categorical; odds ratio [OR] 2.95), HDL cholesterol (OR 0.94) and triglycerides (OR 1.01) were independent predictors of TPV >= 40 mL. We also found that HDL cholesterol (OR 0.86), hypertension (OR 2.0) and waist circumference (OR 1.09) were significantly associated with TZV >= 20 mL. On age-adjusted logistic regression analysis, MetS was significantly associated with IPP >= 10 mm (OR 34.0; P < 0.01), TZV >= 20 mL (OR 4.40; P < 0.01) and TPV >= 40 mL (OR 5.89; P = 0.03). CONCLUSION: We found an association between MetS and BPE, demonstrating a relationship with IPP. PMID- 28872763 TI - Anion Layering and Steric Hydration Repulsion on Positively Charged Surfaces in Aqueous Electrolytes. AB - The molecular structure at charged solid/liquid interfaces is vital for many chemical or electrochemical processes, such as adhesion, catalysis, or the stability of colloidal dispersions. How cations influence structural hydration forces and interactions across negatively charged surfaces has been studied in great detail. However, how anions influence structural hydration forces on positively charged surfaces is much less understood. Herein we report force versus distance profiles on freshly cleaved mica using atomic force microscopy with silicon tips. We characterize steric anion hydration forces for a set of common anions (Cl- , ClO4- , NO3- , SO42- and PO43- ) in pure acids at pH ~1, where protons are the co-ions. Solutions containing anions with low hydration energies exhibit repulsive structural hydration forces, indicating significant ion and/or water structuring within the first 1-2 nm on a positively charged surface. We attribute this to specific adsorption effects within the Stern layer. In contrast, ions with high hydration energies show exponentially repulsive hydration forces, indicating a lower degree of structuring within the Stern layer. The presented data demonstrates that anion hydration forces in the inner double layer are comparable to cation hydration forces, and that they qualitatively correlate with hydration free energies. This work contributes to understanding interaction processes in which positive charge is screened by anions within an electrolyte. PMID- 28872765 TI - Digital health technology and diabetes management. AB - Diabetes care is largely dependent on patient self-management and empowerment, given that patients with diabetes must make numerous daily decisions as to what to eat, when to exercise, and determine their insulin dose and timing if required. In addition, patients and providers are generating vast amounts of data from many sources, including electronic medical records, insulin pumps, sensors, glucometers, and other wearables, as well as evolving genomic, proteomic, metabolomics, and microbiomic data. Multiple digital tools and apps have been developed to assist patients to choose wisely, and to enhance their compliance by using motivational tools and incorporating incentives from social media and gaming techniques. Healthcare teams (HCTs) and health administrators benefit from digital developments that sift through the enormous amounts of patient-generated data. Data are acquired, integrated, analyzed, and presented in a self explanatory manner, highlighting important trends and items that require attention. The use of decision support systems may propose data-driven actions that, for the most, require final approval by the patient or physician before execution and, once implemented, may improve patient outcomes. The digital diabetes clinic aims to incorporate all digital patient data and provide individually tailored virtual or face-to-face visits to those persons who need them most. Digital diabetes care has demonstrated only modest HbA1c reduction in multiple studies and borderline cost-effectiveness, although patient satisfaction appears to be increased. Better understanding of the barriers to digital diabetes care and identification of unmet needs may yield improved utilization of this evolving technology in a safe, effective, and cost-saving manner. PMID- 28872766 TI - HT-SuperSAGE of the gut tissue of a Vip3Aa-resistant Heliothis virescens (Lepidoptera: Noctuidae) strain provides insights into the basis of resistance. AB - Multitoxin Bt-crops expressing insecticidal toxins with different modes of action, for example, Cry and Vip, are expected to improve resistance management in target pests. While Cry1A resistance has been relatively well characterized in some insect species, this is not the case for Vip3A, for which no mechanism of resistance has yet been identified. Here we applied HT-SuperSAGE to analyze the transcriptome of the gut tissue of tobacco budworm Heliothis virescens (F.) laboratory-selected for Vip3Aa resistance. From a total of 1 324 252 sequence reads, 5 895 126-bp tags were obtained representing 17 751 nonsingleton unique transcripts (UniTags) from genetically similar Vip3Aa-resistant (Vip-Sel) and susceptible control (Vip-Unsel) strains. Differential expression was significant (>=2.5 fold or <=0.4; P < 0.05) for 1989 sequences (11.2% of total UniTags), where 420 represented overexpressed (OE) and 1569 underexpressed (UE) genes in Vip-Sel. BLASTN searches mapped 419 UniTags to H. virescens sequence contigs, of which, 416 (106 OE and 310 UE) were unambiguously annotated to proteins in NCBI nonredundant protein databases. Gene Ontology distributed 345 of annotated UniTags in 14 functional categories with metabolism (including serine-type hydrolases) and translation/ribosome biogenesis being the most prevalent. A UniTag homologous to a particular member of the REsponse to PAThogen (REPAT) family was found among most overexpressed, while UniTags related to the putative Vip3Aa-binding ribosomal protein S2 (RpS2) were underexpressed. qRT-PCR of a subset of UniTags validated the HT-SuperSAGE data. This study is the first providing lepidopteran gut transcriptome associated with Vip3Aa resistance and a foundation for future attempts to elucidate the resistance mechanism. PMID- 28872767 TI - One hundred twenty-five fat myringoplasties: Does marginal perforation matter? PMID- 28872768 TI - Skene's gland adenocarcinoma with intestinal differentiation: A case report and literature review. AB - Adenocarcinoma of Skene's gland (the female homolog to the male prostate) is extremely rare, with only a few cases reported. We present a case of Skene's gland adenocarcinoma with intestinal differentiation. The patient was a 69-year old Japanese woman who was operated on for a recurrent tumor of the external ostium of the urethra. Histopathologically, the tumor showed glandular and cribriform patterns with a signet-ring cell component in a mucus lake. Immunohistochemically, the tumor cells were positive for prostate specific acid phosphatase (PSAP), and AMACR, and negative for Nkx3.1 or prostate specific antigen (PSA). Although in situ lesion could not be discovered, positive immunostainings for Nkx3.1, PSAP, and androgen receptor in the remaining paraurethral glands around the tumor indirectly but strongly suggest that the tumor had originated from Skene's gland. This tumor also showed intestinal differentiation as suggested histologically and by positive immunostainings for CDX2, MUC2, and CK20, along with negative immunostaining for CK7. It is often very difficult to identify the origin of a female urethral carcinoma. In such cases, immunohistochemical features can be an essential clue to the origin. We therefore present this instructive case with a literature review. PMID- 28872769 TI - Consideration of the Development of the Gastrointestinal Tract in the Choice of Species for Regulatory Juvenile Studies. AB - Although the rat is close to being the automatic choice for regulatory juvenile toxicity studies, there are several shortcomings in this model. Choosing a species should take into serious consideration the importance of gastrointestinal tract development in the period before weaning as this may have a major effect on exposure. A comparison of the anatomical changes in the stomach and small intestine of mini-pig and rat show that the mini-pig is a far closer model for man than is the rat, although there are a few unusual aspects of small intestinal development in the mini-pig. Considerations of the development of the gastrointestinal tract and choice of species have the potential to affect safety assessment and should be a prime consideration when planning an investigation. Birth Defects Research 110:56-62, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28872770 TI - Hormone-secreting adrenal tumours cause severe hypertension and high rates of poor pregnancy outcome; a UK Obstetric Surveillance System study with case control comparisons. AB - OBJECTIVE: To examine the management and outcomes of adrenal tumours in pregnancy. DESIGN: A national observational, cohort study over 4 years using the UK Obstetric Surveillance System (UKOSS). SETTING: Consultant-led obstetric units. PATIENTS: Women with phaeochromocytoma, primary aldosteronism or Cushing's syndrome diagnosed before or during pregnancy. METHODS: Clinical features of UKOSS cases were compared with those of women with adrenal tumours reported from 1985-2015. Nested case-control comparisons involving the UKOSS cases as well as those identified in the literature were performed for pregnancy outcome data using UKOSS controls with uncomplicated singleton (n = 2250) pregnancy and data from the Office of National Statistics (ONS). MAIN OUTCOME MEASURES: Incidence, management and frequency of adverse maternal and offspring outcomes of adrenal tumours in pregnancy. RESULTS: Fifteen pregnant women met the inclusion criteria: ten phaeochromocytoma, three primary aldosteronism and two Cushing's syndrome. All of the tumours had an incidence rate <2 per 100 000 pregnancies. Clinical symptoms were similar to those in non-pregnant women due to the hormones released. All women had severe hypertension, and in those diagnosed in pregnancy prior to conception. There was a significantly increased risk of adverse pregnancy outcomes in affected women, with increased rates of stillbirth, preterm labour and operative delivery. CONCLUSIONS: Adrenal tumours are associated with increased risks for pregnant women and their babies. Data on these tumours to inform practice are limited and international collaborative efforts are likely to be needed. TWEETABLE ABSTRACT: Study of hormone-secreting adrenal tumours in pregnancy linked with high BP and high rates of fetal morbidity. PMID- 28872772 TI - President's Letter September 2017. PMID- 28872771 TI - Screening for bipolar disorder with self-administered questionnaires: A critique of the concept and a call to stop publishing studies of their performance in psychiatric samples. PMID- 28872773 TI - Exploring provider and parental perceptions to influenza vaccination in the inpatient setting. AB - BACKGROUND: Hospitalization provides an ideal opportunity for immunization, but few studies have explored provider and parental attitudes toward pediatric inpatient vaccination against influenza. OBJECTIVES: The objectives were to determine provider and caregiver attitudes and explore potential barriers to inpatient influenza vaccination. METHODS: We developed and distributed two surveys to parents/caregivers as well as providers of general pediatric inpatients at Children's Hospital Colorado between October 2014 and March 2015 assessing attitudes toward influenza and inpatient influenza vaccination. We analyzed the Likert scale responses using univariate analyses and multiple logistic regression to assess associations between responses and vaccination status. RESULTS: The overall response rate was 95% and 58% for parents and providers, respectively. Parents of hospitalized children who agreed that flu vaccines are safe (adjusted OR 2.50 [95%CI 1.76-3.58]), and that the influenza vaccine is needed every year had higher odds of having a vaccinated child (adjusted OR 3.30 [95%CI 2.30-4.81]). Most providers (91%) agree that influenza vaccination is an important priority among inpatients, but believe that parental misconceptions and their reluctance for inpatient vaccination are the most important barriers to influenza vaccination. Providers forgetting to ask about vaccination status and order the vaccine are the next most commonly identified barriers. In contrast, most parents surveyed had favorable attitudes toward inpatient influenza vaccination and disagreed that their child was too sick to receive the vaccine during hospitalization. PMID- 28872774 TI - Prospective randomised non-inferiority trial of pelvic drain placement vs no pelvic drain placement after robot-assisted radical prostatectomy. AB - OBJECTIVE: To determine if eliminating the prophylactic placement of a pelvic drain (PD) after robot-assisted radical prostatectomy (RARP) affects the incidence of early (90-day) postoperative adverse events. PATIENTS AND METHODS: In this parallel-group, blinded, non-inferiority trial, we randomised patients planning to undergo RARP to one of two arms: no drain placement (ND) or PD placement. Patients with demonstrable intraoperative leakage upon bladder irrigation were excluded. Randomisation sequence was determined a priori using a computer algorithm, and included a stratified design with respect to low vs intermediate/high D'Amico risk classifications. Surgeons remained blinded to the randomisation arm until final eligibility was verified at the end of the RARP. The primary endpoint was overall incidence of 90-day complications which, based on our standard treatment using PD retrospectively, was estimated at 13%. The non inferiority margin was set at 10%, and the planned sample size was 312. An interim analysis was planned and conducted when one-third of the planned accrual and follow-up was completed, to rule out futility if the delta margin was in excess of 0.1389. RESULTS: From 2012 to 2016, 189 patients were accrued to the study, with 92 patients allocated to the ND group and 97 to the PD group. Due to lower than expected accrual rates, accrual to the study was halted by regulatory entities, and we did not reach the intended accrual goal. The ND and PD groups were comparable for median PSA level (6.2 vs 5.8 ng/mL, P = 0.5), clinical stage (P = 0.8), D'Amico risk classification (P = 0.4), median lymph nodes dissected (17 vs 18, P = 0.2), and proportion of patients receiving an extended pelvic lymph node dissection (70.7% vs 79.4%, P = 0.3). Incidence of 90-day overall and major (Clavien-Dindo grade >III) complications in the ND group (17.4% and 5.4%, respectively) was not inferior to the PD group (26.8% and 5.2%, respectively; P < 0.001 and P = 0.007 for difference of proportions <10%, respectively). Symptomatic lymphocoele rates (2.2% in the ND group, 4.1% in the PD group) were comparable between the two arms (P = 0.7). CONCLUSIONS: Incidence of adverse events in the ND group was not inferior to the group who received a PD. In properly selected patients, PD placement after RARP can be safely withheld without significant additional morbidity. PMID- 28872775 TI - The impact of unilateral oophorectomy on ovarian reserve in assisted reproduction: a systematic review and meta-analysis. AB - BACKGROUND: Women following unilateral oophorectomy (UO) are occasionally encountered during assisted reproduction treatment. OBJECTIVE: To explore the impact of UO on ovarian reserve in assisted reproduction. SEARCH STRATEGY: An electronic database search was performed using PubMed, EBSCO, ISI, Trip, ClinicalTrial.gov and the Cochrane library followed by a manual search to identify published research between January 1978 and December 2015. SELECTION CRITERIA: Controlled studies that compared infertile women following UO undergoing IVF-ET treatment with women with two intact ovaries. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted the data concerning the impact of UO on ovarian reserve tests, ovarian response to controlled ovarian hyperstimulation and clinical pregnancy rate. Meta-analysis was performed using these measures. MAIN RESULTS: Twenty-one studies were eligible for quantitative analysis. They included 1045 and 18 172 IVF cycles in women with one and two intact ovaries, respectively. Basal FSH weighted mean difference (WMD) was significant (2.01 IU/l; 95% CI: 0.24-3.79, P = 0.026). Similarly, the WMD of serum E2 level on the day of hCG administration was significant (WMD: -431 pg/ml; 95% CI: -616 to -246, P < 0.001). However, the weighted overall odds ratio (OR) of clinical pregnancy between women with a single ovary and women with two ovaries was comparable (overall OR: 0.76; 95% CI: 0.57-1.00, P = 0.054). All eligible studies were retrospectively conducted and the heterogeneity among ovarian response measures was high. CONCLUSIONS: Available pooled data supports an adverse effect of UO on ovarian reserve involving the quantity but not the quality of the ovarian pool. TWEETABLE ABSTRACT: Review finds women with one ovary removed have less IVF capacity but the same pregnancy rate as women with two ovaries. PMID- 28872776 TI - Social determinants of influenza hospitalization in the United States. AB - BACKGROUND: Influenza hospitalizations result in substantial morbidity and mortality each year. Little is known about the association between influenza hospitalization and census tract-based socioeconomic determinants beyond the effect of individual factors. OBJECTIVE: To evaluate whether census tract-based determinants such as poverty and household crowding would contribute significantly to the risk of influenza hospitalization above and beyond individual-level determinants. METHODS: We analyzed 33 515 laboratory-confirmed influenza-associated hospitalizations that occurred during the 2009-2010 through 2013-2014 influenza seasons using a population-based surveillance system at 14 sites across the United States. RESULTS: Using a multilevel regression model, we found that individual factors were associated with influenza hospitalization with the highest adjusted odds ratio (AOR) of 9.20 (95% CI 8.72-9.70) for those >=65 vs 5-17 years old. African Americans had an AOR of 1.67 (95% CI 1.60-1.73) compared to Whites, and Hispanics had an AOR of 1.21 (95% CI 1.16-1.26) compared to non-Hispanics. Among census tract-based determinants, those living in a tract with >=20% vs <5% of persons living below poverty had an AOR of 1.31 (95% CI 1.16 1.47), those living in a tract with >=5% vs <5% of persons living in crowded conditions had an AOR of 1.17 (95% CI 1.11-1.23), and those living in a tract with >=40% vs <5% female heads of household had an AOR of 1.32 (95% CI 1.25 1.40). CONCLUSION: Census tract-based determinants account for 11% of the variability in influenza hospitalization. PMID- 28872777 TI - Orexin A increases sympathetic nerve activity through promoting expression of proinflammatory cytokines in Sprague Dawley rats. AB - AIM: Accumulating evidence suggests that orexin signalling is involved in the regulation of blood pressure and cardiovascular function. However, the underlying mechanisms are not clear. Here, we test the hypothesis that upregulated orexin A signalling in the paraventricular nucleus (PVN) increases sympathetic nerve activity (SNA) through stimulating expression of proinflammatory cytokines (PICs). METHODS: In vivo sympathetic nerve recordings were performed to test the impact of PVN orexin signalling on sympathetic outflow in Sprague Dawley (SD) rats. Real-time PCR was carried out to assess effects of central administration of orexin A on PVN PICs expression in SD rats. To test whether orexin A-induced increases in PICs were exclusively mediated by orexin receptor 1 (OX1R), OX1R expressing PC12 (PC12-OX1R) cells were incubated with different dose of orexin A, and then, PICs mRNA and immunoreactivity were measured. RESULTS: Orexin A microinjection (25 pmol) into the PVN significantly increased splanchnic SNA (93.5%) and renal SNA (83.3%) in SD rats, and these increases were attenuated by OX1R antagonist SB408124. Intracerebroventricular injection of orexin A (0.2 nmol) into SD rats increased mRNA levels of PICs including IL-1-beta (2.7-fold), IL-6 (1.7-fold) and TNF-alpha (1.5-fold), as well as Fra1 (1.6-fold) in the PVN. Orexin A treatment in PC12-OX1R cells resulted in a dose- and time-dependent increase in the expression of PICs and Fra1, a subunit of AP1 transcriptional factor. The increase in the PICs was blocked by AP1 blocker curcumin. CONCLUSION: Paraventricular nucleus orexin system activation is involved in SNA regulation maybe through triggering AP1-PICs pathway. PMID- 28872779 TI - Metal-Free Boron-Containing Heterogeneous Catalysts. AB - Metal-free catalysts have distinct advantages over metal and metal oxide catalysts, such as lower cost as well as higher reliability and sustainability. Among the nonmetal compounds used in catalysis, boron-containing compounds with a few unique properties have been developed. In this Minireview, the recent advances in the field of boron-containing metal-free catalysts are presented, including binary and ternary boron-containing catalytic materials. Additionally, the three main applications in catalysis are considered, namely, electrocatalysis, thermal catalysis, and photocatalysis, with the role of boron discussed in depth for each specific catalytic application. Boron-containing compounds could have a substantial impact on the field of metal-free catalysts in the future. PMID- 28872778 TI - Effects of thiazolidinedione in patients with active bladder cancer. AB - OBJECTIVE: To examine the influence of perioperative thiazolidinedione (TZD) on cancer-specific outcomes in patients with diabetes mellitus (DM) undergoing radical cystectomy (RC) for urothelial carcinoma (UC). PATIENTS AND METHODS: A retrospective cohort of 173 patients with DM undergoing RC from 2005 to 2010 was identified. Of those, 53 were on TZD treatment at the time of RC, with 33 patients taking pioglitazone. Baseline clinicopathological characteristics, as well as cancer-specific survival (CSS), recurrence-free survival (RFS), and overall survival (OS) were compared between the patients on and off TZD therapy at the time of RC. In subgroup analysis, outcomes in patients specifically taking pioglitazone at the time of RC were compared to those not on a TZD. RESULTS: Baseline clinicopathological characteristics were similar between patients on and off TZD therapy at the time of RC. Overall, the median CSS rate was not reached in either group (P = 0.7). The estimated 5-year CSS was 67.8% in the non-TZD group and 66.3% in the TZD group. On multivariate analysis incorporating patient age, pathological T-staging, and adjuvant chemotherapy, TZD use was found not to be a significant predictor for CSS (hazard ratio 1.20, 95% confidence interval 0.66-2.17; P = 0.5). Additionally, RFS (P= 0.3) and OS (P = 0.2) were also similar between the two groups without adjusting for other variables. Comparison between patients taking pioglitazone vs patients not taking TZD yielded similar CSS (P = 0.2), RFS (P = 0.5), and OS (P= 0.2). CONCLUSIONS: CSS, as well as RFS and OS after RC were not compromised in patients on TZD therapy at the time of RC. Additional investigation is warranted in patients with non-muscle-invasive bladder cancer and muscle-invasive bladder cancer undergoing bladder-sparing procedures to assess the safety of using TZD in the setting of active UC. PMID- 28872780 TI - Impaired renal function affects clinical outcomes and management of patients with heart failure. AB - AIMS: Inpatients with heart failure and renal impairment have poor outcomes and variable quality of care. We investigate treatment practice and outcomes in an unselected real-world cohort using historical creatinine measurements. METHODS AND RESULTS: Admissions between 1/4/2013 and 30/4/2015 diagnosed at discharge with heart failure were retrospectively analysed. Stages of chronic kidney disease (CKD) and acute kidney injury (AKI) were calculated from creatinine at discharge and 3-12 months before admission. We identified 1056 admissions of 851 patients (mean age 76 years, 56% Caucasian, 36% with diabetes mellitus, 54% with ischaemic heart disease, and 57% with valvular heart disease). CKD was common; 36%-Stage 3a/b, 11%-Stage 4/5; patients were older, more often diabetic, with higher potassium, lower haemoglobin, and more oedema but similar prevalence of left ventricular systolic dysfunction (LVSD) compared patients with Stages 0-2. AKI was present in 17.0% (10.4%-Stage 1, 3.7%-Stage 2, and 2.9%-Stage 3); these had higher potassium and lower haemoglobin than patients with no AKI. Length of stay was longer in Stage 4/5 CKD [11 days; P = 0.008] and AKI [13 days; P = 0.006]. Mortality was higher with Stage 4/5 CKD (13.8% compared with 7.7% for Stages 0-2 CKD (P = 0.036)] and increased with AKI (5%-no AKI, 20.9%-Stage 1, 35.9%-Stage 2, and 48.4%-Stage 3; P < 0.001). Adjusted for age, diabetes, and LVSD, both AKI and Stage 4/5 CKD were independent predictors of in-hospital mortality. In survivors with LVSD, the discharge prescription of angiotensin converting enzyme inhibitors/angiotensin receptor blockers decreased with progressive CKD, [84%-no-mild, 59%-moderate, and 36%-severe CKD; P < 0.001]; this was not purely explained by hyperkalaemia. CONCLUSIONS: Inpatients with heart failure and renal impairment, acute and chronic, failed to receive recommended therapy and had poor outcomes. PMID- 28872781 TI - A method for assessment of the dynamic response of the arterial baroreflex. AB - AIM: The baroreflex is a key mechanism in cardiovascular regulation, and alterations in baroreceptor function are seen in many diseases, including heart failure, obesity and hypertension. We propose a new method for analysing baroreceptor function from continuous blood pressure (BP) and heart rate (HR) in both health and disease. METHODS: Forty-eight-hour data series of BP and HR were collected with telemetry. Sprague Dawley rats on standard chow (n = 11) served as controls, while rats on a high-fat, high-fructose (HFHC) diet (n = 6) constituted the obese-hypertensive model. A third group of rats underwent autonomic blockade (n = 6). An autoregressive-moving-average with exogenous inputs (ARMAX) model was applied to the data and compared with the alpha-coefficient. RESULTS: Autonomic blockade caused a significant reduction in the strength of the baroreflex as estimated by ARMAX [ARMAX- baroreflex sensitivity (BRS)] -0.03 +/- 0.01 vs. -0.19 +/- 0.04 bpm heartbeat-1) . Both methods showed a ~50% reduction in BRS in the obese-hypertensive group compared with control (body weight 531 +/- 27 vs. 458 +/ 19 g, P < 0.05; mean arterial pressure 119 +/- 3 vs. 102 +/- 1 mmHg, P < 0.05; ARMAX-BRS -0.08 +/- 0.01 vs. -0.15 +/- 0.01 bpm heartbeat-1 , P < 0.05; alpha coefficient BRS 0.51 +/- 0.07 vs. 0.89 +/- 0.07 ms mmHg-1 , P < 0.05). The ARMAX method additionally showed the open-loop gain of the baroreflex to be reduced by ~50% in the obese-hypertensive group (-2.3 +/- 0.3 vs. -4.1 +/- 0.3 bpm, P < 0.05), while the rate constant was similar between groups. CONCLUSION: The ARMAX model represents an efficient method for estimating several aspects of the baroreflex. The open-loop gain of the baroreflex was attenuated in obese hypertensive rats compared with control, while the time response was similar. The algorithm can be applied to other species including humans. PMID- 28872783 TI - Effect of Video-Assisted Teaching Module (VATM) on Knowledge of ASHAs regarding RNTCP in Kuchinda Block of Sambalpur (Odisha). AB - Infectious disease is a major public health issue for both developed and developing countries. Among infectious diseases, tuberculosis (TB) is most prevalent in the develop- ing countries. India is the highest TB burden country in the world and accounts for nearly one fifth (20%) of global burden of tuberculosis. A pre-experimental design where pre- and post-test without control group with experimental approach was undertaken in Kuchinda block of Sambalpur district (Odisha) with the objectives to assess effectiveness of Video-assisted Teaching Module (VATM) on knowledge of Accredited Social Health Activists (ASHAs) regarding Revised National Tuberculosis Control Programme (RNTCP) Data were collected from 52 ASHAs, selected by systematic random sampling technique through structured questionnaire. The overall mean score in pre-test was 23.31+/-3.07 which is 58.27 percent of maximum score and good knowledge whereas it was 34.35+/ 3.56 while post-test it was 85.87 percent of maximum score during post-test showing a difference of 27.6 percent effectiveness. Highly significant (p<0.01) differ- ence was found between pre- and post-test knowledge score and no significant (>0.05) association was found between post-test knowledge score when compared to all the demographic variables of ASHAs. PMID- 28872782 TI - Erosion of the long process of the incus with incomplete ossicular discontinuity in simple chronic otitis media: Should we reconstruct or leave it be? AB - OBJECTIVE: To determine whether patients with simple chronic otitis media and incomplete ossicular discontinuity should undergo ossicular reconstruction. DESIGN: Prospective, randomised surgical trial comparing no intervention with incus interposition over a 5-year period. SETTING: Tertiary referral hospital. PARTICIPANTS: Seventy-six participants with simple chronic otitis media and erosion of the long process of the incus but apparent good transmission throughout the ossicular chain as tested intra-operatively. Forty-four patients had partial erosion of the incus but still bony contact with the stapes head (Group A-Type I), and 32 had mainly connective tissue binding the incus and stapes (Group B-Type II). Each of these groups was randomised to either leaving the ossicular chain as it was (A1 and B1) or performing an incus interposition (A2 and B2). MAIN OUTCOME MEASURES: Average postoperative air-bone gap and the degree of ABG closure. A postoperative air-bone gap under 20 dB was considered a successful result. RESULTS: In group A, there was no significant difference between no intervention and incus interposition. In group B, patients in the no reconstruction subgroup had a significantly worse hearing result than the incus interposition subgroup (postoperative air-bone gap of 27.5 dB and 31% closure within 20 dB vs 15 dB and 75% closure). CONCLUSIONS: For Type I patients, the postoperative hearing results were similar for the reconstruction and no reconstruction groups. For Type II patients, the results clearly favour reconstruction. PMID- 28872784 TI - Determinants of Health Care Services Utilisation for Childhood illness in a selected village of Jhajjar, Haryana - A Survey. AB - This quantitative community-based study identifies-households, primary caregivers (PCGs), child, demographic factors and health care services characteristics and the pattern of health care services utilisationfor childhood illnesses. A cross sectional household sur- vey was conducted in a ,selected village of Jhajjar district of Haryana from June 2011 to June 2012, in which 1265 households were contacted. Total 340 primary care givers of children suffering from illness currently or during last 2 weeks .were- interviewed using a semi-structured interview schedule. One way ANOVA and the chi-square test were used to determine the association with selected variables (p<0.05, CI 95%). Major- ity of primary care givers were mothers 269 (79.1%), in the age group of 25- 35 years (149, 43.8%) with mean age 28.2 ? 9.9 years (15-70). Majority of sick children 328 (96.4%) were between 2 months to 5 years, male (206, 60.6%). Majority of sick children suffered from cold and cough (218, 64.1%) During the current illness majority of PCGS 205 (60.3%) had been to the private health care facility to seek the treatment. Signft- cant relationship- was found between the private health care facility utilisation and the selected variables. All primary care givers despite low socio economic status, health care services from private sector due to availability and accessibility of health care profes- sionals even in the evening and night time, quick relief and good individual attention by them without loss of wages. PMID- 28872785 TI - Health Related Quality of Life of Children with Chronic Illness. AB - A descriptive survey was carried out with the aim of determining the health related quality of life (HRQOL) of hospitalised children .with chronic illness. Data was col- lected from 148 children with chronic illness admitted in selected paediatric wards of tertiary care hospitals and their parents. The results showed that 51 percent of the children scored below the median of total HRQOL score. Children with cancer 34 (91.9%) and thalassemia 33 (89.2%) reported a low HRQOL. Children with chronic illness especially cancer and thalassemia had signficantly low HRQOL compared to children with other illnesses. Gender, diagnosis, frequency of hospitalisation, duration of illness and type of treatment received were the predic- tive of HRQOL of these children. PMID- 28872786 TI - Effect of Curry Leaves in the Control of Blood Sugar among Diabetic Clients in Selected Urban Areas of Mangalore. PMID- 28872787 TI - Effect of Knowledge on the Attitude and Practice of Hand Washing Techniques among Staff Nurses Working in Paediatric Units of Selected Tertiary Hospital. PMID- 28872788 TI - Effect of Structured Teaching Program on Breast Cancer and Breast Self Exanination among Students in Nursing Colleges of Assam. AB - With a view to assess the effectiveness of structures teaching programme on breast can- cer and breast self-examination, a quasi-experimental with pre-test post-test without control group design and an evaluative research approach was undertaken on, 100 female nursing degree students. Proportionate stratified sampling technique was used In select- tg nursing students. Prior to imnpleme'nting structured teaching programme the nursing students haid moderate knowledge, cattitude and practice, whereas after implementation of structured teaching programme nursing 'students' knowledge and ability to peform breast self examinationi was significantly improved with difference:'of mean percentage revealing effectiveness of structured teaching programme. A positive correlation of knowi . edge and attitude of nursing students was also found before the study, and there wasl not much change in attitude level of nursing students as it was moderately favorable prior to the study. . PMID- 28872790 TI - Ruggero Bortolami (1926-2014): in memoriam. PMID- 28872789 TI - Clinical Leadership Issues and Qualities among Selected Clinical Nurse Leaders in Medical Wards of Christian Medical College, Vellore. PMID- 28872792 TI - Obituary: Prof. Laurentiu Mircea Popescu. Bucharest 1944-2015. PMID- 28872791 TI - Obituary: Prof. Giuseppe Carlo Balboni, Ferrara 1.12.1923 - Firenze 8.9.2014. PMID- 28872793 TI - Tumor angiogenesis. From bench to bedside. AB - Starting with the hypothesis of Judah Folkman that tumor growth is angiogenesis dependent, this area of research has a solid scientific foundation. More than 30 years ago, Folkman found a revolutionary new way to think about cancer. He postulated that in order to survive and grow, tumors require blood vessels and that by cutting off the blood supply a cancer could be starved into remission. Several clinical studies have shown a positive correlation between the number of vessels in the tumor, metastasis formation and prognosis. The genetic instability of tumor cells permits the occurrence of multiple genetic alterations that facilitate tumor progression and metastasis, and cell clones with diverse biological aggressiveness may coexist within the same tumor. These two properties allow tumors to acquire resistance to cytotoxic agents. Inhibiting angiogenesis is a major area of therapeutic development for the treatment of cancer. Whereas conventional chemotherapy, radiotherapy and immunotherapy are directed against tumor cells, anti-angiogenic therapy is aimed at the vasculature of a tumor and will either cause total tumor regression or keep tumors in a state of dormancy. Even though numerous compounds inhibit angiogenesis, few of them have proved effective in vivo, and only a couple of agents have been able to induce tumor regression. Bevacizumab is considered to be the first specific angiogenesis inhibitor for clinical oncology. PMID- 28872794 TI - Radiological anatomy of the breast. AB - Breast cancer is the most frequent cancer site in women (28.8% of all cancer sites), the seconc most common in the world with an estimated 1.67 million new cases diagnosed in 2012 (25% of all cancers) and an estimated lifetime risk of 1/9 women. It is the fifth cause of tumor death overall (7.5%) and the first in women. Diagnostic senology has the purpose of the early diagno sis of breast cancer. The aim of this paper is to evaluate the role of all imaging techniques in studying the norma morphological anatomy of the breast. Knowing the normal anatomy of the breast is essentia to integrate all available imaging techniques in order to distinguish normal from pathologica structures. PMID- 28872795 TI - Osteoimmunology represents a link between skeletal and immune system. AB - There is a complex interplay between the cells of the immune system and bone. These inter- actions are not only mediated by the release of cytokines and chemokines but also by direct cell-cell contact. Studies of intracellular signaling mechanisms in osteoclasts have revealed that numerous immunomodulatory molecules are involved in the regulation of bone metabolism. Recently, it was proposed that immunoreceptors found in the immune cells are also an essen- tial signal for osteoclasts activation, along with receptor activator of NF-icB (RANK) ligand (RANKL). Collectively, these and similar observations regarding cross regulation between the immune and skeletal systems constitute the field of osteoimmunology. Here we briefly high- light core areas of interest and selected recent advances in this field. PMID- 28872796 TI - Stature estimation and formulation of based on ulna length in Kurdish racial subgroup. AB - Measuring stature is useful for forensic and anthropometrical sciences. The present study was con- ducted to calculate the stature from ulna length among Kurdish racial subgroup living in Iran. In this study, 50 females aged 19-24 were recruited. The ulna length of subjects was taken indepen- dently on left and right sides using a digital sliding caliper. The height was measured between vertex and floor. The height (Y) was also estimated by linear regression formulas from the length of right (X1) or left side ulna (X2). For right side, Y1 = 59.48 + 4.005 X1 +/- 4.09295 (R=0.753); for left side, Y2 = 63.44 +3.887 X2 +/- 4.24106 (R=0.731). The derived formulae are population specific and are designed for use in forensic and anthropometric skeletal analysis of Kurdish racial subgroup. These data provide a scientific basis for further investigations on racial subgroups living in Iran. PMID- 28872797 TI - Serum relaxin levels in subjects with multiple sclerosis. AB - Multiple Sclerosis is an inflammatory, auto-immune, neurodegenerative disease of the central nervous system. The disease has a prevalence of approx 1:700 with at least 2.5 million cases worldwide. It is the leading, non-trauma cause of physical disability among young and mid- dle-aged adults. Recently developed therapies do reduce disease activity but only modestly, with all of the available agents producing significant side effects that reduce compliance, and/ or serious risk for adverse events. Relaxin has been long-recognized to play a critical role in pregnancy. Recent investigations have revealed that relaxin may be an important regulator of inflammation and immune processes. This is due to the ability of relaxin to promote the pro- duction of glucocorticoid receptors, increase serum levels of the adrenocorticotropic hormone and inhibiting cell mediated pro-inflammatory activity by stimulation of the peroxisome prolif- erator-activated receptor gamma. This study found serum relaxin levels to be elevated in sub- jects with multiple sclerosis. Production of relaxin is down regulated by a negative feedback loop through its own receptor binding. Decreased receptor binding may contribute to the high- er level of relaxin seen in these patients and may lead to dysregulation of the inflammatory and immune pathways. PMID- 28872798 TI - Study on incidence of sacralisation of fifth lumbar vertebra in South Indian population. AB - The lumbosacral region is of interest because of increased incidence of low back pain resulting from stress and strain. The lumbosacral spine supports and transmits weight of the body to the inferior extremity and thus plays an important role in posture. In lumbosacral transitional vertebra either the fifth lumbar vertebra may show assimilation to sacrum (sacralisation) or the first lumbar vertebra may show transition to lumbar configuration (lumbarisation). Due to the association between lumbosacral vertebral anomalies with low back pain, early disc degenera- tion in young individuals and other spinal pathology, the present study was conducted in the Department of Anatomy, ESIC Medical College & PGIMSR, Chennai, India. Sacral bones were observed for sacral cornua, sacral hiatus and variations like sacralisation of fifth lumbar verte- bra. Sacralisation was observed in three bones, complete in one and incomplete in two bones. The possible origin of the anomaly and its relevance to clinics are discussed. PMID- 28872799 TI - An osteologic study of human ethmoidal foramina with special reference to their classification and symmetry. AB - The present investigation was designed to study the anatomy of the ethmoidal foramina in adult human dry skulls. In addition to investigate the number of ethmoidal foramina that can be found on the orbital wall, we also addressed their classification and symmetry. The analy- sis of 1089 orbits demonstrated that the average number of ethmoidal foramina/orbit was 2.07 (range 0 to 4). As for their classification, we devised the relative depth index (RDI) to differenti- ate the anterior from the posterior ethmoidal foramina. The index represents the ratio "distance of the foramen from the anterior lacrimal crest/length of the medial orbital wall". The average index of the anterior and posterior ethmoidal foramina were 0.53+/-0.04 and 0.84+/-0.06 respective- ly. As the mean of the two indexes was 0.685, we used the latter value as a sort of numerical watershed to define the domains of the anterior and of the posterior ethmoidal foramina on the orbital wall. Thus all ethmoidal foramina with an RDI : 0.68 were considered anterior ethmoi- dal foramina and all ethmoidal foramina with an RDI 0.69 were considered posterior ethmoi- dal foramina. In this way it is possible to properly classify foramina on orbits with 1,.3 or 4 ethmoidal foramina. As for their symmetry, in contrast to what had been previously reported, we observed that in most cases ethmoidal foramina have a highly symmetric arrangement both in terms of number of foramina on fellow orbits and of position along the orbital wall. PMID- 28872800 TI - Morphological study of the effects of aqueous leaf extract of Xylopia aethiopica on the pancreas in diabetic rats. AB - To investigate the histological and immunohistochemical effects of aqueous leaf extract of Xylo- pia aethiopica on the pancreas in streptozotocin-induced diabetic rats, 30 adult Wistar rats were divided into three groups (n=10). Group A was the control (administered with equivalent vol- ume of citrate buffer), group B animals were made diabetic by a single intraperitoneal injection of streptozotocin dissolved in citrate buffer (65 mg/kg), group C animals were made diabetic as above and treated with 200mg/kg body weight of aqueous leave extract of Xylopia aethiop- ica for 25 days. Upon animal sacrifice, the pancreas were excised, fixed in 10% formol saline and processed for light microscopy and immunohistochemistry.. The results revealed destruc- tion of the islet cells in the untreated diabetic group as compared with the controls. The extract treated group was characterized by recovery/regenerative processes indicated by improvement in islet morphology. In untreated diabetic rats immunoreactive P cells were sparse, at variance from the controls. The group treated with aqueous leaf extract of Xylopia aethiopica revealed more intense staining for insulin and significant (p<0.05) increase in the percentage of immuno- labelled surface area when compared with the untreated diabetic group, suggesting the ability of P cells to secrete insulin in the extract treated rats. We conclude that the aqueous leaf extract of Xylopia aethiopica improves recovery process of P-cells in streptozotocin-induced diabetic rats and might become useful in the management of diabetes related complications. PMID- 28872801 TI - Persistent median artery of the forearm and palm: a cadaver study into its origin, course, fate and clinical significance. AB - The median artery is the axis artery of forearm till the 811 week of gestation and thereafter nor- mally regresses, only its proximal part remaining patent as the companion artery of the medi- an nerve in adults. A large, well developed persistent median artery extended to the palm and contributed to its vascular supply in 6 out of 100 upper limbs dissected. Dissection was used to demonstrate the persistent median arteries from their origin to termination. The persistent median artery originated from the ulnar artery in the cubital fossa. It pierced the median nerve, descended anterior t4 the nerve'in a common sheath and passed deep to the flexor retinaculum. An accessory head of flexor pollicis longus, which is a usual finding associated with the persis- tent median artery, was seen in one forearm. The superficial palmar arch was not seen in any specimen with persistent median artery. In all the specimens with persistent median artery, the lateral half of the palm and lateral 21/2 digits were supplied by it, whereas the medial half of palm and the medial 21/2 digits were supplied by the ulnar artery. The persistent median artery may contribute to median nerve compression neuropathy. The variations in the vascular supply of hand have clinical implications. PMID- 28872802 TI - Ectopic third molar tooth on the infratemporal surface of maxilla. AB - Ectopic eruption of a tooth within the dentate region of the jaws is often noticed in clinical practice and is well documented in the literature but the ectopic eruption into the non dentate region is rare. Diverse anatomical locations such as nasal cavity, nasal septum, mandibular condyle, coronoid process, the palate and the maxillary sinus can infrequently be non dentate sites of ectopic eruptions of teeth. While conducting an anthropometric study on 100 skulls incidental and interesting case of ectopic maxillary third molar tooth was found. The tooth was partially erupted with the unerupted part lying impacted in the posterior wall of maxilla. The case is reported and discussed for its significant clinical implications. PMID- 28872803 TI - Direct origin of the right colic artery from the abdominal aorta. AB - An isolated right colic artery originating directly from the abdominal aorta was incidentally observed during diagnostic spinal angiography. Variations in origin of the right colic artery are reviewed, and their embryology and potential clinical implications discussed. PMID- 28872804 TI - Ocular anatomy in medieval arabic medicine. A review. AB - In medieval Arabic medicine Ophthalmology had a central role. Ocular anatomy was described in many ophthalmological treatises of the physicians of the time. These physicians followed the doctrines of Galen according ocular anatomy, nevertheless their contribution to the history of ocular anatomy was the presentation of ocular anatomical sketches in their manuscripts for the fist time in medical history. PMID- 28872805 TI - Endocrine cells distribution in human proximal small intestine: an immunohistochemical and morphometrical study. AB - Atrophy of the pancreatic remnant after pancreaticoduodenectomy might be consequent to dereg- ulation of pancreatic endocrine stimuli after duodenal removal. Relative technical surgical solu- tion could be the anastomosis of the 1st jejunal loop to the stomach and the 2nd to the pancreatic stump. Data on the distribution of endocrine cells within the proximal intestine might represent the lacking tile of the problem. Our aims were to investigate the distribution pattern of seroto- nin, cholecystokinin and secretin cells in the duodenum, the 1st and 2nd jejunal loops of humans. Bowel specimens of ten patients submitted to pancreaticoduodenectomy were collected; immuno- histochemical reactions and morphometric analyses were performed. A general ab-oral decrease of enteroendocrine cells was found. The rate of serotonin cells showed a significant 30.67+/-8.13% reduction starting from the 1s' jejunal loop versus duodenum. The rate of both cholecystokinin and secretin cells in the duodenum was superimposable to that in the 1st jejunal loop, with a sig- nificant 62.88+/ 4.80% loss of cholecystokinin and 39.5+/-9.31% of secretin cells in the 2nd loop. After removal of duodenum, preservation of the 1st jejunal loop could impact the function of pancreatic remnant maintaining the physiological enteroendocrine stimulus for pancreatic secretion that can compensate, at least in part for the abolished duodenal hormonal release. PMID- 28872806 TI - A scoping review of the uses of the care index in children. AB - OBJECTIVE: To conduct a scoping review of literature to describe how the care index (CI) and restorative index (RI) are used in child populations and to determine whether they are fit for purpose. BASIC RESEARCH DESIGN: Scoping review conducted using the Arksey and O'Malley (2005) framework. METHOD: Electronic and manual literature searches (1980-2015) were conducted. Titles and abstracts were screened, full-texts of potential studies were reviewed two reviewers extracted data independently, followed by data charting and summarising. RESULTS: Out of 104 articles meeting all criteria, most were cross-sectional (92%), and 56% were conducted in UK and Brazil. Most commonly (63%) studies used CI and RI to obtain epidemiological data on dental care levels. Of the studies that defined CI and RI, most used and specified the standard definition. The CI and RI scores varied either due to patient related factors such as age, gender or dental care related factors including, cost of treatment and method of provider remuneration. CONCLUSION: Overall, it is recommended that future studies should clearly state the definitions and thresholds used to obtain CI and RI, which would enable comparison between communities and allow temporal trends to be studied. Additionally, deriving separate CI and RI scores for groups based on caries extent would help to highlight inequalities in the provision of care. Further research is needed to explore the applicability of CI and RI to changing approaches to caries management with current care recommendations emphasising on minimal treatment and secondary prevention. PMID- 28872807 TI - Using Normalisation Process Theory to investigate the implementation of school based oral health promotion. AB - : Despite the considerable improvement in oral health of children in the UK over the last forty years, a significant burden of dental caries remains prevalent in some groups of children, indicating the need for more effective oral health promotion intervention (OHPI) strategies in this population. OBJECTIVE: To explore the implementation process of a community-based OHPI, in the North East of England, using Normalisation Process Theory (NPT) to provide insights on how effectiveness could be maximised. METHODS: Utilising a generic qualitative research approach, 19 participants were recruited into the study. In-depth interviews were conducted with relevant National Health Service (NHS) staff and primary school teachers while focus group discussions were conducted with reception teachers and teaching assistants. Analyses were conducted using thematic analysis with emergent themes mapped onto NPT constructs. RESULTS: Participants highlighted the benefits of OHPI and the need for evidence in practice. However, implementation of 'best evidence' was hampered by lack of adequate synthesis of evidence from available clinical studies on effectiveness of OHPI as these generally have insufficient information on the dynamics of implementation and how effectiveness obtained in clinical studies could be achieved in 'real life'. This impacted on the decision-making process, levels of commitment, collaboration among OHP teams, resource allocation and evaluation of OHPI. CONCLUSIONS: A large gap exists between available research evidence and translation of evidence in OHPI in community settings. Effectiveness of OHPI requires not only an awareness of evidence of clinical effectiveness but also synthesised information about change mechanisms and implementation protocols. PMID- 28872808 TI - The oral health condition and treatment needs assessment of nursing home residents in Flanders (Belgium). AB - OBJECTIVES: A study was conducted of nursing home residents with limited access to regular oral health care services to evaluate their oral health status, to perform an assessment of the need for oral treatment and to determine the possible predicting value of age, gender, care dependency and income level on their oral health status and treatment needs. MATERIALS AND METHODS: Three experienced dentists collected clinical oral health data with a mobile dental unit in 23 nursing homes. Socio-demographic data were extracted from the residents' records in the nursing home. Besides the descriptive and bivariate analysis, a general linear mixed model analysis was also performed with the nursing home as random effect. RESULTS: The study sample consisted of 1,226 residents with a mean age of 83.9 years, of which 41.9% were edentulous. The mean D3MFt in the dentate group was 24.5 and 77% needed extractions or fillings. In the group of residents wearing removable dentures, 36.9% needed repair, rebasing or renewal of the denture. The mixed model analysis demonstrated that with each year a resident gets older, the oral health outcomes get worse and that men have worse oral health and higher treatment needs than women. However, the level of income and care dependency had a less extensive role in predicting the oral health outcomes. CONCLUSIONS: The nursing home residents presented a poor overall oral health status and high dental and prosthetic treatment needs. Gender and age were important predicting variables for the oral health outcomes. PMID- 28872809 TI - Prevalence, severity and extent of chronic periodontitis among Sri Lankan adults. AB - OBJECTIVE: to determine the prevalence, severity and extent of chronic periodontitis among 30-60 year old adults residing in Colombo district, Sri Lanka. BASIC RESEARCH DESIGN: a cross-sectional study with interviews and oral examinations. PARTICIPANTS: 1400, 30-60 year olds residing in Colombo district. RESULTS: the prevalence of mild, moderate and severe chronic periodontits was 1.4%, 36.1% and 13.5% respectively and the prevalence was significantly associated with sex, age group, ethnicity, level of education, smoking status and self-reported diabetes. The mean probing pocket depth (PPD) was 2.05mm (SE=0.02) and of the sample, 77% and 31% had at least one site with PPD of >=4 and >=6mm respectively. The mean clinical attachment loss (CAL) was 2.53mm (SE=0.03) and 99% and 81% of the sample had at least one site with CAL of >=3mm and >=5mm respectively. The extent of periodontitis determined according to the mean percentage of sites with >=4 and >=6mm of PPD were 8.40 (SE=0.34) and 1.37 (SE=0.11) respectively. Further, the extent of periodontitis according to the mean percentages of sites with >=3 and >=5mm of CAL were 39.73 (SE=0.66) and 10.95 (SE=0.43) respectively. CONCLUSIONS: the prevalence, severity and extent of chronic periodontits are high among adults in Colombo district. Their periodontal status was poorer than in previously reported studies conducted in the same district. PMID- 28872810 TI - The caries experience of 5 year-old children in Scotland in 2013-2014, and in England and Wales in 2014-2015. Reports of cross-sectional dental surveys using BASCD criteria. AB - OBJECTIVE: We report the findings from and comment on the surveys of the oral health of 5-year-old children undertaken in Scotland (2013-14), Wales (2014-15) and England (2014-15). This was the fourteenth survey in Scotland since 1988. In England and Wales it is the third survey since 2007 when changes were required in consent arrangements. METHOD: Representative samples were drawn within Health Boards across Scotland and local authorities across England and Wales. Consent was sought via opt-out parental consent in Scotland and opt-in parental consent in England and Wales. Children examined were those aged five in England and those in Primary 1 (school year aged 5 to 6) in Scotland and Wales. Examinations were conducted in schools by trained and calibrated examiners. Caries was visually diagnosed at the dentinal threshold. RESULTS: There is a continuing decline in d3mft in all three countries. d3mft was 1.27 (opt-out consent) for Scotland, 0.84 for England (opt-in consent) and 1.29 for Wales (opt-in consent). Tooth decay levels remain higher in more deprived areas across Great Britain, with clear inequalities gradients demonstrated across all geographies. Attempts to measure changes in dental health inequalities across the three countries show no conclusive trends. CONCLUSION: Inter-country comparisons provide further oral health intelligence despite differences in approach and timing. The third surveys in England and Wales using the new consent arrangements have enabled trend analysis. Dental health inequalities gradients were shown across all geographies and all of the indicators of inequality. PMID- 28872811 TI - Preferences for dental decisional control and associations with quality of life among third molar patients attending public dental services. AB - OBJECTIVES: To explore (1) the prevalence of dental decisional control preferences (DDCP) among third molar (TM) patients attending public dental services and associated individual's characteristics, and (2) the association between DDCP and quality of life (QoL). METHOD: Participants were adult public dental patients with internet access referred for TM consultation. Collected data included patients' socio-demographic variables, the Control Preferences Scale (CPS), the Oral Health Impact Profile (OHIP-14) and the EuroQol EQ-5D-5L. RESULTS: Participants (n=163) were mainly females (73.6%) with a mean age of 26.2 years (SD=8.3). Most participants preferred an active DDCP (n=71, 44.1%) or a collaborative DDCP (n=60, 37.3%) while a minority preferred a passive DDCP (n=30, 18.6%). Gender (P=.05) and education (P=.03) were associated with DDCP. In a multinomial logistic regression model for DDCP, females were more likely to have an active DDCP (OR=2.73, P=.04) as were participants who had tertiary education (OR=2.72, P=.04). In a linear regression model for OHIP-14, active (P=.05) and collaborative DDCP (P=.04) were associated with less impact on oral health related QoL. CONCLUSION: Patients attending public dental services preferred to be involved (either actively or collaboratively) in dental treatment decision making. Being a female and/or having tertiary education were associated with an active DDCP. The positive association between patients' involvement in decision making and oral health-related QoL might support the benefit for enhancing patients' involvement in decision-making. PMID- 28872812 TI - Type 2 diabetes as a risk indicator for dental caries in Korean adults: the 2011 2012 Korea national health and nutrition examination survey. AB - OBJECTIVES: The associations between type 2 diabetes (T2D) and untreated dental caries was examined. This study hypothesized that there would be a positive association between T2D and the prevalence of decayed permanent teeth (DT) in representative Korean adults. METHODS: The information was derived from the Korea National Health and Nutrition Examination Survey conducted in 2011-2012. Sociodemographic and lifestyle variables, anthropometric and biochemical status, metabolic health and glucose tolerance status, oral health behaviors, and dental caries index were evaluated. RESULTS: The number of DT had a positive association with degree of fasting plasma glucose (FPG) level, and glycated hemoglobin (HbA1c) (p-value = 0.045 and 0.007, respectively). The levels of FPG and HbA1c increased with the number of DT (p for trend = 0.009 and 0.004, respectively). The prevalence of untreated caries uncontrolled T2D participants was about 26% higher than those with normal glucose tolerance levels after adjusting for potential confounders including diets and socioeconomic status (OR [95% CI] = 1.26 [1.02, 1.56]). CONCLUSIONS: T2D is an independent risk indicator for untreated caries in Korean adults. PMID- 28872813 TI - Development and validation of the Child Oral Health Impact Profile - Preschool version. AB - OBJECTIVE: The Child Oral Health Impact Profile (COHIP) is a validated instrument created to measure the oral health-related quality of life of school-aged children. The purpose of this study was to develop and validate a preschool version of the COHIP (COHIP-PS) for children aged 2-5. BASIC RESEARCH DESIGN: The COHIP-PS was developed and validated using a multi-stage process consisting of item selection, face validity testing, item impact testing, reliability and validity testing, and factor analysis. PARTICIPANTS: A cross-sectional convenience sample of caregivers having children 2-5 years old from four groups completed item clarity and impact forms. Groups were recruited from pediatric health clinics or preschools/daycare centers, speech clinics, dental clinics, or cleft/craniofacial centers. Participants had a variety of oral health-related conditions, including caries, congenital orofacial anomalies, and speech/language deficiencies such as articulation and language disorders. MAIN OUTCOME MEASURE: COHIP-PS. RESULTS: The COHIP-PS was found to have acceptable internal validity (a = 0.71) and high test-retest reliability (0.87), though internal validity was below the accepted threshold for the community sample. While discriminant validity results indicated significant differences across study groups, the overall magnitude of differences was modest. Results from confirmatory factor analyses support the use of a four-factor model consisting of 11 items across oral health, functional well-being, social-emotional well-being, and self-image domains. CONCLUSIONS: Quality of life is an integral factor in understanding and assessing children's well-being. The COHIP-PS is a validated oral health-related quality of life measure for preschool children with cleft or other oral conditions. PMID- 28872814 TI - Association between excessive Internet use and oral health behaviors of Korean adolescents: A 2015 national survey. AB - OBJECTIVE: This study aimed to investigate excessive Internet use's (EIU's) association with oral health behaviors among Korean adolescents. BASIC RESEARCH DESIGN: This cross-sectional study was based on the 11th Korea Youth Risk Behavior Web-based Survey (2015). PARTICIPANTS: 68,043 school students aged 13-18 years (35,204 boys and 32,839 girls). Data on, 45,271 (23,354 males and 21,917 females using the Internet on weekdays) and 49,324 (27,448 males and 21,876 females using the Internet on weekends) were analyzed after excluding questionnaires with missing values. MAIN OUTCOME MEASURES: The key variables were oral health behaviors (tooth-brushing frequency and tooth brushing after lunch at school, and preventive oral health behaviors), EIU (hours of Internet use on weekdays and weekends, excluding use for academic purposes). RESULTS: Compared to the general groups, the odds ratio (OR) for less tooth-brushing was 4.04 (95%CI=2.990-5.459) and 3.55-fold higher (95% CI=2.703-4.659) in the high-risk groups for weekday and weekend EIU, respectively. For post-lunch tooth-brushing, compared to the general groups, the OR for less tooth-brushing was 1.7-fold higher in the high-risk groups for EIU during weekdays and weekends. The OR for no preventive behavior was significantly higher in the high-risk groups than in the potential-risk and general groups. CONCLUSIONS: Policies moderating adolescents' EIU may enable appropriate oral health behaviors. PMID- 28872816 TI - Superhydrophilic Wrinkle-Free Cotton Fabrics via Plasma and Nanofluid Treatment. AB - We demonstrate in this study a wrinkle-free, superhydrophilic cotton fabric (contact angle ~0 degrees ) by uniformly attaching specially engineered nanoparticles to plasma-pretreated cotton fabric. Because of their highly charged nature, the nanoparticles are firmly anchored on the fabric via electrostatic interactions, as confirmed by microscopy and chemical analyses. The durability of wetting behavior and wrinkle-free property of the nanoparticle-coated fabrics were evaluated via aging, laundering, and abrasion tests. The strongly attached coatings are stable enough to maintain their superhydrophilic nature even after 60 days of aging at room temperature, 50 laundering cycles, and 25 000 abrasion cycles. Moreover, the nanoparticle-coated superhydrophilic fabrics exhibit great wrinkle-recovery property, tensile strength, and abrasion resistance performance up to 25 000 abrasion cycles. PMID- 28872817 TI - Carboplatin-Loaded, Raman-Encoded, Chitosan-Coated Silver Nanotriangles as Multimodal Traceable Nanotherapeutic Delivery Systems and pH Reporters inside Human Ovarian Cancer Cells. AB - Ovarian cancer is a common cause of cancer death in women and is associated with the highest mortality rates of all gynecological malignancies. Carboplatin (CBP) is the most used cytotoxic agent in the treatment of ovarian cancer. Herein, we design and assess a CBP nanotherapeutic delivery system which allows combinatorial functionalities of chemotherapy, pH sensing, and multimodal traceable properties inside live NIH:OVCAR-3 ovarian cancer cells. In our design, a pH-sensitive Raman reporter, 4-mercaptobenzoic acid (4MBA) is anchored onto the surface of chitosan-coated silver nanotriangles (chit-AgNTs) to generate a robust surface-enhanced Raman scattering (SERS) traceable system. To endow this nanoplatform with chemotherapeutic abilities, CBP is then loaded to 4MBA-labeled chit-AgNTs (4MBA-chit-AgNTs) core under alkaline conditions. The uptake and tracking potential of CBP-4MBA-chit-AgNTs at different Z-depths inside live ovarian cancer cells is evaluated by dark-field and differential interference contrast (DIC) microscopy. The ability of CBP-4MBA-chit-AgNTs to operate as near infrared (NIR)-responsive contrast agents is validated using two noninvasive techniques: two-photon (TP)-excited fluorescence lifetime imaging microscopy (FLIM) and confocal Raman microscopy (CRM). The most informative data about the precise localization of nanocarriers inside cells correlated with intracellular pH sensing is provided by multivariate analysis of Raman spectra collected by scanning CRM. The in vitro cell proliferation assay clearly shows the effectiveness of the prepared nanocarriers in inhibiting the growth of NIH:OVCAR 3 cancer cells. We anticipate that this class of nanocarriers holds great promise for application in image-guided ovarian cancer chemotherapy. PMID- 28872818 TI - Lowering Band Gap of an Electroactive Metal-Organic Framework via Complementary Guest Intercalation. AB - A new honeycomb-shaped electroactive metal-organic framework (MOF) has been constructed from an electron deficient naphthalenediimide (NDI) ligand equipped with two terminal salicylic acid groups. pi-Intercalation of electron-rich planar tetrathiafulvalene (TTF) guests between the NDI ligands stacked along the walls lowers the electronic band gap of the material by ca. 1 eV. An improved electron delocalization through the guest-mediated pi-donor/acceptor stacks is attributed to the diminished band gap of the doped material, which forecasts an improved electrical conductivity. PMID- 28872819 TI - A Facile Approach To Prepare Tough and Responsive Ultrathin Physical Hydrogel Films as Artificial Muscles. AB - We report a facile approach to prepare ultrathin physical hydrogel films based on the Marangoni effect, which drives an ethanol solution of poly(stearyl acrylate co-acrylic acid) (P(SA-co-AAc)) to rapidly spread on the water surface. The subsequent solvent exchange leads to sol-gel transition, where the long alkyl chains of SA units segregate to form physical cross-linking junctions. The resultant disk-shaped single-network (SN) gel films are uniform with tunable thickness (40-80 MUm) and diameter (5-12 cm) and possess robust mechanical properties with tensile breaking stress, sigmab, and breaking strain, epsilonb, being 0.3-1.1 MPa and 30-290%, respectively. The mechanical properties of SN gel films can be further improved by introducing ductile poly(N-isopropylacrylamide) (PNIPAm) into the preformed gel matrix, which forms strong hydrogen bonds with the first network. The obtained physical double-network (DN) hydrogel films are transparent and show excellent mechanical performances with sigmab of 3-5 MPa and epsilonb of 100-500%. Due to the ultrathin thickness of gel films and response of PNIPAm to saline solutions, the tough DN gel films exhibit fast response (<=60 s) and large stroke force (0.5 MPa) after switching the environment from water bath to saline solution, making them an ideal material to design artificial muscles, soft actuators, and chemomechanical devices. PMID- 28872820 TI - Selective Inactivation of Bacteriophage in the Presence of Bacteria by Use of Ground Rh-Doped SrTiO3 Photocatalyst and Visible Light. AB - Bacteriophage (denoted as phage) infection in the bacterial fermentation industry is a major problem, leading to the loss of fermented products such as alcohol and lactic acid. Currently, the prevention of phage infection is limited to biological approaches, which are difficult to apply in an industrial setting. Herein, we report an alternative chemical approach using ground Rh-doped SrTiO3 (denoted as g-STO:Rh) as a visible-light-driven photocatalyst. The g-STO:Rh showed selective inactivation of phage without bactericidal activity when irradiated with visible light (lambda > 440 nm). After inactivation, the color of g-STO:Rh changed from gray to purple, suggesting that the Rh valence state partially changed from 3+ to 4+ induced by photocatalysis, as confirmed by diffuse reflectance spectroscopy. To study the effect of the Rh4+ ion on phage inactivation under visible-light irradiation, the survival rate of phage for g STO:Rh was compared to that for ground Rh,Sb-codoped SrTiO3 (denoted as g STO:Rh,Sb), where the change of Rh valence state from 3+ to 4+ is almost suppressed under visible-light irradiation due to charge compensation by the Sb5+ ion. Only g-STO:Rh effectively inactivated phage, which indicated that Rh4+ ion induced by photocatalysis particularly contributed to phage inactivation under visible-light irradiation. These results suggested that g-STO:Rh has potential as an antiphage material in bacterial fermentation. PMID- 28872821 TI - Correction to "Organic Field-Effect Transistors with Macroporous Semiconductor Films as High-Performance Humidity Sensors". PMID- 28872822 TI - Corrugation in the Weakly Interacting Hexagonal-BN/Cu(111) System: Structure Determination by Combining Noncontact Atomic Force Microscopy and X-ray Standing Waves. AB - Atomically thin hexagonal boron nitride (h-BN) layers on metallic supports represent a promising platform for the selective adsorption of atoms, clusters, and molecular nanostructures. Specifically, scanning tunneling microscopy (STM) studies revealed an electronic corrugation of h-BN/Cu(111), guiding the self assembly of molecules and their energy level alignment. A detailed characterization of the h-BN/Cu(111) interface including the spacing between the h-BN sheet and its support-elusive to STM measurements-is crucial to rationalize the interfacial interactions within these systems. To this end, we employ complementary techniques including high-resolution noncontact atomic force microscopy, STM, low-energy electron diffraction, X-ray photoelectron spectroscopy, the X-ray standing wave method, and density functional theory. Our multimethod study yields a comprehensive, quantitative structure determination including the adsorption height and the corrugation of the sp2 bonded h-BN layer on Cu(111). Based on the atomic contrast in atomic force microscopy measurements, we derive a measurable-hitherto unrecognized-geometric corrugation of the h-BN monolayer. This experimental approach allows us to spatially resolve minute height variations in low-dimensional nanostructures, thus providing a benchmark for theoretical modeling. Regarding potential applications, e.g., as a template or catalytically active support, the recognition of h-BN on Cu(111) as a weakly bonded and moderately corrugated overlayer is highly relevant. PMID- 28872823 TI - Programmed Self-Assembly of Branched Nanocrystals with an Amphiphilic Surface Pattern. AB - Site-selective surface modification on the shape-controlled nanocrystals is a key approach in the programmed self-assembly of inorganic colloidal materials. This study demonstrates a simple methodology to gain self-assemblies of semiconductor nanocrystals with branched shapes through tip-to-tip attachment. Short-chained water-soluble cationic thiols are employed as a surface ligand for CdSe tetrapods and CdSe/CdS core/shell octapods. Because of the less affinity of arm-tip to the surface ligands compared to the arm-side wall, the tip-surface becomes uncapped to give a hydrophobic nature, affording an amphiphilic surface pattern. The amphiphilic tetrapods aggregated into porous agglomerates through tip-to-tip connection in water, while they afforded a hexagonally arranged Kagome-like two dimensional (2D) assembly by the simple casting of aqueous dispersion with the aid of a convective self-assembly mechanism. A 2D net-like assembly was similarly obtained from amphiphilic octapods. A dissipative particle dynamics simulation using a planar tripod model with an amphiphilic surface pattern reproduced the formation of the Kagome-like assembly in a 2D confined space, demonstrating that the lateral diffusion of nanoparticles and the firm contacts between the hydrophobic tips play crucial roles in the self-assembly. PMID- 28872824 TI - Transition State Analysis of Adenosine Triphosphate Phosphoribosyltransferase. AB - Adenosine triphosphate phosphoribosyltransferase (ATP-PRT) catalyzes the first step in histidine biosynthesis, a pathway essential to microorganisms and a validated target for antimicrobial drug design. The ATP-PRT enzyme catalyzes the reversible substitution reaction between phosphoribosyl pyrophosphate and ATP. The enzyme exists in two structurally distinct forms, a short- and a long-form enzyme. These forms share a catalytic core dimer but bear completely different allosteric domains and thus distinct quaternary assemblies. Understanding enzymatic transition states can provide essential information on the reaction mechanisms and insight into how differences in domain structure influence the reaction chemistry, as well as providing a template for inhibitor design. In this study, the transition state structures for ATP-PRT enzymes from Campylobacter jejuni and Mycobacterium tuberculosis (long-form enzymes) and from Lactococcus lactis (short-form) were determined and compared. Intrinsic kinetic isotope effects (KIEs) were obtained at reaction sensitive positions for the reverse reaction using phosphonoacetic acid, an alternative substrate to the natural substrate pyrophosphate. The experimental KIEs demonstrated mechanistic similarities between the three enzymes and provided experimental boundaries for quantum chemical calculations to characterize the transition states. Predicted transition state structures support a dissociative reaction mechanism with a DN*AN? transition state. Weak interactions from the incoming nucleophile and a fully dissociated ATP adenine are predicted regardless of the difference in overall structure and quaternary assembly. These studies establish that despite significant differences in the quaternary assembly and regulatory machinery between ATP-PRT enzymes from different sources, the reaction chemistry and catalytic mechanism are conserved. PMID- 28872825 TI - Flexible Polymer/Metal/Polymer and Polymer/Metal/Inorganic Trilayer Transparent Conducting Thin Film Heaters with Highly Hydrophobic Surface. AB - Polymer/metal/polymer and polymer/metal/inorganic trilayer-structured transparent electrodes with fluorocarbon plasma polymer thin film heaters have been proposed. The polymer/metal/polymer and polymer/metal/inorganic transparent conducting thin films fabricated on a large-area flexible polymer substrate using a continuous roll-to-roll sputtering process show excellent electrical properties and visible light transmittance. They also exhibit water-repelling surfaces to prevent wetting and to remove contamination. In addition, the adoption of a fluorocarbon/metal/fluorocarbon film permits an outer bending radius as small as 3 mm. These films have a sheet resistance of less than 5 Omega sq-1, sufficient to drive light-emitting diode circuits. The thin film heater with the fluorocarbon/Ag/SiNx structure exhibits excellent heating characteristics, with a temperature reaching 180 degrees C under the driving voltage of 13 V. Therefore, the proposed polymer/metal/polymer and polymer/metal/inorganic transparent conducting electrodes using polymer thin films can be applied in flexible and rollable displays as well as automobile window heaters and other devices. PMID- 28872826 TI - In-Situ Fixation of All-Inorganic Mo-Fe-S Clusters for the Highly Selective Removal of Lead(II). AB - The selective adsorption by suitable substrate materials is considered one of the most economical methods. In this work, an all-inorganic bimetallic Mo-Fe-S cluster is facilely achieved through in situ chemical fixation of tetrathiomolybdate (TTM) on Fe3O4 nanoparticles (NPs) at room temperature (donated as FeMoS NPs). The bimetallic building blocks on the obtained FeMoS NPs possess a monovacancy species of sulfur, endowing FeMoS NPs with a selectivity order of Zn2+, Mn2+, Ni2+ < Cd2+ ? Cu2+ < Pb2+ for metal-ion adsorption, a novel application for the Mo-Fe-S clusters. Particularly, with the highest selectivity for Pb2+ (Kd ~ 107), which is about 3 * 103-1 * 106 times higher than those for other ions and has exceeded that of a series of outstanding sorbents reported for Pb2+, FeMoS NPs can efficiently reduce the concentration of Pb2+ from ~10 ppm to an extremely low level of ~1 ppb. This facile and rational fabrication of the Mo Fe-S cluster with Fe3O4 represents a feasible approach to cheaply develop novel and efficient materials for the selective removal of lead(II). PMID- 28872827 TI - Rare Earth Polyoxometalates. AB - Longstanding and important applications make use of the chemical and physical properties of both rare earth metals and polyoxometalates of early transition metals. The catalytic, optical, and magnetic features of rare earth metal ions are well-known, as are the reversible multielectron redox and photoredox capabilities of polyoxomolybdates and polyoxotungstates. The combination of rare earth ions and polyoxometalates in discrete molecules and coordination polymers is of interest for the unique combination of chemical and physical properties that can arise. This Account surveys our efforts to synthesize and investigate compounds with rare earth ions and polyoxometalates (RE-POMs), sometimes with carboxylate-based organic coligands. Our general synthetic approach is "bottom up", which affords well-defined nanoscale molecules, typically in crystalline form and amenable to single-crystal X-ray diffraction for structure determination. Our particular focus is on elucidation of the physical properties conferred by the different structural components with a view to ultimately being able to tune these properties chemically. For this purpose, we employ a variety of spectroscopic, magnetochemical, electrochemical, and scattering techniques in concert with theoretical modeling and computation. Studies of RE-POM single molecule magnets (SMMs) have utilized magnetic susceptibility, inelastic neutron scattering, and ab initio calculations. These investigations have allowed characterization of the crystal field splitting of the rare earth(III) ions that is responsible for the SMM properties of slow magnetic relaxation and magnetization quantum tunneling. Such SMMs are promising for applications in quantum computing and molecular spintronics. Photophysical measurements of a family of hybrid RE-POMs with organic ligands have afforded insights into sensitization of Tb(III) and Eu(III) emission through both organic and polyoxometalate chromophores in the same molecule. Detailed variable-temperature studies have revealed the temperature dependence of the POM-based sensitization, which is relevant for potential applications in phosphor thermometry. Novel RE POM coordination polymers demonstrate the promise of higher-dimensional materials for catalytic and sensing applications that can make use of either or both rare earth and polyoxometalate capabilities. Finally, structural, electrochemical, and density functional theory studies on a family of modular RE-POMs that incorporate molybdotungstates with amino acid coligands have revealed how closed Mo-oxo loops that are reduced preferentially can act as electron reservoirs in mixed-metal molybdotungstates. This has important implications for mixed-metal polyoxometalates in redox and photoredox catalysis. Notably, these hybrid RE-POMs are stable in solution and maintain the chirality induced by amino acid ligands. The RE-POMs surveyed in this Account provide a glimpse of possible structural features that are accessible with this family of compounds. The studies of the ensuing chemical and physical properties reveal the promise of RE-POMs for diverse and varied applications and lay an excellent foundation for the future development of this new class of functional materials. PMID- 28872828 TI - Bioengineering Bacterially Derived Immunomodulants: A Therapeutic Approach to Inflammatory Bowel Disease. AB - Bacterial enteric pathogens have evolved efficient mechanisms to suppress mammalian inflammatory and immunoregulatory pathways. By exploiting the evolutionary relationship between the gut and pathogenic bacteria, we have developed a potential mucosal therapeutic. Our findings suggest that engineered preparations of the Salmonella acetyltransferase, AvrA, suppress acute inflammatory responses such as those observed in inflammatory bowel disease (IBD). We created 125 nm diameter cross-linked protein nanoparticles directly from AvrA and carrier protein to deliver AvrA in the absence of Salmonella. AvrA nanoparticles are internalized in vitro and in vivo into barrier epithelial and lamina propria monocytic cells. AvrA nanoparticles inhibit inflammatory signaling and confer cytoprotection in vitro, and in murine colitis models, we observe decreased clinical and histological indices of inflammation. Thus, we have combined naturally evolved immunomodulatory proteins with modern bioengineering to produce AvrA nanoparticles, a potential treatment for IBD. PMID- 28872829 TI - Guest-Responsive Metal-Organic Frameworks as Scaffolds for Separation and Sensing Applications. AB - Metal-organic frameworks (MOFs) have evolved to be next-generation utility materials because of their serviceability in a wide variety of applications. Built from organic ligands with multiple binding sites in conjunction with metal ions/clusters, these materials have found profound advantages over their other congeners in the domain of porous materials. The plethora of applications that these materials encompass has motivated material chemists to develop such novel materials, and the catalogue of MOFs is thus ever-escalating. One key feature that MOFs possess is their responsiveness toward incoming guest molecules, resulting in changes in their physical and chemical properties. Such uniqueness generally arises owing to the influenceable ligands and/or metal units that govern the formation of these ordered architectures. The suitable host-guest interactions play an important role in determining the specific responses of these materials and thus find important applications in sensing, catalysis, separation, conduction, etc. In this Account, we focus on the two most relevant applications based on the host-guest interactions that are carried out in our lab, viz., separation and sensing of small molecules. Separation of liquid-phase aromatic hydrocarbons by less energy-intensive adsorption processes has gained attention recently. Because of their tailored structures and functionalized pore surfaces, MOFs have become vital candidates in molecular separation. Prefunctionalization of MOFs by astute choice of ligands and/or metal centers results in targeted separation processes in which the molecular sieving effect plays a crucial role. In this view, separation of C6 and C8 liquid aromatic hydrocarbons, which are essential feedstock in various chemical industries, is one area of research that requires significant attention because of the gruesome separation techniques adopted in such industries. Also, from the environmental perspective, separation of oil/water mixtures demands significant attention because of the hazards of marine oil spillage. We have achieved successful separation of such by careful impregnation of hydrophobic moieties inside the nanochannels of MOFs, resulting in unprecedented efficiency in oil/water separation. Also, recognition of small molecules using optical methods (fluorescence, UV, etc.) has been extended to achieve sensing of various neutral species and anions that are important from environmental point of view. Incorporation of secondary functional groups has been utilized to sense nitroaromatic compounds (NACs) and other small molecules such as H2S, NO, and aromatic phenols. We have also utilized the postfunctionalization strategy via ion exchange to fabricate MOFs for sensing of environmentally toxic and perilous anionic species such as CN- and oxoanions. Our current endeavors to explore the applicability of MOFs in these two significant areas have widened the scope of research, and attempts to fabricate MOFs for real-time applications are underway. PMID- 28872830 TI - Probing Photothermal Effects on Optically Trapped Gold Nanorods by Simultaneous Plasmon Spectroscopy and Brownian Dynamics Analysis. AB - Plasmonic gold nanorods are prime candidates for a variety of biomedical, spectroscopy, data storage, and sensing applications. It was recently shown that gold nanorods optically trapped by a focused circularly polarized laser beam can function as extremely efficient nanoscopic rotary motors. The system holds promise for applications ranging from nanofluidic flow control and nanorobotics to biomolecular actuation and analysis. However, to fully exploit this potential, one needs to be able to control and understand heating effects associated with laser trapping. We investigated photothermal heating of individual rotating gold nanorods by simultaneously probing their localized surface plasmon resonance spectrum and rotational Brownian dynamics over extended periods of time. The data reveal an extremely slow nanoparticle reshaping process, involving migration of the order of a few hundred atoms per minute, for moderate laser powers and a trapping wavelength close to plasmon resonance. The plasmon spectroscopy and Brownian analysis allows for separate temperature estimates based on the refractive index and the viscosity of the water surrounding a trapped nanorod. We show that both measurements yield similar effective temperatures, which correspond to the actual temperature at a distance of the order 10-15 nm from the particle surface. Our results shed light on photothermal processes on the nanoscale and will be useful in evaluating the applicability and performance of nanorod motors and optically heated nanoparticles for a variety of applications. PMID- 28872831 TI - Novel Vilazodone-Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation. AB - Depression is one of the most frequent psychiatric complications of Alzheimer's disease (AD), affecting up to 50% of the patients. A novel series of hybrid molecules were designed and synthesized by combining the pharmacophoric features of vilazodone and tacrine as potential multitarget-directed ligands for the treatment of AD with depression. In vitro biological assays were conducted to evaluate the compounds; among the 30 hybrids, compound 1e showed relatively balanced profiles between acetylcholinesterase inhibition (IC50 = 3.319 +/- 0.708 MUM), 5-HT1A agonist (EC50 = 107 +/- 37 nM), and 5-HT reuptake inhibition (IC50 = 76.3 +/- 33 nM). Compound 1e displayed tolerable hepatotoxicity and moderate hERG inhibition activity, and could penetrate the blood-brain barrier in vivo. Furthermore, an oral intake of 30 mg/kg 1e.HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice and alleviate the depressive symptom in tail suspension test. The effectivity of 1e validates the rationality of our design strategy. PMID- 28872832 TI - Chemically Modified, alpha-Amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) Receptor RNA Aptamers Designed for in Vivo Use. AB - Glutamate ion channels have three subtypes, that is, alpha-amino-3-hydroxy-5 methyl-4-isoxazole (AMPA), kainate, and N-methyl-d-aspartate (NMDA) receptors. Excessive activity of these receptor subtypes either individually or collectively is involved in various neurological disorders. RNA aptamers as antagonists of these receptors are potential therapeutics. For developing aptamer therapeutics, the RNA aptamers must be chemically modified to become ribonuclease-resistant or stable in biological fluids. Using systematic evolution of ligands by exponential enrichment (SELEX) and a chemically modified library, prepared enzymatically (i.e., the library contains RNAs with 2'-fluoro modified nucleoside triphosphates or ATPs, CTPs and UTPs, but regular GTPs), we have isolated an aptamer. The short aptamer (69 nucleotides) FN1040s selectively inhibits the GluA1 and GluA2Qflip AMPA receptor subunits, whereas the full-length aptamer (101 nucleotides) FN1040 additionally inhibits GluK1, but not GluK2, kainate receptor, and GluN1a/2A and GluN1a/2B, the two major native NMDA receptors. The two aptamers show similar potency (2-4 MUM) and are stable with a half-life of at least 2 days in serum containing medium or cerebrospinal fluid. Therefore, these two aptamers are amenable for in vivo use. PMID- 28872833 TI - Covalent Porphyrin Framework-Derived Fe2P@Fe4N-Coupled Nanoparticles Embedded in N-Doped Carbons as Efficient Trifunctional Electrocatalysts. AB - A new porous covalent porphyrin framework (CPF) filled with triphenylphosphine was designed and synthesized using the rigid tetrakis(p-bromophenyl)porphyrin (TBPP) and 1,3,5-benzenetriboronic acid trivalent alcohol ester as building blocks. The carbonization of this special CPF has afforded coupled Fe2P and Fe4N nanoparticles embedded in N-doped carbons (Fe2P/Fe4N@N-doped carbons). This CPF serves as an "all in one" precursor of Fe, N, P, and C. The porous property and solid skeleton of the CPF endow Fe2P/Fe4N@N-doped carbons with porous structure and a high degree of graphitization. As a result, Fe2P/Fe4N@N-doped carbons exhibited highly efficient multifunctional electrocatalytic performance for water splitting and oxygen electroreduction. Typically, Fe2P/Fe4N@C-800, obtained at a heat-treatment temperature of 800 degrees C, showed an ORR half-wave potential of 0.80 V in alkaline media and 0.68 V in acidic media, close to that of commercial Pt/C catalysts. Fe2P/Fe4N@C-800 also displayed efficient OER and HER activities, comparable to other phosphide and nitride electrocatalysts. The coupled Fe4N and Fe2P nanoparticles embedded in carbons exert unique catalytic efficiency for water splitting and fuel cells. PMID- 28872834 TI - The Curious Case of Fluorination of Conjugated Polymers for Solar Cells. AB - Organic solar cells (OSCs) have been a rising star in the field of renewable energy since the introduction of the bulk heterojunction (BHJ) in 1992. Recent advances have pushed the efficiencies of OSCs to over 13%, an impressive accomplishment via collaborative efforts in rational materials design and synthesis, careful device engineering, and fundamental understanding of device physics. Throughout these endeavors, several design principles for the conjugated donor polymers used in such solar cells have emerged, including optimizing the conjugated backbone with judicious selection of building blocks, side-chain engineering, and substituents. Among all of the substituents, fluorine is probably the most popular one; improved device characteristics with fluorination have frequently been reported for a wide range of conjugated polymers, in particular, donor-acceptor (D-A)-type polymers. Herein we examine the effect of fluorination on the device performance of solar cells as a function of the position of fluorination (on the acceptor unit or on the donor unit), aiming to outline a clear understanding of the benefits of this curious substituent. As fluorination of the acceptor unit is the most adopted strategy for D-A polymers, we first discuss the effect of fluorination of the acceptor units, highlighting the five most widely utilized acceptor units. While improved device efficiency has been widely observed with fluorinated acceptor units, the underlying reasons vary from case to case and highly depend on the chemical structure of the polymer. Second, the effect of fluorination of the donor unit is addressed. Here we focus on four donor units that have been most studied with fluorination. While device-performance-enhancing effects by fluorination of the donor units have also been observed, it is less clear that fluorine will always benefit the efficiency of the OSC, as there are several cases where the efficiency drops, in particular with "over-fluorination", i.e., when too many fluorine substituents are incorporated. Finally, while this Account focuses on studies in which the polymer is paired with fullerene derivatives as the electron accepting materials, non fullerene acceptors (NFAs) are quickly becoming key players in the field of OSCs. The effect of fluorination of the polymers on the device performance may be different when NFAs are used as the electron-accepting materials, which remains to be investigated. However, the design of fluorinated polymers may provide guidelines for the design of more efficient NFAs. Indeed, the current highest performing OSC (~13%) features fluorination on both the donor polymer and the non fullerene acceptor. PMID- 28872835 TI - Revisiting the Quinoxalinedione Scaffold in the Construction of New Ligands for the Ionotropic Glutamate Receptors. AB - More than two decades ago, the quinoxalinedione scaffold was shown to act as an alpha-amino acid bioisoster. Following extensive structure-activity relationship (SAR) studies, the antagonists DNQX, CNQX, and NBQX in the ionotropic glutamate receptor field were identified. In this work, we revisit the quinoxalinedione scaffold and explore the incorporation of an acid functionality in the 6 position. The SAR studies disclose that by this strategy it was possible to tune in iGluR selectivity among the AMPA, NMDA, and KA receptors, and to some extent also obtain full receptor subtype selectivity. Highlights of the study of 44 new analogues are compound 2m being a high affinity ligand for native AMPA receptors (IC50= 0.48 MUM), analogues 2e,f,h,k,v all displayed selectivity for native NMDA receptors, and compounds 2s,t,u are selective ligand for the GluK1 receptor. Most interestingly, compound 2w was shown to be a GluK3-preferring ligand with full selectivity over native AMPA, KA and NMDA receptors. PMID- 28872836 TI - Catalytic Palladium Film Deposited by Scalable Low-Temperature Aqueous Combustion. AB - This article describes a novel method for depositing a dense, high quality palladium thin film via a one-step aqueous combustion process which can be easily scaled up. Film deposition of Pd from aqueous solutions by conventional chemical or electrochemical methods is inhibited by hydrogen embrittlement, thus resulting in a brittle palladium film. The method outlined in this work allows a direct aqueous solution deposition of a mirror-bright, durable Pd film on substrates including glass and glassy carbon. This simple procedure has many advantages including a very high deposition rate (>10 cm2 min-1) and a relatively low deposition temperature (250 degrees C), which makes it suitable for large-scale industrial applications. Although preparation of various high-quality oxide films has been successfully accomplished via solution combustion synthesis (SCS) before, this article presents the first report on direct SCS production of a metallic film. The mechanism of Pd film formation is discussed with the identification of a complex formed between palladium nitrate and glycine at low temperature. The catalytic properties and stability of films are successfully tested in alcohol electrooxidation and electrochemical oxygen reduction reaction. It was observed that combustion deposited Pd film on a glassy carbon electrode showed excellent catalytic activity in ethanol oxidation without using any binder or additive. We also report for the first time the concept of a reusable "catalytic flask" as illustrated by the Suzuki-Miyaura cross-coupling reaction. The Pd film uniformly covers the inner walls of the flask and eliminates the catalyst separation step. We believe the innovative concept of a reusable catalytic flask is very promising and has the required features to become a commercial product in the future. PMID- 28872837 TI - Enhanced Solar Cell Conversion Efficiency of InGaN/GaN Multiple Quantum Wells by Piezo-Phototronic Effect. AB - The piezo-phototronic effect is the tuning of piezoelectric polarization charges at the interface to largely enhance the efficiency of optoelectronic processes related to carrier separation or recombination. Here, we demonstrated the enhanced short-circuit current density and the conversion efficiency of InGaN/GaN multiple quantum well solar cells with an external stress applied on the device. The external-stress-induced piezoelectric charges generated at the interfaces of InGaN and GaN compensate the piezoelectric charges induced by lattice mismatch stress in the InGaN wells. The energy band realignment is calculated with a self consistent numerical model to clarify the enhancement mechanism of optical generated carriers. This research not only theoretically and experimentally proves the piezo-phototronic effect modulated the quantum photovoltaic device but also provides a great promise to maximize the use of solar energy in the current energy revolution. PMID- 28872839 TI - Buyid Silk and the Tale of Bibi Shahrbanu: Identification of Biomarkers of Artificial Aging (Forgery) of Silk. AB - Buyid silk forgery is one of the most famous silk forgeries in the world. In 1924 1925, excavation of the Bibi Shahrbanu site in Iran unearthed several silk textiles. The silks were thought to be of the Buyid period (934-1062 BCE) of the Persian Empire and have since been known as the "Buyid silks". In the 1930s, more silk appeared and was reported as being from the Buyid period as well. Controversy over the authenticity of these silks escalated after the purchase of the silks by museums throughout the world. Extensive investigations of several of these silks have been conducted over the years with respect to iconography, weaving patterns, dyes/mordant, style, and even radiocarbon dating. It was found that most of the silks are not from Buyid period. To test the authenticity of these silk fabrics, the recently developed silk dating technique using amino acid racemization (AAR) in conjunction with capillary electrophoresis mass spectrometry was applied to 13 Buyid silk specimens from the Textile Museum collections. Among these silk specimens, the AAR ratios of only one specimen were consistent with authentic silk fabrics collected from various museums. In addition, the aspartic acid racemization ratio of this specimen was also consistent with its 14C dating. The other "Buyid silks" showed excessive levels of amino acid racemization not only for aspartic acid, but also for phenylalanine and tyrosine, inconsistent with racemization rates of these amino acids in authentic historical silk fabrics. Treatment of modern silk with a base at different pH and temperature reproduced the AAR pattern of the Buyid silks, implying that chemical treatment with a base at relatively high temperatures was perhaps the method used to artificially age these fabrics. The results imply that the racemization ratios of aspartic acid, phenylalanine, and tyrosine can be used as biomarkers for identification of naturally versus artificially aged silk. PMID- 28872838 TI - Electrochemical Induced Calcium Phosphate Precipitation: Importance of Local pH. AB - Phosphorus (P) is an essential nutrient for living organisms and cannot be replaced or substituted. In this paper, we present a simple yet efficient membrane free electrochemical system for P removal and recovery as calcium phosphate (CaP). This method relies on in situ formation of hydroxide ions by electro mediated water reduction at a titanium cathode surface. The in situ raised pH at the cathode provides a local environment where CaP will become highly supersaturated. Therefore, homogeneous and heterogeneous nucleation of CaP occurs near and at the cathode surface. Because of the local high pH, the P removal behavior is not sensitive to bulk solution pH and therefore, efficient P removal was observed in three studied bulk solutions with pH of 4.0 (56.1%), 8.2 (57.4%), and 10.0 (48.4%) after 24 h of reaction time. While P removal efficiencies are not generally affected by bulk solution pH, the chemical physical properties of CaP solids collected on the cathode are still related to bulk solution pH, as confirmed by structure characterizations. High initial solution pH promotes the formation of more crystalline products with relatively high Ca/P molar ratio. The Ca/P molar ratio increases from 1.30 (pH 4.0) to 1.38 (pH 8.2) and further increases to 1.55 (pH 10.0). The formation of CaP precipitates was a typical crystallization process, with an amorphous phase formed at the initial stage which then transforms to the most stable crystal phase, hydroxyapatite, which is inferred from the increased Ca/P molar ratio from 1.38 (day 1) to the theoretical 1.76 (day 11) and by the formation of needle-like crystals. Finally, we demonstrated the efficiency of this system for real wastewater. This, together with the fact that the electrochemical method can work at low bulk pH, without dosing chemicals and a need for a separation process, highlights the potential application of the electrochemical method for P removal and recovery. PMID- 28872840 TI - Ancillary Ligand Effects upon the Photochemistry of Mn(bpy)(CO)3X Complexes (X = Br-, PhCC-). AB - The photochemistry of two Mn(bpy)(CO)3X complexes (X = PhCC-, Br-) has been studied in the coordinating solvents THF (terahydrofuran) and MeCN (acetonitrile) employing time-resolved infrared spectroscopy. The two complexes are found to exhibit strikingly different photoreactivities and solvent dependencies. In MeCN, photolysis of 1-(CO)(Br) [1 = Mn(bpy)(CO)2] affords the ionic complex [1 (MeCN)2]Br as a final product. In contrast, photolysis of 1-(CO)(CCPh) in MeCN results in facial to meridional isomerization of the parent complex. When THF is used as solvent, photolysis results in facial to meridional isomerization in both complexes, though the isomerization rate is larger for X = Br-. Pronounced differences are also observed in the photosubstitution chemistry of the two complexes where both the rate of MeCN exchange from 1-(MeCN)(X) by THFA (tetrahydrofurfurylamine) and the nature of the intermediates generated in the reaction are dependent upon X. DFT calculations are used to support analysis of some of the experiments. PMID- 28872841 TI - Chiral Ramachandran Plots I: Glycine. AB - Ramachandran plots (RPs) map the wealth of conformations of the polypeptide backbone and are widely used to characterize protein structures. A limitation of the RPs is that they are based solely on two dihedral angles for each amino acid residue and provide therefore only a partial picture of the conformational richness of the protein. Here we extend the structural RP analysis of proteins from a two-dimensional (2D) map to a three-dimensional map by adding the quantitative degree of chirality-the continuous chirality measure (CCM)-of the amino acid residue at each point in the RP. This measure encompasses all bond angles and bond lengths of an amino acid residue. We focus in this report on glycine (Gly) because, due to its flexibility, it occupies a large portion of the 2D map, thus allowing a detailed study of the chirality measure, and in order to evaluate the justification of classically labeling Gly as the only achiral amino acid. We have analyzed in detail 4366 Gly residues extracted from high resolution crystallographic data of 160 proteins. This analysis reveals not only that Gly is practically always conformationally chiral, but that upon comparing with the backbone of all amino acids, the quantitative chirality values of Gly are of similar magnitudes to those of the (chiral) amino acids. Structural trends and energetic considerations are discussed in detail. Generally we show that adding chirality to Ramachandran plots creates far more informative plots that highlight the sensitivity of the protein structure to minor conformational changes. PMID- 28872842 TI - Core-Shell-Shell Multifunctional Nanoplatform for Intracellular Tumor-Related mRNAs Imaging and Near-Infrared Light Triggered Photodynamic-Photothermal Synergistic Therapy. AB - A multifunctional nanoplatform, which generally integrates biosensing, imaging diagnosis, and therapeutic functions into a single nanoconstruct, has great important significance for biomedicine and nanoscience. Here, we developed a core shell-shell multifunctional polydopamine (PDA) modified upconversion nanoplatform for intracellular tumor-related mRNAs detection and near-infrared (NIR) light triggered photodynamic and photothermal synergistic therapy (PDT-PTT). The nanoplatform was constructed by loading a silica shell on the hydrophobic upconversion nanoparticles (UCNPs) with hydrophilic photosensitizer methylene blue (MB) entrapped in it, and then modifying PDA shells through an in situ self polymerization process, thus yielding a core-shell-shell nanoconstruct UCNP@SiO2 MB@PDA. By taking advantages of preferential binding properties of PDA for single stranded DNA over double-stranded DNA and the excellent quenching property of PDA, a UCNP@SiO2-MB@PDA-hairpin DNA (hpDNA) nanoprobe was developed through adsorption of fluorescently labeled hpDNA on PDA shells for sensing intracellular tumor-related mRNAs and discriminating cancer cells from normal cells. In addition, the fluorescence resonance energy transfer from the upconversion fluorescence (UCF) emission at 655 nm of the UCNPs to the photosensitizer MB molecules could be employed for PDT. Moreover, due to the strong NIR absorption and high photothermal conversion efficiency of PDA, the UCF emission at 800 nm of the UCNPs could be used for PTT. We demonstrated that the UCNP@SiO2-MB@PDA irradiated with NIR light had considerable PDT-PTT effect. These results revealed that the developed multifunctional nanoplatform provided promising applications in future oncotherapy by integrating cancer diagnosis and synergistic therapy. PMID- 28872843 TI - Diffusion-Controllable Biomineralization Conducted In Situ in Hydrogels Based on Reversibly Cross-Linked Hyperbranched Polyglycidol. AB - We present biocompatible hydrogel systems suitable for biomineralization processes based on hyperbranched polyglycidol cross-linked with acrylamide copolymer bearing carbonyl-coordinated boronic acid. At neutral pH, diol functional groups of HbPGL react with boronic acid of polyacrylamide to generate 3D network in water by the formation of boronic ester cross-links. The dynamic associative/dissociative characteristics of the cross-links makes the network reversible. The presented hydrogels display self-healing properties and are injectable, facilitating gap filing of bone tissue. The 1H HR MAS DOSY NMR studies reveal that acrylamide copolymer plays the role of the network framework, whereas HbPGL macromolecules, due to their compact structure, move between reactive sites of the copolymer. The influence of the copolymer macromolecules entanglements and overall polymer concentrations on macromolecules mobility and stress relaxation processes is investigated. The process of hydrogel biomineralization results from hydrolysis of 1-naphthyl phosphate calcium salt catalyzed by encapsulation in hydrogel alkaline phosphatase. The environment of the hydrogel is entirely neutral toward the enzyme. However, the activity of alkaline phosphatase encapsulated within the hydrogel structure is diffusion limited. In this article, based on the detailed characteristics of three model hydrogel systems, we demonstrate the influence of the hydrogel permeability on the encapsulated enzyme activity and calcium phosphate formation rate. The 1H HR MAS DOSY NMR is used to monitor diffusion low-molecular weight compound within hydrogels, whereas 31P HR MAS NMR facilitates monitoring of the progress of biomineralization in situ within hydrogels. The results show a direct correlation between low molecular diffusivity in hydrogels and network dynamics. We demonstrate that the morphology of in situ-generated calcium phosphate within three model HbPGL/poly(AM-ran-APBA) hydrogels of different low molecular permeability varies substantially from sparsely deployed large, well-defined crystals to an even distribution within the polymers polycrystalline continuous network. PMID- 28872844 TI - MdFDIA: A Mass Defect Based Four-Plex Data-Independent Acquisition Strategy for Proteome Quantification. AB - Data-independent acquisition (DIA) has recently emerged as a powerful quantitative approach for large-scale proteome quantification, providing a sensitive and reproducible alternative to data-dependent acquisition (DDA). However, lack of compatible multiplexed quantification methods is a bottleneck of DIA. To alleviate this challenge, we present a mass defect based four-plex data independent acquisition strategy, termed "MdFDIA", for parallel analysis of four different protein samples in a DIA experiment without the additional complexity of tandem mass spectrometry (MS2) spectra. MdFDIA is a hybrid approach that combines stable isotope labeling with amino acids in cell culture (SILAC) and dimethyl labeling. Briefly, the isotopes 13C615N2-lysine (+8.0142 Da, light) and D8-lysine (+8.0512 Da, heavy) were metabolically embedded in different proteome samples during cell culture. Then, two 13C615N2-lysine and D8-lysine labeled protein samples were digested with Lys-C, followed by in vitro labeling with light (213CD2H, +34.06312 Da) and heavy (2CD3, +34.06896 Da) dimethyl groups, respectively, producing four different pseudoisobaric labeled protein samples. The labeled samples were then equally mixed and analyzed by DIA. The subtle mass differences between the four labeled forms in MS2 scans can be resolved on an Orbitrap Fusion Lumos instrument to facilitate quantification without abundance information encoded in MS2 spectra. Additionally, a systematic investigation was carried out and revealed that MdFDIA enabled a significant decrease of the adverse impact on the accuracy of the quantitative assays arising from the chromatographic isotope effect, especially the deuterium effect, which typically occurs in a DDA experiment. Additionally, MdFDIA provided a method for validating the fragment type in the DIA spectra identification result. Furthermore, MdFDIA was applied to quantitative proteome analyses of four different breast cancer cell lines, demonstrating the feasibility of this strategy for biological applications. PMID- 28872845 TI - Iron(III) Metallacryptand and Metallacryptate Assemblies Derived from Aroylbis(N,N-diethylthioureas). AB - The reaction of isophthaloylbis(N,N-diethylthiourea), H2L1, with FeCl3.6H2O gives the dinuclear tris-complex [Fe2(L1)3] (5), possessing a cryptand-like structure. A similar reaction with the ligand 2,6-dipicolinoylbis(N,N-diethylthiourea), H2L2, however, results in the formation of the anionic, mononuclear Fe(III) complex [Fe(L2)2]- (6), which could be isolated as its "Tl+ salt" by the subsequent addition of Tl(NO3). A tighter view to the solid state structure of the obtained product, however, characterizes compound 6 as a one-dimensional coordination polymer, in which four-coordinate Tl+ ions connect the {[Fe(L2)2]-} units to infinite chains. When Fe3+ ions and Tl+ ions are added to H2L2 simultaneously in a one-pot reaction, a different product is obtained: a cationic trinuclear complex of the composition {M?[Fe2(L2)3]}+. It has been isolated as a PF6- salt and represents a {2}-metallacryptate with a nine-coordinate Tl+ ion in the central void. Structurally related products of the compositions {M?[Fe2(L2)3]}(PF6) (M = Na+, K+, Rb+) (8(PF6)) could be isolated from analogous reactions with alkaline salts instead of Tl(NO3). {2}-Metallacryptates with larger central voids were synthesized with the ether-spaced aroylbis(N,N diethylthiourea) H2L3. The compounds {M?[Fe2(L3)3]}(PF6) (M = K+, Rb+, Tl+ or Cs+) (9(PF6)) were prepared by a similar protocol like those with H2L2 with the simultaneous addition of the metal ions to a solution of H2L3. Due to the larger spacer between the aroylthiourea units, the coordination number of the central M+ ions is 12 by six carbonyl and six ether oxygen atoms. All products were characterized by elemental analysis, IR spectroscopy, and X-ray structure analysis. Cyclic voltammetric studies were carried out with the three representative complexes [Fe2(L1)3], {K?[Fe2(L2)3]}(PF6), and {K?[Fe2(L3)3]}(PF6). The obtained voltammograms indicate the dependence of the redox properties of the oligonuclear systems on the conjugation in the organic backbones of the ligands. PMID- 28872846 TI - Tuning the Diiron Core Geometry in Carboxylate-Bridged Macrocyclic Model Complexes Affects Their Redox Properties and Supports Oxidation Chemistry. AB - We introduce a novel platform to mimic the coordination environment of carboxylate-bridged diiron proteins by tethering a small, dangling internal carboxylate, (CH2)nCOOH, to phenol-imine macrocyclic ligands (H3PIMICn). In the presence of an external bulky carboxylic acid (RCO2H), the ligands react with [Fe2(Mes)4] (Mes = 2,4,6-trimethylphenyl) to afford dinuclear [Fe2(PIMICn)(RCO2)(MeCN)] (n = 4-6) complexes. X-ray diffraction studies revealed structural similarities between these complexes and the reduced diiron active sites of proteins such as Class I ribonucleotide reductase (RNR) R2 and soluble methane monooxygenase hydroxylase. The number of CH2 units of the internal carboxylate arm controls the diiron core geometry, affecting in turn the anodic peak potential of the complexes. As functional synthetic models, these complexes facilitate the oxidation of C-H bonds in the presence of peroxides and oxo transfer from O2 to an internal phosphine moiety. PMID- 28872848 TI - Trace Material Capture by Controlled Liquid Droplets on a Superhydrophobic/Hydrophilic Surface. AB - A liquid droplet in contact with a superhydrophobic surface can be used to collect dissolved trace materials after evaporating the solvent. This process effect enhances detection limits, but a liquid droplet easily rolls off a superhydrophobic surface. Keeping it at a specific collecting spot area is challenging. Here the means for controlling and capturing a liquid droplet on a superhydrophobic surface is demonstrated. To induce a liquid droplet to a collecting spot, its rolling direction was controlled by two superhydrophobic fabric guides. The liquid droplet was then captured by hydrophilic polymer and hydrophilic nanoparticles at the measuring spot. After removing the solvent, the trace compounds were evaluated with a colorimetric analysis visible to the naked eye. PMID- 28872849 TI - Thiol-Induced Synthesis of Phosphine-Protected Gold Nanoclusters with Atomic Precision and Controlling the Structure by Ligand/Metal Engineering. AB - Efficient synthesis of atomically precise phosphine-capped gold nanocluster (with >10 metal atoms) is important to deeply understand the relationship between structure and properties. Herein, we successfully utilize the thiol-induced synthesis method and obtain three atomically precise phosphine-protected gold nanoclusters. Single-crystal X-ray structural analysis reveals that the nanoclusters are formulated as [Au13(Dppm)6](BPh4)3, [Au18(Dppm)6Br4](BPh4)2, and [Au20(Dppm)6(CN)6] (where Dppm stands for bis(diphenylphosphino)methane), which are further confirmed by electrospray ionization mass spectrometry, thermogravimetric analysis, and X-ray photoelectron spectroscopy. Meanwhile, [Au18(Dppm)6Br4](BPh4)2 could be converted into [Au13(Dppm)6](BPh4)3 and [Au20(Dppm)6(CN)6] by engineering the surface ligands under excess PPh3 or moderate NaBH3CN, respectively. Furthermore, according to the different binding ability of silver with halogen, we successfully achieved target metal exchange on [Au18(Dppm)6Br4](BPh4)2 with Ag-SAdm (where HS-Adm stands for 1-adamantane mercaptan) complex and obtained [AgxAu18-x(Dppm)6Br4](BPh4)2 (x = 1, 2) alloy nanoclusters. Our work will contribute to more intensive understanding on synthesizing phosphine-protected nanoclusters as well as shedding light on the structure-property correlations in the nanocluster range. PMID- 28872847 TI - His-Tag-Mediated Dimerization of Chemoreceptors Leads to Assembly of Functional Nanoarrays. AB - Transmembrane chemotaxis receptors are found in bacteria in extended hexagonal arrays stabilized by the membrane and by cytosolic binding partners, the kinase CheA and coupling protein CheW. Models of array architecture and assembly propose receptors cluster into trimers of dimers that associate with one CheA dimer and two CheW monomers to form the minimal "core unit" necessary for signal transduction. Reconstructing in vitro chemoreceptor ternary complexes that are homogeneous and functional and exhibit native architecture remains a challenge. Here we report that His-tag-mediated receptor dimerization with divalent metals is sufficient to drive assembly of nativelike functional arrays of a receptor cytoplasmic fragment. Our results indicate receptor dimerization initiates assembly and precedes formation of ternary complexes with partial kinase activity. Restoration of maximal kinase activity coincides with a shift to larger complexes, suggesting that kinase activity depends on interactions beyond the core unit. We hypothesize that achieving maximal activity requires building core units into hexagons and/or coalescing hexagons into the extended lattice. Overall, the minimally perturbing His-tag-mediated dimerization leads to assembly of chemoreceptor arrays with native architecture and thus serves as a powerful tool for studying the assembly and mechanism of this complex and other multiprotein complexes. PMID- 28872850 TI - Enhancing the Mass Spectrometry Sensitivity for Oligonucleotide Detection by Organic Vapor Assisted Electrospray. AB - There are two challenges in oligonucleotide detection by liquid chromatography coupled with mass spectrometry (LC-MS), the serious ion suppression effects caused by ion-pair reagents and the low detection sensitivity in positive mode MS. In this study, highly concentrated alcohol vapors were introduced into an enclosed electrospray ionization chamber, and oligonucleotides could be well detected in negative mode MS even with 100 mM triethylammonium acetate (TEAA) as an ion-pair reagent. The MS signal intensity was improved 600-fold (for standard oligonucleotide dT15) by the isopropanol vapor assisted electrospray, and effective ion-pair LC separation was feasibly coupled with high-sensitive MS detection. Then, oligonucleotides were successfully detected in positive mode MS with few adducts by propanoic acid vapor assisted electrospray. The signal intensity was enhanced more than 10-fold on average compared with adding acids into the electrospray solution. Finally, oligonucleotides and peptides or histones were simultaneously detected in MS with little interference with each other. Our strategy provides a useful alternative for investigating the biological functions of oligonucleotides. PMID- 28872851 TI - Erythrocyte Membrane-Wrapped pH Sensitive Polymeric Nanoparticles for Non-Small Cell Lung Cancer Therapy. AB - The application of nano drug delivery systems (NDDSs) may enhance the effectiveness of chemotherapeutic drugs in vivo. However, the short blood circulation time and poor drug release profile in vivo are still two problems with them. Herein, by using red blood cell membrane (RBCm) wrapping and pH sensitive technology, we prepared RBCm wrapped pH sensitive poly(l-gamma glutamylcarbocistein)-paclitaxel (PGSC-PTX) nanoparticles (PGSC-PTX@RBCm NPs), to prolong the circulation time in blood and release PTX timely and adequately in acidic tumor environment. The PGSC-PTX NPs and PGSC-PTX@RBCm NPs showed spherical morphology with average sizes about 50 and 100 nm, respectively. The cytotoxicity of PGSC-PTX@RBCm NPs was considerably decreased compared with that of PGSC-PTX NPs. PTX release from PGSC-PTX and PGSC-PTX@RBCm NPs at pH 6.5 was remarkably higher than those at pH 7.4, respectively. The PGSC-PTX@RBCm NPs exhibited remarkably decreased uptake by macrophages than PGSC-PTX NPs. The area under the curve within 72 h (AUC0-72h) for is significantly higher than PGSC-PTX NPs. The PGSC-PTX@RBCm NPs also showed significantly stronger growth-inhibiting effect on tumor than PGSC-PTX NPs. These results indicated that PGSC-PTX@RBCm NPs have acidic drug release sensitivity, the characteristics of long circulation, and remarkable tumor growth inhibiting effect. This study may provide an effective strategy for improving the antitumor effect of NDDS. PMID- 28872852 TI - Hydroxyapatites: Key Structural Questions and Answers from Dynamic Nuclear Polarization. AB - We demonstrate that NMR/DNP (Dynamic Nuclear Polarization) allows an unprecedented description of carbonate substituted hydroxyapatite (CHAp). Key structural questions related to order/disorder and clustering of carbonates are tackled using distance sensitive DNP experiments using 13C-13C recoupling. Such experiments are easily implemented due to unprecedented DNP gain (orders of magnitude). DNP is efficiently mediated by quasi one-dimensional spin diffusion through the hydroxyl columns present in the CHAp structure (thought of as "highways" for spin diffusion). For spherical nanoparticles and phi < 100 nm, it is numerically shown that spin diffusion allows their study as a whole. Most importantly, we demonstrate also that the DNP study at 100 K leads to data which are comparable to data obtained at room temperature (in terms of spin dynamics and line shape resolution). Finally, all 2D DNP experiments can be interpreted in terms of domains exhibiting well identified types of substitution: local order and carbonate clustering are clearly favored. PMID- 28872854 TI - Kinetics and Mechanism of the Chlorate-Nitrous Acid Reaction. AB - The chlorate-nitrous acid reaction was investigated in acid media, using a high concentration of reagents. It was followed via ultraviolet-visible light (UV-vis) spectroscopy and presented a complex behavior. The order of reagents, and the products formed by this reaction, are dependent on the concentration of reagents. For the high concentration set we used, the reaction has shown a first-order behavior for H+ and HNO2, and an order equal to 0.79 for chlorate. In this case, chlorine dioxide is formed. Moreover, chlorine dioxide starts to form only after all HNO2 has been consumed. This is the first time chlorine dioxide was observed to be formed by this reaction. Reduction of the concentration of reagents decreases the order of HNO2 to 0.91 and no chlorine dioxide is formed. An isosbestic point was found at 312 nm, which indicates a 1:1 ratio between nitrate ion and nitrous acid species. A model, with 14 independent species and 12 reactions is presented, which is able to simulate the experimental behavior for the low and high concentrations sets of reagents and it is a significant improvement in the understanding of the complex nitrogen and chlorine aqueous chemistry. PMID- 28872853 TI - New Insights into DNA Polymerase Function Revealed by Phosphonoacetic Acid Sensitive T4 DNA Polymerases. AB - The bacteriophage T4 DNA polymerase (pol) and the closely related RB69 DNA pol have been developed into model enzymes to study family B DNA pols. While all family B DNA pols have similar structures and share conserved protein motifs, the molecular mechanism underlying natural drug resistance of nonherpes family B DNA pols and drug sensitivity of herpes DNA pols remains unknown. In the present study, we constructed T4 phages containing G466S, Y460F, G466S/Y460F, P469S, and V475W mutations in DNA pol. These amino acid substitutions replace the residues in drug-resistant T4 DNA pol with residues found in drug-sensitive herpes family DNA pols. We investigated whether the T4 phages expressing the engineered mutant DNA pols were sensitive to the antiviral drug phosphonoacetic acid (PAA) and characterized the in vivo replication fidelity of the phage DNA pols. We found that G466S substitution marginally increased PAA sensitivity, whereas Y460F substitution conferred resistance. The phage expressing a double mutant G466S/Y460F DNA pol was more PAA-sensitive. V475W T4 DNA pol was highly sensitive to PAA, as was the case with V478W RB69 DNA pol. However, DNA replication was severely compromised, which resulted in the selection of phages expressing more robust DNA pols that have strong ability to replicate DNA and contain additional amino acid substitutions that suppress PAA sensitivity. Reduced replication fidelity was observed in all mutant phages expressing PAA-sensitive DNA pols. These observations indicate that PAA sensitivity and fidelity are balanced in DNA pols that can replicate DNA in different environments. PMID- 28872855 TI - Degrading and Phytoextracting Atrazine Residues in Rice (Oryza sativa) and Growth Media Intensified by a Phase II Mechanism Modulator. AB - Atrazine (ATZ) residue in farmland is one of the environmental contaminants seriously affecting crop production and food safety. Understanding the regulatory mechanism for ATZ metabolism and degradation in plants is important to help reduce ATZ potential toxicity to both plants and human health. Here, we report our newly developed engineered rice overexpressing a novel Phase II metabolic enzyme glycosyltransfearse1 (ARGT1) responsible for transformation of ATZ residues in rice. Our results showed that transformed lines, when exposed to environmentally realistic ATZ concentration (0.2-0.8 mg/L), displayed significantly high tolerance, with 8-27% biomass and 36-56% chlorophyll content higher, but 37-69% plasma membrane injury lower than untransformed lines. Such results were well confirmed by ARGT1 expression in Arabidopsis. ARGT1-transformed rice took up 1.6-2.7 fold ATZ from its growth medium compared to its wild type (WT) and accumulated ATZ 10%-43% less than that of WT. A long-term study also showed that ATZ in the grains of ARGT1-transformed rice was reduced by 30-40% compared to WT. The ATZ-degraded products were characterized by UPLC/Q-TOF-MS/MS. More ATZ metabolites and conjugates accumulated in ARGT1-transformed rice than in WT. Eight ATZ metabolites for Phase I reaction and 10 conjugates for Phase II reaction in rice were identified, with three ATZ-glycosylated conjugates that have never been reported before. These results indicate that ARGT1 expression can facilitate uptake of ATZ from environment and metabolism in rice plants. PMID- 28872856 TI - Evidence of Coupled Carbon and Iron Cycling at a Hydrocarbon-Contaminated Site from Time Lapse Magnetic Susceptibility. AB - Conventional characterization and monitoring of hydrocarbon (HC) pollution is often expensive and time-consuming. Magnetic susceptibility (MS) has been proposed as an inexpensive, long-term monitoring proxy of the degradation of HC. We acquired repeated down hole MS logging data in boreholes at a HC-contaminated field research site in Bemidji, MN, USA. The MS data were analyzed in conjunction with redox conditions and iron availability within the source zone to better assess whether MS can serve as a proxy for monitoring HC contamination in unconsolidated sediments. The MS response at the site diminished during the sampling period, which was found to coincide with depletion of solid phase iron in the source zone. Previous geochemical observations and modeling at the site suggest that the most likely cause of the decrease in MS is the transformation of magnetite to siderite, coupled with the exhaustion of ferrihydrite. Although the temporal MS response at this site gives valuable field-scale evidence for changing conditions of iron cycling and stability of iron minerals it does not provide a simple proxy for long-term monitoring of biodegradation of hydrocarbons in the smear zone. PMID- 28872857 TI - Cross-Linked Collagen Triple Helices by Oxime Ligation. AB - Covalent cross-links are crucial for the folding and stability of triple-helical collagen, the most abundant protein in nature. Cross-linking is also an attractive strategy for the development of synthetic collagen-based biocompatible materials. Nature uses interchain disulfide bridges to stabilize collagen trimers. However, their implementation into synthetic collagen is difficult and requires the replacement of the canonical amino acids (4R)-hydroxyproline and proline by cysteine or homocysteine, which reduces the preorganization and thereby stability of collagen triple helices. We therefore explored alternative covalent cross-links that allow for connecting triple-helical collagen via proline residues. Here, we present collagen model peptides that are cross-linked by oxime bonds between 4-aminooxyproline (Aop) and 4-oxoacetamidoproline placed in coplanar Xaa and Yaa positions of neighboring strands. The covalently connected strands folded into hyperstable collagen triple helices (Tm ~ 80 degrees C). The design of the cross-links was guided by an analysis of the conformational properties of Aop, studies on the stability and functionalization of Aop-containing collagen triple helices, and molecular dynamics simulations. The studies also show that the aminooxy group exerts a stereoelectronic effect comparable to fluorine and introduce oxime ligation as a tool for the functionalization of synthetic collagen. PMID- 28872858 TI - Fast and Reliable Thermodynamic Approach for Determining the Protonation State of the Asp Dyad. AB - The protonation state of the asp dyad is significantly important in revealing enzymatic mechanisms and developing drugs. However, it is hard to determine by calculating free energy changes between possible protonation states, because the free energy changes due to protein conformational flexibility are usually much larger than those originating from different locations of protons. Sophisticated and computationally expensive methods such as free energy perturbation, thermodynamic integration (TI), and quantum mechanics/molecular mechanics are therefore usually used for this purpose. In the present study, we have developed a simple thermodynamic approach to effectively eliminating the free energy changes arising from protein conformational flexibility and estimating the free energy changes only originated from the locations of protons, which provides a fast and reliable method for determining the protonation state of asp dyads. The test of this approach on a total of 15 asp dyad systems, including BACE-1 and HIV 1 protease, shows that the predictions from this approach are all consistent with experiments or with the computationally expensive TI calculations. It is clear that our thermodynamic approach could be used to rapidly and reliably determine the protonation state of the asp dyad. PMID- 28872859 TI - Lipophilization of Resveratrol and Effects on Antioxidant Activities. AB - Resveratrol (R), a polyphenol, was structurally modified via esterification with selected fatty acids to expand its potential application in lipophilic foods, drugs, and cosmetics. The esterification was carried out using 12 different fatty acids with varying chain lengths and degrees of unsaturation (C3:0-C22:6). Two monoesters, two diesters, and one triester were identified by high-performance liquid chromatography-mass spectrometry, and the monoesters (R-3-O monodocosahexaenoate and R-4'-O-monodocosahexaenoate) were structurally confirmed by nuclear magnetic resonance. The lipophilicity of resveratrol and its alkyl esters was calculated using ALOGPS 2.1. Resveratrol exhibited greater antioxidant activity in both 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and 2,2'-azino bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation scavenging assays. Resveratrol esters with long-chain fatty acids (C18:0 and C18:1) showed higher antioxidant activity in the DPPH radical scavenging assay, whereas short chain fatty acid (C3:0, C4:0, and C6:0) showed higher antioxidant activity in the ABTS radical cation scavenging assay. The results may imply that resveratrol derivatives could be used in lipophilic media as health beneficial antioxidants. PMID- 28872860 TI - Charge and Energy Transfer Dynamics in Dimethylsilylene-Spaced Aminostyrene Stilbene Monomer Using Time-Resolved Techniques. AB - We used transient absorption and time-correlated single photon counting (TCSPC) techniques to investigate the charge transfer reaction in monosilylene-spaced aminostyrene stilbene monomer. With 266 nm excitation, both stilbene (sti) and aminostyrene (ast) moieties were excited. In nonpolar solvents, the transient absorption band centered at 600 nm appeared promptly and is assigned to the excited state of sti*; this state relaxes at time constant 1.2-1.4 ps and is explained to proceed energy transfer to ast 1pipi*. The second transient band at 460 nm is assigned to absorption of ast 2pipi*; this state accessed from direct excitation has a lifetime 65 ps. This agrees with the observation of 85-89 ps emission decay from the TCSPC measurements. In polar solvent, an excited absorption band centered at 530 nm appeared with a rise time constant 0.2-0.6 ps. This band is assigned to the charge transfer state. This charge transfer process occurs as the acceptor fluorophore (sti) is excited and the electron moves from the occupied pi orbital of donor ast to sti* forming ast+sti-. This rise time corresponds to the combined processes of charge and energy transfers. The second rise in this charge-transfer state at time constant 0.74-1.5 ps is observed and assigned to occur from electron hopping from ast 2pi* orbital to sti pi*. The third time constant 18-31 ps is observed and is attributed to conversion of anti to syn form in the charge-transfer state because the syn form is more polar and further stabilized in polar environment. A rapid charge transfer process in monosilylene-spaced system although two Si-C single bonds are used as spacer is possibly because of the short distance of the ast and the sti conjugated systems, resulting in pi orbital overlap between donor and acceptor. PMID- 28872861 TI - Entropic Anomaly Observed in Lipid Polymorphisms Induced by Surfactant Peptide SP B(1-25). AB - The N-terminal 25 amino-acid residues of pulmonary surfactant protein B (SP-B1 25) induces unusual lipid polymorphisms in a model lipid system, 4:1 DPPC/POPG, mirroring the lipid composition of native pulmonary surfactant. It is widely suggested that SP-B1-25-induced lipid polymorphisms within the alveolar aqueous subphase provide a structural platform for rapid lipid adsorption to the air water interface. Here, we characterize in detail the phase behavior of DPPC and POPG in hydrated lipid assemblies containing therapeutic levels of SP-B1-25 using 2H and 31P solid state NMR spectroscopy. The appearance of a previously observed isotropic lipid phase is found to be highly dependent on the thermal cycling of the samples. Slow heating of frozen samples leads to phase separation of DPPC into a lamellar phase whereas POPG lipids interact with the peptide to form an isotropic phase at physiologic temperature. Rapid heating of frozen samples to room temperature leads to strongly isotropic phase behavior for both DPPC and POPG lipids, with DPPC in exchange between isotropic and interdigitated phases. 31P T2 relaxation times confirm the isotropic phase to be consistent with a lipid cubic phase. The observed phases exhibit thermal stability up to physiologic temperature (37 degrees C) and are consistent with the formation of a ripple phase containing a large number of peptide-induced membrane structural defects enabling rapid transit of lipids between lipid lamellae. The coexistance of a lipid cubic phase with interdigitated lipids suggests a specific role for the highly conserved N-terminus of SP-B in stabilizing this unusual lipid polymorphism. PMID- 28872862 TI - Packing Arrangements and Intersheet Interaction of Alanine Oligopeptides As Revealed by Relaxation Parameters Obtained from High-Resolution 13C Solid-State NMR. AB - Alanine oligopeptides provide a key structure of the crystalline domains of the silks from spiders and wild silkworm and also the sequences included in proteins such as antifreeze proteins and amyloids. In this paper, the local dynamics of alanine oligopeptides, (Ala)3, (Ala)4, and (Ala)6 were examined by high resolution 13C solid-state NMR. The 13C spin-lattice relaxation times (T1's) for the Cbeta4 carbons of antiparallel (AP)-beta-sheet (Ala)4 significantly prolonged and the correlation time was estimated as 3.6 * 10-11 s which was shorter than those of other carbons in the AP-beta-sheet (Ala)4 (2.8 * 10-10 s). The T1 values for the Cbeta carbons of (Ala)6 showed significantly longer correlation time (8.8 * 10-9 s) than those of AP-beta-sheet (Ala)4. It is thus revealed that AP-beta sheet (Ala)6 exhibited stronger intersheet interaction than those of AP-beta sheet (Ala)4. The 13C spin-spin relaxation times (T2's) for the Cbeta4 carbons showed longer than those of the other Cbeta1-3 carbons of AP-beta-sheet (Ala)4. T2 values of Cbeta carbons reflect the slow time-scale (~70 kHz) backbone motions. The C-terminal forms strong hydrogen bonds with water molecules and thus the backbone motion is slower than ~70 kHz, while the central backbone motions are faster than ~70 kHz in the AP-beta-sheet (Ala)4. PMID- 28872863 TI - Metalation and Selective Oxidation of Diphenyl-23-oxa-, -thia-, and -selena-21 carbaporphyrins. AB - The availability of diphenyl-23-oxa-, -thia-, and -selena-21-carbaporphyrins has enabled the reactivity of these systems to be investigated and contrasted. All three heterocarbaporphyrins reacted with palladium(II) acetate in refluxing chloroform-acetonitrile to give organometallic palladium(II) derivatives in good yields. These structures are stable and give UV-vis spectra that show increasing broadening and bathochromic shifts as the size of the heteroatom increases. Nickel(II) acetate in refluxing N,N-dimethylformamide reacted with the oxa- and thiacarbaporphyrins under nitrogen to give the corresponding nickel(II) complexes, but the selenacarbaporphyrin did not metalate under these conditions. The NMR spectra for all of the metal complexes showed that they possess strong diamagnetic ring currents, although the palladium complexes gave larger downfield shifts that were slightly diminished when larger heteroatoms were present in the porphyrinoid cavity. Reactions of the oxacarbaporphyrin with nickel(II) acetate in the presence of air led to a unique oxidation reaction that afforded a weakly diatropic 21-oxycarbaporphyrin, and low yields of a related product were also obtained from the thiacarbaporphyrin. PMID- 28872864 TI - Measurement of the Energy and High-Pressure Dependence of X-ray-Induced Decomposition of Crystalline Strontium Oxalate. AB - We report measurements of the X-ray-induced decomposition of crystalline strontium oxalate (SrC2O4) as a function of energy and high pressure in two separate experiments. SrC2O4 at ambient conditions was irradiated with monochromatic synchrotron X-rays ranging in energy from 15 to 28 keV. A broad resonance of the decomposition yield was observed with a clear maximum when irradiating with ~20 keV X-rays and ambient pressure. Little or no decomposition was observed at 15 keV, which is below the Sr K-shell energy of 16.12 keV, suggesting that excitation of core electrons may play an important role in the destabilization of the C2O42- anion. A second experiment was performed to investigate the high-pressure dependence of the X-ray-induced decomposition of strontium oxalate at fixed energy. SrC2O4 was compressed in a diamond anvil cell (DAC) in the pressure range from 0 to 7.6 GPa with 1 GPa increments and irradiated in situ with 20 keV X-rays. A marked pressure dependence of the decomposition yield of SrC2O4 was observed with a decomposition yield maximum at around 1 GPa, suggesting that different crystal structures of the material play an important role in the decomposition process. This may be due in part to a phase transition observed near this pressure. PMID- 28872865 TI - A Versatile and Efficient Strategy to Discrete Conjugated Oligomers. AB - An efficient and scalable strategy to prepare libraries of discrete conjugated oligomers (D = 1.0) using the combination of controlled polymerization and automated flash chromatography is reported. From this two-step process, a series of discrete conjugated materials from dimers to tetradecamers could be isolated in high yield with excellent structural control. Facile and scalable access to monodisperse libraries of different conjugated oligomers opens pathways to designer mixtures with precise composition and monomer sequence, allowing exquisite control over their physical, optical, and electronic properties. PMID- 28872866 TI - Switching of Charge Transport Pathways via Delocalization Changes in Single Molecule Metallacycles Junctions. AB - To explore the charge transport through metalla-aromatics building blocks, three metallacycles complexes were synthesized, and their single-molecule conductances were characterized by using mechanically controllable break junction technique. It is found that the conductance of the metallacycles junction with phosphonium group is more than 1 order of magnitude higher than that without phosphonium group. X-ray diffraction and UV-vis absorption spectroscopy suggested that the attached phosphonium group makes metallacycles more delocalized, which shortened the preferred charge transport pathway and significantly enhanced the single molecule conductance. This work revealed that the delocalization of metalla aromatics could be used to switch the charge transport pathway of single-molecule junctions and thus tune the charge transport abilities significantly. PMID- 28872867 TI - Multidrug, Anti-HIV Amorphous Solid Dispersions: Nature and Mechanisms of Impacts of Drugs on Each Other's Solution Concentrations. AB - Drug therapy has been instrumental in prolonging the lives of patients infected by human immunodeficiency virus (HIV). In order to combat development of resistance, therapies involving three or more drugs in combination are recommended by the World Health Organization (WHO) to suppress HIV and prevent development of acquired immune deficiency syndrome (AIDS). It is desirable for multidrug combinations to be coformulated into single dosage forms where possible, to promote patient convenience and adherence to dosage regimens, for which amorphous solid dispersion (ASD) is particularly well-suited. We investigated multidrug ASDs of three model anti-HIV drugs, ritonavir (Rit), etravirine (Etra), and efavirenz (Efa), in cellulosic polymer matrices. We hypothesized that the presence of multiple drugs would reduce crystallization tendency, thereby providing stable, supersaturating formulations for bioavailability enhancement. We explored new ASD polymers including cellulose acetate suberate (DSSub 0.9, CASub) and cellulose acetate adipate propionate (DSAd 0.9, CAAdP), and control commercial cellulosic polymers including 6 carboxycellulose acetate butyrate (CCAB) and carboxymethyl cellulose acetate butyrate (CMCAB). We succeeded in preparing three-drug ASDs containing very high drug loadings (45% drug total; 15% of each drug); each polymer tested was effective at stabilizing the amorphous drugs in the solid phase, as demonstrated by XRD, SEM, and DSC studies. In pH 6.8 dissolution studies ASDs released each anti-HIV drug over 8 h, affording supersaturated solutions of each drug, but unexpectedly failing in some cases to reach maximum possible supersaturation. In a second set of dissolution studies (pH 6.8), the cause of the observed solution concentration limitations was investigated by studying release from single- and two-drug ASDs. Concentrations of Rit, Etra, and Efa achieved from three-drug ASDs were higher than those achieved from crystalline drugs. Surprisingly, however, there was a decrease in the achieved drug concentrations of both Rit and Efa when they dissolved together, while Etra solution concentration was enhanced by the presence of Rit and Efa in the ASD. We demonstrate that these effects have to do primarily with solution phase interactions between the anti-HIV drugs, rather than from the drugs influencing each other's release rate, and we suggest that such observations may indicate an important, previously inadequately recognized, and general phenomenon for ASDs containing multiple hydrophobic drugs. PMID- 28872868 TI - Electronic Substituent Effects of Guests on the Conformational Network and Binding Behavior of Oxatub[4]arene. AB - A series of quaternary ammonium guests have been synthesized, and their binding behavior with oxatub[4]arene have been studied. In particular, remote electronic substituents of the guests can significantly affect the binding affinities mainly through a field/inductive effect by following a linear free energy relationship. More surprisingly, oxatub[4]arene, with a complex conformational network, shows a large amplitude of conformational change in response to the remote electronic substituents on the guests. This novel mode of synthetic molecular recognition may also have biological relevance. PMID- 28872869 TI - Demystifying Multitask Deep Neural Networks for Quantitative Structure-Activity Relationships. AB - Deep neural networks (DNNs) are complex computational models that have found great success in many artificial intelligence applications, such as computer vision1,2 and natural language processing.3,4 In the past four years, DNNs have also generated promising results for quantitative structure-activity relationship (QSAR) tasks.5,6 Previous work showed that DNNs can routinely make better predictions than traditional methods, such as random forests, on a diverse collection of QSAR data sets. It was also found that multitask DNN models-those trained on and predicting multiple QSAR properties simultaneously-outperform DNNs trained separately on the individual data sets in many, but not all, tasks. To date there has been no satisfactory explanation of why the QSAR of one task embedded in a multitask DNN can borrow information from other unrelated QSAR tasks. Thus, using multitask DNNs in a way that consistently provides a predictive advantage becomes a challenge. In this work, we explored why multitask DNNs make a difference in predictive performance. Our results show that during prediction a multitask DNN does borrow "signal" from molecules with similar structures in the training sets of the other tasks. However, whether this borrowing leads to better or worse predictive performance depends on whether the activities are correlated. On the basis of this, we have developed a strategy to use multitask DNNs that incorporate prior domain knowledge to select training sets with correlated activities, and we demonstrate its effectiveness on several examples. PMID- 28872870 TI - Single-Crystal Thin Films of Cesium Lead Bromide Perovskite Epitaxially Grown on Metal Oxide Perovskite (SrTiO3). AB - High-quality metal halide perovskite single crystals have low defect densities and excellent photophysical properties, yet thin films are the most sought after material geometry for optoelectronic devices. Perovskite single-crystal thin films (SCTFs) would be highly desirable for high-performance devices, but their growth remains challenging, particularly for inorganic metal halide perovskites. Herein, we report the facile vapor-phase epitaxial growth of cesium lead bromide perovskite (CsPbBr3) continuous SCTFs with controllable micrometer thickness, as well as nanoplate arrays, on traditional oxide perovskite SrTiO3(100) substrates. Heteroepitaxial single-crystal growth is enabled by the serendipitous incommensurate lattice match between these two perovskites, and overcoming the limitation of island-forming Volmer-Weber crystal growth is critical for growing large-area continuous thin films. Time-resolved photoluminescence, transient reflection spectroscopy, and electrical transport measurements show that the CsPbBr3 epitaxial thin film has a slow charge carrier recombination rate, low surface recombination velocity (104 cm s-1), and low defect density of 1012 cm-3, which are comparable to those of CsPbBr3 single crystals. This work suggests a general approach using oxide perovskites as substrates for heteroepitaxial growth of halide perovskites. The high-quality halide perovskite SCTFs epitaxially integrated with multifunctional oxide perovskites could open up opportunities for a variety of high-performance optoelectronics devices. PMID- 28872872 TI - Nucleus-Independent Chemical Shifts: A Simple and Efficient Aromaticity Probe. PMID- 28872871 TI - Chitosan-Promoted Direct Electrochemistry of Human Sulfite Oxidase. AB - Direct electrochemistry of human sulfite oxidase (HSO) has been achieved on carboxylate-terminated self-assembled monolayers cast on a Au working electrode in the presence of the promoter chitosan. The modified electrode facilitates a well-defined nonturnover redox response from the heme cofactor (FeIII/II) in 750 mM Tris, MOPS, and bicine buffer solutions. The formal redox potential of the nonturnover response varies slightly depending on the nature of the thiol monolayer on the Au electrode. Upon addition of sulfite to the cell a pronounced catalytic current from HSO-facilitated sulfite oxidation is observed. The measured catalytic rate constant (kcat) is around 0.2 s-1 (compared with 26 s-1 obtained from solution assays), which indicates that interaction of the enzyme with the electrode lowers overall catalysis although native behavior is retained in terms of substrate concentration dependence, pH dependence, and inhibition effects. In contrast, no catalytic activity is observed when HSO is confined to amine-terminated thiol monolayers although well-defined noncatalytic responses from the heme cofactor are still observed. These differences are linked to flexibility of HSO, which can switch between active and inactive conformations, and also competitive ion exchange processes at the electrode surface involving the enzyme and substrate. PMID- 28872873 TI - Synthesis and Stability of Water-in-Oil Emulsion Using Partially Reduced Graphene Oxide as a Tailored Surfactant. AB - Graphene oxide (GO) is widely known as an amphiphile having hydrophilic oxygen functionality and unoxidized graphitic patches as the hydrophobic domains. Exploiting this amphiphilicity, GO serves as a surfactant to stabilize oil-water interfaces. While there are numerous reports on GO as a surfactant, most of these reports concern oil-in-water (O/W) emulsions, and there are very few on the formation of water-in-oil (W/O) emulsions. We prepared W/O emulsions using partially reduced graphene oxide (prGO) as a surfactant. The partial reduction introduces a subtle hydrophilic-lipophilic balance (HLB), which favors the formation of the W/O emulsion. The morphological features and rheological characteristics of the W/O emulsion with 75:25 water-to-oil ratio were investigated and analyzed in detail. The W/O emulsion was found to have polydispersity with wide range of droplet sizes varying between 2 to 500 MUm. Using confocal microscopy, the role of parameters such as extent of reduction, continuous phase volume fraction and the concentration of GO on the stability, microstructure and variation of droplet size distribution of the W/O emulsion were carefully monitored. With prGO concentration as large as 0.05% (w/w), highly concentrated emulsion will form, and are stable up to 20 days from formation; destabilization occurred from sedimentation and subsequent coalescence as the partially reduced GO was limited by its dispersion ability in the oil-phase studied here. Understanding the mechanisms behind the transient stability will enable the development of novel emulsion compositions containing GO as a multifunctional additive. PMID- 28872874 TI - Ultralight Conductive Silver Nanowire Aerogels. AB - Low-density metal foams have many potential applications in electronics, energy storage, catalytic supports, fuel cells, sensors, and medical devices. Here, we report a new method for fabricating ultralight, conductive silver aerogel monoliths with predictable densities using silver nanowires. Silver nanowire building blocks were prepared by polyol synthesis and purified by selective precipitation. Silver aerogels were produced by freeze-casting nanowire aqueous suspensions followed by thermal sintering to weld the nanowire junctions. As prepared silver aerogels have unique anisotropic microporous structures, with density precisely controlled by the nanowire concentration, down to 4.8 mg/cm3 and an electrical conductivity up to 51 000 S/m. Mechanical studies show that silver nanowire aerogels exhibit "elastic stiffening" behavior with a Young's modulus up to 16 800 Pa. PMID- 28872875 TI - Influence of Solvent Relaxation on Ultrafast Excited-State Proton Transfer to Solvent. AB - A thorough understanding of the microscopic mechanism of excited-state proton transfer (ESPT) and the influence of the solvent environment on its dynamics are of great fundamental interest. We present here a detailed investigation of an ESPT to solvent (DMSO) using time-resolved broadband fluorescence and transient absorption spectroscopies. All excited-state species are resolved spectrally and kinetically using a global target analysis based on the two-step Eigen-Weller model. Reversibility of the initial short-range proton transfer producing excited contact ion pairs (CIP*) is observed unambiguously in fluorescence and must be explicitly considered to obtain the individual rate constants. Close inspection of the early dynamics suggests that the relative populations of the protonated form (ROH*) and CIP* are governed by solvent relaxation that influences the relative energies of the excited states. This constitutes a breakdown of the Eigen-Weller model, although the overall agreement between the data and the analysis using classical rate equations is excellent. PMID- 28872876 TI - Formation of Spherulitic J-Aggregates from the Coassembly of Lithocholic Acid and Cyanine Dye. AB - Supramolecular aggregates of organic dyes through noncovalent interactions have attracted great interest because they exhibit collective optical and excitonic properties. We report the formation of spherulitic J-aggregates from the coassembly of lithocholic acid (LCA) and 3,3'-diethylthiacarbocyanine iodide (DiSC2(3)) in ammonia solution. Each spherulite contains a core, which serves as a nucleus for the growth of radially oriented J-aggregate fibrils. We find that the growth of spherulitic J-aggregates exhibits a sigmoidal kinetic curve with an initial lag time, followed by a period of rapid growth and a finally slow approach to equilibrium. PMID- 28872877 TI - Time-Resolved Neutron Reflectivity during Supported Membrane Formation by Vesicle Fusion. AB - The formation of supported lipid bilayers (SLB) on hydrophilic substrates through the method of unilamelar vesicle fusion is used routinely in a wide range of biophysical studies. In an effort to control and better understand the fusion process on the substrate, many experimental studies employing different techniques have been devoted to the elucidation of the fusion mechanism. In the present work, we follow the kinetics of membrane formation using time-resolved (TR) neutron reflectivity, focusing on the structural changes near the solid/liquid interface. A clear indication of stacked bilayer structure is observed during the intermediate phase of SLB formation. Adsorbed lipid mass decrease is also measured in the final stage of the process. We have found that it is essential for the analysis of the experimental results to treat the shape of adsorbed lipid vesicles on an attractive substrate theoretically. The overall findings are discussed in relation to proposed fusion mechanisms from the literature, and we argue that our observations favor a model involving enhanced adhesion of incoming vesicles on the edges of already-formed bilayer patches. PMID- 28872878 TI - Ultrafast Charge-Transfer Dynamics in the Iron-Sulfur Complex of Rhodobacter capsulatus Ferredoxin VI. AB - Iron-sulfur proteins play essential roles in various biological processes. Their electronic structure and vibrational dynamics are key to their rich chemistry but nontrivial to unravel. Here, the first ultrafast transient absorption and impulsive coherent vibrational spectroscopic (ICVS) studies on 2Fe-2S clusters in Rhodobacter capsulatus ferreodoxin VI are characterized. Photoexcitation initiated populations on multiple excited electronic states that evolve into each other in a long-lived charge-transfer state. This suggests a potential light induced electron-transfer pathway as well as the possibility of using iron-sulfur proteins as photosensitizers for light-dependent enzymes. A tyrosine chain near the active site suggests potential hole-transfer pathways and affirms this electron-transfer pathway. The ICVS data revealed vibrational bands at 417 and 484 cm-1, with the latter attributed to an excited-state mode. The temperature dependence of the ICVS modes suggests that the temperature effect on protein structure or conformational heterogeneities needs to be considered during cryogenic temperature studies. PMID- 28872879 TI - Optically Controlled Electron-Transfer Reaction Kinetics and Solvation Dynamics: Effect of Franck-Condon States. AB - Experimental results for optically controlled electron-transfer reaction kinetics (ETRK) and nonequilibrium solvation dynamics (NESD) of Coumarin 480 in DMPC vesicle show their dependence on excitation wavelength lambdaex. However, the celebrated Marcus theory and linear-response-theory-based approaches for ETRK and NESD, respectively, predict both of the processes to be independent of lambdaex. The above said lacuna in these theories prompted us to develop a novel theory in 1D space, where the effect of innumerable Franck-Condon states is included through lambdaex. The present theory not only sheds light on the origin of failure of the existing theories but also gives the correct trend for the effect of lambdaex on ETRK and NESD. More importantly, the calculated results of NESD are in excellent agreement with the experimental results for different values of lambdaex. The new theory will therefore advance the knowledge of scientific community on the dynamics of photoinduced nonequilibrium processes. PMID- 28872880 TI - Identification of Potential Small Molecule Binding Pockets in p38alpha MAP Kinase. AB - Given the essential role played by protein kinases in regulating cellular pathways, their dysregulation can result in the onset and/or progression of various human diseases. Structural analysis of diverse protein kinases suggests that these proteins exhibit a remarkable plasticity that allows them to adopt distinct conformations in response to interactions with other proteins, providing an opportunity for designing allosteric modulators. The present work reports the results of an in silico screening study aimed at identifying novel prospective allosteric binding sites in the paradigmatic p38alpha MAP kinase. The process was carried out using a protein ensemble generated from a 6 MUs accelerated molecular dynamics simulation. The results of this calculation were first used to study the flexibility of the protein using Principal Component Analysis, followed by a Cluster Analysis aimed at producing an ensemble of conformations representative of the sampling process. Representative structures of the diverse clusters were subsequently screened for hot spots using FTMAP. The procedure permitted the identification of diverse allosteric sites of p38alpha already described in the literature including the DFG pocket, the lipid binding pocket, the DEF site, the docking groove, the CD and ED sites, and the backside site as well as a novel site recently reported: the A-loop regulatory site. Furthermore, the study also permitted the identification of ten novel prospective allosteric sites named NP1 to NP10, involving in most of the cases protein structural elements that control kinase activation including the activation loop, the catalytic loop, the alphaC helix, the L16 loop, and the glycine-rich loop. PMID- 28872881 TI - Protecting a Diamond Quantum Memory by Charge State Control. AB - In recent years, solid-state spin systems have emerged as promising candidates for quantum information processing. Prominent examples are the nitrogen-vacancy (NV) center in diamond, phosphorus dopants in silicon (Si:P), rare-earth ions in solids, and VSi-centers in silicon-carbide. The Si:P system has demonstrated that its nuclear spins can yield exceedingly long spin coherence times by eliminating the electron spin of the dopant. For NV centers, however, a proper charge state for storage of nuclear spin qubit coherence has not been identified yet. Here, we identify and characterize the positively charged NV center as an electron-spin less and optically inactive state by utilizing the nuclear spin qubit as a probe. We control the electronic charge and spin utilizing nanometer scale gate electrodes. We achieve a lengthening of the nuclear spin coherence times by a factor of 4. Surprisingly, the new charge state allows switching of the optical response of single nodes facilitating full individual addressability. PMID- 28872882 TI - Two-Dimensional Active Tuning of an Aluminum Plasmonic Array for Full-Spectrum Response. AB - Color pixels composed of plasmonic nanostructures provide a highly promising approach for new display technologies, capable of vivid, robust coloration and incorporating the use of low-cost plasmonic materials, such as aluminum. Here we report a plasmonic device that can be tuned continuously across the entire visible spectrum, based on integrating a square array of aluminum nanostructures into an elastomeric substrate. By stretching the substrate in either of its two dimensions, the period and therefore the scattering color can be modified to the blue or the red of the at-rest structure, spanning the entire visible spectrum. The unique two-dimensional design of this structure enables active mechanical color tuning, under gentle elastic modulation with no more than 35% strain. We also demonstrate active image switching with this structure. This design strategy has the potential to open the door for next-generation flexible photonic devices for a wide variety of visible-light applications. PMID- 28872883 TI - Plastic Poisson's Ratio of Nanoporous Metals: A Macroscopic Signature of Tension Compression Asymmetry at the Nanoscale. AB - The suggestion, based on atomistic simulation, of a surface-induced tension compression asymmetry of the strength and flow stress of small metal bodies so far lacks experimental confirmation. Here, we present the missing experimental evidence. We study the transverse plastic flow of nanoporous gold under uniaxial compression. Performing mechanical tests in electrolyte affords control over the surface state. Specifically, the surface tension, gamma, can be varied in situ during plastic flow. We find that decreasing gamma leads to an increase of the effective macroscopic plastic Poisson ratio, nuP. Finite element simulations of a network with surface tension confirm the notion that nuP of nanoporous gold provides a signature for a local tension-compression asymmetry of the nanoscale struts that form the network. We show that gamma promotes compression while impeding tensile elongation. Because the transverse strain is partly carried by the elongation of ligaments oriented normal to the load axis, the surface-induced tension-compression asymmetry acts to reduce nuP. Our experiment confirms a decisive contribution of the surface tension to small-scale plasticity. PMID- 28872885 TI - Visible-Light-Triggered Uncaging of Carbonyl Sulfide for Hydrogen Sulfide (H2S) Release. AB - Generation of hydrogen sulfide (H2S) is challenging and few methods are capable of localized delivery of this gas. Here, a boron dipyrromethene-based carbamothioate (BDP-H2S) that is uncaged by visible light of 470 nm to generate carbonyl sulfide (COS), which is rapidly hydrolyzed to H2S in the presence of carbonic anhydrase, a widely prevalent enzyme, is reported. PMID- 28872884 TI - Facile Synthesis of Catalytic AuPd Nanoparticles within Capillary Microreactors Using Polyelectrolyte Multilayers for the Direct Synthesis of H2O2. AB - Microreactors present innovative solutions for problems pertaining to conventional reactors and therefore have seen successful application in several industrial processes. Yet, its application in heterogeneously catalyzed gas liquid reactions has been challenging, mainly due to the lack of an easy and flexible methodology for catalyst incorporation inside these reactors. Herein, we report a facile technique for obtaining small (<2 nm) and well-distributed catalytic nanoparticles on the walls of silica-coated capillaries, that act as micro(channel) reactors. These particles are formed in situ on the reactor walls using polyelectrolyte multilayers (PEMs), built by layer-by-layer self-assembly. Manipulating the PEMs' synthesis condition gives easy control over metal loading, without compromising on particle size. Both monometallic (Au and Pd) and bimetallic (AuPd) nanoparticles were successfully obtained using this technique. Finally, these catalytic microreactors were found to exhibit exceptional activity for the direct synthesis of hydrogen peroxide from H2 and O2. PMID- 28872886 TI - Microwave-convective drying of food materials: A critical review. AB - Microwave convective drying (MCD) is gaining increasing interest due to its unique volumetric heating capability and ability to significantly reduce drying time and improve food quality. The main objective of this paper is to discuss, critically analyze and evaluate the recent advances in MCD and suggest the future directions in this field. The main focus of this paper is the mathematical modeling and experimental investigations in microwave convective drying of food materials. Recent developments in mathematical modeling of MCD is discussed and existing experimental setup and their advantages and disadvantages are discussed and analysed. Long drying time is a concern in food industries. Reductions in drying time by applying MCD compared to convection drying are calculated and discussed. It was apparent that the proper integration of mathematical modeling and experimental technique is the best way to maximize the advantages of this drying method. Although a plethora of research is being carried out on this topic, there is still need for research to develop fundamental modeling to optimize the process parameters and scale up this technology for the industrial application. Overall, the review provides an in-depth insight into the latest development of MCD and its mathematical modeling approaches and will hopefully serve to inspire future work in the field. PMID- 28872887 TI - Learning From Mistakes: An Experience of an Evolving Unit. PMID- 28872888 TI - Wait Times Less Than 2 Weeks Minimize No-Show Rates in Cardiology Practices. PMID- 28872889 TI - Association Between the Lower Extremity Deep Venous Thrombosis, the Warfarin Maintenance Dose, and CYP2C9*3, CYP2D6*10, and CYP3A5*3 Genetic Polymorphisms: A Case-Control Study. AB - OBJECTIVE: This study explored the association between the CYP2C9*3/CYP2D6*10/CYP3A5*3 genetic polymorphisms with lower extremity deep venous thrombosis (LEDVT) and the warfarin maintenance dose. METHODS: Five hundred thirty-six patients who were pathologically diagnosed with LEDVT after surgery were included in the LEDVT group. At the same time, 540 patients without LEDVT who underwent surgery were recruited as the control group. Patients were given warfarin at an initial dose of 2.5-3.0 mg. Blood samples were collected to detect the initial and stable international normalized ratio (INR) values. The warfarin maintenance dose was obtained if the INR remained within a range of 2.0 3.0 for 3 consecutive days. The genotype distribution and haplotype analysis of the CYP2C9*3/CYP2D6*10/CYP3A5*3 alleles were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) testing and SHEsis software, respectively. Logistic regression analysis was used to analyze the risk and protective factors for LEDVT. RESULTS: The A/G genotypes, G/G genotypes, and G allele of CYP3A5*3 in the LEDVT group were observed with increased frequency compared with the control group. The LEDVT group displayed a higher ACG haplotype frequency, and lower ACA and ATA haplotype frequencies than the control group. Age, diabetes, low-density lipoprotein, CYP3A5*3 and the ACG haplotype were independent risk factors for LEDVT. High-density lipoprotein and the ACA haplotype were independent protective factors for LEDVT. The genotype distributions of the CYP2C9*3, CYP2D6*10, and CYP3A5*3 genetic polymorphisms were associated with the warfarin maintenance dose. CONCLUSION: The CYP3A5*3 genetic polymorphism may be an important risk factor for LEDVT. Moreover, CYP2C9*3, CYP2D6*10, and CYP3A5*3 are associated with the warfarin maintenance dose. PMID- 28872890 TI - Synergistic Association of Genetic Variants with Environmental Risk Factors in Susceptibility to Essential Hypertension. AB - AIMS: Essential hypertension (EH) is a disease in which both environment and genes have an important role. This study was designed to identify the interaction model between genetic variants and environmental risk factors that most highly potentiates EH development. METHODS: We performed a case-control study with 1641 participants (mean age 50.6 +/- 8.1 years), specifically 848 patients with EH and 793 controls, adjusted for gender and age. Traditional risk factors, biochemical and genetic parameters, including the genotypic discrimination of 14 genetic variants previously associated with EH, were investigated. Multifactorial dimensionality reduction (MDR) software was used to analyze gene-environment interactions. Validation was performed using logistic regression analysis with environmental risk factors, significant genetic variants, and the best MDR model. RESULTS: The best model indicates that the interactions among the ADD1 rs4961 640T allele, diabetes, and obesity (body mass index >=30) increase approximately four-fold the risk of EH (odds ratio = 3.725; 95% confidence interval: 2.945 4.711; p < 0.0001). CONCLUSION: This work showed that the interaction between the ADD1 rs4961 variant, obesity, and the presence of diabetes increased the susceptibility to EH four-fold. In these circumstances, lifestyle adjustment and diabetes control should be intensified in patients who carry the ADD1 variant. PMID- 28872891 TI - Closing the Deal: A Cross-Cultural Comparison of Treatment Resistance. AB - This study investigates patient resistance to doctors' treatment recommendations in a cross-national comparison of primary care. Through this lens, we explore English and American patients' enacted priorities, expectations, and assumptions about treating routine illnesses with prescription versus over-the-counter medications. We perform a detailed analysis of 304 (American) and 393 (English) naturally occurring treatment discussions and conclude that American and English patients tend to use treatment resistance in different prescribing contexts to pursue different ends. While American patients are most likely to resist recommendations for non-prescription treatment and display an expectation for prescription treatment in these interactions, English patients show a high level of resistance to recommendations for all types of treatment and display an expectation of cautious prescribing. These behavioral trends reflect broader structural forces unique to each national context and ultimately maintain distinct cultural norms of good-practice prescribing. PMID- 28872892 TI - Prepregnancy Body Mass Index Shift Across Gestation: An Association with Breastfeeding Practices? AB - BACKGROUND: Research has shown that mother's obesity and underweight are major risk factors for reduced initiation, duration, and exclusivity of breastfeeding. OBJECTIVE: We compared breastfeeding practices from discharge until the third postnatal month in women, accounting to prepregnancy body mass index (BMI) and its shift across gestation. STUDY DESIGN: Data on maternal shifts in BMI category from prepregnancy to gestational BMI by gestational weight gain (GWG) were defined according to 2009 Institute of Medicine (IOM) guidelines. Logistic regression models were estimated to assess the effect of prepregnancy and gestational BMI on breastfeeding, adjusting for clinically relevant factors. RESULTS: The analysis included 658 women. According to prepregnancy BMI, 84 (12.8%) mothers were underweight, 444 (67.4%) were normal weight, 94 (14.3%) were overweight, and 36 (5.5%) were obese. Although in the range defined by IOM 2009, GWG shifted across the BMI categories in 445 (67.6%). Thus, while underweight women shifted in higher BMI categories, normal weight women category halved (230, 35%), and both overweight women (301, 45.7%) and obese women (127, 19.3%) tripled. Breastfeeding patterns at discharge, at first month, and at third month were comparable among prepregnancy and gestational BMI groups, except for prepregnancy BMI groups at third month (p 0.03). At multivariable analysis, neither prepregnancy BMI nor gestational BMI was associated with reduced exclusive breastfeeding within 3 months after discharge. CONCLUSIONS: Prepregnancy BMI and gestational BMI, in women with adequate GWG, do not affect exclusive breastfeeding initiation, duration, and exclusivity until the third month postpartum. Women need information and support to gain adequate weight during pregnancy. PMID- 28872893 TI - Pharmacotherapy Assessment of Patients With Isolation Precautions at a University Hospital. PMID- 28872894 TI - Knockdown of Long Noncoding RNA Small Nucleolar RNA Host Gene 12 Inhibits Cell Growth and Induces Apoptosis by Upregulating miR-138 in Nonsmall Cell Lung Cancer. AB - Small nucleolar RNA host gene 12 (SNHG12) is a novel long noncoding RNA identified to be upregulated and functions as an oncogene in several cancers. However, the function of SNHG12 and its target genes in modulating nonsmall cell lung cancer (NSCLC) development are rarely reported. In the present study, we validated that SNHG12 was overexpressed, while miR-138 was low-expressed, in NSCLC cells compared with normal human lung epithelial cells. SNHG12 harbored the binding site of miR-138 and inversely regulated the expression miR-138. Knockdown of SNHG12 inhibited proliferation and colony-forming ability, induced apoptosis, and increased caspase-3 activity of NSCLC cells, whereas miR-138 downregulation restored these effects. Furthermore, SNHG12 knockdown decreased volumes and weight of xenograft tumors in a NSCLC mouse model. Taken together, these findings suggested that knockdown of SNHG12 suppressed cell growth and induced apoptosis by upregulating miR-138 in NSCLC. PMID- 28872896 TI - Factors Affecting Caregivers' Views on Reporting Adverse Events. PMID- 28872895 TI - Hyaluronic Acid Accelerates Tendon-to-Bone Healing After Rotator Cuff Repair. AB - BACKGROUND: There is growing evidence that the subacromial injection of hyaluronic acid (HA) is effective for pain relief in rotator cuff tears; however, its effect on tendon-to-bone healing remains unknown. PURPOSE: To examine the effect of HA on the chondrogenesis of mesenchymal stem cells (MSCs) in vitro and on tendon-to-bone healing in a rotator cuff repair model. STUDY DESIGN: Controlled laboratory study. METHODS: Bilateral complete tears of the infraspinatus tendon were made in rabbits and subsequently repaired. Before closure, 1 mL HA was applied to the repaired site, and phosphate-buffered saline was used in the opposite side as a control. Biomechanical, histological, and immunohistochemical analyses were performed at 4, 8, and 12 weeks after surgery. After euthanizing each animal, the bone marrow was isolated from the femoral bone in the same rabbits. Then, MSCs were cultured in media for chondrogenic differentiation, and the chondral pellet production and cartilage-related gene expression levels in the cells were examined at various concentrations of HA. RESULTS: At 4 and 8 weeks after surgery, ultimate load-to-failure was significantly greater in the HA group than in the control group (45.61 +/- 9.0 N vs 32.42 +/- 9.4 N at 4 weeks, 90.7 +/- 16.0 N vs 66.97 +/- 10.0 N at 8 weeks; both P < .05) but not at 12 weeks after surgery (109.6 +/- 40.2 N vs 108.1 +/- 42.6 N, P > .05). Linear stiffness was not significant throughout the time point evaluation. The chondroid formation area at the tendon-bone interface stained by safranin O (control vs HA group) was 0.33% +/- 0.7% versus 13.5% +/- 12.3% at 4 weeks after surgery ( P < .05) and 3.0% +/- 5.9% versus 12.9% +/- 12.9% at 8 weeks after surgery ( P < .05), but there was no significant difference at 12 weeks after surgery. Maturity of collagen at the repaired site stained by PicroSirius Red (control vs HA group) was 16.2 +/- 10.6 versus 43.5 +/- 21.3 at 4 weeks after surgery ( P < .05), but there were no significant differences at 8 and 12 weeks after surgery. MSCs were cultured in media for chondrogenic differentiation, and the chondral pellet production and cartilage-related gene expression levels in the cells were examined at various concentrations of HA. The number of CD44-positive cells (control vs HA group) was 8.3% +/- 1.4% versus 26.2% +/- 5.2% at 3 days after surgery ( P < .05), 1.8% +/- 1.1% versus 26.6% +/- 11.6% at 4 weeks after surgery ( P < .05), 0.6% +/- 0.9% versus 0.5% +/- 0.6% at 8 weeks after surgery ( P > .05), and 1.8% +/- 4.0% versus 5.4% +/- 4.2% at 12 weeks after surgery ( P > .05). Compared with the control group, HA significantly increased the volume of cartilaginous pellet produced by MSCs (0.0016 +/- 0.0015 mm3 at 0 mg/mL of HA, 0.0041 +/- 0.0023 mm3 at 1.0 mg/mL, and 0.0041 +/- 0.0018 mm3 at 4.0 mg/mL), with increased mRNA expression (relative ratio to control) of type 2 collagen (1.34 +/- 0.38), SOX9 (1.58 +/- 0.31), and aggrecan (1.30 +/- 0.22) genes in the pellet ( P < .01). CONCLUSION: HA accelerated tendon-to-bone healing in the rotator cuff repair model, enhancing the biomechanical strength and increasing chondroid formation and tendon maturity at the tendon-bone interface. Based on the data of in vitro experiments, HA-activated MSCs may play a crucial role in the acceleration of tendon-to-bone healing. CLINICAL RELEVANCE: The data suggest the relevance of clinical application of HA to accelerate tendon to-bone healing. It may decrease the number of retears after surgery. PMID- 28872897 TI - A Novel Strategy to Seek Biosignatures at Enceladus and Europa. AB - A laboratory experiment is suggested in which conditions similar to those in the plume ejecta from Enceladus and, perhaps, Europa are established. With the use of infrared spectroscopy and polarimetry, the experiment might identify possible biomarkers in differential measurements of water from the open ocean, hydrothermal vents, and abiotic water samples. Should the experiment succeed, large telescopes could be used to acquire sensitive infrared spectra of the plumes of Enceladus and Europa, as the satellites transit the bright planetary disks. The extreme technical challenges encountered in so doing are similar to those of solar imaging spectropolarimetry. The desired signals are buried in noisy data in the presence of seeing-induced image motion and a changing natural source. Some differential measurements used for solar spectropolarimetry can achieve signal-to-noise ratios of 105 even in the presence of systematic errors 2 orders of magnitude larger. We review the techniques and likelihood of success of such an observing campaign with some of the world's largest ground-based telescopes, as well as the long-anticipated James Webb Space Telescope. We discuss the relative merits of the new 4 m Daniel K. Inouye Solar Telescope, as well as the James Webb Space Telescope and larger ground-based observatories, for observing the satellites of giant planets. As seen from near Earth, transits of Europa occur regularly, but transits of Enceladus will begin again only in 2022. Key Words: Spectroscopy-Spectropolarimetry-Life origins. Astrobiology 17, 852 861. PMID- 28872898 TI - Effects of a Telephone- and Web-based Coping Skills Training Program Compared with an Education Program for Survivors of Critical Illness and Their Family Members. A Randomized Clinical Trial. AB - RATIONALE: Many survivors of critical illness and their family members experience significant psychological distress after patient discharge. OBJECTIVES: To compare the effects of a coping skills training (CST) program with an education program on patient and family psychological distress. METHODS: In this five center clinical trial, adult patients who received mechanical ventilation for more than 48 hours and one family member of each patient were randomized to six weekly CST telephone sessions plus access to a study website or a critical illness education program. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the patient Hospital Anxiety and Depression Scale (HADS) score at 3 months. Secondary outcomes included 3- and 6-month HADS subscales and the Impact of Events Scale-Revised. Among the 175 patients randomized to CST (n = 86) or education (n = 89), there was no significant difference between CST and education in either 3-month HADS scores (difference, 1.3; 95% confidence interval [CI], 0.9 to 3.4; P = 0.24) or secondary patient and family outcomes. In prespecified analyses, among patients with high baseline distress (n = 60), CST recipients had greater improvement in 6-month HADS score (difference, -4.6; 95% CI, -8.6 to 0.6; P = 0.02) than the education group. Among patients ventilated longer than 7 days (n = 47), education recipients had greater improvement in 3-month HADS score (difference, -4.0; 95% CI, -8.1 to -0.05; P = 0.047) than the CST group. CONCLUSIONS: CST did not improve psychological distress symptoms compared with an education program. However, CST improved symptoms of distress at 6 months among patients with high baseline distress, whereas the education program improved distress at 3 months among those ventilated for more than 7 days. Future efforts to address psychological distress among critical illness survivors should target high-risk populations. Clinical trial registered with www.clinicaltrials.gov (NCT01983254). PMID- 28872899 TI - Two Novel Variants Affecting CDKL5 Transcript Associated with Epileptic Encephalopathy. AB - BACKGROUND: Variants in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been reported as being etiologically associated with early infantile epileptic encephalopathy type 2 (EIEE2). We report on two patients, a boy and a girl, with EIEE2 that present with early onset epilepsy, hypotonia, severe intellectual disability, and poor eye contact. METHODS: Massively parallel sequencing (MPS) of a custom-designed gene panel for epilepsy and epileptic encephalopathy containing 112 epilepsy-related genes was performed. Sanger sequencing was used to confirm the novel variants. For confirmation of the functional consequence of an intronic CDKL5 variant in patient 2, an RNA study was done. RESULTS: DNA sequencing revealed de novo variants in CDKL5, a c.2578C>T (p. Gln860*) present in a hemizygous state in a 3-year-old boy, and a potential splice site variant c.463+5G>A in heterozygous state in a 5-year-old girl. Multiple in silico splicing algorithms predicted a highly reduced splice site score for c.463+5G>A. A subsequent mRNA study confirmed an aberrant shorter transcript lacking exon 7. CONCLUSIONS: Our data confirmed that variants in the CDKL5 are associated with EIEE2. There is credible evidence that the novel identified variants are pathogenic and, therefore, are likely the cause of the disease in the presented patients. In one of the patients a stop codon variant is predicted to produce a truncated protein, and in the other patient an intronic variant results in aberrant splicing. PMID- 28872900 TI - Enceladus Plume Structure and Time Variability: Comparison of Cassini Observations. AB - During three low-altitude (99, 66, 66 km) flybys through the Enceladus plume in 2010 and 2011, Cassini's ion neutral mass spectrometer (INMS) made its first high spatial resolution measurements of the plume's gas density and distribution, detecting in situ the individual gas jets within the broad plume. Since those flybys, more detailed Imaging Science Subsystem (ISS) imaging observations of the plume's icy component have been reported, which constrain the locations and orientations of the numerous gas/grain jets. In the present study, we used these ISS imaging results, together with ultraviolet imaging spectrograph stellar and solar occultation measurements and modeling of the three-dimensional structure of the vapor cloud, to constrain the magnitudes, velocities, and time variability of the plume gas sources from the INMS data. Our results confirm a mixture of both low and high Mach gas emission from Enceladus' surface tiger stripes, with gas accelerated as fast as Mach 10 before escaping the surface. The vapor source fluxes and jet intensities/densities vary dramatically and stochastically, up to a factor 10, both spatially along the tiger stripes and over time between flyby observations. This complex spatial variability and dynamics may result from time variable tidal stress fields interacting with subsurface fissure geometry and tortuosity beyond detectability, including changing gas pathways to the surface, and fluid flow and boiling in response evolving lithostatic stress conditions. The total plume gas source has 30% uncertainty depending on the contributions assumed for adiabatic and nonadiabatic gas expansion/acceleration to the high Mach emission. The overall vapor plume source rate exhibits stochastic time variability up to a factor ~5 between observations, reflecting that found in the individual gas sources/jets. Key Words: Cassini at Saturn-Geysers-Enceladus-Gas dynamics-Icy satellites. Astrobiology 17, 926-940. PMID- 28872901 TI - Nylon Mesh Device for Vitrification of Large Quantities of Rat Pancreatic Islets. AB - The practical requirements of islet transplantation necessitate that a large quantity of pancreatic islets be cryopreserved for a long period of time in a simple and convenient manner. We cryopreserved rat islets (size range 101-150 MUm in mean diameter) by vitrification with either a Cryotop(r) device or a o = 57 MUm nylon mesh device in units of 10 islets, or by conventional freezing with a Bicell(r) vessel in units of 50 islets. Postwarm/thaw survival rates of the islets were 68.1% +/- 5.9%, 64.1% +/- 3.5%, and 47.7 +/- 1.2% following Cryotop vitrification, nylon mesh vitrification, and Bicell freezing, respectively (p < 0.05). Glucose-stimulated insulin secretion in the two vitrification groups (stimulus index [SI] = 3.1-3.9) was superior to that in the freezing group (SI = 0.8). Additional experiments involved scaling-up the cryopreservation process using the nylon mesh device in units of 10, 50, or 100 islets. Increased numbers of islets per device had no adverse effects on cryosurvival (58.6%-68.5%) or insulin secretion potential (SI = 2.8-4.2). As the nylon mesh device does not require the handling of individual islets with glass pipettes, pre- and postvitrification islet treatment is less complicated. Therefore, nylon mesh can serve as a simple cryodevice for the vitrification of large quantities of rat pancreatic islets. PMID- 28872902 TI - Maturational Trajectory of Processing Speed Performance in Pediatric Multiple Sclerosis. AB - Processing speed is a frequently affected cognitive domain in pediatric multiple sclerosis (MS) and is commonly assessed using the Symbol Digit Modalities Test (SDMT). The objective of this study was to determine maturational trajectories in SDMT performance and baseline factors affecting trajectories in a sample of 82 pediatric MS individuals. Performance on the SDMT increased with age in patients with pediatric MS followed by a subsequent decline. Furthermore, patients who were older at disease onset and had a higher IQ showed greater gains with age, suggesting that these factors may be protective with respect to cognitive maturation in pediatric MS. PMID- 28872903 TI - In vitro Biological Effects of Sulforaphane (SFN), Epigallocatechin-3-gallate (EGCG), and Curcumin on Breast Cancer Cells: A Systematic Review of the Literature. AB - Much of the recent research in neoplasia has been focusing on the epigenetics of cancer cells, particularly as regards the search for potential molecular biomarkers that could be used for early diagnosis, effective treatment, and prognosis of several types of cancer. Carcinogenesis often starts with mutations in oncogenes and tumor suppressor genes, and it leads to anomalies in cellular processes as vital as cell cycle regulation and apoptosis. Because malignant changes arise as a result of genetic as well as epigenetic mechanisms, one possible means of intervention involves reprogramming gene expression, so as to at least in part-revert the molecular alterations. DNA methylation and demethylation, acetylation and deacetylation of histones, and microRNAs are a few examples of the epigenetic mechanisms responsible for tumor development and progression. Many biologically active compounds present in food-including sulforaphane, curcumin, and epigallocatechin-have been found to modulate those processes. We here systematically review information on the effects of such bioactive dietary compounds on human breast cancer cell lines, and explore the mechanisms underlying those effects with a view to their potential therapeutic application. PMID- 28872904 TI - Carvacrol Induces Reactive Oxygen Species (ROS)-mediated Apoptosis Along with Cell Cycle Arrest at G0/G1 in Human Prostate Cancer Cells. AB - Carvacrol, a major monoterpenoid phenol from Origanum and Thymus species, has been shown to exhibit antiproliferative and anticancer properties in a few recent studies. Nevertheless, detailed mechanism of the action of this compound in prostate cancer has not been elucidated yet. Therefore, in the current study, we examined the anticancer activity and mechanism of the action of carvacrol against human prostate cancer cells. It was found that the treatment of DU145 cells with carvacrol decreased cell viability in a concentration and time-dependent manner. The antiproliferative action of carvacrol leads to induction of apoptosis as confirmed by nuclear condensation, Annexin V-FITC/PI positive cells, and caspase 3 activation. In addition, carvacrol augmented reactive oxygen species generation and disruption in the mitochondrial membrane potential which has not been reported in the previous studies of carvacrol with prostate cancer. Moreover, carvacrol-induced apoptosis of prostate cancer cells was also accompanied by significant amount of growth arrest at the G0/G1 phase of the cell cycle which has also not been documented previously. To sum up, this study has established that carvacrol could be a promising chemotherapeutic agent and could have a direct practical implication and translational relevance to prostate cancer patients as Origanum consumption may retard prostate cancer progression. PMID- 28872907 TI - Edaravone and its clinical development for amyotrophic lateral sclerosis. AB - The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS. PMID- 28872905 TI - Web-based Health Information Seeking and eHealth Literacy among Patients Living with Chronic Obstructive Pulmonary Disease (COPD). AB - Many people living with Chronic Obstructive Pulmonary Disease (COPD) have low general health literacy; however, there is little information available on these patients' eHealth literacy, or their ability to seek, find, understand, and appraise online health information and apply this knowledge to address or solve disease-related health concerns. A nationally representative sample of patients registered in the COPD Foundation's National Research Registry (N = 1,270) was invited to complete a web-based survey to assess socio-demographic (age, gender, marital status, education), health status (generic and lung-specific health related quality of life), and socio-cognitive (social support, self-efficacy, COPD knowledge) predictors of eHealth literacy, measured using the 8-item eHealth literacy scale (eHEALS). Over 50% of the respondents (n = 176) were female (n = 89), with a mean age of 66.19 (SD = 9.47). Overall, participants reported moderate levels of eHealth literacy, with more than 70% feeling confident in their ability to find helpful health resources on the Internet. However, respondents were much less confident in their ability to distinguish between high and low-quality sources of web-based health information. Very severe versus less severe COPD (beta = 4.15), lower lung-specific health-related quality of life (beta = -0.19), and greater COPD knowledge (beta = 0.62) were significantly associated with higher eHealth literacy. Higher COPD knowledge was also significantly associated with greater knowledge (rho = 0.24, p = .001) and use (rho = 0.24, p = .001) of web-based health resources. Findings emphasize the importance of integrating skill-building activities into comprehensive patient education programs that enable patients with severe cases of COPD to identify high-quality sources of web-based health information. Additional research is needed to understand how new social technologies can be used to help medically underserved COPD patients benefit from web-based self-management support resources. PMID- 28872908 TI - Pharmacokinetic profile of edaravone: a comparison between Japanese and Caucasian populations. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) affects persons of all races, and there continues to be a need for effective therapies to treat the disease. OBJECTIVE: To compare the pharmacokinetics (PK) of edaravone between Japanese and Caucasian populations. METHODS: Data from five PK studies among Japanese and Caucasian healthy volunteers were pooled and evaluated. In population PK (PPK) modelling, compartment models and other models with linear elimination were evaluated for appropriateness. Covariate effects by race, sex, weight, and age were investigated to explain variability in PK parameters. Simulations of the final PPK model were performed using a virtual population based on ALS clinical trials. RESULTS: The analysis included 86 subjects. A three-compartment model with Michaelis-Menten plus linear elimination was selected as the best fit model. Race was statistically detected as a covariate for the second peripheral volume of distribution (V2), indicating a 26% increase for Caucasian subjects compared to Japanese subjects. However, based on simulation of PPK model for a virtual ALS population, the small difference of V2 was associated with a difference of Ctau around 1 ng/mL after infusion, which was minimal compared to Cmax of approximately 1000 ng/ml. CONCLUSION: The PPK analyses demonstrated no clinically relevant difference in the PK profiles of edaravone by race, sex, weight, or age. PMID- 28872909 TI - Introduction to supplement: the current status of treatment for ALS. AB - ALS is a lethal neurodegenerative disease wherein the diagnosis is often delayed. Our understanding of the pathobiology is slowly expanding, and the number of new genes is rapidly increasing. The development of potential treatments targeting specific mechanisms is beginning to offer hope. Evidence-based treatments and the development of quality measures have raised the standard of care. The current status of treatment for ALS includes one drug riluzole that slows progression modestly, and another drug edaravone that was recently approved by FDA to slow ALS progression. Multidisciplinary clinics and symptomatic treatments ease the burden of ALS and prolong life. An overview of these treatments is provided here. PMID- 28872910 TI - Full Issue PDF, Volume 18, Issue S1. PMID- 28872911 TI - What can we learn from the edaravone development program for ALS? AB - Edaravone's development into an ALS therapeutic has been a process which began with preclinical studies regarding its potential in targeting ALS. Despite edaravone's inability to show benefit in a general ALS population, an important post-hoc analysis showed that a clinical subset of patients had benefit. Most importantly, a subsequent study examining the capacity of edaravone to have benefit in this specific subset of ALS patients was successful in meeting its primary outcome measures. Questions regarding whether the dosing regimen could be simplified or improved, the duration of the effects, and the timing of the potential treatment to different stages of disease remain to be answered. However, the benefit of this compound in delivering a meaningful therapy to ALS patients and the lessons learned with regard to its development should widen interest in clinical research so that additional strategies for treating ALS may become available to patients. PMID- 28872912 TI - An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe. AB - BACKGROUND: There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between different countries and regions. OBJECTIVE: To assess similarities and differences in clinical practice and treatment guidelines for ALS, and also to compare the demographics and rate of progression of disease in patients with ALS enrolled in clinical trials in Japan, the US, and Europe. METHODS: We performed a review of clinical studies published since 2000 to compare the demographics and characteristics of patients with ALS. Progression of ALS disease was assessed in patients receiving placebo. The changes per month in ALSFRS-R score were calculated and compared between the studies. RESULTS: Overall, diagnostic criteria, recognition of ALS symptoms, comorbidities, use of riluzole, and nutritional, and respiratory support were similar. Regarding demographics and characteristics, there were no clear differences in the incidence of sporadic ALS (range 91-98%), bulbar onset (range 11-41%), and median time from onset to diagnosis (range 9-14 months) among the populations despite the difference in race between regions. However, use of tracheostomy-based invasive respiratory support was higher in Japan (29-38%) than in the US (4%) and Europe (1-31%). Rate of progression of disease was similar between the US and Europe study populations (range -0.89 to -1.60 points/month), and the Japanese study populations (range -1.03 to -1.21 points/month). CONCLUSION: There is evidence to support the generalisability of data from the Japanese ALS trial experience to the US and Europe populations in early to mid stage of ALS. PMID- 28872913 TI - Post-hoc analysis of randomised, placebo-controlled, double-blind study (MCI186 19) of edaravone (MCI-186) in amyotrophic lateral sclerosis. AB - Post-hoc analyses of the ALS Functional Rating Scale-Revised (ALSFRS-R) score data, the primary endpoint in the 24-week double-blind placebo-controlled study of edaravone (MCI186-19, NCT01492686), were performed to confirm statistical robustness of the result. The previously reported original analysis had used a last observation carried forward (LOCF) method and also excluded patients with fewer than three completed treatment cycles. The post-hoc sensitivity analyses used different statistical methods as follows: 1) including all patients regardless of treatment cycles received (ALL LOCF); 2) a mixed model for repeated measurements (MMRM) analysis; and 3) the Combined Assessment of Function and Survival (CAFS) endpoint. Findings were consistent with the original primary analysis in showing superiority of edaravone over placebo. We also investigated the distribution of change in ALSFRS-R total score across all patients in the study as well as which ALSFRS-R items and domains may have contributed to the overall efficacy findings. The distribution of changes in ALSFRS-R total score from baseline to the end of cycle 6 (ALL LOCF) shifted in favour of edaravone compared to placebo. Edaravone was descriptively favoured for each ALSFRS-R item and each of the four ALSFRS-R domains at the end of cycle 6 (ALL LOCF), suggesting a generalised effect of edaravone in slowing functional decline across all anatomical regions. The effect of edaravone appeared to be similar in patients with bulbar onset and limb onset. Together, these observations would be consistent with its putative neuroprotective effects against the development of oxidative damage unspecific to anatomical regions. PMID- 28872914 TI - Post-hoc analysis of MCI186-17, the extension study to MCI186-16, the confirmatory double-blind, parallel-group, placebo-controlled study of edaravone in amyotrophic lateral sclerosis. AB - In the 24-week double-blind study of edaravone in ALS (MCI186-16), edaravone did not show a statistically significant difference versus placebo for the primary efficacy endpoint. For post-hoc analyses, two subpopulations were identified in which edaravone might be expected to show efficacy: the efficacy-expected subpopulation (EESP), defined by scores of >=2 points on all 12 items of the ALS Functional Rating Scale-Revised (ALSFRS-R) and a percent predicted forced vital capacity (%FVC) >=80% at baseline; and the definite/probable EESP 2 years (dpEESP2y) subpopulation which, in addition to EESP criteria, had definite or probable ALS diagnosed by El Escorial revised criteria, and disease duration of <=2 years. In the 36-week extension study of MCI186-16, a 24-week double-blind comparison followed by 12 weeks of open-label edaravone (MCI186-17; NCT00424463), analyses of ALSFRS-R scores of the edaravone-edaravone group and edaravone placebo group for the full analysis set (FAS) and EESP, as prospectively defined, were reported in a previous article. Here we additionally report results in patients who met dpEESP2y criteria at the baseline of MCI186-16. In the dpEESP2y, the difference in ALSFRS-R changes from 24 to 48 weeks between the edaravone edaravone and edaravone-placebo groups was 2.79 (p = 0.0719), which was greater than the differences previously reported for the EESP and the FAS. The pattern of adverse events in the dpEESP2y did not show any additional safety findings to those from the earlier prospective study. In conclusion, this post-hoc analysis suggests a potential effect of edaravone between 24 and 48 weeks in patients meeting dpEESP2y criteria at baseline. PMID- 28872915 TI - Exploratory double-blind, parallel-group, placebo-controlled study of edaravone (MCI-186) in amyotrophic lateral sclerosis (Japan ALS severity classification: Grade 3, requiring assistance for eating, excretion or ambulation). AB - Our objective was to explore the efficacy and safety of edaravone in amyotrophic lateral sclerosis (ALS) patients with a Japan ALS severity classification of Grade 3. In a 24-week, double-blind, randomized study, 25 patients who met all of the following criteria were enrolled: Japan ALS severity classification Grade 3; definite, probable, or probable-laboratory supported ALS (El Escorial/revised Airlie House); forced vital capacity (%FVC) >=60%; duration of disease <=3 years at consent; and change in the revised ALS functional rating scale (ALSFRS-R) score of -1 to -4 points during the 12-week pre-observation period. Patients received edaravone (n = 13) or placebo (n = 12) for six cycles. The efficacy outcome was change in the ALSFRS-R score. The least-squares mean change in the ALSFRS-R score +/- standard error during the 24-week treatment was -6.52 +/- 1.78 in the edaravone group and -6.00 +/- 1.83 in the placebo group; the difference of -0.52 +/- 2.46 was not statistically significant (p = 0.835). Incidence of adverse events was 92.3% (12/13) in the edaravone group and 100.0% (12/12) in the placebo group. There was no intergroup difference in the changes in the ALSFRS-R score. The incidences of adverse events were similar in the two groups. PMID- 28872916 TI - Post-hoc analysis of open-label extension period of study MCI186-19 in amyotrophic lateral sclerosis. AB - Study MCI186-19 investigated the safety and efficacy of edaravone in the treatment of ALS. The 24-week, double-blind period was followed by a 24-week, open-label, active extension period. Patients originally receiving edaravone continued edaravone (E-E group, n = 65), and patients originally receiving placebo switched to edaravone (P-E group, n = 58). Because no statistical tests had been prospectively planned in the open-label period, we performed post-hoc analyses to assist in the interpretation of efficacy data. A mixed model for repeated measures (MMRM) and the Combined Assessment of Function and Survival (CAFS) were assessed. Additionally, slopes of time-dependent change between baseline in cycle 1 and the end of cycle 6 (24 weeks double-blind) and between the end of cycle 6 and end of cycle 12 (24 weeks open-label) were calculated using a random coefficient model including all available data during each period. At week 48, the MMRM analysis showed significantly less decline in ALS Functional Rating Scale-Revised (ALSFRS-R) total score in the E-E group than in the P-E group (least-squares mean change from baseline +/- standard error, 4.17 +/- 1.40, p = 0.0037), meaning that the differences in the ALSFRS-R total score during the 24-week double-blind period were maintained in patients receiving edaravone for an additional 24 weeks. The CAFS endpoint (p = 0.0089) supported this finding. The slope analysis during the double-blind period showed a significant difference between the treatment groups, while there was no significant difference between the groups during the active extension period. These analyses suggest a potential benefit of early and continued edaravone treatment over delayed edaravone treatment. PMID- 28872917 TI - A post-hoc subgroup analysis of outcomes in the first phase III clinical study of edaravone (MCI-186) in amyotrophic lateral sclerosis. AB - Our first phase III study failed to demonstrate efficacy of edaravone for amyotrophic lateral sclerosis (ALS) compared to placebo. Here, we performed post hoc subgroup analysis to identify a subgroup in which edaravone might be expected to show efficacy. We focussed on two newly defined subgroups, EESP and dpEESP2y. The EESP was defined as the efficacy-expected subpopulation with % forced vital capacity of >=80%, and >=2 points for all item scores in the revised ALS functional rating scale (ALSFRS-R) score before treatment. The dpEESP2y was defined as the greater-efficacy-expected subpopulation within EESP having a diagnosis of 'definite' or 'probable' ALS according to the El Escorial revised Airlie House diagnostic criteria and onset of disease within two years. The primary endpoint of the post-hoc analysis was the change in the ALSFRS-R score during the 24-week treatment period. The intergroup differences of the least squares mean change in the ALSFRS-R score +/- standard error during treatment were 0.65 +/- 0.78 (p = 0.4108) in the full analysis set, 2.20 +/- 1.03 (p = 0.0360) in the EESP, and 3.01 +/- 1.33 (p = 0.0270) in the dpEESP2y. Edaravone exhibited efficacy in the dpEESP2y subgroup. A further clinical study in patients meeting dpEESP2y criteria is warranted. PMID- 28872918 TI - Exploratory double-blind, parallel-group, placebo-controlled extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis. AB - Following the first phase III study of edaravone for amyotrophic lateral sclerosis (ALS), this extension study was performed to evaluate longer-term efficacy and safety. Patients given edaravone in the first 24-week phase III study (Cycles 1-6) were randomised to edaravone (E-E) or placebo (E-P) in the subsequent 24-week double-blind period (Cycles 7-12). Patients given placebo in phase III were switched to edaravone (P-E). Subsequently, all patients received edaravone for 12 weeks (Cycles 13-15). Efficacy endpoints included revised ALS Functional Rating Scale (ALSFRS-R) score. Analysis populations were the full analysis set (FAS) and the efficacy-expected subpopulation (EESP) defined by post hoc analysis of the first phase III study. The least-squares mean and standard error of the intergroup difference (E-E vs. E-P) of change in the ALSFRS-R score from Cycles 7-12 was 1.16 +/- 0.93 (p = 0.2176) in the FAS, and 1.85 +/- 1.14 (p = 0.1127) in the EESP. The ALSFRS-R score changed almost linearly in the E-E group throughout Cycles 1-15 (60 weeks). The incidence of serious adverse events associated with ALS progression was higher in E-E than in E-P. Edaravone might have potential efficacy for up to 15 cycles when used to treat patients in the EESP with careful safety monitoring. PMID- 28872920 TI - Open-label 24-week extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis. AB - We aimed to explore the longer-term efficacy and safety of edaravone in an active treatment extension period following the double-blind period of the second phase III study. Patients who met all the following criteria (scores >=2 points on all 12 items of the revised amyotrophic lateral sclerosis functional rating scale [ALSFRS-R], forced vital capacity >=80%, definite or probable ALS, and disease duration <=2 years) were randomised to 60 mg intravenous edaravone or placebo for six cycles in the double-blind period, and then offered the opportunity to proceed to this 24-week open-label extension period. One hundred and twenty-three of 137 patients continued to the extension period: 65 edaravone-edaravone (E-E group) and 58 placebo-edaravone (P-E group). Change (mean +/- standard deviation; SD) in the ALSFRS-R score from baseline in the double-blind period was -4.1 +/- 3.4 and -6.9 +/- 5.1 in the E-E group and P-E group, respectively, while it was 8.0 +/- 5.6 in the E-E group and -10.9 +/- 6.9 in the P-E group over the whole 48 week period. The ALSFRS-R score changed almost linearly throughout Cycles 1-12 in the E-E group. The most commonly reported adverse events were constipation, dysphagia, and contusion. There was no sudden deterioration in the ALSFRS-R score of the E-E group. No safety concerns related to edaravone were detected. PMID- 28872919 TI - A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies. AB - BACKGROUND: There continues to be a need for new therapies to treat ALS. OBJECTIVE: Provide an overview of safety for edaravone in ALS patients during the first six cycles of treatment. METHODS: Analysis was based on three randomised, placebo-controlled clinical trials. Endpoints included treatment-emergent adverse events (TEAEs), including AEs leading to discontinuation, serious adverse events (SAEs), and deaths. RESULTS: The analysis included a total of 368 patients (184 in the edaravone group and placebo group, respectively). Of those, 94.6% of the edaravone group and 90.2% of placebo group completed six cycles of therapy. Baseline characteristics were comparable between the two groups. TEAE incidence in the edaravone group and placebo group was 87.5% and 87.0%, respectively. TEAEs ocurring at >=2% incidence in the edaravone group compared to placebo were contusion (14.7% vs. 8.7%), gait disturbance (12.5% vs. 9.2%), headache (8.2% vs. 5.4%), eczema (6.5% vs. 2.2%), dermatitis contact (6.0% vs. 3.3%), respiratory disorder (4.3% vs. 1.1%), and glucose urine present (3.8% vs. 1.6%). There was no imbalance in TEAEs leading to discontinuation (2.2% [edaravone], and 5.4% [placebo]). SAE incidence was 17.4% in the edaravone group and 22.3% in placebo group. Treatment-emergent deaths occurred in 2.2% in the edaravone group and 1.1% in placebo group, all respiratory in nature and attributed to worsening ALS. CONCLUSION: Data collected from three double-blind assessments found that while some TEAEs were more common in the edaravone group compared to placebo, the overall incidences of SAEs, deaths, and discontinuations due to AEs were similar or less for edaravone compared to placebo. PMID- 28872921 TI - Circulating Long Noncoding RNAs as Potential Biomarkers of Sepsis: A Preliminary Study. AB - OBJECTIVE: Long noncoding RNAs (lncRNAs) are becoming promising biomarker candidates in various diseases as assessed via sequencing technologies. Sepsis is a life-threatening disease without ideal biomarkers. The aim of this study was to investigate the expression profile of lncRNAs in the peripheral blood of sepsis patients and to find potential biomarkers of sepsis. METHODS: A lncRNA expression profile was performed using peripheral blood from three sepsis patients and three healthy volunteers using microarray screening. The differentially expressed lncRNAs were validated by real-time quantitative polymerase chain reaction (qRT PCR) in a further set of 22 sepsis patients and 22 healthy volunteers. RESULTS: Among 1316 differentially expressed lncRNAs, 771 were downregulated and 545 were upregulated. Results of the qRT-PCR were consistent with the microarray data. lncRNA ENST00000452391.1, uc001vji.1, and uc021zxw.1 were significantly differentially expressed between sepsis patients and healthy volunteers. Moreover, lncRNA ENST00000504301.1 and ENST00000452391.1 were significantly differentially expressed between sepsis survivors and nonsurvivors. CONCLUSION: The lncRNA expression profile in the peripheral blood of sepsis patients significantly differed from that of healthy volunteers. Circulating lncRNAs may be good candidates for sepsis biomarkers. PMID- 28872922 TI - miR-1297 Promotes Cell Proliferation of Non-Small Cell Lung Cancer Cells: Involving in PTEN/Akt/Skp2 Signaling Pathway. AB - Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a lipid and protein phosphatase and possesses an antitumor effect in lung cancers. miRNAs are reportedly abnormally expressed in human lung cancers. However, whether miRNA contributes to PTEN expression in non-small cell lung cancers (NSCLCs) has not been clearly clarified. In the present study, we found that miR-1297 probably binds with 3'UTR sequence of PTEN and negatively regulated the levels of PTEN in NSCLC cells. First, the expression levels of PTEN and Skp2 were detected by western blotting in NSCLC specimens and paired normal tissue specimens. The results showed that decreased levels of PTEN were detected in NSCLC tissues, compared with paired control tissues (**p < 0.01). The expression levels of PTEN were conversely correlated with the levels of Skp2 in clinical NSCLC specimens and NSCLC cell line. Transfection with miR-1297 mimic significantly promoted cell viability of A549 cells and NCI-H460 cells by downregulating the level of PTEN and upregulating the expression of Skp2. Interestingly, knockdown of Skp2 did not affect the expression of PTEN in A549 cells. Thus, miR-1297 might work as an oncogene by regulating PTEN/Akt/Skp2 signaling pathway in NSCLC cells. PTEN and Skp2 might be the potential targets in the clinical therapy of lung cancers. PMID- 28872923 TI - Implementing and evaluating an interprofessional minority health conference for social work and healthcare professionals. AB - Interprofessional education (IPE) is one strategy for addressing health inequities; however, little attention has been paid to continuing IPE for practicing social work and healthcare professionals. This article offers guidance to faculty in social work and health-related academic units on offering continuing IPE on the topic of minority health. An interprofessional group of faculty offered a day-long conference on minority health, ethics, and social justice. The conference goal was to promote interprofessional communication in a co-learning environment and promote dialogue on social determinants of health and health equity in the state. Data were obtained from surveys and analysis of work plans developed during the conference. Workshop participants were majority White (62%), social workers (79%), and practiced for 14 years on average. The most useful topics were dementia and polypharmacy. Takeaway strategies included interprofessional work, being mindful of access to resources, and engagement in continuing education. Lessons learned include plan in advance for all professions; recruit faculty and students from multiple departments to increase interprofessional diversity; offer strategies and incentives to increase student participation; be strategic about conference location and format; and identify a strategic format and theme. IPE is a means of preparing learners for working together in their future careers to provide high-quality patient-centred care and reduce health disparities. Professional development can provide an opportunity to enhance skills to address health disparities, and learning can be significantly enhanced when participants connect with colleagues from different professions, discuss diverse opinions, and share successful practices. PMID- 28872924 TI - Editorial. PMID- 28872926 TI - Thalidomide: Rebirth of a Gestational Antiemetic? PMID- 28872925 TI - Starting Dose of Sorafenib for the Treatment of Hepatocellular Carcinoma: A Retrospective, Multi-Institutional Study. AB - Purpose Sorafenib is currently the only Food and Drug Administration-approved first-line therapy for patients with advanced hepatocellular carcinoma. There are few data examining how sorafenib starting dose may influence patient outcomes and costs. Patients and Methods We retrospectively evaluated 4,903 patients from 128 Veterans Health Administration hospitals who were prescribed sorafenib for hepatocellular carcinoma between January 2006 and April 2015. After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HRs) were calculated using Cox regression and were tested against a noninferiority margin of HR = 1.1. A matched multivariate logistic regression was performed to adjust for potential confounders. The primary end point was overall survival (OS) of patients who were prescribed standard starting dosage sorafenib (800 mg/d per os) versus that of patients who were prescribed reduced starting dose sorafenib (< 800 mg/d per os). Results There were 3,094 standard dose sorafenib patients (63%) and 1,809 reduced starting dose sorafenib patients (37%). Reduced starting dose sorafenib patients had more Barcelona Clinic Liver Cancer stage D ( P < .001), higher Model for End-Stage Liver Disease Sodium scores ( P < .001), higher Child-Turcotte-Pugh scores ( P < .001), and higher Cirrhosis Comorbidity Index scores ( P = .01). Consequently, reduced starting dose sorafenib patients had lower OS (median, 200 v 233 days, HR = 1.10). After propensity score matching and adjusting for potential confounders, there was no longer a significant OS difference (adjusted hazard ratio [HRadj], 0.92; 95% CI, 0.83 to 1.01), and this fell significantly below the noninferiority margin ( P < .001). Reduced starting dose sorafenib patients experienced significantly lower total cumulative sorafenib cost and were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% v 10.8%; P = .047). Conclusion The initiation of sorafenib therapy at reduced dosages was associated with reduced pill burden, reduced treatment costs, and a trend toward a decreased rate of discontinuing sorafenib because of adverse events. Reduced dosing was not associated with inferior OS relative to standard dosing. PMID- 28872927 TI - An Investigation of Cardiovascular Risks in a Group of Children and Adolescents Who Use Atypical Antipsychotics. AB - This study was conducted to identify the metabolic parameters and body measurements associated with cardiovascular risks in a group of children and adolescents who as part of inpatient treatment received atypical antipsychotics at a psychiatric hospital in Turkey. Body mass indexes (BMIs), waist circumferences (WCs), diastolic blood pressures (DBPs), systolic blood pressures (SBPs) and heart rates (HRs) of the patients were evaluated during hospitalization and at discharge. A statistically significant difference was found among the mean BMIs, WCs, DBPs and HRs of the patients at the stages of their hospitalization and discharge (p < 0.05). On the basis of the study findings, it is recommended that mental health nurses evaluate these risk factors in children and adolescents and provide education on this subject to the patients and their families. PMID- 28872929 TI - Spatial Distribution of Naturally Occurring 210Po and 226Ra in Children's Teeth. AB - Deciduous and permanent teeth extracted from juveniles for orthodontic purposes have been analysed using alpha-sensitive plastic track detectors for the spatial distribution of total alpha-activity and naturally occurring 210Pb-supported 210Po and 226Ra. The distribution of these radionuclides is nonuniform, with 210Po being primarily associated with outer enamel and 226Ra with the pulp. The observations suggest that 210Pb/210Po concentrates at the interface of enamel with saliva or blood, by means of unidirectional ionic exchange with calcium. In contrast, 226Ra concentrates in the predentine band at the interface with pulp and with systemic blood circulation, where its uptake is permitted by the incomplete calcification in this band. Activity concentration was measured in 900 teeth. Total concentration on the outer enamel surface of deciduous teeth, permanent teeth from children ?10 years and permanent teeth from children > 10 years give respective mean values of 8.63+/-0.26, 5.76+/-0.48 and 7.00+/-0.15 Bq kg-1. 226Ra concentration on the corresponding longitudinal sections comprising pulp, dentine and annular enamel give respective mean values of 0.715+/-0.055, 0.418+/-0.083 and 0.514+/-0.029 Bq kg-1. Mean activity concentration in 32 foetal teeth was 2.05+/-0.31 Bq kg-1. The results form the basis of more detailed studies of (1) age-dependent uptake of alpha-radionuclides in teeth and their microdistribution, and (2) the geographical variation in activity concentration with respect to environmental factors such as domestic radon exposure. PMID- 28872928 TI - Sex/Gender Differences in Cotinine Levels Among Daily Smokers in the Pennsylvania Adult Smoking Study. AB - BACKGROUND: This study was conducted to determine sex/gender differences in smoke exposure and to quantify the role of potential predictors including puffing behaviors, nicotine dependence, and non-nicotinic factors. METHODS: The Pennsylvania Adult Smoking Study (PASS) of 332 adult cigarette smokers utilized portable handheld topography devices to capture the smokers' profiles in a naturalistic environment. Sex/gender differences in salivary biomarkers were modeled using ANCOVA to account for measures of dependence (Fagerstrom Test for Nicotine Dependence, nicotine metabolite ratio [3-hydroxycotinine/cotinine]), and nondependence covariates including anthropomorphic factors and stress. The Blinder-Oaxaca method was used to decompose the sex/gender differences in nicotine uptake due to covariates. RESULTS: Men had significantly higher cotinine levels (313.5 ng/mL vs. 255.8 ng/mL, p < 0.01), cotinine +3-hydroxycotinine levels, (0.0787 mol/L vs. 0.0675 mol/L, p = 0.01), puff volumes (52.95 mL vs. 44.77 mL, p < 0.01), and a lower nicotine metabolite ratio (0.396 vs. 0.475, p = 0.01) than women. The mean Fagerstrom Test for Nicotine Dependence score did not differ between men and women (p = 0.24). Women had a higher mean Hooked on Tobacco Checklist score than men (7.64 vs. 6.87, p < 0.01). In multivariate analysis, nicotine metabolite levels were not significantly different by sex. Decomposition results show that ten predictors can explain 83% of the sex/gender differences in cotinine uptake. Height was the greatest contributor to these differences, followed by average puff volume. Conclusion and Impact: The higher levels of nicotine metabolites in men, compared to women, can be explained by height, weight, puff volume, and nicotine metabolism. PMID- 28872930 TI - Inconsistence between number and function of autoreactive T cells in the course of experimental autoimmune encephalomyelitis. AB - BACKGROUND: Mouse experimental autoimmune encephalomyelitis (EAE) is widely used model of multiple sclerosis (MS). The role of autoreactive CD4+ and CD8+ T cells in the development of mouse EAE has been demonstrated. However, little information is available about the relation between the frequency and reactivity of myelin antigen-reactive CD4+ and CD8+ T cells in secondary lymphoid organs and their relevance with the inflammation and pathological lesion of CNS during the course of EAE mouse model. METHODS: In this study, an EAE model with a clinical course containing acute onset, peak and chronic remission stages was established in C57BL/6J mice by myelin oligodendrocyte protein (MOG)35-55 peptide immunization, and followed by the monitoring of clinical and pathological parameters and autoreactive T cells at different stages during the course. RESULTS: The dynamic changes of inflammatory infiltration, myelin loss, and astrocyte proliferation in brain and spinal cord were highly consistent with clinical severity observed in EAE course. However, the frequencies of both MOG specific CD4+ and CD8+ T cells in secondary lymphoid organs presented different dynamic trends from the IFN-gamma production by MOG-reactive T cells. Meanwhile, the IL-17 production by MOG-reactive CD4+ T cells was consistent with the proliferation of MOG-specific CD4+ T cells. CONCLUSIONS: Both CD4+ and CD8+ T cells were most sensitive to MOG antigen stimulation for IFN-gamma production during the early stage of EAE, but then rapidly lost the function despite their vigorous proliferation at the peak stage and later. PMID- 28872931 TI - Factors Perceived by Rehabilitation Professionals to Influence the Provision of Assistive Technology to Children: A Systematic Review. AB - BACKGROUND: The use of Assistive Technology (AT) by children with disabilities has been associated with significant development and improvement in outcomes within all spheres of life. However, AT is often underutilized. Appropriate selection of AT by rehabilitation professionals could improve the satisfaction of the user and their family with their AT. DATA SOURCES: A systematic search identified six studies that investigate the factors that occupational therapists, physiotherapists, as well as speech and language pathologists perceive to influence their provision of AT to children. Study appraisal: Two qualitative and four quantitative articles were identified. Both article types were appraised using the Mixed Methods Appraisal tool (Pluye et al., 2011 ). Synthesis method: A process of deductive thematic analysis by using themes from the Assistive Technology Device Selection Framework (Scherer et al., 2007 ), was followed by inductive thematic analysis to uncover subthemes. Data from all six articles are synthesized to provide a view of factors that are perceived to influence AT selection. Implications of findings: Within a family-centered perspective, both family and child expectations and preferences should be considered. Professionals should consider the influence of their own preferences and knowledge on the AT they recommend. PMID- 28872932 TI - Native tissue repair versus mesh repair in pelvic organ prolapse surgery. AB - In pelvic organ prolapse, the anatomical defects develop at the anterior (anterior vaginal wall), the posterior (posterior vaginal wall) and the apical (the uterus/cervix or the apex of the vagina, vaginal vault or cuff scar after hysterectomy) compartments. These defects occur in more than one compartment. Treatment of pelvic organ prolapse is commonly surgical, aiming to restore the anatomy of structures supporting the pelvic organs. The surgical repair techniques are classified as 'native tissue repair (NTR)' when only pelvic organ support tissues are used and 'augmented repair (AR)' when some other material (prosthesis or graft) is used to reinforce the defective support system. In this review, issues related to the basic science of meshes, and NTR versus mesh or graft AR procedures for pelvic organ prolapse are discussed while considering the varying risks and benefits according to the prolapsed compartment. PMID- 28872934 TI - Normobaric hyperoxygenation: a potential neuroprotective therapy for acute ischemic stroke? PMID- 28872933 TI - Improving the asthma disparity gap with legal advocacy? A qualitative study of patient-identified challenges to improve social and environmental factors that contribute to poorly controlled asthma. AB - OBJECTIVE: To identify challenges that disadvantaged adults with asthma face in mitigating social and environmental factors associated with poor symptom control. METHODS: Using a community-engaged approach, we partnered with a community health center in New Haven, CT to conduct in-person interviews and a written survey of asthmatic adults with poor symptom control. Using the constant comparative method, we analyzed participant interviews to establish emerging themes and identify common barriers to improved outcomes. Through a written survey utilizing clinically validated questions, we assessed information on access to medical care, asthma control, and selected social and environmental risk factors. RESULTS: Twenty-one patients (mean age 47, 62% female, 71% Black, 95% insured by Medicaid) participated. The average Asthma Control Test (ACT) score was 11.6. Seventy-six percent of participants were currently employed and of those, 75% reported work-related symptoms. Among participants currently in housing, 59% reported exposure to domiciliary mice and 47% to mold. We identified three themes that summarize the challenges the study participants face: 1) Lack of knowledge about home and workplace asthma triggers; 2) Lack of awareness of legal rights or resources available to mitigate adverse conditions in the home or work environment; and 3) Fear of retaliation from landlords or employers, including threats of eviction, sexual assault, and job loss. CONCLUSION: Patients with poorly controlled asthma in a disadvantaged urban northeast community identified common barriers in both the domestic and work environments that impeded attainment of symptom control. These challenges may be best addressed through legal advocacy for those most at risk. PMID- 28872935 TI - Asthma severity and heterogeneity: Insights from prevalence trends and associated demographic variables and anthropometric indices among Israeli adolescents. AB - OBJECTIVES: While asthma presents various clinical forms with different levels of severity, it is unclear whether asthma severities are a consequence of disease management or varied etiologies. We sought to investigate this question. METHODS: This paper presents a cross-sectional study of 113,671 Israeli adolescents. Prevalence rates of mild and moderate-to-severe asthma over a 24-year period were calculated and multivariate regression models (outcomes: different asthma severity, reference: subjects without asthma) were performed to analyze associations with anthropometric indices and socio-demographic variables, in males and females separately. RESULTS: The prevalence of mild asthma increased until birth years 1976-1980 and then steadily decreased. In contrast, the prevalence of moderate-to-severe asthma was relatively stable until birth years 1976-1980, then rose steeply until 1986-1990 and subsequently plateaued in the early 1990s. Obesity was positively associated with both mild and moderate-to severe asthma in males (Odds Ratio (OR) [95%CIs]: 1.61 [1.37-1.89] and 1.63 [1.34 1.98], respectively) and females (1.54 [1.10-2.16] and 1.54 [1.20-1.98], respectively). Family size greater than three siblings was negatively associated with both mild and moderate-to-severe asthma in males (0.62 [0.56-0.68] and 0.59 [0.52-0.68]) and females (0.71 [0.60-0.83] and 0.73 [0.63-0.83]). In contrast, in males, underweight was only associated with mild asthma (1.54 [1.22-1.94]) but not with moderate-to-severe asthma. In females, overweight was only associated with moderate-to-severe asthma (1.21 [1.00-1.46]) and rural residence was only associated with mild asthma (1.26 [1.09-1.47]). CONCLUSIONS: The differences between mild and moderate-to-severe asthma enhance asthma phenotype characterization, with respect to secular trends and associated variables, and indicate varied etiologies. PMID- 28872936 TI - Quantitative and Qualitative Evaluations of the Enhanced Logo-autobiography Program for Korean-American Women. AB - This study extends Bernstein et al.'s (2016) investigation of the effects of the Enhanced Logo-autobiography Program on Korean-American women's depressive symptoms, coping strategies, purpose in life, and posttraumatic growth by analyzing quantitative and qualitative data. This study's participants significantly improved on quantitative measures of depression, coping strategies, purpose in life, and post-traumatic growth at eight weeks post-intervention and follow-up. The qualitative content analysis revealed 17 themes with five essential themes. The program's activity to promote purpose in life through posttraumatic growth facilitated participants' recovery from traumatic experiences. Standardized guidelines are needed to conduct this program in Korean community centers. PMID- 28872938 TI - Laps or lengths? The effects of different exercise programs on asthma control in children. AB - INTRODUCTION: Exercise training has been shown in numerous studies to improve lung function and asthma control in children with asthma. Swimming has been shown to be of benefit in children with asthma, but which form of exercise is better for asthmatics has not been determined to date. The aim of this study was to examine if swimming improved lung function and asthma symptoms in asthmatic children when compared with different forms of exercise and a control group. METHODS: Subjects with asthma were randomly assigned to either one of three different exercise training groups (swimming, football, and basketball) or a control group. Spirometry was performed before and after and the subjects were asked to keep asthma diaries and perform daily peak flow measurements. RESULTS: 41 children and adolescents between the ages of 9 and 16 participated in the study. After completing the training, children across all three exercise programs had significantly higher forced vital capacity (FVC) percentage values when compared to the control group. The swimming group demonstrated a significant increase in the percentage peak expiratory flow (PEF) following the exercise program when compared with the control group (78.3 +/- 9.3 versus 89.0 +/- 14.9, p = 0.04). All children on exercise training programs reported an improvement in their asthma symptoms via asthma diaries. CONCLUSION: This study suggests that a swimming training program is more beneficial in terms of peak flow measurements when compared with other exercise training programs. PMID- 28872937 TI - Treatment of rhinophyma with the VersajetTM Hydrosurgery System and autologous cell suspension (ReCELL(r)): A case report. AB - This is a case report of a 63-year-old male patient who presented with rhinophyma of 17 years duration. Several medical treatments were applied previously, with no response or poor improvement. We present our experience by combining the VersajetTM Hydrosurgery System and ReCELL(r) in a heavy smoker patient, which led to a good aesthetic outcome. With the combined technique, we did not encounter any difficulties either within the operation or in the follow-up period. We obtained less complications and faster wound healing, which in return led to higher patient satisfaction. PMID- 28872939 TI - Psychometric Evaluation of the Young Children's Participation and Environment Measure (YC-PEM) for use in Singapore. AB - AIMS: To estimate the psychometric properties of a culturally adapted version of the Young Children's Participation and Environment Measure (YC-PEM) for use among Singaporean families. METHODS: This is a prospective cohort study. Caregivers of 151 Singaporean children with (n = 83) and without (n = 68) developmental disabilities, between 0 and 7 years, completed the YC-PEM (Singapore) questionnaire with 3 participation scales (frequency, involvement, and change desired) and 1 environment scale for three settings: home, childcare/preschool, and community. Setting-specific estimates of internal consistency, test-retest reliability, and construct validity were obtained. RESULTS: Internal consistency estimates varied from .59 to .92 for the participation scales and .73 to .79 for the environment scale. Test-retest reliability estimates from the YC-PEM conducted on two occasions, 2-3 weeks apart, varied from .39 to .89 for the participation scales and from .65 to .80 for the environment scale. Moderate to large differences were found in participation and perceived environmental support between children with and without a disability. CONCLUSIONS: YC-PEM (Singapore) scales have adequate psychometric properties except for low internal consistency for the childcare/preschool participation frequency scale and low test-retest reliability for home participation frequency scale. The YC-PEM (Singapore) may be used for population-level studies involving young children with and without developmental disabilities. PMID- 28872941 TI - A Haplotype Common to Intermediate Radiosensitivity Variants of Ataxia telangiectasia in the UK. AB - In a study of ataxia-telangiectasia (A-T) in the UK, patients in 10 out of 60 families were shown to have a much lower level of chromosomal radiosensitivity compared with the majority of patients. In some patients the level of radiosensitivity was hardly distinguishable from normal. Patients in this group, however, could be distinguished clinically from the majority either by the later onset of severe cerebellar features or the slower rate of progress of the disorder. By using highly polymorphic microsatellite repeat markers a chromosome 11q22-23 haplotype common to the majority of these patients, and not occurring in any non-A-T chromosome in 60 families, was identified on one chromosome. The haplotype probably defines the region of the A-T gene in these families and the mutation associated with this haplotype may be much less severe than the second mutation thereby producing the slightly milder phenotype. PMID- 28872942 TI - Radiation Checkpoints in Model Systems. AB - The response to DNA damaging agents includes a delay to progression through the cell cycle. Irradiation of premitotic cells causes a delay to mitosis and irradiation of G1 and S phase cells causes a delay to DNA synthesis. These delays have become known as checkpoints. The mechanisms that mediate the mitotic (or G2) checkpoint delay have recently come under study in yeast model systems. Work in the eukaryotic organisms S. cerevisiae and S. pombe has identified at least seven proteins controlling the interactions between DNA damage and cell cycle progression. Genetic analysis of this checkpoint pathway has identified substantial overlap with the feedback controls that co-ordinate progression through the cell cycle. Molecular analysis has revealed structural conservation between these highly diverged yeasts, which suggests that similar proteins may act in related pathways in mammalian cells. In addition, the rad24 and rad25 genes of S. pombe (which are involved in the radiation checkpoint) encode functionally overlapping essential proteins that are highly conserved in mammalian cells. Studies of checkpoints in the yeasts may therefore help to define the signal pathways that control cell cycle delay in mammalian cells following irradiation, some of which have been proposed to be deficient in A-T cells. PMID- 28872940 TI - Itm2a silencing rescues lamin A mediated inhibition of 3T3-L1 adipocyte differentiation. AB - Dysregulation of adipose tissue metabolism is associated with multiple metabolic disorders. One such disease, known as Dunnigan-type familial partial lipodystrophy (FPLD2) is characterized by defective fat metabolism and storage. FPLD2 is caused by a specific subset of mutations in the LMNA gene. The mechanisms by which LMNA mutations lead to the adipose specific FPLD2 phenotype have yet to be determined in detail. We used RNA-Seq analysis to assess the effects of wild-type (WT) and mutant (R482W) lamin A on the expression profile of differentiating 3T3-L1 mouse preadipocytes and identified Itm2a as a gene that was upregulated at 36 h post differentiation induction in these cells. In this study we identify Itm2a as a novel modulator of adipogenesis and show that endogenous Itm2a expression is transiently downregulated during induction of 3T3 L1 differentiation. Itm2a overexpression was seen to moderately inhibit differentiation of 3T3-L1 preadipocytes while shRNA mediated knockdown of Itm2a significantly enhanced 3T3-L1 differentiation. Investigation of PPARgamma levels indicate that this enhanced adipogenesis is mediated through the stabilization of the PPARgamma protein at specific time points during differentiation. Finally, we demonstrate that Itm2a knockdown is sufficient to rescue the inhibitory effects of lamin A WT and R482W mutant overexpression on 3T3-L1 differentiation. This suggests that targeting of Itm2a or its related pathways, including autophagy, may have potential as a therapy for FPLD2. PMID- 28872943 TI - Genetic Haplotyping of Ataxia-telangiectasia Families Localizes the Major Gene to an ~ 850 kb Region on Chromosome 11q23.1. AB - The genotyping data given localize the major A-T gene to an ~ 850 kb region. They also localize the group A A-T gene (ATA) to a region that contains the ~ 850 kb region. They are compatible with linking A-TFresno to 11q22-23. NBS-V2 does not link to this region. Four non-linking families contain only single affecteds, suggesting that these may be spontaneous mutations rather than evidence for an A T gene outside the 11q22-23 region. Finally, two other non-linking families contain recombinant haplotypes that are compatible with a second A-T gene at 11q22-23, slightly distal to the ~ 850 kb region. However, convincing evidence for a second gene is still lacking. PMID- 28872945 TI - Participants. PMID- 28872944 TI - Defect in Radiation Signal Transduction in Ataxia-telangiectasia. AB - Exposure of mammalian cells to ionizing radiation causes a delay in progression through the cycle at several checkpoints. Cells from patients with ataxia telangiectasia (A-T) ignore these checkpoint controls postirradiation. The tumour suppressor gene product p53 plays a key role at the G1/S checkpoint preventing the progression of cells into S phase. The induction of p53 by radiation is reduced and/or delayed in A-T cells, which appears to account for the failure of delay at the G1/S checkpoint. We have investigated further this defect in radiation signal transduction in A-T. While the p53 response was defective after radiation, agents that interfered with cell cycle progression such as mimosine, aphidicolin and deprivation of serum led to a normal p53 response in A-T cells. None of these agents caused breaks in DNA, as determined by pulse-field gel electrophoresis, in order to elicit the response. Since this pathway is mediated by protein kinases, we investigated the activity of several of these enzymes in control and A-T cells. Ca+2-dependent and -independent protein kinase C activities were increased by radiation to the same extent in the two cell types, a variety of serine/threonine protein kinase activities were approximately the same and anti-tyrosine antibodies failed to reveal any differences in protein phosphorylation between A-T and control cells. It is not evident what is the nature of the defect in signal transduction in A-T cells. However, it is clear that the p53 response is normal in these cells after exposure to some agents and it is mediated through protein kinase C or another serine/threonine kinase. PMID- 28872946 TI - V(D)J Recombination and Ataxia-telangiectasia: A Review. AB - I review one aspect of the A-T phenotype, the remarkable and fascinating increase of lymphocytes carrying chromosomal aberrations caused by V(D)J site-specific recombination. The review is organized to first present the facts of V(D)J recombination and the findings in this regard in A-T patients. Other populations that demonstrate similar increases in such chromosomal aberrations are then presented and a hypothesis is offered as to the basis and relevance of these increases vis-a-vis A-T. The contribution of V(D)J recombination to the clonal proliferations and frank lymphoid malignancies seen in A-T patients is briefly discussed. I conclude with some speculative comments extending the observations presented into a more global consideration of a possible function of an A-T gene. PMID- 28872947 TI - Clinical and Genetic Features of Ataxia-telangiectasia. AB - There are several variants of ataxia-telangiectasia (A-T): classical A-T with marked radiation sensitivity; classical A-T with intermediate levels of radiation sensitivity; mild A-T with intermediate levels of radiation sensitivity; A-T without telangiectasia; A-T without oculomotor apraxia; and A-T with microcephaly. These disorders are probably caused by different allelic mutations, because affected sibs resemble the index patients, and because there is an association of certain haplotypes of 11q22-23 with specific phenotypes. The Nijmegen Breakage Syndrome, with its lack of ataxia, seems on clinical grounds to be a different disorder. Although A-T is almost always inherited as an autosomal recessive, there are some unusual features; an unexpectedly low parental consanguinity rate, an incidence in sibs that is < 0.25, and occurrence of disease in many different races and in the offspring of mixed race unions. Moreover, looking at haplotypes from 63 UK patients, there is a remarkably low incidence of homozygosity. An autosomal recessive condition that is deficient in parental consanguinity, and in homozygosity for the region around the gene, can be explained by J. H. Edwards' hyopothesis that homozygosity for alleles at a neighbouring locus are lethal early in embryogenesis. Other possible mechanisms to explain the unusual genetic features are discussed. PMID- 28872948 TI - Enhanced Chromosomal Response of Ataxia-telangiectasia Cells to Specific Types of DNA Double-strand Breaks. AB - The chromosomal response of two ataxia-telangiectasia (A-T) lymphoblastoid cell lines (A-T-PA and A-T-KM) to restriction endonucleases (RE) is compared with that of a normal (N-SW) lymphoblastoid cell line. The RE used were PvuII (generating DNA double-strand breaks with blunt termini), BamHI (cohesive termini with 4 base, 5' overhangs) and PstI (cohesive termini with 4 base 3' overhangs). Chromatid aberrations were analysed in cells 5 h after treatment. Cells were porated using streptolysin O to allow entry of RE. Both A-T lines showed an enhanced frequency of chromatid breaks in G2 phase compared with normal cells in response to RE. The enhanced response of A-T cells was most marked in the case of PvuII treatment when the enhancement ratios were 2.5 and 4.2 for A-T-PA and A-T KM respectively. However, the frequency of DNA double-strand breaks (dsb), measured by neutral filter elution, were considerably lower in A-T-PA cells than N-SW, due to a lower efficiency of poration. When A-T-PA cells were treated with streptolysin O at a higher concentration (0.3 Units/ml), a condition that apparently led to a similar level of poration in A-T-PA as in N-SW cells treated with 0.06 Units/ml as judged by the similar number of dsb induced in the two lines for a given PvuII concentration, the enhancement ratio for A-T-PA cells treated with PvuII increased from 2.5 to 5.8. BamHI and PstI were found to be less clastogenic in all three cell lines as found previously for Chinese hamster cells, although part of this effect may be due to a lower activity, particularly in the case of PstI. However, even at a 4-6-fold higher concentration, BamHI was still less clastogenic than PvuII. It is concluded that dsb with blunt termini are more clastogenic than those with cohesive termini. The results suggest that the chromosomal sensitivity of A-T cells may result from a defect causing a higher rate of conversion of dsb into chromatid aberrations. PMID- 28872949 TI - Expression of the Candidate A-T Gene ATDC Is Not Detectable in a Human Cell Line with a Normal Response to Ionizing Radiation. AB - Nucleotide sequence analysis of a candidate gene for A-T group D (ATDC) demonstrated that it is related to a group of proteins that contain both zinc finger and leucine zipper motifs. The presence of a leucine zipper suggested that this protein might form homodimers, and this was confirmed by means of the two hybrid system in yeast. The activity of some proteins that form homodimers can be effectively eliminated by overexpression of inactive forms of the protein that bind to the wild-type protein to create a dominant negative phenotype. An ATDC cDNA containing a 37 amino acid deletion in the zinc finger region (ATDCDelta) was therefore transfected into colorectal carcinoma human tumour cells (RKO) to determine whether its expression would produce a response to radiation similar to that seen in A-T cells. RKO cells have been shown to have normal radiosensitivity and cell cycle regulation and, therefore, seemed ideal for this study. Despite the fact that the A-T gene has been found to be important in the radiation damage response, no ATDC mRNA transcripts were detectable in the RKO cell line. In addition, the RKO subclones expressing the ATDCDelta mRNA showed no change in radiosensitivity or cell cycle regulation. These results do not support the conclusion that ATDC is an A-T gene, and suggest that the ATDC protein acts indirectly to suppress radiosensitivity in A-T cells. PMID- 28872950 TI - After-thoughts and Conclusions on the Nature of the A-T Gene. PMID- 28872952 TI - Radiation-induced G2 Delay and Spontaneous Chromosome Aberrations in Ataxia telangiectasia Homozygotes and Heterozygotes. AB - The extent of cell cycle delay of lymphocytes X-irradiated in G2 phase was measured by mitotic inhibition determinations in 66 controls, 14 ataxia telangiectasia (A-T) homozygotes and 27 obligate heterozygotes. Homozygotes had a significantly reduced mitotic index (MI) in unirradiated samples and showed significantly less radiation-induced mitotic inhibition than controls. This confirms our earlier disputed observations on A-T fibroblasts and demonstrates a G2 checkpoint defect in addition to the well-known defects in S phase and at the G1-S phase transition. There are two separate and opposite abnormal G2 responses of A-T cells; a primary event in which cells in G2 at the time of irradiation suffer less delay than controls, and a secondary event in which cells irradiated at earlier stages of the cycle are more delayed when they pass into G2. The MI of unirradiated heterozygote cells and the extent of mitotic inhibition were indistinguishable from controls. Spontaneous unstable chromosome aberrations were, as previously reported, significantly higher in homozygotes than in controls. This was true for breaks, but not for gaps. There was a suggestion of an increase in breaks in heterozygotes, but a much larger study would be required to confirm or refute this. PMID- 28872953 TI - Expression of a Candidate Ataxia-telangiectasia Group D Gene in Cultured Fibroblast Cell Lines and Human Tissues. AB - A candidate gene for ataxia-telangiectasia group D (ATDC) has been cloned (Kapp et al. 1992), sequenced and found to be a member of a recently reported gene family (Leonhardt et al. 1994). Transcriptional behaviour of ATDC has been examined in a number of cell lines and human tissues using a 3.0 kb cloned cDNA as a probe. Three normal and two ataxia-telangiectasia (A-T) group D, non transformed fibroblast cell lines produced a 2.4 kb mRNA transcript. The size of mRNA transcripts seen and the level of expression differ in different human tissues. Many tissues have multiple transcripts of ATDC and the most prominent transcripts observed were 3.0, 2.4 and 1.6 kb. Two out of three SV-40 transformed normal and one SV-40-transformed A-T group D fibroblast cell lines demonstrated no transcription of ATDC by RNA blotting analysis. These results suggest that SV 40 transformation may affect the expression of ATDC. Reverse transcription polymerase chain reaction analysis showed that ATDC was expressed at low levels in all of these cells. Additional Northern blot analysis demonstrated that X irradiation with 10 Gy had no effect on ATDC expression at 1, 4 and 24 h after irradiation in either SV-40-transformed normal or in SV-40-transformed A-T group D fibroblast cell lines. Further understanding of ATDC will require cloning of additional transcripts and studies of ATDC protein behaviour. PMID- 28872954 TI - Prenatal Diagnosis of Ataxia-telangiectasia and Nijmegen Breakage Syndrome by the Assay of Radioresistant DNA Synthesis. AB - Prenatal diagnosis was performed in 16 pregnancies at risk of ataxia telangiectasia (A-T) or Nijmegen Breakage Syndrome (NBS). Radioresistant DNA synthesis (RDS) was investigated in cultured chorionic villus (CV) cells and/or amniotic fluid (AF) cells. In four pregnancies, an affected foetus was diagnosed with increased RDS in cultured CV cells. In three of the four cases confirmation of the diagnosis was obtained by analysis of AF cells and/or skin fibroblasts from the foetus cultured after termination of the pregnancy; in the fourth case a fibroblast culture from the aborted foetus failed. In one case, only AF cells could be analysed in a late stage of pregnancy; pregnancy was terminated due to intermediate/equivocal results but the foetal fibroblasts showed normal RDS. Normal RDS was demonstrated in the other 11 pregnancies at 25% risk either by analysis of CV cells (nine cases) or of AF cells (two cases). In some cases the (normal) results on the CV cells were corroborated by subsequent analysis of AF cells. The results suggest that RDS analysis of CV cells allows reliable prenatal diagnosis of A-T/NBS. However, amniocentesis may be necessary to confirm normal results on CV cells if the foetus is female (because of the risk of maternal cell contamination) or in the rare case of equivocal results. PMID- 28872956 TI - Nijmegen Breakage Syndrome: A Progress Report. AB - We report the findings in the first 30 patients with the Nijmegen Breakage Syndrome (NBS). All had microcephaly from birth, short stature and a 'bird-like' face. Most of them suffered from recurrent respiratory tract infections. Intelligence was normal in half of the patients. Serum immunoglobulins were disturbed in 22/25 patients investigated (IgG deficiency, IgA deficiency, IgG2 and IgG4 deficiency) and T cell defects were found in 23/24 patients tested. The immunodeficiency appears to be more severe than in A-T. Chromosomal aberrations in cultured T lymphocytes occurred preferentially in chromosomes 7 and 14 and at the same breakpoints as in A-T. However, the percentage of chromosome 7 and/or 14 rearrangements was significantly higher in NBS patients than in A-T patients (p < 0.0005). Inv(7) was amongst the most frequently detected aberration in NBS cells as it is in A-T cells. Large clones of cells with rearrangements of chromosome 14 were rare in NBS. Of the first 19 reported patients eight have already developed a malignancy: seven a lymphoma and one a meningioma. It is noteworthy that both the tendency to express rearrangements of chromosomes 7 and 14 and the tendency to develop a malignancy is much higher in NBS than in A-T. Whether there is any causal relationship is as yet unknown. PMID- 28872957 TI - Cloning Efficiency and Spontaneous Mutant Frequency in Circulating T-lymphocytes in Ataxia-telangiectasia Patients. AB - The mutant frequency at the hprt locus in circulating T-lymphocytes has been determined in 16 ataxia-telangiectasia (A-T) patients, 19 A-T heterozygotes and 12 A-T sibs. Mutant frequency in the A-T patients is highly significantly elevated as a group, even when the relatively poor cloning efficiency of many of the A-T lymphocyte samples is taken into account. However, within the A-T set, considerable variation in both cloning efficiency and mutant frequency is seen. Cellular radiation sensitivity, measured by clonal survival assays and chromosome breakage, also varies, as do the clinical symptoms of the patients, including the age at which they become wheelchair bound and the severity of their telangiectasia. Here all the information available to us on this group of patients is presented in an attempt to discern if there is any relationship between those cellular characteristics we have observed and the severity of the symptoms and progression of the disease in the patients. Although we feel that it may be relevant that the adult patients in our study all have mutant frequencies that are not highly elevated, insufficient data are available at present to resolve any relationship between the heterogeneous clinical symptoms and cellular responses seen in the A-T patients as a group. PMID- 28872958 TI - Genetic and Physical Mapping of the Ataxia-telangiectasia Locus on Chromosome 11q22-q23. AB - The identification of A-T gene(s) using both positional and functional cloning techniques has been a major objective in A-T research over the past 10 years. Functional cloning, using complementation of the radiosensitivity phenotype, has met with some success, although technical problems remain to be overcome. Recent progress, however, in both genetic and physical mapping of the A-T locus on chromosome 11q22-q23, described in this review, suggests that the positional cloning of candidate genes should be achieved in the very near future. The region of the chromosome containing the gene(s) has been identified, and is no more than 1.6 Mb in size. The detailed physical characterization of this region, as a preliminary to candidate gene isolation, is now underway. There are, however, still some unresolved issues, most notably the existence of four A-T complementation groups, with the resulting supposition that these equate to a number of different genes. Although genetic linkage evidence does not support the hypothesis of genetic heterogeneity, the possibility of a cluster of genes at the 11q22-23 locus cannot be ruled out. It is likely that the explanations for this and other problems such as discrepancies in expected levels of consanguinity, and difficulties in the classification of atypical phenotypes will become much more obvious once a gene or genes have been cloned. PMID- 28872959 TI - Testing the Role of p53 in the Expression of Genetic Instability and Apoptosis in Ataxia-telangiectasia. AB - We have obtained initial evidence supporting a new model for the human disease ataxia-telangiectasia (A-T), in which the A-T and p53 genes play crucial roles in a signal transduction network that activates multiple cellular functions in response to DNA damage. Three of the model's predictions were tested. (1) Disrupting cell cycle checkpoints should increase spontaneous rates in normal cells. In order to interfere with the G1/S checkpoint, we transfected a normal cell line with vectors expressing either a dominant-negative p53ala143 mutant or a human papilloma virus E6 gene. These transformants showed 10-80-fold elevations in spontaneous recombination rates when compared with their parent. (2) A-T cells should be sensitive to DNA damage-induced apoptosis. Widespread apoptosis was detectable in four A-T fibroblast lines, but not two control lines, beginning 24 h after exposure to X-rays or streptonigrin, but not UV. Streptonigrin also induced widespread apoptosis in A-T lymphoblasts but not in control lymphoblasts. (3) Disruption of p53 function in A-T cells should increase their mutagen resistance by interfering with apoptosis. Stable transfection of either the p53143ala or the HPV18 E6 construct was associated with acquisition of streptonigrin and radiation resistance, while transfection with the p53143ala construct did not affect the streptonigrin sensitivity of a control cell line. PMID- 28872960 TI - Physical and Genetic Mapping at the ATA/ATC Locus on Chromosome 11q22-23. AB - Genetic heterogeneity in ataxia-telangiectasia (A-T) points to four different genes responsible for this disease. The two major A-T genes, ATA and ATC, were localized by genetic analysis close to each other on chromosome 11q22-23, prompting efforts of positional cloning. Essential steps in positional cloning are long-range cloning of the genomic region of interest, and derivation of highly polymorphic markers that would allow further reduction of the interval carrying the A-T gene. We constructed genomic contigs across the D11S611-D1S424 region harbouring the ATA and ATC genes in yeast artificial chromosome (YAC) vectors. These contigs were used as a fine mapping tool and enabled us to localize along the A-T region, eight microsatellite markers generated randomly by genome mapping centres. In addition, we used specific YAC clones to generate five new microsatellite markers based on polymorphic CA repeats. Recombination mapping based on Israeli A-T families indicates that the ATC gene is distal to the locus D11S1817. Further linkage analysis using these markers is expected to reduce the major A-T locus considerably to a size appropriate for cosmid cloning and identification of transcribed sequences. PMID- 28872961 TI - Cellular Radiosensitivity in Ataxia-telangiectasia. AB - Hypersensitivity to both the cell-killing and chromosome-damaging effects of ionizing radiations, and other agents causing DNA breakage, is a consistent feature of cells from individuals with the cancer-prone disorder ataxia telangiectasia (A-T). Evidence for a defect in DNA strand break rejoining is slight, but a higher-than-normal level of chromosomal breaks persists in irradiated A-T cells. There is also evidence for elevated frequencies of DNA recombination and deletion mutation in A-T cells; these responses may be linked through a loss of fidelity in rejoining DNA breaks through recombination mechanisms. Additionally the regulation of cell-cycle responses is altered in A-T cells: in all phases of the cycle there is some loss of 'checkpoint' function shortly after irradiation, allowing cells to continue cycling despite extensive DNA damage. However, on present evidence, radiation hypersensitivity cannot be explained simply by this loss of regulatory function. It is suggested that the A T gene product acts in the early stages of a DNA damage-recognition pathway, normally interacting with regulatory proteins such as p53, but also with proteins involved in the processing of DNA breaks. Reduced efficiency in this type of signalling function could well explain the link between radiosensitivity and cancer proneness. PMID- 28872962 TI - The Nature of Ataxia-telangiectasia: Problems and Perspectives. PMID- 28872963 TI - Possible Role of Chromatin Alteration in the Radiosensitivity of Ataxia telangiectasia. AB - Cells derived from individuals with ataxia-telangiectasia (A-T) are known to exhibit increased sensitivity to ionizing radiation and certain radiomimetic chemical agents. Here we summarize our findings regarding the role of chromosome damage and repair in this radiosensitivity. Lymphoblastoid cells derived from A-T homozygotes were characterized for initial chromosome (premature chromosome condensation) and DNA (neutral filter elution) damage and repair kinetics in cells from G1 and G2 cell cycle phases. Despite initial levels of DNA damage being similar to normal controls, A-T cells exhibited nearly a two-fold higher initial amount of chromosome damage. Different A-T cell lines exhibited differing chromosome repair capacities compared with control lymphoblastoid cell lines. These results suggest that A-T cells have an altered chromatin structure whereby DNA double-strand breaks are apparently more efficiently converted into chromosome breaks. Four A-T heterozygote cell lines were examined for chromosome damage and repair in the same fashion and all exhibited increased levels of chromosome damage, although the degree of sensitivity was more prominent in G2 phase cells (two-fold higher) than in G1 phase cells (1.5-fold higher than normal controls). These results suggest that A-T heterozygotes also exhibit an altered chromatin structure which impacts on chromosome damage expression. Of interest, A T cells also exhibited increased chromosome stickiness after irradiation, and telomere regions appeared to be frequently involved. While the molecular basis for preferential telomere involvement is not understood, these results again suggest that structural alterations in the chromatin of A-T cells may play an important role in A-T radiosensitivity. PMID- 28872964 TI - Ataxia-telangiectasia in Italy: Genetic Analysis. AB - Genetic analysis was performed on 72 Italian A-T families ascertained through 91 probands. The frequency of the A-T gene was estimated through Dahlberg's formula, which uses the frequencies of first cousin marriages among the patients' parents and in the general population. Data on consanguinity in the general population were obtained from the collection of Catholic Church dispensations for the period 1910-1964. Accurate estimates of the disease frequency were made by subdividing data into 5-year periods and between provinces, in order to take into account temporal (decrease over time) and spatial (higher frequency in Southern Italy) heterogeneity. The estimate of the gene frequency for the whole sample was q = 0.012 +/- 0.0065, corresponding to a heterozygote frequency of 2.34% and to a disease frequency of 1 in 7090. When considering q before and after 1970, there was an apparent increase of heterozygote frequency from 1.69 to 3.43%, perhaps due to a better ascertainment of the disease in the latter period. A segregation ratio of 0.249 +/- 0.043 was obtained by analyzing the offspring of the 72 families under the model of incomplete multiple selection. This value is not significantly different from 0.25, as expected for an autosomal recessive disease. PMID- 28872965 TI - Functional Complementation Studies with X-ray-sensitive Mutants of Chinese Hamster Cells Closely Resembling Ataxia-telangiectasia Cells. AB - In order to isolate a human gene complementing the defect in A-T-like hamster cell mutants, the mutants were used as recipients for genomic DNA transfection, using either HeLa chromosomal DNA or DNA from a human cosmid library. Three primary transformants with an intermediate X-ray sensitivity and almost normal sensitivity to MMS, but retaining radioresistant DNA synthesis (RDS), were obtained. To identify the human chromosome that complements the defect in the A-T like mutants, and to assess the degree of complementation for survival and RDS, microcell-mediated chromosome transfer was used. At least 20 independent hybrid clones between the mutant and each one of the human chromosomes 1, 2, 4, 5, 15, 17 or 18 were isolated. All hybrid clones remained X-ray sensitive, except one with chromosome 4, and another with chromosome 15, both showing an intermediate X ray sensitivity. By using in situ hybridization we found that this partial correction was due to the presence of a mouse chromosome. In these two hybrids containing the mouse chromosome together with human chromosome 4 or 15, RDS was fully complemented only in the hybrid with chromosome 4 but not in the one containing chromosome 15, suggesting that RDS and X-ray sensitivity may be complemented independently. PMID- 28872967 TI - DNA Marker D11S384 Shows Zero Recombination with the Ataxia-telangiectasia Locus in North American Families. AB - At the genetic locus D11S384, one probe detects a Taq1 RFLP and another detects a RFMP. In 52 pedigrees of North American A-T patients, parental haplotypes based on these two bi-allelic systems have a heterozygosity of 0.69 and a PIC of 0.64. No recombinant events between D11S384 and the A-T locus were detected in the 43 pedigrees in which this marker locus was informative. PMID- 28872968 TI - Preface. PMID- 28872969 TI - Cancer Risks in A-T Heterozygotes. AB - It is well established that ataxia-telangiectasia (A-T) patients suffer a grossly elevated risk of cancer, particularly lymphoma and leukaemia, but the possibility of an excess cancer risk of cancer in heterozygotes carriers of A-T mutations is more controversial. A number of studies indicate that female relatives of A-T patients suffer excess risk of breast cancer; based on an overview of all currently available data the estimated relative risk of breast cancer to A-T heterozygotes is 3.9-fold (95% CI 2.1-7.2). There is some suggestion that relative risk declines with age. In contrast, there is no consistent evidence of a risk from any other cancer; the estimated risk from all studies is 1.9 (95% CI 1.5-2.5) but some studies show a larger effect whilst others show no excess risk. On the basis of these results and the likely frequency of the A-T gene, A-T heterozygotes would account for between 1 and 13% of breast cancer cases, with 3.8% being the best estimate. However, unless the breast cancer risk has been seriously underestimated, the A-T gene will make little contribution to familial breast cancer. PMID- 28872970 TI - Interleukin-4 and Interleukin-10 Gene Polymorphisms in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Changes in cytokine expression have been frequently found in patients with inflammatory bowel disease (IBD). Cytokine values outside the normal range may be somewhat related to common polymorphisms within cytokine genes. OBJECTIVE: The present study was designed to investigate the possible association between polymorphisms within Interleukin IL-4 and IL-10 genes and susceptibility to and clinical features of IBD. METHODS: The study population was composed of 140 healthy controls and 75 patients with IBD (40 patients with Crohn's disease (CD) and 35 patients with ulcerative colitis (UC)). Genotyping was performed using polymerase chain reaction with sequence-specific primers. RESULTS: Higher frequencies for the C allele of IL-4-590 polymorphism (P < 0.0001; odds ratio [OR], 5.68; 95% confidence interval [95% CI], 3.28-9.83) and for the T allele of IL-4-1098 polymorphism (P = 0.016; OR, 1.83; 95% CI, 1.11-3.02) were observed in the whole group of IBD patients. The IL-4-590 C allele was also significantly overrepresented when IBD patients were subdivided into CD and UC (P < 0.0001; OR, 5.2-6.28). While the IL-4-1098 T allele was present at higher frequencies in patients with UC (P = 0.05; OR, 1.95), but not in CD (P = 0.09). Multiple pairwise comparisons indicated that genotypes of all polymorphisms investigated within IL-4 gene are correlated with IBD, CD, and UC. Haplotype analysis showed that the IL-4-1098/-590 TC haplotype might predispose individuals to IBD, CD, and UC whereas the IL-4-1098/-590 TT and GC haplotypes have a protective effect. On the contrary, neither allele nor genotype frequencies of IL-10 polymorphisms (IL 10-1082 A > G, IL-10-592 A > C, and IL-10-819 T > C) were associated with IBD, CD, or UC. CONCLUSIONS: The present study suggests that IL-4 polymorphisms might play a role in susceptibility to IBD and its major subtypes in the Iranian population. PMID- 28872972 TI - Expression and Significance of Th17 and Treg Cells in Pulmonary Infections with Gram-Negative Bacteria. AB - The aim of this study was to investigate the expression and significance of T helper type 17 (Th17) and regulatory T (Treg) cells in severe pulmonary infection with gram-negative bacteria (GNB). The peripheral venous blood (PVB) and bronchoalveolar lavage fluid (BALF) were collected from patients receiving mechanical ventilation in the intensive care unit (ICU) owing to: (1) pulmonary GNB infection (group I) and (2) nonpulmonary infection (group NI). Patients from the two groups were matched based on their Acute Physiology and Chronic Health Evaluation II (APACHE II) scores and were recruited in the same period. The levels of Th17 and Treg cells in the PVB and BALF were measured by flow cytometry. (1) The levels of Th17 and Treg cells in the PVB and BALF of the infection group (I) were significantly higher than those of the noninfection group (NI) (p < 0.01), and the levels decreased significantly after treatment (p < 0.01). (2) The Treg/Th17 cell ratio in the PVB and BALF of group I was significantly lower than those of group NI and after treatment (p < 0.01). (3) The levels of Th17 and Treg cells in the PVB and BALF could not predict the 28 day mortality (p > 0.05). The expression of Th17 and Treg cells was abnormal in patients with severe pulmonary GNB infection. Our data suggest an overactive immune response in the early stages of inflammation, but the levels of Treg and Th17 cells failed to predict the 28-day mortality. PMID- 28872971 TI - Phenotypic and Functional Characteristics of Th17 (CD4+IL17A+) Cells in Human Oral Squamous Cell Carcinoma and Its Clinical Relevance. AB - Recent studies have suggested an important role of T helper 17 (Th17) cells in tumor biology however, their phenotypic and functional aspects are poorly understood in context with oral cancer. We therefore, investigated the various phenotypic and functional markers of Th17 cells elucidating their relevance in oral squamous cell carcinoma (OSCC). Multi-color flow cytometry (FACs) was used to analyze the frequency and different markers of circulating Th17 cells ex vivo in peripheral blood mono-nuclear cells (PBMCs) from 69 OSCC patients and 35 healthy controls. Percent Mean +/- SEM of different types of cells were compared between the two groups using Mann-Whitney U test. We found significantly (p < 0.0001) increased frequency of Th17 cells in patients as compared to controls. These cells were found to express CCR6 profoundly but not CXCR4, CD62L, and CCR7 as chemokine receptors. Additionally, it expressed HLA-DR, CD69, and CD25 moderately but CD28 and CD161 highly. The cytokine profiling revealed 3 subsets namely Th17/1 (IL17A+IFNgamma+), Th17/inflammatory (IL17A+IL8+), and Th17/2 (IL17A+IL4+) which were found to be elevated in patients as compared to controls. The early stage patients had a shift toward Th17/1 type and vice versa. Our results suggest that Th17 cells may have effector immune functions in oral cancer immunity through CCR6, CD161, HLA-DR, CD69, CD28 receptors and inducing Th17/1 type of cells expressing polyfunctional antitumor IFNgamma cytokine. Thus, novel immune-boosting regimens based on enhancement of Th17 cells in oral cancer patients may provide therapeutic benefits in them. PMID- 28872974 TI - The Postoperative Immunosuppressive Phenotypes of Peripheral T Helper Cells Are Associated with Poor Prognosis of Breast Cancer Patients. AB - PURPOSE: T helper cells play essential roles in anti-tumor immune response. However, the postoperative changes of peripheral T cell subsets and their clinical significance in breast cancer patients remain largely unknown. METHODS: We evaluated the perioperative changes of T lymphocyte subsets in invasive breast cancer (IBC) patients and breast fibroadenoma (BF) patients preoperatively (preop) and 6, 24, 72 hours postoperatively (POH6, POH24, and POH72). Proportions of CD3, CD4, CD8, T helper (Th) 1, Th2, Th17 cells, regulatory T cells (Treg), and CD4+/CD8+, Th1/Th2 ratio were detected by flow cytometry. Changes in T helper cell quantity were correlated to clinicopathological parameters. Furthermore, we explored the association between the perioperative variations of T cell subsets and disease-free survival (DFS) of IBC patients. RESULTS: In IBC patients, Th1 cells diminished while Tregs elevated in postoperative 72 hours in the peripheral blood. In contrast, no significant perioperative changes of T cell subsets were observed in BF patients. Postoperative lower Th1 cells at POH 72 of IBC patients were correlated with greater tumor burden, HER2 positive and Ki67 positive. The increased Tregs at POH 72 of IBC patients were correlated with larger tumor size and HER2 positive. Th1 cell decline and Treg increment were both associated with shorter DFS in IBC patients. CONCLUSIONS: The variations of peripheral T helper cell subsets showed postoperative immunosuppression and were associated with poor prognosis in IBC patients. PMID- 28872973 TI - Splenectomy-Induced Leukocytosis Promotes Intratumoral Accumulation of Myeloid Derived Suppressor Cells, Angiogenesis and Metastasis. AB - BACKGROUND: Enlargement of the spleen is commonly observed in animal models of cancer. Here, in a breast cancer model, it was aimed to determine the effect of splenectomy on circulating and tumor-infiltrating myeloid-derived suppressor cells (MDSCs), tumor angiogenesis, and metastasis. METHODS: Mice were inoculated with 4T1 breast cancer cells and underwent splenectomy or sham laparotomy. Tumor growth and survival of animals were followed. Macroscopic and histopathological analyses were performed to determine splenomegaly and metastasis. Immunophenotyping of myeloid cells was performed with flow cytometric analysis of CD11b, Gr-1, F4/80, CD206, CD11c, and F4/80 markers. Suppressive function of MDSCs on T cell proliferation was studied in cocultures. Tumor angiogenesis and granulocytic myeloid cell infiltration in the metastatic foci were studied by CD31 and Ly6G immunohistochemistry, respectively. RESULTS: The mice bearing breast tumors underwent total splenectomy at an early time point of tumorigenesis when only low levels of MDSCs had accumulated in the spleen. Circulating and tumor-infiltrating MDSCs, and tumor-associated macrophages (TAMs) were increased following splenectomy. Nevertheless, splenectomy could only lead to a temporary deceleration in tumor growth but favored lung metastasis and angiogenesis in the long run. CONCLUSION: Our data demonstrated a link among splenectomy-induced leukocytosis, accumulation of circulating and tumor-infiltrating MDSC, and enhanced angiogenesis and metastasis. Therefore, as a part of oncological surgery, favorable and unfavorable facets of the splenectomy must be considered to improve therapeutic efficacy. PMID- 28872975 TI - Characterization of Inflammasome Components in Pig Intestine and Analysis of the Influence of Probiotic Enterococcus Faecium during an Escherichia Coli Challenge. AB - The aim of the present study was to investigate systematically the expression of inflammasome components in pig intestine and to analyze the influence of age and long-term supplementation with the probiotic Enterococcus faecium NCIMB 10415 (E. faecium). In order to examine probiotic effects on the inflammasomes during a challenge with pathogens, enterotoxigenic Escherichia coli (ETEC) and E. faecium were directly added to pig jejunum in Ussing chambers. The mRNA expression of inflammasome components generally decreased in an oral-aboral direction in intestinal tissues. In 29-day-old piglets, the expression levels of NLRP3 were significantly higher and ASC (apoptotic speck-like protein containing a caspase recruitment domain) expression were lower compared with those in the ileum of 70 day-old pigs (p <= 0.05). Long-term supplementation with E. faecium significantly increased ASC expression levels in the jejunum and ileum of 29-day-old piglets compared to control animals (p <= 0.05). Ex vivo addition of ETEC or E. faecium did not affect mRNA expression of inflammasome components significantly, whereas IL-1beta protein release was significantly elevated in ETEC-incubated jejunum (p <= 0.05), providing evidence for the functional activation of the inflammasome, which was prevented by pre-incubation with E. faecium. We conclude that pre incubation with E. faecium has a protective effect during ETEC challenge; this effect is probably not located at the inflammasome transcription level. The results of this study of the expression and regulation of inflammasome components in pigs are similar to those obtained in humans, reinforcing the use of pigs as a suitable model for translational inflammasome research. PMID- 28872976 TI - Serum IL-6 and IL-8 Correlate with Prognostic Factors in Ovarian Cancer. AB - The aim of the study was to correlate serum levels of IL-2, IL-5, IL-6, IL-8, IL 10, and TNF-alpha with clinical, laboratory, and pathological prognostic factors in patients with primary ovarian malignancy. Patients treated at the Pelvic Mass Ambulatory of the Discipline of Gynecology and Obstetrics/Oncology Research Institute (IPON) of the UFTM with confirmed diagnosis of malignant ovarian neoplasia (n = 26) were evaluated. Serum collection was performed preoperatively for the determination of tumor markers. The cytokines IL-2, IL-5, IL-6, IL-8, IL 10, and TNF-alpha were assayed by enzyme-linked immunosorbent assay (ELISA). The prognostic factors were compared using the Mann-Whitney test, with significance level lower than 0.05. When evaluating IL6, it was observed that higher serum levels were associated with overall survival less than 60 months (p = 0.0382). In the evaluation of IL8, higher serum levels were associated with neutrophil-to lymphocyte ratio (NLR) >= 4 and platelet-to-lymphocyte ratio (PLR) >= 200 (p = 0.0198 and p = 0.0072, respectively), altered values of serum CA125 (p = 0.0457), and stage IIIC (p = 0.0486). Therefore, increased levels of IL-6 and IL-8 are associated with factors of worse prognosis in ovarian cancer. Additional studies with a larger sample of patients are needed to confirm the role of cytokines as prognostic factors, in the definition of treatment, and in the development of future target therapies. PMID- 28872977 TI - Growth Differentiation Factor-15 (GDF-15) Level and Relation to Clinical Manifestations in Egyptian Systemic Sclerosis patients: Preliminary Data. AB - AIM OF THE WORK: This study aims to assess Growth differentiation factor-15 (GDF 15) level in Scleroderma patients and its relation to disease manifestations. PATIENTS AND METHODS: This study included 55 scleroderma patients and 40 age and sex matched healthy volunteers. All patients were subjected to full history taking, thorough clinical examination, and laboratory investigations. GDF-15 serum levels were analyzed in patients and controls using human GDF-15 immunoassay Quantikine ELISA kit. RESULTS: The GDF-15 serum level was significantly higher in Systemic sclerosis (SSc) patients in comparison to healthy control individuals, p-value = 0.004. In addition, the GDF-15 serum levels increased in a significant way in patients with diffuse SSc than those with limited SSc, p = 0.026. Also, we had discovered a significant positive correlation between serum GDF-15 levels and the modified Rodnan score of the SSc patients, r = 0.442, p = 0.001 and a significant association was found between high GDF-15 level and SSc patients with interstitial pulmonary fibrosis (IPF) as compared to healthy controls (p = 0.002). However, no significant difference was found between SSc patients without IPF and healthy subjects regarding GDF-15 level (p = 0.106). CONCLUSION: GDF-15 serum levels were elevated in patients with SSc and correlated with the extent of skin fibrosis, and it was found to be higher in SSc patients with IPF. Such results may suggest a pivotal role of GDF 15 in fibrotic changes in SSc, and GDF-15 could be a treatment target in SSc patients in future. PMID- 28872978 TI - Electing Full Code in Hospice: Patient Characteristics and Live Discharge Rates. AB - BACKGROUND: It is unknown how many hospice enrollees elect to be full code and if this is associated with higher hospice live discharge rates. OBJECTIVE: To measure the rates of hospice enrollees electing full code, the characteristics predicting full code status, and the association of full code status with various hospice live discharge patterns. DESIGN: Retrospective cohort study of electronic medical record data. SETTING/SUBJECTS: A total of 25,636 decedents enrolled in two Michigan hospices between 2009 and 2014. MEASUREMENTS: Code status was defined as full code versus do-not-resuscitate (DNR) orders. Covariates include demographics, location (home, hospice facility, nursing home, and hospital), primary diagnosis, and length of stay. Hospice live discharge was defined as short (0-14 days), medium (15-179 days), and long (>179 days). RESULTS: A total of 12.9% of hospice enrollees elected full code status. This was significantly (p < 0.05) predicted by male sex, younger age, nonwhite race, home setting of care, and cancer diagnosis. Those with full code status had 1.76 times the adjusted odds of hospice live discharge compared with those with DNR orders (95% confidence interval [CI] 1.44-2.16) and 2.47 times the odds of short live discharge (95% CI 1.69-3.62) with no significant difference in long live discharge. The association of full code orders with hospice live discharge was stronger for nonwhite enrollees, with a live discharge rate of 23.8% versus 11.6% for African Americans with full code versus DNR orders. CONCLUSIONS: Those electing full code status on admission to hospice are at high risk of live hospice discharge after short enrollments, particularly nonwhite enrollees. PMID- 28872979 TI - Bone marrow adipocytes. AB - Adipocytes were identified in human bone marrow more than a century ago, yet until recently little has been known about their origin, development, function or interactions with other cells in the bone marrow. Little functional significance has been attributed to these cells, a paradigm that still persists today. However, we now know that marrow adipose tissue increases with age and in response to a variety of physiologic induction signals. Bone marrow adipocytes have recently been shown to influence other cell populations within the marrow and can affect whole body metabolism by the secretion of a defined set of adipokines. Recent research shows that marrow adipocytes are distinct from white, brown and beige adipocytes, indicating that the bone marrow is a distinct adipose depot. This review will highlight recent data regarding these areas and the interactions of marrow adipose tissue (MAT) with cells within and outside of the bone marrow. PMID- 28872981 TI - Sex differences in outcomes after discharge from Alberta emergency departments for asthma: A large population-based study. AB - OBJECTIVE: Asthma exacerbations frequently result in emergency department (ED) visits. While sex differences have been identified in some asthma studies, there is a paucity of literature on sex differences in the ED setting, especially population-based ones. This study examines sex differences in important outcomes of patients discharged from EDs for acute asthma in Alberta, Canada. METHODS: Alberta residents aged from 2 to 55 years discharged from EDs with a primary diagnosis of asthma during 1999-2011 were identified from administrative databases from a single-payer health care system for the entire geographic region of Alberta. Multivariable Cox regression models analyzed time to first follow-up physician or specialist visit, and logistic regression models analyzed the binary outcome of ED return within 30 days for asthma. RESULTS: There were 115,853 discharged patients analyzed (40.4% and 59.1% female in pediatric and adult groups, respectively). Approximately 26% of patients revisited the ED during 1999 2011 and 5.1% did so within 30 days. Women had higher odds of a 30-day ED return after ED discharge than men (unadjusted odds ratio [uOR] = 1.26; 95% confidence interval [CI] 1.17-1.36). Time to first non-ED physician follow-up was shorter for girls (unadjusted hazard ratio [uHR] = 1.05; 95%CI 1.03-1.07) and women (uHR = 1.62; 95%CI 1.59-1.64) than for boys and men, respectively. Significant interactions between sex and age, socio-economic status, area of residence, and comorbidities were identified and changed the effect of sex on outcomes. CONCLUSIONS: In conclusion, women return to EDs within 30 days of discharge for acute asthma more often than men. Time to first non-ED physician follow-up for children and adults differed by sex. Multiple factors likely contribute to these differences; however, identifying these differences is critical to understand the influence of sex on health behaviors and outcomes. PMID- 28872982 TI - Amelogenesis Imperfecta: A Non-Invasive Approach to Improve Esthetics in Young Patients. Report of Two Cases. AB - : Objective-Evaluate esthetic and functional efficacy of infiltrant resin (Icon, DMG, Hamburg, Germany) in Amelogenesis Imperfecta's treatment. STUDY DESIGN: Two adolescent patients, G.S. (13 years old) and C.M. (15 years old), affected by the hypomaturation type of Amelogenesis Imperfecta, were treated with Icon resin and were followed for twelve months. RESULTS: Treated teeth show an excellent aesthetical result immediately after the resin application, effect that lasts in the long-term (six and twelve months follow-up examinations); the dental wear's progression seems to be clinically arrested. CONCLUSIONS: Resin infiltration has proven to be a minimal invasive treatment for dental discoloration, less aggressive than conventional procedures. This approach might be recommended for a stable esthetical improvement in moderate AI's lesions especially in children and adolescents. PMID- 28872980 TI - The recycling endosome protein RAB-10 promotes autophagic flux and localization of the transmembrane protein ATG-9. AB - Macroautophagy/autophagy involves the formation of an autophagosome, a double membrane vesicle that delivers sequestered cytoplasmic cargo to lysosomes for degradation and recycling. Closely related, endocytosis mediates the sorting and transport of cargo throughout the cell, and both processes are important for cellular homeostasis. However, how endocytic proteins functionally intersect with autophagy is not clear. Mutations in the DAF-2/insulin-like IGF-1 (INSR) receptor at the permissive temperature result in a small increase in GFP::LGG-1 foci, i.e. autophagosomes, but a large increase at the nonpermissive temperature, allowing us to control the level of autophagy. In a RNAi screen for endocytic genes that alter the expression of GFP::LGG-1 in daf-2 mutants, we identified RAB-10, a small GTPase that regulates basolateral endocytosis. Loss of rab-10 in daf-2 mutants results in more GFP::LGG-1-positive foci at the permissive, but less GFP::LGG-1 or SQST-1::GFP foci at the nonpermissive temperature. As previously reported, loss of rab-10 alone resulted in an increase of GFP:LGG-1 foci. Exposure of rab-10 mutant animals to chloroquine, a known inhibitor of autophagic flux, failed to increase the number of GFP::LGG-1 foci. Moreover, colocalization between LMP-1::tagRFP and GFP::LGG-1 (the lysosome and autophagosome reporters) was decreased in daf-2; rab-10 dauers at the nonpermissive temperature. Intriguingly, RAB-10 was required to maintain the normal size of GFP::ATG-9 positive structures in daf-2 mutants at both the permissive and nonpermissive temperature. Finally, we found that RAB-10 GTPase cycling was required to control the size of GFP::ATG-9 foci. Collectively, our data support a model where rab-10 controls autophagic flux by regulating autophagosome formation and maturation. PMID- 28872983 TI - Prevalence and Associated Factors of Tooth Erosion in 8 -12-Year-Old Brazilian Schoolchildren. AB - OBJECTIVE: This study estimated the prevalence, distribution and associated factors of tooth erosion in Brazilian schoolchildren. STUDY DESIGN: A cross sectional study was carried out in a representative sample of children aged 8-12 years-old from public and private schools. Six calibrated examiners assessed tooth erosion (O'Sullivan index) and other oral conditions (dental trauma, enamel defects, plaque, dental caries and dental crowding). Socio-demographic and behavioral data were collected using questionnaires. Interviews were conducted in children and in parents. Data were analyzed using Poisson regression model considering the cluster sample (Prevalence Ratio-PR; 95% Confidence Interval-CI). RESULTS: A total of 1,210 children participated and were examined. Tooth erosion was observed in 25.1% of the children. Lesions were mostly observed in enamel and less than a half of the buccal surface was affected. The type of school and age were significant associated with higher prevalence of tooth erosion and dental crowding was associated with less probability of tooth erosion significantly. Acidic food or drinks were not associated with dental erosion. CONCLUSION: The prevalence of tooth erosion in the studied population was high. Erosive lesions were not severe, confined in enamel. Tooth erosion was associated with age, type of school, socioeconomic level and dental crowding. PMID- 28872984 TI - Autotransplantation: A Reliable Treatment Modality for Severely Malpositioned Teeth. AB - Maxillary canines are the most commonly impacted teeth, second only to third molars. Various treatment methods may be used to recover impacted maxillary canines. This is a report of a 14-year-old girl with a severely malpositioned impacted right maxillary canine which accompanied severe root resorption of adjacent tooth, treated by autotransplantation with a computer aided rapid prototyping model as a surgical guide. This case report demonstrates that autotransplantation can be a reliable treatment alternative, in cases with a severely malpositioned impacted canine, providing acceptable prognosis. PMID- 28872985 TI - A Controlled Study of Pre-Eruptive Intracoronal Resorption and Dental Development. AB - AIM: To compare the prevalence of PEIR in Australian and Saudi Arabian children and to investigate the relationship of PEIR with dental development. STUDY DESIGN: Panoramic (PAN) radiographs of 842 Australian and 456 Saudi children were screened for PEIR. The dental ages of the children with and without PEIR were assessed from the PAN radiographs using the method of Demirjian and co-workers. RESULTS: The subject prevalence of PEIR was not statistically significant between Australian (2%) and Saudi children (0.6%) (p>0.1). The teeth most commonly affected by PEIR were the mandibular second molars and premolars. Dental impaction was observed in 31% of teeth with PEIR compared to only 0.1% of control teeth (p<0.0001). Children with PEIR showed a mean delay in dental development of 0.54+/-0.85 years compared with ageand gender-matched controls (p<0.0001). CONCLUSIONS: The present study provides the first evidence that there are no differences in PEIR prevalence between Australian and Saudi populations, and that dental development is significantly delayed in children with PEIR. PMID- 28872986 TI - Effect of Qmix and Other Irrigants on Dentin Adhesives in Pulp Chambers of Primary Teeth: SEM Study. AB - OBJECTIVE: To compare the effect of different endodontic irrigants on microleakage of adhesives used within pulp chamber of primary molars. STUDY DESIGN: 72 Primary molars were divided into 6 groups, according to 3 irrigants and 2 adhesives used. After de-roofing the pulp chamber, pulp was extirpated. In 36 samples, pulp chambers were bonded with Xeno V+ after irrigation with either QMix (Group1); 17%EDTA+5%NaOCl (Group2) or normal saline (Group3) and in other half samples, pulp chambers were bonded with SinglebondUniversal after irrigation with either QMix (Group 4); 17%EDTA+5% NaOCl (Group5) or normal saline (Group 6). All the samples were restored with Filtek Z350. Ten teeth from each group were assessed for dye penetration. Two samples in each group were viewed under scanning electron microscope. Data was statistically analyzed using Mann-Whitney and Kruskal Wallis tests at a significance level of P < 0.05. RESULTS: Mean microleakage scores were: Group 1-1.5+/-0.70, Group 2-1.6+/-.51, Group 3-2.4+/ 0.96, Group 4-1.2+/-0.42, Group 5-1.2+/-0.42, Group 6-1.1+/-0.32. CONCLUSIONS: Irrigation with QMix significantly reduced the microleakage of XenoV+ but had no significant effect on microleakage of SinglebondUniversal. Irrigation with EDTA/NaOCl or QMix had no detrimental effect on the sealing ability of either of the adhesive tested. PMID- 28872987 TI - Using Quality Improvement Methods to Implement an Early Childhood Oral Health Initiative: A Federally Qualified Health Center Pilot Study. AB - OBJECTIVES: To assess the use of quality improvement (QI) methods to implement an early childhood oral health program (Baby Oral Health Program-bOHP) in four federally qualified health center (FQHC) dental clinics. STUDY DESIGN: Using a mixed-methods study design, survey responses, administrative data, QI project templates, and focus group measures were collected. Plan-Do-Study-Act (PDSA) cycles as mini-projects to improve the implementation of bOHP were examined. Data analysis included descriptive qualitative reviews and quantitative statistics at baseline, six, and 12 months following the intervention. RESULTS: Twenty-three dental team providers in one urban and three rural clinics participated. Successful QI mini-projects included shortening time period between accepted referral and patient visits, improved documentation of caregiver interview, and efficiency of the infant oral health examination. Lack of change in provider confidence was observed, regardless of years of practice (p=0.93), years of employment (p=0.39), and dental team age (p=0.85). Qualitative reviews highlighted mixed QI results related to training and limited resources invested on follow-up of QI implementation. CONCLUSIONS: A low cost, low resource pilot QI program as part of bOHP implementation showed mixed success, highlighting the critical role of training, staff committment, and leadership support to assure sustainable oral health programs in high-risk populations. PMID- 28872988 TI - Effect of Sedation with Midazolam and Time to Discharge among Pediatric Dental Patients. AB - OBJECTIVE: The aim of this study was to examine the recovery time of children who underwent conscious sedation with oral or rectal midazolam. STUDY DESIGN: The medical files in the Department of Pediatric Dentistry of all the children who underwent conscious sedation with midazolam between 3/2013-4/2016 were examined. The total duration of sedation and time to discharge were calculated. Descriptions of the children's behavior before and during sedation were compared. RESULTS: The files of 120 children were retrieved. They included 64 girls, mean (+/- standard deviation) age 5.7 +/- 2.67 years and 56 boys, mean age 4.9 +/-1.06 years. The mean weight for the entire cohort was 18.7 +/- 5.2 kg. Eighty-one children (67.5%) received oral sedation and 39 (32.5%) received rectal sedation. The mean total duration of sedation was 105 +/- 26 min, and the mean time to discharge after treatment was 55:17 +/- 22:30 min. A hundred and seven children exhibited positive behavior before undergoing sedation, but the behavior deteriorated during sedation in 36 cases. CONCLUSION: The time to discharge post midazolam sedation correlated to the child's age and weight and total amount of administered midazolam. Sedation negatively affected behavior in 43.6% of the cases. PMID- 28872989 TI - Orthodontic Treatment in Conjunction with Twin-bock Treatment and Growth Hormone Therapy in Silver Russell Syndrome. AB - Silver-Russell syndrome (SRS) is a very rare genetic disorder characterized by intrauterine growth retardation, short stature, and typical craniofacial abnormalities including micrognathia. While growth hormone (GH) therapy in children with SRS significantly improves somatic growth, functional orthopedic treatment can also be effective in adolescents with mandibular deficiency. We report the effects of Phase 1 functional orthopedic treatment of a twin-block appliance in conjunction with GH administration in a 9-year-old boy with GH deficiency and SRS, and the result of the subsequent Phase 2 orthodontic treatment. PMID- 28872990 TI - Plunging Ranula Occurring Without its Oral Counterpart: A Case Report. AB - A ranula is a lesion that arises from mucin spillage from the sublingual or submandibular gland ducts, beneath the mucosa of the oral floor. A plunging or cervical ranula dissects the mylohyoid muscle and appears as a submandibular swelling. Rarely, a plunging ranula is encountered without its oral counterpart. Here, we report a rare case of a plunging ranula that occurred without its oral counterpart in a 11-year-old male patient. We have also discussed the pathogenesis and treatment options for the ranula. PMID- 28872991 TI - Understanding and Appraising Systematic Reviews and Meta-Analysis. AB - Systematic reviews and meta-analysis seek to answer a pre-framed research question to lead to a valid answer through a systematic, explicit and reproducible method of locating; identifying, including and appraising appropriate trials. The results are synthesized considering the methodological rigor of included trials. While the meta-analysis quantitatively pools the results from individual included studies, the systematic review summarizes the findings as qualitative conclusions. These reviews are crux of evidence based dentistry for various stake-holders, i.e., clinicians, researchers and policy makers. Although the meticulous methodology of systematic review and meta analysis minimizes the elements of bias, yet the validity and reliability of their findings should be explored prior to translating their conclusions to practice. The goal of this paper is to familiarize readers with rationale, conduct and appraisal of systematic review and meta-analysis. Further, guidance is provided on tracing potential elements of bias in the review to enable readers to judge the quality of evidence generated from the review. PMID- 28872992 TI - Caries Progression Rate in Primary Teeth: A Retrospective Study. AB - OBJECTIVES: The rate of caries progression in primary teeth has rarely been studied, with most studies on early childhood caries reporting the percentage of lesions that remain at a certain stage of disease over a period of time. The aim of the present study was to examine the prevalence and behavior of proximal and occlusal carious lesions in primary teeth among children from low socio-economic status. STUDY DESIGN: This retrospective study was based on bite-wing radiographs of 95 children aged 5-12 taken at 6-12 months intervals, with a follow-up period of at least three years. One hundred thirty-five teeth and 141 tooth surfaces were examined. The degree of proximal surfaces and occlusal caries advancement was scored and statistical analyses (Mann-Whitney, Kruskal-Wallis and Kaplan Meier analysis) were performed to evaluate caries progression rate. RESULTS: The results revealed that approximately 0.8 years were required for a carious lesion to progress from the outer enamel to the dentino-enamel junction, and an additional 1.4 years for it to reach the inner part of the dentin. CONCLUSIONS: The caries progression rate found in the present study is more rapid than previously found and affects more the lower socio economic population. PMID- 28872993 TI - A Clinical Evaluation of Deproteinization and Different Cavity Designs on Resin Restoration Performance in MIH-Affected Molars: Two-Year Results. AB - BACKGROUND: The aim of this study was to evaluate the clinical effects of deproteinization of the hypomineralized enamel and different cavity designs on the performance of the composite resin restorations(CRRs) placed into the cavities of MIH (molar incisor hypomineralization)-affected molars. STUDY DESIGN: 95 MIH-affected permanent first molars (PFMs) and 31 caries but not MIH-affected PFMs (126 teeth in total) were included in the study. The MIH-affected molars were divided into three groups. In Group I, all hypomineralized tissue was removed until healthy enamel was reached. In Group II, carious and cheesy hypomineralized tissue was removed until a reasonable resistance was detected in the hypomineralized tissue. In Group III, cavities designed as Group II, differently from this group deproteinization of the left hypomineralized tissue was performed prior to the placement of CRRs. Group IV served as the control group consisting of unaffected carious PFMs. Restorations were evaluated according to modified USPHS criteria for 24 months. RESULTS: The retention rates were 93.7% for Group I, 80.7% for Group II, 93.5% for Group III and 100% for Group IV. The success rate for the restorations in Group II proved significantly lower (p<0.05) than that of the other three groups. No significant difference in success rates was observed between Group I, Group III and Group IV (p>0.05) at the end of 24 months. CONCLUSIONS: Failure of the restorations was predominant in the group that the hypomineralized tissue was left surrounding the cavities. Deproteinization of the hypomineralized enamel was found to enhance the retention rates of CRRs. PMID- 28872994 TI - Comparison of Cytotoxicity of New Nanohybrid Composite, Giomer, Glass Ionomer and Silver Reinforced Glass Ionomer using Human Gingival Fibroblast Cell Line. AB - AIM: The objective of this study was to investigate the cytotoxic effects of new nanohybrid composite, giomer, conventional and resin modified and silver reinforced glass ionomer cements and compare the biocompatibility of these dental materials in cell culture. STUDY DESIGN: Five cylindrical specimens were made of each material, using a mold (2mm. thick and 5 mm in diameter). For HGF, cells were cultured in RPMI-1640 medium. After attaining 80% confluence, cells were treated with different doses of five tested materials for 24h. Then cell cytotoxicity was assessed using MTT assay. The data were analyzed using Kruskal Wallis and Dunn test. RESULTS: The materials evaluated on HGF cells, showed significantly more cytotoxicity in silver reinforced glass ionomer but nanohybrid composite shows mild cytotoxic effect. However, giomer shows no significant cytotoxicity and conventional and resin modified glass ionomer enhance cell proliferation. CONCLUSIONS: Silver reinforced glass ionomer induced a significant high cytotoxic effect over a wide range of concentration. Therefore, higher attention should be focused on this restorative dental material, which should be chosen for further investigations. PMID- 28872995 TI - Eva Vacuum-Formed Alternative Splinting of Alveolar Fractures in Primary Dentition: A Case Report. AB - : Alveolar fractures treatment includes repositioning of displaced segments and splinting. In children, splinting procedures may occasionally present clinical problems resulting from fewer teeth available for splinting or presence of occlusal disturbances. An alternative clinical approach for splinting in alveolar fractures of primary dentition is described. CLINICAL CASE: A 4.5-year-old girl was referred to our clinic 8 hours after a fall accident. Clinical examination revealed mandibular alveolar process segmental fracture in the right canine area with frontal dislodgement of the labial cortical bone resulting to occluding inability. The area was anaesthetized, cleaned and the dislodged bone was manually repositioned, followed by an EVA copolymer splint for fixation as a result of patient's deep bite impeding regular wire-composite splint. The cap splint that was fabricated on a cast made after an alginate impression, was set on the mandibular dentition and immobilized in the primary molars with acid-etch adhesive and flowable resin composite. Following splint removal after 4 weeks and follow-up visits, successful healing was observed clinically and radiographically with no pathological signs and symptoms. CONCLUSION: The described alternative splinting method in alveolar fractures of primary dentition is a valuable clinical tool for peediatric dentists, easily accepted by children in cases where regular splinting methods cannot be used. PMID- 28872996 TI - American Society of Clinical Oncology Statement on the Impact of Utilization Management Policies for Cancer Drug Therapies. PMID- 28872997 TI - Treatment of tumor lysis syndrome in children with leukemia/lymphoma in resource limited settings-Efficacy of a fixed low-dose rasburicase. AB - Rasburicase is a novel drug used during the management of tumor lysis syndrome. In countries with limited resources, it is frequently given at a lower dose and only for the treatment of established tumor lysis syndrome and not as prophylaxis. A retrospective study was conducted in the department of pediatric oncology at a tertiary referral oncology center in south India to analyze the use of rasburicase over the past 3 years. Data of all the 18 children (< 14 years of age) who were given rasburicase for the management of hyperuricemia were collected and analyzed. With a mean rasburicase dose of 0.085 mg/kg, hyperuricemia was managed efficiently without the need for a hemodialysis in 16 children (88.8 %). The fall in mean serum uric acid levels after the administration of a single dose of rasburicase at 4, 24, and 48 hours was 31.18 %, 64.8 %, and 74.5 %, respectively. Rasburicase efficiently decreases the uric acid levels to a normal level within a short period. In resource-limited settings, rasburicase at a lower dose is a promising option for managing hyperuricemia in the event of a tumor lysis syndrome. PMID- 28872998 TI - "Being Bipolar": A Qualitative Analysis of the Experience of Bipolar Disorder as Described in Internet Blogs. AB - In the light of debates about the nature of bipolar disorder (BD), the current article presents a thematic analysis of Internet "blogs" by self-identified bipolar sufferers. Extreme and frequent fluctuation of mood was considered the principal feature of BD, along with a broad range of other problems. BD was often invoked as an explanation for life difficulties or lack of achievement, and was mostly regarded as a brain disease. Most bloggers emphasized the importance of drug treatment, along with the self-management techniques. The blogs present a "bipolar identity," which is much broader than traditional definitions, are based on a medicalized model of the disorder, and are connected to the moral function of enabling people to externalize unwanted aspects of the self. PMID- 28872999 TI - Analysis of the early cellular and humoral responses of Galleria mellonella larvae to infection by Candida albicans. AB - Galleria mellonella larvae were administered an inoculum of Candida albicans and the response to infection over 24 hours was monitored. The yeast cell density in infected larvae declined initially but replication commenced six hours post infection. The hemocyte density decreased from 5.2 * 106/ml to 2.5 * 106/ml at 2 hours but increased to 4.2 * 106 at 6 hours and decreased subsequently. Administration of beta - glucan to larvae also caused a fluctuation in hemocyte density (5.1 +/- 0.22 * 106/ml (0 hour) to 6.25 +/- 0.25 * 106/ml (6 hour) (p < 0.05) to 5 +/- 2.7 * 106 (24 hour)) and the population showed an increase in the density of small, granular cells at 24 hours (p < 0.05). Hemocytes from larvae inoculated with beta - glucan for 6 or 24 hours showed faster killing of C. albicans cells (53 +/- 4.1% (p < 0.01), 64 +/- 3.7%, (p < 0.01), respectively) than hemocytes from control larvae (24 +/- 11%) at 60 min. Proteomic analysis indicated increased abundance of immune related proteins cecropin-A (5 fold) and prophenoloxidase-activating proteinase-1 (5 fold) 6 hours post infection but by 24 hours there was elevated abundance of muscle (tropomyosin 2 (141 fold), calponin (66 fold), troponin I (62 fold)) and proteins indicative of cellular stress (glutathione-S-transferase-like protein (114 fold)), fungal dissemination (muscle protein 20-like protein (174 fold)) and tissue breakdown (mitochondrial cytochrome c (10 fold)). Proteins decreased in abundance at 24 hour included beta - 1,3 - glucan recognition protein precursor (29 fold) and prophenoloxidase subunit 2 (25 fold). PMID- 28873000 TI - Immunohistochemical Analysis Using Antipodocalyxin Monoclonal Antibody PcMab-47 Demonstrates Podocalyxin Expression in Oral Squamous Cell Carcinomas. AB - Podocalyxin is a CD34-related type I transmembrane protein that is highly glycosylated with N-glycan, O-glycan, and keratan sulfate. Podocalyxin was originally found in the podocytes of rat kidney and is reportedly expressed in many types of tumors, including brain tumors, colorectal cancers, and breast cancers. Overexpression of podocalyxin is an independent predictor of progression, metastasis, and poor outcome. We recently immunized mice with recombinant human podocalyxin, which was produced using LN229 glioblastoma cells, and produced a novel antipodocalyxin monoclonal antibody (mAb), PcMab-47, which reacts with endogenous podocalyxin-expressing cancer cell lines and normal cell lines independent of glycosylation in Western blot, flow cytometry, and immunohistochemical analyses. In this study, we performed immunohistochemical analysis against oral cancers using PcMab-47. PcMab-47-stained oral squamous cell carcinoma cells in a cytoplasmic pattern and detected 26/38 (68.4%) of oral squamous cell carcinoma cells on tissue microarrays. These results indicate that PcMab-47 is useful in detecting podocalyxin of oral cancers for immunohistochemical analysis. PMID- 28873001 TI - Toward the Drug Factory Microbiome: Microbial Community Variations in Antibiotic Producing Clean Rooms. AB - Microbiome projects are currently booming around the globe, enabled by advances in culture-independent microbial community analysis and high-throughput sequencing. One emerging application of microbiome science involves exploring microbial diversity in built environments, and one unexplored built environment is the pharmaceutical factory, notably factories producing antibiotics, as they could be enriched in antibiotic-resistant microbes. To examine the drug factory microbiome, we launched this interdisciplinary hypothesis-generating study to benchmark culture-independent microbiome analysis in drug manufacturing units producing antibiotics and nonantibiotic drugs, against traditional microbial identification and quantification techniques. Over a course of 4 months, we prospectively collected 234 samples from antibiotic (kanamycin and amoxicillin) and nonantibiotic (acetaminophen) production clean rooms within a pharmaceutical factory in Egypt. All samples were analyzed by traditional culture-based methods, and microbial communities of representative samples were profiled by16S rRNA gene sequencing. In addition, antibiotic resistance profiles of some samples were determined, and representative resistance genes were screened. The 16S rRNA analysis revealed a typical predominance of Proteobacteria (36%), Firmicutes (31%), and Bacteroidetes (16%). The microbial composition of the samples was highly affected by the use of water, environmental conditions during the production process, the presence of personnel, and the type of the product. The effect of these factors was confirmed by total aerobic microbial counts and identification of biomarker microbes. In conclusion, these observations can aid in the future for optimal design and management of pharmaceutical manufacturing units, and speak to a greater need for implementing microbiome research in the quality assurance of built environments. PMID- 28873002 TI - Reduced virulence of a pseudorabies virus isolate from wild boar origin in domestic pigs correlates with hampered visceral spread and age-dependent reduced neuroinvasive capacity. AB - Morbidity and mortality associated with pseudorabies virus (PRV) infection are dependent on the age of the pig and the virulence of the strain. PRV strains circulating in wild boar are considered to be low virulent, but no mechanistic explanation for their reduced virulence is available. Here infection of 2- and 15 week-old domestic pigs with the PRV wild boar strain BEL24043 did not induce clinical symptoms in 15-week-old pigs, but resulted in important neurological and respiratory disease in 2-week-old piglets. A detailed study of the (neuro) pathogenesis and associated cytokine mRNA expression showed that the reduced virulence of the wild boar strain, compared to what was previously reported for the virulent domestic NIA3 strain, is due to a severely hampered spread to visceral organs in pigs of both age categories and to an efficient suppression of viral replication at primary replication sites of 15-week-old pigs and to a lesser extent in those of 2-week-old piglets. The age-dependent difference in induced symptoms seems to be due to an immature development state of the immune and/or nervous system in 2-week-old pigs. An extensive viral replication associated with a robust expression of cytokine-related mRNA was found in the olfactory bulb of 2-week-old piglets, correlating with observed neurological disease. Neuroinvasion also occurred via the trigeminal route in 2-week-old pigs, but viral replication was efficiently suppressed in the trigeminal ganglion in the presence of a moderate induction of cytokine-related mRNA. Viral replication in the peripheral and central nervous system of 15-week-old pigs was limited and efficiently suppressed. PMID- 28873003 TI - Coordination between bZIP28 and HSFA2 in the regulation of heat response signals in Arabidopsis. AB - Heat stress can have detrimental effects on yield production worldwide. Although bZIP28 and HSFA2 were identified as putative heat sensors in plants, coordination between them has not been uncovered. In this study, the deficiency in bZIP28 did not affect heat tolerance in plants. However, the plants lacking bZIP28 showed enhanced activation of APXs-, MBF1c-and HSPs-dependent pathways as well as higher level of HsfA2 transcripts and H2O2 accumulation, suggesting that these pathways might compensate for the deficiency in bZIP28 during heat stress. In addition, requirement of HSFA2 for the activation of APXs-dependent pathway during heat stress was supported by the analyses of plants lacking HSFA2. Our study demonstrated the flexible mode of heat response pathways involving bZIP28, HSFA2 and ROS-dependent signals. PMID- 28873005 TI - Recycling the danger via lipid droplet biogenesis after autophagy. AB - Fatty acids are an important cellular energy source under starvation conditions. However, excessive free fatty acids (FFAs) in the cytoplasm cause lipotoxicity. Therefore, it is important to understand the mechanisms by which cells mobilize lipids and maintain a homeostatic level of fatty acids. Recent evidence suggests that cells can break down lipid droplets (LDs), the intracellular organelles that store neutral lipids, via PNPLA2/adipose triglyceride lipase and a selective type of macroautophagy/autophagy termed lipophagy, to release FFAs under starvation conditions. FFAs generated from LD catabolism are either transported to mitochondria for beta-oxidation or converted back to LDs. The biogenesis of LDs under starvation conditions is mediated by autophagic degradation of membranous organelles and requires diacylglycerol O-acyltransferase 1, which serves as an adaptive cellular protective mechanism against lipotoxicity. PMID- 28873004 TI - A glutathione peroxidase from Antarctic psychrotrophic bacterium Pseudoalteromonas sp. ANT506: Cloning and heterologous expression of the gene and characterization of recombinant enzyme. AB - A glutathione peroxidase (GPx) gene, designated as PsGPx, was cloned from Antarctic psychrotrophic bacterium Pseudoalteromonas sp. ANT506 and expressed in Escherichia coli. The full-length PsGPx contained a 585-bp encoding 194 amino acids with predicted molecular masses of approx. 21.7 kDa. Multiple sequence alignments revealed that PsGPx belonged to the thioredoxin-like superfamily. PsGPx was heterologously overexpressed in E. coli, purified and characterized. The maximum catalytic temperature and pH value for recombinant PsGPx (rPsGPx) were 30 degrees C and pH 9.0, respectively. rPsGPx retained 45% of the maximum activity at 0 degrees C and exhibited high thermolability with a half-life of approx. 40 min at 40 degrees C. In addition, the enzymatic activity of rPsGPx was still manifested under 3 M NaCl. The Km and Vmax values of the recombinant enzyme using GSH and H2O2 as substrates were 1.73 mM and 16.28 nmol/mL/min versus 2.46 mM and 21.50 nmol/mL/min, respectively. PMID- 28873007 TI - Bioengineering of crop plants for improved tetrahydrofolate production. AB - De novo synthesis of folates in plants is tightly regulated through feedback regulation of certain pathway catalysts. Recently, we investigated the prospects of incessant production of folates in an evolutionary conjunction, through the overexpression of feedback targeted and evolutionarily conserved heterologous E.coli dihydroneopterin aldolase (EcDHNA) in tobacco. 1 The enhanced production of folates in the transgenic lines was associated with differential allosteric regulatory cavities accessible at EcDHNA surface having critical amino-acid differences as Ile 64 (His_63), Val 70 (Phe_69), His 75 (Arg_78) and Arg 79 (Glu_72). These structural characteristics are indicative of evolutionary signatures of the catalytic feedback-regulation of folate manufacturing. We exploited the biotechnological potential of such allosterically diverged trans DHNA for improved folate production in plants. Nonetheless, genetic manipulation of single enzymes modulating complex pathways such as folate biosynthesis is often inadequate to achieve desired phenotypes; therefore, multi-gene integration with explicit genic-combination for folate enrichment in plants has also been projected for future folate agri-biofortification schemes. PMID- 28873008 TI - Induction of adipose and hepatic SWELL1 expression is required for maintaining systemic insulin-sensitivity in obesity. AB - Obesity is associated with a loss of insulin-sensitivity and systemic dysglycemia, resulting in Type 2 diabetes, however the molecular mechanisms underlying this association are unclear. Through adipocyte patch-clamp studies, we recently showed that SWELL1 is required for the Volume-Regulated Anion Current (VRAC) in adipocytes and that SWELL1-mediated VRAC is activated by both mechanical and pathophysiological adipocyte expansion. We also demonstrated that adipocyte SWELL1 is required for maintaining insulin signaling and glucose homeostasis, particularly in the setting of obesity. Here we show that SWELL1 protein expression is induced in subcutaneous fat, visceral fat and liver in the setting of obesity. Long- term AAV/rec2-shRNA mediated SWELL1 knock-down in both fat and liver are associated with increased weight gain, increased adiposity and exacerbated insulin resistance in mice raised on a high-fat diet. These data further support the notion that SWELL1 induction occurs in insulin- sensitive tissues (liver and adipose) in the setting of over-nutrition and contributes to improved systemic glycemia by supporting enhanced insulin-sensitivity. PMID- 28873006 TI - A role for cellular senescence in birth timing. AB - Senescence contributes to the local and systemic aging of tissues and has been associated with age-related diseases. Recently, roles for this process during pregnancy have come to light, the dysregulation of which has been associated with adverse pregnancy outcomes such as preterm birth. Here, we summarize recent advances that support a role for senescence in birth timing and propose new aspects of study in this emerging field. PMID- 28873009 TI - 89Zr-mAb3481 PET for HER3 tumor status assessment during lapatinib treatment. AB - Treatment of human epidermal growth factor receptor 2 (HER2)-driven breast cancer with tyrosine kinase inhibitor lapatinib can induce a compensatory HER3 increase, which may attenuate antitumor efficacy. Therefore, we explored in vivo HER3 tumor status assessment after lapatinib treatment with zirconium-89 (89Zr)-labeled anti HER3 antibody mAb3481 positron emission tomography (PET). Lapatinib effects on HER3 cell surface expression and mAb3481 internalization were evaluated in human breast (BT474, SKBR3) and gastric (N87) cancer cell lines using flow cytometry. Next, in vivo effects of daily lapatinib treatment on89Zr-mAb3481 BT474 and N87 xenograft tumor uptake were studied. PET-scans (BT474 only) were made after daily lapatinib treatment for 9 days, starting 3 days prior to 89Zr-mAb3481 administration. Subsequently, ex vivo 89Zr-mAb3481 organ distribution analysis was performed and HER3 tumor levels were measured with Western blot and immunohistochemistry. In vitro, lapatinib increased membranous HER3 in BT474, SKBR3 and N87 cells, and consequently mAb3481 internalization 1.7-fold (BT474), 1.4-fold (SKBR3) and 1.4-fold (N87). 89Zr-mAb3481 BT474 tumor uptake was remarkably high at SUVmean 5.6+/-0.6 (51.8+/-7.7%ID/g) using a 10 MUg 89Zr mAb3481 protein dose in vehicle-treated mice. However, compared to vehicle, lapatinib did not affect 89Zr-mAb3481 ex vivo uptake in BT474 and N87 tumors, while HER3 tumor expression remained unchanged. In conclusion, lapatinib increased in vitro HER3 tumor cell expression, but not when these cells were xenografted. 89Zr-mAb3481 PET accurately reflected HER3 tumor status. 89Zr mAb3481 PET showed high, HER3-specific tumor uptake, and such an approach might sensitively assess HER3 tumor heterogeneity and treatment response in patients. PMID- 28873010 TI - Regulatory interplay between LEAFY, APETALA1/CAULIFLOWER and TERMINAL FLOWER1: New insights into an old relationship. AB - The gene regulatory network comprised of LEAFY (LFY), APETALA1 (AP1), the AP1 paralog CAULIFLOWER (CAL), and TERMINAL FLOWER1 (TFL1) is a major determinant of the flowering process in Arabidopsis thaliana. TFL1 activity in the shoot apical meristem provides inflorescence identity while the transcription factors LFY and AP1/CAL confer floral identity to emerging floral primordia. It has been thought that LFY and AP1/CAL control the onset of flowering in part by repressing TFL1 expression in flowers. However, in the June issue of Plant Physiology, we reported that LFY and AP1 act antagonistically in the regulation of several key flowering regulators, including TFL1. Specifically, TFL1 transcription was suppressed by AP1 but promoted by LFY. Here, we present additional evidence for the role of LFY as an activator of TFL1 and propose that this regulatory activity is pivotal for the indeterminate growth of the SAM during the reproductive phase of development. PMID- 28873011 TI - Response to Blood Meal in the Fat Body of Anopheles stephensi Using Quantitative Proteomics: Toward New Vector Control Strategies Against Malaria. AB - Malaria remains a grand challenge for disruptive innovation in global health therapeutics and diagnostics. Anopheles stephensi is one of the major vectors of malaria in Asia. Vector and transmission control are key focus areas in the fight against malaria, a field of postgenomics research where proteomics can play a substantive role. Moreover, to identify novel strategies to control the vector population, it is necessary to understand the vector life processes at a global and molecular scale. In this context, fat body is a vital organ required for vitellogenesis, vector immunity, vector physiology, and vector-parasite interaction. Given its central role in energy metabolism, vitellogenesis, and immune function, the proteome profile of the fat body and the impact of blood meal (BM) ingestion on the protein abundances of this vital organ have not been investigated so far. Therefore, using a proteomics approach, we identified the proteins expressed in the fat body of An. stephensi and their differential expression in response to BM ingestion. In all, we identified 3,218 proteins in the fat body using high-resolution mass spectrometry, of which 483 were found to be differentially expressed in response to the BM ingestion. Bioinformatics analysis of these proteins underscored their role in amino acid metabolism, vitellogenesis, lipid transport, signal peptide processing, mosquito immunity, and oxidation-reduction processes. Interestingly, we identified five novel genes, which were found to be differentially expressed upon BM ingestion. Proteins that exhibited altered expression in the present study are potential targets for vector control strategies and development of transmission blocking vaccines in the fight against malaria. PMID- 28873014 TI - Impact of Preanalytical Variations in Blood-Derived Biospecimens on Omics Studies: Toward Precision Biobanking? AB - Research data and outcomes do vary across populations and persons, but this is not always due to experimental or true biological variation. Preanalytical components of experiments, be they biospecimen acquisition, preparation, storage, or transportation to the laboratory, may all contribute to apparent variability in research data, outcomes, and interpretation. The present review article and biobanking innovation analysis offer new insights with a summary of such preanalytical variables, for example, the type of blood collection tube, centrifugation conditions, long-term sample storage temperature, and duration, on output of omics analyses of blood-derived biospecimens: whole blood, serum, plasma, buffy coat, and peripheral blood mononuclear cells. Furthermore, we draw parallels from the field of precision medicine in this study, with a view to the future of "precision biobanking" wherein such preanalytical variations are carefully taken into consideration so as to minimize their influence on outcomes of omics data, analyses, and sensemaking, particularly in clinical omics applications. We underscore the need for using broadly framed, critical, independent, social and political science, and humanities research so as to understand the multiple possible future trajectories of, and the motivations and values embedded in, precision biobanking that is increasingly relevant in the current age of Big Data. PMID- 28873012 TI - Altered virulence of Highly Pathogenic Avian Influenza (HPAI) H5N8 reassortant viruses in mammalian models. AB - Recently identified highly pathogenic avian influenza (HPAI) H5N8 viruses (clade 2.3.4.4) are relatively low to moderately pathogenic in mammalian hosts compared with HPAI H5N1 viruses. In this study, we generated reassortant viruses comprised of A/MD/Korea/W452/2014(H5N8) with substitution of individual genes from A/EM/Korea/W149/2006(H5N1) to understand the contribution of each viral gene to virulence in mammals. Substituting the PB2 gene segment or the NA gene segment of the H5N8 virus by that from the H5N1 virus resulted in significantly enhanced pathogenicity compared with the parental H5N8 virus in mice. Of note, substitution of the PB2 gene segment of the H5N8 virus by that from the H5N1 virus resulted in a 1000-fold increase in virulence for mice compared with the parental virus (MLD50 decreased from 105.8 to 102.5 EID50). Further, the W452W149PB2 virus also induced the highest virus titers in lungs at all time points and the highest levels of inflammatory cytokine responses among all viruses tested. This high virulence phenotype was also confirmed by high viral titers in the respiratory tracts of infected ferrets. Further, a mini-genome assay revealed that W452W149PB2 has significantly increased polymerase activity (p < 0.001). Taken together, our study demonstrates that a single gene substitution from other avian influenza viruses can alter the pathogenicity of recent H5N8 viruses, and therefore emphasizes the need for intensive monitoring of reassortment events among co-circulating avian and mammalian viruses. PMID- 28873013 TI - Involvement of the specific nucleolar protein SURF6 in regulation of proliferation and ribosome biogenesis in mouse NIH/3T3 fibroblasts. AB - The nucleolar proteins which link cell proliferation to ribosome biogenesis are regarded to be potentially oncogenic. Here, in order to examine the involvement of an evolutionary conserved nucleolar protein SURF6/Rrp14 in proliferation and ribosome biogenesis in mammalian cells, we established stably transfected mouse NIH/3T3 fibroblasts capable of conditional overexpression of the protein. Cell proliferation was monitored in real-time, and various cell cycle parameters were quantified based on flow cytometry, Br-dU-labeling and conventional microscopy data. We show that overexpression of SURF6 accelerates cell proliferation and promotes transition through all cell cycle phases. The most prominent SURF6 pro proliferative effects include a significant reduction of the population doubling time, from 19.8 +/- 0.7 to 16.2 +/- 0.5 hours (t-test, p < 0.001), and of the length of cell division cycle, from 17.6 +/- 0.6 to 14.0 +/- 0.4 hours (t-test, p < 0.001). The later was due to the shortening of all cell cycle phases but the length of G1 period was reduced most, from 5.7 +/- 0.4 to 3.8 +/- 0.3 hours, or by ~30%, (t-test, p < 0.05). By Northern blots and qRT-PCR, we further showed that the acceleration of cell proliferation was concomitant with an accumulation of rRNA species along both ribosomal subunit maturation pathways. It is evident, therefore, that like the yeast homologue Rrp14, mammalian SURF6 is involved in various steps of rRNA processing during ribosome biogenesis. We concluded that SURF6 is a novel positive regulator of proliferation and G1/S transition in mammals, implicating that SURF6 is a potential oncogenic protein, which can be further studied as a putative target in anti-cancer therapy. PMID- 28873016 TI - Minimally Invasive Removal of Nonmobile Zygomatic Dental Implants Affected by Peri-Implantitis and Chronic Sinusitis. PMID- 28873015 TI - Periodontal pathogens promote epithelial-mesenchymal transition in oral squamous carcinoma cells in vitro. AB - Epithelial-mesenchymal transition (EMT) is potentially involved in increasing metastasis of oral squamous cell carcinoma (OSCC). Periodontal pathogens are well known for their ability to induce intense immune responses and here we investigated whether they are involved in inducing EMT. Cultures of OSCC cell line (H400) were treated separately with heat-killed periodontal pathogens F. nucleatum, or P. gingivalis or E. coli LPS for 8 d. EMT-associated features were assayed using sq-PCR and PCR-arrays, for EMT-related markers, and ELISAs for TGF beta1, TNF-alpha, and EGF. The migratory ability of cells was investigated using scratch and transwell migration assays. E-cadherin and vimentin expression was assessed using immunofluorescence while Snail activation was detected with immunocytochemistry. In addition, the integrity of the cultured epithelial layer was investigated using transepithelial electrical resistance (TEER). PCR data showed significant upregulation after 1, 5, and 8 d in transcription of mesenchymal markers and downregulation of epithelial ones compared with unstimulated controls, which were confirmed by immunofluorescence. Periodontal pathogens also caused a significant increase in level of all cytokines investigated which could be involved in EMT-induction and Snail activation. Exposure of cells to the bacteria increased migration and the rate of wound closure. Downregulation of epithelial markers also resulted in a significant decrease in impedance resistance of cell monolayers to passage of electrical current. These results suggested that EMT was likely induced in OSCC cells in response to stimulation by periodontal pathogens. PMID- 28873017 TI - Reactive Fibrous Hyperplasia of Peri-implant Mucosa. PMID- 28873018 TI - TIP60 Histone Acetyltransferase in Adipose Tissue: Possible Linkages with Breast Cancer Development? PMID- 28873019 TI - The Effects of In-Hospital Intravenous Cold Saline in Postcardiac Arrest Patients Treated with Targeted Temperature Management. AB - BACKGROUND: Recent data suggest that rapid infusion of intravenous (IV) cold saline for Targeted Temperature Management (TTM) after cardiac arrest is associated with higher rates of rearrest, pulmonary edema, and hypoxia, with no difference in neurologic outcomes or survival when administered by Emergency Medical Services. We sought to determine the effects of IV cold saline administration in the hospital setting in postcardiac arrest patients to achieve TTM and its effect on clinical parameters and neurologic outcomes. METHODS AND RESULTS: A cohort of 132 patients who completed TTM after cardiac arrest in a single institution was retrospectively studied. Patients who did not receive cold saline were matched by age, gender, Glasgow coma scale, downtime, and presenting rhythm to patients who received cold saline. Demographics, cardiac rearrest, diuretic use, time to target temperature, and Cerebral Performance Category (CPC) scores were recorded among other variables. Patients who received cold saline achieved target temperature sooner (280 vs. 345 minutes, p = 0.05), had lower lactate levels on day 1 (4.2 +/- 3.5 mM vs. 6.0 +/- 4.9 mM, p = 0.019) and day 2 (1.3 +/- 2.2 mM vs. 2.2 +/- 3.2 mM, p = 0.046), increased incidence of pulmonary edema (51.5% vs. 31.8%, p = 0.006), and increased diuretic utilization (63.6% vs. 42.4%, p = 0.014). There was no significant difference in cardiac rearrest, arterial oxygenation, and CPC scores (ps > 0.05). CONCLUSIONS: Infusion of IV cold saline is associated with shorter time to target temperature, increased incidence of pulmonary edema, and diuretic use, with no difference in cardiac rearrest, survival, and neurologic outcomes. PMID- 28873020 TI - Assessing the Detection of Middle East Respiratory Syndrome Coronavirus IgG in Suspected and Proven Cases of Middle East Respiratory Syndrome Coronavirus Infection. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory disease with significant mortality. Two testing methods are currently used for MERS-CoV diagnostics: nucleic acid detection (the gold standard) and serological analysis. In this study, we evaluated the detection of MERS-CoV-IgG in suspected and proven cases of MERS-CoV infection. We enrolled 174 patients: 113 had respiratory symptoms/suspected MERS-CoV infection, 31 had confirmed influenza A or B infection, 23 had a recent confirmed MERS-CoV infection, and 7 had confirmed MERS-CoV infection 1 year before. All underwent MERS-CoV RNA and MERS-CoV-IgG testing. Thirty patients were found to be MERS-CoV RNA positive; however, during serological analysis, only 6 (3.4%) patients were positive for MERS-CoV-IgG, 1 (0.6%) patient was equivocal, and 167 (96%) patients were negative. Among the serological positives, four were recently MERS-CoV RNA positive and two were MERS CoV RNA negative. No cross-reactivity to influenza A or B was detected. Based on the lack of correlation between nucleic acid and serological analysis, we conclude that MERS-CoV-IgG testing may not be suitable for diagnosing acute infection or estimating its prevalence during an outbreak. In addition, our findings show that MERS-CoV-IgG may not have significant value in determining disease severity or prognosis. PMID- 28873021 TI - Parameters to Define Peri-Implantitis: A Review and a Proposed Multi-Domain Scale. AB - Peri-implant diseases have received much attention since dental implants are generally used in contemporary dentistry. Several contributing factors associated with the development of peri-implant diseases have also been investigated. The prevalence of peri-implantitis has been reported but with great heterogeneity because of a lack of a universally accepted classification system that could define the extent and severity of peri-implantitis. Several parameters-including radiographic bone loss, probing depth, bleeding on probing, and suppuration-have been introduced in these reports to assist with clinical diagnosis. This article provides an objective evaluation of these parameters based on currently available evidence, offers further recommendations, and proposes a multidomain scale for diagnosis of peri-implantitis. Future investigations and modifications may be needed to develop a comprehensive, evidence-based classification system that addresses the multifactorial etiology of peri-implant diseases. PMID- 28873022 TI - Seroprevalence of Leptospirosis, Brucellosis, and Q Fever in a Wild Red Deer (Cervus elaphus) Population Kept in a Fenced Reserve in Absence of Contact with Livestock. AB - Wildlife health is of interest for public and animal health because wild animals have been identified as important sentinels for the surveillance for zoonotic pathogens. This work investigated Brucella spp., Coxiella burnetii, and Leptospira spp. infection seroprevalence in a free-ranging red deer population. The study was conducted in a fenced reserve with controlled hunting activity in central Spain with animals that did not have any contact with livestock. Sampling was performed at two time points before and 5 years after the implementation of new management measures, including a reduction in the red deer population in the reserve. In addition, the presence of Leptospira DNA was tested in placental and fetal samples from seropositive pregnant animals. Antibodies against Brucella and Coxiella were not detected in any sample. The seroprevalence of Leptospira was 9.4% (13/137) in the first sampling for serovars Canicola and Panama. Five years later, the prevalence rose to 38.5% (97/252) with Pomona, the only serovar detected. Animals older than 2 years (50%; 70/140) were more likely to be Pomona seropositive than animals <=2 years old (25.2%; 27/107; p < 0.001). Leptospira DNA was not detected in any sample tested. In conclusion, wild red deer in this area without contact with livestock seem not to play an important role in Brucella spp. and C. burnetii maintenance. The high seroprevalence of Leptospira spp. serogroup Pomona could indicate a risk for people with narrow contact with these animals, but the carrier status was not assessed. Consequently, it is unknown if red deer would represent a risk for human infection. Considering that wild boar could be the source of infection to red deer, the role of wild boar in the spread of leptospirosis and the risk for human infection should be investigated. PMID- 28873023 TI - Influence of Bisphosphonates on Implant Failure Rates and Characteristics of Postmenopausal Woman Mandibular Jawbone. AB - Rehabilitation of oral function using dental implants is clinically effective and highly predictable. Both bone quantity and quality at the implant site affect the success of the procedure. However, the effect of bisphosphonate (BP) use on mandibular bone quality has not been well documented. The purpose of this retrospective cohort study was to evaluate the bone mineral density (BMD) and cortical thickness of the mandible, as well as the influence of BP use on early implant failure. Twenty-five female patients (>=60 years of age) were selected from among 93 candidates with partially edentulous posterior mandibles. Eleven patients had received BP therapy using alendronate (BP group), and 14 patients had received alternate therapy (non-BP group). Cortical and trabecular BMD was measured using quantitative computed tomography. Cortical thickness was measured using computed tomography. The BMDs and cortical thicknesses of the two groups were compared. The results were as follows: (1) Cortical BMD was significantly higher in the BP group, (2) trabecular BMD was not affected by BP use, and (3) Cortical thickness was affected by the duration of BP use. These results indicate that BP use affects the quality and quantity of the cortical bone in the partially edentulous posterior mandible of patients with osteoporosis, which should be considered prior to treatment with dental implants in patients taking BPs. PMID- 28873024 TI - Serological Survey of Zoonotic Viruses in Invasive and Native Commensal Rodents in Senegal, West Africa. AB - Increasing studies on rodent-borne diseases still highlight the major role of rodents as reservoirs of numerous zoonoses of which the frequency is likely to increase worldwide as a result of accelerated anthropogenic changes, including biological invasions. Such a situation makes pathogen detection in rodent populations important, especially in the context of developing countries characterized by high infectious disease burden. Here, we used indirect fluorescent antibody tests to describe the circulation of potentially zoonotic viruses in both invasive (Mus musculus domesticus and Rattus rattus) and native (Mastomys erythroleucus and Mastomys natalensis) murine rodent populations in Senegal (West Africa). Of the 672 rodents tested, we reported 22 seropositive tests for Hantavirus, Orthopoxvirus, and Mammarenavirus genera, and no evidence of viral coinfection. This study is the first to report serological detection of Orthopoxvirus in rodents from Senegal, Mammarenavirus in R. rattus from Africa, and Hantavirus in M. m. domesticus and in M. erythroleucus. Further specific identification of the viral agents highlighted here is urgently needed for crucial public health concerns. PMID- 28873025 TI - Analysis of head impacts during sub-elite hurling practice sessions. AB - The reported incidence of head and neck injuries in hurling is 0.12 per 1000 hours, but no previous research has quantified head impact characteristics in this sport. Here, a wireless accelerometer and gyroscope captured head impacts, in 20 senior club level hurling players. Peak linear and rotational acceleration and impact location were recorded during three hurling training sessions, each player participating once. A mean of 27.9 impacts (linear acceleration >10g) per player, per session were recorded; 1314 impacts during a total exposure time of 247 minutes. Only 2.6% impacts had peak linear acceleration of >70g and 6.2% had peak rotational acceleration >7900 rad/s2. There were significant differences in the number and magnitude of impacts, quantified by the accelerometer, between three training sessions of differing intensity (n2 0.03-0.09, p < 0.001). This study represents a first step in quantifying head impacts during hurling, demonstrating the feasibility of this technology in the field. The sensors were able to discriminate between sessions of varying intensity. These data can be used to develop athlete monitoring protocols and may be useful in developing innovative helmet-testing standards for hurling. The potential for this technology to provide feedback has clinical utility for team medical personnel. PMID- 28873026 TI - Impact of Ionizing Radiation on the Cardiovascular System: A Review. AB - Radiation therapy has become one of the main forms of treatment for various types of cancers. Cancer patients previously treated with high doses of radiation are at a greater risk to develop cardiovascular complications later in life. The heart can receive varying doses of radiation depending on the type of therapy and can even reach doses in the range of 17 Gy. Multiple studies have highlighted the role of oxidative stress and inflammation in radiation-induced cardiovascular damage. Doses of ionizing radiation below 200 mGy, however, have been shown to have beneficial effects in some experimental models of radiation-induced damage, but low-dose effects in the heart is still debated. Low-dose radiation may promote heart health and reduce damage from oxidative stress and inflammation, however there are few studies focusing on the impact of low-dose radiation on the heart. In this review, we summarize recent studies from animal models and human data focusing on the effects and mechanism(s) of action of radiation-induced damage to the heart, as well as the effects of high and low doses of radiation and dose rates. PMID- 28873027 TI - The CGL1 (HeLa * Normal Skin Fibroblast) Human Hybrid Cell Line: A History of Ionizing Radiation Induced Effects on Neoplastic Transformation and Novel Future Directions in SNOLAB. AB - Cellular transformation assays have been utilized for many years as powerful in vitro methods for examining neoplastic transformation potential/frequency and mechanisms of carcinogenesis for both chemical and radiological carcinogens. These mouse and human cell based assays are labor intensive but do provide quantitative information on the numbers of neoplastically transformed foci produced after carcinogenic exposure and potential molecular mechanisms involved. Several mouse and human cell systems have been generated to undertake these studies, and they vary in experimental length and endpoint assessment. The CGL1 human cell hybrid neoplastic model is a non-tumorigenic pre-neoplastic cell that was derived from the fusion of HeLa cervical cancer cells and a normal human skin fibroblast. It has been utilized for the several decades to study the carcinogenic/neoplastic transformation potential of a variety of ionizing radiation doses, dose rates and radiation types, including UV, X ray, gamma ray, neutrons, protons and alpha particles. It is unique in that the CGL1 assay has a relatively short assay time of 18-21 days, and rather than relying on morphological endpoints to detect neoplastic transformation utilizes a simple staining method that detects the tumorigenic marker alkaline phosphatase on the neoplastically transformed cells cell surface. In addition to being of human origin, the CGL1 assay is able to detect and quantify the carcinogenic potential of very low doses of ionizing radiation (in the mGy range), and utilizes a neoplastic endpoint (re-expression of alkaline phosphatase) that can be detected on both viable and paraformaldehyde fixed cells. In this article, we review the history of the CGL1 neoplastic transformation model system from its initial development through the wide variety of studies examining the effects of all types of ionizing radiation on neoplastic transformation. In addition, we discuss the potential of the CGL1 model system to investigate the effects of near zero background radiation levels available within the radiation biology lab we have established in SNOLAB. PMID- 28873028 TI - Randomized Prospective Evaluation of Intraoperative Intravenous Acetaminophen in Pediatric Adenotonsillectomy. AB - Objective To establish the safety and efficacy of single-dose intraoperative intravenous (IV) acetaminophen in postoperative pain management following adenotonsillectomy in addition to a standardized regimen of oral pain medication. Study Design Randomized, controlled prospective clinical trial. Setting Single academic medical center. Subjects and Methods Patients between the ages of 3 and 17 years scheduled for tonsillectomy or adenotonsillectomy by a single surgeon between December 2014 and November 2016 were recruited. Patients were randomly assigned to 1 of 2 groups; group 1 received a single intraoperative dose of IV acetaminophen, and group 2 did not. Induction and maintenance of anesthesia, as well as operative technique, were standardized. Nursing pain scores, pain medications administered, and recovery times were reviewed during the 24-hour postoperative period. Postoperative pain regimen included standing alternating oral acetaminophen and ibuprofen. Results In total, 260 patients were included in the study, and 131 (50.4%) received a single intraoperative dose of IV acetaminophen. Patients receiving IV acetaminophen were more likely to experience postoperative nausea and vomiting than patients who did not receive IV acetaminophen (1.53% vs 0.00%, P = .016). There were no significant differences noted for postoperative pain scores, requirements for breakthrough pain medications, time to discharge from the recovery room or hospital, or postoperative complications. Conclusion The use of a single intraoperative dose of IV acetaminophen was associated with minimal additional adverse effects. However, a single intraoperative IV dose of acetaminophen added to standard narcotic and nonnarcotic pain medication does not provide a statistically significant improvement in pain control. PMID- 28873029 TI - CYP450 Genotype/Phenotype Concordance in Mexican Amerindian Indigenous Populations-Where to from Here for Global Precision Medicine? AB - Global precision medicine demands characterization of drug metabolism and phenotype variation in diverse populations, including the indigenous societies. A related question is the extent to which CYP450 drug metabolizing enzyme genotype and phenotype data are concordant and whether they can be used interchangeably. These issues are increasingly debated as precision medicine continues to expand as a popular research topic worldwide. We report here the first study in clinically relevant CYP450 drug metabolism phenotypes and genotypes in Mexican Amerindian indigenous subjects. In a large sample of 450 unrelated and medication free Mexican Amerindian indigenous healthy persons from four Mexican states (Chihuahua, Durango, Nayarit, and Sonora), we performed multiplexed phenotyping for the CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 drug metabolizing enzymes using the CEIBA cocktail and genotyped the same pathways for functional polymorphic variation. Remarkable interindividual variability was found for the actual drug metabolizing capacity of all the enzymes analyzed, and, more specifically, the metabolic ratios calculated were significantly different across individuals with different number of active alleles for CYP2C9, CYP2C19, and CYP2D6. The drug metabolizing capacity "predicted" from the genotype determined was not in accordance with the actual capacity "measured" by phenotyping in several individuals for CYP2C9, CYP2C19, and CYP2D6. Consequently, a more extensive genotyping of the main CYP enzymes, including rare variants, together with the analysis of the actual drug metabolizing capacity using an appropriate phenotyping approach will add valuable information for accurate drug metabolism studies, especially useful in understudied populations such as Mexican Amerindians. In sum, this study demonstrates that current personalized medicine strategies based on "predicted" phenotype from genotyping of alleles with high frequency in European populations are not adequate for Mestizos and Native American populations. PMID- 28873030 TI - Differences in hamstring activation characteristics between the acceleration and maximum-speed phases of sprinting. AB - This study aimed to investigate activation characteristics of the biceps femoris long head (BFlh) and semitendinosus (ST) muscles during the acceleration and maximum-speed phases of sprinting. Lower-extremity kinematics and electromyographic (EMG) activities of the BFlh and ST muscles were examined during the acceleration sprint and maximum-speed sprint in 13 male sprinters during an overground sprinting. Differences in hamstring activation during each divided phases and in the hip and knee joint angles and torques at each time point of the sprinting gait cycle were determined between two sprints. During the early stance of the acceleration sprint, the hip extension torque was significantly greater than during the maximum-speed sprint, and the relative EMG activation of the BFlh muscle was significantly higher than that of the ST muscle. During the late stance and terminal mid-swing of maximum-speed sprint, the knee was more extended and a higher knee flexion moment was observed compared to the acceleration sprint, and the ST muscle showed higher activation than that of the BFlh. These results indicate that the functional demands of the medial and lateral hamstring muscles differ between two different sprint performances. PMID- 28873033 TI - Corrigendum. AB - Zhu J, Lu T, Chen F, et al. Choline protects against intestinal failure associated liver disease in parenteral nutrition-fed immature rats [published online November 17, 2016]. JPEN J Parenter Enteral Nutr. (Original DOI: 10.1177/0148607116677048 ). PMID- 28873031 TI - Surgical Treatment for Early Stage Glottic Carcinoma with Involvement of the Anterior Commissure. AB - Objective Assessment of the value of transoral laser microsurgery (TLM) compared with open surgery (OS) for early stage squamous cell carcinoma of the glottic larynx with special regard to involvement of the anterior commissure (AC). Study Design Case series with chart review. Setting Tertiary care otolaryngology clinic. Subjects and Methods Review of clinicopathological data of all patients with previously untreated T1a, T1b, and T2 glottic squamous cell carcinoma of the larynx who were consecutively enrolled over a 10-year period (January 1, 1992, to December 31, 2002). Results Local recurrence rate was 20.4% (10 of 49) for TLM and 10.7% (3 of 28) for OS. Comparison of the TLM and OS groups regarding local recurrence rates revealed a significant difference only for tumors invading the AC ( P = .046). Within the TLM group, tumors with involvement of the AC showed a significantly higher recurrence rate (38.1%; 8 of 21) compared with tumors without involvement of the AC (7.1%; 2 of 28; P = .008). In the OS group, involvement of the AC revealed no significant difference ( P = .45). The overall survival in both groups was comparable in both groups (TLM, 93.9%; OS, 89.3%; P = .47). Conclusion TLM and OS are equally effective surgical treatments for early stage glottic cancer without involvement of the AC, with selection of treatment based on pretreatment endoscopy. However, TLM is associated with less morbidity. In case of invasion of the AC, OS yields lower recurrence rates. PMID- 28873034 TI - The Absence of HCV RNA and NS5A Protein in Peripheral Blood Mononuclear Cells Is a Prognostic Tool for Sustained Virological Response. AB - Hepatitis C Virus (HCV) infection is a major health concern worldwide. The presence of both HCV viral RNA and NS5A proteins in peripheral blood mononuclear cells (PBMCs) indicate the efficacy of the treatment during sustained virological response (SVR) and end of treatment response (ETR). The main objective of this study was to detect the absence or presence of HCV RNA and NS5A proteins in PBMCs. Blood samples were taken from selected patients (Islamabad, Pakistan) before treatment, at ETR, and during SVR. Two hundred HCV responders to pegylated IFN-alpha-2a plus ribavirin were selected. HCV RNA was extracted from the patients to determine the viral load by reverse transcription (RT)-polymerase chain reaction before treatment. Out of 200 patients, 152 (76%) and 48 (24%) achieved positive and negative ETR, respectively. Among ETR patients, 134 (88.2%) showed SVR, whereas 18 (11.8%) displayed relapse. The male to female ratio was 92:108 with mean age of 37.4 years. Among 152 ETR-positive patients, 29 (19%) patients' PBMCs were positive for HCV RNA and 27 (17.8%) were positive for NS55A proteins. Patients having HCV RNA in PBMCs showed higher relapse frequency compared with patients lacking it. Similarly, patients having NS5A protein showed significantly higher relapse frequency compared with patients lacking it. All PBMC-positive samples were of genotype 3a. In addition, patients with positive NS5A in their PBMCs showed greater risk of relapse compared with patients having HCV RNA. We conclude that the absence of both viral HCV and proteins can be used as an indicator for diagnosis of SVR in the future. PMID- 28873035 TI - Potential Reservoir and Associated Factors for West Nile Virus in Three Distinct Climatological Zones. AB - West Nile virus (WNV) is a zoonotic single-strand RNA arbovirus (family Flaviviridae: Flavivirus), transmitted among avian hosts in enzootic cycles by a mosquito vector. The virus has a significant disease effect on humans and equines when it bridges into a cycle with various sequelae with epidemic potential. This study was carried out to identify the potential spectrum of WNV hosts in three geographic areas with climatologically distinct features: Malaysia, Qatar, and the United States of America (U.S.). Serum samples were collected from avian and mammal species suspected to be reservoirs for the virus at these areas in a cross sectional epidemiologic study. The samples were tested for the presence of antibodies against the virus using an enzyme-linked immunosorbent assay. Data on putative risk factors were also collected and analyzed for significance of association with seropositivity using the logistic regression analysis. Among the tested avian and mammalian species, raccoons had the highest seroconversion rate (54%) followed by crows (30%), horses (27%), camels (10%), other avian species (7%), and canine species (3%). It was almost twice as likely to detect seroconversion among these mammalian and avian species in the fall in comparison to other seasons of the year. Only mammalian and avian species and seasons of the year were significantly associated with the likelihood of seroconversion to WNV when we controlled for other factors in the multivariate analysis. Our data from the U.S. showed that raccoons and camels are susceptible to infection by the virus and may play a role in the perpetuation of endemic foci for the disease. PMID- 28873036 TI - The Effect of Action Observation Training on Balance and Sit to Walk in Chronic Stroke: A Crossover Randomized Controlled Trial. AB - The aim of this study was to investigate the effects of an action observation training on balance and sit to walk in chronic stroke. Twenty-four chronic stroke patients participated in this study. Participants were randomly allocated to either the landscape imagery observation physical training group (LIOPT) or the action observation physical training group (AOPT). LIOPT observed a landscape picture for 2 min 30 s while the AOPT group observed related video recording. Both groups underwent a physical training session after the observation session for 12 min 30 s and the sessions were repeated twice a day, 3 times a week for 6 weeks. Outcome measures included Time Up and Go Test (TUG), Dynamic Gait Index (DGI), Weight Distribution Index (WDI), and limit of stability (LOS). Between group and within-group comparisons were analyzed using the Mann-Whitney U test and Wilcoxon signed rank test, respectively. The AOPT and LIOPT groups have shown statistically significant differences in TUG, DGI, WDI, and LOS over time. However, no significant difference was observed in terms of TUG, DGI and WDI, but only in LOS between groups. These findings suggest that action observation training and physical training are effective to improve sit to walk and balance ability of chronic stroke patients. PMID- 28873037 TI - Breeding Zebrafish: A Review of Different Methods and a Discussion on Standardization. AB - In recent years, a rapidly increasing number of scientific papers have been published that utilize zebrafish (Danio rerio) as an alternative model organism in the study of a wide range of biological phenomena from cancer to behavior. This is, in large part, due to the prolific nature, relative ease of maintenance, and sufficiently high genetic homology of zebrafish to humans. With the surge of zebrafish use in animal research, the variations in methodologies of breeding and husbandry of this species have also increased. Investigators usually focus on the development and implementation of rigorous laboratory control that is specific to their studies. We suggest that the same scrutiny and attention may be required for the methods of breeding and housing of zebrafish. This article reviews a variety of zebrafish husbandry and breeding techniques and conditions employed around the world. It discusses factors ranging from numerous aspects of rearing/housing conditions through the sex ratio of the breeding group to the composition of the diet of zebrafish that may vary across laboratories. It provides some feedback on the potential pros and cons of the different methods. It argues that there is a substantial need for systematic analysis of these methods, that is, the effects of environmental factors on zebrafish health and breeding. It also discusses the question as to whether some degree of standardization of these methods is needed to enhance cross-laboratory comparability of results. PMID- 28873040 TI - The Ways Women Age: Using and Refusing Cosmetic Intervention. PMID- 28873039 TI - Especial Skills in Experienced Archers. AB - Especial skills are skills that are distinctive by virtue of massive practice within the narrow contexts in which they are expressed. In the first demonstration of especial skills, Keetch, Schmidt, Lee, and Young (2005) showed that experienced basketball players are better at shooting baskets from the foul line, where they had massive amounts of practice, than would expected from their success at other locations closer to or farther from the basket. Similar results were obtained for baseball throwing. The authors asked whether especial skills hold in archery, a sport requiring less movement. If the emergence of especial skills depends on large-scale movement, one would expect archery to escape so called especialism. But if the emergence of especial skills reflects a more general tendency for highly specific learning, experienced archers should show especial skills. The authors obtained evidence consistent with the latter prediction. The expert archers did much better at their most highly practiced distance than would be expected by looking at the overall function relating shooting score to distance. We offer a mathematical model to account for this result. The findings attest to the generality of the especial skills phenomenon. PMID- 28873041 TI - "Booster Days": An educational initiative to develop a community of practice of primary care collaborative memory clinics. AB - This study explores the value of a Booster Day education initiative for clinicians working in interprofessional Primary Care Collaborative Memory Clinics (PCCMC) to share updates in dementia care, challenging cases, key lessons learned, and best practices, as a mechanism to foster learning and support the PCCMC Community of Practice (CoP). Between 2010 and 2016, 17 annual Booster Days were delivered to health professionals who completed the PCCMC training program. All participants were invited to complete an evaluation survey in which they identified the ways in which the sessions have been helpful; 89% (1361/1530) completed surveys. The Booster Days were valued as opportunities for networking to learn from other clinicians, fostering a sense of community, learning new information, learning to support practice improvements, and team building. An annual Booster Day that incorporates active participant engagement, information sharing, and networking may effectively support CoPs, learning, team building, and practice change within interprofessional teams. PMID- 28873038 TI - Autophagy-mediated regulation of phytohormone metabolism during rice anther development. AB - Autophagy has recently been shown to be required for postmeiotic anther development including anther dehiscence, programmed cell death-mediated degradation of the tapetum and pollen maturation in rice. Several phytohormones are known to play essential roles during male reproductive development including pollen maturation. However, the relationship between phytohormone metabolism and autophagy in plant reproductive development is unknown. We here comprehensively analyzed the effect of autophagy disruption on phytohormone contents in rice anthers at the flowering stage, and found that endogenous levels of active-forms of gibberellins (GAs) and cytokinin, trans-zeatin, were significantly lower in the autophagy-defective mutant, Osatg7-1, than in the wild type. Treatment with GA4 partially recovered maturation of the mutant pollens, but did not recover the limited anther dehiscence as well as sterility phenotype. These results suggest that autophagy affects metabolism and endogenous levels of GAs and cytokinin in rice anthers. Reduction in bioactive GAs in the autophagy-deficient mutant may partially explain the defects in pollen maturation of the autophagy-deficient mutant, but tapetal autophagy also plays other specific roles in fertilization. PMID- 28873042 TI - Too many Asians in universities? The effect of social dominance orientation on support for admissions limits. AB - This paper tests the hypothesis that support for limits on the admission of Asian students into universities is motivated by people's social motivation-namely, the desire to maintain the status hierarchy. Study 1 found that, among participants who evaluated a proposed limit to the number of Asian applicants admitted to universities, social dominance orientation (SDO) was positively related to policy support. Conversely, among participants who evaluated a proposed limit on White admits, SDO was negatively related to policy support. Study 2 found that the perceived threat of the group getting admitted at high rates explained differential support of policies that seek to limit group-specific admissions. In all, these findings suggest that attitudes toward changes in campus demographics may be rooted in a desire to maintain the status hierarchy. PMID- 28873043 TI - Recovering Process from Child Sexual Abuse During Adulthood from an Integrative Approach to Solution-Focused Therapy: A Case Study. AB - In recent times, strengths-based recovery approaches that focus on the present and build strategies that look toward the future have become popular. However, some cases require the consideration of experiences from previous stages of the clients' development. This single-case study explores the psychotherapeutic process of a middle-aged woman who presented with a history of child sexual abuse (incest) and a long-term adult diagnosis of depression that was treated in public health services. This psychotherapy involved an integrative approach to solution focused therapy; specifically, the approach proposed by Yvonne Dolan to work with adult survivors of sexual abuse, in conjunction with techniques and strategies from the transtheoretical model. Measures incorporating therapeutic working alliance and outcomes were administered over sessions. Results showed positive outcomes from this therapeutic intervention, which remained at 3-month and 12 month follow-ups. Implications for practitioners' specialist practice in health services are discussed, given the complexity of comorbid mental health conditions with a history of child sexual abuse. PMID- 28873044 TI - Loaded hip thrust-based PAP protocol effects on acceleration and sprint performance of handball players. AB - This study aimed to investigate the acute effects of two barbell hip thrust-based (BHT) post-activation potentiation (PAP) protocols on subsequent sprint performance. Using a crossover design, eighteen handball athletes performed maximal 15-m sprints before and 15s, 4min and 8min after two experimental protocols consisting of BHT loaded with either 50% or 85% 1RM (50PAP and 85PAP, respectively), in order to profile the transient PAP effects. The resulting sprint performances were significantly impaired at 15s only after the 85PAP protocol, which induced likely and very likely greater decreases compared to the 50PAP. At 4min and 8min, significant improvements and very likely beneficial effects were observed in the 10m and 15m performances following both protocols. Significant differences were found when comparing the two PAPs over time; the results suggested very likely greater performance improvements in 10m following the 85PAP after 4min and 8min, and possible greater performance improvements in 15m after 4min. Positive correlations between BHT 1RMs values and the greatest individual PAP responses on sprint performance were found. This investigation showed that both moderate and intensive BHT exercises can induce a PAP response, but the effects may differ according to the recovery following the potentiating stimulus and the individual's strength level. PMID- 28873045 TI - Gadolinium Chelate Safety in Pregnancy: Barely Detectable Gadolinium Levels in the Juvenile Nonhuman Primate after in Utero Exposure. AB - Purpose To determine whether gadolinium remains in juvenile nonhuman primate tissue after maternal exposure to intravenous gadoteridol during pregnancy. Materials and Methods Gravid rhesus macaques and their offspring (n = 10) were maintained, as approved by the institutional animal care and utilization committee. They were prospectively studied as part of a pre-existing ongoing research protocol to evaluate the effects of maternal malnutrition on placental and fetal development. On gestational days 85 and 135, they underwent placental magnetic resonance imaging after intravenous gadoteridol administration. Amniocentesis was performed on day 135 prior to administration of the second dose of gadoteridol. After delivery, the offspring were followed for 7 months. Tissue samples from eight different organs and from blood were harvested from each juvenile macaque. Gadolinium levels were measured by using inductively coupled plasma mass spectrometry. Results Gadolinium concentration in the amniotic fluid was 0.028 * 10-5 %ID/g (percentage injected dose per gram of tissue) 50 days after administration of one gadoteridol dose. Gadolinium was most consistently detected in the femur (mean, 2.5 * 10-5 %ID/g; range, [0.81-4.1] * 10-5 %ID/g) and liver (mean, 0.15 * 10-5 %ID/g; range, [0-0.26] * 10-5 %ID/g). Levels were undetectable in the remaining sampled tissues, with the exception of one juvenile skin sample (0.07 * 10-5 %ID/g), one juvenile spleen sample (0.039 * 10-5 %ID/g), and one juvenile brain (0.095 * 10-5 %ID/g) and kidney (0.13 * 10-5 %ID/g) sample. Conclusion The presence of gadoteridol in the amniotic fluid after maternal injection enables confirmation that it crosses the placenta. Extremely low levels of gadolinium are found in juvenile macaque tissues after in utero exposure to two doses of gadoteridol, indicating that a very small amount of gadolinium persists after delivery. (c) RSNA, 2017. PMID- 28873047 TI - Gadolinium Retention in the Rat Brain: Assessment of the Amounts of Insoluble Gadolinium-containing Species and Intact Gadolinium Complexes after Repeated Administration of Gadolinium-based Contrast Agents. AB - Purpose To evaluate the speciation of gadolinium-containing species after multiple administrations of the gadolinium-based contrast agents (GBCAs) gadodiamide and gadoteridol and to quantify the amount of intact gadolinium complexes and insoluble gadolinium-containing species. Materials and Methods A total dose of 13.2 mmol per kilogram of body weight of each GBCA was administered in healthy Wistar rats over a period of 8 weeks. Three days after the final administration, rats were sacrificed, and the brains were excised and divided into three portions. Each portion of brain homogenate was divided into two parts, one for determination of the total gadolinium concentration with inductively coupled plasma mass spectrometry and one for determination of the amount of intact GBCA and gadolinium-containing insoluble species. Relaxometric measurements of gadodiamide and gadolinium trichloride in the presence of polysialic acid were also performed. Results The mean total gadolinium concentrations for gadodiamide and gadoteridol, respectively, were 0.317 MUg/g +/ 0.060 (standard deviation) and 0.048 MUg/g +/- 0.004 in the cortex, 0.418 MUg/g +/- 0.078 and 0.051 MUg/g +/- 0.009 in the subcortical brain, and 0.781 MUg/g +/- 0.079 and 0.061 MUg/g +/- 0.012 in the cerebellum. Gadoteridol comprised 100% of the gadolinium species found in rats treated with gadoteridol. In rats treated with gadodiamide, the largest part of gadolinium retained in brain tissue was insoluble species. In the cerebellum, the amount of intact gadodiamide accounts for 18.2% +/- 10.6 of the total gadolinium found therein. The mass balance found for gadolinium implies the occurrence of other soluble gadolinium-containing species (approximately 30%). The relaxivity of the gadolinium polysialic acid species formed in vitro was 97.8 mM/sec at 1.5 T and 298 K. Conclusion Gadoteridol was far less retained, and the entire detected gadolinium was intact soluble GBCA, while gadodiamide yielded both soluble and insoluble gadolinium containing species, with insoluble species dominating. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28873046 TI - Functional Brain Connectome and Its Relation to Hoehn and Yahr Stage in Parkinson Disease. AB - Purpose To use resting-state functional magnetic resonance (MR) imaging and graph theory approaches to investigate the brain functional connectome and its potential relation to disease severity in Parkinson disease (PD). Materials and Methods This case-control study was approved by the local research ethics committee, and all participants provided informed consent. There were 153 right handed patients with PD and 81 healthy control participants recruited who were matched for age, sex, and handedness to undergo a 3-T resting-state functional MR examination. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 90 brain regions, and the topologic properties were analyzed by using graph theory approaches. Nonparametric permutation tests were used to compare topologic properties, and their relationship to disease severity was assessed. Results The functional connectome in PD showed abnormalities at the global level (ie, decrease in clustering coefficient, global efficiency, and local efficiency, and increase in characteristic path length) and at the nodal level (decreased nodal centralities in the sensorimotor cortex, default mode, and temporal-occipital regions; P < .001, false discovery rate corrected). Further, the nodal centralities in left postcentral gyrus and left superior temporal gyrus correlated negatively with Unified Parkinson's Disease Rating Scale III score (P = .038, false discovery rate corrected, r = -0.198; and P = .009, false discovery rate corrected, r = 0.270, respectively) and decreased with increasing Hoehn and Yahr stage in patients with PD. Conclusion The configurations of brain functional connectome in patients with PD were perturbed and correlated with disease severity, notably with those responsible for motor functions. These results provide topologic insights into understanding the neural functional changes in relation to disease severity of PD. (c) RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on September 11, 2017. PMID- 28873048 TI - Gene Ontology-Based Analysis of Zebrafish Omics Data Using the Web Tool Comparative Gene Ontology. AB - Gene Ontology (GO) analysis is a powerful tool in systems biology, which uses a defined nomenclature to annotate genes/proteins within three categories: "Molecular Function," "Biological Process," and "Cellular Component." GO analysis can assist in revealing functional mechanisms underlying observed patterns in transcriptomic, genomic, and proteomic data. The already extensive and increasing use of zebrafish for modeling genetic and other diseases highlights the need to develop a GO analytical tool for this organism. The web tool Comparative GO was originally developed for GO analysis of bacterial data in 2013 ( www.comparativego.com ). We have now upgraded and elaborated this web tool for analysis of zebrafish genetic data using GOs and annotations from the Gene Ontology Consortium. PMID- 28873049 TI - Biomarkers of antioxidant status and lipid peroxidation in elderly patients with hypertension. AB - OBJECTIVE: The objective of the present study was to examine selected parameters of the blood redox system in elderly patients with hypertension.examine selected parameters of the blood redox system in elderly patients with hypertension. METHODS: We analyzed differences in redox-associated molecules and enzymes among elderly hypertensive subjects (age above 65 years, n = 49) and two groups of normotensive subjects (<65 years old - Control group I; n = 27, and >65 - Control group II; n = 30). RESULTS: Decreased activity of antioxidant enzymes, increased lipid peroxidation and reduced production of nitric oxide were observed in hypertensive subjects, compared to healthy younger controls, or those of the same age. In healthy controls, an age-related decrease in the production of nitric oxide and the activities of SOD-1 and GPx-1 was also evident. The pathology of hypertension was characterised by further, significant decreases in the values of these parameters. When the subgroups of females and males were compared to their respective controls, a compromised redox balance was observed that was more evident in female hypertensives. DISCUSSION: Hypertension in elderly patients is accompanied by changes in biomarkers of antioxidant status and lipid peroxidation status, which significantly differ from those observed in healthy ageing subjects. Our study also suggests that the relationship of gender and changes in redox balance with regard to hypertension should be further explored. PMID- 28873051 TI - Mental Health of Transgender People in Hong Kong: A Community-Driven, Large-Scale Quantitative Study Documenting Demographics and Correlates of Quality of Life and Suicidality. AB - A community-driven survey of 106 transgender people (the first such survey in Hong Kong) showed that: (1) more than half the sample (50.9%) had a university degree or higher qualification; (2) despite this, 43.4% had a monthly income below HK$6,000 (about USD$775); (3) 66% reported "fair" or "poor" quality of life; (4) 67% of the sample (87.1% of respondents aged 15-24 years) had contemplated suicide; and (5) 20.8% of the sample (35.5% of respondents aged 15 24 years) had attempted suicide. It was found that (1) those who were single, had a lower monthly income, and identified as transgender women reported lower quality of life; and (2) those who were younger and on a lower income expressed higher suicidality. The findings suggest that service providers and policy makers urgently need to address the mental health needs of transgender people, particular younger transgender people. PMID- 28873050 TI - Randomized pilot trial measuring knowledge acquisition of opioid education in emergency department patients using a novel media platform. AB - BACKGROUND: The number of active opioid analgesic prescriptions has risen steadily, causing increases in nonmedical opioid use, addiction, and overdose. Insufficient focus on patient discharge instructions has contributed to lack of patient awareness regarding dangers of opioids. This study examines whether an educational Khan Academy-style animation discharge instruction on the dangers and safe usage of opioid analgesics elicits higher knowledge acquisition than current standard of care. Additionally, it measures the feasibility of implementing this video discharge instruction in the emergency department (ED). METHODS: Fifty-two English-speaking patients aged 18 years or older receiving an opioid prescription were enrolled in this study. Patients were randomized into 2 groups. The standard of care group received verbal instruction and an informational sheet, whereas the video animation group received a 6-minute video on proper usage of opioids in addition to standard of care. Video content was sourced from samhsa.gov and administered within the ED prior to discharge. Both groups received a 26-question test regarding the dangers and safe usage of opioids immediately after education. An unpaired t test compared knowledge acquisition between the 2 groups. RESULTS: Fifty-four patients were approached, 52 patients enrolled; 27 in the standard group and 25 in the animation group. The standard of care group averaged 65% knowledge acquisition (16.8/26 correct), whereas the animation group averaged 82% acquisition (21.2/26 correct). The video animation significantly increased patient knowledge acquisition about opioid medications' risks and proper usage and disposal (P = .001). CONCLUSION: It can be concluded that medical knowledge acquisition is improved in the video animation group compared with the current standard of care (P = .001). It can also be concluded that it is feasible to implement a novel media platform to educate patients receiving opioid analgesics in the ED (96.1%). PMID- 28873052 TI - The Importance of Holding Water: Salinity and Chemosensory Cues Affect Zebrafish Behavior. AB - The zebrafish is becoming a popular model organism for studying numerous biological phenomena. Among these are brain function and behavior, including social behavior. Although usually neglected, few studies have already demonstrated that even trivial factors, such as features of the holding water may alter zebrafish behavior. In this study, we employed a 2 * 2 between-subject experimental design, exposing zebrafish to water of either high or low salinity and with chemosensory/olfactory cues of conspecifics either present or absent (while maintaining pH, temperature, nitrate, nitrite, and ammonia levels constant). We presented moving images of conspecifics to experimental zebrafish and analyzed their behavioral responses using video tracking. We found significant interaction between salinity and olfactory cues. For example, zebrafish exposed to their home tank water (high salinity with chemosensory/olfactory cues present) stayed significantly closer to the bottom of their tank compared with fish exposed to the other water conditions, and fish exposed to water with chemosensory/olfactory cues significantly reduced their turns compared with fish exposed to water without chemosensory/olfactory cues. These differences signify the impact environmental factors, for example, fluctuations in salinity level and presence or absence of chemosensory/olfactory cues, may have on zebrafish behavior. We conclude that maintaining stable environmental conditions and specifying and reporting them precisely are important for reducing error variation and for making results across independent studies more comparable. PMID- 28873054 TI - The readability of scientific texts is decreasing over time. AB - Clarity and accuracy of reporting are fundamental to the scientific process. Readability formulas can estimate how difficult a text is to read. Here, in a corpus consisting of 709,577 abstracts published between 1881 and 2015 from 123 scientific journals, we show that the readability of science is steadily decreasing. Our analyses show that this trend is indicative of a growing use of general scientific jargon. These results are concerning for scientists and for the wider public, as they impact both the reproducibility and accessibility of research findings. PMID- 28873055 TI - SAW Synthesis With IDTs Array and the Inverse Filter: Toward a Versatile SAW Toolbox for Microfluidics and Biological Applications. AB - Surface acoustic waves (SAWs) are versatile tools to manipulate fluids at small scales for microfluidics and biological applications. A nonexhaustive list of operations that can be performed with SAW includes sessile droplet displacement, atomization, division, and merging but also the actuation of fluids embedded in microchannels or the manipulation of suspended particles. However, each of these operations requires a specific design of the wave generation system, the so called interdigitated transducers (IDTs). Depending on the application, it might indeed be necessary to generate focused or plane, propagating or standing, and aligned or shifted waves. Furthermore, the possibilities offered by more complex wave fields such as acoustical vortices for particle tweezing and liquid twisting cannot be explored with classical IDTs. In this paper, we show that the inverse filter technique coupled with an IDTs array enables us to synthesize all classical wave fields used in microfluidics and biological applications with a single multifunctional platform. It also enables us to generate swirling SAWs, whose potential for the on-chip synthesis of tailored acoustical vortices has been demonstrated lately. The possibilities offered by this platform are illustrated by performing many operations successively on sessile droplets with the same system. PMID- 28873053 TI - C. elegans avoids toxin-producing Streptomyces using a seven transmembrane domain chemosensory receptor. AB - Predators and prey co-evolve, each maximizing their own fitness, but the effects of predator-prey interactions on cellular and molecular machinery are poorly understood. Here, we study this process using the predator Caenorhabditis elegans and the bacterial prey Streptomyces, which have evolved a powerful defense: the production of nematicides. We demonstrate that upon exposure to Streptomyces at their head or tail, nematodes display an escape response that is mediated by bacterially produced cues. Avoidance requires a predicted G-protein-coupled receptor, SRB-6, which is expressed in five types of amphid and phasmid chemosensory neurons. We establish that species of Streptomyces secrete dodecanoic acid, which is sensed by SRB-6. This behavioral adaptation represents an important strategy for the nematode, which utilizes specialized sensory organs and a chemoreceptor that is tuned to recognize the bacteria. These findings provide a window into the molecules and organs used in the coevolutionary arms race between predator and potential prey. PMID- 28873056 TI - Foreground Detection With Simultaneous Dictionary Learning and Historical Pixel Maintenance. AB - Foreground detection is fundamental in surveillance video analysis and meaningful toward object tracking and higher level tasks, such as anomaly detection and activity analysis. Nevertheless, existing methods are still limited in accurately detecting the foreground due to the complex scene settings. To robustly handle the diverse background variations and foreground challenges, this paper proposes a Background REpresentation approach With Dictionary Learning and Historical Pixel Maintenance (BREW-DLHPM). Specifically, a dictionary learning problem is formulated at the frame level to adaptively represent the background signals with the varied structure information captured, while a pixel-level maintenance is exploited to grasp the dynamic nature of historical information under the help of the learned background. The simultaneous utilization of dictionary learning and historical pixel maintenance facilitates the accurate description of the background and thus guides a wise foreground detection decision. The proposed BREW-DLHPM has been evaluated on the prestigious change detection challenge data set against 11 state-of-the-art foreground detection approaches and encouraging performances have been achieved by our method. PMID- 28873057 TI - Similarity of Scenic Bilevel Images. AB - This paper presents a study of bilevel image similarity, including new objective metrics intended to quantify similarity consistent with human perception, and a subjective experiment to obtain ground truth for judging the performance of the objective similarity metrics. The focus is on scenic bilevel images, which are complex, natural or hand-drawn images, such as landscapes or portraits. The ground truth was obtained from ratings by 77 subjects of 44 distorted versions of seven scenic images, using a modified version of the SDSCE testing methodology. Based on hypotheses about human perception of bilevel images, several new metrics are proposed that outperform existing ones in the sense of attaining significantly higher Pearson and Spearman-rank correlation coefficients with respect to the ground truth from the subjective experiment. The new metrics include adjusted percentage error, bilevel local direction, and connected components comparison. Combinations of these metrics are also proposed, which exploit their complementarity to attain even better performance. These metrics and the ground truth are then used to assess the relative severity of various kinds of distortion and the performance of several lossy bilevel compression methods. PMID- 28873058 TI - DehazeNet: An End-to-End System for Single Image Haze Removal. AB - Single image haze removal is a challenging ill-posed problem. Existing methods use various constraints/priors to get plausible dehazing solutions. The key to achieve haze removal is to estimate a medium transmission map for an input hazy image. In this paper, we propose a trainable end-to-end system called DehazeNet, for medium transmission estimation. DehazeNet takes a hazy image as input, and outputs its medium transmission map that is subsequently used to recover a haze free image via atmospheric scattering model. DehazeNet adopts convolutional neural network-based deep architecture, whose layers are specially designed to embody the established assumptions/priors in image dehazing. Specifically, the layers of Maxout units are used for feature extraction, which can generate almost all haze-relevant features. We also propose a novel nonlinear activation function in DehazeNet, called bilateral rectified linear unit, which is able to improve the quality of recovered haze-free image. We establish connections between the components of the proposed DehazeNet and those used in existing methods. Experiments on benchmark images show that DehazeNet achieves superior performance over existing methods, yet keeps efficient and easy to use. PMID- 28873059 TI - Traction-assisted Internal Negative Pressure Wound Therapy With Bridging Retention Sutures to Facilitate Staged Closure of High-risk Wounds Under Tension. AB - BACKGROUND/OBJECTIVE: Loss of domain often complicates attempts at delayed wound closure in regions of high tension. Wound temporization with traction-assisted internal negative pressure wound therapy (NPWT), using bridging retention sutures, can minimize the effects of edema and elastic recoil that contribute to progressive tissue retraction over time. The investigators evaluated the safety and efficacy of this technique for complex wound closure. MATERIALS AND METHODS: Between May 2015 and November 2015, 18 consecutive patients underwent staged reconstruction of complex and/or contaminated soft tissue defects utilizing either conventional NPWT or modified NPWT with instillation and continuous dermatotraction via bridging retention sutures. Instillation of antimicrobial solution was reserved for wounds containing infected/exposed hardware or prosthetic devices. Demographic data, wound characteristics, reconstructive outcomes, and complications were reviewed retrospectively. RESULTS: Eighteen wounds were treated with traction-assisted internal NPWT using the conventional (n = 11) or modified instillation (n = 7) technique. Defects involved the lower extremity (n = 14), trunk (n = 3), and proximal upper extremity (n = 1), with positive cultures identified in 12 wounds (67%). Therapy continued for 3 to 8 days (mean, 4.3 days), resulting in an average wound surface area reduction of 78% (149 cm2 vs. 33 cm2) at definitive closure. Seventeen wounds (94%) were closed directly, whereas the remaining defect required coverage with a local muscle flap and skin graft. At final follow-up (mean, 12 months), 89% of wounds remained closed. In 2 patients with delayed, recurrent periprosthetic infection (mean, 7.5 weeks), serial debridement/hardware removal mandated free tissue transfer for composite defect reconstruction. CONCLUSION: Traction-assisted internal NPWT provides a safe and effective alternative to reduce wound burden and facilitate definitive closure in cases where delayed reconstruction of high tension wounds is planned. PMID- 28873060 TI - A Retrospective Crossover Study of the Use of Aseptically Processed Placental Membrane in the Treatment of Chronic Diabetic Foot Ulcers. AB - BACKGROUND: In a recently published, prospective randomized controlled trial (RCT) comparing aseptically processed dehydrated human amnion/chorion allograft (dHACA) to standard of care (SOC), 85% wound closure rates were reported in the dHACA arm while only 25% of patients in the SOC arm healed. OBJECTIVE: The purpose of this retrospective crossover study is to evaluate the effectiveness of dHACA in those patients that failed to respond to the SOC treatments and who exited the original study after failing up to 12 weeks of SOC treatment. MATERIALS AND METHODS: Patients with nonhealing wounds from the SOC arm after exit from the original study were offered weekly adjunctive applications of dHACA (AmnioBand; Musculoskeletal Transplant Foundation, Edison, NJ) for up to 12 weeks. The primary endpoint was the proportion of wounds completely healed at 12 weeks. Secondary endpoints included the difference in wound area from baseline to the end of study and the percentage area reduction (PAR). RESULTS: Eleven patients were eligible to participate; wounds for 9 of the 11 patients healed (82%). The mean wound area decreased from 1.7 cm2 to 0.2 cm2 (P = .0005), with a corresponding mean PAR of 92%. Of the 2 wounds that failed to heal, 1 diabetic foot ulcer (DFU) decreased in area by 91% and the other by 26%. CONCLUSION: The results of this crossover study support the conclusions of the original RCT, which determined that aseptically processed dHACA is an effective means to treat recalcitrant DFUs. Further studies, including comparative clinical trials, may offer additional information on this unique aseptically processed graft in the healing of indolent wounds. PMID- 28873062 TI - A Prospective, Randomized, Controlled Clinical Trial to Assess Use of 2% Lidocaine Irrigation to Prevent Abdominal Surgical Site Infection. AB - Surgical site infections (SSI) are the third most common nosocomial infection, increasing morbidity and mortality rates of patients as well as their costs of care, but longer-term follow up studies and data are limited. Lidocaine, in addition to being a readily available and accessible local anesthetic, is known to have bacteriostatic properties. A prospective, descriptive, controlled, randomized clinical trial was conducted among patients scheduled to undergo abdominal sur- gery in the general surgical unit of a Mexican hospital. The purpose of the study was to assess the incidence of SSIs in general and to compare the 30-day postoperative infection outcomes of saline irrigation to saline irrigation followed by 2% lidocaine application before skin closure in wounds grade II to IV per the Centers for Disease Control and Prevention surgical wound classi cation. All patients received systemic antibiotics before surgery. Eighty-four (84) patients (40 men and 44 women; mean age 49.02 +/- 19.9 years, range 18-92 years), 39 in the control and 45 in the experimental group, completed the 30-day follow-up without experiencing nonsurgery-related complications. The overall incidence of SSIs (speci cally, seromas and abscesses) was 17.86%; the incidence of abscess formation was 7.14%. The overall incidence of SSIs in the lidocaine group was 8.89% compared to 28.2% in the saline only group (P = .02); the relative risk was 1.8 (P = .02; 95% CI 1.19-2.74) and 0.45 (P = .02; 95% CI 0.19-1.06) in the saline and lidocaine groups, respectively. Hemoglobin and albumin levels were signi cantly lower in patients who did compared to those who did not develop an SSI (P = .02 and .04, respectively). No signi cant SSI rate differences were seen between patients who did and did not have a drain placed. In patients who developed an abscess, Escherichia coli was the most prevalent bacteria and present in 40% of collected uid. While carefully controlled clinical studies are needed, lidocaine appears to be a viable option to decrease the incidence of SSI if applied as irrigation before wound closure in patients undergoing abdominal surgery. PMID- 28873063 TI - A Descriptive, Cross-sectional Study to Assess Quality of Life and Sexuality in Turkish Patients with a Colostomy. AB - A stoma affects personality, self-esteem, and body image, inevitably impacting lifestyle and quality of life (QOL). A descriptive, cross-sectional study was conducted between May 1, 2015 and May 1, 2016 to evaluate the effect of a stoma on sexual function and QOL among patients receiving care in a general surgery clinic of a university hospital in the western region of Turkey.Eligibility requirements included patients willing to participate, >18 years of age, with a colostomy for at least 4 months, who were married and/or with a sexual partner and in otherwise good physical and mental health with no rectal nerve damage or receiving radio- or chemotherapy. Data were collected during face-to-face interviews. Demographic variables (age, gender, body mass index [BMI], educational status, income level); and clinical information (duration of the precipitating disease, and stoma duration, cause, and type) were collected, and the International Index of Erectile Function (IIEF) measure; the Index of Female Sexual Function (IFSF); and a Stoma Quality of Life Scale (SQOLS) were completed. Statistical analyses were performed using descriptive statistics, Spearman's correlation coefficient, and the Mann-Whitney U test. Of the 57 study participants, 57.9% were >60 years old (mean age: 59.81 +/- 10.12), more than half (57.92%) were male, 33.3% had a permanent stoma, and the mean duration of the stoma was 9.60 +/- 6.40 months. Scores for all 3 outcomes were low; mean IIEF score was 3.64 +/- 2.47 (range 2-10), mean IFSF score was 13.04 +/- 5.19 (range 9 29), and mean SQOLS was 45.10 +/- 18.88 (range 0-100). Eighteen (18) of the 33 men (54.5%) had severe, 5 (15.2%) had moderate, and 9 (27.3%) had mild erectile dysfunction. The IFSF total score for all female patients was <30; all female patients experienced sexual dysfunction. A negative correlation between age and the SQOLS subscale sexuality/body image was found (rs = -0.305, P <.05). A positive correlation was found among BMI, erectile function (rs = 0.350, P <.05), sexual desire (rs = 0.474, P <.01), and intercourse satisfaction (rs = 0.385, P <.05). These study results provide reference data for future study and underscore the importance of assessing and addressing QOL and sexuality concerns among patients with a colostomy. PMID- 28873064 TI - A Systematic Review and Meta-analysis of Exercise Intervention for the Treatment of Calf Muscle Pump Impairment in Individuals with Chronic Venous Insufficiency. AB - Exercise intervention for individuals with chronic venous insufficiency (CVI) and venous leg ulcers (VLUs) is recommended to improve function of the calf muscle pump (CMP). A systematic review with meta-analysis was conducted to measure the effects of exercise (including function of the CMP, ankle strength, range of motion [ROM], and healing rates) for VLUs. Four (4) databases (Cumulative Index to Nursing and Applied Health Literature, 1981; MEDLINE, 1964; Scopus, 1966; and EMBASE, 1947) were searched for relevant articles from the date of index inception to January 2016. All study types that evaluated the effect of exercise on the function of the CMP in patients with CVI were included; narrative and systematic studies were excluded. All data were extracted by 1 reviewer onto a predetermined form and verified by a second reviewer. Data extracted included number of patients, primary diagnosis, patient demographics, study location, wound characteristics, inclusion/exclusion criteria, exercise group details, control group details, co-interventions, primary outcome measures, secondary outcome measures, wound healing measures, blinding, intention to treat, and study design. A total of 1325 articles was screened; 14 met the inclusion criteria (total study participants = 519). CMP hemodynamics were assessed using air plethysmography measurement results from the included studies. A meta-analysis of 8 articles was distilled to 3 with relevant data (83 participants) that found a significant increase on CMP ejection fraction in favor of the exercise group (Hedge's g = 0.83; 95% CI 0.35-1.30, P <.001) compared to control. CMP residual venous fraction also favored the exercise group (Hedge's g = 0.42; 95% CI -0.03 0.862, P = .066). Ankle ROM was higher in the exercise group (116 participants; Hedge's g = 0.62; 95% CI -0.15-1.39, P = .116); however, these differences were not significantly different from controls. Exercise directed at improving calf muscle strength and ankle ROM for individuals with or at risk for VLUs improves CMP hemodynamics and function. Additional research using larger sample sizes to confirm the role of exercise in healing VLUs is warranted. PMID- 28873065 TI - Mechanisms of tail resorption during anuran metamorphosis. AB - Amphibian metamorphosis has historically attracted a good deal of scientific attention owing to its dramatic nature and easy observability. However, the genetic mechanisms of amphibian metamorphosis have not been thoroughly examined using modern techniques such as gene cloning, DNA sequencing, polymerase chain reaction or genomic editing. Here, we review the current state of knowledge regarding molecular mechanisms underlying tadpole tail resorption. PMID- 28873066 TI - Preliminary study of the association between the elimination parameters of phenytoin and phenobarbital. AB - BACKGROUND: Therapeutic drug monitoring is essential for both phenytoin and phenobarbital therapy given their narrow therapeutic indexes. Nevertheless, the measurement of either phenytoin or phenobarbital concentrations might not be available in some rural hospitals. Information assisting individualized phenytoin and phenobarbital combination therapy is important. This study's objective was to determine the relationship between the maximum rate of metabolism of phenytoin (Vmax) and phenobarbital clearance (CLPB), which can serve as a guide to individualized drug therapy. METHODS: Data on phenytoin and phenobarbital concentrations of 19 epileptic patients concurrently receiving both drugs were obtained from medical records. Phenytoin and phenobarbital pharmacokinetic parameters were studied at steady-state conditions. The relationship between the elimination parameters of both drugs was determined using simple linear regression. RESULTS: A high correlation coefficient between Vmax and CLPB was found [r=0.744; p<0.001 for Vmax (mg/kg/day) vs. CLPB (L/kg/day)]. Such a relatively strong linear relationship between the elimination parameters of both drugs indicates that Vmax might be predicted from CLPB and vice versa. CONCLUSIONS: Regression equations were established for estimating Vmax from CLPB, and vice versa in patients treated with combination of phenytoin and phenobarbital. These proposed equations can be of use in aiding individualized drug therapy. PMID- 28873067 TI - Association of histological chorioamnionitis and magnesium sulfate treatment in singleton and dichorionic twin pregnancies with preterm premature rupture of membranes: preliminary observations. AB - Objective To evaluate the possible association between antenatal magnesium sulfate treatment with histological chorioamnionitis in patients with singleton or dichorionic twins that had preterm premature rupture of the membranes. Methods This was an observational study performed in patients admitted to the hospital with rupture of membranes before 34 weeks' gestation. The primary outcome was histological chorioamnionitis and the primary predictor was antenatal magnesium sulfate treatment. A logistic regression model was used without consideration of other antenatal medical treatments. Results Among 107 patients with preterm deliveries, 57 were admitted to the hospital before 34 weeks' gestation with preterm premature rupture of membranes. Fifty-cases were excluded from the analysis because they were admitted after 34 weeks' gestation, delivered before 24 weeks' gestation or had intrauterine fetal demise or monochorionic twins. The logistic regression analysis adjusting for maternal age, gravidity, parity, multiple gestation, gestational age at delivery, and birthweight, indicated that patients with singleton pregnancies and histological chorioamnionitis had received magnesium sulfate antenatally more frequently (chi2=6.46; P=0.01). The association between histological chorioamnionitis and magnesium sulfate treatment was not found among patients with dichorionic twin pregnancies with one intact gestational sac. Conclusions In this cohort of patients with preterm premature rupture of membranes admitted to the hospital before 34 week's gestation, those with singleton pregnancies treated antenatally with magnesium sulfate for neonatal neuroprotection had a greater rate of histological chorioamnionitis. PMID- 28873068 TI - Neuroinflammation and physical exercise as modulators of adult hippocampal neural precursor cell behavior. AB - The dentate gyrus of the hippocampus is a plastic structure where adult neurogenesis constitutively occurs. Cell components of the neurogenic niche are source of paracrine as well as membrane-bound factors such as Notch, Bone Morphogenetic Proteins, Wnts, Sonic Hedgehog, cytokines, and growth factors that regulate adult hippocampal neurogenesis and cell fate decision. The integration and coordinated action of multiple extrinsic and intrinsic cues drive a continuous decision process: if adult neural stem cells remain quiescent or proliferate, if they take a neuronal or a glial lineage, and if new cells proliferate, undergo apoptotic death, or survive. The proper balance in the molecular milieu of this neurogenic niche leads to the production of neurons in a higher rate as that of astrocytes. But this rate changes in face of microenvironment modifications as those driven by physical exercise or with neuroinflammation. In this work, we first review the cellular and molecular components of the subgranular zone, focusing on the molecules, active signaling pathways and genetic programs that maintain quiescence, induce proliferation, or promote differentiation. We then summarize the evidence regarding the role of neuroinflammation and physical exercise in the modulation of adult hippocampal neurogenesis with emphasis on the activation of progression from adult neural stem cells to lineage-committed progenitors to their progeny mainly in murine models. PMID- 28873069 TI - Fred: a GPU-accelerated fast-Monte Carlo code for rapid treatment plan recalculation in ion beam therapy. AB - Ion beam therapy is a rapidly growing technique for tumor radiation therapy. Ions allow for a high dose deposition in the tumor region, while sparing the surrounding healthy tissue. For this reason, the highest possible accuracy in the calculation of dose and its spatial distribution is required in treatment planning. On one hand, commonly used treatment planning software solutions adopt a simplified beam-body interaction model by remapping pre-calculated dose distributions into a 3D water-equivalent representation of the patient morphology. On the other hand, Monte Carlo (MC) simulations, which explicitly take into account all the details in the interaction of particles with human tissues, are considered to be the most reliable tool to address the complexity of mixed field irradiation in a heterogeneous environment. However, full MC calculations are not routinely used in clinical practice because they typically demand substantial computational resources. Therefore MC simulations are usually only used to check treatment plans for a restricted number of difficult cases. The advent of general-purpose programming GPU cards prompted the development of trimmed-down MC-based dose engines which can significantly reduce the time needed to recalculate a treatment plan with respect to standard MC codes in CPU hardware. In this work, we report on the development of fred, a new MC simulation platform for treatment planning in ion beam therapy. The code can transport particles through a 3D voxel grid using a class II MC algorithm. Both primary and secondary particles are tracked and their energy deposition is scored along the trajectory. Effective models for particle-medium interaction have been implemented, balancing accuracy in dose deposition with computational cost. Currently, the most refined module is the transport of proton beams in water: single pencil beam dose-depth distributions obtained with fred agree with those produced by standard MC codes within 1-2% of the Bragg peak in the therapeutic energy range. A comparison with measurements taken at the CNAO treatment center shows that the lateral dose tails are reproduced within 2% in the field size factor test up to 20 cm. The tracing kernel can run on GPU hardware, achieving 10 million primary [Formula: see text] on a single card. This performance allows one to recalculate a proton treatment plan at 1% of the total particles in just a few minutes. PMID- 28873071 TI - Guillain-Barre Syndrome and Swallowing Dysfunction. AB - PURPOSE: Patients with Guillain-Barre syndrome (GBS), especially severe cases that require treatment in intensive care units, often experience swallowing difficulties. However, the oropharyngeal function of patients with GBS not treated in intensive care units is not typically evaluated using neurophysiological techniques. METHODS: Electrophysiological techniques were used to determine dysphagia limit and sequential water swallowing values in an electromyography laboratory. RESULTS: This study assessed 18 patients with GBS who were not treated in the intensive care unit between 4 and 45 days after their hospital admission; 18 healthy volunteers were used as a control group. Of the 18 patients with GBS, 7 exhibited the clinical involvement of either a single cranial nerve or a combination of cranial nerves while 11 did not show any lower cranial nerve involvement. Clinical dysphagia was observed in seven patients and six of these cases involved a lower cranial nerve while five patients without cranial nerve involvement had silent dysphagia according to the dysphagia limit test. In addition, the duration of sequential swallowing was significantly prolonged in all patients with GBS compared with the control subjects. CONCLUSIONS: The present findings demonstrated that neurophysiological techniques are useful and easily applicable for patients with GBS and that there were no complications. Furthermore, cranial nerve involvement in patients with GBS likely increased the incidence of oropharyngeal dysphagia, and subclinical dysphagia may be present in this population as well. Therefore, neurophysiological techniques can be initially used and then repeated during follow-up visits for all types of patients with GBS. PMID- 28873070 TI - Functional assessment of genetic variants located in the promoter of SHP1 (NR0B2). AB - Small heterodimer partner 1 (SHP1, NR0B2) is a member of the superfamily of nuclear receptors (NRs). Even if this orphan receptor, unlike other NRs, lacks the DNA-binding domain, it is capable of regulating transcription by repressing the activity of other NRs by direct protein-protein interaction. Accordingly, SHP1 is part of negative feedback loops of the transcriptional regulation of genes involved in drug metabolism and various metabolic pathways including bile acid and glucose homeostasis. Although it is known that several interacting partners of SHP1 also modulate its expression, there is little information about genetic variability of this regulatory mechanism. Our study aimed to identify genetic variants in the NR0B2 promoter region and to determine their impact on NR0B2 transcription. For this, DNA samples originating from 119 participants of the population-based cohort Study of Health in Pomerania were analyzed by Sanger sequencing revealing four genetic variants: NR0B2:c.-594T>C (rs71636795), NR0B2:c.-414G>C (newly identified), NR0B2:c.-423C>T (rs78182695), and NR0B2:c. 224delCTGA (rs145613139) localized in the 5' untranslated region of NR0B2. The impact of these variants on transactivation of the NR0B2 promoter by NRs known to be regulators of SHP1 expression (hepatocyte nuclear factor 4alpha, liver receptor homolog-1, and farnesoid X receptor) was assessed in a cell-based reporter gene assay, showing that transactivation by hepatocyte nuclear factor 4alpha and liver receptor homolog-1 was significantly decreased in the presence of the genetic variant NR0B2:c.-594T>C, even though this effect was cell specific. However, SHP1 mRNA expression in a small collection of human kidney samples was not affected by these genetic variants. PMID- 28873072 TI - Amplitude-Integrated EEG and Brain Sparing in Preterm Small-for-Gestational-Age Infants. AB - PURPOSE: Preterm small-for-gestational-age (SGA) infants are at risk for a high mortality rate and impaired cognitive development. Only a few studies have focused on amplitude-integrated EEG (aEEG) in preterm SGA infants. They have been shown to have a slower rate of brain maturation, but these findings have not consistently been related to neurodevelopmental outcomes. The aim of our study was to evaluate early aEEG monitoring in SGA compared with adequate-for gestational-age preterms. METHODS: This prospective cohort study enrolled infants with very low birth weight who were admitted to the neonatal intensive care unit at Hospital Puerta del Mar, Cadiz, Spain, from June 2009 to September 2012. This study was a subanalysis of SGA from the global cohort previously described by our group. Adverse outcome included severe intraventricular hemorrhage and/or death. Cerebral function was monitored using aEEG recordings during the first 72 hours of life. RESULTS: Preterm SGA infants (18 SGA in the global cohort of 92 patients) had lower 1- and 5-minute Apgar scores, higher score for neonatal acute physiology perinatal extension II scores, and higher proportion of adverse outcomes. When comparing preterm adequate-for-gestational-age infants with SGA infants with good prognosis, those with SGA had more mature and continuous aEEG patterns. Low margin amplitude depression was not as severe in these patients, and a higher proportion of these patients developed sleep-wake cycles. CONCLUSIONS: The results of our study suggest that SGA infants with a good prognosis have a more mature aEEG pattern than preterm adequate-for-gestational age patients with the same outcome. These findings support the brain sparing theory in SGA infants. PMID- 28873073 TI - EEG Characteristics in Cooled and Rewarmed Periods in Post-cardiac Arrest Therapeutic Hypothermia Patients: Erratum. PMID- 28873074 TI - Adipose-derived cellular therapies in solid organ and vascularized-composite allotransplantation. AB - PURPOSE OF REVIEW: Controlling acute allograft rejection following vascularized composite allotransplantation requires strict adherence to courses of systemic immunosuppression. Discovering new methods to modulate the alloreactive immune response is essential for widespread application of vascularized composite allotransplantation. Here, we discuss how adipose-derived cellular therapies represent novel treatment options for immune modulation and tolerance induction in vascularized composite allotransplantation. RECENT FINDINGS: Adipose-derived mesenchymal stromal cells are cultured from autologous or allogeneic adipose tissue and possess immunomodulatory qualities capable of prolonging allograft survival in animal models of vascularized composite allotransplantation. Similar immunosuppressive and immunomodulatory effects have been observed with noncultured adipose stromal-vascular-fraction-derived therapies, albeit publication of in-vivo stromal vascular fraction cell modulation in transplantation models is lacking. However, both stromal vascular fraction and adipose derived mesenchymal stem cell therapies have the potential to effectively modulate acute allograft rejection via recruitment and induction of regulatory immune cells. SUMMARY: To date, most reports focus on adipose derived mesenchymal stem cells for immune modulation in transplantation despite their phenotypic plasticity and reliance upon culture expansion. Along with the capacity for immune modulation, the supplemental wound healing and vasculogenic properties of stromal vascular fraction, which are not shared by adipose derived mesenchymal stem cells, hint at the profound therapeutic impact stromal vascular fraction derived treatments could have on controlling acute allograft rejection and tolerance induction in vascularized composite allotransplantation. Ongoing projects in the next few years will help design the best applications of these well tolerated and effective treatments that should reduce the risk/benefit ratio and allow more patients access to vascularized composite allotransplantation therapy. PMID- 28873075 TI - Intraoperative magnesium sulphate decreases agitation and pain in patients undergoing functional endoscopic surgery: A randomised double-blind study. AB - BACKGROUND: Postoperative agitation is harmful for the patient as it may be associated with removal of catheters, nasal packs, oxygen masks and self-injury, and pose a danger to operating theatre staff. OBJECTIVE: The current study investigated the potential role of magnesium sulphate in treatment of postoperative agitation following functional endoscopic sinus surgery. DESIGN: A randomised, double-blinded, placebo-controlled trial. SETTING: ENT operating room, Menofia University Hospitals, Egypt. PATIENTS: A total of 312 adult patients (171 men and 141 women) were enrolled in the study. Eighteen patients (10 men and eight women) were excluded; data from 294 patients were analysed. Inclusion criteria were age between 20 and 60 years, American Society of Anesthesiologists' physical status 1 or 2 scheduled for functional endoscopic sinus surgery. Exclusion criteria were hypertension, cardiac ischaemia, cerebrovascular insufficiency, neuromuscular diseases, pregnancy, prolonged treatment with calcium-channel blockers, diabetic neuropathy or a known allergy to magnesium compounds. INTERVENTIONS: Patients were allocated randomly to either the magnesium group (a magnesium infusion of 30 mg kg in the first hour followed by 9 mg kg h until the end of the surgical procedure) or the control group (0.9% saline at the same volume and rate). Hypotensive anaesthesia was induced by nitroglycerine 5 to 20 MUg kg min. In the postanaesthetic care unit (PACU), patients were assessed for agitation and pain using the Richmond agitation sedation scale and numerical rating scale, respectively. PRIMARY OUTCOME: The incidence and severity of agitation measured 5 min after admission to the PACU. RESULTS: Magnesium reduced postoperative agitation at time 0 (P = 0.009) and 5, 10, 15 and 30 min after PACU admission (P < 0.0001) as well as total agitation score [3 (0 to 6) versus 9 (0 to 12), P < 0.0001]. Magnesium also reduced pain [4.5 (4 to 5) versus 6 (5 to 6.25), P < 0.0001] and length of PACU stay (88 +/- 23 versus 111 +/- 31 min, P < 0.0001). The magnesium group consumed less pethidine in PACU compared with the control group (43 +/- 15 and 59 +/- 19 mg, respectively, P < 0.0001). The intraoperative end-tidal CO2 tension was comparable between groups (4.7 +/- 0.7 versus 4.8 +/- 1.2 kPa). CONCLUSION: Intraoperative infusion of magnesium in patients undergoing endoscopic sinus surgery reduced postoperative agitation, pethidine consumption and pain assessed in the PACU. It also decreased the length of stay in PACU compared with the control group. TRIAL REGISTRATION: The current study was registered according to WHO and ICMJE standards on 7 January 2014, under registration number PACTR 201402000737691. PMID- 28873077 TI - Strong PSMA Radioligand Uptake by Rectal Carcinoma: Who Put the "S" in PSMA? Evaluation and Preliminary Experience on 16 Patients: Erratum. PMID- 28873076 TI - Women awaken faster than men after electroencephalogram-monitored propofol sedation for colonoscopy: A prospective observational study. AB - BACKGROUND: Sedation for colonoscopy using intravenous propofol has become standard in many Western countries. OBJECTIVE: Gender-specific differences have been shown for general anaesthesia in dentistry, but no such data existed for gastrointestinal endoscopy. DESIGN: A prospective observational study. SETTING: An academic teaching hospital of Hannover Medical School. PATIENTS: A total of 219 patients (108 women and 111 men) scheduled for colonoscopy. INTERVENTION: Propofol sedation using electroencephalogram monitoring during a constant level of sedation depth (D0 to D2) performed by trained nurses or physicians after a body-weight-adjusted loading dose. MAIN OUTCOME MEASURES: The primary end-point was the presence of gender-specific differences in awakening time (time from end of sedation to eye-opening and complete orientation); secondary outcome parameters analysed were total dose of propofol, sedation-associated complications (bradycardia, hypotension, hypoxaemia and apnoea), patient cooperation and patient satisfaction. Multivariate analysis was performed to correct confounding factors such as age and BMI. RESULTS: Women awakened significantly faster than men, with a time to eye-opening of 7.3 +/- 3.7 versus 8.4 +/- 3.4 min (P = 0.005) and time until complete orientation of 9.1 +/- 3.9 versus 10.4 +/- 13.7 min (P = 0.008). The propofol dosage was not significantly different, with some trend towards more propofol per kg body weight in women (3.98 +/- 1.81 mg versus 3.72 +/- 1.75 mg, P = 0.232). CONCLUSION: The effect of gender aspects should be considered when propofol is used as sedation for gastrointestinal endoscopy. That includes adequate dosing for women as well as caution regarding potential overdosing of male patients. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02687568). PMID- 28873078 TI - Multidimensional Prognostic Modelling in People With Chronic Axial Low Back Pain. AB - OBJECTIVES: To derive prognostic models for people with chronic low back pain (CLBP) (n=294) based upon an extensive array of potentially prognostic multidimensional factors. MATERIALS AND METHODS: This study entered multidimensional data (demographics, pain characteristics, pain responses to movement, behaviors associated with pain, pain sensitivity, psychological, social, health, lifestyle) at baseline, and interventions undertaken, into prognostic models for pain intensity, disability, global rating of change and bothersomeness at 1-year. RESULTS: The prognostic model for higher pain intensity (explaining 23.2% of the variance) included higher baseline pain intensity and punishing spousal interactions, and lower years in education, while participating in exercise was prognostic of lower pain intensity. The model for higher disability (33.6% of the variance) included higher baseline disability, longer forward bending time, psychological principal component scores representing negative pain-related cognitions and punishing spousal interactions; while exercising was prognostic of lower disability. The odds of reporting global rating of change much/very much improved were increased by participating in exercise, having leg pain as well as CLBP and having greater chronic pain acceptance. The receiver operating characteristic area under the curve was 0.72 indicating acceptable discrimination. The odds of reporting very/extremely bothersome CLBP were increased by having higher baseline pain intensity, longer forward bending time and receiving injection(s); while higher age, more years in education and having leg pain decreased the odds (receiver operating characteristic area under the curve, 0.80; acceptable discrimination). DISCUSSION: The variance explained by prognostic models was similar to previous reports, despite an extensive array of multidimensional baseline variables. This highlights the inherent multidimensional complexity of CLBP. PMID- 28873079 TI - A Network Analysis of Depressive Symptoms in Individuals Seeking Treatment for Chronic Pain. AB - OBJECTIVES: Major depression in the context of chronic pain has been conceptualized implicitly as a latent variable, in which symptoms are viewed as manifestations of an underlying disorder. A network approach provides an alternative model and posits that symptoms are causally connected, rather than merely correlated, and that disorders exist as systems, rather than as entities. The present study applied a network analysis to self-reported symptoms of major depression in patients with chronic pain. The goals of the study were to describe the network of depressive symptoms in individuals with chronic pain and to illustrate the potential of network analysis for generating new research questions and treatment strategies. MATERIALS AND METHODS: Patients (N=216) admitted to an interdisciplinary chronic pain rehabilitation program provided symptom self-reports using the Patient Health Questionnaire-9. Well-established network analyses methods were used to illustrate the network of depressive symptoms and determine the centrality of each symptom (ie, the degree of connection with other symptoms in the network). RESULTS: The most central symptoms were difficulty concentrating, loss of interest or pleasure, depressed mood, and fatigue, although the relative position of each symptom varied slightly, depending on the centrality measure considered. DISCUSSION: Consistent with past research with patients undergoing treatment for major depression, the current findings are supportive of a model in which depressive symptoms are causally connected within a network rather than being manifestations of a common underlying disorder. The research and clinical implications of the findings, such as developing treatments targeting the most central symptoms, are discussed. PMID- 28873080 TI - Multiplex molecular diagnostic tests and the management of diarrhea: the wave of the future? PMID- 28873081 TI - Impact of Tag Single Nucleotide Polymorphisms (SNPs) in CCL11 Gene on Risk of Subtypes of Ischemic Stroke in Xinjiang Han Populations. AB - BACKGROUND CCL11 is an important inflammatory cytokine associated with inflammation-related diseases such as atherosclerosis and stroke. The aim of this study was to investigate the relationship between CCL11 gene polymorphism with subtypes of ischemic stroke in Xinjiang Han populations. MATERIAL AND METHODS The improved multiple ligase detection reaction (iMLDR) method was used to analyze the genotypes of 6 tag SNPs in the CCL11 gene (rs1129844, rs17809012, rs1860183, rs1860184, rs4795898, and rs4795895) in a case-control study of 406 lacunar stroke patients, 214 large-artery atherosclerotic (LAA) stroke patients, and 425 controls. RESULTS We found the GG genotype of rs4795895 was significantly associated with increased risk of lacunar stroke (adjusted OR=1.676, 95%CI=1.117 2.515), and the GA genotype of rs17809012 was associated with a significant increase in risk of LAA stroke (adjusted OR=1.337, 95%CI=1.127-1.585). Hypertension stratification analyses showed that the GA genotype of rs17809012 was significantly associated with LAA stroke in the hypertensive group (adjusted OR=1.274, 95%CI=1.015-1.601). In the non-hypertensive group, the GA genotype of rs17809012 was significantly associated with LAA stroke (adjusted OR=1.361, 95%CI=1.041-1.780). The GG genotype of rs4795895 (adjusted OR=1.147, 95%CI=1.115 4.134) and the TT genotype of rs1860184 were significantly associated with lacunar stroke (adjusted OR=2.440, 95%CI=1.550-3.840). CONCLUSIONS This study demonstrates that the CCL11 gene could play an important role in the pathogenesis of lacunar stroke and LAA stroke in the Han population of China. PMID- 28873082 TI - Ffar2 expression regulates leukaemic cell growth in vivo. AB - BACKGROUND: Activation of free fatty acid receptor 2 (FFAR2) by microbiota derived metabolites (e.g., propionate) reduces leukaemic cell proliferation in vitro. This study aims to test whether Ffar2 expression per se also influences leukaemia cell growth in vivo. METHODS: Bcr-Abl-expressing BaF cells were used as a leukaemia model and the role of Ffar2 was evaluated in Balb/c mice after lentiviral shRNA transduction. RESULTS: Our data formally establish that reduced leukaemic cell proliferation is associated with increased Ffar2 expression in vivo and in vitro. Going beyond association, we point out that decreasing Ffar2 expression fosters cancer cell growth in vitro and in vivo. CONCLUSIONS: Our data demonstrate the role of Ffar2 in the control of leukaemic cell proliferation in vivo and indicate that a modulation of Ffar2 expression through nutritional tools or pharmacological agents may constitute an attractive therapeutic approach to tackle leukaemia progression in humans. PMID- 28873083 TI - SKLB188 inhibits the growth of head and neck squamous cell carcinoma by suppressing EGFR signalling. AB - BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. Several small molecule EGFR inhibitors have been tested in clinical trials for treatment of HNSCC, but none of them are more effective than the current chemotherapeutic drugs. Thus, it is urgently needed to develop novel EGFR inhibitors for HNSCC treatment. METHODS: By screening an in-house focused library containing approximately 650 000 known kinase inhibitors and kinase inhibitor-like compounds containing common kinase inhibitor core scaffolds, we identified SKLB188 as a lead compound for inhibition of EGFR. The anticancer effects of SKLB188 on HNSCC cells were investigated by in vitro cell growth, cell cycle and apoptosis assays, as well as in vivo FaDu xenograft mouse model. Molecular docking, in vitro kinase profiling and western blotting were performed to characterise EGFR as the molecular target. RESULTS: SKLB188 inhibited HNSCC cell proliferation by inducing G1 cell cycle arrest, which was associated with downregulating the expression of Cdc25A, cyclins D1/A and cyclin-dependent kinases (CDK2/4), and upregulating the expression of cyclin-dependent kinase (CDK) inhibitors (p21Cip1 and p27Kip1), leading to decreased phosphorylation of Rb. SKLB188 also induced caspase-dependent apoptosis of HNSCC cells by downregulating the expression of Mcl-1 and survivin. Molecular docking revealed that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay showed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC50=5 nM). Western blot analysis demonstrated that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose-dependently inhibited FaDu xenograft growth in nude mice, and concurrently inhibited the phosphorylation of Erk1/2 and Akt in the tumours. CONCLUSIONS: SKLB188 potently inhibits the growth of HNSCC cells in vitro and in vivo by targeting EGFR signalling. The results provide a basis for further clinical investigation of SKLB188 as a targeted therapy for HNSCC. Our findings may open a new avenue for development of novel EGFR inhibitors for treatment of HNSCC and other cancers. PMID- 28873085 TI - The association between fasting blood glucose and the risk of primary liver cancer in Chinese males: a population-based prospective study. AB - BACKGROUND: To investigate the association between fasting blood glucose (FBG) levels and the risk of incident primary liver cancer (PLC) in Chinese males, a large prospective cohort was performed in the current study. METHODS: A total of 109 169 males participating in the routine checkups every two years were recruited in the Kailuan male cohort study since May 2006. Cox proportional hazards regression models and restricted cubic spline (RCS) were used to evaluate the association between levels of baseline FBG and the risk of incident PLC. RESULTS: Compared to the males with normal FBG (3.9?FBG<6.1 mmol l-1), the males with impaired fasting glucose (IFG: 6.1?FBG<7.0 mmol l-1) and diabetes mellitus (DM: FBG ?7.0 mmol l-1) had a 60% (95% CI: 1.09-2.35) and a 58% (95% CI: 1.07 2.34) higher risk of incident PLC, respectively. Subgroup analysis found that IFG increased the risk of PLC among the non-smoker (HR=1.73, 95% CI: 1.01-2.98) and current alcohol drinker (HR=1.80, 95% CI: 1.03-3.16). While DM increased the risk of PLC especially among the males with normal BMI (<25 kg m-2) (HR=1.76, 95% CI: 1.05-2.94) and the HBV negativity (HR=1.89, 95% CI: 1.16-3.09), RCS analysis showed a positive non-linearly association between the FBG levels and the risk of PLC (p-overall=0.041, p-non-linear=0.049). CONCLUSIONS: Increased FBG may be an important and potentially modifiable exposure that could have key scientific and clinical importance for preventing PLC development. PMID- 28873084 TI - A phase I/II study of KW-2478, an Hsp90 inhibitor, in combination with bortezomib in patients with relapsed/refractory multiple myeloma. AB - BACKGROUND: KW-2478 is a novel non-ansamycin Hsp90 inhibitor with modest single agent activity in relapsed/refractory myeloma but which shows synergistic antimyeloma activity with bortezomib (BTZ) in preclinical studies. This study determined the safety, preliminary clinical activity, and pharmacokinetics of KW 2478, an Hsp90 inhibitor, in combination with BTZ in patients with relapsed/refractory multiple myeloma (MM). METHODS: Phase I dose escalation determined the recommended phase II dose (RP2D) of KW-2478 plus BTZ, which was then used during phase II. RESULTS: The maximum tolerated dose was not reached during phase I and the RP2D was KW-2478 175 mg m-2 plus BTZ 1.3 mg m-2 on days 1, 4, 8, and 11 every 3 weeks. In the efficacy evaluable phase I/II population treated at the RP2D (n=79), the objective response rate was 39.2% (95% confidence interval: 28.4-50.9%), clinical benefit rate 51.9% (40.4-63.3%), median progression-free survival 6.7 (5.9-not reached (NR)) months, and median duration of response 5.5 (4.9-NR) months. In the phase I/II safety population (n=95), the most frequently observed treatment-related grade 3/4 adverse events were diarrhoea, fatigue, and neutropenia (each in 7.4% of patients), and nausea and thrombocytopenia (each in 5.3%). CONCLUSIONS: KW-2478 plus BTZ was well tolerated with no apparent overlapping toxicity in patients with relapsed/refractory MM. The antimyeloma activity of KW-2478 in combination with BTZ as scheduled in this trial appeared relatively modest; however, the good tolerability of the combination would support further exploration of alternate dosing schedules and combinations. PMID- 28873087 TI - Women's and men's reports of past-year prevalence of intimate partner violence and rape and women's risk factors for intimate partner violence: A multicountry cross-sectional study in Asia and the Pacific. AB - BACKGROUND: Understanding the past-year prevalence of male-perpetrated intimate partner violence (IPV) and risk factors is essential for building evidence-based prevention and monitoring progress to Sustainable Development Goal (SDG) 5.2, but so far, population-based research on this remains very limited. The objective of this study is to compare the population prevalence rates of past-year male perpetrated IPV and nonpartner rape from women's and men's reports across 4 countries in Asia and the Pacific. A further objective is to describe the risk factors associated with women's experience of past-year physical or sexual IPV from women's reports and factors driving women's past-year experience of partner violence. METHODS AND FINDINGS: This paper presents findings from the United Nations Multi-country Study on Men and Violence in Asia and the Pacific. In the course of this study, in population-based cross-sectional surveys, 5,206 men and 3,106 women aged 18-49 years were interviewed from 4 countries: Cambodia, China, Papua New Guinea (PNG), and Sri Lanka. To measure risk factors, we use logistic regression and structural equation modelling to show pathways and mediators. The analysis was not based on a written plan, and following a reviewer's comments, some material was moved to supplementary files and the regression was performed without variable elimination. Men reported more lifetime perpetration of IPV (physical or sexual IPV range 32.5%-80%) than women did experience (physical or sexual IPV range 27.5%-67.4%), but women's reports of past-year experience (physical or sexual IPV range 8.2%-32.1%) were not very clearly different from men's (physical or sexual IPV range 10.1%-34.0%). Women reported much more emotional/economic abuse (past-year ranges 1.4%-5.7% for men and 4.1%-27.7% for women). Reports of nonpartner rape were similar for men (range 0.8%-1.9% in the past year) and women (range 0.4%-2.3% in past year), except in Bougainville, where they were higher for men (11.7% versus 5.7%). The risk factor modelling shows 4 groups of variables to be important in experience of past-year sexual and/or physical IPV: (1) poverty, (2) all childhood trauma, (3) quarrelling and women's limited control in relationships, and (4) partner factors (substance abuse, unemployment, and infidelity). The population attributable fraction (PAF) was largest for quarrelling often, but the second greatest PAF was for the group related to exposure to violence in childhood. The relationship control variable group had the third highest PAF, followed by other partner factors. Currently married women were also more at risk. In the structural model, a resilience pathway showed less poverty, higher education, and more gender-equitable ideas were connected and conveyed protection from IPV. These are all amenable risk factors. This research was cross-sectional, so we cannot be sure of the temporal sequence of exposure, but the outcome being a past-year measure to some extent mitigates this problem. CONCLUSIONS: Past-year IPV indicators based on women's reported experience that were developed to track SDG 5 are probably reasonably reliable but will not always give the same prevalence as may be reported by men. Report validity requires further research. Interviews with men to track past-year nonpartner rape perpetration are feasible and important. The findings suggest a range of factors are associated with past-year physical and/or sexual IPV exposure; of particular interest is the resilience pathway suggested by the structural model, which is highly amenable to intervention and explains why combining economic empowerment of women and gender empowerment/relationship skills training has been successful. This study provides additional rationale for scaling up violence prevention interventions that combine economic and gender empowerment/relationship skills building of women, as well as the value of investing in girls' education with a view to long-term violence reduction. PMID- 28873086 TI - Anti-Mullerian hormone and endometrial cancer: a multi-cohort study. AB - BACKGROUND: The Mullerian ducts are the embryological precursors of the female reproductive tract, including the uterus; anti-Mullerian hormone (AMH) has a key role in the regulation of foetal sexual differentiation. Anti-Mullerian hormone inhibits endometrial tumour growth in experimental models by stimulating apoptosis and cell cycle arrest. To date, there are no prospective epidemiologic data on circulating AMH and endometrial cancer risk. METHODS: We investigated this association among women premenopausal at blood collection in a multicohort study including participants from eight studies located in the United States, Europe, and China. We identified 329 endometrial cancer cases and 339 matched controls. Anti-Mullerian hormone concentrations in blood were quantified using an enzyme-linked immunosorbent assay. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) across tertiles and for a doubling of AMH concentrations (ORlog2). Subgroup analyses were performed by ages at blood donation and diagnosis, oral contraceptive use, and tumour characteristics. RESULTS: Anti-Mullerian hormone was not associated with the risk of endometrial cancer overall (ORlog2: 1.07 (0.99-1.17)), or with any of the examined subgroups. CONCLUSIONS: Although experimental models implicate AMH in endometrial cancer growth inhibition, our findings do not support a role for circulating AMH in the aetiology of endometrial cancer. PMID- 28873088 TI - Identifying genetic variants that affect viability in large cohorts. AB - A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE epsilon4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 * 10-6 for fathers and P~2.0 * 10-3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 * 10-3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans. PMID- 28873090 TI - Deficiencies in Natura 2000 for protecting recovering large carnivores: A spotlight on the wolf Canis lupus in Poland. AB - If protected areas are to remain relevant in our dynamic world they must be adapted to changes in species ranges. In the EU one of the most notable such changes is the recent recovery of large carnivores, which are protected by Natura 2000 at the national and population levels. However, the Natura 2000 network was designed prior to their recent recovery, which raises the question whether the network is sufficient to protect the contemporary ranges of large carnivores. To investigate this question we evaluated Natura 2000 coverage of the three wolf Canis lupus populations in Poland. Wolf tracking data showed that wolves have recolonised almost all suitable habitat in Poland (as determined by a recent habitat suitability model), so we calculated the overlap between the Natura 2000 network and all wolf habitat in Poland. On the basis of published Natura 2000 criteria, we used 20% as the minimum required coverage. At the national level, wolves are sufficiently protected (22% coverage), but at the population level, the Baltic and Carpathian populations are far better protected (28 and 47%, respectively) than the endangered Central European Lowland population (12%). As Natura 2000 insufficiently protects the most endangered wolf population in Poland, we recommend expansion of Natura 2000 to protect at least an additional 8% of wolf habitat in western Poland, and discuss which specific forests are most in need of additional coverage. Implementation of these actions will have positive conservation implications and help Poland to fulfil its Habitats Directive obligations. As it is likely that similar gaps in Natura 2000 are arising in other EU member states experiencing large carnivore recoveries, particularly in Central Europe, we make the case for a flexible approach to Natura 2000 and suggest that such coverage evaluations may be beneficial elsewhere. PMID- 28873089 TI - Tempo and rates of diversification in the South American cichlid genus Apistogramma (Teleostei: Perciformes: Cichlidae). AB - Evaluating biodiversity and understanding the processes involved in diversification are noticeable conservation issues in fishes subject to large, sometimes illegal, ornamental trade purposes. Here, the diversity and evolutionary history of the Neotropical dwarf cichlid genus Apistogramma from several South American countries are investigated. Mitochondrial and nuclear markers are used to infer phylogenetic relationships between 31 genetically identified species. The monophyly of Apistogramma is suggested, and Apistogramma species are distributed into four clades, corresponding to three morphological lineages. Divergence times estimated with the Yule process and an uncorrelated lognormal clock dated the Apistogramma origin to the beginning of the Eocene (~ 50 Myr) suggesting that diversification might be related to marine incursions. Our molecular dating also suggests that the Quaternary glacial cycles coincide with the phases leading to Apistogramma speciation. These past events did not influence diversification rates in the speciose genus Apistogramma, since diversification appeared low and constant through time. Further characterization of processes involved in recent Apistogramma diversity will be necessary. PMID- 28873091 TI - Helicobacter pylori infection perturbs iron homeostasis in gastric epithelial cells. AB - The iron deficiency anaemia that often accompanies infection with Helicobacter pylori may reflect increased uptake of iron into gastric epithelial cells. Here we show an infection-associated increase in total intracellular iron levels was associated with the redistribution of the transferrin receptor from the cell cytosol to the cell surface, and with increased levels of ferritin, an intracellular iron storage protein that corresponded with a significant increase in lysosomal stores of labile iron. In contrast, the pool of cytosolic labile iron was significantly decreased in infected cells. These changes in intracellular iron distribution were associated with the uptake and trafficking of H. pylori through the cells, and enhanced in strains capable of expressing the cagA virulence gene. We speculate that degradation of lysosomal ferritin may facilitate H. pylori pathogenesis, in addition to contributing to bacterial persistence in the human stomach. PMID- 28873093 TI - Machine learning techniques for the optimization of joint replacements: Application to a short-stem hip implant. AB - Today, different implant designs exist in the market; however, there is not a clear understanding of which are the best implant design parameters to achieve mechanical optimal conditions. Therefore, the aim of this project was to investigate if the geometry of a commercial short stem hip prosthesis can be further optimized to reduce stress shielding effects and achieve better short stemmed implant performance. To reach this aim, the potential of machine learning techniques combined with parametric Finite Element analysis was used. The selected implant geometrical parameters were: total stem length (L), thickness in the lateral (R1) and medial (R2) and the distance between the implant neck and the central stem surface (D). The results show that the total stem length was not the only parameter playing a role in stress shielding. An optimized implant should aim for a decreased stem length and a reduced length of the surface in contact with the bone. The two radiuses that characterize the stem width at the distal cross-section in contact with the bone were less influential in the reduction of stress shielding compared with the other two parameters; but they also play a role where thinner stems present better results. PMID- 28873094 TI - Analysis of water level variation of lakes and reservoirs in Xinjiang, China using ICESat laser altimetry data (2003-2009). AB - This study utilizes ICESat Release 33 GLA14 data to analyse water level variation of Xinjiang's lakes and reservoirs from 2003 to 2009. By using Landsat images, lakes and reservoirs with area larger than 1 km2 are numerically delineated with a software tool. Based on ICESat observations, we analyse the characteristics of water level variation in different geographic environments, as well as investigate the reasons for the variation. Results indicate that climatic warming contributes to rising water levels in lakes in mountainous areas, especially for lakes that are recharged by snow and glacial melting. For lakes in oases, the water levels are affected jointly by human activity and climate change, while the water levels of reservoirs are mainly affected by human activity. Comparing the annual average rates of water levels, those of lakes are higher than those of reservoirs in oasis areas. The main reasons for the decreasing water levels in desert regions are the reduction of recharged runoff and high evaporation. By analysing the variation of water levels and water volume in different geologic environments, it is found that water level and volume increased in mountainous regions, and decreased in oasis regions and desert regions. Finding also demonstrate that decreasing volume is greater than increasing volume, which results in decreasing total volume of Xinjiang lakes and reservoirs. PMID- 28873095 TI - Longistyline C acts antidepressant in vivo and neuroprotection in vitro against glutamate-induced cytotoxicity by regulating NMDAR/NR2B-ERK pathway in PC12 cells. AB - Depressive disorder is a common psychiatric disease which ranks among the leading cause of disability worldwide. The antidepressants presently used had low cure rate and caused a variety of side-effects. The screening of antidepressant drugs is usually used classic behavioural tests and neuroprotective strategy. Longistyline C, a natural stilbene isolated from the leaves of Cajanuscajan (L.) Millsp, was firstly investigated the antidepressant effect using animal behavioural tests, and studied the neuroprotection and its possible signaling pathways on glutamate-induced injury in PC12 cells. The results of animal test demonstrated that longistyline C had the antidepressant activity, which the effect is similar to the positive control. In current study, we investigated the effect of longistyline C on glutamate-induced injury in PC12 cells and explored its possible signaling pathways. The results demonstrated that pretreatment with longistyline C at the concentrations of 2-8 MUmol/L for 24 h had a significant reduction of the cytotoxicity induced by glutamate (15 mmol/L) in PC12 cells using MTT, lactate dehydrogenase (LDH) release assay and Annexin V-PI double staining. Subsequently, we found that pretreatment with longistyline C (8 MUmol/L) could drastically down-regulate the over-expression of NMDAR/NR2B and Ca2+/calmodulin-dependent protein kinase II (CaMKII), up-regulate the expressions of p-ERK and p-CREB and alleviate ER stress. In conclusison, longistyline C is most possibly through regulating NMDAR/NR2B-ERK1/2 related pathway and restoring endoplasmic reticulum function to exert neuroprotective effect against glutamate induced injury in PC12 cells. PMID- 28873096 TI - Chronic obstructive pulmonary disease candidate gene prioritization based on metabolic networks and functional information. AB - Chronic obstructive pulmonary disease (COPD) is a multi-factor disease, in which metabolic disturbances played important roles. In this paper, functional information was integrated into a COPD-related metabolic network to assess similarity between genes. Then a gene prioritization method was applied to the COPD-related metabolic network to prioritize COPD candidate genes. The gene prioritization method was superior to ToppGene and ToppNet in both literature validation and functional enrichment analysis. Top-ranked genes prioritized from the metabolic perspective with functional information could promote the better understanding about the molecular mechanism of this disease. Top 100 genes might be potential markers for diagnostic and effective therapies. PMID- 28873092 TI - Effect of cervical cancer education and provider recommendation for screening on screening rates: A systematic review and meta-analysis. AB - BACKGROUND: Although cervical cancer is largely preventable through screening, detection and treatment of precancerous abnormalities, it remains one of the top causes of cancer-related morbidity and mortality globally. OBJECTIVES: The objective of this systematic review is to understand the evidence of the effect of cervical cancer education compared to control conditions on cervical cancer screening rates in eligible women population at risk of cervical cancer. We also sought to understand the effect of provider recommendations for screening to eligible women on cervical cancer screening (CCS) rates compared to control conditions in eligible women population at risk of cervical cancer. METHODS: We used the PICO (Problem or Population, Interventions, Comparison and Outcome) framework as described in the Cochrane Collaboration Handbook to develop our search strategy. The details of our search strategy has been described in our systematic review protocol published in the International Prospective Register of systematic reviews (PROSPERO). The protocol registration number is CRD42016045605 available at: http://www.crd.york.ac.uk/prospero/display_record.asp?src=trip&ID=CRD42016045605. The search string was used in Pubmed, Embase, Cochrane Systematic Reviews and Cochrane CENTRAL register of controlled trials to retrieve study reports that were screened for inclusion in this review. Our data synthesis and reporting was guided by the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). We did a qualitative synthesis of evidence and, where appropriate, individual study effects were pooled in meta-analyses using RevMan 5.3 Review Manager. The Higgins I2 was used to assess for heterogeneity in studies pooled together for overall summary effects. We did assessment of risk of bias of individual studies included and assessed risk of publication bias across studies pooled together in meta-analysis by Funnel plot. RESULTS: Out of 3072 study reports screened, 28 articles were found to be eligible for inclusion in qualitative synthesis (5 of which were included in meta-analysis of educational interventions and 8 combined in meta-analysis of HPV self-sampling interventions), while 45 were excluded for various reasons. The use of theory based educational interventions significantly increased CCS rates by more than double (OR, 2.46, 95% CI: 1.88, 3.21). Additionally, offering women the option of self-sampling for Human Papillomavirus (HPV) testing increased CCS rates by nearly 2-fold (OR = 1.71, 95% CI: 1.32, 2.22). We also found that invitation letters alone (or with a follow up phone contact), making an appointment, and sending reminders to patients who are due or overdue for screening had a significant effect on improving participation and CCS rates in populations at risk. CONCLUSION: Our findings supports the implementation of theory-based cervical cancer educational interventions to increase women's participation in cervical cancer screening programs, particularly when targeting communities with low literacy levels. Additionally, cervical cancer screening programs should consider the option of offering women the opportunity for self-sample collection particularly when such women have not responded to previous screening invitation or reminder letters for Pap smear collection as a method of screening. PMID- 28873097 TI - Assessment of the antioxidant and antibacterial activities of different olive processing wastewaters. AB - Olive processing wastewaters (OPW), namely olive mill wastewater (OMW) and table olive wastewaters (TOW) were evaluated for their antibacterial activity against five Gram-positive and two Gram-negative bacteria using the standard disc diffusion and thin layer chromatography (TLC)-bioautography assays. Disc diffusion screening and bioautography of OMW were compared to the phenolic extracts of table-olive brines. Positive activity against S. aureus was demonstrated. The optimization of chromatographic separation revealed that hexane/acetone in the ratio of 4:6 was the most effective for phenolic compounds separation. A HPLC-MS analysis was performed showing that only two compounds, hydroxytyrosol and tyrosol, were the predominant phenolic compounds in all OPW. The phenolic extract of OMW generated by a semi-modern process showed the highest free radical-scavenging activity (DPPH assay) compared to the other phenolic extracts. It is apparent from the present study that OPW are a rich source of antioxidants suitable for use in food, cosmetic or pharmaceutical applications. PMID- 28873098 TI - The impact of using chickpea flour and dried carp fish powder on pizza quality. AB - Pizza being the most popular food worldwide, quality and sensory appeal are important considerations during its modification effort. This study was aimed to evaluate the quality of pizza made using two different sources of proteins, chickpea (Cicer arietinum) flour and dried carp fish powder (Cyprinus carpio). Analysis indicated nutrients richness specificity of chickpea flour (higher fiber, energy, iron, zinc, linoleic acid and total nonessential amino acids) and dried carp fish powder (higher contents of protein, fats, ash, oleic acid and total essential amino acids) complementing wheat flour to enhance nutritional value of pizza. Total plate count and thiobarbituric acid were increased (P<0.05) in dried carp fish powder after 45 days of storage, but no Coliform were detected. Wheat flour was substituted with 5, 7.5 and 10% chickpea flour or dried carp fish powder and chemical, textural, sensory and storage evaluation parameters of in pizza were investigated. Dried carp fish powder increased (P<0.05) contents of protein, ash, fats, zinc and protein digestibility of pizza. Chickpea flour increased iron and zinc contents of the pizza. Water activity (aw) was decreased in fish powder and chickpea pizza. Pizza firmness and gumminess were significantly (p<0.05) increased at every level of protein source, but cohesiveness was decreased with 10% chickpea flour. Pizza chewiness was the same (P>0.05) across the levels of two protein sources. Springiness was decreased (P<0.05) with high level (10%) dried fish powder and low/intermediate level of chickpea flour. Chickpea and dried carp fish incorporation up to 7.50% in pizza at the expense of wheat flour had no effect (P>0.05) on all sensorial parameters except for odor values. The results could be useful in utilization of chickpea flour and carp fish powder in designing nutritious pizza for consumers. PMID- 28873100 TI - Topical cannabinoids in dermatology. AB - Topical cannabinoids are increasingly utilized by dermatology patients for a range of disorders; however, the acceptance of these over-the-counter products has far outpaced scientific investigation into their safety and efficacy. Here, we review the studies of topical cannabinoids in skin conditions and assess their current place in dermatology practice. PMID- 28873099 TI - Patient safety competency and educational needs of nursing educators in South Korea. AB - BACKGROUND: Nursing educators must be qualified to teach patient safety to nursing students to ensure patient safety in the clinical field. The purpose of this study was to assess nursing educators' competencies and educational needs for patient safety in hospitals and nursing schools. METHOD: A mixed-methods sequential explanatory design employed a survey and focus group interview with nursing educators (school clinical instructors and hospital nurse preceptors). Thirty-eight questionnaires filled out by clinical instructors from six four-year nursing universities and 106 questionnaires from nurse preceptors from three high level general hospitals in the Seoul metropolitan area were analyzed to obtain quantitative data. Focus group interviews were conducted among six clinical instructors from one nursing school and four nurse preceptors from one high-level general hospital in Seoul. RESULTS: Nursing educators had higher levels of attitude compared with relatively lower levels of skill and knowledge regarding patient safety. They reported educational needs of "medication" and "infection prevention" as being higher and "human factors" and "complexity of systems" as being lower. Nursing educators desired different types of education for patient safety. CONCLUSION: It is necessary to enhance nursing educators' patient safety skills and knowledge by developing and providing an integrated program of patient safety, with various teaching methods to meet their educational needs. The findings of this study provide the basic information needed to reform patient safety education programs appropriately to fit nursing educators' needs and their patient safety competencies in both clinical practice and academia. Furthermore, the findings have revealed the importance of effective communication between clinical and academic settings in making patient safety education seamless. PMID- 28873101 TI - Rosacea treatment schema: an update. PMID- 28873102 TI - Black adherence nodules on the scalp hair shaft. PMID- 28873103 TI - Large hyperpigmented nodule on the leg. PMID- 28873104 TI - Management of trauma and burn scars: the dermatologist's role in expanding patient access to care. AB - Recent advances in laser surgery and our understanding of wound healing have ushered in a new era of trauma and burn scar management. Traditional therapy has centered around scar excision followed by primary closure or tissue replacement with flaps and grafts. This approach represents a perpetuation of the common fallacy that extensive scar improvement requires extensive surgical intervention. Laser surgery in conjunction with pharmacotherapy and minor tissue-conserving surgery produces well-healed and remodeled existing tissue that provides the most natural appearance and function of the skin. Now, patients' hypertrophic, contracted, and disfiguring scars represent their most valuable reconstructive anatomy. With this paradigm shift, dermatologists are uniquely positioned to provide transformative and cost-effective scar therapy due to their proficiency in the necessary treatment modalities and expertise in the utilization of local anesthesia. We hope to further expand military and civilian patient access to such care in their local community through peer education and advocacy. We present a brief overview and outline of scar treatment practices that can be performed by dermatologists in office using devices and techniques they often already possess. PMID- 28873105 TI - Hair and scalp disorders in adult and pediatric patients with skin of color. AB - As increasing numbers of patients of African descent seek treatment for hair and scalp-related diseases, it is imperative that all dermatologists be adequately trained to address the concerns of this patient population. We present must-know information to effectively approach the concerns of patients with seborrheic dermatitis, acquired trichorrhexis nodosa, acne keloidalis nuchae, pseudofolliculitis barbae, alopecia, and common pediatric hair and scalp disorders. PMID- 28873107 TI - What's eating you? sticktight flea revisited. AB - The sticktight flea (Echidnophaga gallinacea) earns its name by embedding its head in the host's skin. It has been found in many species of birds and mammals, including humans. The sticktight flea is found worldwide in the tropics, subtropics, and temperate zones, and it is the only representative of this genus found in the United States. Bites from fleas cause irritation and itching for hosts including humans, typically resulting in clusters of firm, pruritic, erythematous papules. Treatment can be tricky, as the fleas can be difficult to remove, and any flea-infested environments should be properly treated to prevent further bites. PMID- 28873106 TI - Comparison of salicylic acid 30% peel and pneumatic broadband light in the treatment of mild to moderately severe facial acne vulgaris. AB - Acne patients experience not only a medical disease but also an aesthetic condition, and this latter complication greatly motivates patients to seek out the best treatment regimen to hasten improvement in their appearance. The available clinical procedures for acne treatment include salicylic acid 30% peel and pneumatic broadband light (PBBL). The objective of this study was to compare the efficacy of salicylic acid 30% peel and PBBL treatments in patients with mild to moderately severe facial acne vulgaris. Twelve patients were recruited for a 12-week prospective, single-blind, randomized, split-face study. Patients were treated with a salicylic acid 30% peel on one side of the face and PBBL treatment was administered on the opposite side of the face for 6 consecutive weeks without other acne treatments. At every visit, treatment evaluations were performed using a modified Global Acne Grading Score (mGAGS), acne quality of life (QOL) questionnaire, Wong-Baker FACES Pain Rating Scale (WBPRS) assessments, and clinical photography. Improvement in acne symptoms was observed for both treatment procedures without significant differences and with minimal side effects. Salicylic acid 30% peel and PBBL were well tolerated in our study, and both clinical procedures were efficacious and well-tolerated by the patients. PMID- 28873108 TI - Phototherapy coding and documentation in the time of biologics. PMID- 28873109 TI - Lack of significant anti-inflammatory activity with clindamycin in the treatment of rosacea: results of 2 randomized, vehicle-controlled trials. AB - Rosacea is a chronic inflammatory skin disease of the face. The objective of the studies described here was to evaluate the efficacy of clindamycin in the treatment of rosacea. Two multicenter, randomized, vehicle-controlled, phase 2 studies were conducted in participants with moderate to severe rosacea. Study A was a 12-week dose-comparison, 5-arm, parallel group comparison of clindamycin cream 1% or vehicle once or twice daily and clindamycin cream 0.3% once daily. Study B was a 2-arm comparison of twice daily clindamycin gel 1% versus vehicle gel. A total of 629 participants (study A, N=416; study B, N=213) were randomized. The results of these studies indicated that clindamycin cream 0.3% and 1% and clindamycin gel 1% were no more effective than the vehicle in the treatment of moderate to severe rosacea, suggesting clindamycin has no intrinsic anti-inflammatory activity in rosacea. PMID- 28873111 TI - Chronic diffuse erythematous papulonodules. PMID- 28873110 TI - Eroded plaque on the lower lip. PMID- 28873112 TI - Dermatofibrosarcoma protuberans. PMID- 28873113 TI - Temporal triangular alopecia acquired in adulthood. PMID- 28873114 TI - Hereditary hypotrichosis simplex of the scalp. PMID- 28873116 TI - Rowell syndrome: targeting a true definition. AB - Ever since a rare syndrome of lupus erythematosus (LE) presenting with erythema multiforme (EM)-like lesions was described in 1963, clinicians have questioned the defining characteristics of the so-called Rowell syndrome (RS) in addition to its very existence as a unique pathological entity. In this article, we present a new case of RS and investigate the various components and criteria that have been outlined in the years since this syndrome's original account. PMID- 28873115 TI - Co-occurrence of steatocystoma multiplex, eruptive vellus hair cysts, and trichofolliculomas. AB - An association between steatocystoma multiplex (SCM) and eruptive vellus hair cysts (EVHCs) has been recognized. Steatocystoma multiplex and EVHC have similar clinical features but distinctive histologic features. Rare cases of co occurrence of these conditions have been known to occur on the trunk and the forehead. We report a rare case of the simultaneous occurrence of SCM, EVHC, and trichofolliculomas localized to the forehead. PMID- 28873117 TI - Evaluating the clinical and demographic features of extrafacial granuloma faciale. AB - Granuloma faciale (GF) is an uncommon cutaneous disease of uncertain etiology that predominantly affects the face. Extrafacial lesions are rare. The purpose of this study was to describe the clinical and demographic features of a series of patients with extrafacial manifestations of GF who were diagnosed and treated at a single center over more than 5 decades. We performed a retrospective medical record analysis for all patients diagnosed with extrafacial GF who were treated at Mayo Clinic (Rochester, Minnesota) from 1959 through 2013. During the study period, extrafacial GF was diagnosed in 10 patients (6 men, 4 women), all of whom were white. The mean age was 58.7 years (range, 26-87 years). Seven patients presented with both facial and extrafacial lesions. Although extrafacial lesions are rare in GF, this condition should be included in the differential diagnosis of well-demarcated plaques and nodules found on the arms and legs. PMID- 28873118 TI - Topical timolol may improve overall scar cosmesis in acute surgical wounds. AB - Acute wounds created by dermatologists following the removal of nonmelanoma skin cancers are closed either by primary or secondary intention, and the best cosmetic outcome is preferentially desired. One parameter that determines the overall cosmesis of the healed wound is its vascularity. Vascular tone results from a complex interplay of a variety of chemokines in the body and their interaction with receptors located on endothelial cell surfaces. In this study, our aim was to determine if topical timolol could improve the overall cosmesis of acute surgical wounds. We determined that patients who treated their acute surgical wounds with topical timolol had improved cosmesis compared to control. PMID- 28873119 TI - The 2017 US Preventive Services Task Force Report on Preschool Vision Screening. PMID- 28873120 TI - The Ideal Blood Pressure Target for Patients With Chronic Kidney Disease Searching for the Sweet Spot. PMID- 28873122 TI - Medicine's Firsts. PMID- 28873123 TI - Human Immunodeficiency Virus Preexposure Prophylaxis for Adolescent Men: How Do We Ensure Health Equity for At-Risk Young Men? PMID- 28873121 TI - Truth Telling in the Setting of Cultural Differences and Incurable Pediatric Illness: A Review. AB - Importance: Navigating requests from parents or family caregivers not to disclose poor prognosis to seriously ill children can be challenging, especially when the requests seem culturally mediated. Pediatric clinicians must balance obligations to respect individual patient autonomy, professional truth telling, and tolerance of multicultural values. Observations: To provide suggestions for respectful and ethically appropriate responses to nondisclosure requests, we used a hypothetical case example of a Middle Eastern adolescent patient with incurable cancer and conducted an ethical analysis incorporating (1) evidence from both Western and Middle Eastern medical literature and (2) theories of cultural relativism and justice. While Western medical literature tends to prioritize patient autonomy and corresponding truth telling, the weight of evidence from the Middle East suggests high variability between and within individual countries, patient physician relationships, and families regarding truth-telling practices and preferences. A common reason for nondisclosure in both populations is protecting the child from distressing information. Cultural relativism fosters tolerance of diverse beliefs and behaviors by forbidding judgment on foreign societal codes of conduct. It does not justify assumptions that all individuals within a single culture share the same values, nor does it demand that clinicians sacrifice their own codes of conduct out of cultural respect. We suggest some phrases that may help clinicians explore motivations behind nondisclosure requests and gently confront conflict in order to serve the patient's best interest. Conclusions and Relevance: It is sometimes ethically permissible to defer to family values regarding nondisclosure, but such deferral is not unique to cultural differences. Early setting of expectations and boundaries, as well as ongoing exploration of family and health care professional concerns, may mitigate conflict. PMID- 28873124 TI - Trends in Dementia Incidence in a Birth Cohort Analysis of the Einstein Aging Study. AB - Importance: Trends in dementia incidence rates have important implications for planning and prevention. To better understand incidence trends over time requires separation of age and cohort effects, and few prior studies have used this approach. Objectives: To examine trends in dementia incidence and concomitant trends in cardiovascular comorbidities among individuals aged 70 years or older who were enrolled in the Einstein Aging Study between 1993 and 2015. Design, Setting, and Participants: In this birth cohort analysis of all-cause dementia incidence in persons enrolled in the Einstein Aging Study from October 20, 1993, through November 17, 2015, a systematically recruited, population-based sample of 1348 participants from Bronx County, New York, who were 70 years or older without dementia at enrollment and at least one annual follow-up was studied. Poisson regression was used to model dementia incidence as a function of age, sex, educational level, race, and birth cohort, with profile likelihood used to identify the timing of significant increases or decreases in incidence. Exposures: Birth year and age. Main Outcomes and Measures: Incident dementia defined by consensus case conference based on annual, standardized neuropsychological and neurologic examination findings, using criteria from the DSM-IV. Results: Among 1348 individuals (mean [SD] baseline age, 78.5 [5.4] years; 830 [61.6%] female; 915 [67.9%] non-Hispanic white), 150 incident dementia cases developed during 5932 person-years (mean [SD] follow-up, 4.4 [3.4] years). Dementia incidence decreased in successive birth cohorts. Incidence per 100 person-years was 5.09 in birth cohorts before 1920, 3.11 in the 1920 through 1924 birth cohorts, 1.73 in the 1925 through 1929 birth cohorts, and 0.23 in cohorts born after 1929. Change point analyses identified a significant decrease in dementia incidence among those born after July 1929 (95% CI, June 1929 to January 1930). The relative rate for birth cohorts before July 1929 vs after was 0.13 (95% CI, 0.04-0.41). Prevalence of stroke and myocardial infarction decreased across successive birth cohorts, whereas diabetes prevalence increased. Adjustment for these cardiovascular comorbidities did not explain the decreased dementia incidence rates for more recent birth cohorts. Conclusions and Relevance: Analyses confirm decreasing dementia incidence in this population based sample. Whether decreasing incidence will contribute to reduced burden of dementia given the aging of the population is not known. PMID- 28873126 TI - Vision Screening in Very Young Children-Making Sense of an Inexorable Diagnostic Process. PMID- 28873127 TI - New Approaches for Appendicitis in Children. PMID- 28873125 TI - Neurological Complications Associated With Anti-Programmed Death 1 (PD-1) Antibodies. AB - Importance: Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established. Objective: To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy. Design, Setting, and Participants: This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti-PD 1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti-PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded. Main Outcomes and Measures: Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score. Results: Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died. Conclusions and Relevance: Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended. In some cases, immune rescue treatment may be required. PMID- 28873130 TI - Neurological Complications of Immunotherapies-Beware of the Checkpoint Ahead. PMID- 28873131 TI - Navigating Nondisclosure Requests in Pediatrics: Honesty and Sensitivity Are Transcultural Practices. PMID- 28873132 TI - Health Care Workforce Development to Enhance Mental and Behavioral Health of Children and Youths. PMID- 28873128 TI - Safety and Feasibility of Antiretroviral Preexposure Prophylaxis for Adolescent Men Who Have Sex With Men Aged 15 to 17 Years in the United States. AB - Importance: Adolescents represent a key population for implementing preexposure prophylaxis (PrEP) interventions worldwide, yet tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for PrEP is only licensed for adults. Objective: To examine the safety of and adherence to PrEP along with changes in sexual risk behavior among adolescent men who have sex with men (MSM). Design, Setting, and Participants: Adolescent Medicine Trials Network for HIV/AIDS Interventions 113 (Project PrEPare) was a PrEP demonstration project that evaluated the safety, tolerability, and acceptability of TDF/FTC and patterns of use, rates of adherence, and patterns of sexual risk behavior among healthy young MSM aged 15 to 17 years. Participants were recruited from adolescent medicine clinics and their community partners in 6 US cities, had negative test results for human immunodeficiency virus (HIV) but were at high risk for acquiring an infection, and were willing to participate in a behavioral intervention and accept TDF/FTC as PrEP. Exposures: All participants completed an individualized evidence-based behavioral intervention and were provided with daily TDF/FTC as PrEP for 48 weeks. Main Outcomes and Measures: The main objectives were to: (1) provide additional safety data regarding TDF/FTC use among young MSM who had negative test results for HIV; (2) examine the acceptability, patterns of use, rates of adherence, and measured levels of tenofovir diphosphate in dried blood spots; and (3) examine patterns of risk behavior when young MSM were provided with a behavioral intervention in conjunction with open-label TDF/FTC. Results: Among 2864 individuals screened (from August 2013 to September 2014), 260 were eligible and 78 were enrolled (mean [SD] age, 16.5 [0.73] years), of whom 2 (3%) were Asian/Pacific Islander, 23 (29%) were black/African American, 11 (14%) were white, 16 (21%) were white Hispanic, and 26 (33%) were other/mixed race/ethnicity. Over 48 weeks of PrEP use, 23 sexually transmitted infections were diagnosed in 12 participants. The HIV seroconversion rate was 6.4 (95% CI: 1.3-18.7) per 100 person-years. Tenofovir diphosphate levels consistent with a high degree of anti-HIV protection (>700 fmol/punch) were found in 42 (54%), 37 (47%), 38 (49%), 22 (28%), 13 (17%), and 17 (22%) participants at weeks 4, 8, 12, 24, 36, and 48, respectively. Conclusions and Relevance: Adolescent Medicine Trials Network for HIV/AIDS Interventions 113 enrolled a diverse sample of adolescent MSM at risk for HIV who consented to study participation. Approximately half achieved protective drug levels during the monthly visits, but adherence decreased with quarterly visits. Youth may need additional contact with clinical staff members to maintain high adherence. Trial Registration: clinicaltrials.gov Identifier: NCT01769456. PMID- 28873129 TI - Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children. AB - Importance: Conventional methods to diagnose and monitor chronic kidney disease (CKD) in children, such as creatinine level and cystatin C-derived estimated glomerular filtration rate (eGFR) and assessment of proteinuria in spot or timed urine samples, are of limited value in identifying patients at risk of progressive kidney function loss. Serum soluble urokinase receptor (suPAR) levels strongly predict incident CKD stage 3 in adults. Objective: To determine whether elevated suPAR levels are associated with renal disease progression in children with CKD. Design, Setting, and Participants: Post hoc analysis of 2 prospectively followed up pediatric CKD cohorts, ie, the ESCAPE Trial (1999-2007) and the 4C Study (2010-2016), with serum suPAR level measured at enrollment and longitudinal eGFR measured prospectively. In the 2 trials, a total of 898 children were observed at 30 (ESCAPE Trial; n = 256) and 55 (4C Study; n = 642) tertiary care hospitals in 13 European countries. Renal diagnoses included congenital anomalies of the kidneys and urinary tract (n = 637 [70.9%]), tubulointerstitial nephropathies (n = 92 [10.2%]), glomerulopathies (n = 69 [7.7%]), postischemic CKD (n = 42 [4.7%]), and other CKD (n = 58 [6.5%]). Total follow-up duration was up to 7.9 years, and median follow-up was 3.1 years. Analyses were conducted from October 2016 to December 2016. Exposures: Serum suPAR level was measured at enrollment, and eGFR was measured every 2 months in the ESCAPE Trial and every 6 months in the 4C Study. The primary end point of CKD progression was a composite of 50% eGFR loss, eGFR less than 10 mL/min/1.73 m2, or initiation of renal replacement therapy. Main Outcomes and Measures: The primary end point in this study was renal survival, defined as a composite of 50% loss of GFR that persisted for at least 1 month, the start of renal replacement therapy, or an eGFR less than 10 mL/min/1.73 m2. Results: Of the 898 included children, 560 (62.4%) were male, and the mean (SD) patient age at enrollment was 11.9 (3.5) years. The mean (SD) eGFR was 34 (16) mL/min/1.73 m2. The 5-year end point-free renal survival was 64.5% (95% CI, 57.4-71.7) in children with suPAR levels in the lowest quartile compared with 35.9% (95% CI, 28.7-43.0) in those in the highest quartile (P < .001). By multivariable analysis, the risk of attaining the end point was higher in children with glomerulopathies and increased with age, blood pressure, proteinuria, and lower eGFR at baseline. In patients with baseline eGFR greater than 40 mL/min/1.73 m2, higher log-transformed suPAR levels were associated with a higher risk of CKD progression after adjustment for traditional risk factors (hazard ratio, 5.12; 95% CI, 1.56-16.7; P = .007). Conclusions and Relevance: Patients with high suPAR levels were more likely to have progression of their kidney disease. Further studies should determine whether suPAR levels can identify children at risk for future CKD. PMID- 28873133 TI - Distribution of Medical Education Debt by Specialty, 2010-2016. PMID- 28873134 TI - Infectious Pneumorrhachis Due to Emphysematous Pyelonephritis. PMID- 28873136 TI - The Harms of Empirical Bowel Regimens: A Teachable Moment. PMID- 28873138 TI - Mistakes Were Made (by Me). PMID- 28873139 TI - Using Risk Stratification to Reduce Medical Errors in Cervical Cancer Prevention. PMID- 28873135 TI - Photoreceptor-Based Biomarkers in AOSLO Retinal Imaging. AB - Improved understanding of the mechanisms underlying inherited retinal degenerations has created the possibility of developing much needed treatments for these relentless, blinding diseases. However, standard clinical indicators of retinal health (such as visual acuity and visual field sensitivity) are insensitive measures of photoreceptor survival. In many retinal degenerations, significant photoreceptor loss must occur before measurable differences in visual function are observed. Thus, there is a recognized need for more sensitive outcome measures to assess therapeutic efficacy as numerous clinical trials are getting underway. Adaptive optics (AO) retinal imaging techniques correct for the monochromatic aberrations of the eye and can be used to provide nearly diffraction-limited images of the retina. Many groups routinely are using AO imaging tools to obtain in vivo images of the rod and cone photoreceptor mosaic, and it now is possible to monitor photoreceptor structure over time with single cell resolution. Highlighting recent work using AO scanning light ophthalmoscopy (AOSLO) across a range of patient populations, we review the development of photoreceptor-based metrics (e.g., density/geometry, reflectivity, and size) as candidate biomarkers. Going forward, there is a need for further development of automated tools and normative databases, with the latter facilitating the comparison of data sets across research groups and devices. Ongoing and future clinical trials for inherited retinal diseases will benefit from the improved resolution and sensitivity that multimodal AO retinal imaging affords to evaluate safety and efficacy of emerging therapies. PMID- 28873137 TI - Association Between More Intensive vs Less Intensive Blood Pressure Lowering and Risk of Mortality in Chronic Kidney Disease Stages 3 to 5: A Systematic Review and Meta-analysis. AB - Importance: Trials in patients with hypertension have demonstrated that intensive blood pressure (BP) lowering reduces the risk of cardiovascular disease and all cause mortality but may increase the risk of chronic kidney disease (CKD) incidence and progression. Whether intensive BP lowering is associated with a mortality benefit in patients with prevalent CKD remains unknown. Objectives: To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) to investigate if more intensive compared with less intensive BP control is associated with reduced mortality risk in persons with CKD stages 3 to 5. Data Sources: Ovid MEDLINE, Cochrane Library, EMBASE, PubMed, Science Citation Index, Google Scholar, and clinicaltrials.gov electronic databases. Study Selection: All RCTs were included that compared 2 defined BP targets (either active BP treatment vs placebo or no treatment, or intensive vs less intensive BP control) and enrolled adults (>=18 years) with CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m2) exclusively or that included a CKD subgroup between January 1, 1950, and June 1, 2016. Data Extraction and Synthesis: Two of us independently evaluated study quality and extracted characteristics and mortality events among persons with CKD within the intervention phase for each trial. When outcomes within the CKD group had not previously been published, trial investigators were contacted to request data within the CKD subset of their original trials. Main Outcome and Measure: All-cause mortality during the active treatment phase of each trial. Results: This study identified 30 RCTs that potentially met the inclusion criteria. The CKD subset mortality data were extracted in 18 trials, among which there were 1293 deaths in 15 924 participants with CKD. The mean (SD) baseline systolic BP (SBP) was 148 (16) mm Hg in both the more intensive and less intensive arms. The mean SBP dropped by 16 mm Hg to 132 mm Hg in the more intensive arm and by 8 mm Hg to 140 mm Hg in the less intensive arm. More intensive vs less intensive BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, 0.76-0.97; P = .01), a finding that was without significant heterogeneity and appeared consistent across multiple subgroups. Conclusions and Relevance: Randomization to more intensive BP control is associated with lower mortality risk among trial participants with hypertension and CKD. Further studies are required to define absolute BP targets for maximal benefit and minimal harm. PMID- 28873140 TI - Association of Evidence-Based Care Processes With Mortality in Staphylococcus aureus Bacteremia at Veterans Health Administration Hospitals, 2003-2014. AB - Importance: Staphylococcus aureus bacteremia is common and frequently associated with poor outcomes. Evidence indicates that specific care processes are associated with improved outcomes for patients with S aureus bacteremia, including appropriate antibiotic prescribing, use of echocardiography to identify endocarditis, and consultation with infectious diseases (ID) specialists. Whether use of these care processes has increased in routine care for S aureus bacteremia or whether use of these processes has led to large-scale improvements in survival is unknown. Objective: To examine the association of evidence-based care processes in routine care for S aureus bacteremia with mortality. Design, Setting, and Participants: This retrospective observational cohort study examined all patients admitted to Veterans Health Administration (VHA) acute care hospitals who had a first episode of S aureus bacteremia from January 1, 2003, through December 31, 2014. Exposures: Use of appropriate antibiotic therapy, echocardiography, and ID consultation. Main Outcomes and Measures: Thirty-day all cause mortality. Results: Analyses included 36 868 patients in 124 hospitals (mean [SD] age, 66.4 [12.5] years; 36 036 [97.7%] male), including 19 325 (52.4%) with infection due to methicillin-resistant S aureus and 17 543 (47.6%) with infection due to methicillin-susceptible S aureus. Risk-adjusted mortality decreased from 23.5% (95% CI, 23.3%-23.8%) in 2003 to 18.2% (95% CI, 17.9%-18.5%) in 2014. Rates of appropriate antibiotic prescribing increased from 2467 (66.4%) to 1991 (78.9%), echocardiography from 1256 (33.8%) to 1837 (72.8%), and ID consultation from 1390 (37.4%) to 1717 (68.0%). After adjustment for patient characteristics, cohort year, and other care processes, receipt of care processes was associated with lower mortality, with adjusted odds ratios of 0.74 (95% CI, 0.68-0.79) for appropriate antibiotics, 0.73 (95% CI, 0.68-0.78) for echocardiography, and 0.61 (95% CI, 0.56-0.65) for ID consultation. Mortality decreased progressively as the number of care processes that a patient received increased (adjusted odds ratio for all 3 processes compared with none, 0.33; 95% CI, 0.30-0.36). An estimated 57.3% (95% CI, 48.4%-69.9%) of the decrease in mortality between 2003 and 2014 could be attributed to increased use of these evidence-based care processes. Conclusions and Relevance: Mortality associated with S aureus bacteremia decreased significantly in VHA hospitals, and a substantial portion of the decreasing mortality may have been attributable to increased use of evidence-based care processes. The experience in VHA hospitals demonstrates that increasing application of these care processes may improve survival among patients with S aureus bacteremia in routine health care settings. PMID- 28873142 TI - Using Outreach to Improve Colorectal Cancer Screening. PMID- 28873141 TI - Organoids Reveal Clues to Gut-Brain Communication. PMID- 28873143 TI - The Potential and Challenges of Expanded Germline Testing in Clinical Oncology. PMID- 28873145 TI - Combination Drug for HCV Infection. PMID- 28873144 TI - Correcting the Medical Literature: "To Err Is Human, to Correct Divine". PMID- 28873146 TI - MRI for Neonates. PMID- 28873147 TI - New Formulation of Lupus Drug. PMID- 28873149 TI - Preimplantation Genetic Diagnosis for Mendelian Conditions. PMID- 28873151 TI - "Found: A One Day Cure for Syphilis". PMID- 28873150 TI - A Bipartisan "Moonshot" in Health: Improving Care for High-Need Patients. PMID- 28873152 TI - Change in Medical Exemptions From Immunization in California After Elimination of Personal Belief Exemptions. PMID- 28873153 TI - Spinal Manipulative Therapy for Low Back Pain. PMID- 28873154 TI - High-Sensitivity Troponin Levels, Ischemia, and Mortality. PMID- 28873155 TI - Managing Conflicts of Interest in Practice Guidelines Panels. PMID- 28873156 TI - Managing Conflicts of Interest in Practice Guidelines Panels. PMID- 28873157 TI - Spinal Manipulative Therapy for Low Back Pain-Reply. PMID- 28873158 TI - High-Sensitivity Troponin Levels, Ischemia, and Mortality-Reply. PMID- 28873159 TI - Managing Conflicts of Interest in Practice Guidelines Panels-Reply. PMID- 28873160 TI - Effect of Physician Notification Regarding Nonadherence to Colorectal Cancer Screening on Patient Participation in Fecal Immunochemical Test Cancer Screening: A Randomized Clinical Trial. AB - Importance: Increasing participation in fecal screening tests is a major challenge in countries that have implemented colorectal cancer (CRC) screening programs. Objective: To determine whether providing general practitioners (GPs) a list of patients who are nonadherent to CRC screening enhances patient participation in fecal immunochemical testing (FIT). Design, Setting, and Participants: A 3-group, cluster-randomized study was conducted from July 14, 2015, to July 14, 2016, on the west coast of France, with GPs in 801 practices participating and involving adult patients (50-74 years) who were at average risk of CRC and not up-to-date with CRC screening. The final follow-up date was July 14, 2016. Interventions: General practitioners were randomly assigned to 1 of 3 groups: 496 received a list of patients who had not undergone CRC screening (patient-specific reminders group, 10 476 patients), 495 received a letter describing region-specific CRC screening adherence rates (generic reminders group, 10 606 patients), and 455 did not receive any reminders (usual care group, 10 147 patients). Main Outcomes and Measures: The primary end point was patient participation in CRC screening 1 year after the intervention. Results: Among 1482 randomized GPs (mean age, 53.4 years; 576 women [38.9%]), 1446 participated; of the 33 044 patients of these GPs (mean age, 59.7 years; 17 949 women [54.3%]), follow-up at 1 year was available for 31 229 (94.5%). At 1 year, 24.8% (95% CI, 23.4%-26.2%) of patients in the specific reminders group, 21.7% (95% CI, 20.5% 22.8%) in the generic reminders group, and 20.6% (95% CI, 19.3%-21.8%) in the usual care group participated in the FIT screening. The between-group differences were 3.1% (95% CI, 1.3%-5.0%) for the patient-specific reminders group vs the generic reminders group, 4.2% (95% CI, 2.3%-6.2%) for the patient-specific reminders group vs the usual care group, and 1.1% (95% CI, -0.6% to 2.8%) for generic reminders group vs the usual care group. Conclusions and Relevance: Providing French GPs caring for adults at average risk of CRC with a list of their patients who were not up-to-date with their CRC screening resulted in a small but significant increase in patient participation in FIT screening at 1 year compared with patients who received usual care. Providing GPs with generic reminders about regional rates of CRC screening did not increase screening rates compared with usual care. Trial Registration: clinicaltrials.gov Identifier: NCT02515344. PMID- 28873161 TI - Effect of Colonoscopy Outreach vs Fecal Immunochemical Test Outreach on Colorectal Cancer Screening Completion: A Randomized Clinical Trial. AB - Importance: Mailed fecal immunochemical test (FIT) outreach is more effective than colonoscopy outreach for increasing 1-time colorectal cancer (CRC) screening, but long-term effectiveness may need repeat testing and timely follow up for abnormal results. Objective: Compare the effectiveness of FIT outreach and colonoscopy outreach to increase completion of the CRC screening process (screening initiation and follow-up) within 3 years. Design, Setting, and Participants: Pragmatic randomized clinical trial from March 2013 to July 2016 among 5999 participants aged 50 to 64 years who were receiving primary care in Parkland Health and Hospital System and were not up to date with CRC screenings. Interventions: Random assignment to mailed FIT outreach (n = 2400), mailed colonoscopy outreach (n = 2400), or usual care with clinic-based screening (n = 1199). Outreach included processes to promote repeat annual testing for individuals in the FIT outreach group with normal results and completion of diagnostic and screening colonoscopy for those with an abnormal FIT result or assigned to colonoscopy outreach. Main Outcomes and Measures: Primary outcome was screening process completion, defined as adherence to colonoscopy completion, annual testing for a normal FIT result, diagnostic colonoscopy for an abnormal FIT result, or treatment evaluation if CRC was detected. Secondary outcomes included detection of any adenoma or advanced neoplasia (including CRC) and screening-related harms (including bleeding or perforation). Results: All 5999 participants (median age, 56 years; women, 61.9%) were included in the intention to-screen analyses. Screening process completion was 38.4% in the colonoscopy outreach group, 28.0% in the FIT outreach group, and 10.7% in the usual care group. Compared with the usual care group, between-group differences for completion were higher for both outreach groups (27.7% [95% CI, 25.1% to 30.4%] for the colonoscopy outreach group; 17.3% [95% CI, 14.8% to 19.8%] for FIT outreach group), and highest in the colonoscopy outreach group (10.4% [95% CI, 7.8% to 13.1%] for the colonoscopy outreach group vs FIT outreach group; P < .001 for all comparisons). Compared with usual care, the between-group differences in adenoma and advanced neoplasia detection rates were higher for both outreach groups (colonoscopy outreach group: 10.3% [95% CI, 9.5% to 12.1%] for adenoma and 3.1% [95% CI, 2.0% to 4.1%] for advanced neoplasia, P < .001 for both comparisons; FIT outreach group: 1.3% [95% CI, -0.1% to 2.8%] for adenoma and 0.7% [95% CI, -0.2% to 1.6%] for advanced neoplasia, P < .08 and P < .13, respectively), and highest in the colonoscopy outreach group (colonoscopy outreach group vs FIT outreach group: 9.0% [95% CI, 7.3% to 10.7%] for adenoma and 2.4% [95% CI, 1.3% to 3.3%] for advanced neoplasia, P < .001 for both comparisons). There were no screening-related harms in any groups. Conclusions and Relevance: Among persons aged 50 to 64 years receiving primary care at a safety-net institution, mailed outreach invitations offering FIT or colonoscopy compared with usual care increased the proportion completing CRC screening process within 3 years. The rate of screening process completion was higher with colonoscopy than FIT outreach. Trial Registration: clinicaltrials.gov Identifier: NCT01710215. PMID- 28873163 TI - Vision Screening in Children. PMID- 28873165 TI - Delivering Emotions. PMID- 28873162 TI - Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. AB - Importance: Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. Objective: To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines. Design, Setting, and Participants: From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. Exposure: Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. Main Outcomes and Measures: Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. Results: Of 1040 patients, the median age was 58 years (interquartile range, 50.5 66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. Conclusions and Relevance: In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. Trial Registration: clinicaltrials.gov Identifier: NCT01775072. PMID- 28873167 TI - Vision Screening in Children Aged 6 Months to 5 Years: Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Preschool vision screening could allow detection and treatment of vision abnormalities during a critical developmental stage, preserving function and quality of life. Objective: To review the evidence on screening for and treatment of amblyopia, its risk factors, and refractive error in children aged 6 months to 5 years to inform the US Preventive Services Task Force. Data Sources: MEDLINE, Cochrane Library, CINAHL, and trial registries through June 2016; references; and experts, with surveillance of the literature through June 7, 2017. Study Selection: English-language randomized clinical trials (RCTs) or prospective cohort studies that evaluated screening, studies evaluating test accuracy, RCTs of treatment vs inactive controls, and cohort studies or case control studies assessing harms. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings. Studies were not quantitatively pooled because of clinical and methodological heterogeneity. Main Outcomes and Measures: Visual acuity, amblyopia, school performance, functioning, quality of life, test accuracy, testability, and harms. Results: Forty studies were included (N = 34 709); 34 evaluated test accuracy. No RCTs compared screening with no screening, and no studies evaluated school performance, function, or quality of life. Studies directly assessing earlier or more intensive screening were limited by high attrition. Positive likelihood ratios were between 5 and 10 for amblyopia risk factors or nonamblyogenic refractive error in most studies of test accuracy and were greater than 10 in most studies evaluating combinations of clinical tests. Inability to cooperate may limit use of some tests in children younger than 3 years. Studies with low prevalence (<10%) of vision abnormalities showed high false-positive rates (usually >75%). Among children with amblyopia risk factors (eg, strabismus or anisometropia), patching improved visual acuity of the amblyopic eye by a mean of less than 1 line on a standard chart after 5 to 12 weeks for children pretreated with glasses (2 RCTs, 240 participants); more children treated with patching than with no patching experienced improvement of at least 2 lines (45% vs 21%; P = .003; 1 RCT, 180 participants). Patching plus glasses improved visual acuity by about 1 line after 1 year (0.11 logMAR [95% CI, 0.05-0.17]) for children not pretreated with glasses (1 RCT, 177 participants). Glasses alone improved visual acuity by less than 1 line after 1 year (0.08 logMAR [95% CI, 0.02-0.15], 1 RCT, 177 participants). Conclusions and Relevance: Studies directly evaluating the effectiveness of screening were limited and do not establish whether vision screening in preschool children is better than no screening. Indirect evidence supports the utility of multiple screening tests for identifying preschool children at higher risk for vision problems and the effectiveness of some treatments for improving visual acuity outcomes. PMID- 28873169 TI - Error in Table. PMID- 28873168 TI - Vision Screening in Children Aged 6 Months to 5 Years: US Preventive Services Task Force Recommendation Statement. AB - Importance: One of the most important causes of vision abnormalities in children is amblyopia (also known as "lazy eye"). Amblyopia is an alteration in the visual neural pathway in a child's developing brain that can lead to permanent vision loss in the affected eye. Among children younger than 6 years, 1% to 6% have amblyopia or its risk factors (strabismus, anisometropia, or both). Early identification of vision abnormalities could prevent the development of amblyopia. Subpopulation Considerations: Studies show that screening rates among children vary by race/ethnicity and family income. Data based on parent reports from 2009-2010 indicated identical screening rates among black non-Hispanic children and white non-Hispanic children (80.7%); however, Hispanic children were less likely than non-Hispanic children to report vision screening (69.8%). Children whose families earned 200% or more above the federal poverty level were more likely to report vision screening than families with lower incomes. Objective: To update the 2011 US Preventive Services Task Force (USPSTF) recommendation on screening for amblyopia and its risk factors in children. Evidence Review: The USPSTF reviewed the evidence on the accuracy of vision screening tests and the benefits and harms of vision screening and treatment. Surgical interventions were considered to be out of scope for this review. Findings: Treatment of amblyopia is associated with moderate improvements in visual acuity in children aged 3 to 5 years, which are likely to result in permanent improvements in vision throughout life. The USPSTF concluded that the benefits are moderate because untreated amblyopia results in permanent, uncorrectable vision loss, and the benefits of screening and treatment potentially can be experienced over a child's lifetime. The USPSTF found adequate evidence to bound the potential harms of treatment (ie, higher false-positive rates in low-prevalence populations) as small. Therefore, the USPSTF concluded with moderate certainty that the overall net benefit is moderate for children aged 3 to 5 years. Conclusions and Recommendations: The USPSTF recommends vision screening at least once in all children aged 3 to 5 years to detect amblyopia or its risk factors. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of vision screening in children younger than 3 years. (I statement). PMID- 28873172 TI - Tachyarrhythmia Onset Captured on Telemetry Deciphers the Diagnosis. PMID- 28873174 TI - Performing Reliable Lens Capsulotomy in the Presence of Corneal Edema With a Femtosecond Laser. AB - Purpose: To determine the effects of the Ziemer LDV Z8 liquid interface femtosecond laser platform during capsulotomy under different energy settings in the presence of corneal edema. Methods: Cadaveric porcine eyes (n = 36) employed at less than 6 and greater than 24 post enucleation hours to simulate clear/edematous corneas, underwent capsulotomy with the Ziemer LDV Z8 femtosecond laser (5-mm diameter, energy 90%, 130%, or 150%). Lens capsules were removed for evaluation by scanning electron microscopy and rupture strengths determined by the single column universal testing system. Following ethical approval, 23 patients had lens capsules removed during routine cataract surgery following manual or Z8 capsulotomy and subjected to TUNEL assay. Results: There was no difference in edge morphology or rupture strength (120, 113, and 118 mN at increasing energy, P = 0.42) in the clear cornea. Only 50% of capsulotomies succeeded at 90% energy in an edematous cornea, improving with increased energy (75% completion at 130%, 100% at 150%). Rupture strength in edematous corneas was not significantly different at 112, 133, and 114 mN for 90%, 130%, and 150%, respectively (P = 0.3). In human samples, increased TUNEL-positive cells were seen at 130% energy, but not at 150% (0.0 manual vs. 0.2 [90%] vs. 2.1 [130%] vs. 0.6 [150%], P < 0.05). Conclusions: Because of the low energy delivered by a femtosecond nanojoule platform, even incremental increases in energy appeared to have minimal effect on lens capsule morphology and strength and negligible influence on cell death. Furthermore, increasing energy appeared to enhance consistency and the ability to complete a capsulotomy in an edematous cornea. PMID- 28873173 TI - Automated Photoreceptor Cell Identification on Nonconfocal Adaptive Optics Images Using Multiscale Circular Voting. AB - Purpose: Adaptive optics scanning light ophthalmoscopy (AOSLO) has enabled quantification of the photoreceptor mosaic in the living human eye using metrics such as cell density and average spacing. These rely on the identification of individual cells. Here, we demonstrate a novel approach for computer-aided identification of cone photoreceptors on nonconfocal split detection AOSLO images. Methods: Algorithms for identification of cone photoreceptors were developed, based on multiscale circular voting (MSCV) in combination with a priori knowledge that split detection images resemble Nomarski differential interference contrast images, in which dark and bright regions are present on the two sides of each cell. The proposed algorithm locates dark and bright region pairs, iteratively refining the identification across multiple scales. Identification accuracy was assessed in data from 10 subjects by comparing automated identifications with manual labeling, followed by computation of density and spacing metrics for comparison to histology and published data. Results: There was good agreement between manual and automated cone identifications with overall recall, precision, and F1 score of 92.9%, 90.8%, and 91.8%, respectively. On average, computed density and spacing values using automated identification were within 10.7% and 11.2% of the expected histology values across eccentricities ranging from 0.5 to 6.2 mm. There was no statistically significant difference between MSCV-based and histology-based density measurements (P = 0.96, Kolmogorov-Smirnov 2-sample test). Conclusions: MSCV can accurately detect cone photoreceptors on split detection images across a range of eccentricities, enabling quick, objective estimation of photoreceptor mosaic metrics, which will be important for future clinical trials utilizing adaptive optics. PMID- 28873175 TI - Development of a Poly-epsilon-Lysine Contact Lens as a Drug Delivery Device for the Treatment of Fungal Keratitis. AB - Purpose: The purpose of this study was to develop a more efficient drug delivery device to overcome the limitations of current drop therapy for the treatment of fungal keratitis. Methods: Amphotericin B (AmpB), 0 to 30 MUg/mL, was associated with a poly-epsilon-lysine (pepsilonK) hydrogel. Fungicidal effect against Candida albicans was assessed at 18 and 42 hours by optical density (OD600) and growth on agar. Tear film dilution effect was mimicked by storage of AmpB pepsilonK gels in 3.4 mL sterile PBS for 24 hours prior to fungal incubation. Drug elution over 96 hours was evaluated by HPLC, and drug stability was tested while associated with the gel by OD600 up to 48 hours. Lack of cytotoxicity toward the HCE-T corneal epithelial cell line was assessed over 7 days. Results: AmpB pepsilonK gels show fungicidal activity in normal conditions (0.057 OD600, SD 0.003, P < 0.005) and in the presence of horse serum (0.048 OD600, SD 0.028 P < 0.005) at 18 hours. The drug release profile was above therapeutic levels (0.188 MUg/mL) for up to 72 hours. Tear dilution had no significant effect at higher concentrations of AmpB (3 to 10 MUg/mL). AmpB pepsilonK gels were not cytotoxic to the HCE-T cell line. Conclusions: We demonstrated that AmpB pepsilonK gels confer sustained therapeutic antifungal activity for at least 48 hours without corneal epithelial cell line cytotoxicity, suggesting their potential for in vivo use as an antifungal bandage contact lens. This could avoid the need for intensive topical medication in the treatment of fungal keratitis. PMID- 28873178 TI - Sentence Added to Author Contributions. PMID- 28873176 TI - Pro-Secretory Activity and Pharmacology in Rabbits of an Aminophenyl-1,3,5 Triazine CFTR Activator for Dry Eye Disorders. AB - Purpose: Pharmacological activation of ocular surface cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels is a potential pro secretory approach to treat dry eye disorders. We previously reported the discovery of aminophenyl-1,3,5-triazines, one of which, N-methyl-N-phenyl-6 (2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (herein called CFTRact K267), fully activated human wildtype CFTR with EC50 ~ 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTRact-K267 were done in adult New Zealand white rabbits. Methods: CFTR chloride conductance was measured in vivo by ocular surface potential differences and in ex vivo conjunctiva by short-circuit current. Tear volume was measured by the Schirmer tear test II and CFTRact-K267 pharmacokinetics and tissue distribution by liquid chromatography/mass spectrometry. Toxicity profile was studied for 28 days with twice-daily topical administration. Results: Electrophysiological measurements in vivo and in ex vivo conjunctiva demonstrated CFTR activation by CFTRact-K267. A single topical dose of 3 nmol CFTRact-K267 increased tear production by >5 mm for 9 hours by the Schirmer tear test, with predicted therapeutic concentrations maintained in tear fluid. No tachyphylaxis was seen following 28-day twice-daily administration, and changes were not observed in corneal surface integrity or thickness, intraocular pressure, or ocular histology. At day 28, CFTRact-K267 was concentrated in the cornea and conjunctiva and was not detectable in blood or peripheral organs. Conclusions: These studies support the development of CFTRact-K267 as a pro-secretory therapy for dry eye disorders. PMID- 28873179 TI - Incorrect Author Affiliation. PMID- 28873180 TI - Omitted Affiliation and Disclaimer. PMID- 28873181 TI - Data Transcription Errors and Missing Footnote in Table. PMID- 28873183 TI - Benefits of Electronic Medical Record Banks. PMID- 28873177 TI - Hypoxia-Inducible Factor-Dependent Expression of Angiopoietin-Like 4 by Conjunctival Epithelial Cells Promotes the Angiogenic Phenotype of Pterygia. AB - Purpose: Disappointing results from clinical studies assessing the efficacy of therapies targeting vascular endothelial growth factor (VEGF) for the treatment of pterygia suggest that other angiogenic mediators may also play a role in its development. We therefore explore the relative contribution of VEGF, hypoxia inducible factor (HIF)-1alpha (the transcription factor that regulates VEGF expression in ocular neovascular disease), and a second HIF-regulated mediator, angiopoietin-like 4 (ANGPTL4), to the angiogenic phenotype of pterygia. Methods: Expression of HIF-1alpha, VEGF, and ANGPTL4 were examined in surgically excised pterygia, and in immortalized human (ih) and primary rabbit (pr) conjunctival epithelial cells (CjECs). Endothelial cell (EC) tubule formation assays using media conditioned by ihCjECs in the presence or absence of inducers/inhibitors of HIF-1 or RNA interference (RNAi) targeting VEGF, ANGPTL4, or both were used to assess their relative contribution to the angiogenic potential of these cells. Results: HIF-1alpha and VEGF expression were detected in 6/6 surgically excised pterygia and localized to CjECs. Accumulation of HIF-1alpha in was confirmed in ihCjECs and prCjECs, including stratified prCjECs grown on collagen vitrigel, and resulted in expression of VEGF and the promotion of EC tubule formation; the latter effect was partially blocked using RNAi targeting VEGF mRNA expression. We demonstrate expression of a second HIF-regulated angiogenic mediator, ANGPTL4, in CjECs in culture and in surgically excised pterygia. RNAi targeting ANGPTL4 inhibited EC tubule formation and was additive to RNAi targeting VEGF. Conclusions: Our results support the development of therapies targeting both ANGPTL4 and VEGF for the treatment of patients with pterygia. PMID- 28873184 TI - Redefining Unexplained Anemia in Elderly. PMID- 28873185 TI - Meta-Epidemiology of Testosterone's Risks and Benefits-Will We Ever Know the Answer? PMID- 28873186 TI - Intensive Blood Pressure Control on Gait Speed and Mobility Limitation for Older Adults. PMID- 28873187 TI - Inaccuracies Describing Results of a Lung Cancer Screening Demonstration Project. PMID- 28873188 TI - Testosterone Replacement Therapy and Cardiovascular Risk-A Closer Look at Additional Parameters. PMID- 28873189 TI - All Types of Hemorrhagic Stroke Are Not Created Equally. PMID- 28873190 TI - Meta-Epidemiology of Testosterone's Risks and Benefits-Will We Ever Know the Answer?-Reply. PMID- 28873191 TI - Meta-Epidemiology of Testosterone's Risks and Benefits-Will We Ever Know the Answer?-Reply. PMID- 28873192 TI - Redefining Unexplained Anemia in Elderly-Reply. PMID- 28873193 TI - Intensive Blood Pressure Control on Gait Speed and Mobility Limitation for Older Adults-Reply. PMID- 28873194 TI - Inaccuracies Describing Results of a Lung Cancer Screening Demonstration Project Reply. PMID- 28873195 TI - All Types of Hemorrhagic Stroke Are Not Created Equally-Reply. PMID- 28873196 TI - Testosterone Replacement Therapy and Cardiovascular Risk-A Closer Look to Additional Parameters. PMID- 28873198 TI - Role of IL17A rs2275913 and rs3748067 polymorphisms in the risk cervical cancer. AB - Cervical cancer is a serious public health problem and is associated with high cancer-related mortality in females worldwide. The expression of IL17A can increase the migration and invasiveness of cervical cancer cells by activating the NF-kappaB signal pathway. Single-nucleotide polymorphisms (SNPs) can alter gene function and protein expression. We examined the association between two IL17A SNPs (rs2275913 and rs3748067) and the risk of cervical cancer. We also investigated the interaction between IL17A -174G/C and -572C/G mutations and environmental factors. Our 1:2 matched case-control study included 185 cervical cancer patients and 370 healthy controls. The IL17A rs2275913 and rs3748067 SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Using logistic regression analysis, we found that individuals harboring the TT genotype of IL17A rs3748067 had an increased risk of cervical cancer compared with those carrying the CC genotype, and the adjusted OR (95%CI) was 6.29 (2.30-19.81). Moreover, individuals carrying the T allele of IL17A rs3748067 were more susceptible to cervical cancer than those with the C allele, and the adjusted OR (95%CI) was 2.31 (1.53-3.50). No significant interaction was observed between the IL17A rs2275913 polymorphism and cervical cancer risk. In conclusion, our study suggests that the IL17A rs3748067 polymorphism is independently associated with the risk of cervical cancer, and has a relationship with human papillomavirus infection with regard to the risk of cervical cancer. PMID- 28873199 TI - Cloning and functional characterization of the HbSYR1 gene encoding a syntaxin related protein in Tibetan hulless barley (Hordeum vulgare L. var. nudum HK. f.). AB - Tibetan barley is a staple food for the natives of Qinghai-Tibet Plateau. Drought causes a reduction in barley production. In this study, the full-length cDNA of a gene encoding a syntaxin-associated protein was cloned from the leaves of a drought-resistant variety of barley, "Himalaya 10"; its expression was evaluated during drought stress and rehydration via real-time PCR. The cloned HbSYR1 cDNA sequence was 1300 bp in length, and included an 840-bp open reading frame that encoded 279 amino acids. Sequence analysis predicted the molecular weight of the encoded protein to be 42.08 kDa, with an isoelectric point of 4.98. ScanProsite analysis showed that the HbSYR1 protein contained a SNARE family characteristic motif, five casein kinase II phosphorylation sites, two N-glycosylation sites, four protein kinase C phosphorylation sites, and two N-myristoylation sites. The TMHMM prediction program indicated that the protein does not contain a transmembrane transfer ribbon. According to the SignalP 3.0 server, this protein does not contain a signal peptide, and is not a secretory protein. Instead, this protein was suggested to be localized in the cytoplasm, as predicted by the protein subcellular localization prediction tool (PSORT). Our results indicated that HbSYR was induced by drought stress and rehydration, and was determined to be a key gene for drought resistance and water retention in barley. PMID- 28873200 TI - Mac-1 deficiency induces respiratory failure by affecting type I alveolar epithelial cells. AB - As a beta2 integrin family member, Mac-1 plays an important role in the inflammatory response. Inflammation and lung injury are closely associated, but the involvement of Mac-1 in the occurrence and development of such pathologies remains poorly understood. We aimed to investigate the relationship between Mac-1 deficiency and respiratory failure in Mac-1 knockout {Mac-1-/-} mice, using C57BL/6J mice as a control. The newborn survival rate of Mac-1-/- mice was calculated, and mouse lung tissue was treated with hematoxylin and eosin and subjected to immunofluorescent staining. Moreover, western blotting and immunohistochemistry were used to detect the expression of molecules specific to type I and type II alveolar epithelial cells, as well as alveolar surfactant proteins secreted by the latter. Survival of Mac-1-/- pups was significantly lower than that of newborn C57BL/6J mice. In a float test, lung tissues from C57BL/6J mice were buoyant, whereas those of Mac-1-/- mice were not. Compared with C57BL/6J mice, expression of proSP-C {specific to type II alveolar epithelial cells} and alveolar surfactant proteins in Mac-1-/- mice was not significantly different, implying that type II cell function was unaltered. However, western blotting revealed expression of T1alpha, Aqp5, and Snx5 {type I alveolar epithelial cell markers} in Mac-1-/- mice to be significantly decreased {P < 0.05}. In conclusion, Mac-1 may play an important role in respiratory failure. Its absence leads to this condition not by influencing type II alveolar epithelial cells or their secreted surfactant proteins, but rather by reducing type I alveolar cell numbers. PMID- 28873201 TI - Mutational screening in the LDLR gene among patients presenting familial hypercholesterolemia in the Southeast of Brazil. AB - Familial hypercholesterolemia (FH) is a dominant, autosomal disease characterized by high LDL levels in blood plasma, and is caused by a defect in the gene encoding the LDL receptor (LDLR). The clinical diagnosis is based on personal and familial history, physical examination findings, and measures of high LDL cholesterol concentrations. LDLR is a cell-surface glycoprotein that controls the level of blood plasma cholesterol and triglyceride by LDLR-mediated endocytosis. Here we sequenced the entire LDLR gene-coding region to screen for mutations in 32 patients diagnosed with FH, and we have found 20 mutations including synonymous, missense, and intronic mutations. Six of them were characterized as pathogenic mutations (D178Y, C184Y, S326C, C681X, IVS7+10G>C, and IVS11-10G>A). We have also found one intronic mutation not described so far (IVS11-63C>A). Our study corroborates the broad spectrum of mutations distributed along the entire LDLR gene, and we suggest that the genes APOB and PCSK9 should also be screened for mutations when considering the diagnosis of FH. It is already known that different types of mutations are directly associated with the phenotype heterogeneity presented by patients. Considering that Brazilian population is highly admixed, it is important to determine the geographic spectrum of LDLR mutations to provide information on the prognosis and treatment of each FH patient. PMID- 28873202 TI - Suppression of the biological activity of neuroglioma cells by down-regulation of miR-1. AB - Neuroglioma is associated with high rates of malignancy, metastasis, and recurrence. Recently, research on the roles of microRNAs (miR) in cancer prognosis has formed an important area of research as differential expression of miRNAs has been observed in different cancers. However, the detailed mechanism by which miRNAs regulate glioma remains unknown. Thus, we investigated the effect of miR-1 on human glioma by inhibiting the expression of miR-1. Anti-miR-1, an anti sense oligonucleotide against miR-1, significantly reduced the level of miR-1 in the human glioma cell line U87 (P < 0.05). Further, cell proliferation and colony formation assays were used to determine the effect of miR-1 on cell growth. The scratch assay and cell migration assay were performed to evaluate cell invasion. Our data demonstrated that the growth of glioma cells was impeded due to the decrease in miR-1 levels, compared to the untransfected control cells (P < 0.05). Interestingly, the invasion and mobility of the cells were also retarded after transfection with anti-miR-1 (P < 0.05). In conclusion, our results indicate that the down-regulation of miR-1 significantly inhibited cell proliferation and reduced cell motility, suggesting that anti-miR-1 could be used as a therapeutic intervention tool to counter the activity of neuroglioma cells. PMID- 28873203 TI - Genetic diversity in a Poincianella pyramidalis (Tul.) L.P. Queiroz population assessed by RAPD molecular markers. AB - Poincianella pyramidalis (Tul.) L.P. Queiroz is an endemic Caatinga (Brazilian savannah biome) species that has been exploited for different purposes, although information is necessary about still existing natural populations. The objective of this study was to evaluate the genetic diversity among 20 P. pyramidalis individuals occurring in a population localized in the Caatinga biome of Paraiba State, aiming at seed collection, using RAPD markers. For the DNA extraction, young shoots of the individuals were used, and amplification was carried out using 20 primers. The obtained markers were converted to a binary matrix, from which a genetic dissimilarity matrix was built using the arithmetic complement of Jaccard's coefficient, and the dendrogram was built by the UPGMA analysis. No amplified fragment was monomorphic, resulting in 100% polymorphism of the analyzed population. The mean genetic diversity among the matrices was 63.28%, ranging from 30.9 to 97.7%. Individuals 09 and 17 showed relevant genetic proximity, and thus planting their seedlings at close sites would not be indicated. The population evaluated in this study showed high genetic diversity, originating twelve groups from the UPGMA hierarchical cluster analysis. Based on the results, individuals 09 and 17 can provide plant material for the evaluation of the physiological performance of P. pyramidalis seeds, and the set of individuals of this population has a high genetic diversity that characterizes them as adequate matrices for projects of restoration and conservation of the seed species. PMID- 28873204 TI - Population genetic structure of three species in the genus Astrocaryum G. Mey. (Arecaceae). AB - We assessed the level and distribution of genetic diversity in three species of the economically important palm genus Astrocaryum located in Para State, in northern Brazil. Samples were collected in three municipalities for Astrocaryum aculeatum: Belterra, Santarem, and Terra Santa; and in two municipalities for both A. murumuru: Belem and Santo Antonio do Taua and A. paramaca: Belem and Ananindeua. Eight microsatellite loci amplified well and were used for genetic analysis. The mean number of alleles per locus for A. aculeatum, A. murumuru, and A. paramaca were 2.33, 2.38, and 2.06, respectively. Genetic diversity was similar for the three species, ranging from HE = 0.222 in A. aculeatum to HE = 0.254 in A. murumuru. Both FST and AMOVA showed that most of the genetic variation was found within populations for all three species, but high genetic differentiation among populations was found for A. aculeatum. Three loci were not in Hardy-Weinberg equilibrium, with populations of A. paramaca showing a tendency for the excess of heterozygotes (FIS = -0.144). Gene flow was high for populations of A. paramaca (Nm = 19.35). Our results suggest that the genetic diversity within populations followed the genetic differentiation among populations due to high gene flow among the population. Greater geographic distances among the three collection sites for A. aculeatum likely hampered gene flow for this species. PMID- 28873205 TI - Molecular mapping and candidate gene analysis for resistance to powdery mildew in Cucumis sativus stem. AB - Powdery mildew (PM) of cucumber (Cucumis sativus), caused by Podosphaera xanthii, is a major foliar disease worldwide and resistance is one of the main objectives in cucumber breeding programs. The resistance to PM in cucumber stem is important to the resistance for the whole plant. In this study, genetic analysis and gene mapping were implemented with cucumber inbred lines NCG-122 (with resistance to PM in the stem) and NCG-121 (with susceptibility in the stem). Genetic analysis showed that resistance to PM in the stem of NCG-122 was qualitative and controlled by a single-recessive nuclear gene (pm-s). Susceptibility was dominant to resistance. In the initial genetic mapping of the pm-s gene, 10 SSR markers were discovered to be linked to pm-s, which was mapped to chromosome 5 (Chr.5) of cucumber. The pm-s gene's closest flanking markers were SSR20486 and SSR06184/SSR13237 with genetic distances of 0.9 and 1.8 cM, respectively. One hundred and fifty-seven pairs of new SSR primers were exploited by the sequence information in the initial mapping region of pm-s. The analysis on the F2 mapping population using the new molecular markers showed that 17 SSR markers were confirmed to be linked to the pm-s gene. The two closest flanking markers, pmSSR27and pmSSR17, were 0.1 and 0.7 cM from pm-s, respectively, confirming the location of this gene on Chr.5. The physical length of the genomic region containing pm-s was 135.7 kb harboring 21 predicted genes. Among these genes, the gene Csa5G623470 annotated as encoding Mlo-related protein was defined as the most probable candidate gene for the pm-s. The results of this study will provide a basis for marker-assisted selection, and make the benefit for the cloning of the resistance gene. PMID- 28873206 TI - Characterization and phylogenetic affiliation of Actinobacteria from tropical soils with potential uses for agro-industrial processes. AB - Secondary metabolites produced by Actinobacteria of tropical soils represent a largely understudied source of novel molecules with relevant application in medicine, pharmaceutical and food industries, agriculture, and environmental bioremediation. The present study aimed to characterize sixty-nine Actinobacteria isolated from compost and tropical soils using morphological, biochemical, and molecular methods. All the isolates showed high variation for morphological traits considering the color of pigments of the aerial and vegetative mycelium and spore chain morphology. The enzymatic activity of amylase, cellulase, and lipase was highly variable. The amylase activity was detected in 53 (76.81%) isolates. Eighteen isolates showed enzymatic index (EI) > 4.0, and the isolates ACJ 45 (Streptomyces curacoi) and ACSL 6 (S. hygroscopicus) showed the highest EI values (6.44 and 6.42, respectively). The cellulase activity varied significantly (P <= 0.05) among the isolates. Twenty-nine isolates (42.02%) showed high cellulase activity, and the isolates ACJ 48 (S. chiangmaiensis) and ACJ 53 (S. cyslabdanicus) showed the highest EI values (6.56 for both isolates). The lipase activity varied statistically (P <= 0.05) with fourteen isolates (20.29%) considered good lipase producers (EI > 2.0). The isolate ACSL 6 (S. hygroscopicus) showed the highest EI value of 2.60. Molecular analysis of partial 16S rRNA gene sequencing revealed the existence of 49 species, being 38 species with only one representative member and 11 species represented by one or more strains. All species belonged to three genera, namely Streptomyces (82.61%), Amycolatopsis (7.25%), and Kitasatospora (10.14%). The present results showed the high biotechnological potential of different Actinobacteria from tropical soils. PMID- 28873207 TI - Characterization of a pepper collection (Capsicum frutescens L.) from Brazil. AB - Germplasm banks are essential as sources of genetic variability for plant breeding programs. To characterize a Brazilian Capsicum frutescens collection, 21 malagueta and 5 Tabasco hot pepper accessions were evaluated under field and greenhouse conditions regarding morphological and molecular traits, as well as resistance to viruses. Morphological characterization was performed using 53 IPGRI (International Plant Genetic Resources Institute) descriptors, 15 vegetative, 13 inflorescence, 22 fruit, and 3 seed. Molecular characterization was carried out with 60 polymorphic markers from 29 RAPD primers. The incidence of major viruses infecting Capsicum spp, Tomato spotted wilt virus (TSWV), Groundnut ringspot virus (GRSV), Potato virus Y (PVY), Pepper yellow mosaic virus (PepYMV), Pepper mild mottle virus (PMMoV), and Cucumber mosaic virus (CMV) was evaluated by ELISA. Based on the average genetic distance among genotypes, six groups were defined for the 53 IPGRI descriptors. When considering only 11 quantitative traits (five vegetative and six fruit), six groups were also determined, and the traits plant canopy width (56.05%) and days to fruiting (25.07%) most explained the genetic diversity among genotypes. Molecular analysis defined five groups of accessions with partial correspondence to the morphological characterization data. The incidence of viruses in field-grown plants varied among genotypes and according to virus species, from 5.6% (GRSV; CNPH 3286) to 100% (PMMoV; CNPH2871), and indicated some accessions as potential sources of virus resistance. These results demonstrate the genetic variability within the group of 26 hot pepper accessions, as well as virus-resistant genotypes that can be used in breeding programs. PMID- 28873208 TI - A Xanthomonas citri subsp citri hypothetical protein related to virulence contains a non-functional HD domain and is implicated in flagellar motility. AB - Citrus canker, caused by the Gram-negative bacterium Xanthomonas citri subsp citri (Xac), severely affects most economically important citrus varieties worldwide. A previous study showed that disruption of the ORF XAC1201 from the Xac 306 strain by transposon Tn5 decreased bacterium virulence in the Rangpur lime host (Citrus limonia L. Osbeck). However, little is known regarding the possible function of the hypothetical protein XAC1201 and how it affects the virulence of Xac 306. Here, we confirmed that disruption of ORF XAC1201 reduces Xac 306 virulence in two different hosts, delaying the onset of typical symptoms. In silico analysis suggested that XAC1201 interacts with the flagellar proteins FliM and FliL, known to be an important factor for virulence. In fact, motility assays revealed that the XAC1201 mutant has a significant difference in motility compared to the wild-type Xac 306. Also, a 3-D structure model revealed modified cofactor binding sites and suggested that XAC1201 has a non-functional HD domain. This hypothesis was confirmed by enzymatic assays performed in purified, XAC1201 recombinant protein expressed in Escherichia coli, which revealed no significant activities previously associated with HD domains for the tested substrates. Thus, the role of the XAC1201 protein in Xac 306 virulence seems to be related to flagellar motility, although a non-classic role for the HD domain cannot be dismissed. PMID- 28873209 TI - ITS2 as a molecular marker for the identification of Diatraea saccharalis and D. flavipennella and possible infection with Cotesia spp. AB - In Brazil, the species Diatraea flavipennella and D. saccharalis play an important role in the sugar and alcohol agribusiness by causing many damages in sugarcane fields. The egg, larva, pupa, and adult stages are very morphologically similar between these species, and the identification can be confused. The internal transcribed spacer 2 (ITS 2) from ribosomal DNA has important features as evolutionary divergence. It is a good marker for species identification, participates in the rDNA processing, and has been applied in phylogenetic and population studies. This study aimed to make available a molecular marker to assist on the identification method of pests' species of Diatraea and to identify possible traces of Cotesia in the resistant host. The DNA was extracted from the egg, larva, and adult samples. PCR amplicons were purified and sequenced. The sequences were analyzed in MEGA 5.01. The ITS 2 length was 410 bp in D. flavipennella and 448 bp in D. saccharalis. The GC content was similar between the species. Three microsatellite loci were present in D. saccharalis and absent in D. flavipennella, contributing to differences in ITS 2 length in the species. An additional 367-bp band was attributed to Cotesia spp. The differences among ITS 2 from D. flavipennella, D. saccharalis, and Cotesia sp were sufficient to identify them on electrophoresis gel and sequencing. The presence of Cotesia sp traits in adult D. flavipennella showed possible host refractoriness, but further studies are necessary. PMID- 28873210 TI - Diallel and prediction (REML/BLUP) for yield components in intervarietal maize hybrids. AB - Genetic improvement is essential to achieve increments in maize (Zea mays L.) grain yield components. It may be obtained through crosses, which enable to exploit the effects of intervarietal heterosis, allelic complementarity, as well as gene actions and effects. This study estimated the components of variance and genetic parameters (REML/BLUP) of an intervarietal diallel to select and predict the best genotypes for maize yield components. The experimental design was randomized blocks containing 60 intervarietal maize hybrids arranged in three repetitions. They were obtained through intervarietal crosses and evaluated in a diallel scheme, where 14 open-pollinated varieties were designated as parentals. Thus, 10 crosses were performed for each hybrid combination to obtain the number of seeds necessary for the competition test. The measured traits were: grain volume relative index, the mass of one hundred grains, and grain yield. The male parents and the additive genetic fraction were determinants for grain volume relative index. Mass of one hundred grains and grain yield were defined by the specific combining ability, and female parents revealed low narrow sense heritability. The female parent Taquarao and male parent Argentino Amarelo presented the best general combining abilities for the measured traits. The specific combining abilities were expressed for crosses AL 25 x Dente de Ouro Roxo, AL 25 x BRS Pampeano, and Taquarao x Argentino Branco. Genetic estimates and predictions were consistent and applicable to breeding programs and could be applied in future quantitative genetic studies of maize. PMID- 28873211 TI - Analysis of genetic variability of commercial melon cultivars using SSR molecular markers. AB - Taking into account the scenario of melon production (Cucumis melo L.) in Brazil, it is notable the importance of the culture in the fruit market. The preference of the national market is concentrated in the fruits of the yellow type. Therefore, it is possible that the genetic base of the commercial cultivars is relatively narrow due to the loss of important genes in the breeding process, and it is possible to introgress external genes for increasing recombination possibilities that generate sources of resistance to the main diseases and superior genotypes. This study evaluated the genetic variability of 87 melon accessions composed of 72 commercial cultivars belonging to the Inodorus and Cantaloupensis groups and 15 plant introductions (PIs). Forty-four polymorphic SSR primers were used to amplify a total of 202 alleles. The expected heterozygosity presented an average of 0.519 and the PIC index of 0.458, being moderately informative. The dendrogram generated for the 72 cultivars grouped the genotypes into 2 main groups, and there was no association with the classification of groups of the genotypes in the grouping. The number of SSR markers was sufficient to predict wide genetic variability among the cultivars studied, with the similarity between 0.35 and 0.98. The dendrogram presented for the 72 cultivars and the 15 PI genotypes was not associated with the classification of the genotypes in the grouping, and the 15 PIs were well dispersed with similarity indexes that resemble the two groups studied. A set of 25 primers was identified that were useful in distinguishing the 72 cultivars. These primers can be used in later research with the cultivars, as well as in crop protection situations, being an important tool in the useful and rapid distinction of genotypes, and in commercial disputes regarding the certification of the main melon cultivars used in the country. PMID- 28873212 TI - Simulation analysis of rectifying microfluidic mixing with field-effect-tunable electrothermal induced flow. AB - We report herein field-effect control on in-phase electrothermal streaming from a theoretical point of view, a phenomenon termed "alternating-current electrothermal-flow field effect transistor" (ACET-FFET), in the context of a new technology for handing analytes in microfluidics. Field-effect control through a gate terminal endows ACET-FFET the ability to generate arbitrary symmetry breaking in the transverse vortex flow pattern, which makes it attractive for mixing microfluidic samples. A computational model is developed to study the feasibility of this new microfluidic device design for micromixing. The influence of various parameters on developing an efficient mixer is investigated, and an integrated layout of discrete electrode array is suggested for achieving high throughput mixing. Our physical demonstration with field-effect electrothermal flow control using a simple electrode structure proves invaluable for designing active micromixers for modern micro total analytical system. PMID- 28873213 TI - Bioethics, children, and the environment. AB - Queer perspectives have typically emerged from sexual minorities as a way of repudiating flawed views of sexuality, mischaracterized relationships, and objectionable social treatment of people with atypical sexuality or gender expression. In this vein, one commentator offers a queer critique of the conceptualization of children in regard to their value for people's identities and relationships. According to this account, children are morally problematic given the values that make them desirable, their displacement of other beings and things entitled to moral protection, not to mention the damaging environmental effects that follow in the wake of population growth. Objectionable views of children are said even to have colonized the view of lesbian, gay, bisexual, and trans (LGBT) people who - with the enthusiastic endorsement of bioethics - increasingly turn to assisted reproductive treatments to have children. In the face of these outcomes, it is better - according to this account - that people reconsider their interest in children. This account is not, however, ultimately strong enough to override people's interest in having children, relative to the benefits they confer and relative to the benefits conferred on children themselves. It is certainly not strong enough to justify differential treatment of LGBT people in matters of assisted reproductive treatments. Environmental threats in the wake of population growth might be managed in ways other than devaluing children as such. Moreover, this account ultimately damages the interests of LGBT people in matters of access, equity, and children, which outcome is paradoxical, given the origins of queer perspectives as efforts to assert and defend the social interests of sexual and gender minorities. PMID- 28873214 TI - Don't let perfect be the enemy of good: How to improve prognostic communication in pediatric oncology. PMID- 28873215 TI - Group genetic counseling: An alternate service delivery model in a high risk prenatal screening population. AB - OBJECTIVE: To address the growing demand for prenatal genetic services, group genetic counseling was explored as an alternative service delivery model for women with a positive prenatal screening result. METHOD: Women were recruited from a prenatal genetic service and systematically allocated to a traditional individual appointment with a genetic counselor or a group genetic counseling session. Questionnaires were administered to assess patient psychological outcomes, knowledge, and satisfaction following individual and group genetic counseling for a positive prenatal screen. Genetic counselor time per type of patient was measured. RESULTS: Of 172 participants, 107 (62.2%) received group genetic counseling and 65 (37.8%) received individual genetic counseling. Both group and individual genetic counseling encounters significantly decreased patient anxiety, increased perceived personal control, decreased decisional conflict, and increased knowledge. Satisfaction was high following both methods. Anxiety was significantly decreased in women who received individual genetic counseling compared with group sessions (P < .001). Genetic counselors spent less time per group patient seen compared with individual patients. CONCLUSION: Group genetic counseling followed by the option of brief individual genetic counseling appears acceptable to women in a high-risk prenatal screening population. The findings support an alternative service delivery model for prenatal genetic services that could optimize the utilization of genetic counseling resources. PMID- 28873216 TI - Molecular interactions of milk protein with phenolic components in oat-based liquid formulations following UHT treatment and prolonged storage. AB - BACKGROUND: Nowadays there is a growing demand for nutritionally balanced breakfast beverages enriched with functional ingredients including wholegrain oat, which is rich in phenolic acids. Such beverages typically contain added food ingredients (e.g. milk protein, sugar and lipids) and undergo thermal processing that initiates many molecular processes. Therefore, this work aims to investigate the molecular interactions between milk protein and phenolic acids that govern bioactivity in model oat-based beverages. RESULTS: Findings showed the susceptibility of ferulic and p-coumaric acids, in model oat beverages, to ultra high temperature (UHT) processing at 145 degrees C for 8 s. Among model beverages, those with added milk protein demonstrated a considerable loss of phenolic acids following UHT processing due to the interaction between these micronutrients and the protein. The nature of molecular interactions was mainly categorized as covalent with hydrogen bonds playing a supportive role. CONCLUSION: UHT processing of oat-based beverage formulations facilitates the formation of protein-phenolic acid complexes, which are largely covalent and static in nature. This finding underlines the ability of UHT treatment to induce chemical modifications of food ingredients. (c) 2017 Society of Chemical Industry. PMID- 28873217 TI - Geriatrics Literature 2016 Year in Review. AB - We present 10 of the most effective articles from 2016 in geriatric medicine. They address wide-ranging topics including the use of antipsychotics for delirium in palliative care, fall prevention and mobility interventions, efficacy and potential risks of testosterone, cranberry capsules and their effect on bacteriuria and pyuria, beta-blockers after acute myocardial infarction in a nursing home population, the effect of a healthy lifestyle on disability, a goals of-care intervention in individuals with advanced dementia, the benefits of regional anesthesia in hip repair, and mindfulness in chronic pain management. PMID- 28873218 TI - Associations Between Falls and Driving Outcomes in Older Adults: Systematic Review and Meta-Analysis. AB - OBJECTIVES: To examine associations between falls and subsequent motor vehicle crashes (MVCs), crash-related injuries, driving performance, and driving behavior. DESIGN: Systematic review and metaanalysis. PARTICIPANTS: Observational studies including drivers aged 55 and older or with a mean age of 65 and older. MEASUREMENTS: Two authors independently extracted study and participant characteristics, exposures, and outcomes and assessed risk of bias. Pooled risk estimates for MVCs and MVC-related injuries were calculated using random-effects models. Other results were synthesized narratively. RESULTS: From 3,286 potentially eligible records, 15 studies (N = 27-17,349 subjects) met inclusion criteria. Risk of bias was low to moderate, except for cross-sectional studies (n = 3), which all had a high potential for bias. A fall history was associated with a significantly greater risk of subsequent MVC (summary risk estimate = 1.40, 95% confidence interval (CI) = 1.20-1.63; I2 = 28%, N = 5 studies). One study found a significantly greater risk of MVC-related hospitalizations and deaths after a fall (hazard ratio = 3.12, 95% CI = 1.71-5.69). Evidence was inconclusive regarding an association between falls and driving cessation and showed no association between falls and driving performance or behavior. CONCLUSION: Falls in older adults appear to be a risk marker for subsequent MVCs and MVC-related injury. Given the nature of the evidence, which is limited to observational studies, the identified associations may also result at least partly from confounding or bias. Further research is needed to clarify the mechanisms linking falls to crash risk and to develop effective interventions to ensure driving safety in older adults with a history of falls. PMID- 28873219 TI - Treatment Effectiveness in Heart Failure with Comorbidity: Lung Disease and Kidney Disease. AB - OBJECTIVES: To assess the clinical effectiveness of beta-blocker therapy in individuals with heart failure (HF) and chronic lung disease and of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) in individuals with HF and chronic kidney disease. DESIGN: Retrospective cohort study. SETTING: Community. PARTICIPANTS: Individuals with HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). METHODS: We undertook separate new-user cohort studies to assess the effectiveness of beta-blocker therapy in treating HF and chronic lung disease and ACE-Is and ARBs in treating HF and chronic kidney disease (CKD). Individuals with a chronic lung disease diagnosis were included in the group with HF and chronic lung disease (International Classification of Diseases, Ninth Revision, codes 490 496, 518). Individuals with an estimated glomerular filtration rate less than 60 mL/min per 1.73 m2 were included in the group with HF and CKD. The clinical outcomes of interest were death from any cause, hospitalization for HF, and hospitalization for any reason. We fitted pooled logistic marginal structural models using inverse probability weighting, stratified according to HF type. RESULTS: For individuals with HFrEF with chronic lung disease, beta-blocker therapy was protective against death (relative risk (RR) = 0.58, 95% confidence interval (CI) = 0.44-0.77) and hospitalization for HF (RR = 0.78, 95% CI = 0.60 1.00). For those with HFpEF, no statistically significant associations between beta-blocker therapy use and any of the outcomes were observed. We found ACE-I and ARB use to be protective against all three outcomes of interest in individuals with HFrEF (death from any cause: RR = 0.60, 95% 0.40-0.91; hospitalization for HF: RR = 0.43, 95% CI = 0.28-0.67; hospitalization for any reason: RR = 0.63, 95% CI = 0.45-0.89, respectively) and those with HFpEF (death from any cause: RR = 0.52, 95% CI = 0.33-0.81; hospitalization for HF: RR = 0.35, 95% CI = 0.18-0.68; hospitalization for any reason: RR = 0.67, 95% CI = 0.47 0.95). CONCLUSION: Large observational studies may allow for identification of important subgroups of individuals with HF that might benefit from existing treatment approaches. Our findings may also better inform the design of more definitive future observational studies and randomized trials. PMID- 28873220 TI - Patterns and Predictors of Frailty Transitions in Older Men: The Osteoporotic Fractures in Men Study. AB - OBJECTIVES: To describe the natural history of frailty transitions in a large cohort of community-dwelling older men and identify predictors associated with progression to or improvement from states of greater frailty. DESIGN: Prospective cohort study. SETTING: Six U.S. sites. PARTICIPANTS: Community-dwelling men aged 65 and older (N = 5,086). MEASUREMENTS: Frailty was measured at baseline and an average of 4.6 years later. Frailty was defined as having three or more of the following components (low lean mass, weakness, self-reported exhaustion, low activity level, and slow walking speed); prefrailty was defined as having one or two components. Separate multivariable logistic regression models were analyzed for progression and improvement in frailty status. RESULTS: Of the 5,086 men, 8% were frail, 46% were prefrail, and 46% were robust at baseline. Between baseline and follow-up, 35% progressed in frailty status or died, 56% had no change in frailty status, and 15% of prefrail or frail participants improved, although only 0.5% improved across two levels, from frail to robust. In multivariable models, factors associated with improvement in frailty status included greater leg power, being married, and good or excellent self-reported health, whereas presence of any instrumental activity of daily living (IADL) limitations, low albumin levels, high interleukin-6 levels, and presence of chronic obstructive pulmonary disease or diabetes mellitus were associated with lower likelihood of improvement in frailty status. CONCLUSION: Improvement in frailty status was possible in this cohort of community-dwelling older men, but improvement from frail to robust was rare. Several predictors were identified as possible targets for intervention, including prevention and management of comorbid medical conditions, prevention of IADL disability, physical exercise, and nutritional and social support. PMID- 28873221 TI - Getting Underneath Observed Frailty Transitions: Meaningful Change, Prevention, and Intervention. PMID- 28873222 TI - Uremic pericarditis, pericardial effusion, and constrictive pericarditis in end stage renal disease: Insights and pathophysiology. AB - A rising prevalence of end-stage renal disease (ESRD) has led to a rise in ESRD related pericardial syndromes, calling for a better understanding of its pathophysiology, diagnoses, and management. Uremic pericarditis, the most common manifestation of uremic pericardial disease, is a contemporary problem that calls for intensive hemodialysis, anti-inflammatories, and often, drainage of large inflammatory pericardial effusions. Likewise, asymptomatic pericardial effusions can become large and impact the hemodynamics of patients on chronic hemodialysis. Constrictive pericarditis is also well documented in this population, ultimately resulting in pericardiectomy for definitive treatment. The management of pericardial diseases in ESRD patients involves internists, cardiologists, and nephrologists. Current guidelines lack clarity with respect to the management of pericardial processes in the ESRD population. Our review aims to describe the etiology, classification, clinical manifestations, diagnostic imaging tools, and treatment options of pericardial diseases in this population. PMID- 28873223 TI - Systemic hypertension in cats with acute kidney injury. AB - OBJECTIVE: To describe the prevalence of systemic hypertension in cats with community-acquired acute kidney injury and investigate its relationship with disease severity. MATERIALS AND METHODS: Retrospective study of cats presenting to the Queen Mother Hospital for Animals, Royal Veterinary College with acute kidney injury between 2007 and 2015. Systolic blood pressure was measured using Doppler sphygmomanometry and systemic hypertension was defined pressures e150 mmHg. Median systolic blood pressure measurement, grade of acute kidney injury (as defined by the International Renal Interest Society), serum creatinine on admission, anuria or oliguria, length of hospitalisation, survival to discharge and six-month survival were all recorded. RESULTS: Forty-six cats were included; 21/48 (48.8%) showed systemic hypertension on admission and was severe (e180 mmHg) in 8/43 (18.6%). During the whole hospitalisation period, systemic hypertension was detected in 27/46 (58.7%) cases and severe in 13/46 (28.2%). Systemic hypertension did not appear to be statistically associated with grade of kidney injury, serum creatinine on presentation, oliguria or anuria. CLINICAL SIGNIFICANCE: Systemic hypertension is common in cats with acute kidney injury but does not appear to be associated with its severity. PMID- 28873224 TI - Disparities in prognosis communication among parents of children with cancer: The impact of race and ethnicity. AB - BACKGROUND: Most parents of children with cancer say they want detailed information about their child's prognosis. However, prior work has been conducted in populations of limited diversity. The authors sought to evaluate the impact of parental race/ethnicity on prognosis communication experiences among parents of children with cancer. METHODS: In total, 357 parents of children with cancer and the children's physicians were surveyed at Dana-Farber Cancer Institute/Boston Children's Hospital and Children's Hospital of Philadelphia. Outcome measures were parental preferences for prognostic information, physician beliefs about parental preferences, prognosis communication processes, and communication outcomes. Associations were assessed by logistic regression with generalized estimating equations to correct for physician clustering. RESULTS: Two hundred eighty-one parents (79%) were white, 23 (6%) were black, 29 (8%) were Hispanic, and 24 (7%) were Asian/other. Eighty-seven percent of parents wanted as much detail as possible about their child's prognosis, with no significant differences by race/ethnicity (P = .75). However, physician beliefs about parental preferences for prognosis communication varied based on parent race/ethnicity, with physicians considering black and Hispanic parents less interested in details about prognosis than whites (P = .003). Accurate understanding of a less favorable prognosis was greater among white (49%) versus nonwhite parents (range, 20%-29%), although this difference was not statistically significant (P = .14). CONCLUSIONS: Most parents, regardless of racial and ethnic background, want detailed prognostic information about their child's cancer. However, physicians underestimate the information needs of black and Hispanic parents. To meet parents' information needs, physicians should ask about parents' information preferences before prognosis discussions. Cancer 2017;123:3995-4003. (c) 2017 American Cancer Society. PMID- 28873226 TI - Doris. PMID- 28873225 TI - Chronic hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD. AB - : We assessed the risk of chronic kidney disease (CKD) in chronic hepatitis C virus (HCV)-infected patients and the incidence reduction of CKD after receipt of HCV treatment. We also evaluated the risk of membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia in chronic HCV patients. A retrospective cohort analysis of the Truven Health MarketScan Database (2008 2015) in the United States was conducted. In a cohort of 56,448 HCV-infected patients and 169,344 propensity score (1:3)-matched non-HCV patients, we examined the association of HCV infection with the incidence of CKD. Of 55,818 HCV patients, 6.6 % (n = 3666), 6.3% (n = 3534), and 8.3% (n = 4628) patients received either interferon-based dual, triple, or all-oral direct acting antiviral agent therapy, respectively, whereas 79% of patients did not receive any HCV treatment. Cox proportional hazards models were used to compare the risk of developing CKD in HCV patients compared with non-HCV patients and treated patients compared with untreated HCV patients. In a multivariate time-varying Cox regression model, HCV-infected patients had a 27% increased risk of CKD compared with non-HCV patients (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.18-1.37). Among HCV patients, individuals who received the minimally effective HCV treatment for dual, triple, or all-oral therapy had a 30% decreased risk of developing CKD (HR, 0.70; 95% CI, 0.55-0.88). In addition, HCV-infected patients experienced a twofold and a nearly 17-fold higher risk of MPGN (HR, 2.23; 95% CI, 1.84-2.71) and cryoglobulinemia (HR, 16.91; 95% CI, 12.00-23.81) respectively, compared with non-HCV patients. CONCLUSION: HCV-infected individuals in the United States are at greater risk of developing CKD, MPGN, and cryoglobulinemia. Minimally effective treatment of HCV infection can prevent the development of CKD, although the association was not significant for all-oral therapy. (Hepatology 2017). PMID- 28873228 TI - Photodegradation of Eumelanin and Pheomelanin and Its Pathophysiological Implications. AB - Eumelanin is photoprotective for pigmented tissues while pheomelanin is phototoxic. In this review, we summarize current understanding of how eumelanin and pheomelanin structures are modified by ultraviolet A (UVA) and also by visible light and how reactive oxygen species participate in those processes. Alkaline hydrogen peroxide oxidation was employed to characterize eumelanin and benzothiazole-type pheomelanin, giving pyrrole-2,3,5-tricarboxylic acid (PTCA) and thiazole-2,4,5-tricarboxylic acid (TTCA), respectively. Reductive hydrolysis with hydroiodic acid gives 4-amino-3-hydroxyphenylalanine (4-AHP) from the benzothiazine moiety of pheomelanin. The results show that the photoaging of eumelanin gives rise to free PTCA (produced by peroxidation in situ) and pyrrole 2,3,4,5-tetracarboxylic acid (PTeCA, produced by cross-linking). The TTCA/4-AHP ratio increases with photoaging, indicating the conversion of benzothiazine to the benzothiazole moiety. Analysis of those markers and their ratios show that both eumelanin and pheomelanin in human retinal pigment epithelium melanosomes undergo extensive structural modifications due to their lifelong exposure to blue light. Using synthetic melanins, we also found that singlet oxygen, in addition to superoxide anions, is photogenerated and quenched upon UVA irradiation. The (patho)physiological significance of those findings is discussed in relation to the tanning process, to melanomagenesis in the skin and to age-related macular degeneration in the eyes. PMID- 28873227 TI - Analysis of moisture, oil, and fatty acid composition of olives by near-infrared spectroscopy: development and validation calibration models. AB - BACKGROUND: Olive is a new, expanding crop in Georgia. Its oil content steadily increases with maturity, but eventually plateaus at the maximum when the olives should be promptly harvested, avoiding overripening and quality degradation. This requires frequent testing. However, olive quality analysis by wet chemistry is laborious, slow and costly, whereas near-infrared reflectance spectroscopy (NIRS), being precise, accurate, rapid and cheap, could be suitable. We developed and validated NIRS calibration models for moisture, fresh-matter-oil (oil-FMO), dry-matter-oil (oil-DMO) and major fatty acid composition analyses. RESULTS: Of the12 models developed, seven constituents - moisture, oil-FMO, oil-DMO, and palmitic, palmitoleic, oleic and linoleic acids (representing 88-97% of the total fatty acids) had low standard errors and high coefficients of determination (R2 = 0.81-0.98; 1 - VR = 0.74-0.86) for both calibration and cross-validation. For these seven constituents, predictions of an independent validation set yielded excellent agreement between the NIRS predicted values and the reference values with low standard error of prediction (SEP), low bias, high coefficient of determination (r2 = 0.80-0.93) and high ratios of performance to deviation (RPD = SD/SEP; 2.21-3.85). CONCLUSION: Precise, accurate and rapid analysis of fresh olives for moisture, oil and major fatty acid composition can be done at a low cost using NIRS, meeting the analytical needs of the industry. (c) 2017 Society of Chemical Industry. PMID- 28873229 TI - Effect of pore size on performance of monolithic tube chromatography of large biomolecules. AB - Effect of pore size on the performance of ion-exchange monolith tube chromatography of large biomolecules was investigated. Radial flow 1 mL polymer based monolith tubes of different pore sizes (1.5, 2, and 6 MUm) were tested with model samples such as 20 mer poly T-DNA, basic proteins, and acidic proteins (molecular weight 14 000-670 000). Pressure drop, pH transient, the number of binding site, dynamic binding capacity, and peak width were examined. Pressure drop-flow rate curves and dynamic binding capacity values were well correlated with the nominal pore size. While duration of the pH transient curves depends on the pore size, it was found that pH duration normalized on estimated surface area was constant, indicating that the ligand density is the same. This was also confirmed by the constant number of binding site values being independent of pore size. The peak width values were similar to those for axial flow monolith chromatography. These results showed that it is easy to scale up axial flow monolith chromatography to radial flow monolith tube chromatography by choosing the right pore size in terms of the pressure drop and capacity. PMID- 28873230 TI - Effect of roasting conditions on the composition and antioxidant properties of defatted walnut flour. AB - BACKGROUND: Walnut oil extraction by pressure systems produces a press cake as a by-product, with many of the beneficial walnut properties. The objective of this work was to evaluate the composition and antioxidant properties of walnut flours submitted to different roasting protocols (50, 100 and 150 degrees C during 30, 60 and 120 min). RESULTS: All walnut flours had about 42% protein and a significant amount of dietary fibre (17%), not being affected by the roasting process. Nonetheless, the fat content increased around 50% in walnuts flours subjected to longer and higher roasting temperatures (150 degrees C). The lipid fraction showed a good nutritional quality with a high vitamin E content (mainly gamma-tocopherol) and fatty acid profile rich in linoleic and linolenic acids. The high phenolic content also provides great antioxidant capacity to the flours. CONCLUSION: Mild roasting of walnuts did not affect the quality of the flours that could be used as a functional ingredient in the food industry. (c) 2017 Society of Chemical Industry. PMID- 28873231 TI - Medical Innovation in a Children's Hospital: 'Diseases desperate grown by desperate appliance are relieved, or not at all'. AB - A balance needs to be struck between facilitating compassionate access to innovative treatments for those in desperate need, and the duty to protect such vulnerable individuals from the harms of untested/unlicensed treatments. We introduced a principle-based framework (2009) to evaluate such requests and describe its application in the context of recently evolved UK, US and European regulatory processes. 24 referrals (20 individual; four group) were received by our quaternary children's hospital Clinical Ethics Committee (CEC) over the 5 year period (2011-16). The CEC-rapid response group evaluated individual cases within 48-hours; the main referrers being haematology/oncology, immunology or transplant services (14). Most requests were for drug/vaccine/pre-trial access (13) or biological/cellular therapies (8). The majority of individual requests were approved (19/20); neutral or negative opinions were given in 5, including 3 group requests. Recently evolved regulatory processes share common criteria and conditions to our framework including: demonstration of clinical need; sound scientific basis with lack of viable alternative; risks-benefit/best interests evaluation; arrangements for fully informed consent; no compromise of arrangements to test treatment for licensing purposes; consideration of resource implications. There are differences between individual processes and with our framework, with respect to procedures, scope, application format, costs and obligation to make available all outcome data. Our experience has emphasized the need for an independent, principled, consistent, fair and transparent response to the increasing demand for innovative treatment on a compassionate basis. We believe that there is a need for harmonization of the recent proliferation of regulation and legislation in this area. PMID- 28873232 TI - Liver size: Waning by day, Waxing by Night. PMID- 28873233 TI - Seasonal variation in hospitalization outcomes in patients admitted for heart failure in the United States. AB - BACKGROUND: There is lack of evidence of the impact of varying season on heart failure (HF) hospitalization outcomes in the U.S. HYPOTHESIS: HF hospitalization outcomes exhibit significant seasonal variation in the U.S. METHODS: Using data from the National Inpatient Sample (2011-2013), seasonal variation was classified based on meteorological classification of Northern Hemisphere-Spring, Summer, Fall, & Winter-and analysis was conducted via multivariable-adjusted mixed-effect model. RESULTS: An estimated 2.8 million adults were hospitalized for HF in the U.S. from 2011 to 2013. Of all hospitalizations, admissions were highest in Winter (27%), followed by Spring (26%), Fall (24%), and Summer (23%). The overall mortality rate was 3.1%. Compared with Spring, there was significantly lower mortality in Summer (odds ratio [OR]: 0.95, 95% CI: 0.91-0.99) and Fall (OR: 0.94, 95% CI: 0.89-0.98), but the highest mortality was in Winter (OR: 1.06, 95% CI: 1.02-1.11). In addition, mean length of stay and median cost of hospitalization were highest in Winter (5.3 days, USD7459, respectively) and lowest in Summer (5.1 days, USD7181, respectively). However, age and sex differences existed (e.g. seasonal variation in inpatient mortality was only significant for patients age >=65 years, and, compared with the Spring season, males had higher risk of inpatient mortality in Winter (OR: 1.10, 95% CI: 1.04 1.17) and females had lower risk of inpatient mortality in Summer (OR: 0.94, 95% CI: 0.88-1.00) and Fall (OR: 0.92, 95% CI: 0.87-0.98). CONCLUSIONS: Among HF patients in the U.S., hospitalization outcomes were worse in Winter but better in Summer. PMID- 28873234 TI - Effect of seasonal climate fluctuations on the evolution of glycoconjugates during the ripening period of grapevine cv. Muscat a petits grains blancs berries. AB - BACKGROUND: Temperature changes and rainfall fluctuations affect the winemaking industry by altering vine phenology, crop yield, must composition and wine quality. Here, the evolution of the varietal aroma potential during ripening over three consecutive seasons has been analyzed considering climate conditions. The effect of season, ripening date and climatic conditions on aroma precursor accumulation in grapes was studied by multivariate analysis and discussed in regard to the potential aromatic quality of the wine. RESULTS: In contrast to musts obtained from grapes harvested in warm and dry seasons (2014 and 2015), musts obtained from grapes harvested in the coolest and most humid year (2013) showed a lower pH, higher total acidity, higher varietal aroma potential index (IPAv), and higher aromatic potential of linalool, geraniol and nerol (typical of the Muscat flavor). CONCLUSION: Considering the three seasons, grapes synthesized and accumulated more precursors when milder temperatures and late rains throughout veraison were recorded. However, we observed a high fluctuation of aroma precursors during the ripening period, so choosing the correct harvesting date (according to grape aroma potential) may overcome some of the negative effects linked to climate conditions. (c) 2017 Society of Chemical Industry. PMID- 28873235 TI - A Kantian ethics approach to moral bioenhancement. AB - It seems, at first glance, that a Kantian ethics approach to moral enhancement would tend towards the position that there could be no place for emotional modulation in any understanding of the endeavour, owing to the typically understood view that Kantian ethics does not allow any role for emotion in morality as a whole. It seems then that any account of moral bioenhancement which places emotion at its centre would therefore be rejected. This article argues, however, that this assumption is incorrect. Given later writings by Kant on the role of sympathy, and taking into account other concerns in Kantian ethics (such as bodily integrity), it may in fact be the case that Kantian ethics would allow for an account of moral bioenhancement through emotional modulation, and that in some (rare) cases such an intervention might even be considered to be a duty. PMID- 28873236 TI - Hepatocellular carcinoma complicating hepatitis E virus-related cirrhosis. PMID- 28873237 TI - Practice makes better: TIPS procedures in referral centers. PMID- 28873238 TI - Cholinergic urticaria patients of different age groups have distinct features. AB - BACKGROUND: Cholinergic urticaria (CholU) is a common skin disease characterized by the development of pinpoint-sized weals and severe itch upon physical exercise. Little is known about the epidemiology of CholU. CholU can occur at any age and has the highest prevalence among young adults. As of now, it is unclear whether patients of different age show differences in the clinical manifestation of CholU, duration of disease, comorbidities or response to treatment. METHODS: Here, we analysed the demographic data and clinical characteristics including disease duration and comorbidities of 200 patients with CholU, 12-76 years of age. RESULTS: We identified two distinct types of CholU, one with early onset (EO, 71%) and one with late onset (LO, 29%). Patients with EO and LO CholU markedly differ in key characteristics: patients with EO, who had a disease onset before the age of 36, showed no gender preponderance and had a significantly higher rate of concomitant atopic dermatitis (16.9% vs 5.2%; P = .028) and higher IgE levels (295.5 vs 267.1 IU/mL; P = .020) as compared to patients with LO, who were mainly female (69%), had a shorter duration of disease (33.3 vs 63.7 months; P = .005), a higher rate of concomitant other forms of urticaria (48.3% vs 33.1%; P = .044) and a higher rate of psychiatric comorbidities (12.1% vs 1.4%; P = .001). CONCLUSION: There are two subtypes of CholU patients with different gender ratios, disease duration and comorbidities. These findings suggest that two distinct underlying pathogenetic pathways are relevant in these two subgroups of patients with CholU. PMID- 28873239 TI - Interventional radiology in bone metastases. AB - Interventional radiology plays a significant role in the treatment of bone metastases by various techniques, percutaneous or endovascular. Vertebroplasty is the most well-studied technique for stabilisation of spine metastases as it induces satisfactory stabilisation of the vertebra and offers clear improvement of the quality of life. Due to the success of this technique cementoplasty of other bones, mainly pelvic girdle, has been largely developed. The development of reinforced cementoplasty allows treatment of pre-fractural osteolysis of some long bones. The heat due to the polymerisation of the cement induces carcinolytic effect but this effect is not as important as that which results from radiofrequency destruction. This last technique appears currently as the most important development to definitively destroy bone metastases and is progressively replacing percutaneous alcoholic destruction of such lesions. Angiographic techniques, such as endovascular embolisation, can also be very useful to reduce the risk of surgical treatment of hyper vascular metastases. Chemoembolisation is currently developed to associate pain relief induced by Endovascular embolisation and the carcinolytic effect obtained by local endovascular chemotherapy. All these techniques should develop largely during the next years. PMID- 28873240 TI - Gastric poorly cohesive carcinoma: a correlative study of mutational signatures and prognostic significance based on histopathological subtypes. AB - AIMS: Genome-wide next-generation sequencing has revealed several driver mutations and has allowed the establishment of a molecular taxonomy of gastric cancer. However, there are few detailed studies on the mutational spectrum of poorly cohesive gastric carcinoma. Thus, this study aim to investigate its mutation profile based on clinicopathological characteristics. METHODS AND RESULTS: Herein, we analysed the mutational pattern of 77 genes in a cohort of 91 patients with poorly cohesive carcinoma by using targeted sequencing, and evaluated the clinicopathological significance of the various mutations based on histological pattern, either signet ring cell (SRC) or other types of poorly cohesive carcinoma (not otherwise specified) (PCC-NOS). Panels of seven (PIK3CA, CDH1, PTEN, RHOA, HDCA9, KRAS, and ATM), three (PIK3CA, CTNNB1, and KRAS) and two (HDCA9 and IGF1R) genes were associated with a diffuse infiltrative growth pattern, lymphovascular invasion, and perineural invasion, respectively. Furthermore, PDGFRB mutations were associated with a favourable prognosis, whereas MET mutations were associated with a poor prognosis. The PCC-NOS predominant type was associated with a greater depth of invasion, lymph node metastasis and poorer prognosis than the SRC-predominant type. Mutations in TP53, BRAF, PI3CA, SMAD4 and RHOA were associated with PCC-NOS. Interestingly, RHOA mutated gastric cancers showed a distinct morphology, as they were characterised by a superficial SRC or tubular component and a deep invasive PCC-NOS component with desmoplasia. CONCLUSIONS: Taken together, our findings demonstrate that gastric poorly cohesive carcinomas show several mutational patterns associated with specific clinicopathological characteristics, and particularly show distinct morphological findings when associated with RHOA mutation. PMID- 28873241 TI - A Eutectic Mixture of Natural Fatty Acids Can Serve as the Gating Material for Near-Infrared-Triggered Drug Release. AB - A smart release system responsive to near-infrared (NIR) light is developed for intracellular drug delivery. The concept is demonstrated by coencapsulating doxorubicin (DOX) (an anticancer drug) and IR780 iodide (IR780) (an NIR-absorbing dye) into nanoparticles made of a eutectic mixture of naturally occurring fatty acids. The eutectic mixture has a well-defined melting point at 39 degrees C, and can be used as a biocompatible phase-change material for NIR-triggered drug release. The resultant nanoparticles exhibit prominent photothermal effect and quick drug release in response to NIR irradiation. Fluorescence microscopy analysis indicates that the DOX trapped in the nanoparticles can be efficiently released into the cytosol under NIR irradiation, resulting in enhanced anticancer activity. A new platform is thus offered for designing effective intracellular drug-release systems, holding great promise for future cancer therapy. PMID- 28873242 TI - Sequential hypoallergenic boiled peanut and roasted peanut oral immunotherapy. PMID- 28873243 TI - Circumventing Intrinsic Metal Reactivity: Radical Generation with Redox-Active Ligands. AB - Nickel complexes have gained sustained attention as efficient catalysts in cross coupling reactions and co-catalysts in dual systems due to their ability to react with radical species. Central to this reactivity is nickel's propensity to shuttle through several accessible redox states from Ni0 to NiIV . Here, we report the catalytic generation of trifluoromethyl radicals from a nickel complex bearing redox-active iminosemiquinone ligands. This unprecedented reactivity is enabled through ligand-based oxidation performing electron transfer to an electrophilic CF3+ source while the nickel oxidation state is preserved. Additionally, extension of this reactivity to a copper complex bearing a single redox equivalent is reported, thus providing a unified reactivity scheme. These results open new pathways in radical chemistry with redox-active ligands. PMID- 28873244 TI - Aging effects in the expression of macrophages in post-treatment apical periodontitis lesions. AB - OBJECTIVES: To evaluate the CD68 immunoexpression in post-treatment apical periodontitis lesions of older patients and compare them with lesions of younger/middle age adults. METHODS: Biopsy specimens from 21 apical periodontitis lesions (12 granulomas and 9 cysts) were selected from older patients and 25 apical periodontitis lesions from younger/middle age adults (12 cysts and 13 granulomas) were selected and analyzed by immunohistochemistry using silanized slides with anti-CD68 antibody. The slides were subdivided in five high-power fields and the images were observed under an optical microscope to evaluate the epithelial and connective tissues. RESULTS: The results showed that there was no statistical difference for the CD68 expression in epithelial tissue of cysts between younger/middle age adults and older patients. However, for the connective tissue of both cysts and granulomas, there was a statistical difference between the two age groups. There was a statistical difference between the epithelial and the connective tissues in cysts of younger/middle age adults, and also when the epithelial tissue of the cysts was compared with connective tissue of the granuloma. In the group of older patients, there was no statistical difference between the connective tissue of the cysts and granulomas. CONCLUSION: The intensity of the macrophage staining was greater in the connective tissue of cysts and granulomas alike in the younger/middle age adult patients, suggesting that these cells participate actively in this tissue. Immune responses in older patients may be compromised, suggesting that there is a greater tendency for the endodontic treatment of these patients to fail. PMID- 28873245 TI - Scenario Analysis for the Safety Assessment of Nuclear Waste Repositories: A Critical Review. AB - A major challenge in scenario analysis for the safety assessment of nuclear waste repositories pertains to the comprehensiveness of the set of scenarios selected for assessing the safety of the repository. Motivated by this challenge, we discuss the aspects of scenario analysis relevant to comprehensiveness. Specifically, we note that (1) it is necessary to make it clear why scenarios usually focus on a restricted set of features, events, and processes; (2) there is not yet consensus on the interpretation of comprehensiveness for guiding the generation of scenarios; and (3) there is a need for sound approaches to the treatment of epistemic uncertainties. PMID- 28873246 TI - Multicriteria Decision Framework for Cybersecurity Risk Assessment and Management. AB - Risk assessors and managers face many difficult challenges related to novel cyber systems. Among these challenges are the constantly changing nature of cyber systems caused by technical advances, their distribution across the physical, information, and sociocognitive domains, and the complex network structures often including thousands of nodes. Here, we review probabilistic and risk-based decision-making techniques applied to cyber systems and conclude that existing approaches typically do not address all components of the risk assessment triplet (threat, vulnerability, consequence) and lack the ability to integrate across multiple domains of cyber systems to provide guidance for enhancing cybersecurity. We present a decision-analysis-based approach that quantifies threat, vulnerability, and consequences through a set of criteria designed to assess the overall utility of cybersecurity management alternatives. The proposed framework bridges the gap between risk assessment and risk management, allowing an analyst to ensure a structured and transparent process of selecting risk management alternatives. The use of this technique is illustrated for a hypothetical, but realistic, case study exemplifying the process of evaluating and ranking five cybersecurity enhancement strategies. The approach presented does not necessarily eliminate biases and subjectivity necessary for selecting countermeasures, but provides justifiable methods for selecting risk management actions consistent with stakeholder and decisionmaker values and technical data. PMID- 28873247 TI - Evaluation and comparison of staining patterns of factor XIIIa (AC-1A1), adipophilin and GATA3 in sebaceous neoplasia. AB - BACKGROUND: Reliable nuclear immunohistochemical stains for sebaceous neoplasms have not been readily available. Positive nuclear staining has been reported for GATA3 and factor XIIIa (AC-1A1). We sought to determine the diagnostic utility of these nuclear stains by comparing their staining pattern to adipophilin, a consistently positive cytoplasmic stain. METHODS: Cases with the diagnosis of sebaceous hyperplasia, sebaceous adenoma, sebaceous epithelioma/sebaceoma, sebaceous carcinoma, and nonsebaceous neoplasms (basal cell carcinoma and squamous cell carcinoma) were examined. Intensity and extent of staining of the basal cells and mature sebocytes were evaluated for each stain. RESULTS: Factor XIIIa (AC-1A1) was 87.3% sensitive and 95.1% specific for all sebaceous neoplasms sand showed high inter-observer reliability. Adipophilin was 83.2% sensitive and 87.8% specific. GATA3 was the least sensitive (80.9%) and specific (75.6%) marker. When factor XIIIa was compared against composite staining of all three markers its staining was still uniquely significant (P = .0210). CONCLUSION: Factor XIIIa (AC-1A1) is a sensitive and specific nuclear marker for sebaceous differentiation. Its diagnostic utility exceeds that of adipophilin. Factor XIIIa should be included in the expanding group of immunohistochemical and special stains which can be utilized to aid in the diagnosis of sebaceous neoplasms. PMID- 28873248 TI - Hydrogen-Bond Weakening through pi Systems: Resonance-Impaired Hydrogen Bonds (RIHB). AB - Redefining interactions: The concept of the resonance-impaired hydrogen bond (RIHB) as an interaction in which a conjugated pi system strongly impairs the formation of a hydrogen bond (HB) is introduced. A typical HB involving charged species can have a formation energy of tens of kcal mol-1 , whereas the corresponding value for the examined RIHB is only 2.6 kcal mol-1 . Quantum chemical topology tools are used to analyse the low formation energy of the studied RIHBs. PMID- 28873249 TI - Pseudomembranous changes in the dermis: A novel observation and potential clue for evolving lipodermatosclerosis? AB - Lipodermatosclerosis (LDS) is a well-recognized form of fibrosing panniculitis. Although chronic cases are readily diagnosed, early and evolving lesions may be clinically mistaken for cellulitis and other forms of panniculitis. Most pathologists are familiar with a pseudomembranous type of fat necrosis as a useful feature of chronic LDS. Although nonspecific, this distinctive pattern of fat necrosis helps in supporting a diagnosis of LDS in the appropriate clinical context. The histopathologic features of early and evolving LDS and those involving the dermis are less well documented. We report a case of early LDS showing extensive pseudomembranous changes in the dermis on a superficial skin biopsy where progression to a classic established lesion was documented clinically. We suspect that this previously unreported and unusual finding may be a histopathologic clue for evolving lesions of LDS. PMID- 28873250 TI - Nanolattices: An Emerging Class of Mechanical Metamaterials. AB - In 1903, Alexander Graham Bell developed a design principle to generate lightweight, mechanically robust lattice structures based on triangular cells; this has since found broad application in lightweight design. Over one hundred years later, the same principle is being used in the fabrication of nanolattice materials, namely lattice structures composed of nanoscale constituents. Taking advantage of the size-dependent properties typical of nanoparticles, nanowires, and thin films, nanolattices redefine the limits of the accessible material property space throughout different disciplines. Herein, the exceptional mechanical performance of nanolattices, including their ultrahigh strength, damage tolerance, and stiffness, are reviewed, and their potential for multifunctional applications beyond mechanics is examined. The efficient integration of architecture and size-affected properties is key to further develop nanolattices. The introduction of a hierarchical architecture is an effective tool in enhancing mechanical properties, and the eventual goal of nanolattice design may be to replicate the intricate hierarchies and functionalities observed in biological materials. Additive manufacturing and self assembly techniques enable lattice design at the nanoscale; the scaling-up of nanolattice fabrication is currently the major challenge to their widespread use in technological applications. PMID- 28873251 TI - Imported fire ant envenomation: A clinicopathologic study of a recognizable form of arthropod assault reaction. AB - BACKGROUND: Skin reactions to the sting of the imported fire ant have characteristic clinicopathological features. METHODS: One case of experimental envenomation was prospectively followed during 48 hours, with biopsies. In addition, 6 cases from our laboratory were retrospectively evaluated histopathologically for the following features: spongiosis, exocytosis (and type of cells), pustule formation, erosion/ulceration, epidermal necrosis, scale/crust, papillary dermal edema, inflammatory dermal infiltrate (cell type, density, depth, distribution, shape), red blood cell extravasation, vasculopathy and vasculitis. RESULTS: The typical lesion follows a very distinctive clinical and histopathologic evolution over 48 hours, with the formation of a subepidermal pustule overlying a wedge-shaped area of dermal collagen basophilic degeneration with scattered neutrophils. In the 6 cases retrieved from our files, the main features were a superficial and deep dermal, perivascular, periadnexal and interstitial infiltrate consisting of neutrophils, with basophilic degeneration of the collagen. A subepidermal pustule was noted in half of the cases. CONCLUSIONS: In biopsies taken in a clinical setting, even in the absence of the characteristic subepidermal pustule, the diagnosis of imported fire ant sting can be suspected if there is a superficial and deep perivascular, periadnexal and interstitial infiltrate composed of neutrophils, with some basophilic denaturation of collagen. PMID- 28873252 TI - Carbonic anhydrase inhibitor acetazolamide shifts synaptic vesicle recycling to a fast mode at the mouse neuromuscular junction. AB - Acetazolamide (AZ), a molecule frequently used to treat different neurological syndromes, is an inhibitor of the carbonic anhydrase (CA), an enzyme that regulates pH inside and outside cells. We combined fluorescent FM styryl dyes and electrophysiological techniques at ex vivo levator auris longus neuromuscular junctions (NMJs) from mice to investigate the modulation of synaptic transmission and vesicle recycling by AZ. Transmitter release was minimally affected by AZ, as evidenced by evoked and spontaneous end-plate potential measurements. However, optical evaluation with FM-styryl dyes of vesicle exocytosis elicited by 50 Hz stimuli showed a strong reduction in fluorescence loss in AZ treated NMJ, an effect that was abolished by bathing the NMJ in Hepes. The remaining dye was quenched by bromophenol, a small molecule capable of diffusing inside vesicles. Furthermore, in transgenic mice expressing Synaptophysin-pHluorin (SypHy), the fluorescence responses of motor nerve terminals to a 50 Hz train of stimuli was decrease to a 50% of controls in the presence of AZ. Immunohistochemistry experiments to evaluate the state of the Myosin light chain kinase (MLCK), an enzyme involved in vesicle recycling, demonstrated that MLCK phosphorylation was much stronger in the presence than AZ than in its absence in 50 Hz stimulated NMJs. We postulate that AZ, via cytosol acidification and activation of MLCK, shifts synaptic vesicle recycling to a fast (kiss-and-run) mode, which changes synaptic performance. These changes may contribute to the therapeutic action reported in many neurological syndromes like ataxia, epilepsy, and migraine. PMID- 28873254 TI - Reduction of Carbonyl Groups by Uranium(III) and Formation of a Stable Amide Radical Anion. AB - Methyl benzoate, N,N-dimethylbenzamide, and benzophenone were reduced by UIII [N(SiMe3 )2 ]3 resulting in uranium(IV) products. Reduction of benzophenone lead to UIV [OC?Ph2 )][N(SiMe3 )2 ]3 , (1.1) which forms the dinuclear complex, [N(SiMe3 )2 ]3 UIV (OCPhPh-CPh2 O)UIV [N(SiMe3 )2 ]3 (1.2), through coupling of the ketyl radical species upon crystallization. Reaction of N,N-dimethylbenzamide with UIII [N(SiMe3 )2 ]3 resulted in UIV [OC?(Ph)(NMe2 )][N(SiMe3 )2 ]3 (2), a uranium(IV) compound and the first example of a charge-separated amide radical. In the case of methyl benzoate, the reduction resulted in UIV (OMe)[N(SiMe3 )2 ]3 (3) and benzaldehyde as the reduced organic fragment. Compound 2 showed the ability to act as a uranium(III) synthon in its reactivity with trimethylsilyl azide, a reaction that yielded UV (=NSiMe3 )[N(SiMe3 )2 ]3 . Additionally, 2 was reduced with potassium graphite resulting in [U(MU-O)[O=C(NMe2 )(Ph)][N(SiMe3 )2 ]2 ]2 (4), a dinuclear uranium compound bridged by oxo ligands. Reduction of 2 in the presence of 15-crown-5 afforded isolation of the mono-oxo compound, [(15 crown-5)2 K][UO[N(SiMe3 )2 ]3 ] (5). The results expand the reduction capabilities of UIII complexes and demonstrate a strategy for isolating novel metal-stabilized radicals. PMID- 28873253 TI - TomExpress, a unified tomato RNA-Seq platform for visualization of expression data, clustering and correlation networks. AB - The TomExpress platform was developed to provide the tomato research community with a browser and integrated web tools for public RNA-Seq data visualization and data mining. To avoid major biases that can result from the use of different mapping and statistical processing methods, RNA-Seq raw sequence data available in public databases were mapped de novo on a unique tomato reference genome sequence and post-processed using the same pipeline with accurate parameters. Following the calculation of the number of counts per gene in each RNA-Seq sample, a communal global normalization method was applied to all expression values. This unifies the whole set of expression data and makes them comparable. A database was designed where each expression value is associated with corresponding experimental annotations. Sample details were manually curated to be easily understandable by biologists. To make the data easily searchable, a user-friendly web interface was developed that provides versatile data mining web tools via on-the-fly generation of output graphics, such as expression bar plots, comprehensive in planta representations and heatmaps of hierarchically clustered expression data. In addition, it allows for the identification of co-expressed genes and the visualization of correlation networks of co-regulated gene groups. TomExpress provides one of the most complete free resources of publicly available tomato RNA-Seq data, and allows for the immediate interrogation of transcriptional programs that regulate vegetative and reproductive development in tomato under diverse conditions. The design of the pipeline developed in this project enables easy updating of the database with newly published RNA-Seq data, thereby allowing for continuous enrichment of the resource. PMID- 28873255 TI - Accelerated 4D self-gated MRI of tibiofemoral kinematics. AB - Anatomical (static) magnetic resonance imaging (MRI) is the most useful imaging technique for the evaluation and assessment of internal derangement of the knee, but does not provide dynamic information and does not allow the study of the interaction of the different tissues during motion. As knee pain is often only experienced during dynamic tasks, the ability to obtain four-dimensional (4D) images of the knee during motion could improve the diagnosis and provide a deeper understanding of the knee joint. In this work, we present a novel approach for dynamic, high-resolution, 4D imaging of the freely moving knee without the need for external triggering. The dominant knee of five healthy volunteers was scanned during a flexion/extension task. To evaluate the effects of non-uniform motion and poor coordination skills on the quality of the reconstructed images, we performed a comparison between fully free movement and movement instructed by a visual cue. The trigger signal for self-gating was extracted using principal component analysis (PCA), and the images were reconstructed using a parallel imaging and compressed sensing reconstruction pipeline. The reconstructed 4D movies were scored for image quality and used to derive bone kinematics through image registration. Using our method, we were able to obtain 4D high-resolution movies of the knee without the need for external triggering hardware. The movies obtained with and without instruction did not differ significantly in terms of image scoring and quantitative values for tibiofemoral kinematics. Our method showed to be robust for the extraction of the self-gating signal even for uninstructed motion. This can make the technique suitable for patients who, as a result of pain, may find it difficult to comply exactly with instructions. Furthermore, bone kinematics can be derived from accelerated MRI without the need for additional hardware for triggering. PMID- 28873257 TI - Deep Uncertainties in Sea-Level Rise and Storm Surge Projections: Implications for Coastal Flood Risk Management. AB - Sea levels are rising in many areas around the world, posing risks to coastal communities and infrastructures. Strategies for managing these flood risks present decision challenges that require a combination of geophysical, economic, and infrastructure models. Previous studies have broken important new ground on the considerable tensions between the costs of upgrading infrastructure and the damages that could result from extreme flood events. However, many risk-based adaptation strategies remain silent on certain potentially important uncertainties, as well as the tradeoffs between competing objectives. Here, we implement and improve on a classic decision-analytical model (Van Dantzig 1956) to: (i) capture tradeoffs across conflicting stakeholder objectives, (ii) demonstrate the consequences of structural uncertainties in the sea-level rise and storm surge models, and (iii) identify the parametric uncertainties that most strongly influence each objective using global sensitivity analysis. We find that the flood adaptation model produces potentially myopic solutions when formulated using traditional mean-centric decision theory. Moving from a single-objective problem formulation to one with multiobjective tradeoffs dramatically expands the decision space, and highlights the need for compromise solutions to address stakeholder preferences. We find deep structural uncertainties that have large effects on the model outcome, with the storm surge parameters accounting for the greatest impacts. Global sensitivity analysis effectively identifies important parameter interactions that local methods overlook, and that could have critical implications for flood adaptation strategies. PMID- 28873256 TI - NYEs/SGRs-mediated chlorophyll degradation is critical for detoxification during seed maturation in Arabidopsis. AB - In the seed industry, chlorophyll (Chl) fluorescence is often used as a major non invasive reporter of seed maturation and quality. Breakdown of Chl is a proactive process during the late stage of seed maturation, as well as during leaf senescence and fruit ripening. However, the biological significance of this process is still unclear. NYE1 and NYE2 are Mg-dechelatases, catalyzing the first rate-limiting step of Chl a degradation. Loss-of-function of both NYE1 and NYE2 not only results in a nearly complete retention of Chl during leaf senescence, but also produces green seeds in Arabidopsis. In this study, we showed that Chl retention in the nye1 nye2 double-mutant caused severe photo-damage to maturing seeds. Upon prolonged light exposure, green seeds of nye1 nye2 gradually bleached out and eventually lost their germination capacity. This organ-specific photosensitive phenotype is likely due to an over-accumulation of free Chl, which possesses photosensitizing properties and causes a burst of reactive oxygen species upon light exposure. As expected, a similar, albeit much milder, photosensitive phenotype was observed in the seeds of d1 d2, a green-seed mutant defective in NYE/SGR orthologous genes in soybean. Taken together, our data suggest that efficient NYEs-mediated Chl degradation is critical for detoxification during seed maturation. PMID- 28873258 TI - The inherent matrix properties of lichen metabolites in matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AB - RATIONALE: Light-absorbing secondary metabolites from lichens were recently reported to exhibit promising Laser Desorption Ionization (LDI) properties, enabling their direct detection from crude lichen extracts. In addition, many of them display close structural homologies to commercial Matrix-Assisted Laser Desorption Ionization (MALDI) matrices, which is incentive for the evaluation of their matrical properties. The current study systematically evaluated the matrix effects of several structural classes of lichen metabolites: monoaromatic compounds, quinone derivatives, dibenzofuran-related molecules and the shikimate derived vulpinic acid. Their matrical properties were tested against a wide range of structurally diverse analytes including alkaloids, coumarins, flavonoids and peptides. METHODS: Triplicate automatic positive-ion mode MALDI analyses were carried out and ionization efficiencies were compared with those of structurally related reference matrices (i.e. DHB, HCCA, dithranol and usnic acid) in terms of (i) analyte absolute intensities and (ii) Matrix Suppressing Effect (MSE) scores. RESULTS: Monoaromatic lichen metabolites revealed matrical properties similar to those of DHB when obtained under comparable experimental conditions. Likewise, anthraquinone metabolites triggered ionization of tested analytes in a similar way to the structurally related dithranol. Finally, dibenzofuran derivatives displayed a broad ionization profile, reminiscent of that of (+)-usnic acid. CONCLUSIONS: Lichen metabolites exhibit interesting MALDI matrix properties, especially for medium and low molecular weight analytes. For many of the tested molecules, matrix ion formation was very limited. This proof-of-concept study paves the way for follow-up investigations to assess the matrix properties of lichen metabolites against a wider array of analytes as well as adapting experimental settings to individually optimize the performance of successfully tested candidates. PMID- 28873259 TI - Increased enteric glial cells in proximal margin of resection is associated with postoperative recurrence of Crohn's disease. AB - BACKGROUND AND AIM: The enteric nervous system can amplify or modulate intestinal inflammation through secretion of neuropeptides, and enteric glial cells have been implicated in the pathophysiology of Crohn's disease. The goal of the study was to search for an association between the density of neurons, neuropeptides, and enteric glial cells and postoperative recurrence. METHODS: The ileal proximal uninflamed section from ileocolonic sample was studied using immunohistochemistry with antibodies directed against vasoactive intestinal polypeptide (VIP), substance P (SP), neuron-specific enolase (NSE), and the glial marker protein S100. The density in the submucosa was calculated, and the relationship of the density of VIP, SP, NSE, and S100 and postoperative disease recurrence was assessed. RESULTS: There were no significant differences between patients with and without postoperative endoscopic recurrence or clinical recurrence for the density of NSE-positive, VIP-positive, or SP-positive neurons in the proximal margin. Interestingly, the density of S100-positive enteric glial cells was significantly increased in patients with endoscopic and clinical recurrence than in subjects without disease recurrence (P ? 0.001). The density of S100-positive enteric glial cells was independently associated with postoperative disease recurrence. CONCLUSIONS: Increased S100-positive enteric glial cells are associated with a high risk of both endoscopic and clinical recurrence after surgery. These findings have implications in individualized postoperative prophylaxis for Crohn's disease. PMID- 28873260 TI - Rotational Spectroscopy Probes Water Flipping by Full Fluorination of Benzene. AB - The topology of the interaction of water with benzene changes drastically upon full H->F substitution on the aromatic ring: the weak O-H???pi hydrogen bond is replaced by a O???pi linkage, of about the same strength. Hexafluorobenzene-water appears to be the prototype system to investigate this kind of weak bond. The pulsed Fourier transform microwave technique has been used for the detection of the rotational spectra of the normal species and five isotopologues which unambiguously led to the identification of the geometry. Quantum mechanical calculations have been performed to interpret the experimental evidence. PMID- 28873261 TI - Impacts of different land management histories on forest change. AB - Many western North American forest types have experienced considerable changes in ecosystem structure, composition, and function as a result of both fire exclusion and timber harvesting. These two influences co-occurred over a large portion of dry forests, making it difficult to know the strength of either one on its own or the potential for an interaction between the two. In this study, we used contemporary remeasurements of a systematic historical forest inventory to investigate forest change in the Sierra Nevada. The historical data opportunistically spanned a significant land management agency boundary, which protected part of the inventory area from timber harvesting. This allowed for a robust comparison of forest change between logged and unlogged areas. In addition, we assessed the effects of recent management activities aimed at forest restoration relative to the same areas historically, and to other areas without recent management. Based on analyses of 22,007 trees (historical, 9,573; contemporary, 12,434), live basal area and tree density significantly increased from 1911 to the early 2000s in both logged and unlogged areas. Both shrub cover and the proportion of live basal area occupied by pine species declined from 1911 to the early 2000s in both areas, but statistical significance was inconsistent. The most notable difference between logged and unlogged areas was in the density of large trees, which declined significantly in logged areas, but was unchanged in unlogged areas. Recent management activities had a varied impact on the forest structure and composition variables analyzed. In general, areas with no recent management activities experienced the greatest change from 1911 to the early 2000s. If approximating historical forest conditions is a land management goal the documented changes in forest structure and composition from 1911 to the early 2000s indicate that active restoration, including fire use and mechanical thinning, is needed in many areas. PMID- 28873263 TI - Continuous infusion of coagulation factor concentrates during intensive treatment. AB - In clinical management of bleeds and surgical procedures in patients suffering from bleeding disorders either repetitive bolus injections (BI) or continuous infusion (CI) can be used for coagulation factor replacement. Continuous infusion seems to be an attractive route of administration and may be considered if replacement therapy is required for more than 3 days. The strongest argument favouring continuous infusion is its superiority in providing the patient with a safe and constant level of the deficient coagulation factor by balancing input with clearance. Furthermore, several studies have shown that coagulation factor consumption may be reduced by CI compared to repetitive bolus injections (BI) since unnecessary peaks of factor level are avoided. Concerns have been raised whether continuous infusion of coagulation concentrates is associated with an increased risk of developing inhibitors. However, available data have so far not shown an increased risk for inhibitor development in severe haemophilia patients with more than 50 exposure days of coagulation factor concentrates. Further, previously reported complications when using CI such as phlebitis at the infusion site and pump failure are nowadays very seldom seen when small amounts of heparin are added to the infusion bag, and increased quality of the pumps are available. Over the last decades, numerous reports have confirmed CI to be a safe and effective mode of coagulation factor replacement even in the most challenging surgical procedures, such as total joint arthroplasties. PMID- 28873264 TI - Patterns of unmet supportive needs and relationship to quality of life in Chinese cancer patients. AB - OBJECTIVE: This study aimed to (1) identify distinct patterns of unmet needs in Chinese cancer patients; (2) examine whether sociodemographic and medical characteristics distinguished these patterns; and (3) examine whether people with distinct patterns reported differential quality of life (QoL). METHODS: This cross-sectional study recruited 301 cancer patients from 2 hospitals in China. The 34-item Supportive Care Needs Survey Short-Form was used to measure unmet needs across 5 domains: physical and daily living, psychological, patient care and support, health systems and information, and sexuality. Latent class analysis was performed to identify patterns of unmet needs across these domains. RESULTS: Four patterns of unmet needs were identified, differing in levels and nature of unmet needs. Participants in class 1 (47%) reported few unmet needs. Patients in class 2 (15%) had moderate levels of unmet needs, displaying similar levels across 5 domains. People in class 3 (25%) and class 4 (13%) reported similarly high levels on "psychological," "health care system and information," "physical and daily living," and "patient care," but differing in "sexuality," with class 3 reporting low levels while class 4 high on "sexuality." None of sociodemographic and medical characteristics distinguished these patterns significantly. Compared to other classes, people in class 1 reported highest levels of QoL. CONCLUSIONS: This study demonstrates the existence of 4 patterns of unmet supportive needs in Chinese cancer patients. Patients with few unmet needs reported the best QoL. PMID- 28873262 TI - Reactivation of TWIST1 contributes to Ewing sarcoma metastasis. AB - BACKGROUND: Ewing sarcoma is a cancer of bone and soft tissue. Despite aggressive treatment, survival remains poor, particularly in patients with metastatic disease. Failure to treat Ewing sarcoma is due to the lack of understanding of the molecular pathways that regulate metastasis. In addition, no molecular prognostic markers have been identified for Ewing sarcoma to risk stratify patients. PROCEDURE: Ewing sarcoma patients were divided into high or low Twist1 gene expression and survival curves were generated using the R2 microarray-based Genomic Analysis platform (http://r2.amc.nl). Tumors from Ewing sarcoma patients were also evaluated for TWIST1 expression by immunohistochemistry. Ewing sarcoma xenografts were established to evaluate the role of TWIST1 in metastasis. The effects of Twist1 on migration and invasion were evaluated using migration and invasion assays in A673 and RDES cells. RESULTS: Twist1 expression was a negative prognostic marker for overall survival in a public Ewing sarcoma patient data set based on Twist1 mRNA levels and in patient tumor samples based on Twist1 immunohistochemistry. TWIST1 is detected in significantly higher percentage of patients with metastatic diseases than localized disease. Using Ewing sarcoma tumor xenografts in mice, we found that suppressing TWIST1 levels suppressed metastasis without affecting primary tumor development. Knockdown of Twist1 inhibited the migration and invasion capability, while overexpression of Twist1 promoted migration and invasion in Ewing sarcoma cells. CONCLUSION: These results suggest that TWIST1 promotes metastasis in Ewing sarcoma and could be used as a prognostic marker for treatment stratification; however, further validation is required in a larger cohort of patients. PMID- 28873265 TI - Dyadic effects of coping strategies, time perspectives, and personality on the quality of life of cancer patients and their caregivers. AB - OBJECTIVE: Researchers are interested in studying whether the quality of life (QoL) of cancer patients and caregivers is influenced by internal psychobehavioral processes (temporality and coping strategies) and the personality traits that they or their relatives experience. We examined these associations in a sample of patient-caregiver dyads by using the actor-partner interdependence model. METHODS: This cross-sectional study involved 156 cancer patient-caregiver dyads. The self-reported data included QoL (Short-Form 36), coping strategies (Brief Coping Orientation to Problems Experienced Scale), time perspectives (Zimbardo Time Perspective Inventory), and personality (Big Five Inventory). The actor-partner interdependence model was used to test the dyadic effect individualizing actor (degree to which the individual's characteristics were associated with their QoL) and partner (degree to which the individual's characteristics were associated with the QoL of the other dyad member) effects. RESULTS: Actor effects were found for patients and caregivers: The use of positive thinking and future/present-hedonistic perspectives were associated with higher QoL; the use of avoidance and past-negative perspective were associated with lower QoL. Partner effects were also found highlighting the specific mechanisms of the interconnections in the patient-caregiver dyad. The patient's QoL was higher when the caregiver used social support and experienced openness. The caregiver's QoL was lower when the patient used social support and avoidance strategies and experienced future perspective. CONCLUSIONS: The examination of the relationships between individuals' QoL and their internal psychobehavioral processes and personality traits will have several applications in the routine clinical management. Individual-level and dyad-level interventions should be proposed: cognitive-rehabilitation, emotional and cognitive self-regulation for time perspectives, and personality constructs. PMID- 28873266 TI - Prospective cohort study of risk factors for extended-spectrum beta-lactamase producing Escherichia coli urinary tract infections in elderly patients admitted to hospital. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli are currently common in community-onset infections, limiting therapeutic options. In this work we aim to identify the prevalence of and risk factors for ESBL producing E. coli in elderly patients with urinary tract infections (UTI) admitted to hospital. METHODS: Prospective cohort study on elderly patients with E. coli UTI admitted to a university hospital in Spain, from January 2013 to December 2015. Clinical features, microbiology and outcomes were recorded from the electronic medical records and reviewed by two researchers. Cases were segregated according to ESBL-producing E. coli. Risk factors for ESBL-producing E. coli were analysed by multivariate analysis. RESULTS: The prevalence of ESBL producing E. coli was 27.4% (85/310). Healthcare-associated UTI was the only risk factor for ESBL-producing E. coli (OR 6.79; 95% CI 3.22-14.31, P < .001) by multivariate analysis. ESBL-producing E. coli was 43.9% in the healthcare associated UTI group and 8.9% in the community-acquired UTI group (P < .001). Inadequate empirical antibiotic therapy and length of stay in hospital were higher in the ESBL-producing E. coli group than in the non-ESBL-producing E. coli group (62.3% vs 5.3% and 6.60 +/- 3.69 days vs 5.61 +/- 3.16 days, respectively). Mortality was not significantly different between groups (13% in ESBL-producing E. coli group vs 7.5% in non-ESBL-producing E. coli group, P = .140). SUMMARY: Healthcare-associated UTI was a risk factor for ESBL-producing E. coli in elderly patients with UTI admitted to hospital. Our results might help clinicians in choosing empirical antibiotics in an overall high rate setting of ESBL-producing E. coli. PMID- 28873267 TI - Administration of adjuvant chemotherapy in older patients with Stage III colon cancer: an observational study. AB - AIM: According to established guidelines, patients with Stage III colon cancer should receive adjuvant chemotherapy. However, a significant proportion do not. This study assessed factors associated with the administration of adjuvant chemotherapy and causes of death. METHODS: Patients with Stage III colon cancer who underwent surgery between 2000 and 2009 were selected from two hospitals in the Netherlands. Patient characteristics including comorbidities and treatment preferences, tumour characteristics and follow-up were extracted from the medical records. The patient and tumour characteristics of patients who did receive chemotherapy were compared with those who did not using chi-squared analysis. Differences between the groups in causes of death were recorded together with the duration of follow-up. RESULTS: A total of 348 patients were included. The median age was 73 years (range 33-93). Over half of the patients received adjuvant chemotherapy (50.6%). Patients who did not receive adjuvant chemotherapy were significantly older (P < 0.001), had more comorbidities (P < 0.001) and were more often living alone (P < 0.001). Patients who received no adjuvant chemotherapy had a reduced overall survival, and the cause of death was more often attributed to other causes (60%) than colon cancer (40%). For patients who received chemotherapy, the cause of death was usually attributed to colon cancer (71%). CONCLUSION: Patients who did not receive adjuvant chemotherapy had a worse overall survival and the majority died due to other causes than colon cancer. In our aging society it will become even more important to develop tools to estimate remaining life expectancy in order to improve the selection of older patients for adjuvant treatments. PMID- 28873268 TI - A novel in vitro model for haematogenous spreading of S. aureus device biofilms demonstrating clumping dispersal as an advantageous dissemination mechanism. AB - Staphylococcus aureus is able to disseminate from vascular device biofilms to the blood and organs, resulting in life-threatening infections such as endocarditis. The mechanisms behind spreading are largely unknown, especially how the bacterium escapes immune effectors and antibiotics in the process. Using an in vitro catheter infection model, we studied S. aureus biofilm growth, late-stage dispersal, and reattachment to downstream endothelial cell layers. The ability of the released biofilm material to resist host response and disseminate in vivo was furthermore studied in whole blood and phagocyte survival assays and in a short term murine infection model. We found that S. aureus biofilms formed in flow of human plasma release biofilm thromboemboli with embedded bacteria and bacteria secreted polysaccharides. The emboli disseminate as antibiotic and immune resistant vehicles that hold the ability to adhere to and initiate colonisation of endothelial cell layers under flow. In vivo experiments showed that the released biofilm material reached the heart similarly as ordinary broth-grown bacteria but also that clumps to some extend were trapped in the lungs. The clumping dispersal of S. aureus from in vivo-like vascular biofilms and their specific properties demonstrated here help explain the pathophysiology associated with S. aureus bloodstream infections. PMID- 28873269 TI - Do therapists' subjective variables impact on psychodynamic psychotherapy outcomes? A systematic literature review. AB - BACKGROUND: Despite growing attention to the general therapist effects in a wide range of clinical settings, little is known about the individual, cross situational, and therapy-nonspecific variables that impact on the differential effectiveness of clinicians. The current study is a systematic review of the evidence relating to the influence of therapist's subjective characteristics on outcomes of psychodynamic psychotherapies. METHOD: A multistage and systematic search of articles published between 1987 and 2017 identified 30 relevant studies, which were organized into 6 areas according to the specific therapist's variable considered. RESULTS: Therapists' interpersonal functioning and skills showed the strongest evidence of a direct effect on treatment outcomes. Furthermore, there were preliminary evidence that therapists' attachment styles, their interpersonal history with caregivers, and their self-concept might affect outcomes through interaction effects with other constructs, such as technical interventions, patient's pathology, and therapeutic alliance. The high variability between studies on therapists' overall reflective or introspective abilities and personality characteristics suggested the need for more systematic research in these areas, whereas therapists' values and attitudes showed small effects on therapeutic outcome. CONCLUSIONS: The present review clarifies how a deep examination of the contribution of therapists' subjective characteristics can help elucidate the complex association between relational and technical factors related to the outcome of psychodynamic treatments. PMID- 28873270 TI - Practical Chemical Synthesis of Atypical Ubiquitin Chains by Using an Isopeptide Linked Ub Isomer. AB - Chemical ubiquitination is an effective approach for accessing structurally defined, atypical ubiquitin (Ub) chains that are difficult to prepare by other techniques. Herein, we describe a strategy that uses a readily accessible premade isopeptide-linked 76-mer (isoUb), which has an N-terminal Cys and a C-terminal hydrazide, as the key building block to assemble atypical Ub chains in a modular fashion. This method avoids the use of auxiliary-modified Lys and instead employs the canonical and therefore more robust Cys-based native chemical ligation technique. The efficiency and capacity of this isoUb-based strategy is exemplified by the cost-effective synthesis of several linkage- and length defined atypical Ub chains, including K27-linked tetra-Ub and K11/K48-branched tri-, tetra-, penta-, and hexa-Ubs. PMID- 28873271 TI - Association of preventable adverse drug events with inpatients' length of stay-A propensity-matched cohort study. AB - PURPOSE: Using clinical administrative data (CAD) of inpatients, we aimed to identify ICD-10 codes coding for potentially preventable inhospital adverse drug events (ADE) that affect the length of hospital stay (LOS) and thus patient well being and cost. METHODS: We retrospectively assessed CAD of all inpatient stays in 2012 of a German university hospital. Predefined ICD-10 codes indicating ADE (ADE codes) were further specified based on expert ratings of the ADE mechanism and ADE preventability in clinical routine to particularly identify preventable inhospital ADE. In a propensity-matched cohort design, we compared patients with one or more ADE codes to control patients with regard to differences in LOS for three situations: all cases with an ADE code, cases with an inhospital ADE code, and cases with a preventable inhospital ADE code. RESULTS: Out of 54 032 cases analysed, in 8.3% (N=4 462) at least one ADE code was present. Nine of 128 evaluated ADE codes were rated as preventable in clinical routine, relating to 220 inpatients (4.9% of all identified inpatients with at least one ADE code and 0.4% of the entire cohort, respectively). Out of 48 072 evaluable inpatients for propensity score matching, 7 938 controls without ADE code and 4 006 cases with ADE code were selected. In all three settings, cases showed prolonged LOS vs controls (delta 1.13 d; 0.88 d and 1.88 d, respectively), significantly exceeding the maximum LOS as defined for each Diagnosis-Related Group. CONCLUSION: Inpatients with ADE codes referring to inhospital, potentially preventable ADE exceeded the maximum hospital stay fully reimbursed by insurance companies, indicating unnecessary long and costly inpatient stays. PMID- 28873272 TI - Pressure-forming method using a single-mouthguard sheet. AB - BACKGROUND/AIM: Mouthguard thickness is important for the prevention of orofacial trauma during sports. However, it is difficult to maintain the necessary thickness after forming the mouthguard. The aim of this study was to evaluate a pressure-forming method using a single-mouthguard sheet. MATERIALS AND METHODS: A mouthguard sheet of 3.8 mm ethylene vinyl acetate was prepared by cutting 3 mm from the anterior margin of the sheet holder with a length of 7 mm and with the width being from the buccal cusp of the upper right first premolar to the buccal cusp of the upper left first premolar and compared with the original sheet. The sheets were pressure-formed when the sheet was heated until the centre was displaced by 15 mm from baseline. The thickness of the mouthguard was measured at the labial surface of the central incisor, and the buccal and occlusal surfaces of the first molar. The fit of the mouthguard was examined at the right central incisor and right first molar by measuring the distance between the mouthguard and the cervical margin of the working model. Differences in the thickness and the fit of the mouthguards between the sheet conditions and the measured regions were analysed by two-way analysis of variance. RESULTS: Mouthguard thickness varied among the measured regions of the central incisors and first molars (P < .01). The greatest thickness was found at the labial surface of the central incisor in mouthguards fabricated using the cut sheet (P < .01). Mouthguard fit did not differ between the two sheets. CONCLUSIONS: The results suggest that a useful mouthguard with proper thickness and fit can be produced with the pressure forming method using a single-mouthguard sheet by cutting the anterior part of the sheet. PMID- 28873273 TI - Docking of Antibodies into the Cavities of DNA Origami Structures. AB - Immobilized antibodies are extensively employed for medical diagnostics, such as in enzyme-linked immunosorbent assays. Despite their widespread use, the ability to control the orientation of immobilized antibodies on surfaces is very limited. Herein, we report a method for the covalent and orientation-selective immobilization of antibodies in designed cavities in 2D and 3D DNA origami structures. Two tris(NTA)-modified strands are inserted into the cavity to form NTA-metal complexes with histidine clusters on the Fc domain. Subsequent covalent linkage to the antibody was achieved by coupling to lysine residues. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) confirmed the efficient immobilization of the antibodies in the origami structures. This increased control over the orientation of antibodies in nanostructures and on surfaces has the potential to direct the interactions between antibodies and targets and to provide more regular surface assemblies of antibodies. PMID- 28873274 TI - Epigenetics at the crossroads between genes, environment and resilience in anxiety disorders. AB - The pathogenesis of anxiety disorders is multifactorial, involving complex interactions between biological factors, environmental influences and psychological mechanisms. Recent advances have highlighted the role of epigenetics in bridging the gap between multiple contributing risk factors toward an increased understanding of the pathomechanisms underlying anxiety. In this review, we present an overview of the current state of knowledge regarding putative risk mechanisms in the pathogenesis of anxiety disorders, placing a particular focus on the role of protective factors serving to buffer a risk factor constellation and the role of epigenetic processes functioning as a potent turnstile changing passage direction toward disorder risk or resilience. We discuss promising future directions in epigenetic research regarding the prediction, prevention and personalized treatment of anxiety disorders. PMID- 28873275 TI - Retrospective evaluation of the prevalence, risk factors, management, outcome, and necropsy findings of acute lung injury and acute respiratory distress syndrome in dogs and cats: 29 cases (2011-2013). AB - OBJECTIVE: To determine the prevalence and risk factors for veterinary acute lung injury (VetALI) and veterinary acute respiratory distress syndrome (VetARDS), assess mechanical ventilation settings and patient outcomes, and to evaluate the relationship of clinical diagnoses with necropsy findings. DESIGN: Retrospective study. SETTING: University teaching hospital. ANIMALS: Twenty-four dogs and 5 cats with a clinical diagnosis of VetALI or VetARDS. Control population includes 24 dogs and 5 cats with a clinical diagnosis of respiratory disease other than VetALI or VetARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: VetALI and VetARDS were diagnosed in 3.2% of dogs and 1.3% of cats presenting to the ICU. Systemic inflammatory response syndrome was the most common inciting condition (16/24 dogs, 2/5 cats), followed by vomiting and subsequent aspiration of gastric contents (9/24 dogs), sepsis (5/24 dogs, 3/5 cats), multiple transfusions (4/24 dogs), trauma (3/24 dogs), and adverse drug reactions (1/24 dogs, 1/5 cats). None of these conditions were found to be significantly associated with a risk of development of VetALI or VetARDS when compared to controls. Twelve dogs (50%) and 4 cats (80%) underwent mechanical ventilation for a median duration of 18 hours in dogs (range: 6-174 h) and 15.5 hours in cats (range: 6-91 h). Overall, 3/29 patients survived to discharge including 2/24 dogs and 1/5 cats. Necropsy results were available for 8/22 dogs and 3/4 cats. A total of 6/8 dogs (75%) dogs and 3/3 (100%) cats met the histopathologic criteria for diagnosis of VetALI or VetARDS. CONCLUSIONS: VetALI and VetARDS can cause life-threatening respiratory distress in dogs and cats necessitating mechanical ventilation in 50% of dogs and 80% of cats in this study. These diseases are associated with a poor clinical outcome and a high rate of humane euthanasia. PMID- 28873277 TI - What are the important outcomes in traumatic dental injuries? An international approach to the development of a core outcome set. AB - BACKGROUND/AIMS: There are numerous treatment options following traumatic dental injury (TDI). Systematic reviews of different treatments are challenging owing to the diversity of outcomes reported between clinical studies. This issue could be addressed through the development and implementation of a agreed and standardized collection of outcomes known as a core outcome set (COS). The aim of this study was to develop a COS for TDI in children and adults. The secondary aim was to establish what, how, when and by whom these outcomes should be measured. MATERIALS AND METHOD: The project was registered with Core Outcomes Measures in Effectiveness Trials (COMET). A web-based survey was developed to capture the opinions of dentists globally as to which outcomes should be recorded. A list of outcomes was entered into a Delphi Survey and scored by an Expert Working Group (EWG). The scoring was repeated, followed by conference calls to discuss, refine and finalize the COS. The EWG split into small groups of subject-specific experts to determine how, when and by whom each outcome would be measured. RESULTS: The questionnaire was completed by 1476 dentists. The EWG identified 13 core outcomes to be recorded for all TDI's. An additional 10 injury-specific outcomes were identified. A table has been produced for each outcome detailing what, when, and how each outcome should be recorded. CONCLUSIONS: A robust consensus process was used to develop an international COS for TDI in children and adults. This includes both generic and injury-specific outcomes across all identified domains. PMID- 28873278 TI - Long-term trends in trait structure of riverine communities facing predation risk increase and trophic resource decline. AB - Many large European rivers have undergone multiple pressures that have strongly impaired ecosystem functioning at different spatial and temporal scales. Global warming and other environmental changes have favored the success of invasive species, deeply modifying the structure of aquatic communities in large rivers. Some exogenous species could alter trophic interactions within assemblages by increasing the predation risk for potential prey species (top-down effect) and limiting the dynamics of others via resource availability limitation (bottom-up effect). Furthermore, large transboundary rivers are complex aquatic ecosystems that have often been poorly investigated so that data for assessing long-term ecological trends are missing. In this study, we propose an original approach for investigating long-term combined effects of global warming, trophic resource decrease, predation risk, and water quality variations on the trait-based structure of macroinvertebrate and fish assemblages over 26 yr (1985-2011) and 427-km stretch of the river Meuse (France and Belgium). The study of temporal variations in biological, physiological, and ecological traits of macroinvertebrate and fish allowed identifying community trends and distinguishing impacts of environmental perturbations from those induced by biological alterations. We provide evidence, for this large European river, of an increase in water temperature (close to 1 degrees C) and a decrease in phytoplankton biomass (-85%), as well as independent effects of these changes on both invertebrate and fish communities. The reduction of trophic resources in the water column by invasive molluscs has dramatically affected the density of omnivorous fish in favor of invertebrate feeders, while scrapers became the major feeding guild among invertebrates. Macroinvertebrate and fish communities have shifted from large-sized organisms with low fecundity to prolific, small-sized organisms, with early maturity, as a response to increased predation pressure. PMID- 28873276 TI - MicroRNAs regulate synaptic plasticity underlying drug addiction. AB - Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction-relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug-addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain, this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small noncoding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction-relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction. PMID- 28873280 TI - A Biomimetic Escape Strategy for Cytoplasm Invasion by Synthetic Particles. AB - The translocation of nanomaterials or complex delivery systems into the cytosol is a major challenge in nanobiotechnology. After receptor-mediated endocytosis, most nanomaterials are sequestered and undergo degradation, therapy inactivation, or exocytosis. Herein we explore a novel surface particle coating made of adsorbed carbon nanotubes that provides coated materials with new properties that reproduce the viral cell-invasive mechanisms, namely, receptor-mediated endocytosis, endolysosomal escape, and cytosolic particle release preserving cell viability. This novel biomimetic coating design will enable the intracytoplasmic delivery of many different functional materials endowed with therapeutic, magnetic, optical, or catalytic functionalities, thus opening the door to a wide array of chemical and physical processes within the cytosolic or nuclear domains, and supporting new developments in the biotechnological, pharmaceutical, and biomedical industries. PMID- 28873279 TI - Differences in bleeding phenotype and provider interventions in postmenarchal adolescents when compared to adult women with bleeding disorders and heavy menstrual bleeding. AB - INTRODUCTION: Due to lack of patient/health care provider awareness causing delayed diagnosis, the bleeding phenotype and provider interventions in adolescents with heavy menstrual bleeding (HMB) and bleeding disorders (BD) may be different when compared to adults. AIM: The aim of this study was to compare/characterize bleeding phenotype and provider interventions in postmenarchal adolescents < 18 years and premenopausal adults >= 18 years with HMB and BD. METHODS: Patient demographics, BD, and provider interventions/therapy details for HMB were compared between both age groups enrolled in the Centers for Disease Control and Prevention (CDC) Female Universal Data Collection (UDC) surveillance project in United States hemophilia treatment centres. Cross sectional descriptive analyses including frequency distributions, summary statistics, bivariate and logistic regression analyses were performed. RESULTS: Of 269 females (79 adolescents; median age 16 years, interquartile range (IQR) = 2; 190 adults; median age 27 years, IQR = 13) evaluated, BD distribution was similar in both groups. Compared to adolescents, adults more often had family history of bleeding (Adjusted odds ratios [AOR] = 2.6, 1.3-5.6), delay in diagnosis (AOR = 2.5, 1.2-4.9), bleeding with dental procedures (AOR = 2.0, 1.0 4.0), gastrointestinal bleeding (AOR = 4.6, 1.0-21.9), anaemia (AOR = 2.7, 1.4 5.2), utilized desmopressin less often (AOR = 0.4, 0.2-0.8) and underwent gynaecologic procedure/surgery more frequently (AOR = 5.9, 1.3-27.3). CONCLUSION: Bleeding phenotypes of adolescents and adults with HMB and BD were different with more frequent bleeding complications, anaemia, gynaecologic procedures/surgeries, less desmopressin use and more delay in diagnosing BD in adults. Longitudinal studies are needed to determine whether improved patient/provider awareness and education will translate to early diagnosis and timely management of BD/HMB in adolescents that may prevent/reduce future haematologic/gynaecologic complications. PMID- 28873281 TI - Passive Picoinjection Enables Controlled Crystallization in a Droplet Microfluidic Device. AB - Segmented flow microfluidic devices offer an attractive means of studying crystallization processes. However, while they are widely employed for protein crystallization, there are few examples of their use for sparingly soluble compounds due to problems with rapid device fouling and irreproducibility over longer run-times. This article presents a microfluidic device which overcomes these issues, as this is constructed around a novel design of "picoinjector" that facilitates direct injection into flowing droplets. Exploiting a Venturi junction to reduce the pressure within the droplet, it is shown that passive injection of solution from a side-capillary can be achieved in the absence of an applied electric field. The operation of this device is demonstrated for calcium carbonate, where highly reproducible results are obtained over long run-times at high supersaturations. This compares with conventional devices that use a Y junction to achieve solution loading, where in-channel precipitation of calcium carbonate occurs even at low supersaturations. This work not only opens the door to the use of microfluidics to study the crystallization of low solubility compounds, but the simple design of a passive picoinjector will find wide utility in areas including multistep reactions and investigation of reaction dynamics. PMID- 28873282 TI - Co9 S8 /Co as a High-Performance Anode for Sodium-Ion Batteries with an Ether Based Electrolyte. AB - Co9 S8 has been regarded as a desirable anode material for sodium-ion batteries because of its high theoretical capacity. In this study, a Co9 S8 anode material containing 5.5 wt % Co (Co9 S8 /Co) was prepared by a solid-state reaction. The electrochemical properties of the material were studied in carbonate and ether based electrolytes (EBE). The results showed that the material had a longer cycle life and better rate capability in EBE. This excellent electrochemical performance was attributed to a low apparent activation energy and a low overpotential for Na deposition in EBE, which improved the electrode kinetic properties. Furthermore, EBE suppressed side reactions of the electrode and electrolyte, which avoided the formation of a solid electrolyte interphase film. PMID- 28873283 TI - In Vivo-Like Culture Conditions in a Bioreactor Facilitate Improved Tissue Quality in Corneal Storage. AB - The cornea is the most-transplanted tissue worldwide. However, the availability and quality of grafts are limited due to the current methods of corneal storage. In this study, a dynamic bioreactor system is employed to enable the control of intraocular pressure and the culture at the air-liquid interface. Thereby, in vivo-like storage conditions are achieved. Different media combinations for endothelium and epithelium are tested in standard and dynamic conditions to enhance the viability of the tissue. In contrast to culture conditions used in eye banks, the combination of the bioreactor and biochrom medium 1 allows to preserve the corneal endothelium and the epithelium. Assessment of transparency, swelling, and the trans-epithelial-electrical-resistance (TEER) strengthens the impact of the in vivo-like tissue culture. For example, compared to corneas stored under static conditions, significantly lower optical densities and significantly higher TEER values were measured (p-value <0.05). Furthermore, healing of epithelial defects is enabled in the bioreactor, characterized by re epithelialization and initiated stromal regeneration. Based on the obtained results, an easy-to-use 3D-printed bioreactor composed of only two parts was derived to translate the technology from the laboratory to the eye banks. This optimized bioreactor facilitates noninvasive microscopic monitoring. The improved storage conditions ameliorate the quality of corneal grafts and the storage time in the eye banks to increase availability and reduce re-grafting. PMID- 28873284 TI - Platelet-rich plasma ultrasound-guided injection in the treatment of carpal tunnel syndrome: A placebo-controlled clinical study. AB - The purpose of this study is to demonstrate whether and to what extent a single injection of platelet-rich plasma (PRP), under ultrasound guidance, can improve the clinical symptoms of patients with a mild to moderate carpal tunnel syndrome (CTS). We conducted a prospective, randomized, clinical study including 50 patients suffering from mild to moderate CTS for a minimum duration of 3 months. Patients were randomly divided into 2 groups: Group A (26 patients) received an ultrasound-guided PRP injection into the carpal tunnel, whereas Group B (24 patients) was injected with placebo (0.9% normal saline). The short- and mid-term outcomes were determined with the use of the Q-DASH questionnaire and the pain scale VAS administered at 0, 4, and 12 weeks follow-up. The success ratio was determined by the difference in the Q-DASH obtained pre-injection minus the final Q-DASH obtained after 12 weeks follow-up. Success was defined as a difference more than 25%. Group A patients demonstrated a 76.9% success as determined by the difference Q-DASH, whereas Group B patients demonstrated 33.3% success, which was significantly less than Group A (Chi2 , p = .011). The findings of this study suggest that a single PRP ultrasound-guided injection has positive effects in patients with CTS. PMID- 28873285 TI - A new allele, HLA-DQA1*02:01:02. AB - The new allele, HLA-DQA1*02:01:02 differs from DQA1*02:01:01:01 by C to T substitution in exon 2. PMID- 28873287 TI - Selective and Efficient Iridium Catalyst for the Reductive Amination of Levulinic Acid into Pyrrolidones. AB - The catalytic reductive amination of levulinic acid (LA) into pyrrolidones with an iridium catalyst using H2 as hydrogen source is reported. The chemoselective iridium catalyst displayed high efficiency for the synthesis of a variety of N substituted 5-methyl-2-pyrrolidones and N-arylisoindolinones. N-Substituted 5 methyl-2-pyrrolidone was also evaluated as a biosourced substitute solvent to NMP (N-methylpyrrolidone) in the catalytic arylation of 2-phenylpyridine. PMID- 28873286 TI - The impact of asthma on the cost effectiveness of surgery for chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: The objective of this work was to evaluate the impact of asthma on the cost-effectiveness profile of endoscopic sinus surgery (ESS) compared to medical therapy for patients with chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: The study design consisted of a cohort-style Markov decision tree cost utility analysis with a 35-year time horizon. Matched cohorts of CRSwNP patients with (n = 95) and without (n = 95) asthma who underwent ESS were compared with cohorts of patients from the national Medical Expenditures Survey Panel (MEPS) database who underwent medical management for chronic rhinosinusitis (CRS). Baseline, 1-year, and 2-year health utility values were calculated from responses to the EuroQol-5 Dimension (EQ-5D) instrument in both cohorts. The primary outcome measure was the incremental cost effectiveness ratio (ICER) for each cohort. RESULTS: The reference cases for CRSwNP patients with and without asthma yielded ICERs for ESS vs medical therapy alone of $12,066 per quality adjusted life year (QALY) and $7,369 per QALY, respectively. At a willingness-to pay threshold of $50,000/QALY, the ICER scatter plots demonstrated 86% and 99% certainty that the ESS strategy was the most cost-effective option for CRSwNP patients with and without asthma, respectively. ESS was not significantly more cost effective for CRSwNP patients without asthma (p = 0.494). CONCLUSION: ESS remains cost effective compared to medical therapy for patients both with and without asthma. While the comorbidity of asthma results in an inferior ICER result, it does not result in a statistically significant negative impact on the overall cost effectiveness of ESS. PMID- 28873288 TI - Early post-natal development of the mandibular permanent first molar in infants with unilateral complete cleft lip and palate. AB - OBJECTIVES: Studies have shown that the mandibular permanent first molar (M1inf ) in young children with isolated cleft palate is characterized by delay in maturation and has reduced crown width. Consequently, it is of interest to investigate the early maturation and width of the follicle and crown of M1inf in children with combined cleft lip and palate. DESIGN: Retrospective, longitudinal study. Cephalometric X-rays of 47 consecutive Danish children with UCCLP (37 males; 10 females) and 44 with unilateral incomplete cleft lip (UICL) (29 males; 15 females) examined at 2 and 22 months of age. UICL served as control group. Maturation (according to Haavikko), width of follicle (FW) and crown (CW) of M1inf were assessed. RESULTS: The maturation of the first mandibular molar was delayed in both genders at 2 and 22 months of age. FW and CW were smaller in children with UCCLP at both 2 and 22 months of age. There was a positive correlation between maturation and FW. CONCLUSIONS: Maturation of the first mandibular molar is delayed in both genders, and FW and CW were reduced in UCCLP compared to controls. Maturation was correlated with FW. PMID- 28873289 TI - Monitoring joint health in haemophilia: Factors associated with deterioration. AB - INTRODUCTION: Joint bleeds in patients with haemophilia may result in haemophilic arthropathy. Monitoring joint health is essential for identifying early signs of deterioration and allows timely adjustment of treatment. AIM: The aim was to describe changes in joint health over 5-10 years follow-up and identify factors associated with joint health deterioration in patients with haemophilia. METHODS: A post hoc analysis was performed from previous cohort studies in patients with moderate/severe haemophilia, >=16 years. Joint health of ankles, knees and elbows was measured with the Haemophilia Joint Health Score (HJHS) from 2006-2008 (T0) to 2011-2016 (T1). Analyses were performed on patient level (DeltaHJHS-total) and joint level (DeltaHJHS-joint). Deterioration was defined as DeltaHJHS-total >=4 and DeltaHJHS-joint >=2. RESULTS: Sixty-two patients (median age 25, 73% severe haemophilia, median [interquartile range] 0.0 [0.0;2.0] joint bleeds between T0 to T1) were included. After median 8 years, HJHS-total deteriorated in 37% and HJHS-joint in 17%. Ankle joints (31%) showed deterioration more often than elbows (19%) and knees (3%). Deterioration of HJHS-total was only associated with severe haemophilia. Deterioration of HJHS-joint was weakly associated with a lower HJHS at baseline and more self-reported limitations in activities, and strongly with more joint bleeds between T0 and T1 and presence of synovitis. CONCLUSION: In 37% of patients with moderate/severe haemophilia and low joint bleeding rates, joint health deteriorated over 5-10 years. Ankle and elbow joints showed deterioration most frequently. Factors found in this study help to identify which joints need frequent monitoring in patients with haemophilia with access to early prophylaxis. PMID- 28873290 TI - Intelligence and Fetal Alcohol Spectrum Disorders: A Review. AB - BACKGROUND: Background: The studies on intelligence in individuals with fetal alcohol exposure are conflicting. Some have found a relevant impairment in this population, while others found results that were consistent with the population at large. OBJECTIVES: Describe the results of studies on intelligence in individuals with Fetal Alcohol Spectrum Disorders. METHODS: Indexed articles of the last 10 years were selected for an integrative literature review. After inclusion and exclusion criteria were satisfied 37 articles were selected. RESULTS: General intelligence, both verbal and non-verbal, is impaired in people who are prenatally exposed to alcohol. There is a tendency to a greater reduction in the Freedom from Distractibility/Working Memory Index of Wechsler Scales. CONCLUSIONS: Reduction in intelligence seems to occur on a continuum similar to the fetal alcohol spectrum. The reduction of the Freedom from Distractibility/Working Memory Index appears to be a reflection of a greater impairment of mathematical ability. PMID- 28873291 TI - Increase in Psychoactive Drug Prescriptions in the Years Following Autism Spectrum Diagnosis: A Population-Based Cohort Study. AB - BACKGROUND: Psychoactive medications are commonly prescribed to autistic individuals, but little is known about how their use changes after diagnosis. OBJECTIVES: This study describes the use of psychoactive drugs in children and young adults newly diagnosed with autism spectrum, between the year before and up to 5 years after diagnosis. METHODS: Multivariable logistic regression was used to examine the relationship between the use psychoactive drugs before the first diagnosis of autism spectrum condition (from 1998 to 2010), and the clinical and demographic characteristics, identified from public health care databases in Quebec. The types of drugs prescribed and psychoactive polypharmacy were evaluated over 5 years of follow-up. Generalized estimating equations (GEE) were used to examine the association of age and time with the use of psychoactive drugs. RESULTS: In our cohort of 2,989 individuals, diagnosis of another psychiatric disorder before autism spectrum strongly predicted psychoactive drug use. We observed that the proportion of users of psychoactive drugs increased from 35.6% the year before, to 53.2% 5 years after the autism spectrum diagnosis. Psychoactive polypharmacy (>=2 psychoactive drug classes) also increased from 9% to 22% in that time. Age and time since diagnosis strongly associated with the types and combinations of psychoactive drugs prescribed. CONCLUSIONS: Psychoactive drug use and polypharmacy increases substantially over time after autism spectrum disorder diagnosis in children. PMID- 28873292 TI - Dose-Exposure Simulation for Piperacillin-Tazobactam Dosing Strategies in Infants and Young Children. AB - BACKGROUND: Extended piperacillin-tazobactam (TZP) infusions have been associated with favourable outcomes. There are currently no pediatric dosing recommendations. OBJECTIVES: To determine appropriate TZP dosing strategies in children 2 months - 6 years according to age and different minimal inhibitory concentrations (MICs). METHODS: Age and weight were simulated for 1000 children. Post-hoc pharmacokinetic parameter estimates were generated using published clearance and volume of distribution data. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 128 mg/L. The pharmacodynamic (PD) target was defined as free piperacillin concentrations above the MIC for >= 50% of the dosing interval. A PTA >= 90% was defined as optimal. RESULTS: PTA decreased as MIC and age increased. In all age groups, standard dosing regimens (240-300 mg/kg/day, 0.5h infusions) failed to reach PTAs >= 90% at MICs >= 16 mg/L. Standard 0.5h infusions reached PTAs >= 90% at MICs up to 8 mg/L in infants > 2 to 6m. No 0.5h infusion reached PTAs >= 90% for MICs >= 4 mg/L in children > 6m. While none of the tested regimens were optimal at MICs > 16 mg/L in children > 6m, 100 mg/kg/dose every 6h as a 3h infusion reached PD target at MICs of 32 mg/L in infants > 2 to 6m. CONCLUSIONS: Up to MICs of 16 mg/L, 90 mg/kg/dose every 8h as a 2h infusion in infants > 2 to 6m and 100 mg/kg/dose every 8h as a 4h infusion in children > 6m-6y achieved PTAs >= 90%. PMID- 28873293 TI - The Role of Midodrine for Hypotension Outside of the Intensive Care Unit. AB - Midodrine is an oral, peripherally acting alpha-adrenergic agonist. After gaining Food and Drug Administration (FDA) approval in 1996 for orthostatic hypotension, its use has evolved to target vasoplegic conditions such as intradialytic hypotension in the end-stage renal disease population, refractory ascites in cirrhotic patients to support diuresis, and in hepatorenal syndrome. Upon oral ingestion, the drug undergoes enzymatic hydrolysis to an active metabolite, desglymidodrine. Its use has been well tolerated at 2.5 mg, 5 mg, and 10 mg oral doses. The most frequently occurring side effects relate directly to its sympathomimetic profile and include piloerection, scalp pruritis, generalized paresthesias, and urinary retention. The vasoplegic profile of sepsis would be a potential target for midodrine therapy. While its use to mediate recovery from septic shock has been suggested, there is a paucity of clinical data supporting its use. Such therapy may be uniquely appropriate in septic patients who are not candidates for intensive care unit (ICU) level of care. PMID- 28873294 TI - PdSe2: Pentagonal Two-Dimensional Layers with High Air Stability for Electronics. AB - Most studied two-dimensional (2D) materials exhibit isotropic behavior due to high lattice symmetry; however, lower-symmetry 2D materials such as phosphorene and other elemental 2D materials exhibit very interesting anisotropic properties. In this work, we report the atomic structure, electronic properties, and vibrational modes of few-layered PdSe2 exfoliated from bulk crystals, a pentagonal 2D layered noble transition metal dichalcogenide with a puckered morphology that is air-stable. Micro-absorption optical spectroscopy and first principles calculations reveal a wide band gap variation in this material from 0 (bulk) to 1.3 eV (monolayer). The Raman-active vibrational modes of PdSe2 were identified using polarized Raman spectroscopy, and a strong interlayer interaction was revealed from large, thickness-dependent Raman peak shifts, agreeing with first-principles Raman simulations. Field-effect transistors made from the few-layer PdSe2 display tunable ambipolar charge carrier conduction with a high electron field-effect mobility of ~158 cm2 V-1 s-1, indicating the promise of this anisotropic, air-stable, pentagonal 2D material for 2D electronics. PMID- 28873295 TI - Combination of Functional Nanoengineering and Nanosecond Laser Texturing for Design of Superhydrophobic Aluminum Alloy with Exceptional Mechanical and Chemical Properties. AB - Industrial application of metallic materials is hindered by several shortcomings, such as proneness to corrosion, erosion under abrasive loads, damage due to poor cold resistance, or weak resistance to thermal shock stresses, etc. In this study, using the aluminum-magnesium alloy as an example of widely spread metallic materials, we show that a combination of functional nanoengineering and nanosecond laser texturing with the appropriate treatment regimes can be successfully used to transform a metal into a superhydrophobic material with exceptional mechanical and chemical properties. It is demonstrated that laser chemical processing of the surface may be simultaneously used to impart multimodal roughness and to modify the composition and physicochemical properties of a thick surface layer of the substrate itself. Such integration of topographical and physicochemical modification leads to specific surface nanostructures such as nanocavities filled with hydrophobic agent and hard oxynitride nanoinclusions. The combination of superhydrophobic state, nano- and micro features of the hierarchical surface, and the appropriate composition of the surface textured layer allowed us to provide the surface with the outstanding level of resistance of superhydrophobic coatings to external chemical and mechanical impacts. In particular, experimental data presented in this study indicate high resistance of the fabricated coatings to pitting corrosion, superheated water vapor, sand abrasive wear, and rapid temperature cycling from liquid nitrogen to room temperatures, without notable degradation of superhydrophobic performance. PMID- 28873296 TI - Formation and Stability of Lipid Membrane Nanotubes. AB - Lipid membrane nanotubes are abundant in living cells, even though tubules are energetically less stable than sheet-like structures. According to membrane elastic theory, the tubular endoplasmic reticulum (ER), with its high area-to volume ratio, appears to be particularly unstable. We explore how tubular membrane structures can nevertheless be induced and why they persist. In Monte Carlo simulations of a fluid-elastic membrane model subject to thermal fluctuations and without constraints on symmetry, we find that a steady increase in the area-to-volume ratio readily induces tubular structures. In simulations mimicking the ER wrapped around the cell nucleus, tubules emerge naturally as the membrane area increases. Once formed, a high energy barrier separates tubules from the thermodynamically favored sheet-like membrane structures. Remarkably, this barrier persists even at large area-to-volume ratios, protecting tubules against shape transformations despite enormous driving forces toward sheet-like structures. Molecular dynamics simulations of a molecular membrane model confirm the metastability of tubular structures. Volume reduction by osmotic regulation and membrane area growth by lipid production and by fusion of small vesicles emerge as powerful factors in the induction and stabilization of tubular membrane structures. PMID- 28873297 TI - Enhancing Upconversion Fluorescence with a Natural Bio-microlens. AB - Upconversion fluorescence has triggered extensive efforts in the past decade because of its superior physicochemical features and great potential in biomedical and biophotonic studies. However, practical applications of upconversion fluorescence are often hindered by its relatively low luminescence efficiency (<1%). Here, we employ a living yeast or human cell as a natural bio microlens to enhance the upconversion fluorescence. The natural bio-microlens, which was stably trapped on a fiber probe, could concentrate the excitation light into a subwavelength region so that the upconversion fluorescence of core-shell NaYF4:Yb3+/Tm3+ nanoparticles was enhanced by 2 orders of magnitude. As a benefit of the fluorescence enhancement, single-cell imaging and real-time detection of the labeled pathogenic bacteria, such as Escherichia coli and Staphylococcus aureus, were successfully achieved in the dark fields. This biocompatible, sensitive, and miniature approach could provide a promising powerful tool for biological imaging, biophotonic sensing, and single-cell analysis. PMID- 28873298 TI - GW Vertex Corrected Calculations for Molecular Systems. AB - Hedin's scheme is solved with the inclusion of the vertex function (GWGamma) for a set of small molecules. The computational scheme allows for the consistent inclusion of the vertex both at the polarizability level and in the self-energy. A diagrammatic analysis shows that the self-energy formed with this four-point vertex does not lead to double counting of diagrams, that can be classified as direct "bubbles" and exchange diagrams. By removing the exchange diagrams from the self-energy, a simpler approximation is obtained, called GWtc-tc. Very good agreement with expensive wave function-based methods is obtained for both approximations. PMID- 28873299 TI - Redox Controls over the Stability of U(IV) in Floodplains of the Upper Colorado River Basin. AB - Aquifers in the Upper Colorado River Basin (UCRB) exhibit persistent uranium (U) groundwater contamination plumes originating from former ore processing operations. Previous observations at Rifle, Colorado, have shown that fine grained, sulfidic, organic-enriched sediments accumulate U in its reduced form, U(IV), which is less mobile than oxidized U(VI). These reduced sediment bodies can subsequently act as secondary sources, releasing U back to the aquifer. There is a need to understand if U(IV) accumulation in reduced sediments is a common process at contaminated sites basin-wide, to constrain accumulated U(IV) speciation, and to define the biogeochemical factors controlling its reactivity. We have investigated U(IV) accumulation in organic-enriched reduced sediments at three UCRB floodplains. Noncrystalline U(IV) is the dominant form of accumulated U, but crystalline U(IV) comprises up to ca. 30% of total U at some locations. Differing susceptibilities of these species to oxidative remobilization can explain this variability. Particle size, organic carbon content, and pore saturation, control the exposure of U(IV) to oxidants, moderating its oxidative release. Further, our data suggest that U(IV) can be mobilized under deeply reducing conditions, which may contribute to maintenance and seasonal variability of U in groundwater plumes in the UCRB. PMID- 28873300 TI - Cryogenic Photochemical Synthesis and Electronic Spectroscopy of Cyanotetracetylene. AB - HC9N is a molecule of astrochemical interest. In this study, it was produced in cryogenic Ar and Kr matrices from UV-photolyzed diacetylene/cyanodiacetylene mixtures. Its strong phosphorescence was discovered and served for the identification of the compound. Vibrationally resolved phosphorescence excitation spectra gave insight into excited singlet electronic states. Two electronic systems were observed around 26 000-34 000 cm-1 and 35 000-50 000 cm-1. Energies of the second excited singlet and the lowest triplet state were derived from analysis of these systems. Vibrational and electronic spectroscopic features were assigned with the assistance of density functional theory calculations. Some trends concerning the electronic spectroscopy of HC2n+1N family molecules are presented. PMID- 28873301 TI - Optimal Tuning of Range-Separated Hybrids for Solvated Molecules with Time Dependent Density Functional Theory. AB - The applicability range of density functional theory (DFT) can be improved with no additional parametrization by imposing some exact conditions. Enforcing equality between the orbital energy of the highest occupied Kohn-Sham orbital and ionization energy, determined from the total energy difference between neutral and ionized states (DeltaKS), leads to the concept of optimally tuned range separated hybrid functionals. Here, we present an alternative tuning scheme for range-separated hybrid functionals based on enforcing the equality between the DeltaKS ionization energy and the ionization energy calculated by means of the time-dependent DFT using the concept of ionization as an excitation to the distant center (OT-IEDC scheme). The scheme can be naturally applied to solvated systems described either within the explicit solvation or dielectric continuum models. We test the performance of the scheme on a benchmark set of molecules. We further show that the scheme allows for reliably modeling liquid phase photoemission spectra. PMID- 28873302 TI - Reduced Drought Tolerance by CRISPR/Cas9-Mediated SlMAPK3 Mutagenesis in Tomato Plants. AB - Drought stress is one of the most destructive environmental factors that affect tomato plants adversely. Mitogen-activated protein kinases (MAPKs) are important signaling molecules that respond to drought stress. In this study, SlMAPK3 was induced by drought stress, and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) system was utilized to generate slmapk3 mutants. Two independent T1 transgenic lines and wild-type (WT) tomato plants were used for analysis of drought tolerance. Compared with WT plants, slmapk3 mutants exhibited more severe wilting symptom, higher hydrogen peroxide content, lower antioxidant enzymes activities, and suffered more membrane damage under drought stress. Furthermore, knockout of SlMAPK3 led to up- or down-regulated expressions of drought stress-responsive genes including SlLOX, SlGST, and SlDREB. The results suggest that SlMAPK3 is involved in drought response in tomato plants by protecting cell membranes from oxidative damage and modulating transcription of stress-related genes. PMID- 28873303 TI - Discovery of Novel Macrocyclic Hedgehog Pathway Inhibitors Acting by Suppressing the Gli-Mediated Transcription. AB - A systemic medicinal chemistry campaign was conducted based on a literature hit compound 5 bearing the 4,5-dihydro-2H-benzo[b][1,5]oxazocin-6(3H)-one core through cyclization of two side substituents of the bicyclic skeleton combined with N-atom walking or ring walking and the central ring expansion or extraction approaches, leading to several series of structurally unique tricyclic compounds. Among these, compound 29a was identified as the most potent against the Hedgehog (Hh) signaling pathway showing an IC50 value of 23 nM. Mechanism studies indicated that compound 29a inhibited the Hh signaling pathway by suppressing the expression of the transcriptional factors Gli rather than by interrupting the binding of Gli with DNA. We further observed that 29a was equally potent against both Smo wild type and the two major resistant mutants (Smo D473H and Smo W535L). It potently inhibited the proliferation of medulloblastoma cells and showed significant tumor growth inhibition in the ptch+/- ;p53-/- medulloblastoma allograft mice model. Though more studies are needed to clarify the precise interaction pattern of 29a with Gli, its promising in vitro and in vivo properties encourage further profiling as a new-generation Hh signaling inhibitor to treat tumors primarily or secondarily resistant to current Smo inhibitors. PMID- 28873304 TI - Multifunctional Bacteria-Driven Microswimmers for Targeted Active Drug Delivery. AB - High-performance, multifunctional bacteria-driven microswimmers are introduced using an optimized design and fabrication method for targeted drug delivery applications. These microswimmers are made of mostly single Escherichia coli bacterium attached to the surface of drug-loaded polyelectrolyte multilayer (PEM) microparticles with embedded magnetic nanoparticles. The PEM drug carriers are 1 MUm in diameter and are intentionally fabricated with a more viscoelastic material than the particles previously studied in the literature. The resulting stochastic microswimmers are able to swim at mean speeds of up to 22.5 MUm/s. They can be guided and targeted to specific cells, because they exhibit biased and directional motion under a chemoattractant gradient and a magnetic field, respectively. Moreover, we demonstrate the microswimmers delivering doxorubicin anticancer drug molecules, encapsulated in the polyelectrolyte multilayers, to 4T1 breast cancer cells under magnetic guidance in vitro. The results reveal the feasibility of using these active multifunctional bacteria-driven microswimmers to perform targeted drug delivery with significantly enhanced drug transfer, when compared with the passive PEM microparticles. PMID- 28873305 TI - Does the Residues Chirality Modify the Conformation of a Cyclo-Dipeptide? Vibrational Spectroscopy of Protonated Cyclo-diphenylalanine in the Gas Phase. AB - The structure of a protonated diketopiperazine dipeptide, cyclo-diphenylalanine, is studied by means of infrared multiple photon dissociation spectroscopy combined with quantum chemical calculations. Protonation exclusively occurs on the oxygen site and, in the most stable conformer, results to an intramolecular OH...pi interaction, accompanied by a CH...pi interaction. Higher-energy conformers with free OH and NH...pi interactions are observed as well, due to kinetic trapping. Optimization of the intramolecular interactions involving the aromatic ring dictates the geometry of the benzyl substituents. Changing the chirality of one of the residues has consequences on the CH...pi interaction, which is of CalphaH...pi nature for LD, while LL shows a CbetaH...pi interaction. Higher-energy conformers also display some differences in the nature of the intramolecular interactions. PMID- 28873307 TI - Optimizing the Energy with Quantum Monte Carlo: A Lower Numerical Scaling for Jastrow-Slater Expansions. AB - We present an improved formalism for quantum Monte Carlo calculations of energy derivatives and properties (e.g., the interatomic forces), with a multideterminant Jastrow-Slater function. As a function of the number Ne of Slater determinants, the numerical scaling of O(Ne) per derivative we have recently reported is here lowered to O(Ne) for the entire set of derivatives. As a function of the number of electrons N, the scaling to optimize the wave function and the geometry of a molecular system is lowered to O(N3) + O(NNe), the same as computing the energy alone in the sampling process. The scaling is demonstrated on linear polyenes up to C60H62 and the efficiency of the method is illustrated with the structural optimization of butadiene and octatetraene with Jastrow-Slater wave functions comprising as many as 200 000 determinants and 60 000 parameters. PMID- 28873306 TI - Mixing Behavior in Binary Anionic Gemini Surfactant-Perfluorinated Fatty Acid Langmuir Monolayers. AB - The miscibility and film structure of mixed Langmuir monolayer films composed of an anionic gemini N,N,N',N'-dialkyl-N,N'-diacetate ethylenediamine surfactant (Ace(12)-2-Ace(12)) with perfluorotetradecanoic acid (C13F27COOH; PF) have been investigated using a variety of thermodynamic and structural characterization methods. The two film components were found to be miscible in monolayers at the air-water interface over a range of compositions and at all but the lowest surface pressures, with attractive interactions occurring between the two components. While pure PF monolayers formed crystalline lattices with hexagonal symmetry and with the surfactant tails oriented normal to the underlying water subphase, the pure gemini surfactant formed amorphous films with little tendency to orient at the subphase. In mixed films with mole ratios of PF:Ace(12)-2 Ace(12) < 2.5, the miscibility of the two components resulted in a nearly complete loss of crystallinity of the PF, though films at higher mole fractions of PF showed some residual crystallinity, albeit with lattice structures that were significantly different from that of pure PF. Miscibility and film structure in this mixed system are discussed in comparison with other mixed gemini surfactant systems in the literature as well as binary mixtures of phospholipids or monomeric fatty acids with PF. PMID- 28873308 TI - Monitoring Charge Separation Processes in Quasi-One-Dimensional Organic Crystalline Structures. AB - We perform the transient absorption spectroscopy experiments to investigate the dynamics of the low-energy collective electron-hole excitations in alpha-copper phthalocyanine thin films. The results are interpreted in terms of the third order nonlinear polarization response function. It is found that, initially excited in the molecular plane, the intramolecular Frenkel exciton polarization reorients with time to align along the molecular chain direction to form coupled Frenkel-charge-transfer exciton states, the eigenstates of the one-dimensional periodic molecular lattice. The process pinpoints the direction of the charge separation in alpha-copper phthalocyanine and similar organic molecular structures. Being able to observe and monitor such processes is important both for understanding the physical principles of organic thin film solar energy conversion device operation and for the development of organic optoelectronics in general. PMID- 28873309 TI - ITO Modification for Efficient Inverted Organic Solar Cells. AB - We demonstrate a facile approach to designing transparent electron-collecting electrodes by depositing thin layers of medium and low work function metals on top of transparent conductive metal oxides (TCOs) such as ITO and FTO. The modified electrodes were fairly stable for months under ambient conditions and maintained their electrical characteristics. XPS spectroscopy data strongly suggested integration of the deposited metal in the TCO structure resulting in additional doping of the conducting oxide at the interface. Kelvin probe microscopy measurements revealed a significant decrease in the ITO work function after modification. Organic solar cells based on three different conjugated polymers have demonstrated state of the art performances in inverted device geometry using Mg- or Yb-modified ITO as electron collecting electrode. The simplicity of the proposed approach and the excellent ambient stability of the modified ITO electrodes allows one to expect their wide utilization in research laboratories and electronic industry. PMID- 28873310 TI - Vertical InAs/InGaAs Heterostructure Metal-Oxide-Semiconductor Field-Effect Transistors on Si. AB - III-V compound semiconductors offer a path to continue Moore's law due to their excellent electron transport properties. One major challenge, integrating III-V's on Si, can be addressed by using vapor-liquid-solid grown vertical nanowires. InAs is an attractive material due to its superior mobility, although InAs metal oxide-semiconductor field-effect transistors (MOSFETs) typically suffer from band to-band tunneling caused by its narrow band gap, which increases the off-current and therefore the power consumption. In this work, we present vertical heterostructure InAs/InGaAs nanowire MOSFETs with low off-currents provided by the wider band gap material on the drain side suppressing band-to-band tunneling. We demonstrate vertical III-V MOSFETs achieving off-current below 1 nA/MUm while still maintaining on-performance comparable to InAs MOSFETs; therefore, this approach opens a path to address not only high-performance applications but also Internet-of-Things applications that require low off-state current levels. PMID- 28873311 TI - Interaction of DNA with Cationic Lipid Mixtures-Investigation at Langmuir Lipid Monolayers. AB - Four different binary lipid mixtures composed of a cationic lipid and the zwitterionic colipids DOPE or DPPC, which show different DNA transfer activities in cell culture models, were investigated at the soft air/water interface to identify transfection efficiency determining characteristics. Langmuir films are useful models to investigate the interaction between DNA and lipid mixtures in a two-dimensional model system by using different surface sensitive techniques, namely, epifluorescence microscopy and infrared reflection-absorption spectroscopy. Especially, the effect of adsorbed DNA on the properties of the lipid mixtures has been examined. Distinct differences between the lipid composites were found which are caused by the different colipids of the mixtures. DOPE containing lipid mixtures form fluid monolayers with a uniform distribution of the fluorescent probe in the presence and absence of DNA at physiologically relevant surface pressures. Only at high nonphysiological pressures, the lipid monolayer collapses and phase separation was observed if DNA was present in the subphase. In contrast, DPPC containing lipid mixtures show domains in the liquid condensed phase state in the presence and absence of DNA in the subphase. The adsorption of DNA at the positively charged mixed lipid monolayer induces phase separation which is expressed in the morphology and the point of appearance of these domains. PMID- 28873312 TI - Efficient Computation of Sparse Matrix Functions for Large-Scale Electronic Structure Calculations: The CheSS Library. AB - We present CheSS, the "Chebyshev Sparse Solvers" library, which has been designed to solve typical problems arising in large-scale electronic structure calculations using localized basis sets. The library is based on a flexible and efficient expansion in terms of Chebyshev polynomials and presently features the calculation of the density matrix, the calculation of matrix powers for arbitrary powers, and the extraction of eigenvalues in a selected interval. CheSS is able to exploit the sparsity of the matrices and scales linearly with respect to the number of nonzero entries, making it well-suited for large-scale calculations. The approach is particularly adapted for setups leading to small spectral widths of the involved matrices and outperforms alternative methods in this regime. By coupling CheSS to the DFT code BigDFT, we show that such a favorable setup is indeed possible in practice. In addition, the approach based on Chebyshev polynomials can be massively parallelized, and CheSS exhibits excellent scaling up to thousands of cores even for relatively small matrix sizes. PMID- 28873313 TI - Large-Scale Condensed Matter DFT Simulations: Performance and Capabilities of the CRYSTAL Code. AB - Nowadays, the efficient exploitation of high-performance computing resources is crucial to extend the applicability of first-principles theoretical methods to the description of large, progressively more realistic molecular and condensed matter systems. This can be achieved only by devising effective parallelization strategies for the most time-consuming steps of a calculation, which requires some effort given the usual complexity of quantum-mechanical algorithms, particularly so if parallelization is to be extended to all properties and not just to the basic functionalities of the code. In this Article, the performance and capabilities of the massively parallel version of the Crystal17 package for first-principles calculations on solids are discussed. In particular, we present: (i) recent developments allowing for a further improvement of the code scalability (up to 32 768 cores); (ii) a quantitative analysis of the scaling and memory requirements of the code when running calculations with several thousands (up to about 14 000) of atoms per cell; (iii) a documentation of the high numerical size consistency of the code; and (iv) an overview of recent ab initio studies of several physical properties (structural, energetic, electronic, vibrational, spectroscopic, thermodynamic, elastic, piezoelectric, topological) of large systems investigated with the code. PMID- 28873314 TI - Integration of Semiconductor Nanowire Lasers with Polymeric Waveguide Devices on a Mechanically Flexible Substrate. AB - Nanowire lasers are integrated with planar waveguide devices using a high positional accuracy microtransfer printing technique. Direct nanowire to waveguide coupling is demonstrated, with coupling losses as low as -17 dB, dominated by mode mismatch between the structures. Coupling is achieved using both end-fire coupling into a waveguide facet, and from nanowire lasers printed directly onto the top surface of the waveguide. In-waveguide peak powers up to 11.8 MUW are demonstrated. Basic photonic integrated circuit functions such as power splitting and wavelength multiplexing are presented. Finally, devices are fabricated on a mechanically flexible substrate to demonstrate robust coupling between the on-chip laser source and waveguides under significant deformation of the system. PMID- 28873315 TI - Quantum-Mechanical Prediction of the Averaged Structure, Anharmonic Vibrational Frequencies, and Intensities of the H2O...trans-HONO Complex and Comparison with the Experiment. AB - The geometrical parameters, the frequencies, and absolute intensities of vibrational transitions of H2O...trans-HONO hydrogen-bonded complex are calculated using the approach earlier tested in calculations of isolated molecules of nitrous acid and complexes of this acid with ammonia. The equilibrium nuclear configuration and potential energy and dipole moment surfaces are calculated by the MP2/aug-cc-pVTZ method with the basis set superposition error taken into account. The fundamental transition frequencies and intensities of the complex are first obtained in the harmonic approximation, and then the energy values, vibrational wave functions, and transition frequencies and intensities are determined from variational solutions of one- to four-dimensional anharmonic equations. The results obtained are compared with the data calculated in the same approximation for an isolated trans-HONO molecule and the NH3...trans HONO complex. The average discrepancy between the anharmonic frequency values and five available experimental data is 15 cm-1. Three absorption bands of trans-HONO with the highest intensity are recommended for detecting the presence of H2O...trans-HONO. PMID- 28873316 TI - On Resolution-of-the-Identity Electron Repulsion Integral Approximations and Variational Stability. AB - The definiteness of the Mulliken and Dirac electron repulsion integral (ERI) matrices is examined for different classes of resolution-of-the-identity (RI) ERI approximations with particular focus on local fitting techniques. For global RI, robust local RI, and nonrobust local RI we discuss the definiteness of the approximated ERI matrices as well as the resulting bounds of Hartree, exchange, and total energies. Lower bounds of Hartree and exchange energy contributions are crucial as their absence may lead to variational instabilities, causing severe convergence problems or even convergence to a spurious state in self-consistent field optimizations. While the global RI approximation guarantees lower bounds of Hartree and exchange energies, local RI approximations are generally unbounded. The robust local RI approximation guarantees a lower bound of the exchange energy but not of the Hartree energy. The nonrobust local RI approximation guarantees a lower bound of the Hartree energy but not of the exchange energy. These issues are demonstrated by sample calculations on carbon dioxide and benzene using the pair atomic RI approximation. PMID- 28873317 TI - Quantitative Analysis of Different Formation Modes of Platinum Nanocrystals Controlled by Ligand Chemistry. AB - Well-defined metal nanocrystals play important roles in various fields, such as catalysis, medicine, and nanotechnology. They are often synthesized through kinetically controlled process in colloidal systems that contain metal precursors and surfactant molecules. The chemical functionality of surfactants as coordinating ligands to metal ions however remains a largely unsolved problem in this process. Understanding the metal-ligand complexation and its effect on formation kinetics at the molecular level is challenging but essential to the synthesis design of colloidal nanocrystals. Herein we report that spontaneous ligand replacement and anion exchange control the form of coordinated Pt-ligand intermediates in the system of platinum acetylacetonate [Pt(acac)2], primary aliphatic amine, and carboxylic acid ligands. The formed intermediates govern the formation mode of Pt nanocrystals, leading to either a pseudo two-step or a one step mechanism by switching on or off an autocatalytic surface growth. This finding shows the importance of metal-ligand complexation at the prenucleation stage and represents a critical step forward for the designed synthesis of nanocrystal-based materials. PMID- 28873318 TI - Effective Interlayer Engineering of Two-Dimensional VOPO4 Nanosheets via Controlled Organic Intercalation for Improving Alkali Ion Storage. AB - Two-dimensional (2D) energy materials have shown the promising electrochemical characteristics for lithium ion storage. However, the decreased active surfaces and the sluggish charge/mass transport for beyond-lithium ion storage that has potential for large-scale energy storage systems, such as sodium or potassium ion storage, caused by the irreversible restacking of 2D materials during electrode processing remain a major challenge. Here we develop a general interlayer engineering strategy to address the above-mentioned challenges by using 2D ultrathin vanadyl phosphate (VOPO4) nanosheets as a model material for challenging sodium ion storage. Via controlled intercalation of organic molecules, such as triethylene glycol and tetrahydrofuran, the sodium ion transport in VOPO4 nanosheets has been significantly improved. In addition to advanced characterization including X-ray diffraction, high-resolution transmission electron microscopy, and X-ray absorption fine structure to characterize the interlayer and the chemical bonding/configuration between the organic intercalants and the VOPO4 host layers, density functional theory calculations are also performed to understand the diffusion behavior of sodium ions in the pure and TEG intercalated VOPO4 nanosheets. Because of the expanded interlayer spacing in combination with the decreased energy barriers for sodium ion diffusion, intercalated VOPO4 nanosheets show much improved sodium ion transport kinetics and greatly enhanced rate capability and cycling stability for sodium ion storage. Our results afford deeper understanding of the interlayer engineering strategy to improve the sodium ion storage performance of the VOPO4 nanosheets. Our results may also shed light on possible multivalent-ion based energy storage such as Mg2+ and Al3+. PMID- 28873319 TI - Facile Thermal and Optical Ignition of Silicon Nanoparticles and Micron Particles. AB - Silicon (Si) particles are widely utilized as high-capacity electrodes for Li-ion batteries, elements for thermoelectric devices, agents for bioimaging and therapy, and many other applications. However, Si particles can ignite and burn in air at elevated temperatures or under intense illumination. This poses potential safety hazards when handling, storing, and utilizing these particles for those applications. In order to avoid the problem of accidental ignition, it is critical to quantify the ignition properties of Si particles such as their sizes and porosities. To do so, we first used differential scanning calorimetry to experimentally determine the reaction onset temperature of Si particles under slow heating rates (~0.33 K/s). We found that the reaction onset temperature of Si particles increased with the particle diameter from 805 degrees C at 20-30 nm to 935 degrees C at 1-5 MUm. Then, we used a xenon (Xe) flash lamp to ignite Si particles under fast heating rates (~103 to 106 K/s) and measured the minimum ignition radiant fluence (i.e., the radiant energy per unit surface area of Si particle beds required for ignition). We found that the measured minimum ignition radiant fluence decreased with decreasing Si particle size and was most sensitive to the porosity of the Si particle bed. These trends for the Xe flash ignition experiments were also confirmed by our one-dimensional unsteady simulation to model the heat transfer process. The quantitative information on Si particle ignition included in this Letter will guide the safe handling, storage, and utilization of Si particles for diverse applications and prevent unwanted fire hazards. PMID- 28873320 TI - Influence of Rhodiola rosea on the heat acclimation process in young healthy men. AB - The adaptogen Rhodiola rosea (RR) may mitigate stress responses and have beneficial effects on endurance capacity (EC) and mental performance. Heat acclimation (HA) improves EC in the heat, but the potential impact of RR on the HA process is unknown. Therefore, our intent was to determine if RR has a positive impact on HA. Twenty male subjects (age, 22.5 +/- 3.0 years) completed 2 EC tests involving walking (6 km.h-1) until volitional exhaustion in a climate chamber (air temperature, 42 degrees C; relative humidity, 18%) before (H1) and after (H2) an 8-day HA period. One group (SHR; n = 10) ingested standardised extract SHR-5 of RR (a single daily dose of 432 mg), while a second group (PLC; n = 10) administered a placebo prior to each HA session. Efficacy of HA was evaluated on the basis of changes that occurred from H1 to H2 in the time to exhaustion (TTE), exercise heart rate (HR), core and skin temperatures (Tc, Tsk), stress hormones, ratings of perceived exertion (RPE) and fatigue (RPF), and thermal sensation (TS). HA significantly increased TTE (133.1 +/- 44.1 min in H1; 233.4 +/- 59.8 min in H2; p < 0.0001) and decreased (p < 0.0001) HR, Tc, Tsk, stress hormones as well as RPE, RPF, and TS. However, the magnitude of all these changes was similar (p > 0.05) in the SHR and PLC groups. These results suggest that the use of RR during HA has no beneficial performance, physiological, or perceptual effects in young healthy males. PMID- 28873321 TI - Separate and combined effects of time of day and verbal instruction on knee extensor neuromuscular adjustments. AB - We examined the effects of time of day and verbal instruction, separately and combined, on knee extensor neuromuscular adjustments, with special reference to rapid muscle force production capacity. Ten healthy male participants performed 4 experimental trials in counterbalanced order: morning "hard-and-fast" instruction, evening hard-and-fast instruction, morning "fast" instruction, and evening fast instruction. During each experimental trial, neuromuscular performance was assessed from the completion of 6 maximal isometric voluntary contractions (rest = 2 min) of the knee extensors with concomitant quadriceps surface electromyography recordings. For each contraction, we determined maximal voluntary force (Fmax), maximal rate of force development (RFDmax) and associated maximal electromechanical delay (EMDmax), and maximal rate of muscle activation (RMAmax). Globally, oral temperature (+2.2%), Fmax (+4.9%) and accompanying median frequency (+6.6%)/mean power frequency (+6.0%) as well as RFDmax (+13.5%) and RMAmax (+15.5%) were significantly higher in the evening than morning (p < 0.05). Conversely, evening in reference to morning values were lower for EMDmax ( 4.3%, p < 0.05). Compared with a hard-and-fast instruction, RFDmax (+30.6%) and corresponding root mean square activity (+18.6%) were globally higher using a fast instruction (p < 0.05), irrespectively of the time of day. There was no significant interaction effect of time of day and verbal instruction on any parameter, except for EMDmax (p = 0.028). Despite diurnal variation in maximal or explosive force production of knee extensors and associated neuromuscular parameters, these adjustments occurred essentially independently of the verbal instruction provided. PMID- 28873322 TI - The effect of exercise preconditioning on stroke outcome in ovariectomized mice with permanent middle cerebral artery occlusion. AB - Exercise preconditioning has been shown to be effective in improving behavioral and neuropathological indices after cerebral ischemia. We evaluated the effect of exercise preconditioning, 17beta-estradiol, and their combination on stroke outcome using an experimental model of stroke in ovariectomized (OVX) mice. OVX mice were randomly assigned to 4 groups as follows: control (stroke), exercise (exercise and stroke), estradiol (17beta-estradiol and stroke), and exercise+estradiol (exercise and 17beta-estradiol and stroke). Exercise preconditioning was performed on a treadmill 5 days/week, 40 min/day, at a speed of 18 m/min for 4 weeks. 17beta-estradiol was gavaged (40 MUg/kg per day) for 4 weeks. Stroke was induced by permanent middle cerebral artery occlusion (pMCAO), and neurological deficits were evaluated 1, 2, and 7 days after stroke. Then, the serum concentrations of matrix metalloproteinase-9 (MMP-9) and interleukin-10 (IL 10) and infarct volumes were assessed. Exercise preconditioning and 17beta estradiol induced a better outcome compared with the control ischemic mice, which was manifested by decrease in MMP-9, increase in IL-10, diminished infarct volume, and improved neurological deficits. Concomitant administration of 17beta estradiol and exercise also significantly improved these parameters. Exercise preconditioning or administration of 17beta-estradiol alone or in combination before pMCAO induced significant neuroprotection in OVX mice. PMID- 28873323 TI - Survey of gene splicing algorithms based on reads. AB - Gene splicing is the process of assembling a large number of unordered short sequence fragments to the original genome sequence as accurately as possible. Several popular splicing algorithms based on reads are reviewed in this article, including reference genome algorithms and de novo splicing algorithms (Greedy extension, Overlap-Layout-Consensus graph, De Bruijn graph). We also discuss a new splicing method based on the MapReduce strategy and Hadoop. By comparing these algorithms, some conclusions are drawn and some suggestions on gene splicing research are made. PMID- 28873324 TI - Proportion and Patterns of Hospice Discharges in Medicare Advantage Compared to Medicare Fee-for-Service. AB - BACKGROUND: When Medicare Advantage (MA) patients elect hospice, all covered services are reimbursed under the Medicare fee-for-service (FFS) program. This financial arrangement may incentivize MA plans to refer persons to hospice near end of life when costs of care typically rise. OBJECTIVE: To characterize hospice discharge patterns for MA versus FFS patients and examine whether patterns differ by MA concentration across hospital referral regions (HRRs). DESIGN AND MEASUREMENT: The rate and pattern of live discharges and length of stay (LOS) between FFS and MA patients were examined. A multivariate mixed-effects model examined whether hospice patients in MA versus FFS had differential patterns of discharges. In addition, we tested whether concentrations of MA hospice patients in a patient's HRR were associated with different patterns of discharges. RESULTS: In fiscal year 2014, there were 1,199,533 hospice discharges with 331,142 MA patients having a slightly higher live discharge rate (15.8%) compared to 868,391 FFS hospice discharges (15.4%). After controlling for patient characteristics, the adjusted odds ratio (AOR) was 1.01 (95% CI 0.99-1.02). MA patients were less likely to have early live discharges (AOR 0.87 95% CI 0.84 0.91) and burdensome transitions (AOR 0.61 95% CI 0.58-0.64) but did not differ in live discharges post 210 days. Among hospice deaths, MA hospice patients were less likely to have a three-day or less LOS (AOR 0.95 95% 0.94-0.96) and a LOS exceeding 180 days (AOR 0.97 95% 0.96-0.99). The concentration of MA patients in a HRR had minimal impact. CONCLUSION: MA hospice patients' discharge patterns raised less concerns than FFS. PMID- 28873325 TI - Moving Forward: Challenges and Directions for Psychopathological Network Theory and Methodology. AB - Since the introduction of mental disorders as networks of causally interacting symptoms, this novel framework has received considerable attention. The past years have resulted in over 40 scientific publications and numerous conference symposia and workshops. Now is an excellent moment to take stock of the network approach: What are its most fundamental challenges, and what are potential ways forward in addressing them? After a brief conceptual introduction, we first discuss challenges to network theory: (1) What is the validity of the network approach beyond some commonly investigated disorders such as major depression? (2) How do we best define psychopathological networks and their constituent elements? And (3) how can we gain a better understanding of the causal nature and real-life underpinnings of associations among symptoms? Next, after a short technical introduction to network modeling, we discuss challenges to network methodology: (4) heterogeneity of samples studied with network analytic models, and (5) a lurking replicability crisis in this strongly data-driven and exploratory field. Addressing these challenges may propel the network approach from its adolescence into adulthood and promises advances in understanding psychopathology both at the nomothetic and idiographic level. PMID- 28873326 TI - External Validation and Comparisons of the Scoring Systems for Predicting Percutaneous Nephrolithotomy Outcomes: A Single Center Experience with 506 Cases. AB - BACKGROUND: To validate and compare the stone scoring systems (stone size [S], tract length [T], obstruction [O], number of involved calices [N], and essence or stone density [E] [S.T.O.N.E.], Guy's Stone Score [GSS], Clinical Research Office of the Endourological Society [CROES], and Seoul National University Renal Stone Complexity [S-ReSC]) used to predict postoperative stone-free status and complications after percutaneous nephrolithotomy (PCNL). METHODS: A total of 567 patients who underwent PCNL for renal stones between January 2012 and August 2015 were included in the recent retrospective study. Sixty-one patients who had not done preoperative CT were excluded from the study. GSS, S.T.O.N.E., S-ReSC, and CROES nephrolithometry scores were calculated for each patient, and their potential association with stone-free status, operative and fluoroscopy time, and length of stay (LOS) was evaluated. Postoperative complications were graded according to the modified Clavien classification, and the correlation of scoring systems with postoperative complications was also investigated. RESULTS: The mean CROES, S.T.O.N.E., GSS, and S-ReSC scores were 203.7 +/- 59.8, 7.52 +/- 1.8, 2.08 +/- 0.9, and 3.35 +/- 2.2, respectively. The overall stone-free rate was 77.9%. All scoring systems were significantly correlated with stone-free status and operation time. While GSS, S.T.O.N.E., and CROES systems were significantly correlated with complication rates (CR), S-ReSC score failed to predict CR. All scoring systems except S.T.O.N.E. were significantly correlated with LOS. CROES and S-ReSC scores were predictive of estimated blood loss (EBL), while GSS and S.T.O.N.E. failed to predict EBL. CONCLUSIONS: Recent study demonstrated that S.T.O.N.E., GSS, CROES, and S-ReSC scoring systems could effectively predict postoperative stone-free status. Although S-ReSC scoring system failed to predict CR, the rest three scoring systems were significantly correlated with postoperative CR. PMID- 28873327 TI - Infiltrating leukocytes surround early Buruli ulcer lesions, but are unable to reach the mycolactone producing mycobacteria. PMID- 28873328 TI - How to Map Theory: Reliable Methods Are Fruitless Without Rigorous Theory. AB - Good science requires both reliable methods and rigorous theory. Theory allows us to build a unified structure of knowledge, to connect the dots of individual studies and reveal the bigger picture. Some have criticized the proliferation of pet "Theories," but generic "theory" is essential to healthy science, because questions of theory are ultimately those of validity. Although reliable methods and rigorous theory are synergistic, Action Identification suggests psychological tension between them: The more we focus on methodological details, the less we notice the broader connections. Therefore, psychology needs to supplement training in methods (how to design studies and analyze data) with training in theory (how to connect studies and synthesize ideas). This article provides a technique for visually outlining theory: theory mapping. Theory mapping contains five elements, which are illustrated with moral judgment and with cars. Also included are 15 additional theory maps provided by experts in emotion, culture, priming, power, stress, ideology, morality, marketing, decision-making, and more (see all at theorymaps.org ). Theory mapping provides both precision and synthesis, which helps to resolve arguments, prevent redundancies, assess the theoretical contribution of papers, and evaluate the likelihood of surprising effects. PMID- 28873331 TI - Biosimilar Clinical Development - Scientific Considerations and New Methodologies. PMID- 28873329 TI - Mitochondrial mutations in human cancer: Curation of translation. AB - As a genetic disease, cancer is caused by the activation of oncogenes and the inhibition of tumor suppressor genes via genetic and epigenetic mechanisms. Given the important role of energy metabolism in tumors, we analyzed the cancer-derived mutations occurring in the DNA of the mitochondrion. Mutations in the mitochondrial DNA (mtDNA) compared to nuclear DNA are 62% decreased relative to the coding length per chromosome. We find that the majority of these mutations affects highly conserved nucleotides - significantly exceeding the conservation of the mtDNA - and are devoid of single nucleotide polymorphisms (SNPs). Surprisingly, the leading resources for tumor genetics information universally use the standard genetic code for translation of nucleotide into amino acid sequences in their online resources. However, the nuclear and mitochondrial genetic codes differ for four codons and the usage of incomplete STOP codons. Hence, we analyze and curate the consequences for all mutations in the mtDNA and comprehensively reclassify missense, nonsense and synonymous mutations accordingly. In total, 10% of the mutations are incorrectly translated leading to significant changes in the distribution of mutation types with tripling of nonsense and 69% loss of nonstop extension mutations. Lastly, we provide a curated dataset of coding and non-coding mitochondrial mutations in cancer merged, standardized, duplicate-free and aggregated from two databases as a resource including orthogonal data on their high conservation and SNPs. This study generally highlights the need to universally regard the important differences between the standard and mitochondrial genetic code in life science research. PMID- 28873332 TI - Use of RGD-Functionalized Sandwich Cultures to Promote Redifferentiation of Human Pancreatic Beta Cells After In Vitro Expansion. AB - Islet transplantation has provided proof of concept that cell therapy can restore normoglycemia in patients with diabetes. However, limited availability of islet tissue severely restricts the clinical use of the treatment. Thus, there is an urgent need to develop new strategies to generate an abundant source of insulin producing cells that could be used to treat diabetes. A potential approach is the in vitro expansion of pancreatic beta cells obtained from cadaveric organ donors. However, when human beta cells are expanded in vitro, they dedifferentiate and lose the expression of insulin, probably as a consequence of pancreatic islet dissociation into single cells. We have studied whether reestablishment of cell cell and cell-matrix relationships with a biomimetic synthetic scaffold could induce redifferentiation of expanded dedifferentiated beta cells. Cells isolated from human islet preparations were expanded in monolayer cultures and allowed to reaggregate into islet-like cell clusters (ICCs). Afterward, ICCs were embedded between two thin layers of the noninstructive self-assembling peptide (SAP), RAD16-I or RAD16-I functionalized with the integrin-binding motif RGD (RAD16 I/RGD) (R: arginine, G: glycine, D: aspartic acid), which was expected to promote cell-extracellular matrix interactions. ICCs cultured with RAD16-I were viable, maintained their cluster conformation, and increased in size by aggregation of ICCs, suggesting a self-organizing process. ICCs cultured in RAD16-I/RGD showed enhanced cell adhesion to RAD16-I matrix and reexpression of the beta cell specific genes, Ins, Pdx1, Nkx6.1, and MafA. Redifferentiation was caused solely by bioactive cues introduced to the RAD16-I peptide since no differentiation factors were added to the culture medium. The results indicate that RGD functionalized SAP in sandwich conformation is a promising three-dimensional platform to induce redifferentiation toward a beta cell phenotype and to generate insulin-expressing cells that could be used in diabetes therapy. PMID- 28873330 TI - Differential expression of virulence genes in Legionella pneumophila growing in Acanthamoeba and human monocytes. AB - Legionella pneumophila, the causative agent of Legionnaires' disease, is widely distributed throughout natural and artificial water systems and can replicate in macrophages and amoebae. Amoebae are the natural hosts of L. pneumophila, whereas macrophages are incidentally infected. The life cycle of L. pneumophila comprises a replicative phase within the Legionella-containing vacuole (LCV) and a transmissive phase during which bacterial cells become motile and are released via killing of the host. Although the host death mechanisms induced by L. pneumophila have been studied, the expression patterns of related L. pneumophila genes have not been reported. The present study compared the expression patterns of host cell death-associated genes in L. pneumophila grown in the human monocytic cell line THP-1 and Acanthamoeba castellanii. Notably, when L. pneumophila was grown in THP-1, expression of the gene flaA, which is involved in the induction of pyroptosis, was downregulated during the course of infection. In contrast, sdhA associated indirectly with host death, was upregulated. Expression of the genes vipD and sidF, which are involved in the induction and suppression of apoptosis, changed by less than 2-fold. Notably, a lower percentage of pyroptotic cells was observed among infected THP-1 cells relative to uninfected cells, and the latter exhibited stronger expression of caspase-1. A different pattern was observed when L. pneumophila was grown in A. castellanii: flaA and vipD were activated, whereas sdhA and sidF were downregulated during the later stage of replication. The percentage of non-viable (annexin-V+ PI+ or annexin V+PI-) A. castellanii organisms increased with Legionella infection, and the expression of metacaspase-1, which is involved in encystation was up-regulated at late infection time. In summary, L. pneumophila can multiply intracellularly in both amoebae and macrophages to induce cell death and secondary infection, and this characteristic is essential for its survival in water and the lungs. The gene expression profiles observed in this study indicated the increased cytotoxicity of L. pneumophila in A. castellanii, suggesting an increased adaptation of Legionella to this host. PMID- 28873333 TI - Role of echocardiography in reducing shock reversal time in pediatric septic shock: a randomized controlled trial. AB - OBJECTIVE: To evaluate the role of echocardiography in reducing shock reversal time in pediatric septic shock. METHODS: A prospective study conducted in the pediatric intensive care unit of a tertiary care teaching hospital from September 2013 to May 2016. Ninety septic shock patients were randomized in a 1:1 ratio for comparing the serial echocardiography-guided therapy in the study group with the standard therapy in the control group regarding clinical course, timely treatment, and outcomes. RESULTS: Shock reversal was significantly higher in the study group (89% vs. 67%), with significantly reduced shock reversal time (3.3 vs. 4.5 days). Pediatric intensive care unit stay in the study group was significantly shorter (8+/-3 vs. 14+/-10 days). Mortality due to unresolved shock was significantly lower in the study group. Fluid overload was significantly lower in the study group (11% vs. 44%). In the study group, inotropes were used more frequently (89% vs. 67%) and initiated earlier (12[0.5-24] vs. 24[6-72]h) with lower maximum vasopressor inotrope score (120[30-325] vs. 170[80-395]), revealing predominant use of milrinone (62% vs. 22%). CONCLUSION: Serial echocardiography provided crucial data for early recognition of septic myocardial dysfunction and hypovolemia that was not apparent on clinical assessment, allowing a timely management and resulting in shock reversal time reduction among children with septic shock. PMID- 28873334 TI - Pregnancy outcome in women with congenital heart disease: A single-center experience. AB - OBJECTIVE: Pregnancies in patients with adult congenital heart disease (ACHD) are often complicated. We aimed to highlight the nature and the rate of these complications in a single-center patient population. METHODS: We retrospectively studied all the pregnancies of women who presented on an outpatient basis, and all pregnancies were reviewed for maternal and fetal outcomes. RESULTS: Of 117 pregnancies from 52 ACHD patients (age at pregnancy 28.3 +/- 6.6 years), 10 were therapeutically aborted. A proportion of 41.1% of the remaining 107 pregnancies were complicated either with cardiac (3.7%), obstetric (15.0%), or fetal/neonatal (11.2%) adverse events or with spontaneous abortion (17.8%). Hospitalization during pregnancy was required in 10 patients. Elective cesarean sections were initially planned for 31% of the 87 pregnancies, which were finally completed, while 8% required an emergency cesarean section, mostly for obstetric reasons. NYHA class deterioration after pregnancy was detected in 9.3% of our cohort. Modified WHO class III/IV, prior medication use, and higher body mass index (BMI) were related to cardiac complications during pregnancy or NYHA deterioration. CONCLUSION: Pregnancies in ACHD patients are at high risk for complications. Advanced modified WHO class, prior medication use, and high BMI were related to adverse cardiac events. PMID- 28873335 TI - Blood pressure response during normocapnic hyperpnoea is blunted in young women compared to men. AB - We hypothesized that young women have a lower arterial blood pressure (BP) response to high inspiratory and expiratory muscle contractions with normocapnic hyperpnoea compared to age-matched men. To test this hypothesis, the cardiovascular response during voluntary normocapnic incremental hyperpnoea was evaluated in young women and compared to that of young men. An incremental respiratory endurance test (IRET) was performed as follows: target minute ventilation was initially set to 30% of the maximal voluntary ventilation (MVV12) and was increased by 10% MVV12 every 3min. The test was terminated when the subject could not maintain the target%MVV. Heart rate and mean arterial BP (MBP) were continuously recorded. The increase in MBP from the baseline (DeltaMBP) during the IRET was lower in women than in men (DeltaMBP, men: +32.1+/-4.6mmHg vs. women: +14.9+/-3.5mmHg at 8min during IRET). This result suggests that young women exhibit a blunted arterial BP response during high-speed inspiratory and expiratory muscle contractions with normocapnic hyperpnoea compared to young men. PMID- 28873336 TI - Characteristics of respiratory outbreaks in care homes during four influenza seasons, 2011-2015. AB - BACKGROUND: Influenza and other respiratory infections can spread rapidly and cause severe morbidity and mortality in care home settings. AIM: This study describes the characteristics of respiratory outbreaks in care homes in Northern Ireland during a four-year period, and aims to identify factors that predict which respiratory outbreaks are more likely to be positively identified as influenza. METHODS: Epidemiological, virological, and clinical characteristics of outbreaks during the study period were described. Variables collected at notification were compared to identify predictors for an outbreak testing positive for influenza. t-Tests and chi2-tests were used to compare means and proportions respectively; significance level was set at 95%. FINDINGS: During the four seasons, 95 respiratory outbreaks were reported in care homes, 70 of which were confirmed as influenza. More than 1000 cases were reported, with 135 associated hospitalizations and 22 deaths. Vaccination uptake in residents was consistently high (mean: 86%); however, in staff it was poorly reported, and, when reported, consistently low (mean: 14%). Time to notification and number of cases at notification were both higher than expected according to national recommendations for reporting outbreaks. No clinically significant predictors of a positive influenza outbreak were identified. CONCLUSION: Respiratory outbreaks in care homes were associated with significant morbidity and mortality, despite high vaccination uptake. The absence of indicators at notification of an outbreak to accurately predict influenza infection highlights the need for prompt reporting and laboratory testing. Raising staff awareness, training in the management of respiratory outbreaks in accordance with national guidance, and improvement of staff vaccination uptake are recommended. PMID- 28873337 TI - Thalamic GABA levels and occupational manganese neurotoxicity: Association with exposure levels and brain MRI. AB - Excessive occupational exposure to Manganese (Mn) has been associated with clinical symptoms resembling idiopathic Parkinson's disease (IPD), impairing cognitive and motor functions. Several studies point towards an involvement of the brain neurotransmitter system in Mn intoxication, which is hypothesized to be disturbed prior to onset of symptoms. Edited Magnetic Resonance Spectroscopy (MRS) offers the unique possibility to measure gamma-amminobutyric acid (GABA) and other neurometabolites in vivo non-invasively in workers exposed to Mn. In addition, the property of Mn as Magnetic Resonance Imaging (MRI) contrast agent may be used to study Mn deposition in the human brain. In this study, using MRI, MRS, personal air sampling at the working place, work history questionnaires, and neurological assessment (UPDRS-III), the effects of chronic Mn exposure on the thalamic GABAergic system was studied in a group of welders (N=39) with exposure to Mn fumes in a typical occupational setting. Two subgroups of welders with different exposure levels (Low: N=26; mean air Mn=0.13+/-0.1mg/m3; High: N=13; mean air Mn=0.23+/-0.18mg/m3), as well as unexposed control workers (N=22, mean air Mn=0.002+/-0.001mg/m3) were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45% (p<0.01, F(1,33)=9.55), as well as significantly worse performance in general motor function (p<0.01, F(1,33)=11.35). However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect. PMID- 28873339 TI - Non-invasive strategies for stimulating endogenous repair and regenerative mechanisms in the damaged heart. AB - The adult myocardium, including human, harbours a population of resident multi potent cardiac stem cells (CSCs), which when stimulated under the right conditions can give rise to new cardiomyocytes and vasculature. Elucidation of the cellular and molecular mechanisms that govern CSC biology and their role in myocardial regeneration will allow the design and development of optimal therapeutic interventions. It is now evident that different growth factors and cytokines govern CSC survival, proliferation, migration and differentiation, as well as playing a role in activating cardiac repair mechanisms such as improving angiogenesis, cardiomyocyte survival and limiting fibrosis. This review article will summarize the evidence for a role of VEGF, NRG-1, IGF-1, HGF, EGF, FGF and TGF-beta1 in modulating the repair and regeneration of cardiac tissue. It will also discuss the use of exosomes and exercise training as interventions to stimulate the endogenous repair and regenerative mechanisms in the damaged heart. PMID- 28873338 TI - Myths and truths about the cellular composition of the human brain: A review of influential concepts. AB - Over the last 50 years, quantitative methodology has made important contributions to our understanding of the cellular composition of the human brain. Not all of the concepts that emerged from quantitative studies have turned out to be true. Here, I examine the history and current status of some of the most influential notions. This includes claims of how many cells compose the human brain, and how different cell types contribute and in what ratios. Additional concepts entail whether we lose significant numbers of neurons with normal aging, whether chronic alcohol abuse contributes to cortical neuron loss, whether there are significant differences in the quantitative composition of cerebral cortex between male and female brains, whether superior intelligence in humans correlates with larger numbers of brain cells, and whether there are secular (generational) changes in neuron number. Do changes in cell number or changes in ratios of cell types accompany certain diseases, and should all counting methods, even the theoretically unbiased ones, be validated and calibrated? I here examine the origin and the current status of major influential concepts, and I review the evidence and arguments that have led to either confirmation or refutation of such concepts. I discuss the circumstances, assumptions and mindsets that perpetuated erroneous views, and the types of technological advances that have, in some cases, challenged longstanding ideas. I will acknowledge the roles of key proponents of influential concepts in the sometimes convoluted path towards recognition of the true cellular composition of the human brain. PMID- 28873342 TI - Testing the Effect of Internal Genes Derived from a Wild-Bird-Origin H9N2 Influenza A Virus on the Pathogenicity of an A/H7N9 Virus. PMID- 28873341 TI - Unsaturated nitrogen-rich polymer poly(l-histidine) gated reversibly switchable mesoporous silica nanoparticles using "graft to" strategy for drug controlled release. AB - : A novel and intelligent pH-controlled system having an "on-off" switch based on poly(l-histidine) (PLH) and poly(ethylene glycol) (PEG) coated mesoporous silica nanoparticles (MSNs) (MSNs-PLH-PEG) was designed and evaluated for tumor specific drug release. The unsaturated nitrogen-rich polymer, PLH, which can change its solubility at different pH values, was employed for establishing the reversible "on-off" switch. In vitro drug release results demonstrated that MSNs-PLH-PEG has a pH-controlled "on-off" profile with the change of pH value between pH 7.4 and 5.0. Furthermore, in vitro cellular uptake study results showed that the entrapped drug could be efficiently released from MSNs-PLH-PEG under acidic endosome/lysosome. In vitro cell cytotoxicity and in vivo antitumor studies results indicated that sorafenib loaded MSNs-PLH-PEG exhibited good anti proliferation and tumor growth inhibition effects. Haemolysis assay and histological analysis of MSNs-PLH-PEG showed negligible haemolysis activity and no visible tissue toxicity at the test dose. This study represents a promising and intelligent pH-controlled intelligent system for drug delivery and controlled release. STATEMENT OF SIGNIFICANCE: A novel pH-controlled intelligent and reversible "on-off" switch system based on poly(l-histidine) and poly(ethylene glycol) coated mesoporous silica nanoparticles (MSNs-PLH-PEG) by "graft to" synthesis method was constructed for tumor specific drug release. The unsaturated nitrogen-rich pH-sensitive polymer, PLH, which can change its solubility in different pH values, was employed as the reversible "on-off" switch in MSNs for the first time. The pH-controlled "on-off" switch manner was observed in the drug release results in vitro. In the in vivo antitumor studies, sorafenib loaded MSNs PLH-PEG could effectively suppressed tumor growth in H22 tumor bearing mice. It is expected that the pH-controlled intelligent "on-off" switch system we designed holds remarkable promise and provides valuable strategy for possible applications in cancer therapy. PMID- 28873340 TI - Personalized polyunsaturated fatty acids as a potential adjunctive treatment for anorexia nervosa. AB - Anorexia nervosa (AN) is a complex psychiatric disorder with high morbidity and mortality rates. While many individuals make full recoveries, up to a third of patients develop a chronic, treatment-resistant form of the illness that leads to a premature death in 15-20% of those affected. There have been few advances in treatment, both in terms of psychological or pharmacologic treatment over the last 30 years. Food aversion is commonly cited by patients with AN as a barrier to normalizing eating and weight. Our group has a keen interest in examining factors that might allow this to be addressed, thus improving treatment outcomes through personalized dietary plans or nutritional supplementation related to underlying genetic status. We demonstrated that polyunsaturated fatty acids (PUFAs)-derived bioactive lipids (eicosanoids) are implicated in not only the risk of AN, but also with its comorbid psychopathology. Of interest, the differential postprandial omega 6-derived eicosanoid shift observed in AN highlights the possibility that the metabolism of PUFAs is an important mechanism underlying the profound food version, contributing to pathological food restriction in AN. A concise knowledge of the relationships among PUFAs, eicosanoids, and AN clinical course and psychopathology could be the key to developing personalized nutritional rehabilitative treatments for those suffering from AN. This paper provides a comprehensive overview of the literature on PUFAs in AN. We also selectively reviewed the clinical benefits PUFA treatments exert in other psychiatric diseases, on weight and appetite regulation, and for resolution of inflammation, all of which are relevant in the disease course and outcome of AN. We propose that personalized PUFA formulation be developed and tested as a novel adjunctive treatment for patients with AN. We hypothesize that with personalized PUFA formulation, food aversion and anxiety about eating will decrease while mood, dietary behavior, and weight restoration will improve in AN, leading to improvements in the overall treatment outcome. PMID- 28873343 TI - Cellular Levels of Signaling Factors Are Sensed by beta-actin Alleles to Modulate Transcriptional Pulse Intensity. PMID- 28873344 TI - Fasting, but Not Aging, Dramatically Alters the Redox Status of Cysteine Residues on Proteins in Drosophila melanogaster. PMID- 28873346 TI - Painful posterior shoulder instability: Anticipating and preventing failure. A study in 25 patients. AB - BACKGROUND: Painful posterior shoulder instability (PPSI) is the least common of the three clinical patterns of posterior shoulder instability. PPSI is defined as pain combined with anatomical evidence of posterior instability but no instability events. MATERIAL AND METHOD: We studied a multicentre cohort of 25 patients with PPSI; 23 were identified retrospectively and had a follow-up of at least 2 years and 2 patients were included prospectively. Most patients engaged in sports. RESULTS: All 25 patients underwent surgery, which usually consisted in arthroscopic capsulo-labral reconstruction. The outcome was excellent in 43% of patients; another 43% had improvements but reported persistent pain. The pain remained unchanged or worsened in the remaining 14% of patients. Causes of failure consisted of a missed diagnosis of shoulder osteoarthritis with posterior subluxation, technical errors, and postoperative complications. The main cause of incomplete improvement with persistent pain was presence of cartilage damage. CONCLUSION: Outcomes were excellent in patients who were free of cartilage damage, bony abnormalities associated with posterior instability (reverse Hill Sachs lesion, erosion or fracture of the posterior glenoid), technical errors, and postoperative complications. PMID- 28873347 TI - Outcomes of capsulolabral reconstruction for posterior shoulder instability. AB - BACKGROUND: Surgical treatment of isolated posterior shoulder instability-a rare and often misdiagnosed condition-is controversial because of poor outcomes. Failure of physical therapy in symptomatic young athletes requires capsulolabral reconstruction or bone block procedures. The goal of this study was to report the outcomes of patients who have undergone surgical capsulolabral reconstruction and to look for risk factors that contribute to failure of this procedure. MATERIAL AND METHOD: We analyzed the outcomes of 101 patients who underwent capsulolabral reconstruction: 83 included retrospectively, 18 included prospectively. The procedures were performed alone or in combination with capsular shift, labral repair, closure of the rotator interval and notch remplissage. The primary endpoint was failure of the procedure, defined as recurrence of the instability and/or pain. We also determined the outcomes based on specific (Walch-Duplay, modified Rowe) and non-specific (Constant, resumption of activities) scores of shoulder instability. RESULTS: The results were satisfactory despite a high failure rate: 35% in the retrospective cohort with 4.8+/-2.6 years' follow-up and 22% in the prospective cohort with 1.1+/-0.3 years' follow-up. The various outcome scores improved significantly. Ninety-two percent of patients returned to work and 80% of athletes returned to their pre-injury level of sports. Eighty five percent of patients were satisfied or very satisfied after the surgery. No risk factors for failure were identified; however, failures were more common in older patients, those who underwent an isolated procedure and those who had unclassified clinical forms. CONCLUSION: Treatment of posterior shoulder instability by capsulolabral reconstruction leads to good clinical outcomes; however, the recurrence rate is high. LEVEL OF EVIDENCE: 4 - retrospective study. PMID- 28873345 TI - Neutrophil chemotaxis and transcriptomics in term and preterm neonates. AB - Neutrophils play a crucial role in combating life-threatening bacterial infections in neonates. Previous studies investigating neonatal cell function have been limited because of restricted volume sampling. Here, using novel microfluidic approaches, we provide the first description of neutrophil chemotaxis and transcriptomics from whole blood of human term and preterm neonates, as well as young adults. Ex vivo percent cell migration, neutrophil velocity, and directionality to N-formylmethionyl-leucyl-phenylalanine were measured from whole blood using time-lapse imaging of microfluidic chemotaxis. Genome-wide expression was also evaluated in CD66b+ cells using microfluidic capture devices. Neutrophils from preterm neonates migrated in fewer numbers compared to term neonates (preterm 12.3%, term 30.5%, P = 0.008) and at a reduced velocity compared to young adults (preterm 10.1 MUm/min, adult 12.7 MUm/min, P = 0.003). Despite fewer neutrophils migrating at slower velocities, neutrophil directionality from preterm neonates was comparable to adults and term neonates. 3607 genes were differentially expressed among the 3 groups (P < 0.001). Differences in gene expression between neutrophils from preterm and term neonates were consistent with reduced pathogen recognition and antimicrobial activity but not neutrophil migration, by preterm neonates. In summary, preterm neonates have significant disturbances in neutrophil chemotaxis compared to term neonates and adults, and these differences in phenotype appear at the transcriptional level to target inflammatory pathways in general, rather than in neutrophil migration and chemotaxis. PMID- 28873348 TI - Management of traumatic meniscal tear and degenerative meniscal lesions. Save the meniscus. AB - Meniscectomy remains one of the most frequent orthopedic procedures, despite meniscal sparing having been advocated for several decades now. Incidence is excessive in the light of scientifically robust studies demonstrating the interest of meniscal repair or of nonoperative treatment for traumatic tear and of nonoperative treatment for degenerative meniscal lesions. It is high time that the paradigm shifted, in favor of meniscal preservation. In traumatic tear, and most particularly longitudinal vertical tear in vascularized zones, repair shows a high success rates in terms of recovery time, functional outcome and cartilage protection. Leaving the meniscus alone may be an option in asymptomatic lesions of the lateral meniscus during anterior cruciate ligament (ACL) reconstruction. Posterior ramp lesions (in associated ACL tear), traumatic root tears and radial lesions are also excellent indications for repair, although it has to be borne in mind that the natural history of these lesions is not completely understood and nonoperative treatment also may be considered. Degenerative meniscal lesions are frequently revealed by MRI in middle-aged or elderly subjects. They are closely related to tissue aging and thus probably to osteoarthritic processes. Meniscectomy was long considered the treatment of choice. All but 1 of the 8 recent randomized studies reported non-superiority of arthroscopy over nonoperative treatment, which should thus be the first-line choice, with arthroscopic meniscectomy reserved for cases of failure, or earlier in case of "considerable" mechanical symptoms. Horizontal cleavage in young athletes is a particular case, requiring meniscal repair, to avoid a meniscectomy, which would inevitably be extensive in a young active patient. More than ever, the take-home message is: save the meniscus! PMID- 28873349 TI - Posterior shoulder instability: Prospective non-randomised comparison of operative and non-operative treatment in 51 patients. AB - BACKGROUND: The management of posterior shoulder instability remains controversial. Consequently, for a symposium on this topic, the French Arthroscopy Society (SFA) conducted a prospective multicentre study comparing outcomes of operative and non-operative treatment. OBJECTIVE: To compare outcomes after operative versus non-operative treatment of posterior shoulder instability. HYPOTHESIS: The surgical treatment of posterior shoulder instability may achieve better clinical outcomes than non-operative treatment in selected patients. MATERIAL AND METHODS: Fifty-one patients were included prospectively then followed-up for 12months. Three groups were defined based on the clinical presentation: recurrent dislocation or subluxation, involuntary instability or voluntary instability that had become involuntary, and shoulder pain with instability. Of the 51 patients, 19 received non-operative therapy involving a three-step rehabilitation programme and 32 underwent surgery with a posterior bone block, labral repair and/orcapsule tightening, or bone defect filling. At inclusion and at last follow-up, the Subjective Shoulder Value (SSV), Rowe score, Walch-Duplay score, and Constant score were determined. RESULTS: The preliminary results after the first 12 months are reported here. In the non-operative and operative groups, the Constant score was 78 versus 87, the Rowe score 64 versus 88, and the Walch-Duplay score 69 versus 82, respectively. These differences were statistically significant (P<0.05). DISCUSSION: To our knowledge, this study is the first comparison of non-operative versus operative treatment in a cohort of patients with documented posterior shoulder instability. Outcomes were better with operative treatment. However, this finding remains preliminary given the short follow-up of only 1 year. LEVEL OF EVIDENCE: III, case-control study. PMID- 28873350 TI - Clinical outcomes of posterior bone block procedures for posterior shoulder instability: Multicenter retrospective study of 66 cases. AB - BACKGROUND: The posterior bone block procedure is a well-known treatment option for posterior shoulder instability. The goal of this retrospective multicenter study was to evaluate the clinical and radiological outcomes of this procedure. MATERIAL AND METHODS: The study cohort consisted of 66 patients (55 men, 11 women) with an average age of 27.8 years who were evaluated clinically and radiologically using a standardized questionnaire after posterior bone block surgery. RESULTS: The Constant score significantly improved postoperatively (P<0.0001). The postoperative Walch-Duplay score was 81.5. The Rowe score was 86.5 points. The pain level (VAS) was significantly reduced after this procedure (P<0.0001). Eighty-five percent of patients were satisfied or very satisfied with the outcome. CONCLUSION: This multicenter study of 66 patients shows that the posterior bone block procedure is an effective technique with good subjective and objective outcomes; however, the possibility of complications cannot be ignored. CLINICAL STUDY: Level of evidence IV. PMID- 28873351 TI - Frequency and pathological characteristics of drug-induced liver injury in a tertiary medical center. AB - Drug-induced liver injury (DILI) accounts for approximately 10% of acute hepatitis cases. DILI can arise as idiosyncratic or intrinsic injury from hundreds of drugs, herbals, and nutritional supplements and is essential to recognize as one of the differential diagnoses of hepatitis in a liver biopsy. The purpose of this study is to investigate the frequency and pathological characteristics of DILI related to the variety of hepatotoxic agents. We searched our pathology database for all patients with hepatitis diagnosed on liver biopsy from January 2012 to May 2016, and selected patients with a diagnosis of DILI. Electronic medical records were reviewed for patient medication list, history of herbal medicine or supplement use, and pre-biopsy liver function test (LFT) results. Clinical and pathologic correlation was used to determine the causative or related agents for DILI. We then assessed histopathologic features of liver injury and categorized biopsy findings as primarily bile duct injury, lobular/portal hepatitis, or mixed changes. Six hundred four total liver biopsies for hepatitis or liver injury were identified, of which 70 cases (11.6%) carried the diagnosis of DILI confirmed by clinical correlation. The most common etiologies associated with DILI were supplements and herbal products (31.4%), antimicrobials (14.3%), chemotherapeutics (11.4%), antilipidemics (7.1%) and immunomodulatory agents (7.1%). LFT results positively correlated with histological findings. Nutritional/herbal supplements have emerged as one of the major hepatotoxicity agents. DILI can manifest as predominantly hepatitis, bile duct injury or combination. Histological pattern recognition in the liver biopsy may help identify specific hepatotoxic agents causing DILI. PMID- 28873352 TI - Immunophenotypic comparison of testicular sclerosing Sertoli cell tumors and Sertoli cell tumors not otherwise specified. AB - Testicular Sertoli cell tumors (SCTs) are rare, and most fall into the category of SCT-not otherwise specified (SCT-NOS). Only a few additional types of SCT are recognized. Sclerosing SCT (S-SCT), originally described in 1991, comprises a small fraction of SCTs and was considered a specific entity until the 2016 revision of the World Health Organization classification of non-germ cell tumors, where it was classified as a morphologic variant of SCT-NOS. In a recent study, differences in expression of PAX2/PAX8, inhibin, androgen receptor, and S100 protein between SCT-NOS and S-SCT were noted in a small number of cases. In this interinstitutional study, we compared the expression of these markers and beta catenin in 11 cases each of SCT-NOS and S-SCT to determine if differences exist that could justify keeping a separate classification of these neoplasms. PAX2/PAX8 cocktail was the only marker that was significantly overexpressed in S SCT. Expression of androgen receptors was strong in S-SCT and variable in SCT-NOS but did not reach statistical significance. Expression of beta-catenin was common in both, whereas inhibin was infrequent. The available material was insufficient for a conclusive evaluation of S100 protein expression. Overall, our results support the inclusion of S-SCT as a morphologic variant of SCT-NOS. Expression of PAX2/PAX8 in S-SCT may reflect an overactive epithelial-to-mesenchymal transition as has been shown in experimental models of acute and chronic seminiferous tubular injury and might be related to the process generating the stroma in these tumors. PMID- 28873353 TI - Primary cutaneous NK/T-cell lymphoma of nasal type: an age-related lymphoproliferative disease? AB - Among extranodal NK/T-cell lymphoma of nasal type (NKTL), the extranasal variant (ENKTL) is known to have a worse prognosis with advanced clinical stage than the nasal variant of NKTL. However, detailed clinicopathological features of the localized extranasal disease have not been well documented in English literature. Here, we described the clinicopathological profiles of 14 patients with stage I ENKTL, including 7 in the skin, 5 in the gastrointestinal tract, and 2 in the central nervous system, highlighting the distinctiveness of the first. The 7 primary cutaneous (PCNKTL) cases were characterized by an older onset age (median, 76 versus 53 years, P=.012) and a more favorable clinical course (P=.041) compared with 17 patients with stages II-IV ENKTL that showed cutaneous involvement. The skin lesions in the PCNKTL group were distributed in the face or neck (n=4) and limbs (n=3) but not the trunk, which was most frequently affected (60%, P=.017) in the latter group. Furthermore, the stage I cutaneous disease showed a female predominance (male-female, 2:5 versus 7:0; P=.021) and a significantly more favorable survival compared with the noncutaneous stage I ENKTL (P=.037). These results suggest that PCNKTL constitute a distinct subgroup in the nasal-type lymphoma spectrum. PMID- 28873355 TI - Pulmonary interstitial glycogenosis associated with a spectrum of neonatal pulmonary disorders. AB - Primary or isolated pulmonary interstitial glycogenosis (PIG) is a rare disease presenting as tachypnea and hypoxemia during the perinatal period. A diffuse interstitial infiltrate with focal hyperinflation is visible on chest imaging. The biopsy findings include diffuse expansion of the interstitium by spindle shaped cells with pale cytoplasm that, on electron microscopy (EM), are poorly differentiated mesenchymal cells containing abundant monoparticulate glycogen. This glycogenosis appears to be a transient abnormality, usually with a favorable prognosis. Recently, cases of PIG, some associated with other pulmonary or systemic abnormalities, have been described. The clinical significance and potential role of PIG changes remain unknown. We report 28 cases of PIG associated with a spectrum of pediatric pulmonary and cardiovascular disorders, including arterial hypertensive changes with and without abnormal alveolar development (n=9), congenital heart disease (CHD; n=4), hyperplasia of pulmonary neuroendocrine cells resembling neuroendocrine hyperplasia of infancy (NEHI, n=5), congenital pulmonary airway malformation (n=5), congenital lobar emphysema (n=4), and Noonan syndrome (n=1). In all cases, PIG was confirmed by positive periodic acid-Schiff (PAS) staining, immunopositivity for vimentin, and EM. Although some patients improved with age, 7 died of respiratory failure or complications of CHD, suggesting that PIG may be clinically significant when associated with other severe disorders. The association of PIG with a spectrum of mostly congenital lung disorders supports its origin as a developmental abnormality of interstitial fibroblast differentiation rather than a nonspecific reactive process. PMID- 28873354 TI - Mutation of NRAS is a rare genetic event in ovarian low-grade serous carcinoma. AB - Activating mutations involving the members of the RAS signaling pathway, including KRAS, NRAS, and BRAF, have been reported in ovarian low-grade serous carcinoma and its precursor lesion, serous borderline tumor (SBT). Whether additional genetic alterations in the RAS oncogene family accumulate during the progression of SBT to invasive low-grade serous carcinoma (LGSC) remains largely unknown. Although mutations of KRAS and BRAF occur at a very early stage of progression, even preceding the development of SBT, additional driving events, such as NRAS mutations, have been postulated to facilitate progression. In this study, we analyzed NRAS exon 3 mutational status in 98 cases that were diagnosed with SBT/atypical proliferative serous tumor, noninvasive LGSC, or invasive LGSC. Of the latter, NRAS Q61R (CAA to CGA) mutations were detected in only 2 of 56 (3.6%) cases. The same mutation was not detected in any of the SBTs (atypical proliferative serous tumors) or noninvasive LGSCs. Mutational analysis for hotspots in KRAS and BRAF demonstrated a wild-type pattern of KRAS and BRAF in one of the NRAS-mutated cases. Interestingly, another LGSC case with NRAS mutation harbored a concurrent BRAF V600L mutation. These findings indicate that, although recurrent NRAS mutations are present, their low prevalence indicates that NRAS plays a limited role in the development of LGSC. Further studies to identify other oncogenic events that drive LGSC progression are warranted. PMID- 28873356 TI - Follicular lymphoma with hyaline-vascular Castleman-like features: analysis of 6 cases and review of the literature. AB - Follicular lymphoma (FL) with features reminiscent of hyaline-vascular Castleman disease (CD) is an unusual morphologic variant that may create diagnostic difficulties. To our knowledge, only 5 cases of this variant have been reported. We describe the clinicopathologic features of 6 cases including 2 men and 4 women with a median age of 63 years (range, 41-77). Morphologically, all lymph node biopsy specimens showed at least a focal area of conventional FL; 4 cases showed neoplastic follicles with hyalinized blood vessels penetrating into germinal centers (lollipop-like lesions); 4 cases had interfollicular areas with increased vascular stroma; 2 cases showed small neoplastic follicles with prominent, onionskin-like mantle zones; and 1 case showed 2 or more germinal centers within follicles (twinning). The small neoplastic follicles were more cellular than lymphocyte-depleted follicles of true hyaline-vascular CD, and the interface between germinal centers and mantle zones was ill defined. No cases showed dysplastic follicular dendritic cells. Immunohistochemistry for BCL-2 was positive in all 6 cases. Flow cytometry immunophenotypic analysis showed a monotypic B-cell population in 2 of 3 cases assessed. Conventional cytogenetic or fluorescence in situ hybridization studies performed in 3 cases showed t(14;18)(q32;q21) or IGH-BCL2, supporting the diagnosis of FL. The cases presented here add clinicopathologic data to the few cases of FL with hyaline vascular CD-like features reported previously in the literature. Distinguishing this variant of FL from hyaline-vascular CD is important given the differences in treatment and prognosis of patients with each disease. PMID- 28873357 TI - Histone deacetylases inhibition: a potential diagnostic and therapeutic target for cancers-reply. PMID- 28873358 TI - 'Slamming' among men who have sex with men accessing general drug services, in response to Schmidt, AJ et al., 2016, Illicit drug use among gay and bisexual men in 44 cities: Findings from the European MSM Internet Survey (EMIS). PMID- 28873359 TI - Determination of genotoxic epoxide at trace level in drug substance by direct injection GC/MS. AB - A novel direct injection gas chromatography method coupled with selective ion monitoring mass spectrometry (GC/SIM-MS) was developed for quantitation of trace levels of high boiling point (HBP) epoxide genotoxic impurity (GTI) in drug substance. The injector temperature was optimized with the aims to minimize matrix effects and enhance SIM signal response. The final injector temperature 160 degrees C was selected after balancing between these two factors. The column screening was conducted as well and MN OPTIMA delta-3 silica capillary column was selected since it showed good peak symmetry without column bleeding. The good linearity was established for the concentration in the range from 0.0045MUg/mL to 0.5MUg/mL with a R2=0.9999. The limit of detection (LOD) and the limit of quantitation (LOQ) were 0.0014MUg/mL and 0.0045MUg/mL, respectively. The recovery which ranged from 95.0% to 112.5% could meet the ICH acceptance criteria. The validation results demonstrated the good linearity, precision and accuracy of the method which can be further adopted as an adequate quality control tool for quantitation of epoxide impurity at trace levels in drug substance and drug product. PMID- 28873360 TI - Bioanalysis of monomethyl fumarate in human plasma by a sensitive and rapid LC MS/MS method and its pharmacokinetic application. AB - Dimethyl fumarate (DMF) is the methyl ester of fumaric acid, after oral administration completely converts to its active metabolite monomethyl fumarate (MMF). A simple, rapid and sensitive LC-MS/MS method was developed and validated for the quantification of MMF in human plasma. Monomethyl fumarate d3 was used as an internal standard (IS). The analyte and the IS were extracted from plasma using a selective solid phase extraction technique. The clean samples were chromatographed on a C18 column using formic acid and acetonitrile (25:75, v/v) as mobile phase. An API-4000 LC-MS/MS system equipped with turbo ion spray (TIS) source and operated in multiple reactions monitoring (MRM) mode was used for the study. The method was validated for linearity in the range of 5.03-2006.92ng/mL. Also, a number of stability tests were conducted to evaluate the stability of analyte, IS in plasma samples and in neat samples, the results comply with recent bioanalytical guidelines. A shortest run time helped us to analyze more than 300 samples in a day. The method was applied to a pharmacokinetic study in ten healthy male Indian subjects and the study data was authenticated by conducting incurred sample reanalysis (ISR). PMID- 28873361 TI - 1H NMR based pharmacometabolomics analysis of urine identifies metabolic phenotype of clopidogrel high on treatment platelets reactivity in coronary artery disease patients. AB - Clopidogrel high on treatment platelets reactivity (HTPR) has burdened achieving optimum therapeutic outcome. Although there are known genetic and non-genetic factors associated with clopidogrel HTPR, which explain in part clopidogrel HTPR, yet, great portion remains unknown, often hindering personalizing antiplatelet therapy. Nuclear magnetic resonance (1H NMR) pharmacometabolomics analysis is useful technique to phenotype drug response. We investigated using 1H NMR analysis to phenotype clopidogrel HTPR in urine. Urine samples were collected from 71 coronary artery disease (CAD) patients who were planned for interventional angiographic procedure prior to taking 600mg clopidogrel loading dose (LD) and 6h post LD. Patients' platelets function testing was assessed with the VerifyNow(r) P2Y12 assay at 6h after LD. Urine samples were analysed using 1H NMR. Multivariate statistical analysis was used to identify metabolites associated with clopidogrel HTPR. In pre-dose samples, 16 metabolites were associated with clopidogrel HTPR. However, 18 metabolites were associated with clopidogrel HTPR in post-dose samples. The pathway analysis of the identified biomarkers reflected that multifactorial conditions are associated with clopidogrel HTPR. It also revealed the implicated role of gut microbiota in clopidogrel HTPR. Pharmacometabolomics not only discovered novel biomarkers of clopidogrel HTPR but also revealed implicated pathways and conditions. PMID- 28873363 TI - Epileptic seizures heralding a relapse in high grade gliomas. AB - PURPOSE: Seizures are a common clinical symptom in high-grade gliomas (HGG). The aim of the study was to investigate the relationship between seizures and HGG relapse (HGG-R). METHODS: We retrospectively evaluated 145 patients who were surgically treated for HGG-R. By analyzing clinical characteristics in these patients (all operated and treated by the same protocol), we identified 37 patients with seizures during follow-up. This cohort was divided into four subgroups according to a) presence or absence of seizures at the time of diagnosis and b) temporal relationship between seizure occurrence and HGG-R during follow-up: subgroup A (25pts) had seizures at follow-up but not at onset, subgroup B (12pts) had seizures both at follow-up and onset, subgroup C (30pts) had seizures before MRI-documented HGG-R, and subgroup D (7pts) had seizures after MRI-documented HGG-R. RESULTS: Although the datum was not statistically significant, survival was longer in patients with seizures during follow-up than in those without seizures (59.3% vs 51.4% alive at 2 years). In 30 patients (subgroup C) seizures heralded HGG-R. In a correlation analysis for this last subgroup, the time interval between seizure and the HGG-R was significantly associated with the number of chemotherapy cycles (r=0.470; p=0.009) and follow up duration (r=0.566; p=0.001). A linear regression model demonstrated a reciprocal association between the above factors and that it may be possible to estimate the timing of HGG-R by combining these data. CONCLUSIONS: Seizures may herald HGG-R before MRI detection of relapse, thus suggesting that seizures should always be considered a red flag during follow-up. PMID- 28873362 TI - Impact of hippocampal subfield histopathology in episodic memory impairment in mesial temporal lobe epilepsy and hippocampal sclerosis. AB - OBJECTIVE: The objective of the study was to analyze preoperative visual and verbal episodic memories in a homogeneous series of patients with mesial temporal lobe epilepsy (MTLE) and unilateral hippocampal sclerosis (HS) submitted to corticoamygdalohippocampectomy and its association with neuronal cell density of each hippocampal subfield. METHODS: The hippocampi of 72 right-handed patients were collected and prepared for histopathological examination. Hippocampal sclerosis patterns were determined, and neuronal cell density was calculated. Preoperatively, two verbal and two visual memory tests (immediate and delayed recalls) were applied, and patients were divided into two groups, left and right MTLE (36/36). RESULTS: There were no statistical differences between groups regarding demographic and clinical data. Cornu Ammonis 4 (CA4) neuronal density was significantly lower in the right hippocampus compared with the left (p=0.048). The groups with HS presented different memory performance - the right HS were worse in visual memory test [Complex Rey Figure, immediate (p=0.001) and delayed (p=0.009)], but better in one verbal task [RAVLT delayed (p=0.005)]. Multiple regression analysis suggested that the verbal memory performance of the group with left HS was explained by CA1 neuronal density since both tasks were significantly influenced by CA1 [Logical Memory immediate recall (p=0.050) and Logical Memory and RAVLT delayed recalls (p=0.004 and p=0.001, respectively)]. For patients with right HS, both CA1 subfield integrity (p=0.006) and epilepsy duration (p=0.012) explained Complex Rey Figure immediate recall performance. Ultimately, epilepsy duration also explained the performance in the Complex Rey Figure delayed recall (p<0.001). SIGNIFICANCE: Cornu Ammonis 1 (CA1) hippocampal subfield was related to immediate and delayed recalls of verbal memory tests in left HS, while CA1 and epilepsy duration were associated with visual memory performance in patients with right HS. PMID- 28873364 TI - Refractory spasms of focal onset-A potentially curable disease that should lead to rapid surgical evaluation. AB - PURPOSE: Infantile spasms (IS) can occur as the only seizure type in children with surgically amenable epilepsies. Although early surgery has shown positive effects, little is known regarding outcomes. METHODS: We retrospectively reviewed all children with IS referred to our tertiary center between 2002 and 2014 and try to define factors of outcome. RESULTS: Sixty-eight children with focal onset seizures were referred: twenty children with a hemispheric implication and 48 with one or more lobes involved. The age of onset was significantly earlier in the hemispheric population (8.0 versus 16.7 months in the focal population). There was no difference in the age of onset between anterior and posterior onset zones, as we could expect regarding the maturation gradient. The epilepsy began earlier in life in tuberous sclerosis than in DNET. Only three children of the 48 non-hemispheric patients had a normal MRI at the time of the surgery. Temporal lobe was involved only in a third of the population. More than 86% of the patients were operated on. Patients with hemispheric lesions were operated on younger (2.6 years+/- 2.1 years) compared to 4.6+/- 3.5 years in the whole population. The most frequent etiologies were in descending order: dysplasia, ganglioglioma or dysembryoplastic tumours and tuberous sclerosis. The global seizure outcome was favorable (Engel 1a) in 74.6% of the patients, and 87.9% if the delay between the first seizure and the surgery was less than 36 months. It fell to 64.7% if the delay exceeded 50 months. CONCLUSION: Spasms of focal onset have a similar postsurgical outcome as other seizure types so surgery may be an excellent option for treating selected patients with focal infantile spasms. Volume and type but not topography of the lesion influence the age of onset. MRI is very helpful to locate the pathology in the pediatric population, since only a small portion had a normal MRI. PMID- 28873365 TI - Deciphering the catalytic amino acid residues of l-2-haloacid dehalogenase (DehL) from Rhizobium sp. RC1: An in silico analysis. AB - The l-2-haloacid dehalogenases (EC 3.8.1.2) specifically cleave carbon-halogen bonds in the L-isomers of halogenated organic acids. These enzymes have potential applications for the bioremediation and synthesis of various industrial products. One such enzyme is DehL, the l-2-haloacid dehalogenase from Rhizobium sp. RC1, which converts the L-isomers of 2-halocarboxylic acids into the corresponding D hydroxycarboxylic acids. However, its catalytic mechanism has not been delineated, and to enhance its efficiency and utility for environmental and industrial applications, knowledge of its catalytic mechanism, which includes identification of its catalytic residues, is required. Using ab initio fragment molecular orbital calculations, molecular mechanics Poisson-Boltzmann surface area calculations, and classical molecular dynamic simulation of a three dimensional model of DehL-l-2-chloropropionic acid complex, we predicted the catalytic residues of DehL and propose its catalytic mechanism. We found that when Asp13, Thr17, Met48, Arg51, and His184 were individually replaced with an alanine in silico, a significant decrease in the free energy of binding for the DehL-l-2-chloropropionic acid model complex was seen, indicating the involvement of these residues in catalysis and/or structural integrity of the active site. Furthermore, strong inter-fragment interaction energies calculated for Asp13 and L-2-chloropropionic acid, and for a water molecule and His184, and maintenance of the distances between atoms in the aforementioned pairs during the molecular dynamics run suggest that Asp13 acts as the nucleophile and His184 activates the water involved in DehL catalysis. The results of this study should be important for the rational design of a DehL mutant with improved catalytic efficiency. PMID- 28873366 TI - Switching-On Adherence in Chronic Myeloid Leukemia. PMID- 28873367 TI - IDH1 Mutation Is an Independent Inferior Prognostic Indicator for Patients with Myelodysplastic Syndromes. AB - BACKGROUND: Genomic sequencing technologies have identified isocitrate dehydrogenase (IDH) mutations in haematological malignancies. The prognostic implications of somatic IDH mutation (mIDH) in myelodysplastic syndromes (MDS) remain controversial. METHODS: Mutations in IDH1 and IDH2 were detected using genomic sequencing technologies in 97 patients with MDS. RESULTS: Seven (7.2%) mutations were identified: 3 in IDH1 (all R132C) and 4 in IDH2 (3 R140Q and 1 R140L). The frequency of mutation was 16.6% (2/12) in refractory anaemia with excess blasts (RAEB)-1 and 14.7% (5/34) in RAEB-2. IDH1/2 mutations were closely associated with higher bone marrow blast counts (median 10.0 vs. 2.3%; p = 0.019) and lower absolute neutrophil counts (median 0.44 * 109/L vs. 1.21 * 109/L; p = 0.027). All IDH mutations were mutually exclusive and heterozygous. IDH mutations were not significantly correlated with any specific karyotype. Patients with IDH1 mutations exhibited shorter overall and progression-free survival (OS and PFS; p = 0.039 and p = 0.042, respectively), whereas IDH2 mutations did not affect OS or PFS (p = 0.560 and p = 0.218, respectively). Multivariate analysis indicated that IDH1 mutation (p = 0.018; hazard ratio [HR] 4.735; 95% confidence interval [CI] 1.299-17.264), karyotype risk (p = 0.036; HR 1.619; 95% CI 1.033-2.539) and the revised International Prognostic Scoring System risk category (p < 0.0001; HR 2.122; 95% CI 1.401-3.213) were independent inferior prognostic factors. CONCLUSIONS: IDH1 mutation is associated with a poor prognosis. PMID- 28873368 TI - Kruppel-Like Factor 2 Regulates Degradation of Type II Collagen by Suppressing the Expression of Matrix Metalloproteinase (MMP)-13. AB - BACKGROUND/AIMS: Kruppel-like factor 2 (KLF2) plays an essential role in the inhibition of endothelial cell and macrophage activation during the inflammatory process. However, the roles of KLF2 in chondrocytes and the pathological progression of osteoarthritis (OA) remain unknown. The aim of this study was to investigate the function of KLF2 in the inhibition of cartilage matrix destruction in chondrocytes. METHODS: RT-PCR and western blot analysis was used to determine the expression of KLF2 in human chondrocytes. Luciferase assay, ELISA assay and MMP-13 enzymatic activity assays were used to investigate the effects of KLF2 in regulating MMP-13 expression. Western blot analysis was used to examine the effects of KLF2 in suppressing degradation of type II collagen. RESULTS: KLF2 is expressed in primary chondrocytes and is downregulated in OA chondrocytes. Expression of KLF2 in primary chondrocytes was reduced in response to IL-1beta. Overexpression of KLF2 robustly inhibited IL-1beta-induced MMP-13 expression. Conversely, knockdown of KLF2 markedly exacerbated MMP-13 expression. Mechanistically, KLF2 could suppress the activation of MMP-13 promoter. However, knockdown of KLF2 could promote the activation of MMP-13 promoter. Importantly, overexpression of KLF2 ameliorated the degradation of type II collagen while silencing of KLF2 exacerbated the degradation of type II collagen induced by IL 1beta. CONCLUSIONS: KLF2 may be a potential therapeutic target for OA treatment. PMID- 28873369 TI - Dexmedetomidine Alleviates Hyperoxia-Induced Acute Lung Injury via Inhibiting NLRP3 Inflammasome Activation. AB - BACKGROUND/AIMS: Dexmedetomidine (Dex), a specific agonist of alpha2 adrenoceptor, has been reported to have extensive pharmacological effects. In this study, we focused on the protective effect of Dex on hyperoxia-induced acute lung injury and further explored its possible molecular mechanisms. METHODS: The model of hyperoxia-induced acute lung injury was established by continuous inhalation of oxygen (FiO2= 0.90) for 7 d in neonatal rats in vivo. The in vitro experiments were carried out in LPS/ATP or hyperoxia-treated RAW264.7 cells. ELISA, western blot, TUNEL staining, and immunohistochemistry staining assays were performed and the commercial kits were used to assess the beneficial effect of Dex on hyperoxia-induced acute lung injury. RESULTS: According to our results, Dex treatment attenuated hyperoxia-induced acute lung injury via decreasing the lung wet/dry(W/D) weight ratio and mitigating pathomorphologic changes. Moreover, the oxidative stress injury, inflammatory reaction, and apoptosis in lung epithelial cells were inhibited by Dex treatment. In addition, the activation of NLRP3 inflammasome was restrained by Dex both in lung tissue in vivo and RAW264.7 cells in vitro. CONCLUSION: These data provide evidence that Dex may ameliorate hyperoxia-induced acute lung injury, which suggests a potential clinical application of Dex in long-term supplemental oxygen therapy. PMID- 28873370 TI - Understanding the Parent Perspective on Prenatal Consultation for Fetuses with Congenital Anomalies. AB - INTRODUCTION: An increasing number of congenital anomalies are diagnosed prenatally. Understanding the implications of these diagnoses on the life of their child is critical for parents, and the surgical consultation is often the primary venue for this education. Little is known about the parent perspective on prenatal consultation. METHODS: Parents undergoing prenatal consultation were identified and in-depth interviews were conducted to explore the following: understanding of the diagnosis, preparedness for postnatal course, and suggestions for improvement. Qualitative analysis was performed to generate themes. RESULTS: Twelve interviews with 16 family members were performed, encompassing a variety of prenatal diagnoses and outcomes. Near-ubiquitous emotions included fear, anxiety, and self-blame. Surgical consultation relieved anxiety for some, but the uncertain outcome increased anxiety in others. Most were satisfied with the information communicated during the encounter; however, those with worse outcomes wished they were better warned. Parents emphasized the importance of support systems and educational materials. CONCLUSIONS: Parents appreciate learning about all potential outcomes for the fetus, even though this generates anxiety. Surgeons should discuss the range of possible outcomes while acknowledging that uncertainty leads to anxiety. It is essential to incorporate the parent perspective when conducting prenatal consultation and training pediatric surgeons in this important practice. PMID- 28873371 TI - Modified Hysterotomy Closure Technique for Open Fetal Surgery. AB - OBJECTIVE: We reviewed our experience with open fetal surgical myelomeningocele repair to assess the efficacy of a new modification of the hysterotomy closure technique regarding hysterotomy complication rates at the time of cesarean delivery. METHODS: A modification of the standard hysterotomy closure was performed on all patients undergoing prenatal myelomeningocele repair. The closure consisted of an interrupted full-thickness #0 polydioxanone (PDS) retention suture as well as a running #0 PDS suture to re-approximate the myometrial edges, and the modification was a third imbricating layer resulting in serosal-to-serosal apposition. A standard omental patch was placed per our routine. Both operative reports and verbal descriptions of hysterotomy from delivering obstetricians were reviewed. RESULTS: A total of 49 patients underwent prenatal repair of myelomeningocele, 43 having adequate follow-up for evaluation. Of those, 95.4% had completely intact hysterotomy closures, with only 1 partial dehiscence (2.3%) and 1 thinned scar (2.3%). There were no instances of uterine rupture. DISCUSSION: In patients undergoing this modified hysterotomy closure technique, a much lower than expected complication rate was observed. This simple modified closure technique may improve hysterotomy healing and reduce obstetric morbidity. PMID- 28873372 TI - Efficacy and Safety of the Oral Multikinase Regorafenib in Metastatic Colorectal Cancer. AB - BACKGROUND/AIM: A clinical trial demonstrated that treatment with oral multikinase regorafenib improved overall survival (OS), progression-free survival (PFS), and disease control [Garcia-Alfonso et al.: J Clin Transl Oncol 2016;18:1072-1081; Bertocchi et al.: J Chemother 2017;29:102-105]. In this study, we aimed to evaluate its effectiveness in Italian patients with hormone refractory metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy with docetaxel plus prednisone. MATERIALS AND METHODS: 60 patients were enrolled. OS has been assessed as the primary endpoint while PFS, quality of life, safety, and response rate represented secondary endpoints. RESULTS: A modest tolerability was observed in our group showing a manageable toxicity profile and a modest objective response rate. It was associated with stable disease. A significant correlation between quality of life and OS was also noticed. CONCLUSIONS: Regorafenib has been proven to be an effective and well tolerated therapeutic option in patients with mCRPC progressing after docetaxel plus prednisone treatment. PMID- 28873374 TI - Characteristics and Prognosis of Oldest Old Subjects with Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is an age-related neurodegenerative disease with unclear characteristics and prognosis in the oldest old (80 years and over). The aim of this study was to compare the oldest old and younger ALS patients in terms of clinical and socio-demographic characteristics, and prognosis. METHODS: ALS incident cases from the register of ALS in Limousin (FRALim), diagnosed between January 2000 and July 2013, were included. Descriptive and comparative analyses by age group were carried out. For time to event univariate analysis, Kaplan-Meier estimator and log rank test were used. Univariate and multivariate survival analyses were carried out with Cox's proportional hazard model. RESULTS: Out of 322 patients, 50 (15.5%) were aged 80 or over ("oldest old" ALS) at the time of diagnosis. Among them, the male:female gender-ratio was 1.27, and 32.6% had a bulbar onset (not different from subjects aged less than 80 years). With increasing age, there was a worsening of the clinical state of the patients at time of diagnosis in terms of weight loss, forced vital capacity, ALSFRS-R and manual muscular testing. Access to ALS referral centres decreased with age, and the use of riluzole tended to be lower in the oldest old group. The median survival of oldest old patients appeared to be 10 months shorter than that of subjects aged less than 80 years (7.4 vs. 17.4 months). CONCLUSION: The survival of oldest old ALS patients is particularly short. It relates to prognostic features at baseline and to an independent effect of advanced age. PMID- 28873375 TI - Non-Invasive Prenatal Testing for Sex Chromosome Aneuploidy in Routine Clinical Practice. AB - OBJECTIVES: To assess the accuracy of non-invasive prenatal testing (NIPT) for sex chromosome aneuploidy (SCA) in routine clinical practice and to review counselling and sonographic issues arising in SCA cases. METHODS: Three specialist Australian obstetric ultrasound and prenatal diagnosis practices offering NIPT after 10 weeks' gestation participated in this study. NIPT was reported for chromosomes 21, 18, 13, X, and Y. RESULTS: NIPT screening was performed in 5,267 singleton pregnancies. The odds of being affected given a positive screening result (OAPR) was lowest for SCAs, most notably for monosomy X (20%). Fewer women underwent invasive prenatal testing when counselled regarding a high risk for SCA (65.5%) compared with those who had a high risk for another aneuploidy (85%). The positive screening rate of NIPT including SCA was 2.3%, but 1.2% if only the autosomal trisomies were included in the panel. CONCLUSION: The addition of SCA testing to NIPT doubles the positive screening rate. The OAPR for SCAs (most notably for monosomy X) is reduced compared with the autosomal trisomies. Clinicians need a more extensive discussion with women prior to the inclusion of the X and Y chromosomes in the NIPT panel, given the complexity in counselling regarding further management and the additional anxiety that these abnormal results may cause. A benefit of sex chromosome analysis is an improvement in antenatal diagnosis of some disorders of sexual development. PMID- 28873373 TI - Biomarkers of Renal Injury in Cirrhosis: Association with Acute Kidney Injury and Recovery after Liver Transplantation. AB - BACKGROUND: To define urine or serum biomarkers in predicting renal function recovery after liver transplantation (LT). METHODS: Adults listed for LT (February 2011-July 2014) and with modified diet for renal disease-6 (MDRD-6) <60 mL/min provided urine/blood samples at baseline and serially until LT for biomarkers in serum (pg/mL) and urine (pg/mg creatinine). RESULTS: Of 271 LT listed patients (mean age 57 years, 63% males, median listing MELD 17.5), 1 year acute kidney injury (AKI) probability was 49%, with odds of 1.3-, 3.0-, 4.6-, and 8.5-fold times for listing MELD 16-20, 21-25, 26-30, and >30, compared to MELD <16. Thirty-seven people died over 1 year from the time of listing, with twofold increased odds with AKI. Among 67 patients with MDRD <60, only urinary epidermal growth factor was different comparing AKI (increase in serum creatinine >=0.3 mg/dL from baseline within past 3 months) vs. no AKI (2,254 vs. 4,253, p = 0.003). Differences between acute tubular necrosis (ATN) and hepatorenal syndrome could not be ascertained for a small sample of 3 patients with ATN. Analyzing 15 of 43 receiving LT and MDRD-6 <30 prior to LT, biomarkers were not different comparing 5 patients recovering renal function (MDRD-6 >50 mL/min) at 6 months vs. 10 without recovery. CONCLUSIONS: AKI is common among LT listed patients, with a negative impact on transplant-free survival. Serum and urine biomarkers are not associated with the recovery of renal function after LT. Multicenter studies are suggested to (a) develop strategies to reduce the development of AKI and (b) derive novel biomarkers for use in accurately predicting renal recovery after LT. PMID- 28873376 TI - Efficacy and Safety of Cathine (Nor-Pseudoephedrine) in the Treatment of Obesity: A Randomized Dose-Finding Study. AB - OBJECTIVE: To investigate the efficacy and safety of increasing doses of cathine (nor-pseudoephedrine) as a weight-lowering agent in patients with obesity. METHODS: Overweight and obese patients (n = 241, mean BMI 34.6 +/- 3.4 kg/m2) were randomly allocated to one of three doses of cathine (16 mg, 32 mg, 53.3 mg) or placebo in addition to a multimodal lifestyle intervention program in a multicenter, double-blind, controlled, dose-finding study for 24 weeks. Primary outcome was weight loss. RESULTS: Treatment with the 3 doses of cathine resulted in a significantly greater weight loss compared to placebo over 24 weeks: 6.5 +/- 4.2 kg for 16 mg cathine, 6.2 +/- 4.7 kg for 32 mg cathine, and 9.1 +/- 5.4 kg for 53.3 mg cathine versus 2.4 +/- 4.4 kg for placebo (each p < 0.01, ANCOVA). The percentage of patients losing > 5% / >10% of initial body weight was significantly greater for all doses of cathine than for placebo (each p < 0.01, chi-square test). Heart rate increased dose-dependently (by 1.2 bpm under 16 mg, 5.8 bpm under 32 mg, and 6.2 bpm under 53.3 mg cathine), but no suspected unexpected serious adverse reactions were noted. The overall dropout rate was 24.9%, with the highest rate in the placebo group (42.3%). CONCLUSION: Cathine appears to be an effective weight-lowering agent for adjunct treatment of obesity, but additional clinical studies on its efficacy and safety are required. PMID- 28873377 TI - Sea Buckthorn (Hippophae rhamnoides L.) Oil Improves Atopic Dermatitis-Like Skin Lesions via Inhibition of NF-kappaB and STAT1 Activation. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to evaluate the topical effects of sea buckthorn (SBT) oil on atopic dermatitis (AD)-like lesions in a mouse model generated by repeated topical administration of DNCB in BALB/c mice. METHODS: DNCB was applied repeatedly on the dorsal skin of mice to induce AD-like lesions. Following AD induction, SBT oil was applied daily on the dorsal skin for 4 weeks. The severity of skin lesions was examined macroscopically and histologically. We further measured the production of MDC/CCL22 and TARC/CCL17 in IFN-gamma/TNF-alpha activated HaCaT cells. RESULTS: Topically applied SBT oil in DNCB-treated mice ameliorated the severity score of dermatitis, decreased epidermal thickness, reduced spleen and lymph node weights, and prevented mast cell infiltration. In addition, SBT oil suppressed the Th2 chemokines TARC and MDC via dose-dependent inhibition of NF-kappaB, JAK2/STAT1, and p38-MAPK signaling pathways in IFN-gamma/TNF-alpha-activated HaCaT cells. CONCLUSION: These results suggest that SBT oil had a beneficial effect on AD-like skin lesions, partially via inhibition of the Th2 chemokines TARC and MDC in inflamed skin. PMID- 28873378 TI - Effect of Cardiac Surgery-Associated Acute Kidney Injury on Long-Term Outcomes of Chinese Patients: A Historical Cohort Study. AB - BACKGROUND/AIMS: To evaluate the long-term outcomes of Chinese patients with cardiac surgery-associated acute kidney injury (CSA-AKI). METHODS: Patients who underwent cardiac surgery with a median 3-year follow-up were enrolled. The long term survival rate and the incidence of chronic kidney disease (CKD) were recorded, and related risk factors were analyzed. RESULTS: Of all 1,363 patients, 457 (33.5%) developed CSA-AKI. The AKI patients had a lower 3-year survival rate (88.8 vs. 97.2%, respectively, p < 0.001) and a higher incidence of CKD stages 3 5 (9.9 vs. 2.3%, respectively, p < 0.001) than the non-AKI patients. Cox regression analysis showed that AKI, atrial fibrillation, chronic cardiac insufficiency, longer surgical duration, respiratory failure after surgery, and longer mechanical ventilation time were associated with long-term mortality, while AKI, older age, and lower baseline kidney function were associated with incident CKD stages 3-5. CONCLUSION: CSA-AKI increased the risk of 3-year mortality and incident CKD stages 3-5. PMID- 28873379 TI - A Novel Long Non-Coding RNA, SOX21-AS1, Indicates a Poor Prognosis and Promotes Lung Adenocarcinoma Proliferation. AB - BACKGROUND: In recent years, long non-coding RNAs (lncRNAs) have been shown to be a novel class of regulators of cancer biological processes. Although lncRNAs are dysregulated in numerous cancer types, limited data are available on the expression profiles and potential functions of lncRNAs in lung adenocarcinoma (LUAD). This study evaluated the expression and biological roles of lncRNA SOX21 antisense RNA 1 (SOX21-AS1) in LUAD. METHODS: Quantitative reverse transcription PCR (qRT-PCR) was performed to detect the expression levels of SOX21-AS1 in 68 pairs of LUAD tissues and corresponding non-tumor tissues. The effect of SOX21 AS1 on proliferation was evaluated by MTT, colony formation, EdU assays, flow cytometric analysis and in vivo tumor formation assays. Real-time PCR, western blot and immunohistochemistry were used to evaluate the mRNA and protein expression of p57. RESULTS: Higher expression levels of SOX21-AS1 positively correlated with tumor size and advanced tumor-node-metastasis (TNM) stage. Multivariate analyses indicated that SOX21-AS1 expression could serve as an independent prognostic factor for overall survival of LUAD. Furthermore, knockdown of SOX21-AS1 significantly inhibited LUAD cell proliferation both in vitro and in vivo and induced cell cycle phase arrest and cell apoptosis. Importantly, through qRT-PCR and western blot analysis, we found that inhibition of SOX21-AS1 remarkably induced p57 expression. CONCLUSIONS: Collectively, our study demonstrates that SOX21-AS1 is involved in the development and progression of LUAD and that SOX21-AS1 may be a potential diagnostic factor as well as a target for new therapies for patients with LUAD. PMID- 28873380 TI - The Endometriosis Fertility Index Is Useful for Predicting the Ability to Conceive without Assisted Reproductive Technology Treatment after Laparoscopic Surgery, Regardless of Endometriosis. AB - OBJECTIVE: The endometriosis fertility index (EFI) is a novel index for predicting pregnancy after surgery. We investigated the utility of the EFI for predicting the ability to conceive without assisted reproductive technology (ART) treatment after laparoscopic surgery. METHODS: From July 2011 through December 2012, we recruited 133 infertile patients who underwent laparoscopy, and the EFI was calculated. After surgery, 55 of 133 achieved pregnancy without ART treatment. We evaluated the factors that predicted a naturally successful pregnancy and compared them between the pregnant and non-pregnant subjects. RESULTS: On a univariate linear regression analysis, we found that a younger age, shorter duration of infertility, and higher EFI were positively associated with a successful pregnancy without ART after laparoscopic surgery (p < 0.05). According to 50th percentile EFI, the cutoff EFI predicting a successful pregnancy without ART was 7, the pregnancy rate in the high-EFI group (EFI; 8-10) was significantly higher than that in the low-EFI group (EFI <=7; p < 0.05), but the duration to natural conception after surgery was similar between the 2 groups. CONCLUSION: The EFI possesses greater predictive power for a successful pregnancy with natural intercourse or intrauterine insemination in infertile patients, regardless of endometriosis, than the Revised-American Society of Reproductive Medicine classification. PMID- 28873382 TI - Development and Anatomy of the Enteroendocrine System in Humans. AB - The gastrointestinal (GI) tract exhibits an enormous surface area that consists mostly of absorptive enterocytes. Enteroendocrine cells (EECs) are found scattered along the GI tract between absorptive enterocytes and other secretory cells, and comprise around 1% of the epithelial cell population. Interestingly, they develop from the same crypt stem cell as the other absorptive or secretory cells of the gut. EECs differentiate along the crypt villus axis and are renewed every 4-6 days, and hence possess a high plasticity. They constitute the largest endocrine system in the human body by secreting multiple peptide hormones to control, for example, postprandial digestion, insulin homeostasis, food intake, and gut motility. For this purpose, most EECs exhibit luminal sensors that detect the GI tract content. Thereafter, they may act either in a classical endocrine fashion, or by paracrine effects on nearby neural and immune cells. This creates a pivotal role for EECs to influence the GI immune system and the enteric nervous system. In this chapter, the anatomical characteristics, development, differentiation and maturation of EECs are described, and their important biological potential illustrated as part of the gut interacting sensory system. PMID- 28873381 TI - The Changing Concept of Gut Endocrinology. AB - Gastrointestinal hormones are released from enteroendocrine cells in the digestive tract. More than 30 hormone genes are expressed, which make the gut the largest endocrine organ in the body. At present, it is feasible to conceive the hormones under 5 headings: the structural homology groups most hormones into 9 families, each of which is assumed to originate from a single gene. Today's hormone gene often has multiple phenotypes due to alternative splicing, tandem organization or differentiated maturation of the prohormone. By these mechanisms, more than 100 different hormonal peptides are released from the gut. Gut hormones are also widely expressed in extraintestinal cells. These cells may release different fragments of the same prohormone due to cell-specific processing pathways. Moreover, endocrine cells, immune cells, neurons, myocytes, kidney cells, sperm cells and cancer cells secrete gut peptides in different ways, so the same peptide may act for instance as a hormone, a neurotransmitter, a cytokine, a growth factor or a fertility factor. The targets of gastrointestinal hormones are specific G-protein coupled receptors that are expressed in the cell membrane all over the body. Thus, each gut hormone constitutes a regulatory system operating in the whole organism. PMID- 28873383 TI - Incretins and Their Endocrine and Metabolic Functions. AB - Incretins are hormones secreted into the blood stream from the gut mucosa in response to nutrient intake. They have been characterized based on their capacity to lower blood glucose levels. The more potent reduction of blood glucose coupled to a more intensive stimulation of insulin secretion, in response to oral glucose uptake, as compared to intravenous glucose infusion has further been termed the "incretin effect." As a prototype incretin hormone, the biology of glucagon-like peptide 1 (GLP-1) has been intensively studied. GLP-1 actions are mediated through cyclic adenosine monophosphate-coupled membrane receptors. Classical physiological effects involve stimulation of insulin secretion from pancreatic beta cells and reduction of glucagon secretion from pancreatic alpha cells, inhibition of gastric motility, and increase of satiety with reduced food uptake. The understanding of these metabolic functions has led to the notion that incretin hormones, and specifically GLP-1, would represent ideal antidiabetic treatment options. As native GLP-1 is degraded by dipeptidyl peptidase type 4 (DPP-4) within minutes, other pharmacological approaches to exploit GLP-1 actions for the treatment of type 2 diabetes have been developed. These include DPP-4 inhibitors as oral medications and GLP-1 receptor agonists (incretin mimetics) as peptide compounds to be injected. PMID- 28873384 TI - Role of Incretin Hormones in Bowel Diseases. AB - Enteroendocrine cells (EEC) have been studied extensively for their ability to regulate gastrointestinal motility and insulin release by secretion of peptide hormones. In particular, the L cell-derived incretin glucagon-like peptide 1 has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes. Yet, accumulating data indicates a critical role for EEC and incretins in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC actively sense the lamina propria and luminal environment including the microbiota via receptors and transporters, subsequently mediating signals by secreting hormones and cytokines. Data indicate that immune cells and cytokine-mediated signaling impacts EEC numbers and function during infection and chronic inflammation of the gut, suggesting EEC not only to play a role in these pathologies but also being a target of inflammatory processes. This review presents data on the interrelation of incretins and inflammatory signaling. It focuses on the impact of intestinal inflammation, in particular inflammatory bowel disease, on EEC and the potential role of EEC and incretins in these pathologies. Furthermore, it highlights endoplasmic reticulum unfolded protein response, cytokines and the intestinal microbiota as possible targets of inflammatory and EEC signaling. PMID- 28873385 TI - Ghrelin and Growth. AB - Ghrelin is a pleiotropic hormone, whose effect on growth hormone secretion, through the growth hormone secretagogue (GHS) receptor, is one of its many actions. Relationships between GHS receptor gene variants and human height, both in healthy individuals and in patients with growth disorders have been identified. These include constitutional delay in growth and puberty, idiopathic short stature, and isolated growth hormone deficiency. In this review, we provide an overview of the role of ghrelin in growth. PMID- 28873386 TI - Development of Sweet Taste Perception: Implications for Artificial Sweetener Use. AB - Humans have an innate liking for sweetness, which may have an evolutionary basis. Sweetness typically signals the presence of calories and nutrients and thus, universal liking for sweet taste once served to support survival. In the modern food supply, however, sweetness is often delivered via added sugars and sweeteners devoid of other beneficial nutrients. Nonnutritive sweeteners (NNS) provide sweetness with no or few calories, and therefore may offer a potential strategy to maintain food and beverage palatability, while reducing the caloric content. Despite marked increases in NNS use, their metabolic and health effects are not well-characterized, and particularly little is known about their effects when exposure starts early in life. Herein, we critically review existing data on NNS exposure in utero, during lactation, and throughout childhood and adolescence with respect to taste preferences, weight trajectory, and development of chronic disease. We specifically focus on potential mechanisms through which sweetness exposure during early development may affect key metabolic outcomes. PMID- 28873387 TI - Just a Gut Feeling: Central Nervous Effects of Peripheral Gastrointestinal Hormones. AB - Despite greater health education, obesity remains one of the greatest health challenges currently facing the world. The prevalence of obesity among children and adolescents and the rising rates of prediabetes and diabetes are of particular concern. A deep understanding of regulatory pathways and development of new anti-obesity drugs with increased efficacy and safety are of utmost necessity. The 2 major biological players in the regulation of food intake are the gut and the brain as peptides released from the gut in response to meals convey information about the energy needs to brain centers of energy homeostasis. There is evidence that gut hormones not only pass the blood-brain barrier and bind to receptors located in different brain areas relevant for body weight regulation, but some are also expressed in the brain as part of hedonic and homeostatic pathways. Regarding obesity interventions, the only truly effective treatment for obesity is bariatric surgery, the long-term benefits of which may actually involve increased activity of gut hormones including peptide YY3-36 and glucagon-like peptide 1. This review discusses critical gut-hormones involved in the regulation of food intake and energy homeostasis and their effects on peripheral tissues versus central nervous system actions. PMID- 28873388 TI - Gastrointestinal Endocrinology in Bariatric Surgery. AB - The long-lasting weight-reducing effect of bariatric surgical procedures cannot simply be explained by the malabsorption of nutrients and the subsequent energy deficit due to this malabsorption. Clinical studies have shown that the reorganization of the anatomy of the gut and the subsequent alterations of gastrointestinal physiology have a large impact on the secretion and function of gastrointestinal hormones, which regulate hunger and satiety. These changes have been named the BRAVE effect: bile flow alteration, reduction of gastric size, anatomical gut rearrangement and altered flow of nutrients, vagal manipulation, and enteric gut modulation. In addition, the metabolic improvements, for example, increased insulin secretion and improved glucose sensitivity after bariatric surgery cannot simply be explained by the weight loss achieved by the operation. Several metabolic improvements occur directly after bariatric surgery even before significant weight loss has occurred. Clinical studies revealed that the altered gastrointestinal physiology and the postoperative profile of gastrointestinal hormones are responsible for these metabolic alterations. Further insights into the changes of gastrointestinal hormone profiles before and after bariatric surgery may open new ways to prevent the surgical procedure and probably obtain equivalent results by nutraceuticals. PMID- 28873389 TI - Treatment of Diabetes and Obesity by Rationally Designed Peptide Agonists Functioning at Multiple Metabolic Receptors. AB - Obesity and its comorbidities such as type 2 diabetes constitute major worldwide health threats, and the identification of an effective medical intervention has emerged as a global priority. The limited effectiveness of historical, anti obesity treatments is commonly attributed to the complexity of the disease and the redundancy of metabolic regulatory mechanisms that sustain body weight. At the forefront of obesity research is the development of combinational drug therapies that simultaneously target multiple regulatory pathways, which promote dysfunctional metabolism. Recently, molecularly crafted unimolecular "multi agonism" of balanced activity at 3 key receptors involved in metabolism and specifically the glucagon-like peptide (GLP)-1 receptor, glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon receptor was reported as superior to conventional monoagonist therapy. These mixed peptide agonists are designed to pharmacologically integrate the insulinotropic and anorexigenic effects of GLP-1, the thermogenic and lipolytic activities of glucagon, and the insulinotropic and insulin sensitizing properties of GIP. The molecular mechanism of these purposefully promiscuous ligands is not completely understood, however, recent studies in pancreatic beta cells point to the prospect of a complex signaling network that can magnify the signaling of multi-agonist ligands. The activation of this signalosome might explain the additional therapeutic benefit inherent to simultaneous cellular activation through multiple metabolic receptors. PMID- 28873390 TI - Gastrointestinal Hormones Induced the Birth of Endocrinology. AB - The physiological studies by British physiologists William Maddock Bayliss and Ernest Henry Starling, at the beginning of the last century, demonstrated the existence of specific messenger molecules (hormones) circulating in the blood that regulate the organ function and physiological mechanisms. These findings led to the concept of endocrinology. The first 2 hormones were secretin, discovered in 1902, and gastrin, discovered in 1905. Both hormones that have been described are produced in the gut. This chapter summarizes the history around the discovery of these 2 hormones, which is perceived as the birth of endocrinology. It is noteworthy that after the discovery of these 2 gastrointestinal hormones, many other hormones were detected outside the gut, and thereafter gut hormones faded from both the clinical and scientific spotlight. Only recently, the clinical importance of the gut as the body's largest endocrine organ producing a large variety of hormones has been realized. Gastrointestinal hormones are essential regulators of metabolism, growth, development and behavior and are therefore the focus of a modern pediatric endocrinologist. PMID- 28873391 TI - High prevalence of thiamine (vitamin B1) deficiency in early childhood among a nationally representative sample of Cambodian women of childbearing age and their children. AB - BACKGROUND: Thiamine deficiency is thought to be an issue in Cambodia and throughout Southeast Asia due to frequent clinical reports of infantile beriberi. However the extent of this public health issue is currently unknown due to a lack of population-representative data. Therefore we assessed the thiamine status (measured as erythrocyte thiamine diphosphate concentrations; eThDP) among a representative sample of Cambodian women of childbearing age (15-49 y) and their young children (6-69 mo). METHODOLOGY/PRINCIPLE FINDINGS: Samples for this cross sectional analysis were collected as part of a national micronutrient survey linked to the Cambodian Demographic and Health Survey (CDHS) 2014. One-sixth of households taking part in the CDHS were randomly selected and re-visited for additional blood sampling for eThDP analysis (719 women and 761 children). Thiamine status was assessed using different cut-offs from literature. Women were mean (SD) 30 (6) y, and children (46% girls) were 41 (17) mo. Women had lower mean (95% CI) eThDP of 150 nmol/L (146-153) compared to children, 174 nmol/L (171 179; P < 0.001). Using the most conservative cut-off of eThDP < 120 nmol/L, 27% of mothers and 15% of children were thiamine deficient, however prevalence rates of deficiency were as high as 78% for mothers and 58% for children using a cut off of < 180 nmol/L. Thiamine deficiency was especially prevalent among infants aged 6-12 mo: 38% were deficient using the most conservative cut-off (< 120 nmol/L). CONCLUSIONS/SIGNIFICANCE: There is a lack of consensus on thiamine status cut-offs; more research is required to set clinically meaningful cut-offs. Despite this, there is strong evidence of suboptimal thiamine status among Cambodian mothers and their children, with infants <12 mo at the highest risk. Based on eThDP from this nationally-representative sample, immediate action is required to address thiamine deficiency in Cambodia, and likely throughout Southeast Asia. PMID- 28873392 TI - An operational approach to high resolution agro-ecological zoning in West-Africa. AB - The objective of this work is to develop a simple methodology for high resolution crop suitability analysis under current and future climate, easily applicable and useful in Least Developed Countries. The approach addresses both regional planning in the context of climate change projections and pre-emptive short-term rural extension interventions based on same-year agricultural season forecasts, while implemented with off-the-shelf resources. The developed tools are applied operationally in a case-study developed in three regions of Guinea-Bissau and the obtained results, as well as the advantages and limitations of methods applied, are discussed. In this paper we show how a simple approach can easily generate information on climate vulnerability and how it can be operationally used in rural extension services. PMID- 28873393 TI - Impact of neoadjuvant chemotherapy and postoperative adjuvant chemotherapy cycles on survival of patients with advanced-stage ovarian cancer. AB - BACKGROUND: There is currently no consensus regarding the optimal number of chemotherapy cycles to be administered before and after interval debulking surgery (IDS) in patients with advanced ovarian cancer. This study aimed to evaluate the impact of the number of neoadjuvant chemotherapy (NAC) and postoperative adjuvant chemotherapy (POAC) cycles on the survival of patients with advanced ovarian cancer undergoing NAC/IDS/POAC. METHODS: We retrospectively reviewed data from 203 patients who underwent NAC/IDS/POAC at Yonsei Cancer Hospital between 2006 and 2016. All patients underwent taxane plus carboplatin chemotherapy for NAC and POAC. The patient outcomes were analyzed according to the number of NAC, POAC, and total chemotherapy (NAC+POAC) cycles. RESULTS: Patients who received fewer than 6 cycles of total chemotherapy (n = 8) had poorer progression-free survival (PFS) and overall survival (OS) than those completing at least 6 cycles (p = 0.005 and p<0.001, respectively). Among patients who completed at least 6 cycles of total chemotherapy (n = 189), Kaplan Meier analysis revealed no significant difference in either PFS or OS according to the number of NAC cycles (1-3 vs. >=4; p = 0.136 and p = 0.267, respectively). Among patients who experienced complete remission after 3 cycles of POAC (n = 98), the addition of further POAC cycles did not improve the PFS or OS (3 vs. >=4; p = 0.641 and p = 0.104, respectively). CONCLUSION: IDS after 4 cycles of NAC may be a safe and effective option when completing 6 cycles of total chemotherapy. Furthermore, the addition of more than 3 cycles of POAC does not appear to influence the survival of patients achieving completion remission after 3 cycles of POAC. PMID- 28873394 TI - Systematic review of clinical trials assessing the therapeutic efficacy of visceral leishmaniasis treatments: A first step to assess the feasibility of establishing an individual patient data sharing platform. AB - BACKGROUND: There are an estimated 200,000 to 400,000 cases of visceral leishmaniasis (VL) annually. A variety of factors are taken into account when considering the best therapeutic options to cure a patient and reduce the risk of resistance, including geographical area, malnourishment and HIV coinfection. Pooled analyses combine data from many studies to answer specific scientific questions that cannot be answered with individual studies alone. However, the heterogeneity of study design, data collection, and analysis often makes direct comparison difficult. Individual Participant Data (IPD) files can be standardised and analysed, allowing detailed analysis of this merged larger pool, but only a small fraction of systematic reviews and meta-analyses currently employ pooled analysis of IPD. We conducted a systematic literature review to identify published studies and studies reported in clinical trial registries to assess the feasibility of developing a VL data sharing platform to facilitate an IPD-based analysis of clinical trial data. Studies conducted between 1983 to 2015 that reported treatment outcome were eligible. PRINCIPAL FINDINGS: From the 2,271 documents screened, 145 published VL clinical trials were identified, with data from 26,986 patients. Methodologies varied for diagnosis and treatment outcomes, but overall the volume of data potentially available on different drugs and dose regimens identified hundreds or possibly thousands of patients per arm suitable for IPD pooled meta-analyses. CONCLUSIONS: A VL data sharing platform would provide an opportunity to maximise scientific use of available data to enable assessment of treatment efficacy, contribute to evidence-based clinical management and guide optimal prospective data collection. PMID- 28873395 TI - Comparing demersal megafaunal species diversity along the depth gradient within the South Aegean and Cretan Seas (Eastern Mediterranean). AB - Knowledge on biodiversity patterns of demersal megafaunal species in the Mediterranean and particularly in its eastern basin is still very scarce. In the present study, fine-scale diversity patterns in relation to depth were analyzed for three major megafaunal groups (fish, cephalopods and crustaceans) in three subareas of the eastern Mediterranean (Crete, Cyclades and Dodecanese islands). The analysis was based on data from the Mediterranean International Trawl Survey conducted during 2005-2014 and the relationship between depth and two different diversity measures (species richness and Shannon-Weaver) was examined using Generalized Additive Modeling (GAM) techniques. Species richness of fish decreased with depth in two of the three subareas (Cyclades, Dodecanese), while the opposite was true for crustaceans in all subareas. Cephalopods had higher species richness at intermediate depths, near the shelf break. Significant differences among subareas were found, with Crete showing a distinct species richness-depth pattern, which was more obvious for fish and cephalopods. The differences among subareas were also highlighted based on the occurrence of alien species of Indo-Pacific origin, which were more frequent in Crete. Our results suggested that the importance of depth-related factors in structuring communities was higher for cephalopods and less important for fish, and that Crete showed a distinct diversity-depth relationship, a fact that can be attributed to its specific geographical and oceanographic characteristics. These results support the current GFCM/FAO's characterization of Crete as a unique geographic subarea. The findings of the study contribute to understanding the causes of underlying diversity patterns and would assist various environmental management actions, particularly those related to the establishment of marine-protected areas. PMID- 28873396 TI - A mouse mastitis model to study the effects of the intramammary infusion of a food-grade Lactococcus lactis strain. AB - Lactococcus lactis is one of the most important microorganisms in the dairy industry and has "generally recognized as safe" (GRAS) status. L. lactis belongs to the group of lactic acid bacteria (LAB) and is encountered in a wide range of environments. Recently, the use of the intramammary infusion of a live culture of LAB has been investigated as a new antibiotic alternative for treating mastitis in dairy ruminants. Controversial results are described in literature regarding its efficacy and safety. In this study we conducted in-depth investigation of the mammary gland immune response induced by intramammary inoculum of a live culture of L. lactis LMG 7930 using the mouse mastitis model. Overnight cultures either of L. lactis (~ 107 CFU) or of the mastitis pathogens Staphylococcus chromogenes (~ 105 CFU) or S. aureus (~ 102 CFU/ml) were injected into the mouse inguinal glands. A double injection, consisting of S. chromogenes first and then L. lactis, was also investigated. Bacterial recovery from the gland and inflammatory cell infiltration were assessed. L. lactis-treated and control glands were analysed for proinflammatory cytokine production. Microbiological results showed that L. lactis was able to survive in the mammary gland 24 h post infection, as were the mastitis pathogens S. chromogenes and S. aureus. L. lactis reduced S. chromogenes survival in the glands and increased its own survival ability by coexisting with the pathogen. Histology showed that L. lactis-treated glands presented variable histological features, ranging from undamaged tissue with no inflammatory cell infiltrate to severe PMN infiltrate with focal areas of tissue damage. S. aureus-treated glands showed the most severe histological grade of inflammation despite the fact that the inoculum size was the smallest. In contrast, most S. chromogenes-treated glands showed normal structures with no infiltration or lesions. Significant increases in IL-1beta and TNF-alpha levels were also found in L. lactis-inoculated glands. The above findings seem to suggest that food-grade L. lactis at a high-inoculum dose such as an overnight culture may elicit a suppurative inflammatory response in the mammary gland, thus becoming a potential mastitis-causing pathogen. Because of the unpredictable potential of L. lactis in acting as a potential mastitis pathogen, this organism cannot be considered a safe treatment for bovine mastitis. PMID- 28873397 TI - Long-term intra-individual reproducibility of heart rate dynamics during exercise and recovery in the UK Biobank cohort. AB - BACKGROUND: The heart rate (HR) response to exercise provides useful information about the autonomic function and has prognostic value, but its reproducibility over a long period of time, a critical requirement for using it as a clinical biomarker, is undetermined. AIM: To determine the intra-individual reproducibility of HR dynamics during sub-maximum exercise and one minute recovery. METHODS: 1187 individuals from the Cardio physical fitness assessment test of the UK Biobank repeated a standard exercise stress test twice (recall time 34.2 +/- 2.8 months) and were prospectively studied. RESULTS: 821 individuals complied with inclusion criteria for reproducibility analysis, including peak workload differences between assessments <=10 W. Intra-individual correlation between HR profile during the first and the second assessment was very high and higher than inter-individual correlation (0.92+/-0.08 vs 0.87+/ 0.11, p<0.01). Intra-individual correlation of indices describing HR dynamics was: rho = 0.81 for maximum HR during exercise; rho = 0.71 for minimum HR during recovery; rho = 0.70 for HR changes during both exercise and recovery; Intra individual correlation was higher for these indices of HR dynamics than for resting HR (rho = 0.64). Bland-Altman plots demonstrated good agreement between HR indices estimated during the first and second assessment. A small but consistent bias was registered for all repeated measurements. The intra individual consistency of abnormal values was about 60-70%. CONCLUSIONS: The HR dynamics during exercise and recovery are reproducible over a period of 3 years, with moderate to strong intra-individual reproducibility of abnormal values. PMID- 28873398 TI - Combining dispersal, landscape connectivity and habitat suitability to assess climate-induced changes in the distribution of Cunningham's skink, Egernia cunninghami. AB - The ability of species to track their climate niche is dependent on their dispersal potential and the connectivity of the landscape matrix linking current and future suitable habitat. However, studies modeling climate-driven range shifts rarely address the movement of species across landscapes realistically, often assuming "unlimited" or "no" dispersal. Here, we incorporate dispersal rate and landscape connectivity with a species distribution model (Maxent) to assess the extent to which the Cunningham's skink (Egernia cunninghami) may be capable of tracking spatial shifts in suitable habitat as climate changes. Our model was projected onto four contrasting, but equally plausible, scenarios describing futures that are (relative to now) hot/wet, warm/dry, hot/with similar precipitation and warm/wet, at six time horizons with decadal intervals (2020 2070) and at two spatial resolutions: 1 km and 250 m. The size of suitable habitat was projected to decline 23-63% at 1 km and 26-64% at 250 m, by 2070. Combining Maxent output with the dispersal rate of the species and connectivity of the intervening landscape matrix showed that most current populations in regions projected to become unsuitable in the medium to long term, will be unable to shift the distance necessary to reach suitable habitat. In particular, numerous populations currently inhabiting the trailing edge of the species' range are highly unlikely to be able to disperse fast enough to track climate change. Unless these populations are capable of adaptation they are likely to be extirpated. We note, however, that the core of the species distribution remains suitable across the broad spectrum of climate scenarios considered. Our findings highlight challenges faced by philopatric species and the importance of adaptation for the persistence of peripheral populations under climate change. PMID- 28873400 TI - SisLeish: A multi-country standardized information system to monitor the status of Leishmaniasis in the Americas. AB - BACKGROUND: In the Americas, leishmaniasis is endemic in 18 countries, and from 2001 through 2015, 17 countries reported 843,931 cases of cutaneous and mucocutaneous leishmaniasis, and 12 countries reported 52,176 cases of visceral leishmaniasis. A Regional Information System (SisLeish) was created in order to provide knowledge of the distribution and tendency of this disease to analyze and monitor the leishmaniasis status. This article analyses the performance and progress of SisLeish from 2012-2015. METHODOLOGY: The performance of SisLeish was evaluated by country adhesion, data completeness and delay in entering the data, and also by the SWOT technique. Furthermore, we outlined the structure and modus operandi of the system and indicators utilized. RESULTS: In 2012, only 18% of the countries entered the data in SisLeish before the deadline, where 66.7% and 50% of the countries with autochthonous CL/ML and VL reported their cases to the system, respectively. Whereas in 2015, 59% of the countries reached the deadline, where 94.4% and 58.3% of the countries reported their CL/ML and VL data, respectively. Regarding data completeness, there was great progress for different variables since its launch, such as gender, which had an approximately 100% improvement from 2012 to 2015. The SWOT analysis of SisLeish showed 12 strengths, 11 opportunities, seven weaknesses and six threats. CONCLUSIONS: From 2012-2015 there has been an improvement in the adhesion, quality and data completeness, showing the effort of the majority of the countries to enhance their national database. The SWOT analysis demonstrated that strengths and opportunities exceed weaknesses and threats; however, it highlighted the system frailties and challenges that need to be addressed. Furthermore, it has stimulated several National Programs to advance their surveillance system. Therefore, SisLeish has become an essential tool to prioritize areas, assist in decision-making processes, and to guide surveillance and control actions. PMID- 28873399 TI - Systematic analysis of transcription start sites in avian development. AB - Cap Analysis of Gene Expression (CAGE) in combination with single-molecule sequencing technology allows precision mapping of transcription start sites (TSSs) and genome-wide capture of promoter activities in differentiated and steady state cell populations. Much less is known about whether TSS profiling can characterize diverse and non-steady state cell populations, such as the approximately 400 transitory and heterogeneous cell types that arise during ontogeny of vertebrate animals. To gain such insight, we used the chick model and performed CAGE-based TSS analysis on embryonic samples covering the full 3-week developmental period. In total, 31,863 robust TSS peaks (>1 tag per million [TPM]) were mapped to the latest chicken genome assembly, of which 34% to 46% were active in any given developmental stage. ZENBU, a web-based, open-source platform, was used for interactive data exploration. TSSs of genes critical for lineage differentiation could be precisely mapped and their activities tracked throughout development, suggesting that non-steady state and heterogeneous cell populations are amenable to CAGE-based transcriptional analysis. Our study also uncovered a large set of extremely stable housekeeping TSSs and many novel stage specific ones. We furthermore demonstrated that TSS mapping could expedite motif based promoter analysis for regulatory modules associated with stage-specific and housekeeping genes. Finally, using Brachyury as an example, we provide evidence that precise TSS mapping in combination with Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-on technology enables us, for the first time, to efficiently target endogenous avian genes for transcriptional activation. Taken together, our results represent the first report of genome-wide TSS mapping in birds and the first systematic developmental TSS analysis in any amniote species (birds and mammals). By facilitating promoter-based molecular analysis and genetic manipulation, our work also underscores the value of avian models in unravelling the complex regulatory mechanism of cell lineage specification during amniote development. PMID- 28873401 TI - Can heat waves change the trophic role of the world's most invasive crayfish? Diet shifts in Procambarus clarkii. AB - In the Mediterranean basin, the globally increasing temperatures are expected to be accompanied by longer heat waves. Commonly assumed to benefit cold-limited invasive alien species, these climatic changes may also change their feeding preferences, especially in the case of omnivorous ectotherms. We investigated heat wave effects on diet choice, growth and energy reserves in the invasive red swamp crayfish, Procambarus clarkii. In laboratory experiments, we fed juvenile and adult crayfish on animal, plant or mixed diets and exposed them to a short or a long heat wave. We then measured crayfish survival, growth, body reserves and Fulton's condition index. Diet choices of the crayfish maintained on the mixed diet were estimated using stable isotopes (13C and 15N). The results suggest a decreased efficiency of carnivorous diets at higher temperatures, as juveniles fed on the animal diet were unable to maintain high growth rates in the long heat wave; and a decreased efficiency of herbivorous diets at lower temperatures, as juveniles in the cold accumulated less body reserves when fed on the plant diet. Heat wave treatments increased the assimilation of plant material, especially in juveniles, allowing them to sustain high growth rates in the long heat wave. Contrary to our expectations, crayfish performance decreased in the long heat wave, suggesting that Mediterranean summer heat waves may have negative effects on P. clarkii and that they are unlikely to boost its populations in this region. Although uncertain, it is possible that the greater assimilation of the plant diet resulted from changes in crayfish feeding preferences, raising the hypotheses that i) heat waves may change the predominant impacts of this keystone species and ii) that by altering species' trophic niches, climate change may alter the main impacts of invasive alien species. PMID- 28873402 TI - Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status. AB - Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10-29, p = 3.83*10-26, p = 4.66*10-11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross sectional data alone and controlled experiments are required to fully characterise the causal factors. PMID- 28873403 TI - DeepPep: Deep proteome inference from peptide profiles. AB - Protein inference, the identification of the protein set that is the origin of a given peptide profile, is a fundamental challenge in proteomics. We present DeepPep, a deep-convolutional neural network framework that predicts the protein set from a proteomics mixture, given the sequence universe of possible proteins and a target peptide profile. In its core, DeepPep quantifies the change in probabilistic score of peptide-spectrum matches in the presence or absence of a specific protein, hence selecting as candidate proteins with the largest impact to the peptide profile. Application of the method across datasets argues for its competitive predictive ability (AUC of 0.80+/-0.18, AUPR of 0.84+/-0.28) in inferring proteins without need of peptide detectability on which the most competitive methods rely. We find that the convolutional neural network architecture outperforms the traditional artificial neural network architectures without convolution layers in protein inference. We expect that similar deep learning architectures that allow learning nonlinear patterns can be further extended to problems in metagenome profiling and cell type inference. The source code of DeepPep and the benchmark datasets used in this study are available at https://deeppep.github.io/DeepPep/. PMID- 28873404 TI - Fibroblast growth factor signaling is required for early somatic gonad development in zebrafish. AB - The vertebrate ovary and testis develop from a sexually indifferent gonad. During early development of the organism, primordial germ cells (the gamete lineage) and somatic gonad cells coalesce and begin to undergo growth and morphogenesis to form this bipotential gonad. Although this aspect of development is requisite for a fertile adult, little is known about the genetic regulation of early gonadogenesis in any vertebrate. Here, we provide evidence that fibroblast growth factor (Fgf) signaling is required for the early growth phase of a vertebrate bipotential gonad. Based on mutational analysis in zebrafish, we show that the Fgf ligand 24 (Fgf24) is required for proliferation, differentiation, and morphogenesis of the early somatic gonad, and as a result, most fgf24 mutants are sterile as adults. Additionally, we describe the ultrastructural elements of the early zebrafish gonad and show that distinct somatic cell populations can be identified soon after the gonad forms. Specifically, we show that fgf24 is expressed in an epithelial population of early somatic gonad cells that surrounds an inner population of mesenchymal somatic gonad cells that are in direct contact with the germ cells, and that fgf24 is required for stratification of the somatic tissue. Furthermore, based on gene expression analysis, we find that differentiation of the inner mesenchymal somatic gonad cells into functional cell types in the larval and early juvenile-stage gonad is dependent on Fgf24 signaling. Finally, we argue that the role of Fgf24 in zebrafish is functionally analogous to the role of tetrapod FGF9 in early gonad development. PMID- 28873405 TI - kWIP: The k-mer weighted inner product, a de novo estimator of genetic similarity. AB - Modern genomics techniques generate overwhelming quantities of data. Extracting population genetic variation demands computationally efficient methods to determine genetic relatedness between individuals (or "samples") in an unbiased manner, preferably de novo. Rapid estimation of genetic relatedness directly from sequencing data has the potential to overcome reference genome bias, and to verify that individuals belong to the correct genetic lineage before conclusions are drawn using mislabelled, or misidentified samples. We present the k-mer Weighted Inner Product (kWIP), an assembly-, and alignment-free estimator of genetic similarity. kWIP combines a probabilistic data structure with a novel metric, the weighted inner product (WIP), to efficiently calculate pairwise similarity between sequencing runs from their k-mer counts. It produces a distance matrix, which can then be further analysed and visualised. Our method does not require prior knowledge of the underlying genomes and applications include establishing sample identity and detecting mix-up, non-obvious genomic variation, and population structure. We show that kWIP can reconstruct the true relatedness between samples from simulated populations. By re-analysing several published datasets we show that our results are consistent with marker-based analyses. kWIP is written in C++, licensed under the GNU GPL, and is available from https://github.com/kdmurray91/kwip. PMID- 28873406 TI - Estimating short-term synaptic plasticity from pre- and postsynaptic spiking. AB - Short-term synaptic plasticity (STP) critically affects the processing of information in neuronal circuits by reversibly changing the effective strength of connections between neurons on time scales from milliseconds to a few seconds. STP is traditionally studied using intracellular recordings of postsynaptic potentials or currents evoked by presynaptic spikes. However, STP also affects the statistics of postsynaptic spikes. Here we present two model-based approaches for estimating synaptic weights and short-term plasticity from pre- and postsynaptic spike observations alone. We extend a generalized linear model (GLM) that predicts postsynaptic spiking as a function of the observed pre- and postsynaptic spikes and allow the connection strength (coupling term in the GLM) to vary as a function of time based on the history of presynaptic spikes. Our first model assumes that STP follows a Tsodyks-Markram description of vesicle depletion and recovery. In a second model, we introduce a functional description of STP where we estimate the coupling term as a biophysically unrestrained function of the presynaptic inter-spike intervals. To validate the models, we test the accuracy of STP estimation using the spiking of pre- and postsynaptic neurons with known synaptic dynamics. We first test our models using the responses of layer 2/3 pyramidal neurons to simulated presynaptic input with different types of STP, and then use simulated spike trains to examine the effects of spike-frequency adaptation, stochastic vesicle release, spike sorting errors, and common input. We find that, using only spike observations, both model based methods can accurately reconstruct the time-varying synaptic weights of presynaptic inputs for different types of STP. Our models also capture the differences in postsynaptic spike responses to presynaptic spikes following short vs long inter-spike intervals, similar to results reported for thalamocortical connections. These models may thus be useful tools for characterizing short-term plasticity from multi-electrode spike recordings in vivo. PMID- 28873407 TI - Photo-affinity labelling and biochemical analyses identify the target of trypanocidal simplified natural product analogues. AB - Current drugs to treat African sleeping sickness are inadequate and new therapies are urgently required. As part of a medicinal chemistry programme based upon the simplification of acetogenin-type ether scaffolds, we previously reported the promising trypanocidal activity of compound 1, a bis-tetrahydropyran 1,4-triazole (B-THP-T) inhibitor. This study aims to identify the protein target(s) of this class of compound in Trypanosoma brucei to understand its mode of action and aid further structural optimisation. We used compound 3, a diazirine- and alkyne containing bi-functional photo-affinity probe analogue of our lead B-THP-T, compound 1, to identify potential targets of our lead compound in the procyclic form T. brucei. Bi-functional compound 3 was UV cross-linked to its target(s) in vivo and biotin affinity or Cy5.5 reporter tags were subsequently appended by Cu(II)-catalysed azide-alkyne cycloaddition. The biotinylated protein adducts were isolated with streptavidin affinity beads and subsequent LC-MSMS identified the FoF1-ATP synthase (mitochondrial complex V) as a potential target. This target identification was confirmed using various different approaches. We show that (i) compound 1 decreases cellular ATP levels (ii) by inhibiting oxidative phosphorylation (iii) at the FoF1-ATP synthase. Furthermore, the use of GFP-PTP tagged subunits of the FoF1-ATP synthase, shows that our compounds bind specifically to both the alpha- and beta-subunits of the ATP synthase. The FoF1 ATP synthase is a target of our simplified acetogenin-type analogues. This mitochondrial complex is essential in both procyclic and bloodstream forms of T. brucei and its identification as our target will enable further inhibitor optimisation towards future drug discovery. Furthermore, the photo-affinity labeling technique described here can be readily applied to other drugs of unknown targets to identify their modes of action and facilitate more broadly therapeutic drug design in any pathogen or disease model. PMID- 28873408 TI - "We need people to collaborate together against this disease": A qualitative exploration of perceptions of dengue fever control in caregivers' of children under 5 years, in the Peruvian Amazon. AB - BACKGROUND: Dengue Fever presents a significant and growing burden of disease to endemic countries, where children are at particular risk. Worldwide, no effective anti-viral treatment has been identified, thus vector control is key for disease prevention, particularly in Peru where no vaccine is currently available. This qualitative study aimed to explore the perceptions of dengue control in caregivers' of children under 5 years in Peru, to help direct future mosquito control programmes and strategy. METHODS: Eighteen semi-structured interviews were conducted in one health centre in Iquitos, Peru. Interviews were audio recorded, transcribed and translated by an independent translator. Data were analysed using an inductive thematic approach. FINDINGS: Three core analytic themes were interpreted: (1) awareness of dengue and its control, (2) perceived susceptibility of children, rural riverside communities and city inhabitants, and (3) perceived responsibility of vector control. Participants were aware of dengue symptoms, transmission and larvae eradication strategies. Misconceptions about the day-time biting behaviour of the Aedes aegypti mosquito and confusion with other mosquito-borne diseases influenced preventative practice. Community-wide lack of cooperation was recognised as a key barrier. This was strengthened by attitudes that the government or health centre were responsible for dengue control and a belief that the disease cannot be prevented through individual actions. Participants felt powerless to prevent dengue due to assumed inevitability of infection and lack of faith in preventative practices. However, children and rural communities were believed to be most vulnerable. CONCLUSIONS: Perceptions of dengue control amongst caregivers to under 5's were important in shaping their likelihood to participate in preventative practices. There is a need to address the perceived lack of community cooperation through strategies creating a sense of ownership of community control and enhancing social responsibility. The belief that dengue cannot be prevented by individual actions in a community also warrants attention. Specific misconceptions about dengue should be addressed through the community health worker system and further research directed to identify the needs of certain vulnerable groups. PMID- 28873409 TI - Fine scale mapping of genomic introgressions within the Drosophila yakuba clade. AB - The process of speciation involves populations diverging over time until they are genetically and reproductively isolated. Hybridization between nascent species was long thought to directly oppose speciation. However, the amount of interspecific genetic exchange (introgression) mediated by hybridization remains largely unknown, although recent progress in genome sequencing has made measuring introgression more tractable. A natural place to look for individuals with admixed ancestry (indicative of introgression) is in regions where species co occur. In west Africa, D. santomea and D. yakuba hybridize on the island of Sao Tome, while D. yakuba and D. teissieri hybridize on the nearby island of Bioko. In this report, we quantify the genomic extent of introgression between the three species of the Drosophila yakuba clade (D. yakuba, D. santomea), D. teissieri). We sequenced the genomes of 86 individuals from all three species. We also developed and applied a new statistical framework, using a hidden Markov approach, to identify introgression. We found that introgression has occurred between both species pairs but most introgressed segments are small (on the order of a few kilobases). After ruling out the retention of ancestral polymorphism as an explanation for these similar regions, we find that the sizes of introgressed haplotypes indicate that genetic exchange is not recent (>1,000 generations ago). We additionally show that in both cases, introgression was rarer on X chromosomes than on autosomes which is consistent with sex chromosomes playing a large role in reproductive isolation. Even though the two species pairs have stable contemporary hybrid zones, providing the opportunity for ongoing gene flow, our results indicate that genetic exchange between these species is currently rare. PMID- 28873410 TI - N-terminally truncated POM121C inhibits HIV-1 replication. AB - Recent studies have identified host cell factors that regulate early stages of HIV-1 infection including viral cDNA synthesis and orientation of the HIV-1 capsid (CA) core toward the nuclear envelope, but it remains unclear how viral DNA is imported through the nuclear pore and guided to the host chromosomal DNA. Here, we demonstrate that N-terminally truncated POM121C, a component of the nuclear pore complex, blocks HIV-1 infection. This truncated protein is predominantly localized in the cytoplasm, does not bind to CA, does not affect viral cDNA synthesis, reduces the formation of 2-LTR and diminished the amount of integrated proviral DNA. Studies with an HIV-1-murine leukemia virus (MLV) chimeric virus carrying the MLV-derived Gag revealed that Gag is a determinant of this inhibition. Intriguingly, mutational studies have revealed that the blockade by N-terminally-truncated POM121C is closely linked to its binding to importin beta/karyopherin subunit beta 1 (KPNB1). These results indicate that N-terminally truncated POM121C inhibits HIV-1 infection after completion of reverse transcription and before integration, and suggest an important role for KPNB1 in HIV-1 replication. PMID- 28873411 TI - Preoperative asymptomatic leukocytosis and postoperative outcome in cardiac surgery patients. AB - BACKGROUND: Despite showing a prognostic value in general surgical patients, preoperative asymptomatic elevated white blood cell (WBC) count is not considered a risk factor for cardiac surgery. Whereas there is sporadic evidence of its value as a preoperative risk marker, it has not been looked at methodically as a specific index of outcome during cardiac surgery. Using a national database we sought to determine the relationship between preoperative WBC count and postoperative outcome in cardiac surgical patients. METHODS: Cardiac surgeries were extracted from the 2007-2013 American College of Surgeons National Surgical Quality Improvement Program database. Leukocytosis was defined by a preoperative WBC count greater than 11,000 cells/MUL. A univariate analysis compared the incidence of adverse outcomes for patients with and without leukocytosis. A multivariate logistic regression model was constructed in order to test whether leukocytosis was an independent predictor of morbidity and mortality. RESULTS: Out of a total of 10,979 cardiac surgery patients 863 (7.8%) had preoperative leukocytosis. On univariate analysis, patients with leukocytosis experienced greater incidences of 30-day mortality, wound complications, and medical complications. Wound complications included surgical site infection as well as wound dehiscence. The medical complications included all other non-surgical causes of increased morbidity and infection leading to urinary tract infection, pneumonia, ventilator dependence, sepsis and septic shock. After stepwise model adjustment, leukocytosis was a strong predictor of medical complications (OR 1.22, 95% CI: 1.09-1.36, p = 0.002) with c-statistic of 0.667. However, after stepwise model adjustment leukocytosis was not a significant predictor of 30-day mortality and wound complications. CONCLUSION: Preoperative leukocytosis is associated with adverse postoperative outcome after cardiac surgery and is an independent predictor of infection-related postoperative complications. PMID- 28873412 TI - Temporal phylogeography of Yersinia pestis in Madagascar: Insights into the long term maintenance of plague. AB - BACKGROUND: Yersinia pestis appears to be maintained in multiple, geographically separate, and phylogenetically distinct subpopulations within the highlands of Madagascar. However, the dynamics of these locally differentiated subpopulations through time are mostly unknown. To address that gap and further inform our understanding of plague epidemiology, we investigated the phylogeography of Y. pestis in Madagascar over an 18 year period. METHODOLOGY/PRINCIPAL FINDINGS: We generated whole genome sequences for 31 strains and discovered new SNPs that we used in conjunction with previously identified SNPs and variable-number tandem repeats (VNTRs) to genotype 773 Malagasy Y. pestis samples from 1995 to 2012. We mapped the locations where samples were obtained on a fine geographic scale to examine phylogeographic patterns through time. We identified 18 geographically separate and phylogenetically distinct subpopulations that display spatial and temporal stability, persisting in the same locations over a period of almost two decades. We found that geographic areas with higher levels of topographical relief are associated with greater levels of phylogenetic diversity and that sampling frequency can vary considerably among subpopulations and from year to year. We also found evidence of various Y. pestis dispersal events, including over long distances, but no evidence that any dispersal events resulted in successful establishment of a transferred genotype in a new location during the examined time period. CONCLUSIONS/SIGNIFICANCE: Our analysis suggests that persistent endemic cycles of Y. pestis transmission within local areas are responsible for the long term maintenance of plague in Madagascar, rather than repeated episodes of wide scale epidemic spread. Landscape likely plays a role in maintaining Y. pestis subpopulations in Madagascar, with increased topographical relief associated with increased levels of localized differentiation. Local ecological factors likely affect the dynamics of individual subpopulations and the associated likelihood of observing human plague cases in a given year in a particular location. PMID- 28873413 TI - Growth standard charts for monitoring bodyweight in dogs of different sizes. AB - Limited information is available on what constitutes optimal growth in dogs. The primary aim of this study was to develop evidence-based growth standards for dogs, using retrospective analysis of bodyweight and age data from >6 million young dogs attending a large corporate network of primary care veterinary hospitals across the USA. Electronic medical records were used to generate bodyweight data from immature client-owned dogs, that were healthy and had remained in ideal body condition throughout the first 3 years of life. Growth centile curves were constructed using Generalised Additive Models for Location, Shape and Scale. Curves were displayed graphically as centile charts covering the age range 12 weeks to 2 years. Over 100 growth charts were modelled, specific to different combinations of breed, sex and neuter status. Neutering before 37 weeks was associated with a slight upward shift in growth trajectory, whilst neutering after 37 weeks was associated with a slight downward shift in growth trajectory. However, these shifts were small in comparison to inter-individual variability amongst dogs, suggesting that separate curves for neutered dogs were not needed. Five bodyweight categories were created to cover breeds up to 40kg, using both visual assessment and hierarchical cluster analysis of breed-specific growth curves. For 20/24 of the individual breed centile curves, agreement with curves for the corresponding bodyweight categories was good. For the remaining 4 breed curves, occasional deviation across centile lines was observed, but overall agreement was acceptable. This suggested that growth could be described using size categories rather than requiring curves for specific breeds. In the current study, a series of evidence-based growth standards have been developed to facilitate charting of bodyweight in healthy dogs. Additional studies are required to validate these standards and create a clinical tool for growth monitoring in pet dogs. PMID- 28873415 TI - Proliferative endocrine effects of adipose tissue from obese animals on MCF7 cells are ameliorated by resveratrol supplementation. AB - Obesity is clearly associated with an increased risk of breast cancer in postmenopausal women. The purpose was to determine if obesity alters the adipocyte adipokine secretion profile, thereby altering the adipose-dependent paracrine/endocrine growth microenvironment surrounding breast cancer cells (MCF7). Additionally, we determined whether resveratrol (RSV) supplementation can counteract any obesity-dependent effects on breast cancer tumor growth microenvironment. Obese ZDF rats received standard chow diet or diet supplemented with 200 mg/kg body weight RSV. Chow-fed Zucker rats served as lean controls. After 6 weeks, conditioned media (CM) prepared from inguinal subcutaneous adipose tissue (scAT) was added to MCF7 cells for 24 hrs. Experiments were also conducted using purified isolated adipocytes to determine whether any endocrine effects could be attributed specifically to the adipocyte component of adipose tissue. scAT from ZDF rats promoted cell cycle entry in MCF7 cells which was counteracted by RSV supplementation. RSV-CM had a higher ratio of ADIPO:LEP compared to ZDF CM. This altered composition of the CM led to increased levels of pAMPKT172, p27, p27T198 and AdipoR1 while decreasing pAktT308 in MCF7 cells grown in RSV-CM compared to ZDF-CM. RSV-CM increased number of cells in G0/G1 and decreased cells in S-phase compared to ZDF-CM. Co-culture experiments revealed that these obesity dependent effects were driven by the adipocyte component of the adipose tissue. Obesity decreased the ratio of adiponectin:leptin secreted by adipocytes, altering the adipose-dependent growth microenvironment resulting in increased breast cancer cell proliferation. Supplementation with RSV reversed these adipose dependent effects suggesting a potential for RSV as a nutritional supplementation to improve breast cancer treatment in obese patients. PMID- 28873414 TI - Influence of transient spatial attention on the P3 component and perception of painful and non-painful electric stimuli in crossed and uncrossed hands positions. AB - Recent reports show that focusing attention on the location where pain is expected can enhance its perception. Moreover, crossing the hands over the body's midline is known to impair the ability to localise stimuli and decrease tactile and pain sensations in healthy participants. The present study investigated the role of transient spatial attention on the perception of painful and non-painful electrical stimuli in conditions in which a match or a mismatch was induced between skin-based and external frames of reference (uncrossed and crossed hands positions, respectively). We measured the subjective experience (Numerical Rating Scale scores) and the electrophysiological response elicited by brief electric stimuli by analysing the P3 component of Event-Related Potentials (ERPs). Twenty two participants underwent eight painful and eight non-painful stimulus blocks. The electrical stimuli were applied to either the left or the right hand, held in either a crossed or uncrossed position. Each stimulus was preceded by a direction cue (leftward or rightward arrow). In 80% of the trials, the arrow correctly pointed to the spatial regions where the stimulus would appear (congruent cueing). Our results indicated that congruent cues resulted in increased pain NRS scores compared to incongruent ones. For non-painful stimuli such an effect was observed only in the uncrossed hands position. For both non-painful and painful stimuli the P3 peak amplitudes were higher and occurred later for incongruently cued stimuli compared to congruent ones. However, we found that crossing the hands substantially reduced the cueing effect of the P3 peak amplitudes elicited by painful stimuli. Taken together, our results showed a strong influence of transient attention manipulations on the NRS ratings and on the brain activity. Our results also suggest that hand position may modulate the strength of the cueing effect, although differences between painful and non-painful stimuli exist. PMID- 28873416 TI - Cost-effectiveness analysis of use of a polypill versus usual care or best practice for primary prevention in people at high risk of cardiovascular disease. AB - BACKGROUND: Clinical trials suggest that use of fixed-dose combination therapy ('polypills') can improve adherence to medication and control of risk factors of people at high risk of cardiovascular disease (CVD) compared to usual care, but cost-effectiveness is unknown. OBJECTIVE: To determine whether a polypill is cost effective compared to usual care and optimal guideline-recommended treatment for primary prevention in people already on statins and/or blood pressure lowering therapy. METHODS: A Markov model was developed to perform a cost-utility analysis with a one year time cycle and a 10 year time horizon to compare the polypill with usual care and optimal implementation of NICE Guidelines, using patient level data from a retrospective cross-sectional study. The model was run for ten age (40 years+) and gender-specific sub-groups on treatment for raised CVD risk with no history of CVD. Published sources were used to estimate impact of different treatment strategies on risk of CVD events. RESULTS: A polypill strategy was potentially cost-effective compared to other strategies for most sub groups ranging from dominance to up to L18,811 per QALY depending on patient sub group. Optimal implementation of guidelines was most cost-effective for women aged 40-49 and men aged 75+. Results were sensitive to polypill cost, and if the annual cost was less than L150, this approach was cost-effective compared to the other strategies. CONCLUSIONS: For most people already on treatment to modify CVD risk, a polypill strategy may be cost-effective compared with optimising treatment as per guidelines or their current care, as long as the polypill cost is sufficiently low. PMID- 28873417 TI - Unwanted effects: Is there a negative side of meditation? A multicentre survey. AB - OBJECTIVES: Despite the long-term use and evidence-based efficacy of meditation and mindfulness-based interventions, there is still a lack of data about the possible unwanted effects (UEs) of these practices. The aim of this study was to evaluate the occurrence of UEs among meditation practitioners, considering moderating factors such as the type, frequency, and lifetime duration of the meditation practices. METHODS: An online survey was developed and disseminated through several websites, such as Spanish-, English- and Portuguese-language scientific research portals related to mindfulness and meditation. After excluding people who did not answer the survey correctly or completely and those who had less than two months of meditation experience, a total of 342 people participated in the study. However, only 87 reported information about UEs. RESULTS: The majority of the practitioners were women from Spain who were married and had a University education level. Practices were more frequently informal, performed on a daily basis, and followed by focused attention (FA). Among the participants, 25.4% reported UEs, showing that severity varies considerably. The information requested indicated that most of the UEs were transitory and did not lead to discontinuing meditation practice or the need for medical assistance. They were more frequently reported in relation to individual practice, during focused attention meditation, and when practising for more than 20 minutes and alone. The practice of body awareness was associated with UEs to a lesser extent, whereas focused attention was associated more with UEs. CONCLUSIONS: This is the first large-scale, multi-cultural study on the UEs of meditation. Despite its limitations, this study suggests that UEs are prevalent and transitory and should be further studied. We recommend the use of standardized questionnaires to assess the UEs of meditation practices. PMID- 28873418 TI - Empirical research on Kano's model and customer satisfaction. AB - Products are now developed based on what customers desire, and thus attractive quality creation has become crucial. In studies on customer satisfaction, methods for analyzing quality attributes and enhancing customer satisfaction have been proposed to facilitate product development. Although substantial studies have performed to assess the impact of the attributes on customer satisfaction, little research has been conducted that quantitatively calculate the odds of customer satisfaction for the Kano classification, fitting a nonlinear relationship between attribute-level performance and customer satisfaction. In the present study, the odds of customer satisfaction were determined to identify the classification of quality attributes, and took customer psychology into account to suggest how decision-makers should prioritize the allocation of resources. A novel method for quantitatively assessing quality attributes was proposed to determine classification criteria and fit the nonlinear relationship between quality attributes and customer satisfaction. Subsequently, a case study was conducted on bicycle user satisfaction to verify the novel method. The concept of customer satisfaction odds was integrated with the value function from prospect theory to understand quality attributes. The results of this study can serve as a reference for product designers to create attractive quality attributes in their products and thus enhance customer satisfaction. PMID- 28873419 TI - Gender and autistic traits modulate implicit motor synchrony. AB - Interpersonal motor synchrony during walking or dancing is universally observed across cultures, and this joint movement was modulated by physical and social parameters. However, human interactions are greatly shaped by our unique traits, and self-related factors are surprisingly little studied in the context of interpersonal motor synchrony. In this study, we investigated two such factors known to be highly associated with motor coordination: gender and autistic traits. We employed a real-world task extending our understanding beyond laboratory tasks. Participants of the same gender were paired up to walk and chat in a natural environment. A cover story was introduced so that participants would not know their walking steps were being recorded and instead believed that their location was being tracked by a global positioning system (GPS), so they would ignore the motor recording. We found that the female pairs' steps were more synchronized than those of the males, and higher autistic tendencies (measured by the autism-spectrum quotient) attenuated synchronous steps. Those who synchronized better had higher impression rating increase for their walking partners (measured by interpersonal judgement scale) than those who synchronized less well. Our results indicated that the participants' joint movements were shaped by predisposed traits and might share similar mechanism with social functions such as empathy. PMID- 28873420 TI - Discovery of a new subgroup of sulfur dioxygenases and characterization of sulfur dioxygenases in the sulfur metabolic network of Acidithiobacillus caldus. AB - Acidithiobacillus caldus is a chemolithoautotrophic sulfur-oxidizing bacterium that is widely used for bioleaching processes. Acidithiobacillus spp. are suggested to contain sulfur dioxygenases (SDOs) that facilitate sulfur oxidation. In this study, two putative sdo genes (A5904_0421 and A5904_1112) were detected in the genome of A. caldus MTH-04 by BLASTP searching with the previously identified SDO (A5904_0790). We cloned and expressed these genes, and detected the SDO activity of recombinant protein A5904_0421 by a GSH-dependent in vitro assay. Phylogenetic analysis indicated that A5904_0421and its homologous SDOs, mainly found in autotrophic bacteria, were distantly related to known SDOs and were categorized as a new subgroup of SDOs. The potential functions of genes A5904_0421 (termed sdo1) and A5904_0790 (termed sdo2) were investigated by generating three knockout mutants (Deltasdo1, Deltasdo2 and Deltasdo1&2), two sdo overexpression strains (OE-sdo1 and OE-sdo2) and two sdo complemented strains (Deltasdo1/sdo1' and Deltasdo2/sdo2') of A. caldus MTH-04. Deletion or overexpression of the sdo genes did not obviously affect growth of the bacteria on S0, indicating that the SDOs did not play an essential role in the oxidation of extracellular elemental sulfur in A. caldus. The deletion of sdo1 resulted in complete inhibition of growth on tetrathionate, slight inhibition of growth on thiosulfate and increased GSH-dependent sulfur oxidation activity on S0. Transcriptional analysis revealed a strong correlation between sdo1 and the tetrathionate intermediate pathway. The deletion of sdo2 promoted bacterial growth on tetrathionate and thiosulfate, and overexpression of sdo2 altered gene expression patterns of sulfide:quinone oxidoreductase and rhodanese. Taken together, the results suggest that sdo1 is essential for the survival of A. caldus when tetrathionate is used as the sole energy resource, and sdo2 may also play a role in sulfur metabolism. PMID- 28873421 TI - Russian isolates enlarge the known geographic diversity of Francisella tularensis subsp. mediasiatica. AB - Francisella tularensis, a small Gram-negative bacterium, is capable of infecting a wide range of animals, including humans, and causes a plague-like disease called tularemia-a highly contagious disease with a high mortality rate. Because of these characteristics, F. tularensis is considered a potential agent of biological terrorism. Currently, F. tularensis is divided into four subspecies, which differ in their virulence and geographic distribution. Two of them, subsp. tularensis (primarily found in North America) and subsp. holarctica (widespread across the Northern Hemisphere), are responsible for tularemia in humans. Subsp. novicida is almost avirulent in humans. The fourth subspecies, subsp. mediasiatica, is the least studied because of its limited distribution and impact in human health. It is found only in sparsely populated regions of Central Asia. In this report, we describe the first focus of naturally circulating F. tularensis subsp. mediasiatica in Russia. We isolated and characterized 18 strains of this subspecies in the Altai region. All strains were highly virulent in mice. The virulence of subsp. mediasiatica in a vaccinated mouse model is intermediate between that of subsp. tularensis and subsp. holarctica. Based on a multiple-locus variable number tandem repeat analysis (MLVA), we show that the Altaic population of F. tularensis subsp. mediasiatica is genetically distinct from the classical Central Asian population, and probably is endemic to Southern Siberia. We propose to subdivide the mediasiatica subspecies into three phylogeographic groups, M.I, M.II and M.III. PMID- 28873422 TI - Evaluating multiple causes of persistent low microwave backscatter from Amazon forests after the 2005 drought. AB - Amazonia has experienced large-scale regional droughts that affect forest productivity and biomass stocks. Space-borne remote sensing provides basin-wide data on impacts of meteorological anomalies, an important complement to relatively limited ground observations across the Amazon's vast and remote humid tropical forests. Morning overpass QuikScat Ku-band microwave backscatter from the forest canopy was anomalously low during the 2005 drought, relative to the full instrument record of 1999-2009, and low morning backscatter persisted for 2006-2009, after which the instrument failed. The persistent low backscatter has been suggested to be indicative of increased forest vulnerability to future drought. To better ascribe the cause of the low post-drought backscatter, we analyzed multiyear, gridded remote sensing data sets of precipitation, land surface temperature, forest cover and forest cover loss, and microwave backscatter over the 2005 drought region in the southwestern Amazon Basin (4 degrees -12 degrees S, 66 degrees -76 degrees W) and in adjacent 8 degrees x10 degrees regions to the north and east. We found moderate to weak correlations with the spatial distribution of persistent low backscatter for variables related to three groups of forest impacts: the 2005 drought itself, loss of forest cover, and warmer and drier dry seasons in the post-drought vs. the pre-drought years. However, these variables explained only about one quarter of the variability in depressed backscatter across the southwestern drought region. Our findings indicate that drought impact is a complex phenomenon and that better understanding can only come from more extensive ground data and/or analysis of frequent, spatially-comprehensive, high-resolution data or imagery before and after droughts. PMID- 28873423 TI - An ImmunoSignature test distinguishes Trypanosoma cruzi, hepatitis B, hepatitis C and West Nile virus seropositivity among asymptomatic blood donors. AB - BACKGROUND: The complexity of the eukaryotic parasite Trypanosoma (T.) cruzi manifests in its highly dynamic genome, multi-host life cycle, progressive morphologies and immune-evasion mechanisms. Accurate determination of infection or Chagas' disease activity and prognosis continues to challenge researchers. We hypothesized that a diagnostic platform with higher ligand complexity than previously employed may hold value. METHODOLOGY: We applied the ImmunoSignature Technology (IST) for the detection of T. cruzi-specific antibodies among healthy blood donors. IST is based on capturing the information in an individual's antibody repertoire by exposing their peripheral blood to a library of >100,000 position-addressable, chemically-diverse peptides. PRINCIPAL FINDINGS: Initially, samples from two Chagas cohorts declared positive or negative by bank testing were studied. With the first cohort, library-peptides displaying differential binding signals between T. cruzi sero-states were used to train an algorithm. A classifier was fixed and tested against the training-independent second cohort to determine assay performance. Next, samples from a mixed cohort of donors declared positive for Chagas, hepatitis B, hepatitis C or West Nile virus were assayed on the same library. Signals were used to train a single algorithm that distinguished all four disease states. As a binary test, the accuracy of predicting T. cruzi seropositivity by IST was similar, perhaps modestly reduced, relative to conventional ELISAs. However, the results indicate that information beyond determination of seropositivity may have been captured. These include the identification of cohort subclasses, the simultaneous detection and discerning of other diseases, and the discovery of putative new antigens. CONCLUSIONS & SIGNIFICANCE: The central outcome of this study established IST as a reliable approach for specific determination of T. cruzi seropositivity versus disease free individuals or those with other diseases. Its potential contribution for monitoring and controlling Chagas lies in IST's delivery of higher resolution immune-state readouts than obtained with currently-used technologies. Despite the complexity of the ligand presentation and large quantitative readouts, performing an IST test is simple, scalable and reproducible. PMID- 28873425 TI - Control of Phlebotomus argentipes (Diptera: Psychodidae) sand fly in Bangladesh: A cluster randomized controlled trial. AB - BACKGROUND: A number of studies on visceral leishmaniasis (VL) vector control have been conducted during the past decade, sometimes came to very different conclusion. The present study on a large sample investigated different options which are partially unexplored including: (1) indoor residual spraying (IRS) with alpha cypermethrin 5WP; (2) long lasting insecticide impregnated bed-net (LLIN); (3) impregnation of local bed-nets with slow release insecticide K-O TAB 1-2-3 (KOTAB); (4) insecticide spraying in potential breeding sites outside of house using chlorpyrifos 20EC (OUT) and different combinations of the above. METHODS: The study was a cluster randomized controlled trial where 3089 houses from 11 villages were divided into 10 sections, each section with 6 clusters and each cluster having approximately 50 houses. Based on vector density (males plus females) during baseline survey, the 60 clusters were categorized into 3 groups: (1) high, (2) medium and (3) low. Each group had 20 clusters. From these three groups, 6 clusters (about 300 households) were randomly selected for each type of intervention and control arms. Vector density was measured before and 2, 4, 5, 7, 11, 14, 15, 18 and 22 months after intervention using CDC light traps. The impact of interventions was measured by using the difference-in-differences regression model. RESULTS: A total of 17,434 sand flies were collected at baseline and during the surveys conducted over 9 months following the baseline measurements. At baseline, the average P. argentipes density per household was 10.6 (SD = 11.5) in the control arm and 7.3 (SD = 8.46) to 11.5 (SD = 20.2) in intervention arms. The intervention results presented as the range of percent reductions of sand flies (males plus females) and rate ratios in 9 measurements over 22 months. Among single type interventions, the effect of IRS with 2 rounds of spraying (applied by the research team) ranged from 13% to 75% reduction of P. argentipes density compared to the control arm (rate-ratio [RR] ranged from 0.25 to 0.87). LLINs caused a vector reduction of 9% to 78% (RR, 0.22 to 0.91). KOTAB reduced vectors by 4% to 73% (RR, 0.27 to 0.96). The combination of LLIN and OUT led to a vector reduction of 26% to 86% (RR, 0.14 to 0.74). The reduction for the combination of IRS and OUT was 8% to 88% (RR, 0.12 to 0.92). IRS and LLIN combined resulted in a vector reduction of 13% to 85% (RR, 0.15 to 0.77). The IRS and KOTAB combination reduced vector densities by 16% to 86% (RR, 0.14 to 0.84). Some intermediate measurements for KOTAB alone and for IRS plus LLIN; and IRS plus KOTAB were not statistically significant. The bioassays on sprayed surfaces or netting materials showed favourable results (>80% mortality) for 22 months (IRS tested for 12 months). In the KOTAB, a gradual decline was observed after 6 months. CONCLUSIONS: LLIN and OUT was the best combination to reduce VL vector densities for 22 months or longer. Operationally, this is much easier to apply than IRS. A cost analysis of the preferred tools will follow. The relationship between vector density (males plus females) and leishmaniasis incidence should be investigated, and this will require estimates of the Entomological Inoculation Rate. PMID- 28873426 TI - DNA in a bottle-Rapid metabarcoding survey for early alerts of invasive species in ports. AB - Biota monitoring in ports is increasingly needed for biosecurity reasons and safeguarding marine biodiversity from biological invasion. Present and future international biosecurity directives can be accomplished only if the biota acquired by maritime traffic in ports is controlled. Methodologies for biota inventory are diverse and now rely principally on extensive and labor-intensive sampling along with taxonomic identification by experts. In this study, we employed an extremely simplified environmental DNA (eDNA) sampling methodology from only three 1-L bottles of water per port, followed by metabarcoding (high throughput sequencing and DNA-based species identification) using 18S rDNA and Cytochrome oxidase I as genetic barcodes. Eight Bay of Biscay ports with available inventory of fouling invertebrates were employed as a case study. Despite minimal sampling efforts, three invasive invertebrates were detected: the barnacle Austrominius modestus, the tubeworm Ficopomatus enigmaticus and the polychaete Polydora triglanda. The same species have been previously found from visual and DNA barcoding (genetic identification of individuals) surveys in the same ports. The current costs of visual surveys, conventional DNA barcoding and this simplified metabarcoding protocol were compared. The results encourage the use of metabarcoding for early biosecurity alerts. PMID- 28873424 TI - Dual specificity phosphatase 6 deficiency is associated with impaired systemic glucose tolerance and reversible weight retardation in mice. AB - Here, we aimed to investigate the potential role of DUSP6, a dual specificity phosphatase, that specifically inactivates extracellular signal-regulated kinase (ERK), for the regulation of body weight and glucose homeostasis. We further assessed whether metabolic challenges affect Dusp6 expression in selected brain areas or white adipose tissue. Hypothalamic Dusp6 mRNA levels remained unchanged in chow-fed lean vs. high fat diet (HFD) fed obese C57Bl/6J mice, and in C57Bl/6J mice undergoing prolonged fasting or refeeding with fat free diet (FFD) or HFD. Similarly, Dusp6 expression levels were unchanged in selected brain regions of Lepob mice treated with 1 mg/kg of leptin for 6 days, compared to pair-fed or saline-treated Lepob controls. Dusp6 expression levels remained unaltered in vitro in primary adipocytes undergoing differentiation, but were increased in eWAT of HFD-fed obese C57Bl/6J mice, compared to chow-fed lean controls. Global chow-fed DUSP6 KO mice displayed reduced body weight and lean mass and slightly increased fat mass at a young age, which is indicative for early-age weight retardation. Subsequent exposure to HFD led to a significant increase in lean mass and body weight in DUSP6 deficient mice, compared to WT controls. Nevertheless, after 26 weeks of high-fat diet exposure, we observed comparable body weight, fat and lean mass in DUSP6 WT and KO mice, suggesting overall normal susceptibility to develop obesity. In line with the increased weight gain to compensate for early-age weight retardation, HFD-fed DUSP6 KO displayed increased expression levels of anabolic genes involved in lipid and cholesterol metabolism in the epididymal white adipose tissue (eWAT), compared to WT controls. Glucose tolerance was perturbed in both chow-fed lean or HFD-fed obese DUSP6 KO, compared to their respective WT controls. Overall, our data indicate that DUSP6 deficiency has limited impact on the regulation of energy metabolism, but impairs systemic glucose tolerance. Our data are in conflict to earlier reports that propose protection from diet-induced obesity and glucose intolerance in DUSP6 deficient mice. Reasons for the discrepancies remain elusive, but may entail differential genetic backgrounds, environmental factors such as the type and source of HFD, or alterations in the gut microbiome between facilities. PMID- 28873427 TI - Computational assessment of the functional role of sinoatrial node exit pathways in the human heart. AB - AIM: The human right atrium and sinoatrial node (SAN) anatomy is complex. Optical mapping experiments suggest that the SAN is functionally insulated from atrial tissue except at discrete SAN-atrial electrical junctions called SAN exit pathways, SEPs. Additionally, histological imaging suggests the presence of a secondary pacemaker close to the SAN. We hypothesise that a) an insulating border SEP anatomical configuration is related to SAN arrhythmia; and b) a secondary pacemaker, the paranodal area, is an alternate pacemaker but accentuates tachycardia. A 3D electro-anatomical computational model was used to test these hypotheses. METHODS: A detailed 3D human SAN electro-anatomical mathematical model was developed based on our previous anatomical reconstruction. Electrical activity was simulated using tissue specific variants of the Fenton-Karma action potential equations. Simulation experiments were designed to deploy this complex electro-anatomical system to assess the roles of border-SEPs and paranodal area by mimicking experimentally observed SAN arrhythmia. Robust and accurate numerical algorithms were implemented for solving the mono domain reaction diffusion equation implicitly, calculating 3D filament traces, and computing dominant frequency among other quantitative measurements. RESULTS: A centre to periphery gradient of increasing diffusion was sufficient to permit initiation of pacemaking at the centre of the 3D SAN. Re-entry within the SAN, micro re-entry, was possible by imposing significant SAN fibrosis in the presence of the insulating border. SEPs promoted the micro re-entry to generate more complex SAN atrial tachycardia. Simulation of macro re-entry, i.e. re-entry around the SAN, was possible by inclusion of atrial fibrosis in the presence of the insulating border. The border shielded the SAN from atrial tachycardia. However, SAN micro structure intercellular gap junctional coupling and the paranodal area contributed to prolonged atrial fibrillation. Finally, the micro-structure was found to be sufficient to explain shifts of leading pacemaker site location. CONCLUSIONS: The simulations establish a relationship between anatomy and SAN electrical function. Microstructure, in the form of intercellular gap junction coupling, was found to regulate SAN function and arrhythmia. PMID- 28873428 TI - Evaluation of robenidine analog NCL195 as a novel broad-spectrum antibacterial agent. AB - The spread of multidrug resistance among bacterial pathogens poses a serious threat to public health worldwide. Recent approaches towards combating antimicrobial resistance include repurposing old compounds with known safety and development pathways as new antibacterial classes with novel mechanisms of action. Here we show that an analog of the anticoccidial drug robenidine (4,6 bis(2-((E)-4-methylbenzylidene)hydrazinyl)pyrimidin-2-amine; NCL195) displays potent bactericidal activity against Streptococcus pneumoniae and Staphylococcus aureus by disrupting the cell membrane potential. NCL195 was less cytotoxic to mammalian cell lines than the parent compound, showed low metabolic degradation rates by human and mouse liver microsomes, and exhibited high plasma concentration and low plasma clearance rates in mice. NCL195 was bactericidal against Acinetobacter spp and Neisseria meningitidis and also demonstrated potent activity against A. baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. in the presence of sub-inhibitory concentrations of ethylenediaminetetraacetic acid (EDTA) and polymyxin B. These findings demonstrate that NCL195 represents a new chemical lead for further medicinal chemistry and pharmaceutical development to enhance potency, solubility and selectivity against serious bacterial pathogens. PMID- 28873430 TI - The impact of rainfall on the temporal and spatial distribution of taxi passengers. AB - This paper focuses on the impact of rainfall on the temporal and spatial distribution of taxi passengers. The main objective is to provide guidance for taxi scheduling on rainy days. To this end, we take the occupied and empty states of taxis as units of analysis. By matching a taxi's GPS data to its taximeter data, we can obtain the taxi's operational time and the taxi driver's income from every unit of analysis. The ratio of taxi operation time to taxi drivers' income is used to measure the quality of taxi passengers. The research results show that the spatio-temporal evolution of urban taxi service demand differs based on rainfall conditions and hours of operation. During non-rush hours, taxi demand in peripheral areas is significantly reduced under increasing precipitation conditions, whereas during rush hours, the demand for highly profitable taxi services steadily increases. Thus, as an intelligent response for taxi operations and dispatching, taxi services should guide cruising taxis to high-demand regions to increase their service time and ride opportunities. PMID- 28873429 TI - CD18 deficiency improves liver injury in the MCD model of steatohepatitis. AB - Neutrophils and macrophages are important constituents of the hepatic inflammatory infiltrate in non-alcoholic steatohepatitis. These innate immune cells express CD18, an adhesion molecule that facilitates leukocyte activation. In the context of fatty liver, activation of infiltrated leukocytes is believed to enhance hepatocellular injury. The objective of this study was to determine the degree to which activated innate immune cells promote steatohepatitis by comparing hepatic outcomes in wild-type and CD18-mutant mice fed a methionine choline-deficient (MCD) diet. After 3 weeks of MCD feeding, hepatocyte injury, based on serum ALT elevation, was 40% lower in CD18-mutant than wild-type mice. Leukocyte infiltration into the liver was not impaired in CD18-mutant mice, but leukocyte activation was markedly reduced, as shown by the lack of evidence of oxidant production. Despite having reduced hepatocellular injury, CD18-mutant mice developed significantly more hepatic steatosis than wild-type mice after MCD feeding. This coincided with greater hepatic induction of pro-inflammatory and lipogenic genes as well as a modest reduction in hepatic expression of adipose triglyceride lipase. Overall, the data indicate that CD18 deficiency curbs MCD mediated liver injury by limiting the activation of innate immune cells in the liver without compromising intrahepatic cytokine activation. Reduced liver injury occurs at the expense of increased hepatic steatosis, which suggests that in addition to damaging hepatocytes, infiltrating leukocytes may influence lipid homeostasis in the liver. PMID- 28873431 TI - Identification of Diatraea spp. (Lepidoptera: Crambidae) based on cytochrome oxidase II. AB - Diatraea spp. (Lepidoptera: Crambidae) are a group of insects that are agriculture pests in many economically relevant crops such as sugarcane, sorghum, corn and rice. Recognized species for this genus respond differentially to natural enemies used in their biological control, emphasizing the importance of species in a regional approach. Currently, identification is based on the male genitalia. However, the availability of specimens collected from field and subjectivity based on the character recognition can seriously hamper species identification, and therefore result in inadequate pest management. To overcome this, individuals of Diatraea spp. preliminarily classified male genitalia and obtained from reared conditions and the field (both derived from natural populations occurring in Colombia) were analyzed using genitalic morphometry and molecular biology specifically using a fragment of the cytochrome oxidase subunit II (CO II) mitochondrial gene. Although morphometric analysis did not show any overriding results regarding genitalia morphology, the bioinformatics analyses of CO II sequences resulted in an adequate classification of the individuals within the recognized species. It also, revealed that the occurrence of clades associated with geographical distribution may be associated with cryptic species. The latter was also confirmed by a Single-Strand Conformation Polymorphism (SSCP) methodology evaluating the same fragment of CO II. This experimental approach allows properly recognizing each species and in consequence is proposed as an effective tool in Diatraea species identification. PMID- 28873432 TI - Analysis of inter-country input-output table based on citation network: How to measure the competition and collaboration between industrial sectors on the global value chain. AB - The input-output table is comprehensive and detailed in describing the national economic system with complex economic relationships, which embodies information of supply and demand among industrial sectors. This paper aims to scale the degree of competition/collaboration on the global value chain from the perspective of econophysics. Global Industrial Strongest Relevant Network models were established by extracting the strongest and most immediate industrial relevance in the global economic system with inter-country input-output tables and then transformed into Global Industrial Resource Competition Network/Global Industrial Production Collaboration Network models embodying the competitive/collaborative relationships based on bibliographic coupling/co citation approach. Three indicators well suited for these two kinds of weighted and non-directed networks with self-loops were introduced, including unit weight for competitive/collaborative power, disparity in the weight for competitive/collaborative amplitude and weighted clustering coefficient for competitive/collaborative intensity. Finally, these models and indicators were further applied to empirically analyze the function of sectors in the latest World Input-Output Database, to reveal inter-sector competitive/collaborative status during the economic globalization. PMID- 28873433 TI - Overview of preventive practices provided by primary care physicians: A cross sectional study in Switzerland and France. AB - BACKGROUND: A range of preventive practices are recommended to reduce the burden of chronic diseases. The aim of our study was to describe the preventive practices of French-speaking primary care physicians. METHODS: A cross-sectional survey was conducted in 2015 in a randomly selected sample of 1100 primary care physicians (700 in Switzerland, 400 in France). The physicians were asked how often they performed the following recommended preventive practices: blood pressure, weight and height measurements, screening for dyslipidemia, screening for alcohol use and brief intervention, screening for smoking (and brief advice for smokers), colon and prostate cancer screening, and influenza immunization. Response options on the five points Likert scale were never, rarely, sometimes, often, always. The physicians were considered to be performing the preventive practice regularly if they declared performing it often or always. RESULTS: 518 participants (47%) returned the questionnaire. The most commonly reported preventive practices were: blood pressure measurement (99%), screening for smoking (95%) and brief advice for smokers (95%). The least frequently reported practices were annual influenza immunization for at-risk patients <65 years (37%), height measurement (53%), screening for excessive alcohol use (60%) and brief advice for at-risk drinkers (67%). All other practices were reported by 70 to 90% of participants. CONCLUSION: Whereas some preventive practices now appear to be part of primary care routine, others were not applied by a large proportion of primary care physicians in our study. Further studies should explore whether these findings are related to miss-knowledge of common guidelines, or other implementation barriers in this primary care context. PMID- 28873434 TI - The latitudinal diversity gradient in South American mammals revisited using a regional analysis approach: The importance of climate at extra-tropical latitudes and history towards the tropics. AB - The latitudinal diversity gradient has been considered a consequence of a shift in the impact of abiotic and biotic factors that limit species distributions from the poles to the equator, thus influencing species richness variation. It has also been considered the outcome of evolutionary processes that vary over geographical space. We used six South American mammal groups to test the association of environmental and evolutionary factors and the ecological structuring of mammal assemblages with spatial variation in taxonomic richness (TR), at a spatial resolution of 110 km x 110 km, at tropical and extra-tropical latitudes. Based on attributes that represent what mammal species do in ecosystems, we estimated ecological diversity (ED) as a mean pairwise ecological distance between all co-occurring taxa. The mean pairwise phylogenetic distance between all co-occurring taxa (AvPD) was used as an estimation of phylogenetic diversity. Geographically Weighted Regression analyses performed separately for each mammal group identified tropical and extra-tropical high R2 areas where environmental and evolutionary factors strongly accounted for richness variation. Temperature was the most important predictor of TR in high R2 areas outside the tropics, as was AvPD within the tropics. The proportion of TR variation accounted for by environment (either independently or combined with AvPD) was higher in tropical areas of high richness and low ecological diversity than in tropical areas of high richness and high ecological diversity. In conclusion, we confirmed a shift in the impact of environmental factors, mainly temperature, that best account for mammal richness variation in extra-tropical regions, whereas phylogenetic diversity best accounts for richness variation within the tropics. Environment in combination with evolutionary history explained the coexistence of a high number of ecologically similar species within the tropics. Consideration of the influence of contemporary environmental variables and evolutionary history is crucial to understanding of the latitudinal diversity gradient. PMID- 28873435 TI - TGF-beta signaling is an effective target to impair survival and induce apoptosis of human cholangiocarcinoma cells: A study on human primary cell cultures. AB - : Cholangiocarcinoma (CCA) and its subtypes (mucin- and mixed-CCA) arise from the neoplastic transformation of cholangiocytes, the epithelial cells lining the biliary tree. CCA has a high mortality rate owing to its aggressiveness, late diagnosis and high resistance to radiotherapy and chemotherapeutics. We have demonstrated that CCA is enriched for cancer stem cells which express epithelial to mesenchymal transition (EMT) traits, with these features being associated with aggressiveness and drug resistance. TGF-beta signaling is upregulated in CCA and involved in EMT. We have recently established primary cell cultures from human mucin- and mixed-intrahepatic CCA. In human CCA primary cultures with different levels of EMT trait expression, we evaluated the anticancer effects of: (i) CX 4945, a casein kinase-2 (CK2) inhibitor that blocks TGF-beta1-induced EMT; and (ii) LY2157299, a TGF-beta receptor I kinase inhibitor. We tested primary cell lines expressing EMT trait markers (vimentin, N-cadherin and nuclear catenin) but negative for epithelial markers, and cell lines expressing epithelial markers (CK19-positive) in association with EMT traits. Cell viability was evaluated by MTS assays, apoptosis by Annexin V FITC and cell migration by wound-healing assay. RESULTS: at a dose of 10 MUM, CX4945 significantly decreased cell viability of primary human cell cultures from both mucin and mixed CCA, whereas in CK19-positive cell cultures, the effect of CX4945 on cell viability required higher concentrations (>30MUM). At the same concentrations, CX4945 also induced apoptosis (3- fold increase vs controls) which correlated with the expression level of CK2 in the different CCA cell lines (mucin- and mixed-CCA). Indeed, no apoptotic effects were observed in CK19-positive cells expressing lower CK2 levels. The effects of CX4945 on viability and apoptosis were associated with an increased number of gamma-H2ax (biomarker for DNA double-strand breaks) foci, suggesting the active role of CK2 as a repair mechanism in CCAs. LY2157299 failed to influence cell proliferation or apoptosis but significantly inhibited cell migration. At a 50 MUM concentration, in fact, LY2157299 significantly impaired (at 24, 48 and 120 hrs) the wound-healing of primary cell cultures from both mucin-and mixed-CCA. In conclusion, we demonstrated that CX4945 and LY2157299 exert relevant but distinct anticancer effects against human CCA cells, with CX4945 acting on cell viability and apoptosis, and LY2157299 impairing cell migration. These results suggest that targeting the TGF-beta signaling with a combination of CX-4945 and LY2157299 could have potential benefits in the treatment of human CCA. PMID- 28873436 TI - Detection of axonal synapses in 3D two-photon images. AB - Studies of structural plasticity in the brain often require the detection and analysis of axonal synapses (boutons). To date, bouton detection has been largely manual or semi-automated, relying on a step that traces the axons before detection the boutons. If tracing the axon fails, the accuracy of bouton detection is compromised. In this paper, we propose a new algorithm that does not require tracing the axon to detect axonal boutons in 3D two-photon images taken from the mouse cortex. To find the most appropriate techniques for this task, we compared several well-known algorithms for interest point detection and feature descriptor generation. The final algorithm proposed has the following main steps: (1) a Laplacian of Gaussian (LoG) based feature enhancement module to accentuate the appearance of boutons; (2) a Speeded Up Robust Features (SURF) interest point detector to find candidate locations for feature extraction; (3) non-maximum suppression to eliminate candidates that were detected more than once in the same local region; (4) generation of feature descriptors based on Gabor filters; (5) a Support Vector Machine (SVM) classifier, trained on features from labelled data, and was used to distinguish between bouton and non-bouton candidates. We found that our method achieved a Recall of 95%, Precision of 76%, and F1 score of 84% within a new dataset that we make available for accessing bouton detection. On average, Recall and F1 score were significantly better than the current state-of the-art method, while Precision was not significantly different. In conclusion, in this article we demonstrate that our approach, which is independent of axon tracing, can detect boutons to a high level of accuracy, and improves on the detection performance of existing approaches. The data and code (with an easy to use GUI) used in this article are available from open source repositories. PMID- 28873437 TI - Three-dimensional hard and soft tissue imaging of the human cochlea by scanning laser optical tomography (SLOT). AB - The present study focuses on the application of scanning laser optical tomography (SLOT) for visualization of anatomical structures inside the human cochlea ex vivo. SLOT is a laser-based highly efficient microscopy technique which allows for tomographic imaging of the internal structure of transparent specimens. Thus, in the field of otology this technique is best convenient for an ex vivo study of the inner ear anatomy. For this purpose, the preparation before imaging comprises decalcification, dehydration as well as optical clearing of the cochlea samples in toto. Here, we demonstrate results of SLOT imaging visualizing hard and soft tissue structures with an optical resolution of down to 15 MUm using extinction and autofluorescence as contrast mechanisms. Furthermore, the internal structure can be analyzed nondestructively and quantitatively in detail by sectioning of the three-dimensional datasets. The method of X-ray Micro Computed Tomography (MUCT) has been previously applied to explanted cochlea and is solely based on absorption contrast. An advantage of SLOT is that it uses visible light for image formation and thus provides a variety of contrast mechanisms known from other light microscopy techniques, such as fluorescence or scattering. We show that SLOT data is consistent with MUCT anatomical data and provides additional information by using fluorescence. We demonstrate that SLOT is applicable for cochlea with metallic cochlear implants (CI) that would lead to significant artifacts in MUCT imaging. In conclusion, the present study demonstrates the capability of SLOT for resolution visualization of cleared human cochleae ex vivo using multiple contrast mechanisms and lays the foundation for a broad variety of additional studies. PMID- 28873439 TI - CRISPR-FOCUS: A web server for designing focused CRISPR screening experiments. AB - The recently developed CRISPR screen technology, based on the CRISPR/Cas9 genome editing system, enables genome-wide interrogation of gene functions in an efficient and cost-effective manner. Although many computational algorithms and web servers have been developed to design single-guide RNAs (sgRNAs) with high specificity and efficiency, algorithms specifically designed for conducting CRISPR screens are still lacking. Here we present CRISPR-FOCUS, a web-based platform to search and prioritize sgRNAs for CRISPR screen experiments. With official gene symbols or RefSeq IDs as the only mandatory input, CRISPR-FOCUS filters and prioritizes sgRNAs based on multiple criteria, including efficiency, specificity, sequence conservation, isoform structure, as well as genomic variations including Single Nucleotide Polymorphisms and cancer somatic mutations. CRISPR-FOCUS also provides pre-defined positive and negative control sgRNAs, as well as other necessary sequences in the construct (e.g., U6 promoters to drive sgRNA transcription and RNA scaffolds of the CRISPR/Cas9). These features allow users to synthesize oligonucleotides directly based on the output of CRISPR-FOCUS. Overall, CRISPR-FOCUS provides a rational and high-throughput approach for sgRNA library design that enables users to efficiently conduct a focused screen experiment targeting up to thousands of genes. (CRISPR-FOCUS is freely available at http://cistrome.org/crispr-focus/). PMID- 28873438 TI - De novo assembly of a transcriptome from the eggs and early embryos of Astropecten aranciacus. AB - Starfish have been instrumental in many fields of biological and ecological research. Oocytes of Astropecten aranciacus, a common species native to the Mediterranean Sea and the East Atlantic, have long been used as an experimental model to study meiotic maturation, fertilization, intracellular Ca2+ signaling, and cell cycle controls. However, investigation of the underlying molecular mechanisms has often been hampered by the overall lack of DNA or protein sequences for the species. In this study, we have assembled a transcriptome for this species from the oocytes, eggs, zygotes, and early embryos, which are known to have the highest RNA sequence complexity. Annotation of the transcriptome identified over 32,000 transcripts including the ones that encode 13 distinct cyclins and as many cyclin-dependent kinases (CDK), as well as the expected components of intracellular Ca2+ signaling toolkit. Although the mRNAs of cyclin and CDK families did not undergo significant abundance changes through the stages from oocyte to early embryo, as judged by real-time PCR, the transcript encoding Mos, a negative regulator of mitotic cell cycle, was drastically reduced during the period of rapid cleavages. Molecular phylogenetic analysis using the homologous amino acid sequences of cytochrome oxidase subunit I from A. aranciacus and 30 other starfish species indicated that Paxillosida, to which A. aranciacus belongs, is not likely to be the most basal order in Asteroidea. Taken together, the first transcriptome we assembled in this species is expected to enable us to perform comparative studies and to design gene-specific molecular tools with which to tackle long-standing biological questions. PMID- 28873440 TI - Risk of gastrointestinal perforation in patients taking oral fluoroquinolone therapy: An analysis of nationally representative cohort. AB - BACKGROUND: Fluoroquinolone is a commonly prescribed antimicrobial agent, and up to 20% of its users registers adverse gastroenterological symptoms. We aimed to evaluate the association between use of fluoroquinolone and gastrointestinal tract perforation. METHODS: We conducted a nested case-control study on a national health insurance claims database between 1998 and 2011. The use of fluoroquinolones was classified into current (< 60 days), past (61-365 days prior to the index date) and any prior year use of fluoroquinolones. We used the conditional logistic regression model to estimate rate ratios (RRs), adjusting or matching by a disease risk score (DRS). RESULTS: We identified a cohort of 17,510 individuals diagnosed with gastrointestinal perforation and matched them to 1,751,000 controls. Current use of fluoroquinolone was associated with the greatest increase in risk of gastrointestinal perforations after DRS score adjustment (RR, 1.90; 95% CI, 1.62-2.22). The risk of gastrointestinal perforation was attenuated for past (RR, 1.33; 95% CI, 1.20-1.47) and any prior year use (RR, 1.46; 95% CI, 1.34-1.59). To gain insights into whether the observed association can be explained by unmeasured confounder, we compared the risk of gastrointestinal perforation between fluoroquinolone and macrolide. Use of macrolide, an active comparator, was not associated with a significant increased risk of gastrointestinal perforation (RR, 1.11, 95%CI, 0.15-7.99). Sensitivity analysis focusing on perforation requiring in-hospital procedures also demonstrated an increased risk associated with current use. To mitigate selection bias, we have also excluded people who have never used fluoroquinolone before or people with infectious colitis, enteritis or gastroenteritis. In both of the analysis, a higher risk of gastrointestinal perforation was still associated with the use of fluoroquinolone. CONCLUSIONS: We found that use of fluoroquinolones was associated with a non-negligible increased risk of gastrointestinal perforation, and physicians should be aware of this possible association. PMID- 28873441 TI - A fully humanized IgG-like bispecific antibody for effective dual targeting of CXCR3 and CCR6. AB - Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic. We therefore hypothesized that simultaneous targeting of both CXCR3 and CCR6 with a bispecific antibody (BsAb) might result in decreased chemotaxis and/or specific depletion of pro-inflammatory T cell subsets. In this study, we designed and characterized a fully humanized BsAb. We show that the BsAb binds to both chemokine receptors, as demonstrated by Flow Cytometry and Surface Plasmon Resonance analysis. Furthermore, we demonstrate that the BsAb effectively blocks cell chemotaxis and induces specific antibody dependent cell-mediated cytotoxicity (ADCC) in vitro. Therefore, we propose that dual targeting of CXCR3 and CCR6 with a fully humanized BsAb may display a potent interventional approach for the treatment of inflammatory and autoimmune diseases. PMID- 28873443 TI - Application of carbon nanoparticles in laparoscopic sentinel lymph node detection in patients with early-stage cervical cancer. AB - OBJECTIVE: To investigate the value of carbon nanoparticles in identifying sentinel lymph nodes in early-stage cervical cancer. METHODS: From January 2014 to January 2016, 40 patients with cervical cancer stage IA2-IIA, based on the International Federation of Gynecology and Obstetrics (FIGO) 2009 criteria, were included in this study. The normal cervix around the tumor was injected with a total of 1 mL of carbon nanoparticles (CNP)at 3 and 9 o'clock. All patients then underwent laparoscopic pelvic lymph node dissection and radical hysterectomy. The black-dyed sentinel lymph nodes were removed for routine pathological examination and immunohistochemical staining. RESULTS: Among the 40 patients, 38 patients had at least one sentinel lymph node (SLN). The detection rate was 95% (38/40). One hundred seventy-three SLNs were detected with an average of 3.9 SLNs per side. 25 positive lymph nodes, which included 21 positive SLNs, were detected in 8 (20%) patients. Sentinel lymph nodes were localized in the obturator (47.97%), internal lilac (13.87%), external lilac (26.59%), parametrial (1.16%), and common iliac (8.67%) regions. The sensitivity of the SLN detection was 100% (5/5), the accuracy was 97.37% (37/38), and the negative predictive value was 100. 0% and the false negative rate was 0%. CONCLUSIONS: Sentinel lymph nodes can be used to accurately predict the pathological state of pelvic lymph nodes in early cervical cancer. The detection rates and accuracy of sentinel lymph node were high. Carbon nanoparticles can be used to trace the sentinel lymph node in early cervical cancer. PMID- 28873442 TI - Use of a novel antigen expressing system to study the Salmonella enterica serovar Typhi protein recognition by T cells. AB - Salmonella enterica serovar Typhi (S. Typhi), the causative agent of the typhoid fever, is a pathogen of great public health importance. Typhoid vaccines have the potential to be cost-effective measures towards combating this disease, yet the antigens triggering host protective immune responses are largely unknown. Given the key role of cellular-mediated immunity in S. Typhi protection, it is crucial to identify S. Typhi proteins involved in T-cell responses. Here, cells from individuals immunized with Ty21a typhoid vaccine were collected before and after immunization and used as effectors. We also used an innovative antigen expressing system based on the infection of B-cells with recombinant Escherichia coli (E. coli) expressing one of four S. Typhi gene products (i.e., SifA, OmpC, FliC, GroEL) as targets. Using flow cytometry, we found that the pattern of response to specific S. Typhi proteins was variable. Some individuals responded to all four proteins while others responded to only one or two proteins. We next evaluated whether T-cells responding to recombinant E. coli also possess the ability to respond to purified proteins. We observed that CD4+ cell responses, but not CD8+ cell responses, to recombinant E. coli were significantly associated with the responses to purified proteins. Thus, our results demonstrate the feasibility of using an E. coli expressing system to uncover the antigen specificity of T-cells and highlight its applicability to vaccine studies. These results also emphasize the importance of selecting the stimuli appropriately when evaluating CD4+ and CD8+ cell responses. PMID- 28873444 TI - Effects of upper-extremity vascular access creation on cardiac events in patients undergoing coronary artery bypass grafting. AB - The present study was conducted to investigate whether upper-extremity vascular access (VA) creation increases the risk for major adverse cardiac events (MACE) and death in patients undergoing coronary artery bypass grafting (CABG) with an in situ left internal thoracic artery (ITA) graft. A total of 111 patients with CABG with a left ITA graft who underwent upper-extremity VA creation were analyzed retrospectively; 93 patients received left VA creation (83.8%, ipsilateral group) and 18 patients received right VA creation (16.2%, contralateral group). The primary outcome was the occurrence of MACE, and the secondary outcome was the composite of MACE or late death. There were no significant differences in the incidence of primary (P = 0.30) or secondary (P = 0.09) outcomes between the two groups. Multivariate regression analysis indicated that prior cerebrovascular accidents (hazard ratio [HR] 3.30; 95% confidence interval [CI] 1.37-7.97; P = 0.01) and type of VA (HR 3.44; 95% CI 1.34-8.82; P = 0.01) were independently associated with MACE; prior peripheral arterial occlusive disease (HR 4.22; 95% CI 1.62-10.98; P<0.01) and type of VA (arteriovenous fistula vs. prosthetic arteriovenous grafting) (HR 3.06; 95% CI, 1.42-6.61; P<0.01) were associated with the composite of MACE or death. The side and location of VA were not associated with MACE or death. Our study showed no definite evidence that ipsilateral VA creation affects the subsequent occurrence of MACE or late death from any cause. The type of VA (a prosthetic arteriovenous grafting) is a significant predictor of the subsequent occurrence of MACE or late death. PMID- 28873446 TI - Epicuticular chemistry reinforces the new taxonomic classification of the Bactrocera dorsalis species complex (Diptera: Tephritidae, Dacinae). AB - Bactrocera invadens Drew, Tsuruta & White, Bactrocera papayae Drew & Hancock, and Bactrocera philippinensis Drew & Hancock, key pest species within the Bactrocera dorsalis species complex, have been recently synonymized under the name Bactrocera dorsalis (Hendel). The closely related Bactrocera carambolae Drew & Hancock remains as a discrete taxonomic entity. Although the synonymizations have been accepted by most researchers, debate about the species limits remains. Because of the economic importance of this group of taxa, any new information available to support or deny the synonymizations is valuable. We investigated the chemical epicuticle composition of males and females of B. dorsalis, B. invadens, B. papayae, B. philippinensis, and B. carambolae by means of one- and two dimensional gas chromatography-mass spectrometry, followed by multiple factor analyses and principal component analysis. Clear segregation of complex cuticule profiles of both B. carambolae sexes from B. dorsalis (Hendel) was observed. In addition to cuticular hydrocarbons, abundant complex mixtures of sex-specific oxygenated lipids (three fatty acids and 22 fatty acid esters) with so far unknown function were identified in epicuticle extracts from females of all species. The data obtained supports both taxonomic synonymization of B. invadens, B. papayae, and B. philippinensis with B. dorsalis, as well as the exclusion of B. carambolae from B. dorsalis. PMID- 28873445 TI - Deleterious effect of Usutu virus on human neural cells. AB - In the last decade, the number of emerging Flaviviruses described worldwide has increased considerably. Among them Zika virus (ZIKV) and Usutu virus (USUV) are African mosquito-borne viruses that recently emerged. Recently, ZIKV has been intensely studied due to major outbreaks associated with neonatal death and birth defects, as well as neurological symptoms. USUV pathogenesis remains largely unexplored, despite significant human and veterinary associated disorders. Circulation of USUV in Africa was documented more than 50 years ago, and it emerged in Europe two decades ago, causing massive bird mortality. More recently, USUV has been described to be associated with neurological disorders in humans such as encephalitis and meningoencephalitis, highlighting USUV as a potential health threat. The aim of this study was to evaluate the ability of USUV to infect neuronal cells. Our results indicate that USUV efficiently infects neurons, astrocytes, microglia and IPSc-derived human neuronal stem cells. When compared to ZIKV, USUV led to a higher infection rate, viral production, as well as stronger cell death and anti-viral response. Our results highlight the need to better characterize the physiopathology related to USUV infection in order to anticipate the potential threat of USUV emergence. PMID- 28873447 TI - Flat and complex temperate reefs provide similar support for fish: Evidence for a unimodal species-habitat relationship. AB - Structural complexity, a form of habitat heterogeneity, influences the structure and function of ecological communities, generally supporting increased species density, richness, and diversity. Recent research, however, suggests the most complex habitats may not harbor the highest density of individuals and number of species, especially in areas with elevated human influence. Understanding nuances in relationships between habitat heterogeneity and ecological communities is warranted to guide habitat-focused conservation and management efforts. We conducted fish and structural habitat surveys of thirty warm-temperate reefs on the southeastern US continental shelf to quantify how structural complexity influences fish communities. We found that intermediate complexity maximizes fish abundance on natural and artificial reefs, as well as species richness on natural reefs, challenging the current paradigm that abundance and other fish community metrics increase with increasing complexity. Naturally occurring rocky reefs of flat and complex morphologies supported equivalent abundance, biomass, species richness, and community composition of fishes. For flat and complex morphologies of rocky reefs to receive equal consideration as essential fish habitat (EFH), special attention should be given to detecting pavement type rocky reefs because their ephemeral nature makes them difficult to detect with typical seafloor mapping methods. Artificial reefs of intermediate complexity also maximized fish abundance, but human-made structures composed of low-lying concrete and metal ships differed in community types, with less complex, concrete structures supporting lower numbers of fishes classified largely as demersal species and metal ships protruding into the water column harboring higher numbers of fishes, including more pelagic species. Results of this study are essential to the process of evaluating habitat function provided by different types and shapes of reefs on the seafloor so that all EFH across a wide range of habitat complexity may be accurately identified and properly managed. PMID- 28873448 TI - Temporal and spatial variation of potassium balance in agricultural land at national and regional levels in China. AB - Linking potassium (K) balance to soil fertility creates a valuable indicator for sustainability assessment in agricultural land-use systems. It is crucial for the efficient use of K resources, food security and resource sustainability to realize soil K balance status in China. Therefore, temporal and spatial changes of K balance for farmland in China from 1980 to 2015 were analyzed at national and regional levels using statistical data and related parameters. At the national scale, K input increased from 6.78 Mt K2O in 1980 to 23.44 Mt K2O in 2015 with an average annual increment of 0.48 Mt K2O, and output changed from 8.10 Mt in 1980 to 21.31 Mt in 2015 with an average annual increment of 0.38 Mt K2O as well. On average, K balance was -24.17, -5.92, 21.31 and 19.50 kg K2O ha-1 in 1980s, 1990s, 2000s and 2010s, respectively. Moreover, the average balance of six regions was considerably different which were -21.37, 1.25, 13.70, -22.79, 99.22 and 7.18 kg K2O ha-1 from 1980 to 2015. The potassium use efficiency (KUE) decreased with time which were 127.09, 104.35, 87.69 and 89.69% in 1980s, 1990s, 2000s and 2010s, respectively, and the decline of slope could also reflect the variation tendency of KUE. Great variation of K balance across different regions demonstrated that fertilizer application and management practices need to be adjusted to local conditions. PMID- 28873449 TI - Benthic community structure on coral reefs exposed to intensive recreational snorkeling. AB - Chronic anthropogenic disturbances on coral reefs in the form of overfishing and pollution can shift benthic community composition away from stony corals and toward macroalgae. The use of reefs for recreational snorkeling and diving potentially can lead to similar ecological impacts if not well-managed, but impacts of snorkeling on benthic organisms are not well understood. We quantified variation in benthic community structure along a gradient of snorkeling frequency in an intensively-visited portion of the Mesoamerican Barrier Reef. We determined rates of snorkeling in 6 water sections and rates of beach visitation in 4 adjacent land sections at Akumal Bay, Mexico. For each in-water section at 1-3 m depth, we also assessed the percent cover of benthic organisms including taxa of stony corals and macroalgae. Rates of recreational snorkeling varied from low in the southwestern to very high (>1000 snorkelers d-1) in the northeastern sections of the bay. Stony coral cover decreased and macroalgal cover increased significantly with levels of snorkeling, while trends varied among taxa for other organisms such as gorgonians, fire corals, and sea urchins. We conclude that benthic organisms appear to exhibit taxon-specific variation with levels of recreational snorkeling. To prevent further degradation, we recommend limitation of snorkeler visitation rates, coupled with visitor education and in-water guides to reduce reef-damaging behaviors by snorkelers in high-use areas. These types of management activities, integrated with reef monitoring and subsequent readjustment of management, have the potential to reverse the damage potentially inflicted on coral reefs by the expansion of reef-based recreational snorkeling. PMID- 28873451 TI - Transfer of the small diatoms Thalassiosira proschkinae and T. spinulata to the genus Minidiscus and their taxonomic re-description. AB - The marine diatoms Thalassiosira proschkinae and T. spinulata are relatively small in size; their taxonomic identities have been debated owing to the diverse morphological variations. In the present study, we isolated both morphotypes from Korean coastal waters and examined their fine structures and conducted molecular sequence comparisons. The morphological and molecular analyses showed that T. proschkinae and T. spinulata were certainly distinct, and phenotypic plasticity of valve structure was not noted. Based on the morphological similarity and phylogenetic relationship, we transferred T. proschkinae and T. spinulata to another genus Minidiscus within Thalassiosirales that includes small-sized species and proposed new combination names, Minidiscus proschkinae (Makarova) Park & Lee comb. nov. and Minidiscus spinulatus (Takano) Park & Lee comb. nov., respectively. The genus description of Minidiscus was emended. PMID- 28873450 TI - Bromide supplementation exacerbated the renal dysfunction, injury and fibrosis in a mouse model of Alport syndrome. AB - A seminal study recently demonstrated that bromide (Br-) has a critical function in the assembly of type IV collagen in basement membrane (BM), and suggested that Br- supplementation has therapeutic potential for BM diseases. Because salts of bromide (KBr and NaBr) have been used as antiepileptic drugs for several decades, repositioning of Br- for BM diseases is probable. However, the effects of Br- on glomerular basement membrane (GBM) disease such as Alport syndrome (AS) and its impact on the kidney are still unknown. In this study, we administered daily for 16 weeks 75 mg/kg or 250 mg/kg (within clinical dosage) NaBr or NaCl (control) via drinking water to 6-week-old AS mice (mouse model of X-linked AS). Treatment with 75 mg/kg NaBr had no effect on AS progression. Surprisingly, compared with 250 mg/kg NaCl, 250 mg/kg NaBr exacerbated the progressive proteinuria and increased the serum creatinine and blood urea nitrogen in AS mice. Histological analysis revealed that glomerular injury, renal inflammation and fibrosis were exacerbated in mice treated with 250 mg/kg NaBr compared with NaCl. The expressions of renal injury markers (Lcn2, Lysozyme), matrix metalloproteinase (Mmp-12), pro-inflammatory cytokines (Il-6, Il-8, Tnf-alpha, Il-1beta) and pro fibrotic genes (Tgf-beta, Col1a1, alpha-Sma) were also exacerbated by 250 mg/kg NaBr treatment. Notably, the exacerbating effects of Br- were not observed in wild-type mice. These findings suggest that Br- supplementation needs to be carefully evaluated for real positive health benefits and for the absence of adverse side effects especially in GBM diseases such as AS. PMID- 28873452 TI - Betting on the fastest horse: Using computer simulation to design a combination HIV intervention for future projects in Maharashtra, India. AB - OBJECTIVE: To inform the design of a combination intervention strategy targeting HIV-infected unhealthy alcohol users in Maharashtra, India, that could be tested in future randomized control trials. METHODS: Using probabilistic compartmental simulation modeling we compared intervention strategies targeting HIV-infected unhealthy alcohol users on antiretroviral therapy (ART) in Maharashtra, India. We tested interventions targeting four behaviors (unhealthy alcohol consumption, risky sexual behavior, depression and antiretroviral adherence), in three formats (individual, group based, community) and two durations (shorter versus longer). A total of 5,386 possible intervention combinations were tested across the population for a 20-year time horizon and intervention bundles were narrowed down based on incremental cost-effectiveness analysis using a two-step probabilistic uncertainty analysis approach. RESULTS: Taking into account uncertainty in transmission variables and intervention cost and effectiveness values, we were able to reduce the number of possible intervention combinations to be used in a randomized control trial from over 5,000 to less than 5. The most robust intervention bundle identified was a combination of three interventions: long individual alcohol counseling; weekly Short Message Service (SMS) adherence counseling; and brief sex risk group counseling. CONCLUSIONS: In addition to guiding policy design, simulation modeling of HIV transmission can be used as a preparatory step to trial design, offering a method for intervention pre selection at a reduced cost. PMID- 28873453 TI - Satellite tagging of rehabilitated green sea turtles Chelonia mydas from the United Arab Emirates, including the longest tracked journey for the species. AB - We collected movement data for eight rehabilitated and satellite-tagged green sea turtles Chelonia mydas released off the United Arab Emirates between 2005 and 2013. Rehabilitation periods ranged from 96 to 1353 days (mean = 437 +/- 399 days). Seven of the eight tagged turtles survived after release; one turtle was killed by what is thought to be a post-release spear gun wound. The majority of turtles (63%) used shallow-water core habitats and established home ranges between Dubai and Abu Dhabi, the same area in which they had originally washed ashore prior to rescue. Four turtles made movements across international boundaries, highlighting that regional cooperation is necessary for the management of the species. One turtle swam from Fujairah to the Andaman Sea, a total distance of 8283 km, which is the longest published track of a green turtle. This study demonstrates that sea turtles can be successfully reintroduced into the wild after sustaining serious injury and undergoing prolonged periods of intense rehabilitation. PMID- 28873454 TI - De novo transcriptome assembly and analysis of differential gene expression in response to drought in European beech. AB - Despite the ecological and economic importance of European beech (Fagus sylvatica L.) genomic resources of this species are still limited. This hampers an understanding of the molecular basis of adaptation to stress. Since beech will most likely be threatened by the consequences of climate change, an understanding of adaptive processes to climate change-related drought stress is of major importance. Here, we used RNA-seq to provide the first drought stress-related transcriptome of beech. In a drought stress trial with beech saplings, 50 samples were taken for RNA extraction at five points in time during a soil desiccation experiment. De novo transcriptome assembly and analysis of differential gene expression revealed 44,335 contigs, and 662 differentially expressed genes between the stress and normally watered control group. Gene expression was specific to the different time points, and only five genes were significantly differentially expressed between the stress and control group on all five sampling days. GO term enrichment showed that mostly genes involved in lipid- and homeostasis-related processes were upregulated, whereas genes involved in oxidative stress response were downregulated in the stressed seedlings. This study gives first insights into the genomic drought stress response of European beech, and provides new genetic resources for adaptation research in this species. PMID- 28873457 TI - Identification of host plant use of adults of a long-distance migratory insect, Mythimna separata. AB - Adults of many insect species often become contaminated with pollen grains when feeding. Identification of plant hosts for M. separata moths could increase our understanding of their geographic origin and the coevolution of M. separata moths and their host plants. However, identifying the diet of noctuid moths using traditional direct observation is limited by their nocturnal and flight habits. In this study, we used core barcode markers and pollen morphology to identify pollen species. We found pollen from 13 plant species belonging to nine families on trapped M. separata moths, mainly from Angiosperm, Dicotyledoneae. Pollen was found on 14.4% and 12.3% of females and males, respectively, and the amount of pollen transported varied with the body part, with the most pollen on the proboscis. We were able to determine from this that the moths visited woody plants more than herbaceous plants, but not significantly so, and that they carried more pollen earlier in the migration season. In this study, we clarified the species and frequencies of pollen deposition on M. separata moths. These findings improve our understanding of the coevolution of the moths and their host plants. Identification of plant hosts for adult moths provides a new means of studying noctuid moth-host plant interactions, and informs the development of more efficient management practices for M. separata. PMID- 28873456 TI - Molecular prediction of lytic vs lysogenic states for Microcystis phage: Metatranscriptomic evidence of lysogeny during large bloom events. AB - Microcystis aeruginosa is a freshwater bloom-forming cyanobacterium capable of producing the potent hepatotoxin, microcystin. Despite increased interest in this organism, little is known about the viruses that infect it and drive nutrient mobilization and transfer of genetic material between organisms. The genomic complement of sequenced phage suggests these viruses are capable of integrating into the host genome, though this activity has not been observed in the laboratory. While analyzing RNA-sequence data obtained from Microcystis blooms in Lake Tai (Taihu, China), we observed that a series of lysogeny-associated genes were highly expressed when genes involved in lytic infection were down-regulated. This pattern was consistent, though not always statistically significant, across multiple spatial and temporally distinct samples. For example, samples from Lake Tai (2014) showed a predominance of lytic virus activity from late July through October, while genes associated with lysogeny were strongly expressed in the early months (June-July) and toward the end of bloom season (October). Analyses of whole phage genome expression shows that transcription patterns are shared across sampling locations and that genes consistently clustered by co-expression into lytic and lysogenic groups. Expression of lytic-cycle associated genes was positively correlated to total dissolved nitrogen, ammonium concentration, and salinity. Lysogeny-associated gene expression was positively correlated with pH and total dissolved phosphorous. Our results suggest that lysogeny may be prevalent in Microcystis blooms and support the hypothesis that environmental conditions drive switching between temperate and lytic life cycles during bloom proliferation. PMID- 28873455 TI - Prediction and analysis of essential genes using the enrichments of gene ontology and KEGG pathways. AB - Identifying essential genes in a given organism is important for research on their fundamental roles in organism survival. Furthermore, if possible, uncovering the links between core functions or pathways with these essential genes will further help us obtain deep insight into the key roles of these genes. In this study, we investigated the essential and non-essential genes reported in a previous study and extracted gene ontology (GO) terms and biological pathways that are important for the determination of essential genes. Through the enrichment theory of GO and KEGG pathways, we encoded each essential/non essential gene into a vector in which each component represented the relationship between the gene and one GO term or KEGG pathway. To analyze these relationships, the maximum relevance minimum redundancy (mRMR) was adopted. Then, the incremental feature selection (IFS) and support vector machine (SVM) were employed to extract important GO terms and KEGG pathways. A prediction model was built simultaneously using the extracted GO terms and KEGG pathways, which yielded nearly perfect performance, with a Matthews correlation coefficient of 0.951, for distinguishing essential and non-essential genes. To fully investigate the key factors influencing the fundamental roles of essential genes, the 21 most important GO terms and three KEGG pathways were analyzed in detail. In addition, several genes was provided in this study, which were predicted to be essential genes by our prediction model. We suggest that this study provides more functional and pathway information on the essential genes and provides a new way to investigate related problems. PMID- 28873459 TI - Divergent LysM effectors contribute to the virulence of Beauveria bassiana by evasion of insect immune defenses. AB - The lysin motif (LysM) containing proteins can bind chitin and are ubiquitous in various organisms including fungi. In plant pathogenic fungi, a few LysM proteins have been characterized as effectors to suppress chitin-induced immunity in plant hosts and therefore contribute to fungal virulence. The effector mechanism is still questioned in fungus-animal interactions. In this study, we found that LysM proteins are also present in animal pathogenic fungi and have evolved divergently. The genome of the insect pathogen Beauveria bassiana encodes 12 LysM proteins, and the genes were differentially transcribed by the fungus when grown in different conditions. Deletion of six genes that were expressed by the fungus growing in insects revealed that two, Blys2 and Blys5, were required for full fungal virulence. Both proteins could bind chitin and Blys5 (containing two LysM domains) could additionally bind chitosan and cellulose. Truncation analysis of Blys2 (containing five LysM domains) indicated that the combination of LysM domains could determine protein-binding affinity and specificity for different carbohydrates. Relative to the wild-type strain, loss of Blys2 or Blys5 could impair fungal propagation in insect hemocoels and lead to the upregulation of antifungal gene in insects. Interestingly, the virulence defects of DeltaBlys2 and DeltaBlys5 could be fully restored by complementation with the Slp1 effector from the rice blast fungus Magnaporthe oryzae. In contrast to Slp1 and Blys2, Blys5 could potentially protect fungal hyphae against chitinase hydrolysis. The results of this study not only advance the understanding of LysM protein evolution but also establish the effector mechanism of fungus-animal interactions. PMID- 28873458 TI - Anti-fibrotic effects of valproic acid in experimental peritoneal fibrosis. AB - BACKGROUND: Progressive fibrous thickening of the peritoneal membrane is a complication of long-term peritoneal dialysis (PD). TGF-beta/Smad pathway activation, inflammation, and neoangiogenesis play important roles in peritoneal membrane (PM) changes induced by PD. Recently, histone deacetilase inhibitors (HDACi) have shown anti-fibrotic and anti-inflammatory effects in different experimental models. These drugs prevent deacetylation of histones causing a loosen chromatin, which in turn induce the expression of some anti-fibrotic genes. In addition, acetylation may increase the activity of proteins involved in tissue fibrosis, such as Smad7. Here, we explored the effect of valproic acid (VPA), an HDACi, on the development of peritoneal fibrosis (PF) in rats. METHODS: PF was induced by daily intraperitoneal injections of 0.1% chlorhexidine gluconate (CG) for 15 consecutive days. Male Wistar rats (250-300 g) were divided into 3 groups: CONTROL, control rats receiving only vehicle; PF, peritoneal fibrosis induced in rats; PF+VPA, rats with PF treated with VPA (300 mg/kg/day by gavage). PF was assessed by Masson's trichrome staining. Inflammation and fibrosis-associated factors were assessed by immunohistochemistry, immunofluorescence, multiplex analysis, and qPCR. RESULTS: Treatment with VPA significantly reduced PM thickness and the expression of myofibroblasts, besides preventing loss of ultrafiltration capacity of the PM. The upregulation of profibrotic factors (TGF-beta, fibronectin, and Smad3) in the PF group was significantly ameliorated by VPA. VPA modulated the TGF/Smad pathway, inhibiting phosphorylated Smad3 expression and inducing an increased Smad7 expression in the FP+VPA group. The neoangiogenesis and the expression of proinflammatory cytokines (TNF-alpha, IL-1beta, MCP-1) observed in the PF group was significantly reduced by VPA. CONCLUSIONS: Our results indicate that VPA suppressed experimental PF through modulation of the TGF-beta/Smad pathway. Interestingly, VPA treatment induced a higher expression of antifibrotic factors, such as Smad7. These results suggest that VPA may represent a potential strategy for treating long term PD complications. PMID- 28873460 TI - Perfluorocarbon emulsions radiosensitise brain tumors in carbogen breathing mice with orthotopic GL261 gliomas. AB - BACKGROUND: Tumour hypoxia limits the effectiveness of radiation therapy. Delivering normobaric or hyperbaric oxygen therapy elevates pO2 in both tumour and normal brain tissue. However, pO2 levels return to baseline within 15 minutes of stopping therapy. AIM: To investigate the effect of perfluorocarbon (PFC) emulsions on hypoxia in subcutaneous and intracranial mouse gliomas and their radiosensitising effect in orthotopic gliomas in mice breathing carbogen (95%O2 and 5%CO2). RESULTS: PFC emulsions completely abrogated hypoxia in both subcutaneous and intracranial GL261 models and conferred a significant survival advantage orthotopically (Mantel Cox: p = 0.048) in carbogen breathing mice injected intravenously (IV) with PFC emulsions before radiation versus mice receiving radiation alone. Carbogen alone decreased hypoxia levels substantially and conferred a smaller but not statistically significant survival advantage over and above radiation alone. CONCLUSION: IV injections of PFC emulsions followed by 1h carbogen breathing, radiosensitises GL261 intracranial tumors. PMID- 28873461 TI - Interleukin-17 induces human alveolar epithelial to mesenchymal cell transition via the TGF-beta1 mediated Smad2/3 and ERK1/2 activation. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic and usually progressive lung disease and the epithelial-mesenchymal transition (EMT) may play an important role in the pathogenesis of pulmonary fibrosis. IL-17 is a proinflammatory cytokine which promotes EMT profiles in lung inflammatory diseases. In this study, we investigated the effect of IL-17 on EMT in alveolar epithelial cell line A549 and the role of TGFbeta1-Smad and ERK signaling pathways in the process. Morphological observation on the cells was performed under inverted microscope. The mRNA and protein expressions of E-cad and alpha-SMA were detected by quantitative RT-PCR and western blotting. The mRNA and protein expressions of TGF-beta1 were analyzed via quantitative RT-PCR and ELISA. Expressions of Smad2/3, p-Smad2/3, ERK1/2, p-ERK1/2 and p-JNK were examined by western blotting. The results indicated that IL-17 can induce A549 cells to undergo morphological changes and phenotypic markers changes, such as down-regulated E-cad expression and up-regulated alpha-SMA expression. Additionally, IL-17 enhanced TGF-beta1 expression and stimulated Smad2/3 and ERK1/2 phosphorylation in A549 cells. However, there were no significant differences in the expression of phosphorylated JNK in A549 cells with or without IL-17 treatment. SB431542 or U0126 treated cells showed inhibited morphological changes and phenotypic markers expression, such as up-regulated E-cad expression and down-regulated alpha-SMA expression. In summary, our results suggest that IL-17 can induce A549 alveolar epithelial cells to undergo EMT via the TGF-beta1 mediated Smad2/3 and ERK1/2 activation. PMID- 28873462 TI - Genetic analysis of indel markers in three loci associated with Parkinson's disease. AB - The causal mutations and genetic polymorphisms associated with susceptibility to Parkinson's disease (PD) have been extensively described. To explore the potential contribution of insertion (I)/deletion (D) polymorphisms (indels) to the risk of PD in a Chinese population, we performed genetic analyses of indel loci in ACE, DJ-1, and GIGYF2 genes. Genomic DNA was extracted from venous blood of 348 PD patients and 325 age- and sex-matched controls without neurodegenerative disease. Genotyping of the indel loci was performed by fragment length analysis after PCR and DNA sequencing. Our results showed a statistically significant association for both allele X (alleles without 5) vs. 5 (odds ratio = 1.378, 95% confidence interval = 1.112-1.708, P = 0.003) and genotype 5/X+X/X vs. 5/5 (odds ratio = 1.681, 95% confidence interval = 1.174-2.407, P = 0.004) in the GIGYF2 locus; however, no significant differences were detected for the ACE and DJ-1 indels. After stratification by gender, no significant differences were observed in any indels. These results indicate that the GIGYF2 indel may be associated with increased risk of PD in northern China. PMID- 28873463 TI - Effects of antimony on redox activities and antioxidant defence systems in sunflower (Helianthus annuus L.) plants. AB - The alterations induced by the toxicity of antimony (Sb) in the roots and leaves of sunflower plants were determined. The plants were grown hydroponically with different concentrations of Sb, a heavy metal which reduces biomass production and growth. There was preferential accumulation of Sb in the tissues of the roots, with the concentrations in the leaves being much lower. The accumulation of other mineral elements was also altered, especially that of Fe and Zn. Chlorophyll content declined, as also did the photosynthetic efficiency, but the carotenoid content remained unaltered. The total content of phenolics, flavonoids, and phenylpropanoid glycosides rose, evidence of their participation in the defence response. Increases were observed in the amount of superoxide anion in both roots and leaves, and in lipid peroxidation levels, especially with the highest Sb concentration of 1.0 mM. The induced oxidative stress leads to a strong increase in the SOD, POX and APX antioxidant activities, while the GR activity was only increased in the leaves and at the 1.0 mM Sb concentration. In contrast, the DHAR activity increased considerably in both organs. The GSNOR activity increased only in roots, and the total RSNOs increased. The total amount of AsA + DHA increased in roots and remained unaltered in leaves, whereas that of GSH + GSSG decreased considerably in all cases. As a whole, these results are evidence for the development of a strong oxidative stress induced by Sb, with there being a clear imbalance in the content of the compounds that constitute the AsA/GSH cycle. 0.5 mM Sb enhances GST expression, especially in leaves. This, together with the increase that was observed in the amount of GSH, may play an important part in detoxification. This oxidative stress affects both the phenolic and the ROS/RNS metabolic processes, which seems to implicate their involvement in the plant's defence and response to the stress. PMID- 28873464 TI - Direct integrin binding to insulin-like growth factor-2 through the C-domain is required for insulin-like growth factor receptor type 1 (IGF1R) signaling. AB - We have reported that integrins crosstalk with growth factors through direct binding to growth factors (e.g., fibroblast growth factor-1, insulin-like growth factor 1 (IGF1), neuregulin-1, fractalkine) and subsequent ternary complex formation with cognate receptor [e.g., integrin/IGF1/IGF1 receptor (IGF1R)]. IGF1 and IGF2 are overexpressed in cancer and major therapeutic targets. We previously reported that IGF1 binds to integrins alphanubeta3 and alpha6beta4, and the R36E/R37E mutant in the C-domain of IGF1 is defective integrin binding and signaling functions of IGF1, and acts as an antagonist of IGF1R. We studied if integrins play a role in the signaling functions of IGF2, another member of the IGF family. Here we describe that IGF2 specifically binds to integrins alphanubeta3 and alpha6beta4, and induced proliferation of CHO cells (IGF1R+) that express alphanubeta3 or alpha6beta4 (beta3- or alpha6beta4-CHO cells). Arg residues to Glu at positions 24, 34, 37 and/or 38 in or close to the C-domain of IGF2 play a critical role in binding to integrins and signaling functions. The R24E/R37E/R38E, R34E/R37E/R38E, and R24E/R34E/R37E/R38E mutants were defective in integrin binding and IGF2 signaling. These mutants suppressed proliferation induced by WT IGF2, suggesting that they are dominant-negative antagonists of IGF1R. These results suggest that IGF2 also requires integrin binding for signaling functions, and the IGF2 mutants that cannot bind to integrins act as antagonists of IGF1R. The present study defines the role of the C-domain in integrin binding and signaling. PMID- 28873465 TI - The games economists play: Why economics students behave more selfishly than other students. AB - Do economics students behave more selfishly than other students? Experiments involving monetary allocations suggest so. This article investigates the underlying motives for the economic students' more selfish behavior by separating three potential explanatory mechanisms: economics students are less concerned with fairness when making allocation decisions; have a different notion of what is fair in allocations; or are more skeptical about other people's allocations, which in turn makes them less willing to comply with a shared fairness norm. The three mechanisms were tested by inviting students from various disciplines to participate in a relatively novel experimental game and asking all participants to give reasons for their choices. Compared with students of other disciplines, economics students were about equally likely to mention fairness in their comments; had a similar notion of what was fair in the situation; however, they expected lower offers, made lower offers, and were less willing to enforce compliance with a fair allocation at a cost to themselves. The economics students' lower expectations mediated their allocation decisions, suggesting that economics students behaved more selfishly because they expected others not to comply with the shared fairness norm. PMID- 28873467 TI - Obesity and risk of death or dialysis in younger and older patients on specialized pre-dialysis care. AB - BACKGROUND: Obesity is associated with increased mortality and accelerated decline in kidney function in the general population. Little is known about the effect of obesity in younger and older pre-dialysis patients. The aim of this study was to assess the extent to which obesity is a risk factor for death or progression to dialysis in younger and older patients on specialized pre-dialysis care. METHOD: In a multicenter Dutch cohort study, 492 incident pre-dialysis patients (>18y) were included between 2004-2011 and followed until start of dialysis, death or October 2016. We grouped patients into four categories of baseline body mass index (BMI): <20, 20-24 (reference), 25-29, and >=30 (obesity) kg/m2 and stratified patients into two age categories (<65y or >=65y). RESULTS: The study population comprised 212 patients younger than 65 years and 280 patients 65 years and older; crude cumulative risk of dialysis and mortality at the end of follow-up were 66% and 4% for patients <65y and 64% and 14%, respectively, for patients >=65y. Among the <65y patients, the age-sex standardized combined outcome rate was 2.3 times higher in obese than those with normal BMI, corresponding to an excess rate of 35 events/100 patient-years. After multivariable adjustment the hazard ratios (HR) (95% CI) for the combined endpoint by category of increasing BMI were, for patients <65y, 0.92 (0.41-2.09), 1 (reference), 1.76 (1.16-2.68), and 1.81 (1.17-2.81). For patients >=65y the BMI specific HRs were 1.73 (0.97-3.08), 1 (reference), 1.25 (0.91-1.71) and 1.30 (0.79-1.90). In the competing risk analysis, taking dialysis as the event of interest and death as a competing event, the BMI-specific multivariable adjusted subdistribution HRs (95% CI) were, for patients <65y, 0.90 (0.38-2.12), 1 (reference), 1.47 (0.96-2.24) and 1.72 (1.15-2.59). For patients >=65y the BMI specific SHRs (95% CI) were 1.68 (0.93-3.02), 1 (reference), 1.50 (1.05-2.14) and 1.80 (1.23-2.65). CONCLUSION: We found that obesity in younger pre-dialysis patients and being underweight in older pre-dialysis patients are risk factors for starting dialysis and for death, compared with those with a normal BMI. PMID- 28873466 TI - Rational design of drug-like compounds targeting Mycobacterium marinum MelF protein. AB - The mycobacterial mel2 locus (mycobacterial enhanced infection locus, Rv1936 1941) is Mycobacterium marinum and M. tuberculosis specific, which can withstand reactive oxygen species (ROS) and reactive nitrogen species (RNS) induced stress. A library of over a million compounds was screened using in silico virtual ligand screening (VLS) to identify inhibitors against the modeled structure of MelF protein expressed by melF of mel2 locus so that M. marinum's ability to withstand ROS/RNS stress could be reduced. The top ranked 1000 compounds were further screened to identify 178 compounds to maximize the scaffold diversity by manually evaluating the interaction of each compound with the target site. M. marinum melF was cloned, expressed and purified as maltose binding protein (MBP)-tagged recombinant protein in Escherichia coli. After establishing the flavin dependent oxidoreductase activity of MelF (~ 84 kDa), the inhibitors were screened for the inhibition of enzyme activity of whole cell lysate (WCL) and the purified MelF. Amongst these, 16 compounds could significantly inhibit the enzyme activity of purified MelF. For the six best inhibitory compounds, the minimal inhibitory concentration (MIC) was determined to be 3.4-19.4 MUM and 13.5-38.8 MUM for M. marinum and M. tuberculosis, respectively. Similarly, the minimal bactericidal concentration (MBC) was determined to be 6.8-38.8 MUM and 27-38.8 MUM against M. marinum and M. tuberculosis, respectively. One compound each in combination with isoniazid (INH) also showed synergistic inhibitory effect against M. marinum and M. tuberculosis with no cytotoxicity in HeLa cells. Interestingly, these inhibitors did not display any non-specific protein-structure destabilizing effect. Such inhibitors targeting the anti-ROS/RNS machinery may facilitate the efficient killing of replicating and nonreplicating mycobacteria inside the host cells. PMID- 28873469 TI - The direct healthcare costs associated with psychological distress and major depression: A population-based cohort study in Ontario, Canada. AB - The objective of our study was to estimate direct healthcare costs incurred by a population-based sample of people with psychological distress or depression. We used the 2002 Canadian Community Health Survey on Mental Health and Well Being and categorized individuals as having psychological distress using the Kessler-6, major depressive disorder (MDD) using DSM-IV criteria and a comparison group of participants without MDD or psychological distress. Costs in 2013 USD were estimated by linking individuals to health administrative databases and following them until March 31, 2013. Our sample consisted of 9,965 individuals, of whom 651 and 409 had psychological distress and MDD, respectively. Although the age-and sex adjusted per-capita costs were similarly high among the psychologically distressed ($3,364, 95% CI: $2,791, $3,937) and those with MDD ($3,210, 95% CI: $2,413, $4,008) compared to the comparison group ($2,629, 95% CI: $2,312, $2,945), the population-wide excess costs for psychological distress ($441 million) were more than twice that for MDD ($210 million) as there was a greater number of people with psychological distress than depression. We found substantial healthcare costs associated with psychological distress and depression, suggesting that psychological distress and MDD have a high cost burden and there may be public health intervention opportunities to relieve distress. Further research examining how individuals with these conditions use the healthcare system may provide insight into the allocation of limited healthcare resources while maintaining high quality care. PMID- 28873468 TI - Neuropsychological functioning, age, and medication adherence in bipolar disorder. AB - OBJECTIVES: Poor adherence to medication is frequent in bipolar disorder (BD) and has been associated with several factors. To date, the relationship between low adherence and neuropsychological functioning in BD is still unclear. As age and neuropsychological functioning might have opposing influences on adherence, our aim was to investigate this link with a particular focus on the effect of age. METHODS: In a cross-sectional study, we included 353 patients divided into two age-groups (16-46; 47-71) from a French cohort diagnosed with BD (type I, II, NOS) and strictly euthymic. All patients had a standardized clinical and neuropsychological assessment and were categorized as high (n = 186) or low (n = 167) adherent based on their score from the Medication Adherence Rating Scale. Clinical information was collected based on a standardized interview and clinical validated scales. Neuropsychological performances were evaluated with an established standardized neuropsychological battery for bipolar disorder patients. After univariate analysis, neuropsychological and clinical predictors of low adherence were included in two age-specific stepwise multiple logistic regressions. RESULTS: A smaller number of hospitalizations (OR = 0.846, p = 0.012), a shorter illness duration (OR = 0.937, p = 0.003) and higher adverse effects (OR = 1.082, p<0.001) were associated with a greater risk of low adherence in the younger patients. In the older patients, low adherence was also predicted by a smaller number of hospitalizations (OR = 0.727, p = 0.008) and higher adverse effects (OR = 1.124, p = 0.005). Interestingly poor inhibition performance was also a significant predictor of low adherence in older patients (OR = 0.924, p = 0.030). CONCLUSIONS: We found an age-specific relationship between cognitive functioning and adherence in patients with BD. Poor inhibition performances predicted low adherence in older patients only. Our results highlight the need to provide age-adapted therapeutic interventions to improve adherence in patients with BD. PMID- 28873472 TI - Incorporating basic and applied approaches to evaluate the effects of invasive Asian Carp on native fishes: A necessary first step for integrated pest management. AB - Numerous studies throughout North America allege deleterious associations among invasive Asian Carp and native fishes; however, no empirical evidence on a system wide scale exists. We used Mississippi River Basin fish community data collected by the Long Term Resource Monitoring program and the Missouri Department of Conservation to evaluate possible interaction between Asian Carp and native fishes. Results from two decades of long-term monitoring throughout much of the Mississippi River suggest that Silver Carp relative abundance has increased while relative abundance (Bigmouth Buffalo [F 3, 8240 = 6.44, P<0.01] and Gizzard Shad [F 3, 8240 = 31.04, P<0.01]) and condition (Bigmouth Buffalo [slope = -0.11; t = 1.71; P = 0.1014] and Gizzard Shad [slope = -0.39; t = -3.02; P = 0.0073]) of native planktivores have declined. Floodplain lake qualitative evaluations yielded similar results; floodplain lake fish communities were likely altered (i.e., reductions in native species) by Silver Carp. Furthermore, laboratory experiments corroborated field evidence; Silver Carp negatively influence native planktivores through competition for prey (all comparisons, P > 0.05). To this end, this study provides evidence that Silver Carp are likely adversely influencing native fishes; however, mere presence of Silver Carp in the system does not induce deleterious effects on native fishes. To the best of our knowledge, this evaluation is the first to describe the effects of Asian Carp throughout the Mississippi River Basin and could be used to reduce the effects of Asian Carp on native biota through an integrated pest management program as suggested by congressional policy. Despite the simplicity of the data analyzed and approach used, this study provides a framework for beginning to identify the interactions of invasive fish pests on native fishes (i.e., necessary first step of integrated pest management). However, knowledge gaps remain. We suggest future efforts should conduct more in depth analyses (i.e., multivariate statistical approaches) that investigate the influence on all native species. PMID- 28873471 TI - Persistence in soil of Miscanthus biochar in laboratory and field conditions. AB - Evaluating biochars for their persistence in soil under field conditions is an important step towards their implementation for carbon sequestration. Current evaluations might be biased because the vast majority of studies are short-term laboratory incubations of biochars produced in laboratory-scale pyrolyzers. Here our objective was to investigate the stability of a biochar produced with a medium-scale pyrolyzer, first through laboratory characterization and stability tests and then through field experiment. We also aimed at relating properties of this medium-scale biochar to that of a laboratory-made biochar with the same feedstock. Biochars were made of Miscanthus biomass for isotopic C-tracing purposes and produced at temperatures between 600 and 700 degrees C. The aromaticity and degree of condensation of aromatic rings of the medium-scale biochar was high, as was its resistance to chemical oxidation. In a 90-day laboratory incubation, cumulative mineralization was 0.1% for the medium-scale biochar vs. 45% for the Miscanthus feedstock, pointing to the absence of labile C pool in the biochar. These stability results were very close to those obtained for biochar produced at laboratory-scale, suggesting that upscaling from laboratory to medium-scale pyrolyzers had little effect on biochar stability. In the field, the medium-scale biochar applied at up to 25 t C ha-1 decomposed at an estimated 0.8% per year. In conclusion, our biochar scored high on stability indices in the laboratory and displayed a mean residence time > 100 years in the field, which is the threshold for permanent removal in C sequestration projects. PMID- 28873470 TI - Comparative genomics and phylogenomic analyses of lysine riboswitch distributions in bacteria. AB - Riboswitches are cis-regulatory elements that regulate the expression of genes involved in biosynthesis or transport of a ligand that binds to them. Among the nearly 40 classes of riboswitches discovered so far, three are known to regulate the concentration of biologically encoded amino acids glycine, lysine, and glutamine. While some comparative genomics studies of riboswitches focusing on their gross distribution across different bacterial taxa have been carried out recently, systematic functional annotation and analysis of lysine riboswitches and the genes they regulate are still lacking. We analyzed 2785 complete bacterial genome sequences to systematically identify 468 lysine riboswitches (not counting hits from multiple strains of the same species) and obtain a detailed phylogenomic map of gene-specific lysine riboswitch distribution across diverse prokaryotic phyla. We find that lysine riboswitches are most abundant in Firmicutes and Gammaproteobacteria where they are found upstream to both biosynthesis and/or transporter genes. They are relatively rare in all other prokaryotic phyla where if present they are primarily found upstream to operons containing many lysine biosynthesis genes. The genome-wide study of the genetic organisation of the lysine riboswitches show considerable variation both within and across different Firmicute orders. Correlating the location of a riboswitch with its genomic context and its phylogenetic relationship with other evolutionarily related riboswitch carrying species, enables identification and annotation of many lysine biosynthesis, transporter and catabolic genes. It also reveals previously unknown patterns of lysine riboswitch distribution and gene/operon regulation and allows us to draw inferences about the possible point of origin of lysine riboswitches. Additionally, evidence of horizontal transfer of riboswitches was found between Firmicutes and Actinobacteria. Our analysis provides a useful resource that will lead to a better understanding of the evolution of these regulatory elements and prove to be beneficial for exploiting riboswitches for developing targeted therapies. PMID- 28873474 TI - The woman who could spell backwards. PMID- 28873475 TI - Woonsocket teens TEACH community health. PMID- 28873473 TI - Comparison of the treatment practice and hospitalization cost of percutaneous coronary intervention between a teaching hospital and a general hospital in Malaysia: A cross sectional study. AB - INTRODUCTION: The increasing disease burden of coronary artery disease (CAD) calls for sustainable cardiac service. Teaching hospitals and general hospitals in Malaysia are main providers of percutaneous coronary intervention (PCI), a common treatment for CAD. Few studies have analyzed the contemporary data on local cardiac facilities. Service expansion and budget allocation require cost evidence from various providers. We aim to compare the patient characteristics, procedural outcomes, and cost profile between a teaching hospital (TH) and a general hospital (GH). METHODS: This cross-sectional study was conducted from the healthcare providers' perspective from January 1st to June 30th 2014. TH is a university teaching hospital in the capital city, while GH is a state-level general hospital. Both are government-funded cardiac referral centers. Clinical data was extracted from a national cardiac registry. Cost data was collected using mixed method of top-down and bottom-up approaches. Total hospitalization cost per PCI patient was summed up from the costs of ward admission and cardiac catheterization laboratory utilization. Clinical characteristics were compared with chi-square and independent t-test, while hospitalization length and cost were analyzed using Mann-Whitney test. RESULTS: The mean hospitalization cost was RM 12,117 (USD 3,366) at GH and RM 16,289 (USD 4,525) at TH. The higher cost at TH can be attributed to worse patients' comorbidities and cardiac status. In contrast, GH recorded a lower mean length of stay as more patients had same-day discharge, resulting in 29% reduction in mean cost of admission compared to TH. For both hospitals, PCI consumables accounted for the biggest proportion of total cost. CONCLUSIONS: The high PCI consumables cost highlighted the importance of cost-effective purchasing mechanism. Findings on the heterogeneity of the patients, treatment practice and hospitalization cost between TH and GH are vital for formulation of cost-saving strategies to ensure sustainable and equitable cardiac service in Malaysia. PMID- 28873477 TI - Senior Physicians: Addressing Age, Ability and Acumen. PMID- 28873476 TI - Antipsychotic Medication Use and Reduction: Unanswered Questions and Policy Implications. PMID- 28873478 TI - The Aging Physician. PMID- 28873479 TI - Cognitive Decline in Physicians and their Patients. PMID- 28873480 TI - Legal Issues and the Aging Physician. PMID- 28873481 TI - Moving Forward: Retirement Opportunities for Senior Physicians. PMID- 28873482 TI - Respiratory viral testing in laboratories serving acute care hospitals in Rhode Island. AB - BACKGROUND: The rapid detection of respiratory viral infections is associated with several positive health outcomes. However, little is known about the availability of rapid respiratory viral testing in acute care hospital laboratories. METHODS: A survey was sent to 13 hospital laboratories assessing results' turnaround time, the number of ordered tests and positive results. RESULTS: Rapid viral panel (RVP), respiratory syncytial virus (RSV), and rapid influenza testing was available in 9 of 13, 13 of 13, and 13 of 13 hospitals, respectively. Results were available within 24 hours of specimen collection in 1 of 9 hospitals for RVP; RSV and rapid influenza results were available within 12 hours in 8 of 13 and 13 of 13 hospitals, respectively. CONCLUSIONS: Rapid diagnosis of respiratory viral infections in RI acute care hospitals can be made for influenza and RSV. However, rapid results for other respiratory viruses are unavailable in most of RI hospitals. [Full article available at http://rimed.org/rimedicaljournal-2017-09.asp]. PMID- 28873483 TI - A rare case of amelanotic anorectal melanoma. AB - We report an exceedingly rare case of amelanotic anorectal melanoma misdiagnosed as hemorrhoids. A 74-year-old man presented with a week's history of "blood on toilet tissue" without bowel complaints or history of cutaneous melanoma. Skin evaluation was normal. Rectal exam was negative for blood, but revealed an anal nodule, interpreted as a hemorrhoid. Hemoglobin was normal; bleeding persisted. After one month, colonoscopy detected a non-pigmented anal lesion. Biopsy showed melanoma. Noncutaneous mucosal melanoma represents 0.03% of new cancer diagnoses Anorectal melanoma accounts for 1% of melanomas and 0.4% of anal malignancies. Uncommonly, this malignancy lacks melanin pigment, complicating detection. Presenting complaints are non-specific rectal bleeding, pain, itching or incontinence, mimicking more common disorders. Dangerous misdiagnosis occurs when benign disease, not malignancy, is suspected. Risk factors for cutaneous melanoma are less frequent. Mucosal melanoma has different genetics. Clinicians must be aware of diagnostic difficulties of anorectal melanoma, especially when amelanotic. [Full article available at http://rimed.org/rimedicaljournal-2017 09.asp]. PMID- 28873484 TI - Multimodality imaging in the diagnosis of a large accessory papillary muscle. AB - An accessory papillary muscle is an uncommon congenital anomaly usually found incidentally on routine cardiac imaging. While frequently asymptomatic, it is occasionally associated with mitral regurgitation, left ventricular dynamic outflow obstruction and hypertrophic cardiomyopathy1 and it is important to differentiate it from other pathological processes including papillary fibroelastoma, left ventricle thrombus, hemangioma, a single papillary muscle with a parachute mitral valve and a left ventricle false tendon. The clinical implication of these findings varies according to the degree of left ventricular out flow obstruction, location and pathology. We report a case that underscores the importance of multimodality imaging in the diagnosis and differentiation of an accessory papillary muscle from other intracardiac masses. [Full article available at http://rimed.org/rimedicaljournal-2017-09.asp]. PMID- 28873485 TI - Suicide deaths among Rhode Island adults aged 25 years and older: An epidemiologic and spatial analysis. PMID- 28873486 TI - Meniscal Ramp Lesion Repair Using the FasT-Fix Technique: Evaluating Healing and Patient Outcomes with Second-Look Arthroscopy. AB - Although the suture-hook technique remains popular for meniscal ramp lesions, which frequently occur after anterior cruciate ligament (ACL) injury, it is unclear whether the all-inside FasT-Fix technique (Smith & Nephew, Andover, MA) is appropriate for the repair of ramp lesions. This study evaluated results of arthroscopic FasT-Fix meniscal ramp lesion repair using second-look arthroscopy. From August 2010 to December 2014, 46 knees diagnosed with combined ACL injury and ramp lesion underwent ACL reconstruction with meniscal repair using the FasT Fix technique. We classified ramp lesions into three types according to tear pattern: meniscotibial ligament tear, meniscocapsular tear, and combined meniscotibial/meniscocapsular tear. Second-look arthroscopy was performed postoperatively. The healing capacity of the ramp lesion was evaluated retrospectively. At the final follow-up (mean = 32 months), the Lysholm knee score and the International Knee Documentation Committee (IKDC) objective score were compared with preoperative scores. All patients (n = 46) underwent a second look arthroscopy, with 45 (97.8%) exhibiting complete or partial healing after the FasT-Fix technique was used in conjunction with ACL reconstruction. The Lysholm knee score and IKDC objective score were significantly better than preoperative scores at final follow-up. The FasT-Fix technique for meniscal ramp lesion repair-when performed with concomitant ACL reconstruction-exhibits excellent healing results. PMID- 28873487 TI - Effectiveness and Safety of Needle Medial Collateral Ligament Pie-Crusting in Total Knee Arthroplasty: A Cadaveric Study. AB - Medial collateral ligament (MCL) pie-crusting technique in total knee arthroplasty (TKA) is one of the methods of medial release. The effects and risks of blade pie-crusting have been reported in previous studies. However, only a few have reported the safety and efficacy of needle pie-crusting. In this cadaveric study, we quantitatively evaluated the amount of gap change by MCL needle pie crusting. We investigated five knees of four fresh human cadavers and performed posterior-stabilized TKA. Only deep MCL release as the medial release was conducted. We punctured the MCL from the deep layer to the superficial layer using a 18 G needle in a 90-degree flexion position for 0, 10, 20, 50, 75, and 100 times. Medial and lateral gaps were measured accurately with a balancer at determined times in 0 and 90-degree flexion positions. Changes in medial and lateral gaps were not significant differences in flexion and extension position. However, in 90-degree flexion, medial gap changes were tended to be larger than lateral gap changes. A 0.6 mm additional medial release and a 0.2 mm additional lateral release were found per 10 times pie crust in flexion position (100 times, p: 0.08). However, large differences existed among the cases. Needle pie-crusting is safer than blade pie-crusting because of the small efficacy of one-time pie crust. MCL needle pie-crusting showed varied effects for each case. This result indicates the risk of relaxation of an unexpected gap. Caution should be taken when choosing between needle pie-crusting and blade pie-crusting. PMID- 28873488 TI - Corrective Intra-articular Osteotomies for Tibial Plateau Malunion. PMID- 28873489 TI - Growth among Twins: Use of Singleton versus Twin-Specific Growth Nomograms. AB - OBJECTIVE: We hypothesized that utilization of a twin-specific nomograms, when compared with one based on singleton data, is less likely to classify twins as having abnormal growth and more likely to identify perinatal morbidity and mortality. MATERIALS AND METHODS: Data were culled from seven Maternal-Fetal Medicine Units (MFMU) studies, the included twin gestations in their study population. Each newborn twin's birth weight percentile was categorized using Alexander et al (singleton data) and Ananth et al (twin data) nomogram. Logistic regression models were adjusted for maternal race and body mass index, neonatal sex, study, and twin correlation. RESULTS: More twins were categorized as small for gestational age (SGA) when singleton nomogram was used (33%) compared with twin nomogram (4%). The use of singleton nomogram revealed a higher composite neonatal morbidity (CNM) and stillbirth rates among SGA twins but a similar neonatal mortality rate when compared with appropriate for gestational age. Correspondingly, when twin-specific nomogram was utilized, the CNM, odds of stillbirth, and neonatal mortality were higher among SGA twins. The rate of large for gestational age among twins was increased with the use of twin-specific nomograms. CONCLUSION: Utilization of twin-specific nomogram is less likely to categorize twins as SGA and more likely to identify those at risk for stillbirth and neonatal mortality. PMID- 28873490 TI - Simultaneous duodenal stenting and endoscopic ultrasound-guided hepaticogastrostomy using a forward-oblique view echoendoscope. PMID- 28873492 TI - [Blood Pressure Measurement and Treatment Targets: Position Paper of the DHL(r) Task Force Scientific Statements and Guidelines]. PMID- 28873491 TI - No Tissue Expression of KRAS or BRAF Mutations in 61 Adult Patients Treated for Esophageal Atresia in Early Childhood. AB - BACKGROUND: Previous studies have reported an association among esophageal atresia (EA), Barrett's esophagus, and esophageal adenocarcinoma later in life. OBJECTIVE: The objective of the article is to evaluate KRAS and BRAF mutations as potential genetic markers for early detection of malignant transformation, we used an ultrasensitive technique to detect tissue expression of KRAS and BRAF mutations in endoscopic biopsies from 61 adult patients under follow-up after treatment for EA. MATERIALS AND METHODS: RNA was extracted from 112 fresh-frozen endoscopic tissue biopsies from 61 adult patients treated for EA in early childhood. RNA was reverse transcribed using the extendable blocking probe reverse transcription method. KRAS codons 12 and 13, as well as BRAF mutations were detected by quantitative polymerase chain reaction. RESULTS: No mutations of KRAS codon 12, KRAS codon 13, or BRAF were found in 112 endoscopic biopsy samples from 61 patients. CONCLUSION: Despite the presence of histological findings indicating long-standing gastroesophageal reflux in 25%, as well as symptomatic gastroesophageal reflux in more than 40%, there was no detectable tissue expression of KRAS or BRAF mutations in this cohort of patients. PMID- 28873493 TI - [Rare differential diagnosis of chronic rhinosinusitis with nasal polyposis (CRSwNP)]. PMID- 28873494 TI - [Acute Flank Pain in Children and Adolescents]. AB - Acute flank pain in children and adolescents is a clinically demanding symptom requiring profound diagnostic work-up. Thorough history taking, careful clinical examination as well as urine and laboratory tests in addition to ultrasound are required to guide towards the diagnosis. This article presents possible underlying conditions with specific diagnostic and therapeutic considerations. PMID- 28873495 TI - [Defect coverage of the hand using a rare Siamese combined flap]. AB - We report 2 cases of extensive soft tissue defects simultaneously affecting the palm and dorsum of the hand. The defect was covered with a Siamese flap combination consisting of a free, distally extended lateral upper arm flap with microvascular anastomosis, and a posterior interosseous artery flap. We discuss possible indications, the operative technique and advantages versus disadvantages of this rarely applied flap combination. PMID- 28873496 TI - [Early active motion management of volar plate disruption of the proximal interphalangeal joint after finger hyperextension injury: extension block splinting versus buddy taping]. AB - Background Volar plate disruption of the proximal interphalangeal joint (PIP) is a common hand injury following finger hyperextension. At our institution, patients presenting with disruptions of the palmar plate (Eaton and Littler types I and II) before 2011 were treated with extension block splinting (group A). Since 2011, all patients with Eaton and Littler types I and II have received buddy taping (group B). The aim of this retrospective study was to compare the respective treatment outcomes. Patients and Methods In this retrospective study, we analysed the data of 44 patients visiting our department with volar plate disruption (Eaton and Littler types I and II) from 2009 to 2012. In group A, 23 patients were treated with custom-made extension block splinting in 10 degrees flexion, compared with 21 patients treated with buddy taping in group B. Both groups received dorsal night splinting in 10 degrees flexion. Results No statistically significant differences between the two groups were found in regard to treatment duration (p = 0,981), amount of required treatment sessions (p = 0,271), total active motion (TAM) (p = 0,693) and extension deficit (p = 0,404) in the PIP joint at the end of treatment, time until hand therapy was started (p = 0,285) or the Eaton und Littler diagnosis (p = 0,241). In the extension block group (group A), 10 out of 23 (44 %) patients after a median of 9 (4-10) weeks of treatment had an excellent result, 11 (48 %) had a good result, and 2 (8 %) patients had a poor result with a median 90 degrees (85-100 degrees ) TAM in the PIP joint and no extension deficit. In group A, all patients received a median of 4 (3-6) treatment sessions. Of those treated with buddy taping (group B), 14 out of 21 (66 %) patients at a median of 6 (4-13) weeks had an excellent result, 6 (29 %) had a good result, and 1 (5 %) patient had a poor result with a median TAM of 95 degrees (82,5-100 degrees ) and no extension deficit. In this group, patients received a total of 4 (3-5) treatment sessions. The type of treatment had no significant influence on the Benke and Stableforth outcome (chi2 = 2,385, df = 3, p = 0,304). No patient developed palmar joint instability. Conclusion No treatment option proved to be superior. We consider buddy taping to be faster, easier and more flexible to use. PMID- 28873497 TI - Calculating Groundwater Response Times for Flow in Heterogeneous Porous Media. AB - Predicting the amount of time required for a transient groundwater response to take place is a practical question that is of interest in many situations. This time scale is often called the response time. In the groundwater hydrology literature, there are two main methods used to calculate the response time: (1) both the transient and steady-state groundwater flow equations are solved, and the response time is taken to be amount of time required for the transient solution to approach the steady solution within some tolerance; and (2) simple scaling arguments are adopted. Certain limitations restrict both of these approaches. In this study, we outline a third method, based on the theory of mean action time. We derive the governing boundary value problem for both the mean and variance of action time for confined flow in two-dimensional heterogeneous porous media. Importantly, we show that these boundary value problems can be solved using widely available software. Applying these methods to a test case reveals the advantages of the theory of mean action time relative to standard methods. PMID- 28873498 TI - A Python Script to Compute Isochrones for MODFLOW. AB - MODFLOW constitutes today the most popular modeling tool in the study of water flow in aquifers and in modeling aquifers. To simplify the interface to MODFLOW various GUI have been developed for the creation of model definition files and for the visualization and interpretation of results. Recently Bakker et al. (2016) developed the FloPy interface to MODFLOW that allows to import and use the produced simulation data using Python. This allows to construct model input files, run the models, read and plot simulations results through Python scripts. In this note, we present a Python program (that uses FloPy) interface that allows us to generate time-related capture zones (isochrones) for confined 2D steady state groundwater flow in unbounded domains, with one or more wells. As an application, we show a validation of the approach and the results of four basic test cases: a homogenous aquifer with one well, a heterogeneous aquifer with one well, an aquifer with four wells located both longitudinal and perpendicular to the flow direction. PMID- 28873500 TI - Simultaneous determination of glaucocalyxin A and glaucocalyxin B in rat plasma by LC-MS/MS and its application to a pharmacokinetic study after oral administration of Rabdosia japonica extract. AB - A specific and sensitive liquid chromatography tandem mass spectrometry (LC MS/MS) method was developed and validated for the analysis of glaucocalyxin A and glaucocalyxin B in rat plasma using praeruptorin A as an internal standard. Separation was performed on a Hypurity C18 column (2.1 * 50 mm, 5 MUm) with isocratic elution using 0.2% formic acid in water-acetonitrile (20:80, v/v). Mass spectrometric detection was conducted using selected reaction monitoring via an electrospray ionization source. Both analytes exhibited good linearity within their concentration ranges (r2 > 0.9932). The lower limit of quantitation of glaucocalyxin A and glaucocalyxin B was 1.10 ng/mL. Intra- and inter-day precision exhibited an RSD within 14.5%, and the accuracy (RE) ranged from -12.1 to 15.0% at the lower limit of quantitation and three quality control levels. The developed assay was successfully applied to a pharmacokinetic study of glaucocalyxin A and glaucocalyxin B in rats after oral administration of Rabdosia japonica extract. PMID- 28873499 TI - Bioremediation in Fractured Rock: 2. Mobilization of Chloroethene Compounds from the Rock Matrix. AB - A mass balance is formulated to evaluate the mobilization of chlorinated ethene compounds (CE) from the rock matrix of a fractured mudstone aquifer under pre- and postbioremediation conditions. The analysis relies on a sparse number of monitoring locations and is constrained by a detailed description of the groundwater flow regime. Groundwater flow modeling developed under the site characterization identified groundwater fluxes to formulate the CE mass balance in the rock volume exposed to the injected remediation amendments. Differences in the CE fluxes into and out of the rock volume identify the total CE mobilized from diffusion, desorption, and nonaqueous phase liquid dissolution under pre- and postinjection conditions. The initial CE mass in the rock matrix prior to remediation is estimated using analyses of CE in rock core. The CE mass mobilized per year under preinjection conditions is small relative to the total CE mass in the rock, indicating that current pump-and-treat and natural attenuation conditions are likely to require hundreds of years to achieve groundwater concentrations that meet regulatory guidelines. The postinjection CE mobilization rate increased by approximately an order of magnitude over the 5 years of monitoring after the amendment injection. This rate is likely to decrease and additional remediation applications over several decades would still be needed to reduce CE mass in the rock matrix to levels where groundwater concentrations in fractures achieve regulatory standards. PMID- 28873501 TI - ERAS-Value based surgery. AB - This paper reviews implementation of ERAS and its financial implications. Literature on clinical outcomes and financial implications were reviewed. Reports from many different surgery types shows that implementation of ERAS reduces complications and shortens hospital stay. These improvements have major impacts on reducing the cost of care even when costs for implementation, and investment in time for personnel and training is accounted for. The conclusion is that ERAS is an excellent example of value based surgery. PMID- 28873502 TI - Bioremediation in Fractured Rock: 1. Modeling to Inform Design, Monitoring, and Expectations. AB - Field characterization of a trichloroethene (TCE) source area in fractured mudstones produced a detailed understanding of the geology, contaminant distribution in fractures and the rock matrix, and hydraulic and transport properties. Groundwater flow and chemical transport modeling that synthesized the field characterization information proved critical for designing bioremediation of the source area. The planned bioremediation involved injecting emulsified vegetable oil and bacteria to enhance the naturally occurring biodegradation of TCE. The flow and transport modeling showed that injection will spread amendments widely over a zone of lower-permeability fractures, with long residence times expected because of small velocities after injection and sorption of emulsified vegetable oil onto solids. Amendments transported out of this zone will be diluted by groundwater flux from other areas, limiting bioremediation effectiveness downgradient. At nearby pumping wells, further dilution is expected to make bioremediation effects undetectable in the pumped water. The results emphasize that in fracture-dominated flow regimes, the extent of injected amendments cannot be conceptualized using simple homogeneous models of groundwater flow commonly adopted to design injections in unconsolidated porous media (e.g., radial diverging or dipole flow regimes). Instead, it is important to synthesize site characterization information using a groundwater flow model that includes discrete features representing high- and low-permeability fractures. This type of model accounts for the highly heterogeneous hydraulic conductivity and groundwater fluxes in fractured-rock aquifers, and facilitates designing injection strategies that target specific volumes of the aquifer and maximize the distribution of amendments over these volumes. PMID- 28873503 TI - Large-scale NMR simulations in liquid state: A tutorial. AB - Liquid state nuclear magnetic resonance is the only class of magnetic resonance experiments for which the simulation problem is solved comprehensively for spin systems of any size. This paper contains a practical walkthrough for one of the many available simulation packages - Spinach. Its unique feature is polynomial complexity scaling: the ability to simulate large spin systems quantum mechanically and with accurate account of relaxation, diffusion, chemical processes, and hydrodynamics. This paper is a gentle introduction written with a PhD student in mind. PMID- 28873504 TI - ERAS-Anticipated outcomes and realistic goals. AB - Enhanced recovery programs emphasize implementation of perioperative measures to reduce stress and restore baseline function. Complications and length of stay are greatly improved as a result, but the field is moving toward more patient centric and longer term outcomes that better reflect functional recovery. Programs demonstrating value in these domains will undoubtedly see corollary gains in traditional metrics. Thus, greater focus on patient well-being and treatment success is key to successful implementation of enhanced recovery. PMID- 28873505 TI - Enhanced recovery after surgery: Pain management. AB - Effective pain management is fundamental to enhanced recovery after surgery. Selection of strategies should be tailored to patient and operation. As well as improving the quality of recovery, effective analgesia reduces the host stress response, facilitates mobilization and allows resumption of oral intake. Multi modal regimens combining paracetamol, non-steroidal anti-inflammatory agents where indicated, a potent opioid and a local anaesthetic technique achieve effective analgesia while limiting the dose and thereby side effects of any one agent. PMID- 28873506 TI - Enhanced recovery after surgery-Summary recommendations. PMID- 28873507 TI - Borrelia burgdorferi outer surface protein C (OspC) binds complement component C4b and confers bloodstream survival. AB - Borrelia burgdorferi (Bb) is the causative agent of Lyme disease in the United States, a disease that can result in carditis, and chronic and debilitating arthritis and/or neurologic symptoms if left untreated. Bb survives in the midgut of the Ixodes scapularis tick, or within tissues of immunocompetent hosts. In the early stages of infection, the bacteria are present in the bloodstream where they must resist clearance by the innate immune system of the host. We have found a novel role for outer surface protein C (OspC) from B. burgdorferi and B. garinii in interactions with the complement component C4b and bloodstream survival in vivo. Our data show that OspC inhibits the classical and lectin complement pathways and competes with complement protein C2 for C4b binding. Resistance to complement is important for maintenance of the lifecycle of Bb, enabling survival of the pathogen within the host as well as in the midgut of a feeding tick when ospC expression is induced. PMID- 28873508 TI - Fecal Immunochemical Test and Fecal Calprotectin Results Show Different Profiles in Disease Monitoring for Ulcerative Colitis. AB - Background/Aims: Both fecal immunochemical test (FIT) and fecal calprotectin (Fcal) results are useful biomarkers for ulcerative colitis (UC). However, the situations in which each marker should be used are largely unknown. Methods: A total of 110 colonoscopy intervals of UC patients were assessed, and correlations between changes in colonoscopic findings and changes in the two aforementioned fecal markers were examined. Results: Among patients with mucosal healing (MH) and negative FIT or Fcal results at the initial colonoscopy, FIT and Fcal findings exhibited accuracies of 93% (38/41) and 79% (26/33), respectively, for predicting the results of the subsequent examination. Among the 24 patients who showed endoscopic activity at the precedent colonoscopy and MH at the subsequent examination, positive-to-negative conversion of FIT and Fcal findings at the subsequent examination was observed in 92% (12/13) and 62% (8/13) of patients, respectively. Among the 43 patients who showed endoscopic activity at both the precedent and subsequent examinations, Fcal findings reflected the change in endoscopic activity better than FIT results (r=0.59, p<0.0001 vs r=0.30, p=0.054). Conclusions: The FIT is useful for confirming MH and the occurrence of relapse. In contrast, Fcal is useful for monitoring the mucosal status of patients with active inflammation. PMID- 28873509 TI - Can More Aggressive Treatment Improve Prognosis in Patients with Hepatocellular Carcinoma? A Direct Comparison of the Hong Kong Liver Cancer and Barcelona Clinic Liver Cancer Algorithms. AB - Background/Aims: In addition to the globally endorsed Barcelona Clinic Liver Cancer (BCLC) staging system, other algorithms or staging systems have been developed, including the Hong Kong Liver Cancer (HKLC) staging system. This study aimed to validate the HKLC staging system relative to the BCLC staging system for predicting survival for hepatocellular carcinoma (HCC) patients in Korea. Methods: From 2004 to 2013, 2,571 patients newly diagnosed with HCC were consecutively enrolled at three Korea University medical centers. Results: Both staging systems differentiated survival well (p<0.001). However, 1-year and 3 year survival were predicted better using the HKLC system than the BCLC system (area under the receiver operating characteristic curve: 0.869 vs 0.856 for 1 year, p=0.002; 0.841 vs 0.827 for 3 years, p=0.010). In hypothetical survival curves, the HKLC system exhibited better median overall survival than the BCLC system (33.1 months vs 19.2 months). In evaluations of prognosis according to either BCLC or HKLC treatment guidelines, risk of death was reduced in the group following only HKLC guidelines compared with the group following only BCLC guidelines (hazard ratio, 0.601; 95% confidence interval, 0.443 to 0.816; p=0.001). Conclusions: Although both staging systems predicted and discriminated HCC prognoses well, the HKLC system showed more encouraging survival benefits than the BCLC system. PMID- 28873510 TI - Knowledge Gaps among Physicians Caring for Multiethnic Populations at Increased Gastric Cancer Risk. AB - Background/Aims: Although gastric cancer (GC) prevalence in the United States overall is low, there is significantly elevated risk in certain racial/ethnic groups. Providers caring for high-risk populations may not be fully aware of GC risk factors and may underestimate the potential for selective screening. Our aim was to identify knowledge gaps among healthcare providers with respect to GC. Methods: An Internet-based survey was distributed to primary care providers (PCPs) and gastroenterologists in New York City, which included questions regarding provider demographics, practice environment, GC risk factors, Helicobacter pylori, and screening practices. Three case vignettes were used to assess clinical management. Results: Of 151 included providers (111 PCPs, 40 gastroenterologists), most reported caring for a racially/ethnically diverse population and 58% recommended GC screening for select populations. Although >85% recommended against testing patients from regions where H. pylori, a known carcinogen, is endemic, <50% were able to correctly identify non-Asian endemic regions. Minorities of respondents correctly identified Hispanic/Latino (29%), Black (22%), and Eastern European/Russian (19.7%) as additional higher-risk races/ethnicities. Vignette-based questions highlighted variability in the management of potentially higher-risk patients. Conclusions: Despite caring for multiracial/ethnic populations, providers demonstrated deficiencies in identifying and managing patients with elevated GC risk. Focused educational efforts should be considered to address these deficiencies. PMID- 28873511 TI - Umbilical Cord Mesenchymal Stem Cell Treatment for Crohn's Disease: A Randomized Controlled Clinical Trial. AB - Background/Aims: Stem cell therapy has been applied to treat a variety of autoimmune diseases, including Crohn's disease (CD), but few studies have examined the use of umbilical cord mesenchymal stem cells (UC-MSCs). This trial sought to investigate the efficacy and safety of UC-MSCs for the treatment of CD. Methods: Eighty-two patients who had been diagnosed with CD and had received steroid maintenance therapy for more than 6 months were included in this study. Forty-one patients were randomly selected to receive a total of four peripheral intravenous infusions of 1*106 UC-MSCs/kg, with one infusion per week. Patients were followed up for 12 months. The Crohn's disease activity index (CDAI), Harvey Bradshaw index (HBI), and corticosteroid dosage were assessed. Results: Twelve months after treatment, the CDAI, HBI, and corticosteroid dosage had decreased by 62.5+/-23.2, 3.4+/-1.2, and 4.2+/-0.84 mg/day, respectively, in the UC-MSC group and by 23.6+/-12.4, 1.2+/-0.58, and 1.2+/-0.35 mg/day, respectively, in the control group (p<0.01, p<0.05, and p<0.05 for UC-MSC vs control, respectively). Four patients developed a fever after cell infusion. No serious adverse events were observed. Conclusions: UC-MSCs were effective in the treatment of CD and produced mild side effects. PMID- 28873512 TI - Significantly enhanced substrate tolerance of Pseudomonas putida nitrilase via atmospheric and room temperature plasma and cell immobilization. AB - The objective of the study was to enhance the substrate tolerance of Pseudomonas putida nitrilase via atmospheric and room temperature plasma (ARTP) and cell immobilization. The mutant library was constructed by ARTP and rapidly screened by an OPA-TCA microscale reaction. A mutant strain of mut-D3 was obtained and its optimum substrate concentration was improved to 150mM from 100mM. It could accumulate 189g/L nicotinic acid (NA) from 3-cyanopyridine (3-CP), which was increased by 42% compared with that of wild type (WT). Additionally, composite immobilization of mut-D3 was performed and SA-PVA immobilized cells could catalyze 250mM 3-CP each batch with finally accumulating 346g/L NA, while free cells accumulated 175g/L NA. These results indicated that the free or immobilized catalysts of mut-D3 could serve as a good choice for NA production. This is the first report on mutation breeding of nitrilase-producing microorganisms by ARTP. PMID- 28873513 TI - Lignin and ash balances of sulfur dioxide-ethanol-water fractionation of sugarcane straw. AB - Lignin and ash material balances of SO2-ethanol-water (AVAP(r)) fractionation of sugarcane (SC) straw were thoroughly studied at various conditions. Most of straw lignin and ash dissolve in the liquor and 40-80% of lignin is precipitated after ethanol removal as a pure (~99%) and sulfur-lean (<2%) fraction. Most of the acid soluble ash and its elements (Na, K, Fe, Al) as well as large portion of silica are removed from the fiber phase. Straw lignin behavior exhibited differences compared to wood lignin including high apparent content in fiber, higher degree of sulfonation of dissolved lignin, and dense char-like precipitate formation upon ethanol removal. Variation in fractionation conditions did not have significant effect on lignin properties, while post-sulfonation was capable of changing its form from char-like to colloidal precipitate. PMID- 28873514 TI - Effect of dietary vitamin E on physicochemical and fatty acid stability of fresh and thawed lamb. AB - This study evaluated the effect of dietary vitamin E supplementation (1000mg of DL-alpha-tocopheryl acetate/kg of basal diet) on physicochemical and fatty acid stability of fresh and thawed lamb leg chops, frozen stored for 3, 6 and 9months. Legs were chopped, modified atmosphere packaged (70%O2/30%CO2) and maintained under retail conditions (4+/-0.5 degrees C, with 14h fluorescent light) for 9days. Muscle alpha-tocopherol concentration was over 3.5-fold higher in supplemented samples than in control lambs. The effect of dietary vitamin E was independent of frozen storage, so these effects were analysed separately. Vitamin E supplementation reduced lipid oxidation (P<=0.001) and decreased metmyoglobin formation, leading to a more attractive colour of meat. Moreover, supplementation led to a higher percentage of polyunsaturated fatty acids. Therefore, vitamin E supplementation could be recommended for preserving either fresh or thawed lamb. PMID- 28873515 TI - Characterization of myofibrils cold structural deformation degrees of frozen pork using hyperspectral imaging coupled with spectral angle mapping algorithm. AB - The study investigated the possibility of using hyperspectral imaging (HSI) in the spectral range of 1000-2200nm to characterize myofibrils cold structural deformation degrees of frozen pork samples. The HSI images of pork samples frozen under different freezing rates were acquired in the frozen state without thawing. The myofibrils cold structural deformation degrees were evaluated by surface hydrophobicity (S0ANS) and Ca2+-ATPase activity. Spectral angle mapping (SAM) algorithm was used for the first time to extract the spectral information for regression. Compared with the optimized partial least square regression (PLSR) models based on selected wavebands by successive projections algorithm (SPA), the optimized PLSR models developed based on the spectral angles calculated by the SAM algorithm achieved comparable or even better performance with R2P of 0.896 for S0ANS and 0.879 for Ca2+-ATPase activity, respectively. The implications of the frozen meat spectrum were also analyzed in the current study. PMID- 28873516 TI - Comparative analysis of pigments in red and yellow banana fruit. AB - Color is an important characteristic determining the fruit value. Although ripe bananas usually have yellow peels, several banana cultivars have red peels. As details of the pigments in banana fruits are unknown, we investigated these pigments contents and compositions in the peel and pulp of red cultivar 'Hongjiaowang' and yellow cultivar 'Baxijiao' by UPLC-PDA-QTOF-MS and HPLC-PDA techniques. The 'Hongjiaowang' peel color was mainly determined by the presence of anthocyanin-containing epidermal cells. Rutinoside derivatives of cyanidin, peonidin, petunidin, and malvidin were unique to the red peel, and possibly responsible for the red color. 'Hongjiaowang' contained higher total content of carotenoids than 'Baxijiao' in both pulp and peel. Lutein, alpha-carotene, and beta-carotene were main carotenoids, which might play a more important role than flavonoids in producing the yellow banana color owing to the properties and distribution in the fruit. The information will help us understand a complete profile of pigments in banana. PMID- 28873518 TI - Impact of Plasmopara viticola infection of Merlot and Cabernet Sauvignon grapes on wine composition and flavor. AB - This work reports the identification of volatile compounds involved in the particular and atypical flavor detected in Vitis vinifera red Merlot and Cabernet Sauvignon wines made with grapes infected and wilted by brown rot (Plasmopara viticola). Must made from withered grapes had green aromas while red wines were marked by intense odor reminiscent of green, herbaceous notes but also figs and cooked fruit. Thanks to GC-O and GC-MS analysis, cooked fruit notes were identified as 3-methyl-2,4-nonanedione, gamma-nonalactone and gamma-decalactone, whereas herbaceous and green aromas were identified as (Z)-1,5-octadien-3-one and 3-isobutyl-2-methoxypyrazine. We show that the organoleptic impact of P. viticola is more pronounced in Merlot wines compared to Cabernet Sauvignon ones. The highest levels of 3-methyl-2,4-nonanedione (75.3ng/L) were found in old Merlot wines made with 20% infected berries, suggesting the incidence of berry quality on the ability of a wine to age. PMID- 28873517 TI - Preconcentration and extraction of lead ions in vegetable and water samples by N doped carbon quantum dot conjugated with Fe3O4 as a green and facial adsorbent. AB - Magnetically N-doped Carbon quantum dots has been synthesized via a simple chemical method and applied as a sorbent for the preconcentration and extraction of trace amounts of Pb2+ from water and vegetable samples followed by flame atomic absorption spectrometric detection. The nanoparticles were characterized by X-ray diffraction, UV-vis spectra, Fourier transform infrared spectroscopy, vibrating sample magnetometer analysis and transmission electron microscopy. A central-composite design was used to find the optimum conditions for the preconcentration procedure through response surface methodology. The effects of various parameters such as the pH value, adsorption time, amount of adsorbent, desorption conditions (type, concentration and volume of the eluent and desorption time), sample volume and interfering ions have been studied. Under the optimized conditions, the calibration graph was linear in the range of 0.3 300MUgL-1 (R2=9992). The detection limit and pre-concentration factor were found to be 0.082MUgL-1 and 265, respectively. PMID- 28873519 TI - Differential expression of albumins and globulins of wheat flours of different technological qualities revealed by nanoUPLC-UDMSE. AB - Soluble proteins were extracted from common wheat flour obtained from nine cultivars of different qualities and were analyzed by nanoUPLC and Ultra Definition Mass Spectrometry (UDMSE) label-free quantitative approach. Collectively, 5894 proteins were identified and quantified with 8 peptides/protein. A total of 414 proteins were found differentially expressed with 85% proteins not yet described in the literature, according to their biological function. Quality-related proteins, such as puroindolines and chaperones, notably involved in the gluten-protein folding process, were up regulated in superior (SP) and medium (MD) flours qualities and down-regulated in the low (LW) ones. Domains related to the chaperones activity were also found up regulated in SP and MD and down-regulated in LW. In this work, nanoUPLC-UDMSE analysis was effective to identify and quantify metabolic proteins, allowing a clear distinction of the wheat flours and providing new perspectives for evaluating the technological quality based on the low abundant proteins of wheat endosperm. PMID- 28873520 TI - Improvement of feed pellet characteristics by dietary pre-gelatinized starch and their subsequent effects on growth and physiology in tilapia. AB - A 9-week study was conducted to compare dietary corn starch (CS) or tapioca starch (TS), with or without being pre-gelatinized (PG), on the growth, feeding efficiencies, plasma and muscle biochemistry, intestinal short chain fatty acids (SCFA), and liver glycogen of triplicate groups of 20 red hybrid tilapia (Orecohromis sp.). Various pellet characteristics were evaluated, along with their surface and cross sectional microstructure. The PG diets had significantly higher water stability, bulk density, and protein solubility, along with a smoother surface. Tilapia fed the TS diet had lower growth than had all other tilapia, but were significantly improved when diet was pre-gelatinized. In the PG treatments, intestinal SCFA significantly decreased while plasma glucose, cholesterol and triglycerides, as well as liver glycogen, significantly increased. Fish fed the CS diet had significantly more long chain polyunsaturated fatty acid than had those fed by other treatments. Pre-gelatinization may improve fish productivity and offer greater flexibility during aquafeed production. PMID- 28873521 TI - Effect of substituted gelling agents from pomegranate peel on colour, textural and sensory properties of pomegranate jam. AB - A series of pomegranate jams were prepared from a Tunisian ecotype (Tounsi) with different amounts of sugar (10, 20 and 30%) and low-methoxylated pectin (0.2, 0.7 and 1.2%). The most appreciated formulation was that contaning 30% sugars and 0.2% pectin. Then, commercial pectin was substituted by other gelling agents (pomegranate peel powders dried at 50 degrees C vs lyophilized, pectin and fibre extracted from pomegranate peel) for the preparation of pomegranate peel-based jams. The elaborated jams were evaluated for physichochemical, colour, texture and sensory characteristics. Results revealed that the jam (JPP2) elaborated with 0.2% pectin extracted from pomegranate peel exhibited similar overall acceptability to that prepared with commercial pectin. However, it was more acceptable than other pomegranate peel-based jams, which was related to a better appreciation of sweetness and colour. According to the colour and texture measurements, this sample (JPP2) was more reddish and less firm than other samples. PMID- 28873522 TI - A bi-layer model for nondestructive prediction of soluble solids content in apple based on reflectance spectra and peel pigments. AB - Hyperspectral imaging technology was used to investigate the effect of various peel colors on soluble solids content (SSC) prediction model and build a SSC model insensitive to the color distribution of apple peel. The SSC and peel pigments were measured, effective wavelengths (EWs) of SSC and pigments were selected from the acquired hyperspectral images of the intact and peeled apple samples, respectively. The effect of pigments on the SSC prediction was studied and optimal SSC EWs were selected from the peel-flesh layers spectra after removing the chlorophyll and anthocyanin EWs. Then, the optimal bi-layer model for SSC prediction was built based on the finally selected optimal SSC EWs. Results showed that the correlation coefficient of prediction, root mean square error of prediction and selected bands of the bi-layer model were 0.9560, 0.2528 and 41, respectively, which will be more acceptable for future online SSC prediction of various colors of apple. PMID- 28873523 TI - Influence of different hydrocolloids on dough thermo-mechanical properties and in vitro starch digestibility of gluten-free steamed bread based on potato flour. AB - The effects of hydrocolloids (hydroxypropylmethylcellulose (HPMC), Carboxymethylcellulose (CMC), xanthan gum (XG), and apple pectin (AP)) at different concentrations on dough thermo-mechanical properties and in vitro starch digestibility of gluten-free potato steamed bread were investigated. Results showed that hydrocolloids addition significantly increased the gelatinization temperature (from 52.0 to 64.2 degrees C) and water absorption (from 56.22 to 66.50%) of potato dough. Moreover, hydrocolloids may be interacted with protein and starch, the density of potato protein bands was decreased by hydrocolloids addition, the reason might be that higher molecular weight complexes might be formed between proteins-hydrocolloids or proteins-proteins, thus change the protein solubility. Furthermore, steamed breads with hydrocolloids presented higher specific volume and lower hardness, and the rapidly digestible starch and estimated glycemic index were significantly decreased from 45.51 to 20.64, from 69.54 to 55.17, respectively. In conclusion, HPMC and XG could be used as improvers in the gluten-free potato steamed bread. PMID- 28873525 TI - Development of validated high-temperature reverse-phase UHPLC-PDA analytical method for simultaneous analysis of five natural isothiocyanates in cruciferous vegetables. AB - In the present study reverse-phase UHPLC-PDA technique was developed at 60 degrees C for simultaneous quantification of allyl, 3-butenyl, 4 (methylthio)butyl, benzyl and phenethyl isothiocyanates. The validation parameter showed a very good linearity, with a correlation coefficient of 1.00 for all detected standard analytes. Also, high precision and accuracy were observed with lowest obtained values of 1.39% and 99.1%, respectively. Different varieties of three plants, viz. Brassica rapa var. rapa L., Raphanus sativus L. var. oleiformis Pers. and Eruca sativa Mill., were analyzed with this method. After analysis, 4-(methylthio)butyl isothiocyanate was observed to be the major component in the varieties of arugula. Allyl, benzyl and phenethyl isothiocyanates were detected in turnip varieties and, in addition, 3-butenyl isothiocyanate was detected in radish varieties. PMID- 28873524 TI - Pyridinium ionic liquid-based liquid-solid extraction of inorganic and organic iodine from Laminaria. AB - A simple, green and effective extraction method, namely, pyridinium ionic liquid- (IL) based liquid-solid extraction (LSE), was first designed to extract the main inorganic and organic iodine compounds (I-, monoiodo-tyrosine (MIT) and diiodo tyrosine (DIT)). The optimal extraction conditions were as follows: ultrasonic intensity 100W, IL ([EPy]Br) concentration 200mM, extraction time 30min, liquid/solid ratio 10mL/g, and pH value 6.5. The morphologies of Laminaria were studied by scanning electron microscopy and transmission electron microscopy. The recovery values of I-, MIT and DIT from Laminaria were in the range of 88% to 94%, and limits of detection were in the range of 59.40 to 283.6ng/g. The proposed method was applied to the extraction and determination of iodine compounds in three Laminaria. The results showed that IL-based LSE could be a promising method for rapid extraction of bioactive iodine from complex food matrices. PMID- 28873526 TI - Characterization and effects of binding of food-derived bioactive phycocyanobilin to bovine serum albumin. AB - Phycocyanobilin (PCB) is a blue tetrapyrrole chromophore of C-phycocyanin, the main protein of the microalga Spirulina, with numerous proven health-related benefits. We examined binding of PCB to bovine serum albumin (BSA) and how it affects protein and ligand stability. Protein fluorescence quenching and microscale thermophoresis demonstrated high-affinity binding (Ka=2*106M-1). Spectroscopic titration with molecular docking analysis revealed two binding sites on BSA, at the inter-domain cleft and at subdomain IB, while CD spectroscopy indicated stereo-selective binding of the P conformer of the pigment to the protein. The PCB protein complex showed increased thermal stability. Although complex formation partly masked the antioxidant properties of PCB and BSA, a mutually protective effect against free radical-induced oxidation was found. BSA could be suitable for delivery of PCB as a food colorant or bioactive component. Our results also highlight subtle differences between PCB binding to bovine vs. human serum albumin. PMID- 28873527 TI - Enzymes loaded chitosan/coconut fibre/zinc oxide nanoparticles strip for polyamine determination. AB - Most often, the immobilized enzyme based quantification is an attractive alternative to other chromatographic, electrochemical and mass spectrometry based methods due to its specificity and simplicity. In the present study, polyamine oxidase specific for spermine and spermidine and diamine oxidase specific for putrescine, were co-immobilized onto a novel chitosan/coconut fibre/zinc oxide nanoparticles (CS/CF/nZnO) hybrid support to yield a polyamine sensing strip. The strip worked optimally at pH 7.0, temperature 25 degrees C and 6min of incubation time. Pretty good values for kinetic constants Kmapp (6.60mM), Vmax (17.69MUmol/min mg protein) and kcatapp (1987.64s-1) as well as for thermal (<50 % activity retained at 40 degrees C), storage (half life-40days) and operational stabilities (<90 % activity retained after 20 reuses) were obtained. The strip was employed for polyamine determination in some of the locally grown fruit and vegetables and the results were found to be comparable, reliable and reproducible. PMID- 28873528 TI - Inhibitory effects of Sichuan pepper (Zanthoxylum bungeanum) and sanshoamide extract on heterocyclic amine formation in grilled ground beef patties. AB - This study evaluated the inhibitory effects of Sichuan pepper (Zanthoxylum bungeanum) and sanshoamide extract on the formation of heterocyclic amines (HAs) in grilled beef patties. The following major HAs were detected and quantified: imidazopyridine (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, PhIP), imidazoquinoxalines (2-amino-3-methyl-3H-imidazo[4,5-f]quinoxaline, IQx; 2-amino 3,8-dimethylimidazo[4,5-f]quinoxaline, MeIOx; 2-amino-3,4,8-trimethyl-3H imidazo[4,5-f]quinoxaline, 4,8-DiMeIQx) and beta-carbolines (9H-pyrido[3,4 b]indole, norharman; 1-methyl-9H-pyrido[3,4-b]indole, harman). The rates of PhIP, IQx, MeIQx and 4,8-DiMeIQx were inhibited significantly by 82%, 61%, 28% and 79%, respectively, in patties treated with a low-concentration of pepper (0.5%), and by 27%, 45%, 44% and 26%, respectively, following treatment with a low concentration sanshoamide extract (0.005%). All inhibition rates exceeded 70% at pepper and sanshoamide extract concentrations of 1.0% and 0.010%, respectively. Harman and norharman could be significantly (p<0.05) enhanced by the addition of all concentrations of Sichuan pepper, however, sanshoamide extract had no significant (p>0.05) effect on them, although 0.005% of the extract could slightly increase the formation of them. Notably, significant correlations were observed between the HA inhibition rates and pepper or sanshoamide extract concentrations, especially for PhIP (r=0.87, p=2.30E-3), IQx (r=0.99, p=5.04E-7) and 4,8-DiMeIQx (r=0.88, p=1.96E-3). These results indicate that Sichuan pepper and sanshoamide extract could inhibit the formation of carcinogenic HAs during thermal preparation of protein-rich foods, and therefore might reduce the risk of chronic diseases associated with the long-term intake of HA-containing food products. PMID- 28873529 TI - Structural characterization of proanthocyanidins from adzuki seed coat. AB - Adzuki bean seed coats contain a variety of pigments with potential bioactivity, including polyphenols, such as proanthocyanidin. To clarify the structure of the pigments from adzuki bean seed coats, the MeOH extract of the seed coats and the extraction residue were subjected to various instrumental analyses and degradation by thiolysis. The MeOH extract was found to contain two types of polymeric red pigments. One of these pigments was assumed to be a simple proanthocyanidin, whereas the other was a complicated polyphenol produced by several modifications and conversions. Direct thiolysis of adzuki seed coat yielded three products as extension subunits. From their chemical structures, a glyoxylic acid-bridged catechin skeleton was suggested as a partial structure of adzuki pigments. PMID- 28873530 TI - Antioxidant activities of ginger extract and its constituents toward lipids. AB - Lipid oxidation-a major cause of food product deterioration-necessitates the use of food additives to inhibit food oxidation. Ginger extract (GE) has been reported to possess antioxidant properties. However, components isolated from ginger have been rarely reported to inhibit fat oxidation. Herein, antioxidant properties of GE and four pure components derived from it (6-gingerol, 8 gingerol, 10-gingerol, and 6-shogaol) were examined and their properties were compared to those of butylated hydroxytoluene. GE and the constituent components exhibited antioxidant properties that might be attributed to their hydroxyl groups and suitable solubilizing side chains. 6-Shogaol and 10-gingerol exhibited higher activity at 60 degrees C than 6-gingerol and 8-gingerol. Low antioxidant activity was detected at high temperatures (120/180 degrees C). Overall, GE displayed the strongest dose-dependent antioxidant properties, especially at high temperatures, thereby demonstrating that GE can be employed as a natural antioxidant in lipid-containing processed foods. PMID- 28873531 TI - Investigation of color-deepening phenomenon in catechin-(4->8)-dimer as a proanthocyanidin model and structural determination of its derivatives by oxidation. AB - To elucidate the mechanism of the color-deepening phenomenon in aged red rice samples, a partial structure of proanthocyanidin, (+)-catechin-(4->8)-dimer (1), was synthesized as a model compound and subjected to chemical oxidation. HPLC analysis of oxidized 1 revealed new peaks which were isolated; among these, four compounds (2-5) having formed intramolecular bonds between the D and B rings were determined. These compounds and their derivatives in red rice extracts were identified by multiple reaction monitoring mass spectrometry. The UV-Vis spectra of 1-5 were recorded to clarify the correlation between the color-deepening effect and their chemical structures. Hence, the spectral absorption maxima between 300 and 500nm, corresponding to the oxidation products, increase. Therefore, the color-deepening phenomenon of red rice is thought to proceed via the formation of intramolecular bonds in proanthocyanidin by oxidation. PMID- 28873532 TI - Effect of sodium alginate with three molecular weight forms on the water holding capacity of chicken breast myosin gel. AB - The effect of 0.1-0.5% (w/w) sodium-alginate (SA) with three molecular-weights (2660, 3890 and 4640kDa) on the water-holding capacity (WHC) of chicken-breast myosin gels was investigated. The results showed that 0.1-0.5% SA of three molecular-weights increased the WHC of myosin-SA gels, and the heavier SA induced a higher WHC. Electrostatic-interactions and hydrogen-bonding contributed to the intermolecular aggregation in the myosin-SA system and enhanced its intermolecular interactions by overcoming the steric hindrance effect of SA with heavier molecules. This aggregation induced the increased turbidity, transition temperature and the decreased surface hydrophobicity of myosin-SA solutions and the formation of an inhomogeneous network with large cavities for entrapping water. The combined effects of stronger intermolecular interactions and the network induced a higher WHC of the gel with heavier SA. It is interesting to understand the gelling mechanism for the protein-polysaccharide system and to efficiently select SA for developing low-fat meat products in industry. PMID- 28873533 TI - Speciation of Zn, Fe, Ca and Mg in wine with the Donnan Membrane Technique. AB - Free concentrations of Zn2+, Fe3+, Ca2+ and Mg2+ in a red wine (Raimat, Catalonia, Spain) have been determined, with the Donnan Membrane Technique (DMT) for the first time. The required equilibration time benefits from the acceptor solution including major cations. K+ and Na+, mainly unbound to any ligand in the sample, have been identified as suitable reference ions. A free Zn concentration of 1.76MUmolL-1 determined with DMT was in excellent agreement with the free Zn concentration independently provided by the electroanalytical technique Absence of Gradients and Nernstian Equilibrium Stripping (AGNES), 1.7MUmolL-1, amounting to 14.4% of the total Zn. The free concentrations found in this wine were 1.79MUmolL-1 Fe3+, 1.11mmolL-1 Ca2+ and 3.4mmolL-1Mg2+ (8.82%, 40% and 57% of their total concentrations). Prior to the application of the techniques to the red wine, they had been cross-validated in Zn-tartrate solutions. PMID- 28873534 TI - Magnesium enriched lactic acid bacteria as a carrier for probiotic ice cream production. AB - The following strains of bacteria: Lactobacillus rhamnosus B 442, Lactobacillus rhamnosus 1937, and Lactococcus lactis JBB 500 were enriched with magnesium ions using Pulsed Electric Fields. The potentially probiotic strains were added to the mixture in the DVS process and applied for the production of ice cream which were then analyzed physicochemically and microbiologically. Results showed that addition of bacteria enriched with magnesium did not change chemical parameters of the ice cream and did not affect the freezing process, meltability, and hardness. No significant differences were noted in colour of the samples. The ice cream with addition of bacteria enriched with magnesium had higher adhesiveness. The results of viability determination showed that the total number of microorganisms in the ice cream was higher than in the starter cultures. Viability of the bacteria enriched with magnesium in the obtained ice cream was lower in comparison to the control samples. PMID- 28873535 TI - Effect of ascorbic acid postharvest treatment on enzymatic browning, phenolics and antioxidant capacity of stored mung bean sprouts. AB - Enzymatic browning limits the postharvest life of minimally processed foods, thus the study selected the optimal inhibitors of polyphenol oxidase (PPO) and evaluated their effect on enzymatic browning, phenolics and antioxidant capacity of stored mung bean sprouts. The sprouts treated with 2mM and 20mM ascorbic acid had a lowered PPO activity; compared to the control by 51% and 60%, respectively. The inhibition was reflected in a significant decrease in enzymatic browning. The sprouts treated with 20mM ascorbic acid had 22% and 23% higher phenolic content after 3 and 7days of storage, respectively. Both storage and ascorbic acid treatment increased potential bioaccessibility of phenolics. Generally, there was no effect of the treatments on the antioxidant capacity; however, a significant increase in the reducing potential was determined for the sprouts washed with 20mM ascorbic acid. In conclusion, ascorbic acid treatments may improve consumer quality of stored sprouts. PMID- 28873536 TI - Development and validation of HPLC method for the determination of ferrocyanide ion in food grade salts. AB - A rapid, simple, and reliable HPLC method was developed and validated to determine the presence of ferrocyanide ions (FeCNs) in food grade salts. An analytical column coupled with a guard column and mobile phase comprised of sodium perchlorate and sodium hydroxide (NaOH) were employed at a detection wavelength of 221nm. Samples were dissolved in 0.02M NaOH solution and filtered. For processed salts including herbs and spices, a C18 cartridge was applied to minimize interference from salt matrices. The method validation was based on linearity, accuracy (recovery), precision, LOD, LOQ, and measurement uncertainty. This method exhibits good linearity from 0.1-10mg/L (r2=0.9999). The LOD and LOQ values were determined to be 0.02 and 0.07mg/kg, respectively. The FeCN recoveries in six salt matrices ranged from 80.3-102.2% (RSD=0.3-4.4%). These results indicate that the proposed method is suitable for FeCN ion determination in various food grade salts. PMID- 28873538 TI - Planar chromatographic screening and quantification of coumarin in food, confirmed by mass spectrometry. AB - A sensitive quantitative screening of coumarin in 43 commercially available cinnamons and cinnamon-containing foods was developed via HPTLC. Complex samples like cinnamon, tea, breakfast cereals, milk rice, jam, cinnamon stars and buns were extracted with methanol only. Separation was performed on silica gel with a mixture of n-hexane, ethyl acetate and ammonia. The specific detection via derivatization with an ethanolic potassium hydroxide solution resulted in fluorescent coumarin zones, measured at 365/>400nm after stabilization. Limits of detection and quantification were 200 and 400pg/band, respectively. Over all different sample types, the contents ranged from 0.3 to 5129mg/kg with a mean repeatability and mean intermediate precision of 4% each. HPTLC-MS of selected zones, eluted via the TLC-MS Interface into MS, confirmed the identity of coumarin. Effect-directed detection as bioanalytical tool for risk assessment showed coumarin to be active against Aliivibrio fischeri bacteria down to 100ng/band. PMID- 28873537 TI - Extraction and detailed characterization of phospholipid-enriched oils from six species of edible clams. AB - Phospholipid (PL)-enriched oils were recovered from six species of edible clams, namely Cyclina sinensis, Mactra chinensis Philippi, Mactra veneriformis Reeve, Meretrix meretrix, Ruditapes phliippinarum and Saxidomus purpurata, using a mixture of ethanol and hexane (1:1, v/v). The oils contained a high proportion of polyunsaturated fatty acids (PUFA) (26.78-45.36% of total FAs), especially eicosapentaenoic acid (EPA) (8.17-10.48% of total FAs) and docosahexaenoic acid (DHA) (7.83-21.34% of total FAs). The oils also contained a high percentage of PL (39.86-74.05% of total lipids). Among PL, phosphatidylcholine (37.40-52.19mol%) and phosphatidylethanolamine (34.74-43.10mol%) were dominant. At least 435, 442, 513, 438, 433 and 437 glycerophospholipid (GP) molecular species were characterized, respectively, in lipids from Cyclina sinensis, Mactra chinensis Philippi, Mactra veneriformis Reeve, Meretrix meretrix, Ruditapes phliippinarum and Saxidomus purpurata. Most of the predominant GP molecular species contained PUFA, mainly EPA and DHA, indicating that clam is a potential resource of PUFA enriched GP. PMID- 28873539 TI - Development of a SBSE-TD method coupled to GC-MS and chemometrics for the differentiation of variety and processing conditions in peach juices. AB - Peach juices of distinct varieties, namely yellow- and red-fleshed, and commercial and freshly blended were analyzed. The method used was based on Stir Bar Sorptive Extraction (SBSE) involving a polydimethylsiloxane-coated stir bar with thermal desorption (TD), followed by gas chromatography coupled to mass spectrometry (GC-MS) analysis. The resulting analytical data included 41 compounds belonging to several chemical classes, such as aldehydes, alcohols, lactones, terpenoids, fatty aldehydes, fatty acids and hydrocarbons. Furthermore, chemometric data treatment using unsupervised analysis (PCA) proved useful to classify peach juices on the basis of variety. Stepwise Linear Discriminant Analysis (SLDA) showed that a reduced number of variables (14 compounds), including lactones (6-pentyl-alpha-pyrone, gamma-decalactone, gamma dodecalactone, and delta-dodecalactone), fatty acids (hexadecanoic acid), fatty aldehydes (tetracosanal and octacosanal), hydrocarbons (C23, C26, C27, C29, and C33), and alcohols (phytol and alpha-tocopherol), were necessary to classify the juice samples according to variety and processing conditions. PMID- 28873540 TI - Quantification of extra virgin olive oil in dressing and edible oil blends using the representative TMS-4,4'-desmethylsterols gas-chromatographic-normalized fingerprint. AB - This paper describes and discusses the application of trimethylsilyl (TMS)-4,4' desmethylsterols derivatives chromatographic fingerprints (obtained from an off line HPLC-GC-FID system) for the quantification of extra virgin olive oil in commercial vinaigrettes, dressing salad and in-house reference materials (i-HRM) using two different Partial Least Square-Regression (PLS-R) multivariate quantification methods. Different data pre-processing strategies were carried out being the whole one: (i) internal normalization; (ii) sampling based on The Nyquist Theorem; (iii) internal correlation optimized shifting, icoshift; (iv) baseline correction (v) mean centering and (vi) selecting zones. The first model corresponds to a matrix of dimensions 'n*911' variables and the second one to a matrix of dimensions 'n*431' variables. It has to be highlighted that the proposed two PLS-R models allow the quantification of extra virgin olive oil in binary blends, foodstuffs, etc., when the provided percentage is greater than 25%. PMID- 28873541 TI - Entrapment of proteins and peptides in chitosan-polyphosphoric acid hydrogel beads: A new approach to achieve both high entrapment efficiency and controlled in vitro release. AB - Bovine serum albumin (BSA), whey protein isolate (WPI), insulin and a casein hydrolysate were entrapped in chitosan-polyphosphoric acid (PPA) beads. The in vitro release of protein from the beads in simulated gastric fluid (SGF, pH 3) and simulated intestinal fluid (SIF, pH 7) was evaluated. High entrapment efficiencies were achieved for intact proteins (>95% in all cases) but entrapment was lower for the casein hydrolysate (circa 50%), possibly indicating a physical or steric entrapment of the proteins in these chitosan-PPA beads. Inhibited release of BSA, in both SGF and SIF, was achieved with low PPA concentration. Insulin and WPI were effectively retained in SGF and gradually released in SIF. Peptides from casein hydrolysate were partially (circa 35%) but quickly released in SGF with no further release in SIF. Overall, these results indicate that chitosan-PPA beads show potential for lower gastrointestinal delivery of bioactive protein material. PMID- 28873542 TI - Fabrication of curcumin-loaded bovine serum albumin (BSA)-dextran nanoparticles and the cellular antioxidant activity. AB - Bovine serum albumin (BSA)-dextran conjugate was prepared with glycation. Self assembly nanoparticles were synthesized with a green, and facile approach. The effects of dry-heating time on the fabrication and characteristics of BSA-dextran conjugate nanoparticles were examined. Stable nanoparticles (<200nm) were formed after only 6h dry-heating because enough dextran was grafted onto the BSA to provide significant steric hindrance. Particle size decreased with the increase of dry-heating time and the lowest particle size (51.2nm) was obtained after 24h dry-heating. The nanoparticles were stable in a wide pH range (pH 2.0-7.0). The particle size of nanoparticles increased to 115nm after curcumin incorporation and was stable even after one-month storage. TEM results demonstrated that curcumin-loaded nanoparticles displayed a spherical structure and were homogeneously dispersed. Curcumin in BSA-dextran nanoparticle showed better stability, compared to free curcumin. In addition, BSA-dextran nanoparticles can improve the cellular antioxidant activity of curcumin in Caco-2 cells. PMID- 28873543 TI - Biochemical degradation and physical migration of polyphenolic compounds in osmotic dehydrated blueberries with pulsed electric field and thermal pretreatments. AB - Fresh blueberries were pretreated by pulsed electric fields (PEF) or thermal pretreatment and then were subject to osmotic dehydration. The changes in contents of anthocyanins, predominantly phenolic acids and flavonols, total phenolics, polyphenol oxidase (PPO) activity and antioxidant activity in the blueberry samples during pretreatment and osmotic dehydration were investigated. Biochemical degradation and physical migration of these nutritive compounds from fruits to osmotic solutions were observed during the pretreatments and osmotic dehydration. PEF pretreated samples had the least degradation loss but the most migration loss of these compounds compared to thermally pretreated and control samples. Higher rates of water loss and solid gain during osmotic dehydration were also obtained by PEF pretreatment, reducing the dehydration time from 130 to 48h. PEF pretreated and dehydrated fruits showed superior appearance to thermally pretreated and control samples. Therefore, PEF pretreatment is a preferred technology that balances nutritive quality, appearance, and dehydration rate. PMID- 28873544 TI - Importance of salt and temperature in myosin polymerization during surimi gelation. AB - To address the effect of absence of NaCl on myosin heavy chain polymerization during two-step surimi gelation (different setting temperatures/times -5 degrees C/24h and 30 degrees C/30min-followed by heating at 90 degrees C/30min) were considered. In gel samples made without salt (Lot A), no myosin heavy chain (MHC) polymerization was observed, only aggregation, as indicated by the electrophoresis in polyacrylamide/agarose gel profile. Moreover, these gels were characterized by weakly stabilized protein networks as denoted by the dynamic oscillatory measurement and FTIR analysis, resulting in poor quality gels. On the other hand, in gels made with added salt, MHC polymerization occurred, as evidenced by the electrophoresis, and the gelation resulted in a well-stabilized protein network with good physicochemical properties. PMID- 28873545 TI - A quick and effective methodology for analyzing dinotefuran and its highly polar metabolites in plum using liquid chromatography-tandem mass spectrometry. AB - A simple and effective method was developed for analyzing dinotefuran and its three metabolites (MNG, UF, and DN) in plum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Due to the polarity and high water miscibility, dinotefuran and some of its metabolites (especially DN) have some limitations to be extracted with acetonitrile and salt following the "QuEChERS" sample preparation methodology. Alternatively, the samples were extracted with methanol, and purified with dispersive-solid phase extraction procedure (d-SPE) using primary secondary amine (PSA) and C18 sorbents after filtration, and mass up. Due to the suppression effect originated from plum matrix, matrix-matched calibration curves, which provided good linearity with coefficient of determination (R2)>=0.998, were used for quantification of all analytes. Blank plum samples fortified with 2 spiking levels (10*LOQ and 50*LOQ) yielded satisfactory recoveries for all tested analytes in the range of 83.01 to 110.18% with relative standard deviation (RSD)<=8.91. The method was successfully applied to field incurred plum samples and dinotefuran and all metabolites were positively detected and quantified. In conclusion, we suggest that the method can be expanded to polar compounds having solvent and partitioning problems in any of the versions of QuEChERS. PMID- 28873546 TI - Reduction of biogenic amines in sufu by ethanol addition during ripening stage. AB - The aim of this study was to investigate the content of biogenic amines (BAs) in different types of sufu samples obtained from different producers, and the effect of ethanol in reducing BA levels during sufu ripening. The results showed that different manufacturing processes altered the distribution of BAs in commercial sufu. Putrescine, cadaverine, histamine, and tryptamine were the main and common BAs in red, white and grey sufu. The contents of putrescine, cadaverine, tryptamine, beta-phenylethylamine and tyramine in the grey sufu of all producer brands were significantly (p<0.05) higher than those in the white and red sufu. The addition of ethanol to the dressing mixture had a significant influence in reducing the total content of BAs in laboratory-made sufu. The slight increase in polypeptide and amino nitrogen contents after the addition of ethanol indicated a reduction in the degradation of water soluble protein. PMID- 28873547 TI - Towards an improved global antioxidant response method (GAR+): Physiological resembling in vitro digestion-fermentation method. AB - The antioxidant capacity of food influences its shelf life and human health. To determine this parameter, the corresponding antioxidant species must first be extracted. Current methods don't adequately address this issue since they rely on extractions with organic solvents or on in vitro digestion without a subsequent fermentation. We present an improved protocol to determine the global antioxidant response of foods (GAR+) including both in vitro digestion and fermentation. All samples should be fermented with the same fresh faecal inoculum in order to decrease variability. In addition, the use of a pool of faeces from healthy donors is strongly recommended to improve repeatability. Although most antioxidant capacity is achieved after digestion, in some foods fermentation plays a role. Thus, the GAR+ method provides reliable values of the antioxidant capacity of foods that are closer to their in vivo activity by including the effects of gut microbiota over non-digested nutrients. PMID- 28873548 TI - Resonance Rayleigh scattering method for the determination of chitosan using erythrosine B as a probe and PVA as sensitization. AB - A highly sensitive resonance Rayleigh scattering (RRS) method for the determination of chitosan (CTS) was developed. In the pH 3.8 Britton-Robinson buffer solution, CTS interacted with erythrosine B (Ery B) to form an ion association complex of [Ery B-CTS] which increased the RRS intensity of the system. With the addition of polyvinyl alcohol (PVA), the RRS intensity was significantly enhanced, and the RRS intensity of the reagent blank(I0) dramatically decreased. The enhanced RRS intensity (DeltaI) was linearly proportional to the concentration of chitosan. Taking the medium molecular weight chitosan as the representative, the linear range of the method was 5.0-100.0ng/mL and the detection limit (DL) was 0.47ng/mL. The effect of the molecular weight of CTS on its accurate quantification was studied. Furthermore the dispersion and stability mechanism of PVA was discussed. Accordingly this assay was applied to detect the concentration of CTS in health products with satisfactory results. PMID- 28873549 TI - Towards an improved Global Antioxidant Response method (GAR+): Physiological resembling in vitro antioxidant capacity methods. AB - Many methods have been developed to measure the antioxidant capacity of foods under non physiological-relevant conditions. In this study, three methods (TEACOH, GEACRED and TEACAAPH) are developed to measure antioxidant capacity at physiological pH, using indigo carmine as a redox dye. TEACOH and TEACAAPH determine foodstuffs' scavenging capacity against hydroxyl (OH) and AAPH radicals, while the third method measures the global reducing capacity of the sample. The results obtained for commercial teas, commercial beverages containing tea as the main ingredient and different solid foods (spinach, onion, salami, etc.) were compared with well-established protocols. The new methods demonstrated good linearity-reproducibility, providing reliable data about the antioxidant capacity of foods under physiological-resembling conditions. The new methods were also useful for evaluating the antioxidant capacity of human plasma after acute intake of tea. The physiological-resembling conditions of these assays and the use of absorbance readings make them suitable for application by any laboratory. PMID- 28873550 TI - Assessment of multiple mycotoxins in breakfast cereals available in the Portuguese market. AB - Mycotoxins are secondary metabolites of fungi that cause toxic and carcinogenic effects. Human exposure to multiple mycotoxins constitutes an increasing health concern due to potential mycotoxins combined effects. The presence of mycotoxins mixtures in foodstuffs as cereals has been reported over the last years, but few studies are available concerning its occurrence in cereals primarily marketed for children, a particular vulnerable population group. The present study aims to assess the co-occurrence of twenty-one mycotoxins and metabolites present in breakfast cereals primarily marketed for children in Portugal. Results showed that 96% of the analysed breakfast cereal samples were contaminated with several mycotoxins. Twenty-two combinations were identified including two to seven different mycotoxins. Conclusions pointed out an urgent need to review legislative limits in food matrices consumed by children and to perform a more accurate risk assessment of children's exposure to mycotoxins mixtures in food. PMID- 28873551 TI - Are tropane alkaloids present in organic foods? Detection of scopolamine and atropine in organic buckwheat (Fagopyron esculentum L.) products by UHPLC-MS/MS. AB - A closer monitoring of tropane alkaloids (TA) in foods is now recommended by the European Commission, following a series of alerts related to the contamination of buckwheat with weeds of the genus Datura. A novel, accurate UHPLC-MS/MS method was developed and validated for the rapid detection of scopolamine and atropine in buckwheat foods. A suitable extraction protocol was set up to maximize recoveries and detection limits in different raw, processed and baked foods. The method offers good performances in terms of sensitivity, accuracy and precision, with LOQs at 0.04 and 0.10ug/kg. The established method is suitable for routine determination of trace levels of TA and was applied to 26 different buckwheat derived organic foods, detecting TA in 3 samples (13.9-83.9ug/kg for atropine and 5.7-10.4ug/kg for scopolamine). Only in one case the level of contamination was relevant in terms of food safety. PMID- 28873552 TI - Polyphenol and l-ascorbic acid content in tomato as influenced by high lycopene genotypes and organic farming at different environments. AB - The accumulation of polyphenols and l-ascorbic acid was evaluated under conventional (integrated pest management, IPM) and organic farming, as means to increase the accumulation of chemoprotective compounds. The effect of genotype was considerably higher than the growing system, in fact it is determining. 'Kalvert', a high-lycopene cultivar, outstood for the accumulation of most polyphenols, though low-carotenoid cultivars with high accumulation were also detected. Organic farming significantly increased the levels of caffeic acid by 20%, but reduced those of ferulic acid and naringenin by 13% and 15% respectively. A strong interaction with the environment was detected: in Navarra the differences were limited, while in Extremadura lower contents of ferulic acid and higher contents of chlorogenic acid and rutin were found in organic farming for certain cultivars. The effect of organic farming on l-ascorbic acid was dependent on cultivar and environment and it only led to an increase in Extremadura by 58%. PMID- 28873553 TI - A preliminary study of continuous milk coagulation using Cynara cardunculus flower extract and calf rennet immobilized on magnetic particles. AB - The aim of this study was to develop a bioreactor design for continuous milk coagulation using a biocatalyst composed of immobilized animal and vegetable rennet on aminated magnetic particles, which has been proven to be an appropriate carrier for enzyme immobilization. Calf and vegetable (Cynara cardunculus) rennets were covalently immobilized on CLEA(r) magnetic supports and the immobilization procedure was optimized in batch mode, by evaluating protein loading, caseinolytic activity and the coagulation properties of skim milk powder and cow's milk. Subsequently the optimal temperature of immobilized coagulant was defined and a technically-friendly enzyme bioreactor was developed in order to carry out a continuous milk coagulation process with the aim of producing soft cheese. PMID- 28873554 TI - Influence of the uronic acid composition on the gastroprotective activity of alginates from three different genus of Tunisian brown algae. AB - Alginates from three genus of Tunisian brown algae were isolated and characterized by size exclusion chromatography and Solid-state NMR spectroscopy. Alginate from Padina pavonica (APP) had the highest molecular weight (Mw) with 147,000g/mol while it was 85,000g/mol for alginate from Cystoseira compressa (ACC) and 58,000g/mol for alginate from Dictyopteris membranaceae (ADM). The mannuronate (M) to guluronate (G) ratios were estimated from spectral deconvolution of the 13C CP/MAS spectra and the results has shown that all the extracts are mannuronic acid-rich alginates with M/G ratio increased in the order ADM - ACC - APP. An interesting gastroprotective effect was observed for the extracts; ADM and ACC exhibited the highest inhibition of gastric lesions, at 50mg/kg, with 83.41% and 75.39% respectively. Otherwise, it has been shown that the gastroprotective effect of alginates depends mainly on their uronic acid composition. PMID- 28873555 TI - The adsorption of orthophosphate onto casein-iron precipitates. AB - This study explored the interactions of orthophosphate with casein-iron precipitates. Casein-iron precipitates were formed by adding ferric chloride at >=10mM to sodium caseinate solutions ranging in concentration from 1 to 3%(w/v). The addition of different concentrations of orthophosphate solution to the casein iron precipitates resulted in gradual adsorption of the orthophosphate, causing re-dispersion of the casein-iron complexes. The interactions of added orthophosphate with iron in the presence and absence of caseins are postulated, and new mechanisms are proposed. The re-dispersed soluble complexes of casein iron-orthophosphate generated using this process could be used as novel iron fortificants. PMID- 28873556 TI - Effect of porcine plasma protein hydrolysates on long-term retrogradation of corn starch. AB - The potential effect of porcine plasma protein hydrolysates (PPPH) on the long term retrogradation of corn starch (CS) was investigated. The differential scanning calorimetry results showed that PPPH significantly reduced the retrogradation enthalpies (DeltaHr) of CS (P<0.05), obviously decreased the crystallization rate constant (k), and enhanced the Avrami exponent (n) (P<0.05). Low-field nuclear magnetic resonance analysis demonstrated that the spin-spin relaxation time (T2) remarkably increased with increasing PPPH concentration during storage at 4 degrees C for 28days (P<0.05). The X-ray diffraction results revealed that the relative crystallinity of retrograded CS decreased from 13.04% to 8.73% with the addition of PPPH. Fourier transform infrared spectroscopy analysis demonstrated that the addition of PPPH led to a decrease in hydrogen bonds within starch. The results demonstrated that the addition of PPPH apparently played a crucial role in retarding the long-term retrogradation of CS. PMID- 28873558 TI - Selective and eco-friendly synthesis of lipoaminoacid-based surfactants for food, using immobilized lipase and protease biocatalysts. AB - Lipoaminoacids, as surfactants, are an excellent option for food industry due to the currently trends in consumption of functional and natural ingredients. Synthesis of lauroyl glycine lipoaminoacid was carried out with a lipase from Pseudomonas stutzeri and a protease from Bacillus subtilis, which were immobilized in octyl-glyoxyl silica and glyoxyl-silica supports, respectively, comparing their catalytic performance. The enzymatic selectivity towards the lipoaminoacid instead of the dipeptide glycylglycine and synthesis yield were evaluated with respect to the characteristics of the immobilized biocatalysts and synthesis conditions. Three solvents were tested as reaction media for evaluating the expressed activity, stability and catalytic behavior during synthesis. Results indicate that both enzymes favor the lauroyl glycine synthesis over the peptide synthesis, but the immobilized protease has the best balance between selectivity and yield: 40% yield for lauroyl glycine and less than 5% for dipeptide after 96h of synthesis, at 45 degrees C and acetone as solvent. PMID- 28873557 TI - A rapid simultaneous determination of methylxanthines and proanthocyanidins in Brazilian guarana (Paullinia cupana Kunth.). AB - Paullinia cupana is a plant native to Brazil that is widely used in traditional medicine as a physical and mental stimulant. It is also used worldwide to produce soft drinks. A method for the simultaneous quantitation of seven markers in guarana by HPLC-PDA was developed, and extraction methods for the determination of methylxanthines and tannins were investigated. Quantified substances were theobromine, theophylline, caffeine, catechin, epicatechin, procyanidins A2 and B2. Results confirmed the satisfactory selectivity and linearity (r2>=0.99) within the mass ranges. Repeatability (RSD<=2.80%), intermediate precision (RSD<=4.47%), accuracy (recoveries from 90.59%-104.67%), and robustness were demonstrated. Extract 1 presented the contents: 0.0177% (+/-1.02%) for theobromine, 0.0131% (+/-1.14%) for theophylline, 2.9429% (+/-1.27%) for caffeine, 0.4563% (+/-1.02%) for catechin, 0.5515% (+/-1.05%) for epicatechin, 0.0607% (+/-2.80%) for A2 and 0.1035% (+/-1.39%) for B2. The method for simultaneous quantitation of seven chemical markers in guarana proved to be reliable using a simple and convenient HPLC setup. PMID- 28873559 TI - Protective effects of soybean protein and egg white protein on the antibacterial activity of nisin in the presence of trypsin. AB - The using of nisin to prevent foodborne pathogens (Staphylococcus aureus and Listeria monocytogenes) from contamination has received broad attentions during meat processing. However, the application of nisin has been limited because its antibacterial activity may be inhibited by trypsin. In this study, the protective effects of soybean protein and egg white protein on antibacterial activity of nisin were evaluated. It could be concluded that exogenous trypsin decreased the antibacterial activity of nisin, soybean protein and egg white protein could keep the nisin activity from enzymolysis of trypsin. Trypsin inhibitors in soybean protein and egg white protein could protect the antibacterial activity of nisin. Nisin with soybean protein or egg white protein in cooked meat product presented better quality preservation effects than nisin alone in the presence of trypsin. The total viable counts (TVC) and total volatile basic nitrogen (TVB-N) of nisin treated group were significantly higher than these in nisin-soybean protein treated and nisin-egg white protein-treated groups with trypsin. This study showed the potential of using soybean protein and egg white protein to stabilize the antibacterial activity of nisin under high trypsin conditions. PMID- 28873560 TI - Portraying and tracing the impact of different production systems on the volatile organic compound composition of milk by PTR-(Quad)MS and PTR-(ToF)MS. AB - The aim of this study was to discover the unique volatile compositional traits of retail milk from different production systems. Forty-four retail milk samples were analyzed, including organic milk (n=10), conventional milk (n=14) and pasture milk (n=20) from winter (n=22) and summer (n=22). Proton transfer reaction quadrupole mass spectrometry (PTR-(Quad)MS) was utilized to obtain the mass-resolved fingerprints (76 masses per sample) of volatile organic compounds (VOCs). Principal component analysis (PCA) and analysis of variance (ANOVA) were performed to evaluate the differences between the groups. The production systems were characterized by six masses, while season showed larger differences, with twenty-two masses discriminating between the milks. For 2 masses, a significant interaction of systems and seasons was observed. The chemical formula of these VOC masses were tentatively identified by Proton Transfer Reaction Time-of-Flight Mass Spectrometric (PTR-(ToF)MS). These results illustrate that the type of feed is reflected in the VOC composition of milks. PMID- 28873561 TI - Magnetic graphene sol-gel hybrid as clean-up adsorbent for acrylamide analysis in food samples prior to GC-MS. AB - Graphene (G) modified with magnetite (Fe3O4) and sol-gel hybrid tetraethoxysilane methyltrimethoxysilane (TEOS-MTMOS) was used as a clean-up adsorbent in magnetic solid phase extraction (MSPE) for direct determination of acrylamide in various food samples prior to gas chromatography-mass spectrometry analysis. Good linearity (R2=0.9990) was achieved for all samples using matrix-matched calibration. The limit of detection (LOD=3*SD/m) obtained was 0.061-2.89ugkg-1 for the studied food samples. Native acrylamide was found to be highest in fried potato with bright-fleshed (900.81ugkg-1) and lowest in toasted bread (5.02ugkg 1). High acrylamide relative recovery (RR=82.7-105.2%) of acrylamide was obtained for spiked (5 and 50ugkg-1) food samples. The Fe3O4@G-TEOS-MTMOS is reusable up to 7 times as a clean-up adsorbent with good recovery (>85%). The presence of native acrylamide was confirmed by mass analysis at m/z=71 ([C3H5NO]+) and m/z=55 ([C3H3O]+). PMID- 28873563 TI - Application of 3,5-bis-(trifluoromethyl)phenyl isothiocyanate for the determination of selected biogenic amines by LC-tandem mass spectrometry and 19F NMR. AB - 3,5-Bis-(trifluoromethyl)phenyl isothiocyanate, was used as a convenient reagent for the derivatization of histamine, tyramine, tryptamine and 2-phenylethylamine, which eliminates the purification step. The obtained derivatives were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, the total amount of these amines was determined by 19F nuclear magnetic resonance analysis. The procedures were optimized and validated for linearity, limit of detection and quantification, intra- and inter-day precision and recovery resulting in good reproducibility and accuracy. The reagent was applied for determination of the above mentioned biogenic amines in beverages, and permitted an undemanding separation and determination of the derivatives. Moreover, it is a convenient reagent for analysis of the total amine content by quantitative 19F NMR. PMID- 28873562 TI - Fast analysis of capsaicinoids in Naga Jolokia extracts (Capsicum chinense) by high-performance liquid chromatography using fused core columns. AB - A rapid high-performance liquid chromatography method with a C18 reverse-phase fused-core column has been developed for the determination and quantification of the main capsaicinoids (nornordihydrocapsaicin, nordihydrocapsaicin, capsaicin, dihydrocapsaicin, homocapsaicin and homodihydrocapsaicin) present in Naga Jolokia peppers. A fused-core KinetexTM C18 column (50*2.1mm i.d.; 2.6MUm) was used for the analysis. The chromatographic separation was obtained with a gradient method in which the mobile phase was water (0.1% acetic acid) as solvent A and acetonitrile (0.1% acetic acid) as solvent B. The separation of all compounds was achieved in less than 3min with a total analysis time (sample-to-sample) of 10min. The robustness of the method was evaluated. The method showed excellent repeatability and intermediate precision expressed as coefficient of variance of less than 2%. The developed method was employed for the quantification of the major capsaicinoids present in different peppers and commercial products containing chilli peppers. PMID- 28873564 TI - Effect of nano packaging on preservation quality of Nanjing 9108 rice variety at high temperature and humidity. AB - A nano packaging material containing nano Ag, nano TiO2, nano attapulgite and SiO2 was prepared, and its impact on quality of Nanjing 9108 rice at 37 degrees C and 85% relative humidity was studied. Effects of the packaging on ambient gases and chromatic aberration of rice were determined. Moreover, oxidation level, molds growth and flavor of rice were also analyzed. Results showed that nano packaging material had antimicrobial effects and maintained low O2 and high CO2 content in the packages. The packages thereby inhibited the growth of molds and the production of fatty acids, restrained the increase of lipase activity, and reduced the oxidation of fats and proteins. As a result, the production of yellow and white-belly rice were inhibited. Furthermore, the color and flavor of rice were maintained. Therefore, the nano-packing material could be applied for preservation of rice to improve preservation quality. PMID- 28873565 TI - The betaine profile of cereal flours unveils new and uncommon betaines. AB - We report the LC-ESI-MS/MS determination of betaines in commercial flours of cereals and pseudocereals most utilized in human nutrition. Results showed that glycine betaine, trigonelline, proline betaine, Nepsilon-trimethyllysine were metabolites common to all examined flours, whereas an uncommon betaine, valine betaine, and glutamine betaine were present only in flours of barley, rye, oat, durum wheat, winter wheat, Triticum dicoccum and Triticum monococcum. Valine betaine and glutamine betaine, the latter never reported before in plants and animals, are not evenly distributed in the Poaceae family, but their presence or absence in flours depends on the subfamily to which the plant belongs. Interestingly, we also report for the first time the occurrence of pipecolic acid betaine (homostachydrine) and its precursor 1,2-N-methylpipecolic acid in rye flour. These two metabolites were not detected in any other cereal or pseudocereal flour, suggesting their potential role as markers of rye flour occurrence in cereal-based foods. PMID- 28873566 TI - Selected chemical composition changes in microwave-convective dried parsley leaves affected by ultrasound and steaming pre-treatments - An optimization approach. AB - Parsley leaves contain a high amount of bioactive components (especially lutein), therefore it is crucial to select the most appropriate pre-treatment and drying conditions, in order to obtain high quality of dried leaves, which was the aim of this study. The optimization was done using response surface methodology (RSM) for the following factors: microwave power (100, 200, 300W), air temperature (20, 30, 40 degrees C) and pre-treatment variant (ultrasound, steaming and dipping as a control). Total phenolic content (TPC), antioxidant activity, chlorophyll and lutein contents (using UPLC-PDA) were determined in dried leaves. The analysed responses were dependent on the applied drying parameters and the pre-treatment type. The possibility of ultrasound and steam treatment application was proven and the optimal processing conditions were selected. PMID- 28873567 TI - Influence of lactic acid bacteria strains on ester concentrations in red wines: Specific impact on branched hydroxylated compounds. AB - This research investigated the influence of lactic acid bacteria (LAB) strains on ester levels in Bordeaux red wines. These wines were made in five Bordeaux areas in two vintages, using three yeast strains. Malolactic fermentation (MLF) was carried out using industrial starters or indigenous strains, each in triplicate. Ester concentrations were determined by liquid-liquid-extraction- or HS-SPME GC/MS at various stages in the winemaking process. The levels of most compounds were slightly impacted by LAB, depending on grape variety. Nevertheless, branched hydroxylated esters, such as ethyl 2-hydroxy-3-methylbutanoate and ethyl 2 hydroxy-4-methylpentanoate were the only compounds to be strongly influenced by the bacteria strain, regardless of matrix composition or the yeasts used for alcoholic fermentation. Moreover, the effect observed after MLF persisted over time, for at least 12months. These esters are apparently important markers of LAB esterase activity. To our knowledge, this was the first time they had been identified in this role. PMID- 28873568 TI - Phenolic contents, cellular antioxidant activity and antiproliferative capacity of different varieties of oats. AB - The objectives of this research were to determine the phenolic contents, oxygen radical absorbance capacities (ORAC), cellular antioxidant activities (CAA), and antiproliferative capacities of nine oat varieties and four brans in China. Of all varieties, Longyan 3 and Beiyan 1 exhibited the highest total avenanthramides (146.94+/-7.31 and 120.95+/-6.66ug/g, respectively) and ORAC values (21.03+/-0.56 and 21.18+/-1.45uM Trolox/g, respectively), while Shaotong exhibited the highest total phenolic acids (143.52+/-9.42ug/g) and CAA values (33.38+/-1.74uM quercetin/100g). The EC50 of antiproliferative capacities ranged from 167.31+/ 6.42 to 233.42+/-21.31mg/mL, with the lowest in Beixiao 8 while the highest in Jinyan 8. ORAC values correlated with avenanthramides while CAA values correlated with phenolic acids. Moreover, phenolic contents, antioxidant properties, and antiproliferative capacities of oat brans was higher than that of corresponding whole oats in most cases. PMID- 28873569 TI - Monitoring protein hydrolysis by pepsin using pH-stat: In vitro gastric digestions in static and dynamic pH conditions. AB - This study intends to demonstrate that acid titration at low pH is very well adapted to the monitoring of pepsin activity. After a description of the underlying principles, this approach was used during in vitro gastric digestions of a model of complex food containing 15wt% of whey proteins, according to both static (2h at pH = 3, Infogest protocol) and dynamic pH conditions (from pH 6.3 down to 2 in 1h). Pepsin activity was quantitatively assessed in all experiments through the calculation of degrees of hydrolysis (DH). Final values of 3.7 and 3.0% were obtained in static and dynamic pH conditions, respectively, and validated using an independent method. Results also show that about 92% of the peptides were detected at pH = 3, and 100% for pH<=2.5. Overall, the proposed approach proved to be very worthy to study protein hydrolysis during in vitro gastric digestions. PMID- 28873570 TI - Effective production of resistant starch using pullulanase immobilized onto magnetic chitosan/Fe3O4 nanoparticles. AB - In this study, pullulanase was firstly immobilized by covalent bonding onto chitosan/Fe3O4 nanoparticles or encapsulation in sol-gel after bonding onto chitosan/Fe3O4 nanoparticles, and then the immobilized pullulanase was used for the effective production of resistant starch (RS). The highest RS content (35.1%) was obtained under the optimized condition of pH 4.4, enzyme concentration of 10ASPU/g and hydrolysis time of 12h when debranched by free pullulsanase, indicating that RS content was significantly (p<0.05) increased when compared to native starch (4.3%) and autoclaved starch (12.5%). Under these conditions, the immobilized pullulanase (10ASPU/g dry starch) yielded higher RS content compared to free enzyme (10ASPU/g dry starch), especially, the pullulanse immobilized by sol-gel encapsulation yielded the highest RS content (43.4%). Moreover, compared to starches hydrolyzed by free pullulanase, starches hydrolyzed by immobilized pullulanase showed a different saccharide profile of starch hydrolysate, including a stronger peak C (MW=5.0*103), as well as exhibited an additional absorption peak around 140 degrees C. Reusability results demonstrated that pullulanase immobilized by sol-gel encapsulation had the advantages of producing higher RS content as well as better operational stability compared to pullulanase immobilized by cross-linking. The resulting enhanced RS content generated by the process described in this work could be used as an adjunct in food processing industries. PMID- 28873571 TI - Production of RS4 from rice starch and its utilization as an encapsulating agent for targeted delivery of probiotics. AB - The research reported in this article is based on the hypothesis that crosslinking of starch can make it a potential wall material for targeted delivery of probiotics by altering its digestion. Three probiotic strains namely Lactobacillus casei, Lactobacillus brevis and Lactobacillus plantarum were microencapsulated with resistant starch. Encapsulation yield (%) of resistant starch microspheres was in the range of 43.01-48.46. The average diameter of resistant starch microparticles was in the range of 45.53-49.29MUm. Fourier transform infrared (FT-IR) spectroscopy of microcapsules showed peaks in the region of 900-1300cm-1 and 2918-2925cm-1 which corresponds to the presence of bacteria. Differential Scanning Calorimeter (DSC) showed better thermal stability of resistant starch microcapsules. Microencapsulated probiotics survived well in simulated gastrointestinal conditions and adverse heat conditions. The viability of the microcapsulated lactobacilli also remained high (>7 log cfu g-1) for 2months at 4 degrees C. The results revealed that resistant starch is the potential new delivery carrier for oral administration of probiotics. PMID- 28873572 TI - Implications of hydration depletion in the in vitro starch digestibility of white bread crumb and crust. AB - The objective of this study was to provide understanding about the efficacy of decreasing dough hydration to slow down starch digestibility in white bread. Breads were made with 45 (low hydration bread, LHB), 60 (intermediate hydration bread, IHB) and 75% (high hydration bread, HHB) water (flour basis). A hydration depletion down to 45%, which is close to the minimum hydration found in commercially available white bread, did not prevent the starch in the crumb from complete gelatinization. However, LHB and IHB crumbs were more resistant to physical breakdown during in vitro digestion than HHB crumbs, resulting in a 96.81% increase of slowly digestible starch (SDS) from 75 to 45% dough hydration. The degree of gelatinization in crust samples was significantly reduced with a depletion in the dough hydration, ranging from 29.90 to 44.36%, which led to an increase of SDS from 7.41 in HHB to 13.78% in LHB (bread basis). PMID- 28873573 TI - Effects of variety, year of cultivation and sulphur supply on the accumulation of free asparagine in the grain of commercial wheat varieties. AB - Free asparagine concentration, which is the determining factor for acrylamide forming potential in cereals, was measured in grain from wheat grown in field trials in the United Kingdom in 2011-2012 and 2012-2013. There were 25 varieties in 2012 and 59 in 2013, with eleven present in both trials. The trials were split plot, with half of each plot supplied with sulphur and the other half not. The varietal means (mmol per kg) for free asparagine in the sulphur-fed wheat ranged from 1.521 to 2.687 in 2011-2012 and 0.708 to 11.29 in 2012-2013. Eight varieties were identified as having consistently low free asparagine concentration. There was a differential response of varieties to sulphur, and much higher levels of free asparagine in 2012-2013 versus 2011-2012. Given the short commercial lifespan of some wheat varieties, it is concluded that information on free asparagine concentration should be made available when a variety is launched. PMID- 28873574 TI - Creaming and oxidative stability of fish oil-in-water emulsions stabilized by whey protein-xanthan-locust bean complexes: Impact of pH. AB - The impact of pH on the physicochemical properties of 10% menhaden oil-in-water (O/W) emulsions containing 2% whey protein isolate (WPI) and 0.1% xanthan (XG) locust bean gum (LBG) mixtures was investigated. The O/W emulsions containing 0.1% XG-LBG mixtures were compared to emulsions with 0.1% XG and 0.1% LBG. The results indicated that stability is dependent on pH and biopolymer type. At both pH 3 and 5, emulsions containing either XG or XG-LBG mixtures had large particle sizes, viscosity, droplet aggregation, and creaming index, resulting in poor physical stability which can be related to the adsorbed protein-polysaccharide interactions. At pH7, the XG-LBG emulsions showed the greatest resistance to phase separation and resulted in stable emulsions. Lipid oxidation measurements also indicated that XG-LBG mixtures can be used to form stable emulsions at pH 3 and pH 7. These results have significant implications for the development of novel structures containing lipid phases susceptible to lipid oxidation. PMID- 28873575 TI - Development of a comprehensive analytical platform for the detection and quantitation of food fraud using a biomarker approach. The oregano adulteration case study. AB - Due to increasing number of food fraud incidents, there is an inherent need for the development and implementation of analytical platforms enabling detection and quantitation of adulteration. In this study a set of unique biomarkers of commonly found oregano adulterants became the targets in the development of a LC MS/MS method which underwent a rigorous in-house validation. The method presented very high selectivity and specificity, excellent linearity (R2>0.988) low decision limits and detection capabilities (<2%), acceptable accuracy (intra assay 92-113%, inter-assay 69-138%) and precision (CV<20%). The method was compared with an established FTIR screening assay and revealed a good correlation of quali- and quantitative results (R2>0.81). An assessment of 54 suspected adulterated oregano samples revealed that almost 90% of them contained at least one bulking agent, with a median level of adulteration of 50%. Such innovative methodologies need to be established as routine testing procedures to detect and ultimately deter food fraud. PMID- 28873576 TI - Revalorisation of rapeseed pomace extracts: An in vitro study into its anti oxidant and DNA protective properties. AB - Rapeseed pomace (RSP) is a waste product obtained after edible oil production from Brassica napus. Analysis of ubiquitous secondary metabolites in RSP samples (two breeds, harvested in 2012/2014 respectively from North East of Scotland) and their ethanol/water (95:5) Soxhlet extracts were carried out. Soxhlet extraction of the RSP (petroleum ether followed by 95% ethanol) gave a solid extract. LC MS/MS data of the extracts revealed several secondary metabolites, with Sinapic acid being the most abundant. Strong antioxidant activities of the Soxhlet extracts were confirmed from the results obtained in the FRAP, DPPH and ORAC assays. Furthermore, for the very first time, RSP extracts (13.9ug/ml) provided complete DNA protection, from oxidative stress induced by AAPH (3.5mM). Therefore the strong antioxidant and DNA protecting properties demonstrated by the RSP extracts in this study warrants further investigation for their revalorisation and potential use as reliable source of antioxidants in different food applications. PMID- 28873577 TI - Formation and properties of viscoelastic masses made from kafirin by a process of simple coacervation from solution in glacial acetic acid using water. AB - Stable viscoelastic masses have been formed from kafirin in a mainly aqueous system. Kafirin was dissolved in glacial acetic acid (GAA) and simple coacervation was performed by rapid addition of 15 degrees C water under low shear. Kafirin precipitated out as a network of hydrated fibrils which could be hand-kneaded into a viscoelastic mass. These could be formed from a very wide range of kafirins, including those where beta- or gamma-subclass expression was suppressed. Kafirin composition influenced the appearance of the masses but did not fundamentally affect stress-relaxation behaviour. Fresh kafirin masses exhibited similar elasticity and viscous flow balance to gluten. They maintained functionality when stored for several days at 10 degrees C but their elastic component increased. FTIR showed that when kafirin was dissolved in GAA its alpha helical conformation increased substantially. Dissociation of the kafirin molecules in GAA, assuming a alpha-helical conformation may have enhanced water binding, enabling viscoelastic mass formation. PMID- 28873578 TI - Effect of post-fermentation and packing stages on the volatile composition of Spanish-style green table olives. AB - The volatile profile of Spanish-style green table olives after fermentation and the changes in volatile compounds that occurred as a result of the post fermentation and subsequent packing stage were explored by solid phase micro extraction (SPME) and gas chromatography coupled to mass spectrometry (GC-MS). Three olive cultivars (Manzanilla, Gordal, and Hojiblanca) were processed and olive samples were taken at three different times throughout the elaboration: after fermentation, after post-fermentation, and after packing. A total of 132 volatile compounds were identified, including 10 phenols, 25 alcohols, 11 acids, 39 esters, 8 hydrocarbons, 14 carbonyl compounds, 17 terpenes, and 6 other compounds. A varying number of compounds from each chemical family underwent significant changes because of the post-fermentation and packing stages. Among them, some typical reaction products of lipid oxidation (e.g. (E)-2-decenal and (E,E)-2,4-decadienal) increased with the post-fermentation in Manzanilla cultivar, and also as a result of packing in all three cultivars. PMID- 28873579 TI - Ionic liquid-based air-assisted liquid-liquid microextraction followed by high performance liquid chromatography for the determination of five fungicides in juice samples. AB - A novel and simple ionic liquid-based air-assisted liquid-liquid microextraction technique combined with high performance liquid chromatography was developed to analyze five fungicides in juice samples. In this method, ionic liquid was used instead of a volatile organic solvent as the extraction solvent. The emulsion was formed by pulling in and pushing out the mixture of aqueous sample solution and extraction solvent repeatedly using a 10mL glass syringe. No organic dispersive solvent was required. Under the optimized conditions, the limits of detection (LODs) were 0.4-1.8MUgL-1 at a signal-to-noise ratio of 3. The limits of quantification (LOQs) set as the lowest spiking levels with acceptable recovery in juices were 10MUgL-1, except for fludioxonil whose LOQ was 20MUgL-1. The proposed method was applied to determine the target fungicides in juice samples, and acceptable recoveries ranging from 74.9% to 115.4% were achieved. PMID- 28873581 TI - A single enzyme PCR-RFLP protocol targeting 16S rRNA/tRNAval region to authenticate four commercially important shrimp species in India. AB - Food authenticity is an issue of major concern for food authorities, as mislabeling represents one of the major commercial frauds. In this study, a novel PCR-RFLP protocol was developed as a tool to authenticate four shrimp products of commercial importance belonging to the family, Penaeidae, viz. Litopenaeus vannamei, Penaeus monodon, P. semisulcatus and Fenneropenaeus indicus. PCR amplification was performed targeting 16S rRNA/tRNAval region having an amplicon size of 530bp using the specific primers for shrimps, 16S-Cru4/16S-Cru3. Subsequent restriction analysis with a single restriction enzyme, Tsp5091, yielded distinct RFLP pattern for each species of shrimps having fragment sizes below 150bp. The unique RFLP patterns were also obtained in processed shrimp products without any degradation or alteration in the major fragments. The method was also validated with commercial shrimp products. Thus, the developed protocol can be performed within 8h using a single enzyme to authenticate four shrimp products of commercial significance. PMID- 28873580 TI - Thermal degradation kinetics of all-trans and cis-carotenoids in a light-induced model system. AB - Thermal degradation kinetics of lutein, zeaxanthin, beta-cryptoxanthin, beta carotene was studied at 25, 35, and 45 degrees C in a model system. Qualitative and quantitative analyses of all-trans- and cis-carotenoids were conducted using HPLC-DAD-MS technologies. Kinetic and thermodynamic parameters were calculated by non-linear regression. A total of 29 geometrical isomers and four oxidation products were detected, including all-trans-, keto compounds, mono-cis- and di cis-isomers. Degradations of all-trans-lutein, zeaxanthin, beta-cryptoxanthin, and beta-carotene were described by a first-order kinetic model, with the order of rate constants as kbeta-carotene>kbeta-cryptoxanthin>klutein>kzeaxanthin. Activation energies of zeaxanthin, lutein, beta-cryptoxanthin, and beta-carotene were 65.6, 38.9, 33.9, and 8.6kJ/moL, respectively. cis-carotenoids also followed with the first-order kinetic model, but they did not show a defined sequence of degradation rate constants and activation energies at different temperatures. A possible degradation pathway of four carotenoids was identified to better understand the mechanism of carotenoid degradation. PMID- 28873582 TI - A study of the tyramine/glucose Maillard reaction: Variables, characterization, cytotoxicity and preliminary application. AB - The tyramine/glucose Maillard reaction was proposed as an emerging tool for tyramine reduction in a model system and two commercial soy sauce samples. The model system was composed of tyramine and glucose in buffer solutions with or without NaCl. The results showed that tyramine was reduced in the model system, and the reduction rate was affected by temperature, heating time, initial pH value, NaCl concentration, initial glucose concentration and initial tyramine concentration. Changes in fluorescence intensity and ultraviolet-visible (UV-vis) absorption spectra showed three stages of the Maillard reaction between tyramine and glucose. Cytotoxicity assay demonstrated that tyramine/glucose Maillard reaction products (MRPs) were significantly less toxic than that of tyramine (p<0.05). Moreover, tyramine concentration in soy sauce samples was significantly reduced when heated with the addition of glucose (p<0.05). Experimental results showed that the tyramine/glucose Maillard reaction is a promising method for tyramine reduction in foods. PMID- 28873583 TI - Analysis of polyphenols in brewer's spent grain and its comparison with corn silage and cereal brans commonly used for animal nutrition. AB - Brewer's spent grain (BSG) could be tested as an alternative source of polyphenols in animal nutrition. Proper extraction and analytical methods are critical for quantification. Thus, extraction for BSG, corn silage, and brans of rice, corn, and wheat were studied for the highest yield of polyphenols. A method for 18 phenolic monomers by HPLC-DAD was developed, validated, and applied to samples. An aqueous solution of NaOH (0.75% w/v) using integral samples for extraction resulted in the highest values for colorimetric measurements in all analyzed sources. Method by maceration showed the highest phenolic yield when applied in corn silage and BSG. However, for brans the best method was microwave assisted. Results from HPLC-DAD analysis clearly showed that native structures of phenolic compounds were simplified to its monomers allowing quantification and sample discrimination. BSG had the highest concentration of polyphenols and could be a promising and innovative source for animal feed studies. PMID- 28873584 TI - Magnetic mesoporous thiourea-formaldehyde resin as selective adsorbent: A simple and highly-sensitive electroanalysis strategy for lead ions in drinking water and milk by solid state-based anodic stripping. AB - A simple and sensitive electroanalysis method has been developed for the direct determination of lead ions of nanomolar levels in real samples of drinking water and milk by employing magnetic mesoporous thiourea-formaldehyde resin (TUF@Fe3O4) nanocomposites as the capturing absorbents. Here, the prepared TUF@Fe3O4 with the large-surface-area mesoporous structure and strong Pb2+-binding ligands could facilitate the selective and large-scale adsorption of Pb2+ ions from the complex sample matrices to be further magnetically separated onto the magnetic electrodes. Moreover, the Pb2+ ions magnetically accumulated were electrochemically measured alternatively by the solid state-based anodic stripping of PbCl2. The detection limit was found to be 0.0070nmolL-1. The as developed Pb2+ electroanalysis method with the magnetic electrodes and TUF@Fe3O4 nanocomposites could avoid the complicated sample preparation and electrode modification, thus holding the great potential of applications for the Pb2+ detection in different real samples. PMID- 28873585 TI - Chemical composition and food uses of teff (Eragrostis tef). AB - Teff (Eragrostis tef) is a cereal native to Ethiopia and Eritrea. It has an excellent adaptability to harsh environmental conditions and plays an important role in food security. In recent years, teff is becoming globally popular due to the attractive nutritional profile such as gluten free and high dietary fiber content. This review documents the recent advances in the genetic diversity, nutritional composition and food uses of teff grain. The attractive nutrients of teff include protein, dietary fiber, polyphenols, and certain minerals. Whole grain teff flour becomes increasingly important in healthy food market, and has been used to produce various gluten free food items such as pasta and bread. Efforts have been made to enhance the sensory quality of teff based products. There is great potential to adapt teff to the other parts of the world for healthy food and beverage production. PMID- 28873586 TI - Isolation of a novel calcium-binding peptide from wheat germ protein hydrolysates and the prediction for its mechanism of combination. AB - To isolate a novel peptide with specific calcium-binding capacity, wheat germ protein was hydrolyzed. The hydrolysates were purified using ultrafiltration, anion-exchange chromatography, gel filtration chromatography, and reversed-phase high performance liquid chromatography. The amino acid sequence of the purified peptide was determined and confirmed to be FVDVT (Phe-Val-Asp-Val-Thr). The calcium-binding capacity of FVDVT reached 89.94+/-0.75%, increased by 86.37% compared to the hydrolysates. The chelating mechanism between FVDVT and calcium was further investigated by Ultraviolet-Visible absorption spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and 1H nuclear magnetic resonances spectroscopy. The results indicated that the oxygen atoms of the carboxy group and the nitrogen atoms of the amido group provided major binding sites. In addition, aspartic acid and threonine show considerable capacity for incorporating with calcium by donating electron pairs. This study provides a feasible approach to isolate calcium-binding peptides and to clarify the possible binding mechanism of calcium and peptide. PMID- 28873587 TI - Untargeted screening of sulfonamides and their metabolites in salmon using liquid chromatography coupled to quadrupole Orbitrap mass spectrometry. AB - An analytical method for the non-target screening of sulfonamides and metabolites in salmon was developed, using automated on-line extraction procedure followed by ultra-high performance liquid chromatography coupled to electrospray ionization quadrupole Orbitrap high-resolution mass spectrometry (UHPLC Q-Orbitrap), including three systematic workflows (i) fully non-targeted data acquisition with fragmentation, (ii) suspect library spectra searching followed by characteristic structural fragments filtering and (iii) confirmation of non-target analytes and structural characterization of unknown analytes based on the availability of reference standards. The estimated performance characteristics were satisfactory complying with the requirements of the guidelines specified in European Commission Decision 2002/657/EC. Four untargeted compounds were identified and confirmed from salmon samples of different origin taken from monitoring control program. PMID- 28873588 TI - Water accelerated transformation of d-limonene induced by ultraviolet irradiation and air exposure. AB - d-Limonene is a fragrant chemical that widely exists in aromatic products. Isotopic labelling of water molecules plus GC-MS and GC-PCI-Q-TOF analyses were used to investigate the influence of water molecules on chemical transformation of d-limonene induced by UV irradiation and air exposure. The results showed that the synergistic effect of UV irradiation, air exposure and water presence could facilitate d-limonene transformation into the limonene oxides: p-mentha-2,8 dienols, hydroperoxides, carveols, l-carvone and carvone oxide. UV irradiation, air exposure, or water alone, however, caused negligible d-limonene transformation. With the aid of isotopic labelling of water and oxygen molecules, it was found that water molecules were split into hydrogen radicals and hydroxyl radicals, and the hydrogen radicals, in particular, promoted the transformation reactions. This study has elucidated the mechanism and factors that influence the transformation of d-limonene, which will benefit industries involved in production and storage of d-limonene-containing products. PMID- 28873589 TI - Control of the gastrointestinal digestion of solid lipid nanoparticles using PEGylated emulsifiers. AB - We prepared solid lipid nanoparticles (SLNs) with tristearin and various emulsifiers which had different chain length PEGs (10-100 times-repetition of ethylene glycol) to control their digestion fate in the gastrointestinal tract. Fabricated SLNs after acidic/high-ionic-strength media treatment were stable regardless of the zeta-potential (ZP) disappearance. Additionally, highly PEGylated SLNs successfully hindered the adsorption of both bile acid (BA) and lipase on the SLN surface, while lowly PEGylated SLNs interrupted that of only lipase. In simulated small intestinal fluid, lipolysis of highly PEGylated SLNs increased with decrease of the emulsifier density on the SLNs, whereas lipolysis of lowly PEGylated SLNs increased with decrease of the particle size. These results suggested that high PEGylation was more efficient than low PEGylation to hinder the lipolysis initiated from the competitive replacement of the SLN covering emulsifiers with BAs. Consequently, the SLN digestion could be controlled by choosing the length and concentration of PEGylated emulsifiers. PMID- 28873591 TI - The functional properties and application of gelatin derived from the skin of channel catfish (Ictalurus punctatus). AB - The objective of this work was to extract gelatin from skin of channel catfish (Ictalurus punctatus) and to study its functional properties and application in ice-cream and beer. SDS-PAGE patterns showed that channel catfish gelatin (CCG) had more high molecular weight components (beta and gamma chains) than had calf bone gelatin (CBG). The viscosity of CCG was 42mPa.s at 10 degrees C, which was three times more than that of CBG. Compared to CBG, CCG presented higher emulsion capacity and stability, as well as higher foaming stability. CCG conferred the ice-cream samples and beer with better mouth feel and clarification effect, respectively. The results indicated that CCG had great potential to be utilized in the food industry. PMID- 28873590 TI - In silico analysis and molecular docking study of angiotensin I-converting enzyme inhibitory peptides from smooth-hound viscera protein hydrolysates fractionated by ultrafiltration. AB - Smooth-hound viscera hydrolysates (SHVHs) were prepared by treatment with Neutrase (SHVH-N) and Purafect (SHVH-P). Hydrolysates were then separated according to their molecular weight, using the ultra-filtration membrane system, into 5 fractions (>=50, 50-5, 5-3, 3-1 and <=1kDa). Fractions showed different amino acid compositions and angiotensin I-converting enzyme (ACE) inhibitory potentials. The SHVH-P-FV (<=1kDa) and SHVH-N-FIV (3-1kDa) fractions showed the best ACE-inhibitory activities with IC50 values of 53.31 and 75.05ug/ml, respectively. According to their high ACE-inhibitory potential, FIV and FV were fractionated by RP-HPLC and then analyzed by LC-MS/MS to identify peptide sequences. A systematic peptidomic study resulted in the identification of numerous novel sequences. Furthermore, in silico data, based on the molecular docking simulation, showed that GPAGPRGPAG, AVVPPSDKM, TTMYPGIA, and VKPLPQSG could bind ACE active site with low interaction scores. Indeed, they share hydrogen bonds and Van der Waals and electrostatic interactions with ACE catalytic pockets. PMID- 28873592 TI - Statistical interpretation of chromatic indicators in correlation to phytochemical profile of a sulfur dioxide-free mulberry (Morus nigra) wine submitted to non-thermal maturation processes. AB - The four different methods of color measurement of wine proposed by Boulton, Giusti, Glories and Commission International de l'Eclairage (CIE) were applied to assess the statistical relationship between the phytochemical profile and chromatic characteristics of sulfur dioxide-free mulberry (Morus nigra) wine submitted to non-thermal maturation processes. The alteration in chromatic properties and phenolic composition of non-thermal aged mulberry wine were examined, aided by the used of Pearson correlation, cluster and principal component analysis. The results revealed a positive effect of non-thermal processes on phytochemical families of wines. From Pearson correlation analysis relationships between chromatic indexes and flavonols as well as anthocyanins were established. Cluster analysis highlighted similarities between Boulton and Giusti parameters, as well as Glories and CIE parameters in the assessment of chromatic properties of wines. Finally, principal component analysis was able to discriminate wines subjected to different maturation techniques on the basis of their chromatic and phenolics characteristics. PMID- 28873593 TI - SPR screening of metal chelating peptides in a hydrolysate for their antioxidant properties. AB - There is a growing need in the industrial sector (health, nutrition and cosmetic) to discover new biomolecules with various physico-chemical and bioactive properties. Various beneficial effects of peptides - notably those produced from protein hydrolysis - are reported in the literature. The antioxidant activity involves various mechanisms, among them metal chelation, studied by UV-visible spectrophotometry. In this paper, we set up an original method of screening metal chelating peptides in a hydrolysate using Surface Plasmon Resonance (SPR) for their antioxidant properties. To date, the empirical approach used several cycles of hydrolysate fractionation and bioactivity evaluation until the isolation of the pure bioactive molecule and its identification. Besides, the detection of metal-chelating peptide is not sensitive enough by spectrophotometry. For the first time, metal chelating peptides were screened in hydrolysates using SPR and a correlation was established between affinity constant determined in SPR and metal chelation capacity determined from UV-visible spectrophotometry. PMID- 28873594 TI - Stable isotope ratio analysis of different European raspberries, blackberries, blueberries, currants and strawberries. AB - To date the stable isotope ratios of berries have never been extensively explored. In this work the H, C, N and O isotopic ratios of 190 samples of different soft fruits (strawberries, raspberries, blueberries, blackberries and currants) produced in a northern Italian region and at two sites in Romania and Poland collected over three harvest years are presented and discussed. The different soft fruits showed a typical range for one or more isotopic parameters that can be used to verify the authenticity of the fruit composition declared on the label. The delta13C and delta15N of pulp and the delta18O of juice can be considered effective tools for identifying the different geographical origin of fruit. A significant effect of crop cover on juice delta18O and fertilisation practices on pulp delta15N was demonstrated and must be considered with attention when evaluating data. PMID- 28873595 TI - Protein degradation and peptide release from milk proteins in human jejunum. Comparison with in vitro gastrointestinal simulation. AB - Human jejunal digests after oral ingestion of casein and whey protein were collected by a nasogastric tube and protein degradation and peptide release was compared with that found in the digests of the same substrates using a standardised protocol. No intact casein was detected in the jejunal nor in the in vitro samples taken during the intestinal phase, while beta-lactoglobulin was found in one hour-jejunal samples in agreement with the in vitro digestion. In vivo and in vitro digests showed comparable peptide profiles and high number of common sequences. A selective precipitation step was used to strengthen the identification of phosphorylated peptides. Most of the sequences found in jejunum, some of them not previously described, were also identified in the simulated digests. Common resistant regions to digestion were identified, revealing that the in vitro protocol constitutes a good approximation to the physiological gastrointestinal digestion of milk proteins. PMID- 28873596 TI - Increase of medium-chain fatty acid ethyl ester content in mixed H. uvarum/S. cerevisiae fermentation leads to wine fruity aroma enhancement. AB - Medium-chain fatty acid (MCFA) ethyl esters, as yeast secondary metabolites, significantly contribute to the fruity aroma of foods and beverages. To improve the MCFA ethyl ester content of wine, mixed fermentations with Hanseniaspora uvarum Yun268 and Saccharomyces cerevisiae were performed. Final volatiles were analyzed by gas solid phase microextraction-chromatography-mass spectrometry, and aroma characteristics were quantitated by sensory analysis. Results showed that mixed fermentation increased MCFA ethyl ester content by 37% in Cabernet Gernischt wine compared to that obtained by pure fermentation. Partial least squares regression analysis further revealed that the improved MCFA ethyl esters specifically enhanced the temperate fruity aroma of wine. The enhancement of MCFA ethyl esters was attributed to the increased contents of MCFAs that could be induced by the presence of H. uvarum Yun268 in mixed fermentation. Meanwhile, the timing of yeast inoculations significantly affected the involving biomass of each strain and the dynamics of ethanol accumulation. PMID- 28873597 TI - A novel antioxidant peptide, purified from Bacillus amyloliquefaciens, showed strong antioxidant potential via Nrf-2 mediated heme oxygenase-1 expression. AB - A novel antioxidant peptide YD1 (~1.0kDa), purified from the strain Bacillus amyloliquefaciens CBSYD1, displayed activity in several in vitro assays and was also efficient against Gram-positive, Gram-negative as well as multidrug resistant (MDR) bacteria. Strain growth was adapted to bile-salt conditions where a clear halos-zone was observed in a bile-salt plate assay and was viable in different digestive track conditions. YD1 treatment on RAW 264.7 cells increased the transcriptional and translational activities of NF-E2-related factor-2 (Nrf 2) through the enhanced levels of heme oxygenase-1 (HO-1). Furthermore, the YD1 treated group showed higher levels of antioxidant enzymes compared to the oxidative stress group. YD1 demonstrated a strong antioxidant activity by decreasing nitric oxide (NO) and reactive oxygen species (ROS) in RAW 264.7 cells. This study suggests that YD1 and the strain could be a natural antioxidant and a probiotic candidate respectively. PMID- 28873598 TI - 1H HR-MAS NMR-based metabolomics study of different persimmon cultivars (Diospyros kaki) during fruit development. AB - 1H HR-MAS NMR spectroscopy was used to track the metabolic changes throughout the whole development of astringent ('Giombo') and non-astringent ('Fuyu') cultivars of persimmon (Diospyros kaki). The NMR data revealed the low concentration of amino acids (threonine, alanine, citrulline and GABA) and organic acids (malic acid). In addition, the signals of carbohydrates (sucrose, glucose and fructose) seemed to play the most important role in the fruit development. In both cultivars, the growth was characterized by fluctuating sucrose concentration along with a constant increase in both glucose and fructose. In the initial growth stage, the polyphenol composition was quite different between the cultivars. Gallic acid was detected throughout the growth of 'Giombo', while for 'Fuyu', signals of polyphenols disappeared over time. Additional multivariate analysis suggested that these cultivars share many metabolic similarities during development. These findings might help the comprehension of fruit development, which in turn, impacts the quality of the fruits. PMID- 28873599 TI - Peptides derived from tryptic hydrolysate of Bacillus subtilis culture suppress fungal spoilage of table grapes. AB - This study confirmed the anti-fungal effect of trypsin-treated Bacillus subtilis culture (BC) (tryptic hydrolysate, TH) on mold growth on Kyoho grapes. We examined the anti-fungal activity of TH by identifying TH peptides and performing a computational docking analysis. TH was more potent than untreated BC in suppressing fungal growth on grapes. Specifically, TH maintained grape freshness by inhibiting respiration and rachis browning, maintaining firmness, and preventing weight loss. Thirty-six inhibitory peptides against beta-1,3-glucan synthase (GS) were screened from 126 TH peptides identified through proteomic analysis. Among them, 13 peptides bound tightly to GS active pockets with lower binding energies than that of GppNHp. The most potent peptides, LFEIDEELNEK and FATSDLNDLYR, were synthesized, and further experiments showed that these peptides had a highly suppressive effect on GS activity and Aspergillus niger and Penicillium chrysogenum growth. Our results confirm that tryptic treatment is effective for improving the anti-fungal activity of BC. PMID- 28873600 TI - Determination of cyanamide residue in 21 plant-derived foods by liquid chromatography-tandem mass spectrometry. AB - Cyanamide is widely used in agriculture, and has a modest toxicity in humans. In the present study, a simple, sensitive, and widely applicable method for detecting cyanamide in 21 plant-derived foods was developed. In the proposed method, after the samples were homogenized and extracted, the method employs clean-up with multi-walled carbon nanotubes (MWCNTs) and derivatization with dansyl chloride. The derivatized sample extracts were quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The mean recoveries were in the range of 67.4%-107.1%, and the RSDs were between 1.0% and 17.8%. The quantification limit in shiitake?, green tea and chinese pepper was 0.05mg/kg, and in others 18 plant-derived foods was 0.01mg/kg. Among the data of 5 different laboratories, the repeatability limits (r) ranged from 0.0010 to 0.0941, and the reproducibility limits (R) ranged from 0.0031 to 0.2667. Moreover, the repeatability among different testing personnels in the same laboratory also has been examined. PMID- 28873601 TI - Production and assessment of Pacific hake (Merluccius productus) hydrolysates as cryoprotectants for frozen fish mince. AB - The aim of this study was to investigate application of fish protein hydrolysates (FPHs) as cryoprotectants for cod fish mince subjected to freeze-thaw abuse. Response surface methodology revealed little difference in cryoprotectant ability between FPHs produced from Pacific hake muscle within the range of conditions studied, namely Flavourzyme(r) enzyme/substrate ratio (E/S 1-4%), time (1-6h) and pH (5-7). When added at 4% or higher concentrations, FPH minimized expressible moisture and cook loss, while maximizing salt extractable protein from freeze thaw abused fish mince, providing similar or better cryoprotection compared to an 8% sucrose-sorbitol blend, and a stabilizing effect of FPH on myosin was observed by differential scanning calorimetry. Sensory evaluation showed that addition of 8% FPH in fish ball products increased the perception of fishiness, saltiness, bitterness and firmness while decreasing moistness. FPH could be a viable alternative to the sugar-based cryoprotectants currently used for frozen fish products. PMID- 28873602 TI - Application of chemometrics to assess the influence of ultrasound frequency, Lactobacillus sakei culture and drying on beef jerky manufacture: Impact on amino acid profile, organic acids, texture and colour. AB - The effects of ultrasound (US) frequency, addition of Lactobacillus sakei culture and drying time on key nutritional (protein, amino acids, and organic acids) and physicochemical properties (texture and colour) of cultured and uncultured beef jerky were evaluated. Cultured and uncultured jerky samples were subjected to US frequencies of 25kHz, 33kHz and 45kHz for 30min prior to marination and drying. Principal component analysis demonstrated a significant effect of beef jerky processing conditions on physicochemical properties. Taurine content of jerky samples was found to increase with an increase in ultrasonic frequencies for cultured samples. No significant changes in colour values were observed for ultrasound pre-treated and control samples. Interactive effects of culture treatment, drying and ultrasonic frequency were observed. This study demonstrates that the nutritional profile of beef jerky can be improved through the incorporation of L. sakei. PMID- 28873603 TI - Further studies on the iodine concentration of conventional, organic and UHT semi skimmed milk at retail in the UK. AB - Milk is the largest source of iodine in UK diets and earlier studies showed organic summer and winter milk to be significantly lower in iodine than conventional milk. One study also showed UHT milk to have lower iodine concentration. The study on winter and UHT milk was small and accordingly a new study is reported here involving conventional, organic and UHT semi-skimmed milk from four supermarkets over a six-month period in summer and winter in two regions of the UK. The results showed organic milk to be 44% lower in iodine than conventional milk (427 vs. 241ug/L, P<0.001) and UHT milk was 27% lower in iodine than conventional milk (427 vs. 314ug/L, P<0.001) although the differences tended to be less in the summer. The results indicate that replacement of conventional milk by organic or UHT milk will increase the risk of sub-optimal iodine status especially for pregnant/lactating women. PMID- 28873604 TI - Effect of six different starter cultures on the concentration of residual nitrite in fermented sausages during in vitro human digestion. AB - The objective of this study was to determine the effect of six different starter cultures of enterobacteria on the concentration of residual nitrite in fermented sausages during in vitro human digestion. Before digestion, the concentration of residual nitrite was dependent on starter culture in fermented sausage and ranged from 25.2 to 33.2mg/kg. Among the six starter cultures of enterobacteria, Pediococcus acidilactici, Pediococcus pentosaceus, and Staphylococcus carnosus showed higher nitrite depletion ability than the other three strains in fermented sausages. The concentration of residual nitrite in fermented sausages was significantly (p<0.05) decreased after stomach digestion and ranged from 17.4 to 21.6mg/kg. Enterobacteria Escherichia coli (E. coli) and/or Lactobacillus casei (L. casei) effectively increased the degree of depletion of residual nitrite in large intestine digestion. In conclusion, starter cultures could influence the concentration of residual nitrite during in vitro human digestion. They could deplete residual nitrite in fermented sausages. PMID- 28873605 TI - An analysis of the changes on intermediate products during the thermal processing of black garlic. AB - The thermal processing of black garlic was simulated. Fresh garlic was incubated at 55 degrees C with 80% humidity and sampled every 5 or 10days. The changes in relevant products were as follows: the fructan content was decreased by 84.79%, and the fructose content was increased by 508.11%. The contents of Maillard reaction intermediate products were first increased and then decreased. The colour of garlic gradually became dark and the pH decreased from 6.13 to 4.00. By analyzing these changes, the mechanism of black garlic formation and the changes on the Maillard reaction were revealed. The sweetness of black garlic resulted mainly from the fructose that was produced, and the black colour was largely due to the Maillard reaction between fructose/glucose and amino acids. An understanding of this process is useful to explain the formation mechanism of black garlic and could lead to better control of the quality of black garlic. PMID- 28873606 TI - Effectiveness of electrolyzed oxidizing water treatment in removing pesticide residues and its effect on produce quality. AB - This study evaluated the effects of electrolyzed oxidizing (EO) water treatment on the removal of pesticide residues (diazinon, cyprodinil and phosmet) from spinach, snap beans and grapes, and the effect on produce quality. High available chlorine content (ACC) and long treatment time of EO water resulted in high pesticide removals. Up to 59.2, 66.5 and 37.1% of diazinon; 43.8, 50.0 and 31.5% of cyprodinil; 85.7, 73.0 and 49.4% of phosmet; were removed from spinach, snap beans and grapes, respectively, after 15min EO water treatment at 120mg/l ACC. EO water was also more effective than electrolyzed reduced water, bleach, VegWash and DI water on pesticide removal. In addition, no significant colour or texture deterioration were found on produce samples treated with EO water. It was concluded, EO water can be very effective in pesticide residue removal from fresh produce without affecting the produce quality. PMID- 28873607 TI - LC-MS/MS profiles and interrelationships between the anti-inflammatory activity, total phenolic content and antioxidant potential of Kalasin 2 cultivar peanut sprout crude extract. AB - Peanut is a potent natural source of phytochemical compounds and is associated with human health. In the present study, we determined the biological activity and chemical constituents of peanuts germinated for 0-9days. The ungerminated seed coat exhibited the highest antioxidant potential, phenolic compound content and anti-inflammatory activity. During the germination process, on the first germination day, root extract showed the highest antioxidant potential, phenolic compound content and anti-inflammatory activity. The kernel exhibited a low phenolic compound content and antioxidant activity at the early stage of germination and significantly increased after 9days of germination. Resveratrol increased to 7.19+/-0.07ug/g dry weight on the second day of germination. LC MS/MS showed a variety of phenolic compounds and stilbene derivatives in different parts of germinated peanut. These results suggest that the peanut sprout exerts high anti-inflammatory effects that may be related to the polyphenolic content and antioxidant properties. PMID- 28873608 TI - Effects of alkali on protein polymerization and textural characteristics of textured wheat protein. AB - The impact of alkali addition on the degree of gluten polymerization and textural characteristics of textured wheat protein was investigated. Results showed that the extrusion process increased the average molecular weight of gluten as evidenced by SDS-PAGE and SDS extractable protein. The addition of alkali not only promoted the degree of gluten polymerization, but also induced dehydroalanine-derived cross-linking. Alkali addition decreased the content of cystine and increased the contents of dehydroalanine and lanthionine. The obvious decrease of free SH showed that dehydroalanine-derived cross-linking was quantitatively less crucial than disulfide cross-linking. Furthermore, the protein cross-linking induced by alkali improved the texture properties of gluten extrudates. SEM analysis showed extrusion under alkaline condition conferred a more fibrous microstructure as a consequence of a compact gluten network. PMID- 28873609 TI - In vitro investigation of anticancer and ACE-inhibiting activity, alpha-amylase and alpha-glucosidase inhibition, and antioxidant activity of camel milk fermented with camel milk probiotic: A comparative study with fermented bovine milk. AB - This study aimed to investigate in vitro the health-promoting benefits (anticancer activity, alpha-amylase and alpha-glucosidase inhibition, angiotensin converting-enzyme (ACE)-inhibition, antioxidant and proteolytic activity) of camel milk fermented with indigenous probiotic strains of Lactobacillus spp., compared with fermented bovine milk. The three camel milk probiotic strains Lb. reuteri-KX881777, Lb. plantarum-KX881772, Lb. plantarum-KX881779 and a control strain Lb. plantarum DSM2468 were employed to ferment camel and bovine milks separately. The proteolytic and antioxidant activity of water soluble extracts (WSEs) from all fermented camel milks were higher than those of fermented bovine milk. alpha-Amylase inhibition of WSEs were >34% in both milk types fermented with all strains during storage periods, except the WSE of camel milk fermented by Lp.K772. The highest ACE-inhibition of the WSE from camel milk fermented by Lr.K777 was >80%. The proliferations of Caco-2, MCF-7 and HELA cells were more inhibited when treated with the WSE of fermented camel milk. PMID- 28873610 TI - Absence of evidence or evidence of absence? A transfer and depletion study of Sudan I in eggs. AB - Sudan I is a carcinogenic industrial azo-dye, forbidden for use in food. However, it has been detected in food on several occasions, such as in paprika, used in animal husbandry to enhance egg yolk colour. Therefore, an animal experiment was designed to simulate the transfer of Sudan I to eggs after its unintentional administration to laying hens. A group of laying hens (n=18) received feed contaminated with Sudan I at the raising concentrations: 0.45mg/kg, 4.97mg/kg and 42.1mg/kg. Residues of Sudan I were detected in egg yolks (0.29+/-0.03ug/kg, mean+/-SD) only after the administration of the feed contaminated with the dye at the highest concentration. The determined concentrations were much lower than expected based on the compound's lipophilicity. In conclusion, the transfer of Sudan I to eggs was limited and strongly dependent on its concentration in feed. PMID- 28873611 TI - A galactomannoglucan derived from Agaricus brasiliensis: Purification, characterization and macrophage activation via MAPK and IkappaB/NFkappaB pathways. AB - In this study, a novel galactomannoglucan named as TJ2 was isolated from Agaricus brasiliensis with microwave extraction, macroporous resin, ion exchange resin and high resolution gel chromatography. TJ2 is composed of glucose, mannose and galactose in the ratio 99.2:0.2:0.6. Infrared spectra (IR), methylation analysis and nuclear magnetic resonance spectra indicated that TJ2 mainly contained a beta (1->3) - linked glucopyranosyl backbone. Interestingly, TJ2 significantly promoted RAW264.7 cell proliferation, and was able to activate the cells to engulf E. coli. In addition, TJ2 induced the expression of Interleukin 1beta (IL 1beta), Interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and cyclooxygenase-2 (Cox-2) in the cells. TJ2 also promoted the production of nitric oxide (NO) by inducing the expression of inducible nitric oxide synthase (iNOS). Moreover, TJ2 is a potent inducer in activating the mitogen-activated protein kinase (MAPK) and inhibitor of nuclear factor-kappa B (IkappaB)/nuclear factor kappa B (NFkappaB) pathways. PMID- 28873612 TI - Synthesis of magnetic graphene/mesoporous silica composites with boronic acid functionalized pore-walls for selective and efficient residue analysis of aminoglycosides in milk. AB - In this study, magnetic graphene/mesoporous silica composites with boronic acid functionalized pore-walls were synthesized for the first time by a two-step post graft method. The obtained nano-composites were proven to hold many attractive features such as large specific surface area, uniform mesopores, high magnetic responsibility, and boronic acid-functionalized inner pore-walls. Aminoglycoside residues in milk were extracted using MG@mSiO2-APB composites as restricted access matrix dispersive solid phase extraction adsorbents through the interaction between boronic acid groups and glucoside structures. Extraction conditions were optimized by studying the SPE parameters. Limits of detection of the method were as low as 5ngmL-1 for streptomycin) and 2ngmL-1 for dihydrostreptomycin. Finally, magnetic graphene/mesoporous silica composites with boronic acid-functionalized pore-walls were successfully applied to residue analysis in milk samples. Compared to the traditional extraction methods, using this nano-composites for aminoglycoside residues analysis in milk is more sensitive, effective and convenient. PMID- 28873613 TI - Simple coupled ultrahigh performance liquid chromatography and ion chromatography technique for simultaneous determination of folic acid and inorganic anions in folic acid tablets. AB - Folic acid plays a significant role during periods of rapid cells division and growth. Pregnant women require folic acid daily, either from dietary supplements or folic acid tablets in order to prevent fetal neural tube defects. In this work, a simple coupled ultrahigh performance liquid chromatography and ion chromatography technique was developed for simultaneous determination of folic acid and inorganic anions in folic acid tablets. A reversed-phase C18 column was used as the pretreatment column for on-line separating inorganic anions from organics. Inorganic anions were concentrated in the concentration column. Under the optimal chromatographic conditions, good sensitivity and linear calibration curves (r>=0.9992) were obtained. Low detection limits were obtained in the range of 0.0032-0.40mgL-1 for all analytes. Repeatability results were satisfactory with relative standard deviations less than 1.50% (n=5). The developed method was utilized to analyze spiked folic acid tablet samples with good measured recoveries (92.4-107.4%). PMID- 28873614 TI - Flavor and chiral stability of lemon-flavored hard tea during storage. AB - Flavor stability of hard tea beverage was investigated over eight weeks of storage. The volatile compounds were analyzed using solid-phase microextraction gas chromatography-mass spectrometry (SPME-GC-MS) and two-dimensional GC-MS. Quantitative analysis showed that the concentrations of linalool, citronellol, geranial, neral, geraniol, and nerol decreased dramatically during storage, whereas alpha-terpineol showed an increasing trend during storage. Heart-cut two dimensional GC-MS (2D-GC-MS) chirality analysis showed that (R)-(+)-limonene, (R) (-)-linalool, (S)-(-)-alpha-terpineol and (S)-(-)-4-terpineol dominated in the fresh hard tea samples, however, the configuration changed during storage for the terpene alcohols. The storage conditions did not change the configuration of limonene. A conversion of (R)-(-)-linalool to (S)-(+) form was observed during storage. Both (S)-alpha-terpineol and (S)-4-terpineol dominated at beginning of the storage, but (R)-(+)-alpha-terpineol became dominated after storage, suggested in addition to isomerization from (S)-alpha-terpineol, other precursors could also generate alpha-terpineol with (R)-isomer preference. PMID- 28873615 TI - Development and validation of LC-MS-based alternative methodologies to GC-MS for the simultaneous determination of triterpenic acids and dialcohols in virgin olive oil. AB - Pentacyclic triterpenes are minor, but very relevant compounds found in virgin olive oil (VOO). A rapid and reliable LC-MS method for determining the triterpenic acids and dialcohols (after ultrasound assisted extraction) from VOO has been developed, giving an alternative to the widely used GC (FID/MS) methodologies. The analytical parameters of the proposed method were exhaustively checked, establishing limits of detection (from 1 to 95ug/l) and quantification, precision (RSD values for inter-day repeatability were found between 4.2 and 7.3% considering area values), trueness (within the range 92.7 and 100.5%) and evaluating possible matrix effect (which was no significant). The method was applied to the analysis of six triterpenic compounds in 11 monovarietal VOOs and the results compared with the quantitative GC-MS data. Moreover, the direct injection (after a simple dilution) of the samples into the LC-MS system was also tested, in an attempt to proffer an even simpler sample treatment. PMID- 28873616 TI - Methodological evaluation of DNA-based molecular keys to identify categories of mislabelling in commercial products from genus Merluccius spp. AB - The large variety of fish formats which are globally commercialized supports use of meta-evaluation studies to test discrimination power among molecular keys available for traceability of highly-degraded and/or chemically-modified DNA material. This paper shows that a combination of DNA identification methods validated for genus Merluccius allows 100% species assignment in hake products and offers higher diagnostic power (97% on products) than individual methods, i.e. Hake-ITS1-RFLP (89%) or Hake-Cytochrome b-RFLP (83%). A global 31% product mislabelling involved 15% of products affected by internal species substitution, as the main cause of mislabelling in ultrafrozen products, and another 16% affected by external species substitution with non-hake species, as the cause of mislabelling in processed and cooked hake-based products. The combination of both DNA keys minimizes the tool-associated rate of diagnostic failure, allowing decoupling of mislabelling categories and maximizing the quantitative adscription of products to species on any kind of hake-based products. PMID- 28873617 TI - Nutritional and bioactive potential of Myrtaceae fruits during ripening. AB - This study aimed to characterize jabuticaba (Myrciaria cauliflora), guabiju (Myrcianthes pungens), and jambolan (Syzygium cumini) in relation to its individual phenolic compounds (LC-ESI-MS/MS), antioxidant capacity, total monomeric anthocyanin, sugars, and minerals during ripening (intermediate and ripe stages). In the three studied fruits, 22 phenolic compounds were quantified, especially phenolic acids and flavonoids, which presented a higher concentration in the intermediate ripening stage. In contrast, the total monomeric anthocyanin, fructose, glucose, Ca, Na values were higher in the ripe stage. In addition, all studied fruits showed expressive antioxidant capacity in both ripening stages: 2569.28 to 5066.35mg AAE 100g-1 DW for DPPH; 13777.52 to 26667.45umol Fe+2 100g-1 DW for FRAP; and 957.72 to 2061.35mg GAE 100g-1 DW for Folin-Ciocalteu reducing capacity. Therefore, our results revealed that these fruits represent a supply of high-value nutrient and bioactive components, especially in the ripe stage. PMID- 28873618 TI - Unravelling proteome changes of chicken egg whites under carbon dioxide modified atmosphere packaging. AB - Unfertilized chicken eggs within 24h of laying were chosen and stored at 25 degrees C and 45% humidity for 0, 20, and 40days. The experimental group (EG) was the carbon dioxide-modified atmosphere packaging (CDMAP) group, whereas the control group (CG) contained eggs without special handling. Egg freshness indexes were measured. The proteome of the egg whites was determined by LC-MS/MS using isobaric tags for relative and absolute quantitation (iTRAQ). A total of 87 proteins were detected. The results indicated that CDMAP can control the change in protein abundance. Using a correlation analysis between the protein abundance and freshness indexes of the EG, Beta-hexosaminidase, Trypsin inhibitor ClTI-1 and Apolipoprotein D were determined to be potential predictors of egg freshness. In comparing the proteomes of the EG and CG, it was concluded that CDMAP could affect the proteins related to egg vitelline membranes, eggshell matrix and metabolic intensity to maintain egg freshness. PMID- 28873619 TI - Long-term field evaluation of the changes in fruit and olive oil chemical compositions after agronomic application of olive mill wastewater with rock phosphate. AB - The objectives of this study were to determine the long-term effects of agronomic application of olive mill wastewater (OMW) with rock phosphate (RP) in a field of olive trees, on olive fruits and oil quality. The results revealed that olive fruits of OMW-RP amended plants had higher contents of polyphenols and mannitol indicating that agronomic application of OMW with RP generated an oxidative stress. Land spreading of OMW with RP altered the relative proportions of individual sugars in leaves and fruits. Consequently, the oil content decreased significantly, and a marked decrease in the contents of carotenoids and chlorophylls was also observed. Changes also took place in the composition of fatty acids, particularly by the increase of linoleic acid and the decrease of oleic acid. Our results suggested that the use of OMW in combination with RP is expected to have a major negative impact on olive fruit and oil quality. PMID- 28873621 TI - Exploitation of alfalfa seed (Medicago sativa L.) flour into gluten-free rice cookies: Nutritional, antioxidant and quality characteristics. AB - In an effort to increase the nutritional value of common gluten-free (GF) cereal based foods, GF cookies using alfalfa seed flour (ASF), at different substitution levels to common rice flour (0% as control, 15%, 30% and 45% w/w), were produced. Crude protein, total dietary fibre, total polyunsaturated, total n-3 and n-6 fatty acid contents increased linearly (p<0.05) by raising the substitution levels of rice with ASF. The hardness, the total phenolic content, the in vitro antioxidant capacity and the resistant starch increased linearly (p<0.05), whereas the starch hydrolysis index decreased linearly (p<0.05) by raising the substitution levels of rice flour with ASF. Despite the fact that ASF-substituted GF cookies had inferior sensory attributes compared to the control, the score given by the panellists remained at fairly good levels for all tested parameters, showing acceptability of the substituted GF cookies. PMID- 28873620 TI - Novel approaches mediated by tailor-made green solvents for the extraction of phenolic compounds from agro-food industrial by-products. AB - An environmentally friendly method for the phenolic compound extraction from agro food industrial by-products was developed in order to contribute with their sustainable valorization. A Natural Deep Eutectic Solvent was chemometrically designed for the first time and compared with traditional solvents in terms of analyte stabilization. The combination of lactic acid, glucose and 15% water (LGH 15) was selected as optimal. A high-efficiency ultrasound-assisted extraction mediated by LGH-15 prior to HPLC-DAD allows the determination of 14 phenols in onion, olive, tomato and pear industrial by-products. NADES synthesis as well as the extraction procedures were optimized by Response Surface Methodology. Thus, phenolic determination in these complex samples was achieved by a simple, non expensive, eco-friendly and robust system. The application to different matrices demonstrated the versatility of the proposed method. NADES opens interesting perspectives for their potential use as vehicles of bioactive compounds as food additives or pharmaceuticals. PMID- 28873622 TI - Effects of cuticular wax on the postharvest quality of blueberry fruit. AB - The blueberry fruit has a light-blue appearance because its blue-black skin is covered with a waxy bloom. This layer is easily damaged or removed during fruit harvesting and postharvest handling. We investigated the effects of wax removal on the postharvest quality of blueberry fruit and their possible mechanisms. The removal of natural wax on the fruit was found to accelerate the postharvest water loss and decay, reduce the sensory and nutritional qualities, and shorten the shelf-life. Wax removal decreased the activities of antioxidant enzymes and contents of antioxidants, and accelerated accumulation of ROS and lipid peroxidation, especially at the later period of storage. Moreover, the organellar membrane structure was disrupted in fruit with wax removed. These results indicate that cuticular wax plays an important role in maintaining the postharvest quality and delaying fruit senescence. The results should improve our understanding for better preservation of postharvest quality of blueberry fruit. PMID- 28873623 TI - Waxy flour degradation - Impact of screw geometry and specific mechanical energy in a co-rotating twin screw extruder. AB - Dextrinization of starch using extrusion processing is crucial to the quality of direct expanded products. To determine the extent of dextrinization, flour samples were extracted from a twin-screw extruder that had been brought to a sudden stop and molecular weights were determined by intrinsic viscosity. The screw profile and moisture feed content had the most significant impact on molecular weight reduction, reducing intrinsic viscosity from 1.75 to 0.70dL/g at the most. The breakdown, as shown by a reduction in intrinsic viscosity, had a strong negative correlation (r=-0.96) with specific mechanical energy. However, the extruder die did not have a measurable impact on the molecular weight reduction of waxy flour. Size exclusion chromatography confirmed intrinsic viscosity measurements were associated with reduction of the size of amylopectin molecules to approximately 1/10 the original molecular weight while native gliadin was nearly eliminated from the waxy flour following the extrusion treatments. PMID- 28873624 TI - Whey-grape juice drink processed by supercritical carbon dioxide technology: Physicochemical characteristics, bioactive compounds and volatile profile. AB - The effect of supercritical carbon dioxide technology (SCCD, 14, 16, and 18MPa at 35+/-2 degrees C for 10min) on whey-grape juice drink characteristics was investigated. Physicochemical characterization (pH, titratable acidity, total soluble solids), bioactive compounds (phenolic compounds, anthocyanin, DPPH and ACE activity) and the volatile compounds were performed. Absence of differences were found among treatments for pH, titratable acidity, soluble solids, total anthocyanin and DPPH activity (p-value>0.05). A direct relationship between SCCD pressure and ACE inhibitory activity was observed, with 34.63, 38.75, and 44.31% (14, 16, and 18MPa, respectively). Regards the volatile compounds, it was noted few differences except by the presence of ketones. The findings confirm the SCCD processing as a potential promising technology to the conventional thermal treatment. PMID- 28873625 TI - Combination of different antifungal agents in oil-in-water emulsions to control strawberry jam spoilage. AB - The combination of antifungal agents (cinnamon bark oil, zinc gluconate and trans ferulic acid) in oil-in-water emulsions to control the fungal spoilage of strawberry jams, minimising essential oil's sensory impact, was evaluated in this work. The in vitro assays of free antifungal agents were performed against five fungal strains; meanwhile, the emulsions assays were conducted against Aspergillus niger given its strong resistance and its relevance in strawberry products. The emulsion formulated with 0.08mg/g of essential oil was able to inhibit mould growth after the incubation period. The incorporation of zinc gluconate or trans-ferulic acid, independently of the concentration used, allowed to reduce a 25% the amount of essential oil needed to inhibit the microbial growth. The combination of antifungal agents in the emulsions has demonstrated to be an effective alternative to reduce the amount of essential oil employed, maintaining the hygienic quality and sensory profile of the strawberry jam. PMID- 28873626 TI - Effectiveness of water-air and octanol-air partition coefficients to predict lipophilic flavor release behavior from O/W emulsions. AB - Flavor release from food matrices depends on the partition of volatile flavor compounds between the food matrix and the vapor phase. Thus, we herein investigated the relationship between released flavor concentrations and three different partition coefficients, namely octanol-water, octanol-air, and water air, which represented the oil, water, and air phases present in emulsions. Limonene, 2-methylpyrazine, nonanal, benzaldehyde, ethyl benzoate, alpha terpineol, benzyl alcohol, and octanoic acid were employed. The released concentrations of these flavor compounds from oil-in-water (O/W) emulsions were measured under equilibrium using static headspace gas chromatography. The results indicated that water-air and octanol-air partition coefficients correlated with the logarithms of the released concentrations in the headspace for highly lipophilic flavor compounds. Moreover, the same tendency was observed over various oil volume ratios in the emulsions. Our findings therefore suggest that octanol-air and water-air partition coefficients can be used to predict the released concentration of lipophilic flavor compounds from O/W emulsions. PMID- 28873627 TI - Statistical pattern recognition classification with computer vision images for assessing the furan content of fried dough pieces. AB - This research tested furan classification models in fried matrices based on the pattern recognition of images. Samples were fried at 150, 160, 170, 180, and 190 degrees C for 5, 7, 9, 11, 13, and 30min. Furan was measured by GC-MS. Corresponding images were acquired and processed to extract 2175 chromatic and textural features. Principal component analysis was used to reduce features to 8 12 principal components. In parallel, sequential forward selection coupled with linear discriminant analysis (LDA) was the best strategy to select only 5-7 features. LDA was the best classifier with 91.39-97.60% recognizing above 113ug/kg and 69.54-83.80% to classify images from class 1 (0-38ug/kg) from class 2 (39-113ug/kg). Also, support vector machine recognized 87.71-96.74% of class 3 (114-398ug/kg) from class 4 (399-646ug/kg). The technique may be used to detect high amount of furan in fried starchy matrices. PMID- 28873628 TI - GC-FID determination of tetramethylpyrazine and acetoin in vinegars and quantifying the dependence of tetramethylpyrazine on acetoin and ammonium. AB - 2,3,5,6-Tetramethylpyrazine (TMP) is an important health functional composition in vinegars, but there are controversial viewpoints about its formation mechanism and scarce relevant records on TMP content enhancement in vinegar products. In this study, a simple and accurate solvent extraction coupled with GC-FID method was developed for the simultaneous determination of TMP and acetoin in vinegars and 137 worldwide samples were analyzed. Meanwhile, the ammonium contents of all the vinegar samples were determined using the salicylate method. By nonlinear surface fitting, the concentrations of TMP in vinegars were found to follow second-order polynomial models of acetoin and ammonium concentrations. By isotopic tracing using 13C labelled acetoin and 15N ammonium, acetoin and ammonium were deduced to be the precursors of TMP in vinegars. PMID- 28873629 TI - Phenolic acids, anthocyanins, proanthocyanidins, antioxidant activity, minerals and their correlations in non-pigmented, red, and black rice. AB - Soluble-free, soluble-conjugated, insoluble-bound phenolics and antioxidant activity, flavonoid (TFC), proanthocyanidins (TPAC), anthocyanins and minerals of fifteen whole rice grains with different colors were investigated. Soluble-free protocatechuic and vanillic acids were only quantified in black rice, which had the most quantities. Non-pigmented rice had no detectable conjugated protocatechuic and 2,5-dihydroxybenzoic acids both of which were found in black and red rice, respectively. The main bound phenolic acids were ferulic and p coumaric, as well as 2,5-dihydroxybenzoic in red rice and protocatechuic and vanillic acids in black rice. Soluble-conjugated phenolics, TFC, and anthocyanins were negatively correlated with L*, b*, C and H degrees values. TPAC was positively correlated with a* (P<0.01). Protocatechuic, vanillic, syringic and ferulic acids were associated with TPC and antioxidant activity in the soluble conjugated fraction while protocatechuic and ferulic acid were correlated with those in the insoluble-bound fraction. Principal component analysis divided samples into non-pigmented, red and black rice groups. PMID- 28873630 TI - Performances of different protocols for exocellular polysaccharides extraction from milk acid gels: Application to yogurt. AB - Dextran or xanthan were used as model exocellular polysaccharides (EPS) to compare the extraction efficiency of EPS from skim milk acid gels using three different protocols. Extraction yields, residual protein concentrations and the macromolecular properties of extracted EPS were determined. For both model EPS, the highest extraction yield (~80%) was obtained when samples were heated in acidic conditions at the first step of extraction (Protocol 1). Protocols that contained steps of acid/ethanol precipitation without heating (Protocols 2 and 3) show lower extraction yields (~55%) but allow a better preservation of the EPS macromolecular properties. Changing the pH of acid gels up to 7 before extraction (Protocol 3) improved the extraction yield of anionic EPS without effect on the macromolecular properties of EPS. Protocol 1 was then applied for the quantification of EPS produced during the yogurt fermentation, while Protocol 3 was dedicated to their macromolecular characterization. PMID- 28873631 TI - Enhancing physicochemical properties of emulsions by heteroaggregation of oppositely charged lactoferrin coated lutein droplets and whey protein isolate coated DHA droplets. AB - The formation and physicochemical stability of mixed functional components (lutein & DHA) emulsions through heteroaggregation were studied. It was formed by controlled heteroaggregation of oppositely charged lutein and DHA droplets coated by cationic lactoferrin (LF) and anionic whey protein isolate (WPI), respectively. Heteroaggregation was induced by mixing the oppositely charged LF lutein and WPI-DHA emulsions together at pH 6.0. Droplet size, zeta-potential, transmission-physical stability, microrheological behavior and microstructure of the heteroaggregates formed were measured as a function of LF-lutein to WPI-DHA droplet ratio. Lutein degradation and DHA oxidation by measurement of lipid hydroperoxides and thiobarbituric acid reactive substances were determined. Upon mixing the two types of bioactive compounds droplets together, it was found that the largest aggregates and highest physical stability occurred at a droplet ratio of 40% LF-lutein droplets to 60% WPI-DHA droplets. Heteroaggregates formation altered the microrheological properties of the mixed emulsions mainly by the special network structure of the droplets. When LF-coated lutein droplets ratios were more than 30% and less than 60%, the mixed emulsions exhibited distinct decreases in the Mean Square Displacement, which indicated that their limited scope of Brownian motion and stable structure. Mixed emulsions with LF-lutein/WPI DHA droplets ratio of 4:6 exhibited Macroscopic Viscosity Index with 13 times and Elasticity Index with 3 times of magnitudes higher than the individual emulsions from which they were prepared. Compared with the WPI-DHA emulsion or LF-lutein emulsion, the oxidative stability of the heteroaggregate of LF-lutein/WPI-DHA emulsions was improved. Heteroaggregates formed by oppositely charged bioactive compounds droplets may be useful for creating specific food structures that lead to desirable physicochemical properties, such as microrheological property, physical and chemical stabilities. PMID- 28873632 TI - Magnesium affects spinach carotenoid bioaccessibility in vitro depending on intestinal bile and pancreatic enzyme concentrations. AB - Magnesium may reduce carotenoid bioavailability by forming insoluble complexes with bile salts/fatty acids, inhibiting micelle formation. Here, we investigated whether altering bile/pancreatin concentration influenced potential negative effects of magnesium on carotenoid bioaccessibility. Spinach (4g) was digested in vitro with added magnesium (0, 200, 400mg/L) and canola oil/coffee creamer, at varying bile extract (1 or 8mM) and pancreatin (100 or 990mg/L) concentrations. Bioaccessibility was determined for beta-carotene, lutein, and total carotenoids via HPLC. Additionally, lipolysis, particle size, and zeta potential of the micellar fractions were investigated. Increasing magnesium concentrations negatively affected carotenoid bioaccessibility (p<0.001), lipolysis, particle size and zeta potential. The impact of magnesium on carotenoid bioaccessibility was modulated mainly by bile concentration, with samples digested with 1mM of bile being more susceptible to inhibitory effects of magnesium than those digested with 8mM (p<0.001). Thus, magnesium was found to potentially interfere with carotenoid bioaccessibility at various physiologically plausible conditions. PMID- 28873633 TI - Metabolomics for organic food authentication: Results from a long-term field study in carrots. AB - Increasing demand for organic products and their premium prices make them an attractive target for fraudulent malpractices. In this study, a large-scale comparative metabolomics approach was applied to investigate the effect of the agronomic production system on the metabolite composition of carrots and to build statistical models for prediction purposes. Orthogonal projections to latent structures-discriminant analysis (OPLS-DA) was applied successfully to predict the origin of the agricultural system of the harvested carrots on the basis of features determined by liquid chromatography-mass spectrometry. When the training set used to build the OPLS-DA models contained samples representative of each harvest year, the models were able to classify unknown samples correctly (100% correct classification). If a harvest year was left out of the training sets and used for predictions, the correct classification rates achieved ranged from 76% to 100%. The results therefore highlight the potential of metabolomic fingerprinting for organic food authentication purposes. PMID- 28873634 TI - Stabilising phycocyanin by anionic micelles. AB - Phycocyanins are pigment-protein complexes with potential application as natural food colourants. The perceived colour of phycocyanins varies with pH, and a method to stabilise the colour over a broad range of pH values is requested by the food industry. In this work, the stabilising effect of sodium dodecyl sulphate (SDS) micelles on pH-induced colour variations of phycocyanin was examined. SDS was shown to stabilise the blue conformation of phycocyanin, preventing formation of the green conformation, which is prevalent at low pH. The studies indicated that the stabilising effect occurred through interaction or entrapment of the non-protonated, circular helical (blue) structure of phycocyanin and the anionic SDS micelles. The interaction prevented conversion into protonated, partially unfolded (green) phycocyanin species. This information opens for new possibilities to stabilise the blue conformation of phycocyanin and to apply the stabilised form in food products as a natural blue food colourant. PMID- 28873635 TI - Effect of storage time and temperature on parent and oxygenated polycyclic aromatic hydrocarbons in crude and refined vegetable oils. AB - Changes in polycyclic (PAH) and oxygenated (OPAH) aromatic hydrocarbon concentrations in vegetable oils during storage for 270days at 25 degrees C or 4 degrees C were investigated. The concentrations of OPAHs and PAHs increased with storage time. The increase in PAH concentration was mainly caused by light PAHs. Total PAH concentrations increased from 33.11-36.77MUg/kg to 45.12-58.04MUg/kg in 26 crude oil samples, while those in 26 refined oil samples increased from 16.52 20.02MUg/kg to 25.73-40.01MUg/kg. Acid value (AV) and peroxide value (POV) also showed an increase during the storage process from 0.08-0.92mg/kg to 0.33 2.98mg/kg, and from 0.08-0.12mmol/kg to 0.33-3.45mmol/kg in 52 tested oils, respectively. AV and POV were within the regulatory limits of China after storage for 270days. However, concentrations of 16 PAHs in all tested oils exceeded 25MUg/kg. The results indicated PAHs and OPAHs formation was better inhibited in oils stored at lower temperature. PMID- 28873636 TI - Microstructure and tuber properties of potato varieties with different genetic profiles. AB - The objectives of this research were to study tuber starch characteristics and chemical - thermal properties of 21 potato varieties, and to determine their genetic diversity through SSR markers. Starch granular size varied among samples, with a wide diameter distribution (5-85MUm), while granule shapes were similar. Differential Scanning Calorimeter analysis showed that the transition temperatures (69 degrees C-74 degrees C) and enthalpies of gelatinization (0.9J/g 3.8J/g) of tubers were also variety dependent. SSR analysis allowed the detection of 157 alleles across all varieties, with an average value of 6.8 alleles per locus. Variety-specific alleles were also identified. SSR-based cluster analysis revealed that varieties with interesting quality attributes were distributed among all clusters and sub-clusters, suggesting that the genetic basis of traits analyzed may differ among our varieties. The information obtained in this study may be useful to identify and develop varieties with slowly digestible starch. PMID- 28873637 TI - Rapid analysis of fungicides in tea infusions using ionic liquid immobilized fabric phase sorptive extraction with the assistance of surfactant fungicides analysis using IL-FPSE assisted with surfactant. AB - A green, simple, inexpensive, and sensitive ionic liquid immobilized fabric phase sorptive extraction method coupled with high performance liquid chromatography was developed for rapid screening and simultaneous determination of four fungicides (azoxystrobin, chlorothalonil, cyprodinil and trifloxystrobin) residues in tea infusions. This IL modified extraction fiber is capable of extracting target analytes directly from complicated tea water matrices with the addition of surfactant. A series of extraction conditions were investigated by one-factor-at-a-time approach and orthogonal test. After a series experiments, the optimum conditions were found to be 10% [HIMIM]NTf2 as coating solution, 2min vortex time, 500MUL acetonitrile as dispersive solvent and 2min desorption time. Under the above conditions, the proposed technique was applied to detect fungicides from real tea water samples with satisfactory results. PMID- 28873638 TI - Impact of fruit texture on the release and perception of aroma compounds during in vivo consumption using fresh and processed mango fruits. AB - Two fresh (fresh cubic pieces, fresh puree) and two dried (dried cubic pieces, dried powder) products were prepared from a homogenous mango fruit batch to obtain four samples differing in texture. The aromatic profiles were determined by SAFE extraction technique and GC-MS analysis. VOCs released during consumption were trapped by a retronasal aroma-trapping device (RATD) and analysed by GC-MS. Twenty-one terpenes and one ester were identified from the exhaled nose-space. They were amongst the major mango volatile compounds, 10 of which were already reported as being potential key flavour compounds in mango. The in vivo release of aroma compounds was affected by the matrix texture. The intact samples (fresh and dried cubic pieces) released significantly more aroma compounds than disintegrated samples (fresh puree, dried powder). The sensory descriptive analysis findings were in close agreement with the in vivo aroma release data regarding fresh products, in contrast to the dried products. PMID- 28873639 TI - Determination of thiabendazole in orange juice using an MISPE-SERS chemosensor. AB - Thiabendazole, a systemic fungicide used to treat vegetables and fruits during postharvest process, persists as detrimental residue to consumers. We combine a molecularly imprinted polymers (MIPs) with surface enhanced Raman spectroscopy (SERS) to form a novel MISPE-SERS chemosensor and determined thiabendazole in orange juice. Kinetic and static adsorption tests validated the efficient and selective adsorption of thiabendazole using synthesized MIPs via precipitation polymerization. Synthesized MIPs were packed into solid phase extraction (SPE) cartridge to serve as tailor-made sorbents for the separation of thiabendazole in orange juice. Silver colloids synthesized by reduction of AgNO3 by trisodium citrate were used as SERS-active substrate to quantify the eluted thiabendazole from MISPE. The overall process including sample preparation and detection took 23min and the limit of detection of this chemosensor was 4ppm for thiabendazole in orange juice. This chemosensor can be used for rapid and sensitive detection of thiabendazole in agri-foods. PMID- 28873640 TI - Evolution of oxidised peptides during the processing of 9months Spanish dry-cured ham. AB - Sensory and nutritional properties of dry-cured ham can be negatively affected due to oxidative modifications of muscle proteins during its processing. In this study, a peptidomic approach has been used in order to study the evolution of oxidised peptides generated throughout the dry-curing process (0, 2, 3.5, 5, 6.5 and 9months), focusing on those derived from major myofibrillar proteins. A total of 67 peptides showing methionine, proline, and tryptophan oxidations were identified in common in all samples by nano liquid chromatography coupled to tandem mass spectrometry for their relative quantification using a label-free methodology, showing the hydrolysis of some of the peptides during the process. So, the peptidomics strategy used in this work has resulted to be very useful as a complementary tool to the methods currently used to study protein oxidation, allowing a better understanding of the oxidation at peptide level and the influence of ham processing conditions. PMID- 28873641 TI - An image analysis of TLC patterns for quality control of saffron based on soil salinity effect: A strategy for data (pre)-processing. AB - Quality of saffron, a valuable food additive, could considerably affect the consumers' health. In this work, a novel preprocessing strategy for image analysis of saffron thin layer chromatographic (TLC) patterns was introduced. This includes performing a series of image pre-processing techniques on TLC images such as compression, inversion, elimination of general baseline (using asymmetric least squares (AsLS)), removing spots shift and concavity (by correlation optimization warping (COW)), and finally conversion to RGB chromatograms. Subsequently, an unsupervised multivariate data analysis including principal component analysis (PCA) and k-means clustering was utilized to investigate the soil salinity effect, as a cultivation parameter, on saffron TLC patterns. This method was used as a rapid and simple technique to obtain the chemical fingerprints of saffron TLC images. Finally, the separated TLC spots were chemically identified using high-performance liquid chromatography-diode array detection (HPLC-DAD). Accordingly, the saffron quality from different areas of Iran was evaluated and classified. PMID- 28873642 TI - Chemical crosslinking improves the gastrointestinal stability and enhances nutrient delivery potentials of egg yolk LDL/polysaccharide nanogels. AB - Egg yolk low density lipoprotein (LDL)/polysaccharide nanogels are newly explored as oral delivery systems with promising encapsulation potentials. Nonetheless, the stability of nanogels against aggregation in gastrointestinal tract remains a challenge. Therefore, chemical crosslinking by 1-ethyl-3-(3-dimethylaminopropyl) and carbodiimide/N-hydroxysuccinimide (EDC/NHS) was adopted to improve the gastrointestinal stability of nanogels. Compared to original uncrosslinked nanogels, crosslinking did not change particle size, polydispersity index (PDI) and morphology, but it reduced surface charge of nanogels. The nano spray dried LDL/CMC/EDC nanogels had relatively poor surface structure with agglomerations. The FT-IR spectra confirmed the formation of new peptide bonds, which significantly improved stability of nanogels under simulated gastrointestinal conditions. Fluorescence spectra evidenced that non-polar microenvironment for curcumin embedded in nanogels was strengthened, which therefore enhanced encapsulation efficiency. Moreover, curcumin exhibited sustained release profile from crosslinked nanogels in simulated gastrointestinal fluids. Overall, our study provided a promising strategy to enhance the stability of LDL-based nanogels in digestive conditions. PMID- 28873643 TI - Influence of seasonal variation and ultra high temperature processing on lipid profile and fat globule structure of Swedish cow milk. AB - To investigate the effects of seasonal variations and processing on cow milk fat, raw milk collected in six individual months and corresponding ultra high temperature (UHT) milk were analyzed. Similar seasonal variations in lipid classes and fatty acid composition were found in raw and UHT milk. Under commercial processing, lipid content was standardized to approximately 1.5% in UHT milk. Decreased diameter of fat droplets (around 1um) and thinner globule membranes were observed, as revealed using confocal laser scanning microscopy (CLSM). The distribution of lipid classes was modified with a decreased proportion of triacylglycerol accompanied by the increase of phospholipids and free fatty acids. Saturated fatty acids C12:0 and C14:0, trans-fatty acids including conjugated linoleic acid (CLA), polyunsaturated fatty acids C18:2(n-6) and C18:3(n-3), showed increased proportions in UHT milk. These results provide an indication of the effect of UHT processing on milk lipid properties. PMID- 28873644 TI - Anti-polymerization activity of tea and fruits extracts during rapeseed oil heating. AB - The aim of the study was to analyze the influence of natural antioxidants on polymerization of partially hydrogenated rapeseed oil heated in 170 degrees C for 40h. In the research ethanolic extracts of green tea leaves (China Lung Ching), yellow tea leaves (China Kakecha), cranberry, blackberry, and lime were used. The yellow and green tea extracts were characterized by the highest content of total polyphenol and antioxidant activity. Polymers of triacylglycerols were found only in the polar fraction of heated oil. During heating, the increase of dimers, trimers, and oligomers was observed. However, it was dependent on the used additives and not directly related to the content of phenolic compounds and their antioxidant activity. The final content of polymers in oil samples increased in the fallowing order: green teadiglucosylated forms than glucosylated ones. This data represents valuable information that may be useful for oenological practices and to valorise these varieties as sources of bioactive compounds. PMID- 28873657 TI - Chemical composition and antioxidant activity of Cichorium spinosum L. leaves in relation to developmental stage. AB - In the present study, chemical composition and bioactivity of Cichorium spinosum leaves were examined at different growth stages for optimum harvest stage and end use assessment. Total fresh weight and number of leaves were higher at 4th growth stage; however, at this stage the end-use is not indicated for raw consumption but mostly for pickled or dried products. Regarding chemical composition, the highest content of tocopherols and minerals was observed in the 1st growth stage, whereas sugars content was the highest in 3rd and 4th growth stage. Polyunsaturated fatty acids content was the highest during the first two growth stages, whereas antioxidant activity, phenolic acids and total phenolic compounds content in the 3rd stage. In conclusion, the results of this study indicate that chemical composition of C. spinosum is highly depended on development stage, and harvest stage should be considered for alternative uses of end-products with high bioactivity. PMID- 28873658 TI - Impact of sulphur fumigation on the chemistry of ginger. AB - Ginger (Zingiberis Rhizoma), a commonly-consumed food supplement, is often sulphur-fumigated during post-harvest handling, but it remains unknown if sulphur fumigation induces chemical transformations in ginger. In this study, the effects of sulphur fumigation on ginger chemicals were investigated by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS)-based metabolomics. The results showed that sulphur fumigation significantly altered the holistic chemical profile of ginger by triggering chemical transformations of certain original components. 6 Gingesulphonic acid, previously reported as a naturally-occurring component in ginger, was revealed to be a sulphur fumigation-induced artificial derivative, which was deduced to be generated by electrophilic addition of 6-shogaol to sulphurous acid. Using UHPLC-QTOF-MS/MS extracting ion analysis with 6 gingesulphonic acid as a characteristic chemical marker, all the commercial ginger samples inspected were determined to be sulphur-fumigated. The research outcomes provide a chemical basis for further comprehensive safety and efficacy evaluations of sulphur-fumigated ginger. PMID- 28873659 TI - Searching for an absolute kinetic scale of antioxidant activity against lipid peroxidation. AB - The inhibition properties of a number of antioxidants against peroxidation, started by a 2,2'-azobis[2-(2-imidazolin-2-yl)propane] radical initiator, of linoleic acid in sodium dodecyl sulfate micelles, have been determined in terms of oxygen consumption by a Clark electrode in an oxygen-tight cell. For the 31 antioxidants investigated at variable concentrations, the experimental results well fit the kinetic equation for competitive reactions. The ratio between the initial rates, monitored in the absence and in the presence of antioxidants, depends linearly on their concentration. From the slopes of these straight lines, an absolute scale of inhibition properties of the lipid peroxidation can be devised. Furthermore, the little difference of the time of complete oxygen consumption on concentration of different antioxidants has been found, indicating a restricted difference towards chemical structure and stoichiometric ratio. Some considerations regarding the mechanisms of inhibition of the lipid peroxidation in micelles, in view of bibliographic data, have been made. PMID- 28873660 TI - Formation of polymeric pigments in red wines through sequential fermentation of flavanol-enriched musts with non-Saccharomyces yeasts. AB - Non-Saccharomyces yeasts may contribute to enrich wine aroma while promoting the formation of stable pigments. Yeast metabolites such as acetaldehyde and pyruvate participate in the formation of stable pigments during fermentation and wine aging. This work evaluated the formation of polymeric pigments in red musts added with (+)-Catechin, ProcyanidinB2 and ProcyanidinC1. The non-Saccharomyces yeasts used were Lachancea thermotolerans, Metschnikowia pulcherrima and Torulaspora delbrueckii in sequential fermentation with Saccharomyces cerevisiae and Schizosaccharomyces pombe. Use of Lachancea thermotolerans led to larger amounts of polymeric pigments in sequential fermentation. (+)-Catechin is the flavanol prone to forming such pigments. The species Metschnikowia pulcherrima produced higher concentration of esters and total volatile compounds. The sensory analysis pointed out differences in fruitiness and aroma quality. The results obtained strengthen the fact that metabolites from non-Saccharomyces yeasts may contribute to form stable polymeric pigments while also influencing wine complexity. PMID- 28873661 TI - Effect of mild thermal treatment on the polymerization behavior, conformation and viscoelasticity of wheat gliadin. AB - The physicochemical properties of gliadin upon mild thermal treatment were studied in terms of polymerization behavior, conformation and viscoelasticity. Gliadin samples were heated at 40, 60 and 90 degrees C for up to 20min. Results showed that alpha-gliadin started to polymerize via disulfide (SS) bonds before gamma-gliadin at 90 degrees C, resulting in the extractability loss in aqueous ethanol. beta-Turn and specific beta-sheet structures were partially conversed to alpha-helices during thermal treatment. Rearrangement of non-covalent forces might contribute to viscosity loss of gliadin at 40 and 60 degrees C. However, the elevated elasticity at 90 degrees C was mainly due to gliadin polymerization while the viscosity variation was resulted from combined effects of non-covalent forces and covalent SS bonds. This study could offer insight into the variation of gliadin characteristics during the early baking process. PMID- 28873662 TI - Factors influencing inhibition of eight polycyclic aromatic hydrocarbons in heated meat model system. AB - Studies on polycyclic aromatic hydrocarbons (PAHs) formation have focused on dynamic studies or research on cooking conditions of meat. This research aimed to elucidate the influence of heating conditions, existence of water, lipid precursors and antioxidants on the formation and inhibition of PAHs in meat model systems by using GC/MS analysis, while mechanisms were evaluated by electron spin resonance (ESR) studies. PAHs formation was more affected by change in temperature than of time. Also, existence of water and antioxidants was an important factor affecting the inhibition of PAHs. In all heated meat model systems the addition of lipid precursors led to significantly increased PAHs (p<0.05). PMID- 28873663 TI - Chemical composition and redox activity of PM0.25 near Los Angeles International Airport and comparisons to an urban traffic site. AB - To investigate the relative impacts of emissions from Los Angeles International Airport (LAX), as well as the impacts of traffic emissions from freeways, on the oxidative potential of particulate matter (PM), PM0.25 were collected at two urban background locations in Los Angeles. Redox activity of the PM samples was measured by means of an in vitro alveolar macrophage assay that quantifies the formation of reactive oxygen species (ROS) in cells, and detailed chemical analyses were performed to determine the speciated chemical composition of collected PM. A molecular marker-based chemical mass balance (MM-CMB) model was applied to estimate the relative contributions from the following primary sources to the organic carbon (OC) component of PM: mobile sources (combined gasoline and diesel vehicles), wood smoke, vegetative detritus, road dust and ship emissions. A source profile of aircraft emissions was not included in the model; however its contribution was estimated from un-apportioned primary OC in the MM-CMB model ("other OC") after accounting for the contribution of secondary organic carbon (SOC) to OC. The contribution of mobile sources to OC was 82% and 28% at the central Los Angeles site (freeway emissions) and the LAX site, respectively. The estimated contribution of aircraft emissions to PM0.25 OC was 36% at the LAX site. ROS activity levels showed little spatial variability, with no statistically significant difference between the averages observed at LAX (24.75+/-4.01MUgZymosan/m3) and central Los Angeles (27.77+/-2 0.32MUgZymosan/m3), suggesting similar levels of inhalation exposure to redox active species of PM0.25. A multiple linear regression analysis indicated that the variability in ROS activity is best explained by the chemical markers of major identified sources: EC emitted by traffic, and sulfur, considered in our study as a potential tracer of aircraft emissions, with statistically significantly higher concentrations of sulfur at the LAX site (p<0.001). PMID- 28873664 TI - Complementarity of three distinctive phytoremediation crops for multiple-trace element contaminated soil. AB - Trace element (TE) contaminated land represents an important risk to the environment and to human health worldwide. These soils usually contain a variety of TEs which can be a challenge for plant-based remediation options. As individual plant species often possess a limited range of TE remediation abilities, functional complementarity principles could be of value for remediation of soil contaminated by multiple TEs using assemblages of species. Monocultures and polycultures of Festuca arundinacea, Medicago sativa and Salix miyabeana were grown for 4months in aged-polluted soil contaminated by Ag, As, Cd, Cr, Cu, Pb, Se and Zn. Above and belowground biomass yields, root surface area (RSA) and TE tissue concentrations were recorded. In monoculture, the greatest aboveground biomass was produced by S. miyabeana (S), the greatest belowground biomass was from M. sativa (M) and F. arundinacea (F) produced the highest RSA. The polycultures of F+M, F+S and F+M+S produced among the highest values across all three traits. F. arundinacea monoculture and its combination with S. miyabeana (F+S) accumulated the highest amounts of total TEs in belowground tissues, whereas the most effective combination (or monoculture) for aboveground extraction yields varied depending on the TE considered. The crops demonstrated complementarity in their biomass allocation patterns as well as facilitative interactions. When considering contamination with a particular TE, the best phytomanagement approach could include a specific monoculture option; however, when above and belowground biomass allocation patterns, TE-remediation abilities as well as nitrogen accessibility are considered, co-cropping all three species (F+M+S) was the most robust scenario for remediation of multiple-TE contaminated land. By more effectively addressing a diversity of TE, species assemblage approaches could represent an important advancement towards enabling the use of plants to address contaminated-land issues worldwide. PMID- 28873665 TI - Land use regression modelling estimating nitrogen oxides exposure in industrial south Durban, South Africa. AB - BACKGROUND: The South Durban (SD) area of Durban, South Africa, has a history of air pollution issues due to the juxtaposition of low-income communities with industrial areas. This study used measurements of oxides of nitrogen (NOx) to develop a land use regression (LUR) model to explain the spatial variation of air pollution concentrations in this area. METHODS: Ambient NOx was measured over two two-week sampling periods at 32 sites using Ogawa badges. Following the ESCAPE approach, an annual adjusted average was calculated for these results and regressed against pre-selected geographic predictor variables in a multivariate regression model. The LUR model was then applied to predict the NOx exposure of a sample of pregnant women living in South Durban. RESULTS: Measured NOx levels ranged from 22.3-50.9MUg/m3 with a median of 36MUg/m3. The model developed accounts for 73% of the variance in ambient NOx measurements using three input variables (length of minor roads within a 1000m radius, length of major roads within a 300m radius, and area of open space within a 1000m radius). Model cross validation yielded a R2 of 0.59. Subsequent participant exposure estimates indicated exposure to ambient NOx ranged from 19.9-53.2MUg/m3, with a mean of 39MUg/m3. DISCUSSION AND CONCLUSION: This is the first study to develop a land use regression model that predicts ambient concentrations of NOx in a South African context. The findings of this study indicate that the participants in the South Durban are exposed to high levels of NOx that can be attributed mainly to traffic. PMID- 28873666 TI - Carbon dioxide accumulation inside vehicles: The effect of ventilation and driving conditions. AB - Limiting the air exchange of passenger vehicles by closing windows and recirculating cabin air (RC) restricts the influx of roadway pollutants and reduces in-vehicle particulate concentrations. However, the carbon dioxide (CO2) exhaled by the occupants can accumulate under these conditions to reach high concentrations. We characterized the factors (ventilation setting, vehicle age, speed, cabin volume, trip duration, and number of occupants) that allow CO2 accumulation to reach concentration thresholds found in other studies to produce cognitive or physiological effects of concern such as fatigue or difficulty concentrating. Ventilation setting was the primary determinant of CO2 accumulation; only the RC setting (and not outside-air intake) ever allows CO2 accumulations to exceed thresholds of concern. Longer trips with multiple occupants are a particular concern. Even so, under RC setting, a 2500ppm threshold-the threshold consistently linked to detrimental cognitive effects would not be exceeded for most one- or even two-occupant average-duration commutes (twenty-six minutes in the U.S.). For multiple passenger commutes and/or longer trips, RC ventilation should be periodically interrupted or partially mixed with outside air to keep CO2 concentrations below 2500ppm. PMID- 28873667 TI - Dietary exposure and neurotoxicity of the environmental free and bound toxin beta N-methylamino-l-alanine. AB - The growing evidence supporting a link between exposure to the naturally occurring toxin beta-N-methylamino-l-alanine (BMAA) and progressive neurodegenerative diseases, has recently arisen the interest of the scientific community. Latest investigations suggest that dietary exposure to this algal toxin may have been largely underestimated. This paper reviews the state of the art regarding BMAA, with special attention paid to its neurotoxicity, its concentration levels in food, and human exposure. As for other environmental toxins, dietary intake is most likely the main route of exposure to BMAA for the general population. However, data concerning BMAA levels in foodstuffs are still scarce. It is concluded that further investigations on dietary intake and potential human health effects are clearly necessary to assess the risks to public health associated with BMAA exposure. Some critical remarks and recommendations on future research in this area are provided, which may help to identify approaches to reduce dietary BMAA exposure. PMID- 28873668 TI - Modeling cereal starch hydrolysis during simultaneous saccharification and lactic acid fermentation; case of a sorghum-based fermented beverage, gowe. AB - Gowe is an acidic beverage obtained after simultaneous saccharification and fermentation (SSF) of sorghum. A previous paper focused on modeling the growth of lactic acid bacteria during gowe processing. This paper focuses on modeling starch amylolysis to build an aggregated SSF model. The activity of alpha-amylase was modeled as a function of temperature and pH, and the hydrolysis rates of both native and soluble starch were modeled via a Michaelis-Menten equation taking into account the maltose and glucose inhibition constants. The robustness of the parameter estimators was ensured by step by step identification in sets of experiments conducted with different proportions of native and gelatinized starch by modifying the pre-cooking temperature. The aggregated model was validated on experimental data and showed that both the pre-cooking and fermentation parameters, particularly temperature, are significant levers for controlling not only acid and sugar contents but also the expected viscosity of the final product. This generic approach could be used as a tool to optimize the sanitary and sensory quality of fermentation of other starchy products. PMID- 28873669 TI - Peptide identification in a salmon gelatin hydrolysate with antihypertensive, dipeptidyl peptidase IV inhibitory and antioxidant activities. AB - Salmon gelatin (Salmo salar, SG) enzymatic hydrolysates were generated using Alcalase 2.4L, Alcalase 2.4L in combination with Flavourzyme 500L, Corolase PP, Promod 144MG and Brewer's Clarex. The hydrolysate generated with Corolase PP for 1h (SG-C1) had the highest angiotensin converting enzyme (ACE, IC50=0.13+/ 0.05mgmL-1) and dipeptidyl peptidase IV (DPP-IV, IC50=0.08+/-0.01mgmL-1) inhibitory activities, and oxygen radical absorbance capacity (ORAC, 540.94+/ 9.57MUmolTEg-1d.w.). The in vitro bioactivities of SG-C1 were retained following simulated gastrointestinal digestion. Administration of SG and SG-C1 (50mgkg-1 body weight) to spontaneously hypertensive rats (SHR) lowered heart rate along with systolic, diastolic and mean arterial blood pressure. The SG-C1 hydrolysate was fractionated using semi-preparative RP-HPLC and the fraction with highest overall in vitro bioactivity (fraction 25) was analysed by UPLC-MS/MS. Four peptide sequences (Gly-Gly-Pro-Ala-Gly-Pro-Ala-Val, Gly-Pro-Val-Ala, Pro-Pro and Gly-Phe) and two free amino acids (Arg and Tyr) were identified in this fraction. These peptides and free amino acids had potent ACE and DPP-IV inhibitory, and ORAC activities. The results show that SG hydrolysates have potential as multifunctional food ingredients particularly for the management of hypertension. PMID- 28873670 TI - Novel bioactive peptides from enzymatic hydrolysate of Sardinelle (Sardinella aurita) muscle proteins hydrolysed by Bacillus subtilis A26 proteases. AB - Sardinelle protein hydrolysate (SPH), prepared by treatment with Bacillus subtilis A26 proteases, was found to exhibit antibacterial, antioxidant and ACE inhibitory activities. SPH, with a degree of hydrolysis of 4%, was fractionated by size exclusion chromatography on a Sephadex G-25 into five major fractions (F1 F5). F2, which exhibited the highest antibacterial and ACE-inhibitory activities, and F4, which exhibited the highest antibacterial and antioxidant activities, were further fractionated by reverse phase-high performance liquid chromatography (RP-HPLC) and then analysed using nano-ESI-LC-MS/MS to identify the sequences of peptides. Eight peptides were identified in the sub-fraction F2-A, nine peptides in the sub-fraction F4-B, and 45 peptides in F4-C. Identified peptides were found to share sequences with previously described bioactive peptides based on Biopep database. The results of this study suggest that SPH is a good source of natural bioactive peptides. Hence, it can be used as a potential ingredient in nutraceutical field. PMID- 28873671 TI - Modifications in bacterial groups and short chain fatty acid production in the gut of healthy adult rats after long-term consumption of dietary Maillard reaction products. AB - Bread crust (BC) is one of the major sources of Maillard reaction products (MRPs) in the Western diet. This work was designed to analyze the impact of diets containing important levels of MRPs from BC on intestinal bacterial growth and short chain fatty acids (SCFAs) production in adult rats. Additionally, the pools of compounds excreted in feces attending to their molecular weights were analyzed. Rats were fed for 88days a control diet or diets containing BC or its soluble high molecular weight (HMW), soluble low molecular weight (LMW) or insoluble fractions, respectively. Intestinal (cecum) microbiota composition was determined by qPCR analysis. Consumption of the BC diet lowered (P<0.05) Lactobacillus spp. and Bifidobacterium spp. log10 counts (8 and 14%, respectively), an effect for which soluble LMW and HMW fractions of BC seemed to be responsible. In these same animals, Escherichia/Shigella counts increased by around 45% (P<0.05), a fact which correlated with a higher production of formic acid in feces (r=0.8197, P=0.0458), and likely caused by the combined consumption of all MRPs contained in the BC. A significant 5-fold increment (P<0.05) was detected in the fecal proportion of propionic acid in the BC group, one of the products that have largely been associated with anti-inflammatory actions. Regarding the distribution of MRPs in feces, only the LMW fed group exhibited a predominance of those ranging between 90,000-1000Da, whereas the rest of the groups presented higher amounts of products above 90,000Da. It is concluded that dietary Maillard reaction products are in vivo fermented by the gut microbiota, thereby changing both the pattern of SCFAs production and the microbiota composition. PMID- 28873672 TI - Recent advances in the identification and authentication methods of edible bird's nest. AB - Edible bird's nest (EBN) is an expensive animal bioproduct due to its reputation as a food and delicacy with diverse medicinal properties. One kilogram of EBN costs ~$6000 in China. EBN and its products are consumed in mostly Asian countries such as China, Hong Kong, Taiwan, Singapore, Malaysia, Indonesia, Vietnam and Thailand, making up almost 1/3 of world population. The rapid growth in EBN consumption has led to a big rise in the trade scale of its global market. Presently, various fake materials such as tremella fungus, pork skin, karaya gum, fish swimming bladder, jelly, agar, monosodium glutamate and egg white are used to adulterate EBNs for earning extra profits. Adulterated or fake EBN may be hazardous to the consumers. Thus, it is necessary to identify of the adulterants. Several sophisticated techniques based on genetics, immunochemistry, spectroscopy, chromatography and gel electrophoresis have been used for the detection of various types of adulterants in EBN. This article describes the recent advances in the authentication methods for EBN. Different genetic, immunochemical, spectroscopic and analytical methods such as genetics (DNA) based techniques, enzyme-linked immunosorbent assays, Fourier transform infrared and Raman spectroscopic techniques, and chromatographic and gel electrophoretic methods have been discussed. Besides, significance of the reported methods that might pertain them to applications in EBN industry has been described. Finally, efforts have been made to discuss the challenges and future perspectives of the authentication methods for EBN. PMID- 28873673 TI - Colloidal properties of sodium caseinate-stabilized nanoemulsions prepared by a combination of a high-energy homogenization and evaporative ripening methods. AB - Nanoemulsions stabilized by sodium caseinate (NaCas) were prepared using a combination of a high-energy homogenization and evaporative ripening methods. The effects of protein concentration and sucrose addition on physical properties were analyzed by dynamic light scattering (DLS), Turbiscan analysis, confocal laser scanning microscopy (CLSM) and small angle X-ray scattering (SAXS). Droplets sizes were smaller (~100nm in diameter) than the ones obtained by other methods (200 to 2000nm in diameter). The stability behavior was also different. These emulsions were not destabilized by creaming. As droplets were so small, gravitational forces were negligible. On the contrary, when they showed destabilization the main mechanism was flocculation. Stability of nanoemulsions increased with increasing protein concentrations. Nanoemulsions with 3 or 4wt% NaCas were slightly turbid systems that remained stable for at least two months. According to SAXS and Turbiscan results, aggregates remained in the nano range showing small tendency to aggregation. In those systems, interactive forces were weak due to the small diameter of flocs. PMID- 28873674 TI - The effect of algae diets (Skeletonema costatum and Rhodomonas baltica) on the biochemical composition and sensory characteristics of Pacific cupped oysters (Crassostrea gigas) during land-based refinement. AB - Oyster refinement, a common practice in France, is aimed at increasing the weight of oyster tissue and influencing the taste properties of the refined oysters. Refinement usually takes place in land-based systems where the oysters are fed with relatively high concentrations of microalgae. In this study the impact of feeding Skeletonema costatum and Rhodomonas baltica on the biochemical composition and sensory characteristics of Pacific cupped oysters (Crassostrea gigas) from the Eastern Scheldt during land-based refinement was studied. After a feeding period of four and seven weeks market-sized oysters were sampled for the analysis of fatty acids, free amino acids and volatile organic compounds and for a sensory evaluation by consumers and an expert panel. The algae Skeletonema costatum showed a lower ?PUFA, ?n-3, ?n-6, C18:2n6, C18:3n3, C18:4n3, C22:6n3 content as compared with Rhodomonas baltica. These differences were also reflected in the fatty acid profile of the oysters fed with the corresponding algae diets. Furthermore, general linear model and principal component analysis showed marked differences in free amino acids and volatile organic compound content between Skeletonema, Rhodomonas fed oysters and reference oysters. For example, threonine, glutamine, leucine, histidine, (E)-2-hexenal, (E)-2octenal, (E)-2-octen-1-ol, (E,E)-2,4-octadien-1-ol, (E,Z)-3,6-nonadien-1-ol and (Z,E)-2,6 nonadienal contents were higher in Skeletonema fed oysters compared to Rhodomonas fed oysters. Sensory differences between the experimental oyster groups were shown. Skeletonema fed Pacific cupped oysters were characterized by a stronger seaweed flavor, higher perceived sweetness and a firmer texture in comparison with Rhodomonas fed oysters. Naive consumers were only able to differentiate between Rhodomonas fed oysters and reference oysters. PMID- 28873675 TI - Influence of Brettanomyces ethylphenols on red wine aroma evaluated by consumers in the United States and Portugal. AB - Brettanomyces may add complexity to wine at low concentrations but at high concentrations, can result in objectionable wines. The objective of this study was to determine the concentrations at which consumers from two different locations were able to detect Brettanomyces volatile compounds present in a red wine. A red wine blend, used in both countries, was spiked to create five treatments containing different concentrations of 4-ethylphenol (4-EP), 4 ethylguiacol (4-EG), and 4-ethylcatechol (4-EC) in a 5:1:1 ratio, respectively. These treatments were evaluated by consumers in the United States and Portugal (n=121) using a difference from control test. Consumers were also classified as having low, medium, or high wine knowledge. Among the spiked samples, the greatest degree of difference was found between the second and third treatments, corresponding to reported detection and recognition threshold ranges of 4-EP and 4-EG. For some treatments, consumers from Portugal classified in the medium or high knowledge level reported significantly higher mean differences from the control than those in the low knowledge group (p<0.05). Results demonstrated consumers' ability to detect differences in red wines due to Brettanomyces volatile compounds. Results provide useful context on how wine knowledge and cultural variants may affect the detection of Brettanomyces. PMID- 28873676 TI - Encapsulation of lutein in liposomes using supercritical carbon dioxide. AB - Liposomes loaded with lutein were prepared utilizing supercritical carbon dioxide (SC-CO2). The effects of pressure, depressurization rate, temperature and lutein to-lipid ratio on particle size distribution, zeta potential, encapsulation efficiency (EE), bioactive loading, morphology, phase transition and crystallinity were investigated. Liposomes prepared by the SC-CO2 method had a particle size of 147.6+/-1.9nm-195.4+/-2.3nm, an encapsulation efficiency of 56.7+/-0.7%-97.0+/-0.8% and a zeta potential of -54.5+/-1.2mV to -61.7+/-0.6mV. A higher pressure (200-300bar) and depressurization rate (90-200bar/min) promoted a higher encapsulation of lutein whereas the lutein-to-lipid ratio had the dominant effect on the morphology of vesicles along with size distribution and EE. X-ray diffraction data implied a substantial drop in the crystallinity of lutein upon its redistribution in the liposome membranes. Differential scanning calorimetry indicated a broadened phase transition upon the simultaneous rearrangement of lutein and phospholipid molecules into liposomal vesicles. The SC-CO2 method resulted in particle characteristics highly associated with the ability of CO2 to disperse phospholipids and lutein molecules. It offers a promising approach to use dense phase CO2 to homogenize hydrophobic or amphiphilic aggregates suspended in an aqueous medium and regulate the vesicular characteristics via pressure and depressurization rate. The SC-CO2 method has potential for scalable production of liposomal nanovesicles with desirable characteristics and free of organic solvents. PMID- 28873677 TI - Effect of the phytate and hydrogen peroxide chemical modifications on the physicochemical and functional properties of wheat starch. AB - To investigate the characteristics of chemically modified wheat starch, such as oxidized (OWS), cross-linked (CLWS) and dual-modified wheat starches, cross linked oxidized (COWS) and oxidized cross-linked (OCWS) wheat starches were obtained by 12% hydrogen peroxide (H2O2) and 2% sodium phytate treatments, respectively. After modifications of wheat starch by cross-linking and oxidization, it was determined that native wheat starch was effectively modified with respect to the structure and physicochemical characteristics, as detected by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), Rapid Visco Analyzer (RVA), scanning electron microscopy (SEM) and X-ray diffraction (XRD). DSC analysis demonstrated that peak temperature (Tp) 64.41 degrees C of the COWS was the highest. The RVA viscosity indexes of CLWS were noticeably increased compared with the other four starches, of which three oxidized starch samples showed lower RVA profiles because of oxidation. The XRD result indicated that cross-linked phosphates from sodium phytate were primarily located in the amorphous regions of starch granules. After modifications by different treatments, the starch samples exhibited different morphological characteristics, including A-type and B-type wheat starch granules, which showed much closer contact with each other by the cross-linking reaction under SEM observations. The functional characteristics, including solubility, swelling power, light transmittance and freeze-thaw stability (FTS), of all five treated and untreated wheat starches demonstrated that COWS had the highest solubility at 0.57 and that CLWS showed the best swelling power at 12.63 (g/g). The paste clarity of COWS was improved to 47.72% higher than that of native starch (7.54%), and the water loss of COWS (21.62%) was the lowest, which is beneficial to the production of quick-frozen food. Our results showed that dual-modified starch by using sodium phytate and hydrogen peroxide had significantly altered structural and functional properties. The present study provides fundamental information of dual-modified wheat starch for its potential industrial application. PMID- 28873678 TI - Structural modification by high-pressure homogenization for improved functional properties of freeze-dried myofibrillar proteins powder. AB - To expand utilization of meat in various products, the structural, physicochemical and functional changes of water soluble myofibrillar protein powder (WSMP-P) were investigated as affected by high-pressure homogenization (HPH) intensities (0-20,000psi). HPH modified the structure of WSMP-P by random dissociation (myofibril and myosin polymer dissociation), partial unfolding and rearrangement (actin trimer formation), producing an amorphous protein structure with high thermal stability. alpha-Helix and beta-turn conversion to beta-sheet structures occurred at pressures above 15,000psi, suggesting an increase in myosin conformation flexibility with minor aggregation. Moreover, HPH was able to improve the water solubility and emulsifying properties of WSMP-P. This might be resulted from its unfolded flexible structure with submicron size and high surface net charge in aqueous suspensions induced by HPH. The findings regarding the improved functionality evidence potential of applying WSMP-P as protein supplements in formulated food or beverage at low ionic conditions. PMID- 28873679 TI - Aroma profile of malbec red wines from La Mancha region: Chemical and sensory characterization. AB - The aroma of La Mancha Malbec red wines over four consecutive vintages was characterized by chemical and sensory analysis. Solid phase extraction (SPE) and gas chromatography-mass spectrometry (GC-MS) were used to isolate and analyze free volatile compounds. Quantitative Descriptive Sensory Analysis (QDA) was carried out to characterize the sensory aroma profile. A total of 79 free volatile compounds were identified and quantified in the wines over these four vintages. Volatile aroma compounds were classified into seven aromatic series and their odour activity values were calculated in order to determine the aroma impact compounds in these wines. The aroma sensory profile of these wines was characterized by red fruit, fresh, prune, liquorice, clove, caramel, leather, tobacco and coffee aromas. This study provides a complete aroma characterization of La Mancha Malbec red wines and it is proposed that these wines can be considered as an alternative to wines from traditional grape varieties of this region. PMID- 28873680 TI - Caramel flavour perception: Impact of the non-volatile compounds on sensory properties and in-vitro aroma release. PMID- 28873681 TI - Characterization of commercial Spanish non-citrus juices: Antioxidant and physicochemical aspects. AB - The presence of many different antioxidant species makes fruit juices to be perceived by populations as a very healthy beverage easy to include in the daily diet. These antioxidant actions have been reported in a large number of papers, however the information correlating the antioxidant profile with the physicochemical characteristics derived from the industrial processing of fruit juices is limited. In a previous paper, our research group demonstrated that the antioxidant properties of citrus juices were underestimated when measuring by traditional methods and that our improved methodology, so-called GAR, is a better approach to analyze the global antioxidant response of juices. In this paper, we confirm that statement, establishing that the overall antioxidant capacity of non citrus juices is 10-times higher with the GAR method (including an in vitro gastrointestinal digestion) that with the other methodologies. In some cases, such as pineapple juice, the antioxidant action was distributed between the soluble and non-soluble fractions almost at 50%. But, surprisingly, in some other (like tomato juice) the non-soluble fraction accounted for the higher antioxidant capacity. This fact definitively underlines the importance of the non-soluble fraction and shows the suitability of the GAR method to consider it. Physicochemical parameters, such as color, fluorescence, 5-hydroxymethylfurfural and furfural contents were correlated with antioxidant characteristics in some samples. Lastly, we unravel a mathematical model to classify non-citrus juices depending on their nature or storage conditions. PMID- 28873682 TI - Quercetin as a tyrosinase inhibitor: Inhibitory activity, conformational change and mechanism. AB - Quercetin, a flavonoid compound, was found to inhibit both monophenolase and diphenolase activities of tyrosinase, and its inhibition against diphenolase activity was in a reversible and competitive manner with an IC50 value of (3.08+/ 0.74)*10-5molL-1. Quercetin bound to tyrosinase driven by hydrophobic interaction, thereby resulted in a conformational change of tyrosinase and its intrinsic fluorescence quenching. Tyrosinase had one binding site for quercetin with the binding constant in the order of magnitude of 104Lmol-1. The molecular docking revealed that quercetin bound to the active site of tyrosinase and chelated a copper with the 3', 4'-dihydroxy groups. It can be deduced that the chelation may prevent the entrance of substrate and then inhibit the catalytic activity of tyrosinase. These findings may be helpful to understand the inhibition mechanism of quercetin on tyrosinase and functional research of quercetin in the treatment of pigmentation disorders. PMID- 28873683 TI - Volatile metabolite profiling reveals the changes in the volatile compounds of new spontaneously generated loquat cultivars. AB - In recent years, the advantageous traits of three new loquat cultivars have drawn the attention of breeders and growers. All three have spontaneously arisen from the 'Algerie' cultivar: the new 'Xirlero' cultivar is a bud mutant of 'Algerie', while 'Amadeo' and 'Raul' arose as chance seedlings. Following a non-targeted approach based on HS-SPME-GC-MS, the volatile compounds profile of the fruits from the new cultivars were obtained and compared to the original 'Algerie' cultivar. Carboxylic acids clearly dominated the volatile profile of all the loquat cultivars, but esters, aldehydes, ketones and alcohols were also predominant compounds. Interestingly when the bud mutant event did not lead to marked changes in the volatile compounds complement, pronounced changes in the volatile composition of chance seedling-generated cultivars 'Amadeo' and 'Raul' were observed. 'Amadeo' fruits showed lower levels of 2-methyl butanoic acid and much higher levels of methylhexanoate, methylbutanoate and 2-hydroxy-5 methylacetophenone. The 'Raul' cultivar also had a distinctive volatile profile characterised by high levels of C6-aldehydes, (E)-2-hexanal, 2-hexenal, (Z)-3 hexenal and hexanal, and several carotenoid-derived volatiles; e.g. 2-pentene-1,4 dione 1-(1,2,2-trimethylcyclopentyl), (S)-dihydroactinidiolide, isodurene, cis geranyl acetone, beta-damascenone, beta-ionone, alpha-ionone and 3,4-dehydro-beta ionone. These changes in volatiles were associated with a more intense flavour in cultivars 'Amadeo' and 'Raul', according to the sensory evaluation of the flavour intensity carried out by a semi-trained panel. A metabolomic correlation network analysis provided insights as to how volatiles were regulated, and revealed that the compounds modified in 'Amadeo' were uncoupled from the rest of the volatilome, while the volatiles modified in 'Raul' changed according to specific groups. To conclude, this work provides a holistic view of how the loquat volatilome was affected, and this information was integrated with the physical chemical-sensory attributes to understand the changes that occur in the new cultivars. PMID- 28873684 TI - Triangulation and the importance of establishing valid methods for food safety culture evaluation. AB - The research evaluates maturity of food safety culture in five multi-national food companies using method triangulation, specifically self-assessment scale, performance documents, and semi-structured interviews. Weaknesses associated with each individual method are known but there are few studies in food safety where a method triangulation approach is used for both data collection and data analysis. Significantly, this research shows that individual results taken in isolation can lead to wrong conclusions, resulting in potentially failing tactics and wasted investments. However, by applying method triangulation and reviewing results from a range of culture measurement tools it is possible to better direct investments and interventions. The findings add to the food safety culture paradigm beyond a single evaluation of food safety culture using generic culture surveys. PMID- 28873685 TI - Consumer perception of salt-reduced breads: Comparison of single and two-bites evaluation. AB - Salt-reduction in processed products has been proposed as a high-impact intervention for reducing the sodium intake at population level. A major limitation for this approach is its potential negative impact on the sensory characteristics of products. The current practice in sensory and consumer science involves single sip/bite evaluations, which may not properly reflect the sensory experience that occurs during product consumption. In this context, the aim of the present work was to compare single and two bite evaluations of consumer sensory and hedonic perception of salt-reduced breads. Five studies with a total of 499 consumers were carried out, in which overall-liking scores of five salt reduced bread samples were collected after the first and the second bite evaluation. In one of the studies consumers also answered a CATA (check-all-that apply) question after the first and the second bite. Neither bite nor the interaction between samples and bite had a significant effect on hedonic scores. However, when hedonic scores were analysed separately for each bite, the overall liking scores from the second bite evaluation better reflected differences among samples according to their salt content in two of the five studies. The sensory characterization of the samples did not largely vary between the first and the second bite. Results suggest that consumers' perception of salt reduced bread samples did not largely vary between a single and a two bites evaluation. Further research is warranted in this regard, in particular considering more complex products. PMID- 28873686 TI - Carotenoid profile of three microalgae/cyanobacteria species with peroxyl radical scavenger capacity. AB - Carotenoids from cyanobacteria Aphanothece microscopica Nageli and green microalgae Chlorella vulgaris and Scenedesmus obliquus were identified. The total carotenoid content, based on dry weight of biomass, of A. microscopica Nageli, C. vulgaris and S. obliquus were 1398.88MUg/g, 1977.02MUg/g and 2650.70MUg/g, respectively. A total of 23 different carotenoids were separated in all the extracts, the major ones being all-trans-beta-carotene (29.3%) and all-trans lutein (28.1%) in Scenedesmus; all-trans-echinenone (22.8%) and all-trans-beta carotene (17.7%) in Chlorella; all-trans-echinenone (28.3%) and all-trans-beta carotene (26.2%) in Aphanothece. The carotenoid extracts were shown to be a potent scavenger of peroxyl radical, with values of 31.1 (Chlorella), 14.0 (Scenedesmus) and 7.3 (Aphanothece) times more potent than alpha-tocopherol. PMID- 28873687 TI - A comparative study of volatile components in Dianhong teas from fresh leaves of four tea cultivars by using chromatography-mass spectrometry, multivariate data analysis, and descriptive sensory analysis. AB - Dianhong teas produced from fresh leaves of different tea cultivars (YK is Yunkang No. 10, XY is Xueya 100, CY is Changyebaihao, SS is Shishengmiao), were compared in terms of volatile compounds and descriptive sensory analysis. A total of 73 volatile compounds in 16 tea samples were tentatively identified. YK, XY, CY, and SS contained 55, 53, 49, and 51 volatile compounds, respectively. Partial least squares-discriminant analysis (PLS-DA) and hierarchical cluster analysis (HCA) were used to classify the samples, and 40 key components were selected based on variable importance in the projection. Moreover, 11 flavor attributes, namely, floral, fruity, grass/green, woody, sweet, roasty, caramel, mellow and thick, bitter, astringent, and sweet aftertaste were identified through descriptive sensory analysis (DSA). In generally, innate differences among the tea varieties significantly affected the intensities of most of the key sensory attributes of Dianhong teas possibly because of the different amounts of aroma active and taste components in Dianhong teas. PMID- 28873688 TI - Combined effects of holy basil essential oil and inlet temperature on lipid peroxidation and survival of Lactobacillus reuteri KUB-AC5 during spray drying. AB - Lipid peroxidation induced by oxidative stress plays an important role in reducing probiotic survival during spray drying. In this study, the probiotic Lactobacillus reuteri KUB-AC5 was co-encapsulated with holy basil essential oil, HBEO (0, 6, and 12mg/ml), by spray drying using skim milk at inlet air temperatures of 130, 140, and 150 degrees C. The microcapsule properties in terms of morphology, size, moisture content, water activity, surface oil, microencapsulation efficiency, antioxidant activity, lipid peroxidation, and cell survival were determined. The result showed that the microcapsules with HBEO had much higher antioxidant activity than the ones without HBEO. The optimal condition of HBEO (6mg/ml) with inlet temperature (130 degrees C) was effective in reducing malondialdehyde (MDA) level and enhancing survival of probiotics. This study indicates the potential role of HBEO in decreasing oxidative stress in probiotics during spray drying, which contributed to an increase in cell survival and health benefits. PMID- 28873689 TI - Liquid chromatography-high resolution mass spectrometry for the analysis of phytochemicals in vegetal-derived food and beverages. AB - The recent years witnessed a change in the perception of nutrition. Diet does not only provide nutrients to meet the metabolic requirements of the body, but it also constitutes an active way for the consumption of compounds beneficial for human health. Fruit and vegetables are an excellent source of such compounds, thus the growing interest in characterizing phytochemical sources, structures and activities. Given the interest for phytochemicals in food, the development of advanced and suitable analytical techniques for their identification is fundamental for the advancement of food research. In this review, the state of the art of phytochemical research in food plants is described, starting from sample preparation, throughout extract clean-up and compound separation techniques, to the final analysis, considering both qualitative and quantitative investigations. In this regard, from an analytical point of view, fruit and vegetable extracts are complex matrices, which greatly benefit from the use of modern hyphenated techniques, in particular from the combination of high performance liquid chromatography separation and high resolution mass spectrometry, powerful tools which are being increasingly used in the recent years. Therefore, selected applications to real samples are presented and discussed, in particular for the analysis of phenols, polyphenols and phenolic acids. Finally, some hot points are discussed, such as waste characterization for high value-compounds recovery and the untargeted metabolomics approach. PMID- 28873690 TI - Nutritional compound analysis and morphological characterization of spider plant (Cleome gynandra) - an African indigenous leafy vegetable. AB - Spider plant is among the important indigenous African leafy vegetables having the potential to contribute to food and nutritional security in sub-Saharan Africa. The main objective of this study was to quantify the mineral concentration, to identify and quantify glucosinolates and flavonoids in spider plant and further to characterize spider plant entries using important morphological traits. Thirty spider plant entries from different African countries, comprising of farmers' cultivars, gene bank accessions and advanced lines were grown in a field experiment and harvested for leaves, stems, flowers and siliques at different developmental stages. Five plant types based on the stem and petiole colorations were identified. Significant genotypic differences were shown for all the morphological traits except for 100 seed weight and silique weight. High mineral concentrations in the leaf tissue were observed especially for potassium, calcium, magnesium, phosphorus, iron, manganese and zinc. The aliphatic 3-hydroxypropyl glucosinolate was the main glucosinolate detected in all tissues with the highest concentrations in the reproductive organs. Glycosides of quercetin, kaempferol and isorhamnetin were the main flavonoids. Isorhamnetin glycosides were detected in trace amounts in both, leaves and inflorescences, while quercetin and kaempferol glycosides were the dominant flavonoids in the leaves and inflorescences, respectively. This knowledge of beneficial nutrient contents is an incentive for promoting spider plant consumption for improved human health while the morphological diversity analysis will be important for the further development of the spider plant germplasm. PMID- 28873691 TI - Encapsulation of lactase in Ca(II)-alginate beads: Effect of stabilizers and drying methods. AB - The purpose of the present work was to analyze the effect of trehalose, arabic and guar gums on the preservation of beta-galactosidase activity in freeze-dried and vacuum dried Ca(II)-alginate beads. Freezing process was also studied as a first step of freeze-drying. Trehalose was critical for beta-galactosidase conservation, and guar gum as a second excipient showed the highest conservation effect (close to 95%). Systems with Tg values ~40 degrees C which were stables at ambient temperature were obtained, being trehalose the main responsible of the formation of an amorphous matrix. Vacuum dried beads showed smaller size (with Feret's diameter below 1.08+/-0.09mm), higher circularity (reaching 0.78+/-0.06) and large cracks in their surface than freeze-dried beads, which were more spongy and voluminous. Ice crystallization of the beads revealed that the crystallization of Ca(II)-alginate system follows the Avrami kinetics of nucleation and growth. Particularly, Ca(II)-alginate showed an Avrami index of 2.03+/-0.07, which means that crystal growing is bidimensional. Neither the addition of trehalose nor gums affected the dimension of the ice growing or its rate. These results open an opportunity in the development of new lactic products able to be consumed by lactose intolerance people. PMID- 28873692 TI - Bioaccessibility and antioxidant activity of free phenolic compounds and oligosaccharides from corn (Zea mays L.) and common bean (Phaseolus vulgaris L.) chips during in vitro gastrointestinal digestion and simulated colonic fermentation. AB - Corn (Zea mays L.) and common beans (Phaseolus vulgaris L.) are alternative suitable ingredients for snacks, because of their content of bioactive compounds such as phenolic compounds (PC) and oligosaccharides (OS). However, there is no information about the transformation of these compounds associated with food matrix during gastrointestinal digestion. Therefore, the objective of this work was to simulate the whole digestion process (mouth to colon) to estimate bioaccessibility and small intestine permeability of free PC and OS, and the antioxidant capacity of free PC. Digested nixtamalized corn-cooked common bean chips exhibited significant different quantities of free PC and OS, and higher antioxidant activity compared to methanolic extract. The free PC showed high values of apparent permeability coefficients (0.023-0.729*10-3), related with their absorption in the small intestine. Both free PC and OS were retained in the non-digestible fraction of chips (10.24-64.4%) and were able to reach the colon. Our results suggest the digestion potential to increase chip bioactive compounds and antioxidant activity. Additional studies are required to evaluate their in vivo effects. PMID- 28873693 TI - Comparison and screening of bioactive phenolic compounds in different blueberry cultivars: Evaluation of anti-oxidation and alpha-glucosidase inhibition effect. AB - This study was aimed to investigate antioxidation and alpha-glucosidase inhibition of the bioactive compounds in three cultivars of blueberry ('Northland' (NL) from the hybrid blueberry (V. corymbosum L.*V. angustifolium Aiton), 'Britewell' (BW), and 'Gardenblue' (GB) from the rabbiteye blueberry (Vaccinium ashei Reade)). A total of eighteen anthocyanins were identified and quantified in Anthocyanins (ACNs), among which four acylated anthocyanins were exclusively found in Northland. The blueberry anthocyanin extracts (BAEs) were further measured the antioxidant activity and alpha-glucosidase inhibition effect. Northland BAEs exhibited significantly superior antioxidant activity compared with BAEs of other cultivars, and the antioxidant activity was correlated with the content of anthocyanins. However, alpha-glucosidase inhibition test showed that Britewell BAEs had the strongest inhibitory effect. BAEs were further separated into anthocyanin fraction (AF) and copigment fraction (CF). Fifteen phenolic acids and four iridoids were identified in CF. In terms of alpha-glucosidase inhibition effects, the CF from three cultivars could inhibit alpha-glucosidase in a dose-dependent manner, while the AF did not show significant inhibitory effects. The blueberry exhibits excellent antioxidant activity and alpha-glucosidase inhibition. PMID- 28873694 TI - Predicting consumer liking and preference based on emotional responses and sensory perception: A study with basic taste solutions. AB - Traditional methods of sensory testing focus on capturing information about multisensory perceptions, but do not necessarily measure emotions elicited by these food and beverages. The objective of this study was to develop an optimum model of predicting overall liking (rating) and preference (choice) based on taste intensity and evoked emotions. One hundred and two participants (51 females) were asked to taste water, sucrose, citric acid, salt, and caffeine solutions. Their emotional responses toward each sample were measured by a combination of a self-reported emotion questionnaire (EsSense25), facial expressions, and autonomic nervous system (ANS) responses. In addition, their perceived intensity and overall liking were measured. After a break, participants re-tasted the samples and ranked them according to their preference. The results showed that emotional responses measured using self-reported emotion questionnaire and facial expression analysis along with perceived taste intensity performed best to predict overall liking as well as preference, while ANS measures showed limited contribution. Contrary to some previous research, this study demonstrated that not only negative emotions, but also positive ones could help predict consumer liking and preference. In addition, since there were subtle differences in the prediction models of overall liking and preference, both aspects should be taken into account to understand consumer behavior. In conclusion, combination of evoked emotions along with sensory perception could help better understand consumer acceptance as well as preference toward basic taste solutions. PMID- 28873695 TI - Lipid-modifying enzymes in oat and faba bean. AB - The aim was to study lipase, lipoxygenase (LOX) and peroxygenase (POX) activities in oat and faba bean samples to be able to evaluate their potential in formation of lipid-derived off-flavours. Lipase and LOX activities were measured by spectroscopy, and POX activities via the formation of epoxides. An ultra-high performance liquid chromatography method was developed to study the formation of fatty acid epoxides. The epoxides of esters were measured by gas chromatography. Mass spectroscopy was used to verify the identity of the epoxides. Both oat and faba bean possessed high lipase activities. In faba bean, LOX catalysed the formation of hydroperoxides, whose break-down products are the likely cause of off-flavours. Since oat had low LOX activity, autoxidation is needed to initiate lipid oxidation. Oat had high POX activity, which is able to convert hydroperoxides to epoxy and hydroxy fatty acids that could contribute significantly to off-flavours. POX activity in the faba bean was low. Thus, in faba bean volatile lipid oxidation products could rapidly be formed by LOX, whereas in oat reactions are slower due to the need of autoxidation prior to further reactions. PMID- 28873696 TI - Enhanced antimicrobial effect of ultrasound by the food colorant Erythrosin B. AB - The synergistic combination of the food colorant Erythrosin B (E-B, FD&C 3) (0, 25, and 50MUM) and low-frequency ultrasound (20kHz, 0.86-0.90WmL-1) was evaluated against Listeria innocua. Although E-B was antibacterial by itself, the inactivation rate significantly increased in a concentration-dependent manner upon exposure to ultrasound and followed a sigmoidal behavior. The enhanced antimicrobial effect of E-B in the presence of ultrasound can be explained in part from a microbubble disappearance study in which it was confirmed that the presence of E-B enhances inertial cavitation, thereby enhancing the antimicrobial effect of ultrasound. The inactivation rate in a sequential treatment, where L. innocua was sonicated for 4min followed by exposure to 25MUM Erythrosin B, was comparable to that obtained by the simultaneous treatment, indicating complementary mechanisms of inactivation. Fluorescence microscopy showed attachment of E-B to the cells, which may explain its intrinsic antimicrobial property. Other mechanism may include the confirmed decrease in the cavitation threshold of water by addition of E-B, resulting in more effective cavitation. The study offers a proof-of-concept of a novel approach to complement ultrasound treatment for enhanced microbial inactivation. PMID- 28873697 TI - Inhibitory effect of phosphates on magnesium lactate efflorescence formation in dry-fermented sausages. AB - This study aimed to prevent the phenomena of efflorescence formation on the surface of dry fermented sausages due to the complexation of efflorescence forming cations with phosphates. Efflorescence formation is a critical issue constituting a major quality defect, especially of dry fermented sausages. Different phosphates (di- and hexametaphosphate) were added (3.0g/kg) to the sausage batter. As a hypothesis, these additives should complex with one of the main efflorescence-causing substances such as magnesium. The formation of efflorescences was determined for dry fermented sausages without phosphate addition, with diphosphate, or hexametaphosphate addition during 8weeks of storage under modified atmosphere. The visual analyses of the sausage surface revealed high amounts of efflorescences for the control (42.2%) and for the sausages with added diphosphate (40.9%), whereas the sausages containing hexametaphosphate had significantly reduced amounts of efflorescence formation, showing only 11.9% efflorescences after 8weeks of storage. This inhibition was a result of strong complexation of hexametaphosphate with magnesium ions, thus preventing the diffusion of magnesium towards the sausage surface. This can be explained by the magnesium content on the sausage surface that increased by 163.9, 127.8, and 52.8% for the sausages without phosphate, diphosphate, and hexametaphosphate addition, respectively. The mass transport of lactate and creatine was not affected by phosphate addition. Isothermal titration calorimetry confirmed that, theoretically, 4.5g/kg of diphosphate or 2.8g/kg hexametaphosphate are required to complex 0.2g/kg magnesium ions naturally occurring in dry fermented sausages and, thus, the chosen overall phosphate concentration of 3.0g/kg was enough when adding hexametaphosphate, but not for diphosphate, to inhibit the efflorescence formation. PMID- 28873698 TI - Phase behaviors involved in surimi gel system: Effects of phase separation on gelation of myofibrillar protein and kappa-carrageenan. AB - Phase behaviors of mixtures of myofibrillar protein and kappa-carrageenan at different mixing ratios and temperatures were examined by digital images and confocal scanning laser microscopy, showing that that the extent of phase separation was enhanced as the ratio of polysaccharides and temperature increased. The zeta potential of the mixtures became less negative as the protein ratio increased, and the complex became saturated at or above the protein/kappa carrageenan ratio of R4 (3.2%:0.8%). Gelation process performed by dynamic rheological analysis demonstrated that the presence of carrageenan decreased the gelation temperature but increased the storage modulus. Analysis of the microstructures of the mixed gels showed that the networks were significantly influenced by the concentrations of kappa-carrageenan. The present work could be applied to evaluate the mechanism of competition between phase separation and gelation in mixtures of proteins and polysaccharides. PMID- 28873699 TI - Phenolics fate in table olives (Olea europaea L. cv. Nocellara del Belice) debittered using the Spanish and Castelvetrano methods. PMID- 28873700 TI - Preparation of chitosan/polyvinyl alcohol blended films containing sulfosuccinic acid as the crosslinking agent using UV curing process. AB - This paper reports on a method of preparing chitosan-based films to which sulfosuccinic acid (SSA) is added for crosslinking agent with/without UV curing treatment and applications of a coating materials for foods. The physical, thermal, and optical properties of the UV cured chitosan-based films are investigated including their tensile strength (TS), elongation at break (%E), degree of swelling (DS), solubility (S), and water vapor absorption as well as their biodegradability in soil and applicability of the coating on a fruit. We also evaluated the physical properties of the prepared films to which glycerol (GL), xylitol (XL), and sorbitol (SO) are added to be used as plasticizers. The surface and topography of the prepared films are investigated by scanning electronic microscopy (SEM) and atomic force microscopy analysis (AFM). The results indicate that the films UV cured for 20min possess optimal physical and thermal properties compared to that of non-cured films. The mechanical, thermal, and water barrier properties of SO-added film are also found to be superior to other films with added GL and XL. The degree of biodegradability revealed that the films are degraded by about 40-65% after 220days. PMID- 28873701 TI - Encapsulation of omega-3 fatty acids in nanoemulsions and microgels: Impact of delivery system type and protein addition on gastrointestinal fate. AB - Carefully designed delivery systems are required to encapsulate and protect omega 3 fatty acids in commercial food and beverage products, but then release them at the required site-of-action within the human gastrointestinal tract (GIT). Previously, we showed that the oxidative stability of flaxseed oil (a plant-based source of omega-3 fatty acids) encapsulated in nanoemulsion droplets or calcium alginate microgels (hydrogel beads) was improved using caseinate as a natural antioxidant. In this study, the impact of caseinate on the digestion of flaxseed oil encapsulated in these delivery systems was investigated using a simulated GIT. The flaxseed oil was incorporated into four delivery systems: nanoemulsions (NE); nanoemulsions mixed with caseinate (NE+C); hydrogel beads (HB); and, hydrogel beads containing caseinate (HB+C). The gastrointestinal fate of the flaxseed oil droplets depended on delivery system type and the presence of protein. The flaxseed oil in the nanoemulsions (NE and NE+C) was rapidly hydrolyzed within the simulated small intestine, with over 76% and 65% of free fatty acids (FFAs) being released in the first 5 minutes, respectively. Conversely, the flaxseed oil in the hydrogel beads (HB and HB+C) was digested much more slowly, with only around 37% and 22% being released in the same period. This knowledge may be useful for designing delivery systems to protect omega-3 fatty acids from oxidation in functional foods, while still allowing them to be released in the GIT. PMID- 28873702 TI - Sensory characterization, physico-chemical properties and somatic yields of five emerging fish species. AB - Aquaculture plays an important role in supplying the fresh fish. However its production is dominated by only few long-established species that in turn limit the variety of available products in the market. Therefore, new fish species need to be properly introduced to create a diversification in the current market. In order to achieve this goal, it is important to know, understand and characterize their quality features so they can be addressed to local and global markets. Sensory, compositional, instrumental texture parameters and somatic properties of five emerging fish species, namely wreckfish, greater amberjack, grey mullet, meagre, and pikeperch, were examined for characterization purposes. Sensory references were specifically developed for the training of the assessors, both from a qualitative and quantitative perspective. Twenty two sensory descriptors were used for describing the samples. Several differences were observed among the measured parameters. Somatic measures revealed the filleting yield to be the most important of them. Regarding the compositional parameters, fat content was among the most relevant discriminating aspect between species, while hardness was among the most differentiating ones when dealing with texture. Greater amberjack was described with sour flavor, pikeperch was associated to an earthy flavor and grey mullet was characterized by bitter flavor. Sensory firmness was clearly distinctive for wreckfish, while meagre related to juicy texture. The analysis of the relationship between all parameters provided important correlations, especially those related to texture parameters, fat content, laminar structure and teeth adherence. The species in this study exhibited a wide range of physicochemical and sensory characteristics that show their potential for being further exploited when designing new products. PMID- 28873703 TI - Oil-in-water emulsions stabilized by tyrosinase-crosslinked potato protein. AB - Potato protein (PP) holds great promise as a non-allergenic food ingredient with high nutritional value. Attempts to modulate its functional properties by crosslinking have not been reported to date. The effect of tyrosinase-mediated crosslinking of PP on the properties of o/w emulsions was studied in the present work. Among the various PPs, protease inhibitors were efficiently crosslinked by the enzyme as determined by SDS-PAGE analysis. Concentrated emulsions comprising 40% olive oil and 6.1% PP (w/w) were fabricated by a shear stress homogenizer. The PP-stabilized emulsions were evaluated after one and 4h of incubation with tyrosinase. Emulsions were characterized by their droplet size distribution, rheological behavior, creaming resistance and microstructure. The crosslinked emulsion had a self-standing elastic gel-like structure after 1h of incubation. Unlike the Newtonian non-crosslinked emulsion, the crosslinked emulsion exhibited a shear-thinning behavior with a 20-fold increase in viscosity. The longer incubation time coupled with shaking at 250rpm for up to 4h resulted in the disruption of the droplets structure and led to a 2-fold decrease in viscosity, compared to the 1-hour crosslinked emulsion. Droplet size distribution showed formation of large particles in the crosslinked emulsion. Microscopy imaging demonstrated formation of aggregated and dense emulsion droplets network, which also contributed to the emulsion gel-like behavior. In the case of the non crosslinked emulsion, severe flocculation and coalescence was observed, regardless of incubation time. The results suggest that tyrosinase crosslinking is a useful method to modulate the properties of PP-based food formulations. PMID- 28873704 TI - Fractionation and identification of antioxidant peptides from an enzymatically hydrolysed Palmaria palmata protein isolate. AB - Proteins derived from the macroalgal species Palmaria palmata have emerged as potential substrates for the generation of bioactive peptides. The aim of this study was to fractionate, identify and characterize antioxidant peptides from a P. palmata protein hydrolysate. The P. palmata protein hydrolysate generated with the food-grade proteolytic enzyme Corolase PP was sequentially fractionated using solid phase extraction and semi-preparative (SP) RP-HPLC. The most active SP-RP HPLC peptide fraction (SP-RP-HPLC-30-F26) was analysed by ESI-MS/MS. Seventeen novel peptide sequences were identified in this fraction. Of the peptides selected for synthesis, Ser-Asp-Ile-Thr-Arg-Pro-Gly-Gly-Asn-Met, showed the highest oxygen radical absorbance capacity (ORAC) and ferric reducing antioxidant power (FRAP) activity with values of 152.43+/-2.73 and 21.23+/-0.90nmolTE/MUmol peptide, respectively. The results presented herein indicate that P. palmata derived peptides may have potential applications as health enhancing ingredients and as food preservatives due to their antioxidant activity. PMID- 28873705 TI - Zebra blenny protein hydrolysates as a source of bioactive peptides with prevention effect against oxidative dysfunctions and DNA damage in heart tissues of rats fed a cholesterol-rich diet. AB - High-cholesterol diet (HCD) is suspected to produce in excess free radicals having adverse effects on human health and causing atherosclerosis damage in heart tissues. In our study, the effects of zebra blenny protein hydrolysates (ZBPHs) were investigated on cardiac oxidant/antioxidant status as well as DNA damage and histopathological disorders in rats, fed with a hypercholesterolemic diet. The molecular weight distribution of the hydrolysates was determined by size exclusion chromatography, which analyzed a representative hydrolysate type with a weight range of 3-20kDa. ZBPHs effectively protected heart genomic DNA against oxidative damage induced by Fenton's reagent. HCD promoted oxidative stress with a rise in serum aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities and thiobarbituric acid reactive substance (TBARS), advanced oxidation protein product (AOPP) and hydrogen peroxide (H2O2) levels in heart tissues. An increase in glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities as well as a fall in ATPase activities and glutathione (GSH) level was also noted in heart of hypercholesterolemic rats. Treatment with ZBPHs ameliorated the biochemical parameters cited above. In addition, pre-treatment with ZBPHs prevented DNA fragmentation. The histopathological findings confirmed the biochemical results and the potential antioxidant activities of ZBPHs which can help the cure and management of cardiovascular diseases induced by high-cholesterol levels. PMID- 28873706 TI - Effect of soft foods on primary human gingival epithelial cell growth and the wound healing process. AB - OBJECTIVES: Investigate the effect of soft diet foods on gingival epithelial cell growth, migration, and mediator secretion. METHODS: Human gingival epithelial cells were stimulated for various time periods with the following soft diet foods: orange juice, drinkable yogurt, and a nutritional drink. Cell growth was determined by an MTT assay and cell migration was investigated by a scratch assay and F-actin filament staining. Keratin production was analyzed by Western blot and wound healing mediators IL-6 and human beta-defensin 2 were quantified by ELISA. RESULTS: We demonstrate, for the first time, that certain soft diet foods increased the production of keratin 5, 14, and 19 by gingival epithelial cells. These proteins were known to be produced by proliferating cells. The soft foods tested also stimulated gingival epithelial cells to produce IL-6 and human beta defensin 2. Soft foods are capable of promoting gingival epithelial cell migration by increasing F-actin production, which is part of the wound healing process. Results varied depending on the foods tested. CONCLUSION: Gingival epithelial cells interacted with the soft diet foods under study. This interaction was shown to upregulate keratin expression, as well as IL-6 and human beta-defensin 2 secretions. Furthermore, following cell wound, the soft foods upregulated post-scratch cell migration and F-actin production. Overall data suggest that the choice of foods in soft diets following oral surgery may influence the wound healing process of gingival epithelial cells. PMID- 28873707 TI - Green tea supplementation produces better neuroprotective effects than red and black tea in Alzheimer-like rat model. AB - : Green tea from Camellia sinensis plays a neuroprotective role in different neurodegenerative conditions, such as memory deficits in Alzheimer disease (AD). However, whether other teas from Camellia sinensis present similar neuroprotective effect still is not clear. Here we investigate effects of green, red and black tea supplementation on memory and hippocampus oxidative status in a rat model of Alzheimer-like disease (AD-like). METHOD: Wistar male rats were supplemented with green, red or black tea during 8weeks before Abeta intra hippocampal injection (2MUL of Abeta-25-35, CA1 region). AD and sham rats were submitted to memory tests. After euthanasia, oxidative status in the bilateral hippocampus was quantified. Green and red teas avoid memory deficits in AD rats, but only green tea also avoids oxidative stress and damage in the hippocampus. Green tea was more effective for neuroprotection than red and black teas from the Camellia sinensis in the AD rat model. PMID- 28873708 TI - Anti-inflammatory effects of egg yolk livetins (alpha, beta, and gamma-livetin) fraction and its enzymatic hydrolysates in lipopolysaccharide-induced RAW 264.7 macrophages. AB - In this study, the egg yolk livetins (alpha, beta, and gamma-livetin) fraction and its hydrolysates, prepared by pepsin and Alcalase, were evaluated for their anti-inflammatory effects using lipopolysaccharide (LPS)-induced RAW 264.7 macrophages as an in vitro model. Enzymatic hydrolysis by pepsin and Alcalase successfully transformed the large molecular weight livetins into low molecular mass peptides mostly below 10kDa. Results revealed that livetins and its hydrolysates (peptides) treatment significantly reduced the inflammatory responses as evidenced by inhibition of production of nitric oxide (NO) (22.7 39.2%), pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha) (36.9-43.2%), interleukin-1beta (IL-1beta) (26.1-50.9%) and interleukin-6 (IL-6) (60.4-69.0%), and the expression of inducible nitric oxide synthase (iNOS) (58.6-62%). Alcalase hydrolysate showed more effects in inhibiting prostaglandin E2 (PGE2) production (30.3%) as well as expression of cyclooxygenase-2 (COX-2) (55.7%). In addition, effect of livetins and its hydrolysates on phagocytic capacity of the macrophages was also evaluated. The results indicate that livetins and its enzymatic hydrolysates significantly (p<0.001, 0.05) enhanced the phagocytic activity of the macrophages. The results suggest that egg yolk livetins and its hydrolysates with anti-inflammatory activity can potentially be used in health food/nutraceutical/pharmaceutical industry for various applications. PMID- 28873709 TI - Yacon syrup: Food applications and impact on satiety in healthy volunteers. AB - Syrup obtained from yacon roots could be well positioned as a nutritional product due to its high fructooligosaccharides (FOS) content. Considering this, we examined the potential food applications of yacon syrup, using the focal group methodology, and its sensorial acceptability when incorporated in yogurt. The beneficial effects of the consumption of yacon syrup were studied over a 2-week period in a double-blind placebo-controlled experiment (namely Test A) and other consistent of only one day of yacon syrup consumption (namely Test B) were also evaluated. The doses of yacon syrup for both experiments were 8.74g of FOS/day. Energy intake, hunger, satiety, fullness and prospective food consumption were assessed with analogue scales at the end of each test. The results indicate that the yogurt was the food most suggested by the focus group, and the average of the scores given to the attributes when the yacon syrup was incorporated into a yogurt were: 7.78 for appearance; 7.72 for aroma; 7.02 for flavor and 6.96 for overall acceptability, corresponding to "like very much" and "like moderately". Furthermore, the results indicate that yacon syrup has a positive effect on appetite and its effect was dependent on gender and period of intervention, being statistically significant (P<0.05) in women, after 2-week period. These findings suggested that increasing FOS intake could help to increase satiety, and consequently, be helpful in the management of type 2-diabetes or control of the current high prevalence of overweight or obesity. PMID- 28873710 TI - Ultrasound assisted acidification of model foods: Kinetics and impact on structure and viscoelastic properties. AB - This work aimed to describe the acidification process of two specific model foods using the ultrasound technology, as well as to evaluate the changes on its viscoelasticity properties. For that, two types of model food were used, with similar composition but different structures: natural melon cylinders and restructured melon-agar cylinders. The acidification process was performed using a citric acid solution (0.2% w/w) assisted with and without ultrasound (40W/L of volumetric power and 20kHz of frequency) at constant temperature (25 degrees C). In addition, the stress relaxation analysis was performed on the cylinders in order to evaluate the changes on the viscoelastic properties. As a result, both ultrasound processing and the different structural conformation of the model foods affected the acidification kinetics, being improved by ultrasound. Further, the acidification process with and without ultrasound affected the mechanical properties of both products, reducing their elasticity. The relaxation data could be described by a Maxwell model with two bodies and a residual spring, providing a possible explanation of the association between the mechanical model parameters and the microstructural conformation of both studied cases. PMID- 28873711 TI - Effect of dairy matrices on the survival of Streptococcus thermophilus, Brevibacterium aurantiacum and Hafnia alvei during digestion. AB - This study evaluated the ability of dairy matrices, different in composition (with and without fat) and structure (liquid and gel), to enhance microorganisms survival through digestion. The viability of three dairy microorganisms Streptococcus thermophilus, Brevibacterium aurantiacum and Hafnia alvei was measured during in vitro and in vivo digestion. S. thermophilus was highly sensitive to gastric stress, and was not found in the duodenal compartment. B. auranticum was moderately sensitive to gastric stress but resistant to duodenal stress. H. alvei was highly resistant to both stresses. LIVE/DEAD confocal microscopy's images, probed the effect of low pH on microorganisms survival. However, in vivo analyses (16S rRNA gene metabarcoding) failed to confirm in vitro observations since tested microorganisms were not detected. Despite of the different evolutions during digestion on buffer capacity, lipolysis, and rheological characteristics, we did not observe any protective effect of the dairy matrices on microorganisms survival. PMID- 28873712 TI - Identification of potential inhibitory peptides of enzymes involved in the metabolic syndrome obtained by simulated gastrointestinal digestion of fermented bean (Phaseolus vulgaris L.) seeds. AB - The aim of this study was to determine the conditions of bean fermentation carried out by Lactobacillus plantarum to obtain biologically active peptide fractions after in vitro digestion. The results suggest that optimum process conditions should be selected according to the specific activity of peptides. Only a fraction with a molecular mass of 3.5-7kDa obtained after fermentation at 22 degrees C for 3h had alpha-amylase inhibitory activity. The optimal fermentation conditions for bean seeds to release peptide fractions with a molecular mass of 3.5-7.0kDa and the highest lipase or ACE inhibitory activity (IC50 1.19 and 0.28mg mL-1, respectively) were determined as 30 degrees C and 3days. The fractions with the highest inhibitory activity were identified by LC MS/MS and the sequences of the peptide derived from bean proteins were determined as INEGSLLLPH, FVVAEQAGNEEGFE, SGGGGGGVAGAATASR, GSGGGGGGGFGGPRR, INEGSLLLPH, GGYQGGGYGGNSGGGYGNRG, GGSGGGGGSSSGRRP, and GDTVTVEFDTFLSR. PMID- 28873713 TI - Bioavailability and new biomarkers of cruciferous sprouts consumption. AB - The evaluation of the bioavailability of bioactive compounds from cruciferous foods is one challenge in the design of clinical trials for studying their functionality. Currently, studies of bioavailability are mainly based of the analysis of total isothiocyanates and indoles, and sulforaphane metabolites after broccoli consumption. However, as far as we are aware, there are not any biomarkers studied or established for the intake of radish sprouts. In this work, a 7-days-cross-over study with fourteen women was undertaken to compare the bioavailability of glucosinolates from broccoli and radish sprouts. The urinary excretion of isothiocyanates, indoles and their metabolites was analysed by UHPLC QqQ-MS/MS. For the first time, sulforaphene, sulforaphane-N-acetyl-l-cysteine (SFN-NAC) and 3,3'-diindolylmethane (DIM), were studied as biomarkers of dietary exposure to radish. The SFN-NAC and DIM were already considered biomarkers of broccoli consumption. Higher excretion of conjugated isothiocyanates and constant excretion of indoles were found during the first 12h after ingestion. Metabolites were excreted homogeneously during the study, suggesting no accumulation. The different urinary biomarker profiles provided new information to distinguish between the consumption of broccoli or radish sprouts. The results provide valuable information to better understand the bioavailability of cruciferous bioactives. PMID- 28873714 TI - Comparison of myosin heavy chain content determined by label-free quantification between porcine longissimus thoracis, psoas major and semimembranosus muscles. AB - The present study was conducted to quantify MHCs in porcine longissimus thoracis (LT), psoas major (PM) and semimembranosus (SM) muscles through the label-free quantification (LFQ). To estimate the accuracy of LFQ, quantitative RT-PCR (qRT PCR), immunohistochemistry (IHC), and Western-blotting (WB) were performed. MHCs 2x, 2a, 2b and slow were identified by LC-MS/MS analysis and 279 ion spectra were selected for LFQ analysis. The content of MHC 2b was higher in LT and in SM than in PM (p<0.05), while the content of MHC slow was highest in PM among the muscles (p<0.01) regardless of LFQ types. Positive correlation coefficients of MHC 2b and MHC slow between LFQ and IHC (relative area composition) and qRT-PCR results partially supported the LFQ results. Though low-abundant peptides should be considered to estimate MHC contents via the spectral count method, LFQ enables the determination of MHC contents at protein level regardless of LFQ types. PMID- 28873715 TI - Anti-inflammatory effects of dulse (Palmaria palmata) resulting from the simultaneous water-extraction of phycobiliproteins and chlorophyll a. AB - The use of dulse (Palmaria palmata) as a source of edible anti-inflammatory products was evaluated in this study. Phycobiliproteins and chlorophyll a were simultaneously extracted from lyophilized dulse leaves via water-extraction, and subjected to thermolysin digestion to produce thermolysin-digested water-extract (d-DWE). d-DWE significantly reduced tumor necrosis factor-alpha, interleukin-6, and nitric oxide in LPS-stimulated murine macrophages (RAW 264.7 cells), and orally administered d-DWE mitigated acute inflammation in carrageenan-induced paw edema of mice. Mass spectrometry revealed d-DWE contained peptide LRDGEIILRY (derived from phycoerythrin beta-chain) and chlorophyll a decomposition products, and they individually reduced the secretion of the proinflammatory mediators in LPS-stimulated RAW 264.7 cells. These results indicate the anti-inflammatory activity could be from a combined effect of phycobiliprotein and chlorophyll a decomposition products prepared from the water-extract of dulse. Thus, inexpensive and safe water-extraction method is effective for the extraction of anti-inflammatory components from dulse. PMID- 28873716 TI - Characterization of four beta-glucosidases acting on isoflavone-glycosides from Bifidobacterium pseudocatenulatum IPLA 36007. AB - Bifidobacterium pseudocatenulatum IPLA 36007 acts on isoflavone glycosides, releasing their corresponding aglycones. This strain-specific activity might be a key step in making isoflavones bioavailable and harnessing their oestrogenic activity. To investigate the molecular mechanisms involved in this activity, four glycosyl hydrolase-encoding genes in the IPLA 36007 genome (AW18_01575, AW18_09810, AW18_08145, and AW18_08090) were selected, synthesized with heterologous promoter and terminator signals (r-beta-gluA, r-beta-gluB, r-beta gluD and r-beta-gluE, respectively), cloned into Escherichia coli, overexpressed as His-tagged proteins, and the enzymes purified and characterized. All four enzymes - GluAHis, GluBHis, GluDHis and GluEHis - proved to have beta-glucosidase activity and deglycosylated (although at different rates) the isoflavone glycosides daidzin and genistin, releasing the aglycone moieties daidzein and genistein, respectively. GluDHis and GluEHis were also shown to hydrolyse beta glucosyl disaccharides such as cellobiose and gentiobiose, while GluAHis and GluBHis did not. Differences in activity were recorded for all four beta glucosidases at different pHs and temperatures under otherwise similar assay conditions, suggesting they have complementary activities under different environmental conditions. Two of the recombinant genes, r-beta-gluA, and r-beta gluD, were cloned and expressed in the model lactic acid bacterium Lactococcus lactis, suggesting starter and probiotic organisms could be endowed with beta glucosidase activity. B. pseudocatenulatum IPLA 36007 contains additional beta glucosidases to those studied in this work, indicating a high level of redundancy for this enzymatic activity. Knowledge of glycoside-degrading enzymes should facilitate the development of novel, more effective or more selective prebiotics or functional foods for the promotion of bifidobacterial numbers in the human gut. It might also be of interest in the development of novel probiotics with specific health-promoting activities. PMID- 28873717 TI - Herbal products containing Hibiscus sabdariffa L., Crataegus spp., and Panax spp.: Labeling and safety concerns. AB - Herbs have been used from ancient times for infusion preparation based on their potential health effects. In particular, the consumption of Hibiscus sabdariffa L., Crataegus spp. and Panax spp. has been largely associated to cardiovascular benefits. In this work, the label information of 52 herbal products for infusion preparation containing the referred herbs was analyzed and discussed, taking into consideration the European Union regulation for herbal products, which intends to protect public health and harmonize the legal framework in Member States. Details about the cardiovascular-related statements and warning notifications about consumption were considered. Also, regulatory issues and possible herb-drug interactions were explored and discussed. A total of 14 of the 52 herbal products selected presented health claims/statements on the label. Hibiscus was present in the majority of the products and, in some cases, it was mentioned only in the ingredients list and not on the product front-of-pack. Despite the promising outcomes of these plants to modulate cardiovascular risk markers, consumers with some sort of cardiovascular dysfunction and/or under medication treatments should be aware to carefully analyze the labels and consult additional information related to these herbal products. Manufacturers have also a huge responsibility to inform consumers by presenting awareness statements. Lastly, health professionals must advise and alert their patients about possible interactions that could occur between the concomitant consumption of drugs and herbs. Overall, there is still a real need of additional studies and clinical trials to better understand herbs effects and establish a science-based guidance to assess their safety. PMID- 28873718 TI - Knowledge, attitudes and practices of food handlers in food safety: An integrative review. AB - This study presents an overview of the relationship between knowledge, attitudes and practices (KAP) of food handlers with training in food safety, in addition to proposing reflections on the training of food handlers, considering its responsibility for food safety and health of consumers. The review was based on the integrative method. The descriptors used were: (food handler), (knowledge, attitudes and practice) and (training). Six databases were searched, 253 articles were consulted and 36 original articles were included. Fifty per cent of the articles pointed that there was no proper translation of knowledge into attitudes/practices or attitudes into practices after training. Knowledge, attitudes and practices of food handlers are important for identifying how efficient training in food safety is allowing prioritize actions in planning training. The evaluation of KAP is the first step to understand the food handler's point of view. After this evaluation other diagnostic strategies become necessary to enhance this understanding. PMID- 28873719 TI - Effect of chemical composition and sonication procedure on properties of food grade soy lecithin liposomes with added glycerol. AB - The effect of two-step and five-step acetone washing of soybean lecithin (SL) on compositional properties of partially purified phosphatidylcholines (PW2 and PW5) was studied. Trace amounts of protein were detected in SL, PW2 and PW5, with a predominance of glutamic acid and aspartic acid. Increasing the number of acetone washing steps significantly reduced the total content of gamma-, delta- and alpha tocopherol. Similar reductions (~90%) of neutral lipids were found in both PW2 and PW5, but the removal of free fatty acids was higher in PW5 than in PW2 (78% vs. 71%). Linoleic acid was the main constituent in both the neutral lipids and the phospholipid fractions of SL, PW2 and PW5, accounting for around 53-59% of total fatty acids; however, a considerable amount of it was removed by increasing the number of washing steps. All phospholipid classes were mostly concentrated in the first two-step washing of lecithin. Further washing increased the concentration of phosphatidylcholine (PC) in PW5, as compared to PW2. Glycerol containing liposomes from PW2 and PW5 were produced using two different-intensity sonication procedures (method A: 120W, 5min; method B: 30W, 2min) using a probe type sonicator (100mL volume suspension). Liposomes of soy lecithin and liposomes of PW5 without glycerol were also obtained by using strong sonication (method A). The liposomal dispersion with the highest purification and the stronger sonication was clearly distinguished from the others, both in particle size and in zeta potential. DSC results showed noticeable interference of glycerol in the membrane structure, but minimal changes in particle size and surface charge. PMID- 28873720 TI - Deciphering the characteristics of soybean oleosome-associated protein in maintaining the stability of oleosomes as affected by pH. AB - The understanding of the behavior of natural oleosomes is very important for leading to advancements in liposome manufacturing. Thus, the aims of this work was to evaluate the stable behaviors of oleosomes with regards to a wide pH range (2.0-11.0) using soybean oleosomes. The conformation changes and surface hydrophobicity of soybean oleosome-associated protein, and as well as zeta potential and particle size distribution of oleosome were investigated. The particle size and zeta-potential of oleosomes, and surface hydrophobicity of oleosome-associated proteins were found to be readily affected by pHs. The secondary structure of oleosome-associated proteins was more susceptible to alkaline treatment than acidic treatment. The most stable oleosomes suspension was occurred at pH9.0. The electrostatic repulsion and hydrophobic interaction simultaneously affected the stability of oleosome. At pH2.0 to 6.0, acidic treatment did not significantly change the secondary structure of oleosome associated proteins. With an increased treatment pH of 8.0-11.0, the contents of alpha-helix and random coil structures of oleosome-associated proteins decreased, while the amount of beta-sheet structures increased. Results highlighted the interesting fact that the aggregation of oleosomes occurring at different pHs was attributed to the synergistic effects between conformation changes and interaction properties of oleosome-associated proteins. PMID- 28873721 TI - Influence of fat structure on the mechanical properties of commercial pate products. AB - Five commercial brand pates were characterized by examining their texture, microstructure, fatty acid composition, melting profile, and polymorphism. Pates evaluated at 4 degrees C showed much higher hardness values compared to when tested at 22 degrees C. Pates with higher fat content and higher saturated fatty acid and triacylglycerol contents were found to be harder. Smaller fat globules were also found to be correlated to higher hardness values. Increases in solid fat content were correlated to an increased hardness at 4 degrees C vs. room temperature but could not explain differences observed at a specific temperature. Powder X-ray diffraction studies demonstrated that while the fat extracted from one of the pates crystallized in a beta polymorphic form; while embedded in a pate protein matrix, it was crystallized in a beta' polymorphic form. This implies an effect of the food matrix on fat crystallization and structure and an interaction between fat and other components present in the food matrix. PMID- 28873722 TI - Comparison between boiling and vacuum cooking (sous-vide) in the bioaccessibility of minerals in bovine liver samples. AB - Only some of ingested nutrients are available for absorption by the organism. The foods generally are submitted to some heat processing that may interfere in the bioaccessibility of nutrients. There are no studies of the influence of cooking under vacuum (sous vide) on the bioaccessibility of minerals. This study evaluated the in vitro bioaccessibility of Ca, Cu, Fe, K, Mg and Zn in bovine liver samples after traditional cooking in water and using the sous vide procedure. All heat treatments of bovine liver promoted the increase of the bioaccessibility of Ca, Cu, Fe, K and Mg, except for Zn when the effect was the opposite. The sous vide method provided higher bioaccessibility of these minerals than cooking in boiling water, except for K when both methods presented equivalent values. Samples of raw liver and liver cooked using sous vide method presented the following percentage of bioaccessible fraction, respectively: 39.7% and 95.8% (Ca), 8.78% and 26.9% (Cu), 8.80% and 39.5% (Fe), 30.2% and 42.6% (K), 26.4% and 43.9% (Mg), 24.8% and 36.3% (Zn). Thus, under the aspect of improvement availability of studied minerals by organism, the sous-vide technique was the most suitable to cook bovine liver. PMID- 28873723 TI - Substrates emulsification process to improve lipase-catalyzed sardine oil glycerolysis in different systems. Evaluation of lipid oxidation of the reaction products. AB - Mono- and diacylglycerols rich in omega-3 have a great interest due to their good bioavailability and oxidation stability compared with other kind of omega-3 concentrates. The main drawback in mono- and diacylglycerols production by glycerolysis is the immiscibility of the substrates, oil and glycerol. To improve mass transfer rates, avoiding the use of organic solvents, emulsification of both reactants as reverse micelles (glycerol-in-oil) was carried out previous to lipase-catalyzed sardine oil glycerolysis. Substrate emulsification yielded higher reaction rates compared to kinetics with no previous emulsification, but still lower than in organic solvents. To avoid the use of organic solvent, SC-CO2 was used as reaction medium but no kinetic advantages were demonstrated in the pressure range from 15 to 25 MPa. By increasing temperature, from 40 to 90 degrees C, reaction rates increased both in a solvent-free system and in SC-CO2 medium. It was also found that an increase in temperature does not lead to an increase in the final oxidation status of the reaction products. This behavior was due to the adsorption capacity of the Lipozyme 435 support, giving lower oxidation status at the highest temperature, 80-90 degrees C. PMID- 28873724 TI - Combinative effect of sardine peptides and quercetin alleviates hypertension through inhibition of angiotensin I converting enzyme activity and inflammation. AB - Hypertension had relation to angiotensin I converting enzyme (ACE) activity and inflammation. In our previous research, sardine peptides (SP) with ACE inhibitory activity were prepared. However, the combinative effect of SP and quercetin (QC) on hypertension alleviation was still unknown. In the present study, the antihypertensive effect of SP and QC was discovered and the optimal proportion of SP and QC (v/v=8:2, with 20.00mg/mL of SP and 12.99MUg/mL of QC for their original concentrations) was screened on ACE activity inhibition in vitro. And the in vivo experiment supported it by indicating that the mixture reduced the systolic blood pressure, heart, left ventricular and kidney weight and their corresponding indices, serum ACE activity, angiotensin-II (ANG-II) and tumor necrosis factor-alpha (TNF-alpha) (in high dose) concentration in SHR rats. Besides, the mixture also lowers NO, TNF-alpha andinterleukin-6 (IL-6) concentration significantly in vitro. Hence, the combinative effect of SP and QC in optimal proportion had stronger inhibition on ACE activity than SP or QC alone, and could alleviate hypertension through inhibition of ACE activity and inflammation. PMID- 28873725 TI - Improved gel functionality of myofibrillar proteins incorporation with sugarcane dietary fiber. AB - The effects of sugarcane dietary fiber (SDF) on the gelation properties of porcine myofibrillar proteins (MP) were studied to understand its mechanism of action in improving gel functionality. Rheological tests on all composite gels (MP with SDF) showed the visco-elastic nature of MP, but the G' significantly increased with contents of SDF and with particle size (P<0.05). However, the delta exhibited the opposite effect. Light microscopy suggested that SDF affected moisture distribution in the gel by drawing water from MP and homogenously embedded in gelation. It is proposed that during the heating the more concentrated MP promoted the unfolding of MP chains and facilitated the formation of beta-sheet instead of alpha-helices, leading to a compact and homogenous three dimensioned network. These results indicated that the SDF changed the water distribution and resulted in the enhanced gelation which reacted to firmly bind SDF and form a synergistic interaction system. PMID- 28873726 TI - Effect of high-pressure treatments on proteolysis, volatile compounds, texture, colour, and sensory characteristics of semi-hard raw ewe milk cheese. AB - High pressure (HP) offers potential industrial applications in cheese preservation, but it is essential to provide knowledge concerning their effects on the ripening process and sensory characteristics. In this study, we investigated the effect of different HP treatments (200-500MPa at 14 degrees C for 10min on day 7) on proteolysis, texture, colour, volatile compounds and sensory characteristics of semi-hard raw ewe milk cheese. HP treatments did not affect pH or dry matter values of 60-day-old cheeses. Treatments at pressure levels up to 400MPa led to significant (P<0.01) increases in the total free amino acids (FAA) content at 60days, compared to control cheese, although the cell-free aminopeptidase activity was lower. HP retarded the formation of some volatile compounds in cheeses, the number of compounds affected by HP being higher as the pressure level increased. Cheeses pressurized at 300-500MPa had lower levels of 2 butanone, 2-butanol, 2-propen-1-ol, 1-butanol and acetic acid than control cheese, cheeses pressurized at 400-500MPa lower levels of 1-propanol, 2-pentanol, and butyric and hexanoic acids, and cheeses pressurized at 500MPa lower levels of ethanol, 3-methyl-1-butanol and 3-methyl-2-buten-1-ol. All HP-treated cheeses showed higher fracturability values, and higher Hue angle and lower a* values than control cheese. Despite the differences detected by instrumental analyses between HP-cheeses and control cheese, few significant differences were found between the sensory characteristics of HP-cheeses and control cheese. Only the pressurization of cheese at 500MPa affected significantly (P<0.01) some of the sensory characteristics, with a negative effect on taste intensity but a positive effect on aroma quality. In summary, HP treatments at 200 and 300MPa showed the mildest effects on the characteristics of semi-hard raw ewe milk cheese. HP treatment of this cheese variety at 300, 400 and 500MPa prevented late blowing defect caused by Clostridium tyrobutyricum (Avila et al., 2016, Food Microbiol. 60, 165-173). Thus, it may be concluded that HP treatment at 300MPa is the most adequate procedure, able to prevent late blowing with minimum changes in cheese characteristics. PMID- 28873727 TI - Impact of fermentation conditions on the quality and sensory properties of a probiotic cupuassu (Theobroma grandiflorum) beverage. AB - The aim of the study was to evaluate the conditions of fermentation pH and temperature and also the fermentation time of Lactobacillus casei in the cupuassu (tropical fruit native to the Brazilian Amazon) beverage. The sugars, organic acids, and antioxidant activity during the fermentation also were investigated. The sensory characteristics were also evaluated. Moreover, the effect of expectation on the acceptability of probiotic and symbiotic cupuassu beverages was rated under three conditions. The blind (consumers were informed that the samples were probiotic and symbiotic beverages and they tasted them); expected (only nutritional claims in short text were informed) and informed (consumers were asked to evaluate the product when they had nutritional information). The conditions for probiotic beverage production were initial pH5.8, the temperature of 30 degrees C, and 18h of fermentation. L. casei had viability higher than 9.34LogCFU/mL with 18h of fermentation. The fructose was the most consumed sugar (84.76%), followed by sucrose (62.10%) and glucose (34.52%). The antioxidant activity increased during the fermentation. The organic acids present in the cupuassu (citric, ascorbic and quinic acids) also supported L. casei growth, being consumed during the fermentation improving the nutritional value of the beverage. The acceptance of the probiotic drink increased when the juice was presented to the informed tasters. Therefore, the nutrition claims were effective in increasing the acceptance. The probiotic cupuassu beverage was well accepted as an alternative functional food. PMID- 28873728 TI - Development and characterization of a new encapsulating agent from orange juice by-products. AB - The replacement of maltodextrins as carriers for the spray drying of sticky and sugar based bioactives is an important development for the food industry. In this work, orange juice industry by-product was used to obtain a high dietary fiber powder to be used as carrier material. This powder was characterized with respect to its physical and chemical properties related to the process of encapsulation by spray drying. Adsorption isotherms of orange waste powder were determined at 30, 45, and 60 degrees C. The data were fitted to several models including two parameter (BET, Halsey, Smith, and Oswin), three-parameter (GAB), and four parameter (Peleg) relationships. The GAB model best fitted the experimental data. The isosteric heat of sorption was determined from the equilibrium sorption data using the Clausius-Clapeyron equation. Isosteric heats of sorption were found to decrease exponentially with increasing moisture content. The enthalpy-entropy compensation theory was applied to the sorption isotherms and indicated an enthalpy controlled sorption process. Glass transition temperatures (Tg) of orange waste powder conditioned at various water activities were determined and a strong plasticizing effect of water on Tg was found. These data were satisfactory correlated by the Gordon and Taylor model. The critical water activity and moisture content for the orange waste powder were 0.82 and 0.18g water/g solids, respectively, at a storage temperature of 25 degrees C. PMID- 28873729 TI - A multifactorial approach in characterizing geographical origin of Sicilian cherry tomatoes using 1H-NMR profiling. AB - In this study, metabolomic analysis of chloroform extracts was performed to characterize cherry tomatoes (cv Naomi and Shiren) grown in different Sicilian areas, using 1H NMR spectroscopy coupled with multivariate statistical analysis. Principal components analysis showed clear discrimination between extracts of cherry tomatoes cultivated in two different seasons (winter and summer) and grown in three areas of Sicily (Gela, Licata, Pachino). In particular, carotenoids and phospholipids mainly were found to be more discriminating metabolites for both cultivars in summer and winter. In the present study, the simple separation only based on production area was found to be inadequate to distinguish the three groups of tomatoes. A clear separation among the different samples groups was obtained using a multifactorial approach not only based on the geographical origin classification, but considering also cultivar, year and seasonality. PMID- 28873730 TI - Probiotics as potential alternative biocontrol agents in the agriculture and food industries: A review. AB - Pathogenic microorganisms are a potential threat to the agriculture and food industries. Food contamination can be happened in the production levels at any point in the chain by pathogenic microorganisms. Conventional methods, such as those involving antibiotics, disinfectants, and physical methods, are commonly used as microbial control strategies. Owing to the limitations of these methods, such as emergence of resistance, low effectiveness, high cost, and detrimental effects on food, health, and the environment, many countries have adopted laws and regulations restricting their use. To overcome these problems, an environmentally friendly, cost-effective alternative approach is urgently needed. Probiotics are live microorganisms that offer health benefits to the host, when consumed in adequate amounts, by providing pathogen protective action and nutritional benefits. From a food microbiological point of view, to use probiotics in animals, there is a reduction of zoonotic pathogens in the gastro intestinal tract (GIT) among animals which prevent the transmission of these pathogens through food. Therefore, probiotics have been proposed as an alternative antimicrobial means to protect against pathogenic microorganisms for better healthcare and food safety. In this review, we discuss probiotics, their selection criteria, mechanisms of action, and their prospects as alternative biocontrol agents, with special emphasis on the agriculture (livestock and aquaculture sectors), and food industries. PMID- 28873731 TI - Comparative proteomic analysis of Cronobacter sakazakii by iTRAQ provides insights into response to desiccation. AB - Cronobacter sakazakii is a foodborne pathogen throughout the world and survives extremely desiccation stress. However, the molecular basis involved in desiccation resistance of C. sakazakii is still unknown. In this study, the potential desiccation resistance factors of C. sakazakii ATCC 29544 were determined using iTRAQ-based quantitative proteomic analysis. A total of 2775 proteins were identified by iTRAQ, of which 233 showed a different protein expression between control group and desiccation stress group. Among these 233 proteins identified as desiccation resistance proteins, there were 146 proteins downregulated and 87 proteins upregulated. According to the comprehensive proteome coverage analysis, C. sakazakii increased its resistance to desiccation by reducing the gene involved with unnecessary survival functions such as those used for virulence, adhesion, invasion and flagella assembly, while increasing gene expression of genes used in withstanding osmotic stress such as those genes involved in trehalose and betaine uptake. However, the mechanism involved in amino acid metabolism in an osmotic stress response, including the producing of gamma-aminobutyric acid in C. sakazakii is still uncertain. This is the first report to determine the potential desiccation resistant factors of C. sakazakii at the proteomic levels. PMID- 28873732 TI - Unprecedented antioxidative and anti-inflammatory aryl polyketides from the brown seaweed Sargassum wightii. AB - Previously undescribed aryl polyketide lactones, 4-(8-ethyl-tetrahydro-7-oxo-2H pyran-5-yl)-propyl-4'-methylbenzoate (compound 1) and methyl-2-(12-oxo-7-phenyl-8 vinyl-1-oxa-4,9-cyclododecadien-3-yl)-acetate (compound 2) were purified from ethyl acetate-methanol fraction of the brown seaweed Sargassum wightii. The structures were proposed based on their NMR and mass spectrometric data. The antioxidative activities of the lactones were significantly greater (P<0.05) (IC50 1,1-diphenyl-2-picrylhydrazyl radical scavenging 0.24-0.32mg/mL) than alpha tocopherol (IC50 0.63mg/mL). The title compounds displayed considerably greater 5 lipoxygenase inhibitory activity (IC50 0.56 and 0.29mg/mL, respectively) in conjunction with higher selectivity indices (anti-cycloxygense-1IC50/anti cycloxygense-2IC50 >1) compared to non-steroidal anti-inflammatory drugs (SIaspirin 0.03, SIibuprofen 0.43). Putative biosynthetic pathway of title polyketide products through polyketide synthase enzyme cascade catalyzed reactions substantiated the structural attributions of the hitherto unreported aryl polyketides. This is the first report of the occurrence and characterization of two rare skeletal types, oxo-2H-pyranyl and oxa-cyclododecadienyl macrolactone featuring the aryl substituent from marine organisms with potential antioxidative and anti-inflammatory activities. PMID- 28873733 TI - Bioaccessibility and antioxidant activity of phenolic compounds in frozen pulps of Brazilian exotic fruits exposed to simulated gastrointestinal conditions. AB - This study characterized the phenolic profile in siriguela, umbu-caja and mangaba, as well in their frozen pulps (FPs). The bioaccessibility of phenolic compounds and the antioxidant activity of the FP dialysates were determined following exposure to simulated gastrointestinal conditions. The profile of phenolic compounds identified in fruit and FPs were relatively similar. After pulp processing, increases of 33.60% and 68.72% in free phenolics were observed for mangaba and umbu-caja, respectively, whereas in siriguela, the free phenolic was reduced by 56.55%. Generally, phenolic levels decreased after exposure to simulated gastric conditions in all FPs. The bioaccessibility of phenolics varied among the evaluated FPs. The highest bioaccessibility was observed for gallic acid in the umbu-caja FP (73.92%) and the lowest for gentisic acid in the mangaba FP (8.71%). Siriguela and umbu-caja FP dialysates presented the highest capacity for the capture of the radical 2,2'-diphenyl-2-picrylhydrazyl hydrate, whereas the mangaba FP dialysate demonstrated the highest iron reducing capacity. PMID- 28873734 TI - Effect of extrusion conditions on the physico-chemical properties and in vitro protein digestibility of canola meal. AB - Canola meal has potential as a high protein food ingredient. The extrusion induced changes in color, pH, extractable protein and in vitro protein digestibility of canola meal under different extrusion conditions was assessed. The extrusion barrel moisture (24%, 30% or 36%) and screw kneading block length (0, 30 or 60mm) were used as independent process parameters. Extrusion at high barrel moisture (36%) favored protein aggregation resulting in lower extractable protein compared to extrusion at the lowest barrel moisture (24%). At lower barrel moisture contents (24% and 30%), a longer kneading block length increased extractable protein but this was not the case at 36% barrel moisture. Canola protein digestibility was improved upon extrusion at 30% barrel moisture but there was no significant change at lower (24%) or higher (36%) barrel moisture. The kneading block length of the screw had no significant effect on the canola protein digestibility within the same barrel moisture level. The relationship between the physico-chemical parameters and in vitro digestibility was examined. This study highlighted the complex interplay of extrusion processing variables that affect protein degradation and the interaction of components, with consequent effects on protein digestibility. PMID- 28873735 TI - Physical properties and FTIR analysis of rice-oat flour and maize-oat flour based extruded food products containing olive pomace. AB - Olive pomace, a waste stream from olive oil processing, was fractionated by centrifugation to obtain a supernatant and a flesh-enriched fraction, and freeze dried to obtain a powder. The dried supernatant contained 5.8% moisture, 4.8% protein, 3.5% fat, 3.5% ash, 82.4% carbohydrate (including 17.2% dietary fiber) and polyphenols (2970mg gallic acid equivalents (GAE)/100g). The dried flesh enriched fraction, contained 5.9% moisture, 13.4% protein, 14.2% fat, 3.5% ash, 63.1% carbohydrate (including 42.7% dietary fiber) and polyphenols (1960mg GAE/100g). The extruded products using rice-oat flour or maize-oat flour mixtures as the base were formulated to contain 5% or 10% olive pomace fractions (dry basis). The extruded products with added olive pomace fractions has higher fiber (2-7g/100g) and polyphenol contents (67-161mg GAE/100g) compared to the corresponding mixtures of rice-oat flour base (0.92g/100g fiber, 20mg GAE/100g) or maize-oat flour base (3.2g/100g fiber, 20mg GAE/100g) without olive pomace fractions. Addition of olive pomace fractions reduced the die pressure and specific mechanical energy during extrusion and resulted in lower radial expansion in the extruded product. The impact of the addition of olive pomace fraction on physical characteristics of the extruded product is higher for rice oat flour base than maize-oat flour base. The underlining mechanism was explained by FTIR analysis. FTIR showed that there were significant changes in the carbohydrate components and the structure of the proteins on extrusion, with consequent effects on the expansion and density of the extruded product. This study showed the feasibility of preparing fiber and polyphenol enriched extruded products by incorporation of olive pomace. This shows the potential of recovery and diversion of edible components from waste streams of olive oil processing for formulation of extruded products. PMID- 28873736 TI - Formation and characterization of supramolecular structures of beta-lactoglobulin and lactoferrin proteins. AB - Combination of beta-lactoglobulin (beta-Lg) and lactoferrin (Lf), biomacromolecules derived from bovine whey, was used in the formation of supramolecular structures by thermal gelation technique to adjust the pH. Furthermore, the influence of the molar ratio, temperature, pH, and heating time in the formation of supramolecular structures were also studied. The characterization of the protein supramolecular structures was performed using dynamic light scattering, zeta potential measurements, molecular spectrofluorimetry, and circular dichroism spectroscopy. The thermal behavior of the pure proteins was investigated by differential scanning calorimetry. The protein denaturation temperatures were of around 85 degrees C for the beta-Lg and around 52 degrees C and 85 degrees C (a small portion) for the Lf. The protein molar ratio of 2:1 Lf/beta-Lg was used to form the structures, whose characterization showed that the best conditions of supramolecular structure formation occurred at pH6.5 and at temperatures of 62.5 degrees C. In those conditions, more stable systems with reduced hydrophobic surface and average sizes between 30 and 100nm were generated. The correlation between pH and temperature suggests that the method of preparation of the supramolecular structure affects its size during storage. PMID- 28873737 TI - An integrated strategy to discover Lactobacillus casei group strains for their potential use as aromatic starters. AB - Lactic acid bacteria are commonly used in dairy industries to acidify milk and to enhance the flavour of the end products thanks to their metabolisms. The formation routes of aroma compounds mainly rely on the specific ability of different species and strains to convert precursors derived from carbohydrate and amino acids catabolism. It is well known that the strains largely involved in the aroma formation of the very appreciated Italian long ripened cheeses belong to the Lactobacillus casei group and origin from raw milk. In this study, a spontaneous fermentation of Parmigiano Reggiano raw milks was carried out to isolate new strains potentially usable as adjunctive aromatic starter. For this reason, specific selection criteria were chosen to isolate strains belonging to L. casei, and L. paracasei species. An integrated approach, by mean of impedance microbiology and SPME GC-MS analysis, was applied to investigate the acidifying performance and the production of volatile compounds of seven strains in UHT whole milk. One of these strains, L. paracasei 4341, appear to be the most interesting one from the technological point of view both for its acidifying and aromatic features. This approach could be employed for selection of the aromatic strains to be potentially used as adjunct starter in dairy sector. PMID- 28873738 TI - Impact of volatile composition on the sensorial attributes of dried paprikas. AB - Here we characterised the aroma of smoked, oven-dried, and sun-dried paprikas by sensorial evaluation and analysis of their volatile profiles. The sensorial panel defined smoked paprikas as having an intense, persistent, smoked odour and flavour and the highest acceptability. The oven-dried paprikas had a fruity odour and flavour related with aroma notes to fresh peppers. The sun-dried paprikas were associated with straw aromas and the worse valued. The chemical classes of volatile compounds also defined the paprika types. The smoked paprikas were richer in alcohols, phenols, pyrroles, and pyranones, whereas the oven-dried samples were characterised by their aldehydes and terpenes. The sun-dried paprikas had significantly lower amounts of odorant substances than the smoked and oven-dried paprikas. The intensity, persistence and smokiness descriptors (associated with smoked paprika) were positively associated with phenols and alcohols. Aldehydes were positively correlated with a fruity descriptor, which defined oven-dried paprikas, and negatively correlated with intensity, persistence, smokiness, toasted, and dried pepper descriptors. The descriptor straw, which defined sun-dried paprikas, was negatively correlated with alcohols, phenols, furans, and pyrroles. PMID- 28873739 TI - Effect of symbiotic interaction between a fructooligosaccharide and probiotic on the kinetic fermentation and chemical profile of maize blended rice beverages. AB - There is an important demand for the development of new non-dairy probiotic beverages in the functional food market. This work aimed to develop new fermented beverages from maize and rice. Lactobacillus plantarum CCMA 0743, Torulaspora delbrueckii CCMA 0235, and the commercial probiotic Lactobacillus acidophilus LACA 4, were used as a mixed starter culture. Two prebiotic concentrations, 20 and 50g/L fructooligosaccharide (FOS) were tested. The growth of L. acidophilus LACA 4 was favored by 50g/L FOS and after refrigerated storage at 4 degrees C for 28days, its population remained above 107CFU/mL. Lactic and acetic acids were the main organic acids detected, at around 3.7 and 0.5g/L, respectively. Ethanol was present at <5g/L in non-alcoholic beverages. Fifty-five volatile compounds including acids, alcohols, aldehydes, esters, ketones, pyrazines and others, were detected. The sensorial analysis demonstrated that >50% of consumers liked slightly or liked extremely the beverages (scores from 6-9). Therefore, potential symbiotic cereal beverages were successfully obtained using a mix of lactic acid bacteria and yeast as a starter culture. This is an important step in the commercial production of alternative beverages from common food substrates for consumers. PMID- 28873740 TI - Identification of peptides with antioxidant and antihypertensive capacities by RP HPLC-Q-TOF-MS in dry fermented camel sausages inoculated with different starter cultures and ripening times. AB - Low molecular weight peptides are produced during meat fermentation. They contribute to generate flavor compounds but they can also exert certain bioactivities. The aim of this work was to evaluate, for the first time, the generation of bioactive peptides during the preparation of dry fermented camel sausages and to study the influence of the ripening time and the starter culture on bacteria growing, peptide concentration and size, and antioxidant and antihypertensive capacities of peptides. Camel meat sausages inoculated with different starter bacteria and non-inoculated were ripened up to 28days. Results demonstrated that bacteria population, peptide concentration, and peptide size were affected by the ripening time and the inoculated bacteria. Moreover, the ripening process resulted in an increasing antioxidant and antihypertensive capacity showing the highest bioactivities in fractions with peptides below 3kDa. Peptides in these fractions were identified by RP-HPLC-Q-TOF-MS analysis. Identified peptides showed common features with peptides with antioxidant or antihypertensive activity. PMID- 28873742 TI - Experimental study of physical and rheological properties of grape juice using different temperatures and concentrations. Part I: Cabernet Sauvignon. AB - The effect of the temperature and concentration on rheological behavior of Cabernet Sauvignon juice concentrates was assessed using a rheometer over a wide range of temperature (1-66 degrees C) and concentrations (13.6-45.0Brix) at shear rates of 0.84-212.1 1/s. The Ostwald-De Waele was the best rheological model fitted the data (R2=0.99957 and relative error=7.77%). The Cabernet Sauvignon juice concentrates presented a non-Newtonian pseudoplastic behavior (n<1). The consistency levels were significantly reduced with the increase of temperature and increased with the increase of the concentrations. The flow activation energy ranged from 28.87 (45.0Brix) to 38.05KJ/mol (37.0Brix) with a R2=0.9798 for both cases. Density and specific heat were influenced by both temperature and concentration; however, thermal conductivity was only influenced by concentration. The Cabernet Sauvignon juice concentrates will be useful as wine chaptalization agent in future studies. PMID- 28873741 TI - Hibiscus sabdariffa L. as a source of nutrients, bioactive compounds and colouring agents. AB - The nutritional and bioactive composition of plants have aroused much interest not only among scientists, but also in people's daily lives. Apart from the health benefits, plants are a source of pigments that can be used as natural food colorants. In this work, the nutritional composition of Hibiscus sabdariffa L. was analysed, as well as its bioactive compounds and natural pigments. Glucose (sugar), malic acid (organic acid), alpha-tocopherol (tocopherol) and linoleic acid (fatty acid) were the major constituents in the corresponding classes. 5 (Hydroxymethyl) furfural was the most abundant non-anthocyanin compound, while delphinidin-3-O-sambubioside was the major anthocyanin both in its hydroethanolic extract and infusion. H. sabdariffa extracts showed antioxidant and antimicrobial activities, highlighting that the hydroethanol extract presents not only lipid peroxidation inhibition capacity, but also bactericidal/fungicidal inhibition ability for all the bacteria and fungi tested. Furthermore, both extracts revealed the absence of toxicity using porcine primary liver cells. The studied plant species was thus not only interesting for nutritional purposes but also for bioactive and colouring applications in food, cosmetic and pharmaceutical industries. PMID- 28873743 TI - Inhibition of tyrosinase by cherimoya pericarp proanthocyanidins: Structural characterization, inhibitory activity and mechanism. AB - In this study, the structure of proanthocyanidins purified from cherimoya (Annona squamosa) pericarp was analyzed by ESI-QTOF-MS and HPLC analyses. The result indicated that these compounds were procyanidin-type proanthocyanidins, consisting mainly of (epi)catechin units linked b y B-type interflavan bonds. The analyses of enzymology showed that the activities of monophenolase and diphenolase of tyrosinase could be powerfully inhibited by the proanthocyanidins. Further researches on the inhibition mechanism demonstrated that they were reversible and competitive inhibitors with the KI value of 27.1+/-3.1MUg/mL. These inhibitors quenched the fluorescence of tyrosinase through a static quenching mechanism and spontaneously formed proanthocyanidins-enzyme complex. Fluorescence changes of proanthocyanidins in the presence of copper ion suggested that the interactions could reduce the fluorescence intensity of these polymers and the molecular docking analysis revealed that copper irons of the enzyme could be chelated by adjacent hydroxyl groups on the B ring of proanthocyanidins. Moreover, proanthocyanidins were proved to be efficient quencher of substrates. These results would lay scientific foundation for their farther application in food and medicine industry. PMID- 28873744 TI - Non-destructive techniques for the detection of fungal infection in cereal grains. AB - Infection of cereal grains by fungi is a serious problem worldwide. Depending on the environmental conditions, cereal grains may be colonised by different species of fungi. These fungi cause reduction in yield, quality and nutritional value of the grain; and of major concern is their production of mycotoxins which are harmful to both humans and animals. Early detection of fungal contamination is an essential control measure for ensuring storage longevity and food safety. Conventional methods for detection of fungal infection, such as culture and colony techniques or immunological methods are either slow, labour intensive or difficult to automate. In recent years, there has been an increasing need to develop simple, rapid, non-destructive methods for early detection of fungal infection and mycotoxins contamination in cereal grains. Methods such as near infrared (NIR) spectroscopy, NIR hyperspectral imaging, and electronic nose were evaluated for these purposes. This paper reviews the different non-destructive techniques that have been considered thus far for detection of fungal infection and mycotoxins in cereal grains, including their principles, application and limitations. PMID- 28873745 TI - Study of the influence of varietal amino acid profiles on the polyfunctional mercaptans released from their precursors. AB - Polyfunctional mercaptans such as 4-mercapto-4-methyl-2-pentanone, 3 mercaptohexanol and 3-mercaptohexyl acetate contribute strongly to the varietal aroma of wines. These compounds are released during alcoholic fermentation from their precursors and their concentration is strongly linked to the grape variety. The aim of this work was to determine the effect of nine different amino acid profiles of grape varieties on the release of these polyfunctional mercaptans and on the consumption of their precursors as well as to determine which are the preferred precursors. A set-up of fermentations of synthetic must was prepared, which simulated the amino acid profiles of nine different grape varieties, containing known amounts of polyfunctional mercaptan precursors as well as the elements necessary for the yeast metabolism. The yeast assimilable nitrogen was adjusted in percentage to reach 150mgN/L in all the fermentations. Polyfunctional mercaptans and their precursors were analyzed in the final wine by gas chromatography coupled to mass spectrometry with negative chemical ionization and ultrahigh liquid performance chromatography coupled to mass spectrometry, respectively. The results showed significant differences in the release of these polyfunctional mercaptans as well as in the consumption of their precursors according to the amino acid profile. Moreover, it was observed that the preferred precursor of 4-mercapto-4-methyl-2-pentanone was its cysteinylated precursor. These results suggest that the amount of the amino acids as well as the ratio between them could modify the amount of polyfunctional mercaptans released. This could be a tool for the wine industry to vary the aromatic profile of wines by increasing or decreasing these volatile thiols. PMID- 28873746 TI - White-fruited strawberry genotypes are not per se hypoallergenic. AB - The strawberry fruit Fra a 1-proteins are homologues of the major birch pollen allergen Bet v 1 and have essential biological functions in pigment formation during fruit ripening. Patients affected by allergy against birch pollen tolerated fruits of a naturally occurring white-fruited F.*ananassa genotype, which showed reduced levels of Fra a 1 proteins along with enzymes of the anthocyanin pigment pathway. We evaluated the cross-reactive allergenic potential of a number of naturally occurring white- and red-fruited strawberry varieties to detect genotypes with low allergenic reactivity, whose fruit might be tolerated by patients with mild allergy. Protein extracts of 51 different strawberry varieties (Fragaria*ananassa, F. vesca, and F. nilgerensis) were screened by Western blot analysis with a polyclonal Fra a 1.02 antibody. Besides, activation of basophils of eight atopic patients allergic to birch pollen were studied using Bet v 1a and different concentrations of 15 selected strawberry protein extracts out of the 51 strawberry genotypes. Median percentages of activated basophils stimulated by extracts from white- and red-fruited genotypes ranged from 36 to 84% and 44 to 76%, respectively indicating that white-fruited strawberry are not per se hypoallergenic. Protein extracts from white-fruited F. vesca cv. Yellow Wonder showed the lowest cross-reactivity but high biological variability. The knowledge about the allergenic potential of different strawberry genotypes may help to improve food safety and can serve as starting point for the development of red-fruited hypoallergenic strawberry cultivars. PMID- 28873748 TI - Chemical quality and oxidative stability of extra virgin olive oils from San Juan province (Argentina). AB - This study provides information about the chemical quality (quality indices, fatty acid profile, total polyphenols (PPs), tocopherols and pigments) and oxidative stability index (OSI) of virgin olive oils of Arbequina, Changlot Real and Coratina cultivars (San Juan province, Argentina). The influence of the cultivar and the effect of earlier harvest dates on the yields (OY), quality and OSI of the oils were also evaluated. All the oils were classified as extra virgin. The OY (L/100kg) averaged: Arbequina=13.2, Changlot Real=21.3, Coratina=18.3. The oleic acid (O) percentage, oleic to linoleic plus linolenic ratio [O/(L+Ln)], PPs and OSI were highly dependent on cultivar (Arbequina0.90) was proposed to simulate the rate of enzyme inactivation under isobaric-isothermal conditions as a function of pressure and temperature. PMID- 28873764 TI - Thermal inactivation of Listeria monocytogenes and Salmonella spp. in sous-vide processed marinated chicken breast. AB - The heat resistance of a cocktail of five Salmonella strains and five L. monocytogenes strains was determined in teriyaki-marinated chicken breasts. Inoculated meat, packaged in bags, were completely immersed in a circulating water bath and cooked to a final temperature of 55, 57.5 or 60 degrees C in 1h, and then held for predetermined times. The surviving Salmonella and L. monocytogenes cells were enumerated by surface plating on XLD agar and Palcam agar, respectively. D-values, determined by linear regression, of Salmonella in chicken breast ranged from 47.65min at 55 degrees C to 7.48min at 60 degrees C; the values for L. monocytogenes ranged from 54.81min at 55 degrees C to 10.39min at 60 degrees C. Marination rendered the pathogen more sensitive to the lethal effect of heat. The results of this study will assist the food industry in ensuring microbiological safety of sous-vide processed marinated chicken breasts. PMID- 28873765 TI - Greek PDO saffron authentication studies using species specific molecular markers. AB - Saffron, the spice produced from the red stigmas of the flower of Crocus sativus L. is a frequent target of fraud and mislabeling practices that cannot be fully traced using the ISO 3632 trade standard specifications and test methods. A molecular approach is proposed herein as a promising branding strategy for the authentication of highly esteemed saffron brands such as the Greek Protected Designation of Origin (PDO) "Krokos Kozanis". Specific ISSR (inter-simple sequence repeat) markers were used to assess for the first time, the within species variability of several populations of C. sativus L. from the cultivation area of "Krokos Kozanis" as well as the potential differences with the band pattern produced by other Crocus species. Then, species-specific markers were developed taking advantage of an advanced molecular technique such as the HRM analysis coupled with universal DNA barcoding regions (trnL) (Bar-HRM) and applied to saffron admixtures with some of the most common plant adulterants (Calendula officinalis, Carthamus tinctorius, Gardenia jasminoides, Zea mays and Curcuma longa). The sensitivity of the procedure was tested for turmeric as a case study whereas HPLC-fluorescence determination of secondary metabolites was also employed for comparison. The overall results indicated that the Bar-HRM approach is quite effective in terms of specificity and sensitivity. Its effectiveness regarding the detection of turmeric was comparable to that of a conventional HPLC method (0.5% vs 1.0%, w/w). Yet, the proposed DNA-based method is much faster, cost-effective and can be used even by non-geneticists, in any laboratory having access to an HRM-capable real-time PCR instrumentation. It can be, thus, regarded as a strong analytical tool in saffron authentication studies. PMID- 28873766 TI - Occurrence and phenotypic and molecular characterization of Listeriamonocytogenes and Salmonella spp. in slaughterhouses in southern Brazil. AB - This study addressed the occurrence of Listeriamonocytogenes and Salmonella spp. in bovine carcasses at two slaughterhouses in southern Brazil. Then, the antimicrobial susceptibility profile and the virulence potential of the isolates were evaluated. Two hundred carcasses were sampled at four steps of the slaughter process, with L. monocytogenes being isolated in 12 and Salmonella spp. in 17 carcasses. All L. monocytogenes isolates carried the hlyA, prfA, plcA, plcB, actA, iap, mpl, inlA, inlB, inlC, and inlJ genes, while Salmonella spp. carried invA and hilA. Among the L. monocytogenes isolates, all of them presented virulence determinants and one showed multi-drug resistance. In relationship to Salmonella spp. isolates, many serogroups frequently related to outbreaks of foodborne diseases were identified and four isolates showed resistance to more than one antimicrobial agent. This data highlights the importance of a rigid hygienic-sanitary control during the slaughter process to reduce the risk of cross-contamination and lower the consumer exposure to L. monocytogenes and Salmonella spp. infections. PMID- 28873767 TI - Comparing Recent Reviews About Touchscreens for Dementia with Lessons Learnt from the Field. AB - Conclusions were synthesised from recent reviews on (touchscreen)technologies and people with dementia and lessons learnt, using these devices in projects in the UK, the Netherlands and Canada. The combined findings provide a strong basis for defining new strategies for exploiting touchscreen technology for people with dementia. PMID- 28873768 TI - Digital Support for Persons with Cognitive Impairment. AB - Cognitive impairment may cause difficulties in planning and initiating daily activities, as well as remembering to do what is scheduled. This study investigates the effectiveness of an interactive web-based mobile reminder calendar that sends text messages to the users mobile phone as support in everyday life, for persons with cognitive impairment due to neurological injury/diagnoses. The study has a randomised controlled trail design with data collection at baseline and at follow-up sessions after two and four months. Data collection started in August 2016 and continues until December 2017. The interactive web-based mobile reminder calendar may give the needed support to remind the person and thus increase the ability to perform activities and to be independence in everyday life. Preliminary results will be presented regarding what effect the interactive web-based mobile reminder calendar have for the participants performance of everyday life activities as well as perceived quality of life. PMID- 28873769 TI - Reconnecting People with Dementia by Using the Interactive Instrument CRDL. AB - Dementia is a progressive brain disease with a decline in functioning over time. CRDL (pronounced as Cradle) is an interactive instrument, developed to stimulate communication between users through sound and touch. It recognises the intention of the touch (tickle, holding, grabbing, fondling, kneading, and tapping) and will adjust the sound accordingly. This qualitative observational study explores whether this innovative product has the potential to be used in elderly care to create a moment of interaction between the person with dementia and someone else or multiple others. In a nursing home facility in the south of the Netherlands CRDL has been studied in one-to-one interaction between a person with dementia and a member of their family, a healthcare professional or a recreational therapist (n = 7), and group interaction between several people with dementia and a healthcare professional or a recreational therapist (n = 5). In the one-to-one interaction study professionals and family members reported that the interaction with CRDL and the person with dementia was a pleasant experience. They also mentioned that it felt familiar and they had the feeling that they were in better contact with the person with dementia. The exit interviews with the professionals and family members indicate that CRDL has the potential to encourage the interaction between the healthcare professional, recreational therapist or family member and the person with dementia. Healthcare professionals and recreational therapists who used CRDL in a group interaction session reported participants were generally fascinated by the object itself, but needed active encouragement to interact. The role of the healthcare professional, recreational therapist or family member seems very important. PMID- 28873770 TI - Independent Living Functions for the Elderly (IN-LIFE): Supporting Communication in Dementia. AB - Independent Living Functions for the Elderly (IN-LIFE) is a 3 year multidisciplinary, multisite European project that aims to prolong and support independent living for people with cognitive impairments, through (ICT) services. Sheffield is one of six research sites and is focused on enhancing communication and conversations using touch screen computers. PMID- 28873771 TI - Using Surface Table Computers to Promote the Well-Being of People with Dementia. AB - As the demographic change progresses, dementia is going to become a prevalent condition in many countries. In order to keep the Quality of Life (QoL) of People with Dementia (PwD) on a steady level, Assistive Technologies (AT) implemented on table-sized Surface Computers (SC) that promote playful and/or reminiscence triggering activities turn out to be valuable tools for dementia care. This article gives an overview over two similar multimedia-based AT systems implemented on Microsoft PixelSense SCs and field-tested in dementia care institutions. The observations indicate that both systems can trigger positive emotions and activities as well as memories. PMID- 28873772 TI - Home Testing of a Digital Prompter for People with Dementia. AB - This technology evaluation study assessed a personalised digital prompter designed for people with dementia, by trialling its use in the home by people with dementia and their carers. Technology based prompting may be used to support people with dementia to complete multi-step tasks in the home, provided that suitable tasks can be chosen and that a carer is able to load appropriate task steps onto the prompter. A prompter was developed specifically for this purpose, along with a detailed guidance manual. Twelve participants with mild or moderate dementia carried out cognitive tests and their carers completed carer burden and carer competence scales. Each pair attended a training session with a researcher and were provided with the prompter and instruction manual. The prompter was trialled at home for four weeks after a one-week familiarisation period, for use with a simple set task and one or two tasks chosen by the participants. Semi structured interviews were used to capture the views of the participants at the start and end of the home testing, and to set and evaluate goals. Chosen tasks included preparing simple food and drinks, and using home appliances including coffee machines and television remote controls. There was a weak correlation between greater goal success for the participants and the carer goal success, number letter switching within the D-KEFS and ACE-III score. A thematic analysis of the interviews revealed three core themes relating to familiarity with technology, utility of the prompter and the cost versus benefit in terms of the effort required to set up the prompter. Factors influencing success could be grouped into: participants' motivation and capability; the design of the prompter; and the details of the task being carried out. Barriers to success included the difficulty of choosing a suitable task and the effort required to break down a task in to appropriate steps. All of the participants with dementia could follow the steps on the prompter, and all of the carers were able to choose, breakdown and load at least one task onto the prompter during the training session, but successful use in the home was varied because of the increased complexity of the home context. Changes to the hardware, software and manual were made in response to the data gathered during the study, in readiness for the planned further testing. PMID- 28873773 TI - Mobile Delivery of Health Information for People with Mild Cognitive Impairment. AB - The design of a smartphone application (app) for promoting healthy lifestyle choices has been investigated for people with mild cognitive impairment. The app was designed to provide health-related messages and assist users to keep track of activities such as walking, eating and drinking water. A reward scheme with gold, silver and bronze awards was incorporated as a means of assisting user motivation. Responses to the app and user feedback were gathered for purposes of evaluation and improvement. Outcomes indicate that the approach has some potential and could have good implications for encouraging positive health related behaviour change in this population, hence prompting further investigation and development of the concept. PMID- 28873774 TI - Interacting with Dementia: The MARIO Approach. AB - MARIO is a companion robot that aims to help people with dementia (PWD) to battle isolation and loneliness by enabling them to stay socially active by providing a number of applications focused on hobbies (music, movies, etc), staying engaged with communities (reading headlines, reading local twitter feeds etc.) and staying connected with family and friends (telephoning them, reading their news from twitter, etc.). This paper presents the results from the initial trials of MARIO interacting with PWD involving a limited set of applications. It confirms some of the challenges hypothesized at the outset of the study and provides guidelines for future development work. PMID- 28873775 TI - Citizen and Stakeholder Perspectives About Approaches to Enhance Equitable Access to Assistive Technologies for Older Adults. AB - Assistive technologies play an important role in promoting healthy aging, independent living and aging-in-place, yet many experience unmet needs. This project reports on three citizen panels and a stakeholder dialogue convened in Canada to spark action towards enhancing equitable access to assistive technologies for older adults. PMID- 28873776 TI - Cross-Cultural Adaptation of a Decision Support System for AT Selection. AB - Older adults may benefit from decision support systems for the selection of assistive technologies. We present a case study cross-cultural adaptation in Canada of a system developed in the United Kingdom. We describe a conceptual framework for examining challenges with cultural and literacy issues and ways to address them. PMID- 28873777 TI - Ethical Issues Related to IT Adoption by Elderly Persons with Cognitive Impairments. AB - Ethical issues arise when the risks and benefits of technology use are unclear or controversial, or their access inequitable. This paper presents a preliminary framework for understanding ethical issues related to IT development and adoption by elderly persons with cognitive impairments and their caregivers. The development of the framework relied on a hybrid qualitative approach that draws on several data sources: 1) systematic literature review, 2) focus groups with IT users, and 3) a reflexive researcher-learning diary.Preliminary findings were synthesized into a coherent model that views IT adoption as the outcome of complex interactions between different factors: 1) Personal factors that include the cognitive abilities of the users, as well as their physical and sensory limitations, and 2) Environmental factors that are related to the technology, the caregivers, and the support networks of the user with cognitive impairment. Findings from this project will help better understand, balance, and responsibly address the competing ethical issues at play in technology development and adoption by elderly persons with cognitive impairments and their caregivers. PMID- 28873778 TI - Lived Experience, Stakeholder Evaluation and the Participatory Design of Assisted Living Technology. AB - This paper presents the theoretical and methodological framework underpinning the advancement of new technology enabling seniors domicile in residential homes to live with independence, quality of life and dignity. In addition, it presents the preliminary findings of this research including the emerging user interface design solution. PMID- 28873779 TI - ICT Inexperienced Elderlies: What Would Attract Elderlies to Use Items of Technology? AB - This paper presents the findings of the first end-user research study with seniors who are not familiar with operating ICT devices, executed as part of the EU-Active and Assisted Living research project Kith & Kin. This project aims at developing an ICT device for these seniors by building on their needs and real capabilities, encouraging communication and fostering social inclusion. PMID- 28873781 TI - Wireless as Enabler of Innovation in 21. AB - This paper overviews new and emerging wireless technologies that could positively impact on the lives of the elderly or disabled, as Social Care users of Assistive Technology (AT) for 'independent living'. Novel Internet of Things (IoT) radio systems and wireless locating systems being researched at The University of Sheffield are discussed in the context of Social Care technology use-cases. PMID- 28873780 TI - Introducing an AT Passport: A Key to Managing Transitions Across the Lifespan. AB - The service delivery of Assistive Technology for access to information and communications technology is frequently fragmented and inconsistent as evidenced by experience in the US and much of Europe (AAATE 2012). AT users can experience hiatuses in their access to appropriate assistive technologies as they transition from home to education, to employment and in the community. An AT Passport can provide a record of Assistive Technology requirement and use across the lifespan. PMID- 28873782 TI - Writing Good-Quality Assistive Technology Assessment Reports. AB - The study reported in this paper developed criteria and guidelines for writing up a good-quality AT Assessment Report - a document which is often required to activate an assistive technology intervention for an individual client. The Report should provide precise recommendations about the assistive solutions that best meet the client's needs, explain the underlying reasoning, provide evidence of appropriateness for the funding agency and set the baseline for later measurement of the outcomes of the intervention. Within this study, forty-eight clients with severe disability conditions were recruited in nine rehabilitation Centers in various regions of Italy. They were assessed for assistive solutions by their rehabilitation teams according to a common protocol; assessment Reports were produced for each client according to the same template, and individual AT interventions were activated following the recommendations. Then the Reports underwent a blind peer-review exercise involving over fifty professionals, who evaluated their quality against ten criteria; based on the findings, the template of the AT Assessment Report was revised and good-practice guidelines were inferred for the contents of each field. Now the final version is freely downloadable and is being used routinely in the Centers that participated in the study. PMID- 28873783 TI - Observing Remote Prescription of AT. AB - A lack of widely accepted guidelines/protocols for remote prescription of assistive technology is noted. This paper reports observations from attempts to use web based videoconferencing with embedded tools for the provision of assistive technology to children with complex needs. PMID- 28873784 TI - Development of National Guidelines for the Ground Rules to Lending Assistive Technology Devices in Finland. AB - Central Hospital Districts (CHD) in Finland provide most of the Assistive Technology Device Services (ATDS). ATDSs have been developing their work and unifying their practices regionally. Each of these 20 CHDs have their own guidelines for the ground rules for lending assistive technology devices. These ground rules include principles of ATD Services and lending rules for different device groups classified by ISO 9999 standard. There has been a growing pressure to unify the practices of ATDS nationally, because of a growing need for devices and economy. A project to unify National Guidelines was set up in spring 2016. There were four different review rounds among CHD ATD services and patient organizations. The Ground Rules will be published in 2017. PMID- 28873785 TI - Access Visits Using Video Communication. AB - An online video communication system is presented that enables Occupational Therapists (OTs) assess patient homes for assistive technology needs before acute care discharge to ensure appropriate independence and recovery conditions. Explorations under multiple conditions revealed perspectives from OTs and volunteer facilitators. Preliminary key findings and insights are reported. PMID- 28873786 TI - Remote Care Technology: A Systematic Overview. AB - The present study was based on a systematic review of reviews and meta-analyses and aimed to identify technologies being used to provide home monitoring to support older adults with chronic diseases and to promote their empowerment, as well as to identify how these technologies impact health related outcomes. PMID- 28873787 TI - The Need for Information on Standards on eAccessibility&eInclusion - Based on the Experience of the EU-Project IN LIFE. AB - Recent investigations in several EU-projects, incl. IN LIFE revealed that experts in the field of eAccessibility & eInclusion (eAcc&eIncl) - but also general ICT developers, decision makers in industry and administration - are quite unaware of the importance of standards for interoperability and sustainability of ICT solutions. Especially, if persons with disabilities (PwD) are concerned, system development and the design of services can become unnecessarily costly. For accessibility in general and eAcc&eIncl in particular, knowing about pertinent standards is becoming an asset of personal competencies of experts and decision makers, and particularly benefit small enterprises. Given the complex world of standardization and the multitude of standards developing organizations (SDOs) easy access to information on standards is critical. PMID- 28873788 TI - Validation of European Portuguese Version of the Kwazo Instrument. AB - Kwazo instrument was designed to assess the customer's satisfaction with prescription and attribution services of assistive technology. This paper presents the cross-cultural translation and validation of the European Portuguese version of the Kwazo, whose psychometric proprieties were assessed by customers of rehabilitation facilities of North and Centre of Portugal. PMID- 28873789 TI - Effectiveness of Service Dogs for Veterans with PTSD: Preliminary Outcomes. AB - Limited scientific evidence on the effectiveness of psychiatric service dogs used by Veterans with post-traumatic stress disorder (PTSD) is available. This study investigated their short-term effectiveness among 15 Canadian veterans who received a first psychiatric service dog. Preliminary results suggest potential beneficial effects at 3 months on the psychiatric symptoms. PMID- 28873790 TI - Measuring AT Usability with the Modified System Usability Scale (SUS). AB - The modified System Usability Scale (SUS) is a widely used generic measure of product usability. This study concerns the usability of mobile shower commodes using correlations between the SUS and AT device-specific measures. Results suggest the modified SUS, and corresponding adjective-anchored rating scale, are appropriate for measuring MSC usability, and have potential for use with other AT devices. PMID- 28873791 TI - Dissemination Strategy of Ambient Assisted Living Project Experience. AB - In an emerging research area, it is imperative that best practice strategies are developed with regard to dissemination of the associated research findings. This paper is a review of strategic methods used to disseminate the results of ongoing research on two ambient assisted living technologies that are being developed with funding. PMID- 28873792 TI - Remote Health Care Provision in Care Homes. AB - A survey was developed to map provision, knowledge, attitudes and views towards videoconferencing in care homes in Yorkshire and The Humber. The survey was sent to 859 care homes, with a 14% response rate. Twelve homes reported using videoconferencing. Non-users appeared skeptical, managers using the system reported improvements in outcomes. PMID- 28873793 TI - Smart Clothing for Falls Protection and Detection: User-Centred Co-Design and Feasibility Study. AB - The prevalence and impact of hip fractures on the health and wealth of nations is a global problem and source of health inequalities. This paper reports on the co design and feasibility testing of a new range of protective, smart clothing. The feasibility of research in a population of older adults in supported living is explored, as are the conceptualisation and measurement of adherence. PMID- 28873794 TI - Perceptions and Use of Technology to Support Older Adults with Multimorbidity. AB - Digital technologies hold great potential to improve and advance home based integrated care for older people living with multiple chronic health conditions. In this paper, we present the results of a user requirement study for a planned digital integrated care system, based on the experiences and needs of key stakeholders. We present rich, multi-stakeholder, qualitative data on the perceptions and use of technology among older people with multiple chronic health conditions and their key support actors. We have outlined our future work for the design of the system, which will involve continuous stakeholder engagement through a user-centred co-design method. PMID- 28873795 TI - Obstacle: A Tool to Assess the Home Environment Designed for All. AB - INTRODUCTION: Elderly prefer to live as long as possible independent in their own home. The occupational therapist can play an important role in this, for instance by giving advice regarding home adaptations or the use of assistive technology in order for the person to function more independently. There is need for a tool that allow to screen the home easily and thorough. AIM: The aim of the study is to develop a screening tool that meets the requirements of occupational therapists to assess the home environment for persons in order to facilitate independent living. METHODS: The screening tool 'Obstacle' was developed and tested in 3 phases within an iterative way using a user-centred design. Firstly, crucial items based on literature and expertise of researchers and occupational therapists in the field were identified and the Obstacle paper version and manual was developed. Secondly, the tool was adapted and digitalised to be used on a tablet. Thirdly, a mini-version of Obstacle was created, being less time consuming and usable as a signalling tool to determine the need for applying the extensive version. The tool was tested by screening homes of 96 elderly in total. Additionally, opinions of 5 elderly, 5 informal caregivers and 5 professional caregivers were gathered with a focus group. RESULTS: The digital screening tool Obstacle is developed and includes 13 rooms to be screened with specific items for each room to be scored. Obstacle was judged very useful by occupational therapists. CONCLUSION: The novelty of this tool is the focus on independent living and the starting point of occupational performance, reduce the risk of falling and facilitating in advising the optimal home adaptations. PMID- 28873797 TI - The Role of Haptics in User Input for People with Motor and Cognitive Impairments. AB - Most input devices, also traditional ones like keyboard and mouse involve at least a certain amount of haptic experience. For instance, they require direct physical contact between user and device and provide direct haptic feedback (e.g., through the physical resistance of a key). However, in the past years, also touchless input devices and techniques gained broader attention as they e.g., allow for a restriction of physical boundaries that limit the possible range of user input activities. This paper discusses the role of haptics in user input with a particular focus on the needs of people with impairments and presents the results of a study comparing three input devices, each involving a different amount of haptic experience. PMID- 28873796 TI - ShopComm: Community-Supported Online Shopping for Older Adults. AB - The United Kingdom has an ageing population whose members experience significant life transitions as they grow older, for example, losing mobility due to deteriorating health. For these adults, digital technology has the potential to sustain their independence and improve their quality of life. However older adults can be reluctant to use digital solutions. In this paper, we review a local charity providing a grocery shopping service for older adults who are unable to go themselves. We explore how older adults perceive the benefits and drawbacks of both physical and digital shopping. Using these insights, we designed ShopComm to enable and support older adults with mobility impairments to shop online. PMID- 28873798 TI - Inclusive Smartphone Interface Design in Context: Co(Re)designing the PIS. AB - User-context optimises smartphone interface-design. Neglect of user-context during development, delays or prevents marginalised-consumer benefit. Working with People with Learning Disability (PWLD) to develop interfaces refined by communication-need will improve User-Experience (UX). In research, a Participant Information Sheet (PIS) discloses planned study-activity. This paper explains co creation of a PIS based on communication-need of PWLD. PMID- 28873799 TI - Human Behavior Drift Detection in a Smart Home Environment. AB - The proposed system aims at elderly people independent living by providing an early indicator of habits changes which might be relevant for a diagnosis of diseases. It relies on Hidden Markov Model to describe the behavior observing sensors data, while Likelihood Ratio Test gives the variation within different time periods. PMID- 28873800 TI - Evaluation Method for an App Involving Kitchen Activities. AB - An app, developed for the national Italian project "Design for all", is evaluated here. This app supports the user in most of his/her cooking activities. The evaluation process integrates different technologies, such as expert interview, cognitive walkthrough and focus group, to consider different aspects that include, but are not limited to, usability and accessibility. PMID- 28873801 TI - Quantitative Indicators for Behaviour Drift Detection from Home Automation Data. AB - Smart Homes diffusion provides an opportunity to implement elderly monitoring, extending seniors' independence and avoiding unnecessary assistance costs. Information concerning the inhabitant behaviour is contained in home automation data, and can be extracted by means of quantitative indicators. The application of such approach proves it can evidence behaviour changes. PMID- 28873802 TI - Electronic Assisted Living Technology: Interim Systematic Review Results - The Evidence for Creative Methodologies. AB - Despite reported benefits of creative methodologies for the design and development of electronic Assisted Living Technologies (eALT), there exists a divide between design and health research, leaving health researchers wishing to pursue creative methods uninformed with regards choice of appropriate methods. This paper describes interim and emerging results from a systematic review which aimed to explore the value of creative methodologies for the design and development of eALT which may form part of the solution to the challenges of the ageing population. PMID- 28873803 TI - Exploring the Use of Technology for Active Aging and Thriving. AB - The study explores how older adults with limited digital experience become users of tablet computers (iPad) with Internet access, and how the tablet computers become part of their daily life facilitating active aging and thriving. Volunteer adolescents were mobilised to teach and follow up the participants regularly. PMID- 28873804 TI - A Study on Evaluations of Living Spaces by Caregivers for Elderly People. AB - Caregivers who provide nursing-care visits to the elderly learn to notice changes in the physical and mental functions of residents by looking for signs of disorder in living spaces and changes in the orderliness of living spaces. In this research, to understand what draws caregiver attention and how they evaluate them, 15 caregivers are interviewed and asked to evaluate images of 33 living spaces. The results show variances in evaluations concerning the degree of clutter of living spaces even among experienced caregivers, but that it is possible to classify the degree of clutter using a two-axis scale. PMID- 28873805 TI - The Application of CSCL Scripts to Support Teaching and Learning for Children with Intellectual Disabilities. AB - This paper describes the application of collaboration scripts to guide social interaction behaviours of children with intellectual disabilities. The use of such scripts demonstrate potential as a means of creating CSCL environments that can be used to provide children with communication and social interaction impairments with a platform for learning and practicing such skills in a meaningful social context. PMID- 28873806 TI - User Centered Reading Intervention for Individuals with Autism and Intellectual Disability. AB - Individuals with autism and intellectual disability (ID) have complex learning needs and often have difficulty in acquiring reading comprehension skills using conventional teaching tools. Evidence based reading interventions for these learners and the use of assistive technology and application of behaviour analysis to develop user-centered teaching is discussed in this paper. PMID- 28873807 TI - Improving the Quality of Life of Persons with Intellectual Disabilities Through ICTs. AB - Removing barriers to accessing Information and Communication Technologies (ICTs) by Persons with Intellectual Disabilities (IDPs) is crucial. Being excluded from ICTs implies being shut down from the information society, but also from accessing essential public services, as well as from the opportunity of living an independent life. The IdICT project has the general objective of increasing the competences of IDPs, their families and the professionals that work with them to exploit ICTs with a Quality of Life approach. To do that, a training platform and a training program has been developed and tested by IDPs, relatives and professionals in six European Countries. PMID- 28873808 TI - Risks of Stigmatisation Resulting from Assistive Technologies for People with Autism Spectrum Disorder. AB - This short paper presents a philosophical analysis of the ways in which assistive technologies (ATs) can result in the stigmatisation of users with ASD. It frames the discussion in the context of the medical and social models of disability and outlines a number of ethical risks that might arise from the project of developing ATs. PMID- 28873809 TI - E-Inclusion: Social Inclusion of Young Adults with Intellectual Disabilities - A Participatory Design. AB - By examining the role of digital tools and social media, this paper discusses an innovative prospective research study to enhance social inclusion of young adults with intellectual disabilities (ID). The paper begins with an overview of how individuals with disabilities have historically been excluded from society based on limited access and minimal opportunities afforded to them. Next, the paper presents the caveats that may hinder the improvement of social inclusion of young adults with ID and the oversights when developing digital technologies. Details about a prospective intervention research study are described that include a mobile application and a social media component. Finally, implications for research and practice are highlighted to emphasize the fundamental call for an insightful deliberation of these caveats that needs to be addressed in the design of a research study of this nature. PMID- 28873810 TI - Managing Weight: What Do People with an Intellectual Disability Want from Mobile Technology? AB - Obesity is a significant health challenge. People with Intellectual Disability (ID) are particularly vulnerable to developing obesity. Mobile technology has been developed to support the management of weight and obesity in the form of apps, although not with people with an ID in mind. As a result existing off-the shelf weight management apps currently available may not be functional in supporting weight reduction within this population. This paper presents the results of consultations with people with ID regarding weight management, comfort with mobile technology and desired characteristics in apps designed for people with ID that target weight management. PMID- 28873811 TI - "Sliders" Android Game - Improving Logical Skills of People with Disabilities. AB - Logic is part of our everyday life. However, there are some cases where people have difficulties using deductive reasoning. The aim of this work is to help people with mild intellectual disability or learning disability to learn the basis of logical thinking. We developed an application on Android operating system to improve logical thinking. PMID- 28873812 TI - Android-Based Daily Routine Organizing Application for Elementary School Students Living with ASD. AB - Today, more and more children with Autism Spectrum disorder are diagnosed, which means that around 1% of the population is concerned. Most of the concerned can acquire daily routine tasks by a bit of help and can fit in the society. As Besio et al. said, "...play is an instinctive need for both humans....In children with disabilities, depending on the type of functional limitations, the spontaneity of play is lost and the activity becomes problematic. Children with cognitive and intellectual impairments have a difficulties in communication, social interactions,....Since play is also a window for children's cognitive development, children may be perceived as more developmentally delayed than they actually are, leading to reduce expectations on the part of adults." The aim of the authors was to create an Android based application which helps 6-9 year old children living with Autism Spectrum disorder to learn everyday tasks and acquire everyday routine. PMID- 28873813 TI - Designing Out the Play: Accessibility and Playfulness in Inclusive Play. AB - Play is an important part of child development, yet disabled children are often excluded from the opportunity to play, either due to lack of accessible toys and games, or social pressures. This paper presents a case study reflecting on the development of Button Bash: a switch accessible game intended to encourage inclusive play between disabled and non-disabled children. In particular, the paper focuses on how changes intended to make the game more accessible tended to make it less playful, and reflects on the relationship between playfulness and accessibility. PMID- 28873814 TI - Interactive Games with an Assistive Robotic System for Hearing-Impaired Children. AB - This paper presents an assistive robotic system, which can recognize and express sign language words from a predefined set, within interactive games to communicate with and teach hearing-impaired children sign language. The robotic system uses audio, visual and tactile feedback for interaction with the children and the teacher/researcher. PMID- 28873815 TI - An Innovative Speech-Based User Interface for Smarthomes and IoT Solutions to Help People with Speech and Motor Disabilities. AB - A better use of the increasing functional capabilities of home automation systems and Internet of Things (IoT) devices to support the needs of users with disability, is the subject of a research project currently conducted by Area Ausili (Assistive Technology Area), a department of Polo Tecnologico Regionale Corte Roncati of the Local Health Trust of Bologna (Italy), in collaboration with AIAS Ausilioteca Assistive Technology (AT) Team. The main aim of the project is to develop experimental low cost systems for environmental control through simplified and accessible user interfaces. Many of the activities are focused on automatic speech recognition and are developed in the framework of the CloudCAST project. In this paper we report on the first technical achievements of the project and discuss future possible developments and applications within and outside CloudCAST. PMID- 28873816 TI - Restoring Speech Following Total Removal of the Larynx. AB - By speech articulator movement and training a transformation to audio we can restore the power of speech to someone who has lost their larynx. We sense changes in magnetic field caused by movements of small magnets attached to the lips and tongue. The sensor transformation uses recurrent neural networks. PMID- 28873817 TI - Cloud-Based Speech Technology for Assistive Technology Applications (CloudCAST). AB - The CloudCAST platform provides a series of speech recognition services that can be integrated into assistive technology applications. The platform and the services provided by the public API are described. Several exemplar applications have been developed to demonstrate the platform to potential developers and users. PMID- 28873818 TI - ISi-Speech: A Digital Training System for Acquired Dysarthria. AB - Speech impairment like dysarthria poses a major risk to participation in society due to reduced speech intelligibility. This paper focuses on the ongoing development of the technology-based pilot training system, ISi-Speech, for treatment of dysarthria incorporating automatic speech recognition, a psychological model of motivation and evidence-based exercises. PMID- 28873820 TI - Non-Visually Performing Analytical Tasks on Statistical Charts. AB - This article proposes a natural language-based approach to accessibility of charts. Formal underpinnings are used to semantically annotate the constituent elements of a vector graphic to support accessing and modifying the content by natural language queries in a web interface. A prototype which lets blind users perform a number of analytical activities on bar charts is introduced. PMID- 28873819 TI - Analysis of an Individual's Language to Improve Efficiency of an AAC System. AB - The paper discusses the collection and analysis of a three-month language sample from an adult using a low-tech augmentative and alternative communication (AAC) system transcribed to analyse the frequency of words and letters to make suggestions for more efficiency. PMID- 28873821 TI - The Language and Communication Characteristics of Communication Aids - A Systematic Review. AB - A systematic review of the language and communication characteristics of communication aids considered in identifying the appropriate aid for a child is introduced. The aim is to improve the decision-making around the provision of symbol communication aids to children. PMID- 28873822 TI - The Hollybank Challenges: AT for People with Profound Disabilities. AB - The use of Assistive Technology with people with profound and multiple disabilities is a specialised subfield. Drawing on its authors' experiences and observations at a UK charitable foundation that offers specialised educational, residential and therapeutic facilities, this paper describes the distinct challenges that present themselves when applying AT to address the needs of this often-overlooked sector of the community. It is hoped that this will help raise awareness and contribute to improving the overall quality of AT provision in this area. PMID- 28873823 TI - Democratisation of AAC Symbol Choices Using Technology. AB - The use of an online voting system has been developed to enable democratic choices of newly designed symbols to support speech, language and literacy skills in a localisation situation. The system works for those using and supporting Augmentative and Alternative Communication (AAC) symbols on electronic systems by the provision of simplified scales of acceptance and adapted grids. The methodology and results highlighted the importance of user participation at the outset and concrete examples of symbol adaptations that were found necessary to ensure higher levels of user satisfaction. Design changes included appropriate local dress codes, linguistic nuances, social settings, the built environment and religious sensitivities. PMID- 28873824 TI - Optimising Service Delivery of AAC AT Devices and Compensating AT for Dyslexia. AB - To promote successful use of Assistive Technology (AT) supporting Augmentative and Alternative Communication (AAC) and compensating for dyslexia, the last steps of their provision, delivery and instruction, use, maintenance and evaluation, were optimised. In co-creation with all stakeholders based on a list of requirements an integral method and tools were developed. PMID- 28873825 TI - Exploring the Perspectives of People Who Use Alternative and Augmentative Communication Aids (AAC). AB - This paper outlines the clinical doctoral research plan (funded by HEE/NIHR Integrated Clinical Academic Programme) to engage the wide range of people who use alternative and augmentative communication (AAC) to understand the perspectives of users in order to develop a Patient Reported Outcome Measure (PROM) to evaluate equipment and services. PMID- 28873826 TI - Technology for Early Detection of Depression and Anxiety in Older People. AB - Under-diagnosis of depression and anxiety is common in older adults. This project took a mixed methods approach to explore the application of machine learning and technology for early detection of these conditions. Mood measures collected with digital technologies were used to predict depression and anxiety status according to the Geriatric Depression Scale (GDS) and the Hospital Anxiety and Depression Scale (HADS). Interactive group activities and interviews were used to explore views of older adults and healthcare professionals on this approach respectively. The results show good potential for using a machine learning approach with mood data to predict later depression, though prospective results are preliminary. Qualitative findings highlight motivators and barriers to use of mental health technologies, as well as usability issues. If consideration is given to these issues, this approach could allow alerts to be provided to healthcare staff to draw attention to service users who may go on to experience depression. PMID- 28873827 TI - A User-Centred Approach Exploring the Potential of a Novel EMG Switch for Control of Assistive Technology. AB - This study examines the potential application of an EMG technology as an assistive control method for individuals with severe physical disabilities. The usability and acceptability of a prototype EMG switch was evaluated with health care professionals, researchers and end users using participatory approaches. PMID- 28873828 TI - Fuzzy Logic to Determine the Likelihood of Survival for Trauma Injury Patients. AB - A system to determine the likelihood of survival for trauma injury patients is being developed. It uses a fuzzy logic approach that can model complex processes without reliance on sophisticated mathematical formulations and may have the potential to be more accurate than the existing approaches. The outline operation of the system that is currently in a prototype stage is described. PMID- 28873829 TI - Development of Technology for Assisting Violent Psychiatric Patients. AB - Forceful restraint of psychiatric patients is lawful only in cases of violent uncontrolled behavior. The methods used to limit physical freedom are mainly mechanical means of confinement. The study presents a novel "Personal Protective System" designed to limit patients' violent actions but allow them free non- violent normal functioning. PMID- 28873830 TI - Embedded Systems and TensorFlow Frameworks as Assistive Technology Solutions. AB - In the field of deep learning, this paper presents the design of a wearable computer vision system for visually impaired users. The Assistive Technology solution exploits a powerful single board computer and smart glasses with a camera in order to allow its user to explore the objects within his surrounding environment, while it employs Google TensorFlow machine learning framework in order to real time classify the acquired stills. Therefore the proposed aid can increase the awareness of the explored environment and it interacts with its user by means of audio messages. PMID- 28873831 TI - Providing Sources of Self-Efficacy Through Technology Enhanced Post-Stroke Rehabilitation in the Home. AB - This research explores the impact of receiving feedback through a Personalised Self-Managed Rehabilitation System (PSMrS) for home-based post-stroke rehabilitation on the users' self-efficacy; more specifically, mastery experiences and the interpretation of biomechanical data. Embedded within a realistic evaluation methodological approach, exploring the promotion of self efficacy from the utilisation of computer-based technology to facilitate post stroke upper-limb rehabilitation in the home included; semi-structured interviews, quantitative user data (activity and usage), observations and field notes. Data revealed that self-efficacy was linked with obtaining positive knowledge of results feedback. Encouragingly, this also transferred to functional activities such as, confidence to carry out kitchen tasks and bathroom personal activities. Findings suggest the PSMrS was able to provide key sources of self efficacy by providing feedback which translated key biomechanical data to the users. Users could interpret and understand their performance, gain a sense of mastery and build their confidence which in some instances led to increased confidence to carry out functional activities. However, outcome expectations and socio-structural factors impacted on the self-efficacy associated with the use of the system. Increasing the understanding of how these factors promote or inhibit self-management and self-efficacy is therefore crucial to the successful adoption of technology solutions and promotion of self-efficacy. PMID- 28873832 TI - Using Machine Learning to Match Assistive Technology to People with Disabilities. AB - This paper describes the initial results of work to create a recommender system to match technology products to people with I/DD by applying machine learning to a large volume of data about: people with I/DD; the technology products they use; and the outcomes they aim to achieve with technology. PMID- 28873833 TI - Mouthsticks - A Participatory Approach. AB - Mouthsticks are quite an old kind of assistive technology (AT) but nevertheless they are up to now the Swiss army knives among AT. Unfortunately the popularity of mouthsticks massively decreased during the 1990s with the result that knowledge about how to produce good mouthsticks got lost and that there are hardly any adaptable mouthsticks available on the market. This paper discusses the development of a personalized mouthstick with the involvement of end users - people with severe physical disabilities - and occupational therapists as experts of everyday use. A participatory approach was chosen. The results of the analysis of a standardized questionnaire, group discussions and a collaborative workshop with IT-designers, polymer engineers, end users, occupational therapists and gender and diversity researchers are presented and discussed. This proved the necessity of the development of a personalized mouthstick. PMID- 28873834 TI - Four Models to Guide AT Projects Intending Innovative Technology Development Outcomes. AB - Generating innovations - including Assistive Technology products or services - requires expertise in project planning and management. University faculty and small businesses ventures often lack such expertise for development and production tasks, yet governments allocate most funding to these sectors. They need help to achieve results. Four evidence-based models now exist to guide investigators intending to generate AT innovations in: 1) standards/guidelines; 2) tools/ instruments; 3) freeware or 4) commercial products. PMID- 28873835 TI - Conjuring up New Technology - Using Magic Objects in Co-Ideation with Stroke Survivors. AB - Ideation means to generate ideas, and when involving non-designers in these activities they need to be informed about the scope of the possibilities without limiting their imagination. This is a general challenge, which becomes particularly important when it comes to advanced technology ideation together with participants that may not have in-depth knowledge of technological designs and solutions. In this study, we supported the ideation process by presenting a kit of magic objects (consisting of cards and physical props) to stroke survivors participating in a co-design workshop carried out within the STARR EU project. The kit was seen to generally work well, but improvements are suggested for the introduction, the design of the cards and the number of objects used. PMID- 28873836 TI - Process Development for the Design and Manufacturing of Personalizable Mouth Sticks. AB - To increase the independence of people with reduced hand/arm functionality, a process to generate personalizable mouth sticks was developed based on the participatory design principle. In a web tool, anybody can choose the geometry and the materials of their mouth piece, stick and tip. Manufacturing techniques (e.g. 3D printing) and materials used in the process are discussed and evaluated. PMID- 28873837 TI - Designing for Mild Cognitive Impairment (MCI): A Design Anthropological Perspective. AB - This paper will present a design anthropological perspective on an ongoing project called 'Living Well with Mild Cognitive Impairment (MCI)'. The project explores how people with MCI (and their families) manage and respond to changes in their memory and thinking. One of the primary aims of this project is to design an online resource that will support people to 'Live Well' within the context of possible cognitive decline. The resource was originally proposed to function as a kind of online community, where users could both share and learn about home-grown strategies for managing the cognitive changes associated with MCI in everyday life. Much of this project has been guided by the methodological approach of design anthropology, which encourages project researchers and stakeholders to critically examine underlying assumptions and conceptual frameworks, which in this case revolve around the disputed MCI category. In this paper we will provide some background to the Living Well project before highlighting a number of key insights attained from design anthropology. PMID- 28873838 TI - Overview of Robotic Devices for Nursing Care Project. AB - METI/AMED are conducting a project on the development and deployment of robotic devices for nursing care to enhance the autonomy of elderly persons and assist care givers. An evaluation protocol is presented and the devices developed in the project are introduced. The devices consist of transfer assist devices (wearable/non-wearable), walking assist devices (outdoor/indoor), safety surveillance sensors (nursing home/private home), bath lift and toilet assist. PMID- 28873839 TI - Development of Robotic Rollators and Walking Trolleys in Japan. AB - In Japan, several types of robotic rollators and walking trolleys have been developed with financial assistance from the Japanese government, and some of them have been commercialized in 2015 and 2016. In this paper, the specifications and features of these devices are presented. Moreover, the physically assistive effects of these devices in elderly users are verified and discussed using the results of fundamental function tests and verification experiments. PMID- 28873840 TI - An Introduction to the Development of Transfer Assistive Robots in Japan. AB - This paper briefly introduces the development of transfer assistive robots in terms of development support. In addition, some products that have been developed are reviewed. Our study reveals there are two development styles with completely opposite directions, namely: complex to simple; and simple to complex. PMID- 28873841 TI - Robots for Elderly Care: Their Level of Social Interactions and the Targeted End User. AB - Robots for older adults have a lot of potential. In order to create an overview of the developments in this area a systematic review of robots for older adults living independently was conducted. Robots were categorized based on their market readiness, the type of provided support (i.e., physical, non-physical, non specified), and the activity domain they claim to support. Additionally, the commercially available robots are places in a proposed framework to help to distinguish the different types of robots and their focus. During the presentation an updated version of the state of the art will be presented. PMID- 28873842 TI - Development of a Robotic System for Enhancing Children's Motivation in Constraint Induced Movement Therapy (CIMT). AB - This paper presents a novel robotic system, which aims to enhance children's motivation through the gamification of the CIMT process. The system offers adjustability of the required movement skills, ensuring children will put increasingly more effort to achieve the rehabilitation goal, while keeping the task fun and engaging. PMID- 28873843 TI - A Robotic Solution for Assisting People with MCI at Home: Preliminary Tests of the ENRICHME System. AB - Robots have the potential to support care and independence of older adults. The ENRICHME project is developing an integrated system composed of a robot, sensors and a networking care platform, aiming at assisting older adults with MCI in their home environment. This paper reports findings of the tests performed on a sample of MCI users and their caregivers, with the first version of the ENRICHME system, in a controlled environment. PMID- 28873844 TI - Design of a Behavior of Robot That Attracts the Interest of the Mildly Demented Elderly. AB - In this study, using the unexpected intervention overturning the interaction amount of the field and the mental model, an interaction of a robot system that enables sustained nonverbal communication with the mildly demented elderly was proposed and its effectiveness was shown in the group home of the mildly demented elderly. PMID- 28873846 TI - Introducing ZORA to Children with Severe Physical Disabilities. AB - The aim of the present study was to explore the potential of a ZORA-robot based intervention in rehabilitation and special education for children with (severe) physical disabilities from the professionals perspective. The qualitative results of this study will be presented. Professionals indicated meaningful application possibilities for ZORA. Overall, ZORA was able to improve motivation, concentration, taking initiative and attention span. Three domains could be identified to be most promising for application of ZORA: (re)learning of movement skills, cognitive skills and communication/social interaction skills. PMID- 28873845 TI - Exploring the Use of a Humanoid Robot to Engage Children with Autism Spectrum Disorder (ASD). AB - We present a study aimed at exploring whether a humanoid robot may improve the effectiveness of educational interventions targeting children with autism spectrum disorders (ASD). Preliminary results with three preschool children with ASD indicate that interacting with a humanoid robot may facilitate engagement and goal achievement in educational activities. PMID- 28873847 TI - Evaluation of Dynamic Arm Supports in Real Life Environments. AB - Dynamic arm supports facilitate the performance of activities of daily living (ADL) in people with upper extremity limitations. For which ADL, and how devices are used in daily life differs between users, imposing a difficulty to the assessment of outcomes. Therefore this study reports on the instruments used in earlier studies. Several instruments in the domains of body functions and activities and participation were identified. Instruments used include patient reported outcome measures, questionnaires, interviews, and arm and hand function tests. PMID- 28873848 TI - Investigating the Effect of Social Robot Embodiment. AB - The experiment described in this paper is an early assessment to identify if the embodiment of a verbal and visual user interaction system in a robot is more effective in people with dementia than when using the same system in a simple laptop. This study provides input for the robot's design. PMID- 28873849 TI - Care Robot ZORA in Dutch Nursing Homes; An Evaluation Study. AB - From May 2016 - November 2016 the use of the ZORA robot was investigated in 15 long-term care facilities for older people. The ZORA robot is built as a social robot and used for pleasure and entertainment or to stimulate physical activities of the residents. PMID- 28873850 TI - Standardization of Care and Assistive Products Involving Robot Technology. AB - An ongoing Japan-wide project for the development and deployment of care and assistive robotic devices is being followed by a program of standardizing some of the outcome technologies while focusing on safe usage. We examine the concept defining the required standard as robotic technology is introduced. Fundamentally, this involves the application of the existing safety standard for service robots used to improve the quality of life. We expect that this program will contribute to enhancing safety in device usage, and further expand the device market by constructing a structure for sharing roles of supporting both the manufacturers and users. PMID- 28873851 TI - Estimation of Injury by Falls for Risk Assessment of Robotic Care Devices. AB - In order for manufacturers of robotic devices for nursing care to predict injury in accidents related to their products, risk assessments are carried out according to various standards e.g. ISO 12100. Probabilities of death, bone fracture and head injury are estimated by analysing data published in Japan and U.S. PMID- 28873852 TI - Development of a Risk Assessment Assistance Tool for Robotic Care Devices. AB - Aiming to eliminate a labor shortage caused by the aging of society, many kinds of service robots are under development. Nursing care for the elderly is considered as a typical application of service robots, especially in Japan. Elderly care robots or robotic care device must be designed with safety, but not a few manufacturers are inexperienced in designing and manufacturing them on the basis of safety. In this paper, we introduce a risk assessment assistance tool for robotic care device targeted for inexperienced manufacturers of risk assessment. PMID- 28873853 TI - Standardization of Assistive Products with Robotic Technology - From a Perspective of ISO/TC173. AB - ISO/TC173 is a technical committee, in charge of international standardization of assistive products (APs). Robotic technology (RT) is currently an important topic in this field. APs with RT will be included in future revisions of the scope of TC173. Cooperation between the AP and RT space is essential to reach suitable solutions of future standardization. PMID- 28873854 TI - IntelliTable: Inclusively-Designed Furniture with Robotic Capabilities. AB - IntelliTable is a new proof-of-principle assistive technology system with robotic capabilities in the form of an elegant universal cantilever table able to move around by itself, or under user control. We describe the design and current capabilities of the table and the human-centered design methodology used in its development and initial evaluation. The IntelliTable study has delivered robotic platform programmed by a smartphone that can navigate around a typical home or care environment, avoiding obstacles, and positioning itself at the user's command. It can also be configured to navigate itself to pre-ordained places positions within an environment using ceiling tracking, responsive optical guidance and object-based sonar navigation. PMID- 28873855 TI - Usability of JACO Arm Interfaces Designed with a User-Centred Design Method. AB - Utility, usability and acceptability of robotic arm for helping motor impairment people (quadriplegic, muscular dystrophy, Amyotrophic Lateral Sclerosis) must be improved. The robotic arm JACO of company (c)Kinova is controlled by a joystick, sometimes unusable by patients. The IRIT laboratory has designed three types of virtual interfaces: one based on virtual keyboards and two others on Pie Menu concepts. These interfaces were designed by mean of a user centred design approach (UCDA) including brain storming, focus group, iterative prototyping and trials. Then an experiment is described with two patients (Spinal Muscular Atrophy and cerebral palsy). This experiment shows that the three interfaces designed by a UCDA are usable by them. PMID- 28873856 TI - Development/Testing of a Monitoring System Assisting MCI Patients: The European Project INLIFE. AB - INLIFE is a project cofounded from the European Union aiming in prolonging independent living of elderly people with cognitive impairment based on open, seamless ICT services supporting communication, daily activities, providing health services and professional care to the elderly. The main innovation stems from ICT solutions offering 19 different services adapted on specific characteristics elderly people with mild cognitive impairment, early and later stages of Dementia, cognitive impairment and co-morbid condition, as well as their formal and informal caregivers. All services have different focus areas and are incorporated into a unified system based on cloud architecture implemented in patients of 6 European countries, including Greece. More than 1200 patients, caregivers and healthcare providers participate in the pilot testing of the project. Primary parameter for assessing the effectiveness of the interventions is their impact on the quality of life of the elderly patients and their caregivers, contributing to prolonging independent living of the affected. A special digital platform has been developed in the Greek pilot site aiming to adapt and monitor all the implemented applications. This includes a medical decision support system that receives biosignals from patients and interaction interfaces in which all participants are involved. Recruitment and patients' participation has already started in the pilot site of Thessaloniki for the services that are to be tested in Greece. PMID- 28873857 TI - Embracing Technological Development and Salutogenic Health Promotion in the Provision of Assistive Technologies. AB - The growing incidence of Noncommunicable Diseases has increased focus on the promotion of physical activity within the therapeutic environment. Research demonstrates a shift in mentality away from the pathogenic orientation of health promotion, resulting in the formation of salutogenic health promotion concepts and assistive technologies that actively promote health. PMID- 28873858 TI - Adaptive Sampling Technique Using Regression Modelling and Fuzzy Inference System for Network Traffic. AB - Electronic-health relies on extensive computer networks to facilitate access and to communicate various types of information in the form of data packets. To examine the effectiveness of these networks, the traffic parameters need to be analysed. Due to quantity of packets, examining their transmission parameters individually is not practical, especially when performed in real time. Sampling allows a subset of packets that accurately represents the original traffic to be chosen. In this study an adaptive sampling method based on regression and fuzzy inference system was developed. It dynamically updates the sampling by responding to the traffic changes. Its performance was found to be superior to the conventional non-adaptive sampling methods. PMID- 28873859 TI - ICT Services for Life Improvement for the Elderly. AB - Integrated care ICT Platform to support patients, care-givers and health/social professionals in the care of dementia and Parkinson's disease with training, empowerment, sensor-based data analysis and cooperation services based on user friendly interfaces. PMID- 28873860 TI - Applying Game Thinking to Slips, Trips and Falls Prevention. AB - Gamification is about the way in which 'game thinking' can engage participants and change behaviours in real, non-game contexts. This paper explores how game thinking can be applied to help prevent slips, trips and falls (STF), which are the largest cause of accidental death in older people across Europe. The paper contributes to the assistive technology, digital health and computer science/human behaviour communities by responding to a gap in the literature for papers detailing the innovation process of developing interventions to improve health and quality of life. The aim of the paper is of interest to the many stakeholders involved in enabling older people to live independent, confident, healthy and safe lives in the community. PMID- 28873861 TI - A Mobile Game for the Social and Cognitive Well-Being of Elderly People in China. AB - China, like many other countries, is facing the challenges of an ageing population. Literature has shown that the lack of social interaction has a negative impact on the physical health of the elderly, and playing games can be beneficial in maintaining or even improving their cognitive abilities. This study describes the design and development process for a social and cognitive mobile game and the related user evaluation in terms of well-being. The objective is to explore the underlying connections between game playing and the improvement of well-being among elderly people in China. PMID- 28873862 TI - Customised City Maps in Mobile Applications for Senior Citizens. AB - Map services should be used in mobile applications for senior citizens. Do the commonly used map services meet the needs of elderly people? - Exemplarily, the contrast ratios of common maps in comparison to an optimized custom rendered map are examined in the paper. PMID- 28873863 TI - Mobile Recommender Apps with Privacy Management for Accessible and Usable Technologies. AB - The paper presents the preliminary results of an ongoing survey of the use of computers and mobile devices, interest in recommender apps and knowledge and concerns about privacy issues amongst English and Italian speaking disabled people. Participants were found to be regular users of computers and mobile devices for a range of applications. They were interested in recommender apps for household items, computer software and apps that met their accessibility and other requirements. They showed greater concerns about controlling access to personal data of different types than this data being retained by the computer or mobile device. They were also willing to make tradeoffs to improve device performance. PMID- 28873864 TI - The Use of Apps for Health in Persons with Multiple Sclerosis, Parkinson's Disease and Stroke - Barriers and Facilitators. AB - INTRODUCTION: The importance of mobile health has increased during recent years but few studies have described the use of apps among persons with neurological disabilities. AIM: The aim of this paper was to describe how persons ageing with a neurological disability experience barriers and facilitators in relation to using apps in everyday life. METHOD: A qualitative approach was used. 16 persons with neurological disorders participated in two group discussions. Data were analyzed by content analysis. RESULTS: The analysis formed four categories; Impairments make apps harder to use, Use of apps is increased by learnability and sharing, Valuating the information in an app, and Apps act supportive and motivating. CONCLUSION: The participants used apps in the same way as persons without disabilities. Impairments and trustworthiness were perceived as barriers, which need to be acknowledged when developing apps for this population. Use of apps was facilitated by the possibility to share data and to connect with others. Apps may have the potential to improve self-management for persons ageing with disabilities but further research is needed. PMID- 28873865 TI - Mobile App Selection Tool (MAST) for Post-Secondary Students with Disabilities. AB - This paper discusses research examining the use of a Mobile Apps Selection Tool (MAST) designed to facilitate the use of the iPad by post-secondary students with disabilities. MAST is a public website that was developed to support students to become independent in their use of the iPad to meet their learning needs. PMID- 28873866 TI - Involving Users in the Evaluation of Apps for Specific Health Conditions. AB - With rapid growth of Internet accessibility over recent years, the way in which we engage with healthcare services and make decisions about our own healthcare has changed. One form of engagement with the Internet is through the use of mobile applications (apps) via mobile devices such as smartphones and tablets. As a result of this, many apps have been developed to target people with varying long term conditions. These apps may aim to help educate individuals about their condition or help them to manage it. Assessing the quality of these apps is crucial especially when considering the risks associated with providing misleading information or unsubstantiated claims. This has led to a growing body of research assessing the quality of apps aimed at people living with varying long term conditions. These attempts have not involved service users to address the suitability of apps for their intended target audiences. This paper presents two examples of how service users and associated healthcare professionals can be involved in the suitability assessment of mobile apps for children and young people with Attention Deficit Hyperactivity Disorder and those living with dementia. PMID- 28873867 TI - Living Lab as an Agile Approach in Developing User-Friendly Welfare Technology. AB - This paper discusses living lab as a method of developing user-friendly welfare technology, and presents a qualitative evaluation research of how living lab tested technologies impacted on the life of healthcare customers and professionals over test periods. PMID- 28873868 TI - Accapto, a Generic Design and Development Toolkit for Accessible Mobile Apps. AB - Smartphones show potential to improve and support the daily lives of people with disabilities. User experience of mobile apps is generally good, but rather unsatisfying for people with disabilities relying on accessibility support. Developers often are not aware of and do not respect this user group. We propose a system supporting developers in early stages of app development. The Accapto toolkit allows modelling accessible smartphone interaction during the design phase. Based on this interaction model the prototype of the resulting app is generated. Predefined accessibility features based on standards and expert knowledge are automatically integrated to enhance accessibility. PMID- 28873869 TI - Designing Web-Apps for All: How Do We Include Those with Cognitive Disabilities? AB - Accessibility guidance for the development of web-apps for users with cognitive disabilities is sorely lacking despite the availability of extensive web content accessibility standards. This paper examines additional requirements suggested by specialists in the field, in order to further aid developers looking to create accessible interactive web experiences for all. PMID- 28873870 TI - "Design for Somebody" - Approach Enabling Mobile Technology Development. AB - This paper presents case examples of Design for Somebody (DfS) philosophy used both in developing novel technologies and modifying existing main stream technologies applicable for users with special needs. DfS embodies variety of mobile technology approaches to generate personalised means to enable and motivate physical, cognitive and social skills development. PMID- 28873871 TI - Recommendations for Age-Appropriate Mobile Application Design. AB - This paper presents recommendations for avoiding or eliminating unnecessary barriers to mobile application usage by older generations. It sets out ten areas of age-appropriate application design. The aim of this paper is to help ensure that the design of mobile applications, including assistive applications, is accessible for elderly persons. PMID- 28873872 TI - Six-and-a-Half-Year Practice of Tactile Map Creation Service. AB - To disseminate the use of tactile maps, a tactile map creation service has been offered according to the demands of blind people and their helpers. From June 2010 to December 2016, 151 tactile maps were created. Three quarters of them were maps of outdoor areas and one fifth were floor plans of a building or property. Half of the outdoor area maps were mobility maps and the other half were city maps. The service users' comments confirmed the usefulness of tactile maps as route maps and as providing information on a city. However, it was revealed that these tactile maps are too complicated for late blind people. PMID- 28873873 TI - Towards Standardised Information Exchange Regarding the Accessibility of Public Transport in Germany. AB - In the innovation project DELFIplus a concept for standardised information on accesssibility of public transport facilities in Germany as a basis for a nationwide electronic journey planner has been elaborated and demonstrated. A handbook describes a pragmatic methodology how to implement the integrated information services in a decentralised structure of information providers. PMID- 28873874 TI - Definition of "Total Accessibility" for Public Transport. AB - The paper describes the approach and results of a German study as an example of strategies in German legislation relating to accessibility in public transport. In the study a participatory approach was followed to reach consensus about the interpretation and definition of a new legislative term "vollstandige Barrierefreiheit (total accessibility)". PMID- 28873875 TI - Image Based Location Estimation for Walking Out of Visual Impaired Person. AB - A new and intelligent walking navigation system could be helpful for visually impaired people so that they do not need helpers or guide dogs on going out. Conventional navigation systems using GPS are not available indoors or undergrounds. A new location estimation method that is available in such situations is necessary. We propose to estimate pedestrian's location with only a single camera attached to the pedestrian. Our proposed method uses only computer vision and no other sensors are needed. The location estimation is achieved by image retrieval. The retrieval database is built from a pre-recorded video taken along a planned walking path. Simple image retrieval using local image features does not work well when the images were taken in different conditions of time and weather. In this paper, we especially explore robustness for the change of sunlight condition due to its recording time. We propose a new method of robust location estimation based on our database built by combining more than one video that is taken under different conditions. Experiment results showed that the accuracy of the location estimation using the proposed database is better than the one from a conventional database built by using a single video. PMID- 28873876 TI - Inertial Measurement Techniques for Human Joints' Movement Analysis. AB - Development and assessment of techniques that allow inertia measurement units consisting of an accelerometer and a gyroscope to be used for monitoring human joints' movements are presented. A new wavelet packet decomposition technique was developed that denoised the accelerometer signals. Investigations on the use of accelerometers to analyse legs' movements are described. PMID- 28873877 TI - Modular Gesture Interface for People with Severe Motor Dysfunction: Foot Recognition. AB - We have collected various gestures from persons with motor dysfunction who cannot use normal interface switches to develop contactless, non-constraining, and inexpensive gesture interfaces for operating PCs by utilizing a commercially available image range sensor. We describe the collection and classification of the gestures and the foot gesture recognition module. PMID- 28873878 TI - Assessing Gait Impairments Based on Auto-Encoded Patterns of Mahalanobis Distances from Consecutive Steps. AB - Insole pressure sensors capture the force distribution patterns during the stance phase while walking. By comparing patterns obtained from healthy individuals to patients suffering different medical conditions based on a given similarity measure, automatic impairment indexes can be computed in order to help in applications such as rehabilitation. This paper uses the data sensed from insole pressure sensors for a group of healthy controls to train an auto-encoder using patterns of stochastic distances in series of consecutive steps while walking at normal speeds. Two experiment groups are compared to the healthy control group: a group of patients suffering knee pain and a group of post-stroke survivors. The Mahalanobis distance is computed for every single step by each participant compared to the entire dataset sensed from healthy controls. The computed distances for consecutive steps are fed into the previously trained autoencoder and the average error is used to assess how close the walking segment is to the autogenerated model from healthy controls. The results show that automatic distortion indexes can be used to assess each participant as compared to normal patterns computed from healthy controls. The stochastic distances observed for the group of stroke survivors are bigger than those for the people with knee pain. PMID- 28873879 TI - Attenuating Tremor Using Passive Devices. AB - Limb tremor is treated with either medication or surgery, both of which may have adverse effects. This paper presents two passive devices for tremor attenuation: One for attenuating pronation/supination tremor of the forearm using a dynamic vibration absorber, and the other for attenuating flexion/extension tremor of the hand using a rotational damper. PMID- 28873880 TI - A Review of Physical Activity Monitoring and Activity Trackers for Older Adults. AB - The objective assessment of physical activity levels through wearable inertial based motion detectors for an automatic, continuous and long-term monitoring of people in free-living environments is a well-known research area in literature. However, their application to older adults can present particular constraints. This paper reviews the methods of measuring physical activity, adoption of wearable devices in older adults, describes and compares existing commercial products encompassing activity trackers tailored for older participants. PMID- 28873881 TI - Developing an Assessment (Tool) for Touch Screen Devices. AB - Touch screen devices have become prevalent in our lives. Assistive technology experts working with people with disabilities face difficulty in understanding and assessing the problems experienced by individuals with disabilities in operating touch screen devices. This paper presents the processes of collecting and creating the required knowledge needed for assessing the user's skills for operating various touch screen devices, in order to develop an application for assessing the user's abilities and limitations. A six step procedure was used to collect and validate the required knowledge for the assessment from a multidisciplinary team. To determine the agreement levels between the experts, content validity was calculated. To test correlation between the experts from the different disciplines, a comparison was made between the discipline groups and their choice of specific skills/measurements. The final number of domains and skills/measurements was 15 domains and 50 skills/measurements. The result of Cronbach's alpha test for the final assessment questionnaire (50 skills/measurements) was 0.94, which indicates a high degree of reliability. The results of Kruskal-Wallis test showed the lack of any significant difference between agreements of the clinicians and the technicians groups, but significant differences were found between the educators and the clinicians groups. Each of the skills appearing in the final questionnaire was illustrated in a flowchart in preparation for developing the assessment (tool) for using touch screen devices. PMID- 28873882 TI - Not Just the Right to a Wheelchair but the Right Wheelchair - Improving Brazilian Wheelchair Service Delivery. AB - This paper discusses the barriers encountered before and after the implementation of good practice in the delivery of wheelchair provision services in Belo Horizonte city, Brazil. The results demystify some participants' initial idea that using an assessment form might take significantly more time. Major barriers to implementation had regard to the assessment of pressure sores and a lack of wheelchair suppliers. PMID- 28873883 TI - One Dimensional Input Device of Electric Wheelchair for Persons with Severe Duchenne Muscular Dystrophy. AB - Persons with severe Duchenne Muscular Dystrophy (DMD) usually have difficult in operating electric wheelchairs (EW) using standard input device due to the lack of muscular power and the deformation of their hands. This paper proposed a novel one dimensional two degree of freedom (1D2F) input device based on the quantitative evaluation of hand function which consists of fingertip force and active range of motion. The validity and the operating features of this device are demonstrated by experiments. PMID- 28873884 TI - Efficiency and Rolling Resistance in Manual Wheelchair Propulsion. AB - The efficiency and the rolling resistance in wheelchair propulsion play an important role in the comfort and the health of wheelchair users in daily life. Here we identify these fundamental interactions of wheelchair-user system on treadmill and on track. We measured the oxygen uptake (input) and the propelling torque (output) as the parameters with velocity and tire pressure. The efficiency increased about 9-13% as the velocity increased on treadmill and it increased around 11-12% as the tire pressure reduced on track. The mean coefficient of rolling resistance was 0.012 on treadmill and that were 0.016 (200 kPa) and 0.026 (30 kPa) on track. Our experimental results indicated that the efficiency and the rolling resistance were strongly dependent on the velocity and tire pressure. PMID- 28873885 TI - Advantages of Unstable Manual Wheelchair. AB - In this study, many test runs were conducted using experimental manual wheelchair on various floor surface conditions. In the result, operability of manual wheelchair would be improved by shifting the position of drive wheels forward. PMID- 28873886 TI - Servomotor Assistance in the Improvement of Manual Wheelchair Mobility. AB - This study reports the development of a servo-controlled power-assisted wheelchair, designed to reduce the loads on the upper limbs while maintaining the drivability of a manual chair. It is presented the concept and implementation of an assisted propulsion system, focusing on the assistance controlling and the torque transmission. PMID- 28873887 TI - MotorSense: Using Motion Tracking Technology to Support the Identification and Treatment of Gross-Motor Dysfunction. AB - MotorSense is a motion detection and tracking technology that can be implemented across a range of environments to assist in detecting delays in gross-motor skills development. The system utilises the motion tracking functionality of Microsoft's KinectTM. It features games that require children to perform graded gross-motor tasks matched with their chronological and developmental ages. This paper describes the rationale for MotorSense, provides an overview of the functionality of the system and illustrates sample activities. PMID- 28873888 TI - Can Automated Facial Expression Analysis Show Differences Between Autism and Typical Functioning? AB - Exploratory analyses of emotional expressions using a commercially available facial expression recognition software are reported, from the context of a serious game for screening purposes. Our results are based on a comparative analysis of two matched groups of kindergarten-age children (high-functioning children with autism spectrum condition: n=13; typically developing children: n=13). Results indicate that this technology has the potential to identify autism specific emotion expression features, and may play a role in affective diagnostic and assistive technologies. PMID- 28873889 TI - Assistive Technology for an Inclusive Society for People with Intellectual Disability. AB - People with intellectual disability (ID), are some of the most stigmatized and marginalized social groups. Ongoing global initiatives such as the United Nations Convention on the Rights of Persons with Disabilities (UNCPD) and Strategic Development Goals (SDGs) aim to accelerate their inclusion into the society. In many high-income countries, deinstitutionalization of care for people with ID forms part of the broader social inclusion agenda for people with ID into the society. Access to appropriate assistive technology (AT) can mediate the ongoing normalization/inclusion efforts for people with ID. AT can enable users with ID to access societal processes such as education, employment, socialization or independent living. Effective use of AT can also enhance the formation and/or maintenance of interpersonal relationships by people with ID, thus promote their social support. PMID- 28873890 TI - Participation and Autonomy for Users with ABI Through Easy Social Media Access. AB - The Mediata app is a mobile application providing easy access to internet and social media for persons with acquired brain injury. This paper presents design, working hypotheses and expected results of a participative user experience study to evaluate the impact of the Mediata application on participation and autonomy of users with acquired brain injury. PMID- 28873892 TI - Digital Skills Development and ICT in Inclusive Education: Experiences from Cyprus Schools. AB - This qualitative research has been a pilot implementation of the ENTELS self assessment framework for schools on digital skills development and Information and Communication Technologies (ICT) in inclusive education, in Cyprus. Results suggest that participant schools overall identified themselves as "getting started" to "some progress" in all areas with the highest evaluation in the one corresponding to "school commitment in the integration of ICT skills of all students, including those with disabilities". The planned and implemented actions which followed have taken into consideration the rating of each school and the theoretical background, aimed at reinforcing the participation of the diverse students and students with disabilities and other educational needs. Final analysis of the actions' effectiveness is planned whereas future tool implementation could concentrate on how to overcome barriers and concerns related to ICT integration for promoting inclusive education. PMID- 28873891 TI - A Self-Assessment Framework for Inclusive Schools Supporting Assistive Technology Users. AB - In order to support schools to assess their performance in supporting children with disabilities in their ICT and ICT-AT needs, a self-assessment framework was developed by a task force of partners and associate partners of the ENTELIS project. The self-assessment tool aims to help educational establishments that welcome learners with disabilities to assess their current outcomes and to plan improvements in supporting these students in increasing digital literacy and developing digital skills. This includes the use of mainstream Information and Communication Technology (ICT) and specially designed digital Assistive Technologies (ICT-AT). This can only successfully happen if schools fully embrace an inclusive approach to education. In this paper the authors describe the development of the framework and the further steps for its use. PMID- 28873893 TI - Web Widgets Barriers for Visually Impaired Users. AB - Currently, websites are mainly composed of web widgets, dynamic elements and updatable sections - like autosuggest list, carousel, slideshow etc. In order to contribute with the development of accessible rich internet applications, this work aims to better understand the interaction of severely visually impaired users with these pages, gathering their main barriers and difficulties. PMID- 28873894 TI - Extraction Methodology of Implicit Didactics in Math Schoolbooks for the Blind. AB - The implicit didactic information embedded in the theoretical part of math schoolbooks is one of the keys for successful learning mathematics, but mostly reserved for sighted students. Thus, the methodology for analyzing this theoretical part of selected math schoolbooks is developed for extracting this implicit didactic information, which will be made accessible. Combined with the blind students' teaching methods in classrooms, a dialog-based assistant concept is suggested for covering core didactics for teaching the blind. PMID- 28873895 TI - Toward Emotionally Accessible Massive Open Online Courses (MOOCs). AB - This paper outlines an approach to evaluating the emotional content of three Massive Open Online Courses (MOOCs) using the affective computing approach of prosody detection on two different text-to-speech voices in conjunction with human raters judging the emotional content of course text. The intent of this work is to establish the potential variation on the emotional delivery of MOOC material through synthetic voice. PMID- 28873896 TI - Auditing the Accessibility of Massive Open Online Courses (MOOCs). AB - The outcome from the research being reported in this paper is the design of an accessibility audit to evaluate Massive Open Online Courses (MOOCs) for accessibility and to arrive at solutions and adaptations that can meet user needs. This accessibility audit includes expert-based heuristic evaluations and user-based evaluations of the MOOC platforms and individual courses. PMID- 28873897 TI - A Community-Level Perspective on Digitally and Socially Including Disabled People. AB - A presentation of findings from the evaluation of the Future Digital Inclusion programme funded by the UK Government Department of Education. Data show the effectiveness of embedding digital inclusion support within wider social inclusion services at the local level, mediated by institutions and organisations which have established pathways to engage socially excluded people, including disabled people. PMID- 28873898 TI - Supporting Disabled People's Independence With Digital Skills in the Community. AB - This presentation discusses research by Good Things Foundation with community organisations supporting disabled people within the national Online Centres network, to explore the barriers to digital inclusion (DI) they face. The research informed a handbook to help similar organisations get disabled people online. PMID- 28873899 TI - Building an Accessible Pictograph Interface for Users with Intellectual Disabilities. AB - This paper presents a pictograph interface for Pictograph-to-Text translation, which facilitates the construction of written text on social media platforms for users with Intellectual Disabilities. For the design of the interface, a user centred approach was adopted. Results show that the target group can appreciate accessing social media through pictograph-based technologies. PMID- 28873900 TI - Inclusive E-Learning - Towards an Integrated System Design. AB - At first sight there seem to be issues combining technical accessibility guidelines and educational needs when designing inclusive E-Learning. Furthermore Universal Design for Learning seems to contradict individualization. In this paper we address both issues with an inclusive E-Learning design for the LAYA system, which targets disabled and non-disabled learners. PMID- 28873901 TI - Co-Creation Learning Procedures: Comparing Interactive Language Lessons for Deaf and Hearing Students. AB - This paper discusses co-creation learning procedures of second language lessons for deaf students, and sign language lessons by a deaf lecturer. The analyses focus on the learning procedure and resulting assessment, considering the disability. Through questionnaires ICT-based co-creative learning technologies are effective and efficient and promote spontaneous learning motivation goals. PMID- 28873902 TI - The WebACS - An Accessible Graphical Editor. AB - This paper is about the solution to accessibility problems met when implementing a graphical editor, a major challenge being the comprehension of the relationships between graphical components, which needs to be guaranteed for blind and vision impaired users. In the concrete case the HTML5 canvas and Javascript were used. Accessibility was reached by implementing a list view of elements, which also enhances the usability of the editor. PMID- 28873903 TI - How Accessible is Weibo for People with Visual Impairments? AB - Weibo is one of the most popular Chinese social media services. The literature has shown that social media have potential to empower people with disabilities. However, digital accessibility is a new area in China and very few studies have focused on the accessibility of Chinese social media services. This research aims to evaluate the accessibility of Weibo for people with visual impairments. A survey, interviews and user testing were used to identify accessibility issues of Weibo. On the basis of the findings, recommendations are made to improve accessibility. PMID- 28873904 TI - DUCK: A DeDUCtive Soft Keyboard for Visually Impaired Users. AB - Touch screens rapidly and significantly replace physical keyboards on mobile devices. Hence, text entry is now dependent on soft keyboards that are widely used by sighted people, but raise accessibility issues for visually impaired users. These users rely on tactile exploration with vocal feedback of the whole screen for entering text, which is time consuming. A software keyboard that aims reducing tactile exploration and speeding up text entry for VI users was designed. It relies on the selection of the first letter of a word and rapid and inaccurate typing of the remaining letters. It then proposes a list of words having the same first letter and a similar total distance between letters. The evaluation with twelve VI users showed that this keyboard is very efficient for words larger than five characters. It also helps preventing certain typing errors. PMID- 28873905 TI - Evaluation of Orientation Performance of Attention Patterns for Blind Person. AB - Tactile walking surface indicators (TWSIs) are installed on footpath to support independent travel for the blind. There are two types of TWSIs, attention patterns and guiding patterns. The attention pattern is usually installed at the crosswalk entrances. The direction of the crossing can be acquired by the row of the projection of the attention pattern through the soles of the shoes. In addition, truncated domes or cones of the attention pattern were arranged in a square grid, parallel or diagonal at 45 degrees to the principal direction of travel. However, the international standard organization (ISO) allows a wide ranging size. In this research, the direction indicating performance was compared at the same intervals for the five diameters specified by the international standard. As a result of the experiment, the diagonal array does not indicate the direction of travel, but the projection row does indicate the direction of travel in the parallel array. When the attention pattern is installed at a crosswalk entrance, a parallel array should be installed in the direction of the crossing. PMID- 28873906 TI - An Analysis and Proposal of 3D Printing Applications for the Visually Impaired. AB - The full 3D printing process is divided into discrete 3 steps. With user-centric approach, the study confirmed that people with visual impairments could use CAD to carry out 3D printing tasks by managing the entire process as long as they had a certain amount of 3D data. PMID- 28873907 TI - Accessibility Analysis of the Eclipse IDE for Users with Visual Impairment. AB - Integrated Development Environments support software developers during their daily work. However, complex graphical interfaces and various functions disable an accessible development environment. We present the results of an online questionnaire, which identifies accessibility issues regarding the Eclipse IDE, and an inclusive tutorial for Eclipse for people with visual impairment. PMID- 28873908 TI - Effects of Optimizing the Scan-Path on Scanning Keyboards with QWERTY-Layout for English Text. AB - Scanning keyboards can be essential tools for individuals with reduced motor function. However, most research addresses layout optimization. Learning new layouts is time-consuming. This study explores the familiar QWERTY layout with alternative scanning paths intended for English text. The results show that carefully designed scan-paths can help QWERTY nearly match optimized layouts in performance. PMID- 28873909 TI - Usability of Optical Mark Reader Sheet as an Answering Tool in Testing. AB - The research result on usability of Optical Mark Reader Sheet (OMRS) being used as the standard answering tool is reported. The use of OMRS significantly requires more answer time than the answer time without OMRS, and the use of assistive devices for OMRS has the possibility to reduce the answer time. PMID- 28873911 TI - Towards a Cognitive Screenreader. AB - This paper describes the current state of development of a tool that assists people with cognitive disabilities while using the internet. The support is provided by interfaces that give additional or alternative information for content or user interaction mechanics that are not understood by the support. PMID- 28873910 TI - Use of Scanning Wizard Can Enhance Text Entry Rate: Preliminary Results. AB - Scanning Wizard software helps scanning users improve the setup of their switch and scanning system. This study is evaluating Scanning Wizard's effectiveness, with nine people who use single-switch scanning participating to date. Text entry rates have improved by an average of 71%, ranging from 29 to 172% improvement. PMID- 28873912 TI - Inclusive Competitive Game Play Through Balanced Sensory Feedback. AB - While game accessibility has improved significantly the last few years, there are still barriers for equal participation and multiplayer issues have been less researched. Game balance is here about making the game fair in a player versus player competitive game. One difficult design task is to balance the game to be fair regardless of visual or hearing capabilities, with clearly different requirements. This paper explores a tentative design method for enabling inclusive competitive game-play without individual adaptations of game rules that could spoil the game. The method involved applying a unified design method to design an unbalanced game, then modifying visual feedback as a hypothetical balanced design, and testing the game with totally 52 people with and without visual or hearing disabilities in three workshops. Game balance was evaluated based on score differences and less structured qualitative data, and a redesign of the game was made. Conclusions are a tentative method for balancing a multiplayer, competitive game without changing game rules and how the method can be applied. PMID- 28873914 TI - Universal Design as a Transformative Agent in Education for All Learners. AB - Universal Design (UD) offers a "whole systems approach" and has the capacity to transform the educational environment to encompass all learners. This paper proposes a new framework for a systems change to address the systemic rigidity that often characterises the education sector today. A human development ecological framework combined with Universal Design (UD) and Universal Design for Learning (UDL) with the potential to transform teaching and learning practices and associated policies, procedures and services for the benefit of all learners. PMID- 28873913 TI - Comparing Accessibility Auditing Methods for Ebooks: Crowdsourced, Functionality Led Versus Web Content Methodologies. AB - This paper presents a gap analysis between crowdsourced functional accessibility evaluations of ebooks conducted by non-experts and the technical accessibility standards employed by developers. It also illustrates how combining these approaches can provide more appropriate information for a wider group of users with print impairments. PMID- 28873915 TI - A Self-Service Approach to Promote Self-Sufficiency, Independence and Inclusion Amongst Disabled Students. AB - This paper presents how SensusAccess has been adapted and is being used in higher education to create inclusive educational environments. Reflecting on challenges of providing alternate versions of educational material to students with disabilities, it also discusses how the service can benefit mainstream learners. PMID- 28873916 TI - ICT and UD: Preliminary Study for Recommendations to Design Accessible University Courses. AB - Starting from the Universal Design in the educational context principles, the experiences gained during the FIRB project "Net@ccessibility" and the high education courses for teachers' specialization on special education, this research will focus on preliminary studies in order to define the recommendations for designing accessible university courses. PMID- 28873917 TI - Universal Design Across the Curriculum: Training for Students and Teachers. AB - Providing an inclusive educational setting for children with disabilities is essential if they are to truly benefit from mainstream education. Universal design (UD) provides a framework to develop our classrooms, materials and methods to accommodate diverse learners and students with special educational needs without the need to retrofit or remove the student from the classroom. This paper outlines the theory and the approach of two training courses on Universal Design developed for teachers and students. PMID- 28873918 TI - Machine Learning Based Evaluation of Reading and Writing Difficulties. AB - The possibility of auto evaluation of reading and writing difficulties was investigated using non-parametric machine learning (ML) regression technique for URAWSS (Understanding Reading and Writing Skills of Schoolchildren) [1] test data of 168 children of grade 1 - 9. The result showed that the ML had better prediction than the ordinary rule-based decision. PMID- 28873919 TI - Development of Mathematical Skills Developing Game Software. AB - Using basic mathematical operations is not easy for everyone. The AndMaths game for Android devices was developed to help elementary school students to learn these basic mathematical skills in the number ranges of twenties, fifties, hundreds and thousands. The user can freely select the number ranges. PMID- 28873920 TI - Lessons from Helen Keller: How to Make the Comics Accessible? AB - This paper addresses the lack of accessibility of the comics for deaf or hard-of hearing readers. Comics are a major cultural object, used in many different contexts with, as much as different purposes (leisure, education, advertising, etc.). We report here the results of an experimentation during a communication operation, including a regular exhibition made of panels and a digital mirroring of the contents, with extra materials and information. This digital part, accessible through our institution website, is the basement of this paper. PMID- 28873921 TI - Education in Care and Technology; Development and Evaluation of a First Cohort of an International Master Course. AB - A report written as a personal communication based on the experience gathered by developing and delivery of a international professional master course. The organization of the curriculum consists of 16 modules. Using a framework of the user centered design and development cycle students receive domain knowledge related to user-orientation, business, innovation and implementation. Also, introduction is given to tools that can be used to investigate certain aspects. The course will be completed by the performance of master thesis research related of a practice oriented problem relevant to the work environment of the student. This master-course has been followed by a first cohort of 8 students. In this report, an evaluation is given on this first delivery. Organization of this course is complicated by the marketing conditions that have to be used. Students and teachers are well supported by the distance based learning environment. The 16 modules representing the content of the course contains a variety of subjects and methods and represents a huge educational load to the students. Translating this content to the development of the own applied research subject contributes to the learning process. The first cohort of students will complete their master thesis in July 2017. Further introduction of new cohorts will mainly depend on the possibility to reduce the financial constraints to participation. PMID- 28873922 TI - Higher Education Beyond Faculties: Interdisciplinary Education in Care and Technology. AB - A Centre of Healthcare and Technology of a Dutch University of Applied Sciences, is presented - and illustrated by project examples - to show how the transitions in the sectors of health care and technology can result in interdisciplinary education in care and technology by means of higher education beyond faculties. PMID- 28873923 TI - Designing Situated Learning Experiences: Interdisciplinary Collaboration for Design Education in Healthcare. AB - This paper describes how the DHW Lab facilitates third mission activities, as well as advancing undergraduate pedagogy and post-graduate research. It suggests there are challenges and opportunities involved in creating a hybrid of two very different organizations, that need to be addressed to advance transdisciplinary education in the 'transformative university'. PMID- 28873924 TI - Simulation in Medical School Education. AB - The Universidade da Beira Interior (UBI), Covilha, Portugal in the medical degree course uses simulation in an integrated and comprehensive program as a pedagogical tool. PMID- 28873925 TI - Roles and Responsibilities of Parents and Therapists in a Kindergarten Treatment Centre. AB - The aim of the study is 1) to gather insights into the current procedure used to coordinate/determine the roles and responsibilities between parents and therapists from a Kindergarten Treatment centre in The Netherlands with respect to the treatment and support of the children and 2) to examine parents and professionals experience in this procedure. PMID- 28873926 TI - Adoption and Use of a Mobile System at Home Care. AB - This research concerns mobile system adoption and use among home care nurses at one home care organization in Finland. The aim was to get insights on somewhat poor adoption and utilization of a mobile system they use. 12 nurses were interviewed and observed at home visit to gain insights on how the system could better facilitate their work routines. A requirement analysis was produced based on the results and is to be discussed with the management of the organization and the service provider. PMID- 28873927 TI - Open DeveloperSpace: An Enabling Infrastructure for Stakeholders to Generate New Access Solutions. AB - The DeveloperSpace, one of the core components of GPII, is a self-sustainable infrastructure and collaborative environment, where developers, implementers, consumers, prosumers and other directly and indirectly involved actors (e.g. teachers, caregivers, clinicians) may interact with and play a role in its viability and the development of new access solutions. PMID- 28873928 TI - Feed3: A Strategy for a 3-Direction Connection Among AT Consumers and Developers. AB - The Feed3 strategy aims to provide AT consumers, developers and manufacturers with Feedback, Feedforwards and FeedPeer mechanisms to collaborate in the development of novel accessible solutions. This strategy was developed as part of the GPII and it is currently adopted by the Unified Listing and DeveloperSpace infrastructure components. PMID- 28873929 TI - Using the Assistance on Demand Platform to Set Up a Network of Assistance Services. AB - The Assistance on Demand (AoD) platform is a novel open-source infrastructure which enables the set-up and web publication of assistance services. This paper focuses on the potential of the AoD functionality to enable the configuration and creation of a Network of Assistance Services (NAS) by non-expert users (e.g. consumers, family members). PMID- 28873930 TI - Use Model for a User Centred Design in Multidisciplinary Teams. AB - The Use Model identifies user groups who will be using services and products the Prosperity4All infrastructure offers. The Model provides developers a tool to keep in mind the full diversity of users while building and designing the infrastructure. PMID- 28873931 TI - Enabling Accessibility Through Model-Based User Interface Development. AB - Adaptive user interfaces (AUIs) can increase the accessibility of interactive systems. They provide personalized display and interaction modes to fit individual user needs. Most AUI approaches rely on model-based development, which is considered relatively demanding. This paper explores strategies to make model based development more attractive for mainstream developers. PMID- 28873932 TI - Stepping Stones for People with Cognitive Disabilities and Low Digital Literacy. AB - The open source components presented have been designed for use by developers creating applications for people with cognitive disabilities or low digital literacy. They provide easy access to common online activities and include configurable levels of complexity to address varying preferences. PMID- 28873933 TI - Gaze-Based Assistive Technology - Use in Everyday Life for Individuals with Impairments. AB - This session focuses on the latest developments of gaze-based assistive technology (AT) and the impact of gaze-based AT interventions in the home and at school. In particular, for play, communication, assessments and early intervention. The discussion focuses on how research findings can advance future developments. PMID- 28873934 TI - The Benefits of Gaze-Based Assistive Technology in Daily Activities for Children with Disabilities. AB - This article reports research findings on how gaze-based assistive technology contributed to performance of daily activities for a group of children with severe physical impairments and without speech. PMID- 28873935 TI - Teachers' Experiences of Hope Using Eye Gaze-Controlled Computers. AB - Technology to control a computer with eye gaze is a fast growing field and has promising implications for people with severe disabilities. 11 school staff was interviewed about teaching using an eye gaze computer for pupils with severe disabilities. The eye gaze computer creates opportunities for the teachers to get a glimpse of emotions and knowledge that is "inside" the pupil's trapped body and creates hope concerning the pupil's future possibilities. The implementation of the eye gaze computer create new imaginations for the future for the pupil and when the teachers are exposing themselves to the uncertainty, hope becomes a source of motivation and behavior. PMID- 28873936 TI - Parent Perception of Two Eye-Gaze Control Technology Systems in Young Children with Cerebral Palsy: Pilot Study. AB - Eye-gaze control technology enables people with significant physical disability to access computers for communication, play, learning and environmental control. This pilot study used a multiple case study design with repeated baseline assessment and parents' evaluations to compare two eye-gaze control technology systems to identify any differences in factors such as ease of use and impact of the systems for their young children. Five children, aged 3 to 5 years, with dyskinetic cerebral palsy, and their families participated. Overall, families were satisfied with both the Tobii PCEye Go and myGaze(r) eye tracker, found them easy to position and use, and children learned to operate them quickly. This technology provides young children with important opportunities for learning, play, leisure, and developing communication. PMID- 28873937 TI - Participation Through Gaze Controlled Computer for Children with Severe Multiple Disabilities. AB - This paper presents work on developing methodology material for use of gaze controlled computers. The target group is families and professionals around children with severe multiple disabilities. The material includes software grids for children at various levels, aimed for communication, leisure and learning and will be available for download. PMID- 28873938 TI - Gaze-Based Assistive Technology for a Toddler with Tetraplegia and Without Speech. AB - This is a case study exploring gaze-based AT as early intervention, for a ten month-old non-verbal child with severe physical impairments. Data was collected repeatedly over time through questionnaires, videos clips, and field observations until the child was three years old. PMID- 28873939 TI - Gaze-Based Assistive Technology - Usefulness in Clinical Assessments. AB - Gaze-based assistive technology was used in informal clinical assessments. Excerpts of medical journals were analyzed by directed content analysis using a model of communicative competence. The results of this pilot study indicate that gaze-based assistive technology is a useful tool in communication assessments that can generate clinically relevant information. PMID- 28873942 TI - Biogeochemical gradients and microbial communities in Winogradsky columns established with polluted wetland sediments. AB - A Winogradsky column is a miniature ecosystem established with enriched sediments that can be used to study the relationship between biogeochemical gradients, microbial diversity and pollutant transformation. Biogeochemical processes and microbial communities changed with time and depth in Winogradsky columns incubated with heavy-metal-polluted wetland sediments for 520 days. 16S rRNA surveys were complemented by geochemical analyses, including heavy metal proportioning, to evaluate gradients in the mostly anoxic columns. Oxygen was depleted below the water-sediment interface (WSI), while NH4+, Fe2+, S2- and acetate increased by one order of magnitude at the bottom. Microbial niche differentiation occurred mainly by depth and from the light-exposed surface to the interior of the columns. Chemical gradients resulting from nutrient uptake by algae, and from iron and sulphate reduction mainly drove diversification. Heavy metal proportioning did not significantly influence microbial diversity as Cu and Zn were immobilised at all depths. Proteobacteria were abundant in the top water and the WSI layers, whereas Firmicutes and Bacteroida dominated down-core. Together with low diversity and richness of communities at the WSI and column bottom, changes in the bacterial community coincided with algal-derived carbon sources and cellulose fermentation, respectively. We expect this study to be the starting point for the use Winogradsky columns to study microbial and geochemical dynamics in polluted sediments. PMID- 28873943 TI - Novel sequence types of extended-spectrum and acquired AmpC beta-lactamase producing Escherichia coli and Escherichia clade V isolated from wild mammals. AB - The closer contact with wildlife due to the growing human population and the destruction of natural habitats emphasizes the need of gaining insight into the role of animals as source of antimicrobial resistance. Here, we aim at characterizing the antimicrobial resistance genes and phylogenetic distribution of commensal Escherichia coli from 62 wild mammals. Isolates exhibiting resistance to >=1 antibiotic were detected in 25.8% of the animals and 6.4% carried an extended-spectrum beta-lactamase (ESBL)/AmpC-producing E. coli. Genetic mechanisms involved in third-generation cephalosporin resistance were as follows: (i) hyperproduction of chromosomal AmpC (hedgehog), (ii) production of acquired CMY-2 beta-lactamase (hedgehog), (iii) production of SHV-12 and CTX-M-14 ESBLs (n = 2, mink and roe-deer). ESBL genes were transferable by conjugation, and blaCMY-2 was mobilized by a 95kb IncI1 plasmid. The distribution of the phylogenetic groups in the E. coli collection studied was B1 (44.6%), B2 (24.6%), E (15.4%), A (4.6%) and F (3.1%). Five isolates (7.7%) were cryptic Escherichia clades (clade IV, 4 mice; clade V, 1 mink). ESBL/AmpC-E. coli isolates showed different sequence types (STs): ST1128/B1, ST4564/B1 (new), ST4996/B1 (new) and a non-registered ST. This study contributes to better understand the E. coli population and antimicrobial resistance flow in wildlife and reports new AmpC-E. coli STs and a first described ESBL-producing Escherichia clade V isolate. PMID- 28873944 TI - Protective efficacy by various doses of a new brucellosis vaccine candidate based on Salmonella strains expressing Brucella abortus BSCP31, Omp3b and superoxide dismutase against brucellosis in murine model. AB - Brucella species are important etiological agents of zoonotic diseases. Attenuated Salmonella strains expressing Brucella abortus BCSP31, Omp3b and superoxide dismutase proteins were tested as vaccine candidates in this study. In order to determine the optimal dose for intraperitoneal (IP) inoculation required to obtain effective protection against brucellosis, mice were immunized with various doses of a mixture of the three vaccine strains. Fifty BALB/c mice were divided into five equal groups (groups A-E). Group A mice were intraperitoneally inoculated with 100 MUL of sterile phosphate-buffered saline. Group B, C, D and E mice were intraperitoneally immunized with approximately 1.2 * 105 colony-forming units (CFU) mL-1 of Salmonella containing pMMP65 in 100 MUL and with 1.2 * 104 CFU mL-1, 1.2 * 105 CFU mL-1 and 1.2 * 106 CFU mL-1 of the mixture of the three strains in 100 MUL, respectively. Serum IgG, tumor necrosis factor alpha and interferon gamma concentrations were significantly higher in group E than in groups A-D. Following challenge with B. abortus 544, the challenge strain was not detected in the spleen of any mouse from group E. Thus, IP immunization with 1.2 * 106 CFU mL-1 of the mixture of the three vaccine strains induced immune responses and provided effective protection against brucellosis in mice. PMID- 28873946 TI - Carbon recycling by cyanobacteria: improving CO2 fixation through chemical production. AB - Atmospheric CO2 levels have reached an alarming level due to industrialization and the burning of fossil fuels. In order to lower the level of atmospheric carbon, strategies to sequester excess carbon need to be implemented. The CO2 fixing mechanism in photosynthetic organisms enables integration of atmospheric CO2 into biomass. Additionally, through exogenous metabolic pathways in these photosynthetic organisms, fixed CO2 can be routed to produce various commodity chemicals that are currently produced from petroleum. This review will highlight studies and modifications to different components of cyanobacterial CO2-fixing systems, as well as the application of these systems toward CO2-derived chemical production. 2,3-Butanediol is given particular focus as one of the most thoroughly studied systems for conversion of CO2 to a bioproduct. PMID- 28873945 TI - Diversity and antimicrobial activity of bacteria isolated from different Brazilian coral species. AB - Corals harbor a wide diversity of bacteria associated with their mucus. These bacteria can play an important role in nutrient cycling, degradation of xenobiotics and defense against pathogens by producing antimicrobial compounds. However, the diversity of the cultivable heterotrophic bacteria, especially in the Brazilian coral species, remains poorly understood. The present work compares the diversity of cultivable bacteria isolated from the mucus and surrounding environments of four coral species present along the Brazilian coast, and explores the antibacterial activity of these bacteria. Bacteria belonging to the phyla Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes were isolated. The mucus environment presented a significantly different bacteria composition, compared to the water and sediment environments, with high abundance of Alcanivorax, Acinetobacter, Aurantimonas and Erythrobacter. No difference in the inhibition activity was found between the isolates from mucus and from the surrounding environment. Eighty-three per cent of the bacteria isolated from the mucus presented antimicrobial activity against Serratia marcescens, an opportunistic coral pathogen, suggesting that they might play a role in maintaining the health of the host. Most of the bacteria isolates that presented positive antimicrobial activity belonged to the genus Bacillus. PMID- 28873947 TI - First report of sasX-positive methicillin-resistant Staphylococcus aureus in Japan. AB - SasX is a known virulence factor of Staphylococcus aureus involved in colonisation and immune evasion of the bacterium. The sasX gene, which is located on the phiSPbeta prophage, is frequently found in the sequence type (ST) 239 S. aureus lineage, which is the predominant healthcare-associated clone in Asian countries. In Japan, ST239 clones have rarely been identified, and sasX-positive strains have not been reported to date. Here, we report the first identification of 18 sasX-positive methicillin-resistant S. aureus (MRSA) strains in Japanese hospitals between 2009 and 2011. All sasX-positive isolates belonged to an ST239 staphylococcal cassette chromosome mec type III (ST239-III) lineage. However, we were unable to identify additional sasX-positive MRSA strains from 2012 to 2016, indicating that the small epidemic of sasX-positive isolates observed in this study was temporary. The sequence surrounding sasX in the strain TOHH628 lacked 51 genes that encode phage packaging and structural proteins, and no bacteriophage was induced by mitomycin C. Additionally, in the TOHH628 strain, the region (64.6 kb) containing sasX showed high identity to the phiSPbeta-like element (71.3 kb) of the Taiwanese MRSA strain Z172. The data strongly suggest that the present sasX-positive isolates found in Japanese hospitals were transmitted incidentally from other countries. PMID- 28873950 TI - Plant Cuttings. PMID- 28873948 TI - Understanding intraspecific variation of floral scent in light of evolutionary ecology. AB - Background and Aims: Among the various floral traits involved in pollinator attraction and potentially under selection mediated by pollinators, floral scent/fragrance has been less investigated than other components of floral phenotype. Whether or not pollinator-mediated selection impacts floral scents depends on the heritability of scent/fragrance and the occurrence of some variation within species. Although most studies have investigated how scent varies among species, growing amounts of data are available on variation at the intraspecific level. Methods: The results of 81 studies investigating intraspecific variation of floral scents in 132 taxa were reviewed. For each study, whether variation was found in either identity, proportion or absolute quantities of volatile organic compounds (VOCs) was recorded, as well as information with the potential to explain variation, such as methodology, plant origin or pollination biology. Key Results: Variation was found for almost all investigated species, both among individuals (among and sometimes within populations) and within individuals across different temporal scales. Cases in which such variation is a possible result of pollinator-mediated selection were analysed, by discussing separately selection related to variation in pollinator identity/behaviour among populations or across time, deceit pollination and sex specific selection. Not surprisingly, in many cases, pollinator-mediated selection alone does not explain the observed variation in floral scent. This led us to review current knowledge on less investigated factors, such as selection mediated by natural enemies, genetic drift and gene flow, environmental constraints, phylogenetic inertia, or biochemical constraints that could be invoked to explain scent variation. Conclusions: This review highlights the great potential of analysing floral scent variation and including it in integrated studies of floral phenotypes. We also have identified the current gaps in our understanding of this complex signal and we propose several methodological and conceptual future directions in this research area. PMID- 28873952 TI - Coronary artery disease: risk factors, haemodynamic significance, anatomic complexity, and platelet lipidome. PMID- 28873951 TI - Position paper of the European Society of Cardiology-working group of coronary pathophysiology and microcirculation: obesity and heart disease. PMID- 28873953 TI - Genome-Wide DNA Methylation Profiling Reveals Epigenetic Adaptation of Stickleback to Marine and Freshwater Conditions. AB - The three-spined stickleback (Gasterosteus aculeatus) represents a convenient model to study microevolution-adaptation to a freshwater environment. Although genetic adaptations to freshwater environments are well-studied, epigenetic adaptations have attracted little attention. In this work, we investigated the role of DNA methylation in the adaptation of the marine stickleback population to freshwater conditions. DNA methylation profiling was performed in marine and freshwater populations of sticklebacks, as well as in marine sticklebacks placed into a freshwater environment and freshwater sticklebacks placed into seawater. We showed that the DNA methylation profile after placing a marine stickleback into fresh water partially converged to that of a freshwater stickleback. For six genes including ATP4A ion pump and NELL1, believed to be involved in skeletal ossification, we demonstrated similar changes in DNA methylation in both evolutionary and short-term adaptation. This suggested that an immediate epigenetic response to freshwater conditions can be maintained in freshwater population. Interestingly, we observed enhanced epigenetic plasticity in freshwater sticklebacks that may serve as a compensatory regulatory mechanism for the lack of genetic variation in the freshwater population. For the first time, we demonstrated that genes encoding ion channels KCND3, CACNA1FB, and ATP4A were differentially methylated between the marine and the freshwater populations. Other genes encoding ion channels were previously reported to be under selection in freshwater populations. Nevertheless, the genes that harbor genetic and epigenetic changes were not the same, suggesting that epigenetic adaptation is a complementary mechanism to selection of genetic variants favorable for freshwater environment. PMID- 28873955 TI - Erratum. PMID- 28873954 TI - Bad Clade Deletion Supertrees: A Fast and Accurate Supertree Algorithm. AB - Supertree methods merge a set of overlapping phylogenetic trees into a supertree containing all taxa of the input trees. The challenge in supertree reconstruction is the way of dealing with conflicting information in the input trees. Many different algorithms for different objective functions have been suggested to resolve these conflicts. In particular, there exist methods based on encoding the source trees in a matrix, where the supertree is constructed applying a local search heuristic to optimize the respective objective function. We present a novel heuristic supertree algorithm called Bad Clade Deletion (BCD) supertrees. It uses minimum cuts to delete a locally minimal number of columns from such a matrix representation so that it is compatible. This is the complement problem to Matrix Representation with Compatibility (Maximum Split Fit). Our algorithm has guaranteed polynomial worst-case running time and performs swiftly in practice. Different from local search heuristics, it guarantees to return the directed perfect phylogeny for the input matrix, corresponding to the parent tree of the input trees, if one exists. Comparing supertrees to model trees for simulated data, BCD shows a better accuracy (F1 score) than the state-of-the-art algorithms SuperFine (up to 3%) and Matrix Representation with Parsimony (up to 7%); at the same time, BCD is up to 7 times faster than SuperFine, and up to 600 times faster than Matrix Representation with Parsimony. Finally, using the BCD supertree as a starting tree for a combined Maximum Likelihood analysis using RAxML, we reach significantly improved accuracy (1% higher F1 score) and running time (1.7-fold speedup). PMID- 28873956 TI - The Estimation of Alzheimer's Disease Causative Genes by Applying an Evolutionary Approach to Medicine. PMID- 28873957 TI - More to the Bunch: Study Finds Large Chromosomal Swaps Key to Banana Domestication. PMID- 28873958 TI - Initial experience with potential application of cardiac magnetic resonance imaging programme for idiopathic monomorphic ventricular arrhythmia in a limited resource environment. PMID- 28873959 TI - Sudden cardiac death among the young in Sweden from 2000 to 2010: an autopsy based study. AB - Aims: To study the incidence and aetiology of sudden cardiac death (SCD) in 1- to 35-year-olds in Sweden from 2000 to 2010. Methods and results: We used the database of the Swedish National Board of Forensic Medicine and the Swedish Cause of Death Registry and identified SCD cases by review of forensic files and death certificates. We identified 552 individuals with SCD in 1- to 35-year-olds; 156 (28%) were women. In 393 (71%), a forensic autopsy had been performed; in 131 (24%), a clinical autopsy had been performed; in 28 (5%) with no autopsy, a cardiac disease was diagnosed before death. The incidence of SCD per 100 000 person-years was 1.3 in 1- to 35-year-olds and 1.8 in 15- to 35-year-olds. In women, the incidence rates yearly decreased during the study period by 11% (95% confidence interval 6.6-14.2). The most common aetiology in 1- to 35-year-olds was sudden arrhythmic death syndrome (31%) and coronary artery disease (15%). In cases with forensic autopsy, death occurred during daily activity (48%), sleep (38%), and physical activity (14%); death was unwitnessed in 60%. Co-morbidity in 15- to 35-year-olds, e.g. psychiatric disorder, obesity, or diabetes, was present in 93/340 (27%) (73 men). Conclusion: The incidence of SCD among 1- to 35-year olds in Sweden during 2000-10 was 1.3 per 100 000 person-years (28% women); incidence was decreasing in women. Sudden arrhythmic death syndrome was the most common diagnosis. Co-morbidity such as psychiatric disorders and obesity was common among men. PMID- 28873960 TI - Cardiac magnetic resonance imaging provides more than a diagnosis. PMID- 28873961 TI - Transcriptome analysis of the response of Burmese python to digestion. AB - Exceptional and extreme feeding behaviour makes the Burmese python (Python bivittatus) an interesting model to study physiological remodelling and metabolic adaptation in response to refeeding after prolonged starvation. In this study, we used transcriptome sequencing of 5 visceral organs during fasting as well as 24 hours and 48 hours after ingestion of a large meal to unravel the postprandial changes in Burmese pythons. We first used the pooled data to perform a de novo assembly of the transcriptome and supplemented this with a proteomic survey of enzymes in the plasma and gastric fluid. We constructed a high-quality transcriptome with 34 423 transcripts, of which 19 713 (57%) were annotated. Among highly expressed genes (fragments per kilo base per million sequenced reads > 100 in 1 tissue), we found that the transition from fasting to digestion was associated with differential expression of 43 genes in the heart, 206 genes in the liver, 114 genes in the stomach, 89 genes in the pancreas, and 158 genes in the intestine. We interrogated the function of these genes to test previous hypotheses on the response to feeding. We also used the transcriptome to identify 314 secreted proteins in the gastric fluid of the python. Digestion was associated with an upregulation of genes related to metabolic processes, and translational changes therefore appear to support the postprandial rise in metabolism. We identify stomach-related proteins from a digesting individual and demonstrate that the sensitivity of modern liquid chromatography/tandem mass spectrometry equipment allows the identification of gastric juice proteins that are present during digestion. PMID- 28873962 TI - A recurrence-based approach for validating structural variation using long-read sequencing technology. AB - Although numerous algorithms have been developed to identify structural variations (SVs) in genomic sequences, there is a dearth of approaches that can be used to evaluate their results. This is significant as the accurate identification of structural variation is still an outstanding but important problem in genomics. The emergence of new sequencing technologies that generate longer sequence reads can, in theory, provide direct evidence for all types of SVs regardless of the length of the region through which it spans. However, current efforts to use these data in this manner require the use of large computational resources to assemble these sequences as well as visual inspection of each region. Here we present VaPoR, a highly efficient algorithm that autonomously validates large SV sets using long-read sequencing data. We assessed the performance of VaPoR on SVs in both simulated and real genomes and report a high-fidelity rate for overall accuracy across different levels of sequence depths. We show that VaPoR can interrogate a much larger range of SVs while still matching existing methods in terms of false positive validations and providing additional features considering breakpoint precision and predicted genotype. We further show that VaPoR can run quickly and efficiency without requiring a large processing or assembly pipeline. VaPoR provides a long read-based validation approach for genomic SVs that requires relatively low read depth and computing resources and thus will provide utility with targeted or low-pass sequencing coverage for accurate SV assessment. The VaPoR Software is available at: https://github.com/mills-lab/vapor. PMID- 28873963 TI - De novo genome assembly and annotation of Australia's largest freshwater fish, the Murray cod (Maccullochella peelii), from Illumina and Nanopore sequencing read. AB - One of the most iconic Australian fish is the Murray cod, Maccullochella peelii (Mitchell 1838), a freshwater species that can grow to ~1.8 metres in length and live to age >=48 years. The Murray cod is of a conservation concern as a result of strong population contractions, but it is also popular for recreational fishing and is of growing aquaculture interest. In this study, we report the whole genome sequence of the Murray cod to support ongoing population genetics, conservation, and management research, as well as to better understand the evolutionary ecology and history of the species. A draft Murray cod genome of 633 Mbp (N50 = 109 974bp; BUSCO and CEGMA completeness of 94.2% and 91.9%, respectively) with an estimated 148 Mbp of putative repetitive sequences was assembled from the combined sequencing data of 2 fish individuals with an identical maternal lineage; 47.2 Gb of Illumina HiSeq data and 804 Mb of Nanopore data were generated from the first individual while 23.2 Gb of Illumina MiSeq data were generated from the second individual. The inclusion of Nanopore reads for scaffolding followed by subsequent gap-closing using Illumina data led to a 29% reduction in the number of scaffolds and a 55% and 54% increase in the scaffold and contig N50, respectively. We also report the first transcriptome of Murray cod that was subsequently used to annotate the Murray cod genome, leading to the identification of 26 539 protein-coding genes. We present the whole genome of the Murray cod and anticipate this will be a catalyst for a range of genetic, genomic, and phylogenetic studies of the Murray cod and more generally other fish species of the Percichthydae family. PMID- 28873964 TI - The pearl oyster Pinctada fucata martensii genome and multi-omic analyses provide insights into biomineralization. AB - Nacre, the iridescent material found in pearls and shells of molluscs, is formed through an extraordinary process of matrix-assisted biomineralization. Despite recent advances, many aspects of the biomineralization process and its evolutionary origin remain unknown. The pearl oyster Pinctada fucata martensii is a well-known master of biomineralization, but the molecular mechanisms that underlie its production of shells and pearls are not fully understood. We sequenced the highly polymorphic genome of the pearl oyster and conducted multi omic and biochemical studies to probe nacre formation. We identified a large set of novel proteins participating in matrix-framework formation, many in expanded families, including components similar to that found in vertebrate bones such as collagen-related VWA-containing proteins, chondroitin sulfotransferases, and regulatory elements. Considering that there are only collagen-based matrices in vertebrate bones and chitin-based matrices in most invertebrate skeletons, the presence of both chitin and elements of collagen-based matrices in nacre suggests that elements of chitin- and collagen-based matrices have deep roots and might be part of an ancient biomineralizing matrix. Our results expand the current shell matrix-framework model and provide new insights into the evolution of diverse biomineralization systems. PMID- 28873965 TI - An expanded mammal mitogenome dataset from Southeast Asia. AB - Southeast (SE) Asia is 1 of the most biodiverse regions in the world, and it holds approximately 20% of all mammal species. Despite this, the majority of SE Asia's genetic diversity is still poorly characterized. The growing interest in using environmental DNA to assess and monitor SE Asian species, in particular threatened mammals-has created the urgent need to expand the available reference database of mitochondrial barcode and complete mitogenome sequences. We have partially addressed this need by generating 72 new mitogenome sequences reconstructed from DNA isolated from a range of historical and modern tissue samples. Approximately 55 gigabases of raw sequence were generated. From this data, we assembled 72 complete mitogenome sequences, with an average depth of coverage of *102.9 and *55.2 for modern samples and historical samples, respectively. This dataset represents 52 species, of which 30 species had no previous mitogenome data available. The mitogenomes were geotagged to their sampling location, where known, to display a detailed geographical distribution of the species. Our new database of 52 taxa will strongly enhance the utility of environmental DNA approaches for monitoring mammals in SE Asia as it greatly increases the likelihoods that identification of metabarcoding sequencing reads can be assigned to reference sequences. This magnifies the confidence in species detections and thus allows more robust surveys and monitoring programmes of SE Asia's threatened mammal biodiversity. The extensive collections of historical samples from SE Asia in western and SE Asian museums should serve as additional valuable material to further enrich this reference database. PMID- 28873966 TI - Draft genome of the Antarctic dragonfish, Parachaenichthys charcoti. AB - The Antarctic bathydraconid dragonfish, Parachaenichthys charcoti, is an Antarctic notothenioid teleost endemic to the Southern Ocean. The Southern Ocean has cooled to -1.8oC over the past 30 million years, and the seawater had retained this cold temperature and isolated oceanic environment because of the Antarctic Circumpolar Current. Notothenioids dominate Antarctic fish, making up 90% of the biomass, and all notothenioids have undergone molecular and ecological diversification to survive in this cold environment. Therefore, they are considered an attractive Antarctic fish model for evolutionary and ancestral genomic studies. Bathydraconidae is a speciose family of the Notothenioidei, the dominant taxonomic component of Antarctic teleosts. To understand the process of evolution of Antarctic fish, we select a typical Antarctic bathydraconid dragonfish, P. charcoti. Here, we have sequenced, de novo assembled, and annotated a comprehensive genome from P. charcoti. The draft genome of P. charcoti is 709 Mb in size. The N50 contig length is 6145 bp, and its N50 scaffold length 178 362 kb. The genome of P. charcoti is predicted to contain 32 712 genes, 18 455 of which have been assigned preliminary functions. A total of 8951 orthologous groups common to 7 species of fish were identified, while 333 genes were identified in P. charcoti only; 2519 orthologous groups were also identified in both P. charcoti and N. coriiceps, another Antarctic fish. Four gene ontology terms were statistically overrepresented among the 333 genes unique to P. charcoti, according to gene ontology enrichment analysis. The draft P. charcoti genome will broaden our understanding of the evolution of Antarctic fish in their extreme environment. It will provide a basis for further investigating the unusual characteristics of Antarctic fishes. PMID- 28873967 TI - Connections between the human gut microbiome and gestational diabetes mellitus. AB - The human gut microbiome can modulate metabolic health and affect insulin resistance, and it may play an important role in the etiology of gestational diabetes mellitus (GDM). Here, we compared the gut microbial composition of 43 GDM patients and 81 healthy pregnant women via whole-metagenome shotgun sequencing of their fecal samples, collected at 21-29 weeks, to explore associations between GDM and the composition of microbial taxonomic units and functional genes. A metagenome-wide association study identified 154 837 genes, which clustered into 129 metagenome linkage groups (MLGs) for species description, with significant relative abundance differences between the 2 cohorts. Parabacteroides distasonis, Klebsiella variicola, etc., were enriched in GDM patients, whereas Methanobrevibacter smithii, Alistipes spp., Bifidobacterium spp., and Eubacterium spp. were enriched in controls. The ratios of the gross abundances of GDM-enriched MLGs to control-enriched MLGs were positively correlated with blood glucose levels. A random forest model shows that fecal MLGs have excellent discriminatory power to predict GDM status. Our study discovered novel relationships between the gut microbiome and GDM status and suggests that changes in microbial composition may potentially be used to identify individuals at risk for GDM. PMID- 28873968 TI - High-precision registration between zebrafish brain atlases using symmetric diffeomorphic normalization. AB - Atlases provide a framework for spatially mapping information from diverse sources into a common reference space. Specifically, brain atlases allow annotation of gene expression, cell morphology, connectivity, and activity. In larval zebrafish, advances in genetics, imaging, and computational methods now allow the collection of such information brain-wide. However, due to technical considerations, disparate datasets may use different references and may not be aligned to the same coordinate space. Two recent larval zebrafish atlases exemplify this problem: Z-Brain, containing gene expression, neural activity, and neuroanatomical segmentations, was acquired using immunohistochemical stains, while the Zebrafish Brain Browser (ZBB) was constructed from live scans of fluorescent reporters in transgenic larvae. Although different references were used, the atlases included several common transgenic patterns that provide potential "bridges" for transforming each into the other's coordinate space. We tested multiple bridging channels and registration algorithms and found that the symmetric diffeomorphic normalization algorithm improved live brain registration precision while better preserving cell morphology than B-spline-based registrations. Symmetric diffeomorphic normalization also corrected for tissue distortion introduced during fixation. Multi-reference channel optimization provided a transformation that enabled Z-Brain and ZBB to be co-aligned with precision of approximately a single cell diameter and minimal perturbation of cell and tissue morphology. Finally, we developed software to visualize brain regions in 3 dimensions, including a virtual reality neuroanatomy explorer. This study demonstrates the feasibility of integrating whole brain datasets, despite disparate reference templates and acquisition protocols, when sufficient information is present for bridging. Increased accuracy and interoperability of zebrafish digital brain atlases will facilitate neurobiological studies. PMID- 28873969 TI - Clinical practice recommendations for native vitamin D therapy in children with chronic kidney disease Stages 2-5 and on dialysis. AB - Vitamin D deficiency is widely prevalent and often severe in children and adults with chronic kidney disease (CKD). Although native vitamin D {25-hydroxyvitamin D [25(OH)D]} is thought to have pleiotropic effects on many organ systems, its skeletal effects have been most widely studied. The 25(OH)D deficiency is causally linked with rickets and fractures in healthy children and those with CKD, contributing to the CKD-mineral and bone disorder (MBD) complex. There are few studies to provide evidence for vitamin D therapy or guidelines for its use in CKD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis WGs have developed recommendations for the evaluation, treatment and prevention of vitamin D deficiency in children with CKD. We present clinical practice recommendations for the use of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) in children with CKD Stages 2-5 and on dialysis. A parallel document addresses treatment recommendations for active vitamin D analogue therapy. The WG has performed an extensive literature review to include meta-analyses and randomized controlled trials in healthy children as well as children and adults with CKD, and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system has been used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD MBD and Dialysis WGs is provided, but clearly GRADE-ed as such and must be carefully considered by the treating physician, and adapted to individual patient needs as appropriate. PMID- 28873970 TI - Immunosuppressive agents in adult kidney transplantation in the National Health Service: a model-based economic evaluation. AB - Background: Immunosuppression is required in kidney transplantation to prevent rejection and prolong graft survival. We conducted an economic evaluation to support England's National Institute for Health and Care Excellence in developing updated guidance on the use of immunosuppression, incorporating new immunosuppressive agents, and addressing changes in pricing and the evidence base. Methods: A discrete-time state transition model was developed to simulate adult kidney transplant patients over their lifetime. A total of 16 different regimens were modelled to assess the cost-effectiveness of basiliximab and rabbit anti-thymocyte globulin (rabbit ATG) as induction agents (with no antibody induction as a comparator) and immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept as maintenance agents (with ciclosporin and azathioprine as comparators). Graft survival was extrapolated from acute rejection rates, graft function and post-transplant diabetes rates, all estimated at 12 months post transplantation. National Health Service (NHS) and personal social services costs were included. Cost-effectiveness thresholds of L20 000 and L30 000 per quality adjusted life year were used. Results: Basiliximab was predicted to be more effective and less costly than rabbit ATG and induction without antibodies. Immediate-release tacrolimus and mycophenolate mofetil were cost-effective as maintenance therapies. Other therapies were either more expensive and less effective or would only be cost-effective if a threshold in excess of L100 000 per quality-adjusted life year were used. Conclusions: A regimen comprising induction with basiliximab, followed by maintenance therapy with immediate release tacrolimus and mycophenolate mofetil, is likely to be effective for uncomplicated adult kidney transplant patients and a cost-effective use of NHS resources. PMID- 28873972 TI - Inflamed fat and mitochondrial dysfunction in end-stage renal disease links to hypoxia-could curcumin be of benefit? PMID- 28873971 TI - Clinical practice recommendations for treatment with active vitamin D analogues in children with chronic kidney disease Stages 2-5 and on dialysis. AB - In patients with chronic kidney disease (CKD), renal synthesis of active vitamin D [1,25-dihydroxyvitamin D (1,25(OH)2D)] declines and is associated with hypocalcaemia, secondary hyperparathyroidism and the spectrum of CKD-mineral and bone disorder (MBD). In advanced CKD, active vitamin D analogues, including alfacalcidol, calcitriol and paricalcitol, are routinely administered. There are few studies on the use of vitamin D analogues in children with CKD and on dialysis. It is difficult to define bone-specific outcomes that can guide treatment with active vitamin D analogues in children with CKD-MBD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD MBD and Dialysis WGs has developed recommendations for the use of active vitamin D therapy in children with CKD and on dialysis. A second document in parallel with this one covers treatment recommendations for native vitamin D therapy. The WGs have performed an extensive literature review to include systematic reviews and randomized controlled trials in adults and children with CKD and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system was used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD-MBD and Dialysis WGs is provided, but clearly GRADE ed as such and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. PMID- 28873974 TI - Therapeutic Drug Monitoring of Fluoxetine, Norfluoxetine and Paroxetine: A New Tool Based on Microextraction by Packed Sorbent Coupled to Liquid Chromatography. AB - The present article reports the first liquid chromatography (LC) assay for the simultaneous quantification of fluoxetine (FLU), its metabolite norfluoxetine (NFLU) and paroxetine (PAR) in human plasma, applying the microextraction by packed sorbent (MEPS) technology in sample preparation. Chromatographic analysis of FLU, NFLU and PAR was achieved in <13 min on a reverse-phase C18 column using isocratic elution and fluorescence detection (FLD). The mobile phase was composed by an aqueous solution of 25 mM sodium phosphate monobasic anhydrous and 7.5 mM di-potassium hydrogen phosphate anhydrous (pH 3.0)/acetonitrile/methanol (70:23:7, v/v/v). The detector was set at 240/312 nm for FLU, NFLU and IS and at 295/350 nm for PAR. The method showed linearity in the ranges of 20-750 ng mL-1 for FLU and NFLU, and 5-750 ng mL-1 for PAR (r2 >= 0.9919). The overall intra- and interday precision did not exceed 13.6% and the corresponding accuracy (bias) ranged from 0.02 to 16.7%. The method was successfully applied in the analysis of authentic plasma samples. Hence, this new MEPS/LC-FLD assay ensures robust and low-cost analyses representing, therefore, a good alternative to support therapeutic drug monitoring and clinical studies involving these antidepressant drugs. PMID- 28873973 TI - Effect of renal transcatheter arterial embolization on quality of life in patients with autosomal dominant polycystic kidney disease. AB - Background: Currently, there are few strategies for improving the quality of life (QOL) in patients with autosomal dominant polycystic kidney disease (ADPKD) and massive kidneys. Renal transcatheter arterial embolization (TAE) reduces kidney volume, but its impact on QOL in ADPKD patients on hemodialysis is unknown. This study investigated the influence of renal TAE on QOL in ADPKD patients with massive kidneys receiving hemodialysis. Methods: This prospective observational study enrolled 188 ADPKD patients on hemodialysis (92 men and 96 women; mean age 56.7 +/- 9.1 years) who underwent renal TAE at Toranomon Hospital between August 2010 and July 2014. The 36-item Short Form Health Survey (SF-36) and our original 15-item questionnaire were used to evaluate QOL. Results: Using a linear mixed model, the least squares mean values of the SF-36 physical component summary (PCS), mental component summary (MCS) and role/social component summary (RCS) before renal TAE were calculated as 38.21 [95% confidence interval (CI) 36.50 39.91], 48.45 (47.05-49.86) and 43.04 (40.70-45.37), respectively. These values improved to 42.0 (40.22-43.77; P < 0.001 versus before TAE), 51.25 (49.78-52.71; P = 0.001) and 49.67 (47.22-52.12; P < 0.001), respectively, 1 year after renal TAE. Scores for abdominal fullness, poor appetite and heartburn showed marked improvement after renal TAE, while scores for fever, bodily pain and sleep disorder also improved slightly, but significantly. Scores for constipation and use of analgesics/sleeping medications/laxatives did not improve significantly. All of the SF-36 scores and the scores for specific symptoms (except bodily pain, snoring and constipation) were significantly correlated with the sequential decrease of the height-adjusted total kidney volume. Conclusions: In ADPKD patients on hemodialysis, renal TAE was effective in improving abdominal fullness, appetite, heartburn and SF-36 scores (MCS and RCS scores), but not for sleep disturbance, constipation and physical strength (PCS score). PMID- 28873975 TI - Comparison of Post-targeted and Pre-targeted Urine Drug Screening by UHPLC-HR QTOFMS. AB - The current illicit drug scene, with its unpredictable appearance of new psychoactive substances, challenges drug-testing laboratories. Ultra-high performance liquid chromatography-high-resolution quadrupole time-of-flight mass spectrometry (UHPLC-HR-QTOFMS) provides an especially versatile analytical platform for responding to this continuous change. QTOFMS can be used to collect nonselective MS/MS by broadband data-independent acquisition (DIA), recording all product ions regardless of the precursor ion. Another approach is to collect selective MS/MS by data-dependent acquisition (DDA), using a narrow precursor mass window with preset criteria such as the presence of a particular ion among a precursor ion list. The present study compared methods based on these two modes of data acquisition on a single UHPLC-HR-QTOFMS instrument setup and using identical sample preparation. The DIA method relied on a post-targeted reverse database search and the DDA method on a spectrum library search, each comprising the same selection of 200 drugs of abuse. The performance between the methods was compared in terms of the limit of identification (LOI) and specificity. The median LOI of the DIA method (8 ng/mL) was lower than that of the DDA method (16 ng/mL). Among the 20 model compounds, a better LOI was obtained with DIA for 13 compounds. DIA was superior in resolving closely eluting and co-eluting isomeric and isobaric compounds. Comparison between the feasibility of DIA and DDA for casework was carried out by analyzing 50 authentic case urine samples. DIA produced 266 identifications involving 46 different substances, and DDA produced 225 identifications involving 42 substances. Moreover, substance identification by DIA was more straightforward and the method was easier to deploy in casework. Nonetheless, the DDA approach with substance-specific collision energies produced informative product ion spectra suitable for occasional confirmatory analyses. PMID- 28873976 TI - Rapid Determination of Aconitum Alkaloids from Human Urine by UHPLC-HRMS. AB - Aconitum alkaloid poisoning is a type of poisoning caused by accidental ingestion and clinical use of herbal drugs in many countries. In this study, we developed an in-syringe dispersive micro solid-phase extraction (DMSPE) method for selective extraction of aconitine, benzoylaconine and aconine from human urine using a type of polymer material. All of the parameters influencing the extraction efficiency such as the type and amount of sorbent, the extraction time and the desorption solvent and volume in DMSPE were carefully investigated and optimized. Using DMSPE method, the absence of evaporation and centrifugation steps reduced the consuming time of sample preparation. Samples were analyzed by ultra high-performance liquid chromatography-high-resolution mass spectrometry on an HSS T3 analytical column. The results showed that the DMSPE method yielded fewer relative and absolute matrix effects, which reduced the sample to sample variability in human urine. The limits of detection and limits of quantitation of this method were determined to be 0.08-0.1 and 0.2-0.3 MUg/L, respectively. The average recoveries of the analytes were between 88.6% and 107.2% with the intra- and interday precisions ranging from 2.1% to 6.4% and from 5.9% to 13.9%, respectively. The method presented here is an efficient, low-cost and selective extraction of aconitine, benzoylaconine and aconine from human urine. PMID- 28873977 TI - One-Step Derivatization-Extraction Method for Rapid Analysis of Eleven Amphetamines and Cathinones in Oral Fluid by GC-MS. AB - A simple analytical method was developed for in-matrix derivatization of 11 amphetamine-like molecules. Ethyl chloroformate as the derivatization reagent and ethyl acetate as the extraction solvent were added directly to oral fluid samples at alkaline pH. Samples were analyzed by gas chromatography-mass spectrometry. Ions monitored for quantification were m/z 44, 91 and 116 for amphetamine (AMP); m/z 58, 91 and 130 for methamphetamine (MA); m/z 44, 105 and 116 for 4 methylamphetamine; m/z 44, 116 and 251 for 3,4-methylenedioxyamphetamine; m/z 58, 130 and 265 for 3,4-methylenedioxymethamphetamine (MDMA); m/z 72, 116 and 144 for 3,4-methylenedioxyethylamphetamine; m/z 44, 105 and 116 for cathinone; m/z 58, 105 and 130 for methcathinone; m/z 58, 119 and 130 for mephedrone; m/z 58, 107 and 130 for ephedrine (EPH); m/z 207, 250 and 322 for fenethylline; m/z 48, 92 and 120 for AMP-D5; m/z 62, 92 and 134 for MA-D5; m/z 48, 120 and 256 for MDA-D5; and m/z 62, 134 and 270 for MDMA-D5. The underlined ions were used as quantifier ions. Calibration curves were linear in the concentration range of 2.5-1,000 ng/mL for all analytes except for EPH, which was linear within 5-1,000 ng/mL. Precision and accuracy were less than 12.9% (relative standard deviation) and +/ 12.8% (bias), respectively, for all analytes. The method was tested in the analysis of oral fluid specimens collected from users. PMID- 28873978 TI - Construction and application of multi-host integrative vector system for xylose fermenting yeast. AB - The xylose-fermenting yeasts (CTG clade yeasts, e.g. Scheffersomyces stipitis, Spathaspora passalidarum, Candida amazonensis and Candida jeffriesii) have the potential to be superior platforms for the conversion of lignocellulosic hydrolysate into fuel-grade ethanol and other chemical products. Here, a genetic expression system compatible with the genetic coding characteristics of CTG clade yeasts was constructed for use in xylose-fermenting yeasts. The pRACTH-gfpm plasmid based on an 18S rDNA shuttle vector was capable of stable integration into the genomes of a wide range of heterologous hosts. Green fluorescent protein was transformed and functionally expressed in S. stipitis, S. passalidarum, C. jeffriesii, C. amazonensis and Saccharomyces cerevisiae under control of the SpADH1 promoter and SpCYC1 terminator. Finally, the expression system was useful in multiple yeast hosts for construction of the plasmid pRACTH-ldh. Scheffersomyces stipitis, S. passalidarum, C. jeffriesii, C. amazonensis and S. cerevisiae were enabled to produce lactate from glucose or xylose by pRACTH-based expression of a heterologous lactate dehydrogenase. Among them, C. amazonensis (pRACTH-ldh) exhibited the highest lactate fermentation capacity, which reached a maximum of 44 g L-1 of lactate with a yield of 0.85 g lactate/g xylose. PMID- 28873979 TI - The recruitment of the Saccharomyces cerevisiae poly(A)-binding protein into stress granules: new insights into the contribution of the different protein domains. AB - The Saccharomyces cerevisiae poly(A)-binding protein Pab1 is a modular protein composed of four RNA recognition motifs (RRM), a proline-rich domain (P) and a C terminus. Thanks to this modularity, Pab1 is involved in different interactions that regulate many aspects of mRNA metabolism, including the assembly of stress granules. In this work, we analyzed the contribution of each domain for the recruitment of the protein within stress granules by comparing the intracellular distribution of synthetic Pab1-GFP variants, lacking one or more domains, with the localization of the endogenous mCherry-tagged Pab1. Glucose starvation and heat shock were used to trigger the formation of stress granules. We found that Pab1 association into these aggregates relies mainly on RRMs, whose number is important for an efficient recruitment of the protein. Interestingly, although the P and C domains do not directly participate in Pab1 association to stress granules, their presence strengthens or decreases, respectively, the distribution of synthetic Pab1 lacking at least one RRM into these aggregates. In addition to describing the contribution of domains in determining Pab1 association within stress granules, the outcomes of this study suggest the modularity of Pab1 as an attractive platform for synthetic biology approaches aimed at rewiring mRNA metabolism. PMID- 28873980 TI - Human primary myeloid dendritic cells interact with the opportunistic fungal pathogen Aspergillus fumigatus via the C-type lectin receptor Dectin-1. AB - Aspergillus fumigatus is an opportunistic fungal pathogen causing detrimental infections in immunocompromised individuals. Dendritic cells (DCs) are potent antigen-presenting cells and recognize the A. fumigatus cell wall component beta 1,3 glucan via Dectin-1, followed by DC maturation and cytokine release. Here, we demonstrate that human primary myeloid DCs (mDCs) interact with different morphotypes of A. fumigatus. Dectin-1 is expressed on mDCs and is down-regulated after contact with A. fumigatus, indicating that mDCs recognize A. fumigatus via this receptor. Blocking of Dectin-1, followed by stimulation with depleted zymosan diminished the up-regulation of the T-cell co-stimulatory molecules CD40, CD80, HLA-DR and CCR7 on mDCs and led to decreased release of the cytokines TNF alpha, IL-8, IL-1beta and IL-10. PMID- 28873981 TI - "His Native, Hot Country"1: Racial Science and Environment in Antebellum American Medical Thought. AB - Relying on a close reading of more than 4,000 medicals student theses, this essay explores the evolving medical approaches to race and environment in the early national and antebellum United States and highlights the role that medical school pedagogy played in disseminating and elaborating racial theory. Specifically, it considers the influence of racial science on medical concepts of the relationship of bodies to climates. At their core, monogenesis-belief in a single, unified human race-and polygenesis-the belief that each race was created separately-were theories about the human body's connections to the natural world. As polygenesis became influential in Atlantic medical thought, physicians saw environmental treatments as a matter of matching bodies to their natural ecology. In the first decades of the nineteenth century, Atlantic physicians understood bodies and places as in constant states of flux. Through proper treatment, people and environments could suffer either degradation or improvement. Practitioners saw African Americans and whites as the same species with their differences being largely superficial and produced by climate. However, by the 1830s and 1840s medical students were learning that each race was inherently different and unalterable by time or temperature. In this paradigm, medical students articulated a vision of racial health rooted in organic relationships between bodies and climates. PMID- 28873982 TI - "Forgotten" Chapters in the History of Transcervical Sterilization: Carl Clauberg and Hans-Joachim Lindemann. AB - Transcervical sterilization is a non-surgical method of permanent female sterilization that is widely used and critically discussed. A review of the historiography of the method reveals that instances of its coercive use are not included in the historical account. This study offers a reexamination of the work of Carl Clauberg and Hans-Joachim Lindemann, to more deeply contextualize within the framework of current usage the coercive use of transcervical sterilization during the Third Reich and in postwar Germany. This inquiry is based on postwar criminal trial records on Clauberg, and on archival documents detailing Lindemann's activities in 1979. A comparative analysis examines arguments by medical historian Karl-Heinz Roth, and identifies shared characteristics and differences between Clauberg and Lindemann, their methods and scientific connections. The results demonstrate that the technique of transcervical sterilization has an abusive potential that may be explained as a function of the person of the physician, of the scientific method itself, and of societal and political influences. The analysis supports the argument that insights from the cases of Clauberg and Lindemann are transferrable geographically and over time, and have the potential to inform current medical practice, such as transcervical sterilization with the Essure device, whose historiographic exploration remains a desideratum. PMID- 28873983 TI - Efficient laboratory evolution of computationally designed enzymes with low starting activities using fluorescence-activated droplet sorting. PMID- 28873984 TI - A role for macromolecular crowding in off-target binding of therapeutic antibodies. AB - The nonspecific binding of certain therapeutic antibodies to tissues or to soluble biomolecules can accelerate their clearance from the circulation and undermine their benefit to patients. This article proposes that tandem amino acid repeat sequences in antibody hypervariable segments, particularly the complementarity determining regions (CDRs), can enhance this off-target binding. This hypothesis is based on two sets of observations. First, in a limited number of cases, antibodies with clusters of amino acid repeats in their CDRs have significantly higher clearance rates in experimental animals than otherwise identical antibodies without the repeats. Second, tandem amino acid repeats are abundant in intracellular hub proteins where they appear to promote the promiscuous binding of these proteins to a wide variety of other molecules. These nonspecific hub protein interactions are highly favored by the intense macromolecular crowding that permeates the cytoplasm. A survey of the variable region sequences of 137 antibodies in various stages of development revealed that 26 have at least one CDR containing a cluster of three closely spaced amino acid repeats. If the overall hypothesis is valid, then it suggests strategies for site directed mutagenesis to improve pharmacokinetic behavior and for the design of more reliable in vitro binding assays to predict off-target binding in vivo. PMID- 28873985 TI - The influence of different linker modifications on the catalytic activity and cellulose affinity of cellobiohydrolase Cel7A from Hypocrea jecorina. AB - Various cellulases consist of a catalytic domain connected to a carbohydrate binding module (CBM) by a flexible linker peptide. The linker if often strongly O glycosylated and typically has a length of 20-50 amino acid residues. Functional roles, other than connecting the two folded domains, of the linker and its glycans, have been widely discussed, but experimental evidence remains sparse. One of the most studied cellulose degrading enzymes is the multi-domain cellobiohydrolase Cel7A from Hypocrea jecorina. Here, we designed variants of Cel7A with mutations in the linker region to elucidate the role of the linker. We found that moderate modification of the linker could result in significant changes in substrate affinity and catalytic efficacy. These changes were quite different for different linker variants. Thus, deletion of six residues near the catalytic domain had essentially no effects on enzyme function. Conversely, a substitution of four glycosylation sites near the middle of the linker reduced substrate affinity and increased maximal turnover. The observation of weaker binding provides some support of recent suggestions that linker glycans may be directly involved in substrate interactions. However, a variant with several inserted glycosylation sites near the CBM also showed lower affinity for the substrate compared to the wild-type, and we suggest that substrate interactions of the glycans depend on their exact location as well as other factors such as changes in structure and dynamics of the linker peptide. PMID- 28873987 TI - Understanding the role of residues around the active site tunnel towards generating a glucose-tolerant beta-glucosidase from Agrobacterium tumefaciens 5A. AB - Most beta-glucosidases are subjected to inhibition by the final hydrolysis product glucose resulting in the accumulation of cellobiose and oligosaccharides. This accumulated cellobiose and oligosaccharides further inhibit the activities of endoglucanase and cellobiohydrolases, resulting in the inhibition of cellulose degradation and a more expensive biofuel. To elucidate the mechanism(s) of glucose tolerance, we designed and characterised six mutations of a moderately glucose-tolerant beta-glucosidase (H0HC94) from the mesophilic bacterium Agrobacterium tumefaciens 5A. The hydrophobicity and steric were varied across non-conserved residues in specific regions of the active site tunnel. In contrast to the uncompetitive inhibition of WT enzyme by glucose, C174V and H229S are competitively inhibited pointing towards a possible glucose-binding site in the protein at these positions. Increasing hydrophobicity at the +1 subsite and increasing hydrophobicity and steric at +2 subsites seemed to be critical for glucose tolerance for this BG. Additionally, in L178E, specific activity was 1.8 times higher on the natural substrate cellobiose while both W127F and L178E mutants showed an enhancement in thermostability. The kinetic stability of W127F, V176A, L178A and L178E also increased between 2- and 3-folds compared to WT. Our results indicate that while the structure between subsites +1 and +2 is critical for the glucose tolerance, the specific residues may not be identical across such enzymes. PMID- 28873988 TI - News From the Foundation for Physical Therapy. PMID- 28873989 TI - Decompressive Hemicraniectomy in the Setting of Poststroke Cerebral Edema: A Case for Early Intervention. PMID- 28873990 TI - Commentary: Results of the ANSWER Trial Using the PulseRider(r) for the Treatment of Broad-necked, Bifurcation Aneurysms. PMID- 28873991 TI - Thrombolytic Removal of Intraventricular Hemorrhage in Treatment of Severe Stroke: Results of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III Trial. PMID- 28873986 TI - Tuning DNA binding affinity and cleavage specificity of an engineered gene targeting nuclease via surface display, flow cytometry and cellular analyses. AB - The combination of yeast surface display and flow cytometric analyses and selections is being used with increasing frequency to alter specificity of macromolecular recognition, including both protein-protein and protein-nucleic acid interactions. Here we describe the use of yeast surface display and cleavage dependent flow cytometric assays to increase the specificity of an engineered meganuclease. The re-engineered meganuclease displays a significantly tightened specificity profile, while binding its cognate target site with a slightly lower, but still sub-nanomolar affinity. When incorporated into otherwise identical megaTAL protein scaffolds, these two nucleases display significantly different activity and toxicity profiles in cellulo. The structural basis for reprogrammed DNA cleavage specificity was further examined via high-resolution X-ray crystal structures of both enzymes. This analysis illustrated the altered protein-DNA contacts produced by mutagenesis and selection, that resulted both in altered readout of those based and a necessary reduction in DNA binding affinity that were necessary to improve specificity across the target site. The results of this study provide an illustrative example of the potential (and the challenges) associated with the use of surface display and flow cytometry for the retargeting and optimization of enzymes that act on nucleic acid substrates in a sequence specific manner. PMID- 28873992 TI - Genetic Susceptibility for Sciatica and Lumbar Disc Herniation. PMID- 28873993 TI - Intraventricular Nimodipine for Aneurysmal Subarachnoid Hemorrhage: Results of the NEWTON Phase 1/2a Study. PMID- 28873994 TI - Cognitive Dysfunction of Astronomical Proportions. PMID- 28873995 TI - Reduced H3K27me3 is a New Epigenetic Biomarker for Pediatric Posterior Fossa Ependymomas. PMID- 28873997 TI - Electrical Stimulation of the Mesial Temporal Lobe to Enhance Memory: More Questions than Answers. PMID- 28873996 TI - Phase I/II Trial of Combination of Temozolomide Chemotherapy and Immunotherapy With Fusions of Dendritic and Glioma Cells in Patients With Glioblastoma. PMID- 28873998 TI - Food and Drug Administration Issues Warning of Neurodevelopmental Risks With General Anesthesia. PMID- 28874001 TI - Forty years of NEUROSURGERY. PMID- 28874000 TI - Dr. Robert H. Wilkins, Past-CNS President and Founding Editor of Neurosurgery, Passes Away. PMID- 28874002 TI - The following is the original Editorial Introduction, written by Dr. Robert H. Wilkins and published in the inaugural issue of Neurosurgery, July 1977. PMID- 28874003 TI - Editorial Notice. PMID- 28874005 TI - Corrigendum. PMID- 28874006 TI - Is the immune response a friend or foe for viral therapy of glioma? PMID- 28874004 TI - Glioma groups classified by IDH and TERT promoter mutations remain stable among primary and recurrent gliomas. PMID- 28874008 TI - STOPPFrail: a misleading name for a potentially useful tool. PMID- 28874009 TI - Response to Dr Caballero-Mora's comments. PMID- 28874007 TI - New horizons in comprehensive geriatric assessment. AB - In this article, we discuss the emergence of new models for delivery of comprehensive geriatric assessment (CGA) in the acute hospital setting. CGA is the core technology of Geriatric Medicine and for hospital inpatients it improves key outcomes such as survival, time spent at home and institutionalisation. Traditionally It is delivered by specialised multidisciplinary teams, often in dedicated wards, but in recent years has begun to be taken up and developed quite early in the admission process (at the 'front door'), across traditional ward boundaries and in specialty settings such as surgical and pre-operative care, and oncology. We have scanned recent literature, including observational studies of service evaluations, and service descriptions presented as abstracts of conference presentations to provide an overview of an emerging landscape of innovation and development in CGA services for hospital inpatients. PMID- 28874010 TI - Not5-dependent co-translational assembly of Ada2 and Spt20 is essential for functional integrity of SAGA. PMID- 28874012 TI - Potential Resting and Breeding Sites of Sand Flies (Diptera: Psychodidae) and Their Habitat Characteristics in Leishmaniasis Foci of Dir Districts, Khyber Pakhtunkhwa, Pakistan. AB - Despite their medical importance, natural breeding sites of sand flies have been poorly explored. Detecting such sites is imperative in vector control strategies. This study aimed to identify potential breeding and resting microhabitats of sand flies and household risk factors associated with cutaneous leishmaniasis transmission in Dir districts, Khyber Pakhtunkhwa, Pakistan. Survey of indoor and outdoor habitats in four tehsils (subdistricts) of upper and lower Dir districts was carried out using sticky traps, flit method, and aspirator. To assess risk factors associated with cutaneous leishmaniasis (CL), questionnaires were administered to household heads. Mud houses and plants belonging to Cucurbitaceae family sheltered highest number of sand flies. Excessive number of flies were collected from indoor sites (common rooms used for both people and animals) compared to outdoor habitats (cattle dungs). Phlebotomus salangensis Artemiev, 1978 and Phlebotomus sergenti were the most widely distributed species, while Sergentomyia bailyi peaked in caves with high organic content in soil. Roof material and ownership of fans were associated with significant risk of CL. Findings of this study present a list of potential breeding sites for sand flies and CL risk factors that can be targeted and implemented in control programs for CL. Further studies are required to elucidate the breeding behavior and preferences of these medically important vectors. PMID- 28874011 TI - Abundance and Bloodfeeding Patterns of Mosquitoes (Diptera: Culicidae) in an Oak Woodland on the Eastern Slope of the Northern Coast Range of California. AB - The abundance and bloodfeeding patterns of mosquitoes was studied from 2008 to 2010 at an 18 ha. oak woodland in Lake County, CA. Host-seeking females were collected weekly from sunset to sunrise by paired dry-ice-baited CDC style traps, whereas resting females were aspirated from paired walk-in red boxes. Sequences of the COI gene amplified from bloodmeals from engorged resting females were used to identify the bloodmeal hosts. Aedes sierrensis (Ludlow) and Aedes increpitus Dyar complex mosquitoes were univoltine, although the timing of emergence and abundance varied temporally and seemed weather dependent. Abundance of both Anopheles franciscanus McCracken and Anopheles freeborni Aitken peaked in mid to late summer. Females of both genera bloodfed primarily on mule deer and black tailed jackrabbits, and few fed on either dogs or humans that were consistently present within the woodland. In contrast, multivoltine Culex tarsalis Coquillett and Culex stigmatosoma Dyar were abundant throughout summer, especially from July to September. Both Culex species bloodfed on a wide variety of avian hosts, with most bloodmeals originating from California scrub-jay, wild turkey, oak titmouse, and house finch. Culex tarsalis fed on proportionately more mammals as summer progressed, peaking at 33% in September. PMID- 28874013 TI - Response: The Geographic Distribution of Ixodes scapularis (Acari: Ixodidae) Revisited: The Importance of Assumptions About Error Balance. PMID- 28874014 TI - Updated Reported Distribution of Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus (Diptera: Culicidae) in the United States, 1995-2016. AB - Aedes (Stegomyia) aegypti (L.) and Aedes (Stegomyia) albopictus (Skuse) are potential vectors of Zika, dengue, and chikungunya viruses in the United States. A Zika virus outbreak in Florida in the summer of 2016, driven by Ae. aegypti and resulting in > 200 locally acquired cases of human illness, underscored the need for up-to-date information on the geographic distribution of Ae. aegypti and Ae. albopictus in the United States. In early 2016, we conducted a survey and literature review to compile county records for presence of Ae. aegypti and Ae. albopictus in the United States from 1995 to 2016. Surveillance for these vectors was intensified across the United States during the summer and fall of 2016. At the end of 2016, we therefore conducted a follow-up survey of mosquito control agencies, university researchers, and state and local health departments to document new collection records for Ae. aegypti and Ae. albopictus. The repeated survey at the end of the year added Ae. aegypti collection records from 38 new counties and Ae. albopictus collection records from 127 new counties, representing a 21 and 10 percent increase, respectively, in the number of counties with reported presence of these mosquitoes compared with the previous report. Moreover, through our updated survey, 40 and 183 counties, respectively, added additional years of collection records for Ae. aegypti and Ae. albopictus from 1995 to 2016. Our findings underscore the continued need for systematic surveillance of Ae. aegypti and Ae. albopictus. PMID- 28874015 TI - Arboviruses Isolated From Mosquitoes Collected in Uganda, 2008-2012. AB - A large number of arthropod-borne viruses are endemic to East Africa. As a part of the process of undertaking a systematic characterization of the mosquito fauna of Uganda, we examined mosquitoes collected from 2008 through early 2012 for known and novel viruses. In all, 8,288 mosquito pools containing 157,554 mosquitoes were tested. Twenty-nine isolations of 11 different viruses were made from mosquitoes of nine distinct species and from pools identified only to genus Culex. Identified viruses were from family Togaviridae, alphaviruses Sindbis and Babanki viruses; family Rhabdoviridae, hapaviruses Mossuril and Kamese viruses; family Flaviviridae, flaviviruses West Nile and Usutu viruses; family Phenuiviridae, phlebovirus Arumowot virus; and family Peribunyaviridae, orthobunyaviruses Witwatersrand, Pongola, and Germiston viruses. In addition, a novel orthobunyavirus, provisionally named Mburo virus, was isolated from Coquillettidia metallica (Theobald). This is the first report of Babanki, Arumowot, and Mossuril virus isolation from Uganda. PMID- 28874018 TI - Erratum. PMID- 28874016 TI - Transmission of the Lyme Disease Spirochete Borrelia mayonii in Relation to Duration of Attachment by Nymphal Ixodes scapularis (Acari: Ixodidae). AB - The recently recognized Lyme disease spirochete, Borrelia mayonii, has been detected in host-seeking Ixodes scapularis Say ticks and is associated with human disease in the Upper Midwest. Although experimentally shown to be vector competent, studies have been lacking to determine the duration of time from attachment of a single B. mayonii-infected I. scapularis nymph to transmission of spirochetes to a host. If B. mayonii spirochetes were found to be transmitted within the first 24 h after tick attachment, in contrast to Borrelia burgdorferi spirochetes (>24 h), then current recommendations for tick checks and prompt tick removal as a way to prevent transmission of Lyme disease spirochetes would need to be amended. We therefore conducted a study to determine the probability of transmission of B. mayonii spirochetes from single infected nymphal I. scapularis ticks to susceptible experimental mouse hosts at three time points postattachment (24, 48, and 72 h) and for a complete feed (>72-96 h). No evidence of infection with or exposure to B. mayonii occurred in mice that were fed upon by a single infected nymph for 24 or 48 h. The probability of transmission by a single infected nymphal tick was 31% after 72 h of attachment and 57% for a complete feed. In addition, due to unintended simultaneous feeding upon some mice by two B. mayonii-infected nymphs, we recorded a single occasion in which feeding for 48 h by two infected nymphs resulted in transmission and viable infection in the mouse. We conclude that the duration of attachment of a single infected nymphal I. scapularis tick required for transmission of B. mayonii appears to be similar to that for B. burgdorferi: transmission is minimal for the first 24 h of attachment, rare up to 48 h, but then increases distinctly by 72 h postattachment. PMID- 28874017 TI - Environmental Drivers of Seasonal Patterns of Host Utilization by Culiseta melanura (Diptera: Culicidae) in Florida. AB - Field studies were carried out in four Florida counties to investigate winter and spring ecology of host use by Culiseta melanura (Coquillet), the primary vector of eastern equine encephalomyelitis virus (EEEV) in North America. Bloodmeal analysis by PCR was used to identify 233 host bloodmeals, which mainly originated from birds (78.5%) and reptiles (17.2%), primarily Anolis spp. lizards. Across counties, the percentage of bloodmeals from reptiles (7-37% depending upon county) increased with increasing day length and temperature in the spring. Multiple logistic regression revealed that differences in reptile host use across collection sites were largely explained by differences in average day length and temperature on the day of collection, and is probably owing to environment-driven behavioral patterns of ectothermic animals. Although past studies have demonstrated reptile biting by epizootic vectors of EEEV, including Culex (Melanoconion) spp., this is the first study to demonstrate widespread and common feeding upon ectothermic hosts by Cs. melanura. This work suggests that reptiles, particularly anole lizards, play a role in the ecology of EEEV in Florida either as amplifying hosts or as noncompetent hosts which dilute vector feedings thereby suppressing transmission. Detailed laboratory studies investigating impacts of environmental variables (temperature and photoperiod) on EEEV competence of anoles are needed to assess whether these animals support virus amplification. PMID- 28874020 TI - Is PMI the Hypothesis or the Null Hypothesis? AB - Over the past several decades, there have been several strident exchanges regarding whether forensic entomologists estimate the postmortem interval (PMI), minimum PMI, or something else. During that time, there has been a proliferation of terminology reflecting this concern regarding "what we do." This has been a frustrating conversation for some in the community because much of this debate appears to be centered on what assumptions are acknowledged directly and which are embedded within a list of assumptions (or ignored altogether) in the literature and in case reports. An additional component of the conversation centers on a concern that moving away from the use of certain terminology like PMI acknowledges limitations and problems that would make the application of entomology appear less useful in court-a problem for lawyers, but one that should not be problematic for scientists in the forensic entomology community, as uncertainty is part of science that should and can be presented effectively in the courtroom (e.g., population genetic concepts in forensics). Unfortunately, a consequence of the way this conversation is conducted is that even as all involved in the debate acknowledge the concerns of their colleagues, parties continue to talk past one another advocating their preferred terminology. Progress will not be made until the community recognizes that all of the terms under consideration take the form of null hypothesis statements and that thinking about "what we do" as a null hypothesis has useful legal and scientific ramifications that transcend arguments over the usage of preferred terminology. PMID- 28874019 TI - Detection in Malaysia of a Borrelia sp. From Haemaphysalis hystricis (Ixodida: Ixodidae). AB - Spirochetes from the Borrelia genus are known to cause diseases in humans, namely Lyme disease and relapsing fever. These organisms are commonly transmitted to humans by arthropod vectors including ticks, mite, and lice. Here, we report the molecular detection of a Borrelia sp. from a Haemaphysalis hystricis Supino tick collected from wildlife in an Orang Asli settlement in Selangor, Malaysia. Phylogenetic analyses of partial 16s rRNA and flaB gene sequences revealed that the Borrelia sp. is closely related to the relapsing fever group borreliae, Borrelia lonestari, Borrelia miyamotoi, and Borrelia theileri, as well as a number of uncharacterized Borrelia sp. from ticks in Portugal and Japan. To our knowledge, this is the first report of a Borrelia sp. detected in H. hystricis, and in Malaysia. The zoonotic potential of this Borrelia sp. merits further investigation. PMID- 28874021 TI - Comment on Seri Masran and Ab Majid 2017. PMID- 28874022 TI - Ex vivo administration of trimetazidine improves post-transplant lung function in pig model. AB - OBJECTIVES: Ex vivo lung perfusion (EVLP) is not only used to assess marginal donor lungs but is also used as a platform to deliver therapeutic agents outside the body. We previously showed the beneficial effects of trimetazidine (TMZ) on ischaemia reperfusion (IR) injury in a rat model. This study evaluated the effects of TMZ in a pig EVLP transplant model. METHODS: Pig lungs were retrieved and stored for 24 h at 4 degrees C, followed by 4 h of EVLP. Allografts were randomly allocated to 2 groups ( n = 5 each). TMZ (5 mg/kg) was added to the prime solution prior to EVLP. After EVLP, left lungs were transplanted and recipients were observed for 4 h. Allograft gas exchange function and lung mechanics were recorded hourly throughout reperfusion. Microscopic lung injury and inflammatory and biochemical parameters were assessed. RESULTS: There was a trend towards better oxygenation during EVLP in the TMZ group ( P = 0.06). After transplantation, pulmonary gas exchange was significantly better during the 4-h reperfusion period and after isolation of the allografts for 10 min ( P < 0.05). Tissue thiobarbituric acid levels, myeloperoxidase activity and protein concentrations in bronchoalveolar lavage samples were significantly lower in the TMZ group at the end of EVLP ( P < 0.05). CONCLUSIONS: Ex vivo treatment of donor lungs with TMZ significantly improved immediate post-transplant lung function. Further studies are warranted to understand the effect of this strategy on long-term lung function. PMID- 28874023 TI - Can we make recovered donor lungs look brand-new again? PMID- 28874025 TI - Contemporary results of aortic valve repair for congenital disease: lessons for management and staged strategy. AB - OBJECTIVES: Any aortic valve (AoV) operation in children (repair, Ross or mechanical replacement) is a palliation and reinterventions are frequent. AoV repair is a temporary solution primarily aimed at allowing the patient to grow to an age when more definitive solutions are available. We retrospectively analysed AoV repair effectiveness across the whole age spectrum of children, excluding neonates and AoV disease secondary to congenital heart disease. METHODS: From 2003 to 2015, 193 consecutive patients were included. The mean age was 9.2 +/- 6.9 years (22% <1 year); 86 (45%) had a preceding balloon valvuloplasty. The indications for the procedure were stenotic (n = 123; 64%), regurgitant (n = 63; 33%) or combined (n = 7; 4%) disease. The procedures performed were commissurotomy shaving (n = 74; 38%), leaflet replacement (n = 78; 40%), leaflet extension (n = 21; 11%) and neocommissure creation (n = 21; 11%). Post-repair geometry was tricuspid in 137 (71%) patients. RESULTS: The 10-year survival rate was 97.1%. Freedom from reoperation and replacement at 7 years was, respectively, 57% (95% confidence interval, 47-66) and 68% (95% confidence interval, 59-76). In multivariate analysis, balloon dilatation before 6 months, the absence of a developed commissure, a non-tricuspid post-repair geometry and cross-clamp duration were predictors for reoperation and replacement. After a mean follow-up period of 5.1 +/- 3.0 years, 145 (75%) patients had a preserved native valve, with undisturbed valve function (peak gradient <40 mmHg, regurgitation <=mild) in 113 (58%). CONCLUSIONS: Aortic valve repair in children is safe and effective in delaying the timing for more definitive solution. Surgical strategy should be individualized according to the age of the patient. Avoidance of early balloon dilatation and aiming for a tricuspid post-repair arrangement may improve outcomes. PMID- 28874024 TI - Transatlantic Editorial on transcatheter aortic valve replacement. PMID- 28874026 TI - Percutaneous coronary interventions with second-generation drug-eluting stent versus off-pump coronary artery bypass grafting: mid-term results. PMID- 28874028 TI - Geographical differences in the ratio of percutaneous and surgical myocardial revascularization procedures in the treatment of coronary artery disease. PMID- 28874029 TI - Are complex aortic valve repairs a real alternative to replacement in children? PMID- 28874027 TI - Coronary artery bypass surgery is superior to second generation drug-eluting stents in three-vessel coronary artery disease: a propensity score matched analysis. AB - OBJECTIVES: Compared with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) appears to be a promising revascularization strategy for multivessel coronary disease. Trials comparing these treatments have not used second-generation drug-eluting stents (2nd DES). We conducted a retrospective evaluation of both treatments using a propensity score-matched analysis (PSMA). METHODS: A total of 537 patients with three-vessel with/without left-main-trunk coronary artery disease underwent CABG (n = 239) or primary PCI using 2nd DES (298) at a single institution. PSMA resulted in 168 matched pairs. For both treatments, Kaplan-Meier analysis and Cox regression were used to compare all-cause mortality, cardiac death, myocardial infarction (MI), stroke rates and target-vessel revascularization (TVR). RESULTS: The CABG group included sicker patients with renal dysfunction, peripheral vascular disease, low ejection fraction and current smokers than those in the PCI group. After PSMA, both groups were well matched in all parameters. Mean follow-up (months) was 32 in CABG and 35 in PCI. In the unmatched patient population, there was no difference in the incidence of all-cause death, cardiac death, MI, or stroke but the incidence of TVR was significantly higher in the PCI group [hazard ratio (HR) 4.63; 95% confidence interval (95% CI) 2.43-8.82; P < 0.001] and, after PSMA, the incidence of all-cause death (HR 2.71; 95% CI 1.14-6.46; P = 0.019) and TVR (HR 9.0; 95% CI 2.73-29.67; P < 0.001) was significantly higher in the PCI group than in the CABG group. CONCLUSIONS: In patients with three-vessel coronary artery disease, CABG is associated with better survival and less revascularization than PCI using 2nd DES at mid-term results. PMID- 28874030 TI - Synergistic effects of remote perconditioning with terminal blood cardioplegia in an in vivo piglet model. AB - OBJECTIVES: This study tested the hypothesis that remote perconditioning offers effective and synergistic cardioprotection to terminal warm blood cardioplegia for prompt ventricular recovery after prolonged cardioplegic arrest in an in vivo piglet model. METHODS: Twenty-four piglets were subjected to 120 min of single dose cardioplegic arrest and were divided into 4 groups according to the mode of reperfusion: control (simple aortic unclamp), remote perconditioning, terminal warm blood cardioplegia or remote perconditioning + terminal warm blood cardioplegia; remote perconditioning (4 cycles of 5-min ischaemia-reperfusion of the lower limb) was applied prior to aortic unclamping. Left ventricular systolic and diastolic functions were assessed by pressure-volume loop analysis at baseline and after 60 min of reperfusion. Biochemical injury was evaluated by plasma troponin T level. RESULTS: The control group showed decreased end-systolic elastance, preload recruitable stroke work and inverse of end-diastolic pressure volume relationship of 51.3 +/- 14.0%, 46.1 +/- 22.5% and 34.8 +/- 14.9%, respectively. Percentage recovery of end-systolic elastance and preload recruitable stroke work were significantly better with terminal warm blood cardioplegia (with or without remote perconditioning) (end-systolic elastance: 95% confidence interval, 38.6-84.1; preload recruitable stroke work: 95% confidence interval, 0.4-54.3). Percentage recovery of inverse of end-diastolic pressure-volume relationship was significantly better in the remote perconditioning groups (with or without terminal warm blood cardioplegia) (95% confidence interval, 1.6-41.6). No synergistic effects of remote perconditioning and terminal warm blood cardioplegia on troponin T release were noted. CONCLUSIONS: Remote perconditioning offers promising synergistic cardioprotection to terminal warm blood cardioplegia, implicating potential clinical benefit by contributing to prompt left ventricular functional recovery during paediatric open-heart surgery. PMID- 28874031 TI - Standardized definitions of structural deterioration and valve failure in assessing long-term durability of transcatheter and surgical aortic bioprosthetic valves: a consensus statement from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) endorsed by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). PMID- 28874032 TI - Standards defining a 'Heart Valve Centre': ESC Working Group on Valvular Heart Disease and European Association for Cardiothoracic Surgery Viewpoint. PMID- 28874033 TI - Thoracic aortic surgery enters the era of big data. PMID- 28874034 TI - The impact of entries and exits on false lumen thrombosis and aortic remodelling. AB - OBJECTIVES: In DeBakey Type I acute aortic dissection, the frozen elephant trunk technique is used for the combined treatment of both the proximal and distal thoracic aorta. Anatomical characteristics of the distal aorta and their impact on false lumen (FL) thrombosis and aortic remodelling were analysed in this study. METHODS: Sufficient pre-, postoperative, and at least one 1-year follow-up computed tomography data sets were available for 63 of 94 patients treated with the frozen elephant trunk for Type I acute aortic dissection between March 2005 and March 2015. Aortic remodelling and FL thrombosis quotients were calculated volumetrically at the stent graft level (A), from A to the coeliac trunk (B) and from B to the bifurcation (C) and were correlated with the number and size of entry tears and aortic branches arising from the FL (exits) in each segment. RESULTS: Positive or stable remodelling was found in Segments A (94%), B (64%) and C (54%), and the FL thrombosis quotient was 98% in A, 68% in B and 39% in C within the first year. FL thrombosis correlated negatively with the total size of the entry (P<0.001) and the number of exits (P<0.001) and positively with the number of true-lumen branches (P<0.001). The exit number was a risk factor for FL patency and a predictor of negative remodelling. CONCLUSIONS: Using frozen elephant trunk technique to treat Type I acute aortic dissection facilitates positive or stable remodelling in nearly all patients at the stent graft level and distally in two-thirds of the patients. FL thrombosis and aortic remodelling are negatively influenced by the number of exits. New endovascular concepts aiming at reducing the number of exits may prevent negative remodelling. PMID- 28874035 TI - Neulich Nachts in Houston. PMID- 28874037 TI - Spotlight on recently published ICVTS articles. PMID- 28874036 TI - Relationship between onset of spontaneous pneumothorax and weather conditions. AB - OBJECTIVES: Spontaneous pneumothorax (SP) results from the rupture of blebs or bullae. It has been suggested that changes in weather conditions may trigger the onset of SP. Our aim was to examine the association between the onset of primary SP with weather changes in the general population in Sapporo, Japan. METHODS: From January 2008 through September 2013, 345 consecutive cases with a diagnosis of primary SP were reviewed. All cases of primary SP developed in the area within 40 km from the Sapporo District Meteorological Observatory. Climatic measurements were obtained from the Observatory, which included 1-h readings of weather conditions. Logistic regression model was used to obtain predicted risks for the onset of SP with respect to weather conditions. RESULTS: SP occurred significantly when the atmospheric pressure decreased by - 18 hPa or less during 96 h before the survey date (odds ratio = 1.379, P = 0.026), when the pressure increased by 15 hPa or more during 72 h before the survey date (odds ratio = 1.095, P = 0.007) and when maximum fluctuation in atmospheric pressure over 22 hPa was observed during 96 h before the survey date (odds ratio = 1.519, P = 0.001). Other weather conditions, including the presence of thunderstorms, were not significantly correlated with the onset of pneumothorax. CONCLUSIONS: Changes in atmospheric pressure influence the onset of SP. Future studies on the relationship between the onset of SP and weather conditions on days other than before the onset and with large number of patients may enable us to predict the onset of SP in various regions and weather conditions. PMID- 28874039 TI - Hepatic and Splenic Volumetry Could Be Used as an Imaging Parameter to Evaluate Fibrosis Grades of the Diffuse Liver Disease Including Nonalcoholic Fatty Liver Disease. PMID- 28874038 TI - Atrophic Gastritis Increases the Risk of Gastric Cancer in Asymptomatic Population in Korea. PMID- 28874040 TI - Direct Acting Antiviral Agents in Korean Patients with Chronic Hepatitis C and Hemophilia Who Are Treatment-Naive or Treatment-Experienced. AB - Background/Aims: Chronic hepatitis C (CHC) is a major comorbidity in patients with hemophilia. Methods: Patients (n=30) were enrolled between September 2015 and April 2016. Twenty-six patients were genotype 1 (1b, n=21; 1a, n=5) and four patients were genotype 2a/2b. Among 21 patients with genotype 1b, Y93H resistance associated variants (RAVs) were detected in three patients (14.3%). We evaluated sustained virologic response (SVRs) at 12 weeks, as well as relapse and safety. Results: Five patients with genotype 1a and three patients with genotype 1b (RAV positive) received ledipasvir/sofosbuvir for 12 weeks. SVR12 rate was 100% (8/8). Eleven patients with genotype 1b were treatment-naive and received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 91% (10/11). One patient experienced viral breakthrough without RAV at 12 weeks. Seven treatment experienced patients with genotype 1b received daclatasvir plus asunaprevir for 24 weeks. SVR12 rate was 85.7% (6/7). One patient experienced viral breakthrough with RAV (L31M, Y93H) at 12 weeks. Four patients with genotype 2a/2b received sofosbuvir plus ribavirin for 12 weeks. SVR12 rate was 100% (4/4). No serious adverse event-related discontinuations were noted. Conclusions: New direct acting antiviral treatment achieved high SVRs rates at 12 weeks in CHC patients with hemophilia without serious adverse events. PMID- 28874041 TI - The Advantage of an Endoscopic Submucosal Tunneling Technique for Rectal Carcinoid Tumors. AB - Endoscopic treatment can be a curative option for small carcinoid tumors with an extremely low risk of metastasis. Since most carcinoid tumors are characterized by a specific growth pattern in the submucosal (SM) layer, specialized endoscopic techniques for deeper resection to achieve clear vertical margins are needed. The endoscopic submucosal dissection (ESD) method in the SM space is superior to conventional endoscopic mucosal resection. However, the standard ESD technique sometimes fails to provide complete deep SM dissection due to insufficient SM lifting. Here, to resolve this problem, we describe our initial experience with an endoscopic SM tunneling technique that is effective for treating rectal carcinoid tumors. PMID- 28874042 TI - Adverse drug reaction monitoring during antimicrobial therapy for septicemia patients at a university hospital in New Delhi. AB - BACKGROUND/AIMS: Adverse drug reaction (ADR) is an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product. The present study was conducted in order to monitor the frequency and severity of ADR during antimicrobial therapy of septicemia. METHODS: A prospective, observational, and noncomparative study was conducted over a period of 6 months on patients of septicemia admitted at a university hospital. Naranjo algorithm scale was used for causality assessment. Severity assessment was done by Hartwig severity scale. RESULTS: ADRs in selected hospitalized patients of septicemia was found to be in 26.5% of the study population. During the study period, 12 ADRs were confirmed occurring in 9, out of 34 admitted patients. Pediatric patients experienced maximum ADRs, 44.4%. Females experienced a significantly higher incidence of ADRs, 66.7%. According to Naranjo's probability scale, 8.3% of ADRs were found to be definite, 58.3% as probable, and 33.3% as possible. A higher proportion of these ADRs, 66.7% were preventable in nature. Severity assessment showed that more than half of ADRs were moderate. Teicoplanin was found to be the commonest antimicrobial agent associated with ADRs, followed by gemifloxacin and ofloxacin. CONCLUSION: The incidence and severity of ADRs observed in the present study was substantially high indicating the need of extra vigilant during the antimicrobial therapy of septicemia. PMID- 28874043 TI - Gastroesophageal Reflux Disease Could Progress to Achalasia. PMID- 28874044 TI - Genetic Design via Combinatorial Constraint Specification. AB - We present a formal language for specifying via constraints a "design space" of DNA constructs composed of genetic parts, and an algorithm for automatically and correctly creating a novel representation of the space of satisfying designs. The language is simple, captures a large class of design spaces, and possesses algorithms for common operations on design spaces. The flexibility of this approach is demonstrated using a 16-gene nitrogen fixation pathway and genetic logic circuits. PMID- 28874045 TI - Anion-Selective Cholesterol Decorated Macrocyclic Transmembrane Ion Carriers. AB - Anion transporters play a vital role in cellular processes and their dysregulation leads to a range of diseases such as cystic fibrosis, Bartter's syndrome and epilepsy. Synthetic chloride transporters are known to induce apoptosis in cancer cell lines. Herein, we report triamide macrocycles that are easily synthesized and externally functionalized by pendant membrane-permeable groups. Among a variety of chains appended onto the macrocycle scaffold, cholesterol is found to be the best with an EC50 value of 0.44 MUM. The macrocycle is highly anion-selective and transports ions via an OH-/X- antiport mechanism. The macrocycle is an interesting scaffold for ion-transport as it is able to discriminate between various anions and shows a preference for SCN- and Cl-. Such anion-selective transporters are highly attractive model systems to study ion-transport mechanisms and could potentially be of high therapeutic value. PMID- 28874046 TI - Intracellular Proteolytic Disassembly of Self-Quenched Near-Infrared Nanoparticles Turning Fluorescence on for Tumor-Targeted Imaging. AB - The design of tumor-targeting, intracellular protease-activatable near-infrared fluorescence (NIRF) nanoprobes is broadly interesting but remains challenging. In this work, we report the rational design of a NIR probe Cys(StBu)-Lys(Biotin)-Lys Lys(Cy5.5)-CBT (1) to facilely prepare the self-quenched nanoparticles 1-NPs for tumor-targeted imaging in vitro and in vivo. The biotinylated 1-NPs could be actively uptaken by biotin receptor-overexpressing tumor cells via receptor mediated endocytosis. Upon intracellular proteolytic cleavage, 1-NPs were disassembled to yield the small molecular probe Lys(Cy5.5)-Luciferin-Lys(Biotin) Lys-OH (1-D-cleaved), accompanied by fluorescence "Turn-On". With this NIRF "Turn On" property, 1-NPs were successfully applied for tumor-targeted imaging. We envision that our nanoparticles could be applied for fluorescence-guided tumor surgery in the near future. PMID- 28874047 TI - Concentration of Beneficial Phytochemicals in Harvested Grain of U.S. Yellow Dent Maize (Zea mays L.) Germplasm. AB - Although previous studies have examined the concentration of various nutritional compounds in maize, little focus has been devoted to the study of commercial maize hybrids or their inbred parents. In this study, a genetically and phenotypically diverse set of maize hybrids and inbreds relevant to U.S. commercial maize germplasm was evaluated for its variability in phytochemical content. Total protein, unsaturated fatty acids, tocopherols, soluble phenolics, and insoluble-bound phenolics were evaluated in this study. Of these compounds, only soluble and insoluble-bound phenolic acids exhibited means and variances that were at least as large as the means and variances reported for other sets of germplasm. This suggests that selection for high phenolic acid content is possible in current U.S. commercial germplasm. In contrast, while the total protein, unsaturated fatty acid, or tocopherol content could possibly be improved using current U.S. commercial germplasm, the results of this study indicate that the incorporation of more diverse sources of germplasm would most likely result in quicker genetic gains. PMID- 28874048 TI - Oxidative Heck Reaction as a Tool for Para-selective Olefination of Aniline: A DFT Supported Mechanism. AB - This study describes the first para-selective palladium-catalyzed alkenylation of tertiary amines. This regioselective C-H activation was conducted without any chelation moieties. A series of olefins were reacted under mild reaction conditions at 60 degrees C, and the corresponding products were obtained in good yields with high selectivity. PMID- 28874049 TI - Understanding the Capsanthin Tails in Regulating the Hydrophilic-Lipophilic Balance of Carbon Dots for a Rapid Crossing Cell Membrane. AB - Here we use natural Chinese paprika to prepare a new kind of amphiphilic carbon dot (A-Dot) that exhibits bright, multicolored fluorescence and contains hydrophilic groups as well as lipophilic capsanthin tails on the surface. It is found that the capsanthin tails in a phospholipid-like structure can promote cell internalization of the A-Dots via crossing cell membranes rapidly in an energy independent fashion. Compared to highly hydrophilic carbon dots (H-Dots), a control sample prepared from the microwave thermolysis of citric acid and ethylenediamine, our synthesized A-Dots can be taken up by CHO, HeLa, and HFF cells more easily. More importantly, we develop a method to calibrate the hydrophilic-lipophilic balance (HLB) values of various kinds of carbon dots (C Dots). HLB values of A-Dots and H-Dots are determined to be 6.4 and 18.4, respectively. Moreover, we discover that the cellular uptake efficiency of C-Dots is closely related to their HLBs, and the C-Dots with an HLB value of around 6.4 cross the cell membrane easier and faster. As we regulate the HLB value of the A Dots from 6.4 to 15.3 by removing the capsanthin tails from their surfaces via alkali refluxing, it is found that the refluxed A-Dots can hardly cross HeLa cell membranes. Our work is an essential step toward understanding the importance of regulating the HLB values as well as the surface polarity of the C-Dots for their practical use in bioimaging and also provides a simple but effective way to judge whether the C-Dots in hand are appropriate for cell imaging. PMID- 28874050 TI - Thermal Gradient Mid- and Far-Infrared Spectroscopy as Tools for Characterization of Protein Carbohydrate Lyophilizates. AB - Protein drugs play an important role in modern day medicine. Typically, these proteins are formulated as liquids requiring cold chain processing. To circumvent the cold chain and achieve better storage stability, these proteins can be dried in the presence of carbohydrates. We demonstrate that thermal gradient mid- and far-infrared spectroscopy (FTIR and THz-TDS, respectively) can provide useful information about solid-state protein carbohydrate formulations regarding mobility and intermolecular interactions. A model protein (BSA) was lyophilized in the presence of three carbohydrates with different size and protein stabilizing capacity. A gradual increase in mobility was observed with increasing temperature in formulations containing protein and/or larger carbohydrates (oligo or polysaccharides), lacking a clear onset of fast mobility as was observed for smaller molecules. Furthermore, both techniques are able to identify the glass transition temperatures (Tg) of the samples. FTIR provides additional information as it can independently monitor changes in protein and carbohydrate bands at the Tg. Lastly, THz-TDS confirms previous findings that protein-carbohydrate interactions decrease with increasing molecular weight of the carbohydrate, which results in decreased protein stabilization. PMID- 28874051 TI - Mechanism of Particle Formation in Silver/Epoxy Nanocomposites Obtained through a Visible-Light-Assisted in Situ Synthesis. AB - A detailed understanding of the processes taking place during the in situ synthesis of metal/polymer nanocomposites is crucial to manipulate the shape and size of nanoparticles (NPs) with a high level of control. In this paper, we report an in-depth time-resolved analysis of the particle formation process in silver/epoxy nanocomposites obtained through a visible-light-assisted in situ synthesis. The selected epoxy monomer was based on diglycidyl ether of bisphenol A, which undergoes relatively slow cationic ring-opening polymerization. This feature allowed us to access a full description of the formation process of silver NPs before this was arrested by the curing of the epoxy matrix. In situ time-resolved small-angle X-ray scattering investigation was carried out to follow the evolution of the number and size of the silver NPs as a function of irradiation time, whereas rheological experiments combined with near-infrared and ultraviolet-visible spectroscopies were performed to interpret how changes in the rheological properties of the matrix affect the nucleation and growth of particles. The analysis of the obtained results allowed us to propose consistent mechanisms for the formation of metal/polymer nanocomposites obtained by light assisted one-pot synthesis. Finally, the effect of a thermal postcuring treatment of the epoxy matrix on the particle size in the nanocomposite was investigated. PMID- 28874052 TI - Erratum. PMID- 28874053 TI - The Unfinished Puzzle of Glutathione Physiological Functions, an Old Molecule That Still Retains Many Enigmas. AB - Glutathione (GSH) is the most abundant nonprotein thiol found in living organisms. Since its discovery 130 years ago, understanding its cellular functions has been the subject of intensive research. Common scientific knowledge states that GSH is a major nonenzymatic antioxidant and redox buffer. Recent approaches that consider GSH compartmentation in the eukaryotic cell challenge this traditional view and reveal novel unexpected insights into GSH metabolism and physiology. This Forum on GSH features six review articles that focus on GSH metabolism and functions in mitochondria and the endoplasmic reticulum; its connection to cellular iron homeostasis, carcinogenesis, and anticancer drug resistance; a revisited view of GSH degradation pathways; and reconsiders old concepts of its mode of action by highlighting the importance of kinetics over thermodynamic redox equilibria. Antioxid. Redox Signal. 27, 1127-1129. PMID- 28874054 TI - Critical View on Mesenchymal Stromal Cells in Regenerative Medicine. AB - SIGNIFICANCE: The belief in the potency of stem cells has resulted in the medical applications of numerous cell types for organ repair, often with the low adherence to methodological stringency. Such uncritical enthusiasm is mainly presented in the approaches employing so-called mesenchymal stem cells (MSC), for the treatment of numerous, unrelated conditions. However, it should be stressed that such broad clinical applications of MSC are mostly based on the belief that MSC can efficiently differentiate into multiple cell types, not only osteoblasts, chondrocytes and adipose cells. Recent Advances: Studies employing lineage tracing established more promising markers to characterize MSC identity and localization in vivo and confirmed the differences between MSC isolated from various organs. Furthermore, preclinical and clinical experiments proved that transdifferentiation of MSC is unlikely to contribute to repair of numerous tissues, including the heart. Therefore, the salvage hypotheses, like MSC fusion with cells in target organs or the paracrine mechanisms, were proposed to justify the widespread application of MSC and to explain transient, if any, effects. CRITICAL ISSUES: The lack of standardization concerning the cells markers, their origin and particularly the absence of stringent functional characterization of MSC, leads to propagation of the worrying hype despite the lack of convincing therapeutic efficiency of MSC. FUTURE DIRECTIONS: The adherence to rigorous methodological rules is necessary to prevent the application of procedures which can be dangerous for patients and scientific research on the medical application of stem cells. Antioxid. Redox Signal. 00, 000-000. PMID- 28874055 TI - Exploring Symptom Clusters in People With Heart Failure. AB - Patients with heart failure (HF) experience multiple symptoms or symptom clusters. The purposes of this study were to (a) determine if distinct latent classes of HF symptoms could be identified, and (b) explore whether sociodemographic and clinical characteristics influenced symptom cluster membership. A total of 4,011 HF patients recruited from outpatient setting completed the Minnesota Living With Heart Failure Questionnaire (MLHFQ), including five physical symptoms (edema, shortness of breath, fatigue-increased need to rest, fatigue-low energy, and sleep difficulties) and three psychological symptoms (worrying, feeling depressed, and cognitive problems). Four distinct classes using latent class profile analysis were identified: low distress (Class 1), physical distress (Class 2), psychological distress (Class 3), and high distress (Class 4). Significant differences among the four latent classes were found for age, education level, and comorbidities. Symptom clusters are useful for recognition of HF symptoms, allowing for the development of strategies that target symptom groups. PMID- 28874056 TI - Ceruloplasmin, a Potential Therapeutic Agent for Alzheimer's Disease. AB - AIMS: Ceruloplasmin (CP), a ferrous oxidase enzyme, plays an important role in regulating iron metabolism and redox reactions. Previous studies showed that CP deficiency contributes to Parkinson's disease by increasing iron accumulation and oxidative stress in the substantia nigra. However, the role of CP in Alzheimer's disease (AD) is unclear. We hypothesized that the lack of CP gene expression would affect the pathogenesis and damage of AD by promoting abnormal iron levels and oxidative stress. RESULTS: AD mouse models were induced in CP knockout mouse either by injection of Abeta25-35 into the lateral ventricle of the brain or transgenic APP expression. CP levels were decreased significantly in the hippocampus of AD patients, as well as Abeta-CP+/+ and APP-CP+/+ mice. Compared to control AD mice, CP gene deletion increased memory impairment and iron accumulation, which could be associated with elevated reactive oxygen species (ROS) levels and lead to cell apoptosis mediated through the Bcl-2/Bax and Erk/p38 signaling pathways in Abeta-CP-/- and APP-CP-/- mice. In contrast, the restoration of CP expression to CP-/- mice through injection of an exogenous expression plasmid into the brain ventricle alleviated Abeta-induced neuronal damage in the hippocampus. INNOVATION: CP alterations in iron contents were mediated through DMT1(-IRE) and changes in ROS levels, which in turn attenuated the progression of AD through the Erk/p38 and Bcl-2/Bax signaling pathways. CONCLUSION: Our results show a protective role of CP in AD and suggest that regulating CP expression in the hippocampus may provide a new neuroprotective strategy for AD. Antioxid. Redox Signal. 28, 1323-1337. PMID- 28874058 TI - Lacosamide-Induced Thrombotic Thrombocytopenic Purpura. PMID- 28874060 TI - Reiki Is Better Than Placebo and Has Broad Potential as a Complementary Health Therapy. AB - This study reviews the available clinical studies of Reiki to determine whether there is evidence for Reiki providing more than just a placebo effect. The available English-language literature of Reiki was reviewed, specifically for peer-reviewed clinical studies with more than 20 participants in the Reiki treatment arm, controlling for a placebo effect. Of the 13 suitable studies, 8 demonstrated Reiki being more effective than placebo, 4 found no difference but had questionable statistical resolving power, and only one provided clear evidence for not providing benefit. Viewed collectively, these studies provide reasonably strong support for Reiki being more effective than placebo. From the information currently available, Reiki is a safe and gentle "complementary" therapy that activates the parasympathetic nervous system to heal body and mind. It has potential for broader use in management of chronic health conditions, and possibly in postoperative recovery. Research is needed to optimize the delivery of Reiki. PMID- 28874059 TI - A Tale of Two Concepts: Harmonizing the Free Radical and Antagonistic Pleiotropy Theories of Aging. AB - SIGNIFICANCE: The two foremost concepts of aging are the mechanistic free radical theory (FRT) of how we age and the evolutionary antagonistic pleiotropy theory (APT) of why we age. Both date from the late 1950s. The FRT holds that reactive oxygen species (ROS) are the principal contributors to the lifelong cumulative damage suffered by cells, whereas the APT is generally understood as positing that genes that are good for young organisms can take over a population even if they are bad for the old organisms. Recent Advances: Here, we provide a common ground for the two theories by showing how aging can result from the inherent chemical reactivity of many biomolecules, not just ROS, which imposes a fundamental constraint on biological evolution. Chemically reactive metabolites spontaneously modify slowly renewable macromolecules in a continuous way over time; the resulting buildup of damage wrought by the genes coding for enzymes that generate such small molecules eventually masquerades as late-acting pleiotropic effects. In aerobic organisms, ROS are major agents of this damage but they are far from alone. CRITICAL ISSUES: Being related to two sides of the same phenomenon, these theories should be compatible. However, the interface between them is obscured by the FRT mistaking a subset of damaging processes for the whole, and the APT mistaking a cumulative quantitative process for a qualitative switch. FUTURE DIRECTIONS: The manifestations of ROS-mediated cumulative chemical damage at the population level may include the often-observed negative correlation between fitness and the rate of its decline with increasing age, further linking FRT and APT. Antioxid. Redox Signal. 29, 1003-1017. PMID- 28874057 TI - Emerging Omics Approaches in Aging Research. AB - SIGNIFICANCE: Aging is a complex trait that is influenced by a combination of genetic and environmental factors. Although many cellular and physiological changes have been described to occur with aging, the precise molecular causes of aging remain unknown. Given the biological complexity and heterogeneity of the aging process, understanding the mechanisms that underlie aging requires integration of data about age-dependent changes that occur at the molecular, cellular, tissue, and organismal levels. Recent Advances: The development of high throughput technologies such as next-generation sequencing, proteomics, metabolomics, and automated imaging techniques provides researchers with new opportunities to understand the mechanisms of aging. Using these methods, millions of biological molecules can be simultaneously monitored during the aging process with high accuracy and specificity. CRITICAL ISSUES: Although the ability to produce big data has drastically increased over the years, integration and interpreting of high-throughput data to infer regulatory relationships between biological factors and identify causes of aging remain the major challenges. In this review, we describe recent advances and survey emerging omics approaches in aging research. We then discuss their limitations and emphasize the need for the further development of methods for the integration of different types of data. FUTURE DIRECTIONS: Combining omics approaches and novel methods for single-cell analysis with systems biology tools would allow building interaction networks and investigate how these networks are perturbed with aging and disease states. Together, these studies are expected to provide a better understanding of the aging process and could provide insights into the pathophysiology of many age associated human diseases. Antioxid. Redox Signal. 29, 985-1002. PMID- 28874063 TI - Venous Thromboprophylaxis With Neuromuscular Stimulation: Is It Calf Muscle Pumping or Just Twitches and Jerks? AB - The common peroneal nerve stimulator (CPNS) is a UK-approved device for reducing venous thromboembolism risk. It resembles a wrist watch and is placed over the common peroneal nerve to fire at 1 electrical impulse/sec. The aim was to quantify the claim that it drives the venous muscle pump and imitates walking. Twelve healthy volunteers performed 10 tip-toe maneuvers and 10 ankle dorsiflexions to imitate walking movements. The reductions in calf volume were recorded using air plethysmography (APG). The common peroneal nerve was stimulated for over 10 seconds at each of the 7 increasing electrical impulse settings, and the volume reductions were measured for comparison. The results are expressed as median (interquartile range) absolute (mL), and percentage reduction in calf volume. Tip-toe and dorsiflexion pumping maneuvers were not significantly different: 59 (33.6-96.1), 81.9% vs 51.4 (34-68.5), 59.7%, respectively ( P = .53). However, they both outperformed the CPNS: 10.8 (7.3-18), 13.2% at P = .002 and P = .002, respectively. Qualitatively, the CPNS registered on the tracings as a small spike (muscle twitch) at low settings, with larger amplitudes (ankle jerk) at higher settings. The CPNS activity spikes were discrete, lasting a median (range) of 0.24 (0.16- .3) seconds. The claim that the CPNS empties veins by pumping is supported statistically. However, the amount is small versus the tip-toe and dorsiflexion maneuvers. Furthermore, the CPNS has a short activity profile on the APG trace. Innovations that produce sustained contraction and involve the posterior calf compartments may improve pumping. PMID- 28874062 TI - Biogenesis of Hydrogen Sulfide and Thioethers by Cystathionine Beta-Synthase. AB - AIMS: The transsulfuration pathway enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase are thought to be the major source of hydrogen sulfide (H2S). In this study, we assessed the role of CBS in H2S biogenesis. RESULTS: We show that despite discouraging enzyme kinetics of alternative H2S-producing reactions utilizing cysteine compared with the canonical condensation of serine and homocysteine, our simulations of substrate competitions at biologically relevant conditions suggest that cysteine is able to partially compete with serine on CBS, thus leading to generation of appreciable amounts of H2S. The leading H2S-producing reaction is condensation of cysteine with homocysteine, while cysteine desulfuration plays a dominant role when cysteine is more abundant than serine and homocysteine is limited. We found that the serine-to-cysteine ratio is the main determinant of CBS H2S productivity. Abundance of cysteine over serine, for example, in plasma, allowed for up to 43% of CBS activity being responsible for H2S production, while excess of serine typical for intracellular levels effectively limited such activity to less than 1.5%. CBS also produced lanthionine from serine and cysteine and a third of lanthionine coming from condensation of two cysteines contributed to the H2S pool. INNOVATION: Our study characterizes the H2S-producing potential of CBS under biologically relevant conditions and highlights the serine-to-cysteine ratio as the main determinant of H2S production by CBS in vivo. CONCLUSION: Our data clarify the function of CBS in H2S biogenesis and the role of thioethers as surrogate H2S markers. Antioxid. Redox Signal. 28, 311-323. PMID- 28874061 TI - Time-Resolved Resting-State Functional Magnetic Resonance Imaging Analysis: Current Status, Challenges, and New Directions. AB - Time-resolved analysis of resting-state functional magnetic resonance imaging (rs fMRI) data allows researchers to extract more information about brain function than traditional functional connectivity analysis, yet a number of challenges in data analysis and interpretation remain. This article briefly summarizes common methods for time-resolved analysis and presents some of the pressing issues and opportunities in the field. From there, the discussion moves to interpretation of the network dynamics observed with rs-fMRI and the role that rs-fMRI can play in elucidating the large-scale organization of brain activity. PMID- 28874064 TI - The Association of Aging With Von Willebrand Factor Levels and Bleeding Risk in Type 1 Von Willebrand Disease. AB - Little is known about aging in von Willebrand disease (VWD). It is uncertain whether VWD patients experience an age-related increase in von Willebrand factor (VWF) levels, and if so, it is unknown whether normalization of VWF levels with aging ameliorates bleeding risk. We aimed to determine the association of age with VWF levels and bleeding risk in patients with type 1 VWD. This is a retrospective chart review of patients with type 1 VWD presenting to the Hemophilia Clinic of Western Pennsylvania for regularly scheduled clinic visits. Data collected included VWF antigen level and condensed molecular and clinical markers for the diagnosis and management of Type 1 (MCMDM-1) VWD bleeding assessment tool (BAT) bleeding score based on bleeding symptoms during the previous 3 years. Thirty-nine patients participated in the study, and 32 were female. The average age of participants was 41.8 +/- 18.0 years. The mean VWF antigen level was 0.83 +/- 0.37 IU/mL, and the mean bleeding score was 2.51 +/- 2.90. The bleeding score was inversely associated with age, beta = -0.080 (SE = 0.023), P < .01. There was a nonsignificant association between VWF antigen levels and age. To our knowledge, this is the first report showing an association between aging and decreased bleeding symptoms in patients with type 1 VWD. Determining whether or not bleeding risk is reduced in older patients with type 1 VWD is essential for optimal clinical management. Moreover, VWF concentrate is costly, and unwarranted use represents a significant waste of health-care dollars. These findings warrant further investigation. PMID- 28874065 TI - Associations between adiposity and repetitive element DNA methylation in healthy postmenopausal women. AB - AIM: To describe the association between adiposity and repetitive element DNA methylation in healthy postmenopausal women. PATIENTS & METHODS: A cross sectional study was conducted using baseline information from 289 women who participated in the Alberta Physical Activity and Breast Cancer Prevention trial. RESULTS: After adjusting for important confounders, long interspersed nuclear element-1 methylation was positively associated with intra-abdominal fat area (p = 0.03), body fat percent (p = 0.048), fat mass (p = 0.01), waist circumference (p = 0.03), hip circumference (p = 0.001), BMI (p = 0.03), current weight (p = 0.002), weight at age 20 (p = 0.02) and adulthood weight gain (p = 0.03). No significant associations were found between any of the adiposity measures and Alu methylation. CONCLUSION: Current and historical adiposity measures are positively associated with long interspersed nuclear element-1 methylation in healthy postmenopausal women. PMID- 28874066 TI - The Role of the Accessory Malleolar Ossicles and Malleolar Avulsion Fractures in Lateral Ankle Ligament Reconstruction. AB - : While it is well known that ankle sprains are one of the most common injuries in the United States, predictive factors regarding failure of conservative treatment are not well known. There are many biomechanical and epidemiological factors that play a role in recurrence and failure of conservative treatment, but most cases are able to be treated with immobilization and/or rest, ice, elevation, physical therapy, and bracing. We propose that one important risk factor is often overlooked simply due to the fact that a vast majority of these cases resolve without the need for surgery. Accessory ossicles and avulsion fractures of the malleoli or talus may represent a predisposition or marker for ligamentous damage that may lead to the need for lateral ankle ligament repair or reconstruction in the future. We have identified 61 consecutive patients who underwent lateral ankle ligament repair or reconstruction by the primary surgeon from the years 2007 to 2017. Out of those patients who met our inclusion and exclusion criteria, 66% had the presence of osseous pathology consisting of accessory ossicles or avulsion fractures of the medial or lateral malleolus or talus. The proportion of osseous pathology seen with lateral ankle ligament repair or reconstruction was higher than what has been previously reported in both operative and nonoperative settings. This may help identify a risk factor for failure of conservative treatment in patients presenting with acute ankle sprains or ankle instability especially in the active cohort. LEVELS OF EVIDENCE: Level IV: Case series. PMID- 28874067 TI - Sural Flap Use for the Treatment of Wounds With Underlying Osteomyelitis: Graft Size a Predictor in Outcome, a Systematic Review. AB - : The sural flap procedure is a versatile technique that can be used to cover many types of defects about the lower extremity. The management of soft tissue defects of the lower extremity with underlying osteomyelitis is difficult. The goal for any of these patients is to create a biomechanically stable foot for weight-bearing purposes with no continued infection. Data were gathered using multiple databases from the years 2000 to 2016. Data were compiled looking at the number of subjects, age, comorbidities, number of complications, number of failures, and average flap size of complications/failures. A total of 110 patients were gathered using 5 separate articles. Twenty-two of the 110 patients had short-term complications. Flap failure was seen in 9/110 patients. A significant difference was noticed in flap size between flap failure and complication groups and nonfailure groups. The average flap size of patients who had some form of complication or failure was 51.87 cm2 in size. The average graft size for patients without complications during their recovery was 36.54 cm2. Within our study, the failure rate of 8.9% and complication rate of 13.7% are consistent with previous reports on sural perforator flaps. Last, with regard to the effect of flap size, there were significant differences between patients with a successful outcome and those who experienced complications or failures. LEVELS OF EVIDENCE: Therapeutic, Level III: Systematic review. PMID- 28874068 TI - Characterization of a novel VIIl sub-genotype of Newcastle disease virus circulating in Iran. AB - Newcastle disease is an economically important and highly contagious disease affecting wild and domestic avian species. Despite extensive vaccination efforts within the poultry industry, Newcastle disease virus (NDV) outbreaks causing significant economic losses still occur. Rural chickens may act as a potential reservoir of NDVs for commercial poultry due to poor biosecurity and inadequate vaccination. The aim of this study was to investigate the phylogenetic relationship and molecular characterization of eight NDVs isolated from backyard poultry in Iran during 2011-2013. The complete coding sequence of fusion (F) and haemagglutinin-neuraminidase (HN) genes of eight NDVs were determined and compared with other published NDVs. Based on inter-population distances and phylogenetic topology between available NDV categories, Iranian isolates formed a novel VIIl sub-genotype distinct from previous groups designated in genotype VII. Furthermore, both F and HN genes of the Iranian isolates shared high nucleotide sequence similarity with viruses isolated in China. All viruses analysed contained a polybasic cleavage site motif (111G/RRRQKR?F117), indicating that all isolates could be categorized as a virulent pathotype. No mutation was observed in the neutralizing epitopes of the F protein. Analysis of amino acids associated with neutralizing antigenic sites within the HN protein revealed that all isolates exhibited a unique amino acid (Q) at position 347. These results emphasize the need for strengthening the biosecurity measures implemented on village flocks and practicing a mandatory vaccination programme for local poultry. Moreover, continuous monitoring of NDVs in different species of birds can help to gain more knowledge about the evolution of this virus and prevent future panzootics. PMID- 28874070 TI - Phytochemical, cytotoxic and chemotaxonomic study on Ajuga forrestii Diels (Labiatae). AB - A phytochemical investigation of Ajuga forrestii Diels led to the isolation of 14 compounds, including eight neo-clerodane diterpenes (1-8), two phytoecdysteroids (9, 11), one stigmastane sterol (10) and three iridoid glycosides (12-14). The structures of these compounds were identified by spectroscopic methods and a comparison of their data with those reported in the literature. This is the first report of compounds 1-14 from A. forrestii. The cytotoxic activities of the aqueous extract of A. forrestii and several compounds have been studied and the chemotaxonomic significance of isolated compounds has also been summarised. PMID- 28874069 TI - Assessment of Health-Related Quality of Life among People Living with HIV in Xinjiang, West China. AB - In total, 679 HIV-positive patients from 4 clinics in Urumqi city were given structured questionnaires by the doctors or nurses treating them. Health-related quality of life (HRQL) was assessed using the Chinese Patient-Reported Outcome Quality of Life-HIV questionnaire versions in Mandarin and Uyghur. This tool has been used in other parts of China and several countries. Compared to France, Australia, United States, Brazil, Thailand, Cambodia, Senegal, and Central Southern China (CS China), the HRQL was significantly lower among HIV-positive patients in Xinjiang, with regard to the dimension of treatment impact and general health score. The health concern was similar to Brazil and Cambodia but lower than other countries and CS China. Our findings showed high stigmatization: 86% of the patients were afraid to tell others they were HIV positive and 69% often felt or always felt depressed. Only 1% of the patients were on antidepressant treatment. PMID- 28874071 TI - Factors Influencing Patient Selection of a Foot and Ankle Surgeon. AB - : An increasingly consumer-centric health insurance market has empowered patients to select the providers of their choice. There is a lack of studies investigating the rationale by which patients select a foot and ankle surgeon. In the present study, 824 consecutive new patients seeking treatment from 3 foot-ankle surgeons were consecutively administered an anonymous questionnaire prior to their first appointment. It included rating the importance of 15 factors regarding specialist selection on a 1 to 10 scale, with 10 designated " Very important" and 1 designated " Not important at all." The remaining questions were multiple choice regarding patient perspectives on other surgeon aspects (appointment availability, waiting room times, clinic proximity, etc). Of 824 consecutive patients administered the survey, 305 (37%) responded. Patients rated board certification (9.24 +/- 1.87) and on-site imaging availability (8.48 +/- 2.37)-on a 1 to 10 scale, with 10 designated "Very important- as the 2 most important criteria in choosing a foot and ankle surgeon. Patients rated advertisements as least important. Among the patients, 91% responded that a maximum of 30 minutes should elapse between clinic check-in and seeing their physician; 61% responded that a maximum of 20 minutes should elapse between clinic check-in and seeing their physician. In the context of an increasingly consumer-driven paradigm of health care delivery and reimbursement, it is important to understand patients' preferences in specialist selection. LEVELS OF EVIDENCE: Level III: Prospective questionnaire. PMID- 28874072 TI - Liposomal formulations in the pharmacological treatment of leishmaniasis: a review. AB - Conventional chemotherapy for leishmaniasis includes considerably toxic drugs and reports of drug-resistance are not uncommon. Liposomal encapsulated drugs appear as an option for the treatment of leishmaniasis, providing greater efficacy for the active and reducing its side effects by promoting superior tissue absorption, favouring drug penetration into the macrophages, and retarding its clearance from the site of action. In this paper, a review on the advances achieved with liposome-based anti-leishmaniasis drug delivery systems is presented. Formulations prepared with either conventional or modified (sugar-coated, cationic, niosomes, peptides- and antibodies-bounded) liposomes for the delivery of pentavalent antimonials, amphotericin B, pentamidine, paromomycyn, and miltefosine were covered. This literature review depicts a scenario of no effective therapeutic agents for the treatment of this neglected disease, where liposomal formulations appear to improve the effectiveness of the available antileishmania agents. PMID- 28874073 TI - Intra-patient dose escalation of panobinostat in patients with relapsed/refractory multiple myeloma. PMID- 28874074 TI - Game of TOR - The Target of Rapamycin Rules Four Kingdoms. PMID- 28874075 TI - [Formula: see text]Congenital heart disease: A primer for the pediatric neuropsychologist. AB - Congenital heart disease (CHD) affects millions of people worldwide, including over one million children in the United States. Approximately 25% of children born with CHD require intensive surgical intervention within the first year of life. Despite improved rates of survival into adulthood - rates that exceed 90% in the modern era - children and adolescents with CHD remain at risk for neurological injury and a range of neurobehavioral and psychosocial challenges that pose a threat to quality of life across the lifespan. Consequently, as experts in both clinical psychology and brain development, neuropsychologists are becoming increasingly involved in cardiac follow-up and monitoring to promote optimal developmental outcomes. The primary objective of this paper is to provide an evidence-based, clinically-oriented primer on CHD for pediatric neuropsychologists working with this growing population of survivors. Following an introduction to current standard-of-care guidelines for managing children and adolescents with CHD, we present an overview of brain development within the context of CHD, review neuropsychological outcomes, examine factors influencing variability in outcomes, and discuss implications and strategies for clinical assessment. PMID- 28874076 TI - Multimodal Fluorescence and Bioluminescence Imaging Reveals Transfection Potential of Intratracheally Administered Polyplexes for Breast Cancer Lung Metastases. AB - Local delivery of anticancer agents or gene therapeutics to lung tumors can circumvent side effects or accumulation in non-target organs, but accessibility via the alveolar side of the blood-air barrier remains challenging. Polyplexes based on plasmid and linear polyethylenimine (LPEI) transfect healthy lung tissue when applied intravenously (i.v.) in the mouse, but direct delivery into the lungs results in low transfection of lung tissue. Nevertheless, LPEI could offer the potential to transfect lung tumors selectively, if accessible from the alveolar side. This study combined near infrared fluorescent protein 720 (iRFP720) and firefly luciferase as reporter genes for detection of tumor lesions and transfection efficiency of LPEI polyplexes, after intratracheal microspraying in mice bearing 4T1 triple negative breast cancer lung metastases. Simultaneous flow cytometric analysis of iRFP720 and enhanced green fluorescent protein expression in vitro demonstrated the potential to combine these reporter genes within transfection studies. Polyplex biophysics was characterized by single nanoparticle tracking analysis (NTA) to monitor physical integrity after microspraying in vitro. 4T1 cells were transduced with iRFP720-encoding lentivirus and evaluated by flow cytometry for stable iRFP720 expression. Growth of 4T1-iRFP720 cells was monitored in Balb/c mice by tomographic near infrared imaging, tissue and tumor morphology by computed tomography and magnetic resonance imaging. In 4T1-iRFP720 tumor-bearing mice, intratracheal administration of luciferase-encoding plasmid DNA by LPEI polyplexes resulted in successful tumor transfection, as revealed by bioluminescence imaging. PMID- 28874077 TI - Effects of sunitinib and bevacizumab on VEGF and miRNA levels on corneal neovascularization. AB - AIM: To evaluate the effects of sunitinib (0.5 mg/ml) and bevacizumab (5 mg/ml) on VEGF-A, VEGFR-2 and microRNA (miRNA) levels on corneal neovascularization (CNV). METHODS: In this study, CNV was induced by silver nitrate application to the cornea, and 40 Albino male rats were equally divided into four subgroups: Group 1 (sunitinib): After silver nitrate application to the cornea, 0.5 mg/ml sunitinib eyedrop was administered twice daily for two weeks (n = 10). Group 2 (bevacizumab): After silver nitrate application to the cornea, 5 mg/ml bevacizumab eyedrop was administered twice daily for two weeks (n = 10). Group 3 (control): After silver nitrate application to the cornea, normal saline eyedrop was administered twice daily for two weeks (n = 10). Group 4 (vehicle): After silver nitrate application to the cornea, 1% DMSO eyedrop was administered twice daily for two weeks (n = 10). After two weeks from the silver nitrate application, corneas were evaluated by hand-held biomicroscope for their vascularization status. Then, corneas were excised and the expression levels of VEGFR-2, VEGF-A and the common miRNA markers for neovascularization (miR-15 b, miR-16, miR-23a, miR-126, miR-188, miR-210, miR-221, miR-222, miR-410 and miR 423) were evaluated by real-time PCR. RESULTS: It was seen that the CNV was decreased in sunitinib- and bevacizumab-administered groups compared to the control and DMSO groups. Also, in comparison with the control group; VEGF-A expression was downregulated by nearly 0.75 times in sunitinib group and nearly 0.52 times in bevacizumab group. VEGFR-2 expression was downregulated by 0.89 times in sunitinib group and 0.68 times in bevacizumab group, compared to the control group. miR-15 b, miR-16 and miR-126 levels were statistically lower in sunitinib and bevacizumab groups, but miR-188 and miR-410 levels were two-fold higher compared to the control group. The miR-210 level was found higher only in sunitinib group compared to the control group. There were no statistically significant changes in miR-23a, miR-221, miR-222 and miR-423 levels among the groups. CONCLUSION: Topical application of bevacizumab (5 mg/ml) and sunitinib (0.5 mg/ml) decreases the levels of VEGFR-2 and VEGF-A in CNV. Further studies are needed for detailed analysis of genes which are targeted by up- or downregulated miRNAs in this study. PMID- 28874078 TI - Behavioral Manipulation by Optogenetics in the Nonhuman Primate. AB - Given their neuroanatomical similarities to humans and their ability to perform complex behaviors, the nonhuman primate has been an important model for understanding complex systems such as sensory processing, motor control, social interaction, and nervous system disorders. Optogenetics offers cell-type specific neural control with millisecond precision, making it a powerful neural modulation technique. Combining optogenetics with the nonhuman primate model promises to lead to significant advances in both basic and applied research. In the past few years, optogenetics has made considerable progress in the nonhuman primate. Here, we systematically review the current state-of-art of optogenetics in the nonhuman primate with an emphasis on behavioral manipulation. Given its recent successes, we believe that the progress in the nonhuman primate will boost the translation of optogenetics to clinical applications in the near future. PMID- 28874079 TI - Migration, Agency, and the Sex Industry: Practitioners' Perspectives on Foreign Sex Workers in Turkey. AB - The article presents the political, economic, and sociocultural factors that make Turkey an attractive destination for foreign sex workers, and reviews trends in official statistics of arrested traffickers, rescued victims, and deportation of migrant illegal sex workers. In-depth interviews of 20 law enforcement and nongovernmental organizations staff members, who in the course of their work come into close contact with foreign sex workers, shed light on the statistics. The interview data provide insights into the structure of the Turkish sex market, the factors that bring foreign women to work in this market, and the impact of legal reforms on the circumstances of foreign sex workers. The article concludes with the implications of the findings for public policy. PMID- 28874081 TI - Physicochemical investigation and in vivo activity of anti-malarial drugs co loaded in Tween 80 niosomes. AB - Drugs used for the treatment and prevention of malaria are often plagued by the problem of development of resistance. This has hampered their therapeutic efficiency and rendered them ineffective for monotherapy. However, if re-packaged and combined properly, many of these neglected anti-malarial drugs can possibly find their way back into the treatment regime. The present study evaluates the use of curcumin (CC) and primaquine (PRI) as an anti-malarial combination, packaged within niosomes, in comparison to their respective monotherapy options. It was observed that in Plasmodium berghei-infected mice, mice treated with a combination of 35 mg/kg of CC along with either 5 mg/kg or 1 mg/kg body weight of PRI demonstrated 100% anti-malarial activity and survivability beyond 20 days. The niosome-based PRI-CC combination therapy provided increased protection and survival rate that was associated with prevention in recrudescence. The findings of the study suggest that niosome-based PRI-CC combination therapy may be a promising approach in the treatment of malaria. PMID- 28874080 TI - Low molecular-weight gel fraction of Aloe vera exhibits gastroprotection by inducing matrix metalloproteinase-9 inhibitory activity in alcohol-induced acute gastric lesion tissues. AB - CONTEXT: Aloe has been used for the prevention and cure of various diseases and symptoms including burns, injuries, oedema and pain. OBJECTIVE: This study determines the specific inhibitory activity of matrix metalloproteinase (MMP)-9 induced by the low molecular-weight gel fraction of Aloe vera (L.) Burm.f. (lgfAv) on alcohol-induced acute gastric lesions. MATERIALS AND METHODS: We examined the protective effects of oral (p.o.) administration of lgfAv (molecular weight cutoff <50.0 kDa, 150.0 mg/kg body weight) in a Balb/c mouse model of alcohol-induced acute gastritis for 1 h exposure. By measuring ulcer index, we compared the antiulcerative activity of the fraction. mRNA expression and immunohistochemical analysis of various biomarkers were performed. RESULTS: The lgfAv-treated mice exhibited drastically fewer ulcer lesions than the untreated control mice did. It featured that lgfAv lessened the ulcer lesions than their relevant controls. Moreover, the transcriptional level of MMP-9 was completely alleviated by lgfAv treatment in alcohol-treated gastritis-induced mice. DISCUSSION: The transcriptional level of MMP-9 was significantly alleviated by lgfAv treatment of the model. However, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry experiments revealed that lgfAv treatment in mucosal tissues had the potential to inhibit the mRNA and protein expression levels of MMP-9, respectively. The protein expression of MMP-9 was closely associated with lgfAv-induced gastroprotection against alcohol-induced gastric lesions. CONCLUSIONS: The present findings suggest that lgfAv has the potential to alleviate alcohol-induced acute gastric lesions, which is mediated in part, mainly by the suppression of the mRNA expression of MMP-9. PMID- 28874082 TI - Impact of Multiple Daily Clinical Pharmacist-Enforced Assessments on Time in Target Sedation Range. AB - OBJECTIVES: Incorporation of a single daily assessment by a clinical pharmacist to improve adherence with a sedation protocol is associated with reduced duration of mechanical ventilation and intensive care unit (ICU) length of stay (LOS). We test the feasibility of incorporating a clinical pharmacist into more frequent sedation assessments and observed whether there are any potential differences in the sedatives administered. METHODS: Prospective, quasi-experimental, pilot study of patients admitted to the medical ICU. Patients were included in the analysis if >=18 years of age within the first 24 hours of initiation of mechanical ventilation. Our primary intent was to test the clinical feasibility surrounding more frequent sedation assessments by a clinical pharmacist by evaluating potential differences in time in target sedation range and sedative administration. Exploratory efficacy end points included time in target sedation range (0 to -2) using the Richmond Agitation Sedation Scale (RASS) and sedative exposure. Patients were assigned to receive either 3 assessments with a clinical pharmacist per day (intervention) or a single assessment by a clinical pharmacist per day (standard of care). During the assessments, clinical pharmacists participated in the RASS administration and made dosing adjustments according to an established sedation protocol. MAIN RESULTS: Seventeen patients were enrolled (n = 6 intervention group, n = 11 standard of care). Duration of mechanical ventilation was similar in the 2 groups (intervention 100.0 hours [52.5-197.5] vs control 76.0 hours [46.0-201.0], P = .95), but patients in the intervention group exhibited a greater percentage time in the target RASS range (intervention 76.0% [53.7-81.5%] vs control 45.2% [35.3-67.0], P = .11) that was not statistically significant. Patients in the intervention group received less fentanyl per day (820.9 ug [227.3-1579.4] vs 1997 ug [1648.2-2477.2], P = .02) than in the control group. CONCLUSION: Incorporating a clinical pharmacist into more frequent daily sedation assessments was associated with a reduction in fentanyl administration. There were no observed differences in time in target sedation range or reduction in duration of mechanical ventilation. PMID- 28874083 TI - Azathioprine-Induced Pancytopenia and Septic Complications: A Probable Cause of Death. AB - Azathioprine, an immunosuppressant which is widely used in the management of the autoimmune neuromuscular disorder. Myasthenia gravis is known to cause myelotoxicity. A 55-year-old male recently diagnosed with myasthenia gravis and chronic kidney disease was put on azathioprine (100 mg/d) along with pyridostigmine and prednisolone. When the treatment was initiated, the hematological reports revealed normal levels of blood count. However, approximately within 3 weeks of continuing the prescribed drugs, the patient was readmitted for complaints of loose watery stools, weakness, and giddiness. Clinical investigations revealed severe pancytopenia, suspecting to be related to azathioprine. The suspected drug (azathioprine) was withdrawn, and the management for pancytopenia was initiated. However, on the second day of hospitalization, the patient underwent cardiac arrest and septic shock which lead to death. Adverse drug reaction assessment revealed a plausible and causal relationship of azathioprine with pancytopenia and other adverse effects seen in this patient. PMID- 28874084 TI - Impaired vagal activity to meal in patients with functional dyspepsia and delayed gastric emptying. AB - Objective This study was performed to investigate impaired vagal activity to meal in patients with functional dyspepsia (FD) with delayed gastric emptying (GE). Methods Eighty-five patients were studied. GE parameters, including those in the overall and proximal stomach, were measured by GE functional tests at the Department of Nuclear Medicine. Autonomic nervous function was tested by spectral analysis of heart rate variability (HRV). The vagal activity and sympathetic activity were analyzed by recording the power in the high-frequency component (HF), low-frequency component (LF), and LF/HF ratio. Results Overall and proximal GE were delayed in 47.2% and 50.9% of the patients, respectively. Spectral analysis of HRV showed that the HF in patients with delayed proximal GE was significantly lower and that the LF/HF ratio was significantly higher than those in patients with normal proximal GE after a meal. Conclusion Delayed proximal GE might be caused by disrupted sympathovagal balance as a result of decreased vagal activity after a meal. Improvement in vagal activity may constitute an effective treatment method for patients with FD. PMID- 28874086 TI - PAcluster: Clustering polyadenylation site data using canonical correlation analysis. AB - Alternative polyadenylation (APA) is a pervasive mechanism that contributes to gene regulation. Increasing sequenced poly(A) sites are placing new demands for the development of computational methods to investigate APA regulation. Cluster analysis is important to identify groups of co-expressed genes. However, clustering of poly(A) sites has not been extensively studied in APA, where most APA studies failed to consider the distribution, abundance, and variation of APA sites in each gene. Here we constructed a two-layer model based on canonical correlation analysis (CCA) to explore the underlying biological mechanisms in APA regulation. The first layer quantifies the general correlation of APA sites across various conditions between each gene and the second layer identifies genes with statistically significant correlation on their APA patterns to infer APA specific gene clusters. Using hierarchical clustering, we comprehensively compared our method with four other widely used distance measures based on three performance indexes. Results showed that our method significantly enhanced the clustering performance for both synthetic and real poly(A) site data and could generate clusters with more biological meaning. We have implemented the CCA-based method as a publically available R package called PAcluster, which provides an efficient solution to the clustering of large APA-specific biological dataset. PMID- 28874085 TI - Comparing the dopaminergic neurotoxic effects of benzylpiperazine and benzoylpiperazine. AB - Benzylpiperazine has been designated as Schedule I substance under the Controlled Substances Act by Drug Enforcement Administration. Benzylpiperazine is a piperazine derivative, elevates both dopamine and serotonin extracellular levels producing stimulatory and hallucinogenic effects, respectively, similar to methylenedioxymethamphetamine (MDMA). However, the comparative neurotoxic effects of Piperazine derivatives (benzylpiperazine and benzoylpiperazine) have not been elucidated. Here, piperazine derivatives (benzylpiperazine and benzoylpiperazine) were synthesized in our lab and the mechanisms of cellular-based neurotoxicity were elucidated in a dopaminergic human neuroblastoma cell line (SH-SY5Y). We evaluated the in vitro effects of benzylpiperazine and benzoylpiperazine on the generation of reactive oxygen species, lipid peroxidation, mitochondrial complex I activity, catalase activity, superoxide dismutase activity, glutathione content, Bax, caspase-3, Bcl-2 and tyrosine hydroxylase expression. Benzylpiperazine and benzoylpiperazine induced oxidative stress, inhibited mitochondrial functions and stimulated apoptosis. This study provides a germinal assessment of the neurotoxic mechanisms induced by piperazine derivatives that lead to neuronal cell death. PMID- 28874087 TI - Systematic investigations of gene effects on both topologies and supports: An Echinococcus illustration. AB - In this paper, we propose a high performance computing toolbox implementing efficient statistical methods for the study of phylogenies. This toolbox, which implements logit models and LASSO-type penalties, gives a way to better understand, measure, and compare the impact of each gene on a global phylogeny. As an application, we study the Echinococcus phylogeny, which is often considered as a particularly difficult example. Mitochondrial and nuclear genomes (19 coding sequences) of nine Echinococcus species are considered in order to investigate the molecular phylogeny of this genus. First, we check that the 19 gene trees lead to 19 totally different unsupported topologies (a topology is the sister relationship when both branch lengths and supports are ignored in a phylogenetic tree), while using the 19 genes as a whole are not sufficient for estimating the phylogeny. In order to circumvent this issue and understand the impact of the genes, we computed 43,796 trees using combinations ranging from 13 to 19 genes. By doing so, 15 topologies are obtained. Four particular topologies, appearing more robust and frequent, are then selected for more precise investigation. Refining further our statistical analysis, a particularly robust topology is extracted. We also carefully demonstrate the influence of nuclear genes on the likelihood of the phylogeny. PMID- 28874088 TI - Focusing solely on the effect of the medication without taking a holistic view of the patient does not seem very constructive. PMID- 28874089 TI - Outcome of Surgeon-Modified Fenestrated/Branched Stent-Grafts for Symptomatic Complex Aortic Pathologies or Contained Rupture. AB - PURPOSE: To analyze the outcome of surgeon-modified fenestrated and branched stent-grafts (sm-FBSG) in high-risk patients with symptomatic complex aortic pathology or contained rupture. METHODS: A single-center retrospective analysis was conducted of 21 consecutive patients (mean age 70 years, range 58-87; 16 men) treated with a sm-FBSG from April 2014 to September 2016. The indications included 11 thoracoabdominal and 10 pararenal aortic pathologies, which presented as symptomatic in 8 and as contained rupture in 13 patients. The mean aneurysm diameter was 7.4+/-2.3 cm. RESULTS: Technical success was 100%. From 1 to 4 (mean 3) renovisceral branch vessels were targeted with fenestrations. The mean length of in-hospital stay was 19 days (range 1-78). There was 1 death within 30 days and 2 further in-hospital deaths. Two patients suffered permanent spinal cord injury, 2 developed respiratory failure, and 2 had renal failure requiring temporary or permanent dialysis. No myocardial infarction, stroke, or bowel ischemia occurred. Six early endoleaks (3 type II and 3 minor type III) were detected. Mean follow-up was 11.2 months (range 2-33) in 17 patients. One late aneurysm-related death occurred. All 13 follow-up imaging studies showed patent target renovisceral vessels, with 1 type I and 2 type II endoleaks. CONCLUSION: Sm-FBSG can be utilized for urgent treatment of complex abdominal and thoracoabdominal aortic pathologies in high-risk patients with anatomy unsuitable for commercially available stent-grafts. PMID- 28874090 TI - Open and cautious towards the "minority view". AB - According to the 'minority view', the initial afferent processing on C1 can be modulated by attention under certain experimental conditions. However, evidence supporting this 'minority view' is relatively rare and needs more replication, and the optimal conditions for eliciting attentional modulations on C1 have not yet been clearly defined. V1-tuned stimuli with distractors, peripheral cuing paradigms, and high perceptual loads seem to be important factors in favor of the 'minority view'. The signal-noise issue for C1, especially between attended and unattended conditions, needs to be considered. PMID- 28874091 TI - Gender in clinical neuropsychology: practice survey trends and comparisons outside the specialty. AB - OBJECTIVE: This paper describes gender-related trends within clinical neuropsychology, based primarily on recurrent practice surveys within the specialty and, to a lesser extent, job-related information from medical specialties and the general U.S. labor market. METHOD: Chronological and cross sectional analyses of professional practice survey data from 2005, 2010, and 2015 relevant to gender. As is common with survey data, descriptive analysis and independent samples t-tests were conducted. Longitudinal data allowed for examination of gender trends, as well as observations of change and stability of factors associated with gender, over time. RESULTS: Women have become dominant in number in clinical neuropsychology, and also comprise a vast majority of practitioners entering the specialty. Gender differences are noted in professional identity, work status, work settings, types of career satisfaction, and retirement expectations. Women are more likely to identify work environment and personal/family obstacles to aspects of career satisfaction. A gender pay gap was found at all time points and is not narrowing. As is true nationally, multiple factors appear related to the gender pay gap in clinical neuropsychology. CONCLUSIONS: Women in neuropsychology are now dominant in number, and their presence is strongly associated with specific practice patterns, such as greater institutional employment, less involvement in forensic practice, and strong involvement in pediatric practice, which may be maintaining the sizeable gender pay gap in neuropsychology. As the proportion of women neuropsychologists continues to increase, flexible work hours, and alternative means of remuneration may be needed to offset current disproportionate family related responsibilities. PMID- 28874093 TI - Comprehensive DNA microarray expression profiles of tumors in tenascin-C-knockout mice. AB - Tenascin-C (TNC), an extracellular matrix glycoprotein, plays a pivotal role in tumor growth. However, the mechanism whereby TNC affects tumor biology remains unclear. To investigate the exact role of TNC in primary tumor growth, a mouse mammary tumor cell line, GLMT1, was first developed. Subsequently, global gene expression in GLMT1-derived tumors was compared between wild-type (WT) and TNC knockout (TNKO) mice. Tumors in WT mice were significantly larger than those in TNKO mice. DNA microarray analysis revealed 447 up and 667 downregulated in the tumors inoculated into TNKO mice as compared to tumors in WT mice. Validation by quantitative gene expression analysis showed that Tnc, Cxcl1, Cxcl2, and Cxcr2 were significantly upregulated in WT mice. We hypothesize that TNC stimulates the CXCL1/2-CXCR2 pathway involved in cancer cell proliferation. PMID- 28874092 TI - Anxiety and Fear of Recurrence Despite a Good Prognosis: An Interview Study with Differentiated Thyroid Cancer Patients. AB - BACKGROUND: Despite a good prognosis, fear of recurrence is prevalent, even several years after a diagnosis of differentiated thyroid cancer (DTC). For this reason, the aim of this study was to make an in-depth exploration of anxiety, sources of anxiety, and protective strategies. METHODS: In order to capture a broad description of the phenomenon, a purposeful, maximum variation sampling strategy regarding age, sex, stage of disease, educational level, and time since diagnosis was used. In total, 21 patients were included in the study. Semi structured interviews were tape-recorded, transcribed verbatim, and analyzed with a qualitative content analysis. RESULTS: Patients with and without recurrences narrated a picture indicating anxiety related to their current situation; future risks and threats were central to this picture. However, they initially minimized or even denied having anxiety, but subsequently described it as a major problem at the end of the interviews. Anxiety was related to risk of recurrence and the risk of developing other cancers, but also to fears of a future situation where no further treatment options were available. Previous experiences of delayed investigations added to these fears. In order to cope, patients developed protective strategies in order to keep evasive and frightening thoughts away. Everyday life, distractions, and focusing on "the small things in life" were examples of such strategies. CONCLUSIONS: Anxiety is a common, although partially hidden, problem in DTC survivors, as they tended to deny it early in the dialogues. As anxiety is clearly related to follow-up routines, these should therefore be revaluated. PMID- 28874094 TI - The Pursuit of Primary Human Goods in Men Desisting From Sexual Offending. AB - The good lives model proposes at least 10 primary human goods that are thought to be common to all individuals which, when secured, contribute to enhanced well being and life satisfaction. Prosocial attainment of primary human goods is thought to promote desistance from crime. However, individuals convicted of sexual offenses face significant obstacles upon their reentry into the community that likely undermine their ability to obtain such goods. The current study explored the pursuit and attainment of primary human goods in a U.S. sample of men convicted of sexual offenses. We interviewed 42 men released into the community to examine the extent to which they desired and pursued primary human goods. Results highlighted that participants valued many of the human goods outlined in the good lives model, but their means to achieve them were restricted considerably by their correctional status. "Interpersonal relationships" and "life/survival" emerged most frequently during the interviews and were identified as the two most important goods. We discuss the negative impact of recent policies on participants' ability to pursue and attain human goods as well as the value of attending regular treatment in obtaining the goods of "knowledge" and "community." Implications for policy and directions for future research are provided. PMID- 28874095 TI - Seasonal Rhythms: The Role of Thyrotropin and Thyroid Hormones. AB - BACKGROUND: Seasonal changes in various physiological events have been reported in humans, including metabolism, immune function, and mood. However, the molecular and endocrine basis of these seasonal changes remains unclear. SUMMARY: Animals that breed seasonally, such as Japanese quail and the Siberian hamster, have sophisticated seasonal mechanisms, and hence they provide excellent opportunities to understand the underlying processes. Functional genomic analysis in quail uncovered the photoperiodic signal transduction pathway, which regulates avian seasonal reproduction: a long-day stimulus induces secretion of thyrotropin (TSH) from the pars tuberalis (PT) of the anterior pituitary gland. This PT derived TSH locally activates thyroid hormone within the hypothalamus, which in turn induces gonadotropin-releasing hormone and then gonadotropin secretion, leading to gonadal growth. CONCLUSIONS: Studies using TSH receptor-null mice confirmed the involvement of PT-derived TSH in mammalian seasonal reproduction. The pars distalis of the anterior pituitary gland is the major source of circulating TSH. Although the pars distalis and PT are in close proximity, tissue specific glycosylation of circulating TSH alters its function to avoid cross talk. PMID- 28874097 TI - Analyzing State Autism Private Insurance Mandates for Allied Health Services: A Pilot Study. AB - Due to the prevalence, severity, and costs associated with autism spectrum disorders (ASDs), it has become a public health issue. In response, state governments have adopted ASD-specific private insurance mandates requiring coverage of ASD screening, diagnosis, and treatment. Despite rapid uptake of these laws, differences exist in the type and levels of coverage, especially for allied health services including occupational therapy. We piloted a structured legal research methodology to code ASD insurance mandates that impact allied health service provisions. State private insurance mandates were obtained from WestlawNext. A coding methodology was piloted on 14 states and included variables for age and service limits, treatments covered, and medical necessity. Coding methods were feasible and highly reliable among raters. Ten of 12 states had a coverage mandate, many with specific provisions for allied health providers. A full analysis of all 50 states is warranted to identify provisions affecting allied health providers serving individuals with ASD. PMID- 28874096 TI - The Benefits of Bimodal Aiding on Extended Dimensions of Speech Perception: Intelligibility, Listening Effort, and Sound Quality. AB - The benefits of combining a cochlear implant (CI) and a hearing aid (HA) in opposite ears on speech perception were examined in 15 adult unilateral CI recipients who regularly use a contralateral HA. A within-subjects design was carried out to assess speech intelligibility testing, listening effort ratings, and a sound quality questionnaire for the conditions CI alone, CIHA together, and HA alone when applicable. The primary outcome of bimodal benefit, defined as the difference between CIHA and CI, was statistically significant for speech intelligibility in quiet as well as for intelligibility in noise across tested spatial conditions. A reduction in effort on top of intelligibility at the highest tested signal-to-noise ratio was found. Moreover, the bimodal listening situation was rated to sound more voluminous, less tinny, and less unpleasant than CI alone. Listening effort and sound quality emerged as feasible and relevant measures to demonstrate bimodal benefit across a clinically representative range of bimodal users. These extended dimensions of speech perception can shed more light on the array of benefits provided by complementing a CI with a contralateral HA. PMID- 28874098 TI - Personal support and expressions of care for pregnant women in Soweto, South Africa. AB - BACKGROUND: Pregnancy is life changing, making great demands on women to adapt physically, psychologically, and socially. Social relationships and the support that flow from these provide a critical role in managing health problems in pregnancy. Isolation and lack of care, in contrast, may lead women to experience increased distress during this time. OBJECTIVE: This study aimed to explore South African women's perception and experience of care and support in pregnancy. METHODS: A life history approach was employed to explore women's experiences of pregnancy and sexual behaviour, with each participant encouraged to narrate important life events from her own perspective. We drew on narrative interviews with 15 pregnant women, conducted between July and October 2015, in which we explored questions regarding pregnancy planning and the provision and receipt of care. A thematic approach was employed to code and analyse the data. RESULTS: Themes that emerged from the interviews showed that participants gained a sense of stability in their lives when they had support in their pregnancy, especially when dealing with challenging situations. This support came variously from family, friends, and social networks. Overall, those participants who mentioned the most support, and its diversity across different groups, reported a better experience of pregnancy. CONCLUSIONS: Women emphasised the importance of social and emotional support in pregnancy. Understanding women's experiences can assist in making pregnancy less overwhelming, and can add to a woman's ability to deal with different challenges before and after the arrival of the new baby. PMID- 28874099 TI - The Health Economics of the spinal cord injury or disease among veterans of war: A systematic review. AB - CONTEXT: Information on health-care utilization and the economic burden of disease are essential to understanding service demands, service accessibility, and practice patterns. This information may also be used to enhance the quality of care through altered resource allocation. Thus, a systematic review of literature on the economic impact of caring for SCI/D veterans would be of great value. OBJECTIVE: To systematically review and critically appraise the literature on the economics of the management of veterans with SCI/D. METHODS: Medline, EMBASE and PsycINFO databases were searched for articles on economic impact of management of SCI/D veterans, published from 1946 to September/2016. The STROBE statement was used to determine publication quality. RESULTS: The search identified 1,573 publications of which 13 articles fulfilled the inclusion/exclusion criteria with 12 articles focused on costs of management of SCI/D veterans; and, one cost-effectiveness analysis. Overall, the health care costs for the management of SCI/D veterans are substantial ($30,770 to $62,563 in 2016 USD per year) and, generally, greater than the costs of caring for patients with other chronic diseases. The most significant determinants of the higher total health-care costs are cervical level injury, complete injury, time period (i.e. first year post-injury and end-of-life year), and presence of pressure ulcers. CONCLUSIONS: There is growing evidence for the economic burden of SCI/D and its determinants among veterans, whereas there is a paucity of comparative studies on interventions including cost-effectiveness analyses. Further investigations are needed to fulfill significant knowledge gaps on the economics of caring for veterans with SCI/D. PMID- 28874100 TI - Immunotherapy options for painful bladder syndrome: what's the potential? AB - INTRODUCTION: Painful bladder syndrome/interstitial cystitis (PBS/IC) is an enigmatic disease characterized by lack of evidence-based knowledge and an ongoing scientific debate regarding its definition, pathogenesis, diagnostic and treatment algorithm. An autoimmune theory for PBS/IC etiology has suggested immunotherapy as a potential treatment choice. Areas covered: In this review, the authors report existing and future immunotherapeutic options, potentially valuable to the management of PBS/IC while evidence for the immunological aspect of PBS/IC pathogenesis are also presented. Relevant data reported in human clinical studies but also in experimental studies using animal PBS/IC models have been reviewed. Expert opinion: Promising data has emerged lately regarding use of immunotherapy drugs for PBS/IC treatment. Specifically, human monoclonal antibodies inhibiting nerve growth factor and tumor necrosis factor-a have shown high efficacy in pain control for PBS/IC. Also, many other agents modulating immunopathways linked to PBS symptom etiology and leading to positive treatment effects have been reported lately mainly in experimental animal studies. Immunotherapy could potentially improve disease-related and patient-reported outcome; nevertheless, lack of consensus regarding PBS/IC diagnostic criteria, leading to high heterogeneity of patients enrolled in PBS/IC treatment studies, and low number of well-designed randomized clinical trials are limitations which must be addressed in the future. PMID- 28874102 TI - Ertapenem-associated neurotoxicity in the spinal cord injury (SCI) population: A case series. AB - Context Ertapenem, a broad spectrum carbapenem antibiotic, is used often in Spinal Cord Injury (SCI) patients due to increased risk factors for multi-drug resistant (MDR) infections in this population. Neurotoxicity, specifically seizures, due to ertapenem is a known adverse effect and has been described previously. Other manifestations such as delirium and visual hallucinations have rarely been reported, and no literature, to the best of our knowledge, specifically describes these effects solely in the SCI population. Findings Four cases of mental status changes and hallucinations in SCI patients attributed to ertapenem therapy are described. Onset of symptoms began between one and six days following initiation of ertapenem and resolved between two to 42 days following discontinuation. Based on the Naranjo probability scale, a probable relationship exists between the adverse events and ertapenem for three out of the four cases. Possible overestimation of renal function and hypoalbuminemia may be contributing factors to the noted adverse reactions. Conclusion/Clinical Relevance The cases described highlight the importance of recognizing ertapenem-associated hallucinations in SCI patients. The population is particularly vulnerable due to risk factors for MDR infections necessitating ertapenem use, possible overestimation of renal function, and a high prevalence of hypoalbuminemia. PMID- 28874101 TI - The Role of Cellular Proliferation in Adipogenic Differentiation of Human Adipose Tissue-Derived Mesenchymal Stem Cells. AB - Mitotic clonal expansion has been suggested as a prerequisite for adipogenesis in murine preadipocytes, but the precise role of cell proliferation during human adipogenesis is unclear. Using adipose tissue-derived human mesenchymal stem cells as an in vitro cell model for adipogenic study, a group of cell cycle regulators, including Cdk1 and CCND1, were found to be downregulated as early as 24 h after adipogenic initiation and consistently, cell proliferation activity was restricted to the first 48 h of adipogenic induction. Cell proliferation was either further inhibited using siRNAs targeting cell cycle genes or enhanced by supplementing exogenous growth factor, basic fibroblast growth factor (bFGF), at specific time intervals during adipogenesis. Expression knockdown of Cdk1 at the initiation of adipogenic induction resulted in significantly increased adipocytes, even though total number of cells was significantly reduced compared to siControl-treated cells. bFGF stimulated proliferation throughout adipogenic differentiation, but exerted differential effect on adipogenic outcome at different phases, promoting adipogenesis during mitotic phase (first 48 h), but significantly inhibiting adipogenesis during adipogenic commitment phase (days 3 6). Our results demonstrate that cellular proliferation is counteractive to adipogenic commitment in human adipogenesis. However, cellular proliferation stimulation can be beneficial for adipogenesis during the mitotic phase by increasing the population of cells capable of committing to adipocytes before adipogenic commitment. PMID- 28874103 TI - Neuroendocrine Regulation of Food Intake in Polycystic Ovary Syndrome. AB - Several peripheral and central signals are involved in the sophisticated regulation of food intake. Women with polycystic ovary syndrome (PCOS) are prone to consume a diet higher in saturated fat and foods with high glycemic index and show impaired appetite regulation and measures of satiety. As a consequence, obesity, mostly of the central type, is prevalent in the syndrome and worsens the endocrine and metabolic profile of the affected patients. This review article briefly analyzes the current knowledge about the neuroendocrine mechanisms underlying the interplay between feeding behavior, obesity, and reproductive abnormalities in PCOS. PMID- 28874104 TI - Ovarian Stimulation in Patients With Cancer: Impact of Letrozole and BRCA Mutations on Fertility Preservation Cycle Outcomes. AB - BACKGROUND: Aromatase inhibitors (AI) have been introduced to reduce estrogen exposure in women with estrogen-sensitive cancer undergoing ovarian stimulation for oocyte/embryo cryopreservation. There have been questions regarding whether the addition of AI and the presence of BRCA mutations affect cycle outcomes. We sought to determine the impact of letrozole and BRCA mutations on fertility preservation (FP) cycle outcomes of patients undergoing ovarian stimulation with an antagonist protocol. METHODS: The data were generated by the secondary analysis of a prospective database of all females diagnosed with cancer who underwent embryo or oocyte cryopreservation for FP. The final analysis included 145 patients stimulated with an antagonist protocol either using letrozole combined with recombinant follicle-stimulating hormone (rFSH; LF, n = 118) or rFSH alone (FA, n = 24). RESULTS: The mean number of total (15.6 [7.9] vs 10.2 [7.8]; P = .004) and mature oocytes (10.4 [5.1] vs 7.8 [3.5]; P = .044) and embryos frozen (7.7 [5.3] vs 5.3 [2.7]; P = .043) were significantly higher after LF stimulation versus FA. In the LF group, women with BRCA mutations produced significantly fewer oocytes (11.0 [8.0] vs 16.4 [7.7], P = .015) and embryos (5.1 [4.4] vs 8.2 [4.7], P = .013), compared to those who were mutation negative. After adjusting for age, body mass index, baseline FSH level, and BRCA status, LF protocol still resulted in higher number of total oocytes (95% confidence interval [CI]: 1.9 to 3.6; P = .002) mature oocyte (95% CI: 0.3 to 1.4; P = .028), and embryo yield (95% CI: 0.7 to 1.4; P = .015). CONCLUSION: In women with cancer undergoing FP, letrozole appears to enhance response to ovarian stimulation while the presence of BRCA mutations is associated with lower oocyte and embryo yield. PMID- 28874105 TI - 18F-Fluorocholine Uptake and Positron Emission Tomography Imaging in Rat Peritoneal Endometriosis. AB - Endometriosis is a debilitating disease that still needs surgery to be confirmed. Endometriosis is associated with increased plasma levels of phosphatidylcholines. 18F-fluorocholine ([18F]FCH) is a radiopharmaceutical that is metabolized to phosphatidylcholine inside the cells and can be traced by positron emission tomography (PET). Here we evaluate [18F]FCH as a potential tool for the noninvasive diagnosis of peritoneal endometriosis. Adult female Wistar rats had autologous uterine fragments dissected and grafted to the peritoneal wall to model peritoneal endometriosis. Ex vivo biodistribution assay and PET imaging studies were performed 30 minutes after [18F]FCH administration. The [18F]FCH uptake was 3-fold higher in endometriotic implant tissues than in muscle or peritoneum. Positron emission tomography imaging revealed the grafted uterine tissue in contrast to surrounding structures. Region-of-interest analysis of the reconstructed images showed higher accumulation of [18F]FCH by endometriotic lesions, 0.34 (0.04)% of injected dose per gram of tissue (ID/g), in comparison with muscle tissue, 0.08 (0.01)% ID/g. However, sham implants with fat tissue were also detectable in PET imaging. These preliminary findings of [18F]FCH uptake by ectopic uterine tissue implants and their localization by PET imaging encourage the future evaluation of this technique to detect small superficial endometriosis lesions in humans. Study protocols need to be further perfected and adapted for tests in women with endometriosis. PMID- 28874106 TI - An Opportunity View of Child Sexual Offending: Investigating Nonpersuasion and Circumstances of Offending Through Criminological Lens. AB - The empirical evidence indicating that sexual offenders against children manipulate their victims to participate in sexual activities dominates the literature on sex offenders and their modus operandi. However, recent evidence suggests that a high proportion of these offenders do not try to persuade their victims for sexual contact in the first place by using coercion or manipulation but simply assault them when an opportunity arises. Using self-reported data from a sample of incarcerated adult sexual offenders against children, we investigate whether sexual offenses against children committed by the use of nonpersuasion are characterized by little planning and by offense features that are indicative of opportunistic offending. We also examine the interaction between the type of offending strategy and the context of abuse. Findings reveal that offenders using nonpersuasion do not seek out potential victims, but rather seize an opportunity to offend. The type of offending strategy also interacts with the context of abuse for most preoffense and offense variables. These interactions are informative of the conditions favoring opportunistic sex offending against children. PMID- 28874107 TI - Corrigendum. PMID- 28874108 TI - Psychometrics and statistics: two pillars of neuropsychological practice. PMID- 28874110 TI - "I Know Correlation Doesn't Prove Causation, but . . .": Are We Jumping to Unfounded Conclusions About the Causes of Sexual Offending? AB - Identifying causes of sexual offending is the foundation of effective and efficient assessment, intervention, and policy aimed at reducing sexual offending. However, studies vary in methodological rigor and the inferences they support, and there are differences of opinion about the conclusions that can be drawn from ambiguous evidence. To explore how researchers in this area interpret the available empirical evidence, we asked authors of articles published in relevant specialized journals to identify (a) an important factor that may lead to sexual offending, (b) a study providing evidence of a relationship between that factor and sexual offending, and (c) the inferences supported by that study. Many participants seemed to endorse causal interpretations and conclusions that went beyond the methodological rigor of the study they identified. Our findings suggest that some researchers may not be adequately considering methodological issues when making inferences about the causes of sexual offending. Although it is difficult to conduct research in this area and all research designs can provide valuable information, sensitivity to the limits methodology places on inferences is important for the sake of accuracy and integrity, and to stimulate more informative research. We propose that increasing attention to methodology in the research community through better training and standards will advance scientific knowledge about the causes of sexual offending, and improve the effectiveness and efficiency of practice and policy. PMID- 28874109 TI - Prospects and Frontiers of Stem Cell Toxicology. AB - The development of stem cell biology has revolutionized regenerative medicine and its clinical applications. Another aspect through which stem cells would benefit human health is their use in toxicology. In fact, owing to their ability to differentiate into all the lineages of the human body, including germ cells, stem cells, and, in particular, pluripotent stem cells, can be utilized for the assessment, in vitro, of embryonic, developmental, reproductive, organ, and functional toxicities, relevant to human physiology, without employing live animal tests and with the possibility of high throughput applications. Thus, stem cell toxicology would tremendously assist in the toxicological evaluation of the increasing number of synthetic chemicals that we are exposed to, of which toxicity information is limited. In this review, we introduce stem cell toxicology, as an emerging branch of in vitro toxicology, which offers quick and efficient alternatives to traditional toxicology assessments. We first discuss the development of stem cell toxicology, and we then emphasize its advantages and highlight the achievements of human pluripotent stem cell-based toxicity research. PMID- 28874111 TI - The Fall in Older Adults: Physical and Cognitive Problems. AB - BACKGROUND: The aging of posture and balance function alters the quality of life in older people and causes serious problems in terms of public health and socio economic costs for our modern societies. METHOD: This article reviews the various causes of imbalance and dizziness in the elderly, and considers how to prevent falls, and how to rehabilitate a faller subject in order to regain a good quality of life. Two effective ways of intervention are discussed, emphasizing the crucial role of physical activity and cognitive stimulation, classic or using the latest technical advances in virtual reality and video games. RESULTS: Fall in the elderly result from aging mechanisms acting on both the sensorimotor and cognitive spheres. The structural and functional integrity of the peripheral sensory receptors and the musculoskeletal system deteriorate with age. The brain ages and the executive functions, memory, learning, cortical processing of information, sharing of attentional resources and concentration, are modified in the elderly. Psychological affective factors such as depression, anxiety and stress contribute also to speed up the sensorimotor and cognitive decline. The rehabilitation of the postural balance in the elderly must take into account all of these components. CONCLUSION: The aging of the population and the increased of lifespan are a challenge for our modern societies regarding the major health and socio-economic questions they raise. The fall in the elderly being one of the dramatic consequences of the aging equilibration function, it is therefore imperative to develop rehabilitation procedures of balance. PMID- 28874113 TI - Editorial:Impacts of Computational Biology to Medicinal Chemistry. PMID- 28874114 TI - Dual transcriptome of the immediate neutrophil and Candida albicans interplay. AB - BACKGROUND: Neutrophils are traditionally considered transcriptionally inactive. Compared to other immune cells, little is known about their transcriptional profile during interaction with pathogens. METHODS: We analyzed the meta transcriptome of the neutrophil-Candida albicans interplay and the transcriptome of C. albicans challenged with neutrophil extracellular traps (NETs) by RNA-Seq, considering yeast and hypha individually in each approach. RESULTS: The neutrophil response to C. albicans yeast and hyphae was dominated by a morphotype independent core response. However, 11 % of all differentially expressed genes were regulated in a specific manner when neutrophils encountered the hyphal form of C. albicans. While involving genes for transcriptional regulators, receptors, and cytokines, the neutrophil core response lacked typical antimicrobial effectors genes. Genes of the NOD-like receptor pathway, including NLRP3, were enriched. Neutrophil- and NET-provoked responses in C. albicans differed. At the same time, the Candida transcriptome upon neutrophil encounter and upon NET challenge included genes from various metabolic processes and indicate a mutual role of the regulators Tup1p, Efg1p, Hap43p, and Cap1p. Upon challenge with neutrophils and NETs, the overall Candida response was partially morphotype specific. Yet again, actual oppositional regulation in yeasts and hyphae was only detected for the arginine metabolism in neutrophil-infecting C. albicans. CONCLUSIONS: Taken together, our study provides a comprehensive and quantitative transcript profile of the neutrophil-C. albicans interaction. By considering the two major appearances of both, neutrophils and C. albicans, our study reveals yet undescribed insights into this medically relevant encounter. Hence, our findings will facilitate future research and potentially inspire novel therapy developments. PMID- 28874115 TI - Genome-wide analysis and expression profiling of zinc finger homeodomain (ZHD) family genes reveal likely roles in organ development and stress responses in tomato. AB - BACKGROUND: Zinc finger homeodomain proteins (ZHD) constitute a plant-specific transcription factor family with a conserved DNA binding homeodomain and a zinc finger motif. Members of the ZHD protein family play important roles in plant growth, development, and stress responses. Genome-wide characterization of ZHD genes has been carried out in several model plants, including Arabidopsis thaliana and Oryza sativa, but not yet in tomato (Solanum lycopersicum). RESULTS: In this study, we performed the first comprehensive genome-wide characterization and expression profiling of the ZHD gene family in tomato (Solanum lycopersicum). We identified 22 SlZHD genes and classified them into six subfamilies based on phylogeny. The SlZHD genes were generally conserved in each subfamily, with minor variations in gene structure and motif distribution. The 22 SlZHD genes were distributed on six of the 12 tomato chromosomes, with segmental duplication detected in four genes. Analysis of Ka/Ks ratios revealed that the duplicated genes are under negative or purifying selection. Comprehensive expression analysis revealed that the SlZHD genes are widely expressed in various tissues, with most genes preferentially expressed in flower buds compared to other tissues. Moreover, many of the genes are responsive to abiotic stress and phytohormone treatment. CONCLUSION: Systematic analysis revealed structural diversity among tomato ZHD proteins, which indicates the possibility for diverse roles of SlZHD genes in different developmental stages as well as in response to abiotic stresses. Our expression analysis of SlZHD genes in various tissues/organs and under various abiotic stress and phytohormone treatments sheds light on their functional divergence. Our findings represent a valuable resource for further analysis to explore the biological functions of tomato ZHD genes. PMID- 28874116 TI - Patterns of host gene expression associated with harboring a foregut microbial community. AB - BACKGROUND: Harboring foregut microbial communities is considered a key innovation that allows herbivorous mammals to colonize new ecological niches. However, the functions of these chambers have only been well studied at the molecular level in ruminants. Here, we investigate gene expression in the foregut chamber of herbivorous rodents and ask whether these gene expression patterns are consistent with results in ruminants. We compared gene expression in foregut tissues of two rodent species: Stephen's woodrat (Neotoma stephensi), which harbors a dense foregut microbial community, and the lab rat (Rattus norvegicus), which lacks such a community. RESULTS: We found that woodrats have higher abundances of transcripts associated with smooth muscle processes, specifically a higher expression of the smoothelin-like 1 gene, which may assist in contractile properties of this tissue to retain food material in the foregut chamber. The expression of genes associated with keratinization and cornification exhibited a complex pattern of differences between the two species, suggesting distinct molecular mechanisms. Lab rats exhibited higher abundances of transcripts associated with immune function, likely to inhibit microbial growth in the foregut of this species. CONCLUSIONS: Some of our results were consistent with previous findings in ruminants (high expression of facilitative glucose transporters, lower expression of B4galnt2), suggestive of possible convergent evolution, while other results were unclear, and perhaps represent novel host microbe interactions in rodents. Overall, our results suggest that harboring a foregut microbiota is associated with changes to the functions and host-microbe interactions of the foregut tissues. PMID- 28874117 TI - BUFET: boosting the unbiased miRNA functional enrichment analysis using bitsets. AB - BACKGROUND: A group of miRNAs can regulate a biological process by targeting genes involved in the process. The unbiased miRNA functional enrichment analysis is the most precise in silico approach to predict the biological processes that may be regulated by a given miRNA group. However, it is computationally intensive and significantly more expensive than its alternatives. RESULTS: We introduce BUFET, a new approach to significantly reduce the time required for the execution of the unbiased miRNA functional enrichment analysis. It derives its strength from the utilization of efficient bitset-based methods and parallel computation techniques. CONCLUSIONS: BUFET outperforms the state-of-the-art implementation, in regard to computational efficiency, in all scenarios (both single- and multi core), being, in some cases, more than one order of magnitude faster. PMID- 28874118 TI - A miRNA catalogue and ncRNA annotation of the short-living fish Nothobranchius furzeri. AB - BACKGROUND: The short-lived fish Nothobranchius furzeri is the shortest-lived vertebrate that can be cultured in captivity and was recently established as a model organism for aging research. Small non-coding RNAs, especially miRNAs, are implicated in age dependent control of gene expression. RESULTS: Here, we present a comprehensive catalogue of miRNAs and several other non-coding RNA classes (ncRNAs) for Nothobranchius furzeri. Analyzing multiple small RNA-Seq libraries, we show most of these identified miRNAs are expressed in at least one of seven Nothobranchius species. Additionally, duplication and clustering of N. furzeri miRNAs was analyzed and compared to the four fish species Danio rerio, Oryzias latipes, Gasterosteus aculeatus and Takifugu rubripes. A peculiar characteristic of N. furzeri, as compared to other teleosts, was a duplication of the miR-29 cluster. CONCLUSION: The completeness of the catalogue we provide is comparable to that of the zebrafish. This catalogue represents a basis to investigate the role of miRNAs in aging and development in this species. PMID- 28874119 TI - Automated segmentation of cerebral deep gray matter from MRI scans: effect of field strength on sensitivity and reliability. AB - BACKGROUND: The cerebral subcortical deep gray matter nuclei (DGM) are a common, early, and clinically-relevant site of atrophy in multiple sclerosis (MS). Robust and reliable DGM segmentation could prove useful to evaluate putative neuroprotective MS therapies. The objective of the study was to compare the sensitivity and reliability of DGM volumes obtained from 1.5T vs. 3T MRI. METHODS: Fourteen patients with MS [age (mean, range) 50.2 (32.0-60.8) years, disease duration 18.4 (8.2-35.5) years, Expanded Disability Status Scale score 3.1 (0-6), median 3.0] and 15 normal controls (NC) underwent brain 3D T1-weighted paired scan-rescans at 1.5T and 3T. DGM (caudate, thalamus, globus pallidus, and putamen) segmentation was obtained by the fully automated FSL-FIRST pipeline. Both raw and normalized volumes were derived. RESULTS: DGM volumes were generally higher at 3T vs. 1.5T in both groups. For raw volumes, 3T showed slightly better sensitivity (thalamus: p = 0.02; caudate: p = 0.10; putamen: p = 0.02; globus pallidus: p = 0.0004; total DGM: p = 0.01) than 1.5T (thalamus: p = 0.05; caudate: p = 0.09; putamen: p = 0.03; globus pallidus: p = 0.0006; total DGM: p = 0.02) for detecting DGM atrophy in MS vs. NC. For normalized volumes, 3T but not 1.5T detected atrophy in the globus pallidus in the MS group. Across all subjects, scan-rescan reliability was generally very high for both platforms, showing slightly higher reliability for some DGM volumes at 3T. Raw volumes showed higher reliability than normalized volumes. Raw DGM volume showed higher reliability than the individual structures. CONCLUSIONS: These results suggest somewhat higher sensitivity and reliability of DGM volumes obtained from 3T vs. 1.5T MRI. Further studies should assess the role of this 3T pipeline in tracking potential MS neurotherapeutic effects. PMID- 28874120 TI - The association between smoking and breast cancer characteristics and outcome. AB - BACKGROUND: Smoking is associated with an increased incidence of hormone receptor positive breast cancer. Data regarding worse breast cancer outcome in smokers are accumulating. Current literature regarding the impact of smoking on breast cancer characteristics is limited. We evaluated the impact of smoking on breast cancer characteristics and outcome. METHODS: This was a retrospective single center study. All women diagnosed from 4/2005 through 3/2012 and treated in our institute for early, estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, whose tumors were sent for Oncotype DX analysis were included. Medical records were reviewed for demographics, clinico pathological parameters, treatment and outcome. Data regarding smoking were retrieved according to patients' history at the first visit in the oncology clinic. Patients were grouped and compared according to smoking history (ever smokers vs. never smokers), smoking status (current vs. former and never smokers) and smoking intensity (pack years >=30 vs. the rest of the cohort). Outcomes were adjusted in multivariate analyses and included age, menopausal status, ethnicity, tumor size, nodal status and grade. RESULTS: A total of 662 women were included. 28.2% had a history of smoking, 16.6% were current smokers and 11.3% were heavy smokers. Smoking had no impact on tumor size, nodal involvement and Oncotype DX recurrence score. Angiolymphatic and perineural invasion rates were higher in current smokers than in the rest of the cohort (10.4% vs. 5.1%, p = 0.045, 8.3% vs. 3.5%, p = 0.031, respectively). Smoking had no other impact on histological characteristics. Five-year disease free survival and overall survival rates were 95.7% and 98.5%, respectively. Smoking had no impact on outcomes. Adjusted disease free survival and overall survival did not influence the results. CONCLUSIONS: Smoking had no clinically significant influence on tumor characteristics and outcome among women with estrogen receptor positive, HER2 negative, early breast cancer. As the study was limited to a specific subgroup of the breast cancer population in this heterogeneous disease and since smoking is a modifiable risk factor for the disease, further research is required to clarify the possible impact of smoking on breast cancer. PMID- 28874121 TI - Characterization of the role of sodium nitroprusside (SNP) involved in long vase life of different carnation cultivars. AB - BACKGROUND: Sodium nitroprusside (SNP) has been previously shown to extend the vase life of various cut flowers; however, its positive effect on extending vase life of carnations has not been well documented. Moreover, the role of SNP in the mechanisms underlying determination of vase life of cut carnations has also not been well addressed. RESULTS: SNP increased vase life of Tico Viola carnations along with their relative fresh weight (RFW). Among the treatments, the flowers treated with 10 mg L-1 SNP had the longest vase life and maximum relative fresh weight (RFW). This was achieved through significant suppression of ethylene production via downregulation of ethylene biosynthesis and petal senescence related genes, and through an increase in the scavenging mechanism of reactive oxygen species (ROS) by antioxidant activity during flower vase life. In addition, the positive efficacy of SNP could also be confirmed using 1 aminocyclopropane-1-carboxylic acid (ACC) and different cultivars, resulting in similar trends for both experiments. CONCLUSION: Taken together, these results suggest that SNP plays a crucial role in multiple modes of action that are associated with the longevity of cut carnation flowers. PMID- 28874122 TI - Doxycycline treatment in dialysis related amyloidosis: discrepancy between antalgic effect and inflammation, studied with FDG-positron emission tomography: a case report. AB - BACKGROUND: No effective treatment is currently available and dialysis related amyloidosis continues to be invalidating in long-term dialysis patients. A recent case series reported reduction of osteoarticular pain on doxycycline treatment, extending the indications of this drug, used in other uncommon forms of amyloidosis, to dialysis patients. Explanations of the antalgic effect were the anti-inflammatory properties and anti-coiling effects of tetracycline. CASE PRESENTATION: Our report regards a 54-year-old woman, who was never transplanted and has been on hemodialysis and hemodiafiltration for overall 37 years, due to renal hypoplasia. In spite of high efficiency hemodiafiltration, she complained of increasing, invalidating osteoarticular pain; history and imaging suggested beta-2 microglobulin amyloid. Positron emission tomography (PET scan) identified metabolically active lesions in the involved settings. Low-dose doxycycline (100 mg/day) was started, leading to a considerable decrease in pain (over 6 months, from 7 to 8 to 4-5 on a 0-10 scale). At 6 months, a PET scan showed unmodified or increased uptake in the involved settings. CONCLUSIONS: In summary, the previously described antalgic effect of doxycycline in dialysis related amyloidosis is confirmed in our case, the first studied using PET scan. The pattern at PET can suggests that the antalgic effect is independent from inflammation and points to other factors, such as interaction with fibril geometry or with bone structure. PMID- 28874123 TI - Impact of multi-professional, scenario-based training on postpartum hemorrhage in Tanzania: a quasi-experimental, pre- vs. post-intervention study. AB - BACKGROUND: Tanzania has a relatively high maternal mortality ratio of 410 per 100,000 live births. Severe postpartum hemorrhage (PPH) is a major cause of maternal deaths, but in most cases, it is preventable. However, most pregnant women that develop PPH, have no known risk factors. Therefore, preventive measures must be offered to all pregnant women. This study investigated the effects of multi-professional, scenario-based training on the prevention and management of PPH at a Tanzanian zonal consultant hospital. We hypothesized that scenario-based training could contribute to improved competence on PPH management, which would result in improved team efficiency and patient outcome. METHODS: This quasi-experimental, pre-vs. post-interventional study involved on site multi-professional, scenario-based PPH training, conducted in a two-week period in October 2013 and another 2 weeks in November 2014. Training teams included nurses, midwives, doctors, and medical attendants in the Department of Obstetrics and Gynecology. After technical skill training on the birthing simulator MamaNatalie(r), the teams practiced in realistic scenarios on PPH. Each scenario was followed by debriefing and repeated scenario. Afterwards, the group swapped roles and the observers became the participants. To evaluate the effects of training, we measured patient outcomes by determining blood transfusion rates. Patient data were collected by randomly sampling Medical birth registry files from the pre-training and post-training study periods (n = 1667 and 1641 files, respectively). Data were analyzed with the Chi-square test, Mann-Whitney U-test, and binary logistic regression. RESULTS: The random patient samples (n = 3308) showed that, compared to pre-training, post-training patients had a 47% drop in whole blood transfusion rates and significant increases in cesarean section rates, birth weights, and vacuum deliveries. The logistic regression analysis showed that transfusion rates were significantly associated with the time period (pre- vs. post-training), cesarean section, patients tranferred from other hospitals, maternal age, and female genital mutilation and cutting. CONCLUSIONS: We found that multi-professional, scenario-based training was associated with a significant, 47% reduction in whole blood transfusion rates. These results suggested that training that included all levels of maternity staff, repeated sessions with realistic scenarios, and debriefing may have contributed to reduced blood transfusion rates in this high-risk maternity setting. PMID- 28874124 TI - Telephone counselling by nurses in Norwegian primary care out-of-hours services: a cross-sectional study. AB - BACKGROUND: The primary care out-of-hours (OOH) services in Norway are characterized by high contact rates by telephone. The telephone contacts are handled by local emergency medical communication centres (LEMCs), mainly staffed by registered nurses. When assessment by a medical doctor is not required, the nurse often handles the contact solely by nurse telephone counselling. Little is known about this group of contacts. Thus, the aim of this study was to investigate characteristics of encounters with the OOH services that are handled solely by nurse telephone counselling. METHODS: Nurses recorded ICPC-2 reason for encounter (RFE) codes and patient characteristics of all patients who contacted six primary care OOH services in Norway during 2014. Descriptive statistics and frequency analyses were applied. RESULTS: Of all telephone contacts (n = 61,441), 23% were handled solely by nurse counselling. Fever was the RFE most frequently handled (7.3% of all nurse advice), followed by abdominal pain, cough, ear pain and general symptoms. Among the youngest patients, 32% of the total telephone contacts were resolved by nurse advice compared with 17% in the oldest age group. At night, 31% of the total telephone contacts were resolved solely by nurse advice compared with 21% during the day shift and 23% in the evening. The share of nurse advice was higher on weekdays compared to weekends (mean share 25% versus 20% respectively). CONCLUSION: This study shows that nurses make a significant contribution to patient management in the Norwegian OOH services. The findings indicate which conditions nurses should be able to handle by telephone, which has implications for training and routines in the LEMCs. There is the potential for more nurse involvement in several of the RFEs with a currently low share of nurse counselling. PMID- 28874125 TI - Prognostic consequences of implementing cancer patient pathways in Denmark: a comparative cohort study of symptomatic cancer patients in primary care. AB - BACKGROUND: Cancer Patient Pathways (CPPs) were introduced in 2000-2015 in several European countries, including Denmark, to reduce the time to diagnosis and treatment initiation and ultimately improve patient survival. Yet, the prognostic consequences of implementing CPPs remain unknown for symptomatic cancer patients diagnosed through primary care. We aimed to compare survival and mortality among symptomatic patients diagnosed through a primary care route before, during and after the CPP implementation in Denmark. METHODS: Based on data from the Danish Cancer in Primary Care (CaP) Cohort, we compared one- and three-year standardised relative survival (RS) and excess hazard ratios (EHRs) before, during and after CPP implementation for seven types of cancer and all combined (n = 7725) by using life-table estimation and Poisson regression. RS estimates were standardised according to the International Cancer Survival Standard (ICSS) weights. In addition, we compared RS and EHRs for CPP and non-CPP referred patients to consider potential issues of confounding by indication. RESULTS: In total, 7725 cases were analysed: 1202 before, 4187 during and 2336 after CPP implementation. For all cancers combined, the RS3years rose from 45% (95% confidence interval (CI): 42;47) before to 54% (95% CI: 52;56) after CPP implementation. The excess mortality was higher before than after CPP implementation (EHR3years before vs. after CPP = 1.35 (95% CI: 1.21;1.51)). When comparing CPP against non-CPP referred patients, we found no statistically significant differences in RS, but we found lower excess mortality among the CPP referred (EHR1year CPP vs. non-CPP = 0.86 (95% CI: 0.73;1.01)). CONCLUSION: We found higher relative survival and lower mortality among symptomatic cancer patients diagnosed through primary care after the implementation of CPPs in Denmark. The observed changes in cancer prognosis could be the intended consequences of finding and treating cancer at an early stage, but they may also reflect lead-time bias and selection bias. The finding of a lower excess mortality among CPP referred compared to non-CPP referred patients indicates that CPPs may have improved the cancer prognosis independently. PMID- 28874127 TI - The values of neutrophil-lymphocyte ratio and/or prostate-specific antigen in discriminating real Gleason score >= 7 prostate cancer from group of biopsy-based Gleason score <= 6. AB - BACKGROUND: The discrepant concordance between biopsy and radical prostatectomy (RP) specimen are well reported. To validate the clinical usefulness of neutrophil-lymphocyte ratio (NLR) in discriminating real GS >= 7 PCa from biopsy based GS <= 6 PCa in comparison with serum total prostate-specific antigen (tPSA) and value of their combination. METHODS: One hundred one patients who underwent physical examinations incidentally found elevated tPSA and subsequently received biopsy with a conclusion of GS <= 6 and RP with an interval of 4-6 weeks after biopsy were enrolled. NLR and tPSA were obtained within 15 days prior to biopsy. Logistic regression model was applied appropriately; McNemar tests and AUC model were performed to evaluate differences among tPSA, NLR and their combination and corresponding diagnostic power respectively. RESULTS: The pathological results from RP specimen comprised 61 patients with GS <= 6 and 100 patients with GS >= 7. Higher tPSA and NLR were significantly associated with patients with actual GS >= 7 (All P < 0.05) concurrently. Multivariate logistic regression indicated that tPSA (OR = 1.088, 95% C.I. = 1.029-1.151, P = 0.003) and NLR (OR = 1.807, 95% C.I. = 1.021-3.200, P = 0.042) could be independent predictors for GS groupings. Under cutoff value of 14.09 ng/ml for tPSA and 2.25 for NLR, the sensitivity, specificity and accuracy were 60.0%, 80.3% and 67.7% for tPSA, 42%, 88.5% and 59.6% for NLR, and 71.0%, 75.4% and 72.7% for combination of tPSA and NLR (tPSA + NLR) respectively. The sensitivity of tPSA + NLR was significantly higher in comparison with tPSA (P = 0.001) and NLR (P < 0.001). Except for sensitivity, no significant difference was found between tPSA and NLR in specificity (P = 0.227) and accuracy (P = 0.132). tPSA got the largest AUC with 0.732 (p < 0.001, 95% C.I.: 0.651-0.813). CONCLUSIONS: Serum tPSA and NLR were significantly elevated among GS >= 7 PCa concurrently. The combination of tPSA and NLR might have additional benefit to biopsy on discriminating real GS >= 7 Pca from biopsy-based GS <= 6 PCa. More stratification models and prospectively multicenter studies are necessary. PMID- 28874126 TI - Development and external validation of nomograms to predict the risk of skeletal metastasis at the time of diagnosis and skeletal metastasis-free survival in nasopharyngeal carcinoma. AB - BACKGROUND: The skeletal system is the most common site of distant metastasis in nasopharyngeal carcinoma (NPC); various prognostic factors have been reported for skeletal metastasis, though most studies have focused on a single factor. We aimed to establish nomograms to effectively predict skeletal metastasis at initial diagnosis (SMAD) and skeletal metastasis-free survival (SMFS) in NPC. METHODS: A total of 2685 patients with NPC who received bone scintigraphy (BS) and/or 18F-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and 2496 patients without skeletal metastasis were retrospectively assessed to develop individual nomograms for SMAD and SMFS. The models were validated externally using separate cohorts of 1329 and 1231 patients treated at two other institutions. RESULTS: Five independent prognostic factors were included in each nomogram. The SMAD nomogram had a significantly higher c-index than the TNM staging system (training cohort, P = 0.005; validation cohort, P < 0.001). The SMFS nomogram had significantly higher c-index values in the training and validation sets than the TNM staging system (P < 0.001 and P = 0.005, respectively). Three proposed risk stratification groups were created using the nomograms, and enabled significant discrimination of SMFS for each risk group. CONCLUSION: The prognostic nomograms established in this study enable accurate stratification of distinct risk groups for skeletal metastasis, which may improve counseling and facilitate individualized management of patients with NPC. PMID- 28874128 TI - Relationship of genetic causes and inhibin B in non obstructive azoospermia spermatogenic failure. AB - BACKGROUND: Chromosomal disorders in non obstructive azoospermia (NOA) may have an important influence on spermatogenesis, which may be reflected by the serum inhibin B levels. Till now, few studies have concerned the relationship of genetic causes and inhibin B in NOA. METHODS: In this retrospective study, 322 men with NOA in Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University were collected. The level of follicle stimulating hormone (FSH), inhibin B, Y chromosome microdeletion test (YCMD) and karyotype were measured. RESULTS: Abnormal karyotypes were present in 38.5% of NOA, and YCMD were present in 18.0%, there was a high correlation between karyotypes and YCMD (chi2 = 11.892, P < 0.001). The level of inhibin B in chromosomal abnormality from lowest to highest was 46,XX (or 45,X), 47, XXY, mosaics, polymorphisms, inversion and translocation. And the level of inhibin B within Non-AZF a&b region deletion was higher than AZF a&b microdeletion. CONCLUSION: According to the level of inhibin B, spermatogenesis in chromosomal abnormality from lowest to highest was 46,XX (or 45,X), 47, XXY, mosaics, polymorphisms, inversion and translocation. And spermatogenesis within Non-AZF a&b region deletion was better than AZF a&b microdeletion. PMID- 28874129 TI - Comparative effectiveness of rivaroxaban versus warfarin or dabigatran for the treatment of patients with non-valvular atrial fibrillation. AB - BACKGROUND: Rivaroxaban is an oral anticoagulant approved in the US for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). We determined the effectiveness and associated risks of rivaroxaban versus other oral anticoagulants in a large real-world population. METHODS: We selected NVAF patients initiating oral anticoagulant use in 2010-2014 enrolled in MarketScan databases. Rivaroxaban users were matched with warfarin and dabigatran users by age, sex, enrolment date, anticoagulant initiation date, and high-dimensional propensity score. Study endpoints, including ischemic stroke, intracranial bleeding (ICB), myocardial infarction (MI), and gastrointestinal (GI) bleeding, were identified from inpatient diagnostic codes. Multivariable Cox models were used to assess associations between type of anticoagulant and outcomes. RESULTS: The analysis included 44,340 rivaroxaban users matched to 89,400 warfarin and 16,957 dabigatran users (38% female, mean age 70) with 12 months of mean follow-up. Anticoagulant-naive rivaroxaban initiators, but not those switching from warfarin, had lower risk of ischemic stroke [hazard ratio (HR) (95% confidence interval (CI)): 0.75 (0.62, 0.91)] and ICB [HR (95%CI): 0.55, (0.39, 0.78)] than warfarin users. In contrast, anticoagulant-experienced rivaroxaban initiators had higher risk of GI bleeding than warfarin users [HR (95%CI): 1.55 (1.32, 1.83)]. Endpoint rates were similar when comparing anticoagulant-naive rivaroxaban and dabigatran initiators, with the exception of higher GI bleeding risk in rivaroxaban users [HR (95%CI) 1.28 (1.06, 1.54)]. There were no significant differences in the risk of MI among the comparison groups. CONCLUSION: In this large real-world sample of NVAF patients, effectiveness and risks of rivaroxaban versus warfarin differed by prior anticoagulant status, while effectiveness of rivaroxaban versus dabigatran differed in GI bleeding risk. PMID- 28874131 TI - A chronic hemodialysis patient with isolated pulmonary valve infective endocarditis caused by non-albicans Candida: a rare case and literature review. AB - BACKGROUND: Isolated pulmonary valve infective endocarditis caused by Candida is rare in chronic hemodialysis patients. The 2009 Infectious Diseases Society of America guidelines suggest the combined use of surgery and antibiotics to treat candidiasis; however, successful nonsurgical treatment of Candida endocarditis has been reported. CASE PRESENTATION: A 63-year-old woman with end-stage kidney disease was admitted to our hospital after experiencing disorientation for 5 days. The patient was permanently bedridden because of depression, and denied active intravenous drug use. She received maintenance hemodialysis through a tunneled-cuffed catheter. An initial blood culture grew Candida guilliermondii without other bacteria. Subsequent blood cultures and tip culture of tunneled cuffed catheter also grew C. guilliermondii, even after caspofungin replaced fluconazole. A 1.2-cm mobile mass was observed on the pulmonary valve. Surgical intervention was suggested, but the family of the patient declined because of her multiple comorbidities. The patient was discharged with a prescription of fluconazole, but she died soon after. CONCLUSION: Our patient is the first case with isolated pulmonary valve endocarditis caused by C. guilliermondii in patients with uremia. Hematologic disorders, in addition to long-term central venous catheter use, prolonged antibiotic intravenous injection, and congenital cardiac anomaly, predispose to the condition. The diagnosis "isolated" pulmonary IE is difficult, and combing surgery with antifungal antibiotics is the appropriate therapeutic management for Candida related pulmonary IE. PMID- 28874130 TI - A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. AB - BACKGROUND: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. METHODS: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. RESULTS: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. CONCLUSION: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries. PMID- 28874132 TI - Bone turnover markers are associated with bone density, but not with fracture in end stage kidney disease: a cross-sectional study. AB - BACKGROUND: Fracture risk is increased in chronic kidney disease (CKD), but assessment of bone fragility remains controversial in these patients. This study investigated the associations between bone turnover markers, bone mineral density (BMD), and prevalent fragility fracture in a cohort of kidney transplantation candidates. METHODS: Volumetric BMD of spine and hip was measured by quantitative computed tomography. Parathyroid hormone (PTH), bone-specific alkaline phosphatase, procollagen type-1 N-terminal propeptide, tartrate resistant alkaline phosphatase, and C- and N-terminal telopeptides of type 1 collagen were analyzed from fasting morning blood samples. Fragility fractures included prevalent vertebral fractures and previous low-trauma clinical fractures. RESULTS: The fracture prevalence was 18% in 157 adult kidney transplant candidates. Fractured patients had reduced BMD and Z-score at both spine and hip. Levels of bone turnover markers were significantly higher in patients on maintenance dialysis than in pre-dialysis patients; but did not differ between patients with and without fracture. There were strong, positive correlations between PTH and all bone turnover markers. PTH was negatively associated with Z score at lumbar spine and total hip; in contrast, bone turnover markers were only negatively associated with total hip Z-score. CONCLUSIONS: Bone turnover markers were negatively associated with bone density, but not associated with prevalent fracture in kidney transplantation candidates. The role of bone turnover markers in assessing bone fragility in CKD will require further investigation. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov with identifier NCT01344434 . PMID- 28874133 TI - Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial. AB - BACKGROUND: Few controlled clinical trials exist to support oral combination therapy in pulmonary arterial hypertension (PAH). METHODS: Patients with PAH (idiopathic [IPAH] or associated with connective tissue disease [APAH-CTD]) taking bosentan (62.5 or 125 mg twice daily at a stable dose for >=3 months) were randomized (1:1) to sildenafil (20 mg, 3 times daily; n = 50) or placebo (n = 53). The primary endpoint was change from baseline in 6-min walk distance (6MWD) at week 12, assessed using analysis of covariance. Patients could continue in a 52-week extension study. An analysis of covariance main-effects model was used, which included categorical terms for treatment, baseline 6MWD (<325 m; >=325 m), and baseline aetiology; sensitivity analyses were subsequently performed. RESULTS: In sildenafil versus placebo arms, week-12 6MWD increases were similar (least squares mean difference [sildenafil-placebo], -2.4 m [90% CI: -21.8 to 17.1 m]; P = 0.6); mean +/- SD changes from baseline were 26.4 +/- 45.7 versus 11.8 +/- 57.4 m, respectively, in IPAH (65% of population) and -18.3 +/- 82.0 versus 17.5 +/- 59.1 m in APAH-CTD (35% of population). One-year survival was 96%; patients maintained modest 6MWD improvements. Changes in WHO functional class and Borg dyspnoea score and incidence of clinical worsening did not differ. Headache, diarrhoea, and flushing were more common with sildenafil. CONCLUSIONS: Sildenafil, in addition to stable (>=3 months) bosentan therapy, had no benefit over placebo for 12-week change from baseline in 6MWD. The influence of PAH aetiology warrants future study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00323297 (registration date: May 5, 2006). PMID- 28874134 TI - Amyotrophic lateral sclerosis modifies progenitor neural proliferation in adult classic neurogenic brain niches. AB - BACKGROUND: Adult neurogenesis persists through life at least in classic neurogenic niches. Neurogenesis has been previously described as reduced in neurodegenerative diseases. There is not much knowledge about is adult neurogenesis is or not modified in amyotrophy lateral sclerosis (ALS). All previous publications has studied the ALS SOD1 (superoxide dismutase) transgenic mouse model. The purpose of this study is to examine the process of adult neurogenesis in classic niches (subventricular zone [SVZ] and subgranular zone [SGZ] of the dentate gyrus) in patients with amyotrophic lateral sclerosis (ALS), both with (ALS-FTD) and without associated frontotemporal dementia (FTD). METHODS: We studied 9 autopsies of patients with ALS (including 2 with ALS-FTD) and 4 controls. ALS was confirmed histologically. Studies of the SVZ and SGZ were conducted using markers of proliferation (Ki-67, PCNA), of pluripotent neural progenitor cells (GFAPdelta), neuroblasts (PSA-NCAM, DCX, TUJ1), and an astrocyte marker (GFAP). Results were analyzed with non-parametric tests. We then studied correlations between the different markers and the percentage of phosphorylated TDP-43 (pTDP-43). RESULTS: We observed a statistically significant increase in proliferation in the SVZ in all patients with ALS. While this increase was more marked in ALS forms associated with dementia, the small sample size does not permit a statistical subgroup analysis. In contrast, proliferation in the SGZ was decreased in all patients. These alterations showed a positive and direct correlation with the percentage of pTDP-43 in the SVZ, and a negative, exponential correlation with that percentage in the SGZ. CONCLUSIONS: We observed alterations of the proliferation of neural progenitor in classic adult neurogenic niches in patients with ALS. The 2 neurogenic niches exhibited opposite changes such that proliferation increased in the SVZ and decreased in the SGZ. PMID- 28874135 TI - Cytotoxicity of replication-competent adenoviruses powered by an exogenous regulatory region is not linearly correlated with the viral infectivity/gene expression or with the E1A-activating ability but is associated with the p53 genotypes. AB - BACKGROUND: Replication-competent adenoviruses (Ad) produced cytotoxic effects on infected tumors and have been examined for the clinical applicability. A biomarkers to predict the cytotoxicity is valuable in a clinical setting. METHODS: We constructed type 5 Ad (Ad5) of which the expression of E1A gene was activated by a 5' regulatory sequences of survivin, midkine or cyclooxygenase-2, which were highly expressed in human tumors. We also produced the same replication-competent Ad of which the fiber-knob region was replaced by that of Ad35 (AdF35). The cytotoxicity was examined by a colorimetric assay with human tumor cell lines, 4 kinds of pancreatic, 9 esophageal carcinoma and 5 mesothelioma. Ad infectivity and Ad-mediated gene expression were examined with replication-incompetent Ad5 and AdF35 which expressed the green fluorescence protein gene. Expression of cellular receptors for Ad5 and AdF35 was also examined with flow cytometry. A transcriptional activity of the regulatory sequences was investigated with a luciferase assay in the tumor cells. We then investigated a possible correlation between Ad-mediated cytotoxicity and the infectivity/gene expression, the transcriptional activity or the p53 genotype. RESULTS: We found that the cytotoxicity was greater with AdF35 than with Ad5 vectors, but was not correlated with the Ad infectivity/gene expression irrespective of the fiber-knob region or the E1A-activating transcriptional activity. In contrast, replication-competent Ad produced greater cytotoxicity in p53 mutated than in wild-type esophageal carcinoma cells, suggesting a possible association between the cytotoxicity and the p53 genotype. CONCLUSIONS: Sensitivity to Ad-mediated cytotoxic activity was linked with the p53 genotype but was not lineally correlated with the infectivity/gene expression or the E1A expression. PMID- 28874136 TI - HiMMe: using genetic patterns as a proxy for genome assembly reliability assessment. AB - BACKGROUND: The information content of genomes plays a crucial role in the existence and proper development of living organisms. Thus, tremendous effort has been dedicated to developing DNA sequencing technologies that provide a better understanding of the underlying mechanisms of cellular processes. Advances in the development of sequencing technology have made it possible to sequence genomes in a relatively fast and inexpensive way. However, as with any measurement technology, there is noise involved and this needs to be addressed to reach conclusions based on the resulting data. In addition, there are multiple intermediate steps and degrees of freedom when constructing genome assemblies that lead to ambiguous and inconsistent results among assemblers. METHODS: Here we introduce HiMMe, an HMM-based tool that relies on genetic patterns to score genome assemblies. Through a Markov chain, the model is able to detect characteristic genetic patterns, while, by introducing emission probabilities, the noise involved in the process is taken into account. Prior knowledge can be used by training the model to fit a given organism or sequencing technology. RESULTS: Our results show that the method presented is able to recognize patterns even with relatively small k-mer size choices and limited computational resources. CONCLUSIONS: Our methodology provides an individual quality metric per contig in addition to an overall genome assembly score, with a time complexity well below that of an aligner. Ultimately, HiMMe provides meaningful statistical insights that can be leveraged by researchers to better select contigs and genome assemblies for downstream analysis. PMID- 28874137 TI - Mitochondrial genomes of blister beetles (Coleoptera, Meloidae) and two large intergenic spacers in Hycleus genera. AB - BACKGROUND: Insect mitochondrial genomes (mitogenomes) exhibit high diversity in some lineages. The gene rearrangement and large intergenic spacer (IGS) have been reported in several Coleopteran species, although very little is known about mitogenomes of Meloidae. RESULTS: We determined complete or nearly complete mitogenomes of seven meloid species. The circular genomes encode 13 protein coding genes (PCGs), 22 transfer RNAs (tRNAs) and two ribosomal RNAs (rRNAs), and contain a control region, with gene arrangement identical to the ancestral type for insects. The evolutionary rates of all PCGs indicate that their evolution is based on purifying selection. The comparison of tRNA secondary structures indicates diverse substitution patterns in Meloidae. Remarkably, all mitogenomes of the three studied Hycleus species contain two large intergenic spacers (IGSs). IGS1 is located between trnW and trnC, including a 9 bp consensus motif. IGS2 is located between trnS2 (UCN) and nad1, containing discontinuous repeats of a pentanucleotide motif and two 18-bp repeat units in both ends. To date, IGS2 is found only in genera Hycleus across all published Coleopteran mitogenomes. The duplication/random loss model and slipped-strand mispairing are proposed as evolutionary mechanisms for the two IGSs (IGS1, IGS2). The phylogenetic analyses using MrBayes, RAxML, and PhyloBayes methods based on nucleotide and amino acid datasets of 13 PCGs from all published mitogenomes of Tenebrionoids, consistently recover the monophylies of Meloidae and Tenebrionidae. Within Meloidae, the genus Lytta clusters with Epicauta rather than with Mylabris. Although data collected thus far could not resolve the phylogenetic relationships within Meloidae, this study will assist in future mapping of the Meloidae phylogeny. CONCLUSIONS: This study presents mitogenomes of seven meloid beetles. New mitogenomes retain the genomic architecture of the Coleopteran ancestor, but contain two IGSs in the three studied Hycleus species. Comparative analyses of two IGSs suggest that their evolutionary mechanisms are duplication/random loss model and slipped strand mispairing. PMID- 28874139 TI - The association of falls with loneliness and social exclusion: evidence from the DEAS German Ageing Survey. AB - BACKGROUND: It remains an open question whether falls are related with social relations, covering subjective (e.g., perceived loneliness) and more objective dimensions (e.g., number of important individuals in regular contact). Consequently, we aimed at examining the association between falls and social ties comprehensively, including loneliness, social exclusion and the number of important people in regular contact. METHODS: Cross-sectional data were used from a population-based sample of community-dwelling individuals aged 40 and over (n = 7808) in Germany. Self-rated loneliness was quantified using a short version of the De Jong Gierveld Loneliness Scale. Perceived social exclusion was measured using a scale developed by Bude and Lantermann. Furthermore and in contrast to the subjective outcome measures, the more objective number of important people in regular contact was also used as outcome variable. The experience of a fall in the preceding 12 months (yes; no) was assessed. RESULTS: Controlling for various possible confounding variables, linear regressions showed that experiencing a fall in the past 12 months was associated with higher social exclusion (beta = .08, p < .001), and increased loneliness (beta = .08, p < .001), whereas it was not associated with the number of important people in regular contact. CONCLUSIONS: Findings stress the relation between falls and feelings of loneliness and social exclusion, whereas falls were unrelated to the more objective measure of number of important people in regular contact, suggesting that falls are particularly related to subjective measures of social ties and relations. This underlines the importance of interventions to prevent falls. Preventing falls in turn might help to prevent loneliness and social exclusion. PMID- 28874138 TI - ERp29 controls invasion and metastasis of gastric carcinoma by inhibition of epithelial-mesenchymal transition via PI3K/Aktsignaling pathway. AB - BACKGROUND: Gastric cancer (GC) accounts for the fourth most occurring malignancy and the third major cause of cancer death. Identifying novel molecular signaling pathways participating in gastric tumorigenesis and progression is pivotal for rational design of targeted therapies to improve advanced GC outcome. Recently, the endoplasmic reticulum (ER) protein 29 (ERp29) has been shown to inversely associate with primary tumor development and function as a tumor suppressor in breast cancer. However, the role of ERp29 in GC patients' prognosis and its function in GC progression is unknown. METHODS: Clinical importance of ERp29 in the prognosis of GC patients was assessed by examining its expression in 148 GC tumor samples and correlation with clinicopathological characteristics and survival of the patients. The function and underlying mechanisms of ERp29 in GC growth, invasion and metastasis were explored both in vitro and in vivo. RESULTS: Downregulation of ERp29 was commonly found in GC tissues and highly correlated with more aggressive phenotypes and poorer prognosis. Functional assays demonstrated that knockdown of ERp29 increased GC cell migration and invasion and promoted metastasis. Conversely, ectopic overexpression of ERp29 produced opposite effects. Mechanistic studies revealed that loss of ERp29 induced an epithelial-to-mesenchymal transition (EMT) in the GC cells through activation of PI3K/Akt pathway signaling. CONCLUSION: These findings suggest that downregulation of ERp29 is probably one of the key molecular mechanisms responsible for the development and progression of GC. PMID- 28874140 TI - The impact of frailty on healthcare utilisation in Ireland: evidence from the Irish longitudinal study on ageing. AB - INTRODUCTION: To examine the impact of frailty on medical and social care utilisation among the Irish community-dwelling older population to inform strategies of integrated care for older people with complex needs. METHODS: Participants aged >=65 years from the Irish Longitudinal Study on Ageing (TILDA) representative of the Irish community-dwelling older population were analysed (n = 3507). The frailty index was used to examine patterns of utilisation across medical and social care services. Multivariate logistic and negative binomial regression models were employed to examine the impact of frailty on service utilisation outcomes after controlling for other factors. RESULTS: The prevalence of frailty and pre-frailty was 24% (95% CI: 23, 26%) and 45% (95% CI: 43, 47%) respectively. Frailty was a significant predictor of utilisation of most social care and medical care services after controlling for the main correlates of frailty and observed individual effects. CONCLUSIONS: Frailty predicts utilisation of many different types of healthcare services rendering it a useful risk stratification tool for targeting strategies of integrated care. The pattern of care is predominantly medical as few of the frail older population use social care prompting questions about sub-groups of the frail older population with unmet care needs. PMID- 28874141 TI - Stress alters the expression of cancer-related genes in the prostate. AB - BACKGROUND: Prostate cancer is a major contributor to mortality worldwide, and significant efforts are being undertaken to decipher specific cellular and molecular pathways underlying the disease. Chronic stress is known to suppress reproductive function and promote tumor progression in several cancer models, but our understanding of the mechanisms through which stress contributes to cancer development and progression is incomplete. We therefore examined the relationship between stress, modulation of the gonadotropin-releasing hormone (GnRH) system, and changes in the expression of cancer-related genes in the rat prostate. METHODS: Adult male rats were acutely or repeatedly exposed to restraint stress, and compared to unstressed controls and groups that were allowed 14 days of recovery from the stress. Prostate tissue was collected and frozen for gene expression analyses by PCR array before the rats were transcardially perfused; and brain tissues harvested and immunohistochemically stained for Fos to determine neuronal activation. RESULTS: Acute stress elevated Fos expression in the paraventricular nucleus of the hypothalamus (PVH), an effect that habituated with repeated stress exposure. Data from the PCR arrays showed that repeated stress significantly increases the transcript levels of several genes associated with cellular proliferation, including proto-oncogenes. Data from another array platform showed that both acute and repeated stress can induce significant changes in metastatic gene expression. The functional diversity of genes with altered expression, which includes transcription factors, growth factor receptors, apoptotic genes, and extracellular matrix components, suggests that stress is able to induce aberrant changes in pathways that are deregulated in prostate cancer. CONCLUSIONS: Our findings further support the notion that stress can affect cancer outcomes, perhaps by interfering with neuroendocrine mechanisms involved in the control of reproduction. PMID- 28874142 TI - Risk factors for increased immune reconstitution in response to Mycobacterium tuberculosis antigens in tuberculosis HIV-infected, antiretroviral-naive patients. AB - BACKGROUND: Little is known regarding the restoration of the specific immune response after combined antiretroviral therapy (cART) and anti-tuberculosis (TB) therapy introduction among TB-HIV patients. In this study, we examined the immune response of TB-HIV patients to Mycobacterium tuberculosis (Mtb) antigens to evaluate the response dynamics to different antigens over time. Moreover, we also evaluated the influence of two different doses of efavirenz and the factors associated with immune reconstitution. METHODS: This is a longitudinal study nested in a clinical trial, where cART was initiated during the baseline visit (D0), which occurred 30 +/- 10 days after the introduction of anti-TB therapy. Follow-up visits were performed at 30, 60, 90 and 180 days after cART initiation. The production of IFN-gamma upon in vitro stimulation with Mtb antigens purified protein derivative (PPD), ESAT-6 and 38 kDa/CFP-10 using ELISpot was examined at baseline and follow-up visits. RESULTS: Sixty-one patients, all ART-naive, were selected and included in the immune reconstitution analysis; seven (11.5%) developed Immune Reconstitution Inflammatory Syndrome (IRIS). The Mtb specific immune response was higher for the PPD antigen followed by 38 kDa/CFP-10 and increased in the first 60 days after cART initiation. In multivariate analysis, the variables independently associated with increased IFN-gamma production in response to PPD antigen were CD4+ T cell counts <200 cells/mm3 at baseline, age, site of tuberculosis, 800 mg efavirenz dose and follow-up CD4+ T cell counts. Moreover, the factors associated with the production of IFN-gamma in response to 38 kDa/CFP-10 were detectable HIV viral load (VL) and CD4+ T cell counts at follow-up visits of >=200 cells/mm3. CONCLUSIONS: These findings highlight the differences in immune response according to the specificity of the Mtb antigen, which contributes to a better understanding of TB-HIV immunopathogenesis. IFN gamma production elicited by PPD and 38 kDa/CFP-10 antigens have a greater magnitude compared to ESAT-6 and are associated with different factors. The low response to ESAT-6, even during immune restoration, suggests that this antigen is not adequate to assess the immune response of immunosuppressed TB-HIV patients. PMID- 28874143 TI - CHEK2 c.1100delC mutation is associated with an increased risk for male breast cancer in Finnish patient population. AB - BACKGROUND: Several susceptibility genes have been established for female breast cancer, of which mutations in BRCA1 and especially in BRCA2 are also known risk factors for male breast cancer (MBC). The role of other breast cancer genes in MBC is less well understood. METHODS: In this study, we have genotyped 68 MBC patients for the known breast or ovarian cancer associated mutations in the Finnish population in CHEK2, PALB2, RAD51C, RAD51D, and FANCM genes. RESULTS: CHEK2 c.1100delC mutation was found in 4 patients (5.9%), which is significantly more frequent than in the control population (OR: 4.47, 95% CI 1.51-13.18, p = 0.019). Four CHEK2 I157T variants were also detected, but the frequency did not significantly differ from population controls (p = 0.781). No RAD51C, RAD51D, PALB2, or FANCM mutations were found. CONCLUSIONS: These data suggest that the CHEK2 c.1100delC mutation is associated with an increased risk for MBC in the Finnish population. PMID- 28874144 TI - Circadian disruption promotes tumor growth by anabolic host metabolism; experimental evidence in a rat model. AB - BACKGROUND: Light at night creates a conflicting signal to the biological clock and disrupts circadian physiology. In rodents, light at night increases the risk to develop mood disorders, overweight, disrupted energy metabolism, immune dysfunction and cancer. We hypothesized that constant light (LL) in rats may facilitate tumor growth via disrupted metabolism and increased inflammatory response in the host, inducing a propitious microenvironment for tumor cells. METHODS: Male Wistar rats were exposed to LL or a regular light-dark cycle (LD) for 5 weeks. Body weight gain, food consumption, triglycerides and glucose blood levels were evaluated; a glucose tolerance test was also performed. Inflammation and sickness behavior were evaluated after the administration of intravenous lipopolysaccharide. Tumors were induced by subcutaneous inoculation of glioma cells (C6). In tumor-bearing rats, the metabolic state and immune cells infiltration to the tumor was investigated by using immunohistochemistry and flow cytometry. The mRNA expression of genes involved metabolic, growth, angiogenes and inflammatory pathways was measured in the tumor microenvironment by qPCR. Tumor growth was also evaluated in animals fed with a high sugar diet. RESULTS: We found that LL induced overweight, high plasma triglycerides and glucose levels as well as reduced glucose clearance. In response to an LPS challenge, LL rats responded with higher pro-inflammatory cytokines and exacerbated sickness behavior. Tumor cell inoculation resulted in increased tumor volume in LL as compared with LD rats, associated with high blood glucose levels and decreased triglycerides levels in the host. More macrophages were recruited in the LL tumor and the microenvironment was characterized by upregulation of genes involved in lipogenesis (Acaca, Fasn, and Ppargamma), glucose uptake (Glut-1), and tumor growth (Vegfalpha, Myc, Ir) suggesting that LL tumors rely on these processes in order to support their enhanced growth. Genes related with the inflammatory state in the tumor microenvironment were not different between LL and LD conditions. In rats fed a high caloric diet tumor growth was similar to LL conditions. CONCLUSIONS: Data indicates that circadian disruption by LL provides a favorable condition for tumor growth by promoting an anabolic metabolism in the host. PMID- 28874145 TI - Propensity score analysis of lung cancer risk in a population with high prevalence of non-smoking related lung cancer. AB - BACKGROUND: Lung cancer has been the leading cause of cancer-related mortality worldwide among both men and women in recent years. There is an increase in the incidence of nonsmoking-related lung cancer in recent years. The purpose of the present study was to investigate multiple potential risk factors for nonsmoking related lung cancer among Asian Ethnic Groups. METHODS: We used a propensity score-mated cohort analysis for this study. We retrospectively review the medical record of 1975 asymptomatic healthy subjects (40 ~ 80 years old) who voluntarily underwent low-dose chest CT from August 2013 to October 2014. Clinical information and nodule characteristics were recorded. RESULTS: A propensity score mated cohort analysis was applied to adjust for potential bias and to create two comparable groups according to family history of lung cancer. For our primary analysis, we matched 392 pairs of subjects with family history of lung cancer and subjects without history. Logistic regression showed that female gender and a family history of lung cancer were the two most important predictor of lung cancer in the endemic area with high prevalence of nonsmoking-related lung cancer (OR = 11.199, 95% CI = 1.444-86.862; OR = 2.831, 95% CI = 1.000136-8.015). In addition, the number of nodules was higher in subjects with family history of lung cancer in comparison with subjects without family history of lung cancer (OR = 1.309, 95% CI = 1.066-1.607). CONCLUSIONS: In conclusion, risk-based prediction model based on the family history of lung cancer and female gender can potentially improve efficiency of lung cancer screening programs in Taiwan. PMID- 28874146 TI - Effect of short-term heart rate variability biofeedback on long-term abstinence in alcohol dependent patients - a one-year follow-up. AB - BACKGROUND: A randomized controlled study (RCT) recently showed that short-term heart rate variability (HRV) biofeedback in addition to standard rehabilitation care for alcohol dependence can reduce craving, anxiety and improve cardiovascular autonomic function. In this one-year follow-up study we aimed to explore whether completion of 2-week HRV-Biofeedback training is associated with long-term abstinence. Furthermore, we sought to identify potential predictors of post-treatment abstinence. METHODS: We conducted a survey on abstinence in patients with alcohol dependence 1 year after completion of an RCT comparing HRV biofeedback in addition to inpatient rehabilitation treatment alone (controls). Abstinence rates were compared and analysed for association with demographic data as well as psychometric and autonomic cardiac assessment before and after completion of the biofeedback training using bivariate and multivariate regression analyses. RESULTS: Out of 48 patients who participated in the RCT, 27 patients (9 females, ages 42.9 +/- 8.6, mean +/- SD) completed our one-year follow-up. When including in the analysis only patients who completed follow-up, the rate of abstinence tended to be higher in patients who underwent HRV biofeedback 1 year earlier compared to those who received rehabilitative treatment alone (66.7% vs 50%, p = ns). This non-significant trend was also observed in the intention-to-treat analysis where patients who did not participate in the follow-up were assumed to have relapsed (46,7% biofeedback vs. 33.3% controls, p = ns). Neither cardiac autonomic function nor psychometric variables were associated with abstinence 1 year after HRV-biofeedback. CONCLUSION: Our follow-up study provide a first indication of possible increase in long-term abstinence after HRV-biofeedback for alcohol dependence in addition to rehabilitation. TRIAL REGISTRATION: The original randomized controlled trial was registered in the German Clinical Trials Register ( DRKS00004618 ). This one year follow-up survey has not been registered. PMID- 28874147 TI - Assessing the activity of nonsense-mediated mRNA decay in lung cancer. AB - BACKGROUND: Inhibition of nonsense-mediated mRNA decay (NMD) in tumor cells can suppress tumor growth through expressing new antigens whose mRNAs otherwise are degraded by NMD. Thus NMD inhibition is a promising approach for developing cancer therapies. Apparently, the success of this approach relies on the basal NMD activity in cancer cells. If NMD is already strongly inhibited in tumors, the approach would not work. Therefore, it is crucial to assess NMD activity in cancers to forecast the efficacy of NMD-inhibition based therapy. METHODS: Here we develop three metrics using RNA-seq data to measure NMD activity, and apply them to a dataset consisting of 72 lung cancer (adenocarcinoma) patients. RESULTS: We show that these metrics have good correlations, and that the NMD activities in adenocarcinoma samples vary among patients: some cancerous samples show significantly stronger NMD activities than the normal tissues while some others show the opposite pattern. The variation of NMD activities among these samples may be partly explained by the varying expression of NMD effectors. CONCLUSIONS: In sum, NMD activity varies among lung cancerous samples, which forecasts varying efficacies of NMD-inhibition based therapy. The developed metrics can be further used in other cancer types to assess NMD activity. PMID- 28874148 TI - Evaluating a Dutch cardiology primary care plus intervention on the Triple Aim outcomes: study design of a practice-based quantitative and qualitative research. AB - BACKGROUND: In an attempt to deal with the pressures on the health-care system and to guarantee sustainability, changes are needed. This study focuses on a cardiology primary care plus intervention. Primary care plus (PC+) is a new health-care delivery model focused on substitution of specialist care in the hospital setting with specialist care in the primary care setting. The intervention consists of a cardiology PC+ centre in which cardiologists, supported by other health-care professionals, provide consultations in a primary care setting. The PC+ centre aims to improve the health of the population and quality of care as experienced by patients, and reduce the number of referrals to hospital-based outpatient specialist care in order to reduce health-care costs. These aims reflect the Triple Aim principle. Hence, the objectives of the study are to evaluate the cardiology PC+ centre in terms of the Triple Aim outcomes and to evaluate the process of the introduction of PC+. METHODS/DESIGN: The study is a practice-based, quantitative study with a longitudinal observational design, and an additional qualitative study to supplement, interpret and improve the quantitative study. The study population of the quantitative part will consist of adult patients (>=18 years) with non-acute and low-complexity cardiology-related health complaints, who will be referred to the cardiology PC+ centre (intervention group) or hospital-based outpatient cardiology care (control group). All eligible patients will be asked to complete questionnaires at three different time points consisting of questions about their demographics, health status and experience of care. Additionally, quantitative data will be collected about health-care utilization and related health-care costs at the PC+ centre and the hospital. The qualitative part, consisting of semi-structured interviews, focus groups, and observations, is designed to evaluate the process as well as to amplify, clarify and explain quantitative results. CONCLUSIONS: This study will evaluate a cardiology PC+ centre using quantitative and supplementary qualitative methods. The findings of both sub-studies will fill a gap in knowledge about the effects of PC+ and in particular whether PC+ is able to pursue the Triple Aim outcomes. TRIAL REGISTRATION: NTR6629 (Data registered: 25-08-2017) (registered retrospectively). PMID- 28874149 TI - Comparison of computed tomography and high-field (3.0 T) magnetic resonance imaging of age-related variances in selected equine maxillary cheek teeth and adjacent tissues. AB - BACKGROUND: Modern imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) have the advantage of producing images without superimposition. Whilst CT is a well-established technique for dental diagnostics, MRI examinations are rarely used for the evaluation of dental diseases in horses. Regarding equine endodontic therapies which are increasingly implemented, MRI could help to portray changes of the periodontal ligament and display gross pulpar anatomy. Knowledge of age-related changes is essential for diagnosis, as cheek teeth and surrounding structures alter with increasing age. The aim of the present study was to highlight the advantages of CT and MRI regarding age-related changes in selected equine cheek teeth and their adjacent structures. RESULTS: The CT and MRI appearances of the maxillary 08 s and 09 s and adjacent structures were described by evaluation of post-mortem examinations of nine horses of different ages (Group A: <6 years, B: 6-15 years, C: >=16 years). Most of the tissues selected were imaged accurately with MRI and CT. Magnetic resonance imaging gives an excellent depiction of soft endo- and periodontal units, and CT of hard dental and bony tissues. Negative correlation between dental age and pulpar sizes was found: 71.3% of the changes in pulp dimensions can be explained by teeth aging. Pulpar sizes ranged from 14.3 to 1.3 mm and were significantly smaller in older horses (p < 0.05). A common pulp chamber was present in 33% of the teeth with a mean dental age of 2.25 years. Ninety-four percent of the 08 and 09 alveoli of all groups were in direct contact with the maxillary sinus. An age-related regression was found (R2 = 0.88) for the distance between alveoli and the infraorbital canal. CONCLUSIONS: The present study provides information about the dental and periodontal age-related morphology and its visibility using different imaging techniques. These results aid in evaluating diagnostic images and in deciding which is the superior imaging modality for clinical cases. PMID- 28874150 TI - What are families most grateful for after receiving palliative care? Content analysis of written documents received: a chance to improve the quality of care. AB - BACKGROUND: Family members are involved in the care of palliative patients at home and therefore, should be viewed as important sources of information to help clinicians better understand the quality palliative care service patients receive. The objective of the study was to analyse what is valued most by family carers undergoing bereavement of a palliative care home service in order to identify factors of quality of care. METHODS: Qualitative exploratory study based on documentary analysis. Content analysis of 77 gratitude documents received over 8 years by a palliative home service in Odivelas, near Lisbon (Portugal) was undertaken, through an inductive approach and using investigator triangulation. Frequency of distinct categories was quantitatively defined. RESULTS: Three different content categories emerged from the analysis: a) Recognition of the care received and the value of particular aspects of care within recognised difficult situations included aspects such as kindness, listening, attention to the family, empathy, closeness, affection and the therapeutic relationships established (63/77 documents); b) Family recognition of the achievements of the palliative care team (29/77) indicated as relief from suffering for the patient and family, opportunity of dying at home, help in facing difficult situations, improvement in quality of life and wellbeing, and feeling of serenity during bereavement; c) Messages of support (45/77) related to the need of resources provided. The relational component emerges as an underlying key aspect of family carers' experience with palliative care home service. CONCLUSION: Family carers show spontaneous gratitude for the professionalism and humanity found in palliative care. The relational component of care emerges as key to achieve a high quality care experience of palliative care homes service, and could be one indicator of quality of palliative care. PMID- 28874151 TI - Effects of Mollugo pentaphylla extract on monosodium urate crystal-induced gouty arthritis in mice. AB - BACKGROUND: Gout is an inflammatory condition induced by the deposition of monosodium urate (MSU) crystals in joints and soft tissues, and it can lead to acute or chronic arthritis. MSU are pro-inflammatory stimuli that can initiate, amplify and sustain an intense inflammatory response. In this study, we evaluated the anti-inflammatory effect of an extract of Mollugo pentaphylla (MPE) on MSU induced gouty arthritis in a mouse model. METHOD: An MSU crystal suspension (4 mg/50 MUL) was injected intradermally into the right paw. The mice were orally administered MPE (150 mg/kg or 300 mg/kg) or the positive control drug colchicine (1 mg/kg) 1 h before the MSU crystals were injected and then once daily for 3 days. The effects of MPE included inflammatory paw edema and pain upon weight bearing activity, and we evaluated the inflammatory cytokine expression and paw tissue inflammation-related gene expression. RESULTS: MPE suppressed inflammatory paw edema and pain in the MSU-induced mice. MPE showed anti-inflammatory activity by inhibiting the production of TNF-alpha, interleukin (IL)-1beta, NLRP3 inflammasome and NF-kappaB. CONCLUSION: These results suggest that MPE has potent anti-inflammatory activities and may be useful as a therapeutic agent against gouty arthritis. PMID- 28874152 TI - A descriptive qualitative examination of knowledge translation practice among health researchers in Manitoba, Canada. AB - BACKGROUND: The importance of effective translation of health research findings into action has been well recognized, but there is evidence to suggest that the practice of knowledge translation (KT) among health researchers is still evolving. Compared to research user stakeholders, researchers (knowledge producers) have been under-studied in this context. The goals of this study were to understand the experiences of health researchers in practicing KT in Manitoba, Canada, and identify their support needs to sustain and increase their participation in KT. METHODS: Qualitative semi-structured interviews were conducted with 26 researchers studying in biomedical; clinical; health systems and services; and social, cultural, environmental and population health research. Interview questions were open-ended and probed participants' understanding of KT, their experiences in practicing KT, barriers and facilitators to practicing KT, and their needs for KT practice support. RESULTS: KT was broadly conceptualized across participants. Participants described a range of KT practice experiences, most of which related to dissemination. Participants also expressed a number of negative emotions associated with the practice of KT. Many individual, logistical, and systemic or organizational barriers to practicing KT were identified, which included a lack of institutional support for KT in both academic and non-academic systems. Participants described the presence of good relationships with stakeholders as a critical facilitator for practicing KT. The most commonly identified needs for supporting KT practice were access to education and training, and access to resources to increase awareness and promotion of KT. While there were few major variations in response trends across most areas of health research, the responses of biomedical researchers suggested a unique KT context, reflected by distinct conceptualizations of KT (such as commercialization as a core component), experiences (including frustration and lack of support), and barriers to practicing KT (for example, intellectual property concerns). CONCLUSIONS: The major findings of this study were the continued variations in conceptualization of KT, and persisting support needs that span basic individual to comprehensive systemic change. Expanding the study to additional regions of Canada will present opportunities to compare and contrast the state of KT practice and its influencing factors. PMID- 28874153 TI - Thioester-containing proteins regulate the Toll pathway and play a role in Drosophila defence against microbial pathogens and parasitoid wasps. AB - BACKGROUND: Members of the thioester-containing protein (TEP) family contribute to host defence in both insects and mammals. However, their role in the immune response of Drosophila is elusive. In this study, we address the role of TEPs in Drosophila immunity by generating a mutant fly line, referred to as TEPq Delta , lacking the four immune-inducible TEPs, TEP1, 2, 3 and 4. RESULTS: Survival analyses with TEPq Delta flies reveal the importance of these proteins in defence against entomopathogenic fungi, Gram-positive bacteria and parasitoid wasps. Our results confirm that TEPs are required for efficient phagocytosis of bacteria, notably for the two Gram-positive species tested, Staphylococcus aureus and Enterococcus faecalis. Furthermore, we show that TEPq Delta flies have reduced Toll pathway activation upon microbial infection, resulting in lower expression of antimicrobial peptide genes. Epistatic analyses suggest that TEPs function upstream or independently of the serine protease ModSP at an initial stage of Toll pathway activation. CONCLUSIONS: Collectively, our study brings new insights into the role of TEPs in insect immunity. It reveals that TEPs participate in both humoral and cellular arms of immune response in Drosophila. In particular, it shows the importance of TEPs in defence against Gram-positive bacteria and entomopathogenic fungi, notably by promoting Toll pathway activation. PMID- 28874154 TI - The Center for Epidemiologic Studies Depression Scale is an adequate screening instrument for depression and anxiety disorder in adults with congential heart disease. AB - BACKGROUND: The Center for Epidemiological Studies Depression Scale (CES-D) is an instrument that is commonly used to screen for depression in patients with chronic disease, but the characteristics of the CES-D in adults with congenital heart disease (CHD) have not yet been studied. The aim of this study was to investigate the criterion validities and the predictive powers of the CES-D for depression and anxiety disorders in adults with CHD. METHODS: Two hundred patients were screened with the CES-D and secondarily interviewed with a diagnostic instrument, i.e., the Mini International Neuropsychiatric Instrument. The sensitivity and specificity values of the CES-D were calculated by cross tabulation at different cutoff scores. Receiver operating characteristic (ROC) curves were used to assess the optimal cutoff point for each disorder and to assess the predictive power of the instrument. RESULTS: The CES-D exhibited satisfactory criterion validities for depression and for all combinations of depression and/or anxiety. With a desired sensitivity of at least 80%, the optimal cutoff scores were 18. The predictive power of the CES-D in the patients was best for major depression and dysthymia (area under the ROC curve: 0.92) followed by the score for any combination of depression and/or anxiety (0.88). CONCLUSION: The use of CES-D to simultaneously screen for both depression and anxiety disorders may be useful in adults with CHD. TRIAL REGISTRATION: CESDEP 212. Registered 2 March 2014 (retrospectively registered). PMID- 28874155 TI - The regulation of ovary and conceptus on the uterine natural killer cells during early pregnancy. AB - Uterine natural killer (uNK) cells are short-lived, terminally differentiated and the most abundant lymphocytes in the uterus which play a crucial role in the spiral arteriole modification and establishment of successful pregnancy. Dysregulation of uNK cells has been linked to gestational implications such as recurrent pregnancy loss, preeclampsia and fetal growth retardation. There is evidence showing that progesterone and estrogen can regulate the recruitment, proliferation, differentiation and function of uNK cells via direct action on intracellular nuclear receptors or through intermediary cells in the uterus during early pregnancy. As the deepening of related research in this field, the role of conceptus in such regulation has received extensive attention, it utilizes endocrine signaling (hCG), juxtacrine signaling (HLA-C, HLA-E, HLA-G) and paracrine signaling (cytokines) to facilitate the activities of uNK cells. In addition, under the influence of ovarian hormones, conceptus can increase expression of PIBF and HLA-G molecules to reduce cytotoxicity of uNK cells and promote angiogenesis. In this review, we aim to concentrate on the novel findings of ovarian hormones in the regulation of uNK cells, emphasize the regulatory role of conceptus on uNK cells and highlight the proposed issues for future research in the field. PMID- 28874156 TI - Job satisfaction and turnover intentions among health care staff providing services for prevention of mother-to-child transmission of HIV in Dar es Salaam, Tanzania. AB - BACKGROUND: Option B+ for the prevention of mother-to-child transmission (PMTCT) of HIV (i.e., lifelong antiretroviral treatment for all pregnant and breastfeeding mothers living with HIV) was initiated in Tanzania in 2013. While there is evidence that this policy has benefits for the health of the mother and the child, Option B+ may also increase the workload for health care providers in resource-constrained settings, possibly leading to job dissatisfaction and unwanted workforce turnover. METHODS: From March to April 2014, a questionnaire asking about job satisfaction and turnover intentions was administered to all nurses at 36 public-sector health facilities offering antenatal and PMTCT services in Dar es Salaam, Tanzania. Multivariable logistic regression models were used to identify factors associated with job dissatisfaction and intention to quit one's job. RESULTS: Slightly over half (54%, 114/213) of the providers were dissatisfied with their current job, and 35% (74/213) intended to leave their job. Most of the providers were dissatisfied with low salaries and high workload, but satisfied with workplace harmony and being able to follow their moral values. The odds of reporting to be globally dissatisfied with one's job were high if the provider was dissatisfied with salary (adjusted odds ratio (aOR) 5.6, 95% CI 1.2-26.8), availability of protective gear (aOR 4.0, 95% CI 1.5 10.6), job description (aOR 4.3, 95% CI 1.2-14.7), and working hours (aOR 3.2, 95% CI 1.3-7.6). Perceiving clients to prefer PMTCT Option B+ reduced job dissatisfaction (aOR 0.2, 95% CI 0.1-0.8). The following factors were associated with providers' intention to leave their current job: job stability dissatisfaction (aOR 3.7, 95% CI 1.3-10.5), not being recognized by one's superior (aOR 3.6, 95% CI 1.7-7.6), and poor feedback on the overall unit performance (aOR 2.7, 95% CI 1.3-5.8). CONCLUSION: Job dissatisfaction and turnover intentions are comparatively high among nurses in Dar es Salaam's public sector maternal care facilities. Providing reasonable salaries and working hours, clearer job descriptions, appropriate safety measures, job stability, and improved supervision and feedback will be key to retaining satisfied PMTCT providers and thus to sustain successful implementation of Option B+ in Tanzania. PMID- 28874157 TI - Male involvement in maternal healthcare through Community- based Health Planning and Services: the views of the men in rural Ghana. AB - BACKGROUND: The need to promote maternal health in Ghana has committed the government to extend maternal healthcare services to the door steps of rural families through the community-based Health Planning and Services. Based on the concerns raised in previous studies that male spouses were indifferent towards maternal healthcare, this study sought the views of men on their involvement in maternal healthcare in their respective communities and at the household levels in the various Community-based Health Planning and Services zones in Awutu-Senya West District in the Central Region of Ghana. METHODS: A qualitative method was employed. Focus groups and individual interviews were conducted with married men, community health officers, community health volunteers and community leaders. The participants were selected using purposive, quota and snowball sampling techniques. The study used thematic analysis for analysing the data. RESULTS: The study shows varying involvement of men, some were directly involved in feminine gender roles; others used their female relatives and co-wives to perform the women's roles that did not have space for them. They were not necessarily indifferent towards maternal healthcare, rather, they were involved in the spaces provided by the traditional gender division of labour. Amongst other things, the perpetuation and reinforcement of traditional gender norms around pregnancy and childbirth influenced the nature and level of male involvement. CONCLUSIONS: Sustenance of male involvement especially, husbands and CHVs is required at the household and community levels for positive maternal outcomes. Ghana Health Service, health professionals and policy makers should take traditional gender role expectations into consideration in the planning and implementation of maternal health promotion programmes. PMID- 28874158 TI - Associations of the APOB rs693 and rs17240441 polymorphisms with plasma APOB and lipid levels: a meta-analysis. AB - BACKGROUND: The associations of the apolipoprotein B gene (APOB) rs693 and rs17240441 polymorphisms with plasma levels of APOB and lipids have been widely explored, but the results were inconclusive. This meta-analysis aimed to clarify the associations of the rs693 and rs17240441 polymorphisms with fasting APOB and lipid levels. METHODS: Sixty-one studies (50,018 subjects) and 23 studies (8425 subjects) were respectively identified for the rs693 and rs17240441 polymorphisms by searching in PubMed, Google Scholar, Web of Science, Cochrane Library, Wanfang, VIP and CNKI databases. The following information was collected for each study: first author, age, gender, ethnicity, health condition, sample size, genotyping, lipid assay method, mean and standard deviation or standard error of APOB and lipid variables by genotypes. A dominant model was used for this meta analysis. RESULTS: The carriers of the rs693 variant allele (T) had higher levels of APOB [standardized mean difference (SMD) = 0.26, 95% confidence interval (CI) = 0.16-0.36, P < 0.01], triglycerides (TG) (SMD = 0.12, 95% CI = 0.05-0.20, P < 0.01), total cholesterol (TC) (SMD = 0.24, 95% CI = 0.17-0.30, P < 0.01) and low density lipoprotein cholesterol (LDL-C) (SMD = 0.22, 95% CI = 0.14-0.30, P < 0.01), and lower levels of high-density lipoprotein cholesterol (HDL-C) (SMD = 0.06, 95% CI = -0.11-0.01, P = 0.01) than the non-carriers. The carriers of the rs17240441 deletion allele had higher levels of APOB (SMD = 0.13, 95% CI = 0.06 0.20, P < 0.01), TC (SMD = 0.17, 95% CI = 0.07-0.26, P < 0.01) and LDL-C (SMD = 0.15, 95% CI = 0.07-0.23, P < 0.01) than the non-carriers. CONCLUSIONS: The rs693 polymorphism is significantly associated with higher levels of APOB, TG, TC and LDL-C, and lower levels of HDL-C. The rs17240441 polymorphism is significantly associated with higher levels of APOB, TC and LDL-C. Further studies are needed to elucidate the underlying mechanisms. PMID- 28874159 TI - A critique of the US Surgeon General's conclusions regarding e-cigarette use among youth and young adults in the United States of America. AB - BACKGROUND: In December 2016, the Surgeon General published a report that concluded e-cigarette use among youth and young adults is becoming a major public health concern in the United States of America. METHODS: Re-analysis of key data sources on nicotine toxicity and prevalence of youth use of e-cigarettes cited in the Surgeon General report as the basis for its conclusions. RESULTS: Multiple years of nationally representative surveys indicate the majority of e-cigarette use among US youth is either infrequent or experimental, and negligible among never-smoking youth. The majority of the very small proportion of US youth who use e-cigarettes on a regular basis, consume nicotine-free products. The sharpest declines in US youth smoking rates have occurred as e-cigarettes have become increasingly available. Most of the evidence presented in the Surgeon General's discussion of nicotine harm is not applicable to e-cigarette use, because it relies almost exclusively on exposure to nicotine in the cigarette smoke and not to nicotine present in e-cigarette aerosol emissions. Moreover, the referenced literature describes effects in adults, not youth, and in animal models that have little relevance to real-world e-cigarette use by youth. The Surgeon General's report is an excellent reference document for the adverse outcomes due to nicotine in combination with several other toxicants present in tobacco smoke, but fails to address the risks of nicotine decoupled from tobacco smoke constituents. The report exaggerates the toxicity of propylene glycol (PG) and vegetable glycerin (VG) by focusing on experimental conditions that do not reflect use in the real-world and provides little discussion of emerging evidence that e-cigarettes may significantly reduce harm to smokers who have completely switched. CONCLUSIONS: The U.S. Surgeon General's claim that e-cigarette use among U.S. youth and young adults is an emerging public health concern does not appear to be supported by the best available evidence on the health risks of nicotine use and population survey data on prevalence of frequent e-cigarette use. Nonetheless, patterns of e-cigarettes use in youth must be constantly monitored for early detection of significant changes. The next US Surgeon General should consider the possibility that future generations of young Americans will be less likely to start smoking tobacco because of, not in spite of, the availability of e-cigarettes. PMID- 28874160 TI - Preterm birth: the role of knowledge transfer and exchange. AB - BACKGROUND: Preterm birth (PTB) is the leading cause of death in children under age five. Healthcare policy and other decision-making relevant to PTB may rely on obsolete, incomplete or inapplicable research evidence, leading to worsened outcomes. Appropriate knowledge transfer and exchange (KTE) strategies are an important component of efforts to reduce the global PTB burden. We sought to develop a 'landscape' analysis of KTE strategies currently used in PTB and related contexts, and to make recommendations for optimising programmatic implementation and for future research. METHODS: In the University of California, San Francisco's Preterm Birth Initiative, we convened a multidisciplinary working group and examined KTE frameworks. After selecting a widely-used, adaptable, theoretically-strong framework we reviewed the literature to identify evidence based KTE strategies. We analysed KTE approaches focusing on key PTB stakeholders (individuals, families and communities, healthcare providers and policymakers). Guided by the framework, we articulated KTE approaches that would likely improve PTB outcomes. We further applied the KTE framework in developing recommendations. RESULTS: We selected the Linking Research to Action framework. Searches identified 19 systematic reviews, including two 'reviews of reviews'. Twelve reviews provided evidence for KTE strategies in the context of maternal, neonatal and child health, though not PTB specifically; seven reviews provided 'cross cutting' evidence that could likely be generalised to PTB contexts. For individuals, families and communities, potentially effective KTE strategies include community-based approaches, 'decision aids', regular discussions with providers and other strategies. For providers, KTE outcomes may be improved through local opinion leaders, electronic reminders, multifaceted strategies and other approaches. Policy decisions relevant to PTB may best be informed through the use of evidence briefs, deliberative dialogues, the SUPPORT tools for evidence-informed policymaking and other strategies. Our recommendations for research addressed knowledge gaps in regard to partner engagement, applicability and context, implementation strategy research, monitoring and evaluation, and infrastructure for sustainable KTE efforts. CONCLUSIONS: Evidence-based KTE, using strategies appropriate to each stakeholder group, is essential to any effort to improve health at the population level. PTB stakeholders should be fully engaged in KTE and programme planning from its earliest stages, and ideally before planning begins. PMID- 28874161 TI - Altered Semmes-Weinstein monofilament test results are associated with oxidative stress markers in type 2 diabetic subjects. AB - BACKGROUND: Different lines of evidence suggest that oxidative stress (OS) is implicated in the pathogenesis of diabetic neuropathy. The Semmes-Weinstein monofilament (SWM) test is an efficient tool for evaluating diabetic polyneuropathy and diabetic foot. In this study, we analyzed the association between OS markers and altered SWM test results in type 2 diabetes (T2DM) patients. METHODS: Seventy T2DM patients were studied and 34 showed altered SWM results. The clinical and biochemical parameters were determined using standardized methods. Levels of oxidized glutathione (GSSG) and malondialdehyde (MDA) were measured in circulating mononuclear cells using high-performance liquid chromatography. RESULTS: We found that T2DM patients with altered SWM test results had significantly higher GSSG (3.53 +/- 0.31 vs. 3.31 +/- 0.35 mmol/ml, p < 0.05) and MDA (1.88 +/- 0.16 vs. 1.75 +/- 0.19 nmol/ml, p < 0.01) values compared to diabetic patients with normal SWM test outcomes. Moreover, altered SWM test results were independently related to age, glycosylated hemoglobin, and GSSG levels, but there was no association between OS markers and altered neuropathy sensitivity score (NSS) values. CONCLUSIONS: Alteration of the glutathione system and MDA values in T2DM patients are associated with loss of proprioceptive (pressure) sensitivity, but not with symptomatic polyneuropathy (as evaluated by NSS). This finding may be important for understanding how OS affects distal symmetric polyneuropathy in diabetic patients. PMID- 28874162 TI - Isolation and characterization of the compounds responsible for the antimutagenic activity of Combretum microphyllum (Combretaceae) leaf extracts. AB - BACKGROUND: Mutations play a major role in the pathogenesis and development of several chronic degenerative diseases including cancer. It follows, therefore that antimutagenic compound may inhibit the pathological process resulting from exposure to mutagens. Investigation of the antimutagenic potential of traditional medicinal plants and compounds isolated from plant extracts provides one of the tools that can be used to identify compounds with potential cancer chemopreventive properties. The aim of this study was to isolate and characterise the compounds responsible for the antimutagenic activity of Combretum microphyllum. METHODS: The methanol leaf extract of C. microphyllum was evaluated for antimutagenicity in the Ames/microsome assay using Salmonella typhimurium TA98. TA100 and TA102. Solvent-solvent fractionation was used to partition the extracts and by using bioassay-guided fractionation, three compounds were isolated. The antimutagenic activity of the three compounds were determined in the Ames test using Salmonella typhimurium TA98, TA100 and TA102. The antioxidant activity of the three compounds were determined by the quantitative 2,2-diphenyl 1-picrylhydrazyl (DPPH)-free radical scavenging method. The cytotoxicity was determined in the MTT assay using human hepatocytes. RESULTS: A bioassay-guided fractionation of the crude extracts for antimutagenic activity led to the isolation of three compounds; n-tetracosanol, eicosanoic acid and arjunolic acid. Arjunolic acid was the most active in all three tested strains with a antimutagenicity of 42 +/- 9.6%, 36 +/- 1.5% and 44 +/- 0.18% in S. typhimurium TA98, TA100 and TA102 respectively at the highest concentration (500 MUg/ml) tested, followed by eicosanoic acid and n-tetracosanol. The antioxidant activity of the compounds were determined using the quantitative 2,2 diphenyl-1 picryhydrazyl (DPPH)-free radical scavenging method. Only arjunolic acid had pronounced antioxidant activity (measured as DPPH-free scavenging activity) with an EC50 value of 0.51 MUg/ml. The cytotoxicity of the isolated compounds were determined in the MTT assay using human hepatocytes. The compounds had low cytotoxicity at the highest concentration tested with LC50 values >200 MUg/ml for n-tetracosanol and eicosanoic acid and 106.39 MUg/ml for arjunolic acid. CONCLUSIONS: Based on findings from this study, compounds in leaf extracts of C. microphyllum protected against 4-NQO and MMC induced mutations as evident in the Ames test. The antimutagenic activity of arjunolic acid may, at least in part, be attributed to its antioxidant activity resulting in the detoxification of reactive oxygen species produced during mutagenesis. PMID- 28874163 TI - Expression of factors involved in apoptosis and cell survival is correlated with enzymes synthesizing lysophosphatidic acid and its receptors in granulosa cells originating from different types of bovine ovarian follicles. AB - BACKGROUND: Lysophosphatidic acid (LPA) regulates reproductive processes in the cow. Ovarian granulosa cells play a pivotal role in follicle growth and development. Nevertheless, the role of LPA in the local regulation of granulosa cell function in different follicle categories in the bovine ovary has not been investigated. METHODS: Ovarian follicles were divided into healthy, transitional and atretic categories. The expression levels of AX, PLA2, LPARs and factors involved in apoptosis and cell survival processes in granulosa cells in different types of follicles were measured by real-time PCR. The correlations between the expression levels of AX, PLA2, LPARs and the examined factors were measured. The immunolocalization of AX, PLA2 and LPARs in different ovarian follicles was examined by immunohistochemistry. Statistical analyses were conducted in GraphPad using a one-way ANOVA followed by the Kruskal-Wallis multiple comparison test or a correlation analysis followed by Pearson's test. RESULTS: The expression levels of AX, PLA2 and LPARs, with the major role of LPAR2 and PLA2, were found in the granulosa cells originating from different follicle types. The expression levels of the factors involved in cell apoptosis (TNFalpha and its receptors, FAS, FASL, CASP3, CASP8, beta-glycan, and DRAK2) were significantly higher in the granulosa cells of the atretic follicles compared to the healthy follicles. A number of correlations between LPARs, AX, PLA2 and factors associated with apoptosis were observed in the atretic but not in the healthy follicles. A greater expression of the factors involved in differentiation and proliferation in the granulosa cells (DICE1 and SOX2) was found in the healthy follicles in comparison with the atretic. A number of correlations between LPARs, AX, PLA2 and the factors associated with cell survival were observed in the healthy but not in the atretic follicles. CONCLUSIONS: Granulosa cells are the target of LPA action and the source of LPA synthesis in the bovine ovarian follicle. We suggest that the participation of LPA in apoptosis in the atretic follicles mainly occurs through the regulation of TNF-alpha-dependent and caspase-induced pathways. In the transitional follicles, LPA might influence the inhibins to shift the balance between the number of healthy and atretic follicles. In the healthy follicle type, LPA, acting via LPAR1, might regulate MCL1 and estradiol-stimulating ERbeta mRNA expression, leading to the stimulation of anti-apoptotic processes in the granulosa cells and their differentiation and proliferation. PMID- 28874164 TI - Radiation-free CMR diagnostic heart catheterization in children. AB - BACKGROUND: Children with heart disease may require repeated X-Ray cardiac catheterization procedures, are more radiosensitive, and more likely to survive to experience oncologic risks of medical radiation. Cardiovascular magnetic resonance (CMR) is radiation-free and offers information about structure, function, and perfusion but not hemodynamics. We intend to perform complete radiation-free diagnostic right heart catheterization entirely using CMR fluoroscopy guidance in an unselected cohort of pediatric patients; we report the feasibility and safety. METHODS: We performed 50 CMR fluoroscopy guided comprehensive transfemoral right heart catheterizations in 39 pediatric (12.7 +/- 4.7 years) subjects referred for clinically indicated cardiac catheterization. CMR guided catheterizations were assessed by completion (success/failure), procedure time, and safety events (catheterization, anesthesia). Pre and post CMR body temperature was recorded. Concurrent invasive hemodynamic and diagnostic CMR data were collected. RESULTS: During a twenty-two month period (3/2015 - 12/2016), enrolled subjects had the following clinical indications: post-heart transplant 33%, shunt 28%, pulmonary hypertension 18%, cardiomyopathy 15%, valvular heart disease 3%, and other 3%. Radiation-free CMR guided right heart catheterization attempts were all successful using passive catheters. In two subjects with septal defects, right and left heart catheterization were performed. There were no complications. One subject had six such procedures. Most subjects (51%) had undergone multiple (5.5 +/- 5) previous X-Ray cardiac catheterizations. Retained thoracic surgical or transcatheter implants (36%) did not preclude successful CMR fluoroscopy heart catheterization. During the procedure, two subjects were receiving vasopressor infusions at baseline because of poor cardiac function, and in ten procedures, multiple hemodynamic conditions were tested. CONCLUSIONS: Comprehensive CMR fluoroscopy guided right heart catheterization was feasible and safe in this small cohort of pediatric subjects. This includes subjects with previous metallic implants, those requiring continuous vasopressor medication infusions, and those requiring pharmacologic provocation. Children requiring multiple, serial X-Ray cardiac catheterizations may benefit most from radiation sparing. This is a step toward wholly CMR guided diagnostic (right and left heart) cardiac catheterization and future CMR guided cardiac intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT02739087 registered February 17, 2016. PMID- 28874165 TI - A prospective study of cancer risk among Agricultural Health Study farm spouses associated with personal use of organochlorine insecticides. AB - BACKGROUND: Organochlorine insecticides (OCs) have historically been used worldwide to control insects, although most have now been banned in developed countries. Evidence for an association between OC exposures and cancer predominantly comes from occupational and population based-studies among men. We evaluated the association between the use of specific OCs and cancer among the female spouses of pesticide applicators in the Agricultural Health Study. METHODS: At enrollment (1993-1997), spouses of private applicators in the cohort provided information about their own use of pesticides, including seven OCs (aldrin, chlordane, dieldrin, DDT, heptachlor, lindane, and toxaphene), and information on potential confounders. We used Poisson regression to estimate relative risks (RRs) and 95% confidence intervals (CIs) for cancers (n >= 3 exposed cases) reported to state cancer registries from enrollment through 2012 (North Carolina) and 2013 (Iowa), and use of the individual OCs, as well as use of any of the specific OCs. RESULTS: Among 28,909 female spouses, 2191 (7.58%) reported ever use of at least one OC, of whom 287 were diagnosed with cancer. Most cancers were not associated with OC use. Risk of glioma was increased among users of at least one OC (Nexposed = 11, RR = 3.52, 95% CI 1.72-7.21) and specifically among lindane users (Nexposed = 3, RR = 4.45, 95% CI 1.36-14.55). Multiple myeloma was associated with chlordane (Nexposed = 6, RR = 2.71, 95% CI 1.12-6.55). Based on 3 exposed cases each, there were also positive associations between pancreatic cancer and lindane, and ER-PR- breast cancer and dieldrin. No other associations with breast cancer were found. CONCLUSIONS: Overall, there were some associations with OC use and cancer incidence, however we were limited by the small number of exposed cancer cases. Future research should attempt to expand on these findings by assessing environmental sources of OC exposures, to fully evaluate the role of OC exposures on cancer risk in women. PMID- 28874166 TI - The porcine virome and xenotransplantation. AB - The composition of the porcine virome includes viruses that infect pig cells, ancient virus-derived elements including endogenous retroviruses inserted in the pig chromosomes, and bacteriophages that infect a broad array of bacteria that inhabit pigs. Viruses infecting pigs, among them viruses also infecting human cells, as well as porcine endogenous retroviruses (PERVs) are of importance when evaluating the virus safety of xenotransplantation. Bacteriophages associated with bacteria mainly in the gut are not relevant in this context. Xenotransplantation using pig cells, tissues or organs is under development in order to alleviate the shortage of human transplants. Here for the first time published data describing the viromes in different pigs and their relevance for the virus safety of xenotransplantation is analysed. In conclusion, the analysis of the porcine virome has resulted in numerous new viruses being described, although their impact on xenotransplantation is unclear. Most importantly, viruses with known or suspected zoonotic potential were often not detected by next generation sequencing, but were revealed by more sensitive methods. PMID- 28874167 TI - Forecasting infectious disease emergence subject to seasonal forcing. AB - BACKGROUND: Despite high vaccination coverage, many childhood infections pose a growing threat to human populations. Accurate disease forecasting would be of tremendous value to public health. Forecasting disease emergence using early warning signals (EWS) is possible in non-seasonal models of infectious diseases. Here, we assessed whether EWS also anticipate disease emergence in seasonal models. METHODS: We simulated the dynamics of an immunizing infectious pathogen approaching the tipping point to disease endemicity. To explore the effect of seasonality on the reliability of early warning statistics, we varied the amplitude of fluctuations around the average transmission. We proposed and analyzed two new early warning signals based on the wavelet spectrum. We measured the reliability of the early warning signals depending on the strength of their trend preceding the tipping point and then calculated the Area Under the Curve (AUC) statistic. RESULTS: Early warning signals were reliable when disease transmission was subject to seasonal forcing. Wavelet-based early warning signals were as reliable as other conventional early warning signals. We found that removing seasonal trends, prior to analysis, did not improve early warning statistics uniformly. CONCLUSIONS: Early warning signals anticipate the onset of critical transitions for infectious diseases which are subject to seasonal forcing. Wavelet-based early warning statistics can also be used to forecast infectious disease. PMID- 28874168 TI - Holocentric chromosome evolution in kissing bugs (Hemiptera: Reduviidae: Triatominae): diversification of repeated sequences. AB - BACKGROUND: The analysis of the chromosomal and genome evolution in organisms with holocentric chromosomes is restricted by the lack of primary constriction or centromere. An interesting group is the hemipteran subfamily Triatominae, vectors of Chagas disease, which affects around 6 to 7 million people worldwide. This group exhibits extensive variability in the number and chromosomal location of repeated sequences such as heterochromatin and ribosomal genes. This paper tries to reveal the significant differences of the repeated sequences among Triatoma species through the use of genomic DNA probes. METHODS: We analysed the chromosomal distribution and evolution of repeated sequences in Triatoma species by genomic in situ hybridization (GISH) using genomic DNA probes from two North American Triatoma species. These genomic probes were hybridized both on their own chromosomes and on other Triatoma species from North and South America, with different amounts and chromosome location of C-heterochromatin. The results were compared with those previously described using South American Triatoma genomic probes. RESULTS: We observed two chromosomal hybridization patterns: (i) very intense hybridization signals concentrated on specific chromosomal regions or particular chromosomes; and (ii) lower intensity hybridization signals dispersed along all chromosomes. Self-GISH on T. rubrofasciata and T. dimidiata chromosomes presented strong hybridization signals on all C-heterochromatin regions. However, when we perform genomic cross-hybridizations, only strong signals are detected on the Y chromosome, leaving the C-heterochromatic autosomal regions unmarked. CONCLUSIONS: We confirm that repeated DNA of the Y chromosome is shared among Triatoma species and probably represents an ancestral character of the Triatomini tribe. On the contrary, autosomal heterochromatic regions are constituted by species-specific DNA repeats, most probably satDNA families, suggesting that Triatoma speciation involved the amplification of diverse types of autosomal repeats. Molecular characterization of principal repetitive DNAs seems to be an appropriate approach to infer evolutionary relationships in triatomines. PMID- 28874169 TI - Transfemoral versus transapical approach for transcatheter aortic valve implantation: hospital outcome and risk factor analysis. AB - BACKGROUND: Transcatheter aortic valve implantation is indicated in high-risk patients with aortic stenosis. We compared the clinical outcome of 180 consecutive patients who underwent transapical (TA) and transfemoral (TF) procedures in a single centre. METHODS: Ninety consecutive TA (TA-group) and 90 consecutive TF (TF-group) were performed from 2009 to 2014. Clinical variables were prospectively collected and retrospectively analysed for hospital outcomes and to identify risk factors for hospital mortality, vascular complications and stroke. RESULTS: Mean age was 80 +/- 8.5 and 83 +/- 8.4 years, in the TA and TF group, respectively. TA-group presented higher prevalence of comorbidities: more vascular disease (79% vs 22%, p < 0.001), chronic pulmonary disease (32% vs 10%, p < 0.001), previous vascular surgery (14% vs 4%, p = 0.039), coronary disease (60% vs 40%, p = 0.007), and previous cardiac surgery (28% vs 17%, p = 0.073). Logistic Euroscore was 36 +/- 15% in the TA-group and 25 +/- 14% in the TF-group (p < 0.001), but hospital mortality was similar (TA:9%, TF:10%, p = 0.799). Access-related vascular complications occurred more often in transfemoral patients (TA:3%, TF:11%, p = 0.081) while major bleeding (TA:3%, TF:4%, p = 1) and stroke (TA:2%, TF:3%, p = 1) were equally distributed. Postoperative renal failure and dialysis were associated with impaired neurological outcome (p = 0.035 and p = 0.020, respectively). Mild to severe paravalvular leak was more prevalent in transfemoral patients (TA:5%, TF:25%, p < 0.001). CONCLUSIONS: In our experience, the TA and TF-group presented different risk profiles but mortality rate and adverse neurological outcome had a similar incidence. The transfemoral approach carried more vascular complications and paravalvular leaks but last-generation devices will improve this outcome. PMID- 28874170 TI - Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis. AB - BACKGROUND: Adenosine-to-inosine (A-to-I) editing of dsRNA by ADAR proteins is a pervasive epitranscriptome feature. Tens of thousands of A-to-I editing events are defined in the mouse, yet the functional impact of most is unknown. Editing causing protein recoding is the essential function of ADAR2, but an essential role for recoding by ADAR1 has not been demonstrated. ADAR1 has been proposed to have editing-dependent and editing-independent functions. The relative contribution of these in vivo has not been clearly defined. A critical function of ADAR1 is editing of endogenous RNA to prevent activation of the dsRNA sensor MDA5 (Ifih1). Outside of this, how ADAR1 editing contributes to normal development and homeostasis is uncertain. RESULTS: We describe the consequences of ADAR1 editing deficiency on murine homeostasis. Adar1 E861A/E861A Ifih1 -/- mice are strikingly normal, including their lifespan. There is a mild, non pathogenic innate immune activation signature in the Adar1 E861A/E861A Ifih1 -/- mice. Assessing A-to-I editing across adult tissues demonstrates that outside of the brain, ADAR1 performs the majority of editing and that ADAR2 cannot compensate in its absence. Direct comparison of the Adar1 -/- and Adar1 E861A/E861A alleles demonstrates a high degree of concordance on both Ifih1 +/+ and Ifih1 -/- backgrounds, suggesting no substantial contribution from ADAR1 editing-independent functions. CONCLUSIONS: These analyses demonstrate that the lifetime absence of ADAR1-editing is well tolerated in the absence of MDA5. We conclude that protein recoding arising from ADAR1-mediated editing is not essential for organismal homeostasis. Additionally, the phenotypes associated with loss of ADAR1 are the result of RNA editing and MDA5-dependent functions. PMID- 28874172 TI - Renal replacement therapy after cardiac surgery: do not ask "When", ask "Why". PMID- 28874171 TI - Long-term treatment with low-dose medicine in chronic childhood eczema: a double blind two-stage randomized control trial. AB - BACKGROUND: The efficacy of low-dose medicine (LDM) in childhood mild/moderate eczema is not known. We conducted a double-blind, two-stage, randomized, placebo controlled clinical trial, lasting 23 months, to address this issue. METHOD: Eighty children with chronic mild/moderate eczema were randomly allocated to Group A (placebo) or Group B (treatment group; Galium-Heel(r), a low-dose multicomponent medicine based upon natural substances; Guna-Interleukin 12 and Guna-Interferon-gamma administered twice a day for six non-consecutive months for each stage). LDM is characterized by the use of biological molecules, such as cytokines, neuropeptides, growth factors, hormones at very low concentrations, which correspond to physiological levels within the human body. The dosage of the cytokines used in this trial (IFN-gamma and IL-12) is 10 fg/ml. The SCORAD index was evaluated by the same operator: subjects with a SCORAD index below 20 were considered to have mild eczema (61/80; mean: 10.79), whereas a SCORAD index between 20-50 indicated moderate eczema (19/80; mean: 26.84). The data of 66/80 children were analyzed in stage 1 and those of 62/66 children in stage 2. The primary outcome measure was reduction of eczema severity assessed by the SCORAD index. Secondary outcomes were disease-free interval, and treatment safety and tolerability. RESULTS: The decrease in disease severity was greater in Group B than in Group A already in stage 1 (a decrease 63.9% versus 53.2%), but the difference was not significant (p = 0.16). Moreover, subjective symptoms (itching and sleep disturbances) initially decreased and then worsened in Group A, whereas itching decreased linearly and sleep disturbances decreased significantly (p=0.049) in Group B. CONCLUSIONS: Preliminary evidence suggests potential benefit, but further work is needed to validate this approach. TRIAL REGISTRATION: The trial was registered with EudraCT number 2010-018640-13 through the database of the National Clinical Trials Monitoring Centre Database (Osservatorio delle Sperimentazioni Cliniche, OsSC) of the Italian Medicines Agency. PMID- 28874173 TI - Ternary cocktail nanoparticles for sequential chemo-photodynamic therapy. AB - BACKGROUND: Previous clinical trials have already demonstrated that combinations of two or more drugs were more effective in the cancer treatment, especially sequential photodynamic design combing with sequential chemotherapy. In our study, we propose a ternary cocktail NP delivery system based on self decomposable NPs, which could realize synergistic chemo-photodynamic therapy through double loading chemo-drugs and multi-level programmable PDT treatment. METHODS: PS drug methylene blue (MB) was encapsulated into the center of the NPsmall, NPbig&thin, and NPbig&thick carriers through "grown-in" loading mechanism, which was released based on the drug concentration difference of the drug release environment. NPsmall, NPbig&thin, and NPbig&thick carriers have three different drug release profiles, which could realize multi-level programmable PDT treatment. At the same time, antitumor drug gemcitabine hydrochloride (GM) and Docetaxel (DTX), were chosen as the double loading chemo drugs that absorbed onto the NPbig&thin and NPbig&thick surface, respectively. In specific, various particle configurations were used for modulating the inner MB sequential release with three pulse Tmax. Also, by adjusting the NPbig&thin and NPbig&thick configuration, the release interval lag time between absorbed GM and DTX can be successfully modulated to achieve maximized chemotherapeutic efficacy. RESULTS: In vitro and in vivo results demonstrated that these three pulses Tmax and the sustained release of MB could maximize the multi-level programmable PDT treatment. And the absorbed GM and DTX also have a release time lag of 12 h, which has been proved as the most effectiveness synergistic interval lag time in the cancer treatment. CONCLUSION: Such a precise sequential release manner ternary cocktail NPs provided a promising platform for efficient and safe chemo photodynamic therapy, which serves as a promising drug delivery system to cure cancer in the future. PMID- 28874174 TI - Bile-stained amniotic fluid: a case report. AB - BACKGROUND: Green-stained amniotic fluid does not always indicate that meconium was passed in utero. CASE PRESENTATION: We report the case of a 2280-g Hispanic preterm female born at 32 weeks of gestation with congenital jejunal atresia. The amniotic fluid was greenish stained; the initial impression was meconium-stained amniotic fluid. Postnatal findings revealed no meconium in her rectum. The content of her first stool appeared sticky and white. CONCLUSION: In the absence of meconium in the rectum, the pediatrician should consider the possibility that the greenish amniotic fluid is not meconium stained, but rather stained with bile due to the fetus vomiting in utero secondary to intestinal obstruction. PMID- 28874175 TI - Effect of exercise type on smoking cessation: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Exercise is one choice of additional treatment for smoking cessation by relieving nicotine withdrawal symptoms and smoking craving. The possible mechanism of the effect of exercise on relieving nicotine withdrawal symptoms and smoking craving is including affect, biological, and cognitive hypotheses. Evidence suggests that different types of exercise have different effects on these mechanisms. Therefore, type of exercise might have effect on smoking cessation. The purpose of this study is to systematically review randomized controlled trials to gain insight into which types of exercise are effective for smoking cessation. METHODS: Publications were systemically searched up to November 2016 in several databases (PubMed, ScienceDirect, PEDro, Web of Science, Scopus and Cochrane Library), using the following keywords: "physical activity", "exercise", "smoking", "tobacco" and "cigarette". The methodological quality was assessed independently by two authors. Meta-analysis was conducted to examine the effectiveness of the type of exercise on smoking cessation. The quality of the evidence was assessed and rated according to the GRADE approach. RESULTS: 20 articles on 19 studies were judged to meet the selection criteria (seven low-risk of bias RCTs and 12 high-risk of bias RCTs). The findings revealed low quality evidence for the effectiveness of yoga for smoking cessation at the end of the treatment. The evidence found for no effect of aerobic exercise, resisted exercise, and a combined aerobic and resisted exercise program on smoking cessation was of low to moderate quality. Furthermore, very low to low quality evidence was found for no effect of physical activity on smoking cessation. CONCLUSIONS: There was no effect of aerobic exercise, resisted exercise, physical activity and combined aerobic and resisted exercise on smoking cessation. There was a positive effect on smoking cessation at the end of treatment in the program where yoga plus cognitive-behavioral therapy (CBT) was used. However, which of the two work is still to be studied. PMID- 28874176 TI - Evaluative reports on medical malpractice policies in obstetrics: a rapid scoping review. AB - BACKGROUND: The clinical specialty of obstetrics is under particular scrutiny with increasing litigation costs and unnecessary tests and procedures done in attempts to prevent litigation. We aimed to identify reports evaluating or comparing the effectiveness of medical liability reforms and quality improvement strategies in improving litigation-related outcomes in obstetrics. METHODS: We conducted a rapid scoping review with a 6-week timeline. MEDLINE, EMBASE, LexisNexis Academic, the Legal Scholarship Network, Justis, LegalTrac, QuickLaw, and HeinOnline were searched for publications in English from 2004 until June 2015. The selection criteria for screening were established a priori and pilot tested. We included reports comparing or evaluating the impact of obstetrics related medical liability reforms and quality improvement strategies on cost containment and litigation settlement across all countries. All levels of screening were done by two reviewers independently, and discrepancies were resolved by a third reviewer. In addition, two reviewers independently extracted relevant data using a pre-tested form, and discrepancies were resolved by a third reviewer. The results were summarized descriptively. RESULTS: The search resulted in 2729 citations, of which 14 reports met our eligibility criteria. Several initiatives for improving the medical malpractice litigation system were found, including no-fault approaches, patient safety policy initiatives, communication and resolution, caps on compensation and attorney fees, alternative payment system and liabilities, and limitations on litigation. CONCLUSIONS: Only a few litigation policies in obstetrics were evaluated or compared. Included documents showed that initiatives to reduce medical malpractice litigation could be associated with a decrease in adverse and malpractice events. However, due to heterogeneous settings (e.g., economic structure, healthcare system) and variation in the outcomes reported, the advantages and disadvantages of initiatives may vary. PMID- 28874177 TI - Improving diets and nutrition through an integrated poultry value chain and nutrition intervention (SELEVER) in Burkina Faso: study protocol for a randomized trial. AB - BACKGROUND: The SELEVER study is designed to evaluate the impact of an integrated agriculture-nutrition package of interventions (including poultry value chain development, women's empowerment activities, and a behavior change communications strategy to promote improved diets and feeding, care, and hygiene practices) on the diets, health, and nutritional status of women and children in Burkina Faso. This paper presents the rationale and study design. METHODS: The impact evaluation involves a cluster randomized controlled trial design that will be implemented in 120 rural communities/villages within 60 communes supported by SELEVER in the Boucle de Mouhoun, Centre-Ouest, and Haut-Bassins regions of Burkina Faso. Communities will be randomly assigned to one of three treatment arms, including: (1) SELEVER intervention group; (2) SELEVER with an intensive WASH component; and (3) control group without intervention. Primary outcomes include the mean probability of adequacy of diets for women and children (aged 2 4 years at baseline), infant and young child feeding practices of caregivers of children aged 0-2 years, and household poultry production and sales. Intermediate outcomes along the agriculture and nutrition pathways will also be measured, including child nutrition status and development. The evaluation will follow a mixed-methods approach, including a panel of child-, household-, community-, and market-level surveys, and data collection points during post-harvest and lean seasons, as well as one year after implementation completion to examine sustainability. DISCUSSION: To our knowledge, this study is the first to rigorously examine from a food systems perspective, the simultaneous impact of scaling-up nutrition-specific and nutrition-sensitive interventions through a livestock value-chain and community-intervention platform, across nutrition, health, and agriculture domains. The findings of this evaluation will provide evidence to support the design of market-based nutrition-sensitive interventions. TRIAL REGISTRATION: ISRCTN registry, ISRCTN16686478 . Registered on 2 December 2016. PMID- 28874178 TI - Relationship between self-efficacy and patient knowledge on adherence to oral contraceptives using the Morisky Medication Adherence Scale (MMAS-8). AB - BACKGROUND: Preconception care, including family planning, is a vital component of healthcare for women of reproductive age. An average female spends the majority of her reproductive life trying to prevent a pregnancy. In order to prevent unintended pregnancy, women often rely on the use of hormonal contraceptives. In the United States, the majority of hormonal contraceptive users are prescribed oral contraceptive pills (OCPs). Reduced adherence to OCPs decreases their ability to prevent pregnancy. The study aimed to measure OCP adherence among female college students, and explore the relationship between OCP adherence, knowledge, and self-efficacy. METHODS: This cross-sectional study recruited a random sample of female college students to participate in an online survey. OCP adherence was based on the 8-item Morisky Medication Adherence Scale (MMAS-8). Secondary reporting of medication adherence included participant reports of the number of missed OCP doses in the previous month and typical month of use. RESULTS: Of the 5000 invited, 1559 (31.3%) completed the survey. Of those responding, 670 (41.3%) reported use of OCPs. A total of 293 (44.3%) OCP users met criteria for low adherence, 241 (36.4%) met criteria for medium adherence, and 128 (19.3%) met criteria for high adherence. Those with high adherence had higher self-efficacy (P < 0.001) and perceived knowledge (p < 0.001). After controlling for other factors, self-efficacy (b = .37) and perceived knowledge (b = .09) remained associated with OCP adherence. CONCLUSION: Less than 20% of respondents met the criteria for high adherence to OCPs. Self-efficacy and knowledge were associated with higher OCP adherence. Targeted interventions from healthcare providers, health educators, and other adherence related media to increase the knowledge and self-efficacy of patients using OCPs may improve adherence rates. Additional research is needed to evaluate the impact of innovative interventions focused on social and behavioral patient factors, like knowledge and self-efficacy, on adherence to OCPs. PMID- 28874179 TI - Report on the development of putative functional SSR and SNP markers in passion fruits. AB - BACKGROUND: Passionflowers Passiflora edulis and Passiflora alata are diploid, outcrossing and understudied fruit bearing species. In Brazil, passion fruit cultivation began relatively recently and has earned the country an outstanding position as the world's top producer of passion fruit. The fruit's main economic value lies in the production of juice, an essential exotic ingredient in juice blends. Currently, crop improvement strategies, including those for underexploited tropical species, tend to incorporate molecular genetic approaches. In this study, we examined a set of P. edulis transcripts expressed in response to infection by Xanthomonas axonopodis, (the passion fruit's main bacterial pathogen that attacks the vines), aiming at the development of putative functional markers, i.e. SSRs (simple sequence repeats) and SNPs (single nucleotide polymorphisms). RESULTS: A total of 210 microsatellites were found in 998 sequences, and trinucleotide repeats were found to be the most frequent (31.4%). Of the sequences selected for designing primers, 80.9% could be used to develop SSR markers, and 60.6% SNP markers for P. alata. SNPs were all biallelic and found within 15 gene fragments of P. alata. Overall, gene fragments generated 10,003 bp. SNP frequency was estimated as one SNP every 294 bp. Polymorphism rates revealed by SSR and SNP loci were 29.4 and 53.6%, respectively. CONCLUSIONS: Passiflora edulis transcripts were useful for the development of putative functional markers for P. alata, suggesting a certain level of sequence conservation between these cultivated species. The markers developed herein could be used for genetic mapping purposes and also in diversity studies. PMID- 28874180 TI - Ureter metastatic castration-resistant prostate cancer: a case report. AB - BACKGROUND: In most cases, prostate cancer metastasizes to the lymph nodes, bone, and liver. In very rare cases, it metastasizes to the ureter. Due to the difficulty in making a preoperative diagnosis, ureteral metastasis from prostate cancer is typically diagnosed after nephroureterectomy. CASE PRESENTATION: A 77 year-old Asian Japanese man with right hydronephrosis and hydroureter was referred to our hospital to undergo further examination due to the suspicion of ureteral cancer. He had been diagnosed 2 years previously with prostate cancer with a Gleason score of 4+5=9. He received radiotherapy and androgen deprivation therapy. A nephroureterectomy was performed for suspected right ureteral cancer. On the basis of a histopathological examination, poorly differentiated adenocarcinoma was suspected, and the tumor cells were positive for prostate specific antigen immunohistochemically. CONCLUSIONS: We herein report a rare case of ureteral metastasis in castration resistant prostate cancer. PMID- 28874181 TI - Effect of an intensive nutrition intervention of a high protein and low glycemic index diet on weight of kidney transplant recipients: study protocol for a randomized clinical trial. AB - BACKGROUND: Excessive weight gain is commonly observed within the first year after kidney transplantation and is associated with negative outcomes, such as graft loss and cardiovascular events. The purpose of this study is to evaluate the effect of a high protein and low glycemic-index diet on preventing weight gain after kidney transplantation. METHODS: We designed a prospective, single center, open-label, randomized controlled study to compare the efficacy of a high protein (1.3-1.4 g/kg/day) and low-glycemic index diet versus a conventional diet (0.8-1.0 g/kg/day of protein) on preventing weight gain after kidney transplantation. A total of 120 eligible patients 2 months after transplantation will be recruited. Patients with an estimated glomerular filtration rate through the modification of diet of renal disease (MDRD) formula < 30 mL/min/1.73 m2 or urinary albumin excretion > 300 mg/24 h will be excluded. Patients' diets will be allocated through simple sequential randomization. Patients will be followed-up for 12 months with nine clinic appointments with a dietitian and the evaluations will include nutritional assessment (anthropometrics, body composition, and resting metabolic rate) and laboratory tests. The primary outcome is weight maintenance or body weight gain under 5% after 12 months. Secondary outcomes include body composition, resting metabolic rate, satiety sensation, kidney function, and other metabolic parameters. DISCUSSION: Diets with higher protein content and lower glycemic index may lead to weight loss because of higher satiety sensation. However, there is a concern about the association of high protein intake and kidney damage. Nevertheless, there is little evidence on the impact of high protein intake on long-term kidney function outcome. Therefore, we designed a study to test if a high protein diet with low-glycemic index will be an effective and safe nutritional intervention to prevent weight gain in kidney transplant patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02883777 . Registered on 3 August 2016. PMID- 28874183 TI - Urethral calculi with a urethral fistula: a case report and review of the literature. AB - BACKGROUND: To explore and summarize the reasons why urethral calculi cause a urethral fistula. CASE PRESENTATION: We retrospectively studied 1 patient in Xiangya hospital and all relevant literature published in English between 1989 and 2015. The patients (including those reported in the literature) were characterized by age, origin, location of calculus, size of calculus, fistulous track, and etiological factors. Most of urethral calculi associated with a urethral fistula were native generated. Urethral calculi can be formed in various locations of the urethra, and the size of the calculus ranged from small (multiple) calculi to giant stones. The fistula external orifice located at the root of the penis was relatively common, and there were various etiological factors, such as urethral strictures, urethral trauma induced by long-term catheterization, lumbar fractures, and congenital anomaly factors. They were managed by the excision of the fistulous tract, retrieval of the urethral stones, and/or debridement and pus drainage operations. CONCLUSION: Some elements, such as trauma, recurrent urinary tract infections, abscess formation induced by long term catheterization, and urethral calculus, may be the risk factors for a urethral fistula. PMID- 28874182 TI - Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease. AB - Pompe disease is a lysosomal storage disorder caused by acid-alpha-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The neurologic phenotype and the persistence of selective muscular weakness in some patients could be attributed to the central nervous system (CNS) storage uncorrected by ERT. GAA-KO 6neo/6neo mice were treated with a single intrathecal administration of adeno-associated recombinant vector (AAV) mediated gene transfer of human GAA at 1 month and their neurologic, neuromuscular, and cardiac function was assessed for 1 year. We demonstrate a significant functional neurologic correction in treated animals from 4 months onward, a neuromuscular improvement from 9 months onward, and a correction of the hypertrophic cardiomyopathy at 12 months. The regions most affected by the disease i.e. the brainstem, spinal cord, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. Muscle glycogen storage is not affected by the treatment, thus suggesting that the restoration of muscle functionality is directly related to the CNS correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients. PMID- 28874184 TI - Multipotent stromal cells/mesenchymal stem cells and fibroblasts combine to minimize skin hypertrophic scarring. AB - BACKGROUND: Transplantation of mesenchymal stem cells (MSC) has been proposed to improve wound healing. However, as these cells only transiently survive in the implantation site, the mechanisms underlying this beneficial healing response are associated with restorative paracrine effects of MSC matricellular factors on resident stromal cells. However, this requires that the recipient has a robust reservoir of viable cells. Here, we examine the influence of MSCs on the behavior of cotransplanted fibroblasts, in a manner to provide augmented cellular reserve to debilitated individuals, specifically focusing on matrix remodeling following in-vivo wounding. METHODS: Using a Hylan-A dermal filler hydrogel containing collagen I and tenascin-C for delivery and increased survival of transplanted cells, we find that cotransplantation of MSCs with fibroblasts reduces scarring. RESULTS: Transplanted xenogeneic MSCs augmented fibroblast proliferation, migration, and extracellular matrix deposition critical for wound closure, and reduced inflammation following wounding. MSCs also corrected matrix remodeling by CXCR3-deficient fibroblasts which otherwise led to hypertrophic scarring. This effect was superior to MSC or fibroblast transplantation alone. CONCLUSIONS: Taken together, these data suggest that MSCs, even if eventually rejected, transplanted with fibroblasts normalize matrix regeneration during healing. The current study provides insight into cellular therapies as a viable method for antifibrotic treatment and demonstrates that even transiently engrafted cells can have a long-term impact via matrix modulation and education of other tissue cells. PMID- 28874185 TI - A novel susceptibility locus in the IL12B region is associated with the pathophysiology of Takayasu arteritis through IL-12p40 and IL-12p70 production. AB - BACKGROUND: A previous study revealed the association between susceptibility to Takayasu arteritis (TAK) and a single nucleotide polymorphism (SNP) rs6871626 located in IL12B, which encodes interleukin (IL)-12p40, a common component of IL 12p70 and IL-23. We investigated the expression of these cytokines in patients with TAK, stratifying them into those with or without the risk allele at the rs6871626 SNP. METHODS: Plasma levels of IL-12p40, IL-12p70, and IL-23 were quantified in 44 patients with TAK and 19 healthy controls (HCs) by enzyme-linked immunosorbent assays. Monocytes were obtained from 20 patients with TAK and 14 HCs, treated with interferon-gamma (IFN-gamma) and lipopolysaccharide, and then supernatant cytokines were quantified. In addition, the ratio of IFN-gamma+ or IL 17A+ cells to CD4+ T cells was measured by flow cytometric analysis of peripheral blood mononuclear cells. RESULTS: The levels of plasma IL-12p40, plasma IL-12p70, and supernatant IL-12p70 were significantly higher in patients with TAK than in HCs, whereas there were no significant differences in the levels of plasma IL-23, supernatant IL-23, or supernatant IL-12p40. The levels of plasma IL-12p70, supernatant IL-12p40, and supernatant IL-12p70 were significantly higher in patients with the risk allele than in those without. The ratio of CD4+IFN-gamma+ cells was significantly higher in patients with the risk allele, whereas CD4+IL 17A+ cells showed no differences. CONCLUSIONS: The rs6871626 SNP in IL12B may influence the increased expression of IL-12p40 and IL-12p70. These enhanced cytokines might play roles in the pathophysiology of TAK. PMID- 28874186 TI - Age-dependent changes in synaptic plasticity enhance tau oligomerization in the mouse hippocampus. AB - The aggregation mechanism of phosphorylated tau is an important therapeutic target for tauopathies, including Alzheimer's disease, although the mechanism by which aggregation occurs is still unknown. Because the phosphorylation process of tau is involved in the trafficking of AMPA receptors, which accompanies the long term depression (LTD) of synapses, we examined the effect of LTD-inducing low frequency stimulation (LFS) on the formation of pathological tau aggregates in adult and aged wild-type mice. Our biochemical analysis demonstrated that LFS led to the formation of sarkosyl-insoluble (SI) tau oligomers in aged hippocampi but not in adult hippocampi in wild-type mice. In parallel, electrophysiological experiments showed an increased contribution of the autophagy-lysosomal pathway (ALP) to LTD during aging, although the other properties of LFS-induced LTD that we investigated were not altered. Thus, we anticipate that the increased contribution of the ALP to the LTD cascade is involved in the age-dependent formation of tau oligomers that results from LFS. Analysis of the LC3 ratio, an indicator of autophagosome formation, showed that LFS increased cleaved LC3 (type II) in the aged hippocampus relative to type I LC3, suggesting potentiation of the ALP accompanied by LTD. Pharmacological inhibition of autophagosome formation depressed LFS-induced oligomerization of tau. Prevention of lysosomal function in the ALP enhanced the formation of tau oligomers by LFS. These results suggest the importance of the autophagosome for the LFS-induced oligomerization of tau and suggest a reason for its age dependency. Interestingly, the lysosomal disturbance promoted the formation of the fibrillar form of aggregates consisting of hyper phosphorylated tau. The LTD-ALP cascade potentially acts as one of the suppliers of pathological aggregates of tau in aged neurons. PMID- 28874187 TI - Prolonged preoperative treatment of acromegaly with Somatostatin analogs may improve surgical outcome in patients with invasive pituitary macroadenoma (Knosp grades 1-3): a retrospective cohort study conducted at a single center. AB - BACKGROUND: This study aimed to investigate preoperative somatostatin analogs (SSAs) treatment on the surgical outcome in patients with acromegaly. METHODS: An analysis of 358 patients with acromegaly was conducted. The preoperative medical therapy group (81 patients) received SSA treatment for at least 3 months prior to surgery, while the primary surgery group (277 patients) underwent transsphenoidal surgery directly. Follow-up duration was >=3 months. Tumor invasion was evaluated by magnetic resonance imaging (MRI) and classified according to the Knosp grading system. RESULTS: Most patients were diagnosed with macroadenoma. Among all patients (Knosp grades 0-4), preoperative SSA therapy did not significantly improve the curative effect of surgery, according to the levels of growth hormone (GH) and/or insulin-like growth factor 1 (IGF-1) markers. In patients with macroadenoma (Knosp grades 1-3), the remission rates were significantly higher in the SSA group compared to the surgery group when considering GH (56.4% vs. 37.3%, P = 0.048) and IGF-1 (43.2% vs. 17.6%, P = 0.004). In the preoperative medical therapy group, long-term use of SSAs (>6 months) led to higher remission rates (GH, 72.2% vs. 51.0%; and IGF-1, 61.1% vs. 29.8%; P = 0.12 and 0.02, respectively]. CONCLUSIONS: The long-term preoperative SSAs treatment may improve the surgical curative rate in acromegalic patients with invasive macroadenomas (Knosp grades 1-3). PMID- 28874188 TI - Determinants of first-time utilization of long-term care services in the Netherlands: an observational record linkage study. AB - BACKGROUND: Since in an ageing society more long-term care (LTC) facilities are needed, it is important to understand the main determinants of first-time utilization of (LTC) services. METHODS: The Andersen service model, which distinguishes predisposing, enabling and need factors, was used to develop a model for first-time utilization of LTC services among the general population of the Netherlands. We used data on 214,821 persons registered in a database of general practitioners (NIVEL Primary Care Database). For each person the medical history was known, as well as characteristics such as ethnicity, income, home ownership, and marital status. Utilization data from the national register on long-term care was linked at a personal level. Generalized Linear Models were used to determine the relative importance of factors of incident LTC-service utilization. RESULTS: Top 5 determinants of LTC are need, measured as the presence of chronic diseases, age, household size, household income and homeownership. When controlling for all other determinants, the presence of an additional chronic disease increases the probability of utilizing any LTC service by 45% among the 20+ population (OR = 1.45, 95% CI: 1.41-1.49), and 31% among the 65+ population (OR = 1.31, 95% CI: 1.27-1.36). With respect to the 20+ population, living in social rent (OR = 2.45, 95% CI = 2.25-2.67, ref. = home owner) had a large impact on utilizing any LTC service. In a lesser degree this was the case for living alone (OR = 1.63, 95% CI = 1.52-1.75, ref. = not living alone). A higher household income was linked with a lower utilization of any LTC service. CONCLUSIONS: All three factors of the Anderson model, predisposing, enabling, and need determinants influence the likelihood of future LTC service utilization. This implies that none of these factors can be left out of the analysis of what determines this use. New in our analysis is the focus on incident utilization. This provides a better estimate of the effects of predictors than a prevalence based analysis, as there is less confounding by changes in determinants occurring after LTC initiation. Especially the need of care is a strong factor. A policy implication of this relative importance of health status is therefore that LTC reforms should take health aspects into account. PMID- 28874189 TI - Intersectin-1s deficiency in pulmonary pathogenesis. AB - Intersectin-1s (ITSN-1s), a multidomain adaptor protein, plays a vital role in endocytosis, cytoskeleton rearrangement and cell signaling. Recent studies have demonstrated that deficiency of ITSN-1s is a crucial early event in pulmonary pathogenesis. In lung cancer, ITSN-1s deficiency impairs Eps8 ubiquitination and favors Eps8-mSos1 interaction which activates Rac1 leading to enhanced lung cancer cell proliferation, migration and metastasis. Restoring ITSN-1s deficiency in lung cancer cells facilitates cytoskeleton changes favoring mesenchymal to epithelial transformation and impairs lung cancer progression. ITSN-1s deficiency in acute lung injury leads to impaired endocytosis which leads to ubiquitination and degradation of growth factor receptors such as Alk5. This deficiency is counterbalanced by microparticles which, via paracrine effects, transfer Alk5/TGFbetaRII complex to non-apoptotic cells. In the presence of ITSN-1s deficiency, Alk5-restored cells signal via Erk1/2 MAPK pathway leading to restoration and repair of lung architecture. In inflammatory conditions such as pulmonary artery hypertension, ITSN-1s full length protein is cleaved by granzyme B into EHITSN and SH3A-EITSN fragments. The EHITSN fragment leads to pulmonary cell proliferation via activation of p38 MAPK and Elk-1/c-Fos signaling. In vivo, ITSN-1s deficient mice transduced with EHITSN plasmid develop pulmonary vascular obliteration and plexiform lesions consistent with pathological findings seen in severe pulmonary arterial hypertension. These novel findings have significantly contributed to understanding the mechanisms and pathogenesis involved in pulmonary pathology. As demonstrated in these studies, genetically modified ITSN 1s expression mouse models will be a valuable tool to further advance our understanding of pulmonary pathology and lead to novel targets for treating these conditions. PMID- 28874190 TI - Functional changes in hippocampal synaptic signaling in offspring survivors of a mouse model of intrauterine inflammation. AB - BACKGROUND: Recent evidence suggests that exposure to intrauterine inflammation causes acute fetal brain injury and is linked to a spectrum of neurobehavioral disorders. In a rodent model of intrauterine inflammation induced by lipopolysaccharide (LPS) exposure in utero, activated microglia can be detected in the hippocampus of offspring survivors, as late as 60 days postnatal (DPN). Given that the hippocampus is important for learning and memory, these results suggest that in utero inflammation underlies long-term cognitive deficits observed in children/survivors. METHODS: An established mouse model of LPS induced intrauterine inflammation was used to study hippocampal function from offspring at 44-59 DPN. Microgliosis was examined at 45 DPN. Extracellular field recordings of synaptic transmission were performed on acute hippocampal slices. RESULTS: LPS offspring mice displayed persistent microglial activation and increased CA3-CA1 excitatory synaptic strength, which can be explained in part by an increase in the probability of glutamate release, and reduced long-term synaptic potentiation compared to control mice. CONCLUSIONS: These results offer a mechanistic explanation for the cognitive and behavioral deficits observed in survivors of preterm birth caused by intrauterine inflammation. PMID- 28874191 TI - Internet or dvd for distance learning to isolated rural health professionals, what is the best approach? AB - BACKGROUND: Distance Learning (DL) is a means to overcome the barriers that prevent health workers access to medical education and training sessions to update their knowledge. The main objective of this study is to compare the knowledge acquisition among practitioners Heads of Health Based Center (HBC) for the management of hypertension in two training modalities, one interactive, via internet (by Visio conferencing and video Conferencing), and other non interactive, via DVD in the three regions (Miarinarivo, Moramanga and Manjakandriana) of Madagascar. METHODS: This is a quasi-experimental study comparing two distance learning methodologies, one via internet (VS or VD) and the other via DVD before and after training. Ninety-two (92) Heads of HBC participated in the training, including 56 via the Internet (24 doctors and 32 paramedics) and 36 via DVD (24 doctors and 12 paramedics). RESULTS: According to the training mode: the mean score of knowledge of the participants was 7 (+ -2) for two terms before training. It is 14 (+ -2.5) in the internet group (VS or VD) and 15 (+ -2.7) in the DVD group after training. The difference between the two groups was not significant p = 0.076. For doctors, the score was 7 (+ -3.1) via internet and 8 (+ -2.3) via DVD in pre test and 14 (+ - 2.4) via internet and 16 (+ -. 2.7) via DVD in post test, the difference between the two training methods was significant (p = 0.008). Among the paramedics, the results are the same for both conditions, 7 (+ - 2.4 to + -3.2) in pre test and 14 (+ - 2.2 to + -2.7) in post test. CONCLUSION: Both training methods have improved participants' knowledge and the DVD mode is the first choice for Heads HBC of Madagascar with the majority located in remote areas. PMID- 28874192 TI - Plasma metabolomic study in Chinese patients with wet age-related macular degeneration. AB - BACKGROUND: Age-related macular degeneration (AMD) is a leading disease associated with blindness. It has a high incidence and complex pathogenesis. We aimed to study the metabolomic characteristics in Chinese patients with wet AMD by analyzing the morning plasma of 20 healthy controls and 20 wet AMD patients for metabolic differences. METHODS: We used ultra-high-pressure liquid chromatography and quadrupole-time-of-flight mass spectrometry for this analysis. The relationship of these differences with AMD pathophysiology was also assessed. Remaining data were normalized using Pareto scaling, and then valid data were handled using multivariate data analysis with MetaboAnalysis software, including unsupervised principal component analysis and supervised partial least squares discriminate analysis. The purpose of the present work was to identify significant metabolites for the analyses. Hierarchical clustering was conducted to identify metabolites that differed between the two groups. Significant metabolites were then identified using the established database, and features were mapped on the Kyoto Encyclopedia of Genes and Genomes. RESULTS: A total of 5443 ion peaks were detected, all of them attributable to the same 10 metabolites. These included some amino acids, isomaltose, hydrocortisone, and biliverdin. The heights of these peaks differed significantly between the two groups. The biosynthesis of amino acids pathways also differed profoundly between patients with wet AMD and controls. CONCLUSIONS: These findings suggested that metabolic profiles and and pathways differed between wet AMD and controls and may provide promising new targets for AMD-directed therapeutics and diagnostics. PMID- 28874193 TI - Extranodal nasal-type natural killer/T-cell lymphoma with penile involvement: a case report and review of the literature. AB - BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) usually presents as a localized disease in the nasal cavity; extension to the male genitourinary system is very rare and has been characterized only recently. Most cases present with predominantly extranodal involvement, advanced stage disease, highly aggressive course, and strong association with Epstein-Barr virus (EBV). While metastasis is common in ENKTLs, the penis is rarely involved in both nasal and non-nasal ENKTLs and only one report was published to date. CASE PRESENTATION: One patient with NK/T-cell lymphoma, presented initially with a penile mass, is reported. The 58-year-old man who presented with progressive painless penile swelling underwent penectomy for penile tumor. Histologically, the glans and foreskin revealed neoplastic infiltration of medium-sized lymphoma cells expressing CD56, CD3, granzyme-B, and labeled for EBV-encoded RNA in situ hybridization. Findings were consistent with NK/T-cell lymphoma. By detailed history, we learned that the patient had nasal obstruction for more than 10 years. Nasopharyngeal involvement was screened with PET-CT; ENKTL was diagnosed after a nasopharyngeal biopsy. The final diagnosis was primary nasal NK/T-cell lymphoma, with metastasis to the penis. Additional sites of disease appeared soon afterward (adrenal gland, liver, spleen and lymph nodes). The patient died within 4 months. CONCLUSION: This study suggested that penile NK/T-cell lymphoma tends to disseminate early and pursues an aggressive course. It is imperative to distinguish nasal NK/T lymphoma from other types of tumors, because the prognosis and treatment differ significantly for secondary metastases. PMID- 28874194 TI - Prophylactic antibiotic use in pediatric patients undergoing urinary tract catheterization: a survey of members of the Society for Pediatric Urology. AB - BACKGROUND: Current organizational guidelines regarding use of antibiotics during urinary tract catheterization are based on limited evidence and are not directly applicable to the pediatric urology population. We seek to improve understanding of this population by first evaluating current practices. This study aims to investigate practice patterns and attitudes of pediatric urologists regarding the use of antibiotics in the setting of urinary tract catheterization. METHODS: An online survey was sent to members of the Society for Pediatric Urology. Questionnaire sections included demographics, general questions about antibiotic use with catheterization, and specific clinical scenarios. Descriptive statistics were used, and chi-square analysis was performed to examine associations between demographics and specific responses. RESULTS: Of 448 pediatric urologists surveyed, 154 (34%) responded to the survey. A majority of surveyed urologists (78%) prescribe daily prophylactic antibiotics with a hypospadias stent in place, but extensive variation in use of antibiotics was reported with other catheters and tubes. Extensive variation in practice patterns was also reported for three case scenarios regarding antibiotic prophylaxis with catheterization. Urologists > 50 years of age and fellowship-trained urologists were more likely to prescribe antibiotics for hypospadias stents (p = 0.02, p = 0.03), but no other significant associations between demographic characteristics and antibiotic use were found. CONCLUSIONS: There is substantial variation in practice patterns among surveyed pediatric urologists regarding prophylactic antibiotic use with urinary catheterization. This variation, combined with a lack of objective data and increasing pressure to decrease infectious complications and combat antibiotic resistance, highlights the need for development of management guidelines for this unique population. PMID- 28874195 TI - Malalignment and malposition of quadriceps-sparing approach in primary total knee arthroplasty: a systematic review and meta-analysis. AB - BACKGROUND: Quadriceps-sparing (QS) approach is considered to be the most minimally invasive surgery for total knee arthroplasty (TKA). We perform this meta-analysis to evaluate whether malalignment and malposition are more biased towards the QS approach compared to the traditional medial parapatellar (MP) approach, which is still controversial. METHODS: According to the PRISMA guidelines, a comprehensive search was conducted in the databases of PubMed, the Cochrane library, and Embase. Relevant measures were extracted independently by two investigators. RESULTS: Five randomized controlled trials (RCTs) and eight retrospective studies including a total of 1261 cases were identified. The QS approach was associated with more outliers of hip-knee-ankle (HKA) angle (p = 0.03), coronal tibial component angle (p = 0.03), and femoral notch (p = 0.05). However, the differences of the outlier of the coronal femoral component angle between the two groups were not statistically significant. CONCLUSIONS: This meta analysis indicates that the QS approach is related to the high risk of malalignment and malposition. However, different studies reported different indicators resulting in small samples for analyzing the radiological outcomes. In addition, both of the relatively long learning curve and the present instruments might increase the risk of malalignment and malposition of the QS approach, which needs further study and improvement. PMID- 28874196 TI - Eating behavior and psychological profile: associations between daughters with distinct eating disorders and their mothers. AB - BACKGROUND: Associations of eating behaviors and psychological profile between mothers and daughters with eating disorders exist, but it is important to dissect the influence of the mother in each specific disorder since all eating disorders must be seen or treated not as one entity. The aim of the present study was to evaluate the association of eating behavior and psychological profile between mothers and daughters with different eating disorders and a control group. METHODS: The study group included young girls with anorexia nervosa (AN, n = 30), bulimia nervosa (BN, n = 30), binge eating disorder (BED, n = 19), and a control group of women (Non-ED, n = 54) together with their mothers. BMI was calculated for dyads and Eating Disorder Inventory, Beck Depression Inventory, Beck Anxiety Inventory, Toronto Alexithymia Scale and Three-Factor Eating Questionnaire were applied. The differences between dyads were tested by Student's t test and Pearson's correlation was used to study the association between BMI, variables of eating behavior and psychological profile in each dyad. RESULTS: The study found significant inverse correlations between the AN dyad; some correlations between the BN dyad, and the highest positive correlations exist in BED dyad, especially in eating behavior. Finally, between the control dyads, low but significant correlations were found in the majority of cases. CONCLUSIONS: The study concluded that the associations between mothers and daughters with distinct eating disorders varied depending on the specific diagnosis of the daughter, indicating it is necessary to analyze them individually, given that there may be different implications for treatment. PMID- 28874197 TI - Environmental drivers of Ixodes ricinus abundance in forest fragments of rural European landscapes. AB - BACKGROUND: The castor bean tick (Ixodes ricinus) transmits infectious diseases such as Lyme borreliosis, which constitutes an important ecosystem disservice. Despite many local studies, a comprehensive understanding of the key drivers of tick abundance at the continental scale is still lacking. We analyze a large set of environmental factors as potential drivers of I. ricinus abundance. Our multi scale study was carried out in deciduous forest fragments dispersed within two contrasting rural landscapes of eight regions, along a macroclimatic gradient stretching from southern France to central Sweden and Estonia. We surveyed the abundance of I. ricinus, plant community composition, forest structure and soil properties and compiled data on landscape structure, macroclimate and habitat properties. We used linear mixed models to analyze patterns and derived the relative importance of the significant drivers. RESULTS: Many drivers had, on their own, either a moderate or small explanatory value for the abundance of I. ricinus, but combined they explained a substantial part of variation. This emphasizes the complex ecology of I. ricinus and the relevance of environmental factors for tick abundance. Macroclimate only explained a small fraction of variation, while properties of macro- and microhabitat, which buffer macroclimate, had a considerable impact on tick abundance. The amount of forest and the composition of the surrounding rural landscape were additionally important drivers of tick abundance. Functional (dispersules) and structural (density of tree and shrub layers) properties of the habitat patch played an important role. Various diversity metrics had only a small relative importance. Ontogenetic tick stages showed pronounced differences in their response. The abundance of nymphs and adults is explained by the preceding stage with a positive relationship, indicating a cumulative effect of drivers. CONCLUSIONS: Our findings suggest that the ecosystem disservices of tick-borne diseases, via the abundance of ticks, strongly depends on habitat properties and thus on how humans manage ecosystems from the scale of the microhabitat to the landscape. This study stresses the need to further evaluate the interaction between climate change and ecosystem management on I. ricinus abundance. PMID- 28874198 TI - Who pays for healthcare in Bangladesh? An analysis of progressivity in health systems financing. AB - BACKGROUND: The relationship between payments towards healthcare and ability to pay is a measure of financial fairness. Analysis of progressivity is important from an equity perspective as well as for macroeconomic and political analysis of healthcare systems. Bangladesh health systems financing is characterized by high out-of-pocket payments (63.3%), which is increasing. Hence, we aimed to see who pays what part of this high out-of-pocket expenditure. To our knowledge, this was the first progressivity analysis of health systems financing in Bangladesh. METHODS: We used data from Bangladesh Household Income and Expenditure Survey, 2010. This was a cross sectional and nationally representative sample of 12,240 households consisting of 55,580 individuals. For quantification of progressivity, we adopted the 'ability-to-pay' principle developed by O'Donnell, van Doorslaer, Wagstaff, and Lindelow (2008). We used the Kakwani index to measure the magnitude of progressivity. RESULTS: Health systems financing in Bangladesh is regressive. Inequality increases due to healthcare payments. The differences between the Gini coefficient and the Kakwani index for all sources of finance are negative, which indicates regressivity, and that financing is more concentrated among the poor. Income inequality increases due to high out-of-pocket payments. The increase in income inequality caused by out-of-pocket payments is 89% due to negative vertical effect and 11% due to horizontal inequity. CONCLUSIONS: Our findings add substantial evidence of health systems financing impact on inequitable financial burden of healthcare and income. The heavy reliance on out-of-pocket payments may affect household living standards. If the government and people of Bangladesh are concerned about equitable financing burden, our study suggests that Bangladesh needs to reform the health systems financing scheme. PMID- 28874199 TI - Hydrolysed protein enteral nutrition is not superior to polymeric whole protein feeding with regard to gastrointestinal feeding tolerance and feeding adequacy. PMID- 28874200 TI - First isolation and genetic characterization of pseudocowpox virus from cattle in Japan. AB - BACKGROUND: Pseudocowpox virus (PCPV) infects cattle worldwide with zoonotic potential but has not been isolated in Japan. Thus, the epidemiological status of PCPV infection in cattle is undetermined. RESULTS: In May 2016, a cattle in a farm in Yamaguchi Prefecture showed white vesicles and hyperemia in the mucosa under the tongue surface, but not on the teats and coronary cushions. A parapoxvirus was isolated from the oral lesion swab and was genetically characterized based on the full-length sequence of B2L gene encoding viral envelope. Phylogenetic analysis showed that the isolated virus was classified into PCPV. CONCLUSION: This case indicates its potential spread in Japan. This is the first report of isolation of PCPV in Japan. PMID- 28874201 TI - Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina. AB - BACKGROUND: Tetrahydrobiopterin (BH4) is an essential cofactor in multiple metabolic processes and plays an essential role in maintaining the inflammatory and neurovascular homeostasis. In this study, we have investigated the deleterious effects of BH4 deficiency on retinal vasculature during development. METHODS: hph-1 mice, which display deficiency in BH4 synthesis, were used to characterize the inflammatory effects and the integrity of retinal microvasculature. BH4 levels in retinas from hph-1 and wild type (WT) mice were measured by LC-MS/MS. Retinal microvascular area and microglial cells number were quantified in hph-1 and WT mice at different ages. Retinal expression of pro inflammatory, anti-angiogenic, and neuronal-derived factors was analyzed by qPCR. BH4 supplementation was evaluated in vitro, ex-vivo, and in vivo models. RESULTS: Our findings demonstrated that BH4 levels in the retina from hph-1 mice were significantly lower by ~ 90% at all ages analyzed compared to WT mice. Juvenile hph-1 mice showed iris atrophy, persistent fetal vasculature, significant increase in the number of microglial cells (p < 0.01), as well as a marked degeneration of the retinal microvasculature. Retinal microvascular alterations in juvenile hph-1 mice were associated with a decreased expression in Norrin (0.2 fold) and its receptor Frizzled-4 (FZD4; 0.51-fold), as well as with an augmented expression of pro-inflammatory factors such as IL-6 (3.2-fold), NRLP-3 (4.4 fold), IL-1beta (8.6-fold), and the anti-angiogenic factor thrombospondin-1 (TSP 1; 17.5-fold). We found that TSP-1 derived from activated microglial cells is a factor responsible of inducing microvascular degeneration, but BH4 supplementation markedly prevented hyperoxia-induced microglial activation in vitro and microvascular injury in an ex-vivo model of microvascular angiogenesis and an in vivo model of oxygen-induced retinopathy (OIR). CONCLUSION: Our findings reveal that BH4 is a key cofactor in regulating the expression of inflammatory and anti-angiogenic factors that play an important function in the maintenance of retinal microvasculature. PMID- 28874202 TI - Ethnobotanical survey of wild food plants traditionally collected and consumed in the Middle Agri Valley (Basilicata region, southern Italy). AB - BACKGROUND: This research was carried out in a scarcely populated area of the Middle Agri Valley (Basilicata region, southern Italy). The aim of the study was to record local knowledge on the traditional uses of wild food plants, as well as to collect information regarding the practices (gathering, processing and cooking) and the medicinal uses related to these plants. METHODS: Fifty-eight people still possessing traditional local knowledge (TLK), 74% women and 26% men, were interviewed between May-August 2012 and January 2013, using open and semi structured ethnobotanical interviews. For each described plant species, the botanical family, the Italian common and folk names, the plant parts used, the culinary preparation and, when present, the medicinal use, were recorded and the relative frequency of citation index (RFC) was determined. RESULTS: The 52 plant species mentioned by the respondents belong to 23 botanical families, with Asteraceae (12 plants) and Rosaceae (7 plants) being most frequently cited. The species with the highest RFC index is Cichorium intybus L. (0.95), followed by Sonchus spp. (S. oleraceus L., S. asper L. and S. arvensis L.) (0.76). The plant parts preferably used are leaves (22 plants), fruits (12) and stems (7). Only six wild plants were indicated as having both food use and therapeutic effect. CONCLUSIONS: The survey conducted on the traditional use of wild food plants in the Middle Agri Valley revealed that this cultural heritage is only partially retained by the population. Over the last few decades, this knowledge has been in fact quickly disappearing along with the people and, even in the rural context of the study area, is less and less handed down to younger generations. Nevertheless, data also revealed that the use of wild plants is recently being revaluated in a way closely related to local habits and traditions. PMID- 28874203 TI - Behcet's disease with recurrent thoracic aortic aneurysm combined with femoral artery aneurysm: a case report and literature review. AB - BACKGROUND: Aneurysm or pseudoaneurysm is the main vascular complication of Behcet's disease. Most hospitals adopt endovascular treatment. CASE PRESENTATION: We report a case of Behcet's disease with recurrent thoracic aortic aneurysm combined with femoral artery aneurysm. The patient underwent two rounds of endovascular surgery, but developed new aneurysms immediately after surgery. Eventually, the patient died due to rupture of recurrent aneurysm. CONCLUSIONS: For vasculo-Behcet's disease, we suggest performing the operation during the stable period. At the same time, glucocorticoids could be used with immunosuppressants preoperatively and postoperatively. PMID- 28874205 TI - Target volume delineation of anal cancer based on magnetic resonance imaging or positron emission tomography. AB - PURPOSE: To compare target volume delineation of anal cancer using positron emission tomography (PET) and magnetic resonance imaging (MRI) with respect to inter-observer and inter-modality variability. METHODS: Nineteen patients with anal cancer undergoing chemoradiotherapy were prospectively included. Planning computed tomography (CT) images were co-registered with 18F-fluorodexocyglucose (FDG) PET/CT images and T2 and diffusion weighted (DW) MR images. Three oncologists delineated the Gross Tumor Volume (GTV) according to national guidelines and the visible tumor tissue (GTVT). MRI and PET based delineations were evaluated by absolute volumes and Dice similarity coefficients. RESULTS: The median volume of the GTVs was 27 and 31 cm3 for PET and MRI, respectively, while it was 6 and 11 cm3 for GTVT. Both GTV and GTVT volumes were highly correlated between delineators (r = 0.90 and r = 0.96, respectively). The median Dice similarity coefficient was 0.75 when comparing the GTVs based on PET/CT (GTVPET) with the GTVs based on MRI and CT (GTVMRI). The median Dice coefficient was 0.56 when comparing the visible tumor volume evaluated by PET (GTVT_PET) with the same volume evaluated by MRI (GTVT_MRI). Margins of 1-2 mm in the axial plane and 7-8 mm in superoinferior direction were required for coverage of the individual observer's GTVs. CONCLUSIONS: The rather good agreement between PET- and MRI based GTVs indicates that either modality may be used for standard target delineation of anal cancer. However, larger deviations were found for GTVT, which may impact future tumor boost strategies. PMID- 28874204 TI - Spotted fever rickettsiae in wild-living rodents from south-western Poland. AB - BACKGROUND: Rickettsiae are obligate intracellular alpha-proteobacteria. They are transmitted via arthropod vectors, which transmit the bacteria between animals and occasionally to humans. So far, much research has been conducted to indicate reservoir hosts for these microorganisms, but our knowledge is still non exhaustive. Therefore, this survey was undertaken to investigate the presence of Rickettsia spp. in wild-living small rodents from south-western Poland. RESULTS: In total, 337 samples (193 from spleen and 144 from blood) obtained from 193 wild living rodents: Apodemus agrarius, Apodemus flavicollis, and Myodes glareolus were tested by qPCR for Rickettsia spp. based on a fragment of gltA gene. The prevalence of infection was 17.6% (34/193). Subsequently, the positive samples were analysed by conventional PCR targeting the gltA gene fragment. The genus Rickettsia was confirmed by sequence analysis in four samples from the blood. In two blood samples from A. agrarius, the identified pathogen was Rickettsia helvetica. The Rickettsia obtained from A. flavicollis was assigned to Rickettsia felis-like organisms group. One isolate from A. agrarius could be determined only to the genus level. CONCLUSIONS: This study shows the presence of Rickettsia DNA in tissues of wild-living rodents, suggesting some potential role of these animals in temporarily maintaining and spreading the bacteria in enzootic cycles. PMID- 28874207 TI - Evaluation of active ingredients and larvicidal activity of clove and cinnamon essential oils against Anopheles gambiae (sensu lato). AB - BACKGROUND: Mosquitoes are well-known vectors of many diseases including malaria and lymphatic filariasis. Uses of synthetic insecticides are associated with high toxicity, resistance, environmental pollution and limited alternative, effective synthetic insecticides. This study was undertaken to evaluate the larvicidal efficacy of clove and cinnamon essential oils against laboratory Anopheles gambiae (sensu stricto) and wild An. arabiensis larvae. METHODS: The standard WHO guideline for larvicides evaluation was used, and the GC-MS machine was used for active compounds percentage composition analysis and structures identification. Probit regression analysis was used for LC50 and LC95 calculations while a t-test was used to test for significant differences between laboratory-reared and wild larvae populations in each concentration of plant extract. RESULTS: Mortality effect of clove and cinnamon essential oils against wild and laboratory-reared larvae had variations indicated by their LC50 and LC95 values. The mortality at different concentrations of cinnamon and clove post-exposure for wild and laboratory-reared larvae were dosage-dependent and were higher for cinnamon than for clove essential oils. The mortality effect following exposure to a blend of the two essential oils was higher for blends containing a greater proportion of cinnamon oil. In the chemical analysis of the active ingredients of cinnamon essential oil, the main chemical content was Eugenol, and the rarest was beta Linalool while for clove essential oil, the main chemical content was Eugenol and the rarest was Bicyclo. CONCLUSION: The essential oils showed a larvicidal effect which was concentration-dependent for both laboratory and wild collected larvae. The active ingredient compositions triggered different responses in mortality. Further research in small-scale should be conducted with concentrated extracted compounds. PMID- 28874208 TI - Throat swabs have no influence on the management of patients with sore throats. AB - BACKGROUND: Throat swabs are neither specific nor sensitive for micro-bacteria causing sore throat symptoms; however, current guidelines suggest they are still useful in some cases. METHOD: Retrospective and prospective analyses were conducted of throat swabs requested within the months of January 2016 and August 2016, respectively. RESULTS: The study comprised 247 patients. Fifty-nine (24 per cent) had a positive culture. Forty-six grew group A beta-haemolytic streptococci, with the remainder growing candida (n = 10), coliform (n = 1) and klebsiella (n = 2). There was no significant difference in culture rates between primary or secondary care sources (chi2 = 0.56, p = 0.45). None of the swabs influenced a variation in patient management from local antimicrobial policies. Current practice has an estimated annual financial impact of L3 434 340 on the National Health Service. CONCLUSION: Throat swabs do not influence the antimicrobial treatment for patients with sore throats, even under current guidelines, and incur unnecessary cost. Current clinical guidelines could be reviewed to reduce the number of throat swabs being conducted unnecessarily. PMID- 28874209 TI - Subclinical levels of anxiety but not depression are associated with planning performance in a large population-based sample. AB - BACKGROUND: Major depression and anxiety disorders are known to negatively influence cognitive performance. Moreover, there is evidence for greater cognitive decline in older adults with generalized anxiety disorder. Except for clinical studies, complex executive planning functions and subclinical levels of anxiety have not been examined in a population-based sample with a broad age range. METHODS: Planning performance was assessed using the Tower of London task in a population-based sample of 4240 participants aged 40-80 years from the Gutenberg Health Study (GHS) and related to self-reported anxiety and depression by means of multiple linear regression analysis. RESULTS: Higher anxiety ratings were associated with lower planning performance (beta = -0.20; p < 0.0001) independent of age (beta = 0.03; p = 0.47). When directly comparing the predictive value of depression and anxiety on cognition, only anxiety attained significance (beta = -0.19; p = 0.0047), whereas depression did not (beta = 0.01; p = 0.71). CONCLUSIONS: Subclinical levels of anxiety but not of depression showed negative associations with cognitive functioning independent of age. Our results demonstrate that associations observed in clinical groups might differ from those in population-based samples, also with regard to the trajectory across the life span. Further studies are needed to uncover causal interrelations of anxiety and cognition, which have been proposed in the literature, in order to develop interventions aimed at reducing this negative affective state and to improve executive functioning. PMID- 28874210 TI - Ultrastructural, Elemental and Mineralogical Analysis of Vascular Calcification in Atherosclerosis. AB - Over the past few decades, remarkable progress has been achieved in terms of understanding the molecular and cellular mechanisms of atherosclerotic vascular calcification and the important role of matrix vesicles in initiating and propagating pathologic tissue mineralization has been widely recognized. Despite these recent advances, however, no definitive data are currently available regarding the texture and composition of the minerals that grow in the vessel wall during the course of the disease. Using different electron microscopy imaging and analysis, we demonstrate that vascular cells can produce and secrete more than one type of matrix vesicles which act as sites for initial mineral deposition independently of their structural features. Our results reveal that apatite formation in the atherosclerotic lesions of the human aorta occur through the deposition of amorphous calcium phosphate that matures over time, transforms into crystalline hydroxyapatite, and radiates towards the lumen of the vesicles, finally forming the calcified spherules. Elemental and mineralogical analyses also demonstrate that the presence of mature and stable amorphous calcium phosphate deposits in the affected tissues is linked to the incorporation of magnesium, which probably delay the conversion to the crystalline phase. Though more rarely, the presence of calcium oxalate crystals has been also documented. PMID- 28874211 TI - Audiological outcome of stapes surgery for far advanced cochlear otosclerosis. AB - BACKGROUND: Patients with advanced otosclerosis can present with hearing thresholds eligible for cochlear implantation. This study sought to address whether stapes surgery in this patient group provides a clinically significant audiological benefit. OBJECTIVES: To assess pre- and post-operative hearing outcomes of patients with advanced otosclerosis, and to determine what proportion of these patients required further surgery including cochlear implantation. METHODS: Between 2002 and 2015, 252 patients underwent primary stapes surgery at our institution. Twenty-eight ears in 25 patients were deemed to have advanced otosclerosis, as defined by pure audiometry thresholds over 80 dB. The patients' records were analysed to determine audiological improvement following stapes surgery, and assess whether any further surgery was required. RESULTS: The audiological outcome for most patients who underwent primary stapes surgery was good. A minority of patients (7 per cent) required revision surgery. Patients who underwent cochlear implantation after stapes surgery (10 per cent) also demonstrated a good audiological outcome. CONCLUSION: Stapes surgery is a suitable treatment option for patients with advanced otosclerosis, and should be considered mandatory, before offering cochlear implantation, for those with a demonstrable conductive component to their hearing loss. A small group of patients get little benefit from surgery and subsequently a cochlear implant should be considered. PMID- 28874212 TI - Mucosal Barrier Injury Central-Line-Associated Bloodstream Infections: What is the Impact of Standard Prevention Bundles? PMID- 28874214 TI - A histopathological connection between a fatal endolymphatic sac tumour and von Hippel-Lindau disease from 1960. AB - OBJECTIVE: To highlight a case from 1960 connecting endolymphatic sac tumour and von Hippel-Lindau disease. CASE REPORT: In 1960, a 24-year-old woman presented with unilateral hearing loss, pulsatile tinnitus and a mass visible on otoscopy. The patient underwent surgical biopsy, which was complicated by haemorrhage, and ultimately resulted in death. At autopsy, a destructive temporal bone neoplasm with cystic and papillary architecture was observed that had eroded into the otic capsule. Intra-abdominal lesions consistent with von Hippel-Lindau disease were also observed, and the surgeon postulated a connection between endolymphatic sac tumour and von Hippel-Lindau disease. METHOD: A review of the literature was carried out using PubMed. CONCLUSION: Endolymphatic sac tumours are rare neoplasms of the temporal bone that can occur sporadically or as part of von Hippel-Lindau disease. The connection between endolymphatic sac tumour and von Hippel-Lindau disease was first proposed in 1988 and formalised in 1997. We believe that this case represents the first documented connection between endolymphatic sac tumour and von Hippel-Lindau disease. PMID- 28874213 TI - Differences in Neurocognitive Impairment Among HIV-Infected Latinos in the United States. AB - OBJECTIVES: Human immunodeficiency virus (HIV) disproportionately affects Hispanics/Latinos in the United States, yet little is known about neurocognitive impairment (NCI) in this group. We compared the rates of NCI in large well characterized samples of HIV-infected (HIV+) Latinos and (non-Latino) Whites, and examined HIV-associated NCI among subgroups of Latinos. METHODS: Participants included English-speaking HIV+ adults assessed at six U.S. medical centers (194 Latinos, 600 Whites). For overall group, age: M=42.65 years, SD=8.93; 86% male; education: M=13.17, SD=2.73; 54% had acquired immunodeficiency syndrome. NCI was assessed with a comprehensive test battery with normative corrections for age, education and gender. Covariates examined included HIV-disease characteristics, comorbidities, and genetic ancestry. RESULTS: Compared with Whites, Latinos had higher rates of global NCI (42% vs. 54%), and domain NCI in executive function, learning, recall, working memory, and processing speed. Latinos also fared worse than Whites on current and historical HIV-disease characteristics, and nadir CD4 partially mediated ethnic differences in NCI. Yet, Latinos continued to have more global NCI [odds ratio (OR)=1.59; 95% confidence interval (CI)=1.13-2.23; p<.01] after adjusting for significant covariates. Higher rates of global NCI were observed with Puerto Rican (n=60; 71%) versus Mexican (n=79, 44%) origin/descent; this disparity persisted in models adjusting for significant covariates (OR=2.40; CI=1.11-5.29; p=.03). CONCLUSIONS: HIV+ Latinos, especially of Puerto Rican (vs. Mexican) origin/descent had increased rates of NCI compared with Whites. Differences in rates of NCI were not completely explained by worse HIV-disease characteristics, neurocognitive comorbidities, or genetic ancestry. Future studies should explore culturally relevant psychosocial, biomedical, and genetic factors that might explain these disparities and inform the development of targeted interventions. (JINS, 2018, 24, 163-175). PMID- 28874206 TI - Variation in monitoring and treatment policies for intracranial hypertension in traumatic brain injury: a survey in 66 neurotrauma centers participating in the CENTER-TBI study. AB - BACKGROUND: No definitive evidence exists on how intracranial hypertension should be treated in patients with traumatic brain injury (TBI). It is therefore likely that centers and practitioners individually balance potential benefits and risks of different intracranial pressure (ICP) management strategies, resulting in practice variation. The aim of this study was to examine variation in monitoring and treatment policies for intracranial hypertension in patients with TBI. METHODS: A 29-item survey on ICP monitoring and treatment was developed on the basis of literature and expert opinion, and it was pilot-tested in 16 centers. The questionnaire was sent to 68 neurotrauma centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. RESULTS: The survey was completed by 66 centers (97% response rate). Centers were mainly academic hospitals (n = 60, 91%) and designated level I trauma centers (n = 44, 67%). The Brain Trauma Foundation guidelines were used in 49 (74%) centers. Approximately 90% of the participants (n = 58) indicated placing an ICP monitor in patients with severe TBI and computed tomographic abnormalities. There was no consensus on other indications or on peri-insertion precautions. We found wide variation in the use of first- and second-tier treatments for elevated ICP. Approximately half of the centers were classified as using a relatively aggressive approach to ICP monitoring and treatment (n = 32, 48%), whereas the others were considered more conservative (n = 34, 52%). CONCLUSIONS: Substantial variation was found regarding monitoring and treatment policies in patients with TBI and intracranial hypertension. The results of this survey indicate a lack of consensus between European neurotrauma centers and provide an opportunity and necessity for comparative effectiveness research. PMID- 28874215 TI - PARTICIPATORY DESIGN OF PEDIATRIC UPPER LIMB PROSTHESES: QUALITATIVE METHODS AND PROTOTYPING. AB - OBJECTIVES: The study aims to develop an understanding of the views of children and adolescents, parents, and professionals on upper limb prosthetic devices to develop and improve device design. Previous research has found that children are dissatisfied with prostheses but has relied heavily on parent proxy reports and quantitative measures (such as questionnaires) to explore their views. METHODS: Thirty-four participants (eight children aged 8-15 years with upper limb difference, nine parents, eight prosthetists, and nine occupational therapists) contributed to the development of new devices through the BRIDGE methodology of participatory design, using focus groups and interviews. RESULTS: The study identified areas for improving prostheses from the perspective of children and adolescents, developed prototypes based on these and gained feedback on the prototypes from the children and other stakeholders (parents and professionals) of paediatric upper limb prostheses. Future device development needs to focus on ease of use, versatility, appearance, and safety. CONCLUSIONS: This study has demonstrated that children and adolescents can and should be involved as equal partners in the development of daily living equipment and that rapid prototyping (three-dimensional printing or additive manufacturing), used within a participatory design framework, can be a useful tool for facilitating this. PMID- 28874216 TI - Nutrient intake, rumen fermentation and growth performance of dairy calves fed extruded full-fat soybean as a replacement for soybean meal. AB - The objective of this study was to investigate the effects of extruded full-fat soybean (ESB) as a replacement for soybean meal (SBM) on nutrient intake, rumen fermentation, and growth performance of dairy calves. A total of 45 male Holstein dairy calves (42.0+/-0.5 kg of BW) were randomly assigned to one of three experimental diets: (1) 0% ESB (Control): 35.3% SBM no ESB; (2) 25% ESB: 27.0% SBM+9.0% ESB; and (3) 50% ESB: 19.0% SBM+19.0% ESB. All calves were weaned on day 56 of age and remained in the study until day 70 of age. During the pre-weaning and overall periods, substituting of SBM with ESB had no effect on intake of starter feed, metabolizable energy (ME), CP and non-fiber carbohydrate (NFC). Compared with the control, 50% ESB resulted in a decrease in starter feed intake, and intakes of other nutrients including CP, NFC and ME during the post-weaning period. Substituting SBM with ESB decreased intake of C16 : 0 and increased intakes of n-9 C18 : 1, n-6 C18 : 2 and n-3 C18 : 3 during the pre-weaning, post weaning and overall periods. Using ESB as a replacement for SBM did not affect average daily gain, feed efficiency, rectal temperature and fecal score over the trial periods. Compared with control, the rumen concentration of NH3-N decreased for 50% ESB on days 35 and 56 of age but not when compared with 25% ESB. Rumen pH, total volatile fatty acids concentrations, and the molar proportions of ruminal acetate, propionate and butyrate were not different among treatments. Body measurements were not affected by the treatments. In conclusion, substitution of SBM with ESB may improve nitrogen utilization efficiency in dairy calves but slightly reduce post-weaning starter intake with no negative outcomes on growth performance and rumen fermentation. PMID- 28874218 TI - Suicide risk assessment among psychiatric inpatients: a systematic review and meta-analysis of high-risk categories. AB - BACKGROUND: The clinical care of psychiatric patients is often guided by perceptions of suicide risk. The aim of this study was to examine the methods and results of studies reporting high-risk models for inpatient suicide. METHODS: We conducted a registered meta-analysis according to PRISMA guidelines. We searched for relevant peer-reviewed cohort and controlled studies indexed in Medline, EMBASE and PsychINFO. RESULTS: The pooled odds ratio (OR) among 18 studies reporting high-risk models for inpatient suicide was 7.1 [95% confidence interval (CI) 4.2-12.2]. Between-study heterogeneity in ORs was very high (range 0-94.8, first quartile 3.4, median 8.8, third quartile 26.1, prediction interval 0.80 63.1, I2 = 88.1%). The meta-analytically derived sensitivity was 53.1% (95% CI 38.2-67.5%, I2 = 95.9%) and specificity was 84.2% (95% CI 71.6-91.9%, I2 = 99.9%) with an associated meta-analytic area under the curve of 0.83. The positive predictive value of risk categorization among six cohort studies was 0.43% (95% CI 0.014-1.3%, I2 = 95.9%). A history of suicidal behavior and depressive symptoms or affective disorder was included in the majority of high-risk models. CONCLUSIONS: Despite the strength of the pooled association between high-risk categorization and suicide, the very high degree of observed heterogeneity indicates uncertainty about our ability to meaningfully distinguish inpatients according to suicide risk. The limited sensitivity and low positive predictive value of risk categorization suggest that suicide risk models are not a suitable basis for clinical decisions in inpatient settings. PMID- 28874219 TI - More Than Meets the Eye: Adenoviral Conjunctivitis in Healthcare Settings. PMID- 28874217 TI - Impact of pre-operative serum 25-hydroxyvitamin D on post-operative serum calcium in patients undergoing total thyroidectomy for benign goitre: retrospective study of 246 patients. AB - OBJECTIVE: To determine whether pre-operative serum 25-hydroxyvitamin D has an impact on post-operative parathyroid hormone and serum calcium levels in patients undergoing total thyroidectomy for benign goitre. METHODS: This single-centre, retrospective study comprised 246 unselected surgical patients who had undergone total thyroidectomy for bilateral, benign, multinodular goitre. The correlation between pre-operative serum 25-hydroxyvitamin D and post-operative serum parathyroid hormone and serum calcium was studied to determine whether low pre operative serum 25-hydroxyvitamin D was predictive of post-operative hypocalcaemia. RESULTS: Seventy-nine patients (32 per cent) had post-operative hypocalcaemia. Eighteen patients (7.32 per cent) experienced unintentional parathyroidectomy (1 parathyroid gland in 15 patients, 2 parathyroid glands in 3 patients). In univariate analysis, pre-operative serum 25-hydroxyvitamin D was not correlated with post-operative serum calcium (p = 0.69) or post-operative serum parathyroid hormone (p = 0.5804). Furthermore, in multivariate analysis, which took into account unintentional parathyroidectomy, no correlation was found (p = 0.33). Bilateral unintentional parathyroidectomy was statistically associated with post-operative hypocalcaemia (p = 0.032). CONCLUSION: Pre operative serum 25-hydroxyvitamin D did not appear to have any impact on post operative serum calcium in patients undergoing total thyroidectomy for benign goitre. PMID- 28874220 TI - Facets of Conscientiousness and risk of dementia. AB - BACKGROUND: Multiple studies have found Conscientiousness to be protective against dementia. The purpose of this study is to identify which specific aspects, or facets, of Conscientiousness are most protective against cognitive impairment and whether these associations are moderated by demographic factors and/or genetic risk. METHODS: Health and Retirement Study participants were selected for analysis if they completed the facets of Conscientiousness measure, scored in the range of normal cognitive functioning at the baseline personality assessment, and had at least one follow-up assessment of cognition over the up to 6-year follow-up (N = 11 181). Cox regression was used to test for risk of incident dementia and risk of incident cognitive impairment not dementia (CIND). RESULTS: Over the follow-up, 278 participants developed dementia and 2186 participants developed CIND. The facet of responsibility had the strongest and most consistent association with dementia risk: every standard deviation increase in this facet was associated with a nearly 35% decreased risk of dementia; self control and industriousness were also protective. Associations were generally similar when controlling for clinical, behavioral, and genetic risk factors. These three facets were also independent predictors of decreased risk of CIND. CONCLUSIONS: The present research indicates that individuals who see themselves as responsible, able to control their behavior, and hard workers are less likely to develop CIND or dementia and that these associations persist after accounting for some common clinical, behavioral, and genetic risk factors. PMID- 28874221 TI - The relationship between tinnitus pitch and parameters of audiometry and distortion product otoacoustic emissions. AB - OBJECTIVES: Chronic tinnitus is associated with reduced auditory input, which results in changes in the central auditory system. This study aimed to examine the relationship between tinnitus pitch and parameters of audiometry and distortion product otoacoustic emissions. For audiometry, the parameters represented the edge frequency of hearing loss, the frequency of maximum hearing loss and the frequency range of hearing loss. For distortion product otoacoustic emissions, the parameters were the frequency of lowest distortion product otoacoustic emission amplitudes and the frequency range of reduced distortion product otoacoustic emissions. METHOD: Sixty-seven patients (45 males, 22 females) with subjective chronic tinnitus, aged 18 to 73 years, were included. RESULTS: No correlation was found between tinnitus pitch and parameters of audiometry and distortion product otoacoustic emissions. However, tinnitus pitch fell mostly within the frequency range of hearing loss. CONCLUSION: The current study seems to confirm the relationship between tinnitus pitch and the frequency range of hearing loss, thus supporting the homeostatic plasticity model. PMID- 28874222 TI - INTEGRATE-HTA: THE PERSPECTIVE OF EUnetHTA. AB - The HTA Core Model (HTACM) of EUnetHTA and the INTEGRATE-HTA Model (IHTAM) both provide HTA experts with advanced guidance on how to assess health technologies. In this study, we examine the similarities and differences of the two models, identifying synergies and opportunities for future collaboration. We also consider how such an alignment of the HTACM and IHTAM might be done in practice and present some alternative practical approaches. Overall the two models share several similarities, primarily the perception of HTA as a multidisciplinary analysis that needs to be adjusted according to the properties of the technology under assessment. PMID- 28874223 TI - Premorbid social adjustment and association with attenuated psychotic symptoms in clinical high-risk and help-seeking youth. AB - BACKGROUND: Attenuated positive symptom syndrome (APSS), characterized by 'putatively prodromal' attenuated psychotic-like pathology, indicates increased risk for psychosis. Poor premorbid social adjustment predicts severity of APSS symptoms and predicts subsequent psychosis in APSS-diagnosed individuals, suggesting application for improving detection of 'true' prodromal youth who will transition to psychosis. However, these predictive associations have not been tested in controls and therefore may be independent of the APSS diagnosis, negating utility for improving prediction in APSS-diagnosed individuals. METHOD: Association between premorbid social maladjustment and severity of positive, negative, disorganized, and general APSS symptoms was tested in 156 individuals diagnosed with APSS and 76 help-seeking (non-APSS) controls enrolled in the Enhancing the Prospective Prediction of Psychosis (PREDICT) study using prediction analysis. RESULTS: Premorbid social maladjustment was associated with social anhedonia, reduced expression of emotion, restricted ideational richness, and deficits in occupational functioning, independent of the APSS diagnosis. Associations between social maladjustment and suspiciousness, unusual thought content, avolition, dysphoric mood, and impaired tolerance to normal stress were uniquely present in participants meeting APSS criteria. Social maladjustment was associated with odd behavior/appearance and diminished experience of emotions and self only in participants who did not meet APSS criteria. CONCLUSIONS: Predictive associations between poor premorbid social adjustment and attenuated psychotic like pathology were identified, a subset of which were indicative of high risk for psychosis. This study offers a method for improving risk identification while ruling out low-risk individuals. PMID- 28874224 TI - Adolescent mental health and behavioural predictors of being NEET: a prospective study of young adults not in employment, education, or training. AB - BACKGROUND: Young adults who are not in employment, education, or training (NEET) are at risk of long-term economic disadvantage and social exclusion. Knowledge about risk factors for being NEET largely comes from cross-sectional studies of vulnerable individuals. Using data collected over a 10-year period, we examined adolescent predictors of being NEET in young adulthood. METHODS: We used data on 1938 participants from the Victorian Adolescent Health Cohort Study, a community based longitudinal study of adolescents in Victoria, Australia. Associations between common mental disorders, disruptive behaviour, cannabis use and drinking behaviour in adolescence, and NEET status at two waves of follow-up in young adulthood (mean ages of 20.7 and 24.1 years) were investigated using logistic regression, with generalised estimating equations used to account for the repeated outcome measure. RESULTS: Overall, 8.5% of the participants were NEET at age 20.7 years and 8.2% at 24.1 years. After adjusting for potential confounders, we found evidence of increased risk of being NEET among frequent adolescent cannabis users [adjusted odds ratio (ORadj) = 1.74; 95% confidence interval (CI) 1.10-2.75] and those who reported repeated disruptive behaviours (ORadj = 1.71; 95% CI 1.15-2.55) or persistent common mental disorders in adolescence (ORadj = 1.60; 95% CI 1.07-2.40). Similar associations were present when participants with children were included in the same category as those in employment, education, or training. CONCLUSIONS: Young people with an early onset of mental health and behavioural problems are at risk of failing to make the transition from school to employment. This finding reinforces the importance of integrated employment and mental health support programmes. PMID- 28874225 TI - Costs Associated with Ebola Preparedness at a Freestanding Pediatric Assessment Center. AB - The 2014-2016 West Africa Ebola outbreak led US hospitals to prepare to treat Ebola patients, with significant attributable costs. A nationwide preparedness transition to a tiered approach allowed regional allocation of preparedness resources for Ebola frontline, assessment, and treatment hospitals. Preparedness costs for assessment centers were significant and largely uncompensated. Infect Control Hosp Epidemiol 2017;38:1367-1369. PMID- 28874226 TI - An updated review of avian-origin Tembusu virus: a newly emerging avian Flavivirus. AB - Tembusu virus (TMUV, genus Flavivirus, family Flaviviridae) was first isolated in 1955 from Culex tritaeniorhynchus mosquitoes in Kuala Lumpur, Malaysia. In April 2010, duck TMUV was first identified as the causative agent of egg-drop syndrome, characterized by a substantial decrease in egg laying and depression, growth retardation and neurological signs or death in infected egg-laying and breeder ducks, in the People's Republic of China. Since 2010, duck TMUV has spread to most of the duck-producing regions in China, including many of the coastal provinces, neighbouring regions and certain Southeast Asia areas (i.e. Thailand and Malaysia). This review describes the current understanding of the genome characteristics, host range, transmission, epidemiology, phylogenetic and immune evasion of avian-origin TMUV and the innate immune response of the host. PMID- 28874227 TI - The impact of virus population diversity on the dynamics of cytomegalovirus DNAemia in allogeneic stem cell transplant recipients. AB - Mixed cytomegalovirus (CMV) infections are associated with delayed viral clearance in solid organ transplant recipients. We investigated whether this could be extrapolated to allogeneic stem cell transplant (allo-SCT) recipients. A total of 48 plasma specimens, obtained during 29 episodes of active CMV infection in 25 non-consecutive allo-SCT patients, were analysed. Baseline blood specimens, drawn shortly prior to the inception of pre-emptive antiviral therapy (pre treatment specimen; n=29), as well as follow-up samples obtained either after the initiation of antiviral therapy (post-treatment specimen; n=15) or during recurrent episodes (n=4) were analysed. Plasma CMV DNA loads were quantified by real-time PCR and the CMV genotyping was performed by ultra-deep sequencing of hypervariable regions in the genes coding for glycoproteins N (gN) and O (gO). A trend towards higher CMV DNA peak loads, longer CMV DNAemia episode durations and slower CMV DNAemia decay rates was observed for episodes with mixed CMV genotype populations compared to those caused by single CMV variants, although the differences did not reach statistical significance. The length of the treatment course required to clear DNAemia was significantly longer in these mixed episodes (P=0.002). Significant changes in the number or frequency of CMV gN or gO genetic variants were documented following the initiation of antiviral therapy or in recurrent episodes. CMV diversity may have a major impact on the kinetics of CMV DNAemia clearance during the treatment of active CMV infection episodes in allo SCT recipients. PMID- 28874229 TI - Molecular evolution and phylogeography of infectious hematopoietic necrosis virus with a focus on its presence in France over the last 30 years. AB - Infectious hematopoietic necrosis virus (IHNV) is among the most important pathogens affecting the salmonid industry. Here, we investigated the molecular evolution and circulation of isolates from 11 countries or regions all over the world, with a special focus on the epidemiological situation in France. The phylogeography, time to the most recent common ancestor (TMRCA) and nucleotide substitution rate were studied using 118 full-length glycoprotein gene sequences isolated from 9 countries (5 genogroups) over a period of 47 years. The TMRCA dates back to 1943, with the L genogroup identified as the likely root (67 %), which is consistent with the first report of this pathogen in the USA. A Bayesian inference approach was applied to the partial glycoprotein gene sequences of 88 representative strains isolated in France over the period 1987-2015. The genetic diversity of these 88 sequences showed mean nucleotide and amino-acid identities of 97.1 and 97.8 %, respectively, and a dN/dS ratio (non-synonymous to synonymous mutations) of 0.25, indicating purifying selection. The French viral populations are divided into eight sub-clades and four individual isolates, with a clear spatial differentiation, suggesting the predominant role of local reservoirs in contamination. The atypical 'signatures' of some isolates underlined the usefulness of molecular phylogeny for epidemiological investigations that track the spread of IHNV. PMID- 28874228 TI - Multivariate Validated Models for Simultaneous Determination of Ibuprofen and Famotidine in the Presence of Related Substances. AB - Two multivariate validated spectrophotometric methods, namely partial least squares (PLS) and principal component regression (PCR), were developed and validated for the determination of ibuprofen and famotidine in presence of famotidine degradation products and ibuprofen impurity (4-isobutylacetophenone). A calibration set was prepared in which the two drugs together with the degradation products and impurity were modeled using a multilevel multifactor design. This calibration set was used to build the PLS and PCR models. The proposed models successfully predicted the concentrations of both drugs in validation samples, with low root mean square error of cross validation (RMSECV) percentage. The method was validated by the estimate of the figures of merit depending on the net analyte signal. The results of the two models showed that the simultaneous determination of both drugs could be performed in the concentration ranges of 100-500 ug/mL for ibuprofen and 5-25 ug/mL for famotidine. The proposed multivariate calibration methods were applied for the determination of ibuprofen and famotidine in their pharmaceutical formulation, and the results were verified by the standard addition technique. PMID- 28874230 TI - Therapeutic effect of autologous compact bone-derived mesenchymal stem cell transplantation on prion disease. AB - Prion diseases are fatal neurodegenerative disorders of humans and animals and no effective treatments are currently available. Allogenic transplantation of immortalized human mesenchymal stem cells (MSCs) can prolong the survival of mice infected with prions. However, autologous transplantation is an appropriate model for evaluating the effects of MSCs on prion diseases. Therefore, we isolated and purified MSCs from the femur and tibia of mice as compact bone-derived MSCs (CB MSCs). Flow cytometric analysis showed that CB-MSCs were negative for myeloid stem cell-derived cell markers CD11b and CD45, but positive for molecules such as Sca-1, CD105 and CD90.2, which are reported to be expressed on MSCs. The ability of CB-MSCs to migrate to brain extracts from prion-infected mice was confirmed by an in vitro migration assay. Intra-hippocampus transplantation of CB-MSCs at 120 days post-inoculation marginally but significantly prolonged the survival of mice infected with the Chandler prion strain. The transplantation of CB-MSCs did not influence the accumulation of disease-specific prion protein. However, the CB-MSC transplantation enhanced microglial activation, which appeared to be polarized to the M2-type activation state. These results suggest that autologous MSC transplantation is a possible treatment for prion diseases, while the modification of microglial activation may be a therapeutic target for neurodegenerative diseases. PMID- 28874231 TI - Genomic characterization of a novel iridovirus from redclaw crayfish Cherax quadricarinatus: evidence for a new genus within the family Iridoviridae. AB - A novel iridovirus, Cherax quadricarinatus iridovirus (CQIV), was identified from diseased C. quadricarinatus in 2014. This virus is considered as a new threat to crustacean aquaculture because it is lethal to both peneaid shrimp and crayfish. Here, we determined the complete genome sequence of CQIV. The double-stranded DNA genome is 165 695 bp in length with a G+C content of 34.6 %. A total of 178 open reading frames (ORFs) have been predicted, encoding hypothetical proteins ranging from 50 to 1327 amino acids. Forty-seven of these exhibit similarities to proteins of known functions. Phylogenetic analysis based on multiple alignments of conserved proteins shows that CQIV clusters with the members of the family Iridoviridae, but is placed in a distinct clade from all the five known genera. It indicates that CQIV may represent a new genus in the family Iridoviridae, for which we propose the name Cheraxvirus based on the host organism. PMID- 28874232 TI - In silico assessment of virulence factors in strains of Streptococcus oralis and Streptococcus mitis isolated from patients with Infective Endocarditis. AB - PURPOSE: Streptococcus oralis and Streptococcus mitis belong to the Mitis group, which are mostly commensals in the human oral cavity. Even though S. oralis and S. mitis are oral commensals, they can be opportunistic pathogens causing infective endocarditis. A recent taxonomic re-evaluation of the Mitis group has embedded the species Streptococcus tigurinus and Streptococcus dentisani into the species S. oralis as subspecies. In this study, the distribution of virulence factors that contribute to bacterial immune evasion, colonization and adhesion was assessed in clinical strains of S. oralis (subsp. oralis, subsp. tigurinus and subsp. dentisani) and S. mitis. METHODOLOGY: Forty clinical S. oralis (subsp. oralis, subsp. dentisani and subsp. tigurinus) and S. mitis genomes were annotated with the pipeline PanFunPro and aligned against the VFDB database for assessment of virulence factors.Results/Key findings. Three homologues of pavA, psaA and lmb, encoding adhesion proteins, were present in all strains. Seven homologues of nanA, nanB, ply, lytA, lytB, lytC and iga, of importance regarding survival in blood and modulation of the human immune system, were variously present in the genomes. Few S. oralis subspecies specific differences were observed. iga homologues were identified in S. oralis subsp. oralis, whereas lytA homologues were identified in S. oralis subsp. oralis and subsp. tigurinus. CONCLUSION: Differences in the presence of virulence factors among the three S. oralis subspecies were observed. The virulence gene profiles of the 40 S. mitis and S. oralis (subsp. oralis, subsp. dentisani and subsp. tigurinus) contribute with important new knowledge regarding these species and new subspecies. PMID- 28874233 TI - Predominance of clarithromycin-susceptible Mycobacterium massiliense subspecies: Characterization of the Mycobacterium abscessus complex at a tertiary acute care hospital. AB - To characterize members of the Mycobacterium abscessus complex, with an emphasis on the correlation between species identification and clarithromycin associated genetic polymorphisms that contribute to inducible and constitutive macrolide resistance. PCR and sequencing analysis was used to elucidate the subspecies, erm(41) genotypes and the presence of rrl mutations. M. abscessus subsp. massiliense was the dominant subspecies (70.2 %), followed by M. abscessus subsp. abscessus (23.8 %) and M. abscessus subsp. bolletii (5.9 %). The majority of M. abscessus and M. bolletii isolates possessed T28 erm(41) sequevar and were inducibly resistant to clarithromycin. All M. massiliense carried the truncated erm(41) and were largely clarithromycin-susceptible (98.3 %). Constitutive resistance involving rrl mutations was rare and seen in only 2 isolates (2.2 %). Subspecies identification was insufficient to predict clarithromycin susceptibility and required the genetic resistance to be determined via sequencing. In our context, rrl mutations were uncommon and may not be an essential test. PMID- 28874234 TI - Retention and topology of the bovine viral diarrhea virus glycoprotein E2. AB - Pestiviruses are enveloped viruses that bud intracellularly. They have three envelope glycoproteins, Erns, E1, and E2. E2 is the receptor binding protein and the main target for neutralizing antibodies. Both Erns and E2 are retained intracellularly. Here, E2 of the bovine viral diarrhea virus (BVDV) strain CP7 was used to study the membrane topology and intracellular localization of the protein. E2 is localized in the ER and there was no difference between E2 expressed alone or in the context of the viral polyprotein. The mature E2 protein was found to possess a single span transmembrane anchor. For the mapping of a retention signal CD72-E2 fusion proteins, as well as E2 alone were analysed. This confirmed the importance of the transmembrane domain and arginine 355 for intracellular retention, but also revealed a modulating effect on retention through the cytoplasmic tail of the E2 protein, especially through glutamine 370. Mutants with a strong impact on retention were tested in the viral context and we were able to rescue BVDV with certain mutations that in E2 alone impaired intracellular retention and lead to export of E2 to the cells surface. PMID- 28874235 TI - Efficacy of recombinant human C1 esterase inhibitor for the treatment of severe hereditary angioedema attacks. AB - BACKGROUND: Severe attacks of hereditary angioedema (HAE) are debilitating and potentially life threatening, and can increase anxiety and the use of medical resources. OBJECTIVE: This post hoc assessment evaluated recombinant human C1 esterase inhibitor (rhC1-INH) used to treat acute severe HAE attacks. METHODS: In a double-blind, randomized-controlled trial (RCT), patients with an HAE attack (baseline visual analog scale score of >=50 mm, with severe attacks defined as >=75 mm) were randomly assigned to receive rhC1-INH (50 IU/kg for patients who weighed <84 kg; 4200 IU for patients who weighed >=84 kg) or placebo. Also, in an open-label extension (OLE) study of rhC1-INH, oropharyngeal-laryngeal attacks were analyzed. Rescue therapy with rhC1-INH 50 IU/kg (<=4200 IU) was permitted after 4 hours or for life-threatening symptoms (in the RCT) or after 1 hour (in the OLE study). The primary end point measured the time to the beginning of symptom relief by using the Treatment Effects Questionnaire. RESULTS: Of 75 adults in the RCT, 43 had severe attacks and received either rhC1-INH (n = 24) or placebo (n = 19). The median (95% confidence interval) time to the onset of symptom relief totaled 90.0 minutes (95% confidence interval, 47.0-120.0 minutes) versus 334.0 minutes (95% confidence interval, 105.0 to not calculable minutes; hazard ratio, 2.5; p = 0.02), for rhC1-INH and placebo, respectively. Open-label rhC1-INH rescue therapy was administered to 1 of 24 in the rhC1-INH group (4.2%) and 10 of 19 in the placebo group (52.6%). During the OLE study, the median onset of symptom relief with rhC1-INH for eight oropharyngeal-laryngeal HAE attacks was 69.0 minutes (95% confidence interval, 59.0-91.0 minutes). CONCLUSION: In the current study, rhC1-INH was efficacious in resolving severe HAE attacks, including oropharyngeal-laryngeal attacks. The rhC1-INH rescue treatment rapidly improved symptoms for patients who received placebo and who experienced worsening or sustained symptoms. PMID- 28874236 TI - Funding antiretroviral treatment for HIV-positive temporary residents in Australia prevents transmission and is inexpensive. AB - : Background The aim of this study is to estimate the reduction in new HIV infections and resultant cost outcomes of providing antiretroviral treatment (ART) through Australia's 'universal access' health scheme to all temporary residents with HIV infection living legally in Australia, but currently deemed ineligible to access subsidised ART via this scheme. METHODS: A mathematical model to estimate the number of new HIV infections averted and the associated lifetime costs over 5 years if all HIV-positive temporary residents in Australia had access to ART and subsidised medical care was developed. Input data came from a cohort of 180 HIV-positive temporary residents living in Australia who are receiving free ART donated by pharmaceutical companies for up to 4 years. RESULTS: Expanding ART access to an estimated total 450 HIV+ temporary residents in Australia for 5 years could avert 80 new infections. The model estimated the total median discounted (5%) cost for ART and associated care to be A$36million, while the total savings in lifetime-discounted costs for the new infections averted was A$22million. CONCLUSIONS: It is estimated that expanded access to ART for all HIV-positive temporary residents in Australia will substantially reduce HIV transmission to their sexual partners at little additional cost. In the context of Australia's National HIV strategy and Australia's endorsement of global goals to provide universal access to ART for all people with HIV, this is an important measure to remove inequities in the provision of HIV-related treatment and care. PMID- 28874237 TI - [Drowning-induced hyperfibrinolytic disseminated intravascular coagulation]. AB - This article summarizes the current knowledge of drowning-induced hyperfibrinolytic disseminated intravascular coagulation. Drowning induces respiratory failure with ensuing cardiac arrest, hypoxaemia and ischaemia. A coagulopathy is induced by ischaemia, acidosis and hypothermia, and clinically the patient develops uncontrolled bleeding due to hyperfibrinolysis. A rapid diagnostic approach is required to recognize this hyperfibrinolytic state, since initiation of treatment with antifibrinolytics and fibrinogen concentrate may bring this life-threatening condition to cessation. PMID- 28874238 TI - [Off-label prescription of psychopharmacological drugs for children and adolescents]. AB - Despite regulatory initiatives, psychopharmacological treatment of adolescents is challenged by missing trial data on efficacy and safety. In Denmark, an estimated mean off-label prescription rate of 30-40% in clinical child- and adolescent mental health services has been found in recent studies. The lowest rates were found for drugs treating ADHD (2-3%), and the highest for antipsychotics (96%) and melatonin (100%). The use of melatonin is growing, while the use of other psychopharmacological drugs appears to be stabilizing or decreasing, in spite of an increased number of adolescents treated in Danish mental health services. PMID- 28874239 TI - [Atypical subcutaneous presentation of a basal cell carcinoma]. AB - Basal cell carcinoma (BCC) have many treatment options either by dermatologist, with excision or radiotherapy. A 78-year-old woman had a BCC removed surgically, and 18 years after she had a subcutaneously located tumour extirpated at the same location. The result of pathological examination was BCC located atypically in the subcutis. Iatrogenic seeding from primary excision or non-radical primary excision may explain this presentation. This is only the second report of subcutaneously located BCC. PMID- 28874240 TI - [Review of online prescriptions of topical steroids for an obese boy with iatrogenic Cushing's syndrome]. AB - A 14-year-old boy with obesity developed iatrogenic Cushing's syndrome after having received topical steroid therapy for psoriasis. The diagnosis was suspected when he developed striae, moon face and stunted growth. A review of the Danish online registration of prescriptions: Shared Medicine Card, revealed that an amount of 5.1 kg topical steroids had been prescribed during a period of twelve months. Blood tests showed stunted cortisol release. Primary obesity in children is associated with increased growth. Decreased growth warrants further investigations for an underlying condition. This case illustrates the usefulness of Shared Medicine Card, especially when multiple physicians are involved. PMID- 28874241 TI - Infant botulism in Denmark from 1995 to 2015. AB - INTRODUCTION: Infant botulism is a rare, probably underdiagnosed, life threatening disease caused by the toxin-producing bacterium Clostridium botulinum. METHODS: We investigated reported cases of infant botulism in Denmark from 1995 to 2015, and compared the incidence with that of other western countries. RESULTS: We found nine cases of infant botulism in Denmark from 1995 to 2015. The incidence of infant botulism in Denmark was similar to that seen in other western countries, but likely underestimated. The source of infection was only confirmed in a single case. Four cases received botulism immune globulin, intravenous (BIG-IV), which was administered within 7-10 days from admission. CONCLUSIONS: Infant botulism is probably underdiagnosed. Increased awareness is crucial to be able to recognise the condition. The time delay from hospital admission to administration of BIG-IV is challenging. Studies have shown that BIG IV reduces both mean duration of intensive care and mean length of hospital stay; however, this was not confirmed in our work due to the limited number of patients. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 28874242 TI - Effects of low-dose recombinant human erythropoietin treatment on cognitive performance. AB - INTRODUCTION: High-dose recombinant human erythropoietin (rhEpo) has been shown to improve cognitive performance in both healthy volunteers and in patients suffering from diseases affecting the brain. The aim of this study was to examine whether administration of low-dose and even micro-dose rhEpo improves cognitive performance in healthy volunteers. METHODS: We enrolled 25 healthy volunteers in a double-blind, randomised, placebo-controlled study to receive either low-dose rhEpo (n = 8, 60 IU/kg/week), micro-dose rhEpo (n = 9, 20 IU/kg/week), or saline (n = 8) for four weeks. Two cognitive performance-tests, the Raven Standard Progressive Matrices (Raven) and the Number Finder (NUFI), were performed during the first and last day of the study period. Semi-structured interviews were conducted weekly and were coded according to a scale. RESULTS: Subjects receiving micro-dose rhEpo improved significantly measured by the Raven score (p = 0.04), and subjects receiving low-dose rhEpo treatment improved significantly measured by the NUFI score (p = 0.047), whereas no improvement was found in experienced cognitive performance in any of the groups. We found no significant difference in either Raven, NUFI or self-reported results between the groups. CONCLUSIONS: In this small study, we found no significant effect of low-dose or micro-dose rhEpo on visual attention, cognitive performance in complex cognitive tasks or self experienced cognitive performance compared with placebo. FUNDING: The Aase and Ejnar Danielsen's Foundation. Danish Ministry of Science, Innovation and Higher Education. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03093506. PMID- 28874243 TI - Central regional anaesthesia in patients with aortic stenosis - a systematic review. AB - INTRODUCTION: Aortic stenosis is a valvular lesion that poses several haemodynamic challenges for the anaesthesiologist. The use of central regional anaesthesia is traditionally regarded as contraindicated in patients with severe aortic stenosis due to its sympatholytic effect, potentially causing loss of vascular tone and ultimately diminished cardiac output. The aim of this paper was to review current literature to find evidence for or against the use of neuroaxial blockade in patients with aortic stenosis. METHODS: We searched PubMed for relevant articles, using the following MeSH terms: "aortic valve stenosis", "epidural anesthesia", "spinal anesthesia" and "epidural analgesia". Only English language literature was included. Papers concerning aortic stenosis and obstetrical anaesthesia were excluded. RESULTS: There are no randomised clinical trials on the subject, and existing literature is extremely sparse. Four retrospective studies and eight case reports counting a total of ten patients were found. All report successful use of neuroaxial blockade in patients with aortic stenosis, without severe haemodynamic alterations. In addition, data indicate that postepidural analgesia improves outcome compared with conventional analgesia. CONCLUSIONS: To the best of our knowledge, there is no clinical evidence supporting the notion that central regional anaesthesia has any adverse effects on patients with aortic stenosis. Carefully managed neuroaxial blockade could become a useful alternative to general anaesthesia in this patient group. However, evidence is sparse and of questionable quality. Large prospective randomised clinical trials are required to establish best practise. PMID- 28874244 TI - The Interplay between Fasting Glucose, Echocardiography, and Biomarkers: Pathophysiological Considerations and Prognostic Implications. AB - BACKGROUND: Traditional cardiovascular risk stratification tools that employ clinical risk factors are limited by their modest discriminative abilities. As such, robust cardiovascular risk assessment, including our understanding of the complex interplay between risk factors, in the primary preventive setting, remains incomplete. Phenotypical heterogeneity may be even greater among subjects with hyperglycemic conditions, i.e., prediabetes and diabetes, which is worrisome, given the dramatic global rise in mean fasting glucose levels, and the strong association with adverse cardiovascular outcomes. The unmet need for refinement or restratification of risk based on these conventional prediction models is only emphasized by our entrance into the era of precision medicine. Potential tools for closing these gaps and increasing our understanding of the pathways from risk factors through subclinical changes to manifest disease include echocardiography and circulating biomarkers. OBJECTIVES: 1) To examine whether greater fasting plasma glucose (FPG) levels were associated with left ventricular mass (LVM), geometric pattern, diastolic function, and concentrations of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-TnT) in apparently healthy, elderly subjects with a preserved LV ejection fraction +/- 50%; 2) To examine whether FPG levels modified the prognostic role of abnormal LVM, geometric pattern, diastolic dysfunction, NT-proBNP, and hs-TnT, in predicting cardiovascular morbidity and mortality; 3) To define the incremental prognostic value of NT-proBNP and hs-TnT for predicting incident cardiovascular outcomes, beyond traditional risk factors, glycemic status, and subclinical echocardiographic abnormalities; 4) To explore the associations of NT-proBNP and hs-TnT with key echocardiographic measures of LV structure and function, including the effects of FPG levels. METHODS: The thesis was based on a series of cross-sectional and prospective observational studies. The study population was derived from the echocardiography subsample (n=1,792) of the Malmo Preventive Project Re-Examination Study (MPP-RES) (2002 2006, n=18,238), a population-based screening program that included inhabitants from Malmo, Sweden, who belonged to prespecified birth cohorts between 1921-1949. Subjects, who underwent echocardiography, were randomly chosen from the three categories defined by base-line FPG, i.e., normal fasting glucose, impaired fasting glucose, and diabetes, including use of anti-diabetic medication. Blood samples for cardiovascular biomarker assessments were drawn at the time of echocardiography and kept frozen until analysis. Outcome data were obtained through national and local registries. The original echocardiography subsample was stratified into patients and apparently healthy subjects, the latter being the focus of this thesis. RESULTS: 1) Subjects with diabetes had a greater prevalence of concentric LV hypertrophy (LVH), grade 2 or 3 diastolic dysfunction, and higher hs-TnT concentrations. Subjects with impaired fasting glucose had the lowest NT-proBNP concentrations. LVMI was primarily associated with diastolic function in subjects with hyperglycemia; 2) LV diastolic dysfunction was associated with an increased risk of incident cardiovascular events, but did not provide discriminative im-provement. Concentric LVH and diastolic dysfunction were more strongly associated with adverse prognosis in subjects with hyper-glycemia. High concentrations of NT-proBNP and hs-TnT predicted incident cardiovascular events, with no effect modification by FPG; 3) NT-proBNP, but not hs-TnT, provided discriminative improvement beyond traditional risk factors, FPG, and LVH and/or diastolic dysfunction; 4) NT-proBNP and hs-TnT were associated with several echocardiographic parameters, but effect sizes were generally modest. Associations between biomarkers and echocardiographic measures were affected by hyperglycemia. CONCLUSIONS: FPG influenced the interplay between subclinical echocardiographic abnormalities, circulating biomarkers, and cardiovascular outcomes at multiple stages, in this cohort of apparently healthy, elderly subjects. Newly diagnosed diabetes, but not impaired fasting glucose, was associated with adverse subclinical changes. The associations between structural echocardiographic abnormalities and biomarker concentrations were stronger in subjects with hyperglycemia. NT-proBNP, but not echocardiographic measures or hs TnT, provided discriminative improvement on top of traditional cardiovascular risk factors. FPG further modified the prognosis re-lated to echocardiographic alterations, but not that predicted by biomarkers. Therefore, FPG should be considered when assessing markers of subclinical cardiovascular alterations. PMID- 28874245 TI - Prosthetic Joint Infection following Total Hip Arthroplasty - Incidence, Mortality and Validation of the Diagnosis in the Danish Hip Arthroplasty Register. AB - Prosthetic joint infection (PJI) is a rare, but devastating complication following primary total hip arthroplasty (THA). As PJI is a rare event, large cohorts of patients are required in order to study this complication. National arthroplasty registers offer such large and unselected cohorts, but studies have shown that these registers - used alone - underestimate the incidence of PJI. The aim of this thesis was to estimate the incidence of PJI and the mortality risk following a PJI by combining data from the Danish Hip Arthroplasty Register (DHR), the National Register of Patients (NRP), the Microbiology Databases, the Civil Registration System, the medical records, the Danish National Prescription Registry and the Clinical Biochemistry Databases. The thesis comprises the following four studies: Study I: The aim of this study was to estimate the "true" incidence of surgically treated PJI following primary THA. To estimate the true incidence, we developed an algorithm that classified the revisions as due to PJI or due to other causes. The algorithm incorporated data from the DHR, the NRP, medical records, the microbiological databases, the prescription database and the clinical biochemistry databases. The one- and five-year cumulative incidences were estimated to be 0.86% (95% confidence interval (CI): 0.77; 0.97) and 1.03% (95% CI: 0.87; 1.22), respectively. These figures are approximately 40% higher than the equivalent figures re-ported by the DHR and the NRP. Study II: The aim of the second study was to validate the PJI diagnosis in the DHR. We did this by comparing the PJI diagnosis in the DHR with the PJI diagnosis derived from the algorithm developed in Study I. We found a sensitivity of 67%, a specificity of 95%, a positive predictive value (PPV) of 77%, and a negative predictive value (NPV) of 92%. When the data from the DHR were linked with data from the microbiology databases, the sensitivity increased to 90% and the specificity also increased (to 100%) along with the PPV (98%) and the NPV (98%). Study III: The aim of the third study was to examine whether the incidence of PJI observed within the first year of primary THA in-creased in the course of the ten-year study period from 2005 to 2014. We used the validated PJI diagnosis described in Study II and found that the incidence of PJI did not appear to be increasing as the relative risk of PJI was 1.05 (95% CI: 0.82; 1.34) for the 2010-2014 period compared with the 2005-2010 period. Nor did we find any changes in the antimicrobial resistance pattern. Study IV: The aim of the fourth study was to estimate the mortality risk following a revision for PJI within one year following a primary THA. When combining data from the DHR with data from the microbiology databases, we found that the mortality risk of patients with a revision for PJI was 2.18 (95% CI: 1.54; 3.08) com-pared with the reference population, and 1.87 (95% CI: 1.11; 3.15) when compared with patients who had an aseptic revision. In conclusion, the incidence of PJI is approximately 40% higher than that reported by the NRP and the DHR. By linkage of the DHR and the microbiology databases, the validity of the PJI diagnosis can be improved notably. By such a combination of data from the DHR and the microbiology databases, we show that the incidence of PJI does not seem to be increasing and that revision for PJI is associated with a high mortality. PMID- 28874246 TI - Early-onset Coronary Artery Disease Clinical and Hereditary Aspects. AB - A family history of coronary artery disease (CAD) is an important risk factor for adverse coronary events, in particular if the disease has an early onset. The risk of CAD is influenced by genetic and environmental factors with a greater genetic contribution earlier in life. Through recent years the advances in genetic techniques has led to an increased understanding of the genetic background of CAD, which may potentially be translated into clinical use. The studies of this thesis aimed to investigate the burden of conventional risk factors and control in early-onset CAD (i.e. < 40 years), and to characterize and quantify subclinical atherosclerosis in their relatives. Furthermore, the aim was to explore the impact of common genetic risk variants on the age of onset, familial clustering and disease severity. In study I, 143 patients with early onset CAD were recruited from the Western Denmark Heart Registry and risk factor control was evaluated. The study revealed that risk factors are common in early onset CAD and that a large room for risk factor improvement remains. In study II, we used coronary computed tomography angiography to compare the coronary plaque burden and characteristics between 88 first-degree relatives of patients with early-onset CAD and 88 controls with no familial predisposition. Relatives had a significantly increased coronary plaque burden, which displayed characteristics associated with myocardial ischemia and adverse coronary events. In study III, 134 patients with early-onset CAD, a cohort of 446 late-onset CAD patients (onset > 55/65 years in males/females), and 89 healthy controls were genotyped for 45 common genetic risk variants and a genetic risk score was calculated as a measure of the polygenetic burden. Early-onset CAD patients had a modestly increased genetic burden compared with late-onset CAD patients and healthy controls; however, the burden did not associate with familial clustering of CAD. Additionally, familial clustering seemed to be stronger associated with CAD disease severity than the polygenetic burden. Our findings emphasize the hereditary component of coronary atherosclerosis and underpin the need for risk factor optimization in early-onset CAD. Furthermore, our data support that yet identified common risk variants may have little clinical relevance in the clinical setting of early-onset CAD. PMID- 28874247 TI - ? PMID- 28874248 TI - ? PMID- 28874249 TI - ? PMID- 28874250 TI - [Interventional radiology in minimally invasive treatments]. AB - Interventional radiology (IR) is a fast expanding field which includes vascular (arterial and venous) as well as non-vascular topics. IR is minimally invasive methods, which are performed under guidance of radiological modalities. The methods are in general patient-friendly and organ-sparing procedures and can often be performed on out-patient basis or with short admission to the hospital and with short reconvalescence and economic advantages compared with corresponding surgical treatments. IR has in some cases substituted former surgical procedures. Technological development has facilitated increasing IR treatment offers and indications, and there is a high level of evidence for many of the offers. PMID- 28874251 TI - [Rapid resolution of acute subdural haematoma with significant impact on clinical outcome]. AB - A 73-year-old woman was admitted to hospital due to anaemia. She suffered a minor head trauma and deteriorated to deep unconsciousness. A CT revealed an acute subdural haematoma (ASDH). Initially, she was not found to be a candidate for neurosurgical intervention, but within 24 hours her level of consciousness improved dramatically, and a renewed CT showed resolution of the ASDH. She underwent acute craniotomy with good outcome. This illustrates the importance of re-evaluation of patients with intracranial haemorrhage. PMID- 28874252 TI - [Neurosyphilis as differential diagnosis in psychiatry]. AB - A 46-year-old previously healthy man was referred to a psychiatric department after debuting with persecutory delusions. He had symptoms of Parkinson's disease as well as a significant impairment of memory and cognitive function. Neurological tests detected discrete balance and rigidity problems. Paraclinical tests were normal, and neurologists explained the symptoms as side effects to the antipsychotic medication. A lumbar puncture showed high concentrations of leukocytes and protein, and syphilis screening was positive. Neurosyphilis often debuts with psychiatric symptoms as seen in this case. PMID- 28874253 TI - [Benzodiazepines still play a role in modern psychiatric therapy]. AB - Benzodiazepines (BZ) are widely used for anxiety across psychiatric diagnoses, but for the last decades regulation has been increasingly tight due to problems with tolerance, addiction, withdrawal symptoms and cognitive side effects. Some guidelines claim that BZ only work for a few weeks, and that BZ cause traffic accidents, increased mortality and dementia. In Denmark, the use of BZ has been substantially reduced. In this article it is argued, that not all patients habituate, that most of the epidemiological findings are hampered by confounding, and that there still is a role for long-term use of BZ in the treatment of anxiety. PMID- 28874254 TI - [The significance of HIV to bone mineral density]. AB - The life expectancy in well-treated HIV-infected persons approaches that of the general population, but HIV-infected persons have a greater incidence of fractures and osteoporosis. A decrease in bone mineral density is observed primarily during the first 1-2 years of antiretroviral therapy. Dual X-ray absorptiometry scan should be considered in HIV-infected men >= 50 years and postmenopausal women. In case of osteoporosis, bisphosphonate treatment should follow guidelines for the general population. Future research should focus on pathogenesis and prevention of bone density loss in HIV. PMID- 28874255 TI - [Acute meningococcal disease in children and adolescents]. AB - Meningococcal disease is a rapidly progressing infection, which continues to cause deaths among children and adolescents. In this review, clinical signs and initial treatment of acute childhood meningococcal disease is described. Operational flow charts have been developed for assessment of non-blanching rash and initial treatment of meningococcal disease. PMID- 28874256 TI - Correction: Impact of nucleic acid and methylated H3K9 binding activities of Suv39h1 on its heterochromatin assembly. PMID- 28874257 TI - Correction: Behavioral-state modulation of inhibition is context-dependent and cell type specific in mouse visual cortex. PMID- 28874258 TI - Acoustic dose-behavioral response relationship in sea bass (Dicentrarchus labrax) exposed to playbacks of pile driving sounds. AB - The foundations of offshore wind turbines are attached to the sea bed by percussion pile driving. Pile driving sounds may affect the behavior of fish. Acoustic dose-behavioral response relationships were determined for sea bass in a pool exposed for 20 min to pile driving sounds at seven mean received root-mean square sound pressure levels [SPLrms; range: 130-166 dB re 1 MUPa; single strike sound exposure level (SELss) range: 122-158; 6 dB steps]. Initial responses (sudden, short-lived changes in swimming speed and direction) and sustained responses (changes in school cohesion, swimming depth, and speed) were quantified. The 50% initial response threshold occurred at an SELss of 131 dB re 1 MUPa2 s for 31 cm fish and 141 dB re 1 MUPa2 s for 44 cm fish; the small fish thus reacted to lower SELss than the large fish. Analysis showed that there is no evidence, even at the highest sound level, for any consistent sustained response to sound exposure by the study animals. If wild sea bass are exposed to pile driving sounds at the levels used in the present study, there are unlikely to be any adverse effects on their ecology, because the initial responses after the onset of the piling sound observed in this study were short-lived. PMID- 28874259 TI - Outcomes from a university-based low-cost in vitro fertilization program providing access to care for a low-resource socioculturally diverse urban community. AB - OBJECTIVE: To report on outcomes from a university-based low-cost and low complexity IVF program using mild stimulation approaches and simplified protocols to provide basic access to ART to a socioculturally diverse low-income urban population. DESIGN: Retrospective cohort study. SETTING: Academic infertility center. PATIENT(S): Sixty-five infertile couples were enrolled from a county hospital serving a low-resource largely immigrant population. INTERVENTIONS(S): Patients were nonrandomly allocated to one of four mild stimulation protocols: clomiphene/letrozole alone, two clomiphene/letrozole-based protocols involving sequential or flare addition of low-dose gonadotropins, and low-dose gonadotropins alone. Clinical fellows managed all aspects of cycle preparation, monitoring, oocyte retrieval, and embryo transfer under an attending preceptor. Retrieval was undertaken without administration of deep anesthesia, and laboratory interventions were minimized. All embryo transfers were performed at the cleavage stage. MAIN OUTCOME MEASURE(S): Sociomedical demographics, treatment response, and pregnancy outcomes were recorded. RESULT(S): From August 2010 to June 2016, 65 patients initiated 161 stimulation IVF cycles, which resulted in 107 retrievals, 91 fresh embryo transfers, and 40 frozen embryo transfer cycles. The mean age of patients was 33.3 years, and mean reported duration of infertility was 5.3 years; 33.5% (54/161) of cycles were cancelled before oocyte retrieval, with 13% due to premature ovulation. Overall, cumulative live birth rates per retrieval including subsequent use of frozen embryos was 29.0%; 44.6% (29/65) of patients enrolled in the program achieved pregnancy. CONCLUSION(S): Use of mild stimulation protocols, simplified monitoring, and minimized laboratory handling procedures enabled access to care in a low-resource socioculturally diverse infertile population. PMID- 28874260 TI - Endometriosis and obstetrics complications: a systematic review and meta analysis. AB - OBJECTIVE: To evaluate the effect of endometriosis on pregnancy outcomes. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women with or without endometriosis. INTERVENTION(S): Electronic databases searched from their inception until February 2017 with no limit for language and with all cohort studies reporting the incidence of obstetric complications in women with a diagnosis of endometriosis compared with a control group (women without a diagnosis of endometriosis) included. MEAN OUTCOME MEASURE(S): Primary outcome of incidence of preterm birth at <37 weeks with meta-analysis performed using the random effects model of DerSimonian and Laird to produce an odds ratio (OR) with 95% confidence interval (CI). RESULT(S): Twenty-four studies were analyzed comprising 1,924,114 women. In most of them, the diagnosis of endometriosis was made histologically after surgery. Women with endometriosis had a statistically significantly higher risk of preterm birth (OR 1.63; 95% CI, 1.32-2.01), miscarriage (OR 1.75; 95% CI, 1.29-2.37), placenta previa (OR 3.03; 95% CI, 1.50 6.13), small for gestational age (OR 1.27; 95% CI, 1.03-1.57), and cesarean delivery (OR 1.57; 95% CI, 1.39-1.78) compared with the healthy controls. No differences were found in the incidence of gestational hypertension and preeclampsia. CONCLUSION(S): Women with endometriosis have a statistically significantly higher risk of preterm birth, miscarriage, placenta previa, small for gestational age infants, and cesarean delivery. PMID- 28874261 TI - Malignancies and infection due to the human immunodeficiency virus. Are these emerging diseases? AB - Since the start of the human immunodeficiency virus (HIV) epidemic, tumour disease among patients has been significant. The collection of malignancies can be divided primarily into 2 groups: those associated with HIV (all of which are related to viral diseases) and those not associated with HIV (only some of which are associated with viral diseases). The origin of these malignancies is multifactorial, and the main causes that have led to an increase in tumour disease are immunosuppression, coinfection with oncogenic viruses and life prolongation secondary to the use of antiretroviral therapy. Establishing the general characteristics of the undiagnosed AIDS tumours is difficult, mainly because they are a highly heterogeneous group formed by malignancies of a diverse nature. The treatments do not differ from those used in the general population, although the management can be more difficult due to the late diagnosis, drug interactions and associated comorbidities. PMID- 28874262 TI - Corrigendum to 'Longitudinal prevalence and faecal shedding of Chlamydia pecorum in sheep' [The Veterinary Journal 201 (2014) 322-326]. PMID- 28874263 TI - Second neoplasms in adult patients submitted to haematopoietic stem cell transplantation. AB - BACKGROUND AND OBJECTIVE: Patients submitted to haematopoietic stem cell transplantation (HSCT) are at increased risk of late complications, such as second neoplasm (SN). The incidence and risk factors of SN in patients receiving HSCT at a single centre were analysed. PATIENTS AND METHODS: The follow-up of adult patients who received a first HSCT (autologous [auto-HSCT] or allogeneic [allo-HSCT]) between January 2000 and December 2015 was reviewed. We collected their demographic characteristics, the primary disease and type of HSCT, and analysed the cumulative incidence of SN and their risk factors. RESULTS: Of 699 transplanted patients (auto-HSCT, n=451; allo-HSCT, n=248), 42 (6%) developed SN (17 haematological and 25 solid), 31 post-auto-HSCT and 11 post-allo-HSCT. Haematologic SN were more frequent after auto-HSCT than after allo-HSCT. The median time between HSCT and SN was 4.09 years [range 0.07-13.15], with no differences between auto-HSCT and allo-HSCT. The cumulative incidence of SN was 5% (95% CI 3-6) at 5 years, 7% (95% CI 5-10) at 10 years and 11% (95% CI 8-15) at 15 years, without differences according to the type of HSCT. Only the age over 40 years correlated with an increased risk of SN. CONCLUSIONS: In this series, the incidence of post-HSCT SN was similar to that previously described. Patients submitted to an auto-HSCT showed a higher frequency of haematologic SN. A higher incidence of SN was detected in patients older than 40 at the time of HSCT. PMID- 28874264 TI - Evolutionary processes shaping diversity across the Homo lineage. AB - Recent fossil finds have highlighted extensive morphological diversity within our genus, Homo, and the co-existence of a number of species. However, little is known about the evolutionary processes responsible for producing this diversity. Understanding the action of these processes can provide insight into how and why our lineage evolved and diversified. Here, we examine cranial and mandibular variation and diversification from the earliest emergence of our genus at 2.8 Ma until the Late Pleistocene (0.126-0.0117 Ma), using statistical tests developed from quantitative genetics theory to evaluate whether stochastic (genetic drift) versus non-stochastic (selection) processes were responsible for the observed variation. Results show that random processes can account for species diversification for most traits, including neurocranial diversification, and across all time periods. Where selection was found to shape diversification, we show that: 1) adaptation was important in the earliest migration of Homo out of Africa; 2) selection played a role in shaping mandibular and maxillary diversity among Homo groups, possibly due to dietary differences; and 3) Homo rudolfensis is adaptively different from other early Homo taxa, including the earliest known Homo specimen. These results show that genetic drift, and, likely, small population sizes were important factors shaping the evolution of Homo and many of its novel traits, but that selection played an essential role in driving adaptation to new contexts. PMID- 28874265 TI - Newly discovered Neanderthal remains from Shanidar Cave, Iraqi Kurdistan, and their attribution to Shanidar 5. AB - The Neanderthal remains from Shanidar Cave, excavated between 1951 and 1960, have played a central role in debates concerning diverse aspects of Neanderthal morphology and behavior. In 2015 and 2016, renewed excavations at the site uncovered hominin remains from the immediate area where the partial skeleton of Shanidar 5 was found in 1960. Shanidar 5 was a robust adult male estimated to have been aged over 40 years at the time of death. Comparisons of photographs from the previous and recent excavations indicate that the old and new remains were directly adjacent to one another, while the disturbed arrangement and partial crushing of the new fossils is consistent with descriptions and photographs of the older discoveries. The newly discovered bones include fragments of several vertebrae, a left hamate, part of the proximal left femur, a heavily crushed partial pelvis, and the distal half of the right tibia and fibula and associated talus and navicular. All these elements were previously missing from Shanidar 5, and morphological and metric data are consistent with the new elements belonging to this individual. A newly discovered partial left pubic symphysis indicates an age at death of 40-50 years, also consistent with the age of Shanidar 5 estimated previously. Thus, the combined evidence strongly suggests that the new finds can be attributed to Shanidar 5. Ongoing analyses of associated samples, including for sediment morphology, palynology, and dating, will therefore offer new evidence as to how this individual was deposited in the cave and permit new analyses of the skeleton itself and broader discussion of Neanderthal morphology and variation. PMID- 28874266 TI - Body size, brain size, and sexual dimorphism in Homo naledi from the Dinaledi Chamber. AB - Homo erectus and later humans have enlarged body sizes, reduced sexual dimorphism, elongated lower limbs, and increased encephalization compared to Australopithecus, together suggesting a distinct ecological pattern. The mosaic expression of such features in early Homo, including Homo habilis, Homo rudolfensis, and some early H. erectus, suggests that these traits do not constitute an integrated package. We examined the evidence for body mass, stature, limb proportions, body size and dental size dimorphism, and absolute and relative brain size in Homo naledi as represented in the Dinaledi Chamber sample. H. naledi stature and body mass are low compared to reported values for H. erectus, with the exception of some of the smaller bodied Dmanisi H. erectus specimens, and overlap with larger Australopithecus and early Homo estimates. H. naledi endocranial volumes (465-560 cc) and estimates of encephalization quotient are also similar to Australopithecus and low compared to all Homo specimens, with the exception of Homo floresiensis (LB1) and the smallest Dmanisi H. erectus specimen (D4500). Unlike Australopithecus, but similar to derived members of genus Homo, the Dinaledi assemblage of H. naledi exhibits both low levels of body mass and dental size variation, with an estimated body mass index of sexual dimorphism less than 20%, and appears to have an elongated lower limb. Thus, the H. naledi bauplan combines features not typically seen in Homo species (e.g., small brains and bodies) with those characteristic of H. erectus and more recent Homo species (e.g., reduced mass dimorphism, elongated lower limb). PMID- 28874267 TI - Facing the facts: The Runx2 gene is associated with variation in facial morphology in primates. AB - The phylogenetic and adaptive factors that cause variation in primate facial form including differences among the major primate clades and variation related to feeding and/or social behavior-are relatively well understood. However, comparatively little is known about the genetic mechanisms that underlie diversity in facial form in primates. Because it is essential for osteoblastic differentiation and skeletal development, the runt-related transcription factor 2 (Runx2) is one gene that may play a role in these genetic mechanisms. Specifically, polymorphisms in the QA ratio (determined by the ratio of the number of polyglutamines to polyalanines in one functional domain of Runx2) have been shown to be correlated with variation in facial length and orientation in other mammal groups. However, to date, the relationship between variation in this gene and variation in facial form in primates has not been explicitly tested. To test the hypothesis that the QA ratio is correlated with facial form in primates, the current study quantified the QA ratio, facial length, and facial angle in a sample of 33 primate species and tested for correlation using phylogenetic generalized least squares. The results indicate that the QA ratio of the Runx2 gene is positively correlated with variation in relative facial length in anthropoid primates. However, no correlation was found in strepsirrhines, and there was no correlation between facial angle and the QA ratio in any groups. These results suggest that, in primates, the QA ratio of the Runx2 gene may play a role in modulating facial size, but not facial orientation. This study therefore provides important clues about the genetic and developmental mechanisms that may underlie variation in facial form in primates. PMID- 28874268 TI - Do juveniles help or hinder? Influence of juvenile offspring on maternal behavior and reproductive outcomes in wild chimpanzees (Pan troglodytes). AB - Compared to great apes, humans maintain a relatively rapid reproductive pace despite long periods of dependency. This seemingly contradictory set of traits is made possible by weaning offspring before nutritional independence and alloparents who help provide care. In traditional societies, this help may be provided to mothers in part by their juvenile offspring who carry, supervise, or provision younger siblings. In contrast to humans, chimpanzees (Pan troglodytes) are nutritionally independent after weaning, yet juveniles continue to travel with their mother and younger sibling for an additional 4-5 years. This continued association could be costly to the mother if she continues to invest in weaned offspring. Alternately, while juvenile chimpanzees do not typically provision younger siblings, their presence and social interaction with infants may allow mothers to focus on other tasks. In this study, we investigate the costs and benefits to mothers of continued association with juveniles in wild chimpanzees. Using 26 years of long-term behavioral data we examined how maternal activity budgets varied based on the presence of a dependent juvenile offspring. We found that continued social interaction between mothers and juveniles does not influence the mother's time allocated to interacting with the younger infant, her feeding, resting, or travel time, or time socializing with other community members. Instead, mothers may benefit from the additional social interaction and/or relationship with their older offspring. Using 45 years of demographic data we found that those offspring who had an older sibling tended to be more likely to survive each year from birth to 8 years than those without an older sibling. Additionally, interbirth intervals were more likely to end when the female had an older offspring present. A mutually beneficial mother-juvenile dynamic in great apes provides insight into continued association between mothers and offspring after nutritional independence and the emergence of juvenile helping during hominin evolution. PMID- 28874269 TI - Locomotion and basicranial anatomy in primates and marsupials. AB - There is ongoing debate in paleoanthropology about whether and how the anatomy of the cranium, and especially the cranial base, is evolving in response to locomotor and postural changes. However, the majority of studies focus on two dimensional data, which fails to capture the complexity of cranial anatomy. This study tests whether three-dimensional cranial base anatomy is linked to locomotion or to other factors in primates (n = 473) and marsupials (n = 231). Results indicate that although there is a small effect of locomotion on cranial base anatomy in primates, this is not the case in marsupials. Instead, facial anatomy likely drives variation in cranial base anatomy in both primates and marsupials, with additional roles for body size and brain size. Although some changes to foramen magnum position and orientation are phylogenetically useful among the hominoids, they do not necessarily reflect locomotion or positional behavior. The interplay between locomotion, posture, and facial anatomy in primates requires further investigation. PMID- 28874271 TI - In pursuit of our ancestors' hand laterality. AB - The aim of this paper is to apply a previously published method (Bargallo and Mosquera, 2014) to the archaeological record, allowing us to identify the hand laterality of our ancestors and determine when and how this feature, which is exhibited most strongly in humans, appeared in our evolutionary history. The method focuses on identifying handedness by looking at the technical features of the flakes produced by a single knapper, and discovering how many flakes are required to ascertain their hand preference. This method can potentially be applied to the majority of archaeological sites, since flakes are the most abundant stone tools, and stone tools are the most widespread and widely preserved remains from prehistory. For our study, we selected two Spanish sites: Gran Dolina-TD10.1 (Atapuerca) and Abric Romani (Barcelona), which were occupied by pre-Neanderthal and Neanderthal populations, respectively. Our analyses indicate that a minimum number of eight flakes produced by the same knapper is required to ascertain their hand preference. Even though this figure is relatively low, it is quite difficult to obtain from many archaeological sites. In addition, there is no single technical feature that provides information about handedness, instead there is a combination of eight technical features, localised on the striking platforms and ventral surfaces. The raw material is not relevant where good quality rocks are used, in this case quartzite and flint, since most of them retain the technical features required for the analysis. Expertise is not an issue either, since the technical features analysed here only correlate with handedness (Bargallo and Mosquera, 2014). Our results allow us to tentatively identify one right-handed knapper among the pre-Neanderthals of level TD10.1 at Gran Dolina (Atapuerca), while four of the five Neanderthals analysed from Abric Romani were right-handed. The hand preference of the fifth knapper from that location (AR5) remains unclear. PMID- 28874270 TI - The evolution of the platyrrhine talus: A comparative analysis of the phenetic affinities of the Miocene platyrrhines with their modern relatives. AB - Platyrrhines are a diverse group of primates that presently occupy a broad range of tropical-equatorial environments in the Americas. However, most of the fossil platyrrhine species of the early Miocene have been found at middle and high latitudes. Although the fossil record of New World monkeys has improved considerably over the past several years, it is still difficult to trace the origin of major modern clades. One of the most commonly preserved anatomical structures of early platyrrhines is the talus. This work provides an analysis of the phenetic affinities of extant platyrrhine tali and their Miocene counterparts through geometric morphometrics and a series of phylogenetic comparative analyses. Geometric morphometrics was used to quantify talar shape affinities, while locomotor mode percentages (LMPs) were used to test if talar shape is associated with locomotion. Comparative analyses were used to test if there was convergence in talar morphology, as well as different models that could explain the evolution of talar shape and size in platyrrhines. Body mass predictions for the fossil sample were also computed using the available articular surfaces. The results showed that most analyzed fossils exhibit a generalized morphology that is similar to some 'generalist' modern species. It was found that talar shape covaries with LMPs, thus allowing the inference of locomotion from talar morphology. The results further suggest that talar shape diversification can be explained by invoking a model of shifts in adaptive peak to three optima representing a phylogenetic hypothesis in which each platyrrhine family occupied a separate adaptive peak. The analyses indicate that platyrrhine talar centroid size diversification was characterized by an early differentiation related to a multidimensional niche model. Finally, the ancestral platyrrhine condition was reconstructed as a medium-sized, generalized, arboreal, quadruped. PMID- 28874272 TI - Postcrania of the most primitive euprimate and implications for primate origins. AB - The fossil record of early primates is largely comprised of dentitions. While teeth can indicate phylogenetic relationships and dietary preferences, they say little about hypotheses pertaining to the positional behavior or substrate preference of the ancestral crown primate. Here we report the discovery of a talus bone of the dentally primitive fossil euprimate Donrussellia provincialis. Our comparisons and analyses indicate that this talus is more primitive than that of other euprimates. It lacks features exclusive to strepsirrhines, like a large medial tibial facet and a sloping fibular facet. It also lacks the medially positioned flexor-fibularis groove of extant haplorhines. In these respects, the talus of D. provincialis comes surprisingly close to that of the pen-tailed treeshrew, Ptilocercus lowii, and extinct plesiadapiforms for which tali are known. However, it differs from P. lowii and is more like other early euprimates in exhibiting an expanded posterior trochlear shelf and deep talar body. In overall form, the bone approximates more leaping reliant euprimates. The phylogenetically basal signal from the new fossil is confirmed with cladistic analyses of two different character matrices, which place D. provincialis as the most basal strepsirrhine when the new tarsal data are included. Interpreting our results in the context of other recent discoveries, we conclude that the lineage leading to the ancestral euprimate had already become somewhat leaping specialized, while certain specializations for the small branch niche came after crown primates began to radiate. PMID- 28874273 TI - Early hominin landscape use in the Lower Omo Valley, Ethiopia: Insights from the taphonomical analysis of Oldowan occurrences in the Shungura Formation (Member F). AB - The Oldowan archeological record of the Shungura Formation, Member F (Lower Omo valley, Ethiopia) comprises more than one hundred occurrences distributed within archeological complexes, where multiple small spots were found in association with one or two larger occurrences. Such spatial patterning could reflect hominin spatial behavior, repeated occupations within a single sedimentary unit, or taphonomic and/or collection biases. Here we test these hypotheses by way of a geoarcheological and taphonomical analysis using four criteria to assess the preservation of the lithic assemblages: (1) size composition, (2) artifact abrasion, (3) bone abrasion, and (4) orientations of lithic artifacts and bones (i.e., fabrics). We propose a new model of taphonomically induced spatial patterning where the multiple, small, well circumscribed occurrences result primarily from post-depositional processes and therefore do not reflect any underlying behavioral patterns. The large number of archeological occurrences documented in Member F, therefore, corresponds to a limited number of primary occupations (<10). The archeological occupation is mainly restricted to the lower part of Member F and may reflect a single or a small number of occupation episodes, which were located on previous levees of the paleo-Omo River, in nearby floodplain areas, or on the riverbank. This strongly suggests that most of the knapping activities originally took place close to the river. This preference of the Omo toolmakers for riverine environments could explain the scarcity of archeological material in the upper part of Member F that comprises primarily distal floodplain sedimentary facies. PMID- 28874274 TI - Evidence of Neanderthals in the Balkans: The infant radius from Kozarnika Cave (Bulgaria). AB - Excavations conducted by a Bulgarian-French team at Kozarnika Cave (Balkans, Bulgaria) during several seasons yielded a long Paleolithic archaeological sequence and led to the discovery of important faunal, lithic, and human samples. This paper aims to describe the unpublished radius shaft of an infant who died approximately before the sixth month postnatal that was recovered from layer 10b, which contained East Balkan Levallois Mousterian with bifacial leaf points. The layer was dated between 130 and 200 ka (large mammals biochronology) and between 128 +/- 13 ka and 183 +/- 14 ka (OSL), i.e. OIS6. Here we show that, given the scarcity of Middle Pleistocene infant remains in general, and Middle Paleolithic human remains from this part of Eastern Europe in particular, the study of the Kozarnika specimen is of special interest. We discuss its place in the Middle Pleistocene European hominine record and substantiate the hypothesis of early Neanderthal presence in the eastern Balkans. PMID- 28874275 TI - Paleolithic subsistence strategies and changes in site use at Klissoura Cave 1 (Peloponnese, Greece). AB - Klissoura Cave 1 in southern Greece preserves a long archaeological sequence that spans roughly 90,000 years and includes Middle Paleolithic, Uluzzian, Upper Paleolithic, and Mesolithic deposits. The site provides a unique opportunity to examine diachronic change and shifts in the intensity of site use across the Late Pleistocene. There is an overall picture of the intensified use of faunal resources at the site, evidenced by a shift from large to small game, and to small fast-moving taxa in particular. This trend is independent of climatic change and fluctuations in site use, and most likely reflects a broader, regional growth of hominin populations. At the same time, multiple lines of evidence (e.g., input of artifacts and features, sedimentation mechanisms, and intensification of faunal resources) indicate that the intensity of site use changed, with a sharp increase from the Middle Paleolithic to Aurignacian. This allows us to address a fundamental issue in the study of human evolution: differences in population size and site use between Neandertals and modern humans. At Klissoura Cave 1, the increase in occupation intensity might be related to population growth or larger group size, but it might also be due to changes in season of site use, more favorable environmental conditions at the beginning of the Upper Paleolithic, and/or changes in the composition of people occupying the site. These explanations are not necessarily mutually exclusive, and indeed the data support a combination of factors. Ascribing the increase in occupation intensity to larger Upper Paleolithic populations more broadly is difficult, particularly because there is little consensus on this topic elsewhere in Eurasia. The data are complicated and vary greatly between sites and regions. This makes Klissoura Cave 1, as the only currently available case study in southeastern Europe, a critical example in understanding the range of variation in demography and site use across the Middle to Upper Paleolithic transition. PMID- 28874277 TI - Corrigendum to "The effect of the stability threshold on time to stabilization and its reliability following a single leg drop jump landing" [J. Biomech. 49(3) (2016) 496-501]. PMID- 28874276 TI - The costal remains of the El Sidron Neanderthal site (Asturias, northern Spain) and their importance for understanding Neanderthal thorax morphology. AB - The study of the Neanderthal thorax has attracted the attention of the scientific community for more than a century. It is agreed that Neanderthals have a more capacious thorax than modern humans, but whether this was caused by a medio lateral or an antero-posterior expansion of the thorax is still debated, and is key to understanding breathing biomechanics and body shape in Neanderthals. The fragile nature of ribs, the metameric structure of the thorax and difficulties in quantifying thorax morphology all contribute to uncertainty regarding precise aspects of Neanderthal thoracic shape. The El Sidron site has yielded costal remains from the upper to the lower thorax, as well as several proximal rib ends (frequently missing in the Neanderthal record), which help to shed light on Neanderthal thorax shape. We compared the El Sidron costal elements with ribs from recent modern humans as well as with fossil modern humans and other Neanderthals through traditional morphometric methods and 3D geometric morphometrics, combined with missing data estimation and virtual reconstruction (at the 1st, 5th and 11th costal levels). Our results show that Neanderthals have larger rib heads and articular tubercles than their modern human counterparts. Neanderthal 1st ribs are smaller than in modern humans, whereas 5th and 11th ribs are considerably larger. When we articulated mean ribs (size and shape) with their corresponding vertebral elements, we observed that compared to modern humans the Neanderthal thorax is medio-laterally expanded at every level, especially at T5 and T11. Therefore, in the light of evidence from the El Sidron costal remains, we hypothesize that the volumetric expansion of the Neanderthal thorax proposed by previous authors would mainly be produced by a medio-lateral expansion of the thorax. PMID- 28874278 TI - Characterization of the age-dependent shape of the pediatric thoracic spine and vertebrae using generalized procrustes analysis. AB - Generalized Procrustes Analysis (GPA) is a superimposition method used to generate size-invariant distributions of homologous landmark points. Several studies have used GPA to assess the three-dimensional (3D) shapes of or to evaluate sex-related differences in the human brain, skull, rib cage, pelvis and lower limbs. Previous studies of the pediatric thoracic vertebrae suggest that they may undergo changes in shape asa result of normative growth. This study uses GPA and second order polynomial equations to model growth and age- and sex related changes in shape of the pediatric thoracic spine. We present a thorough analysis of the normative 3D shape, size, and orientation of the pediatric thoracic spine and vertebrae as well as equations which can be used to generate models of the thoracic spine and vertebrae for any age between 1 and 19years. Such models could be used to create more accurate 3D reconstructions of the thoracic spine, generate improved age-specific geometries for finite element models (FEMs) and used to assist clinicians with patient-specific planning and surgical interventions for spine deformity. PMID- 28874279 TI - Midwifery Education. PMID- 28874280 TI - Response to Edith Cowan students. PMID- 28874281 TI - Response to Letter to the Editor by Council of Deans of Nursing and Midwifery. PMID- 28874282 TI - SMAD4 gene mutation increases the risk of aortic dilation in patients with hereditary haemorrhagic telangiectasia. AB - BACKGROUND: Mutations in the genes ENG, ACVRL1 and SMAD4 that are part of the transforming growth factor-beta signalling pathway cause hereditary haemorrhagic telangiectasia (HHT). Mutations in non-HHT genes within this same pathway have been found to associate with aortic dilation. Therefore, we investigated the presence of aortic dilation in a large cohort of HHT patients as compared to non HHT controls. METHODS: Chest computed tomography of consecutive HHT patients (ENG, ACVRL1 and SMAD4 mutation carriers) and non-HHT controls were reviewed. Aortic root dilation was defined as a z-score>1.96. Ascending and descending aorta dimensions were corrected for age, gender and body surface area. RESULTS: In total 178 subjects (57.3% female, mean age 43.9+/-14.9years) were included (32 SMAD4, 47 ENG, 50 ACVRL1 mutation carriers and 49 non-HHT controls). Aortopathy was present in a total of 42 subjects (24% of total). Aortic root dilatation was found in 31% of SMAD4, 2% of ENG, 6% of ACVRL1 mutation carriers, and 4% in non HHT controls (p<0.001). The aortic root diameter was 36.3+/-5.2mm in SMAD4 versus 32.7+/-3.9mm in the non-SMAD4 group (p=0.001). SMAD4 was an independent predictor for increased aortic root (beta-coefficient 3.5, p<0.001) and ascending aorta diameter (beta-coefficient 1.6, p=0.04). CONCLUSIONS: SMAD4 gene mutation in HHT patients is independently associated with a higher risk of aortic root and ascending aortic dilation as compared to other HHT patients and non-HHT controls. PMID- 28874283 TI - Mortality in adults with congenital heart disease. AB - AIM: Retrospective ascertainment of the causes of mortality in the adult congenital heart disease (ACHD) cohort of the Royal Melbourne Hospital (RMH). METHODS: Deceased patients (n=73) of the 2519 ACHD patients in the Royal Melbourne Hospital registry (commenced in 1991) were identified. Retrospective analysis was undertaken. Age, gender of deceased individuals, and frequency and cause of death in different congenital diagnosis groups was explored. RESULTS: Between 1991 and 2015, death occurred in 3.3% of the ACHD cohort. Median age at death was 32years (IQR 26-41.5) and 51% were male. The most frequent underlying cardiac conditions were Eisenmenger's syndrome (22%), pulmonary atresia and ventricular septal defect+/-major aorto-pulmonary collateral arteries (12%), Tetralogy of Fallot (10%), transposition of great arteries (TGA) with intact ventricular septum (8%), single ventricle (8%) and congenitally corrected TGA (5%). The cause of death was available from medical records in 60 (82%) of the 73 patients. The majority of deaths were due to cardiac causes (67%) including sudden death (40%), heart failure (13%), and documented ventricular arrhythmias (8%). The most common non-cardiac cause of death was sepsis (10%). CONCLUSION: The majority of deaths in this group were due to cardiac causes with sudden death and heart failure being the most common. Identification of risk factors for sudden death might assist identification of patients who may benefit from preventative therapies including implantable cardiac defibrillator. PMID- 28874284 TI - Gender-specific care for adults with congenital heart disease: A look in the future? PMID- 28874285 TI - International collaborative initiative towards improving the lives of patients after the Fontan operation: A call for action. PMID- 28874286 TI - SMAD4 gene mutation and risk of aortic dilation: Lessons from hereditary hemorrhagic telangiectasia. PMID- 28874287 TI - Can we do more to risk stratify and improve survival in ACHD? PMID- 28874288 TI - Atrial fibrillation: Utility of CHADS2 and CHA2DS2-VASc scores as predictors of readmission, mortality and resource utilization. AB - BACKGROUND: CHADS2 and CHA2DS2-VASc scores are widely used for thromboembolic risk assessment in Atrial Fibrillation(AF) cohort, however further utilization to predict outcomes is understudied. METHOD: HCUP's National Readmission Data(NRD) 2013 was queried for AF admissions using ICD-9-CM code 427.31 in principal diagnosis field. Patients with mitral valve disease or repair/or replacement were excluded to estimate population with non-valvular AF only. CHADS2 and CHA2DS2 VASc were calculated for each patient. Hierarchical two-level logistic and linear models were used to evaluate study outcomes in terms of mortality, 30 or 90-day readmissions, length of stay(LOS) and cost. RESULT: Of 116,450 principal non valvular AF admissions(50.2% female and 43.1% age>=75years) 29,179 patients were readmitted, with total 40,959 readmissions. Higher CHADS2 and CHA2DS2-VASc score were associated with increased mortality from 0.4% for CHADS2 of 0 to 3.2% for score of 6 and from 0.2% for CHA2DS2-VASc of 0 to 3.2% for score>=8. LOS increased from 2.20days for CHADS2 of 0 to 5.08days for score of 6, while cost increased from $7888 to $11,151. 30-day readmission rate increased from 8.9% for CHADS2 of 0 to 26.0% for score of 6, and 90-day readmission rate increased from 15.2% to 39%. CHA2DS2-VASc scoring similarly demonstrated a trend towards increasing readmission rate, LOS and cost for higher scores. Also, similar results were seen in hierarchical modeling with increment of CHADS2 and CHA2DS2 VASc scores. CONCLUSION: CHADS2 and CHA2DS2-VASc scores can be used as quick surrogate markers for predicting outcomes beyond thromboembolic risk. Physician familiarity with these systems makes them easy to use bedside clinical tools to improve outcomes and resource allocation. PMID- 28874289 TI - Clinical predictors of challenging atrioventricular node ablation procedure for rate control in patients with atrial fibrillation. AB - INTRODUCTION: Atrioventricular node (AVN) ablation is usually a simple procedure but may sometimes be challenging. We aimed at identifying pre-procedural clinical predictors of challenging AVN ablation. METHODS: Patients referred for AVN ablation from 2009 to 2015 were retrospectively included. Baseline clinical data, procedural variables and outcomes of AVN ablation were collected. A "challenging procedure" was defined 1) total radiofrequency delivery to get persistent AVN block>=400s, 2) need for left-sided arterial approach or 3) failure to obtain AVN ablation. RESULTS: 200 patients were included (71+/-10years). A total of 37 (18.5%) patients had "challenging" procedures (including 9 failures, 4.5%), while 163 (81.5%) had "non-challenging" ablations. In multivariable analysis, male sex (Odds ratio (OR)=4.66, 95% confidence interval (CI): 1.74-12.46), body mass index (BMI, OR=1.08 per 1kg/m2, 95%CI 1.01-1.16), operator experience (OR=0.40, 95%CI 0.17-0.94), and moderate-to-severe tricuspid regurgitation (TR, OR=3.65, 95%CI 1.63-8.15) were significant predictors of "challenging" ablations. The proportion as a function of number of predictors was analyzed (from 0 to 4, including male sex, operator inexperience, a BMI>23.5kg/m2 and moderate-to-severe TR). There was a gradual increase in the risk of "challenging" procedure with the number of predictors by patient (No predictor: 0%; 1 predictor: 6.3%; 2 predictors: 16.5%; 3 predictors: 32.5%; 4 predictors: 77.8%). CONCLUSIONS: Operator experience, male sex, higher BMI and the degree of TR were independent predictors of "challenging" AVN ablation procedure. The risk increases with the number of predictors by patient. PMID- 28874290 TI - The CHADS2 and CHA2DS2-VASc scores for predicting healthcare utilization and outcomes: Observations on the Appropriate Use and Misuse of Risk scores. PMID- 28874291 TI - His bundle ablation. Simple things aren't always easy. PMID- 28874292 TI - Malignant cardiac phenotypic expression of Danon disease (LAMP2 cardiomyopathy). AB - INTRODUCTION: Danon disease is an X-linked lysosomal condition that causes a deficiency of lysosome-associated membrane protein 2 (LAMP2) gene. It is characterized clinically by a triad of skeletal myopathy, cardiomyopathy, and intellectual disability. METHODS: We examined clinical, echocardiographic, and genetic data on 5 patients with Danon disease, highlighting their clinical course and outcomes. RESULTS: All patients presented phenotypically with hypertrophic cardiomyopathy and later developed systolic dysfunction. The mean age at diagnosis was 19years (11-31years). All patients had diastolic dysfunction (mean e' of 5cm/s [3.5-6cm/s], mean E/e' of 17 [15-21]). Three patients required cardiac transplantation (ages 15, 27, and 42). Of the two deaths in this group, both were in women. CONCLUSION: We highlight the aggressive cardiac phenotype of Danon disease in our clinical experience with rapid progression to end-stage cardiomyopathy; this progression occurred in both men and women. A timely diagnosis and an early referral for cardiac transplantation is crucial for improved outcomes. PMID- 28874294 TI - Cardiac Danon disease: Insights and challenges. PMID- 28874293 TI - A plea for an early ultrasound-clinical integrated approach in patients with acute heart failure. A proactive comment on the ESC Guidelines on Heart Failure 2016. AB - BACKGROUND: The European Association of Cardiology (ESC) Guidelines on the diagnosis and treatment of acute heart failure (AHF) indicate prompt therapy initiation and performance of relevant investigations as paramount. Specifically, echocardiography prior to treatment is advocated only with hemodynamic instability, and the evaluation of clinical signs of peripheral perfusion and congestion is suggested as guidance for early interventions. Given the growing body of evidence on the diagnostic/monitoring capabilities of bedside ultrasound (including focused cardiac ultrasound, comprehensive echocardiography, lung ultrasound), we discuss the potential benefit of an integrated clinical/ultrasound approach at the very early stages of acute heart failure. METHODS AND RESULTS: We proposed a narrative review of the current evidence on the clinical-ultrasound integrated approach to AHF, with special emphasis on the components of the early diagnostic-therapeutic workup where cardiac, inferior vena cava and lung ultrasound showed high diagnostic accuracy and the capability of substantially changing an exclusively clinically-oriented patient management. A proactive comment to the ESC guidelines is made, suggesting an integration of clinical and biochemical assessment, as defined by guidelines, with combined bedside ultrasound on may help in the definition of AHF pathophysiology and treatment. CONCLUSION: A multi-organ integrated clinical-ultrasound approach should be advocated as part of the clinical-diagnostic workup at AHF very early phase. Whenever competence and technology available, bedside ultrasound, along with clinical and biochemical assessment, should target AHF profiling, identify the cause of AHF, and subsequently aid disease course and response to treatment monitoring. PMID- 28874295 TI - The "hands-on" patient-centered method: An old approach for a new perspective in acute heart failure. PMID- 28874296 TI - International opinion on priorities in research for small abdominal aortic aneurysms and the potential path for research to impact clinical management. PMID- 28874297 TI - Patients with non-ST segment elevation acute coronary syndromes managed without coronary revascularization: A population needing treatment improvement. AB - NSTE-ACS patients are a heterogeneous population, with different clinical features and prognosis. A large proportion of them is medically managed, without any revascularization. In the EYSHOT and FAST-MI registries such patients were 40% and 35%, respectively. These patients are at higher risk of adverse cardiovascular events and have a worse prognosis compared with those receiving revascularization. Medically managed NSTE-ACS patients consist of different subgroups: those not undergoing coronary angiography, those without significant coronary artery disease, and those with coronary stenoses not referred to revascularization. Patients with NSTE-ACS for whom a conservative strategy without coronary angiogram is planned must be very carefully selected. In patients with comorbidities, frailty, or advanced age, a careful balance between benefits and risks is needed to choice the management strategy (perform or not coronary angiography and/or revascularization), as evidence-based medicine data are lacking in the setting of frailty and comorbidities. In this decisional process, it should be also taken into consideration the role of coronary anatomy in risk stratification and treatment guidance. NSTE-ACS patients managed without revascularization less frequently receive guideline-recommended pharmacological treatment. Dual antiplatelet therapy (DAPT) is recommended for 12months also in medically managed patients, after careful balancing of ischemic and bleeding risk. In these patients it is mandatory to optimize pharmacological treatment, including antiplatelet therapy, to improve outcome. In NSTE-ACS medically managed, the proportion of patients discharged with DAPT should be increased in comparison with current practice, and the use of ticagrelor in place of clopidogrel should be considered in selected patients. PMID- 28874298 TI - Survival and resource utilization in patients with chest pain evaluated with cardiac troponin T compared with high-sensitivity cardiac troponin T. AB - BACKGROUND: It is uncertain how the implementation of high-sensitivity cardiac troponin T (hs-cTnT) has affected the survival of patients with chest pain in the emergency department (ED). We studied prognosis and resource utilization in terms of coronary angiographies and revascularizations (percutaneous coronary intervention or coronary artery bypass grafting) in patients evaluated with hs cTnT compared with conventional troponin T (cTnT). METHODS: All patients >25years presenting with chest pain and at least one troponin level analyzed in the ED at the Karolinska University Hospital, Sweden, were included. Hazard ratios (HR) for all-cause mortality, coronary angiographies and revascularizations were adjusted for age, sex and comorbidities during 1year of follow-up comparing patients tested with hs-cTnT (December 10, 2010 to December 31, 2013) with patients tested with cTnT (January 1, 2009 to December 9, 2010). RESULTS: In total, 31,904 patients were included (n=12,485 tested with cTnT and n=24,729 using hs-cTnT). Patient characteristics, comorbidities, and medications were similar during the study period. The absolute risk of all-cause mortality was 3.7% for those tested with cTnT compared with 3.4% for hs-cTnT. After adjustment for confounders, an increased all-cause mortality was observed for patients tested with hs-cTnT (HR 1.15; 95% confidence interval (CI) 1.02-1.29). Coronary angiographies increased by 13% (HR 1.13; 95% CI 1.00-1.28) and revascularizations by 18% (HR 1.18; 95% CI 1.01-1.37) when using hs-cTnT. CONCLUSIONS: In an observational cohort study including patients with chest pain in the ED we found a small increase in mortality, coronary angiographies and revascularizations after the introduction of hs-cTnT. PMID- 28874299 TI - Aggressive management of non-ST-segment elevation acute coronary syndrome: Evidence or faith? PMID- 28874300 TI - Challenges in using high-sensitive troponin reporting in clinical practice-The important role of appropriate use in the context of clinical evaluation. PMID- 28874301 TI - Polymer-free amphilimus-eluting stent versus biodegradable polymer biolimus eluting stent in patients with and without diabetes mellitus. AB - OBJECTIVES: This study sought to compare clinical outcome of polymer-free amphilimus-eluting stent (PF-AES) versus biodegradable-polymer biolimus-eluting stent (BD-BES) in "all-comer" diabetes mellitus (DM) and non-DM patients who underwent percutaneous coronary intervention. BACKGROUND: The PF-AES has shown promising preliminary results in patients with DM. METHODS: Data from 2 multicentre-national registries (the ASTUTE and the INSPIRE-1) were used to analyse 1776 patients stratified in non-DM and DM. A double 1:1 propensity-score matched analysis (PF-AES vs. BD-BES) was performed in each group to adjust for clinical and procedural characteristics. Primary stent-efficacy and stent-safety endpoints were 1-year target-lesion revascularization (TLR) and target-lesion failure (TLF, composed of cardiac-death, target-vessel myocardial infarction and any TLR). RESULTS: After propensity-score matching, 850 patients were stratified as non-DM (425 PF-AES/425 BD-BES) and 480 as DM patients (240 PF-AES/240 BD-BES). Both TLF (20 of 425 [5%] vs. 24 of 425 [6%]; Plog-rank=0.527) and TLR (9 of 425 [2%] vs. 18 of 425 [4%]; Plog-rank=0.079) were similar between PF-AES and BD-BES in non-DM patients. In DM, TLF (12 of 240 [5%] vs. 31 of 240 [13%]; Plog rank=0.002) and TLR (9 of 240 [4%] vs. 21 of 240 [9%]; Plog-rank=0.019) were significantly lower in PF-AES compared to BD-BES. Upon multivariate analysis, the most powerful predictors of TLF were chronic kidney disease in non-DM (OR 4.24, 95% CI: 2.07-8.70, p<0.001) and stent type in DM patients (OR 2.76, 1.36-5.56, p=0.005). CONCLUSIONS: This matched-cohort study suggests that PF-AES has better safety and efficacy profile than BD-BES in patients with DM. PMID- 28874303 TI - Airway Management in an Infant with a Large Supraglottic Mass after Failed Fiberoptic Intubation. AB - BACKGROUND: Fiberoptic bronchoscope-guided tracheal intubation is the gold standard for managing patients with supraglottic growths. In infants with a large and overhanging epiglottis, the success of fiberoptic-guided intubation relies heavily on the available space between the inferior surface of the epiglottis and the posterior pharyngeal wall or, more specifically, the superior surface of the supraglottic growth. CASE REPORT: We describe the inability to negotiate the tip of the fiberscope between the epiglottis and the supraglottic growth and the successful use of direct laryngoscopy to improve the available space along with the usefulness of "bubbling of air" to locate the glottic opening in an infant. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We emphasize the role of the emergency physician in managing such patients. Most of the time, the setting is not ideal in such emergency situations and the most qualified clinician to treat them is the emergency physician. The knowledge and skills of the emergency physician, along with awareness of the possible techniques for airway management, can be lifesaving. PMID- 28874302 TI - Psychiatric Emergencies for Physicians: Clinical Management and Approach to Distinguishing Pheochromocytoma From Psychiatric and Thyrotoxic Diseases in the Emergency Department. PMID- 28874305 TI - Vitamin D supplementation in the critically ill: Response letter to interesting points. PMID- 28874304 TI - Effect of Cricoid Pressure on the Insertion Efficacy of Six Supraglottic Devices: A Crossover Randomized Simulation Trial. AB - BACKGROUND: No study has ever compared the efficacy of various types of supraglottic devices (SGDs) for securing the airway under cricoid pressure. OBJECTIVE: This study aimed to evaluate the efficacy of six SGDs, LMA-ProSeal (ProSeal), LMA-Classic (Classic), Laryngeal Tube (LT), LMA-Supreme (Supreme), air Q (air-Q), and i-gel (i-gel), in airway management under cricoid pressure using a manikin. METHODS: Fifteen novice doctors and 16 experienced doctors used the six SGDs under cricoid or sham pressure on an adult manikin. Insertion time, successful ventilation rate, and subjective insertion difficulty on a visual analogue scale (VAS) were measured. RESULTS: Both novice and experienced doctors had a significantly lower ventilation success rate under cricoid pressure than under sham pressure when using the ProSeal, Classic, and LT, but not when using the other three SGDs. Novice doctors required a significantly longer insertion time under cricoid pressure than under sham pressure with all SGDs. Experienced doctors required a significantly longer insertion time under cricoid pressure than with sham pressure when using the ProSeal, Classic, and LT, but not when using the other three SGDs. Subjective insertion difficulty on VAS was significantly higher under cricoid pressure than under sham pressure with all six SGDs. CONCLUSION: Ventilation success rate under cricoid pressure was significantly lower than under sham pressure when using the ProSeal, Classic, and LT, but not when using the other three SGDs in both novice and experienced doctors. PMID- 28874306 TI - Visible light photocatalytic disintegration of waste activated sludge for enhancing biogas production. AB - Biogas production using waste activated sludge (WAS) is one of the most demanding technologies for sludge treatment and generating energy in sustainable manner. The present study deals with the photocatalytic pretreatment of WAS using ZnO ZnS@polyaniline (ZnO-ZnS@PANI) nanocomposite as means for increasing its degradability for improved biogas production by anaerobic digestion (AD). Photocatalysis accelerated the hydrolysis of WAS and increased the sCOD by 6.7 folds after 6 h and transform tCOD into bioavailable sCOD. After the AD of WAS, a removal of organic matter (60.6%) and tCOD (69.3%) was achieved in photocatalytic pretreated sludge. The biogas production was 1.6 folds higher in photocatalytic sludge with accumulative biogas up to 1645.1 ml L-1vs after 45 days compared with the raw sludge (1022.4 ml L-1VS). Moreover, the photocatalysis decrease the onset of methanogenesis from 25 to 12 days while achieve the maximum conversion rate of reducing sugars into organic acids at that time. These results suggested that photocatalysis is an efficient pretreatment method and ZnO-ZnS@PANI can degrade sludge efficiently for enhance biogas production in anaerobic digestion process. PMID- 28874307 TI - Prosthetic mitral valve paravalvular leak: A problem that requires dexterity. AB - Prosthetic valve paravalvular leak (PVL) is a known and relatively common complication of surgical valve replacement, which may lead to significant morbidity. Patients with significant mitral valve replacement (MVR) PVL typically present with symptoms of heart failure and elevated filling pressures or with hemolytic anemia. Percutaneous closure of these leaks has become the preferred therapy. Percutaneous closure of MVR PVL can be technically challenging, given the anatomy of the approach (trans-septal, trans-apical), the level of associated comorbidities and the geographic location of the paravalvular defect. Steerable catheters offer a unique ability to position themselves coaxial to the PVL. The Dexterity catheter (Spirus Medical LLC, Bridgewater, MA, USA) is a semi-rigid steerable catheter used in our lab with the ability to articulate at two separate points on the distal tip and flex greater than 360 degrees. We present cases of surgical valves that developed PVL which underwent successful repair with a Dexterity catheter. PMID- 28874308 TI - Accuracy and reproducibility of a newly developed tool for volume measurements of the arm using 3D stereophotogrammetry. AB - BACKGROUND: Lymph edema of the arm is a common complication after breast cancer treatment. To evaluate lymph edema volume and treatment outcome, an easy to use, objective quantification method of arm volume is necessary. Most often, water displacement is used to measure arm volume, as it is an easy and robust method that can be performed at any place with a simple equipment. However, when using water displacement, no exact localization of volume difference can be seen. To accurately measure hand and forearm volumes separately, an in-house-developed device was constructed for an accurate landmark placement. METHOD: An in-house developed measurement tool was used for placing artificial landmarks proximal to the wrist crease on ten healthy subjects. Three-dimensional (3D) images of the hand and forearm were acquired, and volume measurements of the hand and forearm were performed. Measurements were repeated to investigate the intra- and inter rater variability caused by the landmark placement. RESULTS: Measuring volume of the hand and forearm while using artificially placed landmarks turned out to be a highly reproducible, quick, and easy procedure. Both intra- and inter-rater variability showed high reproducibility for hand (ICC = 0.96 and 0.98, respectively) and forearm (ICC = 0.99 and 0.99, respectively) volumes. CONCLUSION: Measuring volumes of the hand and forearm while using artificially placed landmarks was found to be a highly reproducible, quick, and easy procedure. The device enables to analyze the localization of lymph edema in greater details. PMID- 28874309 TI - [Cor triatriatum, an unusual cause of a cardioembolic cerebrovascular event in adults. Presentation of a case]. PMID- 28874310 TI - Comment on "Orthostatic myoclonus after brain tumor radiation: Insights from two lesional cases". PMID- 28874311 TI - Reply to van Gerpen and Hassan comment on "Orthostatic myoclonus after brain tumor radiation: Insights from two lesional cases". PMID- 28874312 TI - Bowel obstruction secondary to an incarcerated Morgagni hernia in an adult patient: a rare complication. PMID- 28874314 TI - Drug discovery for the treatment of substance use disorders: novel targets, repurposing, and the need for new paradigms. AB - Drug addiction treatment medications available nowadays are limited in both efficacy and number. The increased understanding of drug addiction circuitries leads the scientific community to look for better molecules and targets for detoxification and relapse prevention. This review focus on known targets (e.g., metabotropic glutamate receptor 5 and GABAB receptor) and on novel potential treatment acting on oxytocin system, which interacts with diverse neurotransmitters, has proved successful in both preclinical and clinical studies on ethanol, cocaine and methamphetamine. A crucial issue is the identification of new investigational paradigms, which may help to predict treatment efficacy and improve effectiveness. PMID- 28874313 TI - New therapeutic perspectives in non-alcoholic steatohepatitis. AB - Management of non-alcoholic steatohepatitis is focused on restitution of metabolic derangement, weight loss and drugs able to improve steatosis, ballooning and fibrosis. Life-style interventions based on Mediterranean diet and increasing physical activity are the first line therapy. In patients with unsuccessful life-style intervention several drugs are under development: agonist PPAR, agonist GLP-1R and agonist FXR together with drugs focussing on inflammation, ballooning, apoptosis and fibrosis. Bariatric surgery or advanced endoscopy are reserved for morbid obese without response to life-style intervention and weighting loss drugs. PMID- 28874316 TI - La Teppe: The Epilepsy Center, Tain l'Hermitage, France. PMID- 28874315 TI - Hand eczema as a risk factor for food allergy among occupational kitchen workers. AB - BACKGROUND: An increasing number of studies in children is highlighting the importance of transdermal routes of exposure to food allergens through damaged skin in the pathogenesis of food allergies. However, data on this in adults are limited. A few case-series studies has documented development of food allergy among kitchen workers with hand eczema after direct contact exposure to foods. METHODS: To explore the significance of hand eczema as a risk factor for food allergies in adults at the epidemiological level, we performed a cross-sectional web-based questionnaire survey on kitchen workers whose exposures were classed as occupational (cooks and food handlers, n = 1592) or non-occupational (housewives, n = 1915). Logistic regression was used to explore the association between the presence/severity of hand eczema and the risk of food allergy after adjustment for potential confounders. RESULTS: Current hand eczema and current diagnosed food allergy were more common among occupational kitchen workers (OKW) than among non-occupational kitchen workers (NOKW) (32.3%-vs-29.9% and 9.9%-vs-3.8%, respectively). Current hand eczema was significantly associated with increased risk of current diagnosed food allergy in OKW (adjusted odds ratio 2.4, 95% CI 1.6-3.7). Those with more severe hand eczema were more likely to suffer from allergic symptoms for foods, and diagnosed food allergy. CONCLUSIONS: This study illustrates a significant public health problem in the adult population, documenting a major impact of hand eczema on the ongoing adult food allergy epidemic. PMID- 28874317 TI - Generalized paroxysmal fast activity in EEG: An unrecognized finding in genetic generalized epilepsy. AB - OBJECTIVE: To study generalized paroxysmal fast activity (GPFA) in patients with genetic generalized epilepsy (GGE). INTRODUCTION: GPFA is an electroencephalographic (EEG) finding in patients with symptomatic generalized epilepsy consisting of 15-25Hz bifrontally predominant generalized fast activity seen predominantly in sleep. Historically GPFA is linked to epileptic encephalopathy with drug resistant epilepsy and intellectual disability. However, GPFA has been rarely described as an atypical finding in patients with GGE without negative prognostic implication. We report cognitive profile and seizure characteristics in seven patients with GGE and GPFA. METHODS: The Vanderbilt EMU and EEG reports were searched for the keywords "idiopathic generalized epilepsy", "GPFA"and "generalized spike and wave discharges (GSWD)". We reviewed the EEG tracings and the electronic medical records of patients thus identified. The seizure type, frequency, neurological work-up, clinical profile and imaging data were recorded. RESULTS: Awake and sleep states were captured on EEGs of all patients. On EEG tracing review six patients were confirmed to have GSWD and GPFA; one patient had GPFA but no GSWD. All patients had normal cognitive function. Four had a normal brain MRI and one a normal head CT (two were never imaged). None of the patients had tonic seizures. The main seizure type was generalized tonic-clonic seizures (GTCS) in five patients, absence in two. Age at onset of epilepsy ranged from 4 to 24years. The mean GTC seizure frequency at the time of EEG was 3; two patients were seizure free on two antiepileptic drugs (AEDs). CONCLUSIONS: GPFA can be an unrecognized electrographic finding in patients with genetic generalized epilepsy. While GPFA remains an important diagnostic EEG feature for epileptic encephalopathy (Lennox-Gastaut syndrome) it is not specific for this diagnosis. Thus, GPFA may have a spectrum of variable phenotypic expression. The finding of GPFA is not necessarily indicative of unfavorable outcome. PMID- 28874318 TI - The Kork Epilepsy Center, Kehl-Kork, Germany. PMID- 28874319 TI - Childhood unusual experiences in community Child and Adolescent Mental Health Services in South East London: Prevalence and impact. AB - BACKGROUND: Distressing 'psychotic-like' or unusual experiences (UEDs) signify increased mental health risk in the general population, including greater likelihood and severity of co-occurring non-psychotic mental health problems, and, from fourteen years of age, increased risk of a future psychotic illness. Healthcare guidelines for under eighteens recommend psychological intervention for UEDs, to reduce current distress and adverse functional impact, and, potentially, future mental health risk. Children tend not to report UEDs unless directly asked, indicating a need for routine screening. We report on the feasibility of a routine screening methodology, and screening outcomes, in Child and Adolescent Mental Health Services (CAMHS) in South East London, United Kingdom. METHOD: Four general community CAMHS teams were invited to screen, by adding a nine-item self-report UED measure to their routine assessment battery. Screening data were collected over 18months from 02/2015 to 07/2016. RESULTS: All but one team agreed to screen. Each team saw around 300 accepted referrals during the audit period (total: 900); 768 of these (85%) were successfully screened; of those screened, 68% (n=524) self-reported UEs, 60% (n=461) with associated distress/adverse functional impact. Screening was acceptable to clinicians, children and families. CONCLUSIONS: Assessing UEDs routinely in CAMHS is feasible, and suggests that around two thirds of assessed referrals could potentially benefit from interventions targeting UEDs. Additional training may be required for the CAMHS workforce to address this need. PMID- 28874320 TI - Exercise training for intermittent claudication. AB - OBJECTIVE: The objective of this study was to provide an overview of evidence regarding exercise therapies for patients with lower extremity peripheral artery disease (PAD). METHODS: This manuscript summarizes the content of a lecture delivered as part of the 2016 Crawford Critical Issues Symposium. RESULTS: Multiple randomized clinical trials demonstrate that supervised treadmill exercise significantly improves treadmill walking performance in people with PAD and intermittent claudication symptoms. A meta-analysis of 25 randomized trials demonstrated a 180-meter increase in treadmill walking distance in response to supervised exercise interventions compared with a nonexercising control group. Supervised treadmill exercise has been inaccessible to many patients with PAD because of lack of medical insurance coverage. However, in 2017, the Centers for Medicare and Medicaid Services issued a decision memorandum to support health insurance coverage of 12 weeks of supervised treadmill exercise for patients with walking impairment due to PAD. Recent evidence also supports home-based walking exercise to improve walking performance in people with PAD. Effective home exercise programs incorporate behavioral change interventions such as a remote coach, goal setting, and self-monitoring. Supervised treadmill exercise programs preferentially improve treadmill walking performance, whereas home-based walking exercise programs preferentially improve corridor walking, such as the 6-minute walk test. Clinical trial evidence also supports arm or leg ergometry exercise to improve walking endurance in people with PAD. Treadmill walking exercise appears superior to resistance training alone for improving walking endurance. CONCLUSIONS: Supervised treadmill exercise significantly improves treadmill walking performance in people with PAD by approximately 180 meters compared with no exercise. Recent evidence suggests that home-based exercise is also effective and preferentially improves over-ground walking performance, such as the 6-minute walk test. PMID- 28874321 TI - Design, synthesis, and SAR study of 3-(benzo[d][1,3]dioxol-5-yl)-N benzylpropanamide as novel potent synergists against fluconazole-resistant Candida albicans. AB - Based on our previous discovery and SAR study on the lead compounds 7d, 5 and berberine which can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, a series of 3 (benzo[d][1,3]dioxol-5-yl)-N-(substituted benzyl)propanamides were designed, synthesized, and evaluated for their in vitro synergistic activity in combination with fluconazole. The series 2a-f were designed by replacing the amide moiety of the lead compound 7d with retro-amide moiety, and compounds 2a and 2b showed more activity than the lead 7d. Furthermore, introducing biphenyl moiety into series 2d-f afforded series 3a-r, most of which exhibited significantly superior activity to the series 2d-f. Especially, compound 3e, at a concentration of 1.0ug/ml, can enhance the susceptibility of fluconazole against fluconazole resistant Candida albicans from 128.0ug/ml to 0.125-0.25ug/ml. A clear SAR of the compounds is discussed. PMID- 28874322 TI - Prevaccination epidemiology of herpes zoster in Denmark: Quantification of occurrence and risk factors. AB - BACKGROUND: Herpes zoster (HZ) is a vaccine-preventable disease caused by reactivation of the varicella-zoster virus. Unfortunately, formulation of recommendations on routine immunization is hampered by a lack of data on disease burden, since most countries do not record cases of HZ in the general population. We developed and validated an algorithm to identify HZ based on routinely collected registry data and used it to quantify HZ occurrence and risk factors in Denmark prior to marketing of the HZ vaccine. METHODS: We included patients aged >=40years with a first-time systemic Acyclovir, Valacyclovir, or Famciclovir prescription or a hospital-based HZ diagnosis in the Danish nationwide health registries during 1997-2013. In a validation substudy (n=176), we computed the proportion of persons with HZ among patients who redeemed antiviral prescriptions. In a cohort study, we computed age-specific rates of HZ (45,297,258 person-years). In a case-control study, we then computed odds ratios (ORs) for common chronic diseases and immunosuppressive factors among HZ cases (n=189,025) vs. matched population controls (n=945,111). RESULTS: Medical record review confirmed HZ in 87% (95% confidence interval: 79-93%) of persons >=40years who dispensed antivirals at doses recommended for HZ. HZ rates increased from 2.15/1000 person-years in 40-year-olds to 9.45/1000 person-years in 95-year-olds. Rates were highest in women. HZ was diagnosed during hospitalization among 3.5%. As expected, persons with severe immunosuppressive conditions had the highest ORs of HZ (between 1.82 and 4.12), but various autoimmune diseases, asthma, chronic kidney disease, and inhaled glucocorticoids were also associated with increased ORs (between 1.06 and 1.64). CONCLUSION: This algorithm is a valid tool for identifying HZ in routine healthcare data. It shows that HZ is common in Denmark, especially in patients with certain chronic conditions. Prioritized vaccination of such high-risk patients might be an option in countries considering alternatives to universal vaccination. PMID- 28874323 TI - The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized, factorial design, placebo-controlled study among Indian infants. AB - BACKGROUND: Strategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function. METHODS: Infants 5weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5mg), probiotic (1010Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix(r), GlaxoSmithKline Biologicals) given at 6 and 10weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14weeks of age based on detection of VP6-specific IgA at >=20U/ml in previously seronegative infants or a fourfold rise in concentration. RESULTS: The study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): -1.4%, 16.2%), p=0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: -4.4%, 13.2%), p=0.272). 16 serious adverse events were recorded, none related to study interventions. CONCLUSIONS: Zinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation. TRIAL REGISTRATION: The trial was registered in India (CTRI/2012/05/002677). PMID- 28874324 TI - Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. AB - The lamin A/C (LMNA) gene encodes lamins A and C, which have an important role in nuclear cohesion and chromatin organization. Mutations in this gene usually lead to the so-called laminopathies, the primary cardiac manifestations of which are dilated cardiomyopathy and intracardiac conduction defects. Some mutations, associated with lipodystrophy but not cardiomyopathy, have been linked to metabolic abnormalities such as diabetes and severe dyslipidemia. Herein we describe a new phenotype associated with a mutation in exon 11 of the LMNA gene: hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. A 64-year-old woman with hypertrophic cardiomyopathy and a point mutation in exon 11 of the LMNA gene (c.1718C>T, Ser573Leu) presented with severe symptomatic ventricular hypertrophy and left ventricular outflow tract obstruction. She underwent septal alcohol ablation, followed by Morrow myectomy. The patient was also diagnosed with severe dyslipidemia, diabetes and obesity, and fulfilled diagnostic criteria for metabolic syndrome. No other characteristics of LMNA mutation-related phenotypes were identified. The development of type III atrioventricular block with no apparent cause, and mildly depressed systolic function, prompted referral for cardiac resynchronization therapy. In conclusion, the association between LMNA mutations and different phenotypes is complex and not fully understood, and can present with a broad spectrum of severity. PMID- 28874325 TI - Current Management of Penile Fracture: An Up-to-Date Systematic Review. AB - INTRODUCTION: Because of the low incidence of penile fracture, many aspects of the diagnostic process and of the surgical and functional outcomes are rarely reported. AIM: To systematically review the current literature on the surgical management of penile fracture, focusing on etiology, diagnosis, functional outcomes, and postoperative complications. METHODS: The present review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) declaration standards for systematic reviews. A systematic search for the terms penile fracture, fracture of penis, trauma of penis, rupture of corpora cavernosa, and immediate management of penile fracture was been carried out in the PubMed, EMBASE, Cochrane, SCOPUS, and Science Citation Index databases. MAIN OUTCOME MEASURES: Etiology of penile fracture, clinical presentation, types of radiologic investigations and their accuracy, surgical approach, suture material used for tunica repair, timing of surgical exploration, intraoperative findings, surgical complications, and functional outcomes. RESULTS: The total number of patients analyzed was 438, and the patients' an average age was 36 years. The most frequent reported cause of penile fracture was sexual intercourse (80% of cases). The most common finding at examination was a penile hematoma (97.5%). Although operator dependent, in experienced hands, ultrasonography was found to be a useful tool in confirming the location of the albuginea tear and identifying the presence of any concomitant urethral injury, helping the surgeon to choose the best surgical approach. Early surgical repair of a penile fracture was found to be a safe procedure, although long-term complications are not uncommon. Tertiary referral centers that managed a larger number of cases seemed to obtain more satisfactory long-term results with a significantly smaller number of complications. CONCLUSION: A low incidence of postoperative complications and full satisfactory functional outcomes are reported when early repair is performed in high-volume centers. Falcone M, Garaffa G, Castiglione F, Ralph DJ. Current Management of Penile Fracture: An Up-to-Date Systematic Review. Sex Med Rev 2018;6:253-260. PMID- 28874326 TI - Ambicor Two-Piece Inflatable Penile Prosthesis: Background and Contemporary Outcomes. AB - INTRODUCTION: The two-piece inflatable penile prosthesis (IPP; Ambicor) might be a preferred option for men with erectile dysfunction (ED) who have significant retroperitoneal scarring, limited manual dexterity, or other issues. There are reported differences in outcomes and patient and partner satisfaction between three-piece and two-piece IPPs. AIM: To report contemporary outcomes, patient and partner satisfaction, and mechanical durability data of the two-piece compared with the three-piece IPP. METHODS: A PubMed search was performed related to two piece penile prostheses. Emphasis was placed on perioperative outcomes and patient and/or partner satisfaction scores. Non-English-language articles were excluded. MAIN OUTCOME MEASURES: Use of the Ambicor two-piece penile prosthesis was assessed by outlining the contemporary literature. The etiology of ED in this population, mechanical attributes, penile morphologic changes, satisfaction, and its use in special populations were reviewed. RESULTS: The most common etiology of ED for placement of the device remains a vasculogenic cause (range = 11-62%). Overall complication rates were 2.1% to 11.2% for the general population. Mechanical failure was seen in 0.7% to 6.1%. Infection rates were 0.7% to 4.8%. Spontaneous deflation was seen in approximately 25%. Higher complication rates were found in transgender patients after neophallus creation and the two-piece IPP could offer better durability compared with the three-piece IPP. Longer operative times, greater use of advanced dilation techniques, and greater length loss also have been reported. Overall satisfaction rates are higher than 85%. CONCLUSION: The predominant etiology of ED for two-piece penile prosthesis placement is vasculogenic. There is a trend toward IPP insertion in patients after radical prostatectomy or who have spinal cord injury. The two-piece device has similar complication rates and high patient satisfaction scores compared with three-piece IPPs. Further larger prospective studies are needed to validate our findings, resolve discrepancies in published outcomes, and contribute to the sparse data on this subject. Ko OS, Bennett NE. Ambicor Two-Piece Inflatable Penile Prosthesis: Background and Contemporary Outcomes. Sex Med Rev 2018;6:319 327. PMID- 28874327 TI - Collagenase Clostridium histolyticum in the Treatment of Peyronie's Disease-A Review of the Literature and a New Modified Protocol. AB - INTRODUCTION: Peyronie's disease (PD) is a common condition that results in penile deformity, which makes sexual intercourse difficult or impossible, and causes psychological, emotional, and relationship difficulties for the man affected and his partner. Collagenase Clostridium histolyticum (CCH; Xiapex, Xiaflex) is the first licensed non-surgical treatment option for PD. The safety and efficacy have been demonstrated in two large phase III randomized controlled trials (IMPRESS I and IMPRESS II). AIM: To review the safety and efficacy of CCH and to introduce a new shortened modified protocol for CCH that was developed by the authors to decrease the cost and duration of treatment. METHODS: A review of the medical literature on CCH for inclusion in this review was obtained by searching the PubMed (from 1946) and Medline (from 1946) medical databases and from the screening of relevant bibliographies. The search terms Xiapex, Xiaflex, collagenase Clostridial histolyticum, and Peyronie's disease were used. Clinical trials in men with PD and scientific articles relating to pharmacologic data were included in the review. When possible, large, randomized, and well-designed trials were selected. MAIN OUTCOME MEASURES: Changes in the angle of penile curvature and in the Peyronie's Disease Questionnaire domains. RESULTS: The clinical trials demonstrate the safety and efficacy of CCH in the treatment of PD. The new modified protocol developed by the authors is as safe and effective as the protocol used in the clinical trials. CONCLUSION: CCH is the first licensed non-surgical treatment for PD. Its safety and efficacy have been demonstrated in large well-designed clinical trials. The new shortened modified protocol decreases the cost and duration of the treatment without compromising the safety and efficacy of the drug. This alteration will allow more patients to benefit from CCH. Abdel Raheem A, Johnson M, Abdel-Raheem T, et al. Collagenase Clostridium histolyticum in the Treatment of Peyronie's Disease-A Review of the Literature and a New Modified Protocol. Sex Med Rev 2017;5:529-535. PMID- 28874328 TI - Self Made Xeno-pericardial Aortic Tubes to Treat Native and Aortic Graft Infections. AB - OBJECTIVES: The most appropriate material for reconstruction of the aorta for native or graft infection remains a matter for debate. This study examines the mid-term outcome of patients and graft durability after in situ aortic reconstruction with self made bovine pericardial tube grafts. METHODS: This was a retrospective analysis of all patients who underwent in situ aortic reconstruction using self made bovine pericardial tube grafts between January 2008 and December 2015 at a tertiary referral centre. Peri-operative and mid-term outcomes including mortality and re-infection were analysed at the end of January 2017. Available follow-up imaging was reviewed to assess graft durability. RESULTS: Bovine pericardial aortic tube grafts were used in 35 patients (86% male) with a median age of 69 years (range 38-84) to reconstruct the ascending aorta or the aortic arch (7), the descending (7), the thoraco-abdominal (7), or the abdominal (14) aorta. Twelve patients (34%) were treated for infection of the native aorta and 23 (66%) for prosthetic graft infection. Twenty-two patients (63%) underwent emergency surgery. Thirty day mortality was 31% (n = 11). Additionally, six patients died during follow-up after a median of 33 months (range 3-70). For the remaining patients, mean follow-up was 48 months (+/- 26) with a mean Follow-Up Index of 0.98 +/- 0.08. There were no readmissions or re operations for re-infection or graft related complications. Follow-up imaging showed no signs of graft degeneration after a median of 15 months (range 3-68). CONCLUSIONS: Surgical treatment of native and aortic graft or endograft infection remains high risk. Self made bovine pericardial tube grafts for in situ reconstruction are a promising option offering many advantages. Despite high early mortality rates, early radiological and mid-term clinical results are good. Definitive eradication of the infection seems feasible after in situ insertion of xeno-pericardial material for aortic repair. PMID- 28874329 TI - Outcome after Turndown for Elective Abdominal Aortic Aneurysm Surgery. AB - OBJECTIVES: The aim was to assess the survival of patients who had been turned down for repair of an abdominal aortic aneurysm (AAA) and to examine the factors influencing this. METHODS: This was a retrospective observational study of a prospectively maintained database of all patients turned down for AAA intervention by the Black Country Vascular Network multidisciplinary team (MDT) from January 2013 to December 2015. Data on AAA size, cardiopulmonary exercise testing (CPET) and cause of death were recorded. RESULTS: There were 112 patients. The median age at turndown was 83.9 years (IQR 10.2 years). The median AAA size at turndown was 63 mm (IQR 16.7 mm). The median follow-up time after turndown was 324 days (IQR 537.5 days). Sixty-four patients (57.1%) were deceased after 2 years, with a median survival time of 462 days (IQR 579 days). Patients who died had a significantly larger AAA dimension (median 65 mm, IQR 18.5 mm) than those surviving to date (median 59 mm, IQR 10 mm, p = .004). Using Cox regression analysis, the probability of 1 year survival in the whole population was 0.614. The probability of 2 year survival was 0.388. When accounting for age, gender, AAA dimension, and British Aneurysm Repair risk score, no factors had significant influence over survival. Of the 64 deceased patients, 30 had an accessible cause of death: 36.7% of these were due to ruptured AAAs. There was no significant difference in AAA size between those dying of ruptures and those dying of other causes (p = .225, mean 74 mm and 67 mm respectively). CONCLUSIONS: Being turned down for AAA repair carries a significant short-term risk of mortality. Those turned down for repair carried significant levels of comorbid disease but no factors considered were found to be independently predictive of the length of survival. PMID- 28874330 TI - Comparison of RIFLE, AKIN, and KDIGO classifications for assessing prognosis of patients on extracorporeal membrane oxygenation. AB - BACKGROUND/PURPOSE: Acute kidney injury (AKI) developing during extracorporeal membrane oxygenation (ECMO) is associated with very poor outcome. The Kidney Disease: Improving Global Outcomes (KDIGO) group published a new AKI definition in 2012. This study analyzed the outcomes of patients treated with ECMO and identified the relationship between the prognosis and the KDIGO classification. METHODS: This study examined total 312 patients initially, and finally reviewed the medical records of 167 patients on ECMO support at a tertiary care university hospital between March 2002 and November 2011. Demographic, clinical, and laboratory variables were retrospectively collected as survival predicators. RESULTS: The overall mortality rate was 55.7%. In the analysis of the areas under the receiver operating characteristic curves, the KDIGO classification showed relatively higher discriminatory power (0.840 +/- 0.032) than the Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal failure (RIFLE) (0.826 +/- 0.033) and Acute Kidney Injury Network (AKIN) (0.836 +/- 0.032) criteria in predicting in-hospital mortality. Furthermore, multiple logistic regression analysis showed that KDIGO, hemoglobin, and Glasgow Coma Scale score on the first day of patients on ECMO were independent predictors for in-hospital mortality. Finally, cumulative survival rates at 6-month follow-up after hospital discharge differed significantly for KDIGO stage 3 versus KDIGO stage 0, 1, and 2 (p < 0.001); and KDIGO stage 2 versus KDIGO stage 0 (p < 0.05). CONCLUSION: For those patients with ECMO support, the KDIGO classification proved to be a more reproducible evaluation tool with excellent prognostic abilities than RIFLE or AKIN classification. PMID- 28874331 TI - Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of Acute-Phase Peyronie's Disease. AB - BACKGROUND: Peyronie's disease (PD), defined as the abnormal formation of fibrous plaque(s) in the tunica albuginea of the penis, is a chronic condition that afflicts 3% to 13% of the US male population; there is no current research on the efficacy and safety of collagenase Clostridium histolyticum (CCH) in the treatment of acute phase PD. AIM: To examine the efficacy and safety of CCH in the treatment of acute-phase PD. METHODS: We retrospectively reviewed the records for all patients treated with CCH for PD from April 2014 through April 2017. Patients who reported penile pain and duration of PD no longer than 12 months at presentation qualified as being in the acute phase of PD. The primary outcomes of interest were final changes in curvature after CCH treatment regardless of the number of CCH cycles received and frequency of treatment-related adverse events. OUTCOMES: Parameters of efficacy and safety were compared between acute- and stable-phase PD. RESULTS: A total of 162 patients were included in the study, of which 36 (22%) qualified as having acute-phase PD (group 1) and the remaining 126 (78%) qualified as having stable-phase PD (group 2). Median duration of PD was 8.5 months (range = 1-12) for group 1 and 18 months (range = 1-492) for group 2. There was no significant difference in final change in curvature between the acute and stable phases of PD (16.7 degrees vs 15.6 degrees ; P = .654). There was no statistically significant difference in frequency of treatment-related adverse events between the acute phase (4 patients, 11%) and the stable phase (12 patients, 10%; P = .778). CLINICAL IMPLICATIONS: CCH therapy is as safe and efficacious in acute-phase PD as it is in stable-phase PD. STRENGTHS AND LIMITATIONS: This is the first report that assesses the safety and efficacy of CCH therapy focusing on acute-phase PD. This study was composed of a large cohort of patients receiving CCH therapy in acute- and stable-phase PD. Limitations include bias associated with retrospective studies, a small sample, and a single center setting. CONCLUSIONS: Although CCH is not clearly indicated for treatment during the acute phase of PD, these results suggest that CCH use during this phase can be effective and safe. There was no statistically significant difference in final change in curvature or treatment-related adverse events after CCH therapy delivered between the acute and stable phases of PD. Nguyen HMT, Anaissie J, DeLay KJ, et al. Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of Acute-Phase Peyronie's Disease. J Sex Med 2017;14:1220-1225. PMID- 28874332 TI - The Relationship Between Incontinence and Erectile Dysfunction After Robotic Prostatectomy: Are They Mutually Exclusive? AB - BACKGROUND: Urinary incontinence (UI) and erectile dysfunction (ED) remain the most common long-term complications of prostatectomy, with a significant impact on sexual health and quality of life. AIMS: To determine the relation between UI and moderate to severe ED and the risk factors for UI in patients undergoing robotic-assisted laparoscopic prostatectomy. METHODS: Patients in our institutional database who underwent robotic-assisted laparoscopic prostatectomy for prostate cancer (2006-2013) and who completed the University of California Los Angeles Prostate Cancer Index and the Sexual Health Inventory for Men (SHIM) surveys at 12 months after prostatectomy were eligible for inclusion. Men who reported use of no urinary pads per day were considered continent, whereas men who used at least one pad per day were considered incontinent. Men with moderate to severe ED based on a SHIM score no higher than 11 were considered to have ED. Patients who had preoperative moderate to severe ED and/or UI based on these definitions were excluded from further analysis. OUTCOMES: A better understanding of what increases the risk for UI after a prostatectomy and how it can co-occur with ED. RESULTS: We analyzed 464 patients who met the inclusion criteria. After prostatectomy, 36% of patients had UI and 47% of patients had moderate to severe ED. Of all patients with ED, 45% (98 of 216) were incontinent compared with 27% (67 of 248) of patients without ED (P < .001). On multivariable analysis, older age at diagnosis (odds ratio [OR] = 1.05, P = .002) and ED (OR = 1.88, P = .005) were independent predictors for incontinence. The use of unilateral nerve sparing (OR = 1.03, P = .94) or no nerve sparing (OR = 0.53, P = .50) during surgery did not have an impact on postoperative incontinence. CLINICAL IMPLICATIONS: Understanding that ED is an independent predictor of UI after robotic-assisted laparoscopic prostatectomy has important clinical implications and suggests a common anatomic pathway. STRENGTHS AND LIMITATIONS: Our focus on different measurements of incontinence and their relation to ED and our use of validated questionnaires to define incontinence and ED were important strengths of this study. Limitations of our study include its retrospective nature and the fact that our results were drawn from a single-center database of a tertiary referral hospital. CONCLUSION: Our results show that the presence of moderate to severe ED after prostatectomy is an independent risk factor for incontinence, suggesting a possible common pathway for these two complications. Further studies to investigate the anatomic and clinical bases of this relation are warranted. Tsikis ST, Nottingham CU, Faris SF. The Relationship Between Incontinence and Erectile Dysfunction After Robotic Prostatectomy: Are They Mutually Exclusive? J Sex Med 2017;14:1241-1247. PMID- 28874333 TI - Prevalence and Risk Factors for Erectile Dysfunction in Chinese Adult Males. AB - BACKGROUND: There is a lack of nationwide epidemiologic survey data on the prevalence estimate of erectile dysfunction (ED) in Chinese men living on the mainland China. AIM: To attain the representative prevalence estimate of ED in the Chinese male population and to analyze potential risk factors associated with ED by demographics, socioeconomic status, and medical comorbidities. METHODS: The study was community based. The five-item Internation Index of Erectile Function questionnaire and in-person interview were used to obtain data. The survey subjects were 5,210 non-institutionalized Chinese men at least 40 years old residing in 30 provinces and autonomies of China. Multiple logistic regression analysis was used to disclose risk factors associated with ED. OUTCOMES: The prevalence estimate of ED was 40.56% in Chinese men at least 40 years old. RESULTS: The prevalence of ED increased with increasing age. A significant high prevalence of ED was observed in men who smoked heavily, were estranged from a partner, had diabetes, and lower urinary tract symptoms from benign prostatic hyperplasia. Smoking more than 30 cigarettes daily and obesity (body mass index >= 30 kg/m2) significantly increased the risk for ED by multivariable-adjusted odds ratios. Stable or erratic sexual partners, personal incomes, alcohol consumption, and cardiovascular and/or cerebrovascular diseases were not risk factors associated with ED prevalence. Other sexual problems commonly seen in this group of men included difficulty achieving erectile rigidness, ejaculation, and climax during intercourse. CLINICAL TRANSLATION: Knowledge on the prevalence of ED and its associated risk factors will help physicians in the clinical management and prevention of ED with the use of counseling for lifestyle adjustment and drug therapy. STRENGTHS AND LIMITATIONS: Data on the influence of psychological conditions on ED were not collected. ED was not categorized as minor, moderate, or severe for analysis during processing of data. CONCLUSION: The national representative prevalence of ED was determined for the first time in the Chinese male population. Zhang X, Yang B, Li N, Li H. Prevalence and Risk Factors for Erectile Dysfunction in Chinese Adult Males. J Sex Med 2017;14:1201 1208. PMID- 28874334 TI - CYP24A1 Mutation in a Girl Infant with Idiopathic Infantile Hypercalcemia. AB - Idiopathic infantile hypercalcemia (IIH) was associated with vitamin-D supplementation in the 1950's. Fifty years later, mutations in the CYP241A gene, involved in the degradation of vitamin-D, have been identified as being a part of the etiology. We report a case of a 21-month old girl, initially hospitalized due to excessive consumption of water and behavioral difficulties. Blood tests showed hypercalcemia and borderline high vitamin-D levels. Renal ultrasound revealed medullary nephrocalcinosis. An abnormality in vitamin-D metabolism was suspected and genetic testing was performed. This revealed the patient to be compound heterozygous for a common (p.E143del) and a novel (likely) disease-causing mutation (p.H83D) in the CYP24A1 gene. The hypercalcemia normalized following a calcium depleted diet and discontinuation of vitamin-D supplementation. Increased awareness of the typical symptoms of hypercalcemia, such as anorexia, polydipsia, vomiting and failure to thrive, is of utmost importance in diagnosing IHH early and preventing long-term complications such as nephrocalcinosis. Further identification of as many disease-causing mutations in the CYP24A1 gene as possible can help identification of predisposed individuals in whom vitamin-D supplementation should be reconsidered. PMID- 28874335 TI - Mobile Apps for Teaching Intubation: Scoping Review and Critical Analysis in eLearning. AB - BACKGROUND: Airway management is a core skill in anesthesia ensuring adequate oxygenation and delivery of inhalational agents for the patient. OBJECTIVE: The goals of this study were to critically evaluate the quality of airway management apps and target revised Bloom's Taxonomy cognitive levels. METHODS: An electronic search using the keywords "airway" and "airway management" was conducted in May 2015 across the App Store, Google Play, BlackBerry World, and Windows Store. Apps were included in the study if their content was related to airway management. App content and characteristics were extracted into a standard form and evaluated. RESULTS: A total of 65 apps met the inclusion criteria, and 73% (47/65) of apps were developed by companies or industry. Anesthesiology trainees were the target audience in only 20% (13/65) of apps. Bag mask ventilation and laryngeal mask airways were covered in only 20% (13/65) of apps. Only 2 apps were supported in the scientific literature. For Bloom's Taxonomy, 37% (24/65) of apps targeted knowledge, 5% (3/65) comprehension, 22% (14/65) application, 28% (18/65) analysis, 9% (6/65) evaluation, and 0% synthesis. Multivariate analysis identified cost of apps, size of apps (MB), and apps targeting trainees and paramedics to be associated with higher levels of cognitive processing of revised Bloom's Taxonomy. CONCLUSIONS: Apps developed for teaching intubation target lower levels of cognitive processing and are largely not validated by research. Cost, app size, and targeted user are associated with higher cognitive levels. Trainees and all users should be aware of the paucity of the published evidence behind the efficacy of some of these apps. PMID- 28874336 TI - Barriers and Facilitators to eHealth Use in Daily Practice: Perspectives of Patients and Professionals in Dermatology. AB - BACKGROUND: The number of eHealth interventions in the management of chronic diseases such as atopic dermatitis (AD) is growing. Despite promising results, the implementation and use of these interventions is limited. OBJECTIVES: This study aimed to assess opinions of the most important stakeholders influencing the implementation and use of eHealth services in daily dermatology practice. METHODS: The perspectives of health care professionals and patients towards the implementation and use of eHealth services in daily practice were assessed by using a mixed method design. A cross-sectional survey based on the eHealth implementation toolkit (eHit) was conducted to explore factors influencing the adoption of eHealth interventions offering the possibility of e-consultations, Web-based monitoring, and Web-based self-management training among dermatologists and dermatology nurses. The perspectives of patients with atopic dermatitis (AD) regarding the use of eHealth services were discussed in an online focus group. RESULTS: Health care professionals (n=99) and patients (n=9) acknowledged the value of eHealth services and were willing to use these digital tools in daily dermatology practice. Key identified barriers (statements with <50% of the participants scoring totally agree or agree) in the implementation and adoption of eHealth interventions included concerns about the availability (12/99, 12%) and allocation (14/99, 14%) of resources, financial aspects (26/99, 26%), reliability, security, and confidentially of the intervention itself (29/99, 29%), and the lack of education and training (6/99, 6%). CONCLUSIONS: Health care professionals and patients acknowledge the benefits arising from the implementation and use of eHealth services in daily dermatology practice. However, some important barriers were identified that might be useful in addressing the implementation strategy in order to enhance the implementation success of eHealth interventions in dermatology. PMID- 28874339 TI - New Zealand campaign calls for action to prevent suicides. PMID- 28874338 TI - Risk assessment for antibiotic resistance in South East Asia. PMID- 28874340 TI - Strengthening laboratory surveillance of antimicrobial resistance in South East Asia. PMID- 28874341 TI - GP who deleted appointment slots to ease workload pressure is spared punishment. PMID- 28874342 TI - Antimicrobial resistance communication activities in South East Asia. PMID- 28874343 TI - David Oliver: "Progressive dwindling," frailty, and realistic expectations. PMID- 28874344 TI - Using information technology to improve surveillance of antimicrobial resistance in South East Asia. PMID- 28874347 TI - Developing a situation analysis tool to assess containment of antimicrobial resistance in South East Asia. PMID- 28874346 TI - Progress towards antimicrobial resistance containment and control in Indonesia. PMID- 28874348 TI - beta-alanine: performance effects, usage and side effects. PMID- 28874349 TI - Inflammation: a key regulator of hematopoietic stem cell fate in health and disease. AB - Hematopoietic stem cells (HSCs) are responsible for lifelong production of blood cells. At the same time, they must respond rapidly to acute needs such as infection or injury. Significant interest has emerged in how inflammation regulates HSC fate and how it affects the long-term functionality of HSCs and the blood system as a whole. Here we detail recent advances and unanswered questions at the intersection between inflammation and HSC biology in the contexts of development, aging, and hematological malignancy. PMID- 28874351 TI - Antimicrobial policy interventions in food animal production in South East Asia. PMID- 28874350 TI - Prognostic significance of baseline metabolic tumor volume in relapsed and refractory Hodgkin lymphoma. AB - Identification of prognostic factors for patients with relapsed/refractory Hodgkin lymphoma (HL) is essential for optimizing therapy with risk-adapted approaches. In our phase 2 study of positron emission tomography (PET)-adapted salvage therapy with brentuximab vedotin (BV) and augmented ifosfamide, carboplatin, and etoposide (augICE), we assessed clinical factors, quantitative PET assessments, and cytokine and chemokine values. Transplant-eligible patients with relapsed/refractory HL received 2 (cohort 1) or 3 (cohort 2) cycles of weekly BV; PET-negative patients (Deauville score <=2) proceeded to autologous stem cell transplantation (ASCT) whereas PET-positive patients received augICE before ASCT. Serum cytokine and chemokine levels were measured at baseline and after BV. Metabolic tumor volume (MTV) and total lesion glycolysis were measured at baseline, after BV, and after augICE. Sixty-five patients enrolled (45, cohort 1; 20, cohort 2); 49 (75%) achieved complete response and 64 proceeded to ASCT. Three-year overall survival and event-free survival (EFS) were 95% and 82%, respectively. Factors predictive for EFS by multivariable analysis were baseline MTV (bMTV) (P < .001) and refractory disease (P = .003). Low bMTV (<109.5 cm3) and relapsed disease identified a favorable group (3-year EFS, 100%). For patients who received a transplant, bMTV and pre-ASCT PET were independently prognostic; 3-year EFS for pre-ASCT PET-positive patients with low bMTV was 86%. In this phase 2 study of PET-adapted therapy with BV and augICE for relapsed/refractory HL, bMTV and refractory disease were independent prognostic factors for EFS. Furthermore, bMTV improved the predictive power of pre-ASCT PET. Future studies should optimize efficacy and tolerability of salvage therapy by stratifying patients according to risk factors such as bMTV. PMID- 28874352 TI - New chapter in tackling antimicrobial resistance in Thailand. PMID- 28874353 TI - Margaret McCartney: Innovation without sufficient evidence is a disservice to all. PMID- 28874354 TI - The Inhibitory Signaling Receptor Protocadherin-18 Regulates Tumor-Infiltrating CD8+ T-cell Function. AB - Cancers are infiltrated with antitumor CD8+ T cells that arise during tumor growth, but are defective in effector phase functions because of the suppressive microenvironment. The reactivation of TILs can result in tumor destruction, showing that lytic dysfunction in CD8+ tumor-infiltrating lymphocytes (TIL) permits tumor growth. Like all memory T cells, TILs express inhibitory signaling receptors (aka checkpoint inhibitor molecules) that downregulate TCR-mediated signal transduction upon TIL interaction with cells expressing cognate ligands, thereby restricting cell activation and preventing the effector phase. Previously, we identified a novel murine CD8+ TIL inhibitory signaling receptor, protocadherin-18, and showed that it interacts with p56lck kinase to abrogate proximal TCR signaling. Here, we show that TILs from mice deleted in protocadherin-18 had enhanced antitumor activity and that coblockade of PD-1 and protocadherin-18 in wild-type mice significantly enhanced TIL effector phase function. These results define an important role for protocadherin-18 in antitumor T-cell activity. Cancer Immunol Res; 5(10); 920-8. (c)2017 AACR. PMID- 28874355 TI - Antibiotic residues in the environment of South East Asia. PMID- 28874356 TI - Impact of beta-adrenergic signaling in PGC-1alpha-mediated adaptations in mouse skeletal muscle. AB - PGC-1alpha has been suggested to regulate exercise training-induced metabolic adaptations and autophagy in skeletal muscle. The factors regulating PGC-1alpha, however, have not been fully resolved. The aim was to investigate the impact of beta-adrenergic signaling in PGC-1alpha-mediated metabolic adaptations in skeletal muscle with exercise training. Muscle was obtained from muscle-specific PGC-1alpha knockout (MKO) and lox/lox mice 1) 3 h after a single exercise bout with or without prior injection of propranolol or 3 h after a single injection of clenbuterol and 2) after 5 wk of wheel running exercise training with or without propranolol treatment or after 5 wk of clenbuterol treatment. A single clenbuterol injection and an acute exercise bout similarly increased the mRNA content of both N-terminal and full-length PGC-1alpha isoforms, and prior propranolol treatment reduced the exercise-induced increase in mRNA of all isoforms. Furthermore, a single clenbuterol injection elicited a PGC-1alpha dependent increase in cytochrome c and vascular endothelial growth factor mRNA, whereas prolonged clenbuterol treatment increased fiber size but reduced capillary density. Exercise training increased the protein content of OXPHOS, LC3I, and Parkin in a PGC-1alpha-dependent manner without effect of propranolol, while an exercise training-induced increase in Akt2 and p62 protein required PGC 1alpha and was blunted by prolonged propranolol treatment. This suggests that beta-adrenergic signaling is not required for PGC-1alpha-mediated exercise training-induced adaptations in mitochondrial proteins, but contributes to exercise training-mediated adaptations in insulin signaling and autophagy regulation through PGC-1alpha. Furthermore, changes observed with acute stimulation of compounds like clenbuterol and propranolol may not lead to corresponding adaptations with prolonged treatment. PMID- 28874357 TI - Reduced obesity, diabetes, and steatosis upon cinnamon and grape pomace are associated with changes in gut microbiota and markers of gut barrier. AB - Increasing evidence suggests that polyphenols have a significant potential in the prevention and treatment of risk factors associated with metabolic syndrome. The objective of this study was to assess the metabolic outcomes of two polyphenol containing extracts from cinnamon bark (CBE) and grape pomace (GPE) on C57BL/6J mice fed a high-fat diet (HFD) for 8 wk. Both CBE and GPE were able to decrease fat mass gain and adipose tissue inflammation in mice fed a HFD without reducing food intake. This was associated with reduced liver steatosis and lower plasma nonesterified fatty acid levels. We also observed a beneficial effect on glucose homeostasis, as evidenced by an improved glucose tolerance and a lower insulin resistance index. These ameliorations of the overall metabolic profile were associated with a significant impact on the microbial composition, which was more profound for the GPE than for the CBE. At the genus level, Peptococcus were decreased in the CBE group. In the GPE-treated group, several key genera that have been previously found to be linked with HFD, metabolic effects, and gut barrier integrity were affected: we observed a decrease of Desulfovibrio, Lactococcus, whereas Allobaculum and Roseburia were increased. In addition, the expression of several antimicrobial peptides and tight junction proteins was increased in response to both CBE and GPE supplementation, indicating an improvement of the gut barrier function. Collectively, these data suggest that CBE and GPE can ameliorate the overall metabolic profile of mice on a high-fat diet, partly by acting on the gut microbiota. PMID- 28874358 TI - Soluble interleukin-13ralpha1: a circulating regulator of glucose. AB - Soluble IL-13 receptor-alpha1, or sIL13ralpha1, is a soluble protein that binds to interleukin-13 (IL-13) that has been previously described in mice. The function of sIL13ralpha1 remains unclear, but it has been hypothesized to act as a decoy receptor for IL-13. Recent studies have identified a role for IL-13 in glucose metabolism, suggesting that a decoy receptor for IL-13 might increase circulating glucose levels. Here, we report that delivery of sIL13ralpha1 to mice by either gene transfer or recombinant protein decreases blood glucose levels. Surprisingly, the glucose-lowering effect of sIL13ralpha1 was preserved in mice lacking IL-13, demonstrating that IL-13 was not required for the effect. In contrast, deletion of IL-4 in mice eliminated the hypoglycemic effect of sIL13ralpha1. In humans, endogenous blood levels of IL13ralpha1 varied substantially, although there were no differences between diabetic and nondiabetic patients. There was no circadian variation of sIL13ralpha1 in normal human volunteers. Delivery of sIL13ralpha1 fused to a fragment crystallizable (Fc) domain provided sustained glucose lowering in mice on a high-fat diet, suggesting a potential therapeutic strategy. These data reveal sIL13ralpha1 as a circulating human protein with an unexpected role in glucose metabolism. PMID- 28874359 TI - Postchallenge hyperglycemia in subjects with low body weight: implication for small glucose volume. AB - A hypothesis that postchallenge hyperglycemia in subjects with low body weight (BW) may be due, in part, to small glucose volume (GV) was tested. We studied 11,411 nondiabetic subjects with a mean BW of 63.3 kg; 5,282 of them were followed for a mean of 5.3 yr. In another group of 1,537 nondiabetic subjects, insulin sensitivity, secretion, and a product of the two (index of whole body insulin action) were determined. Corrected 2 h-plasma glucose (2hPGcorr) during a 75-g oral glucose tolerance test in subjects with BW <= 59 kg was calculated as 2hPGcorr = deltaPG2h . ECW/[16.1 (males) or 15.3 (females)] + fasting PG (FPG), where deltaPG2h is plasma glucose increment in 2 h; ECW is extracellular water (surrogate of GV); FPG is fasting plasma glucose; and 16.1 and 15.3 are ECW of men and women, respectively, with BW = 59 kg. Multivariate analyses for BW with adjustment for age, sex, and percent body fat were undertaken. BW was, across its entire range, positively correlated with FPG (P < 0.01). Whereas BW was correlated with 2hPG and deltaPG in a skewed J-shape, with inflections at around 60 kg (P for nonlinearity < 0.01 for each). Nonetheless, in those with BW <= 59 kg, insulin sensitivity, secretion, and action were unattenuated, and incident diabetes was less compared with heavier counterparts. BW was linearly correlated with 2hPGcorr, i.e., the J-shape correlation was mitigated by the correction. In conclusion, postchallenge hyperglycemia in low BW subjects is in part due to small GV rather than impaired glucose metabolism. PMID- 28874361 TI - Over 65s flu vaccination programme was ineffective, data show. PMID- 28874360 TI - Antibiotic use in South East Asia and policies to promote appropriate use: reports from country situational analyses. PMID- 28874363 TI - One Health approach to tackle antimicrobial resistance in South East Asia. PMID- 28874362 TI - Drug resistance in malaria, tuberculosis, and HIV in South East Asia: biology, programme, and policy considerations. PMID- 28874364 TI - Individual clinicians were culpable in blood scandal, says former health secretary. PMID- 28874365 TI - Antibiotic resistance and its containment in India. PMID- 28874367 TI - Leukaemia cutis of the scalp. PMID- 28874366 TI - Strengthening infection prevention and control and systematic surveillance of healthcare associated infections in India. PMID- 28874368 TI - Immunodeficiency and Intermittent Dosing Promote Acquired Rifamycin Monoresistance in Murine Tuberculosis. AB - More-permissive preclinical models may be useful in evaluating antituberculosis regimens for their propensity to select drug-resistant mutants. To evaluate whether acquired rifamycin monoresistance could be recapitulated in mice and, if so, to evaluate the effects of immunodeficiency, intermittent dosing, and drug exposures, athymic nude and BALB/c mice were infected. Controls received daily rifapentine alone or 2 months of rifampin, isoniazid, pyrazinamide, and ethambutol, followed by 4 months of rifampin/isoniazid, either daily or twice weekly with one of two isoniazid doses. Test groups received the same intensive regimen followed by once-weekly rifapentine or isoniazid/rifapentine with rifapentine doses of 10, 15, or 20 mg/kg of body weight plus one of two isoniazid doses. All combination regimens rendered BALB/c mouse cultures negative but selected mutants resistant to isoniazid (8.5%, 12/140) or rifampin (3.5%, 5/140) in nude mice (P < 0.001). Intermittently dosed intensive-phase therapy selected isoniazid and rifampin resistance in 10% (8/80, P < 0.001) and 20% (16/80, P = 0.009) of nude mice, respectively, compared to 0% treated with a daily regimen. Once-weekly rifapentine-containing continuation-phase regimens selected rifampin resistant mutants at a rate of 18.0% (18/100, P = 0.035 compared to rifampin/isoniazid regimens). Higher isoniazid doses in the intermittent treatment control regimen and higher rifapentine doses in once-weekly regimens were associated with less selection of isoniazid resistance. Acquired resistance, including rifamycin monoresistance, was more likely to occur in nude mice despite administration of combination therapy. These results recapitulate clinical outcomes and indicate that nude mice may be useful for evaluating the ability of novel regimens to prevent the selection of resistance. PMID- 28874369 TI - Transcriptional and Mutational Profiling of an Aminoglycoside-Resistant Pseudomonas aeruginosa Small-Colony Variant. AB - Pseudomonas aeruginosa is a major causative agent of both acute and chronic infections. Although aminoglycoside antibiotics are very potent drugs against such infections, antibiotic failure is steadily increasing mainly because of increasing resistance of the bacteria. Many molecular mechanisms that determine resistance, such as acquisition of genes encoding aminoglycoside-inactivating enzymes or overexpression of efflux pumps, have been elucidated. However, there are additional, less well-described mechanisms of aminoglycoside resistance. In this study, we profiled a clinical tobramycin-resistant P. aeruginosa strain that exhibited a small-colony variant (SCV) phenotype. Both the resistance and colony morphology phenotypes were lost upon passage of the isolate under rich medium conditions. Transcriptional and mutational profiling revealed that the SCV harbored activating mutations in the two-component systems AmgRS and PmrAB. Introduction of these mutations individually into type strain PA14 conferred tobramycin and colistin resistance, respectively. However, their combined introduction had an additive effect on the tobramycin resistance phenotype. Activation of the AmgRS system slightly reduced the colony size of wild-type PA14, whereas the simultaneous overexpression of gacA, the response regulator of the GacSA two-component system, further reduced colony size. In conclusion, we uncovered combinatorial influences of two-component systems on clinically relevant phenotypes such as resistance and the expression of the SCV phenotype. Our results clearly demonstrate that the combined activation of P. aeruginosa two component systems has pleiotropic effects with unforeseen consequences. PMID- 28874370 TI - N-Acetylglucosamine-1-Phosphate Transferase, WecA, as a Validated Drug Target in Mycobacterium tuberculosis. AB - The mycobacterial phosphoglycosyltransferase WecA, which initiates arabinogalactan biosynthesis in Mycobacterium tuberculosis, has been proposed as a target of the caprazamycin derivative CPZEN-45, a preclinical drug candidate for the treatment of tuberculosis. In this report, we describe the functional characterization of mycobacterial WecA and confirm the essentiality of its encoding gene in M. tuberculosis by demonstrating that the transcriptional silencing of wecA is bactericidal in vitro and in macrophages. Silencing wecA also conferred hypersensitivity of M. tuberculosis to the drug tunicamycin, confirming its target selectivity for WecA in whole cells. Simple radiometric assays performed with mycobacterial membranes and commercially available substrates allowed chemical validation of other putative WecA inhibitors and resolved their selectivity toward WecA versus another attractive cell wall target, translocase I, which catalyzes the first membrane step in the biosynthesis of peptidoglycan. These assays and the mutant strain described herein will be useful for identifying potential antitubercular leads by screening chemical libraries for novel WecA inhibitors. PMID- 28874371 TI - Commercial Intravenous Immunoglobulin Preparations Contain Functional Neutralizing Antibodies against the Staphylococcus aureus Leukocidin LukAB (LukGH). AB - The pathogenesis of Staphylococcus aureus is mediated by an array of important virulence factors, including the two-component leukocidin family of toxins. LukAB (also known as LukGH), the most recently discovered leukocidin, is potently lethal to phagocytes, produced during invasive human disease, and present in all known clinical isolates of S. aureus Intravenous immunoglobulin (IVIg) is often used clinically in severe S. aureus infections. The primary aim of this study was to assess the binding and neutralization potential of IVIg against LukAB. A secondary aim was to examine the lot-to-lot variability of IVIg in the binding and neutralization of LukAB. We studied 24 distinct lots of IVIg and compared them to serum from children with invasive S. aureus infection (in the acute and convalescent phases) and from healthy, uninfected controls. We found that all lots of IVIg contained functional antibodies targeting LukAB. After adjusting for total antibody content per sample, we found that the amount of anti-LukAB antibody in IVIg was similar to that seen with healthy controls and less than that seen with patients with invasive S. aureus infection. IVIg samples had lower neutralization capacity than samples from healthy controls and children with invasive infection. IVIg had remarkably little lot-to-lot variation in LukAB binding but had significantly more variation in toxin neutralization. These results represent the first report of functional antibodies against the important S. aureus leukocidin LukAB in IVIg. Given the frequent clinical use of IVIg for severe S. aureus infections, improving our understanding of functional antibody properties exhibited by this therapeutic is essential. PMID- 28874372 TI - Multiple Modes of Action of a Monoclonal Antibody against Multidrug-Resistant Escherichia coli Sequence Type 131-H30. AB - The multidrug-resistant H30 subclone of extraintestinal pathogenic Escherichia coli sequence type 131 (ST131-H30) has spread worldwide. This clone expresses a conserved lipopolysaccharide (LPS) O antigen, O25b. Previously, we described monoclonal antibodies (MAbs) specific to the O25b antigen and characterized them as diagnostic and therapeutic tools. In this study, evidence is provided that besides the previously shown complement-mediated bactericidal effect, an O25b specific humanized MAb, A1124, also enhances opsonophagocytic uptake by the murine macrophage cell line RAW 264.7. Both phagocyte-dependent killing and phagocyte-independent killing, triggered by A1124, were confirmed in human whole blood. Furthermore, A1124 was shown to neutralize endotoxin activity of purified LPS of clinical isolates. This activity was demonstrated in vitro using both RAW 264.7 cells and a human Toll-like receptor 4 (TLR4) reporter cell line, as well as in a murine model of endotoxemia using purified LPS for challenge. Significant protective efficacy of A1124 at low doses (<1 mg/kg of body weight) was shown in murine and rat models of bacteremia. The contribution of the bactericidal and anti-inflammatory effects was dissected in the mouse bacteremia model through depletion of complement with cobra venom factor (CVF). Protective efficacy was lost in complement-depleted mice, suggesting the essential role of complement mediated activities for protection in this model. These data suggest that A1124 exhibits different mechanisms of action, namely, direct complement-mediated and opsonophagocytic killing as well as endotoxin neutralization in various challenge models. Which of these activities are the most relevant in a clinical setting will need to be addressed by future translational studies. PMID- 28874373 TI - Hyperbaric Oxygen Sensitizes Anoxic Pseudomonas aeruginosa Biofilm to Ciprofloxacin. AB - Chronic Pseudomonas aeruginosa lung infection is characterized by the presence of endobronchial antibiotic-tolerant biofilm, which is subject to strong oxygen (O2) depletion due to the activity of surrounding polymorphonuclear leukocytes. The exact mechanisms affecting the antibiotic susceptibility of biofilms remain unclear, but accumulating evidence suggests that the efficacy of several bactericidal antibiotics is enhanced by stimulation of aerobic respiration of pathogens, while lack of O2 increases their tolerance. In fact, the bactericidal effect of several antibiotics depends on active aerobic metabolism activity and the endogenous formation of reactive O2 radicals (ROS). In this study, we aimed to apply hyperbaric oxygen treatment (HBOT) to sensitize anoxic P. aeruginosa agarose biofilms established to mimic situations with intense O2 consumption by the host response in the cystic fibrosis (CF) lung. Application of HBOT resulted in enhanced bactericidal activity of ciprofloxacin at clinically relevant durations and was accompanied by indications of restored aerobic respiration, involvement of endogenous lethal oxidative stress, and increased bacterial growth. The findings highlight that oxygenation by HBOT improves the bactericidal activity of ciprofloxacin on P. aeruginosa biofilm and suggest that bacterial biofilms are sensitized to antibiotics by supplying hyperbaric O2. PMID- 28874374 TI - Structure and Dynamics of FosA-Mediated Fosfomycin Resistance in Klebsiella pneumoniae and Escherichia coli. AB - Fosfomycin exhibits broad-spectrum antibacterial activity and is being reevaluated for the treatment of extensively drug-resistant pathogens. Its activity in Gram-negative organisms, however, can be compromised by expression of FosA, a metal-dependent transferase that catalyzes the conjugation of glutathione to fosfomycin, rendering the antibiotic inactive. In this study, we solved the crystal structures of two of the most clinically relevant FosA enzymes: plasmid encoded FosA3 from Escherichia coli and chromosomally encoded FosA from Klebsiella pneumoniae (FosAKP). The structure, molecular dynamics, catalytic activity, and fosfomycin resistance of FosA3 and FosAKP were also compared to those of FosA from Pseudomonas aeruginosa (FosAPA), for which prior crystal structures exist. E. coli TOP10 transformants expressing FosA3 and FosAKP conferred significantly greater fosfomycin resistance (MIC, >1,024 MUg/ml) than those expressing FosAPA (MIC, 16 MUg/ml), which could be explained in part by the higher catalytic efficiencies of the FosA3 and FosAKP enzymes. Interestingly, these differences in enzyme activity could not be attributed to structural differences at their active sites. Instead, molecular dynamics simulations and hydrogen-deuterium exchange experiments with FosAKP revealed dynamic interconnectivity between its active sites and a loop structure that extends from the active site of each monomer and traverses the dimer interface. This dimer interface loop is longer and more extended in FosAKP and FosA3 than in FosAPA, and kinetic analyses of FosAKP and FosAPA loop-swapped chimeric enzymes highlighted its importance in FosA activity. Collectively, these data yield novel insights into fosfomycin resistance that could be leveraged to develop new strategies to inhibit FosA and potentiate fosfomycin activity. PMID- 28874375 TI - Subinhibitory Dalbavancin Attenuates Exotoxin Production from Methicillin Sensitive and Methicillin-Resistant Staphylococcus aureus In Vitro. AB - This study investigated the effects of subinhibitory doses of the lipoglycopeptide antibiotic dalbavancin on Staphylococcus aureus toxin production in vitroS. aureus toxin production levels were compared to those seen with the natural glycopeptide antibiotic vancomycin and with representative beta-lactam and oxazolidinone antibiotics. While neither dalbavancin nor vancomycin adversely affected toxin production, of these glycopeptide antibiotics, only dalbavancin significantly attenuated toxin production at subinhibitory concentrations. These findings support the recent success of dalbavancin for treatment of staphylococcal infections. PMID- 28874377 TI - High-Level Resistance to Colistin Mediated by Various Mutations in the crrB Gene among Carbapenemase-Producing Klebsiella pneumoniae. AB - Mutations in crrAB genes encoding a two-component regulator involved in modifications of lipopolysaccharide were searched for among a collection of colistin-resistant Klebsiella pneumoniae isolates. Four isolates, respectively, producing carbapenemases NDM-1, OXA-181, or KPC-2 showed mutated CrrB proteins compared with those in wild-type strains. Complementation assays with a wild-type CrrB protein restored the susceptibility to colistin in all cases, confirming the involvement of the identified substitutions in the resistance phenotype. PMID- 28874376 TI - Genomics and Susceptibility Profiles of Extensively Drug-Resistant Pseudomonas aeruginosa Isolates from Spain. AB - This study assessed the molecular epidemiology, resistance mechanisms, and susceptibility profiles of a collection of 150 extensively drug-resistant (XDR) Pseudomonas aeruginosa clinical isolates obtained from a 2015 Spanish multicenter study, with a particular focus on resistome analysis in relation to ceftolozane tazobactam susceptibility. Broth microdilution MICs revealed that nearly all (>95%) of the isolates were nonsusceptible to piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, imipenem, meropenem, and ciprofloxacin. Most of them were also resistant to tobramycin (77%), whereas nonsusceptibility rates were lower for ceftolozane-tazobactam (31%), amikacin (7%), and colistin (2%). Pulsed-field gel electrophoresis-multilocus sequence typing (PFGE-MLST) analysis revealed that nearly all of the isolates belonged to previously described high risk clones. Sequence type 175 (ST175) was detected in all 9 participating hospitals and accounted for 68% (n = 101) of the XDR isolates, distantly followed by ST244 (n = 16), ST253 (n = 12), ST235 (n = 8), and ST111 (n = 2), which were detected only in 1 to 2 hospitals. Through phenotypic and molecular methods, the presence of horizontally acquired carbapenemases was detected in 21% of the isolates, mostly VIM (17%) and GES enzymes (4%). At least two representative isolates from each clone and hospital (n = 44) were fully sequenced on an Illumina MiSeq. Classical mutational mechanisms, such as those leading to the overexpression of the beta-lactamase AmpC or efflux pumps, OprD inactivation, and/or quinolone resistance-determining regions (QRDR) mutations, were confirmed in most isolates and correlated well with the resistance phenotypes in the absence of horizontally acquired determinants. Ceftolozane-tazobactam resistance was not detected in carbapenemase-negative isolates, in agreement with sequencing data showing the absence of ampC mutations. The unique set of mutations responsible for the XDR phenotype of ST175 clone documented 7 years earlier were found to be conserved, denoting the long-term persistence of this specific XDR lineage in Spanish hospitals. Finally, other potentially relevant mutations were evidenced, including those in penicillin-binding protein 3 (PBP3), which is involved in beta-lactam (including ceftolozane-tazobactam) resistance, and FusA1, which is linked to aminoglycoside resistance. PMID- 28874378 TI - Mycobacterium abscessus WhiB7 Regulates a Species-Specific Repertoire of Genes To Confer Extreme Antibiotic Resistance. AB - Mycobacterium abscessus causes acute and chronic bronchopulmonary infection in patients with chronic lung damage, of which cystic fibrosis (CF) patients are particularly vulnerable. The major threat posed by this organism is its high intrinsic antibiotic resistance. A typical treatment regimen involves a 6- to 12 month-long combination therapy of clarithromycin and amikacin, with cure rates below 50% and multiple side effects, especially due to amikacin. In the present work, we show that M. abscessuswhiB7, a homologue of Mycobacterium tuberculosis and Mycobacterium smegmatis whiB7 with previously demonstrated effects on intrinsic antibiotic resistance, is strongly induced when exposed to clinically relevant antibiotics that target the ribosome: erythromycin, clarithromycin, amikacin, tetracycline, and spectinomycin. The deletion of M. abscessuswhiB7 results in sensitivity to all of the above-mentioned antibiotics. Further, we have defined and compared the whiB7 regulon of M. abscessus with the closely related nontuberculous mycobacterium (NTM) M. smegmatis to demonstrate the induction of a species-specific repertoire of genes. Finally, we show that one such gene, eis2, is specifically induced in M. abscessus by whiB7 and contributes to its higher levels of intrinsic amikacin resistance. This species-specific pattern of gene induction might account for the differences in drug susceptibilities to other antibiotics and between different mycobacterial species. PMID- 28874379 TI - Antagonism between Front-Line Antibiotics Clarithromycin and Amikacin in the Treatment of Mycobacterium abscessus Infections Is Mediated by the whiB7 Gene. AB - Combinations of antibiotics, each individually effective against Mycobacterium abscessus, are routinely coadministered based on the concept that this minimizes the spread of antibiotic resistance. However, our in vitro data contradict this assumption and instead document antagonistic interactions between two antibiotics (clarithromycin and amikacin) used to treat M. abscessus infections. Clinically relevant concentrations of clarithromycin induced increased resistance to both amikacin and itself. The induction of resistance was dependent on whiB7, a transcriptional activator of intrinsic antibiotic resistance that is induced by exposure to many different antibiotics. In M. abscessus, the deletion of whiB7 (MAB_3508c) resulted in increased sensitivity to a broad range of antibiotics. WhiB7 was required for transcriptional activation of genes that confer resistance to three commonly used anti-M. abscessus drugs: clarithromycin, amikacin, and tigecycline. The whiB7-dependent gene that conferred macrolide resistance was identified as erm(41) (MAB_2297), which encodes a ribosomal methyltransferase. The whiB7-dependent gene contributing to amikacin resistance was eis2 (MAB_4532c), which encodes a Gcn5-related N-acetyltransferase (GNAT). Transcription of whiB7 and the resistance genes in its regulon was inducible by subinhibitory concentrations of clarithromycin but not by amikacin. Thus, exposure to clarithromycin, or likely any whiB7-inducing antibiotic, may antagonize the activities of amikacin and other drugs. This has important implications for the management of M. abscessus infections, both in cystic fibrosis (CF) and non-CF patients. PMID- 28874380 TI - The Global Regulatory Cyclic AMP Receptor Protein (CRP) Controls Multifactorial Fluoroquinolone Susceptibility in Salmonella enterica Serovar Typhimurium. AB - Fluoroquinolone antibiotics are prescribed for the treatment of Salmonella enterica infections, but resistance to this family of antibiotics is growing. Here we report that loss of the global regulatory protein cyclic AMP (cAMP) receptor protein (CRP) or its allosteric effector, cAMP, reduces susceptibility to fluoroquinolones. A Deltacrp mutation was synergistic with the primary fluoroquinolone resistance allele gyrA83, thus able to contribute to clinically relevant resistance. Decreased susceptibility to fluoroquinolones could be partly explained by decreased expression of the outer membrane porin genes ompA and ompF with a concomitant increase in the expression of the ciprofloxacin resistance efflux pump gene acrB in Deltacrp cells. Expression of gyrAB, which encode the DNA supercoiling enzyme GyrAB, which is blocked by fluoroquinolones, and expression of topA, which encodes the dominant supercoiling-relaxing enzyme topoisomerase I, were unchanged in Deltacrp cells. Yet Deltacrp cells maintained a more relaxed state of DNA supercoiling, correlating with an observed increase in topoisomerase IV (parCE) expression. Surprisingly, the Deltacrp mutation had the unanticipated effect of enhancing fitness in the presence of fluoroquinolone antibiotics, which can be explained by the observation that exposure of Deltacrp cells to ciprofloxacin had the counterintuitive effect of restoring wild-type levels of DNA supercoiling. Consistent with this, Deltacrp cells did not become elongated or induce the SOS response when challenged with ciprofloxacin. These findings implicate the combined action of multiple drug resistance mechanisms in Deltacrp cells: reduced permeability and elevated efflux of fluoroquinolones coupled with a relaxed DNA supercoiling state that buffers cells against GyrAB inhibition by fluoroquinolones. PMID- 28874381 TI - Efficacy of a New Recrystallized Enrofloxacin Hydrochloride-Dihydrate against Leptospirosis in a Hamster Model. AB - A trial on Syrian hamsters (Mesocricetus auratus) infected with Leptospira interrogans serovar Canicola was established to compare treatment efficacies of daily intramuscular (i.m.) injections of either 10 mg/kg of 5% enrofloxacin (Baytril [BE]; Bayer Animal Health, Mexico) or the same dose of enrofloxacin hydrochloride-dihydrate (enro-C). Hamsters were experimentally infected via the oral submucosa with 400 microorganisms/animal, in a sequential time schedule aligned to the initial treatment day, and were treated in groups as follows: a group treated with 5% enrofloxacin daily for 7 days after 24 h of infection (group BE24); a group treated as described for group BE24 but with enro-C (enro C24); a group also treated with 5% enrofloxacin but starting at 72 h after infection (BE74); a group treated as described for group BE74 but with injection of enro-C (enro-C74). An untreated-uninfected control group (group CG-) and an infected-untreated control group (group CG+) were assembled (n = 18 in all groups). Weights and temperatures of the hamsters were monitored daily for 28 days. After hamsters were euthanatized or following death, necropsy, histopathology, macroscopic agglutination tests (MAT), bacterial culture, and PCR were performed. The mortality rates were 38.8% in group BE24 and 100% in group BE74 No mortality was observed in group enro-C24, and 11.1% mortality was recorded in group enro-C74 The mortality rates in groups CG+ and CG- were 100% and zero, respectively. Combined necropsy and histopathologic findings revealed signs of septicemia and organ damage in groups BE24, BE72, and CG+ Groups enro C24 and CG- showed no lesions. Moderated lesions were registered in 3 hamsters in group enro-C72 MAT results were positive in 83.3% of BE24 hamsters (83.3%) and 100% of BE72 and CG+ hamsters; MAT results were positive in 16.7% in group Enro C24 and 38.9% in group enro-C72 Only 4/18 were PCR positive in group enro-C72 and only 1 in group enro-C24 (P < 0.05). It can be concluded that enro-C may be a viable option to treat leptospirosis in hamsters and that this may be the case in other species. PMID- 28874382 TI - Evaluation of the Innate Immune Modulator Acitretin as a Strategy To Clear the HIV Reservoir. AB - The persistence of HIV despite suppressive antiretroviral therapy is a major roadblock to HIV eradication. Current strategies focused on inducing the expression of latent HIV fail to clear the persistent reservoir, prompting the development of new approaches for killing HIV-positive cells. Recently, acitretin was proposed as a pharmacological enhancer of the innate cellular defense network that led to virus reactivation and preferential death of infected cells. We evaluated the capacity of acitretin to reactivate and/or to facilitate immune mediated clearance of HIV-positive cells. Acitretin did not induce HIV reactivation in latently infected cell lines (J-Lat and ACH-2). We could observe only modest induction of HIV reactivation by acitretin in latently green fluorescent protein-HIV-infected Jurkat cells, comparable to suboptimal concentrations of vorinostat, a known latency-reversing agent (LRA). Acitretin induction was insignificant, however, compared to optimal concentrations of LRAs. Acitretin failed to reactivate HIV in a model of latently infected primary CD4+ T cells but induced retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling (MAVS) expression in infected and uninfected cells, confirming the role of acitretin as an innate immune modulator. However, this effect was not associated with selective killing of HIV-positive cells. In conclusion, acitretin-mediated stimulation of the RIG-I pathway for HIV reactivation is modest and thus may not meaningfully affect the HIV reservoir. Stimulation of the RIG-I-dependent interferon (IFN) cascade by acitretin may not significantly affect the selective destruction of latently infected HIV-positive cells. PMID- 28874383 TI - Transcriptome Analysis Suggests That Chromosome Introgression Fragments from Sea Island Cotton (Gossypium barbadense) Increase Fiber Strength in Upland Cotton (Gossypium hirsutum). AB - As high-strength cotton fibers are critical components of high quality cotton, developing cotton cultivars with high-strength fibers as well as high yield is a top priority for cotton development. Recently, chromosome segment substitution lines (CSSLs) have been developed from high-yield Upland cotton (Gossypium hirsutum) crossed with high-quality Sea Island cotton (G. barbadense). Here, we constructed a CSSL population by crossing CCRI45, a high-yield Upland cotton cultivar, with Hai1, a Sea Island cotton cultivar with superior fiber quality. We then selected two CSSLs with significantly higher fiber strength than CCRI45 (MBI7747 and MBI7561), and one CSSL with lower fiber strength than CCRI45 (MBI7285), for further analysis. We sequenced all four transcriptomes at four different time points postanthesis, and clustered the 44,678 identified genes by function. We identified 2200 common differentially-expressed genes (DEGs): those that were found in both high quality CSSLs (MBI7747 and MBI7561), but not in the low quality CSSL (MBI7285). Many of these genes were associated with various metabolic pathways that affect fiber strength. Upregulated DEGs were associated with polysaccharide metabolic regulation, single-organism localization, cell wall organization, and biogenesis, while the downregulated DEGs were associated with microtubule regulation, the cellular response to stress, and the cell cycle. Further analyses indicated that three genes, XLOC_036333 [mannosyl oligosaccharide-alpha-mannosidase (MNS1)], XLOC_029945 (FLA8), and XLOC_075372 (snakin-1), were potentially important for the regulation of cotton fiber strength. Our results suggest that these genes may be good candidates for future investigation of the molecular mechanisms of fiber strength formation and for the improvement of cotton fiber quality through molecular breeding. PMID- 28874384 TI - Heart Failure Is Common and Under-Recognized in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia. AB - BACKGROUND: Heart failure (HF) prevalence in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) varies depending on study cohort and is not well characterized. This study sought to determine prevalence and predictors of HF in ARVC/D. METHODS AND RESULTS: Clinical HF, defined as at least 1 HF sign or symptom, was retrospectively adjudicated for 289 patients meeting ARVC/D Task Force Criteria. HF was present in 142 patients (49%): 113 had isolated RV involvement and 29 had evidence of LV dysfunction. Average age of HF onset was 40+/-14 years. Most commonly reported symptoms were exertional dyspnea (78%) and fatigue (73%). Only 40% (n=57/142) had signs of volume overload. Left-sided HF signs were rare. Patients with clinical HF before ARVC/D diagnosis (n=31) were older (P=0.005) and met fewer Task Force Criteria (P=0.013) than those who developed HF after ARVC/D presentation. Female sex (odds ratio, 2.2; 95% confidence interval, 1.21-4.01; P=0.01) and lateral precordial T-wave inversions (odds ratio, 9.87; 95% confidence interval, 1.07-91.1; P=0.043) were associated with increased odds of HF. Additionally, patients with symptomatic LV dysfunction had higher odds of lateral precordial T-wave inversions (odds ratio, 18.4; 95% confidence interval, 2.92-116.18; P=0.002). Patients with HF were more likely to undergo heart transplantation (15/142 versus 1/147; P<0.001) or die during study follow-up period (7 versus 0; P=0.007). CONCLUSIONS: HF symptoms, especially exertional dyspnea, are common in ARVC/D; yet, classic left-sided signs are typically absent and less than half have evidence of volume overload. Given the unique predominately right-sided phenotype, a large portion of patients with HF may be under-recognized. PMID- 28874385 TI - Do studies calculate the NNT appropriately? PMID- 28874386 TI - Value of SMBG in non-insulin-treated type 2 diabetes. PMID- 28874387 TI - Antibiotic prescribing: patient need or prescriber habit? PMID- 28874388 TI - Diagnosis and investigation of fungal skin and nail infections. PMID- 28874389 TI - European guideline on antimicrobial resistance. PMID- 28874390 TI - Brimonidine gel and adverse cardiovascular effects. PMID- 28874391 TI - ? Vortioxetine for acute depression in adults. PMID- 28874392 TI - Zika virus has oncolytic activity against glioblastoma stem cells. AB - Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients. PMID- 28874394 TI - Looking beyond the thyroid: advances in the understanding of pheochromocytoma and hyperparathyroidism phenotypes in MEN2 and of non-MEN2 familial forms. AB - Over the last years, the knowledge of MEN2 and non-MEN2 familial forms of pheochromocytoma (PHEO) has increased. In MEN2, PHEO is the second most frequent disease: the penetrance and age at diagnosis depend on the mutation of RET Given the prevalence of bilateral PHEO (50% by age 50), adrenal sparing surgery, aimed at sparing a part of the adrenal cortex to avoid adrenal insufficiency, should be systematically considered in patients with bilateral PHEO. Non-MEN2 familial forms of PHEO now include more than 20 genes: however, only small phenotypic series have been reported, suggesting that phenotypic features of isolated hereditary PHEO must be better explored, and follow-up series are needed to better understand the outcome of patients carrying mutations of these genes. The first part of this review will mainly focus on these points. In the second part, a focus will be given on MEN2 and non-MEN2 familial forms of hyperparathyroidism (HPTH). Again, the management of MEN2 HPTH should be aimed at curing the disease while preserving an optimal quality of life by a tailored parathyroidectomy. The phenotypes and outcome of MEN1-, MEN4- and HRPT2-related HPTH are briefly described, with a focus on the most recent literature data and is compared with familial hypocalciuric hypercalcemia. PMID- 28874393 TI - TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis. AB - Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression. PMID- 28874395 TI - CELF1 Mediates Connexin 43 mRNA Degradation in Dilated Cardiomyopathy. AB - RATIONALE: Downregulation of Cx43 (connexin 43), the major cardiac gap junction protein, is often associated with arrhythmia, dilated cardiomyopathy (DCM), and heart failure. However, the cause of the reduced expression remains elusive. Reinduction of a nuclear RNA-binding protein CELF1 (CUGBP Elav-like family member 1) in the adult heart has been implicated in the cardiac pathogenesis of myotonic dystrophy type 1. However, how elevated CELF1 level leads to cardiac dysfunction, such as conduction defect, DCM, and heart failure, remains unclear. OBJECTIVE: We investigated the mechanism of CELF1-mediated Cx43 mRNA degradation and determined whether elevated CELF1 expression is also a shared feature of the DCM heart. METHODS AND RESULTS: RNA immunoprecipitation revealed the involvement of CELF1 regulated genes, including Cx43, in controlling contractility and conduction. CELF1 mediated Cx43 mRNA degradation by binding the UG-rich element in the 3' untranslated region of Cx43. Mutation of the nuclear localization signal in CELF1 abolished the ability to downregulate Cx43 mRNA, so nuclear localization was required for its function. We further identified a 3' to 5' exoribonuclease, RRP6 (ribosomal RNA processing protein 6), as a CELF1-interacting protein. The interaction of CELF1 and RRP6 was RNA-independent and nucleus specific. With knockdown of endogenous RRP6, CELF1 failed to downregulate Cx43 mRNA, which suggests that RRP6 was required for CELF1-mediated Cx43 mRNA degradation. In addition, increased CELF1 level accompanied upregulated RRP6, and reduced Cx43 level was detected in mouse models with DCM, including myotonic dystrophy type 1 and CELF1 overexpression models and a myocardial infarction model. Importantly, depletion of CELF1 in the infarcted heart preserved Cx43 mRNA level and ameliorated the cardiac phenotypes of the infarcted heart. CONCLUSIONS: Our results suggest a mechanism for increased CELF1 expression downregulating Cx43 mRNA level and a pathogenic role for elevated CELF1 level in the DCM heart. PMID- 28874396 TI - Body Height and Incident Risk of Venous Thromboembolism: A Cosibling Design. AB - BACKGROUND: Body height has been associated with an increased risk of venous thromboembolism (VTE), but the association can be confounded with shared familial factors (genetic/environmental). A cosibling design is useful for deeper understanding about the relationship between VTE and height. METHODS AND RESULTS: From Swedish national registry databases, we used a corelative design with full siblings alongside a general Swedish population sample. A cohort of male conscripts (n=1 610 870), born in 1951 to 1992 without previous VTE, was followed from enlistment (1969-2010) until 2012. Another cohort of first-time pregnant women (n=1 093 342) from the medical birth register, without previous VTE, was followed from first pregnancy (1982-2012) until 2012. Using the Multi-Generation Register, we identified all full-sibling pairs discordant for height. This cosibling design allowed for adjustment for familial factors (genetic/environmental). Compared with the tallest women (>185 cm) and men (>190 cm), there was a graded decreased risk by lower height for both men and women. The risk was lowest in women and men with the shortest stature (<155 and <160 cm, respectively): hazard ratios=0.31 (95% confidence interval, 0.22-0.42) and 0.35 (95% confidence interval, 0.22-0.55), respectively. There was a graded association also in the cosibling design comparing siblings with varying degree of discordance for height (reference was the taller sibling): >=10 cm difference between brothers hazard ratios=0.69 (95% confidence interval, 0.61-0.78) and sisters hazard ratios=0.65 (95% confidence interval, 0.52-0.80), respectively. CONCLUSIONS: Height is an independent predictor of VTE. The use of sibling pairs reduces the likelihood that familial confounding explains the results. The findings are important for the understanding of the pathogenesis of VTE. PMID- 28874397 TI - Insights From the Positive Association of Height With Incident Venous Thromboembolism. PMID- 28874398 TI - Solid-phase reverse transfection for intracellular delivery of functionally active proteins. AB - Delivery of large and functionally active biomolecules across cell membranes presents a challenge in cell biological experimentation. For this purpose, we developed a novel solid-phase reverse transfection method that is suitable for the intracellular delivery of proteins into mammalian cells with preservation of their function. We show results for diverse application areas of the method, ranging from antibody-mediated inhibition of protein function to CRISPR/Cas9 based gene editing in living cells. Our method enables prefabrication of "ready to transfect" substrates carrying diverse proteins. This allows their easy distribution and standardization of biological assays across different laboratories. PMID- 28874399 TI - Children with mental health disorders have lower symptoms of depression 3 years after contact with mental health services. PMID- 28874400 TI - Sustaining CBE-Life Sciences Education. PMID- 28874401 TI - EDC IMPACT: Chemical UV filters can affect human sperm function in a progesterone like manner. AB - Human sperm cell function must be precisely regulated to achieve natural fertilization. Progesterone released by the cumulus cells surrounding the egg induces a Ca2+ influx into human sperm cells via the CatSper Ca2+-channel and thereby controls sperm function. Multiple chemical UV filters have been shown to induce a Ca2+ influx through CatSper, thus mimicking the effect of progesterone on Ca2+ signaling. We hypothesized that these UV filters could also mimic the effect of progesterone on sperm function. We examined 29 UV filters allowed in sunscreens in the US and/or EU for their ability to affect acrosome reaction, penetration, hyperactivation and viability in human sperm cells. We found that, similar to progesterone, the UV filters 4-MBC, 3-BC, Meradimate, Octisalate, BCSA, HMS and OD-PABA induced acrosome reaction and 3-BC increased sperm penetration into a viscous medium. The capacity of the UV filters to induce acrosome reaction and increase sperm penetration was positively associated with the ability of the UV filters to induce a Ca2+ influx. None of the UV filters induced significant changes in the proportion of hyperactivated cells. In conclusion, chemical UV filters that mimic the effect of progesterone on Ca2+ signaling in human sperm cells can similarly mimic the effect of progesterone on acrosome reaction and sperm penetration. Human exposure to these chemical UV filters may impair fertility by interfering with sperm function, e.g. through induction of premature acrosome reaction. Further studies are needed to confirm the results in vivo. PMID- 28874402 TI - Transplantation of Kidneys from HCV-Positive Donors: How to Best Use a Scarce Resource. PMID- 28874403 TI - New Insights into Fuel Choices of Nephron Progenitor Cells. PMID- 28874404 TI - Pediatric Price Transparency: Still Opaque With Opportunities for Improvement. AB - OBJECTIVES: Price transparency is gaining importance as families' portion of health care costs rise. We describe (1) online price transparency data for pediatric care on children's hospital Web sites and state-based price transparency Web sites, and (2) the consumer experience of obtaining an out-of pocket estimate from children's hospitals for a common procedure. METHODS: From 2015 to 2016, we audited 45 children's hospital Web sites and 38 state-based price transparency Web sites, describing availability and characteristics of health care prices and personalized cost estimate tools. Using secret shopper methodology, we called children's hospitals and submitted online estimate requests posing as a self-paying family requesting an out-of-pocket estimate for a tonsillectomy-adenoidectomy. RESULTS: Eight children's hospital Web sites (18%) listed prices. Twelve (27%) provided personalized cost estimate tool (online form n = 5 and/or phone number n = 9). All 9 hospitals with a phone number for estimates provided the estimated patient liability for a tonsillectomy adenoidectomy (mean $6008, range $2622-$9840). Of the remaining 36 hospitals without a dedicated price estimate phone number, 21 (58%) provided estimates (mean $7144, range $1200-$15 360). Two of 4 hospitals with online forms provided estimates. Fifteen (39%) state-based Web sites distinguished between prices for pediatric and adult care. One had a personalized cost estimate tool. CONCLUSIONS: Meaningful prices for pediatric care were not widely available online through children's hospital or state-based price transparency Web sites. A phone line or online form for price estimates were effective strategies for hospitals to provide out-of-pocket price information. Opportunities exist to improve pediatric price transparency. PMID- 28874405 TI - Pediatric Price Transparency: Time to Come Out of the Dark. PMID- 28874406 TI - Revisiting the Role of Csp Family Proteins in Regulating Clostridium difficile Spore Germination. AB - Clostridium difficile causes considerable health care-associated gastrointestinal disease that is transmitted by its metabolically dormant spore form. Upon entering the gut, C. difficile spores germinate and outgrow to produce vegetative cells that release disease-causing toxins. C. difficile spore germination depends on the Csp family of (pseudo)proteases and the cortex hydrolase SleC. The CspC pseudoprotease functions as a bile salt germinant receptor that activates the protease CspB, which in turn proteolytically activates the SleC zymogen. Active SleC degrades the protective cortex layer, allowing spores to outgrow and resume metabolism. We previously showed that the CspA pseudoprotease domain, which is initially produced as a fusion to CspB, controls the incorporation of the CspC germinant receptor in mature spores. However, study of the individual Csp proteins has been complicated by the polar effects of TargeTron-based gene disruption on the cspBA-cspC operon. To overcome these limitations, we have used pyrE-based allelic exchange to create individual deletions of the regions encoding CspB, CspA, CspBA, and CspC in strain 630Deltaerm Our results indicate that stable CspA levels in sporulating cells depend on CspB and confirm that CspA maximizes CspC incorporation into spores. Interestingly, we observed that csp and sleC mutants spontaneously germinate more frequently in 630Deltaerm than equivalent mutants in the JIR8094 and UK1 strain backgrounds. Analyses of this phenomenon suggest that only a subpopulation of C. difficile 630Deltaerm spores can spontaneously germinate, in contrast with Bacillus subtilis spores. We also show that C. difficile clinical isolates that encode truncated CspBA variants have sequencing errors that actually produce full-length CspBA.IMPORTANCEClostridium difficile is a leading cause of health care associated infections. Initiation of C. difficile infection depends on spore germination, a process controlled by Csp family (pseudo)proteases. The CspC pseudoprotease is a germinant receptor that senses bile salts and activates the CspB protease, which activates a hydrolase required for germination. Previous work implicated the CspA pseudoprotease in controlling CspC incorporation into spores but relied on plasmid-based overexpression. Here we have used allelic exchange to study the functions of CspB and CspA. We determined that CspA production and/or stability depends on CspB and confirmed that CspA maximizes CspC incorporation into spores. Our data also suggest that a subpopulation of C. difficile spores spontaneously germinates in the absence of bile salt germinants and/or Csp proteins. PMID- 28874407 TI - Anaerobic Mycobacterium tuberculosis Cell Death Stems from Intracellular Acidification Mitigated by the DosR Regulon. AB - Mycobacterium tuberculosis is a strict aerobe capable of prolonged survival in the absence of oxygen. We investigated the ability of anaerobic M. tuberculosis to counter challenges to internal pH homeostasis in the absence of aerobic respiration, the primary mechanism of proton efflux for aerobic bacilli. Anaerobic M. tuberculosis populations were markedly impaired for survival under a mildly acidic pH relative to standard culture conditions. An acidic environmental pH greatly increased the susceptibilities of anaerobic bacilli to the collapse of the proton motive force by protonophores, to antimicrobial compounds that target entry into the electron transport system, and to small organic acids with uncoupling activity. However, anaerobic bacilli exhibited high tolerance against these challenges at a near-neutral pH. At a slightly alkaline pH, which was near the optimum intracellular pH, the addition of protonophores even improved the long-term survival of bacilli. Although anaerobic M. tuberculosis bacilli under acidic conditions maintained 40% lower ATP levels than those of bacilli under standard culture conditions, ATP loss alone could not explain the drop in viability. Protonophores decreased ATP levels by more than 90% regardless of the extracellular pH but were bactericidal only under acidic conditions, indicating that anaerobic bacilli could survive an extreme ATP loss provided that the external pH was within viable intracellular parameters. Acidic conditions drastically decreased the anaerobic survival of a DosR mutant, while an alkaline environment improved the survival of the DosR mutant. Together, these findings indicate that intracellular acidification is a primary challenge for the survival of anaerobic M. tuberculosis and that the DosR regulon plays a critical role in sustaining internal pH homeostasis.IMPORTANCE During infection, M. tuberculosis bacilli are prevalent in environments largely devoid of oxygen, yet the factors that influence the survival of these severely growth-limited and metabolically limited bacilli remain poorly understood. We determined how anaerobic bacilli respond to fluctuations in environmental pH and observed that these bacilli were highly susceptible to stresses that promoted internal acidic stress, whereas conditions that promoted an alkaline internal pH promoted long-term survival even during severe ATP depletion. The DosR regulon, a major regulator of general hypoxic stress, played an important role in maintaining internal pH homeostasis under anaerobic conditions. Together, these findings indicate that in the absence of aerobic respiration, protection from internal acidification is crucial for long-term M. tuberculosis survival. PMID- 28874408 TI - Defining the Mechanical Determinants of Kingella kingae Adherence to Host Cells. AB - Kingella kingae is an important pathogen in young children and initiates infection by colonizing the posterior pharynx. Adherence to pharyngeal epithelial cells is an important first step in the process of colonization. In the present study, we sought to elucidate the interplay of type IV pili (T4P), a trimeric autotransporter adhesin called Knh, and the polysaccharide capsule in K. kingae adherence to host cells. Using adherence assays performed under shear stress, we observed that a strain expressing only Knh was capable of higher levels of adherence than a strain expressing only T4P. Using atomic force microscopy and transmission electron microscopy (TEM), we established that the capsule had a mean depth of 700 nm and that Knh was approximately 110 nm long. Using cationic ferritin capsule staining and thin-section transmission electron microscopy, we found that when bacteria expressing retractile T4P were in close contact with host cells, the capsule was absent at the point of contact between the bacterium and the host cell membrane. In a T4P retraction-deficient mutant, the capsule depth remained intact and adherence levels were markedly reduced. These results support the following model: T4P make initial contact with the host cell and mediate low-strength adherence. T4P retract, pulling the organism closer to the host cell and displacing the capsule, allowing Knh to be exposed and mediate high strength, tight adherence to the host cell surface. This report provides the first description of the mechanical displacement of capsule enabling intimate bacterial adherence to host cells.IMPORTANCE Adherence to host cells is an important first step in bacterial colonization and pathogenicity. Kingella kingae has three surface factors that are involved in adherence: type IV pili (T4P), a trimeric autotransporter adhesin called Knh, and a polysaccharide capsule. Our results suggest that T4P mediate initial contact and low-strength adherence to host cells. T4P retraction draws the bacterium closer to the host cell and causes the displacement of capsule. This displacement exposes Knh and allows Knh to mediate high-strength adherence to the host cell. This work provides new insight into the interplay of T4P, a nonpilus adhesin, and a capsule and their effects on bacterial adherence to host cells. PMID- 28874409 TI - Extracellular SalB contributes to intrinsic cephalosporin resistance and cell envelope integrity in Enterococcus faecalis. AB - Enterococci are major causes of hospital-acquired infections. Intrinsic resistance to cephalosporins is a universal trait among clinically relevant enterococci. Cephalosporin resistance enables enterococci to proliferate to high densities in the intestines of patients undergoing cephalosporin treatment, a precursor to the emergence of infection. However, the genetic and biochemical mechanisms of intrinsic cephalosporin resistance in enterococci are not well understood. A two-component signal transduction system, CroR/S, is required for cephalosporin resistance in enterococci. Although the CroR/S regulon is not well defined, one gene reported to be CroR-dependent in Enterococcus faecalis JH2-2 encodes an extracellular putative peptidoglycan hydrolase, SalB. To test the hypothesis that SalB is responsible for CroR-dependent cephalosporin resistance, we examined DeltasalB mutants in multiple genetic lineages of E. faecalis, revealing that SalB is required not only for intrinsic cephalosporin resistance but also for maintenance of cell envelope integrity in the absence of antibiotic stress. The N-terminal signal sequence is necessary for SalB secretion, and secretion is required for SalB to promote cephalosporin resistance. Functional dissection revealed that the C-terminal SCP domain of SalB is essential for biological activity, and identified three residues within the SCP domain that are required for the stability and function of SalB. Additionally, we found that, in contrast to E. faecalis JH2-2, SalB is not regulated by the CroR/S two-component system in E. faecalis OG1, suggesting diversity in the CroR/S regulon among distinct lineages of E. faecalisImportance Resistance to cephalosporins is universal among clinically relevant enterococci, enabling enterococcal proliferation to high densities in the intestines of patients undergoing cephalosporin treatment, a precursor to the emergence of infection. Disabling cephalosporin resistance could therefore reduce the incidence of enterococcal infections. However, the genetic and biochemical mechanisms of cephalosporin resistance are not well understood. The significance of this work is the identification of a novel extracellular factor (SalB) that promotes cephalosporin resistance in E. faecalis, which could potentially serve as a target for therapeutics that impair enterococcal cephalosporin resistance. Additionally, our work highlights the importance of the C-terminal SCP domain of SalB, including several conserved residues within the SCP domain, for the ability of SalB to promote cephalosporin resistance. PMID- 28874410 TI - Identification and Characterization of the Major Porin of Desulfovibrio vulgaris Hildenborough. AB - Due in large part to their ability to facilitate the diffusion of a diverse range of solutes across the outer membrane (OM) of Gram-negative bacteria, the porins represent one of the most prominent and important bacterial membrane protein superfamilies. Notably, for the Gram-negative bacterium Desulfovibrio vulgaris Hildenborough, a model organism for studies of sulfate-reducing bacteria, no genes for porins have been identified or proposed in its annotated genome. Results from initial biochemical studies suggested that the product of the DVU0799 gene, which is one of the most abundant proteins of the D. vulgaris Hildenborough OM and purified as a homotrimeric complex, was a strong porin candidate. To investigate this possibility, this protein was further characterized biochemically and biophysically. Structural analyses via electron microscopy of negatively stained protein identified trimeric particles with stain filled depressions and structural modeling suggested a beta-barrel structure for the monomer, motifs common among the known porins. Functional studies were performed in which crude OM preparations or purified DVU0799 was reconstituted into proteoliposomes and the proteoliposomes were examined for permeability against a series of test solutes. The results obtained establish DVU0799 to be a pore-forming protein with permeability properties similar to those observed for classical bacterial porins, such as those of Escherichia coli Taken together, these findings identify this highly abundant OM protein to be the major porin of D. vulgaris Hildenborough. Classification of DVU0799 in this model organism expands the database of functionally characterized porins and may also extend the range over which sequence analysis strategies can be used to identify porins in other bacterial genomes.IMPORTANCE Porins are membrane proteins that form transmembrane pores for the passive transport of small molecules across the outer membranes of Gram-negative bacteria. The present study identified and characterized the major porin of the model sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough, observing its preference for anionic sugars over neutral ones. Its predicted architecture appears to be novel for a classical porin, as its core beta-barrel structure is of a type typically found in solute specific channels. Broader use of the methods employed here, such as assays for channel permeability and electron microscopy of purified samples, is expected to help expand the database of confirmed porin sequences and improve the range over which sequence analysis-based strategies can be used to identify porins in other Gram-negative bacteria. Functional characterization of these critical gatekeeping proteins from divergent Desulfovibrio species should offer an improved understanding of the physiological features that determine their habitat range and supporting activities. PMID- 28874412 TI - Isolation of a Membrane Protein Complex for Type VII Secretion in Staphylococcus aureus. AB - The ESAT6-like secretion system (ESS) of Staphylococcus aureus promotes effector protein transport across the bacterial envelope. Genes in the ESS cluster are required for S. aureus establishment of persistent abscess lesions and the modulation of immune responses during bloodstream infections. However, the biochemical functions of most of the ESS gene products, specifically the identity of secretion machine components, are unknown. Earlier work demonstrated that deletion of essB, which encodes a membrane protein, abolishes S. aureus ESS secretion. Loss-of-function mutations truncating the essB gene product cause dominant-negative phenotypes on ESS secretion, suggesting that EssB is a central component of the secretion machinery. To test this prediction, we purified native and affinity-tagged EssB from staphylococcal membranes via dodecyl-maltoside extraction, identifying a complex assembled from five proteins, EsaA, EssA, EssB, EssD, and EsxA. All five proteins are essential for secretion, as knockout mutations in the corresponding genes abolish ESS transport. Biochemical and bacterial two-hybrid analyses revealed a direct interaction between EssB and EsaA that, by engaging a mobile machine component, EsxA, may also recruit EssA and EssD.IMPORTANCE Type VII secretion systems support the lifestyle of Gram-positive bacteria, including important human pathogens such as Bacillus anthracis, Mycobacterium tuberculosis, and Staphylococcus aureus Genes encoding SpoIIIE-FtsK like ATPases and WXG100-secreted products are conserved features of type VII secretion pathways; however, most of the genes in T7SS clusters are not conserved between different bacterial species. Here, we isolate a complex of proteins from the membranes of S. aureus that appears to represent the core secretion machinery, designated ESS. These results suggest that three membrane proteins, EsaA, EssB, and EssA, form a secretion complex that associates with EssC, the SpoIIIE-FtsK-like ATPase, and with EsxA, a mobile machine component and member of the WXG100 protein family. PMID- 28874411 TI - Complementary Methodologies To Investigate Human Gut Microbiota in Host Health, Working towards Integrative Systems Biology. AB - In 1680, Antonie van Leeuwenhoek noted compositional differences in his oral and fecal microbiota, pioneering the study of the diversity of the human microbiome. From Leeuwenhoek's time to successful modern attempts at changing the gut microbial landscape to cure disease, there has been an exponential increase in the recognition of our resident microbes as part of ourselves. Thus, the human host and microbiome have evolved in parallel to configure a balanced system in which microbes survive in homeostasis with our innate and acquired immune systems, unless disease occurs. A growing number of studies have demonstrated a correlation between the presence/absence of microbial taxa and some of their functional molecules (i.e., genes, proteins, and metabolites) with health and disease states. Nevertheless, misleading experimental design on human subjects and the cost and lack of standardized animal models pose challenges to answering the question of whether changes in microbiome composition are cause or consequence of a certain biological state. In this review, we evaluate the state of the art of methodologies that enable the study of the gut microbiome, encouraging a change in broadly used analytic strategies by choosing effector molecules (proteins and metabolites) in combination with coding nucleic acids. We further explore microbial and effector microbial product imbalances that relate to disease and health. PMID- 28874414 TI - A Radiomics Nomogram for the Preoperative Prediction of Lymph Node Metastasis in Bladder Cancer. AB - Purpose: To develop and validate a radiomics nomogram for the preoperative prediction of lymph node (LN) metastasis in bladder cancer.Experimental Design: A total of 118 eligible bladder cancer patients were divided into a training set (n = 80) and a validation set (n = 38). Radiomics features were extracted from arterial-phase CT images of each patient. A radiomics signature was then constructed with the least absolute shrinkage and selection operator algorithm in the training set. Combined with independent risk factors, a radiomics nomogram was built with a multivariate logistic regression model. Nomogram performance was assessed in the training set and validated in the validation set. Finally, decision curve analysis was performed with the combined training and validation set to estimate the clinical usefulness of the nomogram.Results: The radiomics signature, consisting of nine LN status-related features, achieved favorable prediction efficacy. The radiomics nomogram, which incorporated the radiomics signature and CT-reported LN status, also showed good calibration and discrimination in the training set [AUC, 0.9262; 95% confidence interval (CI), 0.8657-0.9868] and the validation set (AUC, 0.8986; 95% CI, 0.7613-0.9901). The decision curve indicated the clinical usefulness of our nomogram. Encouragingly, the nomogram also showed favorable discriminatory ability in the CT-reported LN negative (cN0) subgroup (AUC, 0.8810; 95% CI, 0.8021-0.9598).Conclusions: The presented radiomics nomogram, a noninvasive preoperative prediction tool that incorporates the radiomics signature and CT-reported LN status, shows favorable predictive accuracy for LN metastasis in patients with bladder cancer. Multicenter validation is needed to acquire high-level evidence for its clinical application. Clin Cancer Res; 23(22); 6904-11. (c)2017 AACR. PMID- 28874413 TI - A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III PIK3CA-Mutant ER-Positive and HER2-Negative Breast Cancer. AB - Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The allosteric pan AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer.Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17.Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery.Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823-32. (c)2017 AACR. PMID- 28874415 TI - Cytokine-Mediated Regulation of Human Lymphocyte Development and Function: Insights from Primary Immunodeficiencies. AB - Cytokine-mediated intracellular signaling pathways are fundamental for the development, activation, and differentiation of lymphocytes. These distinct processes underlie protection against infectious diseases after natural infection with pathogens or immunization, thereby providing the host with long-lived immunological memory. In contrast, aberrant cytokine signaling can also result in conditions of immune dysregulation, such as early-onset autoimmunity. Thus, balanced signals provided by distinct cytokines, and delivered to specific cell subsets, are critical for immune homeostasis. The essential roles of cytokines in human immunity have been elegantly and repeatedly revealed by the discovery of individuals with mutations in cytokine ligands, receptors, and downstream transcription factors that cause primary immunodeficiency or autoimmune conditions. In this article, we review how the discovery and characterization of such individuals has identified nonredundant, and often highly specialized, functions of specific cytokines and immune cell subsets in human lymphocyte biology, host defense against infections, and immune regulation. PMID- 28874416 TI - Growth Differentiation Factor 15 Mediates Systemic Glucose Regulatory Action of T Helper Type 2 Cytokines. AB - T-helper type 2 (Th2) cytokines, including interleukin (IL)-13 and IL-4, produced in adipose tissue, are critical regulators of intra-adipose and systemic lipid and glucose metabolism. Furthermore, IL-13 is a potential therapy for insulin resistance in obese mouse models. Here, we examined mediators produced by adipocytes that are responsible for regulating systemic glucose homeostasis in response to Th2 cytokines. We used RNA sequencing data analysis of cultured adipocytes to screen factors secreted in response to recombinant IL-13. Recombinant IL-13 induced expression of growth differentiation factor 15 (GDF15) via the Janus kinase-activated STAT6 pathway. In vivo administration of alpha galactosylceramide or IL-33 increased IL-4 and IL-13 production, thereby increasing GDF15 levels in adipose tissue and in plasma of mice; however, these responses were abrogated in STAT6 knockout mice. Moreover, administration of recombinant IL-13 to wild-type mice fed a high-fat diet (HFD) improved glucose intolerance; this was not the case for GDF15 knockout mice fed the HFD. Taken together, these data suggest that GDF15 is required for IL-13-induced improvement of glucose intolerance in mice fed an HFD. Thus, beneficial effects of Th2 cytokines on systemic glucose metabolism and insulin sensitivity are mediated by GDF15. These findings open up a potential pharmacological route for reversing insulin resistance associated with obesity. PMID- 28874419 TI - Early intervention in Crohn's disease: towards disease modification trials. AB - Crohn's disease (CD) is a chronic progressive destructive inflammatory bowel disease. As in rheumatoid arthritis, there is increasing evidence that early treatment initiation with disease-modifying agents, such as biological drugs, may lead to complete disease control, prevention of disease progression thus protecting against irreversible damage and restoration of normal quality of life. Data from randomised clinical trials with immunosuppressants and biologics suggest that treating patients with a disease duration of <2 years and an absence of complications may significantly reduce the risk for complications and increase time in remission in patients with CD. Moreover, rapid disease control may effectively prevent disease progression and allow dose reduction or even withdrawal of treatment, reducing the risk of long-term adverse events and healthcare costs. However, prospective disease modification trials are needed to confirm these initial results. Here we review the literature regarding early intervention in adult patients with CD and propose criteria for future disease modification trials. PMID- 28874417 TI - alpha-Catenin homodimers are recruited to phosphoinositide-activated membranes to promote adhesion. AB - A unique feature of alpha-catenin localized outside the cadherin-catenin complex is its capacity to form homodimers, but the subcellular localization and functions of this form of alpha-catenin remain incompletely understood. We identified a cadherin-free form of alpha-catenin that is recruited to the leading edge of migrating cells in a phosphatidylinositol 3-kinase-dependent manner. Surface plasmon resonance analysis shows that alpha-catenin homodimers, but not monomers, selectively bind phosphatidylinositol-3,4,5-trisphosphate-containing lipid vesicles with high affinity, where three basic residues, K488, K493, and R496, contribute to binding. Chemical-induced dimerization of alpha-catenin containing a synthetic dimerization domain promotes its accumulation within lamellipodia and elaboration of protrusions with extended filopodia, which are attenuated in the alpha-cateninKKR<3A mutant. Cells restored with a full-length, natively homodimerizing form of alpha-cateninKKR<3A display reduced membrane recruitment, altered epithelial sheet migrations, and weaker cell-cell adhesion compared with WT alpha-catenin. These findings show that alpha-catenin homodimers are recruited to phosphoinositide-activated membranes to promote adhesion and migration, suggesting that phosphoinositide binding may be a defining feature of alpha-catenin function outside the cadherin-catenin complex. PMID- 28874420 TI - The Evolution of the Use of beta-Blockers to Treat Heart Failure: A Conversation With Finn Waagstein, MD. AB - Finn Waagstein was born in Copenhagen in 1938. He graduated from Aarhus University Medical School in 1964. He received his cardiology training in the Sahlgrenska University Hospital at the University of Gothenburg, Sweden. He was appointed Associate Professor in 1980, and he assisted in establishing and directing the first Swedish heart transplant program. From 1990 he directed the heart failure and cardiomyopathy research programs. He is currently Professor of Cardiology and senior physician at Wallenberg Laboratory. In 2002, he was awarded the King Faisal International Prize for Medicine. PMID- 28874418 TI - Therapeutic endoscopy-related GI bleeding and thromboembolic events in patients using warfarin or direct oral anticoagulants: results from a large nationwide database analysis. AB - OBJECTIVE: To compare the risks of postendoscopy outcomes associated with warfarin with direct oral anticoagulants (DOACs), taking into account heparin bridging and various types of endoscopic procedures. DESIGN: Using the Japanese Diagnosis Procedure Combination database, we identified 16 977 patients who underwent 13 types of high-risk endoscopic procedures and took preoperative warfarin or DOACs from 2014 to 2015. One-to-one propensity score matching was performed to compare postendoscopy GI bleeding and thromboembolism between the warfarin and DOAC groups. RESULTS: In the propensity score-matched analysis involving 5046 pairs, the warfarin group had a significantly higher proportion of GI bleeding than the DOAC group (12.0% vs 9.9%; p=0.002). No significant difference was observed in thromboembolism (5.4% vs 4.7%) or in-hospital mortality (5.4% vs 4.7%). The risks of GI bleeding and thromboembolism were greater in patients treated with warfarin plus heparin bridging or DOACs plus bridging than in patients treated with DOACs alone. Compared with percutaneous endoscopic gastrostomy, patients who underwent endoscopic submucosal dissection, endoscopic mucosal resection and haemostatic procedures including endoscopic variceal ligation or endoscopic injection sclerotherapy were at the highest risk of GI bleeding among the 13 types of endoscopic procedures, whereas those who underwent lower polypectomy endoscopic sphincterotomy or endoscopic ultrasound guided fine needle aspiration were at moderate risk. CONCLUSION: The risk of postendoscopy GI bleeding was higher in warfarin than DOAC users. Heparin bridging was associated with an increased risk of bleeding and did not prevent thromboembolism. The bleeding risk varied by the type of endoscopic procedure. PMID- 28874421 TI - Combination Therapy to Target Reperfusion Injury After ST-Segment-Elevation Myocardial Infarction: A More Effective Approach to Cardioprotection. PMID- 28874422 TI - Chronic Myocardial Infarction: Where Is It Located? PMID- 28874423 TI - Effect of Empagliflozin on the Metabolic Signature of Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease. PMID- 28874424 TI - Letter by Jiang et al Regarding Article, "Fire Simulation and Cardiovascular Health in Firefighters". PMID- 28874425 TI - Letter by Jin-Shan and Xue-Bin Regarding Article, "Fire Simulation and Cardiovascular Health in Firefighters". PMID- 28874426 TI - Response by Hunter and Mills to Letters Regarding Article, "Fire Simulation and Cardiovascular Health in Firefighters". PMID- 28874427 TI - Correction to: Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association. PMID- 28874428 TI - Correction to: Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. PMID- 28874429 TI - Correction to: Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. PMID- 28874430 TI - Kingella kingae: From carriage to infection. PMID- 28874431 TI - Association between oropharyngeal carriage of Kingella kingae and osteoarticular infection in young children: a case-control study. AB - BACKGROUND: Kingella kingae has been increasingly identified in patients with osteoarticular infections. Our main objective was to evaluate the association between carriage of K. kingae in the oropharynx of preschool children and osteoarticular infections. METHODS: We conducted this prospective case-control study in 2 tertiary care pediatric hospitals (Canada and Switzerland) between 2014 and 2016. Potential cases were children aged 6 to 48 months with a presumptive diagnosis of osteoarticular infection according to the treating emergency physician. Confirmed cases were those with diagnosis of osteomyelitis or septic arthritis proven by positive findings on technetium-labelled bone scan or magnetic resonance imaging or identification of a microorganism in joint aspirate or blood. For each case, we recruited 4 age-matched controls from among children presenting to the same emergency department for trauma. The independent variable was presence of oropharyngeal K. kingae DNA identified by a specific polymerase chain reaction assay. We determined the association between oropharyngeal carriage of K. kingae and definitive osteoarticular infection. RESULTS: The parents of 77 children admitted for suspected osteoarticular infection and 286 controls were invited to participate and provided informed consent. We identified K. kingae in the oropharynx of 46 (71%) of 65 confirmed cases and 17 (6%) of 286 controls; these results yielded an odds ratio of 38.3 (95% confidence interval 18.5-79.1). INTERPRETATION: Detection of oropharyngeal K. kingae was strongly associated with osteoarticular infection among children presenting with symptoms suggestive of such infection. PMID- 28874433 TI - An emerging multidrug-resistant bacteria. PMID- 28874432 TI - Stopping anticoagulation in a woman with unprovoked venous thromboembolism. PMID- 28874434 TI - Brown tumours of the spine presenting with acute urine incontinence. PMID- 28874435 TI - Supporting Bill S-206 protects Canadian children from violence. PMID- 28874436 TI - Residual poststroke disability is another opportunity to reduce long-term morbidity and mortality. PMID- 28874437 TI - Doctors mobilize against tax changes. PMID- 28874438 TI - Future of health system hinges on collaboration: outgoing CMA pres. PMID- 28874439 TI - CMA members gathered in Quebec for 150th annual meeting. PMID- 28874440 TI - Blocking gp130 signaling suppresses autotaxin expression in adipocytes and improves insulin sensitivity in diet-induced obesity. AB - Autotaxin (ATX), which is highly expressed and secreted by adipocytes, functions as the key enzyme to generate lysophosphatidic acid (LPA) from lysophosphatidylcholine. Adipose tissue is the main source of circulating ATX that modulates plasma LPA levels. Upregulation of ATX expression in obese patients and mice is closely related with insulin resistance and impaired glucose tolerance. However, the mechanism of ATX expression in adipocytes remains largely unknown. In this study, we found that glycoprotein 130 (gp130)-mediated Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) activation was required for abundant ATX expression in adipocytes. Through gp130, the interleukin 6 (IL-6) family cytokines, such as IL-6, leukemia inhibitory factor, cardiotrophin-1, and ciliary neurotrophic factor, upregulated ATX expression in adipocytes. ATX contributes to the induction of insulin resistance and lipolysis in IL-6-stimulated adipocytes. Oral administration of gp130 inhibitor SC144 suppressed ATX expression in adipose tissue, decreased plasma ATX, LPA, and FFA levels, and significantly improved insulin sensitivity and glucose tolerance in high-fat diet-fed obese mice. In summary, our results indicate that the activation of gp130-JAK-STAT3 pathway by IL-6 family cytokines has an important role in regulating ATX expression in adipocytes and that gp130 is a promising target in the management of obesity-associated glucose metabolic diseases. PMID- 28874441 TI - Comprehensive analyses of oxidized phospholipids using a measured MS/MS spectra library. AB - Oxidized phospholipids (OxPLs) are widely held to be associated with various diseases, such as arteriosclerosis, diabetes, and cancer. To characterize the structure-specific behavior of OxPLs and their physiological relevance, we developed a comprehensive analytical method by establishing a measured MS/MS spectra library of OxPLs. Biogenic OxPLs were prepared by the addition of specific oxidized fatty acids to cultured cells, where they were incorporated into cellular phospholipids, and untargeted lipidomics by LC-quadrupole/TOF-MS was applied to collect MS/MS spectra for the OxPLs. Based on the measured MS/MS spectra for about 400 molecular species of the biogenic OxPLs, we developed a broad-targeted lipidomics system using triple quadrupole MS. Separation precision of structural isomers was optimized by multiple reaction monitoring analysis and this system enabled us to detect OxPLs at levels as low as 10 fmol. When applied to biological samples, i.e., mouse peritoneal macrophages, this system enabled us to monitor a series of OxPLs endogenously produced in a 12/15-lipoxygenase dependent manner. This advanced analytical method will be useful to elucidate the structure-specific behavior of OxPLs and their physiological relevance in vivo. PMID- 28874442 TI - Use of next-generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is a heritable condition of severely elevated LDL cholesterol, caused predominantly by autosomal codominant mutations in the LDL receptor gene (LDLR). In providing a molecular diagnosis for FH, the current procedure often includes targeted next-generation sequencing (NGS) panels for the detection of small-scale DNA variants, followed by multiplex ligation-dependent probe amplification (MLPA) in LDLR for the detection of whole-exon copy number variants (CNVs). The latter is essential because ~10% of FH cases are attributed to CNVs in LDLR; accounting for them decreases false negative findings. Here, we determined the potential of replacing MLPA with bioinformatic analysis applied to NGS data, which uses depth-of-coverage analysis as its principal method to identify whole-exon CNV events. In analysis of 388 FH patient samples, there was 100% concordance in LDLR CNV detection between these two methods: 38 reported CNVs identified by MLPA were also successfully detected by our NGS method, while 350 samples negative for CNVs by MLPA were also negative by NGS. This result suggests that MLPA can be removed from the routine diagnostic screening for FH, significantly reducing associated costs, resources, and analysis time, while promoting more widespread assessment of this important class of mutations across diagnostic laboratories. PMID- 28874443 TI - Amelioration of diet-induced steatohepatitis in mice following combined therapy with ASO-Fsp27 and fenofibrate. AB - Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD progresses from benign steatosis to steatohepatitis (NASH) to cirrhosis and is linked to hepatocellular carcinoma. No targeted treatment is currently approved for NAFLD/NASH. We previously showed that fat-specific protein 27 (FSP27), a lipid droplet-associated protein that controls triglyceride turnover in the hepatocyte, is required for fasting- and diet-induced triglyceride accumulation in the liver. However, silencing Fsp27 with antisense oligonucleotides (ASOs) did not improve hepatosteatosis in genetic nor nutritional mouse models of obesity. Herein, we tested the therapeutic potential of ASO-Fsp27 when used in combination with the PPARalpha agonist fenofibrate. C57BL/6 mice were fed a high-trans-fat, high-cholesterol, high-fructose diet for eight weeks to establish NASH, then kept on diet for six additional weeks while dosed with ASOs and fenofibrate, alone or in combination. Data show that ASO Fsp27 and fenofibrate synergize to promote resistance to diet-induced obesity and hypertriglyceridemia and to reverse hepatic steatosis, inflammation, oxidative stress, and fibrosis. This multifactorial improvement of liver disease noted when combining both drugs suggests that a course of treatment that includes both reduced FSP27 activity and activation of PPARalpha could provide therapeutic benefit to patients with NAFLD/NASH. PMID- 28874444 TI - Modulation of CD4+ and CD8+ T Cell Function and Cytokine Responses in Strongyloides stercoralis Infection by Interleukin-27 (IL-27) and IL-37. AB - Strongyloides stercoralis infection is associated with diminished antigen specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4+ and CD8+ T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis infected individuals and 10 uninfected individuals stimulated with parasite antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with parasite antigen stimulation. There was no induction of any T cell response in uninfected individuals following parasite antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-gamma), IL-5, IL-9, IL-17, and IL 22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection. PMID- 28874445 TI - Gamma Interferon Mediates Experimental Cerebral Malaria by Signaling within Both the Hematopoietic and Nonhematopoietic Compartments. AB - Experimental cerebral malaria (ECM) is a gamma interferon (IFN-gamma)-dependent syndrome. However, whether IFN-gamma promotes ECM through direct and synergistic targeting of multiple cell populations or by acting primarily on a specific responsive cell type is currently unknown. Here, using a panel of cell- and compartment-specific IFN-gamma receptor 2 (IFN-gammaR2)-deficient mice, we show that IFN-gamma causes ECM by signaling within both the hematopoietic and nonhematopoietic compartments. Mechanistically, hematopoietic and nonhematopoietic compartment-specific IFN-gammaR signaling exerts additive effects in orchestrating intracerebral inflammation, leading to the development of ECM. Surprisingly, mice with specific deletion of IFN-gammaR2 expression on myeloid cells, T cells, or neurons were completely susceptible to terminal ECM. Utilizing a reductionist in vitro system, we show that synergistic IFN-gamma and tumor necrosis factor (TNF) stimulation promotes strong activation of brain blood vessel endothelial cells. Combined, our data show that within the hematopoietic compartment, IFN-gamma causes ECM by acting redundantly or by targeting non-T cell or non-myeloid cell populations. Within the nonhematopoietic compartment, brain endothelial cells, but not neurons, may be the major target of IFN-gamma leading to ECM development. Collectively, our data provide information on how IFN gamma mediates the development of cerebral pathology during malaria infection. PMID- 28874447 TI - Salmonella utilizes zinc to subvert anti-microbial host defense of macrophages via modulation of NF-kappaB signaling. AB - Zinc sequestration by macrophages is considered a crucial host defense strategy against infection with the intracellular bacterium Salmonella Typhimurium. However, the underlying mechanisms remain elusive. In this study we found zinc to favor pathogen survival within macrophages. Salmonella-hosting macrophages contained higher free zinc levels than uninfected macrophages and cells that successfully eliminated bacteria, which was paralleled by impaired production of reactive oxygen (ROS) and nitrogen (RNS) species in bacteria-harboring cells. A profound, zinc-mediated inhibition of NF-kappaB p65 transcriptional activity affecting expression of the ROS- and RNS-forming enzymes phos47 and iNOS provided a mechanistic explanation for this phenomenon. Macrophages responded to infection by enhanced expression of zinc scavenging methallothioneins-1 and 2, whose genetic deletion caused a rise of free zinc levels, reduced ROS and RNS production and increased survival of Salmonella Our data suggest that Salmonella invasion of macrophages results in a bacteria-driven rise of intracellular zinc levels which weakens anti-microbial defense and the ability of macrophages to eradicate the pathogen. Thus, limitation of cytoplasmic zinc levels may help to control infection with intracellular bacteria. PMID- 28874446 TI - Characterization of Two Novel Lipopolysaccharide Phosphoethanolamine Transferases in Pasteurella multocida and Their Role in Resistance to Cathelicidin-2. AB - The lipopolysaccharide (LPS) produced by the Gram-negative bacterial pathogen Pasteurella multocida has phosphoethanolamine (PEtn) residues attached to lipid A, 3-deoxy-d-manno-octulosonic acid (Kdo), heptose, and galactose. In this report, we show that PEtn is transferred to lipid A by the P. multocida EptA homologue, PetL, and is transferred to galactose by a novel PEtn transferase that is unique to P. multocida called PetG. Transcriptomic analyses indicated that petL expression was positively regulated by the global regulator Fis and negatively regulated by an Hfq-dependent small RNA. Importantly, we have identified a novel PEtn transferase called PetK that is responsible for PEtn addition to the single Kdo molecule (Kdo1), directly linked to lipid A in the P. multocida glycoform A LPS. In vitro assays showed that the presence of a functional petL and petK, and therefore the presence of PEtn on lipid A and Kdo1, was essential for resistance to the cationic, antimicrobial peptide cathelicidin 2. The importance of PEtn on Kdo1 and the identification of the transferase responsible for this addition have not previously been shown. Phylogenetic analysis revealed that PetK is the first representative of a new family of predicted PEtn transferases. The PetK family consists of uncharacterized proteins from a range of Gram-negative bacteria that produce LPS glycoforms with only one Kdo molecule, including pathogenic species within the genera Vibrio, Bordetella, and Haemophilus We predict that many of these bacteria will require the addition of PEtn to Kdo for maximum protection against host antimicrobial peptides. PMID- 28874448 TI - Glycinergic Input to the Mouse Basal Forebrain Cholinergic Neurons. AB - The basal forebrain (BF) receives afferents from brainstem ascending pathways, which has been implicated first by Moruzzi and Magoun (1949) to induce forebrain activation and cortical arousal/waking behavior; however, it is very little known about how brainstem inhibitory inputs affect cholinergic functions. In the current study, glycine, a major inhibitory neurotransmitter of brainstem neurons, and gliotransmitter of local glial cells, was tested for potential interaction with BF cholinergic (BFC) neurons in male mice. In the BF, glycine receptor alpha subunit-immunoreactive (IR) sites were localized in choline acetyltransferase (ChAT)-IR neurons. The effect of glycine on BFC neurons was demonstrated by bicuculline-resistant, strychnine-sensitive spontaneous IPSCs (sIPSCs; 0.81 +/- 0.25 * 10-1 Hz) recorded in whole-cell conditions. Potential neuronal as well as glial sources of glycine were indicated in the extracellular space of cholinergic neurons by glycine transporter type 1 (GLYT1)- and GLYT2-IR processes found in apposition to ChAT-IR cells. Ultrastructural analyses identified synapses of GLYT2-positive axon terminals on ChAT-IR neurons, as well as GLYT1-positive astroglial processes, which were localized in the vicinity of synapses of ChAT-IR neurons. The brainstem raphe magnus was determined to be a major source of glycinergic axons traced retrogradely from the BF. Our results indicate a direct effect of glycine on BFC neurons. Furthermore, the presence of high levels of plasma membrane glycine transporters in the vicinity of cholinergic neurons suggests a tight control of extracellular glycine in the BF.SIGNIFICANCE STATEMENT Basal forebrain cholinergic (BFC) neurons receive various activating inputs from specific brainstem areas and channel this information to the cortex via multiple projections. So far, very little is known about inhibitory brainstem afferents to the BF. The current study established glycine as a major regulator of BFC neurons by (1) identifying glycinergic neurons in the brainstem projecting to the BF, (2) showing glycine receptor alpha subunit-immunoreactive (IR) sites in choline acetyltransferase (ChAT)-IR neurons, (3) demonstrating glycine transporter type 2 (GLYT2)-positive axon terminals synapsing on ChAT-IR neurons, and (4) localizing GLYT1-positive astroglial processes in the vicinity of synapses of ChAT-IR neurons. The effect of glycine on BFC neurons was demonstrated by bicuculline-resistant, strychnine-sensitive spontaneous IPSCs recorded in whole-cell conditions. PMID- 28874449 TI - Human Amygdala Tracks a Feature-Based Valence Signal Embedded within the Facial Expression of Surprise. AB - Human amygdala function has been traditionally associated with processing the affective valence (negative vs positive) of an emotionally charged event, especially those that signal fear or threat. However, this account of human amygdala function can be explained by alternative views, which posit that the amygdala might be tuned to either (1) general emotional arousal (activation vs deactivation) or (2) specific emotion categories (fear vs happy). Delineating the pure effects of valence independent of arousal or emotion category is a challenging task, given that these variables naturally covary under many circumstances. To circumvent this issue and test the sensitivity of the human amygdala to valence values specifically, we measured the dimension of valence within the single facial expression category of surprise. Given the inherent valence ambiguity of this category, we show that surprised expression exemplars are attributed valence and arousal values that are uniquely and naturally uncorrelated. We then present fMRI data from both sexes, showing that the amygdala tracks these consensus valence values. Finally, we provide evidence that these valence values are linked to specific visual features of the mouth region, isolating the signal by which the amygdala detects this valence information.SIGNIFICANCE STATEMENT There is an open question as to whether human amygdala function tracks the valence value of cues in the environment, as opposed to either a more general emotional arousal value or a more specific emotion category distinction. Here, we demonstrate the utility of surprised facial expressions because exemplars within this emotion category take on valence values spanning the dimension of bipolar valence (positive to negative) at a consistent level of emotional arousal. Functional neuroimaging data showed that amygdala responses tracked the valence of surprised facial expressions, unconfounded by arousal. Furthermore, a machine learning classifier identified particular visual features of the mouth region that predicted this valence effect, isolating the specific visual signal that might be driving this neural valence response. PMID- 28874451 TI - Mendelism: New Insights from Gregor Mendel's Lectures in Brno. AB - Interpretation of Gregor Mendel's work has previously been based on study of his published paper "Experiments in Plant Hybridization." In contrast, the lectures that he gave preceding publication of this work have been largely neglected for more than 150 years. Here, we report on and interpret the content of Mendel's previous two lectures, as they were reported in a local newspaper. We comprehensively reference both the text of his paper and the historical background of his experiments. Our analysis shows that while Mendel had inherited the traditional research program on interspecific hybridization in plants, he introduced the novel method of ratio analysis for representing the variation of unit-characters among offspring of hybrids. His aim was to characterize and explain the developmental features of the distributional pattern of unit characters in two series of hybrid experiments, using self-crosses and backcrosses with parents. In doing so, he not only answered the question of what the unit-characters were and the nature of their hierarchical classification, but also successfully inferred the numerical principle of unit-character transmission from generation to generation. He also established the nature of the composition and behaviors of reproductive cells from one generation to the next. Here we highlight the evidence from Mendel's lectures, clearly announcing that he had discovered the general law of cross-generation transmission of unit-characters through reproductive cells containing unit-factors. The recovered content of these previous lectures more accurately describes the work he performed with his garden peas than his published paper and shows how he first presented it in Brno. It is thus an invaluable resource for understanding the origin of the science of genetics. PMID- 28874450 TI - Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability. AB - Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase expressing neurons (Hdc-Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep.SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA mediated mechanisms that regulate behavioral arousal. PMID- 28874454 TI - Waddington Redux: De Novo Mutations Underlie the Genetic Assimilation of Stress Induced Phenocopies in Drosophila melanogaster. PMID- 28874456 TI - Correction for Jutras et al., "Changes in Bacterial Growth Rate Govern Expression of the Borrelia burgdorferi OspC and Erp Infection-Associated Surface Proteins". PMID- 28874457 TI - Correction for Chenail et al., "Borrelia burgdorferi cp32 BpaB Modulates Expression of the Prophage NucP Nuclease and SsbP Single-Stranded DNA-Binding Protein". PMID- 28874453 TI - DNA Replication Control During Drosophila Development: Insights into the Onset of S Phase, Replication Initiation, and Fork Progression. AB - Proper control of DNA replication is critical to ensure genomic integrity during cell proliferation. In addition, differential regulation of the DNA replication program during development can change gene copy number to influence cell size and gene expression. Drosophila melanogaster serves as a powerful organism to study the developmental control of DNA replication in various cell cycle contexts in a variety of differentiated cell and tissue types. Additionally, Drosophila has provided several developmentally regulated replication models to dissect the molecular mechanisms that underlie replication-based copy number changes in the genome, which include differential underreplication and gene amplification. Here, we review key findings and our current understanding of the developmental control of DNA replication in the contexts of the archetypal replication program as well as of underreplication and differential gene amplification. We focus on the use of these latter two replication systems to delineate many of the molecular mechanisms that underlie the developmental control of replication initiation and fork elongation. PMID- 28874452 TI - Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research. AB - Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies. PMID- 28874458 TI - The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E-cadherin mediated adherens junctions. AB - The tumor necrosis factor receptor-associated factor 2 (TRAF2) is a second messenger adaptor protein that plays an essential role in propagating TNF-alpha mediated signaling pathways. Modulation of TRAF2 activity by ubiquitination is well studied; however, the deubiquitinating enzyme (DUB), which regulates TRAF2 stability, has not been identified. Here we reveal USP48 as the first identified DUB to deubiquitinate and stabilize TRAF2 in epithelial cells. Down-regulation of USP48 increases K48-linked polyubiquitination of TRAF2 and reduces TRAF2 protein levels. Interestingly, USP48 only targets the TRAF2 related to JNK pathway, not the TRAF2 related to NF-kappaB and p38 pathways. USP48 is serine phosphorylated in response to TNF-alpha. The phosphorylation is catalyzed by glycogen synthase kinase 3beta (GSK3beta), ultimately resulting in increases in USP48 DUB activity. Furthermore, we reveal a new biologic function of TRAF2 that contributes to epithelial barrier dysfunction, which is attenuated by knockdown of USP48. Inhibition of TRAF2/JNK pathway increases E (epithelial)-cadherin expression and enhances epithelial barrier integrity, while knockdown of USP48 attenuates TNF alpha/JNK pathway and increases E-cadherin expression and cell-cell junction in epithelial cells. These data, taken together, indicate that USP48 stabilizes TRAF2, which is promoted by GSK3beta-mediated phosphorylation. Further, down regulation of USP48 increases E-cadherin expression and epithelial barrier integrity through reducing TRAF2 stability.-Li, S., Wang, D., Zhao, J., Weathington, N. M., Shang, D., Zhao, Y. The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E-cadherin-mediated adherens junctions. PMID- 28874459 TI - Protease-activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating. AB - Mucociliary clearance, driven by the engine of ciliary beating, is the primary physical airway defense against inhaled pathogens and irritants. A better understanding of the regulation of ciliary beating and mucociliary transport is necessary for identifying new receptor targets to stimulate improved clearance in airway diseases, such as cystic fibrosis and chronic rhinosinusitis. In this study, we examined the protease-activated receptor (PAR)-2, a GPCR previously shown to regulate airway cell cytokine and mucus secretion, and transepithelial Cl- current. PAR-2 is activated by proteases secreted by airway neutrophils and pathogens. We cultured various airway cell lines, primary human and mouse sinonasal cells, and human bronchial cells at air-liquid interface and examined them using molecular biology, biochemistry, and live-cell imaging. We found that PAR-2 is expressed basolaterally, where it stimulates both intracellular Ca2+ release and Ca2+ influx, which activates low-level nitric oxide production, increases apical membrane Cl- permeability ~3-5-fold, and increases ciliary beating ~20-50%. No molecular or functional evidence of PAR-4 was observed. These data suggest a novel and previously overlooked role of PAR-2 in airway physiology, adding to our understanding of the role of this receptor in airway Ca2+ signaling and innate immunity.-McMahon, D. B., Workman, A. D., Kohanski, M. A., Carey, R. M., Freund, J. R., Hariri, B. M., Chen, B., Doghramji, L. J., Adappa, N. D., Palmer, J. N., Kennedy, D. W., Lee, R. J. Protease-activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating. PMID- 28874460 TI - Citric Acid Metabolism in Resistant Hypertension: Underlying Mechanisms and Metabolic Prediction of Treatment Response. AB - Resistant hypertension (RH) affects 9% to 12% of hypertensive adults. Prolonged exposure to suboptimal blood pressure control results in end-organ damage and cardiovascular risk. Spironolactone is the most effective drug for treatment, but not all patients respond and side effects are not negligible. Little is known on the mechanisms responsible for RH. We aimed to identify metabolic alterations in urine. In addition, a potential capacity of metabolites to predict response to spironolactone was investigated. Urine was collected from 29 patients with RH and from a group of 13 subjects with pseudo-RH. For patients, samples were collected before and after spironolactone administration and were classified in responders (n=19) and nonresponders (n=10). Nuclear magnetic resonance was applied to identify altered metabolites and pathways. Metabolites were confirmed by liquid chromatography-mass spectrometry. Citric acid cycle was the pathway most significantly altered (P<0.0001). Metabolic concentrations were quantified and ranged from ng/mL malate to MUg/mL citrate. Citrate and oxaloacetate increased in RH versus pseudoresistant. Together with alpha-ketoglutarate and malate, they were able to discriminate between responders and nonresponders, being the 4 metabolites increased in nonresponders. Combined as a prediction panel, they showed receiver operating characteristiccurve with area under the curve of 0.96. We show that citric acid cycle and deregulation of reactive oxygen species homeostasis control continue its activation after hypertension was developed. A metabolic panel showing alteration before spironolactone treatment and predicting future response of patients is shown. These molecular indicators will contribute optimizing the rate of control of RH patients with spironolactone. PMID- 28874461 TI - Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism. AB - The brain-specific isoform of renin (Ren-b) has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-bNull mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-bNull mice are unknown. Fluid intake was similar in control and Ren-bNull mice at baseline and both exhibited an equivalent dipsogenic response to deoxycorticosterone acetate-salt. Dehydration promoted increased water intake in Ren-bNull mice, particularly after deoxycorticosterone acetate-salt. Ren-bNull and control mice exhibited similar body weight when fed a chow diet. However, when fed a high-fat diet, male Ren-bNull mice gained significantly less weight than control mice, an effect blunted in females. This difference was not because of changes in food intake, energy absorption, or physical activity. Ren-bNull mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue, suggesting increased thermogenesis. Ren-bNull mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased brown adipose tissue glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS. PMID- 28874462 TI - beta-Arrestin2 Improves Post-Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca2+-ATPase-Dependent Positive Inotropy in Cardiomyocytes. AB - Heart failure is the leading cause of death in the Western world, and new and innovative treatments are needed. The GPCR (G protein-coupled receptor) adapter proteins betaarr (beta-arrestin)-1 and betaarr-2 are functionally distinct in the heart. betaarr1 is cardiotoxic, decreasing contractility by opposing beta1AR (adrenergic receptor) signaling and promoting apoptosis/inflammation post myocardial infarction (MI). Conversely, betaarr2 inhibits apoptosis/inflammation post-MI but its effects on cardiac function are not well understood. Herein, we sought to investigate whether betaarr2 actually increases cardiac contractility. Via proteomic investigations in transgenic mouse hearts and in H9c2 rat cardiomyocytes, we have uncovered that betaarr2 directly interacts with SERCA2a (sarco[endo]plasmic reticulum Ca2+-ATPase) in vivo and in vitro in a beta1AR dependent manner. This interaction causes acute SERCA2a SUMO (small ubiquitin like modifier)-ylation, increasing SERCA2a activity and thus, cardiac contractility. betaarr1 lacks this effect. Moreover, betaarr2 does not desensitize beta1AR cAMP-dependent procontractile signaling in cardiomyocytes, again contrary to betaarr1. In vivo, post-MI heart failure mice overexpressing cardiac betaarr2 have markedly improved cardiac function, apoptosis, inflammation, and adverse remodeling markers, as well as increased SERCA2a SUMOylation, levels, and activity, compared with control animals. Notably, betaarr2 is capable of ameliorating cardiac function and remodeling post-MI despite not increasing cardiac betaAR number or cAMP levels in vivo. In conclusion, enhancement of cardiac betaarr2 levels/signaling via cardiac-specific gene transfer augments cardiac function safely, that is, while attenuating post MI remodeling. Thus, cardiac betaarr2 gene transfer might be a novel, safe positive inotropic therapy for both acute and chronic post-MI heart failure. PMID- 28874463 TI - Is beta-Arrestin 2 a Magic Bullet for Heart Failure Treatment? PMID- 28874464 TI - MAS1 Receptor Trafficking Involves ERK1/2 Activation Through a beta-Arrestin2 Dependent Pathway. AB - The MAS1 receptor (R) exerts protective effects in the brain, heart, vessels, and kidney. R trafficking plays a critical function in signal termination and propagation and in R resensitization. We examined MAS1R internalization and trafficking on agonist stimulation and the role of beta-arrestin2 in the activation of ERK1/2 (extracellular signal-regulated kinase 1/2) and Akt after MAS1R stimulation. Human embryonic kidney 293T cells were transfected with the coding sequence for MAS1R-YFP (MAS1R fused to yellow fluorescent protein). MAS1R internalization was evaluated by measuring the MAS1R present in the plasma membrane after agonist stimulation using a ligand-binding assay. MAS1R trafficking was evaluated by its colocalization with trafficking markers. MAS1R internalization was blocked in the presence of shRNAcaveolin-1 and with dominant negatives for Eps15 (a protein involved in endocytosed Rs by clathrin-coated pits) and for dynamin. After stimulation, MAS1R colocalized with Rab11-a slow recycling vesicle marker-and not with Rab4-a fast recycling vesicle marker-or LysoTracker-a lysosome marker. Cells transfected with MAS1R showed an increase in Akt and ERK1/2 activation on angiotensin-(1-7) stimulation, which was blocked when the clathrin-coated pits pathway was blocked. Suppression of beta-arrestin2 by shRNA reduced the angiotensin-(1-7)-induced ERK1/2 activation, whereas Akt activation was not modified. We conclude that on agonist stimulation, MAS1R is internalized through clathrin-coated pits and caveolae in a dynamin-dependent manner and is then slowly recycled back to the plasma membrane. MAS1R induced Akt and ERK1/2 activation from early endosomes, and the activation of ERK1/2 was mediated by beta-arrestin2. Thus, MAS1R activity and density may be tightly controlled by the cell. PMID- 28874465 TI - Mechanisms and Subclinical Consequences of Aortic Stiffness. PMID- 28874467 TI - An Evolutionarily Conserved Pathway Essential for Orsay Virus Infection of Caenorhabditis elegans. AB - Many fundamental biological discoveries have been made in Caenorhabditis elegans The discovery of Orsay virus has enabled studies of host-virus interactions in this model organism. To identify host factors critical for Orsay virus infection, we designed a forward genetic screen that utilizes a virally induced green fluorescent protein (GFP) reporter. Following chemical mutagenesis, two Viro (virus induced reporter off) mutants that failed to express GFP were mapped to sid-3, a nonreceptor tyrosine kinase, and B0280.13 (renamed viro-2), an ortholog of human Wiskott-Aldrich syndrome protein (WASP). Both mutants yielded Orsay virus RNA levels comparable to that of the residual input virus, suggesting that they are not permissive for Orsay virus replication. In addition, we demonstrated that both genes affect an early prereplication stage of Orsay virus infection. Furthermore, it is known that the human ortholog of SID-3, activated CDC42 associated kinase (ACK1/TNK2), is capable of phosphorylating human WASP, suggesting that VIRO-2 may be a substrate for SID-3 in C. elegans A targeted RNA interference (RNAi) knockdown screen further identified the C. elegans gene nck 1, which has a human ortholog that interacts with TNK2 and WASP, as required for Orsay virus infection. Thus, genetic screening in C. elegans identified critical roles in virus infection for evolutionarily conserved genes in a known human pathway.IMPORTANCE Orsay virus is the only known virus capable of naturally infecting the model organism Caenorhabditis elegans, which shares many evolutionarily conserved genes with humans. We exploited the robust genetic tractability of C. elegans to identify three host genes, sid-3, viro-2, and nck 1, which are essential for Orsay virus infection. Mutant animals that lack these three genes are highly defective in viral replication. Strikingly, the human orthologs of these three genes, activated CDC42-associated kinase (TNK2), Wiskott Aldrich syndrome protein (WASP), and noncatalytic region of tyrosine kinase adaptor protein 1 (NCK1) are part of a known signaling pathway in mammals. These results suggest that TNK2, WASP, and NCK1 may play important roles in mammalian virus infection. PMID- 28874466 TI - An Alternative STAT Signaling Pathway Acts in Viral Immunity in Caenorhabditis elegans. AB - Across metazoans, innate immunity is vital in defending organisms against viral infection. In mammals, antiviral innate immunity is orchestrated by interferon signaling, activating the STAT transcription factors downstream of the JAK kinases to induce expression of antiviral effector genes. In the nematode Caenorhabditis elegans, which lacks the interferon system, the major antiviral response so far described is RNA interference (RNAi), but whether additional gene expression responses are employed is not known. Here we show that, despite the absence of both interferon and JAK, the C. elegans STAT homolog STA-1 orchestrates antiviral immunity. Intriguingly, mutants lacking STA-1 are less permissive to antiviral infection. Using gene expression analysis and chromatin immunoprecipitation, we show that, in contrast to the mammalian pathway, STA-1 acts mostly as a transcriptional repressor. Thus, STA-1 might act to suppress a constitutive antiviral response in the absence of infection. Additionally, using a reverse genetic screen, we identify the kinase SID-3 as a new component of the response to infection, which, along with STA-1, participates in the transcriptional regulatory network of the immune response. Our work uncovers novel physiological roles for two factors in viral infection: a SID protein acting independently of RNAi and a STAT protein acting in C. elegans antiviral immunity. Together, these results illustrate the complex evolutionary trajectory displayed by innate immune signaling pathways across metazoan organisms.IMPORTANCE Since innate immunity was discovered, a diversity of pathways has arisen as powerful first-line defense mechanisms to fight viral infection. RNA interference, reported mostly in invertebrates and plants, as well as the mammalian interferon response and JAK/STAT pathway are key in RNA virus innate immunity. We studied infection by the Orsay virus in Caenorhabditis elegans, where RNAi is known to be a potent antiviral defense. We show that, in addition to its RNAi pathway, C. elegans utilizes an alternative STAT pathway to control the levels of viral infection. We identify the transcription factor STA-1 and the kinase SID-3 as two components of this response. Our study defines C. elegans as a new example of the diversity of antiviral strategies. PMID- 28874468 TI - TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions. AB - Receptor molecules play key roles in the cellular entry of picornaviruses, and TIM1 (HAVCR1) is widely accepted to be the receptor for hepatitis A virus (HAV), an unusual, hepatotropic human picornavirus. However, its identification as the hepatovirus receptor predated the discovery that hepatoviruses undergo nonlytic release from infected cells as membrane-cloaked, quasi-enveloped HAV (eHAV) virions that enter cells via a pathway distinct from naked, nonenveloped virions. We thus revisited the role of TIM1 in hepatovirus entry, examining both adherence and infection/replication in cells with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-engineered TIM1 knockout. Cell culture-derived, gradient-purified eHAV bound Huh-7.5 human hepatoma cells less efficiently than naked HAV at 4 degrees C, but eliminating TIM1 expression caused no difference in adherence of either form of HAV, nor any impact on infection and replication in these cells. In contrast, TIM1-deficient Vero cells showed a modest reduction in quasi-enveloped eHAV (but not naked HAV) attachment and replication. Thus, TIM1 facilitates quasi-enveloped eHAV entry in Vero cells, most likely by binding phosphatidylserine (PtdSer) residues on the eHAV membrane. Both Tim1-/-Ifnar1-/- and Tim4-/-Ifnar1-/- double-knockout mice were susceptible to infection upon intravenous challenge with infected liver homogenate, with fecal HAV shedding and serum alanine aminotransferase (ALT) elevations similar to those in Ifnar1-/- mice. However, intrahepatic HAV RNA and ALT elevations were modestly reduced in Tim1-/-Ifnar1-/- mice compared to Ifnar1-/- mice challenged with a lower titer of gradient-purified HAV or eHAV. We conclude that TIM1 is not an essential hepatovirus entry factor, although its PtdSer-binding activity may contribute to the spread of quasi-enveloped virus and liver injury in mice.IMPORTANCE T cell immunoglobulin and mucin-containing domain protein 1 (TIM1) was reported more than 2 decades ago to be an essential cellular receptor for hepatitis A virus (HAV), a picornavirus in the Hepatovirus genus, resulting in its designation as "hepatitis A virus cellular receptor 1" (HAVCR1) by the Human Genome Organization Gene Nomenclature Committee. However, recent studies have shown that HAV exists in nature as both naked, nonenveloped (HAV) virions and membrane-cloaked, quasi enveloped infectious virus (eHAV), prompting us to revisit the role of TIM1 in viral entry. We show here that TIM1 (HAVCR1) is not an essential cellular receptor for HAV entry into cultured cells or required for viral replication and pathogenesis in permissive strains of mice, although it may facilitate early stages of infection by binding phosphatidylserine on the eHAV surface. This work thus corrects the published record and sets the stage for future efforts to identify specific hepatovirus entry factors. PMID- 28874469 TI - Fibrinogen Activates the Capture of Human Plasminogen by Staphylococcal Fibronectin-Binding Proteins. AB - Invasive bacterial pathogens can capture host plasminogen (Plg) and allow it to form plasmin. This process is of medical importance as surface-bound plasmin promotes bacterial spread by cleaving tissue components and favors immune evasion by degrading opsonins. In Staphylococcus aureus, Plg binding is in part mediated by cell surface fibronectin-binding proteins (FnBPs), but the underlying molecular mechanism is not known. Here, we use single-cell and single-molecule techniques to demonstrate that FnBPs capture Plg by a sophisticated activation mechanism involving fibrinogen (Fg), another ligand found in the blood. We show that while FnBPs bind to Plg through weak (~200-pN) molecular bonds, direct interaction of the adhesins with Fg through the high-affinity dock, lock, and latch mechanism dramatically increases the strength of the FnBP-Plg bond (up to ~2,000 pN). Our results point to a new model in which the binding of Fg triggers major conformational changes in the FnBP protein, resulting in the buried Plg binding domains being projected and exposed away from the cell surface, thereby promoting strong interactions with Plg. This study demonstrated a previously unidentified role for a ligand-binding interaction by a staphylococcal cell surface protein, i.e., changing the protein orientation to activate a cryptic biological function.IMPORTANCEStaphylococcus aureus captures human plasminogen (Plg) via cell wall fibronectin-binding proteins (FnBPs), but the underlying molecular mechanism is not known. Here we show that the forces involved in the interaction between Plg and FnBPs on the S. aureus surface are weak. However, we discovered that binding of fibrinogen to FnBPs dramatically strengthens the FnBP Plg bond, therefore revealing an unanticipated role for Fg in the capture of Plg by S. aureus These experiments favor a model where Fg-induced conformational changes in FnBPs promote their interaction with Plg. This work uncovers a previously undescribed activation mechanism for a staphylococcal surface protein, whereby ligand-binding elicits a cryptic biological function. PMID- 28874470 TI - Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of Staphylococcus aureus towards Polymyxins. AB - Staphylococcus aureus is intrinsically resistant to polymyxins (polymyxin B and colistin), an important class of cationic antimicrobial peptides used in treatment of Gram-negative bacterial infections. To understand the mechanisms underlying intrinsic polymyxin resistance in S. aureus, we screened the Nebraska Transposon Mutant Library established in S. aureus strain JE2 for increased susceptibility to polymyxin B. Nineteen mutants displayed at least 2-fold reductions in MIC, while the greatest reductions (8-fold) were observed for mutants with inactivation of either graS, graR, vraF, or vraG or the subunits of the ATP synthase (atpA, atpB, atpG, or atpH), which during respiration is the main source of energy. Inactivation of atpA also conferred hypersusceptibility to colistin and the aminoglycoside gentamicin, whereas susceptibilities to nisin, gallidermin, bacitracin, vancomycin, ciprofloxacin, linezolid, daptomycin, and oxacillin were unchanged. ATP synthase activity is known to be inhibited by oligomycin A, and the presence of this compound increased polymyxin B-mediated killing of S. aureus Our results demonstrate that the ATP synthase contributes to intrinsic resistance of S. aureus towards polymyxins and that inhibition of the ATP synthase sensitizes S. aureus to this group of compounds. These findings show that by modulation of bacterial metabolism, new classes of antibiotics may show efficacy against pathogens towards which they were previously considered inapplicable. In light of the need for new treatment options for infections with serious pathogens like S. aureus, this approach may pave the way for novel applications of existing antibiotics.IMPORTANCE Bacterial pathogens that cause disease in humans remain a serious threat to public health, and antibiotics are still our primary weapon in treating bacterial diseases. The ability to eradicate bacterial infections is critically challenged by development of resistance to all clinically available antibiotics. Polymyxins constitute an important class of antibiotics for treatment of infections caused by Gram-negative pathogens, whereas Gram-positive bacteria remain largely insusceptible towards class of antibiotics. Here we performed a whole-genome screen among nonessential genes for polymyxin intrinsic resistance determinants in Staphylococcus aureus We found that the ATP synthase is important for polymyxin susceptibility and that inhibition of the ATP synthase sensitizes S. aureus towards polymyxins. Our study provides novel insights into the mechanisms that limit polymyxin activity against S. aureus and provides valuable targets for inhibitors to potentially enable the use of polymyxins against S. aureus and other Gram-positive pathogens. PMID- 28874471 TI - Methionine Sulfoxide Reductase A (MsrA) and Its Function in Ubiquitin-Like Protein Modification in Archaea. AB - Methionine sulfoxide reductase A (MsrA) is an antioxidant enzyme found in all domains of life that catalyzes the reduction of methionine-S-sulfoxide (MSO) to methionine in proteins and free amino acids. We demonstrate that archaeal MsrA has a ubiquitin-like (Ubl) protein modification activity that is distinct from its stereospecific reduction of MSO residues. MsrA catalyzes this Ubl modification activity, with the Ubl-activating E1 UbaA, in the presence of the mild oxidant dimethyl sulfoxide (DMSO) and in the absence of reductant. In contrast, the MSO reductase activity of MsrA is inhibited by DMSO and requires reductant. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis reveals that MsrA-dependent Ubl conjugates are associated with DNA replication, protein remodeling, and oxidative stress and include the Ubl-modified MsrA, Orc3 (Orc1/Cdc6), and Cdc48d (Cdc48/p97 AAA+ ATPase). Overall, we found archaeal MsrA to have opposing MSO reductase and Ubl modifying activities that are associated with oxidative stress responses and controlled by exposure to mild oxidant.IMPORTANCE Proteins that are damaged by oxidative stress are often targeted for proteolysis by the ubiquitin-proteasome system (UPS). The mechanisms that control this response are poorly understood, especially under conditions of mild oxidative stress when protein damage is modest. Here, we discovered a novel function of archaeal MsrA in guiding the Ubl modification of target proteins in the presence of mild oxidant. This newly reported activity of MsrA is distinct from its stereospecific reduction of methionine-S-sulfoxide to methionine residues. Our results are significant steps forward, first, in elucidating a protein factor that guides Ubl modification in archaea, and second, in providing an insight into oxidative stress responses that can trigger Ubl modification in a cell. PMID- 28874472 TI - Dehydrosqualene Desaturase as a Novel Target for Anti-Virulence Therapy against Staphylococcus aureus. AB - Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is a life-threatening pathogen in hospital- and community-acquired infections. The golden-colored carotenoid pigment of S. aureus, staphyloxanthin, contributes to the resistance to reactive oxygen species (ROS) and host neutrophil-based killing. Here, we describe a novel inhibitor (NP16) of S. aureus pigment production that reduces the survival of S. aureus under oxidative stress conditions. Carotenoid components analysis, enzyme inhibition, and crtN mutational studies indicated that the molecular target of NP16 is dehydrosqualene desaturase (CrtN). S. aureus treated with NP16 showed increased susceptibility to human neutrophil killing and to innate immune clearance in a mouse infection model. Our study validates CrtN as a novel druggable target in S. aureus and presents a potent and effective lead compound for the development of virulence factor-based therapy against S. aureusIMPORTANCES. aureus staphyloxanthin contributes substantially to pathogenesis by interfering with host immune clearance mechanisms, but it has little impact on ex vivo survival of the bacterium. Agents blocking staphyloxanthin production may discourage the establishment and maintenance of bacterial infection without exerting selective pressure for antimicrobial resistance. Our newly discovered CrtN inhibitor, NP16, may offer an effective strategy for combating S. aureus infections. PMID- 28874474 TI - Pyruvate Accumulation Is the First Line of Cell Defense against Heat Stress in a Fungus. AB - Heat tolerance is well known to be key to fungal survival in many habitats, but our mechanistic understanding of how organisms adapt to heat stress is still incomplete. Using Metarhizium robertsii, an emerging model organism for assessing evolutionary processes, we report that pyruvate is in the vanguard of molecules that scavenge heat-induced reactive oxygen species (ROS). We show that, as well as inducing a rapid burst of ROS production, heat stress also downregulates genes for pyruvate consumption. The accumulating pyruvate is the fastest acting of several M. robertsii ROS scavengers, efficiently reducing protein carbonylation, stabilizing mitochondrial membrane potential, and promoting fungal growth. The acetate produced from pyruvate-ROS reactions itself causes acid stress, tolerance to which is regulated by Hog1 mitogen-activated protein kinase. Heat stress also induces pyruvate accumulation in several other fungi, suggesting that scavenging of heat-induced ROS by pyruvate is widespread.IMPORTANCE Heat is a dangerous challenge for most organisms, as it denatures proteins and induces the production of ROS that inactivate proteins, lipid membranes, and DNA. How organisms respond to this stress is not fully understood. Using the experimentally tractable insect pathogen Metarhizium robertsii as a model organism, we show for the first time that heat stress induces pyruvate production and that this functions as the first line of defense against heat-induced ROS. Heat stress also induces rapid pyruvate accumulation in other fungi, suggesting that pyruvate is a common but unappreciated defense against stress. PMID- 28874473 TI - Revitalization of a Forward Genetic Screen Identifies Three New Regulators of Fungal Secondary Metabolism in the Genus Aspergillus. AB - The study of aflatoxin in Aspergillus spp. has garnered the attention of many researchers due to aflatoxin's carcinogenic properties and frequency as a food and feed contaminant. Significant progress has been made by utilizing the model organism Aspergillus nidulans to characterize the regulation of sterigmatocystin (ST), the penultimate precursor of aflatoxin. A previous forward genetic screen identified 23 A. nidulans mutants involved in regulating ST production. Six mutants were characterized from this screen using classical mapping (five mutations in mcsA) and complementation with a cosmid library (one mutation in laeA). The remaining mutants were backcrossed and sequenced using Illumina and Ion Torrent sequencing platforms. All but one mutant contained one or more sequence variants in predicted open reading frames. Deletion of these genes resulted in identification of mutant alleles responsible for the loss of ST production in 12 of the 17 remaining mutants. Eight of these mutations were in genes already known to affect ST synthesis (laeA, mcsA, fluG, and stcA), while the remaining four mutations (in laeB, sntB, and hamI) were in previously uncharacterized genes not known to be involved in ST production. Deletion of laeB, sntB, and hamI in A. flavus results in loss of aflatoxin production, confirming that these regulators are conserved in the aflatoxigenic aspergilli. This report highlights the multifaceted regulatory mechanisms governing secondary metabolism in Aspergillus Additionally, these data contribute to the increasing number of studies showing that forward genetic screens of fungi coupled with whole-genome resequencing is a robust and cost-effective technique.IMPORTANCE In a postgenomic world, reverse genetic approaches have displaced their forward genetic counterparts. The techniques used in forward genetics to identify loci of interest were typically very cumbersome and time-consuming, relying on Mendelian traits in model organisms. The current work was pursued not only to identify alleles involved in regulation of secondary metabolism but also to demonstrate a return to forward genetics to track phenotypes and to discover genetic pathways that could not be predicted through a reverse genetics approach. While identification of mutant alleles from whole-genome sequencing has been done before, here we illustrate the possibility of coupling this strategy with a genetic screen to identify multiple alleles of interest. Sequencing of classically derived mutants revealed several uncharacterized genes, which represent novel pathways to regulate and control the biosynthesis of sterigmatocystin and of aflatoxin, a societally and medically important mycotoxin. PMID- 28874477 TI - Market Concentration. PMID- 28874475 TI - Broad-Host-Range Expression Reveals Native and Host Regulatory Elements That Influence Heterologous Antibiotic Production in Gram-Negative Bacteria. AB - Heterologous expression has become a powerful tool for studying microbial biosynthetic gene clusters (BGCs). Here, we extend the transformation-associated recombination cloning and heterologous expression platform for microbial BGCs to include Gram-negative proteobacterial expression hosts. Using a broad-host-range expression platform, we test the implicit assumption that biosynthetic pathways are more successfully expressed in more closely related heterologous hosts. Cloning and expression of the violacein BGC from Pseudoalteromonas luteoviolacea 2ta16 revealed robust production in two proteobacterial hosts, Pseudomonas putida KT2440 and Agrobacterium tumefaciens LBA4404, but very little production of the antibiotic in various laboratory strains of Escherichia coli, despite their closer phylogenetic relationship. We identified a nonclustered LuxR-type quorum sensing receptor from P. luteoviolacea 2ta16, PviR, that increases pathway transcription and violacein production in E. coli by ~60-fold independently of acyl-homoserine lactone autoinducers. Although E. coli harbors the most similar homolog of PviR identified from all of the hosts tested, overexpression of various E. coli transcription factors did not result in a statistically significant increase in violacein production, while overexpression of two A. tumefaciens PviR homologs significantly increased production. Thus, this work not only introduces a new genetic platform for the heterologous expression of microbial BGCs, it also challenges the assumption that host phylogeny is an accurate predictor of host compatibility.IMPORTANCE Although Gram-positive heterologous hosts such as Streptomyces have been developed and optimized to support diverse secondary metabolic reactions, there has been comparatively less work on Gram-negative hosts, some of which grow faster and are easier to work with. This work presents a new genetic platform for direct cloning and broad-host range heterologous expression of BGCs in Gram-negative proteobacterial expression hosts, and we leverage this platform to uncover regulatory elements that influence violacein expression from Pseudoalteromonas Although it is often assumed that BGCs will be more successfully expressed in more closely related hosts, our work suggests that this may not be a general rule of thumb, as heterologous production of natural products can be influenced by specific host regulatory and/or biosynthetic elements, and the identity and effectiveness of those elements are difficult to predict. We argue for the use of a diverse set of heterologous hosts, which may also provide insights into the BGC biosynthetic mechanism and the biological function of BGCs. PMID- 28874478 TI - Health Care Market Concentration Trends In The United States: Evidence And Policy Responses. AB - Policy makers and analysts have been voicing concerns about the increasing concentration of health care providers and health insurers in markets nationwide, including the potential adverse effect on the cost and quality of health care. The Council of Economic Advisers recently expressed its concern about the lack of estimates of market concentration in many sectors of the US economy. To address this gap in health care, this study analyzed market concentration trends in the United States from 2010 to 2016 for hospitals, physician organizations, and health insurers. Hospital and physician organization markets became increasingly concentrated over this time period. Concentration among primary care physicians increased the most, partially because hospitals and health care systems acquired primary care physician organizations. In 2016, 90 percent of Metropolitan Statistical Areas (MSAs) were highly concentrated for hospitals, 65 percent for specialist physicians, 39 percent for primary care physicians, and 57 percent for insurers. Ninety-one percent of the 346 MSAs analyzed may have warranted concern and scrutiny because of their concentration levels in 2016 and changes in their concentrations since 2010. Public policies that enhance competition are needed, such as stricter enforcement of antitrust laws, reducing barriers to entry, and restricting anticompetitive behaviors. PMID- 28874476 TI - Mechanisms of Resistance to Folate Pathway Inhibitors in Burkholderia pseudomallei: Deviation from the Norm. AB - The trimethoprim and sulfamethoxazole combination, co-trimoxazole, plays a vital role in the treatment of Burkholderia pseudomallei infections. Previous studies demonstrated that the B. pseudomallei BpeEF-OprC efflux pump confers widespread trimethoprim resistance in clinical and environmental isolates, but this is not accompanied by significant resistance to co-trimoxazole. Using the excluded select-agent strain B. pseudomallei Bp82, we now show that in vitro acquired trimethoprim versus co-trimoxazole resistance is mainly mediated by constitutive BpeEF-OprC expression due to bpeT mutations or by BpeEF-OprC overexpression due to bpeS mutations. Mutations in bpeT affect the carboxy-terminal effector-binding domain of the BpeT LysR-type activator protein. Trimethoprim resistance can also be mediated by dihydrofolate reductase (FolA) target mutations, but this occurs rarely unless BpeEF-OprC is absent. BpeS is a transcriptional regulator that is 62% identical to BpeT. Mutations affecting the BpeS DNA-binding or carboxy terminal effector-binding domains result in constitutive BpeEF-OprC overexpression, leading to trimethoprim and sulfamethoxazole efflux and thus to co-trimoxazole resistance. The majority of laboratory-selected co-trimoxazole resistant mutants often also contain mutations in folM, encoding a pterin reductase. Genetic analyses of these mutants established that both bpeS mutations and folM mutations contribute to co-trimoxazole resistance, although the exact role of folM remains to be determined. Mutations affecting bpeT, bpeS, and folM are common in co-trimoxazole-resistant clinical isolates, indicating that mutations affecting these genes are clinically significant. Co-trimoxazole resistance in B. pseudomallei is a complex phenomenon, which may explain why resistance to this drug is rare in this bacterium.IMPORTANCEBurkholderia pseudomallei causes melioidosis, a tropical disease that is difficult to treat. The bacterium's resistance to antibiotics limits therapeutic options. The paucity of orally available drugs further complicates therapy. The oral drug of choice is co-trimoxazole, a combination of trimethoprim and sulfamethoxazole. These antibiotics target two distinct enzymes, FolA (dihydrofolate reductase) and FolP (dihydropteroate synthase), in the bacterial tetrahydrofolate biosynthetic pathway. Although co-trimoxazole resistance is minimized due to two-target inhibition, bacterial resistance due to folA and folP mutations does occur. Co trimoxazole resistance in B. pseudomallei is rare and has not yet been studied. Co-trimoxazole resistance in this bacterium employs a novel strategy involving differential regulation of BpeEF-OprC efflux pump expression that determines the drug resistance profile. Contributing are mutations affecting folA, but not folP, and folM, a folate pathway-associated gene whose function is not yet well understood and which has not been previously implicated in folate inhibitor resistance in clinical isolates. PMID- 28874479 TI - Insurer Market Power Lowers Prices In Numerous Concentrated Provider Markets. AB - Using prices of hospital admissions and visits to five types of physicians, we analyzed how provider and insurer market concentration-as measured by the Herfindahl-Hirschman Index (HHI)-interact and are correlated with prices. We found evidence that in the range of the Department of Justice's and Federal Trade Commission's definition of a moderately concentrated market (HHI of 1,500-2,500), insurers have the bargaining power to reduce provider prices in highly concentrated provider markets. In particular, hospital admission prices were 5 percent lower and cardiologist, radiologist, and hematologist/oncologist visit prices were 4 percent, 7 percent, and 19 percent lower, respectively, in markets with high provider concentration and insurer HHI above 2,000, compared to such markets with insurer HHI below 2,000. We did not find evidence that high insurer concentration reduced visit prices for primary care physicians or orthopedists, however. The policy dilemma that arises from our findings is that there are no insurer market mechanisms that will pass a portion of these price reductions on to consumers in the form of lower premiums. Large purchasers of health insurance such as state and federal governments, as well as the use of regulatory approaches, could provide a solution. PMID- 28874480 TI - Corporate Investors Increased Common Ownership In Hospitals And The Postacute Care And Hospice Sectors. AB - The sharing of investors across firms is a new antitrust focus because of its potential negative effects on competition. Historically, the ability to track common investors across the continuum of health care providers has been limited. Thus, little is known about common investor ownership structures that might exist across health care delivery systems and how these linkages have evolved over time. We used data from the Provider Enrollment, Chain, and Ownership System of the Centers for Medicare and Medicaid Services to identify common investor ownership linkages across the acute care, postacute care, and hospice sectors within the same geographic markets. To our knowledge, this study provides the first description of common investor ownership trends in these sectors. We found that the percentage of acute care hospitals having common investor ties to the postacute or hospice sectors increased from 24.6 percent in 2005 to 48.9 percent in 2015. These changes have important implications for antitrust, payment, and regulatory policies. PMID- 28874481 TI - Physician Practice Consolidation Driven By Small Acquisitions, So Antitrust Agencies Have Few Tools To Intervene. AB - The growing concentration of physician markets throughout the United States has been raising antitrust concerns, yet the Department of Justice and the Federal Trade Commission have challenged only a small number of mergers and acquisitions in this field. Using proprietary claims data from states collectively containing more than 12 percent of the US population, we found that 22 percent of physician markets were highly concentrated in 2013, according to federal merger guidelines. Most of the increases in physician practice size and market concentration resulted from numerous small transactions, rather than a few large transactions. Among highly concentrated markets that had increases large enough to raise antitrust concerns, only 28 percent experienced any individual acquisition that would have been presumed to be anticompetitive under federal merger guidelines. Furthermore, most acquisitions were below the dollar thresholds that would have required the parties to report the transaction to antitrust authorities. Under present mechanisms, federal authorities have only limited ability to counteract consolidation in most US physician markets. PMID- 28874482 TI - Coping With Concentration. AB - Provider market power is a powerful driver of high health care costs in the United States. Despite decades of antitrust litigation and regulatory interventions, the problem has worsened and threatens to undermine the benefits of market-based policies. A critical but neglected challenge for all health care reform proposals relying on market competition to address costs is finding effective tools to address the extant market power of dominant hospitals, hospital systems, and many specialty physician practices. This article analyzes the principal market-oriented approaches that have been used in the past and proposed for the future. It argues that antitrust law has an important but constrained role to play and has proved to be especially inept in dealing with extant market power. It finds serious deficiencies in the conduct decrees imposed by some courts and in open-ended regulatory regimes such as those established by Certificate of Public Advantage laws. Although not without administrative complications, policies that target providers who possess market power by capping prices may be the most effective means to control costs and retain the benefits of a competitive delivery system. PMID- 28874483 TI - Beyond Antitrust: Health Care And Health Insurance Market Trends And The Future Of Competition. AB - The United States relies on competition to balance costs and quality in the health care system. But concentration is increasing throughout the hospital, physician, and insurer markets. Midsize community hospitals face declining demand and growing competition from both larger hospitals and smaller freestanding diagnostic and surgical centers, leaving the midsize hospitals vulnerable to closure or merger with other facilities. Competition among insurers has been limited by the development of hospital systems that extend the bargaining power of "must-have" hospitals (those perceived to provide the best care for complex and less common conditions) across local health care markets. Government antitrust enforcement could play an important role in maintaining competition in both the hospital and insurer markets, but in many markets, the impact of that enforcement has been limited to date. Policy makers should consider supplementing antitrust activities with strategies that combine competition and regulation-for example, by regulating selected prices and structuring competition to cover entire insurance markets. PMID- 28874484 TI - Regulated Medicare Advantage And Marketplace Individual Health Insurance Markets Rely On Insurer Competition. AB - Two important individual health insurance markets-Medicare Advantage and the Marketplaces-are tightly regulated but rely on competition among insurers to supply and price health insurance products. Many local health insurance markets have little competition, which increases prices to consumers. Furthermore, both markets are highly subsidized in ways that can exacerbate the impact of market power-that is, the ability to set price above cost-on health insurance prices. Policy makers need to foster robust competition in both sectors and avoid designing subsidies that make the market-power problem worse. PMID- 28874485 TI - A Physician's Perspective On Vertical Integration. AB - Vertical integration has been a central feature of health care delivery system change for more than two decades. Recent studies have demonstrated that vertically integrated health care systems raise prices and costs without observable improvements in quality, despite many theoretical reasons why cost control and improved quality might occur. Less well studied is how physicians view their newfound partnerships with hospitals. In this article I review literature findings and other observations on five aspects of vertical integration that affect physicians in their professional and personal lives: patients' access to physicians, physician compensation, autonomy versus system support, medical professionalism and culture, and lifestyle. I conclude that the movement toward physicians' alignment with and employment in vertically integrated systems seems inexorable but that policy should not promote such integration either intentionally or inadvertently. Instead, policy should address the flaws in current payment approaches that reward high prices and excessive service use-outcomes that vertical integration currently produces. PMID- 28874486 TI - Reducing Hospital Readmissions Through Preferred Networks Of Skilled Nursing Facilities. AB - Establishing preferred provider networks of skilled nursing facilities (SNFs) is one approach hospital administrators are using to reduce excess thirty-day readmissions and avoid Medicare penalties or to reduce beneficiaries' costs as part of value-based payment models. However, hospitals are also required to provide patients at discharge with a list of Medicare-eligible providers and cannot explicitly restrict patient choice. This requirement complicates the development of a SNF network. Furthermore, there is little evidence about the effectiveness of network development in reducing readmission rates. We used a concurrent mixed-methods approach, combining Medicare claims data for the period 2009-13 with qualitative data gathered from interviews during site visits to hospitals in eight US markets in March-October 2015, to examine changes in rehospitalization rates and differences in practices between hospitals that did and did not develop formal SNF networks. Four hospitals had developed formal SNF networks as part of their care management efforts. These hospitals saw a relative reduction from 2009 to 2013 in readmission rates for patients discharged to SNFs that was 4.5 percentage points greater than the reduction for hospitals without formal networks. Interviews revealed that those with networks expanded existing relationships with SNFs, effectively managed patient data, and exercised a looser interpretation of patient choice. PMID- 28874487 TI - High Levels Of Capitation Payments Needed To Shift Primary Care Toward Proactive Team And Nonvisit Care. AB - Capitated payments in the form of fixed monthly payments to cover all of the costs associated with delivering primary care could encourage primary care practices to transform the way they deliver care. Using a microsimulation model incorporating data from 969 US practices, we sought to understand whether shifting to team- and non-visit-based care is financially sustainable for practices under traditional fee-for-service, capitated payment, or a mix of the two. Practice revenues and costs were computed for fee-for-service payments and a range of capitated payments, before and after the substitution of team- and non visit-based services for low-complexity in-person physician visits. The substitution produced financial losses for simulated practices under fee-for service payment of $42,398 per full-time-equivalent physician per year; however, substitution produced financial gains under capitated payment in 95 percent of cases, if more than 63 percent of annual payments were capitated. Shifting to capitated payment might create an incentive for practices to increase their delivery of team- and non-visit-based primary care, if capitated payment levels were sufficiently high. PMID- 28874488 TI - Narrow Networks On The Health Insurance Marketplaces: Prevalence, Pricing, And The Cost Of Network Breadth. AB - Anecdotal reports and systematic research highlight the prevalence of narrow network plans on the Affordable Care Act's health insurance Marketplaces. At the same time, Marketplace premiums in the period 2014-16 were much lower than projected by the Congressional Budget Office in 2009. Using detailed data on the breadth of both hospital and physician networks, we studied the prevalence of narrow networks and quantified the association between network breadth and premiums. Controlling for many potentially confounding factors, we found that a plan with narrow physician and hospital networks was 16 percent cheaper than a plan with broad networks for both, and that narrowing the breadth of just one type of network was associated with a 6-9 percent decrease in premiums. Narrow network plans also have a sizable impact on federal outlays, as they depress the premium of the second-lowest-price silver plan, to which subsidy amounts are linked. Holding all else constant, we estimate that federal subsidies would have been 10.8 percent higher in 2014 had Marketplaces required all plans to offer broad provider networks. Narrow networks are a promising source of potential savings for other segments of the commercial insurance market. PMID- 28874489 TI - Most Marketplace Plans Included At Least 25 Percent Of Local-Area Physicians, But Enrollment Disparities Remained. AB - The Affordable Care Act allows commercial insurers participating in the Marketplaces to vary the size of their provider networks as long as the providers are "sufficient" in numbers and types. Concerns have been growing over the increasing use of restricted-provider or narrow networks in Marketplace plans because of their implications for reduced access to care, but little is known about the breadth and stability of these networks over time or what types of enrollees choose such plans. Using national data, we found that in 2016, 60 percent of provider networks in plans offered in the federally facilitated Marketplaces included at least one-quarter of local-area physicians, and that consumers' access to broad-network plans remained stable between 2015 and 2016. Hispanic and low-income people made up a disproportionate share of enrollees in smaller-network plans (those with fewer than one-quarter of local-area physicians). It will be important to monitor the impact of narrow networks on access to and quality of care as well as on health outcomes. PMID- 28874490 TI - Networks In ACA Marketplaces Are Narrower For Mental Health Care Than For Primary Care. AB - There is increasing concern about the extent to which narrow-network plans, generally defined as those including fewer than 25 percent of providers in a given health insurance market, affect consumers' choice of and access to specialty providers-particularly in mental health care. Using data for 2016 from 531 unique provider networks in the Affordable Care Act Marketplaces, we evaluated how network size and the percentage of providers who participate in any network differ between mental health care providers and a control group of primary care providers. Compared to primary care networks, participation in mental health networks was low, with only 42.7 percent of psychiatrists and 19.3 percent of nonphysician mental health care providers participating in any network. On average, plan networks included 24.3 percent of all primary care providers and 11.3 percent of all mental health care providers practicing in a given state-level market. These findings raise important questions about provider side barriers to meeting the goal of mental health parity regulations: that insurers cover mental health services on a par with general medical and surgical services. Concerted efforts to increase network participation by mental health care providers, along with greater regulatory attention to network size and composition, could improve consumer choice and complement efforts to achieve mental health parity. PMID- 28874491 TI - Substantial Churn In Health Insurance Offerings By Small Employers, 2014-15. AB - New data for 2014-15 from the Medical Expenditure Panel Survey-Insurance Component longitudinal survey show substantial churn in insurance offers by small employers (those with fifty or fewer workers), with 14.6 percent of employers that offered insurance in 2014 having dropped it in 2015 and 5.5 percent of those that did not offer it adding coverage. PMID- 28874492 TI - Newly Eligible Enrollees In Medicaid Spend Less And Use Less Care Than Those Previously Eligible. AB - Understanding the health care spending and utilization of various types of Medicaid enrollees is important for assessing the budgetary implications of both expansion and contraction in Medicaid enrollment. Despite the intense debate surrounding the Affordable Care Act (ACA), however, little information is available on the spending and utilization patterns of the nonelderly adult enrollees who became newly eligible for Medicaid under the ACA. Using data for 2012-14 from the Medical Expenditure Panel Survey, we compared health care spending and utilization of newly eligible Medicaid enrollees with those of nondisabled adults who were previously eligible and enrolled. We found that average monthly expenditures for newly eligible enrollees were $180-21 percent less than the $228 average for previously eligible enrollees. Utilization differences between these groups likely contributed to this differential. PMID- 28874493 TI - Medicaid Expansion For Adults Had Measurable 'Welcome Mat' Effects On Their Children. AB - Before the implementation of the Affordable Care Act (ACA), most children in low income families were already eligible for public insurance through Medicaid or the Children's Health Insurance Program. Increased coverage observed for these children since the ACA's implementation suggest that the legislation potentially had important spillover or "welcome mat" effects on the number of eligible children enrolled. This study used data from the 2013-15 American Community Survey to provide the first national-level (analytical) estimates of welcome-mat effects on children's coverage post ACA. We estimated that 710,000 low-income children gained coverage through these effects. The study was also the first to show a link between parents' eligibility for Medicaid and welcome-mat effects for their children under the ACA. Welcome-mat effects were largest among children whose parents gained Medicaid eligibility under the ACA expansion to adults. Public coverage for these children increased by 5.7 percentage points-more than double the 2.7-percentage-point increase observed among children whose parents were ineligible for Medicaid both pre and post ACA. Finally, we estimated that if all states had adopted the Medicaid expansion, an additional 200,000 low-income children would have gained coverage. PMID- 28874494 TI - Despite Boosting Children's Coverage Rates To Historic Levels, Medicaid And CHIP Face An Uncertain Future. AB - The Children's Health Insurance Program (CHIP), which was enacted twenty years ago, covers uninsured children who do not qualify for Medicaid but lack access to affordable coverage. Together these safety-net programs have boosted the health insurance coverage rate among US children to historic levels, exceeding 95 percent of children in 2015. However, the future of both CHIP and Medicaid is uncertain. In the current congressional debate over the Affordable Care Act, Medicaid has become a target for potential funding reductions and other changes that would undermine the scope of children's coverage. Congress has yet to act to extend CHIP funding beyond September 30, 2017, when the current appropriation expires. State and federal policy makers should act now to preserve the foundation of coverage currently in place while striving to ensure that every child in the United States has health coverage. PMID- 28874495 TI - Sustained Gains In Coverage, Access, And Affordability Under The ACA: A 2017 Update. AB - The significant gains in health insurance coverage and improvements in health care access and affordability that followed the implementation of the key coverage provisions of the Affordable Care Act in 2014 have persisted into 2017. Adults in all parts of the country, of all ages, and across all income groups have benefited from a large and sustained increase in the percentage of the US population that has health insurance. The gains have been particularly striking among low- and moderate-income Americans living in states that expanded Medicaid. Our latest survey data from the Urban Institute's 2017 Health Reform Monitoring Survey shows that only 10.2 percent of nonelderly adults are now uninsured-a decline of almost 41 percent from the period before implementation of the ACA. Nonetheless, repealing and replacing the ACA remained under consideration during the summer of 2017, along with more systematic changes to the financing of the Medicaid program. Many people will be at substantial risk if key components of the law are repealed or otherwise changed without carefully considering the health and financial consequences for those projected to lose coverage. Though the politics of health reform are challenging, opportunities exist to create a more equitable and efficient health care system. PMID- 28874496 TI - Access To Obstetric Services In Rural Counties Still Declining, With 9 Percent Losing Services, 2004-14. AB - Recent closures of rural obstetric units and entire hospitals have exacerbated concerns about access to care for more than twenty-eight million women of reproductive age living in rural America. Yet the extent of recent obstetric unit closures has not yet been measured. Using national data, we found that 9 percent of rural counties experienced the loss of all hospital obstetric services in the period 2004-14. In addition, another 45 percent of rural US counties had no hospital obstetric services at all during the study period. That left more than half of all rural US counties without hospital obstetric services. Counties with fewer obstetricians and family physicians per women of reproductive age and per capita, respectively; a higher percentage of non-Hispanic black women of reproductive age; and lower median household incomes and those in states with more restrictive Medicaid income eligibility thresholds for pregnant women had higher odds of lacking hospital obstetric services. The same types of counties were also more likely to experience the loss of obstetric services, which highlights the challenge of providing adequate geographic access to obstetric care in vulnerable and underserved rural communities. PMID- 28874497 TI - Mortality In Rural China Declined As Health Insurance Coverage Increased, But No Evidence The Two Are Linked. AB - Health insurance holds the promise of improving population health and survival and protecting people from catastrophic health spending. Yet evidence from lower- and middle-income countries on the impact of health insurance is limited. We investigated whether insurance expansion reduced adult mortality in rural China, taking advantage of differences across Chinese counties in the timing of the introduction of the New Cooperative Medical Scheme (NCMS). We assembled and analyzed newly collected data on NCMS implementation, linked to data from the Chinese Center for Disease Control and Prevention on cause-specific, age standardized death rates and variables specific to county-year combinations for seventy-two counties in the period 2004-12. While mortality rates declined among rural residents during this period, we found little evidence that the expansion of health insurance through the NCMS contributed to this decline. However, our relatively large standard errors leave open the possibility that the NCMS had effects on mortality that we could not detect. Moreover, mortality benefits might arise only after many years of accumulated coverage. PMID- 28874499 TI - Maternal And Child Health: Foundations' Funding. PMID- 28874498 TI - 'Go Back To California': When Providers Fail Transgender Patients. AB - A transgender doctor is mistreated by a health care provider-and wants to make the system better for patients like her. PMID- 28874500 TI - Reducing TB Among Central Asia Labor Migrants. PMID- 28874501 TI - Retraction. PMID- 28874502 TI - Is external fixation a better way than plaster to supplement K-wires in non comminuted distal radius fractures? AB - BACKGROUND: Distal radius fractures represent about one-sixth of all fractures. There is still no consensus on the treatment of this fracture. We have several issues to assess and address; one of them is the fixation method. We tried to compare the effectiveness of two methods of stabilisation of distal radial fracture. Comparison between the techniques of Kirschner wire (K-wire) fixation with plaster and K-wire fixation with external fixation (Ex-Fix) was undertaken to assess which treatment modality gives better results in patients with distal radius fracture Frykman VII and VIII with no metaphyseal comminution. METHOD: Fifty-six patients were chosen randomly and then allocated to two different modalities of stabilisation randomly as well, they were followed up; three of them were lost to follow-up because of death and two moved away from the area. Fifty-one patients were randomised in two groups: 24 were treated with K-wire and spanning Ex-Fix supplementation and 27 were treated with K-wires and plaster. Patients were prospectively monitored following the operation with a minimum follow-up of 1 year. Measurement of range of motion was obtained after surgery. Visual Analogue Scale (VAS) scores for pain and satisfaction levels were also recorded. RESULTS: There was statistically significant difference in favour of the Ex-Fix patient group for pain (VAS, Ex-Fix group: mean 14.9; plaster group: mean 28.1) and satisfaction (Ex-Fix group: mean 89.7;plaster group: mean 76.3). Although one would expect that range of motion would be reduced in the Ex-Fix group, there were no statistically significant differences found, with the exception of supination where results were in favour of the Ex-Fix group (mean 54.4; plaster group: mean 45.2). CONCLUSION: In our study, xternal fixator (Ex Fix) supplementation of K-wiring favoured patients with distal radius fracture, even though there was no metaphyseal comminution, and therefore is suggested in contrast to plaster supplementation. PMID- 28874503 TI - Risk factors for amendment in type, duration and setting of prescribed outpatient parenteral antimicrobial therapy (OPAT) for adult patients with cellulitis: a retrospective cohort study and CART analysis. AB - PURPOSE OF THE STUDY: To measure the percentage rate and risk factors for amendment in the type, duration and setting of outpatient parenteral antimicrobial therapy (OPAT) for the treatment of cellulitis. STUDY DESIGN: A retrospective cohort study of adult patients receiving OPAT for cellulitis was performed. Treatment amendment (TA) was defined as hospital admission or change in antibiotic therapy in order to achieve clinical response. Multivariable logistic regression (MVLR) and classification and regression tree (CART) analysis were performed. RESULTS: There were 307 patients enrolled. TA occurred in 36 patients (11.7%). Significant risk factors for TA on MVLR were increased age, increased Numerical Pain Scale Score (NPSS) and immunocompromise. The median OPAT duration was 7 days. Increased age, heart rate and C reactive protein were associated with treatment prolongation. CART analysis selected age <64.5 years, female gender and NPSS <2.5 in the final model, generating a low-sensitivity (27.8%), high-specificity (97.1%) decision tree. CONCLUSIONS: Increased age, NPSS and immunocompromise were associated with OPAT amendment. These identified risk factors can be used to support an evidence-based approach to patient selection for OPAT in cellulitis. The CART algorithm has good specificity but lacks sensitivity and is shown to be inferior in this study to logistic regression modelling. PMID- 28874504 TI - Proteome Analysis of Hypoxic Glioblastoma Cells Reveals Sequential Metabolic Adaptation of One-Carbon Metabolic Pathways. AB - Rapidly proliferating tumors are exposed to a hypoxic microenvironment because of their density, high metabolic consumption, and interruptions in blood flow because of immature angiogenesis. Cellular responses to hypoxia promote highly malignant and metastatic behavior, as well as a chemotherapy-resistant state. To better understand the complex relationships between hypoxic adaptations and cancer progression, we studied the dynamic proteome responses of glioblastoma cells exposed to hypoxia via an innovative approach: quantification of newly synthesized proteins using heavy stable-isotope arginine labeling combined with accurate assessment of cell replication by quantification of the light/heavy arginine ratio of peptides in histone H4. We found that hypoxia affects cancer cells in multiple intertwined ways: inflammation, typically with over-expressed glucose transporter (GLUT1), DUSP4/MKP2, and RelA proteins; a metabolic adaptation with overexpression of all glycolytic pathway enzymes for pyruvate/lactate synthesis; and the EMT (epithelial-mesenchymal transition) and cancer stem cell (CSC) renewal with characteristic morphological changes and mesenchymal/CSC protein expression profiles. For the first time, we identified the vitamin B12 transporter protein TCN2, which is essential for one-carbon metabolism, as being significantly downregulated. Further, we found, by knockdown and overexpression experiments, that TCN2 plays an important role in controlling cancer cell transformation toward the highly aggressive mesenchymal/CSC stage; low expression of TCN2 has an effect similar to hypoxia, whereas high expression of TCN2 can reverse it. We conclude that hypoxia induces sequential metabolic responses of one-carbon metabolism in tumor cells. Our mass spectrometry data are available via ProteomeXchange with identifiers PXD005487 (TMT-labeling) and PXD007280 (label-free). PMID- 28874505 TI - Molecular recognition of pre-tRNA by Arabidopsis protein-only Ribonuclease P. AB - Protein-only ribonuclease P (PRORP) is an enzyme responsible for catalyzing the 5' end maturation of precursor transfer ribonucleic acids (pre-tRNAs) encoded by various cellular compartments in many eukaryotes. PRORPs from plants act as single-subunit enzymes and have been used as a model system for analyzing the function of the metazoan PRORP nuclease subunit, which requires two additional proteins for efficient catalysis. There are currently few molecular details known about the PRORP-pre-tRNA complex. Here, we characterize the determinants of substrate recognition by the single subunit Arabidopsis thaliana PRORP1 and PRORP2 using kinetic and thermodynamic experiments. The salt dependence of binding affinity suggests 4-5 contacts with backbone phosphodiester bonds on substrates, including a single phosphodiester contact with the pre-tRNA 5' leader, consistent with prior reports of short leader requirements. PRORPs contain an N-terminal pentatricopeptide repeat (PPR) domain, truncation of which results in a >30-fold decrease in substrate affinity. While most PPR-containing proteins have been implicated in single-stranded sequence-specific RNA recognition, we find that the PPR motifs of PRORPs recognize pre-tRNA substrates differently. Notably, the PPR domain residues most important for substrate binding in PRORPs do not correspond to positions involved in base recognition in other PPR proteins. Several of these residues are highly conserved in PRORPs from algae, plants, and metazoans, suggesting a conserved strategy for substrate recognition by the PRORP PPR domain. Furthermore, there is no evidence for sequence-specific interactions. This work clarifies molecular determinants of PRORP-substrate recognition and provides a new predictive model for the PRORP substrate complex. PMID- 28874507 TI - A Specific Gibberellin 20-Oxidase Dictates the Flowering-Runnering Decision in Diploid Strawberry. AB - Asexual and sexual reproduction occur jointly in many angiosperms. Stolons (elongated stems) are used for asexual reproduction in the crop species potato (Solanum tuberosum) and strawberry (Fragaria spp), where they produce tubers and clonal plants, respectively. In strawberry, stolon production is essential for vegetative propagation at the expense of fruit yield, but the underlying molecular mechanisms are unknown. Here, we show that the stolon deficiency trait of the runnerless (r) natural mutant in woodland diploid strawberry (Fragaria vesca) is due to a deletion in the active site of a gibberellin20-oxidase (GA20ox) gene, which is expressed primarily in the axillary meristem dome and primordia and in developing stolons. This mutation, which is found in all r mutants, goes back more than three centuries. When FveGA20ox4 is mutated, axillary meristems remain dormant or produce secondary shoots terminated by inflorescences, thus increasing the number of inflorescences in the plant. The application of bioactive gibberellin (GA) restored the runnering phenotype in the r mutant, indicating that GA biosynthesis in the axillary meristem is essential for inducing stolon differentiation. The possibility of regulating the runnering flowering decision in strawberry via FveGA20ox4 provides a path for improving productivity in strawberry by controlling the trade-off between sexual reproduction and vegetative propagation. PMID- 28874508 TI - ABA-Induced Stomatal Closure Involves ALMT4, a Phosphorylation-Dependent Vacuolar Anion Channel of Arabidopsis. AB - Stomatal pores are formed between a pair of guard cells and allow plant uptake of CO2 and water evaporation. Their aperture depends on changes in osmolyte concentration of guard cell vacuoles, specifically of K+ and Mal2- Efflux of Mal2 from the vacuole is required for stomatal closure; however, it is not clear how the anion is released. Here, we report the identification of ALMT4 (ALUMINUM ACTIVATED MALATE TRANSPORTER4) as an Arabidopsis thaliana ion channel that can mediate Mal2- release from the vacuole and is required for stomatal closure in response to abscisic acid (ABA). Knockout mutants showed impaired stomatal closure in response to the drought stress hormone ABA and increased whole-plant wilting in response to drought and ABA. Electrophysiological data show that ALMT4 can mediate Mal2- efflux and that the channel activity is dependent on a phosphorylatable C-terminal serine. Dephosphomimetic mutants of ALMT4 S382 showed increased channel activity and Mal2- efflux. Reconstituting the active channel in almt4 mutants impaired growth and stomatal opening. Phosphomimetic mutants were electrically inactive and phenocopied the almt4 mutants. Surprisingly, S382 can be phosphorylated by mitogen-activated protein kinases in vitro. In brief, ALMT4 likely mediates Mal2- efflux during ABA-induced stomatal closure and its activity depends on phosphorylation. PMID- 28874510 TI - Some Like It HOT: Protein Translation and Heat Stress in Plants. PMID- 28874511 TI - RETRACTION. PMID- 28874509 TI - The Maize Imprinted Gene Floury3 Encodes a PLATZ Protein Required for tRNA and 5S rRNA Transcription through Interaction with RNA Polymerase III. AB - Maize (Zea mays) floury3 (fl3) is a classic semidominant negative mutant that exhibits severe defects in the endosperm but fl3 plants otherwise appear normal. We cloned the fl3 gene and determined that it encodes a PLATZ (plant AT-rich sequence and zinc binding) protein. The mutation in fl3 resulted in an Asn-to-His replacement in the conserved PLATZ domain, creating a dominant allele. Fl3 is specifically expressed in starchy endosperm cells and regulated by genomic imprinting, which leads to the suppressed expression of fl3 when transmitted through the male, perhaps as a consequence the semidominant behavior. Yeast two hybrid screening and bimolecular luciferase complementation experiments revealed that FL3 interacts with the RNA polymerase III subunit 53 (RPC53) and transcription factor class C 1 (TFC1), two critical factors of the RNA polymerase III (RNAPIII) transcription complex. In the fl3 endosperm, the levels of many tRNAs and 5S rRNA that are transcribed by RNAPIII are significantly reduced, suggesting that the incorrectly folded fl3 protein may impair the function of RNAPIII. The transcriptome is dramatically altered in fl3 mutants, in which the downregulated genes are primarily enriched in pathways related to translation, ribosome, misfolded protein responses, and nutrient reservoir activity. Collectively, these changes may lead to defects in endosperm development and storage reserve filling in fl3 seeds. PMID- 28874512 TI - Validation, Quality, Education, Advocacy, and Outreach: SNMMI-TS Goals. PMID- 28874513 TI - Joint Review Committee on Educational Programs in Nuclear Medicine Technology. PMID- 28874514 TI - Technologist News. PMID- 28874515 TI - Transitions. PMID- 28874517 TI - Ruminant neurological disease: a retrospective cohort study. AB - Between January 2006 and June 2016, 96 ruminants with neurological signs were donated to the Scottish Centre for Production Animal Health and Food Safety (SCPAHFS), University of Glasgow, by veterinarians in the field representing 5.4 per cent of all submissions. Forty-seven different neurological presenting signs were reported with 79 per cent of the donated patients presenting with abnormal gait. All cases presenting with abnormalities in more than 4 out of 10 neurological categories died or were euthanased on welfare grounds. Calves were significantly more likely to present with neurological disorders than adult cattle compared with the proportion of calves: cows in the Scottish cattle population and total case population donated to SCPAHFS. Lesions were most commonly localised to the spinal cord in sheep 47 per cent (16), the peripheral nervous system in cattle 45 per cent (28) and to the brain in the overall population 41 per cent (39). The most common aetiology of neurological pathologies observed was infectious or inflammatory 28 per cent (27). Definitive diagnoses could be reached in 84 per cent (81) of patients. When postmortem reports were available, they produced a diagnosis in 70 per cent (52) of cases and contradicted clinical diagnoses in 38 per cent (26) of cases. The most frequently diagnosed conditions in ruminants over the 10 years were spastic paresis, vertebral osteomyelitis and listeriosis. PMID- 28874516 TI - Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells. AB - The regulation of AMH production by follicular cells is poorly understood. The purpose of this study was to determine the role of the oocyte-secreted factors, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), on AMH production in primary human cumulus cells. Cumulus cells from IVF patients were cultured with a combination of GDF9, BMP15, recombinant FSH and specific signaling inhibitors. Stimulation with GDF9 or BMP15 separately had no significant effect on AMH mRNA levels. In contrast, simultaneous stimulation with GDF9 and BMP15 (G + B) resulted in a significant increase in AMH mRNA expression. Increasing concentration of G + B (0.6, 2.5, 5 and 10 ng/mL) stimulated AMH in a dose-dependent manner, showing a maximal effect at 5 ng/mL. Western blot analyses revealed an average 16-fold increase in AMH protein levels in cells treated with G + B when compared to controls. FSH co-treatment decreased the stimulation of AMH expression by G + B. The stimulatory effect of G + B on the expression of AMH was significantly decreased by inhibitors of the SMAD2/3 signaling pathway. These findings show for the first time that AMH production is regulated by oocyte secreted factors in primary human cumulus cells. Moreover, our novel findings establish that the combination of GDF9 + BMP15 potently stimulates AMH expression. PMID- 28874518 TI - Internal Associations of the Acidic Region of Upstream Binding Factor Control Its Nucleolar Localization. AB - Upstream binding factor (UBF) is a member of the high-mobility group (HMG) box protein family, characterized by multiple HMG boxes and a C-terminal acidic region (AR). UBF is an essential transcription factor for rRNA genes and mediates the formation of transcriptionally active chromatin in the nucleolus. However, it remains unknown how UBF is specifically localized to the nucleolus. Here, we examined the molecular mechanisms that localize UBF to the nucleolus. We found that the first HMG box (HMG box 1), the linker region (LR), and the AR cooperatively regulate the nucleolar localization of UBF1. We demonstrated that the AR intramolecularly associates with and attenuates the DNA binding activity of HMG boxes and confers the structured DNA preference to HMG box 1. In contrast, the LR was found to serve as a nuclear localization signal and compete with HMG boxes to bind the AR, permitting nucleolar localization of UBF1. The LR sequence binds DNA and assists the stable chromatin binding of UBF. We also showed that the phosphorylation status of the AR does not clearly affect the localization of UBF1. Our results strongly suggest that associations of the AR with HMG boxes and the LR regulate UBF nucleolar localization. PMID- 28874519 TI - A Histone Code Reader and a Transcriptional Activator Interact to Regulate Genes for Salt Tolerance. AB - Plant homeodomain (PHD) finger proteins are involved in various developmental processes and stress responses. They recognize and bind to epigenetically modified histone H3 tail and function as histone code readers. Here we report that GmPHD6 reads low methylated histone H3K4me0/1/2 but not H3K4me3 with its N terminal domain instead of the PHD finger. GmPHD6 does not possess transcriptional regulatory ability but has DNA-binding ability. Through the PHD finger, GmPHD6 interacts with its coactivator, LHP1-1/2, to form a transcriptional activation complex. Using a transgenic hairy root system, we demonstrate that overexpression of GmPHD6 improves stress tolerance in soybean (Glycinemax) plants. Knocking down the LHP1 expression disrupts this role of GmPHD6, indicating that GmPHD6 requires LHP1 functions during stress response. GmPHD6 influences expression of dozens of stress-related genes. Among these, we identified three targets of GmPHD6, including ABA-stress-ripening-induced CYP75B1 and CYP82C4 Overexpression of each gene confers stress tolerance in soybean plants. GmPHD6 is recruited to H3K4me0/1/2 marks and recognizes the G-rich elements in target gene promoters, whereas LHP1 activates expression of these targets. Our study reveals a mechanism involving two partners in a complex. Manipulation of the genes in this pathway should improve stress tolerance in soybean or other legumes/crops. PMID- 28874520 TI - SIPP, a Novel Mitochondrial Phosphate Carrier, Mediates in Self-Incompatibility. AB - In Solanaceae, the S-specific interaction between the pistil S-RNase and the pollen S-Locus F-box protein controls self-incompatibility (SI). Although this interaction defines the specificity of the pollen rejection response, the identification of three pistil essential modifier genes unlinked to the S-locus (HT-B, 120K, and NaStEP) unveils a higher degree of complexity in the pollen rejection pathway. We showed previously that NaStEP, a stigma protein with homology with Kunitz-type protease inhibitors, is essential to SI in Nicotiana spp. During pollination, NaStEP is taken up by pollen tubes, where potential interactions with pollen tube proteins might underlie its function. Here, we identified NaSIPP, a mitochondrial protein with phosphate transporter activity, as a novel NaStEP-interacting protein. Coexpression of NaStEP and NaSIPP in pollen tubes showed interaction in the mitochondria, although when expressed alone, NaStEP remains mostly cytosolic, implicating NaSIPP-mediated translocation of NaStEP into the organelle. The NaSIPP transcript is detected specifically in mature pollen of Nicotiana spp.; however, in self-compatible plants, this gene has accumulated mutations, so its coding region is unlikely to produce a functional protein. RNA interference suppression of NaSIPP in Nicotiana spp. pollen grains disrupts the SI by preventing pollen tube inhibition. Taken together, our results are consistent with a model whereby the NaStEP and NaSIPP interaction, in incompatible pollen tubes, might destabilize the mitochondria and contribute to arrest pollen tube growth. PMID- 28874521 TI - Combinatorial interaction network of abscisic acid receptors and coreceptors from Arabidopsis thaliana. AB - The phytohormone abscisic acid (ABA) is induced in response to abiotic stress to mediate plant acclimation to environmental challenge. Key players of the ABA signaling pathway are the ABA-binding receptors (RCAR/PYR1/PYL), which, together with a plant-specific subclade of protein phosphatase 2C (PP2C), form functional holoreceptors. The Arabidopsis genome encodes nine PP2C coreceptors and 14 different RCARs, which can be divided into three subfamilies. The presence of these gene families in higher plants points to the existence of an intriguing regulatory network and poses questions as to the functional compatibility and specificity of receptor-coreceptor interactions. Here, we analyzed all RCAR-PP2C combinations for their capacity to regulate ABA signaling by transient expression in Arabidopsis protoplasts. Of 126 possible RCAR-PP2C pairings, 113 were found to be functional. The three subfamilies within the RCAR family showed different sensitivities to regulating the ABA response at basal ABA levels when efficiently expressed. At exogenous high ABA levels, the RCARs regulated most PP2Cs and activated the ABA response to a similar extent. The PP2C AHG1 was regulated only by RCAR1/PYL9, RCAR2/PYL7, and RCAR3/PYL8, which are characterized by a unique tyrosine residue. Site-directed mutagenesis of RCAR1 showed that its tyrosine residue is critical for AHG1 interaction and regulation. Furthermore, the PP2Cs HAI1 to HAI3 were regulated by all RCARs, and the ABA receptor RCAR4/PYL10 showed ABA-dependent PP2C regulation. The findings unravel the interaction network of possible RCAR-PP2C pairings and their different potentials to serve a rheostat function for integrating fluctuating hormone levels into the ABA-response pathway. PMID- 28874522 TI - Efficient stimulus-secretion coupling at ribbon synapses requires RIM-binding protein tethering of L-type Ca2+ channels. AB - Fast neurotransmitter release from ribbon synapses via Ca2+-triggered exocytosis requires tight coupling of L-type Ca2+ channels to release-ready synaptic vesicles at the presynaptic active zone, which is localized at the base of the ribbon. Here, we used genetic, electrophysiological, and ultrastructural analyses to probe the architecture of ribbon synapses by perturbing the function of RIM binding proteins (RBPs) as central active-zone scaffolding molecules. We found that genetic deletion of RBP1 and RBP2 did not impair synapse ultrastructure of ribbon-type synapses formed between rod bipolar cells (RBCs) and amacrine type-2 (AII) cells in the mouse retina but dramatically reduced the density of presynaptic Ca2+ channels, decreased and desynchronized evoked neurotransmitter release, and rendered evoked and spontaneous neurotransmitter release sensitive to the slow Ca2+ buffer EGTA. These findings suggest that RBPs tether L-type Ca2+ channels to the active zones of ribbon synapses, thereby synchronizing vesicle exocytosis and promoting high-fidelity information transfer in retinal circuits. PMID- 28874523 TI - Escherichia coli responds to environmental changes using enolasic degradosomes and stabilized DicF sRNA to alter cellular morphology. AB - Escherichia coli RNase E is an essential enzyme that forms multicomponent ribonucleolytic complexes known as "RNA degradosomes." These complexes consist of four major components: RNase E, PNPase, RhlB RNA helicase, and enolase. However, the role of enolase in the RNase E/degradosome is not understood. Here, we report that presence of enolase in the RNase E/degradosome under anaerobic conditions regulates cell morphology, resulting in Ecoli MG1655 cell filamentation. Under anaerobic conditions, enolase bound to the RNase E/degradosome stabilizes the small RNA (sRNA) DicF, i.e., the inhibitor of the cell division gene ftsZ, through chaperon protein Hfq-dependent regulation. RNase E/enolase distribution changes from membrane-associated patterns under aerobic to diffuse patterns under anaerobic conditions. When the enolase-RNase E/degradosome interaction is disrupted, the anaerobically induced characteristics disappear. We provide a mechanism by which Ecoli uses enolase-bound degradosomes to switch from rod shaped to filamentous form in response to anaerobiosis by regulating RNase E subcellular distribution, RNase E enzymatic activity, and the stability of the sRNA DicF required for the filamentous transition. In contrast to Ecoli nonpathogenic strains, pathogenic Ecoli strains predominantly have multiple copies of sRNA DicF in their genomes, with cell filamentation previously being linked to bacterial pathogenesis. Our data suggest a mechanism for bacterial cell filamentation during infection under anaerobic conditions. PMID- 28874524 TI - Direct dating of Neanderthal remains from the site of Vindija Cave and implications for the Middle to Upper Paleolithic transition. AB - Previous dating of the Vi-207 and Vi-208 Neanderthal remains from Vindija Cave (Croatia) led to the suggestion that Neanderthals survived there as recently as 28,000-29,000 B.P. Subsequent dating yielded older dates, interpreted as ages of at least ~32,500 B.P. We have redated these same specimens using an approach based on the extraction of the amino acid hydroxyproline, using preparative high performance liquid chromatography (Prep-HPLC). This method is more efficient in eliminating modern contamination in the bone collagen. The revised dates are older than 40,000 B.P., suggesting the Vindija Neanderthals did not live more recently than others across Europe, and probably predate the arrival of anatomically modern humans in Eastern Europe. We applied zooarchaeology by mass spectrometry (ZooMS) to find additional hominin remains. We identified one bone that is Neanderthal, based on its mitochondrial DNA, and dated it directly to 46,200 +/- 1,500 B.P. We also attempted to date six early Upper Paleolithic bone points from stratigraphic units G1, Fd/d+G1 and Fd/d, Fd. One bone artifact gave a date of 29,500 +/- 400 B.P., while the remainder yielded no collagen. We additionally dated animal bone samples from units G1 and G1-G3 These dates suggest a co-occurrence of early Upper Paleolithic osseous artifacts, particularly split-based points, alongside the remains of Neanderthals is a result of postdepositional mixing, rather than an association between the two groups, although more work is required to show this definitively. PMID- 28874525 TI - Differential diagnosis of Alzheimer's disease using spectrochemical analysis of blood. AB - The progressive aging of the world's population makes a higher prevalence of neurodegenerative diseases inevitable. The necessity for an accurate, but at the same time, inexpensive and minimally invasive, diagnostic test is urgently required, not only to confirm the presence of the disease but also to discriminate between different types of dementia to provide the appropriate management and treatment. In this study, attenuated total reflection FTIR (ATR FTIR) spectroscopy combined with chemometric techniques were used to analyze blood plasma samples from our cohort. Blood samples are easily collected by conventional venepuncture, permitting repeated measurements from the same individuals to monitor their progression throughout the years or evaluate any tested drugs. We included 549 individuals: 347 with various neurodegenerative diseases and 202 age-matched healthy individuals. Alzheimer's disease (AD; n = 164) was identified with 70% sensitivity and specificity, which after the incorporation of apolipoprotein epsilon4 genotype (APOE epsilon4) information, increased to 86% when individuals carried one or two alleles of epsilon4, and to 72% sensitivity and 77% specificity when individuals did not carry epsilon4 alleles. Early AD cases (n = 14) were identified with 80% sensitivity and 74% specificity. Segregation of AD from dementia with Lewy bodies (DLB; n = 34) was achieved with 90% sensitivity and specificity. Other neurodegenerative diseases, such as frontotemporal dementia (FTD; n = 30), Parkinson's disease (PD; n = 32), and progressive supranuclear palsy (PSP; n = 31), were included in our cohort for diagnostic purposes. Our method allows for both rapid and robust diagnosis of neurodegeneration and segregation between different dementias. PMID- 28874526 TI - Identification of individuals by trait prediction using whole-genome sequencing data. AB - Prediction of human physical traits and demographic information from genomic data challenges privacy and data deidentification in personalized medicine. To explore the current capabilities of phenotype-based genomic identification, we applied whole-genome sequencing, detailed phenotyping, and statistical modeling to predict biometric traits in a cohort of 1,061 participants of diverse ancestry. Individually, for a large fraction of the traits, their predictive accuracy beyond ancestry and demographic information is limited. However, we have developed a maximum entropy algorithm that integrates multiple predictions to determine which genomic samples and phenotype measurements originate from the same person. Using this algorithm, we have reidentified an average of >8 of 10 held-out individuals in an ethnically mixed cohort and an average of 5 of either 10 African Americans or 10 Europeans. This work challenges current conceptions of personal privacy and may have far-reaching ethical and legal implications. PMID- 28874527 TI - Dissection of the Drosophila neuropeptide F circuit using a high-throughput two choice assay. AB - In their classic experiments, Olds and Milner showed that rats learn to lever press to receive an electric stimulus in specific brain regions. This led to the identification of mammalian reward centers. Our interest in defining the neuronal substrates of reward perception in the fruit fly Drosophila melanogaster prompted us to develop a simpler experimental approach wherein flies could implement behavior that induces self-stimulation of specific neurons in their brains. The high-throughput assay employs optogenetic activation of neurons when the fly occupies a specific area of a behavioral chamber, and the flies' preferential occupation of this area reflects their choosing to experience optogenetic stimulation. Flies in which neuropeptide F (NPF) neurons are activated display preference for the illuminated side of the chamber. We show that optogenetic activation of NPF neuron is rewarding in olfactory conditioning experiments and that the preference for NPF neuron activation is dependent on NPF signaling. Finally, we identify a small subset of NPF-expressing neurons located in the dorsomedial posterior brain that are sufficient to elicit preference in our assay. This assay provides the means for carrying out unbiased screens to map reward neurons in flies. PMID- 28874528 TI - EIN2 mediates direct regulation of histone acetylation in the ethylene response. AB - Ethylene gas is essential for developmental processes and stress responses in plants. Although the membrane-bound protein EIN2 is critical for ethylene signaling, the mechanism by which the ethylene signal is transduced remains largely unknown. Here we show the levels of H3K14Ac and H3K23Ac are correlated with the levels of EIN2 protein and demonstrate EIN2 C terminus (EIN2-C) is sufficient to rescue the levels of H3K14/23Ac of ein2-5 at the target loci, using CRISPR/dCas9-EIN2-C. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) and ChIP-reChIP-seq analyses revealed that EIN2-C associates with histone partially through an interaction with EIN2 nuclear-associated protein1 (ENAP1), which preferentially binds to the genome regions that are associated with actively expressed genes both with and without ethylene treatments. Specifically, in the presence of ethylene, ENAP1-binding regions are more accessible upon the interaction with EIN2, and more EIN3 proteins bind to the loci where ENAP1 is enriched for a quick response. Together, these results reveal EIN2-C is the key factor regulating H3K14Ac and H3K23Ac in response to ethylene and uncover a unique mechanism by which ENAP1 interacts with chromatin, potentially preserving the open chromatin regions in the absence of ethylene; in the presence of ethylene, EIN2 interacts with ENAP1, elevating the levels of H3K14Ac and H3K23Ac, promoting more EIN3 binding to the targets shared with ENAP1 and resulting in a rapid transcriptional regulation. PMID- 28874529 TI - Synchronous volcanic eruptions and abrupt climate change ~17.7 ka plausibly linked by stratospheric ozone depletion. AB - Glacial-state greenhouse gas concentrations and Southern Hemisphere climate conditions persisted until ~17.7 ka, when a nearly synchronous acceleration in deglaciation was recorded in paleoclimate proxies in large parts of the Southern Hemisphere, with many changes ascribed to a sudden poleward shift in the Southern Hemisphere westerlies and subsequent climate impacts. We used high-resolution chemical measurements in the West Antarctic Ice Sheet Divide, Byrd, and other ice cores to document a unique, ~192-y series of halogen-rich volcanic eruptions exactly at the start of accelerated deglaciation, with tephra identifying the nearby Mount Takahe volcano as the source. Extensive fallout from these massive eruptions has been found >2,800 km from Mount Takahe. Sulfur isotope anomalies and marked decreases in ice core bromine consistent with increased surface UV radiation indicate that the eruptions led to stratospheric ozone depletion. Rather than a highly improbable coincidence, circulation and climate changes extending from the Antarctic Peninsula to the subtropics-similar to those associated with modern stratospheric ozone depletion over Antarctica-plausibly link the Mount Takahe eruptions to the onset of accelerated Southern Hemisphere deglaciation ~17.7 ka. PMID- 28874530 TI - Abrupt climate changes during Termination III in Southern Europe. AB - The Late Quaternary glacial-interglacial transitions represent the highest amplitude climate changes over the last million years. Unraveling the sequence of events and feedbacks at Termination III (T-III), including potential abrupt climate reversals similar to those of the last Termination, has been particularly challenging due to the scarcity of well-dated records worldwide. Here, we present speleothem data from southern Europe covering the interval from 262.7 to 217.9 kyBP, including the transition from marine isotope stage (MIS) 8 to MIS 7e. High resolution delta13C, delta18O, and Mg/Ca profiles reveal major millennial-scale changes in aridity manifested in changing water availability and vegetation productivity. uranium-thorium dates provide a solid chronology for two millennial scale events (S8.1 and S8.2) which, compared with the last two terminations, has some common features with Heinrich 1 and Heinrich 2 in Termination I (T-I). PMID- 28874531 TI - Female exogamy and gene pool diversification at the transition from the Final Neolithic to the Early Bronze Age in central Europe. AB - Human mobility has been vigorously debated as a key factor for the spread of bronze technology and profound changes in burial practices as well as material culture in central Europe at the transition from the Neolithic to the Bronze Age. However, the relevance of individual residential changes and their importance among specific age and sex groups are still poorly understood. Here, we present ancient DNA analysis, stable isotope data of oxygen, and radiogenic isotope ratios of strontium for 84 radiocarbon-dated skeletons from seven archaeological sites of the Late Neolithic Bell Beaker Complex and the Early Bronze Age from the Lech River valley in southern Bavaria, Germany. Complete mitochondrial genomes documented a diversification of maternal lineages over time. The isotope ratios disclosed the majority of the females to be nonlocal, while this is the case for only a few males and subadults. Most nonlocal females arrived in the study area as adults, but we do not detect their offspring among the sampled individuals. The striking patterns of patrilocality and female exogamy prevailed over at least 800 y between about 2500 and 1700 BC. The persisting residential rules and even a direct kinship relation across the transition from the Neolithic to the Bronze Age add to the archaeological evidence of continuing traditions from the Bell Beaker Complex to the Early Bronze Age. The results also attest to female mobility as a driving force for regional and supraregional communication and exchange at the dawn of the European metal ages. PMID- 28874532 TI - Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury. AB - Ineffective myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system's remarkable regenerative capacity, but the molecular mechanisms driving PNS myelin clearance are incompletely understood. We set out to discover new pathways of PNS myelin clearance to identify novel strategies for activating myelin clearance in the injured central nervous system, where myelin debris is not cleared efficiently. Here we show that Schwann cells, the myelinating glia of the PNS, collaborate with hematogenous macrophages to clear myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated myelin clearance, to the repertoire of cellular machinery used to clear myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating myelin clearance after CNS injury. PMID- 28874534 TI - Treg-specific IL-27Ralpha deletion uncovers a key role for IL-27 in Treg function to control autoimmunity. AB - Dysregulated Foxp3+ Treg functions result in uncontrolled immune activation and autoimmunity. Therefore, identifying cellular factors modulating Treg functions is an area of great importance. Here, using Treg-specific Il27ra-/- mice, we report that IL-27 signaling in Foxp3+ Tregs is essential for Tregs to control autoimmune inflammation in the central nervous system (CNS). Following experimental autoimmune encephalomyelitis (EAE) induction, Treg-specific Il27ra-/ mice develop more severe EAE. Consistent with the severe disease, the numbers of IFNgamma- and IL-17-producing CD4 T cells infiltrating the CNS tissues are greater in these mice. Treg accumulation in the inflamed CNS tissues is not affected by the lack of IL-27 signaling in Tregs, suggesting a functional defect of Il27ra-/- Tregs. IL-10 production by conventional CD4 T cells and their CNS accumulation are rather elevated in Treg-specific Il27ra-/- mice. Analysis with Treg fate-mapping reporter mice further demonstrates that IL-27 signaling in Tregs may control stability of Foxp3 expression. Finally, systemic administration of recombinant IL-27 in Treg-specific Il27ra-/- mice fails to ameliorate the disease even in the presence of IL-27-responsive conventional CD4 T cells. These findings uncover a previously unknown role of IL-27 in regulating Treg function to control autoimmune inflammation. PMID- 28874533 TI - Type 1 diabetes induction in humanized mice. AB - There is an urgent and unmet need for humanized in vivo models of type 1 diabetes to study immunopathogenesis and immunotherapy, and in particular antigen-specific therapy. Transfer of patient blood lymphocytes to immunodeficient mice is associated with xenogeneic graft-versus-host reactivity that complicates assessment of autoimmunity. Improved models could identify which human T cells initiate and participate in beta-cell destruction and help define critical target islet autoantigens. We used humanized mice (hu-mice) containing robust human immune repertoires lacking xenogeneic graft-versus-host reactivity to address this question. Hu-mice constructed by transplantation of HLA-DQ8+ human fetal thymus and CD34+ cells into HLA-DQ8-transgenic immunodeficient mice developed hyperglycemia and diabetes after transfer of autologous HLA-DQ8/insulin-B:9-23 (InsB:9-23)-specific T-cell receptor (TCR)-expressing human CD4+ T cells and immunization with InsB:9-23. Survival of the infused human T cells depended on the preexisting autologous human immune system, and pancreatic infiltration by human CD3+ T cells and insulitis were observed in the diabetic hu-mice, provided their islets were stressed by streptozotocin. This study fits Koch's postulate for pathogenicity, demonstrating a pathogenic role of islet autoreactive CD4+ T cell responses in type 1 diabetes induction in humans, underscores the role of the target beta-cells in their immunological fate, and demonstrates the capacity to initiate disease with T cells, recognizing the InsB:9-23 epitope in the presence of islet inflammation. This preclinical model has the potential to be used in studies of the pathogenesis of type 1 diabetes and for testing of clinically relevant therapeutic interventions. PMID- 28874535 TI - A chloroplast thylakoid lumen protein is required for proper photosynthetic acclimation of plants under fluctuating light environments. AB - Despite our increasingly sophisticated understanding of mechanisms ensuring efficient photosynthesis under laboratory-controlled light conditions, less is known about the regulation of photosynthesis under fluctuating light. This is important because-in nature-photosynthetic organisms experience rapid and extreme changes in sunlight, potentially causing deleterious effects on photosynthetic efficiency and productivity. Here we report that the chloroplast thylakoid lumenal protein MAINTENANCE OF PHOTOSYSTEM II UNDER HIGH LIGHT 2 (MPH2; encoded by At4g02530) is required for growth acclimation of Arabidopsis thaliana plants under controlled photoinhibitory light and fluctuating light environments. Evidence is presented that mph2 mutant light stress susceptibility results from a defect in photosystem II (PSII) repair, and our results are consistent with the hypothesis that MPH2 is involved in disassembling monomeric complexes during regeneration of dimeric functional PSII supercomplexes. Moreover, mph2-and previously characterized PSII repair-defective mutants-exhibited reduced growth under fluctuating light conditions, while PSII photoprotection-impaired mutants did not. These findings suggest that repair is not only required for PSII maintenance under static high-irradiance light conditions but is also a regulatory mechanism facilitating photosynthetic adaptation under fluctuating light environments. This work has implications for improvement of agricultural plant productivity through engineering PSII repair. PMID- 28874537 TI - Correction to Supporting Information for Kliethermes and Crabbe, Genetic independence of mouse measures of some aspects of novelty seeking. PMID- 28874536 TI - MicroRNA-277 targets insulin-like peptides 7 and 8 to control lipid metabolism and reproduction in Aedes aegypti mosquitoes. AB - Hematophagous female mosquitoes transmit numerous devastating human diseases, including malaria, dengue fever, Zika virus, and others. Because of their obligatory requirement of a vertebrate blood meal for reproduction, these mosquitoes need a lot of energy; therefore, understanding the molecular mechanisms linking metabolism and reproduction is of particular importance. Lipids are the major energy store providing the fuel required for host seeking and reproduction. They are essential components of the fat body, a metabolic tissue that is the insect analog of vertebrate liver and adipose tissue. In this study, we found that microRNA-277 (miR-277) plays an important role in regulating mosquito lipid metabolism. The genetic disruption of miR-277 using the CRISPR Cas9 system led to failures in both lipid storage and ovary development. miR-277 mimic injection partially rescued these phenotypic manifestations. Examination of subcellular localization of FOXO protein via CRISPR-assisted, single-stranded oligodeoxynucleotide-mediated homology-directed repair revealed that insulin signaling is up-regulated in response to miR-277 depletion. In silico target prediction identified that insulin-like peptides 7 and 8 (ilp7 and ilp8) are putative targets of miR-277; RNA immunoprecipitation and a luciferase reporter assay confirmed that ilp7 and ilp8 are direct targets of this miRNA. CRISPR-Cas9 depletion of ilp7 and ilp8 led to metabolic and reproductive defects. These depletions identified differential actions of ILP7 and ILP8 in lipid homeostasis and ovarian development. Thus, miR-277 plays a critical role in mosquito lipid metabolism and reproduction by targeting ilp7 and ilp8, and serves as a monitor to control ILP7 and ILP8 mRNA levels. PMID- 28874538 TI - Retraction for Wang et al., Somatic hypermutation maintains antibody thermodynamic stability during affinity maturation. PMID- 28874540 TI - Correction for Holmes et al., Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence. PMID- 28874541 TI - Correction for Koren and Feingold, Aerosol-cloud-precipitation system as a predator-prey problem. PMID- 28874539 TI - Detection of immune responses after immunotherapy in glioblastoma using PET and MRI. AB - Contrast-enhanced MRI is typically used to follow treatment response and progression in patients with glioblastoma (GBM). However, differentiating tumor progression from pseudoprogression remains a clinical dilemma largely unmitigated by current advances in imaging techniques. Noninvasive imaging techniques capable of distinguishing these two conditions could play an important role in the clinical management of patients with GBM and other brain malignancies. We hypothesized that PET probes for deoxycytidine kinase (dCK) could be used to differentiate immune inflammatory responses from other sources of contrast enhancement on MRI. Orthotopic malignant gliomas were established in syngeneic immunocompetent mice and then treated with dendritic cell (DC) vaccination and/or PD-1 mAb blockade. Mice were then imaged with [18F]-FAC PET/CT and MRI with i.v. contrast. The ratio of contrast enhancement on MRI to normalized PET probe uptake, which we term the immunotherapeutic response index, delineated specific regions of immune inflammatory activity. On postmortem examination, FACS-based enumeration of intracranial tumor-infiltrating lymphocytes directly correlated with quantitative [18F]-FAC PET probe uptake. Three patients with GBM undergoing treatment with tumor lysate-pulsed DC vaccination and PD-1 mAb blockade were also imaged before and after therapy using MRI and a clinical PET probe for dCK. Unlike in mice, [18F]-FAC is rapidly catabolized in humans; thus, we used another dCK PET probe, [18F]-clofarabine ([18F]-CFA), that may be more clinically relevant. Enhanced [18F]-CFA PET probe accumulation was identified in tumor and secondary lymphoid organs after immunotherapy. Our findings identify a noninvasive modality capable of imaging the host antitumor immune response against intracranial tumors. PMID- 28874542 TI - Self-report captures 27 distinct categories of emotion bridged by continuous gradients. AB - Emotions are centered in subjective experiences that people represent, in part, with hundreds, if not thousands, of semantic terms. Claims about the distribution of reported emotional states and the boundaries between emotion categories-that is, the geometric organization of the semantic space of emotion-have sparked intense debate. Here we introduce a conceptual framework to analyze reported emotional states elicited by 2,185 short videos, examining the richest array of reported emotional experiences studied to date and the extent to which reported experiences of emotion are structured by discrete and dimensional geometries. Across self-report methods, we find that the videos reliably elicit 27 distinct varieties of reported emotional experience. Further analyses revealed that categorical labels such as amusement better capture reports of subjective experience than commonly measured affective dimensions (e.g., valence and arousal). Although reported emotional experiences are represented within a semantic space best captured by categorical labels, the boundaries between categories of emotion are fuzzy rather than discrete. By analyzing the distribution of reported emotional states we uncover gradients of emotion-from anxiety to fear to horror to disgust, calmness to aesthetic appreciation to awe, and others-that correspond to smooth variation in affective dimensions such as valence and dominance. Reported emotional states occupy a complex, high dimensional categorical space. In addition, our library of videos and an interactive map of the emotional states they elicit (https://s3-us-west 1.amazonaws.com/emogifs/map.html) are made available to advance the science of emotion. PMID- 28874544 TI - Single rat muscle Na+ channel mutation confers batrachotoxin autoresistance found in poison-dart frog Phyllobates terribilis. AB - Poison-dart Phyllobates terribilis frogs sequester lethal amounts of steroidal alkaloid batrachotoxin (BTX) in their skin as a defense mechanism against predators. BTX targets voltage-gated Na+ channels and enables them to open persistently. How BTX autoresistance arises in such frogs remains a mystery. The BTX receptor has been delineated along the Na+ channel inner cavity, which is formed jointly by four S6 transmembrane segments from domains D1 to D4. Within the P. terribilis muscle Na+ channel, five amino acid (AA) substitutions have been identified at D1/S6 and D4/S6. We therefore investigated the role of these naturally occurring substitutions in BTX autoresistance by introducing them into rat Nav1.4 muscle Na+ channel, both individually and in combination. Our results showed that combination mutants containing an N1584T substitution all conferred a complete BTX-resistant phenotype when expressed in mammalian HEK293t cells. The single N1584T mutant also retained its functional integrity and became exceptionally resistant to 5 uM BTX, aside from a small residual BTX effect. Single and combination mutants with the other four S6 residues (S429A, I433V, A445D, and V1583I) all remained highly BTX sensitive. These findings, along with diverse BTX phenotypes of N1584K/A/D/T mutant channels, led us to conclude that the conserved N1584 residue is indispensable for BTX actions, probably functioning as an integral part of the BTX receptor. Thus, complete BTX autoresistance found in P. terribilis muscle Na+ channels could emerge primarily from a single AA substitution (asparagine->threonine) via a single nucleotide mutation (AAC->ACC). PMID- 28874543 TI - Structure of the Ebola virus envelope protein MPER/TM domain and its interaction with the fusion loop explains their fusion activity. AB - Ebolavirus (EBOV), an enveloped filamentous RNA virus causing severe hemorrhagic fever, enters cells by macropinocytosis and membrane fusion in a late endosomal compartment. Fusion is mediated by the EBOV envelope glycoprotein GP, which consists of subunits GP1 and GP2. GP1 binds to cellular receptors, including Niemann-Pick C1 (NPC1) protein, and GP2 is responsible for low pH-induced membrane fusion. Proteolytic cleavage and NPC1 binding at endosomal pH lead to conformational rearrangements of GP2 that include exposing the hydrophobic fusion loop (FL) for insertion into the cellular target membrane and forming a six-helix bundle structure. Although major portions of the GP2 structure have been solved in pre- and postfusion states and although current models place the transmembrane (TM) and FL domains of GP2 in close proximity at critical steps of membrane fusion, their structures in membrane environments, and especially interactions between them, have not yet been characterized. Here, we present the structure of the membrane proximal external region (MPER) connected to the TM domain: i.e., the missing parts of the EBOV GP2 structure. The structure, solved by solution NMR and EPR spectroscopy in membrane-mimetic environments, consists of a helix turn-helix architecture that is independent of pH. Moreover, the MPER region is shown to interact in the membrane interface with the previously determined structure of the EBOV FL through several critical aromatic residues. Mutation of aromatic and neighboring residues in both binding partners decreases fusion and viral entry, highlighting the functional importance of the MPER/TM-FL interaction in EBOV entry and fusion. PMID- 28874545 TI - Increasing the breadth and potency of response to the seasonal influenza virus vaccine by immune complex immunization. AB - The main barrier to reduction of morbidity caused by influenza is the absence of a vaccine that elicits broad protection against different virus strains. Studies in preclinical models of influenza virus infections have shown that antibodies alone are sufficient to provide broad protection against divergent virus strains in vivo. Here, we address the challenge of identifying an immunogen that can elicit potent, broadly protective, antiinfluenza antibodies by demonstrating that immune complexes composed of sialylated antihemagglutinin antibodies and seasonal inactivated flu vaccine (TIV) can elicit broadly protective antihemagglutinin antibodies. Further, we found that an Fc-modified, bispecific monoclonal antibody against conserved epitopes of the hemagglutinin can be combined with TIV to elicit broad protection, thus setting the stage for a universal influenza virus vaccine. PMID- 28874547 TI - Biodiversity promotes primary productivity and growing season lengthening at the landscape scale. AB - Experiments have shown positive biodiversity-ecosystem functioning (BEF) relationships in small plots with model communities established from species pools typically comprising few dozen species. Whether patterns found can be extrapolated to complex, nonexperimental, real-world landscapes that provide ecosystem services to humans remains unclear. Here, we combine species inventories from a large-scale network of 447 1-km2 plots with remotely sensed indices of primary productivity (years 2000-2015). We show that landscape-scale productivity and its temporal stability increase with the diversity of plants and other taxa. Effects of biodiversity indicators on productivity were comparable in size to effects of other important drivers related to climate, topography, and land cover. These effects occurred in plots that integrated different ecosystem types (i.e., metaecosystems) and were consistent over vast environmental and altitudinal gradients. The BEF relations we report are as strong or even exceed the ones found in small-scale experiments, despite different community assembly processes and a species pool comprising nearly 2,000 vascular plant species. Growing season length increased progressively over the observation period, and this shift was accelerated in more diverse plots, suggesting that a large species pool is important for adaption to climate change. Our study further implies that abiotic global-change drivers may mediate ecosystem functioning through biodiversity changes. PMID- 28874546 TI - Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. AB - The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types. PMID- 28874548 TI - Subnational mobility and consumption-based environmental accounting of US corn in animal protein and ethanol supply chains. AB - Corn production, and its associated inputs, is a relatively large source of greenhouse gas emissions and uses significant amounts of water and land, thus contributing to climate change, fossil fuel depletion, local air pollutants, and local water scarcity. As large consumers of this corn, corporations in the ethanol and animal protein industries are increasingly assessing and reporting sustainability impacts across their supply chains to identify, prioritize, and communicate sustainability risks and opportunities material to their operations. In doing so, many have discovered that the direct impacts of their owned operations are dwarfed by those upstream in the supply chain, requiring transparency and knowledge about environmental impacts along the supply chains. Life cycle assessments (LCAs) have been used to identify hotspots of environmental impacts at national levels, yet these provide little subnational information necessary for guiding firms' specific supply networks. In this paper, our Food System Supply-Chain Sustainability (FoodS3) model connects spatial, firm specific demand of corn purchasers with upstream corn production in the United States through a cost minimization transport model. This provides a means to link county-level corn production in the United States to firm-specific demand locations associated with downstream processing facilities. Our model substantially improves current LCA assessment efforts that are confined to broad national or state level impacts. In drilling down to subnational levels of environmental impacts that occur over heterogeneous areas and aggregating these landscape impacts by specific supply networks, targeted opportunities for improvements to the sustainability performance of supply chains are identified. PMID- 28874549 TI - Molecular basis of mammalian transmissibility of avian H1N1 influenza viruses and their pandemic potential. AB - North American wild birds are an important reservoir of influenza A viruses, yet the potential of viruses in this reservoir to transmit and cause disease in mammals is not well understood. Our surveillance of avian influenza viruses (AIVs) at Delaware Bay, USA, revealed a group of similar H1N1 AIVs isolated in 2009, some of which were airborne-transmissible in the ferret model without prior adaptation. Comparison of the genomes of these viruses revealed genetic markers of airborne transmissibility in the Polymerase Basic 2 (PB2), PB1, PB1-F2, Polymerase Acidic-X (PA-X), Nonstructural Protein 1 (NS1), and Nuclear Export Protein (NEP) genes. We studied the role of NS1 in airborne transmission and found that NS1 mutants that were not airborne-transmissible caused limited tissue pathology in the upper respiratory tract (URT). Viral maturation was also delayed, evident as strong intranuclear staining and little virus at the mucosa. Our study of this naturally occurring constellation of genetic markers has provided insights into the poorly understood phenomenon of AIV airborne transmissibility by revealing a role for NS1 and characteristics of viral replication in the URT that were associated with airborne transmission. The transmissibility of these viruses further highlights the pandemic potential of AIVs in the wild bird reservoir and the need to maintain surveillance. PMID- 28874551 TI - Self-healing catalysis in water. AB - Principles for designing self-healing water-splitting catalysts are presented together with a formal kinetics model to account for the key chemical steps needed for self-healing. Self-healing may be realized if the catalysts are able to self-assemble at applied potentials less than that needed for catalyst turnover. Solution pH provides a convenient handle for controlling the potential of these two processes, as demonstrated for the cobalt phosphate (CoPi) water splitting catalyst. For Co2+ ion that appears in solution due to leaching from the catalyst during turnover, a quantitative description for the kinetics of the redeposition of the ion during the self-healing process has been derived. The model reveals that OER activity of CoPi occurs with negligible film dissolution in neutral pH for typical cell geometries and buffer concentrations. PMID- 28874550 TI - Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice. AB - Down syndrome (DS) caused by trisomy of chromosome 21 is the most common genetic cause of intellectual disability. Although the prenatal diagnosis of DS has become feasible, there are no therapies available for the rescue of DS-related neurocognitive impairment. A growth inducer newly identified in our screen of neural stem cells (NSCs) has potent inhibitory activity against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and was found to rescue proliferative deficits in Ts65Dn-derived neurospheres and human NSCs derived from individuals with DS. The oral administration of this compound, named ALGERNON (altered generation of neurons), restored NSC proliferation in murine models of DS and increased the number of newborn neurons. Moreover, administration of ALGERNON to pregnant dams rescued aberrant cortical formation in DS mouse embryos and prevented the development of abnormal behaviors in DS offspring. These data suggest that the neurogenic phenotype of DS can be prevented by ALGERNON prenatal therapy. PMID- 28874553 TI - QnAs with Pardis Sabeti. PMID- 28874552 TI - Global transcriptional regulatory network for Escherichia coli robustly connects gene expression to transcription factor activities. AB - Transcriptional regulatory networks (TRNs) have been studied intensely for >25 y. Yet, even for the Escherichia coli TRN-probably the best characterized TRN several questions remain. Here, we address three questions: (i) How complete is our knowledge of the E. coli TRN; (ii) how well can we predict gene expression using this TRN; and (iii) how robust is our understanding of the TRN? First, we reconstructed a high-confidence TRN (hiTRN) consisting of 147 transcription factors (TFs) regulating 1,538 transcription units (TUs) encoding 1,764 genes. The 3,797 high-confidence regulatory interactions were collected from published, validated chromatin immunoprecipitation (ChIP) data and RegulonDB. For 21 different TF knockouts, up to 63% of the differentially expressed genes in the hiTRN were traced to the knocked-out TF through regulatory cascades. Second, we trained supervised machine learning algorithms to predict the expression of 1,364 TUs given TF activities using 441 samples. The algorithms accurately predicted condition-specific expression for 86% (1,174 of 1,364) of the TUs, while 193 TUs (14%) were predicted better than random TRNs. Third, we identified 10 regulatory modules whose definitions were robust against changes to the TRN or expression compendium. Using surrogate variable analysis, we also identified three unmodeled factors that systematically influenced gene expression. Our computational workflow comprehensively characterizes the predictive capabilities and systems level functions of an organism's TRN from disparate data types. PMID- 28874554 TI - Effects of thymic selection on T cell recognition of foreign and tumor antigenic peptides. AB - The advent of cancer immunotherapy has generated renewed hope for the treatment of many malignancies by introducing a number of novel strategies that exploit various properties of the immune system. These therapies are based on the idea that cytotoxic T lymphocytes (CTLs) directly recognize and respond to tumor associated neoantigens (TANs) in much the same way as they would to foreign peptides presented on cell surfaces. To date, however, nearly all attempts to optimize immunotherapeutic strategies have been empirical. Here, we develop a model of T cell selection based on the assumption of random interaction strengths between a self-peptide and the various T cell receptors. The model enables the analytical study of the effects of selection on the CTL recognition of TANs and completely foreign peptides and can estimate the number of CTLs that can detect donor-matched transplants. We show that negative selection thresholds chosen to reflect experimentally observed thymic survival rates result in near-optimal production of T cells that are capable of surviving selection and recognizing foreign antigen. These analytical results are confirmed by simulation. PMID- 28874555 TI - A trans-acting leader RNA from a Salmonella virulence gene. AB - Bacteria use flagella to move toward nutrients, find its host, or retract from toxic substances. Because bacterial flagellum is one of the ligands that activate the host innate immune system, its synthesis should be tightly regulated during host infection, which is largely unknown. Here, we report that a bacterial leader mRNA from the mgtCBR virulence operon in the intracellular pathogen Salmonella enterica serovar Typhimurium binds to the fljB coding region of mRNAs in the fljBA operon encoding the FljB phase 2 flagellin, a main component of bacterial flagella and the FljA repressor for the FliC phase 1 flagellin, and degrades fljBA mRNAs in an RNase E-dependent fashion during infection. A nucleotide substitution of the fljB flagellin gene that prevents the mgtC leader RNA mediated down-regulation increases the fljB-encoded flagellin synthesis, leading to a hypermotile phenotype inside macrophages. Moreover, the fljB nucleotide substitution renders Salmonella hypervirulent, indicating that FljB-based motility must be compromised in the phagosomal compartment where Salmonella resides. This suggests that this pathogen promotes pathogenicity by producing a virulence protein and limits locomotion by a trans-acting leader RNA from the same virulence gene during infection. PMID- 28874556 TI - RPE65 has an additional function as the lutein to meso-zeaxanthin isomerase in the vertebrate eye. AB - Carotenoids are plant-derived pigment molecules that vertebrates cannot synthesize de novo that protect the fovea of the primate retina from oxidative stress and light damage. meso-Zeaxanthin is an ocular-specific carotenoid for which there are no common dietary sources. It is one of the three major carotenoids present at the foveal center, but the mechanism by which it is produced in the eye is unknown. An isomerase enzyme is thought to be responsible for the transformation of lutein to meso-zeaxanthin by a double-bond shift mechanism, but its identity has been elusive. We previously found that meso zeaxanthin is produced in a developmentally regulated manner in chicken embryonic retinal pigment epithelium (RPE)/choroid in the absence of light. In the present study, we show that RPE65, the isomerohydrolase enzyme of the vertebrate visual cycle that catalyzes the isomerization of all-trans-retinyl esters to 11-cis retinol, is also the isomerase enzyme responsible for the production of meso zeaxanthin in vertebrates. Its RNA is up-regulated 23-fold at the time of meso zeaxanthin production during chicken eye development, and we present evidence that overexpression of either chicken or human RPE65 in cell culture leads to the production of meso-zeaxanthin from lutein. Pharmacologic inhibition of RPE65 function resulted in significant inhibition of meso-zeaxanthin biosynthesis during chicken eye development. Structural docking experiments revealed that the epsilon ring of lutein fits into the active site of RPE65 close to the nonheme iron center. This report describes a previously unrecognized additional activity of RPE65 in ocular carotenoid metabolism. PMID- 28874557 TI - Mesoscale martensitic transformation in single crystals of topological defects. AB - Liquid-crystal blue phases (BPs) are highly ordered at two levels. Molecules exhibit orientational order at nanometer length scales, while chirality leads to ordered arrays of double-twisted cylinders over micrometer scales. Past studies of polycrystalline BPs were challenged by the existence of grain boundaries between randomly oriented crystalline nanodomains. Here, the nucleation of BPs is controlled with precision by relying on chemically nanopatterned surfaces, leading to macroscopic single-crystal BP specimens where the dynamics of mesocrystal formation can be directly observed. Theory and experiments show that transitions between two BPs having a different network structure proceed through local reorganization of the crystalline array, without diffusion of the double twisted cylinders. In solid crystals, martensitic transformations between crystal structures involve the concerted motion of a few atoms, without diffusion. The transformation between BPs, where crystal features arise in the submicron regime, is found to be martensitic in nature when one considers the collective behavior of the double-twist cylinders. Single-crystal BPs are shown to offer fertile grounds for the study of directed crystal nucleation and the controlled growth of soft matter. PMID- 28874559 TI - Correction for KonDo et al., Toll ligand Spatzle3 controls melanization in the stripe pattern formation in caterpillars. PMID- 28874558 TI - Glacier shrinkage driving global changes in downstream systems. AB - Glaciers cover ~10% of the Earth's land surface, but they are shrinking rapidly across most parts of the world, leading to cascading impacts on downstream systems. Glaciers impart unique footprints on river flow at times when other water sources are low. Changes in river hydrology and morphology caused by climate-induced glacier loss are projected to be the greatest of any hydrological system, with major implications for riverine and near-shore marine environments. Here, we synthesize current evidence of how glacier shrinkage will alter hydrological regimes, sediment transport, and biogeochemical and contaminant fluxes from rivers to oceans. This will profoundly influence the natural environment, including many facets of biodiversity, and the ecosystem services that glacier-fed rivers provide to humans, particularly provision of water for agriculture, hydropower, and consumption. We conclude that human society must plan adaptation and mitigation measures for the full breadth of impacts in all affected regions caused by glacier shrinkage. PMID- 28874560 TI - Ultrafast fluorescent decay induced by metal-mediated dipole-dipole interaction in two-dimensional molecular aggregates. AB - Two-dimensional molecular aggregate (2DMA), a thin sheet of strongly interacting dipole molecules self-assembled at close distance on an ordered lattice, is a fascinating fluorescent material. It is distinctively different from the conventional (single or colloidal) dye molecules and quantum dots. In this paper, we verify that when a 2DMA is placed at a nanometric distance from a metallic substrate, the strong and coherent interaction between the dipoles inside the 2DMA dominates its fluorescent decay at a picosecond timescale. Our streak-camera lifetime measurement and interacting lattice-dipole calculation reveal that the metal-mediated dipole-dipole interaction shortens the fluorescent lifetime to about one-half and increases the energy dissipation rate by 10 times that expected from the noninteracting single-dipole picture. Our finding can enrich our understanding of nanoscale energy transfer in molecular excitonic systems and may designate a unique direction for developing fast and efficient optoelectronic devices. PMID- 28874561 TI - Localized CD47 blockade enhances immunotherapy for murine melanoma. AB - CD47 is an antiphagocytic ligand broadly expressed on normal and malignant tissues that delivers an inhibitory signal through the receptor signal regulatory protein alpha (SIRPalpha). Inhibitors of the CD47-SIRPalpha interaction improve antitumor antibody responses by enhancing antibody-dependent cellular phagocytosis (ADCP) in xenograft models. Endogenous expression of CD47 on a variety of cell types, including erythrocytes, creates a formidable antigen sink that may limit the efficacy of CD47-targeting therapies. We generated a nanobody, A4, that blocks the CD47-SIRPalpha interaction. A4 synergizes with anti-PD-L1, but not anti-CTLA4, therapy in the syngeneic B16F10 melanoma model. Neither increased dosing nor half-life extension by fusion of A4 to IgG2a Fc (A4Fc) overcame the issue of an antigen sink or, in the case of A4Fc, systemic toxicity. Generation of a B16F10 cell line that secretes the A4 nanobody showed that an enhanced response to several immune therapies requires near-complete blockade of CD47 in the tumor microenvironment. Thus, strategies to localize CD47 blockade to tumors may be particularly valuable for immune therapy. PMID- 28874562 TI - Stability of equidimensional pseudo-single-domain magnetite over billion-year timescales. AB - Interpretations of paleomagnetic observations assume that naturally occurring magnetic particles can retain their primary magnetic recording over billions of years. The ability to retain a magnetic recording is inferred from laboratory measurements, where heating causes demagnetization on the order of seconds. The theoretical basis for this inference comes from previous models that assume only the existence of small, uniformly magnetized particles, whereas the carriers of paleomagnetic signals in rocks are usually larger, nonuniformly magnetized particles, for which there is no empirically complete, thermally activated model. This study has developed a thermally activated numerical micromagnetic model that can quantitatively determine the energy barriers between stable states in nonuniform magnetic particles on geological timescales. We examine in detail the thermal stability characteristics of equidimensional cuboctahedral magnetite and find that, contrary to previously published theories, such nonuniformly magnetized particles provide greater magnetic stability than their uniformly magnetized counterparts. Hence, nonuniformly magnetized grains, which are commonly the main remanence carrier in meteorites and rocks, can record and retain high-fidelity magnetic recordings over billions of years. PMID- 28874563 TI - Epigenetic control via allosteric regulation of mammalian protein arginine methyltransferases. AB - Arginine methylation on histones is a central player in epigenetics and in gene activation and repression. Protein arginine methyltransferase (PRMT) activity has been implicated in stem cell pluripotency, cancer metastasis, and tumorigenesis. The expression of one of the nine mammalian PRMTs, PRMT5, affects the levels of symmetric dimethylarginine (SDMA) at Arg-3 on histone H4, leading to the repression of genes which are related to disease progression in lymphoma and leukemia. Another PRMT, PRMT7, also affects SDMA levels at the same site despite its unique monomethylating activity and the lack of any evidence for PRMT7 catalyzed histone H4 Arg-3 methylation. We present evidence that PRMT7-mediated monomethylation of histone H4 Arg-17 regulates PRMT5 activity at Arg-3 in the same protein. We analyzed the kinetics of PRMT5 over a wide range of substrate concentrations. Significantly, we discovered that PRMT5 displays positive cooperativity in vitro, suggesting that this enzyme may be allosterically regulated in vivo as well. Most interestingly, monomethylation at Arg-17 in histone H4 not only raised the general activity of PRMT5 with this substrate, but also ameliorated the low activity of PRMT5 at low substrate concentrations. These kinetic studies suggest a biochemical explanation for the interplay between PRMT5 and PRMT7-mediated methylation of the same substrate at different residues and also suggest a general model for regulation of PRMTs. Elucidating the exact relationship between these two enzymes when they methylate two distinct sites of the same substrate may aid in developing therapeutics aimed at reducing PRMT5/7 activity in cancer and other diseases. PMID- 28874564 TI - Endodermal germ-layer formation through active actin-driven migration triggered by N-cadherin. AB - Germ-layer formation during gastrulation is both a fundamental step of development and a paradigm for tissue formation and remodeling. However, the cellular and molecular basis of germ-layer segregation is poorly understood, mostly because of the lack of direct in vivo observations. We used mosaic zebrafish embryos to investigate the formation of the endoderm. High-resolution live imaging and functional analyses revealed that endodermal cells reach their characteristic innermost position through an active, oriented, and actin-based migration dependent on Rac1, which contrasts with the previously proposed differential adhesion cell sorting. Rather than being attracted to their destination, the yolk syncytial layer, cells appear to migrate away from their neighbors. This migration depends on N-cadherin that, when imposed in ectodermal cells, is sufficient to trigger their internalization without affecting their fate. Overall, these results lead to a model of germ-layer formation in which, upon N-cadherin expression, endodermal cells actively migrate away from their epiblastic neighbors to reach their internal position, revealing cell-contact avoidance as an unexplored mechanism driving germ-layer formation. PMID- 28874565 TI - Virulence protein VirD5 of Agrobacterium tumefaciens binds to kinetochores in host cells via an interaction with Spt4. AB - The bacterium Agrobacterium tumefaciens causes crown gall tumor formation in plants. During infection the bacteria translocate an oncogenic piece of DNA (transferred DNA, T-DNA) into plant cells at the infection site. A number of virulence proteins are cotransported into host cells concomitantly with the T-DNA to effectuate transformation. Using yeast as a model host, we find that one of these proteins, VirD5, localizes to the centromeres/kinetochores in the nucleus of the host cells by its interaction with the conserved protein Spt4. VirD5 promotes chromosomal instability as seen by the high-frequency loss of a minichromosome in yeast. By using both yeast and plant cells with a chromosome that was specifically marked by a lacO repeat, chromosome segregation errors and the appearance of aneuploid cells due to the presence of VirD5 could be visualized in vivo. Thus, VirD5 is a prokaryotic virulence protein that interferes with mitosis. PMID- 28874567 TI - Correction for Schuth et al., Effective intermediate-spin iron in O2-transporting heme proteins. PMID- 28874566 TI - Cellular responses to human cytomegalovirus infection: Induction of a mesenchymal to-epithelial transition (MET) phenotype. AB - Human cytomegalovirus (HCMV) is the prototypical human beta-herpes virus. Here we perform a systems analysis of the HCMV host-cell transcriptome, using gene set enrichment analysis (GSEA) as an engine to globally map the host-pathogen interaction across two cell types. Our analysis identified several previously unknown signatures of infection, such as induction of potassium channels and amino acid transporters, derepression of genes marked with histone H3 lysine 27 trimethylation (H3K27me3), and inhibition of genes related to epithelial-to mesenchymal transition (EMT). The repression of EMT genes was dependent on early viral gene expression and correlated with induction E-cadherin (CDH1) and mesenchymal-to-epithelial transition (MET) genes. Infection of transformed breast carcinoma and glioma stem cells similarly inhibited EMT and induced MET, arguing that HCMV induces an epithelium-like cellular environment during infection. PMID- 28874568 TI - Proteoliposome-based full-length ZnT8 self-antigen for type 1 diabetes diagnosis on a plasmonic platform. AB - Identified as a major biomarker for type 1 diabetes (T1D) diagnosis, zinc transporter 8 autoantibody (ZnT8A) has shown promise for staging disease risk and disease diagnosis. However, existing assays for ZnT8 autoantibody (ZnT8A) are limited to detection by soluble domains of ZnT8, owing to difficulties in maintaining proper folding of a full-length ZnT8 protein outside its native membrane environment. Through a combined bioengineering and nanotechnology approach, we have developed a proteoliposome-based full-length ZnT8 self-antigen (full-length ZnT8 proteoliposomes; PLR-ZnT8) for efficient detection of ZnT8A on a plasmonic gold chip (pGOLD). The protective lipid matrix of proteoliposomes improved the proper folding and structural stability of full-length ZnT8, helping PLR-ZnT8 immobilized on pGOLD (PLR-ZnT8/pGOLD) achieve high-affinity capture of ZnT8A from T1D sera. Our PLR-ZnT8/pGOLD exhibited efficient ZnT8A detection for T1D diagnosis with ~76% sensitivity and ~97% specificity (n = 307), superior to assays based on detergent-solubilized full-length ZnT8 and the C-terminal domain of ZnT8. Multiplexed assays using pGOLD were also developed for simultaneous detection of ZnT8A, islet antigen 2 autoantibody, and glutamic acid decarboxylase autoantibody for diagnosing T1D. PMID- 28874569 TI - Dorsolateral prefrontal cortex GABA deficit in older adults with sleep-disordered breathing. AB - Sleep-disordered breathing (SDB) is a common disorder in aging that is associated with cognitive decline, including significant executive dysfunction, for which the neurobiological underpinnings remain poorly understood. Using proton magnetic resonance spectroscopy (1H MRS), this study assessed whether dysregulation of the homeostatic balance of the major inhibitory and excitatory amino acid neurotransmitter systems of gamma-aminobutyric acid (GABA) and glutamate, respectively, play a role in SDB. Levels of GABA and those of the combined resonances of glutamate and glutamine (Glx), were measured by 1H MRS in the left dorsolateral prefrontal cortex (l-DLPFC) and bilateral hippocampal regions of 19 older adults (age +/- SD: 66.1 +/- 1.9 years) with moderate to severe SDB, defined as having an Apnea-Hypopnea Index (AHI) greater than 15 as assessed by polysomnography, and in 14 older adults (age +/- SD: 62.3 +/- 1.3 years) without SDB (AHI < 5). In subjects with SDB, levels of l-DLPFC GABA, but not Glx, were significantly lower than in control subjects (P < 0.0002). Additionally, there was a negative correlation between l-DLPFC GABA levels, but not Glx, and SDB severity by AHI (r = -0.68, P < 0.0001), and a positive correlation between l DLPFC GABA levels, but not Glx, and minimal oxygen saturation during sleep (r = 0.62, P = 0.0005). By contrast, no group differences or oxygenation associations were found for levels of GABA or Glx in right or left hippocampal region. These findings are interpreted in terms of a pathophysiological model of SDB in which hypoxia-mediated inhibitory neurotransmission deficit in DLPFC could lead to hyperexcitability and, potentially neuronal dysfunction and cognitive decline. PMID- 28874570 TI - Loquacious-PD facilitates Drosophila Dicer-2 cleavage through interactions with the helicase domain and dsRNA. AB - Loquacious-PD (Loqs-PD) is required for biogenesis of many endogenous siRNAs in Drosophila In vitro, Loqs-PD enhances the rate of dsRNA cleavage by Dicer-2 and also enables processing of substrates normally refractory to cleavage. Using purified components, and Loqs-PD truncations, we provide a mechanistic basis for Loqs-PD functions. Our studies indicate that the 22 amino acids at the C terminus of Loqs-PD, including an FDF-like motif, directly interact with the Hel2 subdomain of Dicer-2's helicase domain. This interaction is RNA-independent, but we find that modulation of Dicer-2 cleavage also requires dsRNA binding by Loqs PD. Furthermore, while the first dsRNA-binding motif of Loqs-PD is dispensable for enhancing cleavage of optimal substrates, it is essential for enhancing cleavage of suboptimal substrates. Finally, our studies define a previously unrecognized Dicer interaction interface and suggest that Loqs-PD is well positioned to recruit substrates into the helicase domain of Dicer-2. PMID- 28874571 TI - Osmotaxis in Escherichia coli through changes in motor speed. AB - Bacterial motility, and in particular repulsion or attraction toward specific chemicals, has been a subject of investigation for over 100 years, resulting in detailed understanding of bacterial chemotaxis and the corresponding sensory network in many bacterial species. For Escherichia coli most of the current understanding comes from the experiments with low levels of chemotactically active ligands. However, chemotactically inactive chemical species at concentrations found in the human gastrointestinal tract produce significant changes in E. coli's osmotic pressure and have been shown to lead to taxis. To understand how these nonspecific physical signals influence motility, we look at the response of individual bacterial flagellar motors under stepwise changes in external osmolarity. We combine these measurements with a population swimming assay under the same conditions. Unlike for chemotactic response, a long-term increase in swimming/motor speeds is observed, and in the motor rotational bias, both of which scale with the osmotic shock magnitude. We discuss how the speed changes we observe can lead to steady-state bacterial accumulation. PMID- 28874572 TI - Dendritic space-filling requires a neuronal type-specific extracellular permissive signal in Drosophila. AB - Neurons sometimes completely fill available space in their receptive fields with evenly spaced dendrites to uniformly sample sensory or synaptic information. The mechanisms that enable neurons to sense and innervate all space in their target tissues are poorly understood. Using Drosophila somatosensory neurons as a model, we show that heparan sulfate proteoglycans (HSPGs) Dally and Syndecan on the surface of epidermal cells act as local permissive signals for the dendritic growth and maintenance of space-filling nociceptive C4da neurons, allowing them to innervate the entire skin. Using long-term time-lapse imaging with intact Drosophila larvae, we found that dendrites grow into HSPG-deficient areas but fail to stay there. HSPGs are necessary to stabilize microtubules in newly formed high-order dendrites. In contrast to C4da neurons, non-space-filling sensory neurons that develop in the same microenvironment do not rely on HSPGs for their dendritic growth. Furthermore, HSPGs do not act by transporting extracellular diffusible ligands or require leukocyte antigen-related (Lar), a receptor protein tyrosine phosphatase (RPTP) and the only known Drosophila HSPG receptor, for promoting dendritic growth of space-filling neurons. Interestingly, another RPTP, Ptp69D, promotes dendritic growth of C4da neurons in parallel to HSPGs. Together, our data reveal an HSPG-dependent pathway that specifically allows dendrites of space-filling neurons to innervate all target tissues in Drosophila. PMID- 28874573 TI - Redefining community based on place attachment in a connected world. AB - The concept of community is often used in environmental policy to foster environmental stewardship and public participation, crucial prerequisites of effective management. However, prevailing conceptualizations of community based on residential location or resource use are limited with respect to their utility as surrogates for communities of shared environment-related interests, and because of the localist perspective they entail. Thus, addressing contemporary sustainability challenges, which tend to involve transnational social and environmental interactions, urgently requires additional approaches to conceptualizing community that are compatible with current globalization. We propose a framing for redefining community based on place attachment (i.e., the bonds people form with places) in the context of Australia's Great Barrier Reef, a World Heritage Area threatened by drivers requiring management and political action at scales beyond the local. Using data on place attachment from 5,403 respondents residing locally, nationally, and internationally, we identified four communities that each shared a type of attachment to the reef and that spanned conventional location and use communities. We suggest that as human-environment interactions change with increasing mobility (both corporeal and that mediated by communication and information technology), new types of people-place relations that transcend geographic and social boundaries and do not require ongoing direct experience to form are emerging. We propose that adopting a place attachment framing to community provides a means to capture the neglected nonmaterial bonds people form with the environment, and could be leveraged to foster transnational environmental stewardship, critical to advancing global sustainability in our increasingly connected world. PMID- 28874574 TI - Effect of cell cycle arrest on intermediate metabolism in the marine diatom Phaeodactylum tricornutum. AB - The inhibitor NU 2058 [6-(cyclohexylmethoxy)-9H-purin-2-amine] leads to G1-phase cell cycle arrest in the marine diatom, Phaeodactylum tricornutum, by binding to two cyclin-dependent kinases, CDKA1 and CDKA2. NU 2058 has no effect on photosynthetic attributes, such as Fv/Fm, chlorophyll a/cell, levels of D2 PSII subunits, or RbcL; however, cell cycle arrest leads to unbalanced growth whereby photosynthetic products that can no longer be used for cell division are redirected toward carbohydrates and triacylglycerols (TAGs). Arrested cells up regulate most genes involved in fatty acid synthesis, including acetyl-CoA carboxylase, and three out of five putative type II diglyceride acyltransferases (DGATs), the enzymes that catalyze TAG production. Correlation of transcriptomes in arrested cells with a flux balance model for P. tricornutum predicts that reactions in the mitochondrion that supply glycerate may support TAG synthesis. Our results reveal that sources of intermediate metabolites and macromolecular sinks are tightly coupled to the cell cycle in a marine diatom, and that arresting cells in the G1 phase leads to remodeling of intermediate metabolism and unbalanced growth. PMID- 28874576 TI - Eighty years of food-web response to interannual variation in discharge recorded in river diatom frustules from an ocean sediment core. AB - Little is known about the importance of food-web processes as controls of river primary production due to the paucity of both long-term studies and of depositional environments which would allow retrospective fossil analysis. To investigate how freshwater algal production in the Eel River, northern California, varied over eight decades, we quantified siliceous shells (frustules) of freshwater diatoms from a well-dated undisturbed sediment core in a nearshore marine environment. Abundances of freshwater diatom frustules exported to Eel Canyon sediment from 1988 to 2001 were positively correlated with annual biomass of Cladophora surveyed over these years in upper portions of the Eel basin. Over 28 years of contemporary field research, peak algal biomass was generally higher in summers following bankfull, bed-scouring winter floods. Field surveys and experiments suggested that bed-mobilizing floods scour away overwintering grazers, releasing algae from spring and early summer grazing. During wet years, growth conditions for algae could also be enhanced by increased nutrient loading from the watershed, or by sustained summer base flows. Total annual rainfall and frustule densities in laminae over a longer 83-year record were weakly and negatively correlated, however, suggesting that positive effects of floods on annual algal production were primarily mediated by "top-down" (consumer release) rather than "bottom-up" (growth promoting) controls. PMID- 28874575 TI - Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation. AB - Muscle stem cells are a potent cell population dedicated to efficacious skeletal muscle regeneration, but their therapeutic utility is currently limited by mode of delivery. We developed a cell delivery strategy based on a supramolecular liquid crystal formed by peptide amphiphiles (PAs) that encapsulates cells and growth factors within a muscle-like unidirectionally ordered environment of nanofibers. The stiffness of the PA scaffolds, dependent on amino acid sequence, was found to determine the macroscopic degree of cell alignment templated by the nanofibers in vitro. Furthermore, these PA scaffolds support myogenic progenitor cell survival and proliferation and they can be optimized to induce cell differentiation and maturation. We engineered an in vivo delivery system to assemble scaffolds by injection of a PA solution that enabled coalignment of scaffold nanofibers with endogenous myofibers. These scaffolds locally retained growth factors, displayed degradation rates matching the time course of muscle tissue regeneration, and markedly enhanced the engraftment of muscle stem cells in injured and noninjured muscles in mice. PMID- 28874577 TI - Stachel-independent modulation of GPR56/ADGRG1 signaling by synthetic ligands directed to its extracellular region. AB - Adhesion G protein-coupled receptors (aGPCRs) play critical roles in diverse biological processes, including neurodevelopment and cancer progression. aGPCRs are characterized by large and diverse extracellular regions (ECRs) that are autoproteolytically cleaved from their membrane-embedded signaling domains. Although ECRs regulate receptor function, it is not clear whether ECRs play a direct regulatory role in G-protein signaling or simply serve as a protective cap for the activating "Stachel" sequence. Here, we present a mechanistic analysis of ECR-mediated regulation of GPR56/ADGRG1, an aGPCR with two domains [pentraxin and laminin/neurexin/sex hormonebinding globulin-like (PLL) and G protein-coupled receptor autoproteolysis-inducing (GAIN)] in its ECR. We generated a panel of high-affinity monobodies directed to each of these domains, from which we identified activators and inhibitors of GPR56-mediated signaling. Surprisingly, these synthetic ligands modulated signaling of a GPR56 mutant defective in autoproteolysis and hence, in Stachel peptide exposure. These results provide compelling support for a ligand-induced and ECR-mediated mechanism that regulates aGPCR signaling in a transient and reversible manner, which occurs in addition to the Stachel-mediated activation. PMID- 28874578 TI - Lawful relation between perceptual bias and discriminability. AB - Perception of a stimulus can be characterized by two fundamental psychophysical measures: how well the stimulus can be discriminated from similar ones (discrimination threshold) and how strongly the perceived stimulus value deviates on average from the true stimulus value (perceptual bias). We demonstrate that perceptual bias and discriminability, as functions of the stimulus value, follow a surprisingly simple mathematical relation. The relation, which is derived from a theory combining optimal encoding and decoding, is well supported by a wide range of reported psychophysical data including perceptual changes induced by contextual modulation. The large empirical support indicates that the proposed relation may represent a psychophysical law in human perception. Our results imply that the computational processes of sensory encoding and perceptual decoding are matched and optimized based on identical assumptions about the statistical structure of the sensory environment. PMID- 28874579 TI - Nitric oxide blocks the development of the human parasite Schistosoma japonicum. AB - Human schistosomiasis, caused by Schistosoma species, is a major public health problem affecting more than 700 million people in 78 countries, with over 40 mammalian host reservoir species complicating the transmission ecosystem. The primary cause of morbidity is considered to be granulomas induced by fertilized eggs of schistosomes in the liver and intestines. Some host species, like rats (Rattus norvegicus), are naturally intolerant to Schistosoma japonicum infection, and do not produce granulomas or pose a threat to transmission, while others, like mice and hamsters, are highly susceptible. The reasons behind these differences are still a mystery. Using inducible nitric oxide synthase knockout (iNOS-/-) Sprague-Dawley rats, we found that inherent high expression levels of iNOS in wild-type (WT) rats play an important role in blocking growth, reproductive organ formation, and egg development in S. japonicum, resulting in production of nonfertilized eggs. Granuloma formation, induced by fertilized eggs in the liver, was considerably exacerbated in the iNOS-/- rats compared with the WT rats. This inhibition by nitric oxide acts by affecting mitochondrial respiration and energy production in the parasite. Our work not only elucidates the innate mechanism that blocks the development and production of fertilized eggs in S. japonicum but also offers insights into a better understanding of host parasite interactions and drug development strategies against schistosomiasis. PMID- 28874580 TI - Molecular mechanism of water reorientational slowing down in concentrated ionic solutions. AB - Water dynamics in concentrated ionic solutions plays an important role in a number of material and energy conversion processes such as the charge transfer at the electrolyte-electrode interface in aqueous rechargeable ion batteries. One long-standing puzzle is that all electrolytes, regardless of their "structure making/breaking" nature, make water rotate slower at high concentrations. To understand this effect, we present a theoretical simulation study of the reorientational motion of water molecules in different ionic solutions. Using an extended Ivanov model, water rotation is decomposed into contributions from large amplitude angular jumps and a slower frame motion which was studied in a coarse grained manner. Bearing a certain resemblance to water rotation near large biological molecules, the general deceleration is found to be largely due to the coupling of the slow, collective component of water rotation with the motion of large hydrated ion clusters ubiquitously existing in the concentrated ionic solutions. This finding is at variance with the intuitive expectation that the slowing down is caused by the change in fast, single-molecular water hydrogen bond switching adjacent to the ions. PMID- 28874581 TI - Discrete modes of social information processing predict individual behavior of fish in a group. AB - Individual computations and social interactions underlying collective behavior in groups of animals are of great ethological, behavioral, and theoretical interest. While complex individual behaviors have successfully been parsed into small dictionaries of stereotyped behavioral modes, studies of collective behavior largely ignored these findings; instead, their focus was on inferring single, mode-independent social interaction rules that reproduced macroscopic and often qualitative features of group behavior. Here, we bring these two approaches together to predict individual swimming patterns of adult zebrafish in a group. We show that fish alternate between an "active" mode, in which they are sensitive to the swimming patterns of conspecifics, and a "passive" mode, where they ignore them. Using a model that accounts for these two modes explicitly, we predict behaviors of individual fish with high accuracy, outperforming previous approaches that assumed a single continuous computation by individuals and simple metric or topological weighing of neighbors' behavior. At the group level, switching between active and passive modes is uncorrelated among fish, but correlated directional swimming behavior still emerges. Our quantitative approach for studying complex, multimodal individual behavior jointly with emergent group behavior is readily extensible to additional behavioral modes and their neural correlates as well as to other species. PMID- 28874582 TI - Beyond sixfold coordinated Si in SiO2 glass at ultrahigh pressures. AB - We investigated the structure of SiO2 glass up to 172 GPa using high-energy X-ray diffraction. The combination of a multichannel collimator with diamond anvil cells enabled the measurement of structural changes in silica glass with total X ray diffraction to previously unachievable pressures. We show that SiO2 first undergoes a change in Si-O coordination number from fourfold to sixfold between 15 and 50 GPa, in agreement with previous investigations. Above 50 GPa, the estimated coordination number continuously increases from 6 to 6.8 at 172 GPa. Si O bond length shows first an increase due to the fourfold to sixfold coordination change and then a smaller linear decrease up to 172 GPa. We reconcile the changes in relation to the oxygen-packing fraction, showing that oxygen packing decreases at ultrahigh pressures to accommodate the higher than sixfold Si-O coordination. These results give experimental insight into the structural changes of silicate glasses as analogue materials for silicate melts at ultrahigh pressures. PMID- 28874584 TI - A classical view on nonclassical nucleation. AB - Understanding and controlling nucleation is important for many crystallization applications. Calcium carbonate (CaCO3) is often used as a model system to investigate nucleation mechanisms. Despite its great importance in geology, biology, and many industrial applications, CaCO3 nucleation is still a topic of intense discussion, with new pathways for its growth from ions in solution proposed in recent years. These new pathways include the so-called nonclassical nucleation mechanism via the assembly of thermodynamically stable prenucleation clusters, as well as the formation of a dense liquid precursor phase via liquid liquid phase separation. Here, we present results from a combined experimental and computational investigation on the precipitation of CaCO3 in dilute aqueous solutions. We propose that a dense liquid phase (containing 4-7 H2O per CaCO3 unit) forms in supersaturated solutions through the association of ions and ion pairs without significant participation of larger ion clusters. This liquid acts as the precursor for the formation of solid CaCO3 in the form of vaterite, which grows via a net transfer of ions from solution according to z Ca2+ + z CO32- -> z CaCO3 The results show that all steps in this process can be explained according to classical concepts of crystal nucleation and growth, and that long-standing physical concepts of nucleation can describe multistep, multiphase growth mechanisms. PMID- 28874583 TI - Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-beta signaling. AB - Smad7 is a negative feedback product of TGF-beta superfamily signaling and fine tunes a plethora of pleiotropic responses induced by TGF-beta ligands. However, its noncanonical functions independent of TGF-beta signaling remain to be elucidated. Here, we show that Smad7 activates signal transducers and activators of transcription 3 (STAT3) signaling in maintaining mouse embryonic stem cell pluripotency in a manner independent of the TGF-beta receptors, yet dependent on the leukemia inhibitory factor (LIF) coreceptor glycoprotein 130 (gp130). Smad7 directly binds to the intracellular domain of gp130 and disrupts the SHP2-gp130 or SOCS3-gp130 complex, thereby amplifying STAT3 activation. Consequently, Smad7 facilitates LIF-mediated self-renewal of mouse ESCs and is also critical for induced pluripotent stem cell reprogramming. This finding illustrates an uncovered role of the Smad7-STAT3 interplay in maintaining cell pluripotency and also implicates a mechanism involving Smad7 underlying cytokine-dependent regulation of cancer and inflammation. PMID- 28874585 TI - Active molecular iodine photochemistry in the Arctic. AB - During springtime, the Arctic atmospheric boundary layer undergoes frequent rapid depletions in ozone and gaseous elemental mercury due to reactions with halogen atoms, influencing atmospheric composition and pollutant fate. Although bromine chemistry has been shown to initiate ozone depletion events, and it has long been hypothesized that iodine chemistry may contribute, no previous measurements of molecular iodine (I2) have been reported in the Arctic. Iodine chemistry also contributes to atmospheric new particle formation and therefore cloud properties and radiative forcing. Here we present Arctic atmospheric I2 and snowpack iodide (I-) measurements, which were conducted near Utqiagvik, AK, in February 2014. Using chemical ionization mass spectrometry, I2 was observed in the atmosphere at mole ratios of 0.3-1.0 ppt, and in the snowpack interstitial air at mole ratios up to 22 ppt under natural sunlit conditions and up to 35 ppt when the snowpack surface was artificially irradiated, suggesting a photochemical production mechanism. Further, snow meltwater I- measurements showed enrichments of up to ~1,900 times above the seawater ratio of I-/Na+, consistent with iodine activation and recycling. Modeling shows that observed I2 levels are able to significantly increase ozone depletion rates, while also producing iodine monoxide (IO) at levels recently observed in the Arctic. These results emphasize the significance of iodine chemistry and the role of snowpack photochemistry in Arctic atmospheric composition, and imply that I2 is likely a dominant source of iodine atoms in the Arctic. PMID- 28874586 TI - Temporal binding function of dorsal CA1 is critical for declarative memory formation. AB - Temporal binding, the process that enables association between discontiguous stimuli in memory, and relational organization, a process that enables the flexibility of declarative memories, are both hippocampus-dependent and decline in aging. However, how these two processes are related in supporting declarative memory formation and how they are compromised in age-related memory loss remain hypothetical. We here identify a causal link between these two features of declarative memory: Temporal binding is a necessary condition for the relational organization of discontiguous events. We demonstrate that the formation of a relational memory is limited by the capability of temporal binding, which depends on dorsal (d)CA1 activity over time intervals and diminishes in aging. Conversely, relational representation is successful even in aged individuals when the demand on temporal binding is minimized, showing that relational/declarative memory per se is not impaired in aging. Thus, bridging temporal intervals by dCA1 activity is a critical foundation of relational representation, and a deterioration of this mechanism is responsible for the age-associated memory impairment. PMID- 28874587 TI - Receptor-mediated chitin perception in legume roots is functionally separable from Nod factor perception. AB - The ability of root cells to distinguish mutualistic microbes from pathogens is crucial for plants that allow symbiotic microorganisms to infect and colonize their internal root tissues. Here we show that Lotus japonicus and Medicago truncatula possess very similar LysM pattern-recognition receptors, LjLYS6/MtLYK9 and MtLYR4, enabling root cells to separate the perception of chitin oligomeric microbe-associated molecular patterns from the perception of lipochitin oligosaccharide by the LjNFR1/MtLYK3 and LjNFR5/MtNFP receptors triggering symbiosis. Inactivation of chitin-receptor genes in Ljlys6, Mtlyk9, and Mtlyr4 mutants eliminates early reactive oxygen species responses and induction of defense-response genes in roots. Ljlys6, Mtlyk9, and Mtlyr4 mutants were also more susceptible to fungal and bacterial pathogens, while infection and colonization by rhizobia and arbuscular mycorrhizal fungi was maintained. Biochemical binding studies with purified LjLYS6 ectodomains further showed that at least six GlcNAc moieties (CO6) are required for optimal binding efficiency. The 2.3-A crystal structure of the LjLYS6 ectodomain reveals three LysM betaalphaalphabeta motifs similar to other LysM proteins and a conserved chitin binding site. These results show that distinct receptor sets in legume roots respond to chitin and lipochitin oligosaccharides found in the heterogeneous mixture of chitinaceous compounds originating from soil microbes. This establishes a foundation for genetic and biochemical dissection of the perception and the downstream responses separating defense from symbiosis in the roots of the 80-90% of land plants able to develop rhizobial and/or mycorrhizal endosymbiosis. PMID- 28874588 TI - Investigation of the mechanism of the SpnF-catalyzed [4+2]-cycloaddition reaction in the biosynthesis of spinosyn A. AB - The Diels-Alder reaction is one of the most common methods to chemically synthesize a six-membered carbocycle. While it has long been speculated that the cyclohexene moiety found in many secondary metabolites is also introduced via similar chemistry, the enzyme SpnF involved in the biosynthesis of the insecticide spinosyn A in Saccharopolyspora spinosa is the first enzyme for which catalysis of an intramolecular [Formula: see text]-cycloaddition has been experimentally verified as its only known function. Since its discovery, a number of additional standalone [Formula: see text]-cyclases have been reported as potential Diels-Alderases; however, whether their catalytic cycles involve a concerted or stepwise cyclization mechanism has not been addressed experimentally. Here, we report direct experimental interrogation of the reaction coordinate for the [Formula: see text]-carbocyclase SpnF via the measurement of [Formula: see text]-secondary deuterium kinetic isotope effects (KIEs) at all sites of [Formula: see text] rehybridization for both the nonenzymatic and enzyme catalyzed cyclization of the SpnF substrate. The measured KIEs for the nonenzymatic reaction are consistent with previous computational results implicating an intermediary state between formation of the first and second carbon-carbon bonds. The KIEs measured for the enzymatic reaction suggest a similar mechanism of cyclization within the enzyme active site; however, there is evidence that conformational restriction of the substrate may play a role in catalysis. PMID- 28874592 TI - Your Genes: Getting the Best Fit. PMID- 28874589 TI - Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. AB - G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT1), its associated G protein, and beta-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT1 signal-transduction pathway inhibiting stress-mediated cytochrome c release and caspase activation. These findings coupled with our observation that mitochondrial MT1 overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, "automitocrine," analogous to "autocrine" when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand-receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology. PMID- 28874590 TI - Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models. AB - Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the alpha4beta2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin alpha-GID that antagonizes it. We developed a docking algorithm, ToxDock, which used ensemble-docking and extensive conformational sampling to dock alpha-GID and its analogs to an alpha4beta2 nAChR homology model. Experimental testing demonstrated that a virtual screen with ToxDock correctly identified three bioactive alpha-GID mutants (alpha-GID[A10V], alpha-GID[V13I], and alpha-GID[V13Y]) and one inactive variant (alpha-GID[A10Q]). Two mutants, alpha-GID[A10V] and alpha-GID[V13Y], had substantially reduced potency at the human alpha7 nAChR relative to alpha-GID, a desirable feature for alpha-GID analogs. The general usefulness of the docking algorithm was highlighted by redocking of peptide toxins to two ion channels and a binding protein in which the peptide toxins successfully reverted back to near-native crystallographic poses after being perturbed. Our results demonstrate that ToxDock can overcome two fundamental challenges of docking large toxin peptides to ion channel homology models, as exemplified by the alpha-GID:alpha4beta2 nAChR complex, and is extendable to other toxin peptides and ion channels. ToxDock is freely available at rosie.rosettacommons.org/tox_dock. PMID- 28874591 TI - Mutation in human CLPX elevates levels of delta-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria. AB - Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of delta-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p.Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism. PMID- 28874593 TI - EGFR Exon 19 Deletion in Pancreatic Adenocarcinoma Responds to Erlotinib, Followed by T790M-Mediated Resistance. AB - The prognosis of metastatic pancreatic cancer remains poor despite recent advances in treatment with multidrug chemotherapy regimens. Use of immune checkpoint inhibitors and molecular targeted therapies has so far been disappointing. This report describes a patient with chemotherapy-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) whose tumor was characterized by an activating mutation in exon 19 of the epidermal growth factor receptor (EGFR). He experienced response to erlotinib for 10 months, and then developed disease progression in association with emergence of the T790M mutation. Activating EGFR mutations in cancers other than lung are uncommon, but when present may predict response to EGFR tyrosine kinase inhibitors (TKIs). Development of the T790M mutation in this case suggests that EGFR-targeted TKIs may follow similar patterns of resistance regardless of tumor type. Although actionable mutations are detected infrequently in PDAC, this case illustrates the potential benefit of offering genomic analysis to all patients with advanced disease. PMID- 28874594 TI - NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017. AB - The prognosis for patients with newly diagnosed acute lymphoblastic leukemia (ALL) has improved with the use of more intensive chemotherapy regimens, tyrosine kinase inhibitors, targeted agents, and allogeneic hematopoietic cell transplantation. However, the management of relapsed or refractory (R/R) ALL remains challenging and prognosis is poor. The NCCN Guidelines for ALL provide recommendations on standard treatment approaches based on current evidence. These NCCN Guidelines Insights summarize treatment recommendations for R/R ALL and highlight important updates, and provide a summary of the panel's discussion and underlying data supporting the most recent recommendations for R/R ALL management. PMID- 28874595 TI - A Randomized Controlled Trial of an Additional Funding Intervention to Improve Clinical Trial Enrollment. AB - Background: A low proportion of adults with cancer are recruited to clinical trials. Cancer Council Victoria provides funding to clinical trial sites through its statewide Cancer Trials Management Scheme (CTMS). Historically, there appeared to be a relationship between budget-allocated funding and the number of patients recruited. A randomized controlled trial was conducted to test whether additional funding in 2013 would increase trial recruitment. Methods: A total of 18 trial centers ("sites") received usual CTMS funds, whereas 16 intervention sites received usual funds plus additional funds, proportional to recruitment in 2011; additional payments to sites in the intervention group ranged from $6,750 to $234,000 AUD (~$6,750-$234,000 USD at the time). This represented an average 11.8% (interquartile range [IQR], 8.0%, 12.3%) increase in sites' budgets. Sites were required to use the funds with the aim of increasing recruitment. The study end point was the number of new participants recruited to trials in 2013. An online survey assessed strategies used to increase recruitment. Results: The median number of new trial recruits per site in 2013 was 21 (IQR, 5-39) in the control arm and 12.5 (IQR, 3.5-44.5) in the intervention arm. The ratio of new trial recruitment numbers at the intervention sites compared with control sites in 2013, adjusting for respective 2012 numbers and institution type, was 0.99 (95% CI, 0.69, 1.43; P=.96). The survey revealed most intervention sites used funding to increase staffing. Conclusions: Additional funding at a site level did not lead to a contemporaneous increase in trial recruitment. PMID- 28874596 TI - A Double-Blind, Randomized, Placebo-Controlled Trial of Panax Ginseng for Cancer Related Fatigue in Patients With Advanced Cancer. AB - Background: Despite the high frequency, severity, and effects of cancer-related fatigue (CRF) on the quality of life (QoL) of patients with cancer, limited treatment options are available. The primary objective of this study was to compare the effects of oral Panax ginseng extract (PG) and placebo on CRF. Secondary objectives were to determine the effects of PG on QoL, mood, and function. Methods: In this randomized, double-blind, placebo-controlled study, patients with CRF >=4/10 on the Edmonton Symptom Assessment System (ESAS) were eligible. Based on a pilot study, we randomized patients to receive either 400 mg of standardized PG twice daily or a matching placebo for 28 days. The primary end point was change in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale from baseline to day 29. Results: Of 127 patients, 112 (88.2%) were evaluable. The mean (SD) FACIT-F subscale scores at baseline, day 15, and day 29 were 22.4 (10.1), 29.9 (10.6), and 30.1 (11.6) for PG (P<.001), and 24.0 (9.4), 30.0 (10.1), and 30.4 (11.5) for placebo (P<.001). Mean (SD) improvement in the FACIT-F subscale at day 29 was not significantly different in the PG than in the placebo group (7.5 [12.7] vs 6.5 [9.9]; P=.67). QoL, anxiety, depression, symptoms, and functional scores were not significantly different between the PG and placebo groups. Improvement in the FACIT-F subscale correlated with baseline scores (P=.0005), Hospital Anxiety and Depression Scale results (P=.032), and sex (P=.023). There were fewer any-grade toxicities in the PG versus placebo group (28/63 vs 33/64; P=.024). Conclusions: Both PG and placebo result in significant improvement in CRF. PG was not significantly superior to placebo after 4 weeks of treatment. There is no justification to recommend the use of PG for CRF. Further studies are needed. Trial Registration: ClinicalTrials.gov identifier: NCT01375114. PMID- 28874597 TI - Risk of Febrile Neutropenia Associated With Select Myelosuppressive Chemotherapy Regimens in a Large Community-Based Oncology Practice. AB - Background: NCCN has classified commonly used chemotherapy regimens into high (>20%), intermediate (10%-20%), or low (<10%) febrile neutropenia (FN) risk categories based primarily on clinical trial evidence. Many chemotherapy regimens, however, remain unclassified by NCCN or lack FN incidence data in real world clinical practice. Patients and Methods: We evaluated incidence proportions of FN and grade 4 and 3/4 neutropenia during the first chemotherapy course among patients from Kaiser Permanente Southern California who received selected chemotherapy regimens without well-established FN risk. Patients given granulocyte colony-stimulating factor (G-CSF) prophylaxis were excluded. Sensitivity analyses were performed to account for FN misclassification and censoring. Results: From 2008 to 2013, 1,312 patients with breast cancer who received docetaxel and cyclophosphamide (TC; n=853) or docetaxel, carboplatin, and trastuzumab (TCH; n=459); 1,321 patients with colorectal cancer who received capecitabine and oxaliplatin (XELOX; n=401) or leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX6; n=920); 307 patients with non-Hodgkin's lymphoma who received bendamustine with or without rituximab; and 181 patients with multiple myeloma who received lenalidomide with or without dexamethasone were included. Crude FN risk was >20% for both breast cancer regimens (TC and TCH). Crude FN risks for XELOX, FOLFOX6, bendamustine, and lenalidomide were <10%; however, when potential FN misclassification and censoring were considered, FN risks were >10%. Conclusions: Our results support published literature highlighting the real world, "high" FN risk of the TC and TCH regimens for breast cancer. There is strong suggestive evidence that FN risks for XELOX, FOLFOX6, bendamustine, and lenalidomide are >10%. Calculation of chemotherapy course-level FN incidence without controlling for differential censoring for patients who discontinued regimens early, or possible FN misclassification, might have resulted in bias toward an underestimation of the true FN risk. These findings help define FN risk of the selected regimens in the real-world setting and inform prophylactic G-CSF use. PMID- 28874598 TI - "Standard Care" in Cancer Clinical Trials: An Analysis of Care Provided to Women in the Control Arms of Breast Cancer Clinical Trials. AB - Background: For trials to validly evaluate new treatments, comparison against the best existing alternative treatment is essential. We reviewed the care provided to women in control arms of breast cancer clinical trials to estimate the proportion consistent with the standard of care as defined in clinical guidelines. Methods: We analyzed phase III randomized controlled breast cancer trials comparing drug treatments with "standard care," enrolling between 2004 and 2014, and registered on ClinicalTrials.gov Our primary outcome was the proportion of trials in which treatment in the control arm was consistent with concurrent NCCN Guidelines. A secondary analysis assessed trials recruiting outside the United States that provided control group therapy not consistent with NCCN Guidelines, comparing them with the German Gynecological Oncology Group (AGO) guidelines. We assessed associations between the primary outcome and a priori selected trial characteristics. Results: This study included 210 trials that recruited 229,182 women worldwide; 29% of trials (60/210) did not provide control group treatment that was consistent with NCCN Guidelines. For trials not recruiting in the United States, results were similar; in 21% of trials, control arm treatment was inconsistent with both AGO and NCCN Guidelines. Factors significantly associated with offering control arm treatment that were inconsistent with guidelines were time period (later trials were less likely to be consistent), breast cancer stage and type (trials in early-stage breast cancer and estrogen receptor-negative disease were less likely consistent), and recruitment in >=4 countries and recruitment outside the United States. Conclusions: To ensure that clinical trials achieve their goal of obtaining the best information to guide patient treatment, the question of how investigators chose and describe "standard care" for control arm participants warrants further investigation. PMID- 28874600 TI - Survivorship Care Planning: Why Is It Taking So Long? AB - Survivorship care planning is a process that focuses on the transition from active cancer treatment to a coordinated and comprehensive care system to address patients' unique needs. Survivorship care plans (SCPs) are increasingly viewed as a key component of survivorship care planning. SCPs have been recommended for >10 years to promote care coordination, communication, and record-keeping efficiency; however, SCP implementation has been challenging. We elaborate on the challenges of SCP implementation, summarize evidence regarding potential methods of promoting SCP implementation, and describe a research agenda for generating more definitive evidence to support SCP implementation in practice. PMID- 28874601 TI - Trials and Tribulations for Adolescents and Young Adults with Cancer: Measuring the Impact of a Community-Based Program. PMID- 28874603 TI - Cancer-associated arginine-to-histidine mutations confer a gain in pH sensing to mutant proteins. AB - The intracellular pH (pHi) of most cancers is constitutively higher than that of normal cells and enhances proliferation and cell survival. We found that increased pHi enabled the tumorigenic behaviors caused by somatic arginine-to histidine mutations, which are frequent in cancer and confer pH sensing not seen with wild-type proteins. Experimentally raising the pHi increased the activity of R776H mutant epidermal growth factor receptor (EGFR-R776H), thereby increasing proliferation and causing transformation in fibroblasts. An Arg-to-Gly mutation did not confer these effects. Molecular dynamics simulations of EGFR suggested that decreased protonation of His776 at high pH causes conformational changes in the alphaC helix that may stabilize the active form of the kinase. An Arg-to-His, but not Arg-to-Lys, mutation in the transcription factor p53 (p53-R273H) decreased its transcriptional activity and attenuated the DNA damage response in fibroblasts and breast cancer cells with high pHi. Lowering pHi attenuated the tumorigenic effects of both EGFR-R776H and p53-R273H. Our data suggest that some somatic mutations may confer a fitness advantage to the higher pHi of cancer cells. PMID- 28874605 TI - Ca2+ and mitochondrial ROS: Both hero and villain in membrane repair. AB - Membrane repair is a symphony of signaling, conducted principally by the steep influx of Ca2+ through an injured membrane. In this issue of Science Signaling, Horn et al reveal unique interplay between Ca2+ influx and mitochondrially generated reactive oxygen species (mtROS) to enhance actin-mediated wound closure for survival of injured mammalian muscle and nonmuscle cells. PMID- 28874604 TI - Mitochondrial redox signaling enables repair of injured skeletal muscle cells. AB - Strain and physical trauma to mechanically active cells, such as skeletal muscle myofibers, injures their plasma membranes, and mitochondrial function is required for their repair. We found that mitochondrial function was also needed for plasma membrane repair in myoblasts as well as nonmuscle cells, which depended on mitochondrial uptake of calcium through the mitochondrial calcium uniporter (MCU). Calcium uptake transiently increased the mitochondrial production of reactive oxygen species (ROS), which locally activated the guanosine triphosphatase (GTPase) RhoA, triggering F-actin accumulation at the site of injury and facilitating membrane repair. Blocking mitochondrial calcium uptake or ROS production prevented injury-triggered RhoA activation, actin polymerization, and plasma membrane repair. This repair mechanism was shared between myoblasts, nonmuscle cells, and mature skeletal myofibers. Quenching mitochondrial ROS in myofibers during eccentric exercise ex vivo caused increased damage to myofibers, resulting in a greater loss of muscle force. These results suggest a physiological role for mitochondria in plasma membrane repair in injured cells, a role that highlights a beneficial effect of ROS. PMID- 28874599 TI - Survivorship, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. AB - Many cancer survivors experience menopausal symptoms, including female survivors taking aromatase inhibitors or with a history of oophorectomy or chemotherapy, and male survivors who received or are receiving androgen-ablative therapies. Sexual dysfunction is also common in cancer survivors. Sexual dysfunction and menopause-related symptoms can increase distress and have a significant negative impact on quality of life. This portion of the NCCN Guidelines for Survivorship provide recommendations for screening, evaluation, and treatment of sexual dysfunction and menopausal symptoms to help healthcare professionals who work with survivors of adult-onset cancer in the posttreatment period. PMID- 28874608 TI - Correction to "6-Mercaptopurine Decreases the Bcl-2/Bax Ratio and Induces Apoptosis in Activated Splenic B Lymphocytes". PMID- 28874606 TI - Bacterial d-amino acids suppress sinonasal innate immunity through sweet taste receptors in solitary chemosensory cells. AB - In the upper respiratory epithelium, bitter and sweet taste receptors present in solitary chemosensory cells influence antimicrobial innate immune defense responses. Whereas activation of bitter taste receptors (T2Rs) stimulates surrounding epithelial cells to release antimicrobial peptides, activation of the sweet taste receptor (T1R) in the same cells inhibits this response. This mechanism is thought to control the magnitude of antimicrobial peptide release based on the sugar content of airway surface liquid. We hypothesized that d-amino acids, which are produced by various bacteria and activate T1R in taste receptor cells in the mouth, may also activate T1R in the airway. We showed that both the T1R2 and T1R3 subunits of the sweet taste receptor (T1R2/3) were present in the same chemosensory cells of primary human sinonasal epithelial cultures. Respiratory isolates of Staphylococcus species, but not Pseudomonas aeruginosa, produced at least two d-amino acids that activate the sweet taste receptor. In addition to inhibiting P. aeruginosa biofilm formation, d-amino acids derived from Staphylococcus inhibited T2R-mediated signaling and defensin secretion in sinonasal cells by activating T1R2/3. d-Amino acid-mediated activation of T1R2/3 also enhanced epithelial cell death during challenge with Staphylococcus aureus in the presence of the bitter receptor-activating compound denatonium benzoate. These data establish a potential mechanism for interkingdom signaling in the airway mediated by bacterial d-amino acids and the mammalian sweet taste receptor in airway chemosensory cells. PMID- 28874609 TI - Modified Medical Research Council Dyspnea Scale in GOLD Classification Better Reflects Physical Activities of Daily Living. AB - BACKGROUND: In multidimensional Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification, the choice of the symptom assessment instrument (modified Medical Research Council dyspnea scale [mMRC] or COPD assessment test [CAT]) can lead to a different distribution of patients in each quadrant. Considering that physical activities of daily living (PADL) is an important functional outcome in COPD, the objective of this study was to determine which symptom assessment instrument is more strongly associated with and differentiates better the PADL of patients with COPD. METHODS: The study included 115 subjects with COPD (GOLD 2-4), who were submitted to spirometry, the mMRC, the CAT, and monitoring of PADL (triaxial accelerometer). Subjects were divided into 2 groups using the cutoffs proposed by the multidimensional GOLD classification: mMRC < 2 and >= 2 and CAT < 10 and >= 10. RESULTS: Both mMRC and CAT reflected the PADL of COPD subjects. Subjects with mMRC < 2 and CAT < 10 spent less time in physical activities < 1.5 metabolic equivalents of task (METs) (mean of the difference [95% CI] = -62.9 [-94.4 to -31.4], P < .001 vs -71.0 [-116 to -25.9], P = .002) and had a higher number of steps (3,076 [1,999-4,153], P < .001 vs 2,688 [1,042 4,333], P = .002) than subjects with mMRC > 2 and CAT > 10, respectively. Physical activities >= 3 METs differed only between mMRC < 2 and mMRC >= 2 (39.2 [18.8-59.6], P < .001). Furthermore, only the mMRC was able to predict the PADL alone (time active, r2 = 0.16; time sedentary, r2 = 0.12; time >= 3 METs, r2 = 0.12) and associated with lung function (number of steps, r2 = 0.35; walking time, r2 = 0.37; time < 1.5 METs, r2 = 0.25). CONCLUSIONS: The mMRC should be adopted as the classification criterion for symptom assessment in the GOLD ABCD system when focusing on PADL. PMID- 28874610 TI - The 2017 Global Initiative for Chronic Obstructive Lung Disease Report and Practice Implications for the Respiratory Therapist. AB - Since 1998, the Global Initiative for Obstructive Lung Disease (GOLD) has worked with health care professionals, medical researchers, and public health officials around the world to optimize the prevention, treatment, and management of COPD. GOLD has continually worked to ensure COPD management strategy recommendations are aligned with current published research. The 2017 GOLD report represents a major revision to GOLD strategy guidelines, the first such major revision in the last 5 years. As such, the 2017 report has significant implications for the diagnosis of COPD, the management of stable disease, and the treatment of exacerbations. As respiratory therapists (RTs) are front-line clinical professionals throughout the COPD continuum of care, a thorough understanding of the new GOLD recommendations for practice is critical. New recommendations regarding diagnosis, severity assessment, and both pharmacologic and nonpharmacologic treatment of COPD are presented, and suggestions for how RTs can integrate these recommendations into COPD care practices are provided. PMID- 28874611 TI - How Should Aerosols Be Delivered During Invasive Mechanical Ventilation? AB - The delivery of aerosols to mechanically ventilated patients presents unique challenges and differs from inhaled drug delivery in spontaneously breathing patients in several respects. Successful aerosol delivery during invasive mechanical ventilation requires careful consideration of a host of factors that influence the amount of drug inhaled by the patient. Pressurized metered-dose inhalers and nebulizers (jet, ultrasonic, and vibrating mesh) are the most commonly used aerosol delivery devices in these patients, although other delivery devices, such as dry powder inhalers, soft mist inhalers, and intratracheal nebulizing catheters, could also be adapted for in-line use. Bronchodilators, inhaled corticosteroids, antibiotics, pulmonary surfactant, mucolytics, biologicals, genes, prostanoids, and other agents are administered by inhalation during mechanical ventilation for a variety of indications. The goals of inhalation therapy during mechanical ventilation could be best achieved by (1) assuring drug delivery; (2) optimizing drug deposition in the lung; (3) providing consistent dosing; (4) avoiding inappropriate therapies; (5) achieving reproducible dosing; (6) employing clinically feasible methods; (7) enhancing the safety of inhaled drugs; and (8) controlling costs of aerosol therapy. The techniques of administration of aerosols with various delivery devices during mechanical ventilation are well known, but there continues to be significant variation in clinical practice and guidelines are needed to provide best practices for a wide range of clinical settings encountered in mechanically ventilated patients. PMID- 28874607 TI - NO-Sensitive Guanylate Cyclase Isoforms NO-GC1 and NO-GC2 Contribute to Noise Induced Inner Hair Cell Synaptopathy. AB - Nitric oxide (NO) activates the NO-sensitive soluble guanylate cyclase (NO-GC, sGC) and triggers intracellular signaling pathways involving cGMP. For survival of cochlear hair cells and preservation of hearing, NO-mediated cascades have both protective and detrimental potential. Here we examine the cochlear function of mice lacking one of the two NO-sensitive guanylate cyclase isoforms [NO-GC1 knockout (KO) or NO-GC2 KO]. The deletion of NO-GC1 or NO-GC2 did not influence electromechanical outer hair cell (OHC) properties, as measured by distortion product otoacoustic emissions, neither before nor after noise exposure, nor were click- or noise-burst-evoked auditory brainstem response thresholds different from controls. Yet inner hair cell (IHC) ribbons and auditory nerve responses showed significantly less deterioration in NO-GC1 KO and NO-GC2 KO mice after noise exposure. Consistent with a selective role of NO-GC in IHCs, NO-GC beta1 mRNA was found in isolated IHCs but not in OHCs. Using transgenic mice expressing the fluorescence resonance energy transfer-based cGMP biosensor cGi500, NO induced elevation of cGMP was detected in real-time in IHCs but not in OHCs. Pharmacologic long-term treatment with a NO-GC stimulator altered auditory nerve responses but did not affect OHC function and hearing thresholds. Interestingly, NO-GC stimulation exacerbated the loss of auditory nerve response in aged animals but attenuated the loss in younger animals. We propose NO-GC2 and, to some degree, NO-GC1 as targets for early pharmacologic prevention of auditory fiber loss (synaptopathy). Both isoforms provide selective benefits for hearing function by maintaining the functional integrity of auditory nerve fibers in early life rather than at old age. PMID- 28874612 TI - Role of Integrated Pulmonary Index in Identifying Extubation Failure. AB - BACKGROUND: The integrated pulmonary index (IPI) utilizes an algorithm based on the measurement of end-tidal carbon dioxide, breathing frequency, heart rate, and oxygen saturation to provide an assessment of the patient's ventilatory status. This clinical trial was designed to determine whether lower IPI values were associated with extubation failure. METHODS: This prospective observational trial was conducted in an academic medical center. After institutional review board approval, 100 mechanically ventilated subjects were enrolled. A stand-alone respiratory monitor that measures IPI was placed on subjects before starting a spontaneous breathing trial and continued for up to 48 h postextubation. Clinicians were blinded, and data were recorded continuously. Extubation failure was defined as the need for positive-pressure ventilation within 48 h after extubation. Mixed-effects regression models were employed to examine differences in IPI patterns between subjects with extubation success or failure. Significant IPI changes from baseline were then evaluated to predict extubation outcome. RESULTS: IPI was successfully recorded on 62 subjects (48 successful and 14 failed extubations). Although mean IPI 5 min before and after extubation were not significantly different, mean IPI 1 h after extubation in the failure group was significantly lower by 1.19 (P = .044) compared with the successful group. Negative change in IPI 1 h after extubation increased odds of failure (odds ratio = 1.57, 95% CI 1.001-2.454). The last mean IPI recorded after extubation was also significantly lower in the failure group compared with the successful group by 3.03 (P < .001). Negative change in the last measured IPI increased odds of failure (odds ratio = 1.72, 95% CI 1.26-2.34). CONCLUSIONS: Declining IPI measurements postextubation are predictive of extubation failure. Further clinical trials are needed to assess the role of IPI in guiding interventions in extubated patients. PMID- 28874613 TI - Diaphragmatic Thickness Fraction in Subjects at High-Risk for COPD Exacerbations. AB - BACKGROUND: Ultrasound-based diaphragmatic thickness fraction is a reflection of the size and function of the diaphragm. This study aimed to examine the value of this measurement in identifying patients with COPD who are at high risk for the development of symptoms and exacerbations. METHODS: This cross-sectional study included 53 subjects with COPD. Respiratory function test results, ultrasonography-based diaphragmatic thickness, symptom scores (modified Medical Research Council dyspnea scale); COPD Assessment Test results, and number of previous exacerbations and admissions were recorded. RESULTS: Only age showed an inverse and weak relation with percent thickness fraction (r = -0.37, P = .006). None of the other variables tested correlated significantly with percent thickness fraction. No association was found between percent thickness fraction and exacerbation frequency, modified Medical Research Council dyspnea scale and COPD Assessment Test symptom scores, or Global Initiative for Chronic Obstructive Lung Disease ABCD risk/symptom assessments. CONCLUSIONS: Diaphragmatic thickness fraction measurements based on diaphragmatic ultrasound assessment in subjects with COPD seemed to be unable to identify subjects at high risk of symptoms and exacerbations as defined by the Global Initiative for Chronic Obstructive Lung Disease ABCD composite disease index. PMID- 28874616 TI - Correction for Fan et al., Overexpression of a pH-sensitive nitrate transporter in rice increases crop yields. PMID- 28874617 TI - Correction for Kidger et al., Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling. PMID- 28874614 TI - News Feature: Singing in the brain. PMID- 28874618 TI - Cholecystectomy in Emilia-Romagna region (Italy): A retrospective cohort study based on a large administrative database. AB - BACKGROUND: The aim of this study was to ascertain the variability and to identify a trend for the outcome of cholecystectomy surgery when used to treat cholelithiasis and acute cholecystitis. METHODS: This was a large retrospective cohort study following patients up to 11 years post surgery, based on administrative data collected from 2002 to 2012 in the Emilia-Romagna Region (Northern Italy) and comparing the effectiveness and efficiency of surgical activity (laparoscopic (LC) and open cholecystectomy (OC)). Analyses included patient characteristics, length of hospital stay, type of admission and mortality risk. Outcomes considered were death from all causes (during the index hospital admission or thereafter), hospital readmissions with cholecystitis or cholelithiasis as principal diagnosis and time to surgery. RESULTS: A total of 84,628 cholecystomies were performed from 2002 to 2012 out of 123,061 admissions with primary diagnostic category of cholecystitis or cholelitiasis. Laparoscopic procedure was used in 69,842 patients. Over time there was a rising linear statistically significant trend in the use of LC. Mortality rate at 1 year of OC treated patients showed a statistically significant difference compared to LC treated patients (using a cohorts match with propensity score). Only a small number of patients with acute cholecystitis was operated according guidelines within 72 hours. CONCLUSIONS: The analysis of aggregate administrative data is a powerful tool to support regional health management, improve the quality of medical care, and assess the appropriateness of therapeutic or diagnostic approaches. It is important to stress a short hospital stay for laparoscopic cholecystectomy patients (50% less than open surgery): this shorter hospital stay leads to a significant economic advantage. Moreover, mortality is significantly higher in open surgery for acute cholecystitis. Interestingly, the same finding was confirmed after 30 days and 1 year, probably due to comorbidities that are more evident in open surgery. KEY WORDS: Cholecystitis, Cholelithiasis, Delivery of health care, Disease management, Surgical. PMID- 28874619 TI - Surgical management of primary and recurrent carcinoma showing thymous-like elements (CASTLE). AB - INTRODUCTION: Carcinoma showing thymous-like elements (CASTLE) is a rare tumor with only a few cases described in the scientific literature. The aim of the present review is to analyze the data available on the therapeutic options employed in CASTLE tumors and to outline the best surgical management to adopt. MATERIALS AND METHODS: English-language articles published from 1985 through November 2016, and related to CASTLE cases were retrieved using the Pubmed database and specific key-words. RESULTS: Eighty seven cases included in 23 papers, published in the period under investigation, were analyzed in detail. The mean age of the patients was 50.2 years and the male to female ratio 1:1.2. There were performed 31 (35.6%) lobectomies, 29 (33.3%) total thyroidectomies, 15 (17.2%) subtotal thyroidectomies, 4 (4.6%) excisions, 3 (3.4%) partial thyroidectomies, 1 (1.1%) hemithyroidectomy, and 8 (9.2%) additional procedures including tracheal, pharyngeal, and esophageal resections. Lymph node dissection and radiotherapy were associated in 59 (67.8%) and 44 (50.6%) cases respectively. Among the patients with available data 62 (75.6%) were free of disease, 16 (19.5%) were alive with disease, 3 (3.7%) died for the disease, and 1 (1.2%) died for cerebrovascular complications at the time of follow-up. Globally 20 (24.4%) cases of local or distant recurrence were reported. Surgery and radiotherapy, alone or in combination were the treatments most frequently used for recurrences. CONCLUSIONS: CASTLE is a rare tumor which generally respond well to complete surgical resection and adjuvant radiotherapy. These treatments can be further employed for the recurrences, which occur in 24.4% of the cases, along with specific chemotherapy regimens and palliative procedures. KEY WORDS: Cancer, CASTLE, Excision, Lobectomy, Thymous-like elements, Thyroidectomy. PMID- 28874620 TI - Diagnostic value of platelet indices in acute appendicitis and comparison with histopathology. AB - BACKGROUND: Acute appendicitis is one of the most common surgical emergencies. An early and accurate diagnosis of acute appendicitis is vital. Evidence for a link between platelets indices and inflammation disease comes from recent studies. We aimed to evaluate preoperative diagnostic values of platelet indices (Mean platelet volume-MPV, Platelet Distribution Width-PDW, Plateletcrit-PCT) and leukocyte count (WBC) in comparison with post-operative histopathology results in patients who underwent appendectomy. METHODS: The 165 patients who underwent appendectomy, were evaluated retrospectively. Patients' demographic characteristics, imaging findings, preoperative laboratory markers and postoperative histopathology results were recorded. The patients were divided into three groups based on the histopathologic findings; perforated appendicitis, acute appendicitis without perforation and negative appendectomy group. The specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of the laboratory markers were measured. Additionally potential correlation among laboratory markers analysed. RESULTS: The negative appendectomy rate was 15.1% in 165 patients. The leukocyte count was statistically higher in acute appendicitis (14.9*103/MUL) group than negative appendectomy (6.9*103/MUL) group. There was also statistically significant difference between groups according to the PCT levels. The leukocyte count achieved sensitivity, specificity, PPV, and NPV of 95.9, 24, 99.1, and 92.7% respectively. A significant positive correlation between WBC and PCT were obtained. Inflammatory markers were not directly related to the severity of the disease. CONCLUSIONS: Elevated leukocyte count and PCT levels support diagnosis of acute appendicitis in correlation with pathological findings. Thereby combination of the inflammatory markers, positive clinical and radiological findings would improve diagnostic accuracy in acute appendicitis. KEY WORDS: Acute appendicitis, Inflammatory markers, Platelet indices. PMID- 28874621 TI - Complications of laparoscopic gastric banding: detection and treatment. AB - INTRODUCTION: Laparoscopic adjustable gastric banding (LAGB) is acknownledged as a popular and effective surgical option in the management of obesity and related metabolic diseases. This procedure is a remarkably safe operation from both a general surgical and bariatric perspective. It facilitates brief hospitalization and can be performed by single incision. METHODS: We analyzed the most common LAGB complications as intraoperative and postoperative gastric perforation, stomach slippage/dilatation, port/tubing complications and intragastric band migration which occurred in our long decades clinical experience. Detection, treatment and rate of presentation of each complication was evaluated. RESULTS: LAGB showed good long term results in terms of weight loss and resolution of obesity related diseases. Moreover, mortality due to obesity and related diseases appeared significantly lower in LAGB patients than in medically treated patients. CONCLUSION: Gastric Banding has a very low rate of early and late complications; these are also less severe when compared to more invasive procedures and are likely to be managed with mini-invasive techniques. In any case referral to a bariatric surgeon is deemed appropriate. KEY WORDS: Complication, Laparoscopic gastric banding, Morbid obesity. PMID- 28874622 TI - Predictors of central lymph node metastasis in papillary thyroid cancer. AB - INTRODUCTION: Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland and although PTC has excellent prognosis, central lymph node (CLN) metastases are not uncommon. Studies have shown that CLN metastases are associated with an increased recurrence rate. The necessity for prophylactic CLN dissection (pCCND) in clinical lymph node negative (cN0) patients remains controversial. The aim of this study was to determine predictors of CLN metastases in cN0 PTC patients who underwent prophylactic CLN dissection. MATERIALS AND METHODS: The medical charts of 97 patients with cN0 PTC who had undergone total thyroidectomy (TT) and pCCND were evaluated retrospectively. The relationship between CLN metastases and risk factors were analyzed. RESULTS: CLN metastases were found in 32 (32.9%) patients. Univariate analysis showed that CLN metastases were significantly associated with male sex and tumor size. In multivariate analysis, tumor size greater than 0.7 cm and male sex were independent predictors for CLN metastases. DISCUSSION: Although oncological benefits of the pCCND in cN0 PTC patients remain controversial, tumor size greater than 0.7cm and male gender may be possible indicators of central lymph node metastasis. KEY WORDS: Central lymph node metastasis, Central lymph node dissection, Papillary Thyroid Cancer, Total thyroidectomy. PMID- 28874623 TI - Factors affecting the conversion to open surgery during laparoscopic cholecystectomy in patients with cholelithiasis undergoing ERCP due to choledocholithiasis. AB - BACKGROUND: The rate of conversion to open surgery is high in laparoscopic cholecystectomy (LC) after Endoscopic Retrograde Cholangiopancreotocography (ERCP). The present study aimed to evaluate the risk factors associated with the conversion to open cholecystectomy and minimize the rate of conversion to open surgery. METHODS: A total of 157 patients admitted to the Ondokuz Mayis University Medical Faculty Hospital due to cholelithiasis and choledocholithiasis between January 2002 and December 2012, and they receiving laparoscopic cholecystectomy were included in the study. The patients were analyzed retrospectively. The predictive factors for conversion to open cholecystectomy were evaluated. Patients were compared to each other in terms of time passing from ERCP to operation, number of ERCPs, stent usage, stone extraction and complications that occurred while waiting for the operation. Patients were separated into three groups according to the time passing from ERCP to laparoscopic cholecystectomy, as follows; group I (short time intervals: 7 days or less): 53 patients, group II (intermediate time intervals: 8-42 days): 70 patients and group III (long time intervals: 43 days and more): 34 patients. RESULTS: Of the 157 patients, 57 were male and 100 were female. The mean age was 54.5 (range: 19-87) years. Of these 157 patients who received laparoscopic cholecystectomy following ERCP, 22 (14%) underwent open surgery. The conversion to open cholecystectomy was distributed in groups, as follows: seven (13.2%) patients in group I, eight (11.4%) patients in group II and seven (20.6%) patients in group III. When the rate of conversion to open surgery was compared between groups, there was no statistically significant difference (p=0.406). The laparoscopic operations were converted to open surgery in 15 (11.3%) of the 133 patients who underwent single ERCP, and in seven (29.2%) of the 24 patients who underwent two or more ERCPs before surgery (p=0.048). The number of ERCPs was determined to be the most important factor that affects the conversion to open surgery in laparoscopic cholecystectomies following ERCP. The removal of stones from the common bile duct, stent placement in the common bile duct, and existence of biliary complications during waiting time from ERCP to LC had no effect on the conversion to open surgery (p=0.454, p=0.058, and p=0.465, respectively). CONCLUSIONS: The results of this study reveal that the timing of LC following ERCP, removal of stones from the common bile duct, stent placement in the common bile duct and the existence of biliary complications during the waiting period have no effect on the rate of conversion to open surgery. The number of ERCPs is the only factor that affects the conversion to open surgery in LC following ERCP. KEY WORDS: Choledocholitiasis, Conversion, Endoscopic retrograde cholangiopancreatography, Laparoscopic cholecystectomy. PMID- 28874624 TI - Feasibility of lymphoscintigraphy for sentinel node identification after neo adjuvant therapy. AB - AIM: To assess the sentinel-node identification rate at lymphoscintigraphy and its technical feasibility after neo-adjuvant treatments. MATERIAL OF STUDY: Between 2000 and 2013, 444 consecutive patients affected by primary locally advanced breast cancer were enrolled in this study. All individuals were candidate for neo-adjuvant treatments and for lymphoscintigraphy before surgery. RESULTS: The median age was 44 years at onset; almost one sentinel node was identified during lymphoscintigraphy in 430 cases. The detection rate at lymphoscintigraphy was 96.9% (95% CI, 94.8-98.1%). Considering the correlation between specific treatments and sentinel node identification rate, we verified that the detection rate did not vary significantly (p=0.53) according to the type of neo-adjuvant therapies administered to the patients. CONCLUSIONS: Our results demonstrated that lymphoscintigraphy for sentinel node identification is a safe and feasible procedure after neo-adjuvant therapies, independently of treatment types. KEY WORDS: Breast Cancer, Neo-Adjuvant Treatment, Sentinel lymphnode biopsy, Lymphoscintigraphy. PMID- 28874625 TI - A rare case of squamous cell carcinoma of a proliferating trichilemmal tumour. AB - INTRODUCTION: Squamous Cell Carcinoma (SCC) includes several subtypes and these can be classified according to their clinical behaviours from the least invasive to the most aggressive. Moreover, it is appropriate to analyse their clinicalpathological patterns 1. In light of its wide histopathological variability, we encountered a rare malignant cutaneous lesion: a SCC of a proliferating trichilemmal tumour (PTT) nature. CASE REPORT: We describe the clinical and pathologic findings of an 82-year-old woman, who developed a SCC with areas of trichilemmal differentiation. It has a surprising thickness of 25 mm, which passes through the dermis, infiltrates the hypodermis and evolves quickly. CONCLUSION: Considering its exophytic growth and the negative results of the post operative tests (ultrasounds confirmed absence of metastasis), the tumour was eradicated thanks to the surgical approach (a 1 cm border wide excision, including the periosteum in the central part of the lesion, followed by its reconstruction using a full-thickness skin graft) and the prompt intervention, without need for further complimentary treatments. The overall aesthetic results were pleasing. KEY WORDS: Adnexal tumour, PPT, SCC, Surgery. PMID- 28874626 TI - Anatomical variations of cervical vein drainage in candidates for neck surgery. AB - : The knowledge of both normal and abnormal anatomy of the veins of the neck may be important for surgeons performing neck surgery, to avoid inadvertent injury to vascular structures. In a 75-year-old man candidated to carotid endarterectomy preoperative CT-scan showed a rare anomaly of the venous drainage in the area of the anterior jugular vein (AJV), that usually begins in the suprahyoid region via the confluence of several superficial veins, to open into the ipsilateral external jugular vein. A large left sided venous trunk, originating from an anomalous proximal confluence with the internal jugular vein, descended in the AJV anatomical position, to cross over the sternum draining into the right subclavian vein. The knowledge of this abnormal anatomy allowed to perform a safe carotid bulb isolation avoiding inadvertent injury to vascular structures. KEY WORDS: Anatomic variations, Anterior jugular vein, Jugular veins, Carotid endarterectomy, Neck surgery. PMID- 28874627 TI - IORT in breast cancer. Our experience of the first patients treated. AB - AIM: The aim of this study was to assess the therapeutic effect of intraoperative radiotherapy, describe the method and examine the results of our experience. BACKGROUND: Breast conserving therapy has recently become a standard treatment modality in patients with early invasive cancer. Radiotherapy, along with surgery, is an integral part of such treatment. The important thing of radiotherapy is to deliver a high dose to the tumour bed. One of the methods is the intraoperative radiotherapy. MATERIALS AND METHODS: The analysis comprised 41 breast cancer patients treated with breast conserving surgery. Patient's range age was 35-80 years. Cancer type distribution inlcuded: 95% ductal carcinoma, 5% other carcinoma. Applicator size: 4 cm. (12%), 5 cm. (64%), 6 cm. (17%), 7 cm. (7%). Electron energies: 6 MeV (22%), 8 MeV (56%), 10 MeV (22%). Intraoperative radiation therapy was delivered in the operating theatre during surgery. After that, all patients were treated with whole breast irradiation. RESULTS: 41 patients treated with IORT procedures completed. In general there were no severe postoperative complications and we did not detect tumor recurrence in any patient even if the time elapsed from the treatment is still short. CONCLUSIONS: Due to its exceptional physical and radiobiological properties, intraoperative radiation therapy can be a good alternative to other methods of boosting dose to the postoperative site in management. KEY WORDS: Breast cancer, IORT, intraoperative radiotherapy, Surgery. PMID- 28874629 TI - The effect of intraperitoneal n-acetylcysteine on postoperative adhesions in rat models. AB - AIM: In this study, we researched the effect of local administration of N acetylcysteine (NAC) on postoperative intraabdominal adhesion formation in the rat models. METHODS: 20 female Wistar Albino rats which were 5-7 months old are used for the study. The rats were divided into two equal groups. Group one was administered saline solution (n=10) while group two was administered NAC (n=10) after caecal abrasion. They were dissected on postoperative tenth day and were examined macroscopically and microscopically for the adhesion formation. Intraperitoneal adhesion formation was scored blinded with Evans model. The most adherent bowel section was excised for histopathologic examination. Mann Whitney U test were used for statistical analysis. RESULTS: In Group one, all rats have had adhesions. None of the rats in Group two had either severe inflammatory cell reaction or dense interstitial fibrosis. Macroscopic adhesion formation and microscopic inflammatory cell reaction and interstitial fibrosis formation after surgery were less at the group two (NAC applied) (p<0.05, p<0.05, p<0.05). CONCLUSION: We believe that the intraperitoneal single dose usage of NAC may be promising for decreasing the postoperative intraabdominal adhesions. KEY WORDS: N acetylcysteine, Postoperative adhesion, Rat, Fibrosis. PMID- 28874630 TI - Decellularized human dermal matrix produced by a skin bank A new treatment for abdominal wall defects. AB - BACKGROUND: Interest is increasing for human decellularized scaffolds for their ability to favor healing and cell infiltration after transplantation, in the treatment of abdominal wall defects. The purpose of the present study is to show the clinical results obtained after the application of human decellularized dermal matrix (HDM) produced by RER Skin Bank, on patients suffering from different abdominal wall defects. METHODS: Between 2012 and 2014, 64 patients, average age 64 years, received HDM, to replace and cover the damage area during abdominal wall surgery. After surgical procedures, all patients were followed weekly for the first month and then monthly up to 6 months postoperative and any major problem or complication were recorded. Six months follow up included abdominal exams, serological tests and MRI analysis in order to evaluate integration of HDM with the patient's surroundings tissues and eventual long-term complications. RESULTS: Incisional hernia was the most frequent clinical condition in which HDM was applied, requiring also the highest amount of human decellularized dermal matrix. One month after the surgical operation, 61 patients revealed a well tolerability of HDM and a normal wound healing was also identified in all the damage areas. Only 3 patients experienced postoperative infections. Moreover the follow up after 6 months reported no signs of dermis rejection and that none of the patients was positive to serological tests. CONCLUSIONS: Human decellularized dermal matrix can be considered a safe and useful bioproduct to treat large abdominal defects, characterized by minor complications and simplicity to be implanted. KEY WORDS: Abdominal wall defects, Human decellularized dermal matrix, Skin Bank, Tissue regeneration. PMID- 28874631 TI - The prognostic role of microsatellite instability in colorectal cancer patients. AB - BACKGROUND: Data from the literature regarding the prognostic role of DNA mismatch repair system (MMR) in colorectal cancer are still controversial. AIM: The aim of the study was to identify the prognostic role of different phenotypic, clinical and pathological characteristics in microsatellite unstable vs. microsatellite stable colorectal cancer in terms of survival and disease free interval. METHODS: We conducted a retrospective study that included a total of 103 patients who underwent curative surgery for colorectal cancer. Immunohistochemistry testing revealed MLH1, MLH2, MLH6, PMS2 genes and mutations of the BRAF gene. We identified three groups of patients: patients with colorectal tumors with MSI produced by hypermethylation, (MLH1/BRAF+) group, patients with microsatellite instable tumours produced by genetic mutations MSI groupb(MLH1, MLH2, MLH6, PMS2) and patients with microsatellite stable tumours (MSS). RESULTS: The study shows that: MSI tumours (MLH1/BRAF+) group occur more frequently in women (p=0.05), on the right side of the colon (p=0.001). The 5 year survival rate was higher in patients with MSI tumours (MLH1/BRAF+) group than in those with microsatellite stable tumours, the differences were not statistically significant ; relapse rate was higher in patients with MSI tumors than in those with MSI tumours (MLH1/BRAF+) group (p=0.03) or with MSS tumors (p=0.004). CONCLUSIONS: The identification of microsatellite unstable colorectal tumours is an important molecular marker with role in recognition subgroups of patients with different phenotypic characteristics, survival and relapse rates. KEY WORDS: Colorectal cancer, Mismatch repair genes, Prognostic role. PMID- 28874632 TI - Duodenal gastrointestinal stromal tumor A case report. AB - AIM: To report an another case of duodenal GIST in patient that was treated with Whipple procedure. MATERIAL OF STUDY: We report a case of 69 years old men that was admitted with melena. The preoperative investigations suggested a suspected duodenal GIST.A Whipple pancreatico-duodenectomy was performed. Only 3-5% of GISTs occur in the duodenum. DISCUSSION: GIST were described as a separate entity by Mazur and Clark in 1983. These tumors are the most common among mesenchymal tumors of the gastrointeninal tract. The clinical presentations of duodenal GIST are highly variable. There is no consensus on the optimal surgical treatment of duodenal GIST.The aim was to achieve a R0-type surgery with complete en bloc surgical resection of the tumor and the surrounding tissue CONCLUSION: In conclusion the duodenal GIST are fairly rare. The clinical symptomatology is very variable even if frequently occur with digestive bleeding. the purpose of the surgery is the complete removal of the tumor (R0) however looking to perform minimum resections. KEY WORDS: GI bleeding, GIST, Pancreaticoduodenectomy. PMID- 28874633 TI - Tumor Budding in Oral Squamous Cell Carcinoma. AB - Tumor budding is defined as the presence of a single tumor cell or a small cluster of up to five cells in the tumor stroma, linking it to the epithelial mesenchymal transition (EMT).1 Imai2 illustrated that tumors with this trait have more aggressive qualities and allocated the term "sprouting" instead of "budding." The term "tumor budding" was coined by Morodomi et al in 1989.3 Tumor budding in vitro or in experiments has been addressed by many names, depending on the researcher's background, few of which are tumor cell dissociation, focal dedifferentia-tion, or EMT.4. PMID- 28874634 TI - Root Canal Morphologies of Mesiobuccal Roots of Maxillary Molars using Cone beam Computed Tomography and Periapical Radiographic Techniques in an Iranian Population. AB - AIM: The aim of this study was to evaluate the accuracy of the results of cone beam computed tomography (CBCT) examinations, confirm the presence or absence of the second mesiobuccal (MB2) root canal in maxillary first and second molars, estimate the distance between the root canal orifices, observe the root types based on Vertucci classification system, and make comparisons between CBCT and periapical techniques in relation to the identification of the root canal form and the second root canal of the MB root. MATERIALS AND METHODS: The CBCT and periapical radiographic data from the Department of Maxillofacial Radiology were used to select 156 individuals (78 females and 78 males) for the evaluation of the anatomy of maxillary first and second molars. RESULTS: The prevalence rate of the second root canal in the MB root in the maxillary first molars was 55.1%, with 44.1 and 63.3% in females and males respectively. The prevalence rate in maxillary second molars was 23.7%, with 15.7 and 30.2% in females and males respectively. In addition, the longest and shortest distances between the root canal orifices were 2.4 and 0.3 mm respectively, with a mean of 1.3 mm. CONCLUSION: There was a significant difference between the results of periapical and CBCT radiographic techniques in relation to the presence or absence of the second root canal in the MB roots of maxillary first and second molars (p < 0.01), with better results being provided by the CBCT technique. CLINICAL SIGNIFICANCE: The results of CBCT images about the existence of the second root canal in the MB roots of maxillary first and second molars are more reliable, and we can use this technique in the finding of additional canals in the clinic. Keyword: Cone beam computed tomography, Dental radiography, Root canal therapy. PMID- 28874635 TI - Effect of Ultrasonic Instrumentation in Treatment of Primary Molars. AB - AIM: The aim of this study is to describe the protocol used in the treatment of pulpally necrosed primary molars and to evaluate the effectiveness of ultrasonic instrumentation technique in primary dentition. MATERIALS AND METHODS: A total of 50 primary molars in 40 children, ranging from 8 to 10 years of age, were endodonti-cally treated using standard protocols and ultrasonic instrumentation. The follow-up was done for each case ranging from 1 to 2/4 years. RESULTS: Clinical and radiographic controls showed a success rate of 97.5%, considering an evaluation time of 19 +/- 9.02 months. CONCLUSION: The use of ultrasonic instrumentation in primary molars with pulpal necrosis succeeded in reducing appointment time and showed a high success rate. CLINICAL SIGNIFICANCE: Ultrasonic instrumentation should be used as a standard protocol in instrumentation of endodontic treatment of primary molars so as to increase the success rate of primary teeth pulpectomies. PMID- 28874636 TI - Growth and Development of Dentofacial Complex influenced by Genetic and Environmental Factors using Monozygotic Twins. AB - AIM: The purpose of this study was to determine the possible effects of genetic and environmental factors on dentofacial complex using monozygotic twins. MATERIALS AND METHODS: The study sample was made of 21 pairs of monozygotic twins (14 female pairs and seven male pairs) between 10 and 25 years. Pretreatment lateral cephalo-grams were used which were traced and digitized, and various landmarks to determine the anteroposterior and vertical proportions were marked. Samples were divided into two groups. The correlation between groups was found by calculating Pearson's product moment correlation coefficients. RESULTS: The range of the correlation coefficient was from 0.705 to 0.952. Gonial angle showed the highest correlation coefficient (0.952), while saddle angle showed the lowest correlation coefficient (0.705). CONCLUSION: The growth and development of craniofacial complex is under mutifactorial control. However, genetic influences do tend to play a dominant role. CLINICAL SIGNIFICANCE: By studying identical twins, we can study about the interaction of the environment with the genes and how it affects the growth and development of the body in general and dentofacial complex in particular. By utilizing twin studies, we can identify whether a particular trait, disease, or disorder is influenced more strongly by genetics or by the environment. Success of orthodontic treatment depends on a proper diagnosis of the problem including its etiological factors. Genetic studies let the orthodontists to understand the effects of genetic and environmental factors in the growth and development of dentofacial complex better and allows to prevent or treat malocclusions and skeletal anomalies in better ways. PMID- 28874637 TI - Readiness of Accredited Social Health Activist Workers for Tobacco Cessation Counseling after a Brief Intervention in Odisha, India: A Quasi-experimental Study. AB - AIM: The aim of the study was (1) to explore the baseline beliefs and practices of accredited social health activist (ASHA) workers of Khurda district of Orissa with respect to tobacco cessation and (2) to assess whether a brief intervention will be effective in improving the beliefs and practices of ASHA workers. The results of this study could be utilized by policy makers for framing important strategies for tobacco cessation in rural areas utilizing ASHA workers. MATERIALS AND METHODS: A quasi-experimental study (before and after comparison) was performed in Khurda district of Orissa to find out whether a brief intervention could improve the beliefs and practices of ASHA workers related to antitobacco counseling in rural areas. A 14-item structured, interviewer-administered questionnaire, written in English (translated in Odiya), was used. The final sample size was estimated as 135. Data were entered into Statistical Package for the Social Sciences (version 21) for analysis. RESULTS: All the mean belief items, practice items, degree of preparedness, and interest in training scores of study population increased significantly from baseline to postintervention. The study population showed a statistically significant improvement in postintervention composite belief and composite practices score. CONCLUSION: The majority of ASHA workers had positive beliefs and favorable practices after attending a brief intervention toward smoking cessation in their community. After attending the intervention, nearly half of the respondents felt themselves either somewhat or very well prepared for tobacco cessation. Most of them showed their interest toward getting further training in the field. CLINICAL SIGNIFICANCE: Training programs and regular tobacco cessation activities should be planned in the primary health-care delivery system of India. PMID- 28874638 TI - Stigma and Discrimination faced by HIV-infected Adults on Antiretroviral Therapy for more than 1 Year in Raichur Taluk, Karnataka, India. AB - AIM: The aim of this study was to evaluate the stress and discrimination faced by human immunodeficiency virus (HIV)-affected adult patients on antiretroviral therapy (ART) for more than 1 year. MATERIALS AND METHODS: A cross-sectional study was carried out among 170 adults on ART, reporting to the ART center of the District Civil Hospital, for more than 1 year in Raichur Taluk, Karnataka, India. Convenience sampling technique was followed. Descriptive statistics was performed (Chi-square test) using Statistical Package for the Social Sciences version 16.0. RESULTS: A total of 156 (91.8%) patients' families had knowledge about their seropositive status. Seventeen (10.9%) HIV-positive patients reported of change in the attitude of their family members. The main reasons for not revealing the HIV status were the internalized stigma and fear of rejection. Women faced greater discrimination from family, friends, and neighbors than men. CONCLUSION: It is necessary to not undermine the effect of rejection due to HIV. It is the only infection that has so many associated social and psychological norms which we need to tend at the earnest. Till date, there is an existence of condescendence toward treatment approach. CLINICAL SIGNIFICANCE: The presence of stigma and the fear of being discriminated could be a major hurdle in the rehabilitation of these patients into the mainstream society. Furthermore, it serves as an existing challenge to ascertain these individuals to achieve overall health. PMID- 28874639 TI - Comparative Analysis of the Water Sorption and Cytotoxicity of Two different Denture Base Systems: An in vitro Study. AB - AIM: Different biomaterials and techniques have been introduced in the field of prosthetic dentistry with the purpose of replacement and rehabilitation of the edentulous areas. Due to their shorter setting time, the light-activated restorative and prosthetic materials have the capability of releasing few amount of cytotoxic materials in the oral cavity. Polymer materials [urethane dimethacrylate (UDMA) and bis-acryl] are assumed to have high mechanical properties. Polymethyl methacrylate (PMMA) offers numerous advantages of being highly esthetic in nature and at the same time being cost-effective. Hence, this study aimed to assess and compare the water sorption and cytotoxicity of light activated UDMA denture base resin and conventional heat-activated PMMA resin. MATERIALS AND METHODS: This study included assessment and comparison of water sorption and cytotoxicity of heat-activated PMMA resin and light-activated UDMA denture base system. Fabrication of heat-activated PMMA resin and UDMA specimens was done by investing the wax patterns in stone molds using manufacturer's instructions. Contraction of the specimens was done for assessment of cytotoxicity and water resorption of the UDMA and PMMA resin samples. All the results were analyzed by Statistical Package for the Social Sciences software version 18.0. Chi-square test and one-way analysis of variance tests were used for the assessment of the level of significance; p < 0.05 was taken as significant. RESULTS: Mean lysis score observed in the PMMA and UDMA groups was 0.4 and 0.3 respectively. While observing at the 3 months time, the mean water resorption in the PMMA and UDMA groups was found to be 37.9 and 40.2 respectively. Significant difference in relation to water resorption was observed between the two study groups only at 3 months time. CONCLUSION: Both materials used in this study are nontoxic. Furthermore, UDMA resin materials exhibited lower water resorption after more than 1 month of time of storage. CLINICAL SIGNIFICANCE: Water resorption is similar for different denture base resin systems till 1 months time. PMID- 28874640 TI - Factors affecting Clinical Outcomes after Treatment of Oral Leukoplakia with CO2 and Diode Laser. AB - INTRODUCTION: To analyze factors that may affect recurrence, development of new lesions, and malignant transformation in patients with oral leukoplakia (OL) following surgical treatment with lasers. MATERIALS AND METHODS: A total of 40 patients were enrolled in this study, 17 females (mean age of 64.5 years; 33-88 years) and 23 males (mean age of 56.6 years; 28-84 years) with an overall mean age of 60.5 years. A total of 49 lesions were diagnosed and treated; 9 patients had more than one site affected. Mean time of follow-up was 22 months (6-71 months). Data were assessed by univariate Cox and multivariate Cox regression analyses. RESULTS: Recurrence (OL at the same site of the initial lesion) was observed in 11 patients (27.5%) while 4 patients (10%) developed new lesions, and 2 patients (5%) experienced malignant transformation. Only two clinical factors were statistically associated with the outcome for the development of new lesions: patients >= 60 years and female gender (p < 0.1). Neither of the outcomes of recurrences and malignant transformations was significantly correlated with any of the risk factors analyzed. CONCLUSION: Surgical laser is not a deterrent for the outcomes evaluated; additionally, the design of this study did not allow us to determine whether the laser treatment had provided a great benefit by significantly reducing the rate of malignant transformation among the patients. CLINICAL SIGNIFICANCE: It is highly important to inform patients with OL that their condition can be treated, when possible, by surgical laser, and that this treatment may be helpful in bringing down the odds of malignant transformation of their lesions. In addition, the patients should also be brought to the attention of the necessity of a continued clinical monitoring regardless of the outcome following a surgical intervention. PMID- 28874641 TI - Intricate Estimation and Evaluation of Mandibular Movements in Geriatric Patients Suffering from Rheumatoid Arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disorder that usually affects joints and making them warm, painful, and swollen. The chief purpose of this study was to evaluate movements of mandible in geriatric patients suffering from RA with or without temporomandibular joint dysfunction. MATERIALS AND METHODS: A total of 45 people were included in this study with age of 60 years and above. Partially or completely edentulous patients were divided into experimental and control group. Experimental group consists of 20 people suffering from arthritis and control group consists of 25 people without arthritis. Movements were recorded with or without prosthesis while mastication in both experimental and control group. RESULTS: Statistical evaluation of two studied groups showed decrease opening angle (p < 0.05) during mastication; however, insertion of new prosthesis showd a significant increase in values in both groups, with an increase in opening and closing angles. CONCLUSION: Positive correlation was found between arthritis and movements of the mandible in older people suffering from RA. CLINICAL SIGNIFICANCE: Patients suffering from RA are having restricted mandibular movements thus imposing an overall negative impact however; presence of prosthesis has been shown to enforce a positive effect on mandibular movement. PMID- 28874642 TI - Measurement of Crestal Cortical Bone Thickness at Implant Site: A Cone Beam Computed Tomography Study. AB - AIM: Dental implants have emerged as a new treatment modality for the majority of patients complaining of missing teeth. Bone quantity and bone quality are among various factors which ensure the longevity of dental implant in the patient's mouth. The assessment of cortical bone thickness of the outer layer and the cancellous bone density by cone beam computed tomography (CBCT) has proved beneficial for the patient. This study aimed at presurgical measurement of crestal bone thickness at various implant sites using CBCT images. MATERIALS AND METHODS: This study was conducted in the Department of Prosthodontics in the year 2015. It included 218 patients who wanted to replace missing teeth. Patients were subjected to CBCT scan using NewTom CBCT machine operating at 120 kVp and 5 mA with a resolution of 0.1 * 0.1 * 0.1 mm3. New Net Technologies (NNT) software with a slice thickness of 0.1 mm was used in this study. A total of 780 implant sites were identified on images of 218 patients. In all patients, the measurement of crestal bone thickness in the region of implant site was performed with NNT software. The buccolingual measurement of crestal bone was done in cross sections obtained after CBCT Results: Out of 218 patients, males were 110 and females were 108. The difference between gender was nonsignificant (p > 0.05). Out of 780 implant sites, 370 were in the maxilla and 410 were in mandible. The difference was nonsignificant (p > 0.05). Out of 780 implant sites, 210 were in anterior maxilla and 160 were in the posterior maxilla. Totally, 235 sites were in anterior mandible and 175 were in the posterior mandible. The distribution was nonsignificant (p = 0.15). The mean crestal bone thickness in anterior maxilla was 0.82 mm, in posterior maxilla was 0.76 mm, in anterior mandible was 1.08 mm, and in posterior mandible was 1.18 mm. The difference among regions was significant (p = 0.01). CONCLUSION: The highest thickness of cortical bone was observed in posterior mandible followed by anterior mandible, anterior maxilla, and posterior maxilla. Thus, considering the less cortical thickness in the posterior maxillary region, the implant placement should be done with proper attention. CLINICAL SIGNIFICANCE: Dental implant is the need of the hour. It is beneficial to patients in terms of longer survival rates. With CBCT, all measurements, such as bone quality and quantity have become easy because of three dimensional nature. This has proved to be beneficial in the analysis of cortical bone thickness as well as measuring the distance from anatomical structures. PMID- 28874643 TI - Evaluation of Apical Vapor Lock Formation and comparative Evaluation of its Elimination using Three different Techniques: An in vitro Study. AB - AIM: The aim of this study was (i) to evaluate the formation of air bubbles in the apical region of root canal (apical vapor lock) during syringe irrigation, using cone beam computed tomography (CBCT) and (ii) comparative evaluation of the elimination of an established vapor lock by EndoActivator, ultrasonics, and manual dynamic agitation (MDA), using CBCT. MATERIALS AND METHODS: A total of 60 extracted human single-rooted teeth were equally divided into three groups of 20 teeth each. The samples were decoronated 17 mm from the apex, cleaned, and shaped to size F4 Protaper using 3% sodium hypochlorite. Samples were irrigated with 3% sodium hypochlorite + cesium chloride radiopaque dye, and preoperative CBCT images were obtained. After formation of apical vapor lock in the scanned teeth, EndoActivator (group I), passive ultrasonic irrigation (group II), and MDA with K file (group III) were performed and the teeth were again placed in CBCT scanner and results analyzed using the chi-square test. RESULTS: The apical vapor lock was formed in all the samples. Out of the 20 teeth in each group, the apical vapor lock was eliminated in 18 samples of EndoActivator group (90%), 16 samples of ultrasonic group (80%), while it was eliminated in 10 samples by MDA (50%). CONCLUSION: It is concluded that (1) apical vapor lock is consistently formed during endodontic irrigation in closed canal systems and (2) sonic activation performs better than the ultrasonics and MDA in eliminating the apical vapor lock, with statistically significant difference between all the three groups (p < 0.05). CLINICAL SIGNIFICANCE: The results suggest that the apical vapor lock (dead water zone) is consistently formed during routine endodontic irrigation which impedes irrigant penetration till the working length, thereby leading to inefficient debridement. Hence, to eliminate this vapor lock, techniques, such as sonics or ultrasonics should be used along with the irrigant after shaping and cleaning of the root canal. PMID- 28874644 TI - Immunohistochemical Expression of Cathepsin D in Primary and Recurrent Squamous Cell Carcinoma. AB - AIM: The aim of this study is to analyze and compare the immunohistochemical expression of cathepsin B in primary oral squamous cell carcinoma (OSCC) and recurrent OSCC. MATERIALS AND METHODS: A total of 50 cases were studied immunohistochemically for rabbit polyclonal antihuman cathepsin D expression. A total of 10 cases of breast carcinoma were taken as positive controls. Immunohistochemical staining was performed using labeled streptavidin-biotin technique. RESULTS: All the 45 cases of OSCC, both primary and recurrent cases included, showed varying grades of cathepsin D immu-noreactivity. Statistical significance at 5% level was observed in cathepsin D expression between the different grades of well, moderate, and poorly differentiated primary squamous cell carcinomas. In the comparison of cathepsin D staining intensity among primary squamous cell carcinomas with and without recurrence, a statistical significance between the groups was observed when the p-value was at 10%, but the same comparison was not significant when the p-value was at 5%. CONCLUSION: Cathepsin D expression in primary squamous cell carcinomas with recurrences was very variable as compared with primary squamous cell carcinomas without recurrences. Comparison of cathepsin D expression in primary with their recurrent counterparts showed mostly similar intensity of expression in recurrent carcinomas, thus suggesting its limited usefulness in predicting recurrence. CLINICAL SIGNIFICANCE: Although cathepsin D might have shown limited usefulness in predicting cancer recurrence, it, however, is a proven valuable tool to detect the aggressiveness of various other tumors, and if corroborated with a larger sample may hold the key to early, more effective, and more specific treatment modalities for cases of oral cancer also. PMID- 28874645 TI - Evaluating Effectiveness of Axiostat Hemostatic Material in achieving Hemostasis and Healing of Extraction Wounds in Patients on Oral Antiplatelet Drugs. AB - AIM: The aim of this study was to evaluate the efficacy of Axiostat Hemostatic Dental dressing in achieving hemostasis postextraction and determining its effect on pain and healing of the extraction wound, compared with control, i.e., conventional method of extraction in patients on oral antiplatelet therapy. MATERIALS AND METHODS: Totally, 40 patients on oral antiplatelet drugs were included in the study and overall 80 extractions were done applying split mouth study design, without altering patient's drug regime. Extraction sites were divided into two groups: Group I received Axiostat Hemostatic Dental Dressing (study site), and group II received conventional method; pressure pack with sterile gauze under biting pressure followed by suturing if required (control site) was used to attain hemostasis. RESULTS: Extraction sites treated with Axiostat Hemostatic Dressing achieved hemostasis earlier (mean 1 minute 13 seconds) compared with control sites (mean = 14 minutes 1 second), which was also statistically significant (p < 0.001). Postoperative pain was considerably lower and significantly better healing was seen in the study group (p < 0.001) compared with the control. CONCLUSION: Axiostat demonstrated to be an effective hemo static agent that considerably lessens the bleeding time in patients on oral antiplatelet drugs postextraction. In addition, it even offered minimal postoperative pain and improved healing of the extraction wound. On comparing the results of this study with our study on HemCon Dental Dressing, Axiostat Dental Dressing (ADD) is found to be as effective and at par in achieving hemostasis in patients on oral antiplatelet therapy. CLINICAL SIGNIFICANCE: The past few decades have seen an upsurge in use of low-dose aspirin either alone or in combination with other drugs. When these patients require dental/maxillofacial treatment, earlier concept of stopping these medications is associated with increased risk of thromboembolic event. The present study highlights an alternative approach using ADD which aids in quick hemostasis, accentuates healing, and reduce postoperative pain. PMID- 28874646 TI - Comparative Evaluation of Two Different Flap Designs and Postoperative Outcome in the Surgical Removal of Impacted Mandibular Third Molar. AB - AIM: The aim of this study is to compare triangular and envelope flap designs and the postoperative outcome in the surgical removal of impacted mandibular third molar. MATERIALS AND METHODS: A total of 50 participants were assessed clinically and were divided randomly into two groups. Group I (participants operated by triangular flap) and group II (participants operated by envelope flap), with 25 participants each between the age group of 20 and 30 years. Patient satisfaction was assessed subjectively using a graded scale from very satisfied to very unsatisfied. The degree of pain was recorded for 7 days with reference to predefined values on visual analog scale (VAS). Trismus was evaluated on the day 3, day 5, and day 7 of the postoperative period in millimeters. Quantitative data were analyzed by unpaired t-test and qualitative data were by Fischer's exact test. RESULTS: The mean overall age is 25.5 years. There was no statistically significant difference between the study groups with respect to age. There was no significant association between the patient satisfaction and flap type (p = 0.684). A significant difference between the study groups on 4th, 5th, and 6th days with respect to pain was observed, wherein fewer subjects operated with triangular flap reported pain. A highly significant difference in mouth opening was observed, with triangular flap group participants having a higher mouth opening than envelope flap subjects on day 7. CONCLUSION: The present study indicated that participants operated by triangular flap had a better mouth opening postoperatively compared with envelope flap participants, whereas there were no significant differences in patient satisfaction and pain scores at the end of the 7th day after third molar surgery. CLINICAL SIGNIFICANCE: Flap design is a significant factor in the surgical removal of impacted third molar, and it influences the severity of complications. Furthermore, it is important for allowing optimal visibility and access to the impacted tooth and also for subsequent healing of the surgically created defect. PMID- 28874647 TI - Force Decay Characteristics of commonly used Elastomeric Chains on Exposure to various Mouth Rinses with different Alcohol Concentration: An in vitro Study. AB - AIM: The aim of this study was to test the effect of varying alcohol concentrations of various commercially available mouth-washes on force decay of elastomeric chains in prestretched and unstretched condition. MATERIALS AND METHODS: A total of five specimen groups were tested with a total sample size of 180 specimens. A specimen is described as a three-link, short module, clear elastomeric chain (3M Unitek, Ortho Plus, Ortho Organizer). The control and test groups were independently submerged in separate 37 degrees C artificial saliva to simulate the oral conditions. Effects of different solution groups and time (initial, 1, 7, 14, 21, and 28 days) on three different elastomeric chains and force (cN) are analyzed with two-way analysis of variance; pair-wise comparisons are done by t-test. RESULTS: Higher mean force was recorded initially followed by 24 hours >7 days >14 days >21 days and 28 days respectively. The difference in mean force decay among the different time intervals was found to be statistically significant (p < 0.001). Among the different solutions, higher mean force was recorded in 21.6% alcohol mixture > Listerine 8.38% > Wokadine > alcohol mixture 8.38% > artificial saliva. CONCLUSION: In conclusion, alcohol-containing mouth rinses cause an increase in force decay of elastomeric chain over time. CLINICAL SIGNIFICANCE: These mouth rinses are commonly recommended during orthodontic treatment. The orthodontist can know better that the alcohol content of the mouth rinses and the structural and molecular modification results in the decay of elastomeric chain. PMID- 28874648 TI - Incidence of Prosthetic Complications associated with Implant-borne Prosthesis in a Sleep Disorder Center. AB - BACKGROUND: Obstructive sleep apnea (OSA) is one of the common prevalent conditions present worldwide. The process of abnormal habits related to clenching and grinding of teeth is referred to as bruxism and is characterized under the heading of parafunctional activity of the masticatory system. Osseointegrated dental implants represent advancements in the field of odontology. Despite its high success rate, failure and complications are often associated with dental implant treatment due to a number of factors. Hence, we aimed for the present study to assess the incidence of prosthetic complications in patients rehabilitated with implant-borne prosthesis in a sleep disorder unit. MATERIALS AND METHODS: The present study included the assessment of all the patients who underwent prosthetic rehabilitation by dental implants. An experienced registered prosthodontist was given duty for examination of all the cases from the record file data. Prosthetic complications in the patients were identified using photographs, radiographs, and all other relevant data of the patients obtained from the record files. All types of complications and other factors were recorded separately and analyzed. RESULTS: While correlating the prosthetic complications in OSA patients grouped based on number of dental implants, nonsignificant results were obtained. Significant correlation was observed while comparing the prosthetic complications divided based on type of prosthesis. Fracture of the porcelain was observed in four and eight cases respectively, of screwed and cemented dental implant cases. CONCLUSION: Some amount of significant correlation existed between the incidences of prosthetic complications and OSA. CLINICAL SIGNIFICANCE: Proper history of the patients undergoing dental implant procedures should be taken to avoid failure. PMID- 28874649 TI - Quantitative Assessment of apically Extruded Bacteria using different Instrumentation Techniques and Preparation Taper. AB - BACKGROUND: Cleaning and shaping of the pulp canal is one of the most important steps of endodontic therapy. Serious complications occur by the apical extrusion of bacteria during the instrumentation procedures. Both crown-down (CD) and full length linear motion (FM) techniques are routinely used as a component of taper rotary instrument procedures for achievement of thorough cleaning and shaping of the pulp canal space. Hence, we aimed for this study to assess the change in the amount of apically extruded bacteria using CD and FM instrumentation techniques produced by differences in taper between the instruments used during biomechanical preparation of root canals. MATERIALS AND METHODS: The present study included assessments of 132 extracted maxillary central incisor teeth. To achieve a uniform teeth length of 21 mm, the height of the tooth crown was reduced for preserving the coronal portion of teeth. A modified glass vial model was constructed for the estimation of amount of bacterial extrusion through the apical region. For filling of each pulp canal specimen, 20 mL of Enterococcus faecalis suspension was used followed by the use of a number 10 K-file for carrying the bacteria down the lengths of pulp canals. All the contaminated teeth specimens were divided into six study groups with groups I to III containing specimens prepared in the CD manner, while groups IV to VI contained specimens prepared in the FM manner. Six teeth were taken as negative control with three specimens with each technique, and another six specimens were taken as positive controls. Cultivable bacterial counts were determined by evaluating 100 mL saline solution from each vial followed by its inoculation on blood agar. All the colony forming unit (CFU) values were log-transformed (base 10), and the results were analyzed by Statistical Package for the Social Sciences software. RESULTS: A significantly lower quantity of CFU values was observed during CD instrumentation procedures with 0.02 files in comparison with all other study groups. However, while comparing both the instrumentation procedures when different taper files, other than 0.02 taper, were used for biomechanical preparation of root canal, nonsignificant results were obtained. CONCLUSION: With 0.02 taper preparations, significantly less amount of extrusion of bacteria is associated when done with CD technique. CLINICAL SIGNIFICANCE: No change in the amount of apical extrusion of bacteria will be seen by changing the type of instrumentation procedures. Amount of bacteria extruded can be minimized using 0.02 taper. Key words: Bacteria, Instrumentation, Taper. PMID- 28874650 TI - Comparison of Proinflammatory Cytokine Levels in Gingival Crevicular Fluid around Dental Implants with Ceramic and Titanium Abutments. AB - BACKGROUND: Considering the high success rate of osseoin-tegration, there is ever increasing use of dental implants. The mechanisms and biologic response of peri implant tissues are different depending on the biocompatibility of the implant material. The aim of this study was to compare the proinflammatory cytokine levels in the gingival crevicular fluid (GCF) around dental implants with ceramic and titanium abutments. MATERIALS AND METHODS: All the patients with dental implants referring to two private offices of two prosthodontists from June to August 2016 were examined in relation to implant health, and eligible subjects, based on inclusion criteria, were included in this study with a slit-mouth design. In this context, on one side titanium implants and, on the other side, ceramic implants were used. Samples were collected from the peri-implant sulcus in each patient and sent to the immunology laboratory for determination of interleukin (IL)-6 and IL-1beta proinflammatory cytokine levels using an enzyme linked immunosorbent assay kit. Data were analyzed with Statistical Package for the Social Sciences version 16. Statistical significance was set at p < 0.05. RESULTS: The results showed lower levels of IL-1beta and IL-6 in the GCF around ceramic abutments compared with titanium implants. In addition, statistical comparison between IL-6 and IL-1beta levels showed higher levels of IL-6 around titanium and ceramic abutments compared with IL-1beta levels. CONCLUSION: Based on the results of this study, the human body immune response to ceramic abutments is much better than that to titanium implants. CLINICAL SIGNIFICANCE: Considering that proinflammatory cytokine levels in GCF around ceramic abutments are lower than titanium ones, ceramic abutments are preferred for clinical usage. PMID- 28874651 TI - Evaluation of the Effect of recasting Nickel-chromium Base Metal Alloy on the Metal-ceramic Bond Strength: An in vitro Study. AB - AIM: The aim of this study was to evaluate the effect of recasting base metal alloy on the metal-ceramic bond strength. MATERIALS AND METHODS: A total of 60 test samples were prepared from new and recast nickel-chromium alloy and divided into six groups. In group A0, test samples were prepared from 100% new alloy. Groups A1, A2, A3, A4, and A5 were prepared from 50% new alloy and 50% casting remnants (sprue and buttons) of the previous group by weight. All these samples were coated with ceramic (IPS d.SIGN and Ivoclar-Vivadent), and samples were then subjected to three-point bending test to evaluate metal-ceramic bond strength. RESULTS: The values were analyzed using one-way analysis of variance and Tukey's post hoc test. The mean bond strength of group A0 was higher than that of groups A1, A2, A3, A4, and A5. CONCLUSION: Metal-ceramic bond strength decreased significantly with multiple recastings. CLINICAL SIGNIFICANCE: Bond strength between metal and ceramic is a crucial factor for the clinical performance of metal-ceramic restorations. Recasting of alloys may affect the metal oxide layer composition and thickness of metal-ceramic interface, and thereby the metal ceramic bond. PMID- 28874652 TI - Three-year Prospective Evaluation of Immediately Loaded Mandibular Implant Overdentures retained with Locator Attachments. AB - INTRODUCTION: Immediate implant-loading protocol has progressed because of various clinical advantages offered by this treatment approach. However, available studies on edentulous patients are still few compared to those in which delayed implant-loading protocol was applied. AIM: This prospective study was to evaluate the implant survival rate and the peri-implant tissue response in a group of patients who received two unsplinted immediately loaded dental implants in the mandibular anterior region to retain a complete overdenture using locator attachments. MATERIALS AND METHODS: A total of 24 edentulous patients with a mean age of 63.4 years were involved in this study following certain inclusion criteria. All patients received a new set of complete dentures before implant positioning. Two Prima Connex tapered implants were put in the interforaminal area of the mandible with a flapless surgical procedure, and the prefabricated dentures were immediately retained with a zest locator attachment. Clinical and radiographic records of the patients were reviewed immediately after placement of the implant, at 3 months, and at 1, 2, and 3 years following fixture installation. The obtained data were analyzed using paired samples t-test and the Wilcoxon signed-rank test at 0.05 significance level. RESULTS: At 3 years, all implants had osseointegrated with a 100% survival rate. In addition, the total mean marginal bone change was -0.89 +/- 0.14 mm, and the mean periotest value was -7.631 +/- 0.921. CONCLUSION: Results of this study propose that immediate loading of mandibular implant overdentures that are retained with locator attachments was a feasible treatment alternative for this particular group of patients. CLINICAL SIGNIFICANCE: Immediate implant- loading of mandibular implant overdentures that are retained with locator attachments is a reliable treatment option Keywords: Immediate implant loading, Implant survival rate, Locator attachments, Overdenture. PMID- 28874653 TI - Shaping of the Root Canal System: A Multistep Technique. AB - AIM: The aim of this scientific work is to illustrate the technique of shaping the root canal system using the multistep technique. BACKGROUND: Over time, various endodontic instrumentation techniques have been put forward, from the "step-back" technique (apical-coronal) to the "crown-down" technique (coronal apical), the "double-flared" technique, and the most recent "single-length" technique. TECHNIQUE: The multistep technique involves six steps, one of the main objectives of these being the safety of the use of mechanical instruments with a reduction in the risk that they fracture. This technique ("mixed") provides for the use of both manual instruments in stainless steel and mechanical instruments in nickel titanium (Ni-Ti). CONCLUSION: The multistep technique is based on a standardized, flexible, and clinical protocol, which can provide for a reduction in the number of endodontic passages and instruments used and, therefore, a simplification of the operating procedure depending on both the difficulty of the root canals and the competence of the operator. CLINICAL SIGNIFICANCE: This technique is a technique for shaping the endodontic space that allows the set objectives of endodontic therapy to be reached in a predictable way with a reduced risk of iatrogenic complications. PMID- 28874654 TI - Agranulocytosis Induced by Sinomenine Hydrochloride. AB - BACKGROUND Sinomenine hydrochloride is an alkaloid that is extracted from the Chinese herbal plant Sinomenium acutum, and is used as a herbal medicine in the treatment or rheumatic disease. This report is the first to describe a case of sinomenine hydrochloride-induced agranulocytosis. CASE REPORT A 44-year-old woman with systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) was treated with sinomenine hydrochloride and developed agranulocytosis with a neutrophil count of 0.01*10^9/L. She subsequently developed an opportunistic bacterial infection. Bone marrow aspiration showed a severe reduction in the proportion of mature granulocytes. The patient discontinued sinomenine hydrochloride therapy and was treated with granulocyte colony-stimulating factor (G-CSF) and antibiotics. The patient showed a return to normal granulocyte levels within ten days of discontinuing treatment with sinomenine hydrochloride. CONCLUSIONS The findings of this case report show that monitoring of bone marrow function and granulocyte levels should be performed during treatment with sinomenine hydrochloride. PMID- 28874655 TI - Serum Neutrophil Gelatinase-Associated Lipocalin and Urinary Kidney Injury Molecule-1 as Potential Biomarkers of Subclinical Nephrotoxicity After Gadolinium Based and Iodinated-Based Contrast Media Exposure in Pediatric Patients with Normal Kidney Function. AB - BACKGROUND New renal biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) show promise in early diagnosis of contrast media induced acute kidney injury (CI-AKI). The purpose of our study was to compare the subclinical nephrotoxicity (a condition without changes in standard renal biomarkers) of gadolinium-based contrast media (Gd DTPA, gadopentetate dimeglumine) and iodinated-based contrast media (iopromide) in pediatric patients with normal kidney function. MATERIAL AND METHODS The first group (n=58) of patients included in the study were undergoing angiography with iopromide, and the second group (n=65) were undergoing magnetic resonance (MR) angiography/urography with Gd-DTPA administration. The concentrations of NGAL and KIM-1 were measured four times in the urine (pre-contrast, then at four hours, 24 hours, and 48 hours after contrast administration), and serum NGAL was measured at 0 (baseline), 24 hours, and 48 hours after contrast exposure. RESULTS After 24 hours, serum NGAL increase of >=25% was noticed in 32.6% of the patients in the iopromide group and in 25.45% of the patients in the gadolinium group, with significantly higher average percent of this increase in first group (62.23% vs. 36.44%, p=0.002). In the Gd-DTPA group, we observed a statistically significant increase in urinary KIM-1 24 hours after the procedure. Normalized urinary KIM-1, 24 hours after contrast exposure, was a better predictive factor for CI-AKI than other biomarkers (AUC 0.757, cut off 214 pg/mg, sensitivity 83.3%, specificity 54.2%, p=0.035). CONCLUSIONS In children with normal renal function, exposure to iodinated-based and gadolinium-based media might lead to subclinical nephrotoxicity, which could be detected using serum NGAL and urinary KIM-1. PMID- 28874656 TI - Land-locked mammalian Golgi reveals cargo transport between stable cisternae. AB - The Golgi is composed of a stack of cis, medial, trans cisternae that are biochemically distinct. The stable compartments model postulates that permanent cisternae communicate through bi-directional vesicles, while the cisternal maturation model postulates that transient cisternae biochemically mature to ensure anterograde transport. Testing either model has been constrained by the diffraction limit of light microscopy, as the cisternae are only 10-20 nm thick and closely stacked in mammalian cells. We previously described the unstacking of Golgi by the ectopic adhesion of Golgi cisternae to mitochondria. Here, we show that cargo processing and transport continue-even when individual Golgi cisternae are separated and "land-locked" between mitochondria. With the increased spatial separation of cisternae, we show using three-dimensional live imaging that cis Golgi and trans-Golgi remain stable in their composition and size. Hence, we provide new evidence in support of the stable compartments model in mammalian cells.The different composition of Golgi cisternae gave rise to two different models for intra-Golgi traffic: one where stable cisternae communicate via vesicles and another one where cisternae biochemically mature to ensure anterograde transport. Here, the authors provide evidence in support of the stable compartments model. PMID- 28874657 TI - Emergence of native peptide sequences in prebiotic replication networks. AB - Biopolymer syntheses in living cells are perfected by an elaborate error correction machinery, which was not applicable during polymerization on early Earth. Scientists are consequently striving to identify mechanisms by which functional polymers were selected and further amplified from complex prebiotic mixtures. Here we show the instrumental role of non-enzymatic replication in the enrichment of certain product(s). To this end, we analyzed a complex web of reactions in beta-sheet peptide networks, focusing on the formation of specific intermediate compounds and template-assisted replication. Remarkably, we find that the formation of several products in a mixture is not critically harmful, since efficient and selective template-assisted reactions serve as a backbone correction mechanism, namely, for keeping the concentration of the peptide containing the native backbone equal to, or even higher than, the concentrations of the other products. We suggest that these findings may shed light on molecular evolution processes that led to current biology.The synthesis of biopolymers in living cells is perfected by complex machinery, however this was not the case on early Earth. Here the authors show the role of non-enzymatic replication in the enrichment of certain products within prebiotically relevant mixtures. PMID- 28874659 TI - Internalized TSH receptors en route to the TGN induce local Gs-protein signaling and gene transcription. AB - A new paradigm of G-protein-coupled receptor (GPCR) signaling at intracellular sites has recently emerged, but the underlying mechanisms and functional consequences are insufficiently understood. Here, we show that upon internalization in thyroid cells, endogenous TSH receptors traffic retrogradely to the trans-Golgi network (TGN) and activate endogenous Gs-proteins in the retromer-coated compartment that brings them to the TGN. Receptor internalization is associated with a late cAMP/protein kinase A (PKA) response at the Golgi/TGN. Blocking receptor internalization, inhibiting PKA II/interfering with its Golgi/TGN localization, silencing retromer or disrupting Golgi/TGN organization all impair efficient TSH-dependent cAMP response element binding protein (CREB) phosphorylation. These results suggest that retrograde trafficking to the TGN induces local Gs-protein activation and cAMP/PKA signaling at a critical position near the nucleus, which appears required for efficient CREB phosphorylation and gene transcription. This provides a new mechanism to explain the functional consequences of GPCR signaling at intracellular sites and reveals a critical role for the TGN in GPCR signaling.Recent investigations suggest that G-protein coupled receptors (GPCRs) can signal during intracellular trafficking. Here the authors use fluorescence microscopy approaches to directly visualize and investigate functional consequences of GPCR-mediated signaling at the Golgi/trans Golgi network. PMID- 28874658 TI - Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer. AB - Advanced prostate cancer (PCa) is a clinical challenge as no curative therapeutic is available. In this context, a better understanding of metastasis and resistance mechanisms in PCa is an important issue. As phosphatase and tensin homolog (PTEN) loss is the most common genetic lesion in such cancer, we investigate human data sets for mechanisms that can constrain cancer evolution in this setting. Here we report a liver X receptor (LXR) signature, which tightly correlates with PTEN loss, in PCa. Accordingly, the LXR pathway is deregulated in prostate carcinomas in Pten-null mice. Genetic ablation of LXRs in Pten-null mice, exacerbates PCa invasiveness and metastatic dissemination, which involves mesenchymal transition and accumulation of matrix metalloproteinases. Mechanistically, PTEN deletion governed LXR transcriptional activity through deregulation of cholesterol de novo synthesis, resulting in accumulation of endogenous LXR ligands. Our study therefore reveals a functional circuit linking PTEN and LXR, and highlights LXRs as metabolic gatekeepers that are able to constrain PCa progression.Treatment of prostate cancer, especially in its advanced stage, is still challenging; therefore, strategies to prevent metastatic dissemination are of great interest. Here the authors reveal a crucial role for liver X receptors in suppressing prostate carcinogenesis and metastatic progression in PTEN-null tumors. PMID- 28874660 TI - Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants. AB - Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1beta administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth.Inflammation mediated by microglia plays a key role in brain injury associated with preterm birth, but little is known about the microglial response in preterm infants. Here, the authors integrate molecular and imaging data from animal models and preterm infants, and find that microglial expression of DLG4 plays a role. PMID- 28874661 TI - A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission. AB - To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes. PMID- 28874662 TI - Cre/lox-assisted non-invasive in vivo tracking of specific cell populations by positron emission tomography. AB - Many pathophysiological processes are associated with proliferation, migration or death of distinct cell populations. Monitoring specific cell types and their progeny in a non-invasive, longitudinal and quantitative manner is still challenging. Here we show a novel cell-tracking system that combines Cre/lox assisted cell fate mapping with a thymidine kinase (sr39tk) reporter gene for cell detection by positron emission tomography (PET). We generate Rosa26 mT/sr39tk PET reporter mice and induce sr39tk expression in platelets, T lymphocytes or cardiomyocytes. As proof of concept, we demonstrate that our mouse model permits longitudinal PET imaging and quantification of T-cell homing during inflammation and cardiomyocyte viability after myocardial infarction. Moreover, Rosa26-mT/sr39tk mice are useful for whole-body characterization of transgenic Cre mice and to detect previously unknown Cre activity. We anticipate that the Cre-switchable PET reporter mice will be broadly applicable for non-invasive long term tracking of selected cell populations in vivo.Non-invasive cell tracking is a powerful method to visualize cells in vivo under physiological and pathophysiological conditions. Here Thunemann et al. generate a mouse model for in vivo tracking and quantification of specific cell types by combining a PET reporter gene with Cre-dependent activation that can be exploited for any cell population for which a Cre mouse line is available. PMID- 28874663 TI - Biosynthesis of the nosiheptide indole side ring centers on a cryptic carrier protein NosJ. AB - Nosiheptide is a prototypal thiopeptide antibiotic, containing an indole side ring in addition to its thiopeptide-characteristic macrocylic scaffold. This indole ring is derived from 3-methyl-2-indolic acid (MIA), a product of the radical S-adenosylmethionine enzyme NosL, but how MIA is incorporated into nosiheptide biosynthesis remains to be investigated. Here we report functional dissection of a series of enzymes involved in nosiheptide biosynthesis. We show NosI activates MIA and transfers it to the phosphopantetheinyl arm of a carrier protein NosJ. NosN then acts on the NosJ-bound MIA and installs a methyl group on the indole C4, and the resulting dimethylindolyl moiety is released from NosJ by a hydrolase-like enzyme NosK. Surface plasmon resonance analysis show that the molecular complex of NosJ with NosN is much more stable than those with other enzymes, revealing an elegant biosynthetic strategy in which the reaction flux is controlled by protein-protein interactions with different binding affinities.Thiopeptides such as nosiheptide are clinically-interesting antimicrobial natural products. Here the authors show the functional dissection of a series of enzymes involved in nosiheptide biosynthesis, revealing a unique biosynthetic pathway that centers on a previously-unknown carrier protein. PMID- 28874664 TI - Signalling strength determines proapoptotic functions of STING. AB - Mammalian cells use cytosolic nucleic acid receptors to detect pathogens and other stress signals. In innate immune cells the presence of cytosolic DNA is sensed by the cGAS-STING signalling pathway, which initiates a gene expression programme linked to cellular activation and cytokine production. Whether the outcome of the STING response varies between distinct cell types remains largely unknown. Here we show that T cells exhibit an intensified STING response, which leads to the expression of a distinct set of genes and results in the induction of apoptosis. Of note, this proapoptotic STING response is still functional in cancerous T cells and delivery of small molecule STING agonists prevents in vivo growth of T-cell-derived tumours independent of its adjuvant activity. Our results demonstrate how the magnitude of STING signalling can shape distinct effector responses, which may permit for cell type-adjusted behaviours towards endogenous or exogenous insults.The cGAS/STING signalling pathway is responsible for sensing intracellular DNA and activating downstream inflammatory genes. Here the authors show mouse primary T cells and T leukaemia are hyperresponsive to STING agonist, and this strong STING signalling is associated with apoptosis induction. PMID- 28874665 TI - Endocytic sorting motif interactions involved in Nef-mediated downmodulation of CD4 and CD3. AB - Lentiviral Nefs recruit assembly polypeptide complexes and target sorting motifs in cellular receptors to induce their internalization. While Nef-mediated CD4 downmodulation is conserved, the ability to internalize CD3 was lost in HIV-1 and its precursors. Although both functions play key roles in lentiviral replication and pathogenicity, the underlying structural requirements are poorly defined. Here, we determine the structure of SIVmac239 Nef bound to the ExxxLM motif of another Nef molecule at 2.5 A resolution. This provides a basis for a structural model, where a hydrophobic crevice in simian immunodeficiency virus (SIV) Nef targets a dileucine motif in CD4 and a tyrosine-based motif in CD3. Introducing key residues into this crevice of HIV-1 Nef enables CD3 binding but an additional N-terminal tyrosine motif is required for internalization. Our resolution of the CD4/Nef/AP2 complex and generation of HIV-1 Nefs capable of CD3 downregulation provide insights into sorting motif interactions and target discrimination of Nef.HIV and simian immunodeficiency virus (SIV) Nef proteins both stimulate the clathrin-mediated endocytosis of CD4 but differ in downmodulation of the immune receptor CD3. Here, the authors present the structure of SIV Nef bound to the ExxxLM motif of another Nef molecule, which allows them to propose a model how Nef recognizes these motifs in CD3 and CD4. PMID- 28874666 TI - Lineage overwhelms environmental conditions in determining rhizosphere bacterial community structure in a cosmopolitan invasive plant. AB - Plant-microbe interactions play crucial roles in species invasions but are rarely investigated at the intraspecific level. Here, we study these interactions in three lineages of a globally distributed plant, Phragmites australis. We use field surveys and a common garden experiment to analyze bacterial communities in the rhizosphere of P. australis stands from native, introduced, and Gulf lineages to determine lineage-specific controls on rhizosphere bacteria. We show that within-lineage bacterial communities are similar, but are distinct among lineages, which is consistent with our results in a complementary common garden experiment. Introduced P. australis rhizosphere bacterial communities have lower abundances of pathways involved in antimicrobial biosynthesis and degradation, suggesting a lower exposure to enemy attack than native and Gulf lineages. However, lineage and not rhizosphere bacterial communities dictate individual plant growth in the common garden experiment. We conclude that lineage is crucial for determination of both rhizosphere bacterial communities and plant fitness.Environmental factors often outweigh host heritable factors in structuring host-associated microbiomes. Here, Bowen et al. show that host lineage is crucial for determination of rhizosphere bacterial communities in Phragmites australis, a globally distributed invasive plant. PMID- 28874667 TI - Erratum: Treating tobacco dependence: guidance for primary care on life-saving interventions. Position statement of the IPCRG. AB - A correction to this article has been published and is linked from the HTML version of this article. PMID- 28874668 TI - Topologically associating domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation. AB - Developmental genes in metazoan genomes are surrounded by dense clusters of conserved noncoding elements (CNEs). CNEs exhibit unexplained extreme levels of sequence conservation, with many acting as developmental long-range enhancers. Clusters of CNEs define the span of regulatory inputs for many important developmental regulators and have been described previously as genomic regulatory blocks (GRBs). Their function and distribution around important regulatory genes raises the question of how they relate to 3D conformation of these loci. Here, we show that clusters of CNEs strongly coincide with topological organisation, predicting the boundaries of hundreds of topologically associating domains (TADs) in human and Drosophila. The set of TADs that are associated with high levels of noncoding conservation exhibit distinct properties compared to TADs devoid of extreme noncoding conservation. The close correspondence between extreme noncoding conservation and TADs suggests that these TADs are ancient, revealing a regulatory architecture conserved over hundreds of millions of years.Metazoan genomes contain many clusters of conserved noncoding elements. Here, the authors provide evidence that these clusters coincide with distinct topologically associating domains in humans and Drosophila, revealing a conserved regulatory genomic architecture. PMID- 28874670 TI - Sargassum muticum and Jania rubens regulate amino acid metabolism to improve growth and alleviate salinity in chickpea. AB - The present study evaluates the potential of Sar gassum muticum (Sar) and Jan ia rubens (Jan) seaweeds for enhancing growth and mitigating soil-salinity in chickpea (Cicer arietinum L.). Under control conditions, Sar and Jan extracts improved chickpea growth which was attributed to their potential for increasing photosynthetic pigments, K+ and amino acids, particularly proline, in comparison with water-sprayed control. Upon stress imposition, chickpea growth was reduced in NaCl concentration-dependent manner, and principal component analysis (PCA) revealed Na+ accumulation and oxidative damage as major determinants of sensitivity at high salinity. Furthermore, amino acid quantification indicated activation/deactivation of overall metabolism in roots/shoots, as an adaptive strategy, for maintaining plant growth under salt stress. Sar and Jan extract supplementations provided stress amelioration, and PCA confirmed that improved growth parameters at high salinity were associated with enhanced activities of superoxide dismutase and peroxidase. Besides, four key amino acids, including serine, threonine, proline and aspartic acids, were identified from roots which maximally contribute to Sar- and Jan-mediated stress amelioration. Sar showed higher effectiveness than Jan under both control and salt stress conditions. Our findings highlight "bio-stimulant" properties of two seaweeds and provide mechanistic insight into their salt-ameliorating action which is relevant for both basic and applied research. PMID- 28874669 TI - Phenotype-driven precision oncology as a guide for clinical decisions one patient at a time. AB - Genomics-driven cancer therapeutics has gained prominence in personalized cancer treatment. However, its utility in indications lacking biomarker-driven treatment strategies remains limited. Here we present a "phenotype-driven precision oncology" approach, based on the notion that biological response to perturbations, chemical or genetic, in ex vivo patient-individualized models can serve as predictive biomarkers for therapeutic response in the clinic. We generated a library of "screenable" patient-derived primary cultures (PDCs) for head and neck squamous cell carcinomas that reproducibly predicted treatment response in matched patient-derived-xenograft models. Importantly, PDCs could guide clinical practice and predict tumour progression in two n = 1 co-clinical trials. Comprehensive "-omics" interrogation of PDCs derived from one of these models revealed YAP1 as a putative biomarker for treatment response and survival in ~24% of oral squamous cell carcinoma. We envision that scaling of the proposed PDC approach could uncover biomarkers for therapeutic stratification and guide real-time therapeutic decisions in the future.Treatment response in patient derived models may serve as a biomarker for response in the clinic. Here, the authors use paired patient-derived mouse xenografts and patient-derived primary culture models from head and neck squamous cell carcinomas, including metastasis, as models for high-throughput screening of anti-cancer drugs. PMID- 28874671 TI - CRISPR-Cas9 mediated one-step disabling of pancreatogenesis in pigs. AB - Genome editing using programmable nucleases has revolutionized biomedical research. CRISPR-Cas9 mediated zygote genome editing enables high efficient production of knockout animals suitable for studying development and relevant human diseases. Here we report efficient disabling pancreatogenesis in pig embryos via zygotic co-delivery of Cas9 mRNA and dual sgRNAs targeting the PDX1 gene, which when combined with chimeric-competent human pluriopotent stem cells may serve as a suitable platform for the xeno-generation of human tissues and organs in pigs. PMID- 28874673 TI - Comparison of musculoskeletal networks of the primate forelimb. AB - Anatomical network analysis is a framework for quantitatively characterizing the topological organization of anatomical structures, thus providing a way to compare structural integration and modularity among species. Here we apply this approach to study the macroevolution of the forelimb in primates, a structure whose proportions and functions vary widely within this group. We analyzed musculoskeletal network models in 22 genera, including members of all major extant primate groups and three outgroup taxa, after an extensive literature survey and dissections. The modules of the proximal limb are largely similar among taxa, but those of the distal limb show substantial variation. Some network parameters are similar within phylogenetic groups (e.g., non-primates, strepsirrhines, New World monkeys, and hominoids). Reorganization of the modules in the hominoid hand compared to other primates may relate to functional changes such as coordination of individual digit movements, increased pronation/supination, and knuckle-walking. Surprisingly, humans are one of the few taxa we studied in which the thumb musculoskeletal structures do not form an independent anatomical module. This difference may be caused by the loss in humans of some intrinsic muscles associated with the digits or the acquisition of additional muscles that integrate the thumb more closely with surrounding structures. PMID- 28874672 TI - Unravelling a stearidonic acid-rich triacylglycerol biosynthetic pathway in the developing seeds of Buglossoides arvensis: A transcriptomic landscape. AB - Buglossoides arvensis is an emerging oilseed crop that is rich in stearidonic acid (SDA) and has several potential applications in human health and nutrition. The molecular basis of SDA biosynthesis in this plant remains unknown due to lack of genomic information. To unravel key genes involved in SDA-rich triacylglycerol (TAG) biosynthesis, we performed transcriptome sequencing of pooled mRNA from five different developmental stages of B. arvensis seeds using Illumina NextSeq platform. De novo transcriptome assembly generated 102,888 clustered transcripts from 39.83 million high-quality reads. Of these, 62.1% and 55.54% of transcripts were functionally annotated using Uniprot-Viridiplantae and KOG databases, respectively. A total of 10,021 SSR-containing sequences were identified using the MISA tool. Deep mining of transcriptome assembly using in silico tools led to the identification of genes involved in fatty acid and TAG biosynthesis. Expression profiling of 17 key transcripts involved in fatty acid desaturation and TAG biosynthesis showed expression patterns specific to the development stage that positively correlated with polyunsaturated fatty acid accumulation in the developing seeds. This first comprehensive transcriptome analysis provides the basis for future research on understanding molecular mechanisms of SDA-rich TAG accumulation in B. arvensis and aids in biotechnological production of SDA in other oilseed crops. PMID- 28874675 TI - Hidden Criticality of Counterion Condensation Near a Charged Cylinder. AB - Counterion condensation onto a charged cylinder, known as the Manning transition, has received a great deal of attention since it is essential to understand the properties of polyelectrolytes in ionic solutions. However, the current understanding is still far from complete and poses a puzzling question: While the strong-coupling theory valid at large ionic correlations suggests a discontinuous nature of the counterion condensation, the mean-field theory always predicts a continuous transition at the same critical point. This naturally leads to a question how one can reconcile the mean-field theory with the strong-coupling prediction. Here, we study the counterion condensation transition on a charged cylinder via Monte Carlo simulations. Varying the cylinder radius systematically in relation to the system size, we find that in addition to the Manning transition, there exists a novel transition where all counterions are bound to the cylinder and the heat capacity shows a drop at a finite Manning parameter. A finite-size scaling analysis is carried out to confirm the criticality of the complete condensation transition, yielding the same critical exponents with the Manning transition. We show that the existence of the complete condensation is essential to explain how the condensation nature alters from continuous to discontinuous transition. PMID- 28874674 TI - Lytic EBV infection investigated by detection of Soluble Epstein-Barr virus ZEBRA in the serum of patients with PTLD. AB - The ZEBRA protein (encoded by the BZLF1 gene), is the major transcription factor of EBV, expressed upon EBV lytic cycle activation. Several studies highlighted the critical role of EBV lytic infection as a risk factor for lymphoproliferative disorders like post-transplant lymphoproliferative disease (PTLD). Here, we use an antigen-capture ELISA assay specifically designed to detecting the circulating soluble ZEBRA (sZEBRA) in serum samples (threshold value determined at 40ng/mL). We retrospectively investigated a population of 66 transplanted patients comprising 35 PTLD. All the samples from a control population (30 EBV seronegative subjects and 25 immunocompetent individuals with EBV serological reactivation), classified as sZEBRA < 40ng/mL were assigned as negative. At PTLD diagnosis, EBV genome (quantified by qPCR with EBV DNA>200 copies/mL) and sZEBRA were detectable in 51% and 60% of cases, respectively. In the patients who developed a pathologically-confirmed PTLD, the mean sZEBRA value in cases, was 399 ng/mL +/- 141 versus 53ng/mL +/- 7 in patients who did not (p < 0,001). This is the first report relating to the detection of the circulating ZEBRA in serum specimens, as well as the first analysis dealing with the lytic cycle of EBV in PTLD patients with this new biomarker. PMID- 28874676 TI - Linc-ing Circulating Long Non-coding RNAs to the Diagnosis and Malignant Prediction of Intraductal Papillary Mucinous Neoplasms of the Pancreas. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective biomarkers for early detection. We hypothesized that circulating long non-coding RNAs (lncRNAs) may act as diagnostic markers of incidentally-detected cystic PDAC precursors known as intraductal papillary mucinous neoplasms (IPMNs) and predictors of their pathology/histological classification. Using NanoString nCounter(r) technology, we measured the abundance of 28 candidate lncRNAs in pre operative plasma from a cohort of pathologically-confirmed IPMN cases of various grades of severity and non-diseased controls. Results showed that two lncRNAs (GAS5 and SRA) aided in differentiating IPMNs from controls. An 8-lncRNA signature (including ADARB2-AS1, ANRIL, GLIS3-AS1, LINC00472, MEG3, PANDA, PVT1, and UCA1) had greater accuracy than standard clinical and radiologic features in distinguishing 'aggressive/malignant' IPMNs that warrant surgical removal from 'indolent/benign' IPMNs that can be observed. When the 8-lncRNA signature was combined with plasma miRNA data and quantitative 'radiomic' imaging features, the accuracy of predicting IPMN pathological classification improved. Our findings provide novel information on the ability to detect lncRNAs in plasma from patients with IPMNs and suggest that an lncRNA-based blood test may have utility as a diagnostic adjunct for identifying IPMNs and their pathology, especially when incorporated with biomarkers such as miRNAs, quantitative imaging features, and clinical data. PMID- 28874677 TI - 2,4-D attenuates salinity-induced toxicity by mediating anatomical changes, antioxidant capacity and cation transporters in the roots of rice cultivars. AB - Growth regulator herbicides are widely used in paddy fields to control weeds, however their role in conferring environmental stress tolerance in the crop plants are still elusive. In this study, the effects of recommended dose of 2,4 dichlorophenoxyacetic acid (2,4-D) on growth, oxidative damage, antioxidant defense, regulation of cation transporter genes and anatomical changes in the roots of rice cultivars XS 134 (salt resistant) and ZJ 88 (salt sensitive) were investigated under different levels of saline stress. Individual treatments of saline stress and 2,4-D application induced oxidative damage as evidenced by decreased root growth, enhanced ROS production, more membrane damage and Na+ accumulation in sensitive cultivar compared to the tolerant cultivar. Conversely, combined treatments of 2,4-D and saline stress significantly alleviated the growth inhibition and oxidative stress in roots of rice cultivars by modulating lignin and callose deposition, redox states of AsA, GSH, and related enzyme activities involved in the antioxidant defense system. The expression analysis of nine cation transporter genes showed altered and differential gene expression in salt-stressed roots of sensitive and resistant cultivars. Together, these results suggest that 2,4-D differentially regulates the Na+ and K+ levels, ROS production, antioxidant defense, anatomical changes and cation transporters/genes in roots of rice cultivars. PMID- 28874678 TI - Mitochondrial cyclophilin D ablation is associated with the activation of Akt/p70S6K pathway in the mouse kidney. AB - The mitochondrial matrix protein cyclophilin D (CypD) is an essential component of the mitochondrial permeability transition pore (MPTP). Here we characterized the effects of CypD ablation on bioenergetics in the kidney. CypD loss triggers a metabolic shift in Ppif-/- male and female mouse kidneys towards glycolysis and Krebs cycle activity. The shift is accompanied by increased glucose consumption and a transcriptional upregulation of effectors of glucose metabolism in the kidney. These included activation of Akt, AMPK (only in males) and p70S6K kinases. Gender specific differences between the Ppif-/- male and female mouse kidneys were observed including activation of pro-surviving ERK1/2 kinase and inhibited expression of pro-apoptotic and pro-fibrotic JNK and TGFbeta1 proteins in Ppif-/- females. They also showed the highest expression of phosphorylated ERK1/2 and Akt S473 proteins of all four investigated animal groups. Furthermore, Ppif-/- females showed higher lactate concentrations and ATP/ADP-ratios in the kidney than males. These metabolic and transcriptional modifications could provide an additional level of protection to Ppif-/- females. In summary, loss of mitochondrial CypD results in a shift in bioenergetics and in activation of glucose-metabolism regulating Akt/AMPK/p70S6 kinase pathways that is expected to affect the capability of Ppif-/- mice kidneys to react to stimuli and injury. PMID- 28874679 TI - The endosomal neuronal proteins Nsg1/NEEP21 and Nsg2/P19 are itinerant, not resident proteins of dendritic endosomes. AB - Membrane traffic critically regulates most aspects of neuronal function. Neurons express many neuronal-specific proteins that regulate membrane traffic, including the poorly understood small transmembrane proteins neural-specific gene 1 and 2 (Nsg1/NEEP21 and Nsg2/P19). Nsg1 has been implicated in regulating endosomal recycling and sorting of several important neuronal receptors. Nsg2 is largely unstudied. At steady-state, Nsg1 and Nsg2 only partially co-localize with known endosomal compartments, and it was suggested that they mark a neuronal-specific endosome. Since Nsg1 localizes to and functions in the dendritic endosome, we set out to discover how Nsg1 and Nsg2 localization to endosomes is regulated in primary rat hippocampal neurons, using quadruple immunolocalization against endogenous proteins, live imaging of dendritic endosomes, and interference approaches against the endosomal regulators Rab5 and Rab7. In contrast to previous conclusions, we now show that Nsg1 and Nsg2 are not resident endosomal proteins, but traffic rapidly from the cell surface to lysosomes and have a half life of less than two hours. Their partial co-localization with canonical endosomal markers thus reflects their rapid flux towards degradation rather than specific targeting to a singular compartment. These findings will require rethinking of how this class of endosomal proteins regulates trafficking of much longer-lived receptors. PMID- 28874680 TI - Prenatal noise stress impairs HPA axis and cognitive performance in mice. AB - Noise stress is a common environmental pollutant whose adverse effect on offspring performance has been less studied. This study was novel in terms of using "noise" as a prenatal stress compared with physical stress to explore the effect of stress during gestation on HPA axis activation, cognitive performance, and motor coordination, as well as in investigating the effect of behavioral assessments on the corticosterone (CORT) levels. Three groups of C57BL/6 mice with a gestational history of either noise stress (NS), physical stress (PS), or no stress were examined in several behavioral tests. Plasma CORT level was significantly higher before starting the behavioral tests in NS group than the two other groups. It was significantly increased after the behavioral tests in both prenatal stressed groups relative to the controls. Stress caused anxiety like behavior and reduced learning and memory performance in both stressed groups compared to the controls, as well as decreased motor coordination in the NS group relative to the other groups. The findings suggested that: prenatal NS severely changes the HPA axis; both prenatal stressors, and particularly NS, negatively impair the offspring's cognitive and motor performance; and, they also cause a strong susceptibility to interpret environmental experiences as stressful conditions. PMID- 28874681 TI - Spatial localization of sound elicits early responses from occipital visual cortex in humans. AB - Much evidence points to an interaction between vision and audition at early cortical sites. However, the functional role of these interactions is not yet understood. Here we show an early response of the occipital cortex to sound that it is strongly linked to the spatial localization task performed by the observer. The early occipital response to a sound, usually absent, increased by more than 10-fold when presented during a space localization task, but not during a time localization task. The response amplification was not only specific to the task, but surprisingly also to the position of the stimulus in the two hemifields. We suggest that early occipital processing of sound is linked to the construction of an audio spatial map that may utilize the visual map of the occipital cortex. PMID- 28874683 TI - Inter-Patient ECG Heartbeat Classification with Temporal VCG Optimized by PSO. AB - Classifying arrhythmias can be a tough task for a human being and automating this task is highly desirable. Nevertheless fully automatic arrhythmia classification through Electrocardiogram (ECG) signals is a challenging task when the inter patient paradigm is considered. For the inter-patient paradigm, classifiers are evaluated on signals of unknown subjects, resembling the real world scenario. In this work, we explore a novel ECG representation based on vectorcardiogram (VCG), called temporal vectorcardiogram (TVCG), along with a complex network for feature extraction. We also fine-tune the SVM classifier and perform feature selection with a particle swarm optimization (PSO) algorithm. Results for the inter-patient paradigm show that the proposed method achieves the results comparable to state of-the-art in MIT-BIH database (53% of Positive predictive (+P) for the Supraventricular ectopic beat (S) class and 87.3% of Sensitivity (Se) for the Ventricular ectopic beat (V) class) that TVCG is a richer representation of the heartbeat and that it could be useful for problems involving the cardiac signal and pattern recognition. PMID- 28874682 TI - Hydrogen peroxide dynamics in subcellular compartments of malaria parasites using genetically encoded redox probes. AB - Redox balance is essential for the survival, growth and multiplication of malaria parasites and oxidative stress is involved in the mechanism of action of many antimalarial drugs. Hydrogen peroxide (H2O2) plays an important role in redox signalling and pathogen-host cell interactions. For monitoring intra- and subcellular redox events, highly sensitive and specific probes are required. Here, we stably expressed the ratiometric H2O2 redox sensor roGFP2-Orp1 in the cytosol and the mitochondria of Plasmodium falciparum (P. falciparum) NF54-attB blood-stage parasites and evaluated its sensitivity towards oxidative stress, selected antimalarial drugs, and novel lead compounds. In both compartments, the sensor showed reproducible sensitivity towards H2O2 in the low micromolar range and towards antimalarial compounds at pharmacologically relevant concentrations. Upon short-term exposure (4 h), artemisinin derivatives, quinine and mefloquine impacted H2O2 levels in mitochondria, whereas chloroquine and a glucose-6 phosphate dehydrogenase (G6PD) inhibitor affected the cytosol; 24 h exposure to arylmethylamino steroids and G6PD inhibitors revealed oxidation of mitochondria and cytosol, respectively. Genomic integration of an H2O2 sensor expressed in subcellular compartments of P. falciparum provides the basis for studying complex parasite-host cell interactions or drug effects with spatio-temporal resolution while preserving cell integrity, and sets the stage for high-throughput approaches to identify antimalarial agents perturbing redox equilibrium. PMID- 28874684 TI - Damage-free peripheral nerve stimulation by 12-ns pulsed electric field. AB - Modern technologies enable deep tissue focusing of nanosecond pulsed electric field (nsPEF) for non-invasive nerve and muscle stimulation. However, it is not known if PEF orders of magnitude shorter than the activation time of voltage gated sodium channels (VGSC) would evoke action potentials (APs). One plausible scenario requires the loss of membrane integrity (electroporation) and resulting depolarization as an intermediate step. We report, for the first time, that the excitation of a peripheral nerve can be accomplished by 12-ns PEF without electroporation. 12-ns stimuli at 4.1-11 kV (3.3-8.8 kV/cm) evoked APs similarly to conventional stimuli (100-250 MUs, 1-5 V, 103-515 V/m), except for having higher selectivity for the faster nerve fibers. Nerves sustained repeated tetanic stimulations (50 Hz or 100 Hz for 1 min) alternately by 12-ns PEF and by conventional pulses. Such tetani caused a modest AP decrease, to a similar extent for both types of stimuli. Nerve refractory properties were not affected. The lack of cumulative damages even from tens of thousands of 12-ns stimuli and the similarities with the conventional stimulation prove VGSC activation by nsPEF without nerve membrane damage. PMID- 28874685 TI - Relative contribution of groundwater to plant transpiration estimated with stable isotopes. AB - Water stored underground in the saturated and subsurface zones below the soil are important sources of water for plants in water-limited ecosystems. The presence of deep-rooted plants worldwide, however, suggests that the use of groundwater is not restricted to arid and seasonally dry ecosystems. We compiled the available data (71 species) on the relative contribution of groundwater to plant water estimated using stable isotopes and mixing models, which provided information about relative groundwater use, and analyzed their variation across different climates, seasons, plant types, edaphic conditions, and landscape positions. Plant use of groundwater was more likely at sites with a pronounced dry season, and represented on average 49 per cent of transpired water in dry seasons and 28 per cent in wet seasons. The relative contribution of groundwater to plant-water uptake was higher on rocky substrates (saprolite, fractured bedrock), which had reduced groundwater uptake when this source was deep belowground. In addition, we found that the connectivity between groundwater pools and plant water may be quantitatively larger and more widespread than reported by recent global estimations based on isotopic averaged values. Earth System Models should account for the feedbacks between transpiration and groundwater recharge. PMID- 28874686 TI - Targeted error-suppressed quantification of circulating tumor DNA using semi degenerate barcoded adapters and biotinylated baits. AB - Ultrasensitive methods for rare allele detection are critical to leverage the full potential offered by liquid biopsies. Here, we describe a novel molecular barcoding method for the precise detection and quantification of circulating tumor DNA (ctDNA). The major benefits of our design include straightforward and cost-effective production of barcoded adapters to tag individual DNA molecules before PCR and sequencing, and better control over cross-contamination between experiments. We validated our approach in a cohort of 24 patients with a broad spectrum of cancer diagnoses by targeting and quantifying single-nucleotide variants (SNVs), indels and genomic rearrangements in plasma samples. By using personalized panels targeting a priori known mutations, we demonstrate comprehensive error-suppression capabilities for SNVs and detection thresholds for ctDNA below 0.1%. We also show that our semi-degenerate barcoded adapters hold promise for noninvasive genotyping in the absence of tumor biopsies and monitoring of minimal residual disease in longitudinal plasma samples. The benefits demonstrated here include broad applicability, flexibility, affordability and reproducibility in the research and clinical settings. PMID- 28874687 TI - Cell based assay identifies TLR2 and TLR4 stimulating impurities in Interferon beta. AB - Immunogenicity can have devastating consequences on the safety and efficacy of therapeutic proteins. Therefore, evaluating and mitigating the risk of product immunogenicity is critical for the development these products. This study, showed that Betaseron and Extavia, which are reported to be more immunogenic among IFNbeta products in clinical usage, contain residual innate immune response modulating impurities (IIRMIs) capable of activating NF-kappaB and induced expression of inflammatory mediators. These IIRMIs were undetectable in Rebif or Avonex. The stimulatory effect was attributed solely to IIRMIs because it was evident in murine cells lacking the interferon receptor (IFNAR). The IIRMIs in Betaseron and Extavia triggered NF-kappaB activation in HEK-293 cells bearing TLR2 and TLR4 in MyD88 dependent manner. Importantly, the IIRMIs in Betaseron induced up-regulation of IL-6, IL-1beta, and ccl5 in the skin of IFNAR knock out mice following subcutaneous administration. This indicates that trace level IIRMIs in Betaseron could contribute to the higher immunogenicity rates seen in clinics. Together these data suggest that cell based assays can reveal subtle but clinically relevant differences in IIRMIs following manufacturing changes or between products with the same active ingredients but different manufacturing processes. Appreciating these differences may inform immunogenicity risk assessments. PMID- 28874688 TI - Maternal Habitual Midday Napping Duration and Frequency are Associated with High Birthweight. AB - Habitual midday napping is a common habit in China, especially for pregnant women. The purpose of this study was to examine whether duration and frequency of maternal habitual midday napping were associated with high birthweight (HBW). A total of 10,482 participants from Healthy Baby Cohort were include in our analysis. The information of the mothers and their infants were abstracted from medical records, or obtained from questionnaire. Logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of habitual midday napping duration and frequency with HBW. Of the participants, 8,705 (83.0%) reported having habitual midday napping. Duration and frequency of napping had a positive association with HBW without adjustment. After controlling for potential confounders, increasing risk of HBW was observed in participants who napped 1.5-2 hours (OR, 1.50, 95% CI, 1.14, 1.98), and >=2 hours (OR, 1.35, 95% CI, 1.03, 1.78) compared with no habitual midday napping. Participants who took naps >=5 days/week had a higher risk of HBW (OR, 1.37, 95% CI, 1.07, 1.77) compared with the women without naps. This suggests that longer (>=1.5 hours) and more frequent (>=5 days/week) maternal habitual midday napping were associated with an increased risk of HBW. PMID- 28874689 TI - Modeling protein quaternary structure of homo- and hetero-oligomers beyond binary interactions by homology. AB - Cellular processes often depend on interactions between proteins and the formation of macromolecular complexes. The impairment of such interactions can lead to deregulation of pathways resulting in disease states, and it is hence crucial to gain insights into the nature of macromolecular assemblies. Detailed structural knowledge about complexes and protein-protein interactions is growing, but experimentally determined three-dimensional multimeric assemblies are outnumbered by complexes supported by non-structural experimental evidence. Here, we aim to fill this gap by modeling multimeric structures by homology, only using amino acid sequences to infer the stoichiometry and the overall structure of the assembly. We ask which properties of proteins within a family can assist in the prediction of correct quaternary structure. Specifically, we introduce a description of protein-protein interface conservation as a function of evolutionary distance to reduce the noise in deep multiple sequence alignments. We also define a distance measure to structurally compare homologous multimeric protein complexes. This allows us to hierarchically cluster protein structures and quantify the diversity of alternative biological assemblies known today. We find that a combination of conservation scores, structural clustering, and classical interface descriptors, can improve the selection of homologous protein templates leading to reliable models of protein complexes. PMID- 28874690 TI - A single neonatal administration of Bisphenol A induces higher tumour weight associated to changes in tumour microenvironment in the adulthood. AB - BPA is an oestrogenic endocrine disrupting chemical compound. Exposure to BPA in as early as pregnancy leads to lifelong effects. Since endocrine and immune systems interact in a bidirectional manner, endocrine disruption may cause permanent alterations of the immune system, affecting a future anti-tumoral response. Neonate (PND 3) female syngeneic BALB/c mice were exposed to a single dose of 250 ug/kg BPA. Once sexual maturity was reached, a mammary tumour was induced injecting 4T1 cells in situ, these cells are derived from a spontaneous adenocarcinoma in a BALB/c mouse and therefore allows for an immunocompetent recipient. After 25 days of injection, showing no major endocrine alterations, BPA-exposed mice developed larger tumours. Tumour leukocytic infiltrate analysis revealed a higher proportion of regulatory T lymphocytes in the BPA-exposed group. RT-PCR analysis of tumour samples showed a decreased expression of TNF alpha and IFN-gamma, as well as the M2 macrophage marker Fizz-1 in the BPA exposed group. Flow cytometry analysis revealed differences in ERalpha expression by T lymphocytes, macrophages and NK cells, both associated to BPA exposure and tumour development. These findings show a new aspect whereby early life BPA exposure can contribute to breast cancer development and progression by modulating the anti-tumoral immune response. PMID- 28874691 TI - Prediction of miRNA-disease Associations using an Evolutionary Tuned Latent Semantic Analysis. AB - MicroRNAs, small non-coding elements implied in gene regulation, are very interesting biomarkers for various diseases such as cancers. They represent potential prodigious biotechnologies for early diagnosis and gene therapies. However, experimental verification of microRNA-disease associations are time consuming and costly, so that computational modeling is a proper solution. Previously, we designed MiRAI, a predictive method based on distributional semantics, to identify new associations between microRNA molecules and human diseases. Our preliminary results showed very good prediction scores compared to other available methods. However, MiRAI performances depend on numerous parameters that cannot be tuned manually. In this study, a parallel evolutionary algorithm is proposed for finding an optimal configuration of our predictive method. The automatically parametrized version of MiRAI achieved excellent performance. It highlighted new miRNA-disease associations, especially the potential implication of mir-188 and mir-795 in various diseases. In addition, our method allowed to detect several putative false associations contained in the reference database. PMID- 28874692 TI - Silver nanoparticle loaded collagen/chitosan scaffolds promote wound healing via regulating fibroblast migration and macrophage activation. AB - Treatment of full-thickness skin defects poses significant clinical challenges including risk of infection and severe scaring. Silver nanoparticle (NAg), an effective antimicrobial agent, has provided a promising therapeutic method for burn wounds. However, the detailed mechanism remains unknown. Hence, we constructed a metallic nanosilver particles-collagen/chitosan hybrid scaffold (NAg-CCS) and investigated its potential effects on wound healing. In vitro scratch assay, immunofluorescence staining and antibacterial activity of the scaffold were all studied. In vivo NAg-CCS was applied in full-thickness skin defects in Sprague-Dawley (SD) rats and the therapeutic effects of treatment were evaluated. The results showed that NAg at a concentration of 10 ppm accelerated the migration of fibroblasts with an increase in expression of alpha-smooth muscle actin (alpha-SMA). Furthermore, in vivo studies showed increased levels of pro-inflammatory and scar-related factors as well as alpha-SMA, while markers for macrophage activation were up-regulated. On day 60 post transplantation of ultra thin skin graft, the regenerated skin by NAg-CCS had a similar structure to normal skin. In summary, we demonstrated that NAg-CCS was bactericidal, anti inflammatory and promoted wound healing potentially by regulating fibroblast migration and macrophage activation, making it an ideal dermal substitute for wound regeneration. PMID- 28874694 TI - Focusing analytes from 50 MUL into 500 pL: On-chip focusing from large sample volumes using isotachophoresis. AB - The use of on-chip isotachophoresis assays for diagnostic applications is often limited by the small volumes of standard microfluidic channels. Overcoming this limitation is particularly important for detection of 'discrete' biological targets (such as bacteria) at low concentrations, where the volume of processed liquid in a standard microchannel might not contain any targets. We present a novel microfluidic chip that enables ITP focusing of target analytes from initial sample volumes of 50 MUL into a concentrated zone with a volume of 500 pL, corresponding to a 100,000-fold increase in mean concentration, and a 300,000 fold increase in peak concentration. We present design considerations for limiting sample dispersion in such large-volume focusing (LVF) chips and discuss the trade-off between assay time and Joule heating, which ultimately governs the scalability of LVF designs. Finally, we demonstrate a 100-fold improvement of ITP focusing performance in the LVF chip as compared to conventional microchannels, and apply this enhancement to achieve highly sensitive detection of both molecular targets (DNA, down to 10 fM) and whole bacteria (down to 100 cfu/mL). PMID- 28874693 TI - Comparative secretome analysis of Rhizoctonia solani isolates with different host ranges reveals unique secretomes and cell death inducing effectors. AB - Rhizoctonia solani is a fungal pathogen causing substantial damage to many of the worlds' largest food crops including wheat, rice, maize and soybean. Despite impacting global food security, little is known about the pathogenicity mechanisms employed by R. solani. To enable prediction of effectors possessing either broad efficacy or host specificity, a combined secretome was constructed from a monocot specific isolate, a dicot specific isolate and broad host range isolate infecting both monocot and dicot hosts. Secretome analysis suggested R. solani employs largely different virulence mechanisms to well-studied pathogens, despite in many instances infecting the same host plants. Furthermore, the secretome of the broad host range AG8 isolate may be shaped by maintaining functions for saprophytic life stages while minimising opportunities for host plant recognition. Analysis of possible co-evolution with host plants and in planta up-regulation in particular, aided identification of effectors including xylanase and inhibitor I9 domain containing proteins able to induce cell death in planta. The inhibitor I9 domain was more abundant in the secretomes of a wide range of necrotising fungi relative to biotrophs. These findings provide novel targets for further dissection of the virulence mechanisms and potential avenues to control this under-characterised but important pathogen. PMID- 28874695 TI - Deep Phospho- and Phosphotyrosine Proteomics Identified Active Kinases and Phosphorylation Networks in Colorectal Cancer Cell Lines Resistant to Cetuximab. AB - Abnormality in cellular phosphorylation is closely related to oncogenesis. Thus, kinase inhibitors, especially tyrosine kinase inhibitors (TKIs), have been developed as anti-cancer drugs. Genomic analyses have been used in research on TKI sensitivity, but some types of TKI resistance have been unclassifiable by genomic data. Therefore, global proteomic analysis, especially phosphotyrosine (pY) proteomic analysis, could contribute to predict TKI sensitivity and overcome TKI-resistant cancer. In this study, we conducted deep phosphoproteomic analysis to select active kinase candidates in colorectal cancer intrinsically resistant to Cetuximab. The deep phosphoproteomic data were obtained by performing immobilized metal-ion affinity chromatography-based phosphoproteomic and highly sensitive pY proteomic analyses. Comparison between sensitive (LIM1215 and DLD1) and resistant cell lines (HCT116 and HT29) revealed active kinase candidates in the latter, most of which were identified by pY proteomic analysis. Remarkably, genomic mutations were not assigned in most of these kinases. Phosphorylation based signaling network analysis of the active kinase candidates indicated that SRC-PRKCD cascade was constitutively activated in HCT116 cells. Treatment with an SRC inhibitor significantly inhibited proliferation of HCT116 cells. In summary, our results based on deep phosphoproteomic data led us to propose novel therapeutic targets against cetuximab resistance and showed the potential for anti-cancer therapy. PMID- 28874696 TI - Metamaterial Perfect Absorber Analyzed by a Meta-cavity Model Consisting of Multilayer Metasurfaces. AB - We demonstrate that the metamaterial perfect absorber behaves as a meta-cavity bounded between a resonant metasurface and a metallic thin-film reflector. The perfect absorption is achieved by the Fabry-Perot cavity resonance via multiple reflections between the "quasi-open" boundary of resonator and the "close" boundary of reflector. The characteristic features including angle independence, ultra-thin thickness and strong field localization can be well explained by this meta-cavity model. With this model, metamaterial perfect absorber can be redefined as a meta-cavity exhibiting high Q-factor, strong field enhancement and extremely high photonic density of states, thereby promising novel applications for high performance sensor, infrared photodetector and cavity quantum electrodynamics devices. PMID- 28874697 TI - Quantum mixed phases of a two-dimensional polarized degenerate Fermi gas in an optical cavity. AB - The coupling of ultracold fermions to a high-finesse optical cavity can result in novel many-body phenomena, and has attracted significant interests at present. Here we consider a realization of the Fermi-Dicke model with controllable parameters, based on a two-dimensional polarized degenerate Fermi gas coupled to an optical cavity. We analytically investigate the ground-state properties of such system under the mean-field approximation. We find the system can exhibit a rich phase diagram depending on the fermion-photon coupling strength and the atomic resonant frequency. Contrasting to the bosonic counterpart, a first-order quantum phase transition between the superradiant phase and the normal phase featuring two Fermi surfaces can occur for the weak atomic resonant frequency, and there is a unique mixed phase where this normal phase and the superradiant phase coexist. The experimental detection of our results is also discussed. PMID- 28874698 TI - Comparative transcriptome analysis of the Pacific White Shrimp (Litopenaeus vannamei) muscle reveals the molecular basis of residual feed intake. AB - Feed efficiency is an economically important trait in genetic improvement programs of L. vannamei. Residual feed intake (RFI), an ideal measure of feed efficiency, is the difference between observed feed intake and expected feed requirement predicted from maintenance and production. Exploring the molecular basis of RFI is essential to facilitate the genetic breeding of feed efficiency in L. vannamei. However, few studies have been reported in this aspect. In this study, we sequenced muscle transcriptomes of a high -efficiency group, a low efficiency group and a control group originating from two families, and compared the gene expression patterns between each extreme group and the control group. A total of 383 differentially expressed genes were identified, most of which were involved in cell proliferation, growth and signaling, glucose homeostasis, energy and nutrients metabolism. Functional enrichment analysis of these genes revealed 13 significantly enriched biological pathways, including signaling pathways such as PI3K-Akt signaling pathway, AMPK signaling pathway and mTOR signaling pathway, as well as some important pathways such as ubiquitin mediated proteolysis, cell cycle, pentose phosphate pathway and glycolysis/gluconeogenesis. These genes and pathways provide initial insight into the molecular mechanisms driving the feed efficiency in L. vannamei. PMID- 28874700 TI - Contribution of C1485T mutation in the HBx gene to human and murine hepatocarcinogenesis. AB - Although Hepatitis B virus (HBV) X gene mutations are frequently detected in HBV related human hepatocellular carcinoma (HCC) patients, causative HBx mutations in the development of HCC have not yet been determined. We herein identified C1485T and C1653T mutations in the HBx gene as independent risk of HCC for HBV through the analysis using serum from chronic hepatitis B patients. We generated transgenic mice expressing wild-type (WT-HBxTg) and mutant (C1485T-HBxTg) HBx to assess the carcinogenic potential of mutated HBx. C1485T-HBxTg mice were more susceptible to diethylnitrosamine-induced hepatocarcinogenesis than WT-HBxTg mice and control non-Tg mice. The promotion of hepatocarcinogenesis in C1485T-HBxTg mice was accompanied by the activation of beta-catenin and Jun N-terminal kinase (JNK) signaling pathways as well as the production of reactive oxygen species, whereas the activation of nuclear factor-kappa B in the livers of C1485T-HBxTg mice was attenuated. These results demonstrate that the HBx C1485T mutation contributes to human and murine hepatocarcinogenesis. PMID- 28874699 TI - Metal concentrations and distributions in the human olfactory bulb in Parkinson's disease. AB - In Parkinson's disease (PD), the olfactory bulb is typically the first region in the body to accumulate alpha-synuclein aggregates. This pathology is linked to decreased olfactory ability, which becomes apparent before any motor symptoms occur, and may be due to a local metal imbalance. Metal concentrations were investigated in post-mortem olfactory bulbs and tracts from 17 human subjects. Iron (p < 0.05) and sodium (p < 0.01) concentrations were elevated in the PD olfactory bulb. Combining laser ablation inductively coupled plasma mass spectrometry and immunohistochemistry, iron and copper were evident at very low levels in regions of alpha-synuclein aggregation. Zinc was high in these regions, and free zinc was detected in Lewy bodies, mitochondria, and lipofuscin of cells in the anterior olfactory nucleus. Increased iron and sodium in the human PD olfactory bulb may relate to the loss of olfactory function. In contrast, colocalization of free zinc and alpha-synuclein in the anterior olfactory nucleus implicate zinc in PD pathogenesis. PMID- 28874702 TI - Non-random transmission of parental alleles into crop-wild and crop-weed hybrid lineages separated by a transgene and neutral identifiers in rice. AB - It is essential to assess environmental impact of transgene flow from genetically engineered crops to their wild or weedy relatives before commercialization. Measuring comparative trials of fitness in the transgene-flow-resulted hybrids plays the key role in the assessment, where the segregated isogenic hybrid lineages/subpopulations with or without a transgene of the same genomic background are involved. Here, we report substantial genomic differentiation between transgene-present and -absent lineages (F2-F3) divided by a glyphosate resistance transgene from a crop-wild/weed hybrid population in rice. We further confirmed that such differentiation is attributed to increased frequencies of crop-parent alleles in transgenic hybrid lineages at multiple loci across the genome, as estimated by SSR (simple sequence repeat) markers. Such preferential transmission of parental alleles was also found in equally divided crop-wild/weed hybrid lineages with or without a particular neutral SSR identifier. We conclude that selecting either a transgene or neutral marker as an identifier to create hybrid lineages will result in different genomic background of the lineages due to non-random transmission of parental alleles. Non-random allele transmission may misrepresent the outcomes of fitness effects. We therefore propose seeking other means to evaluate fitness effects of transgenes for assessing environmental impact caused by crop-to-wild/weed gene flow. PMID- 28874701 TI - Restless legs syndrome in Parkinson disease: Clinical characteristics, abnormal iron metabolism and altered neurotransmitters. AB - Relationships among clinical characteristics, iron metabolism and neurotransmitters in Parkinson disease (PD) patients with restless legs syndrome (RLS) remains unclear. We divided 218 patients into PD with and with no RLS (PD RLS and PD-NRLS) groups by RLS-rating scale (RLS-RS) score. Motor and non-motor symptoms were rated by related scales. Iron and related proteins, and neurotransmitters in cerebrospinal fluid (CSF) and serum were measured. PD-RLS frequency was 40.37%. PD-RLS group had longer duration, higher stage and scores of motor symptoms, depression, anxiety, sleep disorders, fatigue and apathy, and increased transferrin and decreased iron, ferritin, dopamine (DA) and 5 hydroxytryptamine (5-HT) in CSF. In CSF of PD-RLS group, RLS-RS score was positively correlated with transferrin level and negatively correlated with iron and ferritin levels; RLS-RS score was negatively correlated with DA and 5-HT levels; transferrin level was negatively correlated with DA and 5-HT levels, and ferritin level was positively correlated with DA level. In serum, PD-RLS group had decreased iron and transferrin levels, which were negatively correlated with RLS-RS score. PD-RLS was common and severer in motor and some non-motor symptoms. Iron deficiency induced by its metabolism dysfunctions in peripheral and central systems might cause PD-RLS through decreasing brain DA and 5-HT. PMID- 28874703 TI - Exact broadband excitation of two-level systems by mapping spins to springs. AB - Designing accurate and high-fidelity broadband pulses is an essential component in conducting quantum experiments across fields from protein spectroscopy to quantum optics. However, constructing exact and analytic broadband pulses remains unsolved due to the nonlinearity and complexity of the underlying spin system dynamics. Here, we present a nontrivial dynamic connection between nonlinear spin and linear spring systems and show the surprising result that such nonlinear and complex pulse design problems are equivalent to designing controls to steer linear harmonic oscillators under optimal forcing. We derive analytic broadband pi/2 and pi pulses that perform exact, or asymptotically exact, excitation and inversion over a defined bandwidth, and also with bounded amplitude. This development opens up avenues for pulse sequence design and lays a foundation for understanding the control of two-level systems.Coherent control of two-level systems is crucial for achieving fidelity in spectroscopy and quantum computing, but inherent nonlinearities and parameter variation have, to date, required an approximate, numerical approach. Here, Li et al. show how to map a spin ensemble to a spring model so analytic pulses can be designed using linear methods. PMID- 28874704 TI - NF-kappaB inhibitors, unique gamma-pyranol-gamma-lactams with sulfide and sulfoxide moieties from Hawaiian plant Lycopodiella cernua derived fungus Paraphaeosphaeria neglecta FT462. AB - LC-UV/MS-based metabolomic analysis of the Hawaiian endophytic fungus Paraphaeosphaeria neglecta FT462 led to the identification of four unique mercaptolactated gamma-pyranol-gamma-lactams, paraphaeosphaerides E-H (1-4) together with one gamma-lactone (5) and the methyl ester of compound 2 (11). The structures of the new compounds (1-5 and 11) were elucidated through the analysis of HRMS and NMR spectroscopic data. The absolute configuration was determined by chemical reactions with sodium borohydride, hydrogen peroxide, alpha-methoxy alpha-(trifluoromethyl)phenylacetyl chlorides (Mosher reagents), and DP4 + NMR calculations. All the compounds were tested against STAT3, A2780 and A2780cisR cancer cell lines, E. coli JW2496, and NF-kappaB. Compounds 1 and 3 strongly inhibited NF-kappaB with IC50 values of 7.1 and 1.5 MUM, respectively. PMID- 28874706 TI - Synthesis of Arbitrary Quantum Circuits to Topological Assembly: Systematic, Online and Compact. AB - It is challenging to transform an arbitrary quantum circuit into a form protected by surface code quantum error correcting codes (a variant of topological quantum error correction), especially if the goal is to minimise overhead. One of the issues is the efficient placement of magic state distillation sub circuits, so called distillation boxes, in the space-time volume that abstracts the computation's required resources. This work presents a general, systematic, online method for the synthesis of such circuits. Distillation box placement is controlled by so-called schedulers. The work introduces a greedy scheduler generating compact box placements. The implemented software, whose source code is available at www.github.com/alexandrupaler/tqec, is used to illustrate and discuss synthesis examples. Synthesis and optimisation improvements are proposed. PMID- 28874705 TI - Serum lysophospholipid levels are altered in dyslipidemic hamsters. AB - Dyslipidemias are common disorders that predispose individuals to severe diseases. It is known that healthy living habits can prevent dyslipidemias if they are diagnosed properly. Therefore, biomarkers that assist in diagnosis are essential. The aim of this study was to identify biomarkers of dyslipidemia progression, which in turn disclose its etiology. These findings will pave the way for examinations of the regulatory mechanisms involved in dyslipidemias. Hamsters were fed either a normal-fat diet (NFD) or a high-fat diet. Some of the NFD-fed animals were further treated with the hyperlipidemic agent Poloxamer 407. Non-targeted metabolomics was used to investigate progressive changes in unknown serum metabolites. The hepatic expression of putative biomarker-related genes was also analyzed. The serum levels of lysophospholipids (Lyso-PLs) and their related enzymes lecithin-cholesterol acyltransferase (LCAT), secreted phospholipase A2 (sPLA2) and paraoxonase-1 were altered in dyslipidemic hamsters. Lysophosphatidylcholine levels were increased in diet-induced dyslipidemic groups, whereas lysophosphatidylethanolamine levels increased in response to the chemical treatment. The liver was significantly involved in regulating the levels of these molecules, based on the modified expression of endothelial lipase (Lipg), sPLA2 (Pla2g2a) and acyltransferases (Lcat and Lpcat3). We concluded that Lyso-PL evaluation could aid in the comprehensive diagnosis and management of lipid disorders. PMID- 28874707 TI - Comprehensive transcriptome profiling of Salvia miltiorrhiza for discovery of genes associated with the biosynthesis of tanshinones and phenolic acids. AB - Tanshinones and phenolic acids are crucial bioactive compounds biosynthesized in Salvia miltiorrhiza. Methyl jasmonate (MeJA) is an effective elicitor to enhance the production of phenolic acids and tanshinones simultaneously, while yeast extract (YE) is used as a biotic elicitor that only induce tanshinones accumulation. However, little was known about the different molecular mechanism. To identify the downstream and regulatory genes involved in tanshinone and phenolic acid biosynthesis, we conducted comprehensive transcriptome profiling of S. miltiorrhiza hairy roots treated with either MeJA or YE. Total 55588 unigenes were assembled from about 1.72 billion clean reads, of which 42458 unigenes (76.4%) were successfully annotated. The expression patterns of 19 selected genes in the significantly upregulated unigenes were verified by quantitative real-time PCR. The candidate downstream genes and other cytochrome P450s involved in the late steps of tanshinone and phenolic acid biosynthesis pathways were screened from the RNA-seq dataset based on co-expression pattern analysis with specific biosynthetic genes. Additionally, 375 transcription factors were identified to exhibit a significant up-regulated expression pattern in response to induction. This study can provide us a valuable gene resource for elucidating the molecular mechanism of tanshinones and phenolic acids biosynthesis in hairy roots of S. miltiorrhiza. PMID- 28874708 TI - Origins of Dirac cone formation in AB3 and A3B (A, B = C, Si, and Ge) binary monolayers. AB - Compared to the pure two-dimensional (2D) graphene and silicene, the binary 2D system silagraphenes, consisting of both C and Si atoms, possess more diverse electronic structures depending on their various chemical stoichiometry and arrangement pattern of binary components. By performing calculations with both density functional theory and a Tight-binding model, we elucidated the formation of Dirac cone (DC) band structures in SiC3 and Si3C as well as their analogous binary monolayers including SiGe3, Si3Ge, GeC3, and Ge3C. A "ring coupling" mechanism, referring to the couplings among the six ring atoms, was proposed to explain the origin of DCs in AB3 and A3B binary systems, based on which we discussed the methods tuning the SiC3 systems into self-doped systems. The first principles quantum transport calculations by non-equilibrium Green's function method combined with density functional theory showed that the electron conductance of SiC3 and Si3C lie between those of graphene and silicene, proportional to the carbon concentrations. Understanding the DC formation mechanism and electronic properties sheds light onto the design principles for novel Fermi Dirac systems used in nanoelectronic devices. PMID- 28874709 TI - Differences between the most used equations in BAT-human studies to estimate parameters of skin temperature in young lean men. AB - Cold exposure is necessary to activate human brown adipose tissue (BAT), resulting in heat production. Skin temperature is an indirect measure to monitor the body's reaction to cold. The aim of this research was to study whether the most used equations to estimate parameters of skin temperature in BAT-human studies measure the same values of temperature in young lean men (n = 11: 23.4 +/ 0.5 years, fat mass: 19.9 +/- 1.2%). Skin temperature was measured with 26 ibuttons at 1-minute intervals in warm and cold room conditions. We used 12 equations to estimate parameters of mean, proximal, and distal skin temperature as well as skin temperature gradients. Data were analysed with Temperatus software. Significant differences were found across equations to measure the same parameters of skin temperature in warm and cold room conditions, hampering comparison across studies. Based on these findings, we suggest to use a set of 14 ibuttons at anatomical positions reported by ISO STANDARD 9886:2004 plus five ibuttons placed on the right supraclavicular fossa, right middle clavicular bone, right middle upper forearm, right top of forefinger, and right upper chest. PMID- 28874710 TI - Effects of toxic Microcystis aeruginosa on the silver carp Hypophthalmichtys molitrix revealed by hepatic RNA-seq and miRNA-seq. AB - High-throughput sequencing was applied to analyze the effects of toxic Microcystis aeruginosa on the silver carp Hypophthalmichthys molitrix. Silver carps were exposed to two cyanobacteria species (toxic and non-toxic) for RNA-seq and miRNA-seq analysis. RNA-seq revealed that the liver tissue contained 105,379 unigenes. Of these genes, 143 were significantly differentiated, 82 were markedly up-regulated, and 61 were remarkably down-regulated. GO term enrichment analysis indicated that 35 of the 154 enriched GO terms were significantly enriched. KEGG pathway enrichment analysis demonstrated that 17 of the 118 enriched KEGG pathways were significantly enriched. A considerable number of disease/immune associated GO terms and significantly enriched KEGG pathways were also observed. The sequence length determined by miRNA-seq was mainly distributed in 20-23 bp and composed of 882,620 unique small RNAs, and 53% of these RNAs were annotated to miRNAs. As confirmed, 272 known miRNAs were differentially expressed, 453 novel miRNAs were predicted, 112 miRNAs were well matched with 7,623 target genes, and 203 novel miRNAs were matched with 15,453 target genes. qPCR also indicated that Steap4, Cyp7a1, CABZ01088134.1, and PPP1R3G were significantly differentially expressed and might play major roles in the toxic, detoxifying, and antitoxic mechanisms of microcystin in fish. PMID- 28874711 TI - Hemoglobin diffusion and the dynamics of oxygen capture by red blood cells. AB - Translational diffusion of macromolecules in cell is generally assumed to be anomalous due high macromolecular crowding of the milieu. Red blood cells are a special case of cells filled quasi exclusively (95% of the dry weight of the cell) with an almost spherical protein: hemoglobin. Hemoglobin diffusion has since a long time been recognized as facilitating the rate of oxygen diffusion through a solution. We address in this paper the question on how hemoglobin diffusion in the red blood cells can help the oxygen capture at the cell level and hence to improve oxygen transport. We report a measurement by neutron spin echo spectroscopy of the diffusion of hemoglobin in solutions with increasing protein concentration. We show that hemoglobin diffusion in solution can be described as Brownian motion up to physiological concentration and that hemoglobin diffusion in the red blood cells and in solutions at similar concentration are the same. Finally, using a simple model and the concentration dependence of the diffusion of the protein reported here, we show that hemoglobin concentration observed in human red blood cells ([Formula: see text]330 g.L -1) corresponds to an optimum for oxygen transport for individuals under strong activity. PMID- 28874713 TI - Reconstructing complex network for characterizing the time-varying causality evolution behavior of multivariate time series. AB - In order to explore the characteristics of the evolution behavior of the time varying relationships between multivariate time series, this paper proposes an algorithm to transfer this evolution process to a complex network. We take the causality patterns as nodes and the succeeding sequence relations between patterns as edges. We used four time series as sample data. The results of the analysis reveal some statistical evidences that the causalities between time series is in a dynamic process. It implicates that stationary long-term causalities are not suitable for some special situations. Some short-term causalities that our model recognized can be referenced to the dynamic adjustment of the decisions. The results also show that weighted degree of the nodes obeys power law distribution. This implies that a few types of causality patterns play a major role in the process of the transition and that international crude oil market is statistically significantly not random. The clustering effect appears in the transition process and different clusters have different transition characteristics which provide probability information for predicting the evolution of the causality. The approach presents a potential to analyze multivariate time series and provides important information for investors and decision makers. PMID- 28874712 TI - pGlyco 2.0 enables precision N-glycoproteomics with comprehensive quality control and one-step mass spectrometry for intact glycopeptide identification. AB - The precise and large-scale identification of intact glycopeptides is a critical step in glycoproteomics. Owing to the complexity of glycosylation, the current overall throughput, data quality and accessibility of intact glycopeptide identification lack behind those in routine proteomic analyses. Here, we propose a workflow for the precise high-throughput identification of intact N glycopeptides at the proteome scale using stepped-energy fragmentation and a dedicated search engine. pGlyco 2.0 conducts comprehensive quality control including false discovery rate evaluation at all three levels of matches to glycans, peptides and glycopeptides, improving the current level of accuracy of intact glycopeptide identification. The N-glycoproteome of samples metabolically labeled with 15N/13C were analyzed quantitatively and utilized to validate the glycopeptide identification, which could be used as a novel benchmark pipeline to compare different search engines. Finally, we report a large-scale glycoproteome dataset consisting of 10,009 distinct site-specific N-glycans on 1988 glycosylation sites from 955 glycoproteins in five mouse tissues.Protein glycosylation is a heterogeneous post-translational modification that generates greater proteomic diversity that is difficult to analyze. Here the authors describe pGlyco 2.0, a workflow for the precise one step identification of intact N-glycopeptides at the proteome scale. PMID- 28874714 TI - Responses of CH4 and N2O fluxes to land-use conversion and fertilization in a typical red soil region of southern China. AB - Land-use conversion and fertilization have been widely reported as important management practices affecting CH4 and N2O fluxes; however, few long-term in situ measurements are available after land-use conversion from rice paddies to upland cultivation, especially those including the initial stages after conversion. A 3 year field experiment was conducted in rice paddies and a newly converted citrus orchard to measure CH4 and N2O fluxes in response to land-use conversion and fertilization in a red soil region of southern China. Annual CH4 and N2O emissions averaged 303.9 kg C ha-1 and 3.8 kg N ha-1, respectively, for the rice paddies over three cultivation years. Although annual N2O emissions increased two to threefold after the conversion of rice paddies to citrus orchard, the substantial reduction in CH4 emissions and even shift into a sink for atmospheric CH4 led to significantly lower CO2-eq emissions of CH4 and N2O in the citrus orchard compared to the rice paddies. Moreover, distinct CH4 emissions were observed during the initial stages and sustained for several weeks after conversion. Our results indicated that the conversion of rice paddies to citrus orchards in this region for higher economic benefits may also lead to lower aggregate CH4 and N2O emissions. PMID- 28874715 TI - Molecular spectrum of laterally coupled quantum rings under intense terahertz radiation. AB - We study the influence of intense THz laser radiation and electric field on molecular states of laterally coupled quantum rings. Laser radiation shows the capability to dissociate quantum ring molecule and add 2-fold degeneracy to the molecular states at the fixed value of the overlapping size between rings. It is shown that coupled to decoupled molecular states phase transition points form almost a straight line with a slope equal to two. In addition, the electric field direction dependent energy spectrum shows unexpected oscillations, demonstrating strong coupling between molecular states. Besides, intraband absorption is considered, showing both blue and redshifts in its spectrum. The obtained results can be useful for the controlling of degeneracy of the discrete energy spectrum of nanoscale structures and in the tunneling effects therein. PMID- 28874716 TI - Cell Spheroids with Enhanced Aggressiveness to Mimic Human Liver Cancer In Vitro and In Vivo. AB - We fabricated a spheroid-forming unit (SFU) for efficient and economic production of cell spheroids. We optimized the protocol for generating large and homogenous liver cancer cell spheroids using Huh7 hepatocellular carcinoma (HCC) cells. The large Huh7 spheroids showed apoptotic and proliferative signals in the centre and at the surface, respectively. In particular, hypoxia-induced factor-1 alpha (HIF 1alpha) and ERK signal activation were detected in the cell spheroids. To diminish core necrosis and increase the oncogenic character, we co-cultured spheroids with 2% human umbilical vein endothelial cells (HUVECs). HUVECs promoted proliferation and gene expression of HCC-related genes and cancer stem cell markers in the Huh7 spheroidsby activating cytokine signalling, mimicking gene expression in liver cancer. HUVECs induced angiogenesis and vessel maturation in Huh7 spheroids in vivo by activating epithelial-mesenchymal transition and angiogenic pathways. The large Huh7 cell spheroids containing HUVECs survived at higher concentrations of anti-cancer drugs (doxorubicin and sorafenib) than did monolayer cells. Our large cell spheroid provides a useful in vitro HCC model to enable intuitive observation for anti-cancer drug testing. PMID- 28874717 TI - Correcting for photodestruction in super-resolution optical fluctuation imaging. AB - Super-resolution optical fluctuation imaging overcomes the diffraction limit by analyzing fluctuations in the fluorophore emission. A key assumption of the imaging is that the fluorophores are independent, though this is invalidated in the presence of photodestruction. In this work, we evaluate the effect of photodestruction on SOFI imaging using theoretical considerations and computer simulations. We find that photodestruction gives rise to an additional signal that does not present an easily interpretable view of the sample structure. This additional signal is strong and the resulting images typically exhibit less noise. Accordingly, these images may be mis-interpreted as being more visually pleasing or more informative. To address this uncertainty, we develop a procedure that can robustly estimate to what extent any particular experiment is affected by photodestruction. We also develop a detailed assessment methodology and use it to evaluate the performance of several correction algorithms. We identify two approaches that can correct for the presence of even strong photodestruction, one of which can be implemented directly in the SOFI calculation software. PMID- 28874718 TI - Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride. AB - Plants, lower eukaryotes, bacteria, and archaebacteria synthesise L-histidine (His) in a similar, multistep pathway that is absent in mammals. This makes the His biosynthetic route a promising target for herbicides, antifungal agents, and antibiotics. The last enzyme of the pathway, bifunctional L-histidinol dehydrogenase (HDH, EC 1.1.1.23), catalyses two oxidation reactions: from L histidinol (HOL) to L-histidinaldehyde and from L-histidinaldehyde to His. Over the course of the reaction, HDH utilises two molecules of NAD+ as the hydride acceptor. The object of this study was the HDH enzyme from the model legume plant, Medicago truncatula (MtHDH). Three crystal structures complexed with imidazole, HOL, and His with NAD+ provided in-depth insights into the enzyme architecture, its active site, and the cofactor binding mode. The overall structure of MtHDH is similar to the two bacterial orthologues whose three dimensional structures have been determined. The three snapshots, with the MtHDH enzyme captured in different states, visualise structural rearrangements that allow for NAD+ binding for the first time. Furthermore, the MtHDH complex with His and NAD+ displays the cofactor molecule situated in a way that would allow for a hydride transfer. PMID- 28874720 TI - Black P/graphene hybrid: A fast response humidity sensor with good reversibility and stability. AB - Black phosphorus (BP) materials have attracted considerable attention owing to their ultra-sensitive humidity sensing characteristics because of the natural absorption of water (H2O) molecules on the BP surface caused by the specific 2D layer-crystalline structure. On the other hand, the BP-based humidity sensor is less repeatable due to the instability of BP with water molecules and the stability of the sensor is reduced. In this study, this limitation of the BP based humidity sensor was overcome by preparing a BP/graphene hybrid as a novel humidity sensing nanostructure. The BP/graphene interface improved the stability of the humidity sensor after a few weeks with a linear response within the relative humidity (RH) range of 15-70%. The sensor's response/recovery speed of the humidity sensor was extremely fast within few seconds. The response (S) of the humidity sensor based on the BP/graphene hybrid is 43.4% at RH = 70%. The estimated response and recovery time of the sensor is only 9 and 30 seconds at RH = 70% at room temperature. The experimental investigation reveals that the BP/graphene hybrid not only improves the reversibility and hysteresis factors but also enhances the stability of the humidity sensor. PMID- 28874719 TI - A mutation in the melon Vacuolar Protein Sorting 41prevents systemic infection of Cucumber mosaic virus. AB - In the melon exotic accession PI 161375, the gene cmv1, confers recessive resistance to Cucumber mosaic virus (CMV) strains of subgroup II. cmv1 prevents the systemic infection by restricting the virus to the bundle sheath cells and impeding viral loading to the phloem. Here we report the fine mapping and cloning of cmv1. Screening of an F2 population reduced the cmv1 region to a 132 Kb interval that includes a Vacuolar Protein Sorting 41 gene. CmVPS41 is conserved among plants, animals and yeast and is required for post-Golgi vesicle trafficking towards the vacuole. We have validated CmVPS41 as the gene responsible for the resistance, both by generating CMV susceptible transgenic melon plants, expressing the susceptible allele in the resistant cultivar and by characterizing CmVPS41 TILLING mutants with reduced susceptibility to CMV. Finally, a core collection of 52 melon accessions allowed us to identify a single amino acid substitution (L348R) as the only polymorphism associated with the resistant phenotype. CmVPS41 is the first natural recessive resistance gene found to be involved in viral transport and its cellular function suggests that CMV might use CmVPS41 for its own transport towards the phloem. PMID- 28874721 TI - Aging-related changes in the diversity of women's skin microbiomes associated with oral bacteria. AB - Skin aging is associated with changes in cutaneous physiology including interactions with a skin microbial community. A striking alteration and diversification in the skin microbiome with aging was observed between two different age groups of 37 healthy Japanese women, i.e. younger adults of 21-37 years old and older adults of 60-76 years old, using bacterial 16S rRNA gene sequencing. The analyses revealed that the alpha diversity/species richness was significantly higher in the older than the younger group for the cheek and forehead microbiomes, while the beta diversity in the overall structure significantly differed particularly for the forearm and scalp microbiomes between the two age groups. Taxonomic profiling showed a striking reduction in the relative abundance of the majority skin genus Propionibacterium in the cheek, forearm and forehead microbiomes of the older adults, and identified 38 species including many oral bacteria that significantly differentiated the two age groups with a skin site dependency. Furthermore, we found chronological age-related and unrelated skin clinical parameters that correlate with the observed changes in the skin microbiome diversity. Thus, our data suggested that the diversification of skin microbiomes in adult women was largely affected by chronological and physiological skin aging in association with oral bacteria. PMID- 28874722 TI - Ameliorative effects of melatonin on dark-induced leaf senescence in gardenia (Gardenia jasminoides Ellis): leaf morphology, anatomy, physiology and transcriptome. AB - Cut gardenia (Gardenia jasminoides Ellis) foliage is widely used as a vase material or flower bouquet indoors; however, insufficient indoor light accelerates its senescence, which shortens its viewing time. In this study, applying melatonin to delay gardenia leaf senescence when exposed to extremely low light condition (darkness), and the results showed that 1.0 mM was the effective concentration. At this concentration, chlorophyll contents and chlorophyll fluorescence parameters (Fv/Fm, Fv/F0 and Y(II)) increased, while the carotenoid and flavonoid contents decreased. Meanwhile, stress physiological indices decreased in response to exogenous melatonin application, whereas an increase in glutamine synthetase activity, water and soluble protein contents was observed. Moreover, exogenous melatonin application also reduced leaf programmed cell death under darkness, increased the endogenous melatonin level, expression levels of tryptophan decarboxylase gene, superoxide dismutase and catalase activities and the ascorbate-glutathione cycle, and maintained more intact anatomical structures. Furthermore, transcriptome sequencing revealed that various biological processes responded to exogenous melatonin application, including carbohydrate metabolism, amino acid metabolism, lipid metabolism, plant hormone signal transduction and pigment biosynthesis. Consequently, dark-induced leaf senescence in gardenia was significantly delayed. These results provided a better understanding for improving the ornamental value of cut gardenia foliage using melatonin. PMID- 28874723 TI - Inducing fluorescence of uranyl acetate as a dual-purpose contrast agent for correlative light-electron microscopy with nanometre precision. AB - Correlative light-electron microscopy (CLEM) combines the high spatial resolution of transmission electron microscopy (TEM) with the capability of fluorescence light microscopy (FLM) to locate rare or transient cellular events within a large field of view. CLEM is therefore a powerful technique to study cellular processes. Aligning images derived from both imaging modalities is a prerequisite to correlate the two microscopy data sets, and poor alignment can limit interpretability of the data. Here, we describe how uranyl acetate, a commonly used contrast agent for TEM, can be induced to fluoresce brightly at cryogenic temperatures (-195 degrees C) and imaged by cryoFLM using standard filter sets. This dual-purpose contrast agent can be used as a general tool for CLEM, whereby the equivalent staining allows direct correlation between fluorescence and TEM images. We demonstrate the potential of this approach by performing multi-colour CLEM of cells containing equine arteritis virus proteins tagged with either green or red-fluorescent protein, and achieve high-precision localization of virus induced intracellular membrane modifications. Using uranyl acetate as a dual purpose contrast agent, we achieve an image alignment precision of ~30 nm, twice as accurate as when using fiducial beads, which will be essential for combining TEM with the evolving field of super-resolution light microscopy. PMID- 28874724 TI - Alcohol amplifies ketamine-induced apoptosis in primary cultured cortical neurons and PC12 cells through down-regulating CREB-related signaling pathways. AB - Recreational use of ketamine (KET) has been increasing worldwide. Previous studies have demonstrated that KET induced neurotoxicity; however, few studies have examined how alcohol (ALC) affects KET-induced neurotoxicity. In light of the fact that some KET abusers combine KET with ALC, the present study was aimed to investigate the effects of ALC on KET-induced neurotoxicity and the underlying mechanism in vitro. Our data revealed that co-treatment with ALC and KET was more detrimental to cell viability than KET single treatment in both PC12 cells and primary cultured rat cortical neurons. Furthermore, ALC exacerbated KET-induced apoptosis characterized by morphological changes and the sub-G1 phase increase, which were mitigated by the pretreatment of CNQX, a known alpha-amino-3-hydroxy-5 methyl-4-isoxazole propionate (AMPA)/kainite (KA) receptor antagonist. In addition, ALC and KET co-treatment led to intracellular Ca2+ overload, down regulation of p-Akt, p-CREB, PKA, CaMK-IV, Bcl-2 and BDNF expression and up regulation of cleaved caspase-3 and Bax expression, which can be attenuated by CNQX pretreatment. These results indicate that the potentiation of ALC on KET induced neurotoxicity was related to the down-regulation of CREB-related pathways. Our present study also indicates that ALC and KET co-abuse might cause serious neurotoxicity which should be conveyed to the public and drew enough attention. PMID- 28874725 TI - Manipulating of Different-Polarized Reflected Waves with Graphene-based Plasmonic Metasurfaces in Terahertz Regime. AB - A graphene-based plasmonic metasurface which can independently control different polarized electromagnetic waves with reasonably small losses in terahertz regime is proposed and demonstrated in this paper. This metasurface is composed of graphene based elements. Owing to anisotropic plasmonic resonance of the graphene based elements, the reflected phases and magnitudes of orthogonally polarized waves can be independently controlled by varying dimensions of the element. Four types of graphene-based plasmonic metasurfaces with different reflected phases distributions are synthesized and simulated, exhibiting diverse functions such as polarized beam splitting, beam deflection, and linear-to-circular polarization conversion. The simulation results demonstrate excellent performances as theoretical expectation. The proposed graphene-based plasmonic metasurface can be applied to realize extremely light-weight, ultra-compact, and high-performances electromagnetic structures for diverse terahertz applications. PMID- 28874726 TI - Remarkable plasticity of Na+, K+-ATPase, Ca2+-ATPase and SERCA contributes to muscle disuse atrophy resistance in hibernating Daurian ground squirrels. AB - We investigated cytosolic calcium (Ca2+) and sarcoplasmic reticulum Ca2+ regulation in skeletal muscle fibers of hibernating Daurian ground squirrels (Spermophilus dauricus), non-hibernating hindlimb-unloaded (HLU) squirrels, and HLU rats to clarify the molecular mechanisms involved in preventing muscle atrophy in hibernators. The Na+, K+-ATPase and Ca2+-ATPase activities in the soleus muscle (SOL) of squirrels were maintained in hibernation, decreased during interbout arousal (IB-A), and increased to autumn/pre-hibernation (AUT/Pre-H) levels in torpor after interbout arousal (Post-IBA), whereas activities in the extensor digitorum longus muscle (EDL) were stable during hibernation, but increased during post-hibernation (Post-H). Activities increased in the SOL of HLU rats, but were stable in HLU squirrels. Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) activity in the SOL decreased in IB-A squirrels, but returned to AUT/Pre-H levels in the Post-IBA group; no significant changes were found in the EDL. SERCA activity increased in the EDL of HLU squirrels and SOL of HLU rats. Compared with AUT/Pre-H, SERCA type 2 protein expression increased in the SOL and EDL of IB-A and Post-IBA squirrels, but increased in the SOL only in HLU animals. We also describe the protein kinase A changes in this paper. Thus, hibernating ground squirrels displayed remarkable Na+, K+-ATPase, Ca2+-ATPase, and SERCA plasticity. PMID- 28874727 TI - Effectiveness of Glenohumeral Joint Dilatation for Treatment of Frozen Shoulder: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - The objective was to explore the effectiveness of glenohumeral joint distension for the treatment of frozen shoulder. We searched electronic data sources including PubMed, Scopus, and Embase from the earliest records available to February 2017. Eleven randomized controlled trials including at least one pair of comparisons between capsular distension and a reference treatment were included, comprising 747 participants. Patients' characteristics, details of reference treatments, aspects of capsular distension therapy, and outcome measurement were evaluated at three points in time: baseline, early following intervention, and at the trial's end. The primary and secondary outcomes were the between-group standardized mean differences of changes in shoulder function and range of motion, respectively. Regarding the long-term primary outcome, the superiority of capsular distension to reference treatments was not identified. One secondary outcome (external rotation limitation) showed a probable early positive response to capsular distension when compared to intra-articular corticosteroid injection. Aspects of approaches, imaging guiding techniques and doses of distension were not found to modify treatment effectiveness. In conclusion, distension of the glenohumeral joint provides a similar long-term efficacy to all reference treatments. A single dose of a corticosteroid-contained regimen introduced through the ultrasound-guided posterior approach is a preferable practice of capsular distension for the management of frozen shoulder. PMID- 28874728 TI - Unpredictability of escape trajectory explains predator evasion ability and microhabitat preference of desert rodents. AB - Mechanistically linking movement behaviors and ecology is key to understanding the adaptive evolution of locomotion. Predator evasion, a behavior that enhances fitness, may depend upon short bursts or complex patterns of locomotion. However, such movements are poorly characterized by existing biomechanical metrics. We present methods based on the entropy measure of randomness from Information Theory to quantitatively characterize the unpredictability of non-steady-state locomotion. We then apply the method by examining sympatric rodent species whose escape trajectories differ in dimensionality. Unlike the speed-regulated gait use of cursorial animals to enhance locomotor economy, bipedal jerboa (family Dipodidae) gait transitions likely enhance maneuverability. In field-based observations, jerboa trajectories are significantly less predictable than those of quadrupedal rodents, likely increasing predator evasion ability. Consistent with this hypothesis, jerboas exhibit lower anxiety in open fields than quadrupedal rodents, a behavior that varies inversely with predator evasion ability. Our unpredictability metric expands the scope of quantitative biomechanical studies to include non-steady-state locomotion in a variety of evolutionary and ecologically significant contexts.Biomechanical understanding of animal gait and maneuverability has primarily been limited to species with more predictable, steady-state movement patterns. Here, the authors develop a method to quantify movement predictability, and apply the method to study escape-related movement in several species of desert rodents. PMID- 28874729 TI - Ratiometric Matryoshka biosensors from a nested cassette of green- and orange emitting fluorescent proteins. AB - Sensitivity, dynamic and detection range as well as exclusion of expression and instrumental artifacts are critical for the quantitation of data obtained with fluorescent protein (FP)-based biosensors in vivo. Current biosensors designs are, in general, unable to simultaneously meet all these criteria. Here, we describe a generalizable platform to create dual-FP biosensors with large dynamic ranges by employing a single FP-cassette, named GO-(Green-Orange) Matryoshka. The cassette nests a stable reference FP (large Stokes shift LSSmOrange) within a reporter FP (circularly permuted green FP). GO- Matryoshka yields green and orange fluorescence upon blue excitation. As proof of concept, we converted existing, single-emission biosensors into a series of ratiometric calcium sensors (MatryoshCaMP6s) and ammonium transport activity sensors (AmTryoshka1;3). We additionally identified the internal acid-base equilibrium as a key determinant of the GCaMP dynamic range. Matryoshka technology promises flexibility in the design of a wide spectrum of ratiometric biosensors and expanded in vivo applications.Single fluorescent protein biosensors are susceptible to expression and instrumental artifacts. Here Ast et al. describe a dual fluorescent protein design whereby a reference fluorescent protein is nested within a reporter fluorescent protein to control for such artifacts while preserving sensitivity and dynamic range. PMID- 28874731 TI - Ultrathin Nafion-filled porous membrane for zinc/bromine redox flow batteries. AB - In this work, we present a 16 MUm-thick Nafion-filled porous membrane for Zn/Br redox flow batteries (ZBBs). By using molecular dynamics simulation and dynamic light scattering analysis, we rationally design Nafion solution for Nafion impregnation into a porous polypropylene (PP) separator. A void-free Nafion/PP membrane is successfully fabricated by using NMP as a solvent for the Nafion solution. The resulting membrane shows a smaller area specific resistance in comparison with 600 MUm-thick, commercial SF-600 porous membrane. Due to its dense morphology, Br2 diffusivity of the Nafion/PP membrane is two orders of magnitude lower than that of SF-600, resulting in a comparable Br2 crossover in spite of 37.5 times smaller membrane thickness. As a result, the ZBB based on the Nafion/PP membrane exhibits a higher energy efficiency, demonstrating that ion exchange membrane can outperform the conventional porous membrane by reducing the membrane thickness with inexpensive porous substrate. PMID- 28874730 TI - A comprehensive characterization of the impact of mycophenolic acid on the metabolism of Jurkat T cells. AB - Metabolic reprogramming is critical for T cell fate and polarization and is regulated by metabolic checkpoints, including Myc, HIF-1alpha, AMPK and mTORC1. Our objective was to determine the impact of mycophenolic acid (MPA) in comparison with rapamycin (Rapa), an inhibitor of mTORC1, on the metabolism of Jurkat T cells. We identified a drug-specific transcriptome signature consisting of the key enzymes and transporters involved in glycolysis, glutaminolysis or nucleotide synthesis. MPA produced an early and transient drop in the intracellular ATP content related to the inhibition of de novo synthesis of purines, leading to the activation of the energy sensor AMPK. MPA decreases glycolytic flux, consistent with a reduction in glucose uptake, but also in the oxidation of glutamine. Additionally, both drugs reduce aerobic glycolysis. The expression of HIF-1alpha and Myc, promoting the activation of glycolysis and glutaminolysis, was inhibited by MPA and Rapa. In conclusion, we report that MPA profoundly impacts the cellular metabolism of Jurkat T cells by generating an energetic distress, decreasing the glycolytic and glutaminolytic fluxes and by targeting HIF-1alpha and Myc. These findings open interesting perspectives for novel combinatorial therapeutic strategies targeting metabolic checkpoints to block the proliferation of T cells. PMID- 28874732 TI - Observation of transverse coherent backscattering in disordered photonic structures. AB - Coherent backscattering, also referred to as weak localization, is an exciting multidisciplinary phenomenon that appears in disordered systems of multiple coherent-wave scattering. Providing proper scattering conditions in (2 + 1) dimensional randomized photonic systems, we optically implement, observe, and analyse transverse coherent backscattering. Ensembles of disordered wave-guide structures are prepared by random-intensity nondiffracting writing entities according to the beam's intensity distribution. The structure size of the induced potentials naturally define an effective mobility edge, and thus, we identify a crucial impact of the plane probe waves' spatial frequency on the strength and shape of the spectral coherent backscattering signal. We additionally observe transverse elastic scattering as a precursor of weak localization. To testify the coherent character as a fundamental condition for coherent backscattering, we propose a scheme to continuously reduce the spatial coherence of the probe beam which directly reduces the degree of localization and coherent backscattering. With our experiments, we propose a testing platform that allows comprehensive examination of coherent backscattering with a broad set of preparation parameters and under uncritical laboratory conditions. Our results are directly transferable to more complex systems of disordered wave potentials, not being restricted to photonic systems. PMID- 28874733 TI - Mitochondrial permeability transition pore: sensitivity to opening and mechanistic dependence on substrate availability. AB - Mitochondrial Ca2+ uptake has a key role in cellular Ca2+ homeostasis. Excessive matrix Ca2+ concentrations, especially when coincident with oxidative stress, precipitate opening of an inner mitochondrial membrane, high-conductance channel: the mitochondrial permeability transition pore (mPTP). mPTP opening has been implicated as a final cell death pathway in numerous diseases and therefore understanding conditions dictating mPTP opening is crucial for developing targeted therapies. Here, we have investigated the impact of mitochondrial metabolic state on the probability and consequences of mPTP opening. Isolated mitochondria were energised using NADH- or FADH2-linked substrates. The functional consequences of Ca2+-induced mPTP opening were assessed by Ca2+ retention capacity, using fluorescence-based analysis, and simultaneous measurements of mitochondrial Ca2+ handling, membrane potential, respiratory rate and production of reactive oxygen species (ROS). Succinate-induced, membrane potential-dependent reverse electron transfer sensitised mitochondria to mPTP opening. mPTP-induced depolarisation under succinate subsequently inhibited reverse electron transfer. Complex I-driven respiration was reduced after mPTP opening but sustained in the presence of complex II-linked substrates, consistent with inhibition of complex I-supported respiration by leakage of matrix NADH. Additionally, ROS generated at complex III did not sensitise mitochondria to mPTP opening. Thus, cellular metabolic fluxes and metabolic environment dictate mitochondrial functional response to Ca2+ overload. PMID- 28874734 TI - Observing the oxidation of platinum. AB - Despite its importance in oxidation catalysis, the active phase of Pt remains uncertain, even for the Pt(111) single-crystal surface. Here, using a ReactorSTM, the catalytically relevant structures are identified as two surface oxides, different from bulk alpha-PtO2, previously observed. They are constructed from expanded oxide rows with a lattice constant close to that of alpha-PtO2, either assembling into spoked wheels, 1-5 bar O2, or closely packed in parallel lines, above 2.2 bar. Both are only ordered at elevated temperatures (400-500 K). The triangular oxide can also form on the square lattice of Pt(100). Under NO and CO oxidation conditions, similar features are observed. Furthermore, both oxides are unstable outside the O2 atmosphere, indicating the presence of active O atoms, crucial for oxidation catalysts.Improving platinum as an oxidation catalyst requires understanding its structure under catalytic conditions. Here, the authors discover that catalytically important surface oxides form only when Pt is exposed to high pressure and temperature, highlighting the need to study catalysts in realistic environments. PMID- 28874735 TI - Electronic structure and topological properties of centrosymmetric MoAs2/WAs2 from first principles. AB - We investigate the electronic structure of group VI-B transition metal di arsenides (TAs2, T = Mo, W). By comparing the formation energies, the centrosymmetric di-arsenides compounds are energetically more stable, in contrast to the di-phosphorides (MoP2/WP2). Both compounds can be well described by a two band model with a pair of well-separated electron/hole bands. The electron/hole carrier density is nearly compensated in MoAs2 (|n e - n h |/n h < 1%). The [Formula: see text] classification for all partially occupied bands are topologically strong (1;001), and therefore robust surface states are expected in these materials. Using the adaptive K-mesh method, no energy degenerate state could be found except the spin degeneracy in the whole Brillouin zone, excluding the possibility of intrinsic Dirac or Weyl points near the Fermi level in the system. PMID- 28874736 TI - GENFIRE: A generalized Fourier iterative reconstruction algorithm for high resolution 3D imaging. AB - Tomography has made a radical impact on diverse fields ranging from the study of 3D atomic arrangements in matter to the study of human health in medicine. Despite its very diverse applications, the core of tomography remains the same, that is, a mathematical method must be implemented to reconstruct the 3D structure of an object from a number of 2D projections. Here, we present the mathematical implementation of a tomographic algorithm, termed GENeralized Fourier Iterative REconstruction (GENFIRE), for high-resolution 3D reconstruction from a limited number of 2D projections. GENFIRE first assembles a 3D Fourier grid with oversampling and then iterates between real and reciprocal space to search for a global solution that is concurrently consistent with the measured data and general physical constraints. The algorithm requires minimal human intervention and also incorporates angular refinement to reduce the tilt angle error. We demonstrate that GENFIRE can produce superior results relative to several other popular tomographic reconstruction techniques through numerical simulations and by experimentally reconstructing the 3D structure of a porous material and a frozen-hydrated marine cyanobacterium. Equipped with a graphical user interface, GENFIRE is freely available from our website and is expected to find broad applications across different disciplines. PMID- 28874737 TI - Genome Analysis of Staphylococcus capitis TE8 Reveals Repertoire of Antimicrobial Peptides and Adaptation Strategies for Growth on Human Skin. AB - Staphylococcus capitis TE8 was isolated from skin surface of a healthy human foot, and exhibited a strong antibacterial activity against Gram-positive bacteria, including Staphylococcus aureus. Whole genome sequence of S. capitis TE8 was obtained by shotgun and paired-end pyrosequencing with a coverage of 109 fold. The draft genome contains 2,516,639 bp in 8 scaffolds with 209 total contigs. The genome contains 2319 protein coding sequences, 58 tRNA and 3 rRNA. Genome sequence analysis revealed 4 distinct gene loci with the ability to encode antimicrobial peptides: (i) an epidermicin gene cluster; (ii) a gallidermin gene cluster; (iii) a gene cluster encoding six phenol soluble modulin (PSM) beta-type peptides (PSMbeta1-beta6) and (iv) an additional gene that belonged to PSMbeta family and encoded a 44 residues long peptide, HTP2388. Synthetic peptides with sequence identical to seven PSMbeta-like peptides i.e. PSMbeta1-beta6 and peptide HTP2388 showed antibacterial activity. Genome sequence also revealed genes for adhesins, intracellular adhesins, osmoadaptation, oxidative and acid stress tolerance possibly responsible for initial attachment, colonization and survival of S. capitis TE8 on human skin. Comparative genome analysis revealed presence of a gamut of genes in S. capitis strains in comparison to Staphylococcus epidermidis and Staphylococcus caprae indicating towards their possible role in better adaptation and survival on human skin. PMID- 28874738 TI - Intermittence and connectivity of interactions in pigeon flock flights. AB - Collective circular motion is a common yet spectacular behavior of pigeon flocks. Efficient and robust inter-individual communication is required for flock coordination during this widely-spreaded movement pattern. When a flock hovers near the home loft, the rotational direction undergoes regular spontaneous variations. Based on intensive analyses of high spatial-temporal resolution GPS data, we quantified the intensity of velocity alignment among different individuals in terms of their velocity fluctuations. It is found that pigeon flocks employ an intermittent interaction (alignment) mechanism, where intra group information transmission is not required at every instant. However, the union of the topologies of several consecutive interaction networks always keeps connected. This biological observation strongly suggests the presence of a jointly connected topology in pigeon flocks, which helps substantially reduce the communication and/or information processing requirements while retaining the agility and stability of the group. Finally, we conducted extensive investigation on the interaction mechanism as well as the spontaneous changes in rotational direction of pigeon flocks. These results shed some light onto the coordination mechanism exploration of bird flocks' collective motions. PMID- 28874740 TI - Unusually high ratio of shear modulus to Young's modulus in a nano-structured gyroid metamaterial. AB - Unlike the constant nature of elastic coefficients of isotropic bulk materials, the Young's (E) and shear (MU) moduli of nano-structured (NS) gyroid metamaterials change with relative density (rho), but at different rates depending on the cell size of the structure. These elastic behaviors displayed by E and MU cause crossover/inversion of these two moduli, such that MU of the NS gyroid metamaterials is greater than E for the structures with rho < 0.23. This peculiar elastic behavior causes NS gyroid metamaterials to display high MU/E values (~1.0), which are more than 250% larger than the typical values of the bulk material (~0.38), indicating that the NS gyroid metamaterial, even if it is light, is resistant to shear deformation. Here, we report the results of molecular dynamics simulations performed to elucidate the reason for unusually high MU/E values in NS gyroid metamaterials. PMID- 28874739 TI - Dioxin Receptor Adjusts Liver Regeneration After Acute Toxic Injury and Protects Against Liver Carcinogenesis. AB - The aryl hydrocarbon receptor (AhR) has roles in cell proliferation, differentiation and organ homeostasis, including the liver. AhR depletion induces undifferentiation and pluripotency in normal and transformed cells. Here, AhR null mice (AhR-/-) were used to explore whether AhR controls liver regeneration and carcinogenesis by restricting the expansion of stem-like cells and the expression of pluripotency genes. Short-term CCl4 liver damage was earlier and more efficiently repaired in AhR-/- than in AhR+/+ mice. Stem-like CK14 + and TBX3 + and pluripotency-expressing OCT4 + and NANOG + cells expanded sooner in AhR-/- than in AhR+/+ regenerating livers. Stem-like side population cells (SP) isolated from AhR-/- livers had increased beta-catenin (beta-Cat) signaling with overexpression of Axin2, Dkk1 and Cyclin D1. Interestingly, beta-Cat, Axin2 and Dkk1 also increased during regeneration but more notably in AhR-null livers. Liver carcinogenesis induced by diethylnitrosamine (DEN) produced large carcinomas in all AhR-/- mice but mostly premalignant adenomas in less than half of AhR+/+ mice. AhR-null tumoral tissue, but not their surrounding non-tumoral parenchyma, had nuclear beta-Cat and Axin2 overexpression. OCT4 and NANOG were nevertheless similarly expressed in AhR+/+ and AhR-/- lesions. We suggest that AhR may serve to adjust liver repair and to block tumorigenesis by modulating stem-like cells and beta-Cat signaling. PMID- 28874741 TI - A functional IFN-lambda4-generating DNA polymorphism could protect older asthmatic women from aeroallergen sensitization and associate with clinical features of asthma. AB - Lambda interferons (IFNLs) have immunomodulatory functions at epithelial barrier surfaces. IFN-lambda4, a recent member of this family is expressed only in a subset of the population due to a frameshift-causing DNA polymorphism rs368234815. We examined the association of this polymorphism with atopy (aeroallergen sensitization) and asthma in a Polish hospital-based case-control cohort comprising of well-characterized adult asthmatics (n = 326) and healthy controls (n = 111). In the combined cohort, we saw no association of the polymorphism with asthma and/or atopy. However, the IFN-lambda4-generating DeltaG allele protected older asthmatic women (>50 yr of age) from atopic sensitization. Further, DeltaG allele significantly associated with features of less-severe asthma including bronchodilator response and corticosteroid usage in older women in this Polish cohort. We tested the association of related IFNL locus polymorphisms (rs12979860 and rs8099917) with atopy, allergic rhinitis and presence/absence of asthma in three population-based cohorts from Europe, but saw no significant association of the polymorphisms with any of the phenotypes in older women. The polymorphisms associated marginally with lower occurrence of asthma in men/older men after meta-analysis of data from all cohorts. Functional and well-designed replication studies may reveal the true positive nature of these results. PMID- 28874742 TI - Global-local processing relates to spatial and verbal processing: implications for sex differences in cognition. AB - Sex differences have been reported for a variety of cognitive tasks and related to the use of different cognitive processing styles in men and women. It was recently argued that these processing styles share some characteristics across tasks, i.e. male approaches are oriented towards holistic stimulus aspects and female approaches are oriented towards stimulus details. In that respect, sex dependent cognitive processing styles share similarities with attentional global local processing. A direct relationship between cognitive processing and global local processing has however not been previously established. In the present study, 49 men and 44 women completed a Navon paradigm and a Kimchi Palmer task as well as a navigation task and a verbal fluency task with the goal to relate the global advantage (GA) effect as a measure of global processing to holistic processing styles in both tasks. Indeed participants with larger GA effects displayed more holistic processing during spatial navigation and phonemic fluency. However, the relationship to cognitive processing styles was modulated by the specific condition of the Navon paradigm, as well as the sex of participants. Thus, different types of global-local processing play different roles for cognitive processing in men and women. PMID- 28874743 TI - Automated analysis of liver fat, muscle and adipose tissue distribution from CT suitable for large-scale studies. AB - Computed Tomography (CT) allows detailed studies of body composition and its association with metabolic and cardiovascular disease. The purpose of this work was to develop and validate automated and manual image processing techniques for detailed and efficient analysis of body composition from CT data. The study comprised 107 subjects examined in the Swedish CArdioPulmonary BioImage Study (SCAPIS) using a 3-slice CT protocol covering liver, abdomen, and thighs. Algorithms were developed for automated assessment of liver attenuation, visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue, thigh muscles, subcutaneous, subfascial (SFAT) and intermuscular adipose tissue. These were validated using manual reference measurements. SFAT was studied in selected subjects were the fascia lata could be visually identified (approx. 5%). In addition, precision of manual measurements of intra- (IPAT) and retroperitoneal adipose tissue (RPAT) and deep- and superficial SAT was evaluated using repeated measurements. Automated measurements correlated strongly to manual reference measurements. The SFAT depot showed the weakest correlation (r = 0.744). Automated VAT and SAT measurements were slightly, but significantly overestimated (<=4.6%, p <= 0.001). Manual segmentation of abdominal sub-depots showed high repeatability (CV <= 8.1%, r >= 0.930). We conclude that the low dose CT-scanning and automated analysis makes the setup suitable for large-scale studies. PMID- 28874744 TI - Digital holographic high-speed 3D imaging for the vibrometry of fast-occurring phenomena. AB - Digital holography allows production of high-speed three-dimensional images at rates over 100,000 frames per second; however, simultaneously obtaining suitable performance and levels of accuracy using digital holography is difficult. This problem prevents high-speed three-dimensional imaging from being used for vibrometry. In this paper, we propose and test a digital holography method that can produce vibration measurements. The method is based on single-shot phase shifting interferometry. Herein, we imaged the surface of a loudspeaker diaphragm and measured its displacement due to the vibrations produced by a frequency sweep signal. We then analyzed the frequency of the experimental data and confirmed that the frequency spectra inferred from the reconstructed images agreed well with the spectra produced by the sound recorded by a microphone. This method can be used for measuring vibrations with three-dimensional imaging for loudspeakers, microelectromechanical systems, surface acoustic wave filters, and biological tissues and organs. PMID- 28874745 TI - Characterization and Metabolic Diversity of Flavonoids in Citrus Species. AB - Flavonoids are widely distributed in plants and play important roles in many biological processes. Citrus fruits are rich dietary sources of flavonoids. However, there have been very few reports about the comprehensive metabolic profile and natural diversity of flavonoids in different tissues of various Citrus cultivars. In this study, based on the 7416 metabolic signals detected with non-targeted metabolomics approach, Principal Component Analysis revealed the flavedo has the largest differences from other tissues in metabolite levels; as many as 198 flavonoid signals were then detected in 62 Citrus germplasms from 5 species mainly cultivated worldwide, while 117 flavonoids were identified, including 39 polymethoxylated flavonoids (PMFs), 7 flavones, 10 C-O glycosylflavonoids, 44 O-glycosylflavonoids, 10 C-glycosylflavonoids and 7 newly annotated O-glycosylpolymethoxylated flavonoids. Tissue-specific accumulations were observed: O-glycosylated flavonoids were abundant in all fruit tissues, while PMFs were accumulated preferentially in the flavedo. Among different species, mandarins had the highest levels of PMFs and O-glycosylpolymethoxylated flavonoids, followed by sweet oranges. Based on the flavonoid profiles, 62 germplasms could be clearly grouped into five distinct clusters via hierarchical clustering analysis, which were perfectly matched with their species, with sweet oranges and mandarins clustering closely and being further away from other three species. PMID- 28874746 TI - RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury. AB - Traumatic spinal cord injury (SCI) causes a cascade of degenerative events including cell death, axonal damage, and the upregulation of inhibitory molecules which prevent regeneration and limit recovery. Repulsive guidance molecule A (RGMa) is a potent neurite growth inhibitor in the central nervous system, exerting its repulsive activity by binding the Neogenin receptor. Here, we show for the first time that inhibitory RGMa is markedly upregulated in multiple cell types after clinically relevant impact-compression SCI in rats, and importantly, also in the injured human spinal cord. To neutralize inhibitory RGMa, clinically relevant human monoclonal antibodies were systemically administered after acute SCI, and were detected in serum, cerebrospinal fluid, and in the injured tissue. Rats treated with RGMa blocking antibodies showed significantly improved recovery of motor function and gait. Furthermore, RGMa blocking antibodies promoted neuronal survival, and enhanced the plasticity of descending serotonergic pathways and corticospinal tract axonal regeneration. RGMa antibody also attenuated neuropathic pain responses, which was associated with fewer activated microglia and reduced CGRP expression in the dorsal horn caudal to the lesion. These results show the therapeutic potential of the first human RGMa antibody for SCI and uncovers a new role for the RGMa/Neogenin pathway on neuropathic pain. PMID- 28874747 TI - Transcriptome analysis of inflammation-related gene expression in endothelial cells activated by complement MASP-1. AB - Mannan-binding lectin-associated serine protease 1 (MASP-1), the most abundant enzyme of the complement lectin pathway, is able to stimulate human umbilical vein endothelial cells (HUVECs) to alter the expression of several cytokines and adhesion molecules. This study has assessed to what extent MASP-1 is able to modify the transcriptional pattern of inflammation-related (IR) genes in HUVECs. We utilized Agilent microarray to analyse the effects of recombinant MASP-1 (rMASP-1) in HUVECs, on a set of 884 IR genes. Gene Set Enrichment Analysis showed an overall activation of inflammation-related genes in response to rMASP 1. rMASP-1 treatment up- and down-regulated 19 and 11 IR genes, respectively. Most of them were previously unidentified, such as genes of chemokines (CXCL1, CXCL2, CXCL3), inflammatory receptors (TLR2, BDKRB2) and other inflammatory factors (F3, LBP). Expression of IR genes changed early, during the first 2 hours of activation. Both p38-MAPK inhibitor and NFkappaB inhibitor efficiently suppressed the effect of rMASP-1. We delineated 12 transcriptional factors as possible regulators of rMASP-1-induced IR genes. Our microarray-based data are in line with the hypothesis that complement lectin pathway activation, generating active MASP-1, directly regulates inflammatory processes by shifting the phenotype of endothelial cells towards a more pro-inflammatory type. PMID- 28874748 TI - Erosion potential of the Yangtze Delta under sediment starvation and climate change. AB - Deltas are widely threatened by sediment starvation and climate change. Erosion potential is an important indicator of delta vulnerability. Here, we investigate the erosion potential of the Yangtze Delta. We found that over the past half century the Yangtze's sediment discharge has decreased by 80% due to the construction of >50,000 dams and soil conservation, whereas the wind speed and wave height in the delta region have increased by 5-7%, and the sea level has risen at a rate of 3 mm/yr. According to hydrodynamic measurements and analyses of seabed sediments, the period when bed shear stress due to combined current wave action under normal weather conditions exceeds the critical bed shear stress for erosion (tau cr ) accounts for 63% of the total observed period on average and can reach 100% during peak storms. This explains why net erosion has occurred in some areas of the subaqueous delta. We also found that the increase with depth of tau cr is very gradual in the uppermost several metres of the depositional sequence. We therefore expect that the Yangtze subaqueous delta will experience continuous erosion under sediment starvation and climate change in the next decades of this century or even a few centuries. PMID- 28874749 TI - Structural and pharmacological basis for the induction of mitochondrial biogenesis by formoterol but not clenbuterol. AB - Mitochondrial dysfunction is associated with numerous acute and chronic degenerative diseases. The beta-2 adrenergic receptor (beta2AR) agonist formoterol induces mitochondrial biogenesis (MB), but other beta2AR agonists, such as clenbuterol, do not. We sought to identify the MB signaling pathway of formoterol and the differences in signaling between these two ligands that result in the differential induction of MB. While formoterol and clenbuterol increased cAMP, only formoterol increased the phosphorylation of Akt and its downstream target eNOS. The increase in Akt phosphorylation was Gbetagamma- and PI3K dependent, and the increase in eNOS phosphorylation was Gbetagamma- and Akt dependent. Only formoterol increased cGMP. Formoterol induced MB as measured by increases in uncoupled cellular respiration and PGC-1alpha and NDUFS1 mRNA expression and was blocked by inhibitors of Gbetagamma, Akt, NOS, and soluble guanylate cyclase. To identify distinct receptor-ligand interactions leading to these differences in signaling, we docked formoterol and clenbuterol to six structures of the beta2AR. Compared to clenbuterol, the methoxyphenyl group of formoterol interacted more frequently with V114 and F193, while its formamide group interacted more frequently with C191. These data indicate that the unique structural features of formoterol allow it to interact with the beta2AR to activate the Gbetagamma-Akt-eNOS-sGC pathway to induce MB. PMID- 28874750 TI - Amixicile, a novel strategy for targeting oral anaerobic pathogens. AB - The oral microflora is composed of both health-promoting as well as disease initiating bacteria. Many of the disease-initiating bacteria are anaerobic and include organisms such as Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, and Tannerella forsythia. Here we investigated a novel therapeutic, amixicile, that targets pyruvate:ferredoxin oxidoreductase (PFOR), a major metabolic enzyme involved in energy generation through oxidative decarboxylation of pyruvate. PFOR is present in these anaerobic pathogenic bacteria and thus we hypothesized that amixicile would effectively inhibit their growth. In general, PFOR is present in all obligate anaerobic bacteria, while oral commensal aerobes, including aerotolerant ones, such as Streptococcus gordonii, use pyruvate dehydrogenase to decarboxylate pyruvate. Accordingly, we observed that growth of the PFOR-containing anaerobic periodontal pathogens, grown in both monospecies as well as multispecies broth cultures was inhibited in a dose-dependent manner while that of S. gordonii was unaffected. Furthermore, we also show that amixicile is effective against these pathogens grown as monospecies and multispecies biofilms. Finally, amixicile is the first selective therapeutic agent active against bacteria internalized by host cells. Together, the results show that amixicile is an effective inhibitor of oral anaerobic bacteria and as such, is a good candidate for treatment of periodontal diseases. PMID- 28874751 TI - Disease mutations reveal residues critical to the interaction of P4-ATPases with lipid substrates. AB - Phospholipid flippases (P4-ATPases) translocate specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. While there is good evidence that the overall molecular structure of flippases is similar to that of P-type ATPase ion-pumps, the transport pathway for the "giant" lipid substrate has not been determined. ATP8A2 is a flippase with selectivity toward phosphatidylserine (PS), possessing a net negatively charged head group, whereas ATP8B1 exhibits selectivity toward the electrically neutral phosphatidylcholine (PC). Setting out to elucidate the functional consequences of flippase disease mutations, we have identified residues of ATP8A2 that are critical to the interaction with the lipid substrate during the translocation process. Among the residues pinpointed are I91 and L308, which are positioned near proposed translocation routes through the protein. In addition we pinpoint two juxtaposed oppositely charged residues, E897 and R898, in the exoplasmic loop between transmembrane helices 5 and 6. The glutamate is conserved between PS and PC flippases, whereas the arginine is replaced by a negatively charged aspartate in ATP8B1. Our mutational analysis suggests that the glutamate repels the PS head group, whereas the arginine minimizes this repulsion in ATP8A2, thereby contributing to control the entry of the phospholipid substrate into the translocation pathway. PMID- 28874752 TI - Investigation of possible phase transition of the frustrated spin-1/2 J 1-J 2-J 3 model on the square lattice. AB - The frustrated spin-1/2 J 1-J 2-J 3 antiferromagnet with exchange anisotropy on the two-dimensional square lattice is investigated. The exchange anisotropy is presented by eta with 0 <= eta < 1. The effects of the J 1, J 2, J 3 and anisotropy on the possible phase transition of the Neel state and collinear state are studied comprehensively. Our results indicate that for J 3 > 0 there are upper limits [Formula: see text] and eta c values. When 0 < J 3 <= [Formula: see text] and 0 <= eta <= eta c , the Neel and collinear states have the same order disorder transition point at J 2 = J 1/2. Nevertheless, when the J 3 and eta values beyond the upper limits, it is a paramagnetic phase at J 2 = J 1/2. For J 3 < 0, in the case of 0 <= eta < 1, the two states always have the same critical temperature as long as J 2 = J 1/2. Therefore, for J 2 = J 1/2, under such parameters, a first-order phase transition between the two states for these two cases below the critical temperatures may occur. When J 2 ? J 1/2, the Neel and collinear states may also exist, while they have different critical temperatures. When J 2 > J 1/2, a first-order phase transition between the two states may also occur. However, for J 2 < J 1/2, the Neel state is always more stable than the collinear state. PMID- 28874753 TI - Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer. AB - Efforts to identify driver mutations in cancer have largely focused on genes, whereas non-coding sequences remain relatively unexplored. Here we develop a statistical method based on characteristics known to influence local mutation rate and a series of enrichment filters in order to identify distal regulatory elements harboring putative driver mutations in breast cancer. We identify ten DNase I hypersensitive sites that are significantly mutated in breast cancers and associated with the aberrant expression of neighboring genes. A pan-cancer analysis shows that three of these elements are significantly mutated across multiple cancer types and have mutation densities similar to protein-coding driver genes. Functional characterization of the most highly mutated DNase I hypersensitive sites in breast cancer (using in silico and experimental approaches) confirms that they are regulatory elements and affect the expression of cancer genes. Our study suggests that mutations of regulatory elements in tumors likely play an important role in cancer development.Cancer driver mutations can occur within noncoding genomic sequences. Here, the authors develop a statistical approach to identify candidate noncoding driver mutations in DNase I hypersensitive sites in breast cancer and experimentally demonstrate they are regulatory elements of known cancer genes. PMID- 28874754 TI - ROS-induced Oxidative Injury involved in Pathogenesis of Fungal Keratitis via p38 MAPK Activation. AB - This study was to explore the mechanism by which reactive oxygen species (ROS) induced oxidative stress involved in the pathogenesis of fungal keratitis using an in vivo experimental keratitis mouse model and an in vitro culture model of human corneal epithelial cells (HCECs). Compared to normal control mice and HCECs, ROS production was markedly increased in fungal corneas and HCECs exposed to Candida albicans, accompanied by p38 mitogen-activated protein kinases (MAPK) activation. Increased products of oxidative markers, malondialdehyde (MDA), 4 hydroxynonenal (HNE), mitochondria DNA 8-OHdG and aconitase-2 were observed in fungal infected corneas and HCECs. Fungal infection also increased the mRNA expression and protein production of heme oxygenase-1 (HMOX1) and cyclooxygenase 2 (COX2), with suppressed levels of antioxidant enzymes, superoxide dismutase-1 (SOD1), glutathione peroxidase-1 (GPx1) and peroxiredoxin-4 (PRDX4). Interestingly, the levels of ROS, oxidative markers and oxygenases were significantly reduced by co-cultured p38 inhibitor SB203580. Furthermore, SB203580 restored the levels of antioxidant enzymes suppressed by fungus. Our findings demonstrated for the first time that ROS-induced oxidative injury is involved in pathogenesis of fungal keratitis via p38 MAPK pathway, suggesting the novel therapeutic targets for the potential treatment of fungal keratitis. PMID- 28874755 TI - SPI-2/CrmA inhibits IFN-beta induction by targeting TBK1/IKKepsilon. AB - Viruses modulate the host immune system to evade host antiviral responses. The poxvirus proteins serine proteinase inhibitor 2 (SPI-2) and cytokine response modifier A (CrmA) are involved in multiple poxvirus evasion strategies. SPI-2 and CrmA target caspase-1 to prevent apoptosis and cytokine activation. Here, we identified SPI-2 and CrmA as negative regulators of virus-triggered induction of IFN-beta. Ectopic expression of SPI-2 or CrmA inhibited virus-triggered induction of IFN-beta and its downstream genes. Consistently, knockdown of SPI-2 by RNAi potentiated VACV-induced transcription of antiviral genes. Further studies revealed that SPI-2 and CrmA associated with TBK1 and IKKepsilon to disrupt the MITA-TBK1/IKKepsilon-IRF3 complex. These findings reveal a novel mechanism of SPI 2/CrmA-mediated poxvirus immune evasion. PMID- 28874756 TI - FOXO1 deletion in keratinocytes improves diabetic wound healing through MMP9 regulation. AB - Keratinocyte migration is a key aspect of re-epithelialization during wound healing. Matrix metalloproteinase 9 (MMP9) contributes to this process and deficiencies in the MMP9 lead to impaired healing. Inappropriate expression of MMP9 also contributes to impaired re-epithelialization. Previously we demonstrated that FOXO1 was activated in wound healing but to higher levels in diabetic wounds. To address mechanisms of impaired re-epithelialization we examined MMP9 expression in vivo in full thickness dermal scalp wounds created in experimental K14.Cre + .Foxo1 L/L mice with lineage-specific Cre recombinase deletion of floxed FOXO1 and compared the results to control littermates. MMP9 was induced during wound healing but at a significantly higher level in diabetic compared to normal wounds. FOXO1 deletion substantially blocked this increase. By chromatin immunoprecipitation FOXO1 was shown to bind to the MMP9 promoter, FOXO1 overexpression increased MMP9 transcriptional activity and increased MMP9 expression stimulated by high glucose was blocked by FOXO1 deletion or FOXO1 knockdown. We also show for the first time that high glucose impairs keratinocyte migration by inducing high levels of MMP9 expression and establish that it involves FOXO1. Thus, FOXO1 drives high levels of MMP9 expression in diabetic wound healing, which represents a novel mechanism for impaired re-epithelization in diabetic wounds. PMID- 28874757 TI - Computational approaches for investigating interfacial adhesion phenomena of polyimide on silica glass. AB - This manuscript provides a comprehensive study of adhesion behavior and its governing mechanisms when polyimide undergoes various modes of detachment from silica glass. Within the framework of steered molecular dynamics, we develop three different adhesion measurement techniques: pulling, peeling, and sliding. Such computational methodologies can be applied to investigate heterogeneous materials with differing interfacial adhesion modes. Here, a novel hybrid potential involving a combination of the INTERFACE force field in conjunction with ReaxFF and including Coulombic and Lennard-Jones interactions is employed to study such interfaces. The studies indicate that the pulling test requires the largest force and the shortest distance to detachment as the interfacial area is separated instantaneously, while the peeling test is observed to exhibit the largest distance for detachment because it separates via line-by-line adhesion. Two kinds of polyimides, aromatic and aliphatic type, are considered to demonstrate the rigidity dependent adhesion properties. The aromatic polyimide, which is more rigid due to the stronger charge transfer complex between chains, requires a greater force but a smaller distance at detachment than the aliphatic polyimide for all of the three methodologies. PMID- 28874758 TI - Sex-Specific Routes To Immune Senescence In Drosophila melanogaster. AB - Animal immune systems change dramatically during the ageing process, often accompanied by major increases in pathogen susceptibility. However, the extent to which senescent elevations in infection mortality are causally driven by deteriorations in canonical systemic immune processes is unclear. We studied Drosophila melanogaster and compared the relative contributions of impaired systemic immune defences and deteriorating barrier defences to increased pathogen susceptibility in aged flies. To assess senescent changes in systemic immune response efficacy we injected one and four-week old flies with the entomopathogenic fungus Beauveria bassiana and studied subsequent mortality; whereas to include the role of barrier defences we infected flies by dusting the cuticle with fungal spores. We show that the processes underlying pathogen defence senescence differ between males and females. Both sexes became more susceptible to infection as they aged. However, we conclude that for males, this was principally due to deterioration in barrier defences, whereas for females systemic immune defence senescence was mainly responsible. We discuss the potential roles of sex-specific selection on the immune system and behavioural variation between males and females in driving these different senescent trends. PMID- 28874759 TI - Prior Exposure to Zika Virus Significantly Enhances Peak Dengue-2 Viremia in Rhesus Macaques. AB - Structural and functional homologies between the Zika and Dengue viruses' envelope proteins raise the possibility that cross-reactive antibodies induced following Zika virus infection might enhance subsequent Dengue infection. Using the rhesus macaque model we show that prior infection with Zika virus leads to a significant enhancement of Dengue-2 viremia that is accompanied by neutropenia, lympocytosis, hyperglycemia, and higher reticulocyte counts, along with the activation of pro-inflammatory monocyte subsets and release of inflammatory mediators. Zika virus infection induced detectable Dengue cross-reactive serum IgG responses that significantly amplified after Dengue-2 virus infection. Serum from Zika virus immune animals collected prior to Dengue-2 infection showed significant capacity for in vitro antibody dependent enhancement of Dengue-1, 2, 3 and 4 serotypes suggesting that pre-existing immunity to Zika virus could potentially enhance infection by heterologous Dengue serotypes. Our results provide first in vivo evidence that prior exposure to Zika virus infection can enhance Dengue infection, which has implications for understanding pathogenesis and the development of vaccines. PMID- 28874761 TI - Quantitative assessment of aeolian desertification dynamics- A case study in north Shanxi of China (1975 to 2015). AB - Aeolian desertification is one of the serious environmental issues in North Shanxi Province. Accurately assessing aeolian desertification dynamics and its causes is essential to formulate an effective strategy for combating aeolian desertification. Here, we adopted remote sensing (RS) images from four periods (1975, 1990, 2000, and 2015) to classify the intensity of aeolian desertified land (ADL). Four intensity grades (i.e., light, moderate, severe, and extremely severe) were categorized based on a series of indices. Then, the RS images were further interpreted coupled with the local climate and socio-economic data to evaluate ADL and its driving force. Results showed that there were 3941.16, 5389.92, 7526.38, and 3752.74 km2 of ADL in the above 4 periods, accounting for 28.56%, 39.06%, 54.53%, and 27.19% of the total study area, respectively. ADL experienced three major development stages: slower expansion during 1975-1990 at a rate of 96.58 km2/year, rapid expansion during 1990-2000 of 213.65 km2/year, and a reversion during 2000-2015 with a net decrease of 251.58 km2/year. The ADL development in north Shanxi was a result of mutual interaction between natural factors and human activities. It is also noted that the human activities were identified as the dominant driving force. PMID- 28874760 TI - Zinc depletion promotes apoptosis-like death in drug-sensitive and antimony resistance Leishmania donovani. AB - Micronutrients are essential for survival and growth for all the organisms including pathogens. In this manuscript, we report that zinc (Zn) chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethylenediamine (TPEN) affects growth and viability of intracellular pathogen Leishmania donovani (LD) by a concentration and time dependent manner. Simultaneous addition of zinc salt reverses the effect of TPEN. Further experiments provide evidence of apoptosis like death of the parasite due to Zn-depletion. TPEN treatment enhances caspase like activity suggesting increase in apoptosis-like events in LD. Specific inhibitors of cathepsin B and Endoclease G block TPEN-induced leishmanial death. Evidences show involvement of reactive oxygen species (ROS) potentially of extra mitochondrial origin in TPEN-induced LD death. Pentavalent antimonials remained the prime source of treatment against leishmaniasis for several decades; however, antimony-resistant Leishmania is now common source of the disease. We also reveal that Zn-depletion can promote apoptosis-like death in antimony-resistant parasites. In summary, we present a new finding about the role of zinc in the survival of drug sensitive and antimony-resistant LD. PMID- 28874762 TI - Cytocompatible Anti-microbial Dressings of Syzygium cumini Cellulose Nanocrystals Decorated with Silver Nanoparticles Accelerate Acute and Diabetic Wound Healing. AB - The ever increasing incidences of non-healing skin wounds have paved way for many efforts on the convoluted process of wound healing. Unfortunately, the lack of relevance and success of modern wound dressings in healing of acute and diabetic wounds still remains a matter of huge concern. Here, an in situ three step approach was embraced for the development of nanocomposite (NCs) dressings by impregnating silver nanoparticles (AgNPs) onto a matrix of cellulose nanocrystals (CNCs) isolated from Syzygium cumini leaves using an environmental friendly approach. Topical application of NCs (ointments and strips) on acute and diabetic wounds of mice documented enhanced tissue repair (~99% wound closure) via decrease in inflammation; increase in angiogenesis, collagen deposition, and rate of neo-epithelialization that ultimately led to formation of aesthetically sound skin in lesser time than controls. Due to the synergistic action of CNCs (having high water uptake capacity) and AgNPs (anti-microbial agents), NCs tend to increase the expression of essential growth factors (FGF, PDGF and VEGF) and collagen while decreasing the pro-inflammatory factors (IL-6 and TNF-alpha) at the same time, thus accelerating healing. The results suggested the potential of these developed anti-microbial, cytocompatible and nanoporous NCs having optimized AgNPs concentration as ideal dressings for effective wound management. PMID- 28874763 TI - Brain grey matter volume alterations associated with antidepressant response in major depressive disorder. AB - Not all patients with major depressive disorder respond to adequate pharmacological therapy. Psychoradiological studies have reported that antidepressant responders and nonresponders show different alterations in brain grey matter, but the findings are inconsistent. The present study reports a meta analysis of voxel-based morphometric studies of patients with major depressive disorder, both antidepressant responders and nonresponders, using the anisotropic effect size version of Seed-based D Mapping to identify brain regions correlated to clinical response. A systematic search was conducted up to June 2016 to identify studies focussing on antidepressant response. In responders across 9 datasets grey matter volume (GMV) was significantly higher in the left inferior frontal gyrus and insula, while GMV was significantly lower in the bilateral anterior cingulate cortex (ACC) and the right superior frontal gyrus (SFG). In nonresponders across 5 datasets GMV was significantly lower in the bilateral ACC, median cingulate cortex (MCC) and right SFG. Conjunction analysis confirmed significant differences in the bilateral ACC and right SFG, where GMV was significantly lower in nonresponders but higher in responders. The current study adds to psychoradiology, an evolving subspecialty of radiology mainly for psychiatry and clinical psychology. PMID- 28874764 TI - Natural (?9-THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB1 receptor. AB - Natural cannabinoids and their synthetic substitutes are the most widely used recreational drugs. Numerous clinical cases describe acute toxic symptoms and neurological consequences following inhalation of the mixture of synthetic cannabinoids known as "Spice." Here we report that an intraperitoneal administration of the natural cannabinoid Delta9-tetrahydrocannabinol (10 mg/kg), one of the main constituent of marijuana, or the synthetic cannabinoid JWH-018 (2.5 mg/kg) triggered electrographic seizures in mice, recorded by electroencephalography and videography. Administration of JWH-018 (1.5, 2.5 and 5 mg/kg) increased seizure spikes dose-dependently. Pretreatment of mice with AM 251 (5 mg/kg), a cannabinoid receptor 1-selective antagonist, completely prevented cannabinoid-induced seizures. These data imply that abuse of cannabinoids can be dangerous and represents an emerging public health threat. Additionally, our data strongly suggest that AM-251 could be used as a crucial prophylactic therapy for cannabinoid-induced seizures or similar life-threatening conditions. PMID- 28874765 TI - Identification of neuromedin U precursor-related peptide and its possible role in the regulation of prolactin release. AB - The discovery of neuropeptides provides insights into the regulation of physiological processes. The precursor for the neuropeptide neuromedin U contains multiple consensus sequences for proteolytic processing, suggesting that this precursor might generate additional peptides. We performed immunoaffinity chromatography of rat brain extracts and consequently identified such a product, which we designated neuromedin U precursor-related peptide (NURP). In rat brain, NURP was present as two mature peptides of 33 and 36 residues. Radioimmunoassays revealed NURP immunoreactivity in the pituitary, small intestine, and brain of rats, with the most intense reactivity in the pituitary. Intracerebroventricular administration of NURP to both male and female rats robustly increased plasma concentrations of prolactin but not of other anterior pituitary hormones. In contrast, NURP failed to stimulate prolactin release from dispersed anterior pituitary cells. Pretreatment of rats with bromocriptine, a dopamine receptor agonist, blocked the prolactin-releasing activity of NURP. In rats pretreated with the antagonist sulpiride, intracerebroventricular administration of NURP did not increase plasma prolactin concentrations more than administration of saline. These data suggest that NURP induces prolactin release by acting indirectly on the pituitary; dopamine from the hypothalamus, which inhibits prolactin release, may be involved in this activity of NURP. PMID- 28874766 TI - Magnetic Control of Magneto-Electrochemical Cell and Electric Double Layer Transistor. AB - A magneto-electrochemical cell and an electric double layer transistor (EDLT), each containing diluted [Bmim]FeCl4 solution, have been controlled by applying a magnetic field in contrast to the control of conventional field effect devices by an applied electric field. A magnetic field of several hundred mT generated by a small neodymium magnet is sufficient to operate magneto-electrochemical cells, which generate an electromotive force of 130 mV at maximum. An EDLT composed of hydrogen-terminated diamond was also operated by applying a magnetic field. Although it showed reversible drain current modulation with a magnetoresistance effect of 503%, it is not yet advantageous for practical application. Magnetic control has unique and interesting characteristics that are advantageous for remote control of electrochemical behavior, the application for which conventional electrochemical devices are not well suited. Magnetic control is opening a door to new applications of electrochemical devices and related technologies. PMID- 28874767 TI - A cross-sectional comparative study of gut bacterial community of Indian and Finnish children. AB - The human gut microbiome plays a crucial role in the compositional development of gut microbiota. Though well documented in western pediatrics population, little is known about how various host conditions affect populations in different geographic locations such as the Indian subcontinent. Given the impact of distinct environmental conditions, our study assess the gut bacterial diversity of a small cohort of Indian and Finnish children and investigated the influence of FUT2 secretor status and birth mode on the gut microbiome of these populations. Using multiple profiling techniques, we show that the gut bacterial community structure in 13-14-year-old Indian (n = 47) and Finnish (n = 52) children differs significantly. Specifically, Finnish children possessed higher Blautia and Bifidobacterium, while genera Prevotella and Megasphaera were predominant in Indian children. Our study also demonstrates a strong influence of FUT2 and birth mode variants on specific gut bacterial taxa, influence of which was noticed to differ between the two populations under study. PMID- 28874768 TI - A new red cell index and portable RBC analyzer for screening of iron deficiency and Thalassemia minor in a Chinese population. AB - Anemia is a widespread public health problem with 1/4 ~1/3 of the world's population being affected. In Southeast Asia, Thalassemia trait (TT) and iron deficiency anemia (IDA) are the two most common anemia types and can have a serious impact on quality of life. IDA patients can be treated with iron supplementation, yet TT patients have diminished capacity to process iron. Therefore, distinguishing between types of anemia is essential for effective diagnosis and treatment. Here, we present two advances towards low-cost screening for anemia. First: a new red-cell-based index, Joint Indicator A, to discriminate between IDA, TT, and healthy children in a Chinese population. We collected retrospective data from 384 Chinese children and used discriminant function analysis to determine the best analytic function to separate healthy and diseased groups, achieving 94% sensitivity and 90% specificity, significantly higher than reported indices. This result is achieved using only three red cell parameters: mean cell volume (MCV), red cell distribution width (RDW) and mean cell hemoglobin concentration (MCHC). Our second advance: the development of a low cost, portable red cell analyzer to measure these parameters. Taken together, these two results may help pave the way for widespread screening for nutritional and genetic anemias. PMID- 28874769 TI - Effect of Surface Plasmon Coupling to Optical Cavity Modes on the Field Enhancement and Spectral Response of Dimer-Based sensors. AB - We present a theoretical approach to narrow the plasmon linewidth and enhance the near-field intensity at a plasmonic dimer gap (hot spot) through coupling the electric localized surface plasmon (LSP) resonance of a silver hemispherical dimer with the resonant modes of a Fabry-Perot (FP) cavity. The strong coupling is demonstrated by the large anticrossing in the reflection spectra and a Rabi splitting of 76 meV. Up to 2-fold enhancement increase can be achieved compared to that without using the cavity. Such high field enhancement has potential applications in optics, including sensors and high resolution imaging devices. In addition, the resonance splitting allows for greater flexibility in using the same array at different wavelengths. We then further propose a practical design to realize such a device and include dimers of different shapes and materials. PMID- 28874770 TI - Visualizing Phonotactic Behavior of Female Frogs in Darkness. AB - Many animals use sounds produced by conspecifics for mate identification. Female insects and anuran amphibians, for instance, use acoustic cues to localize, orient toward and approach conspecific males prior to mating. Here we present a novel technique that utilizes multiple, distributed sound-indication devices and a miniature LED backpack to visualize and record the nocturnal phonotactic approach of females of the Australian orange-eyed tree frog (Litoria chloris) both in a laboratory arena and in the animal's natural habitat. Continuous high definition digital recording of the LED coordinates provides automatic tracking of the female's position, and the illumination patterns of the sound-indication devices allow us to discriminate multiple sound sources including loudspeakers broadcasting calls as well as calls emitted by individual male frogs. This innovative methodology is widely applicable for the study of phonotaxis and spatial structures of acoustically communicating nocturnal animals. PMID- 28874771 TI - Immunization with alkyl hydroperoxide reductase subunit C reduces Fusobacterium nucleatum load in the intestinal tract. AB - Fusobacterium nucleatum (Fn) is an important tumour-associated bacterium in colorectal cancer (CRC). The antioxidant protein alkyl hydroperoxide reductase subunit C (AhpC) can induce strong antibacterial immune response during various pathogen infections. Our study aimed to evaluate the efficacy of Fn-AhpC as a candidate vaccine. In this work, by western blot analysis, we showed that Fn-AhpC recombinant protein could be recognized specifically by antibodies present in the sera of CRC patients; using the mouse Fn-infection model, we observed that systemic prophylactic immunization with AhpC/alum conferred significant protection against infection in 77.3% of mice. In addition, we measured the anti AhpC antibody level in the sera of CRC patients and found that there was no obvious increase of anti-AhpC antibodies in the early-stage CRC group. Furthermore, we treated Fn with the sera from both immunized mice and CRC patients and found that sera with high anti-AhpC antibodies titre could inhibit Fn growth. In conclusion, our findings support the use of AhpC as a potential vaccine candidate against inhabitation or infection of Fn in the intestinal tract, which could provide a practical strategy for the prevention of CRC associated with Fn infection. PMID- 28874772 TI - Antibody-dependent fragmentation is a newly identified mechanism of cell killing in vivo. AB - The prevailing view is that therapeutic antibodies deplete cells through opsonization and subsequent phagocytosis, complement-dependent lysis or antibody dependent cellular-cytotoxicity. We used high resolution in vivo imaging to identify a new antibody-dependent cell death pathway where Kupffer cells ripped large fragments off crawling antibody-coated iNKT cells. This antibody-dependent fragmentation process resulted in lethality and depletion of crawling iNKT cells in the liver sinusoids and lung capillaries. iNKT cell depletion was Fcy-receptor dependent and required iNKT cell crawling. Blood, spleen or joint iNKT cells that did not crawl were not depleted. The antibody required high glycosylation for sufficiently strong binding of the iNKT cells to the Fc Receptors on Kupffer cells. Using an acetaminophen overdose model, this approach functionally depleted hepatic iNKT cells and affected the severity of liver injury. This study reveals a new mechanism of antibody-dependent killing in vivo and raises implications for the design of new antibodies for cancer and auto-reactive immune cells. PMID- 28874773 TI - Cortical and trabecular morphology is altered in the limb bones of mice artificially selected for faster skeletal growth. AB - Bone strength is influenced by mineral density and macro- and microstructure. Research into factors that contribute to bone morphology and strength has focused on genetic, environmental and morphological factors (e.g., body mass index), but little is known regarding the impact of rates of skeletal elongation on adult skeletal morphology and strength. Using micro-CT, we examined the impact of rates of skeletal elongation on bone cortical and trabecular morphology, and on rates of estrogen-dependent bone loss in the tibia in CD-1 mice, and in mice with accelerated skeletal growth (Longshanks). Groups of adult mice (n = 7/group) were subjected to ovariectomy or sham surgeries, scanned for 6 weeks, and indices of bone morphology were collected. Results show that Longshanks mice had significantly less trabecular bone at skeletal maturity, characterized by fewer, thinner trabeculae, and furthermore lost trabecular bone more slowly in response to ovariectomy. Artificial selection for rapid skeletal growth relative to somatic growth thus had a significant impact on trabecular bone morphology in Longshanks. Our data do not unequivocally demonstrate a causal relationship between rapid bone growth and reduced trabecular bone quality, but suggest that rapid linear bone growth may influence the risk of cancellous bone fragility. PMID- 28874775 TI - First-principles calculations on Fe-Pt nanoclusters of various morphologies. AB - Bimetallic FePt nanoparticles with L1 0 structure are attracting a lot of attention due to their high magnetocrystalline anisotropy and high coercivity what makes them potential material for storage of ultra-high density magnetic data. FePt nanoclusters are considered also as nanocatalysts for growth of carbon nanotubes of different chiralities. Using the DFT-LCAO CRYSTAL14 code, we have performed large-scale spin-polarized calculations on 19 different polyhedral structures of FePt nanoparticles in order to estimate which icosahedral or hcp structured morphology is the energetically more preferable. Surface energy calculations of all aforementioned nanoparticles indicate that the global minimum corresponds to the nanocluster possessing the icosahedron "onion-like" structure and Fe43Pt104 morphology where the outer layer consists of Pt atoms. The presence of the Pt-enriched layer around FePt core explains high oxidation resistance and environmental stability, both observed experimentally. PMID- 28874774 TI - Current-direction/amplitude-dependent single channel gating kinetics of mouse pannexin 1 channel: a new concept for gating kinetics. AB - The detailed single-channel gating kinetics of mouse pannexin 1 (mPanx1) remains unknown, although mPanx1 is reported to be a voltage-activated anion-selective channel. We investigated characteristics of single-channel conductances and opening and closing rates of mPanx1 using patch-clamp techniques. The unitary current of mPanx1 shows outward rectification with single-channel conductances of ~20 pS for inward currents and ~80 pS for outward currents. The channel open time for outward currents (Cl- influx) increases linearly as the amplitude of single channel currents increases, while the open time for inward currents (Cl- efflux) is constant irrespective of changes in the current amplitude, as if the direction and amplitude of the unitary current regulates the open time. This is supported by further observations that replacement of extracellular Cl- with gluconate- diminishes the inward tail current (Cl- efflux) at a membrane potential of -100 mV due to the lowered outward current (gluconate- influx) at membrane potential of 100 mV. These results suggest that the direction and rate of charge-carrier movement regulate the open time of mPanx1, and that the previously reported voltage-dependence of Panx1 channel gating is not directly mediated by the membrane potential but rather by the direction and amplitude of currents through the channel. PMID- 28874776 TI - N-P Fertilization Stimulates Anaerobic Selenium Reduction in an End-Pit Lake. AB - Selenium (Se), an essential micro nutrient, is toxic to aquatic life at slightly higher water concentrations. Watersheds receiving leachate from selenium rich sources require large-scale, long-term treatment to mitigate Se toxicity. We applied the principles of anaerobic bacterial bioreactors, previously successful in small scale Se mitigation, to a whole end-pit lake ecosystem. Fertilization of the lake with N and P increased primary production, creating a meromictic, anoxic layer, and enhanced the habitat for locally present, anaerobic, Se and sulfur reducing bacteria. Within two years, Se concentrations were reduced ten-fold, reaching water-quality guideline values. The successful experiment demonstrated a novel treatment of large volumes of Se-contaminated water, and introduced an inexpensive method to mitigate a persistent aquatic pollutant of global concern. PMID- 28874777 TI - Prevalence, Awareness and Associated Risk Factors of Diabetes among Adults in Xi'an, China. AB - The study aimed to investigate the prevalence, awareness, treatment and glycaemic control of diabetes and its associated risk factors among adults in Xi'an, China. We collected data among participants aged 18 years or older through a self developed questionnaire and an additional health examination. A total of 8150 participants were included, with an overall prevalence of diabetes of 8.0%. Among 655 participants with diabetes, 52.5% were aware they had diabetes, 48.1% took antidiabetic treatment, and 19.1% had their fasting blood glucose level at less than 7.0 mmol/l. Older age, lower educational level, higher body mass index, larger waist circumference, having an unhealthy diet and having more comorbidities were positively associated with the risk of diabetes. Participants who were older, who had higher education and who had more comorbidities were more aware that they had diabetes. Being older age, having higher education and having more comorbidities were also factors for better treatment. Participants who were older were more likely to have their glucose level controlled. The prevalence of diabetes among adults in Xi'an is high, with suboptimal awareness, treatment, and glycaemic control rates. Comprehensive integrated strategies based on risk factors should be implemented to improve the prevention and glycaemic control of diabetes. PMID- 28874778 TI - The impact of temporal modulations in irradiance under light adapted conditions on the mouse suprachiasmatic nuclei (SCN). AB - Electrophysiological responses of SCN neurons to light steps are well established, but responses to more natural modulations in irradiance have been much less studied. We address this deficit first by showing that variations in irradiance for human subjects are biased towards low temporal frequencies and small magnitudes. Using extracellular recordings we show that neurons in the mouse SCN are responsive to stimuli with these characteristics, tracking sinusoidal modulations in irradiance best at lower temporal frequencies and responding to abrupt changes in irradiance over a range of commonly encountered contrasts. The spectral sensitivity of these light adapted responses indicates that they are driven primarily by cones, but with melanopsin (and/or rods) contributing under more gradual changes. Higher frequency modulations in irradiance increased time averaged firing of SCN neurons (typically considered to encode background light intensity) modestly over that encountered during steady exposure, but did not have a detectable effect on the circadian phase resetting efficiency of light. Our findings highlight the SCN's ability to encode naturalistic temporal modulations in irradiance, while revealing that the circadian system can effectively integrate such signals over time such that phase resetting responses remain proportional to the mean light exposure. PMID- 28874779 TI - Relation between characteristics of carotid atherosclerotic plaques and brain white matter hyperintensities in asymptomatic patients. AB - White matter hyperintensities (WMH) can be incidentally found in patients with carotid atherosclerosis on brain magnetic resonance imaging (MRI). We investigated the relationship between WMH and characteristics of carotid plaques in asymptomatic patients without indication for carotid revascularization. We prospectively screened 235 consecutive patients with carotid stenosis <70%. After excluding patients with confounding causes of cerebral damage, 67 asymptomatic patients underwent carotid computed tomography angiography (CTA), contrast enhanced ultrasound and brain MRI. Number and quantitative measurement of volume of WMH were associated with history of resistant hypertension, degree of stenosis (Doppler) and presence of an ulcerated plaque at CTA (p < 0.05). At multivariate regression analysis, resistant hypertension was independently associated with both number and volume of WMH, presence of an ulcer with number of WMH and degree of stenosis with WMH volume (p < 0.05), although WMH were equally distributed in both hemispheres irrespectively of plaque side. In conclusion, in asymptomatic patients with carotid plaques <70%, a higher burden of WMHs is associated with history of resistant hypertension that could be the expression of microvascular damage. Stenosis severity and presence of plaque ulceration are also associated with WMH burden although their causative relation is not supported by the bilateral distribution of WMH. PMID- 28874780 TI - Significance of penile hypersensitivity in premature ejaculation. AB - To assess the correlation between penile hypersensitivity and premature ejaculation (PE), a total of 420 consecutive subjects attending our andrologic clinic for suspected PE were enrolled. The entire cohort was asked to complete the self-report intravaginal ejaculation latency time (IELT) by stopwatch. According to the IELT, the subjects were classified into 3 groups. Vibratory thresholds were recorded at the glans penis and penile shaft using a biothesiometer. We found that vibratory thresholds in the glans penis and penile shaft were significantly lower in both mild and severe PE group than in the control group (3.81 +/- 0.57 and 3.54 +/- 0.43 vs 4.73 +/- 0.77 for glans penis p = 0.000; 3.64 +/- 0.52 and 3.37 +/- 0.50 vs 4.62 +/- 0.69 for penile shaft p = 0.002). The vibratory threshold decreased as the disease aggravated. In the mild and severe PE groups, a significant positive correlation was detected between the mean values of IELT and the vibratory thresholds. Furthermore, in the receiver operating characteristics curve analysis, the area under the curve of the glans penis and penile shaft vibratory thresholds predicting severe PE were 0.852 and 0.893 respectively. Our study established a dose-dependent association between penile vibratory threshold and PE. Therefore, the vibratory threshold can serve as a potential marker for predicting the severity of PE. PMID- 28874781 TI - Immunization of cervidized transgenic mice with multimeric deer prion protein induces self-antibodies that antagonize chronic wasting disease infectivity in vitro. AB - Chronic wasting disease (CWD) is the most contagious prion disease. It is expanding rapidly in North America, was found recently in Europe, and the potential for transmission to humans cannot be excluded yet. We hypothesized that it is possible to prevent peripheral CWD infection and CWD prion shedding by inducing auto-antibodies against the cellular prion protein (PrPC) by active vaccination. Our objective is to overcome self-tolerance against PrP by using a multimeric recombinant PrP (recPrP) as an immunogen. We expressed in E. coli, purified and refolded four immunogens: cervid and murine recPrP in monomeric and dimeric form. Testing immunogenicity in sera of the vaccinated transgenic mice expressing cervid PrP revealed that all four immunogens effectively overcame self tolerance against the prion protein as shown by high antibody titers. Confocal microscopy analysis revealed effective binding of post-immune sera to surface located PrPC in both murine and cervid PrP expressing cultured cells. Remarkably, the post-immune auto-antibodies effectively inhibited CWD-induced prion conversion in RT-QuIC assay when incubated with either PrP substrate or CWD seed. Furthermore, they mitigated prion propagation in CWD-infected cervid-PrP expressing RK13 cells. Together, multimeric recombinant cervid PrP effectively overcomes self-tolerance to PrP and induces auto-antibodies that interfere with CWD conversion in vitro. PMID- 28874782 TI - Dihydrocapsaicin Attenuates Blood Brain Barrier and Cerebral Damage in Focal Cerebral Ischemia/Reperfusion via Oxidative Stress and Inflammatory. AB - This study investigated the effect of dihydrocapsaicin (DHC) on cerebral and blood brain barrier (BBB) damage in cerebral ischemia and reperfusion (I/R) models. The models were induced by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. The rats were divided into five groups: sham, or control group; vehicle group; and 2.5 mg/kg, 5 mg/kg, and 10 mg/kg BW DHC-treated I/R groups. After 24 h of reperfusion, we found that DHC significantly reduced the area of infarction, morphology changes in the neuronal cells including apoptotic cell death, and also decreased the BBB damage via reducing Evan Blue leakage, water content, and ultrastructure changes, in addition to increasing the tight junction (TJ) protein expression. DHC also activated nuclear-related factor 2 (Nrf2) which involves antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase (GPx), and significantly decreased oxidative stress and inflammation via down-regulated reactive oxygen species (ROS), NADPH oxidase (NOX2, NOX4), nuclear factor kappa-beta (NF-KB), and nitric oxide (NO), including matrix metalloproteinases-9 (MMP-9) levels. DHC protected the cerebral and the BBB from I/R injury via attenuation of oxidative stress and inflammation. Therefore, this study offers to aid future development for protection against cerebral I/R injury in humans. PMID- 28874783 TI - Hyperactive TGF-beta Signaling in Smooth Muscle Cells Exposed to HIV-protein(s) and Cocaine: Role in Pulmonary Vasculopathy. AB - We earlier demonstrated synergistic increase in the proliferation of pulmonary smooth muscle cells on exposure to HIV-proteins and/or cocaine due to severe down modulation of bone morphogenetic protein receptor (BMPR) axis: the anti proliferative arm of TGF-beta super family of receptors. Here, now we demonstrate the effect of HIV-Tat and cocaine on the proliferative TGF-beta signaling cascade. We observed a significant increase in the secretion of TGF-beta1 ligand along with enhanced protein expression of TGFbeta Receptor (TGFbetaR)-1, TGFbetaR 2 and phosphorylated SMAD2/3 in human pulmonary arterial smooth muscle cells on treatment with cocaine and Tat. Further, we noticed an increase in the levels of p-TAK1 complexed with TGFbetaR-2. Concomitant to this a significant increase in the activation of TAK1-mediated, SMAD-independent downstream signaling molecules: p-MKK4 and p-JNK was observed. However, activation of MKK3/6-p38MAPK, another axis downstream of TAK1 was found to be reduced due to attenuation in the protein levels of BMPR2. Both SMAD and non-SMAD dependent TGFbetaR cascades were found to contribute to hyper-proliferation. Finally the increase in the levels of phosphorylated TGFbetaR1 and TGFbetaR2 on exposure to HIV-proteins and cocaine was confirmed in pulmonary smooth muscle cells from cocaine injected HIV transgenic rats and in total lung extracts from HIV infected cocaine and/or opioid users. PMID- 28874784 TI - Mapping the Spatial Distribution and Characteristics of Lineaments Using Fractal and Multifractal Models: A Case Study from Northeastern Yunnan Province, China. AB - This study describes the fractal dimensions of the spatial distributions of lineaments as an index of the complexity of faults, and the results could provide new insights into the migration of ore-bearing fluid. The Segment Tracing Algorithm method is employed to extract the lineaments in northeast Yunnan Province from a remote sensing image. Box-counting fractal and multifractal models are used to analyze the fractal and multifractal spatial distribution characteristics of the linear structures. The different directions of the linear structure fractal dimensions are similar in the study area. The fractal dimensions of all lineaments, northeast trending lineaments and northwest trending lineaments are 1.98, 1.94 and 1.95, respectively. The dimensions of four large ore deposit fields, Kuangshanchang, Qilinchang, Maozu, and Lemachang, are 1.93, 1.92, 1.95, and 1.93, respectively. The fractal dimensions of these four fields are greater than those of the South China lineaments. The super-large and large ore deposits are consistent with fractal dimensions with high values. The scale index and the singular index show nonlinear relationships with any real number, and the fractal dimension spectrum has a unimodal curve. This study provides a useful reference for deposit exploration in areas with topographies similar to that in northeastern Yunnan. PMID- 28874786 TI - The Exchange Bias of LaMnO3/LaNiO3 Superlattices Grown along Different Orientations. AB - With the goal of observing and explaining the unexpected exchange bias effect in paramagnetic LaNiO3-based superlattices, a wide range of theoretical and experimental research has been published. Within the scope of this work, we have grown high-quality epitaxial LaMnO3(n)-LaNiO3(n) (LMO/LNO) superlattices (SLs) along (001)-, (110)-, and (111)-oriented SrTiO3 substrates. The exchange bias effect is observed in all cases, regardless of growth orientation of the LMO/LNO SLs. As a result of a combination of a number of synchrotron based x-ray spectroscopy measurements, this effect is attributed to the interfacial charge transfer from Mn to Ni ions that induces localized magnetic moments to pin the ferromagnetic LMO layer. The interaction per area between interfacial Mn and Ni ions is nearly consistent and has no effect on charge transfer for different orientations. The discrepant charge transfer and orbital occupancy can be responsible for the different magnetic properties in LMO/LNO superlattices. Our experimental results present a promising advancement in understanding the origin of magnetic properties along different directions in these materials. PMID- 28874785 TI - Decidualisation and placentation defects are a major cause of age-related reproductive decline. AB - Mammalian reproductive performance declines rapidly with advanced maternal age. This effect is largely attributed to the exponential increase in chromosome segregation errors in the oocyte with age. Yet many pregnancy complications and birth defects that become more frequent in older mothers, in both humans and mice, occur in the absence of karyotypic abnormalities. Here, we report that abnormal embryonic development in aged female mice is associated with severe placentation defects, which result from major deficits in the decidualisation response of the uterine stroma. This problem is rooted in a blunted hormonal responsiveness of the ageing uterus. Importantly, a young uterine environment can restore normal placental as well as embryonic development. Our data highlight the pivotal, albeit under-appreciated, impact of maternal age on uterine adaptability to pregnancy as major contributor to the decline in reproductive success in older females.Advanced maternal age has been associated with lower reproductive success and higher risk of pregnancy complications. Here the authors show that maternal ageing-related embryonic abnormalities in mouse are caused by decidualisation and placentation defects that can be rescued by transferring the embryo from an old to a young uterus. PMID- 28874787 TI - Blue Laser Diode Based Free-space Optical Data Transmission elevated to 18 Gbps over 16 m. AB - Up to 18-Gbps direct encoding of blue laser diode (BLD) is demonstrated for free space data transmission. By reshaping the orthogonal frequency multiplexed (16 QAM OFDM) stream with sidelobe filtering, the raw data rate expedites from 17.2 to 18.4 Gbps. Employing an ultrafast p-i-n photodiode with smaller active area diameter and lower noise equivalent power significantly enlarges the data rate by 1.6 Gbps or upgrades the signal-to-noise ratio (SNR) by 0.2 dB. Replacing the 80 mW BLD with the 120-mW one essentially increases the received SNR by 0.4 dB under enhanced modulation throughput. Reinforcing the beam collimation and collection by increasing the numerical aperture with a plano-convex hyper-hemispherical lens further improves the SNR by 0.6 dB. After optimization, the 16-QAM OFDM data with and without sidelobe filtering are respectively delivered at raw data rates of 16.4 and 18 Gbps with spectral-density usage efficiency as high as 4 bit/s/Hz over 16 m in free space, wherein the BLD carried QAM-OFDM data stream remains its capacity after reformation with sidelobe filtering as the superior inter-carrier interference immunity reinforces. PMID- 28874788 TI - Comprehensive transcriptome mining of the direct conversion of mesodermal cells. AB - The direct reprogramming of somatic cells is a promising approach for regenerative medicine, especially in the production of mesoderm layer-derived cells. Meta-analysis studies provide precise insight into the undergoing processes and help increase the efficiency of reprogramming. Here, using 27 high throughput expression data sets, we analyzed the direct reprogramming of mesodermal cells in humans and mice. Fibroblast-derived cells showed a common expression pattern of up- and down-regulated genes that were mainly involved in the suppression of the fibroblast-specific gene expression program, and may be used as markers of the initiation of reprogramming. Furthermore, we found a specific gene expression profile for each fibroblast-derived cell studied, and each gene set appeared to play specific functional roles in its cell type, suggesting their use as markers for their mature state. Furthermore, using data from protein-DNA interactions, we identified the main transcription factors (TFs) involved in the conversion process and ranked them based on their importance in their gene regulatory networks. In summary, our meta-analysis approach provides new insights on the direct conversion of mesodermal somatic cells, introduces a list of genes as markers for initiation and maturation, and identifies TFs for which manipulating their expression may increase the efficiency of direct conversion. PMID- 28874789 TI - Infrared probe of pseudogap in electron-doped Sr2IrO4. AB - We report on infrared spectroscopy experiments on the electronic response in (Sr1 x La x )2IrO4 (x = 0, 0.021, and 0.067). Our data show that electron doping induced by La substitution leads to an insulator-to-metal transition. The evolution of the electronic structure across the transition reveals the robustness of the strong electronic correlations against the electron doping. The conductivity data of the metallic compound show the signature of the pseudogap that bears close similarity to the analogous studies of the pseudogap in the underdoped cuprates. While the low energy conductivity of the metallic compound is barely frequency dependent, the formation of the pseudogap is revealed by the gradual suppression of the featureless conductivity below a threshold frequency of about 17 meV. The threshold structure develops below about 100 K which is in the vicinity of the onset of the short-range antiferromagnetic order. Our results demonstrate that the electronic correlations play a crucial role in the anomalous charge dynamics in the (Sr1-x La x )2IrO4 system. PMID- 28874790 TI - Microscale Liquid Transport in Polycrystalline Inverse Opals across Grain Boundaries. AB - Delivering liquid through the void spaces in porous metals is a daunting challenge for a variety of emerging interface technologies ranging from battery electrodes to evaporation surfaces. Hydraulic transport characteristics of well ordered porous media are governed by the pore distribution, porosity, and morphology. Much like energy transport in polycrystalline solids, hydraulic transport in semi-ordered porous media is predominantly limited by defects and grain boundaries. Here, we report the wicking performances for porous copper inverse opals having pore diameters from 300 to 1000 nm by measuring the capillary-driven liquid rise. The capillary performance parameter within single crystal domain (K ij /R eff = 10-3 to 10-2 um) is an order of magnitude greater than the collective polycrystal (K eff /R eff = ~10-5 to 10-3 um) due to the hydraulic resistances (i.e. grain boundaries between individual grains). Inspired by the heterogeneity found in biological systems, we report that the capillary performance parameter of gradient porous copper (K eff /R eff = ~10-3 um), comparable to that of single crystals, overcomes hydraulic resistances through providing additional hydraulic routes in three dimensions. The understanding of microscopic liquid transport physics through porous crystals and across grain boundaries will help to pave the way for the spatial design of next-generation heterogeneous porous media. PMID- 28874791 TI - Disease reservoirs: from conceptual frameworks to applicable criteria. AB - Central to the One Health approach and any disease eradication program is the question of whether a pathogen has a non-human reservoir. Despite well established conceptual frameworks that define a reservoir of infection, empirical characterization of reservoirs often remains controversial, challenging and sometimes misleading. What is essentially missing are applicable requirements that standardize the use of the term 'reservoir of infection' across multiple disciplines. We propose an empirical framework, considering maintenance and feasible transmission of a pathogen, to standardize the acceptance of a disease reservoir across multiple disciplines. We demonstrate the intended use of these requirements by applying them to different diseases that are known to infect both humans and animals. PMID- 28874795 TI - Tailoring the thermal conductivity of the powder bed in Electron Beam Melting (EBM) Additive Manufacturing. AB - Metallic powder bed additive manufacturing is capable of producing complex, functional parts by repeatedly depositing thin layers of powder particles atop of each other whilst selectively melting the corresponding part cross-section into each layer. A weakness with this approach arises when melting overhanging features, which have no prior melted material directly beneath them. This is due to the lower thermal conductivity of the powder relative to solid material, which as a result leads to an accumulation of heat and thus distortion. The Electron Beam Melting (EBM) process alleviates this to some extent as the powder must first be sintered (by the beam itself) before it is melted, which results in the added benefit of increasing the thermal conductivity. This study thus sought to investigate to what extent the thermal conductivity of local regions in a titanium Ti-6Al-4V powder bed could be varied by imparting more energy from the beam. Thermal diffusivity and density measurements were taken of the resulting sintered samples, which ranged from being loosely to very well consolidated. It was found that the calculated thermal conductivity at two temperatures, 40 and 730 degrees C, was more than doubled over the range of input energies explored. PMID- 28874792 TI - Surveillance for highly pathogenic influenza A viruses in California during 2014 2015 provides insights into viral evolutionary pathways and the spatiotemporal extent of viruses in the Pacific Americas Flyway. AB - We used surveillance data collected in California before, concurrent with, and subsequent to an outbreak of highly pathogenic (HP) clade 2.3.4.4 influenza A viruses (IAVs) in 2014-2015 to (i) evaluate IAV prevalence in waterfowl, (ii) assess the evidence for spill-over infections in marine mammals and (iii) genetically characterize low-pathogenic (LP) and HP IAVs to refine inference on the spatiotemporal extent of HP genome constellations and to evaluate possible evolutionary pathways. We screened samples from 1496 waterfowl and 1142 marine mammals collected from April 2014 to August 2015 and detected IAV RNA in 159 samples collected from birds (n=157) and pinnipeds (n=2). HP IAV RNA was identified in three samples originating from American wigeon (Anas americana). Genetic sequence data were generated for a clade 2.3.4.4 HP IAV-positive diagnostic sample and 57 LP IAV isolates. Phylogenetic analyses revealed that the HP IAV was a reassortant H5N8 virus with gene segments closely related to LP IAVs detected in mallards (Anas platyrhynchos) sampled in California and other IAVs detected in wild birds sampled within the Pacific Americas Flyway. In addition, our analysis provided support for common ancestry between LP IAVs recovered from waterfowl sampled in California and gene segments of reassortant HP H5N1 IAVs detected in British Columbia, Canada and Washington, USA. Our investigation provides evidence that waterfowl are likely to have played a role in the evolution of reassortant HP IAVs in the Pacific Americas Flyway during 2014-2015, whereas we did not find support for spill-over infections in potential pinniped hosts. PMID- 28874794 TI - Impact of different promoters, promoter mutation, and an enhancer on recombinant protein expression in CHO cells. AB - In the present study, six commonly used promoters, including cytomegalovirus major immediate-early (CMV), the CMV enhancer fused to the chicken beta-actin promoter (CAG), human elongation factor-1alpha (HEF-1alpha), mouse cytomegalovirus (mouse CMV), Chinese hamster elongation factor-1alpha (CHEF 1alpha), and phosphoglycerate kinase (PGK), a CMV promoter mutant and a CAG enhancer, were evaluated to determine their effects on transgene expression and stability in transfected CHO cells. The promoters and enhancer were cloned or synthesized, and mutation at C-404 in the CMV promoter was generated; then all elements were transfected into CHO cells. Stably transfected CHO cells were identified via screening under the selection pressure of G418. Flow cytometry, qPCR, and qRT-PCR were used to explore eGFP expression levels, gene copy number, and mRNA expression levels, respectively. Furthermore, the erythropoietin (EPO) gene was used to test the selected strong promoter. Of the six promoters, the CHEF-1alpha promoter yielded the highest transgene expression levels, whereas the CMV promoter maintained transgene expression more stably during long-term culture of cells. We conclude that CHEF-1alpha promoter conferred higher level of EPO expression in CHO cells, but the CMV promoter with its high levels of stability performs best in this vector system. PMID- 28874796 TI - Controlled self-organization of polymer nanopatterns over large areas. AB - Self-assembly methods allow to obtain ordered patterns on surfaces with exquisite precision, but often lack in effectiveness over large areas. Here we report on the realization of hierarchically ordered polymethylmethacrylate (PMMA) nanofibres and nanodots over large areas from solution via a fast, easy and low cost method named ASB-SANS, based on a ternary solution that is cast on the substrate. Simple changes to the ternary solution composition allow to control the transition from nanofibres to nanodots, via a wide range of intermediate topologies. The ternary solution includes the material to be patterned, a liquid solvent and a solid substance able to sublimate. The analysis of the fibres/dots width and inter-pattern distance variations with respect to the ratio between the solution components suggests that the macromolecular chains mobility in the solidified sublimating substance follows Zimm-like models (mobility of macromolecules in diluted liquid solutions). A qualitative explanation of the self-assembly phenomena originating the observed nanopatterns is given. Finally, ASB-SANS-generated PMMA nanodots arrays have been used as lithographic masks for a silicon substrate and submitted to Inductively Coupled Plasma-Reactive Ion Etching (ICP-RIE). As a result, nanopillars with remarkably high aspect ratios have been achieved over areas as large as several millimeters square, highlighting an interesting potential of ASB-SANS in practical applications like photon trapping in photovoltaic cells, surface-enhanced sensors, plasmonics. PMID- 28874797 TI - Impact of second-line cetuximab-containing therapy in patients with KRAS wild type metastatic colorectal cancer: results from the ITACa randomized clinical trial. AB - The ITACa trial was designed to define the role of cetuximab (Cet) and bevacizumab (Bev) in combination with standard chemotherapy (CT, FOLFIRI or FOLFOX4) as first- and second-line treatment in metastatic colorectal cancer. All patients with WT KRAS tumors who had been enrolled in the first-line trial were randomized onto two independent second-line trials: CT or CT + Cet (study 2A) and CT + Bev or CT + Bev + Cet (study 2B). Patients with mutated KRAS were not eligible for randomization and were treated with CT alone (study 2A) or CT + Bev (study 2B). The primary endpoint was progression-free survival (PFS). 48 and 56 KRAS WT patients were randomized while 31 and 40 KRAS mutated patients were treated without randomization. Study 2A: median PFS was 3.4 (95%CI 2.3-4.6) and 6.2 (95%CI 4.3-7.8) months for the CT and CT + Cet arms, respectively, with a hazard ratio (HR) = 0.64 (95%CI 0.35-1.16, p = 0.144). Study 2B: median PFS was 7.7 (95%CI 4.1-10.1) and 4.9 (95%CI 3.2-7.0) months for CT + Bev and CT + Cet + Bev arms, respectively, with a HR = 1.31 (95%CI 0.76-2.26, p = 0.330). Notwithstanding limitations due to the small sample size, among patients with WT KRAS the addition of Cet to second-line CT increased PFS, whereas the addition of Cet to CT + Bev was associated with worse PFS. PMID- 28874798 TI - A rare-earth free magnesium alloy with improved intrinsic ductility. AB - Metals are the backbone of manufacturing owing to their strength and formability. Compared to polymers they have high mass density. There is, however, one exception: magnesium. It has a density of only 1.7 g/cm3, making it the lightest structural material, 4.5 times lighter than steels, 1.7 times lighter than aluminum, and even slightly lighter than carbon fibers. Yet, the widespread use of magnesium is hampered by its intrinsic brittleness. While other metallic alloys have multiple dislocation slip systems, enabling their well-known ductility, the hexagonal lattice of magnesium offers insufficient modes of deformation, rendering it intrinsically brittle. We have developed a quantum mechanically derived treasure map which screens solid solution combinations with electronic bonding, structure and volume descriptors for similarity to the ductile magnesium-rare earth alloys. Using this insight we synthesized a surprisingly simple, compositionally lean, low-cost and industry-compatible new alloy which is over 4 times more ductile and 40% stronger than pure magnesium. The alloy contains 1 wt.% aluminum and 0.1 wt.% calcium, two inexpensive elements which are compatible with downstream recycling constraints. PMID- 28874799 TI - A Metabolomics Signature Linked To Liver Fibrosis In The Serum Of Transplanted Hepatitis C Patients. AB - Liver fibrosis must be evaluated in patients with hepatitis C virus (HCV) after liver transplantation because its severity affects their prognosis and the recurrence of HCV. Since invasive biopsy is still the gold standard to identify patients at risk of graft loss from rapid fibrosis progression, it becomes crucial the development of new accurate, non-invasive methods that allow repetitive examination of the patients. Therefore, we have developed a non invasive, accurate model to distinguish those patients with different liver fibrosis stages. Two hundred and three patients with HCV were histologically classified (METAVIR) into five categories of fibrosis one year after liver transplantation. In this cross-sectional study, patients at fibrosis stages F0-F1 (n = 134) were categorised as "slow fibrosers" and F2-F4 (n = 69) as "rapid fibrosers". Chloroform/methanol serum extracts were analysed by reverse ultra high performance liquid chromatography coupled to mass spectrometry. A diagnostic model was built through linear discriminant analyses. An algorithm consisting of two sphingomyelins and two phosphatidylcholines accurately classifies rapid and slow fibrosers after transplantation. The proposed model yielded an AUROC of 0.92, 71% sensitivity, 85% specificity, and 84% accuracy. Moreover, specific bile acids and sphingomyelins increased notably along with liver fibrosis severity, differentiating between rapid and slow fibrosers. PMID- 28874800 TI - Mechanism of splenic cell death and host mortality in a Plasmodium yoelii malaria model. AB - Malaria is a fatal disease that displays a spectrum of symptoms and severity, which are determined by complex host-parasite interactions. It has been difficult to study the effects of parasite strains on disease severity in human infections, but the mechanisms leading to specific disease phenotypes can be investigated using strains of rodent malaria parasites that cause different disease symptoms in inbred mice. Using a unique mouse malaria model, here we investigated the mechanisms of splenic cell death and their relationship to control of parasitemia and host mortality. C57BL/6 mice infected with Plasmodium yoelii nigeriensis N67C display high levels of pro-inflammatory cytokines and chemokines (IL-6, IFN gamma, TNF-alpha, CXCL1, and CCL2) and extensive splenic damage with dramatic reduction of splenic cell populations. These disease phenotypes were rescued in RAG2-/-, IFN-gamma-/-, or T cell depleted mice, suggesting IFN-gamma and T cell mediated disease mechanisms. Additionally, apoptosis was one of the major pathways involved in splenic cell death, which coincides with the peaks of pro inflammatory cytokines. Our results demonstrate the critical roles of T cells and IFN-gamma in mediating splenic cell apoptosis, parasitemia control, and host lethality and thus may provide important insights for preventing/reducing morbidity associated with severe malaria in humans. PMID- 28874801 TI - Divergent Evolution of Carbonaceous Aerosols during Dispersal of East Asian Haze. AB - Wintertime East Asia is plagued by severe haze episodes, characterized by large contributions of carbonaceous aerosols. However, the sources and atmospheric transformations of these major components are poorly constrained, hindering development of efficient mitigation strategies and detailed modelling of effects. Here we present dual carbon isotope (delta13C and Delta14C) signatures for black carbon (BC), organic carbon (OC) and water-soluble organic carbon (WSOC) aerosols collected in urban (Beijing and BC for Shanghai) and regional receptors (e.g., Korea Climate Observatory at Gosan) during January 2014. Fossil sources (>50%) dominate BC at all sites with most stemming from coal combustion, except for Shanghai, where liquid fossil source is largest. During source-to-receptor transport, the delta13C fingerprint becomes enriched for WSOC but depleted for water-insoluble OC (WIOC). This reveals that the atmospheric processing of these two major pools are fundamentally different. The photochemical aging (e.g., photodissociation, photooxidation) during formation and transport can release CO2/CO or short-chain VOCs with lighter carbon, whereas the remaining WSOC becomes increasingly enriched in delta13C. On the other hand, several processes, e.g., secondary formation, rearrangement reaction in the particle phase, and photooxidation can influence WIOC. Taken together, this study highlights high fossil contributions for all carbonaceous aerosol sub-compartments in East Asia, and suggests different transformation pathways for different classes of carbonaceous aerosols. PMID- 28874802 TI - Erratum: "Calibration-on-the-spot": How to calibrate an EMCCD camera from its images. AB - This corrects the article DOI: 10.1038/srep28680. PMID- 28874803 TI - Tumor cells and their crosstalk with endothelial cells in 3D spheroids. AB - Recapitulating the tumor microenvironment is a central challenge in the development of experimental model for cancer. To provide a reliable tool for drug development and for personalized cancer therapy, it is critical to maintain key features that exist in the original tumor. Along with this effort, 3-dimentional (3D) cellular models are being extensively studied. Spheroids are self-assembled cell aggregates that possess many important components of the physiological spatial growth and cell-cell interactions. In this study we aimed to investigate the interconnection between tumor and endothelial cells (EC) in hybrid spheroids containing either tumor cell (TC) lines or patient derived cancer cells. Preparation protocols of hybrid spheroids were optimized and their morphology and tissue-like features were analyzed. Our finding show that capillary-like structures are formed upon assembly and growth of TC:EC spheroids and that spheroids' shape and surface texture may be an indication of spatial invasiveness of cells in the extra-cellular matrix (ECM). Establishing a model of hybrid tumor/stroma spheroids has a crucial importance in the experimental approach for personalized medicine, and may offer a reliable and low-cost method for the goal of predicting drug effects. PMID- 28874804 TI - Whole Transcriptome Analysis of Notochord-Derived Cells during Embryonic Formation of the Nucleus Pulposus. AB - Recapitulation of developmental signals represents a promising strategy for treating intervertebral disc degeneration. During development, embryonic notochord-derived cells (NDCs) are the direct progenitors of cells that populate the adult nucleus pulposus (NP) and are an important source of secreted signaling molecules. The objective of this study was to define global gene expression profiles of NDCs at key stages of embryonic disc formation. NDCs were isolated from Shh-cre;ROSA:YFP mice at embryonic day 12.5 and postnatal day 0, representing opposite ends of the notochord to NP transformation. Differences in global mRNA abundance across this developmental window were established using RNA Seq. Protein expression of selected molecules was confirmed using immunohistochemistry. Principal component analysis revealed clustering of gene expression at each developmental stage with more than 5000 genes significantly differentially expressed between E12.5 and P0. There was significantly lower mRNA abundance of sonic hedgehog pathway elements at P0 vs E12.5, while abundance of elements of the transforming growth factor-beta and insulin-like growth factors pathways, and extracellular matrix components including collagen 6 and aggrecan, were significantly higher at P0. This study represents the first transcriptome wide analysis of embryonic NDCs. Results suggest signaling and biosynthesis of NDCs change dramatically as a function of developmental stage. PMID- 28874805 TI - Modular assembly of a protein nanotriangle using orthogonally interacting coiled coils. AB - Synthetic protein assemblies that adopt programmed shapes would support many applications in nanotechnology. We used a rational design approach that exploits the modularity of orthogonally interacting coiled coils to create a self assembled protein nanotriangle. Coiled coils have frequently been used to construct nanoassemblies and materials, but rarely with successful prior specification of the resulting structure. We designed a heterotrimer from three pairs of heterodimeric coiled coils that mediate specific interactions while avoiding undesired crosstalk. Non-associating pairs of coiled-coil units were strategically fused to generate three chains that were predicted to preferentially form the heterotrimer, and a rational annealing process led to the desired oligomer. Extensive biophysical characterization and modeling support the formation of a molecular triangle, which is a shape distinct from naturally occurring supramolecular nanostructures. Our approach can be extended to design more complex nanostructures using additional coiled-coil modules, other protein parts, or templated surfaces. PMID- 28874806 TI - Self-powered Real-time Movement Monitoring Sensor Using Triboelectric Nanogenerator Technology. AB - The triboelectric nanogenerator (TENG) has great potential in the field of self powered sensor fabrication. Recently, smart electronic devices and movement monitoring sensors have attracted the attention of scientists because of their application in the field of artificial intelligence. In this article, a TENG finger movement monitoring, self-powered sensor has been designed and analysed. Under finger movements, the TENG realizes the contact and separation to convert the mechanical energy into electrical signal. A pulse output current of 7.8 MUA is generated by the bending and straightening motions of the artificial finger. The optimal output power can be realized when the external resistance is approximately 30 MOmega. The random motions of the finger are detected by the system with multiple TENG sensors in series. This type of flexible and self powered sensor has potential applications in artificial intelligence and robot manufacturing. PMID- 28874807 TI - Integrated Analysis of Copy Number Variations and Gene Expression Profiling in Hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the top three cancer killers worldwide. To identify CNV-driven differentially expressed genes (DEGs) in HBV related HCC, this study integrated analysis of copy number variations (CNVs) and gene expression profiling. Significant genes in regions of CNVs were overlapped with those obtained from the expression profiling. 93 CNV-driven genes exhibiting increased expression in the duplicated regions and 45 showing decreased expression in the deleted regions were obtained, which duplications and deletions were mainly documented at chromosome 1 and 4. Functional and pathway enrichment analyses were performed using DAVID and KOBAS, respectively. They were mainly enriched in metabolic process and cell cycle. Protein-protein interaction (PPI) network was constructed by Cytoscape, then four hub genes were identified. Following, survival analyses indicated that only high NPM1 expression was significantly and independently associated with worse survival and increased recurrence in HCC patients. Moreover, this correlation remained significant in patients with early stage of HCC. In addition, we showed that NPM1 was overexpressed in HCC cells and in HCC versus adjacent non-tumor tissues. In conclusion, these results showed that integrated analysis of genomic and expression profiling might provide a powerful potential for identifying CNV driven genes in HBV related HCC pathogenesis. PMID- 28874808 TI - RERT: A Novel Regression Tree Approach to Predict Extrauterine Disease in Endometrial Carcinoma Patients. AB - Some aspects of endometrial cancer (EC) preoperative work-up are still controversial, and debatable are the roles played by lymphadenectomy and radical surgery. Proper preoperative EC staging can help design a tailored surgical treatment, and this study aims to propose a new algorithm able to predict extrauterine disease diffusion. 293 EC patients were consecutively enrolled, and age, BMI, children's number, menopausal status, contraception, hormone replacement therapy, hypertension, histological grading, clinical stage, and serum HE4 and CA125 values were preoperatively evaluated. In order to identify before surgery the most important variables able to classify EC patients based on FIGO stage, we adopted a new statistical approach consisting of two-steps: 1) Random Forest with its relative variable importance; 2) a novel algorithm able to select the most representative Regression Tree (RERT) from an ensemble method. RERT, built on the above mentioned variables, provided a sensitivity, specificity, NPV and PPV of 90%, 76%, 94% and 65% respectively, in predicting FIGO stage > I. Notably, RERT outperformed the prediction ability of HE4, CA125, Logistic Regression and single cross-validated Regression Tree. Such algorithm has great potential, since it better identifies the true early-stage patients, thus providing concrete support in the decisional process about therapeutic options to be performed. PMID- 28874809 TI - Forensic age prediction for saliva samples using methylation-sensitive high resolution melting: exploratory application for cigarette butts. AB - There is high demand for forensic age prediction in actual crime investigations. In this study, a novel age prediction model for saliva samples using methylation sensitive high resolution melting (MS-HRM) was developed. The methylation profiles of ELOVL2 and EDARADD showed high correlations with age and were used to predict age with support vector regression. ELOVL2 was first reported as an age predictive marker for saliva samples. The prediction model showed high accuracy with a mean absolute deviation (MAD) from chronological age of 5.96 years among 197 training samples. The model was further validated with an additional 50 test samples (MAD = 6.25). In addition, the age prediction model was applied to saliva extracted from seven cigarette butts, as in an actual crime scene. The MAD (7.65 years) for these samples was slightly higher than that of intact saliva samples. A smoking habit or the ingredients of cigarettes themselves did not significantly affect the prediction model and could be ignored. MS-HRM provides a quick (2 hours) and cost-effective (95% decreased compared to that of DNA chips) method of analysis. Thus, this study may provide a novel strategy for predicting the age of a person of interest in actual crime scene investigations. PMID- 28874811 TI - Effect of Fusidic Acid on the Kinetics of Molecular Motions During EF-G-Induced Translocation on the Ribosome. AB - The translocation step of protein synthesis entails binding and dissociation of elongation factor G (EF-G), movements of the two tRNA molecules, and motions of the ribosomal subunits. The translocation step is targeted by many antibiotics. Fusidic acid (FA), an antibiotic that blocks EF-G on the ribosome, may also interfere with some of the ribosome rearrangements, but the exact timing of inhibition remains unclear. To follow in real-time the dynamics of the ribosome tRNA-EF-G complex, we have developed a fluorescence toolbox which allows us to monitor the key molecular motions during translocation. Here we employed six different fluorescence observables to investigate how FA affects translocation kinetics. We found that FA binds to an early translocation intermediate, but its kinetic effect on tRNA movement is small. FA does not affect the synchronous forward (counterclockwise) movements of the head and body domains of the small ribosomal subunit, but exerts a strong effect on the rates of late translocation events, i.e. backward (clockwise) swiveling of the head domain and the transit of deacylated tRNA through the E' site, in addition to blocking EF-G dissociation. The use of ensemble kinetics and numerical integration unraveled how the antibiotic targets molecular motions within the ribosome-EF-G complex. PMID- 28874810 TI - Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells. AB - Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells. PMID- 28874812 TI - Towards a new paleotemperature proxy from reef coral occurrences. AB - Global mean temperature is thought to have exceeded that of today during the last interglacial episode (LIG, ~ 125,000 yrs b.p.) but robust paleoclimate data are still rare in low latitudes. Occurrence data of tropical reef corals may provide new proxies of low latitude sea-surface temperatures. Using modern reef coral distributions we developed a geographically explicit model of sea surface temperatures. Applying this model to coral occurrence data of the LIG provides a latitudinal U-shaped pattern of temperature anomalies with cooler than modern temperatures around the equator and warmer subtropical climes. Our results agree with previously published estimates of LIG temperatures and suggest a poleward broadening of the habitable zone for reef corals during the LIG. PMID- 28874813 TI - FunctionAnnotator, a versatile and efficient web tool for non-model organism annotation. AB - ABSATRACT: Along with the constant improvement in high-throughput sequencing technology, an increasing number of transcriptome sequencing projects are carried out in organisms without decoded genome information and even on environmental biological samples. To study the biological functions of novel transcripts, the very first task is to identify their potential functions. We present a web-based annotation tool, FunctionAnnotator, which offers comprehensive annotations, including GO term assignment, enzyme annotation, domain/motif identification and predictions for subcellular localization. To accelerate the annotation process, we have optimized the computation processes and used parallel computing for all annotation steps. Moreover, FunctionAnnotator is designed to be versatile, and it generates a variety of useful outputs for facilitating other analyses. Here, we demonstrate how FunctionAnnotator can be helpful in annotating non-model organisms. We further illustrate that FunctionAnnotator can estimate the taxonomic composition of environmental samples and assist in the identification of novel proteins by combining RNA-Seq data with proteomics technology. In summary, FunctionAnnotator can efficiently annotate transcriptomes and greatly benefits studies focusing on non-model organisms or metatranscriptomes. FunctionAnnotator, a comprehensive annotation web-service tool, is freely available online at: http://fa.cgu.edu.tw/ . This new web-based annotator will shed light on field studies involving organisms without a reference genome. PMID- 28874814 TI - T-bet, but not Gata3, overexpression is detrimental in a neurotropic viral infection. AB - Intracerebral Theiler's murine encephalomyelitis virus (TMEV) infection in mice induces inflammatory demyelination in the central nervous system. Although C57BL/6 mice normally resistant to TMEV infection with viral clearance, we have previously demonstrated that RORgammat-transgenic (tg) C57BL/6 mice, which have Th17-biased responses due to RORgammat overexpression in T cells, became susceptible to TMEV infection with viral persistence. Here, using T-bet-tg C57BL/6 mice and Gata3-tg C57BL/6 mice, we demonstrated that overexpression of T bet, but not Gata3, in T cells was detrimental in TMEV infection. Unexpectedly, T bet-tg mice died 2 to 3 weeks after infection due to failure of viral clearance. Here, TMEV infection induced splenic T cell depletion, which was associated with lower anti-viral antibody and T cell responses. In contrast, Gata3-tg mice remained resistant, while Gata3-tg mice had lower IFN-gamma and higher IL-4 production with increased anti-viral IgG1 responses. Thus, our data identify how overexpression of T-bet and Gata3 in T cells alters anti-viral immunity and confers susceptibility to TMEV infection. PMID- 28874815 TI - Injectable and thermosensitive TGF-beta1-loaded PCEC hydrogel system for in vivo cartilage repair. AB - Chondral defects pose a great challenge for clinicians to manage owing to the limited capacity for self-healing. Various traditional approaches have been adopted for the repair of these defects with unsatisfactory results. Cartilage tissue engineering techniques have emerged as promising strategies to enhance regeneration and overcome these traditional shortcomings. The cell-homing based technique is considered the most promising owing to its unique advantages. Thermosensitive hydrogels have been applied as scaffolds for biomedical applications with smart sol-gel response for altering environmental temperature. Transforming growth factor (TGF)-beta1 is considered to be capable of promoting chondrogenesis. In this study, a novel TGF-beta1-loaded poly(epsilon caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) hydrogel was fabricated using simple procedures. Hydrogel characterization, rheological testing, component analysis, and assessment of sol-gel transition, in vitro degradation, and TGF-beta1 release confirmed that this material possesses a porous microstructure with favorable injectability and sustained drug release. Full-thickness cartilage defects were induced on rat knees for in vivo cartilage repair for eight weeks. Micro-CT and histological evaluation provided further evidence of the optimal capacity of this novel hydrogel for cartilage regeneration with respect to that of other methods. Moreover, our results demonstrated that the cell-free hydrogel is thermosensitive, injectable, biodegradable, and capable of in vivo cartilage repair and possesses high potential and benefits for acellular cartilage tissue engineering and clinical application in the future. PMID- 28874816 TI - Protein tyrosine phosphatase non-receptor 22 and C-Src tyrosine kinase genes are down-regulated in patients with rheumatoid arthritis. AB - Several protein tyrosine phosphatase non-receptor 22 (PTPN22) single-nucleotide polymorphisms (SNPs) have been significantly related with rheumatoid arthritis (RA) susceptibility. Nevertheless, its potential influence on PTPN22 expression in RA has not been completely elucidated. Furthermore, PTPN22 binds to C-Src tyrosine kinase (CSK) forming a key complex in autoimmunity. However, the information of CSK gene in RA is scarce. In this study, we analyzed the relative PTPN22 and CSK expression in peripheral blood from 89 RA patients and 43 controls to determine if the most relevant PTPN22 (rs2488457, rs2476601 and rs33996649) and CSK (rs34933034 and rs1378942) polymorphisms may influence on PTPN22 and CSK expression in RA. The association between PTPN22 and CSK expression in RA patients and their clinical characteristics was also evaluated. Our study shows for the first time a marked down-regulation of PTPN22 expression in RA patients carrying the risk alleles of PTPN22 rs2488457 and rs2476601 compared to controls (p = 0.004 and p = 0.007, respectively). Furthermore, CSK expression was significantly lower in RA patients than in controls (p < 0.0001). Interestingly, a reduced PTPN22 expression was disclosed in RA patients with ischemic heart disease (p = 0.009). The transcriptional suppression of this PTPN22/CSK complex may have a noteworthy clinical relevance in RA patients. PMID- 28874817 TI - Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. AB - Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy for the management of solid tumor malignancies. In ovarian cancer, this is in part due to an immunosuppressive cytokine and cellular tumor microenvironment which suppresses adoptively transferred T cells. We engineered an armored CAR T cell capable of constitutive secretion of IL-12, and delineate the mechanisms via which these CAR T cells overcome a hostile tumor microenvironment. In this report, we demonstrate enhanced proliferation, decreased apoptosis and increased cytotoxicity in the presence of immunosuppressive ascites. In vivo, we show enhanced expansion and CAR T cell antitumor efficacy, culminating in improvement in survival in a syngeneic model of ovarian peritoneal carcinomatosis. Armored CAR T cells mediated depletion of tumor associated macrophages and resisted endogenous PD-L1-induced inhibition. These findings highlight the role of the inhibitory microenvironment and how CAR T cells can be further engineered to maintain efficacy. PMID- 28874818 TI - Endothelial Cell Culture Under Perfusion On A Polyester-Toner Microfluidic Device. AB - This study presents an inexpensive and easy way to produce a microfluidic device that mimics a blood vessel, serving as a start point for cell culture under perfusion, cardiovascular research, and toxicological studies. Endpoint assays (i.e., MTT reduction and NO assays) were used and revealed that the components making up the microchip, which is made of polyester and toner (PT), did not induce cell death or nitric oxide (NO) production. Applying oxygen plasma and fibronectin improved the adhesion and proliferation endothelial cell along the microchannel. As expected, these treatments showed an increase in vascular endothelial growth factor (VEGF-A) concentration profiles, which is correlated with adherence and cell proliferation, thus promoting endothelialization of the device for neovascularization. Regardless the simplicity of the device, our "vein on-a-chip" mimetic has a potential to serve as a powerful tool for those that demand a rapid microfabrication method in cell biology or organ-on-a-chip research. PMID- 28874819 TI - Selection for energy efficiency drives strand-biased gene distribution in prokaryotes. AB - Lagging-strand genes accumulate more deleterious mutations. Genes are thus preferably located on the leading strand, an observation known as strand-biased gene distribution (SGD). Despite of this mechanistic understanding, a satisfactory quantitative model is still lacking. Replication-transcription collisions induce stalling of the replication machinery, expose DNA to various attacks, and are followed by error-prone repairs. We found that mutational biases in non-transcribed regions can explain ~71% of the variations in SGDs in 1,552 genomes, supporting the mutagenesis origin of SGD. Mutational biases introduce energetically cheaper nucleotides on the lagging strand, and result in more expensive protein products; consistently, the cost difference between the two strands explains ~50% of the variance in SGDs. Protein costs decrease with increasing gene expression. At similar expression levels, protein products of leading-strand genes are generally cheaper than lagging-strand genes; however, highly-expressed lagging genes are still cheaper than lowly-expressed leading genes. Selection for energy efficiency thus drives some genes to the leading strand, especially those highly expressed and essential, but certainly not all genes. Stronger mutational biases are often associated with low-GC genomes; as low-GC genes encode expensive proteins, low-GC genomes thus tend to have stronger SGDs to alleviate the stronger pressure on efficient energy usage. PMID- 28874820 TI - Image-based closed-loop feedback for highly mono-dispersed microdroplet production. AB - Micron-scale droplets isolated by an immiscible liquid can provide miniaturised reaction vessels which can be manipulated in microfluidic networks, and has seen a rapid growth in development. In many experiments, the precise volume of these microdroplets is a critical parameter which can be influenced by many external factors. In this work, we demonstrate the combination of imaging-based feedback and pressure driven pumping to accurately control the size of microdroplets produced in a microfluidic device. The use of fast-response, pressure-driving pumps allows the microfluidic flow to be quickly and accurately changed, while directly measuring the droplet size allows the user to define the more meaningful parameters of droplet size and generation frequency rather than flow rates or pressures. The feedback loop enables the drift correction of pressure based pumps, and leads to a large increase in the mono-dispersity of the droplets produced over long periods. We also show how this can be extended to control multiple liquid flows, allowing the frequency of droplet formation or the average concentration of living cells per droplet to be controlled and kept constant. PMID- 28874821 TI - Sprint interval training decreases left-ventricular glucose uptake compared to moderate-intensity continuous training in subjects with type 2 diabetes or prediabetes. AB - Type 2 diabetes mellitus (T2DM) is associated with reduced myocardial glucose uptake (GU) and increased free fatty acid uptake (FFAU). Sprint interval training (SIT) improves physical exercise capacity and metabolic biomarkers, but effects of SIT on cardiac function and energy substrate metabolism in diabetic subjects are unknown. We tested the hypothesis that SIT is more effective than moderate intensity continuous training (MICT) on adaptations in left and right ventricle (LV and RV) glucose and fatty acid metabolism in diabetic subjects. Twenty-six untrained men and women with T2DM or prediabetes were randomized into two-week long SIT (n = 13) and MICT (n = 13) interventions. Insulin-stimulated myocardial GU and fasted state FFAU were measured by positron emission tomography and changes in LV and RV structure and function by cardiac magnetic resonance. In contrast to our hypothesis, SIT significantly decreased GU compared to MICT in LV. FFAU of both ventricles remained unchanged by training. RV end-diastolic volume (EDV) and RV mass increased only after MICT, whereas LV EDV, LV mass, and RV and LV end-systolic volumes increased similarly after both training modes. As SIT decreases myocardial insulin-stimulated GU compared to MICT which may already be reduced in T2DM, SIT may be metabolically less beneficial than MICT for a diabetic heart. PMID- 28874822 TI - Carbon Dots-AS1411 Aptamer Nanoconjugate for Ultrasensitive Spectrofluorometric Detection of Cancer Cells. AB - In the present study, a sensitive and selective signal-on method for aptamer based spectrofluorometric detection of cancer cells is introduced. AS1411, a nucleolin aptamer, is wrapped around water-soluble carbon dots and used as a probe for the detection of several types of cancer cells. Nucleolin, is overexpressed on the surface of cancer cells. Mouse breast 4T1, human breast MCF7, and human cervical HeLa cancer cells were selected as target cells, while human foreskin fibroblast cells HFFF-PI6 served as control cells. For the sensitive and selective spectrofluorimetric detection of target cancer cells in the presence of control cells, the cells were incubated in carbon dots-aptamer solutions, the cell suspensions were subsequently centrifuged and the fluorescence intensities were measured as an analytical signal. The specific targeting of cancer cells by AS1411 aptamers causes the release of carbon dots and enhances the fluorescence intensity. A calibration curve with a dynamic range between 10-4500 4T1 cells and detectability of roughly 7 cells was obtained. In addition, no significant change in the signal was detected by modifying the amount of human foreskin fibroblast control cells. Our results demonstrate similar responses to human MCF7 breast and cervical HeLa cancer cells. PMID- 28874823 TI - Role of Smad3 and p38 Signalling in Cigarette Smoke-induced CFTR and BK dysfunction in Primary Human Bronchial Airway Epithelial Cells. AB - Mucociliary clearance (MCC) is a major airway host defence system that is impaired in patients with smoking-associated chronic bronchitis. This dysfunction is partially related to a decrease of airway surface liquid (ASL) volume that is in part regulated by apically expressed cystic fibrosis transmembrane conductance regulator (CFTR) and large-conductance, Ca2+-activated, and voltage dependent K+ (BK) channels. Here, data from human bronchial epithelial cells (HBEC) confirm that cigarette smoke not only downregulates CFTR activity but also inhibits BK channel function, thereby causing ASL depletion. Inhibition of signalling pathways involved in cigarette smoke-induced channel dysfunction reveals that CFTR activity is downregulated via Smad3 signalling whereas BK activity is decreased via the p38 cascade. In addition, pre-treatment with pirfenidone, a drug presently used to inhibit TGF-beta signalling in idiopathic pulmonary fibrosis, ameliorated BK dysfunction and ASL volume loss. Taken together, our results highlight the importance of not only CFTR but also BK channel function in maintaining ASL homeostasis and emphasize the possibility that pirfenidone could be employed as a novel therapeutic regimen to help improve MCC in smoking-related chronic bronchitis. PMID- 28874824 TI - eIF4B phosphorylation at Ser504 links synaptic activity with protein translation in physiology and pathology. AB - Neuronal physiology requires activity-driven protein translation, a process in which translation initiation factors are key players. We focus on eukaryotic initiation factor 4B (eIF4B), a regulator of protein translation, whose function in neurons is undetermined. We show that neuronal activity affects eIF4B phosphorylation and identify Ser504 as a phosphorylation site regulated by casein kinases and sensitive to the activation of metabotropic glutamate receptors. Ser504 phosphorylation increases eIF4B recruitment to the pre-initiation complex and influences eIF4B localization at synapses. Moreover, Ser504 phosphorylation modulates the translation of protein kinase Mzeta. Therefore, by sensing synaptic activity, eIF4B could adjust translation to neuronal needs, promoting adaptive changes in synaptic plasticity. We also show that Ser504 phosphorylation is increased in vivo in a rat model of epilepsy during epileptogenesis i.e. when translation drives maladaptive synaptic changes. We propose eIF4B as a mediator between neuronal activity and translation, with relevance in the control of synaptic plasticity. PMID- 28874825 TI - Knockout of the ATPase inhibitory factor 1 protects the heart from pressure overload-induced cardiac hypertrophy. AB - Mitochondrial ATP synthase catalyzes the coupling of oxidative phosphorylation. Under pathological conditions, ATP synthase hydrolyzes ATP to replenish protons from the matrix into the intermembrane space, sustaining mitochondrial membrane potential. ATPase inhibitory factor 1 (IF1) is a nuclear-encoded, ATP synthase interacting protein that selectively inhibits the hydrolysis activity of ATP synthase, which may render the protective role of IF1 in ischemic hearts. However, the in vivo cardiac function of IF1 and the potential therapeutic application targeting IF1 remain obscure. In the present study, we uncovered that IF1 is upregulated in mouse hearts with pressure overload-induced hypertrophy and in human hearts with dilated cardiomyopathy. IF1 knockout (KO) mice were protected against cardiac dysfunction and pathological development induced by transverse aortic constriction (TAC) or isoproterenol infusion. The reduced ATP hydrolysis activated AMPK activity in IF1 KO hearts, which together facilitated autophagy. These results suggest that IF1 upregulation in the failing heart may be a maladaptive response. Inhibiting IF1 in the hypertrophied heart not only prevents cell death from excessive mitochondrial depolarization but also activates AMPK signaling and increases autophagy. Therefore, IF1 inhibition may serve as a potential therapeutic target in treating pathological cardiac hypertrophy and heart failure. PMID- 28874826 TI - Deep-level phylogeny of Cicadomorpha inferred from mitochondrial genomes sequenced by NGS. AB - Recent development and advancement of next-generation sequencing (NGS) technologies have enabled the determination of mitochondrial genome (mitogenome) at extremely efficiency. In this study, complete or partial mitogenomes for 19 cicadomorphan species and six fulgoroid species were reconstructed by using the method of high-throughput sequencing from pooled DNA samples. Annotation analyses showed that the mitogenomes obtained have the typical insect mitogenomic content and structure. Combined with the existing hemipteran mitogenomes, a series of datasets with all 37 mitochondrial genes (up to 14,381 nt total) under different coding schemes were compiled to test previous hypotheses of deep-level phylogeny of Cicadomorpha. Thirty-seven species representing Cicadomorpha constituted the ingroup. A taxon sampling with nine species from Fulgoroidea and six from Heteroptera comprised the outgroup. The phylogenetic reconstructions congruently recovered the monophyly of each superfamily within Cicadomorpha. Furthermore, the hypothesis (Membracoidea + (Cicadoidea + Cercopoidea)) was strongly supported under the heterogeneous CAT model. PMID- 28874827 TI - Pregnancy-Associated Plasma Protein-A2 and Anthropometry, Lifestyle, and Biochemical Factors in a Human Adult Population. AB - Pregnancy-associated plasma protein-A2 (PAPP-A2), a metalloproteinase purportedly related to pregnancy, foetal growth and development, has recently been described essential for pre-adult growth. Thus, we measured PAPP-A2 in plasma of a non pregnant population and determined its associations with lifestyle, anthropometric or biochemical factors. In this cross-sectional study of 387 participants (20-70 years) randomly drawn from registration offices near Berlin, Germany, socio-economic and lifestyle factors were assessed by questionnaires, and anthropometric measures and blood samples were taken by trained personnel. Blood was analysed for standard clinical parameters. PAPP-A2 concentration was measured by ELISA. Generalized linear models were used to estimate associations with anthropometric and biochemical factors adjusted for age, sex, and weight. Adjusted mean PAPP-A2 concentration was slightly higher in women (283 pg/mL) than in men (261 pg/mL, p = 0.05) and positively correlated with age (r = 0.17, p = 0.001). PAPP-A2 concentration was inversely associated with body mass index (-2.7 pg/mL per kg/m2, p = 0.03) and weight (-1.0 pg/mL per kg, p = 0.01) and positively associated with gamma-glutamyl transferase (13.6 pg/mL per SD, p = 0.02), aspartate transaminase (18.5 pg/mL per SD, p = 0.002) and lactate dehydrogenase (14.9 pg/mL per SD, p = 0.02). Our results support that PAPP-A2, beyond its established role in early growth and development is relevant in adult metabolisms. PMID- 28874828 TI - SRSF1 suppresses selection of intron-distal 5' splice site of DOK7 intron 4 to generate functional full-length Dok-7 protein. AB - Dok-7 is a non-catalytic adaptor protein that facilitates agrin-induced clustering of acetylcholine receptors (AChR) at the neuromuscular junction. Alternative selection of 5' splice sites (SSs) of DOK7 intron 4 generates canonical and frame-shifted transcripts. We found that the canonical full-length Dok-7 enhanced AChR clustering, whereas the truncated Dok-7 did not. We identified a splicing cis-element close to the 3' end of exon 4 by block-scanning mutagenesis. RNA affinity purification and mass spectrometry revealed that SRSF1 binds to the cis-element. Knocking down of SRSF1 enhanced selection of the intron distal 5' SS of DOK7 intron 4, whereas MS2-mediated artificial tethering of SRSF1 to the identified cis-element suppressed it. Isolation of an early spliceosomal complex revealed that SRSF1 inhibited association of U1 snRNP to the intron distal 5' SS, and rather enhanced association of U1 snRNP to the intron-proximal 5' SS, which led to upregulation of the canonical DOK7 transcript. Integrated global analysis of CLIP-seq and RNA-seq also indicated that binding of SRSF1 immediately upstream to two competing 5' SSs suppresses selection of the intron distal 5' SS in hundreds of human genes. We demonstrate that SRSF1 critically regulates alternative selection of adjacently placed 5' SSs by modulating binding of U1 snRNP. PMID- 28874829 TI - Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity. AB - Butyrylcholinesterase (BChE) is an enzyme with broad substrate and ligand specificities and may function as a generalized bioscavenger by binding and/or hydrolyzing various xenobiotic agents and toxicants, many of which target the central and peripheral nervous systems. Variants of BChE were rationally designed to increase the enzyme's ability to hydrolyze the psychoactive enantiomer of cocaine. These variants were cloned, and then expressed using the magnICON transient expression system in plants and their enzymatic properties were investigated. In particular, we explored the effects that these site-directed mutations have over the enzyme kinetics with various substrates of BChE. We further compared the affinity of various anticholinesterases including organophosphorous nerve agents and pesticides toward these BChE variants relative to the wild type enzyme. In addition to serving as a therapy for cocaine addiction-related diseases, enhanced bioscavenging against other harmful agents could add to the practicality and versatility of the plant-derived recombinant enzyme as a multivalent therapeutic. PMID- 28874831 TI - Converting highly productive arable cropland in Europe to grassland: -a poor candidate for carbon sequestration. AB - Sequestration of atmospheric CO2 as organic carbon by agricultural soils (SOC) is promoted as a climate change mitigation option. IPCC provides guidelines for determining carbon stocks and sequestration potential, incentivising policy changes towards management of farmland for carbon sequestration. However, the basis of the assumption that agricultural soils can sequester significant atmospheric CO2 has been questioned. We sought to determine the potential for conversion of arable cropland to grassland to sequester carbon in the short to medium term and potential limiting factors. There were no differences in SOC stocks in the top 30 cm between grassland up to 17 years old and arable cropland at 14 sites across the UK. However, SOC showed different distribution patterns, being concentrated in the top 10 cm under grassland. Soil microbial communities were significantly different between arable and grassland, with higher biomass and lesser dominance by bacteria in grassland soils. A land use conversion experiment showed these changes occurred within one year of land use change. Failure of grassland soils to accumulate SOC was attributed to reduced available soil nitrogen, resulting in low productivity. The implications of these results for carbon sequestration in soils as a climate change mitigation strategy are discussed. PMID- 28874830 TI - Riparian plant litter quality increases with latitude. AB - Plant litter represents a major basal resource in streams, where its decomposition is partly regulated by litter traits. Litter-trait variation may determine the latitudinal gradient in decomposition in streams, which is mainly microbial in the tropics and detritivore-mediated at high latitudes. However, this hypothesis remains untested, as we lack information on large-scale trait variation for riparian litter. Variation cannot easily be inferred from existing leaf-trait databases, since nutrient resorption can cause traits of litter and green leaves to diverge. Here we present the first global-scale assessment of riparian litter quality by determining latitudinal variation (spanning 107 degrees ) in litter traits (nutrient concentrations; physical and chemical defences) of 151 species from 24 regions and their relationships with environmental factors and phylogeny. We hypothesized that litter quality would increase with latitude (despite variation within regions) and traits would be correlated to produce 'syndromes' resulting from phylogeny and environmental variation. We found lower litter quality and higher nitrogen:phosphorus ratios in the tropics. Traits were linked but showed no phylogenetic signal, suggesting that syndromes were environmentally determined. Poorer litter quality and greater phosphorus limitation towards the equator may restrict detritivore-mediated decomposition, contributing to the predominance of microbial decomposers in tropical streams. PMID- 28874833 TI - Stem cells: R-spondin 3 is a critical regulator of gastric antral stem cell homeostasis. PMID- 28874834 TI - Immunology: LCMs and the liver: additional surveillance. PMID- 28874832 TI - Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1DeltaE9 murine model of Alzheimer's disease. AB - Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer's disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APPSWE/PS1DeltaE9 mouse model of amyloidosis is commensurate with reductions in amyloid-beta (Abeta) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE/PS1DeltaE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long term alterations of gut microbial genera (predominantly Lachnospiraceae and S24 7) and reduction in brain Abeta deposition in aged APPSWE/PS1DeltaE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD. PMID- 28874835 TI - Pancreatic cancer: Exosomes for targeting KRAS in the treatment of pancreatic cancer. PMID- 28874836 TI - Oesophagus: Symptom perception in patients with NERD: do nerves matter? PMID- 28874837 TI - Plasmonic trapping of nanoparticles by metaholograms. AB - Manipulation of nanoparticles in solution is of great importance for a wide range of applications in biomedical, environmental, and material sciences. In this work, we present a novel plasmonic tweezers based on metahologram. We show that various kinds of nanoparticles can be stably trapped in a surface plasmon (SP) standing wave generated by the constructive interference between two coherent focusing SPs. The absence of the axial scattering force and the enhanced gradient force enable to avoid overheating effect while maintaining mechanical stability even under the resonant condition of the metallic nanoparticle. The work illustrates the potential of such plasmonic tweezers for further development in lab-on-a-chip devices. PMID- 28874838 TI - Structural determinants of 5',6'-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel. AB - TRPV4 cation channel activation by cytochrome P450-mediated derivatives of arachidonic acid (AA), epoxyeicosatrienoic acids (EETs), constitute a major mechanisms of endothelium-derived vasodilatation. Besides, TRPV4 mechano/osmosensitivity depends on phospholipase A2 (PLA2) activation and subsequent production of AA and EETs. However, the lack of evidence for a direct interaction of EETs with TRPV4 together with claims of EET-independent mechanical activation of TRPV4 has cast doubts on the validity of this mechanism. We now report: 1) The identification of an EET-binding pocket that specifically mediates TRPV4 activation by 5',6'-EET, AA and hypotonic cell swelling, thereby suggesting that all these stimuli shared a common structural target within the TRPV4 channel; and 2) A structural insight into the gating of TRPV4 by a natural agonist (5',6'-EET) in which K535 plays a crucial role, as mutant TRPV4-K535A losses binding of and gating by EET, without affecting GSK1016790A, 4alpha phorbol 12,13-didecanoate and heat mediated channel activation. Together, our data demonstrates that the mechano- and osmotransducing messenger EET gates TRPV4 by a direct action on a site formed by residues from the S2-S3 linker, S4 and S4 S5 linker. PMID- 28874839 TI - The Schistosoma mansoni genome encodes thousands of long non-coding RNAs predicted to be functional at different parasite life-cycle stages. AB - Next Generation Sequencing (NGS) strategies, like RNA-Seq, have revealed the transcription of a wide variety of long non-coding RNAs (lncRNAs) in the genomes of several organisms. In the present work we assessed the lncRNAs complement of Schistosoma mansoni, the blood fluke that causes schistosomiasis, ranked among the most prevalent parasitic diseases worldwide. We focused on the long intergenic/intervening ncRNAs (lincRNAs), hidden within the large amount of information obtained through RNA-Seq in S. mansoni (88 libraries). Our computational pipeline identified 7029 canonically-spliced putative lincRNA genes on 2596 genomic loci (at an average 2.7 isoforms per lincRNA locus), as well as 402 spliced lncRNAs that are antisense to protein-coding (PC) genes. Hundreds of lincRNAs showed traits for being functional, such as the presence of epigenetic marks at their transcription start sites, evolutionary conservation among other schistosome species and differential expression across five different life-cycle stages of the parasite. Real-time qPCR has confirmed the differential life-cycle stage expression of a set of selected lincRNAs. We have built PC gene and lincRNA co-expression networks, unraveling key biological processes where lincRNAs might be involved during parasite development. This is the first report of a large scale identification and structural annotation of lncRNAs in the S. mansoni genome. PMID- 28874840 TI - UPLC-Q-TOF/MS-based metabonomic studies on the intervention effects of aspirin eugenol ester in atherosclerosis hamsters. AB - Based on the pro-drug principle, aspirin and eugenol were used to synthesize aspirin eugenol ester (AEE) by esterification reaction. In present study, the anti-atherosclerosis effects of AEE were investigated in hamsters with the utilization of metabonomic approach based on UPLC-Q-TOF/MS. Biochemical parameters and histopathological injures in stomach, liver and aorta were evaluated. In atherosclerotic hamster, oral administration of AEE normalized biochemical profile such as reducing TG, TCH and LDL, and significantly reduced body weight gain, alleviated hepatic steatosis and improved pathological lesions in aorta. Slight damages in stomach mucous were found in AEE group. Plasma and urine samples in control, model and AEE groups were scattered in the partial least squares-discriminate analysis (PLS-DA) score plots. Thirteen endogenous metabolites in plasma such as lysophosphatidylcholine (LysoPC), leucine and valine, and seventeen endogenous metabolites in urine such as citric acid, phenol sulphate and phenylacetylglycine were selected as potential biomarkers associated with atherosclerosis. They were considered to be in response to anti atherosclerosis effects of AEE, mainly involved in glycerophospholipid metabolism, amino acid metabolism and energy metabolism. This study extended the understanding of endogenous alterations of atherosclerosis and offered insights into the pharmacodynamic activity of AEE. PMID- 28874841 TI - Epiphyseal bone formation occurs via thyroid hormone regulation of chondrocyte to osteoblast transdifferentiation. AB - Endochondral ossification in the diaphysis of long bones has been studied in depth during fetal development but not postnatally in the epiphysis. Immunohistochemical studies revealed that Sox9 and Col2 expressing immature chondrocytes in the epiphysis transition into prehypertrophic and hypetrophic chondrocytes and finally into osteoblasts expressing Col1 and BSP during postnatal day 7-10, when serum levels of thyroid hormone (TH) rise. Lineage tracing using Rosa-td tomato Col2-Cre-ERT2 mice treated with tamoxifen indicated that the same Col2 expressing chondrocytes expressed prehypertrophic, hypertrophic, and subsequently bone formation markers in a sequential manner in euthyroid but not hypothyroid mice, thus providing evidence that chondrocyte to osteoblast transdifferentiation is TH-dependent. Vascular invasion was apparent at the time of bone formation but not earlier. In vitro studies revealed that TH acting via TRalpha1 promoted expression of SHH while TRbeta1 activation increased IHH but inhibited SHH expression. SHH promoted expression of markers of immature chondrocytes but inhibited chondrocyte hypertrophy while IHH promoted chondrocyte hypertrophy. Based on our data, we propose a model in which TH acting through TRalpha1 and TRbeta1, respectively, fine tune levels of SHH and IHH and, thereby control the transit of proliferating immature chondrocytes into mature hypertrophic chondrocytes to become osteoblasts at the epiphysis. PMID- 28874842 TI - Investigation of Mitochondrial Metabolic Response to Doxorubicin in Prostate Cancer Cells: An NADH, FAD and Tryptophan FLIM Assay. AB - Prostate cancer (PCa) is one of the leading cancers in men in the USA. Lack of experimental tools that predict therapy response is one of the limitations of current therapeutic regimens. Mitochondrial dysfunctions including defective oxidative phosphorylation (OXPHOS) in cancer inhibit apoptosis by modulating ROS production and cellular signaling. Thus, correction of mitochondrial dysfunction and induction of apoptosis are promising strategies in cancer treatment. We have used Fluorescence Lifetime Imaging Microscopy (FLIM) to quantify mitochondrial metabolic response in PCa cells by tracking auto-fluorescent NAD(P)H, FAD and tryptophan (Trp) lifetimes and their enzyme-bound fractions as markers, before and after treatment with anti-cancer drug doxorubicin. A 3-channel FLIM assay and quantitative analysis of these markers for cellular metabolism show in response to doxorubicin, NAD(P)H mean fluorescence lifetime (taum) and enzyme-bound (a2%) fraction increased, FAD enzyme-bound (a1%) fraction was decreased, NAD(P)H a2%/FAD-a1% FLIM-based redox ratio and ROS increased, followed by induction of apoptosis. For the first time, a FRET assay in PCa cells shows Trp-quenching due to Trp-NAD(P)H interactions, correlating energy transfer efficiencies (E%) vs NAD(P)H-a2%/FAD-a1% as sensitive parameters in predicting drug response. Applying this FLIM assay as early predictor of drug response would meet one of the important goals in cancer treatment. PMID- 28874843 TI - Multiple mining impacts induce widespread changes in ecosystem dynamics in a boreal lake. AB - In order to satisfy the needs of constant economic growth, the pressure to exploit natural resources has increased. Since accessible mineral resources are becoming scarce, the mining industry is constantly looking for novel techniques to allow commercial exploitation of lower-grade deposits. However, mining can have considerable impacts on freshwater ecosystems. Here, we present the ecological damage inflicted by mine water originating from the massive Terrafame Talvivaara polymetal mine (central Finland), where bioheap leaching is being applied to high-sulphur low-grade ore. We found that saline mine water has turned the lake meromictic, and sediment is heavily contaminated. As a result, important zooplankton and phytoplankton groups have been significantly altered. As the exploitation of poor-grade deposits is the future of the mining industry globally, water management should be taken to a higher level in order to proceed towards a sustainable mining sector. PMID- 28874844 TI - Serum Monounsaturated Triacylglycerol Predicts Steatohepatitis in Patients with Non-alcoholic Fatty Liver Disease and Chronic Hepatitis B. AB - Chronic liver disease is associated with lipid metabolic disruption. We carried out a study to determine serum lipidomic features of patients with non-alcoholic fatty liver disease (NAFLD) and active chronic hepatitis B (CHB) and explored the biomarkers for non-alcoholic steatohepatitis (NASH). Serum lipidomic profiles of healthy controls (n = 23) and of biopsy-proven NAFLD (n = 42), CHB with NAFLD (n = 22) and without NAFLD (n = 17) were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry. There were distinct serum lipidome between groups of NAFLD and CHB without NAFLD. Most of the neutral lipids and ceramide were elevated in the NAFLD group but were decreased in the CHB without NAFLD group. Plasmalogens were decreased in both groups. Triacylglycerols (TAGs) with lower carbon numbers and double bonds were increased in subjects with NASH. Serum monounsaturated TAG was a significant predictor of NASH (OR = 3.215; 95%CI 1.663-6.331) and positively correlated with histological activity (r = 0.501; P < 0.001). It showed good predictability for NASH in the NAFLD group [area under the receiver operating characteristic curves (AUROC) = 0.831] and was validated in the CHB group (AUROC = 0.833); this characteristic was superior to that of cytokeratin-18 and alanine transaminase. The increase in monounsaturated TAG might be a specific marker for NASH in both NAFLD and CHB patients. PMID- 28874845 TI - M2-like macrophages in the fibrotic liver protect mice against lethal insults through conferring apoptosis resistance to hepatocytes. AB - Acute injury in the setting of liver fibrosis is an interesting and still unsettled issue. Most recently, several prominent studies have indicated the favourable effects of liver fibrosis against acute insults. Nevertheless, the underlying mechanisms governing this hepatoprotection remain obscure. In the present study, we hypothesized that macrophages and their M1/M2 activation critically involve in the hepatoprotection conferred by liver fibrosis. Our findings demonstrated that liver fibrosis manifested a beneficial role for host survival and apoptosis resistance. Hepatoprotection in the fibrotic liver was tightly related to innate immune tolerance. Macrophages undertook crucial but divergent roles in homeostasis and fibrosis: depleting macrophages in control mice protected from acute insult; conversely, depleting macrophages in fibrotic liver weakened the hepatoprotection and gave rise to exacerbated liver injury upon insult. The contradictory effects of macrophages can be ascribed, to a great extent, to the heterogeneity in macrophage activation. Macrophages in fibrotic mice exhibited M2-preponderant activation, which was not the case in acutely injured liver. Adoptive transfer of M2-like macrophages conferred control mice conspicuous protection against insult. In vitro, M2-polarized macrophages protected hepatocytes against apoptosis. Together, M2-like macrophages in fibrotic liver exert the protective effects against lethal insults through conferring apoptosis resistance to hepatocytes. PMID- 28874846 TI - Hyaluronic Acid Coated Chitosan Nanoparticles Reduced the Immunogenicity of the Formed Protein Corona. AB - Studying the interactions of nanoparticles (NPs) with serum proteins is necessary for the rational development of nanocarriers. Optimum surface chemistry is a key consideration to modulate the formation of the serum protein corona (PC) and the resultant immune response. We investigated the constituent of the PC formed by hyaluronic acid-coated chitosan NPs (HA-CS NPs). Non-decorated chitosan NPs (CS NPs) and alginate-coated chitosan NPs (Alg-CS NPs) were utilized as controls. Results show that HA surface modifications significantly reduced protein adsorption relative to controls. Gene Ontology analysis demonstrates that HA-CS NPs were the least immunogenic nanocarriers. Indeed, less inflammatory proteins were adsorbed onto HA-CS NPs as opposed to CS and Alg-CS NPs. Interestingly, HA CS NPs differentially adsorbed two unique anti-inflammatory proteins (ITIH4 and AGP), which were absent from the PC of both controls. On the other hand, CS and Alg-CS NPs selectively adsorbed a proinflammatory protein (Clusterin) that was not found on the surfaces of HA-CS NPs. While further studies are needed to investigate abilities of the PCs of only ITIH4 and AGP to modulate the interaction of NPs with the host immune system, our results suggest that this proof-of-concept could potentially be utilized to reduce the immunogenicity of a wide range of nanomaterials. PMID- 28874847 TI - A guanine derivative as a new MEK inhibitor produced by Streptomyces sp. MK63 43F2. AB - Mitogen-activated protein kinase (MAPK) pathways that direct cellular responses are involved in various biological processes; the RAS-RAF-MEK-ERK pathway is one of the most important MAPK pathways. It is frequently activated in human malignant tumors such as melanomas, thyroid tumors and colorectal carcinomas. Therefore, targeting this pathway has been considered an attractive strategy for new anticancer drugs. In particular, MEK is a promising target because it is a kinase that directly phosphorylates ERK. We performed a screening to discover new MEK inhibitors, and found a guanine derivative produced by Streptomyces sp. MK63 43F2. This guanine derivative was identified to be 2-amino-4-methoxy-5 cyanopyrrolo[2,3-d]pyrimidine (1) through spectroscopic analysis. Compound 1 inhibited MEK1 kinase activity in an ATP-dependent manner and suppressed the phosphorylation of ERK in cancer cells and cell proliferation. Therefore, 1 might be a potent lead compound for new MEK inhibitors.The Journal of Antibiotics advance online publication, 6 September 2017; doi:10.1038/ja.2017.100. PMID- 28874848 TI - Suppressive drug combinations and their potential to combat antibiotic resistance. AB - Antibiotic effectiveness often changes when two or more such drugs are administered simultaneously and unearthing antibiotic combinations with enhanced efficacy (synergy) has been a longstanding clinical goal. However, antibiotic resistance, which undermines individual drugs, threatens such combined treatments. Remarkably, it has emerged that antibiotic combinations whose combined effect is lower than that of at least one of the individual drugs can slow or even reverse the evolution of resistance. We synthesize and review studies of such so-called 'suppressive interactions' in the literature. We examine why these interactions have been largely disregarded in the past, the strategies used to identify them, their mechanistic basis, demonstrations of their potential to reverse the evolution of resistance and arguments for and against using them in clinical treatment. We suggest future directions for research on these interactions, aiming to expand the basic body of knowledge on suppression and to determine the applicability of suppressive interactions in the clinic. PMID- 28874849 TI - Inhibitory effect of obovatol from Magnolia obovata on the Salmonella type III secretion system. AB - In many pathogenic Gram-negative bacteria, such as Salmonella, Escherichia coli, Yersinia and Chlamydia spp., which cause diseases in humans, the type III secretion system (TTSS) is an important virulence factor that translocates effector proteins into the cytosol of host cells. Thus, the TTSS is a good target for antibacterial agents. Here we used a hemolysis assay to search for TTSS inhibitors and found that a compound from Magnolia obovata called obovatol blocks the TTSS of Salmonella. Obovatol showed potent inhibitory activity (IC50=19.8 MUM) against the TTSS-related hemolysis of Salmonella, which was not due to a reduction of bacterial growth. Instead, the compound inhibited bacterial motility, TTSS-related mRNA expression and effector protein secretion. These data demonstrate the inhibitory effect of obovatol on the Salmonella TTSS and suggest that it could be useful for the prevention and supplementary treatment of bacterial infections. PMID- 28874851 TI - Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core. AB - The hamigeran family of natural products has been the target of numerous synthetic efforts because of its biological activity and interesting structural properties. Herein, we disclose our efforts toward the synthesis of hamigerans C and D, unique among the initially isolated members because of their 6-7-5 carbocyclic core. Our approach directly targets this tricyclic motif by sequential Negishi and Heck coupling reactions, yielding an advanced intermediate with all necessary carbons and sufficient functionality poised for completion of the synthesis of these two natural products. PMID- 28874850 TI - Structures and biological activities of novel 4'-acetylated analogs of chrysomycins A and B. AB - Two new 4'-acetylated analogs of chrysomycin were discovered during the screening for antitumor agents from the metabolites of actinomycetes. Their structures and physicochemical properties were determined by standard spectrometric analyses. Their cytotoxicities and antimicrobial activities were evaluated against a panel of cancer cell lines and microbes. While acetylation reinforced the cytotoxicity of chrysomycin B, it weakened the activity of chrysomycin A. Chrysomycin A and its acetylated analog showed high cytotoxicity toward most of the cancer cells with IC50s less than 10 ng ml-1. The 4'-acetyl-chrysomycin A was predominantly observed in nuclei at concentrations where the autofluorescence was observable. Chrysomycins were effective toward Gram-positive bacteria. The 4'-acetylated chrysomycin A and B had MICs of 0.5-2 MUg ml-1 and 2 to greater than 64 MUg ml-1, respectively, toward Gram-positive bacteria including MRSA and VRE. PMID- 28874852 TI - Acoustic allometry revisited: morphological determinants of fundamental frequency in primate vocal production. AB - A fundamental issue in the evolution of communication is the degree to which signals convey accurate ("honest") information about the signaler. In bioacoustics, the assumption that fundamental frequency (f o) should correlate with the body size of the caller is widespread, but this belief has been challenged by various studies, possibly because larynx size and body size can vary independently. In the present comparative study, we conducted excised larynx experiments to investigate this hypothesis rigorously and explore the determinants of f o. Using specimens from eleven primate species, we carried out an inter-specific investigation, examining correlations between the minimum f o produced by the sound source, body size and vocal fold length (VFL). We found that, across species, VFL predicted minimum f o much better than body size, clearly demonstrating the potential for decoupling between larynx size and body size in primates. These findings shed new light on the diversity of primate vocalizations and vocal morphology, highlighting the importance of vocal physiology in understanding the evolution of mammal vocal communication. PMID- 28874853 TI - Editorial: Direct Antiviral Agents Eliminate the Age Barrier to Treatment of Chronic Hepatitis C. AB - Interferon-based therapy for chronic hepatitis C in elderly patients, who are at greatest risk for advanced disease, resulted in low sustained virologic response rates, poor tolerability, a significant frequency of adverse events leading to treatment discontinuation, and the occasional precipitation of hepatic decompensation. In contrast, in the era of direct-acting antiviral therapy, age is no longer a predictor of response rates in those with or without cirrhosis and adverse events are much less frequent. The benefits of treatment of the elderly appear to outweigh potential risks but long-term follow-up is necessary, particularly in those with advanced disease. PMID- 28874855 TI - Ileocecal Resection in Crohn's Disease: REMIND Group Study. PMID- 28874854 TI - Corrigendum: Rural and Urban Residence During Early Life Is Associated with a Lower Risk of Inflammatory Bowel Disease: A Population-Based Inception and Birth Cohort Study. AB - This corrects the article DOI: 10.1038/ajg.2017.208. PMID- 28874856 TI - Continuing Medical Education Questions: September 2017: Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. PMID- 28874857 TI - Sweet's Syndrome: An Unusual Extraintestinal Manifestation of Inflammatory Bowel Disease. PMID- 28874858 TI - Continuing Medical Education: September 2017: Fecal Incontinence Is Associated With Mortality Among Older Adults With Complex Needs: An Observational Cohort Study. PMID- 28874859 TI - Editorial: Severe Acute Liver Injury: Cause Connects to Outcome. AB - Severe acute liver injury (ALI) is a common condition with little objective study of its natural history and outcomes. In this paper by Koch et al. and the Acute Liver Failure (ALF) Study Group, the authors utilize a consensus definition of ALI requiring newly elevated bilirubin, alanine aminotransferase (ALT), and international normalized ration (INR) without evidence of hepatic encephalopathy (HE), with HE as the key differentiator of ALI from ALF. They show significantly higher rates of progression to ALF, liver transplantation, or death in non acetaminophen etiologies of ALI. This study's findings provide guidance in supporting careful allocation of scarce critical care and liver transplant resources for ALI patients. PMID- 28874860 TI - Radiology Prep to the Rescue: Radiocontrast Enema After Failure of Oral Bowel Preparation for Patients with an Ileocolonic Fistula. PMID- 28874861 TI - Response to Thompson. PMID- 28874862 TI - Pre-Study ERCP Practice as a Confounder With Respect to ERCP Results. PMID- 28874864 TI - Continuing Medical Education: September 2017: Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. PMID- 28874863 TI - Editorial: Widening the Use of the Functional Lumen Imaging Probe to Kids With Eosinophilic Esophagitis: Esophageal Narrowing is not Just an Adult Problem. AB - The functional lumen imaging probe (FLIP) provides objective measurement of esophageal distensibility, thus offering a unique and potentially valuable assessment in eosinophilic esophagitis (EoE). Menard-Katcher and colleagues report the first study evaluating use of FLIP in pediatric patients that demonstrated a reduction in esophageal distensibility in patients with EoE compared to patients without EoE. An increase in esophageal distensibility was observed with age among pediatric patients without EoE, but not among those with EoE. While this study further supports the promise of esophageal distensibility assessment in EoE, future work remains needed to optimize FLIP utilization in both research and clinical settings. PMID- 28874865 TI - Response to Malleo et al. PMID- 28874866 TI - Reply to Huang et al. PMID- 28874867 TI - Submucosal Tunneling and Endoscopic Resection of a Huge Gastric Lipoma. PMID- 28874868 TI - Low Frequency of Follow-Up Examinations in the Initial Years From the Diagnosis of Low-Risk Pancreatic BD-IPMNs: The Right Choice? PMID- 28874869 TI - Can Transient Elastography Predict Fibrosis Regression in Patients with Chronic Hepatitis B During Long-Term Antiviral Therapy? PMID- 28874872 TI - Continuing Medical Education Questions: September 2017: Fecal Incontinence Is Associated With Mortality Among Older Adults With Complex Needs: An Observational Cohort Study. PMID- 28874871 TI - Response to Dhoble et al. PMID- 28874873 TI - The overlaying oil type influences in vitro embryo production: differences in composition and compound transfer into incubation medium between oils. AB - The oil overlay micro-drop system is widely used for cultures of mammalian gametes and embryos. We evaluated hereby the effects of two unaltered commercial oils- Sigma mineral oil (S-MO) and Nidoil paraffin oil (N-PO)-on in vitro embryo production (IVP) outcomes using a pig model. The results showed that while either oil apparently did not affect oocyte maturation and fertilization rates, S-MO negatively affected embryo cleavage rates, blastocyst formation rates, and, consequently, total blastocyst efficiency of the system. No differences in the oxidation state were found between the oils or culture media incubated under S-MO or N-PO. Although both oils slightly differed in elemental composition, there were no differences in the concentrations of elements between fresh media and media incubated under oils. By contrast, we demonstrated clear oil-type differences in both the composition of volatile organic compounds (VOC) and the transfer of some of these VOC's (straight-chain alkanes and pentanal and 1,3 diethyl benzene) to the culture medium, which could have influenced embryonic development. PMID- 28874874 TI - 3-Mercaptopyruvate sulfurtransferase produces potential redox regulators cysteine and glutathione-persulfide (Cys-SSH and GSSH) together with signaling molecules H2S2, H2S3 and H2S. AB - Cysteine-persulfide (Cys-SSH) is a cysteine whose sulfhydryl group is covalently bound to sulfur (sulfane sulfur). Cys-SSH and its glutathione (GSH) counterpart (GSSH) have been recognized as redox regulators, some of which were previously ascribed to cysteine and GSH. However, the production of Cys-SSH and GSSH is not well understood. Here, we show that 3-mercaptopyruvate sulfurtransferase (3MST) produces Cys-SSH and GSSH together with the potential signaling molecules hydrogen per- and tri-sulfide (H2S2 and H2S3). Cys-SSH and GSSH are produced in the brain of wild-type mice but not in those of 3MST-KO mice. The levels of total persulfurated species in the brain of 3MST-KO mice are less than 50% of that in the brain of wild-type mice. Purified recombinant 3MST and lysates of COS cells expressing 3MST showed that Cys-SSH and GSSH were produced in the presence of physiological concentrations of cysteine and glutathione, while those with longer sulfur chains, Cys-SSnH and GSSnH, were produced in the presence of lower than physiological concentrations of cysteine and glutathione. The present study provides new insights into the production and physiological roles of these persulfurated species as well as the therapeutic targets for diseases in which these molecules are involved. PMID- 28874875 TI - The role of histone modification and a regulatory single-nucleotide polymorphism (rs2071166) in the Cx43 promoter in patients with TOF. AB - Abnormal level of Cx43 expression could result in CHD. Epigenetic modification and disease-associated, non-coding SNPs might influence gene transcription and expression. Our study aimed to determine the role of histone modification and an rSNP (rs2071166) in the Cx43 promoter in patients with TOF. Our results indicate that H3K18ac bind to Cx43 promoter and that their levels are reduced in TOF patients relative to controls. The relationship between the non-coding SNP in the Cx43 gene and TOF patients was evaluated in 158 patients and 300 controls. The C allele of rs2071166 was confirmed to result in an increased risk of TOF (OR = 1.586, 95%CI 1.149-2.189). Individuals with the CC genotype at rs2071166 also showed a significant susceptibility to TOF (OR = 2.961, 95%CI 1.452-6.038). The mRNA level in TOF who were CC genotype was lower than that in patients with the AA/AC genotype. Functional analysis in cells and transgenic zebrafish models showed that rs2071166 decreased the activity of the promoter and could block the interaction between RXRalpha and RARE. This is the first study to illustrate that epigenetic modification and an rSNP in the Cx43 promoter region play a critical role in TOF by impacting the transcriptional activity and expression level of Cx43. PMID- 28874876 TI - An ultra-compact rejection filter based on spoof surface plasmon polaritons. AB - In this paper, we propose a scheme to construct a new type of ultra-compact rejection filter by loading split-ring resonators (SRRs) on the transmission line of spoof surface plasmon polaritons (SPPs). From the dispersion analysis of the spoof SPP transmission line with and without the SRR loading, we clearly reveal the mechanism of the rejection characteristic for this compact filter. Meanwhile, we fabricate two spoof SPPs waveguides loaded with different amounts of metamaterials particles, and experimentally test them using an Agilent Vector Network Analyzer (VNA) and a homemade near-field scanning system. Both the simulated and measured results agree well with our theoretical analysis and demonstrate the excellent filtering characteristics of our design. The isolation of both filters can be less than -20 dB, and even reach -40 dB at rejection frequencies. The proposed rejection and stop-band filters show important potentials to develop integrated plasmonic functional devices and circuits at microwave and terahertz frequencies. PMID- 28874877 TI - Bone regeneration in minipigs by intrafibrillarly-mineralized collagen loaded with autologous periodontal ligament stem cells. AB - Biomimetic intrafibrillarly-mineralized collagen (IMC) is a promising scaffold for bone regeneration because of its structural and functional similarity to natural bone. The objective of this study was to evaluate the bone regeneration potential of IMC loaded with autologous periodontal ligament stem cells (PDLSCs) in large bone defects in minipigs. A macroporous IMC with a bone-like subfibrillar nanostructure was fabricated using a biomimetic bottom-up approach. Non-healing full thickness defects were established on the cranial bone in minipigs, and IMC and hydroxyapatite (HA) scaffolds seeded with autologous PDLSCs were implanted into these defects. Computed tomographic imaging, histology staining, and atomic force microscopy were applied to evaluate to the quantity, micro/nano structures, and mechanical performance of the neo-bone after 12 weeks of implantation. Compared with HA, IMC showed superior regeneration properties characterized by the profuse deposition of new bony structures with a normal architecture and vascularization. Immunohistochemistry showed that the runt related transcription factor 2 and transcription factor Osterix were highly expressed in the neo-bone formed by IMC. Furthermore, the nanostructure and nanomechanics of the neo-bone formed by IMC were similar to that of natural bone. This study provides strong evidence for the future clinical applications of the IMC-based bone grafts. PMID- 28874878 TI - Growth, structure, and luminescence properties of novel silica nanowires and interconnected nanorings. AB - Novel silica nanowires and interconnected nanorings were firstly synthesized on a graphite paper by typical thermal catalytic chemical vapor deposition method, using silicon and carbon black powders as raw materials. The field emission scanning electron microscopy, energy dispersive x-ray spectroscopy, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and transmission electron microscopy were used to investigate the composition and structure characterization, which indicates that the silica nanowires and interconnected nanorings were amorphous. The growth of the as-prepared silica nanowires and interconnected nanorings was related to the vapor-liquid-solid mechanism, but the nanowire-ring structure may be due to the polycentric nucleation and periodic stable growth with gradual direction changes. The room temperature photoluminescence emission spectrum showed that the silica nanostructures emitted strong blue light at 460 nm, resulting from the combination of neutral oxygen vacancy (=Si-Si=) and selftrapped excitons. The as synthesized novel silica nanowires and interconnected nanorings could be a potential candidate for applications in future light-emitting diodes and optoelectronic nanodevices. PMID- 28874879 TI - Violet Laser Diode Enables Lighting Communication. AB - Violet laser diode (VLD) based white-light source with high color rendering index (CRI) for lighting communication is implemented by covering with Y3Al5O12:Ce3+ (YAG:Ce) or Lu3Al5O12:Ce3+/CaAlSiN3:Eu2+ (LuAG:Ce/CASN:Eu) phosphorous diffuser plates. After passing the beam of VLD biased at 70 mA (~2I th ) through the YAG:Ce phosphorous diffuser, a daylight with a correlated color temperature (CCT) of 5068 K and a CRI of 65 is acquired to provide a forward error correction (FEC) certified data rate of 4.4 Gbit/s. By using the VLD biased at 122 mA (~3.5I th ) to excite the LuAG:Ce/CASN:Eu phosphorous diffuser with 0.85-mm thickness, a warm white-light source with a CCT of 2700 K and a CRI of 87.9 is obtained at a cost of decreasing transmission capacity to 2.4 Gbit/s. Thinning the phosphor thickness to 0.75 mm effectively reduces the required bias current by 32 mA to achieve the same CCT for the delivered white light, which offers an enlarged CRI of 89.1 and an increased data rate of 4.4 Gbit/s. Further enlarging the bias current to 105 mA remains the white-light transmission capacity at 4.4 Gbit/s but reveals an increased CCT of 3023 K and an upgraded CRI of 91.5. PMID- 28874880 TI - Monitoring Pertussis Infections Using Internet Search Queries. AB - This study aims to assess the utility of internet search query analysis in pertussis surveillance. This study uses an empirical time series model based on internet search metrics to detect the pertussis incidence in Australia. Our research demonstrates a clear seasonal pattern of both pertussis infections and Google Trends (GT) with specific search terms in time series seasonal decomposition analysis. The cross-correlation function showed significant correlations between GT and pertussis incidences in Australia and each state at the lag of 0 and 1 months, with the variation of correlations between 0.17 and 0.76 (p < 0.05). A multivariate seasonal autoregressive integrated moving average (SARIMA) model was developed to track pertussis epidemics pattern using GT data. Reflected values for this model were generally consistent with the observed values. The inclusion of GT metrics improved detective performance of the model (beta = 0.058, p < 0.001). The validation analysis indicated that the overall agreement was 81% (sensitivity: 77% and specificity: 83%). This study demonstrates the feasibility of using internet search metrics for the detection of pertussis epidemics in real-time, which can be considered as a pre-requisite for constructing early warning systems for pertussis surveillance using internet search metrics. PMID- 28874881 TI - Oceanographic drivers of the vertical distribution of a highly migratory, endothermic shark. AB - Salmon sharks Lamna ditropis are highly migratory, upper trophic level predators in North Pacific ecosystems. We analysed a multi-year satellite tag dataset to investigate the habitat use of female salmon sharks across their broad range in the eastern North Pacific (NEP) and identified key environmental factors that influence vertical distribution. Salmon sharks displayed remarkable plasticity in habitat use across disparate oceanographic regions in the NEP and increased utilization of deeper waters in offshore habitats. Diel shifts in vertical distribution and behaviour were consistently observed across their range and likely reflect shifts in their foraging ecology. Salmon sharks utilized a broad thermal niche and exhibited submergence behaviour, possibly for thermal refuge, when encountering sea surface temperatures outside their preferred temperature distribution. Moreover, the vertical distribution of salmon sharks indicates they were able to exploit low dissolved oxygen environments (<1-3 ml l-1), occasionally for extended periods of time in offshore habitats. However, salmon sharks generally reduced their use of deeper waters when encountering the combination of cold temperatures (<6 degrees C) and low dissolved oxygen concentrations (<1-3 ml l-1). Combining vertical distribution with high resolution horizontal movements furthers our understanding of the ecological and environmental drivers of movement across short (diel) and long-term (migratory) scales. PMID- 28874883 TI - xSyn: A Software Tool for Identifying Sophisticated 3-Way Interactions From Cancer Expression Data. AB - BACKGROUND: Constructing gene co-expression networks from cancer expression data is important for investigating the genetic mechanisms underlying cancer. However, correlation coefficients or linear regression models are not able to model sophisticated relationships among gene expression profiles. Here, we address the 3-way interaction that 2 genes' expression levels are clustered in different space locations under the control of a third gene's expression levels. RESULTS: We present xSyn, a software tool for identifying such 3-way interactions from cancer gene expression data based on an optimization procedure involving the usage of UPGMA (Unweighted Pair Group Method with Arithmetic Mean) and synergy. The effectiveness is demonstrated by application to 2 real gene expression data sets. CONCLUSIONS: xSyn is a useful tool for decoding the complex relationships among gene expression profiles. xSyn is available at http://www.bdxconsult.com/xSyn.html. PMID- 28874882 TI - Glucosyltransferase Activity of Clostridium difficile Toxin B Triggers Autophagy mediated Cell Growth Arrest. AB - Autophagy is a bulk cell-degradation process that occurs through the lysosomal machinery, and many reports have shown that it participates in microbial pathogenicity. However, the role of autophagy in Clostridium difficile infection (CDI), the leading cause of antibiotics-associated diarrhea, pseudomembranous colitis and even death in severe cases, is not clear. Here we report that the major virulent factor toxin B (TcdB) of Clostridium difficile elicits a strong autophagy response in host cells through its glucosyltransferase activity. Using a variety of autophagy-deficient cell lines, i.e. HeLa/ATG7 -/-, MEF/atg7 -/-, MEF/tsc2 -/-, we demonstrate that toxin-triggered autophagy inhibits host cell proliferation, which contributes to TcdB-caused cytopathic biological effects. We further show that both the PI3K complex and mTOR pathway play important roles in this autophagy induction process and consequent cytopathic event. Although the glucosyltransferase activity of TcdB is responsible for inducing both cell rounding and autophagy, there is no evidence suggesting the causal relationship between these two events. Taken together, our data demonstrate for the first time that the glucosyltransferase enzymatic activity of a pathogenic bacteria is responsible for host autophagy induction and the following cell growth arrest, providing a new paradigm for the role of autophagy in host defense mechanisms upon pathogenic infection. PMID- 28874884 TI - Quality by Design-Applied Liquid Chromatography-Tandem Mass Spectrometry Determination of Enzalutamide Anti-Prostate Cancer Therapy Drug in Spiked Plasma Samples. AB - This research article presents the Quality by Design (QbD)-finalised conditions for a method that uses liquid chromatography-tandem mass spectrometry for the determination of concentration of enzalutamide (ENZ), an atypical anticancer drug, in a drug formulation and in spiked plasma samples. Critical process attributes (CPA) considered to be the influential parameters in separation, identification, and quantification processes by ultrahigh-performance liquid chromatography-electrospray ionisation-tandem mass spectrometry (UHPLC-ESI-MS/MS) were organic content, buffer strength, pH modifier, flow rate, spray voltage, sheath gas, and auxiliary gas that alter critical analytical attributes, such as retention time (R1) and area (R2). These factors were evaluated first in a factorial design (Taguchi orthogonal array design) and then extensively in a central composite design (CCD) to zero-in on the mobile phase for the quantification of ENZ standard drug and along with its internal standard (ENZIS) in spiked plasma samples and in formulation. Pareto chart from initial factorial design (Taguchi orthogonal array design) model suggested which of the CPA factors should be given the weightage, that is, to be exhaustively analysed in the CCD and response surface analysis. The elaborated parameters proposed by World Health Organization were studied by method validation, ie, selectivity, linearity, accuracy, precision repeatability system-suitability tests, method robustness/ruggedness, sensitivity, and stability. The strategy followed gives an insight on the development of a robust QbD-compliant quantitative UHPLC-ESI-MS/MS method for ENZ drug containing plasma samples (spiked). PMID- 28874885 TI - Ethanol Extract of Blighia sapida Stem Bark Show Remarkable Prophylactic Activity in Experimental Plasmodium berghei-Infected Mice. AB - This work explores the antiplasmodial potential of ethanol extract of Blighia sapida (Lin. Sapindaceae) in chloroquine (CQ)-resistant Plasmodium berghei (ANKA strain)-infected mice. Chloroquine-resistant (ANKA) strain of P berghei was inoculated intraperitoneally into Swiss albino mice. Mice were treated orally for 4 consecutive days, before and after inoculation (prophylactic, suppressive, and curative models) with graded doses of the plant extracts with Artemether Lumefantrine (Coartem) as control. Prophylactically, the extract showed a remarkable activity in the chemosuppression of P berghei parasites (P < .01) ranging from 57% to 36.5% at doses of 200 to 800 mg/kg, respectively, whereas Coartem (10 mg/kg) produced 62.1% chemosuppression. No significant chemosuppression was observed in the curative and suppressive models. The plant extract appeared to be safe at the highest dose tested (5000 mg/kg) for acute toxicity, with no adverse effect on the different organs. The plant extract possesses prophylactic antimalarial activity, which supports its use in the prevention of malaria. PMID- 28874887 TI - When the patient is also a carer. PMID- 28874886 TI - In Search for Optimal Targets for Intraoperative Fluorescence Imaging of Peritoneal Metastasis From Colorectal Cancer. AB - Peritoneal metastasis (PM) occurs in about 10% of patients with colorectal cancer (CRC). Fluorescence imaging can enhance contrast between cancerous and benign tissue, enabling the surgeon to clearly visualize PM during cytoreductive surgery. This study assessed the suitability of different biomarkers as potential targets for tumor-targeted imaging of PM of CRC. Tissue samples from primary tumor and PM from patients with CRC were obtained from the pathology archives and immunohistochemical stainings were performed. Overexpression of the epithelial cell adhesion molecule (EpCAM) and carcinoembryonic antigen (CEA) was seen in 100% of PM samples and the expression was strong in >70% of samples. Tyrosine kinase Met (C-Met) and folate receptor alpha overexpression was seen in 20% of PM samples. For successful application of tumor-targeted intraoperative fluorescence imaging of PM, biomarkers need to be identified. We demonstrated that both EpCAM and CEA are suitable targets for fluorescence imaging of PM in patients with CRC. PMID- 28874888 TI - Women with cancer in low-income countries. PMID- 28874889 TI - User survey of Nanny Angel Network, a free childcare service for mothers with cancer. AB - PURPOSE: The purpose of the present study was to determine user satisfaction with Nanny Angel Network (nan), a free childcare service for mothers undergoing cancer treatment. METHODS: All 243 living mothers who had used the nan service were invited by telephone to participate in an online research survey; 197 mothers (81%) consented to participate. The survey, sent by e-mail, consisted of 39 items divided into these categories: demographics, supports, use, satisfaction, and general comments. RESULTS: Of the 197 mothers who consented to receive the e mailed survey, 104 (53%) completed it. More than 90% of the mothers were very satisfied with the help and support from their Nanny Angel. Many mothers mentioned that the Nanny Angel was most helpful during treatment and medical appointments, with 75% also mentioning that their Nanny Angel helped them to adhere to their scheduled medical appointments. However, 64% felt that they had not received enough visits from their Nanny Angel. CONCLUSIONS: Satisfaction with the nan childcare provider was high, but mothers wished the service had been available to them more often. Our study highlights the importance of providing childcare to mothers with inadequate support systems, so as to allow for greater adherence to treatment and medical appointments, and for more time to recover. PMID- 28874890 TI - Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations. AB - BACKGROUND: In the present study, we examined the pattern of metastatic spread in patients with advanced non-small-cell lung cancer (nsclc) and the effect of EGFR mutations. METHODS: Patients were identified from a provincial cancer registry, and individual medical records were reviewed. Patients were included if they had stage iv nsclc and underwent diagnostic EGFR mutation testing. Patients were divided into EGFR mutation-positive (EGFR+) and EGFR wild type (wt) cohorts. The primary endpoint was the cumulative incidence for each metastatic site: lung, bone, brain, liver, adrenal glands, distant nodes, and other. Cumulative incidence curves were estimated using a competing-risks method. The secondary outcome was survival. RESULTS: Of the 543 identified patients, 121 (22.3%) tested as EGFR+, and 422 (77.7%) tested as EGFR wt. The incidence of brain (39.2% vs. 28.2%, p = 0.038) and lung (61.2% vs. 51.0%, p = 0.048) metastasis was higher in the EGFR+ cohort than in the EGFR wt cohort. In the EGFR+ cohort, a higher incidence of liver metastasis was associated with the exon 21 mutation subtype than with the exon 19 deletion subtype [23% vs. 7%, p < 0.01; hazard ratio (hr): 3.47]. Median survival was significantly longer for the EGFR+ cohort than for the EGFR wt cohort (22.4 months vs. 7.9 months, p < 0.001). In multivariable analysis, brain (hr: 1.73), liver (hr: 1.69), and bone (hr: 1.89) metastases were associated with worse survival. CONCLUSIONS: Rates of lung and brain metastases are higher in EGFR mutation carriers, even when adjusted for differences in survival. Brain, liver, and bone metastases are independent negative prognostic factors for survival. PMID- 28874891 TI - Real-life treatment of metastatic colorectal cancer with regorafenib: a single centre review. AB - BACKGROUND: Various tyrosine kinase signalling pathways affect the development and progression of colorectal cancer (crc). In clinical trials, regorafenib has been associated with a survival benefit in metastatic crc (mcrc). We assessed the safety and efficacy of regorafenib in real-world patients. METHODS: In a retrospective review of patients with mcrc treated with regorafenib at our institution from 2013 to 2015, patient demographics, treatment, and survival data were collected. Progression-free survival (pfs) and overall survival (os) were estimated using the Kaplan-Meier method. RESULTS: In total, 48 patients were offered regorafenib, and 35 (73%) started treatment. Of the patients who started regorafenib, 57% were men. Median age in the cohort was 61 years, and all patients had a performance status in the range 0-2. Time from diagnosis of mcrc to regorafenib treatment was more than 18 months in 71% of patients. Starting dose was 160 mg in 54% of the patients, 120 mg in 40%, and 80 mg in 6%. Dose reductions occurred in 34% of the patients, and interruptions, in 29%. Best response was progressive disease (60%) and stable disease (17%); response in the rest of the patients was unknown. The most common adverse events on regorafenib (any grade) were fatigue (57%), hyperbilirubinemia (43%), thrombocytopenia (37%), anorexia (31%), and hypertension (31%). The most common grade 3 or 4 adverse events were fatigue (29%), hypophosphatemia (17%), weight loss (11%), and hyperbilirubinemia (9%). Common reasons for discontinuing regorafenib included progressive disease (51%) and toxicity (26%). In patients treated with regorafenib, pfs was 2.4 months (95% confidence interval: 1.8 to 3.3 months) and os was 5.6 months (95% confidence interval: 3.7 to 8.9 months). No factors were associated with survival in univariate or multivariate analysis. CONCLUSIONS: In a real-world setting, regorafenib is associated with survival similar to that reported in the randomized controlled trials, but at the expense of toxicity leading to discontinuation in many patients. Future studies of regorafenib should focus on identifying the patients most likely to benefit and on minimizing toxicity. PMID- 28874892 TI - Treatment patterns and trends in patients dying of prostate cancer in Quebec: a population-based study. AB - INTRODUCTION: Since just after the year 2000 in Quebec, the management of metastatic castration-resistant prostate cancer (mcrpc) has evolved considerably, with the inclusion of docetaxel-based chemotherapy, bone-targeted therapies (zoledronic acid and denosumab), and more recently, abiraterone, enzalutamide, and cabazitaxel for docetaxel-refractory patients. In the present study, we aimed to analyze contemporary mcrpc management patterns and therapy utilization trends in Quebec. METHODS: The study cohort consisted of patients dying of prostate cancer (pca) between January 2001 and December 2013, selected from Quebec public health care insurance databases. Patient selection was based on death from a pca related cause or therapy used according to the Canadian Urological Association guidelines on mcrpc management. Treatments included chemotherapy (mitoxantrone before 2005 and docetaxel after 2005), abiraterone, bone-targeted therapy (zoledronic acid or denosumab, or both), and palliative radiation therapy (rt). During the study period, neither enzalutamide nor cabazitaxel was publicly reimbursed in Quebec, and as a result, no capture of their use was possible for this study. Multivariate logistic regression was used to identify factors associated with the probability of receiving chemotherapy, bone-targeted therapies, and palliative rt before death from pca. RESULTS: Overall, the database search identified 3106 patients who died of pca between January 2001 and December 2013. Median age of death was 78 years. Of those 3106 patients, just 2568 (83%) received mcrpc-specific treatments: chemotherapy, abiraterone, palliative rt, or bone-targeted therapy; the other 17% of the patients were managed solely with maximum androgen blockade (androgen deprivation therapy plus anti-androgens) despite a record of pca-related death. Logistic regression analyses indicate that patients dying after 2005 were more likely to have received chemotherapy [odds ratio (or): 1.51; 95% ci: 1.22 to 1.85] and bone targeted therapy (or: 1.97; 95% ci: 1.64 to 2.37). Age was a significant predictor for the use of chemotherapy, bone-targeted therapy, and palliative rt (ors in the range 0.96-0.98, p < 0.05). CONCLUSIONS: Patient age seems to be a strong determinant in the of selection mcrpc therapy, affecting the probability of the use of chemotherapy, bone-targeted therapy, or palliative rt. Although chemotherapy is still used only in a small percentage of patients, the introduction of new therapies-such as bone-targeted therapy, docetaxel, and abiraterone-affected treatment selection over time. The availability of enzalutamide since February 2014 will likely produce additional changes in mcrpc management. PMID- 28874893 TI - Systemic therapy in incurable gastroenteropancreatic neuroendocrine tumours: a clinical practice guideline. AB - PURPOSE: The purpose of the present review was to determine which antineoplastic systemic therapy is most effective in improving clinical outcomes for patients with incurable gastroenteropancreatic neuroendocrine tumours (nets). METHODS: A systematic search (2008-2016) of the literature in the medline and embase databases and the Cochrane Database of Systematic Reviews was conducted; abstracts from the American Society of Clinical Oncology, the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, the European Society for Medical Oncology, the European Cancer Congress, the European Neuroendocrine Tumor Society, and the North American Neuroendocrine Tumor Society were reviewed. Draft recommendations were created, and a comprehensive review process was undertaken. Outcomes-including progression-free survival (pfs), overall survival, objective response rate, adverse events, and quality of life-were extracted from each of the studies. RESULTS: Eleven randomized controlled trials (rcts), sixteen nonrandomized prospective studies, and thirteen retrospective studies met the inclusion criteria. CONCLUSIONS: Patients with well-or moderately-differentiated pancreatic nets (pnets) should receive targeted therapy (that is, everolimus or sunitinib), and patients with non-pnets should be offered either targeted therapy (that is, everolimus) or somatostatin analogues (ssas-that is, octreotide long acting release or lanreotide). Evidence from two phase iii trials demonstrated a significant pfs benefit for patients with pnets. For patients with non-pnets, the evidence comes from subgroup analyses of rcts, as well as from a planned interim analysis. Although the evidence has limitations, the rarity of the disease, coupled with the difficulty of conducting methodologically sound trials in the affected population, means that treatment decisions have to make use of the best available evidence. Because of insufficient evidence for both pnets and non pnets, no evidence-based recommendation can be made for or against other types of targeted therapy, other ssas, chemotherapy, or combination therapy. PMID- 28874894 TI - Acute care hospitalization near the end of life for cancer patients who die in hospital in Canada. AB - Acute care hospitals have a role in managing the health care needs of people affected by cancer when they are at the end of life. However, there is a need to provide end-of-life care in other settings, including at home or in hospice, when such settings are more appropriate. Using data from 9 provinces, we examined indicators that describe the current landscape of acute care hospital use at the end of life for patients who died of cancer in hospital in Canada. Interprovincial variation was observed in acute care hospital deaths, length of stay in hospital, readmission to hospital, and intensive care unit use at the end of life. High rates of acute care hospital use near the end of life might suggest that community and home-based end-of-life care might not be suiting patient needs. PMID- 28874895 TI - Wherein the authors attempt to minimize the confusion generated by their study "Breast cancer mortality after a diagnosis of ductal carcinoma in situ" by several commentators who disagree with them and a few who don't: a qualitative study. PMID- 28874896 TI - Phase I/II trial of dose-reduced capecitabine in elderly patients with advanced colorectal cancer. AB - BACKGROUND: Combination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial. METHODS: A multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1-14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity. RESULTS: Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0-50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh). CONCLUSIONS: Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc. PMID- 28874897 TI - Oral Chinese herbal medicine as maintenance treatment after chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: The concept of maintenance therapy in cancer treatment is currently under debate because of modest survival benefits, added toxicity, economic considerations, and quality-of-life concerns. Traditional Chinese Medicine (tcm) is widely used in China for cancer patients, offering the advantages of low toxicity and enhancement of quality of life. However, no systematic reviews or meta-analyses have assessed the role of tcm as maintenance treatment for non small-cell lung carcinoma. METHODS: We searched the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, PubMed, embase, and the Cochrane Library databases for all eligible studies. The endpoints were overall survival (os), progression-free survival (pfs), the 1-year and 2-year survival rates, and performance status. Our meta-analysis used a fixed-effects model and a random-effects model for heterogeneity in the Stata software application (version 11.0: StataCorp LP, College Station, TX, U.S.A.), with the results expressed as hazard ratios (hrs) or risk ratios (rrs), with their corresponding 95% confidence intervals (95% cis). RESULTS: Sixteen randomized studies representing 1150 patients met the inclusion criteria. Compared with best supportive care, observation, or placebo, tcm as maintenance treatment was associated with a significant increase in os (hr: 0.49; 95% ci: 0.35 to 0.68; p < 0.001), pfs (hr: 0.66; 95% ci: 0.51 to 0.84; p = 0.001), and 2-year survival rate (rr: 0.63; 95% ci: 0.44 to 0.92, p = 0.017), and a significant improvement in performance status (rr: 0.68; 95% ci: 0.61 to 0.75; p < 0.001). CONCLUSIONS: For patients who show non-progression-including stable disease, partial response, or complete response after first-line chemotherapy, including those with poor quality of life, oral Chinese herbal medicine can be considered an efficient and safe maintenance therapy strategy. PMID- 28874898 TI - Experiences of Canadian oncologists with difficult patient deaths and coping strategies used. AB - OBJECTIVES: We aimed to explore and identify what makes patient death more emotionally difficult for oncologists and how oncologists cope with patient death. METHODS: A convenience sample of 98 Canadian oncologists (50 men, 48 women) completed an online survey that included a demographics section and a section about patient death. RESULTS: More than 80% of oncologists reported that patient age, long-term management of a patient, and unexpected disease outcomes contributed to difficult patient loss. Other factors included the doctor-patient relationship, identification with the patient, caregiver-related factors, oncologist-related factors, and "bad deaths." Oncologists reported varying strategies to cope with patient death. Most prevalent was peer support from colleagues, including nurses and other oncologists. Additional strategies included social support, exercise and meditation, faith, vacations, and use of alcohol and medications. CONCLUSIONS: Oncologists listed a number of interpersonal and structural factors that make patient death challenging for them to cope with. Oncologists reported a number of coping strategies in responding to patient death, including peer support, particularly from nursing colleagues. No single intervention will be suitable for all oncologists, and institutions wishing to help their staff cope with the emotional difficulty of patient loss should offer a variety of interventions to maximize the likelihood of oncologist participation. PMID- 28874899 TI - Clinical results of accelerated hypofractionated radiotherapy for central-type small lung tumours. AB - PURPOSE: We evaluated the efficacy and toxicity of accelerated hypofractionated radiotherapy (ahypof-rt) for central-type small lung tumours. METHODS: Between November 2006 and January 2015, 40 patients with central-type small lung tumours underwent ahypof-rt delivered using 10 MV X-rays and a coplanar 3-field technique. The number of fractions ranged from 24 to 28, with a fraction size of 2.5-3 Gy. A total dose of 69-75 Gy to the isocentre of the planning target volume was administered to each patient. Cumulative survival and local control rates were calculated using the Kaplan-Meier method. RESULTS: The 27 men and 13 women enrolled in the study had a median age of 79 years (range: 60-87 years). The tumour stage was T1a in 9 patients, T1b in 17 patients, and T2a in 14 patients, with a median size of 26.5 cm (range: 11-49 cm). The median follow-up period was 23 months. A complete response was achieved in 3 patients (7.5%), and a partial response, in 17 patients (42.5%). The overall 2-year and 3-year local control rates were 87.3% and 81.8% respectively; the 2-year and 3-year overall survival rates were 78.9% and 66.7% respectively. Grade 3 pneumonitis occurred in 3 patients; no other severe adverse events (>=grade 3) were observed in any patient. CONCLUSIONS: Accelerated hypofractionated radiotherapy using a fraction size of 2.5-3 Gy was highly safe and can be a more effective treatment option than conventional radiotherapy for patients with central-type small lung tumours. PMID- 28874900 TI - Exercise for people with cancer: a systematic review. AB - BACKGROUND: This systematic review was completed by the Exercise for People with Cancer Guideline Development Group, a group organized by Cancer Care Ontario's Program in Evidence-Based Care (pebc). It provides background and guidance for clinicians with respect to exercise for people living with cancer in active and post treatment. It focuses on the benefits of specific types of exercise, pre screening requirements for new referrals, safety concerns, and delivery models. METHODS: Using the pebc's standardized approach, medline and embase were systematically searched for existing guidelines, systematic reviews, and primary literature. RESULTS: The search identified two guidelines, eighteen systematic reviews, and twenty-nine randomized controlled trials with relevance to the topic. The present review provides conclusions about the duration, frequency, and intensity of exercise appropriate for people living with cancer. CONCLUSIONS: The evidence shows that exercise is safe and provides benefit in quality of life and in muscular and aerobic fitness for people with cancer both during and after treatment. The evidence is sufficient to support the promotion of exercise for adults with cancer, and some evidence supports the promotion of exercise in group or supervised settings and for a long period of time to improve quality of life and muscular and aerobic fitness. Exercise at moderate intensities could also be sustainable for longer periods and could encourage exercise to be continued over an individual's lifetime. It is important that a pre-screening assessment be conducted to evaluate the effects of disease, treatments, and comorbidities. PMID- 28874901 TI - Adrenocortical carcinoma: patterns of care and role of adjuvant radiation therapy a population-based study and review of the literature. AB - PURPOSE: We reviewed the experience of a tertiary cancer centre in the management of adrenocortical carcinoma (acc) treated over 40 years. We also searched the literature for guidelines related to the treatment of acc and for evidence for adjuvant radiation therapy (rt). METHODS: In a retrospective chart review, acc patients treated between January 1974 and December 2013 were identified, and patient demographics and tumour characteristics were extracted. Outcomes data, including dates and sites of failure, vital status, and cause of death, were collected. Overall survival was estimated using the Kaplan- Meier method. A medline search using PubMed, Ovid, and embase was used to review the literature about the role of rt and any available management guidelines for acc. RESULTS: Of 81 patients identified during the chart review, 39 had confirmed acc. In 32 patients, surgical resection was performed, including in 2 patients with M1 disease. Of those 32 patients, 16 received adjuvant systemic treatment (mitotane or concurrent chemoradiation). Only 6 patients received adjuvant rt, of whom 3 are still alive (2 living with distant failure). At a median follow-up of 3.8 years, 28 patients had died (72%), 10 were living (26%), and 1 had been lost to follow-up. Of the 22 patients for whom failure data were available, 2 experienced local failure, and the rest, distant failure. CONCLUSIONS: The current data are insufficient to make treatment recommendations. Use of collaborative databases and consensus about diagnostic and therapeutic guidelines are warranted for better identification of optimum management. Adjuvant rt could be a reasonable option for R1 disease, but further research is needed. PMID- 28874902 TI - Lymph node retrieval rates in melanoma: a quality assessment parameter. AB - INTRODUCTION: Regional lymph node dissection (rlnd) for melanoma with nodal metastasis is a specialized procedure that is associated with improved disease specific survival in selected patients. Furthermore, there is evidence that a higher lymph node retrieval rate (lnrr) is associated with improved local control. Currently, no consensus has been reached on the definition of an adequate lnrr. A minimum lnrr has been proposed as a quality assessment parameter that has to be validated. METHODS: We conducted a retrospective cohort analysis at the Princess Margaret Cancer Centre (University Health Network, Toronto, ON). The lnrrs for all patients who underwent rlnd for malignant cutaneous melanoma during 2000-2010 were recorded. Indications for rlnd were a positive sentinel lymph node biopsy or clinical lymphadenopathy (palpable or radiologically detected). RESULTS: Of the 207 identified rlnds, 146 (70.5%) were subsequent to a positive sentinel lymph node biopsy, and 61 (29.5%) were performed for clinical lymphadenopathy. The median lnrr was 24 nodes (range: 9-47 nodes; 10th percentile: 14 nodes) for axillary rlnd, 12 nodes (range: 5-30 nodes; 10th percentile: 8 nodes) for inguinal rlnd, and 16 nodes (range: 10-21 nodes; 10th percentile: 11 nodes) for ilioinguinal rlnd. The results were similar when comparing patients with positive sentinel lymph nodes and those with clinical lymphadenopathy, and the same surgical techniques were used in both groups. CONCLUSIONS: The lnrrs at our institution are similar to rates reported at other tertiary-care melanoma centres. A minimum acceptable lnrr can be considered a quality assessment parameter in the surgical management of melanoma with nodal metastasis. PMID- 28874903 TI - Pomalidomide desensitization in a patient hypersensitive to immunomodulating agents. AB - Despite progressive treatments with tandem stem-cell transplantation, patients with incurable myeloma eventually succumb to relapsed or refractory disease if left untreated. Promising agents such as proteasome inhibitors and immunomodulating imide drugs (imids), including the newer-generation agent pomalidomide, in combination with lower-dose dexamethasone, have been shown to be effective and to significantly improve and prolong survival in pretreated patients. Although the incidence of pomalidomide hypersensitivity reaction (hsr) in this class of drugs is not as well known, we have documented cutaneous toxicity (grade 3 by the Common Terminology Criteria for Adverse Events, version 4) in 2 separate cases (not yet published). Because the imids are chemically, structurally, and pharmacologically similar, it is not unreasonable to consider possible cross-reactivity in pomalidomide recipients who developed hsr when receiving previous lines of imids. As a patient's advocate, it is only prudent to provide a responsible, and yet practical, means to better address cross sensitivity for patients. Intervention with the use of a rapid desensitization program (rdp) as a preventive measure should be introduced before initiating pomalidomide. Such a proactive measure for the patient's safety will ensure a smooth transition into pomalidomide treatment. A hsr can be either related or non related to immunoglobulin E. As imids become an essential treatment backbone for myeloma and other plasma-cell diseases, an increasing number of patients could experience skin and other life-threatening toxicities, resulting in unnecessary discontinuation of these life-prolonging agents. An extemporaneously prepared pomalidomide suspension developed at our centre enables patients to undergo rdp safely. Patients enjoy a good quality of life and clinical response after the rdp procedure. PMID- 28874905 TI - Communication and informed consent ... a story. PMID- 28874904 TI - Extrahepatic metastasis of hepatocellular carcinoma arising from a hepatic adenoma without concurrent intrahepatic recurrence. AB - Hepatocellular carcinoma (hcc) arising from a hepatic adenoma is a rare phenomenon accounting for fewer than 5% of hcc cases; it seldom recurs after resection of the primary tumour. We report a case of extrahepatic metastasis of hcc arising from a hepatic adenoma that presented as a solitary sternal metastasis without any evidence of intrahepatic recurrence. Our patient was initially treated with radiation therapy and bland embolization, without response. Subsequently, the patient developed progressive disease while taking sorafenib. He later received chemotherapy with docetaxel and gemcitabine, with the development of multiple pulmonary and splenic nodules. However, he remained free of intrahepatic recurrence. To the best of our knowledge, this is the first case of extrahepatic metastasis of hcc arising from a hepatic adenoma without evidence of intrahepatic recurrence. PMID- 28874906 TI - Megafauna of the UKSRL exploration contract area and eastern Clarion-Clipperton Zone in the Pacific Ocean: Annelida, Arthropoda, Bryozoa, Chordata, Ctenophora, Mollusca. AB - BACKGROUND: There is growing interest in mining polymetallic nodules from the abyssal Clarion-Clipperton Zone (CCZ) in the tropical Pacific Ocean. Despite having been the focus of environmental studies for decades, the benthic megafauna of the CCZ remain poorly known. To predict and manage the environmental impacts of mining in the CCZ, baseline knowledge of the megafauna is essential. The ABYSSLINE Project has conducted benthic biological baseline surveys in the UK Seabed Resources Ltd polymetallic-nodule exploration contract area (UK-1). Prior to ABYSSLINE research cruises in 2013 and 2015, no biological studies had been done in this area of the eastern CCZ. NEW INFORMATION: Using a Remotely Operated Vehicle and Autonomous Underwater Vehicle (as well as several other pieces of equipment), the megafauna within the UK Seabed Resources Ltd exploration contract area (UK-1) and at a site ~250 km east of the UK-1 area were surveyed, allowing us to make the first estimates of megafaunal morphospecies richness from the imagery collected. Here, we present an atlas of the abyssal annelid, arthropod, bryozoan, chordate, ctenophore and molluscan megafauna observed and collected during the ABYSSLINE cruises to the UK-1 polymetallic-nodule exploration contract area in the CCZ. There appear to be at least 55 distinct morphospecies (8 Annelida, 12 Arthropoda, 4 Bryozoa, 22 Chordata, 5 Ctenophora, and 4 Mollusca) identified mostly by morphology but also using molecular barcoding for a limited number of animals that were collected. This atlas will aid the synthesis of megafaunal presence/absence data collected by contractors, scientists and other stakeholders undertaking work in the CCZ, ultimately helping to decipher the biogeography of the megafauna in this threatened habitat. PMID- 28874907 TI - Synergistic Effect of Pleuromutilins with Other Antimicrobial Agents against Staphylococcus aureus In Vitro and in an Experimental Galleria mellonella Model. AB - Invasive infections due to Staphylococcus aureus, including methicillin-resistant S. aureus are prevalent and life-threatening. Combinations of antibiotic therapy have been employed in many clinical settings for improving therapeutic efficacy, reducing side effects of drugs, and development of antibiotic resistance. Pleuromutilins have a potential to be developed as a new class of antibiotics for systemic use in humans. In the current study, we investigated the relationship between pleuromutilins, including valnemulin, tiamulin, and retapamulin, and 13 other antibiotics representing different mechanisms of action, against methicillin-susceptible and -resistant S. aureus both in vitro and in an experimental Galleria mellonella model. In vitro synergistic effects were observed in combination of all three study pleuromutilins with tetracycline (TET) by standard checkerboard and/or time-kill assays. In addition, the combination of pleuromutilins with ciprofloxacin or enrofloxacin showed antagonistic effects, while the rest combinations presented indifferent effects. Importantly, all study pleuromutilins in combination with TET significantly enhanced survival rates as compared to the single drug treatment in the G. mellonella model caused by S. aureus strains. Taken together, these results demonstrated synergy effects between pleuromutilins and TET against S. aureus both in vitro and in vivo. PMID- 28874908 TI - Application of the Intuitionistic Fuzzy InterCriteria Analysis Method with Triples to a Neural Network Preprocessing Procedure. AB - The approach of InterCriteria Analysis (ICA) was applied for the aim of reducing the set of variables on the input of a neural network, taking into account the fact that their large number increases the number of neurons in the network, thus making them unusable for hardware implementation. Here, for the first time, with the help of the ICA method, correlations between triples of the input parameters for training of the neural networks were obtained. In this case, we use the approach of ICA for data preprocessing, which may yield reduction of the total time for training the neural networks, hence, the time for the network's processing of data and images. PMID- 28874909 TI - Identification of Anisomerous Motor Imagery EEG Signals Based on Complex Algorithms. AB - Motor imagery (MI) electroencephalograph (EEG) signals are widely applied in brain-computer interface (BCI). However, classified MI states are limited, and their classification accuracy rates are low because of the characteristics of nonlinearity and nonstationarity. This study proposes a novel MI pattern recognition system that is based on complex algorithms for classifying MI EEG signals. In electrooculogram (EOG) artifact preprocessing, band-pass filtering is performed to obtain the frequency band of MI-related signals, and then, canonical correlation analysis (CCA) combined with wavelet threshold denoising (WTD) is used for EOG artifact preprocessing. We propose a regularized common spatial pattern (R-CSP) algorithm for EEG feature extraction by incorporating the principle of generic learning. A new classifier combining the K-nearest neighbor (KNN) and support vector machine (SVM) approaches is used to classify four anisomerous states, namely, imaginary movements with the left hand, right foot, and right shoulder and the resting state. The highest classification accuracy rate is 92.5%, and the average classification accuracy rate is 87%. The proposed complex algorithm identification method can significantly improve the identification rate of the minority samples and the overall classification performance. PMID- 28874910 TI - Different Angiogenic Potentials of Mesenchymal Stem Cells Derived from Umbilical Artery, Umbilical Vein, and Wharton's Jelly. AB - Human mesenchymal stem cells derived from the umbilical cord (UC) are a favorable source for allogeneic cell therapy. Here, we successfully isolated the stem cells derived from three different compartments of the human UC, including perivascular stem cells derived from umbilical arteries (UCA-PSCs), perivascular stem cells derived from umbilical vein (UCV-PSCs), and mesenchymal stem cells derived from Wharton's jelly (WJ-MSCs). These cells had the similar phenotype and differentiation potential toward adipocytes, osteoblasts, and neuron-like cells. However, UCA-PSCs and UCV-PSCs had more CD146+ cells than WJ-MSCs (P < 0.05). Tube formation assay in vitro showed the largest number of tube-like structures and branch points in UCA-PSCs among the three stem cells. Additionally, the total tube length in UCA-PSCs and UCV-PSCs was significantly longer than in WJ-MSCs (P < 0.01). Microarray, qRT-PCR, and Western blot analysis showed that UCA-PSCs had the highest expression of the Notch ligand Jagged1 (JAG1), which is crucial for blood vessel maturation. Knockdown of Jagged1 significantly impaired the angiogenesis in UCA-PSCs. In summary, UCA-PSCs are promising cell populations for clinical use in ischemic diseases. PMID- 28874911 TI - A Ligation of the Lacrimal Excretory Duct in Mouse Induces Lacrimal Gland Inflammation with Proliferative Cells. AB - The lacrimal gland secretes tear fluids to ocular surface, which plays an indispensable role in maintaining the health of the ocular epithelia and protecting the ocular surface from the external environment. The dysfunction of the lacrimal glands causes dry eye disease due to a reduction in tear volume. The dry eye disease is becoming a popular public disease, for the number of patients is increasing, who have subjective symptom and loss of vision, which affect the quality of life. Inflammatory change in the damaged lacrimal gland has been reported; however, a major challenge is to establish a simple animal model to observe the changes. Here, we demonstrated an injury model by ligating the main excretory duct of the lacrimal gland, which is a simple and stable way to clearly understand the mechanism of lacrimal gland inflammation. We observed the process of injury and proliferation of the lacrimal gland and detected a population of lacrimal gland epithelial cells with proliferation potential which were also nestin-positive cells following duct ligation. This study successfully established an injury model to observe the tissue injury process of the lacrimal gland, and this model will be useful for analysis of the inflammation and proliferation mechanism in the future. PMID- 28874912 TI - Prescription database analyses indicates that the asthma medicine montelukast might protect against dementia: a hypothesis to be verified. AB - BACKGROUND: It has recently been shown that the leukotriene receptor antagonist montelukast rejuvenates aged brains in rats. The question is whether this commonly used, systemic, anti-asthmatic medicine has a similar effect in humans? RESULTS: We approached this issue by doing statistical analyses based on the Norwegian Prescription Database. The Database lists all prescription-based medications in Norway, but not drugs given to people who are in hospitals or nursing homes. The question asked was whether users of montelukast, compared to users of inhalation asthma medicine, live longer, and are less likely to develop dementia. A small, non-significant protective effect on the use of dementia medicine became significant when adjusting for other prescriptions (based on the notion that montelukast users on average are less healthy). A possible protective effect was substantiated by looking at the lack of prescriptions as a proxy for dementia-related residency in nursing homes, and the risk of death. CONCLUSIONS: The present results suggest that montelukast may alleviate the cognitive decline associated with human aging. However, further data, preferably based on controlled clinical trials, are required. PMID- 28874914 TI - Acupuncture and Integrative Medicine: A Confession. PMID- 28874913 TI - Brief internet-based cognitive behavior therapy program with a supplement drink improved anxiety and somatic symptoms in Japanese workers. AB - BACKGROUND: Self-help cognitive behavior therapy (CBT) is a useful approach for the treatment of psychological problems. Recent research on the effectiveness of self-help internet-based CBT (ICBT) indicates that the paradigm moderately improves psychological problems. Furthermore, previous studies have shown that food and drinks containing supplements improve various health conditions. We investigated the effect of a brief self-help ICBT administered with a supplement drink on psychological well-being and somatic symptoms. METHODS: In total, 101 healthy workers were enrolled in the 4-week ICBT program, which consisted of psychoeducation on stress management, behavior activation, and cognitive restructuring. The supplement soft drink was taken every day during the program. The participants were instructed to watch on-demand video clips and read the self help guidebook and supporting comic strip weekly on the Internet or smartphone. The Japanese version of the Profile of Mood States (POMS) was administered before and after completion of the program. Scores on the POMS tension-anxiety (POMS TA), depression (POMS-D), and fatigue (POMS-F) subscales were used to assess the effect of the program. Somatic symptoms were assessed using the Brief Job Stress Questionnaire. RESULTS: In total, 75 participants continued the program for 4 weeks; however, of those, 27 failed to complete all weekly tasks or meet the post assessment deadlines. Therefore, the data of 48 participants were included in the analysis. Pre-post intervention comparisons using paired t-tests revealed significant improvement on the POMS-TA, but not the POMS-D or POMS-F subscales. Moreover, participants reported a significant reduction in the severity of low back pain. CONCLUSION: Our brief intervention moderately improved anxiety levels and the symptom of low back pain. These findings suggest that the brief ICBT program is effective in non-patient populations. Future directions for brief ICBT are discussed. TRIAL REGISTRATION: This study was registered on February 10, 2016 at UMIN. The registration number is UMIN000020962. PMID- 28874915 TI - Integrative Medicine for Military Injuries Special Issue of Medical Acupuncture: Introduction. PMID- 28874916 TI - Evolving Approaches to Care for Those in Harm's Way. PMID- 28874917 TI - Discovery of the Healing Highway. PMID- 28874918 TI - Integrative Health in the Veterans Health Administration. PMID- 28874919 TI - Medical Acupuncture Meets the Military. PMID- 28874920 TI - The Manual Stimulation of Acupuncture Points in the Treatment of Post-Traumatic Stress Disorder: A Review of Clinical Emotional Freedom Techniques. AB - Background: The manual stimulation of acupuncture points has been combined with components of cognitive and exposure therapies into a clinical and self-help approach known as Emotional Freedom Techniques (EFT). More than 40 clinical trials and four meta-analytic reviews of EFT treatments have demonstrated large effect sizes with a range of conditions, including pain, PTSD (in both civilian and military veteran populations), phobias, anxiety, and depression. Objective: This review describes the approach, with a focus on PTSD in veterans and service members, provides an overview of how EFT is most commonly applied, and outlines obstacles and cautions related to its implementation. Methods: Peer-reviewed clinical trials and meta-analyses of EFT in the treatment of PTSD are assessed to identify the characteristics of the approach that render it suitable for the treatment of PTSD. Results: The literature demonstrates that remediation of PTSD and comorbid conditions is typically accomplished within brief time frames, ranging from one session for phobias to between four and ten sessions for PTSD. Clinical EFT has been shown to regulate stress hormones and limbic function and to improve various neurologic markers of general health. The epigenetic effects of EFT include upregulation of immunity genes and downregulation of inflammation genes. Six dismantling studies have indicated that the acupressure component of EFT is an active ingredient and not placebo. Conclusions: Seven empirically supported strengths of the approach were identified that make it especially suitable for use with veterans and active military: (1) the depth and breadth of treatment effects; (2) the relatively brief timeframes required for successful treatment; (3) the low risk of adverse events; (4) the minimal training time required for the approach to be applied effectively; (5) the simultaneous reduction of physical and psychologic symptoms; (6) the utility and cost effectiveness of clinical EFT in a large group format; and (7) the method's adaptability to online and telemedicine applications. PMID- 28874921 TI - Functional Medicine Approach to Traumatic Brain Injury. AB - Background: The U.S. military has seen dramatic increases in traumatic brain injuries (TBIs) among military personnel due to the nature of modern-day conflicts. Conventional TBI treatment for secondary brain injuries has suboptimal success rates, and patients, families, and healthcare professionals are increasingly turning to alternative medicine treatments. Objective: Effective treatments for the secondary injury cascades that occur after an initial brain trauma are unclear at this time. The goal of successful treatment options for secondary TBI injuries is to reduce oxidative stress, excitotoxicity, and inflammation while supporting mitochondrial functions and repair of membranes, synapses, and axons. Intervention: A new paradigm of medical care, known as functional medicine, is increasing in popularity and acceptance. Functional medicine combines conventional treatment methods with complementary, genetic, holistic, and nutritional therapies. The approach is to assess the patient as a whole person, taking into account the interconnectedness of the body and its unique reaction to disease, injury, and illness while working to restore balance and optimal health. Functional medicine treatment recommendations often include the use of acupuncture, Ayurveda, chiropractic manipulation, detoxification programs, herbal and homeopathic supplements, specialized diets, massage, meditation and mindfulness practices, neurobiofeedback, nutritional supplements, t'ai chi, and yoga. At present, some of these alternative treatments appear to be beneficial, but more research is needed to validate reported outcomes. Conclusions: Few clinical studies validate the effectiveness of alternative therapies for TBIs. However, further clinical trials and empirical studies warrant further investigation based on some reported positive results from research studies, case histories, anecdotal evidence, and widespread popularity of some approaches. To date, only nutritional therapies and hyperbaric oxygen therapy have shown the most promise and potential for improved outcomes for the treatment of secondary TBI injuries. PMID- 28874922 TI - An Overview of the Use of Neurofeedback Biofeedback for the Treatment of Symptoms of Traumatic Brain Injury in Military and Civilian Populations. AB - Background: Neurofeedback, a type of biofeedback, is an operant conditioning treatment that has been studied for use in the treatment of traumatic brain injury (TBI) in both civilian and military populations. In this approach, users are able to see or hear representations of data related to their own physiologic responses to triggers, such as stress or distraction, in real time and, with practice, learn to alter these responses in order to reduce symptoms and/or improve performance. Objective: This article provides a brief overview of the use of biofeedback, focusing on neurofeedback, for symptoms related to TBI, with applications for both civilian and military populations, and describes a pilot study that is currently underway looking at the effects of a commercial neurofeedback device on patients with mild-to-moderate TBIs. Conclusions: Although more research, including blinded randomized controlled studies, is needed on the use of neurofeedback for TBI, the literature suggests that this approach shows promise for treating some symptoms of TBI with this modality. With further advances in technology, including at-home use of neurofeedback devices, preliminary data suggests that TBI survivors may benefit from improved motivation for treatment and some reduction of symptoms related to attention, mood, and mindfulness, with the addition of neurofeedback to treatment. PMID- 28874923 TI - Noninvasive Brain Stimulation, Maladaptive Plasticity, and Bayesian Analysis in Phantom Limb Pain. AB - Introduction: Phantom limb pain (PLP) is a common and poorly understood pathology of difficult medical control that progressively takes place after amputation occurs. Objective: This article discusses the multifactorial bases of PLP. These bases involve local changes at the stump level, spinal modifications of excitability, deafferentation, and central sensitization, leading to the development of maladaptive plasticity, and consequentially, defective processing of sensory information by associative neural networks. These changes can be traced by neurophysiology and imaging topographical studies, indicating a degree of cortical reorganization that perpetuates pain and discomfort. Intervention: Noninvasive brain stimulation can be an alternative way to manage PLP. This article discusses two techniques-transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS)-that have shown promising results for controlling PLP. The modulation that both techniques rely on is based on synaptic mechanisms linked to long-term potentiation and long-term depression phenomena. By applying tDCS or rTMS, clinicians can target processes associated with central sensitization and maladaptive plasticity, while promoting adequate sensory information processing by integrative cognitive behavioral techniques in a comprehensive rehabilitation program. Conclusions: Understanding PLP from a dynamic neurocomputational perspective will help to develop better treatments. Furthermore, Bayesian analysis of sensory information can help guide and monitor therapeutic interventions directed toward PLP resolution. PMID- 28874924 TI - Reduction in Pain Medication Prescriptions and Self-Reported Outcomes Associated with Acupuncture in a Military Patient Population. AB - Background: Acupuncture is being offered to patients as part of routine medical care in selected military bases in the United States. There is little published information about the clinical outcomes associated with acupuncture in these clinical settings. Objective: The goal of this research was to assess clinical outcomes observed among adult patients who received acupuncture treatments at a United States Air Force medical center. Materials and Methods: This retrospective chart review was performed at the Nellis Family Medicine Residency in the Mike O'Callaghan Military Medical Center at Nellis Air Force Base in Las Vegas, NV. The charts were from 172 consecutive patients who had at least 4 acupuncture treatments within 1 year. The main outcome measures were prescriptions for opioid medications, muscle relaxants, benzodiazepines, and nonsteroidal anti inflammatory drugs (NSAIDS) in the 60 days prior to the first acupuncture session and in the corresponding 60 days 1 year later; and Measure Yourself Medical Outcome Profile (MYMOP2) values for symptoms, ability to perform activities, and quality of life. Results: Opioid prescriptions decreased by 45%, muscle relaxants by 34%, NSAIDs by 42%, and benzodiazepines by 14%. MYMOP2 values decreased 3.50 3.11 (P < 0.002) for question 1, 4.18-3.46 (P < 0.00001) for question 3, and 2.73 2.43 (P < 0.006) for question 4. Conclusions: In this military patient population, the number of opioid prescriptions decreased and patients reported improved symptom control, ability to function, and sense of well-being after receiving courses of acupuncture by their primary care physicians. PMID- 28874925 TI - Controlled Rhythmic Yogic Breathing as Complementary Treatment for Post-Traumatic Stress Disorder in Military Veterans: A Case Series. AB - Background: Post-traumatic stress disorder (PTSD) is a cluster of symptoms in which a person persistently relives a traumatic event, through recurring thoughts, nightmares, and flashbacks for at least 1 month or more. There are various behavioral and medical treatment options for PTSD. Mind-body techniques, such as biofeedback and breathing-based stress reduction, have shown some promise in the treatment of PTSD symptoms. The purpose of this case series was to examine controlled yogic breathing as a complementary treatment of PTSD in military veterans. A retrospective review was performed from 2012 to 2016 in 3 cases, and participant demographics, member statements, and PTSD Checklist-Military Version (PCL-M) scores, pre-and-post course, were extracted. Cases: Three military veterans with PTSD participated in a standardized 5-day course designed to teach them controlled rhythmic yogic breathing exercises. Results: Subjectively, all 3 participants reported a decrease in PTSD symptoms after the course. Objectively, all 3 participants had a reduction in their overall PCL-M scores after the course. Among all 3 participants, there were score decreases in the Avoidance and Increased Arousal categories. The most dramatic improvement occurred in the participant with the most severe symptoms. Conclusions: Controlled yogic breathing, specifically Sudarshan Kriya (SKY), appeared to reduce the symptoms of PTSD in 3 veterans of the Armed Services. PMID- 28874927 TI - Six Sessions of Emotional Freedom Techniques Remediate One Veteran's Combat Related Post-Traumatic Stress Disorder. AB - Background: Reports show high rates of post-traumatic stress disorder (PTSD) in Veterans who served in the Gulf Wars. Emotional Freedom Techniques (EFT) comprises an evidence-based practice that is highly effective at reducing symptom severity in Veterans with PTSD. The case report here is of one of the Veterans who participated in a replication study of the first Veteran Stress Research Study conducted by Church et al. Results of that study demonstrated that EFT was highly effective at treating the psychologic symptoms of PTSD. Similar results have been found in the replication study conducted by Geronilla et al. Case: RM is a young Marine Reservist who served in Iraq and returned with PTSD. He participated in the Veteran Stress Project replication study wherein he received 6 sessions of EFT. EFT is explained and a sample treatment session is described. A discussion of some of the changes that have occurred for RM is included. Results: The patient's PTSD scores dropped from a high clinical score of 60 before treatment to 40 after 6 sessions and to a clinical score of 22 at 6 months follow-up. His insomnia, which had been at a clinical level, reduced as did his pain and measures of psychologic distress, as measured in the Symptom Assessment 45 instrument. Conclusion: Six sessions of EFT reduced PTSD scores dramatically and improved RM's life. He continues to use EFT to manage any stress in his life. PMID- 28874926 TI - CranioSacral Therapy and Visceral Manipulation: A New Treatment Intervention for Concussion Recovery. AB - Background: Military service members and veterans face health issues related to traumatic brain injury (TBI), especially during combat, use of heavy equipment, and exposures to environmental hazards and explosives. There were 400,000 TBIs reported in deployed U.S. troops in 2012. Athletes are also subject to TBI. Studies have indicated that some manual therapies could be helpful for treating patients who have post-concussive syndrome. Objective: This case series report describes the effects of CranioSacral Therapy (CST), Visceral Manipulation (VM), and Neural Manipulation (NM) modalities for treating patients who have post concussion syndrome. The goal of this study was to evaluate these effects on immobility, pain intensity, quality of life, sleep disorders, and cognition in these patients. Materials and Methods: This single-blinded case series was conducted at the Upledger Institute, in West Palm Beach, FL. The patients were 11 male retired professional football players from the National Football League and the Canadian Football League who had been medically diagnosed with post concussion syndrome. Each participant received a morning and afternoon 2-hour session of these three specific manual therapies, which were capable of accessing and addressing the structural, vascular, and neurologic tissues of the cranium and brain-as well addressing far-reaching ramifications throughout the body following trauma. The main outcome measures were scores on the: Impact Neurocognitive Test; Dynavisiontm Test; Short Form-36 Quality of Life Survey, Headache Impact Test, Dizziness Handicap Inventory; a numeric pain rating scale; orthopedic range of motion tests (ROM); and vestibular testing. Hours of sleep were also checked. These outcome measures were registered at baseline, after treatment, and after a 3-month follow up. Results: Statistically significant differences were seen with a decrease in overall pain rating scale scores (P = 0.0448), and cervicogenic pain levels decreased (P = 0.0486). There were statistically significant increases in Dynavision Average Reaction Time (P = 0.0332), Memory Test (P = 0.0156) scores, and cervical ROM scores (P = 0.0377). Hours of sleep averaged 2 hours on the first day of treatment and increased to 4.0 hours at the end of treatment and were continuing to increase, as noted at a 3-month evaluation. Conclusions: Ten sessions of specific CST/VM/NM therapy resulted in statistically greater improvements in pain intensity, ROM, memory, cognition, and sleep in concussed patients. PMID- 28874928 TI - Magnetic Resonance Imaging Utilization in an Emergency Department Observation Unit. AB - INTRODUCTION: Emergency department observation units (EDOUs) are a valuable alternative to inpatient admissions for ED patients needing extended care. However, while the use of advanced imaging is becoming more common in the ED, there are no studies characterizing the use of magnetic resonance imaging (MRI) examinations in the EDOU. METHODS: This institutional review board-approved, retrospective study was performed at a 999-bed quaternary care academic Level I adult and pediatric trauma center, with approximately 114,000 ED visits annually and a 32-bed adult EDOU. We retrospectively reviewed the EDOU patient database for all MRI examinations done from October 1, 2013, to September 30, 2015. We sought to describe the most frequent uses for MRI during EDOU admissions and reviewed EDOU length of stay (LOS) to determine whether the use of MRI was associated with any change in LOS. RESULTS: A total of 22,840 EDOU admissions were recorded during the two-year study period, and 4,437 (19%) of these patients had a least one MRI examination during their stay; 2,730 (62%) of these studies were of the brain, head, or neck, and an additional 1,392 (31%) were of the spine. There was no significant difference between the median LOS of admissions in which an MRI study was performed (17.5 hours) and the median LOS (17.7 hours) of admissions in which an MRI study was not performed [p=0.33]. CONCLUSION: Neuroimaging makes up the clear majority of MRI examinations from our EDOU, and the use of MRI does not appear to prolong EDOU LOS. Future work should focus on the appropriateness of these MRI examinations to determine potential resource and cost savings. PMID- 28874929 TI - Trends and Characteristics of Emergency Department Visits for Fall-Related Injuries in Older Adults, 2003-2010. AB - INTRODUCTION: One third of older adults fall each year, and falls are costly to both the patient in terms of morbidity and mortality and to the health system. Given that falls are a preventable cause of injury, our objective was to understand the characteristics and trends of emergency department (ED) fall related visits among older adults. We hypothesize that falls among older adults are increasing and examine potential factors associated with this rise, such as race, ethnicity, gender, insurance and geography. METHODS: We conducted a secondary analysis of data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) to determine fall trends over time by examining changes in ED visit rates for falls in the United States between 2003 and 2010, detailing differences by gender, sociodemographic characteristics and geographic region. RESULTS: Between 2003 and 2010, the visit rate for falls and fall-related injuries among people age >= 65 increased from 60.4 (95% confidence interval [CI][51.9-68.8]) to 68.8 (95% CI [57.8-79.8]) per 1,000 population (p=0.03 for annual trend). Among subgroups, visits by patients aged 75-84 years increased from 56.2 to 82.1 per 1,000 (P <.01), visits by women increased from 67.4 to 81.3 (p = 0.04), visits by non-Hispanic Whites increased from 63.1 to 73.4 (p < 0.01), and visits in the South increased from 54.4 to 71.1 (p=0.03). CONCLUSION: ED visit rates for falls are increasing over time. There is a national movement to increase falls awareness and prevention. EDs are in a unique position to engage patients on future fall prevention and should consider ways they can also partake in such initiatives in a manner that is feasible and appropriate for the ED setting. PMID- 28874930 TI - Prevalence of Intracranial Hemorrhage after Blunt Head Trauma in Patients on Pre injury Dabigatran. AB - INTRODUCTION: Dabigatran etexilate was the first direct-acting oral anticoagulant approved in the United States. The prevalence of intracranial hemorrhage after blunt head trauma in patients on dabigatran is currently unknown, complicating adequate ability to accurately compare the risks and benefits of dabigatran to alternative anticoagulants. We aimed to determine the prevalence of intracranial hemorrhage for patients on dabigatran presenting to a Level I trauma center. METHODS: This is a retrospective observational study of adult patients on dabigatran who presented to a Level I trauma center and received cranial computed tomography (CT) following blunt head trauma. Patients who met inclusion criteria underwent manual chart abstraction. Our primary outcome was intracranial hemorrhage on initial cranial CT. RESULTS: We included a total of 33 eligible patient visits for analysis. Mean age was 74.8 years (SD 11.2, range 55-91). The most common cause of injury was ground-level fall (n = 22, 66.7%). One patient (3.0%, 95% confidence interval [CI] 0.[1-15.8%]) had intracranial hemorrhage on cranial CT. No patients (0%, 95% CI [0-8.7%]) required neurosurgical intervention. One in-hospital death occurred from infection. CONCLUSION: To our knowledge, this is the first study to evaluate the prevalence of intracranial hemorrhage after blunt head trauma for patients on dabigatran presenting to the emergency department, including those not admitted. The intracranial hemorrhage prevalence in our study is similar to previous reports for patients on warfarin. Further studies are needed to determine if the prevalence of intracranial hemorrhage seen in our patient population is true for a larger patient population in more diverse clinical settings. PMID- 28874931 TI - Congratulations, You're Pregnant! Now About Your Shifts . . . : The State of Maternity Leave Attitudes and Culture in EM. AB - INTRODUCTION: Increasing attention has been focused on parental leave, but little is known about early leave and parental experiences for male and female attending physicians. Our goal was to describe and quantify the parental leave experiences of a nationally representative sample of emergency physicians (EP). METHODS: We conducted a web-based survey, distributed via emergency medicine professional organizations, discussion boards, and listservs, to address study objectives. RESULTS: We analyzed data from 464 respondents; 56% were women. Most experienced childbirth while employed as an EP. Fifty-three percent of women and 60% of men reported working in a setting with a formal maternity leave policy; however, 36% of women and 18% of men reported dissatisfaction with these policies. Most reported that other group members cover maternity-related shift vacancies; a minority reported that pregnant partners work extra shifts prior to leave. Leave duration and compensation varied widely, ranging from no compensated leave (18%) to 12 or more weeks at 100% salary (7%). Supportive attitudes were reported during pregnancy (53%) and, to a lesser degree (43%), during leave. Policy improvement suggestions included the development of clear, formal policies; improving leave duration and compensation; adding paternity and adoption leave; providing support for physicians working extra to cover colleagues' leave; and addressing breastfeeding issues. CONCLUSION: In this national sample of EPs, maternity leave policies varied widely. The duration and compensation during leave also had significant variation. Participants suggested formalizing policies, increasing leave duration and compensation, adding paternity leave, and changing the coverage for vacancies to relieve burden on physician colleagues. PMID- 28874932 TI - Emergency Department Use across 88 Small Areas after Affordable Care Act Implementation in Illinois. AB - INTRODUCTION: This study analyzes changes in hospital emergency department (ED) visit rates before and after the 2014 Affordable Care Act (ACA) insurance expansions in Illinois. We compare the association between population insurance status change and ED visit rate change between a 24-month (2012-2013) pre-ACA period and a 24-month post-ACA (2014-2015) period across 88 socioeconomically diverse areas of Illinois. METHODS: We used annual American Community Survey estimates for 2012-2015 to obtain insurance status changes for uninsured, private, Medicaid, and Medicare (disability) populations of 88 Illinois Public Use Micro Areas (PUMAs), areas with a mean of about 90,000 age 18-64 residents. Over 12 million ED visits to 201 non-federal Illinois hospitals were used to calculate visit rates by residents of each PUMA, using population-based mapping weights to allocate visits from zip codes to PUMAs. We then estimated n=88 correlations between population insurance-status changes and changes in ED visit rates per 1,000 residents comparing the two years before and after ACA implementation. RESULTS: The baseline PUMA uninsurance rate ranged from 6.7% to 41.1% and there was 4.6-fold variation in baseline PUMA ED visit rates. The top quartile of PUMAs had >21,000 reductions in uninsured residents; 16 PUMAs had at least a 15,000 person increase in Medicaid enrollment. Compared to 2012-2013, 2014-2015 average monthly ED visits by the uninsured dropped 42%, but increased 42% for Medicaid and 10% for the privately insured. Areas with the largest increases in Medicaid enrollment experienced the largest growth in ED use; change in Medicaid enrollment was the only significant correlate of area change in total ED visits and explained a third of variation across the 88 PUMAs. CONCLUSION: ACA implementation in Illinois accelerated existing trends towards greater use of hospital ED care. It remains to be seen whether providing better access to primary and preventive care to the formerly uninsured will reduce ED use over time, or whether ACA insurance expansion is a part of continued, long-term growth. Monitoring ED use at the local level is critical to the success of new home- and community-based care coordination initiatives. PMID- 28874933 TI - Head CT for Minor Head Injury Presenting to the Emergency Department in the Era of Choosing Wisely. AB - INTRODUCTION: The Choosing Wisely campaign currently recommends avoiding computed tomography (CT) of the head in low-risk emergency department (ED) patients with minor head injury, based on validated decision rules. However, the degree of adherence to this guideline in clinical practice is unknown. The objective of this study was to evaluate adherence to the Choosing Wisely campaign's recommendations regarding head CT imaging of patients with minor head injury in the ED. METHODS: We conducted a retrospective cohort study of adult ED patients at a Level I trauma center. Patients aged >= 18 years who presented to the ED with minor head injury were identified via International Classification of Diseases, 9th Revision, Clinical Modification codes. Medical record abstraction was conducted to determine the presence of clinical symptoms of the NEXUS II criteria, medical resource use, and head CT findings. We used descriptive statistics to characterize the study sample, and proportions were used to quantify guidelines adherence. RESULTS: A total of 489 subjects met inclusion criteria. ED providers appropriately applied the Choosing Wisely criteria for 75.5% of patients, obtaining head CTs when indicated by the NEXUS II rule (41.5%), and not obtaining head CTs when the NEXUS II criteria were not met (34.0%). However, ED providers obtained non-indicated CTs in 23.1% of patients. Less than 2% of the sample did not receive a head CT when imaging was indicated by NEXUS II. CONCLUSION: ED providers in our sample had variable adherence to the Choosing Wisely head-CT recommendation, especially for patients who did not meet the NEXUS II criteria. PMID- 28874934 TI - Emergency Physician-performed Transesophageal Echocardiography in Simulated Cardiac Arrest. AB - INTRODUCTION: Transesophageal echocardiography (TEE) is a well-established method of evaluating cardiac pathology. It has many advantages over transthoracic echocardiography (TTE), including the ability to image the heart during active cardiopulmonary resuscitation. This prospective simulation study aims to evaluate the ability of emergency medicine (EM) residents to learn TEE image acquisition techniques and demonstrate those techniques to identify common pathologic causes of cardiac arrest. METHODS: This was a prospective educational cohort study with 40 EM residents from two participating academic medical centers who underwent an educational model and testing protocol. All participants were tested across six cases, including two normals, pericardial tamponade, acute myocardial infarction (MI), ventricular fibrillation (VF), and asystole presented in random order. Primary endpoints were correct identification of the cardiac pathology, if any, and time to sonographic diagnosis. Calculated endpoints included sensitivity, specificity, and positive and negative predictive values for emergency physician (EP)-performed TEE. We calculated a kappa statistic to determine the degree of inter-rater reliability. RESULTS: Forty EM residents completed both the educational module and testing protocol. This resulted in a total of 80 normal TEE studies and 160 pathologic TEE studies. Our calculations for the ability to diagnose life-threatening cardiac pathology by EPs in a high-fidelity TEE simulation resulted in a sensitivity of 98%, specificity of 99%, positive likelihood ratio of 78.0, and negative likelihood ratio of 0.025. The average time to diagnose each objective structured clinical examination case was as follows: normal A in 35 seconds, normal B in 31 seconds, asystole in 13 seconds, tamponade in 14 seconds, acute MI in 22 seconds, and VF in 12 seconds. Inter rater reliability between participants was extremely high, resulting in a kappa coefficient across all cases of 0.95. CONCLUSION: EM residents can rapidly perform TEE studies in a simulated cardiac arrest environment with a high degree of precision and accuracy. Performance of TEE studies on human patients in cardiac arrest is the next logical step to determine if our simulation data hold true in clinical practice. PMID- 28874935 TI - Increased Computed Tomography Utilization in the Emergency Department and Its Association with Hospital Admission. AB - INTRODUCTION: Our goal was to investigate trends in computed tomography (CT) utilization in emergency departments (EDs) and its association with hospitalization. METHODS: We conducted an analysis of an administrative claims database of U.S. privately insured and Medicare Advantage enrollees. We identified ED visits from 2005 through 2013 and assessed for CT use, associated factors, and hospitalization after CT, along with patient demographics. We used both descriptive methods and regression models adjusted for year, age, sex, race, geographic region, and Hwang comorbidity score to explore associations among CT use, year, demographic characteristics, and hospitalization. RESULTS: We identified 33,144,233 ED visits; 5,901,603 (17.8%) involved CT. Over time, CT use during ED visits increased 59.9%. CT use increased in all age groups but decreased in children since 2010. In propensity-matching analysis, odds of hospitalization increased with age, comorbidities, male sex, and CT use (odds ratio, 2.38). Odds of hospitalization over time decreased more quickly for patients with CT. CONCLUSION: CT utilization in the ED has increased significantly from 2005 through 2013. For children, CT use after 2010 decreased, indicating caution about CT use. Male sex, older age, and higher number of comorbidities were predictors of CT in the ED. Over time, odds of hospitalization decreased more quickly for patients with CT. PMID- 28874936 TI - Factors Influencing Participation in Clinical Trials: Emergency Medicine vs. Other Specialties. AB - INTRODUCTION: This study investigated factors that influence emergency medicine (EM) patients' decisions to participate in clinical trials and whether the impact of these factors differs from those of other medical specialties. METHODS: A survey was distributed in EM, family medicine (FM), infectious disease (ID), and obstetrics/gynecology (OB/GYN) outpatient waiting areas. Eligibility criteria included those who were 18 years of age or older, active patients on the day of the survey, and able to complete the survey without assistance. We used the Kruskal-Wallis test and ordinal logistic regression analyses to identify differences in participants' responses. RESULTS: A total of 2,893 eligible subjects were approached, and we included 1,841 surveys in the final analysis. Statistically significant differences (p<=0.009) were found for eight of the ten motivating factors between EM and one or more of the other specialties. Regardless of a patient's gender, race, and education, the relationship with their doctor was more motivating to patients seen in other specialties than to EM patients (FM [odds ratio {OR}:1.752, 95% confidence interval {CI}{1.285-2.389}], ID [OR:3.281, 95% CI{2.293-4.695}], and OB/GYN [OR:2.408, 95% CI{1.741-3.330}]). EM's rankings of "how well the research was explained" and whether "the knowledge learned would benefit others" as their top two motivating factors were similar across other specialties. All nine barriers showed statistically significant differences (p<=0.008) between EM and one or more other specialties. Participants from all specialties indicated "risk of unknown side effects" as their strongest barrier. Regardless of the patients' race, "time commitment" was considered to be more of a barrier to other specialties when compared to EM (FM [OR:1.613, 95% CI{1.218-2.136}], ID [OR:1.340, 95% CI{1.006-1.784}], or OB/GYN [OR:1.901, 95% CI{1.431-2.526}]). Among the six resources assessed that help patients decide whether to participate in a clinical trial, only one scored statistically significantly different for EM (p<0.001). EM patients ranked "having all material provided in my own language" as the most helpful resource. CONCLUSION: There are significant differences between EM patients and those of other specialties in the factors that influence their participation in clinical trials. Providing material in the patient's own language, explaining the study well, and elucidating how their participation might benefit others in the future may help to improve enrollment in EM-based clinical trials. PMID- 28874937 TI - Antimicrobial Therapy for Pneumonia in the Emergency Department: The Impact of Clinical Pharmacists on Appropriateness. AB - INTRODUCTION: Pneumonia impacts over four million people annually and is the leading cause of infectious disease-related hospitalization and mortality in the United States. Appropriate empiric antimicrobial therapy decreases hospital length of stay and improves mortality. The objective of our study was to test the hypothesis that the presence of an emergency medicine (EM) clinical pharmacist improves the timing and appropriateness of empiric antimicrobial therapy for community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP). METHODS: This was a retrospective observational cohort study of all emergency department (ED) patients presenting to a Midwest 60,000-visit academic ED from July 1, 2008, to March 1, 2016, who presented to the ED with pneumonia and received antimicrobial therapy. The treatment group consisted of patients who presented during the hours an EM pharmacist was present in the ED (Monday-Friday, 0900-1800). The control group included patients presenting during the hours when an EM clinical pharmacist was not physically present in the ED (Monday-Friday, 1800-0900, Saturday/Sunday 0000-2400 day). We defined appropriate empiric antimicrobial therapy using the Infectious Diseases Society of America consensus guidelines on the management of CAP, and management of HCAP. RESULTS: A total of 406 patients were included in the final analysis (103 treatment patients and 303 control patients). During the hours the EM pharmacist was present, patients were significantly more likely to receive appropriate empiric antimicrobial therapy (58.3% vs. 38.3%; p<0.001). Regardless of pneumonia type, patients seen while an EM pharmacist was present were significantly more likely to receive appropriate antimicrobial therapy (CAP, 77.7% vs. 52.9% p=0.008, HCAP, 47.7% vs. 28.8%, p=0.005). There were no significant differences in clinical outcomes. CONCLUSION: The presence of an EM clinical pharmacist significantly increases the likelihood of appropriate empiric antimicrobial therapy for patients presenting to the ED with pneumonia. PMID- 28874938 TI - Availability and Accuracy of EMS Information about Chronic Health and Medications in Cardiac Arrest. AB - INTRODUCTION: Field information available to emergency medical services (EMS) about a patient's chronic health conditions or medication therapies could help direct patient care or be used to investigate outcome disparities. However, little is known about the field availability or accuracy of information of chronic health conditions or chronic medication treatments in emergent circumstances, especially when the patient cannot serve as an information resource. We evaluated the prehospital availability and accuracy of specific chronic health conditions and medication treatments among out-of-hospital cardiac arrest (OHCA) patients. METHODS: The investigation was a retrospective cohort study of adult persons suffering ventricular fibrillation OHCA treated by EMS in a large metropolitan county from January 1, 2007, to December 31, 2013. The study was designed to determine the availability and accuracy of EMS ascertainment of selected chronic health conditions and medication treatments. We evaluated chronic health conditions of "any heart disease," congestive heart failure (CHF), and diabetes and medication treatments of beta blockers and loop diuretics using two distinct sources: 1) EMS report, and 2) hospital record specific to the OHCA event. Because hospital information was considered the gold standard, we restricted the primary analysis to those who were admitted to hospital. RESULTS: Of the 1,496 initially eligible patients, 387 could not be resuscitated and were pronounced dead in the field, one patient was left alive at scene due to Physician's Orders for Life-sustaining Treatment (POLST) orders, 125 expired in the emergency department (n=125), and 983 were admitted to hospital. A total of 832 of 1,496 (55.6%) had both sources of data for comparison and comprised the primary analytic group. Using the hospital record as the gold standard, EMS ascertainment had a sensitivity of 0.79 (304/384) and a specificity of 0.88 (218/248) for any prior heart disease; sensitivity 0.45 (47/105) and specificity 0.87 (477/516) for CHF; sensitivity 0.71 (143/201) and specificity 0.98 (416/424) for diabetes; sensitivity 0.70 (118/169) and specificity 0.94 (273/290) for beta blockers; sensitivity 0.70 (62/89) and specificity 0.97 (358/370) for loop diuretics. CONCLUSION: In this cohort of OHCA, information about selected chronic health conditions and medication treatments based on EMS ascertainment was available for many patients, generally revealing moderate sensitivity and greater specificity. PMID- 28874939 TI - Rapid Primary Care Follow-up from the ED to Reduce Avoidable Hospital Admissions. AB - INTRODUCTION: Hospital admissions from the emergency department (ED) now account for approximately 50% of all admissions. Some patients admitted from the ED may not require inpatient care if outpatient care could be optimized. However, access to primary care especially immediately after ED discharge is challenging. Studies have not addressed the extent to which hospital admissions from the ED may be averted with access to rapid (next business day) primary care follow-up. We evaluated the impact of an ED-to-rapid-primary-care protocol on avoidance of hospitalizations in a large, urban medical center. METHODS: We conducted a retrospective review of patients referred from the ED to primary care (Weill Cornell Internal Medicine Associates - WCIMA) through a rapid-access-to-primary care program developed at New York-Presbyterian / Weill Cornell Medical Center. Referrals were classified as either an avoided admission or not, and classifications were performed by both emergency physician (EP) and internal medicine physician reviewers. We also collected outcome data on rapid visit completion, ED revisits, hospitalizations and primary care engagement. RESULTS: EPs classified 26 (16%) of referrals for rapid primary care follow-up as avoided admissions. Of the 162 patients referred for rapid follow-up, 118 (73%) arrived for their rapid appointment. There were no differences in rates of ED revisits or subsequent hospitalizations between those who attended the rapid follow-up and those who did not attend. Patients who attended the rapid appointment were significantly more likely to attend at least one subsequent appointment at WCIMA during the six months after the index ED visit [N=55 (47%) vs. N=8 (18%), P=0.001]. CONCLUSION: A rapid-ED-to-primary-care-access program may allow EPs to avoid admitting patients to the hospital without risking ED revisits or subsequent hospitalizations. This protocol has the potential to save costs over time. A program such as this can also provide a safe and reliable ED discharge option that is also an effective mechanism for engaging patients in primary care. PMID- 28874940 TI - Pediatric Patients Discharged from the Emergency Department with Abnormal Vital Signs. AB - INTRODUCTION: Children often present to the emergency department (ED) with minor conditions such as fever and have persistently abnormal vital signs. We hypothesized that a significant portion of children discharged from the ED would have abnormal vital signs and that those discharged with abnormal vital signs would experience very few adverse events. METHODS: We performed a retrospective chart review encompassing a 44-month period of all pediatric patients (aged two months to 17 years) who were discharged from the ED with an abnormal pulse rate, respiratory rate, temperature, or oxygen saturation. We used a local quality assurance database to identify pre-defined adverse events after discharge in this population. Our primary aim was to determine the proportion of children discharged with abnormal vital signs and the frequency and nature of adverse events. Additionally, we performed a sub-analysis comparing the rate of adverse events in children discharged with normal vs. abnormal vital signs, as well as a standardized review of the nature of each adverse event. RESULTS: Of 33,185 children discharged during the study period, 5,540 (17%) of these patients had at least one abnormal vital sign. There were 24/5,540 (0.43%) adverse events in the children with at least one abnormal vital sign vs. 47/27,645 (0.17%) adverse events in the children with normal vital signs [relative risk = 2.5 (95% confidence interval, 1.6 to 2.4)].However, upon review of each adverse event we found only one case that was related to the index visit, was potentially preventable by a 23-hour hospital observation, and caused permanent disability. CONCLUSION: In our study population, 17% of the children were discharged with at least one abnormal vital sign, and there were very few adverse (0.43%) events associated with this practice. Heart rate was the most common abnormal vital sign leading to an adverse event. Severe adverse events that were potentially related to the abnormal vital sign(s) were exceedingly rare. Additional research is needed in broader populations to better determine the rate of adverse events and possible methods of avoiding them. PMID- 28874941 TI - Predictors of Return Visits Among Insured Emergency Department Mental Health and Substance Abuse Patients, 2005-2013. AB - INTRODUCTION: Our goal was to describe the pattern and identify risk factors of early-return ED visits or inpatient admissions following an index mental health and substance abuse (MHSA)-related ED visit in the United States. METHODS: We performed a retrospective cohort study using Optum Labs Data Warehouse, a nationally representative database containing administrative claims data on privately insured and Medicare Advantage enrollees. Authors identified patients presenting to an ED with a primary diagnosis of MHSA between 2005 and 2013 who were discharged home. Study inclusion required continuous insurance enrollment for the 12 months preceding and the 31 days following the index ED visit. During the study period we included only the first ED visit for each patient. RESULTS: A total of 49,672 (14.2%) had a return visit to the ED or had a hospitalization within 30 days following discharge. Mean time to the next ED visit or inpatient admission was 11.7 days. An increased age (age 65+ vs. age <18 years; OR 1.65, 95% CI [1.57 to 1.74]), chronic medical comorbidities (Hwang comorbidity 5+ vs 0; OR 1.31, 95% CI [1.27 to 1.35]), prior ED and inpatient utilization (4+ visits vs 0 visits; OR 5.59, 95% CI [5.41 to 5.78]) were associated with return visits within 30 days following discharge. CONCLUSION: In an analysis of nearly 350,000 ED visits for MHSA, 14.2 % of patients returned to the ED or hospital within 30 days. This study identified a number of factors associated with return visits for acute care. PMID- 28874942 TI - Effect Of A "No Superuser Opioid Prescription" Policy On ED Visits And Statewide Opioid Prescription. AB - INTRODUCTION: The U.S. opioid epidemic has highlighted the need to identify patients at risk of opioid abuse and overdose. We initiated a novel emergency department- (ED) based interventional protocol to transition our superuser patients from the ED to an outpatient chronic pain program. The objective was to evaluate the protocol's effect on superusers' annual ED visits. Secondary outcomes included a quantitative evaluation of statewide opioid prescriptions for these patients, unique prescribers of controlled substances, and ancillary testing. METHODS: Patients were referred to the program with the following inclusion criteria: >= 6 visits per year to the ED; at least one visit identified by the attending physician as primarily driven by opioid-seeking behavior; and a review by a committee comprising ED administration and case management. Patients were referred to a pain management clinic and informed that they would no longer receive opioid prescriptions from visits to the ED for chronic pain complaints. Electronic medical record (EMR) alerts notified ED providers of the patient's referral at subsequent visits. We analyzed one year of data pre- and post referral. RESULTS: A total of 243 patients had one year of data post-referral for analysis. Median annual ED visits decreased from 14 to 4 (58% decrease, 95% CI [50 to 66]). We also found statistically significant decreases for these patients' state prescription drug monitoring program (PDMP) opioid prescriptions (21 to 13), total unique controlled-substance prescribers (11 to 7), computed tomography imaging (2 to 0), radiographs (5 to 1), electrocardiograms (12 to 4), and labs run (47 to 13). CONCLUSION: This program and the EMR-based alerts were successful at decreasing local ED visits, annual opioid prescriptions, and hospital resource allocation for this population of patients. There is no evidence that these patients diverted their visits to neighboring EDs after being informed that they would not receive opioids at this hospital, as opioid prescriptions obtained by these patients decreased on a statewide level. This implies that individual ED protocols can have significant impact on the behavior of patients. PMID- 28874943 TI - Loaded Questions: Internet Commenters' Opinions on Physician-Patient Firearm Safety Conversations. AB - INTRODUCTION: Medical and public health societies advocate that healthcare providers (HCPs) counsel at-risk patients to reduce firearm injury risk. Anonymous online media comments often contain extreme viewpoints and may therefore help in understanding challenges of firearm safety counseling. To help inform injury prevention efforts, we sought to examine commenters' stated opinions regarding firearm safety counseling HCPs. METHODS: Qualitative descriptive analysis of online comments posted following news items (in May-June, 2016) about a peer-reviewed publication addressing when and how HCPs should counsel patients regarding firearms. RESULTS: Among 871 comments posted by 522 individuals, most (57%) were generally negative toward firearm discussions, 17% were positive, and 26% were neutral/unclear. Two major categories and multiple themes emerged. "Areas of agreement" included that discussions may be valuable (1) when addressing risk of harm to self or others, (2) in pediatric injury prevention, and (3) as general safety education (without direct questioning), and that (4) HCPs lack gun safety and cultural knowledge. "Areas of tension" included whether (1) firearms are a public health issue, (2) counseling is effective prevention practice, (3) suicide could/should be prevented, and (4) firearm safety counseling is within HCPs' purview. CONCLUSION: Among this set of commenters with likely extreme viewpoints, opinions were generally negative toward firearm safety conversations, but with some support in specific situations. Providing education, counseling, or materials without asking about firearm ownership was encouraged. Engaging firearm advocates when developing materials may enhance the acceptability of prevention activities. PMID- 28874944 TI - Using Geospatial Mapping to Determine the Impact of All-Terrain Vehicle Crashes on Both Rural and Urban Communities. AB - INTRODUCTION: Deaths and injuries from all-terrain vehicle (ATV) crashes result in approximately 700 deaths each year and more than 100,000 emergency department (ED) visits. Common misconceptions about ATV crashes are a significant barrier to injury prevention efforts, as is the lack of key information about where and how crashes occur. The purpose of this study was to determine ATV crash patterns within a state, and to compare and contrast characteristics of these crashes as a function of crash-site rurality. METHODS: We performed descriptive, comparative, and regression analyses using a statewide off-road vehicle crash and injury database (2002-2013). Comparisons were performed by rurality as defined using the Rural Urban Commuting Area (RUCA) coding system, and we used geographic information system (GIS) software to map crash patterns at the zip code and county levels. RESULTS: ATV crashes occurred throughout the state; 46% occurred in urban and 54% in rural zip code areas. Comparisons of rider and crash characteristics by rurality showed similarities by sex, age, seating position, on vs. off the road, and crash mechanism. Conversely, helmet use was significantly lower among victims of isolated rural crashes as compared to other victims (p=0.004). Crashes in isolated rural and small rural areas accounted for only 39% of all crashes but resulted in 62% of fatalities. In both rural and urban areas, less than one-quarter of roadway injuries were traffic related. Relative crash rates varied by county, and unique patterns were observed for crashes involving youth and roadway riders. During the study period, 10% and 50% of all crashes occurred in 2% and 20% of the state's counties, respectively. CONCLUSION: This study suggests that ATV crashes are a public health concern for both rural and urban communities. However, isolated rural ATV crash victims were less likely to be helmeted, and rural victims were over-represented among fatalities. Traffic was not the major factor in roadway crashes in either rural or urban areas. Unique crash patterns for different riding populations suggest that injury prevention experts and public policy makers should consider the potential impact of geographical location when developing injury prevention interventions. PMID- 28874945 TI - Pediatric Exposures to Topical Benzocaine Preparations Reported to a Statewide Poison Control System. AB - INTRODUCTION: Topical benzocaine is a local anesthetic commonly used to relieve pain caused by teething, periodontal irritation, burns, wounds, and insect bites. Oral preparations may contain benzocaine concentrations ranging from 7.5% to 20%. Pediatric exposure to such large concentrations may result in methemoglobinemia and secondarily cause anemia, cyanosis, and hypoxia. METHODS: This is a retrospective study of exposures reported to a statewide poison control system. The electronic health records were queried for pediatric exposures to topical benzocaine treated at a healthcare facility from 2004 to 2014. Cases of benzocaine exposure were reviewed for demographic and clinical information, and descriptive statistical analysis was performed. RESULTS: The query resulted in 157 cases; 58 were excluded due to co-ingestants, or miscoding of non-benzocaine exposures. Children four years of age and younger represented the majority of cases (93%) with a median age of 1 year. There were 88 cases of accidental/ exploratory exposure, while 6 cases resulted from therapeutic application or error, 4 cases from adverse reactions, and 1 case from an unknown cause. Asymptomatic children accounted for 75.5% of cases, but major clinical effects were observed in 5 patients. Those with serious effects were exposed to a range of benzocaine concentrations (7.5-20%), with 4 cases reporting methemoglobin levels between 20.2%-55%. Methylene blue was administered in 4 of the cases exhibiting major effects. CONCLUSION: The majority of exposures were accidental ingestions by young children. Most exposures resulted in minor to no effects. However, some patients required treatment with methylene blue and admission to a critical care unit. Therapeutic application by parents or caregivers may lead to adverse effects from these commonly available products. PMID- 28874946 TI - What Did You Google? Describing Online Health Information Search Patterns of ED patients and Their Relationship with Final Diagnoses. AB - INTRODUCTION: Emergency department (ED) patients' Internet search terms prior to arrival have not been well characterized. The objective of this analysis was to characterize the Internet search terms patients used prior to ED arrival and their relationship to final diagnoses. METHODS: We collected data via survey; participants listed Internet search terms used. Terms were classified into categories: symptom, specific diagnosis, treatment options, anatomy questions, processes of care/physicians, or "other." We categorized each discharge diagnosis as either symptom-based or formal diagnosis. The relationship between the search term and final diagnosis was assigned to one of four categories of search/diagnosis combinations (symptom search/symptom diagnosis, symptom search/formal diagnosis, diagnosis search/symptom diagnosis, diagnosis search/formal diagnosis), representing different "trajectories." RESULTS: We approached 889 patients; 723 (81.3%) participated. Of these, 177 (24.5%) used the Internet prior to ED presentation; however, seven had incomplete data (N=170). Mean age was 47 years (standard deviation 18.2); 58.6% were female and 65.7% white. We found that 61.7% searched symptoms and 40.6% searched a specific diagnosis. Most patients received discharge diagnoses of equal specificity as their search terms (34% flat trajectory-symptoms and 34% flat trajectory diagnosis). Ten percent searched for a diagnosis by name but received a symptom based discharge diagnosis with less specificity. In contrast, 22% searched for a symptom and received a detailed diagnosis. Among those who searched for a diagnosis by name (n=69) only 29% received the diagnosis that they had searched. CONCLUSION: The majority of patients used symptoms as the basis of their pre-ED presentation Internet search. When patients did search for specific diagnoses, only a minority searched for the diagnosis they eventually received. PMID- 28874947 TI - Diagnostic Accuracy of Ultrasound for Identifying Shoulder Dislocations and Reductions: A Systematic Review of the Literature. AB - INTRODUCTION: Patients with shoulder dislocations commonly present to the emergency department. Ultrasound has the potential to save time, radiation exposure, healthcare costs, and possible need for re-sedation. We conducted this systematic review to compare the diagnostic accuracy of ultrasound compared with plain radiography in the assessment of shoulder dislocations. METHODS: We searched PubMed, Scopus, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials for relevant trials. Primary data and test characteristics were obtained for all included studies. We used QUADAS-2 to assess study quality. Meta-analysis was not performed due to significant heterogeneity. RESULTS: Four studies met our inclusion criteria, comprising 531 assessments with 202 dislocations. Most studies had a sensitivity of 100% for identifying dislocations. One study demonstrated a sensitivity of 54%, and another had only one dislocation that was misidentified. All studies were 100% specific for detecting dislocation. CONCLUSION: Ultrasound may be considered as an alternative diagnostic method for the detection of shoulder dislocation and reduction, but further studies are necessary before routine use. PMID- 28874948 TI - Impact of Internally Developed Electronic Prescription on Prescribing Errors at Discharge from the Emergency Department. AB - INTRODUCTION: Medication errors are common, with studies reporting at least one error per patient encounter. At hospital discharge, medication errors vary from 15%-38%. However, studies assessing the effect of an internally developed electronic (E)-prescription system at discharge from an emergency department (ED) are comparatively minimal. Additionally, commercially available electronic solutions are cost-prohibitive in many resource-limited settings. We assessed the impact of introducing an internally developed, low-cost E-prescription system, with a list of commonly prescribed medications, on prescription error rates at discharge from the ED, compared to handwritten prescriptions. METHODS: We conducted a pre- and post-intervention study comparing error rates in a randomly selected sample of discharge prescriptions (handwritten versus electronic) five months pre and four months post the introduction of the E-prescription. The internally developed, E-prescription system included a list of 166 commonly prescribed medications with the generic name, strength, dose, frequency and duration. We included a total of 2,883 prescriptions in this study: 1,475 in the pre-intervention phase were handwritten (HW) and 1,408 in the post-intervention phase were electronic. We calculated rates of 14 different errors and compared them between the pre- and post-intervention period. RESULTS: Overall, E prescriptions included fewer prescription errors as compared to HW-prescriptions. Specifically, E-prescriptions reduced missing dose (11.3% to 4.3%, p <0.0001), missing frequency (3.5% to 2.2%, p=0.04), missing strength errors (32.4% to 10.2%, p <0.0001) and legibility (0.7% to 0.2%, p=0.005). E-prescriptions, however, were associated with a significant increase in duplication errors, specifically with home medication (1.7% to 3%, p=0.02). CONCLUSION: A basic, internally developed E-prescription system, featuring commonly used medications, effectively reduced medication errors in a low-resource setting where the costs of sophisticated commercial electronic solutions are prohibitive. PMID- 28874949 TI - Sepsis Definitions: The Search for Gold and What CMS Got Wrong. AB - On October 1, 2015, the United States Centers for Medicare and Medicaid Services (CMS) issued a core measure addressing the care of septic patients. These core measures are controversial among healthcare providers. This article will address that there is no gold standard definition for sepsis, severe sepsis or septic shock and the CMS-assigned definitions for severe sepsis and septic shock are premature and inconsistent with evidence-based definitions. PMID- 28874950 TI - Appropriateness of Bolus Antihypertensive Therapy for Elevated Blood Pressure in the Emergency Department. AB - INTRODUCTION: While moderate to severely elevated blood pressure (BP) is present in nearly half of all emergency department (ED) patients, the incidence of true hypertensive emergencies in ED patients is low. Administration of bolus intravenous (IV) antihypertensive treatment to lower BP in patients without a true hypertensive emergency is a wasteful practice that is discouraged by hypertension experts; however, anecdotal evidence suggests this occurs with relatively high frequency. Accordingly, we sought to assess the frequency of inappropriate IV antihypertensive treatment in ED patients with elevated BP absent a hypertensive emergency. METHODS: We performed a retrospective cohort study from a single, urban, teaching hospital. Using pharmacy records, we identified patients age 18-89 who received IV antihypertensive treatment in the ED. We defined treatment as inappropriate if documented suspicion for an indicated cardiovascular condition or acute end-organ injury was lacking. Data abstraction included adverse events and 30-day readmission rates, and analysis was primarily descriptive. RESULTS: We included a total of 357 patients over an 18-month period. The mean age was 55; 51% were male and 93% black, and 127 (36.4%) were considered inappropriately treated. Overall, labetalol (61%) was the most commonly used medication, followed by enalaprilat (18%), hydralazine (18%), and metoprolol (3%). There were no significant differences between appropriate and inappropriate BP treatment groups in terms of clinical characteristics or adverse events. Hypotension or bradycardia occurred in three (2%) patients in the inappropriate treatment cohort and in two (1%) patients in the appropriately treated cohort. Survival to discharge and 30-day ED revisit rates were equivalent. CONCLUSION: More than one in three patients who were given IV bolus antihypertensive treatment in the ED received such therapy inappropriately by our definition, suggesting that significant resources could perhaps be saved through education of providers and development of clearly defined BP treatment protocols. PMID- 28874951 TI - Severe Hyperkalemia: Can the Electrocardiogram Risk Stratify for Short-term Adverse Events? AB - INTRODUCTION: The electrocardiogram (ECG) is often used to identify which hyperkalemic patients are at risk for adverse events. However, there is a paucity of evidence to support this practice. This study analyzes the association between specific hyperkalemic ECG abnormalities and the development of short-term adverse events in patients with severe hyperkalemia. METHODS: We collected records of all adult patients with potassium (K+) >=6.5 mEq/L in the hospital laboratory database from August 15, 2010, through January 30, 2015. A chart review identified patient demographics, concurrent laboratory values, ECG within one hour of K+ measurement, treatments and occurrence of adverse events within six hours of ECG. We defined adverse events as symptomatic bradycardia, ventricular tachycardia, ventricular fibrillation, cardiopulmonary resuscitation (CPR) and/or death. Two emergency physicians blinded to study objective independently examined each ECG for rate, rhythm, peaked T wave, PR interval duration and QRS complex duration. Relative risk was calculated to determine the association between specific hyperkalemic ECG abnormalities and short-term adverse events. RESULTS: We included a total of 188 patients with severe hyperkalemia in the final study group. Adverse events occurred within six hours in 28 patients (15%): symptomatic bradycardia (n=22), death (n=4), ventricular tachycardia (n=2) and CPR (n=2). All adverse events occurred prior to treatment with calcium and all but one occurred prior to K+-lowering intervention. All patients who had a short-term adverse event had a preceding ECG that demonstrated at least one hyperkalemic abnormality (100%, 95% confidence interval [CI] [85.7-100%]). An increased likelihood of short-term adverse event was found for hyperkalemic patients whose ECG demonstrated QRS prolongation (relative risk [RR] 4.74, 95% CI [2.01-11.15]), bradycardia (HR<50) (RR 12.29, 95%CI [6.69-22.57]), and/or junctional rhythm (RR 7.46, 95%CI 5.28-11.13). There was no statistically significant correlation between peaked T waves and short-term adverse events (RR 0.77, 95% CI [0.35 1.70]). CONCLUSION: Our findings support the use of the ECG to risk stratify patients with severe hyperkalemia for short-term adverse events. PMID- 28874952 TI - Duration of Mechanical Ventilation in the Emergency Department. AB - INTRODUCTION: Due to hospital crowding, mechanically ventilated patients are increasingly spending hours boarding in emergency departments (ED) before intensive care unit (ICU) admission. This study aims to evaluate the association between time ventilated in the ED and in-hospital mortality, duration of mechanical ventilation, ICU and hospital length of stay (LOS). METHODS: This was a multi-center, prospective, observational study of patients ventilated in the ED, conducted at three academic Level I Trauma Centers from July 2011 to March 2013. All consecutive adult patients on invasive mechanical ventilation were eligible for enrollment. We performed a Cox regression to assess for a mortality effect for mechanically ventilated patients with each hour of increasing LOS in the ED and multivariable regression analyses to assess for independently significant contributors to in-hospital mortality. Our primary outcome was in hospital mortality, with secondary outcomes of ventilator days, ICU LOS and hospital LOS. We further commented on use of lung protective ventilation and frequency of ventilator changes made in this cohort. RESULTS: We enrolled 535 patients, of whom 525 met all inclusion criteria. Altered mental status without respiratory pathology was the most common reason for intubation, followed by trauma and respiratory failure. Using iterated Cox regression, a mortality effect occurred at ED time of mechanical ventilation > 7 hours, and the longer ED stay was also associated with a longer total duration of intubation. However, adjusted multivariable regression analysis demonstrated only older age and admission to the neurosciences ICU as independently associated with increased mortality. Of interest, only 23.8% of patients ventilated in the ED for over seven hours had changes made to their ventilator. CONCLUSION: In a prospective observational study of patients mechanically ventilated in the ED, there was a significant mortality benefit to expedited transfer of patients into an appropriate ICU setting. PMID- 28874953 TI - Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production. AB - Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases), but only at very high concentrations (10-2-10-1 M) that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain. PMID- 28874955 TI - Terahertz endoscopic imaging for colorectal cancer detection: Current status and future perspectives. AB - Terahertz (THz) imaging is progressing as a robust platform for myriad applications in the field of security, health, and material science. The THz regime, which comprises wavelengths spanning from microns to millimeters, is non ionizing and has very low photon energy: Making it inherently safe for biological imaging. Colorectal cancer is one of the most common causes of death in the world, while the conventional screening and standard of care yet relies exclusively on the physician's experience. Researchers have been working on the development of a flexible THz endoscope, as a potential tool to aid in colorectal cancer screening. This involves building a single-channel THz endoscope, and profiling the THz response from colorectal tissue, and demonstrating endogenous contrast levels between normal and diseased tissue when imaging in reflection modality. The current level of contrast provided by the prototype THz endoscopic system represents a significant step towards clinical endoscopic application of THz technology for in-vivo colorectal cancer screening. The aim of this paper is to provide a short review of the recent advances in THz endoscopic technology and cancer imaging. In particular, the potential of single-channel THz endoscopic imaging for colonic cancer screening will be highlighted. PMID- 28874956 TI - Use and barriers to chromoendoscopy for dysplasia surveillance in inflammatory bowel disease. AB - Traditionally, patients with inflammatory bowel disease (IBD) have been thought to be at increased risk of developing colitis-associated colorectal cancer. Although there are recent data suggesting that rates of colitis-associated cancer in IBD patients is declining, current guidelines still recommend regular dysplasia surveillance for early detection and prevention of neoplasia in patients with IBD. White-light endoscopy with random biopsies has been the traditional approach for dysplasia detection; however, newer technologies and approaches have emerged. One method, dye-based chromoendoscopy, has the potential to detect more dysplasia. However, longitudinal data to showing a benefit in morbidity or mortality from the use of chromoendoscopy are still lacking. Many societies have included recommendation on the use of chromoendoscopy with targeted biopsies as a method of surveillance for colitis - associated colorectal cancer. This narrative review seeks to outline data on dysplasia detection as well as barriers to the implementation of dye-based chromoendoscopy for the prevention and early detection of colitis-associated colorectal cancer. PMID- 28874954 TI - Aging: Molecular Pathways and Implications on the Cardiovascular System. AB - The world's population over 60 years is growing rapidly, reaching 22% of the global population in the next decades. Despite the increase in global longevity, individual healthspan needs to follow this growth. Several diseases have their prevalence increased by age, such as cardiovascular diseases, the leading cause of morbidity and mortality worldwide. Understanding the aging biology mechanisms is fundamental to the pursuit of cardiovascular health. In this way, aging is characterized by a gradual decline in physiological functions, involving the increased number in senescent cells into the body. Several pathways lead to senescence, including oxidative stress and persistent inflammation, as well as energy failure such as mitochondrial dysfunction and deregulated autophagy, being ROS, AMPK, SIRTs, mTOR, IGF-1, and p53 key regulators of the metabolic control, connecting aging to the pathways which drive towards diseases. In addition, senescence can be induced by cellular replication, which resulted from telomere shortening. Taken together, it is possible to draw a common pathway unifying aging to cardiovascular diseases, and the central point of this process, senescence, can be the target for new therapies, which may result in the healthspan matching the lifespan. PMID- 28874957 TI - Evolution of stereoscopic imaging in surgery and recent advances. AB - In the late 1980s the first laparoscopic cholecystectomies were performed prompting a sudden rise in technological innovations as the benefits and feasibility of minimal access surgery became recognised. Monocular laparoscopes provided only two-dimensional (2D) viewing with reduced depth perception and contributed to an extended learning curve. Attention turned to producing a usable three-dimensional (3D) endoscopic view for surgeons; utilising different technologies for image capture and image projection. These evolving visual systems have been assessed in various research environments with conflicting outcomes of success and usability, and no overall consensus to their benefit. This review article aims to provide an explanation of the different types of technologies, summarise the published literature evaluating 3D vs 2D laparoscopy, to explain the conflicting outcomes, and discuss the current consensus view. PMID- 28874958 TI - Endoscopic ultrasonography - emerging applications in hepatology. AB - The inspection of the liver is a valuable part of the upper endoscopic ultrasonography (EUS) studies, regardless of the primary indication for the examination. The detailed images of the liver segments provided by EUS allows the use of this technique in the study of parenchymal liver disease and even in the diagnosis and classification of focal liver lesions. EUS has also emerged as an important tool in understanding the complex collateral circulation in patients with portal hypertension and their clinical and prognostic value. Recently, EUS guided portal vein catheterization has been performed for direct portal pressure measurement as an alternative method to evaluate portal hemodynamics. In this review, the authors summarize the available evidence regarding the application of EUS to patients with liver diseases and how we can apply it in our current clinical practice. PMID- 28874959 TI - Clinical impact of confocal laser endomicroscopy in the management of gastrointestinal lesions with an uncertain diagnosis. AB - AIM: To evaluate the clinical impact of confocal laser endomicroscopy (CLE) in the diagnosis and management of patients with an uncertain diagnosis. METHODS: A retrospective chart review was performed. Patients who underwent CLE between November 2013 and October 2015 and exhibited a poor correlation between endoscopic and histological findings were included. Baseline characteristics, indications, previous diagnostic studies, findings at the time of CLE, clinical management and histological results were analyzed. Interventions based on CLE findings were also analyzed. We compared the diagnostic accuracy of CLE and target biopsies of surgical specimens. RESULTS: A total of 144 patients were included. Of these, 51% (74/144) were female. The mean age was 51 years old. In all, 41/144 (28.4%) lesions were neoplastic (13 bile duct, 10 gastric, 8 esophageal, 6 colonic, 1 duodenal, 1 rectal, 1 ampulloma and 1 pancreatic). The sensitivity, specificity, positive predictive value, negative predictive value, and observed agreement when CLE was used to detect N-lesions were 85.37%, 87.38%, 72.92%, 93.75% and 86.81%, respectively. Cohen's Kappa was 69.20%, thus indicating good agreement. Changes in management were observed in 54% of the cases. CONCLUSION: CLE is a new diagnostic tool that has a significant clinical impact on the diagnosis and treatment of patients with uncertain diagnosis. PMID- 28874960 TI - Impact of laparoscopic liver resection on bleeding complications in patients receiving antithrombotics. AB - AIM: To assess the impact of laparoscopic liver resection (LLR) on surgical blood loss (SBL), especially in patients with antithrombotics for thromboembolic risks. METHODS: Consecutive 258 patients receiving liver resection at our institution between 2010 and 2016 were retrospectively reviewed. Preoperative antithrombotic therapy (ATT; antiplatelets and/or anticoagulation) was regularly used in 100 patients (ATT group, 38.8%) whereas not used in 158 (non-ATT group, 61.2%). Our perioperative management of high thromboembolic risk patients included maintenance of preoperative aspirin monotherapy for patients with antiplatelet therapy and bridging heparin for patients with anticoagulation. In both ATT and non-ATT groups, outcome variables of patients undergoing LLR were compared with those of patients receiving open liver resection (OLR), and the independent risk factors for increased SBL were determined by multivariate analysis. RESULTS: This series included 77 LLR and 181 OLR. There were 3 thromboembolic events (1.2%) in a whole cohort, whereas increased SBL (>= 500 mL) and postoperative bleeding complications (BCs) occurred in 66 patients (25.6%) and 8 (3.1%), respectively. Both in the ATT and non-ATT groups, LLR was significantly related to reduced SBL and low incidence of BCs, although LLR was less performed as anatomical resection. Multivariate analysis showed that anatomical liver resection was the most significant risk factor for increased SBL [risk ratio (RR) = 6.54, P < 0.001] in the whole cohort, and LLR also had the significant negative impact (RR = 1/10.0, P < 0.001). The same effects of anatomical resection (RR = 15.77, P < 0.001) and LLR (RR = 1/5.88, P = 0.019) were observed when analyzing the patients in the ATT group. CONCLUSION: LLR using the two-surgeon technique is feasible and safely performed even in the ATT-burdened patients with thromboembolic risks. Independent from the extent of liver resection, LLR is significantly associated with reduced SBL, both in the ATT and non-ATT groups. PMID- 28874961 TI - Correlation of abnormal histology with endoscopic findings among mycophenolate mofetil treated patients. AB - AIM: To describe all abnormal histological findings and their associated endoscopic presentation in patients using mycophenolate mofetil (MMF). METHODS: A retrospective review of all individuals prescribed MMF within 6 mo of a colonoscopy or flexible sigmoidoscopy between 07/2009 and 09/2015 was performed within Northwell Health system. Records were analyzed for age, gender, procedure indication, MMF indication, and both gross and microscopic findings. Only reports with abnormal histology were included. RESULTS: One hundred and eighty-four procedures from 170 patients were found, of which 39 met inclusion criteria. Fifty-one point three percent were female. MMF was used for solid organ transplant in 71.8%. Diarrhea was the indication for 71.8% of colonoscopies. Fifty-nine percent of reports revealed gross and microscopic abnormalities while 41.0% had only microscopic findings. Only 11 patients' reports (28.2%) indicated a specific histopathology of MMF colitis. Among the entire group, only 23.1% of abnormal histology was isolated proximal to the splenic flexure. CONCLUSION: Our results demonstrate a high rate of left sided disease and microscopic findings without gross mucosal abnormalities among patients using MMF. Also, a broader definition of MMF-colonopathy may be appropriate, with a majority of our abnormal histology falling outside of the more narrowly defined MMF-colitis category. Given the high frequency of isolated microscopic abnormalities and distal disease, sigmoidoscopy with random biopsies may be an appropriate, less invasive initial endoscopic examination in selected MMF patients. PMID- 28874962 TI - Usefulness of the Hook knife in flexible endoscopic myotomy for Zenker's diverticulum. AB - AIM: To investigate the outcome of flexible endoscopic myotomy performed with the Hook knife in patients with symptomatic Zenker's diverticulum (ZD). METHODS: All consecutive patients treated for ZD at our institution between 7/2012 and 12/2016 were included. The flexible endoscopic soft diverticuloscope-assisted technique with endoclips placement and Hook knife myotomy were performed in all patients. Here we report a retrospective review of prospectively collected data. Demographics, dysphagia score (Dakkak and Bennett), associated symptoms and adverse events were collected pre-procedure, at 2 and 6 mo post-procedure, and at the end of the follow-up period. Clinical success was defined as at least 1-point improvement in dysphagia score and a residual dysphagia score <= 1, with no need for reintervention. Dysphagia scores were compared before treatment and at end-of follow-up using the Wilcoxon test. RESULTS: Twenty-four patients were included. Mean size of ZD was 3.0 cm (range 2-8 cm). Mean number of sessions was 1.17/patient (range 1-3 sessions). Overall clinical success was 91.7%. Two adverse events (8.3%) occurred, and both were managed conservatively. No bleeding or perforation was reported. Mild pain was reported by 9 patients (37.5%). Median hospital stay was 1 d (range 1-6). Median follow-up was 19.5 mo (range 6-53). Mean +/- SD dysphagia score was 2.25 +/- 0.89 before treatment and decreased to 0.41 +/- 0.92 at end-of-follow-up (P < 0.001). Regurgitation and cough dropped from 91.7% and 50% to 12.5% and 0% at the end of follow-up, respectively. Recurrence was observed in 3 patients, and all 3 were symptom-free after one more session. CONCLUSION: The Hook knife, used in the soft diverticuloscope-assisted technique setting, is efficient and safe for treatment of ZD. PMID- 28874963 TI - Russell body gastritis with Dutcher bodies evaluated using magnification endoscopy. AB - Russell body gastritis (RBG) is an unusual type of chronic gastritis characterized by marked infiltration of Mott cells, which are plasma cells filled with spherical eosinophilic bodies referred to as Russell bodies. It was initially thought that Helicobacter pylori (H. pylori) infection was a major cause of RBG and that the infiltrating Mott cells were polyphenotypic; however, a number of cases of RBG without H. pylori infection or with monoclonal Mott cells have been reported. Thus, diagnostic difficulty exists in distinguishing RBG with monoclonal Mott cells from malignant lymphoma. Here, we report an unusual case of an 86-year-old-Japanese man with H. pylori-positive RBG. During the examination of melena, endoscopic evaluation confirmed a 13-mm whitish, flat lesion in the gastric antrum. Magnification endoscopy with narrow-band imaging suggested that the lesion was most likely a poorly differentiated adenocarcinoma. Biopsy findings were consistent with chronic gastritis with many Mott cells with intranuclear inclusions referred to as Dutcher bodies. Endoscopic submucosal dissection confirmed the diagnosis of RBG with kappa-restricted monoclonal Mott cells. Malignant lymphoma was unlikely given the paucity of cytological atypia and Ki-67 immunoreactivity of monoclonal Mott cells. This is the first reported case of RBG with endoscopic diagnosis of malignant tumor and the presence of Dutcher bodies. PMID- 28874964 TI - Simultaneous Courvoisier's and double duct signs. AB - Presence of Courvoisier's or double duct signs in a jaundiced patient is suggestive of malignant obstruction of the pancreaticobiliary ductal system. The oncologic impact of the simultaneous occurrence of these signs on the survival of patients with periampullary cancer is unknown. We report a case of obstructive jaundice secondary to an ampullary cancer demonstrating the Courvoisier's sign on clinical examination and a double duct sign on imaging. The patient underwent a pancreaticoduodenectomy which confirmed an ampullary adenocarcinoma. PMID- 28874965 TI - Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis. AB - Recent studies have implicated the prorenin receptor (PRR) is associated with pancreatic tumorigenesis. We therefore investigated the role of PRR in pancreatic tumorigenesis and assessed whether PRR can serve as a target for imaging diagnosis at early stages of PDAC. Here we show that aberrant expression of PRR in premalignant PanIN lesions, and human PDAC samples, and PDAC cell lines, particularly in Panc-1 cells. Interestingly, PRR expression was positively associated with PDAC progression. Moreover, overexpression of human PRR resulted in increased cell proliferation and decreased apoptosis, while knockdown of human PRR caused decreased cell proliferation and enhanced apoptosis in pancreatic cancer cells. We also observed that overexpression of human PRR enhanced MAPK and PI3K/Akt signaling pathways in PDAC cells, while knockdown of human PRR suppressed both of pathways. The confocal imaging analysis showed that human PRR was highly expressed in Panc-1, ASPC, and Miapaca cells, whereas BXPC-3, and HPAC cells had a significantly lower fluorescent signals. Consistently, the single photon emission computed tomography (SPET/CT) showed that the uptake of anti-PRR labelled with 125I was higher in Panc-1 and ASPC tumors-bearing mice after 96 hours injection. Importantly, tumors in pancreas of Pdx1-cre; LSL-KrasG12D mice had a significant increased PRR expression and accumulation of radioactivity at 96 h after injection. These data suggest that 125I-anti-PRR can detect the orthotopic tumors in Pdx1-cre; LSL-KrasG12D mice. Therefore, anti-PRR labelled with 125I is a promising radiotracer for imaging diagnosis at early stages of pancreatic cancer. PMID- 28874967 TI - Behavior of Injured Lamina in Lumbar Burst Fractures during Reduction Maneuvers: A Biomechanical Study. AB - STUDY DESIGN: An experimental biomechanical study. PURPOSE: This study aims to investigate the behavior of a lamina injury in lumbar burst fractures during reduction maneuvers. OVERVIEW OF LITERATURE: Lumbar burst fractures are frequently accompanied by a lamina fracture. Many researchers concluded that any reduction maneuver will close the fractured lamina edges and possibly crush the entrapped neural elements. This conclusion did not rely on solid biomechanical trials and was based primarily on clinical experience. METHODS: Eighteen fresh frozen lamb spines were randomly divided into three groups. Using the preinjury and the dropped-mass technique, a burst fracture model was developed. A central laminectomy of 5 mm of the L3 lumbar spine was created to mimic a complete type of lamina fracture. To measure the movement of the fractured laminar edges, two holes were drilled on both sides of the upper and lower regions of the lamina to allow for optic marker placement. A single specific spine movement was applied to each group: traction, flexion, and extension. Gap changes were measured by camera extensometers. RESULTS: After traction, the average values of the upper and lower aspects of the lamina interval showed narrowing of 1.65+/-0.82 mm and 1.97+/-1.14 mm, respectively. No statistical significance was detected between the two aspects. The upper and lower regions of the lamina gap behaved differently during extension. At 10 degrees , 20 degrees , and 30 degrees , the upper part of the lamina interval was widened by an average of 0.016+/-0.024, 0.29+/-0.32, and 1.73+/-1.45 mm, respectively, whereas the lower part was narrowed by an average of 0.023+/-0.012, 0.47+/-0.038, and 1.94+/-1.46 mm, respectively. CONCLUSIONS: Neural element crushing may take place, particularly at the lower aspect of the fractured lamina gap during extension and throughout the whole lamina gap during traction. The lamina gap widens during flexion. Reduction maneuvers should be attempted after exploring the fractured lamina to prevent further neurological compromise. PMID- 28874966 TI - Characterization of acetate transport in colorectal cancer cells and potential therapeutic implications. AB - Acetate, together with other short chain fatty acids has been implicated in colorectal cancer (CRC) prevention/therapy. Acetate was shown to induce apoptosis in CRC cells. The precise mechanism underlying acetate transport across CRC cells membrane, that may be implicated in its selectivity towards CRC cells, is not fully understood and was addressed here. We also assessed the effect of acetate in CRC glycolytic metabolism and explored its use in combination with the glycolytic inhibitor 3-bromopyruvate (3BP). We provide evidence that acetate enters CRC cells by the secondary active transporters MCT1 and/or MCT2 and SMCT1 as well as by facilitated diffusion via aquaporins. CRC cell exposure to acetate upregulates the expression of MCT1, MCT4 and CD147, while promoting MCT1 plasma membrane localization. We also observed that acetate increases CRC cell glycolytic phenotype and that acetate-induced apoptosis and anti-proliferative effect was potentiated by 3BP. Our data suggest that acetate selectivity towards CRC cells might be explained by the fact that aquaporins and MCTs are found overexpressed in CRC clinical cases. Our work highlights the importance that acetate transport regulation has in the use of drugs such as 3BP as a new therapeutic strategy for CRC. PMID- 28874968 TI - Posterior-Only Approach with Pedicle Screws for the Correction of Scheuermann's Kyphosis. AB - STUDY DESIGN: Retrospective study (level of evidence: level 3). PURPOSE: The purpose of this study was to evaluate the clinical and radiological results of the posterior-only approach with pedicle screws for the treatment of Scheuermann's kyphosis (SK). OVERVIEW OF LITERATURE: The correction of SK with instrumentation can be performed using posterior-only or combined anterior posterior procedures. With the use of all-pedicle screw constructs in spine surgery, the posterior-only approach has become a popular option for the definitive treatment of SK. In a nationwide study involving 2,796 patients, a trend toward posterior-only fusion with lower complication rates was reported. METHODS: We retrospectively reviewed the data of patients who underwent posterior only correction for SK between January 2005 and May 2013. Patients with a definite diagnosis of SK who fulfilled the minimum follow-up criterion of 24 months were included. The thoracic kyphosis (T5-T12), lumbar lordosis (L1-S1), and thoracolumbar junction (T10-L2) angles were measured from preoperative, postoperative, and last control radiographs. Sagittal balance, thoracic length, thoracic diameter, Voutsinas index and the sacral slope, pelvic tilt, proximal junction kyphosis, and distal junction kyphosis angles were also measured. RESULTS: Forty-five patients underwent surgery for the treatment of SK between 2005 and 2013. After applying the exclusion criteria, 20 patients (18 males and 2 females) with a mean age of 19 years were included. The mean thoracic kyphosis angle was 79.8 degrees preoperatively, 44.6 degrees postoperatively, and 44.9 degrees at the last control. There were statistically significant differences between preoperative and postoperative values in the thoracic kyphosis and lumbar lordosis angles, thoracic length, thoracic diameter, and Voutsinas index (p<0.05). CONCLUSIONS: The clinical and radiological results of the current study suggest that posterior-only fusion is an efficient technique for the treatment of SK. PMID- 28874969 TI - Cross-Cultural Adaptation, Validity, and Reliability of the Persian Version of the Orebro Musculoskeletal Pain Screening Questionnaire. AB - STUDY DESIGN: Observational study. PURPOSE: To cross-culturally translate the Orebro Musculoskeletal Pain Screening Questionnaire (OMPQ) into Persian and then evaluate its psychometric properties (reliability, validity, ceiling, and flooring effects). OVERVIEW OF LITERATURE: To the authors' knowledge, prior to this study there has been no validated instrument to screen the risk of chronicity in Persian-speaking patients with low back pain (LBP) in Iran. The OMPQ was specifically developed as a self-administered screening tool for assessing the risk of LBP chronicity. METHODS: The forward-backward translation method was used for the translation and cross-cultural adaptation of the original questionnaire. In total, 202 patients with subacute LBP completed the OMPQ and the pain disability questionnaire (PDQ), which was used to assess convergent validity. 62 patients completed the OMPQ a week later as a retest. RESULTS: Slight changes were made to the OMPQ during the translation/cultural adaptation process; face validity of the Persian version was obtained. The Persian OMPQ showed excellent test-retest reliability (intraclass correlation coefficient=0.89). Its internal consistency was 0.71, and its convergent validity was confirmed by good correlation coefficient between the OMPQ and PDQ total scores (r=0.72, p<0.05). No ceiling or floor effects were observed. CONCLUSIONS: The Persian version of the OMPQ is acceptable for the target society in terms of face validity, construct validity, reliability, and consistency. It is therefore considered a useful instrument for screening Iranian patients with LBP. PMID- 28874970 TI - Prolonged Physiotherapy versus Early Surgical Intervention in Patients with Lumbar Disk Herniation: Short-term Outcomes of Clinical Randomized Trial. AB - STUDY DESIGN: Randomized controlled trial. PURPOSE: We compared the disability and functional outcome after conservative treatment with prolonged physiotherapy versus early surgical intervention in patients with lumbar disk herniation. OVERVIEW OF LITERATURE: Lumbar disk herniation is one of the most common causes of job-related disability in individuals less than 45 years old. Conservative treatment is the initial pathway for the majority of patients but the duration of conservative treatment remains debatable and the adverse effects of prolonged conservative treatment are still unclear. Prolonged duration of symptoms before surgical intervention is associated with worse outcomes than a short period of symptoms. METHODS: From June 2011 to July 2013, 60 patients with lumbar disk herniation at our institute were randomized into two groups. Group I was treated with prolonged physiotherapy and rehabilitation for 6 months, while group II was treated with early surgical discectomy. Oswestry disability index was used to assess disability, while the Prolo economic outcome rating scale was used to assess the work status. RESULTS: Most patients were males between 21 and 45 years old (mean age, 35.88+/-7.15). There was significant improvement in the disability and work status in both groups without statistically significant differences in the disability score at the second or third assessment. However, the Prolo scale became significantly better in group I than in group II patients during the second and third assessments. CONCLUSIONS: A prolonged physiotherapy and rehabilitation program is a beneficial and successful treatment in patients with recently diagnosed lumbar disk herniation. PMID- 28874971 TI - Adjacent Disc Stress Following Floating Lumbar Spine Fusion: A Finite Element Study. AB - STUDY DESIGN: Experimental study. PURPOSE: The study aimed to develop a finite element (FE) model to determine the stress on the discs adjacent to the fused segment following different types of floating lumbar spinal fusions. OVERVIEW OF LITERATURE: The quantification of the adjacent disc stress following different types of floating lumbar fusions has not been reported. The magnitude of the stress on the discs above and below the floating fusion remains unknown. METHODS: A computer-aided engineering-based approach using implicit FE analysis was employed to assess the stress on the lumbar discs above and below the floating fusion segment (L4-L5) following anterior and posterior lumbar spine fusions at one, two, and three levels (with and without instrumentation). RESULTS: Both discs suprajacent and infrajacent to the floating fusion experienced increased stress, but the suprajacent disc experienced relatively high stress level. Instrumentation increased the stress on the discs suprajacent and infrajacent to the floating fusion, but the magnitude of stress on the suprajacent disc remained relatively high. CONCLUSIONS: The FE model was employed under similar loading and boundary conditions to provide quantitative data, which will be useful for clinicians to understand the probable long-term effects of floating fusions. PMID- 28874972 TI - Microsurgical Treatment of Sporadic and von Hippel-Lindau Disease Associated Spinal Hemangioblastomas: A Single-Institution Experience. AB - STUDY DESIGN: Retrospective cohort study. PURPOSE: To examine the clinical profile and surgical complications in patients with spinal hemangioblastomas and to evaluate the long-term outcome in them. OVERVIEW OF LITERATURE: Although considered to be histologically benign, hemangioblastomas may cause significant neurological deficits. The proportion of spinal hemangioblastomas associated with von Hippel-Lindau (VHL) disease has been estimated be 13%-59%. Preoperative neurological function correlates with postoperative neurological status. Studies have shown no difference in outcomes between sporadic and VHL-associated spinal hemangioblastomas. METHODS: This retrospective study included 14 consecutive patients treated for spinal hemangioblastomas at our institute between January 2000 and June 2013. The mean follow-up period was 5 years. Magnetic resonance imaging of the complete neuraxis was performed in all cases, and preoperative embolization was performed in two cases. RESULTS: In total, 14 patients underwent 18 surgeries, of which 15 were for spinal hemangioblastomas. Of all the patients, 86% had motor weakness and 79% presented with sensory disturbances. Preoperative McCormick functional grades were grade I in 7 (50%), grade II in 3 (21%), and grade III in 4 (29%) patients; 50% patients were diagnosed with VHL disease. All patients underwent complete resection of the tumor. Eight patients experienced deterioration in their neurological status in the immediate postoperative period; among them, five had gradual improvement. At 5-year follow-up, 11 (78.57%) patients showed good functional outcomes. CONCLUSIONS: Microsurgical excision of spinal hemangioblastomas can cause postoperative morbidity, mainly in the form of neurological deterioration. Almost half of our patients had deterioration in the McCormick grade in the immediate postoperative period. However, a complete microsurgical excision can result in good long-term functional outcomes, as most of the immediate postoperative neurological deterioration in our patients was reversible. There was no difference in the long-term functional outcomes between sporadic and VHL-associated spinal hemangioblastomas. PMID- 28874974 TI - Evaluation of Sagittal Spine-Pelvis-Lower Limb Alignment in Elderly Women with Pelvic Retroversion while Standing and Walking Using a Three-Dimensional Musculoskeletal Model. AB - STUDY DESIGN: In vivo biomechanical study using a three-dimensional (3D) musculoskeletal model for elderly individuals with or without pelvic retroversion. PURPOSE: To evaluate the effect of pelvic retroversion on the sagittal alignment of the spine, pelvis, and lower limb in elderly females while standing and walking. OVERVIEW OF LITERATURE: Patients with hip-spine syndrome have concurrent hip-joint and spine diseases. However, the dynamic sagittal alignment between the hip joint and spine has rarely been investigated. We used a 3D musculoskeletal model to evaluate global spinopelvic parameters, including spinal inclination and pelvic tilt (PT). METHODS: A total of 32 ambulant females (mean age=78 years) without assistance were enrolled in the study. On the basis of the radiographic measurement for PT, participants were divided into the pelvic retroversion group (R-group; PT>=20 degrees ) and the normal group (N-group; PT<20 degrees ). A 3D musculoskeletal motion analysis system was used to analyze the calculated value for the alignment of spine, pelvis, and lower limb, including calculated (C)-PT, sagittal vertical axis (C-SVA), pelvic incidence, lumbar lordosis, T1 pelvic angle (C-TPA), as well as knee and hip flexion angles while standing and walking. RESULTS: While standing, C-PT and C-TPA in the R group were significantly larger than those in the N-group. Hip angle was significantly smaller in the R-group than in the N-group, unlike knee angle, which did not show difference. While walking, C-SVA and C-TPA were significantly increased, whereas C-PT decreased compared with those while standing. The maximum hip-flexion angle was significantly smaller in the R-group than in the N-group. There was a significant correlation between the radiographic and calculated parameters. CONCLUSIONS: The 3D musculoskeletal model was useful in evaluating the sagittal alignment of the spine, pelvis, and leg. Spinopelvic sagittal alignment showed deterioration while walking. C-PT was significantly decreased while walking in the R-group, indicating possible compensatory mechanisms attempting to increase coverage of the femoral head. The reduction in the hip flexion angle in the R-group was also considered as a compensatory mechanism. PMID- 28874973 TI - Inhibiting Vascular Endothelial Growth Factor in Injured Intervertebral Discs Attenuates Pain-Related Neuropeptide Expression in Dorsal Root Ganglia in Rats. AB - STUDY DESIGN: An experimental animal study. PURPOSE: To evaluate effects of anti vascular endothelial growth factor (VEGF) on the content and distribution of the calcitonin gene-related peptide (CGRP) in the dorsal ganglia in a rat model. OVERVIEW OF LITERATURE: Increased expression of VEGF in degenerative disc disease increases the levels of inflammatory cytokines and nerve ingrowth into the damaged discs. In animal models, increased levels of VEGF can persist for up to 2 weeks after an injury. METHODS: Through abdominal surgery, the dorsal root ganglia (DRG) innervating L5/L6 intervertebral disc were labeled (FluoroGold neurotracer) in 24, 8-week old Sprague Dawley rats. The rats were randomly allocated to three groups of eight rats each. The anti-VEGF group underwent L5/6 intervertebral disc puncture using a 26-gauge needle, intradiscal injection of 33.3 ug of the pegaptanib sodium, a VEGF165 aptamer. The control-puncture group underwent disc puncture and intradiscal injection of 10 uL saline solution, and the sham-surgery group underwent labeling but no disc puncture. Two rats in each group were sacrificed on postoperative days 1, 7, 14, and 28 after surgery. L1-L6 DRGs were harvested, sectioned, and immunostained to detect the content and distribution of CGRP. RESULTS: Compared with the control, the percentage of CGRP positive cells was lower in the anti-VEGF group (p<0.05; 40.6% and 58.1% on postoperative day 1, 44.3% and 55.4% on day 7, and 42.4% and 59.3% on day 14). The percentage was higher in the control group compared with that of the sham group (p<0.05; sham group, 34.1%, 40.7%, and 33.7% on postoperative days 1, 7, and 14, respectively). CONCLUSIONS: Decreasing CGRP-positive cells using anti VEGF therapy provides fundamental evidence for a possible therapeutic role of anti-VEGF in patients with discogenic lower back pain. PMID- 28874975 TI - Radiologic and Clinical Courses of Degenerative Lumbar Scoliosis (10 degrees -25 degrees ) after a Short-Segment Fusion. AB - STUDY DESIGN: Retrospective study. PURPOSE: We report the surgical outcomes of small degenerative lumbar scoliosis (DLS) patients treated by a short-segment fusion and followed for a minimum of 5 years. OVERVIEW OF LITERATURE: Several surgical options are available for the treatment of DLS, such as decompression only, decompression plus a short-segment fusion, or decompression with a long segment fusion. Few studies have evaluated the results of a short-segment fusion in patients with DLS over time. METHODS: Seventy small DLS patients (Cobb's angle, 10 degrees -25 degrees ) with a minimum follow-up of 5 years were treated with a short-segment fusion between March 2004 and February 2010. The mean patient age was 71 (male:female=16:54), with a follow-up of 6.5 years (range, 5.0 11.6). The Cobb's angle, 1 and 2 segment coronal upper intervertebral angle, 1 and 2 segment sagittal upper intervertebral angle, the lumbar lordosis angle, and the C7 plumb lines (coronal and sagittal) were evaluated using simple radiographs, and visual analog scale (VAS), back pain was assessed preoperatively, immediately after surgery, and at 3, 6, and 12 months and 3 and 5 years after surgery. To identify factors influencing the radiologic progression, age, number of fusion segments, vertebral levels of fusion, body mass index, lowest instrumented vertebra (L5 or S1), bone mineral density (>-2.5, <=-2.5), and the presence of an interbody fusion were analyzed. RESULTS: The Cobb's angle and 1 segment coronal upper intervertebral angle showed more progression during follow up, particularly at 6 and 12 months after surgery. Clinical outcomes and radiological results were found to be significantly associated (p=0.041). No statistically significant association was found between other factors affecting radiologic progression from postoperative 6 months to 1 year. CONCLUSIONS: Radiologic variables (the Cobb's angle and coronal upper intervertebral angle-1) should be carefully considered and clinical caution exercised from 6 to 12 months after short-segment fusion in small DLS (10 degrees -25 degrees ). PMID- 28874976 TI - Preliminary Results of Relationship between Preoperative Walking Ability and Magnetic Resonance Imaging Morphology in Patients with Lumbar Canal Stenosis: Comparison between Trefoil and Triangle Types of Spinal Stenosis. AB - STUDY DESIGN: Cross-sectional. PURPOSE: To examine the relationship between magnetic resonance imaging (MRI) morphology stenosis grades and preoperative walking ability in patients with lumbar canal stenosis (LCS). OVERVIEW OF LITERATURE: No previous study has analyzed the correlation between MRI morphology stenosis grades and walking ability in patients with LCS. METHODS: This prospective study included 98 consecutive patients with LCS who were candidates for surgery. Using features identified in T2-weighted axial magnetic, stenosis type was determined at the maximal stenosis level, and only trefoil and triangle stenosis grade types were considered because of sufficient sample size. Intraobserver and interobserver reliability were assessed by calculating weighted kappa coefficients. Symptom severity was evaluated via the Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ). Walking ability was assessed using the Self-Paced Walking Test (SPWT) and JOABPEQ subscales. Demographic characteristics, SPWT scores, and JOABPEQ scores were compared between patients with trefoil and triangle stenosis types. RESULTS: The mean patient age was 58.1 (standard deviation, 8.4) years. The kappa values of the MRI morphology stenosis grade types showed a perfect agreement between the stenosis grade types. The trefoil group (n=53) and triangle group (n=45) showed similar preoperative JOABPEQ subscale scores (e.g., low back pain, lumbar function, and mental health) and were not significantly different in age, BMI, duration of symptoms, or lumbar stenosis levels (all p>0.05); however, trefoil stenosis grade type was associated with a decreased walking ability according to the SPWT and JOABPEQ subscale scores. CONCLUSIONS: These findings suggest preoperative walking ability is more profoundly affected in patients with trefoil type stenosis than in those with triangle type stenosis. PMID- 28874977 TI - Validation of the Iranian Version of the ECOS-16 Questionnaire in Patients with Osteoporotic Vertebral Fractures. AB - STUDY DESIGN: Prospective clinical study. PURPOSE: To translate and validate the Quality of Life Questionnaire of the European Foundation for Osteoporosis (ECOS 16) in patients with osteoporotic vertebral fractures in Iran. OVERVIEW OF LITERATURE: It is important to assess the psychometric properties of instruments measuring patient-reported outcomes. METHODS: The translation was performed using the backward-forward translation method. The final version was generated by consensus among the translators. Every woman who had a T-score of <-2.5 completed ECOS-16. Patients were divided into two study groups according to the World Health Organization's criteria: those with at least one vertebral fracture (surgery group) and those with no fractures (control group). They were asked to respond to the questionnaire at three points in time: preoperative and twice within 1-week interval after surgery assessments (6-month follow-up). The 36-item short-form health survey (SF-36) also was completed. The psychometric properties of the questionnaire were assessed using internal consistency, test-retest reliability, convergent validity, discriminant validity, and responsiveness. RESULTS: Of 137 recruited women, 39 underwent surgery and 98 did not. Analysis of the ECOS-16 scales showed an appropriate reliability with Cronbach's alpha of >0.70 for all scales. Test-retest reliability as indicated by intraclass correlation coefficient was found to be 0.85 (0.68-0.91). Additionally, the correlation of each item with its hypothesized domain of the ECOS-16 showed acceptable results, suggesting that the items had a substantial relationship with their own domains. Further analysis also indicated that the questionnaire was responsive to change (effect size, 0.85; standardized response mean, 0.93) (p<0.001). Significant correlations existed between scores of similar subscales of ECOS-16 and SF-36 (p<0.001). CONCLUSIONS: ECOS-16 is an acceptable, reliable, valid, and responsive measure to assess the quality of life in patients with osteoporotic vertebral fractures. PMID- 28874978 TI - Prevalence, Patterns, and Genetic Association Analysis of Modic Vertebral Endplate Changes. AB - STUDY DESIGN: A prospective genetic association study. PURPOSE: The etiology of Modic changes (MCs) is unclear. Recently, the role of genetic factors in the etiology of MCs has been evaluated. However, studies with a larger patient subset are lacking, and candidate genes involved in other disc degeneration phenotypes have not been evaluated. We studied the prevalence of MCs and genetic association of 41 candidate genes in a large Indian cohort. OVERVIEW OF LITERATURE: MCs are vertebral endplate signal changes predominantly observed in the lumbar spine. A significant association between MCs and lumbar disc degeneration and nonspecific low back pain has been described, with the etiopathogenesis implicating various mechanical, infective, and biochemical factors. METHODS: We studied 809 patients using 1.5-T magnetic resonance imaging to determine the prevalence, patterns, distribution, and type of lumbar MCs. Genetic association analysis of 71 single nucleotide polymorphisms (SNPs) of 41 candidate genes was performed based on the presence or absence of MCs. SNPs were genotyped using the Sequenome platform, and an association test was performed using PLINK software. RESULTS: The mean age of the study population (n=809) was 36.7+/-10.8 years. Based on the presence of MCs, the cohort was divided into 702 controls and 107 cases (prevalence, 13%). MCs were more commonly present in the lower (149/251, 59.4%) than in the upper (102/251, 40.6%) endplates. L4-5 endplates were the most commonly affected levels (30.7%). Type 2 MCs were the most commonly observed pattern (n=206, 82%). The rs2228570 SNP of VDR (p=0.02) and rs17099008 SNP of MMP20 (p=0.03) were significantly associated with MCs. CONCLUSIONS: Genetic polymorphisms of SNPs of VDR and MMP20 were significantly associated with MCs. Understanding the etiopathogenetic mechanisms of MCs is important for planning preventive and therapeutic strategies. PMID- 28874979 TI - Serotonergic Antidepressants Are Associated with Increased Blood Loss and Risk for Transfusion in Single-Level Lumbar Fusion Surgery. AB - STUDY DESIGN: Retrospective case-control study. PURPOSE: The purpose of this study was to examine the effect of antidepressants on blood loss and transfusion requirements in spinal surgery patients. OVERVIEW OF LITERATURE: Several studies have shown an increase in perioperative bleeding in orthopedic surgery patients on antidepressant drug therapy, yet no study has examined the impact of these agents on spinal surgery patients. METHODS: Charts of patients who underwent single-level spinal fusion (posterior lumbar interbody fusion with posterior instrumentation) performed by five fellowship-trained surgeons at a tertiary spine center between 2008 and 2013, were retrospectively reviewed. Exclusion criteria included select medical comorbidities, select drug therapy, and Amercian Society of Anesthesiologists Physical Status Classification score of greater than 2. Serotonergic antidepressants were examined in multivariate analysis to assess their predictive value on estimated blood loss and risk of transfusion. RESULTS: A total of 235 patients, of which 52% were female, were included. Allogeneic blood was transfused in 7% of patients. The average estimated blood loss was 682+/-463 mL. Selective serotonin reuptake inhibitors were taken by 10% of all patients. Multivariable regression analysis showed that intake of selective serotonin reuptake inhibitors was a significant predictor for blood loss (average increase of 34%, p=0.015) and for the need of allogeneic blood transfusion (odds ratio, 4.550; p=0.029). CONCLUSIONS: There was a statistically significant association between selective serotonin reuptake inhibitors and both increased blood loss and risk of allogeneic red blood cell transfusion. Surgeons and perioperative providers should take these findings into account when assessing patients' preoperative risk for blood loss and transfusion. PMID- 28874980 TI - Prevalence and Risk Factors for Low Back Pain in 1,355 Young Adults: A Cross Sectional Study. AB - STUDY DESIGN: Cross-sectional study. PURPOSE: To evaluate the prevalence and various risk factors for low back pain (LBP) in young adults in India. OVERVIEW OF LITERATURE: LBP is an emerging problem in adolescents, with an incidence that is the highest in the third decade of life worldwide. Various risk factors such as obesity, smoking, family history, stress, and exercise have been described in the literature. This study was conducted because of paucity of data in the Indian literature. METHODS: A total of 1,355 (741 males and 641 females) young Indian Administrative Service aspirants and medical postgraduate aspirants aged 18-35 years were enrolled in the study. The subjects completed a detailed, semi structured questionnaire that gathered data regarding their sociodemographic profile and factors considered to be risk factors for LBP. Anthropometric measurements, including height and weight, were measured and body mass index was calculated. RESULTS: Most subjects (90.6%) were aged 20-29 years (mean, 24.49; range, 18-35 years). Results indicated that the following factors were associated with LBP in young adults: marital status, previous history of spine problems, strenuous exercise, job satisfaction, monotony, stress, daily number of studying hours, and family history of spine problems (p<0.05). However, age, sex, smoking, alcoholism, coffee intake, mode and duration of travel, diet, frequency of weightlifting, wearing heels, studying posture, and frequency and type of sports activities were not associated with LBP. CONCLUSIONS: The study identified various modifiable and non-modifiable risk factors that precipitated LBP in young adult Indians. Identifying these risk factors at an early stage will prevent LBP progression to a chronic disease state, thereby improving an individual's quality of life and increasing productivity. PMID- 28874981 TI - Functional and Radiological Outcomes of Anterior Decompression and Posterior Stabilization via Posterior Transpedicular Approach in Thoracic and Thoracolumbar Pott's Disease: A Retrospective Study. AB - STUDY DESIGN: This is a retrospective study. PURPOSE: To determine the efficacy and safety of a posterior transpedicular approach with regard to functional and radiological outcomes in people with thoracic and thoracolumbar spinal tuberculosis. OVERVIEW OF LITERATURE: Spinal tuberculosis can cause serious morbidity, including permanent neurological deficits and severe deformities. Medical treatment or a combination of medical and surgical strategies can control the disease in most patients, thereby decreasing morbidity incidence. A debate always existed regarding whether to achieve both decompression and stabilization via a combined anterior and posterior approach or a single posterior approach exists. METHODS: The study was conducted at the Indian Spinal injuries Centre and included all patients with thoracic and thoracolumbar Pott's disease who were operated via a Posterior transpedicular approach. Data regarding 60 patients were analyzed with respect to the average operation time, preoperative and postoperative, 6 months and final follow-up American Spinal Injury Association (ASIA) grading, bony fusion, implant loosening, implant failure, preoperative, postoperative, 6 months and final follow-up kyphotic angles, a loss of kyphotic correction, Oswestry disability index (ODI) score, and visual analog scale (VAS) score. Data were analyzed using either a paired t -test or a Wilcoxon Signed Rank test. RESULTS: The mean operation time was 260+/-30 minutes. Fifty-five patients presented with evidence of successful bony fusion within a mean period of 6+/-1.5 months. Preoperative dorsal and lumbar angles were significantly larger than postoperative angles, which were smaller than final follow-up angles. The mean kyphotic correction achieved was 12.11+/-14.8, with a mean decrease of 5.97 and 19.1 in VAS and ODI scores, respectively. CONCLUSIONS: Anterior decompression and posterior stabilization via a posterior transpedicular approach are safe and effective procedures, with less intraoperative surgical duration and significant improvements in clinical and functional status. PMID- 28874982 TI - Measurement of Milwaukee Brace Pad Pressure in Adolescent Round Back Deformity Treatment. AB - STUDY DESIGN: In this prospective study, we measured the pad pressures of the Milwaukee brace in adolescent hyperkyphosis treatment. PURPOSE: We evaluated the skin-brace interface forces exerted by the main pads of the Milwaukee brace. OVERVIEW OF LITERATURE: A fundamental factor associated with brace effectiveness in spinal deformity is pad force adjustment. However, few studies have evaluated the in-brace force magnitude and its effect on curve correction. METHODS: Interface forces at four pads of the Milwaukee brace were measured in 73 patients withround back deformity (mean age, 14.04+/-1.97 years [range, 10-18]; mean initial Cobb angle,67.70 degrees +/-9.23 degrees [range, 50 degrees -86 degrees ]). We used a modified aneroid sphygmomanometer to measure the shoulder and kyphosis pad pressures. Each patient underwent measurement in the standing and sitting positions during inhalation/exhalation. RESULTS: The mean pad pressures were significantly higher in the standing than in thesitting position, and significantly higher pressures were observed during inhalation compared toexhalation (p=0.001).There were no statistically significant differences between right and left shoulder pad pressures (p>0.05); however, the pressure differences between the right and left kyphosis pads were statistically significant (p<0.05). In a comparison of corrective forces with bracing for less or more than 6 months, corrective force was larger with bracing for less than 6 months (p=0.02). In the standing position, there were no statistically significant correlations between pad pressures and kyphosis curve correction. CONCLUSIONS: In the sitting position, there was a trend toward lower forces at the skin-brace interface; therefore, brace adjustment in the standing position may be useful and more effective. There was no significant correlation between the magnitude of the pad pressures and the degree of in-brace curve correction. PMID- 28874983 TI - Posterior Vertebrectomy and Circumferential Fusion for the Treatment of Advanced Thoracolumbar Kummell Disease with Neurologic Deficit. AB - STUDY DESIGN: Single-center, retrospective case series. PURPOSE: To investigate the effectiveness of posterior vertebrectomy and circumferential fusion in patients with advanced Kummell disease with neurologic deficit. OVERVIEW OF LITERATURE: Various surgical options exist for the treatment of Kummell disease, and determination of the appropriate treatment is based on the clinical and radiologic status of the patient. However, surgical intervention is required for patients with advanced Kummell disease accompanied by neurologic deficit. METHODS: We retrospectively analyzed 22 neurologically compromised patients with advanced Kummell disease who were treated surgically at Ewha Womans Hospital between January 2011 and January 2014. The surgical approach used by us was a posterior vertebrectomy with mesh cage insertion and segmental cement-augmented pedicle screw fixation. The tissue from the corpectomy was histopathologically examined. Anterior vertebral height, kyphotic angle, visual analog scale (VAS) score, and the Frankel classification were used to evaluate the efficacy of the procedure. RESULTS: The mean follow-up period was 26 months (range, 13-40 months). VAS score, anterior vertebral height, kyphotic angle, and neurologic state were significantly improved immediately postoperatively and at the last follow-up compared with preoperatively (p<0.05). Most patients exhibited intravertebral clefts on imaging, and postoperative pathology revealed bone necrosis. CONCLUSIONS: Posterior vertebrectomy with mesh cage insertion and segmental cement-augmented pedicle screw fixation is an effective approach for treating patients with advanced Kummell disease with neurologic deficit. PMID- 28874984 TI - Neuropathic Pain after Spinal Surgery. AB - Neuropathic pain after spinal surgery, the so-called failed back surgery syndrome (FBSS), is a frequently observed troublesome disease entity. Although medications may be effective to some degree, many patients continue experiencing intolerable pain and functional disability. Only gabapentin has been proven effective in patients with FBSS. No relevant studies regarding manipulation or physiotherapy for FBSS have been published. Spinal cord stimulation (SCS) has been widely investigated as a treatment option for chronic neuropathic pain, including FBSS. SCS was generally accepted to improve chronic back and leg pain, physical function, and sleep quality. Although the cost effectiveness of SCS has been proved in many studies, its routine application is limited considering that it is invasive and is associated with safety issues. Percutaneous epidural adhesiolysis has also shown good clinical outcomes; however, its effects persisted for only a short period. Because none of the current methods provide absolute superiority in terms of clinical outcomes, a multidisciplinary approach is required to manage this complex disease. Further studies concerning the etiology, diagnosis, treatment, and cost effectiveness of FBSS are warranted to deepen our understanding of this condition. PMID- 28874985 TI - An Updated Overview of Low Back Pain Management in Primary Care. AB - Currently, guidelines for lower back pain (LBP) treatment are needed. We reviewed the current guidelines and high-quality articles to confirm the LBP guidelines for the Korean Society of Spine Surgery. We searched available databases for high quality articles in English on LBP published from 2000 to the present year. Literature searches using these guidelines included studies from MEDLINE, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Embase. We analyzed a total of 132 randomized clinical trials, 116 systematic reviews, 9 meta-analyses, and 4 clinical guideline reviews. We adopted the SIGN checklist for the assessment of article quality. Data were subsequently abstracted by a reviewer and verified. Many treatment options exist for LBP, with a variety of recommendation grades. We assessed the recommendation grade for general behavior, pharmacological therapy, psychological therapy, and specific exercises. This information should be helpful to physicians in the treatment of LBP patients. PMID- 28874986 TI - Neuropathic Pain Related with Spinal Disorders: A Systematic Review. AB - Systematic literature review. To review the evidence from high-quality studies regarding the treatment of neuropathic pain originating specifically from spinal disorders. In general, treatment guidelines for neuropathic pain cover all its various causes, including medical disease, peripheral neuropathy, and cancer. However, the natural history of neuropathic pain originating from spinal disorders may differ from that of the pain originating from other causes or lesions. An expert research librarian used terms related to neuropathic pain and spinal disorders, disc herniation, stenosis, and spinal cord injury to search in MEDLINE, Embase, and Cochrane CENTRAL for primary research from January 2000 to October 2015. Among 2,313 potential studies of interest, 25 randomized controlled trials (RCTs) and 21 systematic reviews (SRs) were included in the analysis. The selection was decided based on the agreement of two orthopedic surgeons. There was a lack of evidence about medication for radiculopathy arising from disc herniation and stenosis, but intervention procedures, including epidural block, showed positive efficacy in radiculopathy and also limited efficacy in spinal stenosis. There was some evidence based on the short-term follow-up regarding surgery being superior to conservative treatments for radiculopathy and stenosis. There was limited evidence regarding the efficacy of pharmacological and electric or magnetic stimulation therapies for neuropathic pain after spinal cord injury. This review of RCTs and SRs with high-quality evidence found some evidence regarding the efficacy of various treatment modalities for neuropathic pain related specifically to spinal disorders. However, there is a need for much more supportive evidence. PMID- 28874987 TI - Letter to the editor: Clinical Use, Quality of Life and Cost-Effectiveness of Spinal Cord Stimulation Used to Treat Patients with Failed Back Surgery Syndrome. PMID- 28874988 TI - Response to: Clinical Use, Quality of Life and Cost-Effectiveness of Spinal Cord Stimulation Used to Treat Failed Back Surgery Syndrome. PMID- 28874989 TI - Evaluation of marginal and internal gaps in single and three-unit metal frameworks made by micro-stereolithography. AB - PURPOSE: The purpose of this study is to compare single and three-unit metal frameworks that are produced by micro-stereolithography. MATERIALS AND METHODS: Silicone impressions of a selected molar and a premolar were used to make master abutments that were scanned into a stereolithography file. The file was processed with computer aided design software to create single and three-unit designs from which resin frameworks were created using micro-stereolithography. These resin frameworks were subjected to investment, burnout, and casting to fabricate single and three-unit metal ones that were measured under a digital microscope by using the silicone replica technique. The measurements were verified by means of the Mann-Whitney U test (alpha=.05). RESULTS: The marginal gap was 101.9 +/- 53.4 um for SM group and 104.3 +/- 62.9 um for TUM group. The measurement of non-pontics in a single metal framework was 93.6 +/- 43.9 um, and that of non-pontics in a three-unit metal framework was 64.9 +/- 46.5 um. The dimension of pontics in a single metal framework was 110.2 +/- 61.4 um, and that of pontics in a three-unit metal framework was 143.7 +/- 51.8 um. CONCLUSION: The marginal gap was smaller for the single metal framework than for the three-unit one, which requires further improvement before it can be used for clinical purposes. PMID- 28874990 TI - In vitro study of the fracture resistance of monolithic lithium disilicate, monolithic zirconia, and lithium disilicate pressed on zirconia for three-unit fixed dental prostheses. AB - PURPOSE: The purpose of this study was to determine fracture resistance and failure modes of three-unit fixed dental prostheses (FDPs) made of lithium disilicate pressed on zirconia (LZ), monolithic lithium disilicate (ML), and monolithic zirconia (MZ). MATERIALS AND METHODS: Co-Cr alloy three-unit metal FDPs model with maxillary first premolar and first molar abutments was fabricated. Three different FDPs groups, LZ, ML, and MZ, were prepared (n = 5 per group). The three-unit FDPs designs were identical for all specimens and cemented with resin cement on the prepared metal model. The region of pontic in FDPs was given 50,000 times of cyclic preloading at 2 Hz via dental chewing simulator and received a static load until fracture with universal testing machine fixed at 10 degrees . The fracture resistance and mode of failure were recorded. Statistical analyses were performed using the Kruskal-Wallis test and Mann-Whitney U test with Bonferroni's correction (alpha=0.05/3=0.017). RESULTS: A significant difference in fracture resistance was found between LZ (4943.87 +/- 1243.70 N) and ML (2872.61 +/- 658.78 N) groups, as well as between ML and MZ (4948.02 +/- 974.51 N) groups (P<.05), but no significant difference was found between LZ and MZ groups (P>.05). With regard to fracture pattern, there were three cases of veneer chipping and two interfacial fractures in LZ group, and complete fracture was observed in all the specimens of ML and MZ groups. CONCLUSION: Compared to monolithic lithium disilicate FDPs, monolithic zirconia FDPs and lithium disilicate glass ceramics pressed on zirconia-based FDPs showed superior fracture resistance while they manifested comparable fracture resistances. PMID- 28874991 TI - Ceramic molar crown reproducibility by digital workflow manufacturing: An in vitro study. AB - PURPOSE: This in vitro study aimed to analyze and compare the reproducibility of zirconia and lithium disilicate crowns manufactured by digital workflow. MATERIALS AND METHODS: A typodont model with a prepped upper first molar was set in a phantom head, and a digital impression was obtained with a video intraoral scanner (CEREC Omnicam; Sirona GmbH), from which a single crown was designed and manufactured with CAD/CAM into a zirconia crown and lithium disilicate crown (n=12). Reproducibility of each crown was quantitatively retrieved by superimposing the digitized data of the crown in 3D inspection software, and differences were graphically mapped in color. Areas with large differences were analyzed with digital microscopy. Mean quadratic deviations (RMS) quantitatively obtained from each ceramic group were statistically analyzed with Student's t test (alpha=.05). RESULTS: The RMS value of lithium disilicate crown was 29.2 (4.1) um and 17.6 (5.5) um on the outer and inner surfaces, respectively, whereas these values were 18.6 (2.0) um and 20.6 (5.1) um for the zirconia crown. Reproducibility of zirconia and lithium disilicate crowns had a statistically significant difference only on the outer surface (P<.001). The outer surface of lithium disilicate crown showed over-contouring on the buccal surface and under contouring on the inner occlusal surface. The outer surface of zirconia crown showed both over- and under-contouring on the buccal surface, and the inner surface showed under-contouring in the marginal areas. CONCLUSION: Restoration manufacturing by digital workflow will enhance the reproducibility of zirconia single crowns more than that of lithium disilicate single crowns. PMID- 28874992 TI - Comparison of traditional and simplified methods for repairing CAD/CAM feldspathic ceramics. AB - PURPOSE: To evaluate the adhesion to CAD/CAM feldspathic blocks by failure analysis and shear bond strength test (SBSt) of different restorative systems and different surface treatments, for purpose of moderate chipping repair. MATERIALS AND METHODS: A self-adhering flowable composite (Vertise Flow, Kerr) containing bi-functional phosphate monomers and a conventional flowable resin composite (Premise Flow, Kerr) applied with and without adhesive system (Optibond Solo Plus, Kerr) were combined with three different surface treatments (Hydrofluoric Acid Etching, Sandblasting, combination of both) for repairing feldspathic ceramics. Two commercial systems for ceramic repairing were tested as controls (Porcelain Repair Kit, Ultradent, and CoJet System, 3M). SBSt was performed and failure mode was evaluated using a digital microscope. A One-Way ANOVA (Tukey test for post hoc) was applied to the SBSt data and the Fisher's Exact Test was applied to the failure analysis data. RESULTS: The use of resin systems containing bi-functional phosphate monomers combined with hydrofluoric acid etching of the ceramic surface gave the highest values in terms of bond strength and of more favorable failure modalities. CONCLUSION: The simplified repairing method based on self-adhering flowable resin combined with the use of hydrofluoric acid etching showed high bond strength values and a favorable failure mode. Repairing of ceramic chipping with a self-adhering flowable resin associated with hydrofluoric acid etching showed high bond strength with a less time consuming and technique-sensitive procedure compared to standard procedure. PMID- 28874993 TI - Evaluation of internal fit of interim crown fabricated with CAD/CAM milling and 3D printing system. AB - PURPOSE: This study is to evaluate the internal fit of the crown manufactured by CAD/CAM milling method and 3D printing method. MATERIALS AND METHODS: The master model was fabricated with stainless steel by using CNC machine and the work model was created from the vinyl-polysiloxane impression. After scanning the working model, the design software is used to design the crown. The saved STL file is used on the CAD/CAM milling method and two types of 3D printing method to produce 10 interim crowns per group. Internal discrepancy measurement uses the silicon replica method and the measured data are analyzed with One-way ANOVA to verify the statistic significance. RESULTS: The discrepancy means (standard deviation) of the 3 groups are 171.6 (97.4) um for the crown manufactured by the milling system and 149.1 (65.9) and 91.1 (36.4) um, respectively, for the crowns manufactured with the two types of 3D printing system. There was a statistically significant difference and the 3D printing system group showed more outstanding value than the milling system group. CONCLUSION: The marginal and internal fit of the interim restoration has more outstanding 3D printing method than the CAD/CAM milling method. Therefore, the 3D printing method is considered as applicable for not only the interim restoration production, but also in the dental prosthesis production with a higher level of completion. PMID- 28874994 TI - Comparison of fit accuracy and torque maintenance of zirconia and titanium abutments for internal tri-channel and external-hex implant connections. AB - PURPOSE: This in vitro study aimed to evaluate the effect of implant connection design (external vs. internal) on the fit discrepancy and torque loss of zirconia and titanium abutments. MATERIALS AND METHODS: Two regular platform dental implants, one with external connection (Branemark, Nobel Biocare AB) and the other with internal connection (Noble Replace, Nobel Biocare AB), were selected. Seven titanium and seven customized zirconia abutments were used for each connection design. Measurements of geometry, marginal discrepancy, and rotational freedom were done using video measuring machine. To measure the torque loss, each abutment was torqued to 35 Ncm and then opened by means of a digital torque wrench. Data were analyzed with two-way ANOVA and t-test at alpha=0.05 of significance. RESULTS: There were significant differences in the geometrical measurements and rotational freedom between abutments of two connection groups (P<.001). Also, the results showed significant differences between titanium abutments of internal and external connection implants in terms of rotational freedom (P<.001). Not only customized internal abutments but also customized external abutments did not have the exact geometry of prefabricated abutments (P<.001). However, neither connection type (P=.15) nor abutment material (P=.38) affected torque loss. CONCLUSION: Abutments with internal connection showed less rotational freedom. However, better marginal fit was observed in externally connected abutments. Also, customized abutments with either connection could not duplicate the exact geometry of their corresponding prefabricated abutment. However, neither abutment connection nor material affected torque loss values. PMID- 28874995 TI - Theoretical axial wall angulation for rotational resistance form in an experimental-fixed partial denture. AB - PURPOSE: The aim of this study was to determine the influence of long base lengths of a fixed partial denture (FPD) to rotational resistance with variation of vertical wall angulation. MATERIALS AND METHODS: Trigonometric calculations were done to determine the maximum wall angle needed to resist rotational displacement of an experimental-FPD model in 2-dimensional plane. The maximum wall angle calculation determines the greatest taper that resists rotation. Two different axes of rotation were used to test this model with five vertical abutment heights of 3-, 3.5-, 4-, 4.5-, and 5-mm. The two rotational axes were located on the mesial-side of the anterior abutment and the distal-side of the posterior abutment. Rotation of the FPD around the anterior axis was counter clockwise, Posterior-Anterior (P-A) and clockwise, Anterior-Posterior (A-P) around the distal axis in the sagittal plane. RESULTS: Low levels of vertical wall taper, <= 10-degrees, were needed to resist rotational displacement in all wall height categories; 2-to-6-degrees is generally considered ideal, with 7-to 10-degrees as favorable to the long axis of the abutment. Rotation around both axes demonstrated that two axial walls of the FPD resisted rotational displacement in each direction. In addition, uneven abutment height combinations required the lowest wall angulations to achieve resistance in this study. CONCLUSION: The vertical height and angulation of FPD abutments, two rotational axes, and the long base lengths all play a role in FPD resistance form. PMID- 28874997 TI - Influence of the material for preformed moulds on the polymerization temperature of resin materials for temporary FPDs. AB - PURPOSE: Temperature increase of 5.5 C can cause damage or necrosis of the pulp. Increasing temperature can be caused not only by mechanical factors, e.g. grinding, but also by exothermic polymerization reactions of resin materials. The aim of this study was to evaluate influences of the form material on the intrapulpal temperature during the polymerization of different self-curing resin materials for temporary restorations. MATERIALS AND METHODS: 30 provisonal bridges were made of 5 resin materials: Prevision Temp (Pre), Protemp 4 (Pro), Luxatemp Star (Lux), Structure 3 (Str) and an experimental material (Exp). Moulds made of alginate (A) and of silicone (S) and vacuum formed moulds (V) were used to build 10 bridges each on a special experimental setup. The intrapulpal temperatures of three abutment teeth (a canine, a premolar, and a molar,) were measured during the polymerization every second under isothermal conditions. Comparisons of the maximum temperature (TMax) and the time until the maximum temperature (tTMax) were performed using ANOVA and Tukey Test. RESULTS: Using alginate as the mould material resulted in a cooling effect for every resin material. Using the vacuum formed mould, TMax increased significantly compared to alginate (P<.001) and silicone (P<.001). In groups Lux, Pro, and Pre, tTMax increased when the vacuum formed moulds were used. In groups Exp and Str, there was no influence of the mould material on tTMax. CONCLUSION: All of the mould materials are suitable for clinical use if the intraoral application time does not exceed the manufacturer's instructions for the resin materials. PMID- 28874996 TI - Accuracy of a separating foil impression using a novel polyolefin foil compared to a custom tray and a stock tray technique. AB - PURPOSE: To compare the dimensional accuracy of three impression techniques- a separating foil impression, a custom tray impression, and a stock tray impression. MATERIALS AND METHODS: A machined mandibular complete-arch metal model with special modifications served as a master cast. Three different impression techniques (n = 6 in each group) were performed with addition-cured silicon materials: i) putty-wash technique with a prefabricated metal tray (MET) using putty and regular body, ii) single-phase impression with custom tray (CUS) using regular body material, and iii) two-stage technique with stock metal tray (SEP) using putty with a separating foil and regular body material. All impressions were poured with epoxy resin. Six different distances (four intra abutment and two inter-abutment distances) were gauged on the metal master model and on the casts with a microscope in combination with calibrated measuring software. The differences of the evaluated distances between the reference and the three test groups were calculated and expressed as mean (+/- SD). Additionally, the 95% confidence intervals were calculated and significant differences between the experimental groups were assumed when confidence intervals did not overlap. RESULTS: Dimensional changes compared to reference values varied between -74.01 and 32.57 um (MET), -78.86 and 30.84 (CUS), and between -92.20 and 30.98 (SEP). For the intra-abutment distances, no significant differences among the experimental groups were detected. CUS showed a significantly higher dimensional accuracy for the inter-abutment distances with 0.02 and -0.08 percentage deviation compared to MET and SEP. CONCLUSION: The separation foil technique is a simple alternative to the custom tray technique for single tooth restorations, while limitations may exist for extended restorations with multiple abutment teeth. PMID- 28874998 TI - Correlation between sagittal condylar guidance angles obtained using radiographic and protrusive occlusal record methods. AB - PURPOSE: This study compared the SCGAs measured in three types of radiographic images (panoramic, CBCT panoramic-section, and CBCT cross-section images) with values measured using the protrusive occlusal record. MATERIALS AND METHODS: SCGAs were measured in 20 patients on a semi-adjustable articulator using the protrusive interocclusal record. Panoramic and CBCT images were obtained. SCGAs were measured on CBCT images in panoramic and cross sections. In all of the radiographic images, SCGAs were measured using the Frankfort horizontal reference line and the mean curvature line. The most-superior and most-inferior points of the curvatures were identified to determine the mean curvature line. Each measurement was performed twice by two operators independently. The data were analyzed by the t-test, Pearson's correlation test, and Cronbach's alpha using SPSS (alpha=.05). RESULTS: The mean right and left SCGAs were as follows: protrusive occlusal record (30.1 and 30.2 degrees, respectively), panoramic (38.9 and 38.7 degrees), CBCT panoramic sections (35.4 and 36.8 degrees), and CBCT cross sections (35.3 and 36.1 degrees). The SCGAs differed significantly among the groups. The Pearson coefficients for the correlations with the protrusive occlusal record measurements on the left and right sides were as follows: panoramic (0.834 and 0.791, respectively), CBCT panoramic-section (0.918 and 0.837), and CBCT cross-section (0.918 and 0.845) images. CONCLUSION: Strong correlations were found between SCGAs obtained using radiographic images and the protrusive occlusal record. PMID- 28874999 TI - Comparison of retention forces with various fabrication methods and materials in double crowns. AB - PURPOSE: The purpose of this study was to analyze the retention force changes and wear behaviours of double-crown systems over long-term use. MATERIALS AND METHODS: Ten groups, each consisting of six samples, were evaluated. Specifically, casting gold alloy primary crown - casting gold alloy secondary crown (AA), laser sintering primary crown - laser sintering secondary crown (LL), casting Cr alloy primary crown - casting Cr alloy secondary crown, (CC) zirconia primary crown - electroformed secondary crown (ZA), and CAD/CAM titanium alloy primary crown - CAD/CAM titanium alloy secondary crown (TT) groups were evaluated at cone angles of 4 degrees and 6 degrees . The samples were subjected to 5,000 insertion-separation cycles in artificial saliva, and the retention forces were measured every 500 cycles. The wear levels were analyzed via SEM at the beginning and end of the 5,000 cycles. RESULTS: In all samples, the retention forces increased when the conus angle decreased. The highest initial and final retention force values were found in the LL-4 degrees group (32.89 N-32.65 N), and the lowest retention force values were found in the ZA6 degrees group (5.41 N-6.27 N). The ZA groups' samples showed the least change in the retention force, and no wear was observed. In the other groups, wear was observed mostly in the primary crowns. CONCLUSION: More predictable, clinically relevant, and less excursive retention forces can be observed in the ZA groups. The retention force values of the LL groups were statically similar to those of the other groups, except the ZA groups. PMID- 28875000 TI - Analysis of crown size and morphology, and gingival shape in the maxillary anterior dentition in Korean young adults. AB - PURPOSE: The aim of this investigation was to analyze the dimensions of clinical crowns and to classify the crown and the gingival type in the anterior teeth in Korean young adults. MATERIALS AND METHODS: Casts were obtained from 50 subjects ranging in age from 24 to 32. Measurements of length and width were made on the casts using a pair of digital calipers on the entire dentition. Crown thickness and papilla height were also measured and MDW/CL (mesiodistal width to clinical length) and CW/CL (cervical width to clinical length) ratios of the maxillary anterior teeth were calculated. The K-clustering method was used for CW/CL to classify the anterior tooth shape into three groups (tapered, ovoid, and square), and one-way analysis of variance and Duncan's post-hoc comparison were used to evaluate statistical significance between the groups. Pearson's correlation analysis was performed between tooth shape and papillary height (PH) to demonstrate the correlation between tooth shape and gingival morphological characteristics. RESULTS: The average length of the maxillary central incisors was 9.89 mm; the mesio-distal width was 8.54 mm; and the ratio of width/length was 0.86 in Korean young adults. The average bucco-palatal thickness of the central incisor was 3.14 mm at the incisal 1/3 aspect. Ovoid type was the most common tooth shape (48%), followed by square type (29%) and taper type (23%) in the central incisors of Korean young adults. Tooth shape and gingival type were correlated with each other. CONCLUSION: New reference data were established for tooth size in Korean young adults and the data show several patterns of tooth shape and gingival type. Clinicians should diagnose and treat based on these characteristics for better results in the Korean population. PMID- 28875001 TI - Immune Thrombocytopenic Purpura and Hemolytic Anemia Secondary to Hepatitis A. AB - Hepatitis A is common in children and usually is a self-limiting disease. Although extrahepatic and hematological immune manifestations following acute hepatitis A virus (HAV) infection have rarely been reported, they are frequently observed in other viral hepatitis. In this paper, we report the case of a 3-year old girl who developed immune thrombocytopenic purpura (ITP) and hemolytic anemia after HAV infection. She was presented with malaise, pallor, ecchymosis, petechiae and purpura on the trunk and extremities. PMID- 28875002 TI - Prevalence of G6PD deficiency in Children with Hepatitis A. AB - Introduction: Hepatitis A virus is the most prevalent viral hepatitis. It is globally a major public health problem with different clinical symptoms. This study aimed at investigating the clinical findings and prevalence of glucose 6 phosphate dehydrogenase (G6PD) deficiency in children with hepatitis A. Materials and Methods: In this prospective study, demographical information, clinical findings, and G6PD level of hepatitis A patients, who were visited at Pediatric Hematology clinic, were entered into the database. The diagnosis of hepatitis A infection was based on the presence of anti-HAV IgM antibody. The activity of G6PD enzyme was measured with florescent spot test. Results: Of the 117 children with hepatitis A, 52 (44.4%) were male and 65 (55.6%) were female. The mean age of these patients was 2.79+/-5.39 years. The most prevalent clinical manifestations were dark yellow urine and anorexia. G6PD deficiency was observed in 26 (26.3%) out of 99 patients whose G6PD levels were measured. Conclusion: Given the high prevalence of G6PD deficiency in this study, the measurement of G6PD level along with other liver and biochemical markers in areas with endemic hepatitis A is recommended. In addition, it is recommended that patients undertake precise monitoring for hemolysis and renal function. PMID- 28875003 TI - Inhibition of Angiogenesis: A Novel Effect of Zataria Multiflora. AB - Background: Angiogenesis, the formation of new blood vessels from preexisting ones, is among the most important physiological and pathological processes that occur in the body. Under pathological conditions such as tumor growth, psoriasis, corneal neovascularization and rheumatoid arthritis, angiogenesis is substantial for the development of the disease. Zataria multiflora is a member of the Labiatae family with a vast range of traditional uses which has been long known and applied in Iran old medicine. The aim of this study was the evaluation of anti-angiogenic potential of Zataria multiflora. Materials and Methods: In this study, human umbilical vein endothelial cells (HUVECs) were isolated from newborn umbilical veins and then cultured for cytotoxicity (LDH test) assay. Regarding LDH results, following tests such as angiogenesis (cytodex-3 micro carrier) and migration (wound healing) tests were designed. Results: The cytotoxicity assays showed no toxicity of Z.multiflora toward HUVECs in the range of 10-450ug/mL of the extract. This extract was also able to inhibit angiogenesis and migration at 200ug/mL. Conclusion: Our data clearly demonstrated an inhibitory effect of Z. multiflora on angiogenesis and migration of HUVECs. Z. multiflora could be introduced as a significant angiogenesis inhibitor for angiogenesis-dependent diseases in further complementary studies. PMID- 28875004 TI - A Comparative Cytotoxic Evaluation of Disulfiram Encapsulated PLGA Nanoparticles on MCF-7 Cells. AB - Background: Disulfiram is oral aldehyde dehydrogenase (ALDH) inhibitor that has been used in the treatment of alcoholism. Recent studies show that this drug has anticancer properties; however, its rapid degradation has limited its clinical application. Encapsulation of disulfiram polymeric nanoparticles (NPs) may improve its anticancer activities and protect rapid degradation of the drug. Materials andMethods: A poly (lactide-co-Glycolide) (PLGA) was developed for encapsulation of disulfiram and its delivery into breast cancer cells. Disulfiram encapsulated PLGA NPs were prepared by nanoprecipitation method and were characterized by Scanning Electron Microscopy (SEM). The loading and encapsulation efficiency of NPs were determined using UV-Visible spectroscopy. Cell cytotoxicity of free and encapsulated form of disulfiram is also determined using MTT assay. Results: Disulfiram encapsulated PLGA NPs had uniform size with 165 nm. Drug loading and entrapment efficiency were 5.35 +/-0.03% and 58.85+/ 1.01%. The results of MTT assay showed that disulfiram encapsulated PLGA NPs were more potent in induction of apoptosis compare to free disulfiram. Conclusion: Based on the results obtained in the present study it can be concluded that encapsulation of disulfiram with PLGA can protect its degradation in improve its cytotoxicity on breast cancer cells. PMID- 28875005 TI - Iron Profile and Inflammatory Status of Overweight and Obese Women in Sari, North of Iran. AB - Background: It has been suggested that inflammatory state due to obesity can lead to alteration in iron metabolism. Women in reproductive age are at higher risk of iron deficiency. In this study, we aimed to evaluate inflammatory status and iron markers in young overweight and obese women. Subjects and Methods: In this study, 120 young and healthy women with a BMI >= 25 kg/m2 were enrolled. Biochemical data including iron profile and inflammatory markers were analyzed using mean +/- standard deviation or median (interquartile range) and multivariate multiple regression model via MANOVA. Results: Iron deficiency anemia (hemoglobin < 120 g/l) and iron deficiency without anemia (serum ferritin<30.0 mg/l) were detected in 21.67% and 33.33% of participants, respectively. Multivariate modeling showed that BMI was a significant predictor of transferrin saturation (p = 0.037), CRP (p = 0.013), soluble transferrin receptor (p=0.045), and soluble transferrin receptor/ ferritin ratio (0.015). Conclusion: The results of this study supported the positive association between obesity and inflammation and mild changes in iron markers. PMID- 28875006 TI - Aberrant Methylation-Mediated Suppression of APAF1 in Myelodysplastic Syndrome. AB - Background: Myelodysplastic syndromes (MDSs) include a diverse group of clonal bone marrow disorders characterized by ineffective hematopoiesis and pancytopenia. It was found that down regulation of APAF1, a putative tumor suppressor gene (TSG), leads to resistance to chemotherapy and disease development in some cancers. In this study, we investigated the relation of APAF1 methylation status with its expression and clinicopathological factors in myelodysplastic syndrome (MDS) patients. Materials andMethods: Methylation Sensitive-High Resolution Melting Curve Analysis (MS-HRM) was employed in studying the methylation of CpG islands in the APAF1promoter region in MDS. Gene expression was analyzed by using real time RT-PCR. Results: 42.6% of patient samples were methylated in promoter region of APAF1analyzed, while methylation of the gene was not seen in controls (P<0.05). Methylation of APAF1was significantly associated with the suppression of its mRNA expression (P=0.00). The methylation status of APAF1in advanced-stage MDS patients (80%) was significantly higher than that of the early-stage MDS patients (28.2%) (P=0.001). The difference in frequency of hypermethylatedAPAF1 gene was significant between good (37.5%) and poor (85.71%) cytogenetic risk groups (P=0.043). In addition, a higher frequency of APAF1hypermethylation was observed in higher-risk MDS group (69.2%) compared to lower-risk MDS group (34.14%) (P=0.026). Conclusion: Our study indicated that APAF1hypermethylation in MDS was associated to high-risk disease classified according to the IPSS, WHO and cytogenetic risk. PMID- 28875008 TI - Renal Hemosiderosis among Iranian Transfusion Dependent beta-Thalassemia Major Patients. AB - Background: In recent years, the success in management of thalassemic patients, has allowed for some previously unrecognized complications including renal abnormalities to emerge. This prospective study aimed to investigate kidney iron overload by means of MRI T2* and also renal function based on laboratory tests for early markers of glomerular and tubular dysfunction among adult Iranian transfusion-dependent thalassemia major patients. Subjects and Methods: Two hundred and two patients with transfusion-dependent beta-thalassemia major were included in this study in Zafar Adult Thalassemia Center, Tehran, Iran. For all patients, kidney MRI T2* as well as evaluation of BUN, creatinine, uric acid, calcium, phosphorus, sodium (Na), potassium (K), total protein, albumin, cystatin C, serum ferritin beta2-microglobulin, NAG (N-acetyl-beta-D-Glucosaminidase), and urine protein were performed. Results: One-hundred and fourteen female and 88 male transfusion-dependent beta-thalassemia major patients with mean age of 30.1 +/- 9.4 participated in the present study. We found that 77.7% of our patients had kidney hemosiderosis based on MRI T2*. Also, 67 patients (33.2%) had elevation of serum cystatin C, and 104 patients (51.5%) had reduced estimated glomerular filtration rate (e-GFR). Increased urinary excretion of NAG and hypercalciuria were found in 50% and 79.2% of participants, respectively. Conclusion: Renal hemosiderosis and asymptomatic renal dysfunction are prevalent among transfusion- dependent beta-thalassemia major patients which necessitate regular screening with early markers of glomerular and tubular dysfunction. Further studies in order to investigate the correlation between renal hemosiderosis and early markers of kidney dysfunction among these patients are recommended. PMID- 28875007 TI - The Impact of Confluence on Bone Marrow Mesenchymal Stem (BMMSC) Proliferation and Osteogenic Differentiation. AB - Background: In the field of cellular therapy, the impact of confluence degreeonharvesting or differentiation of BMMSCs and the effect of cell-to-cell contact remain controversial. Therefore, the effect of confluence on properties of BMMSCs was studied and efficiency of confluence-associated osteogenic differentiation was identified. Materials andMethods: The impact of 20, 50, 70, 80 and 100% confluences on proliferation properties of BMMSCs, expression of ERK and p-ERK proteins and glucose consumption rate was studied. Efficiency of confluence-associated osteogenic differentiation was identified by determining calcium deposition, Alizarin Red staining, ALP activity and expression of osteopontin and osteocalcin genes. Results: There was a correlation between confluence % and BMMSCs density. Viability was declined at the lower and higher confluences. The highest CFU-F, Brd-U uptake and population doubling were obtained at 80% confluence. ERK band intensity in 100% confluent BMMSCs was lower compared to other confluences. Bands of p-ERK were highly detectable in 70% and 80% confluences. Glucose consumption rate of 70% and 80% confluences in the last days were higher than 20% and 100% confluences. Although higher osteogenic differentiation was estimated at 80% confluence using calcium deposition, Alizarin Red staining and ALP activity, it was also extended at 100% confluence Osteopontin gene was expressed among all confluences including 100% confluence, while osteocalcin gene was expressed highly in 70% confluent cells. Conclusion: We concluded that the optimum seeding density for maximal expansion and harvesting purposes is 80% confluence and for osteogenic differentiation up to 100% confluence is also acceptable. PMID- 28875009 TI - ABO Incompatibility and Hematopoietic Stem Cell Transplantation Outcomes. AB - Introduction: The increased risk of hemolytic reactions and erythrocyte recovery delay in ABO incompatible hematopoietic stem cell transplantation (HSCT) are well established. Effects of ABO incompatibility on other transplantation outcomes are evaluated in this study. Subjects and Methods: We prospectively followed 501 patients undergoing allogeneic stem cell transplantation regarding their ABO compatibility groups for a median time of 34.7 months. Patients were studied in minor, major and bidirectional mismatched and matched groups. Results: Mean survival time (OS) was lower in minor mismatched group (p-value= 0.017). Minor and bidirectional mismatched groups received significantly more packed cell units than matched group (p-value < 0.0001 and p-value =0.002, respectively).Mean number of platelet unit infusion was significantly more in major mismatched recipients than matched group (p- value=0.031). Death rate was much more than expected in minor mismatched group. Two cases of PRCA (pure red cell aplasia) were found in major mismatched group. No statistically significant difference was found in the incidence of acute GVHD, chronic GVHD, time to neutrophil recovery, relapse- free survival, non-relapse mortality and relapse rate among groups. Conclusion: In order to prevent complications of ABO-incompatible SCT such as decrease in OS and the need for more transfusions, choosing ABO-compatible donors would improve transplantation outcomes. PMID- 28875010 TI - Anti-Apoptotic Effects of Osteopontin via the Up-Regulation of AKT/mTOR/beta Catenin Loop in Acute Myeloid Leukemia Cells. AB - Background: The conventional chemotherapeutic regimens which applied for treatment of acute myeloid leukemia (AML) mostly target tumor bulk but not leukemic stem cells (LSCs). Aberrant expression or activation of mediators such as osteopontin (OPN) or PI3K/PTEN/Akt/mTOR pathway plays a key role in making prone to develop leukemia. Preventing or treating cancer by curcumin (CUR) has been suggested recently. CUR induces apoptosis and growth inhibition through various mechanisms in leukemic cells. In present study, we tried to measure the toxic response in vitro to CUR for evaluation ofchangesin cell viability, survival and molecular-mediated resistance in primary AML cells. Materials and Methods: Isolated primary CD34+/CD38- bone marrow derived AML cells were treated with CUR, Daunorubicin (DNR) and/or their combination by MTT assay, Annexin V/PI staining, and colony-formation. The mRNA expression of OPN/AKT/mTOR/PTEN/beta catenin genes was measured by Real-Time PCR. The siRNA against OPN was applied for CUR- treated cells. Results: Growth inhibition effect of DNR increased in combination with CUR on primary CD34+/CD38- AML cells. Suppression of OPN with siRNA increased the cytotoxic effects of CUR. Likewise, OPN gene expression increased in response to CUR treatment in AML cells. AKT, mTOR, beta-catenin or PTEN gene expression increased by CUR, but OPN siRNA decreased the level of mRNA expression of mentioned molecular pathway. Conclusion: The chemo-resistance of AML cells against therapy might be relevant to increasing of OPN mRNA expression and activity of other mediators including AKT, mTOR, PTEN, and beta-catenin. In this context, targeting of OPN might be more impact on CD34+ AML cells. PMID- 28875011 TI - Evaluation of E-cadherin Expression in Gastric Cancer and Its Correlation with Clinicopathologic Parameters. AB - Background: Gastric cancer is one of the most common cancers in the world. There are many genomic and molecular factors that cause gastric cancer to occur. Also, many markers that associate with tumor invasiveness have been known. E-cadherin is a calcium- mediated cell adhesion molecule. In some studies, abnormal expression of E-cadherin has been seen in gastric carcinoma. However, in the studies done there has been some conflicting information about abnormal expression of this marker in a variety of gastric carcinoma and also about the expression of this marker and its correlation with various clinicopathologic factors of tumor. Subjects andMethods: A case control study was performed on total or partial gastrectomy tissue samples obtained from 70 patients with gastric cancer and adjacent non-neoplastic tissues. The immunohistochemistry was used to assess E-cadherin expression. The correlation between abnormal E-cadherin expression and tumor histopathology was evaluated in all patients. Results: Among 70 patients who were analyzed, 48.6% showed abnormal E-cadherin expression. A significant correlation was seen between abnormal E-cadherin expression and tumor stage, grade, lymph node metastasis, tumor phenotype, tumor type, depth of invasion and age. Conclusion: Abnormal E-cadherin expression is a common phenomenon in gastric cancer. Because there was a strong correlation between abnormal E-cadherin expression and tumor stage, tumor grade, depth of invasion and regional lymph node involvement, this marker may be used as a predictive factor for tumor invasiveness in gastric cancer. PMID- 28875012 TI - Xmn1-158 gammaGVariant in B-Thalassemia Intermediate Patients in South-East of Iran. AB - Background: Xmn-1 polymorphism of ??Gglobin gene (HBG2) is a prominent quantitative trait loci (QTL) in beta-thalassemia intermediate (beta-TI). In current study, we evaluated the frequency of Xmn-1 polymorphism and its association with beta-globin gene (HBB) alleles and Hb F level in beta-TI patients in Sistan and Balouchestan province, south-east of Iran. Subjects and Methods: 45 beta-TI patients were enrolled. HBB gene mutations and Xmn-1 polymorphism were determined by amplification-refractory mutation system (ARMS) PCR method. Hemoglobin profile was determined using capillary electrophoresis. Results: The study participants consisted of 26 (58%) males and 19 (42%) females. Mean age of the patients was 10.7+/-3.1 years old. Overall, Xmn-1 polymorphism was observed in 28 (62%) patients. Homozygous (TT) and heterozygous (CT) genotypes of the polymorphism represented with frequencies of 12 (26%) and 16 (35%), respectively. Main recognized HBB gene mutation was IVSI-5(G>C) with homozygous frequency of 44%. Non-zero (beta+) alleles of HBB gene constituted 11.1 % (4 patients with heterozygous beta+ and one with homozygous beta+ genotype). Hb F level was significantly higher in patients with at least one Xmn 1allele (67.9+/-[Formula: see text]17.9%) than those without the polymorphism (19.5+/-20.3%, P<0.0001). Also, patients with homozygous genotype demonstrated significantly higher Hb F compared to heterozygous (CT) cases (respective percentages of 85+/-[Formula: see text]6.8 and 54.7+/-[Formula: see text]10.5, p<0.0001). Conclusion: Our results highlighted the role of Xmn-1 polymorphism as the main phenotypic modifier in beta-TI patients in Sistan and Balouchestan province. PMID- 28875013 TI - Simultaneous oral administration of Salmonella Infantis and S. Typhimurium in chicks. AB - BACKGROUND: To confirm the hypothesis that Salmonella enterica subspecies enterica serovar (S.) Infantis has higher basic reproductive rates in chicks compared with other Salmonella serovars, 1-day-old specific-pathogen-free chicks (n = 8) were challenged simultaneously with S. Infantis and S. Typhimurium per os. Challenged chicks (Group A) were then housed with non-infected chicks (Group B, n = 4) for 6 days (from 2 to 8 days of age). Group B birds were then housed with other non-infected birds (Group C, n = 4), which were then transferred to cages containing a further group of untreated chicks (Group D, n = 2). A control group consisting of four non-infected chicks was used for comparison. All chickens were humanely sacrificed at 18 days of age, and Salmonella from bowel and liver samples were enumerated. RESULTS: Both serovars were isolated from all groups except the control group. S. Typhimurium was isolated at a greater frequency than S. Infantis from the bowel samples of chicks from Groups B, C and D, while no differences in colonisation rates were observed between the two serovars in liver samples from Groups B, C and D. S. Typhimurium, but not S. Infantis, was immunohistochemically detected in the lamina propria of the cecum and rectum in five birds of Group A. Despite the competitive administration, neither of the two serovars completely excluded the other, and no differences were observed in basic reproductive rates between the two serovars. CONCLUSIONS: These findings, together with data from previous studies, suggest that the initial quantitative domination of S. Infantis in chicken flocks may explain why this serovar is predominant in broiler chickens. PMID- 28868132 TI - Comprehensive comparison of Pacific Biosciences and Oxford Nanopore Technologies and their applications to transcriptome analysis. AB - Background: Given the demonstrated utility of Third Generation Sequencing [Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT)] long reads in many studies, a comprehensive analysis and comparison of their data quality and applications is in high demand. Methods: Based on the transcriptome sequencing data from human embryonic stem cells, we analyzed multiple data features of PacBio and ONT, including error pattern, length, mappability and technical improvements over previous platforms. We also evaluated their application to transcriptome analyses, such as isoform identification and quantification and characterization of transcriptome complexity, by comparing the performance of size-selected PacBio, non-size-selected ONT and their corresponding Hybrid-Seq strategies (PacBio+Illumina and ONT+Illumina). Results: PacBio shows overall better data quality, while ONT provides a higher yield. As with data quality, PacBio performs marginally better than ONT in most aspects for both long reads only and Hybrid-Seq strategies in transcriptome analysis. In addition, Hybrid-Seq shows superior performance over long reads only in most transcriptome analyses. Conclusions: Both PacBio and ONT sequencing are suitable for full-length single-molecule transcriptome analysis. As this first use of ONT reads in a Hybrid-Seq analysis has shown, both PacBio and ONT can benefit from a combined Illumina strategy. The tools and analytical methods developed here provide a resource for future applications and evaluations of these rapidly changing technologies. PMID- 28868139 TI - The choice between surgical scrubbing and sterile covering before or after induction of anaesthesia: A prospective study. AB - Background : Day surgery is increasing, and safe and effective logistics are sought. One part of the in-theatre logistics commonly discussed is whether surgical scrub and sterile covering should be done before or after induction of anaesthesia. The aim of the present study was to compare the impact of surgical scrub and sterile covering before vs. after the induction of anaesthesia in male patients scheduled for open hernia repair. Methods : This is a prospective randomised study. Sixty ASA 1-3 patients scheduled for open hernia repair were randomised to surgical scrub and sterile covering before or after induction of anaesthesia; group "awake" and "anaesthetised". Need for vasoactive medication during anaesthesia was primary study objective. Duration of anaesthesia and surgery, theatre time, recovery room stay and time to discharge, patients and theatre nurses experiences and willingness to have the same logistics on further potential surgeries, by a questionnaire provided before discharge was also assessed. Results : The duration of anaesthesia was shorter and doses of propofol and remifentanil were reduced by 10 and 13%, respectively, in the awake group. We found still no difference in the need for vasoactive medication during anaesthesia Time in recovery area was significantly reduced in the awake group 39 (SD 15) vs. 48 SD 16) (p<0.05), but time to discharge was not different. There was further no difference in the patients' assessment of quality of care, and only one patient in the awake group would prefer to be anaesthetised on a future procedure. All nurses found pre-anaesthesia scrubbing acceptable as routine. Conclusion : Surgical scrub and sterile covering before the induction of anaesthesia can be done safely and without jeopardising patients' quality of care and possibly improve perioperative logistics. Further studies are warranted assessing impact of awake scrubbing and sterile covering on quality and efficacy of perioperative care. PMID- 28875016 TI - Does crystallography need a new name? AB - Our notion of crystallography and how we communicate it needs to adapt to the major emerging frontiers of science in order to ensure that our community continues to thrive. PMID- 28875017 TI - Small crystals, fast dynamics and noisy data are indeed beautiful. AB - Structural biology at hard X-ray free-electron lasers is evolving rapidly beyond the experimental styles long established at storage ring sources. The comprehensive review by John Spence [IUCrJ (2017), 4, 322-339] provides magisterial oversight of recent developments. PMID- 28875018 TI - Everyone needs good neighbours - the intricate relationship between the acetylcholine-receptor channel and its membrane environment. AB - A short commentary is given on the article in this issue by Nigel Unwin [IUCrJ (2017), 4, 393-399] on 'Segregation of lipids near acetylcholine-receptor channels imaged by cryo-EM'. PMID- 28875019 TI - Protein crystallography and drug discovery: recollections of knowledge exchange between academia and industry. AB - The development of structure-guided drug discovery is a story of knowledge exchange where new ideas originate from all parts of the research ecosystem. Dorothy Crowfoot Hodgkin obtained insulin from Boots Pure Drug Company in the 1930s and insulin crystallization was optimized in the company Novo in the 1950s, allowing the structure to be determined at Oxford University. The structure of renin was developed in academia, on this occasion in London, in response to a need to develop antihypertensives in pharma. The idea of a dimeric aspartic protease came from an international academic team and was discovered in HIV; it eventually led to new HIV antivirals being developed in industry. Structure guided fragment-based discovery was developed in large pharma and biotechs, but has been exploited in academia for the development of new inhibitors targeting protein-protein interactions and also antimicrobials to combat mycobacterial infections such as tuberculosis. These observations provide a strong argument against the so-called 'linear model', where ideas flow only in one direction from academic institutions to industry. Structure-guided drug discovery is a story of applications of protein crystallography and knowledge exhange between academia and industry that has led to new drug approvals for cancer and other common medical conditions by the Food and Drug Administration in the USA, as well as hope for the treatment of rare genetic diseases and infectious diseases that are a particular challenge in the developing world. PMID- 28875020 TI - XFELs for structure and dynamics in biology. AB - The development and application of the free-electron X-ray laser (XFEL) to structure and dynamics in biology since its inception in 2009 are reviewed. The research opportunities which result from the ability to outrun most radiation damage effects are outlined, and some grand challenges are suggested. By avoiding the need to cool samples to minimize damage, the XFEL has permitted atomic resolution imaging of molecular processes on the 100 fs timescale under near physiological conditions and in the correct thermal bath in which molecular machines operate. Radiation damage, comparisons of XFEL and synchrotron work, single-particle diffraction, fast solution scattering, pump-probe studies on photosensitive proteins, mix-and-inject experiments, caged molecules, pH jump and other reaction-initiation methods, and the study of molecular machines are all discussed. Sample-delivery methods and data-analysis algorithms for the various modes, from serial femtosecond crystallo-graphy to fast solution scattering, fluctuation X-ray scattering, mixing jet experiments and single-particle diffraction, are also reviewed. PMID- 28875022 TI - NMR crystallography: structure and properties of materials from solid-state nuclear magnetic resonance observables. AB - This topical review provides a brief overview of recent developments in NMR crystallography and related NMR approaches to studying the properties of molecular and ionic solids. Areas of complementarity with diffraction-based methods are underscored. These include the study of disordered systems, of dynamic systems, and other selected examples where NMR can provide unique insights. Highlights from the literature as well as recent work from my own group are discussed. PMID- 28875021 TI - What macromolecular crystallogenesis tells us - what is needed in the future. AB - Crystallogenesis is a longstanding topic that has transformed into a discipline that is mainly focused on the preparation of crystals for practising crystallo graphers. Although the idiosyncratic features of proteins have to be taken into account, the crystallization of proteins is governed by the same physics as the crystallization of inorganic materials. At present, a diversified panel of crystallization methods adapted to proteins has been validated, and although only a few methods are in current practice, the success rate of crystallization has increased constantly, leading to the determination of ~105 X-ray structures. These structures reveal a huge repertoire of protein folds, but they only cover a restricted part of macromolecular diversity across the tree of life. In the future, crystals representative of missing structures or that will better document the structural dynamics and functional steps underlying biological processes need to be grown. For the pertinent choice of biologically relevant targets, computer-guided analysis of structural databases is needed. From another perspective, crystallization is a self-assembly process that can occur in the bulk of crowded fluids, with crystals being supramolecular assemblies. Life also uses self-assembly and supramolecular processes leading to transient, or less often stable, complexes. An integrated view of supramolecularity implies that proteins crystallizing either in vitro or in vivo or participating in cellular processes share common attributes, notably determinants and antideterminants that favour or disfavour their correct or incorrect associations. As a result, under in vivo conditions proteins show a balance between features that favour or disfavour association. If this balance is broken, disorders/diseases occur. Understanding crystallization under in vivo conditions is a challenge for the future. In this quest, the analysis of packing contacts and contacts within oligomers will be crucial in order to decipher the rules governing protein self assembly and will guide the engineering of novel biomaterials. In a wider perspective, understanding such contacts will open the route towards supramolecular biology and generalized crystallogenesis. PMID- 28875023 TI - Stochastic polarity formation in molecular crystals, composite materials and natural tissues. AB - This topical review summarizes the theoretical and experimental findings obtained over the last 20 years on the subject of growth-induced polarity formation driven by a Markov chain process. When entering the growing surface of a molecular crystal, an inorganic-organic composite or a natural tissue, the building blocks may undergo 180 degrees orientational disorder. Driven by configurational entropy, faulted orientations can promote the conversion of a growing non-polar seed into an object showing polar domains. Similarly, orientational disorder at the interface may change a polar seed into a two-domain state. Analytical theory and Monte Carlo simulations were used to model polarity formation. Scanning pyroelectric, piezoresponse force and phase-sensitive second-harmonic microscopies are methods for investigating the spatial distribution of polarity. Summarizing results from different types of materials, a general principle is provided for obtaining growth-induced polar domains: a non-zero difference in the probabilities for 180 degrees orientational misalignments of building blocks, together with uni-directional growth, along with Markov chain theory, can produce objects showing polar domains. PMID- 28875024 TI - Making crystals with a purpose; a journey in crystal engineering at the University of Bologna. AB - The conceptual relationship between crystal reactivity, stability and meta stability, solubility and morphology on the one hand and shape, charge distribution, chirality and distribution of functional groups over the molecular surfaces on the other hand is discussed, via a number of examples coming from three decades of research in the field of crystal engineering at the University of Bologna. The bottom-up preparation of mixed crystals, co-crystals and photoreactive materials starting from molecular building blocks across the borders of organic, organometallic and metalorganic chemistry is recounted. PMID- 28875025 TI - Structure-directing effects of ionic liquids in the ionothermal synthesis of metal-organic frameworks. AB - Traditional synthesis of metal-organic frameworks (MOFs) involves the reaction of a metal-containing precursor with an organic linker in an organic solvent at an elevated temperature, in what is termed a 'solvothermal' reaction. More recently, many examples have been reported of MOF synthesis in ionic liquids (ILs), rather than an organic solvent, in 'ionothermal' reactions. The high concentration of both cations and anions in an ionic liquid allows for the formation of new MOF structures in which the IL cation or anion or both are incorporated into the MOF. Most commonly, the IL cation is included in the open cavities of the MOF, countering the anionic charge of the MOF framework itself and acting as a template around which the MOF structure forms. Ionic liquids can also serve other structure-directing roles, for example, when an IL containing a single enantiomer of a chiral anion leads to a homochiral MOF, even though the IL anion is not itself incorporated into the MOF. A comprehensive review of ionothermal syntheses of MOFs, and the structure-directing effects of the ILs, is given. PMID- 28875026 TI - Segregation of lipids near acetylcholine-receptor channels imaged by cryo-EM. AB - Rapid communication at the chemical synapse depends on the action of ion channels residing in the postsynaptic membrane. The channels open transiently upon the binding of a neurotransmitter released from the presynaptic nerve terminal, eliciting an electrical response. Membrane lipids also play a vital but poorly understood role in this process of synaptic transmission. The present study examines the lipid distribution around nicotinic acetylcholine (ACh) receptors in tubular vesicles made from postsynaptic membranes of the Torpedo ray, taking advantage of the recent advances in cryo-EM. A segregated distribution of lipid molecules is found in the outer leaflet of the bilayer. Apparent cholesterol-rich patches are located in specific annular regions next to the transmembrane helices and also in a more extended 'microdomain' between the apposed delta subunits of neighbouring receptors. The particular lipid distribution can be interpreted straightforwardly in relation to the gating movements revealed by an earlier time resolved cryo-EM study, in which the membranes were exposed briefly to ACh. The results suggest that in addition to stabilizing the protein, cholesterol may play a mechanical role by conferring local rigidity to the membrane so that there is productive coupling between the extracellular and membrane domains, leading to opening of the channel. PMID- 28875027 TI - Viscous hydrophilic injection matrices for serial crystallography. AB - Serial (femtosecond) crystallography at synchrotron and X-ray free-electron laser (XFEL) sources distributes the absorbed radiation dose over all crystals used for data collection and therefore allows measurement of radiation damage prone systems, including the use of microcrystals for room-temperature measurements. Serial crystallography relies on fast and efficient exchange of crystals upon X ray exposure, which can be achieved using a variety of methods, including various injection techniques. The latter vary significantly in their flow rates - gas dynamic virtual nozzle based injectors provide very thin fast-flowing jets, whereas high-viscosity extrusion injectors produce much thicker streams with flow rates two to three orders of magnitude lower. High-viscosity extrusion results in much lower sample consumption, as its sample delivery speed is commensurate both with typical XFEL repetition rates and with data acquisition rates at synchrotron sources. An obvious viscous injection medium is lipidic cubic phase (LCP) as it is used for in meso membrane protein crystallization. However, LCP has limited compatibility with many crystallization conditions. While a few other viscous media have been described in the literature, there is an ongoing need to identify additional injection media for crystal embedding. Critical attributes are reliable injection properties and a broad chemical compatibility to accommodate samples as heterogeneous and sensitive as protein crystals. Here, the use of two novel hydro-gels as viscous injection matrices is described, namely sodium carb oxy-methyl cellulose and the thermo-reversible block polymer Pluronic F-127. Both are compatible with various crystallization conditions and yield acceptable X-ray background. The stability and velocity of the extruded stream were also analysed and the dependence of the stream velocity on the flow rate was measured. In contrast with previously characterized injection media, both new matrices afford very stable adjustable streams suitable for time-resolved measurements. PMID- 28875028 TI - Halogen bonding in hypervalent iodine and bromine derivatives: halonium salts. AB - Halogen bonds have been identified in a series of ionic compounds involving bromonium and iodonium cations and several different anions, some also containing hypervalent atoms. The hypervalent bromine and iodine atoms in the examined compounds are found to have positive sigma-holes on the extensions of their covalent bonds, while the hypervalent atoms in the anions have negative sigma holes. The positive sigma-holes on the halogens of the studied halonium salts determine the linearity of the short contacts between the halogen and neutral or anionic electron donors, as usual in halogen bonds. PMID- 28875029 TI - Validation of experimental charge-density refinement strategies: when do we overfit? AB - A cross-validation method is supplied to judge between various strategies in multipole refinement procedures. Its application enables straightforward detection of whether the refinement of additional parameters leads to an improvement in the model or an overfitting of the given data. For all tested data sets it was possible to prove that the multipole parameters of atoms in comparable chemical environments should be constrained to be identical. In an automated approach, this method additionally delivers parameter distributions of k different refinements. These distributions can be used for further error diagnostics, e.g. to detect erroneously defined parameters or incorrectly determined reflections. Visualization tools show the variation in the parameters. These different refinements also provide rough estimates for the standard deviation of topological parameters. PMID- 28875030 TI - Grazing-incidence small-angle X-ray scattering (GISAXS) on small periodic targets using large beams. AB - Grazing-incidence small-angle X-ray scattering (GISAXS) is often used as a versatile tool for the contactless and destruction-free investigation of nano structured surfaces. However, due to the shallow incidence angles, the footprint of the X-ray beam is significantly elongated, limiting GISAXS to samples with typical target lengths of several millimetres. For many potential applications, the production of large target areas is impractical, and the targets are surrounded by structured areas. Because the beam footprint is larger than the targets, the surrounding structures contribute parasitic scattering, burying the target signal. In this paper, GISAXS measurements of isolated as well as surrounded grating targets in Si substrates with line lengths from 50 um down to 4 um are presented. For the isolated grating targets, the changes in the scattering patterns due to the reduced target length are explained. For the surrounded grating targets, the scattering signal of a 15 um * 15 um target grating structure is separated from the scattering signal of 100 um * 100 um nanostructured surroundings by producing the target with a different orientation with respect to the predominant direction of the surrounding structures. As virtually all litho-graphically produced nanostructures have a predominant direction, the described technique allows GISAXS to be applied in a range of applications, e.g. for characterization of metrology fields in the semiconductor industry, where up to now it has been considered impossible to use this method due to the large beam footprint. PMID- 28875032 TI - Healing X-ray scattering images. AB - X-ray scattering images contain numerous gaps and defects arising from detector limitations and experimental configuration. We present a method to heal X-ray scattering images, filling gaps in the data and removing defects in a physically meaningful manner. Unlike generic inpainting methods, this method is closely tuned to the expected structure of reciprocal-space data. In particular, we exploit statistical tests and symmetry analysis to identify the structure of an image; we then copy, average and interpolate measured data into gaps in a way that respects the identified structure and symmetry. Importantly, the underlying analysis methods provide useful characterization of structures present in the image, including the identification of diffuse versus sharp features, anisotropy and symmetry. The presented method leverages known characteristics of reciprocal space, enabling physically reasonable reconstruction even with large image gaps. The method will correspondingly fail for images that violate these underlying assumptions. The method assumes point symmetry and is thus applicable to small angle X-ray scattering (SAXS) data, but only to a subset of wide-angle data. Our method succeeds in filling gaps and healing defects in experimental images, including extending data beyond the original detector borders. PMID- 28875031 TI - Serial millisecond crystallography of membrane and soluble protein microcrystals using synchrotron radiation. AB - Crystal structure determination of biological macromolecules using the novel technique of serial femtosecond crystallography (SFX) is severely limited by the scarcity of X-ray free-electron laser (XFEL) sources. However, recent and future upgrades render microfocus beamlines at synchrotron-radiation sources suitable for room-temperature serial crystallography data collection also. Owing to the longer exposure times that are needed at synchrotrons, serial data collection is termed serial millisecond crystallography (SMX). As a result, the number of SMX experiments is growing rapidly, with a dozen experiments reported so far. Here, the first high-viscosity injector-based SMX experiments carried out at a US synchrotron source, the Advanced Photon Source (APS), are reported. Microcrystals (5-20 um) of a wide variety of proteins, including lysozyme, thaumatin, phycocyanin, the human A2A adenosine receptor (A2AAR), the soluble fragment of the membrane lipoprotein Flpp3 and proteinase K, were screened. Crystals suspended in lipidic cubic phase (LCP) or a high-molecular-weight poly(ethylene oxide) (PEO; molecular weight 8 000 000) were delivered to the beam using a high viscosity injector. In-house data-reduction (hit-finding) software developed at APS as well as the SFX data-reduction and analysis software suites Cheetah and CrystFEL enabled efficient on-site SMX data monitoring, reduction and processing. Complete data sets were collected for A2AAR, phycocyanin, Flpp3, proteinase K and lysozyme, and the structures of A2AAR, phycocyanin, proteinase K and lysozyme were determined at 3.2, 3.1, 2.65 and 2.05 A resolution, respectively. The data demonstrate the feasibility of serial millisecond crystallography from 5-20 um crystals using a high-viscosity injector at APS. The resolution of the crystal structures obtained in this study was dictated by the current flux density and crystal size, but upcoming developments in beamline optics and the planned APS-U upgrade will increase the intensity by two orders of magnitude. These developments will enable structure determination from smaller and/or weakly diffracting microcrystals. PMID- 28875033 TI - Exploring the salt-cocrystal continuum with solid-state NMR using natural abundance samples: implications for crystal engineering. AB - There has been significant recent interest in differentiating multicomponent solid forms, such as salts and cocrystals, and, where appropriate, in determining the position of the proton in the X-H?A-YX-?H-A+-Y continuum in these systems, owing to the direct relationship of this property to the clinical, regulatory and legal requirements for an active pharmaceutical ingredient (API). In the present study, solid forms of simple cocrystals/salts were investigated by high-field (700 MHz) solid-state NMR (ssNMR) using samples with naturally abundant 15N nuclei. Four model compounds in a series of prototypical salt/cocrystal/continuum systems exhibiting {PyN?H-O-}/{PyN+-H?O-} hydrogen bonds (Py is pyridine) were selected and prepared. The crystal structures were determined at both low and room temperature using X-ray diffraction. The H-atom positions were determined by measuring the 15N-1H distances through 15N-1H dipolar interactions using two dimensional inversely proton-detected cross polarization with variable contact time (invCP-VC) 1H->15N->1H experiments at ultrafast (nuR >= 60-70 kHz) magic angle spinning (MAS) frequency. It is observed that this method is sensitive enough to determine the proton position even in a continuum where an ambiguity of terminology for the solid form often arises. This work, while carried out on simple systems, has implications in the pharmaceutical industry where the salt/cocrystal/continuum condition of APIs is considered seriously. PMID- 28875034 TI - Crystal structure across the beta to alpha phase transition in thermoelectric Cu2 x Se. AB - The crystal structure uniquely imparts the specific properties of a material, and thus provides the starting point for any quantitative understanding of thermoelectric properties. Cu2-x Se is an intensely studied high performing, non toxic and cheap thermoelectric material, and here for the first time, the average structure of beta-Cu2-x Se is reported based on analysis of multi-temperature single-crystal X-ray diffraction data. It consists of Se-Cu layers with additional copper between every alternate layer. The structural changes during the peculiar zT enhancing phase transition mainly consist of changes in the inter layer distance coupled with subtle Cu migration. Just prior to the transition the structure exhibits strong negative thermal expansion due to the reordering of Cu atoms, when approached from low temperatures. The phase transition is fully reversible and group-subgroup symmetry relations are derived that relate the low temperature beta-phase to the high-temperature alpha-phase. Weak superstructure reflections are observed and a possible Cu ordering is proposed. The structural rearrangement may have a significant impact on the band structure and the Cu rearrangement may also be linked to an entropy increase. Both factors potentially contribute to the extraordinary zT enhancement across the phase transition. PMID- 28875035 TI - Classification of crystal structure using a convolutional neural network. AB - A deep machine-learning technique based on a convolutional neural network (CNN) is introduced. It has been used for the classification of powder X-ray diffraction (XRD) patterns in terms of crystal system, extinction group and space group. About 150 000 powder XRD patterns were collected and used as input for the CNN with no handcrafted engineering involved, and thereby an appropriate CNN architecture was obtained that allowed determination of the crystal system, extinction group and space group. In sharp contrast with the traditional use of powder XRD pattern analysis, the CNN never treats powder XRD patterns as a deconvoluted and discrete peak position or as intensity data, but instead the XRD patterns are regarded as nothing but a pattern similar to a picture. The CNN interprets features that humans cannot recognize in a powder XRD pattern. As a result, accuracy levels of 81.14, 83.83 and 94.99% were achieved for the space group, extinction-group and crystal-system classifications, respectively. The well trained CNN was then used for symmetry identification of unknown novel inorganic compounds. PMID- 28875036 TI - Active-site protein dynamics and solvent accessibility in native Achromobacter cycloclastes copper nitrite reductase. AB - Microbial nitrite reductases are denitrifying enzymes that are a major component of the global nitrogen cycle. Multiple structures measured from one crystal (MSOX data) of copper nitrite reductase at 240 K, together with molecular-dynamics simulations, have revealed protein dynamics at the type 2 copper site that are significant for its catalytic properties and for the entry and exit of solvent or ligands to and from the active site. Molecular-dynamics simulations were performed using different protonation states of the key catalytic residues (AspCAT and HisCAT) involved in the nitrite-reduction mechanism of this enzyme. Taken together, the crystal structures and simulations show that the AspCAT protonation state strongly influences the active-site solvent accessibility, while the dynamics of the active-site 'capping residue' (IleCAT), a determinant of ligand binding, are influenced both by temperature and by the protonation state of AspCAT. A previously unobserved conformation of IleCAT is seen in the elevated temperature series compared with 100 K structures. DFT calculations also show that the loss of a bound water ligand at the active site during the MSOX series is consistent with reduction of the type 2 Cu atom. PMID- 28875037 TI - Effect of swap disorder on the physical properties of the quaternary Heusler alloy PdMnTiAl: a first-principles study. AB - Heusler alloys crystallize in a close-packed cubic structure, having a four-atom basis forming a face-centred cubic lattice. By selecting different composite elements, Heusler alloys provide a large family of members for frontier research of spintronics and magnetic materials and devices. In this paper, the structural, electronic and magnetic properties of a novel quaternary Heusler alloy, PdMnTiAl, have been investigated using a first-principles computational materials calculation. It was found that the stable ordered structure is a non-magnetic Y type1, in good agreement with the Slater-Pauling rule. From the band structure and the density of states, it is predicted that this Y-type1 configuration is a new gapless semi-metal material. Furthermore, it was discovered that the Pd-Mn swap-disordered structure is more stable than the Y-type1 structure. The present work provides a guide for experiments to synthesize and characterize this Heusler alloy. PMID- 28875040 TI - A Review of Neurogenic Stunned Myocardium. AB - Neurologic stunned myocardium (NSM) is a phenomenon where neurologic events give rise to cardiac abnormalities. Neurologic events like stroke and seizures cause sympathetic storm and autonomic dysregulation that result in myocardial injury. The clinical presentation can involve troponin elevation, left ventricular dysfunction, and ECG changes. These findings are similar to Takotsubo cardiomyopathy and acute coronary syndrome. It is difficult to distinguish NSM from acute coronary syndrome based on clinical presentation alone. Because of this difficulty, a patient with NSM who is at high risk for coronary heart disease may undergo cardiac catheterization to rule out coronary artery disease. The objective of this review of literature is to enhance physician's awareness of NSM and its features to help tailor management according to the patient's clinical profile. PMID- 28875039 TI - Nucleolar and coiled-body phosphoprotein 1 (NOLC1) regulates the nucleolar retention of TRF2. AB - Telomeric repeat-binding factor 2 (TRF2) was reported to localize in the nucleolus of human cells in a cell cycle-dependent manner; however, the underlying mechanism remains unclear. Here, we found that nucleolar and coiled body phosphoprotein 1 (NOLC1) interacted with TRF2 and mediated the shuttling of TRF2 between the nucleolus and nucleus in human 293T and HepG2 cells. Ablation of NOLC1 expression increased the number of nuclear TRF2 foci and decreased the nucleolar level of TRF2. Conversely, NOLC1 overexpression promoted the nucleolar accumulation of TRF2. NOLC1 overexpression also increased the number of 53BP1 foci and induced the DNA damage response. In addition, co-expression of TRF2 rescued NOLC1 overexpression-induced cell cycle arrest and apoptosis. PMID- 28875038 TI - Novel Imaging Techniques for Heart Failure. AB - Imaging techniques play a main role in heart failure (HF) diagnosis, assessment of aetiology and treatment guidance. Echocardiography is the method of choice for its availability, cost and it provides most of the information required for the management and follow up of HF patients. Other non-invasive cardiac imaging modalities, such as cardiovascular magnetic resonance (CMR), nuclear imaging positron emission tomography (PET) and single-photon emission computed tomography (SPECT) and computed tomography (CT) could provide additional aetiological, prognostic and therapeutic information, especially in selected populations. This article reviews current indications and possible future applications of imaging modalities to improve the management of HF patients. PMID- 28875041 TI - Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome. AB - INTRODUCTION: This observational study was designed to evaluate the efficacy of ultramicronized palmitoylethanolamide (um-PEA) (Normast(r)) administration, as add-on therapy for chronic pain, in the management of pain-resistant patients affected by failed back surgery syndrome. METHODS: A total of 35 patients were treated with tapentadol (TPD) and pregabalin (PGB). One month after the start of standard treatment, um-PEA was added for the next two months. Pain was evaluated by the Visual Analogue Scale (VAS) at the time of enrollment (T0) and after one (T1), two (T2), and three (T3) months. RESULTS: After the first month with TDP + PGB treatment only, VAS score decreased significantly from 5.7 +/- 0.12 at the time of enrollment (T0) to 4.3 +/- 0.11 (T1) (p < 0.0001); however, it failed to provide significant subjective improvement in pain symptoms. Addition of um-PEA led to a further and significant decrease in pain intensity, reaching VAS scores of 2.7 +/- 0.09 (T2) and 1.7 +/- 0.11 (T3, end of treatment) (p < 0.0001) without showing any side effects. CONCLUSIONS: This observational study provides evidence, albeit preliminary, for the efficacy and safety of um-PEA (Normast) as part of a multimodal therapeutic regimen in the treatment of pain-resistant patients suffering from failed back surgery syndrome. PMID- 28875042 TI - Everyday Health among Older People: A Comparison between Two Countries with Variant Life Conditions. AB - This study described health factors of importance for everyday health, such as pain, tiredness, and sleeping problems, in a cross-national context. Data for persons 60+ years were obtained from the Poverty and Health in Aging study, Bangladesh, and the Swedish National Study on Aging and Care-Blekinge. The strongest associations with everyday health in Sweden were found for pain and tiredness, while in Bangladesh they were financial status, tiredness, and sleeping problems. As similarities were found regarding the associations of tiredness on everyday health, tiredness may be a universal predictor of everyday health in older adults irrespective of country context. PMID- 28875043 TI - The Role of Endoplasmic Reticulum Stress in Cardiovascular Disease and Exercise. AB - Endoplasmic reticulum (ER) stress, which is highly associated with cardiovascular disease, is triggered by a disturbance in ER function because of protein misfolding or an increase in protein secretion. Prolonged disruption of ER causes ER stress and activation of the unfolded protein response (UPR) and leads to various diseases. Eukaryotic cells respond to ER stress via three major sensors that are bound to the ER membrane: activating transcription factor 6 (ATF6), inositol-requiring protein 1alpha (IRE1alpha), and protein kinase RNA-like ER kinase (PERK). Chronic activation of ER stress causes damage in endothelial cells (EC) via apoptosis, inflammation, and oxidative stress signaling pathways. The alleviation of ER stress has recently been accepted as a potential therapeutic target to treat cardiovascular diseases such as heart failure, hypertension, and atherosclerosis. Exercise training is an effective nonpharmacological approach for preventing and alleviating cardiovascular disease. We here review the recent viewing of ER stress-mediated apoptosis and inflammation signaling pathways in cardiovascular disease and the role of exercise in ER stress-associated diseases. PMID- 28875044 TI - Decreased Rivaroxaban Levels in a Patient with Cerebral Vein Thrombosis Receiving Phenytoin. AB - Combined use of antiepileptic drugs and anticoagulants is common. We describe the first case documenting laboratory interaction between rivaroxaban and phenytoin. A 48-year-old woman was admitted to our hospital due to cerebral venous thrombosis, bilateral pulmonary embolism, and deep vein thrombosis. She came from a small town with difficult access to warfarin monitoring. She was receiving phenytoin 100 mg three times daily (t.i.d.) and started enoxaparin 60 mg twice daily (b.i.d.). An abdominal mass was diagnosed and removed by laparoscopy (gastrointestinal stromal tumor). On day 5, she was switched to rivaroxaban 15 mg b.i.d. First peak anti-Factor Xa was 70 ng/ml (reference value: 100-300 ng/ml). She was discharged on rivaroxaban 15 mg b.i.d. and phenytoin 100 mg t.i.d. A week later, anti-Xa levels were 90 ng/ml. Due to concerns about thrombosis progression, she was switched to dabigatran. During follow-up, she remained asymptomatic and thrombin time >180 s was measured several times along 3 months as surrogate for dabigatran activity. Phenytoin is a combined CYP3A4 and P glycoprotein inducer, which might reduce rivaroxaban levels. Dabigatran is substrate of P-glycoprotein, meaning potential malabsorption. Despite unavailability of plasmatic dabigatran essays, our patient improved her symptoms without further symptomatic thromboembolism. Facing these interactions, either monitoring serum levels of anticoagulants or other therapeutic options should be considered. PMID- 28875045 TI - The Training Effect of Early Intervention with a Hybrid Assistive Limb after Total Knee Arthroplasty. AB - After total knee arthroplasty (TKA), it is important for patients to show early improvements in knee joint function and walking to regain independence in performing the activities of daily life. We conducted for 4 weeks an intervention one week after TKA using a hybrid assistive limb (HAL: unilateral leg type) as an exoskeleton robotic device to facilitate knee joint function and walking. The intervention improved the range of knee extension movement safely and without pain compared to preoperation. In addition, we found that training with the HAL improved walking ability, speed, and rate, as well as the time taken to perform the timed up and go (TUG) test compared to preoperation. The strength of the quadriceps muscle did not improve with training; however, the patient was able to induce a knee extensor moment during the initial stance phase, as measured by kinetics and kinematics, and these actions could be performed without pain. HAL training soon after TKA improved knee joint function in a 76-year-old patient who presented with OA of the knee. The improvements in knee extension lag and knee extensor moment allowed the patient to walk without pain and regain ADL in comparison with preoperation. PMID- 28875046 TI - Ganglioneuroma of the External Auditory Canal and Middle Ear. AB - OBJECTIVE: We report an extremely rare case of ganglioneuroma involving the external auditory canal and middle ear. CASE REPORT: Ganglioneuromas are rare benign mature tumors thought to originate from sympathetic ganglions, with the highest incidence in the retroperitoneum, adrenal medulla, and posterior mediastinum. We present a case of ganglioneuroma of the external auditory canal and middle ear. At the age of 12 months, the patient was diagnosed with neuroblastoma stage IV with metastasis to the squamous temporal bone, bone marrow, and skull base. He received a high-risk protocol regimen resulting in complete remission. The patient later presented with recurrent right ear discharge at the age of six years and was diagnosed with ganglioneuroma of external auditory canal and middle ear after appropriate investigations. We report in this article the clinical presentation, investigations, surgical intervention, and follow-up. CONCLUSION: After the literature review and to our knowledge, this is the first reported case of its kind. Ganglioneuroma maturing from neuroblastoma is one of the theories describing pathophysiology of the disease. Ganglioneuroma should be considered in the differential diagnosis of patients presenting with recurrent ear discharge and decreased hearing in treated cases of neuroblastoma with metastases to temporal bone. PMID- 28875047 TI - Value-Based Health Technology Assessment and Health Informatics. PMID- 28875048 TI - Text Mining in Biomedical Domain with Emphasis on Document Clustering. AB - OBJECTIVES: With the exponential increase in the number of articles published every year in the biomedical domain, there is a need to build automated systems to extract unknown information from the articles published. Text mining techniques enable the extraction of unknown knowledge from unstructured documents. METHODS: This paper reviews text mining processes in detail and the software tools available to carry out text mining. It also reviews the roles and applications of text mining in the biomedical domain. RESULTS: Text mining processes, such as search and retrieval of documents, pre-processing of documents, natural language processing, methods for text clustering, and methods for text classification are described in detail. CONCLUSIONS: Text mining techniques can facilitate the mining of vast amounts of knowledge on a given topic from published biomedical research articles and draw meaningful conclusions that are not possible otherwise. PMID- 28875049 TI - Fall Detection System for the Elderly Based on the Classification of Shimmer Sensor Prototype Data. AB - OBJECTIVES: Falling in the elderly is considered a major cause of death. In recent years, ambient and wireless sensor platforms have been extensively used in developed countries for the detection of falls in the elderly. However, we believe extra efforts are required to address this issue in developing countries, such as Pakistan, where most deaths due to falls are not even reported. Considering this, in this paper, we propose a fall detection system prototype that s based on the classification on real time shimmer sensor data. METHODS: We first developed a data set, 'SMotion' of certain postures that could lead to falls in the elderly by using a body area network of Shimmer sensors and categorized the items in this data set into age and weight groups. We developed a feature selection and classification system using three classifiers, namely, support vector machine (SVM), K-nearest neighbor (KNN), and neural network (NN). Finally, a prototype was fabricated to generate alerts to caregivers, health experts, or emergency services in case of fall. RESULTS: To evaluate the proposed system, SVM, KNN, and NN were used. The results of this study identified KNN as the most accurate classifier with maximum accuracy of 96% for age groups and 93% for weight groups. CONCLUSIONS: In this paper, a classification-based fall detection system is proposed. For this purpose, the SMotion data set was developed and categorized into two groups (age and weight groups). The proposed fall detection system for the elderly is implemented through a body area sensor network using third-generation sensors. The evaluation results demonstrate the reasonable performance of the proposed fall detection prototype system in the tested scenarios. PMID- 28875050 TI - Development and Evaluation of an Obesity Ontology for Social Big Data Analysis. AB - OBJECTIVES: The aim of this study was to develop and evaluate an obesity ontology as a framework for collecting and analyzing unstructured obesity-related social media posts. METHODS: The obesity ontology was developed according to the 'Ontology Development 101'. The coverage rate of the developed ontology was examined by mapping concepts and terms of the ontology with concepts and terms extracted from obesity-related Twitter postings. The structure and representative ability of the ontology was evaluated by nurse experts. We applied the ontology to the density analysis of keywords related to obesity types and management strategies and to the sentiment analysis of obesity and diet using social big data. RESULTS: The developed obesity ontology was represented by 8 superclasses and 124 subordinate classes. The superclasses comprised 'risk factors,' 'types,' 'symptoms,' 'complications,' 'assessment,' 'diagnosis,' 'management strategies,' and 'settings.' The coverage rate of the ontology was 100% for the concepts and 87.8% for the terms. The evaluation scores for representative ability were higher than 4.0 out of 5.0 for all of the evaluation items. The density analysis of keywords revealed that the top-two posted types of obesity were abdomen and thigh, and the top-three posted management strategies were diet, exercise, and dietary supplements or drug therapy. Positive expressions of obesity-related postings has increased annually in the sentiment analysis. CONCLUSIONS: It was found that the developed obesity ontology was useful to identify the most frequently used terms on obesity and opinions and emotions toward obesity posted by the geneal population on social media. PMID- 28875051 TI - Statistics and Deep Belief Network-Based Cardiovascular Risk Prediction. AB - OBJECTIVES: Cardiovascular predictions are related to patients' quality of life and health. Therefore, a risk prediction model for cardiovascular conditions is needed. METHODS: In this paper, we propose a cardiovascular disease prediction model using the sixth Korea National Health and Nutrition Examination Survey (KNHANES-VI) 2013 dataset to analyze cardiovascular-related health data. First, statistical analysis was performed to find variables related to cardiovascular disease using health data related to cardiovascular disease. Second, a model of cardiovascular risk prediction by learning based on the deep belief network (DBN) was developed. RESULTS: The proposed statistical DBN-based prediction model showed accuracy and an ROC curve of 83.9% and 0.790, respectively. Thus, the proposed statistical DBN performed better than other prediction algorithms. CONCLUSIONS: The DBN proposed in this study appears to be effective in predicting cardiovascular risk and, in particular, is expected to be applicable to the prediction of cardiovascular disease in Koreans. PMID- 28875052 TI - Prevalence of Sharing Access Credentials in Electronic Medical Records. AB - OBJECTIVES: Confidentiality of health information is an important aspect of the physician patient relationship. The use of digital medical records has made data much more accessible. To prevent data leakage, many countries have created regulations regarding medical data accessibility. These regulations require a unique user ID for each medical staff member, and this must be protected by a password, which should be kept undisclosed by all means. METHODS: We performed a four-question Google Forms-based survey of medical staff. In the survey, each participant was asked if he/she ever obtained the password of another medical staff member. Then, we asked how many times such an episode occurred and the reason for it. RESULTS: A total of 299 surveys were gathered. The responses showed that 220 (73.6%) participants reported that they had obtained the password of another medical staff member. Only 171 (57.2%) estimated how many time it happened, with an average estimation of 4.75 episodes. All the residents that took part in the study (45, 15%) had obtained the password of another medical staff member, while only 57.5% (38/66) of the nurses reported this. CONCLUSIONS: The use of unique user IDs and passwords to defend the privacy of medical data is a common requirement in medical organizations. Unfortunately, the use of passwords is doomed because medical staff members share their passwords with one another. Strict regulations requiring each staff member to have it's a unique user ID might lead to password sharing and to a decrease in data safety. PMID- 28875053 TI - Validation of Joint Position Sense of Dorsi-Plantar Flexion of Ankle Measurements Using a Smartphone. AB - OBJECTIVES: This study evaluated and validated the reliability of smartphones as measuring equipment for the dorsi-plantar flexion of ankle joint position sense (JPS) ability. METHODS: The subjects were 20 healthy young students in their 20s. We confirmed the concurrent validity by comparison with existing electrogoniometer data. The reliability of the smartphone was confirmed using the test-retest method. RESULTS: In the case of dorsiflexion, there was no significant difference between the smartphone and electrogoniometer groups (p > 0.05). Regarding the correlation, it was significantly high (r = 0.65, p < 0.05), and ICC(3,1) was good (ICC(3,1) = 0.79). For the case of plantar flexion, there was no significant difference between the smartphone and electrogoniometer groups (p > 0.05), the correlation was significantly high (r = 0.69, p < 0.05), and the ICC(3,1) was very good (ICC(3,1) = 0.82). In the case of dorsiflexion, there was no significant difference between test and retest (p > 0.05), the correlation was intermediate (r = 0.59, p < 0.05), and the ICC(3,1) value was good (ICC(3,1) = 0.74). For plantar flexion, there was no significant difference between test and retest (p > 0.05), the correlation was significantly high (r = 0.63, p < 0.05), and the ICC(3,1) was good (ICC(3,1) = 0.76). CONCLUSIONS: The results showed that smartphones provide high validity and reliability as measurement equipment for JPS of dorsi-plantar flexion of the ankle. Finally, the study also considers that smartphone-based JPS measuring methods may replace the traditional and expensive methods that are currently being used for the same purpose. PMID- 28875054 TI - Current Status of Electronic Medical Record Systems in Hospitals and Clinics in Korea. AB - OBJECTIVES: Many healthcare organizations and professionals have had interests in healthcare information and communication technology (ICT). The objective of this study was to investigate the current status of overall healthcare ICT, especially focusing on Electronic Medical Record (EMR) systems in Korea. METHODS: This study used a part of the nationwide survey collected for the OECD benchmarking ICT study. The Health Insurance Review and Assessment Service conducted the survey from November 19, 2013 to January 10, 2014. This study followed the methodological guidelines of the OECD. A total of 2,093 hospitals and clinics, including long-term care hospitals, participated in the survey. Among them, 554 hospitals and 906 clinics were included in this study for the generalization of the results. RESULTS: The adoption rates of EMR systems were 96.3% in hospitals and 95.7% in clinics. Most of the hospitals and clinics had high rates of healthcare information exchange (HIE) within the organization; however, there were extremely low HIE rates among external organizations. Most of the hospitals and clinics had EMR systems with clinical-decision-supporting functionalities. Ninety-six percent of the EMR systems of the hospitals and 89.2% of the clinic systems had checking functions, such as alerts or reminders, on contraindications of drug-drug and drug-age interaction. CONCLUSIONS: Korea has maintained a high healthcare ICT status compared to countries in the European Union. The EMR systems of hospitals and clinics in Korea had sophisticated functionalities; however, their HIE status was extremely low, which indicates the need for healthcare ICT standardization. PMID- 28875055 TI - Pilot Algorithm Designed to Help Early Detection of HMG-CoA Reductase Inhibitor Induced Hepatotoxicity. AB - OBJECTIVES: To enable early detection of adverse drug reactions (ADRs) in patients using HMG-CoA reductase inhibitors (statins), we developed an algorithm that automatically detects liver injury caused by statins from Electronic Medical Record (EMR) data. We verified the performance of our algorithm through manual ADR assessment and a direct chart review. METHODS: The subjects in this study were patients who had been prescribed a statin for the first time among outpatients in Seoul St. Mary's Hospital in Korea between January 2009 and December 2012. We extracted basic information about the patients, including laboratory information, underlying disease, diagnosis information, prescription information, and concomitant drugs. We developed an automatic ADR detection algorithm by using EMR data. We validated the results of the algorithm through a chart review. RESULTS: We developed the algorithm to assess ADR occurrences based on alanine transaminase (ALT) and alkaline phosphatase (ALP) levels. According to the proposed algorithm, any of these result options could be attained: ADR-free, little association, strong association, and weak association or indeterminable. The results of the ADR assessments obtained using the proposed algorithm showed that the data of 126 patients (1.4% of all 9,241 patients) included suspicious figures, thus indicating the possibility of an ADR. In the EMR chart review for verifying the algorithm, ADRs of 33 patients were not associated with statin use; therefore, the ADR occurrence rate was found to be 1.0% (93/9,241). Therefore, the positive predictive value was calculated to be 73.8% (93/126; 95% confidence interval, 69.2%-77.6%). No differences were observed between statin types (p = 0.472). CONCLUSIONS: For early detection of statin-induced liver injury, we developed an automatic ADR assessment algorithm. We expect that algorithms that are more reliable can be developed if we conduct supplement clinical studies with a focus on adverse drug effects. PMID- 28875056 TI - Blogs as Channels for Disseminating Health Technology Innovations. AB - OBJECTIVES: The objective of this study was to describe the features of health informatics blogs on the Internet. METHODS: A search was conducted in August, 2016 using the search engine, Google, and key words: 'mobile health blog,' 'telehealth/telemedicine blog,' 'Electronic Health Record blog,' 'personalized health record blog,' 'population health decision support system blog,' and 'public/population health dashboard blog.' The first 24 blogs resulting from each key word search were recorded, generating 144 blogs. A total of 109 unique blogs resulted after removing duplicates and non-functional sites. RESULTS: Blogs with '.com' extensions were most prevalent (72%, n = 79). More than half of the blogs (79%, n = 86) were created by industries. Mobile health (88%, n = 96), telehealth (82%, n = 89), and health IT (78%, n = 85) were the predominant topics covered. Health providers (44%, n = 48), industries (33%, n = 36), patients/consumers (25%, n = 27) and payers/insurance providers (19%, n = 21) constituted the most common target audience. Blogs catering to payers commonly used '.org' extension (n = 10 out of 21), compared to '.com' (n = 7) or '.gov' (n = 2) (p < 0.0001). Significant differences were also observed by topics covered health IT (p = 0.007), subscription (p = 0.048) and LinkedIn social media (p = 0.019) across the website extensions. CONCLUSIONS: Further research is needed to examine the use of blogs as channels of communication of best evidence in health informatics research among diverse stakeholders. The role of blogs as policy informatics tools need to be evaluated in order for stakeholders to collaborate, coordinate and share opportunities and challenges of various public health programs and policies. PMID- 28875057 TI - Citation Analysis for Biomedical and Health Sciences Journals Published in Korea. AB - OBJECTIVES: A citation analysis of biomedical and health sciences journals was conducted based on their enlistment in journal databases to identify the factors contributing to the citation metrics. METHODS: Among the 1,219 academic journals managed by the National Center for Medical Information and Knowledge at the Korea Centers for Disease Control and Prevention, 556 journals were included for analysis as of July 2016. The characteristics of the journals include history years, publication media, language, open-access policy as well as the status enlisted in international and domestic databases, such as Science Citation Index (SCI), Scopus, Medline, PubMed Central, Embase, and Korea Citation Index (KCI). Six bibliometric measures were collected from SCI, Scopus, and KCI as of 2015, the most recent disclosure year. Analyses of group differences and influential factors were conducted using t-tests, Mann-Whitney tests, and multiple regression. RESULTS: Journal characteristics, such as history years, publication media, and open-access policy, were not significant factors influencing global or domestical citation of the journals. However, global citations were higher for SCI and Medline enlisted journals than for their counterparts. Among KCI journals, the KCI impact factors of journals published in English only were lower. CONCLUSIONS: Efforts by journals to be enlisted in international databases, especially in SCI and Medline, are critical to enhance their global circulation. However, articles published in English only hinder the use of domestic researchers. Different strategies are required for enhancing international and domestic readerships. PMID- 28875058 TI - Hierarchical Genetic Algorithm and Fuzzy Radial Basis Function Networks for Factors Influencing Hospital Length of Stay Outliers. AB - OBJECTIVES: Controlling hospital high length of stay outliers can provide significant benefits to hospital management resources and lead to cost reduction. The strongest predictive factors influencing high length of stay outliers should be identified to build a high-performance prediction model for hospital outliers. METHODS: We highlight the application of the hierarchical genetic algorithm to provide the main predictive factors and to define the optimal structure of the prediction model fuzzy radial basis function neural network. To establish the prediction model, we used a data set of 26,897 admissions from five different intensive care units with discharges between 2001 and 2012. We selected and analyzed the high length of stay outliers using the trimming method geometric mean plus two standard deviations. A total of 28 predictive factors were extracted from the collected data set and investigated. RESULTS: High length of stay outliers comprised 5.07% of the collected data set. The results indicate that the prediction model can provide effective forecasting. We found 10 common predictive factors within the studied intensive care units. The obtained main predictive factors include patient demographic characteristics, hospital characteristics, medical events, and comorbidities. CONCLUSIONS: The main initial predictive factors available at the time of admission are useful in evaluating high length of stay outliers. The proposed approach can provide a practical tool for healthcare providers, and its application can be extended to other hospital predictions, such as readmissions and cost. PMID- 28875059 TI - Comparison of Three Internship Training Sites for an Undergraduate Health Information Management Program in Saudi Arabia. AB - OBJECTIVES: While internship training is well established for medical records and for healthcare quality improvement, it is not quite so for training related to IT/health informatics. A comparison was made on the hospital-based IT/health informatics internship training received by students completing their training at the Imam AbdulRahman Bin Faisal University (IAU) in the Eastern province of Saudi Arabia. METHODS: The three hospitals studied all have the Joint Commission International accreditation and advanced Electronic Health Record (EHR) systems. Over the period from 2011 to 2015, interns from the IAU prepared 120 reports based on their training at these three hospitals. Data abstraction was done on the internship reports, and the results were summarized and interpreted. RESULTS: The study found wide differences in the training received at these hospitals. The main reason for the differences is whether or not the EHR system used in the hospital was a commercial one or developed in-house. CONCLUSIONS: The hospital that had developed its own EHR system made more use of health information management interns during their IT rotation in comparison to hospitals which had adopted commercial EHR systems. Recommendations are made of both local relevance and of international relevance. PMID- 28875060 TI - Assessment of the Drug-Drug Interaction Potential Between Theacrine and Caffeine in Humans. AB - Objective: Theacrine, a methylurate class purine alkaloid, triggers diverse pharmacologic responses, including psychostimulatory activity by modulation of adenosinergic and dopaminergic pathways. In a double-blind, placebo-controlled study, theacrine increased energy, concentration, and mood, while reducing fatigue. Because caffeine, a methylxanthine purine alkaloid, is frequently coadministered with theacrine, we sought to determine if a pharmacokinetic and/or pharmacodynamic interaction existed between theacrine and caffeine. Methods: Eight healthy adults received theacrine, as TeaCrine(r) (25 or 125 mg), caffeine (150 mg), or a combination of theacrine (125 mg) and caffeine (150 mg) in a randomized, double-blind crossover study. Blood samples were collected over a 24 hour period and analyzed by Liquid chromatrography-mass spectrometry/mass spectrometry (LC-MS/MS) for theacrine, caffeine, and paraxanthine. Pharmacodynamic response markers, heart rate and blood pressure, were recorded. Results: Theacrine pharmacokinetics was similar following administration of theacrine alone. Caffeine coadministration increased maximum plasma concentration and area under the curve of theacrine without altering theacrine half-life. Theacrine had no impact on caffeine or paraxanthine pharmacokinetics. There was no difference between treatment groups with regard to heart rate or systolic/diastolic blood pressure. Conclusions: Coadministration of theacrine and caffeine results in a clinically significant pharmacokinetic interaction, viz., increased theacrine exposure. Enhanced oral bioavailability is the most likely mechanism by which caffeine alters theacrine exposure. However, further studies examining the contribution of presystemic elimination mechanisms, for example, efflux transport and/or gut metabolism, to theacrine bioavailability are needed to confirm the exact mechanism(s). Hemodynamic parameters were unaltered despite the pharmacokinetic interaction, suggesting that coadministration of caffeine and theacrine is safe at the doses administered. PMID- 28875061 TI - Impact of Caffeine Boluses and Caffeine Discontinuation on Apnea and Hypoxemia in Preterm Infants. AB - Background: Apnea of prematurity often occurs during and following caffeine therapy. We hypothesized that number of apnea events would be impacted by adjustments in caffeine therapy. Materials and Methods: An automated algorithm was used in all infants <=32 weeks gestation admitted to a level IV Neonatal Intensive Care Unit from 2009 to 2014 to analyze chest impedance, electrocardiogram, and oxygen saturation data around the time of serum caffeine levels, caffeine boluses while on maintenance therapy, and caffeine discontinuation. Episodes of central apnea/bradycardia/desaturation (ABDs), and percent time with SpO2 <88% and <75% were measured. Results: ABDs were analyzed in 302 preterm infants (mean gestational age 27.6 weeks) around the time of 485 serum caffeine levels, 90 caffeine boluses, and 273 episodes of caffeine discontinuation. Higher serum caffeine levels were not associated with fewer ABDs or higher heart rate. For caffeine boluses given due to clinically recognized spells, hypoxemia and algorithm-detected ABDs decreased day 1-2 after the bolus compared to the day before and day of the bolus (mean 4.4 events/day after vs. 6.6 before, p = 0.004). After caffeine discontinuation, there was no change in hypoxemia and a small increase in ABDs (2 events/day 3-5 days after discontinuation vs. 1 event/day before and >5 days after, p < 0.01). This increase in ABDs occurred irrespective of gestational age, respiratory support, or postmenstrual age at the time caffeine was stopped. Conclusions: In this retrospective analysis, caffeine boluses and caffeine discontinuation were associated with a small change in the number of ABD events in preterm infants. PMID- 28875062 TI - Interactions Between Energy Drink Consumption and Sleep Problems: Associations with Alcohol Use Among Young Adolescents. AB - Background: Energy drink consumption and sleep problems are both associated with alcohol use among adolescents. In addition, caffeine consumption (including energy drinks) is associated with sleep problems. However, information about how these three constructs may interact is limited. The goal of this study was to examine potential interactions between energy drink consumption and sleep problems in the concurrent prediction of alcohol use among young adolescents. Coffee and soda consumption were also examined for comparison. Methods: Participants from the Camden Youth Development Study were included (n = 127; mean age = 13.1; 68% Hispanic, 29% African American) and questionnaire measures of frequency of caffeinated beverage consumption (energy drinks, coffee, and soda), sleep (initial insomnia, sleep disturbances, daytime fatigue, and sleep duration), and alcohol consumption were used. Regression analyses were conducted to examine interactions between caffeinated beverage consumption and sleep in the concurrent prediction of alcohol use. Results: Energy drink consumption interacted with initial insomnia and daytime fatigue to concurrently predict particularly frequent alcohol use among those with either of these sleep-related problems and energy drink consumption. The pattern of results for coffee consumption was similar for insomnia but reached only a trend level of significance. Results of analyses examining soda consumption were nonsignificant. Conclusions: Young adolescents who both consume energy drinks and experience initial insomnia and/or daytime fatigue are at particularly high risk for alcohol use. Coffee consumption appears to be associated with similar patterns. Longitudinal research is needed to explain the developmental pathways by which these associations emerge, as well as mediators and moderators of these associations. PMID- 28875063 TI - Organo-Selenium Coatings Inhibit Gram-Negative and Gram-Positive Bacterial Attachment to Ophthalmic Scleral Buckle Material. AB - PURPOSE: Biofilm formation is a problem for solid and sponge-type scleral buckles. This can lead to complications that require removal of the buckle, and result in vision loss due to related ocular morbidity, primarily infection, or recurrent retinal detachment. We investigate the ability of a covalent organo selenium coating to inhibit biofilm formation on a scleral buckle. METHODS: Sponge and solid Labtican brand scleral buckles were coated with organo-selenium coupled to a silyation reagent. Staphylococcus aureus biofilm formation was monitored by a standard colony-forming unit assay and the confocal laser scanning microscopy, while Pseudomonas aeruginosa biofilm formation was examined by scanning electron microscopy. Stability studies were done, by soaking in phosphate buffer saline (PBS) at room temperature for 2 months. Toxicity against human corneal epithelial cell was examined by growing the cells in the presence of organo-selenium-coated scleral buckles. RESULTS: The organo-selenium coating inhibited biofilm formation by gram-negative and gram-positive bacteria. The buckle coatings also were shown to be fully active after soaking in PBS for 2 months. The organo-selenium coatings had no effect on the viability of human corneal epithelial cells. CONCLUSIONS: Organo-selenium can be used to covalently coat a scleral buckle, which is stable and inhibits biofilm formation for gram negative and gram-positive bacteria. The organo-selenium buckle coating was stable and nontoxic to cell culture. TRANSLATIONAL RELEVANCE: This technology provides a means to inhibit bacterial attachment to devices attached to the eye, without damage to ocular cells. PMID- 28875064 TI - Imaging of Retinal Vascular Layers: Adaptive Optics Scanning Laser Ophthalmoscopy Versus Optical Coherence Tomography Angiography. AB - PURPOSE: Retinal vascular networks are observed as a layered structure residing in a nerve fiber layer and an inner nuclear layer of the retina. This study aimed to evaluate reflectance confocal adaptive optics scanning laser ophthalmoscopy (AO-SLO) for imaging of the layered retinal vascular networks. METHODS: This study included 16 eyes of 16 healthy cases. On the fovea, 2.8- and 3.0 mm2-areas were imaged using a prototype AO-SLO and optical coherence tomography angiography (OCTA), respectively. AO-SLO images focused on the nerve fiber and photoreceptor layers were recorded in the area. Two different vessel images (capillary networks in the superficial layer and in all layers) were generated to examine if the deep capillary network could be distinguished. We compared AO-SLO with OCTA in imaging of the layered retinal vascular networks. RESULTS: Sufficient images of capillary networks for analysis could be generated when the motion contrast was enhanced with AO-SLO movies in seven cases (43.8%). The deep capillary network could be distinguished in the merged image. Vascular depiction performance in AO-SLO was significantly better than in OCTA at both 0.5- and 1.0-mm areas from the fovea (P < 0.05). CONCLUSIONS: Retinal vascular imaging using AO-SLO might be a useful adjunct to OCTA as a supportive method to evaluate the retina in healthy patients and patients with disease. TRANSLATIONAL RELEVANCE: In cases requiring accurate and detailed retinal vasculature observation, AO-SLO might be useful for evaluating retinal vascular lesions as a supportive imaging method of OCTA. PMID- 28875065 TI - BioFuelDB: a database and prediction server of enzymes involved in biofuels production. AB - BACKGROUND: In light of the rapid decrease in fossils fuel reserves and an increasing demand for energy, novel methods are required to explore alternative biofuel production processes to alleviate these pressures. A wide variety of molecules which can either be used as biofuels or as biofuel precursors are produced using microbial enzymes. However, the common challenges in the industrial implementation of enzyme catalysis for biofuel production are the unavailability of a comprehensive biofuel enzyme resource, low efficiency of known enzymes, and limited availability of enzymes which can function under extreme conditions in the industrial processes. METHODS: We have developed a comprehensive database of known enzymes with proven or potential applications in biofuel production through text mining of PubMed abstracts and other publicly available information. A total of 131 enzymes with a role in biofuel production were identified and classified into six enzyme classes and four broad application categories namely 'Alcohol production', 'Biodiesel production', 'Fuel Cell' and 'Alternate biofuels'. A prediction tool 'Benz' was developed to identify and classify novel homologues of the known biofuel enzyme sequences from sequenced genomes and metagenomes. 'Benz' employs a hybrid approach incorporating HMMER 3.0 and RAPSearch2 programs to provide high accuracy and high speed for prediction. RESULTS: Using the Benz tool, 153,754 novel homologues of biofuel enzymes were identified from 23 diverse metagenomic sources. The comprehensive data of curated biofuel enzymes, their novel homologs identified from diverse metagenomes, and the hybrid prediction tool Benz are presented as a web server which can be used for the prediction of biofuel enzymes from genomic and metagenomic datasets. The database and the Benz tool is publicly available at http://metabiosys.iiserb.ac.in/biofueldb& http://metagenomics.iiserb.ac.in/biofueldb. PMID- 28875066 TI - Genes of the major histocompatibility complex highlight interactions of the innate and adaptive immune system. AB - BACKGROUND: A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC) molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA) or heterozygosity at the MHC are more important. METHODS: To do this we used captive house sparrows (Passer domesticus) to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. RESULTS: Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral) were associated with several different alleles. DISCUSSION: We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic. PMID- 28875067 TI - High incidence of cervical ribs indicates vulnerable condition in Late Pleistocene woolly rhinoceroses. AB - Mammals as a rule have seven cervical vertebrae, a number that remains remarkably constant. Changes of this number are associated with major congenital abnormalities (pleiotropic effects) that are, at least in humans, strongly selected against. Recently, it was found that Late Pleistocene mammoths (Mammuthus primigenius) from the North Sea have an unusually high incidence of abnormal cervical vertebral numbers, approximately ten times higher than that of extant elephants. Abnormal numbers were due to the presence of large cervical ribs on the seventh vertebra, indicating a homeotic change from a cervical rib less vertebra into a thoracic rib-bearing vertebra. The high incidence of cervical ribs indicates a vulnerable condition and is thought to be due to inbreeding and adverse conditions that may have impacted early pregnancies in declining populations. In this study we investigated the incidence of cervical ribs in another extinct Late Pleistocene megaherbivore from the North Sea and the Netherlands, the woolly rhinoceros (Coelodonta antiquitatis). We show that the incidence of abnormal cervical vertebral numbers in the woolly rhinoceros is unusually high for mammals (15,6%, n = 32) and much higher than in extant Rhinoceratidae (0%, n = 56). This indicates that woolly rhinoceros lived under vulnerable conditions, just like woolly mammoths. The vulnerable condition may well have contributed to their eventual extinction. PMID- 28875068 TI - Skin bacterial microbiome of a generalist Puerto Rican frog varies along elevation and land use gradients. AB - Host-associated microbial communities are ubiquitous among animals, and serve important functions. For example, the bacterial skin microbiome of amphibians can play a role in preventing or reducing infection by the amphibian chytrid fungus, Batrachochytrium dendrobatidis. Evidence suggests that environmental bacteria likely serve as a source pool for at least some of the members of the amphibian skin bacterial community, underscoring the potential for local environmental changes to disrupt microbial community source pools that could be critical to the health of host organisms. However, few studies have assessed variation in the amphibian skin microbiome along clear environmental gradients, and so we know relatively little about how local environmental conditions influence microbiome diversity. We sampled the skin bacterial communities of Coqui frogs, Eleutherodactylus coqui (N = 77), along an elevational gradient in eastern Puerto Rico (0-875 m), with transects in two land use types: intact forest (N = 4 sites) and disturbed (N = 3 sites) forest. We found that alpha diversity (as assessed by Shannon, Simpson, and Phylogenetic Diversity indices) varied across sites, but this variation was not correlated with elevation or land use. Beta diversity (community structure), on the other hand, varied with site, elevation and land use, primarily due to changes in the relative abundance of certain bacterial OTUs (~species) within these communities. Importantly, although microbiome diversity varied, E. coqui maintained a common core microbiota across all sites. Thus, our findings suggest that environmental conditions can influence the composition of the skin microbiome of terrestrial amphibians, but that some aspects of the microbiome remain consistent despite environmental variation. PMID- 28875069 TI - Mutation detection and prenatal diagnosis of XLHED pedigree. AB - BACKGROUND: The phenotypic characters of X -linked Hypohidrotic Ectodermal Dysplasia (XLHED) are the dysplasia of epithelial- and mesenchymal-derived organs. Ectodysplasin (EDA) is the causative gene of XLHED. METHODS: The current study reported a large Chinese XLHED pedigree. The genomic DNA of adult and fetus was extracted from peripheral blood and shed chorion cell respectively. The nucleotide variation in EDA gene was screened through direct sequencing the coding sequence. The methylation state of EDA gene's promoter was evaluated by pyrosequencing. RESULTS: This Chinese XLHED family had two male patients and three carriers. All of them were with a novel EDA frameshift mutation. The mutation, c.172-173insGG, which leads to an immediate premature stop codon in exon one caused severe structural changes of EDA. Prenatal diagnosis suggested that the fetus was a female carrier. The follow-up observation of this child indicated that she had mild hypodontia of deciduous teeth at age six. The methylation level of EDA gene's promoter was not related to carriers' phenotype changes in this family. DISCUSSION: We reported a new frameshift mutation of EDA gene in a Chinese family. Prenatal diagnosis can help to predict the disease status of the fetus. PMID- 28875070 TI - Dinosaur origin of egg color: oviraptors laid blue-green eggs. AB - Protoporphyrin (PP) and biliverdin (BV) give rise to the enormous diversity in avian egg coloration. Egg color serves several ecological purposes, including post-mating signaling and camouflage. Egg camouflage represents a major character of open-nesting birds which accomplish protection of their unhatched offspring against visually oriented predators by cryptic egg coloration. Cryptic coloration evolved to match the predominant shades of color found in the nesting environment. Such a selection pressure for the evolution of colored or cryptic eggs should be present in all open nesting birds and relatives. Many birds are open-nesting, but protect their eggs by continuous brooding, and thus exhibit no or minimal eggshell pigmentation. Their closest extant relatives, crocodiles, protect their eggs by burial and have unpigmented eggs. This phylogenetic pattern led to the assumption that colored eggs evolved within crown birds. The mosaic evolution of supposedly avian traits in non-avian theropod dinosaurs, however, such as the supposed evolution of partially open nesting behavior in oviraptorids, argues against this long-established theory. Using a double checking liquid chromatography ESI-Q-TOF mass spectrometry routine, we traced the origin of colored eggs to their non-avian dinosaur ancestors by providing the first record of the avian eggshell pigments protoporphyrin and biliverdin in the eggshells of Late Cretaceous oviraptorid dinosaurs. The eggshell parataxon Macroolithus yaotunensis can be assigned to the oviraptor Heyuannia huangi based on exceptionally preserved, late developmental stage embryo remains. The analyzed eggshells are from three Late Cretaceous fluvial deposits ranging from eastern to southernmost China. Reevaluation of these taphonomic settings, and a consideration of patterns in the porosity of completely preserved eggs support an at least partially open nesting behavior for oviraptorosaurs. Such a nest arrangement corresponds with our reconstruction of blue-green eggs for oviraptors. According to the sexual signaling hypothesis, the reconstructed blue green eggs support the origin of previously hypothesized avian paternal care in oviraptorid dinosaurs. Preserved dinosaur egg color not only pushes the current limits of the vertebrate molecular and associated soft tissue fossil record, but also provides a perspective on the potential application of this unexplored paleontological resource. PMID- 28875071 TI - Intraclutch eggshell colour variation in birds: are females able to identify their eggs individually? AB - BACKGROUND: One possibility suggested regarding female post-mating strategies is differential allocation into offspring investment. Female birds produce not only the largest, but also most colourful eggs of all oviparous taxa. Larger eggs provide space for bigger embryos, or more nutrition for their development, but the question why eggs are more colourful and why there is variation in eggshell colouration remains. In this context, the focus of interest has been to explain inter-clutch variation but in many bird species, eggshell colouration also varies within a clutch. Surprisingly, less attention has been paid to this phenomenon. Therefore, we propose the "female egg recognition" hypothesis, suggesting that mothers use colour characteristics to interpret egg attributes and allocate further investment into each egg accordingly. To evaluate the feasibility of the hypothesis, we tested several underlying predictions and examined their suitability using a dataset from our tree sparrow (Passer montanus) study. We predict (i) substantial within-clutch variation in eggshell colouration which, (ii) should be related to laying sequence, (iii) reflect egg quality and, (iv) should stimulate a female response. METHODS: Eggshell coloration data were obtained via digital photography under standardized conditions, taken after clutch completion. Lightness (L*), representing the achromatic properties of an egg has been chosen as the most important predictor in dark cavities and was related to egg quality and position in the nest. RESULTS: In our tree sparrows, first and mainly last eggs were less pigmented, providing information about laying order. Egg volume, which predicts chick quality, positively correlates with eggshell coloration. Finally, we could show that female tree sparrows placed darker, but not bigger, eggs into more central incubation positions. DISCUSSION: All basic prerequisites for the "female egg recognition" hypothesis are fulfilled. In this context practicability and feasibility of the hypothesis and alternative explanations are discussed. However future work is necessary to determine a direct effect on offspring condition. PMID- 28875072 TI - PrePhyloPro: phylogenetic profile-based prediction of whole proteome linkages. AB - Direct and indirect functional links between proteins as well as their interactions as part of larger protein complexes or common signaling pathways may be predicted by analyzing the correlation of their evolutionary patterns. Based on phylogenetic profiling, here we present a highly scalable and time-efficient computational framework for predicting linkages within the whole human proteome. We have validated this method through analysis of 3,697 human pathways and molecular complexes and a comparison of our results with the prediction outcomes of previously published co-occurrency model-based and normalization methods. Here we also introduce PrePhyloPro, a web-based software that uses our method for accurately predicting proteome-wide linkages. We present data on interactions of human mitochondrial proteins, verifying the performance of this software. PrePhyloPro is freely available at http://prephylopro.org/phyloprofile/. PMID- 28875073 TI - The microbial biosphere of the coral Acropora cervicornis in Northeastern Puerto Rico. AB - BACKGROUND: Coral reefs are the most biodiverse ecosystems in the marine realm, and they not only contribute a plethora of ecosystem services to other marine organisms, but they also are beneficial to humankind via, for instance, their role as nurseries for commercially important fish species. Corals are considered holobionts (host + symbionts) since they are composed not only of coral polyps, but also algae, other microbial eukaryotes and prokaryotes. In recent years, Caribbean reef corals, including the once-common scleractinian coral Acropora cervicornis, have suffered unprecedented mortality due to climate change-related stressors. Unfortunately, our basic knowledge of the molecular ecophysiology of reef corals, particularly with respect to their complex bacterial microbiota, is currently too poor to project how climate change will affect this species. For instance, we do not know how light influences microbial communities of A. cervicornis, arguably the most endangered of all Caribbean coral species. To this end, we characterized the microbiota of A. cervicornis inhabiting water depths with different light regimes. METHODS: Six A. cervicornis fragments from different individuals were collected at two different depths (three at 1.5 m and three at 11 m) from a reef 3.2 km off the northeastern coast of Puerto Rico. We characterized the microbial communities by sequencing the 16S rRNA gene region V4 with the Illumina platform. RESULTS: A total of 173,137 good-quality sequences were binned into 803 OTUs with a 97% similarity. We uncovered eight bacterial phyla at both depths with a dominance of 725 Rickettsiales OTUs (Proteobacteria). A fewer number (38) of low dominance OTUs varied by depth and taxa enriched in shallow water corals included Proteobacteria (e.g. Rhodobacteraceae and Serratia) and Firmicutes (Streptococcus). Those enriched in deeper water corals featured different Proteobacterial taxa (Campylobacterales and Bradyrhizobium) and Firmicutes (Lactobacillus). DISCUSSION: Our results confirm that the microbiota of A. cervicornis inhabiting the northeastern region of Puerto Rico is dominated by a Rickettsiales-like bacterium and that there are significant changes in less dominant taxa at different water depths. These changes in less dominant taxa may potentially impact the coral's physiology, particularly with respect to its ability to respond to future increases in temperature and CO2. PMID- 28875074 TI - Atropos: specific, sensitive, and speedy trimming of sequencing reads. AB - A key step in the transformation of raw sequencing reads into biological insights is the trimming of adapter sequences and low-quality bases. Read trimming has been shown to increase the quality and reliability while decreasing the computational requirements of downstream analyses. Many read trimming software tools are available; however, no tool simultaneously provides the accuracy, computational efficiency, and feature set required to handle the types and volumes of data generated in modern sequencing-based experiments. Here we introduce Atropos and show that it trims reads with high sensitivity and specificity while maintaining leading-edge speed. Compared to other state-of-the art read trimming tools, Atropos achieves significant increases in trimming accuracy while remaining competitive in execution times. Furthermore, Atropos maintains high accuracy even when trimming data with elevated rates of sequencing errors. The accuracy, high performance, and broad feature set offered by Atropos makes it an appropriate choice for the pre-processing of Illumina, ABI SOLiD, and other current-generation short-read sequencing datasets. Atropos is open source and free software written in Python (3.3+) and available at https://github.com/jdidion/atropos. PMID- 28875075 TI - New insights into Mesozoic cycad evolution: an exploration of anatomically preserved Cycadaceae seeds from the Jurassic Oxford Clay biota. AB - Most knowledge concerning Mesozoic Era floras has come from compression fossils. This has been augmented in the last 20 years by rarer permineralized material showing cellular preservation. Here, we describe a new genus of anatomically preserved gymnosperm seed from the Callovian-Oxfordian (Jurassic) Oxford Clay Formation (UK), using a combination of traditional sectioning and synchrotron radiation X-ray micro-tomography (SRXMT). Oxfordiana motturii gen. et sp. nov. is large and bilaterally symmetrical. It has prominent external ribs, and has a three-layered integument comprising: a narrow outer layer of thick walled cells; a thick middle parenchymatous layer; and innermost a thin fleshy layer. The integument has a longitudinal interior groove and micropyle, enveloping a nucellus with a small pollen chamber. The large size, bilateral symmetry and integumentary groove demonstrate an affinity for the new species within the cycads. Moreover, the internal groove in extant taxa is an autapomorphy of the genus Cycas, where it facilitates seed germination. Based upon the unique seed germination mechanism shared with living species of the Cycadaceae, we conclude that O. motturii is a member of the stem-group lineage leading to Cycas after the Jurassic divergence of the Cycadaceae from other extant cycads. SRXMT-for the first time successfully applied to fossils already prepared as slides-reveals the distribution of different mineral phases within the fossil, and allows us to evaluate the taphonomy of Oxfordiana. An early pyrite phase replicates the external surfaces of individual cells, a later carbonate component infilling void spaces. The resulting taphonomic model suggests that the relatively small size of the fossils was key to their exceptional preservation, concentrating sulfate reducing bacteria in a locally closed microenvironment and thus facilitating soft tissue permineralization. PMID- 28875076 TI - Validation and description of two new north-western Australian Rainbow skinks with multispecies coalescent methods and morphology. AB - While methods for genetic species delimitation have noticeably improved in the last decade, this remains a work in progress. Ideally, model based approaches should be applied and considered jointly with other lines of evidence, primarily morphology and geography, in an integrative taxonomy framework. Deep phylogeographic divergences have been reported for several species of Carlia skinks, but only for some eastern taxa have species boundaries been formally tested. The present study does this and revises the taxonomy for two species from northern Australia, Carlia johnstonei and C. triacantha. We introduce an approach that is based on the recently published method StarBEAST2, which uses multilocus data to explore the support for alternative species delimitation hypotheses using Bayes Factors (BFD). We apply this method, jointly with two other multispecies coalescent methods, using an extensive (from 2,163 exons) data set along with measures of 11 morphological characters. We use this integrated approach to evaluate two new candidate species previously revealed in phylogeographic analyses of rainbow skinks (genus Carlia) in Western Australia. The results based on BFD StarBEAST2, BFD* SNAPP and BPP genetic delimitation, together with morphology, support each of the four recently identified Carlia lineages as separate species. The BFD StarBEAST2 approach yielded results highly congruent with those from BFD* SNAPP and BPP. This supports use of the robust multilocus multispecies coalescent StarBEAST2 method for species delimitation, which does not require a priori resolved species or gene trees. Compared to the situation in C. triacantha, morphological divergence was greater between the two lineages within Kimberley endemic C. johnstonei, which also had deeper divergent histories. This congruence supports recognition of two species within C. johnstonei. Nevertheless, the combined evidence also supports recognition of two taxa within the more widespread C. triacantha. With this work, we describe two new species, Carlia insularis sp. nov and Carlia isostriacantha sp. nov. in the northwest of Australia. This contributes to increasing recognition that this region of tropical Australia has a rich and unique fauna. PMID- 28875077 TI - Uncovering unseen fungal diversity from plant DNA banks. AB - Throughout the world DNA banks are used as storage repositories for genetic diversity of organisms ranging from plants to insects to mammals. Designed to preserve the genetic information for organisms of interest, these banks also indirectly preserve organisms' associated microbiomes, including fungi associated with plant tissues. Studies of fungal biodiversity lag far behind those of macroorganisms, such as plants, and estimates of global fungal richness are still widely debated. Utilizing previously collected specimens to study patterns of fungal diversity could significantly increase our understanding of overall patterns of biodiversity from snapshots in time. Here, we investigated the fungi inhabiting the phylloplane among species of the endemic Hawaiian plant genus, Clermontia (Campanulaceae). Utilizing next generation DNA amplicon sequencing, we uncovered approximately 1,780 fungal operational taxonomic units from just 20 DNA bank samples collected throughout the main Hawaiian Islands. Using these historical samples, we tested the macroecological pattern of decreasing community similarity with decreasing geographic proximity. We found a significant distance decay pattern among Clermontia associated fungal communities. This study provides the first insights into elucidating patterns of microbial diversity through the use of DNA bank repository samples. PMID- 28875078 TI - Genotyping-by-sequencing enables linkage mapping in three octoploid cultivated strawberry families. AB - Genotyping-by-sequencing (GBS) was used to survey genome-wide single-nucleotide polymorphisms (SNPs) in three biparental strawberry (Fragaria * ananassa) populations with the goal of evaluating this technique in a species with a complex octoploid genome. GBS sequence data were aligned to the F. vesca 'Fvb' reference genome in order to call SNPs. Numbers of polymorphic SNPs per population ranged from 1,163 to 3,190. Linkage maps consisting of 30-65 linkage groups were produced from the SNP sets derived from each parent. The linkage groups covered 99% of the Fvb reference genome, with three to seven linkage groups from a given parent aligned to any particular chromosome. A phylogenetic analysis performed using the POLiMAPS pipeline revealed linkage groups that were most similar to ancestral species F. vesca for each chromosome. Linkage groups that were most similar to a second ancestral species, F. iinumae, were only resolved for Fvb 4. The quantity of missing data and heterogeneity in genome coverage inherent in GBS complicated the analysis, but POLiMAPS resolved F. * ananassa chromosomal regions derived from diploid ancestor F. vesca. PMID- 28875079 TI - Distribution and biological implications of plastic pollution on the fringing reef of Mo'orea, French Polynesia. AB - Coral reef ecosystems of the South Pacific are extremely vulnerable to plastic pollution from oceanic gyres and land-based sources. To describe the extent and impact of plastic pollution, the distribution of both macro- (>5 mm) and microplastic (plastic < 5 mm) of the fringing reef of an isolated South Pacific island, Mo'orea, French Polynesia was quantified. Macroplastic was found on every beach on the island that was surveyed. The distribution of this plastic was categorized by site type and by the presence of Turbinaria ornata, a common macroalgae on Mo'orea. Microplastics were discovered in the water column of the fringing reef of the island, at a concentration of 0.74 pieces m-2. Additionally, this study reports for the first time the ingestion of microplastic by the corallimorpha Discosoma nummiforme. Microplastics were made available to corallimorph polyps in a laboratory setting over the course of 108 h. Positively and negatively buoyant microplastics were ingested, and a microplastic particle that was not experimentally introduced was also discovered in the stomach cavity of one organism. This study indicates that plastic pollution has the potential to negatively impact coral reef ecosystems of the South Pacific, and warrants further study to explore the broader potential impacts of plastic pollution on coral reef ecosystems. PMID- 28875080 TI - Experimental moose reduction lowers wolf density and stops decline of endangered caribou. AB - The expansion of moose into southern British Columbia caused the decline and extirpation of woodland caribou due to their shared predators, a process commonly referred to as apparent competition. Using an adaptive management experiment, we tested the hypothesis that reducing moose to historic levels would reduce apparent competition and therefor recover caribou populations. Nested within this broad hypothesis were three specific hypotheses: (1) sport hunting could be used to substantially reduce moose numbers to an ecological target; (2) wolves in this ecosystem were primarily limited by moose abundance; and (3) caribou were limited by wolf predation. These hypotheses were evaluated with a before-after control impact (BACI) design that included response metrics such as population trends and vital rates of caribou, moose, and wolves. Three caribou subpopulations were subject to the moose reduction treatment and two were in a reference area where moose were not reduced. When the moose harvest was increased, the moose population declined substantially in the treatment area (by 70%) but not the reference area, suggesting that the policy had the desired effect and was not caused by a broader climatic process. Wolf numbers subsequently declined in the treatment area, with wolf dispersal rates 2.5* greater, meaning that dispersal was the likely mechanism behind the wolf numerical response, though reduced recruitment and starvation was also documented in the treatment area. Caribou adult survival increased from 0.78 to 0.88 in the treatment area, but declined in the reference. Caribou recruitment was unaffected by the treatment. The largest caribou subpopulation stabilized in the treatment area, but declined in the reference area. The observed population stability is comparable to other studies that used intensive wolf control, but is insufficient to achieve recovery, suggesting that multiple limiting factors and corresponding management tools must be addressed simultaneously to achieve population growth. PMID- 28875081 TI - The jaw is a second-class lever in Pedetes capensis (Rodentia: Pedetidae). AB - The mammalian jaw is often modelled as a third-class lever for the purposes of biomechanical analyses, owing to the position of the resultant muscle force between the jaw joint and the teeth. However, it has been proposed that in some rodents the jaws operate as a second-class lever during distal molar bites, owing to the rostral position of the masticatory musculature. In particular, the infraorbital portion of the zygomatico-mandibularis (IOZM) has been suggested to be of major importance in converting the masticatory system from a third-class to a second-class lever. The presence of the IOZM is diagnostic of the hystricomorph rodents, and is particularly well-developed in Pedetes capensis, the South African springhare. In this study, finite element analysis (FEA) was used to assess the lever mechanics of the springhare masticatory system, and to determine the function of the IOZM. An FE model of the skull of P. capensis was constructed and loaded with all masticatory muscles, and then solved for biting at each tooth in turn. Further load cases were created in which each masticatory muscle was removed in turn. The analyses showed that the mechanical advantage of the springhare jaws was above one at all molar bites and very close to one during the premolar bite. Removing the IOZM or masseter caused a drop in mechanical advantage at all bites, but affected strain patterns and cranial deformation very little. Removing the ZM had only a small effect on mechanical advantage, but produced a substantial reduction in strain and deformation across the skull. It was concluded that the masticatory system of P. capensis acts as a second class lever during bites along almost the entire cheek tooth row. The IOZM is clearly a major contributor to this effect, but the masseter also has a part to play. The benefit of the IOZM is that it adds force without substantially contributing to strain or deformation of the skull. This may help explain why the hystricomorphous morphology has evolved multiple times independently within Rodentia. PMID- 28875082 TI - The Brazilian version of the 20-item rapid estimate of adult literacy in medicine and dentistry. AB - BACKGROUND: The misunderstanding of specific vocabulary may hamper the patient health provider communication. The 20-item Rapid Estimate Adult Literacy in Medicine and Dentistry (REALMD-20) was constructed to screen patients by their ability in reading medical/dental terminologies in a simple and rapid way. This study aimed to perform the cross-cultural adaptation and validation of this instrument for its application in Brazilian dental patients. METHODS: The cross cultural adaptation was performed through conceptual equivalence, verbatim translation, semantic, item and operational equivalence, and back-translation. After that, 200 participants responded the adapted version of the REALMD-20, the Brazilian version of the Rapid Estimate of Adult Literacy in Dentistry (BREALD 30), ten questions of the Brazilian National Functional Literacy Index (BNFLI), and a questionnaire with socio-demographic and oral health-related questions. Statistical analysis was conducted to assess the reliability and validity of the REALMD-20 (P < 0.05). RESULTS: The sample was composed predominantly by women (55.5%) and white/brown (76%) individuals, with an average age of 39.02 years old (+/-15.28). The average REALMD-20 score was 17.48 (+/-2.59, range 8-20). It displayed a good internal consistency (Cronbach's alpha = 0.789) and test-retest reliability (ICC = 0.73; 95% CI [0.66 - 0.79]). In the exploratory factor analysis, six factors were extracted according to Kaiser's criterion. The factor I (eigenvalue = 4.53) comprised four terms- "Jaundice", "Amalgam", "Periodontitis" and "Abscess"-accounted for 25.18% of total variance, while the factor II (eigenvalue = 1.88) comprised other four terms-"Gingivitis", "Instruction", "Osteoporosis" and "Constipation"-accounted for 10.46% of total variance. The first four factors accounted for 52.1% of total variance. The REALMD-20 was positively correlated with the BREALD-30 (Rs = 0.73, P < 0.001) and BNFLI (Rs = 0.60, P < 0.001). The scores were significantly higher among health professionals, more educated people, and individuals who reported good/excellent oral health conditions, and who sought preventive dental services. Distinctly, REALMD-20 scores were similar between both participants who visited a dentist <1 year ago and >=1 year. Also, REALMD-20 was a significant predictor of self reported oral health status in a multivariate logistic regression model, considering socio-demographic and oral health-related confounding variables. CONCLUSION: The Brazilian version of the REALMD-20 demonstrated adequate psychometric properties for screening dental patients in relation to their recognition of health specific terms. This instrument can contribute to identify individuals with important dental/medical vocabulary limitations in order to improve the health education and outcomes in a person-centered care model. PMID- 28875083 TI - Relying on known or exploring for new? Movement patterns and reproductive resource use in a tadpole-transporting frog. AB - Animals relying on uncertain, ephemeral and patchy resources have to regularly update their information about profitable sites. For many tropical amphibians, widespread, scattered breeding pools constitute such fluctuating resources. Among tropical amphibians, poison frogs (Dendrobatidae) exhibit some of the most complex spatial and parental behaviors-including territoriality and tadpole transport from terrestrial clutches to ephemeral aquatic deposition sites. Recent studies have revealed that poison frogs rely on spatial memory to successfully navigate through their environment. This raises the question of when and how these frogs gain information about the area and suitable reproductive resources. To investigate the spatial patterns of pool use and to reveal potential explorative behavior, we used telemetry to follow males of the territorial dendrobatid frog Allobates femoralis during tadpole transport and subsequent homing. To elicit exploration, we reduced resource availability experimentally by simulating desiccated deposition sites. We found that tadpole transport is strongly directed towards known deposition sites and that frogs take similar direct paths when returning to their home territory. Frogs move faster during tadpole transport than when homing after the deposition, which probably reflects different risks and costs during these two movement phases. We found no evidence for exploration, neither during transport nor homing, and independent of the availability of deposition sites. We suggest that prospecting during tadpole transport is too risky for the transported offspring as well as for the transporting male. Relying on spatial memory of multiple previously discovered pools appears to be the predominant and successful strategy for the exploitation of reproductive resources in A. femoralis. Our study provides for the first time a detailed description of poison frog movement patterns during tadpole transport and corroborates recent findings on the significance of spatial memory in poison frogs. When these frogs explore and discover new reproductive resources remains unknown. PMID- 28875084 TI - Prevalence of bacterial vaginosis in Portuguese pregnant women and vaginal colonization by Gardnerella vaginalis. AB - BACKGROUND: We aimed to determine the prevalence of vaginal colonization by Gardnerella vaginalis and of bacterial vaginosis (BV) in Portuguese pregnant women, and to identify risk factors for BV and G. vaginalis colonization in pregnancy. METHODS: A cross-sectional study was conducted among pregnant women aged >= 18 years who were attending in two public hospitals of the Northwest region of Portugal. Epidemiological data was collected by anonymous questionnaire. BV was diagnosed by Nugent criteria and G. vaginalis presence was identified by polymerase chain reaction. Crude associations between the study variables and BV or G. vaginalis colonization were quantified by odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: The prevalences of BV and of G. vaginalis colonization among Portuguese pregnant women were 3.88% and 67.48%, respectively. Previous preterm delivery and colonization by G. vaginalis were factors with very high OR, but only statistically significant for a 90% CI. Conversely, higher rates of G. vaginalis colonization were found in women with basic educational level (OR = 2.77, 95% CI [1.33-5.78]), during the second trimester of pregnancy (OR = 6.12, 95% CI [1.80-20.85]) and with BV flora (OR = 8.73, 95% CI [0.50-153.60]). DISCUSSION: Despite the lower number of women with BV, prevalence ratios and association with risk factors were similar to recent European studies. However, the percentage of healthy women colonized by G. vaginalis was significantly higher than many previous studies, confirming that G. vaginalis colonization does not always lead to BV development. PMID- 28875085 TI - Remote sensing and spatial statistical techniques for modelling Ommatissus lybicus (Hemiptera: Tropiduchidae) habitat and population densities. AB - In order to understand the distribution and prevalence of Ommatissus lybicus (Hemiptera: Tropiduchidae) as well as analyse their current biographical patterns and predict their future spread, comprehensive and detailed information on the environmental, climatic, and agricultural practices are essential. The spatial analytical techniques such as Remote Sensing and Spatial Statistics Tools, can help detect and model spatial links and correlations between the presence, absence and density of O. lybicus in response to climatic, environmental, and human factors. The main objective of this paper is to review remote sensing and relevant analytical techniques that can be applied in mapping and modelling the habitat and population density of O. lybicus. An exhaustive search of related literature revealed that there are very limited studies linking location-based infestation levels of pests like the O. lybicus with climatic, environmental, and human practice related variables. This review also highlights the accumulated knowledge and addresses the gaps in this area of research. Furthermore, it makes recommendations for future studies, and gives suggestions on monitoring and surveillance methods in designing both local and regional level integrated pest management strategies of palm tree and other affected cultivated crops. PMID- 28875086 TI - Fourteen new species of Oecetis McLachlan, 1877 (Trichoptera: Leptoceridae) from the Neotropical region. AB - BACKGROUND: The caddisfly genus Oecetis currently contains 534 valid species. Its larval stages are found in freshwaters around the world. The adults can be distinguished from other Leptoceridae by the unbranched forewing M vein and the exceptionally long maxillary palps. In the Neotropical region, 55 species of Oecetis have been recorded and most of them can be placed in one of the six species groups known from this biogeographical region: the avara-, falicia-, inconspicua-, punctata-, punctipennis-, and testacea-groups. More than 50% of the known diversity of Neotropical Oecetis has been described in the past 40 years. Here, we describe an additional 14 new species of Oecetis to further document the diversity of this genus in the Neotropical region. METHODS: The descriptions and illustrations presented here are based on male specimens. Specimens were collected with Malaise traps or ultraviolet light traps. They were preserved in alcohol or pinned as stated in material examined section. Specimens had their genitalia prepared in 85% lactic acid to better observe internal characters and illustrations were aided by the use of a microscope with drawing tube attached. RESULTS AND DISCUSSION: This study raises the number of species of Oecetis in the Neotropics from 55 to 69. Eight of the new species presented here could not be reliably placed in one of the known species groups (Oecetis acuticlasper n. sp., Oecetis flinti n. sp., Oecetis carinata n. sp., Oecetis cassicoleata n. sp., Oecetis blahniki n. sp., Oecetis gibbosa n. sp., Oecetis licina n. sp., and Oecetis pertica n. sp.). The others are placed in the punctata-group (Oecetis bidigitata n. sp., Oecetis quasipunctata n. sp.), testacea-group (Oecetis plenuspinosa n. sp.), and falicia-group (Oecetis calori n. sp., Oecetis hastapulla n. sp., Oecetis machaera n. sp.). Most of the diagnostic characters rely on structures of the inferior appendages and phallic apparatus, and the shape of tergum X. PMID- 28875088 TI - Unique Association of Multiple Seminal Vesicle Cysts with Contralateral Renal Agenesis: A Rare Variant of Zinner Syndrome. AB - Zinner syndrome is a rare developmental anomaly of the Wolffian (mesonephric) duct which is characterised by a triad of obstruction of the ejaculatory duct, the ipsilateral seminal vesicle cyst, and the ipsilateral renal agenesis. The aim of this case report is to emphasize the importance of radiological imaging in diagnosing the condition and to report its rare unusual variant. PMID- 28875087 TI - Tracing hepatitis B virus (HBV) genotype B5 (formerly B6) evolutionary history in the circumpolar Arctic through phylogeographic modelling. AB - BACKGROUND: Indigenous populations of the circumpolar Arctic are considered to be endemically infected (>2% prevalence) with hepatitis B virus (HBV), with subgenotype B5 (formerly B6) unique to these populations. The distinctive properties of HBV/B5, including high nucleotide diversity yet no significant liver disease, suggest virus adaptation through long-term host-pathogen association. METHODS: To investigate the origin and evolutionary spread of HBV/B5 into the circumpolar Arctic, fifty-seven partial and full genome sequences from Alaska, Canada and Greenland, having known location and sampling dates spanning 40 years, were phylogeographically investigated by Bayesian analysis (BEAST 2) using a reversible-jump-based substitution model and a clock rate estimated at 4.1 * 10-5 substitutions/site/year. RESULTS: Following an initial divergence from an Asian viral ancestor approximately 1954 years before present (YBP; 95% highest probability density interval [1188, 2901]), HBV/B5 coalescence occurred almost 1000 years later. Surprisingly, the HBV/B5 ancestor appears to locate first to Greenland in a rapid coastal route progression based on the landscape aware geographic model, with subsequent B5 evolution and spread westward. Bayesian skyline plot analysis demonstrated an HBV/B5 population expansion occurring approximately 400 YBP, coinciding with the disruption of the Neo-Eskimo Thule culture into more heterogeneous and regionally distinct Inuit populations throughout the North American Arctic. DISCUSSION: HBV/B5 origin and spread appears to occur coincident with the movement of Neo-Eskimo (Inuit) populations within the past 1000 years, further supporting the hypothesis of HBV/host co expansion, and illustrating the concept of host-pathogen adaptation and balance. PMID- 28875089 TI - Use of a Teledentistry-based Program for Screening of Early Childhood Caries in a School Setting. AB - Aim The aim of this study was to assess the reliability and feasibility of using teledentistry for the screening and diagnosis of dental caries in children between the age groups of three to six years. Design This study included a total of 318 school-going children whose caries scores were calculated by visual method and using digital photographs generated by an intraoral camera by two examiners: examiner 1 and examiner 2 (E1 and E2). Intra-examiner and inter-examiner variability were determined. Reliability was compared across the three groups. Results Intra-examiner and inter-examiner variability when compared revealed no significant difference. A Cronbach's alpha of 0.983 was generated, which shows high reliability. Conclusions Effective screening for early childhood caries (ECC) in young children was possible with digital images generated in a school setting, thus paving the way for the application of teledentistry as effective means for the diagnosis of dental caries. PMID- 28875090 TI - Regression of a Fungating Tumor After Hypofractionated Radiation Therapy in a Patient With Metastatic Breast Cancer. AB - Radiation therapy is a well-established palliative treatment for symptomatic metastases from breast cancer. This is also true of symptomatic primary breast tumors in patients with metastatic disease or in those who are medically inoperable. Further, local progression in the chest wall can severely impair quality of life, with local pain, bleeding, and significant impact on one's self image. Here, we present the case of a patient who showed an exceptional response to a palliative hypofractionated radiation course to her bleeding, fungating breast primary. PMID- 28875091 TI - Demographics of Head and Neck Cancer Patients: A Single Institution Experience. AB - Introduction Head and neck cancer (HNC) comprises a diverse group of oncological entities, originating from various tissue types and organ localizations, situated in the topographical regions of the head and neck (H&N). This single institution retrospective study was aimed at establishing the HNC patient demographics and categorizing the individual incidence of H&N malignancies, regarding their organ of origin and main histopathological type. Materials and methods All histologically verified cases of HNC from a single tertiary referral center were reviewed in a descriptive retrospective manner. Data sampling period was 47 months. Results Male to female ratio of the registered HNC cases was 3.24:1. The mean age of diagnosis was 63.84 +/- 12.65 years, median 65 years. The most common HNC locations include the larynx 30.37% (n = 188), lips and oral cavity 29.08% (n = 180), pharynx 20.03% (n = 124) and salivary glands 10.94% (n = 68), with other locations such as the external nose, nasal cavity and sinuses and auricle and external ear canal harboring a minority of the cases. The main histopathological groups include squamous cell carcinoma 76.74% (n = 475) and adenocarcinoma 6.14% (n = 38), with other malignant entries such as other epithelial malignancies, primary tonsillar, mucosa-associated lymphoid tissue or parenchymal lymphomas, connective tissue neoplasias, neuroendocrine and vascular malignancies diagnosed in a minority of cases. Conclusion Considered to be relatively rare, HNC represents a diverse group of oncological entities with individual and specific demographic characteristics. The reported single institution results appear representative of the national incidence and characteristics of HNC. PMID- 28875092 TI - Thoracolumbar Cortical Screw Placement with Interbody Fusion: Technique and Considerations. AB - A surge in interest in cortical bone trajectory (CBT), first described by Santoni in 2009, may be a result of its numerous advantages, including reduced surgical incision length and lateral dissection, limited disruption of the facet joints, and decreased blood loss. In addition, CBT offers improved screw pullout strength and the ability to perform hybrid constructs with pedicle screws using minimally invasive approaches. However, one of the main limitations of the technique involves the small screw size, which limits the potential for long-segment constructs. We describe a technique involving a more in-line anatomical trajectory, allowing for larger screw diameters. A feasibility study using a cadaveric model was performed and evaluated. Moreover, a focused review of the literature on the use of CBT was performed. Screw entry points are located along the inferomedial aspect of the facet and angled superolaterally. The use of this technique allows for the placement of larger screws (4.5 to 6.5 mm diameter) without pedicle breaches along with the alignment of screw heads from L1 to S1. In addition, the technique can be performed using stereotactic navigation or fluoroscopy. A direct, more in-line technique allows for larger screws to be placed using CBT. This technique can be combined with minimally invasive approaches. The potential advantages of the CBT technique support its use as a probable alternative to traditional pedicle screw fixation techniques. PMID- 28875093 TI - Association of Lipid Profile in Pregnancy with Preeclampsia, Gestational Diabetes Mellitus, and Preterm Delivery. AB - Introduction During the last two trimesters of pregnancy, glucose is spared (for the foetus), while the concentration of fatty acids in plasma increases, which can create complications like preeclampsia, gestational diabetes mellitus (GDM), and preterm delivery. Aim To study the association of serum lipid levels during the second and third trimesters with the development of pregnancy-associated diseases, such as preeclampsia, GDM, and preterm delivery. Methods and Materials The present study was carried out at MGM Hospital, Navi Mumbai, India. Two hundred antenatal cases from October 2012 to October 2014 were enrolled after giving an informed consent. A lipid profile was recorded for each subject and was later accessed. The lipid profile of the subjects having either GDM, preterm, or preeclampsia was further used to find an association with the individual disorders. Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) version 20 (IBM SPSS Statistics, Armonk, NY). All reported p-values are two-tailed, and confidence intervals were calculated at the 95% level. Results In preeclamptic patients, the mean systolic blood pressure was 151.40 mm/Hg and the mean diastolic blood pressure was 74.03 mm/Hg in the third trimester. In preeclamptic patients, the mean serum triglyceride levels in the second trimester were 204.00 mg/dl, while the mean was 243.20 mg/dl in the third trimester. In GDM patients, the mean serum triglyceride was 214.33 mg/dl in the second trimester, while it was 230.50 mg/dl in the third trimester. In patients with preterm, the mean triglycerides levels were 212.83 mg/dl and 240.16 mg/dl in the second and third trimesters, respectively. In preeclamptic patients, the mean serum cholesterol levels in the second trimester were 210 mg/dl, while in the third trimester, the mean was 243.60 mg/dl. In GDM patients, the mean serum cholesterol was 223.50 mg/dl and 242.83 mg/dl in the second and third trimester, respectively. The mean cholesterol levels in patients with preterm in second and third trimesters were 213.33 mg/dl and 243.66 mg/dl, respectively. Out of the total 200 patients, 168 had no complications, while 20 (10%) had preeclampsia, six (3%) had gestational diabetes mellitus, and the other six {3%} had preterm deliveries. Conclusion An association between maternal early pregnancy triglyceridaemia and the subsequent risk of preeclampsia, gestational diabetes, and preterm deliveries was observed. The occurrence of preeclampsia, gestational diabetes, and preterm deliveries cannot be predicted based on the values of serum cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipoprotein cholesterol (VLDL-C). Hence, estimation of lipid profile is strongly recommended during pregnancy to prevent the deleterious effect of hyperlipidaemia associated with pregnancy. PMID- 28875094 TI - Successful Trial of Octreotide and Ketorolac for the Management of Increased Biliary Drain Output: A Case Report. AB - We describe a 69-year-old male patient with the status of obstructive jaundice post percutaneous biliary drainage for prior obstructive jaundice and who presented with a complaint of generalized weakness and increased output from the drainage tube. The patient developed worsening jaundice, which was noted to be obstructive in nature with a marked dilatation of the biliary tree and a distal obstruction of the common bile duct. Subsequently, a percutaneous biliary drain was placed for symptomatic management. However, the patient continued to have increased output from the drain, approximating 3-4 liters a day, which made the patient dependent on continuous intravenous hydration. The case presented a therapeutic challenge in reducing the drainage amount. We have tried a successful approach based on the physiologic effect of octreotide and nonsteroidal anti inflammatory drugs (NSAIDs) in the formation of bile secretion. This approach has not been clearly described in the literature. We highlight the importance of further study to validate the use of these medications in similar clinical scenarios. PMID- 28875095 TI - Evaluation of Prostatic Lesions by Transrectal Ultrasound, Color Doppler, and the Histopathological Correlation. AB - Objective To evaluate the role of a transrectal ultrasound (TRUS) guided biopsy and a color Doppler test in the detection of prostate cancer in patients with increased serum prostate-specific antigen (PSA) levels and/or an abnormal digital rectal examination (DRE). Method A total of 40 cases, ranging in age from 50 to 80 years and showing increased serum PSA levels (4-10 ng/ml) and/or abnormal DRE, were enrolled and underwent TRUS evaluation followed by color Doppler flowmetric studies. A TRUS-guided biopsy was performed in all the cases. The findings were confirmed histopathologically. Data were analyzed using the chi-square test. Results Histopathologically, a total of 13 cases (32.5%) were malignant. On TRUS, irregular shape, heterogeneous echotexture loss of differentiation between the peripheral and internal zones, less mean weight of the prostate, and capsular invasion were significantly associated with malignancy. On flowmetry, moderate vascularity and focal asymmetry were significantly associated with malignancy. The combined use of TRUS and color Doppler flowmetry was found to be 100% sensitive and 92.6% specific and had a positive predictive value (PPV) and a negative predictive value (NPV) of 86.7% and 100%, respectively. Conclusion TRUS with color Doppler flowmetry was highly sensitive and specific in the detection of prostate malignancy. PMID- 28875097 TI - Sustained, Long-Term Maintenance of Remission with Single-Agent Veliparib in Recurrent Triple-Negative Breast Cancer. AB - Triple-negative breast cancers (TNBC) have poorer outcomes than hormone positive or human epidermal growth factor receptor 2 (HER2)-positive breast cancers, with chemotherapy being the usual standard of care. Veliparib, a poly ADP-ribose polymerase (PARP) inhibitor, has been studied in both breast cancer susceptibility genes 1 and 2 (BRCA)-mutation related and sporadic cancers as a single agent and in combination with chemotherapy. Here, we describe a patient whose metastatic recurrence of TNBC was treated with combination chemotherapy and veliparib followed by maintenance single-therapy veliparib. PMID- 28875096 TI - Narrow Complex Ventricular Tachycardia. AB - Myocardial infarctions are frequently complicated by tachyarrhythmias, which commonly have wide QRS complexes (QRS duration > 120 milliseconds). Many published criteria exist to help differentiate between ventricular and supraventricular mechanisms. We present a case of a 61-year-old male with a history of hypertension, hyperlipidemia and coronary artery disease with prior stenting of the right coronary artery (RCA). He had been noncompliant with his antiplatelet medication and presented with cardiac arrest secondary to in-stent thrombosis. He was resuscitated and his RCA was re-stented, after which he made a good neurological recovery. During cardiac rehabilitation several weeks post intervention, he was noted to have sustained tachycardia with associated nausea and lightheadedness, but no palpitation symptoms, chest pain or loss of consciousness. He was sent to the emergency department, where his electrocardiogram showed a tachycardia at 173 beats per minute which was regular, with a relatively narrow QRS duration (maximum of 115-120 msec in leads I and AVL) with a slurred QRS upstroke. This morphology was significantly different from his QRS complex during sinus rhythm. Intravenous diltiazem was ineffective but an amiodarone bolus terminated the tachycardia. The patient was admitted to the coronary care unit and treated with intravenous amiodarone infusion. A subsequent electrophysiology study was performed, showing inducibility of the clinical tachycardia. Atrioventricular (AV) dissociation was present during the induced arrhythmia, confirming the diagnosis of ventricular tachycardia. An implantable cardiac defibrillator was placed and the patient was discharged. PMID- 28875098 TI - Oxidative stabilization of polyacrylonitrile nanofibers and carbon nanofibers containing graphene oxide (GO): a spectroscopic and electrochemical study. AB - In this study, a precursor for carbon nanofibers (CNF) was fabricated via electrospinning and carbonized through a thermal process. Before carbonization, oxidative stabilization should be applied, and the oxidation mechanism also plays an important role during carbonization. Thus, the understanding of the oxidation mechanism is an essential part of the production of CNF. The oxidation process of polyacrylonitrile was studied and nanofiber webs containing graphene oxide (GO) are obtained to improve the electrochemical properties of CNF. Structural and morphological characterizations of the webs are carried out by using attenuated total reflectance Fourier transform infrared spectroscopy and Raman spectroscopy, scanning electron microscopy, atomic force microscopy and transmission electron microscopy. Mechanical tests are performed with a dynamic mechanical analyzer, and thermal studies are conducted by using thermogravimetric analysis. Electrochemical impedance spectroscopy, and cyclic voltammetry are used to investigate capacitive behavior of the products. The proposed equivalent circuit model was consistent with charge-transfer processes taking place at interior pores filled with electrolyte. PMID- 28875099 TI - Surface functionalization of 3D-printed plastics via initiated chemical vapor deposition. AB - 3D printing is a useful fabrication technique because it offers design flexibility and rapid prototyping. The ability to functionalize the surfaces of 3D-printed objects allows the bulk properties, such as material strength or printability, to be chosen separately from surface properties, which is critical to expanding the breadth of 3D printing applications. In this work, we studied the ability of the initiated chemical vapor deposition (iCVD) process to coat 3D printed shapes composed of poly(lactic acid) and acrylonitrile butadiene styrene. The thermally insulating properties of 3D-printed plastics pose a challenge to the iCVD process due to large thermal gradients along the structures during processing. In this study, processing parameters such as the substrate temperature and the filament temperature were systematically varied to understand how these parameters affect the uniformity of the coatings along the 3D-printed objects. The 3D-printed objects were coated with both hydrophobic and hydrophilic polymers. Contact angle goniometry and X-ray photoelectron spectroscopy were used to characterize the functionalized surfaces. Our results can enable the use of iCVD to functionalize 3D-printed materials for a range of applications such as tissue scaffolds and microfluidics. PMID- 28875100 TI - Development of an advanced diagnostic concept for intestinal inflammation: molecular visualisation of nitric oxide in macrophages by functional poly(lactic co-glycolic acid) microspheres. AB - We here describe a new approach to visualise nitric oxide (NO) in living macrophages by fluorescent NO-sensitive microspheres based on poly(lactic-co glycolic acid) (PLGA). PLGA microspheres loaded with NO550 dye were prepared through a modified solvent-evaporation method. Microparticles were characterized by a mean hydrodynamic diameter of 3000 nm, zeta potential of -26.000 +/- 0.351 mV and a PDI of 0.828 +/- 0.298. Under abiotic conditions, NO release was triggered through UV radiation (254 nm) of 10 mM sodium nitroprusside dehydrate (SNP). After incubation, AZO550 microspheres exhibited an about 8-fold increased emission at 550 nm compared to NO550 particles. For biotic NO release, RAW 264.7 murine macrophages were activated with lipopolysaccharide (LPS) of Salmonella typhimurium. After treatment with NO550 microparticles, only activated cells caused a green particle fluorescence and could be detected by laser scanning microscopy. NO release was confirmed indirectly with Griess reaction. Our functional NO550 particles enable a simple and early evaluation of inflammatory and immunological processes. Furthermore, our results on particle-based NO sensing and previous studies in targeting intestinal inflammation via (PLGA) based microspheres demonstrate that an advanced concept for visualizing intestinal inflammation is tangible. PMID- 28875101 TI - Group-13 and group-15 doping of germanane. AB - Germanane, a hydrogen-terminated graphane analogue of germanium has generated interest as a potential 2D electronic material. However, the incorporation and retention of extrinsic dopant atoms in the lattice, to tune the electronic properties, remains a significant challenge. Here, we show that the group-13 element Ga and the group-15 element As, can be successfully doped into a precursor CaGe2 phase, and remain intact in the lattice after the topotactic deintercalation, using HCl, to form GeH. After deintercalation, a maximum of 1.1% As and 2.3% Ga can be substituted into the germanium lattice. Electronic transport properties of single flakes show that incorporation of dopants leads to a reduction of resistance of more than three orders of magnitude in H2O containing atmosphere after As doping. After doping with Ga, the reduction is more than six orders of magnitude, but with significant hysteretic behavior, indicative of water-activation of dopants on the surface. Only Ga-doped germanane remains activated under vacuum, and also exhibits minimal hysteretic behavior while the sheet resistance is reduced by more than four orders of magnitude. These Ga- and As-doped germanane materials start to oxidize after one to four days in ambient atmosphere. Overall, this work demonstrates that extrinsic doping with Ga is a viable pathway towards accessing stable electronic behavior in graphane analogues of germanium. PMID- 28875102 TI - Uptake and intracellular accumulation of diamond nanoparticles - a metabolic and cytotoxic study. AB - Diamond nanoparticles, known as nanodiamonds (NDs), possess several medically significant properties. Having a tailorable and easily accessible surface gives them great potential for use in sensing and imaging applications and as a component of cell growth scaffolds. In this work we investigate in vitro interactions of human osteoblast-like SAOS-2 cells with four different groups of NDs, namely high-pressure high-temperature (HPHT) NDs (diameter 18-210 nm, oxygen terminated), photoluminescent HPHT NDs (diameter 40 nm, oxygen-terminated), detonation NDs (diameter 5 nm, H-terminated), and the same detonation NDs further oxidized by annealing at 450 degrees C. The influence of the NDs on cell viability and cell count was measured by the mitochondrial metabolic activity test and by counting cells with stained nuclei. The interaction of NDs with cells was monitored by phase contrast live-cell imaging in real time. For both types of oxygen-terminated HPHT NDs, the cell viability and the cell number remained almost the same for concentrations up to 100 ug/mL within the whole range of ND diameters tested. The uptake of hydrogen-terminated detonation NDs caused the viability and the cell number to decrease by 80-85%. The oxidation of the NDs hindered the decrease, but on day 7, a further decrease was observed. While the O terminated NDs showed mechanical obstruction of cells by agglomerates preventing cell adhesion, migration and division, the H-terminated detonation NDs exhibited rapid penetration into the cells from the beginning of the cultivation period, and also rapid cell congestion and a rapid reduction in viability. These findings are discussed with reference to relevant properties of NDs such as surface chemical bonds, zeta potential and nanoparticle types. PMID- 28875103 TI - Process-specific mechanisms of vertically oriented graphene growth in plasmas. AB - Applications of plasma-produced vertically oriented graphene nanosheets (VGNs) rely on their unique structure and morphology, which can be tuned by the process parameters to understand the growth mechanism. Here, we report on the effect of the key process parameters such as deposition temperature, discharge power and distance from plasma source to substrate on the catalyst-free growth of VGNs in microwave plasmas. A direct evidence for the initiation of vertical growth through nanoscale graphitic islands is obtained from the temperature-dependent growth rates where the activation energy is found to be as low as 0.57 eV. It is shown that the growth rate and the structural quality of the films could be enhanced by (a) increasing the substrate temperature, (b) decreasing the distance between the microwave plasma source and the substrate, and (c) increasing the discharge power. The correlation between the wetting characteristics, morphology and structural quality is established. It is also demonstrated that morphology, crystallinity, wettability and sheet resistance of the VGNs can be varied while maintaining the same sp3 content in the film. The effects of the substrate temperature and the electric field in vertical alignment of the graphene sheets are reported. These findings help to develop and optimize the process conditions to produce VGNs tailored for applications including sensing, field emission, catalysis and energy storage. PMID- 28875104 TI - Air-water interface of submerged superhydrophobic surfaces imaged by atomic force microscopy. AB - Underwater air retention of superhydrophobic hierarchically structured surfaces is of increasing interest for technical applications. Persistent air layers (the Salvinia effect) are known from biological species, for example, the floating fern Salvinia or the backswimmer Notonecta. The use of this concept opens up new possibilities for biomimetic technical applications in the fields of drag reduction, antifouling, anticorrosion and under water sensing. Current knowledge regarding the shape of the air-water interface is insufficient, although it plays a crucial role with regards to stability in terms of diffusion and dynamic conditions. Optical methods for imaging the interface have been limited to the micrometer regime. In this work, we utilized a nondynamic and nondestructive atomic force microscopy (AFM) method to image the interface of submerged superhydrophobic structures with nanometer resolution. Up to now, only the interfaces of nanobubbles (acting almost like solids) have been characterized by AFM at these dimensions. In this study, we show for the first time that it is possible to image the air-water interface of submerged hierarchically structured (micro-pillars) surfaces by AFM in contact mode. By scanning with zero resulting force applied, we were able to determine the shape of the interface and thereby the depth of the water penetrating into the underlying structures. This approach is complemented by a second method: the interface was scanned with different applied force loads and the height for zero force was determined by linear regression. These methods open new possibilities for the investigation of air retaining surfaces, specifically in terms of measuring contact area and in comparing different coatings, and thus will lead to the development of new applications. PMID- 28875105 TI - Near-infrared-responsive, superparamagnetic Au@Co nanochains. AB - This manuscript describes a new type of nanomaterial, namely superparamagnetic Au@Co nanochains with optical extinctions in the near infrared (NIR). The Au@Co nanochains were synthesized via a one-pot galvanic replacement route involving a redox-transmetalation process in aqueous medium, where Au salt was reduced to form Au shells on Co seed templates, affording hollow Au@Co nanochains. The Au shells serve not only as a protective coating for the Co nanochain cores, but also to give rise to the optical properties of these unique nanostructures. Importantly, these bifunctional, magneto-optical Au@Co nanochains combine the advantages of nanophotonics (extinction at ca. 900 nm) and nanomagnetism (superparamagnetism) and provide a potentially useful new nanoarchitecture for biomedical or catalytic applications that can benefit from both activation by light and manipulation using an external magnetic field. PMID- 28875107 TI - Transport characteristics of a silicene nanoribbon on Ag(110). AB - We present the transport characteristics of individual silicene nanoribbons (SiNRs) grown on Ag(110). By lifting up a single SiNR with a low-temperature scanning tunneling microscope tip, a nanojunction consisting of tip, SiNR and Ag is fabricated. In the differential conductance spectra of the nanojunctions fabricated by this methodology, a peak appears at the Fermi level which is not observed in the spectra measured either for the SiNRs before being lifted up or the clean Ag substrate. We discuss the origin of the peak as it relates to the SiNR. PMID- 28875106 TI - Effect of the fluorination technique on the surface-fluorination patterning of double-walled carbon nanotubes. AB - Double-walled carbon nanotubes (DWCNTs) are fluorinated using (1) fluorine F2 at 200 degrees C, (2) gaseous BrF3 at room temperature, and (3) CF4 radio-frequency plasma functionalization. These have been comparatively studied using transmission electron microscopy and infrared, Raman, X-ray photoelectron, and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. A formation of covalent C-F bonds and a considerable reduction in the intensity of radial breathing modes from the outer shells of DWCNTs are observed for all samples. Differences in the electronic state of fluorine and the C-F vibrations for three kinds of the fluorinated DWCNTs are attributed to distinct local surroundings of the attached fluorine atoms. Possible fluorine patterns realized through a certain fluorination technique are revealed from comparison of experimental NEXAFS F K-edge spectra with quantum-chemical calculations of various models. It is proposed that fluorination with F2 and BrF3 produces small fully fluorinated areas and short fluorinated chains, respectively, while the treatment with CF4 plasma results in various attached species, including single or paired fluorine atoms and -CF3 groups. The results demonstrate a possibility of different patterning of carbon surfaces through choosing the fluorination method. PMID- 28875108 TI - Three-in-one approach towards efficient organic dye-sensitized solar cells: aggregation suppression, panchromatic absorption and resonance energy transfer. AB - In the present study, protoporphyrin IX (PPIX) and squarine (SQ2) have been used in a co-sensitized dye-sensitized solar cell (DSSC) to apply their high absorption coefficients in the visible and NIR region of the solar spectrum and to probe the possibility of Forster resonance energy transfer (FRET) between the two dyes. FRET from the donor PPIX to acceptor SQ2 was observed from detailed investigation of the excited-state photophysics of the dye mixture, using time resolved fluorescence decay measurements. The electron transfer time scales from the dyes to TiO2 have also been characterized for each dye. The current-voltage (I-V) characteristics and the wavelength-dependent photocurrent measurements of the co-sensitized DSSCs reveal that FRET between the two dyes increase the photocurrent as well as the efficiency of the device. From the absorption spectra of the co-sensitized photoanodes, PPIX was observed to be efficiently acting as a co-adsorbent and to reduce the dye aggregation problem of SQ2. It has further been proven by a comparison of the device performance with a chenodeoxycholic acid (CDCA) added to a SQ2-sensitized DSSC. Apart from increasing the absorption window, the FRET-induced enhanced photocurrent and the anti-aggregating behavior of PPIX towards SQ2 are crucial points that improve the performance of the co sensitized DSSC. PMID- 28875109 TI - Collembola cuticles and the three-phase line tension. AB - The cuticles of most springtails (Collembola) are superhydrophobic, but the mechanism has not been described in detail. Previous studies have suggested that overhanging surface structures play an important role, but such structures are not a universal trait among springtails with superhydrophobic cuticles. A novel wetting experiment with a fluorescent dye revealed the extent of wetting on exposed surface structures. Using simple wetting models to describe the composite wetting of the cuticular surface structures results in underestimating the contact angles of water. Including the three-phase line tension allows for a prediction of contact angles in the observed range. The discrepancy between the contact angle predicted by simple models and those observed is especially large in the springtail Cryptopygus clavatus which changes, seasonally, from superhydrophobic to wetting without a large change in surface structure; C. clavatus does not have overhanging surface structures. This large change in observed contact angles can be explained with a modest change of the three-phase line tension. PMID- 28875110 TI - Monomorphic xanthomatous type of xanthogranuloma: a rare entity. AB - Xanthogranuloma is an uncommon tumor in the ocular adnexa. It usually presents as diffuse lid swelling with or without orbital involvement. Xanthogranulomas can be associated with systemic comorbidities. They are diagnosed by their characteristic pathological finding. They are further subclassified based on immunohistochemistry. We present two cases with lid swelling which were diagnosed to be xanthogranuloma. Our cases were special because of the unique presentation as localized monomorphic lesions. PMID- 28875111 TI - Carotid cavernous fistula masquerading as delayed suprachoroidal hemorrhage after trabeculectomy. AB - Objective: Carotid cavernous fistulae (CCFs) are abnormal communications between the cavernous sinus and the carotid arterial system. Based on the etiology, CCFs can be traumatic, spontaneous and rarely iatrogenic. We report an interesting case of new onset CCF associated with shallow choroidal detachment after trabeculectomy surgery. Method: Observational case report Result: A 69-year-old male patient presented with complain of proptosis, congestion, and gross diminution of vision in the left eye following trabeculectomy elsewhere. Delayed suprachoroidal hemorrhage was diagnosed by the primary physician and the patient was on oral steroids. On USG-B scan, choroidal detachment and a dilated superior ophthalmic vein were seen. A digital subtraction angiogram showed type D CCF. In view of nil visual prognosis, he was treated conservatively and was referred to a neuroradiologist for further management. Conclusion: CCFs have been rarely reported after intraocular surgeries. Till date, there is one case report of CCF complicating cataract surgery. Interestingly, CCFs has not been reported complicating trabeculectomy surgery. Dural CCFs although uncommon should be considered a close differential of hemorrhagic choroidal detachment, a relatively common complication following intraocular surgery. PMID- 28875112 TI - Bilateral corneal perforation due to MRSA keratitis in a crosslinking patient. AB - Introduction: The cornea may become infected and perforated after epithelium-on collagen crosslinking. Case presentation: A healthy 33-year-old male who underwent corneal collagen crosslinking in both eyes developed a purulent keratitis and bilateral corneal perforations, requiring bilateral penetrating keratoplasties. He was exposed to methicillin resistant staphylococcus aureus (MRSA) by a family member with a tracheostomy and was treated with MRSA-directed antibiotics. After prolonged recovery and treatment of his infection, he had acceptable but limited uncorrected visual acuity, with excellent corrected visual acuity. Conclusion: While epithelium-on crosslinking is commonly thought to be associated with a lower risk of postoperative infection, this case illustrates that even epithelium-on treatment may present the patient with a risk of infection. Patients in higher risk groups who are exposed to infectious disease may be more predisposed. PMID- 28875113 TI - Fully Endoscopic Minimally Invasive Transrectus Capitis Posterior Muscle Triangle Approach to the Posterolateral Condyle and Jugular Tubercle. AB - Background We evaluated a transrectus capitis posterior muscle triangle approach to the posterolateral foramen magnum, occipital condyles, jugular tubercle, and the fourth ventricle. We also assessed factors that affect the amount of bone removal required. Objective To evaluate if the proposed approach is as effective as standard open approaches to expose the lateral portion of the foramen magnum. Methods The proposed minimally invasive fully endoscopic approach was performed in 15 cadaveric specimens using 4-mm (0- and 45-degree) endoscopes. Results Using a 5-cm straight paramedian incision, the rectus capitis posterior minor and major muscles were partially removed unilaterally, providing a corridor through the muscles to reach the foramen magnum region. After meticulous soft tissue dissection, key anatomical landmarks can be identified such as the greater occipital nerve, the vertebral artery that wraps around the atlanto-occipital joint, and the bony protuberance that heralds the occipital condyle. A suboccipital craniotomy associated with the transcondylar, supracondylar or paracondylar approach is performed depending on the amount of bone removal desired to maximize the surgical view. By doing so, the jugular foramen can be exposed laterally as well as the fourth ventricle medially. Conclusion The proposed endoscopic approach can provide access through the transrectus capitis posterior muscle triangle leading directly to the occipital condyle. A stepwise approach is critical to gain a surgical corridor to the inferolateral petroclival region and the fourth ventricle. PMID- 28875114 TI - Comparative Proteomic Profiling Using Two-Dimensional Gel Electrophoresis and Identification via LC-MS/MS Reveals Novel Protein Biomarkers to Identify Aggressive Subtypes of WHO Grade I Meningioma. AB - Background Meningomas represent the most common primary intracranial tumor. The majority are benign World Health Organization (WHO) Grade I lesions, but a subset of these behave in an aggressive manner. Protein biomarkers are needed to distinguish aggressive from benign Grade I lesions. Materials and Methods Pooled protein lysates were derived from five clinically aggressive Grade I and five typically benign WHO Grade I tumors snap frozen at the time of surgery. Proteins were separated in each group using two-dimensional gel electrophoresis (2DGE) and protein spots of interest were identified using liquid chromatography-mass spectrometry (LC-MS). Potential biomarker candidates were validated using western blot assays in individual tumor samples and by tissue microarray (TMA). Results Seven candidate biomarkers were obtained from the 2DGE and validated via western blot and TMA. Biomarker validation data allowed for the creation of predictive models using binary logistical regression that correctly identified 85.9% of aggressive tumors within the larger cohort of Grade I meningioma. Conclusion Simple protein separation by 2DGE and identification of candidate biomarkers by LC-MS allowed for the identification of seven candidate biomarkers that when used in predictive models accurately distinguish aggressive from benign behavior in WHO Grade I meningioma. PMID- 28875115 TI - Advantages and Complications of Fisch Partial Mastoidotympanectomy for Tumors of the Retromandibular Fossa and Poststyloid Space. AB - Objective This study aims to characterize a single surgeon's experience with resection of tumors of the retromandibular fossa and poststyloid space utilizing the Fisch partial mastoidotympanectomy (FPMT) technique of partial temporal bone resection. Design Retrospective review. Setting Academic medical center. Participants Seven patients who underwent tumor resection with FPMT. Main Outcome Measures Complications. Results Six males and one female underwent FPMT, with ages ranging from 44 to 79 years. The facial nerve was sacrificed in six cases, no cases were converted to more extensive temporal bone resection procedures, and no postoperative hearing loss occurred. The only intraoperative complication experienced was a violation of the external auditory canal in four cases, which resulted in postoperative wound healing issues in two cases. Conclusions FPMT allows for the release of tumors of the poststyloid space and retromandibular fossa without compromise of hearing status. Preservation of external auditory canal soft tissues is challenging, and the violation is experienced relatively frequently due to shearing forces during soft tissue retraction. When encountered, robust repair of defects is encouraged to prevent further wound healing complications. PMID- 28875116 TI - Performance of Robotic Assistance for Skull Base Biopsy: A Phantom Study. AB - Objectives This study aims to evaluate the feasibility of a custom robot system guided by optical cone beam computed tomography (CBCT)-based navigation for skull base biopsy. Design An accuracy study was conducted. Setting Platform for navigation and robot-aided surgery technology. Participants Phantom skull. Main Outcome Measures The primary outcome measure was to investigate the accuracy of robot-assisted needle biopsy for skull base tumors. A 14-gauge needle was automatically inserted by the five degrees of freedom robot into the intended target, guided by optical navigation. The result was displayed on the graphical user interface after matrix transformation. Postoperative image scanning was performed, and the result was verified with image fusion. Results All 20 interventions were successfully performed. The mean deviation of the needle tip was 0.56 +/- 0.22 mm (measured by the navigation system) versus 1.73 +/- 0.60 mm (measured by image fusion) ( p < 0.05). The mean insertion depth was 52.3 mm (range: 49.7-55.2 mm). The mean angular deviations off the x-axis, y-axis, and z axis were 1.51 +/- 0.67, 2.33 +/- 1.65, and 1.47 +/- 1.16 degrees, respectively. Conclusions The experimental results show the robot system is efficient, reliable, and safe. The navigation accuracy is a significant factor in robotic procedures. PMID- 28875117 TI - Fascia Lata Free Flap Anastomosed to the Superior Trochlear System for Reconstruction of the Anterior Skull Base. AB - Objectives This study aims to introduce a novel technique for the reconstruction of the anterior skull base using a free vascularized anterolateral thigh fascia lata free flap (FLFF) anastomosed to the superior trochlear artery (STA). Methods The diameter of the STA was measured in 38 (76 sides) computed tomography angiographies (CTAs). Independently, six cadaver heads were used to measure the diameter of the supratrochlear system, and the model was applied to one of them. Results In women, the average diameter of the STA was 2.5 and 2.8 mm 2 for the right and left sides, respectively; for men, it was 3.0 and 3.2 mm 2 , respectively. In cadavers, the average diameter of both STA was 2.5 mm 2 . There was no statistical difference when comparing the right and left STA diameters between the CTA from women and men ( p < 0.208 and < 0.492, respectively). An FLFF advanced through the nose was anastomosed to the STA to reconstruct the anterior skull base. Conclusion The STA is a constant vessel with a 2.5 to 3.0 mm 2 diameter in men and women that can be used as a recipient free flap vessel. The FLFF can cover the entire skull base. This is a novel method to reconstruct the anterior skull base when local flaps are not available. PMID- 28875118 TI - Multimodality Management of Cavernous Sinus Hemangiomas-An Institutional Experience. AB - Objective Cavernous sinus hemangiomas (CSHs) are benign lesions accounting for less than 2% of the cavernous sinus tumors. They provide a formidable surgical challenge because of their vascularity and their being surrounded by critical neurovascular structures. In this study, one of the largest in available literature, we analyze our experience in the management of these unusual tumors and review the available literature. Materials This is a retrospective analysis of patients who were managed surgically (both microsurgical and Gamma knife radiosurgery [GKRS]) for CSH at our Institution from 2007 to 2015. Complete demographic, clinical-radiologic surgical records were analyzed. Follow-up data were collected from the hospital records. Results Total 23 patients were managed. Among these, 15 patients underwent microsurgery (group 1) whereas 8 underwent GKRS (group 2). Predominant clinical presentation in both the groups included headache and involvement of multiple cranial nerves. Five patients in group 1 had deteriorating vision. The volume of tumors ranged from 29 to 115 cm 3 (mean = 64.57 cm 3 ) in group 1 and from 2.1 to 11.6 cm 3 in group 2. GKRS was performed with a mean dose of 13 Gy, an average isodose line of 50% with an average coverage of 96%. In group 1, the follow-up period ranged from 6 to 62 months (mean = 29.4 months). The extraocular movement (EOM) preservation rate in our series was not favorable, as most patients presented late with large tumors and established deficits. Recurrence/residual tumor was seen in two cases. In group 2, the follow-up was 5 to 48 months. All of them showed significant reduction in size. Conclusion Both surgery and radiosurgery are highly effective in the management of CSHs. They are complementary to each other, with individual characteristics-the size and volume of the lesion-being the main factors in deciding the choice of treatment. PMID- 28875119 TI - Indocyanine Green Fluorescence to Evaluate Nasoseptal Flap Viability in Endoscopic Endonasal Cranial Base Surgery. AB - Objectives The pedicled nasoseptal flap (NSF) has dramatically reduced postoperative cerebrospinal fluid leakage following endoscopic endonasal approach (EEA) surgery. Although rare, its arterial supply may be damaged during harvest or may be preoperatively damaged for numerous reasons. Early recognition permits harvesting a contralateral flap before sacrificing its pedicle as part of the surgical exposure or use of an alternative flap. Design Technical feasibility study and case series. Setting Tertiary care university-associated medical center. Participants Five patients requiring an EEA with NSF reconstruction. Main Outcome Measures During NSF harvest, intravenous indocyanine green (IVICG) was administered, and a customized endoscopic system was used to visualize the emerging fluorescence. At the end of each case, just before final positioning of the NSF, additional IVICG was administered, and the custom endoscope was again introduced to evaluate fluorescence. Results In four patients, the entire NSF fluoresced brightly with IVICG on initial harvest and before final positioning. One patient showed heterogeneous fluorescence of the pedicle and distal parts of the NSF at both stages. All NSFs healed well without complication. Conclusion IVICG facilitates real-time evaluation NSF's arterial supply. This may provide early recognition of arterial compromise, allowing the harvest of alternate flaps or modification of surgery. PMID- 28875120 TI - Rater Reliability of the Hardy Classification for Pituitary Adenomas in the Magnetic Resonance Imaging Era. AB - Objectives The Hardy classification is used to classify pituitary tumors for clinical and research purposes. The scale was developed using lateral skull radiographs and encephalograms, and its reliability has not been evaluated in the magnetic resonance imaging (MRI) era. Design Fifty preoperative MRI scans of biopsy-proven pituitary adenomas using the sellar invasion and suprasellar extension components of the Hardy scale were reviewed. Setting This study was a cohort study set at a single institution. Participants There were six independent raters. Main Outcome Measures The main outcome measures of this study were interrater reliability, intrarater reliability, and percent agreement. Results Overall interrater reliability of both Hardy subscales on MRI was strong. However, reliability of the intermediate scores was weak, and percent agreement among raters was poor (12-16%) using the full scales. Dichotomizing the scale into clinically useful groups maintained strong interrater reliability for the sellar invasion scale and increased the percent agreement for both scales. Conclusion This study raises important questions about the reliability of the original Hardy classification. Editing the measure to a clinically relevant dichotomous scale simplifies the rating process and may be useful for preoperative tumor characterization in the MRI era. Future research studies should use the dichotomized Hardy scale (sellar invasion Grades 0-III versus Grade IV, suprasellar extension Types 0-C versus Type D). PMID- 28875121 TI - Spontaneous Cerebrospinal Fluid Rhinorrhea: Association with Body Weight and Imaging Data. AB - Objective Spontaneous cerebrospinal fluid rhinorrhea (SCSFR) might be the only clinical manifestation of idiopathic intracranial hypertension (IIH), which has been historically related to overweight. Our goal was to search for an association between SCSFR and increased body weight on the one hand and SCSFR and imaging findings suggestive of IIH on the other hand. Materials and Methods We retrospectively collected clinical and radiological data of patients operated on endoscopically for SCSFR in our institution from 1993 to 2013. Analyzed factors were body mass index (BMI), extended sphenoid sinus pneumatization on computed tomography, and empty sella and distention of the optic nerve sheath on magnetic resonance imaging. Results There were 15 patients: 8 females/7 males; mean age 50 years. Primary surgical success rate was 86.7%. Regarding body weight, 80% were overweight (BMI >= 25) versus 32% in the French general population ( p < 0.001). Among patients with SCSFR, 20% were obese (BMI >= 30) versus 15% in French individuals without SCSFR ( p = 0.483). Increased pneumatization of sphenoid sinuses was observed in 92.9 versus 27.5% in the general population ( p < 0.0001). Empty sella was found in 46.2 versus 3% in the general population ( p < 0.00001). Dilation of the optic nerve sheath was observed in 46.2 versus 15% in the general population ( p < 0.01). Conclusion We found statistically significant associations between SCSFR and overweight, increased pneumatization of sphenoid sinuses, empty sella, and dilation of optic nerve sheath, but not with obesity, which did not have any additional impact of CSF leak than did overweight. PMID- 28875122 TI - The Utility of Sentinel Node Biopsy for Sinonasal Melanoma. AB - Objective Report two positive sentinel node biopsies for sinonasal melanoma. Design Retrospective review. Setting Academic tertiary care center. Participants Patients who underwent sentinel node biopsy for sinonasal melanoma between November 1, 2014 and November 1, 2015. Main Outcome Measures Clinical course. Results Two patients were identified. Patient 1 (83M) presented with a sinonasal melanoma anterior to the left inferior turbinate and was clinically N0 neck. Lymphoscintigraphy revealed two sentinel nodes in the ipsilateral and three in the contralateral cervical basins. The left level I sentinel node was positive for melanoma and lymphadenectomy showed no additional metastases. Patient 2 (71F) presented after incomplete resection of a sinonasal melanoma of the left posterior maxillary sinus wall and was clinically N0 neck. Lymphoscintigraphy with single-photon emission computed tomography (SPECT/CT) localization revealed one sentinel node in the parapharyngeal space and another in the ipsilateral cervical basin. Metastatic melanoma was found in both nodes and completion lymphadenectomy was negative for additional disease. Both patients developed distant metastasis in less than 1 year after surgical resection but responded well to adjuvant immunomodulatory chemotherapeutic agents. Conclusion Sentinel node biopsy for sinonasal melanoma can provide crucial clinical evidence of regional metastasis prior to overt clinical signs and symptoms. This intraoperative tool has the potential to improve detection of regional metastasis and improve long-term outcomes of this aggressive malignancy. PMID- 28875123 TI - Costs and Perioperative Outcomes Associated with Open versus Endoscopic Resection of Sinonasal Malignancies with Skull Base Involvement. AB - Objective To compare financial and perioperative outcomes between endoscopic and open surgical approaches in the surgical management of sinonasal malignancies. Design Retrospective chart review. Setting Tertiary care hospital. Participants Patients undergoing surgical resection of a sinonasal malignancy from January 2000 to December 2014. Main Outcome Measures In-hospital costs, complications, and length of stay (LOS). Results Of 106 patients, 91 received open surgery (19 free flap and 72 non-free flap) and 15 were treated with purely endoscopic approaches. Free flaps had a significantly higher average cost, operative time, and LOS compared to both non-free flap ( p < 0.001, < 0.001, and < 0.01) and endoscopic ( p = 0.01, 0.04, and < 0.01) groups. There were no significant differences in average costs between endoscopic and non-free flap groups ($19,157 vs. $14,806, p = 0.20) or LOS (5.7 vs. 6.4 days, p = 0.72). Compared with the non-free flap group, the endoscopic group had a longer average operative time (8.3 vs. 5.5 hours, p < 0.01) and higher rates of cerebrospinal fluid (CSF) leak (13 vs. 0%, p = 0.01) and intensive care unit (ICU) admission (80 vs. 36%, p < 0.01). Surgical approach (open vs. endoscopic) was not a significant predictor of any financial or perioperative outcome on multivariable analysis. Conclusion Hospital costs are comparable between endoscopic and open approaches when no free tissue reconstruction is required. Longer operative times, higher CSF leak rates, and our institutional protocol necessitating ICU admission for endoscopic cases may account for the failure to demonstrate cost savings with endoscopic surgery. PMID- 28875124 TI - Tetanus attacks an old person with inadequate vaccination showing 'Risus Sardonicus' face. PMID- 28875125 TI - Ultrasound diagnosis of fractures in mass casualty incidents. AB - The role of point-of-care ultrasound in mass casualty incidents (MCIs) is still evolving. Occasionally, hospitals can be destroyed by disasters resulting in large number of trauma patients. CAVEAT and FASTER ultrasound protocols, which are used in MCIs, included extremity ultrasound examination as part of them. The literature supports the use of ultrasound in diagnosing extremity fractures both in hospitals and MCIs. The most recent systematic review which was reported by Douma-den Hamer et al in 2016 showed that the pooled ultrasound sensitivity and specificity for detecting distal forearm fractures was 97% and 95% respectively. Nevertheless, majority of these studies were in children and they had very high heterogeneity. The portability, safety, repeatability, and cost-effectiveness of ultrasound are great advantages when treating multiply injured patients in MCIs. Its potential in managing fractures in MCIs needs to be further defined. The operator should master the technique, understand its limitations, and most importantly correlate the sonographic findings with the clinical ones to be useful. This editorial critically reviews the literature on this topic, describes its principles and techniques, and includes the author's personal learned lessons so that trauma surgeons will be encouraged to use ultrasound to diagnose fractures in their own clinical practice. PMID- 28875126 TI - Postoperative deep shoulder infections following rotator cuff repair. AB - Rotator cuff repair (RCR) is one of the most commonly performed surgical procedures in orthopaedic surgery. The reported incidence of deep soft-tissue infections after RCR ranges between 0.3% and 1.9%. Deep shoulder infection after RCR appears uncommon, but the actual incidence may be higher as many cases may go unreported. Clinical presentation may include increasing shoulder pain and stiffness, high temperature, local erythema, swelling, warmth, and fibrinous exudate. Generalized fatigue and signs of sepsis may be present in severe cases. Varying clinical presentation coupled with a low index of suspicion may result in delayed diagnosis. Laboratory findings include high erythrocyte sedimentation rate and C-reactive protein level, and, rarely, abnormal peripheral blood leucocyte count. Aspiration of glenohumeral joint synovial fluid with analysis of cell count, gram staining and culture should be performed in all patients suspected with deep shoulder infection after RCR. The most commonly isolated pathogens are Propionibacterium acnes, Staphylococcus epidermidis, and Staphylococcus aureus. Management of a deep soft-tissue infection of the shoulder after RCR involves surgical debridement with lavage and long-term intravenous antibiotic treatment based on the pathogen identified. Although deep shoulder infection after RCR is usually successfully treated, complications of this condition can be devastating. Prolonged course of intravenous antibiotic treatment, extensive soft-tissue destruction and adhesions may result in substantially diminished functional outcomes. PMID- 28875127 TI - Synthesis of evidence for the treatment of intersection syndrome. AB - Intersection syndrome is a rare sports overuse injury occurring through friction at the intersection of the first and second compartment of the forearm. Differential diagnosis must be carefully made, especially from De Quervain tendonsynovitis. Clinical examination provides with the necessary information for diagnosis, still magnetic resonance imaging scans and ultrasonography may assist in diagnosis. Treatment consists mainly of rest, use of a thumb spica splint, analgetic and oral nonsteroidal anti-inflammatory drugs and after 2-3 wk progressive stretching and muscle strengthening. Should symptoms persist beyond this time, corticosteroid injections adjacent to the site of injury may be useful. In refractory cases, surgical intervention is warranted. PMID- 28875128 TI - Ponseti method treatment of neglected idiopathic clubfoot: Preliminary results of a multi-center study in Nigeria. AB - AIM: To evaluate the effectiveness of the Ponseti method for initial correction of neglected clubfoot cases in multiple centers throughout Nigeria. METHODS: Patient charts were reviewed through the International Clubfoot Registry for 12 different Ponseti clubfoot treatment centers and 328 clubfeet (225 patients) met inclusion criteria. All patients were treated by the method described by Ponseti including manipulation and casting with percutaneous Achilles tenotomy as needed. RESULTS: A painless plantigrade foot was obtained in 255 feet (78%) without the need for extensive soft tissue release and/or bony procedures. CONCLUSION: We conclude that the Ponseti method is a safe, effective and low-cost treatment for initial correction of neglected idiopathic clubfoot presenting after walking age. Long-term follow-up will be required to assess outcomes. PMID- 28875130 TI - Ipsilateral femur and tibia fractures in pediatric patients: A systematic review. AB - AIM: To better understand how pediatric floating knee injuries are managed after the wide spread use of new orthopaedic technology. METHODS: We searched EMBASE, COCHRANE and MEDLINE computerized literature databases from the earliest date available in the databases to February 2017 using the following search term including variants and pleural counterparts: Pediatric floating knee. All studies were thoroughly reviewed by multiple authors. Reference lists from all articles were scrutinized to identify any additional studies of interest. A final database of individual patients was assembled from the literature. Univariate and multivariate statistical tests were applied to the assembled database to assess differences in outcomes. RESULTS: The English language literature contains series with a total of 97 pediatric patients who sustained floating knee injuries. Patients averaged 9.3 years of age and were mostly male (73). Approximately 25% of the fractures were open injuries, more tibia (27) than femur (10). Over 75% of the fractures of both the tibia and the femur involved the diaphysis. More than half (52) of the patients were treated non-operatively for both fractures. As a sequela of the injury 32 (33%) patients were left with a limb length discrepancy, 24 (25%) patients had lengthening of the injured limb at follow up, while 8 (8%) had shortening of the affected limb. Infection developed in 9 patients and 3 had premature physeal closure. Younger patients were more likely to be treated non operatively (P < 0.001) and patients treated with operative intervention had statistically significant shorter hospital length of stays (P = 0.001). CONCLUSION: Given the predominance of non-operative management in published studies, the available literature is not clinically relevant since the popularization of internal fixation for pediatric long-bone fractures. PMID- 28875131 TI - Femoral positioning influences ipsi-and contralateral anterior cruciate ligament rupture following its reconstruction: Systematic review and meta-analysis. AB - AIM: To systematically review the incidence of ipsilateral graft re-rupture and contralateral anterior cruciate ligament (ACL) rupture following its reconstruction, with special attention to the femoral drilling technique. METHODS: Systematic review and meta-analysis of high-level prospective studies searched in MEDLINE database following PRISMA statement. The rate of ipsilateral graft re-rupture and contralateral rupture in patients submitted to either transtibial (TT) technique (isometric) or anteromedial (AM) technique (anatomic) was compared. RESULTS: Eleven studies met the criteria and were included in final analysis. Reconstructions using the AM technique had a similar chance of contralateral ACL rupture when compared to the chance of ipsilateral graft failure (OR = 1.08, P = 0.746). In reconstructions using TT technique, the chance of contralateral ACL rupture was approximately 1.5 times higher than ipsilateral graft failure (OR = 1.49, P = 0.048). Incidence of contralateral lesions were similar among the techniques TT (7.4%) and AM (7.0%) (P = 0.963), but a trend could be noticed with a lower incidence of lesion in the ipsilateral limb when using the TT technique (4.9%) compared to the AM technique (6.5%) (P = 0.081). CONCLUSION: ACL reconstruction by TT technique leads to lower incidence of graft re-injury than contralateral ACL lesion. There is no difference between the chance of re-injury after AM technique and the chance of contralateral ACL lesion (native ligament) with either technique. PMID- 28875129 TI - Functional outcomes of traumatic and non-traumatic rotator cuff tears after arthroscopic repair. AB - AIM: To compare the functional outcomes of traumatic and non-traumatic rotator cuff tears after arthroscopic repair. METHODS: Eighty-seven patients with rotator cuff tears following arthroscopic treatment were divided into traumatic and non traumatic tear groups. Postoperative muscle strength and outcomes using the modified University of California, Los Angeles score were evaluated. Sex, age, affected limb and dominant limb were correlated between groups. Muscle strength of the repaired and unaffected shoulders was compared. Rotator cuff injury size was measured. RESULTS: Of the 87 patients who underwent rotator cuff repairs, 35 had traumatic tears and 52 had non-traumatic tears. In patients with non traumatic tears, the average age was 59 years, 74.5% were female, 96.1% were right-hand dominant and 92.3% had their dominant shoulder affected. Patients with traumatic tears were 59.5 years old on average, 51.4% were female, 91.4% were right-hand dominant and 88.5% had their dominant shoulder affected. No difference existed in the mean modified University of California, Los Angeles score between patients with traumatic tears (33.7) compared with those with non-traumatic tears (32.8). No strength differences were observed between groups: The strength difference between the non-affected and affected sides was 1.21 kg in the non traumatic group and 1.39 kg in the traumatic group (P = 0.576), while the strength ratio between the non-affected/affected sides was 0.805 in the non traumatic group and 0.729 in the traumatic group (P = 0.224). CONCLUSION: The functional results of traumatic rotator cuff repairs are similar to non-traumatic tears. Both outcomes are satisfactory. PMID- 28875132 TI - Open wound management of esophagocutaneous fistula in unstable cervical spine after corpectomy and multilevel laminectomy: A case report and review of the literature. AB - A 67-year-old female patient developed an esophagocutaneous fistula 4 mo after C4 and C5 partial corpectomy. Plain radiograph and computed tomography (CT) scan of cervical spine showed inferior screws pullout with plate migration that caused the esophageal perforation. Management included removal of anterior hardware, revision C4-5 corpectomy, iliac crest strut autograft and halo orthosis immobilization. The fistula was treated using antibiotics and a 10-french gauge rubber tube for daily irrigation and Penrose drain. At 3 mo, the esophagocutaneous fistula healed and the patient resumed oral feeding. Six months follow-up CT scan showed sound fusion with graft incorporation. At two-year follow-up, patient denied any neck pain or dysphagia. This case report presents a successful outcome of a conservative open wound management without attempted repair. The importance of this case report is to highlight this treatment method that may be considered in such a rare complication particularly if surgical repair failed. PMID- 28875133 TI - Bennett's fracture associated with fracture of Trapezium - A rare injury of first carpo-metacarpal joint. AB - Association of fracture of trapezium with Bennett's fracture is very rare and makes reduction and stabilisation more difficult. We are reporting a rare case of Bennett's fracture with fracture of the trapezium and subluxation of the carpo metacarpal joint (CMC) joint. The patient was a 47-year-old school teacher who fell from his motorbike on his outstretched right dominant hand. Radiographs and computed tomography showed fracture of the trapezium with subluxation of the CMC joint, associated with Bennett's fracture. Open reduction and internal fixation was carried out. Trapezium was reduced first and secured with a 2 mm diameter screw. Bennett's fracture was then reduced and fixed with two per-cutaneously placed Kirchner's wires. CMC was stabilised with per-cutaneous Kirchner's wires. Latest follow up at 12 mo showed a healed fracture with good reduction of the CMC joint. Clinically patient had no pain and normal extension, abduction and opposition of the thumb. QuickDASH score was 3.9/100. Thus, fracture of trapezium associated with a Bennett's fracture is a rare injury and if ignored it may lead to poor results. This injury is more challenging to manage than an isolated Bennett's fracture as anatomical reduction of the trapezium with reduction of the first CMC is needed. Fracture of the trapezium should be fixed first as this will provide a stable base for reduction of the Bennett's fracture. PMID- 28875134 TI - The conquest of errors. PMID- 28875135 TI - Clinical and biological analysis in graftless maxillary sinus lift. AB - Maxillary sinus lift for dental implant installation is a well-known and versatile technique; new techniques are presented based on the physiology of intrasinus bone repair. The aim of this review was to determine the status of graftless maxillary sinus lift and analyze its foundations and results. A search was conducted of the literature between 1995 and 2015 in the Medline, ScienceDirect, and SciELO databases using the keywords "maxillary sinus lift," "blood clot," "graftless maxillary sinus augmentation," and "dental implant placement." Ten articles were selected for our analysis of this technique and its results. Despite the limited information, cases that were followed for at least six months and up to four years had a 90% success rate. Published techniques included a lateral window, elevation of the sinus membrane, drilling and dental implant installation, descent of the membrane with variations in the installation of the lateral wall access and suturing. The physiology behind this new bone formation response and the results of the present research were also discussed. We concluded that this is a promising and viable technique under certain inclusion criteria. PMID- 28875136 TI - Maximal strength and endurance scores of the tongue, lip, and cheek in healthy, normal Koreans. AB - OBJECTIVES: The purpose of this study was to establish normative data for healthy Korean adults by measuring the maximal strength and endurance scores of the tongue, lip, and cheek, and to examine correlations between these measurements. MATERIALS AND METHODS: This study included 120 subjects that were divided into three groups according to age: young (20-39 years), middle-aged (40-59 years), and older (over 60 years); and by gender. Measurements were taken using the Iowa Oral Performance Instrument (IOPI). RESULTS: The mean maximal tongue strengths were as follows: young men (46.7+/-10.2 kPa) and women (32.1+/-7.9 kPa), middle aged men (40.9+/-9.3 kPa) and women (36.9+/-8.6 kPa), and older men (35.2+/-9.0 kPa) and women (34.5+/-6.9 kPa). The mean tongue endurance scores were: young men (28.8+/-12.6 seconds) and women (20.8+/-13.5 seconds), middle-aged men (17.0+/ 8.5 seconds) and women (15.3+/-5.2 seconds), and older men (15.8+/-6.7 seconds) and women (17.9+/-8.1 seconds). The mean maximal lip strengths were: young men (11.6+/-3.0 kPa) and women (11.4+/-3.8 kPa), middle-aged men (11.4+/-4.2 kPa) and women (11.1+/-5.1 kPa), and older men (14.5+/-3.9 kPa) and women (11.7+/-2.6 kPa). The mean lip endurance scores were: young men (41.1+/-23.9 seconds) and women (22.4+/-21.7 seconds), middle-aged men (24.3+/-10.3 seconds) and women (30.5+/-13.4 seconds), and older men (24.9+/-11.0 seconds) and women (12.8+/-7.6 seconds). The mean maximal cheek strengths were: young men (24.5+/-4.6 kPa) and women (20.5+/-4.3 kPa), middle-aged men (25.2+/-6.4 kPa) and women (21.2+/-5.5 kPa), and older men (22.4+/-5.3 kPa) and women (18.0+/-4.8 kPa). The mean cheek endurance scores were: young men (47.8+/-24.4 seconds) and women (43.9+/-25.0 seconds), middle-aged men (27.3+/-11.3 seconds) and women (20.0+/-14.6 seconds), and older men (21.7+/-14.5 seconds) and women (17.2+/-11.4 seconds). CONCLUSION: The data collected in this study will provide an important database of standardized measurements for maximal strength and endurance scores of the tongue, lip and cheek in healthy, normal Koreans. PMID- 28875137 TI - Risk factor analysis of additional administration of sedative agent and patient dissatisfaction in intravenous conscious sedation using midazolam for third molar extraction. AB - OBJECTIVES: The primary purpose of this study was to investigate the factors related with additional administration of sedative agent during intravenous conscious sedation (IVS) using midazolam (MDZ). The secondary purpose was to analyze the factors affecting patient satisfaction. MATERIALS AND METHODS: Clinical data for 124 patients who had undergone surgical extraction of mandibular third molar under IVS using MDZ were retrospectively investigated in this case-control study. The initial dose of MDZ was determined by body mass index (BMI) and weight. In the case of insufficient sedation at the beginning of surgery, additional doses were injected. During surgery, peripheral oxygen saturation, bispectral index score (BIS), heart rate, and blood pressure were monitored and recorded. The predictor variables were sex, age, BMI, sleeping time ratio, dental anxiety, Pederson scale, and initial dose of MDZ. The outcome variables were additional administration of MDZ, observer's assessment of alertness/sedation, intraoperative amnesia, and patient satisfaction. Descriptive statistics were computed, and the P-value was set at 0.05. RESULTS: Most patients had an adequate level of sedation with only the initial dose of MDZ and were satisfied with the treatment under sedation; however, 19 patients needed additional administration, and 13 patients were unsatisfied. In multivariable logistic analysis, lower age (odds ratio [OR], 0.825; P=0.005) and higher dental anxiety (OR, 5.744; P=0.003) were related to additional administration; lower intraoperative amnesia (OR, 0.228; P=0.002) and higher BIS right before MDZ administration (OR, 1.379; P=0.029) had relevance to patient dissatisfaction. CONCLUSION: The preoperative consideration of age and dental anxiety is necessary for appropriate dose determination of MDZ in the minor oral surgery under IVS. The amnesia about the procedure affects patient satisfaction positively. PMID- 28875138 TI - New method for an evaluation of the esthetical improvements resulting from a mandibular angle reduction. AB - OBJECTIVES: This paper proposes Han's ratio as an objective and quantitative comparative result obtained from pre and postoperative data in patients with a mandibular angle reduction. MATERIALS AND METHODS: Thirty patients, 12 men and 18 women, who visited the Department of Oral and Maxillofacial Surgery with the chief complaints of skeletal mandibular prognathism and prominent mandibular angle were selected. The subjects were classified into 3 groups according to the types of surgical procedures involved. Group A consisted of patients who underwent mandibular angle resection and mandibular setback. Group B was comprised of patients with mandibular angle resection, mandibular setback and genioplasty. Group C consisted of patients with mandibular angle resection, mandibular setback, Le Fort I osteotomy, and genioplasty. The landmarks placed in pre and postoperative frontal photographs were used to obtain the Han's ratio in each group. The Han's ratios were compared pre- and postoperation and according to the surgical techniques applied. RESULTS: Of the 3 groups who had undergone a mandibular angle resection, all showed a statistically significant increase in Han's ratio. On the other hand, there was no statistically significant difference based on the surgical techniques used. CONCLUSION: The ratio of the lateral lower face proposed in this study is a potential indicator of postoperative esthetic enhancement in mandibular angle reduction surgery. PMID- 28875139 TI - A comparative study of quality of life of families with children born with cleft lip and/or palate before and after surgical treatment. AB - OBJECTIVES: The aim of this study was to compare the quality of life (QoL) of parents/caregivers of children with cleft lip and/or palate before and after surgical repair of an orofacial cleft. MATERIALS AND METHODS: Families of subjects who required either primary or secondary orofacial cleft repair who satisfied the inclusion criteria were recruited. A preoperative and postoperative health-related QoL questionnaire, the 'Impact on Family Scale' (IOFS), was applied in order to detect the subjectively perceived QoL in the affected family before and after surgical intervention. The mean pre- and postoperative total scores were compared using paired t-test. Pre- and postoperative mean scores were also compared across the 5 domains of the IOFS. RESULTS: The proportion of families whose QoL was affected before surgery was 95.7%. The domains with the greatest impact preoperatively were the financial domain and social domains. Families having children with bilateral cleft lip showed QoL effects mostly in the social domain and 'impact on sibling' domain. Postoperatively, the mean total QoL score was significantly lower than the mean preoperative QoL score, indicating significant improvement in QoL (P<0.001). The mean postoperative QoL score was also significantly lower than the mean preoperative QoL score in all domains. Only 3.2% of the families reported affectation of their QoL after surgery. The domains of mastery (61.3%) with a mean of 7.4+/-1.8 and finance (45.1%) with a mean score of 7.2+/-1.6 were those showing the greatest postoperative impact. The proportion of families whose QoL was affected by orofacial cleft was markedly different after treatment (95.7% preoperative and 3.2% postoperative). CONCLUSION: Caring for children with orofacial clefts significantly reduces the QoL of parents/caregivers in all domains. However, surgical intervention significantly improves the QoL of the parents/caregivers of these children. PMID- 28875141 TI - Intramuscular hemangioma in buccal cheek: a case report. AB - Hemangioma is the most common benign tumor of a vascular origin, and is characterized by the abnormal proliferation of blood vessels. Intramuscular hemangioma (IMH) usually involves the skeletal muscles of the trunk or limbs, but rarely occurs in the head and neck region. This case report presents a patient with IMH showing multiple phleboliths in the buccal cheek. A 13-year-old boy was referred for the evaluation and management of painful swelling of the left cheek that had gradually increased in size over a 6 year duration. The examination revealed a palpable firm mass. Reddish-blue buccal mucosa color was observed with an aciniform shape. Preoperative magnetic resonance imaging (MRI) showed a vascular tumor in the left side adjacent to the buccinator and depressor orbicularis oris muscles. Surgical resection under general anesthesia was performed via the intraoral approach. The mass and phleboliths were extracted successfully. A histopathological examination confirmed the diagnosis of IMH. In conclusion, clinicians should be aware of the possibility of IMH in cases of a palpable mass with multiple nodules deep within the muscle in the buccal cheek. Among the several diagnostic tools, MRI provides essential information on the extent and surrounding anatomy of IMH. PMID- 28875140 TI - Recording natural head position using an accelerometer and reconstruction from computed tomographic images. AB - OBJECTIVES: The concept of natural head position (NHP) was first introduced by Broca in 1862, and was described as a person's stable physiologic position "when a man is standing and his visual axis is horizontal." NHP has been used routinely for clinical examination; however, a patient's head position is random during cone-beam computed tomography (CBCT) acquisition. To solve this problem, we developed an accelerometer to record patients' NHP and reproduce them for CBCT images. In this study, we also tested the accuracy and reproducibility of our accelerometer. MATERIALS AND METHODS: A total of 15 subjects participated in this study. We invented an accelerometer that measured acceleration on three axes and that could record roll and pitch calculations. Recorded roll and pitch data for each NHP were applied to a reoriented virtual image using three-dimensional (3D) imaging software. The data between the 3D models and the clinical photos were statistically analyzed side by side. Paired t-tests were used to statistically analyze the measurements. RESULTS: The average difference in the angles between the clinical photograph and the 3D model was 0.04 degrees for roll and 0.29 degrees for pitch. The paired ttests for the roll data (P=0.781) and the pitch data (P=0.169) showed no significant difference between the clinical photographs and the 3D model (P>0.05). CONCLUSION: By overcoming the limitations of previous NHP-recording techniques, our new method can accurately record patient NHP in a time-efficient manner. Our method can also accurately transfer the NHP to a 3D virtual model. PMID- 28875142 TI - Van der Woude syndrome presenting as a single median lower lip pit with associated dental, orofacial and limb deformities: a rare case report. AB - Although it is a rare developmental malformation, van der Woude syndrome is the most common form of syndromic orofacial clefting, accounting for approximately 2% of all cleft cases. The lower lip pits with or without a cleft lip or palate is characteristic of the syndrome. Findings, such as hypodontia, limb deformities, popliteal webs, ankylogossia, ankyloblepheron, and genitourinary and cardiovascular abnormalities, are rarely associated with the syndrome. This paper reports a rare case of van der Woude syndrome in a 10-year-old male patient with a single median lower lip pit and a repaired bilateral cleft lip and cleft palate that were associated with microstomia, hypodontia, and clubbing of the left foot with syndactyly of the second to fifth lesser toes of the same foot. PMID- 28875143 TI - A case of bisphosphonate-related osteonecrosis of the jaw with a particularly unfavourable course: a case report. AB - Bisphosphonates are drugs used to treat osteoclast-mediated bone resorption, including osteoporosis, Paget disease, multiple myeloma, cancer-related osteolysis, and malignant hypercalcemia. The use of these drugs has increased in recent years as have their complications, especially bisphosphonate-related osteonecrosis of the jaw (BRONJ), which more frequently affects the mandible. Here we report a case of BRONJ with a particularly unfavorable course due to cervical inflammation that developed into necrotizing fasciitis, followed by multiorgan involvement leading to septic shock and death. PMID- 28875144 TI - Lateral approach for maxillary sinus membrane elevation without bone materials in maxillary mucous retention cyst with immediate or delayed implant rehabilitation: case reports. AB - This case series study demonstrates the possibility of successful implant rehabilitation without bone augmentation in the atrophic posterior maxilla with cystic lesion in the sinus. Sinus lift without bone graft using the lateral approach was performed. In one patient, the cyst was aspirated and simultaneous implantation under local anesthesia was performed, whereas the other cyst was removed under general anesthesia, and the sinus membrane was elevated in a second process, followed by implantation. In both cases, tapered 11.5-mm-long implants were utilized. With all of the implants, good stability and appropriate bone height were achieved. The mean bone level gain was 5.73 mm; adequate bone augmentation around the implants was shown, the sinus floor was moved apically, and the cyst was no longer radiologically detected. Completion of all of the treatments required an average of 12.5 months. The present study showed that sufficient bone formation and stable implantation in a maxilla of insufficient bone volume are possible through sinus lift without bone materials. The results serve to demonstrate, moreover, that surgical treatment of mucous retention cyst can facilitate rehabilitation. These techniques can reduce the risk of complications related to bone grafts, save money, and successfully treat antral cyst. PMID- 28875145 TI - Actinomyces: a deceptive infection of oral cavity. AB - Actinomycosis is an infrequent chronic infection regarded as the most misdiagnosed disease by experienced clinicians. The Office of Rare Diseases at the National Institute of Health has also listed this disease as a "rare disease." This article presents a case report of actinomycosis of the alveolus with unusual clinical features but a successful resolution. It also states the importance of biopsy of deceptive inflammatory lesions that do not respond or recur after conventional treatment modalities. PMID- 28875146 TI - Importance of serial changes in biomarkers in idiopathic pulmonary fibrosis. AB - The clinical significance of serial changes in serum biomarkers in patients with idiopathic pulmonary fibrosis (IPF) remains to be established. This retrospective study was conducted to clarify the associations of serial changes in serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) with changes in physiological indices and overall mortality in IPF. The study subjects were 75 patients with IPF. The 6 month change in serum KL-6 was significantly correlated with changes in the percentage of the predicted forced vital capacity (FVC % pred) and the percentage of the predicted diffusing capacity of the lung for carbon monoxide (% DLCO), while the 6 month change in serum SP-D was correlated only with % DLCO. During the mean follow-up period of 647 days, 22 (29.3%) patients died. An increase in serum KL-6 over a 6 month period was a significant predictor of mortality even after adjustment for %FVC, % DLCO and serum KL-6 at the baseline (hazard ratio 1.10 per 100 U.mL-1, 95% CI 1.01-1.18, p=0.03), whereas the 6 month increase in serum SP-D was not significant. Serial measurements of serum KL-6 may provide additional prognostic information compared to that provided by physiological parameters in patients with IPF. PMID- 28875147 TI - Protected sampling is preferable in bronchoscopic studies of the airway microbiome. AB - The aim was to evaluate susceptibility of oropharyngeal contamination with various bronchoscopic sampling techniques. 67 patients with obstructive lung disease and 58 control subjects underwent bronchoscopy with small-volume lavage (SVL) through the working channel, protected bronchoalveolar lavage (PBAL) and bilateral protected specimen brush (PSB) sampling. Subjects also provided an oral wash (OW) sample, and negative control samples were gathered for each bronchoscopy procedure. DNA encoding bacterial 16S ribosomal RNA was sequenced and bioinformatically processed to cluster into operational taxonomic units (OTU), assign taxonomy and obtain measures of diversity. The proportion of Proteobacteria increased, whereas Firmicutes diminished in the order OW, SVL, PBAL, PSB (p<0.01). The alpha-diversity decreased in the same order (p<0.01). Also, beta-diversity varied by sampling method (p<0.01), and visualisation of principal coordinates analyses indicated that differences in diversity were smaller between OW and SVL and OW and PBAL samples than for OW and the PSB samples. The order of sampling (left versus right first) did not influence alpha- or beta-diversity for PSB samples. Studies of the airway microbiota need to address the potential for oropharyngeal contamination, and protected sampling might represent an acceptable measure to minimise this problem. PMID- 28875148 TI - Long-Term Bond Strength of Two Benzalkonium Chloride-Modified Adhesive Systems to Eroded Dentin. AB - This study investigated the effect of benzalkonium chloride (BAC) modification of two adhesive systems on long-term bond strength to normal and artificially eroded dentin. A total of 128 extracted human molars were sectioned and the buccal and oral surfaces of each molar were ground until the dentin. One half was left untreated (normal dentin) while the other half underwent artificial erosion. Resin composite was bonded to the buccal or oral surface following treatment with Adper Scotchbond 1XT or OptiBond FL without or with 1% BAC incorporation. Shear bond strength (SBS) was measured after 24 h (100% humidity, 37 degrees C) or 1 year (tap water, 37 degrees C). SBS results were statistically analyzed (alpha = 0.05). SBS was significantly lower to artificially eroded dentin than to normal dentin (p < 0.001). Storage for 1 year had no effect on SBS to normal dentin but led to a significant decrease in SBS to artificially eroded dentin (p < 0.001). BAC incorporation decreased the 24 h SBS to normal dentin (p = 0.018), increased the 24 h SBS to eroded dentin (p = 0.001), and had no effect on the 1-year SBS for either substrate. Consequently, BAC incorporation did not improve bond durability. PMID- 28875149 TI - Resistance to Chronic Toxoplasma gondii Infection Induced by a DNA Vaccine Expressing GRA16. AB - Toxoplasma gondii can infect all warm-blooded animals including human beings. T. gondii dense granule protein 16 (TgGRA16) as a crucial virulence factor could modulate the host gene expression. Here, a DNA vaccine expressing TgGRA16 was constructed to explore the protective efficacy against T. gondii infection in Kunming mice. The immune responses induced by pVAX-GRA16 were also evaluated. Mice immunized with pVAX-GRA16 could elicit higher levels of specific IgG antibody and strong cellular response compared to those in controls. The DNA vaccination significantly increased the levels of cytokines (IFN-gamma, IL-2, IL 4, and IL-10) and the percentages of CD4+ and CD8+ T cells in mice. After lethal challenge, mice immunized with pVAX-GRA16 (8.4 +/- 0.78 days) did not show a significant longer survival time than that in controls (7.1 +/- 0.30 days) (p > 0.05). However, in chronic toxoplasmosis model (administration of 10 brain cysts of PRU strain orally), numbers of tissue cysts in mice immunized with pVAX-GRA16 were significantly reduced compared to those in controls (p < 0.05) and the rate of reduction could reach 43.89%. The results indicated that the TgGRA16 would be a promising vaccine candidate for further development of effective epitope-based vaccines against chronic T. gondii infection in mice. PMID- 28875150 TI - Transpseudarthrosis Osteotomy with Interbody Fusion for Kyphotic Spinal Pseudarthrosis in Ankylosing Spondylitis by a Single Posterior Approach: A Retrospective Study and a Brief Relevant Literature Review. AB - OBJECTIVE: To explore the safety and efficacy of transpseudarthrosis osteotomy with interbody fusion in the treatment of Ankylosing Spondylitis (AS) patients with kyphotic spinal pseudarthrosis by a single posterior approach. METHODS: Twelve consecutive patients with spinal pseudarthrosis underwent transpseudarthrosis osteotomy and interbody fusion with a polyetheretherketone (PEEK) cage by a single posterior approach. The operative time, intraoperative blood loss, and complications were recorded. Radiographic and clinical results were assessed preoperatively and at the final follow-up. RESULTS: The average operative time was 201.9 min and the mean blood loss was 817.5 ml. The visual analogue scale (VAS) improved significantly from 6.7 preoperatively to 1.1 at the final follow-up. The average correction of the segmental kyphosis at the level of the pseudarthrosis was 22.3 degrees . Bony fusion was achieved in all patients, and there was no obvious loss of correction at follow-up. CONCLUSION: Transpseudarthrosis osteotomy at the level of the pseudarthrosis can be safely performed and surgical repair of pseudarthrosis with interbody fusion by a single posterior approach was feasible. PMID- 28875151 TI - Molecular Characterization, Structural Modeling, and Evaluation of Antimicrobial Activity of Basrai Thaumatin-Like Protein against Fungal Infection. AB - A thaumatin-like protein gene from Basrai banana was cloned and expressed in Escherichia coli. Amplified gene product was cloned into pTZ57R/T vector and subcloned into expression vector pET22b(+) and resulting pET22b-basrai TLP construct was introduced into E. coli BL21. Maximum protein expression was obtained at 0.7 mM IPTG concentration after 6 hours at 37 degrees C. Western blot analysis showed the presence of approximately 20 kDa protein in induced cells. Basrai antifungal TLP was tried as pharmacological agent against fungal disease. Independently Basrai antifungal protein and amphotericin B exhibited their antifungal activity against A. fumigatus; however combined effect of both agents maximized activity against the pathogen. Docking studies were performed to evaluate the antimicrobial potential of TLP against A. fumigatus by probing binding pattern of antifungal protein with plasma membrane ergosterol of targeted fungal strain. Ice crystallization primarily damages frozen food items; however addition of antifreeze proteins limits the growth of ice crystal in frozen foods. The potential of Basrai TLP protein, as an antifreezing agent, in controlling the ice crystal formation in frozen yogurt was also studied. The scope of this study ranges from cost effective production of pharmaceutics to antifreezing and food preserving agent as well as other real life applications. PMID- 28875152 TI - Artificial Cardiac Muscle with or without the Use of Scaffolds. AB - During the past several decades, major advances and improvements now promote better treatment options for cardiovascular diseases. However, these diseases still remain the single leading cause of death worldwide. The rapid development of cardiac tissue engineering has provided the opportunity to potentially restore the contractile function and retain the pumping feature of injured hearts. This conception of cardiac tissue engineering can enable researchers to produce autologous and functional biomaterials which represents a promising technique to benefit patients with cardiovascular diseases. Such an approach will ultimately reshape existing heart transplantation protocols. Notable efforts are accelerating the development of cardiac tissue engineering, particularly to create larger tissue with enhanced functionality. Decellularized scaffolds, polymer synthetics fibrous matrix, and natural materials are used to build robust cardiac tissue scaffolds to imitate the morphological and physiological patterns of natural tissue. This ultimately helps cells to implant properly to obtain endogenous biological capacity. However, newer designs such as the hydrogel scaffold-free matrix can increase the applicability of artificial tissue to engineering strategies. In this review, we summarize all the methods to produce artificial cardiac tissue using scaffold and scaffold-free technology, their advantages and disadvantages, and their relevance to clinical practice. PMID- 28875153 TI - Three Months of Progressive High-Load Versus Traditional Low-Load Strength Training Among Patients With Rotator Cuff Tendinopathy: Primary Results From the Double-Blind Randomized Controlled RoCTEx Trial. AB - BACKGROUND: Progressive high-load exercise (PHLE) has led to positive clinical results in patients with patellar and Achilles tendinopathy. However, its effects on rotator cuff tendinopathy still need to be investigated. PURPOSE: To assess the clinical effects of PHLE versus low-load exercise (LLE) among patients with rotator cuff tendinopathy. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients with rotator cuff tendinopathy were recruited and randomized to 12 weeks of PHLE or LLE, stratified for concomitant administration of corticosteroid injection. The primary outcome measure was change from baseline to 12 weeks in the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, assessed in the intention-to-treat population. RESULTS: A total of 100 patients were randomized to PHLE (n = 49) or LLE (n = 51). Mean changes in the DASH questionnaire were 7.11 points (95% CI, 3.07-11.16) and 8.39 points (95% CI, 4.35-12.44) in the PHLE and LLE groups, respectively; this corresponded to a statistically nonsignificant adjusted mean group difference of -1.37 points (95% CI, -6.72 to 3.99; P = .61). Similar nonsignificant results were seen for pain, range of motion, and strength. However, a significant interaction effect was found between the 2 groups and concomitant corticosteroid use (P = .028), with the largest positive change in DASH in favor of PHLE for the group receiving concomitant corticosteroid. CONCLUSION: The study results showed no superior benefit from PHLE over traditional LLE among patients with rotator cuff tendinopathy. Further investigation of the possible interaction between exercise type and corticosteroid injection is needed to establish optimal and potentially synergistic combinations of these 2 factors. REGISTRATION: NCT01984203 (ClinicalTrials.gov identifier): Rotator Cuff Tendinopathy Exercise Trial (RoCTEx). PMID- 28875154 TI - Structural and Anatomic Restoration of the Anterior Cruciate Ligament Is Associated With Less Cartilage Damage 1 Year After Surgery: Healing Ligament Properties Affect Cartilage Damage. AB - BACKGROUND: Abnormal joint motion has been linked to joint arthrosis after anterior cruciate ligament (ACL) reconstruction. However, the relationships between the graft properties (ie, structural and anatomic) and extent of posttraumatic osteoarthritis are not well defined. HYPOTHESES: (1) The structural (tensile) and anatomic (area and alignment) properties of the reconstructed graft or repaired ACL correlate with the total cartilage lesion area 1 year after ACL surgery, and (2) side-to-side differences in anterior-posterior (AP) knee laxity correlate with the total cartilage lesion area 1 year postoperatively. STUDY DESIGN: Controlled laboratory study. METHODS: Sixteen minipigs underwent unilateral ACL transection and were randomly treated with ACL reconstruction or bridge-enhanced ACL repair. The tensile properties, cross-sectional area, and multiplanar alignment of the healing ACL or graft, AP knee laxity, and cartilage lesion areas were assessed 1 year after surgery. RESULTS: In the reconstructed group, the normalized graft yield and maximum failure loads, cross-sectional area, sagittal and coronal elevation angles, and side-to-side differences in AP knee laxity at 60 degrees of flexion were associated with the total cartilage lesion area 1 year after surgery (R2 > 0.5, P < .04). In the repaired group, normalized ACL yield load, linear stiffness, cross-sectional area, and the sagittal and coronal elevation angles were associated with the total cartilage lesion area (R2 > 0.5, P < .05). Smaller cartilage lesion areas were observed in the surgically treated knees when the structural and anatomic properties of the ligament or graft and AP laxity values were closer to those of the contralateral ACL-intact knee. Reconstructed grafts had a significantly larger normalized cross sectional area and sagittal elevation angle (more vertical) when compared with repaired ACLs (P < .02). CONCLUSION: The tensile properties, cross-sectional area, and multiplanar alignment of the healing ACLs or grafts and AP knee laxity in reconstructed knees were associated with the extent of tibiofemoral cartilage damage after ACL surgery. CLINICAL RELEVANCE: These data highlight the need for novel ACL injury treatments that can restore the structural and anatomic properties of the torn ACL to those of the native ACL in an effort to minimize the risk of early-onset posttraumatic osteoarthritis. PMID- 28875155 TI - Risk of Tuberculosis Infection and Disease for Health Care Workers: An Updated Meta-Analysis. AB - BACKGROUND: Tuberculosis (TB) remains a major challenge to global health. Healthcare workers (HCWs) appear to be at increased risk of TB compared with the general population, despite efforts to scale up infection control and reduce nosocomial TB transmission. This review aims to provide an updated estimate of the occupational risk of latent TB infection (LTBI) and active TB among HCWs compared with the general population. METHODS: A systematic review was performed to identify studies published over the last 10 years reporting TB prevalence or incidence among HCWs and a control group. Pooled effect estimates were calculated to determine the risk of infection. RESULTS: Twenty-one studies met the inclusion criteria, providing data on 30961 HCWs across 16 countries. Prevalence of LTBI among HCWs was 37%, and mean incidence rate of active TB was 97/100000 per year. Compared with the general population, the risk of LTBI was greater for HCWs (odds ratio [OR], 2.27; 95% confidence interval [CI], 1.61-3.20), and the incidence rate ratio for active TB was 2.94 (95% CI, 1.67-5.19). Comparing tuberculin skin test and interferon-gamma release assay, OR for LTBI was found to be 1.72 and 5.61, respectively. CONCLUSIONS: The overall risk of both LTBI and TB to HCWs continues to be significantly higher than that of the general population, consistent with previous findings. This study highlights the continuing need for improvements in infection control and HCW screening programs. PMID- 28875156 TI - Asporin stably expressed in the surface layer of mandibular condylar cartilage and augmented in the deeper layer with age. AB - Mandibular condylar cartilage (MCC) exhibits dual roles both articular cartilage and growth center. Of many growth factors, TGF-beta has been implicated in the growth of articular cartilage including MCC. Recently, Asporin, decoy to TGF beta, was discovered and it blocks TGF-beta signaling. Asporin is expressed in a variety of tissues including osteoarthritic articular cartilage, though there was no report of Asporin expression in MCC. In the present study, we investigated the temporal and spatial expression of Asporin in MCC. Gene expression profile of MCC and epiphyseal cartilage in tibia of 5 weeks old ICR mice were firstly compared with microarray analysis using the laser capture microdissected samples. Variance of gene expression was further confirmed by real-time RT-PCR and immunohistochemical staining at 1,3,10, and 20 weeks old. TGF-beta and its signaling molecule, phosphorylated Smad-2/3 (p-Smad2/3), were also examined by immunohistochemical staining. Microarray analysis revealed that Asporin was highly expressed in MCC. Real-time RT-PCR analysis confirmed that the fibrous layer of MCC exhibited stable higher Asporin expression at any time points as compared to epiphyseal cartilage. This was also observed in immunohistochemical staining. Deeper layer in MCC augmented Asporin expression with age. Whereas, TGF beta was stably highly observed in the layer. The fibrous layer of MCC exhibited weak staining of p-Smad2/3, though the proliferating layer of MCC was strongly stained as compared to epiphyseal cartilage of tibia at early time point. Consistent with the increase of Asporin expression in the deeper layer of MCC, the intensity of p-Smad-2/3 staining was decreased with age. In conclusion, we discovered that Asporin was stably expressed at the fibrous layer of MCC, which makes it possible to manage both articular cartilage and growth center at the same time. PMID- 28875157 TI - Sex hormones and quantitative ultrasound parameters at the heel in men and women from the general population. AB - PURPOSE/INTRODUCTION: The present study investigates potential associations between liquid chromatography-mass spectrometry (LC-MS) measured sex hormones, dehydroepiandrosterone sulphate, sex hormone-binding globulin (SHBG) and bone ultrasound parameters at the heel in men and women from the general population. METHODS: Data from 502 women and 425 men from the population-based Study of Health in Pomerania (SHIP-TREND) were used. Cross-sectional associations of sex hormones including testosterone (TT), calculated free testosterone (FT), dehydroepiandrosterone sulphate (DHEAS), androstenedione (ASD), estrone (E1) and SHBG with quantitative ultrasound (QUS) parameters at the heel, including broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI) were examined by analysis of variance (ANOVA) and multivariable quantile regression models. RESULTS: Multivariable regression analysis showed a sex specific inverse association of DHEAS with SI in men (Beta per SI unit = - 3.08, standard error (SE) = 0.88), but not in women (Beta = - 0.01, SE = 2.09). Furthermore, FT was positively associated with BUA in men (Beta per BUA unit = 29.0, SE = 10.1). None of the other sex hormones (ASD, E1) or SHBG was associated with QUS parameters after multivariable adjustment. CONCLUSIONS: This cross sectional population-based study revealed independent associations of DHEAS and FT with QUS parameters in men, suggesting a potential influence on male bone metabolism. The predictive role of DHEAS and FT as a marker for osteoporosis in men warrants further investigation in clinical trials and large-scale observational studies. PMID- 28875158 TI - Thirty days of spaceflight does not alter murine calvariae structure despite increased Sost expression. AB - Previously our laboratory documented increases in calvaria bone volume and thickness in mice exposed to 15 days of spaceflight aboard the NASA Shuttle mission STS-131. However, the tissues were not processed for gene expression studies to determine what bone formation pathways might contribute to these structural adaptations. Therefore, this study was designed to investigate both the structural and molecular changes in mice calvariae after a longer duration of spaceflight. The primary purpose was to determine the calvaria bone volume and thickness of mice exposed to 30 days of spaceflight using micro-computed tomography for comparison with our previous findings. Because sclerostin, the secreted glycoprotein of the Sost gene, is a potent inhibitor of bone formation, our second aim was to quantify Sost mRNA expression using quantitative PCR. Calvariae were obtained from six mice aboard the Russian 30-day Bion-M1 biosatellite and seven ground controls. In mice exposed to 30 days of spaceflight, calvaria bone structure was not significantly different from that of their controls (bone volume was about 5% lower in spaceflight mice, p = 0.534). However, Sost mRNA expression was 16-fold (16.4 +/- 0.4, p < 0.001) greater in the spaceflight group than that in the ground control group. Therefore, bone formation may have been suppressed in mice exposed to 30 days of spaceflight. Genetic responsiveness (e.g. sex or strain of animals) or in-flight environmental conditions other than microgravity (e.g. pCO2 levels) may have elicited different bone adaptations in STS-131 and Bion-M1 mice. Although structural results were not significant, this study provides biochemical evidence that calvaria mechanotransduction pathways may be altered during spaceflight, which could reflect vascular and interstitial fluid adaptations in non-weight bearing bones. Future studies are warranted to elucidate the processes that mediate these effects and the factors responsible for discordant calvaria bone adaptations between STS-131 and Bion-M1 mice. PMID- 28875159 TI - Myxoma Virus Optimizes Cisplatin for the Treatment of Ovarian Cancer In Vitro and in a Syngeneic Murine Dissemination Model. AB - A therapeutic approach to improve treatment outcome of ovarian cancer (OC) in patients is urgently needed. Myxoma virus (MYXV) is a candidate oncolytic virus that infects to eliminate OC cells. We found that in vitro MYXV treatment enhances cisplatin or gemcitabine treatment by allowing lower doses than the corresponding IC50 calculated for primary OC cells. MYXV also affected OC patient ascites-associated CD14+ myeloid cells, one of the most abundant immunological components of the OC tumor environment; without causing cell death, MYXV infection reduces the ability of these cells to secrete cytokines such as IL-10 that are signatures of the immunosuppressive tumor environment. We found that pretreatment with replication-competent but not replication-defective MYXV sensitized tumor cells to later cisplatin treatments to drastically improve survival in a murine syngeneic OC dissemination model. We thus conclude that infection with replication-competent MYXV before cisplatin treatment markedly enhances the therapeutic benefit of chemotherapy. Treatment with replication competent MYXV followed by cisplatin potentiated splenocyte activation and IFNgamma expression, possibly by T cells, when splenocytes from treated mice were stimulated with tumor cell antigen ex vivo. The impact on immune responses in the tumor environment may thus contribute to the enhanced antitumor activity of combinatorial MYXV-cisplatin treatment. PMID- 28875160 TI - Design of ultrathin Pt-Mo-Ni nanowire catalysts for ethanol electrooxidation. AB - Developing cost-effective, active, and durable electrocatalysts is one of the most important issues for the commercialization of fuel cells. Ultrathin Pt-Mo-Ni nanowires (NWs) with a diameter of ~2.5 nm and lengths of up to several micrometers were synthesized via a H2-assisted solution route (HASR). This catalyst was designed on the basis of the following three points: (i) ultrathin NWs with high numbers of surface atoms can increase the atomic efficiency of Pt and thus decrease the catalyst cost; (ii) the incorporation of Ni can isolate Pt atoms on the surface and produce surface defects, leading to high catalytic activity (the unique structure and superior activity were confirmed by spherical aberration-corrected electron microscopy measurements and ethanol oxidation tests, respectively); and (iii) the incorporation of Mo can stabilize both Ni and Pt atoms, leading to high catalytic stability, which was confirmed by experiments and density functional theory calculations. Furthermore, the developed HASR strategy can be extended to synthesize a series of Pt-Mo-M (M = Fe, Co, Mn, Ru, etc.) NWs. These multimetallic NWs would open up new opportunities for practical fuel cell applications. PMID- 28875161 TI - Crystal structures of a ZIP zinc transporter reveal a binuclear metal center in the transport pathway. AB - Zrt/Irt-like proteins (ZIPs) play fundamental roles in metal metabolism/homeostasis and are broadly involved in numerous physiological and pathological processes. The lack of high-resolution structure of the ZIPs hinders understanding of the metal transport mechanism. We report two crystal structures of a prokaryotic ZIP in lipidic cubic phase with bound metal substrates (Cd2+ at 2.7 A and Zn2+ at 2.4 A). The structures revealed a novel 3+2+3TM architecture and an inward-open conformation occluded at the extracellular side. Two metal ions were trapped halfway through the membrane, unexpectedly forming a binuclear metal center. The Zn2+-substituted structure suggested asymmetric functions of the two metal-binding sites and also revealed a route for zinc release. Mapping of disease-causing mutations, structure-guided mutagenesis, and cell-based zinc transport assay demonstrated the crucial role of the binuclear metal center for human ZIP4. A metal transport mechanism for the ZIP from Bordetella bronchiseptica was proposed, which is likely applicable to other ZIPs. PMID- 28875162 TI - Antiferroic electronic structure in the nonmagnetic superconducting state of the iron-based superconductors. AB - A major problem in the field of high-transition temperature (Tc) superconductivity is the identification of the electronic instabilities near superconductivity. It is known that the iron-based superconductors exhibit antiferromagnetic order, which competes with the superconductivity. However, in the nonmagnetic state, there are many aspects of the electronic instabilities that remain unclarified, as represented by the orbital instability and several in plane anisotropic physical properties. We report a new aspect of the electronic state of the optimally doped iron-based superconductors by using high-energy resolution angle-resolved photoemission spectroscopy. We find spectral evidence for the folded electronic structure suggestive of an antiferroic electronic instability, coexisting with the superconductivity in the nonmagnetic state of Ba1-x K x Fe2As2. We further establish a phase diagram showing that the antiferroic electronic structure persists in a large portion of the nonmagnetic phase covering the superconducting dome. These results motivate consideration of a key unknown electronic instability, which is necessary for the achievement of high-Tc superconductivity in the iron-based superconductors. PMID- 28875163 TI - Functional vascularized lung grafts for lung bioengineering. AB - End-stage lung disease is the third leading cause of death worldwide, accounting for 400,000 deaths per year in the United States alone. To reduce the morbidity and mortality associated with lung disease, new therapeutic strategies aimed at promoting lung repair and increasing the number of donor lungs available for transplantation are being explored. Because of the extreme complexity of this organ, previous attempts at bioengineering functional lungs from fully decellularized or synthetic scaffolds lacking functional vasculature have been largely unsuccessful. An intact vascular network is critical not only for maintaining the blood-gas barrier and allowing for proper graft function but also for supporting the regenerative cells. We therefore developed an airway-specific approach to removing the pulmonary epithelium, while maintaining the viability and function of the vascular endothelium, using a rat model. The resulting vascularized lung grafts supported the attachment and growth of human adult pulmonary cells and stem cell-derived lung-specified epithelial cells. We propose that de-epithelialization of the lung with preservation of intact vasculature could facilitate cell therapy of pulmonary epithelium and enable bioengineering of functional lungs for transplantation. PMID- 28875164 TI - Increasing drought in Jordan: Climate change and cascading Syrian land-use impacts on reducing transboundary flow. AB - In countries where severe drought is an anticipated effect of climate change and in those that heavily depend on upstream nations for fresh water, the effect of drier conditions and consequent changes in the transboundary streamflow regime induced by anthropogenic interventions and disasters leads to uncertainty in regional water security. As a case in point, we analyze Jordan's surface water resources and agricultural water demand through 2100, considering the combined impacts of climate change and land-use change driven by the Syrian conflict. We use bias-corrected regional climate simulations as input to high-resolution hydrologic models to assess three drought types: meteorological (rainfall decrease), agricultural (soil moisture deficit), and hydrologic (streamflow decline) under future scenarios. The historical baseline period (1981-2010) is compared to the future (2011-2100), divided into three 30-year periods. Comparing the baseline period to 2070-2100, average temperature increases by 4.5 degrees C, rainfall decreases by 30%, and multiple drought-type occurrences increase from ~8 in 30 years to ~25 in 30 years. There is a significant increase in the contemporaneous occurrence of multiple drought types along with an 80% increase in simultaneous warm and dry events. Watershed simulations of future transboundary Yarmouk-Jordan River flow from Syria show that Jordan would receive 51 to 75% less Yarmouk water compared to historical flow. Recovery of Syrian irrigated agriculture to pre-conflict conditions would produce twice the decline in transboundary flow as that due to climate change. In Jordan, the confluence of limited water supply, future drought, and transboundary hydrologic impacts of land use severely challenges achieving freshwater sustainability. PMID- 28875166 TI - Observation of prethermalization in long-range interacting spin chains. AB - Although statistical mechanics describes thermal equilibrium states, these states may or may not emerge dynamically for a subsystem of an isolated quantum many body system. For instance, quantum systems that are near-integrable usually fail to thermalize in an experimentally realistic time scale, and instead relax to quasi-stationary prethermal states that can be described by statistical mechanics, when approximately conserved quantities are included in a generalized Gibbs ensemble (GGE). We experimentally study the relaxation dynamics of a chain of up to 22 spins evolving under a long-range transverse-field Ising Hamiltonian following a sudden quench. For sufficiently long-range interactions, the system relaxes to a new type of prethermal state that retains a strong memory of the initial conditions. However, the prethermal state in this case cannot be described by a standard GGE; it rather arises from an emergent double-well potential felt by the spin excitations. This result shows that prethermalization occurs in a broader context than previously thought, and reveals new challenges for a generic understanding of the thermalization of quantum systems, particularly in the presence of long-range interactions. PMID- 28875165 TI - Identifying key intermediates generated in situ from Cu(II) salt-catalyzed C-H functionalization of aromatic amines under illumination. AB - Copper compounds involved in photocatalysis have recently spurred considerable interest for their novel transformations. However, mechanistic investigations are still in infancy. We find a new type of reaction, that is, Cu(II) salt-catalyzed C-H functionalization of aromatic amines triggered by visible light irradiation. An array of mechanistic observations, including high-resolution mass spectrometry, ultraviolet-visible absorption spectrum, electron spin resonance, x ray absorption near-edge structure, and density functional theory calculation, have identified the key intermediates generated in situ in the transformation. Integration of single-electron transfer, singlet oxygen (1O2), and new absorption species, intermediate I and intermediate II formed in situ from Cu(II) salts and substrate amines or imines, respectively, is responsible for the N-H and C-H bond activation of secondary amines to couple with nucleophiles in air, thereby leading to the formation of quinoline, indolo[3,2-c]quinoline, beta-amino acid, and 1,4-dihydropyridine derivatives in moderate to good yields under visible light irradiation at room temperature. PMID- 28875167 TI - Tunable electroresistance and electro-optic effects of transparent molecular ferroelectrics. AB - Recent progress in molecular ferroelectrics (MOFEs) has been overshadowed by the lack of high-quality thin films for device integration. We report a water-based air-processable technique to prepare large-area MOFE thin films, controlled by supersaturation growth at the liquid-air interface under a temperature gradient and external water partial pressure. We used this technique to fabricate ImClO4 thin films and found a large, tunable room temperature electroresistance: a 20 fold resistance variation upon polarization switching. The as-grown films are transparent and consist of a bamboo-like structure of (2,[Formula: see text],0) and (1,0,[Formula: see text]) structural variants of R3m symmetry with a reversible polarization of 6.7 MUC/cm2. The resulting ferroelectric domain structure leads to a reversible electromechanical response of d33 = 38.8 pm/V. Polarization switching results in a change of the refractive index, n, of single domains, [Formula: see text]. The remarkable combination of these characteristics renders MOFEs a prime candidate material for new nanoelectronic devices. The information that we present in this work will open a new area of MOFE thin-film technologies. PMID- 28875168 TI - Ceftazidime-avibactam has potent sterilizing activity against highly drug resistant tuberculosis. AB - There are currently many patients with multidrug-resistant and extensively drug resistant tuberculosis. Ongoing transmission of the highly drug-resistant strains and high mortality despite treatment remain problematic. The current strategy of drug discovery and development takes up to a decade to bring a new drug to clinical use. We embarked on a strategy to screen all antibiotics in current use and examined them for use in tuberculosis. We found that ceftazidime-avibactam, which is already used in the clinic for multidrug-resistant Gram-negative bacillary infections, markedly killed rapidly growing, intracellular, and semidormant Mycobacterium tuberculosis in the hollow fiber system model. Moreover, multidrug-resistant and extensively drug-resistant clinical isolates demonstrated good ceftazidime-avibactam susceptibility profiles and were inhibited by clinically achievable concentrations. Resistance arose because of mutations in the transpeptidase domain of the penicillin-binding protein PonA1, suggesting that the drug kills M. tuberculosis bacilli via interference with cell wall remodeling. We identified concentrations (exposure targets) for optimal effect in tuberculosis, which we used with susceptibility results in computer aided clinical trial simulations to identify doses for immediate clinical use as salvage therapy for adults and young children. Moreover, this work provides a roadmap for efficient and timely evaluation of antibiotics and optimization of clinically relevant dosing regimens. PMID- 28875169 TI - A polyaromatic nanocapsule as a sucrose receptor in water. AB - Selective recognition of saccharides by artificial receptors in water is a challenging goal due to their strong hydrophilicities and complex molecular structures with subtle regio- and stereochemical differences. We report the selective and efficient encapsulation of d-sucrose within a coordination-driven molecular capsule from natural saccharide mixtures in water (~100% selectivity, >85% yield, and ~103 M-1 binding constant). Unlike previous artificial receptors and natural receptors that rely on multiple hydrogen-bonding interactions, theoretical calculations and control experiments indicate that the observed unique selectivity arises from multiple CH-pi interactions between the sucrose hydrocarbon backbone and the shape-complementary polyaromatic cavity (~1 nm in diameter) of the capsule. PMID- 28875170 TI - Photoinduced nanobubble-driven superfast diffusion of nanoparticles imaged by 4D electron microscopy. AB - Dynamics of active or propulsive Brownian particles in nonequilibrium status have recently attracted great interest in many fields including artificial micro/nanoscopic motors and biological entities. Understanding of their dynamics can provide insight into the statistical properties of physical and biological systems far from equilibrium. We report the translational dynamics of photon activated gold nanoparticles (NPs) in water imaged by liquid-cell four dimensional electron microscopy (4D-EM) with high spatiotemporal resolution. Under excitation of femtosecond laser pulses, we observed that those NPs exhibit superfast diffusive translation with a diffusion constant four to five orders of magnitude greater than that in the absence of laser excitation. The measured diffusion constant follows a power-law dependence on the laser fluence and a linear increase with the laser repetition rate, respectively. This superfast diffusion of the NPs is induced by a strong random driving force arising from the photoinduced steam nanobubbles (NBs) near the NP surface. In contrast, the NPs exhibit a superfast ballistic translation at a short time scale down to nanoseconds. Combining with a physical model simulation, this study reveals a photoinduced NB propulsion mechanism for propulsive motion, providing physical insights into better design of light-activated artificial micro/nanomotors. The liquid-cell 4D-EM also provides the potential of studying other numerical dynamical behaviors in their native environments. PMID- 28875171 TI - Perovskite nanocomposites as effective CO2-splitting agents in a cyclic redox scheme. AB - We report iron-containing mixed-oxide nanocomposites as highly effective redox materials for thermochemical CO2 splitting and methane partial oxidation in a cyclic redox scheme, where methane was introduced as an oxygen "sink" to promote the reduction of the redox materials followed by reoxidation through CO2 splitting. Up to 96% syngas selectivity in the methane partial oxidation step and close to complete conversion of CO2 to CO in the CO2-splitting step were achieved at 900 degrees to 980 degrees C with good redox stability. The productivity and production rate of CO in the CO2-splitting step were about seven times higher than those in state-of-the-art solar-thermal CO2-splitting processes, which are carried out at significantly higher temperatures. The proposed approach can potentially be applied for acetic acid synthesis with up to 84% reduction in CO2 emission when compared to state-of-the-art processes. PMID- 28875172 TI - The biodiversity cost of carbon sequestration in tropical savanna. AB - Tropical savannas have been increasingly viewed as an opportunity for carbon sequestration through fire suppression and afforestation, but insufficient attention has been given to the consequences for biodiversity. To evaluate the biodiversity costs of increasing carbon sequestration, we quantified changes in ecosystem carbon stocks and the associated changes in communities of plants and ants resulting from fire suppression in savannas of the Brazilian Cerrado, a global biodiversity hotspot. Fire suppression resulted in increased carbon stocks of 1.2 Mg ha-1 year-1 since 1986 but was associated with acute species loss. In sites fully encroached by forest, plant species richness declined by 27%, and ant richness declined by 35%. Richness of savanna specialists, the species most at risk of local extinction due to forest encroachment, declined by 67% for plants and 86% for ants. This loss highlights the important role of fire in maintaining biodiversity in tropical savannas, a role that is not reflected in current policies of fire suppression throughout the Brazilian Cerrado. In tropical grasslands and savannas throughout the tropics, carbon mitigation programs that promote forest cover cannot be assumed to provide net benefits for conservation. PMID- 28875173 TI - Enhanced photovoltaic performance and stability with a new type of hollow 3D perovskite {en}FASnI3. AB - Perovskite solar cells have revolutionized the fabrication of solution processable solar cells. The presence of lead in the devices makes this technology less attractive, and alternative metals in perovskites are being researched as suitable alternatives. We demonstrate a new type of tin-based perovskite absorber that incorporates both ethylenediammonium (en) and formamidinium (FA), forming new materials of the type {en}FASnI3. The three dimensional ASnI3 structure is stable only with methylammonium, FA, and Cs cations, and the bandgap can be tuned with solid solutions, such as ASnI3-x Br x . We show that en can serve as a new A cation capable of achieving marked increases in the bandgap without the need for solid solutions. The en introduces a new bandgap tuning mechanism that arises from massive Schottky style defects. In addition, incorporation of the en cation in the structure markedly increases the air stability and improves the photoelectric properties of the tin-based perovskite absorbers. Our best-performing {en}FASnI3 solar cell has the highest efficiency of 7.14%, which is achieved for a lead-free perovskite cell, and retains 96% of its initial efficiency after aging over 1000 hours with encapsulation. Our results introduce a new approach for improving the performance and stability of tin-based, lead-free perovskite solar cells. PMID- 28875174 TI - Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity. AB - We recently developed base editing, the programmable conversion of target C:G base pairs to T:A without inducing double-stranded DNA breaks (DSBs) or requiring homology-directed repair using engineered fusions of Cas9 variants and cytidine deaminases. Over the past year, the third-generation base editor (BE3) and related technologies have been successfully used by many researchers in a wide range of organisms. The product distribution of base editing-the frequency with which the target C:G is converted to mixtures of undesired by-products, along with the desired T:A product-varies in a target site-dependent manner. We characterize determinants of base editing outcomes in human cells and establish that the formation of undesired products is dependent on uracil N-glycosylase (UNG) and is more likely to occur at target sites containing only a single C within the base editing activity window. We engineered CDA1-BE3 and AID-BE3, which use cytidine deaminase homologs that increase base editing efficiency for some sequences. On the basis of these observations, we engineered fourth generation base editors (BE4 and SaBE4) that increase the efficiency of C:G to T:A base editing by approximately 50%, while halving the frequency of undesired by-products compared to BE3. Fusing BE3, BE4, SaBE3, or SaBE4 to Gam, a bacteriophage Mu protein that binds DSBs greatly reduces indel formation during base editing, in most cases to below 1.5%, and further improves product purity. BE4, SaBE4, BE4-Gam, and SaBE4-Gam represent the state of the art in C:G-to-T:A base editing, and we recommend their use in future efforts. PMID- 28875176 TI - Lactoferricin Peptides Increase Macrophages' Capacity To Kill Mycobacterium avium. AB - Mycobacterial infections cause a significant burden of disease and death worldwide. Their treatment is long, toxic, costly, and increasingly prone to failure due to bacterial resistance to currently available antibiotics. New therapeutic options are thus clearly needed. Antimicrobial peptides represent an important source of new antimicrobial molecules, both for their direct activity and for their immunomodulatory potential. We have previously reported that a short version of the bovine antimicrobial peptide lactoferricin with amino acids 17 to 30 (LFcin17-30), along with its variants obtained by specific amino acid substitutions, killed Mycobacterium avium in broth culture. In the present work, those peptides were tested against M. avium living inside its natural host cell, the macrophage. We found that the peptides increased the antimicrobial action of the conventional antibiotic ethambutol inside macrophages. Moreover, the d enantiomer of the lactoferricin peptide (d-LFcin17-30) was more stable and induced significant killing of intracellular mycobacteria by itself. Interestingly, d-LFcin17-30 did not localize to M. avium-harboring phagosomes but induced the production of proinflammatory cytokines and increased the formation of lysosomes and autophagosome-like vesicles. These results lead us to conclude that d-LFcin17-30 primes macrophages for intracellular microbial digestion through phagosomal maturation and/or autophagy, culminating in mycobacterial killing. IMPORTANCE The genus Mycobacterium comprises several pathogenic species, including M. tuberculosis, M. leprae, M. avium, etc. Infections caused by these bacteria are particularly difficult to treat due to their intrinsic impermeability, low growth rate, and intracellular localization. Antimicrobial peptides are increasingly acknowledged as potential treatment tools, as they have a high spectrum of activity, low tendency to induce bacterial resistance, and immunomodulatory properties. In this study, we show that peptides derived from bovine lactoferricin (LFcin) improve the antimicrobial activity of ethambutol against Mycobacterium avium growing inside macrophages. Moreover, the d enantiomer of a short version of lactoferricin containing amino acids 17 to 30 (d LFcin17-30) causes intramacrophagic death of M. avium by increasing the formation of lysosomes and autophagosomes. This work opens the way to the use of lactoferricin-derived peptides to treat infections caused by mycobacteria and highlights important modulatory effects of d-FLcin17-30 on macrophages, which may be useful under other conditions in which macrophage activation is needed. PMID- 28875177 TI - The Potential Therapeutic Agent Mepacrine Protects Caco-2 Cells against Clostridium perfringens Enterotoxin Action. AB - Clostridium perfringens enterotoxin (CPE) causes the diarrhea associated with a common bacterial food poisoning and many antibiotic-associated diarrhea cases. The severity of some CPE-mediated disease cases warrants the development of potential therapeutics. A previous study showed that the presence of mepacrine inhibited CPE-induced electrophysiology effects in artificial lipid bilayers lacking CPE receptors. However, that study did not assess whether mepacrine inactivates CPE or, instead, inhibits a step in CPE action. Furthermore, CPE action in host cells is complex, involving the toxin binding to receptors, receptor-bound CPE oligomerizing into a prepore on the membrane surface, and beta hairpins in the CPE prepore inserting into the membrane to form a pore that induces cell death. Therefore, the current study evaluated the ability of mepacrine to protect cells from CPE. This drug was found to reduce CPE-induced cytotoxicity in Caco-2 cells. This protection did not involve mepacrine inactivation of CPE, indicating that mepacrine affects one or more steps in CPE action. Western blotting then demonstrated that mepacrine decreases CPE pore levels in Caco-2 cells. This mepacrine-induced reduction in CPE pore levels did not involve CPE binding inhibition but rather an increase in CPE monomer dissociation due to mepacrine interactions with Caco-2 membranes. In addition, mepacrine was also shown to inhibit CPE pores when already present in Caco-2 cells. These in vitro studies, which identified two mepacrine-sensitive steps in CPE-induced cytotoxicity, add support to further testing of the therapeutic potential of mepacrine against CPE-mediated disease. IMPORTANCEClostridium perfringens enterotoxin (CPE) causes the gastrointestinal (GI) symptoms of a common bacterial food poisoning and several nonfoodborne human GI diseases. A previous study showed that, via an undetermined mechanism, the presence of mepacrine blocks CPE-induced electrophysiologic activity in artificial membranes. The current study now demonstrates that mepacrine also inhibits CPE-induced cytotoxicity in human enterocyte-like Caco-2 cells and that mepacrine does not directly inactivate CPE. Instead, this drug reduces both CPE pore formation and CPE pore activity in Caco-2 cells. These results suggest mepacrine as a therapeutic candidate for treating CPE-mediated GI diseases. PMID- 28875179 TI - Ultrasound Diagnoses of an Iliac Artery Aneurysm during the Second Trimester of Preganancy. PMID- 28875178 TI - Genetic Validation of Leishmania donovani Lysyl-tRNA Synthetase Shows that It Is Indispensable for Parasite Growth and Infectivity. AB - Leishmania donovani is a protozoan parasite that causes visceral leishmaniasis. Increasing resistance and severe side effects of existing drugs have led to the need to identify new chemotherapeutic targets. Aminoacyl-tRNA synthetases (aaRSs) are ubiquitous and are required for protein synthesis. aaRSs are known drug targets for bacterial and fungal pathogens. Here, we have characterized and evaluated the essentiality of L. donovani lysyl-tRNA synthetase (LdLysRS). Two different coding sequences for lysyl-tRNA synthetases are annotated in the Leishmania genome database. LdLysRS-1 (LdBPK_150270.1), located on chromosome 15, is closer to apicomplexans and eukaryotes, whereas LdLysRS-2 (LdBPK_300130.1), present on chromosome 30, is closer to bacteria. In the present study, we have characterized LdLysRS-1. Recombinant LdLysRS-1 displayed aminoacylation activity, and the protein localized to the cytosol. The LdLysRS-1 heterozygous mutants had a restrictive growth phenotype and attenuated infectivity. LdLysRS-1 appears to be an essential gene, as a chromosomal knockout of LdLysRS-1 could be generated when the gene was provided on a rescuing plasmid. Cladosporin, a fungal secondary metabolite and a known inhibitor of LysRS, was more potent against promastigotes (50% inhibitory concentration [IC50], 4.19 uM) and intracellular amastigotes (IC50, 1.09 uM) than were isomers of cladosporin (3-epi-isocladosporin and isocladosporin). These compounds exhibited low toxicity to mammalian cells. The specificity of inhibition of parasite growth caused by these inhibitors was further assessed using LdLysRS-1 heterozygous mutant strains and rescue mutant promastigotes. These inhibitors inhibited the aminoacylation activity of recombinant LdLysRS. Our data provide a framework for the development of a new class of drugs against this parasite. IMPORTANCE Aminoacyl-tRNA synthetases are housekeeping enzymes essential for protein translation, providing charged tRNAs for the proper construction of peptide chains. These enzymes provide raw materials for protein translation and also ensure fidelity of translation. L. donovani is a protozoan parasite that causes visceral leishmaniasis. It is a continuously proliferating parasite that depends heavily on efficient protein translation. Lysyl-tRNA synthetase is one of the aaRSs which charges lysine to its cognate tRNA. Two different coding sequences for lysyl-tRNA synthetases (LdLysRS) are present in this parasite. LdLysRS-1 is closer to apicomplexans and eukaryotes, whereas LdLysRS-2 is closer to bacteria. Here, we have characterized LdLysRS-1 of L. donovani. LdLysRS-1 appears to be an essential gene, as the chromosomal null mutants did not survive. The heterozygous mutants showed slower growth kinetics and exhibited attenuated virulence. This study also provides a platform to explore LdLysRS-1 as a potential drug target. PMID- 28875175 TI - Importance of Resolving Fungal Nomenclature: the Case of Multiple Pathogenic Species in the Cryptococcus Genus. AB - Cryptococcosis is a major fungal disease caused by members of the Cryptococcus gattii and Cryptococcus neoformans species complexes. After more than 15 years of molecular genetic and phenotypic studies and much debate, a proposal for a taxonomic revision was made. The two varieties within C. neoformans were raised to species level, and the same was done for five genotypes within C. gattii. In a recent perspective (K. J. Kwon-Chung et al., mSphere 2:e00357-16, 2017, https://doi.org/10.1128/mSphere.00357-16), it was argued that this taxonomic proposal was premature and without consensus in the community. Although the authors of the perspective recognized the existence of genetic diversity, they preferred the use of the informal nomenclature "C. neoformans species complex" and "C. gattii species complex." Here we highlight the advantage of recognizing these seven species, as ignoring these species will impede deciphering further biologically and clinically relevant differences between them, which may in turn delay future clinical advances. PMID- 28875180 TI - Lung Ultrasound for the Detection of Pneumothorax Might Be Misleading in Patients Following Lung Transplantation. PMID- 28875181 TI - Rational design of NIR-emitting iridium(iii) complexes for multimodal phosphorescence imaging of mitochondria under two-photon excitation. AB - A series of NIR-emitting iridium(iii) complexes were developed for multimodal phosphorescence imaging (NIR imaging, phosphorescence lifetime imaging and time gated imaging) of mitochondria in living cells, 3D multicellular spheroids (MTCCs) and hippocampus slice under two-photon excitation. PMID- 28875182 TI - Synthesis and characterization of Lewis base stabilized mono- and di-organo aluminum radicals. AB - Two cyclic (alkyl)(amino)carbene (cAAC) stabilized mononuclear neutral radicals of aluminum have been synthesized. They contain an ethyl [(cAAC)2AlClEt (1)] and as well a diethyl group [(cAAC)2AlEt2 (2)], and have been prepared from the reduction of EtAlCl2 and Et2AlCl, respectively, with KC8. Compounds 1 and 2 are monoradicals, which were confirmed by EPR measurements to have the spin located on the carbene carbon of one of the cAAC ligands. PMID- 28875183 TI - ZORRO: zirconium oxide resonators for all-in-one Raman and whispering-gallery mode optical sensing. AB - We report the observation of whispering-gallery modes in 2 MUm-sized SiO2/ZrO2 core/shell beads utilized as all-dielectric Raman enhancers. This allows us to achieve simultaneous optical and Raman ultrasensitive detection with a single spectral analysis. This opportunity opens exciting perspectives for the multimodal chemical sensing and fabrication of optical fiber devices. PMID- 28875185 TI - Highly selective tridentate fluorescent probes for visualizing intracellular Mg2+ dynamics without interference from Ca2+ fluctuation. AB - We developed highly selective fluorescent Mg2+ probes based on a novel tridentate Mg2+-selective chelator. The superior selectivity for Mg2+ over Ca2+ enabled the detection of intracellular Mg2+ concentration changes without any response to Ca2+ influx. The new probes are potential keys to elucidating intracellular Mg2+ dynamics under conditions of extremely sharp Ca2+ fluctuation. PMID- 28875184 TI - Applications of vibrational tags in biological imaging by Raman microscopy. AB - As a superb tool to visualize and study the spatial-temporal distribution of chemicals, Raman microscopy has made a big impact in many disciplines of science. While label-free imaging has been the prevailing strategy in Raman microscopy, recent development and applications of vibrational/Raman tags, particularly when coupled with stimulated Raman scattering (SRS) microscopy, have generated intense excitement in biomedical imaging. SRS imaging of vibrational tags has enabled researchers to study a wide range of small biomolecules with high specificity, sensitivity and multiplex capability, at a single live cell level, tissue level or even in vivo. As reviewed in this article, this platform has facilitated imaging distribution and dynamics of small molecules such as glucose, lipids, amino acids, nucleic acids, and drugs that are otherwise difficult to monitor with other means. As both the vibrational tags and Raman instrumental development progress rapidly and synergistically, we anticipate that this technique will shed light onto an even broader spectrum of biomedical problems. PMID- 28875186 TI - New homoleptic bis(pyrrolylpyridiylimino) Mg(ii) and Zn(ii) complexes as catalysts for the ring opening polymerization of cyclic esters via an "activated monomer" mechanism. AB - The reaction of MgBu2 and ZnEt2 or Zn{N[Si(CH3)3]2}2 with a tridentate monoanionic pyrrolylpyridiylimino [N-,N,N] proligand gave homoleptic species, as exclusive products, in high yields. The complexes were characterized in solution by 1D and 2D NMR analysis and by single crystal X-ray crystallography. The new homoleptic complexes were tested as initiators in the polymerization of epsilon caprolactone and lactide in the presence of an exogenous alcohol. For both complexes, the polymerizations proceed via an "activated monomer" mechanism that, in the case of the magnesium complex, was correlated with the coordinative flexibility of the ligands, resulting in extremely high productivities under mild conditions. PMID- 28875187 TI - Volatile heterometallics: structural diversity of Pd-Pb beta-diketonates and correlation with thermal properties. AB - Volatile heterobimetallics based on Pb(ii) hexafluoroacetylacetonate as a host material and a range of Pd(ii) complexes containing both various donor atoms and terminal substituents in the beta-diketonate ligand have been studied to trace the influence of the nature of the initial monometallic complexes on the structure, composition and thermal properties of heterobimetallic compounds. The structural variety and stoichiometry of the heterobimetallic compounds are caused by various combinations of the competing donor-acceptor interactions between the constituting monometallic moieties. The major structure forming factor is the metallophilic interaction between Pd and Pb atoms resulting in polynuclear structures with a specific topology. The structural motif (discrete or polymeric) for the compounds significantly depends on the structure and composition of the initial monometallic complexes. The approach for explaining and predicting the thermal stability of these compounds is proposed by using their structural data and the results of quantum chemistry calculations. PMID- 28875188 TI - Alterations to metabolically active bacteria in the mucosa of the small intestine predict anti-obesity and anti-diabetic activities of grape seed extract in mice. AB - Epidemiological and clinical studies suggest that grapes and grape-derived products may reduce the risk for chronic disease. Grape seed extract specifically has been gaining interest due to its reported ability to prevent weight gain, moderate hyperglycemia, and reduce inflammation. The purpose of this study was to examine the long-term effects of two doses of grape seed extract (10 and 100 mg kg-1 body wt per d in mice) on markers of metabolic syndrome in the context of a moderately high-fat diet. After 12 weeks, the lower dose of grape seed extract was more effective at inhibiting fat gain and improving glucose tolerance and insulin sensitivity. Neither the high fat diet nor grape seed extract altered skeletal muscle substrate metabolism. Most interestingly, when examining the profile of metabolically active microbiota in the mucosa of the small intestine, cecum, and colonic tissue, grape seed extract seemed to have the most dramatic effect on small intestinal tissue, where the population of Firmicutes was lower compared to control groups. This effect was not observed in the cecal or colonic tissues, suggesting that the main alterations to gut microbiota due to flavan-3 ol supplementation occur in the small intestine, which has not been reported previously. These findings suggest that grape seed extract can prevent early changes in glucose tolerance and alter small intestinal gut microbiota, prior to the onset of skeletal muscle metabolic derangements, when grape seed extract is consumed at a low dose in the context of a moderately high fat diet. PMID- 28875189 TI - Dibenzazepinyl ureas as dual NMR and CD probes of helical screw-sense preference in conformationally equilibrating dynamic foldamers. AB - Conformationally mobile oligomers with helical structures, or 'dynamic foldamers', may populate a mixture of screw-sense conformers whose relative proportion has been used as a means of communicating information on a molecular scale. The dibenzazepinyl urea provides a means of quantifying both the sense and degree of this screw-sense preference through a combination of circular dichroism (CD) and NMR spectroscopy. The dibenzazepinyl urea probe is synthetically versatile, readily accessible, and easy to introduce to the terminus of an amide or a urea foldamer. PMID- 28875190 TI - Metallic borophene polytypes as lightweight anode materials for non-lithium-ion batteries. AB - Applications of rechargeable non-lithium-ion batteries (Na+, K+, Ca2+, Mg2+, and Al3+ NLIBs) are significantly hampered by the deficiency of suitable electrode materials. Searching for anode materials with desirable electrochemical performance is urgent for the large-scale energy storage demands of next generation renewable energy technologies. In this study, three types of recently synthesized borophenes are predicted to serve as high-performing anodes for NLIBs based on density functional theory. All the borophenes considered here are metallic with favorable in-plane stiffness. Dirac fermions were identified in two types of borophenes, guaranteeing their high electron mobility. Moreover, borophene configuration-dependent metal-ion migration, theoretical capacities, and open-circuit voltages were demonstrated with respect to the different adsorption behaviors and atom mass densities of anode materials. Our results provide insights into the configuration-dependent electrode performance of borophene and the corresponding metal-ion storage mechanism. PMID- 28875191 TI - A single-round selection of selective DNA aptamers for mammalian cells by polymer enhanced capillary transient isotachophoresis. AB - A single-round DNA aptamer selection for mammalian cells was successfully achieved for the first time using a capillary electrophoresis (CE)-based methodology called polymer-enhanced capillary transient isotachophoresis (PectI). The PectI separation yielded a single peak for the human lung cancer cell line (PC-9) complexed with DNA aptamer candidates, which was effectively separated from a free randomized DNA library peak, ensuring no contamination from free DNA in the PC-9-DNA aptamer complex fraction. The DNA aptamer candidates obtained after a single-round selection employing counter selection with HL-60 were proven to bind selectively and form kinetically stable complexes with PC-9 cells. Interestingly, most aptamer candidates showed high binding ability (Kd = 70-350 nM) with different extents of binding on the cell surface. These facts proved that a single-round selection for mammalian cells by PectI is feasible to obtain various types of aptamer candidates, which have high-affinity even for non overexpressed but unique targets on the cell surface in addition to overexpressed targets. PMID- 28875192 TI - Phase separation and physico-chemical processes at microscopic and macroscopic levels in MWCNT laden polymer blends using a unique droplet based architecture. AB - We propose a unique contact-free droplet based architecture in which thermally induced instabilities can be used to precisely alter the phase separation behavior in a dynamically asymmetric polymer blend (solution of PS/PVME in toluene) by controlling the external heating rates and concentration of added nanoparticles (multi-walled carbon nanotube particles, MWCNTs). In addition, by tuning the heating rates, distinctly different macroscopic morphologies (hollow shell or globular mass) can be obtained as a final structure in such droplets. Furthermore, the process of separation is temporally aggravated by several orders (about 3-5 orders) as compared to the traditional bulk processing techniques (thin film of blends). Faster production rate and high throughput promise a new spray-based architecture for producing phase separated structures. Addition of MWCNTs in the polymer blend delays the separation phenomenon as it interacts with the polymers and alters the stability criteria. Furthermore, addition of nanoparticles also introduces a different mode of instability at higher external heating rates. Heat accumulation due to particles causes boiling of the solvent (toluene) trapped inside the droplet which leads to subsequent explosion of the entire droplet, in addition to the phase separation phenomena (at the microscopic level). Volumetric expansion due to bubble growth leads to the formation of a unique hollow structure which is distinctly different from the globular mass obtained at lower heating rates. PMID- 28875193 TI - Exciton transport in pi-conjugated polymers with conjugation defects. AB - In pi-conjugated polymers for photovoltaic applications, intrinsic conjugation defects are known to play crucial roles in impacting exciton transport after photoexcitation. However, the understanding of the associated microscopic processes still remains limited. Here, we present a theoretical investigation of the effects of different conjugation defects on the dynamics of exciton transport in two linearly coupled poly(p-phenylene vinylene) (PPV) molecules. The model system is constructed by employing an extended version of the Su-Schrieffer Heeger model and the exciton behaviors are simulated by means of a quantum nonadiabatic dynamics. We identify two types of conjugation defects, i.e., weakening conjugation and strengthening conjugation, which are demonstrated to play different roles in impacting the dynamics of exciton transport in the system. The weakening conjugation acts as an energy well inclined to trap a moving exciton, while the strengthening conjugation acts as an energy barrier inclined to block the exciton. We also systematically simulate both intrachain and interchain dynamics of exciton transport, and find that an exciton could experience a "short-time delaying", "trapping", "blocking", or "hopping" process, which is determined by the defect type, strength, and position. These findings provide a microscopic understanding of how the exciton transport dynamics can be impacted by conjugation defects in an actual polymer system. PMID- 28875194 TI - Correcting transmission losses in short-wave infrared spatially offset Raman spectroscopy measurements to enable reduced fluorescence through-barrier detection. AB - Spatially offset Raman spectroscopy (SORS) is a proven technique for sub-surface detection. SORS is able to separate Raman signals from a container and its contents, thereby demonstrating application to through-barrier detection for defence and security. Whilst SORS has been demonstrated to reduce fluorescence from the barrier (or surface), fluorescence from the sample (or sub-surface) can still be problematic for some materials when using Raman excitation wavelengths typical in commercially available instrumentation (e.g. 785 nm). Previous work has demonstrated that short-wave infrared (SWIR) excited SORS (e.g. 1064 nm) can reduce fluorescence from the sample and barrier, thereby providing the potential to detect a wider range of materials through a wider range of barriers. In this paper we highlight an additional challenge for detection through some plastic container materials (e.g. high density polyethylene (HDPE) and other opaque plastics) that absorb and scatter both incident and Raman scattered photons in the SWIR band, leading to distortion of the resultant SORS spectrum. The existence of this effect and its impact is explored, along with a potential solution to overcome this challenge that uses multi-wavelength Raman excitation to avoid the detrimental HDPE absorption region. PMID- 28875195 TI - Dynamics of ethyl cellulose nanoparticle self-assembly at the interface of a nematic liquid crystal droplet. AB - Design and fabrication of many next-generation liquid crystal (LC)-based devices rely on nematic LC domains in the form of drops or emulsions. In addition to surfactants, solid nanoparticles may be used to stabilize LC-in-water Pickering emulsions, possibly adding new dimensions to device functionality. In this work we quantitatively study the adsorption of ethyl cellulose (EC) nanoparticles, as a colloid model system, on the 4-cyano-4'-pentylbiphenyl (5CB)-water interface via a series of dynamic interfacial tension measurements. It is found that the planar alignment of 5CB molecules at the interface with water is unaffected by particle adsorption, but a significant reduction of the interfacial tension over time occurs. It is also found that adsorption of EC nanoparticles to the LC-water interface is irreversible and results in close hexagonal packing. This study demonstrates a systematic approach to quantitatively investigate the effect of nanoparticles on the stabilization of LC emulsions. PMID- 28875196 TI - Preparation and antithrombotic activity identification of Perinereis aibuhitensis extract: a high temperature and wide pH range stable biological agent. AB - In this work, a thermal and wide pH range (from 1 to 13) stable biological agent was extracted from Perinereis aibuhitensis (P. aibuhitensis), and the antithrombotic activity of this P. aibuhitensis extract (PaE) was investigated. In vitro antithrombotic activity test indicated that PaE could significantly extend the clotting time of recalcified rabbit blood: the clotting time of the 10 mg mL-1, 20 mg mL-1 and 40 mg mL-1 PaE groups increased by 24.24%, 68.64% and 130.76%, respectively. Further platelet poor plasma (PPP) coagulation study proved that PaE could obviously inhibit the intrinsic coagulation pathway and slightly inhibit the extrinsic coagulation pathway. Moreover, PaE could effectively inhibit fibrinogen turning into fibrin induced by thrombin. More importantly, PaE exhibited thermal stability, since P. aibuhitensis was boiled in the PaE preparation process, as well as tolerance to strong acid and alkali, since its fibrinogen inhibition activity was retained after treatment with a wide range of pH value conditions. Finally, the antithrombotic activity ingredients in PaE were preliminarily identified, the results of which indicated that the ingredients were ethanol insoluble, insensitive to papain and pepsin, and could be degraded by H2O2. Additionally, we demonstrated that PaE at a concentration of not more than 20 mg mL-1, the concentration at which PaE showed high anticoagulant activity, exhibited favorable biocompatibility via in vitro hemolysis rate test and MTT assay. In summary, the results evidenced that this conveniently prepared and stable PaE was a safe and effective antithrombotic agent, and had the potential to be utilized for antithrombotic food development. PMID- 28875197 TI - Analysis of Warburg's impedance and its equivalent electric circuits. AB - The derivation of Warburg's impedance is revisited and critically analyzed. We show that the original derivation where the electric current is assumed to be due only to the diffusion of ions, as proposed by Warburg, raises some fundamental questions. The roles of the drift current, in the absence of which the equilibrium is never reached in the dc case, and of the displacement current, which is important even in the low frequency region where the Warburg's impedance appears, are discussed. Finally, the utility of models based on equivalent electric circuits, ladder networks, or transmission lines in the analysis of impedance spectroscopy data is investigated. PMID- 28875198 TI - The role of amino acid side chains in stabilizing dipeptides: the laser ablation Fourier transform microwave spectrum of Ac-Val-NH2. AB - The steric effects imposed by the isopropyl group of valine in the conformational stabilization of the capped dipeptide N-acetyl-l-valinamide (Ac-Val-NH2) have been studied by laser ablation molecular beam Fourier transform microwave (LA-MB FTMW) spectroscopy. The rotational and quadrupole coupling constants of the two 14N nuclei determined in this work show that this dipeptide exists as a mixture of C7 and C5 conformers in the supersonic expansion. The conformers are stabilized by a C[double bond, length as m-dash]OH-N intramolecular hydrogen bond closing a seven- or a five-membered ring, respectively. The observation of both conformers is in good agreement with previous results on the related dipeptides containing different residues, confirming that the polarity/non-polarity of the side chains of the amino acid is responsible for the conformational locking/unlocking. The voluminous isopropyl group is not able to prevent the less stable C5 conformer from forming but it destabilizes the C[double bond, length as m-dash]OH-N interaction. PMID- 28875199 TI - Superlinear amplification of the first hyperpolarizability of linear aggregates of DANS molecules. AB - A bottom-up modelling strategy is adopted to discuss the linear and nonlinear optical spectra of a prototypical push-pull dye, 4-dimethylamino-4'-nitrostilbene (DANS), in different environments, from solutions to linear aggregates, fully accounting for the molecular polarity and polarizability. In particular, we demonstrate a large amplification of the first hyperpolarizability of linear aggregates with a superlinear dependence on the aggregate size. Results are discussed with reference to recent experiments for DANS molecules aligned inside single-wall carbon nanotubes, leading to a complete and internally consistent description of the observed spectral properties in terms of ~7 aligned molecules, reducing by an order of magnitude the size of the aggregate estimated in the hypothesis of linear amplification, as expected for non-interacting molecules. This has important implications for material design: it is possible to obtain a large amplification of the first hyperpolarizability by aligning just a few DANS molecules (or more generally, a few polar dyes showing normal solvatochromism) without the need to grow large ordered systems. PMID- 28875200 TI - Enhanced photocatalytic reduction activity of uranium(vi) from aqueous solution using the Fe2O3-graphene oxide nanocomposite. AB - Photocatalytic technologies are a potential solution for remediation of radioactive wastewater, including the reduction of radioactive hexavalent uranium, which is commonly found in wastewater from the nuclear industry. In this study, Fe2O3-graphene oxide composites were synthesized by an easy and scalable impregnation method as a catalyst for the reduction of U(vi). X-ray photoelectron spectroscopy analysis and high-resolution transmission electron microscopy images of this composite clearly showed that the Fe2O3 nanoparticles exist in the layered structure of graphene oxide. The photocatalytic activity of the Fe2O3 graphene oxide composite was evaluated by the reduction of U(vi) to U(iv) in aqueous solution under visible light. The results showed that the photocatalytic process of the Fe2O3-graphene oxide composite was always faster than that of the Fe2O3 nanoparticles. Moreover, the experimental kinetic data for the catalytic process followed a pseudo-first-order model. The stability of the Fe2O3-graphene oxide composites was studied over successive experiments, with the photocatalytic reduction efficiency of U(vi) decreasing to 76.0% after four cycles. Based on these experimental results, the enhanced photocatalytic activity and stability of Fe2O3-graphene oxide composites can be attributed to the improved adsorption properties of U(vi) at GO and the electron transfer from iron oxide to GO. PMID- 28875201 TI - Ginseng (Panax ginseng Meyer) oligopeptides regulate innate and adaptive immune responses in mice via increased macrophage phagocytosis capacity, NK cell activity and Th cells secretion. AB - Traditionally used as a restorative medicine, ginseng (Panax ginseng Meyer) has been the most widely used and acclaimed herb in Chinese communities for thousands of years. To investigate the immune-modulating activity of ginseng oligopeptides (GOP), 420 healthy female BALB/c mice were intragastrically administered distilled water (control), whey protein (0.15 g per kg body weight (BW)), and GOP 0.0375, 0.075, 0.15, 0.3 and 0.6 g per kg BW for 30 days. Blood samples from mice were collected from the ophthalmic venous plexus and then sacrificed by cervical dislocation. Seven assays were conducted to determine the immunomodulatory effects of GOP on innate and adaptive immune responses, followed by flow cytometry to investigate spleen T lymphocyte sub-populations, multiplex sandwich immunoassays to investigate serum cytokine and immunoglobulin levels, and ELISA to investigate intestinally secreted immunoglobulin to study the mechanism of GOP affecting the immune system. Our results showed that GOP was able to enhance innate and adaptive immune responses in mice by improving cell-mediated and humoral immunity, macrophage phagocytosis capacity and NK cell activity. Notably, the use of GOP revealed a better immune-modulating activity compared to whey protein. We conclude that the immune-modulating activity might be due to the increased macrophage phagocytosis capacity and NK cell activity, and the enhancement of T and Th cells, as well as IL-2, IL-6 and IL-12 secretion and IgA, IgG1 and IgG2b production. These results indicate that GOP could be considered a good candidate that may improve immune functions if used as a dietary supplement, with a dosage that ranges from 0.3 to 0.6 g per kg BW. PMID- 28875203 TI - Gold-catalyzed domino cyclization-alkynylation reactions with EBX reagents: new insights into the reaction mechanism. AB - Gold-catalyzed domino processes constitute a useful alternative to C-H functionalization for the synthesis of functionalized (hetero)arenes. Herein, we report computational studies on the gold-catalyzed cyclization alkynylation of keto-allenes with ethynylbenziodoxole (EBX) reagents, which identified a gold(i) picolinate complex as the active catalyst, giving the first mechanistic insights into this transformation. PMID- 28875202 TI - Direct self-focusing synthesis of monodisperse [Au8(PPh3)7]2+ nanoclusters. AB - Direct and scalable synthesis of monodisperse gold nanoclusters is highly desired but remains a great challenge due to the complexity of chemical reactions. In this regard, a suitable precursor is important as it can simplify the synthesis processes and offer controllability in tuning the product. In this study, we found that Au(PPh3)2Cl could be used as an effective precursor for the direct synthesis of atomically monodisperse [Au8(PPh3)7]2+ nanoclusters without the need of tedious post-synthetic purification steps. The Au(PPh3)2Cl precursor could be directly reduced by NaBH4 (0.25 molar equivalent) in a dichloromethane solution; this produced Au8 clusters with a 35% reaction yield. Time-dependent mass spectrometry and in situ UV-vis absorption spectroscopy reveal that the synthesis process is initiated by the rapid formation of the Au6-Au8 mixture, followed by a slow spontaneous self-focusing process that converges the mixture into atomically monodisperse Au8. The success of this direct synthesis has been hypothesized to arise from the relatively stronger Au(i)Au(i) aurophilic attraction between Au(i) PPh3 complexes that facilitates the aggregation of Au(i)-PPh3 on Au(0) cores. PMID- 28875204 TI - A pentadentate nitrogen-rich copper electrocatalyst for water reduction with pH dependent molecular mechanisms. AB - The new pentadentate 3d9 complex [CuII(LN2Py3)](PF6)2 (1) based on a nitrogen rich framework acts as an electrocatalyst toward dihydrogen production from water. This species is active at pHs 7 and 2.5 yielding respective TON3h values of 1670 and 3900. Comparison of the molecular structure of 1 with that of the reduced [CuI(LN2Py3)]PF6 (2) evidences elongated Cu-N bond lengths resulting from an increased electron density around the 3d10 CuI center. The absence of nanoparticulate formation indicates that molecular mechanisms prevail at both pHs. Furthermore, experimental and DFT data support that distinct mechanisms are operative: while the metal center plays a key role at pH 7, one dangling pyridine moiety gets protonated at pH 2.5 and becomes actively involved in a relay mechanism. In both cases the CuIII-H- intermediate seems to be bypassed by PCET processes. PMID- 28875205 TI - New insights and perspectives into biological materials for flexible electronics. AB - Biological materials have robust hierarchical structures capable of specialized functions and the incorporation of natural biologically active components, which have been finely tuned through millions of years of evolution. These highly efficient architectural designs afford remarkable transport and mechanical properties, which render them attractive candidates for flexible electronic sensing technologies. This review provides a comprehensive overview of the fundamental aspects and applications of biological materials for flexible electronic devices and discusses various classes of biological materials by describing their unique structures and functions. We discuss the effect of the biological activity of biological materials on the improved properties in detail, because this effect overcomes the limited bioavailability and restricted morphology of materials generally encountered in traditional flexible electronic devices. We also summarize various approaches for the design and functionalization of natural materials and their applications in flexible electronic devices for use in biomedical, electron, energy, environmental and optical fields. Finally, we provide new insights and perspectives to further describe trends for future generations of biological materials, which are likely to be critical components (building blocks or elements) in future flexible electronics. PMID- 28875206 TI - Embedding heteroatoms: an effective approach to create porphyrin-based functional materials. AB - Incorporation of planarized heteroatom(s) onto the porphyrin periphery is an effective approach to create porphyrin-based functional materials. In the last three decades, such an "embedding heteroatom" strategy has been actively explored in order to realize attractive electronic, optical, and electrochemical properties. This review aims to cover a variety of synthetic methodologies that have been developed for the construction of heteroatom-embedded porphyrins. Moreover, we also summarize their structure-property relationships as well as possible applications in various research fields including artificial photosynthesis, molecular engineering, organic electronics, and bioimaging. PMID- 28875207 TI - Single-molecule conductance of DNA gated and ungated by DNA-binding molecules. AB - The single-molecule conductance of DNA was found to increase by over four fold upon intercalation, while the conductance nearly unaltered upon groove-binding. These effects are interpreted on the basis of the electronic interaction of the DNA-binding molecules with the stacked DNA bases. PMID- 28875208 TI - A one-pot multicomponent approach to a new series of morphine derivatives and their biological evaluation. AB - A novel and facile domino reaction has been developed to synthesize a variety of new derivatives from hydromorphone, amines and paraformaldehyde in good yields in a catalyst-free fashion with high atom efficiency. The products show a mixed MOR/DOR biological characteristic which makes them valuable for further study as opioid analgesics. PMID- 28875209 TI - Transition metal mediated carbonylative benzannulations. AB - In carbonylative benzannulations, feedstock carbon monoxide is converted to a benzene ring, which is one of the most fundamentally important and common rings in natural products and pharmaceutical compounds. Carbon monoxide, however, is rather inert in the absence of transition metals. Historically, carbonylative benzannulations have been mediated by stoichiometric chromium and iron in the form of Fischer carbenes. Recently, a number of transition metal-catalyzed carbonylative benzannulations have been developed, and almost all of them involve rhodium catalysts. This review will briefly discuss the mechanism and applications of carbonylative benzannulations involving Fischer carbenes and compare them with the more recent transition metal-catalyzed processes, including [3 + 2 + 1] cycloadditions, [5 + 1] cycloadditions, and other less common cycloadditions. PMID- 28875210 TI - Tetra-functional double-decker silsesquioxanes as anchors for reactive functional groups and potential synthons for hybrid materials. AB - A series of double-decker silsesquioxane derivatives with four reactive functional groups were designed, efficiently synthesized, and characterized. These novel inorganic-organic hybrids show highly attractive features for applications as building blocks with Si-O-Si rigid cores (good thermal properties) with four reactive moieties, which can be functionalized in further processes. PMID- 28875211 TI - Recent advances in transition-metal-catalyzed reactions of alkynes with isoxazoles. AB - Isoxazoles, as masked 1,3-dicarbonyl equivalents, have proven to be versatile building blocks and pivotal intermediates for the construction of a variety of useful azacycles with molecular complexity. As a result, a range of new reactions have been discovered based on isoxazoles in the past decade. However, the relevant reactions of isoxazoles with alkynes have seldom been explored. In this review, we will focus on the recent progress in the transition-metal-catalyzed formal annulations for the efficient synthesis of N-heterocycles between alkynes and isoxazoles by highlighting their specificity and applicability, and the mechanistic rationale is presented where possible. PMID- 28875212 TI - A 2.5D approach to the mechanics of electrospun fibre mats. AB - In this paper, a discrete random network modelling approach specific to electrospun networks is presented. Owing to the manufacturing process, fibres in these materials systems have an enormous length, as compared to their diameters, and form sparse networks since fibre contact over thickness is limited to a narrow range. Representative volume elements are generated, in which fibres span the entire domain, and a technique is developed to apply computationally favourable periodic boundary conditions despite the initial non-periodicity of the networks. To capture sparsity, a physically motivated method is proposed to distinguish true fibre cross-links, in which mechanical interaction takes place, from mere fibre intersections. The model is exclusively informed by experimentally accessible parameters, demonstrates excellent agreement with the mechanical response of electrospun fibre mats, captures typical microscopic deformation patterns, and provides information on the kinematics of fibres and pores. This ability to address relevant mechanisms of deformation at both micro- and macroscopic length scales, together with the moderate computational cost, render the proposed modelling approach a highly qualified tool for the computer based design and optimization of electrospun networks. PMID- 28875213 TI - Mass spectrometry based identification of galectin-3 interacting proteins potentially involved in lung melanoma metastasis. AB - Adhesive interactions between molecules on tumor cells and those on target organs play a key role in organ specific metastasis. Poly-N-acetyl-lactosamine (polyLacNAc) substituted N-oligosaccharides on melanoma cell surface glycoproteins promote lung specific metastasis via galectin-3 by facilitating their arrest and extravasation. This study reports the identification and characterization of galectin-3 interacting proteins using a combination of galectin-3 sepharose affinity and leucoagglutinating phytohemagglutinin (L-PHA) columns. A total of 83 proteins were identified as galectin-3 interacting glycoproteins, of which 35 were constituents of the L-PHA bound fraction, suggesting that these proteins carry polyLacNAc substituted beta1,6 branched N glycans. The identities of some of these proteins, like LAMP-1, LAMP-3, basigin, embigin, and alpha5 and beta1 Integrin, have been confirmed by western blotting, and functional relevance with respect to metastatic properties has been established. PMID- 28875214 TI - Diterpenoids of terrestrial origin. AB - Covering: January to December, 2016 previous review Nat. Prod. Rep., 2016, 33, 1227-1238This review covers the isolation and chemistry of diterpenoids from terrestrial as opposed to marine sources and includes labdanes, clerodanes, abietanes, pimaranes, kauranes, cembrenes and their cyclization products. There are 205 references. PMID- 28875215 TI - Stereodivergent Mannich reaction of bis(trimethylsilyl)ketene acetals with N-tert butanesulfinyl imines by Lewis acid or Lewis base activation, a one-pot protocol to obtain chiral beta-amino acids. AB - We report a one-pot synthesis of chiral beta2,2,3-amino acids by the Mannich addition of bistrimethylsilyl ketene acetals to N-tert-butanesulfinyl imines followed by the removal of the chiral auxiliary. The synthesis and isolation of pure beta-amino acid hydrochlorides were conducted under mild conditions, without strong bases and this method is operationally simple. The stereoselective reaction was promoted by two different activation methods that lead to different stereoisomers: (1) Lewis Acid (LA) catalysis with boron trifluoride diethyl etherate and (2) Lewis Base (LB) catalysis with tetrabutylammonium difluorotriphenylsilicate. The reaction presented good diastereoselectivity with LB activation and moderate to good dr with LA catalysis. The exceptions in both protocols were imines with electron donating groups in the aromatic ring. PMID- 28875216 TI - A crystalline AlPO4-5 intermediate: designed synthesis, structure, and phase transformation. AB - AlPO4-5 is the most extensively studied material in exploring the crystallization mechanism of aluminophosphate molecular sieves, and it can be synthesized using 4 dimethylaminopyridine (DMAP) as an organic structure-directing agent (OSDA). Achieving the AlPO4-5 intermediate in the crystalline form would be of great importance and significance for this purpose. In this study, we proposed a concept that by carefully regulating the synthesis conditions, crystalline alumimophosphate intermediates could be rationally prepared. A crystalline AlPO4 5 intermediate, (C7H11N2)2(H3O)(Al3P4O16).(H2O)2.5 (1), was, therefore, synthesized by significantly increasing the amounts of orthophosphoric acid and DMAP. The intermediate 1 consists of alternating organic DMAP and inorganic [Al3P4O16]3- layers with abundant hydrogen bonds and can transform to the AlPO4-5 framework upon heating in air or through a steam-assisted conversion (SAC) method. To unravel the role of DMAP in the transformation, pure AlPO4-5 (2) was also synthesized by altering the synthesis conditions. The supramolecular assembly templating (SAT) effects of DMAP in 1 and 2 were verified via fluorescence spectra. Thus, the pi-pi stacking interactions between the DMAP molecules and the abundant hydrogen bonds between the adjacent layers are considered to be important for the phase transformation of 1. This crystalline intermediate would promote the understanding of the crystallization mechanism in the system of aluminophosphate molecular sieves. PMID- 28875217 TI - Tandem radical cyclization to construct poly-brominated 2-oxindoles. AB - Catalytic amounts of TBHP (15 mol%) promoted tribromomethylation of activated alkenes has been developed. This method provided a metal-free aerobic way to construct tribromomethylated 2-oxindoles from the reaction of readily available N arylacrylamides with CBr4via a proposed tandem radical cyclization process. Air is used as an efficient terminal oxidant in this transformation. The formation of 1,1-dibromoolefin derivatives was also realized at higher temperature under neat conditions. PMID- 28875218 TI - Synthesis, characterisation and in vitro cytotoxicity of mixed ligand Pt(ii) oxadiazoline complexes with hexamethylenetetramine and 7-nitro-1,3,5 triazaadamantane. AB - trans-Platinum(ii) oxadiazoline complexes with 7-nitro-1,3,5-triazaadamantane (NO2-TAA) or hexamethylenetetramine (hmta) ligands have been synthesised from trans-[PtCl2(PhCN)2] via cycloaddition of nitrones to one of the coordinated nitriles, followed by exchange of the other nitrile by NO2-TAA or hmta. Stoichiometric control allows for the selective synthesis of mono- and dinuclear complexes where 7-NO2TAA and hmta act as mono- and bidentate ligands, respectively. Precursors and the target complexes trans [PtCl2(hmta)(oxadiazoline)], trans-[PtCl2(NO2-TAA)(oxadiazoline)] and trans [{PtCl2(oxadiazoline)}2(hmta)] were characterised by elemental analysis, IR and multinuclear (1H, 13C, 195Pt) NMR spectroscopy. DFT (B3LYP/6-31G*/LANL08) and AIM calculations suggest a stronger bonding of hmta with the [PtCl2(oxadiazoline)] fragment, in agreement with the experimentally observed reactivity in the ligand exchange (hmta > 7-NO2TAA). Replacement of the nitrile by hmta is predicted to be more exothermic than that with 7-NO2-TAA, although the activation barriers are similar. Protonation of the non-coordinated N atoms is anticipated to weaken the Pt-N bond and lower the activation barrier for ligand exchange. This effect might help activate these compounds in a slightly acidic environment such as some tumour tissues. Ten of the new compounds were tested for their in vitro cytotoxicity in the human cancer cell lines HeLa and A549. Some of the mononuclear complexes are more potent than cisplatin, and their activity is still high in A549 where cisplatin shows little effect. The dinuclear complexes are inactive, presumably due to their lipophilicity and reduced solubility in water. PMID- 28875219 TI - Reproducible fiber optofluidic laser for disposable and array applications. AB - Disposable sensors are widely used in biomedical detection due to their inherent safety, ease of use and low cost. An optofluidic laser is a sensitive bioassay platform; however, demonstrating its fabrication cheaply and reproducibly enough for disposable use has been challenging. Here, we report a low-cost, reproducible fiber optofluidic laser (FOFL) using a microstructured optical fiber (MOF). The MOF not only supports the whispering gallery modes for lasing but also serves as a microfluidic channel for sampling the liquid gain medium via capillary force. Because of the precise control of its geometry (delta < 0.4%) during the fiber drawing process, good reproducibility in laser intensity (delta = 6.5%) was demonstrated by changing 10 sections of the MOF. The strong coupling between the in-fiber resonator and gain medium enables a low threshold of 3.2 MUJ mm-2. The angular dependence of the laser emission was observed experimentally and analyzed with numerical simulations. An array of the FOFLs was also demonstrated. This technology has great potential for low-cost bioassay applications. PMID- 28875220 TI - Nut consumption in relation to all-cause and cause-specific mortality: a meta analysis 18 prospective studies. AB - Several previous meta-analyses show a consistent inverse association between nut consumption and all-cause mortality, but the associations with cause-specific mortality remain uncertain. A recent meta-analysis on nut consumption and multiple health outcomes combined incidence and mortality outcomes across most of the analyses, which may have introduced heterogeneity across studies. We conducted an updated meta-analysis to evaluate the nut-mortality association. We searched PubMed and EMBASE and we contacted authors for additional data. The final analyses included 18 prospective studies. The random-effects summary RRs for high compared with low nut consumption were 0.81 (95% CI: 0.78-0.84) for all cause mortality (18 studies with 81 034 deaths), 0.75 (95% CI: 0.71-0.79) for CVD mortality (17 studies with 20 381 deaths), 0.73 (95% CI: 0.67-0.80) for CHD mortality (14 studies with 10 438 deaths), 0.82 (95% CI: 0.73-0.91) for stroke mortality (13 studies with 4850 deaths) and 0.87 (95% CI: 0.80-0.93) for cancer mortality (11 studies 21 353 deaths). These results were broadly consistent within subgroups according to various study and population characteristics and within sensitivity analyses that took into account potential confounders. Peanut (5 studies) and tree nut (3 studies) consumption were similarly associated with mortality risks. Dose-response analyses suggested evidence for nonlinear associations between nut consumption and mortality (P-nonlinearity <0.001 for all outcomes except cancer mortality), with mortality risk levelling off at the consumption of about 3 servings per week (12 g d-1). Our findings suggest that nut consumption is associated with reduced all-cause and cause-specific mortality, with the strongest reduction for CHD mortality. Both tree nuts and peanuts may lower mortality and most of the survival benefits may be achieved at a relative low level of nut consumption. PMID- 28875221 TI - Cardiac tamponade by colon. PMID- 28875223 TI - Circulating adipokines are associated with pre-eclampsia in women with type 1 diabetes. AB - AIMS/HYPOTHESIS: The incidence of pre-eclampsia, a multisystem disorder of pregnancy, is fourfold higher in type 1 diabetic than non-diabetic women; it is also increased in women with features of the metabolic syndrome and insulin resistance. In a prospective study of pregnant women with type 1 diabetes, we measured plasma levels of adipokines known to be associated with insulin resistance: leptin, fatty acid binding protein 4 (FABP4), adiponectin (total and high molecular weight [HMW]; also known as high molecular mass), retinol binding protein 4 (RBP4) and resistin and evaluated associations with the subsequent development of pre-eclampsia. METHODS: From an established prospective cohort of pregnant type 1 diabetic women, we studied 23 who developed pre-eclampsia and 24 who remained normotensive; for reference values we included 19 healthy non diabetic normotensive pregnant women. Plasma adipokines were measured (by ELISA) in stored samples from three study visits (Visit 1- Visit 3) at different gestational ages (mean +/- SD): Visit 1, 12.4 +/- 1.8 weeks; Visit 2, 21.7 +/- 1.4 weeks; and Visit 3, 31.4 +/- 1.5 weeks. All the women were free of microalbuminuria and hypertension at enrolment. All study visits preceded the clinical onset of pre-eclampsia. RESULTS: In all groups, leptin, the ratio of leptin to total or HMW adiponectin, FABP4 concentration, ratio of FABP4 to total or HMW adiponectin and resistin level increased, while total and HMW adiponectin decreased, with gestational age. At Visit 1: (1) in diabetic women with vs without subsequent pre-eclampsia, leptin, ratio of leptin to total or HMW adiponectin, and ratio of FABP4 to total or HMW adiponectin, were increased (p < 0.05), while total adiponectin was decreased (p < 0.05); and (2) in normotensive diabetic vs non-diabetic women, total adiponectin was elevated (p < 0.05). At Visits 2 and 3: (1) the primary findings in the two diabetic groups persisted, and FABP4 also increased in women with subsequent pre-eclampsia (p < 0.05); and (2) there were no differences between the two normotensive groups. By logistic regression analyses after covariate adjustment (HbA1c, insulin kg-1 day-1 and gestational age), the best predictive models for pre-eclampsia were as follows: Visit 1, doubling of leptin, OR 9.0 (p < 0.01); Visit 2, doubling of the leptin:total adiponectin ratio, OR 3.7 (p < 0.05); and Visit 3, doubling of FABP4 concentration, OR 25.1 (p < 0.01). The associations were independent of BMI. CONCLUSIONS/INTERPRETATION: As early as the first trimester in type 1 diabetic women, adipokine profiles that suggest insulin resistance are associated with subsequent pre-eclampsia, possibly reflecting maternal characteristics that precede pregnancy. These associations persist in the second and third trimesters, and are independent of BMI. Insulin resistance may predispose women with type 1 diabetes to pre-eclampsia. PMID- 28875224 TI - The influence of fibromyalgia on achieving remission in patients with long standing rheumatoid arthritis. AB - To investigate the influence of fibromyalgia (FM) on achieving remission defined on the basis of the Simplified Disease Activity Index (SDAI) remission criteria in patients with long-standing rheumatoid arthritis (RA). This observational longitudinal cohort consisted of long-standing RA patients being treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biological DMARDs (bDMARDs). After 6 months of follow-up, the patients fulfilling or not fulfilling the remission criteria were identified and compared with each other in terms of the presence of FM, neuropathic pain, and other comorbidities. At the end of the 6-month observation period, 24 of the 117 patients (20.4%) met the SDAI remission criteria. Logistic regression analysis showed that the modified Rheumatic Disease Comorbidity Index (mRDCI) (p = 0.0001), the FM presence (p = 0.0001), and the 36-item short-form health survey Mental Component Summary (SF-36 MCS) Score (p = 0.0088) were the strongest predictors of not being in SDAI remission. None of the patients with concomitant FM (17.1%) achieved SDAI remission. In comparison with the non-FM patients, the patients with RA and FM patients had worse scores on the SF-36 MCS (p = 0.011), on the sleep Visual Analogue Scale (VAS) (p = 0.018), on the self-counts of tender joints (p = 0.039), and on the PainDetect Questionnaire (PDQ) (p = 0.001). To avoid over treatment, an assessment of FM should be considered in RA patients who do not fulfil the remission criteria. PMID- 28875225 TI - Methodological quality evaluation of systematic reviews or meta-analyses on ERCC1 in non-small cell lung cancer: a systematic review. AB - PURPOSES: To assess the methodological quality of systematic reviews (SRs) or meta-analysis concerning the predictive value of ERCC1 in platinum chemotherapy of non-small cell lung cancer. METHODS: We searched the PubMed, EMbase, Cochrane library, international prospective register of systematic reviews, Chinese BioMedical Literature Database, China National Knowledge Infrastructure, Wan Fang and VIP database for SRs or meta-analysis. The methodological quality of included literatures was evaluated by risk of bias in systematic review (ROBIS) scale. RESULTS: Nineteen eligible SRs/meta-analysis were included. The most frequently searched databases were EMbase (74%), PubMed, Medline and CNKI. Fifteen SRs did additional retrieval manually, but none of them retrieved the registration platform. 47% described the two-reviewers model in the screening for eligible original articles, and seven SRs described the two reviewers to extract data. In methodological quality assessment, inter-rater reliability Kappa was 0.87 between two reviewers. Research question were well related to all SRs in phase 1 and the eligibility criteria was suitable for each SR, and rated as 'low' risk bias. But the 'high' risk bias existed in all the SRs regarding methods used to identify and/or select studies, and data collection and study appraisal. More than two third of SRs or meta-analysis were finished with high risk of bias in the synthesis, findings and the final phase. CONCLUSIONS: The study demonstrated poor methodological quality of SRs/meta-analysis assessing the predictive value of ERCC1 in chemotherapy among the NSCLC patients, especially the high performance bias. Registration or publishing the protocol is recommended in future research. PMID- 28875226 TI - [Treatment of degenerative meniscal lesions : From eminence to evidence-based medicine]. AB - BACKGROUND: The treatment of degenerative meniscal lesions has received increased attention since the publication of several Level 1 studies over the last few years. The following review of literature including the consensus statement given by ESSKA reports on the management of patients with degenerative meniscal lesions. MATERIAL AND METHODS: The analysis includes the literature of Level 1 to 4 studies and the statement of the consensus group of ESSKA concerning the surgical or conservative management of these patients. RESULTS: Meniscal lesions cause progression in osteoarthritis. Patients presenting a combination of degenerative meniscal lesion and osteoarthritis show inferior clinical outcome. The average clinical outcome after surgical treatment was 70 points based on the Lysholm score. Level 1 studies show no difference in clinical outcome. However, over 30% of these patients require arthroscopy at the second stage after an interval of 3 to 6 months. Patients presenting a flap tear or complaining about mechanical symptoms show poor outcome after conservative treatment. DISCUSSION: Level 1 studies have focused on very selected patients. These patients do not represent the daily practice of orthopaedic surgeons. The findings of the level 1 studies should, therefore, not be generalized. According to the consensus statement of ESSKA, the treatment of degenerative meniscal lesions should start with conservative management. In the case of persistent symptoms, surgery should be considered after 3 months. In the case of mechanical symptoms, arthroscopy might be indicated earlier. Arthroscopy in advanced osteoarthritic knees is not indicated due to inferior clinical outcome. PMID- 28875227 TI - "That is why I have trust": unpacking what 'trust' means to participants in international genetic research in Pakistan and Denmark. AB - Trust features prominently in a number of policy documents that have been issued in recent years to facilitate data sharing and international collaboration in medical research. However, it often remains unclear what is meant by 'trust'. By exploring a concrete international collaboration between Denmark and Pakistan, we develop a way of unpacking trust that shifts focus from what trust 'is' to what people invest in relationships and what references to trust do for them in these relationships. Based on interviews in both Pakistan and Denmark with people who provide blood samples and health data for the same laboratory, we find that when participants discuss trust they are trying to shape their relationship to researchers while simultaneously communicating important hopes, fears and expectations. The types of trust people talk about are never unconditional, but involve awareness of uncertainties and risks. There are different things at stake for people in different contexts, and therefore it is not the same to trust researchers in Pakistan as it is in Denmark, even when participants donate to the same laboratory. We conclude that casual references to 'trust' in policy documents risk glossing over important local differences and contribute to a de politicization of basic inequalities in access to healthcare. PMID- 28875229 TI - Scaling to the Organism: An Innovative Model of Dynamic Exposure Hotspots in Stream Systems. AB - In flowing systems, fluctuations in the frequency, magnitude, and duration of exposure occurs due to turbulence and geomorphology, causing spatial and temporal variations in chemical exposure at the scale of the organism. Spatial models representing toxicant distribution at the appropriate scales of stream organisms are noticeably missing from the literature. To characterize the fine scale distribution of pollutants in freshwater streams at the scale of a benthic organism, nine artificial stream habitats were created (riffle, pool, run, bend, woody debris) with either sand or gravel substrate. Dopamine was released as a chemical tracer, mimicking a groundwater source, and measurements were recorded with a microelectrode and Epsilon electrochemical recording system. Proxies for the frequency, magnitude, and duration of chemical exposure were extracted. Geographic information systems and an inverse distance weight interpolation technique were used to predict spatially the chemical distribution throughout the habitats. Spatial and temporal variations of exposure were exhibited within and across habitats, indicating that the frequency, magnitude, and duration of exposure is influenced by the organism's location within a habitat and the habitat it resides in. The run and pool with sand substrate contained the greatest frequency, magnitude, and duration of exposure, suggesting a more detrimental exposure compared to other habitats. Differences in peak heights within and across habitats are orders of magnitude in value. Spatial and temporal fluctuations of fine scale exposure need to be considered in both ecotoxicology and water quality modeling to represent and understand the exposure of pollutants impacting benthic organisms. PMID- 28875228 TI - Myocardial deformation assessed by longitudinal strain: Chamber specific normative data for CMR-feature tracking from the German competence network for congenital heart defects. AB - PURPOSE: Left ventricular two-dimensional global longitudinal strain (LS) is superior to ejection fraction (EF) as predictor of outcome. We provide reference data for atrial and ventricular global LS during childhood and adolescence by CMR feature tracking (FT). METHODS: We prospectively enrolled 115 healthy subjects (56 male, mean age 12.4 +/- 4.1 years) at a single institution. CMR consisted of standard two-dimensional steady-state free-precession acquisitions. CMR-FT was performed on ventricular horizontal long-axis images for derivation of right and left atrial (RA, LA) and right and left ventricular (RV, LV) peak global LS. End diastolic volumes (EDVs) and EF were measured. Correlations were explored for LS with age, EDV and EF of each chamber. RESULTS: Mean+/-SD of LS (%) for RA, RV, LA and LV were 26.56+/-10.2, -17.96+/-5.4, 26.45+/-10.6 and -17.47+/-5, respectively. There was a positive correlation of LS in LA, LV, RA and RV with corresponding EF (all P<0.05); correlations with age were weak. Gender-wise differences were not significant for atrial and ventricular LS, strain rate and displacement. Inter- and intra-observer comparisons showed moderate agreements. CONCLUSIONS: Chamber-specific nomograms for paediatric atrial and ventricular LS are provided to serve as clinical reference, and to facilitate CMR-based deformation research. KEY POINTS: * No normative data exist for CMR-derived global longitudinal strain in the young. * This prospective study provides reference data for atrial and ventricular longitudinal strain. * The data will serve as reference for CMR-based clinical and research use. PMID- 28875230 TI - B-Flow Sonography for Evaluation of Basal Cerebral Arteries in Newborns. AB - The aim of the study was to evaluate the B-flow sonography (BFS) to image the basal cerebral arteries in newborn infants. For this purpose 34 newborns, who underwent standardized ultrasound of the brain including BFS, color Doppler (CDS) and power Doppler (PDS) techniques were retrospectively assessed. Delineation of the anterior communicating (Acom), the posterior communicating (Pcom), the middle cerebral (M1 and M2 segments), the anterior cerebral (A1 and A2 segments), and the posterior cerebral artery (P1 and P2 segments) were visually scored. Vessel delineation was better with BFS compared with CDS and PDS for the M2 segment (p = 0.0006 and p = 0.0136) and P2 segment (p = 0.0021 and p = 0.0014). Superior detectability was also noted for the Pcom with BFS compared with PDS (p = 0.0062). For all other vessel segments no significant differences were found. In conclusion BFS is feasible to image the basal cerebral arteries in newborns with an equal or better vessel delineation compared with standard vascular ultrasound methods. PMID- 28875232 TI - Spatiotemporal variations of the start of thermal growing season for grassland on the Qinghai-Tibetan Plateau during 1961-2014. AB - The start of thermal growing season (STGS) is an important indicator for climate change effects on regional plant growth and development. This study comprehensively investigated and compared the spatiotemporal variations in STGS at 0 degrees C (STGS_0), 5 degrees C (STGS_5), and 10 degrees C (STGS_10) thresholds for grassland on the Qinghai-Tibetan Plateau (QTP) during 1961-2014. Although elevation was the predominant influencing factor of the spatial variations of STGSs, the effect of latitude should not be ignored at the low elevation regions, especially for the STGS with a low-temperature threshold (e.g., STGS_0). With the decrease of temperature thresholds, the effect of elevation became weaker, while the effect of latitude became stronger. Significant advancing trends were observed in all the three STGSs, with greater advancing rate for STGS_0 (0.23 days.year-1) than that of STGS_5 (0.15 days.year 1) and STGS_10 (0.16 days.year-1). More obvious advancing trends were found after 1980, which coincided with more rapid climate warming. The advancing trends weakened after 1998 when climate warming hiatus occurred. Since positive and negative impacts may be simultaneously induced by the advanced STGSs, more observations are still needed to analyze their impacts on the growth and development of alpine grassland on the QTP. PMID- 28875231 TI - Cativic acid-caffeic acid hybrid exerts cytotoxic effects and induces apoptotic death in human neuroblastoma cells. AB - The development of hybrids from natural products is a promising strategy for drug discovery. In cancer therapy, there is a need to discover novel agents that can induce apoptosis in cancer cells. To contribute to this field of interest, we investigated the effect of a synthetic hybrid from cativic acid and caffeic acid (5) on viability, proliferation, and apoptosis in human neuroblastoma cells (IMR 32). Three hybrids were prepared via Mitsunobu esterification from 17 hydroxycativic acid (1) and natural phenols. Cell viability was analyzed by MTT assay. SYTOX green and LDH leakage were used to determine the cytotoxic effect. Caspase-3 activity, cell cycle phases, and proliferation were analyzed in order to characterize the biological effects of hybrid 5. The mitogen-activated protein kinase (MAPK) status was evaluated for elucidating the potential mechanisms involved in hybrid 5 effect. Hybrid 5 reduced the viability of IMR-32 cells in a time- and concentration-dependent manner (IC50 = 18.0 +/- 1.3 MUM) as a result of its antiproliferative effect through changes in the cell cycle distribution and induction of apoptosis associated with activation of caspase-3. Exposure to 5 triggered ERK1/2 activation and nuclear translocation. Hybrid 5 also promoted an increase in nuclear localization of the transcription factor c-Jun. Inhibition of ERK1/2 and JNK potentiated 5-induced inhibition of IMR-32 viability. Hybrid 5 displays cell growth inhibition by promoting cell cycle arrest and apoptosis, through ERK1/2 and JNK participation. PMID- 28875233 TI - Glutamate-Dependent Translational Control of Glutamine Synthetase in Bergmann Glia Cells. AB - Glutamate is the major excitatory transmitter of the vertebrate brain. It exerts its actions through the activation of specific plasma membrane receptors expressed both in neurons and in glial cells. Recent evidence has shown that glutamate uptake systems, particularly enriched in glia cells, trigger biochemical cascades in a similar fashion as receptors. A tight regulation of glutamate extracellular levels prevents neuronal overstimulation and cell death, and it is critically involved in glutamate turnover. Glial glutamate transporters are responsible of the majority of the brain glutamate uptake activity. Once internalized, this excitatory amino acid is rapidly metabolized to glutamine via the astrocyte-enriched enzyme glutamine synthetase. A coupling between glutamate uptake and glutamine synthesis and release has been commonly known as the glutamate/glutamine shuttle. Taking advantage of the established model of cultured Bergmann glia cells, in this contribution, we explored the gene expression regulation of glutamine synthetase. A time- and dose-dependent regulation of glutamine synthetase protein and activity levels was found. Moreover, glutamate exposure resulted in the transient shift of glutamine synthetase mRNA from the monosomal to the polysomal fraction. These results demonstrate a novel mode of glutamate-dependent glutamine synthetase regulation and strengthen the notion of an exquisite glia neuronal interaction in glutamatergic synapses. PMID- 28875234 TI - In obesity even young women suffer from urogynecological symptoms. AB - PURPOSE: To evaluate the occurrence of urogynecological symptoms in obese women treated in a university outpatient clinic for obesity, setting a focus on younger women. METHODS: In this explorative, prospective, cross-sectional, single-center, multidisciplinary clinical trial, all consecutively recruited women received the Prolapse Quality of Life questionnaire (P-QOL) for data acquisition. The total study population (TSP) and a subgroup (SG) aged 18-49 years were evaluated descriptively regarding symptom demonstration. RESULTS: Of the TSP (n = 166, mean age 40.2, standard deviation (SD) 12.98, mean body mass index (BMI) 45 kg/m2, SD 8.44) 105 (63%) and of the SG (n = 125, mean age 34.6, SD 9.29, mean BMI 44.9 kg/m2, SD 8.26) 72 (58%) women suffered from urinary incontinence (UI) being most impaired by stress urinary incontinence (SUI; TSP: 25%; SG: 27%) and least by urge urinary incontinence (UUI; TSP: 15%; SG: 11%). A significant correlation in the TSP between UI and age was detectable (p < 0.001, r phi = 0.37), but not between UI and BMI (p = 0.296, r phi = 0.08). The highest QOL impairment is detected for the domain general health perceptions [GHP; TSP & SG score >50 (score scale 0-100)]. Women with UI are significantly more affected than women with pelvic organ prolapse (GHP UI: TSP p = 0.04, SG p = 0.037; GHP POP: TSP p = 0.081, SG p = 0.659). CONCLUSIONS: A remarkable number of young obese women mentioned urogynecological symptoms and quality-of-life impairment. The P-QOL questionnaire proved to be an easily applicable tool to scan for concerned obese women. Its use in non-urogynecological departments, as performed, enables an early introduction of symptomatic women to urogynecologists, possibly preventing future growing urogynecological health issues. PMID- 28875235 TI - Incidence of bullous pemphigoid in Sweden 2005-2012: a nationwide population based cohort study of 3761 patients. AB - Studies that report the incidence of bullous pemphigoid from validated nationwide population-based registries are rare. The aim of this study was to estimate the incidence of bullous pemphigoid in Sweden 2005-2012. A population-based open cohort study was designed including all patients diagnosed by a dermatologist with bullous pemphigoid (BP) in Sweden from 2005 to 2012 (n = 3761), identified from the National Patient Register (NPR). The diagnosis of bullous pemphigoid in the NPR was recently validated from medical records, histopathological and immunopathological data by our group in a previous study. The average annual incidence of bullous pemphigoid was 7.1/100,000 (95% CI 6.5-7.7). Female to male ratio was 1.2:1, mean age at diagnosis was 78.9 years. The age-specific incidence rate increased markedly after 80 years of age with an incidence peak between 90 and 99 years of age, 81.9/100,000 (95% CI 75.0-89.2). This large nationwide cohort study presents an adjusted incidence of BP of 7.1/100,000 (95% CI 6.5-7.7) in Sweden. The incidence of bullous pemphigoid is higher than expected and bullous pemphigoid is a common disease in the elderly population. PMID- 28875236 TI - Bisphosphonate drug holidays in postmenopausal osteoporosis: effect on clinical fracture risk. AB - : A cohort of 183 postmenopausal women, who had either discontinued or continued bisphosphonates (BPs) after first-line therapy, was used to investigate the relationships between "drug holiday" and clinical fracture. The risk of new clinical fractures was found to be 40% higher in women who had taken a BP "drug holiday." INTRODUCTION: BPs are the most widely used treatment for postmenopausal osteoporosis. The optimal treatment duration, however, remains unclear. The purpose of this study was to evaluate the fracture risk in postmenopausal women with osteoporosis after discontinuing BP treatment (BP "drug holiday"). METHODS: A retrospective analysis was performed at Lille University Hospital (LUH) on postmenopausal women with osteoporosis who had taken a "drug holiday" or continued treatment after first-line BP therapy (3 to 5 years). The occurrence of new clinical fractures during follow-up was also explored. Cox proportional hazards models were used to investigate the relationships between BP "drug holiday" and the occurrence of clinical fractures, while controlling for confounding factors. Survival without new clinical fractures was analyzed using Kaplan-Meier curves and log-rank tests. RESULTS: One hundred eighty-three women (mean age: 61.8 years; SD: 8.7) who had previously undergone BP treatment for 3 to 5 years were enrolled in our study. The patients had received alendronate (n = 81), risedronate (n = 73), zoledronic acid (n = 20), and ibandronate (n = 9). In 166 patients ("drug holiday" group: n = 31; continuous-treatment group: n = 135), follow-up ranged from 6 to 36 months (mean duration: 31.8 months; SD: 8.2). The incidences of new clinical fractures during follow-up were 16.1% (5/31) and 11.9% (16/135). After full adjustment, the hazard ratio of new clinical fractures among "drug holiday" patients was 1.40 (95% CI: 1.12-1.60; p = 0.0095). CONCLUSIONS: After first-line BP therapy in postmenopausal women with osteoporosis, the risk of new clinical fractures was 40% higher in subjects who took a bisphosphonate drug holiday. PMID- 28875239 TI - Spatial variance of POPs and heavy metals in transformer oil-contaminated soil around Tamil Nadu. AB - The persistent organic pollutants in the environment are one of the global issues to their unregulated disposal and informal recycling. This study investigates the contamination of soil with polychlorinated biphenyls (PCBs), polyaromatic hydrocarbons (PAHs), phenolic compounds and heavy metals via spillage of transformer oil (TO). Fresh TO (FTO), used TO (UTO) and soil samples were analysed using GC-MS to confirm the presence of 8 PCB congeners, 16 PAHs and 24 types of phenolic compounds and using inductively coupled plasma optical emission spectrometry to confirm the presence of 7 heavy metals. The chromatographic analysis revealed the levels of mono-, di-, tri-, tetra-, penta-, hexa-, hepta- and octachlorobiphenyls in FTO to be 5.63, 25.24, 0.195, 0.185, 2.169, 1.023 and 5.28 mg/L and the level of mono-, di-, tri-, tetra-, penta- and hexachlorobiphenyls in UTO to be 0.27, 1.21, 1.31, 0.80, 1.77 and 3.90 mg/L. Analysis of soil from 10 different TO-contaminated sites showed the presence of PCBs, PAHs, phenolic compounds and heavy metals in the concentration range of 0.53-42.87 mg/kg, 3.19-246.6 MUg/kg, 0.01-4086.45 MUg/kg and 1.0-401.3 mg/kg, respectively. The variation in the concentration of these compounds and heavy metals among different sampling sites was determined using principal component analysis (PCA), metric multi-dimensional scaling (MDS) and Bray-Curtis cluster analysis (Bu-CA). The toxicity equivalence factor and the mechanism involved in the disruption of endocrine system are discussed. Thus, this study exemplifies the need for complete ban of PCB-containing TOs in developing countries and urges the need for technology for the disposal of TO. PMID- 28875237 TI - Uncoupling Protein 2 Inhibition Exacerbates Glucose Fluctuation-Mediated Neuronal Effects. AB - Though glucose fluctuations have been considered as an adverse factor for the development of several diabetes-related complications, their impact in the central nervous system is still not fully elucidated. This study was conducted to evaluate the responses of neuronal cells to different glycemic exposures alongside to elucidate the role of uncoupling protein 2 (UCP2) in regulating such responses. To achieve our goals, primary cortical neurons were submitted to constant high (HG)/low (LG) or glucose level variations (GVs), and the pharmacological inhibition of UCP2 activity was performed using genipin. Results obtained show that GV decreased neuronal cells' viability, mitochondrial membrane potential, and manganese superoxide dismutase activity and increased reactive oxygen species (ROS) production. GV also caused an increase in the glutathione/glutathione disulfide ratio and in the protein expression levels of nuclear factor E2-related factor 2 (NRF2), UCP2, NADH-ubiquinone oxidoreductase chain 1 (ND1), and mitochondrially encoded cytochrome c oxidase I (MTCO1), both mitochondrial DNA encoded subunits of the electron transport chain. Contrariwise, genipin abrogated all those compensations and increased the levels of caspase 3 like activity, potentiated mitochondrial ROS levels, and the loss of neuronal synaptic integrity, decreased the protein expression levels of NRF1, and increased the protein expression levels of UCP5. Further, in the control and LG conditions, genipin increased mitochondrial ROS and the protein expression levels of UCP4, postsynaptic density protein 95 (PSD95), ND1, and MTCO1. Overall, these observations suggest that UCP2 is in the core of neuronal cell protection and/or adaptation against GV-mediated effects and that other isoforms of neuronal UCPs can be upregulated to compensate the inhibition of UCP2 activity. PMID- 28875241 TI - Primary Formation Path of Formaldehyde in Hydrothermal Vents. AB - Formaldehyde is abundant in the universe and one of the fundamental molecules for life. Hydrothermal vents produce a substantial amount of hydrogen molecules by serpentinization and promote reductive reactions of single carbon compounds. The abundance of formaldehyde is expected to be low due to the high Gibbs free energy in hydrothermal vents. We consider two competing formation pathways of formaldehyde: (1) the reduction of CO by H2 and (2) the reduction of HCOOH by H2 to form a methanediol, followed by the dehydration of the methanediol. We performed a number of quantum chemical simulations to examine the formation of formaldehyde in the gas phase as well as in aqueous solution. The energy barrier is significantly reduced by the catalytic effect of water molecules in aqueous solution and becomes lowest when a water cluster consisted of 5 water molecules catalyzes the reduction. The energy barrier to form a methanediol by the reduction of HCOOH is lower by 17.5 kcal/mol than that to form a formaldehyde by the reduction of CO. Considering the low energy barrier to dehydrate methanediol, the primary pathway to form formaldehyde in hydrothermal vents is concluded to be the reduction of HCOOH by H2, followed by the dehydration of methanediol. PMID- 28875240 TI - Potential predictive factors for microvascular invasion in hepatocellular carcinoma classified within the Milan criteria. AB - BACKGROUND: Microvascular invasion (mvi) is an important risk factor for recurrent hepatocellular carcinoma (HCC), even after curative liver resection or orthotopic liver transplantation. However, mvi is difficult to detect preoperatively. The aim of this study was to clarify the risk factors of postoperative recurrence and investigate predictive factors of mvi before hepatectomy for HCC classified within the Milan criteria. METHODS: One hundred fifty-nine patients with hepatocellular carcinoma (HCC) classified within the Milan criteria, who underwent hepatectomy, were enrolled in this study. We investigated the risk factors of recurrence. In addition, we divided them into two groups: mvi-negative group and mvi-positive group, based on pathological findings after surgery. We compared the clinicopathological factors between the two groups and determined the risk factors for mvi. RESULTS: Overall survival rate at 1, 3, and 5 years were 91.6%, 80.5%, and 74.9%, and the recurrence-free survival rate at 1, 3, and 5-years were 72.3%, 51.6%, and 37.2%. Risk factor analysis for tumor recurrence revealed that total bilirubin, albumin, ICGR15, AFP L3, tumor number, mvi, and tumor stage had a significant predictive value. Multivariate analysis revealed that tumor number and mvi were significant independent risk factors for tumor recurrence. Predictive analysis for risk factors of mvi revealed that multiple tumors and AFP-L3 > 10% were significant independent risk factors for mvi in HCC classified within the Milan criteria. CONCLUSIONS: The mvi was one of the independent risk factors for tumor recurrence in HCC classified within the Milan criteria. Multiple tumors and high AFP-L3 value were independent predictive factors for mvi. PMID- 28875242 TI - Preoperative Needs-Based Education to Reduce Anxiety, Increase Satisfaction, and Decrease Time Spent in Day Surgery: A Randomized Controlled Trial. AB - BACKGROUND: Too much or too little information during patient education can increase patient anxiety. Needs-based patient education helps to determine the appropriate amount of information required to provide education based on patient needs. This study aimed to compare needs-based patient education with traditional patient education in reducing preoperative anxiety. METHODS: This was a prospective, multicenter, single-blind, randomized controlled trial with a 1:1 allocation ratio. Patients undergoing day surgery were randomized into a study group (needs-based education) or a control group (traditional education). The primary outcome was patient anxiety. Secondary outcomes were patient satisfaction and time spent in patient education. Patients completed questionnaires to evaluate their anxiety and satisfaction before patient education, after patient education, and after surgery. RESULTS: In total, 450 patients were randomized and analyzed (study group n = 225, control group n = 225). Comparisons before education, after education, and after surgery showed that there was a significant decrease in patient anxiety and an increase in satisfaction in both groups (p < 0.001). The comparison between needs-based education and traditional education showed a greater decrease in anxiety (7.09 +/- 7.02 vs. 5.33 +/- 7.70, p = 0.001) and greater increase in satisfaction (21.1 +/- 16.0 vs. 16.0 +/- 21.6, p < 0.001) in the needs-based group. The needs-based group also had significantly less education time than the traditional group (171.8 +/- 87.59 vs. 236.32 +/- 101.27 s, p < 0.001). CONCLUSION: Needs-based patient education is more effective in decreasing anxiety, increasing patient satisfaction, and reducing time spent in education compared with traditional patient education. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT03003091. PMID- 28875243 TI - Outcome after neoadjuvant chemotherapy in estrogen receptor-positive and progesterone receptor-negative breast cancer patients: a pooled analysis of individual patient data from ten prospectively randomized controlled neoadjuvant trials. AB - PURPOSE: The estrogen receptor (ER) is involved in control of progesterone receptor (PgR) expression and lack of PgR may be also a surrogate of altered growth factor signaling. The aim of this study was therefore to investigate PgR expression as predictive factor for response to neoadjuvant therapy and long-term outcome. METHODS: Five thousand and six hundred and thirteen patients with primary breast cancer and positive ER expression from ten German neoadjuvant trials of anthracycline and taxane-based chemotherapy were included. Pathologic complete response (pCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and local recurrence-free survival (LRFS) were compared according to PgR expression. RESULTS: The lack of PgR expression (1172 patients) was associated with grade 3 (38.4 vs. 26.3%; p < 0.001), nodal involvement (>cN2) (6.8% vs. 4.7%; p = 0.004), and HER2 positivity (36.2 vs. 22.3%; p < 0.001). pCR rates of PgR-negative tumors were higher in the entire cohort (13.8 vs. 7.5%; p < 0.001) and in the HER2-negative subgroup (11.2 vs. 5.8%; p < 0.001). In multivariable logistic regression, PgR negativity was an independent predictive factor for pCR overall (OR 1.76; p < 0.001) and in the HER2-negative patients (OR 1.99; p < 0.001). Patients with PgR-negative disease had significantly worse outcome (p < 0.001, respectively). Multivariable Cox regression analysis revealed that PgR was an independent prognostic factor for DFS, OS, DDFS, and LRFS. CONCLUSION: ER-positive/PgR-negative breast carcinomas are associated with higher response but also worse long-term outcome after neoadjuvant therapy. PgR negativity is an independent predictive factor for pCR after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer. PMID- 28875244 TI - Improving Fab' fragment retention in an autonucleolytic Escherichia coli strain by swapping periplasmic nuclease translocation signal from OmpA to DsbA. AB - OBJECTIVES: To reduce unwanted Fab' leakage from an autonucleolytic Escherichia coli strain, which co-expresses OmpA-signalled Staphylococcal nuclease and Fab' fragment in the periplasm, by substituting in Serratial nuclease and the DsbA periplasm translocation signal as alternatives. RESULTS: We attempted to genetically fuse a nuclease from Serratia marcescens to the OmpA signal peptide but plasmid construction failed, possibly due to toxicity of the resultant nuclease. Combining Serratial nuclease to the DsbA signal peptide was successful. The strain co-expressing this nuclease and periplasmic Fab' grew in complex media and exhibited nuclease activity detectable by DNAse agar plate but its growth in defined medium was retarded. Fab' coexpression with Staphylococcal nuclease fused to the DsbA signal peptide resulted in cells exhibiting nuclease activity and growth in defined medium. In cultivation to high cell density in a 5 l bioreactor, DsbA-fused Staphylococcal nuclease co-expression coincided with reduced Fab' leakage relative to the original autonucleolytic Fab' strain with OmpA-fused staphylococcal nuclease. CONCLUSIONS: We successfully rescued Fab' leakage back to acceptable levels and established a basis for future investigation of the linkage between periplasmic nuclease expression and leakage of co-expressed periplasmic Fab' fragment to the surrounding growth media. PMID- 28875245 TI - The relation of somatotypes and stress response to central serous chorioretinopathy. AB - PURPOSE: To investigate a possible relationship between central serous chorioretinopathy (CSC) and specific body types and compositions (somatotypes), and to examine the cortisol stress response among CSC patients of different somatotypes in comparison with healthy subjects. METHODS: Prospective case control study. A group of 28 patients with a previous or current diagnosis of CSC was compared with a group of 26 healthy subjects. Anthropometric measurements were used to estimate somatotype ratings in all subjects. Serum cortisol was measured at rest and following a stress-inducing computerized test in order to estimate response to stress in both groups. The main outcome measures included somatotype categorization and the change in serum cortisol following stress in both groups. RESULTS: No significant difference in somatotype composition was found between the groups. There was no statistically significant difference between the groups in the elevation of cortisol following the stress-inducing test. The sample size was too small to exclude or find any significant difference between the different 13 subgroups of somatotype composition in the elevation of cortisol. CONCLUSIONS: Our study did not show a typical somatotype related to CSC. While previous studies showed higher cortisol values in CSC patients, we did not see a higher elevation in blood cortisol following a stress response in this group in comparison with healthy subjects. PMID- 28875246 TI - Elevated serum 14-3-3eta protein may be helpful for diagnosis of early rheumatoid arthritis associated with secondary osteoporosis in Chinese population. AB - Osteoporosis (OP) is one of the signs of bone damage in rheumatoid arthritis (RA). The 14-3-3eta protein is an inflammatory protein, which has been reported to be associated with rheumatoid arthritis (RA). This is to determine the serum levels of 14-3-3eta protein, evaluate its diagnostic value in early RA, and clear out its significance in RA with secondary osteoporosis. Two hundred fifty-nine RA patients and 80 age and sex-matched healthy controls were included. Assays of serum 14-3-3eta protein were done for all participants by enzyme-linked immunosorbent assay (ELISA). Dual-energy X-ray absorptiometry (DEXA) was used to measure bone mineral density (BMD). Serum 14-3-3eta protein level was significantly high in RA (2.49/4.72), compared with controls (P < 0.0001). Positive rate of 14-3-3eta protein in RA was 97.3%, which was higher than that in controls (chi 2 = 276.641, P < 0.0001). Serum 14-3-3eta protein level in early RA was significantly higher than that in established RA (3.91/4.82 vs 2.01/3.29, Z = 2.624, P < 0.05). The positive rate among three groups (normal control, early RA group, established RA group) differed from each other (chi 2 = 131.396, P < 0.0001). Results of ROC curve indicated the cutoff point of 14-3-3eta protein for diagnosis of early RA was 0.879 ng/ml (P < 0.0001). Linear correlation analysis found that serum 14-3-3eta protein positively correlated with VAS and HAQ (P < 0.0001), negatively correlated with BMD at lumbar spine and femur in RA (P < 0.0001). Serum 14-3-3eta protein among groups of bone mass normal (2.73/3.79), osteopenia (3.15/4.86), and osteoporosis (6.34/6.42) was different in early RA patients (chi 2 = 7.974, P < 0.05). Serum 14-3-3eta protein levels increase significantly in patients with RA (especially in early RA). There are close relationships between serum 14-3-3eta protein and clinical symptoms and osteoporosis in patients with RA. PMID- 28875247 TI - "It Was Supposed To Be a Onetime Thing": Experiences of Romantic and Sexual Relationship Typologies Among Young Gay, Bisexual, and Other Men Who Have Sex with Men. AB - Young gay, bisexual, and other men who have sex with men (MSM) are at elevated risk for HIV infection, highlighting the need to understand the elements of prevention and risk associated with their relationships. We employed a phenomenological approach to explore how young MSM become involved in different romantic and sexual experiences. We analyzed 28 semi-structured interviews conducted with young MSM living in Michigan. Using a phenomenological approach, we analyzed the data using an inductive coding strategy and thematic analysis. Participants defined their romantic and sexual interactions with a limited set of partner classifications (e.g., dating, hooking up, friends-with-benefits), but recognized how these classifications were shifting, sometimes unexpectedly so (e.g., a date turning into a hook up and vice versa). Young MSM described relationships in transition that at times defied available typologies or hybridized elements of multiple partner types at once. Based on our analyses, we underscore the need to acknowledge the fluctuating and contextual nature of young MSM's romantic and sexual experiences. We discuss the relevance of our findings in terms of the developmental period of young adulthood and the implications our findings have HIV prevention efforts among young MSM. PMID- 28875248 TI - Assessing health-related quality of life in patients with breast cancer: a reply to Maratia et al. PMID- 28875249 TI - From the 7th Joint Italian-German Purine Club Meeting to European Purine Club Meetings. PMID- 28875250 TI - Effect of iris registration on outcomes of FEMTOLASIK for myopia and myopic astigmatism. AB - PURPOSE: To compare the visual and refractive outcomes after FEMTOLASIK with and without iris registration. METHODS: In this randomized, prospective, comparative, contralateral eye study, 118 eyes of 59 patients with myopia and myopic astigmatism underwent LASIK using the Femto LDV femtosecond laser (160 um) and the MEL80 with or without iris registration. For each patient, iris registration FEMTOLASIK was performed on one eye and non-iris registration FEMTOLASIK was performed on the other eye, assigned at random. Patients were evaluated before and 12 months. Uncorrected visual acuity, best-corrected visual acuity, manifest refraction, contrast sensitivity, and higher-order aberrations (HOAs) were evaluated. RESULTS: At 12 months, the mean UDVA was 0.002 +/- 0.07 logMAR (20/19) in iris registration eyes and 0.00 +/- 0.06 logMAR (20/24) in non-iris registration eyes (P = 0.9). 61% of iris registration eyes and 71.2% of non-iris registration eyes achieved a UDVA of 20/20 or better (P = 0.31); 98.3% of eyes with the iris registration FEMTOLASIK and 94.9% with the non-iris registration FEMTOLASIK were within +/-0.50 D from emmetropia (P = 0.71). No statistically significant difference was found in postoperative contrast sensitivity between groups at 3, 6, 12, or 18 cycles/degree (P > 0.05). There was significant increase in total HOA root mean square in two groups. The mean error magnitude of surgically induced astigmatism 12 months postoperatively was -0.33 in iris registration eyes and -0.24 in the non-iris registration eyes (P = 0.36). CONCLUSIONS: FEMTOLASIK with and without iris registration provides similar results in myopic and myopic astigmatism patients. PMID- 28875251 TI - The effect of substrate/inoculum ratio on the kinetics of methane production in swine wastewater anaerobic digestion. AB - Methane production from swine wastewater was evaluated by using sewage sludge as inoculum in three substrate to inoculum ratios (SIRs) named A (1:1), B (3:1) and C (6:1), with the objective to identify the proportion that optimizes the performance of the process. Duplicated batch bioreactors of 1 L capacity under mesophilic conditions were used to carry out the experiment. The highest biogas yield was observed in A treatment (554 +/- 75 mL/g volatile solid (VS)). Cumulative methane production decreased from 382 +/- 22 to 232 +/- 5 mL/g VS when SIR increased from 1:1 to 6:1. The first-order model and the modified Gompertz equation were used to model the experimental cumulative methane yield giving adjustments with coefficients of determination of 96 and 99% respectively. The effect of the SIR was analysed based on the kinetic parameters of the Gompertz equation, which are methane production potential, maximum methane production rate and lag-phase time. The best performance in terms of the kinetic parameters was obtained for treatment A; however, treatment B could still ensure a stable process. The use of higher inoculum concentration generated 463.1% higher methane production rate and required 77.3% shorter adaptation time (lag phase) in the SIR range studied. When higher SIR was used (e.g. 14:1, previous work), it could be observed that the Gompertz equation also adjusted adequately the experimental data (R 2 > 0.99) although the lag-phase time did not remain in a linear relationship with SIR but exponentially above SIR = 6:1. These results demonstrated that when a low amount of inoculum was used, the adaptation time of microorganisms resulted much higher than expected delaying the methane production and extending the time needed to achieve adequate performance of the process. PMID- 28875253 TI - Health Related Quality of Life in Children and Caregivers with Controlled versus Uncontrolled Asthma. PMID- 28875252 TI - Childhood Trauma and Two Stages of Alcohol Use in African American and European American Women: Findings from a Female Twin Sample. AB - The current investigation assessed for moderating effects of childhood trauma on genetic and environmental contributions to timing of alcohol use initiation and alcohol use disorder in African American (AA) and European American (EA) women. Data were drawn from diagnostic telephone interviews conducted with 3786 participants (14.6% AA) in a longitudinal female twin study. Childhood trauma was defined alternately as child maltreatment and more broadly to include other events (e.g., witnessing violence). Phenotypic associations between childhood trauma and alcohol outcomes were estimated using logistic regression analyses. Twin modeling was conducted to test for moderating effects of childhood trauma on the contributions of genetic and environmental factors to timing of initiation and alcohol use disorder. Under both definitions, childhood trauma was associated with early initiation (relative risk ratios: 1.90, 1.72) and alcohol use disorder (odds ratios: 1.92, 1.76). Yet gene by environment effects were observed only for child maltreatment and timing of initiation in EA women, with heritable influences less prominent in those who had experienced child maltreatment (0.35, 95% CI: 0.05-0.66 vs. 0.52, 95% CI: 0.30-0.73). We found more similarities than differences in the association of childhood trauma with alcohol outcomes across racial/ethnic groups, trauma type, and stages of alcohol use. However, findings suggest that the relative contribution of genetic factors to alcohol outcomes differs by childhood maltreatment history in EA women specifically in the earliest stage of alcohol use. PMID- 28875254 TI - Medical Education Then and Now. PMID- 28875255 TI - ERCP or NO ERCP: the case report of a frail patient. PMID- 28875256 TI - Response to the Letter to the Editor Regarding "Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials". PMID- 28875257 TI - Non-participation in systematic screening for osteoporosis-the ROSE trial. AB - : Population-based screening for osteoporosis is still controversial and has not been implemented. Non-participation in systematic screening was evaluated in 34,229 women age 65-81 years. Although participation rate was high, non participation was associated with comorbidity, aging other risk factors for fractures, and markers of low social status, e.g., low income, pension, and living alone. A range of strategies is needed to increase participation, including development of targeted information and further research to better understand the barriers and enablers in screening for osteoporosis. INTRODUCTION: Participation is crucial to the success of a screening program. The objective of this study was to analyze non-participation in Risk-stratified Osteoporosis Strategy Evaluation, a two-step population-based screening program for osteoporosis. METHODS: Thirty-four thousand two hundred twenty-nine women aged 65 to 81 years were randomly selected from the background population and randomized to either a screening group (intervention) or a control group. All women received a self-administered questionnaire designed to allow calculation of future risk of fracture based on FRAX. In the intervention group, women with an estimated high risk of future fracture were invited to DXA scanning. Information on individual socioeconomic status and comorbidity was obtained from national registers. RESULTS: A completed questionnaire was returned by 20,905 (61%) women. Non completion was associated with older age, living alone, lower education, lower income, and higher comorbidity. In the intervention group, ticking "not interested in DXA" in the questionnaire was associated with older age, living alone, and low self-perceived fracture risk. Women with previous fracture or history of parental hip fracture were more likely to accept screening by DXA. Dropping out when offered DXA, was associated with older age, current smoking, higher alcohol consumption, and physical impairment. CONCLUSIONS: Barriers to population-based screening for osteoporosis appear to be both psychosocial and physical in nature. Women who decline are older, have lower self-perceived fracture risk, and more often live alone compared to women who accept the program. Dropping out after primary acceptance is associated not only with aging and physical impairment but also with current smoking and alcohol consumption. Measures to increase program participation could include targeted information and reducing physical barriers for attending screening procedures. PMID- 28875258 TI - Molecular analysis of oxalate-induced endoplasmic reticulum stress mediated apoptosis in the pathogenesis of kidney stone disease. AB - Oxalate, a non-essential end product of metabolism, causes hyperoxaluria and eventually calcium oxalate (CaOx) stone disease. Kidney cells exposed to oxalate stress results in generation of reactive oxygen species (ROS) and progression of stone formation. Perturbations in endoplasmic reticulum (ER) result in accumulation of misfolded proteins and Ca2+ ions homeostasis imbalance and serve as a common pathway for various diseases, including kidney disorders. ER stress induces up-regulation of pro-survival protein glucose-regulated protein 78 (GRP78) and pro-apoptotic signaling protein C/EBP homologous protein (CHOP). Since the association of oxalate toxicity and ER stress on renal cell damage is uncertain, the present study is an attempt to elucidate the interaction of GRP78 with oxalate by computational analysis and study the role of ER stress in oxalate mediated apoptosis in vitro and in vivo. Molecular docking results showed that GRP78-oxalate/CaOx interaction takes place. Oxalate stress significantly up regulated expression of ER stress markers GRP78 and CHOP both in vitro and in vivo. Exposure of oxalate increased ROS generation and altered antioxidant enzyme activities. N-Acetyl cysteine treatment significantly ameliorated oxalate mediated oxidative stress and moderately attenuated ER stress marker expression. The result indicates oxalate toxicity initiated oxidative stress-induced ER stress and also activating ER stress mediated apoptosis directly. In addition, the up-regulation of transforming growth factor beta-1 revealed oxalate may induce kidney fibrosis through ER stress-mediated mechanisms. The present study provide insights into the pathogenic role of oxidative and ER stress by oxalate exposure in the formation of calcium oxalate stone. PMID- 28875259 TI - The impact of obesity on 30-day complications in pediatric surgery. AB - PURPOSE: To examine the effects of obesity on specialty-specific surgical outcomes in children. MATERIALS AND METHODS: Retrospective cohort study using the National Surgical Quality Improvement Program, Pediatric, 2012-2014. Patients included those aged 2-17 years who underwent a surgical procedure in one of six specialties. Obesity was the primary patient variable of interest. Outcomes of interest were postoperative complications and operative times. Odds ratios for development of postoperative complications were calculated using stepwise multivariate regression analysis. RESULTS: Obesity was associated with a significantly greater risk of wound complications (OR 1.24, 95% CI 1.13-1.36), but decreased risk of non-wound complications (OR 0.68, 95% CI 0.63-0.73) and morbidity (OR 0.79, 95% CI 0.75-0.84). Obesity was not a significant factor in predicting postoperative complications in patients undergoing otolaryngology or plastic surgery procedures. Anesthesia times and operative times were significantly longer for obese patients undergoing most types of pediatric surgical procedures. CONCLUSION: Obesity confers an increased risk of wound complications in some pediatric surgical specialties and is associated with overall decreased non-wound complications and morbidity. These findings suggest that the relationship between obesity and postoperative complications is complex and may be more dependent on underlying procedure- or specialty-related factors than previously suspected. PMID- 28875260 TI - Geosmithia-Ophiostoma: a New Fungus-Fungus Association. AB - In Europe as in North America, elms are devastated by Dutch elm disease (DED), caused by the alien ascomycete Ophiostoma novo-ulmi. Pathogen dispersal and transmission are ensured by local species of bark beetles, which established a novel association with the fungus. Elm bark beetles also transport the Geosmithia fungi genus that is found in scolytids' galleries colonized by O. novo-ulmi. Widespread horizontal gene transfer between O. novo-ulmi and Geosmithia was recently observed. In order to define the relation between these two fungi in the DED pathosystem, O. novo-ulmi and Geosmithia species from elm, including a GFP tagged strain, were grown in dual culture and mycelial interactions were observed by light and fluorescence microscopy. Growth and sporulation of O. novo-ulmi in the absence or presence of Geosmithia were compared. The impact of Geosmithia on DED severity was tested in vivo by co-inoculating Geosmithia and O. novo-ulmi in elms. A close and stable relation was observed between the two fungi, which may be classified as mycoparasitism by Geosmithia on O. novo-ulmi. These results prove the existence of a new component in the complex of organisms involved in DED, which might be capable of reducing the disease impact. PMID- 28875261 TI - The Low-Affinity Binding of Second Generation Radiotracers Targeting TSPO is Associated with a Unique Allosteric Binding Site. AB - [11C]-PK11195 (PK11195) has been widely used with positron emission tomography (PET) to assess levels of the translocator protein 18 kDa (TSPO) as a marker of neuroinflammation. Recent ligands, such as [11C]-PBR28 and [11C]-DPA713, have improved signal-to-noise ratio and specificity for TSPO over PK11195. However, these second generation radiotracers exhibit binding differences due to a single polymorphism (rs6971) that leads to three genotypes: C/C, C/T and T/T associated with high, mixed and low binding affinities, respectively. Here we report that [3H]-DPA-713 in the presence of cholesterol or PK11195 has an accelerated dissociation rate from TSPO in platelets isolated from individuals with the T/T genotype. This allosteric interaction was not observed in platelets isolated from individuals with the C/C or C/T genotype. The results provide a molecular rationale for low binding affinity of T/T TSPO and further support the exclusion of these subjects from PET imaging studies using second generation TSPO ligands. PMID- 28875262 TI - Erratum to: Asparagine synthetase deficiency-report of a novel mutation and review of literature. PMID- 28875263 TI - Pillar of strength: Columnar cactus as a key factor in Yoreme heritage and wildland preservation. AB - The persistence of traditional cultures and modes of land use within rapidly changing, globalized societies is a central issue in understanding ecological and cultural change in the Anthropocene. Located in the heart of the Green Revolution, the Yoreme (Mayo) people of the Mayo Valley in Mexico still obtain a significant proportion of their sustenance from wild ecosystems in the midst of this intensive technological and agricultural development. They live in and around the thornscrub dominated by pitaya (Stenocereus thurberi (Engelm.) Buxb.). In this study, we hypothesize that pitaya supports Yoreme heritage and sustenance amidst anthropogenic changes to the landscape, and we asked three specific questions: What is the land-use status of the S. thurberi habitat? What are its potential uses? Does S. thurberi provide economic value? To address these questions, we conducted interviews, vegetation surveys, and land-use analysis based on geographic information systems. We found that (a) land conversion of the pitaya-rich thornscrub is occurring at a precipitous rate, (b) local producers preserve and adapt their traditions, and (c) S. thurberi supports Yoreme heritage while providing economic benefit. The resulting land-use projections along with the cultural value of pitaya products shows the importance of conserving land and promoting sustainable projects instead of clearing land for other uses. If habitat shrinking continues at the current rate, it is likely that both Yoreme livelihoods and continued cultural practices will suffer. PMID- 28875264 TI - Gas-Phase Stability of Negatively Charged Organophosphate Metabolites Produced by Electrospray Ionization and Matrix-Assisted Laser Desorption/Ionization. AB - The formation mechanisms of singly and multiply charged organophosphate metabolites by electrospray ionization (ESI) and their gas phase stabilities were investigated. Metabolites containing multiple phosphate groups, such as adenosine 5'-diphosphate (ADP), adenosine 5'-triphosphate (ATP), and D-myo-inositol-1,4,5 triphosphate (IP3) were observed as doubly deprotonated ions by negative-ion ESI mass spectrometry. Organophosphates with multiple negative charges were found to be unstable and often underwent loss of PO3-, although singly deprotonated analytes were stable. The presence of fragments due to the loss of PO3- in the negative-ion ESI mass spectra could result in the misinterpretation of analytical results. In contrast to ESI, matrix-assisted laser desorption ionization (MALDI) produced singly charged organophosphate metabolites with no associated fragmentation, since the singly charged anions are stable. The stability of an organophosphate metabolite in the gas phase strongly depends on its charge state. The fragmentations of multiply charged organophosphates were also investigated in detail through density functional theory calculations. Graphical Abstract. PMID- 28875265 TI - Possible Role of IL-25 in Eosinophilic Lung Inflammation in Patients with Chronic Eosinophilic Pneumonia. AB - PURPOSE: Interleukin (IL)-25 and IL-33 induce IL-5 production by various types of cells, such as type 2 helper T (Th2) cells and type 2 innate lymphoid cells. The number of Th2 cells and concentration of IL-5 in the bronchoalveolar lavage fluid (BALF) are increased in patients with eosinophilic pneumonia (EP). To examine the contribution of IL-25 and IL-33 to eosinophilic inflammation of the lung in humans, we evaluated IL-5, IL-25 and IL-33 levels in the BALF of patients with EP. METHODS: IL-5, IL-25, and IL-33 concentrations in the BALF were measured by enzyme-linked immunosorbent assay in patients with acute eosinophilic pneumonia (AEP), chronic eosinophilic pneumonia (CEP), idiopathic pulmonary fibrosis (IPF), and sarcoidosis. RESULTS: The absolute number of eosinophils, and IL-5 levels, but not IL-33 levels, in the BALF were significantly higher in patients with EP than in patients with IPF and sarcoidosis. IL-25 levels in the BALF were significantly higher in patients with CEP, but not in patients with AEP, than in patients with IPF and sarcoidosis. The absolute number of eosinophils was significantly correlated with the IL-5 concentration in the BALF of patients with EP. IL-5 concentrations were significantly correlated with IL-25 concentrations in the BALF of patients with CEP, but not in patients with AEP. IL-5 levels were not correlated with IL-33 levels in the BALF of patients with EP. CONCLUSIONS: Our findings suggest that IL-25 plays an important role via IL-5 in eosinophilic lung inflammation in patients with CEP. PMID- 28875266 TI - CSF-1R Inhibitor Development: Current Clinical Status. AB - PURPOSE OF REVIEW: Colony-stimulating factor 1 receptor (CSF-1R) and its ligands, CSF-1 and interleukin 34 (IL-34), regulate the function and survival of tumor associated macrophages, which are involved in tumorigenesis and in the suppression of antitumor immunity. Moreover, the CSF-1R/CSF-1 axis has been implicated in the pathogenesis of pigmented villonodular synovitis (PVNS), a benign tumor of the synovium. As advanced or metastatic malignant solid tumors and relapsed/refractory PVNS remain unresolved therapeutic problems, new approaches are needed to improve the outcome of patients with these conditions. RECENT FINDINGS: In solid tumors, targeting CSF-1R via either small molecules or antibodies has shown interesting results in vitro but limited antitumor activity in vivo. Concerning PVNS, clinical trials assessing CSF-1R inhibitors have revealed promising initial outcomes. Blocking CSF-1/CSF-1R signaling represents a promising immunotherapy approach and several new potential combination therapies for future clinical testing. PMID- 28875268 TI - High prevalence of papillary thyroid carcinoma in nodular Hashimoto's thyroiditis at the first diagnosis and during the follow-up. AB - BACKGROUND: The association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) remains to be elucidated. MATERIALS AND METHODS: A total of 484 HT patients were retrospectively subdivided into two groups: 243 without thyroid nodules, TNs (HTN-) and 241 with TNs (HTN+). Fine-needle aspiration cytology was available in 152 HTN+ patients. This group was compared to a group of 161 patients with nodular goiter (NG) without HT. Finally, 70 HTN+ and 37 NG patients underwent surgery. RESULTS: A very high prevalence of suspicious/malignant cytology (Thy 4-5) at the first diagnosis (38/124; 31%) and during the follow-up (6/28; 22%) was found in HTN+ group. In HTN- group, 22/130 (17%) patients developed TN, but none showed malignant features during the follow up. HTN+ patients had higher prevalence of Thy 4-5 (44/152 = 28.9%) compared to NG patients (12/161 = 7.4%, p < 0.0001). Increased independent odds ratio (OR) for malignancy was conferred by serum TSH > 1.0 MUUI/ml, [OR 1.93, 95% confidence interval (CI) 1.41-2.64, p < 0.0001], male sex (OR 3.44, CI 1.48-8.02, p = 0.004) and HT (OR 3.14; CI 1.08-9.31, p < 0.05). Malignant histology (mostly PTC) was confirmed higher in HTN+ (48/70, 68.6%) compared to NG (15/37, 40.5%; p < 0.05). Higher prevalence of extrathyroidal infiltration (24/48, 50%) and vascular invasion (25/48, 52%) was found in HTN+ vs NG (2/15, 1.3% p < 0.01), (3/16, 1.8% p < 0.05), respectively. CONCLUSIONS: This study confirms higher prevalence of suspicious/malignant cytology and PTC at histology in nodular HT compared to NG, without evidence of malignancy in non-nodular HT patients during the follow-up. PMID- 28875269 TI - The Programming Optimization of Capacitorless 1T DRAM Based on the Dual-Gate TFET. AB - The larger volume of capacitor and higher leakage current of transistor have become the inherent disadvantages for the traditional one transistor (1T)-one capacitor (1C) dynamic random access memory (DRAM). Recently, the tunneling FET (TFET) is applied in DRAM cell due to the low off-state current and high switching ratio. The dual-gate TFET (DG-TFET) DRAM cell with the capacitorless structure has the superior performance-higher retention time (RT) and weak temperature dependence. But the performance of TFET DRAM cell is sensitive to programming condition. In this paper, the guideline of programming optimization is discussed in detail by using simulation tool-Silvaco Atlas. Both the writing and reading operations of DG-TFET DRAM depend on the band-to-band tunneling (BTBT). During the writing operation, the holes coming from BTBT governed by Gate2 are stored in potential well under Gate2. A small negative voltage is applied at Gate2 to retain holes for a long time during holding "1". The BTBT governed by Gate1 mainly influences the reading current. Using the optimized programming condition, the DG-TFET DRAM obtains the higher current ratio of reading "1" to reading "0" (107) and RT of more than 2 s. The higher RT reduces the refresh rate and dynamic power consumption of DRAM. PMID- 28875267 TI - Kingdom Chromista and its eight phyla: a new synthesis emphasising periplastid protein targeting, cytoskeletal and periplastid evolution, and ancient divergences. AB - In 1981 I established kingdom Chromista, distinguished from Plantae because of its more complex chloroplast-associated membrane topology and rigid tubular multipartite ciliary hairs. Plantae originated by converting a cyanobacterium to chloroplasts with Toc/Tic translocons; most evolved cell walls early, thereby losing phagotrophy. Chromists originated by enslaving a phagocytosed red alga, surrounding plastids by two extra membranes, placing them within the endomembrane system, necessitating novel protein import machineries. Early chromists retained phagotrophy, remaining naked and repeatedly reverted to heterotrophy by losing chloroplasts. Therefore, Chromista include secondary phagoheterotrophs (notably ciliates, many dinoflagellates, Opalozoa, Rhizaria, heliozoans) or walled osmotrophs (Pseudofungi, Labyrinthulea), formerly considered protozoa or fungi respectively, plus endoparasites (e.g. Sporozoa) and all chromophyte algae (other dinoflagellates, chromeroids, ochrophytes, haptophytes, cryptophytes). I discuss their origin, evolutionary diversification, and reasons for making chromists one kingdom despite highly divergent cytoskeletons and trophic modes, including improved explanations for periplastid/chloroplast protein targeting, derlin evolution, and ciliary/cytoskeletal diversification. I conjecture that transit peptide-receptor-mediated 'endocytosis' from periplastid membranes generates periplastid vesicles that fuse with the arguably derlin-translocon-containing periplastid reticulum (putative red algal trans-Golgi network homologue; present in all chromophytes except dinoflagellates). I explain chromist origin from ancestral corticates and neokaryotes, reappraising tertiary symbiogenesis; a chromist cytoskeletal synapomorphy, a bypassing microtubule band dextral to both centrioles, favoured multiple axopodial origins. I revise chromist higher classification by transferring rhizarian subphylum Endomyxa from Cercozoa to Retaria; establishing retarian subphylum Ectoreta for Foraminifera plus Radiozoa, apicomonad subclasses, new dinozoan classes Myzodinea (grouping Colpovora gen. n., Psammosa), Endodinea, Sulcodinea, and subclass Karlodinia; and ranking heterokont Gyrista as phylum not superphylum. PMID- 28875270 TI - Molecular evidence of tick-borne pathogens in Hyalomma anatolicum ticks infesting cattle in Xinjiang Uygur Autonomous Region, Northwestern China. AB - Although tick-borne pathogens have been widely reported in ticks in China, there is little information available on the prevalence of information in Hyalomma ticks from cattle. This study aims to determine the occurrence of pathogens in Hyalomma anatolicum collected from cattle in Xinjiang Uygur Autonomous Region, China, by PCR, sequencing and phylogenetic analysis. Borrelia burgdorferi s.s., Rickettsia massiliae and Anaplasma bovis were identified, whereas DNA of Ehrlichia species and an Anaplasma platys-like pathogen were also detected. Our findings highlight the risk of infection of animals and humans with these pathogens in north-western China. PMID- 28875271 TI - Comparative Effects of Schisandrin A, B, and C on Acne-Related Inflammation. AB - Inflammatory responses induced by Propionibacterium acnes are a major etiological factor in the pathogenesis of acne vulgaris. Schisandrin A, schisandrin B, and schisandrin C are the representative lignans of Schisandra chinensis (Turcz.) Baill. extract. Although anti-inflammatory effects of the lignans have been shown, their effects on acne-related inflammation caused by P. acnes have not been investigated and compared. We pretreated THP-1 human monocytic cells with 5, 10, and 20 MUM schisandrin A, B, and C, and stimulated the cells with P. acnes. Schisandrin B and C inhibited the release of inflammatory cytokines at a concentration of 5 MUM, while schisandrin A required a concentration of 10 MUM to exert the effects. All of the schisandrins decreased the levels of toll-like receptor 2, and schisandrin B and C reduced the intracellular mRNA expression of the receptor gene. We also studied the influence of schisandrins on the MAPK signaling pathway. Schisandrin A suppressed the P. acnes-induced activation of JNK, while exerting only a weak effect on ERK and p38. Schisandrin B exerted a strong effect on p38, a lesser effect on ERK, and almost no effect on JNK. Schisandrin C inhibited the phosphorylation of all three proteins, especially ERK. Furthermore, the three lignans also prevented the nuclear translocation of NF-kappaB. These results contribute to our understanding of the mechanisms underlying the effects of the three lignans on P. acnes-induced inflammation and suggest that schisandrins might be developed as pharmacological agents for acne therapy. PMID- 28875272 TI - LARSTM in ACL reconstruction: evaluation of 60 cases with 5-year minimum follow up. AB - PURPOSE: The injury of anterior cruciate ligament (ACL) causes joint instability and, in the absence of adequate treatment, progressive joint deterioration, meniscal lesions and development of post-traumatic osteoarthritis. METHODS: The purpose of this study was to evaluate the clinical, functional and radiographic outcomes and complications in a consecutive case series of 60 patients with minimum follow-up of 5 years who underwent an arthroscopic surgery for ACL reconstruction using LARSTM ligament. Patients with concomitant meniscal or chondral lesions in the same knee were excluded. RESULTS: The subjective evaluation of the patients involved in the study (Lysholm score, IKDC score and Tegner activity level scale) shows good/excellent results. The range of movement is optimal in most patients, and pain symptoms are considered mild. A total of 31.25% of the patients did not change their lifestyle that they had before the injury. None of the patients underwent resurgery in the same knee. In 85.4% of cases, X-ray images showed no signs of osteoarthritis after ACL reconstruction. CONCLUSIONS: Comparable with other series showed in the literature, this study assesses that the use of LARSTM in reconstruction of ACL is an excellent option for treating >40-year-old patients requesting rapid return to daily activities/sports also at the first surgery. By restoring knee stability, articular degeneration at short and medium follow-up was avoided. PMID- 28875273 TI - Host Genotype and Nitrogen Form Shape the Root Microbiome of Pinus radiata. AB - A central challenge in community ecology is understanding the role that phenotypic variation among genotypes plays in structuring host-associated communities. While recent studies have investigated the relationship between plant genotype and the composition of soil microbial communities, the effect of genotype-by-environment interactions on the plant microbiome remains unclear. In this study, we assessed the influence of tree genetics (G), nitrogen (N) form and genotype-by-environment interaction (G x N) on the composition of the root microbiome. Rhizosphere communities (bacteria and fungi) and root-associated fungi (including ectomycorrhizal and saprotrophic guilds) were characterised in two genotypes of Pinus radiata with contrasting physiological responses to exogenous organic or inorganic N supply. Genotype-specific responses to N form influenced the composition of the root microbiome. Specifically, (1) diversity and composition of rhizosphere bacterial and root-associated fungal communities differed between genotypes that had distinct responses to N form, (2) shifts in the relative abundance of individual taxa were driven by the main effects of N form or host genotype and (3) the root microbiome of the P. radiata genotype with the most divergent growth responses to organic and inorganic N was most sensitive to differences in N form. Our results show that intraspecific variation in tree response to N form has significant consequences for the root microbiome of P. radiata, demonstrating the importance of genotype-by-environment interactions in shaping host-associated communities. PMID- 28875274 TI - A Study of Moisture Sorption and Dielectric Processes of Starch and Sodium Starch Glycolate : Theme: Formulation and Manufacturing of Solid Dosage Forms Guest Editors: Tony Zhou and Tonglei Li. AB - PURPOSE: This study explored the potential of combining the use of moisture sorption isotherms and dielectric relaxation profiles of starch and sodium starch glycolate (SSG) to probe the location of moisture in dried and hydrated samples. METHODS: Starch and SSG samples, dried and hydrated, were prepared. For hydrated samples, their moisture contents were determined. The samples were probed by dielectric spectroscopy using a frequency band of 0.1 Hz to 1 MHz to investigate their moisture-related relaxation profiles. The moisture sorption and desorption isotherms of starch and SSG were generated using a vapor sorption analyzer, and modeled using the Guggenheim-Anderson-de Boer equation. RESULTS: A clear high frequency relaxation process was detected in both dried and hydrated starches, while for dried starch, an additional slower low frequency process was also detected. The high frequency relaxation processes in hydrated and dried starches were assigned to the coupled starch-hydrated water relaxation. The low frequency relaxation in dried starch was attributed to the local chain motions of the starch backbone. No relaxation process associated with water was detected in both hydrated and dried SSG within the frequency and temperature range used in this study. The moisture sorption isotherms of SSG suggest the presence of high energy free water, which could have masked the relaxation process of the bound water during dielectric measurements. CONCLUSION: The combined study of moisture sorption isotherms and dielectric spectroscopy was shown to be beneficial and complementary in probing the effects of moisture on the relaxation processes of starch and SSG. PMID- 28875275 TI - Decision-Making for the Management of Cystic Lesions of the Pancreas: How Satisfied Are Patients with Surgery? AB - INTRODUCTION: This study aims to understand patients' perspectives and satisfaction with choosing surgery for the treatment of pancreatic cystic lesions (PCLs). METHODS: A 62-question survey was administered to 113 patients who had a resection for a PCL by 12 surgeons at two pancreatic specialty centers (2004 2016). Patients' final diagnoses and perioperative outcomes were correlated to the survey's results using univariate analysis. RESULTS: Fear of cancer was quite or extremely important in most respondents' decision to have surgery (95.4%). Respondents were quite or fully satisfied with the outcomes of surgery (91.1%) and with the decision-making process (89.3%). Distress from anxiety about the cyst before surgery (58.6%) largely outweighed that from postsurgical lifestyle changes (14.4%). Furthermore, 88.7% of patients with pathologically non-malignant disease were quite or fully satisfied with their decision to have surgery, and patients with mucinous neoplasms reported high satisfaction rates independent of grade of dysplasia or malignancy (p = 0.641). CONCLUSION: Patients with a resected PCL are highly satisfied with their decision to have surgery, regardless of the final diagnosis or clinical outcome. Fear of cancer is the main driver in the decision-making process, and the anxiety of harboring a cyst is a greater cause of distress than are postsurgical lifestyle changes. PMID- 28875276 TI - Epigenetic and genetic landscape of uterine leiomyomas: a current view over a common gynecological disease. AB - PURPOSE: Despite the numerous studies on the factors involved in the genesis and growth of uterine leiomyomas, the pathogenesis of these tumors remains unknown. Intrinsic abnormalities of the myometrium, abnormal myometrial receptors for estrogen, and hormonal changes or altered responses to ischemic damage during the menstrual period may be responsible for the initiation of (epi)genetic changes found in these tumors. Considering these elements, we aimed to offer an overview about epigenetic and genetic landscape of uterine leiomyomas. METHODS: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. RESULTS: Several studies showed that leiomyomas have a monoclonal origin. Accumulating evidence converges on the risk factors and mechanisms of tumorigenesis: the translocation t (12;14) and deletion of 7q were found in the highest percentages of recurrence; dysregulation of the HMGA2 gene has been mapped within the critical 12q14-q15 locus. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has been poorly explored. The growth factors with mitogenic activity, such as transforming growth factor-beta3, fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I are elevated in fibroids and may have a role as effectors of the tumor promotion. CONCLUSION: The new clues on genetics and epigenetics, as well as about the growth factors that control normal and pathological myometrial cellular biology may be of great help for the development of new effective and less invasive therapeutic strategies in the near future. PMID- 28875277 TI - [Critical illness myopathy and polyneuropathy]. AB - An average of 50-80% of patients treated in the intensive care unit is affected by disturbances of neuromuscular functions due to damage to the nerves and muscles, which has led to the terms critical illness polyneuropathy and myopathy. Both components occur in 30-50% of patients, while the others predominantly show a pure myopathy, while pure neuropathy is rare. Meanwhile, the descriptive term of the concept as intensive care unit-acquired weakness (ICUAW) is preferred. The most significant risk factors for the development of ICUAW are sepsis, multiorgan dysfunction and acute respiratory distress syndrome (ARDS). In at least one third of patients, persistent impairment by paralysis, sensory disturbances and balance problems persist when they leave the ICU. At approximately 10%, these leg accentuated and highly everyday relevant disorders persist over the first year after ICU therapy. Pure myopathy rarely leads to residual disturbances, while the neuropathic component is responsible for long-term impairments. PMID- 28875278 TI - Investigation of peri-implant tissue conditions and peri-implant tissue stability in implants placed with simultaneous augmentation procedure: a 3-year retrospective follow-up analysis of a newly developed bone level implant system. AB - BACKGROUND: Guided bone regeneration (GBR) has been proven to be a reliable therapy to regenerate missing bone in cases of atrophy of the alveolar crest. The aim of the present retrospective analysis was to assess peri-implant tissue conditions and document peri-implant tissue stability in C-Tech implants when placed simultaneously with a GBR augmentation procedure. METHODS: A total of 47 implants, which were placed simultaneously with a GBR procedure with a synthetic bone substitute material in 20 patients, were investigated clinically and radiologically at least 3 years after loading. Implant survival, the width and thickness of peri-implant keratinized gingiva, probing depth, bleeding on probing (BOP), the Pink Esthetic Score (PES), peri-implant bone loss, and the presence of peri-implant osteolysis were determined. RESULTS: The follow-up investigation revealed a survival rate of 100% and only low median rates for probing depths (2.7 mm) and BOP (30%). The mean PES was 10.1 from the maximum value of 14. No osseous peri-implant defects were obvious, and the mean bone loss was 0.55 mm. CONCLUSIONS: In conclusion, implants placed in combination with a GBR procedure can achieve long-term stable functionally and esthetically satisfying results for replacing missing teeth in cases of atrophy of the alveolar crest. PMID- 28875280 TI - Metastases to the Parathyroid Glands: A Comprehensive Literature Review of 127 Reported Cases. AB - Metastases to the head and neck organs are uncommon, potentially representing the initial presentation of an occult malignancy. Single case reports and small series report metastases to the parathyroid gland, but there is no large review of the literature on secondary tumors involving the parathyroid glands. A review of the English literature between 1950 and 2017 was performed of all metastases or secondary involvement of the parathyroid glands. One hundred and twenty-seven cases of metastatic tumors were reported, although potentially significantly unrepresented in autopsy series (parathyroid glands are not routinely examined) and due to reporting bias. Women were affected more commonly than men (5.8:1; 99 vs. 17, respectively), with a mean age at presentation of 58.5 years, when reported. The most common primary sites of malignancies that metastasized to the parathyroid glands were breast carcinomas (66.9%, n = 85), melanoma (11.8%, n = 15), and lung carcinoma (5.5%, n = 7), with carcinomas representing 86.6% of metastases. Metastases were nearly always identified as part of widely metastatic disease, with only five (3.2%) cases reported as isolated metastases. Tumor-to tumor metastases comprised 5.5% of all metastases to the parathyroid glands (metastases to parathyroid adenoma). A significant clinical finding of metastases to the parathyroid glands was the development of deranged calcium homeostasis, well beyond the 9 (7.2%) cases with primary parathyroid gland disease present. Although concurrent conditions (renal disease; bone metastases) may partially affect calcium metabolism, the onset of calcium derangement seemed to coincide with parathyroid gland metastases and not systemic disease. In summary, metastases to the parathyroid glands are uncommon, potentially under-recognized in patients who have otherwise widely metastatic tumors. Women are affected more often than men, with breast carcinomas (66.9%) and melanoma (11.8%) the most common primary tumors. Calcium homeostasis is affected, probably as a result of parathyroid gland parenchymal destruction. PMID- 28875279 TI - Trauma to the Superior Mesenteric Artery and Superior Mesenteric Vein: A Narrative Review of Rare but Lethal Injuries. AB - Mesenteric vessels, including the superior mesenteric artery (SMA) and vein (SMV), provide and drain the rich blood supply of the midgut and hindgut. SMA and SMV injuries are rare and often lethal. Clinical management of these injuries is not well established, but treatment options include operative, non-operative, and endovascular strategies. A narrative review of the literature was conducted using MEDLINE Complete-EBSCO. Relevant studies, specifically those focusing on diagnosis and management of SMA and SMV injuries, were selected. Only original reports and collected series were selected to prevent duplication of cases. A search of the literature for mesenteric arterial injuries yielded 87 studies. Vessel-specific breakdown of the studies yielded 40 with SMA injuries and 41 with SMV injuries. These searches were winnowed to 26 individual studies, which were included in this collective review. Limitations of this study are similar to all narrative literature reviews: the dependence on previously published research and availability of references as outlined in our methodology. Although historically rare, mesenteric vessel injuries are seen with increasing incidence and continue to present a challenge to trauma surgeons due to their daunting mortality rates. Currently, universal treatment guidelines do not exist, but the various options for their management have been extensively reviewed in the literature. PMID- 28875281 TI - Ecotoxicity and antibiotic resistance of a mixture of hospital and urban sewage in a wastewater treatment plant. AB - Hospital and urban effluents are a source of diverse pollutants such as organic compounds, heavy metals, detergents, disinfectants, pharmaceuticals, and microorganisms resistant to antibiotics. Usually, these two types of effluent are mixed in the sewage network, but a pilot site in France now allows studying them separately or mixed to understand more about their characteristics and the phenomena that occur following their mixing. In this study, their ecotoxicity (Daphnia magna mobility, Pseudokirchneriella subcapitata growth, Brachionus calyciflorus reproduction, and SOS Chromotest) and antibiotic resistance (integron quantification) were assessed during mixing and treatment steps. The main results of this study are (i) the ecotoxicity and antibiotic resistance potentials of hospital wastewater are higher than in urban wastewater and (ii) mixing two different effluents does not lead to global synergistic or antagonistic effects on ecotoxicity and antibiotic resistance potential. The global additivity effect observed in this case must be confirmed by other studies on hospital and urban effluents on other sites to improve knowledge relating to this source of pollution and its management. PMID- 28875282 TI - Refining Coats' disease by ultra-widefield imaging and optical coherence tomography angiography. AB - PURPOSE: The purpose of our study was to describe ultra-widefield (UWF) imaging and optical coherence tomography angiography (OCT-A) findings in affected and fellow eyes of patients with Coats' disease. METHODS: Consecutive patients affected by Coats' disease were prospectively recruited at the Department of Ophthalmology, San Raffaele Hospital, Milan, Italy in this cross-sectional, observational study. Patients underwent UWF color fundus photographs, UWF green autofluorescence, UWF fluorescein angiography (FA), optical coherence tomography (OCT), with 3 * 3 mm and 6 * 6 mm OCT-A scans of the macula. Images were qualitatively evaluated by two independent operators for the presence of pathology. RESULTS: Eleven patients affected by Coats' disease (eight males, mean age 17.1 +/- 6.7 years). Nine and two patients had a clinical diagnosis of unilateral and bilateral disease, respectively. Five eyes had macular fibrosis. All clinically affected eyes exhibited retinal pathology at UWF imaging with the temporal sector most involved followed by the inferior, nasal, superior and macula. In all eyes with macular fibrosis, OCT-A revealed replacement of the foveal avascular zone with coarse vessels suggestive of vascularized fibrosis and flow void area in the choriocapillaris due to a masking effect; type 3 neovascularization was seen in 75% of cases. Seven out of nine clinically unaffected fellow eyes showed retinal pathology at UWF FA with the temporal quadrant most involved. CONCLUSION: We demonstrated that Coats' disease is a highly asymmetric bilateral disease and that UWF imaging is able to identify more retinal pathology than standard fundus imaging, thus guiding proper retinal photocoagulation. OCT-A allowed easy identification of type 3 neovascularization in a proportion of patients with macular fibrosis. PMID- 28875283 TI - Structural and biochemical characterization of DAXX-ATRX interaction. PMID- 28875284 TI - Predictive role of loco-regional radiotherapy among metastatic breast cancer patients who had undergone primary tumor surgery. PMID- 28875285 TI - Current status of cardiovascular surgery in Japan, 2013 and 2014: a report based on the Japan Cardiovascular Surgery Database 5. Thoracic aortic surgery. AB - BACKGROUND: Although open aortic repair (OAR) is still considered to be a standard treatment for thoracic aortic diseases, the indications for thoracic endovascular treatment (TEVAR)/hybrid aortic repair (HAR) have expanded in recent years. The purpose of this study was to review the current status of treatment of thoracic aortic diseases in Japan. METHODS: Data for 2013 and 2014 concerning surgery for diseases of the thoracic/thoracoabdominal aorta were extracted from the Japan Cardiovascular Surgery Database (JCVSD). The number of cases and operative mortality were evaluated in terms of pathologic diagnosis (acute dissection, chronic dissection, ruptured aneurysm, unruptured aneurysm), treatment modality (OAR, HAR, TEVAR), JapanSCORE (JS; <5%, 5-10%, 10-15%, >=15%), and their correlations. RESULTS: There were 30,271 total cases in this study and the overall operative mortality was 5.9%. Among the three types of treatment, 73.2% of patients underwent OAR (root 98.3%; ascending 97.4%; root to arch 95.5%; arch 81.7%; descending 34.2%; thoracoabdominal 64.4%). While the rate of OAR was negatively correlated with JS for the treatment of the thoracoabdominal region (JS < 5, 80.4%; 5% <= JS < 10, 67.6%; 10% <= JS < 15, 58.8%; JS >= 15, 55.7%), a correlation was not observed in other anatomic regions. The operative mortality associated with OAR was well reflected by JS (JS < 5, 2.1%; 5% <= JS < 10, 5.5%; 10% <= JS < 15, 10.2%; JS >= 15, 20.3%); however, the operative mortality associated with TEVAR/HAR was less than that with JS. CONCLUSIONS: The distribution of treatment differs depending on the site of disease and is not markedly influenced by JS. It is clear that JS is a reliable tool for estimating operative mortality in OAR. However, the observed operative mortality was lower than the JS in TEVAR/HAR, and a new risk score for TEVAR/HAR should be established. PMID- 28875286 TI - Learning About the Management of Physical Illness During the Postgraduate Training to Become a Good Psychiatrist. PMID- 28875287 TI - The Wandering Spleen. AB - ?. PMID- 28875288 TI - Severe leptospirosis in Morocco: comparative data from the Amazonian area. PMID- 28875289 TI - [Diagnostics of malignant melanoma of the skin : Recommendations of the current S3 guidelines on histology and molecular pathology]. AB - The updated S3 guidelines on malignant melanoma were established in August 2016. The principles of diagnostics and classification are based on the histopathological results from the primary tumor and if necessary the sentinel lymph nodes. The most important factor for prognosis is the tumor thickness according to Breslow and the detection of sentinel node micrometastases. The surgical safety margin after excision is dependent on the tumor thickness. Furthermore, ulceration of the primary tumor and presence of mitosis in melanomas less than 1 mm in thickness are also considered in the T-classification. The sentinel lymph nodes should be prepared according to established procedures using HE staining and immunohistochemical methods. The largest tumor diameter of a micrometastasis should be measured in tenths of a millimeter (Rotterdam classification). Molecular pathology testing for mutations in the BRAF and NRAS oncogenes should be carried out in patients with metastatic disease or surgically non-resectable tumors. In addition c-KIT mutations should be tested in acral lentiginous and mucosal melanomas. Treatment with signal transduction inhibitors is possible when mutations have been detected. PMID- 28875290 TI - Evaluation of [99mTc]Radiolabeled Macrophage Mannose Receptor-Specific Nanobodies for Targeting of Atherosclerotic Lesions in Mice. AB - PURPOSE: Macrophage accumulation characterizes the development of atherosclerotic plaques, and the presence of certain macrophage subsets might be an indicator of plaque phenotype and (in)stability. The macrophage mannose receptor (MMR) is expressed on alternatively activated macrophages and found at sites of intraplaque hemorrhage and neovascularization. It has been proposed as target to identify vulnerable plaques. Therefore, we aimed to assess the feasibility of using anti-MMR nanobodies (Nbs) as molecular tracers for nuclear imaging in an animal model of atherosclerosis. PROCEDURE: Anti-MMR and control Nb, radiolabeled with Tc-99m, were injected in ApoE-/- and/or C57Bl/6 mice (n = 6). In vivo competition studies involving pre-injection of excess of unlabeled anti-MMR Nb (n = 3) and injection of anti-MMR Nb in MMR-/- mice (n = 3) were performed to demonstrate specificity. At 3 h p.i. radioactive uptake in organs, tissues and aorta segments were evaluated. Autoradiography and immunofluorescence were performed on aortic sections. RESULTS: Significantly higher uptake was observed in all aortic segments of ApoE-/- mice injected with anti-MMR Nb compared to control Nb (1.36 +/- 0.67 vs 0.38 +/- 0.13 percent of injected dose per gram (%ID/g), p <= 0.001). Surprisingly, high aortic uptake was also observed in C57Bl/6 mice (1.50 +/- 0.43%ID/g, p >= 0.05 compared to ApoE-/-), while aortic uptake was reduced to background levels in the case of competition and in MMR-/- mice (0.46 +/- 0.10 and 0.22 +/- 0.06%ID/g, respectively; p <= 0.001). Therefore, expression of MMR along healthy aortas was suggested. Autoradiography showed no specific radioactive signal within atherosclerotic plaques, but rather localization of the signal along the aorta, correlating with MMR expression in perivascular tissue as demonstrated by immunofluorescence. CONCLUSIONS: No significant uptake of MMR-specific Nb could be observed in atherosclerotic lesions of ApoE-/- mice in this study. A specific perivascular signal causing a non-negligible background level was demonstrated. This observation should be considered when using MMR as a target in molecular imaging of atherosclerosis, as well as use of translational animal models with vulnerable plaques. PMID- 28875291 TI - Persistence Behavior of Penoxsulam Herbicide in Two Different Soils. AB - Penoxsulam, a new post emergence herbicide is suspected to be toxic to aquatic organisms, crop plants and also to soil microbial community even at low concentrations. Laboratory studies were therefore performed to examine the persistence of, penoxsulam in two different soils at two application rates (0.5 and 1.0 ug g-1). The study revealed that the dissipation followed the first order kinetics with a half life of 3.48 and 3.57 days at 0.5 ug g-1 and 4.1 and 4.17 days at 1.0 ug g-1 fortification rate. Both microbial- and photo-degradation seemed to play a vital role in the dissipation of penoxsulam. The results of LC MS/MS revealed that one minor and five major metabolites were formed during the degradation process of the herbicide and the cleavage of sulfonamide bridge served as the major metabolic pathway. PMID- 28875292 TI - Restless farewell. PMID- 28875293 TI - Nickel accumulation and its effect on growth, physiological and biochemical parameters in millets and oats. AB - With the boom in industrialization, there is an increase in the level of heavy metals in the soil which drastically affect the growth and development of plants. Nickel is an essential micronutrient for plant growth and development, but elevated level of Ni causes stunted growth, chlorosis, nutrient imbalance, and alterations in the defense mechanism of plants in terms of accumulation of osmolytes or change in enzyme activities like guiacol peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD). Ni-induced toxic response was studied in seedlings of finger millet, pearl millet, and oats in terms of seedling growth, lipid peroxidation, total chlorophyll, proline content, and enzymatic activities. On the basis of germination and growth parameters of the seedling, finger millet was found to be the most tolerant. Nickel accumulation was markedly lower in the shoots as compared to the roots, which was the highest in finger millet and the lowest in shoots of oats. Plants treated with a high concentration of Ni showed significant reduction in chlorophyll and increase in proline content. Considerable difference in level of malondialdehyde (MDA) content and activity of antioxidative enzymes indicates generation of redox imbalance in plants due to Ni induced stress. Elevated activities of POD and SOD were observed with high concentrations of Ni while CAT activity was found to be reduced. It was observed that finger millet has higher capability to maintain homeostasis by keeping the balance between accumulation and ROS scavenging system than pearl millet and oats. The data provide insight into the physiological and biochemical changes in plants adapted to survive in Ni-rich environment. This study will help in selecting the more suitable crop species to be grown on Ni-rich soils. PMID- 28875294 TI - A median sacral artery anterior to the iliocaval junction: a case report anatomical considerations and clinical relevance for spine surgery. AB - BACKGROUND AND IMPORTANCE: The median sacral artery (MSA) is a relatively small vessel that always arises from the posterior, terminal part of the infrarenal aorta. In most cases, the MSA runs behind the iliocaval junction. Here, we describe a very rare case of an MSA running in front of this junction. CASE REPORT: During a human cadaveric dissection of the retroperitoneal area, we unexpectedly observed that the MSA passed in front of the left common iliac vein. CONCLUSION: The anatomy of the MSA has been extensively described and variations are quite rare. On the basis of this specific case, knowledge of the anatomic interactions between the MSA and other lumbar retroperitoneal vessels may help to avoid potential complications during surgery. PMID- 28875295 TI - A prospective randomized comparison among SWL, PCNL and RIRS for lower calyceal stones less than 2 cm: a multicenter experience : A better understanding on the treatment options for lower pole stones. AB - PURPOSE: To prospectively evaluate the efficacy and safety of RIRS, SWL and PCNL for lower calyceal stones sized 1-2 cm. MATERIALS AND METHODS: Patients with a single lower calyceal stone with an evidence of a CT diameter between 1 and 2 cm were enrolled in this multicenter, randomized, unblinded, clinical trial study. Patients were randomized into three groups: group A: SWL (194 pts); group B: RIRS (207 pts); group C: PCNL (181 pts). Patients were evaluated with KUB radiography (US for uric acid stones) at day 10 and a CT scan after 3 months. The CONSORT 2010 statement was adhered to where possible. The collected data were analyzed. RESULTS: The mean stone size was 13.78 mm in group A, 14.82 mm in group B and 15.23 mm in group C (p = 0.34). Group C compared to group B showed longer operative time [72.3 vs. 55.8 min (p = 0.082)], fluoroscopic time [175.6 vs. 31.8 min (p = 0.004)] and hospital stay [3.7 vs. 1.3 days (p = 0.039)]. The overall stone-free rate (SFR) was 61.8% for group A, 82.1% for group B and 87.3% for group C. The re-treatment rate was significantly higher in group A compared to the other two groups, 61.3% (p < 0.05). The auxiliary procedure rate was comparable for groups A and B and lower for group C (p < 0.05). The complication rate was 6.7, 14.5 and 19.3% for groups A, B and C, respectively. CONCLUSIONS: RIRS and PCNL were more effective than SWL to obtain a better SFR and less auxiliary and re-treatment rate in single lower calyceal stone with a CT diameter between 1 and 2 cm. RIRS compared to PCNL offers the best outcome in terms of procedure length, radiation exposure and hospital stay. ISRCTN 55546280. PMID- 28875296 TI - A Moderator Model of Alcohol Use and Dating Aggression among Young Adults. AB - Dating aggression has been identified as a priority public health concern. Although alcohol use is a known robust risk factor for dating aggression involvement, such usage is neither necessary nor sufficient for dating aggression involvement. As such, a growing topic of interest is a better understanding of when, and for whom, alcohol use increases risk. A theoretical moderator model posits that associations between alcohol use and dating aggression involvement vary depending on both background (e.g., psychopathology) and situational (e.g., relationship characteristics) risk factors. Alcohol use is thought to be more strongly associated with dating aggression in the context of these other risk factors. Using an intensive longitudinal design, we collected six waves of data spanning 6 months from 120 participants (60 females; M age W1 = 22.44). Alcohol use and relationship risk were both associated with increases in dating aggression involvement. Consistent with a moderator model, interactions emerged between alcohol use and relationship risk for subsequent dating aggression involvement. The findings underscore the importance of alcohol use and relationship risk for the development of intervention and prevention programs. PMID- 28875298 TI - 2D longitudinal LV speckle tracking strain pattern in breast cancer survivors: sports activity vs exercise as prescription model. AB - Prevention strategies are important to optimize and to manage heart care in breast cancer survivors. Regular physical activity at moderate intensity is normally proposed to maintain myocardial performance; however, no data is available about the different impact of different levels of physical exercise. 2D speckle tracking echocardiography (2DSTE) is an accepted method for early detection of myocardial dysfunction. The study aims to monitor the cardiac performances in breast cancer survivors by 2DSTE analysis to manage sports activity vs physical activity. Two groups of previous breast cancer survivors (33 BCS) trained at moderate intensity and 55 athletes practicing dragon boat (DBA) sport were enrolled. They were matched with two healthy subjects groups: 23 competitive female athletes practicing different sports and 20 healthy women trained with exercise as prescription model. All women were studied by a complete echo examination including LV global longitudinal strain (GLS) assessment (XStrain-Esaote). EF and GS are only significantly higher in healthy subjects ( 25.4 +/- 2.1). Nevertheless, GLS values are within the normal range for all groups. Particularly, GS does not show any significant differences among subjects (-19.93 +/- 4) practicing exercise as prescription when compared to the DBA competitive trained group. 2DSTE method is an appropriate method to supervise the intensity of exercise in breast cancer patients. Particularly, GLS can optimize and improve cancer therapy supporting and creating efficiencies within the health system confirming the role of the exercise prescription therapy in maintaining normal heart function. PMID- 28875297 TI - Breathing-motion-compensated robotic guided stereotactic body radiation therapy : Patterns of failure analysis. AB - PURPOSE: We retrospectively evaluated the patterns of failure for robotic guided real-time breathing-motion-compensated (BMC) stereotactic body radiation therapy (SBRT) in the treatment of tumors in moving organs. PATIENTS AND METHODS: Between 2011 and 2016, a total of 198 patients with 280 lung, liver, and abdominal tumors were treated with BMC-SBRT. The median gross tumor volume (GTV) was 12.3 cc (0.1 372.0 cc). Medians of mean GTV BEDalpha/beta =10 Gy (BED = biological effective dose) was 148.5 Gy10 (31.5-233.3 Gy10) and prescribed planning target volume (PTV) BEDalpha/beta =10 Gy was 89.7 Gy10 (28.8-151.2 Gy10), respectively. We analyzed overall survival (OS) and local control (LC) based on various factors, including BEDs with alpha/beta ratios of 15 Gy (lung metastases), 21 Gy (primary lung tumors), and 27 Gy (liver metastases). RESULTS: Median follow-up was 10.4 months (2.0-59.0 months). The 2-year actuarial LC was 100 and 86.4% for primary early and advanced stage lung tumors, respectively, 100% for lung metastases, 82.2% for liver metastases, and 90% for extrapulmonary extrahepatic metastases. The 2-year OS rate was 47.9% for all patients. In uni- and multivariate analysis, comparatively lower PTV prescription dose (equivalence of 3 * 12-13 Gy) and higher average GTV dose (equivalence of 3 * 18 Gy) to current practice were significantly associated with LC. For OS, Karnofsky performance score (100%), gender (female), and SBRT without simultaneous chemotherapy were significant prognostic factors. Grade 3 side effects were rare (0.5%). CONCLUSIONS: Robotic guided BMC-SBRT can be considered a safe and effective treatment for solid tumors in moving organs. To reach sufficient local control rates, high average GTV doses are necessary. Further prospective studies are warranted to evaluate these points. PMID- 28875299 TI - 1H, 13C and 15N resonance assignments and secondary structures of cyclophilin 2 from Trichomonas vaginalis. AB - Cyclophilins are peptidyl prolyl isomerases that play an important role in a wide variety of biological functions like protein folding and trafficking, intracellular and extracellular signaling pathways, nuclear translocation and in pre-mRNA splicing. Two cyclophilins have been identified in the parasitic organism Trichomonas vaginalis and were named as TvCyP1 and TvCyP2. The 2 enzymes have been found to interact with Myb transcription factors in the parasite which regulate the iron induced expression of ap65-1 gene leading to cytoadherence of the parasite to human vaginal epithelial cells to cause the disease trichomoniasis. TvCyP2 was found to interact specifically with Myb3 to regulate nuclear translocation of the transcription factor. It would be intriguing to identify the binding site of both proteins as it could pave way to newer targets for drug discovery. Here we report the 1H, 13C and 15N resonance assignments and secondary structure information of TvCyP2 that could help us investigate the interaction between Myb3 and TvCyP2 in detail using NMR. PMID- 28875301 TI - No Need for Prophylactic Abdominal Ice Packing During Radioembolization. PMID- 28875303 TI - RGO and Three-Dimensional Graphene Networks Co-modified TIMs with High Performances. AB - With the development of microelectronic devices, the insufficient heat dissipation ability becomes one of the major bottlenecks for further miniaturization. Although graphene-assisted epoxy resin (ER) display promising potential to enhance the thermal performances, some limitations of the reduced graphene oxide (RGO) nanosheets and three-dimensional graphene networks (3DGNs) hinder the further improvement of the resulting thermal interface materials (TIMs). In this study, both the RGO nanosheets and 3DGNs are adopted as co modifiers to improve the thermal conductivity of the ER. The 3DGNs provide a fast transport network for phonon, while the presence of RGO nanosheets enhances the heat transport at the interface between the graphene basal plane and the ER. The synergy of these two modifiers is achieved by selecting a proper proportion and an optimized reduction degree of the RGO nanosheets. Moreover, both the high stability of the thermal conductivity and well mechanical properties of the resulting TIM indicate the potential application prospect in the practical field. PMID- 28875302 TI - Laparoscopic approaches to complicated diverticulitis. AB - BACKGROUND: The objective of this article is to review the evolving role of laparoscopic surgery in the treatment of complicated diverticulitis. PURPOSE: The authors attempted to give readers a concise insight into the evidence available in the English language literature. This study does not offer a systematic review of the topic, rather it highlights the role of laparoscopy in the treatment of complicated diverticulitis. CONCLUSIONS: New level 1 evidence suggest that observation rather than elective resection following nonoperative management of diverticulitis with abscess and/or extraluminal air is not below the standard of care. Implementation of nonoperative management may result in increased prevalence of sigmoid strictures. PMID- 28875304 TI - Evaluation of the acaricidal activity of thymol incorporated in two formulations for topical use against immature stages of Rhipicephalus sanguineus sensu lato (Latreille, 1806) (Acari: Ixodidae). AB - The objective of this study was to assess, for the first time, the in vitro acaricidal activity of two topical formulations containing thymol, on immature stages of Rhipicephalus sanguineus sensu lato. For this purpose, two base formulations were prepared: an oil-in-water (O/W) emulsion and a hydroalcoholic solution, containing different thymol concentrations (0.5 to 20 mg/mL). We used the larval packet test for non-engorged larvae and nymphs, and the immersion test for engorged larvae and nymphs. For emulsion, a mortality rate of 94.2% was achieved at 0.75 mg/mL in non-engorged larvae. For engorged larvae, there was 95.0% mortality at 5.0 mg/mL. Non-engorged nymphs showed 83.3% mortality at 2.5 mg/mL, and for engorged nymphs, 86.0% mortality was verified at 5.0 mg/mL. For the hydroalcoholic solution, the mortality found for non-engorged larvae was 88.1% at 2.5 mg/mL. For engorged larvae, the highest mortality was 25.0% at 20 mg/mL; non-engorged nymphs had 91.0% mortality at 1.0 mg/mL and for engorged nymphs; the maximum value verified was 18.3% mortality at 20 mg/mL. Preliminary stability tests were carried, and the hydroalcoholic solution remained stable under all the conditions analyzed. The O/W emulsion showed signs of early instability at the concentration of 5.0 mg/mL. The results obtained indicate that the acaricidal activity of thymol, when included in the proposed formulations, was enhanced against non-engorged larvae with topical treatment in comparison with data in the literature. Although there were variations in toxicity between the different stages, these formulations are promising for future therapeutic use. PMID- 28875300 TI - Advances in the Application and Impact of MicroRNAs as Therapies for Skin Disease. AB - The advent of RNA interference (RNAi) technology has profoundly impacted molecular biology research and medicine but has also advanced the field of skin care. Both effector molecules of RNAi, short-interfering RNA molecules and microRNAs (miRNAs), have been explored for their relative impact and utility for treating a variety of skin conditions. These post-transcriptional RNA regulatory molecules down-modulate protein expression through targeting of the 3' untranslated regions of messenger RNAs, leading to their degradation or repression through sequestration. As researchers hunt for genetic linkages to skin diseases, miRNA regulators have emerged as key players in the biology of keratinocytes, fibroblasts, melanocytes, and other cells of the skin. Herein, we attempt to coalesce the current efforts to combat various skin disorders and diseases through the development of miRNA-based technologies. PMID- 28875305 TI - Highly efficient base editing in human tripronuclear zygotes. PMID- 28875306 TI - Maternal serum calcitriol during pregnancy and risk of childhood onset type 1 diabetes. PMID- 28875307 TI - The parA Region of Broad-Host-Range PromA Plasmids Is a Carrier of Mobile Genes. AB - The ecological competences in microbiomes are driven by the adaptive capabilities present within microbiome members. Horizontal gene transfer (HGT) promoted by plasmids provides a rapid adaptive strategy to microbiomes, an interesting feature considering the constantly changing conditions in most environments. This study examined the parA locus, found in the highly promiscuous PromA class of plasmids, as the insertion site for incoming genes. A novel PCR system was designed that enabled examining insertions into this locus. Microbiomes of mangrove sediments, salt marsh, mycosphere, and bulk soil revealed habitat specific sets of insertions in this plasmid region. Furthermore, such habitats could be differentiated based on patterns of parA-inserted genes, and the genes carried by these plasmids. Thus, a suite of dioxygenase-related genes and transposase elements were found in oil-affected mangroves, whereas genes involved in nitrogen and carbon cycling were detected in salt marsh and soils. All genes detected could be associated with capabilities of members of the microbiome to adapt to and survive in each habitat. The methodology developed in this work was effective, sensitive, and practical, allowing detection of mobilized genes between microorganisms. PMID- 28875308 TI - Physical, Social, and Political Inequities Constraining Girls' Menstrual Management at Schools in Informal Settlements of Nairobi, Kenya. AB - Access to adequate water and sanitation is limited in informal settlements, contributing to girls' challenges managing menstruation at school, especially when they cannot access materials to absorb menstrual blood and appropriate facilities for hygiene. This study documents differences between girls' experience of menstruation at public schools (where the Kenyan government provides menstrual pads) and private schools (where pads are not provided) in two informal settlements of Nairobi, Kenya. Results showed that supply chains to public schools were not reliable, and equitable pad provision was not assured. Girls in private schools struggled to access pads because they were not provided. Sanitation facilities were physically available, but Muslim girls were unable to practice ablution due to the design of toilets in our study schools. Girls experienced fear and anxiety due to harassment from male peers and had incomplete information about menstruation from teachers. Findings suggest that practitioners and policy-makers should acknowledge the diversity of school populations and monitor programs to ensure efforts do not contribute to inequity. PMID- 28875309 TI - Early life adversity influences stress response association with smoking relapse. AB - RATIONALE: We examined the hypothesis that stress-related blunting of cortisol in smokers is particularly pronounced in those with a history of severe life adversity. OBJECTIVES: The two aims of this study were first to examine hormonal, craving, and withdrawal symptoms during ad libitum smoking and after the first 24 h of abstinence in smokers who experienced high or low levels of adversity. Second, we sought to examine the relationship between adversity and hypothalamic pituitary-adrenal (HPA) hormones to predict relapse during the first month of a smoking cessation attempt. METHODS: Hormonal and self-report measures were collected from 103 smokers (49 women) during ad libitum smoking and after the first 24 h of abstinence. HPA hormones were measured during baseline rest and in response to acute stress in both conditions. All smokers were interested in smoking cessation, and we prospectively used stress response measures to predict relapse during the first 4 weeks of the smoking cessation attempt. RESULTS: The results showed that high adversity was associated with higher distress and smoking withdrawal symptoms. High level of early life adversity was associated with elevated HPA activity, which was found in both salivary and plasma cortisol. Enhanced adrenocorticotropic hormone (ACTH) stress response was evident in high adversity but not in low-adversity relapsers. CONCLUSIONS: This study demonstrated that early life adversity is associated with stress-related HPA responses. The study also demonstrated that, among smokers who experienced a high level of life adversity, heightened ACTH and cortisol responses were linked with increased risk for smoking relapse. PMID- 28875311 TI - Bisphenol A exposure perturbs visual function of adult cats by remodeling the neuronal activity in the primary visual pathway. AB - Bisphenol A (BPA), a common environmental xenoestrogen, has been implicated in physiological and behavioral impairment, but the neuronal basis remains elusive. Although various synaptic mechanisms have been shown to mediate BPA-induced brain deficits, there are almost no reports addressing its underlying physiological mechanisms at the individual neuron level, particularly in the primary visual system. In the present study, using multiple-channel recording technique, we recorded the responses of single neurons in the primary visual system of cats to various direction stimuli both before and after BPA exposure. The results showed that the orientation selectivity of neurons in the primary visual cortex (area 17, A17) was obviously decreased after 2 h of intravenous BPA administration (0.2 mg/kg). Moreover, there were worse performances of information transmission of A17 neurons, presenting markedly decreased signal-to-noise ratio (SNR). To some extent, these functional decreases were attributable to the altered information inputs from lateral geniculate nucleus (LGN), which showed an increased spontaneous activity. Additionally, local injection of BPA (3.3 MUg/ml) in A17 resulted in an obvious increase in orientation selectivity and a decrease in neuronal activity, involving enhanced activity of fast-spiking inhibitory interneurons. In conclusion, our results first demonstrate that acute BPA exposure can restrict the visual perception of cats, mainly depending on the alteration of the LGN projection, not the intercortical interaction. Importantly, BPA-induced-brain deficits might not only be confined to the cortical level but also occur as early as at the subcortical level. PMID- 28875310 TI - Simultaneous analysis of multiple T helper subsets in leprosy reveals distinct patterns of Th1, Th2, Th17 and Tregs markers expression in clinical forms and reactional events. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Previous studies have demonstrated that the difference among clinical forms of leprosy can be associated with the immune response of patients, mainly by T helper (Th) and regulatory T cells (Tregs). Then, aiming at clarifying the immune response, the expression of cytokines related to Th1, Th2, Th17 and Tregs profiles were evaluated by qPCR in 87 skin biopsies from leprosy patients. Additionally, cytokines and anti-PGL-1 antibodies were determined in serum by ELISA. The results showed that the expression of various targets (mRNA) related to Th1, Th2, Th17 and Tregs were significantly modulated in leprosy when compared with healthy individuals, suggesting the presence of a mixed profile. In addition, the targets related to Th1 predominated in the tuberculoid pole and side and Th2 and Tregs predominated in the lepromatous pole and side; however, Th17 targets showed a mixed profile. Concerning reactional events, Tregs markers were decreased and IL 15 was increased in reversal reaction and IL-17F, CCL20 and IL-8 in erythema nodosum leprosum, when compared with the respective non-reactional leprosy patients. Additionally, ELISA analysis demonstrated that IL-22, IL-6, IL-10 and anti-PGL-1 antibody levels were significantly higher in the serum of patients when compared with healthy individuals, and IL-10 and anti-PGL-1 antibodies were also increased in the lepromatous pole and side. Together, these results indicate that Th1, Th2 and Th17 are involved in the determination of clinical forms of leprosy and suggest that decreased Tregs activity may be involved in the pathogenesis of reactional events. PMID- 28875312 TI - Indication of extrahepatic bile duct resection for gallbladder cancer. AB - PURPOSE: Extrahepatic bile duct (EHBD) resection is performed as part of radical cholecystectomy for gallbladder (GB) cancer. However, the indication for EHBD resection is still controversial. The aim of the present study was to evaluate the prognostic value of this procedure. METHODS: Patients who underwent surgical resection for GB cancer with curative intent were enrolled. We divided GB cancer into two categories based on the tumor location: proximal-type and distal-type tumors. The former refers to tumors involving the neck or cystic duct, while the latter comprises tumors located between the body and fundus. RESULTS: This study included 80 patients, 40 each with proximal- and distal-type tumors. Proximal tumor location, lymph node metastasis, and a serum carcinoembryonic antigen level > 5.0 ng/mL were independent predictors of poor prognosis. The 5-year survival rates of patients with proximal-type and distal-type tumors were 33.3 and 73.5%, respectively. Patients with proximal-type tumors showed significantly lower rates of R0 resection, more frequently had >= 3 metastatic lymph nodes, and exhibited a higher rate of perineural invasion. EHBD resection improved prognoses only in patients with proximal-type tumors but not in those with distal-type tumors. In the former group, EHBD resection significantly reduced the rate of local or regional lymph node recurrence. CONCLUSIONS: Extended cholecystectomy with EHBD resection should be performed for patients with GB cancer involving the neck and cystic duct to reduce local and regional lymph node recurrence and achieve better prognosis. PMID- 28875313 TI - Hip fracture risk in patients with burn injury: a retrospective cohort study in Taiwan. AB - : This work aimed to evaluate the hip fracture risk for patients with burn injury. A total of 16,430 patients with burn injury had an adjusted hazard ratio of 1.54 to encounter a hip fracture, compared with controls without the injury. These results encourage future studies focusing on mechanisms leading to fracture associated with burn injury. INTRODUCTION: The relationship between burn injury and hip fracture risk is unclear. We conducted a retrospective cohort study to investigate this relationship. METHODS: From insurance data of Taiwan, we identified a cohort with 16,430 burn patients in 2000-2010 and a comparison cohort of 65,716 persons without the history of burn, frequency matched by sex, age, and diagnosis date. Both cohorts were followed up to the end of 2011 to evaluate the risk of hip fracture. RESULTS: Patients with burn injury were 1.62 fold more likely than comparisons to encounter a hip fracture (6.95 vs. 4.28 per 1000 person-years), with an adjusted hazard ratio (aHR) of 1.54 (95% confidence interval (CI) = 1.40-1.68). The fracture incidence increased with age and is slightly greater for women than for men in both cohorts. The fracture risk was greater for patients with burn in the eyes, face, and head with an incidence of 7.14 per 1000 person-years, or an aHR of 2.09 (95% CI = 1.53, 2.86). Diabetes and osteoporosis were also associated with an increased hip fracture risk. CONCLUSION: Burn injury is associated with an increased risk of hip fracture. Diabetes and osteoporosis are associated with an enhanced risk. PMID- 28875314 TI - A Systematic Literature Review of Economic Evaluations of Antibiotic Treatments for Clostridium difficile Infection. AB - BACKGROUND AND OBJECTIVE: Clostridium difficile infection (CDI) is associated with high management costs, particularly in recurrent cases. Fidaxomicin treatment results in lower recurrence rates than vancomycin and metronidazole, but has higher acquisition costs in Europe and the USA. This systematic literature review summarises economic evaluations (EEs) of fidaxomicin, vancomycin and metronidazole for treatment of CDI. METHODS: Electronic databases (MEDLINE(r), Embase, Cochrane Library) and conference proceedings (ISPOR, ECCMID, ICAAC and IDWeek) were searched for publications reporting EEs of fidaxomicin, vancomycin and/or metronidazole in the treatment of CDI. Reference bibliographies of identified manuscripts were also reviewed. Cost-effectiveness was evaluated according to the overall population of patients with CDI, as well as in subgroups with severe CDI or recurrent CDI, or those at higher risk of recurrence or mortality. RESULTS: Overall, 27 relevant EEs, conducted from the perspective of 12 different countries, were identified. Fidaxomicin was cost-effective versus vancomycin and/or metronidazole in 14 of 24 EEs (58.3%), vancomycin was cost effective versus fidaxomicin and/or metronidazole in five of 27 EEs (18.5%) and metronidazole was cost-effective versus fidaxomicin and/or vancomycin in two of 13 EEs (15.4%). Fidaxomicin was cost-effective versus vancomycin in most of the EEs evaluating specific patient subgroups. Key cost-effectiveness drivers were cure rate, recurrence rate, time horizon, drug costs and length and cost of hospitalisation. CONCLUSIONS: In most EEs, fidaxomicin was demonstrated to be cost-effective versus metronidazole and vancomycin in patients with CDI. These results have relevance to clinical practice, given the high budgetary impact of managing CDI and increasing restrictions on healthcare budgets. OTHER: This analysis was initiated and funded by Astellas Pharma Inc. PMID- 28875315 TI - Carotid artery stiffness evaluated early by wave intensity in normal left ventricular function in post-radiotherapy patients with nasopharyngeal carcinoma. AB - PURPOSE: This study aims to assess carotid elasticity early in normal left ventricular function in post-radiotherapy patients with nasopharyngeal carcinoma (NPC) by wave intensity. METHODS: Sixty-seven post-radiotherapy patients all with normal left ventricular function were classified into group NPC1 and group NPC2 based on their carotid intima-media thickness. Thirty age- and sex-matched NPC patients without any history of irradiation and chemotherapy were included as a control group. Carotid parameters, including stiffness constant (beta), pressure strain elastic modulus (Ep), arterial compliance (AC), stiffness constant pulse wave velocity (PWVbeta), and wave intensity pulse wave velocity (PWVWI) were measured. RESULTS: There were no significant differences in conventional echocardiographic variables among the three groups. In comparison with the control group, beta, Ep, PWVbeta, and PWVWI were significantly increased, while AC was significantly decreased in the NPC1 and NPC2 groups, and there were differences between the NPC1 group and NPC2 group (all P < 0.05). CONCLUSION: This study suggested that carotid artery stiffness increased with reduced carotid compliance in post-RT with NPC. PMID- 28875316 TI - Reply to the letter to the editor concerning: Chronic rhinosinusitis with nasal polyps are associated with chronic otitis media in the elderly. PMID- 28875317 TI - Editorial: Do Orthopaedic Surgeons Belong on the Sidelines at American Football Games? PMID- 28875319 TI - Kisspeptin expression features in the arcuate and anteroventral periventricular nuclei of hypothalamus of letrozole-induced polycystic ovarian syndrome in rats. AB - PURPOSE: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of the reproductive system characterized by polycystic ovaries and androgen excess. Letrozole is a nonsteroidal aromatase inhibitor that is used in experimental research to induce PCOS. Kisspeptin is an essential protein in regulation of cyclicity. Kisspeptin receptor is expressed in the hypothalamus and pituitary glands, and kisspeptin containing neurons are affected from sex steroid hormones. We aimed to investigate the number of kisspeptin-positive cells in the arcuate (Arc) and anteroventral periventricular nuclei (AVPV) of hypothalamus in the letrozole-induced PCOS. METHODS: 40 female Wistar rats were divided into the proestrus control, diestrus control, proestrus vehicle, diestrus vehicle and letrozole. Animals were sacrificed after 3 weeks, and sera, ovary and brain samples were harvested for further evaluations. RESULTS: Letrozole group had high weight gain, high numbers of ovarian follicular cysts, high levels of luteinizing hormone and testosterone and increase number of kisspeptin-positive cells in the Arc nucleus, as compared with the control groups (P <= 0.05 vs. proestrus control and proestrus vehicle). Letrozole group showed a decrease in the number of kisspeptin-positive cells in the AVPV nucleus (P <= 0.05 vs. proestrus control and proestrus vehicle). CONCLUSION: Our findings show that the number of kisspeptin-positive cells may be affected from letrozole, and that the changes in the number of these cells may be in favor of the appearance of PCOS features in this group. PMID- 28875320 TI - [Low back pain in rheumatoid arthritis]. AB - Low back pain (LBP) in patients with rheumatoid arthritis (RA) has so far been of little concern in clinical investigations. The main focus of scientific publications on spinal problems in RA was the cervical spine. In a recent study, we could demonstrate that LBP in RA patients leads to a significantly higher degree of disability and depression as well as to a reduction in quality of life compared to RA patients without LBP. If there is a specific reason for the additional symptom of LBP, such as spinal stenosis or segmental instability, surgical treatment may be indicated to improve disability and quality of life. For a successful outcome of spinal surgery it is important to address the specific aspects of RA patients, such as poor bone quality and the immunosuppressive effect of antirheumatic drug treatment. Whenever possible, minimally invasive surgical techniques should be used and the immunosuppressive medication should be stopped before surgery. PMID- 28875321 TI - Admission-to-discharge temperature reduction in decompensated heart failure is associated with rehospitalization. AB - INTRODUCTION: Decreasing body temperature on first follow-up visit-relative to discharge-predicts early rehospitalization in heart failure (HF). We studied whether admission-to-discharge temperature reduction was associated with increased HF rehospitalization in the ESCAPE trial. METHODS: We compared patients with or without >=1 degrees C decrease in temperature from admission-to discharge. The study endpoint was rehospitalization due to HF for up to 6 months after discharge. RESULTS: Among 354 patients (average age 57 years, 73% men) with recorded admission and discharge temperature, 22 (6.2%) had an admission-to discharge temperature reduction >=1 oC. Patients with admission-to-discharge temperature reduction >=1 oC had higher frequency of rehospitalization for HF (68.2% vs. 44.3%, estimated odds ratio [OR] 2.697, 95% confidence interval [CI] 1.072-6.787, P = 0.029) despite a significantly higher admission temperature. On multivariate analysis, admission-to-discharge temperature reduction >=1 oC predicted rehospitalization for HF (OR 2.02, 95% CI 1.028-3.966, P = 0.041) after adjustment for age, BMI, baseline Na, creatinine, ejection fraction and discharge NYHA class. A standard logistic model treating temperature change as a continuous variable, and a model using a restricted cubic spline, did not demonstrate a statistically significant relationship between temperature reduction and HF rehospitalization. Subsequently, an altered logistic model was fit expressing the log odds of HF rehospitalization as a piecewise linear function of temperature decrease; this model did demonstrate statistical significance (P = 0.013) with an estimated odds ratio of 1.140 per 0.1 oC beyond 0.5 oC. CONCLUSION: Admission-to discharge temperature reduction >=1 oC is an unfavorable prognostic sign associated with future rehospitalization due to HF. PMID- 28875318 TI - Influence of gut microbiota on the development and progression of nonalcoholic steatohepatitis. AB - INTRODUCTION: Nonalcoholic steatohepatitis (NASH) is characterized by the presence of steatosis, inflammation, and ballooning degeneration of hepatocytes, with or without fibrosis. The prevalence of NASH has increased with the obesity epidemic, but its etiology is multifactorial. The current studies suggest the role of gut microbiota in the development and progression of NASH. The aim is to review the studies that investigate the relationship between gut microbiota and NASH. These review also discusses the pathophysiological mechanisms and the influence of diet on the gut-liver axis. RESULT: The available literature has proposed mechanisms for an association between gut microbiota and NASH, such as: modification energy homeostasis, lipopolysaccharides (LPS)-endotoxemia, increased endogenous production of ethanol, and alteration in the metabolism of bile acid and choline. There is evidence to suggest that NASH patients have a higher prevalence of bacterial overgrowth in the small intestine and changes in the composition of the gut microbiota. However, there is still a controversy regarding the microbiome profile in this population. The abundance of Bacteroidetes phylum may be increased, decreased, or unaltered in NASH patients. There is an increase in the Escherichia and Bacteroides genus. There is depletion of certain taxa, such as Prevotella and Faecalibacterium. CONCLUSION: Although few studies have evaluated the composition of the gut microbiota in patients with NASH, it is observed that these individuals have a distinct gut microbiota, compared to the control groups, which explains, at least in part, the genesis and progression of the disease through multiple mechanisms. Modulation of the gut microbiota through diet control offers new challenges for future studies. PMID- 28875322 TI - Application of in-plant control measures in some Egyptian micro-scale dairy enterprises and its impact on heavy metal contents of their products. AB - Egypt is encouraging micro-scale enterprises as proved to be one of the most important reasons of economic growth. Most of the annual milk production is processed in micro-scale dairy enterprises located in squatter areas with high health risks and negative environmental impact. The aim of this study was to assess the effectiveness of in-plant control measures in controlling lead and cadmium levels in dairy products from nine Egyptian micro-scale enterprises. The results revealed that white cheese enterprises had the highest mean lead and cadmium contents; both in their raw milk (0.712 and 0.134 mg/L, respectively) and final products (0.419 and 0.061 mg/kg). Higher compliance percentages were found with cadmium levels specified in the Egyptian standards than with lead levels and ranged from 59.4% in raw milk to 100% in dry milk for cadmium levels and from 8.3% in white cheese to 66.7% in ice cream for lead; moreover, none of the collected raw milk samples were complying with the lead levels. After implementation of in-plant control measures, lower lead levels were found in all samples with reduction percentages ranging from 35.2% in raw milk from the ice cream enterprises to 73.2% in yoghurt; moreover, higher percentages of samples complied with cadmium levels. This study highlights the urgent need for applying in-plant control measures to the Egyptian micro-scale dairy enterprises to improve both safety and quality of their products. PMID- 28875323 TI - Evodiamine Inhibits Angiotensin II-Induced Rat Cardiomyocyte Hypertrophy. AB - OBJECTIVE: To investigate the effects of evodiamine (Evo), a component of Evodiaminedia rutaecarpa (Juss.) Benth, on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) and further explore the potential mechanisms. METHODS: Cardiomyocytes from neonatal Sprague Dawley rats were isolated and characterized, and then the cadiomyocyte cultures were randomly divided into control, model (Ang II 0.1 MUmol/L), and Evo (0.03, 0.3, 3 MUmol/L) groups. The cardiomyocyte surface area, protein level, intracellular free calcium ([Ca2+]i) concentration, activity of nitric oxide synthase (NOS) and content of nitric oxide (NO) were measured, respectively. The mRNA expressions of atrial natriuretic factor (ANF), calcineurin (CaN), extracellular signal-regulated kinase-2 (ERK-2), and endothelial nitric oxide synthase (eNOS) of cardiomyocytes were analyzed by real time reverse transcriptionpolymerase chain reaction. The protein expressions of calcineurin catalytic subunit (CnA) and mitogen-activated protein kinase phosphatase-1 (MKP-1) were detected by Western blot analysis. RESULTS: Compared with the control group, Ang II induced cardiomyocytes hypertrophy, as evidenced by increased cardiomyocyte surface area, protein content, and ANF mRNA expression; increased intracellular free calcium ([Ca2+]i) concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but decreased MKP-1 protein expression (P<0.05 or P<0.01). Compared with Ang II, Evo (0.3, 3 MUmol/L) significantly attenuated Ang II-induced cardiomyocyte hypertrophy, decreased the [Ca2+]i concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but increased MKP-1 protein expression (P<0.05 or P<0.01). Most interestingly, Evo increased the NOS activity and NO production, and upregulated the eNOS mRNA expression (P<0.05). CONCLUSION: Evo signifificantly attenuated Ang II-induced cardiomyocyte hypertrophy, and this effect was partly due to promotion of NO production, reduction of [Ca2+]i concentration, and inhibition of CaN and ERK-2 signal transduction pathways. PMID- 28875324 TI - [Extreme obesity-particular aspect of invasive and noninvasive ventilation]. AB - The obesity rate is increasing worldwide and the percentage of obese patients in the intensive care unit (ICU) is rising concomitantly. Ventilatory support strategies in obese patients must take into account the altered pathophysiological conditions. Unfortunately, prospective randomized multicenter trials on this subject are lacking. Therefore, current strategies are based on the individual experiences of ICU physicians and single-center studies. Noninvasive ventilation (NIV) in critically ill patients with acute respiratory failure and obesity hypoventilation syndrome (OHS) is an efficient treatment option and should be provided as early as possible is an effort to avoid intubation. Patient positioning is also crucial: half-sitting positions (>45 degrees ) improve lung compliance and functional residual capacity in patients with respiratory failure. Transpulmonary pressure measurements or the Acute Respiratory Distress Syndrome (ARDS) Network tables may help to adjust the optimal positive end-expiratory pressure (PEEP). The tidal volume should be adapted to the ideal and not the actual bodyweight (Vt = 6 ml/kg of ideal bodyweight) to avoid lung damage and (additional) right ventricular stress. Under particular conditions, inspiratory pressures >30 cmH2O may be tolerated for a limited duration. Early tracheostomy combined with termination/reduction of sedation and relaxation is controversy discussed in the literature as a therapeutic option during invasive ventilation of morbidly obese patients. However, data on early tracheotomy in obese respiratory failure patients are rare and this should be regarded as an individual treatment attempt only. In cases of refractory lung failure, venovenous extracorporeal membrane oxygenation (vv-ECMO) is an option despite anatomic changes in morbid obesity. PMID- 28875325 TI - [Response evaluation in nuclear medicine : Criteria, results and pitfalls]. AB - CLINICAL/METHODICAL ISSUE: Established criteria to categorize metabolic tumor response to cytotoxic chemotherapies may not be suited to capture the effects of therapy with immune checkpoint inhibitors (ICI) or with kinase inhibitors (KI), such as BRAF or MEK inhibitors. NUCLEAR MEDICINE STANDARD METHODS: To assess the metabolic response to cytotoxic chemotherapy by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG), the criteria of the European Organization for Research and Treatment of Cancer (EORTC) and the positron emission tomography response criteria in solid tumors (PERCIST) were conceived. The salient features of both criteria are detailed in a comparative way. PERFORMANCE AND ACHIEVEMENTS: To date only retrospective data exist for the evaluation of therapies with either ICI or KI. They show that response to ICI cannot be reliably determined using the established criteria. Employing the EORTC criteria the responses to KI can be adequately ascertained so that the metabolic tumor response in FDG-PET is regarded as a surrogate marker for the efficacy of these drugs. PRACTICAL RECOMMENDATIONS: Tumor response to therapy with ICI cannot at present be assessed with FDG-PET. Responses to BRAF and MEK inhibitors are, however, assessable using the criteria that were originally developed to evaluate responses to cytotoxic chemotherapy. PMID- 28875326 TI - Neuroradiologic Characteristics of Primary Angiitis of the Central Nervous System According to the Affected Vessel Size. AB - INTRODUCTION: Magnetic resonance imaging (MRI) has an important impact in diagnosing primary angiitis of the central nervous system (PACNS). However, neuroradiologic findings may vary immensely, making an easy and definite diagnosis challenging. METHODS: In this retrospective, single center study, we analyzed neuroradiologic findings of patients with PACNS diagnosed at our hospital between 2009 and 2014. Furthermore, we classified patients according to the affected vessel size and compared imaging characteristics between the subgroups. RESULTS: Thirty-three patients were included (mean age 43 [+/-15.3] years, 17 females) in this study. Patients with positive angiographic findings were classified as either medium or large vessel PACNS and presented more ischemic lesions (p < 0.001) and vessel wall enhancement (p = 0.017) compared to patients with small vessel PACNS. No significant differences were detected for the distribution of contrast-enhancing lesions (parenchymal or leptomeningeal), hemorrhages, or lesions with mass effect. Twenty-five patients underwent brain biopsy. Patients with medium or large vessel PACNS were less likely to have positive biopsy results. DISCUSSION: It is essential to differentiate between small and medium/large vessel PACNS since results in MRI, digital subtraction angiography and brain biopsy may differ immensely. Since image quality of MR scanners improves gradually and brain biopsy may often be nonspecific or negative, our results emphasize the importance of MRI/MRA in the diagnosis process of PACNS. PMID- 28875327 TI - The Effects of Selenium Supplementation on Gene Expression Related to Insulin and Lipid in Infertile Polycystic Ovary Syndrome Women Candidate for In Vitro Fertilization: a Randomized, Double-Blind, Placebo-Controlled Trial. AB - : This study was conducted to evaluate the effects of selenium supplementation on gene expression related to insulin and lipid in infertile women with polycystic ovary syndrome (PCOS) candidate for in vitro fertilization (IVF). This randomized double-blind, placebo-controlled trial was conducted among 40 infertile women with PCOS candidate for IVF. Subjects were randomly allocated into two groups to intake either 200-MUg selenium (n = 20) or placebo (n = 20) per day for 8 weeks. Gene expression levels related to insulin and lipid were quantified in lymphocytes of women with PCOS candidate for IVF with RT-PCR method. Results of RT-PCR demonstrated that after the 8-week intervention, compared with the placebo, selenium supplementation upregulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) (1.06 +/- 0.15-fold increase vs. 0.94 +/- 0.18-fold reduction, P = 0.02) and glucose transporter 1 (GLUT-1) (1.07 +/- 0.20-fold increase vs. 0.87 +/- 0.18-fold reduction, P = 0.003) in lymphocytes of women with PCOS candidate for IVF. In addition, compared with the placebo, selenium supplementation downregulated gene expression of low-density lipoprotein receptor (LDLR) (0.88 +/- 0.17-fold reduction vs. 1.05 +/- 0.22-fold increase, P = 0.01) in lymphocytes of women with PCOS candidate for IVF. We did not observe any significant effect of selenium supplementation on gene expression levels of lipoprotein(a) [LP(a)] in lymphocytes of women with PCOS candidate for IVF. Overall, selenium supplementation for 8 weeks in lymphocytes of women with infertile PCOS candidate for IVF significantly increased gene expression levels of PPAR-gamma and GLUT-1 and significantly decreased gene expression levels of LDLR, but did not affect LP(a). CLINICAL TRIAL REGISTRATION NUMBER: http://www.irct.ir : IRCT201704245623N113. PMID- 28875328 TI - [Critical consideration of the European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas]. PMID- 28875329 TI - The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. AB - The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8+ T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer. PMID- 28875330 TI - Liposomes co-Loaded with 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3 (PFKFB3) shRNA Plasmid and Docetaxel for the Treatment of non-small Cell Lung Cancer. AB - PURPOSE: Non-small cell lung cancer is the leading cause of cancer related deaths globally. Considering the side effects and diminishing chemosensitivity to chemotherapy, novel treatment approaches are sought. Hence, we aim to develop a liposomal co-delivery system of pDNA expressing shRNA against PFKFB3 (pshPFKFB3) and docetaxel (DTX). METHODS: Cationic DTX liposomes complexed with pshPFKFB3 (PSH-DL) were developed. In vitro cell line studies were performed to evaluate transfection, PFKFB3 mRNA silencing, cytotoxicity, pGP inhibition, and protein markers expression. In vivo efficacy study was performed in A549 xenograft nude mice model. RESULTS: Cytotoxicity studies showed significantly enhanced anticancer activity of PSH-DL against individual treatment alone confirming the chemoenhancing effect of pshPFKFB3 on DTX activity. Fluorescence microscopy and RT-PCR showed effective transfection and RNAi by pshPFKFB3. pGP inhibition assay and western blotting revealed that PFKFB3 downregulation caused diminution of pGP activity leading to changes in cell cycle (Cdk2), survival (survivin), apoptosis (Bcl2 and cleaved caspase 3) and stress (p-JNK and p-p38) markers so that induces apoptosis by PSH-DL in NSCLC cells. PSH-DL also showed ~3.8-fold reduction in tumor volume in A549 xenograft model which was significantly higher than individual treatments alone. CONCLUSION: Targeting PFKFB3 through shRNA based RNAi is a promising approach for potentiating activity of DTX in NSCLC. PMID- 28875331 TI - Implication of connexin30 on the stemness of glioma: connexin30 reverses the malignant phenotype of glioma by modulating IGF-1R, CD133 and cMyc. AB - Gap-junctional intercellular communication (GJIC) plays a major role in the malignant growth of glioma. Although the mechanistic aspects of GJIC have been extensively studied, the role of connexins in the regulation of the malignant behavior of glioma stem cells (GSCs) remains unclear. In our previous studies, we have shown that connexin30 can interfere with the insulin-like growth factor 1 receptor (IGF-1R), which is known for self-renewal and pluripotency. Following our earlier in vitro observation, in this work, we aimed to study the consequence of this influence of Cx30 on IGF-1R by evaluating the marker of GSCs, CD133 and oncoprotein, cMyc. We strengthened our basis by examining human glioma samples of different grades as well as rat C6 xenografts (Cx30-transfected and -non transfected C6 cells) along with the sphere formation assays in vitro. Investigation of stemness-related CD133 and cMyc in human samples and rat xenografts exhibited a reciprocal relationship between Cx30 and IGF-1R in the low and high grades (HG) of glioma. Cx30 was completely abolished in HG; levels of IGF-1R, CD133 and cMyc expression were positively correlated with HG. Cx30 transfection could attenuate the malignant burden of glioma in rat xenografts. Cx30 transfection also altered the tumor sphere formation of C6 glioma cells in vitro, an important property of GSCs, and there was a significant reduction of CD133 and cMyc expression by Cx30 both in vitro and in vivo. These factors indicate that dysfunction of Cx30 plays a crucial role in the prevention of the stemness of glioma, and the exploitation of this feature will help in the management of glioma. PMID- 28875332 TI - The Population Education Transition Curve: Education Gradients Across Population Exposure to New Health Risks. AB - The salutary effect of formal education on health-risk behaviors and mortality is extensively documented: ceteris paribus, greater educational attainment leads to healthier lives and longevity. Even though the epidemiological evidence has strongly indicated formal education as a leading "social vaccine," there is intermittent reporting of counter-education gradients for health-risk behavior and associated outcomes for certain populations during specific periods. How can education have both beneficial and harmful effects on health, and under which contexts do particular effects emerge? It is useful to conceptualize the influence of education as a process sensitive to the nature, timing of entry, and uniqueness of a new pleasurable and desirable lifestyle and/or product (such as smoking) with initially unclear health risks for populations. Developed herein is a hypothesis that the education gradient comprises multiple potent pathways (material, psychological, cognitive) by which health-risk behaviors are influenced, and that there can be circumstances under which pathways act in opposite directions or are differentially suppressed and enhanced. We propose the population education transition (PET) curve as a unifying functional form to predict shifting education gradients across the onset and course of a population's exposure to new health risks and their associated consequences. Then, we estimate PET curves for cases with prior epidemiological evidence of heterogeneous education gradients with health-risk behaviors related to mass produced cigarettes in China and the United States; saturated fats, sugar, and processed food diets in Latin America; and HIV infection in sub-Saharan Africa. Each offers speculation on interactions between environmental factors during population exposure and education pathways to health-risk behaviors that could be responsible for the temporal dynamics of PET curves. Past epidemiological studies reporting either negative or positive education gradients may not represent contradictory findings as much as come from analyses unintentionally limited to just one part of the PET process. Last, the PET curve formulation offers richer nuances about educational pathways, macro-historical population dynamics, and the fundamental cause of disease paradigm. PMID- 28875333 TI - Circulating pro-angiogenic and anti-angiogenic microRNA expressions in patients with acute ischemic stroke and their association with disease severity. AB - The main objectives of this study are to evaluate 28 selected pro-angiogenic and anti-angiogenic microRNA (miRNA) expressions in plasma of acute ischemic stroke (AIS) patients and controls and to assess the correlations of these miRNAs with risk and severity of AIS. In the exploring stage, 10 AIS patients and 10 controls with vascular risk factors were enrolled. And in the validating stage, 106 AIS patients and 110 controls with the same eligibility were recruited. Blood samples were collected from participants within 24 h post the onset of symptoms, and plasma levels of miRNAs were evaluated by the qPCR method. In the exploring stage, 11 differentially expressed miRNAs (DEM) were identified and included into the validating stage. In the validating stage, the expression of miR-126, miR 130a, and miR-378 in plasma declined in the AIS patients; however, miR-222, miR 218, and miR-185 plasma levels were elevated. Univariate and multivariate logistic regression analysis disclosed that miR-126, miR-130a, miR-222, miR-218, and miR-185 were independent predicting factors for AIS. When these five DEMs were combined together, they presented a good diagnostic value with an area under curve (AUC) value of 0.767 (95% CI 0.705-0.829), sensitivity of 87.7%, and specificity of 54.5% at best cutoff point. Additionally, miR-126, miR-378, miR 101, miR-222, miR-218, and miR-206 were associated with National Institutes of Health Stroke Scale (NIHSS) score. Circulating miR-126, miR-130a, miR-222, miR 218, and miR-185 could be served as promising and independent biomarkers for risk of AIS, and miR-126, miR-378, miR-222, miR-101, miR-218, and miR-206 could be used for disease severity management of AIS. PMID- 28875334 TI - Preoperative Prognostic Factors After Liver Resection for Non-Colorectal, Non Neuroendocrine Liver Metastases and Validation of the Adam Score in an Asian Population. AB - BACKGROUND: Historically, the benefit of liver resection for non-colorectal, non neuroendocrine (NCNN) liver metastases has been controversial. This study aims to determine the preoperative prognostic factors of liver resection for NCNN liver metastases and validate the Adam score in an Asian population. METHODS: Consecutive patients who underwent liver resection for NCNN liver metastases were identified retrospectively from a prospective liver resection database of the single institution between 2001 and 2014. Univariate Cox regression models were used to identify associations with outcome variables. Recurrence-free interval and overall survival were determined using the Kaplan-Meier method and compared using log-rank test. RESULTS: Seventy-eight consecutive patients were identified, which met the study criteria. Univariate analysis demonstrated that adenocarcinoma histology of primary cancer, disease-free interval and number of nodules were significant predictors of survival. Four of the six components of Adam score were significant predictors of survival. These were the presence of extrahepatic metastases, R2 resection, disease-free interval and type of a primary tumour. The total Adam score was also a significant predictor of survival. CONCLUSION: Liver resection for NCNN liver metastases is a safe and viable treatment option in carefully selected patients. Significant preoperative prognostic factors include adenocarcinoma primary tumours, disease-free interval and number of nodules. The total Adam score was a good predictor of overall survival and can be used to risk stratify patients undergoing hepatic resection for NCNN liver metastases. PMID- 28875335 TI - Facilitation of Fast Backward Priming After Left Cerebellar Continuous Theta Burst Stimulation. AB - Traditional theories of backward priming account only for the priming effects found at long stimulus onset asynchronies (SOAs). Here, we suggest that the presence of backward priming at short SOAs may be related to the integrative role of the cerebellum. Previous research has shown that the right cerebellum is involved in forward associative priming. Functional magnetic resonance imaging reveals some activation of the left cerebellar hemisphere during backward priming; but what this activation represents is unclear. Here we explore this issue using continuous theta-burst transcranial magnetic stimulation (cTBS) and associative priming in a lexical decision task. We tested the hypothesis that the left cerebellum plays a role in backward priming and that this is dissociated from the role of the right cerebellum in forward priming. Before and after cTBS was applied to their left and right cerebellar hemispheres, participants completed a lexical decision task. Although we did not replicate the forward priming effect reported in the literature, we did find a significant increase in backward priming after left relative to right cerebellar cTBS. We consider how theories of cerebellar function in the motor domain can be extended to language and cognitive models of backward priming. PMID- 28875336 TI - Progression of liver fibrosis can be controlled by adequate chelation in transfusion-dependent thalassemia (TDT). AB - A substantial proportion of patients with transfusion-dependent beta-thalassemia major suffer from chronic liver disease. Iron overload resulting from repeated transfusions and HCV infection has been implicated in the development of liver fibrosis. Hepatic siderosis and fibrosis were assessed in 99 transfusion dependent thalassemia (TDT) patients using transient elastography (TE) and liver iron concentration (LIC) assessed by T2*MRI at baseline and after 4 years. Data were analyzed retrospectively. At baseline, the overall mean liver stiffness measurement (LSM) was 7.4 +/- 3.2 kPa and the mean LIC was 4.81 +/- 3.82 mg/g dw (n = 99). Data available at 4 +/- 1.5 years showed a significant reduction in LSM (6.6 +/- 3.2 kPa, p 0.017) and hepatic siderosis measured by LIC (3.65 +/- 3.45 mg/g dw, p 0.001). This result was confirmed when considering patients with iron overload at the time of the first measurement (n = 41) and subjects treated with a stable dose of deferasirox over the entire period of observation (n = 39). A reduction of LSM, yet not statistically significant, was achieved in patients on combined deferoxamine + deferiprone, while the group on deferoxamine (n = 11) remained stable over time. HCV-RNA positivity was found in 33 patients at T0, 20 of which were treated during the observation period. Patients who underwent anti HCV therapy showed a more evident reduction in LSM (9 +/- 3 vs 7 +/- 3.1 kPa, p 0.016). Adequate chelation therapy is mandatory in order to prevent liver disease progression in TDT. Patients could benefit from regular non-invasive assessment of liver fibrosis by TE to indirectly monitor treatment adequacy and therapeutic compliance. PMID- 28875337 TI - Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene. AB - Hydroxysteroid (17beta) dehydrogenase 10 (HSD10) and mitochondrial acetoacetyl CoA thiolase (beta-KT) are two adjacent enzymes for the degradation of isoleucine, thus HSD10 and beta-KT deficiencies are confusing at an early stage because of nearly the same elevation of typical metabolites in urine, such as 2 methyl-3-hydroxybutyric acid (2M3HBA) and tiglylglycine (TG). In order to better understand the differences between these two disorders, we described the clinical and molecular characteristics of two HSD10 deficiency patients and four beta-KT deficiency patients. beta-KT deficiency patients had a much more favorable outcome than that of HSD10 deficiency patients, indicating that the multifunction of HSD10, especially neurosteroid metabolic activity, other than only enzymatic degradation of isoleucine, is involved in the pathogenesis of HSD10 deficiency. Two different mutations, a novel mutation p.Ile175Met and a reported mutation p.Arg226Gln, were detected in the HSD17B10 gene of HSD10 deficiency patients. Six different mutations, including four known mutations: p.Ala333Pro, p.Thr297Lys, c.83_84delAT, c.1006-1G > C, and two novel mutations: p.Thr277Pro and c.121-3C > G were identified in the ACAT1 gene of beta-KT deficiency patients. In general, DNA diagnosis played an important role in distinguishing between these two disorders. PMID- 28875338 TI - The Significance of SCC and CEA mRNA in the Pleural Cavity After Lymphadenectomy in Esophageal Cancer Patients who Underwent Preoperative Treatment. AB - BACKGROUND: This report focuses on the surgical manipulation and spread of cancer cells. Our previous study suggested an association between a poor prognosis and positive pleural lavage cytology after resection of esophageal cancer without preoperative treatment. However, little is known regarding the clinical significance of the lavage procedure in esophageal cancer patients who undergo preoperative treatment. METHODS: A cohort of 94 patients with squamous cell carcinoma of the esophagus who underwent esophagectomy with radical lymph node dissection was prospectively analyzed for free cancer cells in the pleural cavity after mediastinal lymphadenectomy. Reverse transcription-polymerase chain reaction was performed to detect free cancer cells in the pleural lavage fluid by measuring squamous cell carcinoma-related antigen (SCC) and carcinoembryonic antigen (CEA). RESULTS: Forty-two patients (44.7%) were positive for SCC after thoracic lymphadenectomy, and 15 patients (15.9%) were positive for CEA. SCC positivity was significantly associated with venous invasion (p = 0.037) and with the clinical response to preoperative treatment (p = 0.001). Furthermore, SCC positivity was associated with poor prognosis compared with negative SCC (p = 0.026). Multivariate analysis revealed that SCC positivity was an independent prognostic factor. Regarding recurrence patterns, SCC positivity tended to be associated with hematogenous recurrence (p = 0.063). Conversely, positive CEA was not associated with any clinicopathological finding, treatment response, prognosis, or recurrence pattern. CONCLUSIONS: Tumor spillage during the evaluated surgical manipulation was assessed in esophageal cancer patients who underwent preoperative treatment. Tumor spillage as evaluated by SCC mRNA was associated with a poor prognosis. PMID- 28875339 TI - C-Arm Cone Beam CT for Intraprocedural Image Fusion and 3D Guidance in Portal Vein Embolization (PVE). AB - PURPOSE: Portal vein embolization (PVE) is applied in patients with extended oncologic liver disease to induce hyperplasia of the future liver remnant and make resection feasible. Ultrasound (US) guidance is the gold standard for percutaneous portal vein access. This study evaluated feasibility and safety of C arm cone beam computed tomography (CBCT) for needle guidance. MATERIALS AND METHODS: In 10 patients, puncture was performed under 3D needle guidance in a CBCT data set. Contrast-enhanced (CE) CBCT was generated (n = 7), or native CBCT was registered to pre-examination CE-CT via image fusion (n = 3). Technical success, number of punctures, puncture time (time between CBCT acquisition and successful portal vein access), dose parameters and safety were evaluated. For comparison, 10 patients with PVE under US guidance were analyzed retrospectively. Study and control group were matched for age, BMI, INR, platelets, portal vein anatomy. RESULTS: All interventions were technically successful without intervention-related complications. In the study group, the mean number of puncture attempts was 3.1 +/- 2.5. Mean puncture time was 12 min (+/-10). Mean total dose area product (DAP) was 288 Gy cm2 (+/-154). The mean relative share of CBCT-related radiation exposure was 6% (+/-3). Intervention times and DAP were slightly higher compared to the control group without reaching significance. CONCLUSION: CBCT-guided PVE is feasible and safe. The relative dose of CBCT is low compared to the overall dose of the intervention. This technique may be a promising approach for difficult anatomic situations that limit the use of US for needle guidance. PMID- 28875340 TI - Corneal features in ocular graft-versus-host disease by in vivo confocal microscopy. AB - PURPOSE: The purpose of our study was to determine the morphological features of the corneal epithelial layers, sub-basal nerve plexus and anterior stroma in patients with ocular graft-versus-host disease (oGVHD) compared to non-GVHD dry eyes and normal controls, using in vivo confocal microscopy (IVCM). METHODS: IVCM was used to capture central cornea images from eight volunteers with normal healthy eyes, ten patients with non-GVHD dry eye syndrome (DES) and 15 patients with clinically diagnosed oGVHD, in a cross-sectional study. Morphological changes of the corneal epithelial layers and anterior stroma, characteristics of corneal nerves and presence of dendritic cells (DCs) were then evaluated. RESULTS: IVCM images obtained from 66 eyes were analyzed. The density of superficial epithelial cells was 636.07 +/- 101.05 cells/mm2 in the oGVHD group, 827 +/- 99.62 cells/mm2 in the DES group and 1277.2 +/- 121.42 cells/mm2 in the control group (P < 0.001). The density of wing cells was 4499.79 +/- 976.36 cells/mm2 in the oGVHD group, 4662.85 +/- 319.72 cells/mm2 in DES group and 6556.38 +/- 503.99 cells/mm2 in the control group (p < 0.001). The density of basal cells was 7850.93 +/- 723.51 cells/mm2 in the oGVHD group, 8570 +/- 913.32 cells/mm2 in DES group and 9759.8 +/- 251.99 cells/mm2 in the control group (p < 0.01). The density of nerve fibers was 11.22 +/- 5.46 mm/mm2 in the oGVHD group, 14.50 +/- 4.27 mm/mm2 in DES group and 19.56 +/- 4.75 mm/mm2 in the control group (p < 0.01). The DC density was 67.88 +/- 71.82 cells/mm2 in the oGVHD group, 40.06 +/- 31.95 cells/mm2 in the DES group and 29.45 +/- 8.1 cells/mm2 in the control group (P > 0.05). Visible networks of activated keratocytes were seen in the anterior stroma of eyes with oGVHD and DES, but not in normal controls. CONCLUSIONS: IVCM revealed distinct microstructural changes in the corneas of patients with oGVHD and DES, similar between the two groups. Our findings suggest implications for use of IVCM to evaluate and monitor patients with dry eyes associated or not with GVHD. PMID- 28875341 TI - How to adjust endoscopic findings to histopathological findings of the stomach: a "histopathology-oriented" correspondence method helps to understand endoscopic findings. AB - BACKGROUND: Endoscopic findings have now become nearly as detailed as histopathological findings. Thus, one-to-one correspondence and precise feedback of histopathological findings is very desirable but may be very difficult to accomplish. We describe a systematic process called the Kyoto One-to-One Correspondence Method (the KOTO Method) that allows detailed adjustments of endoscopic findings to match histopathological findings. METHODS AND RESULTS: By comparing endoscopic and stereoscopic images of the gastric mucosa, we could obtain one-to-one correspondence between endoscopic images and equivalent histology in 44 of 47 fields. CONCLUSIONS: The histological structure of gastric cancers of the same histological subtype may not be similar. One-to-one correspondence between endoscopic images and gastric mucosal histology (histopathology-oriented correspondence) will improve endoscopic diagnosis and provide more useful information for pathological diagnosis. PMID- 28875342 TI - Undiagnosed renal sarcoidosis in a patient with chronic interstitial nephritis. AB - A 53-year-old female was admitted to hospital, with acute elevation of SCr and hypercalcemia, on a 5-year history of chronic interstitial nephritis and stage III chronic kidney disease (CKD). Extensive workup failed to yield a definitive diagnosis concerning the cause of the disorder. Intense uptake of 18F-FDG in the spleen and liver was detected by PET/CT imaging with negative angiotensin converting enzyme (ACE) in serum. The spleen and the hypermetabolism nodules of the liver were resected for histopathologic examination and turned out to be noncaseating granulomas, likely sarcoidosis. Combined with clinical features, the final diagnosis for this patient was sarcoidosis, involving the kidneys, spleen, liver, and lungs. PMID- 28875343 TI - Production of tartaric acid using immobilized recominant cis-epoxysuccinate hydrolase. AB - OBJECTIVE: To investigate the expression and immobilization of recombinant cis epoxysuccinate hydrolase (ESH), and its application in the biological production of L-(+)-tartaric acid. RESULTS: E. coli BL21 (DE3)/pET11a-ESH (His) was engineered to express recombinant ESH. The enzyme had an activity of 262 U mg-1. The recombinant ESH was immobilized on agarose Ni-IDA matrix with metal ion affinity interaction to improve its thermostability and pH stability. The immobilization efficiency and activity yield were 94 and 95%, respectively. The specific catalytic efficiency of immobilized ESH was 104 mg U-1 h-1 during the continuous enzymatic production process. CONCLUSION: ESH with a histidine tag was immobilized and used for the continuous production of L-(+)-tartaric acid. PMID- 28875344 TI - Sweet's syndrome: a clinical entity need to discriminate against acute haematogenous periprosthetic joint infection. AB - Sweet's syndrome (SS) or acute febrile neutrophilic dermatosis is an uncommon condition. It is characterized by fever, polymorphonuclear leukocytosis, painful erythematous cutaneous plaques, and dense dermal infiltrate of neutrophils without vasculitis at the site of skin lesions. Lesions in SS might enlarge and coalesce with increasing dermal oedema, resulting in pseudo-vesicular appearance mimicking joint infections. Here, a rare case of SS mimicking acute haematogenous periprosthetic infection in a 74-year-old woman with a history of total knee arthroplasty is reported. This report aims to elaborate clinical various manifestations of SS in a patient with a history of total knee arthroplasty. In addition, this report describes how to discriminate inflammation between SS and periprosthetic joint infection. Level of evidence V. PMID- 28875345 TI - Modified Hyperbranched Polyglycerol as Dispersant for Size Control and Stabilization of Gold Nanoparticles in Hydrocarbons. AB - Hyperbranched polyglycerol (HPG) is modified with dodecanethiol (DS) via the "thiol-ene" click reaction to obtain an amphiphilic product DSHPG. The molecular structures of DSHPG samples are characterized by NMR, FTIR, and GPC, and the thermal behaviors are characterized by DSC and TGA. Gold nanoparticles (Au NPs) are prepared with DSHPG as the stabilizer and surface-modification reagent. The size of Au NPs can be tuned by changing the molecular weight of HPG. It is observed that the HPG molecular weights of 1123, 3826, and 55,075 lead to the NP diameters of 4.1 nm for Au@DSHPG-1, 9.7 nm for Au@DSHPG-2, and 15.1 nm for Au@DSHPG-3, respectively. The morphology and size of Au NPs are characterized by TEM and DLS. Especially, the dispersion abilities of Au NPs in different pure solvents and co-solvent mixtures are investigated. The long alkyl chains on DSHPG give the ability of Au NPs to be well dispersed in nonpolar solvents. Hydrocarbon based nanofluids can be obtained from the hydrophobic Au NPs dispersed into a series of hydrocarbons. The dispersion stability for Au NPs in hydrocarbons is monitored by UV-Vis spectroscopy, and the relative concentration of Au NPs is observed to still maintain over 80% after 3600 h. PMID- 28875346 TI - CFTR supports cell death through ROS-dependent activation of TMEM16F (anoctamin 6). AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is the essential chloride and bicarbonate channel in the apical membrane of epithelial cells. CFTR was also proposed earlier to conduct glutathione (GSH) out of airway epithelial cells to be enriched in the apical airway surface liquid to neutralize reactive oxygen species (ROS). Although earlier studies suggested that release of GSH by wild type (wt) CFTR may lead to an increase in cytosolic ROS, we did not detect different ROS levels in cells expressing wt-CFTR and mutant F508del-CFTR, independent of CFTR-activation or exposure to the ROS donor tert-butyl hydroperoxide. The Ca2+-activated phospholipid scramblase and ion channel TMEM16F (anoctamin 6, ANO6) is also expressed in airway cells. ANO6 produced outwardly rectifying Cl- currents (ORCC) and scrambled plasma membrane phospholipids when activated by increase in cytosolic ROS and consecutive peroxidation of plasma membrane lipids. ANO6 activity is enhanced by CFTR, probably through translocation of signaling proteins to the plasma membrane. The present data suggest that enhanced cell death in CFTR-expressing cells is due to upregulation of ANO6-activity. In ANO6 knockout mice, the number of apoptotic cells in the intestinal epithelium was strongly reduced, supporting the role of ANO6 for cell death. Thus, ANO6 and CFTR act cooperatively on ROS-mediated cell death, which is not further augmented by cAMP-dependent stimulation. We propose that ANO6 supports cell death correlated with expression of CFTR, possibly by inducing ferroptosis. PMID- 28875347 TI - The relationship between contrast sensitivity and retinal nerve fiber layer thickness in patients with glaucoma. AB - PURPOSE: To evaluate the correlation between contrast sensitivity (CS) and retinal nerve fiber layer (RNFL) in different areas of vision. METHODS: This report is a sub-analysis of a prospective, observational cohort study investigating changes in performance-based assessment, vision-related quality of life, and clinical measures in patients with moderate to advanced glaucoma. The study included 161 participants with at least a 2-year history of glaucoma who underwent annual testing for 4 years. Contrast sensitivity was measured using the Spaeth/Richman contrast sensitivity (SPARCS) test, while RNFL thickness (RNFLT) was measured using Cirrus optical coherence tomography (OCT). Statistical analyses were performed to determine correlations between CS and RNFLT; the correlations were calculated for each annual visit, totaling four correlation coefficients for each patient over the course of 4 years. RESULTS: The SPARCS score in the left upper area of vision correlated the most strongly with the RNFLT of the inferior quadrant for both eyes at each annual visit, specifically in the seven o'clock sector for the left eye and the six o'clock sector for the right eye (p < 0.05). There were no discernible trends for the correlations between the other areas of CS and RNFL quadrants or clock hours over the 4 years of the study. Linear regression between the SPARCS total score and average RNFLT showed a significant direct correlation at each visit (p < 0.01). CONCLUSIONS: Contrast sensitivity in the left upper area of vision for both eyes correlated most strongly with the thickness of the inferior quadrant of the RNFL. These fibers project to the temporal portion of the right occipital lobe, implying a potential center for contrast perception in this area. The longitudinal nature of the study suggests that CS may be a predictive tool for changes in RNFL in patients with glaucoma. Despite this finding, retinal damage and its relationship to CS was diffuse. In addition, SPARCS was shown to predict RNFLT. Further research is warranted to understand how CS can be used as a tool in the clinical setting. PMID- 28875348 TI - Effects of dominant and non-dominant passive arm manoeuvres on the neurovascular coupling response. AB - PURPOSE: Models designed to study neurovascular coupling (NVC) describe a possible cerebral hemisphere dominance dependent on task completed and preference in handedness. We investigated whether passive arm manoeuvre performed with dominant (Dom-Arm) or non-dominant arm (ND-Arm) stimulated haemodynamic differences in either contralateral (Cont-H) or ipsilateral (Ipsil-H) cerebral hemisphere. METHODS: Healthy individuals lying in supine position, had measurements of beat-to-beat blood pressure (BP, mmHg), electrocardiogram (HR, bpm), end-tidal CO2 (etCO2, mmHg), and bilateral insonation of the middle cerebral arteries (MCA, cm s-1). Arm movement was performed for 60 s with passive flexion and extension of the elbow (1 Hz), before manoeuvre was repeated on other arm. Data were normalised and effect of treatment was analysed for differences between manoeuvres and within each time period. RESULTS: Seventeen (eight males) healthy volunteers, aged 56 +/- 7 years, were studied. Dom-Arm and ND-Arm manoeuvres stimulated a comparable temporal response in peripheral and cerebral haemodynamic parameters between Cont-H and Ipsil-H. CONCLUSIONS: Both manoeuvres can be used to evoke similar bilateral MCA responses in assessing NVC. This finding should lead to more efficient protocols when using passive arm movement for NVC studies in healthy subjects. PMID- 28875349 TI - Variations in optic nerve head morphology by intraocular pressure in open-angle glaucoma. AB - PURPOSE: To compare optic disc topography in eyes in three intraocular pressure (IOP) groups of <15 mmHg, 15-20 mmHg, and >=21 mmHg using spectral domain optical coherence tomography (SD-OCT) and confocal scanning laser ophthalmoscopy, adjusting for the degree of damage, as measured by retinal nerve fiber layer (RNFL) thickness and average visual field loss. METHODS: A total of 184 eyes of 112 patients with primary open-angle glaucoma were recruited into groups based on baseline untreated intraocular pressure (IOP) of <15 mmHg (normal-tension glaucoma [NTG], very low), 15-20 mmHg (NTG, medium), or >=21 mmHg (high-tension glaucoma [HTG]). Patients underwent scanning laser ophthalmoscopy, SD-OCT, and Humphrey visual field testing. Univariate and multivariate models were created, accounting for degree of retinal ganglion cell (RGC) loss by either OCT RNFL thickness or visual field mean deviation (MD). RESULTS: Univariate and multivariate analyses demonstrated no morphological differences in HRT or OCT parameters among IOP groups that met Bonferroni-corrected statistical significance when using either MD or OCT RNFL as the damage criterion (p < 0.0063). The mean cup depth was shallower for the IOP <15 mmHg group than the IOP >=21 mmHg group (p < 0.05) for both MD (p < 0.011) and OCT RNFL (p < 0.014). CONCLUSION: Normal-tension and high-tension glaucoma are not distinguishable by optic nerve head topography with HRT and OCT when the degree of damage by Humphrey visual field testing is taken into account. PMID- 28875350 TI - Enantioconvergent hydrolysis of racemic styrene oxide at high concentration by a pair of novel epoxide hydrolases into (R)-phenyl-1,2-ethanediol. AB - OBJECTIVES: To prepare (R)-phenyl-1,2-ethanediol ((R)-PED) with high enantiomeric excess (ee p) and yield from racemic styrene oxide (rac-SO) at high concentration by bi-enzymatic catalysis. RESULTS: The bi-enzymatic catalysis was designed for enantioconvergent hydrolysis of rac-SO by a pair of novel epoxide hydrolases (EHs), a Vigna radiata EH3 (VrEH3) and a variant (AuEH2A250I) of Aspergillus usamii EH2. The simultaneous addition mode of VrEH3 and AuEH2A250I, exhibiting the highest average turnover frequency (aTOF) of 0.12 g h-1 g-1, was selected, by which rac-SO (10 mM) was converted into (R)-PED with 92.6% ee p and 96.3% yield. Under the optimized reaction conditions: dry weight ratio 14:1 of VrEH3 expressing E. coli/vreh3 to AuEH2A250I-expressing E. coli/Aueh2 A250I and reaction at 20 degrees C, rac-SO (10 mM) was completely hydrolyzed in 2.3 h, affording (R)-PED with 98% ee p. At the weight ratio 0.8:1 of rac-SO to two mixed dry cells, (R)-PED with 97.4% ee p and 98.7% yield was produced from 200 mM (24 mg/ml) rac-SO in 10.5 h. CONCLUSIONS: Enantioconvergent hydrolysis of rac-SO at high concentration catalyzed by both VrEH3 and AuEH2A250I is an effective method for preparing (R)-PED with high ee p and yield. PMID- 28875351 TI - Parents' Perspectives About Adolescent Boys' Involvement in Biomedical HIV Prevention Research. AB - Research on the use of pre-exposure prophylaxis (PrEP) among adolescents at high risk for HIV is urgently needed, and parents' perspectives on these studies are essential for guiding the responsible conduct of adolescent PrEP research. We conducted interviews with 30 parents of adolescent boys (50% known/presumed heterosexual; 50% sexual minority) to understand their views of research risks and benefits and parental permission regarding their son's involvement in a hypothetical PrEP adherence trial. Parents identified several health and educational benefits of the study and expressed that waiving parental permission would overcome barriers to accessing PrEP, particularly for youth who may benefit most. Among their concerns were medication non-adherence and risk compensation. Parents provided suggestions to facilitate informed, rational, and voluntary participation decisions and protect youth's safety if parental permission was waived. These findings can inform ways to increase parental trust in PrEP research and create adequate protections for adolescent participants. PMID- 28875353 TI - Does shape affect function? Articulatory skills in babbling of infants with deformational plagiocephaly. AB - PURPOSE: The purpose of this study was to quantitatively analyse pre-speech/early language skills in healthy full-term infants with moderate or severe deformational plagiocephaly (DP) and in infants without any skull asymmetry. METHODS: At 6 and 12 months, 51 children with DP (41 moderate, 10 severe cases) were studied, along with 15 infants serving as control. Deformational plagiocephaly (DP) was objectively determined based on cranial vault asymmetry (CVA) using 3D stereophotogrammetry (3dMDhead System(r) and Analytics 4.0, Cranioform(r)). Articulatory skills in babbling were assessed using the articulatory skill (ART-index) and mean syllable number (MSN). At 12 months, standardized parental questionnaires were used to evaluate early language outcomes. RESULTS: Overall, 3546 vocalizations were studied. Statistical tests did not reveal any significant differences of the ART-index between the three groups (ANOVA, F[2,63] = 0.24, p = 0.24). MSN likewise did not differ between the three shape groups (Kruskal-Wallis, p = 0.84). Among the children assigned to the at-risk group for language outcomes at 12 months were seven members of the symmetrical shape group (vs. seven assigned to the normally developing group), nine of the moderate DP group (vs. 27), and one of the severe DP group (vs. six). Fisher's exact test was used to analyse whether helmet therapy in the moderate DP group affected the results by influencing language outcomes, but did not reveal any significant influence (p = 0.712). CONCLUSIONS: The results of this study do not support arguments suggesting that DP is a cognitive risk condition. The suggestion that a direct neurophysiological relationship exists between a DP condition and a cognitive developmental delay remains controversial. PMID- 28875352 TI - Specificity of Reward Sensitivity and Parasympathetic-Based Regulation among Children with Attention-Deficit/Hyperactivity and Disruptive Behavior Disorders. AB - Attention-deficit/hyperactivity disorder (ADHD) is associated with disruptionsin reward sensitivity and regulatory processes. However, it is unclear whether thesedisruptions are better explained by comorbid disruptive behavior disorder (DBD)symptomology. This study sought to examine this question using multiple levels ofanalysis (i.e., behavior, autonomic reactivity). One hundred seventeen children (aged 6 to 12 years; 72.6% male; 69 with ADHD) completed theBalloon Analogue Risk Task (BART) to assess external reward sensitivity behaviorally.Sympathetic-based internal reward sensitivity and parasympathetic based regulationwere indexed via cardiac pre-ejection period (PEP) and respiratory sinus arrhythmia(RSA), respectively. Children with ADHD exhibited reduced internal reward sensitivity (i.e.,lengthened PEP; F(1,112)=4.01, p=0.047) compared to healthy controls and werecharacterized by greater parasympathetic based dysregulation (i.e., reduced RSAaugmentation F(1,112)=10.12, p=0.002). However, follow-up analyses indicated theADHD effect was better accounted for by comorbid DBD diagnoses; that is, childrenwith ADHD and comorbid ODD were characterized by reduced internal rewardsensitivity (i.e., lengthened PEP; t=2.47, p=0.046) and by parasympathetic-baseddysregulation (i.e., reduced RSA augmentation; t=3.51, p=0.002) in response to rewardwhen compared to typically developing youth. Furthermore, children with ADHD and comorbid CD exhibited greater behaviorally-based external reward sensitivity (i.e.,more total pops; F(3,110)= 5.96, p=0.001) compared to children with ADHD only (t=3.87, p=0.001) and children with ADHD and ODD (t=3.56, p=0.003). Results suggest that disruptions in sensitivity to reward may be betteraccounted for, in part, by comorbid DBD.Key Words: attention-deficit/hyperactivity disorder, autonomic nervous system,disruptive behavior disorders, reward sensitivityPowered. PMID- 28875354 TI - [Life after Acute Kidney Injury : Long-term consequences and implications for clinical practice]. AB - Acute kidney injury (AKI) is a common complication in critically ill patients and is accompanied by significantly increased mortality and morbidity. Those complications are not limited to the acute phase of the illness, but may also affect a patient's risk profile long after AKI. Recovery of renal function is observed in the majority of patients although this rate significantly deteriorates with increasing severity of the AKI. After an AKI episode, the long term risk for the development of chronic kidney disease (CKD) is considerably increased, as well as the risk for cardiovascular and neurological complications. Follow-up of these patients should include general nephroprotective measures such as controlling hypertension as well as avoiding nephrotoxic drugs, as well as repeated evaluations of renal function. PMID- 28875355 TI - Is there an association between flow diverter fish mouthing and delayed-type hypersensitivity to metals?-a case-control study. AB - PURPOSE: Flow diverters are increasingly used in the treatment of complex and giant intracranial aneurysms. However, they are associated with complications like late aneurysmal rupture. Additionally, flow diverters show focal structural decrease in luminal diameter without any intimal hyperplasia. This resembles a "fish mouth" when viewed en face. In this pilot study, we tested the hypothesis of a possible association between flow diverter fish-mouthing and delayed-type hypersensitivity to its metal constituents. METHODS: We retrospectively reviewed patient records from our center between May 2010 and November 2015. A total of nine patients had flow diverter fish mouthing. A control group of 25 patients was selected. All study participants underwent prospective patch test to detect hypersensitivity to flow diverter metal constituents. Analysis was performed using logistic regression analysis and Wilcoxon sign rank sum test. Univariate and multivariate analyses were performed to test variables to predict flow diverter fish mouthing. RESULTS: The association between flow diverter fish mouthing and positive patch test was not statistically significant. In multivariate analysis, history of allergy and maximum aneurysm size category was associated with flow diverter fish mouthing. This was further confirmed on Wilcoxon sign rank sum test. CONCLUSION: The study showed statistically significant association between flow diverter fish mouthing and history of contact allergy and a small aneurysmal size. Further large-scale studies are needed to detect a statistically significant association between flow diverter fish mouthing and patch test. We recommend early and more frequent follow-up imaging in patients with contact allergy to detect flow diverter fish mouthing and its subsequent evolution. PMID- 28875356 TI - Response to "Commentary on: Undertreatment trend in elderly lung cancer patients in Brazil"-Jing-lan Tang, Chun-jie Hou. PMID- 28875357 TI - Combined Effects of Temperature and the Microcystin MC-LR on the Feeding Behavior of the Rotifer Brachionus calyciflorus. AB - The aim of this study was to investigate the responses in filtration and grazing rates of five rotifer strains of the species Brachionus calyciflorus under different temperatures and MC-LR concentrations. The results showed that strain identity, MC-LR concentration, temperature, and the interactions of these factors significantly affected both response variables, with the exception of the interaction of strain and MC-LR on the grazing rates. At low MC-LR concentrations and for the control group, the filtration and grazing rates increased with increasing temperature. The filtering and grazing rates of B. calyciflorus exposed to higher MC-LR concentrations, however, showed no evident enhancement with increasing of temperature. At high temperatures, the filtration and grazing rates of all rotifer strains decreased significantly with increasing concentration of MC-LR, however B. calyciflorus exhibited a refractory stability in the presence of increased MC-LR levels at lower temperatures. PMID- 28875358 TI - Determination of Critical Quality Attributes for a Biotherapeutic in the QbD Paradigm: GCSF as a Case Study. AB - Estimating impact of the various product-related variants and impurities on a biotherapeutic's safety and efficacy is an essential requirement in the quality by design paradigm. In view of the limited role that clinical studies offer in this regard, we demonstrate a preclinical approach to achieve this for granulocyte colony-stimulating factor (GCSF). While our repeated-dose toxicity data suggest that these variants do not elicit any adverse effects or histopathological changes, aggregated GCSF impurity caused sluggishness in animal behavior manifested by a possible muscular injury. Cell assay data revealed that the cys-64-cys74 disulfide bond in reduced GCSF imparts stabilization in absence of the cys-36-cys42 bond. PK data demonstrate variability in half lives of different species when compared to the native GCSF. PD data along with differential expression of JAK-2 and STAT5a genes show that all the tested variants triggered the required signal transduction pathways for neutrophil proliferation and activation. PMID- 28875359 TI - Volatile Chemical Emission as a Weapon of Rearguard Action: A Game-Theoretic Model of Contest Behavior. AB - We use a game-theoretic model to explore whether volatile chemical (spiroacetal) emissions can serve as a weapon of rearguard action. Our basic model explores whether such emissions serve as a means of temporary withdrawal, preventing the winner of the current round of a contest from translating its victory into permanent possession of a contested resource. A variant of this model explores an alternative possibility, namely, that such emissions serve as a means of permanent retreat, attempting to prevent a winner from inflicting costs on a fleeing loser. Our results confirm that the underlying logic of either interpretation of weapons of rearguard action is sound; however, empirical observations on parasitoid wasp contests suggest that the more likely function of chemical weapons is to serve as a means of temporary withdrawal. While our work is centered around the particular biology of contest behavior in parasitoid wasps, it also provides the first contest model to explicitly consider self inflicted damage costs and thus responds to a recent call by empiricists for theory in this area. PMID- 28875360 TI - [Recurrent instability and instability arthropathy]. AB - Capsulolabral reconstruction (Bankart repair) is recommended as the first line treatment in young and functionally demanding active patients with anteroinferior shoulder instability, due to the high tendency to recurrent dislocation. This has become established both for arthroscopic and open primary shoulder stabilization with good clinical outcome; nevertheless, recurrence of dislocation is reported in up to 25% of patients. Risk factors for failed surgery are patient (e.g. young age, male gender and contact sports) and surgery (e.g. primarily underestimated glenoid bone loss, Hill-Sachs lesion, non-treatment of bipolar defects or malpositioned anchors) related. In the management of recurrent instability, it is necessary to carry out a thorough clinical investigation in addition to extended diagnostics with X-ray and computed tomography. A second Bankart repair is only indicated in patients with low demands and without any glenoid bone loss. In the majority of patients, bony augmentation of the glenoid is necessary and realized by coracoid or iliac crest bone block transfer. The Latarjet procedure is biomechanically advantageous due to the additional sling effect of the conjoined tendons and both techniques show good clinical outcomes and a low recurrence rate. Furthermore, engaging Hill-Sachs lesions also require additional treatment. Remplissage of the infraspinatus muscle, iliac crest bone block transfer and partial joint replacement are viable options. A final consensus for treatment of Hill-Sachs lesions has yet to be defined. Dislocation arthropathy is an underestimated complication as a result of frequent recurrent dislocations. After development of dislocation arthropathy, patients reported a painful restriction of range of motion rather than instability. Arthroscopic arthrolysis and comprehensive arthroscopic management (CAM procedure) are possible joint preserving treatment options. PMID- 28875361 TI - Solvation free energies and partition coefficients with the coarse-grained and hybrid all-atom/coarse-grained MARTINI models. AB - We present the estimation of solvation free energies of small solutes in water, n octanol and hexane using molecular dynamics simulations with two MARTINI models at different resolutions, viz. the coarse-grained (CG) and the hybrid all atom/coarse-grained (AA/CG) models. From these estimates, we also calculate the water/hexane and water/octanol partition coefficients. More than 150 small, organic molecules were selected from the Minnesota solvation database and parameterized in a semi-automatic fashion. Using either the CG or hybrid AA/CG models, we find considerable deviations between the estimated and experimental solvation free energies in all solvents with mean absolute deviations larger than 10 kJ/mol, although the correlation coefficient is between 0.55 and 0.75 and significant. There is also no difference between the results when using the non polarizable and polarizable water model, although we identify some improvements when using the polarizable model with the AA/CG solutes. In contrast to the estimated solvation energies, the estimated partition coefficients are generally excellent with both the CG and hybrid AA/CG models, giving mean absolute deviations between 0.67 and 0.90 log units and correlation coefficients larger than 0.85. We analyze the error distribution further and suggest avenues for improvements. PMID- 28875363 TI - Implantation of Unibody Single-Branched Stent Graft for Patients with Type B Aortic Dissections Involving the Left Subclavian Artery: 1-Year Follow-Up Outcomes. AB - OBJECTIVE: To report the early results of castor device, a kind of unibody single branched stent graft, in the treatment of type B aortic dissection (TBAD) involving the LSA. METHODS: From April 2013 to February 2014, 21 patients with TBADs underwent TEVAR with LSA revascularization by unibody single-branched stent grafts. Three patients with penetrating aortic ulcers in the aortic arch received additional reconstruction of left common carotid artery with chimney technique. Follow-up evaluations were conducted with computed tomography angiography (CTA) at 6, 12 months and annually after that. RESULTS: All of the proximal entry tears were completely excluded. Good patency of the grafts was found in all cases. A small type I endoleak occurred in one patient during the procedure. Perioperative mortality is null, and there was no occurrence of serious complications. All patients completed the follow-up except one lost contact after discharge. One death occurred within 6 months after the operation, resulting from myocardial infarction, considered unrelated to the stent implantation. No endoleak occurred during follow-up. One compression of a chimney stent and one twist of side branch graft of castor were observed in 2 different patients, respectively. In other cases, CTA scans showed good patency of both the branched and chimney grafts. Two patients had partial thrombosis of the false lumen during follow-up. In other patients, complete thrombosis in the false lumen in thoracic aorta was revealed. CONCLUSION: The single-branched stent graft was safe and efficient in the 1-year follow-up. Further studies are required to determine its long-term outcomes. PMID- 28875362 TI - Propofol Attenuates Inflammatory Response in LPS-Activated Microglia by Regulating the miR-155/SOCS1 Pathway. AB - Propofol is a widely used intravenous anesthetic agent with potential neuroprotective effect in diverse models of neuronal injury, including ischemic stroke and traumatic brain injury. However, few studies have been carried out to determine the effects and molecular mechanisms of propofol in classic microglial activation (M1 activation) related to neuronal injury. This study explored the anti-inflammatory effects of propofol in LPS-activated BV2 microglia. Propofol potently decreased the pro-inflammatory mediators, such as nitric oxide, TNF alpha, and IL-6, at both the transcriptional and translational levels. Furthermore, propofol suppressed the expression of miR-155 in LPS-activated cells. Knockdown of miR-155 attenuated the anti-inflammatory effect of propofol in cells after LPS exposure. miR-155 was also confirmed as a negative regulator of SOCS1 expression. The inhibitory effect of propofol on LPS-induced inflammation involved the upregulation of SOCS1. Overall, these results suggest that propofol can suppress the neuroinflammatory response of microglia to LPS through the regulation of the miR-155/SOCS1 pathway. PMID- 28875364 TI - Age- and sex-based resource utilisation and costs in patients with acute chest pain undergoing cardiac CT angiography: pooled evidence from ROMICAT II and ACRIN PA trials. AB - OBJECTIVES: To determine resource utilisation according to age and gender specific subgroups in two large randomized diagnostic trials. METHODS: We pooled patient-specific data from ACRIN-PA 4005 and ROMICAT II that enrolled subjects with acute chest pain at 14 US sites. Subjects were randomized between a standard work-up and a pathway utilizing cardiac computed tomography angiography (CCTA) and followed for the occurrence of acute coronary syndrome (ACS) and resource utilisation during index hospitalisation and 1-month follow-up. Study endpoints included diagnostic accuracy of CCTA for the detection of ACS as well as resource utilisation. RESULTS: Among 1240 patients who underwent CCTA, negative predictive value of CCTA to rule out ACS remained very high (>=99.4%). The proportion of patients undergoing additional diagnostic testing and cost increased with age for both sexes (p < 0.001), and was higher in men as compared to women older than 60 years (43.1% vs. 23.4% and $4559 +/- 3382 vs. $3179 +/- 2562, p < 0.01; respectively). Cost to rule out ACS was higher in men (p < 0.001) and significantly higher for patients older than 60 years ($2860-5935 in men, p < 0.001). CONCLUSIONS: CCTA strategy in patients with acute chest pain results in varying resource utilisation according to age and gender-specific subgroups, mandating improved selection for advanced imaging. KEY POINTS: * In this analysis, CAD and ACS increased with age and male gender. * CCTA in patients with acute chest pain results in varying resource utilisation. * Significant increase of diagnostic testing and cost with age for both sexes. * Cost to rule out ACS is higher in men and patients >60 years. * Improved selection of subjects for cardiac CTA result in more resource-driven implementation. PMID- 28875365 TI - The preoperative albumin level is an independent prognostic factor for optimally debulked epithelial ovarian cancer. AB - PURPOSE: A low albumin level has been reported to be a prognostic factor for various cancers. The aim of this study was to determine the association between preoperative serum albumin level and survival in patients with epithelial ovarian cancer (EOC). METHODS: Records of 337 patients with EOC that underwent optimal cytoreductive surgery were retrospectively reviewed. Threshold albumin level was planned as 32.5 g L-1 due to the statistical analyses. RESULTS: Mean overall survival was 51.5 months. Area under the ROC curve was found statistically significant for the discriminative role of albumin for survival outcome (AUC = 0.857, 95% CI 0.813-0.90, P < 0.001). The best cut-off point for albumin was determined as 32.5 g L-1. The sensitivity rate, specificity rate, positive and negative predictive values, and accuracy rate for this cut-off level were found 67.2, 91.2, 81.2, 83.1, and 82.5%, respectively. Preoperative hypoalbuminemia was noted in 101 (30.0%) of the patients, of which 6.2% had an albumin level <25 g L 1. The albumin level was independently and significantly associated with overall survival (HR 2.6; 95% CI 2.1-3.1; P < 0.001). Subgroup analysis showed that patients with an albumin level <32.5 and >=32.5 g L-1 had mean estimated overall survival of 40.6 and 96.0 months, respectively. Age, stage, and presence of ascites were the other independent significant factors. CONCLUSIONS: The preoperative albumin level is an independent prognostic factor for overall survival in optimally debulked EOC patients. Further investigations about preoperative albumin level in prognostic models will contribute to the literature. PMID- 28875367 TI - Differential item functioning by language on the PROMIS(r) physical functioning items for children and adolescents. AB - PURPOSE: To assess the equivalence of self-reports of physical functioning between pediatric respondents to the English- and Spanish-language patient reported outcomes measurement information system (PROMIS(r)) physical functioning item banks. METHODS: The PROMIS pediatric physical functioning item banks include 29 upper extremity items and 23 mobility items. A sample of 5091 children and adolescents (mean age = 12 years, range 8-17; 49% male) completed the English language version of the items. A sample of 605 children and adolescents (mean age = 12 years, range 8-17; 55% male; 96% Hispanic) completed the Spanish-language version of the items. RESULTS: We found language (English versus Spanish) differential item functioning (DIF) for 4 upper extremity items and 7 mobility items. Product-moment correlations between estimated upper extremity and mobility scores using the English versus the equated Spanish item parameters for Spanish language respondents were 0.98 and 0.99, respectively. After excluding cases with significant person misfit, we found DIF for the same 4 upper extremity items that had DIF in the full sample and for 12 mobility items (including the same 7 mobility items that had DIF in the full sample). The identification of DIF items between English- and Spanish-language respondents was affected slightly by excluding respondents displaying person misfit. CONCLUSIONS: The results of this study provide support for measurement equivalence of self-reports of physical functioning by children and adolescents who completed the English- and Spanish language surveys. Future analyses are needed to replicate the results of this study in other samples. PMID- 28875366 TI - Saikosaponin D relieves unpredictable chronic mild stress induced depressive-like behavior in rats: involvement of HPA axis and hippocampal neurogenesis. AB - RATIONALE: Saikosaponin D (SSD), a major bioactive component isolated from Radix Bupleuri, has been reported to exert neuroprotective properties. OBJECTIVES: The present study was designed to investigate the anti-depressant-like effects and the potential mechanisms of SSD. METHODS: Behavioural tests including sucrose preference test (SPT), open field test (OFT) and forced swim test (FST) were performed to study the antidepressant-like effects of SSD. In addition, we examined corticosterone and glucocorticoid receptor (GR) levels to evaluate hypothalamic-pituitary-adrenal (HPA) axis function. Furthermore, hippocampal neurogenesis was assessed by testing doublecortin (DCX) levels, and neurotrophic molecule levels were also investigated in the hippocampus of rats. RESULTS: We found that unpredictable chronic mild stress (UCMS) rats displayed lost body weight, decreased sucrose consumption in SPT, reduced locomotive activity in OFT, and increased immobility time in FST. Chronic treatment with SSD (0.75, 1.50 mg/kg) remarkably ameliorated the behavioral deficiency induced by UCMS procedure. SSD administration downregulated elevated serum corticosterone levels, as well as alleviated the suppression of GR expression and nuclear translocation caused by UCMS, suggesting that SSD is able to remit the dysfunction of HPA axis. In addition, Western blot and immunohistochemistry analysis showed that SSD treatment significantly increased the generation of neurons in the hippocampus of UCMS rats indicated by elevated DCX levels. Moreover, hippocampal neurotrophic molecule levels of UCMS rats such as phosphorylated cAMP response element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were raised after SSD treatment. CONCLUSIONS: Together, Our results suggest that SSD opposed UCMS induced depressive behaviors in rats, which was mediated, partially, by the enhancement of HPA axis function and consolidation of hippocampal neurogenesis. PMID- 28875368 TI - Relative abundance of beta-thalassemia-related mutations in southern China correlates with geographical coordinates. PMID- 28875369 TI - [Personalized oncology]. AB - CLINICAL ISSUE: Innovative next generation sequencing (NGS) technologies and comprehensive sequencing investigations in large patient cohorts have paved the way for very promising personalized treatment strategies based on the molecular characteristics of individual tumors. STANDARD TREATMENT: Targeted therapies, such as tyrosine kinase inhibitors, antibodies and modern immunotherapeutic approaches are well established as monotherapy and combination therapy for many hematological and oncological malignancies. TREATMENT INNOVATIONS: A plethora of innovative therapies targeting various components of intracellular signaling cascades and effective mechanisms against oncogenes as well as the availability of NGS technologies enable personalized cancer treatment based on the molecular profiles of individual tumors and genetic stratification, within clinical trials. DIAGNOSTIC WORK-UP: Comprehensive genetic approaches including cancer gene panel sequencing, whole exome, whole genome and transcriptome sequencing are carried out to a varying extent and particularly in the academic setting. PERFORMANCE: Principally, a comprehensive characterization of tumors in addition to DNA and RNA sequencing that also incorporates epigenetic, metabolomic, and proteomic alterations would be desirable. A comprehensive clinical implementation of integrative, multidimensional genetic typing is, however, currently not possible. ACHIEVEMENTS: It remains to be demonstrated whether these approaches will translate into significantly better outcomes for patients and whether they can be increasingly implemented in the routine diagnostic work-up. PRACTICAL RECOMMENDATIONS: The selection of diagnostic tools in individual cases and the extent of genomic analyses in the clinical context, need to take the availability of methods as well as the present clinical situation into account. PMID- 28875370 TI - How prepared are pharmacists to support atrial fibrillation patients in adhering to newly prescribed oral anticoagulants? AB - Background The New Medicines Service (NMS) was implemented in the United Kingdom in 2011 and first evaluated in 2014, showing 10% increase on adherence. Objective To assess community pharmacists' current practice, knowledge and confidence in supporting patients' adherence as part of the NMS for patients on Oral Anti Coagulants (OACs) for stroke prevention in Atrial Fibrillation. Setting Community pharmacists in London. Method An online cross-sectional survey was sent to pharmacists from their Local Pharmaceutical Committees and advertised by the Royal Pharmaceutical Society. Analysis was undertaken in SPSs v23 considering a confidence level of 95%. Main outcome measures pharmacists reported confidence of providing the NMS on OACs; training needs and skills for supporting adherence. Results A total of 257 valid responses were analysed (6.8% response rate; {Cronbach's alpha = 0.676-0.892}). Data indicates that over a 2-month period, 25% of pharmacists had completed >=6 NMS consultations for all OACs, of which 11% for new oral anticoagulants (NOACs). The key priorities in counselling items during the NMS consultation were to discuss actions to take when bleeding occurs, followed by supporting adherence. Pharmacists were more confident in their knowledge, skills and access to resources for Vitamin-K Antagonists (VKAs) than for NOACs (p < 0.005). Results also highlight pharmacists' unfamiliarity with alert cards, lower for NOACs than VKAs (p < 0.001), albeit perceived as critically important. Half the sample mentioned to use the British National Formulary as information resource. Conclusion Results suggest the provision of NMS for NOACs is low. Supporting pharmacists with tailored education and adherence support might foster dissemination. PMID- 28875371 TI - The effective systematic heparin pre-treatment on thrombus formation on pulmonary artery catheter tips during pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: a randomized, double-blind study. AB - Pulmonary artery (PA) catheters are routinely used for hemodynamic management in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA). Tip-associated thrombi are frequently detected and might increase the peri-operative risk in these patients. The aim of the study was to investigate the effects of low-dose heparinization before the insertion of the PA catheter on thrombus formation and thrombus weight during PEA surgery. From September 2013 to February 2015, 60 CTEPH patients undergoing PEA were included in the study and randomized into two groups of 30 patients each, including a heparin group (heparin bolus (70 IU per kg body weight) administration before PA catheter insertion) and a control group (pretreatment with placebo). During the PEA procedure the distal part of the PA catheter was drawn out of the PA and thrombus presence and weight were recorded. There were no significant differences in baseline characteristics between the two groups. Twelve patients (20%) had thrombophilic disorders. In the control group, thrombi were detected in 17 patients (57%) with a median thrombus weight of 27 mg (IQR 41). In the heparin group, tip-associated thrombi were found in five patients (17%) with a median weight of 12 mg (IQR 7). There were no bleeding complications in either group. This study demonstrates a high risk of PA catheter-related thrombi in patients with CTEPH. Prophylactic administration of low-dose heparin reduces thrombus formation and thrombus weight without an increased rate of bleeding complications. PMID- 28875372 TI - Comparison of EMA-, PMA- and DNase qPCR for the determination of microbial cell viability. AB - Ethidium monoazide (EMA) quantitative polymerase chain reaction (qPCR), propidium monoazide (PMA)-qPCR and DNase treatment in combination with qPCR were compared for the determination of microbial cell viability. Additionally, varying EMA and PMA concentrations were analysed to determine which dye and concentration allowed for the optimal identification of viable cells. Viable, heat treated (70 degrees C for 15 min) and autoclaved cultures of Legionella pneumophila, Pseudomonas aeruginosa, Salmonella typhimurium, Staphylococcus aureus and Enterococcus faecalis were utilised in the respective viability assays. Analysis of the viable and heat-treated samples indicated that variable log reductions were recorded for both EMA [log reductions ranging from 0.01 to 2.71 (viable) and 0.27 to 2.85 (heat treated)], PMA [log reductions ranging from 0.06 to 1.02 (viable) and 0.62 to 2.46 (heat treated)] and DNase treatment [log reductions ranging from 0.06 to 0.82 (viable) and 0.70 to 2.91 (heat treated)], in comparison to the no viability treatment controls. Based on the results obtained, 6 MUM EMA and 50 MUM PMA were identified as the optimal dye concentrations as low log reductions were recorded (viable and heat-treated samples) in comparison to the no viability treatment control. In addition, the results recorded for the 6 MUM EMA concentration were comparable to the results obtained for both the 50 MUM PMA and the DNase treatment. The use of EMA-qPCR (6 MUM) may therefore allow for the rapid identification and quantification of multiple intact opportunistic pathogens in water sources, which would benefit routine water quality monitoring following disinfection treatment. PMID- 28875373 TI - Differentiating brain radionecrosis from tumour recurrence: a role for contrast enhanced ultrasound? AB - Differentiating radionecrosis from tumour recurrence is a major issue in neuro oncology. Conventional imaging is far from being validated as an alternative to histological assessment. We report the case of a patient operated on for suspected recurrence of brain metastasis 9 months after cyberknife radiosurgery. While magnetic resonance imaging showed strong enhancement of the lesion, intraoperative contrast-enhanced ultrasonography (CEUS) surprisingly did not different from what is expected for brain metastases. Histopathological examination documented radionecrosis. For the first time, we describe radionecrosis with CEUS; further investigation is needed; however, the lack of enhancement could represent an important hallmark in differential diagnosis with neoplastic tissue. PMID- 28875375 TI - Germ cell line during the seasonal sexual rest of clams: finding niches of cells for gonad renewal. AB - Reconstitution and renewal of tissues are key topics in developmental biology. In this brief work, we analyzed the wintry spent phase of the reproductive cycle in the Manila clam Ruditapes philippinarum (Bivalvia, Veneridae) in order to study the gonad rebuilding that in this species occurs at the beginning of the warmer months. We labeled VASA homolog protein-a germ cell marker-and compared the histological observations of the spent phase with those of the previously analyzed gametogenic phase. In R. philippinarum, during the reproductive season, most of the body mass is represented by sack-like structures (acini) full of developing gametes. In that period, VASA-stained cells are present at the basal pole of the gut epithelium, in the connective tissue, and around the acini. We here show that during the spent phase large portions of the intestine lack such cell type, except for some areas showing a few faintly VASA-stained cells. Cells with similar nuclear morphology are present among loosely organized cells of connective tissue, sometimes as single units, sometimes in small groups, rarely partially organized in primordial gonadic structures. These observations match the findings of RNA-targeting studies that during the spent phase identified the source of bivalve germ cells within the connective tissue in the form of quiescent units and add new information on the possible maintenance of VASA stained, multipotent cells among the batiprismatic cells of the intestine during the whole life span of these bivalves. PMID- 28875374 TI - Yttrium-90 radioembolization treatment for unresectable hepatocellular carcinoma: a single-centre prognostic factors analysis. AB - The aim of this study was to evaluate the efficacy and the safety of Y90 radioembolization (Y90-RE) in patients with unresectable hepatocellular carcinoma (HCC) analysing our results and correlating them with independent prognostic factors for overall survival (OS) and for complications. Forty-three patients with advanced inoperable HCC including those with multiple bilobar lesions or portal vein thrombosis (PVT) treated with Y90-RE were reviewed. Treatment efficacy and safety were evaluated. Survival was calculated by the Kaplan-Meier method. Univariate analyses were performed for identifying potential prognostic factors. Radiologic response was evaluated with the modified Response Evaluation Criteria in Solid Tumours (mRECIST) criteria. Clinical toxicities were prospectively recorded. Median overall progression-free survival and OS were 27.7 and 16.8 months, respectively. Longer median OS was revealed in those without PVT (p = 0.0241) and those whose pre-treatment haemoglobin values was higher (p = 0.0471). According with mRECIST criteria, we observed a disease control rate of 69.2 and 61.9% at 3- and 6-month follow-up, respectively. Complications developed in 28 patients (65.1%), among which grade 2-3 events were reported in 17 patients. We noted that activity administered dose presented a correlation with intra-procedural toxicity (p = 0.039259) while common hepatic artery use as release site was associated with a most frequent presentation of remote adverse events. Y90-RE is an alternative treatment with a promising outcome for poor-risk advanced inoperable HCC. PVT and pre-treatment haemoglobin values can be predictors of efficacy. Activity administered dose and arterial release site can be predictors of safety. PMID- 28875376 TI - Handling aberrant vessels located in the posterior bladder wall in surgery for abnormally invasive placenta: a non/less-touch technique. AB - BACKGROUND: At cesarean hysterectomy for abnormally invasive placenta, rupture of aberrant vessels around the uterus causes massive bleeding. PURPOSE: This study aimed at describing a technique to reduce bleeding from aberrant vessels at the posterior bladder wall in this surgery. METHODS: The bladder is filled with 200 300 mL of water during handling the posterior bladder wall. RESULTS: This technique facilitates understanding that some aberrant vessels do not have communications with the cervix-uterus. Some aberrant vessels have communication with the cervix-uterus and this technique makes cutting and ligation of these vessels easy. CONCLUSIONS: Filling the bladder may reduce bleeding from the posterior bladder wall at cesarean hysterectomy for abnormally invasive placenta. PMID- 28875378 TI - HIV and AIDS Act: What Healthcare Workers Need to Know? PMID- 28875377 TI - Chromogranins: from discovery to current times. AB - The discovery in 1953 of the chromaffin granules as co-storage of catecholamines and ATP was soon followed by identification of a range of uniquely acidic proteins making up the isotonic vesicular storage complex within elements of the diffuse sympathoadrenal system. In the mid-1960s, the enzymatically inactive, major core protein, chromogranin A was shown to be exocytotically discharged from the stimulated adrenal gland in parallel with the co-stored catecholamines and ATP. A prohormone concept was introduced when one of the main storage proteins collectively named granins was identified as the insulin release inhibitory polypeptide pancreastatin. A wide range of granin-derived biologically active peptides have subsequently been identified. Both chromogranin A and chromogranin B give rise to antimicrobial peptides of relevance for combat of pathogens. While two of the chromogranin A-derived peptides, vasostatin-I and pancreastatin, are involved in modulation of calcium and glucose homeostasis, respectively, vasostatin-I and catestatin are important modulators of endothelial permeability, angiogenesis, myocardial contractility, and innate immunity. A physiological role is now evident for the full-length chromogranin A and vasostatin-I as circulating stabilizers of endothelial integrity and in protection against myocardial injury. The high circulating levels of chromogranin A and its fragments in patients suffering from various inflammatory diseases have emerged as challenges for future research and clinical applications. PMID- 28875379 TI - Tumor vessel disintegration by maximum tolerable PFKFB3 blockade. AB - Blockade of the glycolytic activator PFKFB3 in cancer cells (using a maximum tolerable dose of 70 mg/kg of the PFKFB3 blocker 3PO) inhibits tumor growth in preclinical models and is currently being tested as a novel anticancer treatment in phase I clinical trials. However, a detailed preclinical analysis of the effects of such maximum tolerable dose of a PFKFB3 blocker on the tumor vasculature is lacking, even though tumor endothelial cells are hyper-glycolytic. We report here that a high dose of 3PO (70 mg/kg), which inhibits cancer cell proliferation and reduces primary tumor growth, causes tumor vessel disintegration, suppresses endothelial cell growth for protracted periods, (model dependently) aggravates tumor hypoxia, and compromises vascular barrier integrity, thereby rendering tumor vessels more leaky and facilitating cancer cell intravasation and dissemination. These findings contrast to the effects of a low dose of 3PO (25 mg/kg), which induces tumor vessel normalization, characterized by vascular barrier tightening and maturation, but reduces cancer cell intravasation and metastasis. Our findings highlight the importance of adequately dosing a glycolytic inhibitor for anticancer treatment. PMID- 28875380 TI - Balloon-occluded retrograde transvenous obliteration of varices: focusing on the portal hemodynamics and the recent techniques. AB - PURPOSE: To evaluate the recent topics of Ballloon-occluded retrograde trasnvenous obliteration(B-RTO). METHOD: We overviewed the recent scientific papers regarding B-RTO. RESULT: B-RTO is a treatment method for occluding varices retrogradely using a sclerosing agent under balloon occlusion of a major draining vein. It has been recognized as an effective treatment method for gastric varices. Hepatic function reserve is improved and liver volume is increased after B-RTO. In recent years, various technical options, such as plug-assisted retrograde transvenous obliteration, coil-assisted retrograde transvenous obliteration, or foam B-RTO, have also been reported. In performing B-RTO, portal hemodynamics must be thoroughly examined radiologically. Judging the classification of the grade of collateral venous hemodynamics is important to select the appropriate embolization technique of B-RTO and to successfully occlude varices. Finally, the word "portosystemic shunt syndrome" has been proposed and the condition should be considered while selecting a treatment for gastric varices. CONCLUSION: B-RTO is effective for gastrointestinal varices and portosystemic shunts. PMID- 28875381 TI - Differential apoptotic response of MC3T3-E1 pre-osteoblasts to biodegradable magnesium alloys in an in vitro direct culture model. AB - The biodegradable magnesium-based implants have been widely utilized in medical orthopedic applications in recent years. We have recently shown that direct culture on Pure Mg and Mg2Ag alloys lead to a progressive differentiation impairment of MC3T3-E1 pre-osteoblasts. In this study, we aimed to analyze the apoptotic reaction of MC3T3-E1 cells in response to the direct culture on Pure Mg, Mg2Ag and Extreme High Pure Mg (XHP Mg) alloy samples. Our results demonstrated that long-term culturing of MC3T3-E1 cells on Pure Mg and Mg2Ag alloys induce time-dependent expression of active caspase-3 (active casp-3) and cleaved PARP-1 (cl. PARP-1), the hallmark of apoptosis reactions concomitant with a significant increase in the number of dead cells. However, direct culture on XHP Mg material results in a lower number of dead cells in comparison to Pure Mg and Mg2Ag alloys. Furthermore, XHP Mg materials influence expression of apoptotic markers in a process resembles that of observed in osteogenic condition apparently indicative of MC3T3-E1 osteodifferentiation. This study indicates that Mg alloy samples mediated differential apoptotic reactions of MC3T3-E1 cells can be ascribed to factors such as distinct topography and hydrophobicity features of Mg material surfaces, contrasting nature/composition of corrosion products as well as different impurities of these materials. Therefore, initial Mg alloys surface preparation, controlling the growth and composition of corrosion products and Mg alloys purity enhancement are necessary steps towards optimizing the Mg alloys usage in medical orthopedic applications. PMID- 28875382 TI - [Tumors of the inner ear and adjacent structures]. AB - Tumors of the inner ear and adjacent structures often present with hearing loss, tinnitus and vertigo due to compression of the traversing cranial nerves. More than 90% of the tumors of the inner ear with or without expansion into the cerebellopontine angle are histologically diagnosed as vestibular schwannomas. Less common tumorous lesions include ectopic meningiomas located in the petrous bone, glomus tympanicum paragangliomas or endolymphatic sac tumors (ELST) originating in the vestibular recess. Most tumors are sporadic, but hereditary disorders have to be considered. Bilateral vestibular schwannomas are indicative of neurofibromatosis type 2 and ELST in conjunction with other abdominal tumors indicates von Hippel-Lindau disease. The neuropathological diagnostics and grading guides the subsequent therapy of these mostly benign lesions. PMID- 28875383 TI - Distribution characteristics of heavy metal(loid)s in aggregates of different size fractions along contaminated paddy soil profile. AB - Soil aggregates exert a significant influence on the retention and availability of heavy metal(loid)s in soil. In this study, the concentration distribution and chemical forms of heavy metals (Cu, Zn, Cd, Pb, and Hg) and a metalloid (As) in different aggregate-sized fractions (2-0.25, 0.25-0.05, 0.05-0.002, and < 0.002 mm) along the profile (0-1, 1-5, 5-15, and 15-25 cm) of a contaminated paddy field were investigated. The results showed that the values of pH, free Fe oxides (Fed), bulk density, and catalase activity gradually increased, whereas the soil organic matter (SOM), cation exchange capacity (CEC), electrical conductivity (EC), microbial biomass carbon (MBC), and urease activity decreased with depth. Long-term heavy metal pollution might impact the catalase activity but showed no obvious influence on the urease activity. Additionally, there was a notable difference in physicochemical properties among the soil aggregates of various particle sizes. The 2-0.25-mm fraction aggregates contained more organic matter, whereas the highest values of CEC and Fed were observed in the < 0.002-mm fraction. The concentrations of all six heavy metals/metalloid decreased with depth. In different layers, Cu and Cd showed the highest concentrations in the 2 0.25 mm-fraction, followed by the < 0.002-mm fraction, whereas the highest concentrations of Zn, Pb, and As appeared in the < 0.002-mm fraction. No obvious distribution regularity was observed for Hg among the aggregates. All of the metal(loid)s had lower activity in the deeper soil layers, except for Hg. Furthermore, Cu and Cd displayed more stable forms in the < 0.002-mm fraction aggregates. PMID- 28875384 TI - Rare cause of delirium and hypoxemia after coronary bypass surgery: transdermal lidocaine patch-associated methemoglobinemia. AB - We present a case of a patient administered parasternal transdermal lidocaine patch therapy as part of a multimodal analgesic regime designed to diminish opioid-associated delirium after coronary bypass surgery. The patient presented with delirium and severe methemoglobinemia (41%) that responded to discontinuation of lidocaine therapy, oxygen administration, and methylene blue administration. The clinical contributors and medicolegal implications of this degree of lidocaine-associated methemoglobin-mediated delirium are presented in the hope of avoiding similar complications in the postoperative setting after coronary bypass surgery. PMID- 28875385 TI - Possible Probiotic Lactic Acid Bacteria Isolated from Oysters (Crassostrea gigas). AB - We attempted to isolate lactic acid bacteria (LAB) from the marine oyster (Crassostrea gigas) and selected several environmental stress-resistant isolates for the development of a future probiotic adjuvant for marine aquaculture. Twenty six presumptive LAB isolates were extracted from oysters and screened (by an agar diffusion assay) for antimicrobial activity toward various pathogens: Vibrio parahaemolyticus, Streptococcus iniae, and Edwardsiella tarda. Eight isolates had an antibacterial activity toward V. parahaemolyticus; in particular, 6 isolates showed a growth-inhibitory activity, with inhibition zone diameters > 15 mm. Of these, 5 isolates (JL17, JL18, JL28, HL7, and HL32) were also active against S. iniae and E. tarda. Enterococcus faecium HL7 was selected as the isolate most resistant to environmental stressors: the minimum NaCl, ethanol, and hydrogen peroxide concentrations at which HL7 cells lost their viability were 1.9 M, 11%, and 0.013%, respectively. When an antibiotic sensitivity test was performed on E. faecium HL7, this isolate was found to be resistant to trimethoprim/sulfamethoxazole, cephalothin, ampicillin, rifampin, gentamicin, cefotaxime, cefepime, cefotetan, nalidixic acid, and kanamycin. While the oyster model studies provided indication that E. faecium HL7 could be a good candidate as biocontrol agent against V. vulnificus, further optimization is needed in the actual animal rearing situation. PMID- 28875386 TI - Novel SPG20 mutation in an extended family with Troyer syndrome. AB - Troyer Syndrome (TRS) is a rare autosomal recessive complicated spastic paraplegia disorder characterized by various neurological and musculoskeletal manifestations. Pathogenicity stems from mutations in SPG20 which encodes Spartin, a multifunctional protein that is thought to be essential for neuron viability. Here we report on the clinical and molecular characterization of TRS in five patients from an extended consanguineous family in the United Arab Emirates. Molecular analysis involved Whole Exome Sequencing and Sanger sequencing for identification and confirmation of the causative variant respectively. In silico tools including CADD and Polyphen-2 were used to assess pathogenicity of the variant. The clinical description of these patients included spastic paraparesis, motor and cognitive delay, gait abnormalities, musculoskeletal features, as well as white matter abnormalities and emotional liability. Molecular analysis revealed a novel homozygous missense mutation in SPG20 (c.1324G > C; p.Ala442Pro) occurring at an evolutionarily conserved residue in the Plant-Related Senescence domain of Spartin. The mutation segregated with the clinical phenotype in all patients. In silico algorithms predict the mutation to be disease causing, and the variant had not been previously reported in public or ethnic specific variant repositories. PMID- 28875387 TI - Intraspecific variation in fruit-frugivore interactions: effects of fruiting neighborhood and consequences for seed dispersal. AB - The extent of specialization/generalization continuum in fruit-frugivore interactions at the individual level remains poorly explored. Here, we investigated the interactions between the Neotropical treelet Miconia irwinii (Melastomataceae) and its avian seed dispersers in Brazilian campo rupestre. We built an individual-based network to derive plant degree of interaction specialization regarding disperser species. Then, we explored how intraspecific variation in interaction niche breadth relates to fruit availability on individual plants in varying densities of fruiting conspecific neighbors, and how these factors affect the quantity of viable seeds dispersed. We predicted broader interaction niche breadths for individuals with larger fruit crops in denser fruiting neighborhoods. The downscaled network included nine bird species and 15 plants, which varied nearly five-fold in their degree of interaction specialization. We found positive effects of crop size on visitation and fruit removal rates, but not on degree of interaction specialization. Conversely, we found that an increase in the density of conspecific fruiting neighbors both increased visitation rate and reduced plant degree of interaction specialization. We suggest that tracking fruit-rich patches by avian frugivore species is the main driver of density-dependent intraspecific variation in plants' interaction niche breadth. Our study shed some light on the overlooked fitness consequences of intraspecific variation in interaction niches by showing that individuals along the specialization/generalization continuum may have their seed dispersed with similar effectiveness. Our study exemplifies how individual-based networks linking plants to frugivore species that differ in their seed dispersal effectiveness can advance our understanding of intraspecific variation in the outcomes of fruit-frugivore interactions. PMID- 28875388 TI - Intrinsic renal cells induce lymphocytosis of Th22 cells from IgA nephropathy patients through B7-CTLA-4 and CCL-CCR pathways. AB - IgA nephropathy (IgAN), the most common glomerulonephritis, has an unclear pathogenesis. The role of Th22 cells, which are intimately related to proteinuria and progression in IgAN, in mediating infection-related IgAN is unclear. This study aimed to characterize the association between intrinsic renal cells (tubular epithelial cells and mesangial cells) and Th22 cells in immune regulation of infection-related IgAN and to elucidate the impact of Th22 lymphocytosis; the proinflammatory cytokines IL-1, IL-6, and TNF-alpha; and CCL chemokines on kidney fibrosis. Hemolytic streptococcus infection induced an increase in IL-1, IL-6, and TNF-alpha, resulting in Th22 cell differentiation from T lymphocytes obtained from patients with IgAN, and the CCL20-CCR6, CCL22 CCR4, and/or CCL27-CCR10 axes facilitated Th22 cell chemotaxis. The increased amount of Th22 cells caused an increase in TGF-beta1 levels, and anti-CD80, anti CD86, and CTLA-4Ig treatment reduced TGF-beta1 levels by inhibiting Th22 lymphocytosis and secretion of cytokines and chemokines, thus potentially relieving kidney fibrosis. Our data suggest that Th22 cells might be recruited into the kidneys via the CCL20-CCR6, CCL22-CCR4, and/or CCL27-CCR10 axes by mesangial cells and tubular epithelial cells in infection-related IgAN. Th22 cell overrepresentation was attributed to stimulation of the B7-CTLA-4Ig antigen presenting pathway and IL-1, IL-6, and TNF-alpha. PMID- 28875390 TI - Core curriculum illustration: pulmonary laceration. AB - This is the 44th installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.erad.org/page/CCIP_TOC . PMID- 28875389 TI - From "The Depleted Self" to "The Will to Believe": Excavating the Hermeneutics of Donald Capps. AB - The concept of "reframing" lies at the heart of the pastoral psychology of Donald Capps. In previous articles I have argued that the process of reframing follows a circular hermeneutics. An excavation of Capps' hermeneutics reveals foundations in the fields of philosophy and psychology. This article focuses on the legacy of Johann Gottfried von Herder, Friedrich Schleiermacher, William James and Paul Ricoeur. It explores the differences and commonalities between William James and Friedrich Schleiermacher's understanding of religious experience as well as Paul Ricoeur's understanding of narrativity and traces these strains to Capps' pastoral psychology. As illustration of his pastoral approach to healing and wholeness the problem of "the depleted self," so prevalent in "our narcissistic age," encounters the healing narrative of Jesus that appeals to "the will to believe." PMID- 28875391 TI - Dynamics of rebounding Bacillus subtilis spores determined using image-charge detection. AB - A novel image-charge detection technique was used to investigate the mechanical elasticity of bare bacterial spores during high-velocity impact. Spores of Bacillus subtilis introduced to vacuum using electrospray and aerodynamic acceleration impacted and rebounded off of a glass plate. A dual-stage, asymmetric image-charge detector measured the velocity and direction of each spore both before and after impact with the glass surface. Two ranges of impact velocity were investigated, with average initial velocities of 197 +/- 17 and 145 +/- 12 m/s. Impacts were strongly inelastic, with most of the translational kinetic energy lost upon impact, similar to polystyrene particles of similar size under similar impact velocities. Specifically, 69% (+/- 16%) and 74% (+/- 11%) of initial kinetic energy was lost in impacts at the two velocity ranges, respectively. The average coefficients of restitution for the two velocity regimes were 0.53 +/- 0.15 and 0.49 +/- 0.12. There was no statistically significant difference in the fractional kinetic energy loss between these two populations. The variance of these results is much larger than experiments using polystyrene spheres of comparable size. These results imply significant plastic deformation of the spore-a striking result given that spores of this strain of B. subtilis are known to survive impacts on glass at these velocities. Triboelectric charge transfer during impact was also observed. Although much is known about spore elasticity from static measurements, this is the first study to investigate the elastic properties of bacterial spores in a dynamic scenario, as well as the first demonstration of an image charge detector for measurements of rebounding particles. PMID- 28875392 TI - Method optimization for heavy metal determination in milk powder: application to milk samples from Greece. AB - The scope of this study was the development, optimization and validation of an analytical method for the determination of selected heavy metals and trace elements (As, Hg, Se, Cd, Cu, Pb, Mn, Fe, Ni, Zn, Cr) in milk powder, using microwave-assisted digestion. A statistical experimental design approach using central composite design (CCD) was carried out, to investigate the effects of three independent pretreatment variables (final digestion temperature ( degrees C), HNO3 concentration (in % w/v), microwave hold time) on the heavy metal recovery of spiked undigested milk powder sample and to calculate the variable factor values which produce the optimum recovery. CCD results revealed that the optimum digestion conditions, with respect to maximum recovery were as follows: temperature 190 degrees C, HNO3 56.8% w/v, and digestion time of 8.47 min. The method was fully validated. Recoveries for all metals ranged between 92 and 108% while intra-day repeatability was below 6.59% (rsd). A certified reference material (ERM BD 150) that included 8 out of the total 11 heavy metals of the present study (Hg, Se, Cd, Cu, Pb, Mn, Ni, and Zn) was used to test the accuracy of the method where acceptable recovery values ranging between 96 and 107% were obtained. High heavy metal recoveries, short digestion time, and low acid consumption were the advantages of the pretreatment method. The analytical process was successfully applied for the determination of heavy metals in different milk samples from the Greek market. Heavy metal concentrations for Ni, Cr, Pb, Cd, Se, Mn, and Cu measured in this study reached 307, 102, 8.01, 5.96, 60.2, 519, and 438 MUg/kg wet weight (ww), respectively. Zn and Fe were found at concentrations ranging 3.21-8.39 and 0.170-10.1 mg/kg ww, respectively. Risk assessment based on the WHO tolerable daily intake levels and the calculated target hazard quotients revealed that the consumption of the selected milk samples is considered safe. PMID- 28875393 TI - EAP viewpoint on unpublished data from paediatric clinical trials. AB - : European children and paediatricians rely heavily on the fair, complete and timely publication of data obtained from paediatric randomised controlled trials (RCTs). Selective publication and reporting of paediatric RCTs is common practice. Industry-sponsored trials are more likely to remain unpublished, and take longer to get published compared with trials sponsored by others. However, also academic sponsors contribute to inefficiencies in publishing clinical data. Publication bias violates the ethical obligation that investigators have towards study participants, leads to considerable inefficiencies in research and a waste of financial and human resources, and has the potential to distort evidence for treatment approaches. CONCLUSION: The European Academy of Paediatrics (EAP) therefore actively supports initiatives that increase the public dissemination of paediatric clinical trial data. The EAP will raise awareness about the guidelines for Good Publication Practice among European paediatricians and subspecialty societies. PMID- 28875394 TI - Genomic-based-breeding tools for tropical maize improvement. AB - Maize has traditionally been the main staple diet in the Southern Asia and Sub Saharan Africa and widely grown by millions of resource poor small scale farmers. Approximately, 35.4 million hectares are sown to tropical maize, constituting around 59% of the developing worlds. Tropical maize encounters tremendous challenges besides poor agro-climatic situations with average yields recorded <3 tones/hectare that is far less than the average of developed countries. On the contrary to poor yields, the demand for maize as food, feed, and fuel is continuously increasing in these regions. Heterosis breeding introduced in early 90 s improved maize yields significantly, but genetic gains is still a mirage, particularly for crop growing under marginal environments. Application of molecular markers has accelerated the pace of maize breeding to some extent. The availability of array of sequencing and genotyping technologies offers unrivalled service to improve precision in maize-breeding programs through modern approaches such as genomic selection, genome-wide association studies, bulk segregant analysis-based sequencing approaches, etc. Superior alleles underlying complex traits can easily be identified and introgressed efficiently using these sequence based approaches. Integration of genomic tools and techniques with advanced genetic resources such as nested association mapping and backcross nested association mapping could certainly address the genetic issues in maize improvement programs in developing countries. Huge diversity in tropical maize and its inherent capacity for doubled haploid technology offers advantage to apply the next generation genomic tools for accelerating production in marginal environments of tropical and subtropical world. Precision in phenotyping is the key for success of any molecular-breeding approach. This article reviews genomic technologies and their application to improve agronomic traits in tropical maize breeding has been reviewed in detail. PMID- 28875396 TI - The Reliability of Bariatric Surgery Videos in YouTube Platform. AB - BACKGROUND: The growing number of bariatric surgery videos shared on YouTube highlights the need for content and quality assessment. The aim of this study was to answer the question 'Is watching these videos useful to surgeons and patients?' METHODS: YouTube was searched using the keywords 'obesity surgery', 'bariatric surgery' and 'weight loss surgery', and 100 videos retrieved using each keyword were classified based on their 'usefulness score' as very useful, useful and not useful. Video content; source; length and number of views, likes and dislikes were recorded. Upload sources included doctors or hospitals (DH), medical web sites or TV channels (MW), commercial web sites (CW) or civilians (CI). Between-group differences were compared. RESULTS: Of the 300 videos watched, 175 were included in the study; 53.7% were useful and 24.6% were very useful. There were no between-group differences in the number of likes (p = 0.480), dislikes (p = 0.592) and views (p = 0.104). Most videos were uploaded by MW and DH, also with no significant differences in the number of likes (p = 0.35), dislikes (p = 0.14) and views (p = 0.93). No videos were found with misleading information. CONCLUSIONS: The popularity of bariatric surgery and interest of both patients and surgeons are increasing daily. Although videos on bariatric surgery on YouTube may be more useful than those on other surgical procedures, it is important that the videos are uploaded by medical professionals and that specific upload and retrieval filters are applied. PMID- 28875395 TI - Cost-effectiveness of orbital atherectomy compared to rotational atherectomy in treating patients with severely calcified coronary artery lesions in Japan. AB - Compared to rotational atherectomy (RA), orbital atherectomy (OA) has been shown to decrease procedure failure and reintervention rates in the treatment of severely calcified coronary artery lesions. Our objective was to explore the cost effectiveness of OA compared to RA in the Japanese healthcare system. A decision analytic model calculated reintervention rates and consequent total 1-year costs. Effectiveness inputs were therapy-specific target lesion revascularization (TLR) rates and all-cause mortality, pooled from clinical studies. Index and reintervention costs were determined based on claims data analysis of n = 33,628 subjects treated in 2014-2016. We computed incremental cost-effectiveness in Japanese Yen (JPY) per life year (LY) gained based on differences in 1-year cost and projected long-term survival, assuming OA device cost between JPY 350,000 and JPY 550,000. OA was found to be associated with improved clinical outcomes (12 month TLR rate 5.0 vs. 15.7%) and projected survival gain (8.34 vs. 8.16 LYs (+0.17), based on 1-year mortality of 5.5 vs. 6.8%). Total 1-year costs were lower for device cost of JPY 430,000 or less, and reached a maximum ICER of JPY 753,445 per LY at the highest assumed device cost, making OA dominant or cost effective across the tested range, at ICERs substantially below the willingness to-pay threshold. In conclusion, orbital atherectomy for the treatment of severely calcified coronary artery lesions, compared to rotational atherectomy, is a cost-effective treatment approach in the Japanese healthcare system due to improved clinical performance. PMID- 28875397 TI - Boceprevir and Antiretroviral Pharmacokinetic Interactions in HIV/HCV Co-infected Persons: AIDS Clinical Trials Group Study A5309s. AB - OBJECTIVE: The objective of this study was to determine the magnitude of drug interactions between the hepatitis C virus (HCV) protease inhibitor boceprevir (BOC) and antiretroviral (ARV) agents in persons with HIV/HCV co-infection. METHODS: Participants taking two nucleos(t)ide analogs with either efavirenz, raltegravir, or ritonavir-boosted atazanavir, darunavir, or lopinavir underwent intensive pharmacokinetic (PK) sampling for ARV 2 weeks before (week 2) and 2 weeks after initiating BOC (week 6) and for BOC at week 6. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare ARV PK at weeks 2 and 6 and BOC PK at week 6 to historical data (HD) in healthy volunteers and HCV mono-infected patients. RESULTS: ARV PK was available for 55 participants. BOC reduced atazanavir and darunavir exposures by 30 and 42%, respectively. BOC increased raltegravir maximum concentration (C max) by 71%. BOC did not alter efavirenz PK. BOC PK was available for 53 participants. BOC exposures were similar in these HIV/HCV co-infected participants compared with HD in healthy volunteers, but BOC minimum concentrations (C min) were lower with all ARV agents (by 34-73%) compared with HD in HCV mono-infected patients. CONCLUSIONS: Effects of BOC on ARV PK in these HIV/HCV co-infected individuals were similar to prior studies in healthy volunteers. However, some differences in the effects of ARV on BOC PK were observed, indicating the magnitude of interactions may differ in HCV infected individuals versus healthy volunteers. Findings highlight the need to conduct interaction studies with HCV therapies in the population likely to receive the combination. PMID- 28875398 TI - Total Hilar En Bloc Resection with Left Hemihepatectomy and Caudate Lobectomy: a Novel Approach for Treatment of Left-Sided Perihilar Cholangiocarcinoma (with Video). AB - BACKGROUND: "Hilar en bloc resection" using a no-touch technique has been advocated as a standard procedure in right-sided hepatectomies for treatment of perihilar cholangiocarcinoma (PHC). In principle, it has never been reported for left-sided tumors. The aim is to describe the procedures of total hilar en bloc resection with left hemihepatectomy and caudate lobectomy (THER-LH) for advanced PHC and discuss feasibility and clinical significance of this novel technique. METHODS: A retrospective study using a prospectively maintained database was performed to identify eight patients who had received THER-LH for advanced PHC from January 2013 to December 2015. The clinicopathological features, surgical procedures, and outcomes of these patients form the basis this study. RESULTS: The operative time was 546 +/- 158 (380-870) min, and estimated blood loss was 875 +/- 690 (400-2500) ml. Time of vessel resection and reconstruction was 25.6 +/- 12.3 min for the portal vein and 19.1 +/- 4.9 min for the hepatic artery. Time of hilum clamping was 27.3 +/- 11.9 (15-41) min. Two patients had Clavien Dindo grade II and IVa complications of bile leakage with one developing intraabdominal abscess and bleeding. There was no perioperative mortality. Histopathologic examination revealed that all of eight patients had tubular adenocarcinoma with microscopic invasion to the resected hepatic arteries and portal veins in seven patients. Negative bile duct margins were achieved in all of them. Three patients developed recurrence and died at 11, 18, and 24 months postoperatively. The remaining patients were alive at the time of last follow-up. The median survival was 24 months with one patient achieving a disease-free survival of 50 months. CONCLUSION: THER-LH is a technically demanding procedure that is safe and feasible that may have some beneficial effects on the prognosis of these patients with advanced PHC. Further studies are required to confirm the oncological superiority and survival benefits of this novel technique. PMID- 28875400 TI - Empirical Consequences of Current Recommendations for the Design and Interpretation of Noninferiority Trials. AB - BACKGROUND: Noninferiority trials are increasingly common, though they have less standardized designs and their interpretation is less familiar to clinicians than superiority trials. OBJECTIVE: To empirically evaluate a cohort of noninferiority trials to determine 1) their interpretation as recommended by CONSORT, 2) choice of alpha threshold and its sidedness, and 3) differences between methods of analysis such as intention-to-treat and per-protocol. DESIGN: We searched MEDLINE for parallel-group randomized controlled noninferiority trials published in the five highest-impact general medical journals between 2011 and 2016. MAIN MEASURES: Data abstracted included trial design parameters, results, and interpretation of results based on CONSORT recommendations. KEY RESULTS: One hundred sixty-three trials and 182 noninferiority comparisons were included in our analysis. Based on CONSORT-recommended interpretation, 79% of experimental therapies met criteria for noninferiority, 13% met criteria for superiority, 20% were declared inconclusive, and 2% met criteria for inferiority. However, for 12% of trials, the experimental therapy was statistically significantly worse than the active control, but CONSORT recommended an interpretation of inconclusive or noninferior. A two-sided alpha equivalent of greater than 0.05 was used in 34% of the trials, and in five of these trials, the use of a standard two-sided alpha of 0.05 led to changes in the interpretation of results that disfavored the experimental therapy. In four of the five comparisons where different methods of analysis (e.g., intention-to-treat and per-protocol) yielded different results, the intention-to-treat analysis was the more conservative. In 11% of trials, a secondary advantage of the new therapy was neither reported nor could it be inferred by reviewers. CONCLUSIONS: In this cohort, the design and interpretation of noninferiority trials led to significant and systematic bias in favor of the experimental therapy. Clinicians should exercise caution when interpreting these trials. Future trials may be more reliable if design parameters are standardized. PMID- 28875403 TI - Erratum. PMID- 28875402 TI - Stable Scalp EEG Spatiospectral Patterns Across Paradigms Estimated by Group ICA. AB - Electroencephalography (EEG) oscillations reflect the superposition of different cortical sources with potentially different frequencies. Various blind source separation (BSS) approaches have been developed and implemented in order to decompose these oscillations, and a subset of approaches have been developed for decomposition of multi-subject data. Group independent component analysis (Group ICA) is one such approach, revealing spatiospectral maps at the group level with distinct frequency and spatial characteristics. The reproducibility of these distinct maps across subjects and paradigms is relatively unexplored domain, and the topic of the present study. To address this, we conducted separate group ICA decompositions of EEG spatiospectral patterns on data collected during three different paradigms or tasks (resting-state, semantic decision task and visual oddball task). K-means clustering analysis of back-reconstructed individual subject maps demonstrates that fourteen different independent spatiospectral maps are present across the different paradigms/tasks, i.e. they are generally stable. PMID- 28875401 TI - Mechanism of salt-induced activity enhancement of a marine-derived laccase, Lac15. AB - Laccase (benzenediol: oxygen oxidoreductases, EC1.10.3.2) is a multi-copper oxidase capable of oxidizing a variety of phenolic and other aromatic organic compounds. The catalytic power of laccase makes it an attractive candidate for potential applications in many areas of industry including biodegradation of organic pollutants and synthesis of novel drugs. Most laccases are vulnerable to high salt and have limited applications. However, some laccases are not only tolerant to but also activated by certain concentrations of salt and thus have great application potential. The mechanisms of salt-induced activity enhancement of laccases are unclear as yet. In this study, we used dynamic light scattering, size exclusion chromatography, analytical ultracentrifugation, intrinsic fluorescence emission, circular dichroism, ultraviolet-visible light absorption, and an enzymatic assay to investigate the potential correlation between the structure and activity of the marine-derived laccase, Lac15, whose activity is promoted by low concentrations of NaCl. The results showed that low concentrations of NaCl exert little influence on the protein structure, which was partially folded in the absence of the salt; moreover, the partially folded rather than the fully folded state seemed to be favorable for enzyme activity, and this partially folded state was distinctive from the so-called 'molten globule' occasionally observed in active enzymes. More data indicated that salt might promote laccase activity through mechanisms involving perturbation of specific local sites rather than a change in global structure. Potential binding sites for chloride ions and their roles in enzyme activity promotion are proposed. PMID- 28875399 TI - Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair. AB - The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair. PMID- 28875404 TI - Growth characteristics and nutrient removal capability of eco-ditch plants in mesocosm sediment receiving primary domestic wastewater. AB - Eco-ditches are being explored to maximize their capability of capturing pollutants and mitigate any harmful side effects in rivers. In this study, mesocosm plastic drum sediment and field experiments were set up to screen 18 plant species found in ditches and identify those with potential for high biomass production and nutrients removal. Terrestrial plants grown in the mesocosm system were shown to be able to acclimate to aquatic conditions and to survive in primary domestic sewage. About 73-95% increase in plant biomass was recorded. Removal efficiencies for total nitrogen, total phosphorus, and ammonium-nitrogen from the sewage of 72-99%, 64-99%, and 75-100%, respectively, were recorded. Furthermore, complete removal of the applied nitrate-nitrogen load was achieved in mesocosm systems. Findings also show that all species, but especially Acorus calamus, Canna indica, Canna lily, Cyperus alternifolius, Colocasia gigantea, Eichhornia crassipes, Iris sibirica, and Typha latifolia had the highest efficiencies for nitrogen and phosphorous removal. The N and P mass balance analysis demonstrated that plant uptake and sediment N and P accumulation accounted for 41-86% and 18-49% of the total influent TN and TP loads, respectively. In addition, the amounts of nitrogen and phosphorous uptake by these plant species were influenced significantly by biomass. The field-culture experiment further identified Canna indica followed by Cyperus alternifolius as the most promising for high biomass production and nutrients uptake. Therefore, these plants may be recommended for extensive use in treating highly eutrophicated rivers. Outcomes of this work can be useful for model design specifications in eco-ditch mitigation of sewage pollution. PMID- 28875405 TI - Appraisal of Transdermal Water-in-Oil Nanoemulgel of Selegiline HCl for the Effective Management of Parkinson's Disease: Pharmacodynamic, Pharmacokinetic, and Biochemical Investigations. AB - In the present study, the potential of transdermal nanoemulsion gel of selegiline hydrochloride for the treatment of Parkinson's disease was investigated. Water-in oil nanoemulsions were developed by comparing low- and high-energy methods and were subjected to thermodynamic stability tests, in vitro permeation, and characterization studies. In vitro studies indicated that components of nanoemulsion acted as permeation enhancers with highest flux of 3.531 +/- 1.94 MUg/cm2/h from nanoemulsion SB6 containing 0.5 mg selegiline hydrochloride, 3% distilled water, 21% S mix (Span 85, Tween 80, PEG 400), and 76% isopropyl myristate by weight. SB6 with the least droplet size of 183.4 +/- 0.35 nm, polydispersity index of 0.42 +/- 0.06 with pH of 5.9 +/- 0.32 and viscosity of 22.42 +/- 0.14 cps was converted to nanoemulsion gel NEGS4 (viscosity = 22,200 +/ 400 cps) by addition of Viscup160(r) for ease of application and evaluated for permeation, safety, and pharmacokinetic profile in Wistar rats. It provided enhancement ratio 3.69 times greater than conventional gel. NEGS4 showed 6.56 and 5.53 times increase in bioavailability in comparison to tablet and conventional gel, respectively, along with sustained effect. Therefore, the developed water-in oil nanoemulsion gel promises to be an effective vehicle for transdermal delivery of selegiline hydrochloride. PMID- 28875406 TI - Subretinal fibrin absorption after 577-nm subthreshold micropulse laser therapy in a CSC case: a brief report. PMID- 28875407 TI - Karyopherin alpha-2 is a reliable marker for identification of patients with high risk stage II colorectal cancer. AB - PURPOSE: Adjuvant chemotherapy (AC) is frequently considered in patients with high-risk stage II colorectal cancer (CRC). Among patients with stage II CRC who do not receive AC because they are not considered to be at high risk, 20-25% will develop recurrence and die from the disease. Elevated levels of KPNA2 have been observed in various cancers, and overexpression of KPNA2 is related to CRC progression. METHODS: We examined the expression of KPNA2 using 293 CRC tissues, including 118 with stage II CRC, and investigated the applicability of KPNA2 as a biomarker to predict high-risk stage II CRC. Moreover, we further investigated the role of KPNA2 as an oncogene in CRC carcinogenesis using in vitro functional studies. RESULTS: High KPNA2 expression was associated with vascular (p = 0.027) and lymphatic invasion (p = 0.009) in patients with stage II CRC. On multivariate analysis, high KPNA2 expression (HR 3.174, 95% CI 2.060-4.889; p < 0.001) was independently associated with survival in patients with CRC. The overall survival rate in patients with high KPNA2 expression was higher than that in patients with low KPNA2 expression in CRC (p < 0.001), even in patients with stage II CRC (p = 0.001). Additionally, KPNA2 was associated with tumorigenesis and cancer progression in CRC cells; high KPNA2 expression was associated with increased cell proliferation (p < 0.05), migration (p = 0.03), invasion (p = 0.001), and semisolid agar colony formation (p < 0.001). CONCLUSION: KPNA2 expression is useful for identification of patients with high-risk stage II CRC who could benefit from AC and that KPNA2 may also be a promising therapeutic target. PMID- 28875408 TI - Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin. AB - PURPOSE: To improve the pharmaceutical properties of amorphous ciprofloxacin (CIP) succinate salts via formulation as polymer/amorphous salt solid dispersions (ASSDs). METHODS: ASSDs consisting of an amorphous CIP/succinic acid 1:1 or 2:1 salt dispersed in PVP or Soluplus were produced by spray drying and ball milling. The solid state characteristics, miscibility, stability, solubility and passive transmembrane permeability of the ASSDs were then examined. RESULTS: The ASSDs had higher glass transition and crystallization temperatures than the corresponding amorphous succinate salts, and were also more stable during long term stability studies. The results of inverse gas chromatography and thermal analysis indicated that the salts and polymers form a miscible mixture. The solubility of the pure drug in water and biorelevant media was significantly increased by all of the formulations. The permeability of the ASSDs did not differ significantly from that of the amorphous CIP succinate salts, however all samples were less permeable than the pure crystalline drug. CONCLUSIONS: The formulation of amorphous CIP succinate salts as ASSDs with polymer improved their long-term stability, but did not significantly affect their solubility or permeability. PMID- 28875409 TI - Disorganization Theory, Neighborhood Social Capital, and Ethnic Inequalities in Intimate Partner Violence between Arab and Jewish Women Citizens of Israel. AB - We draw on social disorganization (SD) theory and social capital to examine the impact of neighborhood environment on the ethnic gap in intimate partner violence (IPV) between Arab and Jewish women in Israel. We linked census data on neighborhood socioeconomic status (SES) to national data we gathered in 2014-2015 on 1401 women (436 Arab, 965 Jewish) age 16-48. Women were interviewed while visiting 65 maternal and child health clinics throughout Israel. We used General Estimated Equation (GEE) multivariate logistic regression models to adjust for clinic cluster effects and estimated the contribution of neighborhood collective efficacy, problems, relative socioeconomic status (SES), bridging and linking social capital, and social support to explaining ethnic inequalities in IPV, while adjusting for women's socioeconomic and socio-demographic characteristics. We found that any IPV is higher among Arab compared to Jewish women (odds ratio (OR) and 95% confidence intervals (CI) = 4.19 (2.72,6.42)). Collective efficacy and social group membership (bridging social capital) had no effect on the ethnic inequality in any IPV and types of IPV. Women's active participation in social groups (linking social capital), higher social support, and living in neighborhoods with relative SES similar to the ethnic group average) had a protective effect from any IPV and physical IPV. Neighborhood problems were associated with increased any IPV and physical IPV. In the final model, the ethnic gap in IPV was reduced but not eliminated (OR (95%CI) = 3.28 (2.01, 5.35). Collective efficacy did not explain the ethnic gap in IPV, while women's active participation (linking social capital) had a protective effect from IPV. Given the protective nature of women's activism in this population, future research should investigate how this might be incorporated into solutions to IPV. In addition, reducing neighborhood problems, improving neighborhood SES, and increasing social support might help reduce IPV among Arab women, thus decreasing the ethnic gap in IPV. PMID- 28875410 TI - High-Risk Geographic Mobility Patterns among Young Urban and Suburban Persons who Inject Drugs and their Injection Network Members. AB - Young people in the USA who inject drugs, particularly those at a risk of residence instability, experience the highest incidence of hepatitis C (HCV) infections. This study examined associations between geographic mobility patterns and sociodemographic, behavioral, and social network characteristics of 164 young (ages 18-30) persons who inject drugs (PWID). We identified a potential bridge sub-population who reported residence in both urban and suburban areas in the past year (crossover transients) and higher-risk behaviors (receptive syringe sharing, multiple sex partners) compared to their residentially localized counterparts. Because they link suburban and urban networks, crossover transients may facilitate transmission of HIV and HCV between higher and lower prevalence areas. Interventions should address risk associated with residential instability, particularly among PWID who travel between urban and suburban areas. PMID- 28875411 TI - Visualizing old biological traces on different materials without using chemicals. AB - During the investigative process that typically follows a criminal act, it may prove necessary to work with and analyze evidence that is not recent but old. This could become necessary, for example, when a crime is discovered some time after it was committed or when a cold case is reopened. Due to this need, the present study focused on the detection and visualization of 2-year-old biological traces. To do so, an alternative light source and different filters were used. The optical behavior of 2-year-old samples of blood, semen, urine, saliva, and sweat located on 19 different materials was documented, analyzed, and compared with the optical behavior of the same samples when they were recent [1]. PMID- 28875412 TI - Characterization of biomarkers in stroke based on ego-networks and pathways. AB - OBJECTIVE: To explore potential biomarkers in stroke based on ego-networks and pathways. RESULTS: EgoNet method was applied to search for the underlying biomarkers in stroke using transcription profiling of E-GEOD-58294 and protein protein interaction (PPI) data. Eight ego-genes were identified from PPI network according to the degree characteristics at the criteria of top 5% ranked z-sore and degree >1. Eight candidate ego-networks with classification accuracy >=0.9 were selected. After performed randomization test, seven significant ego-networks with adjusted p value < 0.05 were identified. Pathway enrichment analysis was then conducted with these ego-networks to search for the significant pathways. Finally, two significant pathways were identified, and six of seven ego-networks were enriched to "3'-UTR-mediated translational regulation" pathway, indicating that this pathway performs an important role in the development of stroke. CONCLUSIONS: Seven ego-networks were constructed using EgoNet and two significant enriched by pathways were identified. These may provide new insights into the potential biomarkers for the development of stroke. PMID- 28875413 TI - Cardiac Palliative Medicine. AB - PURPOSE OF REVIEW: Heart failure is an illness with high morbidity and mortality that affects 5.7 million Americans. As advanced heart therapies become more prevalent care for patients and families is becoming more complex. The American Heart Association has released a policy statement recommending continuous, high quality access to palliative care for all patients with heart failure, and the Center for Medicare Services requires palliative care involvement in mechanical circulatory support teams. RECENT FINDINGS: The National Quality Forum developed eight domains of palliative care that are required for high-quality delivery of comprehensive palliative care. This article assesses each domain and how it pertains to evolving care of patients with advanced heart failure. Leadership from heart failure teams should review the domains of palliative care to ensure they are improving primary palliative care skills as well as identifying areas needed to improve funding so that patients have access to comprehensive specialty level palliative care. PMID- 28875414 TI - Legal Status, Time in the USA, and the Well-Being of Latinos in Los Angeles. AB - In the USA, undocumented Latino immigrants may have poorer health because of barriers to health care, stressors, and detrimental effects of immigration enforcement. Previous immigrant health research, however, suggests that recently arrived Latino immigrants have better health than US-born Latinos and their health deteriorates over time. Given the current environments that undocumented immigrants face, legal status is a structural factor that likely influences the patterns of immigrant health. Therefore, the aim of this study was to examine the extent to which physical and mental health differed by legal status and duration in the USA for the Latino population in Los Angeles County, California. We conducted analysis of Latino respondents (n = 1396) to the Los Angeles Family and Neighborhood Survey (L.A.FANS) Wave II. We examined self-reported health, depression measured by the Composite International Diagnostic Interview-Short Form, and blood pressure collected by trained interviewers. Respondents reported their legal status, time in the USA, and other sociodemographic characteristics. Regression models were used to test associations between each outcome and 1) legal status and 2) legal status by duration (<= 15 and > 15 years) in the USA. Without taking duration into account, we found no significant differences in outcomes between undocumented, documented, or US-born Latinos. Taking duration into account, shorter duration undocumented immigrants had worse self-reported health than the US born. Undocumented immigrants, regardless of duration, had higher blood pressure than documented immigrants who had been in the USA for less time and the same level of blood pressure as the US born. In contrast, shorter duration documented immigrants had lower blood pressure compared to longer duration documented immigrants and US-born counterparts, and marginally lower blood pressure than shorter duration undocumented immigrants. The findings suggest that the "health advantage" generally presumed to exist among immigrants may not affect undocumented immigrants. PMID- 28875416 TI - NMR study of non-structural proteins-part III: 1H, 13C, 15N backbone and side chain resonance assignment of macro domain from Chikungunya virus (CHIKV). AB - Macro domains are conserved protein domains found in eukaryotic organisms, bacteria, and archaea as well as in certain viruses. They consist of 130-190 amino acids and can bind ADP-ribose. Although the exact role of these domains is not fully understood, the conserved binding affinity for ADP-ribose indicates that this ligand is important for the function of the domain. Such a macro domain is also present in the non-structural protein 3 (nsP3) of Chikungunya Alphavirus (CHIKV) and consists of 160 amino acids. In this study we describe the high yield expression of the macro domain from CHIKV and its preliminary structural analysis via solution NMR spectroscopy. The macro domain seems to be folded in solution and an almost complete backbone assignment was achieved. In addition, the alpha/beta/alpha sandwich topology with 4 alpha-helices and 6 beta-strands was predicted by TALOS+. PMID- 28875415 TI - Connective tissue growth factor (CTGF) in age-related vascular pathologies. AB - Connective tissue growth factor (CTGF, also known as CCN2) is a matricellular protein expressed in the vascular wall, which regulates diverse cellular functions including cell adhesion, matrix production, structural remodeling, angiogenesis, and cell proliferation and differentiation. CTGF is principally regulated at the level of transcription and is induced by mechanical stresses and a number of cytokines and growth factors, including TGFbeta. In this mini-review, the role of age-related dysregulation of CTGF signaling and its role in a range of macro- and microvascular pathologies, including pathogenesis of aorta aneurysms, atherogenesis, and diabetic retinopathy, are discussed. A potential role of CTGF and TGFbeta in regulation and non-cell autonomous propagation of cellular senescence is also discussed. PMID- 28875417 TI - Chlorogenic acid regulates apoptosis and stem cell marker-related gene expression in A549 human lung cancer cells. AB - Previous studies indicated that chlorogenic acid, a compound present in many fruits and vegetables, has anti-cancer activities. We report that chlorogenic acid regulates the expression of apoptosis-related genes and self-renewal-related stem cell markers in cancer cells. The lung cancer cell line A549 was cultured with or without chlorogenic acid. The presence of chlorogenic acid decreased cell proliferation as measured by MTT activity. Polymerase chain reaction (PCR) showed that treatment of cells with chlorogenic acid reduced the expression of BCL2 but increased that of both BAX and CASP3. Chlorogenic acid enhanced annexin V expression as measured using fluorescently labeled annexin V. Chlorogenic acid also induced p38 MAPK and JNK gene expression. Meanwhile, several agents, including SB203580 (p38 MAP kinase inhibitor), N-acetylcysteine (antioxidant inhibitor), dipyridamole (phosphodiesterase inhibitor), and apocynin (NADPH oxidase inhibitor) blocked chlorogenic acid-induced BAX gene expression. Chlorogenic acid reduced gene expression levels of stem cell-associated markers NANOG, POU5F1, and SOX2. Together these results indicate that chlorogenic acid affects the expression of apoptosis-related genes that are part of oxidative stress and p38 MAP-dependent pathways, as well as genes encoding stem cell markers. In conclusion, chlorogenic acid may contribute to the polyphenolic anti cancer effect associated with consumption of vegetables and fruits. PMID- 28875418 TI - Microbial production of poly-gamma-glutamic acid. AB - Poly-gamma-glutamic acid (gamma-PGA) is a natural, biodegradable and water soluble biopolymer of glutamic acid. This review is focused on nonrecombinant microbial production of gamma-PGA via fermentation processes. In view of its commercial importance, the emphasis is on L-glutamic acid independent producers (i.e. microorganisms that do not require feeding with the relatively expensive amino acid L-glutamic acid to produce gamma-PGA), but glutamic acid dependent production is discussed for comparison. Strategies for improving production, reducing costs and using renewable feedstocks are discussed. PMID- 28875419 TI - Lactulose decreases neuronal activation and attenuates motor behavioral deficits in hyperammonemic rats. AB - Lactulose is a nonabsorbable disaccharide commonly used in clinical practice to treat hepatic encephalopathy. However, its effects on neuropsychiatric disorders and motor behavior have not been fully elucidated. Male Wistar rats were bile duct ligated, and 3 weeks after surgery, treated with lactulose administrated by gavage (1.43 or 3.57 g/kg), once a day for seven days. Plasma levels of ammonia, aspartate aminotransferase, total bilirubin, and creatinine were quantified and histopathological analysis of the livers was performed. Locomotor activity measurements were performed in an open field. The expression of water channel aquaporin-4 was investigated and the analysis of Fos protein immunoreactivity was used to evaluate the pattern of neural activation in brain areas related to motor behavior. Bile-duct ligated rats showed hyperammonemia, loss of liver integrity and function, impaired locomotor activity, reduced aquaporin-4 protein expression, and neuronal hyperactivity. Lactulose treatment was able to reduce ammonia plasma levels, despite not having an effect on biochemical parameters of liver function, such as aspartate aminotransferase activity and total bilirubin levels, or on the cirrhotic hepatic architecture. Lactulose was also able to reduce the locomotor activity impairments and to mitigate or reverse most changes in neuronal activation. Lactulose had no effect on reduced aquaporin-4 protein expression. Our findings confirm the effectiveness of lactulose in reducing hyperammonemia and neuronal hyperactivity in brain areas related to motor behavior, reinforcing the importance of its clinical use in the treatment of the symptoms of cirrhosis-associated encephalopathy. PMID- 28875420 TI - Prognostic Value of Preoperative Serum Carcinoembryonic Antigen and Carbohydrate Antigen 19-9 After Resection of Ampullary Cancer. AB - BACKGROUND: The purpose of this study is to investigate the prognostic value of pre-resection serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 after resection of ampullary cancer (AC) in consideration of intestinal (IT) and pancreatobiliary (PT) subtypes. METHODS: Overall survival (OS) analysis of patients undergoing curative resection of ampullary cancer. RESULTS: Elevated preoperative CEA (P = 0.013) and CA 19-9 levels (P = 0.030) were significant prognostic factors. Subgroup analysis, however, showed both markers having prognostic value only for the IT subgroup. Pre-resection CEA within normal range identified a subgroup of IT patients with an excellent median survival of 145 months. Compared to other AC patients, this low-risk ITCEA- subpopulation was characterized by less frequent advanced pT stages (pT3/pT4, 41 vs. 62%; P = 0.047) and lymph node involvement (pN+, 30 vs. 65%; P = 0.001). OS of this subgroup was significantly better compared to other AC patients (145 vs. 25 months; HR = 3.8; P < 0.001). By multivariate survival analysis, the patient age, the PT subtype, and an elevated pre-resection serum CEA value were identified as independent prognostic variables. CONCLUSIONS: In AC, the histomorphologic subclassification is highly relevant regarding the prognostic value of preoperative serum CEA and CA 19-9. IT-patients with normal preoperative CEA represent a favorable subgroup with excellent long-term survival. PMID- 28875421 TI - Brief Report: Relationship Between ADOS-2, Module 4 Calibrated Severity Scores (CSS) and Social and Non-Social Standardized Assessment Measures in Adult Males with Autism Spectrum Disorder (ASD). AB - The ADOS-2 Modules 1-3 now include a standardized calibrated severity score (CSS) from 1 to 10 based on the overall total raw score. Subsequent research published CSS for Module 4 (Hus, Lord, Journal of Autism and Developmental Disorders 44(8):1996-2012, 2014); however more research is needed to examine the psychometric properties of this CSS. Forty males with ASD completed an assessment battery consisting of ADOS-2 Module 4 and other clinical measures assessing core ASD symptomology and comorbidity. Pearson correlation analyses found that CSS did not correlate with measures that assessed core social deficits of ASD or general psychiatric co-morbidity, but CSS did correlate negatively with intellectual quotient. These findings provide information on the limitations and relevance of CSS to be taken into account in future clinical evaluations of ASD. PMID- 28875422 TI - Public Health and Public Order Outcomes Associated with Supervised Drug Consumption Facilities: a Systematic Review. AB - PURPOSE OF REVIEW: Supervised drug consumption facilities (SCFs) have increasingly been implemented in response to public health and public order concerns associated with illicit drug use. We systematically reviewed the literature investigating the health and community impacts of SCFs. RECENT FINDINGS: Consistent evidence demonstrates that SCFs mitigate overdose-related harms and unsafe drug use behaviours, as well as facilitate uptake of addiction treatment and other health services among people who use drugs (PWUD). Further, SCFs have been associated with improvements in public order without increasing drug-related crime. SCFs have also been shown to be cost-effective. This systematic review suggests that SCFs are effectively meeting their primary public health and order objectives and therefore supports their role within a continuum of services for PWUD. Additional studies are needed to better understand the potential long-term health impacts of SCFs and how innovations in SCF programming may help to optimize the effectiveness of this intervention. PMID- 28875423 TI - Glucose homeostasis in GHD children during long-term replacement therapy: a case control study. AB - PURPOSE: To evaluate glucose homeostasis in children with growth hormone (GH) deficiency (GHD) receiving long-term replacement therapy. METHODS: We evaluated glucose, insulin, HOmeostasis Model Assessment (HOMA-IR), and HbA1c in 100 GHD children at diagnosis and during 5 years of therapy. One hundred healthy children comparable to patients were evaluated at baseline and after 1 and 5 years. RESULTS: No difference was detected at baseline between GHD patients and controls in glucose (79.58 +/- 9.96 vs. 77.18 +/- 8.20 mg/dl), insulin (4.50 +/- 3.24 vs. 4.30 +/- 2.60 uU/ml), HbA1c (5.20 +/- 0.31 vs. 5.25 +/- 0.33%) levels, and HOMA IR (0.93 +/- 0.72 vs. 0.86 +/- 0.61). One year of GH was associated with a significant increase in insulin (7.21 +/- 4.84, p < 0.001) and HOMA-IR (1.32 +/- 0.98, p < 0.001) in GHD children, which became different from controls (p < 0.001 and p = 0.004). These parameters did not change further during the following years of treatment in GHD subjects. In contrast, controls did not show significant changes in insulin (4.40 +/- 2.60) and HOMA-IR (0.82 +/- 0.60) during the first year; however, at the fifth year of the study a significant increase in insulin (6.50 +/- 3.50, p = 0.004) and HOMA-IR (1.29 +/- 0.54, p < 0.001) was documented, making these parameters comparable between patients and controls. CONCLUSIONS: Our results suggest that growth hormone (GH) treatment is not associated with significant impairment of insulin sensitivity in GHD children. The slight impairment observed in GHD adolescents after long-term GH is comparable to that physiologically occurring in healthy pubertal subjects. PMID- 28875424 TI - Structural basis for DAXX interaction with ATRX. PMID- 28875425 TI - Initiating human articular chondrocyte re-differentiation in a 3D system after 2D expansion. AB - Cartilage damage affects a large population via acute and chronic injury and disease. Since native cartilage does not self-renew, cartilage tissue engineering has gained traction as a potential treatment. However, a limiting factor is that the primary cell type in cartilage, the articular chondrocyte, tends to de differentiate when grown on 2D surfaces for in vitro expansion. Thus, 3D systems are being developed and used to counter this loss of chondrogenic capabilities. We hypothesize that a 3D matrix that can be remodeled may be more supportive of the chondrogenic phenotype of encapsulated articular chondrocytes than a 2D surface and may allow for the re-differentiation of chondrocytes after 2D expansion. Hence, in this study, enzymatically degradable polyethylene glycol (PEG) hydrogels containing two different protease degradable peptide segments, with different degradation rates, were tested in combination with chondrogenic medium as a 3D in vitro culture system to better recapitulate the native environment of human articular chondrocytes (hACs). In addition, the effect of incorporation of the integrin binding ligand Arg-Gly-Asp (RGD) in the hydrogels was explored. Hydrogels crosslinked with a slower degrading crosslinker and not functionalized with RGD maintained hAC viability and led to increased GAG production and chondrogenic gene expression over time, suggesting that this system can initiate hAC re-differentiation after 2D expansion. PMID- 28875426 TI - Analysis of Proteins, Protein Complexes, and Organellar Proteomes Using Sheathless Capillary Zone Electrophoresis - Native Mass Spectrometry. AB - Native mass spectrometry (MS) is a rapidly advancing field in the analysis of proteins, protein complexes, and macromolecular species of various types. The majority of native MS experiments reported to-date has been conducted using direct infusion of purified analytes into a mass spectrometer. In this study, capillary zone electrophoresis (CZE) was coupled online to Orbitrap mass spectrometers using a commercial sheathless interface to enable high-performance separation, identification, and structural characterization of limited amounts of purified proteins and protein complexes, the latter with preserved non-covalent associations under native conditions. The performance of both bare-fused silica and polyacrylamide-coated capillaries was assessed using mixtures of protein standards known to form non-covalent protein-protein and protein-ligand complexes. High-efficiency separation of native complexes is demonstrated using both capillary types, while the polyacrylamide neutral-coated capillary showed better reproducibility and higher efficiency for more complex samples. The platform was then evaluated for the determination of monoclonal antibody aggregation and for analysis of proteomes of limited complexity using a ribosomal isolate from E. coli. Native CZE-MS, using accurate single stage and tandem-MS measurements, enabled identification of proteoforms and non-covalent complexes at femtomole levels. This study demonstrates that native CZE-MS can serve as an orthogonal and complementary technique to conventional native MS methodologies with the advantages of low sample consumption, minimal sample processing and losses, and high throughput and sensitivity. This study presents a novel platform for analysis of ribosomes and other macromolecular complexes and organelles, with the potential for discovery of novel structural features defining cellular phenotypes (e.g., specialized ribosomes). Graphical Abstract ?. PMID- 28875427 TI - Epileptic seizures in nonalcoholic Wernicke's encephalopathy: a case report and literature review. AB - Wernicke encephalopathy (WE) is characterized by eye signs, cerebellar dysfunction, and confusion. Epileptic seizures are rare in nonalcoholic WE. We reviewed the clinical, laboratory, radiological, and prognostic characteristics of nonalcoholic WE accompanied by epileptic seizures. We reported 1 case and searched similar cases using PubMed, WoK, Ovid, and Embase. WE was diagnosed according to dietary deficiencies, clinical symptoms and brain magnetic resonance imaging (MRI). We reviewed 13 patients (median age, 27 years; 5 men) with clear histories of thiamine deficiency and symptoms of typical WE. The type of epileptic seizures reported in the 13 cases reviewed was generically reported as seizures or convulsions in 4 patients; 7 patients had generalized tonic-clonic seizures, 1 partial seizure, and 1 generalized convulsive status epileptics. Two patients had epileptic seizures as the first symptom of WE. Laboratory tests mainly indicated metabolic acidosis and electrolyte disturbances. Electroencephalography may present as normal patterns, increased slow waves or epileptic discharge. Six patients had cortical lesions on brain MRI. These lesions were usually diffuse and band-like, and sometimes involved all lobes either symmetrically or asymmetrically, with the frontal lobe as the most susceptible area. All cortical lesions were accompanied by non-cortical lesions typical of WE. Brain MRI abnormalities, after thiamine treatment, mostly disappeared on follow-up MRIs. The patients had good prognoses. Only 1 patient had repeated seizures, and there were no comas or deaths. Patients with nonalcoholic WE accompanied by seizures are young and generally have good prognoses. Most patients experienced generalized convulsive seizures, which may have been related to abnormal cerebral cortical metabolism due to subacute thiamine deficiency. PMID- 28875429 TI - Regional Differences in Cerebral Glucose Metabolism After Cardiac Arrest and Resuscitation in Rats Using [18F]FDG Positron Emission Tomography and Autoradiography. AB - BACKGROUND: Cardiac arrest is an important cause of morbidity and mortality. Brain injury severity and prognosis of cardiac arrest patients are related to the cerebral areas affected. To this aim, we evaluated the variability and the distribution of brain glucose metabolism after cardiac arrest and resuscitation in an adult rat model. METHODS: Ten rats underwent 8-min cardiac arrest, induced with a mixture of potassium and esmolol, and resuscitation, performed with chest compressions and epinephrine. Eight sham animals received anesthesia and experimental procedures identical to the ischemic group except cardiac arrest induction. Brain metabolism was assessed using [18F]FDG autoradiography and small animal-dedicated positron emission tomography. RESULTS: The absolute glucose metabolism measured with [18F]FDG autoradiography 2 h after cardiac arrest and resuscitation was lower in the frontal, parietal, occipital, and temporal cortices of cardiac arrest animals, showing, respectively, a 36% (p = 0.006), 32% (p = 0.016), 36% (p = 0.009), and 32% (p = 0.013) decrease compared to sham group. Striatum, hippocampus, thalamus, brainstem, and cerebellum showed no significant changes. Relative regional metabolism indicated a redistribution of metabolism from cortical area to brainstem and cerebellum. CONCLUSIONS: Our data suggest that cerebral regions have different susceptibility to moderate global ischemia in terms of glucose metabolism. The neocortex showed a higher sensibility to hypoxia-ischemia than other regions. Other subcortical regions, in particular brainstem and cerebellum, showed no significant change compared to non ischemic rats. PMID- 28875428 TI - Timed Release of Cerebrolysin Using Drug-Loaded Titanate Nanospheres Reduces Brain Pathology and Improves Behavioral Functions in Parkinson's Disease. AB - Previous studies from our laboratory show that intraperitoneal injections of 1 metyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP, 20 mg/kg) daily within 2-h intervals for 5 days in mice induce Parkinson's disease (PD)-like symptoms on the 8th day. A significant decrease in dopamine (DA) and its metabolites 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) along with a marked decrease in the number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) and striatum (STr) confirms the validity of this model for studying PD. Since cerebrolysin (CBL) is a well-balanced composition of several neurotrophic factors and active peptide fragments, in the present investigation we examined the timed release of CBL using titanate nanospheres (TiNS) in treating PD in our mouse model. Our observations show that TiNS-CBL (in a dose of 3 ml/kg, i.v.) given after 2 days of MPTP administration for 5 days resulted in a marked increase in TH-positive cells in the SNpc and STr as compared to normal CBL. Also, TiNS-CBL resulted in significantly higher levels of DA, DOPAC, and HVA in SNpc and STr on the 8th day as compared to normal CBL therapy. TiNS-CBL also thwarted increased alpha-synuclein levels in the brain and in the cerebrospinal fluid (CSF) as well as neuronal nitric oxide synthase (nNOS) in the in PD brain as compared to untreated group. Behavioral function was also significantly improved in MPTP-treated animals that received TiNS-CBL. These observations are the first to demonstrate that timed release of TiNS-CBL has far more superior neuroprotective effects in PD than normal CBL. PMID- 28875431 TI - Concurrent uptake and metabolism of dyestuffs through bio-assisted phytoremediation: a symbiotic approach. AB - Manipulation of bio-technological processes in treatment of dyestuffs has attracted considerable attention, because a large proportion of these synthetic dyes enter into natural environment during synthesis and dyeing operations that contaminates different ecosystems. Moreover, these dyestuffs are toxic and difficult to degrade because of their synthetic origin, durability, and complex aromatic molecular structures. Hence, bio-assisted phytoremediation has recently emerged as an innovative cleanup approach in which microorganisms and plants work together to transform xenobiotic dyestuffs into nontoxic or less harmful products. This manuscript will focus on competence and potential of plant-microbe synergistic systems for treatment of dyestuffs, their mixtures and real textile effluents, and effects of symbiotic relationship on plant performances during remediation process and will highlight their metabolic activities during bio assisted phytodegradation and detoxification. PMID- 28875430 TI - Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L in psoriasis patients. AB - : The purpose of this study is to assess the measurement properties of EQ-5D-5L compared to EQ-5D-3L in psoriasis patients. METHODS: A cross-sectional survey was carried out at an academic dermatology clinic in Hungary. Psoriasis patients completed the EQ-5D-3L, EQ-5D-5L and Dermatology Life Quality Index (DLQI) questionnaires, and Psoriasis Area and Severity Index (PASI) was assessed. The UK value sets were used to calculate the 3L and 5L index scores. We tested the feasibility, ceiling effect, redistribution properties, the level of inconsistency and informativity (Shannon and Shannon Evenness indices). Spearman's rank-order correlations were performed between EQ-5D, EQ VAS, DLQI and PASI scores. Known-groups validity was evaluated by comparing age groups, clinical subtypes and treatment groups. RESULTS: Mean age of the 238 patients was 47 years, and 36.6% of them received biological therapy. Mean EQ-5D index score was 0.77 (SD: 0.26) with the 3L and 0.84 (SD: 0.19) with the 5L. The overall ceiling effect decreased from 37.1 (3L) to 32.9% (5L). Shannon index improved significantly for most dimensions, but Shannon Evenness index improved only in three dimensions. Compared to the 3L, the 5L version confirmed a better convergent validity with PASI, but not with the DLQI. Known-groups validity was equally demonstrated both for the 5L and 3L. CONCLUSIONS: The EQ-5D-5L seems to improve measurement properties by reducing ceiling effects, strengthening correlations with PASI and improving informativity. Follow-up studies are needed to test responsiveness and reliability in psoriasis. PMID- 28875432 TI - A meta-analytic review of the association between cortisol reactivity in response to a stressor and attention-deficit hyperactivity disorder. AB - A substantial literature suggests that abnormal cortisol reactivity may be a vulnerability for deleterious mental health outcomes, including ADHD. ADHD has been linked with difficulty in emotion regulation and increased risk of experiencing stressors, both of which may be related to psychobiological abnormalities (e.g., abnormal cortisol reactivity). Research has been mixed regarding the association between cortisol reactivity and ADHD. Therefore, the present meta-analytic review (k = 12) sought to quantify this association and review the relevant methodological issues and theoretical implications of this area of research. Overall, no effect was found between cortisol reactivity and ADHD (r = 0), although significant heterogeneity in the analyses suggested that there might be moderators of this association, if one does exist. Results highlight the importance of addressing limitations of the current literature on cortisol reactivity and ADHD and exploring additional indices of emotion regulation that may be associated with ADHD. Implications for future research efforts are discussed. PMID- 28875434 TI - Nonlinear and Nonsymmetric Single-Molecule Electronic Properties Towards Molecular Information Processing. AB - This review highlights molecular design for nonlinear and nonsymmetric single molecule electronic properties such as rectification, negative differential resistance, and switching, which are important components of future single molecule information processing devices. Perspectives on integrated "molecular circuits" are also provided. Nonlinear and nonsymmetric single-molecule electronics can be designed by utilizing (1) asymmetric molecular cores, (2) asymmetric anchoring groups, (3) an asymmetric junction environment, and (4) asymmetric electrode materials. This review mainly focuses on the design of molecular cores. PMID- 28875433 TI - Crucial microRNAs and genes in metformin's anti-pancreatic cancer effect explored by microRNA-mRNA integrated analysis. AB - Despite great improvements in surgical procedures and chemotherapy, pancreatic cancer remains one of the most aggressive and fatal human malignancies, with a low 5-year survival rate. Therefore, novel therapeutic strategies for the prevention and treatment of pancreatic cancer are urgently needed. The present study aimed to investigate the mechanisms by which metformin exerts its anticancer effects on the microRNA-mRNA interactions in human pancreatic cancer. Microarray and systematic analyses revealed that the anti-pancreatic cancer effects of metformin were correlated with 3 up-regulated microRNAs and 4 of their target mRNAs. In addition, the microarray and systematic analyses ultimately demonstrated that 3 microRNAs regulated 4 key mRNAs in a sub-pathway of pancreatic cancer and then affected growth, angiogenesis, and apoptosis. This finding may provide a deeper understanding of the mechanisms by which metformin suppresses proliferation and angiogenesis and promotes apoptosis in pancreatic cancer cells. Collectively, this experiment improves the understanding of the mechanisms by which metformin suppresses pancreatic cancer and indicates that metformin, the most commonly used drug for the treatment of diabetes mellitus, may be a promising candidate agent for the treatment of pancreatic cancer. PMID- 28875435 TI - Client and Partner Violence Among Urban Female Exotic Dancers and Intentions for Seeking Support and Justice. AB - Urban female exotic dancers are thought to experience unique risk for violence and barriers to care, though limited research has focused on this aspect of urban sex industries. We characterize recent client-perpetrated and intimate partner violence (IPV) and their correlates, and describe women's intentions for violence related help-seeking, among venue-based exotic dancers in a high-risk urban environment. We conducted a cross-sectional study with new female exotic dancers (n = 117) in Baltimore, MD. Over one third (36%) reported intimate partner violence (IPV), and 16% reported client physical or sexual violence, in the six months prior to the survey. Both forms of violence were correlated with arrest, sex trade, substance use, and childhood abuse. Violence-related help-seeking intentions were highest for club management. Intentions to seek help from police and violence-related support hotlines were lowest among those with recent experiences of violence. Recent violence, particularly from intimate partners, was pervasive in this sample of female exotic dancers, and enabled by substance use, criminal history, and sex trade. Preferences for help within venues, rather than the justice sector and publicly funded support services, indicate the need for systems reform to meet the needs of this high-risk group of women. PMID- 28875436 TI - Predictors of Daily Pain Medication Use in Individuals with Recurrent Back Pain. AB - PURPOSE: A key component to chronic pain management regimens is the use of analgesic medications. Psychological factors, such as mood states, may also affect the use of pain medications for individuals with chronic pain, but few observational studies have examined how these factors may predict pain medication use at the daily level. METHODS: Daily assessments from 104 individuals with back pain were used to examine fluctuations in daily pain intensity, mood, sleep quality, and physical activity as predictors of the likelihood of pain medication (opioid and non-opioid) use and levels of medication use on the same day. RESULTS: Pain intensity and mood ratings significantly predicted whether participants used pain medication on the same day, while only pain intensity predicted whether participants used more medication than usual. Further, current opioid users were more likely to increase the amount of their medication use on days of higher pain. DISCUSSION: This article identifies fluctuations in daily pain intensity and mood as salient predictors of daily pain medication use in individuals with recurrent back pain. The current study is among the first to highlight both pain and mood states as predictors of daily pain medication use in individuals with back pain, though future studies may expand on these findings through the use of higher-resolution daily medication use variables. PMID- 28875437 TI - Child with Dysuria and/or Hematuria. AB - Dysuria and/or hematuria are common and worrisome symptoms for most parents. Dysuria results from excessive bladder muscle contraction and peristaltic activity of the edematous and inflamed urethral mucosa. Though urinary tract infection remains the commonest cause for dysuria, non-infectious causes should also be kept in mind. Equating all cases of dysuria to urinary infection is not incorrect. Hematuria can be both macroscopic and microscopic and an important sign of genitourinary tract disease. However, systemic causes like bleeding disorder or malignancy can also present with hematuria. A thorough history and physical examination is important for arriving at a diagnosis. The investigations for both the symptoms and the urgency with which the tests are required are dictated by the patient's clinical presentation. PMID- 28875438 TI - Non-invasive Evaluation of NAFLD with Indocyanine Green Clearance Test: a Preliminary Study in Morbidly Obese Patients Undergoing Bariatric Surgery. AB - BACKGROUND: Overweight and obesity dramatically increased in the last years. Hepatic complication of obesity, integrated in the term of non-alcoholic fatty liver disease (NAFLD), is a spectrum of abnormality ranging from steatosis to non alcoholic steatohepatitis (NASH), potentially leading to cirrhosis. Liver biopsy remains the gold standard to evaluate the stage of NAFLD; however, the procedure is invasive. The indocyanine green (ICG) clearance test is performed since years to assess hepatic function before partial hepatectomy, or after liver transplantation. This study was designed to detect liver complications with the ICG clearance test in a population of obese patients scheduled for bariatric surgery. METHODS: In a prospective cohort study, morbidly obese individuals receiving bariatric surgery with scheduled hepatic biopsies were investigated. Liver function was determined by the ICG test preoperatively, and blood samples were collected. Liver biopsy specimens were obtained for each patient and classified according to the NAFLD activity score (NAS) by a single pathologist that was blinded to the results of the ICG test. RESULTS: Twenty-six patients were included (7 male and 19 female). The mean age of participants was 45.8 years; the mean body mass index was 41.4 kg/m2. According to the NAS, 6 (23.1%) patients revealed manifest NASH, and 5 patients were considered borderline (19.2%). A closed correlation was observed between the ICG clearance test and hepatic steatosis (r = 0.43, p = 0.03), NAS (r = 0.44, p = 0.025), and fibrosis (r = 0.49, p = 0.01). CONCLUSIONS: In obese patients, non-invasive evaluation of liver function with the indocyanine green clearance test correlated with histological features of NAFLD. This may detect non-invasively hepatopathy in obese population and could motive biopsy. PMID- 28875439 TI - Current status and future prospects for human papillomavirus vaccines. AB - Cervical cancer is the fourth most frequent cancer among women worldwide. Human papillomaviruses (HPVs) cause almost all cervical cancers in low-income countries. Three prophylactic HPV virus-like particle-based vaccines have been licensed to date, and they have all shown high efficacy and reliable safety profiles. However, isolated safety issues have resulted in a reluctance to use these vaccinations. In addition, the high prices of the vaccinations have caused the inequitable distribution of the vaccine: the prices are unaffordable for low income countries. Meanwhile, great effort has been put into the development of therapeutic HPV vaccines, including protein/peptide-, live vector-, DNA- and cell based vaccines. These new vaccines have considerable therapeutic potential but limited practical use. The development of immune checkpoint inhibitors and personalized immunotherapy remain challenges for future study. In this article, the current status of the licensed vaccines, therapeutic HPV vaccines and biosimilars, and new platforms for HPV vaccines, are reviewed, and safety issues related to the licensed vaccines are discussed. In addition, the prospects for HPV vaccines are considered. PMID- 28875441 TI - Letter to the Editor: False-positive Cultures After Native Knee Aspiration: True or False. PMID- 28875440 TI - Targeting brain tumors by intra-arterial delivery of cell-penetrating peptides: a novel approach for primary and metastatic brain malignancy. AB - Computational modeling shows that intra-arterial delivery is most efficient when the delivered drugs rapidly and avidly bind to the target site. The cell penetrating peptide trans-activator of transcription (TAT) is a candidate carrier molecule that could mediate such specificity for brain tumor chemotherapeutics. To test this hypothesis we first performed in vitro studies testing the uptake of TAT by one primary and three potentially metastatic brain cancer cell lines (9L, 4T-1, LLC, SKOV-3). Then we performed in vivo studies in a rat model where TAT was delivered either intra-arterially (IA) or intravenously (IV) to 9L brain tumors. We observed robust uptake of TAT by all tumor cell lines in vitro. Flow cytometry and confocal microscopy revealed a rapid uptake of fluorescein-labeled TAT within 5 min of exposure to the cancer cells. IA injections done under transient cerebral hypoperfusion (TCH) generated a four-fold greater tumor TAT concentration compared to conventional IV injections. We conclude that it is feasible to selectively target brain tumors with TAT-linked chemotherapy by the IA-TCH method. PMID- 28875442 TI - Erratum to: Assessing Cyanobacterial Harmful Algal Blooms as Risk Factors for Amyotrophic Lateral Sclerosis. PMID- 28875444 TI - Erratum to: What is the Difference in Morphologic Features of the Thoracic Pedicle Between Patients With Adolescent Idiopathic Scoliosis and Healthy Subjects? A CT-based Case-control Study. PMID- 28875443 TI - Sinonasal Tract Alveolar Rhabdomyosarcoma in Adults: A Clinicopathologic and Immunophenotypic Study of Fifty-Two Cases with Emphasis on Epithelial Immunoreactivity. AB - Sinonasal tract (SNT) alveolar rhabdomyosarcoma (ARMS) are frequently misdiagnosed, especially in adults. Fifty-two adult (>=18 years) patients with SNT ARMS were reviewed and characterized by immunohistochemistry and molecular studies. Twenty-six females and 26 males (18-72 years; mean 43.2 years), presented after a short duration (mean 2.6 months) with a large (mean 5.5 cm) destructive nasal cavity mass, involving multiple contiguous paranasal sites (n = 46) and with cervical adenopathy (n = 41). The tumors showed an alveolar, nested to solid growth pattern below an intact, but often involved (n = 9) epithelium with frequent necrosis (n = 37), destructive bone invasion (n = 30), and lymphovascular invasion (n = 25). The neoplastic cells were dyshesive and dilapidated, with crush artifacts. Rhabdoid features (n = 36) and tumor cell multinucleation (n = 28) were common. Mitotic counts were high (mean 17/10 HPFs). The neoplastic cells showed the following immunohistochemical positive findings: desmin (100%), myogenin (100%), MYOD1 (100%), MSA (96%), SMA (52%), CAM5.2 (50%), AE1/AE3 (36%); other positive markers included S100 protein (27%), CD56 (100%), synaptophysin (35%), and chromogranin (13%). Overall, 54% show epithelial marker reactivity. Molecular studies showed FOXO1 translocations (81%) with PCR demonstrating PAX3 in 72.7% tested. Patients presented with high stage (IV 24; III 26) and metastatic disease (lymph nodes n = 41; distant metastases n = 25) (IRSG grouping). Surgery (n = 16), radiation (n = 41) and chemotherapy (n = 45) yielded an overall survival of 36.1 months (mean; range 2.4-286); 18 alive without disease (mean 69.6 months); 7 alive with disease (mean 11.0 months); 1 dead without disease (63.7 months); and 26 dead with disease (mean 18.5 months). SNT ARMS frequently present in adults as a large, destructive midline mass of short symptom duration, with high stage disease. The alveolar to solid pattern of growth of cells with rhabdoid-plasmacytoid features suggests the diagnosis, but epithelial immunohistochemistry markers are present in 54% of cases, leading to misdiagnosis as carcinomas if muscle markers are not also performed. Overall survival of 36.1 months is achieved with multimodality therapy, but 64% have incurable disease (16.9 months). Mixed anatomic site (p = 0.02) was a significant adverse prognostic indicator, while stage (0.06) and tumor size >5 cm (0.06) approached marginal significance. PMID- 28875445 TI - Reply to the Letter to the Editor: False-positive Cultures After Native Knee Aspiration: True or False. PMID- 28875446 TI - Evaluating the potential genotoxicity of phthalates esters (PAEs) in perfumes using in vitro assays. AB - We previously reported high levels of phthalate esters (PAEs) added as solvents or fixatives in 47 brands of perfumes. Diethyl phthalate was the most abundant compound (0.232-23,649 ppm), and 83.3% of the perfumes had levels >1 ppm, the threshold limit cited by a Greenpeace investigation. All samples had dimethyl phthalate levels higher than its threshold limit of 0.1 ppm, and 88, 38, and 7% of the perfumes had benzyl butyl phthalate, di(2-ethylhexyl) phthalate, and dibutyl phthalate levels, respectively, above their threshold limits. The role of PAEs as endocrine disruptors has been well documented, but their effect on genotoxic behavior has received little attention. We used in vitro single-cell gel electrophoresis (comet) and micronucleus (MN) assays with human lymphoblastoid TK6 cells to evaluate the genotoxic potency of 42 of the same perfumes and to determine its association with PAEs. All perfumes induced more DNA damage than a negative control (NEG), >= 90% of the samples caused more damage than cells treated with the vehicles possibly used in perfume's preparations such as methanol (ME) and ethanol (ET), and 11.6% of the perfumes caused more DNA damage than a positive control (hydrogen peroxide). Chromosome breakage expressed as MN frequency was higher in cells treated with 71.4, 64.3, 57.1, and 4.8% of the perfumes than in NEG, cells treated with ME or ET, and another positive control (x-rays), respectively. The genotoxic responses in the comet and MN assays were not correlated. The comet assay indicated that the damage in TK6 cells treated with five PAEs at concentrations of 0.05 and 0.2 ppm either individually or as a mixture did not differ significantly from the damage in cells treated with the perfumes. Unlike the comet assay, the sensitivity of the MN assay to PAEs was weak at both low and high concentrations, and MN frequencies were generally low. This study demonstrates for the first time the possible contribution of PAEs in perfumes to DNA damage and suggests that their use as solvents or fixatives should be regulated. Other ingredients with mutagenic/genotoxic properties, however, may also have contributed to the DNA damage. Future studies should focus on applying a series of assays that use different cellular models with various endpoints to identify the spectrum of genotoxic mechanisms involved. PMID- 28875447 TI - Public Mistrust of the U.S. Health Care System's Profit Motives: Mixed-Methods Results from a Randomized Controlled Trial. AB - BACKGROUND: Decision makers are increasingly tasked with reducing health care costs, but the public may be mistrustful of these efforts. Public deliberation helps gather input on these types of issues by convening a group of diverse individuals to learn about and discuss values-based dilemmas. OBJECTIVE: To explore public perceptions of health care costs and how they intersect with medical mistrust. DESIGN AND PARTICIPANTS: This mixed-methods study analyzed data from a randomized controlled trial including four public deliberation groups (n = 96) and a control group (n = 348) comprising English-speaking adults aged 18 years and older. Data were collected in 2012 in four U.S. regions. APPROACH: We used data from four survey items to compare attitude shifts about costs among participants in deliberation groups to participants in the control group. We qualitatively analyzed deliberation transcripts to identify themes related to attitude shifts and to provide context for quantitative results about attitude shifts. KEY RESULTS: Deliberation participants were significantly more likely than control group participants to agree that doctors and patients should consider cost when making treatment decisions (beta = 0.59; p < 0.01) and that people should consider the effect on group premiums when making treatment decisions (beta = 0.48; p < 0.01). Qualitatively, participants mistrusted the health care system's profit motives (e.g., that systems prioritize making money over patient needs); however, after grappling with patient/doctor autonomy and learning about and examining their own views related to costs during the process of deliberation, they largely concluded that payers have the right to set some boundaries to curb costs. CONCLUSIONS: Individuals who are informed about costs may be receptive to boundaries that reduce societal health care costs, despite their mistrust of the health care system's profit motives, especially if decision makers communicate their rationale in a transparent manner. Future work should aim to develop transparent policies and practices that earn public trust. PMID- 28875448 TI - Clinical outcomes of AF patients treated with the first and second-generation of circular mapping and ablation catheter: insights from a real world multicenter experience. AB - PURPOSE: Complete pulmonary vein isolation (PVI) is the best documented target for catheter ablation, and different technologies have shown comparable outcomes. The multielectrode phased-RF/duty cycled (PhRF/DC) pulmonary vein ablation catheter (PVAC) and its second generation (PVAC-GOLD) have shown promising clinical results in single and multicenter experiences. Our aim is to assess and compare the safety and efficacy in the real clinical practice among two generations of circular PhRF/DC catheters by performing PVI in patients suffering from recurrent atrial fibrillation (AF). METHODS: Eighty-four AF patients treated with PVAC and 64 with PVAC-GOLD were prospectively followed in five Italian cardiology centers in the mainframe of the 1STOP-ClinicalService project. RESULTS: Fluoroscopic and total procedure time were significantly different in the two groups. In particular, in the PVAC-GOLD group, the mean fluoroscopic time was 22.8 +/- 12.7 min vs 31.6 +/- 18.9 in the PVAC group (p = 0.002), and the mean total procedure duration was 117.6 +/- 36.0 vs 147.4 +/- 40.6, in the PVAC GOLD group and the PVAC group, respectively (p = 0.001). Only two out of 148 patients reported a peri-procedural complication. Over 20.9 +/- 12.0 months of follow-up, AF recurrence occurred in 58 patients. Kaplan-Meier freedom from AF recurrence did not differ between the two groups (64.1 +/- 10% in the PVAC group vs 68.2 +/- 9% in the PVAC-GOLD group at 1 year, p = ns). CONCLUSIONS: In our multicenter analysis, AF ablation using two generations of circular PhRF/DC catheters is safe and effective. No difference was observed in terms of safety and efficacy of the AF ablation between the two catheters, with the mean procedural time being shorter in the PVAC-GOLD group. PMID- 28875450 TI - Cryo-EM structure of Mycobacterium smegmatis ribosome reveals two unidentified ribosomal proteins close to the functional centers. PMID- 28875449 TI - An extracorporeal carbon dioxide removal (ECCO2R) device operating at hemodialysis blood flow rates. AB - BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2R) systems have gained clinical appeal as supplemental therapy in the treatment of acute and chronic respiratory injuries with low tidal volume or non-invasive ventilation. We have developed an ultra-low-flow ECCO2R device (ULFED) capable of operating at blood flows comparable to renal hemodialysis (250 mL/min). Comparable operating conditions allow use of minimally invasive dialysis cannulation strategies with potential for direct integration to existing dialysis circuitry. METHODS: A carbon dioxide (CO2) removal device was fabricated with rotating impellers inside an annular hollow fiber membrane bundle to disrupt blood flow patterns and enhance gas exchange. In vitro gas exchange and hemolysis testing was conducted at hemodialysis blood flows (250 mL/min). RESULTS: In vitro carbon dioxide removal rates up to 75 mL/min were achieved in blood at normocapnia (pCO2 = 45 mmHg). In vitro hemolysis (including cannula and blood pump) was comparable to a Medtronic Minimax oxygenator control loop using a time-of-therapy normalized index of hemolysis (0.19 +/- 0.04 g/100 min versus 0.12 +/- 0.01 g/100 min, p = 0.169). CONCLUSIONS: In vitro performance suggests a new ultra-low-flow extracorporeal CO2 removal device could be utilized for safe and effective CO2 removal at hemodialysis flow rates using simplified and minimally invasive connection strategies. PMID- 28875451 TI - Increase in the circulating endocannabinoid 2-arachidonoylglycerol is associated with gabapentin use in septic ICU patients. PMID- 28875452 TI - Long non-coding RNA tagging and expression manipulation via CRISPR/Cas9-mediated targeted insertion. PMID- 28875453 TI - Laboratory Study Comparing Pharmacopeial Testing of Nebulizers with Evaluation Based on Nephele Mixing Inlet Methodology. AB - Determination of fine droplet dose with preparations for nebulization, currently deemed to be the metric most indicative of lung deposition and thus in vivo responses, involves combining two procedures following practice as described in the United States Pharmacopeia and the European Pharmacopeia. Delivered dose (DD) is established by simulating tidal breathing at the nebulizer, collecting the medication on a filter downstream of the nebulizer mouthpiece/facemask. Fine droplet fraction (FDF 25 years) prognoses. The gender, location, and width of keratinized mucosa affected the development of peri-implantitis, resulting in late failures. Implant-supported overdentures were frequently repaired. Tooth implant-supported prostheses are not recommended for long-term survival. PMID- 28875461 TI - The Doctor Is In: Media Portrayals of Psychiatrists and Their Influence on Canadian Medical Students' Recruitment into Psychiatry. PMID- 28875462 TI - Influence of soil physical properties and vegetation coverage at different slope aspects in a reclaimed dump. AB - Vegetation coverage is an important parameter for affecting soil erosion and the physical and chemical properties of soil. To analyze the mutual influence between vegetation coverage and soil quality at different slope aspects in a reclaimed dump, fitting analyses were built between the normalized difference vegetation index and soil physical properties at each slope aspect. Twenty six quadrats were sampled in slope-platform alternate mode. Each quadrat was 10 m * 10 m. Vegetation index and soil physical properties were measured and calculated. Through curve fitting analysis, the results showed that soil bulk density has a negative correlation with the vegetation index on shady and half shady slopes, sunny slopes, and half sunny slopes. Soil porosity has a positive correlation with the vegetation index on shady and half shady slopes, sunny slope, and half sunny slope. The soil mass water content has a concave function relationship with the vegetation index on shady and half shady slopes and has a quadratic function relationship with the vegetation index on sunny and half sunny slopes, with the parabola moving upwards. The soil gravel content has a linear relationship with the vegetation index on shady and half shady slopes, and the image has a negative slope with a quadratic function relationship to the vegetation index on sunny slope and half sunny slope, with the parabola moving downwards. Due to differences among hydrothermal conditions, the relationship between vegetation coverage and soil quality indicators at different slope aspects is different; therefore, reasonable improvement of soil quality indicators on sunny and half sunny slopes could help plants to grow. These findings feed into a reference document that sets out how vegetation and soil quality may be improved in mining areas. PMID- 28875463 TI - Assessment of cough strength in patients with a tracheostomy. PMID- 28875464 TI - Changes in Tryptophan Catabolite (TRYCAT) Pathway Patterning Are Associated with Mild Impairments in Declarative Memory in Schizophrenia and Deficits in Semantic and Episodic Memory Coupled with Increased False-Memory Creation in Deficit Schizophrenia. AB - Evidence indicates that schizophrenia and in particular negative symptoms and deficit schizophrenia are accompanied by neurocognitive impairments and changes in the patterning of the tryptophan catabolite (TRYCAT) pathway. This cross sectional study was carried out to examine the associations between cognitive functions (as measured with Consortium to Establish a Registry for Alzheimer's disease (CERAD)) and TRYCAT pathway patterning in patients with (n = 40) and without (n = 40) deficit schizophrenia and normal controls (n = 40). Cognitive measures were assessed with the Verbal Fluency Test (VFT), Boston Naming Test (BNT), Mini-Mental State Examination (MMSE), Word List Memory (WLM), Constructional Praxis, Word List Recall (WLRecall), and Word List Recognition (WLRecognition), while TRYCAT measurements assessed the IgA/IgM responses to noxious TRYCATs, namely quinolinic acid (QA), 3-OH-kynurenine (3HK), picolinic acid (PA), and xanthurenic (XA) acid, and more protective (PRO) TRYCATs, including kynurenic acid (KA) and anthranilic acid (AA). IgA NOX/PRO, IgM KA/3HK, and IgA/IgM NOX/PRO ratios were computed. Schizophrenia was accompanied by lower VFT and WLM, while BNT (dysnomia) and MMSE are significantly lower in multiple- than first-episode schizophrenia. Deficit schizophrenia is strongly associated with worse outcomes on VFT, MMSE, WLM, WLRecall, WLRecognition, and delayed recall savings and increased false memories. Around 40-50% of the variance in negative symptoms' scores was explained by VFT, WLM, WLRecall, and MMSE. Increases in IgA NOX/PRO, IgM KA/3HK, and/or IgA/IgM NOX/PRO ratios were associated with impairments in VFT, BNT, MMSE, WLM, WLRecall, WLRecognition, and false-memory creation. In conclusion, nondeficit schizophrenia is accompanied by mild memory impairments, while disease progression is accompanied by broader cognitive impairments. Deficit schizophrenia and negative symptoms are strongly associated with deficits in working memory, delayed recall and recognition, and increased false-memory creation. These cognitive impairments and memory deficits are in part explained by increased production and/or attenuated regulation of TRYCATs with neurotoxic, excitotoxic, immune-inflammatory, oxidative, and nitrosative potential, which may contribute to neuroprogression. PMID- 28875465 TI - Measles, Rubella and Varicella IgG Seroprevalence in a Large Refugee Cohort in Germany in 2015: A Cross-Sectional Study. AB - INTRODUCTION: The current extent of migration to the European continent is associated with exceptional humanitarian challenges. In 2015, Western Europe faced an enormous immigration of refugees with largely unknown protection status against communicable diseases. To adapt vaccination strategies, we aimed at assessing seroprevalences against three of the most relevant vaccine preventable diseases (VPD) in a large representative cohort. METHODS: IgG seroprevalences for rubella, varicella (n = 554) and measles (n = 552) were analyzed in inhabitants of a Northern German refugee camp in the summer of 2015. RESULTS: Of the refugees, 77.9% were male (mean age 27.4 years for male and 26.8 years for female migrants). Most refugees came from the Eastern Mediterranean region (83.4%), followed by immigrants from Eastern Europe (7.4%), Africa (4.6%), or other regions (4.5%). The vast majority of migrants were protected against the three VPD: overall IgG seropositivity was 88.5% for measles, 77.9% for rubella and 95.9% for varicella. However, seroprevalences showed age- and origin-dependent differences. Varicella immunity, for example, was lowest in the youngest age group of both genders (10.1% of male/4.5% of female seronegative refugees <18 years vs. 100% seropositivity in men and women >49 years of age), and Sudanese migrants displayed particularly low rates of protection against varicella. CONCLUSION: In accordance with previous studies, our analyses show an overall satisfactory seropositivity against measles, rubella, and varicella in refugees entering Europe during the current exodus. However, this rate is not sufficient for preventing transmission. For example, the rate of 12.9-17.9% female refugees at reproductive age unprotected against measles and the low protection levels against varicella in minors observed in our cohort emphasizes the need for stringent vaccination strategies in refugees coming to Europe during the current crisis. PMID- 28875467 TI - Erratum to: Breast Cancer Risk Associated with Genotype Polymorphisms of the Aurora Kinase a Gene (AURKA): a Case-Control Study in a High Altitude Ecuadorian Mestizo Population. PMID- 28875466 TI - Native Mass Spectrometry, Ion mobility, and Collision-Induced Unfolding Categorize Malaria Antigen/Antibody Binding. AB - Plasmodium vivax Duffy Binding Protein (PvDBP) is a promising vaccine candidate for P. vivax malaria. Recently, we reported the epitopes on PvDBP region II (PvDBP-II) for three inhibitory monoclonal antibodies (2D10, 2H2, and 2C6). In this communication, we describe the combination of native mass spectrometry and ion mobility (IM) with collision induced unfolding (CIU) to study the conformation and stabilities of three malarial antigen-antibody complexes. These complexes, when collisionally activated, undergo conformational changes that depend on the location of the epitope. CIU patterns for PvDBP-II in complex with antibody 2D10 and 2H2 are highly similar, indicating comparable binding topology and stability. A different CIU fingerprint is observed for PvDBP-II/2C6, indicating that 2C6 binds to PvDBP-II on an epitope different from 2D10 and 2H2. This work supports the use of CIU as a means of classifying antigen-antibody complexes by their epitope maps in a high throughput screening workflow. Graphical Abstract ?. PMID- 28875468 TI - Multifunctional, JNK-inhibiting nanotherapeutics for augmented elastic matrix regenerative repair in aortic aneurysms. AB - Growth of abdominal aortic aneurysms (AAA), localized aortal wall expansions, is driven by the disruption and subsequent loss of aortal wall elastic fibers by matrix metalloproteases (MMPs). Since elastic fibers do not naturally regenerate or repair, arresting/reversing AAA growth has not been possible. Previously, we showed utility of doxycycline (DOX), an MMP inhibitor drug, to stimulate elastic matrix neoassembly and crosslinking at low microgram per milliliter doses in addition to inhibiting MMPs. We currently show in aneurysmal smooth muscle cell (SMC) cultures that effects of exogenous DOX in this dose range are linked to its upregulation of transforming growth factor beta (TGF-beta1) via its inhibition of the regulatory protein c-Jun-N-terminal kinase 2 (JNK 2). We have identified a DOX dose range that stimulates elastogenesis and crosslinking without adversely impacting cell viability. Using JNK 2 inhibition as a metric for pro-regenerative matrix effects of DOX, we further demonstrate that sustained, steady-state release of DOX at the useful dose, from poly(ethylene glycol)-poly(lactic glycolic acid) nanoparticles (NPs), provides pro-elastogenic and anti-proteolytic effects that could potentially be more pronounced than that of exogenous DOX. We attribute these outcomes to previously determined synergistic effects provided by cationic amphiphile groups functionalizing the polymer NP surface. Released DOX inhibited expression and phosphorylation of JNK to likely increase expression of TGF-beta1, which is known to increase elastogenesis and lysyl oxidase-mediated crosslinking of elastic matrix. Our results suggest that JNK inhibition is a useful metric to assess pro-elastic matrix regenerative effects and point to the combinatorial regenerative benefits provided by DOX and cationic-functionalized NPs. PMID- 28875469 TI - A Panel of Autoantibodies Against Neural Proteins as Peripheral Biomarker for Pesticide-Induced Neurotoxicity. AB - In the present study, we screened the sera of subjects chronically exposed to mixtures of pesticides (composed mainly of organophosphorus compounds (OPs) and others) and developed neurological symptoms for the presence of autoantibodies against cytoskeletal neural proteins. OPs have a well-characterized clinical profile resulting from acute cholinergic crisis. However, some of these compounds cause neuronal degeneration and demyelination known as organophosphorus compound induced delayed neurotoxicity (OPIDN) and/or organophosphorus compound-induced chronic neurotoxicity (OPICN). Studies from our group have demonstrated the presence of autoantibodies to essential neuronal and glial proteins against cytoskeletal neural proteins in patients with chemical-induced brain injury. In this study, we screened the serum of 50 pesticide-exposed subjects and 25 non exposed controls, using Western blot analysis against the following proteins: neurofilament triplet proteins (NFPs), tubulin, microtubule-associated tau proteins (Tau), microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), glial fibrillary acidic protein (GFAP), calcium-calmodulin kinase II (CaMKII), glial S100-B protein, and alpha synuclein (SNCA). Serum reactivity was measured as arbitrary chemiluminescence units. As a group, exposed subjects had significantly higher levels of autoantibody reactivity in all cases examined. The folds of increase in of autoantibodies against neural proteins of the subjects compared to healthy humans in descending order were as follows: MBP, 7.67, MAG 5.89, CaMKII 5.50, GFAP 5.1, TAU 4.96, MAP2 4.83, SNCA 4.55, NFP 4.55, S-100B 2.43, and tubulin 1.78. This study has demonstrated the presence of serum autoantibodies to central nervous system-specific proteins in a group of farmers chronically exposed to pesticides who developed neurological signs and symptoms of neural injury. These autoantibodies can be used as future diagnostic/therapeutic target for OP-induced neurotoxicity. PMID- 28875470 TI - The impact of the survivorship care plan on health care use: 2-year follow-up results of the ROGY care trial. AB - PURPOSE: The purpose of this paper was to assess the impact of survivorship care plan (SCP) provision and moderating factors on health care use following endometrial cancer treatment. METHODS: Women newly diagnosed with endometrial cancer were included in a pragmatic cluster randomized trial at 12 hospitals in the Netherlands and were randomly assigned to SCP or usual care (n = 221; 75% response). The SCP was generated using the web-based Registrationsystem Oncological GYnecology (ROGY) and provided tailored information regarding disease, treatment, and possible late-effects. Cancer-related use of general practitioner, specialist, and additional health care was collected through questionnaires after diagnosis and at 6-, 12-, and 24-month follow-up and compared using linear multilevel regression analyses. RESULTS: Women who received an SCP had more cancer-related primary care visits compared to the usual care arm during the first year after diagnosis (beta = 0.7, p < 0.01). At 6-month follow up, women in the SCP group used more additional health care compared to women receiving usual care (24 vs. 11%, p = 0.04). Women with anxious symptoms (p = 0.03) and women who received radiotherapy (p = 0.01) had a higher primary care use within the first year after treatment, when receiving an SCP. CONCLUSIONS: The SCP increases primary health care consumption the first year after treatment, particularly in women treated with radiotherapy and women with anxious symptoms. IMPLICATIONS FOR CANCER SURVIVORS: These findings imply that the SCP enables women in need of supportive care to seek relevant care at an early stage after treatment. Whether this results in improved patient-reported outcomes in the long term needs to be further studied. PMID- 28875471 TI - Optimization of Curcuma Oil/Quinine-Loaded Nanocapsules for Malaria Treatment. AB - Quinine, a treatment used in chloroquine-resistant falciparum malaria, was loaded into poly(E-caprolactone) or Eudragit(r) RS100 nanocapsules using Curcuma oil as the oil-based core. Until now, the effect of cationic nanocapsules on malaria has not been reported. A 24 factorial design was adopted using, as independent variables, the concentration of Curcuma oil, presence of quinine, type of polymer, and aqueous surfactant. Diameter, zeta potential, and pH were the responses studied. The formulations were also evaluated for drug content, encapsulation efficiency, photostability, and antimalarial activity against Plasmodium berghei-infected mice. The type of polymer influenced all of the responses studied. Quinine-loaded Eudragit(r) RS100 (F13) and PCL nanocapsules (F9), both with polysorbate 80 coating, showed nanometric particle size, positive zeta potential, neutral pH, high drug content, and quinine photoprotection ability; thus, these nanocapsules were selected for in vivo tests. Both formulations showed lower levels of parasitemia from the beginning of the experiment (5.78 +/- 3.60 and 4.76 +/- 3.46% for F9 and F13, respectively) and highest survival mean time (15.3 +/- 2.0 and 14.9 +/- 5.6 days for F9 and F13, respectively). F9 and F13 showed significant survival curve compared to saline, thus demonstrating that nanoencapsulation improved bioefficacy of QN and co encapsulated curcuminoids, regardless of the surface charge. PMID- 28875472 TI - Evaluation of Novel 64Cu-Labeled Theranostic Gadolinium-Based Nanoprobes in HepG2 Tumor-Bearing Nude Mice. AB - Radiation therapy of liver cancer is limited by low tolerance of the liver to radiation. Radiosensitizers can effectively reduce the required radiation dose. AGuIX nanoparticles are small, multifunctional gadolinium-based nanoparticles that can carry radioisotopes or fluorescent markers for single-photon emission computed tomography (SPECT), positron emission tomography (PET), fluorescence imaging, and even multimodality imaging. In addition, due to the high atomic number of gadolinium, it can also serve as a tumor radiation sensitizer. It is critical to define the biodistribution and pharmacokinetics of these gadolinium based nanoparticles to quantitate the magnitude and duration of their retention within the tumor microenvironment during radiotherapy. Therefore, in this study, we successfully labeled AGuIX with 64Cu through the convenient built-in chelator. The biodistribution studies indicated that the radiotracer 64Cu-AGuIX accumulates to high levels in the HepG2 xenograft of nude mice, suggesting that it would be a potential theranostic nanoprobe for image-guided radiotherapy in HCC. We also used a transmission electron microscope to confirm AGuIX uptake in the HepG2 cells. In radiation therapy studies, a decrease in 18F-FDG uptake was observed in the xenografts of the nude mice irradiated with AGuIX, which was injected 1 h before. These results provide proof-of-concept that AGuIX can be used as a theranostic radiosensitizer for PET imaging to guide radiotherapy for liver cancer. PMID- 28875473 TI - Visible Light-Driven Photocatalytic Performance of N-Doped ZnO/g-C3N4 Nanocomposites. AB - N-doped ZnO/g-C3N4 composites have been successfully prepared via a facile and cost-effective sol-gel method. The nanocomposites were systematically characterized by XRD, FE-SEM, HRTEM, FT-IR, XPS, and UV-vis DRS. The results indicated that compared with the pure N-doped ZnO, the absorption edge of binary N-doped ZnO/g-C3N4 shifted to a lower energy with increasing the visible-light absorption and improving the charge separation efficiency, which would enhance its photocatalytic activity. Compared with the pure g-C3N4, ZnO, N-doped ZnO and the composite ZnO/g-C3N4, the as-prepared N-doped ZnO/g-C3N4 exhibits a greatly enhanced photocatalytic degradation of methylene blue and phenol under visible light irradiation. Meanwhile, N-doped ZnO/g-C3N4 possesses a high stability. Finally, a proposed mechanism for N-doped ZnO/g-C3N4 is also discussed. The improved photocatalysis can be attributed to the synergistic effect between N doped ZnO and g-C3N4, including the energy band structure and enhanced charge separation efficiency. PMID- 28875474 TI - No advantage for remembering horizontal over vertical spatial locations learned from a single viewpoint. AB - Previous behavioral and neurophysiological research has shown better memory for horizontal than for vertical locations. In these studies, participants navigated toward these locations. In the present study we investigated whether the orientation of the spatial plane per se was responsible for this difference. We thus had participants learn locations visually from a single perspective and retrieve them from multiple viewpoints. In three experiments, participants studied colored tags on a horizontally or vertically oriented board within a virtual room and recalled these locations with different layout orientations (Exp. 1) or from different room-based perspectives (Exps. 2 and 3). All experiments revealed evidence for equal recall performance in horizontal and vertical memory. In addition, the patterns for recall from different test orientations were rather similar. Consequently, our results suggest that memory is qualitatively similar for both vertical and horizontal two-dimensional locations, given that these locations are learned from a single viewpoint. Thus, prior differences in spatial memory may have originated from the structure of the space or the fact that participants navigated through it. Additionally, the strong performance advantages for perspective shifts (Exps. 2 and 3) relative to layout rotations (Exp. 1) suggest that configurational judgments are not only based on memory of the relations between target objects, but also encompass the relations between target objects and the surrounding room-for example, in the form of a memorized view. PMID- 28875475 TI - Immunological and Virological Responses to Highly Active Antiretroviral Therapy in HIV-1 Infected Children. AB - OBJECTIVE: To evaluate immunological and virological outcomes in human immunodeficiency virus (HIV) infected children at six months of highly active antiretroviral therapy (HAART). METHODS: Records of HIV infected children <15-y old were reviewed to identify those who were initiated highly active antiretroviral therapy between 2010 and 2014 and had CD4+ T cell percentage and HIV-1 viral load report at baseline visit and after 6 mo of initiation of the treatment. RESULTS: Seventy-four HIV infected children [26% girls, median age IQR 36 (24-108) mo] were included in the study. At the end of six months of HAART, median increase of 11% (6-15%) in CD4+ T cell percentage from the baseline levels was observed; nineteen (26%) children showed an increase in CD4+ T cell percentage of 15% or more at 6 mo. Viral load was undetectable (<47 copies/ml) in 27 (36.4%) children; 21 (28.3%) children had 47- < 500 copies/ml; 16 (21.6%) children had 500- < 10,000 copies/ml and 10 (13.5%) children had >=10,000 copies/ml. At six months, only 15 (20.2%) children exhibited positive immuno virological response to HAART (>= 15% increase in CD4% and <47 HIV-1 RNA copies/ml). CONCLUSIONS: While HAART was effective in improving the immunological and virological parameters in the index cohort of children, virological responses were less robust. PMID- 28875476 TI - Treatment of primary membranous nephropathy: where are we now? AB - In the last 10 years, basic science and clinical research have made important contributions to the understanding and management of primary membranous nephropathy (MN). The identification of antibodies directed against the M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A protein have added a new perspective on diagnosis, monitoring the immunological activity, predicting prognosis and guiding therapy in patients with primary MN. Mounting evidence suggests that quantification and follow-up of antiPLA2R Abs levels can help in assessing prognosis and evaluate the response to treatment. The kidney disease improving global outcomes guidelines published in 2012 have not been updated. New data on the use of rituximab suggest it should be considered as a potential initial therapy in the treatment of patients with primary MN. PMID- 28875478 TI - Erratum to: Effectiveness, Adverse Effects and Drug Compliance of Long-Acting Injectable Risperidone in Children and Adolescents. PMID- 28875477 TI - Effects of PON1 Gene Promoter DNA Methylation and Genetic Variations on the Clinical Outcomes of Dual Antiplatelet Therapy for Patients Undergoing Percutaneous Coronary Intervention. AB - INTRODUCTION AND OBJECTIVE: The relationship between either paraoxonase 1 (PON1) gene promoter DNA methylation or genetic variations and bleeding or major adverse cardiac events after dual antiplatelet therapy has been incompletely characterized. We aimed to systematically investigate the role of genetic variations and DNA methylation of the PON1 CpG island promoter on the clinical outcomes of dual antiplatelet therapy for patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI). METHODS: This study included 653 patients with CAD undergoing PCI and receiving dual antiplatelet therapy. Genomic DNAs were isolated from whole blood and were genotyped for the three single nucleotide polymorphisms (SNPs) of the PON1 gene. The DNA methylation levels in the PON1 promoter region were determined by bisulfite sequencing or pyrosequencing at five CpG sites (positions -142, -161, -163, -170, and -184 from the transcription start site). Clopidogrel and its metabolites in plasma were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and platelet function analysis was performed using the VerifyNow assay. RESULTS: Statistically significant associations between methylation levels at five PON1 CpG sites and bleeding were observed: -184 [odds ratio (OR) 0.98, 95% confidence interval (CI) 0.96-1.00, p = 0.028]; -170 (OR 0.99, 95% CI 0.97-1.00, p = 0.048); -163 (OR 0.98, 95% CI 0.96-1.00, p = 0.029); 161 (OR 0.98, 95% CI 0.97-1.00, p = 0.026); and -142 (OR 0.98, 95% CI 0.97-1.00, p = 0.042) at a false discovery rate of <5%. Statistical analysis also revealed that aspirin reaction units (ARUs) were significantly associated with PON1 methylation level at CpG site -163 (p = 0.0342). The ARUs of patients with the PON1 126 CC genotype was 527 +/- 94, which was higher than the ARUs (473 +/- 89) of patients with the 126 CG genotype (p = 0.0163). Multivariate logistic regression analysis indicated that the PON1 methylation level at CpG site -161 (OR 0.95, 95% CI 0.92-0.98, p = 0.002) and the use of angiotensin-converting enzyme inhibitors (OR 0.48, 95% CI 0.26-0.89, p = 0.021) were associated with a decreased risk of bleeding events. CONCLUSIONS: Hypomethylation of CpGs in the PON1 promoter may be a weak, albeit statistically significant, risk factor of bleeding after dual antiplatelet therapy. Further large-scale studies are needed to verify our results. PMID- 28875479 TI - Development of an Enantioselective and Biomarker-Informed Translational Population Pharmacokinetic/Pharmacodynamic Model for Etodolac. AB - Cyclooxygenase-2 (COX-2) isoform has a critical role in the development of pain. Inhibition of COX-2 in vitro serves as a biomarker for nonsteroidal anti inflammatory drugs (NSAIDs). The NSAID concentrations yielding 80% COX-2 inhibition (IC80) correlate with therapeutic doses to achieve analgesia across multiple COX-2 inhibitors. However, there are no time-course models relating COX 2 inhibition with decreased pain. This study aimed to characterize the relationship between NSAID concentrations, in vitro COX-2 inhibition, and acute pain decrease in humans over time by a translational approach using clinical pharmacokinetic and literature reported in vitro and clinical pharmacodynamic data. In a two-way cross-over study, eight healthy volunteers received 300 and 400 mg racemic etodolac, a preferential COX-2 inhibitor. R- and S-etodolac were determined by LC-MS/MS and simultaneously modeled. Literature in vitro IC50 data for COX-2 inhibition by S-etodolac were used to fit adjusted pain score profiles from dental patients receiving etodolac. External model qualification was performed using published ibuprofen data. Etodolac absorption was highly variable due to gastric transit kinetics and low aqueous solubility. The disposition parameters differed substantially between enantiomers with a total clearance of 2.21 L/h for R-etodolac and 26.8 L/h for S-etodolac. Volume of distribution at steady-state was 14.6 L for R-etodolac and 45.8 L for S-etodolac. Inhibition of COX-2 by 78.1% caused a half-maximal pain decrease. The time-course of pain decrease following ibuprofen was successfully predicted via the developed translational model. This proposed enantioselective pharmacodynamic-informed approach presents the first quantitative time-course model for COX-2 induced pain inhibition in patients. PMID- 28875480 TI - Erratum to: Rationale and design of oBservational clinical Research In chronic kidney disease patients with renal anemia: renal proGnosis in patients with Hyporesponsive anemia To Erythropoiesis-stimulating agents, darbepoetiN alfa (BRIGHTEN Trial). PMID- 28875481 TI - Proteinuria Predicts Resistance to Antiplatelet Therapy in Ischemic Stroke. AB - The occurrence of a stroke while on antiplatelet agents presents a therapeutic dilemma. One of the main causes for recurrent strokes is antiplatelet resistance more commonly known as high on treatment platelet reactivity (HTPR). Prior studies have established that proteinuria is associated with HTPR following myocardial infarction. Here, we investigated whether dipstick proteinuria correlates with HTPR in patients presenting with stroke. We performed a retrospective cohort analysis of 102 patients admitted for a recurrent ischemic stroke that had either a VerifyNow aspirin or VerifyNow clopidogrel laboratory test performed to assess platelet reactivity. Dipstick proteinuria was defined as > 30 mg/dl (2+ or more). HTPR was defined as an aspirin resistance unit > 550 for aspirin and a P2Y12 reactivity unit > 208 for clopidogrel. Patients with proteinuria on dipstick were significantly more likely to have HTPR to either aspirin (p value 0.017) or clopidogrel (p value 0.017). After controlling for age, smoking, diabetes, hypertension, CAD and GFR, proteinuria was an independent predictor of HTPR for patient taking aspirin (p = 0.025). Platelet resistance is an entity that undermines the activity of antiplatelet agents in reducing stroke risk. Here, we demonstrate an association with increased platelet reactivity and proteinuria. This highlights a potential new therapeutic target in reducing future stroke risk. PMID- 28875484 TI - Women's Auto/Biography and Dissociative Identity Disorder: Implications for Mental Health Practice. AB - Dissociative Identity Disorder (DID) is an uncommon disorder that has long been associated with exposure to traumatic stressors exceeding manageable levels commonly encompassing physical, psychological and sexual abuse in childhood that is prolonged and severe in nature. In DID, dissociation continues after the traumatic experience and produces a disruption in identity where distinct personality states develop. These personalities are accompanied by variations in behaviour, emotions, memory, perception and cognition. The use of literature in psychiatry can enrich comprehension over the subjective experience of a disorder, and the utilisation of 'illness narratives' in nursing research have been considered a way of improving knowledge about nursing care and theory development. This research explores experiences of DID through close textual reading and thematic analysis of five biographical and autobiographical texts, discussing the lived experience of the disorder. This narrative approach aims to inform empathetic understanding and support the facilitation of therapeutic alliances in mental healthcare for those experiencing the potentially debilitating and distressing symptoms of DID. Although controversies surrounding the biomedical diagnosis of DID are important to consider, the lived experiences of those who mental health nurses encounter should be priority. PMID- 28875483 TI - Comparison of diagnostic accuracy in sepsis between presepsin, procalcitonin, and C-reactive protein: a systematic review and meta-analysis. AB - BACKGROUND: The soluble cluster of differentiation 14 (or presepsin) is a free fragment of glycoprotein expressed on monocytes and macrophages. Although many studies have been conducted recently, the diagnostic performance of presepsin for sepsis remains debated. We performed a systematic review and meta-analysis of the available literature to assess the accuracy of presepsin for the diagnosis of sepsis in adult patients and compared the performance between presepsin, C reactive protein (CRP), and procalcitonin (PCT). METHODS: A comprehensive systemic search was conducted in PubMed, EMBASE, and Google Scholar for studies that evaluated the diagnostic accuracy of presepsin for sepsis until January 2017. The hierarchical summary receiver operating characteristic method was used to pool individual sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and area under the receiver operating characteristic curve (AUC). RESULTS: Eighteen studies, comprising 3470 patients, met our inclusion criteria. The pooled diagnosis sensitivity and specificity of presepsin for sepsis were 0.84 (95% CI 0.80-0.87) and 0.76 (95% CI 0.67-0.82), respectively. Furthermore, the pooled DOR, PLR, NLR, and AUC were 16 (95% CI 10-25), 3.4 (95% CI 2.5-4.6), 0.22 (95% CI 0.17-0.27), and 0.88 (95% CI 0.85-0.90), respectively. Significant heterogeneity was found in both sensitivities (Cochrane Q = 137.43, p < 0.001, I 2 = 87.63%) and specificities (Cochrane Q = 180.76, p < 0.001, I 2 = 90.60%). Additionally, we found no significant difference between presepsin and PCT (AUC 0.87 vs. 0.86) or CRP (AUC 0.85 vs. 0.85). However, for studies conducted in ICU, the pooled sensitivity of presepsin was found to be higher than PCT (0.88, 95% CI 0.82-0.92 vs. 0.75, 95% CI 0.68-0.81), while the pooled specificity of presepsin was lower than PCT (0.58, 95% CI 0.42-0.73 vs. 0.75, 95% CI 0.65-0.83). CONCLUSION: Based on the results of our meta-analysis, presepsin is a promising marker for diagnosis of sepsis as PCT or CRP, but its results should be interpreted more carefully and cautiously since too few studies were included and those studies had high heterogeneity between them. In addition, continuing re-evaluation during the course of sepsis is advisable. PMID- 28875486 TI - Metabolism in Immune Cell Differentiation and Function. AB - The immune system is a central determinant of organismal health. Functional immune responses require quiescent immune cells to rapidly grow, proliferate, and acquire effector functions when they sense infectious agents or other insults. Specialized metabolic programs are critical regulators of immune responses, and alterations in immune metabolism can cause immunological disorders. There has thus been growing interest in understanding how metabolic processes control immune cell functions under normal and pathophysiological conditions. In this chapter, we summarize how metabolic programs are tuned and what the physiological consequences of metabolic reprogramming are as they relate to immune cell homeostasis, differentiation, and function. PMID- 28875485 TI - Application of the thermostable beta-galactosidase, BgaB, from Geobacillus stearothermophilus as a versatile reporter under anaerobic and aerobic conditions. AB - Use of thermophilic organisms has a range of advantages, but the significant lack of engineering tools limits their applications. Here we show that beta galactosidase from Geobacillus stearothermophilus (BgaB) can be applicable in a range of conditions, including different temperatures and oxygen concentrations. This protein functions both as a marker, promoting colony color development in the presence of a lactose analogue S-gal, and as a reporter enabling quantitative measurement by a simple colorimetric assay. Optimal performance was observed at 70 degrees C and pH 6.4. The gene was introduced into G. thermoglucosidans. The combination of BgaB expressed from promoters of varying strength with S-gal produced distinct black colonies in aerobic and anaerobic conditions at temperatures ranging from 37 to 60 degrees C. It showed an important advantage over the conventional beta-galactosidase (LacZ) and substrate X-gal, which were inactive at high temperature and under anaerobic conditions. To demonstrate the versatility of the reporter, a promoter library was constructed by randomizing sequences around -35 and -10 regions in a wild type groES promoter from Geobacillus sp. GHH01. The library contained 28 promoter variants and encompassed fivefold variation. The experimental pipeline allowed construction and measurement of expression levels of the library in just 4 days. This beta galactosidase provides a promising tool for engineering of aerobic, anaerobic, and thermophilic production organisms such as Geobacillus species. PMID- 28875487 TI - Metabolic Regulation of T Cell Immunity. AB - It is becoming increasingly clear that cellular metabolism plays a critical role in the propagation of appropriate, effective, and pathologic immune responses. In this chapter, we detail the metabolic pathways involved in T cell activation and differentiation, highlighting specific factors responsible for directing the processes that lead to metabolic programming at important stages in the dynamic life cycle of this immune cell lineage. Additionally, this chapter will discuss how key metabolites are acquired, touching on the factors and conditions regulating the expression of crucial transporter molecules in response to activation and pathological states. PMID- 28875488 TI - Transcriptional Regulation of T Cell Metabolism Reprograming. AB - T cell activation, differentiation, and function are tightly regulated by a complex network of transcription factors, epigenetic modifications, and signaling pathways of both TCR and cytokines. Over the past decade, it is increasingly clear that T cell immune responses are also regulated by their associated metabolic reprograming. Compared with relatively well-understood transcriptional regulation of T cell activation, differentiation, and function, less is known about the transcriptional regulation of T cell metabolic reprograming during T cell immune responses. In this review, we first describe how signaling pathways of TCR and cytokines regulate metabolic reprograming and then focus on transcription factors that control metabolic pathways and outcomes of T cell immune responses. A better understanding of T cell metabolic regulation will provide new strategies and targets for the treatment of T cell-related diseases. PMID- 28875489 TI - Adipose Tissue-Resident Regulatory T Cells. AB - Tissue-resident immune cells play critical roles in regulating tissue function and homeostasis. Obesity-associated visceral adipose tissue inflammation is attributed to the accumulation of M1 macrophages which produce inflammatory cytokines like TNF-alpha, IL-6, and expansion of effector T cells like Th1 cells, CD8+ cytotoxic T cells which produce interferon-gamma to further add to the severity of inflammation in the visceral adipose tissue. Regulatory T cells have been reported to exert key roles in suppressing inflammation, thus maintaining the homeostasis of immune responses, and visceral adipose Tregs exert critical roles in defending against obesity-associated metabolic disorders. They inhibit the infiltration of effector T cells and facilitate the reconstitution of adipose tissue macrophages from M1 to M2 phenotype. What is more, they can take up lipids from the adipocytes through CD36 which is driven by PPARgamma. Here we review the recent progress in adipose tissue-resident regulatory T cells (Tregs), a subpopulation of CD4+ T cells which suppress adipose tissue inflammation. PMID- 28875490 TI - Immune Cell Metabolism in Tumor Microenvironment. AB - Tumor microenvironment (TME) is composed of tumor cells, immune cells, cytokines, extracellular matrix, etc. The immune system and the metabolisms of glucose, lipids, amino acids, and nucleotides are integrated in the tumorigenesis and development. Cancer cells and immune cells show metabolic reprogramming in the TME, which intimately links immune cell functions and edits tumor immunology. Recent findings in immune cell metabolism hold the promising possibilities toward clinical therapeutics for treating cancer. This chapter introduces the updated understandings of metabolic reprogramming of immune cells in the TME and suggests new directions in manipulation of immune responses for cancer diagnosis and therapy. PMID- 28875491 TI - Regulation of Metabolism Across Different Subsets of T Cells in Cancer. AB - T cells play a critical role to defend against tumor and maintain immune homeostasis. The diverse functions of T cells require precise regulation of metabolic pathways. Recent studies reveal that metabolic changes are tightly linked to the activation and function of T cells. Given the importance of these cells in tumor progression, it is important to understand how the tumor microenvironment regulates metabolism of T cells and how the metabolic reprogramming of T cells affects tumor growth. Here, we review new findings and discuss how metabolic reprogramming of different types of T cells affects the immune response in tumors. PMID- 28875492 TI - Innate and Adaptive Immune Cell Metabolism in Tumor Microenvironment. AB - During an immune response, leukocytes undergo major changes in growth and function that are tightly coupled to dynamic shifts in metabolic processes. Immunometabolism is an emerging field that investigates the interplay between immunological and metabolic processes. The immune system has a key role to play in controlling cancer initiation and progression. Increasing evidence indicates the immunosuppressive nature of the local environment in tumor. In tumor microenvironment, immune cells collectively adapt in a dynamic manner to the metabolic needs of cancer cells, thus prompting tumorigenesis and resistance to treatments. Here, we summarize the latest insights into the metabolic reprogramming of immune cells in tumor microenvironment and their potential roles in tumor progression and metastasis. Manipulating metabolic remodeling and immune responses may provide an exciting new option for cancer immunotherapy. PMID- 28875493 TI - Prevalence of high risk HPV DNA in esophagus is high in Brazil but not related to esophageal squamous cell carcinoma. AB - BACKGROUNDS: The first publication that associated Human Papillomavirus (HPV) infection and esophageal cancer was published in 1982. However, data are still contradictory and require further investigation. The aim of this study was to identify high risk HPV DNA in esophageal tissue of patients with and without esophageal squamous cell carcinoma (ESCC) and correlate HPV presence with classical risk factors. METHODS: Invited patients signed the informed consent form, and interviews were conducted in order to obtain information about sociodemographic and lifestyle behavior. During endoscopy, esophageal biopsies were collected from case and controls. Multiplex polymerase chain reaction genotyping was conducted on endoscopic biopsies to identify HPV types and HPV-16 was further evaluated by specific PCR real time. RESULTS: Among 87 cases, 12 (13.8%) had tumors harboring high risk HPV DNA and among 87 controls, 12 (13.8%) had high risk HPV DNA (OR:1.025 [CI:0.405:2.592]). Variables regarding consumption of alcohol and use of tobacco continued to characterize risk factors even after adjustments by presence or absence of high risk HPV. CONCLUSION: HPV was demonstrated to be frequently and similarly associated to normal and malignant esophageal tissues, but not as an independent risk factor to esophageal cancer. IMPACT: To contribute to the Brazilian population data on this subject, which is still contradictory. PMID- 28875495 TI - Rational design of Meso-2,3-butanediol dehydrogenase by molecular dynamics simulation and experimental evaluations. AB - Meso-2,3-butanediol dehydrogenase (meso-2,3-BDH) catalyzes NAD+ -dependent conversion of meso-2,3-butanediol to acetoin, a crucial external energy storage molecule in fermentive bacteria. In this study, the active tunnel of meso-2,3-BDH was identified. The two short alpha helixes positioned away from the alpha4-helix possibly expose the hydrophobic ligand-binding cavity, gating the exit of product and cofactor from the activity pocket. Further MM/GBSA-binding free energy analysis shows that Phe212 and Asn146 function as the key product-release sites. Site-directed mutagenesis experiments targeted to the sites show that the kcat of Phe212Tyr is enhanced up to (4-8)-fold. The original activity of Asn146Gln is retained, but the activity of Asn146Ala mutation is lost. These results could provide helpful guidance on rational design of short-chain dehydrogenases/reductases. PMID- 28875494 TI - Abundance of small mammals in the Atlantic Forest (ASMAF): a data set for analyzing tropical community patterns. AB - Local abundance results from the interaction between populational and environmental processes. The abundance of the species in a community is also one of the most basic descriptors of its structure. Despite its importance, information about species abundances is fragmentary, creating a knowledge gap about species abundances known as the Prestonian Shortfall. Here we present a comprehensive data set of small mammal abundance in the Atlantic Forest. Data were extracted from 114 published sources and from unpublished data collected by our research groups spanning from 1943 to 2017. The data set includes 1,902 records of at least 111 species in 155 localities, totaling 42,617 individuals represented. We selected studies that (1) were conducted in forested habitats of the Atlantic Forest, (2) had a minimum sampling effort of at least 500 trap nights, and (3) contained species abundance data in detail. For each study, we recorded (1) latitude and longitude, (2) name of the locality, (3) employed sampling effort, (4) type of traps used, (5) study year, (6) country, and (7) species name with (8) its respective abundances. For every locality, we also obtained information regarding its (9) ecoregion, (10) predominant vegetation type, and (11) biogeographic subdivision. Whenever necessary, we also (12) updated the species names as new species were described and some genera suffered taxonomic revision since the publication. The localities are spread across the Atlantic Forest and most of the small mammal species known to occur in Atlantic Forest are present in the data set, making it representative of communities of the entire biome. This data set can be used to address various patterns in community ecology and geographical ecology, as the relation between local abundance and environmental suitability, hypothesis regarding local and regional factors on community structuring, species abundance distributions (SAD), functional and phylogenetic mechanisms on community assembling. PMID- 28875496 TI - G protein-coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1. AB - The putative cannabinoid receptor GPR55 has been shown to play a tumor-promoting role in various cancers, and is involved in many physiological and pathological processes of the gastrointestinal (GI) tract. While the cannabinoid receptor 1 (CB1 ) has been reported to suppress intestinal tumor growth, the role of GPR55 in the development of GI cancers is unclear. We, therefore, aimed at elucidating the role of GPR55 in colorectal cancer (CRC), the third most common cancer worldwide. Using azoxymethane (AOM)- and dextran sulfate sodium (DSS)-driven CRC mouse models, we found that GPR55 plays a tumor-promoting role that involves alterations of leukocyte populations, i.e. myeloid-derived suppressor cells and T lymphocytes, within the tumor tissues. Concomitantly, expression levels of COX-2 and STAT3 were reduced in tumor tissue of GPR55 knockout mice, indicating reduced presence of tumor-promoting factors. By employing the experimental CRC models to CB1 knockout and CB1 /GPR55 double knockout mice, we can further show that GPR55 plays an opposing role to CB1 . We report that GPR55 and CB1 mRNA expression are differentially regulated in the experimental models and in a cohort of 86 CRC patients. Epigenetic methylation of CNR1 and GPR55 was also differentially regulated in human CRC tissue compared to control samples. Collectively, our data suggest that GPR55 and CB1 play differential roles in colon carcinogenesis where the former seems to act as oncogene and the latter as tumor suppressor. PMID- 28875498 TI - Comparative Study of Effects of Vonoprazan and Esomeprazole on Antiplatelet Function of Clopidogrel or Prasugrel in Relation to CYP2C19 Genotype. AB - Drug-drug interaction between antiacid and antiplatelet agents has not been fully elucidated. Vonoprazan, a new potassium competitive acid blocker, has been available in Japan. CYP2C19 and CYP3A4 are involved in the metabolism of clopidogrel, prasugrel, esomeprazole, and vonoprazan. Using a P2Y12 assay, we compared the effects of vonoprazan and esomeprazole on the antiplatelet functions of clopidogrel or prasugrel in 31 healthy Japanese volunteers (14 CYP2C19 homo extensive (homo-EMs), nine hetero-extensive (hetero-EMs), and eight poor metabolizers (PMs)). Vonoprazan decreased the median inhibition of platelet aggregation (IPA) values of clopidogrel and prasugrel more potently than esomeprazole (P < 0.001 for clopidogrel and P = 0.011 for prasugrel). The same tendencies were observed when stratified by CYP2C19 genotype groups (P = 0.004 in homo-EMs, 0.033 in hetero-EMs, and 0.043 in PMs). Vonoprazan attenuated the antiplatelet function of clopidogrel more potently than esomeprazole. Esomeprazole did not affect that of prasugrel irrespective of CYP2C19 genotype. PMID- 28875497 TI - Cancer Screening of Older Adults in Israel According to Life Expectancy: Cross Sectional Study. AB - OBJECTIVES: To examine over-screening of older Israelis for colon and breast cancer. DESIGN: Cross sectional. SETTING: Clalit Health Services (CHS), Israel's largest health maintenance organization (HMO), provides care for more than half of the country's population and operates a national age-based programs for cancer screening. PARTICIPANTS: All community-dwelling members aged 65 to 79 in 2014 (N = 370,876). MEASUREMENTS: We used CHS data warehouse to evaluate cancer screening during 2014. Life expectancy (LE) was estimated using the validated Schonberg index. RESULTS: Almost one-quarter (23.1%; 15.6% of adults aged 65-74, 42.7% of adults aged 75-79) of the study population had an estimated LE of less than 10 years. Annual fecal occult blood test and biannual mammography rates among adults aged 65 to 74 with a LE of 10 years or longer were 37.1% and 70.0%, respectively. Rates dropped after age 75 (4.0%, 19.5%) and to a lesser extent with a LE of less than 10 years (31.6%, 56.4%). Prostate-specific antigen testing is not part of the national screening program, and the proportion of people tested (42.6%), did not vary similarly with age of 75 and older (43.2%) or LE of less than 10 years (38.1%). CONCLUSION: The cancer screening inclusion criteria of the national referral system have a strong effect on receipt of screening; LE considerations are less influential. Some method of estimating LE could be incorporated into algorithms to improve individualized cancer screening to reduce over- and underscreening of older adults. PMID- 28875499 TI - The intestinal microbiota determines the colitis-inducing potential of T-bet deficient Th cells in mice. AB - Conflicting evidence has been provided as to whether induction of intestinal inflammation by adoptive transfer of naive T cells into Rag-/- mice requires expression of the transcription factor T-bet by the T cells. Here, we formally show that the intestinal microbiota composition of the Rag-/- recipient determines whether or not T-bet-deficient Th cells can induce colitis and we have resolved the differences of the two microbiomes, permissive or non-permissive to T-bet-independent colitis. Our data highlight the dominance of the microbiota over particular T cell differentiation programs in the pathogenesis of chronic intestinal inflammation. PMID- 28875500 TI - Thorny ganglion cells in marmoset retina: Morphological and neurochemical characterization with antibodies against calretinin. AB - In primates, over 17 morphological types of retinal ganglion cell have been distinguished by their dendritic morphology and stratification, but reliable markers for specific ganglion cell populations are still rare. The calcium binding protein calretinin is known to be expressed in the inner nuclear and the ganglion cell layer of marmoset retina, however, the specific cell type(s) expressing calretinin in the ganglion cell layer are yet to be determined. Here, we identified calretinin positive retinal ganglion cells in the common marmoset Callithrix jacchus. Double labeling with the ganglion cell marker RBPMS demonstrated that the large majority (80%) of the calretinin positive cells in the ganglion cell layer are ganglion cells, and 20% are displaced amacrine cells. The calretinin positive ganglion cells made up on average 12% of the total ganglion cell population outside of the foveal region and their proportion increased with eccentricity. Prelabeling with antibodies against calretinin and subsequent intracellular injection with DiI revealed that the large majority of the injected cells (n = 74) were either narrow thorny or broad thorny ganglion cells, 14 cells were displaced amacrine cells. Narrow thorny cells were further distinguished into outer and inner stratifying cells. In addition, weakly labeled cells with a large soma were identified as parasol ganglion cells. Our results show that three types of thorny ganglion cells in marmoset retina can be identified with antibodies against calretinin. Our findings are also consistent with the idea that the proportion of wide-field ganglion cell types increases in peripheral retina. PMID- 28875502 TI - Modified RS-LAMP assay and use of lateral flow devices for rapid detection of Leifsonia xyli subsp. xyli. AB - : Ratoon stunt (RS) caused by bacterium Leifsonia xyli subsp. xyli (Lxx) results in substantial yield losses in sugarcane (Saccharum sp. L. hybrid). Since RS does not produce reliable symptoms in the field, laboratory-based techniques are necessary for detection. Loop-mediated isothermal amplification (LAMP) assay overcomes the limitations of laboratory-based techniques which are costly, time consuming and cannot be used for near-field detection. A sensitive LAMP assay was developed to detect Lxx at 65 degrees C in 30 min. However, carry-over contamination affected the reliability of the assay. In the present study, contaminants were successfully eliminated by incorporation of uracil nucleoside glycosylase (1 U MUl-1 ) into the LAMP assay and incubation for 10 min at 37 degrees C. To avoid the use of colorimetric reagents, lateral flow devices were successfully used for the detection of LAMP products and were equally sensitive to detection by agarose gel electrophoresis. The use of exudate from leaf sheath discs as an alternate template for the LAMP assay was found to be less sensitive than xylem sap. The preprepared master mix could be stored for up to 4 months at 20 degrees C without any reduction in performance. These changes make the assay suitable for near-field detection in laboratories with basic facilities. SIGNIFICANCE AND IMPACT OF THE STUDY: This study presents a modified loop mediated isothermal amplification (LAMP) assay for the detection of Leifsonia xyli subsp. xyli. Modifications include incorporation of uracil nucleoside glycosylase to eliminate carry-over contamination and substitution of colorimetric detection for the use of lateral flow devices. LAMP master mix was preprepared and was stably stored up to 4 months at -20 degrees C. Sugarcane leaf sheaths worked well as a substitute to xylem sap as template, although the sensitivity was lower. These modifications allow the assay to be conducted without contamination concerns and reduction in set up time, making it ideal for near-field diagnosis. PMID- 28875503 TI - Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. AB - This review focuses on the classification, diagnosis and natural history of congenital neutropenia (CN). CN encompasses a number of genetic disorders with chronic neutropenia and, for some, affecting other organ systems, such as the pancreas, central nervous system, heart, bone and skin. To date, 24 distinct genes have been associated with CN. The number of genes involved makes gene screening difficult. This can be solved by next-generation sequencing (NGS) of targeted gene panels. One of the major complications of CN is spontaneous leukaemia, which is preceded by clonal somatic evolution, and can be screened by a targeted NGS panel focused on somatic events. PMID- 28875501 TI - The protein kinase C super-family member PKN is regulated by mTOR and influences differentiation during prostate cancer progression. AB - BACKGROUND: Phosphoinositide-3 (PI-3) kinase signaling has a pervasive role in cancer. One of the key effectors of PI-3 kinase signaling is AKT, a kinase that promotes growth and survival in a variety of cancers. Genetically engineered mouse models of prostate cancer have shown that AKT signaling is sufficient to induce prostatic epithelial neoplasia (PIN), but insufficient for progression to adenocarcinoma. This contrasts with the phenotype of mice with prostate-specific deletion of Pten, where excessive PI-3 kinase signaling induces both PIN and locally invasive carcinoma. We reasoned that additional PI-3 kinase effector kinases promote prostate cancer progression via activities that provide biological complementarity to AKT. We focused on the PKN kinase family members, which undergo activation in response to PI-3 kinase signaling, show expression changes in prostate cancer, and contribute to cell motility pathways in cancer cells. METHODS: PKN kinase activity was measured by incorporation of 32 P into protein substrates. Phosphorylation of the turn-motif (TM) in PKN proteins by mTOR was analyzed using the TORC2-specific inhibitor torin and a PKN1 phospho-TM specific antibody. Amino acid substitutions in the TM of PKN were engineered and assayed for effects on kinase activity. Cell motility-related functions and PKN localization was analyzed by depletion approaches and immunofluorescence microscopy, respectively. The contribution of PKN proteins to prostate tumorigenesis was characterized in several mouse models that express PKN transgenes. The requirement for PKN activity in prostate cancer initiated by loss of phosphatase and tensin homolog deleted on chromosome 10 (Pten), and the potential redundancy between PKN isoforms, was analyzed by prostate-specific deletion of Pkn1, Pkn2, and Pten. RESULTS AND CONCLUSIONS: PKN1 and PKN2 contribute to motility pathways in human prostate cancer cells. PKN1 and PKN2 kinase activity is regulated by TORC2-dependent phosphorylation of the TM, which together with published data indicates that PKN proteins receive multiple PI-3 kinase-dependent inputs. Transgenic expression of active AKT and PKN1 is not sufficient for progression beyond PIN. Moreover, Pkn1 is not required for tumorigenesis initiated by loss of Pten. Triple knockout of Pten, Pkn1, and Pkn2 in mouse prostate results in squamous cell carcinoma, an uncommon but therapy resistant form of prostate cancer. PMID- 28875504 TI - Zenker's diverticulum: Submucosal tunneling endoscopic septum division (Z-POEM). PMID- 28875506 TI - Medications Recommended for Secondary Prevention After First Acute Coronary Syndrome: Effectiveness of Treatment Combinations in a Real-Life Setting. AB - Long-term effectiveness of evidence-based cardiovascular medications (EBCMs) indicated after acute coronary syndrome (ACS) needs to be assessed considering the combination effects for these drugs recommended in association. Using a nationwide database, we conducted a cohort study to evaluate the effectiveness of all possible incomplete EBCMs-based combinations as compared to that associating the four recommended EBCMs over up to 5 years of follow-up. Among the 31,668 patients included, 22.9% had ACS recurrence or died during follow-up. The risks associated with the use of 3-EBCM based combinations were 1.46 (95% confidence interval: 1.33-1.60) for the combinations without statins, 1.30 (1.17-1.43) for the combinations without angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 1.11 (0.98-1.25) for the combinations without antiplatelet agents, and 0.99 (0.89-1.10) for the combination without beta-blockers. These findings question the interest of maintaining long-term treatment with beta blockers in addition to the other EBCMs for post-ACS secondary prevention. PMID- 28875505 TI - ATLANTIC BATS: a data set of bat communities from the Atlantic Forests of South America. AB - Bats are the second most diverse mammal order and they provide vital ecosystem functions (e.g., pollination, seed dispersal, and nutrient flux in caves) and services (e.g., crop pest suppression). Bats are also important vectors of infectious diseases, harboring more than 100 different virus types. In the present study, we compiled information on bat communities from the Atlantic Forests of South America, a species-rich biome that is highly threatened by habitat loss and fragmentation. The ATLANTIC BATS data set comprises 135 quantitative studies carried out in 205 sites, which cover most vegetation types of the tropical and subtropical Atlantic Forest: dense ombrophilous forest, mixed ombrophilous forest, semideciduous forest, deciduous forest, savanna, steppe, and open ombrophilous forest. The data set includes information on more than 90,000 captures of 98 bat species of eight families. Species richness averaged 12.1 per site, with a median value of 10 species (ranging from 1 to 53 species). Six species occurred in more than 50% of the communities: Artibeus lituratus, Carollia perspicillata, Sturnira lilium, Artibeus fimbriatus, Glossophaga soricina, and Platyrrhinus lineatus. The number of captures divided by sampling effort, a proxy for abundance, varied from 0.000001 to 0.77 individuals.h-1 .m-2 (0.04 +/- 0.007 individuals.h-1 .m-2 ). Our data set reveals a hyper-dominance of eight species that together that comprise 80% of all captures: Platyrrhinus lineatus (2.3%), Molossus molossus (2.8%), Artibeus obscurus (3.4%), Artibeus planirostris (5.2%), Artibeus fimbriatus (7%), Sturnira lilium (14.5%), Carollia perspicillata (15.6%), and Artibeus lituratus (29.2%). PMID- 28875507 TI - The aetiology of B-cell lymphoid malignancies with a focus on chronic inflammation and infections. AB - B-cell malignancies are a heterogeneous group of lymphoproliferative disorders with different molecular characteristics and clinical course. It is increasingly recognized that the group displays considerable heterogeneity also regarding aetiologic factors. Here, we summarize the latest developments in the aetiology of B-cell lymphoid malignancy subtypes focusing on immune perturbation. Severe immune suppression constitutes a strong and well-established risk factor for aggressive subtypes (e.g. diffuse large B-cell and Burkitt lymphoma), but appears unrelated to risk of common low-grade subtypes (e.g. follicular and mantle cell lymphoma). Inflammation and infections are known co-factors amongst the immunosuppressed; however, immune stimulation is now recognized as a crucial determinant of lymphomagenesis also amongst immunocompetent individuals. This is best exemplified in marginal zone lymphomas where local chronic inflammation and infection in the stomach, ocular adnexa and salivary glands have been directly linked with the development of oligoclonal and monoclonal malignant B-cell populations. Aggressive subtypes (e.g. diffuse large B-cell lymphoma) are increasingly linked with features of systemic immune stimulation including autoimmune/inflammatory disease and subclinical cytokine elevations. Lifestyle factors (e.g. high body mass index, cigarette smoking) are associated with risk of diffuse large B-cell and follicular lymphoma, respectively, possibly mediated through inflammation. Recent genome-wide association studies further underline the importance of immune function by linking several subtypes to variations in the human leucocyte antigen (HLA) class genes. In the future, improved knowledge of mechanistic pathways of inflammation/infections in lymphoma development may translate to active measures of prevention or treatment, as is already the case for some low-grade lymphoma subtypes. PMID- 28875508 TI - Evolution of HIV/AIDS response in Brazil: Policy innovations and challenges in the fourth decade of the epidemic. AB - Brazil was the first low- and middle-income country to provide universal treatment access to people living with the acquired immunodeficiency syndrome (AIDS), becoming a widely acclaimed model for best practice to managing this epidemic. However, we know little about important challenges to the key pillars of Brazil's response. This article discusses how the evolution of the country's health system institutions and international advancements in AIDS treatment and prevention affected the national response. Decentralization of health system resources and policy making brought fresh challenges to the centralized governance of the national AIDS program and to civil society, weakening their coordination and advocacy capacity. Regardless, AIDS treatment and prevention strategies in Brazil remain aligned with the current international protocols, but unfortunately have been restricted in some geographic areas and/or populations. PMID- 28875509 TI - A Newly Designed Composite Gel Polymer Electrolyte Based on Poly(Vinylidene Fluoride-Hexafluoropropylene) (PVDF-HFP) for Enhanced Solid-State Lithium-Sulfur Batteries. AB - Developing high-performance solid-state electrolytes is crucial for the innovation of next-generation lithium-sulfur batteries. Herein, a facile method for preparation of a novel gel polymer electrolyte (GPE) based on poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP) is reported. Furthermore, Li1.5 Al0.5 Ti1.5 (PO4 )3 (LATP) nanoparticles as the active fillers are uniformly embedded into the GPE to form the final PVDF-HFP/LATP composite gel polymer electrolyte (CPE). Impressively, the obtained CPE demonstrates a high lithium ion transference number of 0.51 and improved electrochemical stability as compared to commercial liquid electrolyte. In addition, the assembled solid-sate Li-S battery with the composite gel polymer electrolyte membrane presents a high initial capacity of 918 mAh g-1 at 0.05 C, and better cycle performance than the counterparts with liquid electrolyte. Our designed PVDF-HFP/LATP composite can be a promising electrolyte for next-generation solid-state batteries with high cycling stability. PMID- 28875510 TI - Copper-Catalyzed Synthesis and Applications of Yndiamides. AB - The first synthetic route to yndiamides, a novel class of double aza-substituted alkyne, has been established by the copper(I)-catalyzed cross-coupling of 1,1 dibromoenamides with nitrogen nucleophiles. The utility of these compounds is demonstrated in a range of transition-metal-catalyzed and acid-catalyzed transformations to afford a wide variety of 1,2-diamide functionalized products. PMID- 28875511 TI - Development and evaluation of a manual for extended brief intervention for alcohol misuse for adults with mild to moderate intellectual disabilities living in the community: The EBI-LD study manual. AB - BACKGROUND: Extended brief interventions for alcohol misuse are effective in the general population. The process of manualising the first ever such intervention for people with mild to moderate intellectual disabilities in the UK is the focus of this study. METHODS: The manual was an adaptation of existing manuals based on Motivational Enhancement and Cognitive Behaviour Therapy and was used in a feasibility randomized controlled trial, the EBI-LD study. The sessions were recorded and scored using an adapted version of the Yale Adherence and Competence Scale (YACS II). Feedback was provided by therapists. The trial is closed. Registered: isrctn.com; ISRCTN58783633. RESULTS: The quality of the sessions provided was rated as good. Therapists were able to cover all topics within each session. Main challenges included session duration and homework task completion. CONCLUSIONS: We recommend the duration of the sessions to be extended to 40 min to accommodate carers in the session and to enhance their support in homework task completion. PMID- 28875512 TI - Modeling conditional dependence among multiple diagnostic tests. AB - When multiple imperfect dichotomous diagnostic tests are applied to an individual, it is possible that some or all of their results remain dependent even after conditioning on the true disease status. The estimates could be biased if this conditional dependence is ignored when using the test results to infer about the prevalence of a disease or the accuracies of the diagnostic tests. However, statistical methods correcting for this bias by modelling higher-order conditional dependence terms between multiple diagnostic tests are not well addressed in the literature. This paper extends a Bayesian fixed effects model for 2 diagnostic tests with pairwise correlation to cases with 3 or more diagnostic tests with higher order correlations. Simulation results show that the proposed fixed effects model works well both in the case when the tests are highly correlated and in the case when the tests are truly conditionally independent, provided adequate external information is available in the form of fixed constraints or prior distributions. A data set on the diagnosis of childhood pulmonary tuberculosis is used to illustrate the proposed model. PMID- 28875513 TI - The Nutrition Care Process Terminology: Changes in perceptions, attitudes, knowledge and implementation amongst Australian dietitians after three years. AB - AIM: Assessing changes in dietetic perceptions, attitudes and knowledge regarding the Nutrition Care Process Terminology (NCPT) is important to determine implementation effectiveness. This study aimed to investigate changes in the perceptions and attitudes of Australian dietitians over a three-year period, identify changes in benefits and barriers to support successful NCPT implementation and determine future directions for NCPT progression. METHODS: An online survey was performed in 2011 and repeated in 2014 by recruiting members of the Dietitians Association of Australia (DAA) through an email link. The survey assessed familiarity, knowledge, attitudes, benefits, barriers, concerns and use of educational enablers around the NCPT. RESULTS: The survey was completed by 218 respondents in 2011 and 205 respondents in 2014. Survey respondents from both years were representative of overall DAA membership. Respondent knowledge of NCPT increased significantly over the three-years, as did confidence, preparation, access to support and training and NCPT usage. Respondent's identification of benefits to implementation increased whilst barriers reduced. Attitudes regarding NCPT implementation were conflicting. CONCLUSIONS: Over three years, improvements were evident in NCPT knowledge, attitudes and usage. However, not all dietitians saw reason to implement NCPT in their practice, and some attitudes have become less supportive. A collective vision is required to foster positive attitudes towards the transformational professional benefits possible from NCPT. With ongoing uptake of electronic health records, the potential for NCPT to evaluate and justify dietetic interventions is increasing. PMID- 28875514 TI - Cancer screening participation in schizophrenic outpatients and the influence of their functional disability on the screening rate: A cross-sectional study in Japan. AB - AIM: The influence of schizophrenic patients' functional disability on cancer screening participation worldwide is unclear. There are few findings on the disparities in schizophrenic patients' participation in cancer screening programs in Asia. The aim of this study was to investigate the screening rate and the associations between screening and symptom severity/functional disability in patients with schizophrenia. METHODS: This cross-sectional study was conducted in a psychiatric hospital outpatient clinic in Japan. We recruited schizophrenic patients meeting the national program criteria for cancer screening for colorectal, gastric, lung, breast, and cervical cancer (n = 224, 223, 224, 110, and 175, respectively). Receipt of cancer screenings was assessed using a self report questionnaire. Scores on the modified Global Assessment of Functioning (mGAF) were evaluated by participants' primary psychiatrists. RESULTS: Rates of cancer screenings were as follows: 24.1% for colorectal, 21.5% for gastric, 30.8% for lung, 25.5% for breast, and 19.4% for cervical cancer. A multivariable logistic analysis showed that a 1-point increase in severity/disability (100 minus mGAF score) was associated with significantly lower odds ratios (OR) for receipt of cancer screenings, except for breast cancer (OR, 0.95, 95% confidence interval [CI], 0.93-0.98 for colorectal; OR, 0.96, 95%CI, 0.93-0.98 for gastric; OR, 0.95, 95%CI, 0.93-0.97 for lung; OR, 0.97, 95%CI, 0.94-1.00 for breast; and OR, 0.95, 95%CI, 0.92-0.98 for cervical cancer). CONCLUSION: The findings demonstrated low rates of cancer screenings in schizophrenic patients in Japan. Our study suggests the need to encourage attendance at cancer screenings, especially in schizophrenic patients with severe symptoms/functional disability. PMID- 28875515 TI - Osteogenesis for postoperative temporal bone defects using human ear adipose derived stromal cells and tissue engineering: An animal model study. AB - Mastoidectomy, the removal of infected mastoid bones, is a common surgical procedure for the treatment of chronic otitis media. Persistent and recurrent otorrhea and accumulation of keratin debris following open cavity mastoidectomy are still bothersome issues for both patients and otologists. In this study, we used human ear adipose-derived stromal cells (hEASCs) in combination with polycaprolactone (PCL) scaffolds and osteogenic differentiation medium (ODM) to regenerate temporal bone defects. The hEASCs showed stem cell phenotypes, and these characteristics were maintained up to passage 5. Mastoid bulla and cranial bone defects were induced in Sprague-Dawley rats using AgNO3 and burr hole drilling, respectively, and the rats were then divided into five groups: (1) control, (2) hEASCs, (3) hEASCs + ODM, (4) hEASCs + PCL scaffolds, and (5) hEASCs + PCL scaffolds + ODM. Osteogenesis was evaluated by micro-computed tomography and histology. Compared with the control group, the groups transplanted with hEASCs and PCL scaffolds had significantly higher bone formation along the periphery of the mastoid bulla area. Moreover, ODM synergistically enhanced bone formation in mastoid bulla defects. Our results suggest that combining hEASCs with PCL scaffolds represents a promising method for anatomical and functional reconstruction of postoperative temporal bone defects following mastoidectomy. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3493-3501, 2017. PMID- 28875516 TI - An Imide-Based Pentacyclic Building Block for n-Type Organic Semiconductors. AB - A new electron-deficient unit with a fused 5-membered heterocyclic ring was developed by replacing a cyclopenta-1,3-diene from electron-rich donor indacenodithiophene (IDT) with a cyclohepta-4,6-diene-1,3-diimde unit. The imide bridge endows dithienylbenzenebisimide (BBI) with a fixed planar configuration and low energy levels for both the highest occupied molecular orbital (HOMO; 6.24 eV) and the lowest unoccupied molecular orbit (LUMO; -2.57 eV). Organic field-effect transistors (OFETs) based on BBI polymers exhibit electron mobility up to 0.34 cm2 V-1 s-1 , which indicates that the BBI is a promising n-type building block for optoelectronics. PMID- 28875517 TI - Are plants sentient? AB - Feelings in humans are mental states representing groups of physiological functions that usually have defined behavioural purposes. Feelings, being evolutionarily ancient, are thought to be coordinated in the brain stem of animals. One function of the brain is to prioritise between competing mental states and, thus, groups of physiological functions and in turn behaviour. Plants use groups of coordinated physiological activities to deal with defined environmental situations but currently have no known mental state to prioritise any order of response. Plants do have a nervous system based on action potentials transmitted along phloem conduits but which in addition, through anastomoses and other cross-links, forms a complex network. The emergent potential for this excitable network to form a mental state is unknown, but it might be used to distinguish between different and even contradictory signals to the individual plant and thus determine a priority of response. This plant nervous system stretches throughout the whole plant providing the potential for assessment in all parts and commensurate with its self-organising, phenotypically plastic behaviour. Plasticity may, in turn, depend heavily on the instructive capabilities of local bioelectric fields enabling both a degree of behavioural independence but influenced by the condition of the whole plant. PMID- 28875518 TI - Quality-of-life evaluation in chronic wounds: comparative analysis of three disease-specific questionnaires. AB - The study directly compared the feasibility and performance of three instruments measuring health-related quality of life (HRQoL) in chronic ulcers: the Freiburg Life Quality Assessment for wounds (FLQA-w), the Cardiff Wound Impact Schedule (CWIS) and the Wurzburg Wound Score (WWS). The questionnaires were evaluated in a randomly assigned order in a longitudinal observational study of leg ulcer patients. Psychometric properties (internal consistency, responsiveness and construct validity) were analysed. Patient acceptance was recorded. Analysis of n = 154 patients revealed good internal consistency (Cronbach's alpha >= 0.85) for all instruments. There were minor floor effects in all questionnaires (<1%) and some ceiling effects in the CWIS. Construct validity was satisfactory, for example, correlation with EuroQoL-5D was r = 0.70 in the FLQA-w, r = 0.47/0.67/0.68 in the CWIS dimensions and r = 0.60 in the WWS. The proportion of missing values was higher in the CWIS, and overall patient acceptance was highest in the FLQA-w for wounds (54% best preferences) and lowest in the WWS (14%). In conclusion, the FLQA-w, the CWIS and the WWS are reliable, sensitive and valid instruments for the assessment of HRQoL in leg ulcers. However, they show differences in clinical feasibility and patient acceptance. PMID- 28875520 TI - Concise Total Synthesis of (-)-Affinisine Oxindole, (+)-Isoalstonisine, (+) Alstofoline, (-)-Macrogentine, (+)-Na -Demethylalstonisine, (-)-Alstonoxine A, and (+)-Alstonisine. AB - A highly enantio- and diastereoselective strategy to access any member of the sarpagine/macroline family of oxindole alkaloids via internal asymmetric induction was developed from readily available d-(+)-tryptophan. At the center of this approach was the diastereospecific generation of the spiro[pyrrolidine-3,3' oxindole] moiety at an early stage via a tert-butyl hypochlorite-promoted oxidative rearrangement of a chiral tetrahydro-beta-carboline derivative. This key branching point determined the spatial configuration at the C-7 spiro center to be entirely 7R or 7S. Other key stereospecific processes were the asymmetric Pictet-Spengler reaction and Dieckmann cyclization, which were scalable to the 600 and 150 gram levels, respectively. Execution of this approach resulted in first enantiospecific total synthesis of (+)-isoalstonisine and (-)-macrogentine from the chitosenine series (7R), as well as (+)-alstonisine, (+)-alstofoline, ( )-alstonoxine A and (+)-Na -demethylalstonisine from the alstonisine series (7S). PMID- 28875521 TI - Chronic myocarditis with a long clinical course: Report of an autopsy case of probable autoimmune myocarditis. AB - The patient was a 54-year-old woman, who died of chronic cardiac insufficiency after a clinical course of 2 years and 4 months. She had complained of myalgia, muscle weakness, and blepharoptosis before the onset of cardiac symptoms, but there was no evidence of myasthenia gravis or collagen-vascular diseases. At autopsy, the heart (280 g) showed marked dilatation of the four chambers and thinning of the ventricular walls. Diffuse and intense lymphocytic infiltration and extensive fibrosis were noted, with the latter being accentuated in the subendocardial and subepicardial zones. Small foci of myocardial necrosis were scattered and a small number of multinucleated giant cells were found, but epithelioid cell granulomas, Aschoff's nodules, and viral inclusion bodies were not observed. Some cardiomyocytes showed the aberrant expression of the HLA-DR antigen. No viral genomes were detected in myocardial tissue using a multivirus real-time polymerase chain reaction. The protracted clinical course, presence of active inflammatory changes at autopsy, expression of the HLA-DR antigen on cardiomyocytes, and absence of viral genomes in myocardial tissue suggest that autoimmune mechanisms played an important role in the pathogenesis and persistence of myocarditis in this patient. PMID- 28875519 TI - Precision Dosing: Public Health Need, Proposed Framework, and Anticipated Impact. PMID- 28875522 TI - Developments in the synthesis of the antiplatelet and antithrombotic drug (S) clopidogrel. AB - S-(+)-Methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H) yl)acetate, also known as (S)-clopidogrel, is marketed under the trade names Plavix and Iscover. It is a potent thienopyridine-class of antithrombotic and antiplatelet drug (antiaggregant). Among the two available stereoisomers of clopidogrel, for pharmaceutical activities only the S-enantiomer is applicable, as no antithrombotic activity is observed in the R-enantiomer and causes political upheavals and social turmoil in animal experiments. Worldwide sales of Plavix amounted to $6.4 billion yearly, which ranks second. Attributed to the increased demand of (S)-clopidogrel drug, it provoked the synthetic community to devise facile synthetic approaches. This review aims to summarize the synthetic methods of (S)-clopidogrel drug reported in the literature. The present review discusses the pros and cons of each synthetic methodology, which would be beneficial to the scientific community for further developments in the synthetic methodologies for (S)-clopidogrel. In addition, the compilation approach of literature-reported synthetic strategies of (S)-clopidogrel in one platform is advantageous, supportive, and crucial for the synthetic community to elect the best synthetic methodology of (S)-clopidogrel and to create new synthesis ideas. PMID- 28875524 TI - Iterative hard thresholding for model selection in genome-wide association studies. AB - : A genome-wide association study (GWAS) correlates marker and trait variation in a study sample. Each subject is genotyped at a multitude of SNPs (single nucleotide polymorphisms) spanning the genome. Here, we assume that subjects are randomly collected unrelateds and that trait values are normally distributed or can be transformed to normality. Over the past decade, geneticists have been remarkably successful in applying GWAS analysis to hundreds of traits. The massive amount of data produced in these studies present unique computational challenges. Penalized regression with the l1 penalty (LASSO) or minimax concave penalty (MCP) penalties is capable of selecting a handful of associated SNPs from millions of potential SNPs. Unfortunately, model selection can be corrupted by false positives and false negatives, obscuring the genetic underpinning of a trait. Here, we compare LASSO and MCP penalized regression to iterative hard thresholding (IHT). On GWAS regression data, IHT is better at model selection and comparable in speed to both methods of penalized regression. This conclusion holds for both simulated and real GWAS data. IHT fosters parallelization and scales well in problems with large numbers of causal markers. Our parallel implementation of IHT accommodates SNP genotype compression and exploits multiple CPU cores and graphics processing units (GPUs). This allows statistical geneticists to leverage commodity desktop computers in GWAS analysis and to avoid supercomputing. AVAILABILITY: Source code is freely available at https://github.com/klkeys/IHT.jl. PMID- 28875525 TI - Efficacy of ketogenic diet for infantile spasms: A systematic review. AB - The aim of this systematic review was to collect and analyze all the RCTs and observational studies investigating the efficacy of ketogenic diet (KD) in infantile spasms (IS) patients after a 1- to 6-month follow-up period, in terms of decrease in seizure frequency of >50% or a seizure-free interval. Moreover, the potential effect of gender, IS etiology, age at onset of IS, and age at start of KD have been investigated. Finally, we evaluated the seizure-free rate at 12 and 24 months of follow-up. In June 2016, a computer search was performed on MedLine (PubMed), EMBASE, and the Cochrane Library. Only, English language studies conducted after 1980 and those reporting in detail the variation in seizure frequency have been selected. Thirteen observational studies (341 patients) were included in the final analysis. A median rate of 64.7% of patients experienced a spasm reduction >50% (IQR: 38.94%). The median spasm-free rate was 34.61% (IQR: 37.94%). IS of unknown etiology seemed to have an increased probability of achieving freedom from seizures (RR: 1.72, 95%CI: 1.18-2.53). Long time follow-up data revealed a median seizure-free rate of 9.54% (IQR: 18.23%). Although the literature is still lacking in high-quality studies, which could provide a stronger level evidence, our findings suggest a potential benefit of KD for drug-resistant IS patients. PMID- 28875526 TI - Towards physiologically meaningful water-use efficiency estimates from eddy covariance data. AB - Intrinsic water-use efficiency (iWUE) characterizes the physiological control on the simultaneous exchange of water and carbon dioxide in terrestrial ecosystems. Knowledge of iWUE is commonly gained from leaf-level gas exchange measurements, which are inevitably restricted in their spatial and temporal coverage. Flux measurements based on the eddy covariance (EC) technique can overcome these limitations, as they provide continuous and long-term records of carbon and water fluxes at the ecosystem scale. However, vegetation gas exchange parameters derived from EC data are subject to scale-dependent and method-specific uncertainties that compromise their ecophysiological interpretation as well as their comparability among ecosystems and across spatial scales. Here, we use estimates of canopy conductance and gross primary productivity (GPP) derived from EC data to calculate a measure of iWUE (G1 , "stomatal slope") at the ecosystem level at six sites comprising tropical, Mediterranean, temperate, and boreal forests. We assess the following six mechanisms potentially causing discrepancies between leaf and ecosystem-level estimates of G1 : (i) non-transpirational water fluxes; (ii) aerodynamic conductance; (iii) meteorological deviations between measurement height and canopy surface; (iv) energy balance non-closure; (v) uncertainties in net ecosystem exchange partitioning; and (vi) physiological within-canopy gradients. Our results demonstrate that an unclosed energy balance caused the largest uncertainties, in particular if it was associated with erroneous latent heat flux estimates. The effect of aerodynamic conductance on G1 was sufficiently captured with a simple representation. G1 was found to be less sensitive to meteorological deviations between canopy surface and measurement height and, given that data are appropriately filtered, to non-transpirational water fluxes. Uncertainties in the derived GPP and physiological within-canopy gradients and their implications for parameter estimates at leaf and ecosystem level are discussed. Our results highlight the importance of adequately considering the sources of uncertainty outlined here when EC-derived water-use efficiency is interpreted in an ecophysiological context. PMID- 28875523 TI - Alcohol consumption and bladder cancer risk with or without the flushing response: The Japan Public Health Center-based Prospective Study. AB - The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95,915 subjects (45,649 men and 50,266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70 1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450, >450 g/week of pure ethanol compared with non-drinkers and occasional drinkers, respectively, indicating an inverted U shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (p for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted. PMID- 28875527 TI - Management of an uncomplicated crown fracture by reattaching the fractured fragment-Case report. AB - Coronal fractures of the anterior teeth are common sequelae of traumatic dental injuries. Reattachment of fractured tooth fragments using dental adhesive techniques offers some advantages, including restoration of the function, esthetics, shape, texture, and brightness of the surface. The present report describes a clinical case of reattachment with a 4-year clinical and radiographic follow up in a permanent maxillary central incisor with an uncomplicated crown fracture. Fragment reattachment is a conservative procedure, preserving esthetics and functionality, and it can provide an immediate positive emotional response from the patient. PMID- 28875528 TI - Transplantation of artificial human lymphatic vascular tissues fabricated using a cell-accumulation technique and their engraftment in mouse tissue with vascular remodelling. AB - Transplantation of engineered tissues with microvascular structure is advancing towards therapeutic application to improve the flow of blood and/or lymphatic fluids. In lymphatic disorders, transplantation of tissue-engineered lymphatic grafts can be an ideal treatment for draining excessive lymphatic fluid. In this study, we examined the transplantation of 3-dimensional artificial human lymphatic network tissue (AHLT) fabricated by the cell accumulation technique into the subcutaneous tissue and fascia of mice. At 2 weeks after transplantation, the AHLT showed engraftment of artificial lymphatic vessels immunopositive for human CD31 and human podoplanin. Notably, we also observed the generation of blood vessel-like structure comprising endothelial cells immunopositive for human CD34 and mural-like cells immunopositive for human CD90 and alphaSMA, which were considered as myofibroblasts. In the fabrication of AHLT in vitro, the sporadic emergence of human CD34-positive/Prox-1-negative sites was observed, followed by the formation of blood vessel-like structure in the graft within 7 days after transplantation. The fine structure of engrafted AHLT observed by transmission electron microscopy showed that the engrafted artificial lymphatic vessels possess the specific structures of native lymphatic capillaries such as loose interendothelial connections and anchoring filaments. In contrast, blood vessel-like structure showed tight interendothelial connections, thick basement membranes, and layers of mural-like cells, which resemble small blood vessels. These results suggested the remodelling of artificial lymphatic network to form blood vessel-like structure associated with mural-like cells along with AHLT fabrication and engraftment. PMID- 28875529 TI - Single-incision robotic cholecystectomy is associated with a high rate of trocar site infection. AB - BACKGROUND: Single-incision robotic cholecystectomy has been developed to decrease post-operative pain and improve cosmetic results. METHODS: Thirty-seven patients underwent single-site robotic cholecystectomy between 2014 and 2015. Postoperative outcomes and costs were compared to reported outcomes for laparoscopic cholecystectomy using the configuration of suprapubic trocars. RESULTS: The median age was comparable between the two groups (46 years in the robotic group vs. 47 years in the laparoscopic group). The operative time was longer in the robotic group (132 minutes) than in the laparoscopic group (53 minutes). The average length of stay was 1 day in the robotic group and 1.7 days in the laparoscopic group. Costs were higher in the robotic group (2229.46 ?) than in the laparoscopic group (1141 ?). In the robotic group, the trocar-site infection rate was 13.5%. CONCLUSION: The robotic approach does not seem to offer additional benefit in terms of surgical outcomes. PMID- 28875530 TI - The Revised Basel Statements on the Future of Hospital Pharmacy: What Do They Mean for Saudi Arabia? AB - OBJECTIVES: To describe the current hospital pharmacy practice in Saudi Arabia according to the revised Basel statements. METHODS: A review of the available data based on published literature in the subject area was carried out. KEY FINDINGS: The original Basel Statements were developed at the 2008 Global Conference on the Future of Hospital Pharmacy in Basel, Switzerland. Representatives from 98 countries, including Saudi Arabia, attended this conference. The revision of the Basel statements simplified and merged many of the original Basel statements. In addition to making the Basel statements more concise, the revision added new statements to reflect global trends and the expanded responsibilities of hospital pharmacists. CONCLUSION: The release of the Basel statements represents an important opportunity to bring Saudi Arabian practices into complete concurrence with international standards and to identify areas that should be prioritized. PMID- 28875531 TI - Pathogen reduction of whole blood: utility and feasibility. AB - OBJECTIVES: To collect information on pathogen reduction applied to whole blood. BACKGROUND: Pathogen reduction (PR) of blood components has been developed over the past two decades, and pathogen-reduced fresh-frozen plasma and platelet concentrates are currently in clinical use. High cost and incomplete coverage of components make PR out of reach for low- and middle-income countries (LMIC). However, should PR become applicable to whole blood (WB), the main product transfused in sub-Saharan Africa, and be compatible with the preparation of clinically suitable components, cost would be minimised, and a range of safety measures in place at high cost in developed areas would become redundant. METHODS: All articles called with "pathogen reduction", "pathogen inactivation" and "whole blood" were retrieved from Medline. References in articles were utilised. RESULTS: One such PR technology (PRT) applied to WB has been developed and has shown efficacious against viruses, bacteria and parasites in vitro; and has been able to inactivate nucleated blood cells whilst retaining the ability to prepare components with acceptable characteristics. The efficacy of this WB PRT has been demonstrated in vivo using the inactivation of Plasmodium falciparum as a model and showing a high degree of correlation between in vitro and in vivo data. Obtaining further evidence of efficacy on other suitable targets is warranted. Shortening of the process, which is currently around 50 min, or increasing the number of units simultaneously processed would be necessary to make PRT WB conducive to LMIC blood services' needs. CONCLUSIONS: Even if not 100% effective against agents that are present in high pathogen load titres, WB PRT could massively impact blood safety in LMIC by providing safer products at an affordable cost. PMID- 28875533 TI - Expanding Anti-Stokes Shifting in Triplet-Triplet Annihilation Upconversion for In Vivo Anticancer Prodrug Activation. AB - A strategy to expand anti-Stokes shifting from the far-red to deep-blue region in metal-free triplet-triplet annihilation upconversion (TTA-UC) is presented. The method is demonstrated by in vivo titration of the photorelease of an anticancer prodrug. This new TTA system has robust brightness and the longest anti-Stokes shift of any reported TTA system. TTA core-shell-structured prodrug delivery capsules that benefit from these properties were developed; they can operate with low-power density far-red light-emitting diode light. These capsules contain mesoporous silica nanoparticles preloaded with TTA molecules as the core, and amphiphilic polymers encapsulating anticancer prodrug molecules as the shell. When stimulated by far-red light, the intense TTA upconversion blue emission in the system activates the anticancer prodrug molecules and shows effective tumor growth inhibition in vivo. This work paves the way to new organic TTA upconversion techniques that are applicable to in vivo photocontrollable drug release and other biophotonic applications. PMID- 28875532 TI - Axin2-mTurquoise2: A novel reporter mouse model for the detection of canonical Wnt signalling. AB - The canonical Wnt signalling pathway has been implicated in organogenesis and self-renewal of essentially all stem cell systems. In vivo reporter systems are crucial to assess the role of Wnt signalling in the biology and pathology of stem cell systems. We set out to develop a Turquoise (TQ) fluorescent protein based Wnt reporter. We used a CRISPR-Cas9 approach to insert a TQ fluorescent protein encoding gene into the general Wnt target gene Axin2, thereby establishing a Wnt reporter mouse similar to previously generated Wnt reporter mice but with the mTurquoise2 gene instead of E. coli-beta-galactosidase (LacZ). The use of mTurquoise2 is especially important in organ systems in which cells need to a be alive for further experimentation such as in vitro activation or transplantation studies. We here report successful generation of Axin2-TQ mice and show that cells from these mice faithfully respond to Wnt signals. High Wnt signals were detected in the intestinal crypts, a classical Wnt signalling site in vivo, and by flow cytometry in the thymus. These mice are an improved tool to further elucidate the role of Wnt signalling in vivo. PMID- 28875534 TI - Postmortem DTI reveals altered hippocampal connectivity in wild sea lions diagnosed with chronic toxicosis from algal exposure. AB - Hundreds of wild California sea lions (Zalophus californianus) exposed to the algal neurotoxin domoic acid are treated in veterinary rehabilitation centers each year. Common chronic effects of toxic exposure in these animals are seizures and hippocampal damage, and they have been proposed as a natural animal model for human epilepsy. Humans with medial temporal lobe epilepsy present with white matter pathology in a number of tracts including the fornix and increased structural connectivity between the hippocampus and thalamus. However, there are no prior data on structural connectivity in sea lion brains, with or without neuropathology. In the present study, we used a novel diffusion tensor imaging technique to obtain high resolution (1mm isotropic) white matter maps in brains obtained opportunistically postmortem from wild sea lions with and without chronic clinical signs of toxic exposure to domoic acid. All animals had received a full veterinary workup and diagnosis prior to euthanasia. We measured hippocampal atrophy morphometrically, and all brains were examined histopathologically. In animals diagnosed with chronic domoic acid toxicosis, the fornix showed signs of altered diffusion properties indicative of pathology; these brains also had increased structural connectivity between hippocampus and thalamus in comparison to brains from animals with no neurological signs. These findings establish further parallels between human medial temporal lobe epilepsy and a naturally occurring condition in wild sea lions and simultaneously advance general knowledge of the deleterious effects of an increasingly common natural toxin. PMID- 28875535 TI - Disrupted intrinsic and remote functional connectivity in heterotopia-related epilepsy. AB - OBJECTIVES: Several neuroimaging studies have examined neural interactions in patients with periventricular nodular heterotopia (PNH). However, features of the underlying functional network remain poorly understood. In this study, we examined alterations in the local (regional) and remote (interregional) cerebral networks in this disorder. METHODS: Twenty-eight subjects all having suffered from PNH with epilepsy, as well as 28 age- and sex- matched healthy controls, were enrolled in this study. Amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) were calculated to detect regional neural function and functional network integration, respectively. RESULTS: Compared with healthy controls, patients with PNH-related epilepsy showed decreased ALFF in the ventromedial prefrontal cortex (vmPFC) and precuneus areas. ALFF values in both areas were negative correlated with epilepsy duration (P < .05, Bonferroni corrected). Furthermore, patients with PNH-related epilepsy had increased remote interregional FC mainly in bilateral prefrontal and parietal cortices, supramarginal gyrus, dorsal cingulate gyrus, and right insula; lower FC was found in posterior brain regions including bilateral parahippocampal gyrus and inferior temporal gyrus. CONCLUSIONS: Focal spontaneous hypofunction, as assessed by ALFF, correlates with epilepsy duration in patients with PNH-related epilepsy. Abnormalities existed both within the default-mode network and then across the whole brain, demonstrating that intrinsic brain dysfunction may be related to specific network interactions. Our findings provide novel understanding of the connectivity-based pathophysiological mechanisms of PNH. PMID- 28875536 TI - Cottrell Scholars: S. Ardo, A. E. Hargrove, N. B. Shustova, Y. Surendranath / TREE Awards: S. M. Cohen, D. S. Ginger / Kolos Medal: W. Thiel / Welch Award: H. P. Steinruck / Sachsischer Verdienstorden: A. Beck-Sickinger, E. Hey-Hawkins, B. Voit. PMID- 28875537 TI - Frequent activity and minimal sedentary time throughout the day: an impractical goal with unproven benefits. PMID- 28875538 TI - A generalized parametric response mapping method for analysis of multi-parametric imaging: A feasibility study with application to glioblastoma. AB - PURPOSE: Parametric response map (PRM) analysis of functional imaging has been shown to be an effective tool for early prediction of cancer treatment outcomes and may also be well-suited toward guiding personalized adaptive radiotherapy (RT) strategies such as sub-volume boosting. However, the PRM method was primarily designed for analysis of longitudinally acquired pairs of single parameter image data. The purpose of this study was to demonstrate the feasibility of a generalized parametric response map analysis framework, which enables analysis of multi-parametric data while maintaining the key advantages of the original PRM method. METHODS: MRI-derived apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps acquired at 1 and 3-months post-RT for 19 patients with high-grade glioma were used to demonstrate the algorithm. Images were first co-registered and then standardized using normal tissue image intensity values. Tumor voxels were then plotted in a four dimensional Cartesian space with coordinate values equal to a voxel's image intensity in each of the image volumes and an origin defined as the multi parametric mean of normal tissue image intensity values. Voxel positions were orthogonally projected onto a line defined by the origin and a pre-determined response vector. The voxels are subsequently classified as positive, negative or nil, according to whether projected positions along the response vector exceeded a threshold distance from the origin. The response vector was selected by identifying the direction in which the standard deviation of tumor image intensity values was maximally different between responding and non-responding patients within a training dataset. Voxel classifications were visualized via familiar three-class response maps and then the fraction of tumor voxels associated with each of the classes was investigated for predictive utility analogous to the original PRM method. Independent PRM and MPRM analyses of the contrast-enhancing lesion (CEL) and a 1 cm shell of surrounding peri-tumoral tissue were performed. Prediction using tumor volume metrics was also investigated. Leave-one-out cross validation (LOOCV) was used in combination with permutation testing to assess preliminary predictive efficacy and estimate statistically robust P-values. The predictive endpoint was overall survival (OS) greater than or equal to the median OS of 18.2 months. RESULTS: Single-parameter PRM and multi-parametric response maps (MPRMs) were generated for each patient and used to predict OS via the LOOCV. Tumor volume metrics (P >= 0.071 +/- 0.01) and single-parameter PRM analyses (P >= 0.170 +/- 0.01) were not found to be predictive of OS within this study. MPRM analysis of the peri-tumoral region but not the CEL was found to be predictive of OS with a classification sensitivity, specificity and accuracy of 80%, 100%, and 89%, respectively (P = 0.001 +/- 0.01). CONCLUSIONS: The feasibility of a generalized MPRM analysis framework was demonstrated with improved prediction of overall survival compared to the original single-parameter method when applied to a glioblastoma dataset. The proposed algorithm takes the spatial heterogeneity in multi-parametric response into consideration and enables visualization. MPRM analysis of peri-tumoral regions was shown to have predictive potential supporting further investigation of a larger glioblastoma dataset. PMID- 28875539 TI - AGO18b negatively regulates determinacy of spikelet meristems on the tassel central spike in maize. AB - The maize tassel represents an indeterminate male inflorescence. The number of primordia that a given inflorescence meristem produces is related to its determinacy, i.e., capacity for continued meristem activity. Transcription factors (TFs) controlling determinacy in tassel axillary meristems are well studied in maize, and small RNAs are known to influence tassel development by repressing targets, including tassel-related TFs. As core components of the RNA inducible silence complex (RISC), Argonaute (AGO) proteins are required for small RNA-mediated repression. Here, we characterized the biological function of AGO18b, a tassel-enriched AGO. The abundance of AGO18b transcripts gradually increased during tassel development from inception to gametogenesis and were enriched in the inflorescence meristem and axillary meristems of the tassel. Repressing AGO18b expression resulted in more spikelets, which contributed to a longer central spike of the tassel. Additionally, the transcripts of several HD ZIP III TFs that were canonical targets of microRNA166 (miR166) accumulated in the AGO18b-repressed lines. We propose that AGO18b is a negative regulator of the determinacy of inflorescence and axillary meristems, and that it acts by interacting with the miR166-HD-ZIP III TF regulatory pathway. PMID- 28875540 TI - The physiological motor patterns produced by neurons in the nucleus retroambiguus in the rat and their modulation by vagal, peripheral chemosensory, and nociceptive stimulation. AB - The nucleus retroambiguus (NRA) is a neuronal cell group in the medullary ventrolateral tegmentum, rostrocaudally between the obex and the first cervical spinal segment. NRA neurons are premotor interneurons with direct projections to the motoneurons of soft palate, pharynx, and larynx in the nucleus ambiguus in the lateral medulla as well as to the motoneurons in the spinal cord innervating diaphragm, abdominal, and pelvic floor muscles and the lumbosacral motoneurons generating sexual posture. These NRA premotor interneurons receive very strong projections from the periaqueductal gray (PAG) in the context of basic survival mechanisms as fight, flight, freezing, sound production, and sexual behavior. In the present study in rat we investigated the physiological motor patterns generated by NRA neurons, as the result of vagal, peripheral chemosensory, and nociceptive stimulation. The results show that the NRA contains phasic respiratory modulated neurons, as well as nonphasic tonically modulated neurons. Stimulation in the various rostrocaudal levels of the NRA generates site-specific laryngeal, respiratory, abdominal, and pelvic floor motor activities. Vagal and peripheral chemosensory stimulation induces both excitatory and inhibitory modulation of phasic NRA-neurons, while peripheral chemosensory and nociceptive stimulation causes excitation and inhibition of nonphasic NRA-neurons. These results are in agreement with the concept that the NRA represents a multifunctional group of neurons involved in the output of the emotional motor system, such as vomiting, vocalization, mating, and changes in respiration. PMID- 28875541 TI - Gene duplication and the evolution of phenotypic diversity in insect societies. AB - Gene duplication is an important evolutionary process thought to facilitate the evolution of phenotypic diversity. We investigated if gene duplication was associated with the evolution of phenotypic differences in a highly social insect, the honeybee Apis mellifera. We hypothesized that the genetic redundancy provided by gene duplication could promote the evolution of social and sexual phenotypes associated with advanced societies. We found a positive correlation between sociality and rate of gene duplications across the Apoidea, indicating that gene duplication may be associated with sociality. We also discovered that genes showing biased expression between A. mellifera alternative phenotypes tended to be found more frequently than expected among duplicated genes than singletons. Moreover, duplicated genes had higher levels of caste-, sex-, behavior-, and tissue-biased expression compared to singletons, as expected if gene duplication facilitated phenotypic differentiation. We also found that duplicated genes were maintained in the A. mellifera genome through the processes of conservation, neofunctionalization, and specialization, but not subfunctionalization. Overall, we conclude that gene duplication may have facilitated the evolution of social and sexual phenotypes, as well as tissue differentiation. Thus this study further supports the idea that gene duplication allows species to evolve an increased range of phenotypic diversity. PMID- 28875542 TI - Analysis on the local structures for 3d1 impurities (Ti3+ and V4+ ) in KTiPO4. AB - Making use of the perturbation formulae for 3d1 ions (Ti3+ and V4+ ) under orthorhombically compressed octahedra, the spin Hamiltonian parameters (g factors: gx , gy , gz and hyperfine structure constants: Ax , Ay , Az ) and local structures of the 3d1 impurity centres C1 , C2 , and C3 in KTiOPO4 crystals are theoretically analyzed in a consistent way. The remarkable local distortions (i.e., the relative axial compression ratios 11.2%, 7.0%, and 5.5% along Z axis and the relative planar bond length variation ratios 15.9%, 7.0%, and 6.0%) are obtained for the [Ti2O6 ]9- cluster on Ti2 site and [VO6 ]8- clusters on Ti1 and Ti2 sites, respectively, in view of the Jahn-Teller effect. The above local orthorhombic distortion parameters in the impurity centres are found to be more significant than the host Ti1 and Ti2 sites in pure KTiOPO4 . The sequences (C1 > C2 > C3 ) of the local orthorhombic distortion parameters rho and tau are in accordance with those of the axial and perpendicular anisotropies Deltag and deltag of g factors, respectively. PMID- 28875543 TI - PDBsum: Structural summaries of PDB entries. AB - PDBsum is a web server providing structural information on the entries in the Protein Data Bank (PDB). The analyses are primarily image-based and include protein secondary structure, protein-ligand and protein-DNA interactions, PROCHECK analyses of structural quality, and many others. The 3D structures can be viewed interactively in RasMol, PyMOL, and a JavaScript viewer called 3Dmol.js. Users can upload their own PDB files and obtain a set of password protected PDBsum analyses for each. The server is freely accessible to all at: http://www.ebi.ac.uk/pdbsum. PMID- 28875544 TI - Identification and characterization of vilazodone metabolites in rats and microsomes by ultrahigh-performance liquid chromatography/quadrupole time-of flight tandem mass spectrometry. AB - RATIONALE: Vilazodone is a selective serotonin reuptake inhibitor (SSRI) used for the treatment of major depressive disorder (MDD). An extensive literature search found few reports on the in vivo and in vitro metabolism of vilazodone. Therefore, we report a comprehensive in vivo and in vitro metabolic identification and structural characterization of vilazodone using ultrahigh performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF/MS/MS) and in silico toxicity study of the metabolites. METHODS: To identify in vivo metabolites of vilazodone, blood, urine and faeces samples were collected at different time intervals starting from 0 h to 48 h after oral administration of vilazodone to Sprague-Dawley rats. The in vitro metabolism study was conducted with human liver microsomes (HLM) and rat liver microsomes (RLM). The samples were prepared using an optimized sample preparation approach involving protein precipitation followed by solid-phase extraction. The metabolites have been identified and characterized by using LC/ESI-MS/MS. RESULTS: A total of 12 metabolites (M1-M12) were identified in in vivo and in vitro matrices and characterized by LC/ESI-MS/MS. The majority of the metabolites were observed in urine, while a few metabolites were present in faeces and plasma. Two metabolites were observed in the in vitro study. A semi-quantitative study based on percentage counts shows that metabolites M11, M6 and M8 were observed in higher amounts in urine, faeces and plasma, respectively. CONCLUSIONS: The structures of all the 12 metabolites were elucidated by using LC/ESI-MS/MS. The study suggests that vilazodone was metabolized via hydroxylation, dihydroxylation, glucuronidation, oxidative deamination, dealkylation, dehydrogenation and dioxidation. All the metabolites were screened for toxicity using an in silico tool. PMID- 28875545 TI - Targeted next-generation sequencing in myelodysplastic syndromes and prognostic interaction between mutations and IPSS-R. AB - A 27-gene panel was used for next-generation sequencing (NGS) in 179 patients (median age 73 years) with primary myelodysplastic syndromes (MDS); risk distribution according to the revised International Prognostic Scoring System (IPSS-R) was 11% very high, 18% high, 17% intermediate, 38% low and 16% very low. At least one mutation/variant was detected in 147 (82%) patients; 23% harbored three or more mutations/variants. The most frequent mutations/variants included ASXL1 (30%), TET2 (25%), SF3B1 (20%), U2AF1 (16%), SRSF2 (16%), TP53 (13%), RUNX1 (11%), and DNMT3A (10%). At a median follow up of 30 months, 148 (83%) deaths and 26 (15%) leukemic transformations were recorded. Multivariable analysis of mutations/variants identified ASXL1 (HR 1.7, 95% CI 1.2-2.5), SETBP1 (HR 4.1, 95% CI 1.6-10.2) and TP53 (HR 2.2, 95% CI 1.3-3.4) as risk factors for overall and SRSF2 (HR 3.9, 95% CI 1.5-10.2), IDH2 (HR 3.7, 95% CI 1.2-11.4), and CSF3R (HR 6.0, 95% CI 1.6-22.6) for leukemia-free survival. Addition of age to the multivariable model did not affect these results while accounting for IPSS-R weakened the significance of TP53 mutations/variants (P = .1). An apparently favorable survival impact of SF3B1 mutations was no longer evident after adjustment for IPSS-R. Approximately 41% and 20% of patients harbored at least one adverse mutation/variant for overall and leukemia-free survival, respectively. Number of mutations/variants did not provide additional prognostic value. The survival impact of adverse mutations was most evident in IPSS-R very low/low risk patients. These observations suggest that targeted NGS might assist in treatment decision-making in lower risk MDS. PMID- 28875546 TI - Limiting Assumptions in the Design of Peptidomimetics. AB - Preclinical Research Limiting the flexibility of organic compounds to enhance their affinity and selectivity for targeting a macromolecule involved in molecular recognition has become a well-developed paradigm in medicinal chemistry. While the role of reverse-turn motifs as peptidomimetics has received the most attention, beta-sheets and helices are also important motifs for protein/protein interactions. The more complicated problem of mimicking the interacting surface of noncontiguous epitopes will not be considered in this review. This limited overview focuses on efforts to use amino acid synthons as secondary-structure mimetics as well as providing examples of peptidomimetic design focused on nonpeptide synthetic chemistry in contrast. In particular, the rationale of optimal design criteria for mimicry and the many naive violations of those criteria made in its pursuit are emphasized. Drug Dev Res 78 : 245-267, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28875547 TI - Immunohistochemical double hit score enhances NCCN-IPI and is associated with detrimental outcomes in refractory or relapsing patients with diffuse large B cell lymphoma. PMID- 28875548 TI - Bacterial contamination of platelet components not detected by BacT/ALERT(r). AB - OBJECTIVES: To investigate the possible causes for false negative results in BacT/ALERT(r) 3D Signature System despite bacterial contamination of platelet units. BACKGROUND: The Northern Ireland Blood Transfusion Service (NIBTS) routinely extends platelet component shelf life to 7 days. Components are sampled and screened for bacterial contamination using an automated microbial detection system, the BacT/ALERT(r) 3D Signature System. We report on three platelet components with confirmed bacterial contamination, which represent false negative BacT/ALERT(r) results and near-miss serious adverse events. METHODS: NIBTS protocols for risk reduction of bacterial contamination of platelet components are described. The methodology for bacterial detection using BacT/ALERT(r) is outlined. Laboratory tests, relevant patient details and relevant follow-up information are analysed. RESULTS: In all three cases, Staphylococcus aureus was isolated from the platelet residue and confirmed on terminal sub-culture using BacT/ALERT(r) . In two cases, S. aureus with similar genetic makeup was isolated from the donors. CONCLUSION: Risk reduction measures for bacterial contamination of platelet components are not always effective. Automated bacterial culture detection does not eliminate the risk of bacterial contamination. Visual inspection of platelet components prior to release, issue and administration remains an important last line of defence. PMID- 28875550 TI - Outcomes of endovascular treatment for acute large-vessel ischaemic stroke more than 6 h after symptom onset. AB - BACKGROUND AND OBJECTIVES: Benefit from endovascular thrombectomy (EVT) for large vessel occlusion (LVO) acute ischaemic stroke (AIS) is well demonstrated. Furthermore, emerging evidence supports efficacy in appropriately selected patients treated beyond current recommendations of 6 h. We evaluated clinical outcomes in patients undergoing late EVT at our institution. METHODS: Retrospective review of prospectively collected clinical database on 355 patients who underwent EVT for LVO AIS. Data collected consisted of patient demographics, radiological findings and outcome details. Outcomes, including 90-day functional status, recanalization, symptomatic intracranial haemorrhage (sICH) and 90-day mortality, for patients undergoing EVT <6 h, >6 h, and >7.3 h, were compared. RESULTS: A total of 355 patients underwent EVT for LVO AIS at our institution during the review period, with 74 (21%) patients treated >=6 h from symptom onset. Successful recanalization was achieved in 285 (80%) patients, with 228 (81%) achieving a mTICI >=2b in the <6 h group, and 57 (77%) in the >6 h group (P = 0.429). Ninety-day functional independence (mRS 0-2) was achieved in 162 (46%) patients, with 130 (46%) achieving a mRS of 0-2 in the <6 h group, and 32 (43%) in the >6 h group (P = 0.643). No significant differences were found in rates of sICH or 90-day mortality. No significant differences in functional independence, recanalization rates, sICH or mortality were identified in patients treated with EVT >7.3 h compared to <7.3 h. CONCLUSIONS: In appropriately selected patients, EVT >6 h was associated with comparable outcomes to those treated <6 h. These data support a physiological approach to patient selection. PMID- 28875549 TI - The contribution of toll-like receptor signaling to the development of liver fibrosis and cancer in hepatocyte-specific TAK1-deleted mice. AB - Hepatocyte death is associated with liver inflammation, fibrosis and hepatocellular carcinoma (HCC). Damaged cells trigger inflammation through activation of Toll-like receptors (TLRs). Although the role of TLR4 in HCC development has been reported, the role of TLR9 in the development of HCC remains elusive. To investigate the role of TLR4 and TLR9 signaling in liver inflammation fibrosis-cancer axis, we took advantage of mice with hepatic deletion of transforming growth factor-beta-activated kinase 1 (Tak1DeltaHep) that develop spontaneous liver injury, inflammation, fibrosis, and HCC, recapitulating the pathology of human HCC. We generated double knockout mice lacking genes of our interest with hepatic Tak1. Tak1DeltaHep mice and Tlr4-deficient Tak1DeltaHep mice had similar serum ALT levels, but Tlr4-deficient Tak1DeltaHep mice exhibited significantly reduced macrophage infiltration, myofibroblast activation and tumor formation. Ablation of TLR9 reduced spontaneous liver injury, inflammation, fibrosis, and cancer development in Tak1DeltaHep mice. In addition, the common adaptor, myeloid differentiation factor 88 (MyD88)-deficient Tak1DeltaHep mice also attenuated liver injury, macrophage recruitment, collagen deposition, and tumor growth compared with control Tak1DeltaHep mice. Genetic ablation of TNF receptor type I (TNFR) in Tak1DeltaHep mice remarkably reduced liver inflammation fibrosis-cancer axis. Surprisingly, disruption of interleukin-1 receptor (IL-1R) had no effect on liver injury and tumor formation, although Il1r-deficient Tak1DeltaHep showed attenuated macrophage infiltration and collagen deposition. In conclusion, TLR4- and TLR9-MyD88 are driving forces of progression to HCC accompanied by liver inflammation and fibrosis in Tak1DeltaHep mice. Importantly, TLR4 and TLR9 downstream TNFR, but not IL-1R signaling is crucial for the development of HCC in Tak1DeltaHep mice. PMID- 28875551 TI - Lung field segmentation using weighted sparse shape composition with robust initialization. AB - PURPOSE: Lung field segmentation for chest radiography is critical to pulmonary disease diagnosis. In this paper, we propose a new deformable model using weighted sparse shape composition with robust initialization to achieve robust and accurate lung field segmentation. METHODS: Our method consists of three steps: initialization, deformation and regularization. The steps of deformation and regularization are iteratively employed until convergence. First, since a deformable model is sensitive to the initial shape, a robust initialization is obtained by using a novel voting strategy, which allows the reliable patches on the image to vote for each landmark of the initial shape. Then, each point of the initial shape independently deforms to the lung boundary under the guidance of the appearance model, which can distinguish lung tissues from nonlung tissues near the boundary. Finally, the deformed shape is regularized by weighted sparse shape composition (SSC) model, which is constrained by both boundary information and the correlations between each point of the deformed shape. RESULTS: Our method has been evaluated on 247 chest radiographs from well-known dataset Japanese Society of Radiological Technology (JSRT) and achieved high overlap scores (0.955 +/- 0.021). CONCLUSIONS: The experimental results show that the proposed deformable segmentation model is more robust and accurate than the traditional appearance and shape model on the JSRT database. Our method also shows higher accuracy than most state-of-the-art methods. PMID- 28875552 TI - Diphenyl-2-pyridylamine-Substituted Porphyrins as Hole-Transporting Materials for Perovskite Solar Cells. AB - The susceptibility of porphyrin derivatives to light-harvesting and charge transport operations have enabled these materials to be employed in solar cell applications. The potential of porphyrin derivatives as hole-transporting materials (HTMs) for perovskite solar cells (PSCs) has recently been demonstrated, but knowledge of the relationships between the porphyrin structure and device performance remains insufficient. In this work, a series of novel zinc porphyrin (PZn) derivatives has been developed and employed as HTMs for low temperature processed PSCs. Key to the design strategy is the incorporation of an electron-deficient pyridine moiety to down-shift the HOMO levels of porphyrin HTMs. The porphyrin HTMs incorporating diphenyl-2-pyridylamine (DPPA) have HOMO levels that are in good agreement with the perovskite active layers, thus facilitating hole transfers from the perovskite to the HTMs. The DPPA-containing zinc porphyrin-based PSCs gave the best performance, with efficiency levels comparable to those of PSCs using spiro-OMeTAD, a current state-of-the-art HTM. In particular, PZn-DPPA-based PSCs show superior air stability, in both doped and undoped forms, to spiro-OMeTAD based devices. PMID- 28875555 TI - Midazolam vs diazepam in prolonged seizures in children: A pharmacoeconomic approach. AB - OBJECTIVE: A previous European cost-utility study reported that use of buccal midazolam in the community setting for the treatment of prolonged seizures (ie, seizures lasting >=5 minutes) in children was associated with an overall ?12 507 399 reduction in annual costs charged to the Italian national health service compared with rectal diazepam. We re-evaluated these findings by applying a more conservative approach. METHODS: The Italian Delphi panel reconvened to apply a more conservative assessment of available reports. A decision-tree model was used, allowing for different treatment pathways depending on whether or not a caregiver administers treatment, an ambulance is required for transport of the child to hospital, and an inpatient stay is required. Direct medical costs were derived from Italian healthcare system data. Estimates of the annual number of prolonged tonic-clonic seizures expected in the country were based on studies which assessed seizure duration using video-EEG recordings and medical records. RESULTS: Although drug acquisition costs were greater for buccal midazolam than for rectal diazepam, the acquisition cost difference was outweighed by larger cost savings resulting mostly from a reduction in hospital admissions. Assuming that 1.2% of tonic and/or clonic seizures occurring in children and adolescents over a 12-month period are prolonged, the annual nationwide reduction in costs from preferring buccal midazolam to rectal diazepam was estimated at ?3 577 587.9. CONCLUSIONS: In this more conservative revised analysis, the high cost of buccal midazolam is still counteracted by greater cost savings compared with rectal diazepam, but cost reduction was less than previously estimated. PMID- 28875554 TI - Histochemical features of aluminum chloride histiocytic reaction and the use of PAS stain to provide a clue to prior subtle biopsy sites. PMID- 28875553 TI - Human brain imaging of nicotinic acetylcholine alpha4beta2* receptors using [18 F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways. AB - Nicotinic acetylcholinergic receptors (nAChR's) have been implicated in several brain disorders, including addiction, Parkinson's disease, Alzheimer's disease and schizophrenia. Here we report in vitro selectivity and functional properties, toxicity in rats, in vivo evaluation in humans, and comparison across species of [18 F]Nifene, a fast acting PET imaging agent for alpha4beta2* nAChRs. Nifene had subnanomolar affinities for halpha2beta2 (0.34 nM), halpha3beta2 (0.80 nM) and halpha4beta2 (0.83 nM) nAChR but weaker (27-219 nM) for hbeta4 nAChR subtypes and 169 nM for halpha7 nAChR. In functional assays, Nifene (100 MUM) exhibited 14% agonist and >50% antagonist characteristics. In 14-day acute toxicity in rats, the maximum tolerated dose (MTD) and the no observed adverse effect level (NOAEL) were estimated to exceed 40 MUg/kg/day (278 MUg/m2 /day). In human PET studies, [18 F]Nifene (185 MBq; <0.10 MUg) was well tolerated with no adverse effects. Distribution volume ratios (DVR) of [18 F]Nifene in white matter thalamic radiations were ~1.6 (anterior) and ~1.5 (superior longitudinal fasciculus). Habenula known to contain alpha3beta2 nAChR exhibited low levels of [18 F]Nifene binding while the red nucleus with alpha2beta2 nAChR had DVR ~1.6-1.7. Females had higher [18 F]Nifene binding in all brain regions, with thalamus showing >15% than males. No significant aging effect was observed in [18 F]Nifene binding over 5 decades. In all species (mice, rats, monkeys, and humans) thalamus showed highest [18 F]Nifene binding with reference region ratios >2 compared to extrathalamic regions. Our findings suggest that [18 F]Nifene PET may be used to study alpha4beta2* nAChRs in various CNS disorders and for translational research. PMID- 28875556 TI - Melatonin alleviates weanling stress in mice: Involvement of intestinal microbiota. AB - Melatonin influences intestinal microbiota and the pathogenesis of various diseases. This study was conducted to explore whether melatonin alleviates weanling stress through intestinal microbiota in a weanling mouse model. Melatonin supplementation in weanling mice (provided in the drinking water at a dosage of 0.2 mg/mL for 2 weeks) significantly improved body weight gain (1.4 +/- 0.03 g/day in melatonin group vs 1.2 +/- 0.06 g/day in control group) and intestinal morphology (ie, villus length, crypt depth, and villus to crypt ratio), but had little effect on the proliferation or apoptosis of intestinal cells, the numbers of Paneth cells and goblet cells, as well as the expression of makers related to enterocytes (sucrase) and endocrine cells (chromogranin A and peptide YY) in the ileum. Melatonin supplementation had little effect on serum levels of amino acids or stress-related parameters (eg, SOD, TNF-alpha, and angiotensin I). 16S rRNA sequencing suggested that melatonin supplementation increased the richness indices of intestinal microbiota (observed species, Chao 1, and ACE) and shaped the composition of intestinal microbiota (eg, increase in the abundance of Lactobacillus [19 +/- 3% in melatonin group vs 6 +/- 2% in control group]), which was demonstrated using an ex vivo proliferation assay and colonic loop proliferation assay. Melatonin supplementation also significantly influenced the metabolism of intestinal microbiota, such as amino acid metabolism and drug metabolism. More importantly, in antibiotic-treated weanling mice and germ-free weanling mice, melatonin failed to affect body weight gain or intestinal morphology. Melatonin significantly reduced (by about 60%) the bacterial load in enterotoxigenic Escherichia coli (ETEC)-infected weanling mice, but had little effect on ETEC load in antibiotic-pretreated animals. In conclusion, melatonin affects body weight gain, intestinal morphology, and intestinal ETEC infection through intestinal microbiota in weanling mice. The findings highlight the importance of intestinal microbiota in mediating the various physiological functions of melatonin in the host. PMID- 28875558 TI - Spinal Cord Stimulator Explantation: Motives for Removal of Surgically Placed Paddle Systems. AB - BACKGROUND: Despite requiring successful trials prior to implantation, spinal cord stimulation (SCS) systems for pain are often later removed. Removing surgically implanted hardware subjects patients to the risks and discomfort of a second surgery, threatens the cost-effectiveness of SCS, and limits the perceived durability of SCS technology for pain problems. OBJECTIVE: To investigate patterns of reasons given among patients who underwent SCS explant surgery (SCSES). METHODS: Retrospective review of SCSES cases over 17 years at Allegheny General Hospital, Pittsburgh, PA. RESULTS: 165 patients underwent SCSES between 1997 and 2014. The top 3 reasons for explantation were inadequate pain control (IPC; 73%), hardware discomfort (22%), and need for magnetic resonance imaging (MRI) (10%). Other less frequent reasons were infection (9%), painful dysesthesias (9%), electrical arcing (4%), resolution of inciting symptoms (4%), weakness (2%), pseudomeningocele (1%) and muscle spasms (1%). CONCLUSION: Inadequate pain control is the most common reason for SCSES. Advances in technology are needed to improve the quality and duration of pain control, as well as to design improvements to make the hardware more comfortable. A significant number of implants are removed due to need for MRI, a fact obviating the need for MRI-compatible systems. Patients considering SCS paddle lead placement should be counseled on the most common reasons for later explantation. PMID- 28875557 TI - Establishing core mental health workforce attributes for the effective mental health care of people with an intellectual disability and co-occurring mental ill health. AB - BACKGROUND: People with intellectual disability experience high rates of mental ill health but multiple barriers to access to quality mental health care. One significant barrier to access is a generalist mental health workforce that lacks capacity, and consensus on what constitutes core workforce competencies in this area. As such, the first step in developing a comprehensive strategy that addresses these barriers is to define the core mental health workforce attributes. METHODS: Thirty-six intellectual disability mental health experts from across Australia participated in a modified online Delphi which aimed to reach consensus on the core attributes required of the generalist mental health workforce. At the end of each Delphi round, descriptive analyses and thematic analyses were completed. RESULTS: Consensus was reached among the participants for 102 attributes across 14 clinical domains. The results highlighted specific attributes in all areas of clinical practice, especially for communication (e.g., utilizes assistive communication technology), assessment (e.g., assess contributing factors to behaviours) and intervention (e.g., uses integrative interventions). CONCLUSION: A comprehensive strategy is required to facilitate the generalist mental health workforce to obtain these attributes. PMID- 28875560 TI - Not changes in membrane fluidity but proteotoxic stress triggers heat shock protein expression in Chlamydomonas reinhardtii. AB - A conserved reaction of all organisms exposed to heat stress is an increased expression of heat shock proteins (HSPs). Several studies have proposed that HSP expression in heat-stressed plant cells is triggered by an increased fluidity of the plasma membrane. Among the main lines of evidence in support of this model are as follows: (a) the degree of membrane lipid saturation was higher in cells grown at elevated temperatures and correlated with a lower amplitude of HSP expression upon a temperature upshift, (b) membrane fluidizers induce HSP expression at physiological temperatures, and (c) membrane rigidifier dimethylsulfoxide dampens heat-induced HSP expression. Here, we tested whether this holds also for Chlamydomonas reinhardtii. We show that heat-induced HSP expression in cells grown at elevated temperatures was reduced because they already contained elevated levels of cytosolic HSP70A/90A that apparently act as negative regulators of heat shock factor 1. We find that membrane rigidifier dimethylsulfoxide impaired translation under heat stress conditions and that membrane fluidizer benzyl alcohol not only induced HSP expression but also caused protein aggregation. These findings support the classical model for the cytosolic unfolded protein response, according to which HSP expression is induced by the accumulation of unfolded proteins. Hence, the membrane fluidity model should be reconsidered. PMID- 28875559 TI - Alginate hydrogels of varied molecular weight distribution enable sustained release of sphingosine-1-phosphate and promote angiogenesis. AB - Alginate hydrogels have been widely validated for controlled release of growth factors and cytokines, but studies exploring sustained release of small hydrophobic lipids are lacking. Sphingosine-1-phosphate (S1P), a bioactive lipid, is an appealing small molecule for inducing blood vessel formation in the context of ischemic conditions. However, there are numerous biological and engineering challenges associated with designing biomaterial systems for controlled release of this lipid. Thus, the objective of this study was to design an injectable, alginate hydrogel formulation that provides controlled release of S1P to establish locally sustained concentration gradients that promote neovascularization. Herein, we varied the molecular weight distribution of alginate polymers within the hydrogel to alter the resultant mechanical properties in a manner that provides control over S1P release. With increasing high molecular weight (HMW) content, the hydrogels exhibited stiffer material properties and released S1P at slower rates. Accordingly, S1P released from hydrogels with 100% HMW content led to enhanced directed migration of outgrowth endothelial cells and blood vessel development assessed using a chick chorioallantoic membrane assay as compared to hydrogels with less HMW content. Overall, this study describes how alginate hydrogels of varied molecular weight may be used to control S1P release kinetics for therapeutic applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 138-146, 2018. PMID- 28875561 TI - Enhanced peripheral nerve regeneration through asymmetrically porous nerve guide conduit with nerve growth factor gradient. AB - In this study, we fabricated a nerve guide conduit (NGC) with nerve growth factor (NGF) gradient along the longitudinal direction by rolling a porous polycaprolactone membrane with NGF concentration gradient. The NGF immobilized on the membrane was continuously released for up to 35 days, and the released amount of the NGF from the membrane gradually increased from the proximal to distal NGF ends, which may allow a neurotrophic factor gradient in the tubular NGC for a sufficient period. From the in vitro cell culture experiment, it was observed that the PC12 cells sense the NGF concentration gradient on the membrane for the cell proliferation and differentiation. From the in vivo animal experiment using a long gap (20 mm) sciatic nerve defect model of rats, the NGC with NGF concentration gradient allowed more rapid nerve regeneration through the NGC than the NGC itself and NGC immobilized with uniformly distributed NGF. The NGC with NGF concentration gradient seems to be a promising strategy for the peripheral nerve regeneration. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 52-64, 2018. PMID- 28875562 TI - A new composite hydrogel combining the biological properties of collagen with the mechanical properties of a supramolecular scaffold for bone tissue engineering. AB - Tissue engineering is a promising alternative to autografts, allografts, or biomaterials to address the treatment of severe and large bone lesions. Classically, tissue engineering products associate a scaffold and cells and are implanted or injected into the lesion. These cells must be embedded in an appropriate biocompatible scaffold, which offers a favourable environment for their survival and differentiation. Here, we designed a composite hydrogel composed of collagen I, an extracellular matrix protein widely used in several therapeutic applications, which we associated with a physical hydrogel generated from a synthetic small amphiphilic molecule. This composite showed improved mechanical and biological characteristics as compared with gels obtained from each separate compound. Incorporation of the physical hydrogel prevented shrinkage of collagen and cell diffusion out of the gel and yielded a gel with a higher elastic modulus than those of gels obtained with each component alone. The composite hydrogel allowed cell adhesion and proliferation in vitro and long-term cell survival in vivo. Moreover, it promoted the differentiation of human adipose derived stem cells in the absence of any osteogenic factors. In vivo, cells embedded in the composite gel and injected subcutaneously in immunodeficient mice produced lamellar osteoid tissue and differentiated into osteoblasts. This study points this new composite hydrogel as a promising scaffold for bone tissue engineering applications. PMID- 28875563 TI - Theoretical and experimental ethics: advocacy for blood donors and beneficiaries of blood transfusions. PMID- 28875564 TI - Fluorescent Organic Nanoaggregates for Selective Recognition of d-(-)-Ribose in Biological Fluids and Oral Supplements. AB - Easily synthesizable, fluorescent, organic nanoaggregates have been utilized, for the first time, in the selective recognition of d-(-)-ribose at pH 5.5 in water. In the self-assembled form, the reactive sites of the monomer units can be properly organized to form an effective "recognition cleft" for ribose (limit of detection ~23 MUm), in which binding mainly occurs through a combination of hydrogen-bonding and CH???pi interactions. The degree of agglomeration shows a profound influence on the extent of ribose sensing. A reduction in the optical response (~1.8-fold) is observed when ribose is allowed to interact with nanoaggregates of smaller dimensions (a decrease in the hydrodynamic diameter from (~212.7+/-10.2) to (~44.6+/-3.5) nm). The protocol is also utilized for the estimation of ribose in human urine samples and oral supplements. Low-cost paper strips have also been developed for rapid, on-site detection of ribose without involving any sophisticated instruments or skilled personnel. PMID- 28875567 TI - Influence of neighboring plants on the dynamics of an ant-acacia protection mutualism. AB - Ant-plant protection symbioses, in which plants provide food and/or shelter for ants in exchange for protection from herbivory, are model systems for understanding the ecology of mutualism. While interactions between ants, host plants, and herbivores have been intensively studied, we know little about how plant-plant interactions influence the dynamics of these mutualisms, despite strong evidence that plants compete for resources, that hosting ants can be costly, and that host-plant provisioning to ants can therefore be constrained by resource availability. We used field experiments in a semiarid Kenyan savanna to examine interactions between the ant-plant Acacia drepanolobium, neighboring grasses, and two species of symbiotic acacia-ants with divergent behaviors: Crematogaster mimosae, an aggressive symbiont that imposes high costs to host trees via consumption of extrafloral nectar, and Tetraponera penzigi, a less protective symbiont that imposes lower costs because it does not consume nectar. We hypothesized that by competing with acacias for resources, neighboring grasses (1) reduce hosts' ability to support costly C. mimosae, while having little or no effect on the ability of hosts to support low-cost T. penzigi, and (2) reduce sapling growth rates irrespective of ant occupant. We factorially manipulated the presence/absence of grasses and the identity of ant occupants on saplings and evaluated effects on colony survivorship and sapling growth rates over 40 weeks. Contrary to prediction, the high-cost/high-reward nectar-dependent mutualist C. mimosae had higher colony-survival rates on saplings with grass neighbors present. Grasses appear to have indirectly facilitated the survival of C. mimosae by reducing water stress on host plants; soils under saplings shaded by grasses had higher moisture content, and these saplings produced more active nectaries than grass-removal saplings. Consistent with prediction, survival of low-cost/low reward T. penzigi did not differ significantly between grass-removal treatments. Saplings occupied by low-cost/low-reward T. penzigi grew 100% more on average than saplings occupied by high-cost/high-reward C. mimosae, demonstrating that mutualist-partner identity strongly and differentially influences demographic rates of young plants. In contrast, contrary to prediction, grass neighbors had no significant net impact on sapling growth rates. Our results suggest that neighboring plants can exert strong and counterintuitive effects on ant-plant protection symbioses, highlighting the need to integrate plant-plant interactions into our understanding of these mutualisms. PMID- 28875566 TI - Structure and development of the subesophageal zone of the Drosophila brain. II. Sensory compartments. AB - The subesophageal zone (SEZ) of the Drosophila brain processes mechanosensory and gustatory sensory input from sensilla located on the head, mouth cavity and trunk. Motor output from the SEZ directly controls the movements involved in feeding behavior. In an accompanying paper (Hartenstein et al., ), we analyzed the systems of fiber tracts and secondary lineages to establish reliable criteria for defining boundaries between the four neuromeres of the SEZ, as well as discrete longitudinal neuropil domains within each SEZ neuromere. Here we use this anatomical framework to systematically map the sensory projections entering the SEZ throughout development. Our findings show continuity between larval and adult sensory neuropils. Gustatory axons from internal and external taste sensilla of the larva and adult form two closely related sensory projections, (a) the anterior central sensory center located deep in the ventromedial neuropil of the tritocerebrum and mandibular neuromere, and (b) the anterior ventral sensory center (AVSC), occupying a superficial layer within the ventromedial tritocerebrum. Additional, presumed mechanosensory terminal axons entering via the labial nerve define the ventromedial sensory center (VMSC) in the maxilla and labium. Mechanosensory afferents of the massive array of chordotonal organs (Johnston's organ) of the adult antenna project into the centrolateral neuropil column of the anterior SEZ, creating the antenno-mechanosensory and motor center (AMMC). Dendritic projections of dye back-filled motor neurons extend throughout a ventral layer of the SEZ, overlapping widely with the AVSC and VMSC. Our findings elucidate fundamental structural aspects of the developing sensory systems in Drosophila. PMID- 28875565 TI - Predicting the risk of cancer after unprovoked venous thromboembolism: external validation of the RIETE score. AB - : Essentials Patients at high-risk of occult cancer may benefit from extensive screening. We validated the RIETE cancer score in the MVTEP study. One in three patients were classified as high-risk, 10% of whom had cancer diagnosed. The RIETE score identifies a subgroup at high risk for cancer. SUMMARY: Background Most recent trials evaluating extensive screening strategies for occult cancer in patients with unprovoked venous thromboembolism have failed, because, among other reasons, of an overall low rate of occult cancer. The RIETE investigators recently proposed a score aimed at identifying a subgroup at higher risk. Methods We retrospectively computed the RIETE score for all patients included in the MVTEP study, which evaluated the accuracy of [18F]fluorodeoxyglucose-positron emission tomography in the screening of occult cancer in patients with unprovoked venous thromboembolism. Performance of the RIETE score was assessed according to the proportion of patients classified in each risk group, and the corresponding rates of cancer diagnosis. Results Among the 386 patients included in the analysis, 136 patients (35.3%) were classified as high risk by the RIETE score. Cancer was diagnosed in 16 (11.8%) of them, whereas it was diagnosed in nine (3.6%) of the 250 patients with a low RIETE cancer score: odds ratio of 3.6 (95% confidence interval [CI] 1.53-8.32). The area under the receiver operating characteristic curve was 0.63 (95% CI 0.51-0.74). Conclusion The RIETE score seems to be able to identify a subgroup at high risk for cancer (10%) in our specific dataset of patients with unprovoked venous thromboembolism. PMID- 28875568 TI - Gene Expression of Matrix Metalloproteinases and their Inhibitors (TIMPs) in Meningiomas of Dogs. AB - BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are considered to be key mediators of tumor invasion and metastasis. MMP-2 and MMP-9 are expressed in meningiomas of dogs, but TIMP expression, and variations of specific MMP/TIMP ratios still are unknown in this tumor. HYPOTHESIS/OBJECTIVES: Expression of MMP/TIMP might increase progressively from grade I to grade III meningioma. Therefore, genetic expression of MMP-2 and MMP-9, and specific TIMP-2 and TIMP-1, respectively, has been investigated in meningiomas of different grades. ANIMALS: Selected formalin-fixed paraffin embedded tissue from 43 meningiomas of dogs was evaluated. METHODS: Genetic material was obtained from pathologic samples and used for quantitative reverse transcriptase real-time polymerase chain reaction (RT-qPCR). RESULTS: MMP-9 was not expressed in all of the tumors, but MMP-2 was significantly more expressed in papillary meningioma. Likewise, the MMP-2/TIMP-2 ratio was numerically higher in papillary meningiomas compared to all grades (>3.5 times) showing a strong bias in favor of metalloproteinase. In the papillary meningioma, TIMP-1 gene expression was significantly higher than in grades I and III. CONCLUSIONS AND CLINICAL IMPORTANCE: MMP-2/TIMP-2 imbalance might contribute to the aggressive biologic behavior of papillary meningiomas in dogs. TIMP-1 expression may play a role independent of MMP-9 expression in neoplastic progression. These results further support that therapeutic and prognostic evaluations of dogs with meningioma need to be addressed according to different histologic patterns as is performed in humans. PMID- 28875569 TI - Group-Based Trajectory Models: Assessing Adherence to Antihypertensive Medication in Older Adults in a Community Pharmacy Setting. AB - Antihypertensive medication nonadherence is highly prevalent, leading to uncontrolled blood pressure. Methods that facilitate the targeting and tailoring of adherence interventions in clinical settings are required. Group-Based Trajectory Modeling (GBTM) is a newer method to evaluate adherence using pharmacy dispensing (refill) data that has advantages over traditional refill adherence metrics (e.g. Proportion of Days Covered) by identifying groups of patients who may benefit from adherence interventions, and identifying patterns of adherence behavior over time that may facilitate tailoring of an adherence intervention. We evaluated adherence to antihypertensive medication in 905 patients over a 12 month period in a community pharmacy setting using GBTM, identifying three subgroups of adherence patterns: 52.8%, 40.7%, and 6.5% had very high, high, and low adherence, respectively. However, GBTM failed to demonstrate predictive validity with blood pressure at 12 months. Further research on the validity of adherence measures that facilitate interventions in clinical settings is required. PMID- 28875570 TI - Is a slow-progression baked milk protocol of oral immunotherapy always a safe option for children with cow's milk allergy? A randomized controlled trial. PMID- 28875571 TI - Crosslinked basement membrane-based coatings enhance glucose sensor function and continuous glucose monitoring in vivo. AB - Overcoming sensor-induced tissue reactions is an essential element of achieving successful continuous glucose monitoring (CGM) in the management of diabetes, particularly when used in closed loop technology. Recently, we demonstrated that basement membrane (BM)-based glucose sensor coatings significantly reduced tissue reactions at sites of device implantation. However, the biocompatible BM-based biohydrogel sensor coating rapidly degraded over a less than a 3-week period, which effectively eliminated the protective sensor coating. In an effort to increase the stability and effectiveness of the BM coating, we evaluated the impact of crosslinking BM utilizing glutaraldehyde as a crosslinking agent, designated as X-Cultrex. Sensor performance (nonrecalibrated) was evaluated for the impact of these X-Cultrex coatings in vitro and in vivo. Sensor performance was assessed over a 28-day time period in a murine CGM model and expressed as mean absolute relative difference (MARD) values. Tissue reactivity of Cultrex coated, X-Cultrex-coated, and uncoated glucose sensors was evaluated over a 28 day time period in vivo using standard histological techniques. These studies demonstrated that X-Cultrex-based sensor coatings had no effect on glucose sensor function in vitro. In vivo, glucose sensor performance was significantly enhanced following X-Cultrex coating throughout the 28-day study. Histological evaluations of X-Cultrex-treated sensors demonstrated significantly less tissue reactivity when compared to uncoated sensors. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 7-16, 2018. PMID- 28875572 TI - Hybrid 3D Printing of Soft Electronics. AB - Hybrid 3D printing is a new method for producing soft electronics that combines direct ink writing of conductive and dielectric elastomeric materials with automated pick-and-place of surface mount electronic components within an integrated additive manufacturing platform. Using this approach, insulating matrix and conductive electrode inks are directly printed in specific layouts. Passive and active electrical components are then integrated to produce the desired electronic circuitry by using an empty nozzle (in vacuum-on mode) to pick up individual components, place them onto the substrate, and then deposit them (in vacuum-off mode) in the desired location. The components are then interconnected via printed conductive traces to yield soft electronic devices that may find potential application in wearable electronics, soft robotics, and biomedical devices. PMID- 28875573 TI - People with intellectual disabilities at the end of their lives: The case for specialist care? AB - BACKGROUND: People with intellectual disabilities have a shorter life expectancy, but healthcare improvements mean that they are beginning to live longer, with associated health difficulties. This means that there is an urgent need to focus research on ageing as well as end-of-life care. This study aimed to explore a specialist intellectual disability service for older people who are dying and how it related to their quality of life and to costs associated with care provided. METHOD: Data were collected for nine residents and 15 staff members of the specialist service. A single case study design with mixed methods including observations, interviews, standardized questionnaires and costs analysis was utilized. RESULTS: We found positive results regarding overall quality of life, although individuals had limited social networks. Placement fees paid by local health trusts and social services departments were slightly higher than the estimated cost of care reflecting good financial management by a small voluntary sector organization. CONCLUSION: Whilst the philosophical arguments around "specialist" care persist, this service fills a gap in intellectual disability care provision. PMID- 28875574 TI - RGD-functionalized polyethylene glycol hydrogels support proliferation and in vitro chondrogenesis of human periosteum-derived cells. AB - The combination of progenitor cells with appropriate scaffolds and in vitro culture regimes is a promising area of research in bone and cartilage tissue engineering. Mesenchymal stem cells (MSCs), when encapsulated within hydrogels composed of the necessary cues and/or preconditioned using suitable culture conditions, have been shown to differentiate into bone or cartilage. Here, we utilized human periosteum-derived cells (hPDCs), a progenitor cell population with MSC characteristics, paired with protease-degradable, functionalized polyethylene glycol (PEG) hydrogels to create tissue-engineered constructs. The objective of this study was to investigate the effects of scaffold composition, exploring the addition of the cell-binding motif Arginine-Glycine-Aspartic Acid (RGD), in combination with various in vitro culture conditions on the proliferation, chondrogenic gene expression, and matrix production of encapsulated hPDCs. In growth medium, the hPDCs in the RGD-functionalized hydrogels maintained high levels of viability and demonstrated an enhanced proliferation when compared with hPDCs in non-functionalized hydrogels. Additionally, the RGD-containing hydrogels promoted higher glycosaminoglycan (GAG) synthesis and chondrogenic gene expression of the encapsulated hPDCs, as opposed to the non-functionalized constructs, when cultured in two different chondrogenic media. These results demonstrate the potential of hPDCs in combination with enzymatically degradable PEG hydrogels functionalized with adhesion ligands for cartilage regenerative applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 33-42, 2018. PMID- 28875575 TI - Can weight gain be prevented in women receiving treatment for breast cancer? A systematic review of intervention studies. AB - BACKGROUND: Obesity and weight gain have been associated with poor disease specific and health-related outcomes in women with breast cancer. OBJECTIVES: This review aimed to evaluate the effectiveness of weight gain prevention interventions among women with breast cancer. METHODS: Completed and ongoing trials evaluating a behaviourally based dietary intervention with or without physical activity and with a focus on weight gain prevention during treatment for breast cancer were reviewed. Weight change and body composition data were extracted. Within-group weight change of +/-1 kg and between-group (intervention versus control) weight difference of >=2 kg were defined as successful weight gain prevention. RESULTS: Five completed trials (seven intervention arms) and five ongoing trials were identified. Completed trials exclusively recruited premenopausal or premenopausal and postmenopausal women. Within-group weight gain was prevented in two intervention arms, two arms achieved weight loss and three arms reported weight gain. Of the five comparisons with control groups, two reported significant differences in weight change between groups. Ongoing trials will provide further evidence on longer-term outcomes, cost-effectiveness and blood markers. CONCLUSION: This small but growing number of studies provides preliminary and promising evidence that weight gain can be prevented in women with breast cancer undergoing chemotherapy. PMID- 28875576 TI - Moral foundations, worldviews, moral absolutism and belief in conspiracy theories. AB - In the present research, we examined whether individual differences in basic moral concerns might be related to a greater endorsement of conspiracy theories. Building on the notion that conspiracy theories often deal with super-individual relevant events in which a group perspective is central, we proposed that individual differences in moral concerns pertaining to group- and community concerns (i.e., binding moral foundations) rather than to individual well-being (i.e., individualising moral foundations) would be positively associated with conspiracy beliefs. We further hypothesised that such relations would be totally mediated by beliefs in a dangerous world and by embracing moral absolutism. We found support for these predictions in two community samples (Ns: 319; 514). Theoretical implications were discussed. PMID- 28875577 TI - Biocompatibility assessment of cyclic olefin copolymers: Impact of two additives on cytotoxicity, oxidative stress, inflammatory reactions, and hemocompatibility. AB - This work reports the biocompatibility evaluation of cyclic olefin copolymers (COC) as candidates for implantable medical devices. The focus was to establish the influence of two major additives (antioxidant and lubricant) on the overall biocompatibility. The cytotoxicity was evaluated according to ISO 10993-5 guidelines using L929 fibroblasts, HUVEC, and THP-1-derived macrophages. Oxidative stress (ROS, GSH/GSSG, and SOD analysis) and pro-inflammatory cytokines (Il-6 and TNF-alpha secretion) were quantified using THP-1 cells in direct contact with films. Hemocompatibility was assessed through haemolysis testing, dynamic blood coagulation, platelet adhesion, and activation (membranous P selectin expression). Results show that the different types of COC have successfully passed the in vitro biocompatibility tests. The presence of antioxidant induces however a slight decrease in ROS production in correlation with a high SOD activity and a modification in blood coagulation profile probably linked to antioxidant recrystallization phenomenon on the surface of COC. The lubricant presence reduced haemolysis, fibrinogen adhesion, and platelet activation. Surface nanotopography of COC highlights different types of needles and globules according to the present additive. Those primary results indicate that COC are promising biomaterial. However, additives influenced some biological parameters pointing out the necessity of a global approach of risk analysis for biocompatibility evaluation. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3333-3349, 2017. PMID- 28875578 TI - Are tanning salons in compliance with German law? An evaluation based on a nationwide representative survey. AB - BACKGROUND: Given the evidence for increased skin cancer risk due to the sunbed use, a regulation of hazardous artificial ultraviolet radiation (UVR regulation) was passed in Germany in 2012. The aim of this study was to explore the advisory services in tanning studios as reported by sunbed users and to evaluate the information provided by the personnel of tanning salons after the UVR regulation was enacted. METHODS: The first wave of the representative National Cancer Aid Monitoring on Sunbed Use included a subgroup of 357 German citizens between 14 and 45 years who had used sunbeds since the UVR regulation was implemented. The participants provided data on sunbed use and related issues in telephone interviews. RESULTS: Although sunbed operators are mandated to offer their customers certain services at least once since the implementation of the UVR regulation, 15.4% of sunbed users were never advised to use protective eyewear during tanning and 13.1% were not provided with eyewear during their last sunbed use. Overall, 66.0% were never offered to develop a tanning schedule, 56.9% were never advised on the risks of UVR, 43.4% were never offered a determination of their skin type and 40.0% of users were never advised on how to use a sunbed safely. CONCLUSIONS: The data showed that 3 years after the UVR regulation was enacted, compliance with this legislation is still not optimal. Binding wording in the legal text and making them applicable to unsupervised sunbeds as well is necessary to extend the impact of this legislation. PMID- 28875580 TI - Silver-Sulfur Hybrid Supertetrahedral Clusters: The Hitherto Missing Members in the Metal-Chalcogenide Tetrahedral Clusters. AB - The synthesis of Group 11 metal chalcogenide supertetrahedral clusters (SCs) still remains a great challenge mainly due to the high tendency of metal aggregation through metallophilicity and global charge balance. Demonstrated herein are the preparation, crystallographic characterization, and optical properties of two stable silver-sulfur SCs through ligand-control; one as a discrete zero-dimensional (0D) V3,4-type cluster and the other as a one dimensional (1D) zigzag chain extended by alternating V3,2-type clusters. The notation Vn,m (where n is the number of metal layers, and m is the number of vacant corners) is used to describe a new series of vacant-corner SCs, which can be derived from the regular Tn clusters. The existence of vacant-corner-type SCs may be ascribed to the low valence and tri-coordinated environment of silver ions. These are the first representatives of structurally determined silver sulfur tetrahedral clusters thus far. This work enriches the coinage-metal chalcogenide tetrahedral cluster portfolio, discovers vacant-corner SCs present in silver-sulfur hybrid tetrahedral clusters, and provides effective means for further development of Group 11 coinage-metal chalcogenide SCs. PMID- 28875579 TI - A cardiac patch from aligned microvessel and cardiomyocyte patches. AB - Cardiac tissue engineering aims to produce replacement tissue patches in the lab to replace or treat infarcted myocardium. However, current patches lack preformed microvascularization and are therefore limited in thickness and force production. In this study, we sought to assess whether a bilayer patch composed of a layer made from human induced pluripotent stem cell-derived cardiomyocytes and a microvessel layer composed of self-assembled human blood outgrowth endothelial cells and pericytes was capable of engrafting on the epicardial surface of a nude rat infarct model and becoming perfused by the host 4 weeks after acute implantation. The bilayer configuration was found to increase the twitch force production, improve human induced pluripotent stem cell-derived cardiomyocyte survival and maturation, and increase patent microvessel lumens compared with time-matched single layer controls after 2 weeks of in vitro culture. Upon implantation, the patch microvessels sprouted into the cardiomyocyte layer of the patch and inosculated with the host vasculature as evidenced by species-specific perfusion labels and erythrocyte staining. Our results demonstrate that the added microvessel layer of a bilayer patch substantially improves in vitro functionality and that the bilayer patch is capable of engraftment with rapid microvessel inosculation on injured myocardium. The bilayer format will allow for scaling up in size through the addition of layers to obtain thicker tissues generating greater force in the future. PMID- 28875581 TI - European guideline for the diagnosis and treatment of insomnia. AB - This European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia. The guideline is based on a systematic review of relevant meta-analyses published till June 2016. The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations. The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e. blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence). Polysomnography can be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence). Cognitive behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). A pharmacological intervention can be offered if cognitive behavioural therapy for insomnia is not sufficiently effective or not available. Benzodiazepines, benzodiazepine receptor agonists and some antidepressants are effective in the short-term treatment of insomnia (<=4 weeks; weak recommendation, moderate quality evidence). Antihistamines, antipsychotics, melatonin and phytotherapeutics are not recommended for insomnia treatment (strong to weak recommendations, low- to very-low-quality evidence). Light therapy and exercise need to be further evaluated to judge their usefulness in the treatment of insomnia (weak recommendation, low-quality evidence). Complementary and alternative treatments (e.g. homeopathy, acupuncture) are not recommended for insomnia treatment (weak recommendation, very-low-quality evidence). PMID- 28875582 TI - Identification of Signaling Pathways Targeted by the Food Contaminant FB1: Transcriptome and Kinome Analysis of Samples from Pig Liver and Intestine. AB - SCOPE: Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium species. In mammals, this toxin causes widespread organ-specific damage; it promotes hepatotoxicity, is immunotoxic, alters intestinal functions etc. Despite its inhibitory effect on de novo ceramide synthesis, its molecular mechanism of action and toxicity is not totally elucidated. METHODS AND RESULTS: To explore the mechanism of FB1 toxicity, we analyzed the transcriptome and the kinome of two organs targeted by FB1: the liver and the jejunum. Pigs were fed for 4 weeks a control diet or a FB1-contaminated diet (10 mg/kg). As expected, FB1-exposed pigs gained less weight and displayed a higher sphinganine/sphingosine ratio. Comparison of the transcriptomes and the kinomes of treated versus control pigs showed striking differences. Among the disrupted pathways in liver and jejunum, we highlight Protein Kinase B (AKT) / Phosphatase and tensin homolog (PTEN) at the intersection of the FB1-modulated pathways. CONCLUSION: Most of the effects of FB1 are mediated by the regulation of ceramide level, which influences protein phosphatase 2 (PP2A) and the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. This pathway might be a new target to counteract toxic effect of Fumonisin B1, which is one of the most spread food contaminant in the world. PMID- 28875583 TI - Quantum Chemical Modeling of Homogeneous Water Oxidation Catalysis. AB - The design of efficient and robust water oxidation catalysts has proven challenging in the development of artificial photosynthetic systems for solar energy harnessing and storage. Tremendous progress has been made in the development of homogeneous transition-metal complexes capable of mediating water oxidation. To improve the efficiency of the catalyst and to design new catalysts, a detailed mechanistic understanding is necessary. Quantum chemical modeling calculations have been successfully used to complement the experimental techniques to suggest a catalytic mechanism and identify all stationary points, including transition states for both O-O bond formation and O2 release. In this review, recent progress in the applications of quantum chemical methods for the modeling of homogeneous water oxidation catalysis, covering various transition metals, including manganese, iron, cobalt, nickel, copper, ruthenium, and iridium, is discussed. PMID- 28875584 TI - Euphorbia tirucalli beta-Amyrin Synthase: Critical Roles of Steric Sizes at Val483 and Met729 and the CH-pi Interaction between Val483 and Trp534 for Catalytic Action. AB - The functions of Val483, Trp534, and Met729 in Euphorbia tirucalli beta-amyrin synthase were revealed by comparing the enzyme activities of site-directed mutants against that of the wild type. The Gly and Ala variants with a smaller bulk size at position 483 predominantly afforded monocyclic camelliol C, which suggested that the orientation of the (3S)-2,3-oxidosqualene substrate was not appropriately arranged in the reaction cavity as a result of the decreased bulk size, leading to failure of its normal folding into the chair-chair-chair-boat boat conformation. The Ile variant, with a somewhat larger bulk, afforded beta amyrin as the dominant product. Intriguingly, various variants of Trp534 exhibited significantly decreased enzymatic activities and provided no aberrantly cyclized products, although the aromatic Phe and Tyr residues were incorporated and the steric sizes of the aliphatic residues were altered. Therefore, the Trp534 residue does not stabilize the transient cation through a cation-pi interaction. Furthermore, the Trp residue, with the largest steric bulk among all natural amino acids, is essential for high enzymatic activity. Robust CH-pi complexation between the Val483 and Trp534 residues is proposed herein. Altering the steric bulk at the Met729 position afforded the pentacyclic skeletons. Thus, Met729 is positioned at the E-ring formation site. More detailed insights into the functions of the Val483, Trp534, and Met729 residues are provided by homology modeling. PMID- 28875585 TI - Peristome-Mimetic Curved Surface for Spontaneous and Directional Separation of Micro Water-in-Oil Drops. AB - Separation of micro-scaled water-in-oil droplets is important in environmental protection, bioassays, and saving functional inks. So far, bulk oil-water separation has been achieved by membrane separation and sponge absorption, but micro-drop separation still remains a challenge. Herein we report that instead of the "plug-and-go" separation model, tiny water-in-oil droplets can be separated into pure water and oil droplets through "go-in-opposite ways" on curved peristome-mimetic surfaces, in milliseconds, without energy input. More importantly, this overflow controlled method can be applied to handle oil-in-oil droplets with surface tension differences as low as 14.7 mN m-1 and viscous liquids with viscosities as high as hundreds centipoises, which markedly increases the range of applicable liquids for micro-scaled separation. Furthermore, the curved peristome-mimetic surface guides the separated drops in different directions with high efficiency. PMID- 28875586 TI - 'It's like a frog leaping about in your chest': Illness and treatment perceptions in persistent atrial fibrillation. AB - OBJECTIVES: Persistent atrial fibrillation (AF) is an abnormal heart rhythm associated with low quality of life (QoL) and significant health-related costs. The purpose of the study was to examine patients' illness and treatment beliefs and ways of coping with AF symptoms, to provide insight into promoting better QoL and treatment-specific management. DESIGN: Beliefs were explored across three procedural treatment groups using a qualitative cross-sectional design. METHODS: Thirty semi-structured interviews were carried out with patients undertaking cardioversion (n = 10), catheter ablation (n = 11) and atrioventricular node ablation (n = 9). Interviews were transcribed and analysed using inductive thematic analysis with elements of grounded theory. RESULTS: An overarching theme of a vicious cycle was evident, which related to perceived lack of knowledge and understanding of AF, attempts to control symptoms and negative emotional reactions to failed control attempts. This vicious cycle related to three subordinate themes: (1) unpredictability and uncertainty of AF and symptoms; (2) coping with symptoms through (a) avoidance (b) all-or-nothing- (c) slowing down behaviours; and (3) concerns and expectations about treatment. CONCLUSIONS: Patients outlined a need to gain control of unpredictable symptoms by monitoring and varying activity levels. These behaviours were often appraised as ineffective at controlling symptoms, leading to heightened uncertainty and increased activity avoidance. Treatment concerns escalated with increasing number and invasiveness of procedures. Improving AF patients' perceived understanding of their illness and treatment and promoting more effective symptom-management strategies may alleviate psychological distress and improve QoL. Themes elaborated on the common sense model whereby patients' beliefs about illness and treatment interact with coping behaviours. Statement of contribution What is already known about this subject? Quality of life (QoL) is disproportionately low in people with persistent atrial fibrillation (psAF). The common-sense model suggests illness perceptions and coping predict QoL in chronic illnesses. No previous studies have examined the idiosyncratic beliefs and coping behaviours of psAF patients. What does this study add? A vicious cycle of perceived lack of understanding of AF, attempts to control AF and distress at failed attempts at control, was a key theme. PsAF patients reported continued avoidance/all-or-nothing behaviours despite symptomatic relief post-procedure, and disengagement from enjoyable activities. PsAF patients reported procedure-specific concerns/expectations, which could be targeted in future interventions aimed at reducing distress. PMID- 28875587 TI - A new mouse line for cell ablation by diphtheria toxin subunit A controlled by a Cre-dependent FLEx switch. AB - Recombinase responsive mouse lines expressing diphtheria toxin subunit A (DTA) are well established tools for targeted ablation of genetically defined cell populations. Here we describe a new knock-in allele at the Gt(Rosa)26Sor locus that retains the best features of previously described DTA alleles-including a CAG promoter, attenuated mutant DTA cDNA, and ubiquitous EGFP labeling-with the addition of a Cre-dependent FLEx switch for tight control of expression. The FLEx switch consists of two pairs of antiparallel lox sites requiring Cre-mediated recombination for inversion of the DTA to the proper orientation for transcription. We demonstrate its utility by Cre-dependent ablation of both a broad domain in the embryonic nervous system and a discrete population of cells in the fetal gonads. We conclude that this new DTA line is useful for targeted ablation of genetically-defined cell populations. PMID- 28875588 TI - Health beliefs of salt intake among patients undergoing haemodialysis. AB - BACKGROUND: High salt intake has been recognised as a risk factor that contributes to a poor outcome in patients with end stage kidney disease (ESKD). This study examined health beliefs about salt intake among patients undergoing haemodialysis. MATERIALS AND METHODS: This was a cross-sectional study using a convenience sample. 307 outpatients completed the health beliefs of sodium intake scale (HBSIS). RESULTS: In this cohort, the score for the perceived self-efficacy subscale (3.59 +/- 0.76) was highest, while the score for perceived barriers (2.52 +/- 0.67) subscale was lowest. These perceived benefits, susceptibility for the reduction, and no reduction of sodium intake subscale scores were significantly higher in female than in male patients (p < 0.05). The scores for the subscale of perceived barriers, and the seriousness for the reduction and no reduction of sodium intake were significantly higher in haemodialysis patients who had been educated above high school compared with patients with middle school education and below (p < 0.05). The scores for the subscale of perceived benefits, susceptibility, and self-efficacy for reduction or no reduction of sodium intake were also significantly higher in haemodialysis patients with higher income compared to those with lower income (p < 0.05 to p < 0.001). The score for the subscale of perceived seriousness for no reduction of sodium intake was significantly higher in patients who had received transplants than in patients who had not received a transplant (p < 0.01). CONCLUSION: Patients undergoing haemodialysis have a low level of health belief about salt intake. PMID- 28875589 TI - Genetic dissection of top three leaf traits in rice using progenies from a japonica * indica cross. AB - The size of the top three leaves of rice plants is strongly associated with yield; thus, it is important to consider quantitative traits representing leaf size (e.g., length and width) when breeding novel rice varieties. It is challenging to measure such traits on a large scale in the field, and little is known about the genetic factors that determine the size of the top three leaves. In the present study, a population of recombinant inbred lines (RILs) and reciprocal single chromosomal segment substitution lines (SSSLs) derived from the progeny of a japonica Asominori * indica IR24 cross were grown under four diverse environmental conditions. Six morphological traits associated with leaf size were measured, namely length and flag leaf, length and flag, second and third leaves. In the RIL population, 49 QTLs were identified that clustered in 30 genomic region. Twenty-three of these QTLs were confirmed in the SSSL population. A comparison with previously reported genes/QTLs revealed eight novel genomic regions that contained uncharacterized ORFs associated with leaf size. The QTLs identified in this study can be used for marker-assisted breeding and for fine mapping of novel genetic elements controlling leaf size in rice. PMID- 28875590 TI - Introduction to passive electron intensity modulation. AB - This work introduces a new technology for electron intensity modulation, which uses small area island blocks within the collimating aperture and small area island apertures in the collimating insert. Due to multiple Coulomb scattering, electrons contribute dose under island blocks and lateral to island apertures. By selecting appropriate lateral positions and diameters of a set of island blocks and island apertures, for example, a hexagonal grid with variable diameter circular island blocks, intensity modulated beams can be produced for appropriate air gaps between the intensity modulator (position of collimating insert) and the patient. Such a passive radiotherapy intensity modulator for electrons (PRIME) is analogous to using physical attenuators (metal compensators) for intensity modulated x-ray therapy (IMXT). For hexagonal spacing, the relationship between block (aperture) separation (r) and diameter (d) and the local intensity reduction factor (IRF) is discussed. The PRIME principle is illustrated using pencil beam calculations for select beam geometries in water with half beams modulated by 70%-95% and for one head and neck field of a patient treated with bolus electron conformal therapy. Proof of principle is further illustrated by showing agreement between measurement and calculation for a prototype PRIME. Potential utilization of PRIME for bolus electron conformal therapy, segmented field electron conformal therapy, modulated electron radiation therapy, and variable surface geometries is discussed. Further research and development of technology for the various applications is discussed. In summary, this paper introduces a practical, new technology for electron intensity modulation in the clinic, demonstrates proof of principle, discusses potential clinical applications, and suggests areas of further research and development. PMID- 28875591 TI - Osteogenic potential of adipogenic predifferentiated human bone marrow-derived multipotent stromal cells for bone tissue-engineering. AB - In the present study, we evaluated the benefits of an adipogenic predifferentiation, the pathway most closely related to osteoblastogenesis, on the pro-osteogenic potential of human adult multipotent bone marrow stromal cells (hBMSCs), both in vitro and in vivo. Adipogenic differentiation of hBMSCs for 14 days resulted in a heterogeneous cell population from which the most adipogenic committed cells were eliminated by their lack of readhesion ability. Our results provided evidence that the select adherent adipogenic differentiated hBMSCs (sAD+ cells) express a gene profile characteristic of both adipogenic and osteogenic lineages. In vitro, when cultured in osteogenic medium, sAD+ differentiated along the osteogenic lineage faster than undifferentiated hBMSCs. In vivo, in an ectopic mouse model, sAD+ exhibited a significantly higher bone formation capability compared with undifferentiated hBMSCs. We sought, then, to investigate the underlying mechanisms responsible for such beneficial effects of adipogenic predifferentiation on bone formation and found that this outcome was not linked to a better cell survival post-implantation. The secretome of sAD+ was both proangiogenic and chemoattractant, but its potential did not supersede the one of undifferentiated hBMSCs. However, using co-culture systems, we observed that the sAD+ paracrine factors were pro-osteogenic on undifferentiated hBMSCs. In conclusion, adipogenic priming endows hBMSCs with high osteogenic potential as well as pro-osteogenic paracrine-mediated activity. This preconditioning appears as a promising strategy for bone tissue engineering technology in order to improve the hBMSC osteogenic potency in vivo. PMID- 28875592 TI - Comparison of linear intrascan and interscan dynamic ranges of Orbitrap and ion mobility time-of-flight mass spectrometers. AB - RATIONALE: The linear intrascan and interscan dynamic ranges of mass spectrometers are important in metabolome and residue analysis. A large linear dynamic range is mandatory if both low- and high-abundance ions have to be detected and quantitated in heavy matrix samples. These performance criteria, as provided by modern high-resolution mass spectrometry (HRMS), were systematically investigated. METHODS: The comparison included two generations of Orbitraps, and an ion mobility quadrupole time-of-flight (QTOF) system In addition, different scan modes, as provided by the utilized instruments, were investigated. Calibration curves of different compounds covering a concentration range of five orders of magnitude were measured to evaluate the linear interscan dynamic range. The linear intrascan dynamic range and the resulting mass accuracy were evaluated by repeating these measurements in the presence of a very intense background. RESULTS: Modern HRMS instruments can show linear dynamic ranges of five orders of magnitude. Often, however, the linear dynamic range is limited by the detection capability (sensitivity and selectivity) and by the electrospray ionization. Orbitraps, as opposed to TOF instruments, show a reduced intrascan dynamic range. This is due to the limited C-trap and Orbitrap capacity. The tested TOF instrument shows poorer mass accuracies than the Orbitraps. In contrast, hyphenation with an ion-mobility device seems not to affect the linear dynamic range. CONCLUSIONS: The linear dynamic range of modern HRMS instrumentation has been significantly improved. This also refers to the virtual absence of systematic mass shifts at high ion abundances. The intrascan dynamic range of the current Orbitrap technology may still be a limitation when analyzing complex matrix extracts. On the other hand, the linear dynamic range is not only limited by the detector technology, but can also be shortened by peripheral devices, where the ionization and transfer of ions take place. PMID- 28875593 TI - Implementing an evidence-based clinical decision support tool to improve the detection, evaluation, and referral patterns of adult chronic kidney disease patients in primary care. AB - BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is undertreated and under recognized in primary care. The majority of primary care providers (PCPs) are not aware or knowledgeable of current CKD guidelines. The purpose of this project was to develop a quality improvement intervention for PCPs through the delivery of evidence-based guidelines at the point of care. METHODS: An evidence-based clinical algorithm was developed in the electronic medical record for providers to access within one organization comprising 11 primary care offices with 80 PCPs. Baseline knowledge surveys and baseline data were obtained in August 2016. A CKD educational intervention and tutorial on a clinical decision support (CDS) tool was presented to physicians, nurse practitioners, and physician assistants. Postimplementation data and knowledge surveys were collected in December 2016. CONCLUSIONS: Most PCPs were willing to use a CKD CDS tool to help them with CKD patients. A CDS tool in addition to an educational intervention can improve PCP knowledge and identification of CKD and early referral to nephrology. IMPLICATIONS FOR PRACTICE: CDS tools can promote evidence-based guided care for PCPs and CKD patients. By using these applications, patients can be properly identified, managed, treated, and appropriately referred to nephrology. PMID- 28875594 TI - Automatic x-ray image contrast enhancement based on parameter auto-optimization. AB - PURPOSE: Insufficient image contrast associated with radiation therapy daily setup x-ray images could negatively affect accurate patient treatment setup. We developed a method to perform automatic and user-independent contrast enhancement on 2D kilo voltage (kV) and megavoltage (MV) x-ray images. The goal was to provide tissue contrast optimized for each treatment site in order to support accurate patient daily treatment setup and the subsequent offline review. METHODS: The proposed method processes the 2D x-ray images with an optimized image processing filter chain, which consists of a noise reduction filter and a high-pass filter followed by a contrast limited adaptive histogram equalization (CLAHE) filter. The most important innovation is to optimize the image processing parameters automatically to determine the required image contrast settings per disease site and imaging modality. Three major parameters controlling the image processing chain, i.e., the Gaussian smoothing weighting factor for the high-pass filter, the block size, and the clip limiting parameter for the CLAHE filter, were determined automatically using an interior-point constrained optimization algorithm. RESULTS: Fifty-two kV and MV x-ray images were included in this study. The results were manually evaluated and ranked with scores from 1 (worst, unacceptable) to 5 (significantly better than adequate and visually praise worthy) by physicians and physicists. The average scores for the images processed by the proposed method, the CLAHE, and the best window-level adjustment were 3.92, 2.83, and 2.27, respectively. The percentage of the processed images received a score of 5 were 48, 29, and 18%, respectively. CONCLUSION: The proposed method is able to outperform the standard image contrast adjustment procedures that are currently used in the commercial clinical systems. When the proposed method is implemented in the clinical systems as an automatic image processing filter, it could be useful for allowing quicker and potentially more accurate treatment setup and facilitating the subsequent offline review and verification. PMID- 28875595 TI - Association of Obesity or Overweight with Bone Health in Childhood and Adolescence: Another Health Risk Never to Be Underestimated. PMID- 28875596 TI - Smartphone Addiction of Adolescents, Not a Smart Choice. PMID- 28875597 TI - Total Occlusion of Pulmonary Arteries by Embolization of Myxoma. PMID- 28875598 TI - Recovery of Proprioception in the Upper Extremity by Robotic Mirror Therapy: a Clinical Pilot Study for Proof of Concept. AB - A novel robotic mirror therapy system was recently developed to provide proprioceptive stimulus to the hemiplegic arm during a mirror therapy. Validation of the robotic mirror therapy system was performed to confirm its synchronicity prior to the clinical study. The mean error angle range between the intact arm and the robot was 1.97 to 4.59 degrees. A 56-year-old male who had right middle cerebral artery infarction 11 months ago received the robotic mirror therapy for ten 30-minute sessions during 2 weeks. Clinical evaluation and functional magnetic resonance imaging (fMRI) studies were performed before and after the intervention. At the follow-up evaluation, the thumb finding test score improved from 2 to 1 for eye level and from 3 to 1 for overhead level. The Albert's test score on the left side improved from 6 to 11. Improvements were sustained at 2 month follow-up. The fMRI during the passive motion revealed a considerable increase in brain activity at the lower part of the right superior parietal lobule, suggesting the possibility of proprioception enhancement. The robotic mirror therapy system may serve as a useful treatment method for patients with supratentorial stroke to facilitate recovery of proprioceptive deficit and hemineglect. PMID- 28875600 TI - Validation of the World Health Organization Enzyme-Linked Immunosorbent Assay for the Quantitation of Immunoglobulin G Serotype-Specific Anti-Pneumococcal Antibodies in Human Serum. AB - The World Health Organization (WHO) enzyme-linked immunosorbent assay (ELISA) guideline is currently accepted as the gold standard for the evaluation of immunoglobulin G (IgG) antibodies specific to pneumococcal capsular polysaccharide. We conducted validation of the WHO ELISA for 7 pneumococcal serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) by evaluating its specificity, precision (reproducibility and intermediate precision), accuracy, spiking recovery test, lower limit of quantification (LLOQ), and stability at the Ewha Center for Vaccine Evaluation and Study, Seoul, Korea. We found that the specificity, reproducibility, and intermediate precision were within acceptance ranges (reproducibility, coefficient of variability [CV] <= 15%; intermediate precision, CV <= 20%) for all serotypes. Comparisons between the provisional assignments of calibration sera and the results from this laboratory showed a high correlation > 94% for all 7 serotypes, supporting the accuracy of the ELISA. The spiking recovery test also fell within an acceptable range. The quantification limit, calculated using the LLOQ, for each of the serotypes was 0.05-0.093 MUg/mL. The freeze-thaw stability and the short-term temperature stability were also within an acceptable range. In conclusion, we showed good performance using the standardized WHO ELISA for the evaluation of serotype specific anti-pneumococcal IgG antibodies; the WHO ELISA can evaluate the immune response against pneumococcal vaccines with consistency and accuracy. PMID- 28875599 TI - The Impact of Middle East Respiratory Syndrome Outbreak on Trends in Emergency Department Utilization Patterns. AB - Changes occurred in the patterns of utilization of emergency medical services during the Middle East respiratory syndrome (MERS) outbreak. The purpose of this study was to analyze the patterns of adult and pediatric patients who visited the emergency department (ED) during the outbreak. This retrospective study was conducted by analyzing changes in the patterns of visits among adult and pediatric patients in the ED at one tertiary teaching hospital in Korea. The study was performed from June 1, 2013 to July 31, 2015. The MERS outbreak period was from June 1 to July 31, 2015, and we compared that period to the same periods in 2013 and 2014. We compared and analyzed the patients' characteristics, emergency severity index (ESI) level at the visit, cause of visit, diagnosis, final dispositions, injury/non-injury, length of stay at the ED (EDLOS), and hospitalization rate. A total of 9,107 patients visited the ED during this period. Of these patients, 2,572 (28.2%) were pediatric patients and 6,535 (71.8%) were adult patients. The most common cause of an ED visit was fever (adult patients: 21.6%, pediatric patients: 56.2%). The proportion of non-urgent visits involving an ESI level of 4 or 5 and the EDLOS decreased significantly in pediatric and adult patients in comparison to that during the past two years. This change was significant in pediatric patients. Among adult patients, the rate of injury decreased, whereas it increased among pediatric patients. During the MERS outbreak period, pediatric ED visits due to non-urgent cases decreased significantly and there were more pronounced differences in ED utilization patterns in pediatric patients than in adult patients. PMID- 28875601 TI - Can the Thiol/Disulfide Imbalance Be a Predictor of Colchicine Resistance in Familial Mediterranean Fever? AB - Familial Mediterranean fever (FMF) is a chronic autoinflammatory condition characterized by fever attacks and recurrent polyserositis. Subclinical inflammation that persists during attack-free periods can result in oxidative stress (OS) damage. Thiol groups bind to reactive oxygen radicals and protect cells and tissues from OS damage. The aim of this study was to investigate the relationship between thiol-disulfide balance and colchicine resistance in FMF patients during an attack or attack-free period. A newly developed spectrophotometric method was used to measure native thiol (NT) and disulfide (DS) levels in FMF patients and an age-sex matched group of healthy controls. NT and DS levels were compared in FMF patients 1) with vs. without colchicine resistance; and 2) during an attack (FMF-AP) vs. attack-free period (FMF-AFP). A total of 118 FMF patients and 60 healthy controls were studied. NT (P < 0.001) and total thiol (TT) (P < 0.001) levels in FMF patients were significantly lower compared to healthy controls. NT (P = 0.030) and TT (P = 0.010) levels of FMF-AP patients were significantly lower than that of FMF-AFP patients. FMF-AP patients had significantly higher DS levels than FMF-AFP patients (P = 0.039). Compared to FMF patients without colchicine resistance, elevated levels of DS (P = 0.019) but not NT (P = 0.620) and TT (P = 0.718) were found in those with colchicine resistance. Thiol-disulfide homeostasis is altered in FMF patients during an attack period and this imbalance may be associated with colchicine resistance. PMID- 28875602 TI - Poorly Differentiated Clusters in Colorectal Adenocarcinomas Share Biological Similarities with Micropapillary Patterns as well as Tumor Buds. AB - In colorectal carcinoma, poorly differentiated clusters (PDCs) are a poor prognostic indicator and show morphological continuity and behavioral similarities to micropapillary patterns (MPPs) as well as tumor buds (TBs). Epithelial-mesenchymal transition (EMT) and inhibition of cancer-stromal interactions may contribute to the development of PDCs. To clarify the biological nature of PDCs, we examined immunohistochemical stainings for beta-catenin, Ki 67, E-cadherin, epithelial cell adhesion molecule (EpCAM), MUC1, and epithelial membrane antigen (EMA), which are associated with EMT and cancer-stromal interactions. The expression frequencies and patterns of PDCs, TBs, and differentiated neoplastic glands from the tumor center (TC) were compared. In the study group (117 cases), the nuclear beta-catenin staining index was higher in PDCs (37.3%) and TBs (43.3%) than in neoplastic glands from TC (8.9%, P < 0.001). The mean Ki-67 labeling index in TC was 71.5%, whereas it was decreased in PDCs (31.2%) and TBs (10.2%, P < 0.001). E-cadherin and EpCAM displayed a tendency to be found along the cell membrane in TC samples (91.5% and 92.3%, respectively), whereas they showed loss of membranous staining in PDC (44.4% and 36.8%, respectively) and TB samples (60.7% and 68.4%, respectively). An inside-out pattern for MUC1 and EMA was frequently observed in PDC (48.7% and 45.3%, respectively) and TB samples (46.2% and 45.3%, respectively), but not in TC samples. Our data demonstrate that there is a pathogenetic overlap among PDCs, TBs, and MPPs and suggest that they might represent sequential growth patterns that branch from common biological processes such as dedifferentiation and alteration in cancer-stromal interactions. PMID- 28875603 TI - Incidence, Predictors, and Clinical Outcomes of New-Onset Diabetes Mellitus after Percutaneous Coronary Intervention with Drug-Eluting Stent. AB - We investigated the incidence, predictors, and long-term clinical outcomes of new onset diabetes mellitus (DM) after percutaneous coronary intervention (PCI) with drug-eluting stent (DES). A total of 6,048 patients treated with DES were retrospectively reviewed and divided into three groups: 1) known DM (n = 2,365; fasting glucose > 126 mg/dL, glycated hemoglobin > 6.5%, already receiving DM treatment, or previous history of DM at the time of PCI); 2) non-DM (n = 3,247; no history of DM, no laboratory findings suggestive of DM at PCI, and no occurrence of DM during follow-up); and 3) new-onset DM (n = 436; non-DM features at PCI and occurrence of DM during follow-up). Among 3,683 non-DM patients, 436 (11.8%) patients were diagnosed with new-onset DM at 3.4 +/- 1.9 years after PCI. Independent predictors for new-onset DM were high-intensity statin therapy, high body mass index (BMI), and high level of fasting glucose and triglycerides. The 8 year cumulative rate of major adverse cardiac events (a composite of cardiovascular death, myocardial infarction, stent thrombosis, or any revascularization) in the new-onset DM group was 19.5%, which was similar to 20.5% in the non-DM group (P = 0.467), but lower than 25.0% in the known DM group (P = 0.003). In conclusion, the incidence of new-onset DM after PCI with DES was not low. High-intensity statin therapy, high BMI, and high level of fasting glucose and triglycerides were independent predictors for new-onset DM. Long-term clinical outcomes of patients with new-onset DM after PCI were similar to those of patients without DM. PMID- 28875604 TI - The Incidence of Riata Defibrillator Lead Failure: a Single-Center Experience. AB - Riata defibrillator leads were recalled due to a high failure rate. This study measured the incidence of externalized conductor (EC) and electrical dysfunction (ED) and sought to determine the predictors of ED with Riata defibrillator leads. We enrolled patients who received Riata(r) or Riata(r) ST silicone defibrillator leads at our center between January 2003 and December 2010. The presence of EC was evaluated with chest radiography. The incidence rates were measured at < 3 years, 3-5 years, and > 5 years after lead implantation. We also investigated the rates of ED and other clinical events during the follow-up period. A total of 44 patients were analyzed. The total cumulative incidence of EC was 27.3%. During the median dwell time (80 months), the incidence of ED was 22.7%. Patients with ED were younger (46.5 vs. 56.5 years, P = 0.018) and had a higher prevalence of cardiomyopathy than those without ED (60.0% vs. 20.6%, P = 0.043). ECs were most frequently detected in patients who underwent X-ray analysis 3-5 years after lead implantation (44.4%). In contrast, ED had a bimodal incidence pattern, with peaks at 5 years (7.0%) and 9 years (5.3%). There was no difference in ED-free survival rate between patients with and without EC (P = 0.628). Given the delayed occurrence of EC and ED after implantation of Riata defibrillator leads, long term close monitoring is critically important. PMID- 28875605 TI - Fate of Neutrophils during the Recovery Phase of Ischemia/Reperfusion Induced Acute Kidney Injury. AB - Effective clearance of inflammatory cells is required for resolution of inflammation. Here, we show in vivo evidence that apoptosis and reverse transendothelial migration (rTEM) are important mechanisms in eliminating neutrophils and facilitating recovery following ischemia/reperfusion injury (IRI) of the kidney. The clearance of neutrophils was delayed in the Bax knockout (KO)(BM) -> wild-type (WT) chimera in which bone marrow derived cells are partially resistant to apoptosis, compared to WT(BM) -> WT mice. These mice also showed delayed functional, histological recovery, increased tissue cytokines, and accelerated fibrosis. The circulating intercellular adhesion molecule-1 (ICAM-1)+ Gr-1+ neutrophils displaying rTEM phenotype increased during the recovery phase and blockade of junctional adhesion molecule-C (JAM-C), a negative regulator of rTEM, resulted in an increase in circulating ICAM-1+ neutrophils, faster resolution of inflammation and recovery. The presence of Tamm-Horsfall protein (THP) in circulating ICAM-1+ neutrophils could suggest that they are derived from injured kidneys. In conclusion, we suggest that apoptosis and rTEM are critically involved in the clearance mechanisms of neutrophils during the recovery phase of IRI. PMID- 28875606 TI - The Relationship between Subclinical Thyroid Disease and Cardiovascular Disease Risk Score in Koreans. AB - Subclinical hyperthyroidism and subclinical hypothyroidism are characterized by abnormal thyroid stimulating hormone (TSH) with normal free thyroxine. Subclinical thyroid diseases, to date, have received less attention compared with other thyroid diseases since they are asymptomatic. This study aimed to verify the association between subclinical thyroid diseases and cardiovascular diseases (CVDs) risk score in the Korean population. This was a population-based cohort study using data collected from 3,722 subjects (aged >= 30 years) during the 6th Korea National Health and Nutrition Examination Survey (KNHANES VI; 2013-2015). Gender-specific Framingham risk scores were calculated to identify the association between subclinical thyroid diseases and 10-year CVD risk score. Complex survey, with consideration of sampling weight, was analyzed using generalized linear models after stratification by gender. The TSH reference range was between 0.61 and 6.91 mIU/L in this study. TSH showed a positive association with the 10-year CVD risk score only in the female population (P = 0.001). There were significant differences in the least squares means of 10-year CVD risk score by the effect of subclinical hypothyroidism compared with euthyroidism (normal group) in females, after adjusting for body mass index, white blood cell, and urine iodine (P = 0.006 and Bonferroni corrected P = 0.012). In conclusion, subclinical hypothyroidism is associated with increased 10-year CVD risk score in the female Korean population aged 30 years or more. Therefore, we recommend to clinically checkup major CVD risk factors in female patients with subclinical hypothyroidism aged 30 years or more. PMID- 28875607 TI - The Role of Overweight and Obesity on Bone Health in Korean Adolescents with a Focus on Lean and Fat Mass. AB - As the associations between pediatric overweight/obesity and bone health remain controversial, we investigated the effects of overweight/obesity as well as lean mass (LM) and fat mass (FM) on bone parameters in adolescents. Bone parameters were evaluated using dual-energy X-ray absorptiometry (DXA) data of 982 adolescents (aged 12-19 years) from the Korea National Health and Nutrition Examination Survey (2009-2010). Z-scores for LM, FM, bone mass, bone mineral density (BMD), and bone mineral apparent density (BMAD) using Korean pediatric reference values were used for analysis. Adolescents with overweight/obesity had significantly higher bone mass and density of the total-body-less-head (TBLH), lumbar spine, and femur neck than underweight or normal-weight adolescents (P < 0.001) after adjusting for vitamin D deficiency, calcium intake, and insulin resistance in both sexes. LM was positively associated with bone parameters at all skeletal sites in both sexes (P < 0.001). FM was negatively related to TBLH BMD in boys (P = 0.018) but was positively associated to BMD and BMAD of the lumbar spine and femur neck in girls. In conclusion, overweight/obesity and LM play a positive role in bone health in adolescents. The effect of FM on bone parameters is sex- and site-specific. PMID- 28875608 TI - Clinical Characteristics of Macrolide-Resistant Mycoplasma pneumoniae from Children in Jeju. AB - Mycoplasma pneumoniae is the major pathogen of community-acquired pneumonia in children. The prevalence of macrolide-resistant M. pneumoniae (MRMP) is important owing to the limited alternative therapies for children. We analyzed 111 M. pneumoniae obtained from 107 children admitted for lower respiratory tract infection at Jeju National University Hospital between 2010 and 2015. Macrolide resistance of M. pneumoniae was searched for using polymerase chain reaction (PCR) and sequencing. Of 107 clinical M. pneumoniae, 11 (10.3%) carried macrolide resistance mutations in the 23S rRNA gene. All macrolide resistance mutations were A2063G transitions. We found an acquired A2063G mutation of M. pneumoniae from a patient during macrolide treatment. Patients' characteristics and clinical severity did not differ between those with MRMP and macrolide-sensitive M. pneumoniae, with the exception of frequent pleural effusion in the MRMP group. The prevalence of MRMP (10.3%) in Jeju Island was relatively lower than those of surrounding countries in East Asia. Previous antimicrobial usage and timing of diagnostic test should be considered when determining of macrolide resistance of M. pneumoniae. PMID- 28875610 TI - Analysis of Pregnancy Outcomes among Interracial Couples in Korea. AB - Although the prevalence of interracial marriages in Korea is increasing, little is known regarding the pregnancy outcomes of interracial couples. The aim of this study was to investigate the differences in pregnancy outcomes between Korean and interracial Korean-foreign couples. Data for infants born in 2011 and 2012 were obtained from the national birth registry of the Korean Statistical Office. The couples were subdivided into Korean father-Korean mother, Korean father-foreign mother, and foreign father-Korean mother groups. Pregnancy outcomes included neonates with low birth weight (< 2,500 g) and those with high birth weight (> 4,000 g). In 2010 and 2011, 888,447 Korean father-Korean mother, 36,024 Korean father-foreign mother, and 4,955 foreign father-Korean mother neonates were delivered in Korea. After adjustment for parental age, educational level, parity, gestational age at delivery, and neonatal sex, the birth weights were found to be different between groups, with the highest number of foreign father-Korean mother and lowest number of Korean father-foreign mother pregnancies. Based on multivariate logistic regression analysis, the risk of low and large birth weights was higher in the Korean father-foreign mother and foreign father-Korean mother groups, respectively, compared with that in the Korean father-Korean mother group. There are significant differences in pregnancy outcomes including birth weights between Korean and interracial Korean-foreign couples. PMID- 28875611 TI - Oncologic Outcomes and Predictive Factors for Recurrence Following Robot-Assisted Radical Cystectomy for Urothelial Carcinoma: Multicenter Study from Korea. AB - The aim of our study was to evaluate intermediate-term oncologic outcomes, predictive factors for recurrence, and recurrence patterns in a multicenter series of patients treated with robot-assisted radical cystectomy (RARC) for urothelial carcinoma (UC) of the bladder. Between 2007 and 2015, 346 patients underwent RARC at multiple tertiary referral centers in Korea. Descriptive statistics were used for demographics and perioperative variables. Survival and recurrence were estimated with Kaplan-Meier analysis. Logistic regression models were used to determine predictors of recurrence. Median follow-up was 33 months (interquartile range [IQR], 7-50). The numbers of patients with organ-confined and lymph node (LN)-positive disease were 237 (68.4%) and 68 (19.7%), respectively. LN density (1-20 vs. > 20) was 13.6% and 6.1%, with a median of 17 nodes removed (IQR, 9-23). In logistic regression analysis, type of LN dissection, and pathologic tumor stage were significant predictors of cancer recurrence and death from cancer. Local, distal recurrence and secondary UC occurred in 7 (2.0%), 53 (15.3%), and 4 (1.2%) patients, respectively. The 5-year overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were 78%, 84%, and 73%, respectively. At last follow-up, RFS for extended pelvic LN dissection vs. standard pelvic LN dissection was 70% and 47% (P = 0.038). In addition, at last follow-up, LN density (0 vs. 1-20 vs. over 20) was 67%, 41%, and 29%, respectively (P < 0.001). Patients undergoing RARC in this multi-institutional cohort demonstrated intermediate-term oncologic outcomes, predictive factors for recurrence, and recurrence patterns that were not unusual. PMID- 28875612 TI - Trends in Testicular Injury in Korea, 1986-2015. AB - The objectives of this study were to investigate patients treated for scrotal trauma at our institute for the last three decades to describe our experience with an emphasis on the etiologies and ultrasonographic findings in these patients. We reviewed medical records of patients who underwent scrotal ultrasonography for evaluation of testicular trauma at our institutes from 1986 to 2015. Trends regarding the etiology of scrotal trauma were evaluated during each decade. The echo pattern and contour definition of the testicular parenchyma and the pattern of hematoma development were recorded to evaluate radiographic findings of testicular injury. The correlation between ultrasonographic and intraoperative findings was assessed. A total of 115 patients were analyzed. Most patients (92.2%) presented with blunt trauma. The most common etiology of testicular trauma was assault during the first and second decades, while injury related to a fall was most common during the third decade. Of the 77 patients (67.0%) who underwent urgent exploration, 46 patients (59.7%) had testicular rupture. Loss of contour definition, heterogeneous echo pattern of the testicular parenchyma, and testicular hematoma showed a moderate to strong degree of correlation with testicular rupture (Spearman correlation co-efficient: 0.5-0.8). Over the past 30 years, the etiology of testicular injury changed from assault to falls or athletic injury and the severity of injury has decreased. Our findings demonstrate the importance of ultrasonography for determining an appropriate management strategy in scrotal trauma. Surgical exploration should be considered in patients with abnormal ultrasonographic findings. PMID- 28875609 TI - Epidemiological Correlation between Fecal Adenovirus Subgroups and Pediatric Intussusception in Korea. AB - We investigated the adenoviral etiology and seasonal epidemic trends in intussusception and each adenoviral subgroup. Also we confirmed whether we can use the adenovirus data of Acute Infectious Agents Laboratory Surveillance Report (AIALSR) as an epidemic predictor of intussusception. Patients with intussusception (n = 126), < 5 years old, were enrolled and matched by age and sex with controls suffering acute gastroenteritis without intussusception (n = 106), all recruited at 8 centers. All fecal specimens were assayed for adenovirus, including subgroups A, B, C, E, and F, with reverse transcriptase polymerase chain reaction (RT-PCR). Adenovirus was detected in 53 cases and 13 controls (P < 0.001). Nonenteric adenoviruses (NEAds) were detected in 51 cases and four controls (P < 0.001). We used Spearman's correlation analysis to analyze the incidence of intussusception and adenoviral epidemic trends, and compared them with fecal and respiratory adenoviral epidemic trends in the AIALSR. The trend of intussusception correlated with total NEAds (r = 0.635; P = 0.011), as did the fecal AIALSR adenovirus trends (r = 0.572; P = 0.026). Among the NEAd subgroups, subgroup C was dominant (P < 0.001), but subgroups B (P = 0.007) and E (P = 0.013) were also significant to intussusception. However, only subgroup C showed a significant epidemic correlation (r = 0.776; P = 0.001) with intussusception. Not respiratory but fecal AIALSR adenovirus trends correlated with the incidence of NEAds and intussusception. We suggest the possibility of using fecal AIALSR adenovirus data as an approximate epidemic predictor of intussusception. PMID- 28875613 TI - Risk Factors for Smartphone Addiction in Korean Adolescents: Smartphone Use Patterns. AB - With widespread use of the smartphone, clinical evidence for smartphone addiction remains unclear. Against this background, we analyzed the effect of smartphone use patterns on smartphone addiction in Korean adolescents. A total of 370 middle school students participated. The severity of smartphone addiction was measured through clinical interviews and the Korean Smartphone Addiction Proneness Scale. As a result, 50 (13.5%) were in the smartphone addiction group and 320 (86.5%) were in the healthy group. To investigate the effect of smartphone use patterns on smartphone addiction, we performed self-report questionnaires that assessed the following items: smartphone functions mostly used, purpose of use, problematic use, and parental attitude regarding smartphone use. For smartphone functions mostly used, the addiction group showed significantly higher scores in "Online chat." For the purpose of use, the addiction group showed significantly higher "habitual use," "pleasure," "communication," "games," "stress relief," "ubiquitous trait," and "not to be left out." For problematic use, the addiction group showed significantly higher scores on "preoccupation," "tolerance," "lack of control," "withdrawal," "mood modification," "conflict," "lies," "excessive use," and "loss of interest." For parental attitude regarding children's smartphone use, the addiction group showed significantly higher scores in "parental punishment." Binary logistic regression analysis indicated that "female," "use for learning," "use for ubiquitous trait," "preoccupation," and "conflict" were significantly correlated with smartphone addiction. This study demonstrated that the risk factors for smartphone addiction were being female, preoccupation, conflict, and use for ubiquitous trait; the protective factor was use for learning. Future studies will be required to reveal the additional clinical evidence of the disease entity for smartphone addiction. PMID- 28875615 TI - Prescription Trends of Psychotropics in Children and Adolescents with Autism Based on Nationwide Health Insurance Data. AB - Children with autism are often medicated to manage emotional and behavioral symptoms; yet, data on such pharmacotherapy is insufficient. In this study, we investigated the Korean National Health Insurance Claims Database (NHICD) information related to autism incidence and psychotropic medication use. From the 2010-2012 NHICD, we selected a total of 31,919,732 subjects under 19 years old. To examine the diagnostic incidence, we selected patients who had at least one medical claim containing an 10th revision of International Statistical Classification of Diseases and Related Health Problems (ICD-10) code for pervasive developmental disorder, F84, not diagnosed in the previous 360 days. Psychotropics were categorized into seven classes. Then, we analyzed the data to determine the mean annual diagnostic incidence and psychotropic prescription trends. Diagnostic incidence was 17,606 for the 3 years, with a mean annual incidence per 10,000 population of 5.52. Among them, 5,348 patients were prescribed psychotropics. Atypical antipsychotics were the most commonly used, followed by antidepressants. An older age, male sex, and the availability of medical aid were associated with a higher rate of prescription than observed for a younger age, female sex, and the availability of health insurance. Psychotropic drugs were used for less than one-third of patients newly diagnosed with autism, and prescription differed by sex and age. Increased diagnostic incidence is associated with an increased prescription of psychotropic drugs. Therefore, medication-related safety data and policies for psychotropic drugs in autism should be prepared. PMID- 28875614 TI - Post-Traumatic Cognition Mediates the Relationship between a History of Sexual Abuse and the Post-Traumatic Stress Symptoms in Sexual Assault Victims. AB - More than half of all sexual assault victims report experiencing sexual victimization more than once. The aim of this paper was to determine the role post-traumatic cognition plays in the relationship between a history of sexual abuse and post-traumatic stress symptoms in sexual assault victims. The relationship between a history of sexual assault and the severity of post traumatic stress symptoms was investigated retrospectively using data from a sexual assault crisis center in Korea. Data on psychological symptoms were collected in person at the initial assessment and by telephone 1 month later using the Post-traumatic Cognitions Inventory and the Post-traumatic Stress Disorder Symptoms Scale: Self-report Version. Of 105 women included in the analysis, 10 (9.5%) reported prior sexual abuse and were classified as sexually revictimized. Revictimized women had more post-traumatic negative cognition at initial assessment (t = -2.98; P = 0.004) and more post-traumatic symptoms at 1 month follow-up (t = -2.39; P = 0.019) than singly victimized women. At 1 month follow-up, the severity of post-traumatic stress symptoms had increased in revictimized women but had decreased slightly in singly victimized women. Negative post-traumatic cognition fully mediated the association between a history of sexual abuse and the severity of post-traumatic stress symptoms. Early detection of sexually revictimized women and tailored service and treatment intervention is needed to better serve this group of victims. Interventions targeted at preventing revictimization or post crime victimization may also help victims recover from the trauma and prevent future abuse. PMID- 28875616 TI - Prescription Pattern of Antidepressants for Children and Adolescents in Korea Based on Nationwide Data. AB - Antidepressant prescription for youths has recently been on the increase. There is a growing concern over the increasing off-label usage of antidepressants. Current data on off-label antidepressant usage vary across countries and healthcare systems. Therefore, we examined the extent and pattern of antidepressant prescription for Korean children and adolescents using population based data. Our data was retrieved from the Korean National Health Insurance Service National Sample Cohort of the year 2013. Among 0.2 million children and adolescents aged 6-18 years from the cohort, subjects who had received any antidepressant medication in the year 2013 were investigated for the prescribed medication, concomitant psychotropic medication, and the associated diagnosis. A total of 2,190 children and adolescents (boys, 55.4%) received antidepressant medication. The most common diagnosis was depressive disorders (n = 469, 21.4%), followed by attention-deficit/hyperactivity disorder (n = 442, 20.2%). Among the prescriptions (n = 3,370), escitalopram (n = 650, 24.1%) and fluoxetine (n = 553, 20.5%) were the two most frequently prescribed drugs. A majority of prescriptions (n = 2,039, 60.5%) included concomitant psychotropic agents, consisting of antipsychotics (n = 901, 26.7%), sedatives (n = 263, 26.3%), medication for attention-deficit/hyperactivity disorder (n = 822, 24.4%), and some others. Our study shows the prescription pattern of antidepressants for children and adolescents in Korea, of which a large proportion is off-label. The results call for close monitoring by clinicians treating this population. PMID- 28875617 TI - Clinical Considerations When Applying Vital Signs in Pediatric Korean Triage and Acuity Scale. AB - Initial vital signs of children at the emergency department may be abnormal because of anxiety and irritability, resulting in unrealistic triage levels. This study aimed to evaluate the effectiveness of pediatric triage by clinical decision based on the patient's general condition. The Pediatric Korean Triage and Acuity Scale (PedKTAS) has been used nationwide for triage since 2016. The triage level, as assessed by an experienced triage nurse and based on the patient's clinical condition, was defined as the 'real practice (RP)-level,' while the re-calculated triage level, as assessed by the direct application of initial vital signs, was defined as the 'simulation (S)-level.' A total of 22,841 patients were triaged during the study period. The hospitalization rate according to RP-PedKTAS levels exhibited a significant correlation with the expected hospitalization rate suggested by the Pediatric Canadian Triage and Acuity Scale (CTAS) (P = 0.002), whereas the S-PedKTAS levels did not (P = 0.151). Compared with the previously reported pediatric CTAS level-specific hospitalization rate and intensive care unit (ICU) admission rate, RP-PedKTAS was significantly correlated with both hospitalization rate and ICU admission rate (P = 0.001 and P = 0.012, respectively). However, S-PedKTAS showed no significant correlation in both (P = 0.267 and P = 0.188, respectively). The determination of triage levels based on clinical decision rather than the direct application of abnormal initial vital signs to PedKTAS is more accurate in predicting the hospitalization rate and ICU admission rate. PMID- 28875618 TI - Intramyocardial Injection of Stem Cells in Pig Myocardial Infarction Model: The First Trial in Korea. AB - Although cell therapy is emerged for cardiac repair, its efficacy is modest by intracoronary infusion. Therefore, we established the intramyocardial delivery technique using a left ventricular (LV) mapping system (NOGA(r) XP) using 18 pigs. After adipose tissue-derived mesenchymal stem cells (ATSCs) were delivered intramyocardially to porcine infarcted heart, LV ejection fraction (EF) was increased, and LV chamber size was decreased. We proved the therapeutic effect of intramyocardial injection of ATSC through a LV mapping system in the porcine model for the first time in Korea. The adoption of this technique may accelerate the translation into a clinical application in the near future. PMID- 28875619 TI - Lead Poisoning at an Indoor Firing Range. AB - In March 2014, a 39-year-old Korean male presented with a 6-month history of various nonspecific symptoms including dizziness, fatigue, asthenia, irritability, elevated blood pressure, palpitation, eyestrain, and tinnitus. His occupational history revealed that he had been working as an indoor firing range manager for 13 months; therefore, he was subjected to a blood lead level (BLL) test. The test results showed a BLL of 64 MUg/dL; hence, he was diagnosed with lead poisoning and immediately withdrawn from work. As evident from the workplace environmental monitoring, the level of lead exposure in the air exceeded its limit (0.015-0.387 mg/m3). He received chelation treatment with calcium-disodium ethylenediaminetetraacetic acid (1 g/day) for 5 days without any adverse effects. In the follow-up results after 2 months, the BLL had decreased to 9.7 MUg/dL and the symptoms resolved. This report represents the first occupational case of lead poisoning in firing ranges in Korea, and this necessitates institutional management to prevent the recurrence of poisoning through this route. Workplace environmental monitoring should be implemented for indoor firing ranges, and the workers should undergo regularly scheduled special health examinations. In clinical practice, it is essential to question the patient about his occupational history. PMID- 28875621 TI - Rare Manifestations of Anaplastic Thyroid Carcinoma: the Role of BRAF Mutation Analysis. AB - Anaplastic thyroid carcinoma (ATC) is difficult to distinguish from other cancers, especially when its pathological features are atypical for ATC or when the tumor is totally undifferentiated and occurs after a considerable lapse of time, in an area remote from the original site of the tumor. Here, we present two patients (68-year-old man and 56-year-old woman) with rare manifestations of ATC, which were initially thought to be other malignancies. Immunohistochemical tests, using various markers, failed to provide information about the origin of these tumors. However, both patients had a history of papillary thyroid carcinoma (PTC) from several years ago and BRAF mutations were observed in the undifferentiated tumors, as well as in the previous PTCs. Therefore, we could make a diagnosis of ATC derived from PTC. As such, BRAF mutation analysis may serve as a useful tool for ATC diagnosis in challenging ATC cases. PMID- 28875622 TI - Primary Pulmonary Extranodal Natural Killer/T-cell Lymphoma, Nasal Type Presenting as Diffuse Ground Glass Opacities: a Case Report. AB - Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTCL) is a rare type of lymphoma that accounts for only 5%-18% of all cases of non-Hodgkin lymphoma (NHL). In published series, 60%-90% of NK/T-cell lymphomas are localized to the nasal and upper airway. We describe a 55-year man who presented with cough, sputum, dyspnea on exertion, and a chest computed tomography scan shows diffuse ground glass opacities (GGOs), suggestive of an interstitial lung disease. He was treated with a corticosteroid and his symptoms improved. However, when the corticosteroid was tapered, his symptoms recurred. The patient underwent a surgical lung biopsy and ENKTCL was diagnosed. We present this case because ENKTCL involving only the lung is very rare but very informative. To our knowledge, our patient is the first case that primary pulmonary ENKTCL is presented with GGOs. PMID- 28875620 TI - MERS-CoV Infection in a Pregnant Woman in Korea. AB - Middle East respiratory syndrome (MERS) is a lethal respiratory disease - caused by MERS-coronavirus (MERS-CoV) which was first identified in 2012. Especially, pregnant women can be expected as highly vulnerable candidates for this viral infection. In May 2015, this virus was spread in Korea and a pregnant woman was confirmed with positive result of MERS-CoV polymerase chain reaction (PCR). Her condition was improved only with conservative treatment. After a full recovery of MERS, the patient manifested abrupt vaginal bleeding with rupture of membrane. Under an impression of placenta abruption, an emergent cesarean section was performed. Our team performed many laboratory tests related to MERS-CoV and all results were negative. We report the first case of MERS-CoV infection during pregnancy occurred outside of the Middle East. Also, this case showed relatively benign maternal course which resulted in full recovery with subsequent healthy full-term delivery without MERS-CoV transmission. PMID- 28875623 TI - Photoacoustic thermal flowmetry with a single light source. AB - We report a photoacoustic thermal flowmetry based on optical-resolution photoacoustic microscopy (OR-PAM) using a single laser source for both thermal tagging and photoacoustic excitation. When an optically absorbing medium is flowing across the optical focal zone of OR-PAM, a small volume of the medium within the optical focus is repeatedly illuminated and heated by a train of laser pulses with a high repetition rate. The average temperature of the heated volume at each laser pulse is indicated by the photoacoustic signal excited by the same laser pulse due to the well-established linear relationship between the Grueneisen coefficient and the local temperature. The thermal dynamics of the heated medium volume, which are closely related to the flow speed, can therefore be measured from the time course of the detected photoacoustic signals. Here, we have developed a lumped mathematical model to describe the time course of the photoacoustic signals as a function of the medium's flow speed. We conclude that the rising time constant of the photoacoustic signals is linearly dependent on the flow speed. Thus, the flow speed can be quantified by fitting the measured photoacoustic signals using the derived mathematical model. We first performed proof-of-concept experiments using defibrinated bovine blood flowing in a plastic tube. The experiment results have demonstrated that the proposed method has high accuracy (~+/-6%) and a wide range of measurable flow speeds. We further validated the method by measuring the blood flow speeds of the microvasculature in a mouse ear in vivo. PMID- 28875624 TI - [Study on status of criteria for formulating specification and grade of Chinese medicinal materials based on filed survey in medicine market]. AB - The commodity specification and grade is an important factor affecting the price of Chinese medicinal materials. Specification and grade standard play an important role in transferring quality information in Chinese medicinal market, which is characterized by highly information asymmetry. This paper analyses and expounds six classification methods of commodity specification and grade of Chinese medicinal materials based on the market investigation carried out in the medicine markets in Anguo, Bozhou, Yulin, Chengdu and so on. This study proposes that to formulate the commodity specification and grade standard of Chinese medicinal materials, their efficacy, inspection, purity and beauty should be taken into account orderly. PMID- 28875625 TI - [Formation and evolution of commodity specification and grade of traditional Chinese medicine]. AB - As an important reference index to evaluate the quality of Chinese medicinal materials, the commodity specification and grade of traditional Chinese medicine has an effect on the medicinal material's price, can promote "high quality and high price" of the traditional Chinese medicine, prompt market transactions more convenient and standard, and has a great significance to the development of the whole traditional Chinese medicine industry. The formation of traditional Chinese medicine specifications and grades experienced a long historical development process. In order to provide the reference for modification of the product specifications and grades standards and management of traditional Chinese medicine products, the author consulted a large number of materia medica books and related references, sorted and analyzed the historical development process. The author divided the formation and development process into four stages, including germination stage before the Southern and Northern Dynasties, development stage of Tang and Song Dynasty, mature period of the Ming and Qing Dynasties and the inheritance development stage since the foundation of the People's Republic. The author believes that the clinical curative effect is the driving force to promote the development of commodity specifications and grades. In addition, the national pharmaceutical policy, international status, the level of science and technology also influence the development of commodity specifications and grades in some extents. Finally, the author provides three piece of suggestions for the modification of the product specifications and grades standards, according to the historical development rule. PMID- 28875626 TI - [Research model on commodity specification standard of radix Chinese materia medica]. AB - As an important part of the market commodity circulation, the standard grade of Chinese traditional medicine commodity is very important to restrict the market order and guarantee the quality of the medicinal material. The State Council issuing the "protection and development of Chinese herbal medicine (2015-2020)" also make clear that the important task of improving the circulation of Chinese herbal medicine industry norms and the commodity specification standard of common traditional Chinese medicinal materials. However, as a large class of Chinese herbal medicines, the standard grade of the radix is more confused in the market circulation, and lack of a more reasonable study model in the development of the standard. Thus, this paper summarizes the research background, present situation and problems, and several key points of the commodity specification and grade standard in radix herbs. Then, the research model is introduced as an example of Pseudostellariae Radix, so as to provide technical support and reference for formulating commodity specifications and grades standard in other radix traditional Chinese medicinal materials. PMID- 28875627 TI - [Qualitative characteristics and classification study on commodity specification and grade standard of Panax notoginseng]. AB - Through the markets investigations and literature surveying, this paper investigates and analyzes the qualitative characteristics and commodity condition of Panax notoginseng. And the samples collected from market and origin were analyzed in order to revise the commodity specification and grade standard of P. notoginseng combined with production practice. In this paper, the authors divide the P. notoginseng into 4 commodity specification which are root (including Cunqi and Dongqi ), Rhizome and rootlet according to different parts and harvest time. And the root were divided into 8 grade which are 20, 30, 40, 60, 80, 120, countless and substandard. The density and internal components between the different commodity specification and grade of P. notoginseng were also compared. As well as the effect of different producing area, cultivation years and harvesting time on the commodity specification and grade of P. notoginseng were researched. On this basis, we revise and improve the commodity specification and grade standard of P. notoginseng. Moreover, we suggest the quality control indexes of P. notoginseng should be developed according to the different medicinal part and commodity specification in CHP. In order to guide the standardized production of traditional Chinese medicine and ensure the quality of medicinal materials, the cultivation years and density of each medicinal materials should also be indicated in CHP. PMID- 28875628 TI - [Analysis of commercial specifications and grades of wild and cultivated Gentianae Macrophyllae Radix based on multi-indicative constituents]. AB - The study is aimed to analyze the commercial specifications and grades of wild and cultivated Gentianae Macrophllae Radix based on multi-indicative constituents. The seven kinds of main chemical components containing in Gentianae Macrophyllae Radix were determined by UPLC, and then the quality levels of chemical component of Gentianae Macrophyllae Radix were clustered and classified by modern statistical methods (canonical correspondence analysis, Fisher discriminant analysis and so on). The quality indices were selected and their correlations were analyzed. Lastly, comprehensively quantitative grade division for quality under different commodity-specifications and different grades of same commodity-specifications of wild and planting were divided. The results provide a basis for a reasonable division of specification and grade of the commodity of Gentianae Macrophyllae Radix. The range of quality evaluation of main index components (gentiopicrin, loganin acid and swertiamarin) was proposed, and the Herbal Quality Index (HQI) was introduced. The rank discriminant function was established based on the quality by Fisher discriminant analysis. According to the analysis, the quality of wild and cultivated Luobojiao, one of the commercial specification of Gentianae Macrophyllae Radix was the best, Mahuajiao, the other commercial specification, was average , Xiaoqinjiao was inferior. Among grades, the quality of first-class cultivated Luobojiao was the worst, of second class secondary, and the third class the best; The quality of the first-class of wild Luobojiao was secondary, and the second-class the best; The quality of the second class of Mahuajiao was secondary, and the first-class was the best; the quality of first-class Xiaoqinjiao was secondary, and the second-class was the better one between the two grades, but not obvious significantly. The method provides a new idea and method for evaluation of comprehensively quantitative on the quality of Gentianae Macrophyllae Radix. PMID- 28875629 TI - [Correspondence analysis between traditional commercial specifications and quantitative quality indices of Notopterygii Rhizoma et Radix]. AB - This paper aims to explore a comprehensive assessment method combined traditional Chinese medicinal material specifications with quantitative quality indicators. Seventy-six samples of Notopterygii Rhizoma et Radix were collected on market and at producing areas. Traditional commercial specifications were described and assigned, and 10 chemical components and volatile oils were determined for each sample. Cluster analysis, Fisher discriminant analysis and correspondence analysis were used to establish the relationship between the traditional qualitative commercial specifications and quantitative chemical indices for comprehensive evaluating quality of medicinal materials, and quantitative classification of commercial grade and quality grade. A herb quality index (HQI) including traditional commercial specifications and chemical components for quantitative grade classification were established, and corresponding discriminant function were figured out for precise determination of quality grade and sub-grade of Notopterygii Rhizoma et Radix. The result showed that notopterol, isoimperatorin and volatile oil were the major components for determination of chemical quality, and their dividing values were specified for every grade and sub-grade of the commercial materials of Notopterygii Rhizoma et Radix. According to the result, essential relationship between traditional medicinal indicators, qualitative commercial specifications, and quantitative chemical composition indicators can be examined by K-mean cluster, Fisher discriminant analysis and correspondence analysis, which provide a new method for comprehensive quantitative evaluation of traditional Chinese medicine quality integrated traditional commodity specifications and quantitative modern chemical index. PMID- 28875630 TI - [Study on commercial specification of atractylodes based on Delphi method]. AB - This research adopts "Delphi method" to evaluate atractylodes traditional traits and rank correlation. By using methods of mathematical statistics the relationship of the traditional identification indicators and atractylodes goods rank correlation was analyzed, It is found that the main characteristics affectingatractylodes commodity specifications and grades of main characters wereoil points of transaction,color of transaction,color of surface,grain of transaction,texture of transaction andspoilage. The study points out that the original "seventy-six kinds of medicinal materials commodity specification standards of atractylodes differentiate commodity specification" is not in conformity with the actual market situation, we need to formulate corresponding atractylodes medicinal products specifications and grades.This study combined with experimental results "Delphi method" and the market actual situation, proposed the new draft atractylodes commodity specifications and grades, as the new atractylodes commodity specifications and grades standards. It provides a reference and theoretical basis. PMID- 28875632 TI - [Research progress of anti-drug resistance in traditional Chinese medicine]. AB - Bacterial drug resistance has been always the focus of the world. With the abuse of antibiotics and the emerging of "Superbug" in the world, the harm of drug resistance to human beings is more and more serious, with an uncontrollable trend. Today, with the relative lack of antibiotics, people pay more attention to Chinese herbal medicines with a wide range of sources, high security, less toxic side effects and mysterious anti-drug resistance mechanism, hoping to find new ways or new ideas to solve the problem of drug resistance. In recent years, the screening, extracting and isolating of effective drug resistance inhibitors from natural plants and traditional Chinese Medicine, as well as the investigation in mechanism of anti-drug resistance, have become a hot research in the field of medicine. In this paper, we would analyze and summarize the action mechanism of bacterial drug resistance, characteristics and advantages of anti-drug resistance of traditional Chinese medicine, as well as the herbal ingredients with anti-drug resistance effect, hoping to provide certain theoretical basis and research ideas for solving the problem of bacterial drug resistance and developing new green Chinese antibiotics. PMID- 28875631 TI - [Research progress on salvianolic acids of Salvia miltiorrhiza]. AB - Salvia miltiorrhiza is one of the most common traditional Chinese medicines. It has rich resources in China. According to modern studies, phenolic acids are the main effective components in S. miltiorrhiza. These components have cardiovascular and cerebrovascular protective effect, and anti-tumor, antioxidant, anti-inflammatory, and antifibrotic activities, etc. It has been widely used for the treatment of cardiovascular and cerebrovascular diseases and others. In this paper, the chemicals and pharmacological effects of phenolic acids from S. miltiorrhiza were summarized in the last decade. Its researches and development prospects were also analyzed for further studying and comprehensive utilization of these phenolic acids. PMID- 28875633 TI - [Balance between cardiovascular pharmacological and hemolytic effects of saponins of Panax notogenseng]. AB - PNS (total saponins of Panax notognseng, PNS) has a clear effect and wide application prospect for cardiovascular diseases. At the same time, saponins have hemolytic properties, which are related to its molecular structure type and dosage. On one hand, this article summarizes the research progress of PNS in heart cerebrovascular pharmacology pharmacological in recent five years, a number of studies both in vitro and in vivo for overall body, organs, cells and molecules, show that PNS could improve myocardial and cerebral ischemia injury, and it has effects in resisting thrombosis, inflammation, oxidation, atherosclerosis, and modulating vascular endothelial cells function and improving the cerebral ischemia injury etc. On the other hand, the hemolysis effect of PNS is closely related to its molecular structure type and administrating dosage. Different structures bring about different hemolysis activities. Structure activity relationship suggests that the length of sugar side chains attached to C 20 and the disaccharide connection mode on C-3 may influence the hemolysis activity of PNS. Within the dose range from 2.5 to 250 mg*L-1, PNS has no hemolysis activity. However, PNS exhibits hemolytic properties at high concentrations(>=500 mg*L-1). Based on the hemolytic or anti-hemolysis characteristics of saponins, and dose-response relationship, the rational clinical application of PNS can be guaranteed by controlling the ratio of hemolytic monosaponins in PNS and improving the hemolytic test method. PMID- 28875634 TI - [SIC algorithm based model updating for near infrared analysis of Salvia miltiorrhiza alcohol extraction process]. AB - The near-infrared (NIR) spectroscopy for offline monitoring of alcohol extraction process of Salvia miltiorrhiza was investigated, with high performance liquid chromatography (HPLC) determination of value for reference. The partial least squares method was adopted to establish the tanshinone IIA quantitative calibration model, so as to detect extraction process of Salvia miltiorrhiza. Because the differences between batches of raw materials may endanger the robustness of the original model, the simple interval calculation (SIC) was applied in updating the near-infrared quantitative model for traditional Chinese medicine extraction process for the first time, and compared with Random Selection (RS) method. SIC's final updating results showed that root mean square with cross validation (RMSECV), root mean square error of prediction (RMSEP) and residual predictive deviation (RPD) of tanshinone IIA were 0.006 8 g*L-1, 0.005 4 g*L-1 and 3.14, respectively; but RS' final updating results showed that RMSECV, RMSEP and RPD were 0.006 4 g*L-1, 0.006 8 g*L-1 and 2.50, respectively. This study suggested that SIC is superior to RS, and provided a research foundation for quality control and monitoring of S. miltiorrhiza extraction process in the future. PMID- 28875635 TI - [Isothermal adsorption, desorptionand thermodynamic properties of Scutellaria baicalensis pieces]. AB - To study the characteristics of adsorption and desorption of Scutellaria baicalensis pieces. On the basic thermodynamic theory, thestatic method was adopted to obtain S. baicalensis pieces' isothermal adsorption and desorption data at 25, 35, 45 C, with the water activity between 0.10 and 0.85. Eight moisture models were selected to fit the data and then evaluated to determine the thermodynamic properties of S. baicalensis pieces. The results show that, among the eight adsorption models, Peleg fit the best, in which absolutely-safe and the relatively-safe moisture contents of S. baicalensis pieces were around 9.22% and 13.51% respectively; the net equivalent heat adsorption and desorption and the differential entropy of S. baicalensis pieces were closely related to moisture content, and decrease within crease of water content; when drying the pieces, 12.0% of moisture content can be taken as the drying end; both of adsorption and desorption processes were driven by enthalpy and non-spontaneous. The study on S. baicalensis pieces' isothermal adsorption and desorption rules can help advance studies on adsorption and desorption rules of Chinese herbal pieces, and play a good guiding role in optimizing storage conditions and drying process of Chinese herbal pieces. PMID- 28875636 TI - [Preparation and in vitro evaluation of tetrandrine-loaded composite microspheres embedded with PLGA nanoparticles]. AB - In this paper, we prepared a type of composite microspheres embedded with poly (lactic-co-glycolic acid) (PLGA) nanoparticles for efficient inhalation delivery of tetrandrine (Tet), which is a traditional Chinese medicine for anticancer, and studied its morphology, drug release profile, cytotoxicity and cellular uptake behavior. PLGA nanoparticles loading tetrandrine were prepared by emulsion solvent diffusion method, and composite microspheres were prepared by spray drying method with mannitol as matrix due to its osmotic effect. Scanning electronic microscopy, dynamic light scattering laser particle analyzer and confocal microscopy were applied to characterize the morphology and size of the microspheres. The drug loading rate, drug encapsulation efficiency and drug release properties were explored by RP-HPLC. The cytotoxicity in A549 cells between crude drug of Tet and Tet-loaded microspheres were compared by MTT assay. The cellular uptake behavior of microspheres in A549 cells was investigated using confocal laser scanning microscopy. The resultant microspheres were composed of 189 nm PLGA nanoparticles exhibited sizes ranging from 1 to 3 MUm, with the highest deposition efficiency. The microspheres can easily be dissolved in a mimic lung environment and release redispersible PLGA nanoparticles. Compared with crude drug of Tet, Tet-loaded microspheres showed a certain sustained release property and higher cytotoxicity effect to A549 cells. The cellular uptake experiment demonstrated a higher excellent penetration ability of cells to nanoparticles and time-dependent uptake process. This study provides a basis for developing new inhalation therapies for lung cancer. PMID- 28875637 TI - [Effect of heating treatment on stability of two coumarins in Angelica dahurica and activity of tyrosinase]. AB - To study the heating treatment of Angelica dahurica under different temperature and time conditions on the stability of coumarins and tyrosinase activity. HPLC method was used to determine the contents of imperatorin and isoimperatorin, and tyrosinase activity was assayed by measuring the oxidation rate of L-DOPA in vitro. After heated, the contents of imperatorin increased. Expect for being heated at 90 C for 2 h, the content of isoimperatorin was higher than crude one. Before and after being heated, A. dahurica showed an activating effect on tyrosinase. In the same temperature and time conditions, the activation rate increased with the rise of concentration of tyrosinase extracts. Heating process for A. dahurica could change the contents of imperatorin and isoimperatorin, mainly increasing their concentrations. PMID- 28875638 TI - [Simultaneous determination of six components in water extract and alcohol precipitation liquid in Astragali Radix by HPLC-UV-ELSD]. AB - A HPLC-UV-ELSD method was established for simultaneous determination of six components in two intermediates of Shenqi Fuzheng injection (SFI) and the feasibility of establishing quantitative analysis of multi-components by single marker (QAMS) methods on different detectors was further explored. Calycosin-7-O beta-D-glucoside and astragloside IV were selected as internal reference substances for respectively flavonoids and saponins, and relative correlation factors (RCF) of formononetin-7-O-beta-D-glucoside, 9, 10-dimethoxypterocarpan-3 O-beta-D-glucopyranoside, 2'-dihydroxy-3', 4'-dimethoxyisoflavan-7-O-beta-D glucopyranoside and astragloside II were calculated. Eventually, quantitative results of the 14 samples were compared between QAMS and external standard method. The sample concentrations calculated by QAMS were similar with concentrations calculated by external standard method, and the absolute values of relative deviations were generally less than 5% according to the UV detection of flavonoids. On the basis of ELSD detection for saponins, however, the absolute values of relative deviation of the two methods ranged from 0.48% to 23.17%. The QAMS method built on ultraviolet (UV) detectors was stable and can be used as a substitute method to reduce the consumption of standard compounds; meanwhile, the accuracy of QAMS method built on evaporative light scattering detector (ELSD) was inferior to that of external standard method, and the working principle of ELSD and feasible concentration range remain to be further studied. PMID- 28875639 TI - [Chemical constituents from Mylabris phalerata and their cytotoxic activity in vitro]. AB - Ten compounds were isolated from Mylabris phalerata by using preparative HPLC and column chromatography over MCI gel. On the basis of physical-chemical properties, NMR and MS data analysis, the compounds were identified as 5'-[(1 R,2 R,3 S,6R)-1 hydroxymethyl-2-methyl-3,6-epoxycyclohexane-1,2-dicarboximide]- ethyl-2'-methyl 2'-butenoate (1),cantharidin (2), cyclo-(L-Pro-L-Ala) (3), cyclo-(R-Pro-R-Leu) (4), cyclo-(S-Pro-R-Leu) (5), cyclo-(D-Pro-L-Tyr) (6), indole-3-aldehyde (7), 3 indoleacetic acid (8), valerolactam (9), and 4-hydroxyphthalid (10).Compound 1 was a new compound, and compounds 2-10 were obtained from this genus for the first time. Compounds 1-9 were subjected to cytotoxic activity on HCT-116, HepG2, BGC-823, NCI-H1650, A2780 cell lines, and only compound 2 showed inhibitory effect on all cancer cell lines. PMID- 28875640 TI - [Flavonoids from Picris davurica]. AB - Eleven compounds were purified from the anti-inflammatory extract of Picris davurica by column chromatograph on HP20 macroporous resin, MCI, sephadex LH-20 and ODS.Their structures were determined by the spectra data of NMR and MS as isoestin 7-O-beta-D-glucopyranosyl-2'-O-alpha-L-arabinopyranoside(1), isoetin-7-O beta-D-glucopyranosyl-2'-O-beta-D-xyloypyranoside(2), isoetin-7-O-beta-D glucopyranosyl-2'-O-alpha-D-glucopy- ranoside(3), isoetin 5'-O-beta-D glucopyranoside(4), isoetin-2'-O-beta-D-xyloypyranoside(5), isoetin-4'-O-beta-D-O beta-D-glucopyranoside(6), isoetin-7-O-beta-D-glucopyranoside(7), isoestin-2'-O alpha-L-arabinopyranoside(8), luteolin-7-O-beta-D-glucopyranosie(9), isoetin(10) and luteolin (11). All compounds were isolated from this plantfor the first time.Among them, compounds 1-8 were isolated from the genus Picris for the first time. PMID- 28875641 TI - [Studies on flavonoids from Cirsium setosum]. AB - To investigate the chemical constituents of ethyl acetate from Cirsium setosum, fifteen flavonoids were obtained by column chromatography on silica gel, MCI, Sephadex LH-20, and preparative HPLC. Their structures were identified as 4',5,6 trihydroxy-7-methoxyflavone(1), 4',5-dihydroxy-7,8-dimethoxyflavone(2), sorbifolin-6-O-beta-glucopyranoside(3), kaempferol-7-O-alpha-L-rhamnoside(4), kaempferol(5), quercetin-3-O-beta-D-glucosyl-7-O-alpha-L-rhamnoside(6), myricetin(7), myricetin-3-O-beta-D-glucoside(8), 5,7- dihydroxy -3',4'- dimethoxyflavone(9), 3',4',5- trihydroxy-3,7-dimethoxyflavone(10), 3',3,4',5 tetrahydroxy-7-methoxyflavone(11), 3'-hydroxy-4',5,7-trimethoxyflavone(12), 7 hydroxy-3',4',5-trimethoxyflavone(13), 4',5-dihydroxy-2',3',7,8 tetramethoxylflavone(14), and 5-hydroxy-2',3',7,8-tetramethoxylflavone(15) by spectroscopic data analysis. All compounds were isolated from this plant for the first time.Compounds(1-15) were evaluated for their hypoglycemic activities by PTP1B enzyme model. Among them, compounds 2, 12, and 14 showed significant PTP1B inhibitory activities with IC50 values of 2.54, 1.85, 2.11 MUmol*L-1, respectively. PMID- 28875642 TI - [Research on concentration of 5 different ginsenosides in Panax japonica collected from different cultivated geographic regions]. AB - In this paper, an HPLC-QqQ-MS method for determination of 5 different ginsenosides of Panax japonica collected from different cultivated geographic regions was established. The separation was performed on a Zorbax XDB-C18 (4.6 mm*100 mm, 1.8 MUm) column with the gradient elution of acetonitrile (contained 0.1% formic acid)-0.1% formic acid water. The flow rate was 0.5 mL*min-1. The colunm temperature was maintained at 30 C. The analytes were detected using electrospray ionization (ESI) in multiple reaction monitoring (MRM) modes. Reaction selected ions were 203.2 for ginsenoside Re, 202.9 for ginsenoside Rg1, 365.0 for ginsenoside Rf, 789.1 for ginsenoside Rd, 360.9 for ginsenoside Ro. Ginsenosides Re, ginsenosides Rg1, ginsenosides Rf, ginsenosides Rd, ginsenosides Ro had good linearity in the ranges of 3.33-66.60 MUg (r=0.999 1),2.83-56.54 MUg (r=0.999 2), 0.32-6.51 MUg (r=0.999 2), 12.55-251.00 MUg (r=0.999 3), 0.85-16.90 MUg (r=0.999 5), respectively. The results of recovery were among 100.8% to 104.6%, and the values of RSD were blow 3.0%. This method is simple, reliable and accurate, and can provide basis for P. japonica basic research. PMID- 28875643 TI - [Simultaneous determination of 5 compounds in Tripterygium hypoglaucum based on ultrasound-assisted ionic liquid coupled with HPLC]. AB - Using six kinds of ionic liquids as extractants, ultrasonic-assisted extraction coupled with HPLC method was developed for the simultaneous determination of wilforgine, wiforizine, triptophenolide, wilforine and triptoquinone A in Tripterygium hypoglaucum. The separation was performed on an Inertsil ODS-4 column with the mobile phase of acetonitrile-0.1% phosphoric acid in gradient elution at a flow rate of 0.75 mL*min-1. Detection wavelength was 220 nm and the column temperature was 30C. Under the optimal extractions, the results showed that triptophenolide and triptoquinone A had the highest extraction yield by using 0.6 mol*L-1 [BMIm]PF6 methanol solution as extraction solvent with the solid-liquid ratio of 1?10. The calibration curves of triptophenolide and triptoquinone A showed a good linearity in the range of 0.000 65-0.026, 0.066 55 2.662 MUg (r=0.999 9)respectively. The average recovery was 102.4% and 97.90% with RSD of 2.5% and 1.5%, respectively. Wilforgine, wiforizine and wilforine had the highest extraction yield when using 0.6 mol* L-1 [BMIm]PF6absolute ethanol solution as extraction solvent with the solid-liquid ratio of 1?10. The content of wilforgine, wiforizine and wilforine from 0.023 9-0.956, 0.002 7-0.108, 0.006 4-0.256 MUg showed a good linearity (r=0.999 9), and the average recovery was 100.6%,99.50% and 98.70% with RSD of 2.1%,1.9% and 2.7%, respectively. The results indicated that this method is convenient, reliable and green, and can be used as a reliableanalytical method for the quality control of T.hypoglaucum. PMID- 28875644 TI - [Research on Chinese medicine pairs effects of Panax notoginseng and Bletilla striata before and after compatibility on contents of notoginsenosides]. AB - To discuss the synergistic mechanism of compatible use of two medicinal herbs,Panax notoginseng and Bletilla striata, an HPLC was established to determine two ginseng saponins (20S)-ginseng saponin Rg3 and ginseng saponin Rh4 contained in single decoction of Panax notoginseng as well as in compound decoction of Panax notoginseng and Bletillastriata in different compatibility ratio (1?0.5, 1?1, 1?2), followed by analyzing the impact of amount of notoginsenosides after compatibility. As a result, compared with the single decoction of Panax notoginseng, the contents of ginseng saponin Rg3 and ginseng saponin Rh4 in the compound decoction of Panax notoginseng and Bletillastriata were on the rise as the increasement of the amount of Bletillastriata. The contents of the notoginsengsaponin R1, ginseng saponin Rg1 and ginseng saponin Rb1 of Panax notoginseng single decoction were significantly decreased after compatibility. Therefore, after compatibility, it was more easy to produce (20S) ginseng saponin Rg3 and ginseng saponin Rh4.This study can extend to a method of preparation of (20S)-ginseng saponin Rg3 and ginseng saponin Rh4. Furthermore, after compatibility, two ginseng saponins which had lipase inhibitory effect were both increased significantly, indicating that the compatibility of these two herb medicines may have effect on losing weight. PMID- 28875645 TI - [Inhibitory effects of extracts from Moutan Cortex on formation of advanced glycation end-products (AGEs) in vitro and specificity screening of its potential active components]. AB - In this study, bovine serum albumin (BSA)/methylglyoxal (MGO) non-enzymatic glycosylation reaction system was used for the evaluation of the inhibitory effects of Moutan Cortex extracts on the formation of AGEs. The HPLC-LC-ESI-MS/MS technology was adopted to test and indentify active components in Moutan Cortex against AGEs formation. The different concentrations of extracts (crude herb concentration 50, 100, 150, 200, 250 g*L-1) from Moutan Cortexwas determined by fluorospectrophotometry, indicating an activity against AGEs formation in different concentrations of extracts, the inhibition ratio were (36.2+/-5.3)%, (43.5+/-6.2)%, (55.4+/-7.8)%, (68.6+/-6.7)%, (70.4+/-8.2)%, respectively after 6 day reaction in a dose dependent manner. Besides, the forming speed of AGEs tended to be steady after 24 h reaction. The HPLC technology was used to analyze chromatograms before and after the incubation of Moutan Cortex and methylglyoxal, identify changes in five chromatographic peaks and show decrease or increase in chromatographic peaks. These substances were trigalloyl glucose, tetragalloyl glucose, galloylpaeoniflorin, hexagalloyl glucose and benzoylpaeoniflorin after LC-ESI-MS/MS identification. Extracts from Moutan Cortex showed the remarkable inhibitory effects against formation of AGEs in BSA/glucose system. Furthermore, these potential active components might be associated with the efficacy of Moutan Cortex on treatment of diabetic nephropathy, which enriches basic studies for Moutan Cortex and provides ideas and reference basis for subsequent studies. PMID- 28875646 TI - [Synergistic protective effect of Scutellariae Radix with Phellodendri Chinensis Cortex on Dioscoreae Bulibferae Rhizoma liver toxicity in rats]. AB - Dioscoreae Bulibferae Rhizoma (RDB) is commonly used in clinical Chinese medicine. It has been used in many kinds of traditional Chinese medicine (TCM), but the toxicity of RDB, easily leads to hepatotoxicity. The objective of the present study is to investigate the synergistic protective effect of Scutellariae Radix (SR) with Phellodendri Chinensis Cortex (PCC) on RDB caused liver toxicity in rats. SD female rats were adopted to establish the hepatotoxicity models by RDB (9 g*kg-1, ig) once daily for 28 consecutive days. After 28 days, liver histological changes were observed, and the activity of transaminase and antioxidant enzymes was evaluated. Morphological and biochemical indicators evaluation showed that, Dioscoreae Bulibferae Rhizoma-induced hepatotoxicity models were successful, and the liver cells were dissolved and swelling with fatty degeneration; inflammatory cells were present in gaps; local punctiformed or lamellar hydropic degeneration was found in liver tissues, with partial necrosis. Indexes of liver function (ALT, AST and ALP) were significantly increased (P<0.05 or P<0.01). The combination of SR and PCC has protective effect on RDB-induced hepatotoxicity in rats. SR+PCC exerted the strongest protective effects against RDB-induced hepatotoxicity. SR, PCC, and SB+CP were observed to exhibit hepatoprotective effect as demonstrated by significant decrease in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) (P<0.05 or P<0.01), and MAD level in liver tissue (P<0.001), significant increase in GSH content in liver tissue (P<0.001), and significant improvement in his to pathologic changes of liver tissues in rats. SR, PCC and their combinations could achieve liver protection effect by reducing ALT, ALP and AST level in serum, increasing GSH level and anti-oxidantability of liver tissues, and reducing hepatic tissue cells injury. PMID- 28875648 TI - [Effect of salvianolic acid A on anesthetized canine experimental myocardial infarction]. AB - Salvianolic acid A (SAA), one of the major active water-soluble salvianolic acids of traditional Chinese medicine Salvia miltiorrhiza Bunge, has been reported to be effective on anti-myocardial ischemia, anti-oxidation and anti-thrombus. This study aimed to investigate appropriate administration route on dogs with acute myocardial ischemia(AMI). Twenty-four dogs were randomized into four groups (n=6), model, oral administration of SAA (8 mg*kg-1), intravenous administration of SAA (4 mg*kg-1), intravenous administration of Herbesser(0.5 mg*kg-1) as positive drug group. AMI model was established by ligating left anterior descending coronary arteries(LAD) of dogs. Changes of ST segment were determined by epicardial electrocardiogram(ECG), coronary blood flow (CBF) and myocardial oxygen consumption were measured by ultrasonic Doppler flow meter, serum creatine kinase (CK) and lactate dehydrogenase (LDH) were observed by fully automatic biochemical analyser. Myocardial infarct size was assessed by nitro blue tetrazolium (NBT) staining. Both oral and intravenous administration of SAA reduced the myocardial infarct area/left ventricle area significantly [(16.73+/ 6.52)% and (13.19+/-2.38)%, compared with (24.35+/-4.89)% in model group, P<0.01). Oral administration of SAA improved the ECG performance of Sigma-ST from 30-190 min after ischemia (P<0.05-0.01), while intravenous SAA had a rapid onset (10-190 min after ischemia, P<0.05-0.01). Compared with model group, oral and intravenous SAA both decreased serum CK and LDH significantly (P<0.05-0.01), while the difference of intravenous administration is more significant. SAA protects myocardium in canine experimental myocardial infarction models. Intravenous administration of SAA alleviates myocardial infarction with greater significance than oral route. PMID- 28875649 TI - [Effect of Cynomorium songaricum polysaccharide on telomere of lung cancer A549 cells]. AB - To study the effect of Cynomorium songaricum polysaccharide (CSRP) on A549 cells telomere of human non-small cell lung cancer, the mice were intragastric administrated with CSRP (0.08 g*kg-1) once daily for 4 days. Then their serum was taken for preparing CSRP drug serum. A549 cells were treated by the drug serum, and the effect of drug serum with different concentrations and different treating time on the proliferation of non-small cell lung cancer A549 cells was determined by MTT test. After treating for 48 hours by the drug serum of different concentrations, the telomere length of the cells was determined by fluorescence quantitative polymerase chain reaction (qPCR); the mRNA expression of telomerase reverse transcriptase (TERT) was determined by RT-qPCR; the cells apoptosis was determined by TUNEL assay. The results demonstrated that CSRP of various concentrations could inhibit the proliferation of the lung cancer A549 cells significantly, and the inhibition effect was strongest at 48 hours with the concentration of 6.0 mL*L-1. At 48 h, that CSRP of the concentrations from 1.5 to 12.0 mL*L-1 could significantly shorten the telomere length of A549 cells, and the effect was strongest with the concentration of 1.5 mg*L-1. CSRP of various concentrations could significantly inhibit the mRNA expression of TERT in A549 cells, and the inhibition effect was stronger when the concentration was >=6.0 mL*L-1. CSRP of various concentrations could promote A549 cells apoptosis, and the effect was stronger when the concentration was >=6.0 mL*L-1. In conclusion, CSRP has the anti-cancer effect, and the action mechanism may be associated with inhibiting TERT mRNA expression, shortening telomere length, inhibiting cells proliferation and promoting cells apoptosis. PMID- 28875647 TI - [Antiemetic activity of effective extract and bioactive compounds in ginger]. AB - To investigate the antiemetic effect of the active extract (ginger ether extract, GEE) and its bioactive compounds in ginger, the pica vomiting model in rats and the gastric emptying model in mice were used to observe the antiemetic effect of GEE in cisplatin-induced pica and gastric emptying, and the main components in GEE were detected by RP-HPLC; in vitro, the antagonist effect of GEE and the four components in it were explored by the contraction of guinea-pig ileum induced by SR57227A and carbachol. The results showed that the amount of Kaolin ingested by rats were declined significantly in all the three groups of GEE (25,50,100 mg*kg 1) (P<0.01), while cisplatin-induced gastric emptying in mice was also suppressed in all the three groups (P<0.01), and 6-gingerol, 8-gingerol,10-gingerol and 6 shogaol were found mainly in GEE by RP-HPLC; the maximum contraction of isolated guinea-pig ileum could be reduced by addition of GEE (2.3, 4.6, 11.5 mg*L-1), 6 gingerol,8-gingerol,10-gingerol or 6-shogaol (1, 2, 5 MUmol*L-1) when the concentration of SR5727A was 1*10-5 mol*L-1 and that of carbachol was 1*10-4 mol*L-1 (P<0.05, P<0.01). In conclusion, 5-HT3 and M3 receptors could be antagonized by GEE and its bioactive compounds 6-gingerol, 8-gingerol, 10 gingerol and 6-shogaol, which may be correlated with the antiemetic mechanism of ginger maybe related to it. PMID- 28875650 TI - [Active compounds from Baoyuan decoction with myocardial protection activities and their potential targets]. AB - Baoyuan decoction (BYD) is a classical Chinese formula for coronary heart disease with Qi deficiency, blood stasis tonifying Qi and Yang deficiency. However, the chemical material basis and underlying action mechanisms of BYD still lack systemic study. In order to clarify the active compounds and the potential action mechanisms of BYD, the oxygen-glucose deprivation/recovery (OGD/R)-induced H9c2 cells injury models was used to screen the monomeric compounds of BYD with myocardial protection activity. PubChem's BioAssay database was then used to analyze the potential targets of active monomeric compounds, classify the predicted biological targets, and analyze the internal relation between active compounds of BYD and biological targets. The screening results showed that BYD aqueous extract and 17 monomeric compounds could significantly increase the survival rate of OGD/R-induced H9c2 myocardial cells. The results of virtual targets screening study showed that 15 monomeric compounds and the potential mechanisms for myocardial protection were related to oxidative stress pathway, calcium ion pathway, mitochondrial protection, anti-apoptosis, etc. These results verified that BYD had myocardial protection effect, which was obtained by network regulation of multi-components and multi-targets. All these results provide the theoretical basis and references for the clinical usage of BYD in treatment of coronary heart disease. PMID- 28875651 TI - [Effect of different processed volatile oils from Angelica sinensis on urinary metabolomics rats]. AB - Different processed volatile oils from AS on urine metabolites of normal rats were analyzed to reveal the possible metabolic pathways. Totally 50 male Waster rats were randomly divided into normal control group, C-ASVO group, J-ASVO group, T-ASVO group and Y-ASVO group, with 10 rats in each group. The normal group was given isovolumetric 0.5% polyoxyethylene sorbitan fatty acid ester(Tween-80), while the other groups were given 0.176 mL*kg-1 different processed volatile oils from AS. Drugs were given for 3 successive days. The urine was collected at 48 h with metabolic cages. GC-MS was employed to detect the metabolic fingerprint of rat urine in different times. Principal component analysis(PCA) and orthogonal partial least-squares discriminant analysis(OPLS-DA) were adopted for a multivariate statistical analysis. Metabolites with potential differences were selected based on the results of variable importance in the projection(VIP) and t test. The metabolic pathway analysis(MetPA) database was built for different metabolites' metabolic pathways. The results showed that compared with the normal group, 31 kinds of endogenous metabolites in the different processed volatile oils from AS groups change significantly(P<0.05). And there were differences in normal rat urine metabolites among the different processed volatile oils from AS, of which the influence degree of J-ASVO was slightly stronger than C-ASVO, T ASVO, and Y-ASVO. Therefore, the metabolism effect may be focused on energy metabolism, amino acid metabolism, fatty acid metabolism and glucose metabolism. This study focused on metabolism and mechanism of different processed volatile oils from AS, and provided new ideas for pharmacological actions of traditional Chinese medicines. PMID- 28875652 TI - [Effects of different preparation technologies on concentrations of puerarin and catalpol in plasma and brain of rats after oral administration]. AB - To compare the effects of different preparation technologies on the concentrations of puerarin and catalpol in plasma and brain of rats after oral administration, in order to lay an experimental basis for developing new oral Zige preparations. The nanocrystal, self-microemulsions (tween-80 and Cremophor RH-40 as emulsifiers) and inclusion complex of HP-beta-CD containing puerarin and catalpol were prepared. The concentrations of puerarin and catalpol in plasma and brain of rats after oral administration were determined by HPLC-MS/MS method. The pharmacokinetic parameters and brain target index were compared. The results showed that preparation technologies had different influences on the concentrations of puerarin and catalpol in plasma and brain. The self microemulsion (tween-80) could significantly increase the oral absorption of puerarin than other technologies(P<0.05), and inclusion complex could remarkably increase the oral absorption of catalpol than nanocrystal(P<0.01). For puerarin, the brain targeting index of inclusion complex was the highest (P<0.05); but for catalpol, the brain targeting index of inclusion complex and self-microemulsions were both higher than nanocrystal (P<0.05). The self-microemulsion(tween-80) had the highest AUCbrain of puerarin than other groups (P<0.01); the inclusion complex had the highest AUCbrain for catalpol, but there was no significant difference compared with self-microemulsions. In conclusion, the self microemulsion (tween-80) technology could increase the amount of puerarin and catalpol in brain, and was expected to be used in new oral Zige preparations. PMID- 28875653 TI - [Effects of combined administration of Paeoniae Radix Alba on local pharmacokinetics of six aconite alkaloids by skin microdialysis in vivo]. AB - The Aconiti Radix Cocta gel and Aconiti Radix Cocta combined with Paeoniae Radix Alba gel were administered to mice. Physiological saline was taken as perfusate. The perfusion rate was 2 MUL*min-1 and the microdialysis samples were collected every 0.5 h intervals for eight times. The six aconitine alkaloids concentration in perfusate were determined by HPLC-MS/MS. The concentration-time curves were plotted, and the pharmacokinetic parameters were calculated and analyzed by SPSS. The effects of Paeoniae Radix Alba on transdermal permeation role of six aconitine alkaloids in herb couple of Paeoniae Radix Alba-Aconiti Radix Cocta were investigated. According to the results, Tmax of the three mono-ester aconitum alkaloids of Aconiti Radix Cocta combined with Paeoniae Radix Alba groups were shortened, meanwhile, Cmax and AUC of benzoylaconine and benzoylhypaconine were increased. However, AUC of the three diester-type alkaloids were reduced, with Tmax of hypaconitine prolonged and Cmax lowered. The study suggested that the combined administration of Aconiti Radix Cocta and Paeoniae Radix Alba promoted the transdermal permeation of mono-ester aconitum alkaloids, and inhibited the absorption of parts of diester-type alkaloids. This study proved the decreasing toxicity and increasing efficacy of the combination of Aconiti Radix Cocta and Paeoniae Radix Alba on the transdermal permeation, and provided a reference for studies on the prescription combination regularity and relevant practices. PMID- 28875655 TI - [Clinical characteristics of traditional Chinese medicine and 40 cases of infertility patients]. AB - In order to understand the characteristics of traditional Chinese medicine(TCM) syndrome types, the typical symptoms of different patients and the analysis of professor MA's medication characteristics of the treatment for infertility patients were analyzed. Totally 40 cases of infertile women treated in Xiyuan hospital and TCM out-patient department of China Academy of Chinese Medical Sciences in the past five years were randomly selected to classify their symptoms, signs and the four diagnostic situations in the first diagnosis, summarize syndromes and typical symptoms and analyze the characteristics of medication with Ma. Randomly selected nearly five years in 40 cases of infertile women with China Academy of Chinese Medical Sciences Xiyuan hospital and Chinese medicine out-patient department treatment, first diagnosed by symptoms, signs and the four diagnostic situation. According to the results, kidney yang deficiency: 10 cases (25%), kidney yin deficiency: 6 cases (15%), phlegm dampness: 3 cases (7.5%), liver qi stagnation: 3 cases (7.5%), blood stasis in the uterus: 7 cases (17.5%), deficiency of kidney yin deficiency and phlegm dampness: 1 cases (2.5%), kidney yin deficiency syndrome of liver qi stagnation: 2 cases (accounted for 5%), deficiency of kidney yang deficiency syndrome of liver qi stagnation: 1 cases (2.5%), phlegm dampness syndrome of liver qi stagnation:1 cases (2.5%), kidney yin deficiency syndrome, blood stasis and stagnation in the uterus 2 cases (accounted for 5%), liver qi stagnation syndrome and blood stasis in the uterus 2 cases (accounted for 5%), deficiency of kidney yang deficiency syndrome of liver qi stagnation syndrome and blood stasis in the uterus, 1 cases (2.5%). Typical symptoms were dominated by backache, pain and cold in the lower abdomen, followed by thirst, dry throat, more menstrual blood clots, more petechial hemorrhages at tongue, dysphoria, premenstrual breast pain, irritability, chest distress and greasy in mouth, leucorrhea, semiliquid stool or coprostasis. 40 cases of infertility patients showed obvious curative effect after the treatment of professor Ma's medication. PMID- 28875654 TI - [Unsupervised data mining for prescription and medication regularity for treatment of cervical vertigo]. AB - Vertebral artery type cervical spondylosis is a common type of cervical spondylosis, also known as cervical vertigo. In recent years, with the increase of people's life pace and the number of office staff, the incidence rate has been rising year by year, with a trend of younger age. Because traditional Chinese medicine has unique advantages in treating cervical vertigo, it is necessary to study the regularity of the Chinese medicine for cervical vertigo. But at present, the research is mainly based on the statistics for frequency and proportion of herbs. In addition, in the process of diagnosis and treatment of Chinese medicine, personal experience also caused differences in prescription compatibility and drug dosage, which makes difficult guarantee for the safety and effectiveness of drug treatment. So, this paper is based on literatures about the traditional Chinese medicine in treatment of cervical vertigo in the past 5 years, by using association rules algorithm, complex system entropy clustering and other non supervised data mining methods. Analysis was made for the use of various drugs in the frequency, the association rules, the core drug combination and the new prescriptions. The traditional Chinese medicine inheritance support system(TCMISS) was utilized to analyze 154 drugs from the 101 prescriptions, determine the use frequency of drugs, analyze the characteristics and the compatibility of core drugs, and dig out 14 core drug combinations and 7 new prescription combinations. The prescription and medication regularities illustrates the drugs for treatment of cervical vertigo, including those for flating liver and suppressing yang, invigorating the circulation of blood to remove blood stasis, reducing water and permeating dampness, increasing qi and activating blood, and nourishing the liver and kidney mainly. Treatment rules are nourishing liver and kidney, invigorating the circulation of blood stasis Tongqiao, reducing phlegm and dampness, flating liver and suppressing yan, dredging collaterals, supplementing qi and nourishing blood. This study aims to summarize frequently used single herbs for vertebral artery type cervical spondylosis, combinations of frequently used herbs and dosage of frequently used herbs with significant efficacy, define the current prescription and medication regularities for treating cervical vertigo and give guidances for clinical mediation. PMID- 28875656 TI - [Comparative analysis between origin of cooked traditional Chinese medicine powder and modern formula granules]. AB - In this study, the origin and causes of cooked traditional Chinese medicine powder were reviewed, and a comprehensive analysis was made for the time background of modern traditional Chinese medicine formula granules and the future development trend, in order to provide reference for application and promotion of traditional Chinese medicine formula granules. By reference to ancient medical books of previous dynasties, a system review was conducted for infancy, formation, maturity and transition of cooked traditional Chinese medicine powder, and a comprehensive analysis was made for the six factors of cooked traditional Chinese medicine powder's maturity in the Song Dynasty. Efforts were made to collect domestic and foreign research literatures of modern formula granules, understand the detailed development, and conduct an objective analysis of the current clinical application of modern formula granules. According to the comparative analysis for the application characteristics of cooked traditional Chinese medicine powder and modern formula granules, 1the popularity of cooked traditional Chinese medicine powder in the Song Dynasty has six factors: soaring numbers of medical students and medical practitioners, high medical expenses due to huge army, rapid population growth, frequent epidemics and increasing diseases, and insufficient finances of central and local governments. 2On the basis of clinical application characteristics of traditional Chinese medicine formula granules, traditional Chinese medicine formula granules contain extracted and concentrated effective components, which guarantee the curative effect, meet modern people's demands for "quick, simple and convenience" traditional Chinese medicine decoctions, show a relatively high cost performance; however, formula granules are restricted by their varieties and lack unified quality control standards, and single-extract formula granules have not synergy and attenuation effects of combined traditional Chinese medicine decoctions, which also restricts its clinical application and promotion. 3Both have advantages in the process of clinical application, and shall be used based on syndromes. In conclusion, traditional Chinese medicine formula granules do not have disadvantages of "difficult, complicated, turbid and disorderly" cooked traditional Chinese medicine powder, and solve such problems as "inflexibility, expensiveness, restriction, disorder and inefficacy", which is the important basis for promoting traditional Chinese medicine formula granules. PMID- 28875657 TI - [Research and development on efficacy of Chinese herbal compound]. AB - The efficacy not only is summarized by clinical effect of Chinese herbal compound on theory of traditional Chinese medicine, but also is manifested to clinical effect by interaction of many intricate chemical substances. The efficacy of Chinese herbal compound is current research focus in field of traditional Chinese medicine. By currently knowing in different aspects which included the progression in efficacy of Chinese herbal compound, symptomatic efficacy of Chinese herbal compound, the relationship between the efficacy and pharmacologic effect of Chinese herbal compound, the efficacy related pharmacodynamic substance and the evaluation of efficacy, it had been summarized mainly problems and methods in research and development process of the efficacy of Chinese herbal compound in this paper. Paper also elucidated problems that need to pay attention in research of efficacy in order to provide references for clinical and experimental studies of efficacy in Chinese herbal compound, boost research and development level of new traditional Chinese drug and facilitate modernization of traditional Chinese medicines. PMID- 28875658 TI - [Steroidal saponins and their pharmacological activities in Solanum plants]. AB - The genus Solanum which is the largest genus in Solanaceae consists of more than 2 000 species, most of them are distributed in tropics and subtropics areas, and only a small amount in temperate regions throughout the world. Steroidal saponins could be found in many species of the Solanum, and they are an important group of natural products exhbiting a number of potent beneficent properties, such as anti tumor, antibacterial, antifungal, anti-inflammatory, antiviral, antioxidant, hypoglycemic, and antihyperlipidemic effects. As supplement, this paper gives a review of different structural categories of steroidal saponins and their pharmacological effects from the solanum plants over the past decade, and it is intended to provide a point of reference for further research on steroidal saponins in Solanum plants. PMID- 28875659 TI - [Advance in treatment of pediatric leukemia through modulating signaling pathways induced by traditional Chinese medicine]. AB - Leukemia is the most common type of cancer in childhood, which is also one of the malignant tumors that can be cured by chemotherapy. However, infection and the side effects of chemotherapy drugs are the causes of death in children with leukemia. Chemotherapy combined with traditional Chinese medicine is used to treatment of pediatric leukemia in clinic. Although traditional Chinese medicine has extensive clinical experience in the treatment of leukemia, the mechanism is not clear. The targeted drugs are attractive for the advantages of the high selectivity and little side effects. Targeted therapies in pediatric leukemia are targeting BCR/ABL, TARA and FLT3 proteins, which activation results in the downstream activation of multiple signaling pathways, including the PI3K/AKT, JNK/STAT, Ras/ERK pathways. In recent years, the target site or the signaling pathways are clear for the traditional Chinese medicine in the treatment of leukemia. In this paper, we review recent studies, summary the traditional Chinese medicine prescriptions and effective ingredients which can regulate the signaling pathways. We view to provide a basis for the treatment of childhood leukemia with traditional Chinese medicine combined with chemotherapy drugs or targeted drugs. PMID- 28875660 TI - [Effects of stocking density and exchanging water frequency on growth and inner quality of Whitmania pigra]. AB - The effects of stocking density and exchanging water frequency on growth, digestive enzyme activity, anti-oxidative enzyme and inner quality of Whitmania pigra Whitman were evaluated with corresponding measures. The results showed that the eventual biomass, specific growth rate, gained weight rate, activities of amylase, lipase, protease, SOD, CAT, and ALP correlated positively with stocking density and negatively with exchanging water frequency (P<0.05). Exchanging water frequency had negative correlation with ammonia nitrogen, nitrite, and hydrogen sulfide while revealed positive correlation with dissolved oxygen in the water. Stocking density and exchanging water frequency showed no significant effects on the contents of moisture, total ash, and acid-insoluble ash. It suggested that the optimum stocking density was 7.5 million per hectare and the appropriate exchanging water interval was 72 h. PMID- 28875661 TI - [Effects of different stocking density and diet on development of Bufo gargarizans tadpoles]. AB - The effects of four different stocking densities and five different diets on the growth of Bufo gargarizans tadpoles were studied to determine the optimum stocking density and diet. For stocking density experiment, the tadpoles were fed respectively at different density of 200, 500, 1 000 and 2 000 tadpoles per square meter. For diet experiment, the tadpoles were divided into five groups fed respectively with five different diets. The body weight, snout-vent length and tail length were measured every seven days, and mortality was recorded. The results showed that: the survival rates of tadpole before metamorphosis and after metamorphosis were from 68.7% to 96.3% and from 5.7% to 36.0%, respectively; the optimum stocking density is 1 000 tadpoles per square meter for the stocking density had no effect on the survival rate of tadpole before metamorphosis, and the tadpoles had the relative large body weight and survival numbers in 1000 tadpoles per square meter; the diet II(37.9% crude protein and 5.7% crude fat), IV (25.1% crude protein and 4.0% crude fat), and V (egg yolk) were all the optimum diets for the diet had no effect on the survival rate of tadpole before metamorphosis and the tadpoles fed with three kinds of diet above had relatively large body weight, and one of these three diets based on their availability and cost should be adopted during breeding period. PMID- 28875662 TI - [Construction of cell factories for production of lupeol in Saccharomyces cerevisiae]. AB - Lupane-type triterpenoids, such as betulinic acid, are derived from lupeol and have excellent properties in anti-HIV, anti-cancer activities and so on. For realizing heterogenous production of lupane-type triterpenoids, our research firstly integrated all the seven genes in the MVA pathway in Saccharomyces cerevisiae to increase the supply of squalene (triterpenoids universal precursor) in a single step using the DNA assembler method. Next, cell factories for production of lupeol was constructed by integrating Arabidopsis thaliana lupeol synthetic gene (AtLUP) into chromosome of triterpenoid chassis strain. Results showed that the MVA pathway, about 20 kb nucleotide length, could be assembled in one-pot process and the doubled MVA pathway could significantly improve squalene by 500-fold, reaching 354.00 mg*L-1. NK2-LUP was obtained by introducing AtLUP gene on chromosome, and could produce 8.23 mg*L-1 lupeol. This study supports the possibility of large-scale biosynthetic pathway assembly in S.cerevisiae and lays the foundation of obtaining cell factories for production of lupan-type triterpenoids at the same time. PMID- 28875663 TI - [Mitogen-activated protein kinase genes of Artemisia annua and their expression analysis under Cadmium stress]. AB - In order to study Artemisia annua under cadmium stress, whether there are corresponding MAPK genes involved in transduction of the cadmium signal. 17 AaMAPK genes, named AaMAPK1-AaMAPK17 repectively, were finally obtained by using Trinity method for de novo assembly of transcripts from SRA database and BLAST search against AtMAPK genes and determing conserved domain using a series of bioinformatics tools. There exist 16 MAPK genes contained T[D/E]Y conserved domains among the obtained genes. The expressions of these genes were analyzed by Real-time PCR under cadmium stress. The results showed that the expressions level of AaMAPK3 and AaMAPK10 were down-regulated and MAPK7, MAPK9 and MAPK12 were up regulated. These indicated that there exist corresponding MAPK genes involved in transduction of the cadmium signal. PMID- 28875664 TI - [Cloning and prokaryotic expression analysis of DNA methyltransferas 1(MET1) in Ganoderma lucidum]. AB - DNA methyltransferase is the key enzyme in the process of DNA methylation, playing an important role in regulation of gene expression in vivo. According to the Ganoderma lucidum transcriptome data, a full-length cDNA sequence of MET1 from G. lucidum was cloned for the first time, the GenBank registration number is KU239998, and we conducted a comprehensive bioinformatics analysis of the genetic characteristics and spatial structure. The prokaryotic expression analysis showed that E.coli[pET28a(+)-GlMET1] in BL21(DE3) could induce objective protein, shaking the culture at 16 C until the host bacterium(A600) was approximately 0.8, and added IPTG to finally concentration of 0.2 mmol*L-1, and then the optimal expression of GlMET1 recombinant protein was accumulated for the induction time of 20 h. The real-time PCR results showed that the expression levels of GlMET1 had obvious differences among varieties of G. lucidum. During the maturity stage, the expression levels of GlMET1 were lower than that in juvenile stage, the results showed that with the growth of G. lucidum, the expression levels of GlMET1 were on the decline. The research provided an important basis for studying the mechanism of DNA methyltransferase thoroughly. PMID- 28875665 TI - [Which one is more important, raw materials or productive technology?--a case study for quality consistency control of Gegen Qinlian decoction]. AB - To investigate the effect of Chinese medicine raw materials and production technology on quality consistency of Chinese patent medicines with Gegen Qinlian decoction as an example, and establish a suitable method for the quality consistency control of Chinese patent medicines. The results showed that the effect of production technology on the quality consistency was generally not more than 5%, while the effect of raw materials was even more than 30%, indicating that the effect of raw materials was much greater than that of the production technology. In this study, blend technology was used to improve the quality consistency of raw materials. As a result, the difference between the product produced by raw materials and reference groups was less than 5%, thus increasing the quality consistence of finished products. The results showed that under the current circumstances, the main factor affecting the quality consistency of Chinese patent medicines was raw materials, so we shall pay more attention to the quality of Chinese medicine's raw materials. Finally, a blend technology can improve the quality consistency of Chinese patent medicines. PMID- 28875666 TI - [Influence of specification on chemical composition of dissolution and hepatocytes toxicity of Polygonum multiflorum]. AB - According to different toxicities of various aqueous extracts of Polygonum multiflorum on hepatocyte, the impacts of chemical composition on the safety of P. multiforum was studied. In this study, 8 main chemical compositions in aqueous extracts of P. multiflorum were determined by the established HPLC method; at the same time, the inhibition ratios of different aqueous extracts of P. multiflorum on L02 cell were determined. Afterwards, the potential compounds related to the toxicity of P. multiforum were tentatively found through a multiple correlation analysis. The results showed that P. multiforum with different chemical compositions exhibited great differences in dissolution. The hepatocyte toxicity of P. multiflorum powder was much greater than P. multiflorum lumps. In addition, three constituents closely related to toxicity of P. multiflorum were found by multiple correlation analysis. The study revealed that chemical composition of P. multiflorum is closely related to the hepatotoxicity, and the hepatotoxicity of P. multiflorum powder is greater than that of other dosage forms. This study indicates that P. multiflorum with different chemical compositions show varying toxicity, which therefore shall be given high attention. PMID- 28875667 TI - [Chinese medicine preparation supramolecular imprinting templates based on in vitro release characteristics of BYHW sustained-release tablet]. AB - The study focused on the in vitro release of Buyanghuanwu (BYHW) elementary osmotic pump sustained release tablets. Its band similarity was calculated by the total quantum statistical moment. Meanwhile, in vitro release characteristics were analyzed to discuss the existence of supramolecular imprinting templates. The results show that the same imprint templates may exist in different structures of traditional Chinese medicine(TCM)'s multi-components. The BYHW sustained release tablets prepared by elementary osmotic pump can meet the objectives of "overall control, synchronous release". However, the supramolecular imprinting templates in TCM compound prescriptions should be further explored, the overall and synchronous release of different components was controlled through imprinting templates, so as to seek the more suitable sustained release preparation technology for multiple components of TCM, and make it in line with the characteristics of TCM. PMID- 28875668 TI - [Matrix formulation of chaizhi cataplasma optimized by D-optimal mixture design combined with multiple mechanical indicators and its in vitro evaluation]. AB - To optimize the matrix formulation of Chaizhi cataplasma (CC) and investigate its release and transdermal absorption properties in vitro. The optimized matrix formulation of cataplasma containing liquid herbal extract is determined by using D-optimal mixture design, with initial bonding strength, endurance bonding strength and gel strength as the evaluating indicators. Modified Franz diffusion cells were used to study the in vitro release and transdermal absorption of geniposide in CC. The optimized matrix formulation of CC contained NP700, aluminum glycinate, tartaric acid, glycerin, PVPK90 and water (9?0.7?0.8?30?5?30.5). Cumulative release rate of geniposide in CC was (77.02+/ 3.73)% in 24 h. The percutaneous penetration rate of geniposide was 7.25 MUg*cm 2*h-1 and the 24 h permeated amount was (156.22+/-4.90) MUg*cm-2. The optimized CC prepared by the D-optimal mixture design showed a good adhesion and formability. The in vitro release of the geniposide in CC was in accordance with the first order equation, while its in vitro transdermal absorption was close to the zero order equation. PMID- 28875669 TI - [Preparation and in vitro evaluation of ampelopsin-loaded nanomicelles]. AB - To improve the solubility and antitumor activity of ampelopsin, ampelopsin-loaded nanomicelles from the mixture of pluronic F127 and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS1000) were prepared by film-thin hydration method, in order to optimize the process conditions and physicochemical properties. The antitumor activities against MCF-7 cells between ampelopsin and nanomicelles were compared by MTT method, respectively. The results showed that the optimal nanomicelles were round with the nanometric size of (22.6+/-0.5) nm, encapsulation efficiency rate of (80.42+/-1.13)%, and drug-loading rate of (4.41+/-0.26)%. The solubility of ampelopsin in mixed nanomicelles significantly increased by 16 times. In different release media, the mixed nanomicelles could release more than 90% of drug in 8 h, and showed stronger cytotoxicity and inhibition against MCF-7 cells (P<0.01). The mixed nanomicelles can be used as new drug delivery system of ampelopsin. PMID- 28875670 TI - [Purification technology of puerarin by agar gel microspheres]. AB - Puerarin is the main active component of flavonoids in Puerariae Lobatae Radix. In this study, agar gel microspheres bonded with beta-cyclodextrin (AG-beta-CD) were synthesized by using economical agar, and then high-purity puerarin was obtained with AB-8 through high-yield separation. With purity and yield of puerarin, and chromatographic purity of related impurities as indexes, four macroporous resins of different properties, namely ADS-7 (high polarity), ADS-17 (medium polarity), ADS-21 (polarity) and AB-8 (weak polarity), were selected for separation of puerarin and technological optimization. In addition, the AG-beta CD purification process was optimized and verified. The results showed that, AB-8 resins showed the best effect and selected as the pre-treatment resins for crude puerarin, and puerarin with the purity of 87.68% showed a recovery rate of 89.66%. The optimized purification process parameters of AG-beta-CD included mobile phase (15% ethanol), loading capacity (the ratio of loading amount to column volume) (1.33 g*L-1), sample concentration (8 g*L-1) and flow rate (1 mL*min-1), puerarin with the purity of 95% showed a recovery rate of more than 97%. PMID- 28875671 TI - [Chemical structure of cyperotundic acid from rhizomes of Cyperus rotundus]. AB - Thirteen compounds were isolated from the ethyl acetate extract of the rhizomes of Cyperus rotundus(Xiangfu) by means of various chromatographic techniques(silica gel, Al2O3, Sephadex LH-20, MCI GEL CHP-20P and HPLC), and their structures were identified as cyperotundic acid(1),(4S, 5E, 10R)-7-oxo trinoreudesm-5-en-4beta-ol(2), 4-hydroxy-4, 7-dimethyl-1-tetralone(3), taraxerone(4), dammaradienyl acetate(5), zeorin(6), sarmentine(7), guineensine(8), pellitorine(9), caprolactam(10), liriodendrin(11), 3-hydroxy-1-(4 hydroxy-3,5-dimethoxyphenyl)-2-[4-(3-hydroxy-1-(E)-propenyl)-2,6 dimethoxyphenoxy]propyl-beta-D-glucopyranoside(12)and 1-(3, 4 methylenedioxyphenyl)-1E-tetradecene(13) by extensive spectroscopic analyses(IR, MS, 1D-and 2D-NMR). Compound 1 was a new rearranged sesquiterpene and named as cyperotundic acid, which did not obey the isoprene rule.Compounds 2-13 were obtained from the genus Cyperus for the first time. PMID- 28875672 TI - [Phenanthrenes from aerial part of Juncus setchuensis with anxiolyticactivity]. AB - Ten phenanthrenes, two organic acids, one organic acid ester and one flavonoid were isolated from the aerial part of Juncus setchuensis by various chromatographic techniques usingsilica gel, polyamide, Sephadex LH-20 as solid phases, and preparative HPLC. Their structures were identified by MS and NMR spectroscopic data as effusol(1), juncusol(2), juncuenin D(3), dehydroeffusol(4), dehydrojuncusol(5), juncuenin B(6),dehydrojuncuenin B(7), 2-methoxyl-7-hydroxyl-1 methyl-5-vinyl phenanthrene(8), 2-hydroxyl-7-carboxy-1-methyl-5-vinyl-9,10 dihydrophenanthrene(9), 2-hydroxyl-7-carboxyl-1-methyl-5-vinylphenanthrene(10), luteolin(11), vanillic acid(12), daphnetin(13), p-coumaric acid(14), respectively. Compound 13 was isolated from the genus Juncus for the first time and compounds 5, 8-12 were isolated from J. setchuensis for the first time. The elevated plus-maze(EPM) was used to evaluate the anxiolytic activity of compounds 6 and 7. Compound 6 at 5 mg*kg-1 and 10 mg*kg-1 showed anxiolytic activity as well as compound 7 at 10 mg*kg-1 and 20 mg*kg-1. PMID- 28875673 TI - [Triterpenoids from Ganoderma theaecolum]. AB - Fifteenlanostane triterpenoids were isolated from the ethanol extract of Ganoderma theaecolum by means of preparative HPLC,column chromatography over silica gel,ODS and were identified as lucidone C(1),lucidone D(2),7-oxo-ganoderic acid Z2(3),7-oxo-ganoderic acid Z(4),ganoderenicacid H(5),ganoderenic acid B(6),3beta,7beta-dihydroyl-11,15,23-trioxo-lanost-8,16-dien-26-oic acid(7),3beta,7beta-dihydroyl-11,15,23-trioxo-lanost-8,16-dien-26-oic acid methyl ester(8),ganolucidic acid B(9),ganolucidate F(10),methyl ganoderate C2(11),ganoderic acid zeta(12),ganoderic acid AP3(13),methyl ganoderate B(14),and ganoderol B(15). Compounds 1-15 were isolated from this specie for the first time. PMID- 28875674 TI - [Determination of ten stilbenes and their antioxidant activity of peony seed coat, seed kernel and seed coat extracts]. AB - The seed of tree peony and herbaceous peony contained a variety of stilbenes which possess many pharmacological activities, such as antitumor, anti inflammatory, allergy and neuraminidase inhibition. In order to develop and use peony seed resources, a simple and sensitive HPLC-DAD was developed for simultaneous determination of 10 stilbenes in peony samples, i.e.,suffruticosol A,suffruticosol B,suffruticosol C,trans-resveratrol,cis-epsilon-viniferin,trans epsilon-viniferin,cis-suffruticosol D,cis-gnetin H,trans-suffruticosol D and trans-gnetin H. At the same time, the scavenging activity of DPPH free radicals was employed to evaluate their antioxidant effect. The results showed that the 10 stilbenes are mainly present in peony seed coat (total content of more than 16.7%) compared to peony seed kernel (total content less than 0.3%), and can be enriched in the extract of peony seed coat (total content of more than 75%) The extract of peony seed coat and 10 stilbenes exhibited significant antioxidant properties. This work provides a foundation for comprehensive utilization of the tree peony and herbaceous peony seed resources. PMID- 28875675 TI - [Antagonism mechanism of gingerols against inflammatory effect of toxic raphides from Pinella pedatisecta]. AB - This study was to investigate the mechanism of gingerols antagonizing the inflammatory effect of toxic raphides from Pinella pedatisecta. Mice peritonitis models induced by toxic raphides from P. pedatisecta were applied to observe the effect of gingerols on inflammatory mediators PGE2 in the exudates of abdominal inflammation in mice; rats peritoneal macrophage in vitro culture models were adopted to study the anti-inflammatory effects of gingerol against toxic raphides, with TNF-alpha and IL-1beta in supernatant as indexes. Scanning electron microscopy was used to observe the changes in surface morphology of macrophages treated by raphides and gingerols. Macrophages-neutrophils co cultured models were used to study the antagonism of gingerols against the effect of toxic raphides' stimulation on neutrophils migration. Results showed that gingerols could significantly inhibit the production of PGE2 in the exudates of abdominal inflammation induced by toxic raphides from P. pedatisecta in mice. Gingerols could significantly inhibit the toxic raphides from P. pedatisecta to induce the release of inflammatory factors, with certain dose dependence. Scanning electron microscopy showed that gingerols could significantly inhibit phagocytosis of macrophages, cytomembrane injury, and neutrophils migration induced by toxic raphides from P. pedatisecta. The results showed that the antagonism mechanism of gingerols against the toxic raphides from P. pedatisecta may be associated with inhibiting the pro-inflammatory toxicity including macrophage activation, inflammatory factors release, and neutrophils migration. PMID- 28875676 TI - [Regulatory effect of Tripterygium wilfordii polycoride (TWP) towards TLR4/MyD88 independent pathway in TNBS/ethanol ulcerative colitis (UC) rat model]. AB - In order to study the regulatory effect of Tripterygium wilfordii polycoride (TWP) towards TLR4/MyD88 independent pathway in TNBS/ethanol ulcerative colitis (UC) rat model, TNBS/ethanol enema was adopted to build TNBS/ethanol UC rat model. After the successful modeling procedure, 90 male Wistar rats are were divided into 6 groups, including namely normal group, model group, TWP low, middle, high dose groups (3, 6, 12 mg*kg-1)and azathioprine (AZA) group (6 g*kg 1), with 15 rats in each group. All rats in each group were administrated with corresponding medicines for 14 days. After 14 days of administration, corresponding colon tissues were taken for general and microscopic evaluation. Western blotting analysis and RT-PCR were adopted to test the mRNA and protein expressions of TLR4/MyD88 independent pathway-related molecules, namely TLR4, TRAM, TRIF, NF-kappaB and IFN-gamma. The results showed that DAI, general and microscopic evaluations all indicated that TNBS/ethanol UC rat model was successful. TWP can improve UC-related clinical manifestation and heal colonic mucosa, which was equal to AZA. RT-PCR and WB results showed that the expression of TLR4/MyD88 independent pathway-related molecules in model group were significantly superior to that in normal group at either mRNA or protein level (P<0.01). Compared with model group, TWP can inhibit the expression of each node in TLR4/MyD88 independent pathway in a dose-dependent manner. The inhibitory effect of TWP with high dose towards the above molecules was inferior to that in model group at either mRNA or protein level (P<0.05). The inhibitory effect of TWP with high dose towards upstream molecules of TLR4/MyD88 independent pathway (TLR4, TRAM, TRIF, NF-kappaB) was slightly superior to AZA group at either mRNA or protein level. However, such inhibitory effect towards terminal inflammatory cytokines (IFN-gamma) was inferior to AZA group at either mRNA or protein level. All the above differences had no statistical significance. Therefore, in TNBS/ethanol UC rat model, TLR4/MyD88 independent pathway took part in regulating inflammation. TWP exerted its anti-inflammation effect by inhibiting the expression of TLR4/MyD88 independent pathway in a dose-dependent manner. PMID- 28875677 TI - [Effects of Shaoyao Gancao decoction on contents of amino acids and expressions of receptors in brains of spastic paralysis rats]. AB - To explore the effects of Shaoyao Gancao decoction on contents of amino acids and expressions of receptors in the brains of spastic paralysis rats, the spastic paralysis rat models of stroke convalescence were made by line tethering method. Baclofen was used as the control group, and the experiment group received Shaoyao Gancao decoction at 3?1 proportions. After 3 weeks, the neurobehavioral scores, muscular tension and pain threshold were measured and compared. High performance liquid chromatography (HPLC) was used to detect the contents of GABA, Gly, Glu, Asp in cerebral cortex. The protein expressions of GABA receptors Aalpha1, B; NMDA receptor NR1, NR2A and NR2B in cerebral cortex were determined by immunohistochemistry assay. The results showed that the Shaoyao Gancao decoction at 3?1 proportion could improve the spastic paralysis state after stroke, significantly improve neurological symptoms (P<0.01), decrease muscular tension (P<0.01) and improve pain threshold (P<0.05) as compared with model group. Simultaneously, the contents of inhibitory amino acids GABA and Gly were increased significantly (P<0.01), while with a decrease tendency in excitatory amino acids Glu and Asp (with no statistical significance). In addition, it could significantly increase the protein expressions of neurotransmitter GABA receptors Aalpha1, and B (P<0.05); reduce the expressions of neurotransmitter NMDA receptors NR1, NR2A and NR2B (P<0.05). These results suggested that the Shaoyao Gancao decoction at 3:1 proportion could effectively relieve spasm and pain. The mechanism might be associated with increasing the contents of inhibitory amino acids and increasing the expressions of their receptors in spastic paralysis rats after stroke, which would consequently enhance the signal transduction of inhibitory amino acids. Meanwhile, there was a decrease tendency in excitatory amino acids, although no significant effect was observed, and it could suppress the expressions of excitatory amino acids receptors, thus weaken the excitatory signal transduction. Thereby the neurotoxicity was relieved eventually. These findings indicated that Shaoyao Gancao decoction could regulate the balance of neurotransmitter system to relieve the spasticity, and eventually achieve tendon tonifying and spasm relieving effect. PMID- 28875678 TI - [Protective effect of seven kinds of phenolic acids of total salvianolic acids components on human umbilical vein endothelial cells with hypoxic injury]. AB - In this paper, human umbilical vein endothelial cells (HUVEC) hypoxic injury models were established by sodium dithionite (Na2S2O4). With the protective effects of total salvianolic acids components (TSAC) against oxidative damage of HUVEC as a starting point, cellviability was measured by MTT colorimetric method; intracellular superoxide dismutase (SOD) activity, malondialdehyde (MDA), lactatedehydrogenase (LDH) level, nitric oxide (NO) level, interleukin6 (IL-6), and human tumor necrosis factor alpha (TNF-alpha) expression were measured by kits, to investigate the effect of seven kinds of phenolic acids of TSAC on Na2S2O4-induced HUVEC hypoxic injury. Based on the "component structure" theory, the contribution of the main components in TSAC for the protective effect on hypoxic injury of HUVEC was studied. The results showed that salvianolic acid B, posrnarinic acid A, salvianolic acid A, lactic acid, and lithospermic acid in TSAC play a larger role in protective effect of hypoxic injury of HUVEC. These five components were administered in combinations respectively, and it was concluded that the four components including salvianolic acid B, posrnarinic acid A, salvianolic acid A, lactic acid could be used as the representative components of TSAC. PMID- 28875679 TI - [Screening of effective ingredients of Yinzhihuang injection against cholestasis and their mechanism]. AB - Chinese herbal medicinal formulation Yinzhihuang injection is widely used in clinic for jaundice and chronic liver diseases in eastern Asian countries. However, the pharmacologically active components and the underlying mechanism are unclear. In this study, 30 male ICR mice were randomly assigned into 6 groups: normal control, model control, chlorogenic acid group, geniposide group, baicalin group and wogonoside group. The liver function, liver pathological changes and bile acid metabolism-related gene expression in mice were assayed. The serum levels of ALT, AST, ALP, TBA in chlorogenic acid group (15.89+/-2.53), (18.32+/ 2.56), (26.38+/-9.87) U*L-1, (40.63+/-7.67) MUmol*L-1, respectively and geniposide group (20.54+/-2.36), (24.28+/-5.19), (35.09+/-5.03) U*L-1, (42.86+/ 7.11) MUmol*L-1, respectively were lower than those in the model control group (59.52+/-10.94), (128.37+/-17.97),(169.52+/-9.62) U*L-1, (132.50+/-33.00) MUmol*L 1, respectively. Hematoxylin-eosin staining showed necrosis, infiltration of inflammation cell in chlorogenic acid group and geniposide group were milder than those in the model control group. Q-PCR analysis revealed the expression of bile acid metabolism-related genes was normalized after treatment with chlorogenic acid or geniposide. Chlorogenic acid and geniposide improved the liver injury and cholestasis effectively, and reversed the mRNA expression of bile acid metabolism related genes induced by ANIT. So, chlorogenic acid and geniposide were protective for cholestasis, suggesting their pharmacodynamic effect in Yinzhihuang injection. PMID- 28875680 TI - [Effects of Tongluo Xingnao effervescent tablets on blood rheology, iNOS, VEGF and LDH-5 in MID rats]. AB - The study was to explore effects of Tongluo Xingnao effervescent tablets on the blood rheology, iNOS, VEGF and LDH-5 in multi-infarct dementia(MID) model rats. Establish MID model rats were induced by microthrombosis, from which 50 successful model rats were randomly divided into five groups, such as the model control group, the dihydroergotoxine mesylate tablets(hydergine) group(0.7 mg*kg 1), Tongluo Xingnao effervescent tablets high-dose, medium-dose and low-dose groups(7.56, 3.78, 1.89 g*kg-1). Another ten rats in the sham group were randomly selected as the parallel control group. Each group was orally administered with drugs for 90 days. The learning and memory ability was evaluated with the Morris water maze test, while the whole blood viscosity and the erythrocyte aggregation index derived from abdominal aorta were measured in different shear rates. In addition, the levels of VEGF and iNOS in the serum were determined by ELISA kits. The expression of LDH-5 in hippocampus of rats was measured with immunohistochemistry and image quantitative analysis. The result showed that Tongluo Xingnao effervescent tablets notably decreased the escape latency of MID model rats, increased times of entering into the escape platform and prolonged retention time in medium ring, meanwhile the whole blood viscosity in MID model rats was also notably reduced in four shear rates, i.e. 1, 5, 30, 200 S-1, erythrocyte aggregation index, serum VEGF and iNOS, and average optical density value of LDH-5, with a statistically significant differences compared with the model control group (P<0.05). In conclusion, Tongluo Xingnao effervescent tablets could improve the ability of learning and memory of MID model rats and the blood rheology, reduce the level of iNOS, VEGF and the expression of LDH-5, and then improved the brain energy supply. PMID- 28875681 TI - [Metabolomics analysis of Tripterygium wilfordii formulation based on theory of detoxicity compatibility]. AB - Tripterygium wilfordii Hook. f. induced-hepatotoxicity was the main limitation for its usage in clinic. Qingluo Tongbi formulation showed obvious attenuation for hepatotoxicity in clinic and fundamental research in vivo. To explore the potential mechanism of the attenuation, we conducted a study on the plasma metabolomic profiles of T. wilfordii and Qingluo Tongbi formulation in rats by a sensitive gas chromatography-mass spectrometry (GC-MS/MS) method. In plasma samples, a total of 72 compounds were analyzed by EI source MS, and were successfully identified by matching NIST database. The semi-quantification results were then calculated by OPLS-DA model with SIMCA-P 13.0 software. The three groups were clearly distinguished in OPLS-DA score plot. In addition, the observation values of Qingluo Tongbi formulation showed the obvious trend towards the control levels, suggesting the detoxicity effect of the formulation. Variation metabolites were further analyzed by VIP and One Way ANOVAs, and the results showed a significant increase in compounds of glycogenic amino acids, such as alanine, proline, serine and glutamine after the administration of T. wilfordii, indicated that the tissue proteins were decomposed and amino acids were leakage into blood. Qingluo Tongbi formulation could reverse the amino acids into normal level. On the contrary, the levels of glucose, lactic acid and hydroxy butyrate decrease, and the formulation can relieve the disorder in the levels of lactic acid, suggesting the regulation of the energy metabolism. Additionally, the level of branched chain amino acid was decreased, suggested the toxicity was induced, but the formulation cannot increase it into the normal levels. Nevertheless, all the above results suggested that the classical Qingluo Tongbi formulation displayed the liver protection effect by adjusting the amino acid levels and regulating the energy metabolism. Qingluo Tongbi formulation was developed based on traditional Chinese medicine theory "detoxicity compatibility", and contained Panax notoginseng (Burk.) F. H. Chen to nourish blood and absorb clots. Modern pharmacology suggested that its liver protection effect was correlated with the promotion of protein synthesis. Another important herb is Rehmannia glutinosa Libosch., which can regulate the energy metabolism. Both were consistent with the metabolomic results in this study, which explained the potential mechanism of "detoxicity compatibility" theory. Therefore, the currently developed metabolomic approach and the obtained results would be highly useful for the comprehensive toxicity studies for other herbal medicines and various complex deoxicity formulations. PMID- 28875682 TI - [Comparison of bioavailability of two kinds of solid dispersion from 10 hydroxycamptothecin in SD rats in vivo]. AB - To improve the bioavailability of 10-hydroxycamptothecin, 10-hydroxycamptothecin solid dispersion(HCPT-SD) and 10-hydroxycamptothecin-phospholipid complex-solid dispersion(HCPT-PC-SD) were prepared, and their solubility and dissolution rate were evaluated in this study. SD rates were administered intragastrically with HCPT-SD or HCPT-PC-SD respectively, then their blood samples were collected at different time intervals. The concentration of HCPT in blood was detected by HPLC method with camptothecin as internal standard, and then its pharmacokinetic parameters were calculated and obtained. The results showed that the Cmax, AUC0-t and AUC0-infinity of both kinds of solid dispersion of HCPT were significantly increased than those of crude drug. The AUC0-t of HCPT-SD was increased by 176.87%, and AUC0-t of HCPT-PC-SD was increased by 254.31% as compared with crude drug. Therefore, the two kinds of solid dispersion of HCPT could significantly enhance the bioavailability of HCPT in SD rates, and the effect of HCPT-PC-SD was more obvious. PMID- 28875683 TI - [Lipid metabolomics in serum of hyperuricemic rats induced by fructose based on UPC2-Q/TOF-MS]. AB - To explore the differences in lipid metabolites in serum of hyperuricemic rats induced by fructose and normal rats by using lipid metabolomics technology, and screen the potential biomarkers related to hyperuricemia. The metabolic fingerprint spectrum of the serum in hyperuricemic rats(model group) and normal rats(control group) was obtained and analyzed by using ultra performance convergence chromatography-tandem-Q-time of flight mass spectrometry(UPC 2 -Q/TOF MS) method and the differences of metabolic spectra between two groups were compared via the multivariate statistical methods to screen differential metabolites. The results indicated that there was significant difference in metabolic spectra between model group and control group, and 11 differential metabolites were screened. Then eight potential biomarkers such as arachidonic acid, palmitic acid, oleic acid and linoleic acid were tentatively identified by using the exact mass number and secondary mass spectrometry(MS/MS spectrum). Therefore, a new research method for lipid metabolomics in serum of hyperuricemic rats induced by fructose was established successfully based on UPC 2 -Q/TOF-MS. What's more, it was speculated that the abnormal metabolism of fatty acid might be associated with the pathogenesis of hyperuricemia, which would provide scientific basis for early detection and prevention of hyperuricemia. PMID- 28875684 TI - [Herbal textural and original plants research on medicines from Salvia in China]. AB - On the basis of review and study on literatures of Chinese medicine, combining the history of medicinal plants of Salvia in China, and investigating the morphological description, geography distribution and therapeutic effects, herbal textural research were carried on the medicinal plants from Salvia. The results showed that the original plant of Danshen is S. miltiorrhiza and related species, the original plant of Dian Danshen is S. yunnanensis, the original plant of Li Zhi Cao is S. plebeia, the original plant of Shi Jian Chuan is Bidens pilosa. or S.chinensis, the original plant of Shu Wei Cao is S. japanica, the original plant of Ye Xia Hong is S. kiangsiensis. And the article aimed to point out the relationship of medicinal plants from Salvia and provided new insight and proof to explore the new natural medicine from medicinal plants of Salvia. PMID- 28875685 TI - [Anti-aging traditional Chinese medicine: potential mechanisms involving AMPK pathway and calorie restriction based on "medicine-food homology" theory]. AB - There have been many reports about the anti-aging effect of traditional Chinese medicine (TCM), but the material basis and mechanism of action have not been clearly elucidated. AMP-activated protein kinase (AMPK) is the receptor of energy metabolism and its life extending effect has been confirmed in different experiments. Over expression or activation with metform in of AAK-2/AMPK has been shown to extend life expectancy in nematodes and Drosophila. The possible downstream pathways of AMPK against aging include TOR/S6k pathway, FOXOs pathway and CRTC pathway. One of the core concepts of traditional Chinese medicine is disease prevention, for which one of manifestations is to improve the body with the same source of medicine and food to achieve longevity. It is possible to activate AMPK to achieve the goal of health preservation and prolonging the life by some of the "medicine-food harmony" treatments. Our survey finds that in "medicine-food harmony" compound TCM, "invigorating the kidney deficiency and promoting blood circulation" class dominates and Salviae Miltiorrhizae Radix Rhizoma, Astragali Radix, Coptidis Rhizoma, Poria, Atractylodes Macrocephalae Rhizoma, Radix et Rhizoma Rhei, and Ginseng Radix et Rhizoma are used in high frequency. Network pharmacology analysis using ingenuity pathway analysis (IPA) software revealed that TCM-derived drugs interacting with AMPK target proteins included berberine, emodin, curcumin, resveratrol, alcohol, cordyceps, arctiin, suggesting in a certain extent the feasibility of "medicine -food homology" drugs to extend the lifespan through the AMPK pathway. Our study combines a comprehensive database query and an IPA network pharmacology analysis to identify Chinese medicine monomer and components that may activate AMPK pathway to delay aging and to discuss the potential of these medicine by improving energy metabolism to delay the aging process, based on the concept of traditional Chinese medicine "medicine-food homology". PMID- 28875686 TI - [Dispute for Japanese(wild) honeysuckle flower based on supermolecular imprinting templates]. AB - More and more disputes have happened to confront us continuously since the separation of Japanese(wild) honeysuckle flower in Chinese Pharmacopoeia in 2005. The state pharmacopeia committee decided to separate Japanese(wild) honeysuckle flower into two species for japanese(wild) honeysuckle flower, but didn't define their the convincing reasons still did not provide to us as a result that two medicines are not described the differences in natural properties, efficiency and indication, usage and dosage, as well as not given a resolving methodand specific solution. It was known for us that in the history of traditional Chinese medicine(TCM), the phenomenenphenomena of the "one drug from multi-species" and "one species for multi-drug" are very ordinary thingswere ubiquitous. Whether separation of the drug species are separated shall be decided to by clinical efficiency. Through Chinese pharmacopoeia (2015 edition) issue of Chinese Pharmacopoeia the 2015 issue of the Chinese Pharmacopoeia, we still cannot find a scientific solution for the dispute of for Japanese (wild) honeysuckle flower, perhaps because of insufficient reorganization of TCM clinical medication regularities, such as "treatment of different diseases with same drug", " treatment of the same disease with different drugs" and "treatment of the same syndrome with multi-prescriptions", and "one prescription treating multiple syndromes"; lack of in-depth analysis for multi-component TCM compounds and autonomisation of "supermolecular template" for organs and meridians; less attention to the advance of efficacy and safety evaluation technologies for multi component TCM compounds; impacts from the medication mode of "one ingredient-one composition-one effect"; as well as insufficient research methods for bioequivalent evaluation in preclinic and clinic studies . The dispute for species combination or separation for Japanese(wild) honeysuckle flower was apparently caused by regional economy, drug biological equivalent of efficacy and safety, but arising from clinical principles for systematical syndrome treatment with TCM, or concepts in the treatment of diseases with TCM or western medicines. This paper focused on current studies on Japanese(wild) honeysuckle flower in the combination with TCM clinical medication regularities, such as "treatment of different diseases with same drug", "treatment of the same disease with different drugs" and "treatment of the same syndrome with multi-prescriptions", and "one prescription treating multiple syndromes", expounded the specific pharmacological regularity of "heterogeneous equivalence" of Japanese (wild) honeysuckle flower, and put forward methods for studying bioequivalence of Japanese(wild) honeysuckle flower, in order to solve the combination and separation of Japanese(wild) honeysuckle flower and lay a foundation for promoting the development of Chinese herbal medicine industry. PMID- 28875687 TI - [Development of molecular pharmacognosy in China based on bibliometric analysis]. AB - The method of bibliometrics was used to analyze the literature about the application of molecular biotechnique to pharmacognosy which were searched and obtained from the CNKI database and Shanghai intellectual property information platform from the year 1995 to 2015.It was found that 22 462 articles were published and the 63% were funded, 50 core institutions and 888 authors, 18 core journals were engaged in this subject.496 items of patents were authorized and 90 kinds of Chinese Materia Medica were involved.In the view of the quantity and quality of published literature, the scale and influence of journals, institutions, and the extent of subject categories have made remarkable achievement. Molecular pharmacognosy has completed the germination stage of a new subject, and has been in a relatively mature and stable development status. PMID- 28875688 TI - Clinical utility of the patency capsule: a large volume center experience. AB - BACKGROUND: In patients with suspected or known obstructive gastrointestinal pathology, the use of patency capsule (PC) aims to minimize the risk of subsequent retention of the endoscopic capsule. However, its clinical utility is not consensual. The aim was to evaluate the indications, results and safety profile of the PC. METHODS: Retrospective analysis of PCs (agile patency capsule) conducted between 2011 and 2015. Patency evaluation was performed after 30 hours, with radiological confirmation if PC was detected. RESULTS: We included 369 PCs, 54% female. The average age was 42+/-16 years. Main indications included suspected Crohn disease (CD) (45%), CD staging (32%), neoplastic diseases (9%), radic enteritis (3%), prior surgery (3%), NSAIDs enteropathy (2%) and anemia (2%). Before the exam 5% of patients were taking constipation-induced medications and 5% reported occlusive symptoms; 38% of patients had previous abdominal surgeries, most often ileal resection due to CD (24%); 42% of patients had previous imaging studies, revealing strictures in 20% and bowel dilation in 11%. Patency capsule was negative (patent gastrointestinal tract) in 73% of cases at 30h and 2% of PCs were fully recovered in the following days. Seven patients (2.5%) showed self-limiting occlusive symptoms during the procedure. All patients with negative PC subsequently performed capsule endoscopy with no cases of retention. History of occlusive symptoms (P=0.023) and strictures in imaging studies (P=0.029) were associated with the detection of the PC at 30 hours. CONCLUSIONS: PC is a safe and effective exam. Occlusive symptoms and imaging strictures were significantly associated with the retention. The retention rate was 25%, a similar result to that described in other series but higher than expected for the various indications, suggesting the importance of new research studies. PMID- 28875689 TI - Liver fibrosis in the context of nonalcoholic steatohepatitis: the role of adipokines. AB - Liver fibrosis is a multifaceted process that occurs as a consequence of chronic liver injury. This process is characterized by inflammation, activation of matrix producing cells, matrix deposition and remodeling, and epithelial cell regeneration. In subjects with chronic liver damage, fibrogenesis is favored by the presence of obesity and insulin resistance, which are also relevant risk factors for the development and progression of nonalcoholic steatohepatitis (NASH). It is now well-known that adipose tissue is not only involved in energy storage but also functions as an endocrine organ that secretes various bioactive substances known as adipokines. This term identifies a group of polypeptide molecules, which exert local, peripheral and/or central actions. Additionally to their well-established role in controlling adipose tissue physiology, energy homeostasis, inflammation and immune function, adipokines have been shown to be involved in different obesity-related diseases, such as hypertension, atherosclerosis and type 2 diabetes. In liver diseases, the biologic actions of these factors may contribute to the mechanisms leading to NASH. In this review, we focus on the role of adipokines in liver fibrogenesis and discuss their potential as regulators of this pathological condition and as targets for future pharmacological treatment strategies of chronic liver diseases. PMID- 28875690 TI - Use of fully covered self-expanding metal stents for benign biliary etiologies: a large multi-center experience. AB - BACKGROUND: Fully-covered self-expandable metal stents (FCSEMS) have been used in benign biliary diseases although reported data is limited. These devices are most commonly used to treat biliary leaks, strictures, or both. The aim of this study was to evaluate effectiveness of FCSEMS in treating benign biliary disease and recognize the associated complications. METHODS: We performed a multicenter longitudinal retrospective cohort study of patients with benign biliary disease needing FCSEMS between 2011 and 2016. Descriptive statistics were performed using SPSS version 24 (SPSS Inc, Chicago, IL, USA) and continuous variables were presented as mean+/-standard deviation. RESULTS: 75, 57% M/43% F, with a mean age of 58.5+/-14.9 years, were included. 64 (85%) had benign strictures, 7 patients had leaks, and 4 patients had both a leak and a stricture. Chronic pancreatitis was the most common cause of BBS (47%) and cholecystectomy was the most common cause of leaks. FCSEMS placement was technically successful in all patients. Four patients died of unrelated causes. A recurrent stricture was observed in 24 (32%) of the patients. Recurrent strictures were most commonly seen in patients with chronic pancreatitis 12/35 (34%). Stent migration occurred in 8/75 patients (10.7%). Seven patients (9.3%) had adverse events, acute pancreatitis (N.=4) was most common. CONCLUSIONS: FCSEMS are safe and effective for treating biliary strictures and leaks. We report decreased rates of stent migration compared to previous studies. Prospective studies are needed to compare plastic stents with FCSEMS, determine optimal stent in-dwell times and cost effectiveness of FCSEMS. PMID- 28875691 TI - Construction and Evaluation of a Targeted Hyaluronic Acid Nanoparticle/Photosensitizer Complex for Cancer Photodynamic Therapy. AB - Photodynamic therapy (PDT) is a novel treatment modality that is under intensive preclinical investigations for a variety of diseases, including cancer. Despite extensive studies in this area, selective and effective photodynamic agents that can specifically accumulate in tumors to reach a therapeutic concentration are limited. Although recent attempts have produced photosensitizers (PSs) complexed with various nanomaterials, the tedious preparation steps and poor tumor efficiency of therapy hamper their utilization. Here, we developed a CD44 targeted nanophotodynamic agent by physically encapsulating a photosensitizer, Ce6, into a hyaluronic acid nanoparticle (HANP), which was hereby denoted HANP/Ce6. Its physical features and capability for photodynamic therapy were characterized in vitro and in vivo. Systemic delivery of HANP/Ce6 resulted in its accumulation in a human colon cancer xenograft model. The tumor/muscle ratio reached 3.47 +/- 0.46 at 4 h post injection, as confirmed by fluorescence imaging. Tumor growth after HANP/Ce6 treatment with laser irradiation (0.15 W/cm2, 630 nm) was significantly inhibited by 9.61 +/- 1.09-fold compared to that in tumor control groups, which showed no change in tumor growth. No apparent systemic and local toxic effects on the mice were observed. HANP/Ce6-mediated tumor growth inhibition was accessed and observed for the first time by 18F fluoro-2-deoxy-d-glucose positron emission tomography as early as 1 day after treatment and persisted for 14 days within our treatment time window. In sum, our results highlight the imaging properties and therapeutic effects of the novel HANP/Ce6 theranostic nanoparticle for CD44-targeted PDT cancer therapy that may be potentially utilized in the clinic. This HANP system may also be applied for the delivery of other hydrophobic PSs, particularly those that could not be chemically modified. PMID- 28875692 TI - Facile Synthesis of Si@SiC Composite as an Anode Material for Lithium-Ion Batteries. AB - Here, we propose a simple method for direct synthesis of a Si@SiC composite derived from a SiO2@C precursor via a Mg thermal reduction method as an anode material for Li-ion batteries. Owing to the extremely high exothermic reaction between SiO2 and Mg, along with the presence of carbon, SiC can be spontaneously produced with the formation of Si. The synthesized Si@SiC was composed of well mixed SiC and Si nanocrystallites. The SiC content of the Si@SiC was adjusted by tuning the carbon content of the precursor. Among the resultant Si@SiC materials, the Si@SiC-0.5 sample, which was produced from a precursor containing 4.37 wt % of carbon, exhibits excellent electrochemical characteristics, such as a high first discharge capacity of 1642 mAh g-1 and 53.9% capacity retention following 200 cycles at a rate of 0.1C. Even at a high rate of 10C, a high reversible capacity of 454 mAh g-1 was obtained. Surprisingly, at a fixed discharge rate of C/20, the Si@SiC-0.5 electrode delivered a high capacity of 989 mAh g-1 at a charge rate of 20C. In addition, a full cell fabricated by coupling a lithiated Si@SiC-0.5 anode and a LiCoO2 cathode exhibits excellent cyclability over 50 cycles. This outstanding electrochemical performance of Si@SiC-0.5 is attributed to the SiC phase, which acts as a buffer layer that stabilizes the nanostructure of the Si active phase and enhances the electrical conductivity of the electrode. PMID- 28875693 TI - Influence of Luminol Doping of Poly(o-phenylenediamine) on the Spectral, Morphological, and Fluorescent properties: A Potential Fluorescent Marker for Early detection and Diagnosis of Leishmania donovani. AB - There has been a steady progress in the development of doped conjugated polymers to remarkably improve their photo physical properties for their application as biomarkers. With a view to enhance the spectral, morphological, and photo physical properties of poly(o-phenylenediamine) (POPD), the present work reports the synthesis of poly(o-phenylenediamine) and doping of this polymer using luminol. The formation of luminol-doped POPD was confirmed by infrared and ultraviolet-visible spectroscopies and X-ray diffraction studies. The energy band gap values and oscillator strength of luminol in acidic, basic, and neutral media were computed by density functional theory calculations using the B3LYP/6-31G (d) basis set and were compared with experimental data. The luminol doped POPDs show significant in vitro anti-leishmanial activity. Live cell imaging also proved that these molecules bind with the organelle of Leishmania also. These luminol doped POPDs were found non-toxic at the used concentrations on THP-1 derived human macrophage cells through methyl tetrazolium (MTT) assay. The results revealed that luminol doped POPDs were potentially non-toxic to human cells though exhibited immense potential to be used as a fluorescent marker to label Leishmania donovani for diagnostic and other studies. PMID- 28875694 TI - Small Molecular TGF-beta1-Inhibitor-Loaded Electrospun Fibrous Scaffolds for Preventing Hypertrophic Scars. AB - Hypertrophic scarring (HS) is a disorder that occurs during wound healing and seriously depresses the quality of human life. Scar-inhibiting scaffolds, though bringing promise to HS prevention, face problems such as the incompatibility of the scaffold materials and the instability of bioactive molecules. Herein, we present a TGF-beta1-inhibitor-doped poly(epsilon-caprolactone) (PCL)/gelatin (PG) coelectrospun nanofibrous scaffold (PGT) for HS prevention during wound healing. The appropriate ratio of PCL to gelatin can avoid individual defects of the two materials and achieve an optimized mechanical property and biocompatibility. The TGF-beta1 inhibitor (SB-525334) is a small molecule and is highly stable during electrospinning and drug release processes. The PGT effectively inhibits fibroblast (the major cell type contributing to scar formation) proliferation in vitro and successfully prevents HS formation during the healing of full-thickness model wounds on rabbit ear. Our strategy offers an excellent solution for potential large-scale production of scaffolds for clinical HS prevention. PMID- 28875695 TI - BODIPY Derivatives for Photodynamic Therapy: Influence of Configuration versus Heavy Atom Effect. AB - Heavy atom effect and configuration are important for BODIPY derivatives to generate singlet oxygen (1O2) for photodynamic therapy. Herein, a series of BODIPY derivatives with different halogens were synthesized. 1O2 quantum yields (QYs) and MTT assay confirm that incorporation of more heavy atoms onto dimeric BODIPY cannot effectively enhance the 1O2 QYs. Rather, the dark toxicity increases. This phenomenon can be attributed to the competition of heavy atom effect and configuration of dimeric BODIPY. In addition the BODIPY derivative with two iodine atoms (BDPI) owns the highest 1O2 QYs (73%) and the lowest phototoxicity IC50 (1 MUM). Furthermore, an in vivo study demonstrates that BDPI NPs can effectively inhibit tumor growth and can be used as a promising threanostic agent for photodynamic therapy in clinic. PMID- 28875696 TI - Surface-Enhanced Raman Spectroscopy-Based Sandwich Immunoassays for Multiplexed Detection of Zika and Dengue Viral Biomarkers. AB - Zika and dengue are mosquito-borne diseases that present similar nonspecific symptoms but possess dramatically different outcomes. The first line of defense in epidemic outbreaks are rapid point-of-care diagnostics. Because many outbreaks occur in areas that are resource poor, assays that are easy to use, inexpensive, and require no power have become invaluable in patient treatment, quarantining, and surveillance. Paper-based sandwich immunoassays such as lateral flow assays (LFAs) are attractive as point-of-care solutions as they have the potential for wider deployability than lab-based assays such as PCR. However, their low sensitivity imposes limitations on their ability to detect low biomarker levels and early diagnosis. Here, we exploit the high sensitivity of surface-enhanced Raman spectroscopy (SERS) in a multiplexed assay that can distinguish between Zika and dengue nonstructural protein 1 (NS1) biomarkers. SERS-encoded gold nanostars were conjugated to specific antibodies for both diseases and used in a dipstick immunoassay, which exhibited 15-fold and 7-fold lower detection limits for Zika NS1 and dengue NS1, respectively. This platform combines the simplicity of a LFA with the high sensitivity of SERS and could not only improve Zika diagnosis but also detect diseases sooner after infection when biomarker levels are low. PMID- 28875697 TI - Transpiration-Inspired Fabrication of Opal Capillary with Multiple Heterostructures for Multiplex Aptamer-Based Fluorescent Assays. AB - In this work we report a method for the fabrication of opal capillary with multiple heterostructures for aptamer-based assays. The method is inspired by plant transpiration. During the fabrication, monodisperse SiO2 nanoparticles (NPs) self-assemble in a glass capillary, with the solvent gradually evaporating from the top end of the capillary. By a simple change of the colloid solution that wicks through the capillary, multiple heterostructures can be easily prepared inside the capillary. On the surface of the SiO2 NPs, polydopamine is coated for immobilization of aminomethyl-modified aptamers. The aptamers are used for fluorescent detection of adenosine triphosphate (ATP) and thrombin. Owing to fluorescence enhancement effect of the photonic heterstructures, the fluorescent signal for detection is amplified up to 40-fold. The limit of detection is 32 MUM for ATP and 8.1 nM for thrombin. Therefore, we believe this method is promising for the fabrication of analytical capillary devices for point-of-care testing. PMID- 28875698 TI - Large-Area Synthesis of a Ni2P Honeycomb Electrode for Highly Efficient Water Splitting. AB - Transition metal phosphides have recently been regarded as robust, inexpensive electrocatalysts for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). Thus far, tremendous scientific efforts have been applied to improve the catalytic activity of the catalyst, whereas the scale-up fabrication of morphology-controlled catalysts while maintaining their desired performance remains a great challenge. Herein, we present a facile and scalable approach to fabricate the macroporous Ni2P/nickel foam electrode. The obtained electrocatalyst exhibits superior bifunctional catalytic activity and durability, as evidenced by a low overpotential of 205 and 300 mV required to achieve a high current density of 100 mA cm-2 for HER and OER, respectively. Such a spray-based strategy is believed to widely adapt for the preparation of electrodes with uniform macroporous structures over a large area (e.g., 100 cm2), which provides a universal strategy for the mass fabrication of high performance water-splitting electrodes. PMID- 28875699 TI - Microwave-Assisted Direct Thioesterification of Carboxylic Acids. AB - A one-pot synthesis of thioesters directly from carboxylic acids, N,N' diphenylthiourea, triethylamine, and primary alkyl halides is described. Microwave-assisted heating and a catalytic amount of 4-(dimethylamino)pyridine (DMAP) further improved the yields. Both aromatic and aliphatic carboxylic acids were converted to the corresponding thioesters, and many functional groups were compatible with this reaction. Several possible reaction intermediates were investigated, and the quaternary ammonium salts, derived from alkyl halides and tertiary amines, were the intermediates to yield thioesters. A new reaction mechanism for this thioesterification is proposed. PMID- 28875700 TI - One-Pot Synthesis of beta-Hydroxysulfones and Its Application in the Preparation of Anticancer Drug Bicalutamide. AB - An efficient one-pot multistep strategy has been developed, comprising auto oxidative difunctionalization of alkenes, oxidation of sulfides, and a further reduction of peroxides for the synthesis of complex beta-hydroxysulfone derivatives from phenthiols and alkenes. This method has several advantageous characteristics, including readily available substrates, low-cost and environmental benign reagents, nontoxic and renewable solvents, and mild reaction conditions. The application of this transformation to the multigram-scale preparation of the anticancer drug bicalutamide is accomplished. PMID- 28875701 TI - Effect of Loop Length and Sequence on the Stability of DNA Pyrimidine Triplexes with TAT Base Triplets. AB - We report the thermodynamic contributions of loop length and loop sequence to the overall stability of DNA intramolecular pyrimidine triplexes. Two sets of triplexes were designed: in the first set, the C5 loop closing the triplex stem was replaced with 5'-CTnC loops (n = 1-5), whereas in the second set, both the duplex and triplex loops were replaced with a 5'-GCAA or 5'-AACG tetraloop. For the triplexes with a 5'-CTnC loop, the triplex with five bases in the loop has the highest stability relative to the control. A loop length lower than five compromises the strength of the base-pair stacks without decreasing the thermal stability, leading to a decreased enthalpy, whereas an increase in the loop length leads to a decreased enthalpy and a higher entropic penalty. The incorporation of the GCAA loop yielded more stable triplexes, whereas the incorporation of AACG in the triplex loop yielded a less stable triplex due to an unfavorable enthalpy term. Thus, addition of the GCAA tetraloop can cause an increase in the thermodynamics of the triplex without affecting the sequence or melting behavior and may result in an additional layer of genetic regulation. PMID- 28875702 TI - Synthesis, Structures, and Properties of Hexapole Helicenes: Assembling Six [5]Helicene Substructures into Highly Twisted Aromatic Systems. AB - Hexapole helicenes 1, which contain six [5]helicene substructures, were synthesized by Pd-catalyzed [2+2+2]cycloadditions of aryne precursor 6. Among the possible 20 stereoisomers, which include ten pairs of enantiomers, HH-1 was obtained selectively. Density functional theory (DFT) calculations identified HH 1 as the second most stable isomer that quantitatively isomerizes under thermal conditions into the most stable isomer (HH-2). Both enantiomers of HH-2 can be separated by chiral HPLC. Single-crystal X-ray diffraction analyses revealed a saddle-like structure for (P,M,P,P,M,P) HH-1 and a propeller-like structure for (P,M,P,M,P,M) HH-2. Because of the helical assembly and the resulting steric repulsion, the structure of HH-1 is significantly distorted and exhibits the largest twisting angle reported so far (up to 35.7 degrees per benzene unit). Electrochemical studies and DFT calculations indicated a narrow HOMO-LUMO gap on account of the extended pi-system. Kinetic studies of the isomerization from HH-1 to HH-2 and the racemization of enantiomerically pure HH-2 were conducted based on 1H NMR spectroscopy, HPLC analysis, and DFT calculations. PMID- 28875703 TI - Doubly Excited Character or Static Correlation of the Reference State in the Controversial 21Ag State of trans-Butadiene? AB - Butadiene is the simplest polyene and has long served as a model system for many chemical and spectroscopic properties. However, this small molecule has presented significant challenges to theoretical chemistry. The 21Ag state, which is dark but photochemically important, is a prime source of this difficulty. Previous studies attributed the notorious difficulty in treating this state to strong double excitation character of the 21Ag state, which prevents the application of linear response (LR) methods. Therefore, one would require methods with much higher computational cost, especially for the analogues of this state in longer polyenes, and consequently studies of longer polyenes are very limited. In the present work, we argue that the difficulty stems more significantly from the inherently multiconfigurational character of the ground state. In addition, we validate the possibility of employing LR time-dependent density functional theory to investigate such a state with reasonable accuracy. PMID- 28875704 TI - Amplifying Progress toward Multiple Development Goals through Resource Recovery from Sanitation. AB - The United Nations' Sustainable Development Goals (SDGs) recognize that current sanitation gaps must be closed to better serve those without access to safely managed systems (Target 6.2: universal sanitation coverage) and those connected to sewers without wastewater treatment (Target 6.3: halving the proportion of untreated wastewater). Beyond mitigating environmental and health concerns, implementing resource recovery sanitation systems could simultaneously improve the availability of agricultural nutrients (SDG 2) and household energy (SDG 7). This study estimates the potential for global, regional, and country-level resource recovery to impact nutrient and household electricity use through 2030. We distinguish impacts from newly installed sanitation systems (to achieve universal coverage), newly treated wastewater systems (to halve the proportion of untreated wastewater), and existing system replacement, while also considering urban and rural disparities and spatial colocation of nutrients with agricultural needs. This work points toward country-specific strategies for deriving the greatest benefit from sanitation investments while also identifying overarching trends to guide international research efforts. Globally, potential nutrient gains are an order of magnitude larger than electricity (a small fraction of total energy), and considerable impacts are possible in the least-developed countries, six of which could double or offset all projected nutrient and electricity use through newly installed sanitation systems. PMID- 28875705 TI - Realizing Synergy between In2O3 Nanocubes and Nitrogen-Doped Reduced Graphene Oxide: An Excellent Nanocomposite for the Selective and Sensitive Detection of CO at Ambient Temperatures. AB - Hierarchical mesoporous In2O3 nanocubes and nitrogen-doped reduced graphene oxide indium oxide nanocube (InNrGO) composites were prepared for carbon monoxide (CO) sensing. The as-synthesized materials were systematically investigated by different characterization techniques such as field emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, thermogravimetic analysis, X-ray photoelectron spectroscopy, micro-Raman, Fourier transform infrared spectroscopy, and photoluminesce analysis. The obtained results are consistent with each other. The CO-sensing characteristics of the In2O3 nanocubes and InNrGO composites were examined at different operating temperatures (35 degrees C < Ts < 300 degrees C) and CO concentrations (1-1000 ppm). Owing to their large surface-to-volume ratio and porosity, the In2O3 nanocubes exhibited a superior sensitivity with a detection limit of 1 ppm at 250 degrees C. Furthermore, to enhance the sensing characteristics and reduce the operating temperature, a composite of NrGO and In2O3 nanocubes was fabricated. The incorporation of NrGO drastically improved the sensing performance of the In2O3 nanocubes, showing an excellent sensitivity (SR ~ 3.6-5 ppm of CO at ~35 degrees C) with appreciably fast response (GammaRES ~ 22 s) and recovery (GammaREC ~ 32 s) times. The sensing studies supported by the structural and morphological material characteristics lead to the plausible sensing mechanism proposed. PMID- 28875706 TI - Dietary Flavonoids and Acarbose Synergistically Inhibit alpha-Glucosidase and Lower Postprandial Blood Glucose. AB - The inhibition of porcine pancreatic alpha-amylase and mammalian alpha glucosidase by 16 individual flavonoids was determined. The IC50 values for baicalein, (+)-catechin, quercetin, and luteolin were 74.1 +/- 5.6, 175.1 +/- 9.1, 281.2 +/- 19.2, and 339.4 +/- 16.3 MUM, respectively, against alpha glucosidase. The IC50 values for apigenin and baicalein were 146.8 +/- 7.1 and 446.4 +/- 23.9 MUM, respectively, against alpha-amylase. The combination of baicalein, quercetin, or luteolin with acarbose showed synergistic inhibition, and the combination of (+)-catechin with acarbose showed antagonistic inhibition of alpha-glucosidase. The combination of baicalein or apigenin with acarbose showed additive inhibition of alpha-amylase at lower concentrations and antagonistic inhibition at a higher concentration. Kinetic studies of alpha glucosidase activity revealed that baicalein alone, acarbose alone, and the combination showed noncompetitive, competitive, and mixed-type inhibition, respectively. Molecular modeling revealed that baicalein had higher affinity to the noncompetitive binding site of maltase, glucoamylase, and isomaltase subunits of alpha-glucosidase, with glide scores of -7.64, -6.98, and -6.88, respectively. (+)-Catechin had higher affinity to the active sites of maltase and glucoamylase and to the noncompetitive site of isomaltase. After sucrose loading, baicalein dose-dependently reduced the postprandial blood glucose (PBG) level in mice. The combination of 80 mg/kg baicalein and 1 mg/kg acarbose synergistically lowered the level of PBG, and the hypoglycemic effect was comparable to 8 mg/kg acarbose. The results indicated that baicalein could be used as a supplemental drug or dietary supplement in dietary therapy for diabetes mellitus. PMID- 28875707 TI - Remote Manipulation of Ligand Nano-Oscillations Regulates Adhesion and Polarization of Macrophages in Vivo. AB - Macrophages play crucial roles in various immune-related responses, such as host defense, wound healing, disease progression, and tissue regeneration. Macrophages perform distinct and dynamic functions in vivo, depending on their polarization states, such as the pro-inflammatory M1 phenotype and pro-healing M2 phenotype. Remote manipulation of the adhesion of host macrophages to the implants and their subsequent polarization in vivo can be an attractive strategy to control macrophage polarization-specific functions but has rarely been achieved. In this study, we grafted RGD ligand-bearing superparamagnetic iron oxide nanoparticles (SPIONs) to a planar matrix via a long flexible linker. We characterized the nanoscale motion of the RGD-bearing SPIONs grafted to the matrix, in real time by in situ magnetic scanning transmission electron microscopy (STEM) and in situ atomic force microscopy. The magnetic field was applied at various oscillation frequencies to manipulate the frequency-dependent ligand nano-oscillation speeds of the RGD-bearing SPIONs. We demonstrate that a low oscillation frequency of the magnetic field stimulated the adhesion and M2 polarization of macrophages, whereas a high oscillation frequency suppressed the adhesion of macrophages but promoted their M1 polarization, both in vitro and in vivo. Macrophage adhesion was also temporally regulated by switching between the low and high frequencies of the oscillating magnetic field. To the best of our knowledge, this is the first demonstration of the remote manipulation of the adhesion and polarization phenotype of macrophages, both in vitro and in vivo. Our system offers the promising potential to manipulate host immune responses to implanted biomaterials, including inflammation or tissue reparative processes, by regulating macrophage adhesion and polarization. PMID- 28875708 TI - FKBP5 methylation as a possible marker for cortisol state and transient cortisol exposure in healthy human subjects. AB - : Current glucocorticoid replacement regimens, in adrenal insufficiency, fail to mimic the physiological cortisol secretion, thereby fostering serious side effects. AIM: To experimentally evaluate the impact of CpG methylation within the FKBP5 gene as a possible short- and long-term marker for cortisol exposure in humans. MATERIALS & METHODS: An ACTH-stimulation test was carried out and methylation status of the FKBP5 gene in leukocytes was determined. RESULTS: A negative correlation between basal levels of methylation and serum cortisol was observed. Individual changes in FKBP5 methylation after 24 h correlated with cortisol responses. CONCLUSION: Considering previous studies conducted with murine leucocytes, FKBP5 methylation may be suitable as a long-term biomarker, rather than acute glucocorticoid exposure, also in humans. PMID- 28875709 TI - Continuous epidural infusion versus programmed intermittent epidural bolus for labor analgesia: optimal configuration of parameters to reduce physician administered top-ups. AB - BACKGROUND AND OBJECTIVES: Programmed intermittent epidural bolus (PIEB) is a delivery mode associated with decreased local analgesia dosing, motor block, and physician-administered top-ups (PATUs) during labor analgesia. We hypothesized that PIEB delivery at different settings will result in fewer PATUs for labor analgesia than the same hourly volume of a continuous epidural infusion (CEI). METHODS: "Before and after" study design of combined spinal-epidural (CSE) for labor, with bupivacaine 0.0625%-fentanyl 2 mcg/ml and patient-controlled epidural analgesia (PCEA; 5 ml bolus with 10 min lock-out). The "before" group (N = 120) received a CEI at 10 ml/hour. PIEB groups received a programmed bolus of 10 ml: every 60 min (PIEB60, N = 120), every 45 min (PIEB45, N = 140), or every 45 min with high flow (500 ml/hour) (PIEB45HF, N = 25). MAIN OUTCOME MEASURES: Number of women requesting a PATU, time intervals from CSE to PATU and to delivery, and obstetric outcomes. RESULTS: There was no difference in the proportion of women requesting PATUs between the CEI and PIEB60 groups (45/120 versus 52/120, respectively; p > .05). The PATU rate was lower in the PIEB45 group compared with the PIEB60 and CEI groups (23/140 versus 52/120 and 45/120, p < .005 and p < .05, respectively), and in the PIEB45HF versus PIEB60 groups (5/25 versus 52/120, p < .05). No difference in other outcomes was observed. CONCLUSIONS: The number of women requesting a PATU was lowest with the PIEB45 and PIEB45HF settings. There were no differences in any other outcomes between groups. This study emphasizes the many variations in programming that need to be further tested to establish the benefits of PIEB delivery compared with traditional CEI with PCEA. PMID- 28875710 TI - Arterial Wall Characteristics in Patients With Peripheral Arterial Disease. Preliminary Data Obtained at Different Arterial Sites by Radiofrequency-Based Wall Tracking System. AB - The common carotid artery (CCA) and the common femoral artery (CFA) have different characteristics. We compared CCA and CFA intima-media thickness (IMT), diameter and stiffness in 50 healthy controls, 50 patients with cardiovascular risk factors (CV-RFs), and 50 patients with peripheral artery diseases (PADs) using radiofrequency-based ultrasound (Rf-US). Common femoral artery-IMT was significantly and similarly increased in patients with both CV-RF and PAD, whereas CCA-IMT was significantly greater only in patients with PAD. Common carotid artery diameter was increased and CFA diameter was decreased in patients with PAD. Common carotid artery and CFA pulse wave velocity (PWV) was increased only in patients with PAD. In the study population, age was directly related to CCA-IMT, diameter, and PWV ( r = .52, .31, and .38; P < .0001 for all) but not to CFA vascular parameters ( P = .10, .62, and .67). Common femoral artery-PWV was inversely related to the ankle-brachial index ( r = -.30; P < .0001). Common femoral artery parameters are less linked to aging than the CCA parameters and may provide additional information on the atherosclerotic process. The Rf-US may be a useful tool for the more complex evaluation of arteries and assessing the impact of age and RFs on arteries. PMID- 28875711 TI - Chemical characterization of polyphenols from Daucus muricatus growing in Algeria by RP-UHPLC-ESI-QTOF-MS/MS. AB - In the present work, reversed phase (RP) ultra-high-performance liquid chromatography (UHPLC) coupled to quadrupole-time-of-flight (QTOF) mass spectrometry in tandem has been used for the identification of the main phenolic compounds in the aerial parts of Daucus muricatus. The characterisation of the compounds was carried out taking into account retention time, mass accurate measurements, the generated molecular formulae and fragmentation pattern. These data were contrasted with literature and databases, as well as with those of authentic standards when possible. The proposed method provided tentative identification of 30 phenolic and other polar compounds, including hydroxycinnamic acid derivatives, flavonoids and hydroxybenzoic acid derivatives. As a note, hydroxycinnamic acid derivatives were found to be the most diverse phenolic class of Daucus muricatus. PMID- 28875712 TI - Political violence and mental health of Bedouin children in the West Bank, Palestine: a cross-sectional study. AB - The Bedouin population is among the most vulnerable in Palestine, subject to forced relocation and lacking basic necessities, including water and electricity. To our knowledge, there are no studies on the mental health of Palestinian Bedouin children. A cross-sectional household survey was conducted examining exposures to traumatic events and mental health among 455 refugee children between the ages of 5-16 years old, and randomly selected from 18 Bedouin communities throughout the West Bank, including East Jerusalem. Mental health status was measured using the Strength and Difficulties Questionnaire. Based on reports by mothers, teachers and children, 44% of the participants in the study had a probable psychiatric disorder. Exposure to traumatic events, fair/poor maternal self-rated mental health, and younger age were positively associated with child mental health problems. The findings highlight the importance of maternal mental health as a contributing factor affecting children's vulnerability. Bedouin mothers and their children need immediate psychosocial intervention, as well as the protection of their basic human rights. PMID- 28875713 TI - The impact of fathers' military deployment on child adjustment. The support needs of primary school children and their families separated during active military service: A pilot study. AB - BACKGROUND: Although direct exposure to war-related trauma negatively impacts children's psychological well-being, little is known about this impact within the context of parental military deployment to a combat zone and 'indirect' experience of the effects of armed conflict. This study investigates the impact of father's military deployment to Afghanistan on child well-being in primary schoolchildren and compares measures of adjustment with a matched group of children with fathers deployed on military training (non-combat) deployment. METHOD: Data were collected within primary schools in 2011-2012 from 52 children aged 8-11 years with fathers deploying to Afghanistan ( n = 26) and fathers deploying on military training ( n = 26) via self-completion of questionnaires assessing symptoms of anxiety, depression, stress and levels of self-esteem. Data were collected in both groups, at pre-, mid- and post-parental deployment. Class teachers and parents (non-deployed) completed a measure of child behaviour and parents completed a measure of parenting stress and general health. RESULTS: Unexpectedly child adjustment difficulties were not significantly raised in children whose parents deployed to Afghanistan. Ratings of behavioural difficulties and depression were low in both groups. However, clinically elevated levels of anxiety and stress symptoms were reported by both groups of children at each stage of deployment. No associations between parental stress, parental mental health and child adjustment were found. CONCLUSION: High levels of children's anxiety and stress reported during fathers' active military service warrant further investigation. Implications for school and health monitoring and CAMHS community liaison work are discussed. PMID- 28875714 TI - Effects of co-exposure to imidacloprid and gibberellic acid on redox status, kidney variables and histopathology in adult rats. AB - Data on the individual nephrotoxic effects of imidacloprid (IMI) and gibberellic acid (GA3) are scarce. Moreover, there is a lack of information about their combined effects on the renal tissue. Our study investigated the effects of IMI and GA3 separately or together on rats kidney. IMI (64 mg/kg bw) was given for 3 weeks by gavage either individually or in combination with GA3 (200 mg/L) via drinking water. IMI associated or no with GA3 increased the levels of kidney malondialdehyde, advanced oxidation protein products, protein carbonyls and metallothionein, plasma creatinine, urea, blood urea nitrogen and lactate dehydrogenase activity. A decline of kidney uric acid level and antioxidant status was also observed. All these changes were supported by histopathological observations. Our results highlighted the role of IMI and/or GA3-induced nephrotoxicity. Co-exposure to IMI and GA3 exhibited synergism in biochemical kidney variables and histopathology and antagonism in physical and morphological parameters. PMID- 28875716 TI - Correction to: Zhu et al., Common and uncommon adverse cutaneous reactions to erlotinib: a study of 20 Chinese patients with cancer. PMID- 28875715 TI - The emerging molecular biology toolbox for the study of long noncoding RNA biology. AB - Long noncoding RNAs (lncRNAs) have been implicated in many biological processes. However, due to the unique nature of lncRNAs and the consequential difficulties associated with their characterization, there is a growing disparity between the rate at which lncRNAs are being discovered and the assignment of biological function to these transcripts. Here we present a molecular biology toolbox equipped to help dissect aspects of lncRNA biology and reveal functionality. We outline an approach that begins with a broad survey of genome-wide, high throughput datasets to identify potential lncRNA candidates and then narrow the focus on specific methods that are well suited to interrogate the transcripts of interest more closely. This involves the use of imaging-based strategies to validate these candidates and observe the behaviors of these transcripts at single molecule resolution in individual cells. We also describe the use of gene editing tools and interactome capture techniques to interrogate functionality and infer mechanism, respectively. With the emergence of lncRNAs as important molecules in healthy and diseased cellular function, it remains crucial to deepen our understanding of their biology. PMID- 28875717 TI - SULT1A1 copy number variation: ethnic distribution analysis in an Indian population. AB - Cytosolic sulfotransferases (SULTs) are phase II detoxification enzymes involved in metabolism of numerous xenobiotics, drugs and endogenous compounds. Interindividual variation in sulfonation capacity is important for determining an individual's response to xenobiotics. SNPs in SULTs, mainly SULT1A1 have been associated with cancer risk and also with response to therapeutic agents. Copy number variation (CNVs) in SULT1A1 is found to be correlated with altered enzyme activity. This short report primarily focuses on CNV in SULT1A1 and its distribution among different ethnic populations around the globe. Frequency distribution of SULT1A1 copy number (CN) in 157 healthy Indian individuals was assessed using florescent-based quantitative PCR assay. A range of 1 to >4 copies, with a frequency of SULT1A1 CN =2 (64.9%) the highest, was observed in our (Indian) population. Upon comparative analysis of frequency distribution of SULT1A1 CN among diverse population groups, a statistically significant difference was observed between Indians (our data) and African-American (AA) (p = 0.0001) and South African (Tswana) (p < 0.0001) populations. Distribution of CNV in the Indian population was found to be similar to that in European-derived populations of American and Japanese. CNV of SULT1A1 varies significantly among world populations and may be one of the determinants of health and diseases. PMID- 28875718 TI - Effect of Field Spread on Resting-State Magneto Encephalography Functional Network Analysis: A Computational Modeling Study. AB - A popular way to analyze resting-state electroencephalography (EEG) and magneto encephalography (MEG) data is to treat them as a functional network in which sensors are identified with nodes and the interaction between channel time series and the network connections. Although conceptually appealing, the network theoretical approach to sensor-level EEG and MEG data is challenged by the fact that EEG and MEG time series are mixtures of source activity. It is, therefore, of interest to assess the relationship between functional networks of source activity and the ensuing sensor-level networks. Since these topological features are of high interest in experimental studies, we address the question of to what extent the network topology can be reconstructed from sensor-level functional connectivity (FC) measures in case of MEG data. Simple simulations that consider only a small number of regions do not allow to assess network properties; therefore, we use a diffusion magnetic resonance imaging-constrained whole-brain computational model of resting-state activity. Our motivation lies behind the fact that still many contributions found in the literature perform network analysis at sensor level, and we aim at showing the discrepancies between source- and sensor-level network topologies by using realistic simulations of resting state cortical activity. Our main findings are that the effect of field spread on network topology depends on the type of interaction (instantaneous or lagged) and leads to an underestimation of lagged FC at sensor level due to instantaneous mixing of cortical signals, instantaneous interaction is more sensitive to field spread than lagged interaction, and discrepancies are reduced when using planar gradiometers rather than axial gradiometers. We, therefore, recommend using lagged interaction measures on planar gradiometer data when investigating network properties of resting-state sensor-level MEG data. PMID- 28875719 TI - The 2016 RANZCP Guidelines for the Management of Schizophrenia and Related Disorders - what's next? AB - OBJECTIVES: The recently published RANZCP guidelines for schizophrenia and related disorders reviewed recent scientific evidence, and, where lacking, referred to clinical expertise to supply a template for raising the standard of care. This paper builds on the guidelines and recommends how they might be used to improve outcomes. METHODS: The guidelines call for evidence-based mental health policies, inclusive of mobilising affected families, communities and the public in support of policies that ensure better care and protect the wellbeing of people with severe mental disorders. The process of preparing the guidelines highlighted the limits of our scientific understanding of schizophrenia and shortcomings in the care currently provided. RESULTS: Writing the guidelines evinced the need for a culture of measuring outcomes and response to treatment, and harnessing such data to monitoring and optimising patient care. CONCLUSIONS: We recommend creation of a national case cohort for mental health research involving a collaborative network of clinical research centres, using the guidelines and generating scientific evidence for translation into clinical practice protocols that enable personalised treatment plans for patients and criteria for the performance of clinical services. PMID- 28875720 TI - Psychiatric advance directives in Australian mental-health legislation. AB - OBJECTIVE: Following the recent widespread reform of mental-health legislation in Australia, psychiatric advance directives (PADs) have now been incorporated in four jurisdictions. We contextualise the potential role for PADs within the Australian legal framework and note their varying introduction across jurisdictions, with a focus on progressive legislation in the Australian Capital Territory (ACT). CONCLUSION: The formal recognition of PADs effectively shifts the trajectory of mental-health law towards a stronger recognition of consumer autonomy, albeit to varying degrees across jurisdictions. The most inspiring of these changes may be seen in the ACT Act, where an innovative framing of PAD provisions creates a safe space for clinicians and patients to engage, build therapeutic alliances and develop appropriate frameworks for further change. PMID- 28875721 TI - When a rash has two names: pese sorcery and kisigo spirits at Lake Tanganyika. AB - This explorative and qualitative study, based on 27 interviews during two months of fieldwork, describes pese, an affliction of the skin that has conspicuously stayed under the radar of medico-anthropological research in Kigoma, a rural city in the northwest Tanzania. The condition reminds of a locally better known condition labeled kisigo, raising the question why two concepts of the same affliction exist side by side. It seems indicative that the two illness concepts stem from different cultures and that each specializes in an explanatory model: the former witchcraft (sorcery) and the latter spirit possession. Moreover, a symbiotic relation seems to exist between the healing traditions of the Bembe and the Ha. Government policies prohibiting witchcraft and targeting traditional healers seem to have created a situation where witchcraft practices and beliefs have come to represent the periphery and survive there, clandestinely. PMID- 28875722 TI - Diabetes injectable therapy: type 2 diabetes management in Danish practice. AB - Most diabetes care is done by GPs in Denmark. This study aimed to identify the barriers for GPs in initiating injectable therapies and reasons for referral to specialists. The web interview conducted included 85 GPs and 30 specialists experienced in type 2 diabetes (T2D). GPs felt more comfortable with initiating the first injectable therapy (defined as a glucagon-like peptide-1 receptor agonist (GLP-1 RA) or basal insulin) than the second (defined as adding a basal insulin in patients treated with a GLP-1 RA (+/- oral anti-diabetic treatments [OADs]), or adding either a GLP-1 RA or a bolus insulin in patients treated with basal insulin (+/- OADs). The main barriers to initiating injectables were related to the complexity of available injectable therapies and the lack of comfort with complex patient profiles, namely patients with difficult glycemia control or significant comorbidities, whom GPs would rather refer to specialists. Main attributes that would increase the GPs' comfort level with initiation of injectables are low risk of hypoglycemia, glycemic control improvement and ease of use of the treatment. An injectable therapy with such attributes could help to overcome barriers to initiating injectable in primary care. PMID- 28875723 TI - Ribociclib for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer. AB - INTRODUCTION: The introduction of CDK4/6 inhibitors, such as ribociclib, has changed the treatment landscape for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer. As first-line treatment of HR+/HER2- MBC, the addition of a CDK4/6 inhibitor to an aromatase inhibitor improves progression free survival compared to an aromatase inhibitor alone. Areas covered: In this drug profile, we review the current market for HR+/HER2- MBC, as well as the characteristics, mechanism, pharmacology, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, toxicities, monitoring, and dosing modification of the CDK4/6 inhibitor ribociclib. Expert commentary: CDK4/6 inhibitors, such as ribociclib, improve outcomes in post-menopausal women with HR+/HER2- MBC. The most common toxicity of ribociclib is neutropenia, which is generally not complicated and can be managed with dose modification and/or supportive care measures. Additional research will help better define the optimal clinical use of ribociclib. PMID- 28875724 TI - The Long and Winding Road Toward Personalized Glycemic Control in the Critically Ill. AB - Hyperglycemia is very common in critically ill patients and interventional studies of intensive insulin therapy with the goal of returning ICU glycemia to normal levels have demonstrated mixed results. A large body of literature has demonstrated that diabetes, per se, is not independently associated with increased risk of mortality in this population and that the relationship of glucose metrics to mortality is different for patients with and without diabetes. Moreover, these relationships are confounded by preadmission glycemia; in this regard, patients with diabetes and good preadmission glucose control, as reflected by HbA1c levels obtained at the time of ICU admission, are similar to patients without diabetes. These data point the way toward an era when blood glucose targets in the ICU will be "personalized," based on assessment of preadmission glycemia. PMID- 28875725 TI - IL-1beta haplotype influences the effect of NOx exposure on gestational age in the South African MACE birth cohort. AB - OBJECTIVE: Cytokines, molecules within the immune system that affect either a pro or anti-inflammatory response, have previously been shown to influence birth outcomes. The maternal cytokine gene-environment interactions are thought to alter their expression, potentially influencing susceptibility to adverse birth outcomes. The aim of this study was to determine the association between the maternal interleukin-1beta (IL-1beta) haplotype and expression variation with oxides of nitrogen (NOx) levels, and thereafter investigate the IL-1beta haplotype-specific effects of NOx exposure levels, IL-1beta mRNA expression and other variables on gestational age. MATERIAL AND METHODS: Using the prospective Mother and Child in the Environment (MACE) birth cohort in Durban, South Africa, 335 participants were genotyped for the IL-1beta haplotype. Previous studies showed that three single nucleotide polymorphisms (SNPs), IL-1beta-1464G/C, 511C/T and -31C/T, constitute the IL-1beta functional haplotype. These SNPs were genotyped using a restriction fragment length polymorphism assay, while IL-1beta mRNA expression was measured using a quantitative real-time polymerase chain reaction assay. Individual estimates of NOx exposure were obtained by land use regression modelling. A multivariate linear regression analysis was employed to test for significant effects on gestational age. RESULTS: IL-1beta mRNA expression was found to possess a haplotype-dependent effect ( p = 0.0001) and its expression levels positively correlated with NOx levels ( r = 0.34; p = 0.006). In the high haplotype model, a unit increase in NOx exposure level was associated with a decrease in gestational age by 1 week ( p = 0.02). Furthermore, gestational age decreased by 0.9 weeks for every unit increase of IL-1beta mRNA expression level ( p = 0.025). HIV-1 positivity was associated with a 0.2-week decrease in gestational age ( p = 0.035) in the intermediate haplotype model and a 0.4-week decrease in the high haplotype model ( p = 0.044). CONCLUSION: These data have implications for better understanding the effect of prenatal NOx exposure on gestational age and demonstrate the role of the IL-1beta haplotype in modulating the effects of NOx exposure. PMID- 28875726 TI - Elevated expression of a pharmacologic Polycomb signature predicts poor prognosis in gastric and breast cancer. AB - AIM: Polycomb Group complexes are epigenetic repressors that silence tumor suppressive genes. Studies demonstrated that pharmacologic inhibition of Polycomb Group complexes with 3-deazaneplanocin A (DZNeP) induces cancer cell death by re expressing silenced genes. Here we evaluate the prognostic significance of DZNeP target genes in gastric and breast cancer. Patients & methods/materials: The prognostic impact of a DZNeP-regulated gene signature was investigated using the KM Plotter and cBio Portal resources containing microarray data from tumor tissue. RESULTS: We report that elevated expression of DZNeP targets is associated with poor clinical outcome in gastric and breast cancer. In gastric cancer, elevated expression of DZNeP signature is inversely correlated with decreased overall survival. In breast cancer, DZNeP signature predicted poor prognosis in HER2+ tumors but not in HER2- neoplasms. CONCLUSION: These findings demonstrate that DZNeP target genes are not predictive of better but rather of poor clinical outcome in gastric and breast cancer. PMID- 28875727 TI - Personality disorder: Good reasons to reclassify. PMID- 28875728 TI - Latent Classes of Maltreatment: A Systematic Review and Critique. AB - This article reviews and critically evaluates available research on latent classes of maltreatment. Three major databases (PsycINFO, Web of Knowledge, and Academic Search Complete) were used to identify studies on latent classes of maltreatment published before June 1, 2016. Of 365 potentially relevant studies, 14 met inclusion criteria for review. Our analysis was guided by the following questions: (a) What observed indicators are being used to model classes of maltreatment? (b) What are the most commonly identified classes of maltreatment? and (c) What are the predictors and outcomes of classes of maltreatment? Across the studies, findings demonstrated how person-centered methods (i.e., latent class/profile analysis) may facilitate the study of maltreatment by concurrently addressing several methodological limitations common to the study of maltreatment, while also addressing heterogeneity in experiences of maltreatment. After providing an account of existing trends within the literature employing person-centered methodology in the study of maltreatment, we offer a critique of extant research, note recent methodological developments, and make numerous recommendations for future research using person-centered approaches to understanding maltreatment. PMID- 28875729 TI - Role of cardiac pacing in congenital complete heart block. AB - INTRODUCTION: Congenital complete heart block affects 1/15,000 live-born infants, predominantly due to atrioventricular nodal injury from maternal antibodies of mothers with systemic lupus erythermatosus or Sjogren's syndrome. The majority of these children will need a pacemaker implanted prior to becoming young adults. This article will review the various patient and technical factors that influence the type of pacemaker implanted, and the current literature on optimal pacing practices. Areas covered: A literature search was performed using PubMed, Embase and Web of Science. Data regarding epicardial versus transvenous implants, pacing induced ventricular dysfunction, alternative pacing strategies (including biventricular pacing, left ventricular pacing, and His bundle pacing), and complications with pacemakers in the pediatric population were reviewed. Expert commentary: There are numerous pacing strategies available to children with congenital complete heart block. The risks and benefits of the initial implant should be weighed against the long-term issues inherent with a life-time of pacing. PMID- 28875731 TI - Outpatient Palliative Cardiology Service Embedded Within a Heart Failure Clinic: Experiences With an Emerging Model of Care. AB - BACKGROUND: The role of palliative care consultation in the outpatient treatment of patients with symptomatic heart failure (HF) is poorly studied. In August 2015, we created an outpatient palliative care service embedded within the HF clinic at Cleveland Clinic main campus. AIM: To characterize patients cared for by our novel outpatient palliative cardiology service, including their degree of HF, symptoms, comorbidities, topics addressed in clinic, palliative treatments prescribed, advanced directives status, and mortality. DESIGN: We conducted a retrospective chart review of all patients evaluated by this outpatient service. RESULTS: Eighty patients were seen in 229 outpatient encounters. The most commonly reported symptoms were tiredness (74%), pain (64%), dyspnea (57%), drowsiness (45%), anxiety (45%), and depression (43%). The most frequently addressed issues were pain management (55%) and advanced care planning (54%). The most common palliative medications prescribed in palliative care clinic were opiates (48%), laxatives (22%), antineuropathics (22%), and antidepressants (16%). The 1-year survival rate was 70% (CI 65-75%). CONCLUSIONS: Embedding palliative medicine services in an HF outpatient clinic is feasible. Patients seen in this setting had an array of quality-of-life limiting symptoms and were medically managed with several interventions familiar to palliative medicine specialists. Outpatients with chronic HF have a significant symptom burden and may benefit from outpatient specialist palliative care. PMID- 28875730 TI - Liquid biopsy for brain tumors. AB - INTRODUCTION: Minimally invasive methods will augment the clinical approach for establishing the diagnosis or monitoring treatment response of central nervous system tumors. Liquid biopsy by blood or cerebrospinal fluid sampling holds promise in this regard. Areas covered: In this literature review, the authors highlight recent studies describing the analysis of circulating tumor cells, cell free nucleic acids, and extracellular vesicles as strategies to accomplish liquid biopsy in glioblastoma and metastatic tumors. The authors then discuss the continued efforts to improve signal detection, standardize the liquid biopsy handling and preparation, develop platforms for clinical application, and establish a role for liquid biopsies in personalized medicine. Expert commentary: As the technologies used to analyze these biomarkers continue to evolve, we propose that there is a future potential to precisely diagnose and monitor treatment response with liquid biopsies. PMID- 28875732 TI - Pain Management Concerns From the Hospice Family Caregivers' Perspective. AB - BACKGROUND: Pain management is a challenging task for family caregivers in home hospice care. However, there are limited studies that examine the challenges regarding pain management in hospice care from family caregivers' perspectives. OBJECTIVES: To identify the challenges related to pain management faced by family caregivers in hospice care and to examine the validity of an existing framework that outlines pain management challenges for hospice family caregivers. DESIGN: We conducted a theory-driven, deductive content analysis of secondary data obtained from hospice family caregivers' interviews from a randomized clinical trial. SETTING/PARTICIPANTS: We included baseline interviews of 15 hospice caregivers of patients from hospice agencies in the States of Washington. The majority of the participants were white and female caregivers. They were spouse/partner or adult child living with the patient. RESULTS: The study identified 5 out of the 6 major themes in the original framework and confirmed that hospice family caregivers face a variety of challenges: caregiver-centric issues, caregiver's medication skills and knowledge, communication and teamwork, organizational skill, and patient-centric issues. A couple of the subthemes in the original framework were not present in our findings. We also expanded the original framework by adding 1 subtheme and revised 2 definitions in the original framework. CONCLUSION: The study provided an investigation on hospice family caregivers' difficulties in pain management. The results can inform health-care providers and researchers of family caregivers' challenges and provide insights for future designs of educational tools targeting pain management strategies, so that family caregivers can perform pain management effectively at home. PMID- 28875733 TI - Are Bereaved Family Members Satisfied With Information Provision About Palliative Care Units in Japan? AB - This study clarified the evaluation of the information about palliative care units (PCUs) from the oncologists by the bereaved family members of Japanese patients with cancer at the time of their first referral. A multicenter questionnaire survey examining the amount, timing, and adequacy of information received about PCUs was conducted. Half of the respondents (N = 465, mean age = 60 years) were spouses. Findings showed that 55% of the respondents thought the amount of information was inadequate and 33% thought the timing of the information about PCU from the oncologist was inadequate. Greater perceived inadequacy of the amount of information was significantly associated with (1) obtaining information from other patients and/or family member who had no experience with PCUs and (2) not acquiring information about the availability of medical staff and medical treatments at PCUs. Greater perceived inadequacy of the timing of the information was significantly associated with acts by the oncologist and/or nurses, such as providing insufficient information or saying there is nothing more that can be done any longer; however, this was not significantly associated with the actual timing of the oncologists' information. Medical staff should understand what information families desire and provide enough detail for patients to imagine accurately what time spent in a PCU would be like. Moreover, practitioners should strive to improve methods of communication and engagement after the information provision, rather than prioritizing the timing of the information. PMID- 28875734 TI - Characterization of the scope and magnitude of biotin interference in susceptible Roche Elecsys competitive and sandwich immunoassays. AB - Background Biotin interference is a significant problem to which at-risk laboratories must now be attuned. We sought to systematically characterize the nature of this interference in Roche immunoassays. Methods Known concentrations of biotin were titrated into serum samples and the effects on competitive and sandwich immunoassays were analysed. The maximum and minimum concentrations examined reflect those likely to be achieved in individuals on 5 to 10 mg supplements at the lower end, and 100 to 300 mg biotin at the high end. Results A high variability in biotin tolerance was observed. Some assays, such as troponin T, TSH and antithyroid antibodies, were extremely sensitive to the lower concentrations of biotin (15.6 and 31.3 ng/mL), whereas the majority of assays were relatively resistant. At concentrations >=500 ng/mL, all assays showed significant interference from biotin but, again, the magnitude of the interference was variable. The more sensitive assays showed profound analytical bias at biotin concentrations that occur with high-dose therapy. Conclusion Our data demonstrate high variability in biotin tolerance across Roche immunoassays. The shape of the dose-response curves provides more detailed information than the single manufacturer-quoted figure for biotin tolerance. Accordingly, these data may be used by laboratories for more accurate risk assessment in predicting the effects of biotin. Our data may also be extrapolated to guide timing of blood tests in patients on high-dose biotin therapy: it demonstrates the number of half lives required to withhold biotin in order to decrease its concentration to below a given assay tolerance. PMID- 28875735 TI - The influence of subliminal crosstalk in dementia narratives. AB - Ethnographic audio-visual research data recorded in a busy dementia care environment were initially considered to be 'contaminated' by unwanted background noise. This included a variety of elements: ambient sound, mechanical noise, non narrative vocalisation and narrative fragments from parallel conversation. Using the methodological lens of conversation analysis, we present an exploration of the striking temporal and sequential resonances between the narrative of one man with dementia and a group of care staff holding a separate conversation some distance away. We suggest that in this and similar settings, where random and intrusive background sounds and conversation form a ubiquitous backdrop, the presence of such 'noise' can have a detectable influence on the content and direction of situated narratives. We argue that rather than attempting to filter out these apparently intrusive sounds from micro-interactional data, interference elements can usefully be incorporated into the analysis of interactions. PMID- 28875736 TI - What makes extra care housing an appropriate setting for people with dementia? An exploration of staff decision-making. AB - Extra care housing facilities in the UK are intended to offer a community-based alternative to care home placement. However, little is known about staff's views of the appropriateness of extra care housing for people with dementia. This paper describes a mixed-methods study which explored this issue using statistical modelling of frontline staff's recommendations of the best care setting for care home entrants; thematic analysis of transcripts from a simulated Resource Allocation Management Panel meeting; and content analysis of care coordinators' reasons for not considering extra care housing in actual care home applications. Frontline practitioners saw extra care housing as a valuable alternative for a significant minority of care home entrants. However, extra care housing was not recommended if people needed care at night. Social care managers expressed general support for the idea of extra care housing, but appeared overwhelmingly focused on maintaining people at home and unsure where in the care pathway extra care housing sat. More evidence is needed on whether extra care housing can be an alternative to care homes and how services should be arranged to meet the needs of people living in extra care housing. PMID- 28875737 TI - The lived experiences of dementia in married couple relationships. AB - : Background and purpose There are a growing number of couples who become affected by dementia as one partner develops the condition while the other becomes a carer. However, our knowledge about the experiences of couples affected by dementia is limited. Very little knowledge about the impact of dementia on couples has been gained in previous research. The aim of this study was to explore the dyadic perspective of dementia within a couple relationship. METHODOLOGY: Six couples were interviewed about their experience of living with dementia. Interview transcripts were subjected to interpretive phenomenological analysis to identify themes across participants' accounts. RESULTS AND CONCLUSION: The analysis revealed three themes: (i) maintaining a bond, (ii) change and adjustment, and (iii) the challenge of coping. The results highlight the importance of studying the dyadic perspective and including people with dementia in research. Couples experienced an enduring commitment to one another as they adjusted to life with dementia. PMID- 28875738 TI - An evaluation of discharge documentation for people with dementia discharged home from hospital - A cross-sectional pilot study. AB - This study evaluated discharge documentation for people with dementia who were discharged home, against expected discharge criteria and determined relationships between compliance scores and outcomes. This cross-sectional study audited discharge documentation and conducted a post discharge survey of carers. There were 73 eligible discharges and clinically significant documentation deficits for people with dementia included: risk assessments of confusion (48%), falls and pressure injury (56%); provision of medication dose-decision aids (53%), provision of contact information for patient support groups (6%) and advance care planning (9%). There was no significant relationship between compliance scores and outcomes. Carer strain was reported to be high for many carers. People with dementia and their carers are more vulnerable and at higher risk of poor outcomes after discharge. There are opportunities for improved provision of medications and risk assessment for people with dementia, provision of information for patient support groups and advanced care planning. PMID- 28875739 TI - Promising effects of nanomedicine in cancer drug delivery. AB - Successful ushering of nanomedicine has shown immense potential in advancing cancer treatment regimens. The unique characteristics of nanoparticles such as their optimal size, shape, efficient surface to volume ratio, surfaces that can be optimally tailored make them very attractive delivery candidates for highly hydrophobic chemotherapeutic agents. Moreover, their inherent capacity to encapsulate these drugs and enhance their solubility profiles offers them unique advantages over conventional treatments. Surface modification with targeting ligands, increased intracellular uptake and prolonged circulation profiles in vivo establish their overall superiority over other treatment regimens. This article attempts to highlight some of these salient features of nanoparticles as drug delivery agents, which makes them more attractive in terms of providing promising opportunities in targeted drug delivery. PMID- 28875740 TI - Smart-device environmental control systems: experiences of people with cervical spinal cord injuries. AB - BACKGROUND: Environmental control systems (ECS) are devices that enable people with severe physical limitations to independently control household appliances. Recent advancements in the area of environmental control technology have led to the development of ECS that can be controlled through mainstream smart-devices. There is limited research on ECS within Australia and no known research addressing smart-device ECS. The current study sought to explore users' experiences with smart-device ECS within Australia. METHODS: The study followed a single embedded case study method. Participants (n = 5) were existing ECS users with a cervical spinal cord injury. Data were collected through semi-structured interviews with participants, reflexive journals and field notes. An inductive approach was used to analyze the data thematically. RESULTS AND CONCLUSIONS: The experience of using a smart-device ECS presented both opportunities and costs to users. The opportunities included: independent control, choice, peace of mind, connection, effective resource use, and control over smart-phone functions and applications. The associated costs included: financial, time, frustration, and technical limitations. While findings are similar to previous research into traditional ECS this study indicates that smart-device ECS also offered a new opportunity for users to access mainstream smart-device functions and applications. Future research should investigate methods and resources that practitioners could utilize to better support new users of smart-device ECS. Implications for Rehabilitation As with traditional environmental control systems, users of smart environmental control systems report increased independence, choice and control. Smart-device environmental control systems provide users with access to mainstream smart-device functions and applications, which facilitate connection to family and the outside world. The costs to the user of smart-device environmental control systems include monetary and time investment, dealing with technical limitations and resulting frustration. Prescribers and installers must consider ways to mitigate these costs experienced by users. PMID- 28875741 TI - Analysis of damage in relation to different classifications of pre-collapse osteonecrosis of the femoral head. AB - Objective This study aimed to investigate the damage pattern of the stress transfer path (STP) for the Japanese Investigation Committee (JIC) classification of pre-collapse osteonecrosis of the femoral head. We aimed to provide a specific biomechanical basis for treatment decisions of each subtype. Methods Five computational models were used in the experiment. Different necrotic classifications were simulated based on the JIC classification system. Damage patterns of the STP were used for qualitative assessment and average stresses were used for quantitative analysis. Results The STP of type A showed a strong similarity to the healthy level, which was consistent with the bone density distribution in X-rays and previous simulations results. The damaged area of principal stress of type B was approximately 25% of the healthy level. The STPs of types C1 and C2 were broken and the damaged areas of principal stress were more than 50% of the healthy level. The efficiency of stress transfer was reduced. Conclusions These results indicate that the damage patterns and stress transfer efficiency of the femoral head are associated with necrotic classifications. PMID- 28875742 TI - Medicated ocular bandages and corneal health: potential excipients and active pharmaceutical ingredients. AB - Corneal blindness can occur due to improper healing of the corneal tissues after induced injury or abrasion which can be accidental, pathogenic, or after corneal surgery. Abnormal regulation of the healing mechanisms can lead to corneal opacity. Reducing inflammation and promoting epithelial wound healing are crucial for scar-free corneal recovery without eyesight complications. Current approaches for corneal wound healing involve amniotic membrane (AM) bandages, bandage contact lenses (BCL), and collagen shields in conjunction with frequent administration of therapeutic eye drops. The problem with eye drops is poor bioavailability and patient incompliance that might lead to corneal wound healing complications and poor clinical outcomes. Various methods have been proposed for loading drugs into medicated bandage lenses. There are advantages and limitations associated with each technique regarding the ease of manufacture, drug loading, release kinetics, and suitability with various therapeutics and hydrogel types. There is still, however, no drug-eluting corneal bandage on the market despite the need for such a convenient and cost-efficient strategy for corneal wound healing. This review will highlight materials and therapeutics that can be used in medicated ocular bandages and various ways of incorporating drugs, while discussing the limitations and challenges associated with bringing medicated ocular bandages in the market. PMID- 28875743 TI - Different routes and forms of uterotonics for treatment of retained placenta: methodological issues. PMID- 28875744 TI - Folic acid-conjugated cationic Ag2S quantum dots for optical imaging and selective doxorubicin delivery to HeLa cells. AB - AIM: We aim to develop folic acid (FA)-conjugated cationic Ag2S near-infrared quantum dots (NIRQDs) for the delivery of doxorubicin (DOX) selectively to folate receptor (FR)-positive cancer cells to achieve enhanced drug efficacy and optical tracking in the NIR region. MATERIALS & METHODS: Cationic Ag2S NIRQDs were decorated with FA using a PEG bridge and loaded with DOX. In vitro studies were performed on FR-positive human cervical carcinoma cells and FR-negative A549 cells. RESULTS: Significantly higher uptake of DOX by human cervical carcinoma cells cells and a greater therapeutic effect along with a strong intracellular optical signal were obtained with DOX-loaded FA-conjugated Ag2S NIRQDs. CONCLUSION: These Ag2S NIRQDs are promising theranostic nanoparticles for receptor-mediated delivery of DOX with enhanced drug efficacy combined with optical imaging. PMID- 28875745 TI - Age-adjusted Charlson Comorbidity Index predicts prognosis of laryngopharyngeal cancer treated with radiation therapy. AB - OBJECTIVES: To examine the ability of comorbidity indices to predict the prognosis of laryngopharyngeal cancer and their association with treatment modalities. METHODS: This retrospective study included 198 patients with laryngeal, hypopharyngeal, and oropharyngeal cancers. The effect of comorbidity indices on overall survival between surgery and (chemo)-radiation therapy ((C)RT) groups was analyzed. The cumulative incidence rates for cancer mortality and other mortalities according to the age-adjusted Charlson Comorbidity Index (ACCI) and Charlson Comorbidity Index (CCI) were compared. RESULTS: Univariate survival analyses showed a significant association between the ACCI and overall survival in the (C)RT group, but not in the surgery group. The association between the CCI and overall survival was not significant in either group. In multivariate analyses, a high ACCI score was an independent prognostic factor in the (C)RT group (HR 2.89, 95% confidence interval (CI) 1.28-6.49), but not in the surgery group (HR 1.39, 95%CI 0.27-5.43). The higher ACCI group had increased mortality from other causes compared with the lower ACCI group (5-year cumulative incidence, 8.5% and 17.8%, respectively, p = .003). CONCLUSION: The ACCI was a better prognostic factor than the CCI. Surgery may be more beneficial than radiation for patients with a high ACCI. PMID- 28875747 TI - ? PMID- 28875746 TI - Plasma renin activity in patients with heart failure and reduced ejection fraction on optimal medical therapy. AB - BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) activation in heart failure with reduced ejection fraction (HFREF) is detrimental through promotion of ventricular remodeling and salt and water retention. AIMS: The aims of this article are to describe RAAS activity in distinct HFREF populations and to assess its prognostic impact. METHODS: Venous blood samples were prospectively obtained in 76 healthy volunteers, 72 patients hospitalized for acute decompensated HFREF, and 78 ambulatory chronic HFREF patients without clinical signs of congestion. Sequential measurements were performed in patients with acute decompensated HFREF. RESULTS: Plasma renin activity (PRA) was significantly higher in ambulatory chronic HFREF (7.6 ng/ml/h (2.2; 18.1)) compared to patients with acute decompensated HFREF (1.5 ng/ml/h (0.8; 5.7)) or healthy volunteers (1.4 ng/ml/h (0.6; 2.3)) (all p < 0.05). PRA was significantly associated with arterial blood pressure and renin-angiotensin system blocker dose. A progressive rise in PRA (+4 ng/ml/h (0.4; 10.9); p < 0.001) was observed in acute decompensated HFREF patients after three consecutive days of decongestive treatment. Only in acute HFREF were PRA levels associated with increased cardiovascular mortality or HF readmissions ( p = 0.035). CONCLUSION: PRA is significantly elevated in ambulatory chronic HFREF patients but is not associated with worse outcome. In contrast, in acute HFREF patients, PRA is associated with cardiovascular mortality or HF readmissions. PMID- 28875748 TI - ? PMID- 28875749 TI - ? PMID- 28875751 TI - ? PMID- 28875750 TI - ? PMID- 28875752 TI - ? PMID- 28875753 TI - ? PMID- 28875754 TI - ? PMID- 28875755 TI - ? PMID- 28875756 TI - ? PMID- 28875757 TI - ? PMID- 28875759 TI - Kaposi sarcoma: An unconventional cause of lower extremity lymphedema. PMID- 28875758 TI - Review of the pathophysiology, diagnosis, and therapy of vulvar leiomyoma, a rare gynecological tumor. AB - The objective of this article is to discuss the pathophysiology, diagnosis, differential diagnosis, and therapy of vulvar leiomyoma. We performed a review of all English-language reports of vulvar leiomyoma published in PubMed from 1978 to 2015 using the following search terms: "vulval leiomyoma," "vulvar leiomyoma," "vulval smooth muscle tumor," and "external genitalia smooth muscle tumor." Vulvar leiomyomas, which are rare benign monoclonal tumors, most commonly occur in the fourth and fifth decades of life. The genetics of vulvar leiomyoma remain undefined. Three principal histological patterns have been identified: spindled, epithelioid, and myxoid. Imaging tests such as ultrasound, endoscopic ultrasound, and magnetic resonance imaging are used in diagnosis. Surgical excision is the only curative treatment for vulvar leiomyomas. Establishment of a full differential diagnosis list and correct final diagnosis before surgery are essential for optimal clinical management. Although recurrence of vulvar leiomyoma is extremely rare, long-term follow-up of all cases is advisable. PMID- 28875760 TI - Redo surgery using IntraLase femtosecond laser for treating a decentered laser in situ keratomileusis flap. AB - Objective Decentered flaps are rarely reported after femtosecond laser-assisted in situ keratomileusis flap procedures. We present a patient with a decentered flap after preparation of a corneal flap using the Femto LDV technique. Methods The 22-year-old man required a redo operation because of a decentered corneal flap. It was performed the same day at the patient's insistence and with his consent. The new corneal flap for the redo surgery was prepared using the femtosecond laser technique and IntraLase. Results Uncorrected visual acuity for each eye was 1.2 during the 12-month follow-up. The results of the Femtosecond laser technique showed good predictability and repeatability regarding the preparation of corneal flaps, but it still may cause some intraoperative complications. Conclusion Once redo surgery is needed, the size and depth of the initially prepared flap should be determined using anterior segment optical coherence tomography to pre-set the parameters for preparation of the redo flap. PMID- 28875761 TI - An Ultralow-Dose 1-Day Protocol With Activities Lower Than 20 MBq for the Detection of Sentinel Lymph Nodes in Breast Cancer-Experiences After 150 Cases. AB - INTRODUCTION: Common protocols for the detection of sentinel lymph nodes in early breast cancer often include the injection of the tracer 1 day before surgery. In order to detect enough activity on the day of surgery, the applied activity in many protocols is as high as several hundred MBq. So far, very few protocols with an activity below 20 MBq have been reported. We developed an ultralow-dose 1-day protocol with a mean activity lower than 20 MBq in order to reduce radiation exposure for patients and staff. Here, we are presenting our experiences in 150 consecutive cases. MATERIALS AND METHODS: A total of 150 patients with clinically and sonographically negative axilla and no multicentricity underwent a sentinel lymph node biopsy using an ultralow-dose protocol performed on the day of surgery. No patient received systemic therapy prior to sentinel node biopsy. After peritumoral injection of the tracer Technetium-99m, a lymphoscintigraphy was performed in all cases. Seven minutes before the first cut, we injected 5 mL of blue dye in the region of the areola. RESULTS: In 148 (98.7%) of 150 patients, at least 1 sentinel lymph node could be identified by lymphoscintigraphy; the detection rate during surgery with combined tracers Technetium-99m and blue dye was 100%. The mean applied activity was 17.8 MBq (9-20). A mean number of 1.3 (0 5) sentinel lymph nodes were identified by lymphoscintigraphy and a mean number of 1.8 (1-5) sentinel lymph nodes were removed during sentinel lymph node biopsy. CONCLUSION: Ultralow-dose 1-day protocols with an activity lower than 20 MBq are a safe alternative to 1-day or 2-day protocols with significantly higher radiation doses in primary surgery for early breast cancer. Using Technetium-99m and blue dye in a dual tracer approach, detection rates of 100% are possible in clinical routine in order to reduce radiation exposure for patients and staff. PMID- 28875762 TI - Predictors of infection in viral-hepatitis related acute liver failure. AB - OBJECTIVE: Infections are common and associated with complications and mortality in acute liver failure (ALF). The temporal relationship between ammonia and infection in ALF patients is unclear. We aimed to evaluate the predictors of infection and its relationship with arterial ammonia levels. MATERIALS AND METHODS: Consecutive ALF patients hospitalized between January 2004 and December 2015, without signs of infection at/within 48 h of admission, were included. Occurrence of infection after 48 h was documented and ammonia levels were estimated for five consecutive days. Multivariate logistic regression analysis was used to assess factors associated with development of infection. Generalized estimating equations (GEE) were used to evaluate five-day time trend of ammonia in patients with and without infection. RESULTS: Of 540 consecutive patients, 120 were infected at admission/within 48 h and were excluded. Of the rest 420 patients, 144 (34.3%) developed infection after 48 h and 276 (65.7%) remained non infected. Infected patients had higher mortality than non-infected patients (61.8% vs 40.0%, p < .001). On multivariate analysis, presence of cerebral edema(HR 2.049; 95%CI, 1.30-3.23), ammonia level on day 3 of admission (HR 1.006; 95%CI, 1.003-1.008), and model for end stage liver disease (MELD) score (HR 1.051; 95%CI, 1.026-1.078) were associated with development of infection. GEE showed group difference in serial ammonia values between infected and non infected patients indicating lack of ammonia decline in infected patients. CONCLUSIONS: Cerebral edema, elevated ammonia on day 3, and higher MELD score predict the development of infection in ALF. Ammonia persists at high levels in infected patients, and elevated ammonia on day 3 is associated with complications and death. PMID- 28875763 TI - Porosity effects of natural latex (Hevea brasiliensis) on release of compounds for biomedical applications. AB - Natural rubber latex biomedical (NRLb) obtained from the rubber tree Hevea brasiliensis has shown great potential in biomedicine and biomaterial applications. NRLb has been utilized as a physical barrier against infectious agents and in the controlled release of drugs and extracts. In the present work, NRLb was polymerized in a lyophilizer using different volumes of water to control the resultant membrane porosity and characterized regarding the surface morphology, water vapour permeability (WVP), mechanical properties, haemolytic activity and cytotoxicity. The release of bovine serum albumin protein from the latex membranes was evaluated. Drug release rates increased with porosity and membranes were able to control protein release up to 12 h. In addition, WVP increased with the quantity of pores. The cell viability observed for the porous membrane was higher than that noted for conventional membranes. In summary, the porosity control of natural latex membranes can be used to modulate properties and make them suitable for biomedical applications, such as wound dressings, modulated gas-exchange membranes and controlled drug delivery systems. PMID- 28875764 TI - Evaluation of adiponectin and leptin levels and oxidative stress in bipolar disorder patients with metabolic syndrome treated by valproic acid. AB - INTRODUCTION: An increased risk for metabolic syndrome (MS) has been described for people with psychotic and mood disorders. The aim of this study was to determine the influence of valproic acid (VPA) treatment on adiponectin, leptin levels and oxidative stress in bipolar disorder (BD). METHODS: Forty patients with BD receiving VPA monotherapy and 20 healthy control subjects were included in this study. BD patients were divided into two groups with and without MS as group 1 and group 2, respectively. Twenty BD patients diagnosed according to the Diagnostic and Statistical Manual for Mental Disorders (DSM IV) were assessed for MS according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) criteria. Adiponectin, leptin, protein carbonyls, sulfhydryl ( SH) and malondialdehyde (MDA) levels were measured in 40 BD patients and 20 control subjects. RESULTS: Serum adiponectin levels were significantly lower in group 1 patients than in group 2 and control subjects ( p<.001). Serum leptin levels were significantly higher in group 1 patients than in group 2 and control subjects ( p<.001). Serum -SH levels were significantly lower in group 2 patients than in group 1 ( p<.001) and control subjects ( p<.05). Serum carbonyl levels were significantly higher in group 1 and group 2 patients than in control subjects ( p<.001). Serum MDA levels were significantly higher in group 1 patients than in group 2 and control subjects ( p<.001). CONCLUSION: These results provide further evidence that VPA treatment for patients with BD contributed to the metabolic disturbances, such as the decreased serum adiponectin and -SH levels, as well as the increased serum leptin, MDA and carbonyl levels. PMID- 28875765 TI - Factors associated with early diagnosis in pediatric vs adult nasopharyngeal carcinoma. AB - OBJECTIVE: To improve understanding of the initial symptom between pediatric and adult nasopharyngeal carcinoma (NPC) and to improve the early diagnosis of NPC. METHODS: This retrospective cohort study included all 353 patients with a primary diagnosis of NPC in the First Affiliated Hospital of Zhengzhou University from January 2010 to December 2016. Of these, 34 patients were 21 years or younger (pediatric); 319 patients, older than 21 years (adult). Data were analyzed after data collection. RESULTS: We found no difference between pediatric and adult patients in terms of their sex distribution (p > .05).Type III, undifferentiated carcinoma is the most common subtype in Pediatric patients, while adult patients had more squamous cell tumors (p < .01). Pediatric patients were more likely to present with stage IV disease (p < .05). Of the 353 patients, 120 (34.0%) had only one presenting symptom initially; however, most patients presented two or more episodes. Neck mass was the most common presenting symptom initially in children and adolescents, while multiple ear symptoms in adult patients (p = .003). The median time from onset of the presenting symptom to diagnosis is three months, adult patient presented longer history (64.7% vs 44.55, p < .05). Of the 319 adult patients, there were 142 which the time from onset of the presenting symptom to diagnosis is less than 3 months and there were 177 more than 3 months, the difference was significant between the two groups (p < .05). There were no differences in the misdiagnosis rate between pediatric and adult (35.1 vs 31.0, p > .05). Among pediatric patients, 31 (91.2%) had positive EBV DNA in peripheral plasma. EBV DNA was significantly associated with stage (p < .05). CONCLUSIONS: Although uncommon, pediatric NPC appears to affect a different patient demographic relative to adult NPC. NPC in children is associated with undifferentiated carcinoma and more advanced disease presentation. PMID- 28875766 TI - Postprandial glucose and healthcare resource use: a cross-sectional survey of adults with diabetes treated with basal-bolus insulin. AB - AIMS: Postprandial glucose (PPG) control is a well-known challenge for diabetes management, yet there is limited research on how PPG affects healthcare resource utilization. This study investigated the association between PPG levels and healthcare resource utilization among adults with diabetes treated with basal bolus insulin. METHODS: A web-based, cross-sectional survey (n = 940) of adults with type 1 or type 2 diabetes and treated with basal and bolus insulins was conducted in Italy, the UK, and the US. Descriptive analyses included frequencies, cross-tabulations, and comparison of means. Incidence-rate ratios (IRR) were calculated using negative binomial regression analysis to investigate the relationship between elevated PPG and healthcare resource utilization. Models controlled for demographic characteristics, duration of diabetes, and diabetes related complications. RESULTS: Among respondents who measured PPG regularly and reported their two highest PPG values in the past week (n = 691), the mean average highest PPG value was 11.9 mmol/L (SD = 4.0). On average, holding other variables constant at their means, a 1 mmol/L increase in PPG was associated with an increase in healthcare resource utilization related to diabetes and elevated PPG, including the expected number of healthcare provider (HCP) visits in the past 6 months (IRR [95% CI] = 1.14 [1.08-1.21], p < .001), the expected number of calls/emails to HCPs in the past 6 months (IRR [95% CI] = 1.12 [1.06-1.19], p < .001), and the expected number of overnight hospitalizations in the past year (IRR [95% CI] = 1.14 [1.07-1.23], p < .001). LIMITATIONS: The study relied on self-reported data, which may be subject to recall bias. Given the cross sectional nature of the study, results should be interpreted with caution. CONCLUSIONS: Increased PPG levels were significantly associated with increased healthcare resource utilization among adults with diabetes. Additional education regarding PPG monitoring may help improve the day-to-day management of diabetes and reduce healthcare costs. PMID- 28875767 TI - Applying stated-preference methods to improve health systems in sub-Saharan Africa: a systematic review. AB - INTRODUCTION: Sub-Saharan African health systems must balance shifting disease burdens with desires for robust institutions. Stated-preference methods have been applied extensively to elicit health care workers' preferences and priorities for rural practice. This systematic review characterizes the range of their applications to African health systems problems. Areas covered: A PRISMA protocol was submitted to PROSPERO. Six databases were queried for peer-reviewed articles using quantitative stated-preference methods to evaluate a health systems-related trade-off. Quality was assessed using the PREFS checklist. Seventy-seven articles published between 1996 and 2017 met review criteria. Methods were primarily choice-based: discrete-choice experiments (n = 46), ranking/allocation techniques (n = 21), conjoint analyses (n = 7), and best-worst scaling (n = 3). Trade-offs fell into six 'building blocks': service features (n = 27), workforce incentives (n = 17), product features (n = 14), system priorities (n = 14), insurance features (n = 4), and research priorities (n = 1). Five countries dominated: South Africa (n = 11), Ghana (n = 9), Malawi (n = 9), Uganda (n = 9), and Tanzania (n = 8). Discrete-choice experiments were of highest quality (mean score: 3.36/5). Expert commentary: Stated-preference methods have been applied to many health systems contexts throughout sub-Saharan Africa. Studies examined established strategic areas, especially primary health care for women, prevention and treatment of infectious diseases, and workforce development. Studies have neglected the emerging areas of non-communicable diseases. PMID- 28875768 TI - Measuring balance confidence after spinal cord injury: the reliability and validity of the Activities-specific Balance Confidence Scale. AB - CONTEXT/OBJECTIVE: The study objectives were to evaluate the test-retest reliability, convergent validity, and discriminative validity of the Activities specific Balance Confidence (ABC) scale in individuals with incomplete spinal cord injury (iSCI). DESIGN: Prospective, cross-sectional study. SETTING: Laboratory. PARTICIPANTS: Twenty-six community-dwelling individuals with chronic iSCI (20 males, 59.7 + 18.9 years old) and 26 age- and sex-matched able-bodied (AB) individuals participated. INTERVENTIONS: None. OUTCOME MEASURES: Measures of balance and gait were collected over two days. Clinical measures included the ABC scale, Mini-Balance Evaluation System's Test, 10-meter Walk Test, SCI Functional Ambulation Profile, manual muscle testing of lower extremity muscles, and measures of lower extremity proprioception and cutaneous pressure sensitivity. Biomechanical measures included the velocity and sway area of centre of pressure (COP) movement during quiet standing. RESULTS: The ABC scale demonstrated high test-retest reliability (intraclass correlation coefficient = 0.93) among participants with iSCI. The minimal detectable change was 14.87%. ABC scale scores correlated with performance on all clinical measures (rho=0.60-0.80, P<0.01), with the exception of proprioception and cutaneous pressure sensitivity (P=0.20-0.70), demonstrating convergent validity. ABC scale scores also correlated with overall COP velocity (rho=-0.69, P<0.001) and COP velocity in the anterior-posterior direction (rho=-0.71, P<0.001). Participants with iSCI scored significantly lower on the ABC scale than the AB participants (P<0.001), and the area under the receiver operating characteristic curve was 0.95, demonstrating discriminative validity. CONCLUSION: The ABC scale is a reliable and valid measure of balance confidence in community-dwelling, ambulatory individuals with chronic iSCI. PMID- 28875770 TI - Evaluating Web-Based Nursing Education's Effects: A Systematic Review and Meta Analysis. AB - This systematic review and meta-analysis investigated whether using web-based nursing educational programs increases a participant's knowledge and clinical performance. We performed a meta-analysis of studies published between January 2000 and July 2016 and identified through RISS, CINAHL, ProQuest Central, Embase, the Cochrane Library, and PubMed. Eleven studies were eligible for inclusion in this analysis. The results of the meta-analysis demonstrated significant differences not only for the overall effect but also specifically for blended programs and short (2 weeks or 4 weeks) intervention periods. To present more evidence supporting the effectiveness of web-based nursing educational programs, further research is warranted. PMID- 28875769 TI - Understanding the cryptic nature of Lassa fever in West Africa. AB - Lassa fever (LF) is increasingly recognized by global health institutions as an important rodent-borne disease with severe impacts on some of West Africa's poorest communities. However, our knowledge of LF ecology, epidemiology and distribution is limited, which presents barriers to both short-term disease forecasting and prediction of long-term impacts of environmental change on Lassa virus (LASV) zoonotic transmission dynamics. Here, we synthesize current knowledge to show that extrapolations from past research have produced an incomplete picture of the incidence and distribution of LF, with negative consequences for policy planning, medical treatment and management interventions. Although the recent increase in LF case reports is likely due to improved surveillance, recent studies suggest that future socio-ecological changes in West Africa may drive increases in LF burden. Future research should focus on the geographical distribution and disease burden of LF, in order to improve its integration into public policy and disease control strategies. PMID- 28875771 TI - The experience of being a participant in one's own care at discharge and at home, following a severe acute exacerbation in chronic obstructive pulmonary disease: a longitudinal study. AB - PURPOSE: In healthcare related to hospital discharge and follow-up, it is acknowledged that patient participation can strengthen self-management in patients with chronic obstructive pulmonary disease. However, the meaning of participation in care following a severe acute exacerbation is less described. Therefore, the aim of this part of a larger study was to explore patients' experiences of participating in their care around discharge and in their subsequent day-to-day care at home. METHOD: The study was designed as a qualitative, longitudinal study. Data were collected by repeated participant observations and in-depth interviews with 15 patients within a period of 18 months post-discharge. A phenomenological-hermeneutic approach was used to interpret the data. RESULTS: Before discharge, the patients struggled to regain a sense of control in their efforts to build up strength, and acquire sufficient clarity and confidence to face self-management at home. At home, the patients strived to comply with advice and encouragement in a struggle to stay motivated and confident, and to ask for help. CONCLUSIONS: With more knowledge about patients' participation in care, healthcare professionals can encounter patients in ways that are sensitive to their specific care and support needs and, thereby, contribute to the promotion of patients' health and well-being. PMID- 28875772 TI - Atypical caudal regression syndrome with agenesis of lumbar spine and presence of sacrum - case report and literature review. AB - CONTEXT: Caudal regression syndrome is a rare disorder, not well described in the literature. FINDINGS: Authors treated two patients with congenital absence of thoracolumbar vertebrae and lower limbs paraplegia. Patients had hypoplasia of the lower trunk and extremities with motion between upper and lower torso. Imaging showed caudal spine agenesis, but cleft sacrum was present. Due to severe kyphotic deformity and spinal instability, deformity correction and posterior fusion was performed at the age 6 and 8. Finally, fusion was achieved in one case and stable but non-fusion kyphotic posture was observed in second. CONCLUSION: surgery in caudal regression syndrome is challenging and bears high risk of complications. PMID- 28875773 TI - Use of mechanical and pharmacological restraint over an eight-year period and its relation to clinical factors. AB - BACKGROUND: Use of restraint and finding the balance between security and ethics is a continuous dilemma in clinical psychiatry. In daily clinic and in planning health-care service, knowledge on the characteristics of restraint situations is necessary to optimize its use and avoid abuse. METHODS: We describe characteristics in the use of pharmacological and mechanical restraint in psychiatric acute wards in a hospital in Middle Norway over an eight-year period. Data on all cases of mechanical and pharmacological restraint from 2004 to 2011 were retrospectively collected from hand-written protocols. Complementary information on the patients was obtained from the hospital patient administrative system. RESULTS: Restraint in acute wards was used on 13 persons per 100,000 inhabitants annually. The percentage of admitted patients exposed to restraint was 1.7%, with a mean of 4.5 cases per exposed patient. Frequency per 100 admitted patients varied from 3.7 (in 2007) to 10 (in 2009). The majority of restraint cases concerned male patients under 50 years and with substance-abuse, psychotic, or affective disorders. Significantly more coercive means were used during daytime compared to night and morning. There was a significant increase in pharmacological coercion during spring and mechanical coercion during summer. CONCLUSIONS: Restraint was used on 1.7% of admitted patients, representing 13 per 100,000 inhabitants per year. Use of restraint was higher during certain periods of the day and was associated with the patient's diagnosis, age, gender, and legal status of hospitalization. There was a marked variation over the years. PMID- 28875780 TI - Role of patient education in postoperative pain management. AB - Postoperative pain continues to be a significant issue in healthcare, with a considerable proportion of patients experiencing severe pain after surgery and finding pain management at home challenging. There are several barriers to effective pain management, involving both patients and healthcare professionals. Patient education may be a useful way to overcome many of these barriers. This article outlines the four stages of the education process, which can be used to provide patient education: assessing the patient's educational needs and potential barriers to learning; setting educational objectives; teaching; and evaluating the patient's learning. This article discusses the issue of postoperative pain and how structured patient education, from admission to discharge, provided by skilled healthcare professionals, may improve postoperative recovery. PMID- 28875781 TI - Student life - Fast track into nursing. AB - A partnership between a specialist mental health charity and a university is helping healthcare assistants (HCAs) take a fast track to becoming registered mental health or learning disability nurses. PMID- 28875782 TI - Improving communication with families in the intensive care unit. AB - Families ('family' will be used in this article to refer to anyone the patient considers significant, whether they are an actual family member or not) of patients who are critically ill have heightened communication needs. Nurses are an important source of information, particularly about day-to-day patient events and progress. Intensive care unit (ICU) nurses are valued by families because they provide clear, jargon-free information about the patient and their condition. However, they have sometimes been criticised for focusing on short term issues while avoiding potentially difficult conversations about long-term outcomes and prognosis. A family conference or meeting is held when bad news has to be communicated to families, prognosis discussed or major decisions made, particularly about treatment withdrawal or resuscitation. These meetings should involve physicians and ICU nurses. Despite family conferences, family members' understanding of patient prognosis, diagnosis and treatment is often suboptimal. A planned and structured approach for these meetings, using quantitative statements for prognostic information, recording and communicating what has been said, and supporting meetings with written information, can improve their effectiveness. These supportive strategies increase understanding and consensus, and prevent the provision of conflicting information. It is important for nurses to be willing to follow up these meetings by supporting families to clarify their understanding and encouraging them to raise concerns and ask questions. PMID- 28875783 TI - Nurses lead the way with webcam consultations. AB - More than a decade ago, Airedale NHS Foundation Trust in West Yorkshire began using a video link to deliver consultations to prisoners at a high-security jail. It meant prisoners no longer had to be escorted to the outpatient department. PMID- 28875785 TI - Student drop-out rates put profession at further risk. AB - Competition is fierce for a place on an undergraduate nursing course, yet a Nursing Standard investigation reveals one in four students who do make the grade end up dropping out. PMID- 28875787 TI - Observing the best of care. AB - In my second year of training as a children's nursing student, I was on placement on a paediatric intensive care unit when I had the opportunity to observe an 11 year-old boy with rheumatic heart disease undergo cardiac surgery. PMID- 28875790 TI - Outdoor spaces improve dementia care. AB - Rachel Potter saw many examples of great practice when she visited residential homes as part of her research into their physical environment. But none sticks in her memory quite as much as the giant rabbits, which were kept as pets at one care home. PMID- 28875798 TI - Singing their way to better health. AB - There's a good reason why I Can Breathe Clearly Now is the signature tune of Edinburgh-based singing group The Cheyne Gang. PMID- 28875796 TI - Resuscitation equipment. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article detailed the cardiopulmonary resuscitation (CPR) equipment required in a standard resuscitation trolley, and outlined the optimal method for arranging this equipment to assist nurses in assessing and managing a patient's airway, breathing and circulation. PMID- 28875803 TI - 'Establish trusting relationships'. AB - Jayne Marshall trained as a nurse at Guy's Hospital in London before starting midwifery training at King's College Hospital in 1982. She became the head of the school of midwifery at Kingston University and St George's University of London in 2014, and in July became the first professor of midwifery at the University of Leicester. PMID- 28875806 TI - District nurse's dedicated care enabled our son to die at home. AB - Our son Stephen died from a brain tumour at the age of just 26. PMID- 28875804 TI - Hepatitis B vaccine shortage. AB - Essential facts The hepatitis B vaccine is highly effective in preventing infection if given before exposure and is also effective post-exposure. Post exposure vaccination should start immediately, ideally within 24 hours. PMID- 28875807 TI - 2020 is too late to solve nurse staffing crisis. AB - The year 2020 appears to be a magical one for the Department of Health (DH). In early August it announced plans to fund an extra 10,000 training places for nurses, midwives and allied health professionals by 2020. PMID- 28875808 TI - Vacancies at all time high. AB - Headlines about the soaring number of vacancies in the NHS in England have prompted warnings that the service is facing desperate problems of understaffing. According to NHS Digital, the number of full-time-equivalent posts available rose from 26,424 in March 2016 to 30,613 in March 2017 - the highest number on record. PMID- 28875809 TI - Women are dying early from drug misuse. AB - Women who misuse drugs are dying prematurely and in increasing numbers. The past decade has seen a 95% rise in the number of women dying as a result of drug misuse: 357 died in 2006, while 697 died in 2016. PMID- 28875810 TI - How to take the strain out of moving jobs. AB - Starting a new job usually means saying goodbye to day-to-day familiarity. Facing change head-on can be exciting but it can also be stressful, and everyone copes differently. PMID- 28875816 TI - Readers' panel - Is it unprofessional for nurses to have tattoos? AB - Our experts consider a hot topic of the day. PMID- 28875815 TI - Why don't people use the phone any more? AB - 'Ping me an email'. To most people, those four words are quite innocuous, nothing to stir the soul or incite anyone to wrath. But to a nurse.... PMID- 28875817 TI - Shameful silence over the attrition rate for nursing students. AB - One in four nursing students drop out of their training courses, yet the bodies responsible remain complacent, showing a shameful disregard for the future of the profession. PMID- 28875821 TI - Be part of the future. AB - One of the busiest university teaching hospitals in the north of England, the Royal Liverpool and Broadgreen University Hospitals NHS Trust provides a range of specialist services to more than 750,000 people a year. PMID- 28875822 TI - We can all help maximise organ donation opportunities. AB - Almost 1,200 families who were approached to donate theirrelative's organs last year declined. For many, this is because they didn't know what their loved one would have wanted. PMID- 28875823 TI - Useful Immunochromatographic Assay of Calprotectin in Gingival Crevicular Fluid for Diagnosis of Diseased Sites in Patients with Periodontal Diseases. AB - BACKGROUND: Calprotectin, an inflammation-related protein, is present in gingival crevicular fluid (GCF) and the determination of calprotectin is useful for diagnosing periodontal diseases. We have recently developed a novel immunochromatographic (IC) chip system (SI-101402) to determine calprotectin levels in GCF. In the present study, the usefulness of this diagnostic system was investigated in patients with periodontal diseases. METHODS: Thirty-six patients with periodontal diseases participated in this clinical test at multiple centers. Periodontitis sites (n=118) and non-periodontitis (healthy) sites (n=120) were selected after periodontal examination. GCF collection and periodontal examination were performed at baseline, after supragingival and subgingival scaling and root planing. Calprotectin amount in GCF was determined using a novel IC chip system and evaluated as a visual score and an IC reader value. The correlation between GCF calprotectin levels, clinical indicators and changes in calprotectin levels by periodontal treatments were investigated. Receiver operating characteristic (ROC) analysis of IC reader value for GCF calprotectin was performed to predict periodontal diseases. RESULTS: The visual score of GCF calprotectin was highly correlated the IC reader value. IC reader values of GCF calprotectin in periodontitis group were higher than those of healthy group at three dental examination stages and they significantly decreased with periodontal treatments. Visual scores and IC reader values of GCF calprotectin were correlated to the levels of clinical indicators. ROC analysis for GCF calprotectin showed an optimal cutoff value to predict periodontal diseases. CONCLUSION: Determination of GCF calprotectin using a novel IC chip system is useful for diagnosis of periodontal diseases. PMID- 28875824 TI - Applications of bauxite residue: A mini-review. AB - Bauxite residue is the waste generated during alumina production by Bayer's process. The amount of bauxite residue (40-50 wt%) generated depends on the quality of bauxite ore used for the processing. High alkalinity and high caustic content in bauxite residue causes environmental risk for fertile soil and ground water contamination. The caustic (NaOH) content in bauxite residue leads to human health risks, like dermal problems and irritation to eyes. Moreover, disposal of bauxite residue requires a large area; such problems can only be minimised by utilising bauxite residue effectively. For two decades, bauxite residue has been used as a binder in cement industries and filler/reinforcement for composite materials in the automobile industry. Valuable metals and oxides, like alumina (Al2O3), titanium oxide (TiO2) and iron oxide Fe2O3, were extracted from bauxite residue to reduce waste. Bauxite residue was utilised in construction and structure industries to make geopolymers. It was also used in the making of glass ceramics and a coating material. Recently bauxite residue has been utilised to extract rare earth elements like scandium (Sc), yttrium (Y), lanthanum (La), cerium (Ce), neodymium (Nd) and dysprosium (Dy). In this review article, the mineralogical characteristics of bauxite residue are summarised and current progresses on utilisation of bauxite residue in different fields of science and engineering are presented in detail. PMID- 28875825 TI - Study of Irisin Hormone Level in Type 2 Diabetic Patients and Patients with Diabetic Nephropathy. AB - BACKGROUND: Type 2 diabetic patients with diabetic nephropathy are associated with multifactorial abnormal energy metabolism. Irisin has been recently introduced as a hormone that is exercise-induced and is secreted by skeletal muscles. It is hypothesized that patients with chronic kidney disease usually have abnormal irisin levels. AIM: We aimed to study the level of Irisin hormone in patients with type 2 diabetes and to document that it is related to diabetic nephropathy. METHODS: The current study included 60 subjects with type 2 diabetes and 30 healthy subjects as a control group. Diabetic subjects were divided into 30 without diabetic complications and 30 with diabetic nephropathy (DN). Serum Irisin levels, fasting blood glucose (FBG), 2hours plasma glucose (2hPG), hemoglobin A1c (HbA1c), kidney functions including serum creatinine and albumin/ creatinine ratio were assessed. RESULTS: There was a statistically significant decrease in Irisin levels in diabetic patients compared to controls (34.46 +/- 15.28 ng/ml vs. 152.600 +/- 39.581 ng/ml, p<0.001). Irisin levels were lower in diabetic patients with DN than in those without complications (20.967 +/- 4.476 ng/ml vs. 47.967 +/- 8.853 ng/ml, p<0.01). There was a statistically significant negative correlation between irisin and serum creatinine (r=-0.729), systolic blood pressure (r=-0.493), diastolic blood pressure (r=-0.625), duration of diabetes (r=-0.942), BMI(r=-0.396), albumin/creatinine ratio (r=-0.696), and HbA1c (r=-0.305) in all type 2 diabetic patients (p<0.05). On performing multivariate regression analysis, we found that the duration of diabetes was the only independent determinant of irisin level. CONCLUSION: There is a decrease in serum irisin level in type 2 diabetic patients with even more significant reduction in patients with diabetic nephropathy. PMID- 28875826 TI - Current Treatment Options for Osteoarthritis. AB - Osteoarthritis (OA) is the most common joint disease and a leading cause for impaired function and disability with significant treatment costs and socio economic burden. Despite recent achievements in the knowledge on disease pathogenesis, the treatment is still a challenge and contrary to the inflammatory joint diseases, no disease-modifying drugs are currently available for OA. Different response in different localizations of the disease further complicates the therapeutic choice. The standard pharmacological treatment includes agents for control of pain and inflammation (non-steroidal anti-inflammatory drugs, analgesics including opioids, intraarticular corticosteroids) and the group of the symptomatic slow acting drugs for OA such as glucosamine sulfate, chondroitin sulfate, diacerein, unsaponifiables extract of soybean and avocado administered orally and intrarticular hyaluronic acid. In addition, a number of studies investigate the efficacy of classic disease-modifying drugs used in inflammatory arthritides and antiresoptive agents as potential future therapies that could prevent structural progression of the disease. In a number of small studies, therapeutic efficacy of hydroxychloroquine (HCT) in OA has been suggested, but the results are contradictory. The first results from a multicenter, randomized, double-blind, placebo-controlled trial focused on symptomatic hand OA were recently reported (British HERO study). It has been concluded that HCQ was not superior than placebo as analgesic treatment or for reduction of the radiographic progression in hand OA. Placebo-controlled trial evaluating the efficacy of HCT in inflammatory and erosive hand OA is under way (OA TREAT study). Another field of recent research is the efficacy of TNF-alpha blockers based on the knowledge of their high efficacy in the inflammatory joint diseases and the significant role of TNF-alpha in the pathogenesis of OA. However, current evidence from the available studies does not support the use of TNF-alpha blockers in OA. The benefit of TNF-alpha blockers in specific sub-groups of patients with higher level of inflammation, objective criteria for the expected responders as well as cost-effectiveness of such treatment is a matter of further research and discussion. New biologic agents that target the nerve growth factor-beta are other currently investigated drugs as a potential symptomatic therapeutic option in OA. Significant research has been also focused on revealing potential symptomatic or eventually disease-modifying efficacy of drugs that target bone metabolism due to contemporary notion for the crucial role of the subchondral bone in OA pathology and the positive association between the increased subchondral bone turnover and the progressive cartilage loss. A significant delay of joint width narrowing vs. placebo has been observed in patients with symptomatic knee OA after treatment with strontium renelate. The intraarticular administration of platelet-rich plasma is evaluated as potential future therapy and has been tried in knee and hip OA with beneficial effect. Based on the current knowledge about the OA pathogenesis and the undergoing studies, new therapies for OA are awaited both as a safe symptomatic treatment - alternative to the conventional treatment options and as a disease-modifying therapy that would revolutionize the contemporary approach to OA. PMID- 28875827 TI - Multiple Myeloma Associated Intestinal Amyloidosis: Intestinal Pseudoobstruction Falsely Considered as an Ascites. AB - INTRODUCTION: Amyloidosis is a group of diseases pathohistologically diagnosed by characteristic extracellular deposition of an abnormal fibrillary protein (i.e. amyloid) into organs, leading to organ dysfunction secondary to destruction of normal tissue architecture. METHODS: Case-report of a 44 year-old female, presenting with massive abdominal distension clinically suspected of ascites. RESULTS: On admission, the patient was complaining of nausea, vomiting, abdominal pain, distension and bloating associated with weight loss and diarrhoea. Her prior medical history revealed a treatment naive viral hepatitis C (HCV) infection with normal liver tests. She was on long term haemodialysis due to end stage renal disease. Based on clinical, laboratory and radiology findings we established the diagnosis of light chain amyloidosis associated with multiple myeloma, complicated with amyloid bowel depositions and intestinal pseudo obstruction. On imaging, diffuse liver enlargement was seen. Liver biopsy could have rendered the possible cause of hepatomegaly, but patient's noncompliance hindered the answer whether liver involvement was the consequence of a chronic hepatitis due to HCV infection or amyloid accumulation. Unfortunately, consequent patient's death prevented specific treatment implementation. CONCLUSION: Patients with multiple myeloma and obscure abdominal complaints should be worked up for amyloidosis. Intestinal pseudo-obstruction due to amyloidosis can imitate in certain instances ascites hence complicating diagnostic algorithm. In such complex clinical cases, close collaboration between surgeon, gastroenterohepatologist and haematologist is necessary. PMID- 28875828 TI - Synergistic Effect of Epidermal Growth Factor Receptor Inhibitors and Ionization Radiation in Cancer Treatment. AB - BACKGROUND: Epidermal Growth Factor Receptor (EGFR) is overexpressed in a variety of cancers and is associated with poor prognosis, low survival rate, and resistance of cancer cells to treatment. OBJECTIVE: This review discusses the combined effect of EGFR inhibitor and radiation therapy in cancer treatment. METHOD: The recent literature and patent applications were considered in which the role of EGFR in cancer and EGFR inhibitors, as well as the preclinical and clinical studies are related to synergistic effects of EGFR inhibitors and ionizing radiation in the treatment of various cancers. RESULTS: The specific inhibition has been introduced as targeted therapy for treatment of cancers. Two major pharmacological approaches for inhibition of EGFR are monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The use of these agents in combination with ionizing radiation results in increasing the cytotoxicity on tumors that are rich in expression of EGFR. CONCLUSION: The combination of EGFR inhibitor and ionizing radiation has synergistic effect and resulted in improvement of radiotherapy in patients. PMID- 28875829 TI - Letter to the Editor: The Versatility of Tumor Suppressor Proteins and its Therapeutic Potential. PMID- 28875830 TI - Is there an Association Between Periodontitis and Atherosclerosis in Adults? A Systematic Review. AB - BACKGROUND: Atherosclerosis is a multifactorial inflammatory disease of the cardiovascular system. It has been suggested that periodontitis, an infectious disease of oral cavity caused by gramnegative anaerobic bacteria, could be linked to atherosclerosis. OBJECTIVE: The objective of this systematic review was to assess the evidence between the association of periodontitis and atherosclerosis in adults. METHODS: A systematic literature search was conducted in 7 databases up to January 2017, according to the Preferential Reports for Systematic Review and Meta-analysis (PRISMA) guidelines. Studies in humans with atherosclerosis were considered eligible when considering a group exposed to periodontitis and a control group (absence of periodontitis), in which the primary outcome was the association between the 2 diseases (atherosclerosis and periodontitis). The synthesis of the qualitative studies included was evaluated using previously validated checklist for assessing the risk of bias. RESULTS: Among the 2138 studies found, 4 observational studies met the eligibility criteria and were included in the qualitative synthesis. All articles were considered adequate, presenting consistent and valid information. The results of the selected studies show the expected effects, being considered as low risk of bias. CONCLUSION: The available evidence indicates an association between the 2 diseases, with elevated levels of inflammatory markers, mainly C-reactive protein and interleukin 6. PMID- 28875831 TI - Animal Models of Focal Cerebral Ischaemia and Haemorrhagic Transformation: Considerations in Experimental Stroke Study Design. AB - BACKGROUND: Ischaemic stroke is often complicated with haemorrhage within the infarct zone or in a remote location especially when treated with intravenous thrombolysis and/or thrombectomy. While these early recanalisation treatments are highly effective, some of the benefit is lost because of haemorrhagic complications and consequential neurological deterioration of the patients. A number of mechanisms have been described that mediate the haemorrhagic changes and several agents have been tested in experimental models for inhibiting post stroke haemorrhage. METHODS: Here, we review and discuss the small animal models of focal cerebral ischaemia and postischaemic stroke haemorrhagic transformation and how these models can best be utilised for developing further insights as well as potential treatment approaches for this serious clinical complication. RESULTS: The need to use appropriate animal models with relevant stroke risk factors to improve the clinical relevance and applicability of findings is becoming ever more apparent. Current focal ischaemia models can be adapted for the study of haemorrhagic transformation post-stroke. CONCLUSION: A number of factors can be added to the animal model design to increase the incidence and/or severity of haemorrhagic transformation post-ischaemic stroke, which can improve clinical relevance, aid the study of the pathophysiology and the future development of novel interventions. PMID- 28875833 TI - Phytocompounds as Potential Agents to Treat Obesity-Cardiovascular Ailments. AB - Obesity is no longer considered as a cosmetic issue as it is a potential risk factor to develop hypertension, type-2 diabetes, cardio vascular diseases (CVDs), infertility, arthritis etc. Apart from genetic factors, changes in life styles, food and work habits have lead to alarming raise in obesity ailments in both developed and developing countries. The excess and unutilized food takenin is converted into lipid components, primarily triglycerides and is stored in the liver, adipose and other tissues; if the positive energy balance extends a longer period it will lead to overweight, obesity and CVDs. Cardiovascular diseases are a group of disorders of the heart and blood vessels and cause greater mortality rate worldwide. Although a number of drugs have been developed to contain these diseases, most of them suffer from significant side effects and some of them have been even withdrawn from markets. In view of this, there is a growing emphasis for natural product based drugs. In this book chapter, the present scenario of obesity-CVDs and their causative factors are described besides mentioning currently available medications to treat them. The role of phytochemicals in treating obesity-CVDs and their possible mode of action is also highlighted. This study strengthens our understanding on obesity-CVDs and paves the way to develop novel and cost-effective plant based drugs/formulations with minimum side effects to treat these lifestyle based diseases. PMID- 28875834 TI - Argemone mexicana: A Boon to Medicinal and Pharmacological Approaches in Current Scenario. AB - Nature is God's gift to human beings. Natural products are a source of new chemical diversity and are the choice of today's world. Nature itself gives remedy to all our health problems. The sources of natural product are plants, animals and microorganisms. Among them plant and its products are more reliable for its renewability and therefore, considered as fortunate thing for human welfare. Our traditional system of medicine which has been followed by our ancestors has its own impact on human life. Due to the inadequate knowledge many plant derived products (drugs) has not yet been explored to the society. We are having many side effects and long term complications in synthetic drugs. Our aim is to mine the precious data about the plant Argemone mexicana. Now-a-days people prefer a drug which has no side effects. For that, the plant Argemone mexicana is a boon to the human being as it has a number of miraculous compounds to cure a various types of diseases. Single plant has a lot of uncountable benefits in drug discovery and which gives a base for new drug discovery. This plant is a weed, easily available and it does not require any special care which forms the base to develop a drug in socio economic form so that it could be made available to all people. This chapter provides an insight into various interesting pharmacological properties viz., Antidiabetic activity , Anti-Cancer activity, Anti-HIV activity, CNS related activities, Wound recovering action, Anti microbial activity, Antioxidant activity, Anti-inflammatory, analgesic, antipyretic activity, Hepatoprotective activity, Anti-fertility activity, Antiallergic activity, Nematicidal activity, Allelopathic effect, Antihelmintic activity, Larvicidal activity, Antifeedant action etc., which has been reviewed from different literatures in scientific journals. This present review would kindle many of the young minds to turn towards the nature i.e., plant based novel drug discovery with in-depth and extensive studies in all relevant aspects. Hence the paramount importance of this review about Argemone mexicana will be very much useful to the society. PMID- 28875832 TI - Structure, Gating and Basic Functions of the Ca2+-activated K Channel of Intermediate Conductance. AB - BACKGROUND: The KCa3.1 channel is the intermediate-conductance member of the Ca2+ activated K channel superfamily. It is widely expressed in excitable and non excitable cells, where it plays a major role in a number of cell functions. This paper aims at illustrating the main structural, biophysical and modulatory properties of the KCa3.1 channel, and providing an account of experimental data on its role in volume regulation and Ca2+ signals. METHODS: Research and online content related to the structure, structure/function relationship, and physiological role of the KCa3.1 channel are reviewed. RESULTS: Expressed in excitable and non-excitable cells, the KCa3.1 channel is voltage independent, its opening being exclusively gated by the binding of intracellular Ca2+ to calmodulin, a Ca2+- binding protein constitutively associated with the C-terminus of each KCa3.1 channel alpha subunit. The KCa3.1 channel activates upon high affinity Ca2+ binding, and in highly coordinated fashion giving steep Hill functions and relatively low EC50 values (100-350 nM). This high Ca2+ sensitivity is physiologically modulated by closely associated kinases and phosphatases. The KCa3.1 channel is normally activated by global Ca2+ signals as resulting from Ca2+ released from intracellular stores, or by the refilling influx through store operated Ca2+ channels, but cases of strict functional coupling with Ca2+ selective channels are also found. KCa3.1 channels are highly expressed in many types of cells, where they play major roles in cell migration and death. The control of these complex cellular processes is achieved by KCa3.1 channel regulation of the driving force for Ca2+ entry from the extracellular medium, and by mediating the K+ efflux required for cell volume control. CONCLUSION: Much work remains to be done to fully understand the structure/function relationship of the KCa3.1 channels. Hopefully, this effort will provide the basis for a beneficial modulation of channel activity under pathological conditions. PMID- 28875835 TI - The Biological Potentialsof Indian Traditional Medicine, Curcumin for Treating Human Diseases. AB - Curcumin is an active compound extracted from the rhizomes of Curcuma longa L. (Turmeric). It possesses a di phenolic structure and there are three important fractions of curcumin namely curcumin, mono-desmethoxycurcumin and bis desmethoxycurcumin. Curcumin is having high medicinal value. It is widely in Ayurveda, Siddha and Unani medicine formulations to treat various diseases. It is effective against microbial pathogens like bacteria, virus and fungi. It is highly potent and kills cancerous cells. Curcumin exhibits antioxidant activity and reduces lipoperoxidation. Cardioprotective nature of curcumin is also reported. It can protect the brain from neurodegenerative disorders caused by oxidative stress. It is safe to use in humans and animals. In addition to its medicinal value, it is also having numerous commercial applications like dyeing, cooking purposes and antiseptics etc. The cultivation of turmeric by means of inorganic inputs makes it contaminated with heavy metals is reported. Improving the biological use of curcumin provides healthy humankind and increases the economic status of a country. PMID- 28875836 TI - Coinhibitory Molecule PD-1 as a Therapeutic Target in the Microenvironment of Multiple Myeloma. AB - BACKGROUND: Patients with Multiple Myeloma suffer from dysregulation of the immune system and new therapeutic options targeting the immune systems such as monoclonal antibodies or specific Cell therapy such as CAR-T cells have entered clinical practice, but the exhausted immune system hampered a more effective immunotherapy. Targeting the immunological dysfunction in the microenviroment might be a potential target for immune-mediated therapies. METHOD: Here we review the current literature and knowledge about the programmed death 1 (PD-1) receptor which is expressed on the surface of exhausted T and B cells and its ligand PD-L1 is expressed on myeloma cells and inhibits T cell-mediated apoptosis. RESULTS: The programmed death 1 (PD-1) receptor is expressed on the surface of exhausted T and B cells and its ligand PD-L1 is expressed on myeloma cells and inhibits Tcell mediated apoptosis. Inhibiting such "checkpoint" by monoclonal antibodies recently has been shown high activity in solid tumors and malignant lymphomas. In patients with multiple myelomaPD-L1 is overexpressed on myeloma cells and PD1 on T-cells suggesting an active role of PD-1/PD-L1 in the immunosuppressive microenvironment. CONCLUSION: Immunotherapies using anti-PD-1/PD-L1 strategies are a promising treatment options for patients with multiple myeloma. PMID- 28875837 TI - Nanoparticles for SPECT and PET imaging: towards personalized medicine and theranostics. AB - PET and SPECT imaging methods can be of excellent assistance for the development of new nanoparticle drug delivery systems, and at the same time, these investigations also offer the opportunity to produce exceptional new diagnostic and therapeutic radiopharmaceuticals, as well. With a multifunctional, nano scaled drug delivery system, the diagnostic (imaging) methods and the therapy (delivering drugs or beta-emitter radionuclides) can be carried out using the same biological and pharmacological mechanisms. By combining therapy and diagnostics in one method or in one specifically targeted nanoparticle system, we can product theranostic pharmaceuticals, and its applications are important elements of personalized medicine. This review takes a short historical look back to the radiocolloids, the great ancestors of (radiolabeled) nanoparticles and then describes the general features of current types of PET and SPECT imaging associated nanoparticle-based products and key radiolabeling methods; entering into details of potential prospective challenges related to radiotheranostic approaches and imaging guided therapy. PMID- 28875838 TI - Biomarkers in atrial fibrillation and heart failure. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice and an important contributor to cardiovascular morbidity and mortality. Although the exact mechanisms behind AF are not completely elucidated, the underlying pathophysiological changes have been well described. Predisposal factors for AF include the older age, the increased left atrial size, the decreased left atrial function, the presence of heart failure and left ventricular systolic dysfunction and the presence of coronary heart disease or pulmonary or mitral valve disease. In addition to these factors, emerging evidence demonstrate that myocardial strain, fibrosis and inflammation, are associated with AF as well as the pathogenesis of the arrhythmia. The natruretic peptide system including Atrial Natriuretic Peptide (ANP), Brain Natriuretic Peptide (BNP) and C-type Natriuretic Peptide (CNP) is indicative of the level of myocardial strain which may predispose to AF. As a result, the aforementioned peptides are increased in AF patients. The levels of myocardial fibrosis biomarkers, such as ST2 and Galectin-3, are elevated suggesting atrial structural abnormalities, while the increased levels of CRP and Interleukin-6 supplement the inflammatory profile of AF patients. Emerging data for the aforementioned biomarkers are discussed in the present review. PMID- 28875839 TI - Repositioning Drugs for Rare Immune Diseases: Hopes and Challenges for a Precision Medicine. AB - Human primary immunodeficiency diseases (PIDs) are a large group of rare diseases and are characterized by a great genetic and phenotypic heterogeneity. A large subset of PIDs is genetically defined, which has a crucial impact for the understanding of the molecular basis of disease and the development of precision medicine. Discovery and development of new therapies for rare diseases has long been de-privileged due to the length and cost of the processes involved. Interest has increased due to stimulatory regulatory and supportive reimbursement environments enabling viable business models. Advancements in biomedical and computational sciences enable the development of rational, designed approaches for identification of novel indications of already approved drugs allowing faster delivery of new medicines. Drug repositioning is based either on clinical analogies of diseases or on understanding of the molecular mode of drug action and mechanisms of the disease. All of these are the basis for the development of precision medicine. PMID- 28875840 TI - Stimuli-responsive carriers for controlled intracellular drug release. AB - Stimuli-responsive carriers are a class of drug delivery systems which can change their physicochemical properties and/or structural conformations in response to specific stimuli. Although passive and active drug targeting has proved to reduce the side effects to normal cells, controlled intracellular drug release should be included in drug carriers to enhance the bioavailability of drugs at the disease site. This review focuses on several recent advances in the development of stimuli-responsive carriers for spatially and temporally controlled release of therapeutic agents in response to intracellular stimuli, such as pH, redox potential, reactive oxygen species, enzyme and temperature. Great efforts are needed to the optimization of stimuli-responsive materials, with emphasis on their molecular designs and formulations, to enable multi-functionality and multiple stimuli-responsiveness in improving the clinical drug efficacy. PMID- 28875841 TI - New Molecular Targets and Strategies for Antimalarial Discovery. AB - Malaria remains a major health problem, especially because of the emergence of resistant P. falciparum strains to artemisinin derivatives. In this context, safe and affordable antimalarial drugs are desperately needed. New proteins have been investigated as molecular targets for research and development of innovative compounds with well-defined mechanism of action. In this review, we highlight genetically and clinically validated plasmodial proteins as drug targets for the next generation of therapeutics. The enzymes described herein are involved in hemoglobin hydrolysis, the invasion process, elongation factors for protein synthesis, pyrimidine biosynthesis, post-translational modifications such as prenylation, phosphorylation and histone acetylation, generation of ATP in mitochondrial metabolism and aminoacylation of RNAs. Significant advances on proteomics, genetics, structural biology, computational and biophysical methods provided invaluable molecular and structural information about these drug targets. Based on this, several strategies and models have been applied to identify and improve lead compounds. This review presents the recent progresses in the discovery of antimalarial drug candidates, highlighting the approaches, challenges, and perspectives to deliver affordable, safe and low single-dose medicines to treat malaria. PMID- 28875843 TI - Dihydroresveratrol Type Dihydrostilbenoids: Chemical Diversity, Chemosystematics, and Bioactivity. AB - BACKGROUND: Dihydrostilbenoids, a diverse class of natural products differing from stilbenoids by the missing double bond in the ethylene chain linking the aromatic moieties, have been reported from fungi, mosses, ferns, and flowering plants. OBJECTIVE: Occurrence, structure, and bioactivity of naturally occurring dihydroresveratrol type dihydrostilbenoids are discussed in this review. METHOD: A Reaxys database search for dihydroresveratrol derivatives with possible substitutions on all atoms, but excluding non-natural products and compounds featuring additional rings involving the ethyl connecting chain, was performed. RESULTS: Structures include simple dihydroresveratrol derivatives, compounds substituted with complex side chains composed of acyl moieties and sugars, and compounds containing polycyclic cores attached to dihydrostilbenoid units. Dihydrostilbenoids have a wide spectrum of bioactivities ranging from expectable antioxidant and anti-inflammatory activities to interesting neuroprotective and anticancer activity. The anticancer activity in particular is very pronounced for some plant-derived dihydrostilbenoids and makes them interesting lead compounds for drug development. Apart from some reports on dihydroresveratrol derivatives as phytoalexins against plant-pathogenic fungi, only very limited information is available on the ecological role of these compounds for the organisms producing them. CONCLUSION: Dihydrostilbenoids are a class of natural products possessing significant biological activities; their scattered but not ubiquitous occurrence throughout the kingdoms of plants and fungi is not easily explained. We are convinced that future studies will identify new sources of dihydrostilbenoids, and we hope that the present review will inspire such studies and will help in directing such efforts to suitable source organisms and towards promising bioactivities. PMID- 28875844 TI - The Clinical translation of Organic Nanomaterials for Cancer Therapy: A Focus on Polymeric Nanoparticles, Micelles, Liposomes and Exosomes. AB - The application of nanotechnology in the medical field is called nanomedicine. Nowadays, this new branch of science is a point of interest for many investigators due to the important advances in which we assisted in the lasts decades, in particular for cancer treatment. Cancer nanomedicine has been applied in different fields such as drug delivery, nanoformulation and nanoanalytical contrast reagents. The application of nanotechnology to pharmaceutical science allowed to build up nanosystems based on at least two stage vectors (drug/nanomaterial), which often shown a better pharmacokinetics (PK), bioavailability and biodistribution. As result of these advantages, the nanomaterials accumulate passively in the tumor (enhanced permeability and retention, EPR) decreasing side effects of free drug. In the last decades, many new drug formulations have been translated from the bench to the bedside. In this review, we describe the main drug nanoformulations based on different types of organic nanoparticles (NPs), the advantages that the new formulations have over to their free drug counterparts and how nanodrugs have improved the clinical care. PMID- 28875845 TI - New trends in anti-cancer therapy: combining conventional chemotherapeutics with novel immunomodulators. AB - Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy. PMID- 28875846 TI - Computational Identification of microRNA-17-3p in Breast Cancer Cells. AB - BACKGROUND: MicroRNAs (miRNAs) are small, highly conserved non-coding RNA molecules involved in the RNA silencing and post-transcriptional regulation of gene expression. miRNAs are well conserved in both plants and animals, and are thought to be a vital and evolutionarily ancient component of gene regulation and also act as oncogenes or tumor suppressors. It is known that Express Sequence Tags (EST) are a short sub-sequence of cDNA sequence, which contain information of condition or tissue specific transcripts (coding and non-coding) of an organism. METHODS: In the present study, we have applied the bioinformatics tools to identify miRNA from breast cancer using EST resource. Through bioinformatics approach, the presence of an EST encoding hsa-miR-17- 3p of breast cancer was identified. RESULTS: Further studies reveal that hsa-miR-17 is confirmed in the breast cancer specific EST sequence among the predicted miRNAs secondary structure. Moreover, miR-17-3p could be responsible for a tumor suppression, which plays a major role in human breast cancer. CONCLUSION: Further studies are required to investigate the molecular mechanisms behind miR-17-3p involves in the suppression of breast cancer cells. Interestingly, our target analysis suggesting that all the targets involved in multiple signaling pathways in different cell regulations moreover, we need to have more number of in vitro and in vivo studies that prove miR-17-3p as candidate microRNA for breast cancer cells. PMID- 28875842 TI - Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy. AB - Chemokines, which have chemotactic abilities, are comprised of over 50 family members. Through binding to the 7-transmembrane domain of G-protein-coupled receptors (GPCR), they function in immune cells by trafficking and regulating cell prolif!eration, differentiation, activation, and migration, homing under both physiologic and pathologic conditions. The alpha-chemokine receptor CXCR4 for the alpha-chemokine stromal cell-derived-factor-1 (SDF-1) is most widely expressed by tumors. CXCL12/CXCR4 axis is a major culprit for human tumor because of its crucial role in tumor initiation and progression by activating a number of signaling pathways, such as ERK1/2, ras, PLC/ MAPK, p38 MAPK, and SAPK/ JNK, as well as regulating cancer stem cells. CXCL12/CXCR4 antagonists have been developed, which have shown promising results in both in vitro and in vivo anti cancer activity in several tumor types. This review provides an evaluation of CXCL12/CXCR4 as a potential therapeutic target for human tumors; it also focuses on the synergistic effects of inhibition of CXCL12/CXCR4 axis and immunotherapy as well as chemotherapy. Together, CXCL12/CXCR4 axis can be a potential therapeutic target for tumors and used with immunotherapy for additive effects. PMID- 28875847 TI - Management of Blood Pressure and Heart Rate in Chronic Kidney Disease. AB - BACKGROUND: Hypertension is considered a major health problem in patients with chronic kidney disease (CKD) as approximately 80-85% of CKD patients' suffer from hypertension in the United States. Hypertension is the second leading cause of CKD after diabetes and is strongly related to morbidity and mortality. It has been found that there is a relation among hypertension, glomerular filtration rate (GFR) and creatinine levels. OBJECTIVE: Since there is a strong relation between hypertension and CKD, and hypertension seems to lead to cardiovascular diseases, which have epidemic proportions in CKD, this review article discusses the etiology of hypertension and the existing optimal therapies that contribute to the hypertension and heart rate management. RESULTS: There are many approaches that contribute to the management of hypertension and heart rate in CKD patients. Lifestyle modifications in combination with drug therapy lead to the better control of hypertension in CKD patients. CONCLUSION: Hypertension is strongly related to cardiovascular diseases in CKD patients. Since this relation exists and hypertension leads to cardiovascular diseases, the management of hypertension and increased heart rate should be a main therapeutic target in these patients. PMID- 28875848 TI - Polymeric Nanocarriers: A New Horizon for the Effective Management of Breast Cancer. AB - BACKGROUND: Delivery of chemotherapeutic drugs for the diagnosis and treatment of cancer is becoming advanced day by day. However, the challenge of the effective delivery system still does exist. In various types of cancers, breast cancer is the most commonly diagnosed cancer among women. Breast cancer is a combination of different diseases. It cannot be considered as only one entity because there are many specific patient factors, which are involved in the development of this disease. Nanotechnology has opened a new area in the effective treatment of breast cancer due to the several benefits offered by this technology. METHODS: Polymeric nanocarriers are among one of the effective delivery systems, which has given promising results in the treatment of breast cancers. Nanocarriers does exert their anticancer effect either through active or passive targeting mode. RESULTS: The use of nanocarriers has been resolute about the adverse effects of chemotherapeutic drugs such as poor solubility and less penetrability in tumor cells. CONCLUSION: The present review is focused on recent developments regarding polymeric nanocarriers, such as polymeric micelles, polymeric nanoparticles, dendrimers, liposomes, nanoshells, fullerenes, carbon nanotubes (CNT) and quantum dots, etc. for their recent advancements in breast cancer therapy. PMID- 28875849 TI - Modulation of both Insulin Resistance and Cancer Growth by Inositol. AB - Insulin resistance indicates a deregulated set of biochemical pathways and physiological functions involved in the pathogenesis of a number of diseases, including type 2 diabetes and cancer. Conversely, a number of synthetic and natural insulin sensitizers, including inositol, have been recognized to exert both anti-diabetic as well as anti-cancer properties. Inositol participates in insulin transduction signaling, and deregulated inositol metabolism has been ascertained in several conditions associated with insulin resistance. Two distinct inositolphosphoglycans released upon insulin stimulation act as insulin mimetic by counteracting hyperinsulinemia, hyperglycemia and their metabolic complications. Additionally, inositol may directly interfere with both glucose metabolism and carcinogenesis by modulating a number of critical processes downstream of insulin stimulation, including anti-oxidant defenses, oxidative glucose metabolism and endocrine modulation. A selected cluster of biochemical factors (PI3K/Akt, PDH and AMPK-related pathways), that are presently considered putative targets for anticancer treatments, are also specifically modulated by inositol or its derivatives. What is more, studies on inositol mechanism of action paved the way in understanding that both insulin resistance and cancer share a few perturbed, critical biochemical pathways. Asides from the basic investigations, preliminary studies in vivo demonstrated the beneficial effect of inositol in fostering glucose homeostasis as well as in antagonizing cancer growth. Thereby, inositol fulfills the requirement to target both insulin resistance and cancer, and its clinical usefulness deserves to be adequately addressed by specific, randomized trials. PMID- 28875850 TI - Pharmacological Aspects of Neuro-Immune Interactions. AB - The use of systematic approach for the analysis of mechanism of action of drugs at different levels of biological organization of organisms is an important task in experimental and clinical pharmacology for drug designing and increasing the efficacy and safety of drugs. The analysis of published data on pharmacological effects of psychotropic drugs possessing immunomodulatory and/or antiviral properties have shown a correlation between central effects of examined drugs associated with the impact on the processes of neurogenesis of adult brain and survival of neurons, and their ability to alter levels of key proinflammatory cytokines. The changes that occur as a result of the influence of pharmacological agents at one of the systems should inevitably lead to the functional reorganization at another. Integrative mechanisms underlying the neuro-immune interactions may explain the "pleiotropic" pharmacological effects of some antiviral and immunomodulatory drugs. Amantadine, which was originally considered as an antiviral agent, was approved as anti-parkinsonic drug after its wide medical use. The prolonged administration of interferon alpha caused depression in 30-45% of patients, thus limiting its clinical use. The antiviral drug "Oseltamivir" may provoke the development of central side effects, including abnormal behavior, delirium, impaired perception and suicides. Anti-herpethetical drug "Panavir" shows pronounced neuroprotective properties. The purpose of this review is to analyze the experimental and clinical data related to central effects of drugs with antiviral or/and immunotropic activity, and to discover the relationship of these effects with changes in reactivity of immune system and proinflammatory response. PMID- 28875851 TI - Urotensin II: Molecular Mechanisms of Biological Activity. AB - Urotensin II (UT II) is an important factor of cellular homeostasis. This regulatory peptide is involved in the pathophysiology of many disorders. For example, it plays an important role in the pathogenesis of acute and chronic diseases, stressful and adaptive reactions of the body, in the development of cardiovascular pathologies, metabolic syndrome, inflammation, liver cirrhosis, renal failure, diabetic nephropathy, reproductive dysfunction, progression of psychosomatic, psychoendocrinal and psychiatric disorders. In this concern, the involvement of UT II in the pathophysiology of many processes determines the perspectives for the development of blockers of urotensin receptors for the treatment of the aforementioned diseases. It is important that even today this kind of perspective is feasible due to the synthesis of a series of GPR14 blockers. The objective of this review is to discuss current molecular mechanisms of biological activity, regulatory functions of UT II, its role in the pathogenesis of different nosologies, as well as analysis of the possible routes of exposure to GPR14 as potential therapeutic targets. PMID- 28875852 TI - Molecular Modeling Studies of Novel Fluoroquinolone Molecules. AB - BACKGROUND: Fluoroquinolones have been the centre of considerable scientific and clinical interest due to their broad spectrum pharmacological activities. Pefloxacin is an analogue of norfloxacin, which is a 3rd generation of fluoroquinolone antibiotic similar to ciprofloxacin. Pefloxacin is used to treat a variety of bacterial infections like respiratory tract, ear, nose and throat (ENT) infections, skin infections, and urinary tract infections. Hydrazone as a pharmacophore unit that attracts the medicinal chemists because of structure activity relationship (SAR) studies of fluoroquinolones especially the functionality at C-3 position. Consequently, recognition and development of potential ligands specifically for a protein target forms the primary goal in drug discovery process. Among the different theoretical approaches available, Gold and Glide are the molecular docking methods which find application protein ligand studies. In the current study, the DNA gyrase of Staphylococcus aureus has been used as the target protein to understand their possible interactions. METHODS: The crystal structure of DNA gyrase (topoisomerase II) was downloaded from the Protein Data Bank (PDB ID: 2XCS, 3FOE) and molecular docking studies were performed using the docking programs like Gold 3.2 (Genetic Algorithm for Ligand Docking), Glide 5.0 (Grid Based Ligand Docking with Energetic). Melting points were uncorrected and determined in open capillary tubes in a melting point apparatus. TLC was performed on silica gel-G and spotting was done using iodine/ KMnO4 staining or UV-light. The following experimental procedures are representive of the general procedures used to synthesize all compounds. RESULTS: The docking experiments of the title compounds with 2.1 A crystal structure of DNA gyrase 2XCS, 3FOE using Gold 3.2 and Glide 5.0 is carried out to understand the binding interactions of the novel ligands with the protein, contributing for antibacterial activity. The compounds in general exhibited good binding interactions like H-bonding interaction and pi-pi interactions which stabilize the protein-ligand complexes and responsible for good fitness scores in both the protocols. CONCLUSION: In summary, a new series of novel pefloxacin hydrazones 5a 5n were studied for their interactions with Staphylococcus aureus DNA gyrase protein by Glide 5.0 and Gold 3.2 molecular docking protocols [PDB IDS: 2XCS, 3FOE]. Among the tested molecules, compound 5g exhibited a good Glide score value of - 7.73 and Glide energy -51.24 with emodel value of -66.16. The nice docking scores of 5g, 5a, 8h, 5m and 5b revealed that these compounds are well accommodated on the active site residues of DNA gyrase enzyme. From the docking study, we have explored the probable binding mode and the binding pattern of compounds 5f, 5l, 5h, 5d, and 5n showed that they strongly interact with in the active site of Staphylococcus aureus of DNA gyrase enzyme. From screening results it is found that compounds having aromatic ring substituted with electron releasing groups are showing potent docking scores and exhibited better fitness than reference compounds CPF and CA4. An efficient combination of molecular modeling and biological activity provided an insight into QSAR guide lines that could aid in further development and optimization of the pefloxacin derivatives. PMID- 28875853 TI - Effectiveness of Cicer arietinum in Cutaneous Problems: Viewpoint of Avicenna and Razi. AB - BACKGROUND: Cicer arietinum is one of the popular legumes in the most parts of the world. It is known for a long time in Asia because of the many possibilities of its application. Cicer arietinum has benefits for the skin regarding safe ingredients. Some of these ingredients are recommended in skin care. METHODS: This study aimed to introduce the benefits of Cicer arietinum by reviewing of traditional literature from 10th to 21th century and also conventional medicine for its safe ingredients by searching the electronic data banks such as ISI, Pub Med and Scopus. RESULTS: The results showed that Cicer arietinum has many ingredients such as Phenolic compounds, allantoin and amino acids that affect the skin problems. Also, great traditional Persian scientists such as Avicenna and Razi suggested about the cutaneous benefits of Cicer arietinum. CONCLUSION: The findings of this study can help the researchers in producing better cosmetic and therapeutic products. PMID- 28875854 TI - Cytomegalovirus Infection: The Neurodevelopmental Peptide Signatures. AB - BACKGROUND AND OBJECTIVE: HCMV infection may cause neurodevelopmental disorders, including intellectual disability, hearing loss, cortical malformations, and calcifications. Theorizing about the still unknown molecular basis of HCMV related diseases, this study analyzes the peptide sharing between HCMV, strains AD169 and Merlin, and human proteins, searching for shared sequences that might lead to crossreactive autoimmune injuries in the brain during immune responses following HCMV infection. METHOD: HCMV proteins were analyzed for peptides shared with the human proteome using the Pir Peptide Match resource. RESULT: Numerous HCMV peptides (ranging from 9 to 13 mer in length) are disseminated through hundreds of human proteins. The peptide sharing mostly involves crucial neurodevelopmental antigens such as PITX3, implicated in the differentiation of meso-diencephalic dopaminergic neurons; SIX3, which controls proper anterioposterior patterning of the diencephalon and formation of the rostral diencephalon during forebrain development; and ZIC2, which plays a fundamental role in the early stage of organogenesis of the central nervous system. CONCLUSION: This study describes a HCMV vs human peptide overlap that may represent a crossreactive platform linking the pathologic sequelae of HCMV infection to the immune anti-HCMV response. The data could inform development of effective and safe immune therapeutic/preventive approaches against HCMV infections. PMID- 28875855 TI - Impurity Profile of Bronchodilators used in Asthma: A Critical Review. AB - BACKGROUND: Asthma is defined as a heterogeneous disease usually characterized by chronic airway inflammation (GINA 2016) affecting almost 334 million people worldwide (Global asthma report 2014). Treatment of asthma with a long-acting bronchodilator is important because it reduces the symptoms that occur at night or in the early morning and it is very effective to use as a long term control medication for asthma by preventing asthmatic symptoms. The main objective of this review is to describe the impurity profile and force degradation studies for three major classes of bronchodilators namely beta2-adrenoceptor agonists, muscarinic receptor antagonists and xanthine. Unidentified and potential toxic impurities are hazardous to health, so in order to increase the safety of drug therapy; impurities should be identified and determined by selective analytical methods. METHODS: Different conditions for degradations like hydrolytic (acidic, basic and neutral), oxidative, photolytic and thermolytic have been discussed in detail for bronchodilators. Furthermore, it is discussed with the name along with number of impurities and degradants present in different matrices including its clinical implication. The name as well as structures of all the observed impurities in different bronchodilators is included, which can aid in impurity profiling. Various analytical methods, including Chromatographic techniques like TLC; HPTLC; HPLC; GC, Spectroscopic techniques like UV; IR; NMR; MS and hyphenated techniques like GC-MS; LC-MS; CE-MS; SFC-MS; LC-NMR; CENMR; LC-FTIR has been used for the identification and quantification of impurities. A general scheme has been presented for the impurity profiling. RESULT: Nineteen articles, six patents and fifteen drugs are included in this review. In that, majority (7) of papers are based on HPLC-UV, 5 papers are based on LC-MS, 2 papers are based on LC-MS-NMR, 1 paper is based on LC-NMR, 1 paper is based on GC-MSNMR, 1 paper is based on GC-UV and 1 paper is based on TLC-UV technique for isolation and characterization of impurities. In salbutamol, 7 degradants were found by LC-MS as compare to 4 degradants by HPLC-UV. In bambuterol, 12 degradants were found by LC-MS-NMR as compare to 4 degradants by LC-MS. CONCLUSION: After a thorough literature search, LC-MS and LC-MS-NMR techniques are found most useful for impurity profiling. In future, LC-DAD-NMR-MS, CE-ESI-FTICR- MS can also be explored for the isolation and characterization of impurities. PMID- 28875856 TI - Identification of 1-Aryl-1H-1,2,3-triazoles as Potential New Antiretroviral Agents. AB - BACKGROUND: Low molecular weight 1-Aryl-1H-1,2,3-triazoles are endowed with various types of biological activities, such as against cancer, HIV and bacteria. Despite the existence of six different classes of antiretroviral drugs in clinical use, HIV/AIDS continue to be an on growing public health problem. OBJECTIVE: In the present study, we synthesized and evaluated thirty 1-Aryl-1H 1,2,3-triazoles against HIV replication. METHOD: The compounds were prepared by Huisgen 1,3-dipolar cycloaddition protocol catalyzed by Cu(I) between aryl azides and propargylic alcohol followed by further esterification and etherification from a nucleophilic substitution with acid chlorides or alkyl bromides in good yields. The compounds were submitted to the inhibition of HIV replication and evaluation of their cytotoxicity. Initially, the compounds were screened at 10 uM and the most active were further evaluated in order to obtain some pharmacological parameters. RESULTS: Thirty molecules were evaluated, six were selected - because they inhibited more than 80% HIV replication. We further showed that two of these compounds are 8-times more potent, and less cytotoxic, than nevirapine, an antiretroviral drug in clinical use. CONCLUSION: We identified very simple triazoles with promissing antiretroviral activities that led to the development of new drugs against AIDS. PMID- 28875857 TI - Is there a Link between Vitamin B and Multiple Sclerosis? AB - BACKGROUND: Damage to the myelin sheath (demyelination) is one of the main manifestations of multiple sclerosis (MS). Interestingly, both MS and vitamin B deficiencies result in severe myelin degeneration, leading to loss in neuronal signal transmission. OBJECTIVE: Deficiency in vitamin B complex vary, although common symptoms include fatigue, increased oxidative stress, inflammation and demyelination. In particular, vitamin B12 (cobalamin) has had increased attention for its role in the methylation process, involvement in myelination and remyelination, and reversal of MS symptoms. METHOD: Here, we discuss the role of vitamin B complex (B1, B2, B3, B4, B5, B6, B7, B9, B12) in MS. RESULTS: The anti inflammatory and re-myelinating attributes of vitamin B complex members are promising, despite limited clinical studies. CONCLUSION: There is an urgent need for larger studies to determine the role of vitamin B supplementation alone, or in combination with other therapeutic agents, in prevention or reversal of MS, and aid in improved quality of life of MS patients. PMID- 28875858 TI - Managing Neuropathic Pain in Multiple Sclerosis: Pharmacological Interventions. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Of the plethora of motor and sensory disturbances experienced by sufferers, neuropathic pain is a highly prevalent and debilitating symptom, and at present remains extremely difficult to treat. Common forms of neuropathic pain seen in MS patients include central neuropathic pain, Lhermitte's phenomenon and trigeminal neuralgia, which are all speculated to arise from specific patterns of lesion formation. OBJECTIVE: Efficacious pharmacological interventions for the treatment of neuropathic pain associated with MS are lacking, and have been largely informed by drug trials in peripheral neuropathies and spinal cord injury. METHOD/RESULTS: Neuropathic pain in MS is inadequately relieved by conventional analgesics, and first-line therapies are generally comprised of anti-depressive and anti-convulsive drugs. A range of alternatives have been proposed and tested with variable success, including cannabinoids and certain opioid analgesics. Animals with experimental autoimmune encephalomyelitis (EAE), an autoimmune model of MS, also exhibit neuropathic pain symptoms. CONCLUSION: Studies aimed at understanding the mechanisms underlying EAE-induced neuropathic pain and investigating the efficacy of novel pharmacological interventions at the animal level offer an exciting area of future research, and may inform future therapeutic options for MS-associated neuropathic pain. PMID- 28875859 TI - Myelin Oligodendrocyte Glycoprotein and Multiple Sclerosis. AB - BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) is located on the external surface of myelin, a membranous component of the central nervous system (CNS) that forms the insulating lipid layer around neurons. The major MOG splicing variant (a1 transcript) encodes a transmembrane protein with an extracellular domain of an Ig variable (IgV) fold. MOG IgV domains from the same or different cells dimerize and contribute to the organization and maintenance of the myelin sheath in neurons. The encepalitogenic T cells recognize MOG and its immunodominant epitopes (epitopes 1-22, 35-55 and 92-106 located at the dimer interface) as foreign antigens and cause the destruction of myelin (demyelination) leading to the clinical condition known as multiple sclerosis (MS). Recognition of the antigen takes place in the context of the trimolecular complex formed by HLA, MOGpeptides and TCR. OBJECTIVE: Understanding the role of MOG in MS. METHOD/RESULTS: We have reviewed herein, the genomic organization of the human MOG gene, the structural characteristics of the MOG protein, the involvement of MOG in MS and clinical studies for the treatment of MS based on MOG peptide analogues. CONCLUSION: Conjugates of antigenic MOG peptides to mannan and combinations of antigenic MOG and other peptides chemically linked to cells of the immune system may modify the immune response, alleviating in some cases the symptoms of MS. PMID- 28875860 TI - Scaffold Hopping Strategy for the Design, Synthesis and Biological Activity Evaluation of Novel Hexacyclic Scutellarein Derivatives with a 1,3-Oxazine Ring Fused at A-ring. AB - BACKGROUND: Discovery of novel agents with anticoagulant and antioxidant activity is very important to treat cerebrovascular disease. Lead compound LR3d discovered in our laboratory exhibited stronger anticoagulant ability and good antioxidant activity, compared with scutellarein (2), which is the major in vivo active metabolite of the natural product scutellarin (1). OBJECTIVE: Design and synthesis novel scutellarein derivatives with improved anticoagulant and antioxidant activity. METHODS: By utilizing a scaffold hopping strategy on LR3d, we describe the design and synthesis of a series of novel hexacyclic scutellarein derivatives 4 with a 1,3-oxazine ring fused at positions 7 and 8 in A ring. The thrombin inhibitory activities of all these new compounds were studied by the analysis of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). The antioxidant abilities of these analogs were evaluated by using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di phenytetrazoliumromide (MTT) method through 1,1- diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay. RESULTS: Nine new hexacyclic scutellarein derivatives with a 1,3-oxazine ring fused at A ring were synthesized, the results of the biological activity evaluation showed that compound 4e exhibited stronger anticoagulant and antioxidant ability compared to LR3d. CONCLUSION: 4e could be used for further development to treat ischemic cerebrovascular disease. PMID- 28875861 TI - Therapeutic Monoclonal Antibodies and Multiple Sclerosis: The Essentials. AB - BACKGROUND: Monoclonal antibodies (mAbs) are now established as targeted therapies for malignancies, transplant rejection, autoimmune and infectious diseases. Two monoclonal antibodies are available for treatment and other antibodies are currently being tested in multiple sclerosis (MS) patients. OBJECTIVES: The purpose of the present review paper is to outline the antibody engineering technologies, the immunologic and pharmacologic concepts of mbs and the current status of treatment in MS with emphasis on clinical efficacy and safety. METHOD: We conducted a through review of the scientific literature published until 31 December 2014 (print and electronic publications) concerning the production, applications and side effects of the use of Mabs. Sixty five articles were used in total (both original research and review papers). CONCLUSION: With the introduction of mAbs the treatment of MS has entered a new era, both with respect to efficacy and target specificity. However, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness, infection and other autoimmune diseases. In addition, unexpected consequences arise from our incomplete knowledge of the immune system. For example, natalizumab, a monoclonal antibody targeting alpha4 integrin on leukocytes increases the risk of developing progressive multifocal leukoencephalopathy, without causing notable immunosuppression. Further study on the use of mabs is required, both in vitro and in the clinical field, in order to increase our knowledge upon these new revolutionary therapeutic agents. PMID- 28875862 TI - An Update on the Role of Matrix Metalloproteinases in the Pathogenesis of Multiple Sclerosis. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases, proteins essential to the degradation of various tissue extracellular matrix proteins. Under normal conditions, MMPs participate in several physiological processes, both in the developing organism and the adult. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), affecting primarily young adults. Inflammatory infiltrations of the CNS parenchyma by autoreactive immune cells, that mediate myelin degradation in the form of the demyelination "plaque", are the pathological hallmark of the disease. Due to their capacity to orchestrate tissue penetration from various cells, MMPs have been elucidated in MS as mediators of blood-brain barrier disruption and CNS inflammation, thus contributing to the disease pathogenesis. OBJECTIVE: This review focuses on clinical and experimental evidence of MMPs' pathogenetic role in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). METHOD: A MEDLINE search was performed for using the following terms: "metalloproteinases", "multiple sclerosis", "experimental autoimmune encephalomyelitis", "central nervous system" and "autoimmunity". RESULTS: Expression patterns of MMPs and their specific inhibitor molecules at the sites of MS and EAE lesions, as well as by specific cell types of the immune system, provide evidence of MMPs' role in the pathogenesis of CNS autoimmunity. Clinical evidence suggests differential profile of MMPs' expression in serum and cerebrospinal fluid (CSF) between MS patients with various disease types and healthy adults, rendering MMPs potential biomarkers for disease incidence and activity. CONCLUSION: MMPs' role in the processes of CNS inflammation, de- and remyelination, confers implications as therapeutic targets, either alone, or in relation with widely-used disease modifying treatments in MS. PMID- 28875864 TI - Pulmonary embolism with cardiac arrest: a STEMI patient's unexpected course. AB - We describe the successful use and complications of bolus-dose alteplase to treat strongly suspected pulmonary embolism (PE) with cardiac arrest in a patient initially presenting as ST-elevation myocardial infarcation (MI). Case description is followed by a review of the indications, safety, and dosing of systemic thrombolytic therapy for high-risk PE in the emergency department (ED). Diagnostic and therapeutic approach to PE in critically ill patients is also considered, including the potential utility of point-of-care ultrasound (PoCUS) in the ED. PMID- 28875863 TI - The Basic Mechanism of Hair Growth Stimulation by Adipose-derived Stem Cells and Their Secretory Factors. AB - BACKGROUND: Adipose-derived stem cells (ADSCs) are mesenchymal stem cells (MSCs) within the stromal vascular fraction of subcutaneous adipose tissue. ADSCs secrete growth factors and other proteins, and have been used to regenerate skin with satisfactory results. OBJECTIVE: This review focuses on the effect of ADSCs and their secretory factors on the stimulation of hair growth in vitro, ex vivo and in vivo. RESULTS: The conditioned media of ADSCs (ADSC-CM) increases the proliferation rate of human follicular cells. ADSCs-derived proteins improve hair growth and protect human dermal papilla cells against cytotoxic injury caused by androgen and reactive oxygen species. Moreover, ADSC-CM induces the anagen phase and promotes hair growth in mice, and enhances the elongation of hair shafts in ex vivo human hair organ cultures. CONCLUSION: ADSC-CM promotes hair growth in vitro, ex vivo, and in vivo. Given that ADSCs are one of the most accessible sources of MSCs, ADSC-derived proteins may be feasible clinical therapeutic agents for the treatment of hair loss. PMID- 28875865 TI - Predictors and correlates of serum 25-hydroxyvitamin D concentrations in young women: results from the Safe-D study. AB - Vitamin D deficiency is a global public health concern. Studies of serum 25 hydroxyvitamin D (25(OH)D) determinants in young women are limited and few include objective covariates. Our aims were to define the prevalence of vitamin D deficiency and examine serum 25(OH)D correlates in an exploratory study of women aged 16-25 years. We studied 348 healthy females living in Victoria, Australia, recruited through Facebook. Data collected included serum 25(OH)D assayed by liquid chromatography-tandem MS, relevant serum biochemistry, soft tissue composition by dual-energy X-ray absorptiometry, skin melanin density, Fitzpatrick skin type, sun exposure using UV dosimeters and lifestyle factors. Mean serum 25(OH)D was 68 (sd 27) nmol/l and 26 % were vitamin D deficient (25(OH)D 2 h in the sun in summer daily, holidaying in the most recent summer period, serum Fe levels, height and multivitamin use were positively associated with 25(OH)D. Fat mass and a blood draw in any season except summer was inversely associated with 25(OH)D. Vitamin D deficiency is common in young women. Factors such as hormonal contraception, sun exposure and sun-related attitudes, as well as dietary supplement use are essential to consider when assessing vitamin D status. Further investigation into methods to safely optimise vitamin D status and to improve understanding of the impact of vitamin D status on long-term health outcomes is required. PMID- 28875866 TI - In Haitian women and preschool children, iron absorption from wheat flour-based meals fortified with sodium iron EDTA is higher than that from meals fortified with ferrous fumarate, and is not affected by Helicobacter pylori infection in children. AB - Fe fortification of wheat flour was proposed in Haiti to combat Fe deficiency, but Fe bioavailability from fortificants has never been investigated in Haitian women or preschool children, two key target groups. We aimed to investigate the bioavailability of ferrous fumarate (FeFum), NaFeEDTA and their combination from fortified wheat flour. We recruited twenty-two healthy mother-child pairs in Port au Prince, Haiti, for an Fe-absorption study. We administered stable Fe isotopes as FeFum or NaFeEDTA individually in low-extraction wheat flour bread rolls consumed by all participants in a randomised, cross-over design. In a final, identical meal, consumed only by the women, FeFum+NaFeEDTA was administered. We measured Fe absorption by using erythrocyte incorporation of stable isotopes 14 d after consumption of each meal, and determined Fe status, inflammatory markers and Helicobacter pylori infection. Fe absorption (geometric mean was 9.24 (95 % CI 6.35, 13.44) and 9.26 (95 % CI 7.00, 12.31) from FeFum and 13.06 (95 % CI 9.23, 19.10) and 12.99 (95 % CI 9.18, 18.39) from NaFeEDTA in mothers and children, respectively (P<0.05 between compounds). Fe absorption from FeFum+NaFeEDTA was 11.09 (95 % CI 7.45, 17.34) and did not differ from the other two meals. H. pylori infection did not influence Fe absorption in children. In conclusion, in Haitian women and children, Fe absorption from NaFeEDTA was 40 % higher than from FeFum, and the combination FeFum+NaFeEDTA did not significantly increase Fe absorption compared with FeFum alone. In the context of Haiti, where the high costs of NaFeEDTA may not be affordable, the use of FeFum at 60 mg Fe/kg flour may be a preferable, cost-effective fortification strategy. PMID- 28875867 TI - Growth performance, nutrient utilisation and carcass composition respond to dietary protein concentrations in broiler chickens but responses are modified by dietary lipid levels. AB - A total of ten experimental diets with protein concentrations ranging from 154 to 400 g/kg and two lipid levels (46 and 85 g/kg) with identical energy densities were offered to 240 male Ross 308 broilers from 7 to 28 d post-hatch. Growth performance was monitored and nutrient utilisation (apparent metabolisable energy (AME), N-corrected AME (AMEn), AME daily intake, AME:gross energy ratios, N retention) was determined. The weight gain response of broiler chickens to dietary protein concentrations in diets containing high and low lipid levels was diverse, with the relevant quadratic regressions being significantly different (P0.05). AMEn was also linearly (P<0.0001) increased with dietary protein concentrations but regressions in diets with low and high lipid content were significantly different (P<0.03). Carcass protein content increased linearly with dietary protein content in diets containing high lipid concentrations (r 0.933, P<0.0001); by contrast, this relationship was quadratic (R 2=0.93, P<0.0001) in diets with low lipid levels. In conclusion, predictably, the effects of dietary protein concentrations on broiler performance were profound; however, the impact of dietary protein on performance in broiler chickens was modified by dietary lipid concentrations. PMID- 28875868 TI - Nutrient intake and dietary changes during a 2-year multi-domain lifestyle intervention among older adults: secondary analysis of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) randomised controlled trial. AB - Advancing age increases the risk for diseases and health concerns like cognitive decline, constituting a major public health challenge. Lifestyle, especially healthy diet, affects many risk factors related to chronic diseases, and thus lifestyle interventions among older adults may be beneficial in promoting successful ageing. We completed a randomised 2-year multi-domain lifestyle intervention trial aiming at prevention of cognitive decline among 631 participants in the intervention and 629 in the control group, aged 60-77 years at baseline. Dietary counselling was one of the intervention domains together with strength exercise, cognitive training and management of CVD risk factors. The aim of this paper was to describe success of the intervention - that is, how an intervention based on national dietary recommendations affected dietary habits as a part of multi-intervention. Composite dietary intervention adherence score comprising nine distinct goals (range 0-9 points from none to achieving all goals) was 5.0 at baseline, and increased in the intervention group after the 1st (P<0.001) and 2nd (P=0.005) year. The difference in change compared with the control group was significant at both years (P<0.001 and P=0.018). Intake of several vitamins and minerals decreased in the control group but remained unchanged or increased in the intervention group during the 2 years. Well targeted dietary counselling may prevent age-related decline in diet quality and help in preventing cognitive decline. PMID- 28875869 TI - Red meat intake is positively associated with non-fatal acute myocardial infarction in the Costa Rica Heart Study. AB - The adverse effect of red meat consumption on the risk for CVD is a major population health concern, especially in developing Hispanic/Latino countries in which there are clear trends towards increased consumption. This population-based case-control study examined the associations between total, processed and unprocessed red meat intakes and non-fatal acute myocardial infarction (MI) in Costa Rica. The study included 2131 survivors of a first non-fatal acute MI and 2131 controls individually matched by age, sex and area of residence. Dietary intake was assessed with a FFQ. OR were estimated by using conditional logistic regression. Higher intakes of total and processed red meat were associated with increased odds of acute MI. The OR were 1.31 (95 % CI 1.04, 1.65) and 1.29 (95 % CI 1.01, 1.65) for the highest quintiles of total red meat (median: 110.8 g or 1 serving/d) and processed red meat intake (median: 36.1 g or 5 servings/week), respectively. There were increasing trends in the odds of acute MI with higher total (P trend=0.01) and processed (P trend=0.02) red meat intakes. Unprocessed red meat intake was not associated with increased odds of acute MI. Substitutions of 50 g of alternative foods (fish, milk, chicken without skin and chicken without fat) for 50 g of total, processed and unprocessed red meat were associated with lower odds of acute MI. The positive association between red meat intake and acute MI in Costa Rica highlights the importance of reducing red meat consumption in middle-income Hispanic/Latino populations. PMID- 28875872 TI - Undergraduate antimicrobial stewardship training for pharmacy students: Creating a foundation for containment of antimicrobial resistance in South Africa. PMID- 28875870 TI - A priori-defined diet quality indices, biomarkers and risk for type 2 diabetes in five ethnic groups: the Multiethnic Cohort. AB - Dietary indices have been related to risk for type 2 diabetes (T2D) predominantly in white populations. The present study evaluated this association in the ethnically diverse Multiethnic Cohort and examined four diet quality indices in relation to T2D risk, homoeostatic model assessment-estimated insulin resistance (HOMA-IR) and biomarkers of dyslipidaemia, inflammation and adipokines. The T2D analysis included 166 550 white, African American, Native Hawaiian, Japanese American and Latino participants (9200 incident T2D cases). Dietary intake was assessed at baseline using a quantitative FFQ and T2D status was based on three self-reports and confirmed by administrative data. Biomarkers were assessed about 10 years later in a biomarker subcohort (n 10 060). Sex- and ethnicity-specific hazard ratios were calculated for the Healthy Eating Index-2010 (HEI-2010), the alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED) and the Dietary Approaches to Stop Hypertension (DASH). Multivariable-adjusted means of biomarkers were compared across dietary index tertiles in the biomarker subcohort. The AHEI-2010, aMED (in men only) and DASH scores were related to a 10 20 % lower T2D risk, with the strongest associations in whites and the direction of the relationships mostly consistent across ethnic groups. Higher scores on the four indices were related to lower HOMA-IR, TAG and C-reactive protein concentrations, not related to leptin, and the DASH score was directly associated with adiponectin. The AHEI-2010 and DASH were directly related to HDL-cholesterol in women. Potential underlying biological mechanisms linking diet quality and T2D risk are an improved lipid profile and reduced systemic inflammation and, with regards to DASH alone, an improved adiponectin profile. PMID- 28875873 TI - South African student protests, 2015 - 2016: The aftermath viewed through Medical Science Honours students at the University of Cape Town. PMID- 28875874 TI - Use of social media by health professionals in South Africa. PMID- 28875871 TI - Wheat germ supplementation alleviates insulin resistance and cardiac mitochondrial dysfunction in an animal model of diet-induced obesity. AB - Obesity is strongly associated with insulin resistance (IR), along with mitochondrial dysfunction to metabolically active tissues and increased production of reactive O2 species (ROS). Foods rich in antioxidants such as wheat germ (WG), protect tissues from damage due to ROS and modulate some negative effects of obesity. This study examined the effects of WG supplementation on markers of IR, mitochondrial substrate metabolism and innate antioxidant markers in two metabolically active tissues (i.e. liver and heart) of C57BL/6 mice fed a high-fat-high-sucrose (HFS) diet. Male C57BL/6 mice, 6-week-old, were randomised into four dietary treatment groups (n 12 mice/group): control (C, 10 % fat kcal), C+10 % WG, HFS (60 % fat kcal) or HFS+10 % WG (HFS+WG). After 12 weeks of treatment, HFS+WG mice had significantly less visceral fat (-16 %, P=0.006) compared with the HFS group. WG significantly reduced serum insulin (P=0.009), the insulinotropic hormone, gastric inhibitory peptide (P=0.0003), and the surrogate measure of IR, homoeostatic model assessment of IR (P=0.006). HFS diet significantly elevated (45 %, P=0.02) cardiac complex 2 mitochondrial VO2, suggesting increased metabolic stress, whereas WG stabilised this effect to the level of control. Consequently, genes which mediate antioxidant defense and mitochondrial biogenesis (superoxide dismutase 2 (Sod2) and PPARgamma coactivator 1-alpha (Pgc1a), respectively) were significantly reduced (P<0.05) in the heart of the HFS group, whereas WG supplementation tended to up-regulate both genes. WG significantly increased hepatic gene expression of Sod2 (P=0.048) but not Pgc1a. Together, these results showed that WG supplementation in HFS diet, reduced IR and improved cardiac mitochondrial metabolic functions. PMID- 28875875 TI - Work-based assessment: A critical element of specialist medical training. PMID- 28875876 TI - Commercial herbal medicines used as African traditional medicines: Ngoma Herbal Tonic Immune Booster interferes with a rapid urine drug screening test. AB - BACKGROUND: The prevalent use of African traditional medicine by the general public has been reported. With commercialisation and marketing, some of the herbal medicines (HMs) used are readily available over the counter, most of them promoted as immune boosters. These commercial HMs have not been taken through clinical trials and other tests that would validate their composition and safety, and other properties such as their effect on laboratory diagnostic tests. OBJECTIVE: To investigate the cross-reactivity of selected HMs with commonly tested drugs of abuse (DoA) using a qualitative rapid urinalysis assay. METHODS: The six HMs selected were bought from local pharmacies. A rapid urinalysis screening test was performed with the Instant View Multi-Drug of Abuse Test kit from Labstix Diagnostics. Drug-free urine (DFU) was pooled from samples donated by healthy volunteers. Urine samples that had tested positive for DoA were obtained from a pharmacology laboratory. Aliquots of the urine samples were spiked with the HMs in neat and diluted form, and tested at various time intervals. RESULTS: The results for the DFU samples spiked with the HMs remained negative. There were no significant changes in pH or specific gravity of the samples. The results of samples that had tested positive for tetrahydrocannabinol (THC) were not altered by five of the HMs when spiked at 40% v/v. The HM Ngoma Herbal Tonic Immune Booster caused false-negative results for the THC test. CONCLUSION: An important finding is that the herbal mixture Ngoma Herbal Tonic Immune Booster caused false-negative results for the cannabinoid screening test. It adds to the list of substances that may be potential adulterants of urine for screening tests. PMID- 28875877 TI - How front-line healthcare workers respond to stock-outs of essential medicines in the Eastern Cape Province of South Africa. AB - Shortages of essential medicines are a daily occurrence in many of South Africa (SA)'s public health facilities. This study focuses on the responses of healthcare workers to stock-outs, investigating how actors at the 'front line' of public health delivery understand, experience and respond to shortages of essential medicines and equipment in their facilities. Findings are based on focus groups, observations and interviews with healthcare workers and patients at healthcare facilities in the Eastern Cape Province of SA, conducted as part of the Mzantsi Wakho study. The research revealed a discrepancy between 'informal' definitions of stock-outs and their reporting through formal stock-out management channels. Front-line healthcare workers had designed their own systems for classifying the severity of stock-outs, based on the product in question, and on their potential to access stocks from other facilities. Beyond formal systems of procurement and supply, healthcare workers had established vast networks of alternative communication and action, often using personal resources to procure medical supplies. Stock-outs were only reported when informal methods of stock sharing did not secure top-up supplies. These findings have implications for understanding the frequency and severity of stock-outs, and for taking action to prevent and manage stock-outs effectively. PMID- 28875878 TI - Facilitating access to adolescent sexual and reproductive health services through legislative reform: Lessons from the South African experience. AB - South Africa (SA) has progressive legislation enabling adolescents to access various sexual- and reproductive-health services (SRH) independently, without consent from parents or legal guardians. This article reviews the SA legislative framework for adolescent access to SRH interventions. It outlines the five approaches adopted in current legislation to address adolescents' capacity to independently consent to specified health interventions, based on age, capacity and public policy requirements, or combinations thereof. Rather than subsume various health interventions under the umbrella of medical treatment, SA has separately legislated on many SRH interventions (e.g. HIV testing, contraceptives and terminations of pregnancy, among others). We identify strengths and weaknesses of the SA approach, and conclude with lessons learned from the SA experience which could inform discussion and debate on the most appropriate ways for countries to consider law reform that facilitates adolescent access to SRH services. PMID- 28875879 TI - Building capacity for development and implementation of clinical practice guidelines. AB - Robust, reliable and transparent methodologies are necessary to ensure that clinical practice guidelines (CPGs) meet international criteria. In South Africa (SA) and other low- and middle-income countries, upskilling and training of individuals in the processes of CPG development is needed. Since de novo CPG development is time-consuming and expensive, new emerging CPG-development approaches (adopting, contextualising, adapting and updating existing good quality CPGs) are potentially more appropriate for our context. These emerging CPG-development methods are either not included or sparsely covered in existing training opportunities. The SA Guidelines Excellence (SAGE) team has responded innovatively to the need for CPG training in SA. We have revised an existing SA course and developed an online, open-access CPG-development toolkit. This Guideline Toolkit is a comprehensive guideline resource designed to assist individuals who are interested in knowing how to develop CPGs. Findings from the SAGE project can now be implemented with this innovative CPG training programme. This level of CPG capacity development has the potential to influence CPG knowledge, development, practices and uptake by clinicians, managers, academics and policy-makers around the country. PMID- 28875880 TI - Orbital apex syndrome after trauma in a 6-year-old - a rare occurrence. AB - Orbital apex syndrome is rare, but can occur as a consequence of trauma from fracture of the medial orbit. This case report highlights the fact that a high index of suspicion is needed when a patient presents with a facial injury, especially in children who cannot give an account of the actual events that transpired. Radiological investigation should be done early when an underlying injury is suspected in a trauma patient. A low threshold for computed tomography should be maintained when proptosis and vision loss are present. PMID- 28875882 TI - Osteosarcoma patient outcomes at a South African tertiary hospital. AB - BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour. There is a high incidence of late presentation in the developing world, posing additional challenges in the treatment of this aggressive disease. OBJECTIVE: To evaluate clinical outcomes of patients with osteosarcoma at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), a tertiary hospital in South Africa, and compare these with similar studies in the developing world. METHODS: This was a retrospective study of 61 patients treated at CMJAH between 2007 and 2011, with a minimum follow-up of 1.3 years (range 1.3 - 6.3). RESULTS: An average of 4.5 months elapsed before patients were first seen at the CMJAH tumour unit. Fifty eight patients (95.1%) initially sought conventional medical care. Three patients (4.9%) presented with pathological fractures. All the patients underwent biopsy, performed an average of 3 weeks after arrival at the tumour unit. In most cases the delay was due to limited access to magnetic resonance imaging. Most patients (n=41, 67.2%) were at Enneking stage 2B, 4 (6.6%) were at stage 2A and 16 (26.2%) were at stage 3. Of the patients, 13 (21.3%) underwent limb salvage procedures, 33 (54.1%) had amputations, 4 (6.6%) refused further treatment and 11 (18.0%) received palliative care only; 55 patients (90.2%) received chemotherapy. Two patients developed local recurrence, one of whom had an amputation and the other further wide excision. Two patients received palliative radiotherapy. Of the patients, 82.0% were HIV-negative, 4.9% HIV-positive and the rest of unknown status. At the time of the study, all but two patients, who came from other countries, were traceable or known to have died. Our overall 1-year and 5-year survival rates were 62.7% (95% confidence interval (CI) 49.1 - 73.9) and 38.1% (95% CI 24.6 - 51.4), respectively. Male patients and those with a higher Enneking stage had a poorer prognosis. CONCLUSION: Although most patients sought conventional medical care, unacceptable delays worsened survival. However, our survival rates are better than those in other developing countries. We advocate that professional, public and political awareness of osteosarcoma be improved as a matter of urgency, to facilitate rapid tertiary referral and expedite management. PMID- 28875881 TI - Declining prevalence of duodenal ulcer at endoscopy in Ile-Ife, Nigeria. AB - BACKGROUND: Duodenal ulcer is the most common peptic ulcer disease worldwide. In the past, sub-Saharan Africa has been described as an area of mixed prevalence for peptic ulcer disease, but recent reports have disputed this. Changes in the prevalence of duodenal ulcer have been reported, with various reasons given for these. OBJECTIVE: To describe the change in endoscopic prevalence of duodenal ulcer at Obafemi Awolowo University Teaching Hospital (OAUTH), Ile-Ife, Nigeria, between January 2000 and December 2010. METHODS: This was a retrospective, descriptive study of patients who underwent upper gastrointestinal endoscopy in the endoscopy unit of OAUTH between January 2000 and December 2010. The data were obtained from the endoscopy register, demographic indices, presenting symptoms and post-endoscopic diagnoses being retrieved for each patient. The study period was divided into the years 2000 - 2004 and 2005 - 2010, the frequencies of duodenal ulcer and other post-endoscopic diagnoses being compared between these two time periods to see whether there were changes. RESULTS: Over the study period, 292 patients (15.8%) were diagnosed with duodenal ulcer, second only to 471 patients (26.2%) with acute gastritis. The prevalence of duodenal ulcer for 2000 - 2004 was 22.9% (n=211 patients) compared with 9.2% (n=81) for 2005 - 2010 (p<0.001). CONCLUSION: There was a significant decline in the endoscopic prevalence of duodenal ulcer over the decade. PMID- 28875883 TI - Central-line-associated bloodstream infections in a resource-limited South African neonatal intensive care unit. AB - BACKGROUND: The rate of central-line-associated bloodstream infection (CLABSI) in South African (SA) public sector neonatal intensive care units (NICUs) is unknown. Tygerberg Children's Hospital (TCH), Cape Town, introduced a neonatal CLABSI surveillance and prevention programme in August 2012. OBJECTIVES: To describe CLABSI events and identify risk factors for development of CLABSI in a resource-limited NICU. METHODS: A retrospective case-control study was conducted using prospectively collected NICU CLABSI events matched to four randomly selected controls, sampled from the NICU registry between 9 August 2012 and 31 July 2014. Clinical data and laboratory records were reviewed to identify possible risk factors, using stepwise forward logistic regression analysis. RESULTS: A total of 706 central lines were inserted in 530 neonates during the study period. Nineteen CLABSI events were identified, with a CLABSI rate of 5.9/1 000 line days. CLABSI patients were of lower gestational age (28 v. 34 weeks; p=0.003), lower median birth weight (1 170 g v. 1 975 g; p=0.014), had longer catheter dwell times (>4 days) (odds ratio (OR) 5.1 (95% confidence interval (CI) 1.0 - 25.4); p=0.04) and were more likely to have had surgery during their NICU stay (OR 3.5 (95% CI 1.26 - 10); p=0.01). Significant risk factors for CLABSI were length of stay >30 days (OR 20.7 (95% CI 2.1 - 203.2); p=0.009) and central line insertion in the operating theatre (OR 8.1 (95% CI 1.2 - 54.7); p=0.03). Gram-negative pathogens predominated (12/22; 54%), with most isolates (10/12; 83%) exhibiting multidrug resistance. CONCLUSION: The TCH NICU CLABSI rate is similar to that reported from resource-limited settings, but exceeds that of high income countries. Prolonged NICU stay and central-line insertion in the operating theatre were important risk factors for CLABSI development. Intensified neonatal staff training regarding CLABSI maintenance bundle elements and hand hygiene are key to reducing CLABSI rates. PMID- 28875884 TI - Residual allergenicity of amino acid-based and extensively hydrolysed cow's milk formulas. AB - BACKGROUND: Criteria for labelling infant feeds as suitable for the dietary management of cow's milk protein allergy (CMPA) rely on proving the hypoallergenicity of such feeds or clinical studies showing that the feeds are tolerated by 90% of children with proven CMPA. South African (SA) labelling legislation does not indicate what testing is necessary to prove hypoallergenicity. OBJECTIVES: To evaluate all extensively hydrolysed cow's milk formulas and amino acid-based formulas available in SA for residual allergen content, protein size and amino-acid content. RESULTS: All amino-acid and extensively hydrolysed formulas were found to be similar in composition, with no residual cow's milk allergens detectable by enzyme-linked immunosorbent assay. Furthermore, proteins were absent and only small molecules in the size range of amino acids and possibly of very small oligopeptides were detected. CONCLUSIONS: These findings indicate that the formulas are extremely likely to be compliant with the definition of hypoallergenicity as tolerance in 90% of proven sufferers from cow's milk allergy. The formulas may therefore be labelled as suitable for the dietary management of infants with CMPA. PMID- 28875885 TI - A review of antenatal corticosteroid use in premature neonates in a middle-income country. AB - BACKGROUND: Antenatal corticosteroid (ANS) use in premature neonates has become a standard of practice. However, there is low ANS coverage in low- to middle-income countries (LMICs). Recent studies have questioned the efficacy of ANSs in such countries. OBJECTIVE: To review the use of ANSs in preterm neonates at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), South Africa. METHODS: This was a retrospective observational study of all neonates with a birth weight of 500 - 1 800 g born at CMJAH between 1 January 2013 and 30 June 2016. Neonatal and maternal characteristics of neonates exposed to ANSs were compared with those of neonates who were not exposed. RESULTS: The ANS coverage of the final sample was 930/2 109 (44.1%). The mean (standard deviation (SD)) birth weight was 1 292.4 (323.2) g and the mean gestational age 30.2 (2.9) weeks. Attending antenatal care and maternal hypertension were associated with increased use of ANSs, whereas vaginal delivery was associated with decreased use. In neonates weighing <1 500 g, the use of ANSs was associated with decreased mortality, decreased intraventricular haemorrhage and decreased patent ductus arteriosus. There was no association between ANSs and respiratory distress syndrome, necrotising enterocolitis, sepsis or need for respiratory support in all premature neonates, and no association with improved outcomes in those weighing >=1 500 g. CONCLUSION: The benefits of ANSs in terms of neonatal morbidity in this study were not as marked as those published in high-income countries. A randomised controlled trial may be indicated in LMICs. PMID- 28875886 TI - White blood cell count and C-reactive protein together remain useful for diagnosis and staging of acute appendicitis in children. AB - BACKGROUND: Acute appendicitis (AA) is the most common acute surgical condition of the abdomen, and the most commonly misdiagnosed. OBJECTIVE: To analyse the white blood cell count (WBCC) and C-reactive protein (CRP) contribution to the diagnosis of AA in children. METHODS: This was a retrospective study of 943 consecutive patients operated on with the preoperative diagnosis of AA, in whom preoperative WBCC and CRP had both been measured. Postoperatively, the patients were divided into three groups: normal appendix (no AA), simple AA and complicated AA. RESULTS: Of the 943 patients, 616 (65.3%) had simple AA. The mean (standard deviation (SD)) age for this group was 9.8 (3.2) years (p<0.01 v. complicated AA), the mean WBCC was 16.5 (5.0) * 109/L (p<0.01 v. complicated AA and no AA), and the mean CRP level was 304.8 (409.5) nmol/L (p<0.01 v. complicated AA). The mean age of the patients with complicated AA (283/943, 30.0%) was 7.9 (3.7) years, the mean WBCC was 17.7 (6.2) * 109/L (p<0.01 v. no AA) and the mean CRP level was 1 076.2 (923.8) nmol/L (p<0.01 v. no AA). The mean age of the patients with no AA (44/943, 4.7%) was 8.8 (3.2) years, the mean WBCC was 13.1 (5.3) * 109/L and the mean CRP was 361.9 (447.6) nmol/L. The WBCC was normal in 113/899 patients with appendicitis (12.6%) and CRP in 139 (15.5%). Both the WBCC and CRP were normal in 17 patients with appendicitis (1.9%). The best receiver operating characteristic (ROC) curve was obtained for WBCC when comparing all AA with no AA: cut-off point 15.0 * 109/L, sensitivity 65%, specificity 68%, area under the curve 0.70. The best ROC curve for CRP was obtained when comparing simple AA with complicated AA: cut-off point 361.9 nmol/L, sensitivity 74%, specificity 74%, area under the curve 0.81. CONCLUSIONS: The WBCC is helpful in diagnosing simple AA and CRP in diagnosing complicated AA. If both are normal, AA is very unlikely. Together the WBCC and CRP are useful tools in diagnosing and staging AA. PMID- 28875887 TI - The spectrum and outcome of paediatric traumatic brain injury in KwaZulu-Natal Province, South Africa has not changed over the last two decades. AB - OBJECTIVES: This retrospective review of a prospectively entered and maintained hybrid electronic trauma registry was intended to develop a comprehensive overview of traumatic brain injury (TBI) in children and adolescents and to compare it with previous audits from our local environment and from other developing world centres. All TBI patients admitted to hospital were included in this study. We reviewed the age, gender, outcomes, radiological findings and treatment of the patients. METHODS: All patients aged <=18 years old who were admitted by the Pietermaritzburg Metropolitan Trauma Service (PMTS) with TBI between December 2012 and December 2016 were included in this audit. RESULTS: During the 4-year period under review, a total of 563 children and adolescents were treated for TBI by the PMTS. The median age was 6.4 years and 29% (n=165) were females. The mechanism of TBI was blunt trauma in 96% (n=544) of cases, with 4% (n=19) suffering penetrating trauma. The penetrating mechanisms included impalement by a cow horn and miscellaneous injuries due to saws, axes, barbed wire, spades, stones and knives. The blunt mechanisms included falls (n=102), assaults (n=108), collapse of a building (n=28), bicycle-related injury (n=14), falling off a moving vehicle (n=280), motor vehicle accident (MVA; n=59), pedestrian vehicle accident (PVA; n=183) and animal-related injuries (n=8). There were 454 (80%) mild, 67 (12%) moderate and 42 (7%) severe cases of TBI. A total of 48 patients were admitted to the intensive care unit and 23 were admitted to the high care unit. Nine patients died. All the deaths were in the MVA and PVA group. The spectrum of TBI as diagnosed on computed tomography scans was nonspecific cerebral contusion (n=92), depressed skull fracture (n=70), sub arachnoid haemorrhage (n=60), extradural haemorrhage (n=41), intracerebral haemorrhage (n=19), free air (n=19), subdural haemorrhage (n=13), intraventricular haemorrhage (n=9). A total of 62 (11%) patients required surgery. CONCLUSION: There is a significant burden of paediatric TBI in Pietermaritzburg. The majority of TBI was related to blunt trauma and assaults were very common. Although the short-term outcomes are good, the long-term consequences are poorly understood. Injury prevention programmes are needed to help reduce this burden of disease and a nationwide trauma registry is long overdue. PMID- 28875888 TI - Concomitant HIV infection in newly diagnosed multiple myeloma patients is hard to recognise and should be tested for routinely in areas of high endemicity. AB - BACKGROUND: Over the past three decades much has changed in the treatment and outcomes of patients suffering concurrently from both multiple myeloma (MM) and HIV. While the prevalence of MM appears to be higher in HIV-positive individuals than in those who are uninfected, early recognition of patients suffering from both diseases is difficult and little information is available on their demographics and clinical presentation. OBJECTIVE: To compare the presenting features of HIV-positive patients diagnosed with MM with those of HIV-negative patients. METHODS: A single-centre, retrospective cohort study included 16 HIV positive and 73 HIV-negative patients diagnosed with MM, in order to compare variables related to the clinical presentation of both conditions. RESULTS: HIV positive patients presented with MM at a significantly younger age, and had fewer osteolytic lesions, less renal impairment and lower neutrophil counts. Disease stage, gender, pathological fractures, bone marrow plasmacytosis, plasmacytomas and lymphocyte counts were comparable, emphasising the difficulty of identifying these patients. The HIV-positive patients had relatively high CD4 counts and a low prevalence of abnormal Freelite kappa/lambda ratios. All HIV-positive patients presented with paraproteins of the immunoglobulin G (IgG) type, implying a possible relationship between MM and an IgG response to HIV antigens. CONCLUSIONS: On the basis of our findings and literature on the treatment of both diseases, we suggest that HIV be tested for routinely in younger MM patients, especially in areas with a high prevalence of HIV. The integration of our results into the sparse knowledge on the role of HIV infection-related MM provides possible new insights into the interaction between these diseases. PMID- 28875889 TI - A third of patients treated at a tertiary-level surgical service could be treated at a secondary-level facility. AB - BACKGROUND: South Africa (SA) has an overburdened public healthcare system. Some patients admitted to Charlotte Maxeke Johannesburg Academic Hospital (CMJAH), SA, may not require tertiary care, but the numbers and details are uncertain. Clinical research in SA is limited by scarce skills and limited access to data. OBJECTIVE: To determine the proportion of and length of stay for secondary-, tertiary- and quaternary-level patients discharged from the Department of Surgery at CMJAH over 1 year. METHODS: This is a retrospective analysis of electronic discharge (ED) summaries from the Department of Surgery at CMJAH between 1 April 2015 and 1 April 2016. An SQL query of the database generated a .csv file of all discharges with the following fields: database reference number, length of stay and level of care. The details of each record were verified by MBBCh V students, using a defined level-ofcare template and the full discharge summary. The data were reviewed by a senior clinician. RESULTS: There were 3 007 discharge summaries - 97 were not classifiable, two were test records and one was a duplicate. These 100 records were excluded. There were no primary-level records. Secondary-level patients represented 29% (854) of those discharged and 19% of total bed days. Tertiary- and quaternary-level patients together represented 71% of the total and 81% of bed days. The average length of stay was 4.31 days for secondary, 6.98 days for tertiary and 9.77 days for quaternary level-of-care allocation. CONCLUSION: Almost one-third (29%) of patients discharged from CMJAH's Department of Surgery were deemed suitable for secondarylevel care. These patients had a shorter length of stay and comprised 19% of total bed days. Students and electronic databases represent an important research resource. PMID- 28875890 TI - New-onset diabetes after transplant: Incidence, risk factors and outcome. AB - BACKGROUND: The outcome of renal transplantation depends on achieving effective immunosuppression while minimising the consequences of such treatment. The occurrence of new-onset diabetes in the post-transplant period has been associated with several risk factors including some immunosuppressive medication. Better understanding of the clinical and genetic risk factors associated with new onset diabetes after transplant (NODAT) could enable risk stratification of patients in the pre-transplant period, with the goal of applying measures that will reduce the incidence. OBJECTIVES: To ascertain the incidence of and clinical and genetic risk factors that predispose to NODAT, and to examine its effect on the outcome of renal transplantation. METHODS: We performed a retrospective cohort review of all renal transplants at Groote Schuur Hospital, Cape Town, South Africa, between 2004 and 2008. Patients who were lost to follow-up or had pre-transplant diabetes or primary non-function were excluded. A subset of the cohort who gave informed consent was enlisted for genetic tests. RESULTS: We identified 111 patients who met the inclusion criteria. The incidence of NODAT was 18.0% (n=20 patients). Risk factors for NODAT included age at transplant (p=0.03), body weight (p=0.04), treatment for acute cellular rejection (p=0.02) and polycystic kidney disease as the cause of renal failure (p=0.005). None of the genes investigated (TCF7L2 rs11196205, rs12255372 and rs7903146 and HNF1beta rs1800575, rs121918671 and rs121918672) was found to be significantly associated with the risk of NODAT. The genotype frequencies for the single-nucleotide polymorphisms studied were closer (although not identical) to those reported for Caucasians than to those reported for the Yoruba (black) population in West Africa. Overall patient survival was 78% at five years, while graft survival was 72%. There was no significant difference in patient or graft survival between the group with NODAT and the group without. CONCLUSIONS: NODAT was common in renal transplant recipients. Some risk factors predate transplant and could be used to risk-stratify patients to determine appropriate risk-reduction strategies. The genetic determinants for NODAT in this population may differ from those reported elsewhere. NODAT had no impact on patient or graft survival in this cohort. PMID- 28875891 TI - Age-group differences in risk perceptions of non-communicable diseases among adults in Diepsloot township, Johannesburg, South Africa: A cross-sectional study based on the Health Belief Model. AB - BACKGROUND: Non-communicable diseases (NCDs) in South Africa (SA) occur simultaneously with an ageing HIV-positive population, resulting in premature deaths in persons <70 years of age. Poor risk perception of NCDs results in poor adoption practices of NCD preventive measures. There is a gap in age-related research regarding risk perceptions of NCDs among the SA population. OBJECTIVE: To investigate age-group differences in risk perceptions of NCDs based on the Health Belief Model. METHODS: This cross-sectional design used secondary data obtained from Community AIDS Response (CARe), Johannesburg, SA. Data were collected by means of a cross-sectional survey in Extension 2 (Blocks I, J, K and L) of Diepsloot township, Johannesburg, SA. The Pearson chi2 test of independence was used to examine the relationship between age groups and risk perceptions of NCDs. A p<0.05 value was considered statistically significant. RESULTS: A total of 2 135 participants were included in the analysis, of whom 71.5% were young adults (18 - 35 years). The mean age of the study participants was 32.1 (standard deviation 9.87) years. Significant associations were found between age groups and risk perceptions of NCDs. More middle-aged adults than young adults and older aged adults perceived family history (74.00% v. 72.74% v. 62.39%, p=0.045) and smoking (83.80% v. 77.20% v. 74.31%, p=0.004) as risk factors that would increase their risk of NCDs. A higher proportion of older-aged adults than young adults and middle-aged adults perceived effects on life and family (89.91% v. 77.39% v. 75.40%, p=0.004) as risks of NCD morbidities. More middle-aged adults than young adults and older-aged adults perceived the usefulness of not smoking (84.60% v. 81.06% v. 74.31%, p=0.028) as an effective NCD preventive measure. More young adults than middle-aged and older-aged adults considered health check-ups (59.31% v. 58.00% v. 41.28%, p=0.001) as a time-consuming process to prevent risks of NCDs. CONCLUSION: Young adults had poorer risk perceptions of NCDs than middle aged and older-aged adults in Diepsloot township, resulting in poor practice of NCD preventive measures among young adults in the area. This may be due to the misunderstanding of the concept of invulnerability, possibly resulting from the limited access and exposure to NCD-related information among young adults compared with middle-aged and older-aged groups. This highlights the need to expand public health education programmes to increase outreach to the young adult population and increase accessibility to information relating to NCD risks, and encourage adoption of NCD preventive measures. PMID- 28875892 TI - Rhodopseudomonas telluris sp. nov., a phototrophic alphaproteobacterium isolated from paddy soil. AB - A strain of anoxygenic phototrophic bacteria isolated from paddy soil (designated strain TUT3615T) was studied taxonomically in comparison with Rhodopseudomonasstrain ATCC 17005 as its nearest phylogenetic relative. Strains TUT3615T and ATCC 17005 had budding rod-shaped cells and showed in vivo absorption maxima at 804 and 860 nm in the near infrared region, indicating the presence of bacteriochlorophyll a. The intracytoplasmic membrane system was of the lamellar type parallel to the cytoplasmic membrane. 16S rRNA gene sequence comparisons showed that strains TUT3615T and ATCC 17005 had a 99.7 % level of similarity to one another and were closest to Rhodopseudomonas palustris ATCC 17001T (98.6 % similarity) among the established species of the genus Rhodopseudomonas. Genomic DNA-DNA hybridization studies revealed that strains TUT3615T and ATCC 17005 had an average similarity level of 65 % to one another and of less than 40 % to the available type strains of Rhodopseudomonas species. Results of phenotypic studies showed that strains TUT3615T and ATCC 17005 could be differentiated from one another and from any previously described species of Rhodopseudomonas. The G+C contents of the genomic DNA of strain TUT3615T and ATCC 17005 were 66.3 and 66.5 mol%, respectively. Based on these data, we propose the name Rhodopseudomonas telluris sp. nov. for strain TUT3615T. The type strain is TUT3615T (=KCTC 23279T=NBRC 107609T). We suspend a proposal to reclassify strain ATCC 17005 as a novel species or subspecies until a genome-wide analysis provides more definite information on its taxonomic position. PMID- 28875893 TI - Description of Oceanispirochaeta sediminicola gen. nov., sp. nov., an obligately anaerobic bacterium isolated from coastal marine sediments, and reclassification of Spirochaeta litoralis as Oceanispirochaeta litoralis comb. nov. AB - An obligately anaerobic spirochaete (strain SY2T) was isolated from coastal marine sediments of Tongyeong-Si, South Korea. Strain SY2T was helical-shaped and Gram-stain-negative. Strain SY2T was able to grow at 10-40 degrees C (optima, 25 30 degrees C), pH 6.3-8.8 (optima, pH 7.0-8.0) and with 1-7 % (optimum, 2-3 %) NaCl concentration. Strain SY2T was negative for catalase and oxidase activity. The major end-products of glucose fermentation were acetate, ethanol, hydrogen and carbon dioxide. C14 : 0, C16 : 0, iso-C15 : 0, iso-C14 : 0 3-OH, iso-C15 : 1 H/C13 : 0 3-OH and iso-C17 : 1omega9c were predominant fatty acids (>5 %) with minor amounts (<5 %) of C18 : 0, iso-C13 : 0, iso-C17 : 0, iso-C17 : 1/anteiso C17 : 1 B and C16 : 1omega6c/C16 : 1omega7c. Diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine were major polar lipids. The genomic DNA G+C content was 53.5 mol%. 16S rRNA gene sequence comparisons indicated that strain SY2T represents a member of the family Spirochaetaceae in the phylum Spirochaetes. Strain SY2T has a sequence similarity of 95.1 % with Spirochaeta litoralis R1T and <90.1 % with other members of the genus Spirochaeta. Distinct morphological, physiological and genotypic differences from the previously described taxa support the classification of strain SY2T as a representative of a novel genus and species in the family Spirochaetaceae, for which the name Oceanispirochaeta sediminicola gen. nov., sp. nov. is proposed. The type strain is SY2T (=KEMB 3001-381T=DSM 104770T=KCTC 15593T). Reclassification of Spirochaeta litoralis as Oceanispirochaeta litoralis comb. nov. is also proposed based on polyphasic taxonomic analyses. PMID- 28875894 TI - Altererythrobacter aquiaggeris sp. nov., isolated from water of an estuary bank. AB - A Gram-stain-negative, oval- or short-rod-shaped and non-motile bacterial strain, designated KEM-3T, was isolated from water of Geumgang Estuary Bank, South Korea, and was subjected to a polyphasic taxonomic study. Strain KEM-3T grew optimally at pH 7.0-8.0, at 25 degrees C and in the presence of 2-3% (w/v) NaCl. The neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain KEM-3T fell within the clade comprising Altererythrobacter species, clustering with Altererythrobacter confluentis KEM-4T and Altererythrobacter gangjinensis KJ7T, with which it exhibited 97.3 and 96.0 % sequence similarity, respectively. The 16S rRNA gene sequence similarity values between strain KEM-3T and the type strains of other Altererythrobacter species were 92.9-95.2 %. The DNA G+C content of strain KEM-3T was determined to be 59.0 mol% and its mean DNA DNA relatedness with A. confluentis KEM-4T was 8.6+/-3.1 %. Strain KEM-3T contained Q-10 as the predominant ubiquinone and summed feature 8 (C18:1omega7c and/or C18:1omega6c), C17:1omega6c and summed feature 3 (C16:1omega6c and/or C16:1omega7c) as the major fatty acids. The major polar lipids were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, a sphingoglycolipid, an unidentified glycolipid and an unidentified phospholipid. Differential phenotypic properties, together with phylogenetic distinctiveness, demonstrated that strain KEM-3T is distinguishable from other Altererythrobacter species. On the basis of the data presented, strain KEM-3T is considered to represent a novel species of the genus Altererythrobacter, for which the name Altererythrobacter aquiaggeris sp. nov. is proposed. The type strain is KEM-3T (=KCTC 52471T=NBRC 112425T). PMID- 28875895 TI - Lysinimicrobium sediminis sp. nov., an actinobacterium isolated from estuary sediment. AB - A novel Gram-stain-positive actinobacterium, designated HT7-17T, was isolated from a sediment sample collected from the estuary of the Tama River, Japan, and its taxonomic position was investigated using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain HT7-17T was closely related to members of the genus Lysinimicrobium, with a similarity range of 97.1-98.2 %. The peptidoglycan type of strain HT7-17T was A4alpha, the predominant menaquinone was demethylmenaquinone DMK-9(H4) and the major fatty acids were anteiso-C15 : 0, C16 : 0 and iso-C16 : 0. The DNA G+C content was 69.9 mol%. These chemotaxonomic features corresponded to those of the genus Lysinimicrobium. Meanwhile, the differences in some phenotypic characteristics, along with the result of DNA-DNA hybridization, indicated that strain HT7-17T should be distinguished from the recognized species of the genus Lysinimicrobium. Therefore, strain HT7-17T represents a novel species of the genus Lysinimicrobium, for which the name Lysinimicrobium sediminis sp. nov. is proposed. The type strain is HT7-17T (=NBRC 112286T=TBRC 7037T). PMID- 28875896 TI - Kryptousia macronema gen. nov., sp. nov. and Kryptousia microlepis sp. nov., nostocalean cyanobacteria isolated from phyllospheres. AB - Tropical ecosystems worldwide host very diverse microbial communities, but are increasingly threatened by deforestation and climate change. Thus, characterization of biodiversity in these environments, and especially of microbial communities that show unique adaptations to their habitats, is a very urgent matter. Information about representatives of the phylum Cyanobacteria in tropical environments is scarce, even though they are fundamental primary producers that help other microbes to thrive in nutrient-depleted habitats, including phyllospheres. In order to increase our knowledge of cyanobacterial diversity, a study was conducted to characterize isolates from Avicennia schaueriana and Merostachys neesii leaves collected at a mangrove and an Atlantic forest reserve located at the littoral of Sao Paulo state, south-east Brazil. The morphological, ultrastructural, phylogenetic, molecular and ecological features of the strains led to the recognition of the new genus Kryptousia, comprising two new species, Kryptousiamacronema gen. nov., sp. nov. and Kryptousiamicrolepis sp. nov., described here according to the International Code of Nomenclature for algae, fungi and plants. The new genus and species were classified in the nostocalean family Tolypotrichaceae. This finding advances knowledge on the microbial diversity of South American ecosystems and sheds further light on the systematics of cyanobacteria. PMID- 28875897 TI - Chitinophaga rhizosphaerae sp. nov., isolated from rhizosphere soil of a tomato plant. AB - An aerobic, Gram-stain-negative, non-spore-forming, non-flagellated, rod-shaped or filamentous bacterial strain, T16R-86T, was isolated from rhizosphere of a tomato plant collected from a farm on Buyeo-gun, Chungcheongnam-do, South Korea. It grew at the temperature range 10-37 degrees C (optimum, 28 degrees C) and pH range 6.0-9.0 (optimum, pH 7.0), and tolerated up to 2 % (w/v) NaCl. According to 16S rRNA gene sequence analysis, strain T16R-86T shared the highest similarity with Chitinophaga barathri YLT18T (96.8 %) and C. pinensis DSM 2588T (96.7 %), forming a subcluster with C. barathri YLT18T, C. cymbidii R156-2T and C. niabensis JS13-10T in the phylogenetic tree. The major fatty acids were iso-C15 : 0, C16 : 1omega5c and iso-C17 : 0 3-OH. The predominant respiratory quinone was menaquinone MK-7. Polar lipids were phosphatidylethanolamine, five unknown aminolipids, an unknown aminophospholipid, one unknown phospholipid and two unknown lipids. The DNA G+C content was 53.6 mol%. The phenotypic, chemotaxonomic and phylogenetic data showed that strain T16R-86T represents a novel species of the genus Chitinophaga, for which the name Chitinophaga rhizosphaerae sp. nov. is proposed. The type strain is T16R-86T (=KACC 18790T=JCM 31600T). PMID- 28875898 TI - Microbacterium hibisci sp. nov., isolated from rhizosphere of mugunghwa (Hibiscus syriacus L.). AB - A Gram-stain-positive, aerobic, non-motile, short-rod shaped actinobacterium, designated THG-T2.14T, was isolated from soil sampled from the rhizosphere of mugunghwa. Growth occurred at 10-40 degrees C (optimum 30 degrees C), at pH 5.0 10.0 (optimum 7.0) and at 0-7.0 % NaCl (optimum 3.0 %). Based on 16S rRNA gene sequence analysis, the nearest phylogenetic neighbours of strain THG-T2.14T were identified as Microbacterium yannicii DSM 23203T (98.8 %), Microbacterium trichothecenolyticum DSM 8608T (98.8 %), Microbacterium arthrosphaerae DSM 22421T (98.7 %) and Microbacterium jejuense KACC 17124T (98.4 %). The major fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, one unidentified lipid, two unidentified phospholipids and two unidentified phosphoglycolipids. The menaquinones were MK-12, and MK-13. The major polyamine was spermidine. The peptidoglycan contained ornithine, alanine, glycine, homoserine and glutamic acid. The diagnostic diamino acid was ornithine. The acyl type of the muramic acid was glycolyl. The whole-cell sugars were rhamnose, ribose, galactose, arabinose, xylose and glucose. The DNA G+C content of strain THG-T2.14T was 71.2 mol%. The DNA-DNA relatedness between strain THG-T2.14T and its closest reference strains were significantly lower than the threshold value of 70 %. On the basis of the phylogenetic analysis, chemotaxonomic data, physiological characteristics and DNA-DNA hybridization data, strain THG-T2.14T represents a novel species of the genus Microbacterium, for which the name Microbacterium hibisci sp. nov. is proposed. The type strain is THG-T2.14T (=KACC 18931T=CCTCC AB 2016180T). PMID- 28875899 TI - Reyranella aquatilis sp. nov., an alphaproteobacterium isolated from a eutrophic lake. AB - A novel Gram-stain-negative, rod-shaped and non-motile bacterial strain, designated strain Seoho-37T, was isolated from a eutrophic lake in South Korea. Polyphasic studies were performed to investigate the taxonomic position of the new isolate. The isolate grew aerobically with 0-1.0 % (w/v) NaCl (optimum 0 %), at pH 6.0-10.0 (optimum pH 7.0-9.0) and at temperatures of 15-36 degrees C (optimum 25-30 degrees C) on R2A medium. In the phylogenetic analysis of 16S rRNA gene sequences, strain Seoho-37T formed a clear cluster with the strains of Reyranella graminifolii, Reyranella massiliensis and Reyranella soli with a bootstrap resampling value of 100 %. DNA-DNA relatedness between strain Seoho-37T and the type strains of each species in the genus Reyranella was <20 %. The genomic DNA G+C content of strain Seoho-37T was 66.5 mol%. Ubiquinone-10 (Q-10) and ubiquinone-9 (Q-9) were found as the respiratory quinones. The cellular polar lipids were identified as diphosphatidylglycerol, phosphatidylglycerol and phosphatidylmethylethanolamine. The major fatty acid components included C16 : 0, summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C18 : 1 2-OH. Based on the above evidence from a polyphasic study, strain Seaho-37T represents a novel species of the genus Reyranella, for which the name Reyranella aquatilis sp. nov. is proposed. The type strain is Seoho-37T (=KCTC 52223T=JCM 31892T). PMID- 28875900 TI - Sulfurivermis fontis gen. nov., sp. nov., a sulfur-oxidizing autotroph, and proposal of Thioprofundaceae fam. nov. AB - A novel Gram-stain-negative, chemolithoautotrophic sulfur oxidizer, strain JG42T, was isolated from a hot spring microbial mat. As an electron donor for autotrophic growth, strain JG42T utilized sulfide, thiosulfate, tetrathionate and elemental sulfur. Cells of strain JG42T were oxidase-positive and catalase negative. The G+C content of the genomic DNA was 65 mol%. The predominant cellular fatty acid was C16 : 0. Phylogenetic analysis of the 16S rRNA gene indicated that strain JG42T belonged to the order Chromatiales, but sequence similarities to the known species were less than 94 %. On the basis of its properties, strain JG42T (=DSM 104776T=NBRC 112696T) is proposed as the type strain of a novel species of a new genus, Sulfurivermis fontis gen. nov., sp. nov., which belongs to the family Thioalkalispiraceae. A new family, Thioprofundaceae fam. nov., is also proposed to accommodate the genus Thioprofundum, transferred from the family Thioalkalispiraceae. PMID- 28875901 TI - Rubrobacter spartanus sp. nov., a moderately thermophilic oligotrophic bacterium isolated from volcanic soil. AB - Bacterial strain HPK2-2T was isolated from soil adjacent to the caldera of Kilauea Volcano in Hawaii Volcanoes National Park. HPK2-2T is a chemoorganoheterotroph that shows optimal growth at 50 degrees C (range 45-55 degrees C) and pH 8.0 (range 5.0-10.0). Sequence analysis of the 16S subunit of the rRNA gene showed that HPK2-2T is most closely related to the type strain of Rubrobactertaiwanensis (ATCC BAA-406T), with which it shared 94.5 % sequence identity. The major fatty acids detected in HPK2-2T were C18 : 0 14-methyl and C16 : 0 12-methyl; internally branched fatty acids such as these are characteristic of the genus Rubrobacter. The only respiratory quinone detected was MK-8, which is the major respiratory quinone for all members of the family Rubrobacteraceae examined thus far. We propose that HPK2-2T represents a novel species of the genus Rubrobacter, for which we propose the name Rubrobacterspartanus (type strain HPK2-2T; DSM 102139T; LMG 29988T). PMID- 28875902 TI - Nocardioides agrisoli sp. nov., isolated from farmland soil. AB - A novel Gram-stain-positive bacterium, designated djl-8T, was isolated from farmland soil in Nanjing, Jiangsu province, PR China. Cells of strain djl-8T were aerobic, non-motile, non-spore-forming and rod-shaped. The organism grew at 25-37 degrees C, pH 5.5-8.0 and 0.5-4.0 % NaCl (w/v). The DNA G+C content was 69.3 mol%. The diagnostic diamino acid in the cell-wall peptidoglycan was LL-2, 6 diaminopimelic acid. The major fatty acids (>5 %) were iso-C16 : 0, anteiso-C17 : 0, iso-C15 : 0, 10-Me C17 : 0 and C17 : 1omega8c. The respiratory quinone was MK 8 (H4) and the major polar lipids were phosphatidylglycerol, phosphatidylinositol, diphosphatidylglycerol and unknown phospholipids. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain djl-8T is a member of the genus Nocardioides and shared the highest similarity with Nocardioides ginkgobilobae SYP-A7303T (97.1 %), followed by Nocardioides soli mbc 2T (96.9 %), Nocardioide spyridinolyticus OS4T (96.6 %) and Nocardioides maradonensis RP-B30T (96.6 %). Strain djl-8T exhibited low DNA-DNA relatedness with Nocardioides ginkgobilobae SYP-A7303T (26.9+/-2.1 %). On the basis of the morphological, physiological, biochemical and chemotaxonomic characteristics presented in this study, strain djl-8T represents a novel species of the genus Nocardioides, for which the name Nocardioides agrisoli sp. nov. is proposed. The type strain is djl-8T (=KCTC 39844T=CCTCC AB 2017058T). PMID- 28875903 TI - Pacificibacter aestuarii sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, strictly aerobic bacterium, designated KJ21T, was isolated from a tidal flat in South Korea. Cells were non-motile rods showing oxidase- and catalase-positive activities. Growth of strain KJ21T was observed at 10-35 degrees C (optimum, 30 degrees C), at pH 6.0-8.5 (optimum, pH 7.0) and in the presence of 1-5 % (w/v) NaCl (optimum, 2 %). Strain KJ21T contained summed feature 8 (comprising C18 : 1omega7c/C18 : 1omega6c), C16 : 0, 10-methyl C19 : 0 and C10 : 0 3-OH as the major fatty acids and ubiquinone-10 as the major isoprenoid quinone. Phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine, an unknown aminolipid and an unknown lipid were detected as the major polar lipids. The G+C content of the genomic DNA was 53.9 mol%. Phylogenic analysis based on 16S rRNA gene sequences showed that strain KJ21T formed a tight phylogenetic lineage with the members of the genus Pacificibacter with a 100 % bootstrap value. Strain KJ21T was most closely related to Pacificibacter maritimus KMM 9031T (98.7 %) and Pacificibacter marinus HDW-9T (98.4 %), and the DNA-DNA relatedness values between strain KJ21T and the type strains of P. maritimus and P. marinus were 46.9+/-4.2 % and 39.8+/-5.7, respectively. On the basis of phenotypic, chemotaxonomic and molecular properties, it is clear that strain KJ21T represents a novel species of the genus Pacificibacter, for which the name Pacificibacter aestuarii sp. nov. is proposed. The type strain is KJ21T (=KACC 19098T=JCM 31805T). PMID- 28875904 TI - Lewinella maritima sp. nov., and Lewinella lacunae sp. nov., novel bacteria from marine environments. AB - Two Gram-staining-negative, rod-shaped, aerobic, marine bacteria, designated HME9321T and HME9359T, were isolated from seawater and lagoon water samples in the Republic of Korea. Phylogenetic analysis of the 16S rRNA gene sequences of the two strains revealed that they belonged to the genus Lewinella within the family Saprospiraceae. The 16S rRNA gene sequence similarity of strain HME9321T showed highest similarities with Lewinella aquimaris HDW-36T (95.2 %), Lewinella marina MKG-38T (94.7 %) and Lewinella xylanilytica 13-9-B8T (94.0 %). Strain HME9359T had highest sequence similarities with Lewinella agarilytica SST-19T (94.7 %), Lewinella persica T-3T (94.1 %) and Lewinella antarctica IMCC3223T (93.3 %). The predominant fatty acids of strain HME9321T were summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), iso-C15 : 0 and summed feature 9 (comprising iso-C16 : 0 10-methyl and/or C17 : 1omega9c) while those of strain HME9359T were summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c) and iso-C15 : 0. The major isoprenoid quinone of both strains was MK-7. Strain HME9321T contained the polar lipids, phosphatidylethanolamine, one unidentified aminolipid, one unidentified phospholipid and nine unidentified polar lipids, while strain HME9359T contained phosphatidylethanolamine, one unidentified phospholipid and nine unidentified polar lipids. The DNA G+C contents of strains HME9321T and HME9359T were 58.7 and 62.0 mol%, respectively. Based on the results of the phenotypic, genotypic, chemotaxonomic and phylogenetic investigation, two novel species, Lewinella maritima sp. nov. and Lewinella lacunae sp. nov. are proposed. The type strains are HME9321T (=KACC 17619T=CECT 8419T) and HME9359T (=KCTC 42187T=CECT 8679T), respectively. PMID- 28875905 TI - Draft genome and description of Consotaella salsifontis gen. nov. sp. nov., a halophilic, free-living, nitrogen-fixing alphaproteobacterium isolated from an ancient terrestrial saline spring. AB - A free-living, nitrogen-fixing, mesophilic and facultative aerobe, designated strain USBA 369T, was isolated from a terrestrial saline spring of the Colombian Andes. The non-sporulating rods (1.5*0.8 um) with rounded ends stained Gram negative and were motile by means of lophotrichous flagella. The strain grew optimally at 30 degrees C, at pH 6.9-7.5 and with 1.5 % (w/v) NaCl. The major fatty acids detected were C18 : 1omega7c and C19 : 0 cyclo omega8c, and the respiratory lipoquinone ubiquinone 10 (Q-10) was present. The genome consisted of 4.65 Mb with a DNA G+C content of 64.3 mol%. A total of 4371 genes were predicted and, of those, 4300 were protein coding genes and 71 were RNA genes. Phylogenetic analysis based on 16S rRNA gene sequence indicated that strain USBA 369T formed a different lineage within the class Alphaproteobacteria, order Rhizobiales, and DNA homology studies with the most closely related genera, Aurantimonas, Aureimonas and Rhizobium (95 % 16S rRNA gene sequence similarity), showed values of <15 %. The phylogenomic analysis provided evidence for clear phylogenetic divergence between strain USBA 369T and the closely related genera. On the basis of the phenotypic, chemotaxonomic and phylogenomic evidence, strain USBA 369T is considered to represent a novel genus and a novel species for which the name Consotaella salsifontis gen. nov., sp. nov. is proposed. The type strain is USBA 369T (=KCTC 22549T=CMPUJ U369T). PMID- 28875906 TI - Nocardia heshunensis sp. nov., an actinomycete isolated from soil. AB - A novel Gram-stain-positive, aerobic, non-motile and acid-fast actinomycete strain, designated CFH S0067T, was isolated from a soil sample collected from Heshun old town in Tengchong, Yunnan province, in south-west PR China. The taxonomic position of strain CFH S0067T was studied in detail using a polyphasic approach. Phylogenetic analysis, based on 16S rRNA gene sequences, revealed that strain CFH S0067T belongs to the genus Nocardia and is closely related to Nocardia concava JCM 12351T (99.3 % similarity), forming a separated branch with this type strain. However, the strain shared 96.0 % gyrB gene sequence similarity with N. concava JCM 12351T. Furthermore, DNA-DNA hybridization showed 56.5+/-0.6 % DNA relatedness between the novel strain and N. concava JCM 12351T. The whole cell hydrolysates contained meso-diaminopimelic acid (type IV) and arabinose, galactose, fructose and mannose. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside and one unidentified lipid. Strain CFH S0067T contained MK-8 (H4omega-cycl) as the predominant menaquinone. C16 : 0, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C18 : 1omega9c and C18 : 0 10 methyl (TBSA) were the major cellular fatty acids. Mycolic acids were also detected. The G+C content of the genomic DNA was determined to be 66.9 mol%. A combination of the low DNA-DNA hybridization values and phenotypic properties demonstrated that strain CFH S0067Tis clearly distinguishable from its most closely related strain, N. concava JCM 12351T. On the basis of this polyphasic study, it is concluded that strain CFH S0067T should be considered to represent a novel species of the genus Nocardia, for which the name Nocardia heshunensis sp. nov. is proposed. The type strain is CFH S0067T (=DSM 46764T=JCM 30085T). PMID- 28875907 TI - Salinirussus salinus gen. nov., sp. nov., isolated from a marine solar saltern. AB - A halophilic archaeal strain, YGH44T, was isolated from the Yinggehai marine solar saltern in Hainan Province of China. Cells were rod-shaped, stained Gram negative and formed red-pigmented colonies on agar plates. Optimal growth was obtained with 3.4 M NaCl (range: 2.6-4.8 M), 0.5 M MgCl2 (range: 0.005-1.0 M), at 37 degrees C (range: 25-55 degrees C) and at pH 7.0 (range: pH 5.0-9.0). The cells lysed in distilled water, and the minimal NaCl concentration to prevent cell lysis was 1.7 M. Phylogenetic tree reconstructions based on 16S rRNA genes and rpoB' genes revealed that strain YGH44T was distinct from the related genera, Halovenus, Halapricum, Halorientalis, Halorhabdus and Halosimplex of the order Halobacteriales. The major polar lipids of the strain were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and three unidentified glycolipids. The DNA G+C content of strain YGH44Twas 69.0 mol%. The phenotypic, chemotaxonomic and phylogenetic properties suggested that strain YGH44T (=CGMCC 1.12234T=JCM 18646T) represents a novel species of a new genus within the order Halobacteriales, for which the name Salinirussus salinus gen. nov., sp. nov. is proposed. PMID- 28875908 TI - Cryptotrichosporon argae sp. nov., Cryptotrichosporon brontae sp. nov. and Cryptotrichosporon steropae sp. nov., isolated from forest soils. AB - Yeast strains belonging to the basidiomycetous genus Cryptotrichosporon were isolated from forest soils in Serra da Arrabida Natural Park in Portugal. Similar to the already-known representatives of this genus, the new isolates formed pigmented colonies of a distinctive pale orange colour. Phylogenetic analyses employing concatenated sequences of the D1/D2 domains of the 26S (large subunit) rRNA gene and the internal transcribed spacer (ITS) region supported the recognition of three novel species: Cryptotrichosporon argae sp. nov. (type strain CM 19T=CBS 14376T=PYCC 7010T=DSM 104550T; MycoBank accession number MB 817168), Cryptotrichosporon brontae sp. nov. (type strain CM 1562T=CBS 14303T=PYCC 7011T=DSM 104551T; MycoBank accession number MB 817077) and Cryptotrichosporon steropae sp. nov. (type strain OR 395T=CBS 14302T=PYCC 7012T=DSM 104552T; MycoBank accession number MB 817078). PMID- 28875909 TI - Brenneria populi subsp. brevivirga subsp. nov. isolated from symptomatic bark of Populus * euramericana canker, and description of Brenneria populi subsp. populi subsp. nov. AB - Two Gram-stain-negative, facultatively anaerobic, motile bacterial strains isolated from symptomatic bark of Populus * euramericana canker in China were investigated using a polyphasic approach, including 16S rRNA gene sequencing, multilocus sequence analysis, and biochemical and physiological assays. 16S rRNA gene sequencing indicated that these strains belonged to the genus Brenneria, family Pectobacteriaceae, and had the highest sequence similarity with Brenneria populi CFCC 11963T (98 %). DNA-DNA hybridization experiments revealed DNA-DNA relatedness values of 72.1-78.2 % between the new isolates and strains of B. populi, revealing that these strains belonged to the same species. The 16S rRNA gene sequencing and multilocus sequence analysis suggested that the two novel strains and those of B. populi are phylogenetically closely related but form two clearly separated subgroups. Based on the data, the two novel isolates represent a subspecies of B. populi for which the name B. populi subsp. brevivirga subsp. nov. is proposed with D8-10-4-5T (=CFCC 11935T=KCTC 42841T) as the type strain, with the automatic creation of B. populi subsp. populi subsp. nov. (type strain D9-5T=CFCC 11963T=KCTC 42088T). PMID- 28875910 TI - The spa typing of methicillin-resistant Staphylococcus aureus isolates by High Resolution Melting (HRM) analysis. AB - Molecular typing is an important tool for control and prevention of infection. A suitable molecular typing method for epidemiological investigation must be easy to perform, highly reproducible, inexpensive, rapid and easy to interpret. In this study, two molecular typing methods including the conventional PCR sequencing method and high resolution melting (HRM) analysis were used for staphylococcal protein A (spa) typing of 30 Methicillin-resistant Staphylococcus aureus (MRSA) isolates recovered from clinical samples. Based on PCR-sequencing method results, 16 different spa types were identified among the 30 MRSA isolates. Among the 16 different spa types, 14 spa types separated by HRM method. Two spa types including t4718 and t2894 were not separated from each other. According to our results, spa typing based on HRM analysis method is very rapid, easy to perform and cost-effective, but this method must be standardized for different regions, spa types, and real-time machinery. PMID- 28875911 TI - Cellvibrio zantedeschiae sp. nov., isolated from the roots of Zantedeschia aethiopica. AB - A bacterial strain, designated TPY-10T, was isolated from calla lily roots in Taiwan and characterized by using a polyphasic taxonomy approach. Cells of strain TPY-10T were Gram-stain-negative, strictly aerobic, motile and creamy white rods. Growth occurred at 15-35 degrees C (optimum, 25-30 degrees C), at pH 6-7 (optimum, pH 6) and with 0-1 % NaCl (optimum, 0 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain TPY-10T belonged to the genus Cellvibrio and was most closely related to Cellvibriomixtus ACM 2601T with sequence similarity of 97.8 %. Strain TPY-10T contained C16 : 0, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C18 : 1omega7c as the predominant fatty acids. The only isoprenoid quinone was Q-9. The major polar lipids were phosphatidylethanolamine and phosphatidylglycerol. The DNA G+C content of the genomic DNA was 49.8 mol%. The DNA-DNA hybridization value for strain TPY-10T with Cellvibriomixtus ACM 2601T was less than 21 %. On the basis of the phylogenetic inference and phenotypic data, strain TPY-10T should be classified as a novel species, for which the name Cellvibrio zantedeschiae sp. nov. is proposed. The type strain is TPY-10T (=BCRC 80525T=LMG 27291T=KCTC 32239T). PMID- 28875912 TI - Labrys soli sp. nov., isolated from the rhizosphere of ginseng. AB - In this study, we describe strain DCY64T that was isolated from the rhizosphere of three-year-old Korean ginseng root. Cells were Gram-reaction negative, oxidase and catalase-positive, strictly aerobic, capsulated, non-motile, non-sporulating and spherical to short rod-shaped. Multiplicative budding cells were produced. Vesicles covered the surface of cells. Phylogenetic analysis placed strain DCY64T within the genus Labrys with the highest similarity to Labrys monachus VKM B 1479T (97.6 % 16S rRNA gene sequence similarity), followed by Labrys okinawensis MAFF 210191T (97.5 %), Labrys miyagiensis G24103T (97.4) and Labrys portucalensis F11T (97.0 %). The genomic DNA G+C content was 63 mol%. The presences of summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), C19 : 1 cyclo omega8c and C16 : 0 as major fatty acids; phosphatidylmonomethylethanolamine, phosphatidylglycerol, phosphatidylcholine and diphosphatidylglycerol as major polar lipids; ubiquinone Q-10 as the predominant quinone and sym-homospermidine as the dominant polyamine were found in strain DCY64T. These chemotaxonomic results were in accordance with those of members of the genus Labrys. However, the absence of C16 : 0 2-OH, C16 : 0 3-OH and C18 : 1 2-OH from the fatty acids profile and differences in minor polar lipids and phenotypic characteristics distinguished strain DCY64T from the closest type strains. The discrimination was also supported by unique enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR) fingerprints, as well as DNA-DNA hybridization values ( <= 48 %) between strain DCY64T and related type strains. Therefore, we propose that strain DCY64T represents a novel species of the genus Labrys. The name Labrys soli sp. nov. is proposed, with DCY64T ( = KCTC 32173T = JCM 19895T) as the type strain. PMID- 28875913 TI - Pedobacter alpinus sp. nov., isolated from a plateau lake. AB - Two Gram-staining-negative, aerobic, non-motile, red-pigment and rod-shaped bacterial strains, designated RSP19T and RSR28, were isolated from lake water and subjected to polyphasic taxonomic studies. Based on 16S rRNA gene sequence analysis, strains RSP19T and RSR28 exhibited 91.4-95.7 % similarity to the type strains of existing species of the genus Pedobacter. The species most closely related phylogenetically were Pedobacter daechungensis (95.7 % sequence similarity), Pedobacter lentus (95.4 %), Pedobacter glucosidilyticus (94.5 %), Pedobacter panaciterrae (94.5 %) and Pedobacter terricola (94.2 %). MK-7 was the sole respiratory quinone. The major polar lipids were phosphatidylethanolamine, one unidentified aminolipid and several unidentified polar lipids. The predominant fatty acids were C16 : 1omega7c, iso-C15 : 0 and iso-C17 : 0 3-OH. The genomic DNA G+C contents were 34.3 and 33.9 mol% for strains RSP19T and RSR28, respectively. Based on the phenotypic characteristics, biochemical properties and genetic analysis, strains RSP19T and RSR28 clearly represent a novel species of the genus Pedobacter, for which the name Pedobacter alpinus is proposed. The type strain is RSP19T ( = CGMCC 1.14040T = KCTC 42456T = NBRC 110967T). PMID- 28875914 TI - Bacillus formosensis sp. nov., isolated from pesticide wastewater. AB - A Gram-stain-positive, endospore-forming rod (designated strain CC-LY275T) was isolated from a pesticide wastewater sample. The isolate grew at a temperature 20 45 degrees C, at pH 7.0-8.0 and tolerated NaCl 6 % (w/v). The most closely related strains in terms of 16S rRNA gene sequence similarity were Bacillus horneckiae (97.1 %) and Bacillus oceanisediminis (96.8 %), respectively. The G+C content of the genomic DNA was 37.9 mol%. Strain CC-LY275T was determined to possess iso-C14 : 0, iso-C15 : 0 and anteiso-C15 : 0 as predominant fatty acids. The major polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. Cell-wall peptidoglycan contained meso-diaminopimelic acid; menaquinone (MK-7) was the predominant respiratory quinone. According to the distinct phylogenetic, phenotypic and chemotaxonomic properties, the name Bacillus formosensis sp. nov. (type strain CC LY275T = BCRC 80443T = JCM 18448T) is proposed. PMID- 28875915 TI - Paenibacillus yunnanensis sp. nov., isolated from Pu'er tea. AB - A novel Gram-staining-positive, aerobic, endospore-forming, rod-shaped bacterial strain, YN2T, was isolated from ripened Pu'er tea. Phylogenetic analysis of 16S rRNA gene sequences showed that the strain represented a novel species of the genus Paenibacillus. The strains most closely related to strain YN2T were Paenibacillus vulneris JCM 18268T and Paenibacillus rigui JCM 16352T, with 16S rRNA similarities of 98.6 and 95.5 %, respectively. Chemotaxonomic data supported the affiliation of the new isolate to the genus Paenibacillus, including MK-7 as the major menaquinone, DNA G+C content of 51 mol%, cell-wall type A1gamma (meso diaminopimelic acid as the diagnostic diamino acid) and anteiso-C15 : 0 and iso C16 : 0 as the major fatty acids. Major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylmonomethylethanolamine and phospholipid. Strain YN2T could be differentiated from recognized species of the genus Paenibacillus based on phenotypic characteristics, chemotaxonomic differences, phylogenetic analysis and DNA-DNA hybridization data. On the basis of evidence from this polyphasic study, Paenibacillus yunnanensis sp. nov., is proposed, with strain YN2T ( = CGMCC 1.12968T = JCM 30953T) as the type strain. PMID- 28875916 TI - Flavobacterium endophyticum sp. nov., a nifH gene-harbouring endophytic bacterium isolated from maize root. AB - A novel Gram-stain-negative, aerobic, rod-shaped bacterium, designated strain 522T, was isolated from surface-sterilized root tissue of maize planted in Fangshan District of Beijing, China. A polyphasic taxonomic study was performed on the new isolate. On the basis of 16S rRNA gene sequence similarity studies, this isolate belonged to the genus Flavobacterium and showed less than 93.9 % similarity to the type strains of all recognized species of the genus Flavobacterium. The predominant respiratory quinone was menaquinone-6 and the polar lipid profile was composed of the major lipids phosphatidylethanolamine, phosphatidylserine and two unidentified amino lipids. The major fatty acids were C15 : 0, iso-C15 : 0, iso-C15 : 1 G and iso-C16 : 0.The G+C content of the DNA was 37.7 mol%. The results of physiological and biochemical tests and the differences in fatty acid profiles allowed the clear phenotypic differentiation of strain 522T from closely related species of the genus Flavobacterium. Strain 522T therefore represents a novel species within the genus Flavobacterium, for which the name Flavobacterium endophyticum sp. nov. is proposed. The type strain is 522T ( = ACCC 19708T = DSM 29537T). PMID- 28875917 TI - Aureibacillus halotolerans gen. nov., sp. nov., isolated from marine sediment. AB - A Gram-staining-positive, strictly aerobic, spore-forming and rod-shaped motile bacterium with peritrichous flagellae, designated strain S1203T, was isolated from the sediment of the northern Okinawa Trough. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain S1203T formed a lineage within the family Bacillaceae that was distinct from the most closely related genera Bacillus, Bhargavaea, Planomicrobium and Virgibacillus with gene sequence similarities ranging from 86.2 to 93.76 %. Optimal growth occurred in the presence of 4-8 % (w/v) NaCl, at pH 7.0-8.0 and 25-32 degrees C. The cell-wall peptidoglycan was based on meso-diaminopimelic acid and unsaturated menaquinone with seven isoprene units (MK-7) as the predominant respiratory quinone. The major fatty acids (>10 % of total fatty acids) were anteiso-C15 : 0, iso-C15 : 0 and C16 : 0.The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, an unidentified glycolipid and an unidentified phospholipid. The DNA G+C content of strain S1203T was 47.7 mol%. On the basis of polyphasic analysis, strainS1203T was considered to represent a novel species in a new genus of the family Bacillaceae, for which the name Aureibacillus halotolerans gen. nov., sp. nov. is proposed; the type strain of Aureibacillus halotolerans is S1203T ( = DSM 28697T = JCM 30067T = MCCC 1K00259T). PMID- 28875918 TI - Amycolatopsis stemonae sp. nov., isolated from a Thai medicinal plant. AB - A novel actinomycete, strain ST1-08T, was isolated from the stem of Stemona sp. in Thailand. The taxonomic position of this isolate was determined by using a polyphasic approach. Strain ST1-08T contained meso-diaminopimelic acid in the cell-wall peptidoglycan, and arabinose and galactose as diagnostic sugars of the whole-cell hydrolysate, which are typical properties of members of the genus Amycolatopsis. Strain ST1-08T grew at 15-40 degrees C, pH 6-9 and on 5 % (w/v) NaCl. Gelatin liquefaction, starch hydrolysis and skimmed milk peptonization were positive. The strain utilized l-arabinose, d-glucose, glycerol, myo-inositol, d mannitol and l-rhamnose. The predominant menaquinone was MK-9(H4) and the major cellular fatty acids were iso-C16 : 0 and iso-C15 : 0.The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, hydroxyl phosphatidylethanolamine, phosphatidylinositol and phosphatidylglycerol. The 16S rRNA gene sequence analysis revealed that the strain was closely related to Amycolatopsis pretoriensis JCM 12673T (98.99 %) and Amycolatopsis lexingtonensis JCM 12672T (98.87 %). The DNA G+C content of strain ST1-08T was 71.2 mol%. The DNA-DNA relatedness values among strain ST1-08T, A. pretoriensis JCM 12673T and A. lexingtonensis JCM 12672T were lower than 70 %, the cut-off level for assigning strains to the same species. On the basis of phenotypic and genotypic characteristics, strain ST1-08T represents a novel species of the genus Amycolatopsis, for which the name Amycolatopsis stemonae is proposed. The type strain is ST1-08T( = JCM 30050T = PCU 339T = TISTR 2278T). PMID- 28875919 TI - Paenibacillus medicaginis sp. nov. a chitinolytic endophyte isolated from a root nodule of alfalfa (Medicago sativa L.). AB - A Gram-stain-variable, short-rod-shaped, endospore-forming, strictly aerobic, non motile, chitinolytic and endophytic bacterium, designated strain CC-Alfalfa-19T, exhibiting unusual bipolar appendages was isolated from a root nodule of alfalfa (Medicago sativa L.) in Taiwan and subjected to a polyphasic taxonomic study. Based on 16S rRNA gene sequence analysis, strain CC-Alfalfa-19T was found to be most closely related to Paenibacillus puldeungensis CAU 9324T (95.2 %), whereas other species of the genus Paenibacillus shared <= 95.0 % sequence similarity. The phylogenetic analysis revealed a distinct phyletic lineage established by strain CC-Alfalfa-19T with respect to other species of the genus Paenibacillus. Fatty acids comprised predominantly anteiso-C15 : 0, C16 : 0, anteiso-C17 : 0 and iso-C16 : 0. Menaquinone 7 (MK-7) was identified as the sole respiratory quinone and the genomic DNA G+C content was 42.7 mol%. Polar lipids included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylmonomethylethanolamine, phosphatidylethanolamine, an unidentified glycolipid and an unidentified lipid. The diagnostic diamino acid found in the cell-wall peptidoglycan was meso diaminopimelic acid. Based on the polyphasic taxonomic evidence that was in line with the genus Paenibacillus and additional distinguishing characteristics, strain CC-Alfalfa-19T is considered to represent a novel species, for which the name Paenibacillus medicaginis sp. nov. (type strain CC-Alfalfa-19T = BCRC 80441T = JCM 18446T) is proposed. PMID- 28875920 TI - Pedobacter ardleyensis sp. nov., isolated from soil in Antarctica. AB - A red-pigmented, non-motile, Gram-stain-negative, rod-shaped bacterium, strain R2 28T, was isolated from a soil sample collected from Ardley Island, South Shetland Islands, Antarctica, and was characterized taxonomically by using a polyphasic approach. The organism grew optimally at 18 degrees C in TSB. On the basis of phylogenetic analyses of the 16S rRNA gene sequence, strain R2-28T was most closely related to the genus Pedobacter of the family Sphingobacteriaceae. The highest levels of 16S rRNA gene sequence similarity were found with respect to Pedobacter alluvionis NWER-II11T (95.6 %) and Pedobacter terrae DS-57T (95.2 %). The DNA G+C content was 39.9 mol%, and MK-7 was the only respiratory quinone. The major polar lipids were phosphatidylethanolamine and a sphingolipid. The predominant cellular fatty acids were iso-C15 : 0, anteiso-C15 : 0, iso-C17 : 0 3 OH and summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c). These chemotaxonomic and phylogenetic data supported the allocation of strain R2-28T to the genus Pedobacter. Additionally, the results of physiological and biochemical tests allowed phenotypic differentiation of strain R2-28T from species of the genus Pedobacter with validly published names. Therefore, strain R2-28T represents a novel species within the genus Pedobacter, for which the name Pedobacter ardleyensis sp. nov. is proposed. The type strain is R2-28T ( = CCTCC AB 2013365T = LMG 28255T). PMID- 28875921 TI - Halobellus ramosii sp. nov., an extremely halophilic archaeon isolated from a saline-wetland wildfowl reserve. AB - An extremely halophilic archaeon, strain S2FP14T, was isolated from a brine sample from the inland hypersaline lake Fuente de Piedra, a saline-wetland wildfowl reserve located in the province of Malaga in southern Spain. Colonies were red-pigmented and the cells were Gram-staining-negative, motile and pleomorphic. S2FP14T was able to grow in media containing 12.5-30 % (w/v) total salts (optimum 20 %) at pH 7-8.5 (optimum 7.5) and at 25-50 degrees C (optimum 37 degrees C). The 16S rRNA gene sequence analysis indicated that this strain represented a member of the genus Halobellus. S2FP14T showed a similarity of 99.5 % to Halobellus inordinatus YC20T, 96.1 % to Halobellus litoreus GX31T, 95.9 % to Halobellus limi TBN53T, 95.5 % to Halobellus rarus YC21T, 95.2 % to Halobellus rufus CBA1103T, 94.6 % to Halobellus salinus CSW2.24.4T and 94.6 % to Halobellus clavatus TNN18T. The rpoB' gene sequence similarity of strain S2FP14T was 97.4 % to 87.6 % with members of genus Halobellus. The major phospholipids of strain S2FP14T were phosphatidylglycerol phosphate methyl ester and phosphatidylglycerosulfate, plus a very small amount of phosphatidylglycerol and an archaeal analogue of bisphosphatidylglycerol. With regard to glycolipid composition, the most abundant glycolipids were the sulfated diglycosyl diphytanilglyceroldiether and a glycosyl-cardiolipin. The G+C content of strain S2FP14T genomic DNA was 61.4 mol%. The DNA-DNA hybridization between strain S2FP14T and Halobellus inordinatus JCM 18361T was 51 %. Based on the phylogenetic, phenotypic and chemotaxonomic features, a novel species, Halobellus ramosii sp. nov. is proposed. The type strain is S2FP14T ( = CECT 8167T = DSM 26177T). PMID- 28875922 TI - Marinibactrum halimedae gen. nov., sp. nov., a gammaproteobacterium isolated from a marine macroalga. AB - Phylogenetic and taxonomic characterization was performed for a bacterium, designated strain Q-192T, isolated from the surface of the green macroalga Halimeda sp., collected from the subtropical Ishigaki Island, Japan. The isolate was a polysaccharide-producing, Gram-stain-negative, aerobic, rod-shaped, motile bacterium with a polar flagellum. The isolate was slightly halophilic, required Na+, Mg2+ and Ca2+ ions for growth, but did not require growth factors. The only isoprenoid quinone was ubiquinone-8.The major cellular fatty acids were C18 : 1omega7c, C16 : 0 and C14 : 0. The main hydroxy fatty acid was C10 : 0 3-OH. The DNA G+C content was 45.9 mol%. Phylogenetic analysis of 16S rRNA gene sequences placed the isolate in the class Gammaproteobacteria. The phylogenetically closest relatives with validly published names were Pseudomaricurvus alkylphenolicus KU41GT, Teredinibacter turnerae T7902T, Pseudoteredinibacter isoporae SW-11T and Simiduia agarivorans SA1T with sequence similarities of 94.5, 94.1, 93.7 and 93.6 %, respectively. The isolate was distinguished from members of these genera by a combination of DNA G+C content, chemotaxonomic characteristics (respiratory quinone system, fatty acid profile and polar lipid composition) and other phenotypic features. Based on phylogenetic, genotypic, chemotaxonomic and phenotypic characteristics, strain Q-192T is considered to represent a novel species of a new genus, for which the name Marinibactrum halimedae gen. nov., sp. nov. is proposed. The type strain of Marinibactrum halimedae is Q-192T ( = NBRC 110095T = NCIMB 14932T). PMID- 28875923 TI - Halarchaeum grantii sp. nov., a moderately acidophilic haloarchaeon isolated from a commercial salt sample. AB - Three moderately acidophilic, halophilic archaeal strains, MH1-243-3T, MH1-243-5 and MH1-243-6, were isolated from a commercial salt sample made from seawater in Okinawa, Japan. Cells of the three strains were pleomorphic and stained Gram negative. Colonies of the strains were orange-red-pigmented. Strain MH1-243-3T was able to grow at 15-27 % (w/v) NaCl (optimum 24 degrees C), at pH 4.5-6.5 (pH 5.5) and at 35-50 degrees C (45 degrees C). Strains MH1-243-5 and MH1-243-6 grew within slightly different ranges (shown in text). The 16S rRNA gene sequences of the three strains were identical, and the closest phylogenetic relative was Halarchaeum salinum MH1-34-1T with 97.0 % similarity. The rpoB' gene sequences of the three strains were also identical, and the closest phylogenetic relative was Halarchaeum acidiphilum JCM 16109T with 92.0 % similarity. The DNA G+C content of MH1-243-3T, MH1-243-5 and MH1-243-6 was 65.2 mol%. The levels of DNA-DNA relatedness amongst the three strains were 84.1-99.8 %, while that between MH1-243-3T and H. salinum MH1-34-1T was 30.6 % and 31.6 % (reciprocally), and those between MH1-243-3T and type strains of other species in the genus Halarchaeum were 42.3-29.4 %. Based on the phenotypic, genotypic and phylogenetic analyses, it is proposed that the isolates should represent a novel species of the genus Halarchaeum, for which the name Halarchaeum grantii sp. nov. is proposed. The type strain is MH1-243-3T ( = JCM 19585T = KCTC 4142T), isolated from commercial sea salt produced in Okinawa, Japan. MH1-243-5 ( = JCM 19586) and MH1-243-6 ( = JCM 18422) are additional strains of the species. PMID- 28875924 TI - Borrelia yangtzensis sp. nov., a rodent-associated species in Asia, is related to Borrelia valaisiana. AB - Twenty-nine isolates of Lyme borreliosis (LB) group spirochaetes collected from ticks and rodents in China and Japan were included in a multilocus sequence analysis (MLSA). Using a different typing system, three of these strains had previously been identified as being divergent from other LB spirochaete species and the name 'Borrelia yangtze' sp. nov. was proposed. The data presented here confirm that the genetic distance, calculated using sequences of MLSA housekeeping genes, to other known LB group spirochaete species was < 95 % and to Borrelia valaisiana was 96.67 % (which represents the most closely related species within the group of LB spirochaetes). This and the fact that these strains are ecologically distinct from B. valaisiana (rodent-transmitted vs bird transmitted) provide strong support for the validation of the proposed species status. We suggest the name Borrelia yangtzensis sp. nov. The type strain is Okinawa-CW62T ( = DSM 24625T = JCM 17189T). PMID- 28875925 TI - Cavicella subterranea gen. nov., sp. nov., isolated from a deep mineral-water aquifer, and emended description of the species Perlucidibaca piscinae. AB - One strain designated W2.09-231T was isolated from an aquifer through a 150-metre deep borehole feeding a mineral-water bottling plant in Central Portugal. Based on 16S rRNA gene sequence analysis, the novel organism is most closely related to the species of the genera Perlucidibaca and Paraperlucidibaca, belonging to the family Moraxellaceae, with 16S rRNA gene pairwise sequence similarity of 94.5 and 93.1 %, respectively. The strain was not pigmented and formed Gram-stain negative, non-motile, short rod-shaped cells. The organism was strictly aerobic, and oxidase- and catalase-positive. Strain W2.09-231T was organotrophic, but grew only on a very limited number of single carbon sources. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and one major unknown phospholipid. Ubiquinone 12 (U-12) was the major respiratory quinone. The DNA G+C content of strain W2.09-231T was 62.0 mol%. Based on phylogenetic, physiological and biochemical characteristics, we describe a novel species of a novel genus represented by strain W2.09-231T ( = CECT 8582T = LMG 28332T) for which we propose the name Cavicella subterranea gen. nov., sp. nov. We also propose to emend the description of the species Perlucidibaca piscinae to reflect new results obtained in this study. PMID- 28875926 TI - Multilocus sequence analysis of the genus Kurthia, and a description of Kurthia populi sp. nov. AB - Four novel bacterial strains belonging to the genus Kurthia were isolated from the surface of a weevil of the family Curculionidae (strain 10y-14T), and from bark samples of hybrid poplar, Populus * euramericana (strains 6-3, 2-5 and 06C10 3-14), in Puyang, Henan Province, China. Phylogenetic analyses of the 16S rRNA gene and multilocus sequence analysis (MLSA) data showed that the four strains form a distinct cluster in the genus Kurthia, indicating that they all belong to a single taxon within the genus. DNA-DNA hybridization levels between strain 10y 4T and Kurthia huakuii LAM0618T and Kurthia massiliensis DSM 24639T were 58.31 and 53.92 %, respectively. This indicates that the four novel strains represent a species distinct from these two closely related species. The DNA G+C content of the novel strains was 42.1-42.6 %. The major fatty acids were iso-C15 : 0 and anteiso-C15 : 0.The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, an unknown phospholipid and unidentified aminophospholipids. The predominant menaquinones were MK-7 (90 %) and MK-6 (10 %). The major cell-wall amino acids were lysine, alanine, glutamic acid and glycine. On the basis of the MLSA and 16S rRNA gene sequence phylogenetic analyses, DNA-DNA reassociation values, DNA base composition, and biochemical and phenotypic characteristics, the four strains are considered to represent a novel species within the genus Kurthia, for which the name Kurthia populi sp. nov. is proposed. The type strain is 10y-14T ( = CFCC 11600T = KCTC 33522T). PMID- 28875927 TI - Ascending aortic diameter is associated with hypertension in Korean men. AB - PURPOSE: The purpose of this study was to evaluate the association between ascending aortic diameter (AAD) as measured with low-dose chest computed tomography (LDCT) and hypertension in Korean men. METHODS: Korean men (n=1,050) who were screened for lung cancer using LDCT imaging at a health promotion center in Seoul, Korea between January 1 and December 31were recruited for the study. AAD is the longest length of ascending aorta measured from approximately 15 mm above left main coronary ostium to the mid-slice level of the right pulmonary artery. RESULTS: AAD were divided into quartiles, and the degree of hypertension was determined based on the quartiles of the AAD using logistic regression. Odds ratios (OR) for the proportion of hypertension in Q2 (1.70, 95% CI: 1.11-2.59), Q3 (2.72, 95% CI: 1.81-4.09) and Q4 (3.94, 95% CI: 2.63-5.89) were significantly greater than that of Q1 (P for trend < 0.001). Even after controlling for confounding covariates of age, BMI, total cholesterol, HDL-cholesterol, fasting glucose, GGT, ALT, eGFR, smoking status and alcohol intake, there was significant correlation. CONCLUSION: AAD was significantly associated with the degree of hypertension. PMID- 28875928 TI - The association of HLA-DQB1*0602 but not HLA-DRB1*15 with obstructive sleep apnea. AB - PURPOSE: Obstructive sleep apnea (OSA) is a sleep breathing disorder with unclear multifactorial pathogenesis. This study aimed to investigate the association between OSA and two human leukocyte antigens (HLA) alleles; DQB1*0602 and DRB1*15. METHODS: Forty patients with OSA and 40 control subjects were enrolled in the study. OSA diagnosis was made utilizing the Apnea-Hypopnea Index (AHI)>=5 in overnight polysomnography (PSG). AHI was also used to determine OSA severity. Controls were randomly selected from healthy volunteers who had a low risk for OSA, utilizing the Berlin Questionnaire. Polymerase chain reaction (PCR) using Sequence Specific Primers (PCR-SSPs) was used to determine the association between HLA (HLA-DQB1*0602 and HLA-DRB1*15) and OSA, then statistical analyses of the results were performed. RESULTS: HLA-DQB1*0602 allele was found in 85% of all OSA patients and 50% of controls (P< 0.001). In patients with severe OSA, HLA DQB1*0602 was present in the 92.9% compared with 66.7% in non-severe OSA (P=0.05). HLA-DRB1*15 allele was found in 15% of OSA patients and 20% of controls, with no difference between the two groups (P=0.556). So statistical difference was found in HLA-DRB1*15 between severe and non-severe OSA (P=0.499). After adjusting for gender, HLA-DQB1*0602 allele was associated with increased odds of OSA (OR = 6.17, 95% CI 1.87-20.3, p = 0.003), but HLA-DRB1*15 allele was not associated with OSA (OR 0.45, 95% CI 0.12-1.73, p = 0.242). CONCLUSIONS: The presence of HLA-DQB1*0602 allele, but not HLA-DRB1*15 allele, was significantly associated with OSA. PMID- 28875929 TI - Pediatric cervical spine injuries with neurological deficits, treatment options, and potential for recovery. AB - PURPOSE: The purpose of the present study was to highlight the challenges in managing cervical spine injuries in children with neurological deficits. INTRODUCTION: Cervical spine injuries in children are relatively rare. Pattern, severity, and level of these injuries are age dependent. Neurological deficits in young children are uncommon and usually have a good potential for recovery. PATIENTS AND METHODS: This report includes four cases with pediatric cervical spine injuries with variable degrees of spinal cord injuries and neurological deficits. All the four patients were five years old or younger at the time of injury. Those patients were presented with different patterns of injuries and the treatment was customized for every patient. Marked neurological improvement occurred in all patients at the last follow-up. CONCLUSION: The treatment of pediatric cervical spine injuries should be individualized. Children with stable injuries should do well with non-operative treatment while operative treatment is recommended when the indication is appropriate and the expertise is available. Neurological deficits due to spinal cord injuries in pediatric patients have a high potential for recovery, provided that adequate management is considered. PMID- 28875930 TI - Light reintroduction after dark exposure reactivates plasticity in adults via perisynaptic activation of MMP-9. AB - The sensitivity of ocular dominance to regulation by monocular deprivation is the canonical model of plasticity confined to a critical period. However, we have previously shown that visual deprivation through dark exposure (DE) reactivates critical period plasticity in adults. Previous work assumed that the elimination of visual input was sufficient to enhance plasticity in the adult mouse visual cortex. In contrast, here we show that light reintroduction (LRx) after DE is responsible for the reactivation of plasticity. LRx triggers degradation of the ECM, which is blocked by pharmacological inhibition or genetic ablation of matrix metalloproteinase-9 (MMP-9). LRx induces an increase in MMP-9 activity that is perisynaptic and enriched at thalamo-cortical synapses. The reactivation of plasticity by LRx is absent in Mmp9-/- mice, and is rescued by hyaluronidase, an enzyme that degrades core ECM components. Thus, the LRx-induced increase in MMP-9 removes constraints on structural and functional plasticity in the mature cortex. PMID- 28875931 TI - Transient hypothyroidism favors oligodendrocyte generation providing functional remyelination in the adult mouse brain. AB - In the adult brain, both neurons and oligodendrocytes can be generated from neural stem cells located within the Sub-Ventricular Zone (SVZ). Physiological signals regulating neuronal versus glial fate are largely unknown. Here we report that a thyroid hormone (T3)-free window, with or without a demyelinating insult, provides a favorable environment for SVZ-derived oligodendrocyte progenitor generation. After demyelination, oligodendrocytes derived from these newly-formed progenitors provide functional remyelination, restoring normal conduction. The cellular basis for neuronal versus glial determination in progenitors involves asymmetric partitioning of EGFR and TRalpha1, expression of which favor glio- and neuro-genesis, respectively. Moreover, EGFR+ oligodendrocyte progenitors, but not neuroblasts, express high levels of a T3-inactivating deiodinase, Dio3. Thus, TRalpha absence with high levels of Dio3 provides double-pronged blockage of T3 action during glial lineage commitment. These findings not only transform our understanding of how T3 orchestrates adult brain lineage decisions, but also provide potential insight into demyelinating disorders. PMID- 28875932 TI - H+- and Na+- elicited rapid changes of the microtubule cytoskeleton in the biflagellated green alga Chlamydomonas. AB - Although microtubules are known for dynamic instability, the dynamicity is considered to be tightly controlled to support a variety of cellular processes. Yet diverse evidence suggests that this is not applicable to Chlamydomonas, a biflagellate fresh water green alga, but intense autofluorescence from photosynthesis pigments has hindered the investigation. By expressing a bright fluorescent reporter protein at the endogenous level, we demonstrate in real time discreet sweeping changes in algal microtubules elicited by rises of intracellular H+ and Na+. These results from this model organism with characteristics of animal and plant cells provide novel explanations regarding how pH may drive cellular processes; how plants may respond to, and perhaps sense stresses; and how organisms with a similar sensitive cytoskeleton may be susceptible to environmental changes. PMID- 28875933 TI - lncRNA requirements for mouse acute myeloid leukemia and normal differentiation. AB - A substantial fraction of the genome is transcribed in a cell-type-specific manner, producing long non-coding RNAs (lncRNAs), rather than protein-coding transcripts. Here, we systematically characterize transcriptional dynamics during hematopoiesis and in hematological malignancies. Our analysis of annotated and de novo assembled lncRNAs showed many are regulated during differentiation and mis regulated in disease. We assessed lncRNA function via an in vivo RNAi screen in a model of acute myeloid leukemia. This identified several lncRNAs essential for leukemia maintenance, and found that a number act by promoting leukemia stem cell signatures. Leukemia blasts show a myeloid differentiation phenotype when these lncRNAs were depleted, and our data indicates that this effect is mediated via effects on the MYC oncogene. Bone marrow reconstitutions showed that a lncRNA expressed across all progenitors was required for the myeloid lineage, whereas the other leukemia-induced lncRNAs were dispensable in the normal setting. PMID- 28875934 TI - ME31B globally represses maternal mRNAs by two distinct mechanisms during the Drosophila maternal-to-zygotic transition. AB - In animal embryos, control of development is passed from exclusively maternal gene products to those encoded by the embryonic genome in a process referred to as the maternal-to-zygotic transition (MZT). We show that the RNA-binding protein, ME31B, binds to and represses the expression of thousands of maternal mRNAs during the Drosophila MZT. However, ME31B carries out repression in different ways during different phases of the MZT. Early, it represses translation while, later, its binding leads to mRNA destruction, most likely as a consequence of translational repression in the context of robust mRNA decay. In a process dependent on the PNG kinase, levels of ME31B and its partners, Cup and Trailer Hitch (TRAL), decrease by over 10-fold during the MZT, leading to a change in the composition of mRNA-protein complexes. We propose that ME31B is a global repressor whose regulatory impact changes based on its biological context. PMID- 28875935 TI - Golgi-independent secretory trafficking through recycling endosomes in neuronal dendrites and spines. AB - Neurons face the challenge of regulating the abundance, distribution and repertoire of integral membrane proteins within their immense, architecturally complex dendritic arbors. While the endoplasmic reticulum (ER) supports dendritic translation, most dendrites lack the Golgi apparatus (GA), an essential organelle for conventional secretory trafficking. Thus, whether secretory cargo is locally trafficked in dendrites through a non-canonical pathway remains a fundamental question. Here we define the dendritic trafficking itinerary for key synaptic molecules in rat cortical neurons. Following ER exit, the AMPA-type glutamate receptor GluA1 and neuroligin 1 undergo spatially restricted entry into the dendritic secretory pathway and accumulate in recycling endosomes (REs) located in dendrites and spines before reaching the plasma membrane. Surprisingly, GluA1 surface delivery occurred even when GA function was disrupted. Thus, in addition to their canonical role in protein recycling, REs also mediate forward secretory trafficking in neuronal dendrites and spines through a specialized GA-independent trafficking network. PMID- 28875938 TI - Secretion Systems Used by Bacteria to Subvert Host Functions. AB - In this review we examine the use of secretion systems by bacteria to subvert host functions. Bacteria have evolved multiple systems to interact with and overcome their eukaryotic host and other prokaryotes. Secretion systems are required for the release of several effectors through the bacterial membrane(s) into the extracellular space or directly into the cytoplasm of the host. We review the secretion systems of Gram-positive and Gram-negative bacteria and describe briefly the structural composition of the seven secretion systems that have been associated with increased virulence through subversion of host functions. Some of the effects of such systems on eukaryotic host processes have been studied extensively. We also describe the best-characterized effectors of each secretion system to give an overview of the molecular mechanisms employed by bacteria to hide from the immune system and convert eukaryotic cells into optimal ecological niches for their replication. PMID- 28875936 TI - High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors. AB - NK cell education is the process through which chronic engagement of inhibitory NK cell receptors by self MHC-I molecules preserves cellular responsiveness. The molecular mechanisms responsible for NK cell education remain unclear. Here, we show that mouse NK cell education is associated with a higher basal activity of the mTOR/Akt pathway, commensurate to the number of educating receptors. This higher activity was dependent on the SHP-1 phosphatase and essential for the improved responsiveness of reactive NK cells. Upon stimulation, the mTOR/Akt pathway amplified signaling through activating NK cell receptors by enhancing calcium flux and LFA-1 integrin activation. Pharmacological inhibition of mTOR resulted in a proportional decrease in NK cell reactivity. Reciprocally, acute cytokine stimulation restored reactivity of hyporesponsive NK cells through mTOR activation. These results demonstrate that mTOR acts as a molecular rheostat of NK cell reactivity controlled by educating receptors and uncover how cytokine stimulation overcomes NK cell education. PMID- 28875937 TI - Notch/Her12 signalling modulates, motile/immotile cilia ratio downstream of Foxj1a in zebrafish left-right organizer. AB - Foxj1a is necessary and sufficient to specify motile cilia. Using transcriptional studies and slow-scan two-photon live imaging capable of identifying the number of motile and immotile cilia, we now established that the final number of motile cilia depends on Notch signalling (NS). We found that despite all left-right organizer (LRO) cells express foxj1a and the ciliary axonemes of these cells have dynein arms, some cilia remain immotile. We identified that this decision is taken early in development in the Kupffer's Vesicle (KV) precursors the readout being her12 transcription. We demonstrate that overexpression of either her12 or Notch intracellular domain (NICD) increases the number of immotile cilia at the expense of motile cilia, and leads to an accumulation of immotile cilia at the anterior half of the KV. This disrupts the normal fluid flow intensity and pattern, with consequent impact on dand5 expression pattern and left-right (L-R) axis establishment. PMID- 28875939 TI - Within-Host Envelope Remodelling and its Impact in Bacterial Pathogen Recognition. AB - Following colonization of host tissues, bacterial pathogens encounter new niches in which they must gain access to nutrients and cope with stresses and defence signals generated by the host. For some pathogens, the adaptation to a new 'within-host' lifestyle involves modifications of envelope components that bear molecular patterns normally recognized by the host innate immune system. These new modified patterns limit host recognition, therefore promoting immune evasion and pathogenicity. In this review, we describe how envelope components like the peptidoglycan or lipopolysaccharide can be altered within the host to impair responses triggered by pattern recognition receptors (PRR). We also discuss the few cases reported to date of chemical modifications that occur in the envelope of some intracellular bacterial pathogens when they reside inside eukaryotic cells. These envelope alterations may have evolved due to the sentinel role performed by PRRs over pathogen-specific molecular patterns. The available data indicate that only selected pathogens seem to evade recognition due to 'within host' envelope changes, with most of them displaying such patterns also in non host environments. Given the importance of these alterations, future studies should focus in the responsible pathogen regulators, most yet unknown, that could be targeted to prevent immune evasion. PMID- 28875940 TI - Subversion of Macrophage Functions by Bacterial Protein Toxins and Effectors. AB - Macrophages represent one of the first lines of host immune defenses against the invasion of pathogenic bacteria. Many receptors, immune signaling pathways and cellular processes in macrophages, including Toll-like receptors, Nod-like receptors, phagocytosis, autophagy and programmed cell death, are involved in combating the infection of bacterial pathogens. For efficient colonization in the host, bacterial pathogens have evolved diverse mechanisms to interfere with macrophage functions to evade host defenses. The major weapons utilized by bacterial pathogens are protein toxins and effectors secreted via specific bacterial secretion systems, including type I-VII secretion apparatuses. In recent years, great advances have been achieved in understanding how bacterial toxins and effectors subvert immune signaling and cellular processes of macrophages. In this review, we focus on the toxins and effectors that modulate the phagocytosis, intracellular immune signaling pathways, autophagy and programmed cell death processes of macrophages from the bacterium Legionella pneumophila, Shigella flexneri, Listeria monocytogenes, Salmonella spp., Yersinia spp., enteropathogenic E. coli and Mycobacterium tuberculosis. PMID- 28875941 TI - Manipulation of Autophagy by Bacterial Pathogens Impacts Host Immunity. AB - Autophagy is a highly conserved catabolic process, degrading unnecessary or damaged components in the eukaryotic cell to maintain cellular homeostasis, but it is also an intrinsic cellular defence mechanism to remove invading pathogens. A crosstalk between autophagy and innate or adaptive immune responses has been recently reported, whereby autophagy influences both, innate and adaptive immunity like the production and secretion of pro-inflammatory cytokines or MHC class II antigen presentation to T cells. Pathogenic bacteria have evolved diverse strategies to manipulate autophagy, mechanisms that also impact host immune responses at different levels. Here we discuss the influence of autophagy on self-autonomous, innate and adaptive immunity and then focus on how bacterial mechanisms that shape autophagy may impact the host immune system. PMID- 28875942 TI - Inflammasome-dependent Mechanisms Involved in Sensing and Restriction of Bacterial Replication. AB - Inflammasomes are multiprotein platforms assembled in the cytosol in response to pathogens and cell stress. Inflammasomes are recognized by their important role on defenses against bacterial infections and have been also implicated in a range of human inflammatory disorders. Intracellular sensors such as NLRP1, NLRP3, NLRC4, AIM2 and Pyrin induce assembly of inflammasomes, while caspase-11 induces the non-canonical pathway for activation of the NLRP3 inflammasome. The formation of the inflammasome leads to caspase-1 activation that triggers pyroptosis and activation of interleukin-1beta (IL-1beta) and IL-18. Pyroptotic cell death and cytokines production are involved in restriction of bacterial replication by limiting the replication niche of intracellular bacteria and by inducing inflammatory responses. In this review we focus on the mechanisms mediated by inflammasome activation that leads to inflammatory responses and restriction of bacterial infection. PMID- 28875943 TI - Molecular Mechanisms Used by Salmonella to Evade the Immune System. AB - Human and animal pathogens are able to circumvent, at least temporarily, the sophisticated immune defenses of their hosts. Several serovars of the Gram negative bacterium Salmonella enterica have been used as models for the study of pathogen-host interactions. In this review we discuss the strategies used by Salmonella to evade or manipulate three levels of host immune defenses: physical barriers, innate immunity and adaptive immunity. During its passage through the digestive system, Salmonella has to face the acidic pH of the stomach, bile and antimicrobial peptides in the intestine, as well as the competition with resident microbiota. After host cell invasion, Salmonella manipulates inflammatory pathways and the autophagy process. Finally, Salmonella evades the adaptive immune system by interacting with dendritic cells, and T and B lymphocytes. Mechanisms allowing the establishment of persistent infections are also discussed. PMID- 28875944 TI - Immune-evasion Strategies of Mycobacteria and Their Implications for the Protective Immune Response. AB - Mycobacteria are intracellular pathogens that have macrophages as their main host cells. However, macrophages are also the primary line of defense against invading microorganisms. To survive in the intracellular compartment, virulent mycobacteria have developed several strategies to modulate the activation and the effector functions of macrophages. Despite this, antigen-specific T cells develop during infection. While T cell responses are critical for protection they can also contribute to the success of mycobacteria as human pathogens, as immunopathology associated with these responses facilitates transmission. Here, we provide a brief overview of different immune-evasion strategies of mycobacteria and their impact on the protective immune response. This understanding will further our knowledge in host-pathogen interactions and may provide critical insights for the development of novel host-specific therapies. PMID- 28875945 TI - Role of Cyclic di-GMP in the Bacterial Virulence and Evasion of the Plant Immunity. AB - Plant pathogenic bacteria are responsible for the loss of hundreds of millions of dollars each year, impacting a wide range of economically relevant agricultural crops. The plant immune system detects conserved bacterial molecules and deploys an arsenal of effective defense measures at different levels; however, during compatible interactions, some pathogenic bacteria suppress and manipulate the host immunity and colonize and infect the plant host. Different bacteria employ similar strategies to circumvent plant innate immunity, while other tactics are specific to certain bacterial species. Recent studies have highlighted the secondary messenger c-di-GMP as a key molecule in the transmission of environmental cues in an intracellular regulatory network that controls virulence traits in many plant pathogenic bacteria. In this review, we focus on the recent knowledge of the molecular basis of c-di-GMP signaling mechanisms that promote or prevent the evasion of bacterial phytopathogens from the plant immune system. This review will highlight the considerable diversity of mechanisms evolved in plant-associated bacteria to elude plant immunity. PMID- 28875946 TI - PVA/Dextran hydrogel patches as delivery system of antioxidant astaxanthin: a cardiovascular approach. AB - After myocardial infarction, the heart's mechanical properties and its intrinsic capability to recover are compromised. To improve this recovery, several groups have developed cardiac patches based on different biomaterials strategies. Here, we developed polyvinylalcohol/dextran (PVA/Dex) elastic hydrogel patches, obtained through the freeze thawing (FT) process, with the aim to deliver locally a potent natural antioxidant molecule, astaxanthin, and to assist the heart's response against the generated myofibril stress. Extensive rheological and dynamo mechanical characterization of the effect of the PVA molecular weight, number of freeze-thawing cycles and Dex addition on the mechanical properties of the resulting hydrogels, were carried out. Hydrogel systems based on PVA 145 kDa and PVA 47 kDa blended with Dex 40 kDa, were chosen as the most promising candidates for this application. In order to improve astaxanthin solubility, an inclusion system using hydroxypropyl-beta-cyclodextrin was prepared. This system was posteriorly loaded within the PVA/Dex hydrogels. PVA145/Dex 1FT and PVA47/Dex 3FT showed the best rheological and mechanical properties when compared to the other studied systems; environmental scanning electron microscope and confocal imaging evidenced a porous structure of the hydrogels allowing astaxanthin release. In vitro cellular behavior was analyzed after 24 h of contact with astaxanthin loaded hydrogels. In vivo subcutaneous biocompatibility was performed in rats using PVA145/Dex 1FT, as the best compromise between mechanical support and astaxanthin delivery. Finally, ex vivo and in vivo experiments showed good mechanical and compatibility properties of this hydrogel. The obtained results showed that the studied materials have a potential to be used as myocardial patches to assist infarcted heart mechanical function and to reduce oxidative stress by the in situ release of astaxanthin. PMID- 28875947 TI - Improved prediction of bimanual movements by a two-staged (effector-then trajectory) decoder with epidural ECoG in nonhuman primates. AB - OBJECTIVE: In arm movement BCIs (brain-computer interfaces), unimanual research has been much more extensively studied than its bimanual counterpart. However, it is well known that the bimanual brain state is different from the unimanual one. Conventional methodology used in unimanual studies does not take the brain stage into consideration, and therefore appears to be insufficient for decoding bimanual movements. In this paper, we propose the use of a two-staged (effector then-trajectory) decoder, which combines the classification of movement conditions and uses a hand trajectory predicting algorithm for unimanual and bimanual movements, for application in real-world BCIs. APPROACH: Two micro electrode patches (32 channels) were inserted over the dura mater of the left and right hemispheres of two rhesus monkeys, covering the motor related cortex for epidural electrocorticograph (ECoG). Six motion sensors (inertial measurement unit) were used to record the movement signals. The monkeys performed three types of arm movement tasks: left unimanual, right unimanual, bimanual. To decode these movements, we used a two-staged decoder, which combines the effector classifier for four states (left unimanual, right unimanual, bimanual movements, and stationary state) and movement predictor using regression. MAIN RESULTS: Using this approach, we successfully decoded both arm positions using the proposed decoder. The results showed that decoding performance for bimanual movements were improved compared to the conventional method, which does not consider the effector, and the decoding performance was significant and stable over a period of four months. In addition, we also demonstrated the feasibility of epidural ECoG signals, which provided an adequate level of decoding accuracy. SIGNIFICANCE: These results provide evidence that brain signals are different depending on the movement conditions or effectors. Thus, the two-staged method could be useful if BCIs are used to generalize for both unimanual and bimanual operations in human applications and in various neuro-prosthetics fields. PMID- 28875948 TI - The tongue microbiome in healthy subjects and patients with intra-oral halitosis. AB - Intra-oral halitosis (IOH) is an unpleasant odor emanating from the oral cavity. It is thought that the microbiota of the dorsal tongue coating plays a crucial role in this condition. The aim of the study was to investigate the composition of the tongue microbiome in subjects with and without IOH. A total of 26 subjects, 16 IOH patients and 10 healthy subjects were recruited based on their organoleptic score and volatile sulfur compound (VSC) measurements. The composition of the tongue microbiome was studied using the 16s amplicon sequencing of the V3-V4 hyper variable region with an Illumina MiSeq. The sequenced data were analyzed using QIIME, and the sequences obtained were distributed across 7 phyla, 27 genera and 825 operational taxonomic units (OTUs). At a higher taxon level, TM7 was associated with IOH patients whereas Gemellaceae was significantly abundant in the healthy subjects. At OTU level, we found several significant OTUs that differentiated the IOH patients from the controls. These included Aggregatibacter (OTU id 4335776), Aggregatibacter segnis (A. segnis), Campylobacter, Capnocytophaga, Clostridiales, Dialister, Leptotrichia, Parvimonas, Peptostreptococcus, Peptococcus, Prevotella, Selenomonas, SR1, Tannerella, TM7-3 and Treponema in the IOH group. In the control group, Aggregatibacter (OTU id 4363066), Haemophilus, Haemophilus parainfluenza (H. parainfluenza), Moryella, Oribacterium, Prevotella, several Streptococcus, Rothia dentocariosa (R. dentocariosa) and OTU from Gemellaceae were significantly abundant. Based on our observation, it was concluded that the bacterial qualitative composition of the IOH and the control group was almost the same, except for the few above-mentioned bacterial species and genera. PMID- 28875949 TI - Community Hemodialysis in China: Opportunities and Challenges. PMID- 28875950 TI - Blocking Posttranslational Core Fucosylation Ameliorates Rat Peritoneal Mesothelial Cell Epithelial-Mesenchymal Transition. AB - Background:: Core fucosylation (CF), catalyzed by alpha-1,6 fucosyltransferase (Fut8) in mammals, plays an important role in pathological processes through posttranslational modification of key signaling receptor proteins, including transforming growth factor (TGF)-beta receptors and platelet-derived growth factor (PDGF) receptors. However, its effect on peritoneal fibrosis is unknown. Here, we investigated its influence on epithelial-mesenchymal transition (EMT) of rat peritoneal mesothelial cells (PMCs) in vitro induced by a high-glucose (HG) culture solution. Methods:: Rat PMCs were first cultured in a HG (2.5%) culture solution to observe the CF expression level (fluorescein isothiocyanate-lens culinaris agglutinin), we next established a knockdown model of rat PMCs in vitro with Fut8 small interfering RNA (siRNA) to observe whether inhibiting CF decreases the messenger RNA (mRNA) expression and protein expression of Fut8 and reverses EMT status. Rat PMCs were randomly divided into control group, mock group (transfected with scrambled siRNA), Fut8 siRNA group, HG group, HG + mock group, and HG + Fut8 siRNA group. Finally, we examined the activation of TGF beta/Smad2/3 signaling and PDGF/extracellular signal-regulated kinase (ERK) signaling to observe the influence of CF on them. Results:: CF, Fut8 mRNA, and protein expression were all significantly upregulated in HG- induced EMT model than those in the control rat PMCs (P < 0.05). Fut8 siRNA successfully blocked CF of TGF-beta receptors and PDGF receptors and attenuated the EMT status (E cadherin and alpha-SMA and phenotypic changes) in HG-induced rat PMCs. In TGF beta/Smad2/3 signaling, Fut8 siRNA did not suppress the protein expression of TGF beta receptors and Smad2/3; however, it significantly suppressed the phosphorylation of Smad2/3 (relative expression folds of HG + Fut8 group vs. HG group: 7.6 +/- 0.4 vs. 15.1 +/- 0.6, respectively, P < 0.05). In PDGF/ERK signaling, Fut8 siRNA did not suppress the protein expression of PDGF receptors and ERK, but it significantly suppressed the phosphorylation of ERK (relative expression folds of HG + Fut8 group vs. HG group: 8.7 +/- 0.9 vs. 15.6 +/- 1.2, respectively, P < 0.05). Blocking CF inactivated the activities of TGF-beta and PDGF signaling pathways, and subsequently blocked EMT. Conclusions:: These results demonstrate that CF contributes to rat PMC EMT, and that blocking it attenuates EMT. CF regulation is a potential therapeutic target of peritoneal fibrosis. PMID- 28875951 TI - Effects of Cyclosporine A on the Development of Metanephros in the Pregnant BALB/c Mice. AB - Background:: Cyclosporine A (CsA) is a commonly used clinical immunosuppressant. However, CsA exposure in rabbits during the gestation period was shown to cause a postnatal decrease in the number of nephrons, with the effects remaining unknown. In this study, we aimed to explore the effects of CsA on metanephros development in the pregnant BALB/c mice. Methods:: Pregnant mice were randomly divided into two groups, and CsA (10 mg.kg-1.d-1) was subcutaneously injected from gestation day 10.5 to day 16.5 in the CsA group, whereas a comparable volume of normal saline was given to the control group. All of the mice were sacrificed on gestation day 17.5 and serum CsA concentration was measured. The fetuses were removed and weighed, and their kidneys were prepared for histological assessment and polymerase chain reaction assay. In an in vitro experiment, embryo kidneys of fetal mice on gestation day 12.5 were used, and CsA (10 MUmol/L) was added in the culture of the CsA group. The growth pattern of the ureteric bud and nephrons was assessed by lectin staining. Results:: No significant differences in the weight of embryo (4.54 +/- 1.22 vs. 3.26 +/- 1.09 mg) were observed between the CsA and control groups, the thickness of the cortical (510.0 +/- 30.3 vs. 350.0 +/- 29.7 MUm, P < 0.05) and nephrogenic zone (272.5 +/- 17.2 vs. 173.3 +/- 24.0 MUm, P < 0.05), and the number of glomeruli (36.5 +/- 0.7 vs. 27.5 +/- 2.1, P < 0.05) were reduced in the CsA group when compared to the control group. The cell proliferation of Ki-67 positive index between control and CsA group (307.0 +/- 20.0 vs. 219.0 +/- 25.0, P < 0.05) in the nephrogenic zone was decreased with the increase of apoptotic cells (17.0 +/- 2.0 vs. 159.0 +/- 33.0, P < 0.05). The mRNA expression of WT-1, Pax2, and Pax8 was downregulated by CsA treatment. As for the in vitro CsA group, the branch number of the ureteric bud was decreased in the CsA-treated group with the nephrons missing in contrast to control after the incubation for 24 h and 72 h (all P < 0.0001). Conclusion:: Treatment of CsA suppressed metanephros development in the pregnant mice; however, the potential action of mechanism needs to be further investigated. PMID- 28875952 TI - Role of R.E.N.A.L. Nephrometry Score in Laparoscopic Partial Nephrectomy. AB - Background:: Preoperative anatomical scoring system is conducive to comparison between treatment options and evaluation of postoperative outcomes in patients with small renal tumors. This study aimed to evaluate the clinical application efficacy of the R.E.N.A.L. nephrometry score (RNS) in predicting perioperative outcomes in patients with renal tumor who underwent laparoscopic partial nephrectomy (LPN). Methods:: The clinical data of 139 patients with renal tumors who underwent LPN between 2009 and 2015 were collected and analyzed. Patients were divided into three groups according to their RNS (low, moderate, and high). Clinical characteristics including perioperative variables, complications, and RNS were compared to evaluate the differences between the three groups. Multivariable logistic regression analysis was used to analyze the risk factors of postoperative complications. Results:: According to the RNS, there were 74, 50, and 15 patients in the low, moderate, and high RNS groups, respectively. There were significant differences in estimated blood loss (EBL; chi2 = 7.285, P = 0.026), warm ischemia time (WIT; chi2 = 13.718, P = 0.001), operation time (OT; chi2 = 6.882, P = 0.032), perioperative creatinine clearance change (PCCC; chi2 = 6.206, P = 0.045), and number of patients with complications (NPC; P = 0.002) among the three groups. The values for EBL, WIT, OT, PCCC, and NPC for patients in the high RNS group were higher than those for patients in the low RNS group. After adjustment for OT, WIT, and EBL, RNS was statistically significantly associated with the risk of postoperative complications in a multivariable logistic regression model (odds ratio = 1.541, 95% confidence interval: 1.059 2.242, P = 0.024). Conclusions:: The RNS is a valuable tool for evaluating the complexity of renal tumor anatomy. It can aid surgeons in preoperative decision making concerning management therapy. Future multicenter, large sample size studies are warranted for evaluating its predicting performance of perioperative outcomes. PMID- 28875953 TI - Roles of Loss of Chromosome 14q Allele in the Prognosis of Renal Cell Carcinoma with C-reactive Protein Abnormity. AB - Background:: Renal cell carcinoma (RCC) is frequently associated with paraneoplastic inflammatory syndrome (PIS). This study aimed at exploring the connections between the survival rate and specific gene alterations and the potential mechanism. Methods:: We retrospectively studied 69 surgical RCC cases from August 2014 to February 2016, including 18 cases of clear cell RCC (ccRCC) demonstrating elevated pretreatment serum C-reactive protein (CRP, Group A). Twelve of the 18 cases were symptomized with febrile episode. We also selected 49 cases of ccRCC with normal pretreatment CRP (Group B). Using 22 microsatellite markers, we compared the incidence of loss of heterozygosity (LOH) between Group A and Group B. All statistical tests are two-sided. Results:: The 3p LOH was common in both Group A (89%) and Group B (92%). The frequency of 14q LOH in Group A (16 of 18) was higher than Group B (4 of 49, chi2 = 40.97 P < 0.0001). The 3p and 14q LOH were the characteristics of ccRCC with elevated acute phase reactants, including PIS, regardless of the presence of metastasis. On the contrary, 14q LOH was a rare genomic alternation in advanced-staged ccRCC without PIS. The overall survival of patients with elevated CRP (33.3%) was lower than its counterparts (6.1%, hazard ratio=1.852, P < 0.0001) in Kaplan-Meier curve. Conclusions:: The results imply that the disruption of a 14q gene(s) might result in not only the inflammatory manifestations in the tumor host but also the poor survival rate as well. The isolation of the gene(s) on 14q might be a vital goal in the treatment of PIS-associated RCC. PMID- 28875954 TI - Stenting of the Portal Vein Combined with Different Numbers of Iodine-125 Seed Strands: Dosimetric Analyses. AB - Background:: Portal-vein stent combined with one iodine-125 (125I) seed strand has become a new treatment for portal vein tumor thrombosis. However, dosimetric aspects of this irradiation stent have not been reported. Therefore, we aimed to undertake dosimetric analyses comparing portal-vein stents combined with different numbers of 125I seed strands. Methods:: A water cylinder was created by a treatment-planning system to simulate a portal-vein stent. The stent was combined with one, two, or three 125I seed strands (Groups I, II, and III, respectively). At different prescribed doses (PDs), 125I seeds of identical activities were loaded on Groups I-III. Conformation number (CN), external volume index, and homogeneity index were calculated. Linear regression analyses were used to evaluate the obtained data. Results:: For identical 125I seed activity, when the 125I seed strand increased from one chain to two, D90 (dose delivered to 90% of the target volume) increased by >=184%; when it increased from two chains to three, D90 increased by >=63%. When the PD was 105 Gy and 125I seed strands increased from one chain to two, V100 (percentage of the target volume receiving >=90% of the PD) increased by 158-249%; when it increased from two chains to three, V100 increased by 7-175%. CN was correlated positively with 125I seed activity (B = 0.479, P < 0.001) and number of 125I seed strands (B = 0.201, P < 0.001) and was independent of PD (B = -0.002, P = 0.078). Conclusions:: A portal vein stent combined with a single 125I seed strand could not meet dosimetry requirements. For a stent combined with two 125I seed strands, when the PD was 105 Gy and seed activity was 0.7 mCi, the dose distribution could satisfy dosimetry requirements. For a stent combined with three 125I seed strands, if the PD was 105, 125, or 145 Gy, the recommended seed activities were 0.5, 0.5, and 0.6 mCi, respectively. PMID- 28875955 TI - Efficacy of Real-world Entecavir Therapy in Treatment-naive Chronic Hepatitis B Patients. AB - Background:: Entecavir (ETV) has been shown to be effective in randomized controlled trials in highly selected patients with hepatitis B virus (HBV) infection. This study aimed to evaluate the efficacy of ETV in chronic hepatitis B (CHB) patients in the real-world setting. Methods:: A total of 233 treatment naive, CHB patients who received at least 12 months of ETV treatment were included in this retrospective study. Rates of virological response (VR), hepatitis B s antigen (HBsAg) loss, hepatitis B e antigen (HBeAg) clearance/seroconversion, virological breakthrough, cirrhosis, and hepatocellular carcinoma were evaluated. Results:: Of 233 patients, 175 patients were male, with mean age of 43 years old, and 135 patients were HBeAg positive. The mean baseline levels of serum alanine aminotransferase and HBV DNA in all patients were 230 U/L and 6.6 log 10 IU/ml, respectively. The mean follow-up period was 28 months. The cumulative rates of achieving VR increased from 3.4% at 3 months to 94.4% at 60 months. Primary nonresponse occurred in 3 (1.3%) patients. Partial VR (PVR) occurred in 61 (26.2%) patients at 12 months. The baseline serum HBV DNA level (hazard ratio [HR], 2.054; P < 0.001) was an independent risk factor for PVR. HBsAg loss did not occur. The cumulative rates of HBeAg clearance increased from 2.2% at 3 months to 28.2% at 60 months. PVR was the significant determinant of HBeAg clearance (HR, 0.341; P = 0.026). Age (HR, 1.072; P = 0.013) and PVR (HR, 5.131; P = 0.017) were the significant determinants of cirrhosis. Conclusions:: ETV treatment was effective for HBV DNA suppression in this study, but HBsAg loss and HBeAg clearance/seroconversion rates were lower compared with previous clinical trials. PVR was associated with HBeAg clearance and cirrhosis. PMID- 28875956 TI - Seroepidemiology of Syphilis Infection among 2 Million Reproductive-age Women in Rural China: A Population-based, Cross-sectional Study. AB - Background:: Quantifying syphilis prevalence is important for planning interventions and advocating for resources on syphilis. However, data on large sample studies regarding the prevalence of syphilis among reproductive-age women in rural China were not available for analysis. The aim of the study was to determine the prevalence, epidemiological characteristics, and related factors of syphilis infection among reproductive-age women in rural China. Methods:: Data were obtained from a nationwide, population-based, cross-sectional study under the National Free Preconception Health Examination Project which covered all the 31 provinces in Mainland China. Women intending to get pregnant within the next 6 months were enrolled between January 1, 2010, and December 31, 2012. Sociodemographic, gynecological and obstetric characteristics, and other relevant information were obtained through face-to-face interviews. Treponema pallidum particle agglutination assay test was used to detect positive samples of syphilis. Univariate and multivariate logistic regressions were performed to assess the associations between syphilis seropositivity and related factors. Results:: The overall seroprevalence of syphilis (SPS) among the 2,044,126 women who received syphilis screening test during 2010-2012 was 0.37% (95% confidence interval [CI]: 0.36-0.37%). The SPS appeared 0.24% (95% CI: 0.23-0.26%) and 0.66% (95% CI: 0.59-0.72%) in women at 21-24 and 40-44 years of age, respectively, showing an increase of SPS, parallel with age, and the difference was significant. SPS was significantly higher in ethnic minorities than that in Han nationality (0.58% vs. 0.35%, respectively, odds ratio [OR] = 1.41, 95% CI: 1.30 1.53) and higher in workers than that in farmers (0.45% vs. 0.36%, respectively, OR = 1.27, 95% CI: 1.14-1.41). Women with primary school or below level had a higher SPS as compared to those with college or above educational level (0.61% vs. 0.32%, respectively, OR = 2.49, 95% CI: 2.14-2.89), and the increase reversely correlated with the levels of education. Women whose spouses were syphilis seropositive had significant greater risk (OR = 48.26, 95% CI: 44.38 52.48) as compared those whose spouses were seronegative. Women who reported having had a history of sexually transmitted infections were more likely to be tested positive for serological syphilis (OR = 27.17, 95% CI: 20.44-36.11) as compared to those without. Conclusions:: High SPS is seen among reproductive-age women in rural China that calls for targeted interventions on syphilis prevention and control in this target population, with emphasis on those who are 35 years of age and above, less educated, being minor ethnicity, workers, and living in the western regions of China. PMID- 28875957 TI - Transition from Tumor Tissue to Bone Marrow in Patients with Appendicular Osteosarcoma after Neoadjuvant Chemotherapy. AB - Background:: Limb-salvage surgery is the standard procedure for the treatment of appendicular osteosarcoma. Precise resection is the trend in limb-salvage surgery. The aim of this study was to evaluate a large series of cases to identify the histological relationship between the tumor and marrow and determine the intramedullary transition type and width from the tumor to normal marrow in patients with osteosarcoma after neoadjuvant chemotherapy. Methods:: One hundred and six osteosarcoma specimens were evaluated. The tissue specimens were sectioned through the coronal axis by an electronic saw. The tissue was immersed in formalin solution for fixation and subsequently decalcified. The interface between the tumor and normal bone marrow was grossly determined and submitted for microscopic evaluation to detect the relationship between the tumor and bone marrow and identify the transition type and width. All histological slides were examined by experienced orthopedic pathologists. Results:: Histologically, the interface between the tumor and normal bone marrow was classified into two patterns: "clear" and "infiltrated." The clear pattern, characterized by a clear boundary between the tumor and marrow, was identified in sixty cases (56.6%). A subtype of the clear type, characterized by fibrous bands between the tumor and marrow, was found in 13 cases (12.3%). The infiltrated pattern, characterized by a boundary with tumor cell clusters embedded in the marrow, was found in 46 cases (43.4%). The infiltrating depth varied from 1 to 4 mm (mean, 2.6 +/- 0.7 mm). No tumor cells were observed in the normal bone marrow areas next to the interface. Conclusions:: The transition from osteosarcoma tissue to bone marrow after neoadjuvant chemotherapy can be divided into two histological patterns: clear and infiltrated. The greatest infiltration width was 4 mm from tumor to normal marrow in this study. This depth should be considered in the presurgical plan. PMID- 28875958 TI - 5-Hydroxytryptamine Changes under Different Pretreatments on Rat Models of Myocardial Infarction and/or Depression. AB - Background:: Psychocardiological researches have suggested a central role of 5 hydroxytryptamine (5-HT) on psychocardiological mechanism. This study aimed to further explore the central role of 5-HT and pretreatment effects of XinLingWan on rats with myocardial infarction (MI) and/or depression. Methods:: Ninety Sprague-Dawley rats were randomly divided into three groups: MI group, depression group, and MI + depression group (n = 30 in each group). Each group was then divided into three subgroups (n = 10 in each subgroup): a negative control subgroup (NCS), a Western medicine subgroup (WMS), and a traditional Chinese medicine subgroup (TCMS), which were received pretreatment once a day for 4 weeks by saline, 20 mg/kg sertraline mixed with 2 ml saline, and 40 mg/kg XingLingWan mixed with 2 ml saline, respectively. Different rat models were established after different pretreatments. Rats were then sacrificed for detection of serum 5-HT, platelet 5-HT, 5-HT2A receptors (5-HT2AR), and serotonin transporter (SERT). Data were analyzed by one-way analysis of variance (ANOVA) and least-significant difference (LSD) testing. Results:: MI group: compared with NCS, there was a significant increase in WMS and TCMS of serum 5-HT (176.15 +/- 11.32 pg/ml vs. 334.50 +/- 29.09 pg/ml and 474.04 +/- 10.86 pg/ml, respectively, both P = 0.000), platelet 5-HT (129.74 +/- 27.17 pg/ml vs. 322.24 +/- 11.60 pg/ml and 340.4 5 +/- 17.99 pg/ml, respectively, both P = 0.000); depression group: compared with NCS, there was a significant increase in WMS and TCMS of serum 5-HT (194.69 +/- 5.09 pg/ml vs. 326.21 +/- 39.98 pg/ml and 456.33 +/- 23.12 pg/ml, respectively, both P = 0.000), platelet 5-HT (175.15 +/- 4.07 pg/ml vs. 204.56 +/- 18.59 pg/ml and 252.03 +/- 22.26 pg/ml, respectively, P = 0.004 and P = 0.000, respectively); MI + depression group: compared with NCS, there was a significant increase in both WMS and TCMS of serum 5-HT (182.50 +/- 10.23 pg/ml vs. 372.55 +/- 52.23 pg/ml and 441.76 +/- 23.38 pg/ml, respectively, both P = 0.000) and platelet 5-HT (180.83 +/- 11.08 pg/ml vs. 221.12 +/- 22.23 pg/ml and 265.37 +/- 29.49 pg/ml, respectively, P = 0.011 and P = 0.000, respectively). Conclusions:: By elevating the amount of 5-HT and modulating 5-HT2AR and SERT levels in serum and platelets, XinLingWan and sertraline were found to exert pretreatment effect on rat models of MI and/or depression. PMID- 28875959 TI - Downregulation of Na+/Ca2+ Exchanger Isoform 1 Protects Isolated Hearts by Sevoflurane Postconditioning but Not by Delayed Remote Ischemic Preconditioning in Rats. AB - Background:: Calcium regulatory proteins-L-type Ca2+ channels (LTCCs), ryanodine receptor 2 (RyR2), and Na+/Ca2+ exchanger isoform 1 (NCX1) have been recognized as important protective mechanisms during myocardial ischemia-reperfusion injury (I/RI). Both sevoflurane postconditioning (SevoPoC) and delayed remote ischemic preconditioning (DRIPC) have been shown to protect the heart against I/RI. In this study, we aimed to compare the effects of SevoPoC and DRIPC on the expression of the three calcium regulatory proteins in an isolated rat heart model. Methods:: After 30-min balanced perfusion, isolated hearts from rats were subjected to 30-min ischemia followed by 60-min reperfusion. Totally 40 isolated hearts were randomly assigned to four groups (n = 10/group): time control group, I/RI group, SevoPoC group, and DRIPC group. The effect of SevoPoC (3% v/v) and DRIPC were observed. Myocardial infarct size (IS), cardiac troponin I level, and heart function were measured. The protein and messenger RNA levels of LTCCs, RyR2, and NCX1 were determined. Results:: Both SevoPoC and DRIPC improved the recovery of myocardial function, and reduced cardiac troponin I release after I/RI. The decrease in IS was more significant in the SevoPoC group than that in the DRIPC group (16.50% +/- 4.54% in the SevoPoC group [P = 0.0006], and 22.34% +/- 4.02% in the DRIPC group [P = 0.0007] vs. 35.00% +/- 5.24% in the I/RI group, respectively). SevoPoC, but not DRIPC significantly inhibited the activity of NCX1 (0.59 +/- 0.09 in the I/RI group vs. 0.32 +/- 0.16 in the SevoPoC group, P = 0.006; vs. 0.57 +/- 0.14 in the DRIPC group, P = 0.072). No statistical significant differences were observed in the expression of LTCCs and RyR2 between SevoPoC and DRIPC. In addition, subsequent correlation analysis showed a significantly positive relationship between the cardiac troponin I level and the protein expression of NCX1 (r = 0.505, P = 0.023). Conclusion:: SevoPoC may be more effective in the cardioprotection than DRIPC partly due to the deactivation of NCX1. PMID- 28875960 TI - Analysis of Macular and Retinal Nerve Fiber Layer Thickness in Children with Refractory Amblyopia after Femtosecond Laser-assisted Laser In situ Keratomileusis: A Retrospective Study. AB - Background:: Localized macular edema and retinal nerve fiber layer (RNFL) thinning have been reported shortly after laser in situ keratomileusis (LASIK) in adults. However, it is still unclear how LASIK affects the retina of children. This study aimed to investigate the macular retina and RNFL thickness in children with refractive amblyopia who underwent femtosecond laser-assisted LASIK (FS LASIK). Methods:: In this study, we included 56 eyes of 32 patients with refractive amblyopia who underwent FS-LASIK in our hospital from January 2012 to December 2016. Foveal (foveal center retinal, parafoveal retinal, and perifoveal), macular inner retinal (superior and inferior), and peripapillary RNFL thicknesses (superior, inferior, temporal, and nasal) were measured using Fourier-domain optical coherence tomography before surgery and 1 day, 3 days, and 1 week after surgery. We divided these patients into three groups based on their refractive error: High myopic group with 22 eyes (equivalent sphere, >6.00 D), mild myopic group with 19 eyes (equivalent sphere, 0-6.00 D), and hyperopic group with 15 eyes (equivalent sphere, >+0.50 D). We compared the macular retina and RNFL thickness before and after LASIK. A paired simple t-test was used for data analysis. Results:: One week after surgery, the visual acuity for all 56 eyes of the 32 patients reached their preoperative best-corrected vision. Visual acuity improved two lines or better for 31% of the patients. The residual refractive errors in 89% of the patients were within +/-0.5 D. In the high myopic group, the foveal center retinal and parafoveal retinal thicknesses were thicker 1 day and 3 days after surgery than before surgery (t = 2.689, P = 0.012; t = 2.383, P = 0.018, respectively); no significant difference was found 1 week after surgery (P > 0.05). The foveal center retinal and parafoveal retinal thicknesses were greater 1 day after surgery than they were before surgery (P = 0.000 and P = 0.005, respectively) in the mild myopic and hyperopic groups. No significant difference was found 3 days or 1 week after surgery (P > 0.05). In all three groups, no significant difference was found in the macular inner retinal or peripapillary RNFL thickness 1 day, 3 days, or 1 week after surgery (P > 0.05). Conclusions:: The foveal center retinal edema after FS-LASIK is mild and reversible in children, that mostly occurred in the high myopic group with no effect on the visual acuity, and is always relieved within 1 week. PMID- 28875961 TI - High Spicy Food Intake and Risk of Cancer: A Meta-analysis of Case-control Studies. AB - Background:: Studies on the association between spicy food intake and cancer risk have reported inconsistent results. We quantitatively assessed this association by conducting a meta-analysis based on evidence from case-control studies. Methods:: PubMed, EMBASE, and the Cochrane Library were searched for eligible publications. Combined odds ratios (OR s) with their 95% confidence interval (CI) were calculated using a random- or fixed-effects model. The methodological quality of the included articles was assessed using the Newcastle-Ottawa scale (NOS). All data were analyzed using STATA 11.0 software (version 11.0; StataCorp., College Station, TX, USA). Subgroup analyses were also performed with stratification by region, sex, number of cases, cancer subtype, source of the control group, and NOS score. Results:: A total 39 studies from 28 articles fulfilled the inclusion criteria for the meta-analysis (7884 patients with cancer and 10,142 controls). Comparison of the highest versus lowest exposure category in each study revealed a significant OR of 1.76 (95% CI = 1.35-2.29) in spite of significant heterogeneity (P < 0.001). In the subgroup analyses, this positive correlation was still found for gastric cancer, different regions, different numbers of cases, different sources of the control group, and high-quality articles (NOS score of >= 7). However, no statistically significant association was observed for women, esophageal cancer, gallbladder cancer, or low-quality articles (NOS score of <7). No evidence of publication bias was found. Conclusions:: Evidence from case-control studies suggested that a higher level of spicy food intake may be associated with an increased incidence of cancer despite significant heterogeneity. More studies are warranted to clarify our understanding of the association between high spicy food intake and the risk of cancer. PMID- 28875962 TI - Urinary Biomarkers for Chronic Kidney Disease with a Focus on Gene Transcript. AB - Objective:: In the upcoming era of precision medicine, searching for the early, noninvasive biomarkers has been the cornerstone and major challenge in the management of chronic kidney disease (CKD). Urine contains rich biological information which could be the ideal source for noninvasive biomarkers of CKD. This review will discuss the recent advance in urinary biomarker. Data Sources:: This review was based on data in articles published in the PubMed databases up to June 20, 2017, with the following keywords: "Chronic kidney disease", "Biomarker", and "Urine". Study Selection:: Original articles and important reviews on urinary biomarker were selected for this review. Results:: Urinary biomarker studies of CKD mainly focused on urine sediment, supernatant, and urinary extracellular vesicles. The gene transcript (microRNA [miRNA], messenger RNA [mRNA]) biomarkers have been recently shown with diagnostic potential for CKD reflecting kidney function and histological change. However, challenges regarding technique and data analysis need to be resolved before translation to clinic. Conclusions:: Different fractions of urine contain rich information for biomarker discovery, among which urine (extracellular vesicles) mRNA, miRNA, might represent promising biomarker for CKD. PMID- 28875963 TI - An Infant with Abernethy Malformation Associated with Heterotaxy and Pulmonary Hypertension. PMID- 28875964 TI - Vascular Graft Bridged En Bloc Resection for Biliopancreatic Cancer Invading the Portal System. PMID- 28875965 TI - Fibronectin Glomerulopathy: A Rare Autosomal Dominant Glomerular Disease. PMID- 28875966 TI - Unexpected Pulmonary Events during Endotracheal Intubation in a Pediatric Patient. PMID- 28875967 TI - Effectiveness of Laparoscopic Sacral Colpopexy for Pelvic Organs Prolapse Diseases. PMID- 28875968 TI - Endoscope-assisted Transoral Approach for Parapharyngeal Space Tumor Resection. PMID- 28875969 TI - [Gastroenterological manifestations of von Hippel-Lindau disease]. AB - Von Hippel-Lindau disease is rare autosomal dominant disorder that results from mutation of VHL gene. Typical manifestations of this syndrome include haemangioblastomas of retina, cerebellum and spinal cord, endolymphatic sac tumors, clear cell cancer and kidney cysts, pheochromocytoma, pancreatic cysts and neuroendocrine tumors. The differential diagnosis of pancreatic lesions in patients with von Hippel Lindau syndrome plays an important role. The pancreas in VHL disease is not only site of benign lesions (cysts, serous systic adenomas) but also of potentially malignant (neuroendocrine) and malignant tumors(metastases).The gastroenterological manifestations can be the first symptoms of von Hippel-Lindau disease. PMID- 28875970 TI - [Evaluation of selected vascular active factors in patients after myocardial infarction subjected to cardiac rehabilitation]. AB - : Atherosclerosis is an inflammatory process that develops in the coronary arteries. Clinically active agents such as proinflammatory interleukins, TNF alpha, tissue inhibitors of metalloproteinases (including TIMP-1), and vascular endothelial growth factor (VEGF), are important factors in the development of acute coronary syndromes. AIM: The aim of the study was to evaluate the effect of cardiac rehabilitation (stage II) on the concentration of selected vascular active factors (IL- 1, IL-6, TIMP-1, VEGF). MATERIALS AND METHODS: The study involved 24 patients after ACS who underwent complex cardiac rehabilitation (stage II) in the Department of Internal Medicine and Cardiac Rehabilitation at the Medical University of Lodz. The study involved 20 men and 4 women aged 42-78 years (average age 58.75 +/- 8.45 years). The ELISA method was used in the vascular endothelial cell assay using readymade sets for determining individual molecules: Human Quantum ELISA Kit (DTM100; R & D Systems, BIOKOM, Poland), Human VEGF Quantikine ELISA Kit (DVE00; R & D Systems, BIOKOM, Poland) Human IL-1 beta / IL-1F2 Quantikine ELISA Kit (DLB50; R & D Systems, BIOKOM, Poland), Human IL-6 Quantikine ELISA Kit (D6050, R & D Systems, BIOKOM, Poland). TIMP-1 concentration is expressed in ng / ml, VEGF in pg / ml, IL-1 in pg / ml, IL-6 pg / ml. The results of the study were analyzed statistically at significance level p <0,05. RESULTS: There was no significant effect of cardiac rehabilitation on vascular endothelial factors: TIMP-1, VEGF, IL-6. Significant effect of cardiac rehabilitation was observed on the increase of IL-1 concentration (p=0.016). CONCLUSIONS: The absence of post-cardiac rehabilitation in patients after ACS, significant changes in vascular endothelial activity, confirm the hypothesis that adequate physical effort does not involve changes in blood concentrations and justifies perception of rehabilitation as a safe and risk-free intervention. PMID- 28875971 TI - [Exercise capacity in patients with pulmonary sarcoidosis]. AB - : Exertional dyspnea is a common manifestation of sarcoidosis. Cardiopulmonary exercise testing (CPET) is a useful tool to evaluate exercise tolerance of sarcoid patients. AIM: The aim of the study was to evaluate of exercise capacity in patients with pulmonary sarcoidosis with regard to duration of the disease. Analysis of differences in physical tolerance between patients with cardiac sarcoidosis and without cardiac sarcoidosis. MATERIALS AND METHODS: 39 patients diagnosed with pulmonary sarcoidosis were enrolled to our study. Cardiopulmonary exercise test was used to assess exercise capacity. According to time passed from diagnosis of sarcoidosis patients were grouped into 2 groups. Cardiac sarcoidosis was diagnosed in 9 subjects (23.07%). The control group consisted of 33 healthy volunteers. RESULTS: The results of the ergospirometry test in patients with lung sarcoidosis showed statistically significant differences in comparison to the control group. The age of patients with pulmonary sarcoidosis correlated negatively with maximal heart rate, oxygen consumption at peak exercise and at anaerobic threshold, breathing frequency at peak exercise, minute ventilation at peak exercise and metabolic equivalent. There was a negative, statistically significant correlation between the oxygen pulse at the peak of exercise and the treatment of steroids in the past. CONCLUSIONS: Exercise limitation in patients with pulmonary sarcoidosis is a consequence of both ventilatory and cardiocirculatory impairment. Patients with longer disease history of sarcoidosis achieved worse results at cardiopulmonary exercise test than patients with shorter disease history. Trend towards worse exercise tolerance in patients with cardiac sarcoidosis compared to patients without cardiac sarcoidosis was observed. PMID- 28875972 TI - [Gastroenterological manifestations of von Hippel-Lindau disease - a case report]. AB - Gastrointestinal organs are involved in the course of von Hippel Lindau disease. Typically pancreas in von Hippel Lindau syndrome is a site of cystic and solid tumors. Differential diagnosis of pancreatic lesions includes benign lesions (cysts, serous cystic adenomas), potentially malignant (neuroendocrine) and malignant tumors(metastases).In this work we present a patient with VHL syndrome with pancreatic cysts and neuroendocrine tumor. PMID- 28875973 TI - [Butamirate citrate in control of cough in respiratory tract inflammation]. AB - Cough is the reflex defense response of the respiratory tract to the present secretions in the throat, trachea and bronchi, and ongoing inflammation in the mucous membranes of the upper and lower respiratory tract. From a practical point of view, cough is dry (unproductive) and productive cough with expulsion of significant amounts of secretion. Drugs used to treat cough differ in both mechanism of action and pharmacokinetic activity. Butamirate citrate belongs to a new class of cough suppressants acting centrally through the receptors in the brainstem. In addition, it has a very beneficial effect, because it reduces the resistance in the airways by inhibiting bronchospasm and anti-inflammatory effect. It is rapidly absorbed after oral administration and its therapeutic plasma concentration is determined after 5-10 minutes of administration, irrespective of the dose. Possible side effects are rarely seen in 0.5-1% of patients, mainly in the form of skin rash, nausea, diarrhea, dizziness, which usually resolves during treatment. The cough effect of most cough suppressants is good, but their mechanisms are different and for that reason they should be individually selected. An important asset of this group of drugs is peripheral activity and effects on bronchodilator muscles, such as in the case of butamirate. Inclusion of this feature is particularly beneficial in chronic inflammatory bronchial diseases. PMID- 28875974 TI - [Functional gastrointestinal disorders in children and adolescents. The Rome IV criteria]. AB - In the work diagnostic criteria of functional disorders of the gastrointestinal tract in children and adolescents aged 4 to 18 years are presented. The criteria were elaborated by experienced experts in pediatrics and gastroenterology and were presented on Digestive Disease Week in San Diego in 2016 as modified IV Rome Criteria. In the work the following functional disorders are discussed: cyclic vomiting syndrome, functional nausea and vomiting, rumination syndrome, aerophagia, functional dyspepsia, irritable bowel syndrome, abdominal migraine, functional abdominal pain - not otherwise specified, functional constipation, nonretentive fecal incontinence. PMID- 28875975 TI - [Autobiographical memory in depressive disorders]. AB - Contemporary research studies regarding autobiographical memory (AM) indicate that its deficits have a significant impact on the development of mental disorders. We find particularly many reports regarding the comorbidity of AM deficits and depressive disorders. The characteristic feature of AM in the people suffering from depressive disorders is the presence of overgeneral autobiographical memory (OGM), i.e. the reminiscences which contain a summary of many emotion-laden situations, yet without significant detail. This type of reminiscences is observed in the patients with depressive disorders and the ones susceptible to the disease but not experiencing presently an episode of depression, as well as the ones being in the phase of disease remission. In recent years, the interest in the significance of negative thinking processes, such as ruminations, as risk factors in the development of depression has been growing. It is emphasized that they are significantly associated with the occurrence of OGM. Research shows that people suffering from OGM and characterised by a rumination-based style of processing experience a greater number of depressive episodes. There are also research studies which confirm that the activities aimed at reducing the number of ruminations influence an improvement of the detail level of reminiscences. These data may serve as valuable therapeutic advice in depression disorders. The aim of the paper is to present results of contemporary research regarding mutual interrelations between autobiographical memory dysfunctions and the occurrence of symptoms of depression and its course. PMID- 28875976 TI - [Atopic dermatitis - risk factors and treatment]. AB - Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by severe itching and eczematic skin lesions. In Poland from 1.5 to 2.5 million people suffer from AD. The pathophysiologic complexity and the wide spectrum of clinical phenotypes cause diagnostic and therapeutic problems and this is the basis for the division of the disease into subtypes. Heterogeneity of the disease is also confirmed in the study of the genotype of the disease. In relation with AZS more than 1000 loci in chromosomes were demonstrated. The roles of certain genes and the pathophysiology of lesions caused by their polymorphism were described. Wide spectrums of AD risk factors are: cigarette smoking, alcohol consumption during pregnancy, obesity and high and low birth weight. The quality of life in patients with AD is impaired, the disease disrupts family and professional relationships. Biological medical products are an example of an individual approach to the treatment of AD. It seems, individual approach to disease and treatment can be a successive solution to the problem. PMID- 28875979 TI - Abstracts from the 2017 Annual Scientific Meeting of the British and Irish Hypertension Society (BIHS). PMID- 28875977 TI - The life and death of immune cell types: the role of BCL-2 anti-apoptotic molecules. AB - Targeting survival mechanisms of immune cells may provide an avenue for immune intervention to dampen unwanted responses (e.g. autoimmunity, immunopathology and transplant rejection) or enhance beneficial ones (e.g. immune deficiency, microbial defence and cancer immunotherapy). The selective survival mechanisms of the various immune cell types also avails the possibility of specific tailoring of such interventions. Here, we review the role of the BCL-2 anti-apoptotic family members (BCL-2, BCL-XL, BCL-W, MCL-1 and A1) on cell death/survival of the major immune cell types, for example, T, NK, B, dendritic cell (DC) lineages. There is both selectivity and redundancy among this family. Selectivity comes partly from the expression levels in each of the cell types. For example, plasmacytoid DC express abundant BCL-2 and are susceptible to BCL-2 antagonism or deficiency, whereas conventional DC express abundant A1 and are susceptible to A1 deficiency. There is, however, also functional redundancy; for example, overexpression of MCL-1 can override BCL-2 antagonism in plasmacytoid DC. Moreover, susceptibility to another anti-apoptotic family member can be unmasked, when one or other member is removed. These dual principles of selectivity and redundancy should guide the use of antagonists for manipulating immune cells. PMID- 28875978 TI - IL4 and IL21 cooperate to induce the high Bcl6 protein level required for germinal center formation. AB - Bcl6 (B-cell lymphoma 6) is a transcriptional repressor and critical mediator of the germinal center reaction during a T-cell-dependent antibody response, where it enables somatic hypermutation of immunoglobulin genes and inhibits terminal differentiation via repression of Blimp1. It can also contribute to the development of diffuse large B-cell lymphoma when expressed inappropriately. Bcl6 regulation is mediated both at the transcriptional and post-transcriptional levels, and in particular a strong signal through the B-cell receptor causes rapid proteasomal degradation of Bcl6. Despite the importance of Bcl6 in both immunity and cancer, little is known about how other extrinsic factors regulate Bcl6 in B cells. Here we show that Bcl6 is indeed highly unstable in B cells after a B-cell receptor (BCR) signal, but that the T-cell-derived cytokines interleukin 4 (IL4) and IL21 counteract BCR-mediated degradation, preserving Bcl6 protein levels. Stat6, downstream of IL4, can induce Bcl6 transcription directly. In vivo, B-cell intrinsic loss of IL4 or IL21 signaling reduces the magnitude or duration of the GC response, respectively, while their combined loss almost completely eliminates the GC response. This work provides key insights into the effect mediated by T-follicular helper cytokines on Bcl6 regulation. PMID- 28875980 TI - Autosomal recessive congenital ichthyosis: CERS3 mutations identified by a next generation sequencing panel targeting ichthyosis genes. AB - There are at least 38 mutant genes known to be associated with the ichthyosis phenotypes, and autosomal recessive congenital ichthyosis (ARCI) is a specific subgroup caused by mutations in 13 different genes. Mutations in some of these genes, such as CERS3 with only two previous reports, are rare. In this study, we identified mutations in candidate genes in consanguineous families with ARCI with a next generation sequencing (NGS) array that incorporates 38 ichthyosis associated genes. We applied this sequencing array to DNA from 140 ichthyosis families with high prevalence of consanguinity. Among these patients we identified six distinct, previously unreported mutations in CERS3 in six Iranian families. These mutations in each family co-segregated with the ichthyosis phenotype. The patients demonstrated collodion membrane at birth, acrogeria, generalized scaling, and hyperlinearity of the palms and soles. The presence of a significant percentage of CERS3 mutations in our cohort depicts a marked difference between the etiology of ichthyoses in genetically poorly characterized regions and well-characterized western populations. Also, it shows that rare alleles are more prevalent in the gene pool of consanguineous populations and emphasizes the importance of these population studies for better understanding of ichthyosis pathogenesis. PMID- 28875983 TI - Enter the Nanoman. PMID- 28875982 TI - Cancer Immunotherapy: From local to global. PMID- 28875981 TI - Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing. AB - Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts. PMID- 28875985 TI - Nanolasing: Multimode superlattice arrays. PMID- 28875986 TI - The power of the tiniest shoot. PMID- 28875988 TI - A cautionary note on graphene anti-corrosion coatings. PMID- 28875984 TI - Multiscale technologies for treatment of ischemic cardiomyopathy. AB - The adult mammalian heart possesses only limited capacity for innate regeneration and the response to severe injury is dominated by the formation of scar tissue. Current therapy to replace damaged cardiac tissue is limited to cardiac transplantation and thus many patients suffer progressive decay in the heart's pumping capacity to the point of heart failure. Nanostructured systems have the potential to revolutionize both preventive and therapeutic approaches for treating cardiovascular disease. Here, we outline recent advancements in nanotechnology that could be exploited to overcome the major obstacles in the prevention of and therapy for heart disease. We also discuss emerging trends in nanotechnology affecting the cardiovascular field that may offer new hope for patients suffering massive heart attacks. PMID- 28875989 TI - The Current State of Pharmacological Treatments for Cannabis Use Disorder and Withdrawal. AB - Cannabis use disorder (CUD) commonly occurs and carries a notable economic and functional burden at both individual and societal levels. While there are no clearly efficacious medication treatments for CUD, 20 years of committed and high quality research in the human laboratory and clinical settings have resulted in medications with demonstrated effectiveness in the treatment of cannabis withdrawal, the ability to reduce cannabis use, and results that point to promising future work. The current state of pharmacology research for CUD highlights the need to consider particular characteristics of patients, such as gender, impulsivity, and severity of cannabis use, when selecting a medication in the off-label treatment of CUD or cannabis withdrawal. As a field, the body of work also exposes some areas in need of improvement in study design, selection of outcome measures, interpretation of results, and the overall process of evaluating candidate medications. Coming to a consensus as a field and addressing these gaps in future research will likely lend itself to further advances in improving the lives of patients with CUD. PMID- 28875991 TI - Nuclear Envelope: Chromosomes: one BAF layer to bind them all. PMID- 28875992 TI - Fluorescence nanoscopy in cell biology. AB - Fluorescence nanoscopy uniquely combines minimally invasive optical access to the internal nanoscale structure and dynamics of cells and tissues with molecular detection specificity. While the basic physical principles of 'super-resolution' imaging were discovered in the 1990s, with initial experimental demonstrations following in 2000, the broad application of super-resolution imaging to address cell-biological questions has only more recently emerged. Nanoscopy approaches have begun to facilitate discoveries in cell biology and to add new knowledge. One current direction for method improvement is the ambition to quantitatively account for each molecule under investigation and assess true molecular colocalization patterns via multi-colour analyses. In pursuing this goal, the labelling of individual molecules to enable their visualization has emerged as a central challenge. Extending nanoscale imaging into (sliced) tissue and whole animal contexts is a further goal. In this Review we describe the successes to date and discuss current obstacles and possibilities for further development. PMID- 28875993 TI - Cell organization by liquid phase separation. PMID- 28875990 TI - Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Delta9-Tetrahydrocannabinol. AB - The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are >550 chemical compounds and >100 phytocannabinoids isolated from cannabis, including Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC-induced anxiety, psychosis, and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from preclinical and human studies, particularly with reference to anxiety and psychosis-like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings, including the individual and interactive effects of CBD and THC. PMID- 28875996 TI - Nanoporous gold assemblies of calixarene-phosphine-capped colloids. AB - The synthesis of high surface-area colloidal assemblies of calixarene-phosphine capped nanoporous gold is reported under reductive electrochemical conditions. These materials uniquely exhibit a remarkably thin wall thickness down to 10 nm, while possessing pore sizes on the order of up to hundreds of nanometers, which can be controlled via choice of organic ligand. PMID- 28875997 TI - Molecular conformations of DNA targets captured by model nanoarrays. AB - An open question in single molecule nanoarrays is how the chemical and morphological heterogeneities of the solid support affect the properties of biomacromolecules. We generated arrays that allowed individually-resolvable DNA molecules to interact with tailored surface heterogeneities and revealed how molecular conformations are impacted by surface interactions. PMID- 28875995 TI - Anti-inflammatory effects of octadecylamine-functionalized nanodiamond on primary human macrophages. AB - Chronic inflammatory disorders such as rheumatoid arthritis are characterized by excessive pro-inflammatory or "M1" activation of macrophages, the primary cells of the innate immune system. Current treatments include delivery of glucocorticoids (e.g. dexamethasone - Dex), which reduce pro-inflammatory M1 behaviour in macrophages. However, these treatments have many off-target effects on cells other than macrophages, resulting in broad immunosuppression. To limit such side effects, drug-incorporated nano- and microparticles may be used to selectively target macrophages via phagocytosis, because of their roles as highly effective phagocytes in the body. In this study, surface-modified nanodiamond (ND) was explored as a platform for the delivery of dexamethasone to macrophages because of ND's rich surface chemistry, which contributes to ND's high potential as a versatile drug delivery platform. After finding that octadecylamine functionalized nanodiamond (ND-ODA) enhanced adsorption of Dex compared to carboxylated ND, the effects of Dex, ND-ODA, and Dex-adsorbed ND-ODA on primary human macrophage gene expression were characterized. Surprisingly, even in the absence of Dex, ND-ODA had strong anti-inflammatory effects, as determined by multiplex gene expression via NanoString and by protein secretion analysis via ELISA. ND-ODA also inhibited expression of M2a markers yet increased the expression of M2c markers and phagocytic receptors. Interestingly, the adsorption of Dex to ND-ODA further increased some anti-inflammatory effects, but abrogated the effect on phagocytic receptors, compared to its individual components. Overall, the ability of ND-ODA to promote anti-inflammatory and pro-phagocytic behaviour in macrophages, even in the absence of loaded drugs, suggests its potential for use as an anti-inflammatory therapeutic to directly target macrophages through phagocytosis. PMID- 28875994 TI - The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis. AB - The discovery of the genetic code and tRNAs as decoders of the code transformed life science. However, after establishing the role of tRNAs in protein synthesis, the field moved to other parts of the RNA world. Now, tRNA research is blooming again, with demonstration of the involvement of tRNAs in various other pathways beyond translation and in adapting translation to environmental cues. These roles are linked to the presence of tRNA sequence variants known as isoacceptors and isodecoders, various tRNA base modifications, the versatility of protein binding partners and tRNA fragmentation events, all of which collectively create an incalculable complexity. This complexity provides a vast repertoire of tRNA species that can serve various functions in cellular homeostasis and in adaptation of cellular functions to changing environments, and it likely arose from the fundamental role of RNAs in early evolution. PMID- 28875998 TI - Large-scale immuno-magnetic cell sorting of T cells based on a self-designed high throughput system for potential clinical application. AB - In this contribution, we designed four types of immuno-magnetic nanoparticles for separation of different T cells (CD3+, CD4+, CD8+ and CD14+ T cells), and we established a new large-scale immuno-magnetic cell sorting procedure to achieve an enrichment of particular T cells using our designed auto-IMACS device. This device could achieve recyclable large-scale cell sorting, for which the throughput of the system reached ~4000 mL and the maximum cell capacity was 4 * 1010. The collected cells were analyzed by flow cytometry and visual cytology data, and the effective selection rates of CD3+, CD4+, CD8+ and CD14+ T cells were 79.3%, 74.1%, 57.1% and 67.9%, respectively. The sorted CD8+ T cells still retained good cytotoxic activity against specific cells. In addition, the sorted T cells can also be further incubated in vitro and proliferated, and even could be infused back into patients for immunotherapy in the near future. PMID- 28875999 TI - A comparison of the human and mouse protein corona profiles of functionalized SiO2 nanocarriers. AB - Nanoparticles are a promising cancer therapy for their use as drug carriers given their versatile functionalization with polyethylene glycol and proteins that can be recognized by overexpressed receptors in tumor cells. However, it has been suggested that in biological fluids, proteins cover nanoparticles, which gives the proteins a biological identity that could be responsible for unexpected biological responses: the so-called protein corona. A relevant biological event that is usually ignored in protein-corona formation is the interspecies differences in protein binding, which can be involved in the discrepancies observed in preclinical studies and the nanoparticle safety and efficiency. Hence, the aim of this study was to determine the differences between human and mouse plasma protein corona profiles in an active therapy model using silicon dioxide nanoparticles (SiO2 nanoparticles) functionalized with polyethylene glycol and transferrin. Functionalized SiO2 nanoparticles were made with a primary particle size of 25 nm and a transferrin content of 50 MUg mg-1 of nanoparticles and were PEGylated with a cross-linker. The proteomic analysis by nanoliquid chromatography tandem-mass spectrometry (nanoLC-MS/MS) showed interspecies differences. The most abundant proteins found in the human protein corona profile were immunoglobulins, actin cytoplasmic 1, hemoglobin subunit beta, serotransferrin, ficolin-3, complement C3, and apolipoprotein A-1. Meanwhile, the mouse protein corona adsorbed the serine protease inhibitor A3K, serotransferrin, alpha-1-antitrypsin 1-2, hemoglobin subunit beta, and fibrinogen gamma and beta chains. These protein-corona profile differences in the functionalized SiO2 nanoparticles indicate that biological responses observed in in vivo models could not be translated to clinical use and must be considered in the interpretation of preclinical trials in order to design more efficient and safer nanomedicines. PMID- 28876000 TI - Efficient and long-lifetime full-color light-emitting diodes using high luminescence quantum yield thick-shell quantum dots. AB - We report full-color quantum-dot-based light-emitting diodes (QLEDs) with high efficiency and long-lifetime by employing high quantum-yield core/shell QDs with thick shells. The increased shell thickness improves the confinement of excitons in the QD cores, and helps to suppress Auger recombination and Forster resonant energy transfer among QDs. Along with optimizing the QD emitting layer thickness and hole transport materials, we achieved significant improvements in device performance as a result of increasing the QD shell thickness to above 5 nm. By using poly[9,9-dioctylfluorene-co-N-[4-(3-methylpropyl)]-diphenylamine] (TFB) as a HTL with a 38 nm thick QD layer, these QLEDs show maximum current efficiencies of 18.9 cd A-1, 53.4 cd A-1, and 2.94 cd A-1, and peak external quantum efficiencies (EQEs) of 10.2%, 15.4%, and 15.6% for red, green, and blue QLEDs, respectively, all of which are well maintained over a wide range of luminances from 102 to 104 cd m-2. To the best of our knowledge, this is the first report of blue QLEDs with etaEQE > 15%. Most importantly, these devices also possess long lifetimes with T70 (the time at which the brightness is reduced to 70% of its initial value) of 117 h (red, with an initial luminance of 8000 cd m-2), 84 h (green, 6000 cd m-2) and 47 h (blue, 420 cd m-2). With further optimization of QD processing and device structures, these LEDs based on thick-shell QDs show great promise for use in next-generation full-color displays and lighting devices. PMID- 28876002 TI - Engineering biodegradable guanidyl-decorated PEG-PCL nanoparticles as robust exogenous activators of DCs and antigen cross-presentation. AB - Nanoparticles (NPs)-based adjuvants are attracting much attention in the development of vaccines. Previously, we reported a type of guanidyl-decorated polymeric NPs used as antigen delivery carriers for the first time. However, its un-degradability may restrict potential clinical translation. More importantly, the specific cellular pathway by which dendritic cells (DCs) endocytosed these NPs and the relationship among guanidyl with the antigen cross-presentation, cytokine secretion, and lymph node targeting still remain unclear. Here, we show NPs assembled by biodegradable methoxyl poly(ethylene glycol)-block-poly(epsilon caprolactone)-graft-poly(2-(guanidyl) ethyl methacrylate) (mPEG-b-PCL-g-PGEM, PECG) copolymers can robustly activate DCs and promote their maturation; additionally antigen cross-presentation was improved both in vitro and in vivo. Significantly, our results also demonstrate the increase of surface guanidyl on nanoparticles modulates the depot effect and lymph node drainage of PECG NPs based adjuvants, as well as immune responses, by regulating the secretion of cytokines including IFN-gamma and TNF-alpha. Our study provides insights into the action of guanidyl-decorated nanoscale adjuvants and new adjuvants for vaccines containing protein antigens. We anticipate the strategy of guanidyl decoration to be a starting point for the development of more exciting immunoadjuvants. PMID- 28876001 TI - Smart candle soot coated membranes for on-demand immiscible oil/water mixture and emulsion switchable separation. AB - Oil/water separation is of great importance for the treatment of oily wastewater, including immiscible light/heavy oil-water mixtures, oil-in-water or water-in-oil emulsions. Smart surfaces with responsive wettability have received extensive attention especially for controllable oil/water separation. However, traditional smart membranes with a switchable wettability between superhydrophobicity and superhydrophilicity are limited to certain responsive materials and continuous external stimuli, such as pH, electrical field or light irradiation. Herein, a candle soot coated mesh (CSM) with a larger pore size and a candle soot coated PVDF membrane (CSP) with a smaller pore size with underwater superoleophobicity and underoil superhydrophobicity were successfully fabricated, which can be used for on-demand immiscible oil/water mixtures and surfactants-stabilized oil/water emulsion separation, respectively. Without any continuous external stimulus, the wettability of our membranes could be reversibly switched between underwater superoleophobicity and underoil superhydrophobicity simply by drying and washing alternately, thus achieving effective and switchable oil/water separation with excellent separation efficiency. We believe that such smart materials will be promising candidates for use in the removal of oil pollutants in the future. PMID- 28876003 TI - Preventing sintering of nanoclusters on graphene by radical adsorption. AB - Metal nanoclusters, supported on inert substrates, exhibiting well-defined shapes and sizes in a broad range of temperatures are a major object of desire in nanotechnology. Here, a technique is presented that improves the thermal stability of monodisperse and crystalline transition metal nanoclusters grown in a regular array on metal-supported graphene. To stabilize the clusters after growth under ultrahigh vacuum the system composed of the aggregates and the graphene/metal interface is exposed to radicals resulting from the dissociation of diatomic gases. As a model system we have used Pt as the metal element for cluster growth and the template consisting of the moire pattern resulting from the lattice mismatch between graphene and the Ir(111) surface. The study has been performed for deuterium and oxygen radicals, which interact very differently with graphene. Our results reveal that after radical exposure the thermally activated motion of Pt nanoclusters to adjacent moire cells and the subsequent sintering of neighbor aggregates are avoided, most pronounced for the case of atomic O. For the case of D the limits of the improvement are given by radical desorption, whereas for the case of O they are defined by an interplay between coalescence and graphene etching followed by Pt intercalation, which can be controlled by the amount of exposure. Finally, we determined the mechanism of how radical adsorption improves the thermal stability of the aggregates. PMID- 28876004 TI - Graphite particles induce ROS formation in cell free systems and human cells. AB - It is commonly accepted that the toxicity of carbonaceous particulate matter (PM) is due to the production of reactive oxygen species (ROS) which induce biological damage in the exposed cells. It is also known that PM produced during the combustion processes consists of a carbonaceous core "dressed" with other organic and/or inorganic materials. In spite of this knowledge, the role of these materials in the production of ROS has not yet been clear. This work aims at understanding whether "naked" carbonaceous particles are capable of forming ROS either in cell-free or in-cell systems. The problem has been treated based on the data collected from pure graphite samples of different sizes obtained by ball milling pure graphite for various lengths of time. The experimental approach considered Raman, ESR (spin trapping), cell viability and fluorescence spectroscopy measurements. These techniques allowed us to carry out measurements both in cell and cell-free systems and the results consistently indicate that also pure naked carbonaceous particles can catalyze the electron transfer that produces superoxide ions. The process depends on the particle size and enlightens the role of the edges of the graphitic platelets. Evidence has been collected that even "naked" graphitic nanoparticles are capable of producing ROS and decreasing the cell viability thus representing a potential danger to human health. PMID- 28876005 TI - The mechanism of excimer formation: an experimental and theoretical study on the pyrene dimer. AB - The understanding of excimer formation in organic materials is of fundamental importance, since excimers profoundly influence their functional performance in applications such as light-harvesting, photovoltaics or organic electronics. We present a joint experimental and theoretical study of the ultrafast dynamics of excimer formation in the pyrene dimer in a supersonic jet, which is the archetype of an excimer forming system. We perform simulations of the nonadiabatic photodynamics in the frame of TDDFT that reveal two distinct excimer formation pathways in the gas-phase dimer. The first pathway involves local excited state relaxation close to the initial Franck-Condon geometry that is characterized by a strong excitation of the stacking coordinate exhibiting damped oscillations with a period of 350 fs that persist for several picoseconds. The second excimer forming pathway involves large amplitude oscillations along the parallel shift coordinate with a period of ~900 fs that after intramolecular vibrational energy redistribution leads to the formation of a perfectly stacked dimer. The electronic relaxation within the excitonic manifold is mediated by the presence of intermolecular conical intersections formed between fully delocalized excitonic states. Such conical intersections may generally arise in stacked pi conjugated aggregates due to the interplay between the long-range and short-range electronic coupling. The simulations are supported by picosecond photoionization experiments in a supersonic jet that provide a time-constant for the excimer formation of around 6-7 ps, in good agreement with theory. Finally, in order to explore how the crystal environment influences the excimer formation dynamics we perform large scale QM/MM nonadiabatic dynamics simulations on a pyrene crystal in the framework of the long-range corrected tight-binding TDDFT. In contrast to the isolated dimer, the excimer formation in the crystal follows a single reaction pathway in which the initially excited parallel slip motion is strongly damped by the interaction with the surrounding molecules leading to the slow excimer stabilization on a picosecond time scale. PMID- 28876006 TI - Charge storage performances and mechanisms of MnO2 nanospheres, nanorods, nanotubes and nanosheets. AB - Manganese dioxide (MnO2) has been widely used as an active material for high performance supercapacitors due to its high theoretical capacitance, high cycling stability, low cost, and environmental friendliness. However, the effect of its crystallographic phase on charge storage performances and mechanisms is not yet clear. Herein, MnO2-based supercapacitors with different structures including nanospheres, nanorods, nanotubes, and nanosheets have been fabricated and investigated. Among such structures, delta-MnO2 nanosheets exhibit the highest specific capacitance of 194.3 F g-1 at 1 A g-1 when compared with other phases and shapes. The maximum specific energy of the delta-MnO2 nanosheet supercapacitor is 23.4 W h kg-1 at 971.6 W kg-1 and the maximum specific power is 4009.2 W kg-1 at 15.9 W h kg-1 with a capacity retention of 97% over 15 000 cycles. The delta-MnO2 nanosheet mainly stores charges via a diffusion-controlled mechanism at the scan rates of 10-100 mV s-1, whilst the alpha-MnO2 with different morphologies including nanospheres, nanorods, and nanotubes store charges via a non-faradaic or non-diffusion controlled process especially at fast scan rates (50-100 mV s-1). Understanding the charge storage performance and mechanism of the MnO2 nanostructures with different crystallographic phases and morphologies may lead to the further development of supercapacitors. PMID- 28876007 TI - Calcium stilbene complexes: structures and dual reactivity. AB - Addition of a calcium hydride complex to diphenylacetylene gave a complex in which the stilbene dianion symmetrically bridges two Ca2+ ions. DFT calculations discuss the effect of the metal stilbene coordination. The stilbene complex reacts as a base (with H2) or an electron donor (with I2) and catalyzes the reduction of diphenylacetylene. PMID- 28876008 TI - A two-step solid-state reaction to synthesize the yellow persistent Gd3Al2Ga3O12:Ce3+ phosphor with an enhanced optical performance for AC-LEDs. AB - By using a two-step solid-state reaction to synthesize the yellow-persistent Gd3Al2Ga3O12:Ce3+ phosphor, both the luminescence and afterglow properties were greatly enhanced. Its internal quantum efficiency reaches as high as 81.9%, indicating its promising application in reducing the flicker effect in AC-LED based white light systems. PMID- 28876009 TI - Cyclohexa-1,3-diene-based dihydrogen and hydrosilane surrogates in B(C6F5)3 catalysed transfer processes. AB - The cyclohexa-1,3-diene motif is introduced as an equally effective alternative to the cyclohexa-1,4-diene platform in B(C6F5)3-catalysed transfer processes. The transfer hydrogenation of alkenes is realised with alpha-terpinene and the related transfer hydrosilylation is achieved with 5-trimethylsilyl-substituted cyclohexa-1,3-diene. Both yields and substrate scope are comparable with the prior systems. PMID- 28876010 TI - Rapid synthesis of lipid nanoparticles containing hydrophobic inorganic nanoparticles. AB - A straightforward "bottom-up" synthesis is described for efficient entrapment of inorganic hydrophobic nanoparticles (HNPs) consisting of iron oxide, gold, or quantum dots within the hydrophobic core of lipid nanoparticles (LNPs). These LNPs consist of hydrophobic "core" lipids such as triolein surrounded by a monolayer of amphipathic "surface" lipids, such as phosphatidylcholine and polyethylene-glycol-lipid. It is shown that rapid, controlled mixing of HNPs, core lipids and surface lipids in an organic solvent with an aqueous phase resulted in stable, monodisperse LNPs containing HNPs (LNP-HNP). This method allows 40-fold more hydrophobic iron oxide nanoparticles (IONPs) to be entrapped within an LNP than previous methods and can be readily extended to encapsulate other HNPs. The LNP-HNP diameter can be modulated over the range of 35-150 nm by varying the flow rate during particle synthesis or by varying the core-to-surface lipid ratio. LNP-IONPs can be generated using a variety of "core" lipids, including other triglycerides as well as cholesteryl-palmitate and tocopherol. Finally, it is shown that LNP-IONPs are accumulated in the liver, resulting in enhanced contrast for in vivo MRI. It is concluded that the bottom-up approach for encapsulating HNPs within LNPs has advantages of homogeneity, reproducibility and stability required for biomedical applications. PMID- 28876011 TI - A study of the prebiotic-like effects of tomato juice consumption in rats with diet-induced non-alcoholic fatty liver disease (NAFLD). AB - Gut microbiota may play a role in the pathogenesis of NAFLD. We investigated whether tomato juice consumption for 5 weeks could ameliorate high-fat diet induced alterations in certain intestinal bacterial groups and products arising from their metabolism (short-chain fatty acids and microbial phenolic catabolites). For this, we used a rat model with NAFLD induced by a high-fat diet, involving four experimental groups: NA (standard diet and water), NL (standard diet and tomato juice), HA (high-fat diet and water) and HL (high-fat diet and tomato juice). The onset of NAFLD impacted the gut microbiota profile, reducing the abundance of Bifidobacterium and Lactobacillus and increasing that of Enterobacteriaceae. Also, reduced concentrations of propionate, butyrate and phenolic catabolites and an increased acetate to propionate (Ac : Pr) ratio were observed. Tomato juice intake partially ameliorated high-fat diet-induced disturbances, particularly by increasing Lactobacillus abundance and diminishing the Ac : Pr ratio, suggesting a potential improvement of the metabolic pattern of NAFLD. PMID- 28876012 TI - First-principles investigation of quantum emission from hBN defects. AB - Hexagonal boron nitride (hBN) has recently emerged as a fascinating platform for room-temperature quantum photonics due to the discovery of robust visible light single-photon emitters. In order to utilize these emitters, it is necessary to have a clear understanding of their atomic structure and the associated excitation processes that give rise to this single photon emission. Here, we performed density-functional theory (DFT) and constrained DFT calculations for a range of hBN point defects in order to identify potential emission candidates. By applying a number of criteria on the electronic structure of the ground state and the atomic structure of the excited states of the considered defects, and then calculating the Huang-Rhys (HR) factor, we found that the CBVN defect, in which a carbon atom substitutes a boron atom and the opposite nitrogen atom is removed, is a potential emission source with a HR factor of 1.66, in good agreement with the experimental HR factor. We calculated the photoluminescence (PL) line shape for this defect and found that it reproduces a number of key features in the experimental PL lineshape. PMID- 28876013 TI - Synthesis of lipo-chitooligosaccharide analogues and their interaction with LYR3, a high affinity binding protein for Nod factors and Myc-LCOs. AB - Lipo-chitotetrasaccharide analogues where one central GlcNAc residue was replaced by a triazole unit have been synthesized from a derivative obtained by chitin depolymerization and a functionalized N-acetyl-glucosamine via the copper catalyzed azide-alkyne cycloaddition. Their evaluation in a binding assay using LYR3, a putative lipo-chitooligosaccharide receptor in Medicago truncatula, shows a complete loss of binding. PMID- 28876014 TI - Tracking the restructuring of oxidized silver-indium nanoparticles under a reducing atmosphere by environmental HRTEM. AB - Multimetallic nano-alloys display a structure and consequently physicochemical properties evolving in a reactive environment. Following and understanding this evolution is therefore crucial for future applications in gas sensing and heterogeneous catalysis. In view hereof, the structural evolution of oxidized Ag25In75 bimetallic nanoparticles under varying H2 partial pressures (PH2) and substrate temperatures (Ts) has been investigated in real-time through environmental transmission microscopy (E-TEM) while maintaining the atomic resolution. Small Ag25In75 bimetallic nanoparticles, produced by laser vaporization, are found (after air transfer) to contain an indium-oxide shell surrounding a silver-rich alloyed phase. For high PH2 and Ts, the direct reduction of the indium oxide shell, immediately followed by the melting or the diffusion onto the carbon substrate of the reduced indium atoms, is found to be the dominant mechanism. This reduction is concomitant with the growth of the core, indicating a partial diffusion of indium atoms from the shell towards the particle volume. The "surviving" particles therefore consist of a silver-indium alloy, very stable and remarkably resistant against oxidation contrary to native clusters. Interestingly, in the (PH2, Ts) space, the transition from "soft" (core shell particles for low (PH2, Ts) values) to "strong" reduction conditions (silver-rich alloys for high (PH2, Ts) products) defines an intermediate domain where the preferred formation of Janus structures is detected. These results are discussed in terms of thermodynamic driving forces in relation to alloying and interface energies. This work shows the potential of high-resolution ETEM for unravelling the mechanisms of nanoparticle reorganization in a chemically reactive environment. PMID- 28876015 TI - Molecular attochemistry in non-polar liquid environments: ultrafast charge migration dynamics through gold-thiolate and gold-selenolate linkages. AB - Molecular attosecond science has already started contributing to our fundamental understanding of ultrafast purely electron dynamics in isolated molecules under vacuum. Extending attosecond science to the liquid phase is expected to offer new insight into the influence of a surrounding solvent environment on the attosecond electron dynamics in solvated molecules. A systematic theoretical investigation of the attochemistry of solvated molecules would help one design attosecond experiments under ambient conditions to explore the attochemistry in a liquid environment. With this goal in mind, for the first time, we have explored the attochemistry of molecules surrounded by different non-polar solvent environments. For this work, we have focused on the attosecond charge conduction through gold-thiolate and gold-selenolate linkages following the vertical ionization of the S/Se(CH3)-CH2-phenyl-X unit anchored to a gold dimeric cluster (Au2), where X represents either a strong electron donating N(CH3)2 group or a strong electron withdrawing NO2 group. To model solvation effects on the attochemistry of molecules containing gold-chalcogen linkages, we have used an implicit solvent model (Polarizable Continuum Model) under the density functional theory (DFT) formalism for non-polar solvents. We have found that the charge migration time scale in molecules becomes faster in the presence of the solvent environment as compared to that under vacuum. Charge oscillation does not damp quickly in molecules surrounded by the solvent environment as compared to that under vacuum. Furthermore, the direction of the charge migration may change in molecules when they are surrounded by the solvent environment as compared to that under vacuum. Thus, the present work has laid the foundation, for the first time, for thinking of the attochemistry into the realm of liquids. PMID- 28876017 TI - Catalyst-free synthesis of 3-sulfone nitrile from sulfonyl hydrazides and acrylonitrile in water. AB - A novel catalyst-free sulfonation reaction for synthesizing 3-sulfone nitrile compounds from sulfonyl hydrazides and acrylonitriles in water, without any metal catalyst, ligand or organic solvent, was demonstrated. This catalyst-free protocol provides a new synthetic method for the construction of 3-sulfone nitrile compounds with excellent yields. The D2O experiment adequately proved that the catalyst-free sulfonation reaction occurs via a Michael addition mechanism and that the hydrogen of 3-sulfone nitrile comes from water. PMID- 28876016 TI - Bioaccumulation of hexachlorobutadiene in pumpkin seedlings after waterborne exposure. AB - Hexachlorobutadiene (HCBD) has been listed as a persistent organic pollutant (POP) in the Stockholm Convention, and is now drawing more and more research interest. However, the understanding of its bioaccumulation, especially in plants, is still very limited. In this work, the behavior of HCBD in aqueous solution and pumpkin seedlings was studied through in-lab hydroponic exposure experiments. It was found that 69% of HCBD volatilized from water to the atmosphere after one day of exposure, and only 1% remained in the solution after four days. This high volatility might be the main cause of the low HCBD levels in aqueous environments. Although a great amount of HCBD volatilized into the atmosphere, only a small proportion of airborne HCBD was captured by the leaves and stems of the blank pumpkin seedling controls. The translocation of HCBD from the leaves to the bottom roots, as well as its release from the roots into the water, was detected. For the exposure groups, the pumpkin seedlings absorbed HCBD from both the hydroponic solution and the air via the roots and leaves, respectively. The concentration of HCBD in the exposed pumpkin roots linearly increased with the continuous addition of HCBD into the exposure system. Upward translocation from the roots to the leaves and downward translocation from the leaves to the roots existed simultaneously in the exposed pumpkin seedlings. However, the concentrations of HCBD in the leaves, stems and roots in the exposure group were much higher than those of the blank plant controls, suggesting little contribution from the airborne HCBD in the hydroponically exposed pumpkin seedlings. The lipid content did not show obvious effects on the bioaccumulation and biodistribution of HCBD in the pumpkin seedlings, indicating that the translocation of HCBD within the pumpkin seedlings might be an active process. This study provided new findings on the environmental behavior of HCBD, which will be helpful for understanding the exposure risks. PMID- 28876018 TI - Gold-catalyzed intramolecular cyclization/condensation sequence: synthesis of 1,2 dihydro[c][2,7]naphthyridines. AB - An efficient gold-catalyzed synthetic protocol for the construction of 1,2 dihydro[c][2,7]naphthyridines from 2-aminophenyl prop-2-yn-1-yl enaminones has been developed. In this organic transformation new C-C and C-N bond formations occur via 6-endo-dig cyclization and condensation. 1,2 Dihydro[c][2,7]naphthyridine derivatives were obtained in good to excellent yields in a one-pot synthesis at ambient temperature. PMID- 28876019 TI - Cerium-catalyzed, oxidative synthesis of annulated, tetrasubstituted dihydrofuran derivatives. AB - Densely functionalized, annulated dihydrofuran derivatives are prepared by a cerium-catalyzed aerobic oxidation reaction. The operationally simple transformation is environmentally and economically benign, since the precatalyst CeCl3.7H2O is non-toxic and inexpensive and the oxidant is simply dioxygen from air. Starting materials are beta-oxoesters and silylenolethers, and the latter are derived from acetoacetate or acetylacetone. The reaction sequence is performed in one flask and consists of alpha-oxidation and Mukaiyama aldol reaction. Apart from tetrahydrocyclopenta[b]furan derivatives one example of a tetrahydrofuro[3,4-b]furan and one tetrahydro-3aH-furo[2,3-c]pyrrole derivative are prepared. PMID- 28876020 TI - Photophysics of N,N-dimethyl-3-(1-indolyl)propan-1-ammonium chloride and related derivatives. AB - The photophysical properties of two new indole derivatives have been examined by steady-state and dynamic spectroscopic methods. The ground-state structures and conformations of 3-(1-indolyl)-N,N-dimethylpropan-1-ammonium chloride (InCl) and 3-(1-indolyl)-N,N,N-trimethylpropan-1-ammonium chloride (MeInCl) have been examined through density functional theory calculations. These calculations reveal a preference for a 'closed' conformation which places the cationic ammonium group in proximity to the pi-electron cloud in low polarity environments. This interaction is best described as an intramolecular hydrogen-pi bond in the case of InCl and a cation-pi interaction for MeInCl. The ground-state conformational equilibria are influenced by changes in the dielectric constant of the solvent, resulting in a variety of photophysical behaviors. The excitation/emission spectra, fluorescence quantum yields, and excited-state lifetimes, are reported for InCl, MeInCl, and a reference compound, 1 methylindole, in 1,4-dioxane (epsilon = 2), acetonitrile (epsilon = 37), and water (epsilon = 78) where solubility allows. Data from these solvents provide evidence for independent fluorescence quenching pathways for InCl and MeInCl. In addition, they lead to insights into the complexities of indole photophysics by demonstrating the sensitivity of the locally-excited states to changes in charge density and solvent environment. PMID- 28876021 TI - First principles study of the Mn-doping effect on the physical and chemical properties of mullite-family Al2SiO5. AB - Transition metal (TM) modification is a common strategy for converting an earth abundant mineral into a cost-effective catalyst for industrial applications. Among a variety of minerals, Al2SiO5, which has three phases, andalusite, sillimanite and kyanite, is emerging as a promising candidate for new catalyst development. In this paper, we use Mn to demonstrate the rationale of 3d TM doping at the Al sites in each of these three phases through first-principles calculations and the cluster expansion method. The results of cluster expansion show that Mn has a strong site preference for the six-coordinated Al octahedral chains in the andalusite and sillimanite phases, while distributing randomly in the kyanite phase. Moreover, Mn can only replace Al in sillimanite and kyanite in low concentrations; however, higher concentrations of Mn can replace Al in andalusite. We found that the concentration sensitivity is due to the Jahn-Teller distortion and 3d orbital splitting. This finding can also explain the low doping concentrations of other 3d TMs (Fe, Cr and V) in Al2SiO5 compounds. Based on the calculated Helmholtz free energy, we constructed a (MnxAl1-x)AlSiO5 temperature composite phase diagram, which explains the physical mechanisms behind the results for 3d transition metal doping and phase transitions in Al2SiO5. This work could shed light on the related physics, chemistry, and geoscience of (MnxAl1-x)AlSiO5, and more importantly, a design rationale for the engineering of cheap catalysts. PMID- 28876022 TI - Shape and size dependent nonlinear refraction and absorption in citrate stabilized, near-IR plasmonic silver nanopyramids. AB - Using a combination of a mild stabilizer and a mild reductant, sodium citrate and hydrazine hydrate, anisotropic silver nanocrystals (NCs) were synthesized with tunable plasmon peaks at 550 nm, 700 nm, 800 nm, 900 nm and 1010 nm (the samples are named Ag-550, Ag-700, Ag-800, Ag-900 and Ag-1010, respectively). TEM investigations revealed that Ag-550 NCs were pentagonal nanoplates while the other four samples were nanopyramids with a pentagonal base with the edge length varying between 15 and 30 nm. The non-linear optical (NLO) properties of these NCs were studied by the Z-scan technique using the CW He-Ne laser (632.8 nm, 15 mW). The shape change from 2D nanoplates (Ag-550) to 3D nanopyramids (Ag-700) resulted in sign reversal of the non-linear refractive index, n2, from a negative (-3.164 * 10-8 cm2 W-1) to a positive one (1.195 * 10-8 cm2 W-1). This corresponds to a change from a self-defocussing effect to a self-focussing one. Besides shape, the size effect is also prominently observed. Amongst nanopyramids, as the edge length increases, n2 increases linearly and reaches a maximum of 3.124 * 10-8 cm2 W-1. Doubling the edge length from 15 nm to 30 nm resulted in 162% increase in n2. On moving from Ag-550 to Ag-900 NCs, with the increasing plasmon wavelength, the non-linear absorption (NLA) coefficient increased exponentially to a high value of 8.52 * 10-4 cm W-1. However, Ag-1010 showed 29% decrease in NLA which is attributed to twinning present in the crystal structure as seen in the HR-TEM images. Due to the tunable NLO properties, these anisotropic Ag NCs hold great potential for applications in optical limiting, switching and data storage. PMID- 28876023 TI - Finite size effects of ionic species sensitively determine load bearing capacities of lubricated systems under combined influence of electrokinetics and surface compliance. AB - The behaviour and health of lubricated systems in various natural and artificial settings are often characterized by their load bearing capacity. This capacity stemming from the lift force associated with confined fluid flow can be significantly altered due to surface compliance and electrokinetic effects. Here, we highlight the influence of finite size of the ionic species participating in electrokinetic transport with substrate compliance in determining the electromechanical characteristics of lubricated systems. With these new considerations, anomalous trends previously observed for the load bearing capacity corresponding to high values of zeta potential are corrected. Simultaneously, trends associated with the finite ionic size are also found to be reversed, but fall in line with the consistent theory. Importantly, despite an intricate interplay among the various influences - electrokinetic, hydrodynamic, geometric, and elastic - previously established trends due to geometric (non parallel slider geometry) and elastic effects are found to persist. Specifically, in the presence of electrokinetic effects, an increase in the obliqueness of the slider geometry results in lower values of load bearing capacity while an increase in the stiffness leads to higher values. These results point to a certain robustness in the overall theory and it is hoped that they can contribute to better practical designs of slider bearings and an improved understanding of lubricated sliding surfaces in biological settings. PMID- 28876024 TI - Direct diversification of unmasked quinazolin-4(3H)-ones through orthogonal reactivity modulation. AB - Here we report a set of direct functionalization methods of unmasked 2 phenylquinazolin-4(3H)-ones, a privileged alkaloid core, without the installation/removal event of protecting groups or exogenous coordinating moieties. Divergent pathways were modulated with transition-metal catalysts by suppressing competitive reactivities, leading to N-arylation, annulative pi extension, or C-H fluorination. PMID- 28876025 TI - Progress towards the broad use of non-peptide synthetic macrocycles in drug discovery. AB - We discuss progress towards addressing three key questions pertaining to the design of screening libraries of synthetic non-peptidic macrocycles (MCs) for drug discovery: What structural and physicochemical properties of MCs maximize the likelihood of achieving strong and specific binding to protein targets? What features render a protein target suitable for binding MCs, and can this information be used to identify suitable targets for inhibition by MCs? What properties of synthetic MCs confer good pharmaceutical properties, and particularly good aqueous solubility coupled with passive membrane permeability? We additionally discuss how the criteria that define a meaningful MC screening hit are linked to the size of the screening library and the synthetic methodology employed in its preparation. PMID- 28876026 TI - [Advances in platform compounds and polymers from vegetable oils]. AB - Vegetable oil is one of the most potential alternatives of petroleum and has become a hot issue in recent years. This review focuses on the influence of vegetable oil structure on platform compounds and polymers properties, and further systematically introduces their developments and the latest progress. Meanwhile, we also summarized the main confronting problems and the future development directions in the research of oil-based platform compounds and polymers. The review provides useful information for readers to fully understand biochemical engineering of vegetable oils and their prospects. PMID- 28876027 TI - [Detection of toxic substances in microbial fuel cells]. AB - Microbial fuel cells (MFCs) is a highly promising bioelectrochemical technology and uses microorganisms as catalyst to convert chemical energy directly to electrical energy. Microorganisms in the anodic chamber of MFC oxidize the substrate and generate electrons. The electrons are absorbed by the anode and transported through an external circuit to the cathode for corresponding reduction. The flow of electrons is measured as current. This current is a linear measure of the activity of microorganisms. If a toxic event occurs, microbial activity will change, most likely decrease. Hence, fewer electrons are transported and current decreases as well. In this way, a microbial fuel cell based biosensor provides a direct measure to detect toxicity for samples. This paper introduces the detection of antibiotics, heavy metals, organic pollutants and acid in MFCs. The existing problems and future application of MFCs are also analyzed. PMID- 28876028 TI - [Program optimization before enucleation on ovine somatic cell nuclear transfer]. AB - Ovine somatic cell nuclear transfer (SCNT) efficiency remains lower. Therefore, we optimized the program before oocyte enucleation on ovine SCNT. Four experiments were done including exposure duration of ovaries (3 h or 3 to 5 h), duration of oocytes maturation (18 h and 24 h), rate of donor adherent and enucleation time of maturate oocyte. The maturation rates of oocyte, fusion rates and cleavation rates of cloned embryos were used to assess the efficiency of different procedures. The maturation rates of ovaries with 3 h exposure was higher than that of 3 to 5 h (60.18% vs 52.50%) (P<0.05). Embryonic development competence had no significant difference (P>0.05). The maturation rates were significantly different between group18 h and 24 h (53.81% vs 89.06%, P<0.01). Embryonic development competence had no significant difference (P>0.05); fusion rates of donor adherent 30% group was higher than that of 10% group. Embryonic development competence had no significant difference (P>0.05). Different adherent donor characterizes the difference in plateau phase. The cleavation rates of 18 hpm group was higher than that of 16 hpm group. Embryonic development competence had no significant difference (P>0.05), the enucleation of 16 hpm group obtained one clone fetus, we got four clone fetus to repeat the 16 hpm group. Five microsatellite was analyzed by PAGE, the bands indicated that fingerprint of cloned fetus were completely the same as those of donor cells. Our data therefore suggests program optimization before enucleation assurance quality of material which be able to improve the quantity and quality of clone embryos, and optimized scheme can obtain clone sheep offspring. PMID- 28876029 TI - [Bioassay-guided isolation of functional components from hot water extract of Chlorella pyrenoidosa]. AB - The main functional ingredients of hot water extract of Chlorella pyrenoidosa (CPE) were investigated through a bioassay-guided fractionation based on free radical scavenging and macrophage proliferation effects. The main functional ingredients of CPE were polysaccharides (PS) that were isolated by high pressure extraction, Sevag method, ethanol precipitation and ultrafiltration separation. Crude polysaccharides were further separated and purified by ion exchange chromatography DEAE52 and size exclusion chromatography Sephadex G-100. The purified fractions were analyzed by gel permeation chromatography. Molecular weights of the purified fractions PS-1-4-2, PS-1-3-2 and PS-2-3-3 were 3.97*104, 2.28*104 and 4.1*103 Da, respectively. Bioassay-guided fractionation results indicated that CPE could remove free radicals and promote Ana-1 cells proliferation, mainly due to its various components working together. The components of free radicals scavenging mainly concentrated in PS-1-3, PS-1-4, PS 2-3 and PS-2-4. The components of Ana-1 proliferation mainly concentrated in PS-1 3, PS-1-4 and PS-2-3. This study established the activity screening method of main functional component from CPE, and got three new functional ingredients. It can be used to guide the development of high value products, further promote the industrialization process of microalgae energy, and realize microalgae 'high value products, microalgae energy and microalgae carbon' integration of exemplary role. PMID- 28876030 TI - [Overexpression and characterization of endo-cellulase A10 from Aspergillus nidulans in Pichia pastoris]. AB - Endo-cellulases are important to efficiently hydrolyze cellulose, and widely used in biotechnology. In this study, we overexpressed and characterized an endo cellulase from Aspergillus nidulans. This endo-cellulase was successfully overexpressed in flasks and fermentor, and its concentration in fermentor reached 0.89 mg/mL. The optimal pH and temperature of the were 4.0 and 80 C respectively, and it was very stable between pH 2.0 and 12.0. It was thermally stable below 60 C, whereas it was inactivated very quickly above 70 C. Its CMCase activity could be enhanced by Co2+, Mn2+ and Fe2+, whereas it was inhibited by Pb2+, Ni2+ and Cu2+. Therefore, this endo-cellulase exhibited good pH stability and thermostability below 60 C, and has the potential as commercial enzymes. PMID- 28876031 TI - [Breeding of peanut variety Yuhua 4 by in vitro mutagenesis]. AB - The embryonic leaflets of peanut (Arachis hypogaea) variety Huayu 20 were used as explants and pingyangmycin as a mutagen to induce somatic embryos. Four weeks after the inoculation, the survived explants were transferred to somatic embryo germination medium containing screening reagent hydroxyproline, and finally 15 regenerated plants were obtained. Pedigree breeding method was used during the following selection breeding, and three lines with significantly increased yield and 23 lines with high oil content were obtained from these mutant offsprings. The line with both high yield and high oil content has passed peanut variety multi-location in Anhui province and was named "Yuhua 4". Its yield was 16.63% higher than that of the control variety Baisha 1016, ranking the first in all the testing varieties. Yuhua 4 showed the characteristics of early maturity, small pod and high oil content. The oil content of kernels was 56.10%, higher than that of original parent Huayu 20 with 49.50% oil content, tested by the Ministry of Agriculture of Oil and Products Quality Supervision, Inspection and Test Center (Wuhan), and the yield was 15% higher than that of Huayu 20. It was concluded that in vitro mutagenesis and target screening was an effective way on creating new germplasm and breeding new variety in peanut. PMID- 28876032 TI - [Efficient identification of gene knockout mutant mediated by CRISPR/Cas9 by CELI crude extracts]. AB - CRISPR/Cas9, emerged as an efficient and powerful gene editing technology, has become the mainstream genome editing technology. Constructing mutants using CRISPR/Cas9 system is of great significance to the functional study and breeding application of useful genes. As the basis of the technology, a method for identification of mutation with efficiency and lower cost is needed. In this report, we studied the factors influencing mutation detected by CEL I crude extracts, such as the amount of protein, enzyme incubation time, PCR buffers. Under the optimized conditions, we can integrate the mutation detection steps into one-tube reaction. We used this system to examine the mutation types and frequency of rice stn1 mediated by CRISPR/Cas9. We also used this method to identify different mutation types including homozygous, heterozygous and bi allelic mutations. The accuracy of this method reached 100% verified by sequencing. Altogether, our results showed that using CELI crude extracts was an efficient and low cost method for identification of CRISPR/Cas9 mediated mutation. PMID- 28876033 TI - [High-level expression and characterization of Selenomonas ruminantium beta xylosidase in Pichia pastoris]. AB - beta-xylosidase (EC 3.2.1.37) is an important part of the xylanolytic enzymes system. In the present research, beta-xylosidase gene Sxa derived from Selenomonas ruminantium was expressed in Pichia pastoris GS115. According to the codon bias and rare codons of P. pastoris, mRNA secondary structure and GC content, Sxa gene was optimized. The optimized full-length gene mSxa was obtained by gene synthesis technique and the recombinant yeast expression vector pPIC9K mSxa was constructed. After being digested by restriction enzyme BglII, the mSxa gene was transformed into P. pastoris GS115. Then, phenotype and geneticin G418 resistance screening, and PCR were adopted to identify the positive transformants. Finally, the recombinant P. pastoris GS115-pPIC9K-mSxa was obtained. Based on enzymatic activity assay, a high-level expression clone was picked up and then the enzymatic characteristics of the recombinant beta xylosidase were studied. The results showed that the molecular weight of the mSxa expressed in P. pastoris G115 was about 66 kDa. The maximum activity was achieved 287.61 IU/mL at fermenter level. Enzymatic characterization showed the beta xylosidase was stable between 40 C and 60 C, and pH between 5.0 and 7.0. The optimal reaction temperature and pH were 55 C and 6.0, and preferentially degrading the beta-xylose glycosidic bond. The enzymatic activity was activated by Mn2+ and Ca2+, and inhibited by Fe3+, Cu2+, Co2+, Mg2+, EDTA and SDS. The study indicates that the modified beta-xylosidase gene mSxa from Selenomonas ruminantium can express successfully with high activity in P. pastoris. The study lays a foundation for further industrial application of the beta-xylosidase. PMID- 28876034 TI - [Purification, characterization and partial primary structure analysis of rutin degrading enzyme in tartary buckwheat seeds]. AB - Rutin-degrading enzymes (RDE) can degrade rutin into poorly water soluble compound, quercetin, and cause the bitter taste in tartary buckwheat. In the present study RDE from Yu 6-21 tartary buckwheat seeds was purified by ammonium sulphate precipitation, followed by hydrophobic interaction chromatography on Phenyl Sepharose CL-4B, ion exchange chromatography on CM-Cellulose and gel filtration chromatography on Sephadex G-150. Purified RDE showed single band with molecular weight of 66 kDa on SDS-PAGE. The optimum pH and temperature of RDE were 5.0 and 50 C respectively. The Km was 0.27 mmol/L, and the Vmax was 39.68 U/mg. The RDE activity could be inhibited by Cu2+, Zn2+, Mn2+ and EDTA, and showed tolerance to 50% methanol (V/V). The N terminal sequence (TVSRSSFPDGFLFGL) was obtained by Edman degradation method and 15 internal peptide sequences were determined by MALDI-TOF-MS (matrix-assisted laser desorption ionization time of flight mass spectrometry). These results established the foundations for identification of the candidate gene of RDE via transcriptome data and further studying RDE biological function. PMID- 28876035 TI - [Separation, purification and antioxidant activity of polysaccharide from Coprinus comatus]. AB - We compared the ways of deproteinization for crude polysaccharides of Coprinus comatus, and finally selected Sevage method as the optimal method. Two main fractions of Ccp-I-A and Ccp-I-B were obtained after DEAE-52 cellulose and Sephadex G-200 chromatography, both were white-floc, soluble in water, insoluble in absolute ethyl alcohol, acetone and other organic solvents. Additionally, Fehling reagent, CTAB, Sulphuric acid-carbazole, I-KI and FeCl3 reaction were all negative. GC analysis showed Ccp-I-A was composed of mannitose, glucose and galactose in molar ratios of 2.03:9.52:1, whereas Ccp-I-B was composed of fucose and galactose with molar ratios of 1:5.21. Antioxidant activity test showed that Ccp-I-A and Ccp-I-B had good scavenging abilities on DPPH and .OH. Compared to Ccp-I-B,the scavenging activity of Ccp-I-A was much stronger, and the scavenging rate could reach 72.1% and 55.3% respectively when the concentration was 300 MUg/mL. PMID- 28876036 TI - [Rapid cryopreservation for Siraitia grosvenorii cells based on cells' capacitance detection]. AB - A rapid quantitative evaluation method for Siraitia grosvenorii cells was successfully developed based on plant cells' capacitance value detected by a viable cell mass monitor and the cryopreservation of S. grosvenorii suspension cells was optimized. The survival rate of S. grosvenorii cells was quantitatively measured by viable cell mass monitor and 2, 3, 5-triphenyltetrazolium chloride (TTC). An optimum cryoprotectant recipe is that the growth medium contained 10% sucrose and 10% DMSO. The experimental results also showed higher cell survival rates and cell viabilities were achieved when suspension cells were treated with pretreatment of 0.2 mol/L sucrose. With the increase of concentration of sucrose, however, the cell survival rate was decreased. And the cell survival rate represented a bell shape with the increase of pretreatment time. The highest cell survival rate and cell viability were obtained with the 9 h' s pretreatment. In addition, there was a good correlation between the cell survival rate measured by cell recovery test and that measured by viable cell mass monitor, while there were no significant differences in the cell morphology and the ability of mogrosides V production by S. grosvenorii cells cultured in suspension after cryopreservation. Therefore, the evaluation method developed based on the viable cell mass monitor has good feasibility and reliability. PMID- 28876038 TI - [Preparation of catalitaxol-deficient defective strains by using ultraviolet mutagenesis]. AB - Secondary metabolites of endophytic fungi FSN002 from Juglans mandshurica Maxim have excellent liver cancer resistance. Preparation of mutant strains is an important means to study the biosynthesis mechanism of catalitaxol. Fungal spores germinating young hyphae with 4 to 6 cells after culturing for 13 hours were used as starting materials of ultraviolet (UV) mutagenesis. UV light intensity and irradiation time have a linear relationship with fungal mortality. The two factors had no obvious interactions. When UV light was 90 000 MUJ/cm2 and irradiation time for 6 s, the mortality of fungi was around 95%. Under the optimization mutation condition, two mutant strains were obtained, of which one lost the synthesis ability of catalitaxol completely, and the another synthetized only 16% catalitaxol of the wild strain. Our findings may serve basis for further study on the biosynthesis mechanism and efficient production of catalitaxol. PMID- 28876037 TI - [Expression, purification, stability and transduction efficiency of GST-SOD1-R9 fusion protein]. AB - The fusion of cell permeable peptide TAT and bifunctional antioxidant enzymes, GST (Glutathione sulfur transferase)-TAT-SOD1 (Cu, Zn superoxide dismutase), is an intracellular superoxide scavenger. Compared with SOD1-TAT, GST-TAT-SOD1 has better protective effect on oxidative damage but less transduction efficiency. A novel cell permeable bifunctional antioxidant enzymes with the fusion of GST, SOD1 and polyarginine R9 was constructed for higher transduction efficiency. The full nucleotide sequence of SOD1-R9 was synthesized and inserted into the prokaryotic expression vector pGEX-4T-1 with the GST tag. After the successful construction of the prokaryotic expression vectors of GST-SOD1-R9, the recombinant vector was then transformed into Escherichia coli BL21 (DE3) and the GST-SOD1-R9 fusion protein was produced with the induction of IPTG. The soluble expression of GST-SOD1-R9 fusion protein was combining with the induction temperature and time. The best soluble expression was obtained with the induction temperature of 25 C and the induction time of 11 h. The fusion protein was purified through the combination of 80% ammonium sulfate precipitation and affinity chromatography using glutathione agarose, and verified by SDS-PAGE and special enzymatic activity. The thermal and pH stability of GST-SOD1-R9 fusion protein were analyzed and the SOD and GST activity of fusion protein were proved to be well maintained under physiological conditions. Finally, the transduction efficiency of GST-SOD1-R9 fusion protein was proved to be better than GST-TAT SOD1 fusion protein (P<0.05). These works establish a foundation for further study of the protective effect of GST-SOD1-R9 fusion protein against oxidative damage. PMID- 28876039 TI - [Enhancing hRANKL production in Escherichia coli by optimizing culture conditions and lysing program]. AB - RANKL/RANK/OPG axis is important in bone metabolism regulation, and becomes a popular research area in bone diseases. RANKL is a critical part of RANKL/RANK/OPG axis, and widely required in bone metabolism research. However, the yield of recombinant soluble human RANKL (hRANKL) in Escherichia coli is much lower than mouse RANKL (mRANKL). In this study, by adjusting and stabilizing the pH value of LB medium at 7.5, lowering the inducing temperature to 16 C and optimizing the lysis program, the yield of soluble hRANKL increased by approximately 5 to 12-fold over the non-adjusted group. Our experiment effectively enhanced soluble hRANKL expression in E. coli and might constitute a meaningful attempt to obtain soluble expression of recombinant protein in E. coli. PMID- 28876040 TI - [Secreted expression of Japanese encephalitis virus prME in Pichia pastoris and immunogenicity evaluation of the virus-like particles in mice]. AB - The study was to express prME protein of Japanese encephalitis virus (JEV) in Pichia pastoris and then to evaluate the immunological properties of the recombinant protein in mice, so as to explore a new way for subunit vaccine development of JEV. The JEV prME gene was amplified by RT-PCR with genome RNA of JEV vaccine strain SA14-14-2 and subcloned into pPICZa-A vector, designated as pPICZalpha-prME. pPICZalpha-SprME was constructed same as pPICZalpha-prME besides with the additional 19 Aa signal peptides coding gene of the JEV cap protein C terminal. The linearized expression vector was integrated into the genome of Pichia pastoris X33 under the control of the alcohol oxidase (AOX1) promoter and induced with methanol during fermentation expression. The expression of JEV prME protein was identified by SDS-PAGE and Western blotting, and then it was purified by S-400 High Resolution HiPrep 16/60 Sephacry. The expressed products of Pichia pastoris were visualized by electron microscopy. In the immunization test, four groups of four-week old female mice were immunized subcutaneously with different doses purified JEV prME protein with complete Freund's adjuvant at a volumetric ratio of 1:1 and a control group was injected with sterile PBS. 10 MUg/dose purified JEV prME protein mixing different doses nucleic acid adjuvant (Naa) was vaccinated in mice as the same mode. SDS-PAGE and Western blotting indicate that JEV prME was not cleaved between prM and E during secreted expression in Pichia pastoris. The purified recombinant prME was eluted in the first eluting peak which indicated that its molecular weight about 1*106 Da to 20*106 Da and may form a multimeric. Both the culture supernatant and the purified protein, examined by electron microscopy, we found to contain JEV virus like particles (VLPs) with diameters of 30-50 nm. The anti-JEV VLPs antibody titration reached peak at 3 wpi and still maintained in mice at 7 wpi inoculated with 10 MUg and 15 MUg prME. The strong antibody response was observed when the mice immunized with prME mixing nucleic acid adjuvant, which elicited high neutralizing antibody titer among 1:80 to 1:160. In conclusion, although JEV prME protein expressed in Pichia pastoris was not cleaved, which formed VLPs and showed efficient immunological properties in mice experiments. PMID- 28876041 TI - [Biocatalytic access to beta-alanine by a two-enzyme cascade synthesis]. AB - Enzymatic synthesis is an important way to produce beta-alanine, but the biological method is expensive generally because of the high price of substrate. In this paper, a two-step enzymatic cascade system was developed, combining L aspartase from Escherichia coli DH5alpha and L-aspartate alpha-decarboxylase from Corynebacterium glutamicum. This system catalyzes Fumarate and ammonia to beta alanine. The optimal ratio of AspA and PanD was 1:80 (W/W), and the concentration of AspA was 10 MUg/mL, at 37 C and pH 7.0. When the concentration of Fumarate was 100 mmol/L, the reaction reached its equilibrium after 8 h, and the yield of beta alanine was 90 mmol/L (7 g/L). The yield of beta-alanine can reach 126 mmol/L (9.8 g/L) when the concentration of Fumarate increased to 200 mmol/L. Extending reaction time, the conversion rate did not change obviously. Using this two-step enzymatic cascade system, beta-alanine from cheaper substrate Fumarate can be obtained. PMID- 28876042 TI - Graphene Oxide-Polycarbonate Track-Etched Nanosieve Platform for Sensitive Detection of Human Immunodeficiency Virus Envelope Glycoprotein. AB - Solid-state nanopores within graphene-based materials are on the brink of fundamentally changing the sensing of desired bioanalytes through ion trafficking across nanoporous membranes. Here, we report on a two-electrode electrochemical biosensor comprised of a graphene oxide-polycarbonate track-etched nanosieve platform for the rapid and sensitive detection of the Human Immunodeficiency Virus Type 1 (HIV-1) envelope glycoprotein ectodomain (gp140MS). We have covalently linked an engineered high-affinity one-domain soluble CD4 fused to a human domain targeting HIV-1 coreceptor binding site and ferrocene (Fc) (2Dm2m) to the nanosieve platform. An exponential decrease in the ionic current resulted from a partial blockade of the nanosieve due to the specific interactions of gp140MS with the 2Dm2m protein, which was immobilized on the nanosieve platform by biolinkage as a function of applied voltages of 0.1-2.0 V. There was no change in current when a nonspecific antigen bovine serum albumin was tested under identical conditions. This platform had high sensitivity, and when the receptor binding phenomenon was tested to identify the minimum concentration of target analyte, the lowest detection limit was as short as 8.3 fM and with sensitivity and response times of 0.87 mA mM-1 cm-1 and 12 s, respectively. In addition to this remarkable sensitivity, our nanobiorecognition platform has the advantage of superior stability due to the few layered graphene oxide laminates. It also exhibits exceptional biomolecule binding and higher reusability, sustainability, and ease of fabrication in a soft mechanism. Real samples of HIV positive and negative patients were successfully tested to confirm the virus by the developed platform. To the best of our knowledge, this is the first time prosperous pervious remembrance surface has been employed in a nanobiosensing application. In light of the recent great trend of using graphene-based nanopore surfaces created by sophisticated ion-beam methods in sensing and sequencing, this hybrid surface nanolayer fabricated by the simple vacuum filtration of a few layered graphene oxide laminates may serve as a good alternative in terms of ease of fabrication without expensive instrumental prerequisites. PMID- 28876043 TI - Solvent-Mediated Intragranular-Coarsening of CH3NH3PbI3 Thin Films toward High Performance Perovskite Photovoltaics. AB - The deposition of dense and uniform perovskite films with large grains is crucial for fabricating high-performance perovskite solar cells (PSCs). High-quality CH3NH3PbI3 films were produced by a self-induced intragranular-coarsening approach. The perovskite precursor solution contained a Lewis base, N,N-dimethyl sulfoxide (DMSO), and was deposited using a gas-assisted, one-step, spin-coating method that was followed by a solvent vapor-assisted annealing treatment using a mix of DMSO and chlorobenzene (CBZ). Combining solvent-engineering with gas assisted deposition helps to form intermediate crystalline entities upon evaporation of the parent solvent but retards the otherwise fast reaction between the precursor ingredients. Subsequent cosolvent annealing induces further grain coarsening via a facilitated dissolution-precipitation process. This technique produced flat CH3NH3PbI3 films featuring large grain microstructures, with well coarsened subgrains and a reduction of intragranular defects that minimized carrier recombination. The optimized CH3NH3PbI3 films exhibited enhanced crystallinity, excellent carrier transport and injection, as well as suppressed charge recombination. Benefiting from these advantages, PSCs based on the optimized perovskite films delivered a power conversion efficiency of 17.99% and a stabilized power output above 17.30%. This study presents an effective strategy for the fabrication of high-quality, hybrid perovskite films with potential applications in optoelectronic devices. PMID- 28876044 TI - High-Performance Nano-Photoinitiators with Improved Safety for 3D Printing. AB - In this work, we report the first hybrid nanosized photoinitiators with low cytotoxicity and migration by coupling of polyhedral oligomeric silsesquioxanes (POSS) to benzophenone derivatives. This new series of photoinitiators were fully characterized and showed many favorable properties such as uniform sizes, extremely low tendency to migrate, less effect on resin viscosity, enhanced thermal stability and mechanical strength, increased photoactivity, and significantly lower cell toxicity compared to their corresponding benzophenone molecules. The utility of these hybrid nanosized photoinitiators in 3D printing was demonstrated in printing of various 3D structures with high resolution and accuracy. PMID- 28876045 TI - Versatile Donor-pi-Acceptor-Type Aggregation-Enhanced Emission Active Fluorophores as Both Highly Efficient Nondoped Emitter and Excellent Host. AB - By employing triphenylamine (TPA) and/or carbazole as donor and cyano group as acceptor, three donor-pi-acceptor (D-pi-A)-type fluorophores, 4,6-di(4 (diphenylamino)phenyl)isophthalonitrile (DTPAIPN), 4-(4-(diphenylamino)phenyl)-6 (3,5-(9,9'-dicarbazolyl)phenyl)isophthalonitrile (TPAmCPIPN), and 4,6-di(3,5 (9,9'-dicarbazolyl)phenyl)isophthalonitrile (DmCPIPN), were designed, synthesized, and characterized for their thermal, photophysical, electrochemical, and electroluminescent properties. All three compounds exhibited excellent thermal and morphological stabilities with thermal decomposition (Td) and glass transition temperature (Tg) values ranging from 396 to 516 degrees C and from 114 to 211 degrees C, respectively. The investigation into the photophysical properties revealed the aggregation-enhanced emission (AEE) feature of these chromophores. The performances of the nondoped devices were significantly improved as compared to those of the doped devices, further confirming the AEE nature. In particular, DmCPIPN-based nondoped device rendered the maximum current efficiency (CE), power efficiency (PE), and external quantum efficiency (EQE) values of 26.6 cd A-1, 22.4 lm W-1, and 8.3%, respectively, in comparison with 9.1 cd A-1, 4.9 lm W-1, and 4.2% for the doped device. The versatility of these new luminogens was demonstrated through the utilization of them as host for highly efficient red phosphorescent organic light-emitting diodes (PHOLEDs). The EQE of the DmCPIPN-hosted device reached as high as 19.3% with a reduced efficiency roll-off of 10.3% at 1000 cd m-2. These results demonstrate that the new luminogens of this work can be used as both nondoped emitter and host for high-performance OLEDs, which facilitates the development of multifunctional materials for OLEDs applications. PMID- 28876046 TI - Electron Bifurcation: Thermodynamics and Kinetics of Two-Electron Brokering in Biological Redox Chemistry. AB - How can proteins drive two electrons from a redox active donor onto two acceptors at very different potentials and distances? And how can this transaction be conducted without dissipating very much energy or violating the laws of thermodynamics? Nature appears to have addressed these challenges by coupling thermodynamically uphill and downhill electron transfer reactions, using two electron donor cofactors that have very different potentials for the removal of the first and second electron. Although electron bifurcation is carried out with near perfection from the standpoint of energy conservation and electron delivery yields, it is a biological energy transduction paradigm that has only come into focus recently. This Account provides an exegesis of the biophysical principles that underpin electron bifurcation. Remarkably, bifurcating electron transfer (ET) proteins typically send one electron uphill and one electron downhill by similar energies, such that the overall reaction is spontaneous, but not profligate. Electron bifurcation in the NADH-dependent reduced ferredoxin: NADP+ oxidoreductase I (Nfn) is explored in detail here. Recent experimental progress in understanding the structure and function of Nfn allows us to dissect its workings in the framework of modern ET theory. The first electron that leaves the two-electron donor flavin (L-FAD) executes a positive free energy "uphill" reaction, and the departure of this electron switches on a second thermodynamically spontaneous ET reaction from the flavin along a second pathway that moves electrons in the opposite direction and at a very different potential. The singly reduced ET products formed from the bifurcating flavin are more than two nanometers distant from each other. In Nfn, the second electron to leave the flavin is much more reducing than the first: the potentials are said to be "crossed." The eventually reduced cofactors, NADH and ferredoxin in the case of Nfn, perform crucial downstream redox processes of their own. We dissect the thermodynamics and kinetics of electron bifurcation in Nfn and find that the key features of electron bifurcation are (1) spatially separated transfer pathways that diverge from a two-electron donor, (2) one thermodynamically uphill and one downhill redox pathway, with a large negative shift in the donor's reduction potential after departure of the first electron, and (3) electron tunneling and activation factors that enable bifurcation, producing a 1:1 partitioning of electrons onto the two pathways. Electron bifurcation is found in the CO2 reducing pathways of methanogenic archaea, in the hydrogen pathways of hydrogenases, in the nitrogen fixing pathway of Fix, and in the mitochondrial charge transfer chain of complex III, cytochrome bc1. While crossed potentials may offer the biological advantage of producing tightly regulated high energy reactive species, neither kinetic nor thermodynamic considerations mandate crossed potentials to generate successful electron bifurcation. Taken together, the theoretical framework established here, focusing on the underpinning electron tunneling barriers and activation free energies, explains the logic of electron bifurcation that enables energy conversion and conservation in Nfn, points toward bioinspired schemes to execute multielectron redox chemistry, and establishes a roadmap for examining novel electron bifurcation networks in nature. PMID- 28876047 TI - Recent Transport History of Fukushima Radioactivity in the Northeast Pacific Ocean. AB - The large inventory of radioactivity released during the March, 2011 Fukushima Dai-ichi nuclear reactor accident in Japan spread rapidly across the North Pacific Ocean and was first observed at the westernmost station on Line P, an oceanographic sampling line extending 1500 km westward of British Columbia (BC), Canada in June 2012. Here, time series measurements of 134Cs and 137Cs in seawater on Line P and on the CLIVAR-P16N 152 degrees W line reveal the recent transport history of the Fukushima radioactivity tracer plume through the northeast Pacific Ocean. During 2013 and 2014 the Fukushima plume spread onto the Canadian continental shelf and by 2015 and early 2016 it reached 137Cs values of 6-8 Bq/m3 in surface water along Line P. Ocean circulation model simulations that are consistent with the time series measurements of Fukushima 137Cs indicate that the 2015-2016 results represent maximum tracer levels on Line P and that they will begin to decline in 2017-2018. The current elevated Fukushima 137Cs levels in seawater in the eastern North Pacific are equivalent to fallout background levels of 137Cs that prevailed during the 1970s and do not represent a radiological threat to human health or the environment. PMID- 28876048 TI - Size Controllable and Surface Tunable Zeolitic Imidazolate Framework-8 Poly(acrylic acid sodium salt) Nanocomposites for pH Responsive Drug Release and Enhanced in Vivo Cancer Treatment. AB - Nanoscale size controllable and surface modifiable zeolitic imidazolate framework 8-poly(acrylic acid sodium salt) (ZIF-8-PAAS) nanocomposites are fabricated by employing PAAS nanospheres as a soft template. These ZIF-8-PAAS nanocomposites have different sizes ranging from 30 to 200 nm and exhibit different crystallinity, and pH sensitivity. These nanocomposites can be employed as vectors to deliver doxorubicin for anticancer therapy, leading to greatly enhanced drug therapeutic efficacy when tested in cell lines and mice model. Systematic toxicity investigation including hematoxylin and eosin staining analysis of tumor and major organs, hematology analysis, and blood chemistry analysis indicates that the nanocomposites possess high biocompatibility. This work provides a strategy to make metal-organic frameworks (MOFs) nanocomposites with size tunability in nanoscale and flexible surface modification for various applications. PMID- 28876049 TI - Periplasmic Binding Protein Dimer Has a Second Allosteric Event Tied to Ligand Binding. AB - The ligand-induced conformational changes of periplasmic binding proteins (PBP) play a key role in the acquisition of metabolites in ATP binding cassette (ABC) transport systems. This conformational change allows for differential recognition of the ligand occupancy of the PBP by the ABC transporter. This minimizes futile ATP hydrolysis in the transporter, a phenomenon in which ATP hydrolysis is not coupled to metabolite transport. In many systems, the PBP conformational change is insufficient at eliminating futile ATP hydrolysis. Here we identify an additional state of the PBP that is also allosterically regulated by the ligand. Ligand binding to the homodimeric apo PBP leads to a tightening of the interface alpha-helices so that the hydrogen bonding pattern shifts to that of a 310 helix, in-turn altering the contacts and the dynamics of the protein interface so that the monomer exists in the presence of ligand. PMID- 28876050 TI - A New Mechanism of Sediment Attachment to Oil in Turbulent Flows: Projectile Particles. AB - The interaction of oil and sediment in the environment determines, to a large extent, the trajectory and fate of oil. Using confocal microscope imaging techniques to obtain detailed 3D structures of oil-particle aggregates (OPAs) formed in turbulent flows, we elucidated a new mechanism of particle attachment, whereby the particles behave as projectiles penetrating the oil droplets to depths varying from ~2 to 10 MUm due to the hydrodynamic forces in the water. This mechanism results in a higher attachment of particles on oil in comparison with adsorption, as commonly assumed. The projectile hypothesis also explains the fragmentation of oil droplets with time, which occurred after long hours of mixing, leading to the formation of massive OPA clusters. Various lines of inquiry strongly suggested that protruding particles get torn from oil droplets and carry oil with them, causing the torn particles to be amphiphillic so that they contribute to the formation of massive OPAs of smaller oil droplets (<~5-10 MUm). Low particle concentration resulted in large, irregularly shaped oil blobs over time, the deformation of which without fragmentation could be due to partial coverage of the oil droplet surface by particles. The findings herein revealed a new pathway for the fate of oil in environments containing non-negligible sediment concentrations. PMID- 28876051 TI - Comprehensive Characterization of the Interaction between Pulsed Electric Fields and Live Cells by Confocal Raman Microspectroscopy. AB - This study reports a comprehensive analysis of the effect of 100 MUs electric pulses on the biochemical composition of live cells using a label-free approach, confocal Raman microspectroscopy. We investigated different regions of interest around the nucleus of the cells and the dose-effect relationship related to different electric pulse parameters. We also extended the study to another cell type. Membrane resealing was monitored by pulsing the cells in reversible or irreversible electropermeabilization condition at different temperatures. Our results confirmed a previous publication showing that proteins and lipids were highly impacted by the delivery of electric pulses. These chemical changes were similar in different locations around the cell nucleus. By sweeping the field magnitude, the number of electric pulses, or their repetition rate, the Raman signatures of live cells appeared to be related to the electropermeabilization state, verified by Yo-Pro-1 uptake. We also demonstrated that the chemical changes in the Raman signatures were cell-dependent even if common features were noticed between the two cell types used. PMID- 28876052 TI - The Phe-Ile Zipper: A Specific Interaction Motif Drives Antiparallel Coiled-Coil Hexamer Formation. AB - Coiled coils are a robust motif for exploring amino acid interactions, generating unique supramolecular structures, and expanding the functional properties of biological materials. A recently discovered antiparallel coiled-coil hexamer (ACC Hex, peptide 1) exhibits a unique interaction in which Phe and Ile residues from adjacent alpha-helices interact to form a Phe-Ile zipper within the hydrophobic core. Analysis of the X-ray crystallographic structure of ACC-Hex suggests that the stability of the six-helix bundle relies on specific interactions between the Phe and Ile residues. The Phe-Ile zipper is unprecedented and represents a powerful tool for utilizing the Phe-Ile interactions to direct supramolecular assembly. To further probe and understand the limits of the Phe-Ile zipper, we designed peptide sequences with natural and unnatural amino acids placed at the Phe and Ile residue positions. Using size exclusion chromatography and small angle X-ray scattering, we found that the proper assembly of ACC-Hex from monomers is sensitive to subtle changes in side chain steric bulk and hydrophobicity introduced by mutations at the Phe and Ile residue positions. Of the sequence variants that formed ACC-Hex, mutations in the hydrophobic core significantly affected the stability of the hexamer, from a DeltaGuw of 2-8 kcal mol-1. Additional sequences were designed to further probe and enhance the stability of the ACC-Hex system by maximizing salt bridging between the solvent exposed residues. Finally, we expanded on the generality of the Phe-Ile zipper, creating a unique sequence that forms an antiparallel hexamer that is topologically similar to ACC-Hex but atomistically unique. PMID- 28876053 TI - Development of Oxygen Consumption Analysis with an on-Chip Electrochemical Device and Simulation. AB - The O2 consumption rate of embryos has been attracting much attention as a key indicator of cell metabolisms and development. In this study, we propose an on chip device that enables the accurate, easy, and noninvasive measurement of O2 consumption rates of single embryos. Pt electrodes and micropits for embryo settlement were fabricated on Si chips via microfabrication techniques. The configuration of the device enables the detection of O2 concentration profiles surrounding the embryos by settling embryos into the pits with a mouth pipet. Moreover, as the detection is based on an electrochemical method, the influence of O2 consumption on the electrodes was also considered. By using a simulator (COMSOL Multiphysics), we estimated the O2 concentration profiles in the device with and without the effects of the electrodes. Based on the simulation results, we developed a normalization process to calculate the precise O2 consumption rate of the sample. Finally, using both the measurement system and the algorithm for the analysis, the respiratory activities of mouse embryos were successfully measured. PMID- 28876054 TI - Probing the Role of the Heme Distal and Proximal Environment in Ligand Dynamics in the Signal Transducer Protein HemAT by Time-Resolved Step-Scan FTIR and Resonance Raman Spectroscopy. AB - HemAT is a heme-containing oxygen sensor protein that controls aerotaxis. Time resolved step-scan FTIR studies were performed on the isolated sensor domain and full-length HemAT proteins as well as on the Y70F (B-helix), L92A (E-helix), T95A (E-helix), and Y133F (G-helix) mutants to elucidate the effect of the site specific mutations on the ligand dynamics subsequent to CO photolysis. The mutations aimed to perturb H-bonding and electrostatic interactions near the heme Fe-bound gaseous ligand (CO) and the heme proximal environment. Rebinding of CO to the heme Fe is biphasic in the sensor domain and full-length HemAT as well as in the mutants, with the exception of the Y133F mutant protein. The monophasic rebinding of CO in Y133F suggests that in the absence of the H-bond between Y133 and the heme proximal H123 residue the ligand rebinding process is significantly affected. The role of the proximal environment is also probed by resonance Raman photodissociation experiments, in which the Fe-His mode of the photoproduct of sensor domain HemAT-CO is detected at a frequency higher than that of the deoxy form in the difference resonance Raman spectra. The role of the conformational changes of Y133 (G-helix) and the role of the distal L92 and T95 residues (E helix) in regulating ligand dynamics in the heme pocket are discussed. PMID- 28876056 TI - Paramagnetism in Metallacarboranes: The Polyhedral Chromadicarbaborane Systems. AB - The chromadicarbaboranes CpCrC2Bn-3Hn-1 (8 <= n <= 12) are of interest in providing stable paramagnetic deltahedral metallaboranes among which the 12 vertex CpCrC2B9H11 has been synthesized by Hawthorne and co-workers. Density functional theory shows that the lowest-energy such structures are quartet spin state Cr(III) structures in which the central CrC2Bn-3 units exhibit most spherical closo deltahedral geometries similar to those found in the borane dianions BnHn2-. Higher-energy doublet CpCrC2Bn-3Hn-1 (8 <= n <= 11) structures are found exhibiting central CrC2Bn-3 isocloso deltahedral geometries, thereby providing a degree 6 vertex for the chromium atom. The lowest-energy CpCrC2Bn-3Hn 1 (8 <= n <= 11) structures all have both carbon atoms at degree 4 vertices. However, the lowest-energy CpCrC2B9H11 structures all have central CrC2B9 icosahedra and thus lack degree 4 vertices for the carbon atoms. For all of the CpCrC2Bn-3Hn-1 (8 <= n <= 12) systems the lowest-energy isomers are those with the maximum number of Cr-C edges in contrast to the related CpCoC2Bn-3Hn-1 systems. PMID- 28876055 TI - Supramolecular Assembly of Peptide Amphiphiles. AB - Peptide amphiphiles (PAs) are small molecules that contain hydrophobic components covalently conjugated to peptides. In this Account, we describe recent advances involving PAs that consist of a short peptide sequence linked to an aliphatic tail. The peptide sequence can be designed to form beta-sheets among the amino acids near the alkyl tail, while the residues farthest from the tail are charged to promote solubility and in some cases contain a bioactive sequence. In water, beta-sheet formation and hydrophobic collapse of the aliphatic tails induce assembly of the molecules into supramolecular one-dimensional nanostructures, commonly high-aspect-ratio cylindrical or ribbonlike nanofibers. These nanostructures hold significant promise for biomedical functions due to their ability to display a high density of biological signals on their surface for targeting or to activate pathways, as well as for biocompatibility and biodegradable nature. Recent studies have shown that supramolecular systems, such as PAs, often become kinetically trapped in local minima along their self assembly reaction coordinate, not unlike the pathways associated with protein folding. Furthermore, the assembly pathway can influence the shape, internal structure, and dimension of nanostructures and thereby affect their bioactivity. We discuss methods to map the energy landscape of a PA structure as a function of thermal energy and ionic strength and vary these parameters to convert between kinetically trapped and thermodynamically favorable states. We also demonstrate that the pathway-dependent morphology of the PA assembly can determine biological cell adhesion and survival rates. The dynamics associated with the nanostructures are also critical to their function, and techniques are now available to probe the internal dynamics of these nanostructures. For example, by conjugating radical electron spin labels to PAs, electron paramagnetic resonance spectroscopy can be used to study the rotational diffusion rates within the fiber, showing a liquidlike to solidlike transition through the cross section of the nanofiber. PAs can also be labeled with fluorescent dyes, allowing the use of super resolution microscopy techniques to study the molecular exchange dynamics between PA fibers. For a weak hydrogen-bonding PA, individual PA molecules or clusters exchange between fibers in time scales as short as minutes. The amount of hydrogen bonding within PAs that dictates the dynamics also plays an important role in biological function. In one case, weak hydrogen bonding within a PA resulted in cell death through disruption of lipid membranes, while in another example reduced hydrogen bonding enhanced growth factor signaling by increasing lipid raft mobility. PAs are a promising platform for designing advanced hybrid materials. We discuss a covalent polymer with a rigid aromatic imine backbone and alkylated peptide side chains that simultaneously polymerizes and interacts with a supramolecular PA structure with identical chemistry to that of the side chains. The covalent polymerization can be "catalyzed" by noncovalent polymerization of supramolecular monomers, taking advantage of the dynamic nature of supramolecular assemblies. These novel hybrid structures have potential in self-repairing materials and as reusable scaffolds for delivery of drugs or other chemicals. Finally, we highlight recent biomedical applications of PAs and related structures, ranging from bone regeneration to decreasing blood loss during internal bleeding. PMID- 28876057 TI - Hemilability of the 1,2-Bis(dimethylphosphino)ethane (dmpe) Ligand in Cp*Mo(NO)(kappa2-dmpe). AB - Reaction of Cp*Mo(NO)Cl2 with 1 equiv of 1,2-bis(dimethylphosphino)ethane (dmpe) in THF at ambient temperature forms [Cp*Mo(NO)(Cl)(kappa2-dmpe)]Cl (1), which is isolable as an analytically pure yellow powder in 65% yield. Further addition of 2 equiv of Cp2Co to 1 in CH2Cl2 affords dark red Cp*Mo(NO)(kappa2-dmpe) (2), which was isolated in 36% yield by recrystallization from Et2O at -30 degrees C. Reaction of a benzene solution of 2 with an equimolar amount of elemental sulfur results in the immediate production of dark blue (MU-S)[Cp*Mo(NO)(kappa1-dmpeS)]2 (3), which is a rare example of a bimetallic transition-metal complex bridged by only a single sulfur atom and involving Mo?S?Mo bonding. In contrast, reaction of 2 with an excess of sulfur in benzene results in the formation of Cp*Mo(NO)(eta2 S2)(kappa1-dmpeS) (4). Complex 4 can also be formed by the addition of elemental sulfur to 3, thereby indicating that 3 is a precursor to 4. Cp*Mo(NO)(kappa2 dmpe) (2) also undergoes interesting transformations when treated with organic bromides. For instance, reaction of 2 with 5 equiv benzyl bromide in THF produces the bimetallic complex (MU-dmpe)[Cp*Mo(NO)Br2]2 (5) and bibenzyl after 4 d at 70 degrees C probably via radical intermediates. In contrast to its reaction with benzyl bromide, complex 2 forms [Mo(NO)Br2(kappa2-dmpe)]2 (6), olefin, alkane, and Cp*H when treated with 5 equiv of 1-bromopropane or 1-bromooctane in THF at 70 degrees C for 72 h. Interestingly, complex 2 does not display any reactivity with bromobenzene or 1-bromoadamantane even after being heated for several days at 70 degrees C. All new complexes were characterized by conventional spectroscopic and analytical methods, and the solid-state molecular structures of most of them were established by single-crystal X-ray crystallographic analyses. PMID- 28876058 TI - Systematic Adjustment of Pitch and Particle Dimensions within a Family of Chiral Plasmonic Gold Nanoparticle Single Helices. AB - Systematically controlling the assembly architecture within a class of chiral nanoparticle superstructures is important for fine-tuning their chiroptical properties. Here, we report a family of chiral gold nanoparticle single helices, varying in helical pitch and nanoparticle dimensions, that is assembled using a series of peptide conjugate molecules Cx-(PEPAuM-ox)2 (PEPAuM-ox = AYSSGAPPMoxPPF; x = 16-22). We demonstrate that the aliphatic tail length (i) can be used as a handle to systematically tune the helical pitch from 80 to 130 nm; and (ii) influences the size, shape, and aspect ratio of the component nanoparticles. Certain members of this family of materials exhibit intense plasmonic chiroptical activity. These studies highlight the multiple levels of structural control that can be achieved within a class of chiral nanoparticle superstructures via careful design and selection of peptide conjugate precursor. PMID- 28876060 TI - Selective Molecular Separation by Interfacially Crystallized Covalent Organic Framework Thin Films. AB - Exponential interest in the field of covalent organic frameworks (COFs) stems from the direct correlation between their modular design principle and various interesting properties. However, existing synthetic approaches to realize this goal mainly result in insoluble and unprocessable powders, which severely restrict their widespread applicability. Therefore, developing a methodology for easy fabrication of these materials remains an alluring goal and a much desired objective. Herein, we have demonstrated a bottom-up interfacial crystallization strategy to fabricate these microcrystalline powders as large-scale thin films under ambient conditions. This unique design principle exploits liquid-liquid interface as a platform, allowing simultaneous control over crystallization and morphology of the framework structure. The thin films are grown without any support in free-standing form and can be transferred onto any desirable substrate. The porous (with Tp-Bpy showing highest SBET of 1 151 m2 g-1) and crystalline thin films, having high chemical as well as thermal stability, also hold the merit to tune the thickness as low as sub-100 nm. These nanostructured thin COF films demonstrate remarkable solvent-permeance and solute-rejection performance. A prominent instance is the Tp-Bpy thin film, which displays an unprecedented acetonitrile permeance of 339 L m-2 h-1 bar-1. PMID- 28876059 TI - Pentalinonsterol, a Constituent of Pentalinon andrieuxii, Possesses Potent Immunomodulatory Activity and Primes T Cell Immune Responses. AB - The use of natural products as adjuvants has emerged as a promising approach for the development of effective vaccine formulations. Pentalinonsterol (PEN) is a recently isolated compound from the roots of Pentalinon andrieuxii and has been shown to possess antileishmanial activity against Leishmania spp. The objective of this study was to examine the immunomodulatory properties of PEN and evaluate its potential as an adjuvant. Macrophages and bone-marrow-derived dendritic cells (BMDCs) were stimulated with PEN and tested for gene expression, cytokine production, and their ability to activate T cells in vitro. PEN was also evaluated for its ability to generate antigen-specific Th1 and Th2 responses in vivo, following ovalbumin (OVA) immunization using PEN as an adjuvant. The results obtained demonstrate that PEN enhances the expression of NF-kappaB and AP1 transcription factors, promotes gene expression of Tnfalpha, Il6, Nos2, and Arg1, and upregulates MHCII, CD80, and CD86 in macrophages. PEN also enhanced IL 12 production in BMDCs and promoted BMDC-mediated production of IFN-gamma by T cells. Further, mice immunized with OVA and PEN showed enhanced antigen-specific Th1 and Th2 cytokines in their splenocytes and lymph node cells, as well as increased levels of IgG1 and IgG2 in their sera. Taken together, this study demonstrates that PEN is a potent immunomodulatory compound and potentially can be used as an adjuvant for vaccine development against infectious diseases. PMID- 28876061 TI - Triggered Release from Lipid Bilayer Vesicles by an Artificial Transmembrane Signal Transduction System. AB - The on-demand delivery of drug molecules from nanoscale carriers with spatiotemporal control is a key challenge in modern medicine. Here we show that lipid bilayer vesicles (liposomes) can be triggered to release an encapsulated molecular cargo in response to an external control signal by employing an artificial transmembrane signal transduction mechanism. A synthetic signal transducer embedded in the lipid bilayer membrane acts as a switchable catalyst, catalyzing the formation of surfactant molecules inside the vesicle in response to a change in external pH. The surfactant permeabilizes the lipid bilayer membrane to facilitate release of an encapsulated hydrophilic cargo. In the absence of the pH control signal, the catalyst is inactive, and the cargo remains encapsulated within the vesicle. PMID- 28876062 TI - Modulation of Glycine-Mediated Spinal Neurotransmission for the Treatment of Chronic Pain. AB - Chronic pain constitutes a significant and expanding worldwide health crisis. Currently available analgesics poorly serve individuals suffering from chronic pain, and new therapeutic agents that are more effective, safer, and devoid of abuse liabilities are desperately needed. Among the myriad of cellular and molecular processes contributing to chronic pain, spinal disinhibition of pain signaling to higher cortical centers plays a critical role. Accumulating evidence shows that glycinergic inhibitory neurotransmission in the spinal cord dorsal horn gates nociceptive signaling, is essential in maintaining physiological pain sensitivity, and is diminished in pathological pain states. Thus, it is hypothesized that agents capable of enhancing glycinergic tone within the dorsal horn could obtund nociceptor signaling to the brain and serve as analgesics for persistent pain. This Perspective highlights the potential that pharmacotherapies capable of increasing inhibitory spinal glycinergic neurotransmission hold in providing new and transformative analgesic therapies for the treatment of chronic pain. PMID- 28876063 TI - Magnetic Interaction Affecting the Zero-Field Single-Molecule Magnet Behaviors in Isomorphic {NiII2DyIII2} and {CoII2DyIII2} Tetranuclear Complexes. AB - Great interest is being shown in investigating magnetic interactions that efficiently influence lanthanide single-molecule magnet behavior. A series of heterometallic complexes [M2Ln2(Hhms)2(CH3COO)6(CH3OH)2(H2O)2].(NO3)2 (M = NiII, Ln = DyIII (1), GdIII (2), and YIII (3); M = CoII, Ln = DyIII (4), GdIII (5), and YIII (6)) have been prepared with a compartmental Schiff-base ligand, 1-(2 hydroxy-3-methoxybenzylidene)-semicarbazide (H2hms), featuring a zigzag-shaped MII-LnIII-LnIII-MII metallic core arrangement. In complexes 1-6, a unique monophenoxo/diacetate asymmetric bridging connects MII ion with LnIII ion, and four acetates bridge two LnIII ions where acetates play essential roles as coligand in generating the tetranuclear units. Magnetic studies reveal the presence of predominant ferromagnetic coupling in DyIII and GdIII derivatives, and slow relaxation of magnetization is observed for {Ni2IIDy2III} and {CoII2DyIII2} with an energy barrier of 16.0 K for {Ni2IIDy2III} and 6.7 K for {CoII2DyIII2} under zero static field. Compared with the analogue {CoII2DyIII2}, the {Ni2IIDy2III} shows longer relaxation time and an absence of the quantum tunnelling of the magnetization (QTM) at low temperatures. Ab initio calculations suggest that the zero-field QTM of {Ni2IIDy2III} is effectively interrupted thanks to the ferromagnetic exchange coupling generated between NiII and DyIII ions. The presence of ferromagnetic exchange between NiII and DyIII ions is more conducive to zero-field single-molecule magnet behaviors than in isomorphic {CoII2DyIII2} where the exchange is antiferromagnetic. PMID- 28876064 TI - Improving the Performance of Long-Range-Corrected Exchange-Correlation Functional with an Embedded Neural Network. AB - A machine-learning-based exchange-correlation functional is proposed for general purpose density functional theory calculations. It is built upon the long-range corrected Becke-Lee-Yang-Parr (LC-BLYP) functional, along with an embedded neural network which determines the value of the range-separation parameter MU for every individual system. The structure and the weights of the neural network are optimized with a reference data set containing 368 highly accurate thermochemical and kinetic energies. The newly developed functional (LC-BLYP-NN) achieves a balanced performance for a variety of energetic properties investigated. It largely improves the accuracy of atomization energies and heats of formation on which the original LC-BLYP with a fixed MU performs rather poorly. Meanwhile, it yields a similar or slightly compromised accuracy for ionization potentials, electron affinities, and reaction barriers, for which the original LC-BLYP works reasonably well. This work clearly highlights the potential usefulness of machine learning techniques for improving density functional calculations. PMID- 28876065 TI - Carbon Monoxide and Its Controlled Release: Therapeutic Application, Detection, and Development of Carbon Monoxide Releasing Molecules (CORMs). AB - Carbon monoxide (CO) is attracting increasing attention because of its role as a gasotransmitter with cytoprotective and homeostatic properties. Carbon monoxide releasing molecules (CORMs) are spatially and temporally controlled CO releasers that exhibit superior and more effective pharmaceutical traits than gaseous CO because of their chemistry and structure. Experimental and preclinical research in animal models has shown the therapeutic potential of inhaled CO and CORMs, and the biological effects of CO and CORMs have also been observed in preclinical trials via the genetic modulation of heme oxygenase-1 (HO-1). In this review, we describe the pharmaceutical use of CO and CORMs, methods of detecting CO release, and developments in CORM design and synthesis. Many valuable clinical CORMs formulated using macromolecules and nanomaterials are also described. PMID- 28876067 TI - Kinetic Analysis of the Multivalent Ligand Binding Interaction between Protein A/G and IgG: A Standard System Setting. AB - Recombinant protein A/G (PAG) has a sequence coding for eight IgG binding sites and has enhanced interspecies affinity. High-frequency sampling of a PAG titration with IgG produces concentration profiles that are sensitive to the kinetic availability of the binding sites. The full kinetic model developed here for IgG binding sequentially to PAG shows only two distinct kinetic processes, describing an initial rapid association of two antibodies to PAG with a rate constant k-fast = (1.86 +/- 0.08) * 106 M-1 s-1 and a slower antibody binding process to all remaining sites, k-slow = (1.24 +/- 0.05) * 104 M-1 s-1. At equilibrium (after 1 h), the maximum IgG occupancy of PAG is 2.8 +/- 0.5, conflicting with the genetic evidence of eight binding sites and suggesting significant steric hindrance of the neighboring IgG binding sites. The phosphate buffered saline (PBS) solution defines a standard system setting, and this may be compared with other settings. The mean association rate of PAG-IgGn in the standard setting is 282 +/- 20% higher than when PAG is tethered to a surface. A systems biology approach requires that a model parameter set that defines a system in a standard setting should be transferable to another system. The transfer of parameters between settings may be performed using activity coefficients characterizing an effective concentration of species in a system, ai = gammaici. The activity correction, gamma, for the eight-site occupancy is gamma = 0.35 +/- 0.06, and mapping from the standard setting to the solution setting suggests gammaPAG-IgG = 0.4 +/- 0.03. The role of activity coefficients and transferability of kinetic parameters between system settings is discussed. PMID- 28876066 TI - Photoactivation of the BLUF Protein PixD Probed by the Site-Specific Incorporation of Fluorotyrosine Residues. AB - The flavin chromophore in blue-light-using FAD (BLUF) photoreceptors is surrounded by a hydrogen bond network that senses and responds to changes in the electronic structure of the flavin on the ultrafast time scale. The hydrogen bond network includes a strictly conserved Tyr residue, and previously we explored the role of this residue, Y21, in the photoactivation mechanism of the BLUF protein AppABLUF by the introduction of fluorotyrosine (F-Tyr) analogues that modulated the pKa and reduction potential of Y21 by 3.5 pH units and 200 mV, respectively. Although little impact on the forward (dark- to light-adapted form) photoreaction was observed, the change in Y21 pKa led to a 4000-fold increase in the rate of dark-state recovery. In the present work we have extended these studies to the BLUF protein PixD, where, in contrast to AppABLUF, modulation in the Tyr (Y8) pKa has a profound impact on the forward photoreaction. In particular, a decrease in Y8 pKa by 2 or more pH units prevents formation of a stable light state, consistent with a photoactivation mechanism that involves proton transfer or proton-coupled electron transfer from Y8 to the electronically excited FAD. Conversely, the effect of pKa on the rate of dark recovery is markedly reduced in PixD. These observations highlight very significant differences between the photocycles of PixD and AppABLUF, despite their sharing highly conserved FAD binding architectures. PMID- 28876068 TI - Relating Nanoscale Accessibility within Plant Cell Walls to Improved Enzyme Hydrolysis Yields in Corn Stover Subjected to Diverse Pretreatments. AB - Simultaneous chemical modification and physical reorganization of plant cell walls via alkaline hydrogen peroxide or liquid hot water pretreatment can alter cell wall structural properties impacting nanoscale porosity. Nanoscale porosity was characterized using solute exclusion to assess accessible pore volumes, water retention value as a proxy for accessible water-cell walls surface area, and solute-induced cell wall swelling to measure cell wall rigidity. Key findings concluded that delignification by alkaline hydrogen peroxide pretreatment decreased cell wall rigidity and that the subsequent cell wall swelling resulted increased nanoscale porosity and improved enzyme binding and hydrolysis compared to limited swelling and increased accessible surface areas observed in liquid hot water pretreated biomass. The volume accessible to a 90 A dextran probe within the cell wall was found to be correlated to both enzyme binding and glucose hydrolysis yields, indicating cell wall porosity is a key contributor to effective hydrolysis yields. PMID- 28876069 TI - Short Enantioselective Total Synthesis of (-)-Rhazinilam Using a Gold(I) Catalyzed Cyclization. AB - (R)-(-)-Rhazinilam has been synthesized in nine steps and 20% overall yield. The key steps involve two metal-catalyzed processes: the enantioselective gold(I) catalyzed cycloisomerization of an allene-functionalized pyrrole and the palladium-catalyzed hydrocarboxylation of a vinyl moiety with formate as a CO surrogate. This novel strategy represents the shortest and highest yielding enantioselective total synthesis of (-)-rhazinilam. PMID- 28876070 TI - Role of Salt, Pressure, and Water Activity on Homogeneous Ice Nucleation. AB - Pure water can be substantially supercooled below the melting temperature without transforming into ice. The achievable supercooling can be enhanced by adding solutes or by applying hydrostatic pressure. Avoiding ice formation is of great importance in the cryopreservation of food or biological samples. In this Letter, we investigate the similarity between the effects of pressure and salt on ice formation using a combination of state-of-the-art simulation techniques. We find that both hinder ice formation by increasing the energetic cost of creating the ice-fluid interface. Moreover, we examine the widely accepted proposal that the ice nucleation rate for different pressures and solute concentrations can be mapped through the activity of water [ Koop , L. ; Tsias , P. Nature , 2000 , 406 , 611 ]. We show that such a proposal is not consistent with the nucleation rates predicted in our simulations because it does not include all parameters affecting ice nucleation. Therefore, even though salt and pressure have a qualitatively similar effect on ice formation, they cannot be quantitatively mapped onto one another. PMID- 28876071 TI - Tabercorymines A and B, Two Vobasinyl-Ibogan-Type Bisindole Alkaloids from Tabernaemontana corymbosa. AB - Tabercorymines A (1) and B (2), two new vobasinyl-ibogan-type bisindole alkaloids with an unprecedented skeleton, were isolated from Tabernaemontana corymbosa. Their structures were established by a combination of spectroscopic data, chemical transformation, single-crystal X-ray diffraction, and ECD calculation. Compound 1 represents a novel bisindole alkaloid, characterized by a caged heteropentacyclic ring system incorporating an unprecedented C-7/C-20 bond in the vobasinyl unit. Alkaloids 1 and 2 showed potent antiproliferative activity against several human cancer cell lines, including vincristine-resistant KB. PMID- 28876072 TI - Binary Colloidal Crystal Films Grown by Vertical Evaporation of Silica Nanoparticle Suspensions. AB - Despite intensive research efforts in the synthesis of binary colloidal crystals, the production of well ordered binary colloidal crystal films over large areas continues to be synthetically challenging. In this paper, we investigate the phase behavior of binary mixtures of l-arginine-stabilized 36 and 22 nm silica nanoparticles deposited as centimeter-scale thin films onto a vertical substrate via evaporative assembly. By adjusting the temperature and relative colloid composition under high humidity conditions, we controlled the order of the resultant colloidal crystal films. The domain size of the AB2 binary crystalline phase increased with an excess of small (B) particles and a very slow evaporation rate below 45 degrees C, with the best results obtained at 30 degrees and 35 degrees C. PMID- 28876073 TI - Molecular Dynamics Simulation of Water Nanodroplet Bounce Back from Flat and Nanopillared Surface. AB - Molecular dynamics simulations of impinging nanodroplets were performed to study the bounce-back condition for flat and nanopillared surfaces. We found that the bounce-back condition can be closely related to the degree of droplet deformation upon collision with the solid surface. When the droplets have little or small deformation, the bounce-back condition solely depends on the hydrophobicity of the surface. On the other hand, when the droplet deformation is large, the impinging velocity dependence of the bounce-back condition becomes stronger due to the increase of the liquid-vapor interfacial area of colliding droplet, which is proportional to the liquid-vapor surface energy. The impinging droplet simulations with nanopillared hydrophobic surfaces were also performed. The contribution of droplet deformation in this case is relatively small because the surface hydrophobicity is enhanced due to the existence of pillars. Finally, we find that the maximum spreading diameter of the impinging droplets exhibits a consistent trend, in terms of the Weber number dependence, as the experimental measurements with macrodroplets. PMID- 28876074 TI - Synthetic Study toward Total Synthesis of (+/-)-Germine: Synthesis of (+/-)-4 Methylenegermine. AB - The total synthesis of 4-methylenegermine is described. PMID- 28876075 TI - Structural Evolution and Formation Mechanism of the Soft Colloidal Arrays in the Core of PAAm Nanofibers by Electrospun Packing. AB - Electrospinning provides a facile and versatile method for generating nanofibers from a large variety of starting materials, including polymers, ceramic, composites, and micro-/nanocolloids. In particular, incorporating functional nanoparticles (NPs) with polymeric materials endows the electrospun fibers/sheets with novel or better performance. This work evaluates the spinnability of polyacrylamide (PAAm) solution containing thermoresponsive poly(N isopropylacrylamide-co-tert-butyl acrylate) microgel nanospheres (PNTs) prepared by colloid electrospinning. In the presence of a suitable weight ratio (1:4) of PAAm and PNTs, the in-fiber arrangements of PNTs-electrospun fibers will evolve into chain-like arrays and beads-on-string structures by confining of PAAm nanofibers, and then the free amide groups of PAAm can bind amide moieties on the surfaces of PNTs, resulting in the assembling of PNTs in the cores of PAAm fibers. The present work serves as a reference in the fabrication of novel thermoresponsive hybrid fibers involving functional nanospheres via electrospun packing. The prepared nanofibers with chain-like and thermoresponsive colloid arrays in the cores are expected to have potential application in various fields. PMID- 28876078 TI - Prolactin monitoring in schizophrenia should be indicated by symptomatology not time. PMID- 28876076 TI - Supramolecular Electronic Interactions in Porphyrin-SWCNT Hybrids through Amidinium-Carboxylate Connectivity. AB - New supramolecular (metal)porphyrin/SWCNT hybrids have been synthesized through a combination of hydrogen bond and electrostatic interactions. Our experimental findings reveal through different techniques (XPS, TGA, UV-vis, Raman, and TEM) an efficient n-doping of the SWCNT from the electron donor (metal)porphyrin through the efficient and strong amidinium-carboxylate connectivity. PMID- 28876077 TI - Biomimetic Synthesis of Macahydantoins A and B from Lepidium meyenii, and Structure Revision of Macahydantoin B as a Class of Thiohydantoin with a 4-Methyl hexahydropyrrolo[1,2-c]imidazole Skeleton. AB - Phytochemical investigation on Lepidium meyenii led to the discovery of macahydantoin C (3), a new thiohydantoin with a 1,3-diazabicyclo[3.3.1]nonane core, the spectral properties of which indicate a potential structural misassignment of its previously reported analogue, macahydantoin B (2a). To probe this hypothesis, a concise, scalable, and biomimetic synthesis of the originally proposed 2a and its revised structure (2b) was efficiently accomplished using the modified Edman degradation as the key step from commercially available materials in 65% (three steps) and 52% (three steps) overall yields, respectively. These synthetic endeavors undoubtedly reassigned the structure of macahydantoin B as an unreported type of thiohydantoin featuring a 4-methyl-hexahydropyrrolo[1,2 c]imidazole scaffold. PMID- 28876079 TI - Commentary on Phillipou et al. (2018), Anorexia nervosa: Eating disorder or body image disorder? PMID- 28876080 TI - Cancer Impact, Complementary/Alternative Medicine Beliefs, and Quality of Life in Cancer Patients. AB - OBJECTIVES: The purpose of this study was to explore the relationships among cancer impact, belief in complementary and alternative medicine (CAM), CAM use, and quality of life (QOL). DESIGN: The study used a cross-sectional, descriptive correlational design with convenience sampling. A total of 122 cancer patients participated. Data were collected at a medical center in Chunghua, Taiwan. The questionnaires included the Chinese version of the Cancer Problem in Living Scale (CPILS), Complementary and Alternative Medicine Belief Inventory (CAMBI), Complementary and Alternative Medicine scale, and Chinese versions of QOL scales, including the Functional Assessment of Cancer Therapy-General (FACT-G). RESULTS: The mean age was 56.5 years, and most participants were male (n = 69, 56.6%), had completed high school or above (n = 56, 45.9%), and were married (n = 109, 89.3%). The most common type of cancer was oral (n = 17, 13.9%), followed by esophageal (n = 15, 12.3%) and colorectal (n = 13, 10.7%). Cancer patients, on average, use one or two types of CAM. The impact of cancer is significantly related to age (F = 7.12, p < 0.05), and income is related to QOL (F = 3.61, p < 0.05). Pearson correlations showed that the use of CAM was positively associated with belief in CAM (CAMBI) (r = 0.26, p = 0.01), and the impact of cancer was highly negatively associated with QOL (r = -0.71, p = 0.001). The predictors of QOL were the impact of cancer and use of CAM, and the impact of cancer accounted for 51% of the variance in QOL. CONCLUSION: This study supports research on the impact of cancer, belief in CAM, and use of CAM as related to QOL in cancer patients. These results can be used to provide options to clinicians and cancer patients. PMID- 28876081 TI - Legislation to Protect Nursing Mothers, Again: A Matter of Public Health and National Security. PMID- 28876082 TI - Co-production of NDM-1 and OXA-232 by ST16 Klebsiella pneumoniae, Italy, 2016. AB - Carbapenem-resistant Klebsiella pneumoniae strains, New Delhi metallo-beta lactamase-1 producers, are still rare in Italy, being endemic in Southeast Asiatic region. In October 2016, a multidrug-resistant K. pneumoniae was isolated from blood and urine of an Italian long-hospitalized patient with urosepsis without travel history abroad. To the best of our knowledge, this is the first report of bacteremia caused by an ST16 K. pneuomoniae New Delhi metallo-beta lactamase-1 and OXA-232 co-producing carbapenemase, in Italy. PMID- 28876083 TI - The redesign of oxazolidinone antibiotics in response to Staphylococcus aureus. PMID- 28876084 TI - Trifluoperazine Activates FOXO1-Related Signals to Inhibit Tumor Growth in Hepatocellular Carcinoma. AB - Schizophrenic patients tend to have reduced incidence of some cancers due to the treatment of antipsychotic drugs with antitumor effects, such as chlorpromazine and trifluoperazine (TFP). Forkhead Box O1 (FOXO1) as tumor suppressor in many malignancies is often inactivated by nuclear export, which could be inhibited by TFP. However, the antitumor efficiency of TFP and related role of FOXO1 in hepatocellular carcinoma (HCC) are unclear. Thus, two HCC cell lines SMMC-7721 and Bel-7402 were treated with different concentrations of TFP and the IC50 was determined. We found that TFP could inhibit the vitality of two cell lines and induce cell cycle arrest at G0/G1. Meanwhile, the apoptosis was also increased and the ability of migration or invasion was found to be impaired by TFP. Interestingly, TFP reversed the cytoplasmic localization of FOXO1 to nuclear and increased its expression in nuclear, and increased the ratio of Bax/Bcl-2. However, knockdown of FOXO1 significantly abrogated the TFP-inducedapoptosis by decreasing the Bcl-2 expression [corrected]. Furthermore, we found that TFP in vivo could effectively restrict the angiogenesis and tumor growth with reduced expression of VEGF, Bcl-2, and PCNA, and increased the nuclear localization of FOXO1, which indicated its antitumor role in HCC. PMID- 28876085 TI - Joint Analysis of SNP-SNP-Environment Interactions for Chronic Dialysis by an Improved Branch and Bound Algorithm. AB - In previous studies, both single-nucleotide polymorphism (SNP)-SNP or gene-gene (G * G) interactions and SNP-environmental factor (G * E) interactions were reported to partially account for "missing" heritability. However, (G * G) * E interactions were less commonly addressed. The purpose of this study was to develop a novel strategy to evaluate possible (G * G) * E interactions in D-loop based chronic dialysis association. Using values from our previously published data set (704 controls and 193 cases) of 77 D-loop SNPs and 7 environmental factors (coronary heart disease, hypertension, diabetes mellitus, triglyceride, cholesterol, blood thiol, and TBARS levels), we compared the performances of G, G * G, G * E, and (G * G) * E. We found that the interactions of four individual SNPs previously associated with a significantly high risk of chronic dialysis [odds ratio (OR) = 1.56-4.93] with environmental factors (G * E) increased the risk of chronic dialysis (maximum OR = 35.43). We then used an improved branch and bound algorithm to identify combinations of two to four SNPs that were most highly associated with chronic dialysis (OR = 9.27-34.39). When the interactions of the two- and three-SNP combinations with environmental factors were evaluated, we found that the (G * G) * E effects increased the risk of chronic dialysis (maximum OR = 8.32-57.54 and OR = 12.52-57.81, respectively; adjusted OR = 8.67 81.81 and OR = 12.29-81.95, respectively). Taken together, the (G * G) * E interactions identified chronic dialysis-associated SNPs that would not have been found using G * G or G * E interactions, suggesting that (G * G) * E interactions may be helpful to solve the problems of missing heritability in association studies. PMID- 28876086 TI - miR-26a-5p Regulates TNRC6A Expression and Facilitates Theca Cell Proliferation in Chicken Ovarian Follicles. AB - Ovarian theca cells play an indispensable role in ovarian follicular development and hormone secretion. miR-26a-5p was reported to be differentially expressed in mature and immature chicken ovaries in our previous study; however, the role of miR-26a-5p in regulating ovarian follicle function is still unclear. In this study, we demonstrated that the expression dynamics of TNRC6A mRNA in either chicken ovaries or follicles showed an opposite trend compared with that of chicken miR-26a-5p expression. miR-26a-5p inhibited TNRC6A mRNA expression by directly targeting its 3'-untranslated region in cultured chicken theca cells. Overexpression of miR-26a-5p promoted chicken follicular theca cell proliferation in vitro. Furthermore, overexpression of miR-26a-5p and knockdown of TNRC6A significantly upregulated the antiapoptotic BCL-2 gene. Taken together, this study revealed the expression dynamics of miR-26a-5p and TNRC6A in chicken ovaries and ovarian follicles and the relationship between the expression of miR 26a-5p and TNRC6A in chicken ovarian theca cells. These results suggest that miR 26a-5p facilitates chicken ovarian theca cell proliferation by targeting the TNRC6A gene. PMID- 28876088 TI - Frontiers in Neural Transplantation and Repair: A Special Issue Based on the 11th ASNTR Meeting. PMID- 28876087 TI - Preparation and Evaluation of 177Lu-Labeled Gemcitabine: An Effort Toward Developing Radiolabeled Chemotherapeutics for Targeted Therapy Applications. AB - OBJECTIVE: Gemcitabine, a nucleoside analogue, is used as a chemotherapeutic drug for the treatment of a wide variety of cancers. Therefore, radiolabeled gemcitabine may have potential as a radiotherapeutic agent for the treatment of various types of cancers. In the present work, an attempt has been made to radiolabel gemcitabine with 177Lu and study the preliminary biological behavior of 177Lu-labeled gemcitabine in tumor-bearing animal model. EXPERIMENTAL: Gemcitabine was coupled with p-NCS-benzyl-DOTA, a bifunctional chelating agent, to facilitate radiolabeling with 177Lu. The p-NCS-benzyl-DOTA-gemcitabine conjugate was radiolabeled with 177Lu, produced in-house and characterized by high-performance liquid chromatography. Tumor targeting potential of the radiolabeled agent was determined by biodistribution studies in Swiss mice bearing fibrosarcoma tumors. RESULTS: 177Lu-gemcitabine was prepared with a radiochemical purity of 95.7% +/- 0.3% under the optimized reaction conditions. The radiolabeled agent showed adequate in vitro stability in normal saline as well as in human blood serum. Preliminary biological studies revealed rapid and significant accumulation of the radiotracer in the tumorous lesions along with fast clearance of activity from blood and other vital organs/tissue. Although tumor uptake gradually reduced with time, tumor to blood and tumor to muscle ratios were improved due to the comparatively faster clearance of activity from the nontarget organs/tissue. CONCLUSION: The present study demonstrates the preliminary potential of 177Lu-gemcitabine for targeted radiotherapy. However, further studies are warranted to assess its potential for radiotherapeutic applications. PMID- 28876089 TI - Magnetic Resonance Tracking of Human CD34 Progenitor Cells Separated by Means of Immunomagnetic Selection and Transplanted into Injured Rat Brain. AB - Magnetic resonance imaging (MRI) provides a noninvasive method for studying the fate of transplanted cells in vivo. We studied whether superparamagnetic nanoparticles (CD34 microbeads), used clinically for specific magnetic sorting, can be used as a magnetic cell label for in vivo cell visualization. Human cells from peripheral blood were selected by CliniMACS(r) CD34 Selection Technology (Miltenyi). Purified CD34+ cells were implanted into rats with a cortical photochemical lesion, contralaterally to the lesion. Twenty-four hours after grafting, the implanted cells were detected in the contralateral hemisphere as a hypointense spot on T2 weighted images; the hypointensity of the implant decreased during the first week. At the lesion site we observed a hypointensive signal 10 days after grafting that persisted for the next 3 weeks, until the end of the experiment. Prussian blue and anti-human nuclei staining confirmed the presence of magnetically labeled human cells in the corpus callosum and in the lesion 4 weeks after grafting. CD34+ cells were also found in the subventricular zone (SVZ). Human DNA (a human-specific 850 base pair fragment of alpha-satellite DNA from human chromosome 17) was detected in brain tissue sections from the lesion using PCR, confirming the presence of human cells. Our results show that CD34 microbeads superparamagnetic nanoparticles can be used as a magnetic cell label for in vivo cell visualization. The fact that microbeads coated with different commercially available antibodies can bind to specific cell types opens extensive possibilities for cell tracking in vivo. PMID- 28876090 TI - Article Commentary: G-CSF-Mobilized Human Peripheral Blood for Transplantation Therapy in Stroke. PMID- 28876092 TI - Abstracts for the 16th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28876093 TI - Effective Cryopreservation of Neural Stem or Progenitor Cells without Serum or Proteins by Vitrification. AB - Development of effective cryopreservation protocols will be essential to realizing the potential for clinical application of neural stem and progenitor cells. Current cryopreservation protocols have been largely employed in research, which does not require as stringent consideration of viability and sterility. Therefore, these protocols involve the use of serum and protein additives, which can potentially introduce contaminants, and slow cooling with DMSO/glycerol-based cryopreservation solutions, which impairs cell survival. We investigated whether serum- and protein-free vitrification is effective for functional cryopreservation of neurosphere cultures of neural stem or progenitor cells. To protect the samples from introduction of other contaminants during handling and cryostorage, an original "straw-in-straw" method (250 MUl sterile straw placed in 500 MUl straw) for direct immersion into liquid nitrogen and storing the samples was also introduced. The protocol employed brief step-wise exposure to vitrification solution composed of ethylene glycol (EG) and sucrose (40% v/v EG, 0.6 M sucrose) and removal of vitrification solution at room temperature. Evaluation of the effects of vitrification revealed that there were no differences between control and vitrified neural stem or progenitor cells in expression of the neural stem or progenitor cell markers, proliferation, or multipotent differentiation. This sterile method for the xeno-free cryopreservation of murine neurospheres without animal or human proteins may have the potential to serve as a starting point for the development of cryopreservation protocols for human neural stem and progenitor cells for clinical use. PMID- 28876102 TI - Introduction. PMID- 28876106 TI - Culture of Keratinocytes for Transplantation without the Need of Feeder Layer Cells. AB - Patients with large burn wounds have a limited amount of healthy donor skin. An alternative for the autologous skin graft is transplantation with autologous keratinocytes. Conventionally, the keratinocytes are cultured with mouse feeder layer cells in medium containing fetal calf serum (FCS) to obtain sufficient numbers of cells. These xenobiotic materials can be a potential risk for the patient. The aim of the present study was to investigate if keratinocytes could be expanded in culture without the need of a feeder layer and FCS. Keratinocytes were cultured on tissue culture plastic with or without collagen type IV coating in medium containing Ultroser G (serum substitute) and keratinocyte growth factor (KGF). An in vitro skin equivalent model was used to examine the capacity of these cells to form an epidermis. Keratinocytes in different passages (P2, P4, and P6) and freshly isolated cells were studied. Keratinocytes grown on collagen type IV were able to form an epidermis at higher passage numbers than cells grown in the absence of collagen type IV (P4 and P2, respectively). In both cases the reconstructed epidermis showed an increased expression of Ki-67, SKALP, involucrin, and keratin 17 compared to normal skin. Only 50,000 keratinocytes grown on collagen type IV in P4 were needed to form 1 cm2 epidermis, whereas 150,000 of freshly isolated keratinocytes were necessary. Using this culture technique sufficient numbers of keratinocytes, isolated from 1 cm2 skin, were obtained to cover 400 cm2 of wound surface in 2 weeks. The results show that keratinocytes can be cultured without the need of a fibroblast feeder layer and FCS and that these cells are still able to create a fully differentiated epidermis. This culture technique can be a valuable tool for the treatment of burn wounds and further development of tissue engineered skin. PMID- 28876107 TI - Inhibition of Apoptosis by Expression of Antiapoptotic Proteins in Recombinant Human Keratinocytes. AB - The Fas ligand/Fas interaction plays an important role in the regulation of immune responses. Allografted cells undergo Fas-mediated apoptosis induced by CD8+ T cells. Our objective was to prevent human keratinocytes from immunologically induced apoptosis. We focused on three proteins with inhibitory function on Fas-mediated apoptosis. Human keratinocytes were transfected with either Flip, Faim, or Lifeguard (LFG). The treatment proved to be practicable and efficient. The recombinant keratinocytes with expression of our target proteins were cocultured with CD8+ T cells and the apoptotic activity was then evaluated. Activation of caspase-8 was detectable in control but not in the recombinant cells. Quantitative analysis revealed significant induction of T-cell-induced apoptosis in nontransfected keratinocytes (p = 0.04, n = 12) but not in Flip (p = 0.66), Faim (p = 0.42), or LFG (p = 0.44) expressing cells. Our results suggest that heterotopic expression of antiapoptotic proteins can induce the resistance of keratinocytes to a major mechanism of rejection. PMID- 28876115 TI - [26th Congress of the Experimental Surgical Section of the Hungarian Surgical Society - Abstracts]. PMID- 28876116 TI - [5th Congress of the Hungarian Association of Young Surgeons, April 7-9, 2017, Balatonalmadi - Abstracts]. PMID- 28876117 TI - [Duodenal leiomyoma - a rare case report]. AB - Neoplasms of the small bowel are rare and comprise only 1-5% of all gastrointestinal neoplasms. The most frequent malignant tumors located in the small bowel are adenocarcinomas, lymphomas and neuroendocrine tumors. Rarely observed are gastrointestinal stromal tumors (GIST), leiomyosarcomas and leiomyomas. Leiomyomas are most frequently seen in the jejunum followed by the ileum and lastly the duodenum. In most cases, a definite diagnosis of these tumors is not possible prior to surgical treatment. The treatment of choice for these tumors is surgery. Surgical treatment of duodenal leiomyomas has been local tumor excision, segmental duodenal resection and pancreaticoduodenectomy. The prognosis for these well-differentiated smooth muscle tumors is favorable. The authors of this article presented a case of a 61-year-old white man who was admitted to the hospital because of diagnosed duodenal tumor. The patient was suffering for periodically appearing blunt pain in the upper abdomen and periodic vomiting for three months. He underwent surgical excision of a benign duodenum neoplasm and left the ward on the seventh day after surgery. After operation, the symptoms of disease were alleviated. The author performed a review of the literature concerning duodenal leiomyoma. PMID- 28876118 TI - [Effects of complement C5a inhibitor therapy in animal models of non-occlusive mesenteric ischemia]. AB - INTRODUCTION: Non-occlusive mesenteric ischemia (NOMI) develops without anatomical causes. Early diagnosis is challenging and treatments are of questionable effectiveness. We investigated the role of complement activation in the pathophysiology of NOMI in animal models through the inhibition of complement C5a. MATERIALS AND METHODS: 60-min partial aortic occlusion (PAO; abdominal aorta, proximal to celiac trunk; mean arterial pressure: 30-40 mmHg) was established in Sprague-Dawley rats (n = 28) and 60-min cardiac tamponade in minipigs (n = 19; mean arterial pressure: 40-50 mmHg) to observe short- and long term circulatory and inflammatory consequences of NOMI. Macro- and microhemodynamics, leukocyte infiltration, plasma levels of inflammatory mediators (endothelin, HMGB-1) were measured. C5a inhibitor (Acetyl-Peptid-A; 4 mg/kg iv) was administered at the 45th min of PAO or tamponade, respectively. RESULTS: Twenty-four hours after PAO systemic inflammatory response increased cardiac output and superior mesenteric artery flow (SMAF). C5a inhibition reduced the elevated cardiac output (203.1 +/- 5 vs 269.6 +/- 8.1 ml/min/kg) and SMAF and increased ileal microcirculation (833.5 +/- 33.8 vs 441.9 +/- 22.4 MUm/s). In pigs, after the tamponade, C5a inhibition reduced the immediate hemodynamic disturbances, temporarily increased SMAF and permanently the ileal microcirculation. The Acetyl-Peptid-A treatment reduced leukocyte infiltration and plasma levels of inflammatory mediators in both NOMI models. CONCLUSIONS: Complement activation plays central role in the macro- and microcirculatory disturbance during NOMI. C5a inhibition reduces the inflammatory activation and influences the hemodynamic consequences of experimental NOMI. PMID- 28876119 TI - ? PMID- 28876120 TI - ? PMID- 28876121 TI - [The role of cone-beam CT during transarterial chemoembolization for liver cancer]. AB - PURPOSE: The role of interventional radiology in the treatment of hepatic malignancies is steeply raising. Our purpose is to present the importance of cone beam CT (CBCT) during TACE (transarterial chemoembolization) procedures for liver tumours. PATIENTS AND METHODS: Between 1st of June 2013 and 31st of July 2016, we performed 130 TACE procedures in 64 patients in the Borsod University Teaching Hospital at Miskolc. During some of the treatments of 44 patients CBCT was also performed. RESULTS: All procedures were successful and carried out safely. CBCT gave new information in 22,7%, that influenced further treatment. It helped to precisely localize tumours, corrected the number or the size of hepatic malignancies. With CBCT it was easier to identify the feeding arteries of the tumour, plan the actual treatment and also to assess the efficacy of the previous treatment. DISCUSSION: The gold standard therapy of intermediate-stage HCC (according to Barcelona's criteria) is TACE. Beside, it can be safely and efficiently performed also in early stage or advanced stage in cases of contraindications for alternative therapies. Cone-beam CT is a dynamic examination which gives you an intraoperative, 3D CT-like imaging in the angio suit, without moving the table or the catheterised patient. Literature has already cited preliminary datas about prolonged survival for those patients treated with the help of CBCT intraoperatively. CONCLUSION: Intraoperative CBCT in patients with TACE treatment for hepatic malignancies can provide information that can improve the therapeutic results. Therefore we suggest the routine use of this imaging option during all TACE procedures if patients are eligible. PMID- 28876122 TI - Activity of 3'-hydroxychalcone against Cryptococcus gattii and toxicity, and efficacy in alternative animal models. AB - AIM: This work aimed to evaluate the activity of 3'-hydroxychalcone against Cryptococcus gattii in planktonic and biofilm forms and their toxicity using alternative animal models. MATERIALS & METHODS: Minimum inhibitory concentration and minimum fungicide concentration were determined. Biofilm formation and the susceptibility tests were performed by the 2,3-bis-(2-methoxy-4-nitro-5 sulfophenyl)-5-[carbonyl(phenylamino)]-2H-tetrazolium hydroxide assay. Toxicity and efficacy were checked in Danio rerio and Galleria mellonella models. RESULTS: The compound 3'-hydroxychalcone showed fungicidal activity against C. gattii in both planktonic and biofilm forms. The toxicity in zebrafish embryos revealed a low lethal concentration. In G. mellonella, the compound did not show antifungal activity and larvae toxicity. CONCLUSION: Because of the activity of 3' hydroxychalcone against C. gattii in vitro, molecular modifications should be made to improve efficacy and to reduce toxicity in vivo. [Formula: see text]. PMID- 28876128 TI - Influence of Inhaled Amiloride on Lung Fluid Clearance in Response to Normobaric Hypoxia in Healthy Individuals. AB - : Wheatley, Courtney M., Sarah E. Baker, Bryan J. Taylor, Manda L. Keller-Ross, Steven C. Chase, Alex R. Carlson, Robert J. Wentz, Eric M. Snyder, and Bruce D. Johnson. Influence of inhaled amiloride on lung fluid clearance in response to normobaric hypoxia in healthy individuals. High Alt Med Biol 18:343-354, 2017. AIM: To investigate the role of epithelial sodium channels (ENaC) on lung fluid clearance in response to normobaric hypoxia, 20 healthy subjects were exposed to 15 hours of hypoxia (fraction of inspired oxygen [FiO2] = 12.5%) on two randomized occasions: (1) inhaled amiloride (A) (1.5 mg/5 mL saline); and (2) inhaled saline placebo (P). Changes in lung fluid were assessed through chest computed tomography (CT) for lung tissue volume (TV), and the diffusion capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) for pulmonary capillary blood volume (VC). Extravascular lung water (EVLW) was derived as TV-VC and changes in the CT attenuation distribution histograms were reviewed. RESULTS: Normobaric hypoxia caused (1) a reduction in EVLW (change from baseline for A vs. P, -8.5% +/- 3.8% vs. -7.9% +/- 5.2%, p < 0.05), (2) an increase in VC (53.6% +/- 28.9% vs. 53.9% +/- 52.3%, p < 0.05), (3) a small increase in DLCO (9.6% +/- 29.3% vs. 9.9% +/- 23.9%, p > 0.05), and (4) CT attenuation distribution became more negative, leftward skewed, and kurtotic (p < 0.05). CONCLUSION: Acute normobaric hypoxia caused a reduction in lung fluid that was unaffected by ENaC inhibition through inhaled amiloride. Although possible amiloride-sensitive ENaC may not be necessary to maintain lung fluid balance in response to hypoxia, it is more probable that normobaric hypoxia promotes lung fluid clearance rather than accumulation for the majority of healthy individuals. The observed reduction in interstitial lung fluid means alveolar fluid clearance may not have been challenged. PMID- 28876129 TI - Relationship Between Occupational Physical Activity and Subclinical Vascular Damage in Moderate-Altitude Dwellers. AB - : Ujka, Kristian, Rosa Maria Bruno, Luca Bastiani, Eva Bernardi, Paolo Sdringola, Nenad Dikic, Bikash Basyal, Sanjeeb Sundarshan Bhandari, Buddha Basnyat, Annalisa Cogo, and Lorenza Pratali. Relationship between occupational physical activity and subclinical vascular damage in moderate-altitude dwellers. High Alt Med Biol. 18:249-257, 2017. BACKGROUND: Occupational physical activity (OPA) has been associated with increased cardiovascular (CV) events. The aim of this study was to investigate the association between OPA and markers of subclinical vascular damage among a moderate-altitude population living in the rural village of Chaurikharka (Nepal; 2600 m sea level). METHODS: Seventy-two individuals (age 42 +/- 15 years, ranges 15-85 years, 23 men) were enrolled. Physical activity (PA) was evaluated using the International Physical Activity Questionnaire (IPAQ). Carotid-femoral pulse wave velocity (PWV), carotid ultrasound assessment, and flow-mediated dilation (FMD) were performed. RESULTS: OPA was 9860 +/- 5385 Metabolic Equivalent of Task (MET)-minutes/week, representing 77% of total energy expenditure, with 97% of the population performing high-intensity PA. In the univariate analysis, OPA was significantly associated with PWV (beta = 0.474, p = 0.001) and carotid stiffness (CS) (beta = 0.29, p = 0.019). In the multivariate analysis, including age, sex, oxygen saturation, mean blood pressure, low-density lipoprotein (LDL), and OPA, OPA remained an independent predictor of PWV (beta = 0.403, p = 0.001) but not of CS (beta = 0.028, p = 0.8). OPA remained an independent predictor of PWV independently from the Framingham risk score (FRS). CONCLUSION: High-intensity OPA shows a positive, independent association with aortic stiffness in Himalayan moderate-altitude dwellers. This study suggests how vigorous OPA performed in moderate altitude may be a CV risk factor. PMID- 28876130 TI - To treat or not to treat: a quantitative review of the effect of biofouling and control methods in shellfish aquaculture to evaluate the necessity of removal. AB - The global growth of farmed shellfish production has resulted in considerable research investigating how biofouling compromises farm productivity. Shellfish fitness can be compared between fouled stock and stock which has undergone treatment. As treatment options are often harsh, they may deleteriously affect stock. The projected impact of biofouling may therefore be confounded by the impact of treatments. Given the substantial cost of fouling removal, some have questioned the necessity of biofouling mitigation strategies. Meta-analysis revealed that biofouling typically reduces shellfish fitness. However, the fitness of treated stock was often lower or equal to fouled control stock, indicating that many common antifouling (AF) strategies are ineffective at enhancing farm productivity. Overall, caution and diligence are required to successfully implement biofouling mitigation strategies. The need remains for increased passive prevention approaches and novel AF strategies suitable for shellfish culture, such as strategic siting of bivalve farms in areas of low biofouling larval supply. PMID- 28876131 TI - Effects of Ultrasound Treatment on Physiochemical Properties and Antimicrobial Activities of Whey Protein-Totarol Nanoparticles. AB - Totarol is a natural antimicrobial compound extracted from the heartwood of Podocarpus totara, a conifer native to New Zealand. The effects of whey protein totarol nanoparticles treated with ultrasound on the physiochemical properties and the growth of Staphylococcus aureus were investigated. The particle size of whey protein-totarol nanoparticles was reduced by ultrasound treatment from 31.24 +/- 5.31 to 24.20 +/- 4.02 nm, and the size distribution was also narrowed by the treatment. Viscosity and modulus data indicated that the flow behaviors of whey protein-totarol nanoparticles seemed to be Newtonian and exerted a typical viscoelastic fluid at protein content of 15% (w/v). Rheological properties were more insensitive to ultrasonic time. Time-killing assays, agar diffusion tests, the cell membrane damage analysis, and microstructure were exploited to study the antibacterial properties of whey protein-totarol nanoparticles. The MIC of whey protein-totarol nanoparticles after ultrasound treatment decreased from 4 to 2 MUg/mL compared with that without ultrasound treatment. Whey protein-totarol nanoparticles treated with ultrasound resulted in a significant (P < 0.05) decrease in time killing after 24 h. The agar diffusion results showed that the inhibition zones of whey protein-totarol nanoparticles were 12 and 36 mm for untreated and treated with ultrasound, respectively. The cell membrane damages and the microstructure changes also proved that whey protein-totarol nanoparticles treated with ultrasound had strong antibacterial activities against S. aureus and that the antibacterial effectiveness enhanced with the increasing of ultrasonic time. These findings suggested that whey protein-totarol nanoparticles treated with ultrasound were more effective against S. aureus than untreated nanoparticles. PMID- 28876132 TI - Removal of Escherichia coli and Enterococcus faecalis after Hand Washing with Antimicrobial and Nonantimicrobial Soap and Persistence of These Bacteria in Rinsates. AB - Food handlers are important sources of contamination in the agricultural environment. This study was conducted (i) to evaluate the activity of antimicrobial soaps against Escherichia coli and Enterococcus faecalis using a hand washing model with soiled hands and (ii) to determine the survival and persistence of these bacteria in rinsates. Sterilized agricultural soil from tomato and pepper farms was inoculated with E. coli or E. faecalis at 103 or 106 CFU/g. Decontaminated hands were placed in contact with contaminated soil for 2 min and were then washed with soaps with or without antimicrobial compounds (citric extracts, chloroxylenol, triclosan, or chlorhexidine gluconate). As the control, hands were washed with sterile distilled water. The levels of bacteria remaining on the hands and recovered from the rinsates were determined using a membrane filtration method and selective media. Antimicrobial soaps removed levels of E. coli similar to those removed by distilled water and nonantimicrobial soap on hands contaminated with E. coli at 103 CFU/g. However, when hands were contaminated with E. coli at 106 CFU/g, more E. coli was removed with the chlorhexidine gluconate soap. When hands were contaminated with E. faecalis at 103 CFU/g, bacteria were removed more effectively with soaps containing chloroxylenol or chlorhexidine gluconate. When hands were contaminated with E. faecalis at 106 CFU/g, all of the antimicrobial soaps were more effective for removing the bacteria than were distilled water and nonantimicrobial soap. E. coli grew in all of the hand washing rinsates except that containing triclosan, whereas E. faecalis from the 106 CFU/g treatments grew in rinsates containing chlorhexidine gluconate and in the distilled water rinsates. Washing with antimicrobial soap was more effective for reducing bacteria on soiled hands than was washing with water or nonantimicrobial soap. However, persistence or growth of bacteria in these rinsates poses health risks. PMID- 28876133 TI - 2015 Outbreak of Cyclosporiasis Linked to the Consumption of Imported Sugar Snap Peas in Ontario, Canada. AB - An outbreak of cyclosporiasis in Ontario, Canada, was investigated in the fall of 2015. Thirty-five confirmed and 10 probable cases were linked to the investigation. Epidemiological and food safety evidence implicated fresh sugar snap peas imported from Guatemala as the source of the outbreak. We describe here the first documented cyclosporiasis outbreak in Canada involving the consumption of sugar snap peas. PMID- 28876134 TI - Investigating predictive power of agency and communion for interprofessional learner outcomes: A before-after study. AB - As interprofessional education (IPE) continues to be instituted, much attention has been paid to training-intervention effectiveness. Less attention has been paid to the selection side of the IPE model; however, efficient delivery is necessary to sustain the development of IPE. This short report investigates the "two big social cognitions" (agency and communion) as individual-difference predictors of attitude change and knowledge acquisition. A 3-week before-after observational design with survey methodology was conducted in a pre-licensure IPE setting (n = 82). Results indicated significant interactions of agency and communion in predicting learner outcomes. Our findings should stimulate future IPE researchers to identify additional, selection-relevant design factors (e.g., individual differences) that may enhance comparative-effectiveness of IPE. PMID- 28876135 TI - Gene Therapy Briefs. PMID- 28876136 TI - Electron Microscopy Observation of Human Pulmonary Ultrastructure in Two Patients with High-Altitude Pulmonary Edema. AB - We examined the pulmonary ultrastructure in tissue from two patients with high altitude pulmonary edema (HAPE) by electron microscopy. In one case, we found that neutrophils were trapped in pulmonary capillary lumen of alveolar-capillary wall and part of the cytoplasm of a neutrophil protruded and adhered to the capillary endothelium. There were several degranulated vacuoles in the cytoplasm of the neutrophil. The pulmonary capillary wall was deformed, thickened, and swollen and there was evidence of degeneration. In another case, infiltration of neutrophils and macrophages, proliferation of type II pneumocytes, and numerous red blood cells were also observed in alveolar air space. These electron microscopic ultrastructural observations illustrate for the first time damage to the pulmonary alveolar-capillary barrier in lung tissue of humans with advanced HAPE. PMID- 28876137 TI - Penetrance and the Healthy Elderly. AB - The variable penetrance of pathogenic variants (PVs) represents a major challenge to the field of human genetics, often complicating clinical decision-making and risk management. Nonpenetrance, the detection of PVs in the absence of disease manifestation, is a common phenomenon, yet, we know very little about the underlying factors, which may protect some individuals and not others. Placing a new focus on the genomic study of the healthy elderly may be pivotal for advancing our understanding of penetrance. Studying those who remain unaffected late into life, despite harboring known genetic risk variants, could provide important insights into disease mechanisms and ultimately inform clinical care, yet, it has received relatively little attention as a research strategy. The ever increasing use of sequencing technology is further driving the requirement to understand the penetrance of ascertained variants. The ASPREE Biobank of Healthy Ageing provides a unique opportunity to address this area of need. DNA has been collected from a cohort of over 14,000 healthy elderly individuals aged 70 years or older enrolled in an aspirin clinical trial. The ASPREE cohort represents a healthy reference population ascertained without the typical biases of a genetic study. The cohort is depleted of expressed monogenetic disease, yet will contain hundreds of elderly individuals with known PVs in clinically actionable genes. Investigating this population along with other cohorts of the healthy elderly will provide critical new knowledge into the penetrance of actionable variants as a foundation for informing clinical care. PMID- 28876138 TI - Aetiology of acquired blepharoptosis in young adults. AB - PURPOSE: To identify the causes of blepharoptosis in young adults, and explore cases that do not fit into current diagnostic categories. METHODS: A retrospective cohort study of all patients aged 18-40 years ("young adults") with acquired blepharoptosis that presented to two specialist ocular plastics practices and a paediatric ophthalmologist over a period of up to 25 years. Each patient was classified according to diagnosis. Where the diagnosis was uncertain, the files were examined in detail to try and further establish a cause. RESULTS: A total of 266 young adult patients were included. The most common causes of acquired blepharoptosis were trauma-related (28.2%) and anophthalmic blepharoptosis (19.9%). In 12.4% of the cases, a definite diagnosis could not be made. Of these, one-third had a history of soft contact lens use, a possible etiologic factor. CONCLUSIONS: The cause of acquired blepharoptosis can usually be established by an appropriate history and examination, with additional diagnostic tests sometimes required. Nearly half of all young adult ptosis is related to trauma or acquired anophthalmos. Around one in eight young adults have blepharoptosis of unknown cause, a group warranting further study. PMID- 28876139 TI - Taxes, bankruptcy costs, and capital structure in for-profit and not-for-profit hospitals. AB - About 60% of the US hospitals are not-for-profit and it is not clear how traditional theories of capital structure should be adapted to understand the borrowing behavior of not-for-profit hospitals. This paper identifies important determinants of capital structure taken from theories describing for-profit firms as well as prior literature on not-for-profit hospitals. We examine the differential effects these factors have on the capital structure of for-profit and not-for-profit hospitals. Specifically, we use a difference-in-differences regression framework to study how differences in leverage between for-profit and not-for-profit hospitals change in response to key explanatory variables (i.e. tax rates and bankruptcy costs). The sample in this study includes most US short term general acute hospitals from 2000 to 2012. We find that personal and corporate income taxes and bankruptcy costs have significant and distinct effects on the capital structure of for-profit and not-for-profit hospitals. Specifically, relative to not-for-profit hospitals: (1) higher corporate income tax encourages for-profit hospitals to increase their debt usage; (2) higher personal income tax discourages for-profit hospitals to use debt; and (3) higher expected bankruptcy costs lead for-profit hospitals to use less debt. Over the past decade, the capital structure of for-profit hospitals has been more flexible as compared to that of not-for-profit hospitals. This may suggest that not-for profit hospitals are more constrained by external financing resources. Particularly, our analysis suggests that not-for-profit hospitals operating in states with high corporate taxes but low personal income taxes may face particular challenges of borrowing funds relative to their for-profit competitors. PMID- 28876140 TI - School nurses' perceptions and experiences with an interprofessional concussion management team in the secondary school setting. AB - Following a concussion, both cognitive and physical rest are imperative aspects of injury management. The inclusion of academic adjustments and the formation of an interprofessional concussion management team (ICMT) provide a mechanism to manage academic issues following a concussion. As one of the sole healthcare providers presents during school hours, the school nurse may offer unique insight regarding the infrastructure of an ICMT in the secondary school setting. The purpose of this study was to explore school nurses' perceptions of and experiences with an ICMT for adolescents following a concussion in the secondary school setting. The consensual qualitative research approach was used to guide this study. Semi-structured individual telephone interviews were conducted with 15 school nurses employed in the secondary school setting across the United States. During data analysis, themes and categories were established based on a consensus process by the research team. Study findings indicated that school nurses identified several stakeholders regarding the concussion management team that are essential to include in the concussion management process. In addition to the school nurse, participants perceived an ICMT should include a physician, athletic trainer, school counsellor, teachers, and other stakeholders such as the patient and their parents. Additionally, participants discussed their perceptions of their own role as a member of an ICMT in the secondary school setting. The inclusion of an ICMT to aid the recovery following a concussion is vital to ensure proper care for the adolescent patient. Furthermore, the school nurse and athletic trainer must effectively collaborate, when possible, to ensure that concussed adolescents are allowed sufficient cognitive rest via the incorporation of academic adjustments during the recovery process. PMID- 28876142 TI - Contributions of team climate in the study of interprofessional collaboration: A conceptual analysis. AB - The concept of team climate is widely used to understand and evaluate working environments. It shares some important features with Interprofessional Collaboration (IPC). The four-factor theory of climate for work group innovation, which underpins team climate, could provide a better basis for understanding both teamwork and IPC. This article examines in detail the common ground between team climate and IPC, and assesses the relevance of team climate as a theoretical approach to understanding IPC. There are important potential areas of overlap between team climate and IPC that we have grouped under four headings: (1) interaction and communication between team members; (2) common objectives around which collective work is organised; (3) responsibility for performing work to a high standard; and (4) promoting innovation in working practices. These overlapping areas suggest common characteristics that could provide elements of a framework for considering the contribution of team climate to collaborative working, both from a conceptual perspective and, potentially, in operational terms as, for example, a diagnostic tool. PMID- 28876141 TI - Utility of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as biomarker to predict therapeutic response to methotrexate in rheumatoid arthritis. AB - The objective of this study was to investigate the usefulness of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in predicting short term therapeutic response to methotrexate (MTX) in rheumatoid arthritis (RA). Patients with active RA, with Disease Activity Score-28 joints (DAS-28) >3.2, starting oral MTX, were included. We measured at baseline, 3 and 6 mo: DAS-28, Health Assessment Questionnaire-Disability Index (HAQ-DI), patient's perception of disease severity, morning stiffness and pain, as well as modifications in sTREM-1 levels. A reduction in DAS-28 > 1.2 at 3 or 6 mo was considered adequate response. A significant decrease in DAS-28 was observed at 3 and 6 mo. HAQ-DI also decreased at 3 and 6 mo. No significant changes were observed in sTREM-1 levels at 3 or 6 mo. Using as cut-off a baseline value of sTREM-1 levels > 390 pg/ml, we obtained low values of sensitivity (61.5%), specificity (59.3%), positive predictive value (59.3%) and negative predictive value (61.5%) for adequate response to MTX at 3 mo. We found no clinical value of sTREM-1 levels in predicting therapeutic response to MTX in RA. Further studies should evaluate if sTREM-1 levels are predictive for other outcomes, including higher structural damage or good response to biologics. PMID- 28876143 TI - Anti-Mullerian hormone levels before and after uterine artery embolization. AB - OBJECTIVE: To determine the effects of uterine artery embolization (UAE) on ovarian reserve as measured by Anti-Mullerian hormone (AMH) levels. MATERIAL AND METHODS: Non-randomized, observational study of 89 women 23-40 years of age who received UAE. Control hormone levels were measured prior to UAE and the first post-embolization measurement was taken at various times post-procedure (mean = 190 +/- 229 days). RESULTS: Historical work verified by our earlier work has shown that AMH levels decline with age. Regression analysis allows us to determine whether UAE contributes to a greater decline in AMH values over that naturally occurring with aging. The effect of the procedure was found to contribute no deleterious effect to the natural decline in AMH levels. In addition, multiple blood draws were obtained from 32 patients up to 47 months post-UAE. Regression studies with these patients as their own controls showed no long-term diminishment of ovarian reserve due to the UAE procedure. CONCLUSIONS: Earlier reported data are consistent with larger sample size. UAE does not affect ovarian reserve in women <40 as evidenced by no significant change in AMH levels after embolization. Women who are of reproductive age and have uterine fibroids can consider UAE without concern for adverse effects on their fertility. PMID- 28876144 TI - Collaborating with medicine? Perceptions of Australian naturopaths on integrating within the conventional medical system. AB - Complementary and alternative medicine (CAM) is an increasingly prevalent part of contemporary health care. Whilst there have been some attempts to understand the dynamics of CAM integration in the health care system from the perspective of conventional care providers and patients, little research has examined the view of CAM practitioners. This study aims to identify the experiences of integration within a conventional healthcare system as perceived by naturopaths. Qualitative semi-structured interviews were conducted using a purposeful sample of 20 practising naturopaths in South East Queensland, Australia to discuss their experiences and perceptions of integrating with conventional medical providers. Analysis of the interviews revealed five broad challenges for the integration of CAM according to naturopaths: competing paradigms between CAM and conventional medicine; co-option of CAM by conventional medical practitioners; the preservation of separate CAM and conventional medical worlds by patients and providers due to lack of formalised relations; negative feedback and biases created through selective or limited experience or information with CAM; and indifferent, reactive and one-sided interaction between CAM and conventional medical providers. Naturopaths support the integration of health services and attempt to provide safe and appropriate care to their patients through collaborative approaches to practice. The challenges identified by naturopaths associated with integration of CAM with conventional providers may impact the quality of care of patients who choose to integrate CAM and conventional approaches to health. Given the significant role of naturopaths in contemporary health-care systems, these challenges require further research and policy attention. PMID- 28876145 TI - Physician associates working in secondary care teams in England: Interprofessional implications from a national survey. AB - Physician associates (PAs) are a new type of healthcare professional to the United Kingdom; however, they are well established in the United States (where they are known as physician assistants). PAs are viewed as one potential solution to the current medical workforce doctor shortage. This study investigated the deployment of PAs within secondary care teams in England, through the use of a cross-sectional electronic, self-report survey. The findings from 14 questions are presented. Sixty-three PAs working in a range of specialties responded. A variety of work settings were reported, most frequently inpatient wards, with work generally taking place during weekdays. Both direct and non-direct patient care activities were reported, with the type of work undertaken varying at times, depending on the presence or absence of other healthcare professionals. PAs reported working within a variety of secondary care team staffing permutations, with the majority of these being interprofessional. Line management was largely provided by consultants; however day-to-day supervision varied, often relating to different work settings. A wide variation in ongoing supervision was also reported. Further research is required to understand the nature of PAs' contribution to collaborative care within secondary care teams in England. PMID- 28876146 TI - Effects of concomitant mild traumatic brain injury on resuming work after suffering from an isolated limb fracture: A cohort study. AB - BACKGROUND: The objective is to explore the effects of concomitant mild traumatic brain injury (mTBI) on return to work (RTW), among patients suffering from an isolated limb fracture. This follow-up study included a total of 170 working age subjects with an isolated limb fracture, and was conducted in a phone interview approximately 1-year post trauma. 41 had experienced an mTBI and 129 did not. METHODS: Data were obtained through a phone interview conducted on average 20.7 months (SD = 9.6 months) post-accident. The main outcome measure was the number of days taken to RTW after the injury. Demographic information was also gathered during the phone interview. Workers' compensation status was obtained through the hospitals' orthopaedic clinic data. RESULTS: The mTBI group took on average 329.7 days (SD = 298.0) to RTW after the injury, as opposed to 150.3 days (SD = 171.3) for the control group (p < 0.001). After excluding patients who received workers' compensation, the mTBI group still missed significantly more days of work (M = 299.4 days; SD = 333.0) than the control group (M = 105.2 days; SD = 121.6) (p < 0.0001). CONCLUSION: This study shows that mTBI increases work disability by preventing working-age individuals from rapidly returning to work. PMID- 28876147 TI - Primary and secondary nonresponse to infliximab: mechanisms and countermeasures. AB - INTRODUCTION: Primary and secondary non-response to infliximab are common in patients with inflammatory bowel disease and remain a management challenge in clinical practice. Areas covered: This article describes the epidemiology, mechanisms and risk factors for primary and secondary nonresponse to infliximab in patients with inflammatory bowel disease. Data on proactive and reactive therapeutic drug monitoring are examined in this review. An algorithm for evaluation and management of non-response to infliximab is provided. Preventative measures are also discussed. Relevant articles were identified after a literature search using PubMed. Search terms included 'infliximab', 'loss of response', 'immunogenicity', and 'drug monitoring'. References of identified articles were also reviewed to identify additional references. Expert opinion: A common cause for primary and secondary non-response include inadequate dosing of infliximab; inadequate dosing can be identified through assessment of drug and anti-drug antibody levels. Therapeutic drug monitoring should be done in patients losing response to infliximab. Use of drug monitoring proactively is still under debate. PMID- 28876148 TI - How Is a Label of Borderline Personality Disorder Constructed on Twitter: A Critical Discourse Analysis. AB - This research took a social constructionist stance and explored how Borderline Personality Disorder (BPD) is constructed by Twitter users who identify with this diagnostic label. Consistent with this position, a critical discourse analysis (CDA) methodology was employed. The data comprised two-hundred and twenty-five tweets. Tweets from professionals, or links to blogs, were excluded, in an attempt to ensure only personal tweets were used. Two interpretative repertoires were produced from the analysis: BPD as an existence of tension and BPD as a different existence. The findings indicated that authors were involved in a negotiation between themselves and BPD, which had an impact upon their felt sense of agency/control over BPD. Likewise, authors constructed themselves in opposition to individuals who did not identify with the diagnosis of BPD. Whilst this provided more favourable positions, it potentially limited access to healthcare professionals and services. The research highlights the importance of the terminology and language clinicians employ when working with clients and other professionals, as they may inadvertently disempower or stigmatise. As CDA does not assume equivalence between individuals' accounts and their internal experiences, future research may need to explore the experience of stigmatisation through social networking sites. PMID- 28876149 TI - Acute post-concussive symptoms in young children. AB - OBJECTIVES: Despite peaks of mild traumatic brain injury (mTBI) incidence in young children, few studies have examined the nature of post-concussive symptoms (PCSs) in children under the age of eight, whilst controlling for pre-injury symptoms and effects of trauma. The current study aimed to identify which PCSs differentiate children with mTBI from trauma controls early post-injury, and whether these differed among preschool and school-aged children. METHODS: The sample comprised 101 children aged 2-12 presenting to an emergency department, with concussion or other minor bodily injury (control). Groups were divided by age (preschool and school-aged). PCSs were assessed within 72 hours post-injury using a comprehensive PCS checklist, administered to their parents via structured interview. RESULTS: Parents of children with mTBI reported significantly more symptoms in their children than parents of children with other minor bodily trauma, p < 0.001, r = 0.84. Parents of preschool and school-aged children reported an equal number of symptoms. However, subtle differences were observed between symptom profiles of preschool and school-aged children. CONCLUSIONS: Primary care clinicians should be aware of post-concussive symptom presentations in children of varying ages, in order to provide optimal care, especially in younger children. Methods of eliciting symptoms may influence the identification of symptoms. This issue warrants further examination in the paediatric population. ABBREVIATIONS ED emergency department; GCS Glasgow coma scale; mTBI mild traumatic brain injury; PCS post-concussive symptoms; PTA post-traumatic amnesia; TC trauma control. PMID- 28876150 TI - Collaborating across the threshold: The development of interprofessional expertise in child safeguarding. AB - This article reports on an empirical study of the expertise that different professionals develop in working together to safeguard children. The research involved three key professional groups who work with children: nursing, teaching, and social work. The methodology used a clinical scenario and critical incident to explore professional perspectives and experiences of collaboration. Data collection was via semi-structured interviews with a sample of 18 practitioners, composed of pre- and post-qualifying practitioners from each professional group. Data analysis was undertaken through an inductive process, with open coding of transcripts followed by the synthesis of themes into a qualitative framework. The findings identified different elements of interprofessional expertise including assessment and decision-making, responsibility, risk and uncertainty, managing relationships, and dealing with conflict and difficulty. Collaborative activity was found to be shaped by the threshold between statutory and non-statutory services and mediated by the relationship between practitioners and parents. The article concludes by exploring constraints and opportunities for addressing potential gaps in interprofessional expertise in this area. PMID- 28876151 TI - Isobaric tags for relative and absolute quantitation proteomics analysis of gene regulation by SprC in Staphylococcus aureus. AB - AIM: To explore the complete gene networks regulated by small RNA SprC and its targets in Staphylococcus aureus. MATERIALS & METHODS: The isobaric tags for relative and absolute quantitation and bioinformatic methods were utilized to identify and analyze the target proteins affected by SprC in S. aureus N315. RESULTS: Proteomic analysis showed that the expression of 44 proteins was modulated by SprC. Further, bioinformatic analysis displayed that these affected proteins mainly associated with metabolic and cellular process, biological regulation and catalytic activity. CONCLUSION: Our data provide a rich resource of SprC targets in S. aureus, although the mechanism of regulation by SprC is yet to be elucidated. PMID- 28876153 TI - Neuropsychological outcome following childhood stroke - a review. AB - OBJECTIVES: Childhood stroke is a rare but devastating occurrence. Its infrequency has meant that a clear body of knowledge has not been fully established regarding its impact on neuropsychological outcome. Our aims were (i) to critically review the recent literature on neuropsychological outcome following childhood stroke; (ii) to investigate the factors related to neuropsychological outcome following childhood stroke. METHODS: Literature searches were conducted and revealed 39 relevant papers from the period 1999 2015. RESULTS: The review found that a significant number of children experience difficulties in a wide range of neuropsychological domains, with particular vulnerabilities noted in attention, speed of information processing and executive functioning. There were inconsistent findings regarding the correlates of neuropsychological outcome, which is likely due to methodological limitations of the studies. CONCLUSIONS: This review strongly indicates that childhood stroke can affect a myriad of neuropsychological domains, with attention, speed of processing and executive function particularly vulnerable. Methodological issues, particularly around heterogeneous samples and measurement difficulties, limit the conclusions that can be drawn regarding the predictors of outcome. PMID- 28876152 TI - Lipophilic fractions from the marine sponge Halichondria sitiens decrease secretion of pro-inflammatory cytokines by dendritic cells and decrease their ability to induce a Th1 type response by allogeneic CD4+ T cells. AB - CONTEXT: Halichondria (Halichondriidae) marine sponges contain components possessing various biological activities, but immunomodulation is not among the ones reported. OBJECTIVE: This study evaluated the immunomodulatory effects of fractions/compounds from Halichondria sitiens Schmidt. MATERIALS AND METHODS: Crude dichloromethane/methanol extracts of H. sitiens were subjected to various chromatographic techniques to obtain fractions/compounds with immunomodulatory activity, using bioassay-guided isolation. The effects of the fractions/compounds were determined by measuring secretion of cytokines and expression of surface molecules by dendritic cells (DCs) and their ability to stimulate and modify cytokine secretion by allogeneic CD4+ T cells. The bioactive fractions were chemically analyzed to identify the immunomodulatory constituents by 1D, 2D NMR, and HRMS data. RESULTS: Several lipophilic fractions from H. sitiens at 10 MUg/mL decreased secretion of the pro-inflammatory cytokines IL-12p40 and IL-6 by the DCs, with maximum inhibition being 64% and 25%, respectively. In addition, fractions B3b3F and B3b3J decreased the ability of DCs to induce T cell secretion of IFN-gamma. Fraction B3b3 induced morphological changes in DCs, characterized by extreme elongation of dendrites and cell clustering. Chemical screening revealed the presence of glycerides and some minor unknown constituents in the biologically active fractions. One new glyceride, 2,3-dihydroxypropyl 2 methylhexadecanoate (1), was isolated from one fraction and two known compounds, 3-[(1-methoxyhexadecyl)oxy]propane-1,2-diol (2) and monoheptadecanoin (3), were identified in another, but none of them had immunomodulatory activity. DISCUSSION AND CONCLUSIONS: These results demonstrate that several lipophilic fractions from H. sitiens have anti-inflammatory effects on DCs and decrease their ability to induce a Th1 type immune response. PMID- 28876154 TI - AAFP Position Statement: Declawing. PMID- 28876155 TI - A study protocol for enriching the interprofessional collaborative competency attainment survey insights. AB - The following short report outlines a proposed study designed to evaluate the Interprofessional Collaborative Competency Attainment Survey and its recommended method of administration. This exploratory study seeks to determine if there is a significant difference between two methods of administration, the recommended and validated retrospective pre-test and post-test, and a traditional pre-test and post-test. If a significant difference does exist, this data will provide a means to determine the effect size of that difference. The comparison will be done using repeated measure ANOVA and the subsequent effect size will be evaluated using Cohen's d. As the retrospective design is utilised to evaluate a change in perceived competency, comparison of data from a traditional pre-test with a retrospective pre-test may provide a means for evaluation of the participants' change in understanding of the construct, and thus a more thorough picture of the forces driving changes to scores. PMID- 28876156 TI - Home-based circuit training program for an adolescent female with severe traumatic brain injury: A case report. AB - Adolescents with traumatic brain injury (TBI) are often discharged from physical therapy (PT) services without transitioning into exertional conditioning programs. Active participation in physical activities with peers at school is essential to achieve a sense of accomplishment and acceptance. Factors such as reduced aerobic fitness and residual gait impairments can lead to limited participation and peer interaction. The purpose of this case report was to describe the impact of home-based circuit training (HBCT) focusing on strength and balance on gait speed (GS), energy expenditure, and functional performance in a 17-year-old female with severe TBI. The participant sustained a TBI from a motor vehicle crash. Although she was ambulatory and independent with the basic activities of daily living following two years of rehabilitation, she presented with activity limitations and participation restrictions at school. The participant performed a 4-week HBCT program developed by a school physical therapist that focused on strength and balance. At the end of 4 weeks, improvements were observed in 6 MWT (change = 79.7 m), GS (change = 0.22 m/s), and the COPM scores (performance score change = 2.8, satisfaction score change = 2.2, MCID = 2). Improvements in functional performance, gait speed, and self perception of occupational performance were observed following 4-week HBCT. Future clinical trials on short duration, HBCT program for children and young adults with TBI are recommended in order to establish effectiveness of HBCT. PMID- 28876157 TI - Physician Aid in Dying: Caught Between the Extremes. PMID- 28876158 TI - Decision to Die. PMID- 28876159 TI - Implementing a Multidisciplinary Approach to Enhance Compliance With Guideline Recommended Prechemotherapy Pneumococcal Vaccination in a Military-Based Medical Oncology Practice. AB - PURPOSE: Patients with cancer are at increased risk for invasive pneumococcal disease, including community-acquired pneumonia. Current Advisory Committee on Immunization Practices and National Cancer Comprehensive Network guidelines recommend pneumococcal vaccination for immunocompromised patients, including patients with cancer. METHODS: We conducted a quality improvement (QI) project to enhance compliance with pneumococcal vaccination in patients before their chemotherapy. Baseline pneumococcal vaccination rates were gathered from July 2013 to June 2014. We reviewed the current guidelines for pneumococcal vaccinations in patients with cancer with physicians and encouraged them to prescribe the pneumococcal vaccination to patients before therapy. We also recruited our clinic nurse practitioner, who meets all patients for chemotherapy teaching, to prescribe the vaccine to patients younger than 65 years of age. RESULTS: During the baseline period, of the 110 patients younger than 65 years who received chemotherapy, seven (6.4%) received the pneumococcal vaccine. Of the 90 patients (median age, 60 years; range, 20 to 86 years) who received chemotherapy during the study period, 58 were younger than 65 years, of whom three patients were already vaccinated before their diagnosis. Twenty-five (45.5%) patients were vaccinated through our QI project. We have improved our compliance with pneumococcal vaccination by 39% ( P < .001). CONCLUSION: We have improved compliance with pneumococcal vaccination in patients with cancer receiving chemotherapy in our clinic through a QI project. We found that screening is best accomplished by a single person who is able to screen all patients. This practice is now a standard of care in our clinic. PMID- 28876160 TI - Abdominal draw-in maneuver combined with simulated weight bearing increases transversus abdominis and internal oblique thickness. AB - The abdominal draw-in maneuver (ADIM) is a method commonly used to reestablish neuromuscular control of the deep spine muscles among individuals with musculoskeletal problems. The purpose of this study was to evaluate the effect of ADIM combined with simulated weight-bearing (SWB) activities in the facilitation of the deep spine muscles. The subjects were 30 young healthy individuals. Ultrasound images were used to measure the relative changes in transverse abdominal (TrA), internal oblique (IO) and external oblique (EO) muscle thickness during a simulated weight-bearing ADIM (SWB-ADIM). A paired t-test was used to determine the differences between the ADIM and SWB-ADIM conditions. The results showed that the thickness of the TrA and IO muscles in the SWB-ADIM condition was significantly higher than in the ADIM-alone condition. Our findings suggest that SWB-ADIM is more effective than ADIM alone for improving the deep spine muscles in real-life situations. PMID- 28876161 TI - Ergonomic interventions for prevention of work-related musculoskeletal disorders in a small manufacturing assembly line. AB - This study involves performing improvements in workstation specification using a three-dimensional human modeling tool and proposing well-balanced work scheduling (WBWS) to prevent work-related musculoskeletal disorders (WMSDs) in a small manufacturing plant. To analyze risk factors of WMSDs, various tasks at 10 different types of workstation were evaluated with detailed motion analysis using a customized checklist. Questionnaires were administered to 27 workers to evaluate symptoms related to WMSDs. Revised workstation specifications were suggested based on anthropometric characteristics of workers using before-after analyses as an engineering control. Additionally, WBWS was proposed as an administrative control to avoid continuous physical stress on specific body parts in repetitive tasks. A software tool for WBWS was developed for convenient and easy application. The results of the study may aid managers in applying ergonomic interventions with time and cost savings, and enhance worker satisfaction and motivation due to improvements in working conditions to prevent WMSDs. PMID- 28876163 TI - Concurrent validity of inclinometer measures of scapular and clavicular positions in arm elevation. AB - OBJECTIVE: To assess concurrent validity, between and within-day reliability of scapular and clavicular digital inclinometer measures. DESIGN: Test-retest and concurrent validity. SETTING: Laboratory. PARTICIPANTS: Twenty-three participants with and without shoulder symptoms. MAIN OUTCOME MEASURES: Static positions of scapular upward rotation, anterior/posterior tilting and clavicular elevation were measured between days with an inclinometer and compared to a 3-dimensional electromagnetic tracking system in different positions of sagittal plane humeral elevation (neutral, 30 degrees , 60 degrees , 90 degrees , 120 degrees ). The two methods were compared using a two-way Analysis of Variance. Linear regressions at each arm position were also performed to further assess concurrent validity. RESULTS: Between-day reliability demonstrated Intraclass Correlation Coefficients >= 0.50 for all comparisons. There were statistically significant differences between methods or interactions of method and arm position for clavicle elevation (p = 0.004, maximum offset between methods 7.7o in the neutral position), and scapular upward rotation (p = 0.001). For scapular upward rotation, the maximum difference between methods was less than 2 degrees across all humeral positions. Clavicle elevation (r = 0.67-0.82) and scapular upward rotation (r = 0.57-0.81) demonstrated higher correlations between measurement methods than scapular anterior/posterior tilt (r = 0.10-0.67). CONCLUSIONS: Concurrent validity in assessing scapular upward rotation and clavicle elevation with an inclinometer was shown when compared with electromagnetic tracking. However, the inclinometer method may not have adequate concurrent validity to clinically measure scapular anterior/posterior tilting. PMID- 28876164 TI - Evaluating the blue-light hazard from solid state lighting. AB - PURPOSE: New light sources including light-emitting diodes (LEDs) have elicited questions about retinal damage, including the blue-light hazard. Some organizations have recommended avoiding using LEDs with correlated color temperatures exceeding 3000 K, since they tend to produce greater short wavelength energy. This article provides quantitative comparisons among light sources and use cases as they affect the blue-light hazard. METHODS: The spectral radiant power characteristics of incandescent, fluorescent, LED and daylight sources were evaluated in terms of blue-light hazard using standard procedures for phakic, aphakic and pseudophakic eyes. RESULTS: Under most use cases, LEDs do not exhibit greater risk for the blue-light hazard than other sources (e.g., incandescent). Because they generally produce little to no ultraviolet energy, LEDs often present less risk to aphakic eyes. CONCLUSIONS: LEDs present no special concerns for the blue-light hazard over some other common sources in typical use cases because photophobic responses limit exposure to bright sources. Where photophobic responses might not occur (e.g., eye surgery patients or premature infants) or where individuals suppress these responses (e.g., stage actors), caution is necessary. Evidence remains inconsistent regarding the risk of human retinal damage from long-term exposures to light insufficient to reach acute blue-light hazard thresholds. PMID- 28876162 TI - Capacity limits of asialoglycoprotein receptor-mediated liver targeting. AB - The abundant cell surface asialoglycoprotein receptor (ASGPR) is a highly selective receptor found on hepatocytes that potentially can be exploited as a selective shuttle for delivery. Various nucleic acid therapeutics that bind ASGPR are already in clinical development, but this receptor-mediated delivery mechanism can be saturated, which will likely result in reduced selectivity for the liver and therefore increase the likelihood for systemic adverse effects. Therefore, when aiming to utilize this mechanism, it is important to optimize both the administration protocol and the molecular properties. We here present a study using a novel ASGPR-targeted antibody to estimate ASGPR expression, turnover and internalization rates in vivo in mice. Using pharmacokinetic data (intravenous and subcutaneous dosing) and an in-silico target-mediated drug disposition (TMDD) model, we estimate an ASGPR expression level of 1.8 million molecules per hepatocyte. The half-life of the degradation of the receptor was found to be equal to 15 hours and the formed ligand-receptor complex is internalized with a half-life of 5 days. A biodistribution study was performed and confirmed the accuracy of the TMDD model predictions. The kinetics of the ASGPR shows that saturation of the shuttle at therapeutic concentrations is possible; however, simulation allows the dosing schedule to be optimized. The developed TMDD model can be used to support the development of therapies that use the ASGPR as a shuttle into hepatocytes. PMID- 28876166 TI - Photo-assisted electrochemical degradation of polychlorinated biphenyls with boron-doped diamond electrodes. AB - The capacity of the photo electro-Fenton (PEF) process to degrade a mixture of seven polychlorinated biphenyl (PCB) congeners was studied. Boron-doped diamond (BDD) sheets were used as anode and cathode in the experimental electrolytic cell that contained Na2SO4 0.05 M at pH 3 as supporting electrolyte for the electro generation of H2O2 at the cathode. The effects of UV light intensity (254 and 365 nm), current density (8, 16 and 24 mA cm-2) and ferrous ion dosage (0.1, 0.2 and 0.3 mM) on PCB (C0 = 50 MUg L-1) degradation were evaluated. The highest level of PCB degradation (97%) was achieved with 16 mA cm-2 of current density, 0.1 mM of ferrous ion and UV light at 365 nm as irradiation source after 6 h of reaction. PCB28, PCB52 and PCB101 were not detected after 0.5, 1.5 and 3 h of reaction, respectively. The degradation of PCB138, PCB153, PCB180 and PCB209 was also high (>95%). The PEF system outperformed other oxidation processes (electro-Fenton, anodic oxidation, Fenton, photo-Fenton and UV photolysis) in terms of reaction rate and degradation efficiency. These results demonstrate for the first time the degradation of PCB209, the most highly chlorinated PCB congener, by an advanced electrochemical oxidation process. PMID- 28876165 TI - Development of "material-specific" hemispheric specialization from beginning to end. AB - Disparity of verbal and performance intelligence (VIQ, PIQ) on the Wechsler scales of intelligence is a conceptually cluttered and empirically weak measure of hemispheric specialization (HS). However, in the context of life span research, it is the only measure that can be exploited meta-analytically with the lesion method from prenatal life to late senescence. We assembled 1917 cases with a unilateral cortical focal brain lesion occurring at all ages and a post-lesion VIQ and PIQ. Lesion locus, volume and side were documented for each case, as well as age at lesion onset, age at first symptoms and age at the IQ test, presence/absence of epilepsy, lesion aetiology, gender, date of publication or of transfer of medical file. With and without covariate adjustment, HS was significant across the life span though its pattern changed. HS increased linearly and highly significantly until late senescence. Only in early adulthood did VIQ appear to vacate the right temporal lobe and occupy the left and PIQ vacate the left parietal lobe and occupy the right until late senescence. Biomaturational factors are more important in the ontogeny of material-specific HS over the whole life span than previously established. PMID- 28876167 TI - Sexual Orientation-Based Discrimination, Excessive Alcohol Use, and Substance Use Disorders Among Sexual Minority Adults. AB - PURPOSE: The purpose of this study was to examine relationships between sexual orientation-based discrimination and excessive alcohol use and substance use disorders and to identify how these relationships differ by sexual identity, sex, race, Hispanic origin, and education among sexual minorities. METHODS: We used logistic regression to analyze associations between discrimination and substance use measures among 1351 gay/lesbian, bisexual, or unsure adults from a nationally representative survey. Differential effects by sexual identity, sex, race, Hispanic origin, and education were assessed using interaction models followed by stratified models. RESULTS: Discrimination was associated with increased odds of the following: exceeding weekly drinking limits [adjusted odds ratio (aOR) = 1.52, 95% confidence interval (CI): 1.12-2.08] among bisexuals, any substance use disorder (aOR = 2.04, 95% CI: 1.41-2.95) and nicotine use disorder (aOR = 1.52, 95% CI: 1.08-2.14) among Hispanic sexual minorities, and exceeding weekly drinking limits (aOR = 1.56, 95% CI: 1.08-2.26) among those with a high school degree or less. CONCLUSION: Sexual orientation-based discrimination was associated with select substance use outcomes, especially among bisexuals, Hispanics, and less educated sexual minority adults, highlighting potential disparities associated with experiencing discrimination. PMID- 28876168 TI - Complete Sequence of pCY-CTX, a Plasmid Carrying a Phage-Like Region and an ISEcp1-Mediated Tn2 Element from Enterobacter cloacae. AB - A plasmid pCY-CTX carrying a phage-like backbone from an extensively drug resistant Enterobacter cloacae strain Guangzhou-ECL001 (previously known as CY01) was identified in this study. By Illumina MiSeq 2 * 250-bp paired-end sequencing, de novo assembly, and PCR, full sequence of pCY-CTX was obtained. Plasmid pCY-CTX was a circular plasmid with a length of 116,700 bp, harboring 136 putative open reading frames with the average G + C content of 50.8%. The backbone of pCY-CTX showed high identity to previously reported phage-like plasmid pHCM2 and phage SSU5. In addition, pCY-CTX contained a distinctive ISEcp1-mediated Tn2 region with two resistance genes blaTEM-1 and blaCTX-M-3. Transposition unit "ISEcp1- blaCTX-M-3- orf477" was inserted into the Tn2 structure, dividing Tn2 into two parts. This represents the first identification of a plasmid carrying a phage like backbone and a distinctive ISEcp1-mediated Tn2 region within blaTEM-1 and blaCTX-M-3 in clinical E. cloacae. The finding of phage-like regions located in plasmids provides a new perspective in gene transfer associated with antimicrobial resistance. PMID- 28876169 TI - NDM-1 Hazard in the Balkan States: Evidence of the First Outbreak of NDM-1 Producing Klebsiella pneumoniae in Bulgaria. AB - New Delhi MBL (NDM) carbapenemase-producing Klebsiella pneumoniae has become one of the most concerning multidrug-resistant pathogens. The Balkan counties are considered a reservoir for the spread of such strains based on several reports documenting NDM infections after hospitalization in this region. Nevertheless, NDM-producing K. pneumoniae have been only occasionally documented from Balkans. The current study documents the first polyclonal outbreak caused by NDM-1 producing K. pneumoniae in Bulgaria. From July 2015 to April 2016, all 25 single patient carbapenem-nonsusceptible K. pneumoniae isolates were collected. Phenotypic and molecular screening revealed that 17 produced NDM-1 carbapenemase. All NDM-1 producers harbored blaCTX-M-15, blaCMY-4, blaTEM-1, and blaOXA-2; five also harbored blaOXA-1. In all cases, blaNDM-1 was flanked upstream by ISAba125 element and downstream by bleMBL. Pulsed-field gel electrophoresis (PFGE) clustered NDM-1-positive isolates into four distinct clonal types, A to D. MLST assigned isolates of the dominant clonal type A (n = 14) to sequence type (ST) 11, while isolates of clonal types B, C, and D to ST16, ST15, and ST391, respectively. Of interest, ST11 isolates belonged to the same PFGE type as those of the recently described NDM-1 ST11 clonal outbreak in Greece. Traveling abroad or overseas hospitalization was not reported in any case, suggesting most likely intra- and interhospital dissemination. The study presents the first polyclonal outbreak of NDM-producing K. pneumoniae in the Balkans and underlines the need for larger epidemiological studies in the region to illustrate commonalities in the transmission of NDM clones and possible sources in the community. PMID- 28876171 TI - Zinc leaching behavior in semi-aerobic landfill. AB - Municipal solid waste landfills require continuous monitoring because that the environmental change may trigger sudden release of heavy metals and need special care. In this research, three simulated landfills with different operation modes were used to investigate the behavior of Zn during the decomposition process. It is difficult to evaluate the effects of landfill operating modes on the release of heavy metals because the Zn concentration variation in leachate is similar in all three landfill types. However, the cumulative amount of Zn leached differed significantly with the landfill degradation degree. Zn can continuously leach from the traditional anaerobic landfill but relatively well retain in the semi aerobic landfill. Leachate recirculation and air exposure not only promote the landfill stabilization process, but also obviously lower the risk of Zn pollution in the leachate by transforming it from unstable fractions to the more stable one, the residual fraction. Although heavy metal experiences vertical migration within the landfill, the transformation process retains it in the refuse and avoids its sudden release. The release of the most active fraction of Zn can be neglected during the rapid degradation stage and the most stable fraction of Zn can always be maintained at a positive level in all landfill modes tested. PMID- 28876170 TI - Transgender Women Living with HIV Frequently Take Antiretroviral Therapy and/or Feminizing Hormone Therapy Differently Than Prescribed Due to Drug-Drug Interaction Concerns. AB - PURPOSE: Both hormone therapy (HT) and antiretroviral therapy (ART) can be lifesaving for transgender women (TW) living with HIV, but each has side effects and potential drug-drug interactions (DDI). We assessed how concerns about HT-ART interactions affect treatment adherence. METHODS: This study used a cross sectional survey of TW (n = 87) in Los Angeles, CA. RESULTS: Fifty-four percent were living with HIV; 64% used HT. Only 49% of TW living with HIV discussed ART HT DDI with their provider; 40% reported not taking ART (12%), HT (12%), or both (16%) as directed due to DDI concerns. CONCLUSION: Imperfect HT/ART use and limited provider communication suggests a need for improved HT-ART integration. PMID- 28876173 TI - Silencing of Putative Cytokinin Receptor Histidine Kinase1 Inhibits Both Inception and Differentiation of Root Nodules in Arachis hypogaea. AB - Rhizobia-legume interaction activates the SYM pathway that recruits cytokinin signaling for induction of nodule primordia in the cortex. In Arachis hypogaea, bradyrhizobia invade through natural cracks developed in the lateral root base and are directly endocytosed in the cortical cells to generate the nodule primordia. To unravel the role of cytokinin signaling in A. hypogaea, RNA interference (RNAi) of cytokinin receptor histidine-kinase1 (AhHK1) was done. AhHK1-RNAi downregulated the expression of type-A response regulators such as AhRR5 and AhRR3 along with several symbiotic genes, indicating that both cytokinin signaling and the SYM pathway were affected. Accordingly, there was a drastic downregulation of nodulation in AhHK1-RNAi roots and the nodules that developed were ineffective. These nodules were densely packed, with infected cells having a higher nucleo-cytoplasmic ratio and distinctively high mitotic index, where the rod-shaped rhizobia failed to differentiate into bacteroids within spherical symbiosomes. In accordance with the proliferating state, expression of a mitotic-cyclin AhCycB2.1 was higher in AhHK1-RNAi nodules, whereas expression of a retinoblastoma-related (AhRBR) nodule that restrains proliferation was lower. Also, higher expression of the meristem maintenance factor WUSCHEL-RELATED HOMEOBOX5 correlated with the undifferentiated state of AhHK1-RNAi nodules. Our results suggest that AhHK1-mediated cytokinin signaling is important for both inception and differentiation during nodule development in A. hypogaea. PMID- 28876172 TI - Variant snRNPs: New players within the spliceosome system. AB - Much evidence is now accumulating that, in addition to their general role in splicing, the components of the core splicing machinery have extensive regulatory potential. In particular, recent evidence has demonstrated that de-regulation of these factors cause the highest extent of alternative splicing changes compared to de-regulation of the classical splicing regulators. This lack of a general inhibition of splicing resonates the differential splicing effects observed in different disease pathologies associated with specific mutations targeting core spliceosomal components. In this review we will summarize what is currently known regarding the involvement of core spliceosomal U-snRNP complexes in perturbed tissue development and human diseases and argue for the existence of a compensatory mechanism enabling cells to cope with drastic perturbations in core splicing components. This system maintains the correct balance of spliceosomal snRNPs through differential expression of variant (v)U-snRNPs. PMID- 28876174 TI - The Bacterial Effector AvrPto Targets the Regulatory Coreceptor SOBIR1 and Suppresses Defense Signaling Mediated by the Receptor-Like Protein Cf-4. AB - Receptor-like proteins (RLPs) and receptor-like kinases (RLKs) are cell-surface receptors that are essential for detecting invading pathogens and subsequent activation of plant defense responses. RLPs lack a cytoplasmic kinase domain to trigger downstream signaling leading to host resistance. The RLK SOBIR1 constitutively interacts with the tomato RLP Cf-4, thereby providing Cf-4 with a kinase domain. SOBIR1 is required for Cf-4-mediated resistance to strains of the fungal tomato pathogen Cladosporium fulvum that secrete the effector Avr4. Upon perception of this effector by the Cf-4/SOBIR1 complex, the central regulatory RLK SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3a (SERK3a) is recruited to the complex and defense signaling is triggered. SOBIR1 is also required for RLP-mediated resistance to bacterial, fungal ,and oomycete pathogens, and we hypothesized that SOBIR1 is targeted by effectors of such pathogens to suppress host defense responses. In this study, we show that Pseudomonas syringae pv. tomato DC3000 effector AvrPto interacts with Arabidopsis SOBIR1 and its orthologs of tomato and Nicotiana benthamiana, independent of SOBIR1 kinase activity. Interestingly, AvrPto suppresses Arabidopsis SOBIR1-induced cell death in N. benthamiana. Furthermore, AvrPto compromises Avr4-triggered cell death in Cf-4-transgenic N. benthamiana, without affecting Cf-4/SOBIR1/SERK3a complex formation. Our study shows that the RLP coreceptor SOBIR1 is targeted by a bacterial effector, which results in compromised defense responses. PMID- 28876175 TI - An application of the Pareto method in surveys to diagnose managers' and workers' perception of occupational safety and health on selected Polish construction sites. AB - The construction industry is an important sector of the economy in Poland. According to the National Labour Inspectorate (PIP) data of 2014, the number of victims of fatal accidents in the construction sector amounted to 80 as compared with 187 injured in all other sectors of economy in Poland. This article presents the results of surveys on the impact of construction worker behaviour on the occupational safety and health outcomes. The surveys took into account the point of view of both construction site management (tactical level) and construction workers (operational level). For the analysis of results, the method of numerical taxonomy and Pareto charts was employed, which allowed the authors to identify the areas of occupational safety and health at both an operational and a tactical level, in which improvement actions needed to be proposed for workers employed in micro, small, medium and large construction enterprises. PMID- 28876176 TI - Gynecomastia: histological appearance in different age groups. AB - OBJECTIVE: Gynecomastia is a common finding in the male population which is mostly idiopathic. The aim of our study was to analyze the histological differences in young and old patient groups and its association with recurrence rates. METHODS: Three hundred and five gynecomastia patients (555 breasts) undergoing surgical treatment from 1997 to 2015 were divided into four groups: Group 1: 13-17 years, Group 2: 18-30 years, Group 3: 31-49 years and Group 4: 50 83 years. They were evaluated concerning clinical classification, histological differences and association with antiandrogen or steroids/immunosuppressive therapy. RESULTS: We found that the rate of florid gynecomastia was higher in older patient groups, while fibrous gynecomastia was more common in adolescents and young adults (p = .0180). Glandular gynecomastia was more frequent in younger patients, while in the older patient groups, lipomatous gynecomastia was more common (p = .0006). Patients presenting with florid gynecomastia showed a higher rate of recurrence than patients with the fibrous type of gynecomastia (12.5 and 4.7%, respectively). Of note, 18.75% of florid gynecomastia was associated with antiandrogen agents or steroid/immunosuppressive therapy, while only 4.69% of fibrous gynecomastia was associated with antiandrogenic or immunosuppressive therapy. However, there was no increase of recurrence rates in patients using antiandrogen agents or undergoing steroid/immunosuppressive therapy. CONCLUSIONS: Fibrous gynecomastia was found to be more common in adolescents and young adults, while the florid type was more frequent in older patients. Patients presenting with florid gynecomastia showed a higher rate of recurrence than patients with the fibrous type of gynecomastia. PMID- 28876177 TI - Ancient Indian concepts about phenomenology, biology, and therapeutics of epilepsy. AB - This article discusses etiology, pathogenesis, symptoms, and treatment of epilepsy, as described in Charaka Samhita (translation: Charaka's Compendium) and Sushruta Samhita, the two core texts of Ayurveda, an ancient system of medicine. Ayurveda emphasized amnesia and loss of consciousness as core features of epileptic seizures (Sanskrit: apasmar; translation: apa negation, smaran memory) and recognized that seizures occur due to a disturbance in brain function or flow of "humors" to the brain. Semiology of various seizure types was well described. Epilepsy was attributed to both internal and multiple exogenous factors. Treatment of epilepsy with formulations of naturally occurring substances, their compounding and use, is described in remarkable detail. Lifestyle modifications to protect people with epilepsy are also documented. Cognitive comorbidities of epilepsy were recognized. Although none of the Ayurveda formulations have any empirical evidence supporting their safety or efficacy in the treatment of epilepsy, studies are needed to generate relevant evidence, to recognize their hazards, and to integrate traditional and complementary systems of medicine with modern health care in an informed and safe manner. PMID- 28876178 TI - Handedness and Reach-to-Place Kinematics in Adults: Left-Handers Are Not Reversed Right-Handers. AB - The primary goal of this study was to examine the relations between limb control and handedness in adults. Participants were categorized as left or right handed for analyses using the Edinburgh Handedness Inventory. Three-dimensional recordings were made of each arm on two reach-to-place tasks: adults reached to a ball and placed it into the opening of a toy (fitting task), or reached to a Cheerio inside a cup, which they placed on a designated mark after each trial (cup task). We hypothesized that limb control and handedness were related, and we predicted that we would observe side differences favoring the dominant limb based on the dynamic dominance hypothesis of motor lateralization. Specifically, we predicted that the dominant limb would be straighter and smoother on both tasks compared with the nondominant limb (i.e., right arm in right-handers and left arm in left-handers). Our results only partially supported these predictions for right-handers, but not for left-handers. When differences between hands were observed, the right hand was favored regardless of handedness group. Our findings suggest that left-handers are not reversed right-handers when compared on interlimb kinematics for reach-to-place tasks, and reaffirm that task selection is critical when evaluating manual asymmetries. PMID- 28876179 TI - The inhibitory effects of Dracocephalum moldavica L. (DML) on rat cerebral ischemia reperfusion injury. AB - Ischemia reperfusion injury (IRI) is closely associated with oxidative stress and inflammatory responses. Dracocephalum moldavica L. (DML), a Chinese herbal medicine is known to exert protective effects on myocardial ischemia reperfusion injury in rats by inhibiting oxidation damage and inflammatory reactions. However, the effectiveness of DML in cerebral ischemia reperfusion injury (CIRI) as a protective substance and the underlying mechanisms remain to be determined. The aim of this study was thus to examine the influence of DML on CIRI using a rat model induced by 2-h transient middle cerebral artery occlusion (MCAO) produced by intraluminal suture blockade followed by 22 h reperfusion. The parameters determined include neurological behavior, histochemical assessment of cerebral infarct volume, and determination of various metabolic biomarkers. Data showed that DML markedly improved neurobehavioral scores and reduced cerebral edema and infarction. In addition, DML significantly reduced malondialdehyde (MDA) content and elevated activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), in addition, marked decrease in levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF alpha). Data suggest that the protective effects of DML on CIRI may be related to processes involving antioxidation and anti-inflammation. PMID- 28876181 TI - Introduction. PMID- 28876182 TI - Commentary on Krupa and Leebens. PMID- 28876180 TI - Description of Bifiguratus adelaidae: The hunt ends for one of the "Top 50 Most Wanted Fungi". PMID- 28876183 TI - Psychotherapy and Experience. PMID- 28876184 TI - Steven and Me. PMID- 28876185 TI - Communion. PMID- 28876186 TI - Introduction. PMID- 28876188 TI - The Impact of Insurance Gain and Discussions with Healthcare Providers on Quitting Smoking. AB - Tobacco use is the leading preventable cause of death in the United States. Analyzing the ability for different mechanisms to reduce smoking rates can provide healthcare systems with information to establish the most effective smoking cessation efforts. Health insurance provides individuals with direct mechanisms to curb smoking behavior, such as access to smoking cessation resources. Gaining insurance may additionally indirectly influence smoking cessation by altering risk perceptions. Behavioral economic theory suggests that gaining health insurance may reduce current smokers' rate of discounting on the future, which could increase smoking cessation. This article aimed to evaluate the impact of insurance status (i.e., gaining any private (n = 681), gaining only public (n = 647), or remaining uninsured (n = 5,056)) as well as the impact of having a discussion with a healthcare provider about quitting smoking on smoking cessation among current adult smokers who were uninsured at the beginning of their data collection. Data for this study came from the Medical Expenditure Panel Survey 2003 to 2014 database. The study found that while individuals gaining public insurance was not statistically associated with smoking cessation, individuals who gained private insurance were more likely to stop smoking than individuals who remained uninsured (OR: 1.330; 95% CI: 1.019,1.737; p = 0.036). Having a discussion with a healthcare provider about quitting smoking was not associated with smoking cessation. These findings indicate that gaining private insurance may impact smoking behavior through mechanisms other than direct access to physician services. PMID- 28876189 TI - Association between positive and negative affect and musculoskeletal pain among US home health aides. AB - As the US population ages, there is an expected increase in demand for home health aides (HHAs); therefore, it is important to ensure their occupational well being. Previous studies have demonstrated associations between negative emotions and musculoskeletal pain. Using survey data collected from 285 HHAs, we characterize the association between affect and musculoskeletal pain. Affect was measured using the Positive and Negative Affect Schedule, while musculoskeletal pain was measured using the Brief Pain Inventory. We found that as positive affect composite score increased, musculoskeletal pain decreased [beta = -0.57, t(124) = -7.01, p < .001]. There was no significant association between the negative affect composite score and musculoskeletal pain. However, several individual moods were associated with decreased or increased pain. These data suggest that some moods may buffer against musculoskeletal pain, while others may predispose HHAs to musculoskeletal pain. PMID- 28876190 TI - Surveillance of asymptomatic carotid artery stenosis: Not all plaques are created equal. PMID- 28876191 TI - Self-Care Practices and the Professional Self. AB - Consistently and actively engaging in self-care has been shown to improve the performance of mental health practitioners by reducing burnout, vicarious trauma, compassion fatigue, and other stress-related psychological problems. Not only is this important to the individual practitioner's well-being, but ethical standards also mandate the recognition and remediation of any physical, mental, or emotional self-impairment to maintain high standards of care for clients. Professionals in small communities, like the Deaf community, however, confront unique challenges in attending to their self-care. This article investigates these challenges-as well as the rewards-experienced by Deaf and hearing counselors working in mental health care with deaf clients. PMID- 28876192 TI - Do We Think Children Need a Mom and Dad?: Understanding How Gender Ideology Impact Attitudes Toward Same-Gender Parent Family Rights. AB - Research and opinion polls demonstrate that attitudes toward same-gender parent families have been improving in recent years among Western countries; however, the history of oppression toward, and misconceptions about, same-gender parent families continue to be demonstrated in Australian family rights policies. Common misconceptions include the belief that children need both male and female role models, and this could be influencing peoples' support for same-gender family rights and having a wider impact on legislation change. Yet a dearth of research exists exploring a connection between gender role beliefs and support for same gender family rights using a broad international sample, including Australia. To investigate this connection, a sample (N = 615) from 18 English-speaking countries responded to a series of questions to determine the importance of gender norm beliefs on same-gender family prejudice. Regression analysis demonstrated that people with traditional beliefs about gender norms were more likely to endorse a negative attitude toward same-gender marriage and same-gender parenting. Findings suggest a link between socially prescribed gender norms and prejudice toward same-gender parent families that may be fueling arguments against same-gender family rights policies. The implications of these findings on same-gender parent families and their rights require future investigation. PMID- 28876193 TI - Maternal and newborn health implementation research: programme outcomes, pathways of change and partnerships for equitable health systems in Uganda. PMID- 28876194 TI - Potential orofacial hazards of resistance training: A controlled comparative study. AB - Objective To evaluate the effect of resistance training (RT) regarding potential hazard for dental wear, tooth abfractions, temporomandibular joint disc displacement, limitation in mouth opening, and existence of cervical spine disorders. The initial study hypothesis was that extensive resistance trainees (ExRT) would suffer from the above-mentioned symptoms more often than recreational trainees (RcT). Methods A controlled comparative study among male gym members via questionnaires and a clinical examination. Results ExRT had a higher prevalence of teeth indentations on the tongue (26% vs. 2% p < 0.001) and a higher prevalence of tooth abfractions than RcT (28% vs. 4% p < 0.005). ExRT exhibited a higher prevalence of cervical movement limitations (p < 0.05) and inadequate posture (p < 0.001). Conclusion RT by itself may not be a risk factor for disc displacement. Nevertheless, it may act as a potential risk factor for irreversible hard tooth tissue damage and contribute to neck postural and mobility impairments. PMID- 28876195 TI - Bifiguratus adelaidae, gen. et sp. nov., a new member of Mucoromycotina in endophytic and soil-dwelling habitats. AB - Illumina amplicon sequencing of soil in a temperate pine forest in the southeastern United States detected an abundant, nitrogen (N)-responsive fungal genotype of unknown phylogenetic affiliation. Two isolates with ribosomal sequences consistent with that genotype were subsequently obtained. Examination of records in GenBank revealed that a genetically similar fungus had been isolated previously as an endophyte of moss in a pine forest in the southwestern United States. The three isolates were characterized using morphological, genomic, and multilocus molecular data (18S, internal transcribed spacer [ITS], and 28S rRNA sequences). Phylogenetic and maximum likelihood phylogenomic reconstructions revealed that the taxon represents a novel lineage in Mucoromycotina, only preceded by Calcarisporiella, the earliest diverging lineage in the subphylum. Sequences for the novel taxon are frequently detected in environmental sequencing studies, and it is currently part of UNITE's dynamic list of most wanted fungi. The fungus is dimorphic, grows best at room temperature, and is associated with a wide variety of bacteria. Here, a new monotypic genus, Bifiguratus, is proposed, typified by Bifiguratus adelaidae. PMID- 28876198 TI - Religion Education as Calling. PMID- 28876197 TI - The impact of FLT3 mutations on treatment response and survival in Chinese de novo AML patients. AB - OBJECTIVE: Two distinct forms of FMS-like tyrosine kinase 3 (FLT3) mutations, internal tandem duplication (ITD) in the juxtamembrane domain and point mutation within the activation loop of the tyrosine kinase domain (TKD), have been identified in considerable number of patients with AML. This study was aimed to analyze the impacts of these mutations on clinical outcomes, and assess the efficacy of different therapeutic regimens (allo-HSCT, sorafenib, or conventional chemotherapy) for AML patients with FLT3 mutations after the standard induction therapy. MATERIALS AND METHODS: We analyzed DNA samples from 158 consecutive de novo AML patients (18-60 years, excluding APL) with FLT3 mutations between July 2010 and October 2015. RESULTS: We found that AML patients with FLT3-TKD mutations have more favorable clinical outcomes than those with FLT3-ITD mutations. We also found that allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients (p < 0.001, p = 0.071). However, compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients. Further study on a large scale is still recommended. CONCLUSIONS: FLT3-TKD-mutated AML patients have more favorable clinical outcomes than those with FLT3-ITD mutations. Allo-HSCT therapy subgroup achieved longer OS and RFS than non-allo-HSCT therapy subgroup for FLT3-ITD positive patients. Compared with the clinical outcomes in non-primary refractory patients, sorafenib did not show an obvious beneficial effect for the primary refractory patients. PMID- 28876199 TI - Self-care among healthcare social workers: An exploratory study. AB - Despite growing interest in self-care, few studies have explicitly examined the self-care practices of healthcare social workers. This exploratory study investigated self-care among practitioners (N = 138) in one southeastern state. Overall, data suggest that healthcare social workers only moderately engaged in self-care. Additionally, analyses revealed significant differences in self-care practices by financial stability, overall health, and licensure status, respectively. Interestingly, perceived health status and current financial situation were significant predictors for overall self-care practices. After a brief review of the literature, this narrative will explicate findings, elucidate discussion points, identify salient implications, and conclude with areas for future research. PMID- 28876201 TI - Response Selection Contributes to the Preparation Cost for Bimanual Asymmetric Movements. AB - Movement preparation of bimanual asymmetric movements takes more time than bimanual symmetric movements in choice reaction-time conditions. This bimanual asymmetric cost may be caused by increased processing demands on any stage of movement preparation. The authors tested the contributions of each stage of movement preparation to the asymmetric cost by using the additive factors method. This involved altering the stimulus contrast, response compatibility, and response complexity. These manipulations changed the processing demands on stimulus identification, response selection, and response programming, respectively. Any manipulation with a larger reaction time cost than control suggests that stage contributes to the bimanual asymmetric cost. The bimanual asymmetric cost was larger for incompatible stimuli, which supports that response selection contributes to the bimanual asymmetric cost. PMID- 28876200 TI - The moderating role of emotional reactivity in the link between parental hostility and eating disorder symptoms in early adolescence. AB - Parent-adolescent relationship quality and affective functioning have been implicated in eating disorder development. This study examined whether maternal and paternal hostility interact to explain adolescents' eating disorder symptoms and whether parental hostility effects are more pronounced among adolescents with high emotional reactivity. A sample of 699 adolescents, ages 11-12 years, reported their parents' hostility and their own eating disorder symptoms, and parents reported adolescents' emotional reactivity. Results from structural equation modeling indicated that for emotionally reactive adolescents, paternal hostility was positively associated with eating disorder symptoms at both high and low levels of maternal hostility. In addition, eating disorder symptoms were amplified when both parents were high in hostility. Findings from this study lend support for the role of emotional reactivity in the link between parent hostility and eating disorder symptoms during adolescence. PMID- 28876202 TI - Implementation of an interprofessional communication and collaboration intervention to improve care capacity for heart failure management in long-term care. AB - Heart failure affects up to 20% of nursing home residents and is associated with high morbidity, mortality, and transfers to acute care. A major barrier to heart failure management in nursing home settings is limited interprofessional communication. Guideline-based heart failure management programs in nursing homes can reduce hospitalisation rates, though sustainability is limited when interprofessional communication is not addressed. A pilot intervention, 'Enhancing Knowledge and Interprofessional Care for Heart Failure', was implemented on two units in two conveniently selected nursing homes to optimise interprofessional care processes amongst the care team. A core heart team was established, and participants received tailored education focused on heart failure management principles and communication processes, as well as weekly mentoring. Our previous work provided evidence for this intervention's acceptability and implementation fidelity. This paper focuses on the preliminary impact of the intervention on staff heart failure knowledge, communication, and interprofessional collaboration. To determine the initial impact of the intervention on selected staff outcomes, we employed a qualitative design, using a social constructivist interpretive framework. Findings indicated a perceived increase in team engagement, interprofessional collaboration, communication, knowledge about heart failure, and improved clinical outcomes. Individual interviews with staff revealed innovative ways to enhance communication, supporting one another with knowledge and engagement in collaborative practices with residents and families. Engaging teams, through the establishment of core heart teams, was successful to develop interprofessional communication processes for heart failure management. Further steps to be undertaken include assessing the sustainability and effectiveness of this approach with a larger sample. PMID- 28876203 TI - Classifying the Severity of COPD: Are We There Yet? Editorial for "Coton, S. et al. Severity of Airflow Obstruction in Chronic Obstructive Pulmonary Disease (COPD): Proposal for a New Classification". PMID- 28876204 TI - External Validation of the COmorbidity Test. AB - The COmorbidity TEst (COTE) is a Chronic Obstructive Pulmonary Disease (COPD) specific co-morbidity score created to predict mortality. Before its wide application at the University of New Mexico we intended to validate it. The study was conducted at the University of New Mexico Hospital (UNMH) in Albuquerque, NM, USA, a tertiary academic hospital. Consecutive patients with the clinical diagnosis of COPD were identified using the hospital's medical records system and included if they were older than 40 years, had smoked at least 20 pack-years and their post bronchodilator forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) was <0.7 without an alternative diagnosis. The data collected included demographics, co-morbidities as described in the COTE, COPD specific therapies, spirometry results and mortality. Of 317 patients 51.4% were male, average age was 65.6 +/- 9.6 years and the mean post-bronchodilator FEV1 percent predicted (FEV1%) was 52.9 +/- 16.9%. 31 (9.8%) patients were on triple long-acting bronchodilator inhaler therapy, 88 (27.8%) on two long-acting bronchodilators and 163 (51.4%) on at least one long-acting bronchodilator. The median follow-up was 3.5 years (IQR = 1.9-6.9). Fifty four patients died by the end of the follow-up period and their median COTE of 4 (IQR = 1-8) was significantly higher than for the survivors with COTE = 1 (IQR = 0-6; p = 0.002). In univariable analyses COTE was positively associated while FEV1%, body mass index (BMI) and gender were negatively associated with all-cause mortality. In multivariable analysis BMI, FEV1% and COTE remained independent predictors for mortality. The COTE is an independent predictor of mortality for COPD patients at UNMH. PMID- 28876206 TI - Editorial. PMID- 28876207 TI - Inheritance of Virulence, Construction of a Linkage Map, and Mapping Dominant Virulence Genes in Puccinia striiformis f. sp. tritici Through Characterization of a Sexual Population with Genotyping-by-Sequencing. AB - Puccinia striiformis f. sp. tritici, the wheat stripe rust pathogen, is a dikaryotic, biotrophic, and macrocyclic fungus. Genetic study of P. striiformis f. sp. tritici virulence was not possible until the recent discovery of Berberis spp. and Mahonia spp. as alternate hosts. To determine inheritance of virulence and map virulence genes, a segregating population of 119 isolates was developed by self-fertilizing P. striiformis f. sp. tritici isolate 08-220 (race PSTv-11) on barberry leaves under controlled greenhouse conditions. The progeny isolates were phenotyped on a set of 29 wheat lines with single genes for race-specific resistance and genotyped with simple sequence repeat (SSR) markers, single nucleotide polymorphism (SNP) markers derived from secreted protein genes, and SNP markers from genotyping-by-sequencing (GBS). Using the GBS technique, 10,163 polymorphic GBS-SNP markers were identified. Clustering and principal component analysis grouped these markers into six genetic groups, and a genetic map, consisting of six linkage groups, was constructed with 805 markers. The six clusters or linkage groups resulting from these analyses indicated a haploid chromosome number of six in P. striiformis f. sp. tritici. Through virulence testing of the progeny isolates, the parental isolate was found to be homozygous for the avirulence loci corresponding to resistance genes Yr5, Yr10, Yr15, Yr24, Yr32, YrSP, YrTr1, Yr45, and Yr53 and homozygous for the virulence locus corresponding to resistance gene Yr41. Segregation was observed for virulence phenotypes in response to the remaining 19 single-gene lines. A single dominant gene or two dominant genes with different nonallelic gene interactions were identified for each of the segregating virulence phenotypes. Of 27 dominant virulence genes identified, 17 were mapped to two chromosomes. Markers tightly linked to some of the virulence loci may facilitate further studies to clone these genes. The virulence genes and their inheritance information are useful for understanding the host-pathogen interactions and for selecting effective resistance genes or gene combinations for developing stripe rust resistant wheat cultivars. PMID- 28876208 TI - Deep Sequencing Uncovers Rice Long siRNAs and Its Involvement in Immunity Against Rhizoctonia solani. AB - Small RNA (sRNA) is a class of noncoding RNA that can silence the expression of target genes. In rice, the majority of characterized sRNAs are within the range of 21 to 24 nucleotides (nt) long, whose biogenesis and function are associated with a specific sets of components, such as Dicer-like (OsDCLs) and Argonaute proteins (OsAGOs). Rice sRNAs longer than 24 nt are occasionally reported, with biogenesis and functional mechanism uninvestigated, especially in a context of defense responses against pathogen infection. By using deep sequencing, we identified a group of rice long small interfering RNAs (lsiRNAs) that are within the range of 25 to 40 nt in length. Our results show that some rice lsiRNAs are differentially expressed upon infection of Rhizoctonia solani, the causal agent of the rice sheath blight disease. Bioinformatic analysis and experimental validation indicate that some rice lsiRNAs can target defense-related genes. We further demonstrate that rice lsiRNAs are neither derived from RNA degradation nor originated as secondary small interfering RNAs (siRNAs). Moreover, lsiRNAs require OsDCL4 for biogenesis and OsAGO18 for function. Therefore, our study indicates that rice lsiRNAs are a unique class of endogenous sRNAs produced in rice, which may participate in response against pathogens. PMID- 28876209 TI - Soil Microbiomes Associated with Verticillium Wilt-Suppressive Broccoli and Chitin Amendments are Enriched with Potential Biocontrol Agents. AB - Two naturally infested Verticillium wilt-conducive soils from the Salinas Valley of coastal California were amended with disease-suppressive broccoli residue or crab meal amendments, and changes to the soil prokaryote community were monitored using Illumina sequencing of a 16S ribosomal RNA gene library generated from 160 bulk soil samples. The experiment was run in a greenhouse, twice, with eggplant as the Verticillium wilt-susceptible host. Disease suppression, plant height, soil microsclerotia density, and soil chitinase activity were assessed at the conclusion of each experiment. In soil with high microsclerotia density, all amendments significantly reduced Verticillium wilt severity and microsclerotia density, and increased soil chitinase activity. Plant height was increased only in the broccoli-containing treatments. In total, 8,790 error-corrected sequence variants representing 1,917,893 different sequences were included in the analyses. The treatments had a significant impact on the soil microbiome community structure but measures of alpha diversity did not vary between treatments. Community structure correlated with disease score, plant height, microsclerotia density, and soil chitinase activity, suggesting that the prokaryote community may affect the disease-related response variables or vice versa. Similarly, the abundance of 107 sequence variants correlated with disease related response variables, which included variants from genera with known antagonists of filamentous fungal plant pathogens, such as Pseudomonas and Streptomyces. Overall, genera with antifungal antagonists were more abundant in amended soils than unamended soils, and constituted up to 8.9% of all sequences in broccoli+crabmeal-amended soil. This study demonstrates that substrate mediated shifts in soil prokaryote communities are associated with the transition of Verticillium wilt-conducive soils to Verticillium wilt-suppressive soils, and suggests that soils likely harbor numerous additional antagonists of fungal plant pathogens that contribute to the biological suppression of plant disease. PMID- 28876210 TI - Statistical Power in Plant Pathology Research. AB - In null hypothesis testing, failure to reject a null hypothesis may have two potential interpretations. One interpretation is that the treatments being evaluated do not have a significant effect, and a correct conclusion was reached in the analysis. Alternatively, a treatment effect may have existed but the conclusion of the study was that there was none. This is termed a Type II error, which is most likely to occur when studies lack sufficient statistical power to detect a treatment effect. In basic terms, the power of a study is the ability to identify a true effect through a statistical test. The power of a statistical test is 1 - (the probability of Type II errors), and depends on the size of treatment effect (termed the effect size), variance, sample size, and significance criterion (the probability of a Type I error, alpha). Low statistical power is prevalent in scientific literature in general, including plant pathology. However, power is rarely reported, creating uncertainty in the interpretation of nonsignificant results and potentially underestimating small, yet biologically significant relationships. The appropriate level of power for a study depends on the impact of Type I versus Type II errors and no single level of power is acceptable for all purposes. Nonetheless, by convention 0.8 is often considered an acceptable threshold and studies with power less than 0.5 generally should not be conducted if the results are to be conclusive. The emphasis on power analysis should be in the planning stages of an experiment. Commonly employed strategies to increase power include increasing sample sizes, selecting a less stringent threshold probability for Type I errors, increasing the hypothesized or detectable effect size, including as few treatment groups as possible, reducing measurement variability, and including relevant covariates in analyses. Power analysis will lead to more efficient use of resources and more precisely structured hypotheses, and may even indicate some studies should not be undertaken. However, the conclusions of adequately powered studies are less prone to erroneous conclusions and inflated estimates of treatment effectiveness, especially when effect sizes are small. PMID- 28876212 TI - International Meeting of Environmental Health and Toxicology (IMEHTox): Advances in Toxicology and Environmental Health in Brazil. PMID- 28876211 TI - Human Papillomavirus-Related Cancer Surveillance, Prevention, and Screening Among Transgender Men and Women: Neglected Populations at High Risk. AB - Researchers and healthcare surveillance systems must clearly disaggregate data for transgender men and women from data for cisgender men and women to identify population-level health disparities and give every person an opportunity for cancer prevention. The limited human papillomavirus (HPV) vaccine recommendations for transgender men and women may be due to the scant literature on cancer prevalence coupled with poor understanding of HPV risks for these populations. Comprehensive cancer screening and prevention initiatives centered on relevant anatomy and sexual risk behaviors that are inclusive of transgender men and women are needed. Moreover, we need specific research to understand the impact of HPV and associated cancers on both transgender men's and women's lives. PMID- 28876213 TI - Effective Anti-miRNA Oligonucleotides Show High Releasing Rate of MicroRNA from RNA-Induced Silencing Complex. AB - MicroRNAs (miRNAs) regulate gene expression by forming RNA-induced silencing complexes (RISCs) and have been considered as promising therapeutic targets. MiRNA is an essential component of RISC for the modulation of gene expression. Therefore, the release of miRNA from RISC is considered as an effective method for the inhibition of miRNA functions. In our previous study, we reported that anti-miRNA oligonucleotides (AMOs), which are composed of the 2'-O-methyl (2' OMe) RNA, could induce the release of miRNA from RISC. However, the mechanisms underlying the miRNA-releasing effects of chemically modified AMOs, which are conventionally used as anti-cancer drugs, are still unclear. In this study, we investigated the relationship between the miRNA releasing rate from RISC and the inhibitory effect on RISC activity (IC50) using conventional chemically modified AMOs. We demonstrated that the miRNA-releasing effects of AMOs are directly proportional to the IC50 values, and AMOs, which have an ability to promote the release of miRNA from RISC, can effectively inhibit RISC activity in living cells. PMID- 28876214 TI - Exposing Northern shrimp (Pandalus borealis) to fish feed containing the antiparasitic drug diflubenzuron caused high mortality during molting. AB - Use of the chitin synthesis inhibitor diflubenzuron (DFB) as an antiparasitic drug in salmon aquaculture raises concern over its impact on marine ecosystems. Further, global drivers, such as ocean warming and acidification (OAW), may increase the toxicity of hazardous substances including DFB. The aim of the present study was to examine the combined effects of DFB-medicated salmon feed on ovigerous Northern shrimp (Pandalus borealis) under Control (pHNBS 8.0, 7.0oC) and OAW conditions (pHNBS 7.6, 9.5oC). DFB-exposed shrimp consumed on average 0.1 0.3 g medicated feed during the 2-week exposure period, and high mortality (61 73%) was documented at both environmental conditions. There was no significant interaction between OAW and DFB. Only 2-7% of DFB-exposed shrimp molted successfully compared to 65% in Control and 63% in OAW. The shrimp molted earlier (shorter intermolt period) and exhibited higher feeding rate at OAW compared to Control conditions. An additional experiment, where female shrimp were exposed to DFB closer to molting, noted increased mortality after only 4 d exposure, and successful molting for some shrimp after 2 to 3 weeks of depuration. High mortality of shrimp exposed to DFB-medicated feed indicates that the use of this feed in aquaculture could affect local shrimp populations. PMID- 28876215 TI - Deaf Families' Unique Experiences and Obstacles. AB - This article focuses on deaf children of deaf parents who grew up using American Sign Language (ASL) in deaf culture. Deaf children of deaf parents described their unique experiences of struggling with obstacles, including quality of education, low expectations from professionals, unwanted sympathy, mental health therapists' lack of cultural competency, and not being asked for valuable perspectives or advice. The advice from deaf children of deaf parents is included in the article. By bringing greater attention to this population, mental health, school, and other professionals can increase their awareness of deaf families' unique needs in their work environment. PMID- 28876216 TI - You're Deaf? Breaking through Myths for Effective Therapeutic Practice. AB - Most mental health practitioners provide services to hearing clients and might be unprepared when a deaf individual requests services. The purpose of this article is to explore commonly held stereotypes and myths about deaf people and to provide guidance to clinicians who encounter deaf clients in their practices. Myths and stereotypes can affect the way clinicians perceive their clients' needs. This can lead to miscommunication, misunderstanding, and misinformation, which can harm the therapeutic relationship, thus making effective therapy unattainable. Clinicians should reframe these beliefs and overcome barriers to make way for the therapeutic process to begin. PMID- 28876217 TI - "We Are Disaster Response Experts": A Qualitative Study on the Mental Health Impact of Volunteering in Disaster Settings Among Combat Veterans. AB - Volunteers serving in a disaster context may experience harmful mental health effects that could impede rescue operations. Exploratory research suggests that combat veterans who volunteer in Team Rubicon (TR)-a disaster relief social service organization with the mission of uniting the skills and experiences of military Veterans with first responders to rapidly deploy emergency response teams-have positive mental health responses when providing disaster relief. The objective of this qualitative study was to identify those nuances associated with combat veterans' mental health response in TR. The study consisted of (N = 9) male combat Veterans who volunteered with TR. Data was thematically analyzed. Results suggested that members did not experience negative mental health effects because of prior military training and preparedness relevant to disaster situations. Positive outcomes in mental health were associated with the uniqueness of peer support in TR and applying skills from military training. Veterans in TR reported that providing disaster relief afforded them the opportunity to continue serving others after having served in the military. Implications for public health social work are discussed as well as the need for further research. PMID- 28876218 TI - Deaf Workers in Restaurant, Retail, and Hospitality Sector Employment: Harnessing Research to Promote Advocacy. AB - A quarter-century after the passage of the Americans with Disabilities Act (ADA, 1990 ), workplace accommodation is still a struggle for deaf employees and their managers. Many challenges are the result of communication barriers that can be overcome through much needed-although often absent-advocacy and training. This article highlights the literature on the employment of deaf individuals in the United States service industries of food service, retail, and hospitality conducted from 2000 to 2016. Exploring dimensions of both hiring and active workplace accommodation, suggestions are made for how social work advocates can harness information and strengthen their approaches for educating managers and supporting workers. PMID- 28876219 TI - Enhancing Person-Centered Care in Long-Term Care. PMID- 28876220 TI - The application of the modified surgical wound dressing in wound care after tracheotomy. AB - INTRODUCTION: This study was performed to observe the efficacy of a modified surgical wound dressing applied as part of decannulation wound care after tracheotomy. METHODS: Eighty-four patients were randomly allocated into a traditional care group, a surgical wound dressing group, and a modified surgical wound dressing group. Each group comprised 28 patients. The following outcomes were observed and analyzed: infection rate, wound closure time, dressing change frequency, cost of wound care, and patients' comfort. RESULTS: The infection rate, wound closure time, dressing change frequency, and cost of wound care were much higher in the traditional care group than in the surgical wound dressing group and modified surgical wound dressing group. The study data indicated that patients in the modified surgical dressing group felt more comfortable than those patients in the other two groups. The differences among the three groups were statistically significant (P < 0.05). DISCUSSION: The design of the herein described modified surgical wound dressing is based on a butterfly shaped adhesive and mirrors the advantages of a modern surgical wound dressing. Its shape is suitable for the physiological structure of the neck, making it more comfortable to use. Aseptic packaging and a high degree of adhesiveness guarantee continuous fixation and pulling. At the same time, the design of the dressing decreases the chance of infection. PMID- 28876221 TI - Rethinking the role of clinical imaging. AB - Radiomics has the potential to improve the management of cancer patients, but further research is required before it can be adopted into routine clinical practice. PMID- 28876223 TI - Rapamycin in mice. PMID- 28876222 TI - Co-expression of xenopsin and rhabdomeric opsin in photoreceptors bearing microvilli and cilia. AB - Ciliary and rhabdomeric opsins are employed by different kinds of photoreceptor cells, such as ciliary vertebrate rods and cones or protostome microvillar eye photoreceptors, that have specialized structures and molecular physiologies. We report unprecedented cellular co-expression of rhabdomeric opsin and a visual pigment of the recently described xenopsins in larval eyes of a mollusk. The photoreceptors bear both microvilli and cilia and express proteins that are orthologous to transporters in microvillar and ciliary opsin trafficking. Highly conserved but distinct gene structures suggest that xenopsins and ciliary opsins are of independent origin, irrespective of their mutually exclusive distribution in animals. Furthermore, we propose that frequent opsin gene loss had a large influence on the evolution, organization and function of brain and eye photoreceptor cells in bilaterian animals. The presence of xenopsin in eyes of even different design might be due to a common origin and initial employment of this protein in a highly plastic photoreceptor cell type of mixed microvillar/ciliary organization. PMID- 28876224 TI - Observation of pseudogap in MgB2. AB - We investigate the electronic structure of a specially prepared highly dense conventional high temperature superconductor, MgB2 employing high resolution photoemission spectroscopy. The spectral evolution close to the Fermi energy is commensurate to BCS descriptions as expected. However, the spectra in the wider energy range reveal emergence of a pseudogap much above the superconducting transition temperature indicating apparent departure from the BCS scenario. The energy scale of the pseudogap is comparable to the energy of E2g phonon mode responsible for superconductivity in MgB2 and the pseudogap can be attributed to the effect of electron-phonon coupling on the electronic structure. These results reveal a scenario of the emergence of the superconducting gap within an electron phonon coupling induced pseudogap and have significant implication in the study of high temperature superconductors. PMID- 28876225 TI - Self-assembled monolayers of sulfonate-terminated alkanethiols investigated by frequency modulation atomic force microscopy in liquid. AB - A molecular-scale understanding of self-assembled monolayers (SAMs) of sulfonate terminated alkanethiols is crucial for interfacial studies of functionalized SAMs and their various applications. However, such an understanding has been difficult to achieve because of the lack of direct information on these molecular-scale structures in real space. In this study, we investigated the structures of sulfonate SAMs of sodium 11-mercapto-1-undecanesulfonate (MUS) by frequency modulation atomic force microscopy (FM-AFM) in liquid. The subnanometer resolution FM-AFM images showed that the single-component MUS SAM prepared in pure water had random surface structures. In contrast, the MUS SAM prepared in a water-ethanol mixed solvent showed periodic striped structures with a flat-lying conformation. The results suggest a significant solvent effect on molecular-scale structures of long-chain sulfonate SAMs. In addition, we investigated the molecular-scale structures of mixed SAMs of MUS and 11-mercapto-1-undecanol (MUO) with alkane chains of the same length. The FM-AFM images of the mixed SAMs showed clear phase separation between MUS SAM and MUO SAM domains. In the MUO SAM domains, the incorporated MUS molecules appeared as protrusions. The results obtained in this study provide direct structural information on long-chain sulfonate and mixed SAMs. PMID- 28876226 TI - Nonadiabatic exchange-correlation kernel for strongly correlated materials. AB - We formulate a rigorous method for calculating a nonadiabatic (frequency dependent) exchange-correlation (XC) kernel appropriate for accurate description of both equilibrium and nonequilibrium properties of strongly correlated systems within the time-dependent density functional theory (TDDFT) via the charge susceptibility, which is in turn obtained from dynamical mean field theory (DMFT) based on the effective multi-orbital Hubbard model. Application to the simple case of the one-orbital Hubbard model already shows the importance of the nonadiabatic kernel as it leads to significant modification of the excitation spectrum-shifting the (adiabatic) peak and disclosing another that is reminiscent of the solution from DMFT. The impact of dynamical effects, naturally included through the nonadiabaticity of the XC kernel, becomes even more transparent in our consideration of the nonequilibrium charge-density response of a multi orbital perovskite, YTiO3, to a perturbation by a femtosecond (fs) laser pulse. These initial results indicate that electron-electron correlations and nonadiabatic features may significantly affect the spectrum and nonequilibrium properties of strongly correlated systems. We also propose an algorithm for extension of the approach to non-linear response. The transparency and computational efficiency of this non-adiabatic TDDFT+DMFT approach opens the door to examination of the spectra and response of multi-orbital systems with many nonequivalent atoms-bulk material, films and nanostructures. PMID- 28876227 TI - Crystal structure of the DNA sequence d(CGTGAATTCACG)2 with DAPI. AB - The structure of 4',6-diamidine-2-phenylindole (DAPI) bound to the synthetic B DNA oligonucleotide d(CGTGAATTCACG) has been solved in space group P212121 by single-crystal X-ray diffraction at a resolution of 2.2 A. The structure is nearly isomorphous to that of the previously reported crystal structure of the oligonucleotide d(CGTGAATTCACG) alone. The adjustments in crystal packing between the native DNA molecule and the DNA-DAPI complex are described. DAPI lies in the narrow minor groove near the centre of the B-DNA fragment, positioned over the A T base pairs. It is bound to the DNA by hydrogen-bonding and van der Waals interactions. Comparison of the two structures (with and without ligand) shows that DAPI inserts into the minor groove, displacing the ordered spine waters. Indeed, as DAPI is hydrophobic it confers this behaviour on the DNA and thus restricts the presence of water molecules. PMID- 28876228 TI - HicAB toxin-antitoxin complex from Escherichia coli: expression and crystallization. AB - Toxin-antitoxin (TA) systems are widespread in both bacteria and archaea, where they enable cells to adapt to environmental cues. TA systems play crucial roles in various cellular processes, such as programmed cell death, cell growth, persistence and virulence. Here, two distinct forms of the type II toxin antitoxin complex HicAB were identified and characterized in Escherichia coli K 12, and both were successfully overexpressed and purified. The two proposed forms, HicABL and HicABS, differed in the presence or absence of a seven-amino acid segment at the N-terminus in the antitoxin HicB. The short form HicABS readily crystallized under the conditions 0.1 M Tris-HCl pH 8.0, 20%(w/v) PEG 6000, 0.2 M ammonium sulfate. The HicABS crystal diffracted and data were collected to 2.5 A resolution. The crystal belonged to space group I222 or I212121, with unit-cell parameters a = 67.04, b = 66.31, c = 120.78 A. Matthews coefficient calculation suggested the presence of two molecules each of HicA and HicBS in the asymmetric unit, with a solvent content of 55.28% and a Matthews coefficient (VM) of 2.75 A3 Da-1. PMID- 28876229 TI - 3,6-Anhydro-L-galactonate cycloisomerase from Vibrio sp. strain EJY3: crystallization and X-ray crystallographic analysis. AB - 3,6-Anhydro-L-galactonate cycloisomerase (ACI), which is found in the marine bacterium Vibrio sp. strain EJY3, converts 3,6-anhydro-L-galactonate into 2-keto 3-deoxygalactonate. ACI is a key enzyme in the metabolic pathway of 3,6-anhydro-L galactose (AHG). Study of AHG metabolism is important for the efficient fermentation of agar and biofuel production, because AHG is a sugar that is non fermentable by commercial microorganisms. The aci gene from Vibrio sp. strain EJY3 was cloned, and the recombinant protein was overexpressed and crystallized in order to determine the structure and understand the function of the protein. The crystals diffracted to 2.2 A resolution and belonged to space group P41212 or P43212, with unit-cell parameters a = b = 87.9, c = 143.5 A. The Matthews coefficient was 2.3 A3 Da-1, with a solvent content of 47%. PMID- 28876230 TI - Characterization and crystal structure of a novel zearalenone hydrolase from Cladophialophora bantiana. AB - Zearalenone (ZEN) is a mycotoxin which causes huge economic losses in the food and animal feed industries. The lactonase ZHD101 from Clonostachys rosea, which catalyzes the hydrolytic degradation of ZEN, is the only known ZEN-detoxifying enzyme. Here, a protein homologous to ZHD101, denoted CbZHD, from Cladophialophora batiana was expressed and characterized. Sequence alignment indicates that CbZHD possesses the same catalytic triad and ZEN-interacting residues as found in ZHD101. CbZHD exhibits optimal enzyme activity at 35 degrees C and pH 8, and is sensitive to heat treatment. The crystal structure of apo CbZHD was determined to 1.75 A resolution. The active-site compositions of CbZHD and ZHD101 were analyzed. PMID- 28876231 TI - The LRR-Roc-COR module of the Chlorobium tepidum Roco protein: crystallization and X-ray crystallographic analysis. AB - Roco proteins are characterized by the presence of a Roc-COR supradomain harbouring GTPase activity, which is often preceded by an LRR domain. The most notorious member of the Roco protein family is the Parkinson's disease-associated LRRK2. The Roco protein from the bacterium Chlorobium tepidum has been used as a model system to investigate the structure and mechanism of this class of enzymes. Here, the crystallization and crystallographic analysis of the LRR-Roc-COR construct of the C. tepidum Roco protein is reported. The LRR-Roc-COR crystals belonged to space group P212121, with unit-cell parameters a = 95.6, b = 129.8, c = 179.5 A, alpha = beta = gamma = 90 degrees , and diffracted to a resolution of 3.3 A. Based on the calculated Matthews coefficient, Patterson map analysis and an initial molecular-replacement analysis, one protein dimer is present in the asymmetric unit. The crystal structure of this protein will provide valuable insights into the interaction between the Roc-COR and LRR domains within Roco proteins. PMID- 28876232 TI - Protein crystallization and initial neutron diffraction studies of the photosystem II subunit PsbO. AB - The PsbO protein of photosystem II stabilizes the active-site manganese cluster and is thought to act as a proton antenna. To enable neutron diffraction studies, crystals of the beta-barrel core of PsbO were grown in capillaries. The crystals were optimized by screening additives in a counter-diffusion setup in which the protein and reservoir solutions were separated by a 1% agarose plug. Crystals were cross-linked with glutaraldehyde. Initial neutron diffraction data were collected from a 0.25 mm3 crystal at room temperature using the MaNDi single crystal diffractometer at the Spallation Neutron Source, Oak Ridge National Laboratory. PMID- 28876233 TI - Ectodomain of plasmodesmata-localized protein 5 in Arabidopsis: expression, purification, crystallization and crystallographic analysis. AB - Plasmodesmata-localized protein 5 (PDLP5) is a cysteine-rich receptor-like protein which is localized on the plasmodesmata of Arabidopsis thaliana. Overexpression of PDLP5 can reduce the permeability of the plasmodesmata and further affect the cell-to-cell movement of viruses and macromolecules in plants. The ectodomain of PDLP5 contains two DUF26 domains; however, the function of these domains is still unknown. Here, the ectodomain of PDLP5 from Arabidopsis was cloned and overexpressed using an insect expression system and was then purified and crystallized. X-ray diffraction data were collected to 1.90 A resolution and were indexed in space group P1, with unit-cell parameters a = 41.9, b = 48.1, c = 62.2 A, alpha = 97.3, beta = 103.1, gamma = 99.7 degrees . Analysis of the crystal content indicated that there are two molecules in the asymmetric unit, with a Matthews coefficient of 2.51 A3 Da-1 and a solvent content of 50.97%. PMID- 28876234 TI - Production, crystallization and structure determination of a mycobacterial glucosylglycerate hydrolase. AB - Glucosylglycerate hydrolase is highly conserved among rapidly growing mycobacteria and has been found to be involved in recovery from nitrogen starvation by promoting the rapid mobilization of the glucosylglycerate that accumulates under these conditions. Here, the production, crystallization and structure determination of glucosylglycerate hydrolase from Mycobacterium hassiacum using two-wavelength anomalous diffraction of selenomethionine substituted crystals are described. The monoclinic (space group P21) crystals diffracted to ~2.0 A resolution at a synchrotron-radiation source and contained four molecules in the asymmetric unit, corresponding to a Matthews coefficient of 3.07 A3 Da-1 and a solvent content of 59.9%. The quality of the experimental phases allowed the automated building of 1677 of the 1792 residues in the asymmetric unit. PMID- 28876236 TI - AUSPEX: a graphical tool for X-ray diffraction data analysis. AB - In this paper, AUSPEX, a new software tool for experimental X-ray data analysis, is presented. Exploring the behaviour of diffraction intensities and the associated estimated uncertainties facilitates the discovery of underlying problems and can help users to improve their data acquisition and processing in order to obtain better structural models. The program enables users to inspect the distribution of observed intensities (or amplitudes) against resolution as well as the associated estimated uncertainties (sigmas). It is demonstrated how AUSPEX can be used to visually and automatically detect ice-ring artefacts in integrated X-ray diffraction data. Such artefacts can hamper structure determination, but may be difficult to identify from the raw diffraction images produced by modern pixel detectors. The analysis suggests that a significant portion of the data sets deposited in the PDB contain ice-ring artefacts. Furthermore, it is demonstrated how other problems in experimental X-ray data caused, for example, by scaling and data-conversion procedures can be detected by AUSPEX. PMID- 28876235 TI - 2017 publication guidelines for structural modelling of small-angle scattering data from biomolecules in solution: an update. AB - In 2012, preliminary guidelines were published addressing sample quality, data acquisition and reduction, presentation of scattering data and validation, and modelling for biomolecular small-angle scattering (SAS) experiments. Biomolecular SAS has since continued to grow and authors have increasingly adopted the preliminary guidelines. In parallel, integrative/hybrid determination of biomolecular structures is a rapidly growing field that is expanding the scope of structural biology. For SAS to contribute maximally to this field, it is essential to ensure open access to the information required for evaluation of the quality of SAS samples and data, as well as the validity of SAS-based structural models. To this end, the preliminary guidelines for data presentation in a publication are reviewed and updated, and the deposition of data and associated models in a public archive is recommended. These guidelines and recommendations have been prepared in consultation with the members of the International Union of Crystallography (IUCr) Small-Angle Scattering and Journals Commissions, the Worldwide Protein Data Bank (wwPDB) Small-Angle Scattering Validation Task Force and additional experts in the field. PMID- 28876238 TI - The structure of the Pfp1 protease from the hyperthermophilic archaeon Thermococcus thioreducens in two crystal forms. AB - The Pfp1 protease, a cysteine protease of unknown specificity from the hyperthermophilic archaeon Thermococcus thioreducens, was crystallized in two distinctive crystal forms: from concentrated citrate in one case and PEG in the other. X-ray data were collected from both crystal forms at room temperature to about 1.9 A resolution using a laboratory source and detector, and the structures were solved by molecular replacement using the Pfp1 protease from Pyrococcus horikoshii as the search model. In the T. thioreducens protease structures, Cys18 residues on adjacent molecules in the asymmetric units form intermolecular disulfide bonds, thereby yielding hexamers composed of three cross-linked, quasi dyad-related dimers with crystallographically exact threefold axes and exhibiting almost exact 32 symmetry. The corresponding residue in P. horikoshii Pfp1 is Tyr18. An individual active site containing Cys100 and His101 also includes a Glu74 residue contributed by a quasi-twofold-related, non-cross-linked subunit. Two catalytic triads are therefore closely juxtaposed about the quasi-twofold axis at the interface of these subunits, and are relatively sequestered within the hexamer cavity. The cysteine in the active site is observed to be oxidized in both of the crystal forms that were studied. PMID- 28876237 TI - Protein structure determination by electron diffraction using a single three dimensional nanocrystal. AB - Three-dimensional nanometre-sized crystals of macromolecules currently resist structure elucidation by single-crystal X-ray crystallography. Here, a single nanocrystal with a diffracting volume of only 0.14 um3, i.e. no more than 6 * 105 unit cells, provided sufficient information to determine the structure of a rare dimeric polymorph of hen egg-white lysozyme by electron crystallography. This is at least an order of magnitude smaller than was previously possible. The molecular-replacement solution, based on a monomeric polyalanine model, provided sufficient phasing power to show side-chain density, and automated model building was used to reconstruct the side chains. Diffraction data were acquired using the rotation method with parallel beam diffraction on a Titan Krios transmission electron microscope equipped with a novel in-house-designed 1024 * 1024 pixel Timepix hybrid pixel detector for low-dose diffraction data collection. Favourable detector characteristics include the ability to accurately discriminate single high-energy electrons from X-rays and count them, fast readout to finely sample reciprocal space and a high dynamic range. This work, together with other recent milestones, suggests that electron crystallography can provide an attractive alternative in determining biological structures. PMID- 28876239 TI - Designing better diffracting crystals of biotin carboxyl carrier protein from Pyrococcus horikoshii by a mutation based on the crystal-packing propensity of amino acids. AB - An alternative rational approach to improve protein crystals by using single-site mutation of surface residues is proposed based on the results of a statistical analysis using a compiled data set of 918 independent crystal structures, thereby reflecting not only the entropic effect but also other effects upon protein crystallization. This analysis reveals a clear difference in the crystal-packing propensity of amino acids depending on the secondary-structural class. To verify this result, a systematic crystallization experiment was performed with the biotin carboxyl carrier protein from Pyrococcus horikoshii OT3 (PhBCCP). Six single-site mutations were examined: Ala138 on the surface of a beta-sheet was mutated to Ile, Tyr, Arg, Gln, Val and Lys. In agreement with prediction, it was observed that the two mutants (A138I and A138Y) harbouring the residues with the highest crystal-packing propensities for beta-sheet at position 138 provided better crystallization scores relative to those of other constructs, including the wild type, and that the crystal-packing propensity for beta-sheet provided the best correlation with the ratio of obtaining crystals. Two new crystal forms of these mutants were obtained that diffracted to high resolution, generating novel packing interfaces with the mutated residues (Ile/Tyr). The mutations introduced did not affect the overall structures, indicating that a beta-sheet can accommodate a successful mutation if it is carefully selected so as to avoid intramolecular steric hindrance. A significant negative correlation between the ratio of obtaining amorphous precipitate and the crystal-packing propensity was also found. PMID- 28876240 TI - Crystal structures of the methyltransferase and helicase from the ZIKA 1947 MR766 Uganda strain. AB - Two nonstructural proteins encoded by Zika virus strain MR766 RNA, a methyltransferase and a helicase, were crystallized and their structures were solved and refined at 2.10 and 2.01 A resolution, respectively. The NS5 methyltransferase contains a bound S-adenosyl-L-methionine (SAM) co-substrate. The NS3 helicase is in the apo form. Comparison with published crystal structures of the helicase in the apo, nucleotide-bound and single-stranded RNA (ssRNA) bound states suggests that binding of ssRNA to the helicase may occur through conformational selection rather than induced fit. PMID- 28876242 TI - Comparison of coagulation, ozone and ferrate treatment processes for color, COD and toxicity removal from complex textile wastewater. AB - In this study, the comparative performance of coagulation, ozone, coagulation + ozone + coagulation and potassium ferrate processes to remove chemical oxygen demand (COD), color, and toxicity from a highly polluted textile wastewater were evaluated. Experimental results showed that ferrate alone had no effect on COD, color and toxicity removal. Whereas, in combination with FeSO4, it has shown the highest removal efficiency of 96.5%, 83% and 75% for respective parameters at the optimal dose of 40 mgL-1 + 3 ml FeSO4 (1 M) in comparison with other processes. A seed germination test using seeds of Spinach (Spinacia oleracea) also indicated that ferrate was more effective in removing toxicity from contaminated textile wastewater. Potassium ferrate also produces less sludge with maximum contaminant removal, thereby making the process more economically feasible. Fourier transform infrared spectroscopy (FTIR) analysis also shows the cleavage of the chromophore group and degradation of textile wastewater during chemical and oxidation treatment processes. PMID- 28876241 TI - Structural insights into the interaction of the conserved mammalian proteins GAPR 1 and Beclin 1, a key autophagy protein. AB - Mammalian Golgi-associated plant pathogenesis-related protein 1 (GAPR-1) is a negative autophagy regulator that binds Beclin 1, a key component of the autophagosome nucleation complex. Beclin 1 residues 267-284 are required for binding GAPR-1. Here, sequence analyses, structural modeling, mutagenesis combined with pull-down assays, X-ray crystal structure determination and small angle X-ray scattering were used to investigate the Beclin 1-GAPR-1 interaction. Five conserved residues line an equatorial GAPR-1 surface groove that is large enough to bind a peptide. A model of a peptide comprising Beclin 1 residues 267 284 docked onto GAPR-1, built using the CABS-dock server, indicates that this peptide binds to this GAPR-1 groove. Mutation of the five conserved residues lining this groove, H54A/E86A/G102K/H103A/N138G, abrogates Beclin 1 binding. The 1.27 A resolution X-ray crystal structure of this pentad mutant GAPR-1 was determined. Comparison with the wild-type (WT) GAPR-1 structure shows that the equatorial groove of the pentad mutant is shallower and more positively charged, and therefore may not efficiently bind Beclin 1 residues 267-284, which include many hydrophobic residues. Both WT and pentad mutant GAPR-1 crystallize as dimers, and in each case the equatorial groove of one subunit is partially occluded by the other subunit, indicating that dimeric GAPR-1 is unlikely to bind Beclin 1. SAXS analysis of WT and pentad mutant GAPR-1 indicates that in solution the WT forms monomers, while the pentad mutant is primarily dimeric. Thus, changes in the structure of the equatorial groove combined with the improved dimerization of pentad mutant GAPR-1 are likely to abrogate binding to Beclin 1. PMID- 28876243 TI - Removal of lead (II) from aqueous solutions using rice straw. AB - Lead (Pb2+) is a heavy metal which is utilized in several industries and can have severe impact on the environment and human health. Research work has been carried out lately on the feasibility of using various low cost materials in the removal of heavy metals from wastewater. In this study, the feasibility of utilizing raw rice straw for removal of Pb2+ from water through biosorption was investigated using batch equilibrium experiments. The effect of several operating parameters on the removal of Pb2+ using rice straw was studied, revealing the optimum parameters at an initial Pb2+ concentration of 40 mg/l were: 30 min contact time at a pH of 5.5, particle size 75-150 MUm and a dose of 4 g/l. A maximum removal of 94% was achieved under optimum conditions. Langmuir and Freundlich isotherm models were used for the evaluation of the equilibrium experimental data. The maximum adsorption capacity of rice straw calculated using the Langmuir isotherm was 42.55 mg/g. PMID- 28876245 TI - Batch versus column modes for the adsorption of radioactive metal onto rice husk waste: conditions optimization through response surface methodology. AB - Batch and column adsorption modes were compared for the adsorption of U(VI) ions using rice husk waste biomass (RHWB). Response surface methodology was employed for the optimization of process variables, i.e., (pH (A), adsorbent dose (B), initial ion concentration (C)) in batch mode. The B, C and C2 affected the U(VI) adsorption significantly in batch mode. The developed quadratic model was found to be validated on the basis of regression coefficient as well as analysis of variance. The predicted and actual values were found to be correlated well, with negligible residual value, and B, C and C2 were significant terms. The column study was performed considering bed height, flow rate and initial metal ion concentration, and adsorption efficiency was evaluated through breakthrough curves and bed depth service time and Thomas models. Adsorption was found to be dependent on bed height and initial U(VI) ion concentration, and flow rate decreased the adsorption capacity. Thomas models fitted well to the U(VI) adsorption onto RHWB. Results revealed that RHWB has potential to remove U(VI) ions and batch adsorption was found to be efficient versus column mode. PMID- 28876244 TI - The economic pre-treatment of coal mine drainage water with caustic and ozone. AB - Coal mine drainage waters are low in pH with varying amounts of iron and manganese and are generally brackish. The Austar Coal Mine in NSW, Australia, sought alternatives to their current lime dosing as the pre-treatment before the downstream reverse osmosis plant. Undesirable operating aspects of the current system include manganese and gypsum scaling/fouling, the need for anti-scalants and reduced water recovery. Thirteen processes for acid mine drainage were initially considered. The preferred process of caustic and ozone for Mn(II) oxidation was pilot tested at up to 0.74 kL/hr at the mine site. Under proper conditions and no aeration, about 81 per cent of the Fe could be removed (initially at 156 mg/L) as green rust. Supplemental aeration followed first-order kinetics and allowed 99.9 per cent Fe(II) oxidation and removal but only with a hydraulic residence time of about 47 minutes. The addition of supplemental Cu catalyst improved Fe removal. Ozone applied after caustic was effective in stoichiometrically oxidising recalcitrant Mn(II) and any remaining Fe(II). Control of the ozonation was achieved using the oxidation reduction potential during oxidation of the Mn(II) species. The use of caustic, followed by ozone, proved economically comparable to the current lime pre-treatment. PMID- 28876246 TI - A comparative study of an up-flow aerobic/anoxic sludge fixed film bioreactor and sequencing batch reactor with intermittent aeration in simultaneous nutrients (N, P) removal from synthetic wastewater. AB - The performance of two bench scale activated sludge reactors with two feeding regimes, continuous fed (an up-flow aerobic/anoxic sludge fixed film (UAASFF) bioreactor) and batch fed (sequencing batch reactor (SBR)) with intermittent aeration, were evaluated for simultaneous nutrients (N, P) removal. Three significant variables (retention/reaction time, chemical oxygen demand (COD): N (nitrogen): P (phosphorus) ratio and aeration time) were selected for modeling, analyzing, and optimizing the process. At high retention time (>=6 h), two bioreactors showed comparable removal efficiencies, but at lower hydraulic retention time, the UAASFF bioreactor showed a better performance with higher nutrient removal efficiency than the SBR. The experimental results indicated that the total Kjeldahl nitrogen removal efficiency in the UAASFF increased from 70.84% to 79.2% when compared to SBR. It was also found that the COD removal efficiencies of both processes were over 87%, and total nitrogen and total phosphorus removal efficiencies were 79.2% and 72.98% in UAASFF, and 71.2% and 68.9% in SBR, respectively. PMID- 28876247 TI - Matrix interference reduction for the analysis of carbohydrate in wastewater using H-point standard addition method. AB - Soluble microbial products, consisting of protein, carbohydrate and humics, are generally considered as the main membrane foulants during the performance of membrane bioreactors. Nitrate and nitrite have been proved to affect the determination of carbohydrate when anthrone-sulfuric acid photometric method is used. In this study, three chemical analytical methods based on photometric assay, including the standard curve method, conventional standard addition method and H-point standard addition method, were assessed for the quantification of carbohydrate in order to reduce the interference. Three methods were carried out for both artificial and real wastewater sample analysis. The results indicated a significant amount of matrix interference, which could be eliminated through the use of H-point standard addition. This study proposed the H-point standard addition method as a more accurate and convenient option for carbohydrate determination. PMID- 28876248 TI - Sorption equilibrium, thermodynamics and pH-indicator properties of cresyl violet dye/bentonite composite system. AB - The aim of the present study was to develop cresyl violet (CV)/bentonite composite system, to investigate the equilibrium sorption of the fluorescent dye on bentonite, to determine the characteristic equilibrium and thermodynamic parameters of the system by appropriate empirical isotherm models and to assess its pH-indicator properties. The absorption characteristics of CV solutions were investigated by UV/VIS spectrophotometer. Equilibrium experiments were conducted and the experimental data were modelled by six mathematical isotherm models. The analyses of the experimental data showed that bentonite exhibited significantly high capacity - 169.92 mg/g, towards CV. The encapsulation efficiency was 85%. The Langmuir, Flory-Huggins and El-Awady models best represented the experimental results. The free Gibbs energy of adsorption (DeltaGo) was calculated on the basis of the values of the equilibrium coefficients determined by the proposed models. The values of DeltaG determined by the Langmuir, Temkin and Flory-Huggins models are within the range -20 to -40 kJ/mol, which indicates that the adsorption process is spontaneous and chemisorption takes place due to charge sharing or transfer from the dye molecules to the sorbent surface as a coordinate type of bond. The investigations of the obtained CV/bentonite hybrid systems for application as pH-markers showed satisfactory results. PMID- 28876249 TI - Growing substrates for aromatic plant species in green roofs and water runoff quality: pilot experiments in a Mediterranean climate. AB - Green roof technology has evolved in recent years as a potential solution to promote vegetation in urban areas. Green roof studies for Mediterranean climates, where extended drought periods in summer contrast with cold and rainy periods in winter, are still scarce. The present research study assesses the use of substrates with different compositions for the growth of six aromatic plant species - Lavandula dentata, Pelargonium odoratissimum, Helichrysum italicum, Satureja montana, Thymus caespititius and T. pseudolanuginosus, during a 2-year period, and the monitoring of water runoff quality. Growing substrates encompassed expanded clay and granulated cork, in combination with organic matter and crushed eggshell. These combinations were adequate for the establishment of all aromatic plants, allowing their propagation in the extensive system located on the 5th storey. The substrate composed of 70% expanded clay and 30% organic matter was the most suitable, and crushed eggshell incorporation improved the initial plant establishment. Water runoff quality parameters - turbidity, pH, conductivity, NH4+, NO3-, PO43- and chemical oxygen demand - showed that it could be reused for non-potable uses in buildings. The present study shows that selected aromatic plant species could be successfully used in green roofs in a Mediterranean climate. PMID- 28876250 TI - Implementation of the anaerobic digestion model (ADM1) in the PHREEQC chemistry engine. AB - Anaerobic digestion is state-of-the-art technology to treat sludge and effluents from various industries. Modelling and optimisation of digestion operations can be advantageously performed using the anaerobic digestion model (ADM1) from the International Water Association. The ADM1, however, lacks a proper physico chemical framework, which makes it difficult to consider wastewater of complex ionic composition and supersaturation phenomena. In this work, we present a direct implementation of the ADM1 within the PHREEQC chemistry engine. This makes it possible to handle ionic strength effects and ion-pairing. Thus, multiple mineral precipitation phenomena can be handled while resolving the ADM1. All these features can be accessed with very little programming effort, while retaining the full power and flexibility of PHREEQC. The distributed PHREEQC code can be easily interfaced with process simulation software for future plant-wide simulation of both wastewater and sludge treatment. PMID- 28876251 TI - Removal of phosphorus using suspended reactive filters (SRFs) - efficiency and potential applications. AB - The removal of phosphorus (P) from agricultural runoff is essential to reduce the threat of eutrophication in bodies of water. In this study, an alternative method of applying P reactive materials (RMs) in the form of suspended reactive filters (SRFs) is presented. The SRF method enables P which has already entered a body of water to be caught. In this study, an autoclaved aerated concrete (AAC) was used as the SRFs. The experiment was carried out in a laboratory in a hydraulic block of 1 m in width and 2 m in length. Three curtains, consisting of eight suspended bags filled with the AAC, were used. The ratio of RM mass to water volume in the hydraulic block was 3:1 (g:dm3). The initial concentration of P amounted to 1.335 mg P-PO4.dm-3. The results demonstrated the successive reduction of P in the water over the experiment duration and the number of cycles in which water passed through the system of curtains. SRFs filled with AAC decreased the level of P-PO4 in the solution to 0.190 mg.dm-3. The highest removal efficiency (50% overall P reduction) was observed at the beginning of experiment, when the average unit sorption amounted to 0.192 mgP-PO4.g-1. PMID- 28876252 TI - Utilization of anaerobic granular sludge for chromium (VI) removal from wastewater: optimization by response surface methodology. AB - In this study, anaerobic granular sludge (AGS) was used as a novel adsorbent for hexavalent chromium (Cr (VI)) removal from aqueous solutions. Factor experiments were conducted to find out the effects of different variables on the biosorption process. Among these terms, the impact of three main independent variables (contact time, initial pH and AGS dosage) on the removal efficiency of Cr (VI) was modeled using a well-fitting polynomial equation (R2 = 0.9044), by conducting 20 batch experiments designed by a central composite. The experimental isotherm data were successfully described by the Freundlich isotherm and the pseudo-second order kinetic model was more suitable for explaining the kinetics process of adsorption. The AGS can be disposed using 0.1 M NaOH with 96.4% desorption efficiency. The results of the analyses (X-ray photoelectron spectroscopy and Fourier transformed infrared spectroscopy) suggested that Cr (VI) adsorption most likely involved electrostatic adsorption, redox reaction and complexation. PMID- 28876253 TI - Pulse electro-coagulation application in treating dibutyl phthalate wastewater. AB - Pulse electro-coagulation (PEC) was applied to treat plastic factory wastewater in this study. One representative plasticizer molecule was chosen for the synthetic wastewater: dibutyl phthalate (DBP). Experiments demonstrated that PEC exhibits superior economic efficiency and removal efficiency compared to traditional electro-coagulation in wastewater treatment. Experimental data also indicated that at a given current density, compared with the aluminum electrode, the iron electrode could more efficiently remove DBP from wastewater. With an initial pH of 8-9, the required energy was 2.5 kWh m-3 for 75% DBP removal in the case of iron as the anode type. In general, the pollutants have been successfully reduced to environmentally acceptable levels under the following operating conditions: iron as the anode type, interelectrode distance of 10 mm, duty cycle of 0.6, pH of 8-9 and current density of 15 mA cm-2 for PEC time >15 min. PMID- 28876254 TI - Separating grey- and blackwater in urban water cycles - sensible in the view of misconnections? AB - The infrastructure approach SEMIZENTRAL has been developed for fast growing cities, to meet their challenges regarding water supply as well as biowaste and wastewater treatment. The world's first full-scale SEMIZENTRAL Resource Recovery Center (RRC) has been implemented in Qingdao (PR China). Greywater (GW) and blackwater (BW) are collected and treated separately. Measurement of influent concentrations differ significantly from the design values. Thus, the operation strategy for the RRC had to be adapted. Amongst other reasons, the changed influent characteristic was caused by misconnections of GW and BW sewers. Already a misconnection rate of 6-8% requires an extension of the GW treatment process for nitrification/denitrification to fulfill effluent standards. Hence, measures should be taken to avoid or reduce misconnections. Nonetheless, in a semi centralized scale (>10,000 inhabitants) a 100% avoidance might not be possible. Thus, consequences from misconnections should be considered during the design of source-oriented infrastructure systems. PMID- 28876255 TI - NaA zeolite derived from blast furnace slag: its application for ammonium removal. AB - In this paper, high value added NaA zeolite material was prepared from blast furnace (BF) slag by hydrothermal method and its adsorption behavior on the removal of ammonium ion was investigated. It was found out that the synthetic NaA cubic zeolite with smaller crystal size obtained at nSiO2/nAl2O3 = 2 and nH2O/nNaOH = 20 showed better adsorption performance. The kinetics of the adsorption of ammonium ion by synthesized NaA zeolite was fitted by the pseudo second-order kinetic model. The intra-particle diffusion modeling reveals that two mixed rate-controlling mechanisms were involved in the adsorption process. The relatively high value of activation energy of 92.3 kJ.mol-1 indicates a high impact of temperature on the adsorption rate, and the nature of ammonium adsorption is chemical reaction rather than physisorption. Based on the thermodynamics calculations, the adsorption of ammonium was found to be an endothermic, spontaneous process. The adsorption isothermal analysis showed that the Langmuir model could be well fitted and a maximum adsorption capacity of 83.3 mg.g-1 of NH4+ was obtained. Thus, it was demonstrated that by forming low cost NaA zeolite and using it for environmental remediation, the synchronous minimization of BF slag and ammonia nitrogen contamination could be achieved. PMID- 28876256 TI - Towards water sensitive cities in Asia: an interdisciplinary journey. AB - Rapid urbanisation, population growth and the effects of climate change drive the need for sustainable urban water management (SUWM) in Asian cities. The complexity of this challenge calls for the integration of knowledge from different disciplines and collaborative approaches. This paper identifies key issues and sets the stage for interdisciplinary research on SUWM in Asia. It reports on the initial stages of a SUWM research programme being undertaken at Monash University, Australia, and proposes a framework to guide the process of interdisciplinary research in urban water management. Three key themes are identified: (1) Technology and Innovation, (2) Urban Planning and Design, and (3) Governance and Society. Within these themes 12 research projects are being undertaken across Indonesia, China, India and Bangladesh. This outward-looking, interdisciplinary approach guides our research in an effort to transgress single discipline solutions and contribute on-ground impact to SUWM practices in Asia. PMID- 28876257 TI - Norwegian study on microbial source tracking for water quality control and pollution removal in constructed wetland treating catchment run-off. AB - This study describes the first Norwegian microbial source tracking (MST) approach for water quality control and pollution removal from catchment run-off in a nature-based treatment system (NBTS) with a constructed wetland. The applied MST tools combined microbial analyses and molecular tests to detect and define the source(s) and dominant origin(s) of faecal water contamination. Faecal indicator bacteria Escherichia coli and host-specific Bacteroidales 16 s rRNA gene markers have been employed. The study revealed that the newly developed contribution profiling of faecal origin derived from the Bacteroidales DNA could quantitatively distinguish between human and non-human pollution origins. Further, the outcomes of the MST test have been compared with the results of both physicochemical analyses and tests of pharmaceutical and personal care products (PPCPs). A strong positive correlation was discovered between the human marker and PPCPs. Gabapentin was the most frequently detected compound and it showed the uppermost positive correlation with the human marker. The study demonstrated that the NBTS performs satisfactorily with the removal of E. coli but not PPCPs. Interestingly, the presence of PPCPs in the water samples was not correlated with high concentrations of E. coli. Neither has the latter an apparent correlation with the human marker. PMID- 28876258 TI - Biosurfactant rhamnolipid enhanced modification of corn stalk and its application for sorption of phenanthrene. AB - The application of modified agricultural wastes for removing polycyclic aromatic hydrocarbons (PAHs) from water is gaining a growing interest. However, most modified methods using synthetic chemicals may cause secondary pollution. To overcome this limitation, in this study, a rhamnolipid modified corn stalk (RL CS) for the removal of phenanthrene (PHE) from aqueous solution was prepared using a rhamnolipid-enhanced acid modification method. RL-CS with higher surface area and lower polarity exhibited higher PHE removal efficiency than that of raw corn stalk (RCS). The adsorption kinetics of RL-CS fitted well with pseudo-second order kinetics (R2 > 0.999). Sorption coefficients and carbon-normalized sorption coefficient of RL-CS were 4.68 and 2.86 times higher than that of RCS. Sorption process of RL-CS was nonlinear. Meanwhile, the sorption was an exothermic process and could occur spontaneously. The present study demonstrated that biosurfactant modified biosorbent RL-CS may be of great potential for the removal of low concentrations of PAHs from the contaminated waters. PMID- 28876259 TI - Powdered grape seeds (PGS) as an alternative biosorbent to remove pharmaceutical dyes from aqueous solutions. AB - An alternative, low-cost and efficient biosorbent, powdered grape seeds (PGS), was prepared from wastes of a wine industry, and used to remove brilliant blue (BB) and amaranth red (AR) dyes from aqueous solutions. The biosorbent was properly characterized before and after the biosorption operation. The potential of PGS to remove BB and AR dyes was investigated thought kinetic, isotherm and thermodynamic studies. The biosorption of BB and AR was favored at pH 1.0 using biosorbent dosage of 0.500 g L-1, being attained more than 85% of removal percentage. For BB and AR dyes, pseudo-second-order and Elovich models were able to explain the biosorption kinetic. The biosorption equilibrium of BB on PGS was well represented by the Langmuir model, while for AR, the Sips model was the most adequate. The maximum biosorption capacities were 599.5 and 94.2 mg g-1 for BB and AR, respectively. The biosorption of BB and AR on PGS was a spontaneous, favorable and endothermic process. These findings indicated that PGS is a low cost and efficient biosorbent, which can be used to treat dye containing waters. PMID- 28876260 TI - Effect of SBR feeding strategy and feed composition on the stability of aerobic granular sludge in the treatment of a simulated textile wastewater. AB - Treatment of the highly polluting and variable textile industry wastewater using aerobic granular sludge (AGS) sequencing batch reactors (SBRs) has been recently suggested. Aiming to develop this technology application, two feeding strategies were compared regarding the capacity of anaerobic-aerobic SBRs to deal with disturbances in the composition of the simulated textile wastewater feed. Both a statically fed, anaerobic-aerobic SBR and an anaerobic plug-flow fed, anaerobic aerobic SBR could cope with shocks of high azo dye concentration and organic load, the overall chemical oxygen demand and color removal yields being rapidly restored to 80%. Yet, subsequent azo dye metabolite bioconversion was not observed, along the 315-day run. Moreover, switching from a starch-based substrate to acetate in the feed composition deteriorated AGS stability. Overall, the plug-flow fed SBR recovered more rapidly from the imposed disturbances. Further research is needed towards guaranteeing long-term AGS stability during the treatment of textile wastewater. PMID- 28876261 TI - Adapted optimization model for planning regional wastewater systems: case study. AB - Wastewater systems are of crucial importance to the promotion of sustainable development. Through an integrated planning approach, the costs can be minimized and the resulting benefits maximized. A planning approach at regional level exploits the economies of scale, while achieving a better environmental performance. In this paper we set out a decision support approach for the planning of regional wastewater systems. Optimization models are used, aimed at finding optimal configurations for the location, type and size of the system's infrastructure: sewers, pump stations, and wastewater treatment plants. Solutions are evaluated in terms of the cost of installing, operating and maintaining the infrastructure, and the water quality in the river that receives the treated wastewater. The river water quality varies in accordance with the effluent discharges, and is assessed using environmental parameters. The models are solved with a simulated annealing algorithm complemented by a local improvement procedure. Its application is illustrated through a case study in the Una river basin region, in Brazil. PMID- 28876262 TI - Enhancing biodegradation and energy generation via roughened surface graphite electrode in microbial desalination cell. AB - The microbial desalination cell (MDC) is known as a newly developed technology for water and wastewater treatment. In this study, desalination rate, organic matter removal and energy production in the reactors with and without desalination function were compared. Herein, a new design of plain graphite called roughened surface graphite (RSG) was used as the anode electrode in both microbial fuel cell (MFC) and MDC reactors for the first time. Among the three type of anode electrodes investigated in this study, RSG electrode produced the highest power density and salt removal rate of 10.81 W/m3 and 77.6%, respectively. Such a power density was 2.33 times higher than the MFC reactor due to the junction potential effect. In addition, adding the desalination function to the MFC reactor enhanced columbic efficiency from 21.8 to 31.4%. These results provided a proof-of-concept that the use of MDC instead of MFC would improve wastewater treatment efficiency and power generation, with an added benefit of water desalination. Furthermore, RSG can successfully be employed in an MDC or MFC, enhancing the bio-electricity generation and salt removal. PMID- 28876263 TI - Electric treatment for hydrophilic ink deinking. AB - Hydrophilic inks have been widely used due to higher printing speed, competitive cost and being healthy non-organic solvents. However, they cause problems in both product quality and process runnability due to their hydrophilic surface wettability, strong negative surface charge and sub-micron size. Electric treatment was shown to be able to increase the ink sizes from 60 nm to 700 nm through electrocoagulation and electrophoresis. In addition, electric treatment assisted flotation could reduce effective residual ink concentration (ERIC) by 90 ppm, compared with only 20 ppm by traditional flotation. Furthermore, the effect of electric treatment alone on ink separation was investigated by two anode materials, graphite and stainless steel. Both of them could remove hydrophilic inks with less than 1% yield loss via electroflotation and electrophoresis. But graphite is a better material as the anode because graphite reduced ERIC by an additional 100 ppm. The yield loss of flotation following electric treatment was also lower by 17% if graphite was the anode material. The difference between the two electrode materials resulted from electrocoagulation and ink redeposition during electric treatment. An electric pretreatment-flotation-hyperwashing process was conducted to understand the deinking performance in conditions similar to a paper mill, and the ERIC was reduced from 950 ppm to less than 400 ppm. PMID- 28876264 TI - Energetic flexibility on wastewater treatment plants. AB - In the future, an additional potential of control reserve as well as storage capacities will be required to compensate fluctuating renewable energy availability. The operation of energy systems will change and flexibility in energy generation and consumption will rise to a valuable asset. Wastewater treatment plants (WWTPs) are capable of providing the flexibility needed, not only with their energy generators but also in terms of their energy consuming aggregates on the plant. To meet challenges of the future in regard to energy purchase and to participate in and contribute to such a volatile energy market, WWTPs have to reveal their energetic potential as a flexible service provider. Based on the evaluated literature and a detailed analysis of aggregates on a pilot WWTP an aggregate management has been developed to shift loads and provide a procedure to identify usable aggregates, characteristic values and control parameters to ensure effluent quality. The results show that WWTPs have a significant potential to provide energetic flexibility. Even for vulnerable components such as aeration systems, load-shifting is possible with appropriate control parameters and reasonable time slots without endangering system functionality. PMID- 28876265 TI - Biomass granulation in an upflow anaerobic sludge blanket reactor treating 500 m3/day low-strength sewage and post treatment in high-rate algal pond. AB - A pilot-scale upflow anaerobic sludge blanket-moving bed biofilm (UASB-MBB) reactor followed by a high-rate algal pond (HRAP) was designed and operated to remove organic matter, nutrients and pathogens from sewage and to facilitate reuse. For an influent chemical oxygen demand (COD) concentration of 233 +/- 20 mg/L, final effluent COD was 50 +/- 6 mg/L. Successful biomass granulation was observed in the sludge bed of the upflow anaerobic sludge blanket (UASB) reactor after 5 months of operation. Ammonia removal in HRAP was 85.1 +/- 2.4% with average influent and effluent ammonia nitrogen concentrations of 20 +/- 3 mg/L and 3 +/- 1 mg/L, respectively. Phosphate removal after treatment in the HRAP was 91 +/- 1%. There was a 2-3 log scale pathogen removal after treatment in HRAP with most probable number (MPN) of the final effluent being 600-800 per 100 mL, which is within acceptable standards for surface irrigation. The blackwater after treatment in UASB-MBBR-HRAP is being reused for gardening and landscaping. This proper hydro-dynamically designed UASB reactor demonstrated successful granulation and moving bed media improved sludge retention in UASB reactor. This combination of UASB-MBB reactor followed by HRAP demonstrated successful sewage treatment for a year covering all seasons. PMID- 28876266 TI - Mechanism and kinetics of dye desorption from dye-loaded carbon (XC-72) with alcohol-water system as desorbent. AB - In this paper, alcohol (methanol, ethanol, n-propanol)-water system was used as solution for the desorption of Acid Orange 7 (AO7), Ponceau 2R and Rhodamine B (RhB) from dye-loaded carbon (XC-72). Excellent degradation efficiency was obtained (desorption efficiency reaches 77.35%, 85.60%, 96.86% for Ponceau 2R, AO7 and Rhodamine B, respectively) and it was significantly influenced by alcohol content and the length of carbon chain in alcohol (hydrophobicity). In addition, desorption kinetics was fitted by a second-order desorption model, and the desorbed quantity at equilibrium (qe) and rate constant (kd) were calculated, respectively. PMID- 28876267 TI - A prototype of novel agro-waste based column bed device for removal of textile dye Optilan Red. AB - The aim of the study was to assess the potentiality of an agro-waste (sugarcane bagasse) for removal of the textile dye (Optilan Red) using novel column based filtration unit with a packed column of chemically treated sugarcane bagasse. The treated and untreated sugarcane bagasse (biosorbent) were characterized by Fourier transform infrared (FT-IR) spectroscopy. Effect of initial dye concentration on percentage removal of dye, equilibrium adsorption of sugarcane bagasse, kinetic studies, breakthrough point equilibrium and desorption of dye from the column material were studied. An inverse dependence of initial dye concentration on percent removal of dye was observed, whereas the equilibrium adsorption (qe) showed a direct relationship with dye concentration. The time required for reaching breakthrough point was 120 min. Desorption of dye through alkali wash resulted in complete desorption after 1 h washing of the column for its reuse for next cycle. FT-IR analysis shows vibration in valence bands of the hydrogen bond of OH group, and the bands of intra-molecular and intermolecular hydrogen bonds, which results in interaction of treated bagasse with Optilan Red textile dye. The present study showed that more than 93% removal of the dye can be achieved in the concentration range 10-50 ppm (aqueous solution). The removal efficiency of the column remained almost unchanged for the treatment of dye-house wastewater spiked with the dye. The agro-waste based treatment process shows a considerable potential for a low-cost treatment of dye contaminated water. PMID- 28876268 TI - Single and combined removal of Cr(VI) and Cd(II) by nanoscale zero-valent iron in the absence and presence of EDDS. AB - This study examined the feasibility of nanoscale zero-valent iron (nZVI) for the single and combined removal of Cr(VI) and Cd(II) with or without ethylene diamine disuccinic acid (EDDS). The effects of pH and dissolved oxygen (DO) on the removal process were investigated. Results show that the single removal of either Cr(VI) or Cd(II) by nZVI was pH dependent, where the higher Cr(VI) removal was achieved under acidic conditions, whereas the higher Cd(II) removal was achieved under alkaline conditions. The presence of DO enhanced Cd(II) removal but inhibited Cr(VI) removal under alkaline conditions. In the co-existence of Cr(VI) and Cd(II), it was found that Cd(II) exerted insignificant effect on Cr(VI) removal, while the presence of Cr(VI) remarkably enhanced the Cd(II) removal. The addition of EDDS exhibited different influences on Cr(VI) and Cd(II) removal, which were associated with pH and DO. The EDDS enhanced Cr(VI) removal at pH 5.6 9.0 in the absence of DO, but decreased Cr(VI) removal at pH 9.0 in the presence of DO. For the removal of Cd(II) at pH 5.6-7.0, either facilitation or inhibition effect of EDDS was observed, depending on EDDS concentration and the co-existence of Cr(VI). However, Cd(II) removal was always significantly inhibited by EDDS at pH 9.0. PMID- 28876269 TI - Info-Gap robustness pathway method for transitioning of urban drainage systems under deep uncertainties. AB - In the urban water cycle, there are different ways of handling stormwater runoff. Traditional systems mainly rely on underground piped, sometimes named 'gray' infrastructure. New and so-called 'green/blue' ambitions aim for treating and conveying the runoff at the surface. Such concepts are mainly based on ground infiltration and temporal storage. In this work a methodology to create and compare different planning alternatives for stormwater handling on their pathways to a desired system state is presented. Investigations are made to assess the system performance and robustness when facing the deeply uncertain spatial and temporal developments in the future urban fabric, including impacts caused by climate change, urbanization and other disruptive events, like shifts in the network layout and interactions of 'gray' and 'green/blue' structures. With the Info-Gap robustness pathway method, three planning alternatives are evaluated to identify critical performance levels at different stages over time. This novel methodology is applied to a real case study problem where a city relocation process takes place during the upcoming decades. In this case study it is shown that hybrid systems including green infrastructures are more robust with respect to future uncertainties, compared to traditional network design. PMID- 28876270 TI - Corrigendum: Water Science and Technology 75 (11), 2527-2537: Modelling and optimization of land use/land cover change in a developing catchment, Ping Xu et al., doi: 10.2166/wst.2017.121. PMID- 28876271 TI - Treatment of Unstable Distal Clavicle Fractures With Multiple Steinmann Pins-A Modification of Neer's Method: A Series of 56 Consecutive Cases. AB - OBJECTIVES: To introduce an alternative fixation technique for Neer type II fractures using Steinmann pins (S-pins). DESIGN: Retrospective case series study. SETTING: Operating room followed by clinic in tertiary hospital. PATIENTS/PARTICIPANTS: Between 2001 and 2013, among 66 consecutive patients diagnosed with Neer type II distal clavicle fractures, 11 patients were excluded and 56 clavicles of 55 patients who underwent surgical treatment with multiple transacromial S-pins were selected for analysis. INTERVENTION: Multiple transacromial S-pin (2.0-mm diameter) fixation was performed. Interfragmentary fixation was performed with 2.7-mm screws in case of oblique fractures. MAIN OUTCOME MEASURES: Radiographic results, complications, and clinical outcomes including the Constant-Murley score, the University of California at Los Angeles Shoulder score, and the disabilities of the arm, shoulder, and hand score were evaluated. RESULTS: Radiologic union was achieved in all patients. Coracoclavicular distance was increased by 6.4% compared with that of the uninjured side (P < 0.001). Fourteen patients had lateral migrations of 1 pin (mean migration distance, 11.6 mm). The mean Constant-Murley score was 94.3 (range, 85-100), mean University of California at Los Angeles score was 33.1 (range, 29-35), and mean disabilities of the arm, shoulder, and hand score was 2.7 (range, 0-8.3). The average follow-up period was 30.5 months (range, 24-81 months). CONCLUSIONS: Good functional and radiologic results were achieved by the insertion of multiple transacromial S-pins with interfragmentary screw fixation. With its wide indication and relatively simple procedure, this technique may be a possible surgical option for the treatment of Neer type II distal clavicle fractures. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28876272 TI - Intramedullary Nail Fixation of Atypical Femur Fractures With Bone Marrow Aspirate Concentrate Leads to Faster Union: A Case-Control Study: Erratum. PMID- 28876273 TI - Assessment of Severe Extremity Wound Bioburden at the Time of Definitive Wound Closure or Coverage (BIOBURDEN Study): Erratum. PMID- 28876275 TI - Outcomes After Severe Distal Tibia, Ankle, and/or Foot Trauma: Comparisons of Limb Salvage versus Transtibial Amputation (OUTLET): Erratum. PMID- 28876274 TI - A Prospective Randomized Trial to Assess Fixation Strategies for Severe Open Tibia Fractures: Modern Ring External Fixators versus Internal Fixation (FIXIT Study): Erratum. AB - In the article that appeared on page S10, several investigators were not included in the METRC group authorship acknowledgement. The correct acknowledgement should include: University of Wisconsin: Christopher Doro, MD; Paul Whiting, MD; David Goodspeed, MD; Gerald Lang, MD. Jose Santayo is incorrectly listed under University of Texas Health Science Center at Houston. The correct affiliation is University of Texas Southwestern Medical Center. PMID- 28876276 TI - Supplemental Perioperative Oxygen To Reduce Surgical Site Infection After High Energy Fracture Surgery (OXYGEN Study): Erratum. PMID- 28876277 TI - Improving Pain Management and Long-Term Outcomes Following High-Energy Orthopaedic Trauma (PAIN Study): Erratum. PMID- 28876279 TI - Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection: A Multi-Center Randomized Controlled Trial (VANCO study): Erratum. PMID- 28876278 TI - A Prospective Randomized Trial to Assess Oral Versus Intravenous Antibiotics for the Treatment of Postoperative Wound Infection After Extremity Fractures (POvIV Study): Erratum. PMID- 28876280 TI - The Trauma Collaborative Care Study (TCCS): Erratum. PMID- 28876281 TI - Human Immunodeficiency Virus, Chlamydia, and Gonorrhea Testing in New York Medicaid-Enrolled Adolescents. AB - BACKGROUND: Although growing public health efforts have been expended on increasing adolescents' access to human immunodeficiency virus (HIV) and sexually transmitted infection (STI) testing, little is known about the current utilization of those services in clinical settings. METHODS: Using 2010 to 2012 New York State Center for Medicare and Medicaid Services Medicaid Analytic eXtract data, we estimated the annual percentage of 13- to 19-year-olds who were tested for HIV, chlamydia (CT), and gonorrhea (GC). A regression analysis was performed to identify factors independently associated with testing utilization. We further examined testing utilization in all adolescent females with 1 or more health care encounter, pregnant females, and adolescents at increased risk for HIV/STI. RESULTS: From 2010 to 2012, HIV, CT, and GC testing rates increased in the overall study population and in most demographic subgroups. Female adolescents, black and Hispanic adolescents, at-risk adolescents, and adolescents with 6 months or longer of enrollment were significantly more likely to be tested. Among adolescent females with 1 or more health care encounter, 19.2% were tested for CT and 16.9% tested for GC in 2012. Among pregnant females, 35.2%, 53.9%, and 46.1% were tested for HIV, CT, and GC, respectively. Among at-risk adolescents, 39.9%, 63.7%, and 54.4% were tested for HIV, CT, and GC, respectively. CONCLUSIONS: Although progress had been made by New York State providers to adhere to recommended testing for adolescents, there was a clear gap between the recommended level of testing and the actual level of utilization among sexually active females, pregnant females, and at-risk adolescents. Opportunities exist for community provider and public health collaboration to increase adolescent HIV and STI testing. PMID- 28876282 TI - Outcomes of Preexposure Prophylaxis Referrals From Public STI Clinics and Implications for the Preexposure Prophylaxis Continuum. AB - BACKGROUND: Human immunodeficiency virus preexposure prophylaxis (PrEP) uptake remains low in high-risk populations. Sexually transmitted infection (STI) clinics reach PrEP-eligible persons and may be ideal settings to model PrEP implementation. METHODS: Consenting PrEP-eligible patients identified at Chicago Department of Public Health STI Clinics were actively referred to PrEP partner sites between June 1, 2015, and May 31, 2016. Outcomes included successful contact by a partner site, linkage to a partner site, and receipt of a PrEP prescription. Bivariable and time to event analyses were conducted to determine significant associations of outcomes. RESULTS: One hundred thirty-seven patients were referred; 126 (92%) were men who have sex with men, and mean age was 29 years. Ninety-eight (72%) were contacted by a PrEP partner, 43 (31%) were linked, and 40 (29%) received a prescription. Individuals aged 25 years and older were more likely to link (odds ratio, 3.10; 95% confidence interval, 1.30-7.41) and receive a PrEP prescription (odds ratio, 2.70; 95% confidence interval, 1.12 6.45) compared with individuals 24 years and younger. The average time between each step was greater for those 24 years and younger compared with those aged 25 years and older for all steps. Time to event analyses revealed that those aged 25 years and older were significantly more likely to receive a prescription compared to those aged 24 years and younger (hazard ratio, 3.62; 95% risk limits, 1.47 8.92). CONCLUSIONS: Preexposure prophylaxis active referrals from STI clinics to partner sites are feasible, though drop out was prominent in the initial steps of the continuum. Youth were less likely to link or receive prescriptions, indicating the need for tailored interventions for this vulnerable population. PMID- 28876283 TI - Correlates of Self-Reported Viral Suppression Among HIV-Positive, Young, Black Men Who Have Sex With Men Participating in a Randomized Controlled Trial of An Internet-Based HIV Prevention Intervention. AB - BACKGROUND: Young, black men who have sex with men are disproportionately impacted by the US HIV epidemic, and HIV-positive, young, black men who have sex with men face stark disparities in HIV clinical outcomes. METHODS: We performed an observational analysis of the 199 HIV-positive black men aged 18 to 30 years followed up for 12 months in healthMpowerment, a randomized controlled trial of an Internet-based HIV prevention intervention, to identify time-varying correlates of self-reported viral suppression using relative risk (RR) regression. RESULTS: Retention at the 12-month visit was 84%. One hundred five (65%) of 162 participants reported being undetectable at baseline. At 3, 6, and 12 months, 83 (72%) of 115, 84 (82%) of 103, and 101 (86%) of 117 reported an undetectable viral load, respectively. In a multivariable model, participants who reported homelessness (RR, 0.85; 95% confidence interval [CI], 0.72-0.99), who had clinically significant depressive symptoms (RR, 0.88; 95% CI, 0.79-0.98), and who used methamphetamine or crack (RR, 0.61; 95% CI, 0.38-0.96) were less likely to report an undetectable viral load. Young men who engaged in condomless insertive anal intercourse were more likely to report viral suppression (RR, 1.14; 95% CI, 1.04-1.24). CONCLUSION: HIV care for young, black men who have sex with men must be multidimensional to address medical needs in the context of mental health, substance use, and housing insecurity. PMID- 28876284 TI - In Vitro Synergy Testing of Gentamicin, an Old Drug Suggested as Future Treatment Option for Gonorrhoea, in Combination With Six Other Antimicrobials Against Multidrug-Resistant Neisseria gonorrhoeae Strains. AB - BACKGROUND: Emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Neisseria gonorrhoeae is a serious concern and combination therapy has been recommended to delay the onset of treatment failures. Gentamicin, an old and inexpensive antibiotic, is recommended in combination with azithromycin for treatment failures cases with the first-line regimen as per the latest Centers for Disease Control and Prevention sexually transmitted disease treatment guidelines. However, not much literature is available on in vitro and in vivo efficacy of this combination. Therefore, this study was carried out to evaluate the in vitro synergy of gentamicin in combination with azithromycin and 5 other antimicrobials. METHODS: In vitro synergy of gentamicin in combination with cefixime, ceftriaxone, spectinomycin, azithromycin, moxifloxacin, and ertapenem was determined by Etest for 75 N. gonorrhoeae strains, of which 65 were MDR and one was XDR. Fractional inhibitory concentration index (FICI) of <=0.5 and >4.0 denoted synergy and antagonism respectively. RESULTS: Maximum efficacy of gentamicin was observed in combination with ertapenem (geometric mean FICI, 0.56) followed by cefixime (FICI, 0.87). There was no antagonism for both these combinations. However, antagonism was demonstrated in 5.3%, 8%, 8%, and 10.7% strains when gentamicin was paired with spectinomycin (FICI, 1.34), ceftriaxone (FICI, 1.13), azithromycin (FICI, 1.49), and moxifloxacin (FICI, 1.30), respectively. CONCLUSIONS: The findings suggest that gentamicin significantly enhances the in vitro therapeutic potency of ertapenem and cefixime which will be potentially effective to control the spread of MDR and XDR N. gonorrhoeae. The study warrants more in vitro studies and clinical trials for gentamicin + azithromycin and other 3 combinations because of considerable antagonism. PMID- 28876285 TI - A Web Application to Facilitate Syphilis Reactor Grid Evaluations. AB - BACKGROUND: Many health departments use a "reactor grid" to determine which laboratory-reported syphilis serologic test results require investigation. We developed a Web-based tool, the Syphilis Reactor Grid Evaluator (SRGE), to facilitate health department reactor grid evaluations and test the tool using data from Seattle & King County, Washington. METHODS: We developed SRGE using the R Shiny Web application framework. When populated with a data set including titer results and final disposition codes, SRGE displays the percent of verified early syphilis cases by serologic titer result and patient age in each cell of the grid. The results can be optionally stratified by sex, test type, and previous rapid plasma reagin titer. The impact of closing laboratory results without investigation in cells selected by the user is dynamically computed. The SRGE calculates the percent of all laboratory reports closed ("efficiency gained"), the proportion of all early syphilis cases closed without investigation ("case finding loss"), and the ratio of percent of cases identified for investigation to percent of all laboratory reports investigated ("efficiency ratio"). After defining algorithms, users can compare them side-by-side, combine subgroup specific algorithms, and export results. We used SRGE to compare the current Public Health-Seattle & King County (PHSKC) reactor grid to 5 alternate algorithms. RESULTS: Of 13,504 rapid plasma reagin results reported to PHSKC from January 1, 2006, to December 31, 2015, 1565 were linked to verified early syphilis cases. Updating PHSKC's current reactor grid could result in an efficiency gain of 4.8% to 25.2% (653-3403 laboratory reports) and case finding loss of 1% to 8.4% (10-99 fewer cases investigated). CONCLUSIONS: The Syphilis Reactor Grid Evaluator can be used to rapidly evaluate alternative approaches to optimizing the reactor grid. Changing the reactor grid in King County to close more laboratory results without investigation could improve efficiency with minimal impact on syphilis case finding. PMID- 28876286 TI - Investigation of Early Syphilis Trends Among Men Who Have Sex With Men to Identify Gaps in Screening and Case-Finding in Baltimore City, Maryland. AB - BACKGROUND: Syphilis incidence is increasing across the United States among men who have sex with men (MSM). Early latent (EL) versus primary and secondary (P&S) syphilis may be an indicator of delayed diagnosis and increased opportunity for transmission. To inform syphilis control strategies and identify potential gaps in case finding, we described recent syphilis trends among MSM and compared characteristics of syphilis cases by diagnosis stage. METHODS: We used public health surveillance data on P&S and EL syphilis diagnoses reported to the Baltimore City Health Department between 2009 and 2015. Differences across diagnosis stage were assessed using Cochran-Armitage and chi tests. RESULTS: Between 2009 and 2015, Baltimore City Health Department received 2436 reports of P&S and EL diagnoses. The majority (61%) of reports were among MSM, among whom 86% were black and 67% were human immunodeficiency virus (HIV)-infected. During this period, P&S and EL syphilis increased by 85% and 245%, respectively (P < 0.0001). MSM with EL versus P&S syphilis were similarly likely to be Black, more likely to be older (P < 0.05), HIV coinfected (P < 0.001), and diagnosed in private health care settings (P < 0.0001), but less likely to report multiple (P < 0.001) and anonymous sex partners (P < 0.001). CONCLUSIONS: In Baltimore City, syphilis diagnoses, particularly EL diagnoses, are increasing rapidly and are concentrated among Black HIV-infected MSM. Significant gaps in identifying MSM with P&S syphilis may exist, specifically among HIV-infected MSM, and those diagnosed in private health care settings. Strategies to address these gaps may include local guidelines and provider education to screen MSM more frequently than CDC currently recommends and regardless of HIV status or risk. PMID- 28876287 TI - Does the Centers for Disease Control and Prevention's Youth Risk Behavior Survey Underreport Risky Sexual Behavior? PMID- 28876288 TI - Heterogeneity of Herpes Simplex Virus Type 2 Seroprevalence From a National Probability Survey In Mexico, 2012. AB - BACKGROUND: Herpes simplex virus type 2 (HSV-2) seroprevalence and associated infection risk factors show differences by regions and countries. The aims of the study were to determine the HSV-2 seroprevalence and to evaluate the risk factors for HSV-2 in a national representative survey among adolescents and adults in Mexico. METHODS: A cross-sectional study was carried out in Mexico on the basis of the National Health and Nutrition Survey 2012, a national representative survey. Demographic, sexual behavior, reproductive health, and lifestyles indicators were considered in the current study. Participants provided biological samples-dried blood spots-to test for HSV-2 antibodies using enzyme-linked immunosorbent assay and Western blot. Bivariate and multivariate analyses were performed to identify variables associated with HSV-2 infections analyzed by sex. RESULTS: National HSV-2 seroprevalence was 9.9%, 2.4% among adolescents and 11.7% among adults with HSV-2 seroprevalence heterogeneous across the country. Women had 12.2% of antibodies against HSV-2 and men had 7.5%. The factors associated with HSV-2 infection among women were age (45-49 years; odds ratio [OR], 19.8), region (southwest; OR, 3.0), urbanization (urban; OR, 1.9), age at sexual debut (<=14 years; OR, 3.4), education level (any; OR, 3.0), and previous abortion (>=2 abortion; OR, 2.1). Among men, age (45-49 years; OR, 11.7), region (southwest; OR, 3.0), urbanization (urban, odds ratio [OR], 1.7), and HIV care (OR, 7.1) were associated with the infection. CONCLUSIONS: Approximately 10% of Mexicans aged 15 to 49 years had HSV-2 antibodies, with differences by sex, region, education level, urbanization, HIV care, and childbirth, highlighting the relevance of health inequalities in the country: social inequalities seem to matter in terms of the probability of HSV-2 infections. PMID- 28876289 TI - Neisseria gonorrhoeae Transmission Among Men Who Have Sex With Men: An Anatomical Site-Specific Mathematical Model Evaluating the Potential Preventive Impact of Mouthwash. AB - BACKGROUND: Gonorrhoea notifications are rapidly rising in men who have sex with men (MSM). We developed a model to assess mouthwash as a novel intervention for gonorrhoea control. METHODS: We developed a model of Neisseria gonorrhoeae (NG) transmission to explain anatomic site-specific prevalence of gonorrhoea among MSM. The model was calibrated to available epidemiological and behavioral data. We estimated the contribution of various sexual acts to gonorrhoea incidence and evaluate the potential impacts of screening scale-up and utilization of mouthwash on the gonorrhoea epidemic. RESULTS: We calibrated the model to prevalence of oropharyngeal, anal, and urethral gonorrhoea of 8.6% (7.7-9.5%), 8.3% (7.4-9.1%), and 0.20% (0.04-0.35%), respectively, among MSM. Oropharynx to oropharynx transmission through kissing is estimated to account for nearly three quarters of all incident cases (71.6% [64.4-80.5%]) of gonorrhoea in MSM. Substantially increasing annual oropharynx screening for gonorrhoea from the current 40% to 100% may only halve the prevalence of gonorrhoea in MSM. In contrast, the use of mouthwash with moderate efficacy (additional 1% clearance per daily use) would further reduce the corresponding prevalence rates to 3.1% (2.2-4.4%), 3.8% (2.3 4.9%), and 0.10% (0.06-0.11%), and a high-efficacy mouthwash (additional 1.5% clearance per daily use) may further halve the gonorrhoea prevalence. Without oropharynx to oropharynx transmission, we could not replicate current prevalence data. CONCLUSIONS: Despite a dearth of empirical data, our model suggests that kissing could potentially play an important role in NG transmission among MSM. Control through sexually transmitted infection screening alone is unlikely to have a substantial impact on the gonorrhoea epidemic in MSM. PMID- 28876290 TI - Performance of Commercial Enzyme-Linked Immunoassays for Diagnosis of Herpes Simplex Virus-1 and Herpes Simplex Virus-2 Infection in a Clinical Setting. AB - BACKGROUND: US Food and Drug Administration-approved enzyme-linked immunoassays (EIA) for determining type-specific herpes simplex virus (HSV) serostatus are widely used in clinical practice. We compared the performance of such assays with the University of Washington Western blot (UW WB) in patients who sought confirmation of their HSV serology result. METHODS: We reviewed charts of all persons evaluated at the Westover Heights Clinic in Portland, Oregon, from July 2010 through September 2015, who had a HSV EIA, followed by UW WB. RESULTS: Of 864 persons, 47% were women. The median age was 36 years (range, 18-73 years). Using UW WB to define infection status, 286 (33%) persons were HSV-1 seropositive only, 104 (12%) were HSV-2 seropositive only, 134 (16%) were both HSV-1 and HSV-2 seropositive, 235 (27%) were HSV seronegative, and 105 (12%) had indeterminate results. Compared with the UW WB as the criterion standard, EIA was 70.2% sensitive and 91.6% specific for HSV-1, and 91.9% sensitive and 57.4% specific for HSV-2.Among 278 persons who were HSV-1 seropositive by EIA, 255 were confirmed by the UW WB (positive predictive value [PPV], 91.7%). Of the 360 persons that were HSV-1 seronegative by the EIA, 252 were seronegative by UW WB (negative predictive value [NPV], 70.0%). Among 381 persons with HSV-2 EIA seropositivity, 193 tested HSV-2 seropositive by the UW WB (PPV, 50.7%). Of the 270 persons HSV-2 seronegative by EIA, 17 were seropositive with the UW WB (NPV, 93.7%). Among 261 persons with an EIA HSV-2 index value = 1.1-2.9, 39.8% of results were confirmed by UW WB, compared with 78.6% of the 70 persons with an EIA index value of 3 or greater (P < 0.001). The risk of false-positive HSV-2 EIA results was higher in those with HSV-1 antibody (47.1% vs 37.1%, P = 0.036). CONCLUSIONS: US Food and Drug Administration-approved EIAs have poor PPV for HSV 2 and poor NPV for HSV-1 in clinical practice. More accurate rapid type-specific HSV antibody tests are needed. PMID- 28876291 TI - Prevalence of Gonorrhea and Chlamydia Testing by Anatomical Site Among Men Who Have Sex With Men in HIV Medical Care, United States, 2013-2014. AB - Fewer than one-third of men who have sex with men were tested for Neisseria gonorrhoeae or Chlamydia trachomatis as part of HIV medical care in the United States in 2013 to 2014, and only 11.6% were tested for either sexually transmitted disease at an extragenital site. PMID- 28876292 TI - Cerebral Syphilitic Gumma Can Arise Within Months of Reinfection: A Case of Histologically Proven Treponema pallidum Strain Type 14b/f Infection With Human Immunodeficiency Virus Positivity. AB - A 44-year-old man with human immunodeficiency virus positivity developed cerebral gumma 6 months after appropriate therapy for secondary syphilis. It was surgically resected and histologically, Treponema pallidum (14b/f, a relatively rare strain type) was proven. A complete set of modern techniques was performed to depict rare complication of this classic disease. PMID- 28876293 TI - The Spatial Association Between Federally Qualified Health Centers and County Level Reported Sexually Transmitted Infections: A Spatial Regression Approach. AB - BACKGROUND: The number of categorical sexually transmitted disease (STD) clinics is declining in the United States. Federally qualified health centers (FQHCs) have the potential to supplement the needed sexually transmitted infection (STI) services. In this study, we describe the spatial distribution of FQHC sites and determine if reported county-level nonviral STI morbidity were associated with having FQHC(s) using spatial regression techniques. METHODS: We extracted map data from the Health Resources and Services Administration data warehouse on FQHCs (ie, geocoded health care service delivery [HCSD] sites) and extracted county-level data on the reported rates of chlamydia, gonorrhea and, primary and secondary (P&S) syphilis (2008-2012) from surveillance data. A 3-equation seemingly unrelated regression estimation procedure (with a spatial regression specification that controlled for county-level multiyear (2008-2012) demographic and socioeconomic factors) was used to determine the association between reported county-level STI morbidity and HCSD sites. RESULTS: Counties with HCSD sites had higher STI, poverty, unemployment, and violent crime rates than counties with no HCSD sites (P < 0.05). The number of HCSD sites was associated (P < 0.01) with increases in the temporally smoothed rates of chlamydia, gonorrhea, and P&S syphilis, but there was no significant association between the number of HCSD per 100,000 population and reported STI rates. CONCLUSIONS: There is a positive association between STI morbidity and the number of HCSD sites; however, this association does not exist when adjusting by population size. Further work may determine the extent to which HCSD sites can meet unmet needs for safety net STI services. PMID- 28876294 TI - Reported Cases of Neurosyphilis Among Early Syphilis Cases-United States, 2009 to 2015. AB - The surveillance of neurosyphilis, an uncommon but severe consequence of syphilis, is complex; surveillance classification of neurosyphilis requires a lumbar puncture and cerebrospinal fluid analysis. We examined the prevalence of reported neurosyphilis among primary, secondary, and early latent syphilis cases reported in the United States from 2009 to 2015. Overall, the prevalence of reported neurosyphilis from 2009 to 2015 was low (0.84%); however, this is likely an underestimate of the true burden in the United States. PMID- 28876295 TI - Y Chromosome DNA in Women's Vaginal Samples as a Biomarker of Recent Vaginal Sex and Condom Use With Male Partners in the HPV Infection and Transmission Among Couples Through Heterosexual Activity Cohort Study. AB - BACKGROUND: Y chromosome DNA from male epithelial and sperm cells was detected in vaginal samples after unprotected sex in experimental studies. We assessed the strength of this association in an observational setting to examine the utility of Y chromosome DNA as a biomarker of recent sexual behaviors in epidemiological studies. METHODS: The HPV (human papillomavirus) Infection and Transmission Among Couples Through Heterosexual Activity cohort study enrolled 502 women attending a university or college in Montreal, Canada, and their male partners from 2005 to 2010. Participants completed self-administered questionnaires. We used real-time polymerase chain reaction to test women's baseline vaginal samples for Y chromosome DNA and assessed which sexual behaviors were independent predictors of Y chromosome DNA positivity and quantity with logistic and negative binomial regression. RESULTS: Y chromosome DNA positivity decreased from 77% in women in partnerships reporting vaginal sex 0 to 1 day ago to 13% in women in partnerships reporting last vaginal sex of 15 or more days ago (adjusted odds ratio, 0.09; 95% confidence interval, 0.02-0.36). The mean proportion of exfoliated vaginal sample cells with Y chromosome DNA was much lower for women who reported always using condoms (0.01%) than for women who reported never using condoms (2.07%) (adjusted ratio, 26.8; 95% confidence interval, 8.9-80.5). No association was found with reported oral/digital sex frequency or concurrency of partnerships. CONCLUSIONS: Y chromosome DNA quantity is strongly associated with days since last vaginal sex and lack of condom use in observational settings. Y chromosome DNA quantity may prove useful as a correlate of recent vaginal sex in observational studies lacking data on sexual behavior, such as surveillance studies of human papillomavirus infection prevalence. PMID- 28876296 TI - Neighborhood Health Care Access and Sexually Transmitted Infections Among Women in the Southern United States: A Cross-Sectional Multilevel Analysis. AB - INTRODUCTION: The United States has experienced an increase in reportable sexually transmitted infections (STIs) while simultaneously experiencing a decline in safety net services for STI testing and treatment. This multilevel study assessed relationships between neighborhood-level access to health care and STIs among a predominantly Human Immunodeficiency Virus (HIV)-seropositive cohort of women living in the south. METHODS: This cross-sectional multilevel analysis included baseline data from HIV-seropositive and HIV-seronegative women enrolled in the Women's Interagency HIV Study sites in Alabama, Florida, Georgia, Mississippi, and North Carolina between 2013 and 2015 (N = 666). Administrative data (eg, United States Census) described health care access (eg, percentage of residents with a primary care provider, percentage of residents with health insurance) in the census tracts where women lived. Sexually transmitted infections (chlamydia, gonorrhea, trichomoniasis, or early syphilis) were diagnosed using laboratory testing. Generalized estimating equations were used to determine relationships between tract-level characteristics and STIs. Analyses were conducted using SAS 9.4. RESULTS: Seventy percent of participants were HIV seropositive. Eleven percent of participants had an STI. A 4-unit increase in the percentage of residents with a primary care provider was associated with 39% lower STI risk (risk ratio, 0.61, 95% confidence interval, 0.38-0.99). The percentage of tract residents with health insurance was not associated with STIs (risk ratio, 0.98, 95% confidence interval, 0.91-1.05). Relationships did not vary by HIV status. CONCLUSIONS: Greater neighborhood health care access was associated with fewer STIs. Research should establish the causality of this relationship and pathways through which neighborhood health care access influences STIs. Structural interventions and programs increasing linkage to care may reduce STIs. PMID- 28876297 TI - What's in a Name? Perceptions of the Terms Sexually Transmitted Disease and Sexually Transmitted Infection Among Late Adolescents. AB - BACKGROUND: There has been a shift from using the term sexually transmitted disease (STD) to sexually transmitted infection (STI), primarily based on conjecture that STI is less stigmatizing. However, there is a dearth of evidence regarding how the public actually perceives these terms. METHODS: Students at a Midwestern university participated in an online survey and were randomized to the open-ended question "What comes to mind when you think of the term sexually transmitted disease (STD)?" (n = 205) or "What comes to mind when you think of the term sexually transmitted infection (STI)?" (n = 208). Conventional content analysis was conducted to identify response themes. Cross tabulations with the chi statistic determined the number of participants that endorsed each theme and any differences between the STD and STI responses. RESULTS: Almost all themes occurred in similar numbers across the STD and STI responses. Overarching themes for both terms were contracted through sex; specific STDs/STIs; severe; negative emotional affect; types of people who get STDs/STIs; physical symptoms; preventable; common; and treatable/curable. However, participants were more likely to mention that STDs were common (P = 0.030) and reported less negative emotional affect for STIs (P = 0.024). Two themes emerged only in the STI group: STDs (P = 0.001) and site of infection (P = 0.003). CONCLUSIONS: With some exceptions, late adolescents have overlapping conceptualizations of the terms STD and STI. The most commonly reported themes revealed likely areas of misinformation. Although language is an important aspect of health communication, more than a terminology change is needed to reduce the stigma associated with STDs/STIs. PMID- 28876299 TI - Utilization of Sexually Transmitted Infection Services at 2 Health Facilities Targeting Men Who Have Sex With Men in South Africa: A Retrospective Analysis of Operational Data. AB - BACKGROUND: Men who have sex with men (MSM) are a key population, particularly vulnerable to sexually transmitted infections (STIs) and HIV, but there are limited data on health programs targeting MSM in Africa. This study aims to describe the utilization of nongovernmental organization-supported sexual health services for MSM at 2 public sector health facilities in Johannesburg, South Africa. METHODS: We retrospectively analyzed routine data over the period of January 2014 to June 2016. We report on service utilization for STI syndromes, HIV testing, and the antiretroviral therapy (ART) program. RESULTS: Some 5796 men visited the facilities. Seven thousand one hundred eighty-eight STI episodes were managed, 68.2% (4903 episodes) of which were classified as male urethritis and 9.8% (704 episodes) as genital ulcers. Positivity yield for first-time HIV tests was 38.0% (205 positive test results) in MSM, compared with 14.1% (471 positive test results) in other men. At the end of the study, there were 1090 clients on ART, and 2-year retention was 82% (95% confidence interval, 78%-85%). There was no difference in retention between MSM and other men (P = 0.49). CONCLUSIONS: This study is the first to show that sexual health services targeting MSM in Africa have managed to attract MSM and other men in need of STI and HIV care. The observed high HIV testing yield among MSM illustrates the relevance of MSM focused services in the South African public health sector, and the good retention on ART demonstrates that high-quality care can be provided to MSM in our setting. PMID- 28876300 TI - What Is the Role of Paired Rapid Plasma Reagin Testing (Simultaneous Testing of Acute and Convalescent Samples) in the Diagnosis of Repeat Syphilis and the Follow-up of Syphilis? AB - BACKGROUND: Repeat syphilis is playing an increasing role in syphilis transmission in several populations. The assessment of repeat syphilis and response to treatment depends on accurately measuring intraindividual changes in non-treponemal tests. For a 0- to 6-month delta rapid plasma reagin (RPR) to be determined by routine individual RPR testing, samples are tested 6 months apart with differences in reagent batches, environmental conditions, and observers all leading to measurement errors. We hypothesized that conducting paired RPR testing (simultaneous testing of acute and convalescent samples) would enable a more accurate determination of delta RPR compared with individual testing. METHODS: A total of 120 study participants with a new diagnosis of syphilis were followed up at 0, 3, 6, 9, 12, 18, and 24 months, with RPR testing performed via individual testing at each study visit and at any suspected repeat syphilis. Rapid plasma reagin paired testing was performed on samples from 0 and 6 months and at any suspected repeat syphilis. RESULTS: The quantitative agreement +/-1 dilution among paired and individual testing was 97.2%. There was no difference in the proportion with serofast status at 6 months: 21 (19.4%) and 19 (17.6%) according to paired and individual testing, respectively (P = 0.726). There was no statistically significant difference between 0- and 6-month delta RPR as determined by paired and individual testing in predicting seroresponse at 12 months (86.1% and 91.6% agreement with 12-month serofast/nonserofast classification, respectively; P = 0.262). CONCLUSIONS: In our setting, individual testing performed equally well compared with paired testing. Follow-up of syphilis will remain onerous for the patient and the health care provider until new tests that can more accurately assess the response to therapy and repeat syphilis/treatment failure are developed. PMID- 28876298 TI - Mailed Human Papillomavirus Self-Collection With Papanicolaou Test Referral for Infrequently Screened Women in the United States. AB - BACKGROUND: Testing for high-risk human papillomavirus (HPV) infection using mailed, self-collected samples is a promising approach to increase screening in women who do not attend clinic screening at recommended intervals. METHODS: To assess this intervention among high-risk women in the United States, 429 women without a Papanicolaou (Pap) test in 4 or more years (overdue by US guidelines) were recruited from the general population. Participants aged 30 to 65 years were mailed a kit to self-collect a cervicovaginal sample at home, return the sample by mail, and receive HPV results by telephone, with referral to follow-up cytological Pap testing at a local clinic. Cervicovaginal self-samples were collected with a Viba brush, stored in Scope mouthwash, and tested by Hybrid Capture 2. Data were collected in 2010 to 2011 and analyzed in 2017. RESULTS: Two thirds (64%) of participants returned a self-collected sample, of whom 15% tested HPV DNA positive. Human papillomavirus self-test-positive women reported higher rates of follow-up Pap tests (82%) than did those with self-test negative results (51%). No demographic differences were found in self-test return rate or HPV positivity. High acceptability was reported in participant surveys: most women (81%) had "mostly positive" overall thoughts about the self-test, and most reported being comfortable receiving the kit in the mail (99%), returning their self-collected sample by mail (82%), and receiving their test results by telephone (97%). CONCLUSIONS: Conducting HPV self-testing through population based recruitment, mailed kit delivery and return by mail, and results delivery by telephone has the potential to reach a broad segment of US underscreened women. PMID- 28876301 TI - Longitudinal Findings on Changes in and the Link Between HIV-Related Communication, Risky Sexual Behavior, and Relationship Status in Men Who Have Sex With Men Living With HIV. AB - BACKGROUND: Reducing the risk of HIV transmission among men who have sex with men (MSM) is a national health priority. This study longitudinally examined changes in and the link between HIV-related communication, unprotected anal intercourse (UAI), and relationship status among MSM. METHODS: Data were obtained from 337 MSM living with HIV who participated in a randomized controlled study. Approximately equal percentages of men were randomized to either the disclosure intervention group or the attention control case management group. Repeated measures were collected at 5 time points for 12 months and included health protective sexual communication (HPSC), HIV disclosure, insertive and receptive UAI, and relationship status. Data were analyzed using mixed-effects models. RESULTS: Independent of the treatment condition, HPSC and HIV disclosure increased over time; insertive UAI showed a curvilinear pattern but no significant decrease over time. Relationship status was related to HIV-related communication and UAI. Greater HPSC was related to less insertive and receptive UAI; disclosure was positively related to insertive UAI. CONCLUSIONS: Based on the findings, prevention programs should continue to focus on improving HIV related communication among MSM and consider relationship status in prevention messages. Intervention studies are needed to continue to identify and test factors that help reduce risky sexual behaviors. PMID- 28876302 TI - Seroprevalence of Chlamydia trachomatis in Inner-City Children and Adolescents Implications for Vaccine Development. AB - BACKGROUND: Prevention of Chlamydia trachomatis infection is an ideal application for a vaccine program, which should optimally be administered before sexual debut. However, there are limited epidemiologic studies of C. trachomatis infection in an unselected pediatric population since routine screening and treatment of pregnant women was implemented in the United States in 1993. METHODS: Anonymized serum samples were obtained from children younger than 21 years in 2 medical centers in Brooklyn, New York, from 2013 to 2015. Anti-C. trachomatis IgG antibody was determined by a validated enzyme immunoassay. Infants younger than 1 year were excluded from the final analysis due to interference of maternal antibody. RESULTS: One thousand two sera were included in the final analysis. Fifty-seven percent were females. No antibody was detected at younger than 11 years. Anti-C. trachomatis IgG antibody was detected in 11.4% and 5.6% of female and male subjects, respectively, older than 11 years (P = 0.0027), and seropositivity increased with age. There was no significant difference in the distribution of age at infection between the centers (P = 0.432), but a difference was detected between genders (P = 0.012) with a higher percentage of female subjects testing positive. CONCLUSIONS: Antibody was first detected at 11 years of age, likely coinciding with sexual debut. The prevalence of antibody was higher and appeared earlier in females, mirroring national surveillance trends based on nucleic acid amplification testing. The delay in male antibody detection may be due to biological or behavioral differences between genders. These data are critical in informing potential C. trachomatis vaccine strategies. PMID- 28876303 TI - Determinants of Human Papillomavirus Vaccination Intention Among Female Sex Workers in Amsterdam, the Netherlands. AB - INTRODUCTION: Female sex workers (FSWs) are at risk for human papillomavirus (HPV)-induced diseases but are currently not targeted by the HPV vaccination program in the Netherlands. We explored determinants of their intention to get vaccinated against HPV in case vaccination would be offered to them. METHODS: In 2016, FSWs 18 years and older having a sexually transmitted infection consultation with the Prostitution & Health Center (P&G292) in Amsterdam, either at the clinic or at their working location, were invited to complete a questionnaire assessing sociopsychological determinants of HPV vaccination intention (scale ranging from -3 to +3). Determinants of HPV vaccination intention were assessed with univariable and multivariable linear regression. In addition, we explored the effect of out-of-pocket payment on intention. RESULTS: Between May and September 2016, 294 FSWs participated. The median age was 29 years (interquartile range, 25-37 years). Human papillomavirus vaccination intention was high (mean, 2.0; 95% confidence interval [CI], 1.8-2.2). In multivariable analysis, attitude (beta = 0.6; 95% CI, 0.5-0.7), descriptive norm (beta = 0.2; 95% CI, 0.1-0.3), self-efficacy (beta = 0.2; 95% CI, 0.1-0.3), beliefs (beta = 0.1; 95% CI, 0.0-0.2), and subjective norm (beta = 0.1; 95% CI, 0.0-0.2) seemed to be the strongest predictors of HPV vaccination intention (R = 0.54). Human papillomavirus vaccination intention decreased significantly to a mean of 0.2 when vaccination would require out-of-pocket payment of &OV0556;350. CONCLUSIONS: The HPV vaccination intention among FSWs seems relatively high and is most strongly constituted in attitudinal, normative, and self-efficacy beliefs. Out-of-pocket payment will probably have a negative impact on their HPV vaccination acceptability. PMID- 28876304 TI - Human Papillomavirus Prevalence Is Associated With Socioeconomic Gradients Within a Medically Underserved Appalachian Region. AB - OBJECTIVES: To assess type-specific prevalence of human papillomavirus (HPV) infection in a medically underserved Appalachian area and to determine whether gradients in poverty are associated with prevalence. METHODS: Among 398 women, a validated assay tested self-collected cervicovaginal samples for 37 HPV types. Three economic strata were created based on household income: below the federal poverty level for 1 person, between the FPLs for families of 1 to 4 persons, and above the FPL for a family of 4. RESULTS: Prevalence was 55.6%, with 33% having at least 1 high-risk infection. Prevalence was 27.8% for 9-valent HPV vaccine preventable types and 39.2% for multiple types. Compared with FPL for a family of 4, women with federal poverty level for 1 person had 3 times greater prevalence, 2.3 times greater prevalence of high-risk types, and 2.5 times greater prevalence of multiple types. CONCLUSION: Human papillomavirus prevalence was high, with one third of the sample having at least 1 high-risk type and those in the lowest income category being disproportionately infected. PMID- 28876305 TI - Sexually Transmitted Disease Testing of Human Immunodeficiency Virus-Infected Men Who Have Sex With Men: Room for Improvement. AB - BACKGROUND: In the United States, sexually transmitted infection (STI) testing is recommended at least annually for sexually active men who have sex with men (MSM). We evaluated human immunodeficiency virus (HIV) providers' STI testing practices and frequency of positive test results. METHODS: We analyzed data from HIV Outpatient Study (HOPS) participants who, from 2007 to 2014, completed a confidential survey about risk behaviors. Using medical records data, we assessed the frequency of gonorrhea, chlamydia, and syphilis testing and positive results during the year after the survey for MSM who reported sex without a condom in the prior 6 months. We compared testing frequency and positivity for men having 1, 2 to 3, and 4 or more sexual partners. Correlates of STI testing were assessed using general linear model to derive relative risks (RR) with associated 95% confidence intervals (CI). RESULTS: Among 719 MSM, testing frequency was 74.5%, 74.3%, and 82.9% for gonorrhea, chlamydia, and syphilis, respectively, and was higher in those men who reported more sexual partners (P < 0.001 for all). In multivariable analysis, testing for gonorrhea was significantly more likely among non-Hispanic black versus white men (RR, 1.17; 95% CI, 1.03-1.33), among men seen in private versus public clinics (RR, 1.16; 95% CI, 1.05-1.28), and among men with 2 to 3 and 4 or more sexual partners versus 1 partner (RR, 1.12; 95% CI, 1.02-1.23, and RR, 1.18; 95% CI, 1.08-1.30, respectively). Correlates of chlamydia and syphilis testing were similar. Test positivity was higher among men with more sexual partners: for gonorrhea 0.0%, 3.0%, and 6.7% for men with 1, 2 to 3, and 4 or more partners, respectively (P < 0.001, syphilis 3.7%, 3.8% and 12.5%, P < 0.001). CONCLUSIONS: Among HIV-infected MSM patients in HIV care who reported sex without a condom, subsequent testing was not documented in clinic records during the following year for up to a quarter of patients. Exploring why STI testing did not occur may improve patient care. PMID- 28876306 TI - Incident Trichomonas vaginalis Is Associated With Partnership Concurrency: A Longitudinal Cohort Study. AB - BACKGROUND: Sexual partner concurrency (PC) has been shown to be a risk factor for a number of sexually transmitted infections but it is unknown if it is a risk factor for Trichomonas vaginalis (TV). OBJECTIVE: We assess if there is an association between PC and incident TV infection. STUDY DESIGN: We used mixed effects logistic regression to assess the association between PC and incident TV in the Longitudinal Study of Vaginal Flora, a cohort study of 3620 women followed quarterly for 5 visits. RESULTS: Trichomonas vaginalis was more common in those reporting definite/possible/unknown PC (15.6%/15.0%/18.3%) than those reporting no PC (5.2%; P < 0.001 for all 3 comparisons). After controlling for a range of confounders, incident TV remained associated with reporting that one's partner definitely (adjusted odds ratio, 5.4; 95% confidence interval, 3.7-8.0) and possibly (adjusted odds ratio, 3.4; 95% confidence interval, 2.2-5.1) engaged in PC in the preceding period. CONCLUSIONS: Partner concurrency was associated with incident TV infection. PMID- 28876307 TI - A Single Question to Examine the Prevalence and Protective Effect of Seroadaptive Strategies Among Men Who Have Sex With Men. AB - BACKGROUND: Seroadaptive behaviors among men who have sex with men (MSM) are common, but ascertaining behavioral information is challenging in clinical settings. To address this, we developed a single seroadaptive behavior question. METHODS: Men who have sex with men 18 years or older attending a sexually transmitted disease clinic in Seattle, WA, from 2013 to 2015, were eligible for this cross-sectional study. Respondents completed a comprehensive seroadaptive behavior questionnaire which included a single question that asked HIV-negative MSM to indicate which of 12 strategies they used in the past year to reduce their HIV risk. HIV testing was performed per routine clinical care. We used the kappa statistic to examine agreement between the comprehensive questionnaire and the single question. RESULTS: We enrolled HIV-negative MSM at 3341 (55%) of 6105 eligible visits. The agreement between the full questionnaire and single question for 5 behaviors was fair to moderate (kappa values of 0.34-0.59). From the single question, the most commonly reported behaviors were as follows: avoiding sex with HIV-positive (66%) or unknown-status (52%) men and using condoms with unknown status partners (53%); 8% of men reported no seroadaptive behavior. Men tested newly HIV positive at 38 (1.4%) of 2741 visits. HIV test positivity for the most commonly reported behaviors ranged from 0.8% to 1.3%. Men reporting no seroadaptive strategy had a significantly higher HIV test positivity (3.5%) compared with men who reported at least 1 strategy (1.3%; P = 0.02). CONCLUSIONS: The single question performed relatively well against a comprehensive seroadaptive behaviors assessment and may be useful in clinical settings to identify men at greatest risk for HIV. PMID- 28876308 TI - The Need to Promote Sexual Health in America: A New Vision for Public Health Action. AB - Sexual health is considered to be a state of wellness with physical, emotional, mental, and social dimensions. Sexual health can contribute to our overall well being in each of these dimensions. However, despite the intrinsic importance and positive aspects of sexuality in our lives, the United States presently faces significant challenges related to the sexual health of its citizens, including human immunodeficiency virus, other sexually transmitted infections, viral hepatitis, unintended pregnancies, sexual violence, sexual dysfunction, and cancers in reproductive tracts with serious disparities among the populations affected. In particular, high rates of poverty, income inequality, low educational attainment, stigma, racism, sexism, and homophobia can make it more difficult for some individuals and communities to protect their sexual health. Given that many pressing public health issues in the United States are related to sexual health and that sexual health has been increasingly recognized as an important national health priority, now is the time to energize and focus our efforts toward optimal sexual health of the population. In this paper, we outline the rationale for addressing sexual health as a means to better promote overall health and address sexuality related morbidities. In addition, we present a logic model outlining an approach for advancing sexual health in the United States, as well as a range of action steps for consideration by public health practitioners, researchers, and policymakers. PMID- 28876309 TI - Use of Patient-Delivered Partner Therapy in US College Settings: Associations With Legality, Perceived Legality and Other Sexual and Reproductive Health Services. AB - BACKGROUND: Young adults, including college students, have higher rates of chlamydia than the general population. Patient-delivered partner therapy (PDPT) is a partner treatment option for sex partners of individuals diagnosed with chlamydia or gonorrhea. We examined college health center use of PDPT in a national sample of colleges. METHODS: During 2014 to 2015, we collected data from 482 colleges and universities (55% of 885 surveyed), weighting responses by institutional characteristics abstracted from a national database (eg, 2-year vs 4-year status). We asked whether the school had a student health center and which sexual and reproductive health (SRH) services were offered. We also assessed the legal and perceived legal status of PDPT in states where schools were located. We then estimated PDPT availability at student health centers and measured associations with legal status and SRH services. RESULTS: Most colleges (n = 367) reported having a student health center; PDPT was available at 36.6% of health centers and associated with perceived legality of PDPT in the state in which the college was located (odds ratio [OR], 4.63; 95% confidence interval [CI], 1.17 18.28). Patient-delivered partner therapy was significantly associated with availability of SRH services, including sexually transmitted disease diagnosis and treatment of STI (56.2% vs 1.1%), gynecological services (60.3% vs 12.2%), and contraceptive services (57.8% vs 7.7%) (all P < .001). Compared with schools taking no action, PDPT was more likely to be available at schools that notified partners directly (OR, 8.29; 95% CI, 1.28-53.85), but not schools that asked patients to notify partners (OR, 3.47; 95% CI, 0.97-12.43). CONCLUSIONS: PDPT was more likely to be available in colleges that offered SRH services and where staff believed PDPT was legal. Further research could explore more precise conditions under which PDPT is used. PMID- 28876310 TI - Prevalence of Anal Dysplasia in Human Immunodeficiency Virus-Infected Transgender Women. AB - Although human immunodeficiency virus-infected men who have sex with men are at high risk for anal cancer, little is known about the prevalence of anal dysplasia in human immunodeficiency virus (HIV)-infected transgender women. Our study found that prevalence rates of abnormal anal cytology and histology in HIV-infected transgender women were similar to those in HIV-infected men who have sex with men. PMID- 28876311 TI - Human Immunodeficiency Virus Status Differentially Associated With Genital and Anal Human Papillomavirus Infection Among Chinese Men Who Have Sex With Men: A Cross-Sectional Survey. AB - BACKGROUND: Little is known about human papillomavirus (HPV) infection and genotypes when considering both anatomic site and human immunodeficiency virus (HIV) status among men who have sex with men (MSM) in low- and middle-income countries. METHODS: A cross-sectional study was conducted among MSM in Beijing, China. HIV serostatus was determined, and genital and anal HPV genotyping were performed from respective swabs. RESULTS: Of 1155 MSM, 817 (70.7%) had testing for genital (611; 52.9%) and/or anal (671; 58.1%) HPV. Preference for insertive anal sex (adjusted odds ratio [aOR], 2.60; 95% confidence interval [CI], 1.42 4.75) and syphilis (aOR, 1.50; 95% CI, 1.01-2.23) were associated with genital HPV. Inconsistent condom use during receptive anal sex (aOR, 1.82; 95% CI, 1.17 2.84), and HIV seropositivity (aOR, 2.90; 95% CI, 1.91-4.42) were associated with anal HPV. Among 465 (40.3%) MSM with specimens from both anatomic sites, anal HPV (68%) was more common than genital HPV (37.8%). Prevalence of anal HPV was higher among HIV-infected than uninfected MSM (P < 0.01). Some oncogenic HPV types were more commonly found at the anal site of HIV-infected MSM (P < 0.01). CONCLUSIONS: Human papillomavirus is highly prevalent among Chinese MSM. Anal HPV was more common than genital HPV, and HIV seropositivity was associated with oncogenic HPV types at the anal site. PMID- 28876312 TI - Screening for Sexually Transmitted Infections in Adolescent Girls and Young Women in Mombasa, Kenya: Feasibility, Prevalence, and Correlates. AB - INTRODUCTION: As adolescents and young women become sexually active, they are at risk of adverse reproductive health outcomes including sexually transmitted infections (STIs). We assessed feasibility and acceptability of STI screening among 15- to 24-year-old women in Mombasa, Kenya. METHODS: After sensitization activities, participants were recruited from 3 high schools and 1 university. Study staff conducted informational sessions. Students interested in participating were given consent forms to take home, and invited to visit our clinic for STI screening. During clinic visits, participants completed a self administered questionnaire and provided a urine specimen for STI testing using a nucleic acid amplification test. RESULTS: Between August 2014 and March 2015, 463 high school and 165 university students collected consent forms. Of these, 293 (63%) from high schools versus 158 (95%) from university attended clinic for STI screening (P < 0.001). Of the 150 (33%) who reported any history of insertive vaginal sex, 78 (52.0%) reported condom use at the last sex act, 31 (20.7%) reported using modern nonbarrier contraceptive methods, and 37 (24.7%) reported not using any contraception at the last sex act. Twenty-six (5.8%) participants were diagnosed with STIs (7 [1.6%] Neisseria gonorrhoeae, 16 [3.6%] Chlamydia trachomatis, 3 [0.7%] Trichomonas vaginalis). In multivariable analyses, reporting receptive vaginal sex without a condom was associated with having a laboratory confirmed STI (odds ratio, 6.21; 95% confidence interval, 1.72-22.28). CONCLUSIONS: These findings support the need for reproductive health interventions to reduce the risk of STIs in a population of adolescent girls and young women in East Africa. PMID- 28876314 TI - Laboratory Processes for Confirmation of Lymphogranuloma Venereum Infection During a 2015 Investigation of a Cluster of Cases in the United States. AB - In September 2015, the Centers for Disease Control and Prevention were notified of a suspected outbreak investigation of lymphogranuloma venereum (LGV) cases by the Michigan Department of Health and Human Services. The Centers for Disease Control and Prevention offered support with a laboratory-developed polymerase chain reaction test for LGV. This note describes the laboratory workflow and procedures used for the laboratory confirmation of LGV infection. PMID- 28876313 TI - Using Multiple Outcomes of Sexual Behavior to Provide Insights Into Chlamydia Transmission and the Effectiveness of Prevention Interventions in Adolescents. AB - BACKGROUND: Mathematical models are important tools for assessing prevention and management strategies for sexually transmitted infections. These models are usually developed for a single infection and require calibration to observed epidemiological trends in the infection of interest. Incorporating other outcomes of sexual behavior into the model, such as pregnancy, may better inform the calibration process. METHODS: We developed a mathematical model of chlamydia transmission and pregnancy in Minnesota adolescents aged 15 to 19 years. We calibrated the model to statewide rates of reported chlamydia cases alone (chlamydia calibration) and in combination with pregnancy rates (dual calibration). We evaluated the impact of calibrating to different outcomes of sexual behavior on estimated input parameter values, predicted epidemiological outcomes, and predicted impact of chlamydia prevention interventions. RESULTS: The two calibration scenarios produced different estimates of the probability of condom use, the probability of chlamydia transmission per sex act, the proportion of asymptomatic infections, and the screening rate among men. These differences resulted in the dual calibration scenario predicting lower prevalence and incidence of chlamydia compared with calibrating to chlamydia cases alone. When evaluating the impact of a 10% increase in condom use, the dual calibration scenario predicted fewer infections averted over 5 years compared with chlamydia calibration alone [111 (6.8%) vs 158 (8.5%)]. CONCLUSIONS: While pregnancy and chlamydia in adolescents are often considered separately, both are outcomes of unprotected sexual activity. Incorporating both as calibration targets in a model of chlamydia transmission resulted in different parameter estimates, potentially impacting the intervention effectiveness predicted by the model. PMID- 28876315 TI - Recurrence of Human Papillomavirus External Genital Wart Infection Among High Risk Adults in Montreal, Canada. AB - OBJECTIVES: The incidence of recurrent genital warts is not well characterized; this is especially true in a post-human papillomavirus (HPV) vaccination era. The objectives of this study were to assess the incidence of subsequent HPV-related external genital warts (EGW) episodes in high-risk male and female adults, as well as ascertain patient profile and disease characteristics, in a real-world Canadian sexual health clinical setting. METHODS: Retrospective chart review study conducted at Clinique medicale l'Actuel, a sexual health clinic in Montreal, Quebec, Canada. Eligible patients were 18 to 45 years of age with a first diagnosis of EGW associated with a HPV infection between July 1, 2006, and June 30, 2012. RESULTS: A total of 400 first-episode EGW cases were identified. Up to 6 subsequent episodes were documented, with 194 (48.5%) patients reporting at least 1 subsequent EGW episode. Median time to first subsequent EGW episode was 3.97 years, and the incidence density rate for all subsequent episodes was 0.18/100 patient-years. Over 90% of patients reported clearance of the first subsequent episode, with median time to clearance of 0.30 years. Regardless of subsequent episode number, greater than 95% of patients received treatment, primarily cryotherapy, with high-risk sexual behavior reducing as number of episodes increased. CONCLUSIONS: Overall, a high rate of subsequent EGW episodes was observed in this high-risk population, despite high treatment rates and improvement in high-risk sexual behavior. These data, assessed in a prevaccination Quebec health care system, may be compared with future EGW rates to assess the impact of a governmentally-funded HPV vaccination program. PMID- 28876316 TI - Using the Revised Centers for Disease Control and Prevention Staging System to Classify Persons Living With Human Immunodeficiency Virus in New York City, 2011 2015. AB - The proportion of persons living with human immunodeficiency virus (HIV) in New York City in stage 1 (CD4 >= 500 cells/mm) increased from 50.6% in 2011 to 59.6% in 2015. The revised Centers for Disease Control and Prevention staging system of HIV infection is a useful tool with which to classify persons living with HIV. PMID- 28876317 TI - Cervical Cancer Screening and Prevention in 78 Sexually Transmitted Disease Clinics-United States, 2014-2015. AB - BACKGROUND: Human papillomavirus (HPV) infections cause approximately 30,700 cancers annually among US men and women, cervical cancer being the most common. Human papillomavirus vaccination is recommended routinely for US girls and boys at age 11 to 12 years, and for those not previously vaccinated, through age 26 and 21 years for women and men, respectively. Our objective was to assess current cervical cancer screening and HPV vaccination practices among sexually transmitted disease (STD) clinics in the United States. METHODS: We surveyed a geographically diverse convenience sample of US STD clinics identified by members of the National Coalition of STD Directors within 65 state, territorial, and local jurisdictions. An online multiple-choice survey about clinical services was administered to clinic directors or designees during October 2014 to February 2015. RESULTS: Survey respondents included 78 clinics from 46 states and territories. Of these clinics, 31 (39.7%) offered both cervical cancer screening and HPV vaccination, 6 (7.7%) offered cervical cancer screening only, 21 (26.9%) offered HPV vaccination only, and 20 (25.6%) offered neither cervical cancer prevention service. Among those not offering the service, the most commonly reported barrier to cervical cancer screening was time constraints (25/41, 61.0%); for HPV vaccination it was reimbursement (11/26, 42.3%). CONCLUSIONS: By early 2015, in a geographically diverse group of 78 STD clinics, 39.7% provided nationally recommended HPV vaccination and cervical cancer screening, whereas 25.6% provided neither. Further research could identify strategies for STD clinics to reduce HPV-associated cancers by increasing provision of HPV vaccination and cervical cancer screening services, particularly among medically underserved populations. PMID- 28876318 TI - The Annual Economic Burden of Syphilis: An Estimation of Direct, Productivity, and Intangible Costs for Syphilis in Guangdong Initiative for Comprehensive Control of Syphilis Sites. AB - BACKGROUND: Syphilis has continuously posed a great challenge to China. However, very little data existed regarding the cost of syphilis. Taking Guangdong Initiative for Comprehensive Control of Syphilis area as the research site, we aimed to comprehensively measure the annual economic burden of syphilis from a societal perspective. METHODS: Newly diagnosed and follow-up outpatient cases were investigated by questionnaire. Reported tertiary syphilis cases and medical institutions cost were both collected. The direct economic burden was measured by the bottom-up approach, the productivity cost by the human capital method, and the intangible burden by the contingency valuation method. RESULTS: Three hundred five valid early syphilis cases and 13 valid tertiary syphilis cases were collected in the investigation to estimate the personal average cost. The total economic burden of syphilis was US $729,096.85 in Guangdong Initiative for Comprehensive Control of Syphilis sites in the year of 2014, with medical institutions cost accounting for 73.23% of the total. Household average direct cost of early syphilis was US $23.74. Average hospitalization cost of tertiary syphilis was US $2,749.93. Of the cost to medical institutions, screening and testing comprised the largest proportion (26%), followed by intervention and case management (22%) and operational cost (21%). Household average productivity cost of early syphilis was US $61.19. Household intangible cost of syphilis was US $15,810.54. CONCLUSIONS: Syphilis caused a substantial economic burden on patients, their families, and society in Guangdong. Household productivity and intangible costs both shared positive relationships with local economic levels. Strengthening the prevention and effective treatment of early syphilis could greatly help to lower the economic burden of syphilis. PMID- 28876319 TI - Trichomonas vaginalis Prevalence and Correlates in Women and Men Attending STI Clinics in Western Canada. AB - Trichomonas vaginalis prevalence (2.8%) in female sexually transmitted infection clinic attendees was within the prevalence of chlamydia (5.8%) and gonorrhea (1.8%), while being very low for male attendees (0.2%). Correlates among women were indigenous ethnicity, other ethnicity, and being symptomatic. PMID- 28876320 TI - Understanding the Effects of Forced Sex on Sexually Transmitted Disease Acquisition and Sexually Transmitted Disease Care: Findings From the National Survey of Family Growth (2011-2013). AB - BACKGROUND: Although there is evidence for heightened sexually transmitted disease (STD) acquisition among women who experienced sexual violence, little is known about their patterns of STD testing, STD diagnosis, and STD treatment. METHODS: Data was drawn from cycle eight of the National Survey of Family Growth (2011-2013). Logistic regression analyses used SUDAAN to examine the link between forced sex and risky sexual behavior as well as forced sex and STD testing, diagnoses, treatment, and connection to care. RESULTS: Women who experienced forced sex were more likely to have risky sex (adjusted odds ratio [AOR], 1.56; 95% confidence interval [CI], 1.08-2.24), risky partners (AOR, 1.90; 95% CI, 1.11 3.23), and report substance abuse (AOR, 1.80; 95% CI, 1.28-2.53) than women who never experienced forced sex. Women who reported forced sex were more likely to be tested for an STD (AOR, 1.67; 95% CI, 1.34-2.09), and be diagnosed with herpes (AOR, 1.94; 95% CI, 1.13-3.32), genital warts (AOR, 2.55; 95% CI, 1.90-3.41), and chlamydia (AOR, 1.83; 95% CI, 1.03-3.25) than those who have never had forced sex. Results indicated a direct relationship between particular STD diagnoses and treatment in the past 12 months (AOR, 6.81; 95% CI, 4.50-10.31). Further analyses indicate that forced sex moderated the link between STD diagnoses and STD treatment (AOR, 0.43; 95% CI, 0.19-0.98). CONCLUSIONS: Results indicate that women who reported experiencing forced sex were more likely to be diagnosed with chlamydia, herpes, and genital warts than women who never had forced sex. There may be a need to pay particular attention to women who experienced forced sex and a history of STDs to ensure that they are retained in care. PMID- 28876321 TI - Provider Adherence to Syphilis Testing Recommendations for Women Delivering a Stillbirth. AB - OBJECTIVE: To assess overall adherence to Centers for Disease Control and Prevention and American College of Obstetrics and Gynecology recommended guidelines for syphilis testing among women who delivered a stillbirth and compare it with other tests recommended for stillbirth evaluation. METHODS: We used MarketScan claims data with 40 million commercially insured and 8 million Medicaid enrollees annually to estimate prenatal care and follow-up testing among women who had stillbirths between January 1, 2013, and December 24, 2013. Stillbirth was identified if women had any International Classification of Disease, Ninth Revision codes related to a stillbirth outcome. Among women with stillbirths, we estimated the proportions of women who received prenatal care and prenatal syphilis testing within 280 days before stillbirth, and testing at the time of stillbirth (syphilis testing, complete blood count, placental examination and autopsy) using Physician's Current Procedural Terminology codes. RESULTS: We identified 3672 Medicaid-insured women and 6023 commercially insured women with stillbirths in 2013. Approximately, 61.7% of Medicaid-insured women and 66.0% of commercially insured women had claims data indicating prenatal syphilis testing. At the time of stillbirth, Medicaid-insured and commercially insured women had similar rates of syphilis testing (6.5% vs 9.3%), placental examination (61.6% vs 57.8%), and complete blood count (31.9% vs 37.6%). Autopsies were too infrequent to be reported. Approximately, 34.6% of Medicaid-insured women and 29.7% of commercially insured women had no syphilis testing either prenatally or at the time of stillbirth. CONCLUSIONS: Syphilis testing among women after stillbirth was less than 10%, illustrating limited adherence to Centers for Disease Control and Prevention and American College of Obstetrics and Gynecology recommendations. Such low prenatal and delivery syphilis testing rates may impact the number of stillbirth cases identified as congenital syphilis cases and reported to the national surveillance system. Our results emphasize the need to improve syphilis testing to improve diagnosis of syphilitic stillbirths, identify women with syphilis infection, and provide treatment to these women to avoid syphilis related adverse outcomes. PMID- 28876322 TI - Wisdom of the Crowds: Crowd-Based Development of a Logo for a Conference Using a Crowdsourcing Contest. AB - BACKGROUND: Crowdsourcing methods have been widely used in business, but rarely in sexual health research. We evaluated a crowdsourced logo contest as part of an international human immunodeficiency virus conference. METHODS: A logo crowdsourcing contest was conducted for the 20th International Acquired Immunodeficiency Syndrome Conference. Crowdsourcing has a group of individuals solve a task, often as part of an open contest. Semistructured interviews were conducted with key informants including contest organizers, contest contributors, and conference attendees. Interviews were transcribed verbatim and analysed using a content analysis approach. RESULTS: In total, 22 interviews were conducted with 3 contest organizers, 7 contest contributors, and 12 conference attendees. All individuals reported that the crowdsourced logo provided benefits beyond branding the conference, including creating a shared sense of purpose among diverse conference participants and explicitly demonstrating the strong community orientation of the conference. Conference organizers and attendees all reported deeper engagement because of the story of the Tanzanian artist who won the contest. Most conference attendees (11/12) preferred the crowdsourced logo compared with the previous company-organized logo, and all (22/22) supported the logo contest continuing. Implementing a logo contest was simple and relatively inexpensive. Stakeholders identified several ways to enhance crowdsourcing logo contest methods including wider promotion of the contest to encourage broader participation, greater transparency in the selection process, and a different prize structure which acknowledges the contribution of more contestants. CONCLUSIONS: We found that a crowdsourcing contest helped engage local and global communities in the lead-up before and during an international conference. Similar participatory events may be useful for sexual health conferences and research projects. PMID- 28876323 TI - Self-Reported Use of Mouthwash and Pharyngeal Gonorrhoea Detection by Nucleic Acid Amplification Test. AB - BACKGROUND: Use of alcohol-containing mouthwash has been found to have an inhibitory effect against pharyngeal gonorrhoea. The aim of this study was to investigate the association between self-reported mouthwash use and pharyngeal gonorrhoea detection among men who have sex with men (MSM). METHODS: A cross sectional survey was conducted between March 23, 2015, and June 30, 2015 among MSM attending the Melbourne Sexual Health Centre in Australia. Men who have sex with men were invited to complete a short questionnaire on mouthwash use and they were also tested for pharyngeal gonorrhoea by nucleic acid amplification test. Multivariate logistic regression was performed to examine the association between mouthwash use and pharyngeal gonorrhoea detection. RESULTS: Of the 823 MSM, pharyngeal gonorrhoea detection decreased significantly with increasing age group (<=24 years, 14.5%; 25-34 years, 10.7%; >=35 years, 6.0%; ptrend = 0.003). The proportion reporting daily use of mouthwash increased significantly with increasing age group (from 10.1% to 14.5% to 19.8%; ptrend = 0.005). However, there was no significant association between pharyngeal gonorrhoea detection and daily use of mouthwash after adjusting for age, number of male sexual partners, human immunodeficiency virus status, and type of mouthwash use. CONCLUSIONS: Although the proportion of daily use of mouthwash increased with age, and pharyngeal gonorrhoea detection decreased with age, the association between self reported mouthwash use and pharyngeal gonorrhoea detection by nucleic acid amplification test was not statistically significant. PMID- 28876324 TI - Men Who Have Sex With Men Seek Timely Human Immunodeficiency Virus Confirmation and Care After Rapid Human Immunodeficiency Virus Self-Test: Data From Partner Services Program, New York City. AB - BACKGROUND: The rapid human immunodeficiency virus (HIV) self-test in the United States has expanded opportunities for HIV testing in nonclinical settings which may increase early diagnosis of HIV infection. However, broad application may be limited by the cost of the test and concerns that self-testers who test positive will not seek timely HIV care. METHODS: We used data from HIV partner services program to compare the sociodemographic characteristics, transmission risk, and clinical stage of persons diagnosed with HIV by report of rapid self-test. Among self-tested persons, we assessed timeliness of seeking definitive testing after self-test and linkage to care. RESULTS: From January 2013 to August 2016, 8032 HIV-positive persons were interviewed. Compared with the 7905 persons who did not self-test, self-tested persons were significantly (all P = <0.0001) male (96% vs 78%), white/non-Hispanic (46% vs 16%), men who have sex with men (92% vs 58%), college educated (67% vs 35%), and residing in medium-high income NYC neighborhoods (51% vs 44%). Higher proportions of self-tested (91%) than non-self tested persons (81%) linked to care within three months of diagnosis. Significantly (P = <0.0001) more persons that self-tested positive (39/44, 89%) than persons that self-tested negative (14/36, 39%) sought laboratory-based HIV test within 1 month of last self-testing; and negative than positive self-tested persons were diagnosed with acute HIV infection (44% vs. 9%, P = <0.0001). CONCLUSIONS: Our findings suggest that men who have sex with men sought timely HIV confirmatory testing and linkage to care after self-test. However, the cost of self-test kit may be an important barrier to its wide adoption across sociodemographic groups. PMID- 28876325 TI - Modernizing Field Services for Human Immunodeficiency Virus and Sexually Transmitted Infections in the United States. AB - Public health field services for sexually transmitted infections (STIs) have not adequately evolved to address the expanding scale of the STI problem, its concentration among men who have sex with men, the emergence of new communication technologies and the availability of antiretroviral therapy as a cornerstone of human immunodeficiency virus (HIV) prevention. Field services need to modernize. Modernization should seek to expand field services objectives beyond sex partner STI testing and treatment to include: HIV testing of persons with bacterial STI and their partners, including efforts to promote frequent HIV/STI testing; increased condom access; linkage and relinkage to HIV care and promotion of viral suppression; preexposure prophylaxis promotion; linkage to long-acting contraception; and referral for health insurance. Field services programs cannot advance these new objectives while simultaneously doing all of the work they have traditionally done. Modernization will require a willingness to reconsider some longstanding aspects of field services work, including the centrality of face-to face interviews and field investigations. Health departments seeking to modernize will need to carefully assess their ongoing activities and reorganize to align the use of field services resources with program priorities. In some instances, this may require reorganization to allow the staff greater specialization and closer integration with surveillance activities. Adapting programs will require new staff training, improvements in data management systems, and a greater investment in monitoring and evaluation. Although modernization is likely to evolve over many years, the time to start is now. PMID- 28876328 TI - The impact of hemoglobin on the efficacy of phototherapy in hyperbilirubinemic infants. AB - BackgroundPhototherapy is the routine treatment for neonatal hyperbilirubinemia. Absorption of light in the skin transforms the native Z,Z-bilirubin to photobilirubins. This study investigates whether the hemoglobin concentration has an impact on efficacy of phototherapy, expressed by the decline of total serum bilirubin concentration (TsB).MethodsA trial was conducted on 93 infants, gestational age >=33 weeks, with uncomplicated hyperbilirubinemia. The infants were treated with conventional phototherapy using LED light for 24 h. The median light irradiance was 66.8 MUW/cm2/nm.ResultsThe median decrease in TsB after 24 h was 121 (57-199) MUmol/l; the median hemoglobin was 12.0 (7.0-14.7) mmol/l. There was a significant effect of hemoglobin concentration on the decrease in TsB of 3.61 MUmol/mmol hemoglobin (P=0.022), after adjusting for initial TsB and postnatal age. That is, assuming the same initial TsB and postnatal age, for each mmol/l increase in hemoglobin, the decrease in TsB was 3.61 MUmol/l smaller. In our hemoglobin range, the decrease in TsB is reduced by 28 MUmol/l (23%).ConclusionIncreasing hemoglobin levels led to a decrease in the efficacy of phototherapy. Our data provide additional support for the conclusion that the transformation of bilirubin to photobilirubins takes place mainly in the superficial capillaries of the skin. PMID- 28876329 TI - At the intersection of systematic and seismic: examining the way forward for pediatric research. PMID- 28876330 TI - Epithelial-mesenchymal transformation and apoptosis in rat urethra development. AB - BackgroundTo examine the mechanism of urethral seam formation during embryonal development of rat urethra.MethodsTime-mated Sprague-Dawley rats were killed and the genital tubercles of male pups harvested on embryonic day (ED) 15, 16, 18, and 19. External morphology was observed under scanning electron microscope. Serial transverse sections were prepared to examine dynamic changes in the urethral seam morphology with hematoxylin-eosin staining, immunohistochemistry, transmission electron microscopy, and double immunofluorescence.ResultsBilateral outgrowth of urethral swelling followed by urethral plate fusion in the midline to form urethral seam was observed from ED 16 onwards. Coexpression of epithelial and mesenchymal markers was observed in several cells at the urethral seam; a few cells with coexpression of epithelial and apoptotic markers were also observed. Mesenchymal transformation of epithelial cells and apoptotic epithelial cells was observed under transmission electron microscope.ConclusionUrethral formation occurs by tubulogenesis, which initiates proximally and progresses distally. This is the first study to demonstrate epithelial-mesenchymal transformation and epithelial cell apoptosis in the urethral seam cells of fetal rats. These findings provide new insights into the mechanisms involved in embryonal development of the urethra. PMID- 28876331 TI - Clinically applicable optical imaging technology for body size and shape analysis: comparison of systems differing in design. AB - BACKGROUND/OBJECTIVES: Recent advances have extended anthropometry beyond flexible tape measurements to automated three-dimensional optical devices that rapidly acquire hundreds of body surface dimensions. Three new devices were recently introduced that share in common inexpensive optical cameras. The design, and thus potential clinical applicability, of these systems differ substantially leading us to critically evaluate their accuracy and precision. SUBJECTS/METHODS: 113 adult subjects completed evaluations by the three optical devices (KX-16 (16 stationary cameras), Proscanner (1 vertically oscillating camera), and Styku scanner (1 stationary camera)), air displacement plethysmography (ADP), dual energy X-ray absorptiometry (DXA) and a flexible tape measure. Optical measurements were compared to reference method estimates that included results acquired by flexible tape, DXA and ADP. RESULTS: Optical devices provided respective circumference and regional volume estimates that overall were well correlated with those obtained from flexible tape measurements (for example, hip circumference: R2, 0.91, 0.90, 0.96 for the KX-16, Proscanner, and Styku scanner, respectively) and DXA (for example, trunk volume: R2, 0.97, 0.97, and 0.98). Total body volumes measured by the optical devices were highly correlated with those from the ADP system (all R2s, 0.99). Coefficient of variations obtained from duplicate measurements (n, 55) were larger in optical than in reference measurements and significant (P<0.05) bias was present for some optical measurements relative to reference method estimates. CONCLUSIONS: Overall, the evaluated optical imaging systems differing in design provided body surface measurements that compared favorably with corresponding reference methods. However, our evaluations uncovered system measurement limitations, such as discrepancies in landmarking, that with correction have the potential to improve future developed devices. PMID- 28876332 TI - Zinc and multivitamin supplementation have contrasting effects on infant iron status: a randomized, double-blind, placebo-controlled clinical trial. AB - BACKGROUND/OBJECTIVES: Zinc (Zn) supplementation adversely affects iron status in animal and adult human studies, but few trials have included young infants. The objective of this study was to determine the effects of Zn and multivitamin (MV) supplementation on infant hematologic and iron status. SUBJECTS/METHODS: In a double-blind RCT, Tanzanian infants were randomized to daily, oral Zn, MV, Zn and MV or placebo treatment arms at the age of 6 weeks of life. Hemoglobin concentration (Hb) and red blood cell indices were measured at baseline and at 6, 12 and 18 months of age. Plasma samples from 589 infants were examined for iron deficiency (ID) at 6 months. RESULTS: In logistic regression models, Zn treatment was associated with greater odds of ID (odds ratio (OR) 1.8 (95% confidence interval (CI) 1.0-3.3)) and MV treatment was associated with lower odds (OR 0.49 (95% CI 0.3-0.9)). In Cox models, MV was associated with a 28% reduction in risk of severe anemia (hazard ratio (HR)=0.72 (95% CI 0.56-0.94)) and a 26% reduction in the risk of severe microcytic anemia (HR=0.74 (0.56-0.96)) through 18 months. No effects of Zn on risk of anemia were seen. Infants treated with MV alone had higher mean Hb (9.9 g/dl (95% CI 9.7-10.1)) than those given placebo (9.6 g/dl (9.4-9.8)) or Zn alone (9.6 g/dl (9.4-9.7)). CONCLUSIONS: MV treatment improved iron status in infancy, whereas Zn worsened iron status but without an associated increase in risk for anemia. Infants in long-term Zn supplementation programs at risk for ID may benefit from screening and/or the addition of a MV supplement. PMID- 28876333 TI - Folate, vitamin B12, homocysteine and polymorphisms in folate metabolizing genes in children with congenital heart disease and their mothers. AB - BACKGROUND/OBJECTIVES: The objective of the study was to assess the role of variations in serum folate, vitamin B12, homocysteine and the presence of genetic polymorphisms as risk factors for congenital heart disease (CHD) in children. SUBJECTS/METHODS: A total of 32 children with CHD, and their mothers and 32 normal children and their mothers formed the study and control groups, respectively. Serum folate, vitamin B12 and homocysteine as well as genetic polymorphisms MTHFR C677->?T, MTHFR A1298->?C, MTR A2756->?G and MTRR A66->?G were assessed. RESULTS: Low serum folate and genetic polymorphisms MTHFR C677->?T and MTRR A66->?G among children and their mothers and high homocysteine among mothers were noted as risk factors for CHD (P<0.05). Vitamin B12 levels were normal and showed no association. Presence of MTHFR C677->?T and MTRR A66->?G, both concurrently among children as well as mothers and simultaneously among mother-child pairs, showed several fold increase in the risk for CHD. On multivariate analysis, the risk factors noted for CHD were presence of MTHFR C677 >?T among children and their mothers and MTRR A66->?G among mothers. Analyses for nutrient-gene interaction revealed significant associations between low serum folate and high serum homocysteine levels, and the presence of selected genetic polymorphisms. CONCLUSIONS: Low serum folate, high homocysteine and presence of selected genetic polymorphisms among children and their mothers were noted as risk factors for CHD. Nutrient-gene interaction being a modifiable risk factor, the study recommends the use of peri-conceptional folate supplementation with vitamin B12 sufficiency for primary prevention of CHD. PMID- 28876334 TI - Whole new concepts of nutrition. PMID- 28876335 TI - Factors associated with the practice of nursing staff sharing information about patients' nutritional status with their colleagues in hospitals. AB - BACKGROUND/OBJECTIVES: Nursing staff have an important role in patients' nutritional care. The aim of this study was to demonstrate how the practice of sharing a patient's nutritional status with colleagues was affected by the nursing staff's attitude, knowledge and their priority to provide nutritional care. SUBJECTS/METHODS: The participants were 492 nursing staff. We obtained participants' demographic data, the practice of sharing patients' nutritional information and information about participants' knowledge, attitude and priority of providing nutritional care by the questionnaire. We performed partial correlation analyses and linear regression analyses to describe the relationship between the total scores of the practice of sharing patients' nutritional information based on their knowledge, attitude and priority to provide nutritional care. RESULTS: Among the 492 participants, 396 nursing staff (80.5%) completed the questionnaire and were included in analyses. Mean+/-s.d. of total score of the 396 participants was 8.4+/-3.1. Nursing staff shared information when they had a high nutritional knowledge (r=0.36, P<0.01) and attitude (r=0.13, P<0.05); however, their correlation coefficients were low. In the linear regression analyses, job categories (beta=-0.28, P<0.01), knowledge (beta=0.33, P<0.01) and attitude (beta=0.10, P<0.05) were independently associated with the practice of sharing information. Nursing staff's priority to provide nutritional care practice was not significantly associated with the practice of sharing information. CONCLUSIONS: Knowledge and attitude were independently associated with the practice of sharing patients' nutrition information with colleagues, regardless of their priority to provide nutritional care. An effective approach should be taken to improve the practice of providing nutritional care practice. PMID- 28876338 TI - Proof of ion-pair structures in ammonium-based protic ionic liquids using combined NMR and DFT/PCM-based chemical shift calculations. AB - The self-assembly of triethylammonium bis(trifluoromethylsulfonyl)imide, i.e. [(C2H5)3NH][TFSI], in chloroform and aqueous solutions has been investigated using 1H NMR spectroscopy and computational (DFT/PCM prediction) methods. We have examined a number of ion pairs formed between the [(C2H5)3NH]+ cation with different conformations of alkyl substituents as well as various dispositions of the multi-site [TFSI]- anion. Based on the agreement between the calculated (DFT) and observed 1H NMR chemical shifts, [(C2H5)3NH][TFSI] in chloroform formed lipophilic complexes with effective N+-HN or N+-HO hydrogen bonding, whereas hydrophilic complexes with Calpha-HO and Calpha-HF hydrogen bonding are found in aqueous solutions. This study provides a new insight into the self-aggregation of ammonium PILs incorporating the widely used [TFSI]- anion and demonstrates the importance of solvent effects on chemical shifts. The simulations with explicit and implicit dielectric continuum solvents are found to be the most realistic method, yielding a representative ensemble of structures. PMID- 28876339 TI - High temperature activation of hematite nanorods for sunlight driven water oxidation reaction. AB - Here we show that chlorine species originating from commonly used iron precursors annihilate the hematite nanorod photocurrent by providing recombination pathways. Although hematite nanorod films could be obtained by thermal decomposition of the iron oxyhydroxide phase (beta-FeOOH), indistinguishable photocurrent responses under dark and sunlight irradiation conditions were observed until the nanorods were annealed (activated) at 750 degrees C. The annealing led to the elimination of observable chlorine species and allowed photocurrent responses of 1.3 mA cm-2 at 1.23 V vs. RHE, which is comparable to the best results found in the literature, suggesting that residual chlorine species from the synthesis can act as electron traps and recombination sites for photogenerated holes. PMID- 28876340 TI - Cisplatin and transplatin interaction with methionine: bonding motifs assayed by vibrational spectroscopy in the isolated ionic complexes. AB - Cisplatin and transplatin (cis- and trans-[PtCl2(NH3)2]) have been allowed to react with methionine (Met) in water solution in a study aimed to characterize the monofunctional complex primarily formed. The thioether function of methionine is known to have a very high affinity for square planar platinum(ii) and sulfur containing biomolecules have been proposed as a cisplatin drug reservoir on the way to platination at DNA. Both cisplatin and transplatin yield [PtCl(NH3)2Met]+ complexes, delivered by electrospray ionization in the gas phase and sampled as isolated species using tools based on mass spectrometry. The collision induced dissociation spectra of both cis-[PtCl(NH3)2Met]+ and trans-[PtCl(NH3)2Met]+ are quite similar and also the transport properties assayed by ion mobility mass spectrometry do not allow any appreciable discrimination. However, the vibrational spectra obtained by IR multiple photon absorption (IRMPD) spectroscopy show distinct features. Their analysis, supported by quantum chemical calculations, has revealed that while cisplatin attack is mainly directed to the sulfur atom of Met, transplatin shows a more balanced partition between sulfur and nitrogen binding. Among the vibrational signatures characterizing cis-[PtCl(NH3)2Met]+ and trans-[PtCl(NH3)2Met]+ complexes, the asymmetric NH2 stretching of the alpha-amino group of the amino acid at ca. 3440 cm-1 is peculiar and diagnostic of S-platination. IRMPD kinetics evaluated at this frequency support the prevailing S-attack by cisplatin while approximately a 1 : 2 ratio of S- versus N-coordination is observed by transplatin, to be possibly related to the trans effect at the platinum center. PMID- 28876341 TI - Interfacial engineering of hole transport layers with metal and dielectric nanoparticles for efficient perovskite solar cells. AB - In this work, we have demonstrated the incorporation of metal (Ag NPs) and dielectric nanoparticles (SiO2 NPs) into the hole transporting layers of inverted PSCs using facile deposition methods. Interfacial engineering in PSCs is accomplished by incorporating 50 nm Ag NPs or SiO2 NPs within the PEDOT:PSS interlayer. Dielectric SiO2 NPs were used for comparison purposes as a control sample to isolate morphological impacts without plasmonic effects. The photovoltaic performance of the devices significantly improved due to increased charge selectivity and enhanced charge collection properties across the interface (HTL). The recombination resistance of the SiO2 NP incorporated HTL based PSCs was 193% higher than that of the conventional devices. In-depth analysis using impedance measurements revealed that devices containing Ag or SiO2 NPs have low electrode polarization and consequently lower charge accumulation at the interface. Lower electrode polarization in the modified devices was also found to improve the charge carrier selectivity, which eventually led to enhanced fill factor and lower parasitic resistances. Interfacial engineering via NPs yielded improvements in the electrical characteristics of non-optical origin, which not only enhanced device performance, but also reduced the hysteresis effects to much lower than in the conventional inverted PSCs based on a pristine PEDOT:PSS interlayer. PMID- 28876347 TI - Temporally controlled growth factor delivery from a self-assembling peptide hydrogel and electrospun nanofibre composite scaffold. AB - Tissue-specific self-assembling peptide (SAP) hydrogels designed based on biologically relevant peptide sequences have great potential in regenerative medicine. These materials spontaneously form 3D networks of physically assembled nanofibres utilising non-covalent interactions. The nanofibrous structure of SAPs is often compared to that of electrospun scaffolds. These electrospun nanofibers are produced as sheets that can be engineered from a variety of polymers that can be chemically modified to incorporate many molecules including drugs and growth factors. However, their macroscale morphology limits them to wrapping and bandaging applications. Here, for the first time, we combine the benefits of these systems to describe a two-component composite scaffold from these biomaterials, with the design goal of providing a hydrogel scaffold that presents 3D structures, and also has temporal control over drug delivery. Short fibres, cut from electrospun scaffolds, were mixed with our tissue-specific SAP hydrogel to provide a range of nanofibre sizes found in the extracellular matrix (10-300 nm in diameter). The composite material maintained the shear-thinning and void filling properties of SAP hydrogels that have previously been shown to be effective for minimally invasive material injection, cell delivery and subsequent in vivo integration. Both scaffold components were separately loaded with growth factors, important signaling molecules in tissue regeneration whose rapid degradation limits their clinical efficacy. The two biomaterials provided sequential growth factor delivery profiles: the SAP hydrogel provided a burst release, with the release rate decreasing over 12 hours, while the electrospun nanofibres provided a more constant, sustained delivery. Importantly, this second release commenced 6 days later. The design rules established here to provide temporally distinct release profiles can enable researchers to target specific stages in regeneration, such as the acute immune response versus sustained protection and survival of cells following injury. In summary, this novel composite material combines the physical advantages of SAP hydrogels and electrospun nanofibres, while additionally providing a superior vehicle for the stabilisation and controlled delivery of growth factors necessary for optimal tissue repair. PMID- 28876348 TI - Responsive, switchable wormlike micelles for CO2/N2 and redox dual stimuli based on selenium-containing surfactants. AB - A dual-stimuli responsive, wormlike micelle system was developed using a switchable selenium-containing surfactant, dihendecylcarboxylic acid sodium selenide (C11-Se-C11), and a commercially available surfactant, cetyltrimethyl ammonium bromide (CTAB). The solution showed a viscoelastic characteristic at low shear frequencies, and the synergism was significant when the concentrations of CTAB and C11-Se-C11 were 145 mM and 25 mM, respectively. Additionally, the system was fast and reversibly responded to CO2 and redox dual stimuli, and it showed a circulatory gel/sol transition, which reflected changes in the self-assembly from entangled worms to rodlike micelles. Moreover, these transitions were switchable at least three times. The dual responsiveness of the solution allowed for precise control of the wormlike micelles, and these micelles will have a wide range of applications in the development of functional materials for pharmaceutical or biomedical materials. PMID- 28876349 TI - Spontaneous emulsification and self-propulsion of oil droplets induced by the synthesis of amino acid-based surfactants. AB - It is well known that oil droplets in or on water exhibit spontaneous movement induced by surfactants, and this self-propulsion is regarded as an important factor in droplet-based models for a living cell. We report here an oil-droplet system spontaneously producing amino acid-based surfactants, which are then utilized for the droplets' self-propulsion. Thus this system is an active system capable of producing the fuel for the propulsion by itself, which can be used as a conceptual model for cell metabolism. PMID- 28876350 TI - Interfacial crowding of nanoplatelets in co-continuous polymer blends: assembly, elasticity and structure of the interfacial nanoparticle network. AB - The sequence of events which leads to the interfacial crowding of plate-like nanoparticles in co-continuous polymer blends is investigated through a combination of morphological and rheological analyses. Very low amounts (~0.2 vol%) of organo-modified clay are sufficient to suppress phase coarsening in a co continuous polystyrene/poly(methyl methacrylate) blend, while lower particle loading allows for a tuning of the characteristic size of the polymer phases at the MUm-scale. In any case, an interfacial network of nanoparticles eventually forms, which is driven by the preferred polymer-polymer interface. The elastic features and stress-bearing ability of this peculiar nanoparticle assembly are studied in detail by means of a descriptive two-phase viscoelastic model, which allows isolation of the contribution of the filler network. The role of the co continuous matrix in driving the space arrangement of the nanoparticles is emphasized by means of comparative analysis with systems based on the same polymers and nanoparticles, but in which the matrix is either a pure polymer or a blend with drop-in-matrix morphology. The relaxation dynamics of the interfacial network was found not to depend on the matrix microstructure, which instead substantially affects the assembly of the nanoplatelets. When the host medium is co-continuous, the particles align along the preferred polymer-polymer interface, percolating at a very low amount (~0.17 vol%) and prevalently interacting edge-to edge. The stress bearing ability of such a network is much higher than that in the case of matrix based on a homogeneous polymer or a drop-in-matrix blend, but its elasticity shows low sensitivity to the filler content. PMID- 28876351 TI - Optimization of a synthetic receptor for dimethyllysine using a biphenyl-2,6 dicarboxylic acid scaffold: insights into selective recognition of hydrophilic guests in water. AB - In the design of small molecule receptors for polar guests, much inspiration has been taken from proteins that have adapted effective ways to selectively bind polar molecules in aqueous environments. Nonetheless, molecular recognition of hydrophilic guests in water by synthetic receptors remains a challenging task. Here we report a new synthetic receptor, A2I, with improved affinity and selectivity for a biologically important polar guest, dimethyllysine (Kme2). A2I was prepared via redesign of a small molecule receptor (A2B) that preferentially binds trimethyllysine (Kme3) using dynamic combinatorial chemistry (DCC). We designed a new biphenyl-2,6-dicarboxylate monomer, I, with the goal of creating a buried salt bridge with Kme2 inside a synthetic receptor. Indeed, incorporation of I into the receptor A2I resulted in a receptor with 32-fold enhancement in binding affinity, which represents the highest affinity receptor for Kme2 in the context of a peptide to date and is tighter than most Kme2 reader proteins. It also exhibits a ~2.5-fold increase in preference for Kme2 vs. Kme3 relative to the parent receptor, A2B. This work provides insight into effective strategies for binding hydrophilic, cationic guests in water and is an encouraging result toward a synthetic receptor that selectively binds Kme2 over other methylation states of lysine. PMID- 28876352 TI - Nanostructured interfacial self-assembled peptide-polymer membranes for enhanced mineralization and cell adhesion. AB - Soft interfacial materials, such as self-assembled polymer membranes, are gaining increasing interest as biomaterials since they can provide selective barriers and/or controlled affinity interactions important to regulate cellular processes. Herein, we report the design and fabrication of multiscale structured membranes integrating selective molecular functionalities for potential applications in bone regeneration. The membranes were obtained by interfacial self-assembly of miscible aqueous solutions of hyaluronan and multi-domain peptides (MDPs) incorporating distinct biochemical motifs, including mineralizing (EE), integrin binding (RGDS) and osteogenic (YGFGG) peptide sequences. Circular dichroism and Fourier transform infrared spectroscopy analyses of the MDPs revealed a predominant beta-sheet conformation, while transmission electron microscopy (TEM) showed the formation of fibre-like nanostructures with different lengths. Scanning electron microscopy (SEM) of the membranes showed an anisotropic structure and surfaces with different nanotopographies, reflecting the morphological differences observed under TEM. All the membranes were able to promote the deposition of a calcium-phosphate mineral on their surface when incubated in a mineralizing solution. The ability of the MDPs, coated on coverslips or presented within the membranes, to support cell adhesion was investigated using primary adult periosteum-derived cells (PDCs) under serum-free conditions. Cells on the membranes lacking RGDS remained round, while in the presence of RGDS they appear to be more elongated and anchored to the membrane. These observations were confirmed by SEM analysis that showed cells attached to the membrane and exhibiting an extended morphology with close interactions with the membrane surface. We anticipate that these molecularly designed interfacial membranes can both provide relevant biochemical signals and structural biomimetic components for stem cell growth and differentiation and ultimately promote bone regeneration. PMID- 28876353 TI - Use of RAFT macro-surfmers for the synthesis of transparent aqueous colloids with tunable interactions. AB - We propose a new method to produce fluorinated nanoparticles (NPs) based on ab initio reversible addition-fragmentation chain transfer (RAFT) emulsion polymerization without the use of toxic surfactants. NP size, surface charge, and chemistry can be controlled via the adoption of different macromolecular transfer agents produced via RAFT polymerization of amphiphilic monomers. Thanks to this versatility, interparticle interactions can be easily tuned by changing solvent composition and temperature. In addition, the refractive index and density of the solvent can simultaneously match those of the NPs by adding sodium polytungstate, an organic salt widely used for density gradient centrifugation. These colloids may be used as model systems for the study of self-assembly and aggregation in aqueous media when optical methods are required. PMID- 28876354 TI - Effects of precursor topology and synthesis under crowding conditions on the structure of single-chain polymer nanoparticles. AB - By means of molecular dynamics simulations, we investigate the formation of single-chain nanoparticles through intramolecular cross-linking of polymer chains, in the presence of their precursors acting as purely steric crowders in concentrated solution. In the case of linear precursors, the structure of the resulting SCNPs is weakly affected by the density at which the synthesis is performed. Crowding has significant effects if ring precursors are used: higher concentrations lead to the formation of SCNPs with more compact and spherical morphologies. Such SCNPs retain in the swollen state (high dilution) the crumpled globular conformations adopted by the ring precursors in the crowded solutions. Increasing the concentration of both the linear and ring precursors up to 30% leads to faster formation of the respective SCNPs, prior to deceleration expected at higher densities. The results presented here propose promising new routes for the synthesis of globular SCNPs, which are usually elusive by conventional methods. PMID- 28876355 TI - Stabilization of anthocyanins in blackberry juice by glutathione fortification. AB - Blackberry anthocyanins provide attractive color and antioxidant activity. However, anthocyanins degrade during juice processing and storage, so maintaining high anthocyanin concentrations in berry juices may lead to greater antioxidant and health benefits for the consumer. This study evaluated potential additives to stabilize anthocyanins during blackberry juice storage. The anthocyanin stabilizing agents used were: glutathione, galacturonic acid, diethylenetriaminepentaacetic acid and tannic acid, which were added at a level of 500 mg L-1. Juice anthocyanin, flavonol, and ellagitannin content and percent polymeric color were measured over five weeks of accelerated storage at 30 degrees C. Glutathione had the greatest protective effect on total anthocyanins and polymeric color. Therefore a second study was performed with glutathione in combination with lipoic and ascorbic acids in an effort to use antioxidant recycling to achieve a synergistic effect. However, the antioxidant recycling system had no protective effect relative to glutathione alone. Glutathione appears to be a promising blackberry juice additive to protect against anthocyanin degradation during storage. PMID- 28876356 TI - A versatile upconversion surface evaluation platform for bio-nano surface selection for the nervous system. AB - There is considerable interest in developing diagnostic nanotools for early detection and delivery of various therapeutic agents for treatment of neurodegenerative diseases. However, a key challenge remains in the selection of suitable surfaces to overcome the nano-bio interface issue, namely that many nanoparticle surfaces demonstrate instability when administered into biological environments and show substantial cytotoxicity to the central nervous system. In this study, we fabricated an evaluation platform for bio-nano surface selection based on the combination of upconversion nanoparticles (UCNPs), cultured neural cells and zebra fish, and systemically demonstrated how it can evaluate the suitability of nanoparticle surfaces for applications in the central nervous system. Firstly, we fabricated highly lanthanide-doped UCNPs, which generate the strongest tissue penetrable emission at 800 nm. We then functionalized these UCNPs with four popular surfaces for evaluation. Next, we systematically evaluated the spectral emission properties, biophysical stability, cytotoxicity and cell uptake capability of these surface-functionalized UCNPs in biological solutions or with cultured NSC-34 cells. Through these studies, PEG-COOH proved to be the superior surface modification. Accordingly, we further confirmed the bioavailability of unmodified and surface modified UCNPs in the spinal cord of living zebrafish. As predicted, PEG-UCNPs displayed excellent dispersal and uptake into spinal motor neurons in living zebrafish. Collectively, this study developed a versatile upconversion platform for systematic evaluation of nanoparticle surfaces, which can provide valuable information via systemic surface evaluation in vitro and in vivo for future construction of multifunctional nanosystems for theranostic applications in neurodegenerative diseases. PMID- 28876357 TI - Phosphate solubilization by endophytic bacteria isolated from banana trees. AB - Forty isolates of endophytic bacteria isolated from banana tree roots were assessed as to their capacity to solubilize phosphate in a solid culture medium supplemented with different inorganic and one organic source of phosphorus. The amount of phosphorus (P) in each liquid medium was quantified, and an indirect assessment of acid phosphatase activity was performed. All assays had a fully randomized design, with three repetitions. Approximately 67.5% of the 40 isolates assessed in solid medium solubilized phosphorus from tricalcium phosphate and 7.5% of the isolates solubilized phosphorus from soy lecithin; no isolates exhibited P solubilization capacity in medium supplemented with iron phosphate. Acid phosphatase activity was detected in 65% of the isolates; Aneurinibacillus sp. and Lysinibacillus sp. isolates presented with the best solubilization indexes. All of the assessed isolates exhibited a capacity to reduce the potential of hydrogen in liquid medium supplemented with tricalcium phosphate. Isolate EB. 78 (Bacillus sp.) exhibited P solubilization capacity in solid media when Ca3(PO4)2 and soy lecithin were used as P sources; this isolate significantly reduced the pH of the liquid medium and exhibited acid phosphatase activity. The results of the present study highlight isolates that exhibit variations in their capacity to solubilize P. These isolates should be used in future tests to assess their field performance. PMID- 28876358 TI - Animal models in biological and biomedical research - experimental and ethical concerns. AB - Animal models have been used in experimental research to increase human knowledge and contribute to finding solutions to biological and biomedical questions. However, increased concern for the welfare of the animals used, and a growing awareness of the concept of animal rights, has brought a greater focus on the related ethical issues. In this review, we intend to give examples on how animals are used in the health research related to some major health problems in Brazil, as well as to stimulate discussion about the application of ethics in the use of animals in research and education, highlighting the role of National Council for the Control of Animal Experimentation (Conselho Nacional de Controle de Experimentacao Animal - CONCEA) in these areas. In 2008, Brazil emerged into a new era of animal research regulation, with the promulgation of Law 11794, previously known as the Arouca Law, resulting in an increased focus, and rapid learning experience, on questions related to all aspects of animal experimentation. The law reinforces the idea that animal experiments must be based on ethical considerations and integrity-based assumptions, and provides a regulatory framework to achieve this. This review describes the health research involving animals and the current Brazilian framework for regulating laboratory animal science, and hopes to help to improve the awareness of the scientific community of these ethical and legal rules. PMID- 28876359 TI - Tracing the origin of the NS1 A188V substitution responsible for recent enhancement of Zika virus Asian genotype infectivity. AB - A recent study showed that infectivity of Zika virus (ZIKV) Asian genotype was enhanced by an alanine-to-valine amino acid substitution at residue 188 of the NS1 protein, but the precise time and location of origin of this mutation were not formally estimated. Here, we applied a Bayesian coalescent-based framework to estimate the age and location of the ancestral viral strain carrying the A188V substitution. Our results support that the ancestral ZIKV strain carrying the A188V substitution arose in Southeastern Asia at the early 2000s and circulated in that region for some time (5-10 years) before being disseminated to Southern Pacific islands and the Americas. PMID- 28876360 TI - All about neosporosis in Brazil. AB - Neospora caninum is protozoan parasite with domestic and wild dogs, coyotes and grey wolves as the definitive hosts and many warm-blooded animals as intermediate hosts. It was cultivated and named in 1988. Neosporosis is a major disease of cattle and has no public health significance. Since 1990's N. caninum has emerged as a major cause of abortion in cattle worldwide, including in Brazil. N. caninum also causes clinical infections in several other animal species. Considerable progress has been made in understanding the biology of N. caninum and there are more than 200 papers on this subject from Brazil. However, most of the reports on neosporosis from Brazil are serological surveys. Overall, little is known of clinical neosporosis in Brazil, particularly cattle. The few reports pertain to sporadic cases of abortion with no information on epidemics or storms of abortion. The objective of the present review is to summarize all reports from Brazil and suggest topic for further research, including prevalence of N. caninum oocysts in soil or in canine feces, and determining if there are additional definitive hosts, other than the domestic dog. There is need for a national survey in cattle using defined parameters. Future researches should focus on molecular characterization of N. caninum strains, possibility of vaccine production and relationship between wildlife and livestock epidemiology. PMID- 28876361 TI - The Five Digits Test in the assessment of older adults with low formal education: construct validity and reliability in a Brazilian clinical sample. AB - INTRODUCTION: In the assessment of older adults with very low formal education, typical tests of selective attention and inhibitory control are biased by reading abilities. In this sense, we aim to assess the psychometric characteristics of the Five Digits Test (FDT), a numerical Stroop paradigm, in older adults without cognitive disorders, with mild cognitive impairment, and with dementia. METHODS: We assessed 211 Brazilian older adults with low formal education using the FDT and other cognitive measures. Construct validity and reliability were assessed by correlations and internal consistency. RESULTS: The FDT test had weak correlations with crystalized intelligence tests and moderate-high correlations with fluid intelligence measures and tests of global cognitive status and executive functions. The split-half coefficient of reliability showed high internal consistency (>0.900). CONCLUSION: Together, the results suggest that the FDT is a valid and reliable measure for the assessment of processing speed and executive functions in older adults with low formal education. PMID- 28876362 TI - Psychotropic prescriptions for the treatment of schizophrenia in an outpatient clinic. AB - INTRODUCTION: There is an unpredictable pattern in the prescription of antipsychotics and other psychotropic medications for the treatment of schizophrenia, particularly in resource-limited settings in developing countries. OBJECTIVE: To determine the psychotropic prescriptions given to patients with schizophrenia in an outpatient clinic of a tertiary hospital and to describe the choices and trends of these prescriptions. METHODS: This was a cross-sectional descriptive study of prescriptions for adults with schizophrenia. After clinical consultation, patients' case notes were randomly selected over a period of 2 years. Using a structured form, data were extracted from the case notes including biodemographic data, psychotropic medications prescribed and changes made to these prescriptions. Data were analyzed by means of descriptive statistics. RESULTS: A total of 103 patients were selected, with a mean age of 35.96+/-9.78 years; 48.5% were males and 51.5% were females; 33% were unemployed and 38% had been hospitalized in the past. There were 231 initial prescriptions and 228 current prescriptions, with about 2.2 prescriptions per patient. Haloperidol (mean dose 14.77+/-6.28mg and 11.44+/-5.55mg for initial and current) and other old-generation antipsychotics were the most commonly prescribed for new cases (98%). Mean duration of psychotropic use was 7.78+/-5.6 years. All the patients were prescribed trihexyphenidyl, and 56.3% of the patients had their medications changed as a result of side effects. CONCLUSION: There was a very high preference for the use of first-generation antipsychotics for all treatment settings (in- and outpatients), a pattern that is likely to persist. PMID- 28876363 TI - Dipyrone in association with atropine inhibits the effect on gastric emptying induced by hypoglycemia in rats. AB - Atropine (AT) and dipyrone (Dp) induce a delay of gastric emptying (GE) of liquids in rats by inhibiting muscarinic receptors and activating beta2 adrenergic receptors, respectively. The objective of the present study was to determine the effects of pretreatment with AT and Dp, given alone or in combination, on the effect of hypoglycemia in the liquid GE in rats. Male Wistar adult rats (280-310 g) were pretreated intravenously with AT, Dp, AT plus Dp or their vehicle and then treated 30 min later with iv insulin or its vehicle (n=8 10 animals/group). Thirty min after treatment, GE was evaluated by determining, in awake rats, the percent gastric retention (%GR) of a saline meal labeled with phenol red administered by gavage. The results indicated that insulin induced hypoglycemia in a dose-dependent manner resulting in a significant reduction in %GR of liquid only at the highest dose tested (1 U/kg). Pretreatment with AT significantly increased %GR in the rats treated with 1 U/kg insulin. Surprisingly, after pretreatment with AT, the group treated with the lowest dose of insulin (0.25 U/kg) displayed significantly lower %GR compared to its control (vehicle-treated group), which was not seen in the non-pretreated animals. Pretreatment with Dp alone at the dose of 40 mg/kg induced an increase in %GR in both vehicle and 0.25 U/kg-treated rats. A higher dose of Dp alone (80 mg/kg) significantly reduced the effect of a marked hypoglycemia induced by 1 U/kg of insulin on GE while in combination with AT the effect was completely abolished. The results with AT suggest that moderate hypoglycemia may render the inhibitory mechanisms of GE ineffective while Dp alone and in combination with AT significantly overcame the effect of hypoglycemia on GE. PMID- 28876364 TI - Silencing of augmenter of liver regeneration inhibited cell proliferation and triggered apoptosis in U266 human multiple myeloma cells. AB - Augmenter of liver regeneration (ALR) is a thermostable cytokine that was originally identified to promote the growth of hepatocytes. This study was conducted to explore the expression and function of ALR in multiple myeloma (MM), a common hematologic malignancy. Real-time PCR and western blot analysis were performed to detect the expression of ALR in U266 human MM cells and healthy peripheral blood mononuclear cells (PBMCs). U266 MM cells were exposed to 20 or 40 MUg/mL of recombinant ALR and tested for cell proliferation. Small interfering RNA-mediated silencing of ALR was done to investigate the role of ALR in cell proliferation, apoptosis, and cytokine production. Compared to PBMCs, U266 MM cells exhibited significantly higher levels of ALR at both the mRNA and protein levels. The addition of recombinant ALR protein significantly promoted the proliferation of U266 cells. In contrast, knockdown of ALR led to a significant decline in the viability and proliferation of U266 cells. Annexin-V/PI staining analysis demonstrated that ALR downregulation increased apoptosis in U266 MM cells, compared to control cells (20.1+/-1.1 vs 9.1+/-0.3%, P<0.05). Moreover, ALR depletion reduced the Bcl-2 mRNA level by 40% and raised the Bax mRNA level by 2-fold. Additionally, conditioned medium from ALR-depleted U266 cells had significantly lower concentrations of interleukin-6 than control cells (P<0.05). Taken together, ALR contributed to the proliferation and survival of U266 MM cells, and targeting ALR may have therapeutic potential in the treatment of MM. PMID- 28876365 TI - Association between ADAM metallopeptidase domain 33 gene polymorphism and risk of childhood asthma: a meta-analysis. AB - This study aimed to investigate the association between ADAM metallopeptidase domain 33 (ADAM33) gene polymorphisms and the risk of childhood asthma. The relevant studies about the relationship between ADAM33 gene polymorphisms and childhood asthma were searched from electronic databases and the deadline of retrieval was May 2016. The single nucleotide polymorphisms (SNPs) of ADAM33 (rs511898, rs2280092, rs3918396, rs528557, rs2853209, rs44707, rs2280091 and rs2280089) were analyzed based on several models including the allele, codominant, recessive and dominant models. The results showed that the ADAM33 rs2280091 polymorphism in all four genetic models was associated with an increased risk of childhood asthma. Positive associations were also found between the polymorphisms rs2280090, rs2787094, rs44707 and rs528557 and childhood asthma in some genetic models. This meta-analysis suggested that ADAM33 polymorphisms rs2280091, rs2280090, rs2787094, rs44707 and rs528557 were significantly associated with a high risk of childhood asthma. PMID- 28876366 TI - Evaluation of the toxicity and hypoglycemic effect of the aqueous extracts of Cnidoscolus quercifolius Pohl. AB - Diabetes mellitus is one of the most common chronic degenerative diseases, and it is estimated to increase worldwide to around 415 million and to impact 642 million in 2040. Research shows that some plants are sources of bioactive compounds against diabetes. Thus, the objective of this work was to evaluate the oral toxicity and the hypoglycemic effect of the aqueous extract of the leaves of Cnidoscolus quercifolius Pohl. Diabetes was induced in Swiss mice with streptozotocin and the mice were treated with an aqueous extract of C. quercifolius leaves for a period of 30 days. Phytochemical analysis showed that the extract was rich in flavonoids, catechins and triterpenoid, which did not show any mortality and behavioral alterations in mice treated with 200, 1000, and 2000 mg/kg body weight of the extract for 14 days. Histopathological analysis of organs (kidney, pancreas, liver) from mice treated with the 2000 mg/kg extract revealed no architectural change. In the present study, we found a 29% reduction in glucose levels in animals receiving 200 mg/kg body weight. These results are very promising because they showed that C. quercifolius had a hypoglycemic effect and did not present oral toxicity, thus being a new source of compounds for the control of diabetes. PMID- 28876368 TI - COMPLEMENTARY AND ALTERNATIVE MEDICINE: A WORLD TO BE EXPLORED. PMID- 28876367 TI - Xuezhikang reduced arterial stiffness in patients with essential hypertension: a preliminary study. AB - This study aimed to test the effects of xuezhikang, a cholestin extract that contains statin-like components, on arterial stiffness in patients with essential hypertension. One hundred hypertensive patients from the Chinese PLA General Hospital were randomly allocated to receive xuezhikang (1200 mg/day, orally) or placebo (same capsules containing only pharmaceutical excipients). Physical examination outcomes, lipid profile, high sensitivity C-reactive protein (hs-CRP) levels, matrix metalloproteinases-9 (MMP-9) levels, and arterial outcomes, including stiffness parameter (beta), pressure-strain elasticity modulus (Ep), arterial compliance (AC), augmentation index (AI), and one-point pulse wave velocity (PWVbeta) were obtained at baseline and after 6 months of the intervention. Xuezhikang significantly reduced beta (8.4+/-3.1 vs 6.8+/-2.1, P=0.007), Ep (122.8+/-43.9 vs 100.7+/-33.2, P=0.009), PWVbeta (6.7+/-1.2 vs 6.1+/ 1.0, P=0.013), low-density lipoprotein cholesterol (3.4+/-0.6 vs 2.9+/-0.5, P=0.001), hs-CRP [2.1 (0.4-10.0) vs 1.4 (0.3-4.1), P=0.020], and MMP-9 (17.2+/ 2.4 vs 12.7+/-3.8, P <0.001) compared to baseline. The placebo had no effect on these parameters. The changes of PWVbeta in the xuezhikang group was significantly associated with the changes of hs-CRP and MMP-9 (r=0.144, P=0.043; r=0.278, P=0.030, respectively) but not with lipid profile changes. Our research showed xuezhikang can improve the parameters of arterial stiffness in hypertensive patients, and its effect was independent of lipid lowering. PMID- 28876369 TI - Quantitative analysis of tongue movement in 14 phonemes of Brazilian Portuguese. AB - Purpose: The aim of this study was to characterize the ultrasonographic pattern of tongue movement in 14 consonant phonemes of Brazilian Portuguese (BP), seeking to identify and describe ultrasonographic parameters that could grasp the difference of manner and place of articulation among these phonemes. Methods: We selected 20 individuals with typical speech production, aged between 20-30 years of both genders. The selected stimuli included the 14 lingual consonant BP phonemes in the intervocalic context of [a]. Data were collected and analyzed with the use of ultrasound, and the AAA (Articulate Assistant Advanced) and the Ultra-CATS (The Ultrasonographic Contour Analyzer for Tongue Surfaces) softwares. Three ultrasound parameters were used for data analysis: anteriority index (AI), global average of tongue height (GA) and relative anteriority index (RAI). Data were statistically analyzed. Results: ANOVA showed a significant effect on the parameters and the RAI differentiated phonemes as the place (alveolar, pre palatal, palatal and velar) and manner of articulation (fricative, nasal and occlusive); GA differentiate phonemes only as the place of articulation (alveolar, pre-palatal and velar). Conclusion: There was no single US parameter that could differentiate place and manner of articulation simultaneously. The clinical application for analysis of speech production disorders require the use of at least two ultrasound parameters: one to distinguish the place and another to distinguish the articulation manner. PMID- 28876370 TI - Cortical maturation of long latency auditory evoked potentials in hearing children: the complex P1-N1-P2-N2. AB - Purpose: The purpose of this study was to monitor the emergence and changes to the components of the Long Latency Auditory Evoked Potentials (LLAEP) in normal hearing children. Methods: This longitudinal study included children of both genders: seven aged between 10 and 35 months, and eight children between 37 and 63 months. The electrophysiological hearing evaluation consisted of analysis of LLAEP obtained in a sound field generated with loudspeakers positioned at an azimuth of 90 degrees , through which the syllable /ba/ was played at an intensity of 70 dB HL. Each child underwent an initial evaluation followed by two re-evaluations three and nine months later. Results: The emergence of LLAEP components across the nine-month follow-up period was observed. P1 and N2 were the most common components in children of this age range. There was no statistically significant difference regarding the occurrence of P1, N1, P2, and N2 components amongst younger and older children. Regarding latency values, the greatest changes overtime were observed in the P1 component for younger children and in the N2 component for older children. Only the P1 component significantly differed between the groups, with the highest latency values observed in younger children. Conclusion: LLAEP maturation occurs gradually and the emergence of complex components appears to be related more to the maturation of the central auditory nervous system than to chronological age. PMID- 28876371 TI - Group climate in the voice therapy of patients with Parkinson's Disease. AB - Purpose: To verify the impact that group dynamics and coaching strategies have on the PD patients voice, speech and communication, as well as the group climate. Methods: 16 individuals with mild to moderate dysarthria due to the PD were divided into two groups: the CG (8 patients), submitted to traditional therapy with 12 regular therapy sessions plus 4 additional support sessions; and the EG (8 patients), submitted to traditional therapy with 12 regular therapy sessions plus 4 sessions with group dynamics and coaching strategies. The Living with Dysarthria questionnaire (LwD), the self-evaluation of voice, speech and communication, and the perceptual-auditory analysis of the vocal quality were assess in 3 moments: pre-traditional therapy (pre); post-traditional therapy (post 1); and post support sessions/coaching strategies (post 2); in post 1 and post 2 moments, the Group Climate Questionnaire (GCQ) was also applied. Results: CG and EG showed an improvement in the LwD from pre to post 1 and post 2 moments. Voice self-evaluation was better for the EG - when pre was compared with post 2 and when post 1 was compared with post 2 - ranging from regular to very good; both groups presented improvement in the communication self-evaluation. The perceptual-auditory evaluation of the vocal quality was better for the EG in the post 1 moment. No difference was found for the GCQ; however, the EG presented lower avoidance scores in post 2. Conclusion: All patients showed improvement in the voice, speech and communication self-evaluation; EG showed lower avoidance scores, creating a more collaborative and propitious environment for speech therapy. PMID- 28876372 TI - Functional Capacity in Congenital Heart Disease: A Systematic Review and Meta Analysis. AB - BACKGROUND: Children and adolescents with congenital heart disease often have alterations in their exercise capacity that can be evaluated by various functional testing. OBJECTIVE: To evaluate the functional capacity of children and adolescents with congenital heart disease (CHD) with systematic review and meta-analyses. METHODS: The review included observational studies, data from the first evaluation of randomized clinical trials or observational follow-up periods after clinical trials which evaluated functional capacity by cardiopulmonary exercise test, stress testing, six-minute walk test or step test, in children and adolescents with CHD, aged between six and 18 years, and comparisons with healthy controls in the same age group. The quantitative assessment was performed by meta analysis, by comparing the maximal oxygen consumption (VO2max) of children and adolescents with CHD and respective control groups. RESULTS: Twenty-five of 2.683 studies identified in the search met the inclusion criteria. The VO2max measurement showed that patients with CHD have a decrease of 9.31 ml/Kg/min (95% CI. -12.48 to -6.13; I2, 94.3%, P for heterogeneity < 0.001) compared with the control group. The meta-analysis of the data of maximum heart rate (HR) reached during cardiopulmonary test and stress testing, retrieved from 18 studies, showed a HR value of -15.14 bpm (95% CI. -20.97 to -9.31; I2, 94.3%, P for heterogeneity < 0.001) compared with the control group. CONCLUSION: Children and adolescents with CHD have lower VO2max and HR compared to controls. PMID- 28876374 TI - Do We Need to Personalize Renal Function Assessment in the Stratification of Patients Undergoing Cardiac Surgery? AB - BACKGROUND: Renal dysfunction is an independent predictor of morbidity and mortality in cardiac surgery. For a better assessment of renal function, calculation of creatinine clearance (CC) may be necessary. OBJECTIVE: To objectively evaluate whether CC is a better risk predictor than serum creatinine (SC) in patients undergoing cardiac surgery. METHODS: Analysis of 3,285 patients registered in a prospective, consecutive and mandatory manner in the Sao Paulo Registry of Cardiovascular Surgery (REPLICCAR) between November 2013 and January 2015. Values of SC, CC (Cockcroft-Gault) and EuroSCORE II were obtained. Association analysis of SC and CC with morbidity and mortality was performed by calibration and discrimination tests. Independent multivariate models with SC and CC were generated by multiple logistic regression to predict morbidity and mortality following cardiac surgery. RESULTS: Despite the association between SC and mortality, it did not calibrate properly the risk groups. There was an association between CC and mortality with good calibration of risk groups. In mortality risk prediction, SC was uncalibrated with values > 1.35 mg /dL (p < 0.001). The ROC curve showed that CC is better than SC in predicting both morbidity and mortality risk. In the multivariate model without CC, SC was the only predictor of morbidity, whereas in the model without SC, CC was not only a mortality predictor, but also the only morbidity predictor. CONCLUSION: Compared with SC, CC is a better parameter of renal function in risk stratification of patients undergoing cardiac surgery. PMID- 28876373 TI - Minimally Invasive Epicardial Pacemaker Implantation in Neonates with Congenital Heart Block. AB - BACKGROUND: Few studies have characterized the surgical outcomes following epicardial pacemaker implantation in neonates with congenital complete atrioventricular block (CCAVB). OBJECTIVE: This study sought to assess the long term outcomes of a minimally invasive epicardial approach using a subxiphoid access for pacemaker implantation in neonates. METHODS: Between July 2002 and February 2015, 16 consecutive neonates underwent epicardial pacemaker implantation due to CCAVB. Among these, 12 (75.0%) had congenital heart defects associated with CCAVB. The patients had a mean age of 4.7 +/- 5.3 days and nine (56.3%) were female. Bipolar steroid-eluting epicardial leads were implanted in all patients through a minimally invasive subxiphoid approach and fixed on the diaphragmatic ventricular surface. The pulse generator was placed in an epigastric submuscular position. RESULTS: All procedures were successful, with no perioperative complications or early deaths. Mean operating time was 90.2 +/- 16.8 minutes. None of the patients displayed pacing or sensing dysfunction, and all parameters remained stable throughout the follow-up period of 4.1 +/- 3.9 years. Three children underwent pulse generator replacement due to normal battery depletion at 4.0, 7.2, and 9.0 years of age without the need of ventricular lead replacement. There were two deaths at 12 and 325 days after pacemaker implantation due to bleeding from thrombolytic use and progressive refractory heart failure, respectively. CONCLUSION: Epicardial pacemaker implantation through a subxiphoid approach in neonates with CCAVB is technically feasible and associated with excellent surgical outcomes and pacing lead longevity. PMID- 28876375 TI - Twenty-four hour Blood Pressure in Obese Patients with Moderate-to-Severe Obstructive Sleep Apnea. AB - BACKGROUND: Obesity, systemic arterial hypertension (SAH) and obstructive sleep apnea (OSA) are closely related. Up to 70% of patients with OSA may be asymptomatic, and there is evidence that these patients have cardiovascular disease, especially nocturnal SAH. OBJECTIVES: The aim of this study was to evaluate 24-hour blood pressure circadian variation in asymptomatic, obese individuals with moderate-to-severe OSA and compare it with that in individuals with mild OSA or without OSA. METHODS: Eighty-six obese subjects aged between 30 and 55 years (BMI 30-39 kg/m2), with casual blood pressure < 140/90 mmHg and without comorbidities were recruited. Eighty-one patients underwent clinical and anthropometric assessment, ambulatory blood pressure monitoring (ABPM), and Watch PAT. Participants were divided into two groups, based on the apnea-hypopnea index (AHI): group 1, with AHI < 15 events/hour, and group 2 with AHI >= 15 events/hour. RESULTS: Compared with group 1, group 2 had higher neck circumference and waist-hip circumference (40.5 +/- 3.2 cm vs. 38.0 +/- 3.7 cm, p = 0.002, and 0.94 +/- 0.05 vs. 0.89 +/- 0.05, p = 0.001, respectively), higher systolic and diastolic blood pressure measured by the 24-h ABPM (122 +/- 6 vs 118 +/- 8 mmHg, p = 0.014, and 78 +/- 6 vs 73 +/- 7 mmHg, p = 0.008, respectively), and higher nocturnal diastolic pressure load (44,6 +/- 25,9% vs 31,3 +/- 27,3%, p = 0,041). Moreover, there was a positive correlation between nocturnal diastolic blood pressure and AHI (r = 0.43, p < 0.05). CONCLUSIONS: Asymptomatic obese subjects with moderate-to-severe OSA have higher systolic and diastolic blood pressure at 24 hours compared with those with absent / mild OSA, despite normal casual blood pressure between the groups. These results indicate that ABPM may be useful in the evaluation of asymptomatic obese patients with moderate-to-severe OSA. PMID- 28876376 TI - Pre-Frailty Increases the Risk of Adverse Events in Older Patients Undergoing Cardiovascular Surgery. AB - BACKGROUND: Frailty is identified as a major predictor of adverse outcomes in older surgical patients. However, the outcomes in pre-frail patients after cardiovascular surgery remain unknown. OBJECTIVE: To investigate the main outcomes (length of stay, mechanical ventilation time, stroke and in-hospital death) in pre-frail patients in comparison with no-frail patients after cardiovascular surgery. METHODS: 221 patients over 65 years old, with established diagnosis of myocardial infarction or valve disease were enrolled. Patients were evaluated by Clinical Frailty Score (CFS) before surgery and allocated into 2 groups: no-frailty (CFS 1~3) vs. pre-frailty (CFS 4) and followed up for main outcomes. For all analysis, the statistical significance was set at 5% (p < 0.05). RESULTS: No differences were found in anthropometric and demographic data between groups (p > 0.05). Pre-frail patients showed a longer mechanical ventilation time (193 +/- 37 vs. 29 +/- 7 hours; p<0.05) than no-frail patients; similar results were observed for length of stay at the intensive care unit (5 +/ 1 vs. 3 +/- 1 days; p < 0.05) and total time of hospitalization (12 +/- 5 vs. 9 +/- 3 days; p < 0.05). In addition, the pre-frail group had a higher number of adverse events (stroke 8.3% vs. 3.9%; in-hospital death 21.5% vs. 7.8%; p < 0.05) with an increased risk for development stroke (OR: 2.139, 95% CI: 0.622-7.351, p = 0.001; HR: 2.763, 95%CI: 1.206-6.331, p = 0.0001) and in-hospital death (OR: 1.809, 95% CI: 1.286-2.546, p = 0.001; HR: 1.830, 95% CI: 1.476-2.269, p = 0.0001). Moreover, higher number of pre-frail patients required homecare services than no-frail patients (46.5% vs. 0%; p < 0.05). CONCLUSION: Patients with pre frailty showed longer mechanical ventilation time and hospital stay with an increased risk for cardiovascular events compared with no-frail patients. PMID- 28876377 TI - Crack-cocaine users have less family cohesion than alcohol users. AB - OBJECTIVE: Many studies correlate characteristics of family functioning and the development of drug addiction. This study sought to evaluate and compare the family environment styles of two groups of psychoactive substance users: 1) alcohol-only users and 2) crack-cocaine users. METHODS: Three hundred and sixty four users of alcohol, crack-cocaine, and other drugs, recruited from research centers in four Brazilian capitals participated in this study. Subjects were evaluated through the Family Environment Scale and the Addiction Severity Index, 6th version (ASI-6). ASI-6 t-scores were compared by analysis of variance (ANOVA) and post-hoc tests. A final model was obtained using a logistic regression analysis. All analyses were adjusted for partner, age, and psychiatric t-score. RESULTS: We found a significant difference between groups in the cohesion subscale (p = 0.044). The post-hoc test revealed a difference of 1.06 points (95%CI 0.11-2.01) between groups 1 (6.45+/-0.28) and 2 (5.38+/-0.20). No significant between-group differences were observed in the other subscales. However, categorical analyses of variables regarding family dynamic showed that crack users more often reported that sometimes people in their family hit each other (30.4% vs. 13.2%, p = 0.007) and that people in their family frequently compared each other regarding work and/or school achievement (57.2% vs. 42.6%, p = 0.041). CONCLUSION: These results suggest that families of crack-cocaine users are less cohesive than families of alcohol users. This type of family environment may affect treatment outcome, and should thus be adequately approached. PMID- 28876378 TI - Screening for common mental disorders using the SRQ-20 in Brazil: what are the alternative strategies for analysis? AB - Objective: To analyze the prevalence of common mental disorders (CMD) assessed with the Self Reporting Questionnaire (SRQ-20), using the established cutoff point, and comparing it with the results of a joint correspondence factor analysis (CFA) and cluster analysis and of a latent class analysis (LCA). Methods: A cross-sectional study was carried out in an urban sample of 1,095 women aged 19 to 55 years. Joint CFA-cluster analysis and LCA were used. Results: We found a high prevalence of CMD, regardless of classification method (37.6% when using the cutoff point; 44.4% and 52% for LCA and joint CFA-cluster, respectively). The alternative analysis strategies describe the cases more efficiently when compared to the traditional cutoff method, especially regarding more severe symptoms. Both alternative strategies also provide a description of the SRQ-20 dimensions in their particularities, which may be useful for the planning and implementation of specific actions in a given population. Conclusion: The SRQ-20 cutoff point seems to underestimate the magnitude of CMD among women. The alternative methods of analysis presented herein highlight the different possibilities of using this important instrument of screening for mental health. PMID- 28876380 TI - Portuguese and Brazilian guidelines for the treatment of depression: exercise as medicine. AB - Depression is a psychiatric disorder and major contributor to the burden of disease worldwide. The strength of evidence of the benefits of exercise as a therapeutic intervention for patients with depression has expanded in the last 30 years. In fact, the available evidence indicates exercise can not only help manage depressive symptoms, but also effect significant improvements in other health outcomes. Clinical guidelines including such recommendations have been issued by different agencies, namely the UK National Institute for Health and Clinical Excellence (NICE), the American Psychiatric Association (APA), and the Royal Australian and New Zealand College of Psychiatrists (RANZCP). With increasing recognition of the benefits of exercise and shortcomings of healthcare systems, other countries, such as Sweden and Canada, have included exercise in their national guidelines for treating depression. Unfortunately, progress in incorporating exercise guidelines into clinical practice has been slow, and Portugal and Brazil reflect this reality. In this update, we reemphasize the importance of bridging this gap and integrating exercise into clinical practice guidelines as an essential component of depression treatment. PMID- 28876379 TI - Clinical outcomes of psychotherapy dropouts: does dropping out of psychotherapy necessarily mean failure? AB - Objective: A large proportion of psychotherapy patients remain untreated, mostly because they drop out. This study compares the short- and long-term outcomes of patients who dropped out of psychotherapy to those of therapy completers. Methods: The sample included 63 patients (23 dropouts and 40 completers) from a controlled clinical trial, which compared narrative therapy vs. cognitive behavioral therapy for major depressive disorder. Patients were assessed at the eighth session, post-treatment, and at 31-month follow-up. Results: Dropouts improved less than completers by the last session attended, but continued to improve significantly more than completers during the follow-up period. Some dropout patients improved with a small dose of therapy (17% achieved a clinically significant change before abandoning treatment), while others only achieved clinically significant change after a longer period (62% at 31-month follow-up). Conclusion: These results emphasize the importance of dealing effectively with patients at risk of dropping out of therapy.Patients who dropped out also reported improvement of depressive symptoms without therapy, but took much longer to improve than did patients who completed therapy. This might be attributable to natural remission of depression. Further research should use a larger patient database, ideally gathered by meta-analysis. PMID- 28876381 TI - Assessment of the antiproliferative and antigenotoxic activity and phytochemical screening of aqueous extracts of Sambucus australis Cham. & Schltdl. (ADOXACEAE). AB - The purpose of this study was to evaluate the antiproliferative and antigenotoxic activity of Sambucus australis Cham. & Schltdl. aqueous extracts on the cell cycle of Allium cepa L. as well as determine the phenolic compounds in such extracts. S. australis inflorescences and leaves of two accessions were used for aqueous extract preparation at concentrations: 0.003 g/ml and 0.012 g/ml. A. cepa bulbs were rooted in distilled water and, subsequently, placed in treatments for 24 hours. Rootlets were collected and fixed in modified Carnoy's solution for 24 hours and kept. The squash technique was performed for slide preparation. Root tips were smashed and stained with 2% acetic orcein, and a total of 4000 cells per treatment were analyzed. The phenolic compounds were determined using high performance liquid chromatography and data was analyzed using the Scott-Knott test. The results show that S. australis aqueous extracts have antiproliferative potential. Besides, the extracts prepared from S. australis leaves of both accessions at a concentration of 0.012 g/ml have shown antigenotoxic activity. The phytochemical analysis allowed us to determine the presence of flavonoids and phenolic acids, of which kaempferol and chrologenic acid were the most predominant compounds in the extracts from the inflorescences and leaves, respectively. PMID- 28876382 TI - Detection, purification and characterization of a lectin from freshwater green algae Spirogyra spp. AB - Freshwater algae are rich sources of structurally biologically active metabolites, such as fatty acids, steroids, carotenoids and polysaccharides. Among these metabolites, lectins stand out. Lectins are proteins or glycoproteins of non-immune origin which bind to carbohydrates or glycoconjugates, without changing ligand structure. Many studies have reported on the use of Spirogyra spp. as effective bioindicators of heavy metals; however, reports on Spirogyra molecular bioprospecting are quite limited. Therefore, this study aimed to detect, isolate, purify and characterize a lectin present in the freshwater green algae Spirogyra. Presence of the lectin protein in the extract was detected by hemagglutination assays. Subsequently, the protein extract was subjected to a sugar inhibition assay to identify the lectin-specific carbohydrate. Following this, the extract was applied to a guar gum column to afford the pure lectin. The lectin was inhibited by N-acetyl-glucosamine and N-acetyl-beta-D-mannose, but more strongly by D-galactose. The apparent molecular mass of the purified lectin was evaluated by Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE). Electrophoretic analysis revealed a single protein band with an apparent molecular mass of 56 kDa. Thus, it could be concluded that a lectin was purified from Spirogyra spp. PMID- 28876383 TI - Correlations of condition factor and gonadosomatic, hepatosomatic and lipo somatic relations of Leptodactylus macrosternum (ANURA: Leptodactylidae) in the Brazilian Semi-arid. AB - The objective of this study was to assess variations of the condition factor (K1) in relation to the gonadosomatic- RGS and energy reserves (hepatosomatic - RWL and liposomatic - RFB relations) of Leptodactylus macrosternum and their relationship to climate variation in the Northeast of Brazil, Caatinga area, state of Paraiba. The animals were captured fortnightly through active collecting, between January and December 2013. Significant differences were observed in the monthly variations of K1, RGS and RFB indices in male and female L. macrosternum over the months of collection. In males, K1 showed no significant relationship with the other variables. In females, RGS values only show notable correlations with RWF and K1 values. K1 values showed significant correlations with all other weight and length ratios. Climate change in the HFOB region showed significant relationships with the variation of the indexes evaluated, with the exception of RWF. The variation of K1, RGS, RWL and RFB values over the months of collection as well as their relation with the local climatic variation, showed a brief reproductive activity for the species. PMID- 28876385 TI - Carbon and nutrient stocks of three Fabaceae trees used for forest restoration and subjected to fertilization in Amazonia. AB - Amazonia is crucial to global carbon cycle. Deforestation continues to be one of the main causes of the release of C into the atmosphere, but forest restoration plantations can reverse this scenario. However, there is still diffuse information about the C and nutrient stocks in the vegetation biomass. We investigated the carbon and nutrient stocks of Fabaceae trees (Inga edulis, Schizolobium amazonicum and Dipteryx odorata) subjected to fertilization treatments (T1 - no fertilization; T2 - chemical; T3 - organic; and T4 - organic and chemical fertilization) in a degraded area of the Balbina Hydroelectric Dam, AM - Brazil. As an early successional species, I. edulis stocked more C and nutrients than the other two species independent of the fertilization treatment, and S. amazonicum stocked more C than D. odorata under T1 and T4. The mixed species plantation had the potential to stock 4.1 Mg C ha-1 year-1, while I. edulis alone could stock 9.4 Mg C ha-1 year-1. Mixing species that rapidly assimilate C and are of significant ecological and commercial value (e.g., Fabaceae trees) represents a good way to restore degraded areas. Our results suggest that the tested species be used for forest restoration in Amazonia. PMID- 28876384 TI - Influence of substrate on the richness and composition of Neotropical cave fauna. AB - The food base in the subterranean environment consists mainly of allochthonous materials. In this environment the resources are distributed generally in a heterogeneous dispersed way and the distribution of resources and their availability determine where the terrestrial invertebrates will reside, which is important for understanding ecological relationships and to establish conservation strategies. Thus, we tested how the complexity of substrates influences the richness and composition of the subterranean terrestrial invertebrates in the Presidente Olegario karst area, southeastern Brazil. We carried out collections in six caves during both dry and wet seasons, using combined collection methods. We observed different distributions in relation to the substrate, because the environmental heterogeneity increases the amount of available niches for the fauna. Some taxa showed a preference for specific substrates, probably related to the availability of food resources and humidity and to body size restriction, emphasizing the niche differentiation between species. Anthropogenic impacts can cause irreversible alterations in the subterranean fauna because the subterranean environment is dependent on the surface for input of trophic resources. On-going impacts in the Presidente Olegario karst area, like agriculture, pastures, gas extraction, and hydroelectric projects, are therefore a serious threat to subterranean biodiversity and this region should be prioritized for conservation. PMID- 28876386 TI - A possible relationship between gluconeogenesis and glycogen metabolism in rabbits during myocardial ischemia. AB - Ischemia is responsible for many metabolic abnormalities in the heart, causing changes in organ function. One of modifications occurring in the ischemic cell is changing from aerobic to anaerobic metabolism. This change causes the predominance of the use of carbohydrates as an energy substrate instead of lipids. In this case, the glycogen is essential to the maintenance of heart energy intake, being an important reserve to resist the stress caused by hypoxia, using glycolysis and lactic acid fermentation. In order to study the glucose anaerobic pathways utilization and understand the metabolic adaptations, New Zealand white rabbits were subjected to ischemia caused by Inflow occlusion technique. The animals were monitored during surgery by pH and lactate levels. Transcription analysis of the pyruvate kinase, lactate dehydrogenase and phosphoenolpyruvate carboxykinase enzymes were performed by qRT-PCR, and glycogen quantification was determined enzymatically. Pyruvate kinase transcription increased during ischemia, followed by glycogen consumption content. The gluconeogenesis increased in control and ischemia moments, suggesting a relationship between gluconeogenesis and glycogen metabolism. This result shows the significant contribution of these substrates in the organ energy supply and demonstrates the capacity of the heart to adapt the metabolism after this injury, sustaining the homeostasis during short-term myocardial ischemia. PMID- 28876387 TI - Assessment of cow and farm level risk factors associated with Ureaplasma diversum in pasture-based dairy systems - A field study. AB - Potential risk factors for Ureaplasma diversum in the vaginal mucus of 1,238 dairy cows were included in a multivariate logistic regression model, based on the cow level (i.e., granular vulvovaginitis [+GVV], yearly milk production [4500 kg or more], pregnancy, predominance of Bos taurus [+Bos Taurus], score of corporal condition [at least 2.5], concomitant positivity for Escherichia coli [+E.coli]), and farm level i.e., milking room hygiene (-Milking room), dunghill location, and replacement female). Ureaplasma diversum was present in 41.1% of the samples. Independent risk factors for U. diversum were +GVV (odds ratio [OR], 1.31); +Mycoplasma spp (OR, 5.67); yearly milk production (4500 kg or more) (OR, 1.99); +Bos taurus (OR, 1.68); +E. coli (OR, 4.96); -milking room (OR, 2.31); and replacement females (OR, 1.89). Ureaplasma diversum vaginal colonization was strongly associated with Mycoplasma spp., E. coli, and number of pregnant cows. PMID- 28876388 TI - Brazilian science communication research: national and international contributions. AB - Science communication has emerged as a new field over the last 50 years, and its progress has been marked by a rise in jobs, training courses, research, associations, conferences and publications. This paper describes science communication internationally and the trends and challenges it faces, before looking at the national level. We have documented science communication activities in Brazil, the training courses, research, financial support and associations/societies. By analyzing the publication of papers, dissertations and theses we have tracked the growth of this field, and compared the level of activity in Brazil with other countries. Brazil has boosted its national research publications since 2002, with a bigger contribution from postgraduate programs in education and communication, but compared to its national research activity Brazil has only a small international presence in science communication. The language barrier, the tradition of publishing in national journals and the solid roots in education are some of the reasons for that. Brazil could improve its international participation, first by considering collaborations within Latin America. International publication is dominated by the USA and the UK. There is a need to take science communication to the next level by developing more sophisticated tools for conceptualizing and analyzing science communication, and Brazil can be part of that. PMID- 28876389 TI - The use of Proteinase K to access genitalia morphology, vouchering and DNA extraction in minute wasps. AB - Genitalia are rich source of characters in insect taxonomy. Usually, they are examined after dissection and cleaning with potassium hydroxide (KOH), procedure that may damage both genital morphological structures and intracellular molecular contents. Enzymatic procedure with Proteinase K has been used to clean muscle off the genitalia while extract DNA, but its damage to the genital structures has not been evaluated. Herein, we qualitatively compare the use of KOH and Proteinase K to prepare genital structures in minute insects (Hymenoptera: Bethylidae). We show that Proteinase K is better to preserve the genital structure and provides quality DNA. PMID- 28876390 TI - The influence of non-steroidal anti-inflammatory drugs and paracetamol used for pain control of orthodontic tooth movement: a systematic review. AB - : The present study aimed to perform a systematic literature review to determine if there is a non-steroidal anti-inflammatory drug (NSAID) that interferes less within tooth movement. This research was performed according to the PRISMA statement. Articles were searched in eight electronic databases (PubMed, Scopus, Embase, Web of Science, LILACS, SciELO, Google Scholar, and Open Grey). Only experimental studies on male Wistar rats were selected, which included experiments related to the influence of NSAIDs on orthodontic movement. Studies in animals with pathological conditions, literature review articles, letters to the editor and/or editorials, case reports, abstracts, books, and book chapters were excluded. Each of the steps of this systematic literature review was performed by two examiners independently. RESULTS: the total sample consisted of 505 articles, from which 6 studies were eligible after a qualitative analysis. From the drugs assessed, paracetamol was unanimous for not interfering within orthodontic movement when compared to the control group. However, drugs such as aspirin, ibuprofen, sodium diclofenac, and selective cyclooxygenase-2 inhibitors caused a reduction in tooth movement when compared to the control group. CONCLUSION: paracetamol could be considered the drug of choice for pain relief because it interferes less within tooth movement. PMID- 28876391 TI - Agronomic viability of New Zealand spinach and kale intercropping. AB - The intercropping is a production system that aims to provide increased yield with less environmental impact, due to greater efficiency in the use of natural resources and inputs involved in the production process. An experiment was carried out to evaluate the agronomic viability of kale and New Zealand spinach intercropping as a function of the spinach transplanting time. (0, 14, 28, 42, 56, 70, 84 and 98 days after transplanting of the kale). The total yield (TY) and yield per harvest (YH) of the kale in intercropping did not differ from those obtained in monoculture. The spinach TY was influenced by the transplanting time, the earlier the transplanting, the higher the TY. The spinach YH was not influenced by the transplanting time, but rather by the cultivation system. In intercropping, the spinach YH was 13.5% lower than in monoculture. The intercropping was agronomically feasible, since the land use efficiency index, which was not influenced by the transplanting time, had an average value of 1.71, indicating that the intercropping produced 71% more kale and spinach than the same area in monoculture. Competitiveness coefficient, aggressiveness and yield loss values showed that kale is the dominating species and spinach is the dominated. PMID- 28876393 TI - A new saurolophine hadrosaurid (Dinosauria: Ornithopoda) from the Upper Cretaceous of Shandong, China. AB - A new saurolophine hadrosaurid, Laiyangosaurus youngi gen. et sp. nov. is described and phylogenetically analyzed based on several cranial elements from the Jingangkou Formation, Wangshi Group, Upper Cretaceous of Laiyang, Shandong, China. Laiyangosaurus youngi differs from other members of the saurolophine clade on the basis of a number of autapomorphies, including a prominent and narrow ridge on the lateral side of the nasal which forms the posterodorsal and posterior margin of the circumnasal depression, a primary ridge that runs along most of the maxillary tooth row that is slightly deflected posteriorly, a retroarticular process of the surangular that is dorsolateroposteriorlly recurved, and orbital margins that are wider than the infratemporal margins of the jugal. This new taxon can be further distinguished by a number of unique combination of characters, including dorsal margin of nasal is flat, absence supracranial crest, a relatively shallow and rostrodorsally directed caudal margin of the lacrimal process of the jugal, and one or more foramina present on the rostral surface of the premaxilla. A phylogenetic analysis indicates that L. youngi comprises a monophyletic clade, which is known as Edmontosaurini. PMID- 28876392 TI - Antifungal and antioxidant activity of fatty acid methyl esters from vegetable oils. AB - Fatty acid methyl esters (FAMEs) were obtained from vegetable oils of soybean, corn and sunflower. The current study was focused on evaluating the antifungal activity of FAMEs mainly against Paracoccidioides spp., as well as testing the interaction of these compounds with commercial antifungal drugs and also their antioxidant potential. FAMEs presented small IC50 values (1.86-9.42 MUg/mL). All three FAMEs tested showed antifungal activity against isolates of Paracoccidioides spp. with MIC values ranging from 15.6-500 ug/mL. Sunflower FAMEs exhibited antifungal activity that extended also to other genera, with an MIC of 15.6 MUg/mL against Candida glabrata and C. krusei and 31.2 MUg/mL against C. parapsilosis. FAMEs exhibited a synergetic effect with itraconazole. The antifungal activity of the FAMEs against isolates of Paracoccidioides spp. is likely due to the presence of methyl linoleate, the major compound present in all three FAMEs. The results obtained indicate the potential of FAMEs as sources for antifungal and antioxidant activity. PMID- 28876394 TI - Efficiency of essential oils of Ocimum basilicum and Cymbopogum flexuosus in the sedation and anaesthesia of Nile tilapia juveniles. AB - This study aimed to verify the sedative and anaesthetic effect of the essential oils of basil (Ocimum basilicum) (EOOB) and lemongrass (Cymbopogum flexuosus) (EOCF) in Nile tilapia juveniles. The fish were transferred to aquaria containing different concentrations of each essential oil: 10, 25, 50, 100, 200, 400 and 600 MUL L-1. The time of sedation ranged from 7 to 31 seconds and the recommended concentration was 10 or 25 MUL L-1 for both essential oils. The best times for anaesthesia and recovery were found for the concentrations of 400 MUL L-1 for EOOB (135.2 and 199.1 seconds, respectively) and 600 MUL L-1 for EOCF (327.1 and 374.8 seconds, respectively). In conclusion, we recommend the use of EOOB and EOCF for the sedation and anaesthesia of Nile tilapia at concentrations of 10-25 (for both), 400 and 600 MUL L-1, respectively. PMID- 28876395 TI - Oral insulin improves metabolic parameters in high fat diet fed rats. AB - INTRODUCTION/AIM: The gut has shown to have a pivotal role on the pathophysiology of metabolic disease. Food stimulation of distal intestinal segments promotes enterohormones secretion influencing insulin metabolism. In diabetic rats, oral insulin has potential to change intestinal epithelium behavior. This macromolecule promotes positive effects on laboratorial metabolic parameters and decreases diabetic intestinal hypertrophy. This study aims to test if oral insulin can influence metabolic parameters and intestinal weight in obese non diabetic rats. METHODS: Twelve weeks old Wistar rats were divided in 3 groups: control (CTRL) standard chow group; high fat diet low carbohydrates group (HFD) and HFD plus daily oral 20U insulin gavage (HFD+INS). Weight and food consumption were weekly obtained. After eight weeks, fasting blood samples were collected for laboratorial analysis. After euthanasia gut samples were isolated. RESULTS: Rat oral insulin treatment decreased body weight gain (p<0,001), fasting glucose and triglycerides serum levels (p<0,05) an increased intestinal weight of distal ileum (P<0,05). Animal submitted to high fat diet presented higher levels of HOMA IR although significant difference to CT was not achieved. HOMA-beta were significantly higher (p<0.05) in HFD+INS. Visceral fat was 10% lower in HFD+INS but the difference was not significant. CONCLUSIONS: In non-diabetic obese rats, oral insulin improves metabolic malfunction associated to rescue of beta-cell activity. PMID- 28876396 TI - Preparation and characterization of alginate and gelatin microcapsules containing Lactobacillus rhamnosus. AB - This paper describes the preparation and characterization of alginate beads coated with gelatin and containing Lactobacillus rhamnosus. Capsules were obtained by extrusion method using CaCl2 as cross linker. An experimental design was performed using alginate and gelatin concentrations as the variables investigated, while the response variable was the concentration of viable cells. Beads were characterized in terms of size, morphology, scanning electron microscopy (SEM), moisture content, Fourier Transform Infrared Spectrometry (FTIR), thermal behavior and cell viability during storage. The results showed that the highest concentration of viable cells (4.2 x 109 CFU/g) was obtained for 1 % w/v of alginate and 0.1 % w/v of gelatin. Capsules were predominantly spherical with a rough surface, a narrow size distribution ranging from 1.53 to 1.90 mm and a moisture content of 97.70 +/- 0.03 %. Furthermore, FTIR and thermogravimetric analysis indicated an interaction between alginate-gelatin. Cell concentration of alginate/gelatin microcapsules was 105 CFU/g after 4 months of storage at 8 oC. PMID- 28876397 TI - Leaf area estimation from linear measurements in different ages of Crotalaria juncea plants. AB - The goal of this study was to estimate the leaf area of Crotalaria juncea according to the linear dimensions of leaves from different ages. Two experiments were conducted with C. juncea cultivar IAC-KR1, in the 2014/2015 sowing seasons. At 59, 82, 102, 129 days after sowing (DAS) of the first and 61, 80, 92, 104 DAS of the second experiment, 500 leaves were collected, totaling 4,000 leaves. In each leaf, the linear dimensions were measured (length, width, length/width ratio and length * width product) and the specific leaf area was determined through Digimizer and Sigma Scan Pro software, after scanning images. Then, 3,200 leaves were randomly separated to generate mathematical models of leaf area (Y) in function of linear dimension (x), and 800 leaves for the models validation. In C. juncea, the leaf areas determined by Digimizer and Sigma Scan Pro software are identical. The estimation models of leaf area as a function of length * width product showed superior adjustments to those obtained based on the evaluation of only one linear dimension. The linear model Y=0.7390x (R2=0.9849) of the real leaf area (Y) as a function of length * width product (x) is adequate to estimate the C. juncea leaf area. PMID- 28876398 TI - Remote sensing of the chlorophyll-a based on OLI/Landsat-8 and MSI/Sentinel-2A (Barra Bonita reservoir, Brazil). AB - In this present research, we assessed the performance of band algorithms in estimating chlorophyll-a (Chl-a) concentration based on bands of two new sensors: Operational Land Imager onboard Landsat-8 satellite (OLI/Landsat-8), and MultiSpectral Instrument onboard Sentinel-2A (MSI/Sentinel-2A). Band combinations designed for Thematic Mapper onboard Landsat-5 satellite (TM/Landsat-5) and MEdium Resolution Imaging Spectrometer onboard Envisat platform (MERIS/Envisat) were adapted for OLI/Landsat-8 and MSI/Sentinel-2A bands. Algorithms were calibrated using in situ measurements collected in three field campaigns carried out in different seasons. The study area was the Barra Bonita hydroelectric reservoir (BBHR), a highly productive aquatic system. With exception of the three band algorithm, the algorithms were spectrally few affected by sensors changes. On the other hands, algorithm performance has been hampered by the bio-optical difference in the reservoir sections, drought in 2014 and pigment packaging. PMID- 28876399 TI - New seminal variety of Stevia rebaudiana: Obtaining fractions with high antioxidant potential of leaves. AB - The aim of this study was to determine the composition and antioxidant potential of leaves of a new variety of Stevia rebaudiana (Stevia UEM-13). Stevia leaves of UEM-13 contain rebaudioside A as the main glycoside, while most wild Stevia plants contain stevioside. Furthermore can be multiplied by seed, which reduces the cost of plant culture techniques as other clonal varieties are multiplied by buds, requiring sophisticated and expensive seedling production systems. Ethanol and methanol were used in the extraction to determine the bioactive compounds. The methanolic extract was fractionated sequentially with hexane, chloroform, ethyl acetate and isobutanol, and the highest concentration of phenolic compounds and flavonoids was obtained in the ethyl acetate fraction (524.20 mg galic acid equivalent/g; 380.62 ug quercetin equivalent/g). The glycoside content varied greatly among the fractions (0.5% - 65.3%). Higher antioxidant potential was found in the methanol extract and the ethyl acetate fraction with 93.5% and 97.32%, respectively. In addition to being an excellent source for obtaining of extracts rich in glycoside, this new variety can also be used as raw material for the production of extracts or fractions with a significant amount of antioxidant activity and potential to be used as additives in food. PMID- 28876400 TI - Biological Activity of Piper aduncum extracts on Anticarsia gemmatalis (Hubner) (Lepidoptera: Erebidae) and Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae). AB - Piper aduncum found naturally in the Amazon and southeastern Brazil, is known for its secondary metabolites that have activity on insects. Anticarsia gemmatalis and Spodoptera frugiperda are among the major insect pests associated with agricultural production. This research evaluated the biological activity of hexane, ethyl acetate, and ethanol extracts of P. aduncum leaves on mortality and duration of larval and pupal periods, as well as weight, width, and length of A. gemmatalis and S. frugiperda pupae. The mortality of A. gemmatalis larvae in trials with P. aduncum extracts were 93.3% (hexane) and 90% (ethyl acetate), estimating LC50 of 6.35 and 5.79 mg/mL, respectively. Mortality in S. frugiperda submitted to the hexane extract ranged from 3.33% to 96.66% (LC50 of 8.22 mg/mL). The ethanol extract induced low mortality (3.33% to 23.33%). The P. aduncum extracts did not affect the development of S. frugiperda pupae. In A. gemmatalis differences in weight and length occurred. The chemical characterization was by GC-MS, which revealed that the major constituent in the hexane extract of P. aduncum was apiol (90.7%). P. aduncum extracts are important and promising components to manage A. gemmatalis and S. frugiperda, which cause extensive production losses. PMID- 28876401 TI - Landslides Zonation Hazard: relation between geological structures and landslides occurrence in hilly tropical regions of Brazil. AB - This paper presents a new approach of landslides zonation hazard studies, based on an integrated study of structural data along with geomorphological and external factors, in a hilly regions of Brazil, covered by a tropical humid rain forest, called Serra do Mar. The Serra do Mar consists of a hilly region along the east coast of Brazil, with high slopes and many geological structures in a gneiss - migmatitic terrain. In contrast to traditional approaches, this method proposes that structural data (foliation, fractures and bedding planes) and its relation with the slope geometry, is important to be consider in the landslide zonation hazard, along with declivity, relative relief, soil and rock properties, land use and vegetation cover and hydrogeological and climate factors. Results show that slopes with high hazard have the same dip direction of geological structures. Landslide zonation hazard using structural data contributes to a better understanding of how these structures, preserved in tropical residual soils, influence on slope stability and generates landslides. PMID- 28876402 TI - Analysis of biofilm production by clinical isolates of Pseudomonas aeruginosa from patients with ventilator-associated pneumonia. AB - OBJECTIVE: To phenotypically evaluate biofilm production by Pseudomonas aeruginosa clinically isolated from patients with ventilator-associated pneumonia. METHODS: Twenty clinical isolates of P. aeruginosa were analyzed, 19 of which were from clinical samples of tracheal aspirate, and one was from a bronchoalveolar lavage sample. The evaluation of the capacity of P. aeruginosa to produce biofilm was verified using two techniques, one qualitative and the other quantitative. RESULTS: The qualitative technique showed that only 15% of the isolates were considered biofilm producers, while the quantitative technique showed that 75% of the isolates were biofilm producers. The biofilm isolates presented the following susceptibility profile: 53.3% were multidrug-resistant, and 46.7% were multidrug-sensitive. CONCLUSION: The quantitative technique was more effective than the qualitative technique for the detection of biofilm production. For the bacterial population analyzed, biofilm production was independent of the susceptibility profile of the bacteria, demonstrating that the therapeutic failure could be related to biofilm production, as it prevented the destruction of the bacteria present in this structure, causing complications of pneumonia associated with mechanical ventilation, including extrapulmonary infections, and making it difficult to treat the infection. PMID- 28876403 TI - Antimicrobial drug-related problems in a neonatal intensive care unit. AB - OBJECTIVE: The goal was to determine the main drug-related problems in neonates who were using antimicrobials. METHOD: This was an observational, prospective and longitudinal study. Drug-related problems were classified according to version 6.2 of the Pharmaceutical Care Network Europe Foundation classification. A descriptive analysis was performed, in which the clinical and therapeutic variables were presented as absolute and relative frequencies or as the mean and standard deviation, as appropriate. RESULTS: In total, 152 neonates with a predominance of males (58.5%), gestational age of 32.7 +/- 4.2 weeks and weight of 1,903.1 +/- 846.9g were included. The main diagnostic hypothesis of infection was early sepsis (66.5%), and 71.7% of the neonates had some risk factor for infection. Among the neonates, 33.6% had at least one drug-related problem. Of these, 84.8% were related to treatment effectiveness and 15.2% to adverse reactions. The main cause of drug-related problems was the selected dose, particularly for aminoglycosides and cephalosporins. CONCLUSION: The use of antimicrobials in the neonatal intensive care is mainly associated with problems related to medication effectiveness, predominantly the prescription of subdoses of antimicrobials, especially aminoglycosides. PMID- 28876404 TI - Contrast-induced acute kidney injury: the importance of diagnostic criteria for establishing prevalence and prognosis in the intensive care unit. AB - OBJECTIVE: To establish whether there is superiority between contrast-induced acute kidney injury and contrast-induced nephropathy criteria as predictors of unfavorable clinical outcomes. METHODS: Retrospective study carried out in a tertiary hospital with 157 patients undergoing radiocontrast infusion for propaedeutic purposes. RESULTS: One hundred forty patients fulfilled the inclusion criteria: patients who met the criteria for contrast-induced acute kidney injury (59) also met the criteria for contrast-induced nephropathy (76), 44.3% met the criteria for KDIGO staging, 6.4% of the patients required renal replacement therapy, and 10.7% died. CONCLUSION: The diagnosis of contrast induced nephropathy was the most sensitive criterion for renal replacement therapy and death, whereas KDIGO showed the highest specificity; there was no correlation between contrast volume and progression to contrast-induced acute kidney injury, contrast-induced nephropathy, support dialysis or death in the assessed population. PMID- 28876405 TI - Oxygen saturation and lactate concentration gradient from the right atrium to the pulmonary artery in the immediate postoperative following cardiac surgery with extracorporeal circulation. AB - OBJECTIVE: This prospective study aimed to characterize the changes in blood lactate concentration and blood oxygen saturation in patients during the immediate postoperative period of cardiac surgery with extracorporeal circulation. METHODS: Blood samples were collected from 35 patients in a rapid and random order from the arterial line and from the proximal and distal port of a pulmonary artery catheter. RESULTS: The results showed no statistically significant differences between the blood oxygen saturation in the right atrium (72% +/- 0.11%) and the blood oxygen saturation in the pulmonary artery (71% +/- 0.08%). The blood lactate concentration in the right atrium was 1.7mmol/L +/- 0.5mmol/L, and the blood lactate concentration in the pulmonary artery was 1.6mmol/L +/- 0.5mmol/L (p < 0.0005). CONCLUSION: The difference between the blood lactate concentration in the right atrium and the blood lactate concentration in the pulmonary artery might be a consequence of the low blood lactate concentration in the blood from the coronary sinus, as it constitutes an important substrate for the myocardium during this period. The lack of differences between the blood oxygen saturation in the right atrium and the percentage of blood oxygen saturation in the pulmonary artery suggests a lower oxygen extraction by the myocardium given a lower oxygen consumption. PMID- 28876407 TI - Alcohol-related blackouts among college students: impact of low level of response to alcohol, ethnicity, sex, and environmental characteristics. AB - Objective: To explore how a genetically-influenced characteristic (the level of response to alcohol [LR]), ethnicity, and sex relate to environmental and attitudinal characteristics (peer drinking [PEER], drinking to cope [COPE], and alcohol expectancies [EXPECT]) regarding future alcohol-related blackouts (ARBs). Methods: Structural equation models (SEMs) were used to evaluate how baseline variables related to ARB patterns in 462 college students over 55 weeks. Data were extracted from a longitudinal study of heavy drinking and its consequences at a U.S. university. Results: In the SEM analysis, female sex and Asian ethnicity directly predicted future ARBs (beta weights 0.10 and -0.11, respectively), while all other variables had indirect impacts on ARBs through alcohol quantities (beta weights ~ 0.23 for European American ethnicity and low LR, 0.21 for cannabis use and COPE, and 0.44 for PEER). Alcohol quantities then related to ARBs with beta = 0.44. The SEM explained 23% of the variance. Conclusion: These data may be useful in identifying college students who are more likely to experience future ARBs over a 1-year period. They enhance our understanding of whether the relationships of predictors to ARBs are direct or mediated through baseline drinking patterns, information that may be useful in prevention strategies for ARBs. PMID- 28876406 TI - Why should we not use APACHE II for performance measurement and benchmarking? PMID- 28876408 TI - Mental health problems among medical students in Brazil: a systematic review and meta-analysis. AB - OBJECTIVE: To provide a comprehensive picture of mental health problems (MHPs) in Brazilian medical students by documenting their prevalence and association with co-factors. METHODS: We systematically searched the MEDLINE/PubMed, SciELO, LILACS, and PsycINFO databases for cross-sectional studies on the prevalence of MHPs among medical students in Brazil published before September 29, 2016. We pooled prevalences using a random-effects meta-analysis, and summarized factors associated with MHP. RESULTS: We included 59 studies in the analysis. For meta analyses, we identified the summary prevalence of different MHPs, including depression (25 studies, prevalence 30.6%), common mental disorders (13 studies, prevalence 31.5%), burnout (three studies, prevalence 13.1%), problematic alcohol use (three studies, prevalence 32.9%), stress (six studies, prevalence 49.9%), low sleep quality (four studies, prevalence 51.5%), excessive daytime sleepiness (four studies, prevalence 46.1%), and anxiety (six studies, prevalence 32.9%). Signs of lack of motivation, emotional support, and academic overload correlated with MHPs. CONCLUSION: Several MHPs are highly prevalent among future physicians in Brazil. Evidence-based interventions and psychosocial support are needed to promote mental health among Brazilian medical students. PMID- 28876409 TI - Poor-quality prenatal dietary patterns are related to the mental health of mothers and children - could dietary improvement break the cycle? PMID- 28876410 TI - Cross-cultural adaptation of the EMIC Stigma Scale for people with leprosy in Brazil. AB - OBJECTIVE: Describe the process of cross-cultural adaptation of the "Explanatory Model Interview Catalog - Stigma Scale" for people affected by leprosy in Brazil. METHODS: After being authorized by the author of the scale to use it in the national context, we initiated the five steps process of cross-cultural adaptation: (1) translation, (2) synthesis meeting, (3) back-translation, (4) committee of experts and (5) pre-test. The internal consistency of the scale was evaluated using Cronbach's alpha coefficient. RESULTS: The 15 items of the scale's original version were translated into Brazilian Portuguese. The adapted scale showed evidence of a good understanding of its content, attested both by experts and members of the target population. Its internal consistency was 0.64. CONCLUSIONS: The adapted instrument shows satisfactory internal consistency. It may be useful in future studies that intend to provide broad situational analysis that supports solid public health programs with a focus on effective stigma reduction. In a later study, the construct's validity, criterion, and reproducibility will be evaluated. OBJETIVO: Descrever o processo de adaptacao transcultural da "Explanatory Model Interview Catalogue - Stigma Scale" para pessoas afetadas por hanseniase no Brasil. METODOS: Apos a autorizacao do autor da escala para seu uso no contexto nacional, deu-se inicio aos cinco passos do processo de adaptacao transcultural: (1) traducao, (2) reuniao de sintese, (3) retrotraducao, (4) comite de peritos e (5) pre-teste. A consistencia interna da escala foi avaliada utilizando o coeficiente alfa de Cronbach. RESULTADOS: Os 15 itens da versao original da escala foram traduzidos para a lingua portuguesa do Brasil. A escala adaptada apresentou evidencia de boa compreensao de seu conteudo, atestada tanto por peritos como por membros da populacao alvo. Sua consistencia interna foi de 0,64. CONCLUSOES: O instrumento adaptado apresenta consistencia interna satisfatoria. Pode ser util em estudos futuros que intencionem viabilizar ampla analise situacional que sustente programas solidos de saude publica com enfoque na efetiva reducao de estigma. Em estudo ulterior sera avaliada a validade de constructo, criterio e reprodutibilidade. PMID- 28876411 TI - Binge drinking and illicit drug use among adolescent students. AB - OBJECTIVE: To estimate the prevalence of illicit drug use and its association with binge drinking and sociodemographic factors among adolescent students. METHODS: This is a cross-sectional study with probabilistic conglomerate sampling, involving 1,154 students, aged 13 to 19 years old, from the public school system, in the city of Olinda, State of Pernambuco, Brazil, carried out in 2014. We used the Youth Risk Behavior Survey questionnaire, validated for use with Brazilian adolescents. The Chi-square test (<= 0.05) and Poisson regression analysis were used to estimate the prevalence ratios, with 95% confidence intervals. RESULTS: Use in life of illicit drugs was four times more prevalent among students who reported binge drinking (95%CI 3.19-5.45). Being in the age group of 16 to 19 years, being male, and having no religion were also significantly associated with illicit drug use. CONCLUSIONS: The prevalence of use in life of illicit drugs was higher in this study than in other studies carried out in Brazil and it was strongly associated with binge drinking. This factor was associated with gender, age, and religion. OBJETIVO: Estimar a prevalencia do uso de drogas ilicitas e sua associacao com binge drinking e fatores sociodemograficos entre estudantes adolescentes. METODOS: Estudo transversal com amostra probabilistica por conglomerado, envolvendo 1.154 estudantes, de 13 a 19 anos de idade, da rede publica de ensino, no municipio de Olinda, PE, 2014. Foi utilizado o questionario Youth Risk Behavior Survey, validado para uso com adolescentes brasileiros. Para analise dos dados foi utilizado o teste do Qui-quadrado (<= 0,05) e analise de regressao de Poisson, para estimar razoes de prevalencia, com intervalos com 95% de confianca. RESULTADOS: O uso na vida de drogas ilicitas foi quatro vezes mais prevalente entre os estudantes que relataram o binge drinking (IC95% 3,19-5,45). Estar na faixa etaria de 16 a 19 anos, ser do sexo masculino e nao ter religiao tambem foram significativamente associados ao uso de drogas ilicitas. CONCLUSOES: A prevalencia do uso de drogas ilicitas na vida foi superior a outros estudos realizados no Brasil e esteve fortemente associado ao binge drinking. Esse fator mostrou associacao com genero, idade e religiao. PMID- 28876413 TI - Experimentation with psychoactive substances by public school students. AB - OBJECTIVE: To analyze the prevalence of exposure to psychoactive substances in public students of basic education and its association with sociodemographic characteristics. METHODS: This is a cross-sectional survey conducted from March to September 2015, involving 1,009 students of the basic and high school education in 20 public schools in the municipality of Aracaju, State of Sergipe, Brazil. The data have been compiled using questionnaires previously applied in national studies of the Brazilian Center for Psychotropic Drugs. The variables have been dichotomized for later logistic regression using the Chi-square test to analyze associations between experimentation with psychoactive substances and other sociodemographic variables; odds ratio and confidence intervals have also been calculated. The level of significance adopted was 5%. RESULTS: We have identified that 69.6% of the students have experimented alcohol and 12.4% cigarettes. Age (>= 15 years) has shown a significant association with experimentation with alcohol (p < 0.001) and cigarettes (p = 0.02), acting as risk factor in both cases (OR = 2.34 and 1, 78, respectively), but it acted as a protective factor for the use of inhalants (p = 0.03 and OR = 0.58) and weight loss medication (p = 0.006 and OR = 0.44). Religious practice had a significant association with experimentation with alcohol (p = 0.01), functioning as a protective factor (OR = 0.56). CONCLUSIONS: We have concluded that the psychoactive substance most experienced by students was alcohol, followed by cigarettes, and chance for experimentation increases after the age of 15. Religious practice, in turn, acts as a protective factor for experimentation with alcohol. OBJETIVO: Analisar a prevalencia de exposicao a substancias psicoativas em estudantes do ensino basico de escolas publicas e sua associacao com caracteristicas sociodemograficas. METODOS: Trata-se de um inquerito transversal realizado de marco a setembro de 2015, envolvendo 1.009 alunos do ensino fundamental e medio em 20 escolas publicas de Aracaju, Sao Cristovao e Nossa Senhora do Socorro. Os dados foram compilados por meio de questionarios aplicados anteriormente em estudos nacionais do Centro Brasileiro de Drogas Psicotropicas. As variaveis foram dicotomizadas para posterior regressao logistica com aplicacao do teste Qui-quadrado para analisar associacoes entre a experimentacao de substancias psicoativas e outras variaveis sociodemograficas, e calculada a razao de chances e seus intervalos de confianca. O nivel de significancia adotado foi de 5%. RESULTADOS: Identificamos que 69,6% dos estudantes tem experimentado alcool e 12,4% cigarro. A idade dos alunos (>= 15 anos) mostrou associacao significativa com a experimentacao de alcool (p < 0,001) e cigarros (p = 0,02), atuando como fator de risco em ambos os casos (OR = 2,34 e 1,78, respectivamente), mas atuando como fator de protecao para o uso de inalantes (p = 0,03 e OR = 0,58) e remedios para emagrecer (p = 0,006 e OR = 0,44). A pratica religiosa apresentou associacao significativa com a experimentacao de alcool (p = 0,01), funcionando como um fator de protecao (OR = 0,56). CONCLUSOES: Conclui-se que a substancia psicoativa mais experimentada pelos estudantes foi o alcool, seguida do cigarro, e que a chance de experimentacao aumenta a partir dos 15 anos. A pratica religiosa, por sua vez, atua como fator de protecao a experimentacao do alcool. PMID- 28876412 TI - Psychological model of ART adherence behaviors in persons living with HIV/AIDS in Mexico: a structural equation analysis. AB - OBJECTIVE: The objective of this study has been to test the ability of variables of a psychological model to predict antiretroviral therapy medication adherence behavior. METHODS: We have conducted a cross-sectional study among 172 persons living with HIV/AIDS (PLWHA), who completed four self-administered assessments: 1) the Psychological Variables and Adherence Behaviors Questionnaire, 2) the Stress-Related Situation Scale to assess the variable of Personality, 3) The Zung Depression Scale, and 4) the Duke-UNC Functional Social Support Questionnaire. Structural equation modeling was used to construct a model to predict medication adherence behaviors. RESULTS: Out of all the participants, 141 (82%) have been considered 100% adherent to antiretroviral therapy. Structural equation modeling has confirmed the direct effect that personality (decision-making and tolerance of frustration) has on motives to behave, or act accordingly, which was in turn directly related to medication adherence behaviors. In addition, these behaviors have had a direct and significant effect on viral load, as well as an indirect effect on CD4 cell count. The final model demonstrates the congruence between theory and data (x2/df. = 1.480, goodness of fit index = 0.97, adjusted goodness of fit index = 0.94, comparative fit index = 0.98, root mean square error of approximation = 0.05), accounting for 55.7% of the variance. CONCLUSIONS: The results of this study support our theoretical model as a conceptual framework for the prediction of medication adherence behaviors in persons living with HIV/AIDS. Implications for designing, implementing, and evaluating intervention programs based on the model are to be discussed. PMID- 28876414 TI - Validity of questions about activities of daily living to screen for dependency in older adults. AB - OBJECTIVE: To determine the criterion validity of the activities of daily living present in functionality questionnaires in older adults for population surveys and to identify which activities are valid to quantify the real daily need for help of this population. METHODS: This is a population sample of older adults stratified by levels of functionality, according to self-perception of dependency in the activities of daily living. Self-perception was compared with the gold standard - direct observation of these activities in the household of older adults by a trained professional, blinded to the answers in the questionnaire. At the visit, it was decided if the older adult needed help to perform any of the activities of daily living for the research. The sensitivity of each activity of daily living was greater when the self-assessment that there was no need for help coincided with the assessment of the professional. Specificity indicates coincidence regarding the need for help in the activities of daily living - coefficients of sensitivity and specificity above 70% were considered as indicative of good validity. RESULTS: Self-assessments showed better sensitivity than specificity - older adults and observers agreed more on daily independency than on dependency. All activities showed sensitivity above 70%. Some activities had low (go shopping: 55%) or very low specificity (brush the hair: 33%). The best specificities were to take a shower and dress up (95.8% for both), among the personal ones, and to use transportation and perform banking transactions (78% for both), among the instrumental ones. CONCLUSIONS: Activities of daily living can be valid indicators of functional dependence. The best coefficients of validity were generally obtained for personal activities. Some activities with good sensitivities and specificities - walk 100 meters, take a shower, and lie down in and get out of the bed - can be used to classify older adults into low, average, and high need for help depending on the affected activities and, therefore, can help in the planning of health services aimed at them. OBJETIVO: Determinar a validade de criterio das atividades de vida diaria constantes em questionarios de funcionalidade em idosos para inqueritos populacionais e identificar quais atividades sao validas para quantificar a necessidade real de ajuda diaria dessa populacao. METODOS: Amostra populacional de idosos estratificada por niveis de funcionalidade, segundo a autopercepcao de dependencia nas atividades de vida diaria. Autopercepcao foi comparada com o padrao ouro - observacao direta no domicilio dos idosos nessas atividades por profissional treinado e cego para respostas no questionario. Na visita decidiu se, para efeito da pesquisa, se o idoso precisava de ajuda para realizar alguma das atividades de vida diaria. A sensibilidade de cada atividade de vida diaria foi maior quando a autoavaliacao de que nao havia necessidade de ajuda coincidiu com a avaliacao do profissional. A especificidade indica coincidencia quanto a necessidade de ajuda na atividades de vida diaria - coeficientes de sensibilidade e especificidade acima de 70% foram considerados indicativos de boa validade. RESULTADOS: As autoavaliacoes mostraram sensibilidade melhor que especificidade - idosos e observadores concordaram mais quanto a independencia do que quanto a dependencia cotidiana. Todas as atividades mostraram sensibilidade acima de 70%. Algumas atividades tiveram uma especificidade baixa (fazer compras: 55%) ou muito baixa (pentear os cabelos: 33%). As melhores especificidades foram tomar banho e vestir-se (95,8% ambas), entre as pessoais, e utilizar transporte e realizar movimento bancario (ambas com 78%), entre as instrumentais. CONCLUSOES: Atividades de vida diaria podem ser indicadores validos de dependencia funcional. Os melhores coeficientes de validade em geral foram obtidos pelas atividades pessoais. Destacam-se algumas atividades com boas sensibilidades e especificidades - andar 100 metros, tomar banho e levantar/deitar na cama - que podem servir para classificar os idosos em baixa, media e alta necessidade de ajuda dependendo das atividades afetadas e, dessa forma, auxiliar no planejamento dos servicos de saude voltados aos idosos. PMID- 28876415 TI - Chronic lymphadenopathy caused by a Brazilian strain of Bartonella henselae. AB - Bartonella henselae is a relevant causative agent of bartonelloses in humans. We described an immunocompetent patient with clinical manifestation of chronic cervical lymphadenopathy after a cat-scratch in her forearm. This case shows B. henselae infection persistence even after prolonged antibiotic treatment. PMID- 28876416 TI - Considerations of potential vectors and animal reservoirs in an emerging cutaneous leishmaniasis area in Sao Domingos ranch, Parana State in Southearn Brazil. AB - The aim of this study was to better understand the dynamics of Leishmania sand flies and reservoirs in Sao Domingos ranch, Arapongas municipality, Parana State, an anthropic environment in an endemic area of cutaneous leishmaniasis (CL). Sand flies were collected in wild animal burrows, residences and in the forest, with Falcao light trap (FA), Shannon trap (SH) and quadrangular pyramidal trap (QP). The search for Leishmania was made on sand flies, biological samples of wild rodents and dogs using PCR and culture; while parasite direct search (DS) was carried out on animal skin lesions; infection of gold hamsters; and indirect immunofluorescence (IIF) test in dog blood samples. Eighty eight (88) sand flies were collected with FA traps and 526 sand flies using the SH trap, with a predominance of Pintomyia fischeri. Six hundred and one (601) specimens of Brumptomyia brumpti were collected in armadillo burrows, with the QP trap. Seventeen (17) wild rodents were captured, six of them had skin lesions with characteristics of Leishmania infection. Even though no positive test was found for Leishmania, epidemiological surveillance should be maintained, remembering that the human buildings are situated only 50 m from the forest. Considering the species of wild animals and sandflies found in Sao Domingos, the negative test found do not exclude the existence of the Leishmania transmission cycle in this preservation area. PMID- 28876417 TI - Prospective study of patients with persistent symptoms of dengue in Brazil. AB - Dengue is an arboviral infection clinically recognized as an acute and self limited disease. Persistence of dengue symptoms is known, but it has been little studied. The aim of this study was to characterize persistent symptoms in 113 patients with dengue followed up clinically and by laboratory testing at a tertiary hospital. Symptoms that persisted for more than 14 days were observed in 61 (54.0%) patients, and six (6.2%) of them had symptoms for 6 months or more. The persistent symptoms identified were myalgia, weakness, hair loss, memory loss, reduced resistance to physical effort, headache, reasoning problems, arthralgia, sleepiness- and emotional lability. The progression to persistent symptoms was significantly associated with hospitalization, older age, more severe disease, the presence of bleeding and comorbidities upon univariate analysis. Upon multivariate analysis, the presence of persistent symptoms continued to be significantly associated only with increased age and dengue with warning signs. The platelet count during the acute phase of the disease was significantly lower in the group with persistent symptoms. In conclusion, the frequency of progression to persistent symptoms in dengue is relevant in patients seen at a tertiary hospital and the persistence of symptoms is more common in patients with dengue with warning signs. PMID- 28876418 TI - A conventional PCR for differentiating common taeniid species of dogs based on in silico microsatellite analysis. AB - Canine taeniids are among the major tapeworms with remarkable medical and economic significance. Reliable diagnosis and differentiation of dog taeniids using simple and sensitive tools are of paramount importance for establishing an efficient surveillance system. Microsatellites as abundant unique tandem repeats of short DNA motifs are useful genetic markers for molecular epidemiological studies. The purpose of the present study was to find a primer pair for rapid differentiation of major tapeworms of dogs, Taenia hydatigena, T. multiceps, T. ovis and Echinococcus granulosus, by screening existing nucleotide data. All the mitochondrial genome records as well as non-coding ITS1 sequences of Taeniidae species were downloaded from Nucleotide database from NCBI. For prediction and analysis of potential loci of STR/SSR in ITS1 as well as mitochondrial regions, we used ChloroMitoSSRDB 2.0 and GMATo v1.2. software. Different tapeworm species were categorized according to different motif sequences and type and size of each microsatellite locus. Three primer sets were designed and tested for differentiating taeniid species and evaluated in a conventional PCR system. Four taeniid species were successfully differentiated using a primer pair in a simple conventional PCR system. We predicted 2-19 and 1-4 microsatellite loci in ITS1 and mitochondrial genome, respectively. In ITS1, 41 Di and 21 Tri motifs were found in the taeniids while the majority of the motifs in the mitochondrial genome were Tetra (89) and Tri (70). It is documented that the number and diversity of microsatellite loci is higher in nuclear ITS1 region than mostly coding mitochondrial genome. PMID- 28876419 TI - Penile prosthesis implantation: A solution or a dilemma for the couple. PMID- 28876420 TI - Treatment of bone and soft tissue tumors of the limbs with conformal radiotherapy and intensity-modulated radiotherapy (IMRT). PMID- 28876421 TI - Secondary syphilis: The great imitator can't be forgotten. AB - Syphilis is an infection caused by Treponema pallidum, mainly transmitted by sexual contact. Since 2001, primary and secondary syphilis rates started to rise, with an epidemic resurgence. The authors describe an exuberant case of secondary syphilis, presenting with annular and lichen planus-like lesions, as well as one mucocutaneous lesion. Physicians must be aware of syphilis in daily practice, since the vast spectrum of its cutaneous manifestations is rising worldwide. PMID- 28876422 TI - Gastric cancer with lesion extending to spleen and perforation into free peritoneum. AB - Perforated gastric carcinoma is a rare condition that is hard to diagnose preoperatively. It is associated with advanced cancer stages and has a high mortality, particularly in cases presenting preoperative shock. Few studies have investigated the presentation and adequate management of these carcinomas. In addition, there are no reports in the literature on perforations extending to the spleen, as described in this case, making the management of these lesions challenging. Our article reports a case of gastric tumor perforation extending to the spleen, which presented as a perforated acute abdomen. The patient was treated with total gastrectomy and D2 lymph node resection with splenectomy and progressed well with current survival of one year at disease stage IV. PMID- 28876423 TI - Thrombosed aneurysm of saphenous vein coronary artery bypass grafting. AB - We describe the case of a male patient, aged 76 years, referred for cardiac investigation due to retrosternal chest pain and dyspnea. He had a history of acute myocardial infarction and angioplasties in the last 30 years, including a saphenous vein coronary artery bypass grafting (SVCABG). Echocardiogram showed hypoechoic oval formation near the right ventricle, suggesting a pericardial cyst. Computed angiotomography revealed a predominantly fusiform and thrombosed aneurysmal dilation of the SVCABG to the right coronary artery. SVCABG aneurysms are very rare and potentially fatal. They usually appear in the late postoperative period, and patients are often asymptomatic. On radiography, it is frequently presented as enlargement of the mediastinum, with echocardiography, computed tomography and magnetic resonance imaging being very useful for diagnosis. Coronary angiography is the gold standard to detect these cases. Our report illustrates a rare situation arising late from a relatively common surgery. Due to its severity, proper recognition in the routine assessment of patients with a similar history is essential. PMID- 28876424 TI - Evaluation of medical interns' attitudes towards relevant aspects of medical practice. AB - Introduction:: In traditional medical school curriculum, sixth-year is the moment in which students experience medical practice more intensively. Attitudes can be considered predictors of behaviors and actions. Evaluating them contributes to improve medical training. Objective:: To evaluate attitudes during medical internship considering medical practice and associated factors in a Brazilian public university. Method:: Cross-sectional study that included 69 students, based on a structured questionnaire and an attitude scale (Colares, 2002). We used descriptive statistics, with classification of the attitude tendency, clusters analysis and F-statistics. Results:: The average age of the participants was 25.1+/-1.9, and 56.5% of them were male. Students presented positive attitudes to emotional aspects in organic diseases, primary health care, the medical contribution to the scientific advancement of medicine, and other aspects of medical activity and health politics; there were conflicting attitudes concerning mental illness and negative attitudes concerning death. Conclusion:: Results show the need for interventions in order to reduce the identified conflicting and negative attitudes. PMID- 28876425 TI - Concomitant testicular infection by Zika virus and Schistosoma mansoni in a Brazilian young boy. AB - Sumary The identification of a escrotal mass without pain or report of trauma should be investigated to rule out scrotal cancer. We report the case of a young Brazilian boy who underwent orchiectomy after magnetic resonance imaging (MRI) and duplex scan (DS) indicating a high possibility of cancer. Blood exams ruled out the possibility of cancer. Testicular biopsy was not indicated. After surgery the diagnostic was extensive orchiepididymitis by Schistosoma. In endemic areas orchiepididymis by Schistosoma should be investigate to avoid unnecessary surgeries. This patient was also infected with Zika virus. PMID- 28876426 TI - Factors associated with burnout syndrome in medical residents of a university hospital. AB - Objective:: To determine the prevalence of burnout syndrome among resident physicians of various specialties and to evaluate associated factors. Method:: The Maslach Burnout Inventory questionnaire and a sociodemographic questionnaire were used to evaluate factors associated with the syndrome. Burnout was defined as the association of high emotional exhaustion, depersonalization and low professional achievement. Multivariate analysis was performed after adjustment of the Poisson model with the identification of risk factors and calculation of prevalence ratios (PR). Of the 250 resident physicians registered with Hospital das Clinicas of Pernambuco, 129 participated in the study. Results:: In the three domains that characterize burnout syndrome, we found a low level of professional achievement in 94.6% of resident physicians interviewed, a high level of depersonalization in 31.8%, and 59.7% with a high level of emotional exhaustion. The prevalence of burnout was 27.9%. Having suffered a stressful event in the last six months (PR: 8.10; 95CI 1.2-57.2) and being a student of surgical specialty (PR: 1.99; 95CI 1.2-3.3) were independently associated with burnout. Conclusion:: The prevalence of burnout found in resident physicians is in accordance with previous Brazilian studies. Residents of surgical specialties and those who suffered some stressful event were identified as susceptible in this study. The early identification of risk factors is fundamental for the implementation of preventive measures against burnout syndrome. PMID- 28876427 TI - Geographical distribution of medical graduates from a public university. AB - Objective:: To evaluate the geographic distribution and career trajectory of medical graduates and the factors associated with their choice of practice location. Method:: A cross-sectional study involving graduates from December 2001 to December 2010 was conducted. A self-administered questionnaire collected demographics and geographic information (place of birth, place of residence at the time of medical school admission, place of residency training and practice location), and reason for choosing the current location. Statistical analyses assessed trends in geographic distribution of graduates, and identified factors associated with location choice (through the population density of the location chosen for professional practice). Results:: A total of 563 graduates completed the questionnaire. Of those, 4.3% (n=24) reported family medicine as their medical specialty, 19.9% (n=112) reported other primary care specialties (internal medicine, pediatrics, surgery and obstetrics-gynecology) and the others chose subspecialties. Larger cities were more likely to be chosen for practice, particularly for newly-graduated doctors. Job invitations received during medical residency training increased the likelihood of choosing high-populated cities. In contrast, job invitations received during medical school increased the likelihood of choosing cities less populated. Amongst those in cities with lower population density, proximity to family members was an additional influencing factor; those who chose more densely populated cities did so because of better infrastructure and recreational options. Conclusion:: Most of the physicians included in this study pursue subspecialties training and were practicing medicine in large cities. Knowing the multiple factors that influenced the choice of practice location can assist in planning future strategies to reduce physician workforce misdistribution. PMID- 28876428 TI - Diagnostic and prognostic performances of serum procalcitonin in patients with bloodstream infections: A parallel, case-control study comprising adults and elderly. AB - Objective:: To examine the diagnostic and prognostic performances of serum procalcitonin (PCT) in adult and elderly patients with bloodstream infections (BSIs). Method:: A total of 176 patients with culture-proven BSIs and 200 healthy counterparts were studied prospectively. Participants were studied in two adult (age<=65 years, n=92) and elderly (age>65 years, n=84) groups. Admission serum PCT level was measured using a standard enzyme-linked immunosorbent assay (ELISA) technique. Results:: The mean serum PCT level (in ng/mL) was significantly higher in cases than in controls (0.18 vs. 0.07, p=0.01 in adults; 0.20 vs. 0.07, p=0.002 in elderly). At cut-off values of 0.09 ng/mL in adults and 0.08 ng/mL in the elderly, the corresponding sensitivity and specificity were 82.6 and 82.0% in adults, and 69.1 and 70.0% in elderly, respectively. At a cut-off value of 0.2 ng/mL, the sensitivity and specificity of serum PCT in predicting 28-day mortality were 81 and 81.7% in adults, and 75 and 80.4% in elderly, respectively. Conclusion:: Although admission serum PCT is a sensitive and specific biomarker for the diagnosis of BSIs in patients younger than 65 years old, its short-term prognostic value is comparable between adults and the elderly. PMID- 28876429 TI - Mueller-Hillis maneuver and angle of progression: Are they correlated? AB - Objective:: Mueller-Hillis maneuver (MHM) and angle of progression (AOP) measured by transperineal ultrasound have been used to assess fetal head descent during the second stage of labor. We aimed to assess whether AOP correlates with MHM in the second stage of labor. Method:: A prospective observational study including women with singleton pregnancy in the second stage of labor was performed. The AOP was measured immediately after the Mueller-Hillis maneuver. A receiver operating characteristics (ROC) curve analysis was performed to determine the best discriminatory AOP cut-off for the identification of a positive MHM. A p value less than 0.05 was considered statistically significant. Results:: One hundred and sixty-six (166) women were enrolled in the study and 81.3% (n=135) had a positive MHM. The median AOP was 143o (106o to 210o). The area under the curve for the prediction of a positive maneuver was 0.619 (p=0.040). Derived from the ROC curve, an AOP of 138.5o had the best diagnostic performance for the identification of a positive MHM (specificity of 65% and a sensitivity of 67%). Conclusion:: An AOP of 138o seems to be associated with a positive MHM in the second stage of labor. PMID- 28876430 TI - Thrombocytopenia as a marker of liver steatosis in a low-endemic area for schistosomiasis mansoni. AB - Introduction:: Thrombocytopenia is commonly found in patients living in highly endemic areas for Schistosoma mansoni. Recently, different degrees of liver steatosis have also been associated with low platelet counts worldwide. We investigated the association of platelet counts with hepatosplenic schistosomiasis and with liver steatosis in an area of low prevalence of schistosomiasis in Brazil. Method:: Pains, a city in the state of Minas Gerais, Brazil, had a population of 8,307 inhabitants and a schistosomiasis prevalence of 8%. Four micro-areas comprising 1,045 inhabitants were selected for this study. Blood sample was collected and a complete blood count (CBC) was performed. Eighty seven (87) patients had low platelet counts (group 1 - 8.3%) and 94 volunteers presenting normal CBC were randomized (group 2 - 8.9%). They underwent clinical and ultrasound examinations. Liver steatosis was determined as either present or absent using abdominal ultrasound. A spleen > 12 cm in length, measured by ultrasound (US), was considered to be increased. Data collected were analyzed using SPSS software version 19.0. Results:: Twenty-two patients (22/25.3%) in group 1 had liver steatosis compared with 11 volunteers (11.7%) in group 2 (p=0.02). Hepatosplenic schistosomiasis was diagnosed in two patients (p>0.05). Conclusion:: Thrombocytopenia was not a good marker of hepatosplenic schistosomiasis mansoni in a low prevalence area in Brazil. Liver steatosis was associated with thrombocytopenia in our study. PMID- 28876431 TI - Analysis of the availability of the resources necessary for urgent and emergency healthcare in Sao Paulo between 2009-2013. AB - Introduction:: The Regulatory Complex is the structure that operationalizes actions for making resources available to meet the needs of urgent and emergency care in the municipality of Sao Paulo. In the case of urgent care, needs are immediate and associated with high morbidity and mortality. Objective:: To identify the most frequently requested resources, the resolution capacity and the mortality rate associated with the unavailability of a certain resource. Method:: Our study was based on data from medical bulletins issued by the Urgent and Emergency Regulation Center (CRUE) in the city of Sao Paulo from 2009 to 2013. Results:: 91,823 requests were made over the five years of the study (2009 to 2013). Neurosurgery requests were the most frequent in all years (4,828, 5,159, 4,251, 5,008 and 4,394, respectively), followed by computed tomography (CT) scans, adult intensive care unit (ICU) beds, cardiac catheterization, and pediatric ICU beds. On average, requests for neurosurgery, adult ICU, pediatric ICU, CT scans, catheterization and vascular surgery were answered in 70%, 27%, 39%, 97%, 87% and 77% of cases. The total number of deaths relating to requests for neurosurgery, CT scans, adult ICU, pediatric ICU, catheterization and vascular surgeon assessment were 182, 9, 1,536, 1,536, 135, 49 and 24 cases, respectively. Conclusion:: There is a lack of resources to meet urgent and emergency needs in the city of Sao Paulo. PMID- 28876432 TI - Hospitalization due to exacerbation of COPD: "Real-life" outcomes. AB - Introduction:: Hospitalization due to chronic obstructive pulmonary disease exacerbation (eCOPD) may indicate worse prognosis. It is important to know the profile of hospitalized patients and their outcome of hospitalization to customize and optimize treatment. Method:: Evaluation of patients hospitalized for eCOPD, with >= 10 pack/years and >= 1 previous spirometry with airway obstruction over the course of one year at the pulmonology service of a general hospital, applying: COPD assessment test (CAT); mMRc and Visual Analogue Scale (VAS) for dyspnea; hospitalized anxiety and depression questionnaire (HAD); Divo's comorbidities and Cote index; spirometry; and laboratory tests including number of eosinophils, C-reactive protein (CRP), brain natriuretic protein (BNP). Patient progression, number of days of hospitalization and hospitalization outcomes were observed. Results:: There were 75 (12%) hospitalizations for eCOPD, with 27 readmissions, nine of which during a period <= 30 days after hospital discharge. The main outcomes were: number of days of hospitalization (17+/-16.5 [2-75]); hospital discharge (30 [62.5%] patients); discharge/rehospitalization (18 [37.5%] patients), eight of them more than once; death (7 [14.5%] patients), five during rehospitalization. We analyzed 48 patients in their first hospitalization. The sample comprised a heterogeneous group separated in three clusters according to age, FEV1, body mass index (BMI) and CAT. The clusters did not correlate with the main outcomes. Conclusion:: Hospitalization for eCOPD is frequent. The number of readmissions was high and associated with death as an outcome. Patients hospitalized for eCOPD were a heterogeneous group separated in three clusters with different degrees of disease severity and no correlation with hospitalization outcomes. PMID- 28876433 TI - Association between physical activity and vitamin D: A narrative literature review. AB - This narrative review of the medical literature assessed whether outdoor and indoor physical activity would increase the plasma levels of vitamin D. Synthesis of this liposoluble vitamin is mainly mediated by sunlight on the skin, where it is activated to perform its main action, which is to control the serum levels of calcium as soon as the element is absorbed in the intestines, assisting in the regulation of bone metabolism. Physical activity is any body movement that results in energy expenditure, while outdoor physical activity refers to physical activity carried out at public parks or other open spaces, as is the case of the popular practice of taking walks. Exercising outdoors would have both the benefits of physical activity and of sun exposure, namely the synthesis of vitamin D. However, according to the studies analyzed, increased plasma concentration of vitamin D occurs with physical activity both indoors and outdoors. PMID- 28876434 TI - A Century of Progressing and Advancing Reproductive Health Care: The 2017 Lasker Bloomberg Public Service Award. PMID- 28876436 TI - Do Schools of Nursing Truly Value Excellence in Teaching? Actions Speak Louder Than Words. PMID- 28876435 TI - Preventing Cancer and Other Diseases Caused by Human Papillomavirus Infection: 2017 Lasker-DeBakey Clinical Research Award. PMID- 28876437 TI - Predictors of Persistence and Success in an Accelerated Online RN-to-BSN Program. AB - BACKGROUND: To meet the increasing demand for RNs to further their education, many colleges of nursing have developed RN-to-baccalaureate nursing (BSN) programs, many of which are delivered online. A better understanding of the demographic and academic characteristics and outcomes of individuals enrolled in online RN-to-BSN programs is needed. METHOD: This article reports a retrospective predictive analysis of 9,567 students enrolled in an online RN-to-BSN program. Outcome variables examined were graduation, timely graduation, and discontinuation. RESULTS: Younger students who received financial aid and had a previous baccalaureate degree reflected the demographic profile associated with the highest likelihood of graduating and graduating sooner. Fewer failed and withdrawn courses also predicted graduation and retention. CONCLUSION: Implications of these findings are that when online programs are designed with persistence in mind, progression to graduation in such programs can be consistent with national benchmarks. The creation of an early identification process for at risk students would have the potential to enhance educational outcomes even further. [J Nurs Educ. 2017;56(9):522-526.]. PMID- 28876438 TI - Influence of Short-Term Study Abroad Experiences on Community Health Baccalaureate Students. AB - BACKGROUND: Very short study abroad programs may be most feasible in undergraduate nursing programs, but little research describes their value for prospective nurses. The narratives of senior baccalaureate nursing students (N = 62) who traveled for 2 weeks to Cape Coast, Ghana, between semesters for a faculty-led community health clinical experience were analyzed. METHOD: Students responded to pre- and posttravel semi-structured, open-ended prompts regarding expectations and perceptions of culture, health, and happiness. Data were analyzed using a qualitative descriptive approach. RESULTS: Four themes emerged related to perceptions of culture, relationships with community, definitions of health and happiness, and adaptability and innovation. African American students' (n = 3) responses highlighted unique themes regarding personal identity. CONCLUSION: Student perceptions of culture demonstrated progression through previously described stages of cultural competence. Relatively novel themes regarding community relationships, perceptions of health and happiness, and adaptability suggest additional value of this short-term study abroad experience for nursing students. [J Nurs Educ. 2017;56(9):528-533.]. PMID- 28876440 TI - Factors Associated With First-Time NCLEX-RN Success: A Descriptive Research Study. AB - BACKGROUND: The purpose of this study was to identify variables associated with scores achieved on the Health Education Systems, Inc. (HESI) exit examination and successful first-time NCLEX-RN(r) pass rates. METHOD: A retrospective descriptive study examined the administrative data of 211 baccalaureate nursing students. RESULTS: Students who completed the program in sequence and scored higher in certain HESI course examinations were more likely to have a better performance on the HESI exit examination. The higher the scores students achieved on the HESI exit examination, the more likely they were to pass the NCLEX-RN on their first attempt. CONCLUSION: These findings add to the growing body of literature seeking to identify variables associated with success in first-time NCLEX-RN success. Further research is needed to identify strategies that can be implemented to ensure timely progression, program completion, and licensure examination success. [J Nurs Educ. 2017;56(9):542-545.]. PMID- 28876439 TI - Evidence-Based Practice in Clinical Nursing Education: A Scoping Review. AB - BACKGROUND: Nursing students require education that integrates evidence-based practice (EBP) knowledge across classroom and clinical settings. This study was conducted to identify and examine the literature related to nursing students' use of evidence in clinical education and to identify associated research gaps. METHOD: A scoping review describing the extent, range, and nature of the research activity focused on students' use of evidence in clinical education. RESULTS: Included studies (N = 37) describe the barriers and facilitators to nursing students' EBP and describe the evaluation of strategies that support nursing students' engagement in EBP. Most commonly identified barriers include a lack of knowledge and skills for EBP; negative attitudes toward EBP in students, faculty, and nurses; and lack of support in the clinical setting. Evaluated strategies included educational sessions and EBP projects, either alone or in combination, as well as other stand-alone interventions. All but two of the intervention studies reported positive subjective or objective outcomes. CONCLUSION: On the basis of these results, educators can engage in combined educational strategies that focus on addressing described barriers. [J Nurs Educ. 2017;56(9):534-541.]. PMID- 28876441 TI - Comparing Professional Values of Sophomore and Senior Baccalaureate Nursing Students. AB - BACKGROUND: The 2015 American Nurses' Association Code of Ethics reinforces professional values in nursing, and nurse educators may need evidence of their students' professional development. METHOD: Using the Nurses Professional Values Scale-Revised (NPVS-R), researchers examined two questions: What is the relative importance of professional values (i.e., caring, trust, justice, activism, and professionalism) for beginning and graduating baccalaureate nursing students, and are there differences in professional values between these students? RESULTS: New and graduating nursing students in the current study had well-developed professional values. Sophomore-level nursing students viewed trust, caring, and justice as significantly more important than activism. Senior-level students perceived trust as significantly more important than activism and professionalism. Although total NPVS-R scores did not differ significantly between cohorts, senior-level students did score significantly higher on activism than sophomore-level students. CONCLUSION: With the revised Code, nurse educators may reevaluate the ethics curriculum. This study suggests opportunity for strengthening values beyond the nurse-client relationship, such as activism and professionalism. [J Nurs Educ. 2017;56(9):546-550.]. PMID- 28876442 TI - Progressive Dosing of Observed Real-Life Clinical Exposure for Nurse Practitioner Training. AB - BACKGROUND: In most advanced practice programs, preceptors are relied on for providing student clinical experiences. Preceptor feedback often indicates that many students show competency deficits in well child care, case presentation, and clinical skills. METHOD: An innovative preclinical experience was developed using nonscripted pediatric patient and family volunteers from the local community. During the three 4-hour experiences, students obtained a health history, performed a full physical examination, and presented their findings using a standardized case presentation format. Student anxiety and levels of confidence were assessed before and after each experience. RESULTS: Student anxiety decreased, and self-confidence and clinical skill competencies improved. Students who participated in the experiences with faculty demonstrated improved entry level competencies, compared with previous cohorts who had not received the intervention. CONCLUSION: Preclinical experiences using pediatric patients improved advanced practice nursing student confidence and competencies and reduced anxiety, improving overall entry-level clinical performance. [J Nurs Educ. 2017;56(9):552-555.]. PMID- 28876443 TI - Innovation in Learning: PhD and DNP Student Collaborations. AB - BACKGROUND: Working together, PhD and Doctor of Nursing Practice (DNP) students can advance knowledge creation and the translation of knowledge into practice. Although different in purpose and education, PhD and DNP programs should prepare students to collaborate throughout their careers. This article describes an innovative pilot project that partnered PhD and DNP students during their graduate programs. METHOD: Group meetings were used to facilitate collaboration among 12 PhD and DNP students interested in pain management. Using a five-stage collaboration process model, students worked together on dissertation and capstone projects. RESULTS: PhD and DNP students collaborated on the completion of dissertation and capstone projects, as well as on publications and presentations. A case example of an effective partnership is included. CONCLUSION: Partnering of PhD and DNP students can further the development of new nursing knowledge and evidence-based practice. Successful collaboration can be facilitated by PhD and DNP faculty. [J Nurs Educ. 2017;56(9):556-559.]. PMID- 28876444 TI - Innovative Use of Service-Learning to Enhance Baccalaureate Nursing Education. AB - BACKGROUND: Service-learning is an established pedagogical approach to nursing education found primarily in community nursing. With changing health care landscapes, the expansion of service-learning projects throughout the nursing program provides opportunities to enrich assessment and critical thinking and amplify exposure to determinants of health. METHOD: Implementing service-learning in foundational nursing courses allows students to be challenged with the application of complex care management within a context of caring, cultural competence, social responsibility, and self-care initiatives. RESULTS: Integrating service-learning throughout the nursing curriculum has the potential to make positive, sustainable changes within a community, while simultaneously preparing students to view clients holistically, think critically, and develop cultural competence. CONCLUSION: Enhancing nursing curriculum by integrating service-learning opportunities can strengthen the learning experience and foster concepts of caring, social responsibility, cultural competence, and self-care. Working with community leaders from diverse groups can lead to sustainable projects that simultaneously benefit the community and nursing education. [J Nurs Educ. 2017;56(9):560-563.]. PMID- 28876445 TI - The Companion Dissertation: Enriching the Doctoral Experience. AB - BACKGROUND: The completion of a doctoral dissertation has traditionally been an individual journey. Innovative approaches, such as the companion dissertation, are helping to shape doctoral education. The companion dissertation is a collaborative inquiry among two or more doctoral students who share mutual research interests. METHOD: Lack of innovative approaches to doctoral dissertation completion led to the development of a companion dissertation. Generative leadership, specifically focused on processes that influence interaction, served as a useful framework to support this form of innovation. RESULTS: The companion dissertation process yielded consideration of differing perspectives, richer data, stronger data analysis, and robust research outcomes. Most important, this approach to research fostered student-to-student connectedness, which was essential to dissertation completion. CONCLUSION: Currently, the attrition rate for PhD students is approximately 30%. Therefore, it becomes imperative to consider innovative approaches to completion of the dissertation process. [J Nurs Educ. 2017;56(9):564-566.]. PMID- 28876446 TI - Use of Simulation to Integrate Cultural Humility Into Advanced Health Assessment for Nurse Practitioner Students. AB - BACKGROUND: Increasing cultural humility among nursing students requires the application of knowledge and skills. The integration of an Objective Structured Clinical Examination (OSCE) offered nurse practitioner students practice in simulation. METHOD: This learning activity included pre- and postassessments of knowledge regarding cultural issues and level of student satisfaction. Course content included an exemplar video and a simulation interview with an African American standardized patient. RESULTS: Of the 65 students enrolled, 97% completed OSCE interviews and 81% completed pre- and postsurveys. A 2-domain 3 * 2-time within-subjects ANOVA indicated a statistically significant interaction effect, reinforced by descriptive statistics. Follow-up paired t tests detected a significantly large knowledge increase. Standardized patient scenarios scored highest for satisfaction, followed by critical thinking, and with self-confidence scoring lowest. CONCLUSION: The favorable knowledge outcomes from this teaching intervention support future applications of OSCE methodology for teaching sensitive cross-cultural content. [J Nurs Educ. 2017;56(9):567-571.]. PMID- 28876448 TI - Engaging Postgraduate Students Undertaking Clinical Pharmacology Using GoSoapBox for Problem-Based Learning. PMID- 28876447 TI - Mask-Ed: Breaking the Barrier of Fear of Intimate Care for Nursing Students. AB - BACKGROUND: Nursing students learn to toilet, shower, and dress patients in the clinical laboratory with simulation modalities that lack the realism necessary to address the fears, values, and beliefs of nudity and intimate contact with patients. METHOD: A high-fidelity Mask-EdTM (KRS [Knowledgeable, Realistic, Spontaneous] simulation) intervention was developed and piloted with first-year nursing students around patient showering to increase confidence and skills around intimate care. RESULTS: Students initially felt intimidated, awkward, nervous, and anxious about showering patients; however, after the Mask-Ed simulation, 93% reported feeling more confident and having insight into the patient experience. The realism of the scenario was a contributing factor. CONCLUSION: Mask-Ed provides a platform for the educator to create realistic scenarios around intimate care that help students prepare, on many levels, for their initial clinical experiences. [J Nurs Educ. 2017;56(9):572-574.]. PMID- 28876449 TI - Two Minutes to Win It: Game for Knowledge and Skills Evaluation. PMID- 28876450 TI - What has become of critique? Reassembling sociology after Latour. AB - This paper offers a defence of sociology through an engagement with Actor Network Theory (ANT) and particularly the critique of 'critical' and politically engaged social science developed by Bruno Latour. It argues that ANT identifies some weaknesses in more conventional sociology and social theory, and suggests that 'critical' and 'public' orientated sociologists can learn from the analytical precision and ethnographic sensibilities that characterize ANT as a framework of analysis and a research programme. It argues, however, that Latour et al. have too hastily dispensed with 'critique' in favour of a value neutral descriptive sociology, and that the symmetrical and horizontalist approach adopted in ANT is particularly ill-suited to the development of scientific knowledge about social structures. It argues that a more straightforwardly realist sociology would share many of the strengths of ANT whilst being better able to interrogate, empirically and normatively, the centres of contemporary social power. PMID- 28876452 TI - Management of primary malignant bone and soft tissue tumors of foot and ankle: Is it worth salvaging? AB - BACKGROUND AND OBJECTIVE: Performing limb salvage with safe margins and preserving meaningful function is very difficult in the setting of primary malignant bone and soft tissue tumors due to the complex and constrained anatomy of the foot and ankle. The study aims to evaluate the efficacy of limb salvage procedures in terms of functional and oncological outcomes. METHODS: Clinical data of 48 patients, who underwent surgical treatment between 1992 and 2015 in our institution, were retrospectively analyzed. Twenty-one (43.7%) patients had unplanned resections elsewhere previously. Limb salvage surgery (LSS) was the index surgery in 43 (89.6%) patients. In the LSS group, 28 (65.1%) received preoperative radiotherapy and 13 (30.2%) underwent complex reconstruction. The functional outcomes were assessed with Musculoskeletal Tumor Society (MSTS) scores. Limb survival and oncological outcomes were evaluated according to Kaplan Meier curves. RESULTS: The mean follow-up time was 32.7 (3-115) months. Mild deformities and wound healing problems were the most common problems. While the functional scores were significantly higher in the LSS group, no significant difference was detected between amputation and LSS patients in terms of survival rates. CONCLUSION: LSS performed in specialized centers is an effective treatment method for malignant tumors of the foot and ankle. PMID- 28876451 TI - Selective HDAC6 inhibition decreases early stage of lupus nephritis by down regulating both innate and adaptive immune responses. AB - We have demonstrated previously that histone deacetylase (HDAC6) expression is increased in animal models of systemic lupus erythematosus (SLE) and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Additionally, we sought to delineate the cellular and molecular mechanism(s) of action of a selective HDAC6 inhibitor in SLE. We treated 20-week-old (early-disease) New Zealand Black (NZB)/White F1 female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for 5 weeks. As the mice aged, we determined autoantibody production and cytokine levels by enzyme-linked immunosorbent assay (ELISA) and renal function by measuring proteinuria. At the termination of the study, we performed a comprehensive analysis on B cells, T cells and innate immune cells using flow cytometry and examined renal tissue for immune-mediated pathogenesis using immunohistochemistry and immunofluorescence. Our results showed a reduced germinal centre B cell response, decreased T follicular helper cells and diminished interferon (IFN)-gamma production from T helper cells in splenic tissue. Additionally, we found the IFN-alpha-producing ability of plasmacytoid dendritic cells was decreased along with immunoglobulin isotype switching and the generation of pathogenic autoantibodies. Renal tissue showed decreased immunoglobulin deposition and reduced inflammation as judged by glomerular and interstitial inflammation. Taken together, these studies show selective HDAC6 inhibition decreased several parameters of disease pathogenesis in lupus-prone mice. The decrease was due in part to inhibition of B cell development and response. PMID- 28876453 TI - Reconstructing the microstructure of polyimide-silicalite mixed-matrix membranes and their particle connectivity using FIB-SEM tomography. AB - Properties of a composite material made of a continuous matrix and particles often depend on microscopic details, such as contacts between particles. Focusing on processing raw focused-ion beam scanning electron microscope (FIB-SEM) tomography data, we reconstructed three mixed-matrix membrane samples made of 6FDA-ODA polyimide and silicalite-1 particles. In the first step of image processing, backscattered electron (BSE) and secondary electron (SE) signals were mixed in a ratio that was expected to obtain a segmented 3D image with a realistic volume fraction of silicalite-1. Second, after spatial alignment of the stacked FIB-SEM data, the 3D image was smoothed using adaptive median and anisotropic nonlinear diffusion filters. Third, the image was segmented using the power watershed method coupled with a seeding algorithm based on geodesic reconstruction from the markers. If the resulting volume fraction did not match the target value quantified by chemical analysis of the sample, the BSE and SE signals were mixed in another ratio and the procedure was repeated until the target volume fraction was achieved. Otherwise, the segmented 3D image (replica) was accepted and its microstructure was thoroughly characterized with special attention paid to connectivity of the silicalite phase. In terms of the phase connectivity, Monte Carlo simulations based on the pure-phase permeability values enabled us to calculate the effective permeability tensor, the main diagonal elements of which were compared with the experimental permeability. In line with the hypothesis proposed in our recent paper (Capek, P. et al. (2014) Comput. Mater. Sci. 89, 142-156), the results confirmed that the existence of particle clusters was a key microstructural feature determining effective permeability. PMID- 28876454 TI - Oxaliplatin-induced increase in splenic volume; irreversible change after adjuvant FOLFOX. AB - BACKGROUND AND OBJECTIVES: Oxaliplatin can cause hepatic sinusoidal obstruction syndrome (SOS). SOS can cause chemotherapy-related adverse effects or morbidity after liver resection. Conventionally, SOS is diagnosed using liver biopsy. Recently, it was reported that increased splenic volume (SV) can be used to detect SOS. In this study, we evaluated the changes in SV during adjuvant chemotherapy. METHODS: We enrolled 103 consecutive patients with stage III and high-risk stage II colorectal cancer treated with mFOLFOX6 (n = 37) or oral fluorouracil and leucovorin (n = 66) after curative surgery. SV was measured three times; pre-operatively, after chemotherapy, and 1 year after chemotherapy. RESULTS: SV was higher after mFOLFOX6 (median 135.89 mL) than pre-operatively (105.75 mL) (P < 0.001); SV at 1-year after finishing mFOLFOX6 (114.16 mL) returned to the same level as before surgery (P = 0.0015). SV increased in 28 patients (75.7%) treated with mFOLFOX6 (95%CI, 61.8-89.5), but had not recovered in 12 of these cases (42.9%) 1 year after finishing treatment (95%CI, 17.3-47.5). In contrast, oral fluorouracil and leucovorin did not change SV. CONCLUSIONS: SV increased after adjuvant mFOLFOX6, and had not recovered in almost half of cases 1-year after finishing chemotherapy. This increase may indicate continuous SOS, which can adversely affect treatment after recurrence. PMID- 28876455 TI - The Age-Friendly Health System Imperative. AB - The unprecedented changes happening in the American healthcare system have many on high alert as they try to anticipate legislative actions. Significant efforts to move from volume to value, along with changing incentives and alternative payment models, will affect practice and the health system budget. In tandem, growth in the population aged 65 and older is celebratory and daunting. The John A. Hartford Foundation is partnering with the Institute for Healthcare Improvement to envision an age-friendly health system of the future. Our current prototyping for new ways of addressing the complex and interrelated needs of older adults provides great promise for a more-effective, patient-directed, safer healthcare system. Proactive models that address potential health needs, prevent avoidable harms, and improve care of people with complex needs are essential. The robust engagement of family caregivers, along with an appreciation for the value of excellent communication across care settings, is at the heart of our work. Five early-adopter health systems are testing the prototypes with continuous improvement efforts that will streamline and enhance our approach to geriatric care. PMID- 28876456 TI - Management of disappearing lesions after chemotherapy for colorectal liver metastases: Relation between detectability and residual tumors. AB - BACKGROUND AND OBJECTIVES: To clarify the detectability of gadolinium ethoxybenzyl diethylene-triamine pantaacetic acid enhanced magnetic resonance imaging (EOB-MRI) and contrast-enhanced intraoperative-ultrasonography (CE-IOUS) for residual disease in disappearing colorectal liver metastases (DLMs) and to seek a better management for DLMs. METHODS: Eighty-two patients who underwent hepatectomy after chemotherapy for colorectal liver metastases were retrospectively reviewed. Lesions which disappear on post-chemotherapy contrast enhance CT were defined as DLMs. All the patients underwent EOB-MRI and CE-IOUS. With pathologic evaluation for resected specimens and clinical observation of anatomically corresponding site for non-resected lesions, detectability of residual disease in DLMs were estimated between these two imaging modalities. RESULTS: Twenty (18%) patients presented with 111 DLMs, and EOB-MRI and CE-IOUS identified 64 (57.6%) and 62 (55.9%), respectively. Residual disease was pathologically confirmed for 69.2% in resected specimens and clinically estimated in 33.3% for non-resected DLMs. EOB-MRI showed a higher accuracy of prediction of residual disease compared with CE-IOUS (0.90 vs 0.70). Of the 11 non-resected lesions which were undetected with CE-IOUS and regrew after surgery, 9 (81.8%) were detected on EOB-MRI. CONCLUSIONS: EOB-MRI may be superior to CE-IOUS in detecting residual tumors for DLMs. Maximum attempt of resection would be needed for visualized lesions in EOB-MRI. PMID- 28876457 TI - Decision of surgical approach for advanced gallbladder adenocarcinoma based on a Bayesian network. AB - BACKGROUND AND OBJECTIVES: To determine whether radical resection can benefit patients with advanced gallbladder adenocarcinoma using a Bayesian network (BN) with clinical data. METHODS: In total, 362 patients who had undergone surgical treatment of gallbladder adenocarcinoma at a tertiary institute were evaluated to establish two BN models using a tree-augmented naive Bayes algorithm. We then chose 250 patients with T3-4N0-2M0 stage gallbladder adenocarcinoma to test the posterior probability after the surgical type was taken into account. RESULTS: In total, 170 patients (<=7 months) and 137 patients (>7 months) were correctly classified in the median survival time model (accuracy, 84.81%), and 204 patients (<=12 months), 15 patients (12-36 months), 17 patients (36-60 months), and 34 patients (>60 months) were correctly classified in the 1-, 3-, and 5-year survival model (accuracy, 74.59%), respectively. Every posterior probability in the two models upregulated the ratio of the longer survival time and suggested a better prognosis for gallbladder adenocarcinoma that can be improved by R0 resection. CONCLUSIONS: These BN models indicate that stages T4 and N2 gallbladder adenocarcinoma are not contraindications for surgery and that R0 resection can improve survival in patients with advanced gallbladder adenocarcinoma. PMID- 28876459 TI - Antibiotic elution from acrylic bone cement loaded with high doses of tobramycin and vancomycin. AB - Two-stage revision treatment of prosthetic joint infection (PJI) frequently employs the use of a temporary bone cement spacer loaded with multiple antibiotic types. Tobramycin and vancomycin are commonly used antibiotics in cement spacers, however, there is no consensus on the relative concentrations and combinations that should be used. Therefore, the purpose of this study was to investigate the influence of dual antibiotic loading on the total antibiotic elution and compressive mechanical properties of acrylic bone cement. Varying concentrations of tobramycin (0-3 g) and vancomycin (0-3 g) were added either alone or in combination to acrylic cement (Palacos R), resulting in 12 experimental groups. Samples were submerged in 37 degrees C saline for 28 d and sampled at specific time points. The collected eluent was analyzed to determine the cumulative antibiotic release. In addition, the cement's compressive mechanical properties and porosity were characterized. Interestingly, the cement with the highest concentration of antibiotics did not possess the best elution properties. Cement samples containing both 3 g of tobramycin and 2 g vancomycin demonstrated the highest cumulative antibiotic release after 28 d, which was coupled with a significant decrease in the mechanical properties and an increased porosity. The collected data also suggests that tobramycin elutes more effectively than vancomycin from cement. In conclusion, this study demonstrates that high antibiotic loading in cement does not necessarily lead to enhanced antibiotic elution. Clinically this information may be used to optimize cement spacer antibiotic loading so that both duration and amount of antibiotics eluted are optimized. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1078-1085, 2018. PMID- 28876458 TI - Seroprevalence of human herpesvirus 8 and its impact on the hemoglobin level in patients of end stage of renal diseases. AB - The incidence of Kaposi's sarcoma (KS) is increasing among renal transplant recipients. Patients with end-stage renal disease (ESRD) are immunocompromised and are candidates for renal transplantation, but HHV8 seroprevalence in ESRD patients has not been well documented. A cross-sectional study of 286 ESRD patients and 281 matched subjects without kidney disease was conducted at the First People's Hospital of Huzhou, Zhejiang province to explore the epidemiologic features of HHV8 among ESRD patients in China. Blood samples were collected and HHV8 antibodies and serologic indices were measured. The seroprevalence of HHV8 was 15.3% for ESRD patients and 8.9% for the comparison group. A significant difference in the geometric mean titer (GMT) of the HHV8 antibodies was detected between ESRD patients and the comparison group (617.1 vs 291.7; P = 0.042). The average level of hemoglobin was 11.56 +/- 1.78 g/dL for the ESRD group and 13.73 +/- 1.42 g/dL for the comparison group, (P > 0.05). Multiple linear regression revealed a negative association between HHV8 infection and plasma hemoglobin concentration (beta = -0.682, P = 0.036). We found a higher HHV8 prevalence and a higher level of HHV8 antibody GMT in ESRD patients than the comparison group, which indicate a high risk of posttransplantation KS. PMID- 28876460 TI - Viral etiology of sporadic cases of parotitis among children in Korea during 2013 2014. AB - Recent years have seen a high incidence of mumps, which is generally diagnosed based on clinical features, especially parotitis, without laboratory confirmation in Korea. To better understand the epidemiology of mumps in Korean children, we investigated sporadic suspected mumps cases with parotitis. In total, 237 buccal swabs or throat swabs collected from children with parotitis who had been clinically diagnosed with mumps were tested using real-time PCR for the detection of six viruses (Epstein-Barr virus, Human herpesvirus 6, Mumps virus, Human parainfluenza virus-1, -2, -3, Human adenovirus, Human bocavirus). Among 237 parotitis cases, 87 (36.7%) were positive for at least one virus; a single infection was observed in 73 (83.9%) cases, and co-infections were detected in 14 (16.1%) cases. Epstein-Barr virus was most frequent (20.7%), followed by human herpesvirus 6 (8.0%), mumps virus (5.5%), human parainfluenza virus-3 (4.6%), human adenovirus (4.2%), and human bocavirus (0.4%). These data suggested that the sporadic suspected mumps in the children might be related to other respiratory viruses rather than to the mumps virus. Our findings also indicate the limitation of clinical diagnosis without laboratory confirmation for mumps and thus highlight the importance of laboratory testing in suspected mumps cases. PMID- 28876461 TI - Jerusalem Special Issue. PMID- 28876462 TI - The Causal Role of Alcohol Use in Adolescent Externalizing and Internalizing Problems: A Mendelian Randomization Study. AB - BACKGROUND: The co-occurrence of alcohol use and externalizing/internalizing problems threatens adolescents' mental health. Research on whether alcohol use and these problems are causal and the direction of the potential causal relationships is needed to understand the mechanisms of the co-occurrence. METHODS: A Mendelian randomization analysis was conducted in which the aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism was used as an instrumental variable for alcohol use phenotypes. In total, 1,608 Chinese adolescents (mean age 14.11 +/- 1.83 years) were genotyped for the ALDH2 rs671 polymorphism. Three externalizing problems (aggression, delinquency, and attention problems) were measured with the Youth Self-Report inventory, and 2 internalizing problems (depression and anxiety) were measured with the self-reported Children's Depression Inventory and the Trait subscale of the State-Trait Anxiety Inventory. RESULTS: Alcohol use was positively associated with all 3 externalizing and 2 internalizing problems, and the ALDH2 polymorphism had a significant effect on alcohol use. Aggression and attention problems were also significantly affected by the ALDH2 polymorphism, whereas no significant association was observed between the ALDH2 polymorphism and delinquency, anxiety, or depression. CONCLUSIONS: The results suggest that alcohol use is a cause of adolescent aggression and attention problems but not adolescent delinquency, anxiety, or depression. PMID- 28876463 TI - Antigenicity reduction contributes mostly to poor detectability of HBsAg by hepatitis B virus (HBV) S-gene mutants isolated from individuals with occult HBV infection. AB - Mutations in hepatitis B virus (HBV) S gene are one of factors contributing to occult HBV infection (OBI). The study aimed to uncover the impact of OBI-related S-gene mutations on the detectability of hepatitis B surface antigen (HBsAg). Nine representative mutations within the major hydrophilic region of the S region were investigated. These included six (M1-M6) from an OBI patient with HBV related hepatocellular carcinoma, and three (M7-M9) from three OBI blood donors. Recombinant plasmids on the basis of pTriEx-mod-1.1 HBV and pcDNA3.1(-)/myc-His A vectors were constructed for each and transfected into HepG2 or Huh7 cells, respectively. Electrochemical luminescence, ELISA, Western blotting, and confocal immunofluorescence were used to examine HBsAg expression and antigenicity. In comparison to wild-type strain, supernatant and intracellular HBsAg levels of the nine mutants were reduced by 56.39-99.09% and 42.76-99.77% upon Roche quantitative Elecsys assay, respectively. Confocal immunofluorescence showed that relative intensity ratios of HBsAg-myc-His fusion protein detected by anti-HBs and anti-His-tag were lower by 11.87-76.27% for the nine mutants compared to the wild-type strain. Specifically, M1-M5 mutants that we firstly found recently were 33.14%, 76.27%, 57.93%, 53.37%, and 40.88% lower, respectively. Consistent results were obtained using double-antibody sandwich ELISA assays (anti-myc + anti-HBs vs anti-myc + anti-His). Antigenicity reduction played a major role for the poor detectability of HBsAg caused by the OBI-related mutations, although decreased HBsAg expression of some mutants and anti-HBs in samples might play coordinated roles. Taken together, antigenicity reduction contributes mostly to poor detectability of HBsAg caused by these OBI-related mutations. PMID- 28876464 TI - Novel mutations in transthyretin gene associated with hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the major health problems with increasing incidence worldwide. We report the elevation in transthyretin (TTR) expression following HCC induction using diethylnitrosamine (DEN) and 2 aminoacetylfluorine (2-AAF) in male Wistar rats. The increase in its expression took place at very early stage and remained elevated throughout HCC progression. The analysis of TTR gene in HCC bearing rats revealed four novel mutations that alter three amino acids at positions 61, 100, and 115. While these mutations do not directly affect the binding of TTR to thyroxine (T4 ), the mutation in amino acid 115 interferes with TTR tetramer formation that leads to its accumulation. Further, the mutated TTR is unable to cleave C-terminal of apolipoprotein A1 (APOA1) that results in abnormal lipid metabolism. This has correlation with development of liver cirrhosis and HCC. Furthermore, the mutated TTR seems to have potential as biomarker for early detection of HCC. PMID- 28876466 TI - Patient-specific in silico models can quantify primary implant stability in elderly human bone. AB - Secure implant fixation is challenging in osteoporotic bone. Due to the high variability in inter- and intra-patient bone quality, ex vivo mechanical testing of implants in bone is very material- and time-consuming. Alternatively, in silico models could substantially reduce costs and speed up the design of novel implants if they had the capability to capture the intricate bone microstructure. Therefore, the aim of this study was to validate a micro-finite element model of a multi-screw fracture fixation system. Eight human cadaveric humerii were scanned using micro-CT and mechanically tested to quantify bone stiffness. Osteotomy and fracture fixation were performed, followed by mechanical testing to quantify displacements at 12 different locations on the instrumented bone. For each experimental case, a micro-finite element model was created. From the micro finite element analyses of the intact model, the patient-specific bone tissue modulus was determined such that the simulated apparent stiffness matched the measured stiffness of the intact bone. Similarly, the tissue modulus of a small damage region around each screw was determined for the instrumented bone. For validation, all in silico models were rerun using averaged material properties, resulting in an average coefficient of determination of 0.89 +/- 0.04 with a slope of 0.93 +/- 0.19 and a mean absolute error of 43 +/- 10 MUm when correlating in silico marker displacements with the ex vivo test. In conclusion, we validated a patient-specific computer model of an entire organ bone-implant system at the tissue-level at high resolution with excellent overall accuracy. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:954-962, 2018. PMID- 28876465 TI - Procyanidin B2 3,3"-di-O-gallate induces oxidative stress-mediated cell death in prostate cancer cells via inhibiting MAP kinase phosphatase activity and activating ERK1/2 and AMPK. AB - Neoplastic cells exhibit higher oxidative stress compared to normal cells; however, antioxidants based clinical trials have mostly failed. Another attractive therapeutic approach is to further increase the oxidative stress in cancer cells leading to cell death. Herein, we show that Procyanidin B2 3,3"-di-O gallate (B2G2), the most active constituent of grape seed extract, treatment causes cell death in human prostate cancer (PCa) cells (LNCaP and 22Rv1) via increasing the reactive oxygen species (ROS) generation. Mechanistically, B2G2 treatment decreased the mitochondrial electron transport chain complex III activity leading to enhanced mitochondrial superoxide generation and decreased ATP production in LNCaP cells. Additional molecular studies revealed that B2G2 induced cell death was mediated mainly through ROS-induced sustained activation of ERK1/2, which was due to inhibition of MAP kinase phosphatase (MKP) activity as over-expression of MKP3 in LNCaP cells conferred significant protection against B2G2-induced cell death. Along with ERK1/2, AMP-activated protein kinase alpha (AMPKalpha) was also activated by B2G2 treatment, and pre-treatment with AMPKalpha inhibitor compound C significantly reversed the cytotoxic effects of B2G2 in LNCaP cells. Furthermore, pre-treatment of MKP3 over-expressing LNCaP cells with compound C further reduced the B2G2-induced cell death, suggesting the involvement of AMPKalpha along with MKP3 and ERK1/2 in the biological effects of B2G2. Together, these results for the first time identified that oxidative stress and MKP3 inhibition play a critical role in B2G2-induced cell death in PCa cells through sustained activation of both ERK1/2 and AMPKalpha. These results offer a unique opportunity to control this deadly malignancy through B2G2 use. PMID- 28876467 TI - Nationwide, population-based study of post radical prostatectomy urinary incontinence correction surgery. AB - OBJECTIVES: To assess the use of post radical prostatectomy (RP) urinary incontinence (PPI) surgery and to investigate factors related to its use. METHODS: Cohort study in Prostate Cancer database Sweden (PCBaSe) of men who underwent primary RP between 1998 and 2012. PPI correction procedures were identified in the Patient Registry. Hazard ratios (HR) and 95% confidence intervals (CIs) of PPI surgeries were estimated. RESULTS: Seven hundred eighty two out of 26 280 (3%) men underwent PPI surgery at a median time of 3 years after RP. There was an eightfold increase in the absolute number of PPI surgeries during 2000-2014 and a threefold increase in the number per 1000 RPs performed. Factors associated with high use PPI surgery were age >70, HR 1.96 (1.54-2.50), and high hospital RP volume (>100 RPs/year), HR 0.81 (0.66-0.99). There was a 10 fold difference in use of PPI surgery per 1000 RPs between the county with the highest versus lowest use. In a subgroup of men with Patient-Reported Outcome Measures (PROM); severe PPI was reported by 7% of men and 24% of them underwent PPI surgery. CONCLUSIONS: Three percent of all men received PPI surgery, with a 10-fold variation among health care providers. Only a quarter of men with severe PPI underwent PPI surgery, suggesting that PPI surgery remains underutilized. PMID- 28876468 TI - S100A16 is a prognostic marker for colorectal cancer. AB - BACKGROUND: S100 is a superfamily of calcium-binding proteins that regulate multiple biological processes and are involved in many diseases. S100A16 has recently been identified to be involved in several cancers such as bladder cancer, lung cancer, and oral squamous cell carcinoma. However, the role of S100A16 expression in the colorectal cancer (CRC) has not been investigated. METHODS: S100A16 protein expression was detected by immunohistochemistry in 296 cases of CRC. Kaplan-Meier survival analysis and Cox regression analysis were performed to evaluate the prognostic significance of S100A16. RESULT: The results showed that the overall survival (OS) of patients with low membrane S100A16 expression was significantly shorter than patients with high expression (P < 0.05). Chi-square analysis showed that S100A16 expression had a positive correlation with tumor grade (P = 0.02). Multivariate analysis identified membrane S100A16 expression as an independent prognostic marker for OS in CRC patients. (P < 0.05). Univariate analysis showed no significant association between cytoplasmic/nuclear S100A16 expression and OS. CONCLUSION: Membrane S100A16 is associated with the prognosis of CRC patients, indicating that S100A16 may be a potential prognostic biomarker and therapeutic target for CRC. PMID- 28876469 TI - Effects of Organic and Conventional Cropping Systems on Technological Properties and Phenolic Compounds of Freshly Harvested and Stored Rice. AB - : This study compared the physicochemical and technological properties of the IRGA 410 rice cultivar, obtained from organic and conventional cropping systems, and showed its susceptibility to changes during storage at 0, 6, and 12 mo. The rice conventional cropping system exhibited greater protein, lipids, and ash levels, and a head rice yield. However, organic rice presented greater total carbohydrates, soluble protein, amylose content, 33% greater free phenolics, and phenolic acids, but exhibited a greater percentage of stained grains during the storage period. The free phenolic content of cooked rice was lower than the free phenolic content of the raw rice. By Liquid chromatography with mass spectrometer (LC-MS) were identified p-coumaric and ferulic acids in both fractions (free and bound). The content of p-coumaric acid and ferulic acid in bound fraction was higher in organic brown rice than in conventional brown rice. At 6 and 12 mo of storage, the main fungi found were Aspergillus sp. and Penicillium sp. Prior to storage, the Bipolaris sp. fungi was identified only in organic rice. For conventional rice, the infestation level by Aspergillus sp. increased from 3% to 70% at the 6th mo of storage. In addition to the advantage of organic rice being free of agrochemicals, this study revealed that natural plant defense compounds could be produced when the rice was subjected to more biotic and abiotic stresses. However, some disadvantages were observed, such as lower protein content and a greater percentage of soluble protein, which favored the breaking of rice in processing, and a greater percentage of grain stained before and during storage. PRACTICAL APPLICATION: The organic and conventional cropping systems affect the physicochemical and technological properties of rice grains, which is one of the main cereals grown and consumed in the world. This study shows the advantages and disadvantages of the cropping system in grain properties that are in the interest of both consumers and processing industries. PMID- 28876470 TI - Structure elucidation of new fusarielins from Fusarium sp. and their antimicrobial activity. AB - Three new fusarielins, 3-epi-fusarielin H (1), 3-O-methyl-fusarielin H (2), and 3 O-methyl-epi-fusarielin H (3), were isolated from the fungus Fusarium sp. together with the known analogues, fusarielins F (4) and G (5). The structures of these compounds were elucidated by analysis of their ESI-HRTOFMS, 1D and 2D NMR spectroscopic data. The new compounds exhibited weak antibacterial effect against Staphylococcus aureus. PMID- 28876471 TI - Taxadiene-5alpha-ol is a minor product of CYP725A4 when expressed in Escherichia coli. AB - CYP725A4 is a P450 enzyme from Taxus cuspidata that catalyzes the formation of taxadiene-5alpha-ol (T5alpha-ol) from taxadiene in paclitaxel biosynthesis. Past attempts expressing CYP725A4 in heterologous hosts reported the formation of 5(12)-oxa-3(11)-cyclotaxane (OCT) and/or 5(11)-oxa-3(11)-cyclotaxane (iso-OCT) instead of, or in addition to, T5alpha-ol. Here, we report that T5alpha-ol is produced as a minor product by Escherichia coli expressing both taxadiene synthase and CYP725A4. The major products were OCT and iso-OCT, while trace amounts of unidentified monooxygenated taxanes were also detected by gas chromatography-mass spectrometry. Since OCT and iso-OCT had not been found in nature, we tested the hypothesis that protein-protein interaction of CYP725A4 with redox partners, such as cytochrome P450 reductase (CPR) and cytochrome b5, may affect the products formed by CYP725A4, possibly favoring the formation of T5alpha-ol over OCT and iso-OCT. Our results show that coexpression of CYP725A4 with CPR from different organisms did not change the relative ratios of OCT, iso OCT, and T5alpha-ol, while cytochrome b5 decreased overall levels of the products formed. Although unsuccessful in finding conditions that promote T5alpha-ol formation over other products, we used our results to clarify conflicting claims in the literature and discuss other possible approaches to produce paclitaxel via metabolic and enzyme engineering. PMID- 28876472 TI - Economic evaluation of dental sealants: A systematic literature review. AB - OBJECTIVES: To systematically review the literature on economic evaluations of dental sealants and examine the costs and effectiveness of caries prevention using sealants. METHODS: Of 21 full-text articles examined, a total of 13 were included in this study. These studies are grouped by the type of intervention as follows: (i) sealants compared with no sealants; (ii) sealants compared with other forms of caries prevention; (iii) resin-based sealants compared with glass ionomer sealants; (iv) different sealing strategies in primary teeth; (v) different sealing strategies in permanent teeth; and (vi) sealants based on school- or clinic-based setting of delivery. All currency is reported in constant 2010 US$. RESULTS: Cost-effectiveness analyses differed due to varying study designs, assumptions, sealant delivery settings, outcomes, caries risk assessment and study durations. Findings varied on the cost-effectiveness of sealants compared with other caries-preventive strategies. Under the assumption of equal caries risk, always sealing primary molars appeared to be the most effective strategy, whereas risk-based sealing was the optimal strategy with differing caries risk. Studies that assessed sealing strategies in permanent teeth reported that risk-based sealing was more cost-effective than not sealing, but they differed on the cost-effectiveness of risk-based seal compared with non-risk based seal. Sealants delivered in school settings had mixed results on costs but were as equally effective as sealants delivered in private practices. CONCLUSIONS: The cost-effectiveness of sealants is dependent on the conditions of delivery. The list of cost-effectiveness ratios for each intervention can support policy makers to estimate expected returns on their investments in dental sealants. PMID- 28876473 TI - Sydney Playground Project: A Cluster-Randomized Trial to Increase Physical Activity, Play, and Social Skills. AB - BACKGROUND: We assessed the effectiveness of a simple intervention for increasing children's physical activity, play, perceived competence/social acceptance, and social skills. METHODS: A cluster-randomized controlled trial was conducted, in which schools were the clusters. Twelve Sydney (Australia) primary schools were randomly allocated to intervention or control conditions, with 226 children (5-7 years old) selected randomly to participate. Data were collected at baseline and after 13 weeks. The intervention consisted of introducing recycled materials without an obvious play purpose into school playgrounds and a risk-reframing workshop for parents and teachers. RESULTS: Children from the intervention schools increased physical activity and reduced sedentary time while control schools decreased physical activity and increased sedentary time. The intervention yielded increases in total accelerometer counts (beta = 9350 counts, 95% CI 3490-1522, p = .002), minutes of moderate/vigorous physical activity (MVPA) (beta = 1.8 min, 95% CI 0.52-3.12, p = .006), and reductions in sedentary time (beta = -2.1 min, 95% CI -3.77-(-0.51), p = .01). Although the changes in time spent in play and nonplay were not statistically different (p = .08) the effect size (d = .27) indicates clinical significance. CONCLUSIONS: This intervention was effective for increasing MVPA during recess and demonstrated capacity to improve play opportunities in school playgrounds. PMID- 28876474 TI - Bullying and HIV Risk Among High School Teenagers: The Mediating Role of Teen Dating Violence. AB - BACKGROUND: Teen dating violence (TDV), bullying, and HIV risk behaviors are public health concerns that impact adolescents in the United States. National estimates reveal high rates of these risk behaviors among high school students. Based on theoretical and empirical evidence, we hypothesized that experiencing teen dating violence (sexual and physical) would mediate the impact of bullying on HIV risk. METHODS: Data were from the 2013 National Youth Behavior Risk Surveillance Survey (YRBSS) among students who answered questions on bullying, TDV, and HIV risk (N = 13,571). The YRBSS is conducted biennially among 9th- to 12th-grade students nationally. We used multiple regression analysis and Hayes' SPSS process macro to examine the 2 study hypotheses. RESULTS: Findings from bivariate analysis suggest an association between bullying and HIV risk. The study also found associations between physical, sexual teen dating violence and HIV risk. Results also indicate that both physical and sexual teen dating violence mediate the association between bullying and HIV risk. CONCLUSION: Our findings suggest that multidimensional interventions should be developed to reduce the rate of teen dating violence and combat bullying as a preventative method for HIV risk among high school students. PMID- 28876475 TI - A School-Based Dental Program Evaluation: Comparison to the Massachusetts Statewide Survey. AB - BACKGROUND: School-based dental programs target high-risk communities and reduce barriers to obtaining dental services by delivering care to students in their schools. We describe the evaluation of a school-based dental program operating in Chelsea, a city north of Boston, with a low-income and largely minority population, by comparing participants' oral health to a Massachusetts oral health assessment. METHODS: Standardized dental screenings were conducted for students in kindergarten, third, and sixth grades. Outcomes were compared in bivariate analysis, stratified by grade and income levels. RESULTS: A greater percentage of Chelsea students had untreated decay and severe treatment need than students statewide. Yet, fewer Chelsea third graders had severe treatment need, and more had dental sealants. There was no significant difference in the percentage of Chelsea students having severe treatment need or dental sealants by income level. CONCLUSIONS: Students participating in our program do not have lower decay levels than students statewide. However, they do have lower levels of severe treatment need, likely due to treatment referrals. Our results confirm that school-based prevention programs can lead to increased prevalence of dental sealants among high-risk populations. Results provide support for the establishment of full service school-based programs in similar communities. PMID- 28876476 TI - School Breakfast Program Participation and Rural Adolescents' Purchasing Behaviors in Food Stores and Restaurants. AB - BACKGROUND: Little is known about adolescents' food purchasing behaviors in rural areas. This study examined whether purchasing food at stores/restaurants around schools was related to adolescents' participation in school breakfast programs and overall diet in rural Minnesota. METHODS: Breakfast-skippers enrolled in a group-randomized intervention in 2014 to 2015 (N = 404 from 8 schools) completed 24-hour dietary recalls and pre/post surveys assessing food establishment purchase frequency. Healthy Eating Index Scores (HEI-2010) were calculated for each student. Student-level school breakfast participation (SBP) was obtained from school food service records. Mixed-effects regression models estimated: (1) whether SBP was associated with store/restaurant use at baseline, (2) whether an increase in SBP was associated with a decrease in store/restaurant use, and (3) whether stores/restaurant use was associated with HEI-2010 scores at baseline. RESULTS: Students with increased SBP were more likely to decrease fast-food restaurant purchases on the way home from school (OR 1.017, 95% CI 1.005, 1.029), but were less likely to decrease purchases at food stores for breakfast (OR 0.979, 95% CI 0.959, 0.999). Food establishment use was associated with lower HEI 2010 dairy component scores (p = .017). CONCLUSIONS: Increasing participation in school breakfast may result in modest changes in purchases at food establishments. PMID- 28876478 TI - Achieving Consensus on Principles of Good Practice for School Health in Independent Schools: A Delphi Study. AB - BACKGROUND: Although the 8 components of the coordinated school health (CSH) framework have been implemented to various degrees in the nation's public schools, principles of good practice (PGPs) to guide health promotion efforts in independent schools do not exist. The purpose of this study was to generate PGPs and rate their feasibility of implementation. METHODS: A modified Delphi process was used to generate PGPs for school health in independent schools and develop consensus regarding their feasibility of implementation. A working group of 6 independent school health professionals (ISHPs) was convened to propose draft PGPs based on the CSH framework. The proposed PGPs were then reviewed by a national and geographically diverse expert panel of 10 school health researchers and 23 ISHPs that completed 3 Delphi rounds to achieve consensus on the PGPs. Of 33 participants originally invited to participate, 27 completed the Delphi process. RESULTS: A total of 27 panelists rated 67 PGPs, provided 399 comments, and achieved consensus using interquartile range on 56 (84%) of the proposed PGPs, 41 of which were rated feasible and 15 somewhat feasible. CONCLUSION: This study has generated empirical support for the feasibility of PGPs for school health in independent schools. PMID- 28876477 TI - A Scoping Review to Address the Culture of Concussion in Youth and High School Sports. AB - BACKGROUND: In 2013, the National Academy of Sciences emphasized the need to develop, implement, and evaluate effective large-scale educational strategies to improve the culture of concussion in youth and high school sports. In support of this recommendation, in this article we summarize research on factors that contribute to the culture of concussion. METHODS: We conducted the literature search using 7 electronic databases. We used a scoping review method to identify studies that addressed knowledge, attitudes, behaviors, use of educational resources, and interventions related to concussion among young athletes, coaches, and parents. RESULTS: Of the 33 articles identified, most focused on concussion education (N = 15), followed by knowledge (N = 13), behaviors (N = 13), and attitudes (N = 5). Three studies addressed multiple study populations. CONCLUSIONS: The rapid spread of concussion education and awareness efforts has outpaced research on effective strategies to improve knowledge, attitudes, and behaviors that contribute to the culture of concussion. Further research is critical to inform the development and implementation of large-scale educational efforts. This research should incorporate rigorous study designs; be inclusive of diverse ages, socioeconomic status, and racial/ethnic groups; and examine opportunities to improve behavioral outcomes around concussion prevention, reporting, and management. PMID- 28876480 TI - Types and Nature of Parental Support for Overweight Students to Cope With Weight Related Teasing. AB - BACKGROUND: Parental support can protect adolescents from various forms of bullying. There is a lack of in-depth information about what social support parents provide to overweight adolescents when they are teased at school. In this study, we took an initial step to address this gap in the literature by describing the types and nature of support that parents provided to their overweight child when they were teased. METHODS: A conversational style semistructured interview/prompts and probes were conducted with 28 volunteering parents. Inductive content analysis was used to analyze the data. Data trustworthiness was established through a variety of strategies. RESULTS: Six themes emerged from the data: (1) having conversations, being encouraging, and "being supportive"; (2) using religion to teach self-acceptance and comfort their child; (3) offering advice on how to cope with the teasing; (4) fostering their child's self-esteem; (5) teaching reality and acceptance of criticism in early life; and (6) seeking support from other parents or professionals. CONCLUSIONS: Parents offered multiple supports for their child when they were teased. This information can facilitate the development of effective family-based interventions on coping with teasing among overweight students. Future research is also needed to examine the effectiveness of the recommended interventions. PMID- 28876479 TI - Relationship Between Adherence to Individual Goals Within the 5-2-1-0 Guidelines for Obesity Prevention and Number of PACER Laps in Adolescents. AB - BACKGROUND: The purpose of this study was to evaluate the relationship between adolescents' adherence to the 5-2-1-0 goals and the number of completed Progressive Cardiovascular Endurance Run (PACER) laps. METHODS: Participants included 1792 students aged 10 to 16 years who were randomly selected across 9 data collection periods between 2012 and 2014. The Survey of Physical Activity and Nutrition was used to measure time spent in physical activity and sedentary behavior, and dietary intake and the dependent variable was the number of PACER laps achieved. The Kruskal-Wallis test and pairwise post hoc comparisons were conducted. RESULTS: Only 0.95% (N = 17) participants met all 4 goals outlined within the 5-2-1-0 guidelines. Whereas 10.04% met 3 (N = 180), 41.63% met 2 (N = 746), 34.99% met 1 (N = 627), and 12.39% did not meet any goals (N = 222). Pairwise comparisons indicated there were significant differences: between groups not meeting any of the 5-2-1-0 goals and other groups (meeting one goal [p = .000], 2 goals [p = .000], 3 goals [p = .000], and all 4 [p = .008]). CONCLUSIONS: The positive relationship between PACER laps and adherence to the 5 2-1-0 goals suggests targeted and sequential behavioral changes may have positive implications on adolescents' cardiovascular fitness and body mass index. PMID- 28876481 TI - Measuring the Implementation of a School Wellness Policy. AB - BACKGROUND: With the rise in childhood obesity, school policies related to nutrition and physical activity have been written and implemented. In this paper, we present a model to evaluate the degree to which state legislation for school health policies are implemented at the school level. METHODS: Using Washington, DC's Healthy Schools Act (HSA) and a self-report measure of the implementation of the HSA, we illustrate the process of developing a composite score that can be used to measure compliance with the provisions of the law. RESULTS: We calculated elementary and middle school composite scores based on the provisions within the HSA. Schools have been successful in implementing nutrition provisions; however, more resources are needed for schools to achieve the minutes of health and physical education. We found statistically significant differences between public charter and traditional public schools on the implementation of the provisions of the HSA. CONCLUSIONS: Understanding how schools are complying with school wellness policies is a next step to determining where additional resources or support are needed in order to support school-wide adoption of healthy policies. PMID- 28876483 TI - HTLV-1 intrafamilial transmission among Japanese immigrants in Brazil. AB - Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The aim of this study was to investigate the intrafamilial transmission of HTLV-1 among Japanese immigrants and their descendants living in a non-endemic area of central Brazil. Six families were investigated. Thirty seven relatives of the six index cases were tested by ELISA for the presence of anti-HTLV antibodies, and the positive cases were confirmed by Western blot. HTLV 1 isolates were genotyped by partial nucleotide sequencing (5' LTR) of the proviral DNA. All individuals, including index cases and relatives, were asymptomatic. In five families, at least one relative was infected with HTLV-1. In all, eight (22%) relatives (one mother, four wives, one brother, and two brothers-in-law) were infected. However, none of the 22 individuals under 55 years of age was infected. In each family, the HTLV-1 sequences from the relatives were identical or almost identical to that of the index case, except in one case. Pedigrees of the families, together with socio-demographic data of the HTLV-1 infected individuals, strongly suggested the occurrence of both vertical and sexual transmission, with breastfeeding as an important risk factor. Whether and why the virus transmission is less effective among younger generations deserves to be further investigated. PMID- 28876484 TI - Is 100% oxygen a sticking plaster for sore neonatal ventilation skills? PMID- 28876485 TI - The care of a child with a newly diagnosed immune thrombocytopenia. PMID- 28876488 TI - Global gains after Helping Babies Breathe. PMID- 28876487 TI - Helping babies breathe can reduce deaths with the right combination of training and expertise. PMID- 28876490 TI - Fetal intra-abdominal umbilical vein varix: retrospective cohort study and systematic review and meta-analysis. AB - OBJECTIVE: To investigate the ultrasound characteristics and outcome of pregnancies with fetal intra-abdominal umbilical vein varix (FIUVV). METHODS: Cases of FIUVV managed at our tertiary university hospital over an 8-year period were reviewed. Information retrieved included gestational age and diameter of the umbilical varix at diagnosis, increase in varix diameter, associated ultrasound or chromosomal anomalies and pregnancy outcome. Furthermore, a systematic review and meta-analysis of series of FIUVV in the literature was performed to assess the incidence of chromosomal anomalies, small-for-gestational age infants and intrauterine fetal demise (IUFD), and to pool odds ratio (OR) estimates on the relationship between the incidence of these outcomes and the presence of additional associated ultrasound anomalies. RESULTS: Thirteen cases of FIUVV were included in the cohort study. Additional ultrasound anomalies were found in two (15.4%) of 13 cases. One case of IUFD was observed and no case of chromosomal anomaly or thrombosis of varix was recorded. A total of five studies comprising 254 cases met the inclusion criteria of the systematic review. FIUVV was associated with additional ultrasound anomalies (non-isolated FIUVV) in 19% (95% CI, 10.9-29.1%) of cases. No case of chromosomal abnormality or IUFD was reported in fetuses with isolated FIUVV. In contrast, in the group of non-isolated FIUVV, the incidence of chromosomal anomalies was 19.6% and that of IUFD was 7.3%, with ORs of 14.8 (95% CI, 2.9-73.0) and 8.2 (95% CI, 1.05-63.1), respectively, when compared with the group of isolated FIUVV. CONCLUSION: When isolated, the outcome of cases affected by FIUVV is usually favorable. In about 20% of cases, additional ultrasound anomalies are found, which are associated with an increased risk for chromosomal abnormalities and IUFD. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28876489 TI - Structural/mechanistic insights into the efficacy of nonclassical beta-lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates. AB - Clavulanic acid and avibactam are clinically deployed serine beta-lactamase inhibitors, important as a defence against antibacterial resistance. Bicyclic boronates are recently discovered inhibitors of serine and some metallo beta lactamases. Here, we show that avibactam and a bicyclic boronate inhibit L2 (serine beta-lactamase) but not L1 (metallo beta-lactamase) from the extensively drug resistant human pathogen Stenotrophomonas maltophilia. X-ray crystallography revealed that both inhibitors bind L2 by covalent attachment to the nucleophilic serine. Both inhibitors reverse ceftazidime resistance in S. maltophilia because, unlike clavulanic acid, they do not induce L1 production. Ceftazidime/inhibitor resistant mutants hyperproduce L1, but retain aztreonam/inhibitor susceptibility because aztreonam is not an L1 substrate. Importantly, avibactam, but not the bicyclic boronate is deactivated by L1 at a low rate; the utility of avibactam might be compromised by mutations that increase this deactivation rate. These data rationalize the observed clinical efficacy of ceftazidime/avibactam plus aztreonam as combination therapy for S. maltophilia infections and confirm that aztreonam-like beta-lactams plus nonclassical beta-lactamase inhibitors, particularly avibactam-like and bicyclic boronate compounds, have potential for treating infections caused by this most intractable of drug resistant pathogens. PMID- 28876491 TI - Longitudinal change of sFlt-1/PlGF ratio in singleton pregnancy with early-onset fetal growth restriction. AB - OBJECTIVE: To describe the evolution of soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF) ratio in the last 5 weeks prior to delivery in singleton pregnancy complicated by early-onset fetal growth restriction (FGR), with or without pre-eclampsia (PE). METHODS: This was a prospective observational cohort study of early-onset FGR cases that underwent serial assessment of maternal serum sFlt-1/PlGF ratio from diagnosis to delivery. Measurements were made at weekly intervals and within the last 48 h before birth. Absolute values and percentage increase between time intervals were computed, and previously described cut-off values of 38 (suspicion of PE), 85 (aids diagnosis of PE) and 655 (high risk for imminent delivery) were used for analysis of the sFlt-1/PlGF ratio. We compared findings between cases with early-onset FGR only (n = 37) and those that additionally developed PE (n = 36). RESULTS: Overall perinatal survival was 63/73 (86.3%). A sFlt-1/PlGF ratio above 38 was observed 4 weeks before delivery in most FGR-only and FGR with PE cases (73% and 100%, respectively), but absolute values of sFlt-1/PlGF were significantly higher in FGR cases with PE. Extremely elevated values of the ratio (>= 655) within the last 48 h before delivery were found in 65% of cases of FGR with PE, but in only 8% of isolated FGR cases (P < 0.001). CONCLUSION: Elevated sFlt-1/PlGF was observed in most early-onset FGR pregnancies from 4 weeks before delivery, and values were even higher if there was concurrent PE. However, serial measurements of the ratio were of limited value, being useful only to anticipate the need for imminent delivery in cases of FGR with PE when sFlt-1/PlGF values >= 655 were reached. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28876492 TI - Total Synthesis and Biological Assessment of Novel Albicidins Discovered by Mass Spectrometric Networking. AB - Natural products represent an important source of potential novel antimicrobial drug leads. Low production by microorganisms in cell culture often delays the structural elucidation or even prevents a timely discovery. Starting from the anti-Gram-negative antibacterial compound albicidin produced by Xanthomonas albilineans, we describe a bioactivity-guided approach combined with non-targeted tandem mass spectrometry and spectral (molecular) networking for the discovery of novel antimicrobial compounds. We report eight new natural albicidin derivatives, four of which bear a beta-methoxy cyanoalanine or beta-methoxy asparagine as the central alpha-amino acid. We present the total synthesis of these albicidins, which facilitated the unambiguous determination of the (2 S,3 R) stereoconfiguration which is complemented by the assessment of the stereochemistry on antibacterial activity. PMID- 28876493 TI - Hearing and neurodevelopmental outcomes for children with asymptomatic congenital cytomegalovirus infection: A systematic review. AB - INTRODUCTION: Congenital CMV is one of the commonest congenital infections and a recognised cause of sensorineural hearing loss and neurodevelopmental impairment. Ninety percent are clinically inapparent at birth but are reported to be at risk of developing such abnormalities throughout childhood, the extent of which requires further elucidation. METHODS: A systematic literature review was conducted using Medline and Embase databases, manual citation review, and personal libraries for articles reporting primary data on hearing and neurodevelopmental outcomes for children with asymptomatic congenital CMV. PROSPERO registration number CRD42015025407. RESULTS: Thirty-seven of 480 articles identified between 1969 and 2016 met the eligibility criteria. Twenty nine of these contributed primary data on hearing outcomes and 20 on neurodevelopmental outcomes (12 of the 37 studies contributed data on both). Cumulative incidence of sensorineural hearing loss with follow-up to at least 5 years was 7% to 11%, which is more than healthy controls but less than children with symptomatic congenital CMV (34%-41%). The onset, course, and severity of hearing loss was variable with no reliable virological prognostic marker. In comparison to controls, children with asymptomatic congenital CMV did not perform worse than controls in neurodevelopmental assessments and performed better than children with symptomatic congenital CMV. CONCLUSIONS: Studies show children with asymptomatic congenital CMV are at increased risk of developing hearing loss but perform equally well on neurodevelopmental assessments when compared with healthy controls. There is no reliable virological marker to determine which infants will develop sequelae. Regular follow-up until school entry is supported by the literature. PMID- 28876494 TI - What proportion of paediatric specialist referrals originates from general practitioners? AB - AIM: To determine (i) the proportion of different referral sources for new referrals to paediatric specialist outpatient clinics and (ii) any association of referral source with utilisation of additional health services. METHODS: Survey of parents presenting with their child at five paediatric specialist outpatient clinics at two Melbourne public hospitals. RESULTS: Just over half (52%) of the respondents were referred by a general practitioner (GP). The remainder were referred by a paediatrician (27%) at hospital discharge (16%) or from the ED (6%). Most respondents (71%) reported that their child also has a referral to see another specialist for the same health concern but had not yet had the consultation; 44% had consulted another doctor for the same health concern between receiving the referral and the appointment. Paediatrician referrals were more likely to see another specialist for the same health concern compared to other referral sources (P = 0.032). CONCLUSION: Only half of the referrals of new patients to paediatric specialist outpatient clinics come from GPs. Future research should investigate whether multiple referral sources have a negative impact on the co-ordination and cost of paediatric health care. PMID- 28876495 TI - Accessing Stable Magnesium Acyl Compounds: Reductive Cleavage of Esters by Magnesium(I) Dimers. AB - The first examples of magnesium acyls, [(Nacnac)Mg{MU-C(Ph)O}(MU-OR)Mg(Nacnac)] (R=Me, tBu or Ph; Nacnac=[HC(MeCNAr)2 ]- ; Ar=C6 H2 Me3 -2,4,6 (Mes Nacnac), C6 H3 Et2 -2,6 (Dep Nacnac), C6 H3 iPr2 -2,6 (Dip Nacnac)), have been prepared by reductive cleavage of a series of esters using dimeric magnesium(I) reducing agents, [{(Nacnac)Mg}2 ]. Crystallographic studies reveal the complexes to be dimeric, being bridged by both phenyl-acyl and alkoxide/aryloxide fragments. The crystal structures, combined with results of spectroscopic and computational studies suggest that the nature of the acyl ligands within these complexes should be viewed as lying somewhere between anionic umpolung acyl and oxo-carbene. However, reactions of the acyl complexes with a variety of organic electrophiles did not provide evidence of umpolung acyl reactivity. A number of attempts to prepare alkoxide free magnesium acyls were carried out, and while these were unsuccessful, they did lead to unusual products, the crystallographic and spectroscopic details of which are discussed. PMID- 28876496 TI - Seroprevalence and incidence of hepatitis E virus among blood donors: A review. AB - Hepatitis E virus (HEV) is an RNA virus with 4 main genotypes. HEV-1 and HEV-2 infect solely humans, while HEV-3 and HEV-4 infect humans and various animals such as pigs, deer, and rabbits. HEV-5 and HEV-6 infect mainly wild boar. Recently, new genotypes, known as HEV-7 and HEV-8, were found to infect camels and humans. HEV is globally distributed into different epidemiological patterns based on socioeconomic factors and ecology. Although HEV is mainly transmitted through the fecal-oral route, it was also recognized as a transfusion-transmitted virus. Transmission through blood donation was documented worldwide with rising annual observations, accounting for more than 2.5% of all transmissions. HEV infection is usually asymptomatic or subclinical in immunocompetent individuals, so it remains questionable whether there is an urgent need to screen for HEV prior to blood transfusion. Moreover, recent studies conducted in the Middle East and North Africa (MENA) region indicate that HEV is highly endemic. Here, we provide a review on HEV epidemiology, transmission, and laboratory diagnosis, giving special emphasis to the newly discovered genotypes, HEV-7 and HEV-8. Furthermore, we underscore the findings of recent HEV seroprevalence and viremia studies among blood donors worldwide. We also shed light on similar studies performed among blood donors in the MENA region. PMID- 28876497 TI - Automated follicle count using three-dimensional ultrasound in polycystic ovarian morphology. PMID- 28876498 TI - Chinese medical students' knowledge, attitude and practice towards human papillomavirus vaccination and their intention to recommend the vaccine. AB - AIM: The human papillomavirus (HPV) vaccine is effective in preventing cervical cancer, but its global uptake rate in vulnerable populations is unsatisfactory. Physician's recommendation is an important determinant for vaccine uptake, but we have limited understanding on the contributing factors of physician's recommendation. This study investigated whether the knowledge, attitudes and vaccination status of medical students would affect their intention to recommend HPV vaccination. METHODS: This is a population-representative survey of medical schools in Hong Kong. RESULTS: Participants included 1022 Chinese medical students (46.9% of all in Hong Kong; 46.3% female). Better HPV-related knowledge and a more positive attitude towards HPV vaccination were important factors predicting vaccine uptake and intention to recommend. HPV vaccination status and intention to receive the vaccine were positively associated with intention to recommend among females. CONCLUSION: Better HPV-related medical education may be a feasible way to promote the HPV vaccine in regions without universal coverage. Medical students who have not received the HPV vaccine should also be encouraged to receive the vaccine. PMID- 28876499 TI - The short-term impact of the alcohol act on alcohol-related deaths and hospital admissions in Scotland: a natural experiment. AB - BACKGROUND AND AIM: The introduction of the Alcohol Act in Scotland on 1 October 2011, which included a ban on multi-buy promotions, was probably associated with a fall in off-trade alcohol sales in the year after its implementation. The aim of this study was to test if the same legislation was associated with reduced levels of alcohol-related deaths and hospital admissions in the 3-year period after its introduction. DESIGN: A natural experiment design using time-series data to assess the impact of the Alcohol Act legislation in Scotland. Comparisons were made with unexposed populations in the rest of Great Britain. SETTING: Scotland with comparable data obtained for geographical control groups in other parts of Great Britain. PARTICIPANTS: For alcohol-related deaths, a total of 17 732 in Scotland and 88 001 in England and Wales throughout 169 4-week periods between January 2001 and December 2013 and for alcohol-related hospital admissions, a total of 121 314 in Scotland and 696 892 in England throughout 182 4-week periods between January 2001 and December 2014. MEASUREMENTS: Deaths and hospital admissions in Scotland and control groups that were wholly attributable to alcohol for consecutive 4-week periods between January 2001 and December 2014. Data were obtained by age, sex and area-based socio-economic position. FINDINGS: There was no evidence to suggest that the Alcohol Act was associated with changes in the overall rate of alcohol-related deaths [incidence rate ratio (IRR) = 0.99, 95% confidence interval (CI) = 0.91-1.07)] or hospital admissions (IRR = 0.98, 95% CI = 0.95-1.02) in Scotland. In control group analyses, the pseudo intervention variable was not associated with a change in alcohol-related death rates in England/Wales (IRR = 0.99, 95% CI = 0.95-1.02), but was associated with an increase in alcohol-related hospital admission rates in England (IRR = 1.05, 95% CI = 1.03-1.07). In combined models, the interaction analysis did not provide support for a 'net effect' of the legislation on alcohol-related deaths in Scotland compared with England/Wales (IRR 0.99, 95% CI = 0.95-1.04), but suggested a net reduction in hospital admissions for Scotland compared with England (IRR = 0.93, 95% CI = 0.87-0.98). CONCLUSION: The implementation of the Alcohol Act in Scotland has not been associated clearly with a reduction in alcohol-related deaths or hospital admissions in the 3-year period after it was implemented in October 2011. PMID- 28876501 TI - Aqueous Voltammetry in the Near Absence of Electrolyte. AB - In order to minimize the incidence of the CO2 hydrolysis and conduct aqueous electrochemistry in the virtual absence of electrolyte, a novel methodology is developed to achieve the near minimum conductivity (~60 nS cm-1 ) for an aqueous solution through in situ deionization with ion exchange resin beads. Aqueous electrochemistry studying the oxidations of platinum, ferrocenemethanol, and hydrogen (H2 ) were conducted in the near complete absence of trace ionic species at a platinum microelectrode (d=10 MUm). Both surface and solution phase electrochemical reactions were clearly observed, indicating that under these conditions there is a sufficiently compressed double layer for an interfacial electron transfer to be driven and the iR effects are significantly smaller than theoretically expected. PMID- 28876502 TI - Self-Assembly of Giant Spherical Liquid-Crystalline Complexes and Formation of Nanostructured Dynamic Gels that Exhibit Self-Healing Properties. AB - Supramolecular self-assembly of 24 forklike mesogenic ligands and 12 transition metal ions led to the formation of giant spherical coordination complexes that exhibit liquid-crystalline (LC) phases. Self-healing LC supramolecular gels were also obtained through the introduction of these LC nanostructured supramolecular giant spherical complexes into dynamic covalent networks formed by cross-linkers and bifunctional polymers. The giant spherical structures of the PdII complexes with 72 rodlike moieties on the periphery were characterized by NMR, diffusion ordered NMR spectroscopy, and mass spectrometry. These complexes are stable and exhibit lyotropic LC behavior, while the mesogenic ligands show thermotropic LC properties. The self-assembled LC structures of the spherical complexes can be tuned by the length of the rodlike moieties. PMID- 28876500 TI - On the integrity of functional brain networks in schizophrenia, Parkinson's disease, and advanced age: Evidence from connectivity-based single-subject classification. AB - Previous whole-brain functional connectivity studies achieved successful classifications of patients and healthy controls but only offered limited specificity as to affected brain systems. Here, we examined whether the connectivity patterns of functional systems affected in schizophrenia (SCZ), Parkinson's disease (PD), or normal aging equally translate into high classification accuracies for these conditions. We compared classification performance between pre-defined networks for each group and, for any given network, between groups. Separate support vector machine classifications of 86 SCZ patients, 80 PD patients, and 95 older adults relative to their matched healthy/young controls, respectively, were performed on functional connectivity in 12 task-based, meta-analytically defined networks using 25 replications of a nested 10-fold cross-validation scheme. Classification performance of the various networks clearly differed between conditions, as those networks that best classified one disease were usually non-informative for the other. For SCZ, but not PD, emotion-processing, empathy, and cognitive action control networks distinguished patients most accurately from controls. For PD, but not SCZ, networks subserving autobiographical or semantic memory, motor execution, and theory-of-mind cognition yielded the best classifications. In contrast, young-old classification was excellent based on all networks and outperformed both clinical classifications. Our pattern-classification approach captured associations between clinical and developmental conditions and functional network integrity with a higher level of specificity than did previous whole-brain analyses. Taken together, our results support resting-state connectivity as a marker of functional dysregulation in specific networks known to be affected by SCZ and PD, while suggesting that aging affects network integrity in a more global way. Hum Brain Mapp 38:5845-5858, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28876503 TI - Functional links between Disabled-2 Ser723 phosphorylation and thrombin signaling in human platelets. AB - : Essentials Disabled-2 (Dab2) phosphorylation status in thrombin signaling of human platelet was investigated. Ser723 was the major Dab2 phosphorylation site in human platelets stimulated by thrombin. Dab2 S723 phosphorylation (pS723) caused the dissociation of Dab2-CIN85 protein complex. Dab2-pS723 regulated ADP release and integrin alphaIIbbeta3 activation in thrombin-treated platelets. SUMMARY: Background Disabled-2 (Dab2) is a platelet protein that is functionally involved in thrombin signaling in mice. It is unknown whether or not Dab2 undergoes phosphorylation during human platelet activation. Objectives To investigate the phosphorylation status of Dab2 and its functional consequences in thrombin-stimulated human platelets. Methods Dab2 was immunoprecipitated from resting and thrombin-stimulated platelet lysates for differential isotopic labeling. After enrichment of the phosphopeptides, the phosphorylation sites were analyzed by mass spectrometry. The corresponding phospho-specific antibody was generated. The protein kinases responsible for and the functional significance of Dab2 phosphorylation were defined by the use of signaling pathway inhibitors/activators, protein kinase assays, and various molecular approaches. Results Dab2 was phosphorylated at Ser227, Ser394, Ser401 and Ser723 in thrombin stimulated platelets, with Ser723 phosphorylation being the most significantly increased by thrombin. Dab2 was phosphorylated by protein kinase C at Ser723 in a Galphaq -dependent manner. ADP released from the stimulated platelets further activated the Gbetagamma -dependent pathway to sustain Ser723 phosphorylation. The Cbl-interacting protein of 85 kDa (CIN85) bound to Dab2 at a motif adjacent to Ser723 in resting platelets. The consequence of Ser723 phosphorylation was the dissociation of CIN85 from the Dab2-CIN85 complex. These molecular events led to increases in fibrinogen binding and platelet aggregation in thrombin-stimulated platelets by regulating alphaIIb beta3 activation and ADP release. Conclusions Dab2 Ser723 phosphorylation is a key molecular event in thrombin-stimulated inside-out signaling and platelet activation, contributing to a new function of Dab2 in thrombin signaling. PMID- 28876504 TI - The First Zero-Length Mass Spectrometry-Cleavable Cross-Linker for Protein Structure Analysis. AB - Combining the properties of a zero-length cross-linker with cleavability by tandem mass spectrometry (MS/MS) poses great advantages for protein structure analysis using the cross-linking/MS approach. These include a reliable, automated data analysis and the possibility to obtain short-distance information of protein 3D-structures. We introduce 1,1'-carbonyldiimidazole (CDI) as an easy-to-use and commercially available, low-cost reagent that ideally fulfils these features. CDI bridges primary amines and hydroxy groups in proteins with the lowest possible spacer length of one carbonyl unit (ca. 2.6 A). The cross-linking reaction can be conducted under physiological conditions in the pH range between 7.2 and 8. Urea and carbamate cross-linked products are cleaved upon collisional activation during MS/MS experiments generating characteristic product ions, greatly improving the unambiguous identification of cross-links. Our innovative analytical concept is exemplified and applied for bovine serum albumin (BSA), wild-type tumor suppressor p53, an intrinsically disordered protein, and retinal guanylyl cyclase activating protein-2 (GCAP-2). PMID- 28876507 TI - Revolutionary leaps in the development of agriculture. PMID- 28876506 TI - Bisphosphonate therapy and osteogenesis imperfecta: The lived experience of children and their mothers. AB - PURPOSE: Osteogenesis imperfecta (OI) is a chronic, genetic condition frequently described as "brittle bones." This condition is expressed by low bone density and characterized by frequent fractures with and without trauma. Additional symptoms include pain, altered growth, and challenges with mobility. This experience has a great impact on the daily life of the child diagnosed with OI and their family. With the introduction of bisphosphonate therapy children diagnosed with OI experienced an increase in bone density that included a change in symptoms and improvement in daily functioning. The purpose of this study was to describe the lived experience of children receiving bisphosphonate therapy for osteogenesis imperfecta (OI) and their mothers. DESIGN AND METHODS: A phenomenological study was conducted using interviews with a purposive sample of six children diagnosed with OI and their six mothers (N = 12). Children ranged in age from 6 to 18 years. The Giorgi (2009) methodology was used to discover the meaning of living day to day since initiating the bisphosphonate infusion therapy. RESULTS: Four themes emerged from the synthesis of the meaning units that reflected the experience that bisphosphonate therapy had on daily life with OI. These four themes explicitly described the phenomena being studied and included living daily life in stride; normalcy is living with uncertainty; renewal with infusions; and making choices and living with the consequences. PRACTICE IMPLICATIONS: Nurses must take an active role in developing and promoting family-centered interventions for transition and support. PMID- 28876505 TI - N-(3-Oxo-acyl)-homoserine lactone induces apoptosis primarily through a mitochondrial pathway in fibroblasts. AB - N-(3-Oxododecanoyl)-l-homoserine lactone (C12) is produced by Pseudomonas aeruginosa to function as a quorum-sensing molecule for bacteria-bacteria communication. C12 is also known to influence many aspects of human host cell physiology, including induction of cell death. However, the signalling pathway(s) leading to C12-triggered cell death is (are) still not completely known. To clarify cell death signalling induced by C12, we examined mouse embryonic fibroblasts deficient in "initiator" caspases or "effector" caspases. Our data indicate that C12 selectively induces the mitochondria-dependent intrinsic apoptotic pathway by quickly triggering mitochondrial outer membrane permeabilisation. Importantly, the activities of C12 to permeabilise mitochondria are independent of activation of both "initiator" and "effector" caspases. Furthermore, C12 directly induces mitochondrial outer membrane permeabilisation in vitro. Overall, our study suggests a mitochondrial apoptotic signalling pathway triggered by C12, in which C12 or its metabolite(s) acts on mitochondria to permeabilise mitochondria, leading to activation of apoptosis. PMID- 28876508 TI - The effects of pirfenidone in patients with an acute exacerbation of interstitial pneumonia. AB - INTRODUCTION: The prognosis of patients with an acute exacerbation of interstitial pneumonia (AE-IP) is poor. Pirfenidone (PFD) reduces the disease progression in idiopathic pulmonary fibrosis. OBJECTIVES: The purpose of this study was evaluating whether the administration of PFD improved the outcomes of AE-IP. METHODS: We conducted a retrospective study of 31 patients with AE-IP who did not recover between 7 and 14 days after an initial treatment. Fourteen patients received PFD within 2 weeks (PFD group) of the AE, while 17 patients were treated without PFD (non-PFD group). The patients' clinical data and computed tomography (CT) scores were analyzed. RESULTS: The survival rate in the PFD group was not significantly different from non-PFD group at 30 (78.6% vs 64.7%, P = .46) and 90 days (64.3% vs 52.9%, P = .72). The white blood cell counts in the PFD group were significantly lower on PFD day 14 than on PFD days 1 and 7. The C-reactive protein levels in the PFD group were also significantly lower on PFD day 7 than on PFD day 1. There were no significant differences regarding the changes of the CT scores. CONCLUSIONS: PFD may reduce the inflammation in AE-IP patients undergoing corticosteroid treatment. PMID- 28876509 TI - Clot waveform analysis: Where do we stand in 2017? AB - Analysis of the optical waveform generated during global coagulation assays, such as activated partial thromboplastin time and prothrombin time, can provide much precious information on the global coagulation state of the plasma sample tested, in addition to a single clotting time. Many studies have been published concerning patient diagnosis and management in haemophilia A, and in the early diagnosis and prognosis of disseminated intravascular coagulation and sepsis. However, many other works have also been published on further potential clinical applications such as lupus anticoagulant diagnosis and anticoagulant monitoring. Altogether, these publications have demonstrated the ability for clot waveform analysis (CWA) to improve patient management, especially as this tool is inexpensive, rapid and readily available on coagulation analysers with optical detection systems. By an extensive review of the literature related to studies performed on CWA, this publication aims at providing a review of current knowledge in this specific field, ranging from research data to potential clinical applications and future trends. PMID- 28876510 TI - Optimization of Photoanodes for Photocatalytic Water Oxidation by Combining a Heterogenized Iridium Water-Oxidation Catalyst with a High-Potential Porphyrin Photosensitizer. AB - The development of water-splitting dye-sensitized photoelectrochemical cells has gained interest owing to their ability to generate renewable fuels from solar energy. In this study, photoanodes were assembled from a SnO2 film sensitized with a combination of a high-potential CF3 -substituted porphyrin dye with a tetrahydropyranyl-protected hydroxamic acid surface-anchoring group and a Cp*Ir (Cp*=pentamethylcyclopentadienyl) water-oxidation catalyst containing a silatrane anchoring group. The dye/catalyst ratios were varied from 2:1 to 32:1 to optimize the photocatalytic water oxidation. Photoelectrochemical measurements showed not only more stable and reproducible photocurrents for lower dye/catalyst ratios but also improved photostability. O2 production was confirmed in real time over a 20 h period with a Clark electrode. Photoanodes prepared from 2:1 and 8:1 dye/catalyst sensitization solutions provided the most active electrodes for photocatalytic water oxidation and performed approximately 30-35 turnovers in 20 h. PMID- 28876511 TI - Recent progress of task-specific ionic liquids in chiral resolution and extraction of biological samples and metal ions. AB - Ionic liquids have been functionalized for modern applications. The functional ionic liquids are also called task-specific ionic liquids. Various task-specific ionic liquids with certain groups have been constructed and exploited widely in the field of separation. To take advantage of their properties in separation science, task-specific ionic liquids are generally used in techniques such as liquid-liquid extraction, solid-phase extraction, gas chromatography, high performance liquid chromatography, and capillary electrophoresis. This review mainly covers original research papers published in the last five years, and we will focus on task-specific ionic liquids as the chiral selectors in chiral resolution and as extractant or sensor for biological samples and metal ion purification. PMID- 28876512 TI - Effect of Stapling Architecture on Physiochemical Properties and Cell Permeability of Stapled alpha-Helical Peptides: A Comparative Study. AB - Stapled peptides have emerged as a new class of targeting molecules with high binding affinity and specificity for intracellular undruggable targets. Their ability to penetrate cell membranes is exceptionally intriguing but remains elusively and controversially discussed. To understand the effect of stapling architectures on their physiochemical properties and to aid in promoting their cell permeability, we report herein a comparative study on the physiochemical properties and cell permeability of stapled alpha-helical peptides with different types of crosslinks. We highlight the decisive impact of the intrinsic properties of the crosslinks on cell permeability rather than the helical contents of the peptides in model amphipathic sequences targeting estrogen receptor-coactivator interaction. We envision this finding to shed further light on the chemical optimization of stapled alpha-helical peptides or macrocyclic cell-penetrating peptides for enhanced cell penetration. PMID- 28876513 TI - Association of clinical trial enrollment and survival using contemporary therapy for pediatric acute lymphoblastic leukemia. AB - While early studies reported superior survival for cancer patients enrolled on clinical trials, recent findings are inconclusive. We investigated the association between enrollment on contemporary trials and event-free survival (EFS) in pediatric B-cell acute lymphoblastic leukemia (B-ALL). In a retrospective cohort of 274 children (1-21 years) treated for B-ALL from 2008 to 2015, 55.5% enrolled with no disparity in enrollment by age, sex, or ethnicity. Three-year EFS was similar for enrolled and not enrolled patients (90.1% [95% CI, 82.5-94.5] versus 86.5% [95% CI, 77.7-92.0]). Clinical trial enrollment did not affect pediatric B-ALL survival, albeit in a limited-size cohort treated at a single academic institution. PMID- 28876514 TI - Maternal concerns and perceptions of elementary school-age children's weight status. AB - PURPOSE: The purpose of this study was to identify characteristics associated with maternal concerns for her child becoming overweight, and how these concerns are related to her perceptions of her child's weight. DESIGN: A school-based sample of 55 children and their mothers from Houston, Texas, participated in a cross-sectional survey. Mothers reported on their concerns and perceptions regarding their child's weight. Child and mother height and weight were directly assessed to calculate body mass index (BMI). Covariate-adjusted logistic regression models were conducted. RESULTS: Over one-third of mothers misperceived their child's weight status [9% (n = 5) overestimated; 27% (n = 15) underestimated]. Mothers of sons were less accurate compared with mothers of daughters. For every one unit increase in maternal BMI, mothers had 13% higher odds of being concerned of their child becoming overweight. Concerned mothers had 82% lower odds of underestimating their child's weight. PRACTICE IMPLICATIONS: In order for school-based childhood obesity prevention and intervention programs to be successful, parents must accurately perceive their elementary school-age child's weight status. School nurses can be vital to these efforts through proper training and resources. Nurses can use the "School Nurse Childhood Obesity Toolkit" and motivational interviewing techniques to address parental concerns and perceptions prior to teaching behavior modification strategies to children/families. PMID- 28876515 TI - Parental Child-Rearing Conflicts Through Adolescence: Trajectories and Associations With Child Characteristics and Externalizing Patterns. AB - Research on longitudinal interparental conflict patterns and offspring development is scarce. The population-based TOPP study (N = 459) was used to investigate (1) child-rearing conflict trajectories through four time points during childhood and adolescence (ages 8-16), and (2) associations between conflict trajectories and child characteristics (i.e., birth order, gender, externalizing patterns from early childhood). Latent profile analysis identified six distinct trajectories. Conflict levels decreased for most respondents over the adolescent offspring period, but offspring's birth order and externalizing problems were related to less typical trajectories and higher levels of conflict. Onset of externalizing problems was of additional importance for the course of parental child-rearing conflicts. The results highlight the perception of the whole family as an interwoven system. PMID- 28876516 TI - Cultivating Conformists or Raising Rebels? Connecting Parental Control and Autonomy Support to Adolescent Delinquency. AB - This study investigates short-term and long-term associations between parenting in early adolescence and delinquency throughout adolescence using data from the National Longitudinal Surveys. Multilevel longitudinal Poisson regressions show that behavioral control, psychological control, and decision-making autonomy in early adolescence (ages 10-11) are associated with delinquency trajectories throughout adolescence (ages 10-17). Path analyses reveal support for three mediation hypotheses. Parental monitoring (behavioral control) is negatively associated with delinquency in the short term and operates partly through changes in self-control. Parental pressure (psychological control) shows immediate and long-lasting associations with delinquency through changes in self-control and delinquent peer pressures. Decision-making autonomy is negatively associated with delinquency in the long term, yet may exacerbate delinquency in early adolescence by increasing exposure to delinquent peers. PMID- 28876517 TI - Erratum. PMID- 28876518 TI - Externalizing Problem Behavior in Adolescence: Parenting Interacting With DAT1 and DRD4 Genes. AB - This study extends previous gene-by-environment (G * E) research through design and methodological advances and examines alternative hypotheses of diathesis stress, vantage sensitivity, and differential susceptibility. In a sample of 984 adolescents and their parents, we examined whether effects of parental support, proactive, punitive, harsh punitive, and psychological control on externalizing problem behavior are moderated by adolescents' genotype for the dopamine transporter (DAT1) or receptor D4 (DRD4) gene. Results provided evidence for main effects of parenting behavior and DRD4, and multiple interaction effects of which one survived Bonferroni correction. Adolescents carrying a long DRD4 variant were more susceptible to the effects of parental proactive control on aggression, for better and for worse. Critical considerations were made regarding the complexity of G * E research. PMID- 28876519 TI - Associations Between Victimization and Adolescents' Self-Reported Responses to Peer Provocation Are Moderated by Peer-Reported Aggressiveness. AB - Many early adolescents experience peer victimization, but little research has examined how they respond to aggression by peers. Thus, in a large sample of early adolescents (N = 648; M age = 12.96; SD = 0.30; 52.0% female), we examined (1) the associations between peer-reported victimization and self-reported responses to peer provocation, and (2) whether these associations were moderated by peer-reported aggression. In particular, we predicted that the reported use of assertion, a strategy generally viewed as socially skillful, would be associated with less victimization, but only for youth low on peer-reported aggression. Results were consistent with this hypothesis. Moreover, seeking adult intervention was associated with greater victimization for youth high on peer reported aggression. Implications for research and practice are discussed. PMID- 28876520 TI - Associations Between School Connection and Depressive Symptoms From Adolescence Through Early Adulthood: Moderation by Early Adversity. AB - Depressive symptomatology is one of the most common and costly threats to American mental health, making the elucidation of environmental influences on depressive symptoms particularly important. Using the National Longitudinal Study of Adolescent Health, this study explores the interaction between environmental risk and protective factors in the etiology of depressive symptoms by asking whether school connection is associated with lower levels of depressive symptoms through early adulthood, and whether connection serves as a protective or promotive factor for youth who experienced early adversity. Findings highlight the importance of school connection in promoting long-term mental health for all youth and suggest that policies and practice supporting school connection may be effective intervention strategies for youth at risk for depressive symptomatology. PMID- 28876521 TI - Passionate Experiences in Adolescence: Situational Variability and Long-Term Stability. AB - This study investigates adolescents' situational passionate experiences, defined as states of strong commitment and intense affect. We examine the extent to which experiencing passion was specific to situations versus individual differences, and explore which activities are likely to elicit adolescents' passion. Using longitudinal experience sampling method (ESM) data from a representative sample of 996 adolescents (54.6% females) in three cohorts (6th, 8th, and 10th grade at baseline), we examine whether adolescents' frequency of passionate experiences remained stable across 2 years. Results of multilevel analyses revealed that situational determinants accounted for 80% of variance in passion, while 20% were due to characteristics of the person that remained stable across 1 week of ESM assessment. An adolescent's percentage of passionate experiences among all observed experiences remained stable across 2 years in rank order and mean level. PMID- 28876523 TI - Support From Parents and Teachers in Relation to Psychosomatic Health Complaints Among Adolescents. AB - This study explores the relative contribution of parental and teacher support to adolescents' psychosomatic health complaints, with a particular focus on gender and age differences. Based on a survey of 49,172 ninth- and eleventh-grade students in Stockholm (2006-2014), structural equation modeling results demonstrated negative associations between parental and teacher support on psychosomatic health complaints. Parental support had a stronger association with the outcome among girls than boys. It was also more important than teacher support for psychosomatic health complaints. Parental support was more important for younger girls' health compared to older girls, with opposite patterns for teacher support. These findings highlight the need to consider gender and age to understand the links between social support and health during adolescence. PMID- 28876524 TI - Technology-Based Communication and the Development of Interpersonal Competencies Within Adolescent Romantic Relationships: A Preliminary Investigation. AB - This study investigated longitudinal associations between adolescents' technology based communication and the development of interpersonal competencies within romantic relationships. A school-based sample of 487 adolescents (58% girls; Mage = 14.1) participated at two time points, one year apart. Participants reported (1) proportions of daily communication with romantic partners via traditional modes (in person, on the phone) versus technological modes (text messaging, social networking sites) and (2) competence in the romantic relationship skill domains of negative assertion and conflict management. Results of cross-lagged panel models indicated that adolescents who engaged in greater proportions of technology-based communication with romantic partners reported lower levels of interpersonal competencies one year later, but not vice versa; associations were particularly strong for boys. PMID- 28876522 TI - Roles of Response Inhibition and Gene-Environment Interplay in Pathways to Adolescents' Externalizing Problems. AB - This study used two waves of data to investigate pathways through which adolescents' response inhibition related to later externalizing problems. A polygenic risk score indexed genetic risk for poor response inhibition. Adolescents' performance on a response inhibition task mediated the relation between adolescents' polygenic risk scores and mother's inconsistent parenting (i.e., evocative rGE), even after controlling for mothers' genetic risk (i.e., passive rGE). Mothers' inconsistent parenting subsequently prospectively predicted adolescents' externalizing problems. Adolescents' response inhibition also prospectively predicted later externalizing behaviors. These findings were subgroup-specific, with greater risk for non-Hispanic Caucasian boys with substance-disordered parents. Results suggest that poor response inhibition may increase risk for adolescents' externalizing problems both directly and by evoking certain environmental conditions. PMID- 28876525 TI - Extracurricular Activities in Multiethnic Middle Schools: Ideal Context for Positive Intergroup Attitudes? AB - This study examined processes by which extracurricular participation is linked with positive ethnic intergroup attitudes in multiethnic middle schools in California. Specifically, the mediating roles of activity-related cross-ethnic friendships and social identities including alliances with multiple groups were examined in a sample including African American or Black, East or South-East Asian, White, and Latino youth (N = 1,446; Mage = 11.60 in sixth grade). Results of multilevel modeling suggested that in addition to activity-related cross ethnic friendships, complex social identities mediated the association between availability of cross-ethnic peers in activities and ethnic intergroup attitudes. Results are discussed in terms of how activities can be structured to promote cross-ethnic relationships and complex social identities, as well as positive ethnic intergroup attitudes. PMID- 28876527 TI - Developmental Trajectories of Nonsuicidal Self-Injury in Adolescence and Intrapersonal/Interpersonal Risk Factors. AB - This 3-wave study investigated the developmental trajectories of nonsuicidal self injury (NSSI) and intrapersonal/interpersonal risk factors among 3,381 Chinese adolescents (56.2% females) aged from 13 to 17 years during a 1-year period. Using an accelerated longitudinal design and latent class growth analysis, we identified four subgroups of NSSI trajectories: negligible (74.6%), experimental (12.8%), moderate decreasing (10.8%), and high fluctuating (1.9%). Adolescents reporting both intrapersonal (i.e., impulsive behaviors and depression) and interpersonal (i.e., unstable relationships and parental criticism) risk factors were significantly more likely to follow the latter three trajectories. The findings of this study suggest there is heterogeneity in NSSI development among adolescents and highlight the contributions of both intrapersonal and interpersonal risk factors in the engagement in NSSI. PMID- 28876528 TI - The Links Between Youth Employment and Educational Attainment Across Racial Groups. AB - Research suggests that the relations between adolescent employment and youth development vary by socioeconomic status (SES) and race/ethnicity. However, it is unclear whether the links between paid work and college outcomes vary by either SES or race/ethnicity, or both. Using data from the Educational Longitudinal Study, we find that low-intensity work during high school is associated with positive college outcomes for almost all students, whereas the associations between high-intensity work and negative postsecondary outcomes are mostly limited to White students. Our results suggest that both differential selections into youth employment and differential consequences of youth employment contribute to these varying links between paid work and educational outcomes across different racial groups. PMID- 28876526 TI - In Search of Modifiable Risk and Protective Factors for Teen Dating Violence. AB - The present research explores the additive and interactive effects of anger or hostility (A/H), acceptance of violence (AoV), and constructive conflict resolution strategies (CRS) on the perpetration of physical and sexual teen dating violence (TDV). Adolescents completed surveys assessing physical and sexual TDV perpetration, A/H, AoV, and positive CRS. While the findings require replication with longitudinal data, the results suggest that developing interventions to modify AoV and A/H may have the potential to prevent instances of TDV perpetration among both boys and girls. The results for CRS were mixed and necessitate further exploration. These cross-sectional data provide insight into potentially fruitful areas of exploration for the development and tailoring of prevention strategies for teens at risk for physical and sexual TDV perpetration. PMID- 28876529 TI - Residential Mobility and Adolescent Achievement and Behavior: Understanding Timing and Extent of Mobility. AB - Residential mobility is generally viewed as an adverse event for adolescents' development. Less is known about whether moving during adolescence, childhood, or both periods explains this connection and whether the extent of mobility matters. Analytic shortcomings with much of the research call into question extant findings. We examined associations between childhood, adolescent, and child adolescent mobility and adolescents' achievement (math and reading) and behavior problems (internalizing and externalizing). With a multisite, longitudinal sample (N = 1,056), we employed propensity score methods, which mitigate concerns about selection bias on observed variables, to investigate relationships. Results suggest that multiple, child-adolescent movers had more internalizing problems in adolescence than their stable peers, but did not differ on externalizing problems or achievement. PMID- 28876530 TI - Social Capital and Adolescent Substance Use: The Role of Family, School, and Neighborhood Contexts. AB - This study assesses the link between social capital factors of norm-setting social arenas including family, school, and neighborhood and adolescent substance use measured by cigarette smoking, alcohol consumption, and illicit drug use among a sample of adolescents in California. The key messages of this study are that socialization processes at different life domains, in varying degrees, are associated with adolescent substance use behavior. Compared with school and neighborhood contexts, family is the most influential setting that should be primarily targeted for youth substance use prevention. Among different aspects of within-family social resources, parental monitoring seems to be the most protective of adolescent substance use. Study implications on family-based interventions are discussed. PMID- 28876531 TI - Treatment of plasminogen deficiency patients with fresh frozen plasma. AB - Congenital plasminogen (Plg) deficiency leads to the development of ligneous membranes on mucosal surfaces. Here, we report our experience with local and intravenous fresh frozen plasma (FFP). We retrospectively reviewed medical files of 17 patients and their eight first-degree relatives. Conjunctivitis was the main complaint. Thirteen patients were treated both with intravenous and conjunctival FFP. Venous thrombosis did not develop in any. Genetic evaluation revealed heterogeneous mutations as well as polymorphisms. Diagnosis and treatment of Plg deficiency is challenging; topical and intravenous FFP may be an alternative treatment. PMID- 28876533 TI - Multi-objective Optimization of Benzamide Derivatives as Rho Kinase Inhibitors. AB - Despite recent advances in Computer Aided Drug Discovery and High Throughput Screening, the attrition rates of drug candidates continue to be high, underscoring the inherent complexity of the drug discovery paradigm. Indeed, a compromise between several objectives is often required to obtain successful clinical drugs. The present manuscript details a multi-objective workflow that integrates the 4D-QSAR and molecular docking methods in the simultaneous modeling of the Rho Kinase inhibitory activity and acute toxicity of Benzamide derivatives. To this end, the pIC50 /pLD50 ratio is considered as the response variable, permitting the concurrent modeling of both properties and representing a shift from classical step-by-step evaluations. The 4D-QSAR strategy is used to generate the Grid Cell Occupancy Descriptors (GCODs), and Stochastic Gradient Boosting (SGB) and Partial Least Squares (PLS) methods as the model fitting techniques. While the statistical parameters for the PLS model do not meet established criteria for acceptability, the SGB model yields satisfactory performance, with correlation coefficients r2 =0.95 and r2 pred=0.65 for the training and test set, respectively. Posteriorly, the structural interpretation of the most relevant GCODs according to the SGB model is performed, allowing for the proposal of 139 novel benzamide derivatives, which are then screened using the same model. Of these 9 compounds were predicted to possess pIC50 /pLD50 ratio values higher than those for the employed dataset. Finally, in order to corroborate the results obtained with the SGB model, a docking simulation was formed to evaluate the binding affinity of the proposed molecules to the ROCK2 active site and 3 chemical structures (i. e. p6, p14 and p131) showed higher binding affinity than the most active compound in the training set, while the rest generally demonstrated comparable behavior. It may therefore be concluded that the consensus models that intertwine the 4D-QSAR and molecular docking methods contribute to more reliable virtual screening and compound optimization experiments. Additionally, the use of multi-objective modeling schemes permits the simultaneous evaluation of different chemical and biological profiles, which should contribute to the control a priori of causative factors for the high attrition rates in later drug discovery phases. PMID- 28876532 TI - Successful treatment with doxorubicin and ifosfamide for mediastinal malignant peripheral nerve sheath tumor with loss of H3K27me3 expression. AB - Malignant peripheral nerve sheath tumor (MPNST) in the thorax is an extremely rare disease, and half of all cases of MPNST are associated with neurofibromatosis type I. Sporadic intrathoracic MPNST is difficult to diagnose and treat. Because of the rarity of intrathoracic MPNST, the optimal method of diagnosis and the efficacy of chemotherapy are unknown. Herein, we present a case of inoperable mediastinal MPNST, in which the diagnosis was immunohistochemically made by the loss of H3K27me3 expression in a transbronchial needle biopsy specimen. The patient showed a good response to doxorubicin plus ifosfamide chemotherapy. The present case highlights that MPNST should be included in the differential diagnosis of non-posterior mediastinum thoracic lesions, and that appropriate diagnosis and treatment for intrathoracic MPNST should be considered in patients with a thoracic mass. PMID- 28876534 TI - Sequential sampling plans and economic injury levels for Empoasca kraemeri on common bean crops at different technological levels. AB - BACKGROUND: Empoasca kraemeri is an important pest on common bean crops at different technological levels. However, for this pest on this crop, economic injury levels have not yet been determined and plan for sequential sampling plans has not yet been developed. Thus, the objectives of this research were to develop E. kraemeri sequential sampling plans and to determine economic injury levels in the common bean at different crop technological levels. RESULTS: Common bean plants tolerate low attack intensities of this pest (up to 1 adult plant-1 ). However, with an increase in attacks, there is a reduction in grain production by the plants. The economic injury levels were 0.48, 0.39 and 0.35 adults sample-1 (leaf beating on a tray) for crops with low (1200 kg ha-1 ), medium (1800 kg ha-1 ) and high (2400 kg ha-1 ) technological levels, respectively. Sequential sampling plans and the standardized plan produced similar decisions. However, in these decisions there was a time saving of more than 60% compared with the standardized plan. CONCLUSION: All three economic injury levels determined and the sequential sampling plans developed in this study are suitable for incorporation into integrated management programs for common bean pests because they can be used by farmers operating at various technological levels to make adequate and rapid decisions. (c) 2017 Society of Chemical Industry. PMID- 28876535 TI - Pre- and Postnatal Lung Development: An Updated Species Comparison. AB - The purpose of this review is to give an outline of respiratory tract morphological and functional development with an emphasis on perinatal and postnatal maturational processes. In view of the rising need for qualitative and quantitative data for the development of pediatric pharmaceuticals, a comparison of the human situation to experimental animal models is made, and functional data as well as suitable models for human airway diseases and functional testing are presented. Birth Defects Research 109:1519-1539, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28876536 TI - Design, Synthesis, SAR and Molecular Modeling Studies of Novel Imidazo[2,1 b][1,3,4]Thiadiazole Derivatives as Highly Potent Antimicrobial Agents. AB - In this study, a novel series of phenyl substituted imidazo[2,1 b][1,3,4]thiadiazole derivatives were synthesized, characterized and explored for antibacterial activity against Gram-negative Escherichia coli, Gram-positive Staphylococcus aureus and Bacillus subtilis and antifungal activity against Candida albicans. Most of the synthesized compounds exhibited remarkable antimicrobial activities, some of which being ten times more potent than positive controls. The most promising compound showed excellent activity with MIC value of 0.03 MUg/ml against both S. aureus and B. subtilis (MIC values of positive compound Chloramphenicol are 0.4 MUg/ml and 0.85 MUg/ml, respectively). Furthermore, structure-activity relationship was also investigated with the help of computational tools. Some physicochemical and ADME properties of the compounds were calculated too. The combination of electronic structure calculations performed at PM6 level and molecular docking simulations using Glide extra precision mode showed that the hydrophobic nature of keto aryl ring with no electron withdrawing substituents at para position enhances activity while electron-donating substituents at the second aryl ring is detrimental to activity. PMID- 28876537 TI - Steroid phobia, Chinese medicine and asthma control. AB - BACKGROUND: Inhaled corticosteroids (ICS) are the mainstay of treatment for asthma. Corticosteroid (CS) phobia and fears are prevalent, and these may influence therapeutic efficacy and asthma control. AIM: The aim of this study was to evaluate if CS fear is associated with asthma control in children. METHODS: Patients aged >4 years with asthma at a pediatric outpatient clinic were surveyed, and the Asthma Control Test (ACT) was used for the assessment of asthma control. RESULTS: Ninety-eight patients and their parents were interviewed. Thirty-four (35%) parents reported moderate or significant CS fear. They were more likely than those with no or little fear to have poorer asthma control (mean ACT scores 21.3 +/- 4.0 vs 23.1 +/- 3.3, P = 0.02), discuss their fears with their doctors (P < 0.001), request CS sparing medications (P = 0.044) and resort to Chinese medicine (CM) usage (P < 0.001). Backward binomial logistic regression showed parents with moderate/significant fears were more likely to discuss their fears with their doctors (OR: 5.21; 95% CI: 1.86-14.59; P = 0.002) and have used CM (OR: 4.28; 95% CI: 1.61-11.41; P = 0.004). CS fear was not translated to reduced self-reported compliance in the prescribed ICS. About 40% of the respondents had ever used Chinese Medicine (CM) with 82% of the users reported having used Chinese herbal medicine and 49% had used cold moxibustion. CONCLUSIONS: CS fear and CM usage are prevalent. Parents with CS fear were more likely to have children with poorer asthma control and have used Chinese medicine. Physicians caring for children with asthma should be aware of parents with CS fear, prepared to address the fear or concerns and offer evidence-based alternative treatment. PMID- 28876539 TI - Medicine in small doses. PMID- 28876540 TI - Laboratory methods cause ultrasensitive prostate-specific antigen fluctuations. PMID- 28876538 TI - Miklos Bodanszky Award Lecture: Advances in the selective targeting of protein phosphatase-1 and phosphatase-2A with peptides. AB - Protein phosphatase-1 and phosphatase-2A are two ubiquitously expressed enzymes known to catalyze the majority of dephosphorylation reactions on serine and threonine inside cells. They play roles in most cellular processes and are tightly regulated by regulatory subunits in holoenzymes. Their misregulation and malfunction contribute to disease development and progression, such as in cancer, diabetes, viral infections, and neurological as well as heart diseases. Therefore, targeting these phosphatases for therapeutic use would be highly desirable; however, their complex regulation and high conservation of the active site have been major hurdles for selectively targeting them in the past. In the last decade, new approaches have been developed to overcome these hurdles and have strongly revived the field. I will focus here on peptide-based approaches, which contributed to showing that these phosphatases can be targeted selectively and aided in rethinking the design of selective phosphatase modulators. Finally, I will give a perspective on www.depod.org, the human dephosphorylation database, and how it can aid phosphatase modulator design. (c) 2017 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. PMID- 28876541 TI - Cholangiocarcinoma after choledochoduodenostomy. PMID- 28876542 TI - Re: Outcome of bridge to surgery stenting for obstructive left colon cancer. PMID- 28876543 TI - Routine magnetic resonance imaging is not the panacea to common duct stones. PMID- 28876544 TI - Response to Re: Outcome of bridge to surgery stenting for obstructive left colon cancer. PMID- 28876545 TI - Administrative data: what surgeons should know about big data. PMID- 28876546 TI - Collaborate or treat intra-abdominal metastatic colon cancer of the liver and peritoneum: which is practical for the colorectal surgeon? PMID- 28876548 TI - Surgeons and big data. PMID- 28876549 TI - Useful laboratory markers for the diagnosis of bone marrow involvement by malignant lymphoma. AB - INTRODUCTION: This study aimed to investigate the effect of bone marrow involvement by malignant lymphoma (BMI) on laboratory data and to determine the useful laboratory markers for diagnosing BMI. METHODS: We compared laboratory data between patients with and without BMI. We performed multivariate logistic regression and receiver operating characteristic (ROC) analyses to evaluate the diagnostic values of independent predictors. RESULTS: In the BMI group, platelets in peripheral blood (PLT) and megakaryocyte count in bone marrow (MgK) were significantly lower than those in the non-BMI group (PLT, P < .0001; MgK, P = .0384). The rate of peripheral blood involvement by malignant lymphoma (PBI), red blood cell distribution width (RDW), D-dimer (DD), soluble interleukin-2 receptor (sIL2R), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) was significantly higher in the BMI group than in the non-BMI group (PBI, P < .0001; RDW, P = .0190; DD, P = .0006; sIL2R, P < .0001; AST, P = .0256; LDH, P = .0002). In multivariate analysis, PBI, PLT, sIL2R, and MgK levels were independent predictors of BMI. CONCLUSION: PBI, PLT, sIL2R, and MgK may be the useful laboratory markers for BMI diagnosis. PMID- 28876551 TI - Breast ductal carcinoma in situ in an unscreened population: presentation, diagnosis and management at a single tertiary centre. AB - BACKGROUND: To determine the clinical presentation of patients presenting with isolated ductal carcinoma in situ at a single tertiary center in the Cape Town, South Africa. To review the diagnostic techniques most commonly used and the primary surgery performed for these patients. METHOD: We performed a retrospective folder review of patients diagnosed with DCIS over a period from Jan 2005 to Dec 2012, at the Combined Breast Cancer Clinic at Groote Schuur Hospital. Patients with a histological diagnosis of DCIS were identified from a prospectively collected patient database and the South African National Health Laboratory System (NHLS) histological reports and operative records. RESULTS: 42 patients with isolated DCIS were identified. This represents 1.1% (42/3636 ) of all breast malignancies managed in this period. The average age of presentation was 58 years. Most patients presented with a breast lump (23/42). The diagnosis was made on core biopsy in 14 patients while 8 patients required excision of the palpable lump to make the diagnosis. 23 patients underwent a primary mastectomy, 6 patients had a wide local excision 8( WLE) and 6 patients had radio-guided occult lesion localization (ROLL) with therapeutic intent. CONCLUSION: Though rare, the management of DCIS in this setting highlights the challenges of diagnosing and managing early breast malignancies in LMICs. PMID- 28876550 TI - Maternal Medicaid Recipient Status and Congenital Malformations among New York State Live Births in 2010. AB - BACKGROUND: Congenital malformations are a leading cause of infant mortality in the United States, and risk for some congenital malformations varies by socioeconomic status (SES). Medicaid provides health insurance for people with low income, and covers approximately half of all live births in the United States. Income level is one aspect of SES. Studies have shown relationships between SES and some congenital malformations. METHODS: This retrospective cohort study examined associations between maternal Medicaid recipient status and 46 congenital malformations in New York State for birth year 2010. The impact of Medicaid continuous enrollment (CE) status was evaluated in a sub-analysis of Medicaid recipients. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals. RESULTS: The study cohort included 240,721 live births, 3778 infants with one or more congenital malformation of interest, and 118,631 maternal Medicaid recipients at the time of the infant's birth. Odds ratios for cleft lip with or without cleft palate and rectal atresia or stenosis were increased for Medicaid recipients compared with non-Medicaid recipients. However, odds ratios for cleft lip with or without cleft palate and rectal atresia or stenosis were decreased for CE compared with non-CE Medicaid recipients. CONCLUSION: Maternal Medicaid recipient status was associated with few of the 46 congenital malformations evaluated. However, some associations found were modified by CE in Medicaid. Birth Defects Research 109:1460-1470, 2017.(c) 2017 Wiley Periodicals, Inc. PMID- 28876552 TI - Breast Cancer and HIV: a South African perspective and a critical review of the literature. AB - BACKGROUND: The diagnosis of breast cancer and concurrent HIV in South Africa is common. The limited current evidence on this subject suggests that the patients thus afflicted appear to be younger, have a more advanced stage of breast cancer, have a higher treatment related complications and poorer outcomes. This paper reviews the literature related to HIV and breast cancer, with a view to improving the standard and quality of care of HIV positive breast cancer patients. METHOD: Pubmed, EBSCOhost, Google scholar and Science Direct electronic databases were searched from 2001 and 2015. using the terms ('HIV' OR 'human immunodeficiency virus' OR 'AIDS' OR 'Acquired Immunodeficiency Syndrome') and 'breast cancer' or 'breast carcinoma' to identify all publications related to HIV and breast cancer. Titles and abstracts were evaluated for eligibility and appropriate full text articles obtained. The data extraction variables included the type of study, year of publication, study setting, participants, sample size, outcome measures and main findings. RESULTS: Only five studies fulfilled the criteria, in respect of the aforementioned maladies, with twenty or more participants in each study. Evidence suggested that breast cancers develop at a much younger age in the HIV positive patient compared to the HIV negative patients, with more aggressive appearing tumour biology. Overall, it appears that HIV positive patients experienced a higher cancer-specific mortality than HIV negative patients, and this is independent of the stage of the cancer or the cancer therapy received, further the relationship between the HIV syndrome and breast cancer is currently marginal and inconclusive, and hence requires further investigation. CONCLUSION: The prescription and administration of chemotherapy is a challenge, with potential complications impacting on the morbidity and mortality in HIV positive patients. Currently there are no reliable predictors of those at risk to complications from chemotherapy; however, being on ART appears to provide an acceptable safety profile. HIV positive patients are best managed in the context of a multi-disciplinary team in order to achieve favourable outcomes in the treatment of cancer. Well-designed prospective trials to assess the response to multimodal therapy, and the long-term outcomes of HIV positive patients with breast cancer are needed. PMID- 28876553 TI - The circumareolar approach to gynecomastia and transgender surgery: modifications to provide correct nipple areolar complex position and shape. AB - BACKGROUND: In surgery for gynaecomastia, excision with minimal scarring and correct position of the nipple areolar complex (NAC) are key to a successful outcome. We report on a pilot study on the use of a circumareolar excision and the use of mathematical vector calculation to position the NAC and execute surgery and report on the outcomes. METHOD: From 2014 to 2015, the authors operated on 9 gynecomastia or transgender patients. Based on research performed by Gertrude Beer, Beckenstein and Shulman we designed a mathematical modification of the technique described by Persichetti to provide correct NAC positioning as well as aesthetically pleasing NAC shape. We utilised the technique in 6 patients, 4 males with gynecomastia and 2 transgender patients. Liposuction was performed as an adjunct as needed. RESULTS: In 5 of the patients, the NAC did move in the direction of the desired vector. The NAC was on average within 0.4 cm of the desired nipple to mid-sternal position. The lateral movement averaged 0.6 cm. We found the modified circumareolar approach to deliver good aesthetic results with predictable NAC movement. Seroma formation was the most common complication. CONCLUSION: The mathematically modified circumareolar approach to transgender and gynecomastia surgery may provide better aesthetic outcomes. Several factors need to be considered in deciding how the oval shaped vector should be designed intraoperatively. The study was limited by small sample size and short follow-up. PMID- 28876554 TI - Surgical anatomy of reduction mammaplasty: a historical perspective and current concepts. AB - Reduction mammaplasty is the volumetric reduction in the bulk of the breast. Techniques have evolved from primarily reducing the breast bulk to reducing with emphasis on functional and aesthetic outcome. The deeper understanding of the surgical anatomy of the breast has guided this development. While Paulus Aegina (sixth century AD), Dieffenbach (1848) and Gaillard-Thomas (1882) set the pace in glandular reduction; Pousson (1897) and Dehner (1908) focused on breast ptosis. It took quite some time before the enigma of the vascularization to the nipple areolar complex could be solved. Progress over a decade saw Thorek's (1922) free nipple grafting replaced by the periareolar de-epithelialization introduced by Schwarzmann (1930); which subsequently gave way to the Gillies and McIndoe (1939) skin-gland undermining technique. The era of breast remodeling while preserving the nipple areolar complex was soon ushered forward. This was driven by Arie (1957), Strombeck (1960) and Pitanguy (1961). The preservation of the subdermal plexus became crucial whilst retaining sensory supply to the breast as the pectoral fascia was spared. Skoog's (1963) nipple transposition without skin gland undermining formed the basis for modern day reduction mammaplasty. Aesthetics was in mind throughout this period as different skin incisions were developed and advanced following Dieffenbach's small submammary incision in 1848. Surgical landmarks that ensured reproducible aesthetic outcomes were described by Penn (1955) and Wise (1956). Liposuction-assisted reduction was introduced by Teimourian in 1985 and is best utilised in patients with predominantly fatty breast tissue. PMID- 28876555 TI - An overview of risk factors for recurrent breast cancer. AB - The multidisciplinary management of Breast Cancer (BC) has evolved over the past 50 years: the patient is offered a choice of surgical procedures with or without radiation therapy, cytotoxics and treatments targeting the nuclei of the cancer cells. This has resulted in a reduction of disease recurrence and a significant increase in 5-year survival. But these good results deteriorate over time and almost 20% women with early stage, oestrogen-receptor (ER) positive BC will suffer recurrent cancer at 10 years. The aim of this review is the identification of risk factors for the recurrence of BC, to examine pathogenic pathways leading to BC and to report on modifications to lifestyle, surgical procedures and treatment regimes which can reduce the recurrence of BC. Patient factors associated with increased risk included the extremes of age, ethnicity, genetic inheritance obesity and alcohol ingestion. Human Immunodeficiency Virus (HIV) was not identified as a cause of BC. Treatment-related factors included microscopically positive excision margins, delay in initiation of adjuvant chemoradiation and lack of compliance with endocrine therapy. Reclassifying BC according to molecular subgroups more accurately identifies patients at risk for recurrence and aids in the appropriate selection of therapy targeted to the primary and lymphatic metastases. PMID- 28876556 TI - Crossbow injury to the neck. AB - Crossbow injuries are uncommon among penetrating trauma. The tendency for a crossbow bolt to remain in situ appears to limit catastrophic haemorrhage despite the involvement of major vessels.1 Here we report our experience with an injury to the left internal jugular vein by a crossbow bolt. The injury was successfully treated by emergency neck exploration. PMID- 28876557 TI - Primary fusobacterium osteomyelitis and pyomyositis of the thigh in an immunocompetent young adult. AB - An unusual case of an immunocompetent young adult with osteomyelitis and pyomyositis of his right thigh is presented. Despite the absence of typical clinical signs, a high index of suspicion and 16S RNA PCR led to an early diagnosis of Fusobacterium infection and subsequent successful multidisciplinary treatment. PMID- 28876558 TI - Parathyroid adenoma with concurrent toxic thyroid adenoma: a rare combination. AB - BACKGROUND: Hypercalcemia in association with hyperthyroidism is a well recognized phenomenon. Primary hyperparathyroidism due to parathyroid adenoma in association with thyroid adenoma is extremely rare. These cases can present a diagnostic and therapeutic challenge to the treating physician as the patient may present with symptoms of either disease. CASE SUMMARY: A 47-year-old female patient presented with non-specific complaints including fatigue and muscle cramps. Diagnostic workup revealed significantly elevated plasma calcium levels in association with hyperthyroidism. There was a considerable delay in measuring the parathyroid hormone levels which were significantly elevated. Nuclear medicine studies revealed features consistent with a parathyroid adenoma and a concurrent thyroid adenoma. The patient was rendered euthyroid and subsequently taken to theatre for a thyroid lobectomy and removal of the associated parathyroid adenoma. One year later the patient remains normocalcemic, euthyroid and clinically well. CONCLUSION: Toxic thyroid adenoma with concurrent parathyroid adenoma and primary hyperparathyroidism is rare. The possibility of primary hyperparathyroidism should be considered where hypercalcemia persists on correcting the hyperthyroidism. Removal of both adenomas will result in cure of the patient. PMID- 28876559 TI - Does gender impact on female doctors'experiences in the training and practice of surgery? A single centre study. AB - BACKGROUND: Surgery has been identified as a male-dominated specialty in South Africa and abroad. This study explored how female registrars perceived the impact of gender on their training and practice of surgery. METHOD: A self-administered questionnaire was used to explore whether females perceived any benefits to training in a male-dominated specialty, their choice of mentors and the challenges that they encountered during surgical training. RESULTS: Thirty-two female registrars participated in the study. The respondents were mainly South African (91%) and enrolled in seven surgical specialties. Twenty-seven (84%) respondents were satisfied with their training and skills development. Twenty four (75%) respondents had a mentor from the department. Seventeen (53%) respondents perceived having received differential treatment due to their gender and 25 (78.2%) thought that the gender of their mentor did not impact on the quality of the guidance received in surgery. Challenges included physical threats to female respondents from patients and disrespect, emotional threats and defaming statements from male registrars. Additional challenges included time constraints for family and academic work, poor work-life balance and being treated differently due to their gender. Seventeen (53%) respondents would consider teaching in the Department of Surgery. CONCLUSION: Generally, females had positive perceptions of their training in Surgery. They expressed concern about finding and maintaining a work-life balance. The gender of their mentor did not impact on the quality of the training but 'bullying' from male peers and selected supervisors occurred. Respondents will continue to recommend the specialty as a satisfying career to young female students. PMID- 28876560 TI - What is the diagnostic yield of colonoscopy in patients with a referral diagnosis of constipation in South Africa? AB - BACKGROUND: Constipation is a common problem for referral to surgical and colorectal units. Its association with colorectal cancer is controversial. Some authors have found an increased incidence while others have not. The aim of this study is to investigate the incidence of colorectal cancer (CRC) and other significant colonoscopic pathologies in patients undergoing colonoscopy for constipation. METHOD: All colonoscopy reports for constipation were retrieved from our database from January 2011 to 30 June 2014. Data extracted included demographics, colonoscopic findings and adequacy of bowel preparation. Exclusion criteria included patients with other symptoms known to be associated with colonic neoplasia such as lower GIT bleeding, loss of weight, patients with associated anaemia, those with abnormalities on imaging, patients with personal or family history of colorectal cancers or colorectal polyps and patients with inflammatory bowel disease. The primary outcome was the presence of neoplasia at colonoscopy and the secondary outcomes were other colonoscopy findings. RESULTS: A total of 985 colonoscopies were performed from January 2011 to June 2014 of which 144 were done for a referral diagnosis of constipation. Eighty eight (61.1%) were female. Their mean age was 58.6 + 13.8 years (range 19-95 years). There were 61 (42.4%) African patients, 38 (26.4%) White, 33 (22.9%) Asians and 12 (8.3%) Coloured patients. Eighty seven (60.4%) patients had a normal colonoscopy, 20 (13.9%) diverticular disease, 14 (9.7%) polyps of which 6 (4.2%) were neoplastic, and 9 (6.3%) had colorectal cancer. CONCLUSION: Constipation is associated with CRC. The presence of constipation should be a criterion for colonoscopy regardless of age or any other associated clinical features. PMID- 28876561 TI - Predictors of emergency colectomy in patients admitted with acute severe ulcerative colitis. AB - BACKGROUND: Acute Severe Ulcerative Colitis (ASUC) is a life-threatening condition which requires urgent and aggressive medical therapy to reduce mortality, morbidity and avoid surgery. To facilitate this process, it is essential to identify patients at high risk of poor outcomes and emergency colectomy. Numerous such risk factors have been described in Western literature, however there is no local data addressing this issue. As such it is unclear if these predictors are applicable in our setting. The aim of this study is thus to identify risk factors for emergency colectomy in patients admitted to Groote Schuur Hospital with ASUC. METHOD: A retrospective cohort study of 98 patients admitted with ASUC between January 2003 and January 2013 was performed. Clinical, demographic, laboratory and endoscopic factors on admission and 3 days thereafter were analysed as predictors of colectomy by univariate and multivariate analysis. RESULTS: Twenty-five percent of the cohort underwent emergency colectomy. On univariate analysis, factors predicting colectomy on admission were exposure to oral corticosteroids (p=0.01), megacolon (p=0.049) or mucosal islands (p=0.04) on abdominal X-ray, and a short duration from UC diagnosis until presentation with ASUC (p=0.04). The only variable that was significantly associated with colectomy on day 3 was serum albumin (p=0.01). This was also the only variable to remain significant on multivariate analysis (OR 0.79, 95% CI 0.65-0.97, p=0.01). CONCLUSION: ASUC is a medical emergency and predicting colectomy risk aids in therapeutic management. The only variable significantly associated with the need for surgery in our study was hypoalbuminaemia on day 3. Given the small study numbers a larger prospective study would be of value. PMID- 28876562 TI - Resection of benign liver tumours: an analysis of 62 consecutive cases treated in an academic referral centre. AB - BACKGROUND: Benign tumours of the liver are increasingly diagnosed and constitute a substantial proportion of all hepatic tumours evaluated and resected at tertiary referral centres. This study assessed the safety and outcome after resection of benign liver tumours at a major referral centre. METHOD: All patients with symptomatic benign liver tumours who underwent resection were identified from a prospective departmental database of a total of 474 liver resections (LRs). Demographic data, operative management and morbidity and mortality using the Accordion classification were analysed. RESULTS: Sixty-two patients (56 women, 6 men, median age 45 years, range 17-82) underwent resection of symptomatic haemangiomata n=23 (37.1%), focal nodular hyperplasia n=19 (30.6%), biliary cystadenoma n=16 (25.8%) and hepatic adenomas n=4 (6.5%). A major resection was required in 25 patients, 14 patients had 4 segments resected, 11 had 3 segments and 37 patients had 2 or fewer segments resected. Median operating time was 169 minutes (range 80-410). Median blood loss was 300 ml (range 50-4500 ml) and an intra-operative blood transfusion was required in 6 patients. Median length of post-operative hospital stay was 7 days (range 4-32). Complications occurred in 11 patients (Accordion grades 1 n=1, 2 n=4, 3 n=1, 4 n=4, 6 n=1). Four patients required re-operation (bleeding n=2, bile leak n=1, small bowel obstruction n=1). An elderly patient died in hospital on day 16 following a postoperative cerebrovascular accident. CONCLUSION: Clinically relevant symptomatic benign liver tumours comprise a substantial proportion of LRs. Our data suggest that resections can be performed safely with minimal blood loss and transfusion requirements. We advocate selective resection according to established indications. Despite the low postoperative mortality rate, the risk of postoperative complications emphasizes the need for careful selection of patients for resection. PMID- 28876563 TI - Defining predictors of mortality in pediatric trauma patients. AB - BACKGROUND: The aim of this study was to describe our cohort of pediatric trauma patients and to analyze their physiological data. The intention was to highlight the difficulty in using systolic blood pressure (SBP) readings in this population and to investigate the role of base excess (BE) in predicting clinical outcomes in pediatric trauma patien. METHOD: The Pietermaritzburg Metropolitan Trauma Service (PMTS) maintains a prospective digital trauma registry, and all pediatric trauma patients admitted to the service for the period January 2012 - July 2016 were included. RESULTS: Out of an original dataset of 1239 pediatric trauma patients admitted to the emergency departments of the PMTS, 26 elective patients and 216 patients with missing SBP were excluded to leave a sample size of 997 patients. The majority of the sample was male accounting for 669 patients (67.2 %) with 327 females (32.8%) and 1 (0.1%) missing data. The mean age (SD) was 7.7 years (3.9) and the median age (IQR) was 8 years (5 - 11). There were 58 children < 2 years of age, 177 between the age of 2 to < 5 years of age, 402 between 5 to < 10 years of age and 360 between 10 and < 15 years of age. The predominant mechanism of injury was blunt trauma (78.4% or 782/997). Penetrating trauma accounted for 11.0% of cases (110/997). The mean systolic BP (SD) across the whole cohort was 110.1 mm Hg (16.9) and the median systolic BP (IQR) was 110 mm Hg (100-119). Mortality rate remains low and then precipitously increases below a SBP of 93 mm Hg in children older than 2 and below 89 mm Hg in children younger than 2. This suggests that a SBP of 93 mm Hg or less in children older than 2 and 89 mm Hg or less in children under 2 years is clinically significant. Similarly, as BE decreased, the mortality risk also increased prominently. CONCLUSION: This study has used a previously described methodology based on large developed world trauma databases and confirms the current thinking that SBP is a late marker and thus not useful in the pediatric population and a better system/ approach is needed. The use of BE in conjunction with SBP may be a more useful means of identifying shock. PMID- 28876564 TI - Oesophageal squamous cell cancer in a South African tertiary hospital: a risk factor and presentation analysis. AB - BACKGROUND: Squamous carcinoma of the oesophagus (SCO) is the most common form of oesophageal cancer in South Africa (SA). Risk factors include male gender, smoking, alcohol consumption and low socio-economic status (SES). This study assessed the risk factors for SCO in KwaZulu-Natal. METHOD: Information on patients managed at Inkosi Albert Luthuli Central Hospital (IALCH), Durban, South Africa, between 1 October 2013 and 31 December 2014 was retrieved from a prospective database of Oesophageal Cancer (OC). Data collected included demographics, risk factors, symptoms and clinical findings. RESULTS: One hundred and fifty-nine patients (159) with SCO were identified. The site of tumour location was in the middle 96 (60.4%), distal 42(26.4%) and proximal 17(10.6%) oesophagus. The male to female ratio was 1:1 with an age range of 22-93 years (mean 60.6; SD+/-12.1). Females were significantly older than males (p = 0.018). Eighty-eight per cent were Black African. Dysphagia was reported in 158 (99.4%) of patients and loss of weight in 149(95.5%). Thirty-six patients were HIV positive (age 52.8; SD+/-9.7) and significantly younger than those without HIV infection (age 61.2; SD+/-11.5). Most patients had low SES and poor dental health. Male patients were significantly more likely to use tobacco (p < 0.001; Odds Ratio (OR) 7.8) and consume alcohol (p < 0.001; OR 7.7) than females who were 2.5 times more likely to report a family history of cancer (p = 0.017; OR 2.6). CONCLUSION: An equal gender distribution was observed. Male patients with SCO reported the expected risk factors; however these were not observed amongst women. SES may contribute to the development of SCO. Poor dental health may be a surrogate marker for low SES and a possible risk factor for SCO. HIV positive individuals present a decade younger when compared with HIV negative patients. PMID- 28876565 TI - Pattern and distribution of peripheral arterial disease in diabetic patients with critical limb ischemia (rutherford clinical category 4-6). AB - BACKGROUND: This study investigated the pattern and distribution of peripheral arterial disease in diabetic patients with critical limb ischaemia (CLI) and to stratify the findings according to the patients' risk factor profile, gender and age group. METHOD: We conducted a one-year prospective descriptive study (January 2014 to December 2014) at Groote Schuur Hospital, University of Cape Town. The research protocol and the informed consent were approved by the Institutional Review Board, and all subjects included in this study gave an informed consent. We included all diabetic patients over the age of 18 years with critical limb ischemia who had pre and post-intervention vascular imaging. The calculated minimum sample size was 63 limbs. We hypothesize that the proportions of arterial segment patency categories and the arterial foot arch status varies according to gender, age group and risk factor combinations in diabetic patients. The Null hypothesis (N0) assumes that the proportions of arterial segment patency categories and arch status are the same in diabetic patients irrespective of gender, age group and risk factor combination. The equality of distribution was analysed using the One Sample Chi-square test. Three risk factor combination groups were analysed: Group 1 (diabetes mellitus, hypertension, dyslipidemia), Group 2 (diabetes mellitus, hypertension, dyslipidemia, ex-smoker) and Group 3 (diabetes mellitus, hypertension, dyslipidemia, smoker). RESULTS: Seventy-one patients were analysed (38 females and 33 males). We recorded the patency grades (ranging from normal to occlusion) of arteries in all 3 lower extremity arterial segments (aortoiliac; femoropopliteal and tibioperoneal segments). Altogether the patency grades of 820 lower extremity arteries were recorded. Diabetics, collectively, were found to have more severe occlusive disease in the tibioperoneal segment (P < .001). Group 3 patients however, had more severe occlusive disease in the femoropopliteal segment compared to the other subgroups (P < .001). Group 1 and Group 2 patients had more severe occlusive disease in the tibioperoneal segment (P < .001). Females were more likely to have complete foot arches (22/37; P = .004) while males tended to have more incomplete foot arches (17/32; P = .048). CONCLUSION: Diabetic patients collectively have severe tibioperoneal occlusive disease. However, Group 3 patients tend to have disproportionately more occlusive disease in the femoropopliteal segment (P < .001). Diabetic female patients with CLI are more likely to have a complete arterial foot arch than males (P = .004). PMID- 28876566 TI - A survey of selected key areas of management of South African neurosurgical patients. AB - BACKGROUND: Previous surveys of neurosurgical patient management, including a South African (SA) survey conducted in 2001, confirmed the existence of significant dissimilarities in management on national and international levels. This survey aimed to determine current SA neurosurgical patient management and to compare this with international trends. METHOD: Questionnaires in multiple choice question (MCQ) and free text entry format covering key areas of neurosurgical practice were emailed to SA neurosurgeons following ethics approval. All responses were captured anonymously. RESULTS: The response rate was 53%. Demographically only 5.7% respondents were younger than 40 years, 59.3% obtained a local college fellowship, 14.8% an international fellowship, 40.7% a MMed and 16.6% obtained more than one postgraduate qualification. Public sector specialists predominantly practised intracranial surgery (69%) while private specialists practised mainly spinal surgery (58%). Years in specialist practice were negatively associated with endoscopic surgery (p = 0.014) and decompressive craniectomies (p = 0.008) but not with other more recently introduced techniques including pedicle screws, neuro-navigation and cell-saver techniques. Age per se had no influence on practice. In subarachnoid haemorrhage (SAH) disease, 88% routinely administered nimodipine, 8% restricting its use to managing vasospasm. Endovascular coiling, more recently introduced for intracranial aneurysm management, was preferred to surgical clipping (54%); 69% preferred total intravenous to inhalational anaesthesia with propofol primarily replacing thiopentone for brain protection. 27% still utilised the sitting position. Only one incident of a postoperative visual defect was recorded with prone positioning. CONCLUSION: With the exception of endoscopic and decompressive craniectomy surgery, overall management in key areas surveyed was in line with international trends. PMID- 28876567 TI - A REVIEW OF PRESENTATIONS TO THE SURGICAL RESEARCH SOCIETY OF SOUTHERN AFRICA AND THE ASSOCIATION OF SURGEONS OF SOUTH AFRICA FROM 2010 TO 2016. AB - This paper looks at research done in South Africa from 2010 to 2016. We reviewed a total of 679 abstracts, posters and oral presentations submitted to the SAJS and the ASSA congresses during this time. During this time 21945 patients were investigated with an average of 577,5 patients per study. Each paper had on average 3,5 authors. The most popular topics are trauma (23%), gastrointestinal surgery (18%) and breast (11%). Upcoming topics include: reducing sepsis, global surgery, procedural discussion, infectious diseases (HIV/ TB), post-operative healing, ENT, neuro, plastic surgery, cardiothoracic and paediatric surgery. The most active centres are the University of KwaZulu-Natal (27%), WITS (22%) and UCT (21%). There has been a marked decrease in animal studies. There has been an increase in work done by surgical registrars, medical officers and students and the number of collaborations between centres and internationally are increasing. PMID- 28876568 TI - AN ANALYSIS OF THE INEQUALITIES BETWEEN THE PUBLIC AND PRIVATE SECTOR IN SOUTH AFRICA. AB - BACKGROUND: The full extent of the global burden of surgical disease is largely unknown, however, the scope of the problem is thought to be large. Despite the substantial burden of surgical disease, surgical services are inaccessible to many of those who need them most. There are disparities between public and private sectors in South Africa, which compounds inequitable access to surgical care. METHOD: This study involved a descriptive analysis of surgical resources and included the total number of hospitals, of hospital beds, the number of surgical beds, the number of general surgeons (specialist and non-specialist), and the number of functional operating theatres in South Africa. A comparison was performed between the public and private sectors. Hospitals were contacted during the period from the 1st October 2014 until the 31st of December 2014. RESULTS: Surgical resources were concentrated in metropolitan areas of urban provinces. There were striking differences between the public and private sectors, where private resources were comparable to those available in high income countries (HICs). CONCLUSION: Improving access to surgical services in lower middle income countries (LMICs) requires addressing gaps between the public and private sector regarding infrastructure, personnel, as well as equipment. South Africa is unique in that although it is classified as an upper middle income country (UMIC), is comprises of two sectors; a public sector which has resources similar to other LMICs, and a private sector which has resources similar to HICs. These data identified disparities between geographic regions which may be contributing to ongoing inequity in South Africa, and by doing so allows for evidence-based planning towards improving surgical infrastructure and workforce. PMID- 28876569 TI - CHOLECYSTECTOMY TRENDS IN SOUTH AFRICA. SHOULD WE BE WORRIED? AB - BACKGROUND: Gallbladder disease is a common and costly pathology worldwide. The development of gallstone disease varies among population groups around the world. Epidemiological studies from African countries, including South Africa, Nigeria, Kenya and Uganda suggest that the rate of gallbladder disease is low in the African population. Very little has been published in the last 20 years about the status of gallbladder disease in South Africa. METHOD: 34294 cholecystectomy specimens were obtained from the NHLS (2003-2015) database. Two periods were analysed, period 1 (2003-2009) and period 2 (2009-2015). RESULTS: In South Africa, the number of cholecystectomies have increased by 37% in period 2. Seven of the eight analysed provinces recorded an increase in the number of cholecystectomies performed. Of these seven, four were a statistically significant increase. The other three provinces also demonstrated an increasing trend but this did not reach statistical significance. The Northern Cape was the only province to record a decline in the number of cholecystectomies. CONCLUSION: The increasing trend in cholecystectomies is certainly worrying from a cost and burden of gallbladder disease standpoint. This is particularly worrisome as our population has generally been regarded as being at low risk for the development of gallbladder disease. The results suggest a possible change in the disease pattern in South Africa. PMID- 28876570 TI - COHORT STUDY ON EMERGENCY GENERAL SURGERY PATIENTS AND AN OBSERVATION UNIT. AB - BACKGROUND: Medium-sized, non-trauma hospitals experience many of the same difficulties as tertiary centres do when it comes to managing emergency general surgery patients. However, acute surgical units are not a financially viable option in these hospitals. To improve the care of emergency general surgery patients at one such hospital, a Rapid Assessment Medical Surgical (RAMS) unit was developed to decrease the time to review and increase the efficiency in caring for these patients. METHOD: To assess the Unit's effect, a prospective analysis was completed of the patients who came through the RAMS unit over a six month period and compared with a retrospective analysis of patients presenting in the same six-month period the year prior to the Unit's instigation. RESULTS: The RAMS unit was effective in providing an avenue for faster review by the surgical team. This resulted in patients leaving the emergency department faster, decreased the number of patients that breached Emergency Department time-targets and increased the number of patients discharged after a period of observation or basic treatments. CONCLUSION: General surgery patients were managed more efficiently with the RAMS unit in place. However, a full cost analysis is required to determine if such units are cost-effective. PMID- 28876571 TI - DUODENECTOMY: MANAGING THE FISTULA. AB - BACKGROUND: Duodenectomy is rarely indicated, however, in certain circumstances may have be performed. Enterocutaneous fistula (ECF) is the main cause of serious adverse outcomes. Its management remains challenging. METHOD: Two cases of emergency duodenectomy are presented. The management of ECF is described and discussed. RESULTS: Case 1: A 22-year-old male presented in septic shock with perforated duodenal ulcer, suffered two cardiac arrests before index surgery. During re-laparotomy for leak, mobilisation resulted in an extensive injury of the duodenum extending to the ampula. A drainage procedure with complete duodenectomy and gastrojejenostomy was performed. The bile and pancreatic ducts were cannulated with infant feeding catheters and were separately pumped in the gastrostomy with a feeding pump. In one week, the patient had oral intake in addition to infused feeds. He remained in hospital for six months, suffered six episodes of gram-negative sepsis requiring antibiotics. Three episodes resulted from blocked catheters and cholangitis. Other were central line sepsis. A reconstruction with separate limbs of jejunum to the bile and pancreatic ducts was performed. He was well at 18 months post final surgery. Case 2: A 63-year-old male presented with a perforated hepatic flexure colonic carcinoma. Intraoperatively, the tumour invaded and partly obstructed the duodenum which was injured during mobilisation. A duodenectomy with the right hemicolectomy was performed. The jejunum was anastomosed to the ampulla. Leaking effluent from a drain was pumped into the gastrostomy. He was discharged in three weeks and continued to transfer the effluent himself with a 60 ml syringe until the leak ceased. Three months post-surgery, he developed metastasis to the drain tract and died in two months. CONCLUSION: Duodenectomy is feasible but complications are difficult to manage. ECF is common and should be managed by pumping the effluent in the gastrostomy until definitive surgery or spontaneous closure of the fistula. PMID- 28876572 TI - HAEMOPERITONEUM SECONDARY TO SNAKE BITE. AB - BACKGROUND: Literature supports that very rarely the venom of "Hemotoxic Snake" (Russell's Vipers) affect haemostasis by secreting thrombin-like enzyme which promotes formation of unstable clots. Such clots could lead to fibrin deposition in micro circulation that in turn consume platelets and coagulation factors (consumption coagulopathy). Clinical presentation is mainly spontaneous bleeding and coagulopathy. In this case the significant effects of altered coagulation were observed in retropetitoneum and the patient presented in casuality as acute abdomen. CASE DESCRIPTION: A 17-years-old boy presented to a tertiary care hospital, complaining of abdominal pain for 5 days and fatigue. He gave a history of snake bite 10 days prior. In order to seek immediate medical care, he went to the community hospital where antivenom was given. Upon examination he was vitally stable. Abdomen was found distended and severely tender. On workup after admission he was found to be anaemic (Hb: 6 g/dl), and damaged clothing profile (PT: 19.5 and INR: 1.7). CT scan showed collection of 7x6.6 cm in right paracolic and right lumbar region, just anterior to the psoas muscle. Active intra abdominal bleeding and few organised hematomas were also appreciated. Prior to the specific management, patient was optimised with PCVS and FFPS. After 28 hours he was explored under G/A. Perioperatively about 1100 ml of blood was evacuated from the peritoneal cavity. Multiple hematomas were drained from retroperitoneum (Zone II), on right side. No active bleeding was noticed from IVC and aorta. Packing done and drains placed. Re-exploration was done after 72 hours. Packs removed and further hemostasis was augmented with fibrillar and gelatin sponge. CONCLUSION: He had steady recovery, with 14 days of hospital stay. One of the concerns in postoperative phase was bradycardia that compelled us to manage it with atropine. PMID- 28876573 TI - HEMOSUCCUS PANCREATICUS FROM RUPTURED SPLENIC VEIN PSEUDOANEURYSM SECONDARY TO NECROTIZING PANCREATITIS: A CASE REPORT. AB - Hemosuccus pancreaticus is a rare cause of gastrointestinal bleeding in which haemorrhage occurs from the ampulla of vater via the pancreatic duct, mostly from ruptured pseudoaneurysms. Our patient is a 25-year-old Filipino male who presented with intermittent epigastric pain associated with melena and decreasing haemoglobin despite multiple blood transfusions. EGD showed erythematous gastric and duodenal mucosa with no evidence of active bleeding. Whole abdominal CT scan with IV contrast showed diffusely prominent pancreas with areas of non enhancement suggestive necrosis. CT scan of the aorta revealed attenuated splenic vein with irregular margin and probable small pseudoaneurysm. Embolisation, which is the primary mode of treatment in a hemodynamically stable patient, was contemplated. However, the patient's relatives opted to pursue surgery which eventually lead to mortality due to complications of the procedure. PMID- 28876574 TI - HOLDING THE TORCH UP HIGH - A MEDICAL HISTORICAL EVALUATION OF SURGICAL ADVANCES DURING THE GREAT WAR 1914-1918, IN MEMORY OF THOSE THAT SERVED AND FELL. AB - "How wide and varied is the experience of the battlefield and how fertile the blood of warriors in raising good surgeons" Sir Clifford Allbutt (1898). With these sentiments of the medical lessons learned in war and conflict, with the background of the poem of "In Flanders Field", written by a doctor who had South African War connections, reasons (the Somme and third Ypres battles) will be given that this was indeed a "GREAT WAR" as the world history, weapons, strategy, tactics and wounding patterns had changed dramatically. These changes are still affecting all at present, as eventually the Second World War came from it, as well as the Cold "Third World" War. In this war most casualties were caused by bomb fragments and the figures were enormous. It was the war of massive troop movements (railroads), the Schlieffen plan, trench warfare, artillery, the machine guns, end of cavalry and the initiation of tanks, air warfare/reconnaissance and gas/chemical warfare. The surgical experiences of previous wars were obsolete. Urgent rethinking of surgical principles and protocols had to be devised, with the death rates of dying due to wounds, sepsis and tetanus exceeding 60 percent of all casualties. Abdominal wounds were treated conservatively, but soon there came advances in resuscitation, anaesthetics, aggressive wound and exploratory surgery, orthopaedics, plastic and reconstructive surgery, physiology, wound pathology and microbiology. All sides concentrated on ambulance stations, field hospitals and then rapid transfer to bigger referral and base hospitals. It seems that lessons learned where indeed exchanged (? by the Red Cross to all combatant medical personal). Even to the present day, frameworks of this are still used effectively (Vietnam War, Falklands War and our recent border wars). The lessons are well learned and the Torch is ours to hold up high! PMID- 28876575 TI - NEONATAL SURGERY, A STUDY OF TWO YEARS AT NELSON MANDELA ACADEMIC HOSPITAL, MTHATHA, EASTERN CAPE. AB - BACKGROUND: Advances in diagnostic techniques and perioperative care have greatly improved the outcome of neonatal surgery. Despite this, disparity still exists in the outcome of neonatal surgery between developed and developing countries. METHOD: We performed a prospective study of neonates admitted and treated due to surgical congenital diseases and other conditions in our hospital from April 2015 to April 2017. RESULTS: There were 19 (28,7%) females and 47 (70,3%) males in this group. It was found that 41 neonates had 7 days after birth or less by a 62% and 25 with more than 7 days by 38%. The Anorectal malformations (ARM) were the most frequent congenital anomaly in 21 patients (47%), followed by Gastroquises with 7 neonates (10,6%), Omphalocele with 8 (12%), and Oesophagus Atresia in 5 neonates (7,5%). Intestinal Malrotation with midgut volvulus, Pyloric Stenoses and Duodenal Atresia in 4 neonates (6,2 % each). Others alterations such as, Ileal Atresia, Strangulated Inguinal Hernia, Limb Gangrene, Necrotizing Enterocolitis, Sacro Coxigeal Theratoma, Megacolon Aganglionic, Colon perforation, Gastric perforation and Hydromethrocolpus accounted in 13 neonates by 19,7% from the total of patients. Ten babies died (15%). CONCLUSION: We conclude that Anorectal Malformations, Gastroquises and Omphalocele were the most frequent malformations. Considering the mortality is above the average of developed countries this could be improved by increasing the knowledge about the neonatal surgery characteristics among medical doctors and improving the necessary facilities and back up. PMID- 28876576 TI - RAPUNZEL SYNDROME - AFRICAN VARIATIONS ON A EUROPEAN FAIRYTALE. AB - BACKGROUND: Trichobezoars are intraluminal accretions of ingested hair. Rapunzel syndrome is a rare and extreme presentation with extension down through into the small intestine. Most frequently reported in children and psychiatric patients, we report on an African series of five patients. METHOD: Five patients presenting with trichobezoars were retrospectively reviewed and analysed with regard to patient background, demographics, clinical presentation, diagnosis, surgical management and complications. RESULTS: Five female patients with a median age of 19 years (range 12-27 years) presented with a clinical spectrum including early satiety, intermittent vomiting with gastric outlet obstruction, abdominal pain and weight loss. Three patients were of Indian ethnicity and two of African ethnicity. Four highly functional individuals (three high school graduates/ students, one university student) and a 12 year old cerebral palsy child known with trichotillomania were diagnosed with trichobezoars following either endoscopy, abdominal CT scan, barium meal or plain abdominal radiography. Two patients presented with sealed/contained gastric perforations, and one with a small bowel perforation. All five bezoars extended into the jejunum, the longest of which measured 1.4 m, and two of which consisted entirely of artificial hair extensions. Various options for removal are described including chemical dissolution, endoscopy, laparoscopy and laparotomy. All five bezoars were removed by laparotomy. All recovered well and four were referred for psychiatric evaluation. CONCLUSION: While trichobezoars are a rare entity, they may present with significant complications in the form of obstructions and perforations. In view of the risk for infection, and the considerable size of many of these bezoars, an open removal is probably safer than any minimally invasive attempt. PMID- 28876577 TI - SURGICAL BURDEN OF DISEASE AT A REGIONAL HOSPITAL IN SOUTH AFRICA. AB - BACKGROUND: There is limited published data describing the nature of surgical admissions at a regional level in the South African context. Worcester Hospital General Surgery has introduced an electronic online database to manage its surgical services. This study uses that database to evaluate the surgical burden of disease for the Cape Winelands East and Overberg districts of the Western Cape. METHOD: Admissions data were prospectively captured from February 2012 to January 2016, then retrospectively reviewed and classified into 5 types: (1) elective surgery/investigations (ESI); (2) trauma; (3) burns; (4) non-traumatic surgical emergencies (NTSE); (5) unplanned readmission within 30 days. All data were entered by attending doctors. (Stellenbosch University HREC # N16/04/054). RESULTS: 9 799 discharge summaries were included for analysis. Mean age of was 43,4 years (95% CI 43,0-43,8 years) and mean length of stay was 4,9 days (95% CI 4,7-5,1 days). 57,6% (5 647) patients were male. NTSE (47,6%), ESI (38,6%) and trauma (11,9%) form the majority of admissions. Common NTSE diagnoses were appendicitis (23,8% of NTSE admissions), peripheral vascular disease (16,8%) and peptic ulcer disease (13,3%). Common ESI diagnoses were gallstone disease (23,1% of ESI diagnoses), inguinal hernia (21,8%), anal disease (10,2%), midline primary hernia (9,1%) and incisional hernia (8,6%). Most prevalent cancer diagnoses were colorectal (17,6% of cancer diagnoses), oesophagus (16,4%), breast (14,0%) and stomach (13,2%). Overall in hospital mortality rate was 2.2% - highest by subtype was burns patients (6,3%). Trend analysis show a statistically significant increase in admission for NTSE (p=0.019) and 30 day readmission rates (p < 0.001) with a decrease in admissions for ESI (p=0.001) over the four year period. CONCLUSION: A precise understanding of burden of disease profile is essential for national, provincial and district resource allocation. Ongoing surveillance such as is performed in this study provides this critical information. PMID- 28876578 TI - THYROID CANCER CONSEQUENCES OF IODINE DEFICIENCY - A PERSISTING WORLDWIDE PROBLEM: CHARACTERISTICS IN DIFFERENT POPULATIONS, PORTUGAL AND SOUTH AFRICA. AB - BACKGROUND: Iodine deficiency (ID) still affects over two billion people worldwide (266 million school aged children). Pathology patterns in ID include: increase in thyroid cancer, higher percentages of follicular and anaplastic cancers and inversion of the papillary/follicular thyroid cancer frequency ratio. China succeeded in eliminating ID through legislation introduced in 1987 aimed at availability of iodized salt countrywide and South Africa through legislation introduced in 1995. Portugal has no national general population data on iodine nutrition (IN). METHOD: Comparative evaluation of thyroid histology reports over a 6 year period in BI and a 5 year period in JHB area. Median urinary iodine concentration (UIC) was possible to obtain from BI. RESULTS: Region of BI: 279 histology reports evaluated - 60 malignancies (21.2%): 31 papillary carcinomas, 22 follicular cancers (18 follicular carcinomas and 4 Hurthle cell tumours), 3 medullary carcinomas and 4 anaplastic carcinomas. Region of JHB: 136 histology reports - 3 malignancies (24.3%): 13 papillary carcinomas, 15 follicular cancers (10 follicular carcinomas and 5 Hurthle cell tumours), 1 medullary carcinoma, 3 anaplastic carcinomas and 1 metastatic carcinoma into the thyroid. There was an overlap in the frequencies of all histology types including relatively high anaplastic carcinoma incidences and papillary to follicular carcinoma ratios close to 1 in both areas. BI area ratio: 1.4 and JHB area ratio 0.87, (overlapping 95% CI's and results of the chi-square calculations). The median UIC of the population sample tested was 62.6 MUg/L, 92% of samples having a UIC < 100 MUg/L. CONCLUSION: During the study periods both regions displayed patterns characteristic of ID with papillary/follicular carcinoma ratios close to 1 and relatively high number of anaplastic carcinomas. ID could be eliminated by availability of affordable iodised salt, promoting sea-based nutrition and a proactive behaviour from an informed population. These measures could be applicable to other populations in different parts of the world. PMID- 28876579 TI - WHERE ARE GENERAL SURGEONS LOCATED IN SOUTH AFRICA? AB - BACKGROUND: Human resources are the backbone of healthcare delivery systems and the lack of surgical workforce in developing countries is often the greatest challenge to providing surgical care. The workforce availability and composition is an important indicator of the strength of the health system. METHOD: A descriptive analysis of the general surgical workforce in South Africa was performed. The total number of specialist and non-specialist general surgeons working in the public sector in South Africa was documented between the periods from the st October 2014 until the 31st of December 2014. RESULTS: There were significant disparities in the number and distribution of general surgeons in South Africa. There were 1.78 specialist general surgeons per 100 000, of which 0.69 per 100 000 specialist general surgeons were working in the public sector. There were 2.90 non-specialist general surgeons per 100 000. There were 6 specialist general surgeons per 100 000 insured population working in the private sector, which is comparable with the United States (US). Urban provinces such as Gauteng, the Western Cape and KwaZulu- Natal had the largest number of specialist general surgeons per 100 000. These areas had the largest number of medical aid beneficiaries and nearly 60% of specialist general surgeons were estimated to work exclusively in the private sector. CONCLUSION: There was a major shortage of surgical providers in South Africa, and in particular the public sector. PMID- 28876580 TI - A FOUR YEAR ACROSS SURGICAL DISCIPLINE PERIOPERATIVE AND INTRAOPERATIVE EXPERIENCE OF PATIENT MANAGEMENT IN A TERTIARY ACADEMIC HOSPITAL - A REVIEW AT DR GEORGE MUKHARI ACADEMIC HOSPITAL. AB - BACKGROUND: The occurrence of iatrogenic injuries related to obstetric and gynaecological procedures can have a significant impact on morbidity as well as mortality to these patients. In this study we reviewed patients presenting with iatrogenic injuries post caesarean section and hysterectomies in order to classify types of injuries frequently encountered as well as the management of these injuries. METHOD: Over a four year period, the records of all patients presenting with iatrogenic injuries post obstetric and gynaecological procedures were reviewed. These injuries were classified according to the type of injury, frequency as well as time taken to identify the iatrogenic injury before any intervention was performed. RESULTS: One hundred and eighty two patients were identified over the four year period and the injuries can be classified as follows: Bladder Injury (28.6%%), Left Ureter Injury(12.1%), Right Ureter Injury(21.4%), Bladder and Ureter Injury (8.2%), Vascular Injury (2.2%), Small Bowel Injury (17.6%), Large Bowel Injury(6.6%), Rectal Injury (2.8%), Appendicectomy (0.6%), Small Bowel and Bladder Injury (5.5%). CONCLUSION: There is a high rate of iatrogenic injuries in this subset of patients. PMID- 28876581 TI - AN INTERNATIONAL COLLABORATIVE RESEARCH NETWORK TO DESCRIBE VARIATION IN GLOBAL CANCER BURDEN. AB - BACKGROUND: Efforts to collect data on cancer in low and middle income countries (LMICs) to date have been registry based and not detailed enough to allow risk adjustment for outcome. This study aimed to describe a novel platform's ability to address knowledge gap in surgical care of cancer in LMICs. METHOD: This study is a cancer-specific analysis of the GlobalSurg-2 study, which aimed to map international variation in operated cancer burden using a protocol-driven, collaborative methodology. Patients were grouped into high, middle and low income groups according to United Nation's Human Development Index (HDI). RESULTS: 259 hospitals across 59 countries uploaded patient-level data on patients undergoing surgery for intra-abdominal cancer, with 77.1% (1770) from high, 16.4% (378) from middle, and 6.5% (149) from low HDI countries. The proportion of patients undergoing surgery for a primary malignant indication cancer was smaller in low HDI (7.7%) and middle- HDI countries (8.2%), than high-HDI countries (20.9%). The most common types of operations performed were colonic resection/stoma formation (44.8%), rectal resections (16.9%), and gastrectomies (13.0%). There was significant regional variation in operated cancer burden. Data on variation in morbidity and mortality were captured. Validation of case ascertainment and data accuracy showed a high-level of concordance. CONCLUSION: The GlobalSurg platform has captured data on the burden of cancer surgery in LMICs. Detailed, frontline data has allowed risk-adjustment to be performed at global scale for the first time and has identified areas to target future research. PMID- 28876582 TI - APPLICATION OF GENE PROFILING IN SELECTION OF ADJUVANT THERAPY IN BREAST CANCER IN A DEVELOPING COUNTRY. AB - BACKGROUND: Outcome series for genetic profile tests (MammaPrint/70GP) with medium-term follow-up are rare. We present an outcome series with 5-year follow up from a developing country. METHOD: From 2006 to 2016, patients with histopathologically confirmed breast cancer (cT0-3 and cN0-1) were selected and decisions on adjuvant therapy post-surgery were based on 70GP. Data on outcomes were collected prospectively. RESULTS: There were 154 patients, 140 luminal type, 13 HER2 type and one triple negative; 57.8% were 70GP low-risk; only one of these did receive chemotherapy; 42.2% were high-risk; 3 patients did not receive chemotherapy. After an average follow-up of 54.1 months, only 3 systemic recurrences occurred (all skeletal metastases); all in the high-risk group that had received chemotherapy. Across both groups overall survival was 99.9% and compliance with the treatment recommendations based on 70GP was >95% in both arms. Two patients each had two tumours in the same breast with divergent 70GP results and were treated in accordance with the High-risk result. Six patients showed discordant 70GP and FISH results for HER2 where three patients did not receive Trastuzumab on basis of 70GP, none of these tumours recurred. A further 11 patients had equivocal immunohistochemistry and a FISH was not done, therapy was decided upon considering the 70GP result and none of these patients had any recurrences. CONCLUSION: Chemotherapy use was much reduced versus the rate of use with conventional methods using 70GP and it may possibly be reasonable to replace immunohistochemistry for ER, PR and HER2 with 70GP especially considering borderline expression. PMID- 28876583 TI - EFFECT OF TIMING OF SOURCE CONTROL IN PATIENTS WITH ACUTE APPENDICITIS. AB - BACKGROUND: It has been well researched that early source control is essential to patient outcome in septic condition. For appendicitis, the point at which waiting for source control affects patient outcome is not well described; the limited data that are available, advocate a decision for operative management to be taken by 72 hrs, but there is no known amount of time which is proportional to adverse patient outcomes. The aim of this study is to determine the optimum time (if any) to achieve source control in patients undergoing emergency surgery for acute appendicitis, using complications, 30-day morbidity and mortality as an analogue for effective source control. METHOD: A prospective clinical database of patients with appendicitis were identified. The data were then entered into an anonymised database and analysed for this series. Patients will be included based on clinical diagnosis made by the consulting doctor responsible for the initial encounter. Upon imaging or surgery should alternate pathology be found patients will be excluded from this study. This study is observational and will have no impact on patient management, therefore participant consent is not required. RESULTS: This study is being conducted from January to December 2017. Data are being collected at present. Provisional results will be presented after provisional statistical analysis. PMID- 28876584 TI - HYDATID DISEASE IN SOUTH-AFRICA - IS IT A DIFFERENT DISEASE IN PATIENTS WITH HIV CO-INFECTION? AB - BACKGROUND: Echinococcus granulosus remains a clinical problem in rural sheep farming communities, with HIV co-infection often seen in patients from endemic regions. METHOD: Data from a prospective database was used to identify patients with and without HIV co-infection that underwent surgery for hepatic hydatid disease between 2012 and 2017. Clinical presentation, preoperative intervention, surgical treatment, postoperative mortality and morbidity are reported according to the Accordion severity score. RESULTS: Twenty-two patients (18 women, 4 men, median age 38 years, range 19-71 years) underwent surgery, of whom 11 (50%) were HIV positive (HIV+). Two patients in each group that presented with jaundice underwent pre-operative biliary drainage (ERCP=3; PTC=1). Four patients (2 in each group) had intraperitoneal rupture on imaging. Three patients (27%), all HIV+, needed emergency surgery. Two HIV+ patients were found to have secondary infected cysts. Pericystectomy was performed in 20 patients and formal resection in 2. In 8 patients, 4 from each group, biliary communication could be identified intraoperatively. Postoperative complications occurred in 10 patients, 5 in each group of which 9 were severe. Two postoperative deaths occurred, one in each group. CONCLUSION: Fifty percent of patients with hydatid disease in our service are co-infected with HIV. HIV+ patients more often had infected cysts and more frequently required emergency surgery. PMID- 28876585 TI - INTERNATIONAL VARIATION IN OUTCOMES FOLLOWING CANCER SURGERY. AB - BACKGROUND: Surgery is an integral part of treatment for cancer, although little data exist about outcomes of cancer surgery across lowmiddle income countries (LMICs). METHOD: This study is a cancer-specific analysis from a multicentre, prospective, observational cohort study including consecutive patients undergoing elective or emergency gastrointestinal resection for cancer between January and July 2016. Patients were grouped into high, middle and low-income countries according to United Nation's Human Development Index (HDI). Factors associated with the 30-day postoperative mortality rate (POMR) were explored using a multilevel, mixed-effects regression model. RESULTS: 2297 patients undergoing cancer surgery from 259 hospitals in 59 countries were included, with 6.5% from low-HDI, 16.4% from middle-HDI and 77.1% from high-HDI countries. In low-HDI countries there were more patients presenting as an emergency than in middle or high-HDI countries (24.2% vs.15.6% vs.14.5%). The 30-day POMR was higher in low- (16.8%) than middle- (6.1%) or high-HDI countries (3.2%). The factors associated with 30-day POMR included low-HDI (OR=1.75, 95% CI=2.66-12.47), an emergency operation (OR=4.31, 95% CI=2.64-7.04), perforation (OR=3.97, 95% CI=1.79-8.82), and ASA III or above (OR=4.05, 95% CI=2.21-7.40). CONCLUSION: There is wide variation in outcomes of surgery for gastrointestinal cancer around the world. More cases needed emergency surgery in LMICs, which may highlight differences in access to care. PMID- 28876586 TI - IS KI67 PREDICTIVE OF TUMOUR RESPONSE TO NEOADJUVANT CHEMOTHERAPY AND TO LONG TERM DISEASE OUTCOME IN BREAST CANCER PATIENTS AT DR GEORGE MUKHARI ACADEMIC HOSPITAL: A PRELIMINARY REPORT. AB - BACKGROUND: The difference in tumour response to neoadjuvant chemotherapy has been attributed to difference in tumour biology. Ki67, a proliferative protein, is one of the molecular markers that are used to predict tumour response to chemotherapy. A high Ki67 index and or a decrease in Ki67 index after a short term of NAC is said to predict clinical and pathological response and thus disease free survival but not over-all survival. METHOD: A prospective study. Core needle biopsy is repeated after 2 cycles of NAC (8 weeks) in Stage IIb and Stage III breast cancer patients and is compared to base-line biopsy. The trend of Ki67 is then compared to clinical response (after 8 weeks) and or pathological response after surgery. RESULTS: Fifty one patients gave consent for repeat biopsy. Biopsy was repeated in 43 patients and repeat Ki67 was only reported in 31 patient aged 32 to 81 years. Thirteen patients with luminal A cancer, 8 luminal B, 3 Her 2+ve and 7 triple negative cancer. Ki67 levels dropped in comparison to baseline values in 14 patients (45,16%), increased in 12 patients (38,71%) and remained stable in 5 patient (16,13%). Fifteen patients (48,39%) had good clinical response. In 9 patients (60%), this correlated with a drop in Ki67, 5 (33,33%) had increase in Ki67 and 1 (6,67%) stable Ki index. Sixteen patients (51,61%) had poor clinical response. In 9 patients (56,25%) this corresponded with increase in Ki67 index, 5 (31,25%) had a decrease in Ki67 value and 2 (12,5%) stable values. CONCLUSION: Due to the small number of patients analysed, it cannot be concluded that clinical response to 2 cycles of NAC (8 weeks) correlated with Ki67 values. A minimum of 100 patients is needed. PMID- 28876587 TI - IS ROUTINE STAGING LAPAROSCOPY IN POTENTIALLY RESECTABLE DISEASE JUSTIFIED IN GASTRIC CANCER? A SINGLE UNIT EXPERIENCE. AB - BACKGROUND: Gastric adenocarcinoma is a heterogenous disease with often a late presentation. Staging laparoscopy (SL) improves the detection of metastases not visible on standard cross-sectional imaging. Routine SL may avoid unnecessary surgical exploration in a significant proportion of patients. METHOD: A retrospective review of a prospectively maintained database was performed identifying the use of routine SL in patients presenting with potentially resectable gastric (GCA) and oesophagogastric junction (OGJ) adenocarcinoma; with patients presenting between April 2013 and April 2017 to a single surgical unit reviewed. RESULTS: A total of 323 patients were identified with 14% African, 21% Caucasian and 75% of Coloured ethnicity. Sixty six per cent of GCA and 62% of OGJ cancers were male. The median age of GCA presentation was 63 years (range 31-88 years) and 61 years (range 37-83 years) for OGJ cancers. Ninety six GCA and 24 OGJ patients were deemed potentially resectable following staging CT, with exclusion of 203 patients irresectable on CT or due to patient comorbidities. 121 pyloric and 44 OG junction palliative stents were subsequently placed. Of the 120 resectable patients, 107 were fit and agreeable to surgery with 84 GCA and 23 OGJ patients proceeding to staging laparoscopy. Twenty eight (33%) of resectable GCA and 7 (30%) of resectable OGJ were deemed irresectable after staging laparoscopy due to occult metastatic disease. The remaining 85 patients resectable after staging laparoscopy were referred for neoadjuvant therapy with 50 eventually presenting for curative surgery (35 were not operated due to disease progression or clinical deterioration). A further 15 patients were found at laparotomy to be locally advanced and irresectable. CONCLUSION: Gastric adenocarcinoma is an aggressive disease presenting late in our environment. Staging laparoscopy should be routinely included in the pre-treatment evaluation, as a third of patients judged resectable on imaging will have occult metastases. PMID- 28876588 TI - POSTOPERATIVE TRANSIENT HYPOPARATHYROIDISM: INCIDENCE AND RISK FACTORS - A SOUTH AFRICAN PERSPECTIVE. AB - BACKGROUND: There is limited published data on the incidence and risk factors for developing postoperative hypoparathyroidism (POHP) in the South African setting. METHOD: All patients who underwent a total thyroidectomy or completion thyroid lobectomy at an academic referral centre from January 2010 to December 2015 were included in this study. Data reviewed included post-operative parathyroid hormone (iPTH) level within 24 hours of surgery, age, gender, type of operation and lymphadenectomy if performed, size and weight of thyroid glands resected, final histological diagnosis, presence of extracapsular extension of carcinomas, number of lymph nodes resected, and the number of parathyroids present in the histology specimen. RESULTS: Twenty nine per cent of patients in this unit were found to have postoperative hypoparathyroidism as defined by their immediate postoperative iPTH levels. No data on 6-8 week or 6 month PTH levels was available. Overall, there was no association between POHP and age or gender. In patients with benign histology, size, measured by weight and volume, was significantly associated with higher rates of POPH. In patients with thyroid carcinoma on final histology, lymphadenectomy and specifically the number of lymph nodes resected were associated with higher rates of POHP. CONCLUSION: The incidence of immediate postoperative hypoparathyroidism is within international standards. Standardised postoperative follow up to determine the proportion of patients with permanent hypoparathyroidism is necessary. With the identification of high risk groups, strategies to improve POPH such as autotransplantation in these subgroups should be considered. PMID- 28876589 TI - RECONSTRUCTION IN LOCALLY ADVANCE BREAST CANCER: WHO, WHAT AND WHEN? AB - BACKGROUND: Locally advanced breast cancer (LABC) is defined as the most advanced stage of non-metastatic breast cancer. While breast reconstruction is not contraindicated in this subset of patients, the decision-making process is influenced by several considerations, including recurrence risk and the need for and timing of adjuvant therapy such as radiotherapy. This retrospective analysis investigates the reconstructive procedures performed on women presenting with locally advanced breast cancer at the Netcare Breast Care Centre (NCBC) in Johannesburg. METHOD: Patients with LABC who underwent breast reconstruction were identified from a database of breast cancer patients presenting to the NCBC during a 1 year period (June 2015 - June 2016). Data collected included demographic details, histology and details regarding surgery and reconstructive procedures. RESULTS: Of the 28 patients initially identified, 6 were excluded due to incomplete information. The remaining 22 patients were all female, with a median age of 60 years (range 24-72 years). The majority (18/22) of the patients presented with infiltrating ductal carcinoma and the luminal B subtype predominated (12/22). Nineteen patients were initiated on neoadjuvant therapy prior to surgery. Breast conservation therapy was possible in 13 patients, the rest underwent mastectomy. Immediate reconstruction was performed in 13/22 patients and immediate-delayed reconstruction in 9/22. All 22 patients in the study group had autologous tissue reconstruction, and the majority (17/22) had a procedure on the contralateral breast at the same time. CONCLUSION: At the NCBC, autologous reconstruction as an immediate or immediate-delayed procedure is the preferred reconstructive strategy in LABC. PMID- 28876590 TI - SURGERY POST NEOADJUVANT THERAPY FOR BREAST CANCER: AN ANALYSIS OF 82 PATIENTS TREATED AT A SPECIALIST UNIT IN JOHANNESBURG. AB - INTRODUCTION: Neoadjuvant therapy in the breast cancer setting not only provides an indication of response to systemic therapy, but also results in tumour downsizing/downstaging, which facilitates breast conservation therapy (BCT). The aim of this retrospective analysis is to examine the surgical management of patients who have received neoadjuvant therapy for breast cancer at the Netcare Breast Care Centre (NCBC) in Johannesburg. METHOD: All breast cancer patients managed surgically at the NCBC after neoadjuvant chemotherapy/primary endocrine therapy were identified from a database of 431 breast cancer patients presenting to this facility from June 2015 to June 2016. Patients with incomplete information were excluded. Demographic information, tumour characteristics and details regarding surgical management were collected and analysed. RESULTS: Seventy-two female patients with a median age of 48 years (range 24-75 years) were included in the analysis. The majority (68/72, 94.4%) had invasive ductal carcinoma. Stage at presentation was stage I in 16 patients (16/72, 22.2%) stage II in 31 patients (31/72 43.1%) and stage III in 25 patients (25/72, 34.7%). Pathologic complete response to neoadjuvant therapy was observed in 31 patients (31/72, 43.1%), partial response in 32 patients (32/72, 44.4%) and poor response in 7 patients (7/72, 9.7%). More than half (49/72, 68.1%) of the patients had BCT. Seventeen of the BCT patients (17/49, 34.7%) had initially presented with locally advanced (stage III) disease. CONCLUSION: BCT is feasible in a significant proportion of patients treated with neoadjuvant therapy for breast cancer. PMID- 28876591 TI - THE AFRICAN SURGICAL OUTCOMES STUDY: A 7-DAY PROSPECTIVE OBSERVATIONAL COHORT STUDY. AB - BACKGROUND: Postoperative mortality represents a major global health burden. There is little internationally comparable data from Africa of outcomes following surgery. METHOD: Seven day, national, multicentre, prospective, observational cohort study of patients >=18 years of age undergoing in-patient surgery in Africa. The primary outcome was in-hospital postoperative surgical complications. Secondary outcomes included; i) in-hospital mortality, ii) and the relationship between postoperative complications and postoperative mortality, and the risk factors independently associated with in-hospital mortality and postoperative complications. RESULTS: 11422 patients participated from 25 countries in Africa. In hospital complications following surgery were observed in 1977/10885 (18.1%, 95% CI 17.4-18.9) patients, and mortality was 239/11193 (2.1%, 95% CI 1.8-2.4). The median duration of hospital stay was 3 (IQR 2-5) days which was significantly increased to 6 (IQR 4-13) days (p<0.001) following a complication. The postoperative admission in intensive care unit was 511/10991 (4.6%, 95% CI 4.3 5.0). When compared to the International Surgical Outcomes Study (ISOS), patients in Africa were twice as likely to die following surgery and following a surgical complication (p<0.001). CONCLUSION: Although, surgical patients in Africa have a lower risk profile than high-income countries, there is a significantly increased mortality following a surgical complication in Africa. PMID- 28876592 TI - UPTAKE AND PERFORMANCE OF CLINICAL BREAST EXAM SCREENING BY TRAINED LAYWOMEN IN MALAWI. AB - BACKGROUND: Breast cancer awareness and early detection are limited in sub saharan Africa. Resource limitations make screening mammography or clinical breast examination (CBE) by physicians or nurses impractical in many settings. We aimed to assess feasibility and performance of CBE by laywomen in urban health clinics. METHOD: Four laywomen were trained to deliver breast cancer educational talks and conduct CBE. Eligible women were 30 years, with no prior breast cancer or breast surgery, and clinic attendance for reasons other than a breast concern. Women with abnormal CBE were referred to a study surgeon. All palpable masses confirmed by surgeon examination were pathologically sampled. Patients with abnormal screening CBE but normal surgeon examination underwent breast ultrasound confirmation. RESULTS: Among 1220 eligible women, 1000 (82%) agreed to CBE. Lack of time (69%) was the commonest reason for refusal. Educational talk attendance was associated with higher CBE participation (83% versus 77%, P1/4 0.012). Among 1000 women screened, 7% had abnormal CBE. Of 45 women with normal CBE randomized to physician examination, 43 had normal examinations and two had axillary lymphadenopathy not detected by CBE. Sixty of 67 women (90%) with abnormal CBE attended the referral visit. Of these, 29 (48%) had concordant abnormal physician examination. Thirty-one women (52%) had discordant normal physician examination, all of whom also had normal breast ultrasounds. Compared with physician examination, sensitivity for CBE by laywomen was 94% (confidence interval (CI, 79%-99%), specificity 58% (CI, 46%-70%), positive predictive value 48% (CI, 35% 62%), and negative predictive value 96% (CI, 85%-100%). Of 13 women who underwent recommended pathologic sampling of a breast lesion, two had cytologic dysplasia and all others benign results. CONCLUSION: CBE uptake in Lilongwe clinics was high. CBE by laywomen compared favourably with physician examination and followup was good. Our intervention can serve as a model for wider implementation. PMID- 28876593 TI - A COMPARISON OF RADIATION EXPOSURE DURING ENDOVASCULAR AORTIC ANEURYSM REPAIR WITH OR WITHOUT ENDOSTAPLING. AB - BACKGROUND: Complications of endovascular aneurysm repair (EVAR) include endoleaks, proximal neck dilatation and stent migration, which have a greater likelihood with larger neck angulations. To mitigate against these complications endostapling of the stent-graft to the aortic wall is being implemented. With this extra stage in EVARs, this study aims to establish whether use of endostapling increases patient radiation exposure. METHOD: A retrospective analysis of a prospectively collected database of patients undergoing infrarenal EVAR and EVAR with endostapling was obtained. Radiation dose, fluoroscopy time, aneurysm size and patient characteristics were collected. Endostapling was performed using the Aptus Endostapling system (Aptus Endosystems Inc, Sunnyvale, Calif). Results are expressed as mean with 95% confidence interval. Statistical significance was set at P < 0.05 and calculated with an unpaired t-test. RESULTS: This study included 30 patients undergoing elective aorto biiliac EVAR with endostapling and 147 patients undergoing elective aorto bi-iliac EVAR without endostapling. Patient characteristics between the two groups were comparable. Within the endostapled group the mean dose area product (DAP) was 5.54 (4.18 6.91) mGy.m2, cumulative air kerma (CAK) 289 (230-348) mGy and fluoroscopy time 35.9 (29.6-42.2) minutes. Within the non-endostapled group the mean DAP was 5.91 (5.07-6.75) mGy.m2, CAK 248 (211-284) mGy and fluoroscopy time 32.5 (28.5-36.5) minutes. There was no statistically significant difference in DAP, CAK or fluoroscopy time between patients undergoing EVAR with or without endostapling. CONCLUSION: Radiation exposure during endovascular aneurysm repairs is a significant hazard to both the patient and the theatre staff. Our study shows that the additional step of endostapling the aortic stent-graft to prevent future reinterventions for endoleaks, stent migration or rupture does not increase radiation exposure to the patient. PMID- 28876594 TI - SALMONELLA TYPHIMURIUM INFECTED ABDOMINAL AORTIC ANEURYSM ENDOVASCULAR REPAIR WITH SECONDARY AORTOENTERIC FISTULA FORMATION. AB - Endovascular aneurysm repair (EVAR) is a widely accepted and used technique for the treatment of abdominal aortic aneurysms (AAA). However, it comes with a unique set of complications, two of the rarer being infection and aorto-enteric fistula formation. Due to the infrequency of the situation, there are currently no guidelines for their management. A 75-year-old male presented with vague abdominal pain and fevers. He was diagnosed with an infected abdominal aortic EVAR stent graft on computer tomography imaging. The stent graft was explanted and an extraanatomical bypass graft inserted. Intra-operative findings were an aorto-enteric fistula and left psoas abscess, both containing copious purulent fluid. He recovered slowly and his intra-operative samples grew Salmonella typhimurium. On review, he was found to have cultured this organism several times over a period of 14 months. It is hypothesised that his EVAR stent graft infection originated from a disseminated salmonella infection. From this case report, the following recommendations have been made. Firstly, if a patient with an EVAR develops a bacteraemia, they should receive pathogenspecific antibiotics for an appropriate length of time with regular surveillance of blood cultures until a negative culture is produced. Secondly, patients may require closer monitoring of their stent graft after a bacteraemia to allow for earlier detection of infection of the graft. Finally, explantation of infected stent grafts and the creation of an extra-anatomical bypass or an in-situ replacement may be the only method for detection of small AEFs; whose presence may change the management options for the patient. Hence, surgical management of infected EVARs and AEFs is still the current recommendation. PMID- 28876595 TI - ACUTE UPPER LIMB ISCHAEMIA IN DIABETIC PATIENTS - A RECENT EXPERIENCE. AB - BACKGROUND: The outcome of acute upper limb ischaemia in diabetic patients is not well known. We report our recent experience with 5 patients. METHOD: Retrospective case reviews. RESULTS: All patients presented with Rutherford 2b ischaemia at a median 1.6 days after symptom onset. Age range: 43-76 years. M:F 1:4. Mean HbA1c: 10.1% (range 6.1 - 14.0) Mean LDL cholesterol: 3.1g/dL (range 1.61 - 4.80) Other comorbidities included: Ischaemic heart disease, atrial fibrillation, dyslipidaemia, hypertension, morbid obesity. One patient was an ex smoker. Four patients had preoperative CT angiograms. All patients underwent Fogarty catheter embolectomy of the forearm and arm arteries as initial procedure as well as forearm fasciotomy in 3 patients. CONCLUSION: Acute upper limb ischaemia in patients with diabetes appears to carry a grave prognosis for limb salvage (20% in this group). Re-intervention was associated with subsequent amputation. Proximal arterial disease can occur but the common finding of occlusive disease in the run-off vessels of the arm, as in this group, may account for the high limb-loss rate. PMID- 28876596 TI - ENDOVASCULAR AORTIC ANEURYSM REPAIR AT JOHANNESBURG ACADEMIC HOSPITALS. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a common disease seen in vascular units. AAA is defined as transverse diameter greater than 3 cm and affects men more than women. Endovascular aortic aneurysm repair (EVAR) is increasingly being used to treat AAA. Renal dysfunction, graft-related endoleaks, graft limb occlusion, device migration and delayed aneurysm rupture are possible complications that have been encountered after EVAR. METHOD: Changes in renal functions after one month, six months and twelve months. The incidence of endoleaks, limb occlusion and re-interventions required. RESULTS: Total of thirty six patients had EVAR done from February 2014 to April 2017. There were two patients who had type 2 endoleaks on completion angiograms, these resolved on one month CT scan. Fourteen patients had post-EVAR imaging at 1, 6 and 12 months which showed no endoleaks. Three patients developed iliac limb occlusion and was appropriately managed with fem-fem crossover. Eight patients had preexiting renal impairment with worsening of renal function in one patient (not requiring dialysis). Three patients developed renal impairment after EVAR. Twenty-two patients are waiting for the follow up imaging and few patients missing follow-up blood tests - this data will be added before the congress. CONCLUSION: The follow up data demonstrates that EVAR can be performed safely in anatomically suitable patients. The limb occlusion rates are within accepted rates to standard vascular registry. The patients who developed renal dysfunction (Glomerular filtration rate between 50-60ml/min/1.73m2) after EVAR remained static for 12 months. PMID- 28876597 TI - RADIATION EXPOSURE DURING INFRARENAL ENDOVASCULAR AORTIC ANEURYSM REPAIR. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms exposes patients and healthcare professions to the deterministic and stochastic effects of ionization radiation. The study aim was to determine our standard of radiation exposure in infrarenal EVARs and compare it against other published data and national guidelines. METHOD: A retrospective analysis of a prospectively collected database of patients undergoing EVARs was obtained. Radiation dose, fluoroscopy time, aneurysm size and patient characteristics were collected. Results are expressed as mean with 95% confidence interval. RESULTS: This study included 147 elective patients undergoing aorto bi-iliac EVAR with a mean age of 76 years from June 2013 until December 2016. The mean dose area product (DAP) was 5.91 (5.07-6.75) mGy.m2, cumulative air kerma (CAK) 248 (211-284) mGy and fluoroscopy time 32.5 (28.5-36.5) minutes. A greater BMI and a longer fluoroscopy time caused a significantly greater DAP to be administered to the patient. The device type, sex, AAA size, smoking status did not significantly effect the DAP administered to the patient. CONCLUSION: Radiation exposure during endovascular aneurysm repairs is a significant hazard to both the patient and the theatre staff. Our study shows that a greater BMI and total fluoroscopy time can cause greater radiation exposure to patient. Anatomical and technical difficulties are also related to increased radiation exposure. Radiation exposure at our centre is below threshold levels suggested by Stecker et al before radiation induced skin injuries can manifest. Additionally, radiation exposure is comparable to other centres but can be reduced further by reducing our fluoroscopy time and adhering to the principles of ALARA (As low as reasonably achievable). PMID- 28876598 TI - SPECTRUM OF DISEASE AND OUTCOME OF PRIMARY AMPUTATION FOR DIABETIC FOOT SEPSIS. AB - BACKGROUND: Guillotine amputation for diabetic foot sepsis followed by an elective refashioning of the stump is regarded as standard practice. Primary amputation is associated with higher reamputation rates. METHOD: A prospective cohort study of 85 patients who underwent surgery for diabetic foot sepsis from 2014 to 2016 at Madadeni Provincial Hospital, KwaZulu-Natal was done. Ethical approval was granted. The Wagner classification (Wag) was used to classify disease severity. Outcome measures included length of hospital stay, mortality and re-amputation rates. RESULTS: Of the 85 patients, females (n=45) accounted for 53% of admissions. The mean age was 61 years (range: 29 to 80 years). The majority of patients were African, n=75 (88%). Only 1 patient presented with diabetic ketoacidosis and 18 (21%) presented with renal failure. Most patients presented with advanced disease: [Wag 5, n=66 (78%); Wag 4, n=12 (14%); Wag 3, n=5 (6%); Wag 2, n=2 (2%)]. The levels of vascular occlusion included aortoiliac disease n=2 (2%), femoro-popliteal disease n=18 (21%), tibio-peroneal disease n=65 (76%). Radiographic features included normal findings n=60 (71%); gas gangrene n=11 (13%), osteitis n=8 (9%). The following amputations were done: AKA, n=29 (34%); BKA, n=39 (46%); TMA, n=8 (9%); Toe-ectomy, n=5 (6%) and Debridement, n=4 (5%). The re-amputation rate to above knee amputation was n= 3/39 (8%). All AKA stumps healed well. The overall in-hospital mortality was n=5 (6%) and mean length of hospital stay was 7.8 days +/-3.83. CONCLUSION: The majority of patients presented with advanced disease requiring a major amputation. A definitive one stage primary amputation is a safe and effective procedure for diabetic foot sepsis and is associated with a low re-amputation rate, length of hospital stay and mortality. A guillotine amputation should be reserved for physiologically unstable patients. PMID- 28876599 TI - A CASE REPORT OF DELAYED PRESENTATION OF A PATIENT WITH A RUPTURED DIAPHRAGM COMPLICATED BY OBSTRUCTED DIAPHRAGMATIC HERNIA WITH GUT GANGRENE. AB - Diaphragmatic rupture is a common occurrence following a major chest trauma and is most commonly associated with road-traffic accidents. Here we report a case of delayed presentation of a 40-year-old man with a ruptured diaphragm with obstruction and bowel infarction, three and a half year following a blunt trauma to chest. This case illustrates how the diagnosis and aggressive management of ruptured diaphragm can be central to life saving and demonstrates the importance of early intervention in cases with features suggestive of compromise of bowel vascularity. Subsequently exploratory laparotomy with resection of gangrenous segment with double barrel ileo-jejunostomy with diaphragmatic repair was done successfully. PMID- 28876600 TI - COMPARATIVE ASSESSMENT OF IN-HOSPITAL TRAUMA MORTALITY AT A SOUTH AFRICAN TRAUMA CENTRE AND MATCHED PATIENTS TREATED IN THE UNITED STATES. AB - BACKGROUND: The unacceptably high rate of death and disability due to injury in sub-Saharan Africa is alarming. The objective of this work is to compare mortality rates between severely injured trauma patients at a high volume trauma centre in South Africa with matched patients in the United States. METHOD: Clinical databases from the Groote Schuur Hospital (GSH) for patients treated in Cape Town, South Africa and the American College of Surgeon's National Trauma Databank (NTDB) for patients treated at large academic trauma centres in the US were used. Coarsened exact matching (CEM) identified the most comparable patient populations based on sex, age, intent, injury type, injury mechanism, Injury Severity Score, Glasgow Coma Score (GCS), and systolic blood pressure. Conditional logistic regression generated odds ratios for mortality among the entire sample and clinically relevant subgroups. RESULTS: CEM matched 97.9% of the GSH patient sample, resulting in 3,206 matched-pairs between the GSH and NTDB cohorts. Conditional logistic regression revealed an odds ratio of mortality of 1.67 (95% CI: 1.10-2.52) for patients at GSH compared to matched patients from the NTDB. Subset analyses revealed significantly increased odds of mortality among patients with blunt injuries (OR 3.40, 95% CI: 1.68-6.88) and patients with a GCS of 8 or lower (OR 4.33, 95% CI:2.10-8.95). No statistically significant difference was identified among patients with penetrating injuries or with a GCS greater than 8 (p-value 0.90 and 0.39, respectively). CONCLUSION: International comparisons of inter-hospital variation in risk adjusted outcomes following trauma can identify opportunities for quality improvement and have the potential to measure the impact of any corrective strategy implemented. PMID- 28876601 TI - LAPAROSCOPIC MANAGEMENT OF RETROPERITONEAL INJURIES IN PENETRATING ABDOMINAL INJURIES. AB - PURPOSE: Laparoscopy in penetrating abdominal injuries is now accepted and practiced in many modern trauma centres. However its role in evaluating and managing retroperitoneal injuries is not yet well established. The aim of this study was to document our experience in using laparoscopy in a setting of penetrating abdominal injuries with suspected retroperitoneal injury in haemodynamically stable patients. METHOD: A retrospective descriptive study of prospectively collected data from a trauma unit at Dr George Mukhari Academic Hospital (DGMAH) was done. All haemodynamically stable patients with penetrating abdominal injury who were offered laparoscopy from January 2012 to December 2015 were reviewed and those who met the inclusion criteria were analysed. RESULTS: A total of 284 patients with penetrating abdominal injuries were reviewed and 56 met the inclusion criteria and were analysed. The median age was 30.8 years (15 60 years) and males constituted 87.5% of the study population. The most common mechanism of injury was penetrating stab wounds (62.5%). Forty-five patients (80.3%) were managed laparoscopically, of these n=16 (28.5%) had retroperitoneal injuries that required surgical intervention. The most commonly injured organ was the colon (19.6%). The conversion rate was 19.6% with most common indication for conversion been active bleeding (14%). The complication rate was 7.14% (N=4) and were all Clavien-Dindo grade 3. There were no recorded missed injuries and no mortality. CONCLUSION: The positive outcomes documented in this study with no missed injuries and absence of mortality suggests that laparoscopy is a feasible option in managing stable patients with suspected retroperitoneal injuries. PMID- 28876602 TI - THE CORRELATION OF CT SCAN IN THE MANAGEMENT OF PENETRATING ABDOMINAL INJURIES. AB - BACKGROUND: Penetrating abdominal trauma contributes significantly to the burden of disease in South Africa. The role of imaging, particularly CT scan in this subset of patients has yet to be established. In this study we reviewed patients with penetrating abdominal injuries and correlated the imaging and intra operative findings. METHOD: Over an 18-month period (June 2015 to January 2017), the database as well as patient records of all patients presenting with penetrating abdominal trauma were reviewed. Patients presenting with haemodynamic instability and peritonitis were excluded from the study and immediately underwent a laparatomy. Patients presenting with penetrating abdominal trauma and who were haemodynamically stable and not peritonitic had imaging done in the form of a CT Scan. The CT scan findings were then correlated with the intraoperative findings. RESULTS: One hundred and thirty one patients with penetrating abdominal trauma were eligible for imaging. Fifty two patients had positive CT scan findings as well as positive intraoperative findings. Seventy nine (60%) had negative findings on CT scan. Off the 79 patients, 59 (74%) had negative imaging findings as well as negative intraoperative findings. Twenty (25%) had negative CT findings but positive intraoperative findings. CONCLUSION: CT scan correlates poorly with intraoperative findings and thus is a poor modality for screening patients. PMID- 28876603 TI - THE ROLE OF LAPAROSCOPY IN BLUNT ABDOMINAL TRAUMA: DIAGNOSTIC, THERAPEUTIC OR BOTH? AB - BACKGROUND: The use of laparoscopy in blunt abdominal trauma is gaining popularity as a useful diagnostic tool to avoid unnecessary laparotomies where there is diagnostic dilemma. But the feasibility of using laparoscopy for therapeutic intervention in these patients has been debated. Even though recent case reports seem to suggest that these patients can be managed using laparoscopy, the practice is not yet wildly adopted. METHOD: A retrospective analysis of a prospectively collected data was done. All adult patients who presented with abdominal trauma and were offered laparoscopic surgery at DGMAH from 2012 to 2015 were reviewed. Data was retrieved from our departmental database and analysed using descriptive statistics. RESULTS: A total of 318 patients were reviewed and 35 patients had blunt abdominal trauma and were included in the study. All the patients were offered laparoscopy. The median age was 30, with 91% of our patients being males. The highest injury severity score calculated was 38. At least 77% of the patients were managed using laparoscopy. This includes 43% who had both diagnostic and therapeutic intervention and 34% had only diagnostic laparoscopy. Eight patients were converted to open surgery mainly due to active bleeding and complex injuries. We did not have any non therapeutic laparotomies, with no documented procedure related morbidity and mortality. CONCLUSION: The positive outcomes seen from the study suggest that laparoscopy can be safe and feasible in both diagnostic and therapeutic interventions in carefully selected blunt abdominal trauma patients. A conversion to open surgery should not be regarded as a failure but rather as a sign of mature and sound clinical judgement acknowledging the limitations of laparoscopy and/or the surgeon. PMID- 28876604 TI - THE USE OF LAPAROSCOPY IN MANAGING PENETRATING THORACOABDOMINAL INJURIES IN AFRICA: 83 CASES REVIEWED. AB - BACKGROUND: The use of laparoscopy in managing haemodynamically stable patients with penetrating thoracoabdominal injuries in developed countries is wildly practiced, but in Africa the use of laparoscopy is still in its infancy stage. We reviewed a single centre experience in using laparoscopy in Africa for management of patients with penetrating diaphragmatic injuries with or without associated intra-abdominal injuries. METHOD: A retrospective analysis of prospectively collected data of patients presenting with penetrating thoracoabdominal injuries was done. All patients offered laparoscopic exploration and repair from January 2012 to December 2015 at Dr George Mukhari Academic Hospital were analysed. Means (+/-SD) were presented for continuous variables and frequencies (%) were presented for categorical variables. RESULTS: A total of 83 stable patients with penetrating thoracoabdominal injuries managed with laparoscopy met the inclusion criteria and were included in the study. The Injury Severity Score ranged from 8 to 24, with a median of 18. The incidence of diaphragmatic injuries was 54%. The majority (46.8%) of patients had Grade 3 (2-10 cm defect) diaphragmatic injury. Associated intra-abdominal injuries requiring intervention were encountered in 28 (62%) patients. At least 93.3% of the patients were treated exclusively with laparoscopy. The morbidity was encountered in 7 (16%) patients; the most common cause was a clotted haemothorax Clavien-Dindo III-b but only one patient required a decortication. There was one non-procedure related mortality. CONCLUSION: A success rate of 93% in using laparoscopy exclusively was documented, with an overall 82% uneventful outcome. The positive outcomes found in this study when laparoscopy was used in stable patients with thoracoabdominal injuries seem to suggest that the presence of peritonitis in stable patient is not a contra indication to laparoscopy and thoracoscopy may be useful especially in right side diaphragmatic injury where the liver can precludes adequate visualisation of the entire diaphragm. PMID- 28876605 TI - TRAUMA LAPAROSCOPY: TEACHING AN OLD DOG NEW TRICKS. AB - BACKGROUND: Diagnostic laparoscopy is well-accepted in management of penetrating abdominal trauma (PAT) with the rate of missed injuries below 1%. However, there is a reluctance to accept therapeutic laparoscopy in trauma society. The main reason is the lack of laparoscopic skills by trauma surgeons. Moreover, no formal laparoscopy training program for trauma exists. The aim of this study was to discuss the trauma laparoscopy training at our institution. METHOD: All patients managed laparoscopically for PAT from January 2012 to December 2015 were included in the study. The seniority of operating surgeon was recorded and correlated with adverse outcomes, and with conversion to open laparotomy. The following groups were identified: surgeon-consultant (SC), assistant-consultant (AC), surgeonsenior- registrar (SSR) and surgeon-junior-registrar (SJC) groups. Laparoscopic manoeuvers used in this cohort were investigated and the set of essential laparoscopic skills was identified. Laparoscopic training program at our institution was described and discussed. RESULTS: Out of 283 patients with PAT approached with laparoscopy 33 (11.7%) were converted to laparotomy. The majority (49.6%) of laparoscopy were performed by a senior registrar. A consultant was an operating surgeon in 21.2% and an assistant in 8% of cases. A consultant was involved in cases with higher severity of injury and the complication rate was higher in the SC and AC groups. Essential laparoscopic skills were mobilisation of abdominal organs, bowel run and intracorporeal suturing. During training, an average senior registrar performed 20% of operations for trauma (a half was done laparoscopically) and trauma constituted 16% of all laparoscopy. CONCLUSION: Laparoscopy for trauma is feasible and safe approach. It can be safely performed by registrars provided that the senior help is on standby. The surgeon performing trauma laparoscopy should have an appropriate mindset and a dexterity with advanced laparoscopic skills. Performing a wide range of nontrauma laparoscopy contributes significantly to performance in trauma laparoscopy. PMID- 28876606 TI - TRAUMA LAPAROSCOPY: WHEN TO START AND WHEN TO CONVERT? AB - BACKGROUND: The use of laparoscopy for stable patients with abdominal trauma is increasing and its accuracy is nearly 100%. However, indications for laparoscopy and for conversion differ among centres. The aim of this study was to investigate indications for trauma laparoscopy and for conversion to laparotomy. METHOD: All trauma patients managed with laparoscopy over a four year period were retrospectively analysed. Indications for laparoscopy, morbidity, and reasons for conversion were investigated and predictors of morbidity and conversion were sought. The management algorithm of trauma patients was reviewed and updated. RESULTS: Laparoscopy was used in 318 stable trauma patients. The conversion rate was 11.7% for penetrating and 22.9% for blunt abdominal trauma patients. The most common reason for conversion was continuous intraabdominal bleeding that could not be controlled quickly. It was followed by multiple complex injuries, haemodynamic instability, and intraoperative visualisation problems. Diagnostic laparoscopy was performed in 45%, and therapeutic laparoscopy in 55% of cases. There were no missed injuries. The complication rate was lower and length of hospital stay (LOS) shorter in the laparoscopic group. Lower pH was associated with conversion. CONCLUSION: The management of all stable trauma patients with laparoscopy appears to be a safe approach. The use of sound laparoscopic equipment by a well-coordinated trauma team with adequate expertise in laparoscopy, adherence to the algorithm, and strict compliance with predetermined procedural steps are fundamental to success. Laparotomy can be avoided in more than 80% of cases. Continuous intraoperative bleeding, complexity of injuries, deterioration of the patient, poor visibility, and equipment failure are indications for conversion. The rate of missed injuries is negligible and comparative with laparotomy. Lower complication rates and a shorter LOS are associated with laparoscopy. However, further studies are needed to identify specific predictors for complications and conversion. PMID- 28876607 TI - LAPAROSCOPIC APPROACH TO COMBINED BILATERAL INGUINAL AND VENTRAL HERNIAS. AB - Herniosis is a well-documented phenomenon amongst patients who develop any hernia over their lifetime. Multiple hernias at different anatomical locations are quite common though they more often occur metachronously. When they present synchronously, there is an additional advantage to tackling these hernias laparoscopically as it affords the advantage of thorough inspection of the entire peritoneal cavity and the ability to address all hernias simultaneously. This video demonstrates one of the modified approached to the groin and midline that facilities a combined procedure without the need for additional port placements. A bilateral TAPP and Midline IPOM repair is performed simultaneously. PMID- 28876608 TI - LAPAROSCOPIC LEFT LATERAL SECTIONECTOMY AT DR GEORGE MUKHARI ACADEMIC HOSPITAL. AB - BACKGROUND: Laparoscopic left lateral sectionectomy has rapidly become a standard of care for patients requiring excision of segments 2 and 3. We present our technique of the resection. METHOD: Videos of patients having had left lateral sectionectomies were reviewed. Patients were placed in supine with reverse Trendelenburg position. Three ports were used: one 12 mm at the umbilicus for the camera, one 12 mm placed 5 cm above and to the right of the umbilicus and one 5 mm port to the left. A Ligasure(r) 5 mm (Covidien(r)) was used to take down the falciform ligament initially staying close to the abdominal wall and then stopping at the bifurcation of the two layers of peritoneum. The triangular ligament was incised to create a window between diaphragm and liver. Unlike open surgery the entire ligament was not mobilised at this stage. A line was scored on the left of the falciform ligament. Transection of the parenchyma was achieved with Ligasure(r). Once the liver parenchyma was thinned, an endostapler - EndoGIA(r) Gold (Covidien(r)) - was be used to complete the transection. It was also possible to dissect out individual vessels and ligate with Hem-o-lok(r) (Teleflex(r)) clips in one case. The cut surface was examined for bleeding or bile leaks. A small pencil drain was placed. RESULTS: Three patients had laparoscopic resections. All were female. Two cases were haemangioma with one diagnosed preoperatively and the other not having typical features on imaging. The third case was a large adenoma in a patient with hepatic adenomatosis. No bile leaks were noted. No patient required blood transfusion. Average length of stay was 1 day. CONCLUSION: Laparoscopic left lateral sectionectomy is a stepping stone to more complex laparoscopic liver resections. It is feasible and safe in a tertiary institute in South Africa. PMID- 28876610 TI - THE OPEN RETRORECTUS AND TRANSVERSUS ABDOMINUS RELEASE. AB - The open retrorectus approach to the repair of incisional hernias remains the gold standard approach despite the availability of multiple options. The addition of a transverses abdominus release to the procedure increases the number of patients and the complexity of the cases for which this approach is suitable. It facilitates midline closure in almost all cases, avoids significant neuromuscular bundle injury and dissection of poorly vascularized subcutaneous tissue, and allows the placement of a very large but simple mesh in a space outside the peritoneal cavity. This video demonstrates the steps involved and the important anatomical details. PMID- 28876609 TI - LAPAROSCOPIC PANCREATICODUODENECTOMY AT DR GEORGE MUKHARI ACADEMIC HOSPITAL: A CASE REPORT. AB - BACKGROUND: The first total laparoscopic pancreaticoduodenectomy was performed in 1994 by Gagner and Pomp. Their comments coupled with the inherent technical difficulties stifled development of the technique. In the last decade there has been a renewed interest in the technique with high volume centres publishing large series. We present our experience with the first operation completed at Dr George Mukhari Academic Hospital. METHOD: Pre-operative CT confirmed a resectable head of pancreas mass. The gastroduodenal artery (GDA) was noted to arise from the right hepatic artery which ran parallel and anterior to the bile duct. Five ports were used. After excluding metastases we proceeded to dissect the hepatoduodenal ligament. A combination of hook diathermy and Harmonic ACE+7(r) (Ethicon(r)) was used. We then entered the lesser sac and ligated the right gastroepiploic vessels and right gastric vessels. The stomach was transected with an Endo GIA(r) Black 60 mm (Covidien(r)). The duodenum was kocherized. The GDA was ligated with a Haemolok(r) (Teleflex(r)) clip. A retropancreatic tunnel was created the pancreas was transected with the energy device. The jejenum was transected 10 cm distal to the ligament of Treitz with an Endo GIA(r) Purple 45 mm and passed posterior to the SMA. The pancreaticojejenostomy was done as per Blumgart with a duct to mucosa anastomosis. The hepaticojejenostomy was completed with 4/0 PDS (Ethicon(r)) continuous. The gastrojejenostomy was completed with 3/0 Maxon (Covidien(r)). The specimen was retrieved via a 5 cm midline incision. Two pencil drains were placed. RESULTS: The patient was transferred to ICU postoperatively. She developed a short period of delirium which resolved spontaneously. No bile or pancreatic leaks were noted. She was discharged on day 28. CONCLUSION: Laparoscopic pancreaticoduodenectomy is technically feasible despite the steep learning curve. The results from large series worldwide suggest a need to encourage and further develop the technique in South Africa. PMID- 28876611 TI - CONSTRUCTION AND VALIDATION OF LOW COST LAPAROSCOPIC SIMULATOR USING ANDROID SMARTPHONE AND POP CAST AND A LAPTOP. AB - Minimal invasive surgery training requires a lot of practice and for this purpose innovative tools are needed to develop methods for practice and training skills outside the operating room. Commercially available devices are readily available but cost effectiveness and availability are major limiting factors in resource limited setting. We present an innovative and cost effective laparoscopic simulator which can be easily manufactured and used for practice of laparoscopic surgery. Using a free android application, such as IP webcam we can relay video to laptop without the use of any cables and uniquely we use the flash of a camera as the light source and a selfie stick for movement of the camera. Use of this type of setup can help to reduce cost of simulated learning in low income countries and makes laparoscopic training facilities readily available. PMID- 28876612 TI - LAPAROSCOPIC VENTRAL HERNIA REPAIR: A SINGLE SURGEON STUDY USING A CIRCUMFERENTIAL TRANSFASCIAL SUTURE TECHNIQUE. AB - BACKGROUND: The ideal technique for ventral primary and incisional hernia repair is unclear. There is a paucity of literature from South African authors. In this report, a standardised technique of intraperitoneal mesh placement and fixation is described. METHOD: A retrospective study of 152 patient records. Each patient underwent laparoscopic ventral hernia repair between 2007 and 2016 by a single surgeon. A standardised technique was used in every operation. In each case a circumferential mesh overlap of 5 centimetres from the defect was achieved. The same composite mesh was used in every operation. The mesh was secured with transfascial Tycron sutures placed around the circumference at 2 centimetre intervals. The correct position of the mesh was confirmed with skin markings from a template, prior to pulling the sutures through the abdominal wall with an Endoclose. RESULTS: 152 patients underwent a total of 154 operations. They were followed up at 2 and 6 weeks postoperatively and longer in many patients. The average follow up time was 327 days.Seromas occurred in 16 patients, one persisting beyond 6 weeks, which resolved after aspiration. Three patients developed abscesses, requiring mesh removal in 2. Hernia recurrences occurred in 3 patients (1.97%). More than one mesh was used in 6 patients. Few patients had any residual pain at 2 weeks and none at 6 weeks. The average hospital stay was 2 days. CONCLUSION: The described standardised technique of laparoscopic ventral hernia repair results in a very secure mesh fixation with evenly distributed load on the mesh. The potential complications associated with tacks, inadequate fixation and cost of tacks are avoided. PMID- 28876613 TI - MANAGEMENT AND OUTCOMES FROM APPENDECTOMY: AN INTERNATIONAL, PROSPECTIVE, MULTICENTRE STUDY. AB - BACKGROUND: To identify variation in surgical management and outcomes of appendicitis across low, middle and high Human Development Index (HDI) country groups. METHOD: Multi-centre, international prospective cohort study of consecutive patients undergoing emergency appendectomy over a 6-month period. Follow-up lasted 30 days. Primary outcome measure was overall complication rate. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high, 1540 middle and 507 low HDI groups). Complications were more frequent in low-HDI (OR 3.81, 95% CI 2.78 to 5.19, p < 0.001) and middle-HDI countries (OR 2.99, 95% CI 2.34-3.84, p < 0.001) compared with high- HDI countries, but differences were adjusted out by case-mix and hospital structural factors. Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33 to 4.99, p=0.005) but not middle-HDI (OR 1.38, 95% CI 0.76 to 2.52, p=0.291) compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low- (41/507, 8.1%) and middle HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer complications (OR 0.55, 95% CI 0.42 to 0.71, p< 0.001) and SSIs (OR 0.22, 95% CI 0.14 to 0.33, p<0.001). The number needed-to-treat with laparoscopic surgery to save an SSI was lower in low-HDI countries (NNT=6, 95% CI 4 to 9) than in high-HDI countries (NNT=9, 95% CI 6 to 16). In propensity-score matched groups within low- and middle- HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11 to 0.44) and SSI (OR 0.21 95% CI 0.09 to 0.45). CONCLUSION: Outcomes from appendectomy vary worldwide. A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. There are profound clinical, operational and financial barriers to the introduction of laparoscopy that if overcome, could result in significantly improved outcomes for patients in low resource environments, with potential for wider health-system benefits. PMID- 28876614 TI - SIGNIFICANT CLINICAL AND PATIENT REPORTED OUTCOMES AT 6 MONTHS FOLLOWING HERNIA REPAIR WITH AN ABSORBABLE FIXATION DEVICE. AB - BACKGROUND: Surgeons utilise various mesh fixation methods during hernia repair which may include tacks/straps and/or sutures. One of these tack/strap choices, is an absorbable fixation device, Securestrap(r) (ETHICON, Somerville, NJ), consisting of polydioxanone and L (-)-lactide/glycolide copolymer. The 6 month clinical results and patient outcomes with Securestrap(r) fixation are reported. METHOD: The International Hernia Mesh Registry, prospective multi-centre registry, designed to collect patient reported, longitudinal data on hernia mesh products and fixation methods. Patients completed the Carolinas Comfort ScaleTM (CCS). Symptomatic patient defined as responding >1 to any CCSTM question. P values obtained by McNemar test and Kaplan Meier methods used to estimate the recurrence rate up to 183 days. RESULTS: Patients enrolled at 17 centres with data on 101 of the 216 patients who had reached the 6 month time point. Demographics were: mean age 53.0 (13.2 SD); mean BMI 33.0 (7.7 SD) kg/m2; females (51.4%); nonsmokers (46.4%). Majority of hernias were incisional/ventral (57.9%) and most were laparoscopic (98.1%). Mesh fixation was with tacks/straps (50.5%) or tacks/straps and sutures (49.5%). Symptomatic CCSTM pains scores improved from baseline to 1 month and improved significantly from 1 month to 6-months (69.1% to 60.6%, p=0.0858; 60.6% to 22.8%, p=0.0002), respectively. Similar results were observed with symptomatic CCSTM movement limitations. The recurrence rate was 1.8% (0.6%-5.4%); 2 medically confirmed; 1 had not yet been assessed. CONCLUSION: Mesh fixation using absorbable tacks/straps with or without additional sutures results showed statistical significant improvement in patient reported outcomes at 6 months as compared to baseline. Follow-up continues. PMID- 28876615 TI - The International Association of Student Surgical Societies: A brief history from 2014-2017. AB - The International Association of Student Surgical Societies (IASSS) was founded in 2011 to link up student surgical societies from around the world. These Societies have been formed by students with an aim to promote interest in surgical education and research amongst undergraduate medical students. Their formation has been fostered by the recent realization that adequate surgical care is a neglected component of global public health.1 The insufficient number of trained surgeons is one of the many barriers to meeting global surgical needs, especially in middle- and low-income countries. This barrier is one the IASSS aims to address.2,3 Since its inauguration, the IASSS has been active in creating opportunities for undergraduate medical students across the world to explore the full spectrum of surgery. PMID- 28876616 TI - 10-year review of Africa's first student surgical society - UCT Surgical Society. AB - The UCT Student Surgical Society is an undergraduate surgical society based at the University of Cape Town (UCT) which aims to promote surgical education amongst medical students early in their medical careers. Founded in 2006, this was Africa's first student surgical society and has been joined by other medical schools in Africa also establishing their own undergraduate student surgical societies. In this review of the first 10 years of the society, we describe its objectives, its evolution and its international role. PMID- 28876617 TI - Efficacy of porcine dermal collagen (PermacolTM) injection for passive faecal incontinence in a dedicated Colorectal Unit at the Wits Donald Gordon Medical Centre. AB - BACKGROUND: Passive faecal incontinence (FI) due to a defect of the internal anal sphincter is a distressing condition and can be difficult to manage medically and surgically. The use of a trans-anally injected bulking agent to improve continence has been published internationally with contradictory results. METHOD: Patients with passive FI due to confirmed internal anal sphincter deficits that had been treated with PermacolTM injections were followed up. They were asked to complete the Wexner faecal incontinence scores and Rockwood QoL scores for both their pre- and post-treatment continence state. RESULTS: Of the 14 patients who completed the questionnaires, most were women with a mean (SD) age of 56.4 (13.4) years. The majority of the patients had a history of a predisposing event. They reported a significant improvement in both the Wexner scores (p < 0.0005) and the Rockwood QoL (p=0.004), including all subsections. The Wexner scores and the Rockwood scores were significantly correlated post-procedure (r= -0.6186; p=0.0183). There were no significant correlations between change in scores and time after procedure. CONCLUSION: Trans-anal submucosal PermacolTM injections produced a significant improvement in both faecal continence and quality of life scores in patients with passive faecal incontinence for up to two years. PMID- 28876618 TI - C-reactive protein as a predictor of severity of appendicitis. AB - BACKGROUND: Complex (perforated or gangrenous) appendicitis has a high rate of morbidity in South Africa. METHOD: The study retrospectively reviewed results from January 2013 to December 2015 at Paarl Hospital in the Western Cape province. All patients who had their appendices surgically removed due to suspected appendicitis and who had preoperative results for CRP and WCC were included. Using the area under the Receiver Operated Characteristics curve we compared the inflammatory markers of 2 groups with histologically proven appendicitis: those with complex (perforated or gangrenous appendix) and those with uncomplicated appendicitis (inflamed appendix). Youden's J statistic was used to determine the optimal cut-off value above which complex appendicitis would be the most likely diagnosis. RESULTS: A total of 591 patients were identified, 385 had results for both WCC and CRP. CRP (AUC 72%) proved to be a fair and WCC (AUC 58%) a poor predictor of complex appendicitis. Cut-off values for CRP and WCC were found to be 215 mg/l and 16.80 109 cells/l respectively. At these threshold values CRP (sensitivity 51.4%, specificity 85.7%, p-value < 0.001, positive predictive value 80.2%, negative predictive value 61%, positive likelihood ratio 3.6 and diagnostic odds ratio 6.35) proved to be much better than WCC (sensitivity 43%, specificity 73.8%, p-value = 0.022, positive predictive value 64.9%, negative predictive value 53.4%, positive likelihood ratio 1.64 and diagnostic odds ratio 2.11) in predicting complex appendicitis. CONCLUSION: CRP is superior to WCC in the differentiation between uncomplicated and complex appendicitis. Using a cut-off value of CRP 215 mg/l is statistically significant in diagnosing complex appendicitis. This value should be used cautiously as many more studies are needed to confirm these findings. PMID- 28876619 TI - Do iatrogenic serosal injuries result in small bowel perforation in a rabbit model? AB - BACKGROUND: Surgical dogma dictates that serosal injuries should be repaired during laparotomy as these injuries may result in localised areas of bowel ischaemia and may perforate. No study has investigated whether there is a correlation between the extent of serosal injuries and the risk for perforation under normal physiological conditions. We hypothesized that small bowel serosal injuries do not result in early or late perforation at physiological intraluminal pressures regardless of their size. METHOD: An in-vivo rabbit small bowel serosal injury model was developed and two experiments were conducted. The first - to determine whether and at which pressures various lengths and circumferences of serosal injuries in small bowel result in immediate bowel perforation - was performed infusing saline into isolated bowel segments with or without a variety of serosal injuries. In the second study - to determine whether or not serosal injuries result in delayed perforation - a range of injuries was created in rabbits and the effect assessed at re-laparotomy 5 days after the creation of the injury. RESULTS: No perforations were observed at the site of serosal injuries at physiological intraluminal pressures. Perforations occurred at 43.7+ 18.6 cmH2O, 23.3+ 14.4 cmH2O, and 24.4+ 23.9 cmH2O for controls, 4 cm long and 100% circumference serosal injuries respectively (p-value = 0.18 for various lengths and 0.71 for various circumferences). No serosal injuries perforated within 72 or 120 hours after creation. CONCLUSION: Small bowel serosal injuries do not perforate or leak at physiological intraluminal pressures, either at the time of creation or up to 120 hours thereafter. PMID- 28876620 TI - Factors influencing medical students in pursuing a career in surgery: a cross sectional survey. AB - BACKGROUND: Many factors play a role in the decision of a medical student to pursue a career in surgery. With a decline in numbers of applications into surgical programmes seen globally, the aim of this study was to determine the factors that influence medical students in pursuing a career in surgery. METHOD: A descriptive, cross-sectional survey was distributed online to all medical students studying at a tertiary, academic institution. Survey items obtained data on demographics, surgical interest and training, as well as factors affecting a surgical career. RESULTS: A total of 245 medical students responded, of which 56% were female. The majority (69%) stated they were interested in pursuing a career in surgery. Despite 75% of respondents stating South Africa was a good place for surgical training, females reported significantly higher levels of agreement that surgical training would be better overseas when compared to males (p = 0.027). Overall, 20% were undecided on what surgical specialty they would pursue. The largest proportion of respondents (33%) stated that 'Length of training' was the main barrier to pursuing a career in surgery. Thirtythree (13.5%) respondents reported 'Female-unfriendly' as a barrier, of whom all were female. The greatest motivator to pursuing a career in surgery was 'Hands-on work', stated by 36% of respondents. CONCLUSION: Though length of surgical training was deemed the principal barrier, the majority of students indicated they would pursue a career in surgery. Despite continued perceptions that surgery poses a female-unfriendly environment as a career, respondents held South African surgical training in high esteem, and were motivated by a clinically hands-on approach. These factors may play an important role in determining methods of improving numbers of surgical applications worldwide. PMID- 28876621 TI - The absolute number of repeat operations for complex intra-abdominal sepsis is not a useful predictor of non-survival. AB - BACKGROUND: When multiple repeat laparotomies are required to manage intra abdominal sepsis, questions about futility of treatment frequently arise. This study focuses specifically on patients who required two or more repeat laparotomies and describes the spectrum of disease necessitating multiple repeat laparotomies and the associated outcomes in the hope of clarifying the issue. METHOD: This study was conducted over a 20-month period (December 2012 - July 2014) at Greys Hospital in Pietermaritzburg, South Africa. All surgical patients at Greys Hospital have admission, discharge and operative data prospectively entered into a computerised electronic registry, the Hybrid Medical Electronic Registry (HEMR). The ethics approval required to maintain this registry has been obtained from the Biomedical Research Ethics Committee (BCA221/13 BREC) of the University of KwaZulu-Natal and from the Research Unit of the Department of Health. Full ethical approval for this study was granted by the University of KwaZulu-Natal Biomedical Research Ethics Committee (BE047/14). All patients aged 13 years and older who needed at least two repeat laparotomies were included in the study. This included general surgical and trauma patients. RESULTS: During the study period, 72 patients required more than one repeat laparotomy and a total of 182 repeat laparotomy operations were performed on this patient cohort. Demographics showed a male predominance, with 54 (75%) being male and 18 (25%) being female patients. The average age was 39 years. General surgical patients accounted for 60% and trauma patients for 40% of the total. The majority of patients required only two repeat laparotomy (65 %), while two patients required a total of 6 repeat laparotomy each, both with an initial diagnosis of appendicitis and both these patients survived. Temporary abdominal closure (TAC) was performed in 26 (36%) of initial laparotomies, while 33 (46%) of patients had an open abdomen at the time of discharge or death. Sixty percent required intensive care or high care unit (ICU/HCU) admission and 53 patients (74%) had a total of 71 documented morbidities. Total mortality for this study was 21%, however there was no correlation between number of procedures and mortality. CONCLUSION: The total number of procedures is associated with increased morbidity rates but not necessarily with increased mortality rates. This is important to consider when the issue of futility of treatment arises, as the absolute number of repeat laparotomies is a poor marker of futility and other factors must be considered. PMID- 28876622 TI - Actinomycosis of the foot - A South African case. AB - Mycetoma is a chronic infection, characterised by severe disability and discomfort to patients. This condition is common throughout tropical regions of the world. The Indian subcontinent and north-east Africa, especially Sudan, bear the majority of the disease burden. Due to the limited resources and isolation of these areas, the condition is usually misdiagnosed or incorrectly managed. The World Health Organisation listed the condition as a "neglected disease" in 2013. The creation of the Mycetoma Research Centre (MRC) by the University of Khartoum in 1991 has greatly contributed to the current understanding of this disabling condition. We report a case of a 17-year-old boy from Port Elizabeth, South Africa. Uncommon in South Africa, this condition is easily misdiagnosed and mismanaged. PMID- 28876623 TI - HIV post-tuberculous broncho-oesophageal fistulas: A surgical solution. AB - We present a patient with HIV/AIDS with multiple tracheo-oesophageal fistulas probably due to previous tuberculosis. An Ivor-Lewis procedure was successfully undertaken following stringent pre-operative preparation. Surgical repair of persistent post-tuberculous tracheo-oesophageal fistulas may be safely undertaken in selected patients with HIV/ AIDS. PMID- 28876624 TI - Lingual Fibrolipoma - A rare clinicopathological entity. AB - Lipoma is a relatively common benign tumour occurring at sites of the body which are rich in adipose tissue. Due to sparsity of adipose tissue within the oral cavity, lipoma rarely presents in this region. Fibrolipoma of the tongue is a rare lesion. There are only 14 cases reported in the literature. An 85-year-old patient presented with a painless mass on the tongue interfering with eating. There were no risk factors for malignancy and no family history of malignant diseases. Although intraoperatively the lesion was locally infiltrative, histopathology revealed a rare benign fibrolipoma. Mainstay of treatment is surgical excision, but the lesion may pose a dilemma for Surgeons as difficulties associated with removal, due to the fibrous and adherent nature of the growth to surrounding tissue, may be mistaken for a cancerous growth. PMID- 28876625 TI - TO ACTIVATE OR NOT TO ACTIVATE? THE CONTROVERSY SURROUNDING TAMOXIFEN TREATMENT AND THROMBOSIS. AB - BACKGROUND: Cancer is associated with hypercoagulability, with therapies including chemotherapy, radiation therapy, surgery and hormone-therapy linked to an increased risk of thrombotic complications. Notwithstanding the contribution of other haematological processes and components, platelets are implicated in contributing to a hypercoagulable state, with breast cancer patients receiving Tamoxifen treatment at a greater risk for thrombotic complications. METHOD: MCF-7 and T47D breast cancer cells were cultured under standard conditions, followed by treatment with 2uM Tamoxifen for 24 hours and co-cultured with whole blood (WB) for 2.5 minutes. WB samples were then treated with red blood cell lysis buffer and processed for flow cytometry. Samples were analysed on the LSR Fortessa by FACSDiva, using an interval gating strategy to determine levels of CD62p expression, and further quantitatively analysed using IBM SPSS v23. RESULTS: Preliminary in vitro Results reveal that Tamoxifen treatment enhances the ability of breast cancer cells to induce platelet activation. The severity of platelet activation is dependent on the sub-phenotype of breast cancer cells used, with T47D cells inducing the highest levels of activation. CONCLUSION: While our data concurs with that of the clinical setting, other laboratory studies show that Tamoxifen prevents platelet activation. Therein lies the controversy - we postulate that experimental design and methodological approaches to this question have resulted in disparate conclusions. Additionally, an understanding of release of mediators of attachment using other techniques could further reveal the underlying assumptions behind these contradictions that ultimately may affect the approach to clinical management. PMID- 28876626 TI - APPLICATION OF GENE PROFILING IN SELECTION OF ADJUVANT THERAPY IN BREAST CANCER IN A DEVELOPING COUNTRY. AB - BACKGROUND: Outcome series for genetic profile tests (MammaPrint/70GP) with medium-term follow-up are rare and the popularity of these tests have now necessitated inclusion into international guidelines. We present here a series with 5-year follow-up from a developing country. METHOD: From 2006 to 2016, patients with histopathologically confirmed breast cancer (cT0-3 and cN0-1) had specimens submitted for 70GP and decisions on adjuvant therapy postsurgery were based on these Results. Data on outcomes were collected prospectively. RESULTS: There were 154 patients: 140 luminal type, 13 HER2 type and one triple negative; 57.8% were 70GP low-risk; only one of these did receive chemotherapy; 42.2% were high-risk; 3 patients did not receive chemotherapy. After an average follow-up of 54.1 months, 3 systemic recurrences occurred (all skeletal metastases), all in the high-risk group that had received chemotherapy. Across both groups overall survival was 99.9% and compliance with the treatment recommendations based on 70GP was > 95% in both arms. Two patients each had two tumours in the same breast with divergent 70GP Results and were treated in accordance with the high-risk result. Six patients showed discordant 70GP and FISH Results for HER2 where three patients did not receive Trastuzumab on basis of 70GP; none of these tumours recurred. A further 11 patients had equivocal Immunohistochemistry and a FISH was not done; therapy was decided upon considering the 70GP result and none of these patients had any recurrences. CONCLUSION: Chemotherapy use was much reduced versus the rate of use with conventional Methods using 70GP and, furthermore, it may be reasonable to replace immunohistochemistry for ER, PR and HER2 with 70GP especially considering borderline expression. PMID- 28876627 TI - BREAST GROSSING PRACTICES AND TURNAROUND- TIMES BEFORE AND AFTER THE INTRODUCTION OF A STANDARD BREAST PATHOLOGY SUBMISSION FORM: AN AUDIT. AB - BACKGROUND: Although the use of a standardized, synoptic pathology report for breast cancer has been demonstrated to improve the quality of reports, the role of a standardized form for the submission of breast cancer excision specimens to the histopathology laboratory has not yet, to our knowledge, been investigated. METHOD: The proforma for oncological breast excisions was devised collaboratively between the pathologists and the surgeons. During the month prior to the introduction of the proforma, and in the three-and-a-half months following the form's rollout, the senior pathology registrar at the CMJAH grossing bench completed an audit form for each breast cancer excision from HJH. The total turn around-time (TAT) for each specimen was calculated retrospectively for each specimen audited. RESULTS: Seventy-eight cases were audited, 17 before the introduction of the proforma and 61 after. The 3 cases received without attached proformas in the second cohort were excluded from the data analysis. The mean grossing time per specimen was unchanged in the two cohorts. The call rate to clinicians decreased from 0.47 to 0.16, as did the rate of required clinician visits to the laboratory (11.8% vs. 6.9%), the percentage of cases in which there was grossing confusion (29.4% vs. 15.5%) and the overall case TAT (18.4 days vs. 16.3 days). None of these Results reached statistical significance. There was, however, a statistically significant reduction in grossing delays (1.76 days vs. 0.0293 days, p = 0.0293) and in percentages of cases with mislabelled or misorientated tissue (29.41% vs. 8.62%, p = 0.0413). CONCLUSION: Our experience is that the use of a proforma in the grossing of breast excision specimens has resulted in an overall improvement in specimen grossing (specifically by reducing grossing delays and tissue mislabelling/misorientation) and has improved communication between surgeons and pathologists in this regard. PMID- 28876628 TI - AXILLARY LYMPH NODE DISSECTION IN INVASIVE BREAST CANCER PATIENTS AT CHARLOTTE MAXEKE JOHANNESBURG ACADEMIC HOSPITAL AND CHRIS HANI BARAGWANATH ACADEMIC HOSPITAL. AB - BACKGROUND: Axillary lymph node dissection (ALND) carries a high morbidity and sentinel node biopsy has become the standard of care in node-negative disease. Patients in our setting are assessed as node-positive on the basis of physical examination and axillary ultrasound and will undergo ALND without prior biopsy. The administration of neoadjuvant chemotherapy (NACT) may downstage the axilla and offer opportunities for axilla-sparing surgery. METHOD: This retrospective cohort study included all female patients older than 18 years of age who underwent axillary surgery in the breast units at Charlotte Maxeke Johannesburg Academic Hospital and Chris Hani Baragwanath Academic Hospital from March 2013 to March 2015. Odds ratios (OR) were calculated for a node-negative ALND after NACT and in the absence of axillary biopsy prior to surgery. RESULTS: We included 509 eligible patients and 391 underwent ALND (76.8%). A total of 99 patients (25.3%) had a node-negative ALND. Amongst these, 47 (47.5%) had received NACT. The risk of a node-negative ALND was not significantly increased when compared to patients who had primary surgery (OR 1.02). Only 41 of the 509 patients (10.5%) had preoperative pathological confirmation of nodal involvement. Patients with preoperative biopsy of the axilla were at reduced risk (OR 0.58) for node negative ALND. CONCLUSION: Of our ALNDs, 25.3% were node-negative. Contributing factors include the lack of preoperative pathological confirmation of nodal involvement. Routine biopsy of suspicious nodes should be introduced in our clinical practice. NACT did not increase the risk. There is a need to specifically evaluate the impact of HIV status on axillary management. PMID- 28876629 TI - CLINICAL BREAST EXAMINATION SCREENING BY TRAINED LAYWOMEN IN MALAWI INTEGRATED WITH OTHER HEALTH SERVICES. AB - BACKGROUND: Breast cancer awareness and early detection are limited in Sub Saharan Africa. Resource limitations make screening mammography or clinical breast examination (CBE) by physicians or nurses impractical in many settings. METHOD: Four laywomen were trained to deliver breast cancer educational talks and conduct CBE. After training, screening was implemented in diverse urban health clinics. Eligible women were 30 years old, with no prior breast cancer or breast surgery, and clinic attendance for reasons other than a breast concern. Women with abnormal CBE were referred to a study surgeon. All palpable masses confirmed by surgeon examination were pathologically sampled. Patients with abnormal screening CBE but normal surgeon examination underwent breast ultrasound confirmation. In addition, 50 randomly selected women with normal screening CBE underwent breast ultrasound, and 45 different women with normal CBE were randomly assigned to surgeon examination. RESULTS: Among 1220 eligible women, 1000 (82%) agreed to CBE. Lack of time (69%) was the commonest reason for refusal. Educational talk attendance was associated with higher CBE participation (83% versus 77%, P 1/4 0.012). Among 1000 women screened, 7% had abnormal CBE. Of 45 women with normal CBE randomised to physician examination, 43 had normal examinations and two had axillary lymphadenopathy not detected by CBE. Sixty of 67 women (90%) with abnormal CBE attended the referral visit. Of these, 29 (48%) had concordant abnormal physician examination. Thirty-one women (52%) had discordant normal physician examination, all of whom also had normal breast ultrasounds. Compared with physician examination, sensitivity for CBE by laywomen was 94% (confidence interval [CI] 79%-99%), specificity 58% (CI, 46%-70%), positive predictive value 48% (CI, 35%-62%), and negative predictive value 96% (CI, 85%-100%). Of 13 women who underwent recommended pathologic sampling of a breast lesion, two had cytologic dysplasia and all others benign Results. CONCLUSION: CBE uptake in Lilongwe clinics was high. CBE by laywomen compared favourably with physician examination and followup was good. Our intervention can serve as a model for wider implementation. Performance in rural areas, effects on cancer stage and mortality, and cost effectiveness require evaluation. PMID- 28876630 TI - IS WAITING THE HARDEST PART? A CRITICAL STUDY OF THE EXPERIENCE OF WOMEN AWAITING BREAST BIOPSY RESULTS. AB - BACKGROUND: Most previous research efforts have focused on the psychological effects of receiving a cancer diagnosis rather than the period of waiting for definitive Results. Early detection of cancer is directly linked to successful treatment regimes, yet these procedures evoke significant anxiety in patients. The long wait for medical test Results in state health institutions, with one of the possible outcomes being a cancer diagnosis, means that the days of waiting can induce emotional distress before the diagnosis has even been given. METHOD: Eight research collaborators were invited to, in their own voice, shed light on their individual experiences while waiting for their biopsy Results to gain an understanding of the experiences of each collaborator by letting her tell her story and to explore the possibility of shared experience between collaborators. Research collaborators at a local, government hospital kept a journal for the two week waiting period for their biopsy Results. Shortly before receiving their Results, they took part in a short semi-structured interview to inquire about their waiting. The theoretical framework used for data interpretation is critical theory focusing on the structures within society and healthcare systems that impact on the experience of waiting. The undercurrent of critical commentary about the roles of the gender, economic, political and cultural factors that contribute to the screening experience for women in South Africa helps to shed light on the complex forces at play within the procedures. RESULTS: The Results indicate that for some women waiting provokes significant psychological stress which manifests in multiple psychological processes including the psychological bracing phenomenon, denial, suppression and negation of their emotional experience all perpetuated by the structures of power within the health care system. CONCLUSION: More understanding of the psychological experience of awaiting a cancer diagnosis is required and there is an important place for qualitative approach to breast cancer research in South Africa. PMID- 28876631 TI - BREAST ARTERIAL CALCIFICATION ON MAMMOGRAPHY - A PROPOSED TOOL TO IDENTIFY WOMEN AT RISK FOR CARDIOVASCULAR DISEASE. AB - BACKGROUND: Calcification of breast arteries, observed on mammography, has been shown to have a positive association with cardiovascular disease and its risk factors, with literature suggesting that its presence should alert the clinician to underlying subclinical disease. METHOD: Of the women referred for mammograms between 1 January 2011 and 31 December 2011, 167 women over the age of 50 years, were included in the study. A retrospective review of the mammograms was done to determine the prevalence of breast arterial calcifications. A questionnaire pertaining to cardiovascular risk factors, including age, smoking status, history of diabetes, hypertension, cholesterol, gout, family history of cardiovascular events and obesity was completed. RESULTS: The prevalence of breast arterial calcification in our study was 21% (95% confidence interval CI 15.1%-27.9%). Controlling for age, only hypertension was significantly associated with the presence of breast arterial calcification (p = 0.011). Smoking (p = 0.18), diabetes (p > 0.09), cholesterol (p = 0.78) and family history (p = 0.31) failed to show a significant association. CONCLUSION: The presence of breast arterial calcification detected on mammogram is associated with hypertension in our study group, but failed to show any significant association with the other cardiovascular risk factors. If found at time of mammogram, the patient should be referred for assessment and, if necessary, treatment of hypertension. PMID- 28876632 TI - AN AUDIT OF PROVIDER DELAY IN NEWLY DIAGNOSED BREAST CANCER IN A CENTRAL REFERRAL HOSPITAL IN JOHANNESBURG, SOUTH AFRICA. AB - BACKGROUND: Breast cancer is one of the most common cancers in women worldwide and accounts for an increasing burden of disease in South Africa. One of the factors identified in improving outcome in patients with newly diagnosed breast cancer is decreased time from recognition of a breast symptom to initiation of primary therapy. METHOD: A total of 257 patients from 1 January 2014 to 31 December 2014 were included in the study. Patient records were examined and date intervals for each patient were recorded from initial presentation to primary therapy. The Results were compared to a standard of 90% of patients reaching primary therapy within 60 days. RESULTS: Median delay (interquartile range) to primary therapy was 49 days (33-80d). The primary chemotherapy group had a median delay of 48 days (30-71d), the primary endocrine therapy group had a 28 days (22 41d) delay, and the primary surgery group had a delay of 73.5 days (39.8-113.5d). The addition of diagnostic surgery to the treatment plan added 37 days to the primary chemotherapy group and 38 days to the primary surgery group. Notably, 101 patients (39.29%) had a delay greater than 60 days. CONCLUSION: The centre did not achieve the standard of 90% of patients reaching primary therapy within 60 days. Specifically, 36.8% of patients in the primary chemotherapy group, 58.3% of patients in the primary surgery group and 11.5% of patients in the primary endocrine therapy group did not reach the target. The delay was most pronounced in the group of patients undergoing primary surgery, with a median time to surgery greater than the target time of 60 days. Factors affecting delay to primary surgery warrant further investigation. PMID- 28876633 TI - THE RATES AND RISK FACTORS FOR LOCAL RECURRENCE OF PHYLLODES TUMOURS IN A SOUTH AFRICAN POPULATION. AB - BACKGROUND: Phyllodes tumours are rare fibroepithelial neoplasms of the breast. The dilemma with phyllodes tumours is their tendency to local recurrence. METHOD: We retrospectively assessed all histological reports of patients diagnosed with a phyllodes tumour after surgery at the University of the Witwatersrand NHLS (National Health Laboratory Service) Anatomical Pathology Laboratories, Johannesburg, South Africa from 1 January 2005 to 30 June 2016. Clinical and histological parameters were analysed. RESULTS: A total of 185 patients were identified. The median age of the patients was 42 years. There were 89 (48.1%) patients with a benign tumour, 34 (18.4%) with a borderline tumour and 62 (33.5%) with a malignant tumour. The size of the tumours ranged from 11 to 460 mm, with a mean of 106.1mm and SD of 79.6. Breast conserving surgery (BCS) was performed on 64.3% of patients and 35.7% of patients had a mastectomy. There was an overall local recurrence rate of 3.78% (2.2% for the benign tumours and 8.1% for the malignant tumours). No clinical or histological factors were found to significantly predict local recurrence. CONCLUSION: Since our study did not find any predictors of local recurrence, we suggest that a wide local excision with 1 cm margins might be unnecessary, and perhaps a negative margin combined with a close follow up for two years after excision is necessary. PMID- 28876634 TI - CLINICAL VS PATHOLOGICAL STAGING OF BREAST CANCER: CAN OUR HANDS COMPETE WITH THE MICROSCOPE? AB - BACKGROUND: Tumour size and axillary nodal status are important predictors of prognosis in breast cancer. The clinical examination of the breast is an essential component of preoperative TNM staging, but the accuracy of this method of assessment has been called into question, especially in the determination of axillary nodal status. METHOD: Data were obtained from a database of breast cancer patients presenting to the Netcare Breast Care Centre in Johannesburg between June 2015 and June 2016. The following cases were excluded: neo-adjuvant chemotherapy / primary endocrine therapy, patients who did not proceed to surgery, surgical margin clearance only, surgical biopsy prior to presentation, incomplete staging information and atypical breast tumours. Clinical evaluation was performed by a senior specialist breast surgeon. The clinical and pathological tumour size (AJCC/ UICC TNM T-stage) and nodal status (AJCC / UICC TNM N-stage) of the remaining patients were analysed for correlation. RESULTS: Two hundred and twenty-nine (n = 229) patients were included in the analysis. All were female, with a mean age of 52 years (range 27-85). The clinical estimation of T-stage correlated with histopathology in 157/229 cases (68.6%). Of the 72 cases where the T- stage did not match, clinical examination underestimated tumour size in 42 patients (58.3%) and overestimated tumour size in 30/72 (41.7%). Clinical examination for axillary lymphadenopathy had a sensitivity of 2.2% (95% CI 0.1 - 13.0%) and a specificity of 99.5% (95% CI 97.0 - 99.9%), positive predictive value (PPV) of 50.0% and negative predictive value (NPV) of 83.6%. CONCLUSION: Even when performed by a specialist, clinical estimation of tumour size is subject to a significant degree of over- and underestimation. Clinical evaluation of axillary nodal status is highly specific, but has a low sensitivity. Findings at clinical examination should therefore be correlated with radiology to facilitate accurate preoperative assessment. PMID- 28876635 TI - THE SURGICAL MANAGEMENT OF CENTRAL BREAST TUMOURS AT A SPECIALIST BREAST UNIT IN JOHANNESBURG, SOUTH AFRICA. AB - BACKGROUND: Central breast tumours are defined as tumours in the retroareolar area, or within 1.5-2.0 cm from the areolar edge. In the past, breast conservation therapy (BCT) for central breast tumours was considered controversial due to concerns regarding oncologic safety and cosmesis. Recent evidence does however suggest that oncoplastic techniques offer a cosmetically acceptable and safe alternative to mastectomy in these tumours. METHOD: Patients with central breast tumours (invasive and in situ) were identified from a breast cancer database of 431 patients who presented to the Netcare Breast Care Centre in Johannesburg over a one-year period (June 2015-June 2016). Patients who were not managed surgically were excluded from analysis. Demographic data and the details of the surgical procedures performed were collected and analysed. RESULTS: Forty patients met the inclusion criteria, all of whom were female. The median patient age was 59 years (range 30-88 years). The majority of the tumours were small, with 29/40 tumours <= 5 cm (<= T2) at presentation. Of the 40 patients, 18 were referred for neo-adjuvant chemotherapy. Surgical management was BCT in 19/40 patients and mastectomy in 21/40. In the BCT group, one patient underwent prosthetic reconstruction, while the rest were reconstructed by reduction mammaplasty (8/18), latissimus dorsi flap (6/18), local parenchymal flap (2/18) and thoracoepigastric flap (2/18). In the mastectomy group, 5/21 patients declined reconstruction. Of the remaining 16 patients, half elected to undergo immediate prosthetic reconstruction and half opted for autologous reconstruction. The autologous reconstructions performed in the mastectomy group were latissimus dorsi flap (4/8), thoracoepigastric flap (3/8) and a combination of thoracoepigastric/LICAP flap (1/8). All the tumours in both the BCT and mastectomy groups had clear resection margins. CONCLUSION: BCT was feasible in approximately half of the patients in this case series. Breast conservation surgery presents a viable surgical alternative to mastectomy in patients with central breast tumours. PMID- 28876636 TI - IDENTIFYING WOMEN AT RISK OF UNCERTAINTY AND POOR QUALITY OF LIFE WHEN UNDERGOING BREAST CANCER SURGERY: A SURVEY-BASED DESCRIPTIVE STUDY. AB - BACKGROUND: Breast cancer is a leading cause of morbidity and mortality in South African women. In resource-limited settings emphasis for disease management is often concentrated on biological control and survival. However, understanding the full biopsychosocial experience of breast cancer is essential in improving access and patient uptake of care. METHOD: A quantitative cross-sectional study was carried out in patients prior to breast surgery. Each participant completed the survey including validated questionnaires of uncertainty, QoL index, social support scale and demographics. RESULTS: Of the 59 women approached, 53 (89.9%) participated. Uncertainty was found in 86.8% (28.3% severe uncertainty) with all newly-diagnosed patients experiencing uncertainty. Patients above 45 years made up 80% of all those who were severely uncertain. Good social support did not affect levels of uncertainty. Conversely QoL was improved in women with at least primary education, and in women above 45 years. Pre-surgical chemotherapy was not associated with either uncertainty or QoL. Greatest uncertainty was reported about the roles of the treating staff and the presence of unanswered questions. CONCLUSION: Older women and those with education more commonly experienced uncertainty, but reported better QoL. The areas of uncertainty can help direct clinicians in limited resources settings to better direct services to help support patients, instituting simple measures of education and orientation. PMID- 28876637 TI - THE LEVEL OF BREAST AND CERVICAL CANCER AWARENESS AMONG WOMEN IN A RURAL AREA OF SOUTH AFRICA. AB - BACKGROUND: In South Africa breast and cervical cancer are the most predominant cancers amongst women, with mortality rates reaching surprising proportions. As a result of the continued rise of these conditions it is vital to determine these women's awareness of both, so as to determine the exact factors contributing to this rise. Whilst both urban and rural areas are afflicted, this study focused primarily on women in a rural area. METHOD: This was a descriptive cross sectional study conducted in a shopping mall located in the rural area of Bushbuckridge, Mpumalanga, South Africa. A total of 300 women of reproductive age were randomly identified and requested to fill out a study questionnaire assessing their level of breast and cervical cancer awareness. RESULTS: A total of 300 women participated in the study. The mean age of participants was 35.66 with a range of 13.53. Overall levels of knowledge about breast and cervical cancer in rural Bushbuckridge were found to be reduced with 66.89% and 74.49% of women who rated themselves with a poor understanding of breast and cervical cancer knowledge respectively. Among the participating women, those over the age of 40, with higher level of education were found to be more cognizant in terms of breast and cervical cancer awareness with a 30% (p = 0.0923) and 52% (p < 0.001) respectively. Their younger and less educated counterparts had a 21% (p = 0.078) and 32% (p = 0.034) awareness of breast and cervical cancer, respectively. The leading source of information for both breast and cervical cancer was healthcare facilities with a 67.11% and 63.5% respectively. CONCLUSION: This study highlights the lack of awareness and knowledge of breast and cervical cancer in women living in the rural area of Bushbuckridge, South Africa. There is also evidence showing that the older and more educated women have better knowledge than their younger and less educated counterparts, therefore there is a need for increased breast and cervical cancer education and awareness campaigns amongst women in rural South Africa. The Results further point to education and availability of health care services as pivotal determinants of health. PMID- 28876638 TI - HEPATOBILIARY FACTORS INFLUENCING MORBIDITY RATES AFTER PANCREATIC STAB WOUNDS. AB - BACKGROUND: Penetrating injuries of the pancreas may result in serious complications. METHOD: A retrospective univariate cohort analysis was done of all pancreatic stab wounds documented in a prospective dedicated departmental pancreatic injury database of 475 patients treated between 1982 and 2016. RESULTS: Eighty-seven (80 men) patients, median age 26 years (range 16-62) had stab wounds of the pancreas. Median RTS was 7.8 (range 2.0-7.8). Injuries involved head/uncinate process (n = 16), neck (n = 2), body (n = 40) and tail (n = 29) of the pancreas. All 87 patients underwent a laparotomy. Sixty-eight patients had AAST grade I or II injuries and 19 had grade III, IV or V pancreatic injuries. Eight (10.3%) of 78 patients had an initial damage control operation. Seventy-four (85.1%) patients had drainage of the pancreas only, eleven had a distal pancreatectomy and two had a Whipple resection. Fourteen patients developed pancreatic complications, of which 8 were fistulae. Four (4.6%) patients died. Grade of pancreatic injury (AAST grade I-II vs grade III-V injuries; p < 0.01), presence of shock on admission (p < 0.01), need for a blood transfusion (p < 0.01) and an associated visceral vascular injury (p < 0.001) had a significant influence on the development of general complications. CONCLUSION: Although mortality was low after a pancreatic stab wound, morbidity was high. Increasing AAST grade of injury, shock on admission to hospital, need for blood transfusion and an associated vascular injury were significant factors related to morbidity. PMID- 28876640 TI - GENE AND PROTEIN EXPRESSION PROFILING OF PANCREATIC TUMOURS REVEAL DYSREGULATED PATHWAYS AND NOVEL POTENTIAL BIOMARKER. AB - BACKGROUND: Pancreatic cancer (PDAC) is a deadly type of cancer with almost an equal amount of new cases and deaths observed yearly. It accounts for about 7% of cancer-related deaths worldwide. In many multi-racial societies including South Africa, the black population has the highest incidence rate. Less than 5% of PDAC patients live up to 5 years. The lack of specific and sensitive diagnostic PDAC biomarkers is strongly responsible for this poor statistic. The discovery of differentially expressed genes and proteins associated with PDAC is crucial to elucidating this condition and may lead to biomarker finding and further understanding of the disease. METHOD: Tissue samples were obtained from Black South African PDAC patients during the Whipple procedure. Using focused arrays and RNA Sequencing, we have shown differentially expressed genes and proteins between tumour and normal tissue samples of PDAC patients in the quest for potential biomarker discovery. Furthermore, we utilised multiple bioinformatics tools to identify pathways and biological processes enriched by differentially expressed genes/proteins, and to discover novel variants and novel potential PDAC biomarkers. Real-time PCR and ELISA were also employed to validate our novel potential PDAC biomarker. RESULTS: We have identified novel 1) potential transcriptomic and 2) proteomic biomarkers of pancreatic cancer. Our identified transcriptomic biomarker has a sensitivity and specificity of 100% and 80% respectively. Furthermore, we observed novel genetic variants and dysregulated pathways occurring during pancreatic carcinogenesis. CONCLUSION: This study has identified novel potential biomarkers which can help in the diagnosis of PDAC. Information obtained from enriched signalling pathways help in further understanding the biology of PDAC. Going forward, the identified novel potential biomarkers need to be further validated in a larger sample number using easily accessible samples like blood. PMID- 28876639 TI - ALTERED METABOLIC PATHWAYS IN CHRONIC PANCREATITIS AND PANCREATIC CANCER. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a devastating diagnosis for any patient as it is associated with a high mortality rate, and has few therapeutic interventions that prolong survival as compared to other cancers. Frequent epidemiological reports on PDAC are available in the developed countries, but in South Africa there is paucity of epidemiological data of this aggressive cancer. Understanding risk factors will help to assess and develop relevant interventions. Knowing the potential factors associated with it will provide information for improved screening and management of potentially curable patients. Furthermore, early diagnosis may increase the survival of PDAC patients in all races and this study may increase awareness of this disease in the population. METHOD: This was a secondary unmatched case-control study to assess risk factors of PDAC at CHBAH and CMJAH Academic Hospitals. All participants were >18 years of age, 139 with PDAC and 139 without PDAC. Data exported from REDCap was analysed, using Stata 13. The exported data included patient demographics, social and medical history. Descriptive statistics used the chi square test and inferential statistics used unconditional multiple logistic regression. Unconditional logistic regression estimated the odds ratios (ORs) in the case control analyses. The likelihood ratio test with a p-value of < 0.10 was accepted to assimilate data fitting into the model. RESULTS: This study showed that the following categories, their odds ratio and 95% confidence interval were statistically significant at p-value < 0.10. The 20-29 age group had odds ratio (OR) of 0.11(0.11-1.00) p = 0.05. The 50-59 age group had OR 2.63(1.03-6.70) p = 0.042. The general worker had OR 1.79(0.93-3.45) p = 0.083. High white meat consumption had OR 0.18(0.04-0.86) p = 0.032. Low fish consumption had OR 2.17(1.06-4.45) p = 0.034. Low consumption of fried food had OR 0.48(0.23-1.00) p = 0.050 and high consumption of vegetables had OR 0.17(0.05-0.61) p = 0.007. CONCLUSION: The main risk factors associated with PDAC are 50-69 age group and longest employment as a general worker. Low consumption of fish is a risk factor based on our findings while on the other hand high consumption of fish has no statistical significance in cases and controls. High consumption of vegetables and white meat are protective against PDAC. PMID- 28876641 TI - GENE AND PROTEIN EXPRESSION PROFILING OF PDAC TUMOURS OBTAINED FROM BLACK SOUTH AFRICAN PATIENTS REVEAL NOVEL POTENTIAL BIOMARKERS. AB - BACKGROUND: Pancreatic cancer (PDAC) is a devastating cancer. It accounts for about 7% of cancer related deaths worldwide. During PDAC, several genes are altered. These alterations consequently lead to the progression of PDAC. Analysis of these alterations in the context of signalling pathways help in understanding the disease. METHOD: 18 Tissue (9 tumour, 9 normal) samples were obtained from Black South African stage I PDAC patients during the Whipple procedure. Utilizing pathway-focused arrays, antibody arrays, and RNA Sequencing differentially expressed genes/proteins in tumour tissues were identified. Additionally, using several bioinformatic tools we have identified dysregulated pathways and biological processes in PDAC. RESULTS: We observed several upregulated pathways occurring in pancreatic carcinogenesis such as IGF/MAPK, Integrin, and Ras signalling pathways. Additionally, downregulated pathways were also observed including the MHC II antigen presentation pathway. CONCLUSION: Information obtained from enriched signalling pathways help in further understanding the biology of PDAC. The dysregulation of these pathways aid in the induction and enhancement of PDAC. Thus, they might serve as potential targets for PDAC management and treatment. PMID- 28876643 TI - THE ROLE OF IL17-A IN THE SECOND HIT OF ACUTE PANCREATITIS. AB - BACKGROUND: Acute pancreatitis is characterised by distinct clinical phases. An initial systemic inflammation response syndrome (SIRS) and occasional subsequent 'second hit' usually initiated by systemic sepsis. The pro-inflammatory T-helper 17 pathway has been shown to be an initiator of early SIRS in AP; however, to date, interleukin-17A has not been evaluated as a marker of the septic second hit in severe acute pancreatitis (SAP). METHOD: Twenty-five (aged 22-78) with mild (n = 12), moderate (n = 5) and severe (n = 8) acute pancreatitis were enrolled. Peripheral blood samples were drawn on days 7, 9, 11 and 13 of illness for routine clinical markers as well as cytokine analysis. Flow cytometry was performed using a Th1/Th2/Th17 Cytokine Bead Array (BD Biosciences). Statistical analysis was performed using a Fisher's exact test and ANOVA, with a p = value of < 0.05 considered significant. RESULTS: The mean concentration of IL-17A (pg/ml) on days 7, 9, 11 and 13 of illness in the mild/moderate group were 18.1, 12.9, 11.9, 18.9 and in the severe group 14.4, 12.9, 18.9, 12.8. There was no statistical significance between the groups. IL-10 was significantly higher in severe acute pancreatitis on days 7, 9, 11 and 13, but IL-6 and IL-2 were only significantly elevated in severe acute pancreatitis on days 9, 11 and 13. No differences were noted between the groups for IL-4, TNF and IFN-gamma. WCC, CRP and PCT were all significantly higher in severe acute pancreatitis over the study days. CONCLUSION: The IL-17A concentration in the study population could not statistically be attributed as the cause of the second hit in acute pancreatitis. Further studies to confirm this are underway. PMID- 28876642 TI - OUTCOME OF LIVER RESECTION FOR CARCINOID NEUROENDOCRINE METASTASES. AB - BACKGROUND: Gastrointestinal carcinoid tumours, despite their low malignant potential, frequently metastasize to the liver. While liver resection improves survival and provides symptomatic relief, multifocal bilobar disease complicates surgical management. METHOD: All patients with carcinoid liver secondaries managed by resection from 1990-2015 were identified from a prospective departmental database. Demographic data, operative management, morbidity using the Accordion classification and mortality were analysed. Survival was assessed using the Kaplan-Meier method. RESULTS: Seventeen patients (9 women, 8 men, median age 55 years, range 31-76) underwent resection. Median number of liver secondaries treated was 3 (range 1-20). Ten patients had major anatomical liver resections. Three patients had 5 segments resected, seven had 4 resected, and seven had <= 2 resected. Each patient had all identifiable liver secondaries resected or ablated. Two also had intraoperative tumour ablation. Nine patients (53%) had a concurrent bowel resection and lymphadenectomy. Median operating time was 255 minutes (range 150-720). Median blood-loss was 800 ml (range 200-10,000). Five patients required intraoperative blood transfusion. Intermittent portal inflow occlusion (56.5 minutes median, range 20-150 minutes) was used in 8 patients. Median postoperative hospital stay was 9 days (range 2-28). Thirteen complications occurred in seven patients. Accordion grade 1 complications were n = 3 (ileus, wound sepsis, confusion), grade 2 n = 4 (delayed gastric emptying, pleural effusion, wound sepsis), grade 3 n = 3 (bile leak, intra-abdominal collection, atelectasis), grade 4 n = 2 (intra-operative bleeding) and grade 6 n = 1 (cardiac failure). One patient required reoperation for bleeding and a bile leak. One patient died of a myocardial infarction 36 hours postoperatively. Sixteen (94%) patients had symptomatic improvement. Five-year actuarial survival rate was 91% (median follow-up 36 months, range 14-86 months). CONCLUSION: Our data show that liver resection can be safely performed for carcinoid secondaries with a good 5-year survival. However, a substantial number of patients require a major liver resection and are best treated at a multidisciplinary referral centre. PMID- 28876644 TI - LIVER FUNCTION TESTS IN PREDICTING CBD STONES IN ACUTE BILIARY PANCREATITIS. AB - BACKGROUND: Acute biliary pancreatitis is a significant cause of pancreatitis. The role and timing of endoscopic retrograde cholangiopancreatography in the setting of acute biliary pancreatitis is still controversial. Persistent choledocholithiasis in acute biliary pancreatitis occurs and establishing which patients require an endoscopic retrograde cholangiopancreatography based on liver function tests only can be challenging. METHOD: Retrospective analysis of the Chris Hani Baragwanath Academic Hospital's ERCP database was performed. All ERCPs performed in patients with acute biliary pancreatitis were identified and analysed. RESULTS: A total of 2830 ERCPs were performed during the study period. In total 99 (3%) were performed for suspected choledocholithiasis in acute biliary pancreatitis with abnormal liver function tests. Thirty (30%) of the ERCPs confirmed choledocholithiasis while the remaining 69 (70%) yielded no choledocholithiasis. A significantly higher proportion of patients with choledocholithiasis required a needle knife sphincterotomy for deep biliary cannulation. The incidence of immediate complications, such as bleeding, false tract formation and perforation were comparable between the two groups. Two models were developed to determine specific cut-off values for conjugated bilirubin, ALP, GGT, AST and ALT. The calculated cut-off values yielded poor correlation between sensitivity and specificity. CONCLUSION: Determining persistent choledocholithiasis in acute biliary pancreatitis based on liver function test alone is not ideal. Using conjugated bilirubin, ALP, GGT, AST and ALT to guide one to perform an ERCP in acute biliary pancreatitis can be misleading. PMID- 28876645 TI - IS HIV STATUS RELEVANT IN ACUTE PANCREATITIS. AB - BACKGROUND: HIV positivity and antiretroviral (ARV) treatment have been described as significant causes of acute pancreatitis prevalence and predictors of poor outcomes. Most data are from the late 1990s and early 2000s, prior to widespread roll out of ARVs and newer agents. This study assessed if there is still a significant difference between HIV positive (HIV+) and negative(HIV-) patients in acute pancreatitis in the presentation and outcomes of acute pancreatitis. METHOD: A retrospective review of a prospectively collected database of patient admission data. The data was collected by an interviewer-administered questionnaire. All patients presenting to Chris Hani Baragwanath Academic Hospital with acute pancreatitis were eligible for inclusion. RESULTS: Of 148 patients, 56 (37.8%) were HIV+ and 92 (62.2%) HIV-. Median age at presentation was 40.5 (18-77); HIV+ 37 (18-61), HIV- 41.5 (19-77)(p = 0.14). Men comprised the majority (58.1%); HIV+ and HIV- (53.6% vs. 60.9%), (p = 0.40). Median BMI on presentation was 23.6 (16.4-41.4), no significant difference between HIV+ ( 23.3 [16.4-38.4]) and HIV-(24.3 [16.7-41.4]) (p = 0.65). Smoking was equal, HIV+ (51.1%) and HIV- (57.1%) (p = 0.59). Alcohol use was not significantly different, HIV+ (88.2%), HIV- (77.3%) (p = 0.20). The predominant aetiology was alcohol, HIV+ (63.6%) and HIV- (58.2%); followed by gallstones, HIV+ (23.6%) and HIV- (27.5%), (p = 0.26). Contrary to prior studies ARVs were not significant (3.6%). The revised Atlanta severity score was severe in 45.3%, HIV+ (46.4%) and HIV- (44.6%) (p = 0.8). The median admission CRP was 49 (< 1-447) in HIV+ and 27 (< 1 406) in HIV- (p = 0.44). Length of stay did not differ significantly, all patients stayed a median of 9 days (0-731), HIV+ 6 days (1-601) and HIV- 12.5 days (0-731), (p = 0.39). CD4 counts were available on 36 of the HIV+ patients and viral load on 19. The range of CD4 levels was 3 to 911 (median 259), and viral loads 0-3 160 000 (median 48). 37 patients were on ARVs and their CD4 ranged 14-681, those not on treatment ranged 3-911. CONCLUSION: In the present era of ARV regimens and universal roll-out, there is no significant difference between HIV+ and HIVpatients in the presentation, aetiology and outcomes of acute pancreatitis. PMID- 28876646 TI - INCIDENTAL GALLBLADDER CANCER - THE FIRST REPORT FROM SUB-SAHARAN AFRICA. AB - BACKGROUND: Incidental gallbladder cancer (iGBC) is found in 0.3-1.5% of cholecystectomy specimens. GBC is uncommon with significant variation amongst geographical regions and ethnic groups. Less than 100 GBC's have been reported in sub Saharan Africa, hence the need for this national audit in South Africa. METHOD: National data was obtained from the South African NHLS for 2003-2015. 34 294 cholecystectomy specimens were included of which 239 were GBCs; 135 were iGBC. RESULTS: iGBC incidence was 0.42% with a male:female ratio of 1:4.6. Mean age was 62.2 (range 20-88; male 64.83 and female 61.67). Indications for surgery were acute cholecystitis in 49% and biliary colic in 44%. GBC T stages were Tis 12.6%, T1a 4.4%, T1b 8.8%, T2 37.8%, T3 13.3% and Tx 22%. Lymph nodes were found in 10 patients, of which 5 were N1. R1 resection occurred in 32.6% of the cohort. Univariate analysis found female sex, chronic inflammation and the presence of dysplasia to be associated with iGBC. No association was found with surgical indication, presence of gallstones or other histological findings (polyps, xanthogranulomatous inflammation, calcification and RAS). Only female gender was associated with iGBCa after multivariate analysis. CONCLUSION: This large series demonstrates a similar incidence of iGBC in an African cohort to those reported from more developed nations, with female gender being the most significant risk factor. Delay in presentation may explain the more advanced stage (T2 and T3) and a resultant high rate of R1 resection. PMID- 28876647 TI - NEEDLE KNIFE SPHINCTEROTOMY - THE CHRIS HANI BARAGWANATH ACADEMIC HOSPITAL EXPERIENCE. AB - BACKGROUND: Deep biliary cannulation is essential in performing a therapeutic ERCP. Cannulation can be enhanced through the utilization of a pre-cut by means of a needle knife sphincterotomy. METHOD: Retrospective analysis of the Chris Hani Baragwanath Academic Hospital's ERCP database was performed. All ERCPs performed with the aid of a needle knife were identified and analysed for successful and unsuccessful deep biliary cannulation. RESULTS: 2830 ERCPs were performed during the study period. 369 (13%) required needle knife sphincterotomies and successful deep biliary cannulation was achieved in 229 (62%) of these patients. Repeat ERCPs were performed on 125 (34%) patients. 61 (49%) of the repeat ERCPs were performed because of previously failed cannulation. 34 (56%) of these repeat ERCPs resulted in successful deep biliary cannulation at re-attempt. 99% of successful cannulations at repeat ERCP had had a needle knife sphincterotomy at the first ERCP. CONCLUSION: Needle knife sphincterotomy improves deep biliary cannulation at initial ERCP and subsequent ERCPs with low incidences of complications. PMID- 28876648 TI - PREVALENCE OF ADENOCARCINOMA OF THE OESOPHAGUS IN TWO TEACHING HOSPITALS IN GAUTENG PROVINCE, SOUTH AFRICA. AB - BACKGROUND: Oesophageal carcinoma is the eighth most common cancer worldwide and sixth most common cause of cancer related mortality. The incidence of oesophageal adenocarcinoma has rapidly risen over the past decades; however squamous cell carcinoma of the oesophagus remains the most common worldwide. The prevalence of oesophageal carcinoma is high in South Africa and contributes significantly to the burden of disease. The prevalence of squamous cell carcinoma is greater than that of adenocarcinoma of the oesophagus but no recent local data is available. This study is Aimed at evaluating the cases of oesophageal carcinoma currently presenting to our institutions. METHOD: This was a retrospective study of all the cases of oesophageal malignancy recorded on the NHLS database at CMJAH and CHBAH from 01 January 2001-31 December 2013. Demographic variables including age, gender and population group where noted were recorded. RESULTS: The prevalence of oesophageal carcinoma in our two teaching hospitals was on a downward trend. There was a significant decrease noted in the SCC subtype. The AC subtype prevalence was on an upward trend. The change of prevalence of AC was determined using chi square analysis and showed a strong level of significance with p < 0.01. CONCLUSION: This study shows trends in the prevalence of oesophageal carcinoma in keeping with that of western populations. Further reduction in the incidence of oesophageal carcinoma in South Africa will necessitate education and screening programs similar to those in western populations. PMID- 28876649 TI - AN EVALUATION OF EPIDEMIOLOGICAL DIFFERENCES IN COLORECTAL CANCER PATIENTS OVER AND UNDER THE AGE OF 50 PRESENTING TO ACADEMIC CENTERS IN JOHANNESBURG. AB - BACKGROUND: As in other developing countries, the nations of Sub-Saharan Africa have seen an increase in the incidence of colorectal cancer. Repeatedly, the indigenous populations have shown a skewing of incidence in favour of patients below the age of 50. As part of a larger study, and through funding from the Medical research Council of South Africa, the Wits MRC Oncology group has set out to identify the epidemiological characteristics and disease progression of patients under the age of 50 presenting with colorectal cancer. METHOD: Data was collected from the clinical experience of patients with colorectal cancer seen in four Wits academic hospitals (CMJAH, CHBH, WDGMC and Edenvale Hospital), through collection of clinical notes, interviews with patients and clinicians. This was achieved through a research nurse and the information was put into a REDCap database for further analysis. RESULTS: On assessment of the data, there was a weak association between those below the age of 50 and black ethnicity and a weak association between those under 50 and male gender. In assessment of the other variables, similarly, association was demonstrated between those over the age of 50 and an abnormal waist circumference. A trend toward a greater BMI amongst the over 50 and lower BMI amongst the under 50 years of age at presentation also appears to be emerging. CONCLUSION: The difference in risk profiling and epidemiology of young verses old patients may indicate a binary predisposition to colorectal cancer. These Results, however, need to be interpreted with caution, numbers accrued in this study are small and the assessments as a result are underpowered. PMID- 28876650 TI - PPH: WHERE DID IT GO WRONG? AB - BACKGROUND: The stapled haemorrhoidopexy has been used for 20 years. A rare but serious complication is stenosis, occurring in 1-2% of cases. The mechanism for this stenosis has never been described. METHOD: The cadavers of five pigs previously euthanised underwent the procedure for prolapse and haemorrhoids (PPH). Four deliberate mistakes were tested: 1) doubling the circular suture back on itself for part of the circumference at the same depth; 2) placing the circular suture at varying depths; 3) placing one bite of the suture deeper and on the opposite wall of the rectum; and 4) firing the stapler with the anvil positioned proximal to the circular suture but with the suture secured tightly to the shaft of the device. RESULTS: Placing the circular suture and doubling the stitch back on itself did not cause stenosis. Placing the circular suture at varying depths resulted in a fold in the rectal mucosa. Placing one bite of the suture deeper and opposite resulted in a large flap of rectal mucosa folded into the staple line. Firing of the stapler outside of the suture produced a complete occlusion of the rectal lumen. CONCLUSION: We have demonstrated reproducible mistakes that consistently result in one of the most serious complications, viz. complete occlusion, and propose that healing of the loose flap may contribute to subsequent partial stenosis. PMID- 28876651 TI - SURVEILLANCE COLONOSCOPY FOR LYNCH SYNDROME IN THE NORTHERN CAPE: DOES DIRECT CONTACT IMPROVE COMPLIANCE? AB - BACKGROUND: The Annual Northern Cape Colonoscopy Outreach program provides surveillance colonoscopy to known Lynch Syndrome individuals in the Northern Cape Province of South Africa. Annual endoscopy is preceded by a preparation visit Aimed at improving attendance by directly imparting information to individuals requiring surveillance. During the preparation trip an attempt is made to reach all individuals scheduled, however due to the vastness of the Northern Cape inevitably every year some areas are not visited. Over the past few years fewer than 25% of participants obtained 100% adherence. METHOD: A randomised controlled crossover trial was developed to take place over two years of endoscopic surveillance. Included participants were randomised to a control group (A) that was not seen prior to colonoscopy, and a test group (B) that was visited by a team from Cape Town preceding surveillance. In the second year of study, the intervention on these groups was reversed. Compliance and understanding of information given was measured in terms of attendance at surveillance in September of each year of study. RESULTS: 78 participants (Group A = 38; Group B = 40) were enrolled. In September 2014, thirty-six (46.2%) participants presented, 19 (50%) from the control group (Group A) and 17 (42.5%) from Group B. In 2015, there was 53% (n = 41) attendance; 21 (55%) from directly contacted Group A, and 20 (50%) from Group B. Direct interaction was found not to significantly impact attendance (p-value = 0.853). Improved attendance was noted in individuals with prior compliance to surveillance (p-value = 0.001). CONCLUSION: Direct interaction with Lynch Syndrome individuals prior to annual surveillance colonoscopy has not shown to positively impact attendance. Interaction and counselling should focus on individuals identified to be defaulting surveillance. PMID- 28876652 TI - UNUSUAL HISTOPATHOLOGIES OF THE APPENDIX. AB - BACKGROUND: Acute appendicitis is a very common surgical emergency. Most commonly, the histopathological findings of the appendix reflect the normal pathophysiology of appendicitis that starts with the luminal obstruction and culminates in florid suppurative, gangrenous or perforated appendix. The treatment is usually straightforward and consists of surgery and antibiotics. Uncommonly, unusual pathologies are identified and require specific management. The literature is scanty about the unusual findings. In a worldwide review of 128 articles, Sami Akbulut has established 1.7% incidence of unusual histopathology led by Enterobius vermicularis (28.4%) followed by carcinoid (21.9%) and schistosomiasis (12.7%). METHOD: A retrospective review of histopathological reports of appendix specimens obtained during appendectomies done between January 2012 and December 2014 in the three academic hospitals of Johannesburg (CHBAH, CMJAH, HJH). All specimens were examined by the National Health Laboratory Services (NHLS). RESULTS: A total of 2408 histopathologies were obtained from the national health laboratory system. 164 specimens were excluded because they were part of colonic resection for conditions unrelated to the appendicitis. From the 2244 specimens analysed, 8.1%, 52.7% and 30.1% were due to normal appendix, acute appendicitis and complicated appendicitis respectively, and the incidence of unusual histopathological findings was 5.3% (119/2244). Of the 2244 specimens analysed the mean age was 25.6 years (2-88yrs) and the gender distribution was 61.9 % males and 38.1% females. The most common unusual causes were parasites (37%) led by schistosomiasis (24.3%), followed by neoplasm (20%) and fibrous obliteration (14.2%). CONCLUSION: Although uncommon (5.3%), the unusual causes of appendicitis may result in an adverse patient outcome and/ or require specific treatment that may be overlooked if histopathology reports are not checked routinely. PMID- 28876653 TI - OUTCOME OF APPENDICITIS IN THE ELDERLY IN UNIVERSITAS AND PELONOMI HOSPITALS. AB - BACKGROUND: In the elderly population, appendicitis still poses a high mortality and morbidity. Morbidity rates of 28-60% and mortality rates of 5-10% have been reported. The mortality rate is even higher in the presence of perforated appendicitis. Various factors have been pointed out to contribute to this trend. METHOD: A retrospective analytical study on all patients over the age of 60 years who had appendectomies at Universitas or Pelonomi Hospital between 01 January 2004 and 31 December 2014 was done. Data of all appendectomy specimens received at Anatomical Pathology was collected and the hospital numbers were retrieved. The patients' clinical records were then scrutinised and the data transferred to an Excel spread sheet. The data was analysed using the Fisher two-tailed test and a p-value of < 0.05 was considered significant. Ethic clearance was obtained from the Health Research Ethics Committee of the Faculty of Health Sciences (ECUFS 57/2015). RESULTS: Sixty-eight elderly patients aged 60 years and older were identified over a period of 10 years. Only 47 patients met the inclusion criteria. Mean age was 67.2 years with male:female ratio of 1:1.2. The average delay to presentation was 3 days. The correct diagnosis was made in 26 (53%) patients. Preoperative imaging was done in four patients (8.5%). Fortytwo patients (89.4%) had a simple appendectomy, while 5 (10.6%) had a right hemicolectomy. Average length of stay (LOS) was six days, while the LOS for perforated appendicitis was 17 days. Ten patients died in hospital, resulting in an inhospital mortality rate of 21%. Eight of these had perforated appendicitis. Twenty-three patients (51.1%) had perforation, 22 (48.9%) did not, while in two this finding was not recorded. Twenty-five patients (53.2%) had complications. Re look laparotomies happened in 12 (25.5%) patients. CONCLUSION: Morbidity and mortality are indeed still high in the elderly population. The incidence of re look laparotomy is high in our institution and this is associated with a higher mortality. If the LOS is corrected, our figures are on par with other institutions. Late presentation and wrong initial diagnosis remain a stumbling block in the management of the elderly patient with appendicitis. PMID- 28876654 TI - ILEOSIGMOID KNOTTING: A ZIMBABWEAN CASE SERIES. AB - BACKGROUND: Ileosigmoid knotting is a rare cause of intestinal obstruction with a rapidly progressive course, for which expedient surgical intervention is required to avoid mortality. METHOD: A combined retrospective and prospective analysis was performed on 16 patients operated on at PGH with an operative diagnosis of ileosigmoid knotting between February 2011 and April 2016. Data inclusive of demographics, time to presentation and surgery, preoperative diagnostic accuracy, incidence of septic shock and mortality was collected. RESULTS: The average age was 37.1 years (range 20-59 years) with a 4.3:1 male to female ratio. Two of the three females were pregnant. Thirteen patients (81.3%) experienced acute onset abdominal pain while asleep. The mean duration of symptoms prior to arrival at PGH was 10.8 hours (range 1-23hours). At admission, four patients (25%) were hypotensive (three more developing hypotension by the time of anaesthetic induction). Nine patients (56%) had leukocytosis and nine patients (56%) had deranged biochemical parameters. The most common preoperative diagnosis was sigmoid volvulus (50%), with no patients having a pre-operative diagnosis of ileosigmoid knotting. All patients had small bowel and sigmoid colon resection and Hartmann's procedure performed due to the presence of gangrene. Six patients (40%) required inotropic support for septic shock, while 57% of patients required transfusion. There was one perioperative death. CONCLUSION: The diagnosis of ileosigmoid knotting needs to be considered in the young male or pregnant female patient with acute nocturnal onset abdominal pain and a rapidly deteriorating clinical course, and with radiological features suggestive of sigmoid volvulus. PMID- 28876655 TI - A RETROSPECTIVE ANALYSIS OF ACUTE APPENDICITIS, RUPTURED APPENDICITIS AND THE LEVEL OF LEUKOCYTOSIS IN PAEDIATRIC SURGICAL PATIENTS OF NELSON MANDELA CENTRAL HOSPITAL. AB - BACKGROUND: Appendicectomy is the most commonly performed operation worldwide. The diagnosis is predominantly based on clinical findings. Some patients will clinically be unclear if ruptured or acute inflamed appendicitis; the level of white cell count has been used as the predictor for ruptured appendicitis. METHOD: This was a retrospective chart review of paediatric surgical patients admitted at Nelson Mandela Central Hospital, Mthatha South Africa. RESULTS: A total of 214 patients with a diagnosis of acute appendicitis. Overall, the ruptured appendicitis was 62% and 38% were inflamed appendicitis. Nature of the acute appendicitis: White cell count, Inflamed, Ruptured, Total p-value < 9.9 21 30 51 0.075, 10-14.9 28 54 82 0.0, 15-19.9 17 29 46 0.012, 20-29.9 5 26 31 0.0 > 30 0 4 4. CONCLUSION: This study has demonstrated that in patients who are diagnosed with acute appendicitis clinically, the normal white cell count does not necessarily rule out ruptured acute appendicitis. But the risks of ruptured acute appendicitis increase with the increase level of white cell count. PMID- 28876656 TI - COLORECTAL CANCER: IS THERE AN ASSOCIATION BETWEEN HIV INFECTION AND THE CLINICOPATHOLOGICAL PICTURE? AB - BACKGROUND: The link between colorectal cancer (CRC) and HIV has not been extensively studied. METHOD: Study setting: Colorectal unit at a tertiary institution. Study population: HIV negative and positive patients with colorectal cancer over 12 years (2005-2016). Study design: This is an analysis of prospectively collected data from a colorectal cancer database archived in the Gastrointestinal Cancer Research Centre, University of KwaZulu-Natal. Demographic details, HIV status, anatomical site, stage, treatment and follow-up were documented. Data was entered into Microsoft Excel(r) and analysed. The study endpoints were clinicopathological pattern, disease distribution, staging and treatment outcomes. RESULTS: Voluntary counselling and testing were performed on 381 out of 1543 CRC. Three hundred and eight patients [M:F 1.6:1] tested negative and 73 [M:F 1:2] tested positive. Mean age was 44.6 + 13.7 and 55 + 14.9 years among HIV positive and negative patients respectively (p < 0.001). Proximal: distal colon ratio was 1.3:1 among HIV positive patients and 1:1.2 for HIV negative patients. Rectal disease occurred with equal frequency in both groups. Stage IV disease occurred 51% and 40% in HIV positive and negative patients respectively. Resection rate was 38% and 56% for HIV positive and HIV negative patients respectively. Follow-up was 5.9 + 4.5 months for HIV positive and 17 + 15.6 months for HIV negative patients. Thirty-one patients (42.5%) have been confirmed dead in HIV positive, and 92 (39%) among HIV negative. Recurrence rate was 1% and 6% for HIV positive and HIV negative patients respectively. CONCLUSION: HIV positive patients tend to present at a younger age with more proximal disease, at an advanced stage. Resection rate was lower among HIV positive individuals. Follow-up was shorter for HIV positive patients and recurrence rate was higher for HIV negative patients. There were more deaths in the HIV positive group during follow-up. PMID- 28876657 TI - COLORECTAL CANCER IN A SOUTH AFRICA URBAN SETTING - A PRELIMINARY ANALYSIS. AB - BACKGROUND: Colorectal cancer (CRC) is the second most common cancer in the world, with an estimated incidence in South Africa of 4-5% of all cancers . Studies show that whites account for the majority of South African patients but blacks for the majority of patients under the age of 50. METHOD: This was a preliminary analysis of the first 113 patients enrolled in a prospective longitudinal study. All CRC patients presenting to the teaching hospitals of the Department of Surgery, University of the Witwatersrand were eligible for inclusion. Data was collected by an interviewer-administered questionnaire and entered into the CRC database. Statistical analysis was performed using SAS version 9.4 for Windows. RESULTS: Patients presented to the three major centres in equal proportions with 68.2% in the public sector and 31.9% in the private sector. The mean age at presentation was 56 years (range 19-84, SD = 13.8), while 53.1% of the patients were male and 56.5% were black African. The mean age at presentation for black patients (53.7years, range 19-78, SD = 14.3) was significantly younger than for white patients (63.4years, range 43-84, SD = 12.6) (p = 0.0017). 83.2% of patients had at least some high school education and the majority (56.6%) lived in their own homes with access to indoor running water (92%) and sanitation (96.5%). All patients had access to electricity. 49.0% reported a family history of cancer, with mother (35%), sibling (33%), and father (25%) most frequently affected. The most common cancer in relatives was CRC (25%). There was a history of smoking in 36.7% of patients. BMI was normal in 45.7% of patients, while 44.8% were overweight. The three most common presenting complaints were weight loss (68.1%), per rectal bleeding (61.1%) and constipation (61.1%). There was no prior GIT diagnosis in 70.9% (n = 110). The most common finding on clinical examination was anaemia (20.0%). The majority of tumours were located in the rectum (49.1%), then the left (29.2 %) and right colon (16.8%). CONCLUSION: The major findings were a tendency to younger age at presentation in black South Africans, and a predominance of tumours in the left colon and rectum. This is in line with previously published data showing a difference in age at presentation and site of tumour according to ethnicity. Risk factors such as smoking and obesity remain noteworthy even in a low-middle income country. PMID- 28876658 TI - LAPAROSCOPIC LAVAGE VERSUS SUCTION ONLY IN COMPLICATED ACUTE APPENDICITIS: A PROSPECTIVE RANDOMISED CONTROL STUDY. AB - BACKGROUND: The role of laparoscopy in complicated appendicitis is increasing. It is unclear in the adult population whether lavage of the pus versus suction only impacts in decreasing postoperative collections. In children there appears to be no difference whether the pus is lavaged or suctioned only. This study will be the first of its kind in the adult population. METHOD: A prospective single blinded randomised control trial was conducted. Ethics clearance was obtained from the review board. Registered on research registry UIN 1718. Patients with suspected acute appendicitis were consented to be enrolled in the study. Those found to have complicated appendicitis (perforation, localised pus or four quadrant pus) at laparoscopy were randomised according to computer generated allotment to either lavage or suction only. Patients who did not have the appendix removed or who were converted to laparotomy were excluded. Lavage consisted of a strict protocol of three litres of lavage with normal saline. Operative time was documented. All patients had an 8 mm pencil drain placed. Postoperatively a minimum of five days of intravenous Coamoxiclav. Complications (relook, percutaneous drain), hospital stay and return of bowel function were recorded. RESULTS: A total of 43 patients were assessed of which 10 were excluded - seven were converted to laparotomies. Also, three had abscesses but appendix was not removed. The remaining 33 patients were analysed. The mean age was 26 years (14-74). Fifteen (45%) patients were lavaged and 18 (55%) were suctioned. Four quadrant pus was present inc4 (26%) of the lavage group versus in 6 (33%) of suctioncgroup. Complications developed in seven patients (46.7%)cwho were lavaged compared to five patients (27.8%) whocreceived suction only. The absolute risk increase is 20% withclavage giving a number needed to harm of 5. The differencecdid not reach significance due to sample size (p = 0.301).cOperative time was longer in the lavage group by 30 minutesc(p = 0.086). If a complication developed then the hospitalcstay was significantly prolonged 13.5 days versus 5 daysc(p < 0,001). The study was stopped by the ethics review boardcdue to the higher rate of complications in the lavage group. CONCLUSION: This pilot study of lavage versus suction only in complicated appendicitis revealed a higher rate of complications in those randomised to lavage. There was also a trend toward longer operating time in those who were lavaged. If a patient develops a complication, then the hospital stay was significantly prolonged. PMID- 28876659 TI - ABDOMINOPERINEAL RESECTION IN THE PRONE POSITION: EARLY OUTCOMES AT A TERTIARY INSTITUTION IN THE WESTERN CAPE, SOUTH AFRICA. AB - BACKGROUND: Abdominoperineal resection (APR) in the prone position is a new technique in the developing world, where colorectal cancer incidence is rising fast and the patient population is different from those in the developed world. Literature is lacking on the outcomes of this technique under these conditions. METHOD: All patients who underwent APR in the prone position for rectal adenocarcinoma from February 2011 to February 2017 were reviewed. Main endpoints were stage at presentation, neoadjuvant treatment, circumferential resection margin involvement, perineal wound complications, length of intensive care unit (ICU) stay and days discharged after surgery. RESULTS: Fifty-four patients were included in the study. The average age of patients was 57 years (range 29-79yrs). Neoadjuvant (NA) chemoradiation was given in 54% while 14% of patients only received NA chemotherapy and 10% short course neoadjuvant radiotherapy. The average stage at presentation for rectal cancer was stage 3B. The circumferential resection margin (CRM) was involved in 14.8% (8/54) of patients. Perineal wound infection was identified in 25% (14/54) of patients and perineal wound dehiscence in 14%. Average length of ICU stay was 4.9 days and patients were discharged on average 10.7 days post operatively. CONCLUSION: Patients in the developing world present with more advanced stage rectal cancer. Complete resection rates for rectal cancer after APR in the prone position compare to those achieved in developed countries. A high perineal wound complication rate was seen in this series. The high percentage of patients with locally advanced disease necessitating neoadjuvant radiotherapy possibly contributed towards this finding. PMID- 28876660 TI - THE HISTOPATHOLOGICAL FINDINGS OF MACROSCOPICALLY NORMAL APPENDIXES REMOVED AT LAPAROSCOPY AT DR. GEORGE MUKHARI ACADEMIC HOSPITAL. AB - BACKGROUND: The question of whether or not to remove a macroscopically normal appendix at surgery has long been debated among surgeons. During the open surgery era, when a 'McBurney' incision was made, the appendix was routinely removed even if it looked macroscopically normal to remove future diagnostic uncertainties. In the modern era, the laparoscopic approach is now favoured, and the question of whether or not a macroscopically normal appendix should be removed is again debated. METHOD: A retrospective, descriptive study of the histopathological findings of macroscopically normal looking appendix removed during laparoscopy between July 2015 and December 2016. RESULTS: During the study period a total of twenty seven macroscopically normal appendixes were removed laparoscopically. All showed histological pathology. The most common histological feature was acute appendicitis in 17 cases (63%). In 8 cases (29%) there was lymphoid hyperplasia only. Other pathologies noted included parasitic infestation in one patient and obstructed lumen in 2 patients. CONCLUSION: Laparoscopic appendectomy is justifiable in the setting of a macroscopically normal looking appendix and no other demonstrable pathology to account for patients' symptoms. PMID- 28876661 TI - THE USE OF LAPAROSCOPY IN MANAGING PENETRATING THORACOABDOMINAL INJURIES IN AFRICA: 83 CASES REVIEWED. AB - BACKGROUND: The use of laparoscopy in managing haemodynamically stable patients with penetrating thoracoabdominal injuries in developed countries is wildly practised, but in Africa the use of laparoscopy is still in its infancy stage. METHOD: A retrospective analysis of prospectively collected data of patients presenting with penetrating thoracoabdominal injuries was done. All patients offered laparoscopic exploration and repair from January 2012 to December 2015 at Dr George Mukhari Academic Hospital were analysed. Means (+/-SD) were presented for continuous variables and frequencies (%) were presented for categorical variables. All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). RESULTS: A total of 83 stable patients with penetrating thoracoabdominal injuries managed with laparoscopy met the inclusion criteria and were included in the study. The Injury Severity Score ranged from 8 to 24, with a median of 18. The incidence of diaphragmatic injuries was 54%. The majority (46.8%) of patients had Grade 3 (2-10 cm defect) diaphragmatic injury. Associated intra-abdominal injuries requiring intervention were encountered in 28 (62%) patients. At least 93.3% of the patients were treated exclusively with laparoscopy. The morbidity was encountered in 7(16%) patients; the most common cause was a clotted haemothorax Clavien-Dindo III-a but only one patient required a decortication. There was one non-procedure related mortality. CONCLUSION: A success rate of 93% in using laparoscopy exclusively was documented, with an overall 82% uneventful outcome. The positive outcomes found in this study when laparoscopy was used in stable patients with thoracoabdominal injuries support similar work done in other trauma centres. However, in addition this study seems to suggest that the presence of peritonitis in stable patients is not a contra indication to laparoscopy and that thoracoscopy may be useful especially in right side diaphragmatic injury where the liver precludes adequate visualization of the entire diaphragm and to thoroughly clean the chest cavity and prevent future complication such as residual clotted haemothorax. PMID- 28876662 TI - THE ROLE OF LAPAROSCOPY IN BLUNT ABDOMINAL TRAUMA: DIAGNOSTIC, THERAPEUTIC OR BOTH? AB - BACKGROUND: The use of laparoscopy in blunt abdominal trauma is gaining popularity as a useful diagnostic tool to avoid unnecessary laparotomies where there is diagnostic dilemma. But the feasibility of using laparoscopy for therapeutic intervention in these patients has been debated. Even though recent case reports seem to suggest that these patients can be managed using laparoscopy, the practice is not yet wildly adopted. METHOD: A retrospective analysis of a prospectively collected data was done. All adult patients who presented with abdominal trauma and were offered laparoscopic surgery at Dr George Mukhari Academic Hospital (DGMAH) from 2012 to 2015 were reviewed. Data was retrieved from our departmental database and analysed using descriptive statistics. RESULTS: A total of 318 patients were reviewed and 35 patients had blunt abdominal trauma and were included in the study. All the patients were offered laparoscopy. The median age was 30, with 91% of our patients males. The highest injury severity score calculated was 38. At least 77% of the patients were managed using laparoscopy. This includes 43% who had both diagnostic and therapeutic intervention and 34% who had only diagnostic laparoscopy. Eight patients were converted to open surgery mainly due to active bleeding and complex injuries. We did not have any non-therapeutic laparotomies. There was no documented procedure-related morbidity and mortality. CONCLUSION: The positive outcomes seen from the study suggest that laparoscopy can be safe and feasible in both diagnostic and therapeutic interventions in carefully selected blunt abdominal trauma patients. A conversion to open surgery should not be regarded as a failure but rather as a sign of mature and sound clinical judgement acknowledging the limitations of laparoscopy and/or the surgeon. PMID- 28876663 TI - THE USE OF COMPUTED TOMOGRAPHIC ANGIOGRAPHY IN THE EVALUATION OF UPPER DIGESTIVE TRACT INJURIES IN PENETRATING NECK TRAUMA. AB - BACKGROUND: Patients who present with penetrating neck injuries undergo both a computed tomographic angiogram (CTA) of the neck to diagnose vascular injuries and a contrasted swallow to diagnose aerodigestive tract injuries. In a resource constrained setting this algorithm is questionable. METHOD: A chart review was performed of all patients who presented to Tygerberg Hospital's trauma unit with penetrating neck injury between 1 January 2013 and 1 January 2016. All unstable patients taken directly to theatre were excluded. The haemodynamically stable patients underwent both a CTA and contrasted swallow. All the CTAs were performed prior to contrast swallow. RESULTS: Of 906 patients, 825 (91%) had stab and 81 (9%) gunshot wounds. Thirty-three (3.6%) patients were diagnosed with upper digestive tract injuries on contrasted swallow. 24 patients had pharyngeal injuries and 9 patients had oesophageal injuries. CTA was suspicious of injury in 16 patients and diagnostic of injury in 4 patients. In 12 CTA scans performed there was no mention of upper digestive tract evaluation. One CTA was falsely negative for injury when compared to contrast swallow. CONCLUSION: CTA reporting does not consistently evaluate the upper digestive tract for injuries. This might be due to reliance on contrasted swallows for diagnosis. There needs to be implementation of standardised reporting on the upper digestive tract when evaluating CTAs for penetrating neck injuries. Further evaluation of the diagnostic accuracy of CTA is needed before contrasted swallows can be omitted in the absence of upper digestive tract injury suggested by CTA. PMID- 28876664 TI - ACCESS TO TERTIARY TRAUMA CARE: CHALLENGES WITHIN A DEVELOPING HEALTH CARE SYSTEM. AB - BACKGROUND: Trauma is a leading cause of mortality the world over, with an increasing impact in low and middle income countries. Oneof the key challenges in tackling the morbidity and mortality associated with the growing trauma epidemic includes the ability to provide timely access to appropriate trauma care. METHOD: A prospective cross-sectional study of 385 consecutive trauma patients admitted at Parirenyatwa Group of Hospitals (PGH) following injury. Data inclusive of demographics, Methods of transfer, time to care and referral patterns was analysed. RESULTS: Over half of all casualties, (54%) were referrals from satellite hospitals. One hundred and twenty-one casualties (31.68%) received pre hospital care by medical personnel. The most common means of transfer of casualties from injury scene was by private vehicle (53%), followed by ambulance (32%) and public transport (8%), but geographical variances were observed. The average transit time from injury was 10.64 hours (SD 23.61) for those injured within Harare. For direct transfers to PGH from within Harare, mean transit times were comparable between use of private vehicles (3.34 hours) and ambulances (3.31 hours). There was correlation between time of injury and method of transfer. There was no correlation between degree of injury according to ISS and transit time (p = 0.24). CONCLUSION: Significant challenges remain in ensuring timely and appropriate transfer of trauma casualties to tertiary care facilities. PMID- 28876665 TI - SPECTRUM OF INTENTIONAL INJURIES IN THE JUVENILE POPULATION TREATED AT A LEVEL ONE TRAUMA CENTRE: A SOUTH AFRICAN PERSPECTIVE. AB - BACKGROUND: South Africa has one of the most violent societies worldwide. The national homicide rate is 34 per 100 000; young males form the majority of this cohort. Comprehensive injury surveillance in low and middle-income countries is limited and there is paucity of data describing the epidemiology and outcomes of intentional injuries within the juvenile population. METHOD: Ethical approval was obtained for this study. The Electronic Trauma Health Registry (eTHR) Application of the Trauma Centre at Groote Schuur Hospital in Cape Town was interrogated over an 18-month period (April 2014 - December 2016) for all patients (aged 12-19 years) treated for non-accidental trauma. The data was then analysed using descriptive statistics. RESULTS: Over the study period, 2903 juvenile patients were admitted to the trauma centre. Intentional injuries (= 1387; 47.8%) accounted for nearly half of the study cohort. Complete datasets were available for 1295 patients. Within this cohort 210 (16.2%) patients were victims of gang related violence. Penetrating injuries were seen in 878 (67.8%) patients, of whom 401 (45.7%) sustained knife injuries and 329 patients (37.5%) sustained gunshot wounds. The most affected body region was the head (n= 388; 30%), followed by the thorax (n= 311; 24%). Permanent disability resulting directly from injury was seen in 5.2% (n = 66) of the patients who survived (n= 1266) and the overall mortality was 2.2% (n = 29). CONCLUSION: Intentional injuries are common within the juvenile population group in Cape Town. Penetrating injuries and gang-related activities account for a large subset of these patients. Whilst the overall mortality is only 2.2%, the permanent disability rate is 5.2% and is likely to have significant public health and economic ramifications for the South African health care system in the future. PMID- 28876666 TI - CIVILIAN GUNSHOT WOUNDS TO THE CHEST: A CLINICOPATHOLOGICAL ANALYSIS OF AN ANNUAL CASELOAD AT A LEVEL 1 TRAUMA CENTRE. AB - BACKGROUND: Gunshot wounds (GSW) to the chest are common presentations to trauma centres both in South Africa and internationally. The clinical management and outcome of GSW to the chest are significantly altered by missile trajectory and the associated anatomical structures injured making them challenging injuries to treat. Currently, the management of GSW chest is based on scant evidence and treatment is typically according to algorithms based largely on the anecdotal experience of high volume institutions and experienced clinicians. METHOD: Ethical approval was obtained for this study. The Electronic Trauma Health Registry (eTHR) Application of the Trauma Centre at Groote Schuur Hospital in Cape Town was interrogated for the year 2015 for all patients with GSW chest. The data was then analysed using descriptive statistics. RESULTS: A total of 141 patients with GSW to the chest were admitted to the Trauma Centre with a median age of 26 years . More than half of the patients, 53.2% (n = 75), sustained an isolated GSW to the chest. Overall, 29.1% (n = 41) patients sustained thoraco abdominal injury, which accounts for a significant higher number of emergency surgeries compared to patients with non thoraco-abdominal injury (54% vs 15%, p = < 0.01). 9.2% (n = 13) of all patients required an emergency thoracotomy or emergency chest surgery (resp. 3.5% and 5.7%) of which 5 patients survived. Overall mortality was 7.1% (n = 10) of which 5 patients died from a thoracic cause. CONCLUSION: Civilian GSW to the chest are common injuries seen in Cape Town, often with concomitant injuries leading to increased morbidity. Significantly more emergency surgeries were done in patients with thoraco abdominal injury. Overall few patients needed chest-related emergency operative intervention (9.2%) with a survival rate of 38.5%. Overall mortality of patients with GSW chest who reached the hospital was 7.1% of whom 50% died from a thoracic cause. PMID- 28876667 TI - EVALUATION OF THORACOSCOPY IN THE DIAGNOSIS OF DIAPHRAGMATIC INJURIES IN PENETRATING THORACOABDOMINAL TRAUMA WITHOUT LUNG DEFLATION AT DR GEORGE MUKHARI ACADEMIC HOSPITAL. AB - BACKGROUND: With a mortality estimated at 25% when missed, diaphragmatic injuries due to penetrating thoracoabdominal trauma present a diagnostic challenge for both the radiologist and the surgeon. In the current literature, chest x-ray has a sensitivity of 27-60% for left-sided injuries and only 17% for right-sided injuries while, CT scan has a sensitivity of 14-61% and a specificity of 76-99%. Thoracoscopy using a single lung ventilation is one of the modalities of choice for the diagnosis of these injuries with a specificity of 100% and a sensitivity of 87.5%. METHOD: This was a prospective study; all stable trauma patients with penetrating thoracoabdominal injury aged 18 years and above admitted to the trauma unit at Dr George Mukhari Academic Hospital during the period of the study were included. All patients with penetrating thoracoabdominal trauma who were unstable, or necessitating prompt management and all paediatric patients were excluded from the study. In theatre, under general anaesthesia, we first performed thoracoscopy without single lung ventilation followed by laparoscopy as control on each patient. Data was collected using a standard proforma by the attending surgeon and was analysed by a statistician using IBM SPSS 22 software. RESULTS: A total of 32 patients met the inclusion criteria of which 4 were female (12.5%) and 28 male (87.5%) with the median age of 29 years. Of the 32 patients, 27 had thoracoabdominal stab wounds (84.3%) and 5 had gunshot wounds (15.6%). Fourteen patients (43.75%) had left sided injury and 18 patients (56.25%) had injury to the right side. The incidence of diaphragmatic injury was 37.5% (n = 12). No injuries were missed on thoracoscopy; there was no mortality or morbidity. CONCLUSION: Thoracoscopy without single lung ventilation is safe and comparable to thoracoscopy with single lung ventilation as a diagnostic tool for diaphragmatic injuries in stable patients with penetrating thoracoabdominal trauma. PMID- 28876668 TI - ACCIDENTAL AND NON-ACCIDENTAL INJURY RELATED ADMISSIONS TO THE PAEDIATRIC INTENSIVE CARE UNIT AT CHRIS HANI BARAGWANATH ACADEMIC HOSPITAL, JOHANNESBURG. AB - BACKGROUND: Paediatric trauma is a major cause of morbidity and mortality in low and middle income countries. Data from these regions describing the extent and severity of this problem is scant. Local data is vital to understanding and responding to the problem of childhood injury. METHOD: A retrospective record review of all trauma cases admitted to the PICU at CHBAH from 1 January 2011 to 31 December 2013 was performed. Descriptive statistics were generated using MS Excel. Students' t test was used for analytic statistics. Ethics clearance was obtained prior to data collection. All children aged 0-16 years were included. RESULTS: A total of 185/919 (20.1%) of all admissions to the PICU were due to childhood trauma. Complete records were found on 66.5% of patients. 57.7% of all admissions were male. Timing of admissions was split almost equally between weekends (49.5%) and weekdays (50.5%). Road traffic injuries (RTI) (65.8%) and toxin ingestion (TI) (17.1%) accounted for the majority of admissions. Children aged 0-4 years accounted for 44.7%, 5-9 years 39.0%, and 10-15 years 16.3% of admissions. The mortality rate was 8.9%. RTI accounted for 63.6% of all mortalities. 64% of mortalities occurred in the 0-4 year cohort, and 36% in the 5 9 year cohort. Mean age of survivors (5.8 years) was significantly higher than nonsurvivors (3.3 years) (p < 0.05). No significant difference was found in mean length of stay of survivors (6.5 days) and non-survivors (10.9 days) (p = 0.05). 89.4% of all children required invasive ventilation on PICU admission. Mean length of ventilation in non-survivors (10.2 days) was significantly longer than survivors (4.5 days). 83.9% (516/615 days) of total days of ventilation were due to RTI and toxin ingestion. CONCLUSION: Preventable injury imposes a significant burden on the health care system, society, families and affected individuals. Local data is vital to recognition of the burden of disease caused by preventable injury and formulating appropriate intervention strategies. Road traffic injuries accounted for the majority of trauma admissions to our PICU. Multi-sectoral sustained action is required to decrease morbidity and mortality associated with preventable childhood injury. PMID- 28876669 TI - THE ROLE OF CT SCAN IN PENETRATING ABDOMINAL TRAUMA. AB - BACKGROUND: Penetrating abdominal trauma contributes significantly to the burden of disease in South Africa. The role of imaging, particularly CT scan in this subset of patients has yet to be established. A correlation between imaging and intraoperative findings could assist with providing a framework for nonoperative management of patients with penetrating abdominal trauma. The role of imaging in blunt abdominal trauma has been established particularly in the patient who is haemodynamically stable. Historically, penetrating trauma to the abdomen has been managed with surgical intervention that achieved the dual purpose of providing a diagnostic as well as therapeutic value. METHOD: A retrospective review of all haemodynamically stable patients who sustained penetrating abdominal trauma and were admitted to a tertiary institution, Dr George Mukhari Academic Hospital situated in Pretoria, South Africa. The time period under review was between June 2015 and December 2016. The source of data was a combination of the database, original patient records and records from radiology. The parameters that were reviewed included CT scan findings and intraoperative findings. RESULTS: A total of 131 patients were enrolled for this study. 74% of patients were found to have a negative CT scan as well as negative intraoperative findings. A total of 25% had positive intraoperative findings despite having a negative CT Scan. CONCLUSION: CT Scan correlates poorly with intraoperative findings. PMID- 28876670 TI - FOLEY-CATHETER BALLOON TAMPONADE (FCBT) FOR PENETRATING NECK INJURIES (PNI) AT GROOTE SCHUUR HOSPITAL: AN UPDATE. AB - BACKGROUND: A previous study from Groote Schuur Hospital (GSH) highlighted the success of FCBT (PNI). METHOD: The records of all patients with PNI requiring FCBT for a neck injury presenting to GSH within an 11-month study period were reviewed. Prospectively captured data on the Electronic Trauma Health Record Application (eTHRApp), was retrospectively analysed. Analysed data included demographics, clinical signs on admission, imaging, management and major outcomes. RESULTS: Over the 11-month study period, 311 patients with PNI were seen, of which 47 patients (15.1%) required FCBT. All were male; mean age of 28.6 years (range 18-48). Most injuries were caused by stab wounds (91.5%) while 4 patients (8.5%) suffered gunshot wounds. The majority of catheters (85.1%) were inserted by the referral institution. A total of 14 arterial injuries were identified, of which only one had ongoing active bleeding with haemodynamic compromise requiring immediate surgical intervention without prior imaging. The remaining 46 patients were imaged with computerised tomography angiography (CTA). A total of 8 major arterial injuries were found, of which six were surgically repaired; and one carotid injury was stented. A further 6 minor arterial injuries were identified and managed expectantly. A further 4 patients required surgery for their neck injuries: 2 had major venous injuries ligated and 2 required surgery for aerodigestive injuries. The remaining patients had their catheter successfully removed at 48-72 hours. There was no significant bleeding observed in any of these patients. There was one mortality caused by a large cerebral infarct from a common carotid artery injury. CONCLUSION: This series shows an increasing use of FCBT for PNI. Major differences from the previous series include the increased use of CT angiography and less reliance on formal angiography for diagnostic purposes. FCBT remains a simple, easy-to-use, yet effective technique. PMID- 28876671 TI - SCREENING FOR AN OCCULT PENETRATING CARDIAC INJURY USING TRANSOESOPHAGEAL ECHCARDIOGRAPHY (TOE): A PROSPECTIVE STUDY. AB - BACKGROUND: 30% of patients with a cardiac injury will present with a penetrating chest wound and be haemodynamically stable, the so-called "occult cardiac injury". Current international practice is to screen for occult cardiac injuries using ultrasound (US) of the pericardial sac. If the US confirms the presence of fluid, then the patient undergoes a subxiphoid pericardial window (SPW) under general anaesthetic. In our experience, US Results in a large number of false positives and unnecessary operations. METHOD: Prospective study on all haemodynamically stable patients over 28-months with stab wound to the chest in the cardiac zone. Routine work-up comprised a CXR, ECG and an ultrasound. All patients with a positive US underwent a TOE prior to the performance of a SPW. The SPW was considered to be positive if there was blood in the pericardial sac. RESULTS: 142 patients underwent a SPW over a period of 28 months with a median age of 29 (range 18-59) years. The sensitivity of US for detecting a haemopericardium was 95% but there were 96 false positives. A total of 51 patients had a TOE prior to the SPW; TOE had a sensitivity of 93%, specificity of 43%, and a positive predictive value of 38% for detecting a haemopericardium. There were 21 false positives and one false negative with TOE. CONCLUSION: TOE has a very high sensitivity for identifying a haemopericardium, but as with US, there is a problem with false positives and in this series a single false negative. SPW remains the screening tool of choice in detecting an occult cardiac injury. PMID- 28876672 TI - CIVILIAN GUNSHOT WOUNDS TO THE CHEST: A CLINICOPATHOLOGICAL ANALYSIS OF AN ANNUAL CASELOAD AT A LEVEL 1 TRAUMA CENTRE. AB - BACKGROUND: Gunshot wounds (GSW) to the chest are common presentations to trauma centres in South Africa. The clinical management and outcome of GSW to the chest are significantly altered by missile trajectory and the associated anatomical structures injured making them challenging injuries to treat. Currently, the management of GSW chest is based on scant evidence and treatment is typically according to algorithms based largely on the anecdotal experience of high volume institutions and experienced clinicians. METHOD: Ethical approval was obtained for this study. The Electronic Trauma Health Registry (eTHR) Application of the Trauma Centre at Groote Schuur Hospital in Cape Town was interrogated for the year 2015 for all patients with GSW chest. The data was then analysed using descriptive statistics. RESULTS: A total of 141 patients with GSW to the chest were admitted to the Trauma Centre with a median age of 26 years. More than half of the patients, 53. 2% (n = 75) sustained an isolated GSW to the chest. Overall, 29.1% (n = 41) patients sustained a thoracoabdominal injury, which accounts for a significant higher amount of emergency surgeries compared to patients with non thoracoabdominal injuries (54% vs 15%, p = < 0.01). 9.2% (n = 13) of all patients required an emergency thoracotomy or emergency chest surgery of which 5 patients survived. Overall mortality was 7.1% (n = 10) of which 5 patients died from a thoracic cause. CONCLUSION: Civilian GSW to the chest are common injuries seen in Cape Town, often with concomitant injuries leading to increased morbidity. Significantly more emergency surgeries were done in patients with thoracoabdominal injury. Overall few patients needed chest-related emergency operative intervention (9.2%) with a survival rate of 38.5%. Overall mortality of patients with GSW chest who reached the hospital was 7.1% of whom 50% died from a thoracic cause. PMID- 28876673 TI - OUTCOMES OF FAILURE OF SELECTIVE NONOPERATIVE MANAGEMENT OF PENETRATING ABDOMINAL TRAUMA [HREC/REF: 679/2013]. AB - BACKGROUND: Selective nonoperative management (NOM) of penetrating abdominal trauma is routinely managed in our trauma center. METHOD: All patients for the period 01 May 2015-15 June 2016 who presented with a penetrating abdominal injury were prospectively entered into an ethics approved database, Ethrapp, and retrospectively reviewed. The patients were categorised into 3 groups: immediate laparotomy, successful NOM and failed NOM. Outcomes included: postoperative complications, mortality and length of hospital stay. RESULTS: A total of 485 patients with penetrating abdominal trauma were managed over the 13-month period. Of these, 219 (45%) were initially selected for NOM and the remaining 266 (55%) patients underwent immediate laparotomy. Twenty-six (26; 12%) failed abdominal observation. Increasing abdominal tenderness and radiological study Results were the primary factors used to determine the need for laparotomy in the NOM group. The median delay to laparotomy was 44.5 hours (27-68). Seven hollow viscus, 13 solid organ and 6 diaphragm injuries were found at laparotomy. There were 22 therapeutic, 2 negative and one non-therapeutic laparotomy. 90% of the immediate group underwent a therapeutic laparotomy. There was no mortality in the NOM group. Complications showed no significant difference. CONCLUSION: The delayed diagnosis and treatment of failed NOM for penetrating abdominal trauma result in morbidity, mortality and hospital stay comparable with those who undergo immediate laparotomy. PMID- 28876674 TI - AN ANALYSIS OF THE INEQUALITIES BETWEEN THE PUBLIC AND PRIVATE SECTOR IN SOUTH AFRICA. AB - BACKGROUND: The full extent of the global burden of surgical disease is largely unknown; however, the scope of the problem is thought to be large. Despite the substantial burden of surgical disease, surgical services are inaccessible to many of those who need them most. There are disparities between public and private sectors in South Africa, which compounds inequitable access to surgical care. METHOD: This study involved a descriptive analysis of surgical resources and included the total number of hospitals, hospital beds, surgical beds, general surgeons (specialist and nonspecialist), and the number of functional operating theatres in South Africa. A comparison was performed between the public sector resources per uninsured population and private sector resources per insured population. Hospitals were contacted during the period 01 October 2014 to 31 December 2014. RESULTS: Surgical resources were concentrated in metropolitan areas of urban provinces. There were striking differences between sectors when a comparison was made between patients with and without health insurance. Private resources were comparable to those available in high income countries (HICs) and were accessible to only 16% of South Africans. CONCLUSION: Improving access to surgical services in lower middle income countries (LMICs) requires addressing gaps between the public and private sector regarding infrastructure, personnel, as well as equipment. South Africa is unique in that although it is classified as an upper middle income country (UMIC), it comprises of two sectors; a public sector which has resources similar to other LMICs, and a private sector which has resources similar to HICs. These data identified disparities between geographic regions which may be contributing to ongoing inequity in South Africa, and by doing so allows for evidence-based planning towards improving surgical infrastructure and workforce. PMID- 28876675 TI - GLOBAL SURGERY - A REVIEW OF THE PAEDIATRIC SURGICAL WORKFORCE IN SOUTH AFRICA. AB - BACKGROUND: Background Surgical conditions lead to premature death and disability resulting in a massive economic burden. Contributing to this global crisis is the lack of data on the limited surgical workforce in many low and middle income countries (LMICs). METHOD: All paediatric surgeons were contacted during the period 1-28 February 2017 via email as well as during a congress which was held at Red Cross War Memorial Children's Hospital, and a database was compiled. An international comparison of South Africa's paediatric surgical workforce was then performed with several countries. RESULTS: The Results showed 5.55 paediatric surgeons per one million population under 14 years. More than half (55%) were male and the average age was 39.5 years. The majority of the paediatric surgical workforce was found in Gauteng (40.0%), followed by the Western Cape (27.7%) and Kwa-Zulu Natal (21.1%). The majority of qualified specialists reportedly worked in the public sector (n = 24), followed by dual practice (n = 21) and lastly in the private sector (n = 8). These numbers fell far below developed countries such as the United Kingdom (UK) and United States of America (USA), but compared favourably with Canada, China and Ireland. CONCLUSION: Strengthening surgical systems, which includes mapping surgical workforce, will reduce the surgical burden of disease and improve health outcomes globally. This description of the paediatric surgical workforce provided insight into the surgical capacity of South Africa. Furthermore, it provided a comparison between South Africa and the rest of the world. PMID- 28876676 TI - FACTORS CONTRIBUTING TO ELECTIVE THEATRE CANCELLATIONS IN THE DEPARTMENT OF SURGERY AT CHBAH. AB - BACKGROUND: Elective theatre cancellations is a common experience the world over that impacts on theatre efficiency with undesirable consequences on the health care system, the patients and their families. It increases costs of running theatres, is a financial burden and emotional strain on patients and their families. METHOD: A retrospective study where 300 cancellations in the Department of Surgery were randomly selected and analysed from the Morbidity and Mortality meetings held at Chris Hani Baragwanath Academic Hospital from November 2015. RESULTS: Of the 1554 elective cases booked during the period under review, there were 294 cancellations resulting in a cancellation rate of 18.9%. Laparoscopic Cholecystectomy was the most common procedure (31.8%) cancelled. The most common reason for cancellation (50%) was time constraints. Administrative related reasons for cancellation were the most common (85%) encountered. The majority of cancellations were judged to be the event of an Unavoidable reason. The majority of the patients cancelled were ASA II and ASA III (77%). The ASA score had no significance on medical related cancellations. CONCLUSION: We reported a comparatively high cancellation rate. Further prospective studies need to be conducted to critically evaluate the reasons behind lack of operative time as the majority of the reasons for cancellation could be potentially avoidable. PMID- 28876677 TI - SURGICAL INFECTIONS AT A REGIONAL HOSPITAL IN GAUTENG: REASONS FOR DELAY TO CARE AND PROFILE OF PATHOLOGY. AB - BACKGROUND: Infection is a common cause for the admission of surgical patients who were initially seen and managed at the primary health care level. Delay to care significantly increases the health care burden of surgical sepsis on affected individuals, the health system and society. METHOD: A prospective descriptive study was performed by means of a confidential questionnaire presented to qualifying patients between February 2014 and October 2016. No minors were included in the study. Descriptive statistics were generated utilising MS Excel. Analytic statistics were facilitated using the t-test, Chi Squared test, Fischer's Exact Test and logistic regression. RESULTS: A total of 89 patients agreed to participate. Abscesses (23/89, 25.8%), diabetic foot (20/89, 22.4%), cellulitis (14/89, 15.7%) and septic burns (10/89, 11.2%) were the most common categories of infection requiring admission. The majority of patients admitted were Black African males (39/89, 43.8%), with no medical aid (88/89, 98.8%), no formal employment (52/89, 58.4%), inhabiting some form of formal housing (80/89, 89.8%), from poor households (defined as annual income < R60 000/year) (66/89, 74.1%), were in charge of decisions regarding personal health (71/89, 79.7%), and first sought help at the primary health care level (local clinic or private physician) (63/89, 70.7%). In total 68.5% (61/89) of patients admitted had a significant delay of > 48 hours from onset of symptoms to presentation to a health care worker. Furthermore, 46.1% (41/89) of patients experienced a significant delay of > 24 hours from presentation to health care worker to admission. The most common reason for delay to care in both groups (50/61, 81.9% and 25/41, 60.1%, respectively) was patients' belief that the problem would resolve itself. CONCLUSION: Urban populations are different to rural populations in terms of barriers to access to health care. Utilisation of primary health care services (private and public) as a first point of contact with the health care system is high. Patients' perception of their own health is an important determinant of their health seeking behaviour. PMID- 28876678 TI - A THIRD OF PATIENTS TREATED AT A TERTIARY LEVEL SURGICAL SERVICE COULD BE TREATED AT A SECONDARY LEVEL FACILITY. AB - BACKGROUND: South Africa has an overburdened public healthcare system. Some admissions to Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) may not require tertiary care. The numbers and details thereof are uncertain. Clinical research is limited by skills and access to data. METHOD: A retrospective analysis of Electronic Discharge (ED) summaries from the Department of Surgery at CMJAH between 01 April 2015 and 01 April 2016. An SQL-query of the database generated a .csv file of all discharges with the fields database reference number, length of stay and level of care. The details and level of care of each record were verified by MBBCh 5 medical students using a defined level of care template with review of the full discharge summary. The data was reviewed by a senior clinician. RESULTS: There were 3007 discharge summaries, 97 were not classifiable, two were test records and one was a duplicate. These 100 records were excluded. There were no primary level records. Secondary level patients represented 29% (854) of patients discharged and 19% of total bed days. Tertiary and quaternary together represented 71% of the total patients and 81% of bed days. The average length of stay was 4.31 days for secondary, 6.98 days for tertiary and 9.77 days for quaternary level of care allocation. CONCLUSION: Almost a third (29%) of patients discharged from CMJAH Department of Surgery were deemed suitable for secondary level care. These admissions have a shorter length of stay and comprise 19% of total bed days. Students and electronic databases are useful research resources. PMID- 28876679 TI - FACTORS LEADING TO DELAYED PRESENTATION OF PATIENTS WITH DIABETIC FOOT SEPSIS AT REGIONAL HOSPITALS IN THE EKURHULENI METROPOLITAN MUNICIPALITY OF GAUTENG PROVINCE. AB - BACKGROUND: Nearly 50% of all diabetes-related admissions are due to diabetic foot problems and diabetes mellitus is the commonest cause for non-traumatic amputation of the lower limb. METHOD: A prospective longitudinal observational study of all patients 18 years and older was conducted. Data collected included demographics, diabetic history and treatment type, comorbidities, prior treatment, clinical findings, treatment method and overall outcome. Data was entered into an Excel spreadsheet for analysis, and categorical data was expressed in percentages whereas continuous data in mean and 95% confidence interval. Incident risk ratio was calculated. Chi square and Student t-test were used when appropriate. Permission to conduct the study was received from HREC at Wits (M160759). RESULTS: 68 patients were studied of which 61.8% (42/68) were males. The average age for males and females was 58.9 and 63.9 years respectively. 90.5% of males and 96.2% of females were known diabetic and 51.5% were on oral hypoglycaemics. 47.1% had prior diabetic education, 36.8% had home haemoglucotest and compliance was good in 39.7%. 71.4% of males and 80.8% of females presented more than two weeks after onset of foot sepsis. Prior use of herbal medication was reported by 16.7% of males compared to 26.9% in females. 69.1% were seen at a clinic and 71.4% were treated with antibiotics before referral. 53.8% of females and 59.5% of males were amputated and mortality was 15.4% and 4.8% for females and male, respectively. CONCLUSION: Majority of patients presenting with diabetic foot sepsis are known with diabetes and are on oral hypoglycaemics. Trial of antibiotic and herbal therapy is attempted for most patients before they are referred. More than 50% end with amputation and mortality is three times higher in females. PMID- 28876680 TI - REGISTRAR PERCEPTIONS ON GENERAL SURGICAL TRAINING IN SOUTH AFRICA: A REPORT BY THE SOUTH AFRICAN SOCIETY OF SURGEONS IN TRAINING (SASSIT). AB - BACKGROUND: Surgical training varies significantly even amongst universities within the same country. This trend is reflected in South Africa and provides an opportunity for innovation to improve the quality of general surgical training. METHOD: A prospective descriptive study was performed by means of a confidential questionnaire distributed to general surgical registrars at all 8 training centres in South Africa. Participants were asked to give comments regarding adequacy of formal academic teaching, level of supervision during surgical procedures, exposure to and training in minimally invasive surgery (MIS), and preparation for examinations. Descriptive statistics were generated with Microsoft Excel. Ethics clearance was obtained from the University of Witwatersrand Human Research Ethics Committee. RESULTS: Of 200 questionnaires distributed, 105 (52.5%) were returned. In total 44% (105/241) of all registrars from 6 training institutions participated. The majority (89.5%; 94/105) of respondents reported that they attended less than 6 hours of formal academic teaching per week and 71.4% (75/105) indicated that their institution offered less than 6 hours of formal academic teaching per week. Furthermore, 76.2% (80/105) of respondents regarded lack of protected academic time as the greatest hindrance to their surgical training and 95.2% (99/105) reported that clinical responsibilities prevented them from attending formal academic teaching regularly. Overall, only 31.4% (33/105), 41.9% (44/105) and 37.1% (39/105) were satisfied with the amount of formal academic teaching, level of supervision during theatre procedures and exposure to MIS, respectively. Lack of resources and lack of appropriate skills were identified as a hindrance to MIS training by 47.6% (50/105) and 28.6% (30/105) of respondents, respectively. CONCLUSION: Surgical registrars are dissatisfied with the amount of formal academic teaching and protected academic time, level of supervision in theatre and their exposure to MIS. These challenges compromise trainees' ability to practise independently on qualification. Numerous interventions are necessary and possible to address these challenges. PMID- 28876681 TI - SOUTH AFRICAN SURGICAL REGISTRAR PERCEPTIONS OF THE RESEARCH PROJECT COMPONENT OF TRAINING: HOPE FOR THE FUTURE? AB - BACKGROUND: The Health Professions Council of South Africa requires that a research project be submitted and passed before registration as a specialist. METHOD: Ethics clearance was received before commencing the study. A questionnaire was developed to collect feedback from surgical registrars throughout South Africa (SA). Completed questionnaires underwent descriptive analysis using MS Excel. Fisher's exact test and the chi2 test were used to compare perceptions of the research-experienced and research-naive groups. RESULTS: All medical schools in SA were sampled, and 51.5% (124/241) of surgical registrars completed the questionnaire. Challenges facing registrars included insufficient time (109/124), inadequate training in the research process (40/124), inadequate supervision (31/124), inadequate financial resources (25/124) and lack of research continuity (11/124). Of the registrars sampled, 67.7% (84/124) believed research to be a valuable component of training. An overwhelming percentage (93.5%, 116/124) proposed a dedicated research block of time as a potential solution to overcoming the challenges encountered. Further proposals included attending a course in research methodology (79/124), supervision by a faculty member with an MMed or higher postgraduate degree (73/124), and greater research exposure as an undergraduate (56/124). No statistically significant differences were found between the perceptions of the research experienced and research-naive groups. CONCLUSION: Challenges facing surgical registrars in their efforts to complete their research projects were identified and solutions to these problems proposed. It is heartening that respondents have suggested solutions to the problems they encounter, and view research as an important component of their careers. PMID- 28876682 TI - DOES GENDER IMPACT ON FEMALE DOCTORS' EXPERIENCES IN THE TRAINING AND PRACTICE OF SURGERY? AB - BACKGROUND: Surgery has been a male-dominated speciality both in South Africa and abroad. METHOD: This mixed methodology case study collected data from a purposive sample of female surgical registrars enrolled at one institution in South Africa. A self-administered questionnaire was used to explore whether or not female doctors perceived any benefits of being in a male-dominated specialty. It explored problems encountered due to gender, the participants' perceptions of the influence of gender on their surgical training, practice and challenges. RESULTS: Thirty-two female registrars participated in the study. The respondents were mainly South African (91%) and enrolled in seven surgical specialities. Twenty seven (84%) respondents were satisfied with their practical training and skills development as surgeons. Twenty-four (75%) respondents had identified a mentor from the department and all respondents indicated that the gender of their mentor did not impact on the quality of their training. Seventeen (53%) respondents perceived having received differential treatment due to their gender and 25 (78.2%) thought that the gender of their mentor did not impact on the quality of the guidance in surgery. Challenges included physical threats to them as females from patients and disrespect, emotional threats and defaming statements from male registrars. Other challenges included time-constraints for family and academic work, poor work life balance and being treated differently due to their gender. Seventeen (53%) respondents would consider teaching in the Department of Surgery. Twenty-five respondents (78%) would recommended the specialty to young female students, as they were convinced that surgery had been the right choice for them. Seventeen respondents (53%) were also open to pursuing teaching posts in the Department of Surgery. CONCLUSION: Generally, females had positive perceptions of their training in Surgery. They expressed concern about finding a worklife balance. The gender of their mentor did not impact on the quality of the training but 'bullying' from male peers and selected supervisors occurred. Respondents will continue to recommend the specialty as a satisfying career to young female students. PMID- 28876683 TI - HISTOLOGICAL EVALUATION OF SMOOTH MUSCLE CELL IN THE PATENT PROCESSUS VAGINALIS. AB - BACKGROUND: Inguinal hernia is a common pathology that necessitates surgical treatment during childhood. Most uncomplicated inguinal scrotal pathologies are considered to occur due to incomplete obliteration of the processes vaginalis (PV). The incomplete obliteration is proposed to be due to the persistence of smooth muscle cell (SMC) in the PV after birth. Immuno-histochemical studies have been published to evaluate the diversity and differentiation of SMC phenotypes in the PV resected in patients' inguinal hernia and hydrocele. METHOD: Sixty-six specimens were collected from consecutive patients undergoing elective surgery for inguinal hernia, undescended testes and hydroceles over an 8-month period. Specimens were collected in standardised manor and sent for histological evaluation. The specimens were evaluated for the presence of SMC microscopically and via special staining. RESULTS: PV specimens in 15/19 female hernias, 11/22 male hernias, 2/6 hydrocele and 5/19 undescended testes contained SMC. The rest of the specimens did not contain SMC. CONCLUSION: There appears to be a strong presence of SMC in female patients, but a weak association of SMC in the PV of male hernia, hydroceles and undescended testes. We therefore conclude that the incomplete obliteration and SMC presence hypothesis does not hold true for male inguinal hernias. Further studies are underway to examine this more closely. PMID- 28876684 TI - DIFFERENCES IN MICROBIOME IN RAT MODELS OF CARDIOVASCULAR DISEASE. AB - BACKGROUND: Recent studies have underscored the important role the gut metagenome in various human diseases, including diabetes and obesity. Hypertension is a major risk factor for cardiovascular disease, stroke, and heart and kidney failure, and affects approximately 25% of the world's adult population. The cause of essential hypertension remains unknown. Patients given antibiotics show blood pressure changes and transfer of gut bacteria from hypertensive to normal WKY rats resulted in the latter developing hypertension. Such studies implicate gut bacteria as having a possible causal role in the development of hypertension. METHOD: Stomach, intestinal and fecal samples were collected from SHR and salt sensitive rats, cultured and identified by matrixassisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) based biotyping and 16SrRNA sequencing. RESULTS: Preliminary Results show an abundance of Escherichia coli , Bacillus cereus , Enterococcus faecilis , Lactobacillus murinus and Staphylococcus scouri in SHR, SSR and control mice. SHR had the least diverse microbiota and had species including Klebsiella pneumonia , Pediococcus acidilactici and Enterococcus gallinarum . While SSR had slightly more diverse isolates as compared to SHR and included Acinetobacter sp, Pseudomonas auriginosa , Corynebacterium ammoniagenes , Micrococcus luteus , and Staphylococcus cohnii . CONCLUSION: Bacteria from the phyla Bacteriodetes and Firmicutes were prevalent in animal models of hypertension. Previous studies have shown that bacteria from these phyla play a role in development of hypertension. Understanding the role played by gut microbiota may provide a novel insight into the aetiology of hypertension. PMID- 28876685 TI - A HISTOPATHOLOGICAL AUDIT OF HYPERPARATHYROIDISM IN THE SOUTH AFRICAN SETTING. AB - BACKGROUND: Hyperparathyroidism is a common endocrine disorder. Parathyroidectomy is indicated for primary and tertiary hyperparathyroidism. Parathyroid adenoma is the cause in close to 85% of cases of primary hyperparathyroidism. METHOD: An audit based on histopathology records of patients who had parathyroidectomy from January 2011 to December 2015 in academic hospitals linked to Wits was conducted. Data collected included patients' demographics and histopathological findings. Categorical data was expressed in number and percentage whereas the mean or median if appropriate was used for continuous data. Chi-square test was used for comparison and a p-value was set at less than 0.05 for significance. The study was partly done by GEMP 3 students and permission to conduct the study was received from HREC at Wits (M160477). RESULTS: A total of 69 records were found of which 67.6% (46/68) were females. Average age for females was 55.0 years (range 25-83) whereas for males was 60.0 years (25-80). Parathyroid adenoma was reported in 75.4% and 69.6% of specimen from females and males, respectively. In 1.5% (1/86) the resected parathyroid was reported to be normal. Concomitant thyroidectomy was done in 17.4% (8/46) of specimens from females and 8.7% (2/23) from males. CONCLUSION: Male patients with hyperparathyroidism present at younger age compared to females. Fewer than expected parathyroidectomies for primary hyperparathyroidism are being performed in the Wits circuit. The commonest findings following parathyroidectomy is parathyroid adenoma. No case of parathyroid cancer was reported. Concomitant thyroidectomy is likely in females. PMID- 28876686 TI - MANAGEMENT OF FAILED MITRAL VALVE REPLACEMENT. THE DURBAN EXPERIENCE. AB - BACKGROUND: Mitral valve replacement is the procedure of choice in patients with severe mitral valve disease. However, these patients are surviving longer and are thus at an increased risk of prosthesis failure or valve-related complications. METHOD: Study setting: Inkosi Albert Luthuli Central Hospital, a tertiary referral Hospital in Durban. Study population: All patients undergoing redo mechanical mitral valve replacement surgery between January 2005 and December 2014. Study design: Retrospective analysis of patients undergoing redo mitral valve replacement. Patients were identified from theatre record books, their files were electronically accessed and pertinent information extracted onto a data capture sheet. Information documented included demographics, duration to failure, INR, Albumin, HIV status, clinical findings and outcome. The data was stored on an Excel datasheet. RESULTS: Fifty-eight patients were documented (mean age 32 +/- 15.81 years; M:F 1:3). Ten patients (17%) were HIV positive (median CD4 count 478). Mean duration between first surgery and redo was 8.8 years. Thirty-five patients (60%) had no co-morbidities. Presenting features at redo surgery were congestive cardiac failure (27), chest pain (11) and palpitations (17). Mean preoperative Ejection Fraction was 51.65 %. Twenty-nine patients (55%) had emergency redo surgery. Twenty-two patients (75%) had acute prosthetic valve thrombosis. Thirty-two patients had tricuspid regurgitation. Original pathology was documented in 23 patients (40%) as Rheumatic valve disease. Prosthetic valve thrombosis was documented in 31 patients (54%). The most commonly used valve was the On-X. Mean presenting INR was 1.96 + 1.2 and mean presenting serum albumin was 36.7 + 7.8 g/l. Forty-one patients (71%) were found to be compliant to Warfarin therapy prior to redo surgery. Mean ICU stay was 6 +9 days. Two patients died postoperatively. Mean followup was 32 + 26.6 months. Twelve patients (20.7%) developed postoperative complications. CONCLUSION: Patients were younger than world literature suggests. Rheumatic heart disease was the common underlying pathology. Prosthetic valve thrombosis was common. More than half had emergency surgery. Mortality rate was negligible. PMID- 28876687 TI - OUTCOMES OF HILAR PEDICLE CONTROL USING SUTURE LIGATION DURING LAPAROSCOPIC SPLENECTOMY. AB - BACKGROUND: Laparoscopic splenectomy is a well described gold standard procedure for various indications. One of the key steps during laparoscopic splenectomy is the hilar pedicle vessels control, which can be challenging in most cases. Most centres around the world recommend the use Ligaclib or endovascular staplers as Methods of choice for hilar pedicle control but the issue is the cost and efficiency of the laparoscopic haemostatic devices. METHOD: A descriptive retrospective study of patients who had laparoscopic splenectomy from 2013 to present. Hilar splenic vessel control was done with suture ligation. We looked at outcomes of patients offered this technique, complications of this technique, and describing the technique of hilar control in laparoscopic splenectomy. RESULTS: Total of 27 patients had laparoscopic splenectomy with splenic hilar pedicle control with suture ligation. Mean operative time, mean blood volume loss, length of hospital stay, postoperative complications conversion to laparotomy. CONCLUSION: Laparoscopic hilar pedicle control with suture ligation is safe and effective for the patient in our hospital setting. PMID- 28876688 TI - MANAGEMENT OF MYELOMENINGOCELE IN THE PROVINCE OF KWAZULU-NATAL, SOUTH AFRICA. AB - BACKGROUND: Spina bifida is the most common of congenital anomalies of the central nervous system that are compatible with life. The most frequent form is myelomeningocele. METHOD: Setting: Neurosurgery Unit, Inkosi Albert Luthuli Central Hospital. Patients: Consecutive children with diagnosis myelomeningocele who were managed at from January 2006 to December 2014. Design: Retrospective analysis of children with myelomeningocele. Multiple logistic regression analysis identified clinical, demographic and surgical variables that were associated with outcome. RESULTS: There were 307 patients of whom 173 were male (57%). One hundred and thirty-five (44%) were delivered via C-section. MMC location was at lumbar [175, 57 %], sacral [21, 7%], thorax [17, 5.5%] and cervical 2 (0.7%). One hundred and fifty-six (51%) presented with CSF leak. One hundred and forty-one (48%) presented with complete paralysis of the lower limbs. The mean age at surgical repair was 4.7 +/- 15.6 months. The dura was repaired primarily in all patients and 20 (7.9%) were operated in conjunction with plastic surgeons. Fifty eight (21%) patients developed wound sepsis of those 35(60%) required surgical debridement, while chemical debridement was sufficient in the rest. The time to wound sepsis was 9.5 +/- 3.6 days. Two hundred and eight (68%) children developed hydrocephalus requiring CSF diversion. In 143 (46%) children a VPS was used to treat HCP, while in 27 (9%) ETV was performed, 33 (23%) developed shunt malfunction due to infection [15, 45%]. The time to shunt infection was 176 +/- 83.3 days. The in-hospital mortality was 27 (9.1%). Wound sepsis and meningitis were associated with death (p < 0.002). The average hospital stay was 20.4 +/- 16.93 days, children with wound sepsis and/or meningitis had longer hospital stay, 38.1 +/- 22.3 days and 40.5 +/- 29.7 days respectively. CONCLUSION: Method of delivery, age at repair, CSF leak and hydrocephalus were not independently associated with infection. Infection was associated with adverse outcomes and yielded longer hospital stay. PMID- 28876689 TI - RAT BITE INJURIES IN CHILDREN ADMITTED AT TEMBISA HOSPITAL. AB - BACKGROUND: Rat bite injuries were observed as early as AD 1300. Up to date no literature exists that looks at the different clinical manifestations of rat bite injuries, and furthers a proposed management plan that is evidence based. METHOD: We studied 59 patients who sustained rat bite injuries from July 2010 to 2014. Injuries were classified based on the pattern and natural history. Epidemiological and clinical data were correlated with the grading system and management employed. RESULTS: The pattern of injury was described and classified into mild, moderate and severe. Children aged 1 year and younger sustained mild forms of injury while those older than 1 year had more moderate to severe injuries (p = 0.0006); that was the very same group that manifested a higher inflammatory response as evidenced by a temperature of > 38o C (p = 0.0238). There was no association between age and anatomical site of injury (p = 0.8313). The highest incidences were seen in Ivory Park (30.5%), which is the largest and most impoverished section in Tembisa. CONCLUSION: In this study, the data showed three distinctive patterns of injury: graded mild, moderate and severe. The mild injuries heal without consequences and may be managed as outpatients. Penicillin monotherapy is sufficient to prevent or treat secondary infection. The few patients who received antirabies treatment did not show clinical benefit, thus we do not recommend its routine use. However, in areas where there is rabies outbreak it may be prudent to prescribe it. Mortality due to rat bite injuries is rare, but disfigurement may be devastating. PMID- 28876690 TI - EVALUATING KIDNEY FUNCTION IN LIVING DONORS IN SOUTH AFRICA. AB - BACKGROUND: Measurement of glomerular filtration rate (GFR) is the best overall index of kidney function. Equations that estimate GFR (eGFR) have been developed for clinical use such as Cockroft and Gault (C+G), four variable Modification of Diet in Renal Disease (4-v MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Although widely used, they have not been validated in Sub-Saharan Africa. METHOD: Data on 350 adults evaluated for live kidney donation from 1996 to 2013 at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) and Wits Donald Gordon Medical Centre (WDGMC) was reviewed. Their eGFR was calculated using CG, 4-v MDRD and CKD-EPI equations. Plasma clearance of 51Cr-EDTA was used as a reference method for mGFR. The equations were also assessed by their sensitivity, specificity, and positive and negative predictive values for identification of subjects with mGFR < 80 mL/min/1.73m2. RESULTS: The majority of potential donors were young Black females. Approximately half were unsuitable for donation mostly due to obesity and hypertension. On Bland Altman Comparisons of eGFR equations to mGFR, the 4-vMDRD equation (with/ without adjustment for ethnicity) showed a negative bias that resulted in average eGFR values between 8 16ml/ min/1.73m2 lower than mGFR respectively (p < 0.0001). CKD-EPI resulted in eGFR values being on average 6.4ml/ min/1.73m2 lower than mGFR (p < 0.0001). There was no significant bias with CG (p = 0.55). For all four equations, the bias decreased as mGFR and age increased and there was no gender effect. The 4-v MDRD and CKD-EPI equations demonstrated higher eGFR for black donors. All four prediction equations had a low sensitivity and poor PPV, with 4v-MDRD (without adjustment for ethnicity) being the most sensitive but least specific. CONCLUSION: For all four eGFR equations, the error statistics worsen as mGFR increases. Adjustment for ethnicity in 4-v MDRD reduced the bias slightly. Overall, the performance of CG was superior to CKD-EPI and 4-v MDRD equations. All four prediction equations had a low sensitivity. This study suggests mGFR should be the gold standard for evaluating living donors in SA. PMID- 28876691 TI - A FOUR YEAR ACROSS SURGICAL DISCIPLINE PERIOPERATIVE AND INTRAOPERATIVE EXPERIENCE OF PATIENT MANAGEMENT IN A TERTIARY ACADEMIC HOSPITAL - A REVIEW. AB - BACKGROUND: There has been a growing trend in the surgical literature to report mortality and morbidity after surgery with preoperative risk adjustment to facilitate meaningful comparisons of surgical outcomes between different surgeons and hospitals. This is a review of the rate of injuries caused by surgeons unintentionally whilst performing procedures in the field of obstetrics and gynaecology, for example, caesarean sections and hysterectomies. METHOD: Data was collected retrospectively over the past four years at Dr George Mukhari Academic Hospital utilising the database and theatre records correlated with patient files. RESULTS: A total of 182 cases were collected spanning the four years reviewed. The injuries were grouped according to the type of injury sustained. Iatrogenic injury to the bladder was the highest at 28.6%. Injury to the right ureter (21.4%) was higher than injuries sustained to the left ureter (12.1%). A combination of bladder and uretric injury was 8.2%. Injuries to the small bowel (17.6%), large bowel (6.6%) and rectum (2.8%). Vascular injuries (2.2%). CONCLUSION: The incidence of gynaecological iatrogenic injury during caesarean section and hysterectomy is higher at Dr George Mukhari Academic Hospital than what is reportedly worldwide. PMID- 28876692 TI - PAEDIATRIC SPLENECTOMY: THE JOHANNESBURG EXPERIENCE. AB - BACKGROUND: Splenectomy is uncommon in children and data on splenectomies in the South African paediatric population is sparse. A deeper understanding of the demographics, indications, techniques, and postoperative management of patients requiring splenectomy may improve care. METHOD: Patient records for all splenectomies performed in children aged 0 to 16 years at Charlotte Maxeke Johannesburg Academic (CMJAH) and Chris Hani Baragwanath Academic Hospitals (CHBAH) between 2000 and 2015 were reviewed. Students' t- and Chi-squared tests were utilised for analytic statistics. RESULTS: Mean age at surgery was 9.9 years with a range of 3 to 16 years. Overall, 91% of splenectomies were performed for haematological disorders with the remaining 9% performed for malignancy or trauma. Two-thirds (67%) of splenectomies were performed open and 33% laparoscopically. Mean postoperative length of stay (LOS) was significantly shorter in the laparoscopic cohort compared to the open cohort (4.5 vs 7.1 days, respectively; p < 0.05). Surgical complications were more common in the laparoscopic group (27%) compared to the open group (9%), as well as in those children older than the mean age at time of surgery. No partial splenectomies were performed. No cases of overwhelming post-splenectomy infection (OPSI) were recorded. In total, 20 patients (61%) were still alive, 3 had died, and 10 had been lost to follow up at study completion. CONCLUSION: Local indications for splenectomy mirror those within international literature. Higher rates of postoperative complication in the open and laparoscopic groups in our series may be due to a learning curve in laparoscopic splenectomy, the low sample size, or the underlying state in which our patients present. Mean postoperative LOS was shorter in the laparoscopic than open group, but relatively longer for both groups than reported in the international literature. Laparoscopy is, as yet, not the preferred technique for splenectomy in our setting. All mortalities were due to progression of underlying disease and no cases of OPSI were recorded. The high rate of loss to follow up in this study is a significant barrier to accurate data collection and reporting. PMID- 28876693 TI - CONTINUATION OF FEEDS IN THE UNSTABLE BURNS PATIENT. AB - BACKGROUND: Early enteral nutrition (EEN) and the continuation of enteral nutrition (EN) are critical factors in burn patients, who typically have higher nutritional needs due to their post-injury hypercatabolic state and their additional need for nutrients to aid in the healing of wounds and skin grafts. In the critically ill patient, EN is the preferred mode of administration; however, controversy exists regarding the concomitant use of EN and intravenous vasopressor agents in the haemodynamically unstable patient. This is because vasoactive substances (e.g. adrenalin) contribute to gut hypoperfusion, thereby increasing the chances of tissue hypoxia and intestinal ischaemia [Wells, 2012]. Consensus is to withhold EN whilst the patient is receiving high dose intravenous vasopressor support. At the Chris Hani Baragwanath Academic Hospital (CHBAH) all patients admitted to the Adult Burns Unit (ABU) receive enteral feeds on admission, irrespective of whether they are receiving vasopressor support or not. METHOD: A retrospective medical record review was conducted at the ABU of CHBAH and included all adult burn ICU patients receiving concomitant EN and vasopressor support for at least two hours or more. The patient register was used to identify the patients admitted to the ICU during the 5-year period from 01 September 2010 to 31 December 2015. The number of patients during this period totalled 1109, of which 475 were admitted to ICU. From this group, only 44 patients met the inclusion criteria (TBSA > 20%; and/or inhalation injury; mechanical ventilation) in addition to receiving concomitant EN and intravenous vasopressor support (i.e. adrenalin). RESULTS: Twenty-five percent of patients (11/44) experienced GIT upset and concomitant high aspirates (> 200 ml/6 hrs) on high doses of adrenalin. Only 9% (4/44) experienced vomiting (V), while 21% (9/44) experienced diarrhoea (D). In only 3 of the 44 patients (7%) were the enteral feeds stopped (V and D in 1 patient; 1 had aspirates > 500 ml; 1 had high aspirates and D). None experienced thrombosis, ischaemia or bowel necrosis. CONCLUSION: In the majority of the haemodynamically unstable burns patients in ICU who received vasopressor support, EN was well tolerated. Even in the patients who experienced intolerance, there were no complications such as ischaemia or bowel necrosis. As such, it would appear that the administration of vasopressors in haemodynamically compromised burn patients is not a contraindication in carefully monitored EEN and ongoing EN. In this study, the concomitant use of EN and vasoactive substances did not place the patients at increased risk for ischaemia or NOBN. However, larger samples would need to be investigated to enable generalisation of the findings to the larger/general population of critically ill burns patients. PMID- 28876694 TI - COMPARING OUTCOMES AFTER LAPAROSCOPIC TOTALLY EXTRAPERITONEAL REPAIR VERSUS OPEN (LICHTENSTEIN) REPAIR OF INGUINOSCROTAL HERNIA AT DR GEORGE MUKHARI ACADEMIC HOSPITAL. AB - BACKGROUND: Inguinal hernia is a common surgical condition. Inguinal hernia can present with a wide variety of symptoms. It can even extend into the scrotum resulting in what is known as an inguinoscrotal hernia. At Dr George Mukhari Hospital, approximately 5-10% of patients with inguinal hernia present with inguinoscrotal hernia. There is paucity of data on the role of laparoscopy in the management of inguinoscrotal hernia. At our institution some of the patients with inguinoscrotal hernia are offered open (Lichtenstein) repair whilst others are offered totally extraperitoneal (TEP) laparoscopic repair. METHOD: We retrospectively reviewed patients' charts to collect information on demographics, comorbidities, smoking history, type of repair, operative time and length of hospital stay from 2014 to 2017. Patients were followed up telephonically for up to 3 years. With the telephonic follow-up we collected data on the time taken to resume normal activities after hernia repair, chronic groin pain, recurrence and seroma formation. RESULTS: Seventeen patients were offered open repair and 13 were offered laparoscopic repair. Average age for patients offered laparoscopic repair was 48 years compared to 40 years in the open group. Operative time was longer with laparoscopic repair. In both groups, patients stayed one day in the hospital post repair. Time taken to return to normal activities was longer with open repair. Sixty-two percent of patients in the laparoscopic arm compared to 88% of patients in the open arm were treated without postoperative complications. Two patients had recurrence, two had chronic groin pain and one developed seroma in the laparoscopic group versus one who had recurrence, one had chronic groin pain and none had seroma in the open group. No mortality was observed in both groups. CONCLUSION: Through our study we were able to show that laparoscopic repair of inguinoscrotal hernia is safe and has comparable postoperative complications to open repair. More studies are still needed on the role of laparoscopy in repairing inguinoscrotal hernia. PMID- 28876695 TI - THE ROLE OF PROCALCITONIN AS A DIAGNOSTIC MARKER OF BACTERIAL SEPSIS IN BURNS. AB - BACKGROUND: Patients with burn wounds are at high risk of infection. Since sepsis contributes significantly to morbidity and mortality, early diagnosis is essential. Procalcitonin (PCT) is a biomarker released in response to inflammation and specifically bacterial infection. It may therefore be a useful biomarker for sepsis in burns. METHOD: All adult patients admitted to two Burns Intensive Care Units in Johannesburg were included in a retrospective data review. Data from the preceding three years related to demographics and sepsis were collated. RESULTS: Records of 178 patients were reviewed. Young black males are most commonly admitted with no significant difference between the public and private sector. The most significant risk factor for sepsis is percentage total body surface area burned (p = 0.012). Significantly more infections occurred in public-sector patients with the public sector treating a greater percentage of patients with more severe burns (92.9 vs. 57.9, p = 0.001). A rise in PCT is a significant biomarker for bacterial infection early after a burn (p = 0.03) but not after day eight. PCT shows correlation with CRP as a biomarker for sepsis (p < 0.001), but not with other biomarkers. Patients who were on inotropes also had a significantly increased PCT level (p = 0.0001). CONCLUSION: While there is some evidence to suggest that PCT may be useful as an adjunct biomarker of infection in burn patients, this evidence is limited and insufficient to change current clinical guidelines. PMID- 28876697 TI - Exposure to key surgical procedures during specialist general surgical training in South Africa. AB - BACKGROUND: The logged experience of specialist general surgical trainees has made it possible to analyse their surgical procedural exposure. METHOD: Logbooks submitted and meeting the minimum requirements for the six final examinations for the fellowship of the College of Surgeons of the CMSA between August 2010 and March 2013 were selected. Consolidated surgical procedural experience was analysed according to procedural category, extent of supervision, procedure complexity and university at which the trainee performed the procedures. RESULTS: The 95 logbooks entered into the study recorded 144 499 procedures, 60.6% of which were unsupervised, 18.5% supervised and 20.9% assisting another surgeon. Major and minor procedures made up 40.4% and 54.6%, respectively, with the remaining 5% categorised as 'other'. A breakdown of procedural exposure per category, including the main contributing or key procedure for each category, is presented. CONCLUSION: Large numbers of procedures are logged by trainees during their surgical training. Inter-university and trainee key procedural exposure in SA differ to a small degree but are striking in some categories. Exposure to key procedures is insufficient in some categories. We are currently unable to assess the quality of training and quality of surgical skills from such logbooks. A standardised electronic logbook will facilitate future analyses of trainee procedural exposure, but other tools will be required to assess the quality of surgical skills training. PMID- 28876696 TI - Developing a clinical model to predict the need for relaparotomy in severe intra abdominal sepsis secondary to complicated appendicitis. AB - BACKGROUND: Complex intra-abdominal sepsis secondary to acute appendicitis is common in South Africa, and management frequently involves relaparotomy. The decision to perform relaparotomy is often difficult, and this study aimed to develop a clinical model to aid the decision-making process. METHOD: The study was conducted from January 2008 to December 2012 at Edendale Hospital, Pietermaritzburg. All patients with intraoperatively confirmed acute appendicitis and all patients in this group who subsequently underwent relaparotomy were included. The clinical course, intraoperative findings and outcome of all patients were recorded until discharge (or death). Using a combination of preoperative and intraoperative parameters, a clinical model was developed to predict the need for relaparotomy. RESULTS: Of the total of 1 000 patients identified, 54.1% were males. The median age for all patients was 21 years. Of 406 relaparotomies, 227 (55.9%) were planned and 179 (44.1%) on demand (expectant treatment). In the relaparotomy group, 367 patients (90.4%) had positive findings. Logistic regression analysis showed that the following four factors accurately predicted the need for subsequent relaparotomy: patients referred from any rural centre, duration of illness >5 days, heart rate >120 bpm, and perforation associated with generalised intraabdominal sepsis. Th is model had a predictive value of >90%. CONCLUSION: We have constructed a model that uses clinical data available at initial laparotomy to predict the need for subsequent relaparotomy in patients with complicated acute appendicitis. It is hoped that this model can be integrated into routine clinical practice, but further study is first needed to validate this model. PMID- 28876698 TI - An audit of trauma-related mortality in a provincial capital in South Africa. AB - BACKGROUND: It has been shown repeatedly that hospital-based mortality data do not capture the actual mortality rate in South Africa, as many corpses are taken directly to the state mortuary. METHOD: A retrospective audit was conducted by reviewing all mortuary reports for the period 1 January 2010 - 31 December 2011. The data recorded included demographics, mechanism of trauma, and cause and site of death. RESULTS: A total of 1 105 trauma victims died. There were 930 males (84.2%) and 175 females (15.8%), of whom 615 were victims of blunt trauma (55.7%) and 490 victims of penetrating trauma (44.3%). The scenes of death were: on scene 584 (52.9%), Edendale Hospital 259 (23.4%), Grey's Hospital 144 (13.0%), Northdale Hospital 68 (6.2%), and 'other' 50 (4.5%). The 'other' group comprised nine deaths at primary healthcare clinics and 41 at private hospitals in Pietermaritzburg. Of deaths related to blunt trauma, 153 (24.9%) were secondary to assault and 462 (75.1%) to a road traffic collision. Of the victims of penetrating trauma, 81 (36.9%) had sustained gunshot wounds and 309 (63.1%) stab wounds. The three leading causes of trauma-related deaths were head injuries (32.6%), polytrauma (29.7%) and chest injuries (27.4%). CONCLUSION: Pietermaritzburg has both a high rate of trauma-related mortality and an immature trauma system, resulting in a significant number of preventable deaths. PMID- 28876699 TI - Propeller flaps for lower-limb trauma. AB - Thee propeller flap has become a versatile and important component in our reconstructive algorithm following complex lower limb trauma. First described by Hyakusoku in 1991, it has since been adapted and modified by Hallock and Teo. This article outlines our experience specifically with perforator pedicled propeller flaps (as per the Tokyo consensus) for traumatic defects of the leg. In this procedure, the reconstructive surgeon skeletonises a single perforator and rotates the skin island on its axis between 90 degrees and 180 degrees to close the defect.The minor blade of the propeller may be designed to close the donor defect completely for the 180 degrees version. The propeller flap has the advantages of local flaps (reliability, contour, texture, 'like-with-like') with additional versatility of design and donor site management, and requires minimal expertise and operative time. PMID- 28876700 TI - Regional anaesthesia for cleft lip surgery in a developing world setting. AB - BACKGROUND: The role of regional anaesthesia in cleft lip surgery in the developing world is not well documented. METHOD: A retrospective chart review of 100 patients aged >14 years who had cleft lip surgery during an Operation Smile South Africa (OSSA) volunteer surgical programme in Madagascar during 2007 and 2008. The nerve blocks used included a bilateral infraorbital nerve block, a dorsalnasal nerve block and a septal block supplemented with peri-incisional local in_ltration. Appropriateness of the regional anaesthesia alone for cleft lip surgery was determined by absence of any intraoperative complications, postoperative complications or conversions to general anaesthesia. RESULTS: Seventy-four patients commenced their operation under regional anaesthesia. There were no intraoperative or postoperative complications documented, and no patient required conversion to general anaesthesia. Two patients required additional analgesia in the immediate postoperative period. CONCLUSION: Regional anaesthesia for cleft lip surgery in patients >14 years of age was well tolerated and associated with few complications. It is a safe and effective option when used as the sole anaesthetic modality for cheiloplasty in the developing world. PMID- 28876701 TI - Haemangiopericytoma/solitary fibrous tumour of the greater omentum. AB - We report a rare case of haemangiopericytoma/solitary _brous tumour of the greater omentum in a 41-year-old woman. It presented as a large mobile abdominal mass measuring 30 * 24 * 8 cm. A computed tomography scan con_rmed the presence of a large vascular tumour, and biochemical tumour markers were non-contributory. The tumour was removed through a conventional laparotomy incision with the aid of a Ligasure dissector. There were no macroscopic metastases, and histologically it was benign. The size of >5 cm, however, suggests that it may have been malignant. In the absence of visible metastases and in view of the favourable histological features, it was decided to follow up the patient very closely and give further treatment if necessary. PMID- 28876702 TI - Largest recorded non-invasive true intrathoracic desmoid tumour. AB - Intrathoracic desmoid tumours are rare soft-tissue neoplasms arising from fascial or musculo-aponeurotic structures, accounting for less than 0.03% of all neoplasms. Most cases in fact represent intrathoracic extension of chest wall tumours. This case report describes the largest recorded true intrathoracic desmoid tumour without mediastinal or chest wall invasion. The tumour was completely excised through a left thoracotomy with negative tumour margins. Management of the patient will involve radiological surveillance. Desmoids are benign tumours that do not metastasise but have a high rate of recurrence, especially if tumour margins are positive after surgical resection. Complete surgical resection is the treatment of choice. Other treatment options include radiotherapy; non-steroidal inflammatory drugs or antioestrogen therapy (tamoxifen) or a combination thereof; and chemotherapy or targeted drug therapy. PMID- 28876703 TI - The mystical foot with pink mushrooms: Imaging of maduromycosis - a rarity in southern Africa. AB - Maduromycoses (Madura foot) are chronic granulomatous subcutaneous infections endemic to certain regions, but not southern Africa. The infection is caused by both pure fungi and bacteria. Imaging plays an important role in assessing the severity of disease and the direction of its spread, assisting in treatment planning and in the monitoring of treatment response. The typical 'dot-in-circle' sign on magnetic resonance imaging is diagnostic of Madura foot. We present the case of an adolescent South African boy who presented with fungoid growths on his foot, typical of this disease. PMID- 28876704 TI - Isolated gallbladder perforation following blunt abdominal trauma. AB - A 32-year-old man sustained an isolated perforation of the gallbladder following blunt abdominal trauma. A preoperative diagnosis was made on an ultrasound scan, which showed a pericholecystic fluid collection only. At laparotomy, a gallbladder perforation at the infundibulum was identified with a localised bile collection, warranting a cholecystectomy. Isolated gallbladder injury from blunt abdominal trauma is rare, and a high index of suspicion is required to establish the diagnosis. Cholecystectomy is the treatment of choice. PMID- 28876705 TI - ? PMID- 28876706 TI - [Acute kidney injury in 2017 - Management in a secondary care hospital: an example of interdisciplinary collaboration]. AB - Acute kidney injury (AKI) is frequent and can lead to serious complications. It is classified according to the degree of renal function impairment and classically divided into three categories: pre-renal, intrinsic and post-renal. Identification of risk factors and wise use of additional tests are crucial to the diagnosis, as there are numerous causes of AKI. Identification and specific treatment of the underlying mechanism are essential, all while protecting the kidney. Resorting to a nephrologist is systematic when there are red flags. Follow-up after resolution of AKI is important as the risk of developing a chronic kidney disease is increased. PMID- 28876707 TI - [Initial management of new onset ascites in patient with cirrhosis]. AB - Ascites is the most frequent complication of cirrhosis and represents a significant change for the patient because the impact on mortality and quality of life is important. The management of a patient with initial onset of ascites includes a full history, a clinical exam and complementary analysis. This systematic approach allows an etiologic diagnosis. The aim of this article is to review the etiologies encountered in the initial onset of ascites in patient suffering from cirrhosis, to help the diagnosis and start initial management. PMID- 28876708 TI - [Creating a stroke unit in a community hospital improves the management of stroke patients]. AB - Dramatic advances in recent years have changed the care of stroke patients. Creation of stroke hubs with centers and units achieved a significant reduction in mortality and morbidity. The indications for acute therapies such as intravenous thrombolysis and endovascular treatment target an increasing proportion of stroke patients. Early rehabilitation and multidisciplinary approaches have become part of the gold standard in stroke care. The creation of additional stroke units and strengthening local synergies should continue in order to propose the best medical treatments for all stroke patients. PMID- 28876710 TI - [Hospital pathway of complex patients in a medical service of a local Hospital]. AB - In the current Swiss medical system, hospital care is provided by both university hospitals and so-called " peripheral " hospitals. While university hospitals offer advanced technology and a wide range of medical specialists, how is care organized within the smaller, less complex structure of a peripheral hospital ? In emergencies, although patients usually go to their local hospital, they should not be exposed to lower quality care. Quality treatment is guaranteed by a well organized structure, supported by a competent team of general doctors and specialists who have access to advanced technology. This article illustrates the journey of a typical patient presenting several common problems that make his case complex to manage, and also illustrates how the internal medicine department of a peripheral hospital operates. PMID- 28876709 TI - [Management and orientation of severely infected patients : relevance of a " Sepsis Fast-Track "]. AB - Sepsis is a syndrome defined by a life-threatening organ dysfunction caused by a dysregulated host response to an infection. The early recognition of this syndrome in the emergency department (ED) can lead to a better prognosis, when associated with a standardized management focusing on identification of the infectious source, its treatment, and appropriate organ support. Therefore, the implementation of a " Sepsis Fast Track ", by analogy with similar protocols regarding stroke or ST-elevated myocardial infarct, deserves interest. The aim of this article is to review the available evidences that support an implementation of such an initiative, and to identify the key elements that permit its integration in the ED setting of a secondary-care hospital. PMID- 28876711 TI - [Post-graduate education in internal medicine : what do residents want ?] AB - The post-graduate education course in general internal medicine - which leads to the accreditation as a specialist - is established by l'Institut Suisse de Formation medicale (ISFM), one of the organs of the FMH (Federatio Medicorum Helveticorum) in collaboration with the Swiss Society of General Internal Medicine (SSGIM). This program sets inter alia the necessary learning steps and defines which tools are efficient in monitoring the teaching program. The specific goals defined in the course are not, however, easily reached, specifically in the internal medicine services of hospitals that are subject to organisational constraints. This is strongly highlighted in the assessments made by residents during these training years. It, therefore, seems necessary to implicate the residents more actively in the definition of the goals of their training to maintain and continuously improve the quality of their post-graduate education. PMID- 28876713 TI - ? PMID- 28876712 TI - [Ethics and the decision of cardiopulmonary resuscitation]. AB - Following the guidelines of the Swiss Academy of Medical Science, most Swiss hospitals have implemented advanced directives that define what should be undertaken in case of cardiorespiratory arrest for every patient. This remains difficult to apply for physicians and difficult to understand for patients. From a medical perspective, some confusion occurs around medical directives. Difficulties include subjective misinterpretation of patient's quality of life, as well as decision making bias. In addition, patients overestimate the cardiopulmonary reanimation success rate, modify their choices with time and health status, and might lack their individual ability of discernment. Patient's autonomy must always be encouraged as long as it stays within the limits of medical indications. PMID- 28876715 TI - ? PMID- 28876714 TI - ? PMID- 28876717 TI - ? PMID- 28876716 TI - ? PMID- 28876718 TI - ? PMID- 28876720 TI - ? PMID- 28876719 TI - ? PMID- 28876885 TI - Inkjet-Printable Hydrochromic Paper for Encrypting Information and Anticounterfeiting. AB - Developing rewritable papers has gathered immense interest in recent times in view of developing sustainability in print media without exhausting environmental resources. We herein present a rapid and facile procedure for the fabrication of a communication medium by treating the surface of a paper with synthetic organic molecules, after which plain water could be used as an ink to print and reprint numerous times on the treated paper before disposal. Interestingly, as the paper comes in contact with water, the molecules are driven to reorganize in a slip stacked arrangement. This alters their ground and excited state properties by hydrogen-bond-assisted nonradiative decay, in which the associated changes are visible to the naked eye. The changes evolved are sensitive to the solubility parameter of the solvent and thermally reversible, thus linking the hydrochromic property to the paper. Against a background of concerns over a rise in counterfeiting and leaks of confidential information, prospects for encrypted communications and anticounterfeiting is herein demonstrated. PMID- 28876886 TI - Confined Catalysis in the g-C3N4/Pt(111) Interface: Feasible Molecule Intercalation, Tunable Molecule-Metal Interaction, and Enhanced Reaction Activity of CO Oxidation. AB - The deposition of a two-dimensional (2D) atomic nanosheet on a metal surface has been considered as a new route for tuning the molecule-metal interaction and surface reactivity in terms of the confinement effect. In this work, we use first principles calculations to systematically explore a novel nanospace constructed by placing a 2D graphitic carbon nitride (g-C3N4) nanosheet over a Pt(111) surface. The confined catalytic activity in this nanospace is investigated using CO oxidation as a model reaction. With the inherent triangular pores in the g C3N4 overlayer being taken advantage of, molecules such as CO and O2 can diffuse to adsorb on the Pt(111) surface underneath the g-C3N4 overlayer. Moreover, the mechanism of intercalation is also elucidated, and the results reveal that the energy barrier depends mainly on the properties of the molecule and the channel. Importantly, the molecule-catalyst interaction can be tuned by the g-C3N4 overlayer, considerably reducing the adsorption energy of CO on Pt(111) and leading to enhanced reactivity in CO oxidation. This work will provide important insight for constructing a promising nanoreactor in which the following is observed: The molecule intercalation is facile; the molecule-metal interaction is efficiently tuned; the metal-catalyzed reaction is promoted. PMID- 28876888 TI - Design of Surface-Coatable NIR-Responsive Fluorescent Nanoparticles with PEI Passivation for Bacterial Detection and Killing. AB - The ability to quickly detect and kill bacteria is crucial in the realm of antibiotic resistance. In this study, we synthesized a detection probe consisting of polyethylenimine (PEI)-passivated polydopamine-based fluorescent carbon (FDA:PEI) nanoparticles, generating a cationic adhesive material for bacterial detection that is surface-coatable, photothermal, and antibacterial. The cationic FDA:PEI nanoparticles effectively bound to the anionic bacterial cell wall, resulting in a dramatic quenching effect visible in fluorescence spectra and confocal images. In this fluorescence on/off system, FDA:PEI nanoparticles showed similar bacterial detection abilities between aqueous- and solid-phase assays. Scanning electron microscopy clearly showed the attachment of FDA:PEI nanoparticles to the surface of bacteria, both in solution and as a coating on the surface of a polypropylene film. In addition to detection, this versatile material was found to have an antibacterial potential, via near-infrared irradiation to induce a heat release, killing bacteria by thermolysis. Thus, by exploiting the cationic and catechol moieties on the surface of polydopamine carbon dots, we developed a novel bacterial-detection platform that can be used in a broad range of conditions. PMID- 28876887 TI - A Ratiometric Fluorescence Universal Platform Based on N, Cu Codoped Carbon Dots to Detect Metabolites Participating in H2O2-Generation Reactions. AB - In this work, a new kind of N, Cu codoped carbon dots (N/Cu-CDs) was prepared via a facile one-pot hydrothermal method by using citric acid monohydrate, copper acetate monohydrate and diethylenetriamine. The prepared N/Cu-CDs with a high quantum yield (50.1%) showed excitation-independent emission at 460 nm. The structure and fluorescence properties of N/Cu-CDs were characterized by high resolution transmission electron microscopy, fluorescence spectrofluorometer, FT IR spectrometer, UV-visible spectrophotometer and X-ray photoelectron spectroscopy. N/Cu-CDs were applied to establishing a ratiometric fluorescence probe toward H2O2 based on the inner filter effect (IFE) between N/Cu-CDs and DAP (2,3-diaminophenazine, the oxidative product of o-phenylenediamine (OPD)), and provided a ratiometric fluorescence universal platform for detection of the metabolites participating in H2O2-generation reactions (cholesterol and xanthine). The proposed method was demonstrated to be ultrasensitive and highly selective for cholesterol and xanthine assay with detection limits of 0.03 and 0.10 MUM, respectively. The fluorescence probe built was applied to the determination of cholesterol and xanthine in human serum with satisfactory results. PMID- 28876889 TI - Meta-Alkoxy-Substituted Difluoroboron Dibenzoylmethane Complexes as Environment Sensitive Materials. AB - The optical properties of meta-alkoxy-substituted difluoroboron dibenzoylmethane dyes were investigated in solution and in the solid state. Meta-alkoxy substitution induced strong intramolecular charge transfer (ICT) from the oxygen donating substituent to the halide and boron acceptors in the excited state, as compared to the pi-pi* transition that is observed with para-alkoxy substitution. The optical properties of para- and meta-substituted alkoxy boron dyes were evaluated by calculations, in dilute solution, and in solid-state films. When embedded in amorphous matrixes (e.g., PLA, PMMA, PS, cholesterol), all dyes showed fluorescence (F) and phosphorescence (P) emission. In this report, we show that meta-substitution resulted in enhanced solvatochromism and an increased phosphorescence-to-fluorescence ratio in solid-state films compared to analogous para-substituted samples. With enhanced phosphorescence intensity via the heavy atom effect, iodo-substituted dyes were further studied in PLA-PEG nanoparticles. Oxygen calibrations revealed stronger phosphorescence and a greater oxygen sensing range for the meta- versus para-alkoxy-substituted dyes, features that are important for oxygen-sensing materials design. PMID- 28876891 TI - Tumor pH-Responsive Release of Drug-Conjugated Micelles from Fiber Fragments for Intratumoral Chemotherapy. AB - The tumor accumulation of micelles is essential to enhance the cellular uptake and extend the release of chemotherapeutic agents. In the previous study camptothecin (CPT)-conjugated micelles (MCPT) were constructed with disulfide linkages and folate moieties for reduction-sensitive release and cell-selective uptake. This study proposes a strategy to integrate the promicelle polymers (PMCPT) into fiber fragments for intratumoral injection, realizing acid-liable release of PMCPT in response to acidic tumor microenvironment and spontaneous self-assembly into MCPT. Acid-liable 2-propionic-3-methylmaleic anhydride (CDM) linked poly(ethylene glycol) initiates the ring-opening polymerization of dl lactide as the fiber matrix. There is no apparent burst release of MCPT from fiber fragments and around 80% of accumulated releases after incubation in pH 6.5 buffers for 40 days. Compared to MCPT freshly prepared via solvent evaporation, the micelles released from fiber fragments reveal similar profiles, such as folate-mediated cellular uptake and glutathione-sensitive drug release. Taking advantage of the aggregation-induced emission (AIE) effect of tetraphenylethylene (TPE) derivatives, TPE-conjugated micelles (MTPE) have been successfully been used to track the self-assembly into micelles after release from fibers and subsequent cell internalization into cytosol. The self-assembly induced fluorescence light-up was also detected after intratumoral injection of fiber fragments. Compared with CPT-loaded fiber fragments and intratumoral or intravenous injection of free MCPT, the sustained release from fiber fragments and high accumulation of micelles in tumors result in significantly higher inhibition of tumor growths, prolongation of animal survival, and induction of tumor cell apoptosis. Thus, the integration of double targeting and double stimuli responsiveness into fragmented fibers provides a feasible strategy to realize the sustained micelle release from fibers and promote the therapeutic efficacy. PMID- 28876890 TI - Bioorthogonal Cycloadditions: Computational Analysis with the Distortion/Interaction Model and Predictions of Reactivities. AB - Bioorthogonal chemistry has had a major impact on the study of biological processes in vivo. Biomolecules of interest can be tracked by using probes and reporters that do not react with cellular components and do not interfere with metabolic processes in living cells. Much time and effort has been devoted to the screening of potential bioorthogonal reagents experimentally. This Account describes how our groups have performed computational screening of reactivity and mutual orthogonality. Our collaborations with experimentalists have led to the development of new and useful reactions. Dozens of bioorthogonal cycloadditions have been reported in the literature in the past few years, but as interest in tracking multiple targets arises, our computational screening has gained importance for the discovery of new mutually orthogonal bioorthogonal cycloaddition pairs. The reactivities of strained alkenes and alkynes with common 1,3-dipoles such as azides, along with mesoionic sydnones and other novel 1,3 dipoles, have been explored. Studies of "inverse-electron-demand" dienes such as triazines and tetrazines that have been used in bioorthogonal Diels-Alder cycloadditions are described. The color graphics we have developed give a snapshot of whether reactions are fast enough for cellular applications (green), adequately reactive for labeling (yellow), or only useful for synthesis or do not occur at all (red). The colors of each box give an instant view of rates, while bar graphs provide an analysis of the factors that control reactivity. This analysis uses the distortion/interaction or activation strain model of cycloaddition reactivity developed independently by our group and that of F. Matthias Bickelhaupt in The Netherlands. The model analyzes activation barriers in terms of the energy required to distort the reactants to the transition state geometry. This energy, called the distortion energy or activation strain, constitutes the major component of the activation energy. The strong bonding interaction between the termini of the two reactants, which we call the interaction energy, overcomes the distortion energy and leads to the new bonds in the products. This Account describes how we have analyzed and predicted bioorthogonal cycloaddition reactivity using the distortion/interaction model and how our experimental collaborators have employed these insights to create new bioorthogonal cycloadditions. The graphics we use document and predict which combinations of cycloadditions will be useful in bioorthogonal chemistry and which pairs of reactions are mutually orthogonal. For example, the fast reaction of 5-phenyl-1,2,4-triazine and a thiacycloheptyne will not interfere with the other fast reaction of 3,6-diphenyl-1,2,4,5-tetrazine and a cyclopropene. No cross reactions will occur, as these are very slow reactions. PMID- 28876892 TI - WO3 and W Thermal Atomic Layer Etching Using "Conversion-Fluorination" and "Oxidation-Conversion-Fluorination" Mechanisms. AB - The thermal atomic layer etching (ALE) of WO3 and W was demonstrated with new "conversion-fluorination" and "oxidation-conversion-fluorination" etching mechanisms. Both of these mechanisms are based on sequential, self-limiting reactions. WO3 ALE was achieved by a "conversion-fluorination" mechanism using an AB exposure sequence with boron trichloride (BCl3) and hydrogen fluoride (HF). BCl3 converts the WO3 surface to a B2O3 layer while forming volatile WOxCly products. Subsequently, HF spontaneously etches the B2O3 layer producing volatile BF3 and H2O products. In situ spectroscopic ellipsometry (SE) studies determined that the BCl3 and HF reactions were self-limiting versus exposure. The WO3 ALE etch rates increased with temperature from 0.55 A/cycle at 128 degrees C to 4.19 A/cycle at 207 degrees C. W served as an etch stop because BCl3 and HF could not etch the underlying W film. W ALE was performed using a three-step "oxidation conversion-fluorination" mechanism. In this ABC exposure sequence, the W surface is first oxidized to a WO3 layer using O2/O3. Subsequently, the WO3 layer is etched with BCl3 and HF. SE could simultaneously monitor the W and WO3 thicknesses and conversion of W to WO3. SE measurements showed that the W film thickness decreased linearly with number of ABC reaction cycles. W ALE was shown to be self-limiting with respect to each reaction in the ABC process. The etch rate for W ALE was ~2.5 A/cycle at 207 degrees C. An oxide thickness of ~20 A remained after W ALE, but could be removed by sequential BCl3 and HF exposures without affecting the W layer. These new etching mechanisms will enable the thermal ALE of a variety of additional metal materials including those that have volatile metal fluorides. PMID- 28876893 TI - Composite Gel Polymer Electrolyte for Improved Cyclability in Lithium-Oxygen Batteries. AB - Gel polymer electrolytes (GPE) and composite GPE (cGPE) using one-dimensional glass microfillers have been developed for their use in lithium-oxygen batteries. Using glass microfillers, tetraglyme solvent, UV-curable polymer, and lithium salt at various concentrations, the preparation of cGPE yielded free-standing films. These cGPEs, with 1 wt % of microfillers, demonstrated increased ionic conductivity and lithium transference number over GPEs at various concentrations of lithium salt. Improvements as high as 50% and 28% in lithium transference number were observed for 0.1 and 1.0 mol kg-1 salt concentrations, respectively. Lithium-oxygen batteries containing cGPE similarly showed superior charge/discharge cycling for 500 mAh g-1 cycle capacity with as high as 86% and 400% increase in cycles for cGPE with 1.0 and 0.1 mol kg-1 over GPE. Results using electrochemical impedance spectroscopy, Raman spectroscopy, and scanning electron microscopy revealed that the source of the improvement was the reduction of the rate of lithium carbonates formation on the surface of the cathode. This reduction in formation rate afforded by cGPE-containing batteries was possible due to the reduction of the rate of electrolyte decomposition. The increase in solvated to paired Li+ ratio at the cathode, afforded by increased lithium transference number, helped reduce the probability of superoxide radicals reacting with the tetraglyme solvent. This stabilization during cycling helped prolong the cycling life of the batteries. PMID- 28876894 TI - High-Efficiency Aqueous-Processed Polymer/CdTe Nanocrystals Planar Heterojunction Solar Cells with Optimized Band Alignment and Reduced Interfacial Charge Recombination. AB - Aqueous-processed nanocrystal solar cells have attracted increasing attention due to the advantage of its environmentally friendly nature, which provides a promising approach for large-scale production. The urgent affair is boosting the power conversion efficiency (PCE) for further commercial applications. The low PCE is mainly attributed to the imperfect device structure, which leads to abundant nonradiative recombination at the interfaces. In this work, an environmentally friendly and efficient method is developed to improve the performance of aqueous-processed CdTe nanocrystal solar cells. Polymer/CdTe planar heterojunction solar cells (PHSCs) with optimized band alignment are constructed, which results in reduced interfacial charge recombination, enhanced carrier collection efficiency and built-in field. Finally, a champion PCE of 5.9%, which is a record for aqueous-processed solar cells based on CdTe nanocrystals, is achieved after optimizing the photovoltaic device. PMID- 28876895 TI - 3D Printing of Photocurable Cellulose Nanocrystal Composite for Fabrication of Complex Architectures via Stereolithography. AB - The advantages of 3D printing on cost, speed, accuracy, and flexibility have attracted several new applications in various industries especially in the field of medicine where customized solutions are highly demanded. Although this modern fabrication technique offers several benefits, it also poses critical challenges in materials development suitable for industry use. Proliferation of polymers in biomedical application has been severely limited by their inherently weak mechanical properties despite their other excellent attributes. Earlier works on 3D printing of polymers focus mainly on biocompatibility and cellular viability and lack a close attention to produce robust specimens. Prized for superior mechanical strength and inherent stiffness, cellulose nanocrystal (CNC) from abaca plant is incorporated to provide the necessary toughness for 3D printable biopolymer. Hence, this work demonstrates 3D printing of CNC-filled biomaterial with significant improvement in mechanical and surface properties. These findings may potentially pave the way for an alternative option in providing innovative and cost-effective patient-specific solutions to various fields in medical industry. To the best of our knowledge, this work presents the first successful demonstration of 3D printing of CNC nanocomposite hydrogel via stereolithography (SL) forming a complex architecture with enhanced material properties potentially suited for tissue engineering. PMID- 28876896 TI - Differential Kinobeads Profiling for Target Identification of Irreversible Kinase Inhibitors. AB - Chemoproteomics profiling of kinase inhibitors with kinobeads enables the assessment of inhibitor potency and selectivity for endogenously expressed protein kinases in cell lines and tissues. Using a small panel of targeted covalent inhibitors, we demonstrate the importance of measuring covalent target binding in live cells. We present a differential kinobeads profiling strategy for covalent kinase inhibitors where a compound is added either to live cells or to a cell extract that enables the comprehensive assessment of inhibitor selectivity for covalent and noncovalent targets. We found that Acalabrutinib, CC-292, and Ibrutinib potently and covalently bind TEC family kinases, but only Ibrutinib also potently binds to BLK. ZAK was identified as a submicromolar affinity Ibrutinib off-target due to covalent modification of Cys22. In contrast to Ibrutinib, 5Z-7-Oxozeaenol reacted with Cys150 next to the DFG loop, demonstrating an alternative route to covalent inactivation of this kinase, e.g., to inhibit canonical TGF-beta dependent processes. PMID- 28876897 TI - Dynamic Equilibrium of Cardiac Troponin C's Hydrophobic Cleft and Its Modulation by Ca2+ Sensitizers and a Ca2+ Sensitivity Blunting Phosphomimic, cTnT(T204E). AB - Several studies have suggested that conformational dynamics are important in the regulation of thin filament activation in cardiac troponin C (cTnC); however, little direct evidence has been offered to support these claims. In this study, a dye homodimerization approach is developed and implemented that allows the determination of the dynamic equilibrium between open and closed conformations in cTnC's hydrophobic cleft. Modulation of this equilibrium by Ca2+, cardiac troponin I (cTnI), cardiac troponin T (cTnT), Ca2+-sensitizers, and a Ca2+ desensitizing phosphomimic of cTnT (cTnT(T204E) is characterized. Isolated cTnC contained a small open conformation population in the absence of Ca2+ that increased significantly upon the addition of saturating levels of Ca2+. This suggests that the Ca2+-induced activation of thin filament arises from an increase in the probability of hydrophobic cleft opening. The inclusion of cTnI increased the population of open cTnC, and the inclusion of cTnT had the opposite effect. Samples containing Ca2+-desensitizing cTnT(T204E) showed a slight but insignificant decrease in open conformation probability compared to samples with cardiac troponin T, wild type [cTnT(wt)], while Ca2+ sensitizer treated samples generally increased open conformation probability. These findings show that an equilibrium between the open and closed conformations of cTnC's hydrophobic cleft play a significant role in tuning the Ca2+ sensitivity of the heart. PMID- 28876899 TI - Using Accurate Mass Gas Chromatography-Mass Spectrometry with the MINE Database for Epimetabolite Annotation. AB - Mass spectrometry-based untargeted metabolomics often detects statistically significant metabolites that cannot be readily identified. Without defined chemical structure, interpretation of the biochemical relevance is not feasible. Epimetabolites are produced from canonical metabolites by defined enzymatic reactions and may represent a large fraction of the structurally unidentified metabolome. We here present a systematic workflow for annotating unknown epimetabolites using high resolution gas chromatography-accurate mass spectrometry with multiple ionization techniques and stable isotope labeled derivatization methods. We first determine elemental formulas, which are then used to query the "metabolic in-silico expansion" database (MINE DB) to obtain possible molecular structures that are predicted by enzyme promiscuity from canonical pathways. Accurate mass fragmentation rules are combined with in silico spectra prediction programs CFM-ID and MS-FINDER to derive the best candidates. We validated the workflow by correctly identifying 10 methylated nucleosides and 6 methylated amino acids. We then employed this strategy to annotate eight unknown compounds from cancer studies and other biological systems. PMID- 28876898 TI - Structural Basis of the Selectivity of GenN, an Aminoglycoside N Methyltransferase Involved in Gentamicin Biosynthesis. AB - Gentamicins are heavily methylated, clinically valuable pseudotrisaccharide antibiotics produced by Micromonospora echinospora. GenN has been characterized as an S-adenosyl-l-methionine-dependent methyltransferase with low sequence similarity to other enzymes. It is responsible for the 3"-N-methylation of 3" dehydro-3"-amino-gentamicin A2, an essential modification of ring III in the biosynthetic pathway to the gentamicin C complex. Purified recombinant GenN also efficiently catalyzes 3"-N-methylation of related aminoglycosides kanamycin B and tobramycin, which both contain an additional hydroxymethyl group at the C5" position in ring III. We have obtained eight cocrystal structures of GenN, at a resolution of 2.2 A or better, including the binary complex of GenN and S adenosyl-l-homocysteine (SAH) and the ternary complexes of GenN, SAH, and several aminoglycosides. The GenN structure reveals several features not observed in any other N-methyltransferase that fit it for its role in gentamicin biosynthesis. These include a novel N-terminal domain that might be involved in protein:protein interaction with upstream enzymes of the gentamicin X2 biosynthesis and two long loops that are involved in aminoglycoside substrate recognition. In addition, the analysis of structures of GenN in complex with different ligands, supported by the results of active site mutagenesis, has allowed us to propose a catalytic mechanism and has revealed the structural basis for the surprising ability of native GenN to act on these alternative substrates. PMID- 28876900 TI - Selective and Cleavable Extraction of Sialo-glycoproteins by Disulfide-Linked Amino-oxy-Functionalized Fe3O4 Magnetic Nanoparticles. AB - The low abundance of sialo-glycoprotein hampered the separation, enrichment, and analysis of sialo-glycoproteins, which are critical for studying their functions. Here, we designed cleavable amino-oxy functionalized magnetic materials and employed to fast and selective isolate sialo-glycoproteins. This includes the ligation of disulfide-linked amino-oxy-functionalized magnetic nanoparticles with periodate-treated glycoproteins or cells, followed by magnetic separation. A reductive reagent could release the sialo-glycoproteins with small molecular fragments on the terminal of glycan chains, and the sialo-glycoproteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. On-bead digestion of the peptides were analyzed by tandem mass spectrometry. The results indicated that this method could selectively separate the majority of cell surface sialo-glycoproteins. PMID- 28876901 TI - Flexible Graphene-Based Wearable Gas and Chemical Sensors. AB - Wearable electronics is expected to be one of the most active research areas in the next decade; therefore, nanomaterials possessing high carrier mobility, optical transparency, mechanical robustness and flexibility, lightweight, and environmental stability will be in immense demand. Graphene is one of the nanomaterials that fulfill all these requirements, along with other inherently unique properties and convenience to fabricate into different morphological nanostructures, from atomically thin single layers to nanoribbons. Graphene-based materials have also been investigated in sensor technologies, from chemical sensing to detection of cancer biomarkers. The progress of graphene-based flexible gas and chemical sensors in terms of material preparation, sensor fabrication, and their performance are reviewed here. The article provides a brief introduction to graphene-based materials and their potential applications in flexible and stretchable wearable electronic devices. The role of graphene in fabricating flexible gas sensors for the detection of various hazardous gases, including nitrogen dioxide (NO2), ammonia (NH3), hydrogen (H2), hydrogen sulfide (H2S), carbon dioxide (CO2), sulfur dioxide (SO2), and humidity in wearable technology, is discussed. In addition, applications of graphene-based materials are also summarized in detecting toxic heavy metal ions (Cd, Hg, Pb, Cr, Fe, Ni, Co, Cu, Ag), and volatile organic compounds (VOCs) including nitrobenzene, toluene, acetone, formaldehyde, amines, phenols, bisphenol A (BPA), explosives, chemical warfare agents, and environmental pollutants. The sensitivity, selectivity and strategies for excluding interferents are also discussed for graphene-based gas and chemical sensors. The challenges for developing future generation of flexible and stretchable sensors for wearable technology that would be usable for the Internet of Things (IoT) are also highlighted. PMID- 28876902 TI - Amino Acid Functionalized Inorganic Nanoparticles as Cutting-Edge Therapeutic and Diagnostic Agents. AB - The field of medical diagnostics and therapeutics is being revolutionized by nanotechnology, from targeted drug delivery to cancer immunotherapy. Inorganic nanoparticles are widely used, albeit problems with agglutination, cytotoxicity, free radical generation, and instability in some biological environments limits their utility. Conjugation of biomolecules such as peptides to the surface of nanoparticles can mitigate such problems, as well as confer specialized theranostic (therapeutic and/or diagnostic) properties, useful across biomedical applications such as vaccines, drug delivery, and in vivo imaging. Coating with amino acids, rather than peptides, offers further a highly cost-effective approach (due to their ease of purification and availability), but is currently an underutilized way to decrease toxicity and enhance stability. Amino acid molecules are small (<200 Da) and have both positive and negative charge groups (zwitterionic) facilitating charge-specific molecule binding. Additionally, amino acids exert by themselves some useful biological functions, with antibacterial and viability enhancing properties (for eukaryotic cells). Overall particle size, nanoparticle core, and the specific amino acid used to functionalize their surface influence their biodistribution, and their effects on host immunity. In this review, we provide for the first time an overview of this emerging field, and identify gaps in knowledge for future research. PMID- 28876903 TI - Label-Free Detection of Bacillus anthracis Spore Uptake in Macrophage Cells Using Analytical Optical Force Measurements. AB - Understanding the interaction between macrophage cells and Bacillus anthracis spores is of significant importance with respect to both anthrax disease progression, spore detection for biodefense, as well as understanding cell clearance in general. While most detection systems rely on specific molecules, such as nucleic acids or proteins and fluorescent labels to identify the target(s) of interest, label-free methods probe changes in intrinsic properties, such as size, refractive index, and morphology, for correlation with a particular biological event. Optical chromatography is a label free technique that uses the balance between optical and fluidic drag forces within a microfluidic channel to determine the optical force on cells or particles. Here we show an increase in the optical force experienced by RAW264.7 macrophage cells upon the uptake of both microparticles and B. anthracis Sterne 34F2 spores. In the case of spores, the exposure was detected in as little as 1 h without the use of antibodies or fluorescent labels of any kind. An increase in the optical force was also seen in macrophage cells treated with cytochalasin D, both with and without a subsequent exposure to spores, indicating that a portion of the increase in the optical force arises independent of phagocytosis. These results demonstrate the capability of optical chromatography to detect subtle biological differences in a rapid and sensitive manner and suggest future potential in a range of applications, including the detection of biological threat agents for biodefense and pathogens for the prevention of sepsis and other diseases. PMID- 28876904 TI - Role of Biocatalysis in Sustainable Chemistry. AB - Based on the principles and metrics of green chemistry and sustainable development, biocatalysis is both a green and sustainable technology. This is largely a result of the spectacular advances in molecular biology and biotechnology achieved in the past two decades. Protein engineering has enabled the optimization of existing enzymes and the invention of entirely new biocatalytic reactions that were previously unknown in Nature. It is now eminently feasible to develop enzymatic transformations to fit predefined parameters, resulting in processes that are truly sustainable by design. This approach has successfully been applied, for example, in the industrial synthesis of active pharmaceutical ingredients. In addition to the use of protein engineering, other aspects of biocatalysis engineering, such as substrate, medium, and reactor engineering, can be utilized to improve the efficiency and cost-effectiveness and, hence, the sustainability of biocatalytic reactions. Furthermore, immobilization of an enzyme can improve its stability and enable its reuse multiple times, resulting in better performance and commercial viability. Consequently, biocatalysis is being widely applied in the production of pharmaceuticals and some commodity chemicals. Moreover, its broader application will be further stimulated in the future by the emerging biobased economy. PMID- 28876905 TI - Specificity and Speed: Tethered Photopharmacology. AB - Genetics and pharmacology are often seen as two distinct approaches to interrogating, elucidating, and manipulating biological systems. The former is renowned for its precision whereas the latter for its fast kinetics, reversibility, and practicality. Here, we show that both can be joined as "tethered pharmacology", wherein a genetically programmed bioconjugation site provides selectivity and a tethered pharmacophore provides function. The speed of onset, and especially cessation, of pharmacological activity can be greatly enhanced by incorporating photoswitches and using light as the trigger ("tethered photopharmacology"). Genetically encoded, tethered photopharmacology is a variant of optogenetics and could even play a role in medicine wherever gene therapy is viable. However, gene therapy may not be necessary if sufficiently selective tethering strategies that operate on wild-type receptors can be developed. PMID- 28876906 TI - Water Issues Related to Transitioning from Conventional to Unconventional Oil Production in the Permian Basin. AB - The Permian Basin is being transformed by the "shale revolution" from a major conventional play to the world's largest unconventional play, but water management is critical in this semiarid region. Here we explore evolving issues associated with produced water (PW) management and hydraulic fracturing water demands based on detailed well-by-well analyses. Our results show that although conventional wells produce ~13 times more water than oil (PW to oil ratio, PWOR = 13), this produced water has been mostly injected back into pressure-depleted oil producing reservoirs for enhanced oil recovery. Unconventional horizontal wells use large volumes of water for hydraulic fracturing that increased by a factor of ~10-16 per well and ~7-10 if normalized by lateral well length (2008-2015). Although unconventional wells have a much lower PWOR of 3 versus 13 from conventional wells, this PW cannot be reinjected into the shale reservoirs but is disposed into nonproducing geologic intervals that could result in overpressuring and induced seismicity. The potential for PW reuse from unconventional wells is high because PW volumes can support hydraulic fracturing water demand based on 2014 data. Reuse of PW with minimal treatment (clean brine) can partially mitigate PW injection concerns while reducing water demand for hydraulic fracturing. PMID- 28876907 TI - One-Step Production of Amphiphilic Nanofibrillated Cellulose Using a Cellulose Producing Bacterium. AB - Nanofibrillated bacterial cellulose (NFBC) is produced by culturing a cellulose producing bacterium (Gluconacetobacter intermedius NEDO-01) with rotation or agitation in medium supplemented with carboxymethylcellulose (CMC). Despite a high yield and dispersibility in water, the product immediately aggregates in organic solvents. To broaden its applicability, we prepared amphiphilic NFBC by culturing strain NEDO-01 in medium supplemented with hydroxyethylcellulose or hydroxypropylcellulose instead of CMC. Transmission electron microscopy analysis revealed that the resultant materials (HE-NFBC and HP-NFBC, respectively) comprised relatively uniform fibers with diameters of 33 +/- 7 and 42 +/- 8 nm, respectively. HP-NFBC was dispersible in polar organic solvents such as methanol, acetone, isopropyl alcohol, acetonitrile, tetrahydrofuran (THF), and dimethylformamide, and was also dispersible in poly(methyl methacrylate) (PMMA) by solvent mixing using THF. HP-NFBC/PMMA composite films were highly transparent and had a higher tensile strength than neat PMMA film. Thus, HP-NFBC has a broad range of applications, including as a filler material. PMID- 28876908 TI - Three-Dimensional Electroconductive Hyaluronic Acid Hydrogels Incorporated with Carbon Nanotubes and Polypyrrole by Catechol-Mediated Dispersion Enhance Neurogenesis of Human Neural Stem Cells. AB - Electrically conductive hyaluronic acid (HA) hydrogels incorporated with single walled carbon nanotubes (CNTs) and/or polypyrrole (PPy) were developed to promote differentiation of human neural stem/progenitor cells (hNSPCs). The CNT and PPy nanocomposites, which do not easily disperse in aqueous phases, dispersed well and were efficiently incorporated into catechol-functionalized HA (HA-CA) hydrogels by the oxidative catechol chemistry used for hydrogel cross-linking. The prepared electroconductive HA hydrogels provided dynamic, electrically conductive three-dimensional (3D) extracellular matrix environments that were biocompatible with hNSPCs. The HA-CA hydrogels containing CNT and/or PPy significantly promoted neuronal differentiation of human fetal neural stem cells (hfNSCs) and human induced pluripotent stem cell-derived neural progenitor cells (hiPSC-NPCs) with improved electrophysiological functionality when compared to differentiation of these cells in a bare HA-CA hydrogel without electroconductive motifs. Calcium channel expression was upregulated, depolarization was activated, and intracellular calcium influx was increased in hNSPCs that were differentiated in 3D electroconductive HA-CA hydrogels; these data suggest a potential mechanism for stem cell neurogenesis. Overall, our bioinspired, electroconductive HA hydrogels provide a promising cell-culture platform and tissue-engineering scaffold to improve neuronal regeneration. PMID- 28876909 TI - Challenges in Coupling Acidity and Salinity Transport in Porous Media. AB - Salinity is an increasingly prescient issue in reactive transport, from low salinity water flooding to fracking brine leakage. Of primary concern is the effect of salinity on surface chemistry. Transport and batch experiments show a strong coupling of salinity and acidity through chemical interactions at the mineral-liquid interface. This coupling is ascribed to the combined effects of ionic strength on electrostatic behavior of the interface and competitive sorption between protons and other cations for binding sites on the surface. The effect of these mechanisms is well studied in batch settings and readily describes observed behavior. In contrast, the transport literature is sparse, primarily applied to synthetic materials, and offers only qualitative agreement with observations. To address, this gap in knowledge, we conduct a suite of column flood experiments through silica sand, systematically varying salinity and acidity conditions. Experiments are compared to a reactive transport model incorporating the proposed coupling mechanisms. The results highlight the difficulty in applying such models to realistic media under both basic and acidic conditions with a single set of parameters. The analysis and experimental results show the observed error is the result of electrostatic assumptions within the surface chemistry model and provide a strong constraint on further model development. PMID- 28876910 TI - Dynamic Transgenerational Fate of Polychlorinated Biphenyls and Dioxins/Furans in Lactating Cows and Their Offspring. AB - We report on two farms in Switzerland heavily contaminated by polychlorinated biphenyls (PCBs) and dioxins (PCDD/Fs), occurring in the first case from diffuse sources and in the second case from PCB-containing wall paint. Extensive measurements of PCBs and PCDD/Fs on site (soil, forage, and paint) and in cattle (blood, fat, and milk) allowed validation of our novel dynamic toxicokinetic model, which includes the transfer of contaminants from the mother cows to their suckling calf and the uptake of soil by grazing cattle. We show that for calves, the mother milk is the main uptake route of contaminants. For both cows and calves, ingestion of contaminated soil, although often overlooked, is an appreciable uptake path. The remediation of the contaminated stable lead to a 2-3 fold reduction of the PCB levels in animals within one year. The transfer of animals to an uncontaminated mountain site during summer proved to be an effective decontamination procedure with up to 50% reduction of the levels within three months. Our study calls for a rapid removal of PCB-containing materials in animal husbandry farms and shows that the diffuse contamination of soils will remain a source for PCBs and PCDD/Fs in our food chain for decades to come. PMID- 28876911 TI - Interaction of Engineered Nanoparticles with the Agri-environment. AB - Nanoparticles with their unique surface properties can modulate the physiological, biochemical, and physicochemical pathways, such as photosynthesis, respiration, nitrogen metabolism, and solute transport. In this context, researchers have developed a wide range of engineered nanomaterials (ENMs) for the improvement of growth and productivity by modulating the metabolic pathways in plants. This class of tailor-made materials can potentially lead to the development of a new group of agrochemical nanofertilizers. However, there are reports that engineered nanomaterials could impart phytotoxicity to edible and medicinal plants. On the contrary, there is a series of ENMs that might be detrimental when applied directly and/or indirectly to the plants. These particles can sometimes readily aggregate and dissolute in the immediate vicinity; the free ions released from the nanomatrix can cause serious tissue injury and membrane dysfunction to the plant cell through oxidative stress. On that note, thorough studies on uptake, translocation, internalization, and nutritional quality assessment must be carried out to understand ENM-plant interactions. This review critically discusses the possible beneficial or adverse aftereffect of nanofertilizers in the immediate environment to interrelate the impacts of ENMs on the crop health and food security management. PMID- 28876912 TI - Stochastic GW Calculations for Molecules. AB - Quasiparticle (QP) excitations are extremely important for understanding and predicting charge transfer and transport in molecules, nanostructures, and extended systems. Since density functional theory (DFT) within the Kohn-Sham (KS) formulation does not provide reliable QP energies, many-body perturbation techniques such as the GW approximation are essential. The main practical drawback of GW implementations is the high computational scaling with system size, prohibiting its use in extended, open boundary systems with many dozens of electrons or more. Recently, a stochastic formulation of GW (sGW) was presented (Phys. Rev. Lett. 2014, 113, 076402) with a near-linear-scaling complexity, illustrated for a series of silicon nanocrystals reaching systems of more than 3000 electrons. This advance provides a route for many-body calculations on very large systems that were impossible with previous approaches. While earlier we have shown the gentle scaling of sGW, its accuracy was not extensively demonstrated. Therefore, we show that this new sGW approach is very accurate by calculating the ionization energies of a group of sufficiently small molecules where a comparison to other GW codes is still possible. Using a set of 10 such molecules, we demonstrate that sGW provides reliable vertical ionization energies in close agreement with benchmark deterministic GW results (J. Chem. Theory Comput, 2015, 11, 5665), with mean (absolute) deviation of 0.05 and 0.09 eV. For completeness, we also provide a detailed review of the sGW theory and numerical implementation. PMID- 28876913 TI - Stereoselective Bioaccumulation of Water and Soil-Associated Dufulin Enantiomers in Tubifex. AB - In this study, the stereoselective bioaccumulation of rac-dufulin, pure S-(+) dufulin, and pure R-(-)-dufulin in Tubifex (Oligochaeta, Tubificida) were analyzed in spiked-water and spiked-soil systems at low and high dose levels. In the bioaccumulation experiments treated with rac-dufulin, the enantioselective behaviors of the enantiomers show that the concentrations of R-(-)-dufulin are higher than those of S-(+)-dufulin at two dose levels. However, when treated with solely pure S-(+)-dufulin and R-(-)-dufulin, no significant difference of concentrations was detected in Tubifex. Furthermore, the calculated accumulation factors in Tubifex indicated that dufulin (racemic or the pure enantiomers) in the spiked-soil treatments had higher bioaccumulation potential than in the spiked-water treatments. The spiked-soil experiments revealed that the dissipation of dufulin in soil was not enantioselective at the enantiomer levels and Tubifex could reduce the concentrations of dufulin in the underlying solid matrix and accelerate its repair and detoxification process. PMID- 28876914 TI - REMPI Spectroscopy of Laser Desorbed Guanosines. PMID- 28876915 TI - Effects of Polar Bear and Killer Whale Derived Contaminant Cocktails on Marine Mammal Immunity. AB - Most controlled toxicity studies use single chemical exposures that do not represent the real world situation of complex mixtures of known and unknown natural and anthropogenic substances. In the present study, complex contaminant cocktails derived from the blubber of polar bears (PB; Ursus maritimus) and killer whales (KW; Orcinus orca) were used for in vitro concentration-response experiments with PB, cetacean and seal spp. immune cells to evaluate the effect of realistic contaminant mixtures on various immune functions. Cytotoxic effects of the PB cocktail occurred at lower concentrations than the KW cocktail (1 vs 16 MUg/mL), likely due to differences in contaminant profiles in the mixtures derived from the adipose of each species. Similarly, significant reduction of lymphocyte proliferation occurred at much lower exposures in the PB cocktail (EC50: 0.94 vs 6.06 MUg/mL; P < 0.01), whereas the KW cocktail caused a much faster decline in proliferation (slope: 2.9 vs 1.7; P = 0.04). Only the KW cocktail modulated natural killer (NK) cell activity and neutrophil and monocyte phagocytosis in a concentration- and species-dependent manner. No clear sensitivity differences emerged when comparing cetaceans, seals and PB. Our results showing lower effect levels for complex mixtures relative to single compounds suggest that previous risk assessments underestimate the effects of real world contaminant exposure on immunity. Our results using blubber-derived contaminant cocktails add realism to in vitro exposure experiments and confirm the immunotoxic risk marine mammals face from exposure to complex mixtures of environmental contaminants. PMID- 28876917 TI - Transformation of Phosphorus during (Hydro)thermal Treatments of Solid Biowastes: Reaction Mechanisms and Implications for P Reclamation and Recycling. AB - Phosphorus (P) is an essential nutrient for all organisms, thus playing unique and critical roles at the food-energy-water nexus. Most P utilized by human activities eventually converges into various solid biowastes, such as crop biomass, animal manures, and sewage sludges. Therefore, integration of efficient P recovery practices into solid biowaste management will not only significantly reduce the dependence on limited geological P resources but also reduce P runoff and related water contamination issues associated with traditional waste management strategies. This study reviews the applications of (hydro)thermal techniques for the treatment of solid biowastes, which can greatly facilitate P recovery in addition to waste volume reduction, decontamination, and energy recovery. Research showed that P speciation (including molecular moiety, complexation state, and mineralogy) can experience significant changes during (hydro)thermal treatments, and are impacted by treatment techniques and conditions. Changes in P speciation and overall properties of the products can alter the mobility and bioavailability of P, and subsequent P reclamation and recycling efficiency of the treatment products. This review summarizes recent progresses in this direction, identifies the challenges and knowledge gaps, and provides a foundation for future research efforts targeting at sustainable management of nutrient-rich biowastes. PMID- 28876916 TI - Molecular Routes to Group IV Magnesium and Calcium Nanocrystalline Ceramics. AB - The effect of alkaline-earth-metal alkoxides on the protonolysis of Cp2M'Cl2 (M' = Ti, Zr, Hf; Cp = cyclopentadiene) was investigated. This approach enabled the design of compounds with well-defined molecular structures to generate high purity binary metal oxides. Single-source molecular precursors with structures of [M2M'2(MU3-OEt)2(MU-OEt)4(OEt)6(EtOH)4] with M = Mg and M' = Ti (1), Zr (2), and Hf (3), [Ca6Ti4(MU6-O)2(MU4-O)2(MU3-OEt)12(OEt)12(EtOH)6Cl4] (4), and [M2M'2(MU4 O)(MU-OEt)5(OEt)4(EtOH)4Cl]n with M = Ca and M' = Zr (5) and Hf (6) were prepared via elimination of the cyclopentadienyl ring from Cp2M'Cl2 as CpH in the presence of M(OEt)2 and ethanol (EtOH) as a source of protons. Meanwhile, similar reactions involving the initial substitution of Cl ligands by OEt groups in Cp2M'Cl2 (M' = Ti, Zr, Hf) resulted in the formation of [M2M'2(MU3-OEt)2(MU OEt)4(OEt)6(EtOH)4] with M = Ca and M' = Ti (7), Zr (8), and Hf (9). The precursors were characterized by elemental analysis, NMR spectroscopy, and single crystal X-ray structural analysis. Magnesium compounds 1-3 decomposed at 750-850 degrees C to give MgTiO3 along with small amounts of Mg2TiO4, Mg2Zr5O12, or Mg2Hf5O12 binary metal oxides. The thermolysis of calcium compounds 4 and 7-9 led to highly pure CaTiO3, CaZrO3, or CaHfO3 perovskite-like oxide particles with diameters of 20-30 nm. PMID- 28876918 TI - Simulating Multiwalled Carbon Nanotube Transport in Surface Water Systems Using the Water Quality Analysis Simulation Program (WASP). AB - Under the Toxic Substances Control Act (TSCA), the Environmental Protection Agency (EPA) is required to perform new chemical reviews of nanomaterials identified in premanufacture notices. However, environmental fate models developed for traditional contaminants are limited in their ability to simulate nanomaterials' environmental behavior by incomplete understanding and representation of the processes governing nanomaterial distribution in the environment and by scarce empirical data quantifying the interaction of nanomaterials with environmental surfaces. In this study, the well-known Water Quality Analysis Simulation Program (WASP) was updated to incorporate particle collision rate and particle attachment efficiency to simulate multiwalled carbon nanotube (MWCNT) fate and transport in surface waters. Heteroaggregation attachment efficiencies (alphahet) values derived from sediment attachment studies are used to parametrize WASP for simulation of MWCNTs transport in Brier Creek, a coastal plain river located in central eastern Georgia, and a tributary to the Savannah River. Simulations using a constant MWCNT load of 0.1 kg d-1 in the uppermost Brier Creek water segment showed that MWCNTs were present predominantly in the Brier Creek water column, while downstream MWCNT surface and deep sediment concentrations exhibited a general increase with time and distance from the source, suggesting that MWCNT releases could have increasing ecological impacts in the benthic region over long time frames. PMID- 28876919 TI - Cirsium maritimum Makino Inhibits the Antigen/Immunoglobulin-E-Mediated Allergic Response In Vitro and In Vivo. AB - We investigated whether Cirsium maritimum Makino can inhibit immunoglobulin-E mediated allergic response in rat basophilic leukemia (RBL-2H3) cells and passive cutaneous anaphylaxis (PCA) in BALB/c mice. In vitro, the ethyl acetate extract of C. maritimum Makino (ECMM) significantly inhibited beta-hexosaminidase release and decreased intracellular Ca2+ levels in RBL-2H3 cells. Moreover, ECMM leaves more strongly suppressed the release of beta-hexosaminidase than ECMM flowers. ECMM leaves also significantly suppressed the PCA reaction in the murine model. High-performance liquid chromatography and 1H and 13C nuclear magnetic resonance indicated that cirsimaritin, a flavonoid, was concentrated in active fractions of the extract. Our findings suggest that ECMM leaves have a potential regulatory effect on allergic reactions that may be mediated by mast cells. Furthermore, cirsimaritin may be the active anti-allergic component in C. maritimum Makino. PMID- 28876920 TI - Oxidative Uranium Release from Anoxic Sediments under Diffusion-Limited Conditions. AB - Uranium (U) contamination occurs as a result of mining and ore processing; often in alluvial aquifers that contain organic-rich, reduced sediments that accumulate tetravalent U, U(IV). Uranium(IV) is sparingly soluble, but may be mobilized upon exposure to nitrate (NO3-) and oxygen (O2), which become elevated in groundwater due to seasonal fluctuations in the water table. The extent to which oxidative U mobilization can occur depends upon the transport properties of the sediments, the rate of U(IV) oxidation, and the availability of inorganic reductants and organic electron donors that consume oxidants. We investigated the processes governing U release upon exposure of reduced sediments to artificial groundwater containing O2 or NO3- under diffusion-limited conditions. Little U was mobilized during the 85-day reaction, despite rapid diffusion of groundwater within the sediments and the presence of nonuraninite U(IV) species. The production of ferrous iron and sulfide in conjunction with rapid oxidant consumption suggested that the sediments harbored large concentrations of bioavailable organic carbon that fueled anaerobic microbial respiration and stabilized U(IV). Our results suggest that seasonal influxes of O2 and NO3- may cause only localized mobilization of U without leading to export of U from the reducing sediments when ample organic carbon is present. PMID- 28876921 TI - Binding of Gallic Acid and Epigallocatechin Gallate to Heat-Unfolded Whey Proteins at Neutral pH Alters Radical Scavenging Activity of in Vitro Protein Digests. AB - Preheated (80 degrees C for 9 min) whey protein isolate (HWPI) was reacted with 20, 120, and 240 MUmol/g (protein basis) gallic acid (GA) or epigallocatechin gallate (EGCG) at neutral pH and 25 degrees C. Isothermal titration calorimetry and fluorometry showed a similar trend that GA binding to HWPI was moderate but weaker than EGCG binding. However, the shift of maximal fluorescence emission wavelength in opposite directions in response to GA (blue) and EGCG (red) suggests discrepant binding patterns. Electrophoresis results showed that EGCG induced formation of HWPI complexes while GA only had a marginal effect. Both free and phenolic-bound HWPI exhibited mild antiradical activity. However, when subjected to in vitro digestion, synergistic radical-scavenging activity was produced between the phenolics and peptides with the highest synergism being observed on 120 MUmol/g phenolics. PMID- 28876922 TI - Rheological Enhancement of Pork Myofibrillar Protein-Lipid Emulsion Composite Gels via Glucose Oxidase Oxidation/Transglutaminase Cross-Linking Pathway. AB - Porcine myofibrillar protein (MP) was modified with glucose oxidase (GluOx)-iron that produces hydroxyl radicals then subjected to microbial transglutaminase (TGase) cross-linking in 0.6 M NaCl at 4 degrees C. The resulting aggregation and gel formation of MP were examined. The GluOx-mediated oxidation promoted the formation of both soluble and insoluble protein aggregates via disulfide bonds and occlusions of hydrophobic groups. The subsequent TGase treatment converted protein aggregates into highly cross-linked polymers. MP-lipid emulsion composite gels formed with such polymers exhibited markedly enhanced gelling capacity: up to 4.4-fold increases in gel firmness and 3.5-fold increases in gel elasticity over nontreated protein. Microstructural examination showed small oil droplets dispersed in a densely packed gel matrix when MP was oxidatively modified, and the TGase treatment further contributed to such packing. The enzymatic GluOx oxidation/TGase treatment shows promise to improve the textural properties of emulsified meat products. PMID- 28876924 TI - Reversible Exchange of L-Type and Bound-Ion-Pair X-Type Ligation on Cadmium Selenide Quantum Belts. AB - CdSe quantum belts of composition {CdSe[n-octylamine]0.53} and protic acids HX (X = Cl, Br, NO3, acetate (OAc), and benzoate (OBz)) react to exchange the L-type amine ligation to bound-ion-pair X-type ligation. The latter ligation has X- anions bound to the nanocrystal surfaces and closely associated LH+ counter cations (protonated n-octylamine or tri-n-octylphosphine (TOP) to balance the surface charges. The compositions of the exchanged QBs are {CdSe[Br]0.44[n octylammonium]0.41}, {CdSe[NO3]0.10[TOPH]0.12}, {CdSe[OBz]0.08[n octylammonium]0.02[TOPH]0.06}, and {CdSe[OAc]0.16[n octylammonium]0.02[TOPH]0.14}. (The HCl-exchanged QBs are insufficiently stable for elemental analysis.) The bound-ion-pair X-type ligation is fully reversed to L-type n-octylamine ligation in the cases of X = NO3, acetate, and benzoate. The ligand exchanges are monitored by absorption spectroscopy, and the exchanged, bound-ion-pair X-type ligated nanocrystals are characterized by a range of methods. PMID- 28876925 TI - On the Calculation of Acyl Chain Order Parameters from Lipid Simulations. AB - For molecular dynamics simulations of biological membrane systems to live up to the potential of providing accurate atomic level detail into membrane properties and functions, it is essential that the force fields used to model such systems are as accurate as possible. One membrane property that is often used to assess force field accuracy is the carbon-hydrogen (or carbon-deuterium) order parameters of the lipid tails, which can be accurately measured using experimental NMR techniques. There are a variety of analysis tools available to calculate these order parameters from simulations and it is essential that these computational tools work correctly to ensure the accurate assessment of the simulation force fields. In this work we compare many of these computational tools for calculating the order parameters of POPC membranes. While tools that work on all-atom systems and tools that work on saturated lipid tails in general work extremely well, we demonstrate that the majority of the tested tools that calculate the order parameters for unsaturated united-atom lipid tails do so incorrectly. We identify tools that do perform accurate calculations and include one such program with this work, enabling rapid and accurate calculation of united-atom lipid order parameters. Furthermore, we discuss cases in which it is nontrivial to appropriately predict the unsaturated carbon order parameters in united-atom systems. Finally, we examine order parameter splitting for carbon 2 in sn-2 lipid chains, demonstrating substantial deviations from experimental values in several all-atom and united-atom lipid force fields. PMID- 28876926 TI - Cryo IR Spectroscopy of [Hemin]+ Complexes in Isolation. AB - We present cryo IR spectra of isolated [Hemin]+ adducts with CO, N2, and O2 ([Hemin(CO)1]+, [Hemin(CO)2]+, [Hemin(14N2)]+, [Hemin(15N2)]+, and [Hemin(O2)]+). Well resolved bands allow for the elucidation of structure and spin multiplicity in conjunction with density functional (DFT) calculations. There is a quartet spin state for the N2 and CO adducts and a sextet spin state for the O2 adduct, where the O2 retains its triplet state. The double CO adsorption induces significant changes in the vibrational patterns of the IR spectra, which we take as strong evidence for a spin quenching into a doublet. Our study characterizes [Hemin]+, which is the Fe3+ oxidation product of heme that is of ubiquitous presence in hemeproteins. PMID- 28876923 TI - Spirohexene-Tetrazine Ligation Enables Bioorthogonal Labeling of Class B G Protein-Coupled Receptors in Live Cells. AB - A new bioorthogonal reactant pair, spiro[2.3]hex-1-ene (Sph) and 3,6-di(2 pyridyl)-s-tetrazine (DpTz), for the strain-promoted inverse electron-demand Diels-Alder cycloaddition, that is, tetrazine ligation, is reported. As compared to the previously reported strained alkenes such as trans-cyclooctene (TCO) and 1,3-disubstituted cyclopropene, Sph exhibits balanced reactivity and stability in tetrazine ligation with the protein substrates. A lysine derivative of Sph, SphK, was site-selectively incorporated into the extracellular loop regions (ECLs) of GCGR and GLP-1R, two members of class B G protein-coupled receptors (GPCRs) in mammalian cells with the incorporation efficiency dependent on the location. Subsequent bioorthogonal reactions with the fluorophore-conjugated DpTz reagents afforded the fluorescently labeled GCGR and GLP-1R ECL mutants with labeling yield as high as 68%. A multitude of functional assays were performed with these GPCR mutants, including ligand binding, ligand-induced receptor internalization, and ligand-stimulated intracellular cAMP accumulation. Several positions in the ECL3s of GCGR and GLP-1R were identified that tolerate SphK mutagenesis and subsequent bioorthogonal labeling. The generation of functional, fluorescently labeled ECL3 mutants of GCGR and GLP-1R should allow biophysical studies of conformation dynamics of this important class of GPCRs in their native environment in live cells. PMID- 28876927 TI - Attenuation of Antioxidant Capacity in Human Breast Cancer Cells by Carbon Monoxide through Inhibition of Cystathionine beta-Synthase Activity: Implications in Chemotherapeutic Drug Sensitivity. AB - Drug resistance is a major impediment to effective treatment of breast cancer. Compared to normal cells, cancer cells have an increased antioxidant potential due to an increased ratio of reduced to oxidized glutathione (GSH/GSSG). This is known to confer therapeutic resistance. Here, we have identified a mechanism, unique to breast cancer cells, whereby cystathionine beta-synthase (CBS) promotes elevated GSH/GSSG. Lentiviral silencing of CBS in human breast cancer cells attenuated GSH/GSSG, total GSH, nuclear factor erythroid 2-related factor 2 (Nrf2), and processes downstream of Nrf2 that promote GSH synthesis and regeneration of GSH from GSSG. Carbon monoxide (CO) reduced GSH/GSSG in three breast cancer cell lines by inhibiting CBS. Furthermore, CO sensitized breast cancer cells to doxorubicin. These results provide insight into mechanism(s) by which CBS increases the antioxidant potential and the ability for CO to inhibit CBS activity to alter redox homeostasis in breast cancer, increasing sensitivity to a chemotherapeutic. PMID- 28876928 TI - MD Simulations of Viruslike Particles with Supra CG Solvation Affordable to Desktop Computers. AB - Viruses are tremendously efficient molecular devices that optimize the packing of genetic material using a minimalistic number of proteins to form a capsid or envelope that protects them from external threats, being also part of cell recognition, fusion, and budding machineries. Progress in experimental techniques has provided a large number of high-resolution structures of viruses and viruslike particles (VLP), while molecular dynamics simulations may furnish lively and complementary insights on the fundamental forces ruling viral assembly, stability, and dynamics. However, the large size and complexity of these macromolecular assemblies pose significant computational challenges. Alternatively, Coarse-Grained (CG) methods, which resign atomistic resolution privileging computational efficiency, can be used to characterize the dynamics of VLPs. Still, the massive amount of solvent present in empty capsids or envelopes suggests that hybrid schemes keeping a higher resolution on regions of interest (i.e., the viral proteins and their surroundings) and a progressively coarser description on the bulk may further improve efficiency. Here we introduce a mesoscale explicit water model to be used in double- or triple-scale simulations in combination with popular atomistic parameters and the CG water used by the SIRAH force field. Simulations performed on VLPs of different sizes, along with a comprehensive analysis of the PDB, indicate that most of the VLPs so far reported are amenable to be handled on a GPU-accelerated desktop computer using this simulation scheme. PMID- 28876929 TI - Solvent Dependence of Double Proton Transfer in the Formic Acid-Formamidine Complex: Path Integral Molecular Dynamics Investigation. AB - Solvent dependence of double proton transfer in the formic acid-formamidine (FA FN) complex at room temperature was investigated by means of ab initio path integral molecular dynamics (AIPIMD) simulation with taking nuclear quantum and thermal effects into account. The conductor-like screening model (COSMO) was applied for solvent effect. In comparison with gas phase, double proton delocalization between two heavy atoms (O and N) in FA-FN were observed with reduced proton transfer barrier height in low dielectric constant medium (<4.8). For dielectric constant medium at 4.8, the chance of finding these two protons are more pronounced due to the solvent effect which completely washes out the proton transfer barrier. In the case of higher dielectric constant medium (>4.8), the ionic species becomes more stable than the neutral ones and the formate anion and formamidium cation are thermodynamically stable. For ab initio molecular dynamics simulation, in low dielectric constant medium (<4.8) a reduction of proton transfer barrier with solvent effect is found to be less pronounced than the AIPIMD due to the absence of nuclear quantum effect. Moreover, the motions of FA-FN complex are significantly different with increasing dielectric constant medium. Such a difference is revealed in detail by the principal component analysis. PMID- 28876930 TI - Effects of Optical Purity and Finite System Size on Self-Assembly of 12 Hydroxystearic Acid in Hexane: Molecular Dynamics Simulations. AB - 12-Hydroxystearic acid (12HSA) and its derivatives are well-known organogelators, and they play critical roles in a variety of applications. The overall aggregate structure of 12HSA is sensitive to the chirality at the 12th carbon, but a fundamental understanding of this dependence is lacking. In this study, molecular dynamics simulations were conducted on microsecond long time scales for (1) (R) 12HSA, (2) (S)-12HSA, and (3) a 50/50 racemic mixture, each solvated at 12.5 wt % in explicit hexane. Self-assembly was accelerated by turning off alkyl chain dihedral gauche states and forcing the molecules to adopt an all-trans conformation. The stability of the resulting aggregates was tested by quenching them with access to gauche states restored. Ordered aggregates produced from optically pure (R)- and (S)-12HSA remained stable for at least 1 MUs. The characteristic ordered structure observed is termed a "ring-of-rings" motif, and it contains two twisted six-membered ringlike bundles connected through acetic acid dimerization and surrounded by six satellite bundles. The chirality at the 12th carbon dictates the overall twist of the rings and thereby the handedness of the aggregates. Racemic mixtures did not produce stable ordered aggregates likely due to insufficient enantiomerically pure ring formation. The most prevalent finite-size effect observed was the stochastic formation of percolating aggregates, which were later avoided by using solvent-permeable, solute impermeable, confining walls. The resulting ordered aggregates were in all important ways identical to those produced in unconfined systems. The combination of cycling off and on gauche states and the semipermeable walls may be an important new way to study the self-assembly underlying aggregation at industrially relevant concentrations of surfactants in organic solvents. PMID- 28876931 TI - Medium-Range Structural Organization of Phosphorus-Bearing Borosilicate Glasses Revealed by Advanced Solid-State NMR Experiments and MD Simulations: Consequences of B/Si Substitutions. AB - The short and intermediate range structures of a large series of bioactive borophosphosilicate (BPS) glasses were probed by solid-state nuclear magnetic resonance (NMR) spectroscopy and atomistic molecular dynamics (MD) simulations. Two BPS glass series were designed by gradually substituting SiO2 by B2O3 in the respective phosphosilicate base compositions 24.1Na2O-23.3CaO-48.6SiO2-4.0P2O5 ("S49") and 24.6Na2O-26.7CaO-46.1SiO2-2.6P2O5 ("S46"), the latter constituting the "45S5 Bioglass" utilized for bone grafting applications. The BPS glass networks are built by interconnected SiO4, BO4, and BO3 moieties, whereas P exists mainly as orthophosphate anions, except for a minor network-associated portion involving P-O-Si and P-O-B[4] motifs, whose populations were estimated by heteronuclear 31P{11B} NMR experimentation. The high Na+/Ca2+ contents give fragmented glass networks with large amounts of nonbridging oxygen (NBO) anions. The MD-generated glass models reveal an increasing propensity for NBO accommodation among the network units according to BO4 < SiO4 < BO3 ? PO4. The BO4/BO3 intermixing was examined by double-quantum-single-quantum correlation 11B NMR experiments, which evidenced the presence of all three BO3-BO3, BO3-BO4, and BO4-BO4 connectivities, with B[3]-O-B[4] bridges dominating. Notwithstanding that B[4]-O-B[4] linkages are disfavored, both NMR spectroscopy and MD simulations established their presence in these modifier-rich BPS glasses, along with non negligible B[4]-NBO contacts, at odds with the conventional structural view of borosilicate glasses. We discuss the relative propensities for intermixing of the Si/B/P network formers. Despite the absence of pronounced preferences for Si-O-Si bond formation, the glass models manifest subtle subnanometer-sized structural inhomogeneities, where SiO4 tetrahedra tend to self-associate into small chain/ring motifs embedded in BO3/BO4-dominated domains. PMID- 28876932 TI - alpha-Alkylidene-gamma-butyrolactone Formation via Bi(OTf)3-Catalyzed, Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols: Understanding Substituent Effects and Predicting E/Z Selectivity. AB - A Bi(OTf)3-catalyzed ring-opening cyclization of (hetero)aryl cyclopropyl carbinols to form alpha-alkylidene-gamma-butyrolactones (ABLs) is reported. This transformation represents different chemoselectivity from previous reports that demonstrated formation of (hetero)aryl-fused cyclohexa-1,3-dienes upon acid promoted cyclopropyl carbinol ring opening. ABLs are obtained in up to 89% yield with a general preference for the E-isomers. Mechanistically, Bi(OTf)3 serves as a stable and easy to handle precursor to TfOH. TfOH then catalyzes the formation of cyclopropyl carbinyl cations, which undergo ring opening, intramolecular trapping by the neighboring ester group, subsequent hydrolysis, and loss of methanol resulting in the formation of the ABLs. The nature and relative positioning of the substituents on both the carbinol and the cyclopropane determine both chemo- and stereoselective outcomes. Carbinol substituents determine the extent of cyclopropyl carbinyl cation formation. The cyclopropane donor substituents determine the overall reaction chemoselectivity. Weakly stabilizing or electron-poor donor groups provide better yields of the ABL products. In contrast, copious amounts of competing products are observed with highly stabilizing cyclopropane donor substituents. Finally, a predictive model for E/Z selectivity was developed using DFT calculations. PMID- 28876933 TI - Namalides B and C and Spumigins K-N from the Cultured Freshwater Cyanobacterium Sphaerospermopsis torques-reginae. AB - Chemical investigations of the terrestrial cyanobacterium Sphaerospermopsis torques-reginae ITEP-024 from northern Brazil afforded namalides B (1) and C (2), the first analogues of this anabaenopeptide-like metabolite to be described. Four other related peptides (3-6), termed spumigins K-N, were also identified. Planar structures and absolute configurations for 1, 2, and 3a-6a were deduced by a combination of 2D NMR, HRMS analysis, and Marfey's methodology. Spumigins K-N (3 6) are the first examples of spumigins containing a 2-hydroxy-4-(4 hydroxyphenyl)butanoic acid (Hhpba) in the N-terminal position. Compounds 1 and 2 inhibited carboxypeptidase A with IC50 values of 0.75 and 2.0 MUM, respectively. PMID- 28876934 TI - "Rigid" Luminescent Soft Materials: Europium-Containing Lyotropic Liquid Crystals Based on Polyoxyethylene Phytosterols and Ionic Liquids. AB - Soft materials of europium beta-diketonate complexes constructed in lyotropic liquid crystals (LLCs) mediated by ionic liquids (ILs) are impressive for their excellent luminescence performance and stability. For the aim to further improve their mechanical processability and luminescent tunablility, the polyoxyethylene phytosterols (BPS-n) were introduced here as structure directing agents to prepare relatively "rigid" lamellar luminescent LLCs in 1-butyl-3-methyl imidazolium hexafluorophosphate by doping europium beta-diketonate complexes with different imidazolium counterions. As a result of the solvophobic sterol ring structure of BPS-n, the more effective isolation and confinement effects of europium complexes could be achieved. The longest fluorescence lifetime and the highest quantum efficiency reported so far for europium containing lyotropic organized soft materials were thus obtained. Changing the molecular structures of BPS-n with different oxyethylene chains or doped complexes with imidazolium counterions of different alkyl chain lengths, the spacings of lamellar LLC matrixes and position of dispersed complexes became tunable. The measured luminescent and rheological properties for such composite LLCs showed a dependence on the rigidity and isolation capability afforded by sterol molecules. It was also found that the increase of counterion alkyl chain length would weaken the LLC matrix's confinement and isolation effects and therefore exhibit the deteriorated luminescence performance. The enhanced luminescence efficiency and stability of doped BPS-n LLCs reflected the excellent segregation of europium complexes from each other and therefore the reduced self-quenching process. The obtained results here present the designability of LLC matrixes and their great potential to promote achieving the luminescence tunability of soft materials. PMID- 28876935 TI - Zerovalent Selenium Adsorption Mechanisms on CaO Surface: DFT Calculation and Experimental Study. AB - Zerovalent Se (Se atom and small Se2 molecule) adsorption mechanisms on a CaO surface were studied by both density functional theory (DFT) calculations and adsorption experiments. Nonvalent Se adsorption on the CaO(001) surface was simulated using a slab model. The adsorption energy, adsorption structure, electron density clouds, and electron properties were calculated. Different Se surface coverages were investigated to elucidate the adsorption process. In the experiments, the Se adsorption products were prepared in a U-shaped quartz reactor at 300 degrees C. The properties were investigated by X-ray photoelectron spectroscopy (XPS), inductively coupled plasma atomic emission spectroscopy (ICP-AES), field emission scanning electron microscopy/energy dispersive X-ray spectroscopy (FE-SEM/EDS), and X-ray diffraction (XRD), respectively. The experimental results match up with the DFT results, which reveal fundamental monochemisorption mechanisms of zerovalent Se on the CaO surface. PMID- 28876936 TI - Influence of Endo- and Exocyclic Heteroatoms on Stabilities and 1,3-Dipolar Cycloaddition Reactivities of Mesoionic Azomethine Ylides and Imines. AB - The geometries, stabilities, and 1,3-dipolar cycloaddition reactivities of 24 mesoionic azomethine ylides and imines were investigated using density functional theory calculations at the M06-2X/6-311+G-(d,p)/M06-2X/6-31G-(d) level. The computed structures highlight how the commonly used "aromatic" resonance form should be replaced by two more accurate resonance structures. Stabilities of the dipoles were assessed by various homodesmotic schemes and are consistent with these compounds being nonaromatic. The activation free energies with ethylene or acetylene range from 11.8 to 36.6 kcal/mol. Within each dipole type, the predicted cycloaddition reactivities correlate with the reaction energies and the resonance stabilization energies provided by the various substituents. Endocyclic (X) heteroatoms increase the reactivity of the 1,3-dipoles in the order of O > NH ? S, whereas exocyclic (Y) substituents increase it in the order of CH2 > NH > O > S. Distortion/interaction analysis indicated that the difference in reactivity between differently substituted 1,3-dipoles is driven by distortion, whereas the difference between azomethine ylides and imines is related to lower interaction energies of imines with the dipolarophiles. PMID- 28876937 TI - Construction of Functionalized Annulated Sulfone via SO2/I Exchange of Cyclic Diaryliodonium Salts. AB - A straightforward protocol for diarylannulated sulfone construction is efficiently established via SO2/I exchange of iodonium(III) salts. Readily available inorganic Na2S2O5 was served as a safe and convenient SO2 surrogate. Diverse functionalized diarylannulated sulfones were smoothly achieved in good to excellent yields with great functional group compatibility. Organic light emitting diodes (OLEDs) material molecules were subsequently established via this method in gram scale. The unsymmetrical conjugated systems with donor-acceptor groups and pi-conjugation bridges motifs, which substantially communicate electron mobility in semiconductor material molecules, were successfully afforded under the facile conditions of the exchange strategy. PMID- 28876939 TI - Seamless Staircase Electrical Contact to Semiconducting Graphene Nanoribbons. AB - Electrical contact to low-dimensional (low-D) materials is a key to their electronic applications. Traditional metal contacts to low-D semiconductors typically create gap states that can pin the Fermi level (EF). However, low-D metals possessing a limited density of states at EF can enable gate-tunable work functions and contact barriers. Moreover, a seamless contact with native bonds at the interface, without localized interfacial states, can serve as an optimal electrode. To realize such a seamless contact, one needs to develop atomically precise heterojunctions from the atom up. Here, we demonstrate an all-carbon staircase contact to ultranarrow armchair graphene nanoribbons (aGNRs). The coherent heterostructures of width-variable aGNRs, consisting of 7, 14, 21, and up to 56 carbon atoms across the width, are synthesized by a surface-assisted self-assembly process with a single molecular precursor. The aGNRs exhibit characteristic vibrational modes in Raman spectroscopy. A combined scanning tunneling microscopy and density functional theory study reveals the native covalent-bond nature and quasi-metallic contact characteristics of the interfaces. Our electronic measurements of such seamless GNR staircase constitute a promising first step toward making low resistance contacts. PMID- 28876940 TI - Structure and Mechanism Revision of a Catalyzed Cyclization of Benzaldehyde Bearing Alkyne-Nitrile. AB - Pt(II)-catalyzed carbocyclization of benzaldehyde containing a keto-nitrile functionality resulted in the formation, respectively, of isochromenes and spiro lactones instead of fused lactams and spiro-lactams as was previously reported. The reaction mechanism was proposed, and the products were identified by multidimensional NMR, IR, and X-ray analysis. The structure of these new products was also confirmed by their synthesis in an unambiguous manner using practical and short approaches. PMID- 28876938 TI - Lessons from the Hamster: Cricetulus griseus Tissue and CHO Cell Line Proteome Comparison. AB - Chinese hamster ovary cells represent the dominant host for therapeutic recombinant protein production. However, few large-scale data sets have been generated to characterize this host organism and derived CHO cell lines at the proteomics level. Consequently, an extensive label-free quantitative proteomics analysis of two cell lines (CHO-S and CHO DG44) and two Chinese hamster tissues (liver and ovary) was used to identify a total of 11 801 unique proteins containing at least two unique peptides. 9359 unique proteins were identified specifically in the cell lines, representing a 56% increase over previous work. Additionally, 6663 unique proteins were identified across liver and ovary tissues, providing the first Chinese hamster tissue proteome. Protein expression was more conserved within cell lines during both growth phases than across cell lines, suggesting large genetic differences across cell lines. Overall, both gene ontology and KEGG pathway analysis revealed enrichment of cell-cycle activity in cells. In contrast, upregulated molecular functions in tissue include glycosylation and lipid transporter activity. Furthermore, cellular components including Golgi apparatus are upregulated in both tissues. In conclusion, this large-scale proteomics analysis enables us to delineate specific changes between tissues and cells derived from these tissues, which can help explain specific tissue function and the adaptations cells incur for applications in biopharmaceutical productions. PMID- 28876941 TI - An Ultrathin Single Crystalline Relaxor Ferroelectric Integrated on a High Mobility Semiconductor. AB - The epitaxial growth of multifunctional oxides on semiconductors has opened a pathway to introduce new functionalities to semiconductor device technologies. In particular, the integration of gate materials that enable nonvolatile or hysteretic functionality in field-effect transistors could lead to device technologies that consume less power or allow for novel modalities in computing. Here we present electrical characterization of ultrathin single crystalline SrZrxTi1-xO3 (x = 0.7) films epitaxially grown on a high mobility semiconductor, Ge. Epitaxial films of SrZrxTi1-xO3 exhibit relaxor behavior, characterized by a hysteretic polarization that can modulate the surface potential of Ge. We find that gate layers as thin as 5 nm corresponding to an equivalent-oxide thickness of just 1.0 nm exhibit a ~2 V hysteretic window in the capacitance-voltage characteristics. The development of hysteretic metal-oxide-semiconductor capacitors with nanoscale gate thicknesses opens new vistas for nanoelectronic devices. PMID- 28876942 TI - Pd-Catalyzed Regio- and Stereoselective C-Nucleoside Synthesis from Unactivated Uracils and Pyranoid Glycals. AB - Pd-catalyzed regio- and stereoselective C-nucleoside synthesis from pyranoid glycals and unactivated N,N-dialkyluracils is described. Depending upon the reaction conditions, either beta-hydride or beta-heteroatom eliminated C nucleosides were obtained exclusively. Different glycals with various protecting groups reacted smoothly. Mechanistically, uracil first undergoes electrophilic palladation regioselectively at the C-5 position to generate the active organopalladium species, which then attacks the glycal in a regio- and stereoselective mode to generate C-nucleosides. The method obviates the use of heavy metals such as mercury or preactivation of protected uracils, making it an attractive strategy for C-nucleoside synthesis. PMID- 28876943 TI - Improving the Performance of Graphene Phototransistors Using a Heterostructure as the Light-Absorbing Layer. AB - Interfacing light-sensitive semiconductors with graphene can afford high-gain phototransistors by the multiplication effect of carriers in the semiconductor layer. So far, most devices consist of one semiconductor light-absorbing layer, where the lack of internal built-in field can strongly reduce the quantum efficiency and bandwidth. Here, we demonstrate a much improved graphene phototransistor performances using an epitaxial organic heterostructure composed of perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) and pentacene as the light-absorbing layer. Compared with single light-absorbing material, the responsivity and response time can be simultaneously improved by 1 and 2 orders of magnitude over a broad band of 400-700 nm, under otherwise the same experimental conditions. As a result, the external quantum efficiency increases by over 800 times. Furthermore, the response time of the heterostructured phototransistor is highly gate-tunable down to sub-30 MUs, which is among the fastest in the sensitized graphene phototransistors interfacing with electrically passive light-absorbing semiconductors. We show that the improvement is dominated by the efficient electron-hole pair dissociation due to interfacial built-in field rather than bulk absorption. The structure demonstrated here can be extended to many other organic and inorganic semiconductors, which opens new possibilities for high-performance graphene-based optoelectronics. PMID- 28876944 TI - Polycyclic Azetidines and Pyrrolidines via Palladium-Catalyzed Intramolecular Amination of Unactivated C(sp3)-H Bonds. AB - A novel strategy to construct complex polycyclic nitrogen-containing heterocycles from aliphatic amines via picolinamide-assisted palladium-catalyzed C-H bond activation reaction was reported. The reaction exhibits broad substrate scope for the synthesis of various azabicyclic scaffolds, including azetidines and tropane class alkaloids. Application of this method to naturally occurring (-)-cis myrtanylamine, an unprecedented type of carbon-carbon bond activation, in which the electron-pair involved initiates an intramolecular "SN2-like" displacement of a cyclopalladium-fragment from a tertiary center, is described. PMID- 28876945 TI - Enantioselective Decarboxylative alpha-Alkynylation of beta-Ketocarbonyls via a Catalytic alpha-Imino Radical Intermediate. AB - A distinctive aminocatalysis via alpha-imino radical is reported on the basis of SET oxidation of a secondary enamine. The combination of chiral primary amine catalysis and visible-light photoredox catalysis enables the enantioselective decarboxylative coupling of propiolic acid and beta-ketocarbonyls to afford alkynylation adducts with high enantioselectivity. Mechanism studies indicate the reaction proceeds via an alpha-imino radical addition. PMID- 28876946 TI - Defects Slow Down Nonradiative Electron-Hole Recombination in TiS3 Nanoribbons: A Time-Domain Ab Initio Study. AB - Layered TiS3 materials hold appealing potential in photovoltaics and optoelectronics due to their excellent electronic and optical properties. Using time domain density functional theory combined with nonadiabatic (NA) molecular dynamics, we show that the electron-hole recombination in pristine TiS3 nanoribbons (NRs) occurs in tens of picoseconds and is over 10-fold faster than the experimental value. By performing an atomistic ab initio simulation with a sulfur vacancy, we demonstrate that a sulfur vacancy greatly reduces electron hole recombination, achieving good agreement with experiment. Introduction of a sulfur vacancy increases the band gap slightly because the NR's highest occupied molecular orbital is lowered in energy. More importantly, the sulfur vacancy partially diminishes the electron and hole wave functions' overlap and reduces NA electron-phonon coupling, which competes successfully with the longer decoherence time, slowing down recombination. Our study suggests that a rational choice of defects can control nonradiative electron-hole recombination in TiS3 NRs and provides mechanistic principles for photovoltaic and optoelectronic device design. PMID- 28876947 TI - Integrin-Assisted T-Cell Activation on Nanostructured Hydrogels. AB - Adoptive cell therapy (ACT) has shown very promising results as treatment for cancer in a few clinical trials, such as the complete remissions of otherwise terminal leukemia patients. Nevertheless, the introduction of ACT into clinics requires overcoming not only medical but also technical challenges, such as the ex vivo expansion of large amounts of specific T-cells. Nanostructured surfaces represent a novel T-cell stimulation technique that enables us to fine-tune the density and orientation of activating molecules presented to the cells. In this work, we studied the influence of integrin-mediated cell-adhesion on T-cell activation, proliferation, and differentiation using nanostructured surfaces, which provide a well-defined system at the nanoscale compared with standard cultures. Specifically, we synthesized a polymeric polyethylene glycol (PEG) hydrogel cross-linked with two fibronectin-derived peptides, cyclic Arg-Gly-Asp (cRGD) and cyclic Leu-Asp-Val (cLDV), that are known to activate different integrins. Moreover, the hydrogels were decorated with a quasi-hexagonal array of gold nanoparticles (AuNPs) functionalized with the activating antibody CD3 to initiate T-cell activation. Both cLDV and cRGD hydrogels showed higher T-cell activation (CD69 expression and IL-2 secretion) than nonfunctionalized PEG hydrogels. However, only the cRGD hydrogels clearly supported proliferation giving a higher proportion of cells with memory (CD4+CD45RO+) than naive (CD4+CD45RA+) phenotypes when interparticle distances smaller than 150 nm were used. Thus, T-cell proliferation can be enhanced by the activation of integrins through the RGD sequence. PMID- 28876948 TI - Thioamide, a Hydrogen Bond Acceptor in Proteins and Nucleic Acids. AB - Thioamides are used as potential surrogates of amides to study the structure and dynamics of proteins and nucleic acids. However, incorporation of thioamides in biomolecules leads to changes in their structures and conformations mostly attributed to the strength of the amide-N-H...S?C hydrogen bond. In most cases, it is considered weak owing to the small electronegativity of sulfur, and in some cases, it is as strong as conventional H-bonds. Herein, adopting PDB structure analysis, NMR spectroscopy, and quantum chemistry calculations, we have shown that thioamides in a geometrical and structural constraint-free environment are capable of forming strong H-bonds like their amide counterparts. These studies also enabled us to determine the amide-N-H...S?C H-bond enthalpy (DeltaH) very precisely. The estimated DeltaH for the amide-N-H...S?C H-bond is ~-30 kJ/mol, which suggests that the amide-N-H...S?C H-bond is a strong H-bond and merits its inclusion in computational force fields for biomolecular structure simulations to explore the role of amide-N-H...S?C H-bonds in nucleobase pairing and protein folding. PMID- 28876949 TI - Combination of Lewis Basic Selenium Catalysis and Redox Selenium Chemistry: Synthesis of Trifluoromethylthiolated Tertiary Alcohols with Alkenes. AB - A new and efficient method for diaryl selenide catalyzed vicinal CF3S hydroxylation of 1,1-multisubstitued alkenes has been developed. Various trifluoromethylthiolated tertiary alcohols could be readily synthesized under mild conditions. This method is also effective for the intramolecular cyclization of alkenes tethered by carboxylic acid, hydroxy, sulfamide, or ester groups and is associated with the introduction of a CF3S group. Mechanistic studies have revealed that the pathway involves a redox cycle between Se(II) and Se(IV) and Lewis basic selenium catalysis. PMID- 28876950 TI - Oxidative Transformation of a Tetrathia S-Confused Isophlorin into Porphyrin Cation. AB - The synthesis and redox properties of first generation S-confused isophlorins are described. Despite structural resemblance to a confused porphyrin, spectroscopic and computational studies reveal weak paratropic ring current effects in these 20pi macrocycles. They display redox properties atypical of parent tetrathia isophlorins. Experimental evidence supports the oxidation of an unstable 19pi neutral radical, as a transient intermediate, for the formation of a unique 18pi aromatic monocationic species. Spectroscopic and structural characterization revealed the substituent dependent macrocycle oxidation unfamiliar to the chemistry of antiaromatic isophlorinoids. PMID- 28876951 TI - Enantioselective Synthesis of 1,2-Diamines Containing Tertiary and Quaternary Centers through Rhodium-Catalyzed DYKAT of Racemic Allylic Trichloroacetimidates. AB - The amination of racemic secondary and tertiary allylic trichloroacetimidates possessing beta-nitrogen substituents and proximal nitrogen-containing heterocycles, via chiral diene-ligated rhodium-catalyzed dynamic kinetic asymmetric transformations (DYKAT), provides branched allylic 1,2-diamines with high enantioselectivity. The catalytic system can be applied to the synthesis of 1,2-diamines possessing two contiguous stereocenters with excellent diastereoselectivity. Furthermore, the nitrogen-containing heterocycles suppress competing vinyl azirdine formation, allowing for the high enantioselective syntheses of 1,2-diamines possessing tertiary and quaternary centers. PMID- 28876952 TI - Azidofluoroalkylation of Alkenes with Simple Fluoroalkyl Iodides Enabled by Photoredox Catalysis. AB - A mild and efficient protocol for photoredox-catalyzed azidofluoroalkylation of simple alkenes is described with readily available fluoroalkyl iodides. This method allows for a direct and regioselective formation of C-RF and C-N3 bonds from the C?C moiety. A variety of fluoroalkyl groups including the CF3 group can be selectively introduced to olefins to afford a series of beta-fluoroalkylated azides. PMID- 28876953 TI - Visible-Light Photoredox Catalyzed Oxidative/Reductive Cyclization Reaction of N Cyanamide Alkenes for the Synthesis of Sulfonated Quinazolinones. AB - An efficient photocatalytic oxidative/reductive cyclization reaction of N cyanamide alkenes with arylsulfinic acids or arylsulfonyl chlorides, which proceeds through C-S, C-C, and C-N bond formations, is reported. This photocatalytic reaction was carried out under mild conditions, which provides a new strategy for the synthesis of sulfonated quinazolinones. Furthermore, a one pot procedure to achieve terminal alkenes has been explored via elimination of the obtained sulfonated quinazolinones under basic conditions. PMID- 28876954 TI - Base-Controlled Reactions through an Aldol Intermediate Formed between 2 Oxoaldehydes and Malonate Half Esters. AB - A practical, atom-economical, base-directed, and highly efficient method for the generation of different selective products through a common aldol intermediate of 2-oxoaldehydes and malonate half esters is successfully developed. The addition of a strong basic environment (potassium tert-butoxide) catalyzed the synthesis of stable decarboxylative aldol products (alpha-hydroxy ketones), while the Doebner modification procedure resulted in decarboxylative elimination to (E) alpha,beta-unsaturated esters in good yields. The application of this method in one pot and one pot/two steps with azoles helped to develop regioselective alpha- and beta-azolated products in appreciable yields. PMID- 28876955 TI - Synthesis of Geminal Azido-Halo Compounds and alpha-Azidoalkyl Esters from Aldehydes via alpha-Azido Alcohols. AB - alpha-Azido alcohols are generated by treating aldehydes with hydrazoic acid in chloroform. These adducts are transformed into geminal azido-halo compounds through the reaction with phosphorus trichloride or phosphorus tribromide, whereas alpha-azidoalkyl esters are isolated after interaction with acyl chlorides. PMID- 28876956 TI - Pd-Catalyzed Thiophene-Aryl Coupling Reaction via C-H Bond Activation in Deep Eutectic Solvents. AB - Direct arylation of 5-octylthieno[3,4-c]pyrrole-4,6-dione with a series of functionalized aryl iodides via C-H bond activation is demonstrated in a deep eutectic solvent made of choline chloride and urea in non-anhydrous conditions and without exclusion of air. This is the first demonstration of a thiophene-aryl coupling via direct arylation in deep eutectic solvents. PMID- 28876957 TI - 2D THz-THz-Raman Photon-Echo Spectroscopy of Molecular Vibrations in Liquid Bromoform. AB - Fundamental properties of molecular liquids are governed by long-range interactions that most prominently manifest at terahertz (THz) frequencies. Here we report the detection of nonlinear THz photon-echo (rephasing) signals in liquid bromoform using THz-THz-Raman spectroscopy. Together, the many observed signatures span frequencies from 0.5 to 8.5 THz and result from couplings between thermally populated ladders of vibrational states. The strongest peaks in the spectrum are found to be multiquantum dipole and 1-quantum polarizability transitions and may arise from nonlinearities in the intramolecular dipole moment surface driven by intermolecular interactions. PMID- 28876958 TI - Directional Growth of DNA-Functionalized Nanorods to Enable Continuous, Site Specific Metallization of DNA Origami Templates. AB - This work examines the anisotropic electroless plating of DNA-functionalized gold nanorods attached to a DNA origami template to fabricate continuous metal structures of rectanglar, square, and T shapes. DNA origami, a versatile method for assembling a variety of 2- and 3-D nanostructures, is utilized to construct the DNA breadboard template used for this study. Staple strands on selective sites of the breadboard template are extended with an additional nucleotide sequence for the attachment of DNA-functionalized gold nanorods to the template via base pairing. The nanorod-seeded DNA templates are then introduced into an electroless gold plating solution to determine the extent to which the anisotropic growth of the nanorods is able to fill the gaps between seeds to create continuous structures. Our results show that the DNA-functionalized nanorods grow anisotropically during plating at a rate that is approximately 4 times faster in the length direction than in the width direction to effectively fill gaps of up to 11-13 nm in length. The feasibility of using this directional growth at specific sites to enable the fabrication of continuous metal nanostructures with diameters as thin as 10 nm is demonstrated and represents important progress toward the creation of devices and systems based on self assembled biological templates. PMID- 28876959 TI - Chirality and neuropsychiatric drugs: an update on stereoselective disposition and clinical pharmacokinetics of bupropion. AB - 1. Bupropion, an antidepressant drug has been approved as a racemate containing equal amounts of R- and S-enantiomers. Recently, the chirality of bupropion has received significant attention in the delineation of stereoselective pharmacokinetic (PK) and disposition data. Although the non-stereoselective metabolism of bupropion was well established, the emerging data suggest that bupropion exhibits complex stereoselective metabolism, leading to the formation of various stereoisomeric metabolites. Along with the chiral PKs of bupropion, hydroxybupropion, threohydrobupropion and erythrohydrobupropion, the metabolism data also provided insights into the roles of both CYP2B6 and CYP2C19 enzymes in the stereoselective disposition. Furthermore, the metabolism studies also suggested specific involvement of CYP2B6 pathway in the stereoselective hydroxylation of bupropion to R,R-hydroxybupropion, which was considered as a better marker for CYP2B6 activity. 2. Other significant learnings were: (1) understanding the in vivo CYP2D6 inhibitory potential of bupropion with respect to the chirality of parent drug and the metabolites; (2) the potential involvement of bupropion and metabolites towards significant down regulation of CYP2D6 mRNA; (3) significant in vivo CYP2D6 inhibitory activity (86%) exhibited by R,R-hydroxybupropion and threohydrobupropion. 3. The newly published data on chiral PKs and disposition of bupropion and its metabolites can be used to gauge the drug-drug interaction potential when bupropion is combined in clinical therapy. Moreover, such data would be useful to understand the consequences (if any), due to the combination of bupropion with other drugs both from a safety and efficacy perspective because of the prevalence of polypharmacy situations in many therapeutic areas including CNS indications. PMID- 28876960 TI - TRPM2: Shredding the mitochondrial network. PMID- 28876962 TI - Gastrointestinal manifestations of primary immune deficiencies in children. AB - Primary immune deficiencies (PID) in children are a rare but serious group of genetic disorders of the immune system which apart from the host's defenses, can also affect every system of the human body, including the gastrointestinal tract. In their severe form they can lead to increased susceptibility to serious infections during infancy and even death. In the less severe form, they can present later in childhood or adolescence with subtle signs and symptoms. As PID can often mimic gastrointestinal diseases, children presenting with atypical gastrointestinal disease and/or failure to respond to conventional therapy should be evaluated for an underlying primary immune disorder and initiated appropriate treatment. The current review of the literature will summarize the gastrointestinal manifestations of primary immune deficiencies in children. PMID- 28876961 TI - Vitamin D Replacement Improves Tear Osmolarity in Patients with Vitamin D Deficiency. AB - BACKGROUND: Vitamin D deficiency is a common health problem worldwide. Many parts of the human eye, including the epithelium of the cornea, lens, ciliary body, and retinal pigment epithelium, as well as the corneal endothelium, ganglion cell layer, and retinal photoreceptors, contain vitamin D receptor (VDR). Dry eye is also a common health problem. An adequate tear film is required for maintaining health and function of the eye. Tear hyperosmolarity is considered to be the cause of ocular surface inflammation, symptoms, and tissue damage. It is well documented that vitamin D has an anti-inflammatory action. We aimed to investigate the effect of vitamin D replacement on tear osmolarity in patients with vitamin D deficiency. METHODS: A total of 44 patients (38 females, six males, mean age:43.5 +/- 12.8 years) with vitamin D deficiency currently managed by the Endocrinology and Metabolism Department of Diskapi Training and Research Hospital in Turkey were enrolled in the study. Patients were given 50,000 units of 25(OH)D3 intramuscularly, once weekly, over a period of eight weeks. All of the patients underwent tear function osmolarity (TFO) measurement initially and eight weeks after vitamin D replacement. Demographic, anthropometric, and biochemistry data of patients were recorded. RESULTS: The mean TFO was significantly decreased (313.7 +/- 17.3 mOsm/L; 302.7 +/- 14.2 mOsm/L, p<0.001) at the end of the second month; 25(OH)D3 concentrations increased from 8.3 +/- 3.5 ng/mL to 68.8 +/- 22.3 ng/mL (p<0.001). The mean levels of hsCRP, FPG, P were 2.5 +/- 2.5 mg/L, 5.09 +/- 0.48 mmol/L, 1.06 +/- 0.16 mmol/L initially, and 3.8 +/- 5.9 mg/L, 5.11 +/- 0.68 mg/dL, 1.09 +/- 0.16 mmol/L after vitamin D replacement, respectively (p>0.05). The mean Ca level was 2.37 +/- 0.07 mmol/L initially and 2.35 +/- 0.07 mmol/L after vitamin D replacement (p<0.05). The change of TFO was negatively correlated with the variation of 25(OH)D3 before and after replacement in patients with dry eye disease (r=-0.390, p=0.049). CONCLUSIONS: As a consequence of the presence of VDR and 1alpha-hydroxylase in different parts of the eye, vitamin D replacement improves tear hyperosmolarity that is considered to be induced by ocular surface inflammation. PMID- 28876963 TI - Candidiasis and the impact of flow cytometry on antifungal drug discovery. AB - INTRODUCTION: Invasive candidiasis continues to be associated with significant morbidity and mortality as well as substantial health care costs nationally and globally. One of the contributing factors is the development of resistance to antifungal agents that are already in clinical use. Moreover, there are known treatment limitations with all of the available antifungal agents. Since traditional techniques in novel drug discovery are time consuming, high throughput screening using flow cytometry presents as a potential tool to identify new antifungal agents that would be useful in the management of these patients. Areas covered: In this review, the authors discuss the use of automated high-throughput screening assays based upon flow cytometry to identify potential antifungals from a library comprised of a large number of bioactive compounds. They also review studies that employed the use of this research methodology that has identified compounds with antifungal activity. Expert opinion: High throughput screening using flow cytometry has substantially decreased the processing time necessary for screening thousands of compounds, and has helped enhance our understanding of fungal pathogenesis. Indeed, the authors see this technology as a powerful tool to help scientists identify new antifungal agents that can be added to the clinician's arsenal in their fight against invasive candidiasis. PMID- 28876964 TI - Flourishing: An Evolutionary Concept Analysis. AB - PURPOSE: Mental health is an important measure of public health (WHO, 2004); however, nursing practice and research continues to prioritize mental illness, rather than well-being (Wand, 2011). Flourishing is a recent concept in the field of well-being. The term has been used sparingly in nursing practice and research, and conceptual clarification is needed to promote comprehensive understanding of the phenomenon. The purpose of this study is to critically analyze flourishing, assess the maturity of the concept, and provide recommendations for future research, education, and practice. METHOD: The concept of flourishing was analyzed using the evolutionary approach to concept analysis (Rodgers, 2000). A search for articles on flourishing within the context of well-being was conducted through CINAHL, MEDLINE, and PsycINFO. A sample of 32 articles and 1 book was reviewed. Data were reviewed for concept attributes, antecedents, consequences, surrogate terms and related concepts. FINDINGS: Four models of flourishing were identified with six overlapping attributes: meaning, positive relationships, engagement, competence, positive emotion, and self-esteem. Limited longitudinal and predictive studies have been conducted, but there is evidence for several antecedents and outcomes of flourishing. Research is ongoing primarily in psychology and sociology and is lacking in other disciplines. DISCUSSION: The concept of flourishing is immature; however, evidence is building for related concepts. A lack of consistent terminology regarding flourishing prevents knowledge development of flourishing as a distinct concept. Further multidisciplinary research is needed to establish standard operational and conceptual definitions and develop effective interventions. PMID- 28876965 TI - Analyzing Decision Logs to Understand Decision Making in Serious Crime Investigations. AB - Objective To study decision making by detectives when investigating serious crime through the examination of decision logs to explore hypothesis generation and evidence selection. Background Decision logs are used to record and justify decisions made during serious crime investigations. The complexity of investigative decision making is well documented, as are the errors associated with miscarriages of justice and inquests. The use of decision logs has not been the subject of an empirical investigation, yet they offer an important window into the nature of investigative decision making in dynamic, time-critical environments. Method A sample of decision logs from British police forces was analyzed qualitatively and quantitatively to explore hypothesis generation and evidence selection by police detectives. Results Analyses revealed diversity in documentation of decisions that did not correlate with case type and identified significant limitations of the decision log approach to supporting investigative decision making. Differences emerged between experienced and less experienced officers' decision log records in exploration of alternative hypotheses, generation of hypotheses, and sources of evidential inquiry opened over phase of investigation. Conclusion The practical use of decision logs is highly constrained by their format and context of use. Despite this, decision log records suggest that experienced detectives display strategic decision making to avoid confirmation and satisficing, which affect less experienced detectives. Application Potential applications of this research include both training in case documentation and the development of new decision log media that encourage detectives, irrespective of experience, to generate multiple hypotheses and optimize the timely selection of evidence to test them. PMID- 28876966 TI - The Effect of Resin Bonding on Long-Term Success of High-Strength Ceramics. AB - Digital manufacturing, all-ceramics, and adhesive dentistry are currently the trendiest topics in clinical restorative dentistry. Tooth- and implant-supported fixed restorations from computer-aided design (CAD)/computer-aided manufacturing (CAM)-fabricated high-strength ceramics-namely, alumina and zirconia-are widely accepted as reliable alternatives to traditional metal-ceramic restorations. Most recent developments have focused on high-translucent monolithic full-contour zirconia restorations, which have become extremely popular in a short period of time, due to physical strength, CAD/CAM fabrication, and low cost. However, questions about proper resin bonding protocols have emerged, as they are critical for clinical success of brittle ceramics and treatment options that rely on adhesive bonds, specifically resin-bonded fixed dental prostheses or partial coverage restorations such as inlays/onlays and veneers. Resin bonding has long been the gold standard for retention and reinforcement of low- to medium-strength silica-based ceramics but requires multiple pretreatment steps of the bonding surfaces, increasing complexity, and technique sensitivity compared to conventional cementation. Here, we critically review and discuss the evidence on resin bonding related to long-term clinical outcomes of tooth- and implant supported high-strength ceramic restorations. Based on a targeted literature search, clinical long-term studies indicate that porcelain-veneered alumina or zirconia full-coverage crowns and fixed dental prostheses have high long-term survival rates when inserted with conventional cements. However, most of the selected studies recommend resin bonding and suggest even greater success with composite resins or self-adhesive resin cements, especially for implant-supported restorations. High-strength ceramic resin-bonded fixed dental prostheses have high long-term clinical success rates, especially when designed as a cantilever with only 1 retainer. Proper pretreatment of the bonding surfaces and application of primers or composite resins that contain special adhesive monomers are necessary. To date, there are no clinical long-term data on resin bonding of partial-coverage high-strength ceramic or monolithic zirconia restorations. PMID- 28876967 TI - Understanding Factors Associated with Singaporean Adolescents' Intention to Adopt Privacy Protection Behavior Using an Extended Theory of Planned Behavior. AB - Using an extended theory of planned behavior (TPB), this study explores how the original TPB variables (attitude, subjective norms, and perceived behavioral control), personality traits, privacy concern, past privacy protection behaviors (PPBs), as well as parental mediation strategies relate to adolescents' intention to engage in privacy protection measures. We administered a cross-sectional survey to a nationally representative sample of adolescents (N = 4,920) in Singapore. The sample comprised 50.5 percent females and 49.5 percent males with age ranging from 13 to 21 years (M = 14.73). Results from the hierarchical regression analysis showed that the proposed extended TPB model received partial support. Subjective norms, among the TPB and other factors, have the strongest relationship with adolescents' intention to engage in PPBs on social network sites. Adolescents' privacy concern and their past PPBs are more important in influencing their future PPB compared with personality traits such as neuroticism and extraversion. Adolescents whose parents have engaged in regulated parental mediation are more likely to protect their privacy on SNSs compared with adolescents whose parents have adopted active mediation style. PMID- 28876968 TI - Corneal Collagen Cross-Linking Complications. AB - Corneal cross-linking was approved by United States Food and Drug Administration for the treatment of progressive keratoconus in April 2016. As this approach becomes more widely used for the treatment of keratoconus and post-laser in situ keratomileusis (LASIK) ectasia, the medical community is becoming more familiar with potential complications associated with this procedure. This article aims to review the reported complications of collagen cross-linking for the treatment of keratoconus and post-LASIK ectasia. PMID- 28876969 TI - Noncognitive Behavioral Changes Associated With Alzheimer's Disease: Implications of Neuroimaging Findings. AB - Alzheimer's disease (AD) is commonly associated with noncognitive behavioral changes (NCBCs). The authors systematically reviewed whether neuroimaging has helped with understanding the pathophysiology, diagnosis, or management of NCBCs associated with AD, including depression, aggression or agitation, anxiety, apathy, psychosis, and sleep disorder. The authors identified dissociable neural substrates with multimodal imaging: depression implicates the lateral and superior prefrontal cortex; apathy and agitation implicate the dorsal anterior cingulate; psychosis implicates right lateralized frontal and medial temporal areas; and anxiety implicates mesial temporal regions. Frontal white matter changes appear to underlie many NCBCs, emphasizing the preventative management of vascular risk factors. Further delineation of underlying neurocircuitry and pathophysiology in larger data sets might lead to biomarker identification for diagnosis and optimizing treatment targets. PMID- 28876970 TI - Responding to Ten Common Delirium Misconceptions With Best Evidence: An Educational Review for Clinicians. AB - Delirium (acute confusion) is a serious, common health condition, and it predicts poor outcomes, including greater rates of mortality, institutionalization, prolonged hospitalization, and cognitive impairment. Expedient diagnosis and management are critical to address modifiable delirium causes and improve both quality of care and outcomes. Moreover, more than a third of delirium is preventable. Despite the clear significance of delirium and our increasingly sophisticated understanding of the condition, the gap between evidence and practice persists. The authors provide an educational review of 10 prevalent misconceptions of delirium pertaining to recognition, etiology, natural history, and best management. The authors respond to each with best evidence. Several themes emerge, chief among which is that casual observation is seldom sufficient to detect delirium. Use of open-ended questions, regular neurocognitive testing, and validated delirium screening instruments will aid in accurately identifying cases of delirium. Delirium is typically multifactorial, with several physiological and/or pharmacological contributors. Because of its multidetermined nature and its relationship with cognitive vulnerability, delirium can persist for days to months after acute causes have resolved. Furthermore, patients often have long-term cognitive impairment after delirium rather than returning to their predelirium cognitive baseline. Finally, nonpharmacological management of delirium is first-line, both for prevention and treatment. Psychotropic drugs such as neuroleptics are not recommended for routine use in delirium. They are best reserved for treating dangerous or distressing symptoms, including severe agitation, psychosis, or emotional lability. Challenging these 10 misconceptions stands to improve patient care, quality of life, and clinical outcomes substantially. PMID- 28876971 TI - SCIENTIFIC PROGRAM OF 35TH WORLD CONGRESS OF ENDOUROLOGY PROGRAM BOOK AND ABSTRACTS. PMID- 28876972 TI - 35TH WORLD CONGRESS OF ENDOUROLOGY COMMITTEES AND AWARDS. PMID- 28876974 TI - Predicting the Trends of Social Events on Chinese Social Media. AB - Growing interest in social events on social media came along with the rapid development of the Internet. Social events that occur in the "real" world can spread on social media (e.g., Sina Weibo) rapidly, which may trigger severe consequences and thus require the government's timely attention and responses. This article proposes to predict the trends of social events on Sina Weibo, which is currently the most popular social media in China. Based on the theories of social psychology and communication sciences, we extract an unprecedented amount of comprehensive and effective features that relate to the trends of social events on Chinese social media, and we construct the trends of prediction models by using three classical regression algorithms. We found that lasso regression performed better with the precision 0.78 and the recall 0.88. The results of our experiments demonstrated the effectiveness of our proposed approach. PMID- 28876977 TI - Patients as Researchers. PMID- 28876976 TI - TRPM4 activation by chemically- and oxygen deprivation-induced ischemia and reperfusion triggers neuronal death. AB - Cerebral ischemia-reperfusion injury triggers a deleterious process ending in neuronal death. This process has two components, a glutamate-dependent and a glutamate-independent mechanism. In the glutamate-independent mechanism, neurons undergo a slow depolarization eventually leading to neuronal death. However, little is known about the molecules that take part in this process. Here we show by using mice cortical neurons in culture and ischemia-reperfusion protocols that TRPM4 is fundamental for the glutamate-independent neuronal damage. Thus, by blocking excitotoxicity, we reveal a slow activating, glibenclamide- and 9 phenanthrol-sensitive current, which is activated within 5 min upon ischemia reperfusion onset. TRPM4 shRNA-based silenced neurons show a reduced ischemia reperfusion induced current and depolarization. Neurons were protected from neuronal death up to 3 hours after the ischemia-reperfusion challenge. The activation of TRPM4 during ischemia-reperfusion injury involves the increase in both, intracellular calcium and H2O2, which may act together to produce a sustained activation of the channel. PMID- 28876975 TI - miR-129-2 mediates down-regulation of progesterone receptor in response to progesterone in breast cancer cells. AB - OBJECTIVE: Hormonal therapy is an important component of first line of treatment for breast cancer. Response to hormonal therapy is influenced by the progesterone receptor (PR)-status of breast cancer patients. However as an early effect, exposure to progesterone decreases expression of PR in breast cancer cells. An understanding of the mechanism underlying down-regulation of PR could help improve response to hormonal therapy. METHODS: We performed small RNA sequencing of breast cancer cells for identification of microRNAs targeting PR in response to progesterone treatment. Biochemical approaches were used to validate the findings in breast cancer cells. RESULTS: Analysis of small RNA sequencing of four breast cancer cell lines treated with progesterone revealed an up-regulation of miR-129-2 independent of the PR status of the cells. We show that miR-129-2 targets 3'UTR of PR to down-regulate its expression. Furthermore, inhibition of miR-129-2 expression rescues the down-regulation of PR in breast cancer cells. Also, the expression levels of miR-129-2 was observed to be elevated in patients with low expression of PR in the TCGA cohort (n = 359). CONCLUSION: miR-129-2 mediates down-regulation of PR in breast cancer cells in response to progesterone, while anti-miR-129-2 could potentiate PR expression levels among patients with inadequate PR levels. Thus, modulation of activity of miR-129-2 could stabilize PR expression and potentially improve response to hormonal therapy under adjuvant or neo-adjuvant settings. PMID- 28876978 TI - Are there superagonists for calcium-activated potassium channels? PMID- 28876979 TI - General anaesthesia for patients with a history of a contrast medium-induced anaphylaxis: a useful prophylaxis? AB - Contrast-enhanced radiological examinations are important diagnostic tools in modern medicine. Currently, all approved and available iodinated and gadolinium based contrast agents are safe and well-tolerated by most patients. However, approximately 2% of patients receiving iodinated contrast media exhibit hypersensitivity reactions. Patients with a history of such a reaction are at increased risk upon reexposure. Therefore, they are subjected to a prophylaxis such as injection of antiallergy drugs or general anaesthesia. The latter procedure is expensive, can burden the patients organism, and besides lacks objective verification. Therefore, the purpose of our review paper is to present and discuss the background and the previous practice, as well as to provide a proposal for a safe individual patient management. PMID- 28876980 TI - The Genetics of Plant Metabolism. AB - Plant metabolic studies have traditionally focused on the role and regulation of the enzymes catalyzing key reactions within specific pathways. Within the past 20 years, reverse genetic approaches have allowed direct determination of the effects of the deficiency, or surplus, of a given protein on the biochemistry of a plant. In parallel, top-down approaches have also been taken, which rely on screening broad, natural genetic diversity for metabolic diversity. Here, we compare and contrast the various strategies that have been adopted to enhance our understanding of the natural diversity of metabolism. We also detail how these approaches have enhanced our understanding of both specific and global aspects of the genetic regulation of metabolism. Finally, we discuss how such approaches are providing important insights into the evolution of plant secondary metabolism. PMID- 28876981 TI - Genetic and Structural Analyses of RRNPP Intercellular Peptide Signaling of Gram Positive Bacteria. AB - Bacteria use diffusible chemical messengers, termed pheromones, to coordinate gene expression and behavior among cells in a community by a process known as quorum sensing. Pheromones of many gram-positive bacteria, such as Bacillus and Streptococcus, are small, linear peptides secreted from cells and subsequently detected by sensory receptors such as those belonging to the large family of RRNPP proteins. These proteins are cytoplasmic pheromone receptors sharing a structurally similar pheromone-binding domain that functions allosterically to regulate receptor activity. X-ray crystal structures of prototypical RRNPP members have provided atomic-level insights into their mechanism and regulation by pheromones. This review provides an overview of RRNPP prototype signaling; describes the structure-function of this protein family, which is spread widely among gram-positive bacteria; and suggests approaches to target RRNPP systems in order to manipulate beneficial and harmful bacterial behaviors. PMID- 28876983 TI - Approaches and Study Skills of Veterinary Medical Students: Effects of a Curricular Revision. AB - The objective of this study was to determine if a revised, recently implemented curriculum, embracing an integrated block design with a focus on student centered, inquiry-based learning, had a different effect on veterinary medical students' approaches to studying than the previous curriculum. A total of 577 students completed a questionnaire consisting of the short version of the Approaches and Study Skills Inventory for Students (ASSIST). It included questions relating to conceptions about learning, approaches to studying, and preferences for different types of courses and teaching. In addition, students were asked to respond to general questions regarding the design of the revised curriculum. The scores for the deep and strategic learning approaches were higher for students studying under the previous curriculum compared to the revised curriculum, despite the fact that the revised curriculum was specifically designed to foster deep learning. The scores for the surface learning approach were lower in the students studying the revised curriculum compared to students studying under the previous curriculum. We identified the following factors affecting student learning: alteration of learning activities, such as problem based learning, from the recommended models; a lack of instructor support for the revised curriculum; assessments that were not aligned to encourage critical thinking; and directed self-learning activities that were too comprehensive to complete in the allotted time. The results of this study can be used to improve the implementation of student-centered and inquiry-based curricula by identifying potential problems that could prevent a deep learning approach in veterinary medical students. PMID- 28876984 TI - Veterinary Curricula Today: Curricular Management and Renewal at AAVMC Member Institutions. AB - Renewing a veterinary curriculum is challenging work and its impact is difficult to measure. Academic leaders are charged with regular review and updating of their curricula, but have few resources available to guide their efforts. Due to the paucity of published veterinary reports, most turn to colleagues at other veterinary schools for insider advice, while a few undertake the task of adapting information from the educational literature to suit the needs of the veterinary profession. In response to this paucity, we proposed a theme issue on curricular renewal and surveyed academic leaders regarding curricular challenges and major renewal efforts underway. We compiled the results of this survey (with respondents from 38 veterinary colleges) as well as publicly available information to create a digest of curricular activities at AAVMC member institutions. This introductory article summarizes the key survey findings, describes the methods used to create the curricular digest, and presents information about key aspects of selected programs. Our overarching research questions were as follows: (1) What was the extent and nature of curricular change at AAVMC-accredited veterinary colleges over the past 5 years? and (2) How are curricula and curricular changes managed at AAVMC accredited veterinary colleges? The appended curricular digests provide selected details of current DVM curricula at participating institutions. Additional articles in this issue report on institutional change efforts in more detail. It is our hope that this issue will help to pave the way for future curricular development, research, and peer to-peer collaboration. PMID- 28876982 TI - Preoperative predicting malignancy in breast mass-like lesions: value of adding histogram analysis of apparent diffusion coefficient maps to dynamic contrast enhanced magnetic resonance imaging for improving confidence level. AB - OBJECTIVE: This study aims to find out the benefits of adding histogram analysis of apparent diffusion coefficient (ADC) maps onto dynamic contrast-enhanced MRI (DCE-MRI) in predicting breast malignancy. METHODS: This study included 95 patients who were found with breast mass-like lesions from January 2014 to March 2016 (47 benign and 48 malignant). These patients were estimated by both DCE-MRI and diffusion-weighted imaging (DWI) and classified into two groups, namely, the benign and the malignant. Between these groups, the DCE-MRI parameters, including morphology, enhancement homogeneity, maximum slope of increase (MSI) and time signal intensity curve (TIC) type, as well as histogram parameters generated from ADC maps were compared. Then, univariate and multivariate logistic regression analyses were conducted to determine the most valuable variables in predicting malignancy. Receiver operating characteristic curve analyses were taken to assess their clinical values. RESULTS: The lesion morphology, MSI and TIC Type (p < 0.05) were significantly different between the two groups. Multivariate logistic regression analyses revealed that irregular morphology, TIC Type II/III and ADC10 were important predictors for breast malignancy. Increased area under curve (AUC) and specificity can be achieved with Model 2 (irregular morphology + TIC Type II/III + ADC10 < 1.047 *10-3 mm2 s-1) as the criterion than Model 1 (irregular morphology + TIC Type II/III) only (Model 2 vs Model 1; AUC, 0.822 vs 0.705; sensitivity, 68.8 vs 75.0%; specificity, 95.7 vs 66.0%). CONCLUSION: Irregular morphology, TIC Type II/III and ADC10 are indicators for predicting breast malignancy. Histogram analysis of ADC maps can provide additional value in predicting breast malignancy. Advances in knowledge: The morphology, MSI and TIC types in DCE-MRI examination have significant difference between the benign and malignant groups. A higher AUC can be achieved by using ADC10 as the diagnostic index than other ADC parameters, and the difference in AUC based on ADC10 and ADCmean was statistically significant. The irregular morphology, TIC Type II/III and ADC10 were significant predictors for malignant lesions. PMID- 28876985 TI - Curriculum Review and Revision at the University of Minnesota College of Veterinary Medicine. AB - Curriculum review is an essential part of ongoing curriculum development, and is a mandate of the American Veterinary Medical Association Council on Education (AVMA COE), the accrediting body of all North American schools and colleges of veterinary medicine. This article describes the steps in curriculum review undertaken by the University of Minnesota College of Veterinary Medicine (UMN CVM) in response to this mandate from the COE and to a recommendation from a recent collegiate review that was part of a larger university-level strategic planning effort. The challenges of reviewing and revising the curriculum within a short time frame were met by appointing a dedicated curriculum review board and by engaging students and faculty groups, both as focus groups and as specific faculty work sections within disciplines. Faculty voting on the process was very valuable as it permitted the curriculum review board and faculty groups to move ahead knowing there was a process in place for reassessment if most faculty did not agree with recommendations. Consistent support from the dean of the college and other administrators was vital in helping maintain momentum for curriculum review. PMID- 28876986 TI - Comparing Tolerance of Ambiguity in Veterinary and Medical Students. AB - Current guidelines suggest that educators in both medical and veterinary professions should do more to ensure that students can tolerate ambiguity. Designing curricula to achieve this requires the ability to measure and understand differences in ambiguity tolerance among and within professional groups. Although scales have been developed to measure tolerance of ambiguity in both medical and veterinary professions, no comparative studies have been reported. We compared the tolerance of ambiguity of medical and veterinary students, hypothesizing that veterinary students would have higher tolerance of ambiguity, given the greater patient diversity and less well-established evidence base underpinning practice. We conducted a secondary analysis of questionnaire data from first- to fourth-year medical and veterinary students. Tolerance of ambiguity scores were calculated and compared using the TAMSAD scale (29 items validated for the medical student population), the TAVS scale (27 items validated for the veterinary student population), and a scale comprising the 22 items common to both scales. Using the TAMSAD and TAVS scales, medical students had a significantly higher mean tolerance of ambiguity score than veterinary students (56.1 vs. 54.1, p<.001 and 60.4 vs. 58.5, p=.002, respectively) but no difference was seen when only the 22 shared items were compared (56.1 vs. 57.2, p=.513). The results do not support our hypothesis and highlight that different findings can result when different tools are used. Medical students may have slightly higher tolerance of ambiguity than veterinary students, although this depends on the scale used. PMID- 28876987 TI - A Novel Approach to Simulation-Based Education for Veterinary Medical Communication Training Over Eight Consecutive Pre-Clinical Quarters. AB - Experiential learning through the use of standardized patients (SPs) is the primary way by which human medical schools teach clinical communication. The profession of veterinary medicine has followed suit in response to new graduates' and their employers' concerns that veterinary interpersonal skills are weak and unsatisfactory. As a result, standardized clients (SCs) are increasingly relied upon as invaluable teaching tools within veterinary curricula to advance relationship-centered care in the context of a clinical scenario. However, there is little to no uniformity in the approach that various colleges of veterinary medicine take when designing simulation-based education (SBE). A further complication is that programs with pre-conceived curricula must now make room for training in clinical communication. Curricular time constraints challenge veterinary colleges to individually decide how best to utilize SCs in what time is available. Because it is a new program, Midwestern University College of Veterinary Medicine (MWU CVM) has had the flexibility and the freedom to prioritize an innovative approach to SBE. The author discusses the SBE that is currently underway at MWU CVM, which incorporates 27 standardized client encounters over eight consecutive pre-clinical quarters. Prior to entering clinical rotations, MWU CVM students are exposed to a variety of simulation formats, species, clients, settings, presenting complaints, and communication tasks. These represent key learning opportunities for students to practice clinical communication, develop self-awareness, and strategize their approach to future clinical experiences. PMID- 28876988 TI - Curricular Review and Renewal at Massey University: A Process to Implement Improved Learning Practices. AB - Curriculum managers of the Bachelor of Veterinary Science program at Massey University have undertaken major curricular review every 5-10 years and also made adjustments to the program as a result of student and other stakeholder feedback. New curricula introduced in 2003 and 2013 aimed to address specific stakeholder requirements in the veterinary, agricultural, and allied industries. The new curricula initially sought to strengthen clinical skills but more recently focused on the core professional skill of client communication, the integration of knowledge and clinical skills, and a better understanding of the effects of herd health interventions on farm economics. The need for greater emphasis on the veterinarian's role in One Health at the intersection of humans, animals, and the environment was also recognized. The most recent curricular review was preceded by faculty enlightenment and discussion about innovative models of medical education with a focus on student-centered and integrated learning. A new curriculum was introduced from 2013 that presented more material in its clinical context, attempted to manage curriculum overload through a focus on Day One Competences, implemented vertical and horizontal integration of subjects, and introduced more problem-based and student-centered learning. Regular reviews of student workload were needed to ensure that the objectives were achieved, but student feedback has generally been positive. PMID- 28876989 TI - The Hidden Curriculum of Veterinary Education: Mediators and Moderators of Its Effects. AB - The "hidden curriculum" has long been supposed to have an effect on students' learning during their clinical education, and in particular in shaping their ideas of what it means to be a professional. Despite this, there has been little evidence linking specific changes in professional attitudes to the individual components of the hidden curriculum. This study aimed to recognize those components that led to a change in students' professional attitudes at a UK veterinary school, as well as to identify the attitudes most affected. Observations were made of 11 student groups across five clinical rotations, followed by semi-structured interviews with 23 students at the end of their rotation experience. Data were combined and analyzed thematically, taking both an inductive and deductive approach. Views about the importance of technical competence and communication skills were promoted as a result of students' interaction with the hidden curriculum, and tensions were revealed in relation to their attitudes toward compassion and empathy, autonomy and responsibility, and lifestyle ethic. The assessment processes of rotations and the clinical service organization served to communicate the messages of the hidden curriculum, bringing about changes in student professional attitudes, while student-selected role models and the student rotation groups moderated the effects of these influences. PMID- 28876990 TI - Curriculum Redesign in Veterinary Medicine: Part I. AB - Curricular review is considered a necessary component for growth and enhancement of academic programs and requires time, energy, creativity, and persistence from both faculty and administration. At Texas A&M College of Veterinary Medicine & Biomedical Sciences (TAMU), the faculty and administration partnered with the university's Center for Teaching Excellence to create a faculty-driven, data enhanced curricular redesign process. The 8-step process begins with the formation of a dedicated faculty curriculum design team to drive the redesign process and to support the college curriculum committee. The next steps include defining graduate outcomes and mapping the current curriculum to identify gaps and redundancies across the curriculum. Data are collected from internal and external stakeholders including veterinary students, faculty, alumni, and employers of graduates. Data collected through curriculum mapping and stakeholder engagement substantiate the curriculum redesign. The guidelines, supporting documents, and 8-step process developed at TAMU are provided to assist other veterinary schools in successful curricular redesign. This is the first of a two part report that provides the background, context, and description of the process for charting the course for curricular change. The process involves defining expected learning outcomes for new graduates, conducting a curriculum mapping exercise, and collecting stakeholder data for curricular evaluation (steps 1-4). The second part of the report describes the development of rubrics that were applied to the graduate learning outcomes (steps 5-8) and engagement of faculty during the implementation phases of data-driven curriculum change. PMID- 28876992 TI - Curricular Renewal at the Southern Tip of Africa: The 2016 Veterinary Curriculum at the University of Pretoria. AB - Four years after the institution of a new curriculum at the University of Pretoria's Faculty of Veterinary Science, a second major curricular renewal was initiated as a result of several pressing drivers, many of which were unique to the national and institutional context. During the project, South African higher education was disrupted by student protests prompted by financial pressures on students, the overt colonial structure of higher education, and the need to accelerate transformation of the sector. A structured curricular renewal process was followed, including the laying down of the principles, the structuring the macro-curriculum as a story, the design of a meso- and micro-curriculum, and the mapping of the curriculum to Day One outcomes. The resulting program is a 6-year bachelor's degree with a blend of discipline and species modules, with the first cohort graduating in 2016. There is a strong focus on skills embodied in a 62 week experiential component, managed using a unique custom-designed online platform for booking placements, documenting exposure, assessing competency, and providing feedback to students. The experiential training includes a large elective component. Several causes of loss of impetus during the process are discussed and proposals are made for avoiding these. The value of accreditation as a driver and a source of inputs is evident. The process has succeeded in producing a significantly reshaped curriculum that has been well received by external stakeholders. PMID- 28876991 TI - Curriculum Redesign in Veterinary Medicine: Part II. AB - Curricular review is considered a necessary component for growth and enhancement of academic programs and requires time, energy, creativity, and persistence from both faculty and administration. On a larger scale, a comprehensive redesign effort involves forming a dedicated faculty redesign team, developing program learning outcomes, mapping the existing curriculum, and reviewing the curriculum in light of collected stakeholder data. The faculty of the Texas A&M University College of Veterinary Medicine & Biomedical Sciences (TAMU) recently embarked on a comprehensive curriculum redesign effort through partnership with the university's Center for Teaching Excellence. Using a previously developed evidence-based model of program redesign, TAMU created a process for use in veterinary medical education, which is described in detail in the first part of this article series. An additional component of the redesign process that is understated, yet vital for success, is faculty buy-in and support. Without faculty engagement, implementation of data-driven curricular changes stemming from program evaluation may be challenging. This second part of the article series describes the methodology for encouraging faculty engagement through the final steps of the redesign initiative and the lessons learned by TAMU through the redesign process. PMID- 28876993 TI - Curricular Revision and Reform: The Process, What Was Important, and Lessons Learned. AB - Beginning in 2005, the Doctor of Veterinary Medicine program at the University of California underwent major curricular review and reform. To provide information for others that follow, we have documented our process and commented on factors that were critical to success, as well as factors we found surprising, difficult, or problematic. The review and reform were initiated by the Executive Committee, who led the process and commissioned the committees. The planning stage took 6 years and involved four faculty committees, while the implementation stage took 5 years and was led by the Curriculum Committee. We are now in year 2 of the institutionalizing stage and no longer refer to our reform as the "new curriculum." The change was driven by a desire to improve the curriculum and the learning environment of the students by aligning the delivery of information with current teaching methodologies and implementing adult learning strategies. We moved from a department- and discipline-based curriculum to a school-wide integrated block curriculum that emphasized student-centered, inquiry-based learning. A limit was placed on in-class time to allow students to apply classroom knowledge by solving problems and cases. We found the journey long and arduous, requiring tremendous commitment and effort. In the change process, we learned the importance of adequate planning, leadership, communication, and a reward structure for those doing the "heavy lifting." Specific to our curricular design, we learned the importance of the block leader role, of setting clear expectations for students, and of partnering with students on the journey. PMID- 28876994 TI - Encouraging Critical Clinical Thinking (CCT) Skills in First-Year Veterinary Students. AB - First-year didactic course instructors at the University of Illinois College of Veterinary Medicine leverage earlier clinical rotation experiences with weekly "Clinical Correlations" exercises to provide early exposure to critical clinical thinking (CCT). This study evaluated the efficacy of individual and paired group exercises on CCT development. Before and after instruction, the Cornell Critical Thinking Test (Level Z) (CCTTZ) was administered. Based on the hypothesis that students with higher scores would coach lower-scoring colleagues during group exercises, heterogeneous groups with similar mean scores were established for the year. Students completed 14 individual and paired group exercises over 6 months. Exercises were designed to increase in complexity and decline in scaffolding. Seven of the exercises were cases using the Applied Learning Platform (ALP) at http://www.whenknowingmatters.com . Student analyses were scored according to a six-category critical-thinking rubric using a 5-point scale. Consistent with our hypothesis, individual and group rubric scores increased significantly, plateauing near the end of the year. Contrary to our hypothesis, mean overall CCTTZ scores did not change, but there was a small statistically significant increase in the ability to assess the validity of an argument. Student attitudes were mixed. Positive comments focused on reinforcement of prior didactic instruction, while negative comments focused on preparation time needed to conduct research on clinical concepts, and on a lack of explicit evaluation by summative examinations. Nonetheless, end-of-year GPAs correlated linearly with cumulative individual rubric scores. In summary, the value of early curriculum CCT training was confirmed when discipline-specific criteria were applied. PMID- 28876995 TI - Benefits and Challenges of Developing a Customized Rubric for Curricular Review of a Residency Program in Laboratory Animal Medicine. AB - Rigorous curricular review of post-graduate veterinary medical residency programs is in the best interest of program directors in light of the requirements and needs of specialty colleges, graduate school administrations, and other stakeholders including prospective students and employers. Although minimum standards for training are typically provided by specialty colleges, mechanisms for evaluation are left to the discretion of program directors. The paucity of information available describing best practices for curricular assessment of veterinary medical specialty training programs makes resources from other medical fields essential to informing the assessment process. Here we describe the development of a rubric used to evaluate courses in a 3-year American College of Laboratory Animal Medicine (ACLAM)-recognized residency training program culminating in a Master of Science degree. This rubric, based on examples from medical education and other fields of graduate study, provided transparent criteria for evaluation that were consistent with stakeholder needs and institutional initiatives. However, its use caused delays in the curricular review process as two significant obstacles to refinement were brought to light: variation in formal education in curriculum design and significant differences in teaching philosophies among faculty. The evaluation process was able to move forward after institutional resources were used to provide faculty development in curriculum design. The use of a customized rubric is recommended as a best practice for curricular refinement for residency programs because it results in transparency of the review process and can reveal obstacles to change that would otherwise remain unaddressed. PMID- 28876996 TI - Veterinary Curriculum Transformation at the University of Illinois, 2006-2016. AB - The organization and delivery of a curriculum is the responsibility of the faculty in educational institutions. Curricular revision is often a hotly debated topic in any college faculty. At the University of Illinois, a 2006 mandate for curriculum modernization from the American Veterinary Medical Association Council on Education provided impetus for a long-discussed curricular revision. After two iterations and a lengthy development process, a new curriculum was gradually implemented at Illinois with the August 2009 matriculation of the Class of 2013. The goals of the revision included earlier clinical exposure for veterinary students through introductions to clinical rotations in years 1 to 3 and an integrated body systems approach in lecture/laboratory courses. A new Clinical Skills Learning Center facilitates development of clinical skills earlier in the curriculum and promotes the development of those skills throughout all 4 years of the curriculum. New outcomes assessments include comprehensive written examinations and Objective Structured Clinical Examinations (OSCEs) in years 2 and 3. Curriculum management, including grading of clinical rotations in all 4 years, is achieved through a commercially available software package. For the past 5 years, when candidates were asked why they chose to apply to Illinois, the new curriculum (27.4%) was the most common answer given during interviews. The Illinois revision has resulted in measurably increased veterinary student self confidence (p<.001) at graduation. PMID- 28876997 TI - Innovative Use of Denver Shunt in a Child with Generalized Lymphatic Anomaly. AB - BACKGROUND: Denver(r) shunts have traditionally been used for palliation of refractory malignant and chylous peritoneal and pleural collections. We describe an innovative use of the Denver shunt in a child with generalized lymphatic anomaly. MATERIALS AND METHODS: Retrospective chart review of a 6-year-old girl with generalized lymphatic anomaly, who presented with refractory lymphorrhea from the labium majus, was performed. This was managed with innovative placement of the Denver shunt between a large abdominal wall cyst and the peritoneal cavity. RESULTS: There was progressive reduction in lymphorrhea with complete cessation at 11 months post shunt placement. At 33-month follow-up, the shunt remains patent with no further lymphorrhea. CONCLUSION: Denver shunts can be utilized for the creation of internal drainage pathways besides its traditional uses for draining peritoneal and pleural fluids. PMID- 28876998 TI - Meiosis-specific localization of the exocytic Rab Ypt2 in fission yeast. AB - Fission yeast Ypt2, an orthologue of the mammalian small GTPase Rab8, is responsible for post-Golgi membrane trafficking. During meiosis, Ypt2 localizes at the spindle pole body (SPB), where it regulates de novo biogenesis of the spore plasma membrane. Recruitment of Ypt2 to the SPB is dependent on its meiosis specific GDP/GTP exchange factor (GEF), the SPB-resident protein Spo13. Here we have examined the SPB recruitment of Ypt2 by Spo13. The GEF activity of Spo13 was required, but not essential for recruitment. Furthermore, Ypt2 recruitment was regulated in a meiosis-specific manner and partially regulated by the nuclear Dbf2-related (NDR) kinase Sid2, indicating the existence of a novel regulatory mechanism for localization of Rab GTPases during meiosis. PMID- 28876999 TI - How Children Solve the Two Challenges of Cooperation. AB - In this review, I propose a new framework for the psychological origins of human cooperation that harnesses evolutionary theories about the two major problems posed by cooperation: generating and distributing benefits. Children develop skills foundational for identifying and creating opportunities for cooperation with others early: Infants and toddlers already possess basic skills to help others and share resources. Yet mechanisms that solve the free-rider problem critical for sustaining cooperation as a viable strategy-emerge later in development and are more sensitive to the influence of social norms. I review empirical studies with children showing a dissociation in the origins of and developmental change seen in these two sets of processes. In addition, comparative studies of nonhuman apes also highlight important differences between these skills: The ability to generate benefits has evolutionary roots that are shared between humans and nonhuman apes, whereas there is little evidence that other apes exhibit comparable capacities for distributing benefits. I conclude by proposing ways in which this framework can motivate new developmental, comparative, and cross-cultural research about human cooperation. PMID- 28877000 TI - Linking Language and Cognition in Infancy. AB - Human language, a signature of our species, derives its power from its links to human cognition. For centuries, scholars have been captivated by this link between language and cognition. In this article, we shift this focus. Adopting a developmental lens, we review recent evidence that sheds light on the origin and developmental unfolding of the link between language and cognition in the first year of life. This evidence, which reveals the joint contributions of infants' innate capacities and their sensitivity to experience, highlights how a precocious link between language and cognition advances infants beyond their initial perceptual and conceptual capacities. The evidence also identifies the conceptual advantages this link brings to human infants. By tracing the emergence of a language-cognition link in infancy, this article reveals a dynamic developmental cascade in infants' first year, with each developmental advance providing a foundation for subsequent advances. PMID- 28877001 TI - Total Laparoscopic Approach for Transhiatal Esophagectomy and Gavriliu's Esophagoplasty in Children with Caustic Esophageal Injuries. AB - BACKGROUND: Esophageal repair after caustic injury is a surgical challenge in children. The aim of this study was to report the first results of a total laparoscopic approach in transhiatal esophagectomy and esophageal replacement by an anisoperistaltic gastric tube. PATIENTS AND METHODS: A retrospective review of data from children operated on with a laparoscopic approach for transhiatal esophagectomy and Gavriliu's esophagoplasty between 2011 and 2015 was performed. Surgical techniques were related with variations for 2 cases, 1 case with robotic assistance and 1 with thoracoscopic assistance. RESULTS: Seven patients were operated on. The median weight was 16 kg. Median duration of mechanical ventilation was 2 days. Total esophagectomy was achieved in all cases. Two patients could eat after a barium swallow 7 days after surgery. The most frequent immediate complication (57%) was anastomotic or gastric tube leakage treated successfully in 100% of the cases with self-expanding metallic stent placement. Seventy-one percent of children presented with stenosis, which responded to pneumatic dilatation in 67% of the cases. Redo surgery was required in 43%, either for anastomosis revision or nonfunctioning gastric tube. With an average follow-up of 51 months, 85.7% of children achieved oral feeding. CONCLUSIONS: Total laparoscopic approach for esophagectomy and esophageal replacement by Gavriliu's anisoperistaltic gastric tube is a feasible technique allowing to shorten the postoperative mechanical ventilation duration and save parietal damage often present in these patients requiring multiple surgery. It appears to have a good long-term tolerance, although the immediate postoperative complication rate remains as high as the open technique. PMID- 28877002 TI - Lymphedema: Pathogenesis and Novel Therapies. AB - Lymphedema affects up to 1 in 6 patients who undergo treatment for a solid tumor in the United States. Its prevalence has increased as more effective oncologic therapies have improved patient survival, but there remains no definitive cure. Recent research has elucidated new details in the pathogenesis of the disease and has demonstrated that it is fundamentally an immunologic process that ultimately results in inflammation, fibroadipose deposition, impaired lymphangiogenesis, and dysfunctional lymphatic pumping. These findings have allowed for the development of novel medical and surgical therapies that may potentially alter the standard of care for a disease that has largely been treated by compression. This review seeks to provide an overview of the emerging therapies and how they can be utilized for effective management of lymphedema. PMID- 28877003 TI - New designs for basket clinical trials in oncology. AB - The established molecular heterogeneity of human cancers has had profound effects on the design of cancer therapeutics. Most cancer drugs are today targeted to molecular alterations present in cancer cells. Tumors of the same primary site, however, often differ with regard to the alterations that they harbor. Consequently, this heterogeneity has required the development of new paradigms for clinical development. In this paper, we review some clinical trial designs finding active use in co-development of therapeutics and predictive biomarkers to inform their use in oncology. PMID- 28877004 TI - Reciprocity Outperforms Conformity to Promote Cooperation. AB - Evolutionary psychologists have proposed two processes that could give rise to the pervasiveness of human cooperation observed among individuals who are not genetically related: reciprocity and conformity. We tested whether reciprocity outperformed conformity in promoting cooperation, especially when these psychological processes would promote a different cooperative or noncooperative response. To do so, across three studies, we observed participants' cooperation with a partner after learning (a) that their partner had behaved cooperatively (or not) on several previous trials and (b) that their group members had behaved cooperatively (or not) on several previous trials with that same partner. Although we found that people both reciprocate and conform, reciprocity has a stronger influence on cooperation. Moreover, we found that conformity can be partly explained by a concern about one's reputation-a finding that supports a reciprocity framework. PMID- 28877006 TI - Presentation of the Ashton Cuckler New Investigator Award to Dr. Heather Stigge. PMID- 28877005 TI - Is There a Trade-Off between Radiation-Stimulated Growth and Metabolic Efficiency? AB - Beneficial protective effects may result from an adaptive respose to low dose radiation exposure. However, such benefits must be accompanied by some form of cost because the responsible biological mechanisms are not normally maintained in an upregulated state. It has been suggested that stimulation of adaptive response mechanisms could be metabolically costly, or that the adaptive response could come at a sacrifice to other physiological processes. We exposed developing lake whitefish embryos to a fractionated regime of gamma radiation (662 keV; 0.3 Gy min-1) to determine whether radiation-stimulated growth was accompanied by a trade-off in metabolic efficiency. Developing embryos were exposed at the eyed stage to different radiation doses delivered in four fractions, ranging from 15 mGy to 8 Gy per fraction, with a 14 day separation between dose fractions. Dry weight and standard length measurements were taken 2-5 weeks after delivery of the final radiation exposure and yolk conversion efficiency was estimated by comparing the unpreserved dry weight of the yolk to the unpreserved yolk-free dry weight of the embryos and normalizing for size-related differences in somatic maintenance. Our results show that the irradiated embryos were 8-10% heavier than the controls but yolk conversion efficiency was slightly improved. This finding demonstrates that stimulated growth in developing lake whitefish embryos is not "paid for" by a trade-off in the efficiency of yolk conversion. PMID- 28877007 TI - Creation of an Esophageal Atresia Animal Model Using a Bifurcated Esophagus to Maintain Digestive Tract Continuity. AB - INTRODUCTION: We previously developed a porcine model of long gap pure esophageal atresia (EA) to aid in the creation of novel devices and techniques for treatment of EA. Shortcomings of the model included difficulty decompressing the proximal esophageal pouch (leading to recurrent aspiration) and a requirement for gastrostomy tube (G-tube) feeds. Therefore, we sought to create a porcine model with a bifurcated esophagus wherein one portion of the esophageal lumen retained patency and the other part mimicked EA. METHODS: After G-tube placement, thoracotomy was performed with subsequent partial stapled transection of the esophagus in a transverse manner, followed by longitudinal, partial stapled transection of the esophagus proximally and distally. Magnets were placed in the esophageal pouches. RESULTS: Proximal and distal esophageal pouches were created while preserving a parallel, narrower segment of continuous esophagus. G-tube feeds were used initially, but the animal ultimately tolerated full nutrition by mouth. The magnets successfully restored esophageal continuity. The animal regained much of the initial weight lost and survived to planned euthanasia. Necropsy revealed anastomosis formation without evidence of leak. CONCLUSIONS: A bifurcated porcine esophagus model was successfully devised, simulating EA while allowing the animal to receive oral feeds and clear oral secretions. This model is anticipated to promote animal well-being and ease of care during future investigations, as well as a platform for the safe development of new therapies for EA. PMID- 28877008 TI - Definitions and statistical properties of master protocols for personalized medicine in oncology. AB - Within the field of cancer research, discovery of biomarkers and genetic mutations that are potentially predictive of treatment benefit is motivating a paradigm shift in how cancer clinical trials are conducted. In this review, we provide an overview of the class of trials known as "master protocols," including basket trials, umbrella trials, and platform trials. For each, we describe standardized terminology, provide a motivating example with modeling details and decision rules, and discuss statistical advantages and limitations. We conclude with a discussion of general statistical considerations and challenges encountered across these types of trials. PMID- 28877009 TI - A Synoptic View of the Ventilation and Circulation of Antarctic Bottom Water from Chlorofluorocarbons and Natural Tracers. AB - Antarctic Bottom Water (AABW) is the coldest, densest, most prolific water mass in the global ocean. AABW forms at several distinct regions along the Antarctic coast and feeds into the bottom limb of the meridional overturning circulation, filling most of the global deep ocean. AABW has warmed, freshened, and declined in volume around the globe in recent decades, which has implications for the global heat and sea level rise budgets. Over the past three decades, the use of tracers, especially time-varying tracers such as chlorofluorocarbons, has been essential to our understanding of the formation, circulation, and variability of AABW. Here, we review three decades of temperature, salinity, and tracer data and analysis that have led to our current knowledge of AABW and how the southern component of deep-ocean ventilation is changing with time. PMID- 28877010 TI - Airway Mucins in Chronic Obstructive Pulmonary Disease. PMID- 28877012 TI - The HITECH Era in Retrospect. PMID- 28877011 TI - Tezepelumab in Adults with Uncontrolled Asthma. AB - BACKGROUND: In some patients with moderate-to-severe asthma, particularly those with noneosinophilic inflammation, the disease remains uncontrolled. This trial evaluated the efficacy and safety of tezepelumab (AMG 157/MEDI9929), a human monoclonal antibody specific for the epithelial-cell-derived cytokine thymic stromal lymphopoietin (TSLP), in patients whose asthma remained uncontrolled despite treatment with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids. METHODS: In this phase 2, randomized, double-blind, placebo-controlled trial, we compared subcutaneous tezepelumab at three dose levels with placebo over a 52-week treatment period. The primary end point was the annualized rate of asthma exacerbations (events per patient-year) at week 52. RESULTS: The use of tezepelumab at a dose of 70 mg every 4 weeks (low dose; 145 patients), 210 mg every 4 weeks (medium dose; 145 patients), or 280 mg every 2 weeks (high dose; 146 patients) resulted in annualized asthma exacerbation rates at week 52 of 0.26, 0.19, and 0.22, respectively, as compared with 0.67 in the placebo group (148 patients). Thus, exacerbation rates in the respective tezepelumab groups were lower by 61%, 71%, and 66% than the rate in the placebo group (P<0.001 for all comparisons). Similar results were observed in patients regardless of blood eosinophil counts at enrollment. The prebronchodilator forced expiratory volume in 1 second at week 52 was higher in all tezepelumab groups than in the placebo group (difference, 0.12 liters with the low dose [P=0.01], 0.11 liters with the medium dose [P=0.02], and 0.15 liters with the high dose [P=0.002]). A total of 2 patients in the medium-dose group, 3 in the high-dose group, and 1 in the placebo group discontinued the trial regimen because of adverse events. CONCLUSIONS: Among patients treated with long-acting beta agonists and medium-to-high doses of inhaled glucocorticoids, those who received tezepelumab had lower rates of clinically significant asthma exacerbations than those who received placebo, independent of baseline blood eosinophil counts. (Funded by MedImmune [a member of the AstraZeneca Group] and Amgen; PATHWAY ClinicalTrials.gov number, NCT02054130 .). PMID- 28877013 TI - The HITECH Era and the Path Forward. PMID- 28877014 TI - Randomized, Controlled Trials in Health Insurance Systems. PMID- 28877015 TI - Buprenorphine for the Neonatal Abstinence Syndrome. PMID- 28877016 TI - Buprenorphine for the Neonatal Abstinence Syndrome. PMID- 28877017 TI - Neobladder Stone. PMID- 28877018 TI - Drug Treatment for Early-Stage COPD. PMID- 28877019 TI - Severe and Difficult-to-Treat Asthma in Adults. PMID- 28877020 TI - Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis. PMID- 28877021 TI - Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis. PMID- 28877022 TI - Zoonotic Chlamydia caviae Presenting as Community-Acquired Pneumonia. PMID- 28877024 TI - Moving Upstream - Anti-TSLP in Persistent Uncontrolled Asthma. PMID- 28877023 TI - Airway Mucin Concentration as a Marker of Chronic Bronchitis. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitic and emphysematous components. In one biophysical model, the concentration of mucin on the airway surfaces is hypothesized to be a key variable that controls mucus transport in healthy persons versus cessation of transport in persons with muco-obstructive lung diseases. Under this model, it is postulated that a high mucin concentration produces the sputum and disease progression that are characteristic of chronic bronchitis. METHODS: We characterized the COPD status of 917 participants from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) using questionnaires administered to participants, chest tomography, spirometry, and examination of induced sputum. Total mucin concentrations in sputum were measured with the use of size-exclusion chromatography and refractometry. In 148 of these participants, the respiratory secreted mucins MUC5AC and MUC5B were quantitated by means of mass spectrometry. Data from chronic-bronchitis questionnaires and data on total mucin concentrations in sputum were also analyzed in an independent 94 participant cohort. RESULTS: Mean (+/-SE) total mucin concentrations were higher in current or former smokers with severe COPD than in controls who had never smoked (3166+/-402 vs. 1515+/-152 MUg per milliliter) and were higher in participants with two or more respiratory exacerbations per year than in those with zero exacerbations (4194+/-878 vs. 2458+/-113 MUg per milliliter). The absolute concentrations of MUC5B and MUC5AC in current or former smokers with severe COPD were approximately 3 times as high and 10 times as high, respectively, as in controls who had never smoked. Receiver-operating characteristic curve analysis of the association between total mucin concentration and a diagnosis of chronic bronchitis yielded areas under the curve of 0.72 (95% confidence interval [CI], 0.65 to 0.79) for the SPIROMICS cohort and 0.82 (95% CI, 0.73 to 0.92) for the independent cohort. CONCLUSIONS: Airway mucin concentrations may quantitate a key component of the chronic bronchitis pathophysiologic cascade that produces sputum and mediates disease severity. Studies designed to explore total mucin concentrations in sputum as a diagnostic biomarker and therapeutic target for chronic bronchitis appear to be warranted. (Funded by the National Heart, Lung, and Blood Institute and others.). PMID- 28877025 TI - Connecting the Dots. PMID- 28877026 TI - Effectiveness of a Third Dose of MMR Vaccine for Mumps Outbreak Control. AB - BACKGROUND: The effect of a third dose of the measles-mumps-rubella (MMR) vaccine in stemming a mumps outbreak is unknown. During an outbreak among vaccinated students at the University of Iowa, health officials implemented a widespread MMR vaccine campaign. We evaluated the effectiveness of a third dose for outbreak control and assessed for waning immunity. METHODS: Of 20,496 university students who were enrolled during the 2015-2016 academic year, mumps was diagnosed in 259 students. We used Fisher's exact test to compare unadjusted attack rates according to dose status and years since receipt of the second MMR vaccine dose. We used multivariable time-dependent Cox regression models to evaluate vaccine effectiveness, according to dose status (three vs. two doses and two vs. no doses) after adjustment for the number of years since the second dose. RESULTS: Before the outbreak, 98.1% of the students had received at least two doses of MMR vaccine. During the outbreak, 4783 received a third dose. The attack rate was lower among the students who had received three doses than among those who had received two doses (6.7 vs. 14.5 cases per 1000 population, P<0.001). Students had more than nine times the risk of mumps if they had received the second MMR dose 13 years or more before the outbreak. At 28 days after vaccination, receipt of the third vaccine dose was associated with a 78.1% lower risk of mumps than receipt of a second dose (adjusted hazard ratio, 0.22; 95% confidence interval, 0.12 to 0.39). The vaccine effectiveness of two doses versus no doses was lower among students with more distant receipt of the second vaccine dose. CONCLUSIONS: Students who had received a third dose of MMR vaccine had a lower risk of mumps than did those who had received two doses, after adjustment for the number of years since the second dose. Students who had received a second dose of MMR vaccine 13 years or more before the outbreak had an increased risk of mumps. These findings suggest that the campaign to administer a third dose of MMR vaccine improved mumps outbreak control and that waning immunity probably contributed to propagation of the outbreak. (Funded by the Centers for Disease Control and Prevention.). PMID- 28877028 TI - Left Ventricular Free-Wall Rupture. PMID- 28877029 TI - Impairments in age-dependent ubiquitin proteostasis and structural integrity of selective neurons by uncoupling Ran GTPase from the Ran-binding domain 3 of Ranbp2 and identification of novel mitochondrial isoforms of ubiquitin conjugating enzyme E2I (ubc9) and Ranbp2. AB - The Ran-binding protein 2 (Ranbp2/Nup358) is a cytoplasmic and peripheral nucleoporin comprised of 4 Ran-GTP-binding domains (RBDs) that are interspersed among diverse structural domains with multifunctional activities. Our prior studies found that the RBD2 and RBD3 of Ranbp2 control mitochondrial motility independently of Ran-GTP-binding in cultured cells, whereas loss of Ran-GTP binding to RBD2 and RBD3 are essential to support cone photoreceptor development and the survival of mature retinal pigment epithelium (RPE) in mice. Here, we uncover that loss of Ran-GTP-binding to RBD3 alone promotes the robust age dependent increase of ubiquitylated substrates and S1 subunit (Pmsd1) of the 19S cap of the proteasome in the retina and RPE and that such loss in RBD3 also compromises the structural integrity of the outer segment compartment of cone photoreceptors only and without affecting the viability of these neurons. We also found that the E2-ligase and partner of Ranbp2, ubc9, is localized prominently in the mitochondrial-rich ellipsoid compartment of photoreceptors, where Ranbp2 is also known to localize with and modulate the activity of mitochondrial proteins. However, the natures of Ranbp2 and ubc9 isoforms to the mitochondria are heretofore elusive. Subcellular fractionation, co-immunolocalization and immunoaffinity purification of Ranbp2 complexes show that novel isoforms of Ranbp2 and ubc9 with molecular masses distinct from the large Ranbp2 and unmodified ubc9 isoforms localize specifically to the mitochondrial fraction or associate with mitochondrial components, whereas unmodified and SUMOylated Ran GTPase are excluded from the mitochondrial fraction. Further, liposome-mediated intracellular delivery of an antibody against a domain shared by the mitochondrial and nuclear pore isoforms of Ranbp2 causes the profound fragmentation of mitochondria and their delocalization from Ranbp2 and without affecting Ranbp2 localization at the nuclear pores. Collectively, the data support that Ran GTPase-dependent and independent and moonlighting roles of Ranbp2 or domains thereof and ubc9 control selectively age-dependent, neural-type and mitochondrial functions. PMID- 28877027 TI - Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Patients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 MUg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between-group difference in the annual decline in the FEV1 before and after bronchodilator use from day 30 to month 24. RESULTS: Of 841 patients who underwent randomization, 388 patients in the tiotropium group and 383 in the placebo group were included in the full analysis set. The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; P<0.001 for all comparisons). There was no significant amelioration of the mean (+/-SE) annual decline in the FEV1 before bronchodilator use: the decline was 38+/-6 ml per year in the tiotropium group and 53+/-6 ml per year in the placebo group (difference, 15 ml per year; 95% confidence interval [CI], -1 to 31; P=0.06). In contrast, the annual decline in the FEV1 after bronchodilator use was significantly less in the tiotropium group than in the placebo group (29+/-5 ml per year vs. 51+/-6 ml per year; difference, 22 ml per year [95% CI, 6 to 37]; P=0.006). The incidence of adverse events was generally similar in the two groups. CONCLUSIONS: Tiotropium resulted in a higher FEV1 than placebo at 24 months and ameliorated the annual decline in the FEV1 after bronchodilator use in patients with COPD of GOLD stage 1 or 2. (Funded by Boehringer Ingelheim and others; Tie-COPD ClinicalTrials.gov number, NCT01455129 .). PMID- 28877030 TI - Radiation Mitigating Properties of Intranasally Administered KL4 Surfactant in a Murine Model of Radiation-Induced Lung Damage. AB - The threat of exposure to ionizing radiation from a nuclear reactor accident or deliberate terrorist actions is a significant public health concern. The lung is particularly susceptible to radiation-induced injury from external sources or inhalation of radioactive particles from radioactive fallout. Radiation-induced lung disease can manifest with an acute radiation pneumonitis and/or delayed effects leading to pulmonary fibrosis. As prior warning of radiation exposure is unlikely, medical countermeasures (MCMs) to mitigate radiation-induced lung disease that can be given in mass-casualty situations many hours or days postirradiation are needed to prevent both early and late lung damage. In this study, KL4 surfactant (lucinactant) was evaluated as a radiation mitigator in a well-characterized mouse model of targeted thoracic radiation exposure, for its effect on both early (several weeks) and late (18 weeks) lung damage. Here, 120 mg/kg total phospholipid of KL4 surfactant was administered twice daily intranasally, (enabling intrapulmonary inhalation of drug) to C57BL/6 mice 24 h after a single 13.5 Gy dose of thoracic irradiation (LD50 dose). Both early and chronic phase (2 and 4 weeks and 18 weeks postirradiation, respectively) assessments were performed. Mice were evaluated for evidence of reduced arterial blood oxygenation and early and chronic lung and systemic inflammation, lung fibrosis and oxidative stress. Analysis was done by performing lung function/respiration dynamics and measuring cellular protein content of bronchoalveolar lavage fluid (BALF), and levels of cytokines, 8-iso-prostaglandin F2alpha, hydroxyproline in lung and plasma, along with evaluating lung histology. The results of this study showed that intranasal delivery of KL4 surfactant was able to preserve lung function as evidenced by adequate arterial oxygen saturation and reduced lung inflammation and oxidative stress; total white count and absolute neutrophil count was decreased in BALF, as were plasma pro inflammatory cytokine levels and biomarker of oxidative stress. KL4 surfactant is a promising MCM for mitigation of lung tissue damage after targeted, thoracic irradiation and has the potential to be developed as a broad-spectrum, multi-use MCM against chemical, biological, radiological or nuclear threat agents with potential to cause lung injury. PMID- 28877032 TI - Bowel endometriosis: a diagnostic and therapeutic challenge. AB - Bowel endometriosis is the most common extragenital manifestation of endometriosis. Clinical suspicion is of utmost importance for achieving its diagnosis. Management of this condition is, however, always challenging to the gynaecologist. We report a case of bowel endometriosis in which the patient presented with dyschezia and haematochezia prior to her menses for the past 2 years. A 44-year-old para two woman presented with worsening dysmenorrhea and dyspareunia. She also experienced dyschezia and haematochezia prior to her menses for the past 2 years. An examination revealed a fixed retroverted uterus. A computed tomography scan showed focal bowel thickening. She underwent a colonoscopy examination and biopsy that revealed stromal endometriosis. She was subsequently treated with dienogest and became asymptomatic. Diagnosis and management of this debilitating illness was revisited and discussed. PMID- 28877033 TI - Nonlinear coherent structures in granular crystals. AB - The study of granular crystals, which are nonlinear metamaterials that consist of closely packed arrays of particles that interact elastically, is a vibrant area of research that combines ideas from disciplines such as materials science, nonlinear dynamics, and condensed-matter physics. Granular crystals exploit geometrical nonlinearities in their constitutive microstructure to produce properties (such as tunability and energy localization) that are not conventional to engineering materials and linear devices. In this topical review, we focus on recent experimental, computational, and theoretical results on nonlinear coherent structures in granular crystals. Such structures-which include traveling solitary waves, dispersive shock waves, and discrete breathers-have fascinating dynamics, including a diversity of both transient features and robust, long-lived patterns that emerge from broad classes of initial data. In our review, we primarily discuss phenomena in one-dimensional crystals, as most research to date has focused on such scenarios, but we also present some extensions to two-dimensional settings. Throughout the review, we highlight open problems and discuss a variety of potential engineering applications that arise from the rich dynamic response of granular crystals. PMID- 28877034 TI - Recent progress on the structure separation of single-wall carbon nanotubes. AB - The mass production of single-structure, single-wall carbon nanotubes (SWCNTs) with identical properties is critical for their basic research and technical applications in the fields of electronics, optics and optoelectronics. Great efforts have been made to control the structures of SWCNTs since their discovery. Recently, the structure separation of SWCNTs has been making great progress. Various solution-sorting methods have been developed to achieve not only the separation of metallic and semiconducting species, but also the sorting of distinct (n, m) single-chirality species and even their enantiomers. This progress would dramatically accelerate the application of SWCNTs in the next generation electronic devices. Here, we review the recent progress in the structure sorting of SWCNTs and outline the challenges and prospects of the structure separation of SWCNTs. PMID- 28877035 TI - Academic Medicine and Medical Professionalism: A Legacy and a Portal Into an Evolving Field of Educational Scholarship. AB - In this Invited Commentary, the author examines two curated Academic Medicine volumes showcasing foundational research and key writings on professionalism in medicine and medical education, collectively spanning from 1994 to 2016. The author reviews the beginnings of the medical professionalism movement and examines how the trends and themes reflected in the first volume-specifically the work to define, assess, and institutionalize professionalism-capture key elements in this movement. He then examines how the trends and themes in the second volume align with and build on those from the first, noting two themes that extend across a number of second volume articles: a unit-of-analysis issue and the challenge of context. The author identifies several topics that have yet to be adequately mined and calls attention to two bridge-spanning articles in the second volume that, respectively, take us into the future (around the topic of identify formation) and back to the past (on the hidden curriculum). Finally, the author reflects on "directions home" in medicine's noble search for its moral core and collective identity. PMID- 28877031 TI - Genetic Associations with Gestational Duration and Spontaneous Preterm Birth. AB - BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0*10 8) or an association with suggestive significance (P<1.0*10-6) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.). PMID- 28877036 TI - Recovery From Ropivacaine-Induced or Levobupivacaine-Induced Cardiac Arrest in Rats: Comparison of Lipid Emulsion Effects. AB - BACKGROUND: Lipid emulsion treatment appears to have application in the treatment of local anesthetic-induced cardiac arrest. To examine whether the efficacy of lipid resuscitation in the treatment of local anesthetic-induced cardiac arrest is affected by lipophilicity, the effects of lipid infusions were compared between levobupivacaine-induced (high lipophilicity) and ropivacaine-induced (lower lipophilicity) rat cardiac arrest model. METHODS: A total of 28 female Sprague-Dawley rats were anesthetized using sevoflurane, which subsequently underwent tracheostomy, followed by femoral artery and vein cannulation. Two hours after the discontinuation of sevoflurane, either levobupivacaine 0.2% (n = 14) or ropivacaine 0.2% (n = 14) was administered at a rate of 2 mg/kg/min to the awake rats. When the pulse pressure decreased to 0, the infusion of local anesthetic was discontinued, and treatment with chest compressions and ventilation with 100% oxygen were immediately initiated. The total doses of local anesthetics needed to trigger the first seizure and pulse pressure of 0 mm Hg were calculated. The 2 groups were each subdivided into a lipid emulsion group (n = 7) and a control group (n = 7). In the lipid emulsion group, 20% lipid emulsion was administered intravenously (5 mL/kg bolus plus continuous infusion of 0.5 mL/kg/min), while in the control group, the same volume of normal saline was administered. Chest compressions were discontinued when the rate-pressure product had increased by more than 20% of baseline. RESULTS: The cumulative doses of levobupivacaine and ropivacaine that produced seizures and 0 pulse pressure showed no significant difference. Mean arterial blood pressure (MAP) values were higher in the levobupivacaine group than in the ropivacaine group after resuscitation was initiated (P < .05). In levobupivacaine-induced cardiac arrest, heart rate and MAP values were higher in the lipid group than in the control group after starting resuscitation (P < .05); all rats in the lipid group achieved spontaneous circulation (rate-pressure product >20% baseline), while only 2 of 7 rats in the control group achieved spontaneous circulation at 10 minutes. In ropivacaine-induced cardiac arrest, there were no significant differences in heart rate and MAP between the lipid and control groups from the start of resuscitation to 10 minutes; spontaneous circulation returned in 6 of 7 lipid group rats, but in only 2 of 7 control group rats at 10 minutes. CONCLUSIONS: Lipid emulsion treatment was more effective for levobupivacaine induced cardiac arrest than for ropivacaine-induced cardiac arrest. Although lipid therapy is also effective for ropivacaine-induced cardiac arrest, it takes more time than in levobupivacaine-induced cardiac arrest. This suggests that the lipophilicity of local anesthetics influences the efficacy of lipid infusion when treating cardiac arrest caused by these drugs. PMID- 28877038 TI - Message from the President of the Eastern Cardiothoracic Surgical Society. PMID- 28877039 TI - Left ventricular dysfunction in a patient with Angelman syndrome. PMID- 28877040 TI - Ischemic conditioning in solid organ transplantation: is it worth giving your right arm for? AB - PURPOSE OF REVIEW: Ischemia reperfusion injury (IRI) is an inevitable complication in solid organ transplantation. Limiting this injury can increase patient and graft survival and can decrease complications associated with transplantation. We provide an extensive literature review analyzing the available evidence for ischemic conditioning in solid organ transplantation, including kidney, liver, heart, and lung. RECENT FINDINGS: Ischemic conditioning strategies are a group of interventions, characterized by episodes of ischemia and reperfusion to an organ which confirm tissue protection. Arguably, transplantation is the ideal setting to use this novel strategy due to the predictable timing and duration of the ischemic insult. Liver transplantation has provided us with the most number of clinical trials, followed by kidney transplantation. Most of these trials have been negative but the methodology has been variable, making comparison difficult. SUMMARY: Despite the promising results seen in animal models, translating these results in clinical trials has proved to be difficult. The promising effects of ischemic conditioning are present in some trials with weaker positive signals existing in other trials. We believe that tailoring trials to allow better comparison will provide positive results in the future. PMID- 28877041 TI - Sodium MRI: a new frontier in imaging in nephrology. AB - PURPOSE OF REVIEW: This review focuses on the recent technological advances in quantitative sodium (Na) MRI to provide a noninvasive measure of tissue viability for use in clinical studies of patients with kidney disease. Na MRI is the only noninvasive imaging technique that allows for the absolute spatial quantification of tissue sodium concentration (TSC), providing assessment of the corticomedullary sodium gradient (CMSG) in the kidney, and allowing measures of TSC in the skin and muscle. RECENT FINDINGS: Na MRI of the kidney has demonstrated the sensitivity to measure the CMSG, providing the normal range in healthy individuals and demonstrating a reduction in CMSG in kidney disease and transplanted kidneys. Studies using Na and H MRI have shown that in humans, skeletal muscle and skin can store sodium without water retention, and that sodium concentrations in muscle and skin increase with advancing age. Recent studies have shown that TSC can be mobilised during haemodialysis, and that skin sodium content links closely to left ventricular mass in patients with chronic kidney disease. SUMMARY: Na MRI is currently a research technique, but with future advances, Na MRI has potential to become a noninvasive renal biomarker and a measure of tissue sodium storage for clinical studies. PMID- 28877042 TI - Hematopoietic cell transplantation for aplastic anemia. AB - PURPOSE OF REVIEW: Improvements in allogeneic hematopoietic cell transplantation (HCT) with better donor selection, conditioning regimens and graft vs. host disease prophylaxis make it reasonable to move HCT earlier in the algorithm for management of severe aplastic anemia (SAA). Recent progress in transplantation is reviewed whereas issues related to developing countries are also addressed. RECENT FINDINGS: Multiple research centers are reporting on clonality, mutations and telomere disorders in SAA, which may help to choose the most appropriate therapy upfront. Eltrombopag, in combination with immunosuppressive therapy (IST), has shown remarkable improvement over historical IST, and long-term follow up is awaited. In younger patients and in experienced centers, matched unrelated donor (MUD) and related haploidentical transplants (haplo-HCT) are being reported with survival approaching that seen with sibling transplants. Literature from resource-limited countries highlight the need to modify guidelines to make them affordable and cost-effective. Bone marrow remains the graft source of choice; peripheral blood stem cells may be acceptable in special circumstances in resource-constrained countries. SUMMARY: The potential of novel research findings and new therapeutic trials should be maximized by validation in different centers, countries and patient populations to provide personalized care to patients with aplastic anemia. PMID- 28877043 TI - One-day low-intensity combined arm-leg (Cruiser) ergometer exercise intervention: cardiorespiratory strain and gross mechanical efficiency in one-legged and two legged exercise. AB - This study aims to research whether there is a difference in cardiorespiratory variables and gross mechanical efficiency (GE) in healthy individuals during low intensity one-legged and two-legged exercise on the combined arm-leg (Cruiser) ergometer and whether motor learning occurs. The outcome of this study will support the use of the Cruiser ergometer in future as a testing and training instrument in the rehabilitation of patients with a lower limb amputation. Twenty eight healthy men participated in this randomized-controlled trial. One group (n=14) used one leg and both arms during the exercise and the other group (n=14) used both legs and both arms. All participants performed a 1-day low-intensity exercise protocol. This included a standardized pretest and post-test of three bouts of 4 min exercise at 40 W and an exercise intervention of seven bouts of 2*4 min exercise at 40 W. The one-legged and two-legged group differed significantly in the heart rate and GE between the pretest and post-test. At the post-test, the one-legged group showed motor learning. GE improved significantly in both groups over the duration of the three exercise bouts of the pretest, but it did not improve during the post-test. There are differences in cardiorespiratory variables and GE between one-legged and two-legged exercise on the Cruiser ergometer. When using this ergometer in the rehabilitation of patients with a lower limb amputation, it is important to consider these differences and the occurrence of motor learning. PMID- 28877044 TI - Novel insights into microbiome in colitis and colorectal cancer. AB - PURPOSE OF REVIEW: Microbiota is a major player in the pathogenesis of inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Here, we summarize the key advances achieved in the past 18 months (ending June 2017) toward a better understanding of the role of microbiota in colitis and CRC development. RECENT FINDINGS: Accumulating evidence shows the essential role of intestinal barrier function (e.g. mucus, IgA, LCN2, LYPD8) in protecting against bacteria induced inflammation and tumor development. Numerous signaling pathways (e.g. TLRs and NLRs), metabolites (e.g. indole, bile acids, retinoic acid) and small noncoding RNAs (e.g. miRNA) have been identified as key mediators regulating host microbe interactions in the intestine. Novel microbial drivers of colitis and tumorigenesis (e.g. Alistipes finegoldii, Atopobium parvalum, Peptostreptococcus anaerobius) have been identified and their disease-promoting activities have been described. SUMMARY: IBD-associated colorectal cancer results from a complex breakdown of communication between the host and its microbiota, involving barrier function, immune signaling and metabolites. PMID- 28877045 TI - Advances in the treatment of gastric cancer. AB - PURPOSE OF REVIEW: To review recent studies in esophagogastric cancer. RECENT FINDINGS: Positive emission tomography (PET) scan in follow-up after curative treatment of esophagogastric cancer did not lead to improved survival. In the preoperative treatment of esophagogastric cancer, the addition of the antivascular endothelial growth factor agent bevacizumab to perioperative chemotherapy with combination epirubicin, cisplatinum, and 5-fluorouracil (5-FU; ECF) failed to improve survival compared with chemotherapy alone. In a head-to head comparison of preoperative chemotherapy for locally advanced gastric and esophagogastric adenocarcinoma, FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) significantly improved overall survival compared with ECF. Assessing response to induction chemotherapy prior to combined preoperative chemoradiotherapy in PET nonresponding patients allowed a change in chemotherapy during subsequent radiotherapy with improved rates of pathologic complete response. In human epidermal growth factor receptor-2-positive advanced esophagogastric adenocarcinoma, second-line treatment with the chemotherapy/trastuzumab drug conjugate emtansine/trastuzumab failed to improve response or overall survival compared with treatment using paclitaxel chemotherapy. The immune checkpoint inhibitor, nivolumab, improved survival in refractory gastric cancer. SUMMARY: Recent studies in gastric cancer clarify the optimal preoperative chemotherapy regimen and the use of PET scan as a response measure of preoperative therapy in esophagogastric cancer, and the role of targeted agents and immune checkpoint inhibitors in metastatic disease. PMID- 28877046 TI - Quantitative Proton Spectroscopy of the Testes at 3 T: Toward a Noninvasive Biomarker of Spermatogenesis. AB - OBJECTIVES: The aim of this study was to compare testicular metabolite concentrations between fertile control subjects and infertile men. MATERIALS AND METHODS: Single voxel proton magnetic resonance spectroscopy (H-MRS) was performed in the testes with and without water suppression at 3 T in 9 fertile control subjects and 9 infertile patients (8 with azoospermia and 1 with oligospermia). In controls only, the T1 and T2 values of water and metabolites were also measured. Absolute metabolite concentrations were calculated using the unsuppressed water signal as a reference and correcting for the relative T1 and T2 weighting of the water and metabolite signals. RESULTS: Testicular T1 values of water, total choline, and total creatine were 2028 +/- 125 milliseconds, 1164 +/- 105 milliseconds, and 1421 +/- 314 milliseconds, respectively (mean +/- standard deviation). T2 values were 154 +/- 11 milliseconds, 342 +/- 53 milliseconds, and 285 +/- 167 milliseconds, respectively. Total choline concentration was lower in patients (mean, 1.5 mmol/L; range, 0.9-2.1 mmol/L) than controls (mean, 4.4 mmol/L; range, 3.2-5.7 mmol/L; P = 4 * 10). Total creatine concentration was likewise reduced in patients (mean, 1.1 mmol/L; range, undetectable -2.7 mmol/L) compared with controls (mean, 3.6 mmol/L; range, 2.5 4.7 mmol/L; P = 1.6 * 10). The myo-inositol signal normalized to the water reference was also lower in patients than controls (P = 4 * 10). CONCLUSIONS: Testicular metabolite concentrations, measured by proton spectroscopy at 3 T, may be valuable as noninvasive biomarkers of spermatogenesis. PMID- 28877047 TI - Autism-spectrum disorders in adolescence and adulthood: focus on sexuality. AB - PURPOSE OF REVIEW: The combination of the core symptoms, characterizing individuals with autism-spectrum disorder (ASD), can lead to problems in romantic relationships and sexual functioning. The purpose of this article is to review studies on sexuality in individuals with ASD published since January 2016. RECENT FINDINGS: Individuals with ASD and especially women show a higher diversity in sexual orientation in comparison with the non-ASD population. Furthermore, ASD women are more frequently in a relationship and usually report more previous sexual experiences. Up to now, sexual education programs specifically addressing the needs of the ASD population were scarce, which was criticized by patients, their parents, and caregivers. With the development of the Tackling Teenage Training program, a psychoeducational intervention designed specifically for ASD individuals was introduced, leading to significant improvements in psychosexual functioning and knowledge. Such programs are needed because a considerable rate of problematic sexual behaviors, including public masturbation and paraphilic sexual interests were found in the ASD population. SUMMARY: Just like their typically developing counterparts, individuals with ASD show the whole range of normal-to-problematic sexual behaviors. Improving sexual knowledge could lead to less inappropriate sexual behaviors and could improve sexual health as part of a healthy and satisfying life. PMID- 28877048 TI - Current opinion in otolaryngology: update on vascular injuries in craniomaxillofacial fractures. AB - PURPOSE OF REVIEW: The primary purpose of this chapter is to define current recommendations for vascular work-up of patients with craniomaxillofacial (CMF) trauma with emphasis on imaging to include intraoperative fluorescence, angiography, and surgical exploration. The second goal is to review current management recommendations for observation versus surgical exploration based on the neck zones of injury. RECENT FINDINGS: Over the past two decades, endovascular techniques are increasingly utilized, particularly in zones I and III of the neck. Additionally, modern advances in radiographic technology have allowed for selective exploration of penetrating zone II injuries. A high suspicion for blunt cerebrovascular injury should be maintained for patients with high-speed deceleration mechanisms of injury, with a majority of patients managed with medical therapy or conservative monitoring over surgical intervention. SUMMARY: CMF fractures are associated with vascular injuries to the intracranial carotid system, extracranial carotid system, or vertebral artery system. A thorough understanding of at risk patients, optimal work-up, and timely treatment algorithms is imperative given the devastating sequellae of stroke and death. PMID- 28877049 TI - Medication Errors at Hospital Admission and Discharge: Risk Factors and Impact of Medication Reconciliation Process to Improve Healthcare. AB - OBJECTIVE: First, the aim of the study was to assess the prevalence, characteristics, and severity of unintended medication discrepancies (UMDs) and medication errors (MEs) at admission and discharge of hospitalization. Second, the aim of the study was to identify clinical and hospitalization factors associated with risk of UMDs as well as characteristics of the medication reconciliation process associated with UMDs detection. METHODS: This prospective observational study included all adult patients admitted from 2013 to 2015 in the Endocrinology-Diabetology-Nutrition Department of Montpellier Hospital, France. Clinical pharmacists conducted medication reconciliation by collecting the best possible medication history from different sources and comparing it with admission and discharge prescriptions to identify discrepancies. Unintended medication discrepancies corrected by the physician were considered as MEs. Risk factors of UMDs were identified with logistic regression. RESULTS: Of 904 patients included, 266 (29.4%) had at least one UMD, at admission or at discharge. In total, 378 (98.2%) of 385 UMDs were considered to be MEs. Most MEs were omissions (59.3%). Medication errors were serious or very serious in 36% of patients and had potentially moderate severity in almost 40% of patients. The risk of UMDs increased constantly with the number of treatments (P < 0.001). Thyroid (adjusted odds ratio [OR] = 1.79, 95% CI = 1.12-2.86) and infectious diseases (adjusted OR = 1.80, 95% CI = 1.17-2.78) were associated with UMDs risk at admission. The best type of source for the detection of UMDs was the general practitioner or nurse (OR = 2.64, 95% CI = 1.51-4.63). CONCLUSIONS: Unintended medication discrepancies are frequent at hospital and depend on intrinsic clinical parameters but also on practice of medication reconciliation process, such as number and type of sources used. PMID- 28877050 TI - Metformin: oxidative and proliferative parameters in-vitro and in-vivo models of murine melanoma. AB - Cutaneous melanoma is one of the most lethal cancers because of its increased rate of metastasis and resistance to available therapeutic options. Early studies indicate that metformin has beneficial effects on some types of cancer, including melanoma. To clarify knowledge of the mechanism of action of metformin on this disease, two treatment-based approaches are presented using metformin on melanoma progression: an in-vitro and an in-vivo model. The in-vitro assay was performed for two experimental treatment periods (24 and 48 h) at different metformin concentrations. The results showed that metformin decreased cell viability, reduced proliferation, and apoptosis was a major event 48 h after treating B16F10 cells. Oxidative stress was characterized by the decrease in total thiol antioxidants immediately following 24 h of metformin treatment and showed an increase in lipid peroxidation. The in-vivo model was performed by injecting B16F10 cells into the subcutaneous of C57/BL6 mice. Treatment with metformin began on day 3 and on day 14, the mice were killed. Treatment of mice with metformin reduced tumor growth by 54% of its original volume compared with nontreatment. The decrease in systemic vascular endothelial growth factor, restoration of antioxidants glutathione and catalase, and normal levels of lipid peroxidation indicate an improved outcome for melanoma following metformin treatment, meeting a need for new strategies in the treatment of melanoma. PMID- 28877051 TI - Presenting features of extremity necrotizing fasciitis in the pediatric patient: a case-control analysis. AB - This analysis sought to develop a tool for early differentiation between pediatric necrotizing fasciitis (NF) of the extremity and more benign infection. All diagnoses of extremity NF, cellulitis, and abscess from a single institution from 2009 to 2015 were included. Vitals and laboratory values were compared between cohorts using analysis of variance and decision tree analysis. NF was associated with thrombocytopenia, hyperthermia, tachycardia, and tachypnea. Decision tree analysis identified C-reactive protein more than 7.0 to be 100% sensitive and 95.7% specific for differentiating NF from cellulitis or abscess. The results offer quantitative support for clinical suspicion of NF in the evaluation of pediatric extremity infection. PMID- 28877052 TI - Diagnostic Efficiency in Digital Pathology: A Comparison of Optical Versus Digital Assessment in 510 Surgical Pathology Cases. AB - Prior work has shown that digital images and microscopic slides can be interpreted with comparable diagnostic accuracy. Although accuracy has been well validated, the interpretative time for digital images has scarcely been studied and concerns about efficiency remain a major barrier to adoption. We investigated the efficiency of digital pathology when compared with glass slide interpretation in the diagnosis of surgical pathology biopsy and resection specimens. Slides were pulled from 510 surgical pathology cases from 5 organ systems (gastrointestinal, gynecologic, liver, bladder, and brain). Original diagnoses were independently confirmed by 2 validating pathologists. Diagnostic slides were scanned using the Philips IntelliSite Pathology Solution. Each case was assessed independently on digital and optical by 3 reading pathologists, with a >=6 week washout period between modalities. Reading pathologists recorded assessment times for each modality; digital times included time to load the case. Diagnostic accuracy was determined based on whether a rendered diagnosis differed significantly from the original diagnosis. Statistical analysis was performed to assess for differences in interpretative times across modalities. All 3 reading pathologists showed comparable diagnostic accuracy across optical and digital modalities (mean major discordance rates with original diagnosis: 4.8% vs. 4.4%, respectively). Mean assessment times ranged from 1.2 to 9.1 seconds slower on digital versus optical. The slowest reader showed a significant learning effect during the course of the study so that digital assessment times decreased over time and were comparable with optical times by the end of the series. Organ site and specimen type did not significantly influence differences in interpretative times. In summary, digital image reading times compare favorably relative to glass slides across a variety of organ systems and specimen types. Mean increase in assessment time is 4 seconds/case. This time can be minimized with experience and may be further balanced by the improved ease of electronic chart access allowed by digital slide viewing, as well as quantitative assessments which can be expedited on digital images. PMID- 28877053 TI - "Atypical" Pleomorphic Lipomatous Tumor: A Clinicopathologic, Immunohistochemical and Molecular Study of 21 Cases, Emphasizing its Relationship to Atypical Spindle Cell Lipomatous Tumor and Suggesting a Morphologic Spectrum (Atypical Spindle Cell/Pleomorphic Lipomatous Tumor). AB - The classification of the until recently poorly explored group of atypical adipocytic neoplasms with spindle cell features, for which recently the term atypical spindle cell lipomatous tumor (ASLT) has been proposed, remains challenging. Recent studies have proposed ASLT as a unique entity with (in at least a significant subset of cases) a specific genetic background, namely deletions/losses of 13q14, including RB1 and its flanking genes RCBTB2, DLEU1, and ITM2B. Similar genetic aberrations have been reported in pleomorphic liposarcomas (PLSs). This prompted us to investigate a series of 21 low-grade adipocytic neoplasms with a pleomorphic lipoma-like appearance, but with atypical morphologic features (including atypical spindle cells, pleomorphic [multinucleated] cells, pleomorphic lipoblasts and poor circumscription), for which we propose the term "atypical" pleomorphic lipomatous tumor (APLT). Five cases of PLS were also included in this study. We used multiplex ligation dependent probe amplification to evaluate genetic changes of 13q14. In addition, array-based comparative genomic hybridization was performed on 4 APLTs and all PLSs. Multiplex ligation-dependent probe amplification showed consistent loss of RB1 and its flanking gene RCBTB2 in all cases of APLT. This genetic alteration was also present in all PLSs, suggesting genetic overlap, in addition to morphologic overlap, with APLTs. However, array-based comparative genomic hybridization demonstrated more complex genetic alterations with more losses and gains in PLSs compared with APLTs. APLTs arose in the subcutis (67%) more frequently than in the deep (subfascial) soft tissues (33%). With a median follow up of 42 months, recurrences were documented in 2 of 12 APLTs for which a long follow-up was available. Herein, we also demonstrate that APLTs share obvious overlapping morphologic, immunohistochemical, genetic and clinical characteristics with the recently defined ASLT, suggesting that they are related lesions that form a spectrum (atypical spindle cell/pleomorphic lipomatous tumor). PMID- 28877054 TI - Melanotic Translocation Renal Cell Carcinoma With a Novel ARID1B-TFE3 Gene Fusion. AB - A 36-year-old male was found to have a 7.0 cm left upper pole renal mass on renal ultrasound. Following nephrectomy, the mass was grossly ill-demarcated, friable and red-brown, invading renal parenchyma, hilar fat and the renal vein. Microscopically, the tumor had a nested and papillary architecture. The cells demonstrated abundant clear and eosinophilic cytoplasm and focal intracytoplasmic melanin pigment. Nucleoli were prominent. By immunohistochemistry, the tumor was positive for TFE3; HMB-45 stained approximately 5% of tumor cells corresponding to the histologic melanin pigment, which was confirmed with Fontana-Masson stain with bleach. Immunostains for PAX8, CD10, MiTF, and CAIX were negative; keratins Cam 5.2 and AE1/AE3 were focally positive. Targeted next-generation sequencing revealed an ARID1B-TFE3 gene fusion. Melanotic Xp11 renal cell carcinoma is a rare, pigment containing translocation variant demonstrating overlapping features with melanoma and is usually associated with an SFPQ-TFE3 gene fusion. The patient is alive and without evidence of disease 7 years after his diagnosis. The combination of high grade histopathology, the presence of melanin, absent PAX8, keratin positivity, and relatively indolent clinical behavior with a unique translocation may warrant recognition as a distinct renal cell carcinoma translocation subtype. PMID- 28877055 TI - Solitary Fibrous Tumors of the Head and Neck: A Multi-Institutional Clinicopathologic Study. AB - Solitary fibrous tumors (SFTs) of the head and neck are uncommon. Lesions previously diagnosed in the head and neck as hemangiopericytomas (HPCs), giant cell angiofibromas (GCAs), and orbital fibrous histiocytomas (OFHs) are now recognized as within the expanded spectrum of SFTs. To better understand the clinicopathologic profile of head and neck SFTs, we performed a multi institutional study of 88 examples. There was no sex predilection (F:M ratio 1.2), and the median patient age was 52 years (range: 15 to above 89 y). The sinonasal tract and orbit were the most common sites involved (30% and 25%), followed by the oral cavity and salivary glands (15% and 14%). Original diagnoses included HPC (25%), SFT (67%), and OFH (6%), with 1 SFT and 1 OFH noted as showing GCA-like morphology. On review, the predominant histologic pattern was classic SFT-like in 53% and cellular (former HPC-like) in 47%; lipomatous differentiation (8%) and GCA-like pattern (7%) were less prevalent. Subsets demonstrated nuclear atypia (23%), epithelioid morphology (15%), or coagulative necrosis (6%). Infiltrative growth (49%) and osseous invasion (82%) were prevalent among evaluable cases. Of the 48 SFTs with follow-up (median: 43 mo), 19 showed recurrence (40%). Of these, 4 patients were alive with disease and 4 dead of disease. Size and mitotic rate were negative prognosticators using a joint prognostic proportional hazards regression model. Three patients experienced metastasis, to lungs, parotid, bone, and skull base, including one case showing overtly sarcomatous "dedifferentiation." As a group, SFTs present in a wide anatomic and morphologic spectrum in the head and neck. Only rare examples metastasize or cause death from disease. However, the fairly high local recurrence rate underscores their aggressive potential and highlights the importance of prospective recognition. PMID- 28877056 TI - PAX8 Expression in a Subset of Malignant Peritoneal Mesotheliomas and Benign Mesothelium has Diagnostic Implications in the Differential Diagnosis of Ovarian Serous Carcinoma. AB - Distinguishing malignant peritoneal mesothelioma (MPM) from serous carcinoma involving the peritoneum remains a diagnostic challenge, particularly in small biopsy and cytology specimens. In this distinction, PAX8 expression has been regarded as a specific marker of serous carcinoma. In addition, BAP1 loss is reportedly specific to MPM, in the distinction from both benign mesothelial lesions and ovarian serous tumors (OSTs). Using immunohistochemistry, we examined PAX8 and BAP1 expression in 27 MPMs, 25 cases of benign mesothelium, and 45 OSTs. Five MPMs were PAX8 (5/27, 18%), while 8 cases of benign mesothelium expressed PAX8 (8/25, 32%). PAX8 expression in mesothelium was significantly more common in women than in men (P=0.01). Sixteen MPMs exhibited BAP1 loss (16/25, 64%), while BAP1 was retained in all benign mesothelium and all OSTs. All cases of PAX8 mesothelium were negative for expression of estrogen receptor. These data show that PAX8 is expressed in both benign and malignant mesothelium, and that BAP1 loss is highly specific for MPM, in the differential with both benign mesothelial proliferations and OTSs. These results also have implications for primary diagnosis and for pathologic staging of OST. Caution should be applied when PAX8 expression is used to distinguish mesothelial and serous proliferations, and BAP1 loss may be confirmatory in cases where mesothelioma is favored. PMID- 28877057 TI - Pleuroparenchymal Fibroelastosis: A Review of Histopathologic Features and the Relationship Between Histologic Parameters and Survival. AB - Pleuroparenchymal fibroelastosis (PPFE) is now a defined clinicopathologic entity in the updated 2013 ATS/ERS classification of idiopathic interstitial pneumonias (IIPs), which has led to a significant increase in cases being diagnosed at our institution. We have therefore reviewed 43 PPFE cases (58 biopsies in total) to assess whether any clinical or histopathologic features provide prognostic information. A semiquantatitive grading system was used to assess extent of fibroblastic foci, intra-alveolar fibroelastosis, visceral pleural fibrosis, chronic inflammation in areas of fibrosis, vascular fibrointimal thickening, and presence of granulomas. Other patterns of interstitial lung disease were also noted, if present. All biopsies showed intra-alveolar fibroelastosis, fibroblastic foci at the leading edge of fibrosis and chronic inflammation within areas of fibrosis, 91% showed vascular fibrointimal thickening of vessels, 73% showed pleural fibrosis, and 35% showed granulomas. Ten cases showed a coexistent IIP (5 showed usual interstitial pneumonia, 5 showed features of hypersensitivity pneumonitis). There was no significant correlation with mortality and severity of histologic parameters, other than a significant decrease in mortality in PPFE with coexistent granulomas, after adjusting for age and gender (hazard ratio, 0.27; P=0.049). Male gender was also associated with an increased risk of mortality, after adjusting for age (hazard ratio, 4.8; P=0.045). PPFE is more common than previously thought, not infrequently showing coexistent pathology, specifically usual interstitial pneumonia and granulomatous lung disease, our data suggesting the latter may have prognostic significance. PMID- 28877058 TI - Nonuniform Distribution of High-risk Human Papillomavirus in Squamous Cell Carcinomas of the Oropharynx: Rethinking the Anatomic Boundaries of Oral and Oropharyngeal Carcinoma From an Oncologic HPV Perspective. AB - The oral cavity and oropharynx have historically been viewed as a single anatomic compartment of the head and neck. The practice of combining the oral cavity and oropharynx has recently been revised, largely owing to the observation that human papillomavirus (HPV)-related carcinogenesis has a strong predilection for the oropharynx but not the oral cavity. The purpose of this study was to determine whether HPV is evenly distributed across squamous cell carcinomas of the oropharynx including those sites that do not harbor tonsillar tissues such as the soft palate. A search of the medical records of the Johns Hopkins Hospital identified 32 primary squamous cell carcinomas of the soft palate (n=31) and posterior pharyngeal wall (n=1). All were evaluated with p16 immunohistochemistry and high-risk HPV in situ hybridization (ISH) (29 by RNA ISH and 3 by DNA ISH). For comparison, we also reviewed the medical records to obtain the HPV status of patients who had undergone HPV testing of primary tonsillar carcinomas over the same time interval as part of their clinical care. High-risk HPV as detected by ISH was present in just 1 (3.1%) of the 32 oropharyngeal squamous cell carcinomas, including 1 of 2 p16-positive carcinomas. The difference in HPV detection rates between tonsillar and nontonsillar sites was significant (1/32, 3.1% vs. 917/997, 92%; P<0.0001). HPV is not frequently detected in squamous cell carcinomas arising from nontonsillar regions of the oropharynx. Indeed, squamous cell carcinomas of the soft palate more closely resemble those arising in the oral cavity than those arising in areas of the oropharynx harboring tonsillar tissue. This finding not only further sharpens our understanding of site-specific targeting by HPV, but may have practical implications regarding HPV testing and even the way the oral vault is oncologically compartmentalized to partition HPV positive from HPV-negative cancers. PMID- 28877059 TI - Choriocarcinoma in Women: Analysis of a Case Series With Genotyping. AB - Choriocarcinoma is an uncommon malignant neoplasm, which can be either gestational or nongestational in origin. Distinction of these subtypes has prognostic and therapeutic implications. Twenty-two tumors were genotyped using polymerase chain reaction amplification of 15 short tandem repeat loci and the amelogenin locus (XY determination). DNA patterns from tumor and maternal tissue, as well as villous tissue from any available prior or concurrent gestation, were compared, to determine gestational versus nongestational nature (containing vs. lacking a paternal chromosome complement, respectively) and the relationship between the tumor and any prior or concurrent gestation. Nineteen tumors were gestational. Of these, 14 were purely androgenetic/homozygous XX: 6 uterine tumors with a concurrent or prior genetically related complete hydatidiform mole (CHM), 4 uterine tumors without an accompanying villous component, 1 uterine cornual tumor separate from a genetically distinct second trimester intrauterine placenta, 1 ectopic ovarian tumor separate from a genetically distinct third trimester intrauterine placenta, and 2 ectopic fallopian tube tumors. Five gestational tumors were biparental: 3 (2 XX, 1 XY) intraplacental choriocarcinomas genetically related to the placenta and 2 uterine tumors without accompanying placental tissue after term deliveries (1 XX 4 weeks postpartum and 1 XYY with allelic imbalances 1 year postpartum; prior placentas not available for analysis). Three tumors were nongestational: all XX with allelic imbalances; 2 ovarian, 1 pelvic. Gestational choriocarcinoma can be androgenetic or biparental. Most are androgenetic/homozygous XX, often associated with a genetically related concurrent or prior CHM, and thus of molar-associated type. These findings support that homozygous XX CHMs are associated with some risk of significant gestational trophoblastic disease. Intraplacental choriocarcinomas are biparental and genetically related to the placenta. Biparental choriocarcinoma detected in a postpartum uterine sample is consistent with undetected intraplacental choriocarcinoma. Eutopic or ectopic androgenetic choriocarcinoma separate from a concurrent intrauterine placenta is not derived from intraplacental tumor and is consistent with either a form of dispermic twin gestation (molar-type choriocarcinoma and coexistent nonmolar fetus) or origin from an antecedent molar pregnancy. While fallopian tube tumors are usually gestational, tumors in other sites (ovary, pelvis) can be nongestational and should not be assumed to be metastatic from a regressed or occult intrauterine or intraplacental gestational tumor. PMID- 28877060 TI - Clinicopathologic Diversity of Undifferentiated Sarcoma With BCOR-CCNB3 Fusion: Analysis of 11 Cases With a Reappraisal of the Utility of Immunohistochemistry for BCOR and CCNB3. AB - Undifferentiated sarcoma harboring the BCOR-CCNB3 fusion is characterized by its predilection to affect skeletons of adolescent males, cellular small round/spindle cell morphology, and CCNB3 immunoreactivity. We analyzed 11 cases of BCOR-CCNB3 sarcoma, 10 of which were identified in a reverse transcription polymerase chain reaction-based screen of 85 patient samples recorded in our database as unclassified small round or spindle cell sarcomas. BCOR rearrangements were confirmed by fluorescence in situ hybridization in 8 tumors. All patients were males aged between 6 and 31 years. In addition to 5 tumors in soft tissue and 4 in the axial or appendicular skeletons, which are typical locations, a tumor was located in the paranasal sinus and another in the lung. Microscopically, the tumors comprised proliferating atypical spindle and/or small round cells with diverse morphologic features such as small concentric whorls, myxoid stroma, a hemangiopericytomatous appearance, and/or hyalinized collagen resembling a solitary fibrous tumor, and angiomatous or slit-like spaces containing extravasated erythrocytes. Tumor cells were immunoreactive to CCNB3 (9/11), BCOR (10/10), TLE1 (6/10), bcl-2 (9/11), CD99 (8/10), CD56 (8/10), c-kit (4/10), and cyclin D1 (10/10). In an immunohistochemical analysis of an additional 412 small round or spindle cell tumors, CCNB3 was detected in 6 (1.5%) and BCOR in 18 (4.4%). Our analysis highlights the varying clinicopathologic features of this tumor, which partially overlap with other small round or spindle cell tumors, including solitary fibrous tumor and vascular tumors. Because CCNB3 and BCOR immunohistochemistry lacks adequate sensitivity and specificity, a molecular genetic approach remains essential for diagnosis. PMID- 28877061 TI - MAML2 Rearrangements in Variant Forms of Mucoepidermoid Carcinoma: Ancillary Diagnostic Testing for the Ciliated and Warthin-like Variants. AB - Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. Recent studies have shown that most MECs harbor gene fusions involving MAML2-an alteration that appears to be specific for MEC, a finding that could be diagnostically useful. While most cases of MEC are histologically straightforward, uncommon variants can cause considerable diagnostic difficulty. We present 2 variants of MEC for which MAML2 studies were crucial in establishing a diagnosis: a previously undescribed ciliated variant, and the recently described Warthin-like variant. All cases of ciliated and Warthin-like MEC were retrieved from the archives of The Johns Hopkins Hospital. Break-apart fluorescence in situ hybridization for MAML2 was performed on all cases. One ciliated MEC and 6 Warthin-like MECs were identified. The ciliated MEC presented as a 4.6 cm cystic lymph node metastasis originating from the tongue base in a 47 year-old woman. The Warthin-like MECs presented as parotid masses ranging in size from 1.2 to 3.3 (mean, 2.7 cm) in 4 women and 2 men. The ciliated MEC consisted of macrocystic spaces punctuated by tubulopapillary proliferations of squamoid cells and ciliated columnar cells. The Warthin-like MECs were comprised of cystic spaces lined by multilayered oncocytic to squamoid cells surrounded by a circumscribed cuff of lymphoid tissue with germinal centers. In these cases, the Warthin-like areas dominated the histologic picture. Conventional MEC, when present, represented a minor tumor component. MAML2 rearrangements were identified in all cases. Warthin-like MEC, and now a ciliated form of MEC, are newly described variants of a common salivary gland carcinoma. Unfamiliarity with these novel forms, unanticipated cellular features (eg, cilia), and morphologic overlap with mundane benign processes (eg, developmental ciliated cysts, Warthin tumor) or other carcinomas (eg, ciliated human papillomavirus-related carcinoma) may render these variants susceptible to misdiagnosis. These unusual variants appear to consistently harbor MAML2 fusions-a finding that establishes a clear link to conventional MEC and provides a valuable adjunct in establishing the diagnosis. PMID- 28877063 TI - Sentinel Lymph Nodes in Classic Invasive Lobular Carcinoma of the Breast: Cytokeratin Immunostain Ensures Detection, and Precise Determination of Extent, of Involvement. AB - The assessment of sentinel lymph nodes (SLN) on hematoxylin and eosin (H&E) stained sections in cases of classic type of invasive lobular carcinoma (cILC) is considered unreliable, particularly in cases with minimal involvement, that is by either isolated tumor cells (pN0i+) or micrometastases (pN1mi). Although the impact of minimal SLN involvement has been shown to be insignificant in most clinical trials (even though cILC was either under-represented or not separated in the respective cohorts), the results of MIRROR trial did emphasize the need for additional therapy in cases with minimally involved SLN to ensure improved disease-free survival. We sought to study the role of cytokeratin immunohistochemistry (CK-IHC) in evaluating SLN in cILC. A total of 582 cILC cases with SLN diagnosed over a 12-year period (2005 to 2016) were reviewed. In all, 394/582 (68%) cases had H&E(-)/CK(-) SLN. In total, 188/582 (32%) cases showed some degree of SLN involvement of which 143/582 (25%) cases had readily identifiable SLN involvement on H&E slides. Overall, 45/582 (7.7%) cases had H&E( )/CK(+) SLN. The following data relate to the latter subset of 45 cases. Mean age of patients: 61 y (range: 32 to 86 y); right: 24 (53%), left: 21 (47%); multifocal and/or multicentric: 22 (49%); mean size: 2.0 cm (range: 0.25 to 4.4 cm); mean number of SLN: 2.5; mean number of involved SLN: 1.2; and cases with prior needle core or excisional biopsy: 45 (100%). CK(+) cells were identified in isolation or in loose clusters, either in subcapsular sinuses or nodal cortex or both. Overall, 30/45 (67%) showed <=200 CK(+) cells (ie, pN0i+), and 15/45 (33%) showed >200 CK(+) cells (ie, pN1mi). In total, 15/45 (33%) cases underwent axillary lymph node dissection, of which 4/45 (9%) cases were positive. cILC recurred in 3/45 (7%) cases. On statistical analyses, the number of CK(+) cells (<=/>200) did not correlate with either axillary lymph node-positivity or with recurrence. Number of CK(+) cells (<=/>200) readily distinguished pN0i+ from pN1mi based on AJCC's numerical criteria. CK(+) cells could be quantified in linear terms (ie, AJCC's size criteria of pN0i+ and pN1mi was applicable) in only 2 cases. On the basis of these findings, the use of CK-IHC staining should be considered for SLN in cases of cILC to ensure detection, and precise determination of extent, of involvement; however, the prognostic significance of this procedure would have to await results of additional studies with long-term follow-up. PMID- 28877062 TI - Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas: Expanding the Genetic Spectrum of Tumors With Overlapping Features With Infantile Fibrosarcoma. AB - Infantile fibrosarcomas (IFS) represent a distinct group of soft tissue tumors occurring in patients under 2 years of age and most commonly involving the extremities. Most IFS show recurrent ETV6-NTRK3 gene fusions, sensitivity to chemotherapy, and an overall favorable clinical outcome. However, outside these well-defined pathologic features, no studies have investigated IFS lacking ETV6 NTRK3 fusions, or tumors with the morphology resembling IFS in older children. This study was triggered by the identification of a novel SEPT7-BRAF fusion in an unclassified retroperitoneal spindle cell sarcoma in a 16-year-old female by targeted RNA sequencing. Fluorescence in situ hybridization screening of 9 additional tumors with similar phenotype and lacking ETV6-NTRK3 identified 4 additional cases with BRAF gene rearrangements in the pelvic cavity (n=2), paraspinal region (n=1), and thigh (n=1) of young children (0 to 3 y old). Histologically, 4 cases including the index case shared a fascicular growth of packed monomorphic spindle cells, with uniform nuclei and fine chromatin, and a dilated branching vasculature; while the remaining case was composed of compact cellular sheets of short spindle to ovoid cells. In addition, a minor small blue round cell component was present in 1 case. Mitotic activity ranged from 1 to 9/10 high power fields. Immunohistochemical stains were nonspecific, with only focal smooth muscle actin staining demonstrated in 3 cases tested. Of the remaining 5 BRAF negative cases, further RNA sequencing identified 1 case with EML4-NTRK3 in an 1-year-old boy with a foot IFS, and a second case with TPM3 NTRK1 fusion in a 7-week-old infant with a retroperitoneal lesion. Our findings of recurrent BRAF gene rearrangements in tumors showing morphologic overlap with IFS expand the genetic spectrum of fusion-positive spindle cell sarcomas, to include unusual presentations, such as older children and adolescents and predilection for axial location, thereby opening new opportunities for kinase targeted therapeutic intervention. PMID- 28877064 TI - Desmoplastic Pattern at the Tumor Front Defines Poor-prognosis Subtypes of Colorectal Cancer. AB - Although recent findings of cancer biology research indicate that prognostic power arises from genes expressed by stromal cells rather than epithelial cells, desmoplastic reaction (DR) has not been completely examined as a prognostic marker for colorectal cancer. A pathologic review of 821 stage II and III patients who underwent R0 resection for colorectal cancer at 4 independent institutions was conducted. DR was classified as mature, intermediate, or immature based on the existence of hyalinized keloid-like collagen and myxoid stroma at the extramural desmoplastic front. Totally, 325, 282, and 214 patients were classified as having mature, intermediate, and immature DR, respectively. DR significantly influenced the recurrence rate in the liver, lung, and peritoneum (P<=0.0001 to 0.01). Five-year relapse-free survival (RFS) rate was the highest in the mature group (85.7%), followed by the intermediate (77.3%) and immature (50.4%) groups. A significant adverse impact of immature stroma on RFS was observed in subset analyses of the 4 institutions. Multivariate analysis revealed that DR, along with T and N stages, is an independent prognostic factor. On the basis of Harrell's concordance index, the prognostic power of DR categorization (0.67) in stratifying RFS was greater than any other conventional prognostic factors, including TNM (0.64), N (0.62) and T stages (0.59), venous invasion (0.59), and tumor grade (0.54). Characterizing DR based on the histologic products of activated fibroblasts is valuable for evaluating prognostic outcomes. To our knowledge, this is the first study reporting a greater prognostic power of histology of the fibrotic stroma than that of tumor factors. PMID- 28877066 TI - Clinicopathologic and Molecular Characteristics of Synchronous Colorectal Carcinoma With Mismatch Repair Deficiency. AB - Synchronous colorectal carcinoma (CRC) is a unique disease associated with a high prevalence (~35%) of microsatellite instability and occasionally with Lynch syndrome. The clinicopathologic and molecular features of synchronous CRC are poorly understood, particularly in Japanese patients. We examined 118 Japanese patients (236 tumors) with synchronous CRC and 117 Japanese patients (117 tumors) with solitary CRC with immunohistochemical staining for TP53 and mismatch repair (MMR) protein (MLH1, MSH2, PMS2, and MSH6) and mutation analyses of KRAS and BRAF genes. The results revealed no significant differences in clinicopathologic, histologic, and molecular findings between the synchronous and solitary CRC groups. Among the 118 synchronous CRC patients, 15 (12.7%) showed loss of MMR protein(s) expression in at least 1 tumor, whereas 103 (87.3%) showed intact expression of all 4 MMR proteins in both tumors. Of note, all patients with MMR deficiency had excellent prognoses. The 15 patients were further subdivided into 2 groups: the Concordant group, with concordant MMR loss (n=9, 7.6%) and the Discordant group, with discordant MMR loss (n=6, 5.1%). The Concordant patients showed concurrent MLH1/PMS2 loss (n=3), concurrent MSH2/MSH6 loss (n=4) and isolated MSH6 loss (n=2) in both tumors, whereas the Discordant patients showed concurrent MLH1/PMS2 loss (n=2), isolated PMS2 loss (n=2) and isolated MSH6 loss (n=2) in a single tumor. On the basis of the MMR expression pattern and BRAF mutation, the Concordant and Discordant groups were suspected to include Lynch syndrome, Lynch-like syndrome and sporadic MLH1 promoter hypermethylated CRC. In addition, KRAS mutation was present in only 1 tumor in a single patient in each group. In conclusion, the frequency of MMR protein deficiency in synchronous CRC in the Japanese population may be lower compared with the reported data from Western populations. MMR protein loss and KRAS and BRAF mutations in synchronous CRCs were heterogenous even in an individual patient. PMID- 28877065 TI - HPV-related Multiphenotypic Sinonasal Carcinoma: An Expanded Series of 49 Cases of the Tumor Formerly Known as HPV-related Carcinoma With Adenoid Cystic Carcinoma-like Features. AB - Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a peculiar neoplasm that is restricted to the sinonasal tract, exhibits features of both a surface-derived and salivary gland carcinoma (particularly adenoid cystic carcinoma), and is associated with high-risk HPV. Given the limited number of published cases, the full clinicopathologic spectrum of this neoplasm is unclear. Here, we present an updated experience of 49 cases. All cases of HMSC were obtained from the authors' files. Immunohistochemistry for p16, c-kit, and myoepithelial cell markers (S100, actin, calponin, p63, and/or p40) was performed along with RNA in situ hybridization for HPV (type 33-specific as well as a high-risk cocktail). Fluorescence in situ hybridization studies for fusions of MYB, NFIB, and MYBL1 was performed on a subset of cases. Clinical follow-up was obtained from medical records. A total of 49 cases of HMSC were collected. Twenty-eight (57%) were from women and 18 (43%) from men, ranging in age from 28 to 90 years (mean, 54 y). Of 40 cases with detailed staging information, 43% of HMSCs presented with a high T-stage (T3 or T4). Histologically, most grew predominantly as solid nests of basaloid cells exhibiting high mitotic rates and frequent necrosis, with histologic and immunohistochemical evidence of myoepithelial differentiation. Most cases also demonstrated foci of cribriform and/or tubular growth, along with an inconspicuous population of ducts. Thirty-four (69%) cases demonstrated an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa. Less consistent histologic features included squamous differentiation within the invasive tumor (n=6), sarcomatoid transformation (n=5) including overt chondroid differentiation (n=3), and prominent epithelial-myoepithelial carcinoma-like growth (n=3). All cases were positive for p16 by immunostaining and HPV by RNA in situ hybridization. Thirty three (67%) were positive for HPV 33. No cases tested for MYB, MYBL1, or NFIB gene fusions were positive. In the 38 cases with follow-up data, (mean follow-up, 42 mo) 14 recurred locally and 2 metastasized (lung, finger). There were no regional lymph node metastases, and no tumor-related deaths. HMSC is a distinct sinonasal neoplasm characterized by myoepithelial differentiation, frequent surface epithelial involvement, and the presence of high-risk HPV (especially type 33). Although it classically exhibits a cribriforming pattern that closely resembles adenoid cystic carcinoma, our expanded series highlights a histologic spectrum that is much broader than previously recognized, warranting a change in terminology. HMSC usually presents as a large and destructive sinonasal mass with high-grade histologic features, but it paradoxically behaves in a relatively indolent manner, underscoring the importance of distinguishing HMSC from true adenoid cystic carcinoma, squamous cell carcinoma, and other histologic mimickers. PMID- 28877067 TI - Diagnostic and Prognostic Biomarkers of Adrenal Cortical Carcinoma. AB - The diagnosis of low-grade adrenal cortical carcinoma (ACC) confined to the adrenal gland can be challenging. Although there are diagnostic and prognostic molecular tests for ACC, they remain largely unutilized. We examined the diagnostic and prognostic value of altered reticulin framework and the immunoprofile of biomarkers including IGF-2, proteins involved in cell proliferation and mitotic spindle regulation (Ki67, p53, BUB1B, HURP, NEK2), DNA damage repair (PBK, gamma-H2AX), telomere regulation (DAX, ATRX), wnt-signaling pathway (beta-catenin) and PI3K signaling pathway (PTEN, phospho-mTOR) in a tissue microarray of 50 adenomas and 43 carcinomas that were characterized for angioinvasion as defined by strict criteria, Weiss score, and mitotic rate-based tumor grade. IGF-2 and proteins involved in cell proliferation and mitotic spindle regulation (Ki67, p53, BUB1B, HURP, NEK2), DNA damage proteins (PBK, gamma-H2AX), regulators of telomeres (DAXX, ATRX), and beta-catenin revealed characteristic expression profiles enabling the distinction of carcinomas from adenomas. Not all biomarkers were informative in all carcinomas. IGF-2 was the most useful biomarker of malignancy irrespective of tumor grade and cytomorphologic features, as juxtanuclear Golgi-pattern IGF-2 reactivity optimized for high specificity was identified in up to 80% of carcinomas and in no adenomas. Loss rather than qualitative alterations of the reticulin framework yielded statistical difference between carcinoma and adenoma. Angioinvasion defined as tumor cells invading through a vessel wall and intravascular tumor cells admixed with thrombus proved to be the best prognostic parameter, predicting adverse outcome in the entire cohort as well as within low-grade ACCs. Low mitotic tumor grade, Weiss score, global loss of DAXX expression, and high phospho-mTOR expression correlated with disease-free survival, but Weiss score and biomarkers failed to predict adverse outcome in low-grade disease. Our results underscore the importance of careful morphologic assessment coupled with ancillary diagnostic and prognostic biomarkers of ACC. PMID- 28877068 TI - MC225, a Novel Probe for P-glycoprotein PET Imaging at the Blood-brain Barrier: In Vitro Cardiovascular Safety Evaluation. AB - The P-glycoprotein (P-gp) substrate MC225, at concentrations <=10 nM, is a valuable radiotracer for positron emission tomography imaging of P-gp function in rats and mice. The aim of this study was to evaluate its potential toxic hazard toward the cardiovascular system through an in-depth analysis of its effects on rat aorta rings, on CaV1.2 channel current (ICa1.2) of A7r5 cells and on Langendorff-perfused rat heart. In aortic rings, MC225 relaxed phenylephrine induced contraction in a concentration-dependent and endothelium-independent manner, with an IC50 value of about 1 MUM. At concentrations >=3 MUM, it antagonized the response to cumulative concentrations of K. MC225, 1 and 10 MUM, inhibited ICa1.2 by 15% and 31%, respectively, without affecting either current activation or inactivation kinetics. In Langendorff-perfused rat hearts, only 10 MUM MC225 significantly decreased left ventricular pressure and increased coronary perfusion pressure while reducing heart rate and prolonging the cardiac cycle length as well as the atrioventricular conduction time (PQ interval) on the electrocardiogram. Lower concentrations of the drug were ineffective. These findings demonstrate that MC225-induced cardiovascular effects took place at concentrations that are at least 2 orders of magnitude higher than those allowing in vivo measurement of P-gp function. Therefore, MC225 represents a promising positron emission tomography tool for in vivo straightforward P-gp quantification. PMID- 28877069 TI - Androgen Receptor is Mostly Not Expressed in Gastric Cancers. PMID- 28877070 TI - Effects of Hydrochloric Acid and Formic Acid Decalcification on Breast Tumor Biomarkers and HER2 Fluorescence In Situ Hybridization. AB - Biomarker analysis of metastatic breast carcinoma (MBC) is routinely recommended by ASCO/CAP guidelines, and establishing a diagnosis of MBC often requires immunohistochemistry (IHC). The reliability of breast tumor biomarkers and breast specific markers on decalcified tissues has not been extensively studied. We performed IHC studies on breast tumors exposed to hydrochloric acid (HCl) and formic acid (FA) decalcification solutions, and HER2 fluorescence in situ hybridization on a subset of these tumors to establish a protocol for handling bone specimens with suspicion for MBC. Fifteen fresh cases of primary breast carcinoma and 8 HER2+ paraffin-embedded core biopsy cases were studied. Fresh tissue was divided into 5 fragments to approximate a bone core biopsy. One fragment (control) was fixed in 10% neutral buffered formalin. The remaining fragments were also exposed to FA or HCl decalcification for 1 or 5 hours. All fragments were embedded in 1 block and tested with an IHC panel. The known HER2+ cases were exposed to either 1 or 5 hours of FA, and HER2 fluorescence in situ hybridization was also performed. Results were interpreted as follows: H-scores for estrogen receptor, progesterone receptor, and GATA-3 were assigned from 0 to 300; HER2, cytokeratin 7, gross cystic disease fluid protein-15, Pax-8, TTF-1, cytokeratin 20, and mammaglobin were scored from 0 to 3+; and Ki67 from 0% to 100%. Mean scores were compared using the t test or Wilcoxon test for paired samples. No significant differences in mean score were seen between NF and 1 hour FA for any IHC immunoreactivity. After 5 hours of FA, only Ki67 average score was significantly less than NF. Mean scores for estrogen receptor, progesterone receptor, HER2, Ki67, and GATA-3 were significantly lower than NF in the tissue after either 1 or 5 hours of HCl. Mean scores for gross cystic disease fluid protein-15, mammaglobin, and cytokeratin 7 staining were not significantly lower than NF after 1 or 5 hours of HCl. PMID- 28877071 TI - Uncommon Localization of Extrarenal Xp11.2 Translocation-associated Renal Cell Carcinoma (RCC): Case Report. AB - The World Health Organization has recognized Xp11.2 translocation-associated renal cell carcinoma (RCC) as a distinct neoplasm that arises within the kidney. Although many reports of extrarenal carcinoma may be found in the literature, to the best of our knowledge, Xp11 translocation-associated RCC with intact kidneys has not been documented. This report describes a multilobulated right retroperitoneal soft tissue mass (7.9*5.3*12.6 cm) of a 37-year-old man complaining of abdominal pain in the right side. The patient underwent a computed tomography-guided biopsy. Microscopic evaluation reveals a tumor with papillary and sheaths architectures with cells revealing clear to eosinophilic cytoplasm. Immunohistochemical evaluation on the biopsy reveals that the tumor is positive for PAX-8, CD10, and TFE3. It is negative for CK7, EMA, Vimentin, RCC, CK8/18, D20, CD3, PLAP, OCT4, CD30, MART-1, Inhibin, S-100, HMB-45, Desmin, SMA, and DOG 1. The diagnosis was malignant epithelioid neoplasm and the diagnosis of translocation RCC was suggested. Excision was recommended. The patient underwent right radical nephrectomy with removal of this large mass. Pathologic examination showed a large cystic and solid, nonhomogenous mass with some necrotic areas, originating from the perirenal fat between the adrenal gland and the kidney. Microscopic features showed a tumor with papillary, rhabdoid, and clear cell features. Immunohistochemical stains showed that the tumor cells positively expressed AMACR, PAX-8, CD10, RCC, and TFE3, but were negative for cytokeratins, vimentin, HMB-45, desmin, SMA, EMA, and MSA. Cytogenetic studies confirmed the diagnosis of Xp11.2 translocation-associated RCC with positive TFE3 gene rearrangement. To the best of our knowledge, this type of extrarenal tumor has never been reported. PMID- 28877072 TI - Does Differentiated Squamous Intraepithelial Neoplasia Occur in the Cervix? AB - BACKGROUND: Invasive cervical cell squamous carcinoma (ICC) classically develops from high grade cervical intraepithelial neoplasia of usual type (uCIN). Differentiated cervical intraepithelial neoplasia (dCIN) analogue to differentiated vulvar intraepithelial neoplasia has not been described in the cervix. METHODS: A pilot case of ICC developing from dCIN with atypia limited to the basal/parabasal layers, focally associated with neoplastic spread above the parabasal layer (usual-like CIN pattern or u-like CIN) was identified. The previous cervical biopsy was under-diagnosed as low grade CIN. A total of 33 consecutive cases of ICC were reviewed to identify dCIN, u-like CIN and uCIN. RESULTS: The ICC developed from dCIN/u-like CIN in 2 patients, 46 and 47-year-old (group 1), mixed dCIN/u-like CIN and uCIN in 7 patients, 36+/-3-year-old (group 2) and from uCIN in 24 patients, 47+/-9-year-old (group 3). In group 1, focal uCIN but not connected to ICC was also seen and Pap smears showed only hyper keratinized cells with mildly atypical nuclei. Endocervical gland involvement by CIN was absent in group 1, focal in group 2 and extensive in group 3. All cases showed diffuse p16 staining. P53 reactivity was noted in basal/parabasal in dCIN, predominantly lower and upper parts of the epithelium in groups 2 and 3, respectively. CONCLUSIONS: Totally, 27% of ICC cases had associated dCIN/u-like CIN and in younger patients than in the uCIN group. Larger studies are needed to confirm dCIN/u-like CIN as significant precursor lesions of ICC. PMID- 28877073 TI - ERG1 Immunohistochemistry: Relevance for Lymph Node Histiocytosis. PMID- 28877074 TI - GATA3 Immunohistochemical Staining in Hodgkin Lymphoma: Diagnostic Utility in Differentiating Classic Hodgkin Lymphoma From Nodular Lymphocyte Predominant Hodgkin Lymphoma and Other Mimicking Entities. AB - BACKGROUND: Classic Hodgkin lymphoma (CHL) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) are clinically distinct entities, with different prognostic and treatment implications. In addition, several large B-cell lymphomas and some T-cell lymphomas can mimic CHL. Differentiating these entities from CHL is crucial for ensuring appropriate therapy. GATA3 is a T-cell transcription factor involved in T-cell maturation and has been previously shown to be overexpressed in CHL cells via gene expression profiling. We investigated the utility of GATA3 immunostain in differentiating CHL from NLPHL and other mimicking entities. MATERIALS AND METHODS: We accrued 17 NLPHLs, 49 CHLs [23 nodular sclerosis (NS), 3 syncytial variants, 3 lymphocyte rich and 13 mixed cellularity types], 4 primary mediastinal large B-cell lymphomas (PMBLs), 2 Epstein-Barr virus (EBV) positive diffuse large B-cell lymphomas (DLBCLs) (EBV+LBCLs), 2 T-cell/histiocyte-rich large B-cell lymphomas (TCHRBCLs), 1 gray zone lymphoma, and 2 tissue microarrays consisting of 72 DLBCLs. One slide from each was stained with GATA3 and percent positive tumor cells and intensity of nuclear expression was semiquantitatively graded independently by 2 board certified hematopathologists. RESULTS: GATA3 was positive in 80% of CHLs. Both percent positivity and intensity of staining varied greatly. Syncytial variant of NS subtype showed the highest positivity rate (3/3; 100%), followed by NS (20/23; 87%), mixed cellularity (9/13; 70%), and lymphocyte rich (2/3; 67%). GATA3 was negative in all NLPHLs, EBV+LBCLs, TCRBCLs, and DLBCLs stained. The single gray zone lymphoma and 3/4 PMBLs were positive. CONCLUSIONS: Nuclear expression of GATA3 can be used to delineate CHL from NLPHL. GATA3 positivity effectively excludes NLPHL with 100% negative predictive value. However, as 20% of CHL can be negative for GATA3, CHL cannot be ruled out with negative GATA3. Additional findings include GATA3 positivity among PMBLs, whereas all 72 DLBCLs were negative for GATA3. This finding further highlights similarities between CHL and PMBL. PMID- 28877075 TI - Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy. AB - Immunotherapy has shown promising results in various types of cancers. Checkpoint inhibitor drugs developed for cancer immunotherapy have been approved by the US Food and Drug Administration (FDA) for patients with advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancers, and refractory Hodgkin lymphoma. In the latest announcement, the FDA has granted accelerated approval to pembrolizumab for pediatric and adult patients with microsatellite instability high (MSI-H) or mismatch repair-deficient solid tumors. This is the first time the agency has approved a cancer treatment based on a common biomarker rather than organ-based approach. MSI-H, either due to inherited germline mutations of mismatch repair genes or epigenetic inactivation of these genes, is found in a subset of colorectal and noncolorectal carcinomas. It is known that MSI-H causes a build up of somatic mutations in tumor cells and leads to a spectrum of molecular and biological changes including high tumor mutational burden, increased expression of neoantigens and abundant tumor-infiltrating lymphocytes. These changes have been linked to increased sensitivity to checkpoint inhibitor drugs. In this mini review, we provide an update on MSI-related solid tumors with special focus on the predictive role of MSI for checkpoint immunotherapy. PMID- 28877076 TI - Disruption of the with no lysine kinase-STE20-proline alanine-rich kinase pathway reduces the hypertension induced by angiotensin II. AB - OBJECTIVE: The hypertensive effect of angiotensin II (AngII), a peptide hormone, is dependent on its intrarenal actions and the activation of the renal Na-Cl cotransporter (NCC), by AngII requires integrity of the with no lysine kinase/STE20-proline alanine-rich kinase (WNK/SPAK) signaling pathway. Here, we analyzed if the integrity of the WNK/SPAK pathway is required for AngII infusion to induce arterial hypertension. METHODS: We tested the effect of AngII or aldosterone administration on the blood pressure and on pNCC/NCC ratio in SPAK knock-in mice in which the kinase and thus NCC cannot be activated by WNK kinases. AngII or aldosterone was infused at 1440 or 700 MUg/kg per day, respectively, for 14 days using osmotic minipumps. The aldosterone-treated mice were exposed to NaCl drinking water (1%) during the hormone administration. The arterial blood pressure was assessed using radiotelemetry. RESULTS: We observed that in the SPAK knock-in mice, the AngII-induced hypertensive effect was significantly reduced and associated with an absence of AngII-induced NCC phosphorylation. In contrast, the hypertensive effect of aldosterone was enhanced and was related with an increased response to amiloride, but not to thiazide-type diuretics, without a significant increase in NCC phosphorylation. CONCLUSION: Our data suggest that AngII-induced hypertension requires, at least partly, NCC activation via the WNK/SPAK signaling pathway, whereas aldosterone-induced hypertension depends on epithelial sodium channel activation in a WNK/SPAK independent manner. SPAK knock-in mice emerge as a useful model to distinguish between the effects of AngII and aldosterone on distal nephrons. PMID- 28877077 TI - Cardiovascular risk and blood pressure lowering treatment among elderly individuals: Evidence for Cardiovascular Prevention from Observational Cohorts in Japan. AB - OBJECTIVE: There is little evidence to support an increased risk of blood pressure (BP) elevation among elderly individuals receiving antihypertensive drug treatment. METHODS: To clarify the impact on BP level and residual cardiovascular risk in treated elderly individuals, we analysed individual participant data of 26 133 residents aged 60-89 years from seven Japanese general populations and cross-classified participants by age category, 60-74 (young-old) versus 75-89 years (old-old), and by usage of antihypertensive medication at baseline survey (1980-1995). RESULTS: During a median follow-up period of 12.7 years, 2451 cardiovascular deaths were observed. Multivariable-adjusted hazard ratios of cardiovascular mortality in treated participants compared with untreated participants were 1.30 [95% confidence intervals, 1.16-1.46) and 1.35 (95% confidence interval, 1.16-1.56) in young-old and old-old participants, respectively. Irrespective of antihypertensive medication, the risk increase of total cardiovascular and stroke mortality with elevation of BP was significant among young-old (P <= 0.0013), but not significant among old-old participants (P >= 0.061). CONCLUSION: Although impact on BP was more evident among young-old than old-old individuals, clinicians who prescribe antihypertensive medication to elderly patients should consider that such patients require further monitoring. PMID- 28877078 TI - Advances in immunotherapy in multiple myeloma. AB - PURPOSE OF REVIEW: Here, we explore the significant progress made in the treatment of multiple myeloma, focusing on immunotherapy and the promise it has offered to patients suffering from advanced disease. RECENT FINDINGS: Multiple myeloma, a B-cell malignancy, is characterized by unregulated plasma cell growth in the bone marrow as well as strong immunosuppression in the tumor microenvironment. mAbs targeting tumor antigens overcome this, increasing T-cell activation, multiple myeloma cell death, and depth of response. Similarly, adoptive T-cell therapy aims to engineer or isolate tumor-specific T cells for a targeted approach. Finally, peptide and dendritic cell/tumor fusion vaccines reeducate the immune system, expanding the immune response and generating long term memory to prevent relapse of disease. Many of these approaches have been combined with existing therapies to enhance antitumor immunity. SUMMARY: Immunotherapeutic approaches have remarkably changed the treatment paradigm for multiple myeloma, and encouraging patient responses have warranted further investigation into mAbs, adoptive T-cell therapy, vaccines, and combination therapy. PMID- 28877080 TI - World Gastroenterology Organisation Global Guidelines: Celiac Disease February 2017. PMID- 28877081 TI - Safety and Efficacy of Wireless pH Monitoring in Patients Suspected of Gastroesophageal Reflux Disease: A Systematic Review. AB - INTRODUCTION: The primary aim of this systematic review was to determine the safety, technical efficacy, and effectiveness of 48-hour wireless pH monitoring (WM) for gastroesophageal reflux disease (GERD), compared with no pH monitoring in patients who failed to tolerate a catheter. In the absence of eligible studies, the secondary aim was to determine these performance characteristics for WM relative to catheter-based pH monitoring (CBM) in patients suspected of GERD, who are able to tolerate a catheter. METHODS: A protocol was registered on the PROSPERO database (CRD42013005852) before conducting the systematic review, which included the study selection criteria, and critical appraisal methods. Several key databases were searched to identify eligible comparative studies. RESULTS: Chest pain occurred more often with WM compared with CBM; however, other adverse events were reported less frequently with WM. Technical failures, mostly due to attachment failures and early capsule detachments, were 3 times higher with WM, compared with CBM, [pooled relative risk (from meta-analysis)=3.3; 95% confidence interval, 1.63-6.81; I=0%; P=0.012; k=8). The sensitivity and specificity of WM varied widely, depending on type of analysis, monitoring time, capsule placement, reference standard, and diagnostic threshold. DISCUSSION: WM is usually better tolerated than CBM but has more technical problems. Test accuracy was highly variable between studies; therefore, conclusions could not be drawn regarding the performance of the 2 tests. To make meaningful comparisons between WM and CBM a consensus is needed on the diagnostic threshold for GERD, monitoring time, appropriate capsule positioning, and the reference standard. PMID- 28877083 TI - Don't fall for predatory publishers. PMID- 28877082 TI - Multidisciplinary Management of Hepatocellular Carcinoma Improves Access to Therapy and Patient Survival. AB - BACKGROUND: Given the complexity of managing hepatocellular carcinoma (HCC), it is widely accepted that a multidisciplinary team approach (tumor boards) offers the best approach to individualize therapy. The aim of this study was to determine utilization of therapies and outcomes for patients with HCC, comparing those managed through our multidisciplinary tumor board (MDTB) to those who were not. METHODS: A database analysis of all patients with HCC managed through our MDTB, from 2007 until 2011, was performed. A database of all patients with HCC from 2002 to 2011, not managed through MDTB, was similarly created. RESULTS: A total of 306 patients with HCC, from 2007 to 2011 were managed through our MDTB, in comparison with 349 patients, from 2002 to 2011 who were not. There were no significant differences in baseline demographic data or model for end-stage liver disease at presentation. Patients managed through MDTB were more likely to present at an earlier tumor stage and with lower serum alpha fetoprotein (AFP) (P=0.007). The odds of receiving any treatment for HCC was higher in patients managed through MDTB (odds ratio, 2.80; 95% confidence interval, 1.71-4.59; P<0.0001) independent of model for end-stage liver disease score, serum AFP, and tumor stage. There was significantly greater survival of patients managed through MDTB (19.1+/-2.5 vs. 7.6+/-0.9 mo, P<0.0001). Independent predictors for improved survival included management through MDTB, receipt of any HCC treatment, lower serum AFP, receipt of liver transplant, and T2 tumor stage. CONCLUSIONS: Patients with HCC managed through a MDTB had significantly higher rates of receipt of therapy and improved survival compared with those who were not. PMID- 28877084 TI - Coronary fluorine-18-sodium fluoride uptake is increased in healthy adults with an unfavorable cardiovascular risk profile: results from the CAMONA study. AB - OBJECTIVE: Coronary artery fluorine-18-sodium fluoride (F-NaF) uptake reflects coronary artery calcification metabolism and is considered to be an early prognostic marker of coronary heart disease. This study evaluated the relationship between coronary artery F-NaF uptake and cardiovascular risk in healthy adults at low cardiovascular risk. PARTICIPANTS AND METHODS: Study participants underwent blood pressure measurements, blood analyses, and coronary artery F-NaF PET/CT imaging. In addition, the 10-year risk for the development of cardiovascular disease, on the basis of the Framingham Risk Score, was estimated. Multivariable linear regression evaluated the dependence of coronary artery F-NaF uptake on cardiovascular risk factors. RESULTS: We recruited 89 (47 men, 42 women) healthy adults aged 21-75 years. Female sex (0.34 kBq/ml; P=0.009), age (0.16 kBq/ml per SD; P=0.002), and BMI (0.42 kBq/ml per SD; P<0.001) were independent determinants of increased coronary artery F-NaF uptake (adjusted R=0.21; P<0.001). Coronary artery F-NaF uptake increased linearly according to the number of cardiovascular risk factors present (P<0.001 for a linear trend). The estimated 10-year risk for the development of cardiovascular disease was on average 2.4 times higher in adults with coronary artery F-NaF uptake in the highest quartile compared with those in the lowest quartile of the distribution (8.0 vs. 3.3%, P<0.001). CONCLUSION: Our findings indicate that coronary artery F NaF PET/CT imaging is feasible in healthy adults at low cardiovascular risk and that an unfavorable cardiovascular risk profile is associated with a marked increase in coronary artery F-NaF uptake. PMID- 28877086 TI - Short article: Retreatment of chronic hepatitis C virus infection after unsuccessful therapy with all-oral direct-acting antiviral regimens: a real-life experience. AB - OBJECTIVE: Few real-life data are available on the retreatment of patients who failed direct-acting antiviral (DAA)-regimens. We reported the outcome of retreatment with approved DAA regimens in a real-life cohort of patients who previously failed an all-oral DAAs combination and we analyzed the association with resistance substitutions (RASs) performed at the time of virological failure. AIM AND METHODS: Next-generation sequencing of the NS3, NS5A, and NS5B regions was performed by Illumina deep sequencing. The sequence reads were analyzed by an in-house pipeline. RESULTS: Of the 16/759 (2%) patients who failed to achieve a sustained virological response at 12 weeks to all-oral DAAs from December 2014 to January 2016, 10 were retreated with licensed DAAs regimens. In all the patients, retreatment was followed by sustained virological response at 12 weeks. Baseline NS3-RASs before retreatment were observed in two patients who failed a sofosbuvir/simeprevir regimen: D168V RAS was detected in a genotype-4 patient, whereas the complex RAS-pattern Q80K, I170V, R155K, D168E was observed in a genotype-1a patient. Only one of the two patients who previously failed ombitasvir, paritaprevir/ritonavir, and dasabuvir underwent RAS analysis at relapse and showed baseline NS5A RAS (M28V) before retreatment. CONCLUSION: These real-life findings indicated a high efficacy of sofosbuvir+NS5A-inihbitors in retreating NS3-experienced patients and also NS5A-experienced patients by using a 24-week course ribavirin-containing regimen. The relevance of hepatitis C virus resistance testing before retreatment remains to be better defined to guide the choice of the new regimen before retreatment in DAA-experienced patients. PMID- 28877085 TI - Current health status and medical therapy of patients with pediatric-onset inflammatory bowel disease: a survey-based analysis on 1280 patients aged 10-25 years focusing on differences by age of onset. AB - OBJECTIVE: There are inconsistent reports on age-related differences in inflammatory bowel disease (IBD). On the basis of patient information, we describe the clinical presentation and therapy in relation to age at diagnosis in longstanding pediatric IBD. PATIENTS AND METHODS: Two surveys were conducted in children and young adults (age: 10-25 years) by pretested postal questionnaires. The main analyses are descriptive, showing proportions and distributions per grouped age of diagnosis. Exploratory logistic regression was used to identify sociodemographic and disease-related factors associated with prognosis. Recent disease course, use of biological therapy, and resecting surgery were chosen as indicators of disease severity. Patients with a diagnosis in infancy (<2 years of age) are presented as a case series. RESULTS: Information of 1280 cases was available [804 Crohn's disease (CD), 382 ulcerative colitis (UC), 94 IBD not specified] (response: 44.6 and 49.6%). Stable remission during the preceding year was reported by 675 (56.7%) patients; 825 (60.9%) patients reported feeling currenty well. Anti-tumor necrosis factor therapy was reported by 33% of CD patients and 9.3% of UC patients, immunomodulation in 82.1 and 63.2%, and corticosteroids by 78.4 and 76.1%, respectively (ever use). Age at diagnosis was not associated with indicators of severe disease. Diagnosis in infancy was reported by 37 patients. CONCLUSION: Our data do not support age at diagnosis related differences in prognosis in pediatric-onset IBD. PMID- 28877087 TI - Percutaneous endoscopic gastrostomy under conscious sedation in patients with amyotrophic lateral sclerosis is safe: an observational study. AB - OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that causes muscle weakness with respiratory and swallowing dysfunction, eventually leading to death. Permanent enteral feeding is indicated in almost all patients. A percutaneous endoscopic gastrostomy (PEG) tube is considered the first choice, usually performed under conscious sedation (intravenous midazolam). Guidelines are very cautious with respect to sedation in ALS because of the risk for respiratory complications. In our tertiary referral hospital, conscious sedation has been used for many years.Our aim was to review 30-day complications in PEG performed under conscious sedation in ALS patients (without noninvasive positive pressure ventilation during the procedure). PATIENTS AND METHODS: A retrospective review, including all ALS patients undergoing PEG under conscious sedation from October 2009 to April 2016, was performed. RESULTS: Analysis included 45 (44% men) patients receiving intravenous midazolam sedation (mean dose 5 mg) during PEG placement, age 36-91 years (mean: 68.7 years). Forced vital capacity (FVC) was 24-116% (mean 68%), of which mild to moderate dysfunction (FVC 50-69%) was present in 42.2% of patients and (very) severe dysfunction (FVC <50%) in 8.8%. No respiratory complications (e.g. aspiration pneumonia) were observed. Other complications, for example, infection, bleeding and peritonitis occurred in, respectively, 8.9, 2.2 and 0%. Mean survival after PEG placement was 13.4 months (range: 1-45 months). CONCLUSION: Conscious sedation during PEG insertion in ALS patients did not lead to respiratory complications or to an increase in other complications. Our data indicate that conscious sedation can be used safely in ALS patients with mild to moderate pulmonary dysfunction. PMID- 28877088 TI - Efficacy and tolerability of culture-guided treatment for Helicobacter pylori infection. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy/tolerability of a culture-guided approach in the eradication of Helicobacter pylori and identify factors associated with antibiotic resistance/treatment failure. PATIENTS AND METHODS: This retrospective single-center study included patients who underwent culture-guided treatment for H. pylori infection, after two ineffective eradication attempts, between October 2012 and December 2016. We assessed the following demographic and clinical data of the patients: sex, age, BMI, alcohol and tobacco consumption, history of dyspepsia, peptic ulceration and first-degree relatives with gastric cancer, antibiotic susceptibility results, treatment composition, tolerability, and success. The treatment success was confirmed by a monoclonal stool antigen test. RESULTS: Culture-guided treatment was performed in 42 patients (57% women, mean age+/-SD: 48.9+/-11.4 years). The rates of antibiotic resistance were as follows: clarithromycin 86%, metronidazole 67%; levofloxacin 52%, tetracycline 2%, and amoxicillin and rifampicin 0%. Double resistance to clarithromycin and metronidazole was found in 59.5% of the patients. Most patients showed resistance to less than three antibiotics, but 31% were resistant to three or more. Intention-to-treat and per-protocol eradication rates were 59.5 and 61.5%. Adverse events occurred in 15 (35.7%) patients, but only two (4.8%) patients did not complete treatment because of adverse events. Only age more than 50 years was associated with resistance to three or more antibiotics. Having a first-degree relative with gastric cancer was associated with treatment failure and having a BMI of at least 25 kg/m protected from failure. CONCLUSION: Third-line culture-guided treatment often fails to eradicate H. pylori infection. We need to find factors other than in-vitro antibiotic resistance to explain these suboptimal results. PMID- 28877089 TI - The maturation of a 'neural-hematopoietic' inflammatory axis in cardiovascular disease. AB - PURPOSE OF REVIEW: Atherogenesis is the result of a complex interplay between lipids and innate immune cells, which are descendants of upstream progenitors residing in hematopoietic organs. In this review, we will discuss recent advances in the connection between hematopoiesis and atherogenesis. RECENT FINDINGS: The relevance of a neural-hematopoietic axis was recently supported by the demonstration of a correlation between metabolic activity in the amygdala and the bone marrow. During follow-up, both amygdalar and bone marrow activities also predicted cardiovascular risk in patients, lending further support to a connection between neural stress and cardiovascular events mediated via increased hematopoietic activity.In parallel, functional changes in hematopoietic stem cells may also convey cardiovascular risk. In experimental models, knock-out of the ten-eleven translocation 2 (TET2) gene leading to monocyte-macrophage hyperresponsiveness, was associated with accelerated atherogenesis in murine experiments. In humans, whole-exome sequencing reporting on the 'clonal hematopoiesis of indeterminate potential' gene substantiated a two-fold elevated risk for developing coronary heart disease compared with noncarriers. SUMMARY: Recent studies support the relevance of a 'neural-hematopoietic' inflammatory axis and clonal hematopoiesis as drivers of atherogenesis in humans. These data warrant further studies addressing the role of novel 'hematopoietic' targets for the treatment of patients with increased cardiovascular risk. PMID- 28877090 TI - Academic Achievement Deficits and Their Neuropsychological Correlates in Children Born Extremely Preterm. AB - OBJECTIVE: The purpose of this study was to examine the risks associated with learning disabilities (LDs) in a large sample of children born extremely preterm. We predicted higher than expected rates of LD, particularly in math, and children with LD in math, reading, or both would have lower intelligence quotients (IQs) and specific patterns of neuropsychological deficits. METHODS: We evaluated academic achievement, rates of LD, and their neuropsychological correlates in the Extremely Low Gestational Age Newborns (ELGANs) Study cohort of 10-year-old children born at 23 to 27 weeks gestational age. Primary analyses focused on children without intellectual disability (verbal IQ > 70 and nonverbal IQ > 70; N = 668). Low achievement was defined as a standard score <=85 on the reading or math measures. RESULTS: The risk of low math achievement scores (27%) was 1.5 times higher than the risk of low reading achievement scores (17%). Children were classified as having LD based on low achievement criteria in reading only (RD, 6.4% of sample), math only (MD, 16.2%), both reading and math (RD/MD, 8.3%), or no reading or math disabilities (No LD, 69.1%). Although all 3 LD groups had multiple neuropsychological weaknesses compared with the No LD group, the RD and MD groups had different patterns of neuropsychological impairment. CONCLUSION: These children from the ELGAN cohort had higher than expected rates of LD, particularly in mathematics, even after taking socioeconomic status into consideration. These results indicate specific cognitive weaknesses that differ between extremely preterm children with RD and MD. PMID- 28877091 TI - Avoiding biopsy for initial diagnosis for celiac disease: are we there yet? PMID- 28877092 TI - Coeliac disease: further evidence that biopsy is not always necessary for diagnosis. PMID- 28877093 TI - Assessment of liver fibrosis with acoustic radiation force impulse in patients with chronic hepatitis C. PMID- 28877096 TI - Clinical Parameter for Deciding the BRAFV600E Mutation Test in Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance Thyroid Nodules: US Features According to TIRADS. AB - This study aimed to investigate the usefulness of a thyroid imaging reporting and data system (TIRADS) to select thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) cytology for additional BRAF mutation testing. Three hundred three thyroid nodules were included. Statistical analysis was performed at both patient and nodule levels according to BRAF mutation positivity and clinical factors. Univariate and multivariate logistic regression analyses were performed to assess independent associations between BRAF mutation positivity and clinical factors. Of 303 AUS/FLUS nodules, 16 (5.3%) of 303 nodules had the BRAF mutation. The frequency of the BRAF mutation according to the TIRADS was 35.7% for category 5, 10.8% for category 4c, 2.5% for category 4b, 1.1% for category 4a, and 0% for category 3 nodules (P < 0.001). On multivariate analysis, BRAF mutation positivity was significantly associated with high suspicion on the TIRADS (odds ratio, 15.247; P < 0.001). In conclusion, the ultrasonography patterns of the TIRADS can be used as a clinical parameter for deciding the BRAF mutation test in thyroid nodules with AUS/FLUS cytology. PMID- 28877095 TI - Hip Surveillance for Children With Cerebral Palsy: A Survey of the POSNA Membership. AB - BACKGROUND: Currently, hip surveillance programs for children with cerebral palsy exist in Europe, Australasia, and parts of Canada, but a neuromuscular hip surveillance program has yet to be adopted in the United States. The purpose of this study was to report the current orthopaedic practice of hip surveillance in children with cerebral palsy, identify areas of practice variation, and suggest steps moving forward to generate guidelines for national neuromuscular hip surveillance. METHODS: The entire membership of the Pediatric Orthopaedic Society of North America (POSNA) was surveyed in 2016 for information regarding their practice for hip surveillance in children with cerebral palsy. Detailed information regarding timing, frequency, and practice of hip surveillance was obtained in answers to 26 different questions. RESULTS: A survey response rate of 27% was obtained (350/1300 members) during the study period. The majority of respondents treated pediatric patients exclusively (97%), worked in an academic practice (70%), and was affiliated with a university (76%). In total, 18% (69/350) of respondents followed a regular cerebral palsy hip surveillance program, about half of whom (44%, 30/69) had adopted the Australian guidelines. Respondents agreed that a dislocated hip in a child with cerebral palsy was painful (90% agreement) and should be prevented by hip surveillance (93% agreement). Furthermore, 93% of respondents indicated they would follow a national surveillance program if one was in place. Age (79%), Gross Motor Function Classification System (81%), and migration percentage (MP) (78%) were all identified as critical elements to a hip surveillance program. The majority of respondents felt that a hip "at risk" for hip displacement had a MP between 20% and 30% (57% of respondents), whereas surgery should be utilized once the MP exceeded 40% (50% of respondents). CONCLUSIONS: Results from this survey demonstrate 90% of respondents agree that a dislocated hip could be painful and 93% would follow a national surveillance program if available. At a societal level, we have the ability to standardize cerebral palsy hip surveillance, thereby decreasing practice variation and improving quality of care delivery. LEVELS OF EVIDENCE: Level V. PMID- 28877097 TI - Application of Transcranial Color Doppler Ultrasonography for Assessing Middle Cerebral Arteries in Rheumatoid Arthritis. AB - To assess the role of ultrasonography for assessing middle cerebral arteries (MCAs) in rheumatoid arthritis (RA). Middle cerebral arteries of 32 RA patients and 32 healthy volunteers were examined by ultrasonography. Peak systolic blood flow velocity (PSV), end-diastolic velocity, and resistance index (RI) of MCA were measured using Doppler ultrasound. Results were expressed as mean +/- SD. No significant difference in peak systolic velocity was obtained between RA patients (52.44 +/- 19.56 cm/s) and healthy volunteers (51.59 +/- 16.83 cm/s, P > 0.05). End-diastolic velocity in RA patients was significantly lower (15.41 +/- 5.44 cm/s vs 24.54 +/- 8.45 cm/s, P < 0.01) and RI markedly higher (0.66 +/- 0.10 vs 0.60 +/- 0.06, P < 0.05) compared with control values. Resistance index in 32 RA patients increased with disease duration (2 months to 31 years), from a median value of 0.350 to 0.830; there was a strong correlation between RI and disease duration (r = 0.965, P < 0.05). A point of 0.64 in receiver operating characteristic curve was chosen as the cutoff point, and the area under the curve was 0.918. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 90.6%, 87.5%,87.9%, 90.3%, and 89.1%, respectively. Color Doppler ultrasound in RA patients with hemodynamic changes of MCAs could be a relatively sensitive tool for the detection of cerebral atherosclerotic lesions. This could enable timely intervention for early clinical reference. PMID- 28877098 TI - A 3-Dimensional Printed Ultrasound Probe Visuospatial Trainer. AB - Training adult learners to use ultrasound in clinical practice relies on the ability of the learner to apply visuospatial concepts to the anatomy of the human body. We describe a visuospatial trainer that replicates the housing of an ultrasound transducer, through which a linear laser projects light in the same plane and orientation as the ultrasonic sound waves. We use this trainer in combination with a porcine heart dissection laboratory to teach bedside cardiac ultrasound and transthoracic echocardiography (TTE). Off-the-shelf components, including an on/off switch, a laser, and 2 ampere batteries are connected in series and placed inside the 3-dimensional (3D)-printed housing. The trainer's laser emission projects a red line that visually represents the ultrasound's field. Learners project the laser against a porcine or human heart in the orientation of the TTE window they wish to obtain and then dissect the heart in that plane, allowing for visualization of how grayscale images are obtained from 3D structures. Previous research has demonstrated that visuospatial aptitude is correlated with ultrasound procedural performance. We present this trainer and educational method as a specific training intervention that could enhance the visuospatial ability of the ultrasound learner. This visuospatial trainer and educational method present a novel process for enhancing learner understanding of 2-dimensional ultrasound images as they relate to 3D structures. Having a clear understanding of how images are generated in cross section may translate into more proficient adaptation of cardiac ultrasound and TTE. PMID- 28877099 TI - Risk of Pulmonary Embolism in Patients With Isolated Great Saphenous Vein Thrombus. AB - Risks associated with isolated great saphenous vein (GSV) thrombosis remain controversial. The purpose of this study is to identify the risk of pulmonary embolism (PE) in patients with isolated GSV thrombosis, particularly those with thrombus within 3 cm of the sapheno-femoral junction. A retrospective chart review of color flow Doppler lower extremity venous ultrasound examinations from an academic hospital from 2011 to 2016 was conducted. Seventy-eight patients were identified as having acute thrombus in their GSV and were then further stratified based on the presence or absence of concomitant deep venous thrombosis (DVT). A control group of 49 patients who presented with leg swelling and were found to have a normal color flow Doppler examination was also identified. Patients without thrombus (n = 49), patients with isolated GSV thrombus (n = 29), and patients with GSV thrombus with concomitant DVT (n = 49) underwent full chart review to determine whether any patients developed PE. This was diagnosed specifically by computed tomography angiogram or ventilation/perfusion scan, within 60 days of initial diagnosis of lower extremity thrombus. In our analysis, there was no significant difference in the risk of PE in patients with isolated GSV thrombus compared with a control group of normal patients (3.5% vs 2.0%, P = 0.38). However, patients with GSV thrombus and concomitant DVT had a significantly increased risk of PE compared with patients with isolated GSV thrombus (26.5% vs 3.5%, P = 0.01). We found that the risk of PE in patients with isolated GSV thrombus is not significantly increased compared with a normal cohort. PMID- 28877100 TI - Abdominal Pain and Vomiting. AB - Abdominal ultrasound of a 28-year-old man with chronic abdominal pain and vomiting demonstrates a dilated aperistaltic distal esophagus, which was confirmed on follow-up esophagram as achalasia. The 2 main types of achalasia are primary and secondary. Primary achalasia occurs with the loss of postganglionic neurons resulting in failed distal esophageal relaxation. Secondary achalasia is esophageal narrowing due to nondenervation causes. The diagnosis of achalasia is typically made with manometry and barium esophagram. PMID- 28877101 TI - Proanthocyanidins prevent ethanol-induced cognitive impairment by suppressing oxidative and inflammatory stress in adult rat brain. AB - Excessive chronic alcohol consumption enhances brain oxidative and inflammatory stress, resulting in cognitive deficit. This study investigated the potential alleviating effects of proanthocyanidins (PACs) on ethanol-induced cognitive impairment and stress in brain regions including the prefrontal cortex, hippocampus, and amygdala. Adult male rats were administered saline, PACs, ethanol, or combinations of ethanol with different doses of PACs for 8 weeks. Then, the Morris water-maze test was performed. Thiobarbituric acid-reactive substances, superoxide dismutase activity, total antioxidant capacity, and nitric oxide were chosen as parameters of oxidative stress, whereas tumor necrosis factor-alpha and interleukin-1beta chosen as parameters of inflammatory stress. The results indicated that ethanol led to cognitive impairment along with enhanced oxidative and inflammatory stress in brain regions, whereas PACs per se had no significant effects. Moreover, coadministration with PACs in ethanol treated rats dose dependently rescued cognitive impairment accompanied by suppressed oxidative and inflammatory stress in brain regions. Thus, the protective effects of PACs on ethanol-induced cognitive impairments may be because of their antioxidant and anti-inflammatory activities. PMID- 28877102 TI - Treadmill exercise modifies dopamine receptor expression in the prefrontal cortex of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder for which there is no cure. PD is a dopamine (DA)-deficit disorder marked by progressive motor and nonmotor disturbances, including cognitive impairment. Executive function (EF) is the most common subtype of cognitive impairment in PD and consists of deficits in number of processes including behavioral flexibility. The prefrontal cortex (PFC) is an important brain region subserving EF. Furthermore, DA plays a key neuromodulatory role in the PFC and altered DA neurotransmission is believed to contribute toward EF deficits in PD. The mechanisms underlying PFC dysfunction are not fully understood and there are no effective treatments for EF deficits in PD. Exercise is a promising therapeutic strategy that may exert beneficial effects on PFC function in PD. Our previous work suggests that exercise improves motor function and restores striatal DA-D2 receptor (DA-D2R) expression after DA depletion. This study builds upon our previous work by exploring whether exercise modulates PFC function, specifically DA levels and DA receptor expression in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-mouse model of DA depletion. We found that exercise restores PFC DA levels, reverses the MPTP-induced increase in DA-D1R and decrease in DA-D4R, and exerts differential effects on D2Rs. The modest effect of exercise in PFC function may suggest that other types of exercise, such as those that are more skill based, would be required to target these cognitive behavioral circuits. PMID- 28877103 TI - Abnormal modification of histone acetylation involved in depression-like behaviors of rats induced by chronically unpredicted stress. AB - Depression is a complex multifactorial mental disorder. Its etiology involves many factors such as social environments, genetics, and psychology. Recent studies have shown that epigenetic modification may be associated with depression. Histone acetylation is one of the main mechanisms of epigenetic modification and plays an important role in genetic expression. In this study, we investigated the role of histone acetylation in the depression-like behaviors of rats undergoing chronically unpredicted stress (CUS) by detecting the mRNA and protein expression of histone deacetylase 5, cAMP-response element-binding protein, and the level of histone acetylated modification of H3K14, H3K23, and H4K16 in the prefrontal cortex and hippocampus of the rats. The results showed that significantly increasing depression-like behaviors were observed with a decreasing histone acetylated modification level, especially on acytelated-H3K14, acytelated-H3K23, and acytelated-H4K16, upregulating histone deacetylase 5 expression and downregulating cAMP-response element-binding protein expression in CUS rats, compared with control rats. The results indicate that the decrease in the histone acetylation modification level may be partly involved in the mechanism of depression-like behaviors of rats induced by CUS. PMID- 28877104 TI - Activation of beta-adrenoceptor facilitates active avoidance learning through enhancement of glutamate levels in the hippocampal dentate gyrus. AB - Long-term potentiation (LTP) is widely accepted as the best studied model for neurophysiological mechanisms that could underlie learning and memory formation. Despite a number of studies indicating that beta-adrenoceptors in the hippocampal dentate gyrus (DG) is involved in the modulation of learning and memory as well as LTP, few studies have used glutamate release as a visual indicator in awake animals to explore the role of beta-adrenoceptors in learning-dependent LTP. Therefore, in the present study, the effects of propranolol (an antagonist of beta-adrenoceptor) and isoproterenol (an agonist of beta-adrenoceptor) on extracellular concentrations of glutamate and amplitudes of field excitatory postsynaptic potential were measured in the DG region during active avoidance learning in freely moving conscious rats. In the control group, the glutamate level in the DG was significantly increased during the acquisition of active avoidance behavior and returned to basal level following extinction training. In propranolol group, antagonism of beta-adrenoceptors in the DG significantly reduced the change in glutamate level, and the acquisition of the active avoidance behavior was significantly inhibited. In contrast, the change in glutamate level was significantly enhanced by isoproterenol, and the acquisition of the active avoidance behavior was significantly accelerated. Furthermore, in all groups, the changes in glutamate level were accompanied by corresponding changes in field excitatory postsynaptic potential amplitude and active avoidance behavior. Our results suggest that activation of beta-adrenoceptors in the hippocampal DG facilitates active avoidance learning by modulations of glutamate level and synaptic efficiency in rats. PMID- 28877105 TI - Context for Practice: Prevention of Pressure Injury and Incontinence-Associated Dermatitis. PMID- 28877106 TI - Letter to the Editor. PMID- 28877108 TI - Prevention of Heel Pressure Injuries and Plantar Flexion Contractures With Use of a Heel Protector in High-Risk Neurotrauma, Medical, and Surgical Intensive Care Units: A Randomized Controlled Trial. AB - PURPOSE: The purpose of this study was to compare the use of a heel protector to standard of care (pillows) in the prevention of hospital-acquired pressure injuries (HAPI) of the heels and prevention of plantar flexion contractures. DESIGN: Randomized controlled trial. SUBJECTS AND SETTING: The study took place on a surgical intensive care unit, medical intensive care unit, and neurotrauma intensive care unit. Inclusion criteria were a minimum of 5 days of sedation related to care for a critical illness, immobility for 6 to 8 hours before study initiation, a Braden Scale for Pressure Sore Risk score 18 or less, and a mobility subscale score 2 or less. Patients were included if they had preexisting heel pressure injury or plantar flexion contracture. The sample comprised 54 subjects; 37 were randomly allocated to the intervention group and 17 to the control group. Their average age-mean (standard deviation)-was 40.7 (14.96) years in the control group and 44.6 (17.15) years in the intervention group. METHODS: Data were collected from patients' electronic medical records. We recorded subject demographics, presence of diabetes mellitus or peripheral vascular disease, Glasgow Coma Scale scores (every shift), Braden Scale for Pressure Sore Risk scores (every shift), heel skin assessments (every shift), goniometric measurements (every other day), and adverse events (every shift). Assessments and measurements were continued until the patient was discharged from the study. RESULTS: None of the patients in the intervention group developed HAPI of the heels, as compared to 7 in the control group (0% vs 41%, P < .001). Patients in the intervention group had a significantly greater decrease in goniometric scores (mean decrease = 1.4 +/- 2.25) compared to the control group by day 3 (mean decrease = 0.1 +/- 0.52 P = .004) and the last study day (mean decrease = 2.0 +/- 3.02 for the intervention group vs 0.07 +/- 0.96 for the control group; P < .001). CONCLUSIONS: Study findings indicate that a heel protector that ensures off-loading and maintains the foot in a neutral position is more effective for prevention of HAPI of the heel and contractures as compared to standard care using pillows to position the heel and redistribute pressure. PMID- 28877110 TI - Predictors of Intraoperative Pressure Injury in Patients Undergoing Major Hepatobiliary Surgery. AB - PURPOSE: The purpose of this study was to identify risk factors associated with pressure injury (PI) development in patients undergoing major hepatobiliary surgery requiring general anesthesia. DESIGN: Retrospective medical review and analysis. SUBJECTS AND SETTING: Medical records from 803 patients undergoing hepatobiliary surgery from October 2015 to October 2016 were reviewed. The study setting was a 3400-bed military academic medical center in the northeast region of China. METHODS: Demographic variables, comorbid conditions, preoperative Braden Scale for Pressure Sore Risk scores, preoperative serum hemoglobin and albumin levels, type of surgery, positioning, surgical time, hypotensive episodes, blood loss, body temperature, and other potential risk factors for PI development were collected. Pressure injury occurrences during a 48-hour period after surgery were recorded along with stage. Data were analyzed using univariate analyses and multivariate logistic regression analysis to build a predictive model for factors associated with PI occurrences. RESULTS: The prevalence of PIs in major hepatobiliary surgery patients was 19.8%, 4.9%, and 4.1% in the immediate postoperative period, on the first day and the second day after surgery, respectively. Pancreaticoduodenectomy surgery (odds ratio [OR]: 3.957, 95% confidence interval [CI]: 2.145-7.302, P < .001), open surgery (OR: 2.917, 95% CI: 1.558-5.463, P = .001), surgical time (cutoff point at 197 minutes for increased risk of PI, OR: 1.004, 95% CI: 1.002-1.006, P = .001), and intraoperative hypotensive episodes (OR: 1.022, 95% CI: 1.005-1.039, P = .010) were associated with an increased likelihood of PI development. CONCLUSION: Among patients undergoing major hepatobiliary surgery such as pancreaticoduodenectomy, prolonged surgical time, open surgery, and intraoperative hypotension were found to be associated with an increased likelihood of developing a PI. Maintaining hemodynamic stability and taking more effective measures for skin care during these procedures may reduce the risk of PI in this vulnerable population. PMID- 28877109 TI - The Efficacy of a Viscoelastic Foam Overlay on Prevention of Pressure Injury in Acutely Ill Patients: A Prospective Randomized Controlled Trial. AB - PURPOSE: The purpose of this study was to compare a viscoelastic foam overlay (VEFO) to a standard hospital mattress for pressure injury (PI) prevention. We also compared interface pressures (IPs) of the VEFO to our facility's standard hospital mattress. DESIGN: Prospective, randomized controlled trial. SUBJECTS AND SETTING: Data analysis was based on 110 participants (55 in each group) who were 19 years or older, had a Braden Scale for Pressure Sore Risk score of 16 or less, and were cared for on a neurology, oncology, or pulmonology inpatient care unit. The research setting was the Samsung Medical Center in Seoul, South Korea. METHODS: Participants were divided into 2 groups: the experimental group were based on a VEFO on top of the standard hospital mattress used in our facility. Participants in the control group were placed on a standard hospital mattress with/without air overlay. All patients were given standard nursing care for prevention of PI. Skin assessments were completed daily over a period of 2 weeks. In addition, we compared IPs of the standard hospital mattress and the VEFO in participants randomly allocated to the intervention group. Interface pressure was measured over the sacral/coccygeal area with subjects in the supine position. Pressures were measured immediately before and immediately following placement of the VEFO and just before data collection began. Data were collected between October 2013 and November 2014. Pressure injury incidence was compared between groups using the chi test, and IPs were compared using the paired t test. INSTRUMENTS: Pressure injury development was determined using the staging system described in guidelines from the National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel, and Pan Pacific Pressure Injury Alliance in 2014. Interface pressure was measured using a device manufactured for this purpose. RESULTS: The incidence of PI development was significantly lower in subjects assigned to the experimental group as compared to those in the control group (3.6%-27.3% over the 2-week data collection period; P = .001). The maximum IP was significantly lower on the VEFO with standard hospital mattress than on the standard hospital mattress (paired t = 8.87, P < .001). CONCLUSIONS: Patients managed with a VEFO had a significantly lower incidence of PI than those managed with a standard hospital mattress. Additional research is needed to further characterize the efficacy of the VEFO, its effect on PI healing, and its effect of PI prevention in high-risk populations such as critically ill patients. PMID- 28877111 TI - Effects of Curvilinear Supine Position on Tissue Interface Pressure: A Prospective Before-and-After Study. AB - PURPOSE: To determine whether a curvilinear supine position increases the contact area between the subject and the surgical table, reduces interface pressures within contact areas, and improves comfort. DESIGN: This observational study was completed to establish proof-of-concept to determine differences between 2 positions (supine and curvilinear) on interface pressure of 5 at-risk anatomical locations, overall contact area, and subjects' comfort level. SUBJECTS AND SETTING: The study was conducted at the operating theater of a tertiary teaching hospital in Wuhan, China. The sample comprised 145 healthy Asian volunteers between 18 and 60 years of age. METHODS: Subjects were placed in the supine and curvilinear supine positions on a surgical table. Contact area and peak interface pressures of 5 at-risk anatomical locations (occiput, scapula, sacrum, calf, and heel) were measured using a pressure mapping system, and the mean and maximum pressures of the overall contact area were calculated. Comfort was assessed by self-report using a Likert scale of 1 to 5. The Wilcoxon paired signed rank test was used to compare differences between the 2 positions, and the Spearman correlation analysis was used to identify associations among outcome variables. RESULTS: Results indicated that whole-body (overall) maximum, average interface pressures, and maximum interface pressures of the sacrum and the heel were decreased significantly, with contact area and comfort-level score increasing from 2438.71 to 2709.68 cm and 3.00 to 4.00, respectively (P < .001). Statistically significant associations were found between the contact area and measures of body morphology; correlation coefficients varied from 0.409 to 0.740 (P < .001). CONCLUSIONS: Curvilinear supine position increased overall contact area with the support surface, reduced interface pressures over contact areas (bony prominences), improved comfort, and enhanced pressure redistribution. Additional research is needed to determine if these effects will reduce intraoperative pressure injury occurrence. PMID- 28877112 TI - WOCN Society Position Paper: Avoidable Versus Unavoidable Pressure Ulcers/Injuries. AB - The issue of whether pressure injuries are avoidable or preventable has been and continues to be an issue of great debate and discussion for many years, and it has significant legal and regulatory implications related to prevention of wounds due to pressure. The following position paper outlines the position of the Wound, Ostomy and Continence Nurses Society (WOCN) on avoidable versus unavoidable pressure injuries. It includes the following information: statement of position, purpose/rationale for the position, definitions of avoidable versus unavoidable pressure injuries, alternative definitions, historical overview, supportive statements from expert opinion and research in the literature, and recommendations for research. PMID- 28877113 TI - Sexual Experiences of Chinese Patients Living With an Ostomy. AB - PURPOSE: The purpose of this study was to examine the sexual experience of Chinese patients with ostomy and associated factors. DESIGN: A prospective descriptive study using self-report questionnaires. SUBJECTS AND SETTING: Seventy five Chinese participants who underwent ostomy surgery in a large cancer specialist hospital in the Hunan province between 2008 and 2013. METHODS: Data were collected face-to-face by the investigators in an outpatient setting from 75 participants who completed the Arizona Sexual Experience Inventory Scale (ASEX). The t test was used to compare variances between sexual function and dysfunction subgroups. A multiple linear regression model was used to analyze factors influencing sexual life after ostomy surgery. RESULTS: The mean ASEX score was 20.56 (5.378) years, which is higher than the standard for sexual dysfunction. The main subsection of sexual dysfunction included sexual arousal, orgasm ability, vaginal lubrication/penile erection, and sexual satisfaction. Significant differences in the ASEX score were observed in subgroups of age, gender, educational level, family relations, operation modes, stoma type, operation time, complications, supporters, self-care ability, and sexual life guidance. Multiple stepwise regression analysis indicated that family relations, operation modes, ostomy type, complications, and sexual life guidance affected sexual experience. CONCLUSION: The findings of this study demonstrate that patients with ostomy experience sexual dysfunction and many factors influence their quality of sexual life. WOC nurses and other healthcare providers should consider providing sexual health education for both the patient and spouse to improve the self-care capacity and quality of sexual life following ostomy surgery. PMID- 28877114 TI - Incontinence Briefs Containing Spiral-Shaped Fiber Acidify Skin pH of Older Nursing Home Residents at Risk for Incontinence-Associated Dermatitis. AB - PURPOSE: The study's purpose was to assess the pH of the skin of older (aged >=75 years) incontinent nursing home residents after exposure to an incontinence brief containing spiral-shaped fiber wet with an alkaline solution mimicking urine or fecal pH and compared to skin pH after exposure to an industry standard brief wet with the same solution and various controls. DESIGN: The design was experimental, as conditions were applied to skin and skin pH was measured in random order, and subjects served as their own controls. SETTING AND SUBJECTS: The setting was a Midwestern nonprofit nursing home. The sample was 26 nursing home residents; their mean age was 87 years (SD = 6 years); 77% were female. Most (69%) had urinary incontinence alone, and 31% had dual urinary and fecal incontinence. METHODS: Skin pH was measured in duplicate on 6 areas of the inner thighs and 6 areas of the volar surface of the forearms. Each area was exposed to 1 of 6 conditions applied in random order: an incontinence brief containing spiral shaped fiber wet with an alkaline solution and one that was dry; a standard incontinence brief (without spiral-shaped fiber) wet with the same alkaline solution and one that was dry; the alkaline solution alone; and normal skin. RESULTS: On both the thighs and the forearms, skin pH was significantly lower (more acidic) after exposure to the incontinence brief containing spiral-shaped fiber wet with an alkaline solution compared to the wet standard brief and all other control conditions (P < .001). On thighs, the mean skin pH was 5.7 (SD = 0.5) after exposure to the wet brief with spiral-shaped fiber versus 6.4 (SD = 0.5) after exposure to the wet standard brief. On forearms, the mean skin pH was 5.3 (SD = 0.4) after exposure to the wet brief with spiral-shaped fiber versus 6.0 (SD = 0.4) after exposure to the wet standard brief. CONCLUSIONS: Incontinence briefs containing a spiral-shaped fiber significantly acidify the pH of the skin exposed to an alkaline solution, while industry standard briefs do not. Since alkaline skin pH is a risk factor for incontinence-associated dermatitis (IAD), results suggest that briefs with spiral-shaped fiber may help prevent IAD. Findings encourage further research. PMID- 28877118 TI - MESSAGE FROM THE EDITOR. PMID- 28877115 TI - Quantitation of 24-Hour Moisturization by Electrical Measurements of Skin Hydration. AB - PURPOSE: The purpose of this study was to quantify the effects of several moisturizers on hydration of the stratum corneum by measuring their effect on electrical conductance over a 24-hour period. DESIGN: Double-blind, randomized controlled trial. SUBJECTS AND SETTING: Twenty-five healthy female volunteers aged 18 to 65 years with dry skin on the lower legs and no other known dermatologic pathology participated in the study. Additional exclusion criteria were pregnant or taking anti-inflammatory steroids. The study was carried out in a clinical research facility in Winnipeg, Manitoba, Canada. METHODS: Subjects underwent a 3-day conditioning period using a natural soap bar on the lower legs and no application of moisturizer to the skin. Participants then came to the test site and equilibrated for at least 30 minutes under controlled conditions of temperature and humidity. After baseline hydration measurements on test sites on the lower legs of each subject, a single application of each of 5 test products at a dose of 2 mg/cm was made. Skin hydration was assessed by electrical conductance measurements with a specialized probe. The probe was briefly placed on the skin surface with light pressure, and the measurement recorded in units of microsiemens (MUS). Conductance was measured at 2, 4, 6, 8, and 24 hours after product applications. RESULTS: Although all but 1 of the test products increased conductance at 2 hours, only 2 moisturizers containing high levels of glycerin (products C and E) maintained increased conductance relative to baseline at 24 hours, +37.8 (P < .001) and +103.5 (P < .001), respectively. CONCLUSIONS: Moisturizers containing high levels of glycerin can provide a measurable moisturization benefit as determined by skin conductance for at least 24 hours after a single application. PMID- 28877119 TI - The Lifestyle Change Experiences of Cancer Survivors. AB - BACKGROUND: Leading a healthy lifestyle not only alleviates the physical problems but also improves the quality of life of cancer survivors. Healthcare professionals should understand the benefits of altering lifestyle behaviors to provide effective intervention programs to assist cancer survivors to improve their health. PURPOSE: The aim of this study was to understand the experiences of cancer survivors in changing their lifestyle after a cancer diagnosis. METHODS: A qualitative descriptive study was conducted on 13 cancer survivors who were sampled purposively from a regional teaching hospital in central Taiwan. Data were collected using in-depth interviews that were guided by semistructured, open ended questions and analyzed using content analysis. RESULTS: The analysis of interview data revealed four main themes: motivation of lifestyle change, exploring ways toward a healthy lifestyle, making adjustments in lifestyle, and feeling the benefits of lifestyle changes. In striving for survival, an unwillingness to bear the suffering from treatment and their acceptance of responsibility and gratitude to family members prompted most of the participants to change their lifestyle proactively. They had received inadequate lifestyle guidance and sought health lifestyle information on their own. After a period of research and self-contemplation, most of the participants adopted a consistently healthy lifestyle, changed their dietary consumption habits, abstained from tobacco and alcohol, and managed emotional problems that were caused by the disease. Participants who changed to a healthy lifestyle realized benefits in the physical, emotional, and life domains. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: It is hoped that these findings help healthcare professionals to better appreciate that a cancer diagnosis is a critical opportunity to link the disease to lifestyle choices in the minds of cancer survivors. Healthcare professionals should ask cancer survivors about their lifestyle and then provide appropriate advice and education on healthy lifestyles and related benefits. PMID- 28877120 TI - Life Experiences of Patients With Glaucoma: A Phenomenological Study. AB - BACKGROUND: Studies that describe the experiences of patients with glaucoma from different cultures may help health professionals gain a broader perspective on this issue. Currently, few qualitative studies describe how patients with glaucoma in Turkey cope with daily life. PURPOSE: The aim of this study was to explore the experiences of patients with glaucoma. METHOD: This descriptive phenomenological study used purposive sampling to enroll 20 patients with glaucoma. A qualitative, in-depth, face-to-face interview technique was used to collect data during January and February 2014. The data were analyzed using to the Van Kaam method. RESULTS: Seven themes were identified, including confirming the diagnosis by acute symptoms or unrelated symptoms, grateful to God for having a non-life-threatening disease, feeling happy after receiving more accurate information, coping with the disease by using eye drops and attending follow-up examinations regularly, managing daily life to avoid further damage to eyesight, emotional reactions related to going blind, and urging family members or friends to attend regular glaucoma checkups. CONCLUSIONS: Patients with glaucoma experience physiological and psychological problems throughout the course of their disease. Being informed and cultural practices such as "praising God" and "resignation" helped patients cope with the disease. Furthermore, because of the cultural characteristic of social collectivism, participants acted to protect the health of others by informing them about glaucoma. IMPLICATIONS FOR PRACTICE: Understanding the experiences of patients with glaucoma is important for nursing practice. Nurses should be encouraged to take a greater role in the care of patients with glaucoma by becoming the primary source of glaucoma disease, treatment, and care-related information. PMID- 28877121 TI - Begin Again and Continue With Life: A Qualitative Study on the Experiences of Cardiac Rehabilitation Patients. AB - BACKGROUND: Cardiovascular diseases are a main cause of mortality worldwide. However, new diagnostic techniques and treatments have increased the rate of survival for patients with cardiovascular disease. Cardiac rehabilitation programs aim to maintain and enhance the quality of life of patients and improve the secondary prevention of coronary artery disease. Suboptimal participation in rehabilitation programs, early exit from these programs, and not achieving lasting changes are cardiac rehabilitation challenges that are associated with health issues, including the increased need for medication, repeated hospitalization, failure in the secondary prevention programs, and long waiting lists. Exploring the meaning of behavioral changes in the context of cardiac rehabilitation may facilitate the design of effective interventions that are critical to achieving the goals of cardiac rehabilitation programs. PURPOSE: This study explored the mechanisms that underlie behavioral changes within cardiac rehabilitation centers. METHODS: We used a descriptive qualitative approach, which is widely acknowledged as the best approach for eliciting in-depth descriptions of behavioral changes in the context of cardiac rehabilitation centers. Using purposive sampling, 15 men and 8 women with coronary heart disease were referred to the two cardiac rehabilitation centers participating in this study. The inclusion criteria were participation in four cardiac rehabilitation sessions and ability and willingness to participate. The data were collected using semistructured in-depth interviews, and the inductive thematic analysis method was used for analysis. RESULTS: "Trying to stay alive" and "begin again" arose as the two main themes related to behavioral change. These themes include the changes in cognition and values that lead to improvements in the process of behavioral change as a major outcome of cardiac rehabilitation. CONCLUSIONS: Using psychosocial interventions such as creating and strengthening hope and meaningful intrinsic motivation in the context of rehabilitation centers often helps deal with these challenges. "Trying to stay alive" may take place before referral to a cardiac rehabilitation center. Therefore, psychosocial nursing interventions such as motivational interviewing are designed to improve a process that may be already underway. Thus, stress and anxiety may be treated based on beliefs and emotions. The primary emphasis in cardiac rehabilitation should include changing the beliefs of the patient and motivating her or him to achieve sustainable behavioral change. PMID- 28877122 TI - Career Obstacles Faced by Female Nurse Academicians in Turkey. AB - BACKGROUND: Most academicians in the nursing field are women, and they face many difficulties throughout the course of their careers for various reasons. PURPOSE: This study aims to determine the career difficulties faced by female academicians in the nursing field. METHODS: This study is descriptive, sectional, and comparative. The study was conducted in cooperation with female academicians in the nursing field (n = 132) from 11 different nursing schools in Turkey's Eastern Anatolia Region providing undergraduate education in nursing. Data were collected using the Female Academicians' Career Obstacles Scale. Ethics committee and required official permissions were obtained from the relevant institutions. Data analysis was conducted in an electronic environment using SPSS for Windows 22.0 package software for statistics. RESULTS: In terms of research outcomes, it was determined that the most significant obstacles reported by female academicians were "organizational culture and politics" (M = 43.92 +/- 12.64) and "playing multiple roles" (M = 31.35 +/- 10.15); the most insignificant obstacles were reported to be "organizational conditions" (M = 21.43 +/- 7.06) and "stereotypical prejudices" (M = 20.44 +/- 6.31). Other obstacles mentioned by the academicians were working as a research assistant with a bachelor's degree, being married with children, studying with young and inexperienced academicians, and serving as department head. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Organizational culture and politics in particular should be reviewed at educational institutions from the perspective of career obstacles, and these principles should be rearranged so that they constitute a supportive work environment. PMID- 28877123 TI - Care, Autonomy, and Gender in Nursing Practice: A Historical Study of Nurses' Experiences. AB - BACKGROUND: Care is the essence of the nursing role and is closely related to the concept of professional autonomy. Autonomy is implicated in power relations between doctors and nurses and between men and women. These relationships are closely linked to care practices and the inequality of nursing and medicine. PURPOSE: The aim of this study was to analyze nursing discourse regarding the concept of care and its relationship to the concept of autonomy and gender. METHODS: This is a historical study based on oral interviews that took place between November 2008 and February 2011. We interviewed 19 nursing professionals who currently worked at the Hospital of the Holy Spirit (near Barcelona) or had worked there between 1961 and 2010. Semistructured interviews were recorded, transcribed, and analyzed. RESULTS: We highlight four main themes: "a real nurse"; "more technology, less care"; "the fragility of autonomy"; and "the invisibility of nursing work." These themes show the contradictions in the nursing profession that are based on the concept of care. However, in daily practice, the concept of care varies. Time pressure distances the nursing practice from its theoretical context. Changes in the concept of care are related to transformations in the health system and nursing work. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Changes related to the autonomy of nursing are related to changes in the concept of care. In practice, care has a biomedical orientation. Care has become technologized and bureaucratized, which reduces the time that is spent with the patient. In a context in which medical authority predominates, nursing's struggle for autonomy is based on the recognition of the value of care. When care becomes invisible, the autonomy of nursing as a profession is threatened. This conclusion allows reflections about shifts in the concept of care and how they affect clinical practice and the autonomy of the nursing profession. PMID- 28877125 TI - Comparison of the Quality of Informal Care of Community-Dwelling Taiwanese Older People. AB - BACKGROUND: With social structures changing and the average life-span of individuals increasing, Taiwan is experiencing a steady rise in its elderly population. Thus, caring for older parentsis an urgent problem. Many foreign caregivers have been hired tocare for older parents.However, measuring the quality ofinformal care has not yet been fully explored in Taiwan, particularly among older people who are cared for by foreign caregivers in home settings. PURPOSE: The purposes of this study were to understand the differences in quality of care for older Taiwanese and to explore the predictors of quality of care in two types of caregiving. METHODS: A comparative descriptive study design was conducted. The study was held in several community healthcare centers in the middle and southern regions of Taiwan. Study data were collected over an 18-month period between 2012 and 2014. t Tests were used to compare continuous variables according to the types of caregiving. Multiple linear regressions with group analyses were performed to evaluate the underlying statistical assumptions. RESULTS: One hundred fifty-nine participants were included. The study results showed that age, activities of daily living level, and quality of care were significantly different between the two types of caregiving. Relationships with caregivers, social support, and depressive symptoms contributed to the quality of care in family caregiving, explaining 50.2% of the variance. Social support and depressive symptoms contributed to the quality of care in foreign caregiving, explaining 36.6% of the variance. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The study results support that the types of primary caregiving affect the quality of care that is received by elderly Taiwanese. This study may be used as a reference for families whose family members need long-term care when considering hiring foreign caregivers as an alternative option to Taiwanese caregivers. PMID- 28877124 TI - Health Sector Reform, Emotional Exhaustion, and Nursing Burnout: A Retrospective Panel Study in Iran. AB - BACKGROUND: Nursing burnout is affected by various factors, including work overload. Since the inauguration of the Health Sector Evolution Plan (HSEP) in Iran in 2014, government hospitals have been required to provide health services to the public at all levels. This decision, however, has increased the volume of patients admitted to government hospitals. Because nurses are on the front line of health services, they are faced with a greater load of care provision. PURPOSE: This study aimed to evaluate nursing burnout before and after HSEP in Iran, with an emphasis on the differences between government and private hospitals. METHOD: This retrospective panel study used Maslach's burnout inventory to evaluate nursing burnout in 371 nurses working in government and private hospitals in Shiraz, Iran, before and 7 months after the health sector reform. Chi-square test and paired t test were used to compare burnout scores. RESULTS: The results showed that nursing burnout had changed significantly after HSEP was launched (p = .030). A more detailed assessment found that burnout and emotional exhaustion had both increased significantly in the government-hospital group (ps = .014 and .001, respectively). However, no significant change in burnout was found in the private-hospital group over the same period. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings of this study indicate an increase in nursing burnout in government hospitals. An important issue in every health sector reform is nursing resource management, with a focus on burnout. Accordingly, policymakers should consider the work overload situation of nurses and work to prevent increased burnout, especially emotional exhaustion. PMID- 28877126 TI - Correlates of Perceived Social Support in Chinese Adult Child Caregivers of Parent Stroke Survivors. AB - BACKGROUND: Prevalence of stroke and traditional filial responsibility involve adult children in caregiving to their parent stroke survivors in China. Support resources are insufficient because of the shrinking size of family and the underdeveloped support system. PURPOSE: The aim of this study was to identify the correlates of perceived social support among adult child caregivers of parent stroke survivors in China. METHODS: A cross-sectional correlational design was used in this study. A nonproportional quota sample of 126 adult child caregivers was recruited from Zhejiang Province, China. Data were collected at either the hospital stroke units or the respondents' homes using structured questionnaires of caregiving dyadic demographics and caregiving characteristics, 14-item Activities of Daily Living, 15-item Mutuality Scale, and 12-item Multidimensional Scale of Perceived Social Support. SPSS 17.0 was used for analysis. RESULTS: Caregivers' mutuality, education, full employment or being retired, monthly income, having a co-carer, and having a father as the care receiver were significantly positively associated with caregivers' perceived social support. However, mutuality was not significantly associated with caregivers' perceived social support after the other factors were adjusted. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Adult child caregivers with higher levels of mutuality, education, or monthly income; who are fully employed or are retired; who have a co-carer; or who are caring for a father perceived more social support. Nursing strategies and social policies need to be directed to enhance caregiver mutuality and support caregiving efforts. PMID- 28877127 TI - Renal Transplant Recipients: The Factors Related to Immunosuppressive Medication Adherence Based on the Health Belief Model. AB - BACKGROUND: Kidney transplant failures are caused primarily by lack of adherence to immunosuppressive medication regimens by patients after transplantation. A number of studies have indicated that health-related beliefs are an effective predictor of health-related behavior. PURPOSE: The aim of this study is to understand the influence of the personal characteristics and health-related beliefs of patients on adherence to treatment with immunosuppressive medication based on the Health Belief Model. METHODS: This cross-sectional study distributed questionnaires to patients who had been recruited via purposive sampling at one medical center in Taipei. All of the potential participants had undergone kidney transplantation at least 6 months previously. The self-developed questionnaire collected data in three areas: personal characteristics, health-related beliefs regarding transplant rejection, and adherence to the immunosuppressive medication regimen. One hundred twenty-two valid questionnaires were received. The collected data were analyzed using descriptive statistics, independent t test, one-way analysis of variance, Pearson's correlation, and multiple regression. RESULTS: Participants who had received dialysis treatment or had experienced rejection perceived susceptibility to rejection more strongly than those who had not. Participants who had undergone transplantation in Taiwan, had experienced more drug-related symptoms, or had contracted severe to extremely severe infections in the past showed lower rates of adherence to treatment with immunosuppressive medication. Adherence to medication regimens correlated negatively with length of time since transplantation. Length of time since transplantation, drug-related symptoms, perceived susceptibility to rejection, and perceived benefits of treatment were identified as major predictors of adherence to immunosuppressive medication regimens. CONCLUSIONS: The results partially conformed to the concepts of the Health Belief Model. Perceived susceptibility to rejection and perceived benefits of adherence to treatment were found to predict adherence rates. Patient education should be enhanced to reduce the risks of rejection and increase adherence rates to improve outcomes. PMID- 28877128 TI - Antioxidant and Trace Element Supplementation Reduce the Inflammatory Response in Critically Ill Burn Patients. AB - Oxidative stress after burn injury induces inflammatory and hypermetabolic responses associated with adverse outcomes. We propose that antioxidant and trace element supplementation may reduce oxidative stress and subsequently alleviate inflammation and hypermetabolism, thus improving clinical outcomes. We conducted a cohort study of adult patients with an acute burn injury admitted to our provincial burn center. Patients in the antioxidant group received an intravenous infusion of multivitamins and trace elements for the first 14 days after admission. The inflammatory profile was assessed at early time points, < 14 days postburn, and later time points, >= 15 days postburn, and included interleukin (IL)-1beta, interferon-gamma, IL-1 receptor antagonist, IL-6, granulocyte macrophage colony-stimulating factor, and FMS-like tyrosine kinase 3 ligand. Hypermetabolism was assessed by resting energy expenditure. Clinical outcomes included mortality, morbidities, hospital length of stay, and infections including days to the last positive culture after injury. We studied 172 patients, mean age 49 +/- 17 years and 33 +/- 13% TBSA burned, with 91 controls and 81 patients in the antioxidant group. Patients in the antioxidant group had significantly lower levels of inflammatory markers at both early and late time points, P < .05. Antioxidant treatment was associated with decreased measure of hypermetabolism, P < .05. Morbidity and mortality were not significantly different between groups. Length of hospital stay was significantly shorter in the antioxidant group when adjusted for patient demographics and injury characteristics (risk ratio (RR), 0.78; 95% confidence interval (CI), 0.66-0.92). In the antioxidant group, while infections were not different, the last positive culture post-injury was documented at median 19 days (Interquartile range (IQR), 11-43 days) compared with controls at 35 days (IQR, 15-59 days), P = .012. Patients receiving antioxidant and trace element supplementation had reduced markers of burn stress-induced inflammation; they were also associated with a decreased hypermetabolic response, shorter length of stay, and improved bacterial clearance. PMID- 28877129 TI - Iatrogenic Full-Thickness Frostbite Injury Caused by the Use of a Conductive Cooling Device. AB - Reports of iatrogenic cold thermal injuries are rare in the literature. Conductive cooling devices, typically employed for their neuroprotective effects, use conductive hydrogel pads to achieve rapid and precise temperature control approaching the level of water immersion. Despite a number of built-in safeguards, prolonged or improper use of these devices can lead to significant thermal injury. To the best of their knowledge, the authors describe the first report of a significant iatrogenic full-thickness injury caused by the use of a surface cooling system in a patient who had recently suffered a cerebrovascular accident. The patient required transfer to the authors' tertiary burn care facility for excisional debridement and coverage with extensive split-thickness skin grafting to the chest, flank, and thighs. The grafts achieved nearly complete take and the patient was ultimately discharged to a rehabilitation facility with improving neurological condition. PMID- 28877130 TI - Fatigue Following Burn Injury: A Burn Model System National Database Study. AB - Fatigue is a commonly reported but not well-documented symptom following burn injury. This study's objective was to determine the frequency and severity of fatigue over time and to identify predictors of fatigue in the adult burn population. Data from the Burn Model System National Database (April 1997 to January 2006) were analyzed. Individuals over 18 years of age who were alive at discharge were included. The vitality subscale of the Short-Form 36 Item Health Survey was examined at preinjury and discharge and at 6, 12, and 24 months postinjury. Mean and number of low vitality scores were calculated at each time interval. Descriptive statistics were generated for demographic and medical data. Cross-sectional regression models analyzed predictors of vitality at 6, 12, and 24 months postinjury. The study included 945 subjects. The population was 72.5% male and had a mean age of 40.6 years and mean burn size of 17.4%. Fatigue symptoms were present in a majority of the population (74.6%) and were most commonly reported at discharge. Although fewer burn survivors reported fatigue symptoms at each subsequent follow-up (P < .001), approximately one-half (49%) of the population continued to report fatigue symptoms at 24 months postinjury. Larger burn size was the only variable that was significant or approaching significance at all follow-up time points (P < .0167). Fatigue symptoms are common after burns and many burn survivors continue to report symptoms at 2 years postinjury. Burn survivors did not return to preinjury fatigue levels, highlighting the importance of understanding and monitoring fatigue. PMID- 28877132 TI - Parameters for Ordering Blood Cultures in Major Burn Injury Patients: Improving Clinical Assessment. AB - Hypermetabolic and catabolic states in large TBSA burns lead to higher basal body temperature and tachycardia. These metabolic changes complicate the diagnosis of bacteremia and sepsis. Current indications for obtaining blood cultures (BCs) in this population are poorly described and nonstandardized. Fever, leukocytosis, and lactic acidosis are common during sepsis. This study aims to identify limits of these parameters with the highest rates of bacteremia. A retrospective review was performed for burn patients with > 20% TBSA between January 2009 and June 2011. BCs were collected with corresponding body temperature, white blood cell (WBC) count, and serum lactate levels. Positive culture rates were analyzed with univariate and multivariate analysis. Seventy-one patients met inclusion criteria and 360 BCs were included in data analysis. Cultures taken with temperature > 38.9 degrees C were significantly more positive (P = .01) than temperatures between 38 and 38.9 degrees C. There were significantly more positive cultures when the WBC count was < 4.5 compared with those >= 4.5 * 103/ul (P = .04). Lactate was an independent predictor of bacteremia (OR, 1.81; 95% CI, 1.21 12.71). Cultures were significantly more positive when the lactate level was >= 2.5 compared with < 2.5 mg/dL (P = .02). A temperature >= 38.5 degrees C and a lactate >= 2.5 mg/dL corresponded to a 28.6% positive culture rate compared with 4.8% for all other scenarios (P = .001). This study demonstrates that body temperature > 38.9 degrees C, WBC < 4.5 * 103/ul, and serum lactate >= 2.5 mg/dL have the highest rate for positive BCs in severe burn patients. A combination of leukopenia and pyrexia as well as lactic acidosis and pyrexia represent even higher specificity for positive BC in these patients. PMID- 28877131 TI - Resolvin D2 Limits Secondary Tissue Necrosis After Burn Wounds in Rats. AB - Secondary burn necrosis is the expansion and deepening of the original burn injury several days after injury. Limiting the extent of secondary burn necrosis may improve outcomes. In this study, we examined the ability of the lipid mediator of inflammation-resolution resolvin D2 (RvD2) and chromatin-lysing enzyme (DNase) to reduce secondary burn necrosis. Male Wistar rats were injured using a brass comb with 4 prongs heated in boiling water. This method created 2 parallel rows of 4 rectangular burned areas separated by 3 unburned interspaces. Starting at 2 hours after the burn injury, rats received either 25 ng/kg RvD2 intravenously daily for 7 days or 200 U/kg DNase every 12 hours for 3 days. We documented the necrosis around the initial wounds by digital photography. We used laser Doppler to assess the total blood flux in the burn area. We evaluated the functionality of the capillary network in the interspaces by optical coherence tomography angiography. We performed histological examination of wound skin tissue samples collected at 14 days postburn. We found that the interspace areas were preserved and had higher blood flow in the RvD2-treated group, while the burn areas expanded into the interspace areas, which were confluent by 7 days postburn, in the control-untreated group. We found a larger monocyte-to neutrophil ratio in the RvD2-treated group compared with the DNase-treated and control groups (P < .05). Overall, RvD2 suppresses secondary necrosis and starts regeneration, highlighting the role of inflammation resolution as a potential therapeutic target in burn care. PMID- 28877133 TI - Tear Dysfunction Syndrome After Burn. AB - The objective of this study was to evaluate tear dysfunction of burn patients objectively. We retrospectively reviewed medical records of patients who had been examined within 1 week after burn injury. Visual acuity, intraocular pressure, cilia burned state, tear film break-up time (TBUT), and fluorescein corneal staining were evaluated. Sixty-four eyes of 32 patients (man 27, female 5) were included. Mean age was 44.41 +/- 12.76 years old. Mean best corrected visual acuity was logMAR 0.04 +/- 0.08, mean intraocular pressure was 13.41 +/- 3.13 mm Hg, and mean TBUT was 5.48 +/- 3.18 seconds. Thirty-four eyes (53.13%) showed burned cilia, 36 eyes (56.25%) showed corneal erosion on fluorescein stating. Intraocular pressure and TBUT were lower in TBSA with burn involved >= 10% group than TBSA with burn involved < 10% group (P = .000; P = .058). The percentage of TBSA of burn involved and tear break up time showed statistically significant negative correlations (r = -0.262; P = .037). Many burn patients have discomfort due to tear dysfunction syndrome. Tear dysfunction may be caused by direct injury of eye burn itself and body fluid deficiency. We recommend that when we treat burn patients, we have to pay attention to their symptoms and manage patient's eye symptoms properly such as routine artificial tear lubricant treatment. PMID- 28877134 TI - The Use of Intravenous and Inhaled Colistin Therapy During a Burn Center Outbreak of Multidrug-Resistant Acinetobacter baumannii. AB - The authors report on the use of combination intravenous and inhaled colistin therapy in 2 patients with major burns admitted to an American Burn Association verified burn center during a multidrug-resistant (MDR) Acinetobacter baumannii outbreak. Both patients had documented, culture-proven MDR Acinetobacter ventilator-associated pneumonia and bacteremia leading to sepsis. Both patients were successfully extubated and subsequently discharged from hospital. In this article, the authors provide the timeline of events and treatments that were used in these 2 cases. Combination intravenous and inhaled colistin therapy may be a valuable tool against MDR Acinetobacter infections. PMID- 28877135 TI - Want Correct Percentage of TBSA Burned? Let a Layman Do the Assessment. AB - Accurate determination of burn size significantly impacts both immediate management and long-term outcome. In the era of evidence-based medicine, the variability in TBSA% assessment shown by traditional methods may prove unacceptable and technology-aided systems become the "accepted standard." The objective of this study was to push this scenario to the limit by investigating the accuracy and consistency of TBSA% estimations using a computer-aided tool. Five Laymen (health care-burn management naive people) were trained on the handling of the technology-aided assessment tool Burn Case 3D(c) and asked to calculate TBSA% for 18 clinical pictures of burns with different patterns and sizes. Forty-four burn Professionals (senior burn surgeons, plastic surgery residents, anesthesiologists, emergency physicians, senior registered nurses) were provided the same pictures and assessed TBSA% using traditional paper-based tools ("Rule of Palm"; "[Wallace] Rule of Nines"; "Lund and Browder chart). The Laymen's computer-aided calculations did not differ significantly (P > .05) from the senior burn surgeons' estimations in 17 of the 18 cases. However, when comparing the Laymen's TBSA% calculations with the whole group Professionals there were significant differences (P < .05) in (again) 17 of the 18 cases. Laymen's calculations were also more consistent (mean SD, 0.95%). The Professionals showed a generalized significant overestimation of TBSA% as compared with the Laymen's calculations (up to 198.5%). Innovative software provide a high potential to improve objectivity and quality of burn assessment in the future. PMID- 28877137 TI - A Systematic Review of NMDA Receptor Antagonists for Treatment of Neuropathic Pain in Clinical Practice. AB - OBJECTIVE: To investigate the efficacy of N-methyl-D-aspartate receptor (NMDAR) antagonists for neuropathic pain (NeuP) and review literature to determine if specific pharmacologic agents provide adequate NeuP relief. METHODS: Literature was reviewed on PubMed using a variety of key words for 8 NMDAR antagonists. These key words include: "Ketamine and Neuropathy," "Ketamine and Neuropathic Pain," "Methadone and Neuropathy," "Methadone and Neuropathic Pain," "Memantine and Neuropathic pain," "Memantine and Neuropathy," "Amantadine and Neuropathic Pain," "Amantadine and Neuropathy," "Dextromethorphan and Neuropathic Pain," "Dextromethorphan and Neuropathy," "Carbamazepine and Neuropathic Pain," "Carbamazepine and Neuropathy," "Valproic Acid and Neuropathy," "Valproic Acid and Neuropathic Pain," "Phenytoin and Neuropathy," and "Phenytoin and Neuropathic Pain." With the results, the papers were reviewed using the PRISMA (Preferred Reporting in Systematic and Meta-Analyses) guideline. RESULTS: A total of 58 randomized controlled trials were reviewed among 8 pharmacologic agents, which are organized by date and alphabetical order. Of the trials for ketamine, 15 showed some benefit for analgesia. Methadone had 3 positive trials, while amantadine and memantine each only had 2 trials showing NeuP analgesic properties. Dextromethorphan and valproic acid both had 4 randomized controlled trials that showed some NeuP treatment benefit while carbamazepine had over 8 trials showing efficacy. Finally, phenytoin only had 1 trial that showed clinical response in treatment. CONCLUSIONS: There are a variety of NMDAR antagonist agents that should be considered for treatment of NeuP. Nevertheless, continued and further investigation of the 8 pharmacologic agents is needed to continue to evaluate their efficacy for treatment of NeuP. PMID- 28877136 TI - Medicate or Meditate? Greater Pain Acceptance is Related to Lower Pain Medication Use in Persons With Chronic Pain and Spinal Cord Injury. AB - OBJECTIVES: There is little information about whether use of pain self-management skills that are common targets of psychosocial interventions for pain are associated with reduced reliance on pain medications. The aim of this study was to test whether higher chronic pain acceptance, which is a readily modified pain self-management approach, is related to lower use of pain medications (eg, opioid medications, and gabapentinoids) in a sample with chronic pain and spinal cord injury (SCI). MATERIALS AND METHODS: This is a cross-sectional survey study of pain medication use, pain severity and distribution (Brief Pain Inventory [BPI]), depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]), and chronic pain acceptance (Chronic Pain Acceptance Questionnaire [CPAQ]) administered to a sample of 120 adults with chronic pain and SCI. RESULTS: Regression results indicated that, above and beyond the effects of pain intensity, pain distribution, and depressive symptoms, higher pain acceptance was related to lower use of all types of pain medications, and lower odds of using opioid medications or gabapentinoids. Pain intensity was not related to pain medication use, but greater pain distribution was related to using more pain medications in general and to greater odds of using gabapentinoids. DISCUSSION: Findings from this study indicate that those with chronic pain and SCI who have a more accepting orientation to pain are less reliant on pain medications, and thereby experience lower risks associated with medication consumption. Longitudinal, daily process, and clinical trial studies are needed to better understand the association between pain acceptance and pain medication consumption. PMID- 28877138 TI - Pain in Children With Developmental Disabilities: Development and Preliminary Effectiveness of a Pain Training Workshop for Respite Workers. AB - INTRODUCTION: Pain in children with intellectual disabilities (ID) is common and complex, yet there is no standard pain training for their secondary caregivers (ie, respite staff). OBJECTIVES: Determine perceived pain training needs/preferences of children's respite staff (phase 1) and, use this information combined with extant research and guidelines to develop and pilot a training (phase 2). METHODS: In phase 1, 22 participants responded to questionnaires and engaged in individual interviews/focus groups about their experiences with pain in children with ID, and perceived training needs/preferences. In phase 2, 50 participants completed knowledge measures and rated the feasibility of, and their own confidence and skill in, pain assessment and management for children with ID immediately before and after completing a pain training. They also completed a training evaluation. RESULTS: Participants viewed pain training as beneficial. Their ideal training involved a half-day, multifaceted in-person program with a relatively small group of trainees incorporating a variety of learning activities, and an emphasis on active learning. Phase 2 results suggested that completion of the 3 to 3.5-hour pain training significantly increased respite workers' pain-related knowledge (effect sizes: r=0.81 to 0.88), as well as their ratings of the feasibility of, and their own confidence and skill in, pain assessment and management in children with ID (effect sizes: r=0.41 to 0.70). The training was rated favorably. DISCUSSION: Training can positively impact respite workers' knowledge and perceptions about pain assessment and management. As such, they may be better equipped to care for children with ID in this area. PMID- 28877140 TI - Prescription Opioid Use and the Risk of Disability. PMID- 28877141 TI - The Incidence of Adverse Childhood Experiences (ACEs) and Their Association With Pain-related and Psychosocial Impairment in Youth With Chronic Pain. AB - OBJECTIVES: Adverse childhood experiences (ACEs) in youth have been found to be frequently associated with several chronic illnesses, including chronic pain. However, this relationship remains poorly understood. Previous research has examined the association between ACEs and chronic pain, but these have primarily been examined in the context of adults with limited assessment of ACEs and individual pain conditions. The primary objectives of this study were to examine the incidence and psychological/pain-related correlates of ACEs in a sample of youth with chronic pain. Exploratory analyses were also examined using primary pain diagnosis and number of pain locations. METHODS: Data were gathered using retrospective data from a clinical databank. Participants were 141 youth aged 9 to 19 with chronic pain who presented for evaluation at a multidisciplinary pain clinic. Information on ACEs exposure, pain diagnostic information, pain-related impairment, and psychosocial functioning were gathered via self-report and retrospective review of the medical record. RESULTS: Results revealed that over 80% of youth with chronic pain reported at least 1 ACE in their lifetime. Further, multiple and univariate analyses of variance revealed that ACEs exposure is significantly associated with greater symptoms of anxiety, depression, and fear of pain, with >=3 ACEs associated with greatest impairment in functioning. No relationships were found between ACEs and increased pain-related disability or pain intensity. DISCUSSION: ACEs exposure in youth with chronic pain occurs frequently and can be associated with increased psychosocial but not functional impairment. Future research is needed to further examine the relationship between ACEs and chronic pain in youth in a prospective manner. PMID- 28877139 TI - Randomized Controlled Trial of Telephone-delivered Cognitive Behavioral Therapy Versus Supportive Care for Chronic Back Pain. AB - OBJECTIVE: The objective of this study was to evaluate the efficacy of a telephone-delivered, home-based cognitive-behavioral intervention for chronic low back pain in comparison to a matched supportive care (SC) treatment. METHODS: Participants (N=66) were patients with chronic back pain that were randomized to either an 8-week Cognitive-Behavioral Therapy (CBT) or a SC condition matched for contact frequency, format, and time. Participants completed validated measures of improvement in back pain disability, pain severity, and overall improvement. RESULTS: Intent-to-treat analyses at posttreatment showed that the treatment groups not show significantly different improvements in back pain disability (mean changes, -2.4 and -2.6 for CBT and SC, respectively; Cohen d, 0.49 and 0.55, respectively) or reductions in pain severity (mean changes, -0.9 and -1.4 for CBT and SC respectively; Cohen d, 0.50, and 0.90, respectively). Participants rated their overall improvement levels at 31% (CBT) versus 18.5% (SC). DISCUSSION: Results from this clinical trial suggest that home-based, telephone delivered CBT and SC treatments did not significantly differ in their benefits for back pain severity and disability, and may warrant further research for applications to hospital settings. Major limitations included recruitment difficulties that underpowered primary analyses, the lack of objective improvement measures, and the absence of a usual care/untreated control group for comparisons. PMID- 28877142 TI - Adding Prefrontal Transcranial Direct Current Stimulation Before Occipital Nerve Stimulation in Fibromyalgia. AB - OBJECTIVES: Fibromyalgia (FM) is a type of chronic musculoskeletal pain without a clear peripheral origin of nociception, often associated with depression. The underlying pathophysiology involves changes in a functional network that is related to pain and emotional processing in the central nervous system. Transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex or the occipital nerve (ON) is a noninvasive neuromodulation technique capable of improving fibromyalgia symptoms. This study aims to test the effect of combining 2 targets of stimulation using tDCS. MATERIALS AND METHODS: We applied ON-tDCS in isolation or coupled with pre-ONS right-anode bifrontal tDCS and assessed its effect on fibromyalgia using the Fibromyalgia Impact Questionnaire, the Beck Depression Inventory, and Numeric Rating Scale for pain scores. These measures were compared with a sham control group using repeated measures analysis of variance. RESULTS: The interaction effect of stimulation trials and the protocols of sham versus ON-tDCS were significant for the impact, distress, and pain caused by fibromyalgia (P<0.05). The interaction effect of trials and protocols of sham versus ON-tDCS with bifrontal tDCS was significant for distress (P<0.01), and it showed a trend of improvement for impact and pain (P<0.1). On the basis of the nonsignificant interaction effect of ON-tDCS versus ON-tDCS with bifrontal tDCS (P>0.1), adding bifrontal tDCS was found not to improve the treatment effect of ON-tDCS in any of the tested clinical outcome measures. DISCUSSION: This study suggests that adding right-anode bifrontal tDCS to ONS has no added benefit in improving fibromyalgia-related symptoms. PMID- 28877143 TI - Stigma and Pain in Adolescents Hospitalized for Sickle Cell Vasoocclusive Pain Episodes. AB - OBJECTIVES: Sickle cell disease (SCD) pain and hospitalizations increase during adolescence and adolescents with SCD may be at-risk for experiencing health related stigma, which may result in poor health outcomes. This study examined relations among health-related stigma, pain interference, social support, quality of life (QOL), and hospital outcomes (ie, loneliness, pain reduction, and length of stay [LOS]) in adolescents hospitalized with SCD pain. MATERIALS AND METHODS: Twelve- to 18-year-old adolescents (N=92) hospitalized with SCD pain completed measures of stigma, pain interference, social support, QOL, and state loneliness. Reduction of pain intensity during hospitalization and LOS were collected from medical chart review. RESULTS: Higher stigma was associated with higher pain interference, lower QOL, more loneliness, and less pain reduction in the hospital. Pain interference was positively associated with LOS. DISCUSSION: These preliminary findings highlight the importance of assessing and addressing SCD related stigma and pain interference in adolescents hospitalized for SCD pain as these factors may influence treatment outcomes. PMID- 28877144 TI - Reductions in Perceived Injustice are Associated With Reductions in Disability and Depressive Symptoms After Total Knee Arthroplasty. AB - INTRODUCTION: Perceptions of injustice have been associated with problematic recovery outcomes in individuals with a wide range of debilitating pain conditions. It has been suggested that, in patients with chronic pain, perceptions of injustice might arise in response to experiences characterized by illness-related pain severity, depressive symptoms, and disability. If symptoms severity and disability are important contributors to perceived injustice (PI), it follows that interventions that yield reductions in symptom severity and disability should also contribute to reductions in perceptions of injustice. The present study examined the relative contributions of postsurgical reductions in pain severity, depressive symptoms, and disability to the prediction of reductions in perceptions of injustice. METHODS: The study sample consisted of 110 individuals (69 women and 41 men) with osteoarthritis of the knee scheduled for total knee arthroplasty (TKA). Patients completed measures of perceived injustice, depressive symptoms, pain, and disability at their presurgical evaluation, and at 1-year follow-up. RESULTS: The results revealed that reductions in depressive symptoms and disability, but not pain severity, were correlated with reductions in perceived injustice. Regression analyses revealed that reductions in disability and reductions in depressive symptoms contributed modest but significant unique variance to the prediction of postsurgical reductions in perceived injustice. DISCUSSION: The present findings are consistent with current conceptualizations of injustice appraisals that propose a central role for symptom severity and disability as determinants of perceptions of injustice in patients with persistent pain. The results suggest that the inclusion of psychosocial interventions that target depressive symptoms and perceived injustice might augment the impact of rehabilitation programs made available for individuals recovering from TKA. PMID- 28877145 TI - European Society of Anaesthesiology and European Board of Anaesthesiology guidelines for procedural sedation and analgesia in adults. AB - : Procedural sedation and analgesia (PSA) has become a widespread practice given the increasing demand to relieve anxiety, discomfort and pain during invasive diagnostic and therapeutic procedures. The role of, and credentialing required by, anaesthesiologists and practitioners performing PSA has been debated for years in different guidelines. For this reason, the European Society of Anaesthesiology (ESA) and the European Board of Anaesthesiology have created a taskforce of experts that has been assigned to create an evidence-based guideline and, whenever the evidence was weak, a consensus amongst experts on: the evaluation of adult patients undergoing PSA, the role and competences required for the clinicians to safely perform PSA, the commonly used drugs for PSA, the adverse events that PSA can lead to, the minimum monitoring requirements and post procedure discharge criteria. A search of the literature from 2003 to 2016 was performed by a professional librarian and the retrieved articles were analysed to allow a critical appraisal according to the Grading of Recommendations Assessment, Development and Evaluation method. The Taskforce selected 2248 articles. Where there was insufficiently clear and concordant evidence on a topic, the Rand Appropriateness Method with three rounds of Delphi voting was used to obtain the highest level of consensus among the taskforce experts.These guidelines contain recommendations on PSA in the adult population. It does not address sedation performed in the ICU or in children and it does not aim to provide a legal statement on how PSA should be performed and by whom. The National Societies of Anaesthesiology and Ministries of Health should use this evidence-based document to help decision-making on how PSA should be performed in their countries. The final draft of the document was available to ESA members via the website for 4 weeks with the facility for them to upload their comments. Comments and suggestions of individual members and national Societies were considered and the guidelines were amended accordingly. The ESA guidelines Committee and ESA board finally approved and ratified it before publication. PMID- 28877146 TI - Eye Protection: Survey of Dermatologists and Office Staff. AB - BACKGROUND: Splash injuries to mucosal membranes during procedures have been well documented in dermatology and carry a potential risk of blood-borne virus transmission. The risk to the ocular mucosa can be minimized with proper eye protection. OBJECTIVE: To examine the prevalence of wearing eye protection during dermatologic procedures by physicians, trainees, and office staff in dermatology. METHODS: A Cross-sectional observational study of US dermatologists, residents, nurses, and medical assistants was performed regarding eye protection during dermatologic procedures. RESULTS: The rates of wearing eye protection in every dermatologic procedure are as follows: dermatologists 42.3%, residents/fellows 39.6%, and nurses/medical assistants 25%. Ninety-eight percent of respondents thought blood-borne illnesses could be transmitted by splash injury. The rates of having splash injury during your career are as follows: dermatologists 73.1%, residents/fellows 16.7%, and nurses/medical assistants 50%. The rates of having a splash injury within the last year are as follows: dermatologists 11.5%, residents/fellows 8.3%, and nurses/medical assistants 35.7%. CONCLUSION: The use of eye protection is an important component of the personal protective equipment to help prevent transmission of blood-borne illnesses. Dermatologists and staff should strive to increase awareness and the use of face masks with eye shields or face mask with separate eye protection in every dermatologic procedure. PMID- 28877147 TI - Restoration of Visual Loss With Retrobulbar Hyaluronidase Injection After Hyaluronic Acid Filler. PMID- 28877148 TI - Treatment of a Chronic Cutaneous Surgical Wound With Platelet-Rich Fibrin. PMID- 28877150 TI - A Combination Flap for Repair of Eclabium. PMID- 28877151 TI - YouTube Videos on Botulinum Toxin A for Wrinkles: A Useful Resource for Patient Education. AB - BACKGROUND: Patients interested in botulinum toxin type A (BTX-A) for wrinkles search for videos on YouTube, but little is known about the quality and reliability of the content. OBJECTIVE: The authors examined the quality, reliability, content, and target audience of YouTube videos on BTX for wrinkles. MATERIALS AND METHODS: In this cross-sectional study, the term "Botox" was searched on YouTube. Sixty relevant videos in English were independently categorized by 2 reviewers as useful informational, misleading informational, useful patient view, or misleading patient view. Disagreements were settled by a third reviewer. Videos were rated on the Global Quality Scale (GQS) (1 = poor, 5 = excellent). RESULTS: Sixty-three percent of the BTX YouTube videos were useful informational (GQS = 4.4 +/- 0.7), 33% as useful patient view (GQS = 3.21 +/- 1.2), 2% as misleading informational (GQS = 1), and 2% as misleading patient view (GQS = 2.5). CONCLUSION: The large number of useful videos, high reliability, and the wide range of content covered suggests that those who search for antiwrinkle BTX videos on YouTube are likely to view high-quality content. This suggests that YouTube may be a good source of videos to recommend for patients interested in BTX. PMID- 28877149 TI - Postoperative Pallor as a Sign of Impending Necrosis. PMID- 28877152 TI - Adverse Events Resulting in After-Hours Calls After Mohs Micrographic Surgery. PMID- 28877153 TI - Drug Delivery After Microneedling: Report of an Adverse Reaction. PMID- 28877155 TI - Lemierre's Syndrome Presenting as Multifocal Pyomyositis in a Young Child. AB - Lemierre's syndrome is more common in young adults and the majority of patients present with pharyngitis. Multifocal pyomyositis is very rare in this setting and in young children. We present here a case of multifocal pyomyositis caused by Fusobacterium spp. in a young child. Fusobacterium should be considered in the differential diagnosis of multifocal pyomyositis of unclear etiology. PMID- 28877154 TI - A Novel, Disease-Specific Self-Report Instrument to Measure Body Image Concerns in Patients With Head and Neck Skin Cancer. AB - BACKGROUND: Skin cancer commonly occurs on areas that are salient to body image perception (i.e., head and neck). Patients with head and neck skin cancer (HNSC) may experience negative body image perceptions related to their disease, which is concerning, given the numerous negative sequelae of poor body image. However, there are no existing disease-specific measures of body image concerns in HNSC. OBJECTIVE: To develop and examine the psychometric properties of a brief self report, disease-specific measure of body image concerns in patients with HNSC-the Body Image Questionnaire (BIQ). MATERIALS AND METHODS: Patients with HNSC completed the BIQ before (n = 239) and 6 months after (n = 80) treatment with Mohs micrographic surgery. Analyses examined the internal consistency, convergent validity, and factor structure of the BIQ. RESULTS: Internal consistency reliability was acceptable, and the measure demonstrated convergent validity with well-being. Four dimensions underlie the BIQ: appearance satisfaction, appearance avoidance, head/neck/skin-specific dissatisfaction, and perceived change. CONCLUSION: The BIQ is a valid and internally reliable disease-specific instrument that measures body image concerns in patients with HNSC. PMID- 28877156 TI - Performance of the QuantiFERON-TB Gold Assay Among HIV-infected Children With Active Tuberculosis in France. AB - BACKGROUND: Data regarding the use of QuantiFERON to assist the diagnosis of active tuberculosis (TB) in HIV-infected children are limited, especially in countries with low incidence of TB/HIV coinfection. METHODS: QuantiFERON results were analyzed in 63 HIV-infected children who presented to our hospital in Paris, France. Seventeen HIV-uninfected children with active TB (4 culture-confirmed) were included for comparison. RESULTS: The 63 HIV-infected children (median age: 11 yr) had 113 QuantiFERON tests. Thirty-four (54%) were born in sub-Saharan Africa. Vertical HIV transmission was documented for 50 of 52 (96%) and stage III HIV-infection for 30 of 50 children (60%). Over the study period, active TB was diagnosed in 7 of 63 HIV-infected children (3 culture-confirmed). Additional ongoing or previous opportunistic infections were present in 4 of 7. QuantiFERON results were positive in 2 of 7 HIV-infected children with active TB (sensitivity: 29%) and 16 of 17 HIV-uninfected children with active TB (sensitivity: 94%). At initial QuantiFERON testing of the 63 HIV-infected children, 8 (13%) had positive results (1, active TB; 5, latent TB; 2, previous TB) and 51 (81%) had negative results. Of 33 children with repeat testing after an initially positive or negative result, the only change was one conversion from a negative to a positive result at the onset of active TB. The 4 children (6%) with indeterminate quantiFERON results had a concomitant opportunistic infection. Results of repeat testing after clinical stabilization were negative in all 4. CONCLUSIONS: QuantiFERON testing performed poorly for active TB diagnosis in this series of children with advanced HIV infection. PMID- 28877157 TI - External Validation of Six Pediatric Fever and Neutropenia Clinical Decision Rules. AB - BACKGROUND: Fever and neutropenia (FN) clinical decision rules (CDRs) are recommended to help distinguish children with cancer at high and low risk of severe infection. The aim of this study was to validate existing pediatric FN CDRs designed to stratify children with cancer at high or low risk of serious infection or medical complication. METHODS: Pediatric CDRs suitable for validation were identified from a literature search. Relevant data were extracted from an existing data set of 650 retrospective FN episodes in children with cancer. The sensitivity and specificity of each of the CDR were compared with the derivation studies to assess reproducibility. RESULTS: Six CDRs were identified for validation: 2 were designed to predict bacteremia and 4 to predict adverse events. Five CDRs exhibited reproducibility in our cohort. A rule predicting bacteremia had the highest sensitivity (100%; 95% confidence interval (CI): 93% 100%) although poor specificity (17%), with only 15% identified as low risk. For adverse events, the highest sensitivity achieved was 84% (95% CI: 75%-90%), with specificity of 29% and 27% identified as low risk. A rule intended for application after a 24-hour period of inpatient observation yielded a sensitivity of 80% (95% CI: 73-86) and specificity of 46%, with 44% identified as low risk. CONCLUSIONS: Five CDRs were reproducible, although not all can be recommended for implementation because of either inadequate sensitivity or failure to identify a clinically meaningful number of low-risk patients. The 24-hour rule arguably exhibits the best balance between sensitivity and specificity in our population. PMID- 28877158 TI - Antibiotic Use in Hospitalized Children With Respiratory Viruses Detected by Multiplex Polymerase Chain Reaction. AB - BACKGROUND: Multiplex polymerase chain reaction-based methods are increasingly used to detect respiratory pathogens in children. While rapid identification of viruses has been shown to reduce antibiotic use, the impact of detecting specific viruses on antibiotic utilization has not been ascertained. This study compared antibiotic utilization among hospitalized children who tested positive for different respiratory viruses at admission. METHODS: A single-center study of hospitalized children under 21 years of age who tested positive at admission for at least 1 respiratory virus by multiplex polymerase chain reaction from October 1, 2012 to October 1, 2015 was performed. Multivariable logistic regression was used to determine the association of testing positive for specific viruses with the use of antibiotics for >= 2 days, adjusted for demographic and clinical characteristics. RESULTS: The study included 1416 patients with a median age of 2.1 years (interquartile range: 0.6-6.2 years). Patients positive for influenza (odds ratio: 2.0, 95% confidence interval: 1.1-3.4) and human metapneumovirus (odds ratio: 2.0, 95% confidence interval: 1.1-3.7) were more likely to receive >= 2 days of treatment compared with patients positive for respiratory syncytial virus (RSV). Other variables affecting prolonged use of antibiotics included respiratory support, primary nonrespiratory diagnosis, complex comorbid conditions and admission to the intensive care unit. CONCLUSIONS: Providers are more likely to use antibiotics in non-RSV-infected patients compared with RSV. These trends likely represent concern about bacterial superinfection and may reflect lack of familiarity with these pathogens. PMID- 28877160 TI - Smarter, not harder. PMID- 28877159 TI - Association Between 25-Hydroxyvitamin D and Epicardial Adipose Tissue in Chinese Non-Obese Patients with Type 2 Diabetes. AB - BACKGROUND Epicardial adipose tissue (EAT) is recognized as a useful indicator for type 2 diabetes mellitus (T2DM) and obesity. However, studies on the association between vitamin D status and EAT thickness in type 2 diabetes (T2D) are limited. In this study, we aimed to evaluate the association of vitamin D (Calcifediol) status and EAT thickness (EATT) in Chinese non-obese patients with T2D. MATERIAL AND METHODS A cross-sectional study was performed among 167 non obese T2D Chinese patients and 82 non-diabetic patients, who are age- and gender matched during the winter months. EATT was evaluated by two-dimensional transthoracic echocardiography. Serum 25-hydroxyvitamin D [25(OH)D, Calcifediol] was examined in the diabetic patients and in the control group. RESULTS The concentration of 25(OH)D was 32.00 nmol/l (19.30-53.70 nmol/l) among diabetic patients. Most (93.4%) of the diabetic patients had hypovitaminosis D. We confirmed a clear negative association between 25(OH)D level and EATT in non obese T2D patients (p=0.01). EATT was significantly correlated with 25(OH)D level (p=0.001) and HOMA-IR (p=0.001). Results of multivariate logistic regression analysis demonstrated increased EATT, which was remarkably associated with 25(OH)D levels (p=0.039), systolic blood pressure (SBP) (p=0.013), HOMA-IR (p=0.030), and waist circumference (p<0.001) in T2D patients after adjusting for the confounding factors. CONCLUSIONS Increased EATT was found in Chinese T2D patients with normal BMI. 25(OH)D and HOMA-IR were independently associated with increased EATT after adjusting for multiple confounders. PMID- 28877162 TI - Correction: Dramatic and concerted conformational changes enable rhodocetin to block alpha2beta1 integrin selectively. AB - [This corrects the article DOI: 10.1371/journal.pbio.2001492.]. PMID- 28877161 TI - Interactive locomotion: Investigation and modeling of physically-paired humans while walking. AB - In spite of extensive studies on human walking, less research has been conducted on human walking gait adaptation during interaction with another human. In this paper, we study a particular case of interactive locomotion where two humans carry a rigid object together. Experimental data from two persons walking together, one in front of the other, while carrying a stretcher-like object is presented, and the adaptation of their walking gaits and coordination of the foot fall patterns are analyzed. It is observed that in more than 70% of the experiments the subjects synchronize their walking gaits; it is shown that these walking gaits can be associated to quadrupedal gaits. Moreover, in order to understand the extent by which the passive dynamics can explain this synchronization behaviour, a simple 2D model, made of two-coupled spring-loaded inverted pendulums, is developed, and a comparison between the experiments and simulations with this model is presented, showing that with this simple model we are able to reproduce some aspects of human walking behaviour when paired with another human. PMID- 28877163 TI - Long-term impact of changing childhood malnutrition on rotavirus diarrhoea: Two decades of adjusted association with climate and socio-demographic factors from urban Bangladesh. AB - BACKGROUND: There is strong association between childhood rotavirus, diarrhoea, climate factors and malnutrition. Conversely, a significant nutritional transition (reduced under-nutrition) with a concurrent increasing trend of rotavirus infection in last decade was also observed among under 5 children, especially in developing countries including Bangladesh. Considering the pathophysiology of rotavirus, there might be an interaction of this nutrition transition which plays a pivotal role in increasing rotavirus infection in addition to climate and other man-made factors in urban areas such as Dhaka, Bangladesh. METHODS: Relevant monthly data from 1993-2012 were extracted from the archive of the Diarrhoeal Disease Surveillance System of icddr, b and linked with data collected from the Dhaka station of the Bangladesh Meteorological Department (mean temperature, rainfall, sea level pressure and humidity). Seasonal autoregressive integrated moving average time series models were deployed to determine the association between the monthly proportion of rotavirus infection and underweight, stunting and wasting adjusting for climate, socio-demographic and sanitation factors. FINDING: The proportion of rotavirus cases among all causes diarrhoea increased from 20% in 1993 to 43% in 2012 (Chi squared for trend p = 0.010). In contrast, underweight, stunting and wasting decreased from 59%-29% (p<0.001); 53%-21% (p<0.001) and 32%-22% (p<0.001) respectively over the same period. Mean ambient temperature increased from 25.76 degrees C-26.62 degrees C (p = 0.07); mean rainfall, sea level pressure and mean humidity decreased from 234.92-111.75 mm (p = 0.5), 1008.30-1006.61 mm of hg (p = 0.02) and 76.63%-70.26% (p<0.001), respectively. In the adjusted model, a decrease in monthly proportion of underweight [coef.: -0.189 (95% CI:-0.376, -0.003)] and wasting [-0.265 ( 0.455, -0.075)] were significantly and inversely associated with rotavirus infection. However, an inverse but insignificant association was observed for stunting [-0.070 (-0.249, 0.109)]. INTERPRETATION: The reduction of acute childhood malnutrition is significantly associated with increasing rotavirus diarrhoea among under-5 children. Thus mass vaccination in addition to interventions directed at man-made modifiable predictors for prevention and control is warranted. PMID- 28877164 TI - In vivo therapeutic effect of combination treatment with metformin and Scutellaria baicalensis on maintaining bile acid homeostasis. AB - The radix of Scutellaria baicalensis (SB) is a herb widely used in traditional Chinese medicine to treat metabolic diseases. Several main components, including baicalin and wogonoside, possess anti-dyslipidemia, anti-obesity and anti diabetic effects. We hypothesized that co-administration of SB extract and metformin exerts a better effect on obesity-induced insulin resistance and lipid metabolism than treatment with metformin alone. We compared the effect of metformin (100 mg/10 mL/kg/day) alone with co-administration of metformin (100 mg/5 mL/kg/day) and SB extract (200 mg/5 mL/kg/day) on Otsuka Long Evans Tokushima Fatty rats, a useful model of type II diabetes with obesity, and used Long-Evans Tokushima Otsuka rats as a control. Weight, fasting glucose, oral glucose tolerance test, intraperitoneal insulin tolerance test, and serum total cholesterol were measured after 12 weeks of drug administration. We observed a synergetic effect of metformin and SB on lowering cholesterol level by excretion of bile acid through feces. We found that this accompanied activation of FXR, CYP7A1 and LDLR genes and repression of HMGCR in the liver. Although there were no significant changes in BSH-active gut microbiota due to high variability, functional prediction with 16S sequences showed increased primary and secondary bile acid biosynthesis in the combination treatment group. Further study is needed to find the specific strains of bacteria which contribute to FXR-related cholesterol and bile acid regulations. PMID- 28877166 TI - Potential of pest regulation by insectivorous birds in Mediterranean woody crops. AB - Regulation of agricultural pests managing their natural enemies represents an alternative to chemical pesticides. We assessed the potential of insectivorous birds as pest regulators in woody crops located in central Spain. A total of 417 nest boxes installed in five field study sites (one vineyard, two fruit orchards, and two olive groves) were monitored for use and breeding of insectivorous birds and other species for four consecutive years (2013-2016). At all field sites except the two olive groves, where birds never occupied the nest boxes, predation experiments were conducted with Greater wax moth (Galleria mellonella) sentinel caterpillars, and food consumption by birds was estimated. Nesting of insectivorous birds, chiefly Great tit (Parus major), and sparrows (Passer domesticus and P. montanus) increased over time, averaging 60% per field site in the vineyard and fruit orchards by the fourth year. Use of nest boxes by sparrows and by Garden dormouse (Eliomys quercinus) was high at the fruit orchards (70%) and the vineyard (30%), respectively. Micro-habitat characteristics (nest box level) and meso-habitat characteristics (patch level) strongly affected use of nest boxes and bird breeding (i.e. number of laid eggs and produced chicks) in different years. Distance to natural or semi-natural vegetation did not consistently affect bird breeding, nor did we see consistent evidence of competition between adjacent breeding birds. Predation rates of sentinel caterpillars were approximately one-third higher near boxes with nesting birds (31.51 +/- 43.13%) than at paired distant areas without nest boxes (22.45% +/- 38.58%). Food consumption by insectivorous birds per ha and breeding season were conservatively estimated to range from 0.02 kg in one fruit orchard to 0.15 kg in the vineyard. We conclude that installation of nest boxes in Mediterranean woody crops enhances populations of insectivorous birds that regulate pests, but that the effects are moderate and highly context-dependent. PMID- 28877165 TI - The effects of an unsupervised water exercise program on low back pain and sick leave among healthy pregnant women - A randomised controlled trial. AB - BACKGROUND: Low back pain is highly prevalent among pregnant women, but evidence of an effective treatment are still lacking. Supervised exercise-either land or water based-has shown benefits for low back pain, but no trial has investigated the evidence of an unsupervised water exercise program on low back pain. We aimed to assess the effect of an unsupervised water exercise program on low back pain intensity and days spent on sick leave among healthy pregnant women. METHODS: In this randomised, controlled, parallel-group trial, 516 healthy pregnant women were randomly assigned to either unsupervised water exercise twice a week for a period of 12 weeks or standard prenatal care. Healthy pregnant women aged 18 years or older, with a single fetus and between 16-17 gestational weeks were eligible. The primary outcome was low back pain intensity measured by the Low Back Pain Rating scale at 32 weeks. The secondary outcomes were self-reported days spent on sick leave, disability due to low back pain (Roland Morris Disability Questionnaire) and self-rated general health (EQ-5D and EQ-VAS). RESULTS: Low back pain intensity was significantly lower in the water exercise group, with a score of 2.01 (95% CI 1.75-2.26) vs. 2.38 in the control group (95% CI 2.12-2.64) (mean difference = 0.38, 95% CI 0.02-0.74 p = 0.04). No difference was found in the number of days spent on sick leave (median 4 vs. 4, p = 0.83), disability due to low back pain nor self-rated general health. There was a trend towards more women in the water exercise group reporting no low back pain at 32 weeks (21% vs. 14%, p = 0.07). CONCLUSIONS: Unsupervised water exercise results in a statistically significant lower intensity of low back pain in healthy pregnant women, but the result was most likely not clinically significant. It did not affect the number of days on sick leave, disability due to low back pain nor self-rated health. TRIAL REGISTRATION: ClinicalTrials.gov NCT02354430. PMID- 28877167 TI - Measuring Dispositional Flow: Validity and reliability of the Dispositional Flow State Scale 2, Italian version. AB - OBJECTIVE: The aim of this study is to evaluate the psychometric properties of the Italian version of the Dispositional Flow Scale-2 (DFS-2), for use with Italian adults, young adults and adolescents. METHOD: In accordance with the guidelines for test adaptation, the scale has been translated with the method of back translation. The understanding of the item has been checked according to the latest standards on the culturally sensitive translation. The scale thus produced was administered to 843 individuals (of which 60.69% female), between the ages of 15 and 74. The sample is balanced between workers and students. The main activities defined by the subjects allow the sample to be divided into three categories: students, workers, athletes (professionals and semi-professionals). RESULTS: The confirmatory factor analysis, conducted using the Maximum Likelihood Estimator (MLM), showed acceptable fit indexes. Reliability and validity have been verified, and structural invariance has been verified on 6 categories of Flow experience and for 3 subsamples with different with different fields of action. Correlational analysis shows significant high values between the nine dimensions. CONCLUSIONS: Our data confirmed the validity and reliability of the Italian DFS-2 in measuring Flow experiences. The scale is reliable for use with Italian adults, young adults and adolescents. The Italian version of the scale is suitable for the evaluation of the subjective tendency to experience Flow trait characteristic in different contest, as sport, study and work. PMID- 28877168 TI - Simple rules can guide whether land- or ocean-based conservation will best benefit marine ecosystems. AB - Coastal marine ecosystems can be managed by actions undertaken both on the land and in the ocean. Quantifying and comparing the costs and benefits of actions in both realms is therefore necessary for efficient management. Here, we quantify the link between terrestrial sediment runoff and a downstream coastal marine ecosystem and contrast the cost-effectiveness of marine- and land-based conservation actions. We use a dynamic land- and sea-scape model to determine whether limited funds should be directed to 1 of 4 alternative conservation actions-protection on land, protection in the ocean, restoration on land, or restoration in the ocean-to maximise the extent of light-dependent marine benthic habitats across decadal timescales. We apply the model to a case study for a seagrass meadow in Australia. We find that marine restoration is the most cost effective action over decadal timescales in this system, based on a conservative estimate of the rate at which seagrass can expand into a new habitat. The optimal decision will vary in different social-ecological contexts, but some basic information can guide optimal investments to counteract land- and ocean-based stressors: (1) marine restoration should be prioritised if the rates of marine ecosystem decline and expansion are similar and low; (2) marine protection should take precedence if the rate of marine ecosystem decline is high or if the adjacent catchment is relatively intact and has a low rate of vegetation decline; (3) land-based actions are optimal when the ratio of marine ecosystem expansion to decline is greater than 1:1.4, with terrestrial restoration typically the most cost-effective action; and (4) land protection should be prioritised if the catchment is relatively intact but the rate of vegetation decline is high. These rules of thumb illustrate how cost-effective conservation outcomes for connected land-ocean systems can proceed without complex modelling. PMID- 28877169 TI - Sleep and eyewitness memory: Fewer false identifications after sleep when the target is absent from the lineup. AB - Inaccurate eyewitness identifications are the leading cause of known false convictions in the United States. Moreover, improving eyewitness memory is difficult and often unsuccessful. Sleep consistently strengthens and protects memory from interference, particularly when a recall test is used. However, the effect of sleep on recognition memory is more equivocal. Eyewitness identification tests are often recognition based, thus leaving open the question of how sleep affects recognition performance in an eyewitness context. In the current study, we investigated the effect of sleep on eyewitness memory. Participants watched a video of a mock-crime and attempted to identify the perpetrator from a simultaneous lineup after a 12-hour retention interval that either spanned a waking day or night of sleep. In Experiment 1, we used a target present lineup and, in Experiment 2, we used a target-absent lineup in order to investigate correct and false identifications, respectively. Sleep reduced false identifications in the target-absent lineup (Experiment 2) but had no effect on correct identifications in the target-present lineup (Experiment 1). These results are discussed with respect to memory strength and decision making strategies. PMID- 28877170 TI - Overtreatment in the United States. AB - BACKGROUND: Overtreatment is a cause of preventable harm and waste in health care. Little is known about clinician perspectives on the problem. In this study, physicians were surveyed on the prevalence, causes, and implications of overtreatment. METHODS: 2,106 physicians from an online community composed of doctors from the American Medical Association (AMA) masterfile participated in a survey. The survey inquired about the extent of overutilization, as well as causes, solutions, and implications for health care. Main outcome measures included: percentage of unnecessary medical care, most commonly cited reasons of overtreatment, potential solutions, and responses regarding association of profit and overtreatment. FINDINGS: The response rate was 70.1%. Physicians reported that an interpolated median of 20.6% of overall medical care was unnecessary, including 22.0% of prescription medications, 24.9% of tests, and 11.1% of procedures. The most common cited reasons for overtreatment were fear of malpractice (84.7%), patient pressure/request (59.0%), and difficulty accessing medical records (38.2%). Potential solutions identified were training residents on appropriateness criteria (55.2%), easy access to outside health records (52.0%), and more practice guidelines (51.5%). Most respondents (70.8%) believed that physicians are more likely to perform unnecessary procedures when they profit from them. Most respondents believed that de-emphasizing fee-for-service physician compensation would reduce health care utilization and costs. CONCLUSION: From the physician perspective, overtreatment is common. Efforts to address the problem should consider the causes and solutions offered by physicians. PMID- 28877171 TI - Preventable proportion of intubation-associated pneumonia: Role of adherence to a care bundle. AB - OBJECTIVE: The aim of the present study was to estimate the preventable proportion of Intubation-Associated Pneumonia (IAP) in the Intensive Care Units (ICUs) participating in the Italian Nosocomial Infections Surveillance in ICUs (SPIN-UTI) network, taking into account differences in intrinsic patients' risk factors, and additionally considering the compliance with the European bundle for IAP prevention. METHODS: A prospective patient-based survey was conducted and all patients staying in ICU for more than 2 days were enrolled in the surveillance. Compliance with the bundle was assessed using a questionnaire for each intubated patient. A twofold analysis by the parametric g-formula was used to compute the number of infections to be expected if the infection incidence in all ICUs could be reduced to that one of the top-tenth-percentile-ranked ICUs and to that one of the ICU with the highest compliance to all five bundle components. RESULTS: A total of 1,840 patients and of 17 ICUs were included in the first analysis showing a preventable proportion of 44% of IAP. In a second analysis on a subset of data, considering compliance with the European bundle, a preventable proportion of 40% of IAP was shown. A significant negative trend of IAP incidences was observed with increasing number of bundle components performed (p<0.001) and a strong negative correlation between these two factors was shown (r = -0.882; p = 0.048). CONCLUSIONS: The g-formula controlled for time-varying factors is a valuable approach for estimating the preventable proportion of IAP and the impact of interventions, based entirely on an observed population in a real-world setting. However, both the study design that cannot definitively prove a causative relationship between bundle compliance and IAP risk, and the small number of patients included in the care bundle compliance analysis, may represent limits of the study and further and larger studies should be conducted. PMID- 28877172 TI - Automated recording of home cage activity and temperature of individual rats housed in social groups: The Rodent Big Brother project. AB - Measuring the activity and temperature of rats is commonly required in biomedical research. Conventional approaches necessitate single housing, which affects their behavior and wellbeing. We have used a subcutaneous radiofrequency identification (RFID) transponder to measure ambulatory activity and temperature of individual rats when group-housed in conventional, rack-mounted home cages. The transponder location and temperature is detected by a matrix of antennae in a baseplate under the cage. An infrared high-definition camera acquires side-view video of the cage and also enables automated detection of vertical activity. Validation studies showed that baseplate-derived ambulatory activity correlated well with manual tracking and with side-view whole-cage video pixel movement. This technology enables individual behavioral and temperature data to be acquired continuously from group-housed rats in their familiar, home cage environment. We demonstrate its ability to reliably detect naturally occurring behavioral effects, extending beyond the capabilities of routine observational tests and conventional monitoring equipment. It has numerous potential applications including safety pharmacology, toxicology, circadian biology, disease models and drug discovery. PMID- 28877174 TI - Access to finance from different finance provider types: Farmer knowledge of the requirements. AB - Analysing farmer knowledge of the requirements of finance providers can provide valuable insights to policy makers about ways to improve farmers' access to finance. This study compares farmer knowledge of the requirements to obtain finance with the actual requirements set by different finance provider types, and investigates the relation between demographic and socioeconomic factors and farmer knowledge of finance requirements. We use a structured questionnaire to collect data from a sample of finance providers and farmers in Java Island, Indonesia. We find that the most important requirements to acquire finance vary among different finance provider types. We also find that farmers generally have little knowledge of the requirements, which are important to each type of finance provider. Awareness campaigns are needed to increase farmer knowledge of the diversity of requirements among the finance provider types. PMID- 28877173 TI - Assessment of WHO criteria for identifying ART treatment failure in Vietnam from 2007 to 2011. AB - OBJECTIVE: We evaluated the sensitivity and specificity of the WHO immunological criteria for detecting antiretroviral therapy (ART) treatment failure in a cohort of Vietnamese patients. We conducted a stratified analysis to determine the effects of BMI, peer support, adherence to antiretroviral (ARV) drugs, age, and gender on the sensitivity and specificity of the WHO criteria. METHODS: We conducted a retrospective cohort study of 605 HIV-infected patients using data previously collected from a cluster randomized control trial study. We compared the sensitivity and specificity of CD4+ counts to the gold standard of virologic testing as a diagnostic test for ART failure at different time points of 12, 18, and 24 months. RESULTS: The sensitivity [95% confidence interval (CI)] of the WHO immunological criteria based on a viral load >= 1000 copies/mL was 12% (5%-23%), 14% (2%-43%), and 12.5% (2%-38%) at 12, 18, and 24 months, respectively. In the same order, the specificity was 93% (90%-96%), 98% (96%-99%), and 98% (96%-100%). The positive predictive values (PPV) at 12, 18, and 24 months were 22% (9%-40%), 20% (3%-56%), and 29% (4%-71%); the negative predictive values (NPV) at the same time points were 87% (84%-90%), 97% (95%-98%), and 96% (93%-98%). The stratified analysis revealed similar sensitivities and specificities. CONCLUSION: The sensitivity of the WHO immunological criteria is poor, but the specificity is high. Although testing costs may increase, we recommend that Vietnam and other similar settings adopt viral load testing as the principal method for determining ART failure. PMID- 28877175 TI - Composing only by thought: Novel application of the P300 brain-computer interface. AB - The P300 event-related potential is a well-known pattern in the electroencephalogram (EEG). This kind of brain signal is used for many different brain-computer interface (BCI) applications, e.g., spellers, environmental controllers, web browsers, or for painting. In recent times, BCI systems are mature enough to leave the laboratories to be used by the end-users, namely severely disabled people. Therefore, new challenges arise and the systems should be implemented and evaluated according to user-centered design (USD) guidelines. We developed and implemented a new system that utilizes the P300 pattern to compose music. Our Brain Composing system consists of three parts: the EEG acquisition device, the P300-based BCI, and the music composing software. Seventeen musical participants and one professional composer performed a copy spelling, a copy-composing, and a free-composing task with the system. According to the USD guidelines, we investigated the efficiency, the effectiveness and subjective criteria in terms of satisfaction, enjoyment, frustration, and attractiveness. The musical participants group achieved high average accuracies: 88.24% (copy-spelling), 88.58% (copy-composing), and 76.51% (free-composing). The professional composer achieved also high accuracies: 100% (copy-spelling), 93.62% (copy-composing), and 98.20% (free-composing). General results regarding the subjective criteria evaluation were that the participants enjoyed the usage of the Brain Composing system and were highly satisfied with the system. Showing very positive results with healthy people in this study, this was the first step towards a music composing system for severely disabled people. PMID- 28877176 TI - Happy creativity: Listening to happy music facilitates divergent thinking. AB - Creativity can be considered one of the key competencies for the twenty-first century. It provides us with the capacity to deal with the opportunities and challenges that are part of our complex and fast-changing world. The question as to what facilitates creative cognition-the ability to come up with creative ideas, problem solutions and products-is as old as the human sciences, and various means to enhance creative cognition have been studied. Despite earlier scientific studies demonstrating a beneficial effect of music on cognition, the effect of music listening on creative cognition has remained largely unexplored. The current study experimentally tests whether listening to specific types of music (four classical music excerpts systematically varying on valance and arousal), as compared to a silence control condition, facilitates divergent and convergent creativity. Creativity was higher for participants who listened to 'happy music' (i.e., classical music high on arousal and positive mood) while performing the divergent creativity task, than for participants who performed the task in silence. No effect of music was found for convergent creativity. In addition to the scientific contribution, the current findings may have important practical implications. Music listening can be easily integrated into daily life and may provide an innovative means to facilitate creative cognition in an efficient way in various scientific, educational and organizational settings when creative thinking is needed. PMID- 28877177 TI - An in vitro diagnostic certified point of care single nucleotide test for IL28B polymorphisms. AB - Numerous genetic polymorphisms have been identified as associated with disease or treatment outcome, but the routine implementation of genotyping into actionable medical care remains limited. Point-of-care (PoC) technologies enable rapid and real-time treatment decisions, with great potential for extending molecular diagnostic approaches to settings with limited medical infrastructure (e.g., CLIA certified diagnostic laboratories). With respect to resource-limited settings, there is a need for simple devices to implement biomarker guided treatment strategies. One relevant example is chronic hepatitis C infection, for which several treatment options are now approved. Single nucleotide polymorphisms (SNPs) in the IL-28B / IFNL3 locus have been well described to predict both spontaneous clearance and response to interferon based therapies. We utilized the Genedrive(r) platform to develop an assay for the SNP rs12979860 variants (CC, CT and TT). The assay utilizes a hybrid thermal engine, permitting rapid heating and cooling, enabling an amplification based assay with genetic variants reported using endpoint differential melting cure analysis in less than 60 minutes. We validated this assay using non-invasive buccal swab sampling in a prospective study of 246 chronic HCV patients, achieving 100% sensitivity and 100% specificity (95% exact CI: 98.8-100%)) in 50 minutes as compared to conventional lab based PCR testing. Our results provide proof of concept that precision medicine is feasible in resource-limited settings, offering the first CE-IVD (in vitro diagnostics) validated PoC SNP test. We propose that IL-28B genotyping may be useful for directing patients towards lower cost therapies, and rationing use of costly direct antivirals for use in those individuals showing genetic risk. PMID- 28877178 TI - To be on the safe site - Ungroomed spots on the bee's body and their importance for pollination. AB - Flower-visiting bees collect large quantities of pollen to feed their offspring. Pollen deposited in the bees' transport organs is lost for the flowers' pollination. It has been hypothesised that specific body areas, bees cannot groom, serve as 'safe sites' for pollen transfer between flowers. For the first time, we experimentally demonstrated the position, area and pollen amount of safe sites at the examples of Apis mellifera and Bombus terrestris by combining artificial contamination of the bees' body with pine or sunflower pollen and the subsequent bees' incomplete grooming. We found safe sites on the forehead, the dorsal thorax and waist, and on the dorsal and ventral abdomen of the bees. These areas were less groomed by the bees' legs. The largest amount of pollen was found on the waist, followed by the dorsal areas of thorax and abdomen. At the example of Salvia pratensis, S. officinalis and Borago officinalis, we experimentally demonstrated with fluorescent dye that the flowers' pollen-sacs and stigma contact identical safe sites. These results confirm that pollen deposition on the bees' safe sites improves pollen transfer to stigmas of conspecific flowers sti. Future research will demonstrate the importance of safe sites for plant pollination under field conditions. PMID- 28877179 TI - Adherence to 6-Mercaptopurine in children and adolescents with Acute Lymphoblastic Leukemia. AB - OBJECTIVE: Studies on children with Acute Lymphoblastic Leukemia (ALL) reported non-adherence in 2-54% of cases. The primary objective of this study was to assess rates of adherence to 6-MP using two different methods in children and adolescents with ALL. Secondary aim was to identify factors that influence adherence to 6-MP in children with ALL. METHODS: All eligible children with ALL who are (<= 19) years old and receive 6-MP therapy for at least 1 month were approached to participate in the study. A total of 52 children with ALL and their primary caregivers were recruited. Adherence measures included an objective method (measuring 6-MP metabolites in packed Red Blood Cells (RBCs)) and a subjective method (using parent and child self-report via the Medication Adherence Report Scale; MARS; Adherence was defined as 90% or greater). RESULTS: Rates of adherence varied across the measurement methods. Packed RBCs sample analysis indicated forty-four patients (84.6%) to be adherent. Using the MARS questionnaires, a total of 49 children (94.2%) were classified as being adherent according to the parental MARS questionnaire scores, while all the 15 children (100%) who answered the MARS (child) questionnaire were classified as adherent. Overall adherence rate was 80.8% within the studied population. CONCLUSION: MARS scale was shown to overestimate adherence compared to measurement of 6-MP metabolites in the blood. A combination of both methods led to increased detection of non-adherence to thiopurine in children with ALL. PMID- 28877180 TI - Decreased complexity of glucose dynamics preceding the onset of diabetes in mice and rats. AB - Continuous glucose monitoring (CGM) is a platform to measure blood glucose (BG) levels continuously in real time with high enough resolution to document their underlying fluctuations. Multiscale entropy (MSE) analysis has been proposed as a measure of time-series complexity, and when applied to clinical CGM data, MSE analysis revealed that diabetic patients have lower MSE complexity in their BG time series than healthy subjects. To determine if the clinical observations on complexity of glucose dynamics can be back-translated to relevant preclinical species used routinely in diabetes drug discovery, we performed CGM in both mouse (ob/ob) and rat (Zucker Diabetic Fatty, ZDF) models of diabetes. We demonstrate that similar to human data, the complexity of glucose dynamics is also decreased in diabetic mice and rats. We show that low complexity of glucose dynamics is not simply a reflection of high glucose values, but rather reflective of the underlying disease state (i.e. diabetes). Finally, we demonstrate for the first time that the complexity of glucose fluctuations in ZDF rats, as probed by MSE analysis, is decreased prior to the onset of overt diabetes, although complexity undergoes further decline during the transition to frank diabetes. Our study suggests that MSE could serve as a novel biomarker for the progression to diabetes and that complexity studies in preclinical models could offer a new paradigm for early differentiation, and thereby, selection of appropriate clinical candidate molecules to be tested in human clinical trials. PMID- 28877181 TI - Motion-based video monitoring for early detection of livestock diseases: The case of African swine fever. AB - Early detection of infectious diseases can substantially reduce the health and economic impacts on livestock production. Here we describe a system for monitoring animal activity based on video and data processing techniques, in order to detect slowdown and weakening due to infection with African swine fever (ASF), one of the most significant threats to the pig industry. The system classifies and quantifies motion-based animal behaviour and daily activity in video sequences, allowing automated and non-intrusive surveillance in real-time. The aim of this system is to evaluate significant changes in animals' motion after being experimentally infected with ASF virus. Indeed, pig mobility declined progressively and fell significantly below pre-infection levels starting at four days after infection at a confidence level of 95%. Furthermore, daily motion decreased in infected animals by approximately 10% before the detection of the disease by clinical signs. These results show the promise of video processing techniques for real-time early detection of livestock infectious diseases. PMID- 28877182 TI - Cryptococcal antigen screening by lay cadres using a rapid test at the point of care: A feasibility study in rural Lesotho. AB - INTRODUCTION: Cryptococcal meningitis is one of the leading causes of death among people with HIV in Africa, primarily due to delayed presentation, poor availability and high cost of treatment. Routine cryptococcal antigen (CrAg) screening of patients with a CD4 count less than 100 cells/mm3, followed by pre emptive therapy if positive, might reduce mortality in high prevalence settings. Using the cryptococcal antigen (CrAg) lateral flow assay (LFA), screening is possible at the point of care (POC). However, critical shortages of health staff may limit adoption. This study investigates the feasibility of lay counsellors conducting CrAg LFA screening in rural primary care clinics in Lesotho. METHODS: From May 2014 to June 2015, individuals who tested positive for HIV were tested for CD4 count and those with CD4 <100 cells/mm3 were screened with CrAg LFA. All tests were performed by lay counsellors. CrAg-positive asymptomatic patients received fluconazole, while symptomatic patients were referred to hospital. Lay counsellors were trained and supervised by a laboratory technician and counsellor activity supervisor. Additionally, nurses and doctors were trained on CrAg screening and appropriate treatment. RESULTS: During the study period, 1,388 people were newly diagnosed with HIV, of whom 129 (9%) presented with a CD4 count <100 cells/mm3. Of these, 128 (99%) were screened with CrAg LFA and 14/128 (11%) tested positive. Twelve of the 14 (86%) were asymptomatic, and received outpatient fluconazole. All commenced ART with a median time to initiation of 15.5 days [IQR: 14-22]. Of the asymptomatic patients, nine (75%) remained asymptomatic after a median time of 5 months [IQR; 3-6] of follow up. One (8%) became co-infected with tuberculosis and died and two were transferred out. The two patients with symptomatic cryptococcal meningitis (CM) were referred to hospital, where they later died. CONCLUSIONS: CrAg LFA screening by lay counsellors followed by pre-emptive fluconazole treatment for asymptomatic cases, or referral to hospital for symptomatic cases, proved feasible. However, regular follow-up to ensure proper management of cryptococcal disease was needed. These early results support the wider use of CrAg LFA screening in remote primary care settings where upper cadres of healthcare staff may be in short supply. PMID- 28877183 TI - Quantitative proteomics analysis reveals the tolerance of wheat to salt stress in response to Enterobacter cloacae SBP-8. AB - Salinity stress adversely affects the plant growth and is a major constraint to agriculture. In the present study, we studied the role of plant growth promoting rhizobacterium (PGPR) Enterobacter cloacae SBP-8 possessing ACC deaminase activity on proteome profile of wheat (Triticum aestivum L.) under high salinity (200 mM NaCl) stress. The aim of study was to investigate the differential expressed protein in selected three (T-1, T-2, T-3) treatments and absolute quantification (MS/MS analysis) was used to detect statistically significant expressed proteins. In this study, we investigated the adaptation mechanisms of wheat seedlings exposed to high concentration of NaCl treatment (200 mM) for 15 days in response to bacterial inoculation based on proteomic data. The identified proteins were distributed in different cellular, biological and molecular functions. Under salt stress, proteins related to ion-transport, metabolic pathway, protein synthesis and defense responsive were increased to a certain extent. A broader comparison of the proteome of wheat plant under different treatments revealed that changes in some of the metabolic pathway may be involved in stress adaption in response to PGPR inoculation. Hierarchical cluster analysis identified the various up-regulated/down-regulated proteins into tested three treatments. Our results suggest that bacterial inoculation enhanced the ability of wheat plant to combat salt stress via regulation of transcription factors, promoting antioxidative activity, induction of defense enzymes, lignin biosynthesis, and acceleration of protein synthesis. PMID- 28877184 TI - Microgravity validation of a novel system for RNA isolation and multiplex quantitative real time PCR analysis of gene expression on the International Space Station. AB - The International Space Station (ISS) National Laboratory is dedicated to studying the effects of space on life and physical systems, and to developing new science and technologies for space exploration. A key aspect of achieving these goals is to operate the ISS National Lab more like an Earth-based laboratory, conducting complex end-to-end experimentation, not limited to simple microgravity exposure. Towards that end NASA developed a novel suite of molecular biology laboratory tools, reagents, and methods, named WetLab-2, uniquely designed to operate in microgravity, and to process biological samples for real-time gene expression analysis on-orbit. This includes a novel fluidic RNA Sample Preparation Module and fluid transfer devices, all-in-one lyophilized PCR assays, centrifuge, and a real-time PCR thermal cycler. Here we describe the results from the WetLab-2 validation experiments conducted in microgravity during ISS increment 47/SPX-8. Specifically, quantitative PCR was performed on a concentration series of DNA calibration standards, and Reverse Transcriptase quantitative PCR was conducted on RNA extracted and purified on-orbit from frozen Escherichia coli and mouse liver tissue. Cycle threshold (Ct) values and PCR efficiencies obtained on-orbit from DNA standards were similar to Earth (1 g) controls. Also, on-orbit multiplex analysis of gene expression from bacterial cells and mammalian tissue RNA samples was successfully conducted in about 3 h, with data transmitted within 2 h of experiment completion. Thermal cycling in microgravity resulted in the trapping of gas bubbles inside septa cap assay tubes, causing small but measurable increases in Ct curve noise and variability. Bubble formation was successfully suppressed in a rapid follow-up on-orbit experiment using standard caps to pressurize PCR tubes and reduce gas release during heating cycles. The WetLab-2 facility now provides a novel operational on orbit research capability for molecular biology and demonstrates the feasibility of more complex wet bench experiments in the ISS National Lab environment. PMID- 28877185 TI - Feet deformities are correlated with impaired balance and postural stability in seniors over 75. AB - OBJECTIVE: Understanding the factors and mechanisms that determine balance in seniors appears vital in terms of their self-reliance and overall safety. The study aimed to determine the relationship between the features of feet structure and the indicators of postural stability in the elderly. METHODS: The study group comprised 80 seniors (41F, 39M; aged 75-85 years). CQ-ST podoscope and the CQ Stab 2P two-platform posturograph were used as primary research tools. The data were analyzed based on Spearman's rank correlation and forward stepwise regression. RESULTS: Analysis of forward stepwise regression identified the left foot length in females and Clarke's angle of the left foot in men as significant and independent predictors of postural up to 30% of the variance of dependent variables. CONCLUSIONS: Longer feet provide older women with better stability, whereas in men, the lowering of the longitudinal arch results in postural deterioration. In the elderly, the left lower limb shows greater activity in the stabilizing processes in the standing position than the right one. In gerontological rehabilitation special attention should be paid to the individually tailored, gender-specific treatment, with a view to enhancing overall safety and quality of seniors' lives. PMID- 28877186 TI - Proof of concept of a 45-second cardiorespiratory fitness self-test for coronary artery disease patients based on accelerometry. AB - Cardiorespiratory fitness (CRF) provides important diagnostic and prognostic information. It is measured directly via laboratory maximal testing or indirectly via submaximal protocols making use of predictor parameters such as submaximal [Formula: see text], heart rate, workload, and perceived exertion. We have established an innovative methodology, which can provide CRF prediction based only on body motion during a periodic movement. Thirty healthy subjects (40% females, 31.3 +/- 7.8 yrs, 25.1 +/- 3.2 BMI) and eighteen male coronary artery disease (CAD) (56.6 +/- 7.4 yrs, 28.7 +/- 4.0 BMI) patients performed a [Formula: see text] test on a cycle ergometer as well as a 45 second squatting protocol at a fixed tempo (80 bpm). A tri-axial accelerometer was used to monitor movements during the squat exercise test. Three regression models were developed to predict CRF based on subject characteristics and a new accelerometer-derived feature describing motion decay. For each model, the Pearson correlation coefficient and the root mean squared error percentage were calculated using the leave-one subject-out cross-validation method (rcv, RMSEcv). The model built with all healthy individuals' data showed an rcv = 0.68 and an RMSEcv = 16.7%. The CRF prediction improved when only healthy individuals with normal to lower fitness (CRF<40 ml/min/kg) were included, showing an rcv = 0.91 and RMSEcv = 8.7%. Finally, our accelerometry-based CRF prediction CAD patients, the majority of whom taking beta-blockers, still showed high accuracy (rcv = 0.91; RMSEcv = 9.6%). In conclusion, motion decay and subject characteristics could be used to predict CRF in healthy people as well as in CAD patients taking beta-blockers, accurately. This method could represent a valid alternative for patients taking beta-blockers, but needs to be further validated in a larger population. PMID- 28877187 TI - Study on launch scheme of space-net capturing system. AB - With the continuous progress in active debris-removal technology, scientists are increasingly concerned about the concept of space-net capturing system. The space net capturing system is a long-range-launch flexible capture system, which has great potential to capture non-cooperative targets such as inactive satellites and upper stages. In this work, the launch scheme is studied by experiment and simulation, including two-step ejection and multi-point-traction analyses. The numerical model of the tether/net is based on finite element method and is verified by full-scale ground experiment. The results of the ground experiment and numerical simulation show that the two-step ejection and six-point traction scheme of the space-net system is superior to the traditional one-step ejection and four-point traction launch scheme. PMID- 28877188 TI - Mitochondrial superclusters influence age of onset of Parkinson's disease in a gender specific manner in the Cypriot population: A case-control study. AB - BACKGROUND: Despite evidence supporting an involvement of mitochondrial dysfunction in the pathogenesis of some neurodegenerative disorders, there are inconsistent findings concerning mitochondrial haplogroups and their association to neurodegenerative disorders, including idiopathic Parkinson's disease (PD). METHODS: To test this hypothesis for the Greek-Cypriot population, a cohort of 230 PD patients and 457 healthy matched controls were recruited. Mitochondrial haplogroup distributions for cases and controls were determined. Association tests were carried out between mitochondrial haplogroups and PD. RESULTS: Mitochondrial haplogroup U was associated with a reduced PD risk in the Cypriot population. After pooling mitochondrial haplogroups together into haplogroup clusters and superclusters, association tests demonstrated a significantly protective effect of mitochondrial haplogroup cluster N (xR) and supercluster LMN for PD risk only in females. In addition, for female PD cases belonging to UKJT and R (xH, xUKJT) haplogroup, the odds of having a later age of onset of PD were 13 and 15 times respectively higher than the odds for female cases with an H haplogroup. CONCLUSION: Statistically significant associations regarding PD risk and PD age of onset were mostly detected for females thus suggesting that gender is a risk modifier between mitochondrial haplogroups and PD status / PD age of onset. The biological mechanisms behind this gender specificity remain to be determined. PMID- 28877189 TI - Programmed cell death-1, PD-1, is dysregulated in T cells from children with new onset type 1 diabetes. AB - BACKGROUND: Programmed death cell 1 (PD-1) is an inhibitor of T cell activation and is also functionally linked to glycolysis. We hypothesized that PD-1 expression is defective in activated T cells from children with type 1 diabetes (T1D), resulting in abnormal T cell glucose metabolism. METHODS: In this pilot study, we enrolled children with new onset T1D within 2 weeks of diagnosis (T1D), unaffected siblings of T1D (SIBS), unaffected, unrelated children (CTRL), children with new onset, and untreated Crohn disease (CD). We repeated the assays 4-6 months post-diagnosis in T1D (T1D follow up). We analyzed anti-CD3/-CD28 stimulated peripheral blood mononuclear cells (PBMC) subsets for PD-1 expression by flow cytometry at baseline and after 24 h in culture. We measured cytokines in the culture medium by multiplex ELISA and glycolytic capacity with a flux analyzer. RESULTS: We enrolled 37 children. T cells derived from subjects with T1D had decreased PD-1 expression compared to the other study groups. However, in T1D follow-up T cells expressed PD-1 similarly to controls, but had no differences in PBMC cytokine production. Nonetheless, T1D follow up PBMCs had enhanced glycolytic capacity compared to T1D. CONCLUSIONS: Activated T cells from T1D fail to upregulate PD-1 upon T-cell receptor stimulation, which may contribute to the pathogenesis of T1D. T1D follow up PBMC expression of PD-1 normalizes, together with a significant increase in glycolysis compared to T1D. Thus, insulin therapy in T1D children is associated with normal PD1 expression and heightened glycolytic capacity in PBMC. PMID- 28877190 TI - Regional differences in treatment rates for patients with chronic hepatitis C infection: Systematic review and meta-analysis. AB - BACKGROUND & AIMS: Treatment rates with interferon-based therapies for chronic hepatitis C have been low. Our aim was to perform a systematic review of available data to estimate the rates and barriers for antiviral therapy for chronic hepatitis C. METHODS: We conducted a systematic review and meta-analysis searching MEDLINE, SCOPUS through March 2016 and abstracts from recent major liver meetings for primary literature with available hepatitis C treatment rates. Random-effects models were used to estimate effect sizes and meta-regression to test for potential sources of heterogeneity. RESULTS: We included 39 studies with 476,443 chronic hepatitis C patients. The overall treatment rate was 25.5% (CI: 21.1-30.5%) and by region 34% for Europe, 28.3% for Asia/Pacific, and 18.7% for North America (p = 0.008). On multivariable meta-regression, practice setting (tertiary vs. population-based, p = 0.04), region (Europe vs. North America p = 0.004), and data source (clinical chart review vs. administrative database, p = 0.025) remained significant predictors of heterogeneity. The overall treatment eligibility rate was 52.5%, and 60% of these received therapy. Of the patients who refused treatment, 16.2% cited side effects, 13.8% cited cost as reasons for treatment refusal, and 30% lacked access to specialist care. CONCLUSIONS: Only one-quarter of chronic hepatitis C patients received antiviral therapy in the pre direct acting antiviral era. Treatment rates should improve in the new interferon free era but, cost, co-morbidities, and lack of specialist care will likely remain and need to be addressed. Linkage to care should even be of higher priority now that well-tolerated cure is available. PMID- 28877191 TI - Indirect adaptive soft computing based wavelet-embedded control paradigms for WT/PV/SOFC in a grid/charging station connected hybrid power system. AB - This paper focuses on the indirect adaptive tracking control of renewable energy sources in a grid-connected hybrid power system. The renewable energy systems have low efficiency and intermittent nature due to unpredictable meteorological conditions. The domestic load and the conventional charging stations behave in an uncertain manner. To operate the renewable energy sources efficiently for harvesting maximum power, instantaneous nonlinear dynamics should be captured online. A Chebyshev-wavelet embedded NeuroFuzzy indirect adaptive MPPT (maximum power point tracking) control paradigm is proposed for variable speed wind turbine-permanent synchronous generator (VSWT-PMSG). A Hermite-wavelet incorporated NeuroFuzzy indirect adaptive MPPT control strategy for photovoltaic (PV) system to extract maximum power and indirect adaptive tracking control scheme for Solid Oxide Fuel Cell (SOFC) is developed. A comprehensive simulation test-bed for a grid-connected hybrid power system is developed in Matlab/Simulink. The robustness of the suggested indirect adaptive control paradigms are evaluated through simulation results in a grid-connected hybrid power system test-bed by comparison with conventional and intelligent control techniques. The simulation results validate the effectiveness of the proposed control paradigms. PMID- 28877193 TI - Body size and substrate type modulate movement by the western Pacific crown-of thorns starfish, Acanthaster solaris. AB - The movement capacity of the crown-of-thorns starfishes (Acanthaster spp.) is a primary determinant of both their distribution and impact on coral assemblages. We quantified individual movement rates for the Pacific crown-of-thorns starfish (Acanthaster solaris) ranging in size from 75-480 mm total diameter, across three different substrates (sand, flat consolidated pavement, and coral rubble) on the northern Great Barrier Reef. The mean (+/-SE) rate of movement for smaller (<150 mm total diameter) A. solaris was 23.99 +/- 1.02 cm/ min and 33.41 +/- 1.49 cm/ min for individuals >350 mm total diameter. Mean (+/-SE) rates of movement varied with substrate type, being much higher on sand (36.53 +/- 1.31 cm/ min) compared to consolidated pavement (28.04 +/- 1.15 cm/ min) and slowest across coral rubble (17.25 +/- 0.63 cm/ min). If average rates of movement measured here can be sustained, in combination with strong directionality, displacement distances of adult A. solaris could range from 250-520 m/ day, depending on the prevailing substrate. Sustained movement of A. solaris is, however, likely to be highly constrained by habitat heterogeneity, energetic constraints, resource availability, and diurnal patterns of activity, thereby limiting their capacity to move between reefs or habitats. PMID- 28877192 TI - The relations between sleep, time of physical activity, and time outdoors among adult women. AB - Physical activity and time spent outdoors may be important non-pharmacological approaches to improve sleep quality and duration (or sleep patterns) but there is little empirical research evaluating the two simultaneously. The current study assesses the role of physical activity and time outdoors in predicting sleep health by using objective measurement of the three variables. A convenience sample of 360 adult women (mean age = 55.38 +/-9.89 years; mean body mass index = 27.74 +/-6.12) was recruited from different regions of the U.S. Participants wore a Global Positioning System device and ActiGraph GT3X+ accelerometers on the hip for 7 days and on the wrist for 7 days and 7 nights to assess total time and time of day spent outdoors, total minutes in moderate-to-vigorous physical activity per day, and 4 measures of sleep health, respectively. A generalized mixed effects model was used to assess temporal associations between moderate-to vigorous physical activity, outdoor time, and sleep at the daily level (days = 1931) within individuals. There was a significant interaction (p = 0.04) between moderate-to-vigorous physical activity and time spent outdoors in predicting total sleep time but not for predicting sleep efficiency. Increasing time outdoors in the afternoon (versus morning) predicted lower sleep efficiency, but had no effect on total sleep time. Time spent outdoors and the time of day spent outdoors may be important moderators in assessing the relation between physical activity and sleep. More research is needed in larger populations using experimental designs. PMID- 28877194 TI - Cluster-based analysis improves predictive validity of spike-triggered receptive field estimates. AB - Spectrotemporal receptive field (STRF) characterization is a central goal of auditory physiology. STRFs are often approximated by the spike-triggered average (STA), which reflects the average stimulus preceding a spike. In many cases, the raw STA is subjected to a threshold defined by gain values expected by chance. However, such correction methods have not been universally adopted, and the consequences of specific gain-thresholding approaches have not been investigated systematically. Here, we evaluate two classes of statistical correction techniques, using the resulting STRF estimates to predict responses to a novel validation stimulus. The first, more traditional technique eliminated STRF pixels (time-frequency bins) with gain values expected by chance. This correction method yielded significant increases in prediction accuracy, including when the threshold setting was optimized for each unit. The second technique was a two step thresholding procedure wherein clusters of contiguous pixels surviving an initial gain threshold were then subjected to a cluster mass threshold based on summed pixel values. This approach significantly improved upon even the best gain thresholding techniques. Additional analyses suggested that allowing threshold settings to vary independently for excitatory and inhibitory subfields of the STRF resulted in only marginal additional gains, at best. In summary, augmenting reverse correlation techniques with principled statistical correction choices increased prediction accuracy by over 80% for multi-unit STRFs and by over 40% for single-unit STRFs, furthering the interpretational relevance of the recovered spectrotemporal filters for auditory systems analysis. PMID- 28877195 TI - Spatial and age-related changes in the microstructure of dystrophic and healthy diaphragms. AB - Duchenne muscular dystrophy (DMD) is a progressive degenerative disease that results in fibrosis and atrophy of muscles. The main cause of death associated with DMD is failure of the diaphragm. The diaphragm is a dome-shaped muscle with a fiber microstructure that differs across regions of the muscle. However, no studies to our knowledge have examined spatial variations of muscle fibers in dystrophic diaphragm or how aging affects those variations in DMD. In this study, diaphragms were obtained from mdx and healthy mice at ages three, seven, and ten months in the dorsal, midcostal, and ventral regions. Through immunostaining and confocal imaging, we quantified sarcomere length, interstitial space between fibers, fiber branching, fiber cross sectional area (CSA), and fiber regeneration measured by centrally located nuclei. Because DMD is associated with chronic inflammation, we also investigated the number of macrophages in diaphragm muscle cross-sections. We saw regional differences in the number of regenerating fibers and macrophages during the progression of DMD in the mdx diaphragm. Additionally, the number of regenerating fibers increased with age, while CSA and the number of branching fibers decreased. Dystrophic diaphragms had shorter sarcomere lengths than age-matched controls. Our results suggest that the dystrophic diaphragm in the mdx mouse is structurally heterogeneous and remodels non-uniformly over time. Understanding regional changes in dystrophic diaphragms over time will facilitate the development of targeted therapies to prevent or minimize respiratory failure in DMD patients. PMID- 28877196 TI - Predicting active-layer soil thickness using topographic variables at a small watershed scale. AB - Knowledge about the spatial distribution of active-layer (AL) soil thickness is indispensable for ecological modeling, precision agriculture, and land resource management. However, it is difficult to obtain the details on AL soil thickness by using conventional soil survey method. In this research, the objective is to investigate the possibility and accuracy of mapping the spatial distribution of AL soil thickness through random forest (RF) model by using terrain variables at a small watershed scale. A total of 1113 soil samples collected from the slope fields were randomly divided into calibration (770 soil samples) and validation (343 soil samples) sets. Seven terrain variables including elevation, aspect, relative slope position, valley depth, flow path length, slope height, and topographic wetness index were derived from a digital elevation map (30 m). The RF model was compared with multiple linear regression (MLR), geographically weighted regression (GWR) and support vector machines (SVM) approaches based on the validation set. Model performance was evaluated by precision criteria of mean error (ME), mean absolute error (MAE), root mean square error (RMSE), and coefficient of determination (R2). Comparative results showed that RF outperformed MLR, GWR and SVM models. The RF gave better values of ME (0.39 cm), MAE (7.09 cm), and RMSE (10.85 cm) and higher R2 (62%). The sensitivity analysis demonstrated that the DEM had less uncertainty than the AL soil thickness. The outcome of the RF model indicated that elevation, flow path length and valley depth were the most important factors affecting the AL soil thickness variability across the watershed. These results demonstrated the RF model is a promising method for predicting spatial distribution of AL soil thickness using terrain parameters. PMID- 28877197 TI - Mimicry and automatic imitation are not correlated. AB - It is widely known that individuals have a tendency to imitate each other. However, different psychological disciplines assess imitation in different manners. While social psychologists assess mimicry by means of action observation, cognitive psychologists assess automatic imitation with reaction time based measures on a trial-by-trial basis. Although these methods differ in crucial methodological aspects, both phenomena are assumed to rely on similar underlying mechanisms. This raises the fundamental question whether mimicry and automatic imitation are actually correlated. In the present research we assessed both phenomena and did not find a meaningful correlation. Moreover, personality traits such as empathy, autism traits, and traits related to self- versus other focus did not correlate with mimicry or automatic imitation either. Theoretical implications are discussed. PMID- 28877198 TI - Correlation between classification and secondary screw penetration in proximal humeral fractures. AB - OBJECTIVES: In this study, we investigated the correlation between fracture classification and secondary screw penetration. METHODS: We retrospectively identified 189 patients with displaced proximal humeral fractures treated by ORIF at our hospital between June 2006 and June 2013. All fractures were classified radiographically before surgery and follow-up for least 2 years after surgery was recommended. At each follow-up, radiographs were taken in three orthogonal views to evaluate secondary screw penetration. RESULTS: The study population consisted of 189 patients. Of these, 70 were male and 119 female, with a mean age of 59.1 years; the mean follow-up time was 28.5 months. Secondary screw penetration occurred in 26 patients. The risk of developing secondary screw penetration was 11.3-fold higher in four-part fractures than two-part fractures (P < 0.05), 8.6 fold higher for type C fractures than type A fractures (P < 0.05) and 11.0-fold higher for medial hinge disruption group than intact medial hinge group fractures (P < 0.05). However there was no difference between three-part fractures and two part fractures (P = 0.374), and between type B and type A fractures (P = 0.195). Age, gender, time to surgery and the number of screw in humeral head had no influence on the secondary screw penetration rate (P > 0.05). CONCLUSIONS: Patients with four-part fractures, type C fractures and medial hinges disruption are vulnerable to secondary screw penetration. This allows additional precautions to be instituted and measures to be taken as needed. PMID- 28877199 TI - DipTest: A litmus test for E. coli detection in water. AB - We have developed a new litmus paper test (DipTest) for detecting Escherichia coli (E. coli) in water samples by performing enzymatic reactions directly on the porous paper substrate. The paper strip consists of a long narrow piece of cellulose blotting paper coated with chemoattractant (at bottom edge), wax hydrophobic barrier (at the top edge), and custom formulated chemical reagents (at reaction zone immediately below the wax hydrophobic barrier). When the paper strip is dipped in water, E. coli in the water sample is attracted toward the paper strip due to a chemotaxic mechanism followed by the ascent along the paper strip toward the reaction zone due to a capillary wicking mechanism, and finally the capillary motion is arrested at the top edge of the paper strip by the hydrophobic barrier. The E. coli concentrated at the reaction zone of the paper strip will react with custom formulated chemical reagents to produce a pinkish red color. Such a color change on the paper strip when dipped into water samples indicates the presence of E. coli contamination in potable water. The performance of the DipTest device has been checked with different known concentrations of E. coli contaminated water samples using different dip and wait times. The DipTest device has also been tested with different interfering bacteria and chemical contaminants. It has been observed that the different interfering contaminants do not have any impact on the DipTest, and it can become a potential solution for screening water samples for E. coli contamination at the point of source. PMID- 28877200 TI - Risk factors of mobile phone use while driving in Queensland: Prevalence, attitudes, crash risk perception, and task-management strategies. AB - Distracted driving is one of the most significant human factor issues in transport safety. Mobile phone interactions while driving may involve a multitude of cognitive and physical resources that result in inferior driving performance and reduced safety margins. The current study investigates characteristics of usage, risk factors, compensatory strategies in use and characteristics of high frequency offenders of mobile phone use while driving. A series of questions were administered to drivers in Queensland (Australia) using an on-line questionnaire. A total of 484 drivers (34.9% males and 49.8% aged 17-25) participated anonymously. At least one of every two motorists surveyed reported engaging in distracted driving. Drivers were unable to acknowledge the increased crash risk associated with answering and locating a ringing phone in contrast to other tasks such as texting/browsing. Attitudes towards mobile phone usage were more favourable for talking than texting or browsing. Lowering the driving speed and increasing the distance from the vehicle in front were the most popular task management strategies for talking and texting/browsing while driving. On the other hand, keeping the mobile phone low (e.g. in the driver's lap or on the passenger seat) was the favourite strategy used by drivers to avoid police fines for both talking and texting/browsing. Logistic regression models were fitted to understand differences in risk factors for engaging in mobile phone conversations and browsing/texting while driving. For both tasks, exposure to driving, driving experience, driving history (offences and crashes), and attitudes were significant predictors. Future mobile phone prevention efforts would benefit from development of safe attitudes and increasing risk literacy. Enforcement of mobile phone distraction should be re-engineered, as the use of task-management strategies to evade police enforcement seems to dilute its effect on the prevention of this behaviour. Some countermeasures and suggestions were proposed in the design of public education campaigns and driver-mobile phone interaction. PMID- 28877201 TI - Acoustic differentiation and behavioral response reveals cryptic species within Buergeria treefrogs (Anura, Rhacophoridae) from Taiwan. AB - Buergeria japonica is a widely distributed treefrog occurring from Ryukyu Archipelago to Taiwan. Across this wide distributional range, we combined molecular, acoustic, morphological, and behavioral characters to clarify the taxonomic status among these insular populations. Genetic differentiation in mitochondrial sequences indicated an over 16% divergence among two deeply divergent clades: Japanese clade distributes in Ryukyu Archipelago and northwestern drainages of Taiwan, while Taiwanese clade distributes in the remaining drainages on Taiwan. The Taiwanese clade can be distinguished from the nominative species not only by molecular and morphological differences, but also distinguishable by considerable acoustic differentiation, which is extraordinarily noticeable for an additional type of long call that never recorded from Japanese clade. The two clades form a parapatric distribution pattern with narrow contact zones both in western and eastern Taiwan. Playback experiments indicated that male frogs show significantly stronger defensiveness against conspecific calls rather than heterospecific calls, indicating that these signals play a crucial role in species recognition. Here we describe the Taiwanese clade as a new species; the behavioral response and the magnitude of gene flow across their contact zones are especially worth for detailed studies. PMID- 28877202 TI - Shorter dialysis session length was not associated with lower mental health and physical functioning in elderly hemodialysis patients: Results from the Japan Dialysis Outcome and Practice Patterns Study (J-DOPPS). AB - BACKGROUND: Health-related quality of life (HRQOL) is often prioritized over long term survival in elderly patients. Although a longer dialysis session length (DSL) has been shown to reduce mortality, its effects on improving the HRQOL are unknown. METHODS: Using data from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS), patients aged >= 65 years on maintenance hemodialysis were enrolled. DSL was categorized as short (<210 minutes), medium (210-240 minutes), or long (>240 minutes). The primary outcomes were changes in mental health (DeltaMH) and physical functioning (DeltaPF) scores assessed using the Japanese version of SF-12, in one year. The differences in the DeltaMH and DeltaPF among the three groups were assessed via regression (beta) coefficients derived using a linear regression model. RESULTS: Of 1,187 patients at baseline, 319 (26.9%) had a short length, 686 (57.8%) a medium length, and 182 (15.3%) a long length. We assessed the DeltaMH data from 793 patients and the DeltaPF data from 738. No significant differences in the DeltaMH were noted for the short or long groups compared with the medium group (score difference: 0.26, 95% confidence interval [CI]: -4.17 to 4.69 for short; score difference: -1.15, 95% CI: -6.17 to 3.86 for long). Similarly, no significant differences were noted for these groups versus the medium group in DeltaPF either (score difference: -1.43, 95% CI: -6.73 to 3.87 for short; score difference: -1.71, 95% CI: -7.63 to 4.22 for long). CONCLUSIONS: A shorter DSL might have no adverse effects on MH or PF for elderly patients. PMID- 28877203 TI - Education of children with disabilities in New Delhi: When does exclusion occur? AB - BACKGROUND: In the new Sustainable Development Goal 4, quality of education defined as equity and inclusion alongside traditional learning outcomes, has replaced the narrow goal of access to primary education stipulated in the Millennium Development Goal 2. Since 2000, considerable progress has been made towards improving access to school for children in India, yet questions remain regarding not just children with disabilities' access and acquisition of basic learning skills, but also completion of learning cycles. METHODS AND FINDINGS: Between November, 2, 2011 and June 20th 2012, we interviewed 1294 households about activity limitations and functioning difficulties associated with a health problem among all family members using a validated screening instruments, as well as questions about access, retention and barriers to education. We found that vulnerable children, particularly children with disabilities are less likely to start school and more likely to drop out of school earlier and before completing their high school education than non-disabled children, showing that the learning process is not inclusive in practice. The gap is wider for girls, economically deprived children, or children from households where the head is uneducated. CONCLUSIONS: Firstly, in order to fill the existing knowledge gap on education of children with disabilities in line with SDG4, not only is there a necessity for relevant data with regards to learning outcomes, but also an urgent requirement for more innovative information pertaining to relational aspects of learning that reflect inclusion. Secondly, a stronger understanding of the implications of early assessment would further promote equity in education. Finally, research should tackle learning as a complex and dynamic phenomenon. Education needs to fulfil its instrumental value, but must also re-claim its intrinsic value that often gets watered down in the journey from policies to implementation. PMID- 28877204 TI - Examining lag effects between industrial land development and regional economic changes: The Netherlands experience. AB - In most empirical applications, forecasting models for the analysis of industrial land focus on the relationship between current values of economic parameters and industrial land use. This paper aims to test this assumption by focusing on the dynamic relationship between current and lagged values of the 'economic fundamentals' and industrial land development. Not much effort has yet been attributed to develop land forecasting models to predict the demand for industrial land except those applying static regressions or other statistical measures. In this research, we estimated a dynamic panel data model across 40 regions from 2000 to 2008 for the Netherlands to uncover the relationship between current and lagged values of economic parameters and industrial land development. Land-use regulations such as land zoning policies, and other land-use restrictions like natural protection areas, geographical limitations in the form of water bodies or sludge areas are expected to affect supply of land, which will in turn be reflected in industrial land market outcomes. Our results suggest that gross domestic product (GDP), industrial employment, gross value added (GVA), property price, and other parameters representing demand and supply conditions in the industrial market explain industrial land developments with high significance levels. It is also shown that contrary to the current values, lagged values of the economic parameters have more sound relationships with the industrial developments in the Netherlands. The findings suggest use of lags between selected economic parameters and industrial land use in land forecasting applications. PMID- 28877205 TI - Identification of Shiga-Toxigenic Escherichia coli outbreak isolates by a novel data analysis tool after matrix-assisted laser desorption/ionization time-of flight mass spectrometry. AB - The fast and reliable characterization of bacterial and fungal pathogens plays an important role in infectious disease control and tracking of outbreak agents. DNA based methods are the gold standard for epidemiological investigations, but they are still comparatively expensive and time-consuming. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a fast, reliable and cost-effective technique now routinely used to identify clinically relevant human pathogens. It has been used for subspecies differentiation and typing, but its use for epidemiological tasks, e. g. for outbreak investigations, is often hampered by the complexity of data analysis. We have analysed publicly available MALDI-TOF mass spectra from a large outbreak of Shiga-Toxigenic Escherichia coli in northern Germany using a general purpose software tool for the analysis of complex biological data. The software was challenged with depauperate spectra and reduced learning group sizes to mimic poor spectrum quality and scarcity of reference spectra at the onset of an outbreak. With high quality formic acid extraction spectra, the software's built in classifier accurately identified outbreak related strains using as few as 10 reference spectra (99.8% sensitivity, 98.0% specificity). Selective variation of processing parameters showed impaired marker peak detection and reduced classification accuracy in samples with high background noise or artificially reduced peak counts. However, the software consistently identified mass signals suitable for a highly reliable marker peak based classification approach (100% sensitivity, 99.5% specificity) even from low quality direct deposition spectra. The study demonstrates that general purpose data analysis tools can effectively be used for the analysis of bacterial mass spectra. PMID- 28877206 TI - Simulation framework for generating intratumor heterogeneity patterns in a cancer cell population. AB - As cancer cell populations evolve, they accumulate a number of somatic mutations, resulting in heterogeneous subclones in the final tumor. Understanding the mechanisms that produce intratumor heterogeneity is important for selecting the best treatment. Although some studies have involved intratumor heterogeneity simulations, their model settings differed substantially. Thus, only limited conditions were explored in each. Herein, we developed a general framework for simulating intratumor heterogeneity patterns and a simulator (tumopp). Tumopp offers many setting options so that simulations can be carried out under various settings. Setting options include how the cell division rate is determined, how daughter cells are placed, and how driver mutations are treated. Furthermore, to account for the cell cycle, we introduced a gamma function for the waiting time involved in cell division. Tumopp also allows simulations in a hexagonal lattice, in addition to a regular lattice that has been used in previous simulation studies. A hexagonal lattice produces a more biologically reasonable space than a regular lattice. Using tumopp, we investigated how model settings affect the growth curve and intratumor heterogeneity pattern. It was found that, even under neutrality (with no driver mutations), tumopp produced dramatically variable patterns of intratumor heterogeneity and tumor morphology, from tumors in which cells with different genetic background are well intermixed to irregular shapes of tumors with a cluster of closely related cells. This result suggests a caveat in analyzing intratumor heterogeneity with simulations with limited settings, and tumopp will be useful to explore intratumor heterogeneity patterns in various conditions. PMID- 28877207 TI - Arbuscular mycorrhizal symbiosis mitigates the negative effects of salinity on durum wheat. AB - Arbuscular mycorrhizal (AM) symbiosis is generally considered to be effective in ameliorating the plant tolerance to salt stress. Unfortunately, the comprehension of the mechanisms implicated in salinity stress alleviation by AM symbiosis is far from being complete. Thus, an experiment was performed by growing durum wheat (Triticum durum Desf.) plants under salt-stress conditions to evaluate the influence of AM symbiosis on both the plant growth and the regulation of a number of genes related to salt stress and nutrient uptake. Durum wheat plants were grown outdoors in pots in absence or in presence of salt stress and with or without AM fungi inoculation. The inoculum consisted of a mixture of spores of Rhizophagus irregularis (formerly Glomus intraradices) and Funneliformis mosseae (formerly G. mosseae). Results indicate that AM symbiosis can alleviate the detrimental effects of salt stress on the growth of durum wheat plants. In fact, under salt stress conditions mycorrhizal plants produced more aboveground and root biomass, had higher N uptake and aboveground N concentration, and showed greater stability of plasma membranes compared to non-mycorrhizal plants. Inoculation with AM fungi had no effect on the expression of the N transporter genes AMT1.1, AMT1.2, and NAR2.2, either under no-stress or salt stress conditions, probably due to the fact that plants were grown under optimal N conditions; on the contrary, NRT1.1 was always upregulated by AM symbiosis. Moreover, the level of expression of the drought stress-related genes AQP1, AQP4, PIP1, DREB5, and DHN15.3 observed in the mycorrhizal stressed plants was markedly lower than that observed in the non-mycorrhizal stressed plants and very close to that observed in the non-stressed plants. Our hypothesis is that, in the present study, AM symbiosis did not increase the plant tolerance to salt stress but instead generated a condition in which plants were subjected to a level of salt stress lower than that of non-mycorrhizal plants. PMID- 28877208 TI - Surveillance for falsified and substandard medicines in Africa and Asia by local organizations using the low-cost GPHF Minilab. AB - BACKGROUND: Substandard and falsified medical products present a serious threat to public health, especially in low- and middle-income countries. Their identification using pharmacopeial analysis is expensive and requires sophisticated equipment and highly trained personnel. Simple, low-cost technologies are required in addition to full pharmacopeial analysis in order to accomplish widespread routine surveillance for poor-quality medicines in low- and middle-income countries. METHODS: Ten faith-based drug supply organizations in seven countries of Africa and Asia were each equipped with a Minilab of the Global Pharma Health Fund (GPHF, Frankfurt, Germany), suitable for the analysis of about 85 different essential medicines by thin-layer chromatography. Each organization was asked to collect approximately 100 medicine samples from private local medicine outlets, especially from the informal sector. The medicine samples were tested locally according to the Minilab protocols. Medicines which failed Minilab testing were subjected to confirmatory analysis in a WHO-prequalified medicine quality control laboratory in Kenya. RESULTS: Out of 869 medicine samples, 21 were confirmed to be substandard or falsified medical products. Twelve did not contain the stated active pharmaceutical ingredient (API), six contained insufficient amounts of the API, and three showed insufficient dissolution of the API. The highest proportion of substandard and falsified medicines was found in Cameroon (7.1%), followed by the Democratic Republic of Congo (2.7%) and Nigeria (1.1%). Antimalarial medicines were most frequently found to be substandard or falsified (9.5% of all antimalarials). Thin-layer chromatography according to the Minilab protocols was found to be specific and reproducible in the identification of medicines which did not contain the stated API. Since only samples which failed Minilab testing were subjected to confirmatory testing using pharmacopeial methods, this study did not assess the sensitivity of the Minilab methodology in the detection of substandard medicines, and may underestimate the prevalence of poor-quality medicines. CONCLUSIONS: Surveillance for poor-quality medicines can be carried out by local organizations in low- and middle-income countries using a simple, low-cost technology. Such surveillance can identify an important subgroup of the circulating substandard and falsified medical products and can help to prevent them from causing harm in patients. A collaboration of the national drug regulatory authorities with faith based organizations and other NGOs may therefore represent a promising strategy towards the Sustainable Development Goal of "ensuring access to quality medicines". PMID- 28877209 TI - Unmet healthcare needs in homeless women with children in the Greater Paris area in France. AB - BACKGROUND: Despite their poor health status, homeless women encounter many barriers to care. The objectives of our study were to estimate the prevalence of unmet healthcare needs in homeless women and to analyse associated relationships with the following factors: financial and spatial access to care, housing history, migration status, healthcare utilisation, victimization history, caring for children, social network and self-perceived health status. METHODS: We used data from 656 homeless women interviewed during the ENFAMS representative survey of sheltered homeless families, conducted in the Paris region in 2013. Structural equation models (SEM) were used to estimate the impact of various factors on homeless women's unmet healthcare needs. RESULTS: Among those interviewed, 25.1% (95%CI[21.3-29.0]) had at least one unmet healthcare need over the previous year. Most had given up on visiting general practitioners and medical specialists. No association with factors related to financial access or to health insurance status was found. However, food insecurity, poor spatial health access and poor self-perceived health were associated with unmet healthcare needs. Self-perceived health appeared to be affected by victimization and depression. DISCUSSION: The lower prevalence of unmet healthcare needs in homeless women compared with women in stable housing situations suggests that homeless women have lower needs perceptions and/or lower expectations of the healthcare system. This hypothesis is supported by the results from SEM. Strategies to provide better access to care for this population should not only focus on financial interventions but also more broadly on spatial healthcare access, cultural norms, and perceptions of health. Reducing their unmet needs and improving their access to healthcare and prevention must include an improvement in their living, financial and housing conditions. PMID- 28877210 TI - Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. AB - Previous data indicate that Tankyrase inhibitors exert anti-growth functions in many cancer cell lines due to their ability to inactivate the YAP protooncogene. In the present manuscript, we investigated the effect of Tankyrase inhibitors on the growth of hepatocellular carcinoma (HCC) cell lines and the molecular mechanisms involved. For this purpose, we performed cell proliferation assay by colony-forming ability in seven human HCC cells subjected to XAV-939 and G007-LK Tankyrase inhibitors. Noticeably, the two Tankyrase inhibitors suppressed the HCC cell growth in a dose-dependent manner. Furthermore, we found that Tankyrase inhibitors synergized with MEK and AKT inhibitors to suppress HCC cell proliferation. At the molecular level, Tankyrase inhibitors significantly decreased YAP protein levels, reduced the expression of YAP target genes, and inhibited YAP/TEAD luciferase reporter activity. In addition, Tankyrase inhibitors administration was accompanied by upregulation of Angiomotin-like 1 (AMOTL1) and Angiomotin-like 2 (AMOTL2) proteins, two major negative regulators of YAP. Altogether, the present data indicate that XAV-939 and G007-LK Tankyrase inhibitors could suppress proliferation of hepatocellular carcinoma cells and downregulate YAP/TAZ by stabilizing AMOTL1 and AMOTL2 proteins, thus representing new potential anticancer drugs against hepatocellular carcinoma. PMID- 28877211 TI - Transcriptomic profiling in muscle and adipose tissue identifies genes related to growth and lipid deposition. AB - Growth performance and meat quality are important traits for the pig industry and consumers. Adipose tissue is the main site at which fat storage and fatty acid synthesis occur. Therefore, we combined high-throughput transcriptomic sequencing in adipose and muscle tissues with the quantification of corresponding phenotypic features using seven Chinese indigenous pig breeds and one Western commercial breed (Yorkshire). We obtained data on 101 phenotypic traits, from which principal component analysis distinguished two groups: one associated with the Chinese breeds and one with Yorkshire. The numbers of differentially expressed genes between all Chinese breeds and Yorkshire were shown to be 673 and 1056 in adipose and muscle tissues, respectively. Functional enrichment analysis revealed that these genes are associated with biological functions and canonical pathways related to oxidoreductase activity, immune response, and metabolic process. Weighted gene coexpression network analysis found more coexpression modules significantly correlated with the measured phenotypic traits in adipose than in muscle, indicating that adipose regulates meat and carcass quality. Using the combination of differential expression, QTL information, gene significance, and module hub genes, we identified a large number of candidate genes potentially related to economically important traits in pig, which should help us improve meat production and quality. PMID- 28877212 TI - Selenium deficiency-induced alterations in ion profiles in chicken muscle. AB - Ion homeostasis plays important roles in development of metabolic diseases. In the present study, we examined the contents and distributions of 25 ions in chicken muscles following treatment with selenium (Se) deficiency for 25 days. The results revealed that in chicken muscles, the top ranked microelements were silicon (Si), iron (Fe), zinc (Zn), aluminum (Al), copper (Cu) and boron (B), showing low contents that varied from 292.89 ppb to 100.27 ppm. After Se deficiency treatment, essential microelements [Cu, chromium (Cr), vanadium (V) and manganese (Mn)], and toxic microelements [cadmium (Cd) and mercury (Hg)] became more concentrated (P < 0.05). Elements distribution images showed generalized accumulation of barium (Ba), cobalt (Co), Cu, Fe and V, while Cr, Mn, and Zn showed pin point accumulations in muscle sections. Thus, the ion profiles were generally influenced by Se deficiency, which suggested a possible role of Se deficiency in muscle dysfunctions caused by these altered ion profiles. PMID- 28877213 TI - Ostracism via virtual chat room-Effects on basic needs, anger and pain. AB - Ostracism is characterized by a social pain provoked by being excluded and ignored. In order to address the effects of social ostracism in virtual non physical interactions, we developed a more realistic paradigm as an alternative to Cyberball and assessed its effects on participant's expression of basic social needs, emotional experience and painful feeling. The chat room consisted of controlled social dialogue interactions between participants and two other (confederate) chat room partners. Exclusion was manipulated by varying the number of messages a participant received (15% and 33% in exclusion and inclusion, respectively). Analysis of participant (N = 54) responses revealed that exclusion induced a lower experience of basic-need states and greater anger, compared with included participants. In addition, excluded participants reported higher levels of two specific self-pain feelings, namely tortured and hurt. Our findings suggest that this procedure is effective in inducing social ostracism in a realistic and yet highly controlled experimental procedure. PMID- 28877214 TI - Direct versus indirect actions of ghrelin on hypothalamic NPY neurons. AB - OBJECTIVES: Assess direct versus indirect action(s) of ghrelin on hypothalamic NPY neurons. MATERIALS AND METHODS: Electrophysiology was used to measure ion channel activity in NPY-GFP neurons in slice preparations. Ca2+ imaging was used to monitor ghrelin activation of isolated NPY GFP-labeled neurons. Immunohistochemistry was used to localize Trpm4, SUR1 and Kir6.2 in the hypothalamus. RESULTS: Acylated ghrelin depolarized the membrane potential (MP) of NPY-GFP neurons in brain slices. Depolarization resulted from a decreased input resistance (IR) in ~70% of neurons (15/22) or an increased IR in the remainder (7/22), consistent with the opening or closing of ion channels, respectively. Although tetrodotoxin (TTX) blockade of presynaptic action potentials reduced ghrelin-induced changes in MP and IR, ghrelin still significantly depolarized the MP and decreased IR in TTX-treated neurons, suggesting that ghrelin directly opens cation channel(s) in NPY neurons. In isolated NPY-GFP neurons, ghrelin produced a sustained rise of [Ca2+]c, with an EC50 ~110 pM. Pharmacologic studies confirmed that the direct action of ghrelin was through occupation of the growth hormone secretagogue receptor, GHS-R, and demonstrated the importance of the adenylate cyclase/cAMP/protein kinase A (PKA) and phospholipase C/inositol triphosphate (PLC/IP3) pathways as activators of 5' AMP-activated protein kinase (AMPK). Activation of isolated neurons was not affected by CNQX or TTX, but reducing [Na+]o suppressed activation, suggesting a role for Na+-permeable cation channels. SUR1 and two channel partners, Kir6.2 and Trpm4, were identified immunologically in NPY-GFP neurons in situ. The actions of SUR1 and Trpm4 modulators were informative: like ghrelin, diazoxide, a SUR1 agonist, elevated [Ca2+]c and glibenclamide, a SUR1 antagonist, partially suppressed ghrelin action, while 9-phenanthrol and flufenamic acid, selective Trpm4 antagonists, blocked ghrelin actions on isolated neurons. Ghrelin activation was unaffected by nifedipine and omega-conotoxin, inhibitors of L- and N-type Ca2+ channels, respectively, while Ni2+, mibefradil, and TTA-P2 completely or partially inhibited ghrelin action, implicating T-type Ca2+ channels. Activation was also sensitive to a spider toxin, SNX-482, at concentrations selective for R-type Ca2+ channels. Nanomolar concentrations of GABA markedly inhibited ghrelin-activation of isolated NPY-GFP neurons, consistent with chronic suppression of ghrelin action in vivo. CONCLUSIONS: NPY neurons express all the molecular machinery needed to respond directly to ghrelin. Consistent with recent studies, ghrelin stimulates presynaptic inputs that activate NPY-GFP neurons in situ. Ghrelin can also directly activate a depolarizing conductance. Results with isolated NPY-GFP neurons suggest the ghrelin-activated, depolarizing current is a Na+ conductance with the pharmacologic properties of SUR1/Trpm4 non-selective cation channels. In the isolated neuron model, the opening of SUR1/Trpm4 channels activates T- and SNX482-sensitive R-type voltage dependent Ca2+ channels, which could contribute to NPY neuronal activity in situ. PMID- 28877215 TI - Is biotechnology (more) acceptable when it enables a reduction in phytosanitary treatments? A European comparison of the acceptability of transgenesis and cisgenesis. AB - Reduced pesticide use is one of the reasons given by Europeans for accepting new genetic engineering techniques. According to the advocates of these techniques, consumers are likely to embrace the application of cisgenesis to apple trees. In order to verify the acceptability of these techniques, we estimate a Bayesian multilevel structural equation model, which takes into account the multidimensional nature of acceptability and individual, national, and European effects, using data from the Eurobarometer 2010 73.1 on science. The results underline the persistence of clear differences between European countries and whilst showing considerable defiance, a relatively wider acceptability of vertical gene transfer as a means of reducing phytosanitary treatments, compared to horizontal transfer. PMID- 28877216 TI - An in vitro lung model to assess true shunt fraction by multiple inert gas elimination. AB - The Multiple Inert Gas Elimination Technique, based on Micropore Membrane Inlet Mass Spectrometry, (MMIMS-MIGET) has been designed as a rapid and direct method to assess the full range of ventilation-to-perfusion (V/Q) ratios. MMIMS-MIGET distributions have not been assessed in an experimental setup with predefined V/Q distributions. We aimed (I) to construct a novel in vitro lung model (IVLM) for the simulation of predefined V/Q distributions with five gas exchange compartments and (II) to correlate shunt fractions derived from MMIMS-MIGET with preset reference shunt values of the IVLM. Five hollow-fiber membrane oxygenators switched in parallel within a closed extracorporeal oxygenation circuit were ventilated with sweep gas (V) and perfused with human red cell suspension or saline (Q). Inert gas solution was infused into the perfusion circuit of the gas exchange assembly. Sweep gas flow (V) was kept constant and reference shunt fractions (IVLM-S) were established by bypassing one or more oxygenators with perfusate flow (Q). The derived shunt fractions (MM-S) were determined using MIGET by MMIMS from the retention data. Shunt derived by MMIMS-MIGET correlated well with preset reference shunt fractions. The in vitro lung model is a convenient system for the setup of predefined true shunt fractions in validation of MMIMS-MIGET. PMID- 28877218 TI - Role of interoceptive accuracy in topographical changes in emotion-induced bodily sensations. AB - The emotion-associated bodily sensation map is composed of a specific topographical distribution of bodily sensations to categorical emotions. The present study investigated whether or not interoceptive accuracy was associated with topographical changes in this map following emotion-induced bodily sensations. This study included 31 participants who observed short video clips containing emotional stimuli and then reported their sensations on the body map. Interoceptive accuracy was evaluated with a heartbeat detection task and the spatial patterns of bodily sensations to specific emotions, including anger, fear, disgust, happiness, sadness, and neutral, were visualized using Statistical Parametric Mapping (SPM) analyses. Distinct patterns of bodily sensations were identified for different emotional states. In addition, positive correlations were found between the magnitude of sensation in emotion-specific regions and interoceptive accuracy across individuals. A greater degree of interoceptive accuracy was associated with more specific topographical changes after emotional stimuli. These results suggest that the awareness of one's internal bodily states might play a crucial role as a required messenger of sensory information during the affective process. PMID- 28877217 TI - Involvement of arginine 878 together with Ca2+ in mouse aminopeptidase A substrate specificity for N-terminal acidic amino-acid residues. AB - Aminopeptidase A (APA) is a membrane-bound zinc metalloprotease cleaving, in the brain, the N-terminal aspartyl residue of angiotensin II to generate angiotensin III, which exerts a tonic stimulatory effect on the control of blood pressure in hypertensive animals. Using a refined APA structure derived from the human APA crystal structure, we docked the specific and selective APA inhibitor, EC33 in the presence of Ca2+. We report the presence in the S1 subsite of Arg-887 (Arg 878 in mouse APA), the guanidinium moiety of which established an interaction with the electronegative sulfonate group of EC33. Mutagenic replacement of Arg 878 with an alanine or a lysine residue decreased the affinity of the recombinant enzymes for the acidic substrate, alpha-L-glutamyl-beta-naphthylamide, with a slight decrease in substrate hydrolysis velocity either with or without Ca2+. In the absence of Ca2+, the mutations modified the substrate specificity of APA for the acidic substrate, the mutated enzymes hydrolyzing more efficiently basic and neutral substrates, although the addition of Ca2+ partially restored the acidic substrate specificity. The analysis of the 3D models of the Arg-878 mutated APAs revealed a change in the volume of the S1 subsite, which may impair the binding and/or the optimal positioning of the substrate in the active site as well as its hydrolysis. These findings demonstrate the key role of Arg-878 together with Ca2 + in APA substrate specificity for N-terminal acidic amino acid residues by ensuring the optimal positioning of acidic substrates during catalysis. PMID- 28877219 TI - A new approach to chromosome-wide analysis of X-linked markers identifies new associations in Asian and European case-parent triads of orofacial clefts. AB - BACKGROUND: GWAS discoveries on the X-chromosome are underrepresented in the literature primarily because the analytical tools that have been applied were originally designed for autosomal markers. Our objective here is to employ a new robust and flexible tool for chromosome-wide analysis of X-linked markers in complex traits. Orofacial clefts are good candidates for such analysis because of the consistently observed excess of females with cleft palate only (CPO) and excess of males with cleft lip with or without cleft palate (CL/P). METHODS: Genotypes for 14,486 X-chromosome SNPs in 1,291 Asian and 1,118 European isolated cleft triads were available from a previously published GWAS. The R-package HAPLIN enables genome-wide-level analyses as well as statistical power simulations for a range of biologic scenarios. We analyzed isolated CL/P and isolated CPO for each ethnicity in HAPLIN, using a sliding-window approach to haplotype analysis and two different statistical models, with and without X inactivation in females. RESULTS: There was a larger number of associations in the Asian versus the European sample, and similar to previous reports that have analyzed the same GWAS dataset using different methods, we identified associations with EFNB1/PJA1 and DMD. In addition, new associations were detected with several other genes, among which KLHL4, TBX22, CPXCR1 and BCOR were noteworthy because of their roles in clefting syndromes. A few of the associations were only detected by one particular X-inactivation model, whereas a few others were only detected in one sex. DISCUSSION/CONCLUSION: We found new support for the involvement of X-linked variants in isolated clefts. The associations were specific for ethnicity, sex and model parameterization, highlighting the need for flexible tools that are capable of detecting and estimating such effects. Further efforts are needed to verify and elucidate the potential roles of EFNB1/PJA1, KLHL4, TBX22, CPXCR1 and BCOR in isolated clefts. PMID- 28877220 TI - Attenuated lipotoxicity and apoptosis is linked to exogenous and endogenous augmenter of liver regeneration by different pathways. AB - Nonalcoholic fatty liver disease (NAFLD) covers a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Free fatty acids (FFA) induce steatosis and lipo-toxicity and correlate with severity of NAFLD. In this study we aimed to investigate the role of exogenous and endogenous ALR (augmenter of liver regeneration) for FFA induced ER (endoplasmatic reticulum) -stress and lipoapoptosis. Primary human hepatocytes or hepatoma cells either treated with recombinant human ALR (rhALR, 15kDa) or expressing short form ALR (sfALR, 15kDa) were incubated with palmitic acid (PA) and analyzed for lipo-toxicity, apoptosis, activation of ER-stress response pathways, triacylglycerides (TAG), mRNA and protein expression of lipid metabolizing genes. Both, exogenous rhALR and cytosolic sfALR reduced PA induced caspase 3 activity and Bax protein expression and therefore lipotoxicity. Endogenous sfALR but not rhALR treatment lowered TAG levels, diminished activation of ER-stress mediators C-Jun N-terminal kinase (JNK), X-box binding protein-1 (XBP1) and proapoptotic transcription factor C/EBP-homologous protein (CHOP), and reduced death receptor 5 protein expression. Cellular ALR exerts its lipid lowering and anti-apoptotic actions by enhancing FABP1, which binds toxic FFA, increasing mitochondrial beta-oxidation by elevating the mitochondrial FFA transporter CPT1alpha, and decreasing ELOVL6, which delivers toxic FFA metabolites. We found reduced hepatic mRNA levels of ALR in a high fat diet mouse model, and of ALR and FOXA2, a transcription factor inducing ALR expression, in human steatotic as well as NASH liver samples, which may explain increased lipid deposition and reduced beta-oxidation in NASH patients. Present study shows that exogenous and endogenous ALR reduce PA induced lipoapoptosis. Furthermore, cytosolic sfALR changes mRNA and protein expression of genes regulating lipid metabolism, reduces ER-stress finally impeding progression of NASH. PMID- 28877222 TI - Taxonomic and functional surrogates of sessile benthic diversity in Mediterranean marine caves. AB - Hard substrates host globally a rich biodiversity, orders of magnitude higher in species number than that in surrounding soft substrates. Among them, marine caves support unique biodiversity and fragile communities but suffer lack of quantitative data on their structure and function, hindering their conservation status assessment. A first approach to the non-destructive ecological monitoring of marine caves by testing surrogates of structural and functional composition of sessile benthos was attempted in two species-rich Mediterranean marine caves. Photographic sampling was performed in different positions on the cave walls, across the horizontal axis, from the entrance inwards. Eighty-four taxa were identified and assigned to 6 biological traits and 32 modalities related to morphology, behavior and ecological affinities, with sponges being the dominant taxon in species richness and coverage. In quest of possible biological surrogates, we examined the spatial variability of the total community structure and function and separately the sponge community structure and function. The observed patterns of the above metrics were significantly correlated with the distance from the entrance, the small-scale variability and their interaction. A positive correlation was found between all examined pairs of those metrics, supporting that: (i) the developed functional approach could be used for the study of marine cave sessile communities, and (ii) sponges could be used as a surrogate taxon for the structural and functional study of these communities. The suggested method could be tested in other types of hard substrate habitats and in multiple locations of the Mediterranean waters, facilitating monitoring schemes and conservation actions. PMID- 28877221 TI - Short-term spheroid culture of primary colorectal cancer cells as an in vitro model for personalizing cancer medicine. AB - Chemotherapy treatment of cancer remains a challenge due to the molecular and functional heterogeneity displayed by tumours originating from the same cell type. The pronounced heterogeneity makes it difficult for oncologists to devise an effective therapeutic strategy for the patient. One approach for increasing treatment efficacy is to test the chemosensitivity of cancer cells obtained from the patient's tumour. 3D culture represents a promising method for modelling patient tumours in vitro. The aim of this study was therefore to evaluate how closely short-term spheroid cultures of primary colorectal cancer cells resemble the original tumour. Colorectal cancer cells were isolated from human tumour tissue and cultured as spheroids. Spheroid cultures were established with a high success rate and remained viable for at least 10 days. The spheroids exhibited significant growth over a period of 7 days and no difference in growth rate was observed for spheroids of different sizes. Comparison of spheroids with the original tumour revealed that spheroid culture generally preserved adenocarcinoma histology and expression patterns of cytokeratin 20 and carcinoembryonic antigen. Interestingly, spheroids had a tendency to resemble tumour protein expression more closely after 10 days of culture compared to 3 days. Chemosensitivity screening using spheroids from five patients demonstrated individual response profiles. This indicates that the spheroids maintained patient-to-patient differences in sensitivity towards the drugs and combinations most commonly used for treatment of colorectal cancer. In summary, short-term spheroid culture of primary colorectal adenocarcinoma cells represents a promising in vitro model for use in personalized medicine. PMID- 28877223 TI - Adhering to a national surgical care bundle reduces the risk of surgical site infections. AB - BACKGROUND: In 2008, a bundle of care to prevent Surgical Site Infections (SSIs) was introduced in the Netherlands. The bundle consisted of four elements: antibiotic prophylaxis according to local guidelines, no hair removal, normothermia and 'hygiene discipline' in the operating room (i.e. number of door movements). Dutch hospitals were advised to implement the bundle and to measure the outcome. This study's goal was to assess how effective the bundle was in reducing SSI risk. METHODS: Hospitals assessed whether their staff complied with each of the bundle elements and voluntary reported compliance data to the national SSI surveillance network (PREZIES). From PREZIES data, we selected data from 2009 to 2014 relating to 13 types of surgical procedures. We excluded surgeries with missing (non)compliance data, and calculated for each remaining surgery with reported (non)compliance data the level of compliance with the bundle (that is, being compliant with 0, 1, 2, 3, or 4 of the elements). Subsequently, we used this level of compliance to assess the effect of bundle compliance on the SSI risk, using multilevel logistic regression techniques. RESULTS: 217 489 surgeries were included, of which 62 486 surgeries (29%) had complete bundle reporting. Within this group, the SSI risk was significantly lower for surgeries with complete bundle compliance compared to surgeries with lower compliance levels. Odds ratios ranged from 0.63 to 0.86 (risk reduction of 14% to 37%), while a 13% risk reduction was demonstrated for each point increase in compliance-level. Sensitivity analysis indicated that due to analysing reported bundles only, we probably underestimated the total effect of implementing the bundle. CONCLUSIONS: This study demonstrated that adhering to a surgical care bundle significantly reduced the risk of SSIs. Reporting of and compliance with the bundle compliance can, however, still be improved. Therefore an even greater effect might be achieved. PMID- 28877224 TI - Transformation products elucidation of forchlorfenuron in postharvest kiwifruit by time-of-flight mass spectrometry. AB - Forchlorfenuron (1-(2-chloro-4-pyridyl)-3-phenylurea, FCF) is a plant growth regulator, being extensively used for increasing kiwifruit size. The toxicological properties of its may persist in their transformation products (TPs) or even higher toxicity than FCF. TPs elucidation of FCF in postharvest kiwifruit (Actinidia chinensis, Chinese gooseberry) by the liquid chromatography ionization hybrid ion trap and time-of-flight mass spectrometry (LC-ESI-IT TOF/MS) in positive mode was the objective of the present study. Fifteen days after full bloom, kiwifruits were dipped for 5s with high dosage FCF solution (60 mg/L), so that sufficient peaks could be detected. The chemical structure of unknown TPs was analyzed in combination of functions of LCMS-IT-TOF, such as high accurate MSn, formula predictor, metabolite structural analysis software MetID Solution, profiling solution metabolomics software, and neutral loss, characteristic isotopic patterns of chlorine, the fragmentation pattern and retention time of standard substances, nitrogen rule, chemical components of kiwifruit. Total 17 TPs were detected via comparisons of their accurate MSn data of commercial analytical standards and synthesized standards with high purity, such as 4-amino-2-chloropyridine, phenylurea, 2-hydroxy-FCF, 1-(2-chloro-6-((3, 4, 5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy) pyridin-4-yl)-3 phenylurea, 1, 3-bis (2-chloropyridin-4-yl) urea, 1,3-diphenylurea, 1-(2 chloropyridin-4-yl)urea, FCF-2-O-beta-D-glucoside, and so on. The major transformation pathways of FCF in kiwifruit were biochemical and photochemical cleavage pathway. The experimental results indicate that LCMS-IT-TOF is powerful and effective tool for identification of FCF TPs. PMID- 28877225 TI - Effect of water-based recovery on blood lactate removal after high-intensity exercise. AB - This study assessed the effectiveness of water immersion to the shoulders in enhancing blood lactate removal during active and passive recovery after short duration high-intensity exercise. Seventeen cyclists underwent active water- and land-based recoveries and passive water and land-based recoveries. The recovery conditions lasted 31 minutes each and started after the identification of each cyclist's blood lactate accumulation peak, induced by a 30-second all-out sprint on a cycle ergometer. Active recoveries were performed on a cycle ergometer at 70% of the oxygen consumption corresponding to the lactate threshold (the control for the intensity was oxygen consumption), while passive recoveries were performed with subjects at rest and seated on the cycle ergometer. Blood lactate concentration was measured 8 times during each recovery condition and lactate clearance was modeled over a negative exponential function using non-linear regression. Actual active recovery intensity was compared to the target intensity (one sample t-test) and passive recovery intensities were compared between environments (paired sample t-tests). Non-linear regression parameters (coefficients of the exponential decay of lactate; predicted resting lactates; predicted delta decreases in lactate) were compared between environments (linear mixed model analyses for repeated measures) separately for the active and passive recovery modes. Active recovery intensities did not differ significantly from the target oxygen consumption, whereas passive recovery resulted in a slightly lower oxygen consumption when performed while immersed in water rather than on land. The exponential decay of blood lactate was not significantly different in water- or land-based recoveries in either active or passive recovery conditions. In conclusion, water immersion at 29 degrees C would not appear to be an effective practice for improving post-exercise lactate removal in either the active or passive recovery modes. PMID- 28877226 TI - Distinct patterns of innate immune activation by clinical isolates of respiratory syncytial virus. AB - Respiratory syncytial virus (RSV) is a major respiratory pathogen of infants and young children. Multiple strains of both subgroup A and B viruses circulate during each seasonal epidemic. Genetic heterogeneity among RSV genomes, in large part due to the error prone RNA-dependent, RNA polymerase, could mediate variations in pathogenicity. We evaluated clinical strains of RSV for their ability to induce the innate immune response. Subgroup B viruses were used to infect human pulmonary epithelial cells (A549) and primary monocyte-derived human macrophages (MDM) from a variety of donors. Secretions of IL-6 and CCL5 (RANTES) from infected cells were measured following infection. Host and viral transcriptome expression were assessed using RNA-SEQ technology and the genomic sequences of several clinical isolates were determined. There were dramatic differences in the induction of IL-6 and CCL5 in both A549 cells and MDM infected with a variety of clinical isolates of RSV. Transcriptome analyses revealed that the pattern of innate immune activation in MDM was virus-specific and host specific. Specifically, viruses that induced high levels of secreted IL-6 and CCL5 tended to induce cellular innate immune pathways whereas viruses that induced relatively low level of IL-6 or CCL5 did not induce or suppressed innate immune gene expression. Activation of the host innate immune response mapped to variations in the RSV G gene and the M2-1 gene. Viral transcriptome data indicated that there was a gradient of transcription across the RSV genome though in some strains, RSV G was the expressed in the highest amounts at late times post-infection. Clinical strains of RSV differ in cytokine/chemokine induction and in induction and suppression of host genes expression suggesting that these viruses may have inherent differences in virulence potential. Identification of the genetic elements responsible for these differences may lead to novel approaches to antiviral agents and vaccines. PMID- 28877227 TI - Hemocyte-mediated phagocytosis differs between honey bee (Apis mellifera) worker castes. AB - Honey bees as other insects rely on the innate immune system for protection against diseases. The innate immune system includes the circulating hemocytes (immune cells) that clear pathogens from hemolymph (blood) by phagocytosis, nodulation or encapsulation. Honey bee hemocyte numbers have been linked to hemolymph levels of vitellogenin. Vitellogenin is a multifunctional protein with immune-supportive functions identified in a range of species, including the honey bee. Hemocyte numbers can increase via mitosis, and this recruitment process can be important for immune system function and maintenance. Here, we tested if hemocyte mediated phagocytosis differs among the physiologically different honey bee worker castes (nurses, foragers and winter bees), and study possible interactions with vitellogenin and hemocyte recruitment. To this end, we adapted phagocytosis assays, which-together with confocal microscopy and flow cytometry allow qualitative and quantitative assessment of hemocyte performance. We found that nurses are more efficient in phagocytic uptake than both foragers and winter bees. We detected vitellogenin within the hemocytes, and found that winter bees have the highest numbers of vitellogenin-positive hemocytes. Connections between phagocytosis, hemocyte-vitellogenin and mitosis were worker caste dependent. Our results demonstrate that the phagocytic performance of immune cells differs significantly between honey bee worker castes, and support increased immune competence in nurses as compared to forager bees. Our data, moreover, provides support for roles of vitellogenin in hemocyte activity. PMID- 28877228 TI - Exploring the possible relationship between ambient heat and sudden infant death with data from Vienna, Austria. AB - A non-linear relationship between maximum ambient temperature and number of sudden infant death syndrome (SIDS) cases had been reported for Montreal, Canada, for the warm season. In particular, high maximum ambient temperatures were found to be extra-hazardous for infants. The study was replicated with data from Vienna, Austria, applying the same statistical approach. Vienna is roughly comparable to Montreal with regard to temperatures in the warm season, size of population, and number of SIDS cases. Although the Viennese study was powerful enough to detect even smaller effects, the Montrealean results could not be confirmed. The Viennese results do not support the hypothesis of a strong effect of maximum ambient temperature on the risk of SIDS during the warm season. PMID- 28877229 TI - Who needs 'lazy' workers? Inactive workers act as a 'reserve' labor force replacing active workers, but inactive workers are not replaced when they are removed. AB - Social insect colonies are highly successful, self-organized complex systems. Surprisingly however, most social insect colonies contain large numbers of highly inactive workers. Although this may seem inefficient, it may be that inactive workers actually contribute to colony function. Indeed, the most commonly proposed explanation for inactive workers is that they form a 'reserve' labor force that becomes active when needed, thus helping mitigate the effects of colony workload fluctuations or worker loss. Thus, it may be that inactive workers facilitate colony flexibility and resilience. However, this idea has not been empirically confirmed. Here we test whether colonies of Temnothorax rugatulus ants replace highly active (spending large proportions of time on specific tasks) or highly inactive (spending large proportions of time completely immobile) workers when they are experimentally removed. We show that colonies maintained pre-removal activity levels even after active workers were removed, and that previously inactive workers became active subsequent to the removal of active workers. Conversely, when inactive workers were removed, inactivity levels decreased and remained lower post-removal. Thus, colonies seem to have mechanisms for maintaining a certain number of active workers, but not a set number of inactive workers. The rapid replacement (within 1 week) of active workers suggests that the tasks they perform, mainly foraging and brood care, are necessary for colony function on short timescales. Conversely, the lack of replacement of inactive workers even 2 weeks after their removal suggests that any potential functions they have, including being a 'reserve', are less important, or auxiliary, and do not need immediate recovery. Thus, inactive workers act as a reserve labor force and may still play a role as food stores for the colony, but a role in facilitating colony-wide communication is unlikely. Our results are consistent with the often cited, but never yet empirically supported hypothesis that inactive workers act as a pool of 'reserve' labor that may allow colonies to quickly take advantage of novel resources and to mitigate worker loss. PMID- 28877230 TI - Decision impact and feasibility of different ASCO-recommended biomarkers in early breast cancer: Prospective comparison of molecular marker EndoPredict and protein marker uPA/PAI-1. AB - BACKGROUND: Adjuvant therapy decisions in early breast cancer are based on accurate risk assessment. Urokinase plasminogen activator (uPA) and plaminogen activator inhibitor-1 (PAI-1) have been the first biomarkers in hormone receptor (HR) positive breast cancer to reach highest level of evidence. The EndoPredict test (EPclin) combines gene expression information with nodal status and tumor size. The aim of this prospective study was to compare uPA/PAI-1 and EPclin as prognostic biomarkers with regard to feasibility, risk stratification and impact on adjuvant therapy recommendation. MATERIALS AND METHOD: 395 patients with HR positive, HER2 negative, intermediate risk breast cancer were enrolled. Relations and concordance of histologic grading as well as EPclin and uPA/PAI-1 values were assessed by Spearman's rank correlation coefficient and Cohen's Kappa. To compare decision impact of EPclin and uPA/PAI-1 three independent case discussions were held: One with known uPA/PAI-1 and EPclin results, one blinded to EPclin alone and another one blinded to both EPclin and uPA/PAI-1. RESULTS: EPclin could be determined in all 395 (100%), uPA/PAI-1 in 190 (48%) of the tumor samples. EPclin allocated 250 patients (63%) to the low-risk group and 145 patients (37%) to the high-risk group, whereas uPA/PAI-1 allocated 88 patients (46%) to the low-risk group and 102 patients (54%) to the high-risk group. In 59% of cases, both tests showed concordant results. EPclin resulted more frequently in a change of therapy recommendation than the uPA/PAI-1 test (46% vs 24%). Recommendation of adjuvant chemotherapy (CTX) was abandoned twice as often by EPclin (45%) compared to uPA/PAI-1 (22%). CONCLUSION: In this first prospective comparison of EPclin and uPA/PAI-1 we found, that EPclin is superior to uPA/PAI-1 with respect to feasibility and decision impact. This leads to substantial avoidance of adjuvant CTX in endocrine-sensitive, HER2-negative breast cancer. Data collection for patients' clinical outcome is ongoing. PMID- 28877231 TI - Functional characterization of T-cells from palatine tonsils in patients with chronic tonsillitis. AB - The palatine tonsils, localized in the oropharynx, are easily accessible secondary lymphoid tissue in humans. Inflammation of the palatine tonsils, local and chronic in case of chronic tonsillitis (CT) or acute in the presence of a peritonsillar abscess (PTA), ranks among the most common diseases in otolaryngology. However, the functionality of tonsillar immune cells, notably T cells, in the context of these immune pathologies is poorly understood. We have examined the functional status of human tonsillar T-cells in CT and compared it to the acute inflammatory setting of a PTA. Patients presenting with CT (n = 10) or unilateral PTA (n = 7) underwent bilateral tonsillectomy and a subgroup of 8 patients underwent additional blood sampling. T-cells were purified via automated magnetic selection and subjected to flow cytometry-based immunophenotyping. In addition, the response to T-cell receptor (TCR) stimulation was assessed at the level of proximal signaling, activation marker expression and proliferation. We observed no difference between the percentage of T helper (CD4(+)) cells from tonsil tissue in CT and PTA, but observed a trend towards a higher percentage of T helper cells in the blood of patients with PTA versus CT, probably reflecting an acute, systemic bacterial infection in the former cohort. Tonsils from CT harbored more PD-1(+) CD4(+) T-cells, pointing to T-cell exhaustion due to chronic infection. This notion was supported by functional studies that showed a tendency to weaker TCR responses of tonsillar T-cells from CT. Intriguingly, tonsillar T-cells recurrently featured a dampened response to T-cell receptor stimulation at the level of receptor proximal signaling steps compared to peripheral T-cells. In sum, our study documents distinct differences in tonsillar T-cell class distribution and function between the various pathological conditions. Our observations are consistent with the concept that tonsillar T cells react to infections by eliciting specific immunological responses in chronic versus acute settings of inflammation. PMID- 28877232 TI - An acute bout of localized resistance exercise can rapidly improve inhibitory control. AB - The positive effect of acute resistance exercise on executive function, such as inhibitory control (IC), is poorly understood. Several previous studies have demonstrated this effect using whole-body resistance exercise. However, it remains unclear whether localized resistance exercise performed using only limited muscle groups could also acutely improve IC. Thus, the present study examined the effect of an acute bout of localized resistance exercise on IC. Twelve healthy men performed a color-word Stroop task (CWST) before and immediately after the experimental conditions, which consisted of 2 resistance exercises and a resting control (CON). Bilateral knee extension was used to create 2 resistance exercise conditions: light-intensity resistance exercise (LRE) and high-intensity resistance exercise (HRE) conditions, which were 40% and 80% of one-repetition maximum, respectively. The resistance exercise session was programmed for 6 sets with 10 repetitions per set. The CWST-measured IC was significantly improved immediately after both LRE and HRE, but it did not improve immediately after CON. However, the improved IC was significantly greater in HRE than in LRE. The present findings showed that IC could be rapidly improved by an acute bout of localized resistance exercise, especially with high-intensity. Therefore, we suggest that in addition to whole-body resistance exercise, localized resistance exercise performed using limited muscle groups may be sufficient for improving IC. PMID- 28877233 TI - High-level dietary cadmium exposure is associated with global DNA hypermethylation in the gastropod hepatopancreas. AB - 5-methylcytosine (5mC) is a key epigenetic mark which influences gene expression and phenotype. In vertebrates, this epigenetic mark is sensitive to Cd exposure, but there is no information linking such an event with changes in global 5mC levels in terrestrial gastropods despite their importance as excellentecotoxicological bioindicators of metal contamination. Therefore, we first evaluated total 5mC content in DNA of the hepatopancreas of adult Cantareus aspersus with the aim to determine whether this epigenetic mark is responsive to Cd exposure. The experiment was conducted under laboratory conditions and involved a continuous exposure, multiple dose- and time-point (14, 28, and 56 days) study design. Hepatopancreas cadmium levels were measured using Flame Atomic Absorption Spectrometry and the percentage of 5-mC in samples using an ELISA-based colorimetric assay. Snail death rates were also assessed. Our results, for the first time, reveal the presence of 5mC in C. aspersus and provide evidence for Cd-induced changes in global 5mC levels in DNA of gastropods and mollusks. Although less sensitive than tissue accumulation, DNA methylation levels responded in a dose- and time-dependent manner to dietary cadmium, with exposure dose having a much stronger effect than exposure duration. An obvious trend of increasing 5mC levels was observed starting at 28 days of exposure to the second highest dose and this trend persisted at the two highest treatments for close to one month, when the experiment was terminated after 56 days. Moreover, a strong association was identified between Cd concentrations in the hepatopancreas and DNA methylation levels in this organ. These data indicate an overall trend towards DNA hypermethylation with elevated Cd exposure. No consistent lethal effect was observed, irrespective of time point and Cd-dosage. Overall, our findings suggest that the total 5mC content in DNA of the hepatopancreas of land snails is responsive to sublethal Cd exposure and give new insights into invertebrate environmental epigenetics. PMID- 28877234 TI - A decision support model for investment on P2P lending platform. AB - Peer-to-peer (P2P) lending, as a novel economic lending model, has triggered new challenges on making effective investment decisions. In a P2P lending platform, one lender can invest N loans and a loan may be accepted by M investors, thus forming a bipartite graph. Basing on the bipartite graph model, we built an iteration computation model to evaluate the unknown loans. To validate the proposed model, we perform extensive experiments on real-world data from the largest American P2P lending marketplace-Prosper. By comparing our experimental results with those obtained by Bayes and Logistic Regression, we show that our computation model can help borrowers select good loans and help lenders make good investment decisions. Experimental results also show that the Logistic classification model is a good complement to our iterative computation model, which motivates us to integrate the two classification models. The experimental results of the hybrid classification model demonstrate that the logistic classification model and our iteration computation model are complementary to each other. We conclude that the hybrid model (i.e., the integration of iterative computation model and Logistic classification model) is more efficient and stable than the individual model alone. PMID- 28877235 TI - Genetic and antigenic characterization of influenza A(H3N2) in Cameroon during the 2014-2016 influenza seasons. AB - The first outbreak of influenza A(H3N2) occurred in 1968 and caused the third flu pandemic of the 20th century. It has affected multiple countries over time. The best strategy to reduce the burden of influenza is through vaccination whose efficacy varies with respect to the circulating strains. This study was performed to better understand the molecular evolution of influenza A(H3N2) and assess vaccine efficacy in Cameroon. Complete sequences of three gene segments were obtained from 2014 to 2016 influenza seasons in Cameroon. Hemagglutinin (HA), Neuraminidase (NA) and matrix (M) genes of 35 A(H3N2) virus strains were amplified and sequenced. Predicted vaccine efficacy was measured using the Pepitope model. Phylogenetic analysis of the HA gene showed that all Cameroonian strains had evolved away from the 3C.1-A/Texas/50/2012-like clade. Globally, 2014 virus strains clustered with the 2015-2016 vaccine strain, 3C.3a A/Switzerland/9715293/2013, whereas 2015 and 2016 virus strains clustered with the 2016-2017 vaccine strain, 3C.2a-A/HongKong/4801/2014. In order to determine the genotypic drug susceptibility to neuraminidase inhibitors and amantadine, the NA and M2 protein coding sequences were analyzed. There was no strain with characteristic mutation for resistance to neuraminidase inhibitors, per contra; all strains possessed the substitution S31N, peculiar of resistance to adamantanes. There was drift in influenza A(H3N2) dominant epitopes B (2014 and 2015) to epitopes A (2016) with a theoretical efficiency in vaccine ranging from low to moderate. The presence of several antigenic site mutations among H3N2 virus strains between 2014-2016 influenza seasons in Cameroon confirms the progressing evolution of circulating H3N2 strains. PMID- 28877237 TI - Correction: Synergy of circulating miR-212 with markers for cardiovascular risks to enhance estimation of atherosclerosis presence. AB - [This corrects the article DOI: 10.1371/journal.pone.0177809.]. PMID- 28877236 TI - DNA aneuploidy relationship with patient age and tobacco smoke in OPMDs/OSCCs. AB - The aim of this study was to investigate the relationship between tobacco smoke habit, patient age, DNA aneuploidy and genomic DNA copy number aberrations (CNAs) in oral potentially malignant disorder (OPMD) and oral squamous cell carcinoma (OSCC) patients. DNA aneuploidy was detected by high-resolution DNA flow cytometry (hr DNA-FCM) on DAPI stained nuclei obtained from multiple tissue samples from OPMDs/OSCCs in 220 consecutive patients. Nuclear genomic aberrations were determined in a subset of 65 patients by genome-wide array comparative genomic hybridization (aCGH) using DNA extracted from either diploid or aneuploid nuclei suspension sorted by FCM. DNA aneuploidy and mean nuclear genomic aberrations were associated with patients' age. In particular, DNA aneuploidy strongly associated with age in non-smoker OPMDs/OSCCs patients. OSCCs from smokers showed a lower prevalence of DNA aneuploidy compared to OSCCs from non smokers. A higher occurrence of DNA aneuploidy (particularly in smokers' OPMDs) was observed in patients characterized by involvement of a single oral subsite. Our study suggests that: 1) DNA aneuploidy in non-smokers is mainly related to aging; 2) OPMDs/OSCCs involving multiple oral subsites in smokers are less likely to develop DNA aneuploidy compared to non-smokers; 3) OSCC development is characterized by both CIN and CIN-independent mechanisms and that the latter are more relevant in smokers. This study provides evidence that DNA diploid OPMDs may be considered at lower risk of cancerization than DNA aneuploid ones in non smokers but not in smokers. PMID- 28877238 TI - Effects of recruitment manoeuvre on perioperative pulmonary complications in patients undergoing robotic assisted radical prostatectomy: A randomised single blinded trial. AB - Robotic-assisted laparoscopic radical prostatectomy (RARP) needs a steep Trendelenburg position and a relatively high CO2 insufflation pressure, and patients undergoing RARP are usually elderly. These factors make intraoperative ventilatory care difficult and increase the risk of perioperative pulmonary complications. The aim was to determine the efficacy of recruitment manoeuvre (RM) on perioperative pulmonary complications in elderly patients undergoing RARP. A total of 60 elderly patients scheduled for elective RARP were randomly allocated to two groups after induction of anaesthesia; positive end expiratory pressure (PEEP) was applied during the operation without RM in the control group (group C) and after RM in the recruitment group (group R). The total number of patients who developed intraoperative desaturation or postoperative atelectasis was significantly higher in group C compared to group R (43.3% vs. 17.8%, P = 0.034). Intraoperative respiratory mechanics, perioperative blood gas analysis, and pulmonary function testing did not show differences between the groups. Adding RM to PEEP compared to PEEP alone significantly reduced perioperative pulmonary complications in elderly patients undergoing RARP. PMID- 28877239 TI - Incidence of and risk factors for newly diagnosed hyperkalemia after hospital discharge in non-dialysis-dependent CKD patients treated with RAS inhibitors. AB - INTRODUCTION: Renin-angiotensin system (RAS) inhibitors have been increasingly prescribed due to their beneficial effects on end-organ protection. Iatrogenic hyperkalemia is a well-known life-threatening complication of RAS inhibitor use in chronic kidney disease (CKD) patients. We hypothesized that CKD patients treated with RAS inhibitors frequently develop hyperkalemia after hospital discharge even if they were normokalemic during their hospitalization because their lifestyles change substantially after discharge. The present study aimed to examine the incidence of newly diagnosed hyperkalemia, the timing of hyperkalemia, and its risk factors in CKD patients treated with RAS inhibitors at the time of hospital discharge. METHODS: We retrospectively enrolled patients aged 20 years or older with CKD G3-5 (estimated glomerular filtration rate < 60 mL/min/1.73 m2) and who were treated with RAS inhibitors and discharged from St. Luke's International Hospital between July 2011 and December 2015. Patients who were under maintenance dialysis or had hyperkalemic events before discharge were excluded. Data regarding the patients' age, sex, CKD stage, diabetes mellitus status, malignancy status, combined use of RAS inhibitors, concurrent medication, and hyperkalemic events after discharge were extracted from the hospital database. Our primary outcome was hyperkalemia, defined as serum potassium >= 5.5 mEq/L. Multiple logistic regression and Kaplan-Meier analyses were performed to identify the risk factors for and the timing of hyperkalemia, respectively. RESULTS: Among the 986 patients, 121 (12.3%) developed hyperkalemia after discharge. In the regression analysis, relative to CKD G3a, G3b [odds ratio (OR): 1.88, 95% confidence interval 1.20-2.97] and G4-5 (OR: 3.40, 1.99-5.81) were significantly associated with hyperkalemia. The use of RAS inhibitor combinations (OR: 1.92, 1.19-3.10), malignancy status (OR: 2.10, 1.14-3.86), and baseline serum potassium (OR: 1.91, 1.23-2.97) were also significantly associated with hyperkalemia. The Kaplan-Meier analysis showed that hyperkalemia was most frequent during the early period after discharge, particularly within one month. CONCLUSION: Hyperkalemia was frequent during the early period after discharge among previously normokalemic CKD patients who were treated with RAS inhibitors. Appropriate follow-up after discharge should be required for these patients, particularly those with advanced CKD or malignancy status, such as hematological malignancy or late-stage malignancy, and those who are treated with multiple RAS inhibitors. PMID- 28877241 TI - Real-time surveillance of heat-related morbidity: Relation to excess mortality associated with extreme heat. AB - The impact of heat on mortality is well documented but deaths tend to occur after (or lag) extreme heat events, and mortality data is generally not available for timely surveillance during extreme heat events. Recently, systems for near-real time surveillance of heat illness have been reported but have not been validated as predictors of non-external cause of deaths associated with extreme heat events. We analyzed associations between daily weather conditions, emergency medical system (EMS) calls flagged as heat-related by EMS dispatchers, emergency department (ED) visits classified as heat-related based on chief complaint text, and excess non-external cause mortality in New York City. EMS and ED data were obtained from data reported daily to the city health department for syndromic surveillance. We fit generalized linear models to assess the relationships of daily counts of heat related EMS and ED visits to non-external cause deaths after adjustment for weather conditions during the months of May-September between 1999 and 2013. Controlling for temporal trends, a 7% (95% confidence interval (CI): 2 12) and 6% (95% CI: 3-10) increase in non-external cause mortality was associated with an increase from the 50th percentile to 99th percentile of same-day and one day lagged heat-related EMS calls and ED visits, respectively. After controlling for both temporal trends and weather, we observed a 7% (95% CI: 3-12) increase in non-external cause mortality associated with one-day lagged heat-related EMS calls and a 5% mortality increase with one-day lagged ED visits (95% CI: 2-8). Heat-related illness can be tracked during extreme heat events using EMS and ED data which are indicators of heat associated excess non-external cause mortality during the warm weather season. PMID- 28877240 TI - Runx1 mediates the development of the granular convoluted tubules in the submandibular glands. AB - The mouse granular convoluted tubules (GCTs), which are only located in the submandibular gland (SMG) are known to develop and maintain their structure in an androgen-dependent manner. We previously demonstrated that the GCTs are involuted by the epithelial deletion of core binding factor beta (CBFbeta), a transcription factor that physically interacts with any of the Runt-related transcription factor (RUNX) proteins (RUNX1, 2 and 3). This result clearly demonstrates that the Runx /Cbfb signaling pathway is indispensable in the development of the GCTs. However, it is not clear which of the RUNX proteins plays useful role in the development of the GCTs by activating the Runx /Cbfb signaling pathway. Past studies have revealed that the Runx /Cbfb signaling pathway plays important roles in various aspects of development and homeostatic events. Moreover, the Runx genes have different temporospatial requirements depending on the biological situation. In the present study, the GCTs of the SMG showed a remarkable phenotype of, which phenocopied the epithelial deletion of Cbfb, in epithelial specific Runx1 conditional knock-out (cKO) mice. The results indicate that Runx1 works as a partner of Cbfb during the development of the GCTs. We also discovered that the depletion of Runx1 resulted in the reduced secretion of saliva in male mice. Consistent with this finding, one of the water channels, Aquaporin-5 (AQP5) was mislocalized in the cytoplasm of the Runx1 mutants, suggesting a novel role of Runx1 in the membrane trafficking of AQP5. In summary, the present findings demonstrated that RUNX1 is essential for the development of the GCTs. Furthermore, RUNX1 could also be involved in the membrane trafficking of the AQP5 protein of the acinar cells in the SMG in order to allow for the proper secretion of saliva. PMID- 28877242 TI - Comparative quantitative proteomic analysis of disease stratified laser captured microdissected human islets identifies proteins and pathways potentially related to type 1 diabetes. AB - Type 1 diabetes (T1D) is a chronic inflammatory disease that is characterized by autoimmune destruction of insulin-producing pancreatic beta cells. The goal of this study was to identify novel protein signatures that distinguish Islets from patients with T1D, patients who are autoantibody positive without symptoms of diabetes, and from individuals with no evidence of disease. High resolution high mass accuracy label free quantitative mass spectrometry analysis was applied to islets isolated by laser capture microdissection from disease stratified human pancreata from the Network for Pancreatic Organ Donors with Diabetes (nPOD), these included donors without diabetes, donors with T1D-associated autoantibodies in the absence of diabetes, and donors with T1D. Thirty-nine proteins were found to be differentially regulated in autoantibody positive cases compared to the no disease group, with 25 upregulated and 14 downregulated proteins. For the T1D cases, 63 proteins were differentially expressed, with 24 upregulated and 39 downregulated, compared to the no disease controls. We have identified functional annotated enriched gene families and multiple protein-protein interaction clusters of proteins are involved in biological and molecular processes that may have a role in T1D. The proteins that are upregulated in T1D cases include S100A9, S100A8, REG1B, REG3A and C9 amongst others. These proteins have important biological functions, such as inflammation, metabolic regulation, and autoimmunity, all of which are pathways linked to the pathogenesis of T1D. The identified proteins may be involved in T1D development and pathogenesis. Our findings of novel proteins uniquely upregulated in T1D pancreas provides impetus for further investigations focusing on their expression profiles in beta cells/ islets to evaluate their role in the disease pathogenesis. Some of these molecules may be novel therapeutic targets T1D. PMID- 28877243 TI - Isolation and characterization of H4N6 avian influenza viruses from mallard ducks in Beijing, China. AB - The novel H7N9 influenza virus, which has caused severe disease in humans in China, is a reassortant with surface genes derived from influenza viruses in wild birds. This highlights the importance of monitoring influenza viruses in these hosts. However, surveillance of influenza virus in wild birds remains very limited in China. In this study, we isolated four H4N6 avian influenza viruses (AIVs) from mallard ducks in Beijing Wetland Park, which is located on the East Asia-Australasia migratory flyway. The gene segments of these Chinese H4N6 viruses were closest to AIVs in wild birds from Mongolia or the Republic of Georgia, indicating the interregional AIV gene flow among these countries. All of our isolates belonged to a novel genotype that was different from other H4N6 viruses isolated in China. We further evaluated the virulence and transmission of two representative H4N6 strains in mammalian models. We found that both of these H4N6 viruses replicated efficiently in mice without adaptation. Additionally, these two strains had a 100% transmission rate in guinea pigs via direct contact, but they had not acquired respiratory droplet transmissibility. These results reveal the potential threat to human health of H4N6 viruses in migratory birds and the need for enhanced surveillance of AIVs in wild birds. PMID- 28877244 TI - The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus. AB - We aimed at investigating whether the frequency and function of T helper 17 (Th17) and regulatory T cells (Treg) are affected by a restriction of dietary sodium intake in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We enrolled RA and SLE patients not receiving drugs known to increase urinary sodium excretion. Patients underwent a dietary regimen starting with a restricted daily sodium intake followed by a normal-sodium daily intake. The timepoints were identified at baseline (T0), after 3 weeks of low-sodium dietary regimen (T3), after 2 weeks of normal-sodium dietary regimen (T5). On these visits, we measured the 24-hour urinary sodium excretion, the frequency and function of Th17 and Treg cells in the peripheral blood, the serum levels of cytokines. Analysis of urinary sodium excretion confirmed adherence to the dietary regimen. In RA patients, a trend toward a reduction in the frequencies of Th17 cells over the low-sodium dietary regimen followed by an increase at T5 was observed, while Treg cells exhibited the opposite trend. SLE patients showed a progressive reduction in the percentage of Th17 cells that reached a significance at T5 compared to T0 (p = 0.01) and an increase in the percentage of Treg cells following the low-sodium dietary regimen at both T1 and T3 compared to T0 (p = 0.04 and p = 0.02, respectively). No significant apoptosis or proliferation modulation was found. In RA patients, we found a reduction at T5 compared to T0 in serum levels of both TGFbeta (p = 0.0016) and IL-9 (p = 0.0007); serum IL-9 levels were also reduced in SLE patients at T5 with respect to T0 (p = 0.03). This is the first study investigating the effects of dietary sodium intake on adaptive immunity. Based on the results, we hypothesize that a restricted sodium dietary intake may dampen the inflammatory response in RA and SLE patients. PMID- 28877245 TI - The effect of engaging unpaid informal providers on case detection and treatment initiation rates for TB and HIV in rural Malawi (Triage Plus): A cluster randomised health system intervention trial. AB - BACKGROUND: The poor face barriers in accessing services for tuberculosis (TB) and Human Immuno-deficiency Virus (HIV) disease. A cluster randomised trial was conducted to investigate the effectiveness of engaging unpaid informal providers (IPs) to promote access in a rural district. The intervention consisted of training unpaid IPs in TB and HIV disease recognition, sputum specimen collection, appropriate referrals, and raising community awareness. METHODS: In total, six clusters were defined in the study areas. Through a pair-matched cluster randomization process, three clusters (average cluster population = 200,714) were allocated to receive the intervention in the Early arm. Eleven months later the intervention was rolled out to the remaining three clusters (average cluster population = 209,564)-the Delayed arm. Treatment initiation rates for TB and Anti-Retroviral Therapy (ART) were the primary outcome measures. Secondary outcome measures included testing rates for TB and HIV. We report the results of the comparisons between the Early and Delayed arms over the 23 month trial period. Data were obtained from patient registers. Poisson regression models with robust standard errors were used to express the effectiveness of the intervention as incidence rate ratios (IRR). RESULTS: The Early and Delayed clusters were well matched in terms of baseline monthly mean counts and incidence rate ratios for TB and ART treatment initiation. However there were fewer testing and treatment initiation facilities in the Early clusters (TB treatment n = 2, TB testing n = 7, ART initiation n = 3, HIV testing n = 20) than in the Delayed clusters (TB treatment n = 4, TB testing n = 9, ART initiation n = 6, HIV testing n = 18). Overall there were more HIV testing and treatment centres than TB testing and treatment centres. The IRR was 1.18 (95% CI: 0.903-1.533; p = 0.112) for TB treatment initiation and 1.347 (CI:1.00-1.694; p = 0.049) for ART initiation in the first 12 months and the IRR were 0.552 (95% CI:0.397-0.767; p<0.001) and 0.924 (95% CI: 0.369-2.309, p = 0.863) for TB and ART treatment initiations respectively for the last 11 months. The IRR were 1.152 (95% CI:1.009 1.359, p = 0.003) and 1.61 (95% CI:1.385-1.869, p<0.001) for TB and HIV testing uptake respectively in the first 12 months. The IRR was 0.659 (95% CI:0.441 0.983; p = 0.023) for TB testing uptake for the last 11 months. CONCLUSIONS: We conclude that engagement of unpaid IPs increased TB and HIV testing rates and also increased ART initiation. However, for these providers to be effective in promoting TB treatment initiation, numbers of sites offering TB testing and treatment initiation in rural areas should be increased. TRIAL REGISTRATION: ClinicalTrials.gov NCT02127983. PMID- 28877246 TI - Prosthetic rehabilitation of oral submucous fibrosis patients: A systematic review of published case reports and case series. AB - BACKGROUND: Oral submucous fibrosis (OSF) is an insidious chronic condition characterized by restricted mouth opening. Prosthetic rehabilitation is challenging for OSF patients as obtaining a good impression requires adequate mouth opening. The aim of the present review is to systematically present the data from case reports published in the English-language literature. METHOD: A comprehensive search of the literature databases (PubMed, Medline, SCOPUS, Web of Science and Google Scholar) along with the references of published articles on prosthetic rehabilitation in OSF patients published to date was conducted. Keywords included a combination of 'Oral submucous fibrosis', 'prosthesis', 'dentures' and/or 'restricted mouth opening'. Citations from selected references and bibliographic linkages taken from similar cases were included in this review. The inclusion criteria selected for case reports on prosthetic rehabilitation in OSF patients, and cases of restricted mouth opening due to causes other than OSF were excluded from the study. RESULTS: A total of 21 cases were identified and analysed from 17 papers published in the English-language literature. Of these, 9 cases employed the sectional denture technique, 4 cases emphasized the need-based treatment approach in which conventional methods were modified, and 4 cases used mouth exercising devices. Finally, 1 case each involved, flexible denture, oral screen prosthesis, oral stents, surgery in conjunction with dentures. CONCLUSION: Prosthetic rehabilitation in OSF patients is a multifaceted approach and should be patient specific, although sectional dentures have achieved the best results. PMID- 28877247 TI - Correction: Evaluation of different mathematical models and different b-value ranges of diffusion-weighted imaging in peripheral zone prostate cancer detection using b-value up to 4500 s/mm2. AB - [This corrects the article DOI: 10.1371/journal.pone.0172127.]. PMID- 28877248 TI - Flying foxes create extensive seed shadows and enhance germination success of pioneer plant species in deforested Madagascan landscapes. AB - Seed dispersal plays a significant role in forest regeneration and maintenance. Flying foxes are often posited as effective long-distance seed dispersers due to their large home ranges and ability to disperse seeds when flying. We evaluate the importance of the Madagascan flying fox Pteropus rufus in the maintenance and regeneration of forests in one of the world's priority conservation areas. We tested germination success of over 20,000 seeds from the figs Ficus polita, F. grevei and F. lutea extracted from bat faeces and ripe fruits under progressively more natural conditions, ranging from petri-dishes to outdoor environments. Seeds from all fig species showed increased germination success after passing through the bats' digestive tracts. Outside, germination success in F. polita was highest in faecal seeds grown under semi-shaded conditions, and seeds that passed through bats showed increased seedling establishment success. We used data from feeding trials and GPS tracking to construct seed shadow maps to visualize seed dispersal patterns. The models use Gaussian probability density functions to predict the likelihood of defecation events occurring after feeding. In captivity, bats had short gut retention times (often < 30 mins), but were sometimes able to retain seeds for over 24h. In the wild, bats travelled 3-5 km within 24-280 min after feeding, when defecation of ingested seeds is very likely. They produced extensive seed shadows (11 bats potentially dispersing seeds over 58,000 ha over 45 total days of tracking) when feeding on figs within their large foraging areas and dispersed the seeds in habitats that were often partially shaded and hence would facilitate germination up to 20 km from the feeding tree. Because figs are important pioneer species, P. rufus is an important dispersal vector that makes a vital contribution to the regeneration and maintenance of highly fragmented forest patches in Madagascar. PMID- 28877249 TI - Silencing of interferon regulatory factor gene 6 in melanoma. AB - BACKGROUND: Methylation of a CpG island (CGI; a dense cluster of CpGs) located in the 5' region of a gene suppresses transcription of that gene. Interferon regulatory factor 6 (IRF6) is associated with the expression of interferon, which is used as an effective adjuvant therapy for melanoma, and is regarded as a tumor suppressor. However, little is known about the methylation status of the IRF6 gene in melanoma. OBJECTIVE: The purpose was to determine the methylation status of the CGI located in the 5' region of IRF6 (5' IRF6 CGI) in melanoma. METHODS: Quantitative real-time methylation-specific PCR (RT-MSP) and bisulfite sequencing were performed to examine IRF6 gene methylation status. Quantitative real-time reverse transcription-PCR (RT-PCR) was performed to examine IRF6 expression. RESULTS: The methylation level of the 5' IRF6 CGI was completely inversely correlated with cell sensitivity to interferon-beta in eight examined melanoma cell lines. These methylation levels were high in the melanoma cell lines with suppression of IRF6 expression and were low in the cell lines with IRF6 expression. The methylation levels of the 5' IRF6 CGI ranged widely from 0.0% to 65.4% in 21 clinical melanoma samples but showed a narrow range of low levels between 0.0% to 7.2% in 24 clinical melanocytic nevus samples. These methylation levels were not associated with clinical parameters except for melanoma subtypes. CONCLUSION: IRF6 is aberrantly silenced by DNA methylation of the 5' IRF6 CGI in melanoma. The methylation status of IRF6 is potentially associated with the sensitivity of melanoma to interferon. PMID- 28877250 TI - The hypermorph FtsA* protein has an in vivo role in relieving the Escherichia coli proto-ring block caused by excess ZapC. AB - Assembly of the proto-ring, formed by the essential FtsZ, FtsA and ZipA proteins, and its progression into a divisome, are essential events for Escherichia coli division. ZapC is a cytoplasmic protein that belongs to a group of non-essential components that assist FtsZ during proto-ring assembly. Any overproduction of these proteins leads to faulty FtsZ-rings, resulting in a cell division block. We show that ZapC overproduction can be counteracted by an excess of the ZipA independent hypermorph FtsA* mutant, but not by similar amounts of wild type FtsA+. An excess of FtsA+ allowed regular spacing of the ZapC-blocked FtsZ-rings, but failed to promote recruitment of the late-assembling proteins FtsQ, FtsK and FtsN and therefore, to activate constriction. In contrast, overproduction of FtsA*, besides allowing correct FtsZ-ring localization at midcell, restored the ability of FtsQ, FtsK and FtsN to be incorporated into active divisomes. PMID- 28877252 TI - The role of ADAM17 in the T-cell response against bacterial pathogens. AB - ADAM17 is a member of the A Disintegrin And Metalloproteinase family of proteases. It is ubiquitously expressed and causes the shedding of a broad spectrum of surface proteins such as adhesion molecules, cytokines and cytokine receptors. By controlled shedding of these proteins from leukocytes, ADAM17 is able to regulate immune responses. Several ADAM17 targets on T cells have been implicated in T-cell migration, differentiation and effector functions. However, the role of ADAM17 in T-cell responses is still unclear. To characterize the function of ADAM17 in T cells, we used Adam17fl/fl*CD4cre+ mice with a T-cell restricted inactivation of the Adam17 gene. Upon stimulation, ADAM17-deficient CD4+ and CD8+ T cells were impaired in shedding of CD62L, IL-6Ralpha, TNF-alpha, TNFRI and TNFRII. Surprisingly, we could not detect profound changes in the composition of major T-cell subsets in Adam17fl/fl*CD4cre+ mice. Following infection with Listeria monocytogenes, Adam17fl/fl*CD4cre+ mice mounted regular listeria-specific CD4+ TH1 and CD8+ T-cell responses and were able to control primary and secondary infections. In conclusion, our study indicates that ADAM17 is either not required in T cells under homoeostatic conditions and for control of listeria infection or can be effectively compensated by other mechanisms. PMID- 28877251 TI - Identification of a novel GJA3 mutation in a large Chinese family with congenital cataract using targeted exome sequencing. AB - Autosomal dominant congenital cataract (ADCC) is a clinically and genetically heterogeneous ocular disease in children that results in serious visual impairments or even blindness. Targeted exome sequencing (TES) is an efficient method used for genetic diagnoses of inherited diseases. In the present study, we used a custom-made TES panel to identify the genetic defect of a four-generation Chinese family with bilateral pulverulent nuclear cataracts. A novel heterozygous missense mutation c.443C>T (p. T148I) in GJA3 was identified. The results of the bioinformatic analysis showed that the mutation was deleterious to the structure and hemichannel function of Cx46 encoded by GJA3. Plasmids expressing wild-type and mutant human Cx46 were constructed and ectopically expressed in human lens epithelial cells (HLECs) or human embryonic kidney (HEK-293) cells. Fluorescent images indicated aggregated signals of mutant protein in the cytoplasm, and a higher protein level was also detected in T148I stable cell lines. In summary, we identified a novel mutation in GJA3 for ADCC, which provided molecular insights into the pathogenic mechanism of ADCC. PMID- 28877253 TI - Revising the lower statistical limit of x-ray grating-based phase-contrast computed tomography. AB - Phase-contrast x-ray computed tomography (PCCT) is currently investigated as an interesting extension of conventional CT, providing high soft-tissue contrast even if examining weakly absorbing specimen. Until now, the potential for dose reduction was thought to be limited compared to attenuation CT, since meaningful phase retrieval fails for scans with very low photon counts when using the conventional phase retrieval method via phase stepping. In this work, we examine the statistical behaviour of the reverse projection method, an alternative phase retrieval approach and compare the results to the conventional phase retrieval technique. We investigate the noise levels in the projections as well as the image quality and quantitative accuracy of the reconstructed tomographic volumes. The results of our study show that this method performs better in a low-dose scenario than the conventional phase retrieval approach, resulting in lower noise levels, enhanced image quality and more accurate quantitative values. Overall, we demonstrate that the lower statistical limit of the phase stepping procedure as proposed by recent literature does not apply to this alternative phase retrieval technique. However, further development is necessary to overcome experimental challenges posed by this method which would enable mainstream or even clinical application of PCCT. PMID- 28877254 TI - Prevalence, awareness, treatment and control of diabetes and impaired fasting glucose in the Southern Cone of Latin America. AB - AIMS: To determine the prevalence, treatment and control of diabetes mellitus (DM) and impaired fasting glucose (IFG) as well as associated factors in the adult population of four cities of the Southern Cone of Latin America (SCLA). METHODS: This is a cross-sectional population-based study that included 7407 adults between 35 and 74 years old in four cities of the SCLA: Temuco (Chile), Marcos Paz and Bariloche (Argentina), and Pando-Barros Blancos (Uruguay). DM was defined as fasting plasma glucose >=126 mg/dL or self-reported history of diabetes. Awareness, treatment, and control of DM were defined as subjects self reporting a DM previous diagnosis, the use of a prescription medication or nonpharmacological intervention for DM, and fasting plasma glucose <126 mg/dl, respectively. RESULTS: Prevalence of DM varied among cities, between 8.4% in Bariloche and 14.3% in Temuco. Prevalence of IFG varied at different sites, from 3.5% in Barros Blancos to 6.8% in Marcos Paz. Of the total number of people with diabetes, 20% were newly diagnosed at the time of the study. Overall, 79.8% of patients with diabetes were aware of their condition. The treatment and control rate were 58.8% and 46.2%, respectively. Older age, family history of diabetes, lower educational attainment, overweight, obesity, central obesity, low physical activity, hypertension, hypercholesterolemia and hypertriglyceridemia were all significantly associated with an increased risk of diabetes. CONCLUSIONS: The prevalence of DM and IFG in the adult population of the SCLA is high and varies among cities. These conditions represent a public health challenge since the rates of awareness, treatment, and control are still low. PMID- 28877255 TI - Characterization of the microDNA through the response to chemotherapeutics in lymphoblastoid cell lines. AB - Recently, a new class of extrachromosomal circular DNA, called microDNA, was identified. They are on average 100 to 400 bp long and are derived from unique non-repetitive genomic regions with high gene density. MicroDNAs are thought to arise from DNA breaks associated with RNA metabolism or replication slippage. Given the paucity of information on this entirely novel phenomenon, we aimed to get an additional insight into microDNA features by performing the microDNA analysis in 20 independent human lymphoblastoid cell lines (LCLs) prior and after treatment with chemotherapeutic drugs. The results showed non-random genesis of microDNA clusters from the active regions of the genome. The size periodicity of 190 bp was observed, which matches DNA fragmentation typical for apoptotic cells. The chemotherapeutic drug-induced apoptosis of LCLs increased both number and size of clusters further suggesting that part of microDNAs could result from the programmed cell death. Interestingly, proportion of identified microDNA sequences has common loci of origin when compared between cell line experiments. While compatible with the original observation that microDNAs originate from a normal physiological process, obtained results imply complementary source of its production. Furthermore, non-random genesis of microDNAs depicted by redundancy between samples makes these entities possible candidates for new biomarker generation. PMID- 28877256 TI - Medication and supplement use in older people with and without intellectual disability: An observational, cross-sectional study. AB - INTRODUCTION: Understanding the medication and supplement use of aging people is critical to ensuring that health service providers in primary care can optimise use of these agents. An increasing number of people with different levels of intellectual disability (ID) are living in the community and becoming for the first time substantial users of primary health care services. This, however, brings new challenges that need to be addressed at the primary health care level. We quantified the use of medicines and food supplements and described the associated patterns of morbidity in the two comparable cohorts of aging population with and without intellectual disability. METHOD: This research aligned participants of 50 years and over who lived in the community from two nationally representative cohorts of older people; those with ID from the Intellectual Disability Supplement (n = 238) and those without ID (n = 8,081) from the Irish Longitudinal Study on Ageing. RESULTS: Data showed that both medication and supplement use in the two groups was prevalent but that those with ID received more of both medications and supplements (e.g. polypharmacy was 39.0% in ID vs. 18.1% in non-ID cohort). Moreover, based on an analysis of the therapeutic groups and medications used that treatment was more intense in the ID cohort (95.8 vs. 7.0 International Non-proprietary Names per 100 participants). Supplement use was almost twice as prevalent in the ID group but substantially less diverse with only 10 types of supplements reported. Morbidity was higher in the ID group and showed a higher prevalence of neurological and mental health disorders. CONCLUSION: The results highlight that the burden of therapy management and the potential risks in those ageing with ID differs substantially from those ageing without ID. Understanding the medication and supplement use of people aging with intellectual disability (ID) is critical to ensuring that health service providers in primary/ambulatory care can optimise use of these agents. PMID- 28877258 TI - An empirical, hierarchical typology of tree species assemblages for assessing forest dynamics under global change scenarios. AB - The composition of tree species occurring in a forest is important and can be affected by global change drivers such as climate change. To inform assessment and projection of global change impacts at broad extents, we used hierarchical cluster analysis and over 120,000 recent forest inventory plots to empirically define forest tree assemblages across the U.S., and identified the indicator and dominant species associated with each. Cluster typologies in two levels of a hierarchy of forest assemblages, with 29 and 147 groups respectively, were supported by diagnostic criteria. Groups in these two levels of the hierarchy were labeled based on the top indicator species in each, and ranged widely in size. For example, in the 29-cluster typology, the sugar maple-red maple assemblage contained the largest number of plots (30,068), while the butternut sweet birch and sourwood-scarlet oak assemblages were both smallest (6 plots each). We provide a case-study demonstration of the utility of the typology for informing forest climate change impact assessment. For five assemblages in the 29 cluster typology, we used existing projections of changes in importance value (IV) for the dominant species under one low and one high climate change scenario to assess impacts to the assemblages. Results ranged widely for each scenario by the end of the century, with each showing an average decrease in IV for dominant species in some assemblages, including the balsam fir-quaking aspen assemblage, and an average increase for others, like the green ash-American elm assemblage. Future work should assess adaptive capacity of these forest assemblages and investigate local population- and community-level dynamics in places where dominant species may be impacted. This typology will be ideal for monitoring, assessing, and projecting changes to forest communities within the emerging framework of macrosystems ecology, which emphasizes hierarchies and broad extents. PMID- 28877260 TI - Correction: Measuring three aspects of motivation among health workers at primary level health facilities in rural Tanzania. AB - [This corrects the article DOI: 10.1371/journal.pone.0176973.]. PMID- 28877257 TI - Rosmarinic acid potentiates carnosic acid induced apoptosis in lung fibroblasts. AB - Pulmonary fibrosis is characterized by over-population and excessive activation of fibroblasts and myofibroblasts disrupting normal lung structure and functioning. Rosemary extract rich in carnosic acid (CA) and rosmarinic acid (RA) was reported to cure bleomycin-(BLM)-induced pulmonary fibrosis. We demonstrate that CA decreased human lung fibroblast (HLF) viability with IC50 value of 17.13+/-1.06 MUM, while RA had no cytotoxic effect. In the presence of 50 MUM of RA, dose-response for CA shifted to IC50 value of 11.70+/-1.46 MUM, indicating synergic action. TGFbeta-transformed HLF, rat lung fibroblasts and L929 cells presented similar sensitivity to CA and CA+RA (20MUM+100MUM, respectively) treatment. Rat alveolar epithelial cells died only under CA+RA treatment, while A549 cells were not affected. Annexin V staining and DNA quantification suggested that HLF are arrested in G0/G1 cell cycle phase and undergo apoptosis. CA caused sustained activation of phospho-Akt and phospho-p38 expression and inhibition of p21 protein.Addition of RA potentiated these effects, while RA added alone had no action.Only triple combination of inhibitors (MAPK-p38, pan-caspase, PI3K/Akt/autophagy) partially attenuated apoptosis; this suggests that cytotoxicity of CA+RA treatment has a complex mechanism involving several parallel signaling pathways. The in vivo antifibrotic effect of CA and RA was compared with that of Vitamine-E in BLM-induced fibrosis model in rats. We found comparable reduction in fibrosis score by CA, RA and CA+RA, attenuation of collagen deposition and normalization of oxidative stress markers. In conclusion, antifibrotic effect of CA+RA is due to synergistic pro-apoptotic action on lung fibroblasts and myofibroblasts. PMID- 28877259 TI - Dominance behaviour in a non-aggressive flatfish, Senegalese sole (Solea senegalensis) and brain mRNA abundance of selected transcripts. AB - Dominance is defined as the preferential access to limited resources. The present study aimed to characterise dominance in a non-aggressive flatfish species, the Senegalese sole (Solea senegalensis) by 1) identifying dominance categories and associated behaviours and 2) linking dominance categories (dominant and subordinate) with the abundance of selected mRNA transcripts in the brain. Early juveniles (n = 74, 37 pairs) were subjected to a dyadic dominance test, related to feeding, and once behavioural phenotypes had been described the abundance of ten selected mRNAs related to dominance and aggressiveness was measured in the brain. Late juveniles were subjected to two dyadic dominance tests (n = 34, 17 pairs), related to feeding and territoriality and one group test (n = 24, 4 groups of 6 fish). Sole feeding first were categorized as dominant and sole feeding second or not feeding as subordinate. Three social behaviours (i. "Resting the head" on another fish, ii. "Approaching" another fish, iii. "Swimming above another" fish) were associated with dominance of feeding. Two other variables (i. Total time occupying the preferred area during the last 2 hours of the 24 h test, ii. Organisms occupying the preferred area when the test ended) were representative of dominance in the place preference test. In all tests, dominant fish compared to subordinate fish displayed a significantly higher number of the behaviours "Rest the head" and "Approaches". Moreover, dominant sole dominated the sand at the end of the test, and in the group test dominated the area close to the feed delivery point before feed was delivered. The mRNA abundance of the selected mRNAs related to neurogenesis (nrd2) and neuroplasticity (c-fos) in dominant sole compared to subordinate were significantly different. This is the first study to characterise dominance categories with associated behaviours and mRNA abundance in Senegalese sole and provides tools to study dominance related problems in feeding and reproduction in aquaculture. PMID- 28877261 TI - Myelodysplastic syndrome patients present more severe respiratory muscle impairment and reduced forced vital capacity: Is disordered inflammatory signaling the culprit? AB - BACKGROUND/OBJECTIVES: The ageing process is associated with gradual decline in respiratory system performance. Anemia is highly prevalent among older adults and usually associated with adverse outcomes. Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies with increasing incidence with age and characterized by anemia and other cytopenias. The main objectives of this study were to evaluate respiratory muscle strength and lung function in elderly patients with anemia, compare data between myelodysplastic syndromes and non clonal anemias and evaluate the influence of serum IL-8 level and NF-kB activity on deteriorate pulmonary function in this specific population. PARTICIPANTS: Individuals aged 60 and older with anemia secondary to MDS, non-clonal anemia and healthy elderly individuals. MEASUREMENTS: Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/ FVC ratio were measured by spirometry. Respiratory muscle strength was evaluated by maximal static respiratory pressures measurement. IL-8 analysis was performed by ELISA and activity of NF-kB by chemiluminescent assay. RESULTS: Mean Hb concentration was comparable between patients with anemia. Significant differences were detected between all patients with anemia and controls for maximum-effort inspiratory mouth pressure (PImax) and also for maximum-effort expiratory mouth pressure (PEmax). The MDS group recorded a significantly lower PImax and PEmax percent predicted when compared to non-clonal anemia group. For FVC and FEV1, a significant difference was found in anemic patients, with even significantly lower values for FVC and FEV1 in MDS group. No significant differences were detected for PImax and PEmax and spirometry parameters when anemic patients were stratified according to the degree of anemia. A significant negative impact in FVC (% pred), PImax (% pred) and PEmax (% pred) was observed in patients with MDS and higher levels of IL-8 or increased activity of NF-kB. CONCLUSION: A negative impact of anemia, independent of its degree, was demonstrated in respiratory muscle strength and lung function particularly in MDS. The well known elevated proinflammatory cytokines in MDS patients were proposed to play a role as was demonstrated by detrimental effect of higher IL-8 and NF-kB in pulmonary function tests in this population. PMID- 28877262 TI - The ER retention protein RER1 promotes alpha-synuclein degradation via the proteasome. AB - Abnormal accumulation of alpha-synuclein (alphaSyn) has been linked to endoplasmic-reticulum (ER) stress, defective intracellular protein/vesicle trafficking, and cytotoxicity. Targeting factors involved in ER-related protein processing and trafficking may, therefore, be a key to modulating alphaSyn levels and associated toxicity. Recently retention in endoplasmic reticulum 1 (RER1) has been identified as an important ER retrieval/retention factor for Alzheimer's disease proteins and negatively regulates amyloid-beta peptide levels. Here, we hypothesized that RER1 might also play an important role in retention/retrieval of alphaSyn and mediate levels. We expressed RER1 and a C-terminal mutant RER1Delta25, which lacks the ER retention/retrieval function, in HEK293 and H4 neuroglioma cells. RER1 overexpression significantly decreased levels of both wild type and A30P, A53T, and E46K disease causal mutants of alphaSyn, whereas the RER1Delta25 mutant had a significantly attenuated effect on alphaSyn. RER1 effects were specific to alphaSyn and had little to no effect on either betaSyn or the Delta71-82 alphaSyn mutant, which both lack the NAC domain sequence critical for synuclein fibrillization. Tests with proteasomal and macroautophagy inhibitors further demonstrate that RER1 effects on alphaSyn are primarily mediated through the ubiquitin-proteasome system. RER1 also appears to interact with the ubiquitin ligase NEDD4. RER1 in human diseased brain tissues co localizes with alphaSyn-positive Lewy bodies. Together, these findings provide evidence that RER1 is a novel and potential important mediator of elevated alphaSyn levels. Further investigation of the mechanism of RER1 and downstream effectors on alphaSyn may yield novel therapeutic targets for modulation in Parkinson disease and related synucleinopathies. PMID- 28877263 TI - The transcriptional landscape of Rhizoctonia solani AG1-IA during infection of soybean as defined by RNA-seq. AB - Rhizoctonia solani Kuhn infects most plant families and can cause significant agricultural yield losses worldwide; however, plant resistance to this disease is rare and short-lived, and therefore poorly understood, resulting in the use of chemical pesticides for its control. Understanding the functional responses of this pathogen during host infection can help elucidate the molecular mechanisms that are necessary for successful host invasion. Using the pathosystem model soybean-R. solani anastomosis group AG1-IA, we examined the global transcriptional responses of R. solani during early and late infection stages of soybean by applying an RNA-seq approach. Approximately, 148 million clean paired end reads, representing 93% of R. solani AG1-IA genes, were obtained from the sequenced libraries. Analysis of R. solani AG1-IA transcripts during soybean invasion revealed that most genes were similarly expressed during early and late infection stages, and only 11% and 15% of the expressed genes were differentially expressed during early and late infection stages, respectively. Analyses of the differentially expressed genes (DEGs) revealed shifts in molecular pathways involved in antibiotics biosynthesis, amino acid and carbohydrate metabolism, as well as pathways involved in antioxidant production. Furthermore, several KEGG pathways were unique to each time point, particularly the up-regulation of genes related to toxin degradation (e.g., nicotinate and nicotinamid metabolism) at onset of necrosis, and those linked to synthesis of anti-microbial compounds and pyridoxine (vitamin B6) biosynthesis 24 h.p.o. of necrosis. These results suggest that particular genes or pathways are required for either invasion or disease development. Overall, this study provides the first insights into R. solani AG1 IA transcriptome responses to soybean invasion providing beneficial information for future targeted control methods of this successful pathogen. PMID- 28877264 TI - Typhoon survivors' subjective wellbeing-A different view of responses to natural disaster. AB - OBJECTIVE: Subjective well-being was evaluated three weeks after Super Typhoon Haiyan struck the Philippines. Based on the Conservation of Resources theory, which focuses on the role of resources in understanding adjustment following trauma, data was collected on lost resources. In line with the Conservation of Resources theory, four categories of resources were defined: objects-residential property; condition-gender health state and witness to injury; personal-coping strategies; energy-relationships. DESIGN AND SETTINGS: Eight hundred thirty-four people from the Philippines filled out self-report measures using an online interview system regarding: socio demographics data, subjective well-being, using the Delighted Terrible Faces Scale (DTS), disaster related experiences, coping strategies, personal relationships, obtained through support sources (close family, relatives and friends, community) and assessing problems with those relationships after Haiyan. RESULTS: Subjective well-being was predicted by the following classes of resources: objects (home damage) condition (self-rated health and witness to injury), personal (positive reframing and self-blame coping strategies) and energy resources (relations and problems in relations). CONCLUSIONS: The results imply the important role individual's resources (i.e. objects, personal characteristics, conditions, and energies) might play in promoting subjective well-being, following natural disaster. PMID- 28877265 TI - Niclosamide induces protein ubiquitination and inhibits multiple pro-survival signaling pathways in the human glioblastoma U-87 MG cell line. AB - Glioblastoma is the most common and lethal malignant primary brain tumor for which the development of efficacious chemotherapeutic agents remains an urgent need. The anti-helminthic drug niclosamide, which has long been in use to treat tapeworm infections, has recently attracted renewed interest due to its apparent anticancer effects in a variety of in vitro and in vivo cancer models. However, the mechanism(s) of action remains to be elucidated. In the present study, we found that niclosamide induced cell toxicity in human glioblastoma cells corresponding with increased protein ubiquitination, ER stress and autophagy. In addition, niclosamide treatment led to down-regulation of Wnt/beta-catenin, PI3K/AKT, MAPK/ERK, and STAT3 pro-survival signal transduction pathways to further reduce U-87 MG cell viability. Taken together, these results provide new insights into the glioblastoma suppressive capabilities of niclosamide, showing that niclosamide can target multiple major cell signaling pathways simultaneously to effectively promote cell death in U-87 MG cells. Niclosamide constitutes a new prospect for a therapeutic treatment against human glioblastoma. PMID- 28877266 TI - Feasibility of using a hand-held device to characterize tendon tissue biomechanics. AB - OBJECTIVES: To examine the feasibility of using the MyotonPRO digital palpation device in measuring the transverse stiffness of tendon tissue. DESIGN: Experimental study. METHODS: The MyotonPRO was used to measure the stiffness and related properties of ballistics gel in comparison with an external materials testing system (PCB electronics). The device was then used to measure the same properties of avian Achilles tendons before and after the removal of the overlying skin and subcutaneous tissue. Next, the test-retest reliability of the Achilles and patellar tendons was determined in humans. Finally, the stiffness of the Achilles tendon was measured before and after competitive running races of varying distances (10, 21 and 42 km, total number of athletes analyzed = 66). RESULTS: The MyotonPRO demonstrated a high degree of consistency when testing ballistics gel with known viscoelastic properties. The presence of skin overlying the avian Achilles tendon had a statistically significant impact on stiffness (p<0.01) although this impact was of very small absolute magnitude (with skin; 728 Nm +/-17 Nm, without skin; Nm 704 Nm +/-7 Nm). In healthy adults of normal body mass index (BMI), the reliability of stiffness values was excellent both for the patellar tendon (ICC, 0.96) and the Achilles tendon (ICC,0.96). In the the field study, men had stiffer tendons than women (p<0.05), and the stiffness of the Achilles tendon tended to increase following running (p = 0.052). CONCLUSIONS: The MyotonPRO can reliably determine the transverse mechanical properties of tendon tissue. The measured values are influenced by the presence of overlying skin, however this does not appear to compromise the ability of the device to record physiologically and clinically relevant measurements. PMID- 28877267 TI - A system dynamics approach to understanding the One Health concept. AB - There have been many terms used to describe the One Health concept, including movement, strategy, framework, agenda, approach, among others. However, the inter relationships of the disciplines engaged in the One Health concept have not been well described. To identify and better elucidate the internal feedback mechanisms of One Health, we employed a system dynamics approach. First, a systematic literature review was conducted via searches in PubMed, Web of Knowledge, and ProQuest with the search terms: 'One Health' and (concept* or approach*). In addition, we used the HistCite(r) tool to add significant articles on One Health to the library. Then, of the 2368 articles identified, 19 were selected for evaluating the inter-relationships of disciplines engaged in One Health. Herein, we report a visually rich, theoretical model regarding interactions of various disciplines and complex problem descriptors engaged in One Health problem solving. This report provides a conceptual framework for future descriptions of the interdisciplinary engagements involved in One Health. PMID- 28877268 TI - Combining PET/CT with serum tumor markers to improve the evaluation of histological type of suspicious lung cancers. AB - OBJECTIVE: Histological type is important for determining the management of patients with suspicious lung cancers. In this study, PET/CT combined with serum tumor markers were used to evaluate the histological type of lung lesions. MATERIALS AND METHODS: Patients with suspicious lung cancers underwent 18F-FDG PET/CT and serum tumor markers detection. SUVmax of the tumor and serum levels of tumor markers were acquired. Differences in SUVmax and serum levels of tumor markers among different histological types of lung cancers and between EGFR mutation statues of adenocarcinoma were compared. The diagnostic efficiencies of SUVmax alone, each serum tumor marker alone, combined tumor markers and the combination of both methods were further assessed and compared. RESULTS: SCC had the highest level of SUVmax, followed by SCLC and adenocarcinoma, and benign lesions had a lowest level. CYFRA21-1 and SCC-Ag were significantly higher in SCC, NSE was significantly higher in SCLC (P<0.001), and CEA was higher in adenocarcinoma (P = 0.343). The diagnostic efficiencies in evaluating histological types of suspicious lung cancers were insufficient when using each serum tumor marker or SUVmax alone. When combined, the AUC, sensitivity and specificity increased significantly (P<0.05 for all). Additionally, to adenocarcinoma, no significant difference was found between EGFR mutation statuses in SUVmax or serum tumor markers (P>0.05 for all). CONCLUSIONS: SUVmax and serum tumor markers show values in evaluating the histological types of suspicious lung cancers. When properly combined, the diagnostic efficiency can increase significantly. PMID- 28877269 TI - Pf16 and phiPMW: Expanding the realm of Pseudomonas putida bacteriophages. AB - We present the analysis of two novel Pseudomonas putida phages, pf16 and phiPMW. Pf16 represents a peripherally related T4-like phage, and is the first of its kind infecting a Pseudomonad, with evidence suggesting cyanophage origins. Extensive divergence has resulted in pf16 occupying a newly defined clade designated as the pf16-related phages, lying at the interface of the Schizo T Evens and Exo T-Evens. Recombination with an ancestor of the P. putida phage AF is likely responsible for the tropism of this phage. phiPMW represents a completely novel Pseudomonas phage with a genome containing substantial genetic novelty through its many hypothetical proteins. Evidence suggests that this phage has been extensively shaped through gene transfer events and vertical evolution. Phylogenetics shows that this phage has an evolutionary history involving FelixO1 related viruses but is in itself highly distinct from this group. PMID- 28877270 TI - Management of pancreatic pseudocysts-A retrospective analysis. AB - BACKGROUND: Pancreatic pseudocysts arise mostly in patients with alcohol induced chronic pancreatitis causing various symptoms and complications. However, data on the optimal management are rare. To address this problem, we analysed patients with pancreatic pseudocysts treated at our clinic retrospectively. METHODS: We searched our clinical database for the diagnosis pancreatitis from 2004 till 2014, selected patients with pseudocysts larger than 10 mm and entered all relevant information in a database for statistical analysis. RESULTS: In total, 129 patients with pancreatic pseudocysts were treated at our institution during the study period. Most patients suffered from alcohol induced chronic pancreatitis (43.4%; 56/129). Pseudocysts were more frequent in female than in male (2:1) and were mainly located in the pancreatic head (47.3%; 61/129). Local complications like obstructive jaundice were associated with the diameter of the cysts (AUC 0.697 in ROC-curve analysis). However, even cysts up to a diameter of 160 mm can regress spontaneously. Besides a lower re-intervention rate in surgically treated patients, endoscopic, percutaneous and surgical drainage are equally effective. Most treatment related complications occur in large pseudocysts located in the pancreatic head. CONCLUSION: Conservative management of large pseudocysts is successful in many patients. Therefore, indication for treatment should be made carefully considering the presence and risk of local complications. Endoscopic and surgical drainage are equally effective. PMID- 28877272 TI - New impact of the Journal of Applied Oral Science. PMID- 28877271 TI - Spinal cord homogenates from SOD1 familial amyotrophic lateral sclerosis induce SOD1 aggregation in living cells. AB - Mutant Cu/Zn superoxide dismutase (SOD1) can confer its misfolding on wild-type SOD1 in living cells; the propagation of misfolding can also be transmitted between cells in vitro. Recent studies identified fluorescently-tagged SOD1G85R as a promiscuous substrate that is highly prone to aggregate by a variety of templates, in vitro and in vivo. Here, we utilized several SOD1-GFP reporter proteins with G37R, G85R, or G93A mutations in SOD1. We observed that human spinal cord homogenates prepared from SOD1 familial ALS (FALS) can induce significantly more intracellular reporter protein aggregation than spinal cord homogenates from sporadic ALS, Alzheimer's disease, multiple system atrophy or healthy control individuals. We also determined that the induction of reporter protein aggregation by SOD1-FALS tissue homogenates can be attenuated by incubating the cells with the SOD1 misfolding-specific antibody 3H1, or the small molecule 5-fluorouridine. Our study further implicates SOD1 as the seeding particle responsible for the spread of SOD1-FALS neurodegeneration from its initial onset site(s), and demonstrates two potential therapeutic strategies for SOD1-mediated disease. This work also comprises a medium-throughput cell-based platform of screening potential therapeutics to attenuate propagated aggregation of SOD1. PMID- 28877274 TI - The effect of silver nanoparticles on composite shear bond strength to dentin with different adhesion protocols. AB - Objective: The purpose of this study was to investigate the effect of silver nanoparticles on composite shear bond strength using one etch and rinse and one self-etch adhesive systems. Material and Methods: Silver nanoparticles were prepared. Transmission electron microscope and X-ray diffraction were used to characterize the structure of the particles. Nanoparticles were applied on exposed dentin and then different adhesives and composites were applied. All samples were tested by universal testing machine and shear bond strength was assesed. Results: Particles with average diameter of about 20 nm and spherical shape were found. Moreover, it was shown that pretreatment by silver nanoparticles enhanced shear bond strength in both etch and rinse, and in self etch adhesive systems (p<=0.05). Conclusions: Considering the positive antibacterial effects of silver nanoparticles, using them is recommended in restorative dentistry. It seems that silver nanoparticles could have positive effects on bond strength of both etch-and-rinse and self-etch adhesive systems. The best results of silver nanoparticles have been achieved with Adper Single Bond and before acid etching. PMID- 28877273 TI - Virtual Reality simulator for dental anesthesia training in the inferior alveolar nerve block. AB - Objectives: This study shows the development and validation of a dental anesthesia-training simulator, specifically for the inferior alveolar nerve block (IANB). The system developed provides the tactile sensation of inserting a real needle in a human patient, using Virtual Reality (VR) techniques and a haptic device that can provide a perceived force feedback in the needle insertion task during the anesthesia procedure. Material and Methods: To simulate a realistic anesthesia procedure, a Carpule syringe was coupled to a haptic device. The Volere method was used to elicit requirements from users in the Dentistry area; Repeated Measures Two-Way ANOVA (Analysis of Variance), Tukey post-hoc test and averages for the results' analysis. A questionnaire-based subjective evaluation method was applied to collect information about the simulator, and 26 people participated in the experiments (12 beginners, 12 at intermediate level, and 2 experts). The questionnaire included profile, preferences (number of viewpoints, texture of the objects, and haptic device handler), as well as visual (appearance, scale, and position of objects) and haptic aspects (motion space, tactile sensation, and motion reproduction). Results: The visual aspect was considered appropriate and the haptic feedback must be improved, which the users can do by calibrating the virtual tissues' resistance. The evaluation of visual aspects was influenced by the participants' experience, according to ANOVA test (F=15.6, p=0.0002, with p<0.01). The user preferences were the simulator with two viewpoints, objects with texture based on images and the device with a syringe coupled to it. Conclusion: The simulation was considered thoroughly satisfactory for the anesthesia training, considering the needle insertion task, which includes the correct insertion point and depth, as well as the perception of tissues resistances during the insertion. PMID- 28877276 TI - Does laser diode irradiation improve the degree of conversion of simplified dentin bonding systems? AB - Objective: This study aimed to investigate the effect of laser diode irradiation on the degree of conversion (DC), water sorption (WS), and water solubility (WSB) of these bonding systems in an attempt to improve their physico-mechanical resistance. Material and Methods: Two bonding agents were tested: a two-step total-etch system [AdperTM Single Bond 2, 3M ESPE (SB)] and a universal system [AdperTM Single Bond Universal, 3M ESPE (SU)]. Square-shaped specimens were prepared and assigned into 4 groups (n=5): SB and SU (control groups - no laser irradiation) and SB-L and SU-L [SB and SU laser (L) - irradiated groups]. DC was assessed using Fourier transform infrared spectroscopy with attenuated total reflectance. Additional uncured resin samples (~3.0 uL, n=5) of each adhesive were also scanned for final DC calculation. For WS/WSB tests, similar specimens (n=10) were prepared and measured by monitoring the mass changes after dehydration/water storage cycles. For both tests, adhesive fluids were dropped into standardized Teflon molds (6.0*6.0*1.0 mm), irradiated with a 970-nm laser diode, and then polymerized with an LED-curing unit (1 W/cm2). Results: Laser irradiation immediately before photopolymerization increased the DC (%) of the tested adhesives: SB-L>SB>SU-L>SU. For WS/WSB (MUg/mm3), only the dentin bonding system (DBS) was a significant factor (p<0.05): SB>SU. Conclusion: Irradiation with a laser diode improved the degree of conversion of all tested simplified dentin bonding systems, with no impact on water sorption and solubility. PMID- 28877275 TI - Evaluation of physicochemical properties of root-end filling materials using conventional and Micro-CT tests. AB - Objective: To evaluate solubility, dimensional stability, filling ability and volumetric change of root-end filling materials using conventional tests and new Micro-CT-based methods. Material and Methods: 7. Results: The results suggested correlated or complementary data between the proposed tests. At 7 days, BIO showed higher solubility and at 30 days, showed higher volumetric change in comparison with MTA (p<0.05). With regard to volumetric change, the tested materials were similar (p>0.05) at 7 days. At 30 days, they presented similar solubility. BIO and MTA showed higher dimensional stability than ZOE (p<0.05). ZOE and BIO showed higher filling ability (p<0.05). Conclusions: ZOE presented a higher dimensional change, and BIO had greater solubility after 7 days. BIO presented filling ability and dimensional stability, but greater volumetric change than MTA after 30 days. Micro-CT can provide important data on the physicochemical properties of materials complementing conventional tests. PMID- 28877277 TI - Treatment of experimental periodontal disease by laser therapy in simvastatin modified rats. AB - Objective: The aim of this study was to evaluate low-level laser therapy (LLLT) as an adjuvant treatment for scaling and root planing (SRP) for the treatment of induced periodontitis in simvastatin-modified rats. Material and Methods: A total of 180 rats were evenly divided into two groups: Veh - receiving oral administration of polyethylene glycol (vehicle); S - receiving oral administration of Simvastatin. Periodontal disease was induced in both groups at the first mandibular molar. After seven days, the ligature was removed and the animals were divided into subgroups according to the following local treatments: NT - no treatment; SRP - scaling and root planing and irrigation with saline solution; and LLLT !- SRP and laser irradiation (660 nm; 0.03 W; 4 J). Ten animals in each subgroup/local treatment were euthanized at 7, 15 and 30 days. Samples of gingival tissue were processed to analyze the tissue oxidative damage and radiographic analysis. Levels of oxidative stress were analyzed by the expressions of Tripeptideglutathione (TG), Malondialdehyde (MDA) and Carbonylated Proteins (CP). Results: The animals in S group had higher levels of TG and lower levels of MDA and CP compared with Veh group (p<0.05). Radiographically, in the intragroup analysis Veh and S, LLLT showed lower bone loss (BL) compared with NT and SRP, in all experimental periods (p<0.01). In addition, a lower BL was observed for the animals of Veh group treated with LLLT compared with treatment SRP in the S group, in all experimental periods. Conclusion: Within the limits of this study, we can conclude that LLLT was effective as adjuvant treatment for SRP protecting against the occurrence of oxidative tissue damages as well as for reducing alveolar bone loss in experimentally induced periodontitis simvastatin modified rats. PMID- 28877278 TI - Effect of photodynamic therapy and non-thermal plasma on root canal filling: analysis of adhesion and sealer penetration. AB - Objective: The aim of this study was to evaluate the effect of photodynamic therapy (PDT) and non-thermal plasma (NTP) on adhesion and sealer penetration in root canals. Material and Methods: Sixty single-rooted premolars were used. The teeth were prepared using a crown-down technique. NaOCl and EDTA were used for irrigation and smear layer removal, respectively. The root canals were divided into three groups: control, PDT, and NTP. After treatments, the roots were filled using gutta-percha and either AH Plus (AHP) or MTA Fillapex (MTAF) sealers. Samples were sectioned at 4, 8, and 12 mm from the apex (1-mm slices)and analyzed by the push-out bond strength test (adhesion) and confocal laser scanning microscopy (sealer penetration). Data were statistically evaluated using Kruskal Wallis, Dunn's, and Spearman's tests. Results: Regarding AHP, bond strength was similar in the NTP group and in the control group, but significantly lower in the PDT group. As to MTAF, both therapies showed lower values than the control group. In the confocal analysis of AHP, maximum and mean penetration, and penetrated area were statistically higher in the control group than in the PDT and NTP groups. Penetrated perimeter was similar among groups. Regarding MTAF, all parameters yielded better results in the NTP than in the control group. The PDT and control groups showed similar results except for penetrated area. Conclusion: PDT and plasma therapy affected the adhesion and sealer penetration of root canals filled with AH Plus and MTA Fillapex and there is no positive correlation between adhesion and sealer penetration. PMID- 28877280 TI - Mechanical properties, water sorption characteristics, and compound release of grape seed extract-incorporated resins. AB - Objective: This study evaluated the effect of grape seed extract (GSE) incorporation on the mechanical properties, water sorption, solubility, and GSE release from the experimental adhesive resins. Material and Methods: An experimental comonomer mixture, consisting of 40% Bis-GMA, 30% Bis MP, 28% HEMA, 0.26% camphorquinone and 1% EDMAB, was used to prepare four GSE-incorporated adhesive resins at concentrations of 0.5, 1, 1.5, and 2 wt%. The neat resin without GSE was used as the control. Six resin beams (25 mm x 2 mm x 2 mm) per group were prepared for flexural strength and modulus of elasticity evaluations using a universal testing machine at a crosshead speed of 1 mm/min. Five disks (6 mm in diameter and 2 mm in thickness) per group were used for microhardness measurements using a Leitz micro-hardness tester with Leica Qgo software. Five disks (7 mm in diameter and 2 mm in thickness) per group were prepared and stored in deionized water for 28 days. Water sorption, solubility, and GSE release in deionized water were calculated for each GSE-incorporated adhesive at the end of 28th day. Data was evaluated using one-way ANOVA and Tukey multiple comparisons. Results: Flexural strength, modulus of elasticity and microhardness of GSE incorporated adhesive decreased significantly with incorporation of 1.5% of GSE (p<0.05). Addition of GSE had no effect on the water sorption of the adhesive resins (p=0.33). The solubility of the resin also increased significantly with incorporation of 1.5% of GSE (p<0.05). Quantities of GSE release increased with increased concentration of GSE in the adhesive resin. Conclusion: Up to 1% of GSE can be incorporated into a dental adhesive resin without interfering with the mechanical properties or solubility of the resins. PMID- 28877279 TI - Development of a self-report questionnaire designed for population-based surveillance of gingivitis in adolescents: assessment of content validity and reliability. AB - Objective: This study aimed to develop and assess the content validity and reliability of a cognitively adapted self-report questionnaire designed for surveillance of gingivitis in adolescents. Material and Methods: Ten predetermined self-report questions evaluating early signs and symptoms of gingivitis were preliminary assessed by a panel of clinical experts. Eight questions were selected and cognitively tested in 20 adolescents aged 12 to 18 years from Santiago de Chile. The questionnaire was then conducted and answered by 178 Chilean adolescents. Internal consistency was measured using the Cronbach's alpha and temporal stability was calculated using the Kappa-index. Results: A reliable final self-report questionnaire consisting of 5 questions was obtained, with a total Cronbach's alpha of 0.73 and a Kappa-index ranging from 0.41 to 0.77 between the different questions. Conclusions: The proposed questionnaire is reliable, with an acceptable internal consistency and a temporal stability from moderate to substantial, and it is promising for estimating the prevalence of gingivitis in adolescents. PMID- 28877281 TI - Effect of vegetable oils applied over acquired enamel pellicle on initial erosion. AB - Objective: The prevalence of dental erosion has been recently increasing, requiring new preventive and therapeutic approaches. Vegetable oils have been studied in preventive dentistry because they come from a natural, edible, low cost, and worldwide accessible source. This study aimed to evaluate the protective effect of different vegetable oils, applied in two concentrations, on initial enamel erosion. Material and Methods: Initially, the acquired pellicle was formed in situ for 2 hours. Subsequently, the enamel blocks were treated in vitro according to the study group (n=12/per group): GP5 and GP100 - 5% and pure palm oil, respectively; GC5 and GC100 - 5% and pure coconut oil; GSa5 and GSa100 5% and pure safflower oil; GSu5 and GSu100 - 5% and pure sunflower oil; GO5 and GO100 - 5% and pure olive oil; CON- - Deionized Water (negative control) and CON+ - Commercial Mouthwash (Elmex(r) Erosion Protection Dental Rinse, GABA/positive control). Then, the enamel blocks were immersed in artificial saliva for 2 minutes and subjected to short-term acid exposure in 0.5% citric acid, pH 2.4, for 30 seconds, to promote enamel surface softening. The response variable was the percentage of surface hardness loss [((SHi - SHf) / SHf )*100]. Data were analyzed by one-way ANOVA and Tukey's test (p<0.05). Results: Enamel blocks of GP100 presented similar hardness loss to GSu100 (p>0.05) and less than the other groups (p<0.05). There was no difference between GP5, GC5, GC100, GSa5, GSu100, GSa100, GSu5, GO5, GO100, CON- and CON+. Conclusion: Palm oil seems to be a promising alternative for preventing enamel erosion. However, further studies are necessary to evaluate a long-term erosive cycling. PMID- 28877282 TI - Two-point discrimination values vary depending on test site, sex and test modality in the orofacial region: a preliminary study. AB - Objective: The aims of the present study were to determine the normal values of TPD in the six trigeminal sites (the forehead, cheek, mentum, upper lip, lower lip, and the tongue tip) and to investigate the effect of the site, sex, and test modality on the TPD perception. Material and Methods: Forty healthy volunteers consisting of age-matched men (20) and women (20) with a mean age of 27.1 years were recruited. One examiner performed the TPD test using a simple hand-operated device, i.e., by drawing compass with a blunt or sharp-pointed tip. The static TPD with a blunt-pointed tip (STPDB), moving TPD with a blunt-pointed tip (MTPDB), and static TPD with a sharp-pointed tip (STPDS) were measured. The predictors were the site, sex, and test modality, and the outcome variable was the TPD value. Three-way ANOVA was used for statistics. Results: The analysis showed a significant effect of the site, sex and test modality on the TPD values. Significant differences between the test sites were observed with the descending order from the forehead and cheek>mentum>upper lip and lower lip>tongue tip and index finger. Women showed lower TPD values than those of men. The STPDS measurements were consistently lower than those of the STPDB and MTPDB. Conclusions: The normal values of TPD in this study suggest that the cheek and forehead were less sensitive than other regions evaluated and women were more sensitive than men. The STPDS was the most sensitive test modality. PMID- 28877283 TI - Bacterial endotoxin adhesion to different types of orthodontic adhesives. AB - Objective: The aim of this study was to assess whether LPS adheres to orthodontic adhesive systems, comparing two commercial brands. Material and Methods: Forty specimens were fabricated from Transbond XT and Light Bond composite and bonding agent components (n=10/component), then contaminated by immersion in a bacterial endotoxin solution. Contaminated and non-contaminated acrylic resin samples were used as positive and negative control groups, respectively. LPS quantification was performed by the Limulus Amebocyte Lysate QCL-1000TM test. Data obtained were scored and subjected to the Chi-square test using a significance level of 5%. Results: There was endotoxin adhesion to all materials (p<0.05). No statistically significant difference was found between composites/bonding agents and acrylic resin (p>0.05). There was no significant difference (p>0.05) among commercial brands. Affinity of endotoxin was significantly greater for the bonding agents (p=0.0025). Conclusions: LPS adhered to both orthodontic adhesive systems. Regardless of the brand, the endotoxin had higher affinity for the bonding agents than for the composites. There is no previous study assessing the affinity of LPS for orthodontic adhesive systems. This study revealed that LPS adheres to orthodontic adhesive systems. Therefore, additional care is recommended to orthodontic applications of these materials. PMID- 28877287 TI - Erratum. AB - [This corrects the article doi: 10.1590/1807-3107BOR-2016.vol30.0134]. PMID- 28877286 TI - ERRATUM. AB - [This corrects the article doi: 10.1590/1678-7757-2016-0322]. PMID- 28877285 TI - Chondroblastic osteosarcoma mimicking periapical abscess. AB - Case report: The present report describes a case of chondroblastic osteosarcoma in the periapical region of teeth #29, #30, and #31 of an 18-year-old male. Clinical history showed self-reported discomfort in the right posterior gingiva for over a month. Physical examination showed a small expansion and redness of the right mandibular buccal and lingual cortical plates, but no signs of pain or inflammation were observed. All the teeth responded positively to pulp sensibility. Periapical and panoramic radiographs showed slight periapical radiolucency in the roots of teeth #29 and #30, clear periodontal ligament space widening, and evident loss of lamina dura. Incisional biopsy was performed, and based on microscopic findings the diagnosis of chondroblastic osteosarcoma was confirmed. Conclusions: Non-endodontic diseases associated with tooth root apex, such as chondroblastic osteosarcoma, should be included in differential diagnosis of jaw lesions that resemble periapical abscess. PMID- 28877284 TI - Caries progression in non-cavitated fissures after infiltrant application: a 3 year follow-up of a randomized controlled clinical trial. AB - Objectives: To evaluate the efficacy of a conservative treatment to prevent the progression of caries using an infiltrant on non-cavitated pit and fissures. Material and Methods: This controlled clinical trial selected 23 volunteers with clinically and radiographically non-cavitated occlusal caries among patients presenting a "rather low" to "very high" caries risk. Eighty-six teeth were randomly divided into two experimental groups: teeth receiving a commercial pit and-fissure sealant (Alpha Seal-DFL) and contralateral teeth receiving Icon infiltrant (DMG). Caries progression was monitored by clinical (laser fluorescence caries detection) and radiographic examination at 12-month intervals over a period of 3 years of monitored caries progression. Probing the sealing materials to detect areas of retention was also used to evaluate marginal integrity. Results: Statistical analysis showed no difference in caries progression using laser fluorescence caries detection when both materials were compared, regardless of the evaluation times (p>0.05). No significance was observed when the marginal sealant integrity of both materials was compared, regardless of the evaluation time (p<0.05). Marginal integrity significantly reduced after 1 year for both materials (p<0.05), but remained stable after 2 and 3 years of evaluation, compared with 1-year results (p>0.05). SEM analysis exhibited a more homogeneous sealing for the infiltrant than obtained by the sealant. Conclusions: The infiltrant was effective to prevent the caries progression in non-cavitated pit-and-fissures after 3 years of clinical evaluation, comparable with the conventional sealant. The infiltrant also presented better results in terms of caries progression at the 3-year evaluation time using the radiographic analysis. PMID- 28877289 TI - Attempting to Define "Hypoallergenic". PMID- 28877290 TI - Error in Affiliation. PMID- 28877288 TI - Effect of rewetting solutions on micropush-out dentin bond strength of new bioceramic endodontic material. AB - To evaluate the influence of rewetting solutions on bond strength to root dentin of conventional gutta-percha (GP) or niobium phosphate glass-based gutta-percha (GNb) associated with a bioceramic sealer. The root canals of 80 human mandibular premolars were prepared using nickel-titanium instruments and irrigation with sodium hypochlorite and EDTA. The teeth were randomly divided into four groups according to the gutta-percha used: GNb or GP associated with EndoSequence BC Sealer (BC) and the solution for rewetting dentin before filling (distilled water; phosphate buffer saline solution - PBS; simulated body fluid - SBF; or no solution). The root canals were filled with a single cone using warm vertical condensation. Micropush-out bond strengths associated with the filling materials in slices from middle root thirds was determined 30 days after root filling. The failure mode was analyzed with stereoscopic lens. The data were statistically analyzed by two-way ANOVA and Holm-Sidak test (p < 0.05). There was significant difference in the types of gutta-percha (p < 0.001) and in the different rewetting solutions (p = 0.003). The interaction between gutta-percha and rewetting solutions was not significant (p = 0.53). The SBF solution provided an increase in bond strength for both gutta-percha solutions. The GNb+BC (3.42 MPa) association increased bond strength when compared with GP+BC (2.0 MPa). The use of SBF as a dentin rewetting solution increased bond strength in the groups studied. Association of GNb with bioceramic sealer was beneficial, increasing the bond strength to dentin when compared with the association with GP. PMID- 28877292 TI - Safety and Outcomes of the Transoral Endoscopic Thyroidectomy Vestibular Approach. AB - Importance: Natural orifice transluminal endoscopic surgery thyroidectomy is a novel approach to avoid surgical scars. Objective: To compare the safety and outcomes of the transoral endoscopic thyroidectomy vestibular approach (TOETVA) with those of open thyroidectomy (OT). Design, Setting, and Participants: This study retrospectively reviewed all TOETVA and OT operations performed from April 1, 2014, through August 31, 2016, at Police General Hospital, Bangkok, Thailand. All patients who underwent TOETVA and patients who underwent OT were included. Exclusion criteria were (1) previous neck surgery, (2) substernal goiter, (3) lymph node or distance metastasis, and (4) suspicious invasion to the adjacent organs. Propensity score matching was conducted to reduce selective bias. Main Outcomes and Measures: Operative time, blood loss, and complications related to thyroid surgery. Results: Of the 425 patients who underwent transoral endoscopic thyroidectomy (mean age, 35.3 [12.1] years; age range, 16-81 years; 389 [92.2%] female), 422 successfully were treated with the TOETVA; 3 patients were converted to a conventional operation because of bleeding. Twenty-five patients (5.9%) had transient recurrent laryngeal nerve palsy, and 46 (10.9%) had transient hypoparathyroidism. None had permanent recurrent laryngeal nerve palsy or permanent hypoparathyroidism. Three patients (0.7%) had transient mental nerve injury; all cases resolved by 4 months. One patient developed postoperative hematoma treated by OT. Twenty patients (4.7%) had seroma treated by simple aspiration. Operative time was longer for the TOETVA compared with the OT group (100.8 [39.7] vs 79.4 [32.1] minutes, P = 1.61 * 10-10). The mean (SD) visual analog scale score for pain was lower in the TOETVA group (1.1 [1.2] vs 2.8 [1.2], P = 2.52 * 10-38). Estimated mean (SD) blood loss (36.9 [32.4] vs 37.6 [23.1] mL, P = .43) and rate of complications (45 of 216 [20.8%] vs 38 of 216 [17.6%], P = .41) were not significantly different in the TOETVA vs OT group. Conclusions and Relevance: The TOETVA was performed as safely as OT, requires only conventional laparoscopic instruments, and avoids incisional scars; thus, the approach may be an option for select patients. PMID- 28877291 TI - Survival and Cardiovascular Outcomes of Patients With Secondary Mitral Regurgitation: A Systematic Review and Meta-analysis. AB - Importance: The outcomes of patients with left ventricular (LV) dysfunction and secondary mitral regurgitation (SMR) are still controversial. Objective: To clarify the role of SMR in the outcomes of patients with ischemic or idiopathic cardiomyopathies. Data Sources: MEDLINE, ISI Web of Science, and Scopus databases were searched for studies published up to March 2017. Study Selection: Studies reporting data on outcomes in patients with SMR were included. Duplicate publication data, studies lacking data on SMR grade and its correlation with outcomes, mixed data on SMR and primary mitral regurgitation, studies not clearly reporting the outcome of interest, and studies with fewer than 100 patients were excluded. Of the initial 3820 articles identified, 1.4% were finally included. Data Extraction and Synthesis: The study met PRISMA requirements. Two of us independently screened articles for fulfillment of inclusion criteria. Main Outcomes and Measures: The primary outcome, set after data collection, was the incidence of all-cause mortality in patients with and without SMR. Secondary outcomes included hospitalization for heart failure (HF), cardiac mortality, and a composite end point of death, HF hospitalization, and cardiac transplant. Results: Fifty-three studies and 45 900 patients were included in the meta analysis. The mean (SD) length of follow-up was 40.8 (22.2) months. In 26 of 36 studies reporting LV function by SMR grade, increasing SMR severity was associated with worse LV function. When SMR was categorized as present or absent, all-cause mortality was significantly higher in the patients with SMR (17 studies, 26 359 patients; risk ratio [RR],1.79; 95% CI, 1.47-2.18; P < .001, I2 = 85%); when SMR was qualitatively graded, the incidence of all-cause mortality was significantly increased in patients having any degree of SMR compared with patients not having SMR (21 studies, 21 081 patients; RR, 1.96; 95% CI, 1.67 2.31; P < .001, I2 = 74%). Finally, when SMR was quantitatively graded, it remained associated with an increased all-cause mortality rate (9 studies, 3649 patients; RR, 1.97; 95% CI, 1.71-2.27; P < .001, I2 = 0%). Moreover, SMR was associated with an increased risk of hospitalization for HF (16 studies, 10 171 patients; RR, 2.26; 95% CI, 1.92-2.67; P < .001, I2 = 41%), cardiac mortality (12 studies, 11 896 patients; RR, 2.62; 95% CI, 1.87-3.69; P < .001, I2 = 74%), and death, HF, and transplant (11 studies, 8256 patients; RR, 1.63; 95% CI, 1.33 1.99; P < .001, I2 = 78%). Conclusions and Relevance: To our knowledge, this study is the first meta-analysis to date to demonstrate that SMR, even when mild, correlates with adverse outcomes in patients with ischemic or idiopathic cardiomyopathies. Because SMR is an intrinsic consequence of LV dysfunction, causality between SMR and mortality should not be implied. PMID- 28877293 TI - Thermodilution vs Estimated Fick Cardiac Output Measurement in Clinical Practice: An Analysis of Mortality From the Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA CART) Program and Vanderbilt University. AB - Importance: Thermodilution (Td) and estimated oxygen uptake Fick (eFick) methods are widely used to measure cardiac output (CO). They are often used interchangeably to make critical clinical decisions, yet few studies have compared these approaches as applied in medical practice. Objectives: To assess agreement between Td and eFick CO and to compare how well these methods predict mortality. Design, Setting, and Participants: This investigation was a retrospective cohort study with up to 1 year of follow-up. The study used data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA CART) program. The findings were corroborated in a cohort of patients cared for at Vanderbilt University, an academic referral center. Participants were more than 15 000 adults who underwent right heart catheterization, including 12 232 in the Veterans Affairs cohort between October 1, 2007, and September 30, 2013, and 3391 in the Vanderbilt cohort between January 1, 1998, and December 31, 2014. Exposures: A single cardiac catheterization was performed on each patient with CO estimated by both Td and eFick methods. Cardiac output was indexed to body surface area (cardiac index [CI]) for all analyses. Main Outcomes and Measures: All-cause mortality over 90 days and 1 year after catheterization. Results: Among 12 232 VA patients (mean [SD] age, 66.4 [9.9] years; 3.3% female) who underwent right heart catheterization in this cohort study, Td and eFick CI estimates correlated modestly (r = 0.65). There was minimal mean difference (eFick minus Td = -0.02 L/min/m2, or -0.4%) but wide 95% limits of agreement between methods ( 1.3 to 1.3 L/min/m2, or -50.1% to 49.4%). Estimates differed by greater than 20% for 38.1% of patients. Low Td CI (<2.2 L/min/m2 compared with normal CI of 2.2 4.0 L/min/m2) more strongly predicted mortality than low eFick CI at 90 days (Td hazard ratio [HR], 1.71; 95% CI, 1.47-1.99; chi2 = 49.5 vs eFick HR, 1.42; 95% CI, 1.22-1.64; chi2 = 20.7) and 1 year (Td HR, 1.53; 95% CI, 1.39-1.69; chi2 = 71.5 vs eFick HR, 1.35; 1.22-1.49; chi2 = 35.2). Patients with a normal CI by both methods had 12.3% 1-year mortality. There was no significant additional risk for patients with a normal Td CI but a low eFick CI (12.9%, P = .51), whereas a low Td CI but normal eFick CI was associated with higher mortality (15.4%, P = .001). The results from the Vanderbilt cohort were similar in the context of a more balanced sex distribution (46.6% female). Conclusions and Relevance: There is only modest agreement between Td and eFick CI estimates. Thermodilution CI better predicts mortality and should be favored over eFick in clinical practice. PMID- 28877294 TI - Administrative Codes for Capturing In-Hospital Cardiac Arrest. PMID- 28877295 TI - Secondary Mitral Regurgitation and Survival in Patients With Left Ventricular Dysfunction. PMID- 28877296 TI - Heterogeneity Within and Between Autism Spectrum Disorder and Attention Deficit/Hyperactivity Disorder: Challenge or Opportunity? PMID- 28877297 TI - Arm Swelling Following Attempted Peripherally Inserted Central Catheter. PMID- 28877298 TI - Association of Intraoperative Radiotherapy in the Treatment of Early-Stage Breast Cancer With Minor Surgical Site Complications in Oncoplastic Breast-Conserving Surgery. PMID- 28877299 TI - Nonoperative Management of Pancreatic Fistula: Why Not an Endoscopic Approach? PMID- 28877300 TI - A Transgender Woman With Anogenital Lichen Sclerosus. PMID- 28877301 TI - Recent Changes in Health Insurance Coverage and Access to Care by Mental Health Status, 2012-2015. PMID- 28877302 TI - Prevention of Anxiety Disorders Across the Lifespan. PMID- 28877303 TI - Association of Guideline Adherence for Serial Evaluations With Survival and Adverse Clinical Events in Patients With Asymptomatic Severe Aortic Stenosis. AB - Importance: For patients with asymptomatic severe aortic stenosis and normal left ventricular function, current practice guidelines empirically recommend serial evaluations every 6 to 12 months. The benefit of this clinical monitoring is unknown. Objective: To determine the association of guideline adherence with clinical outcomes in patients with asymptomatic severe aortic stenosis. Design, Setting, and Participants: This retrospective cohort study involved 300 patients with asymptomatic severe aortic stenosis who were seen in the ambulatory Minneapolis Heart Institute at Abbott Northwestern Hospital. Rates of survival and adverse clinical events, including myocardial infarction, stroke, and heart failure hospitalization, were compared between patients who adhered to serial evaluation guidance and those who did not. Medical records were reviewed from July 25, 2007, to December 6, 2012. Data analysis took place from February 4, 2017, to July 10, 2017. Main Outcomes and Measures: All-cause mortality, heart failure hospitalization, and major adverse clinical events during follow-up. Results: The study population of 300 comprised 143 men (47.7%) and had a mean (SD) age of 78.6 (11.5) years. There were no differences in age, race/ethnicity, sex, comorbidities, insurance status, left ventricular function, and aortic stenosis severity between patients with (n = 202) and patients without (n = 98) guideline adherence. Aortic valve replacement (surgical or catheter based) was performed more frequently (54.0% vs 19.4%; P < .001) and the median (interquartile range) time for this performance was earlier (2.2 [1.2-3.6] years vs 3.5 [2.0-5.8] years; P < .001) in patients with guideline adherence. All-cause mortality was higher for nonadherent patients (hazard ratio [HR], 1.57; 95% CI, 1.07-2.30; P < .001), and these patients also had a higher rate of hospital admission for heart failure decompensation in follow-up (HR, 1.66; 95% CI, 1.27 2.18; P < .001). Four-year survival that is free from death and heart failure hospitalization was higher for adherent patients than for nonadherent patients (38.7% vs 23.3%; P < .001), and this difference remained significant in models adjusted for baseline variables (adjusted HR, 1.54; 95% CI, 1.04-2.29; P = .03). Conclusions and Relevance: The findings of this study support the need for close monitoring of patients with asymptomatic severe aortic stenosis and help to validate current guidelines for serial evaluations. These findings also support initiatives to improve guideline adherence in clinical practice. PMID- 28877304 TI - Thyroid Surgery Through the Mouth Might Not Be as Crazy as It Sounds. PMID- 28877305 TI - Incorrect Spelling of Author's Name. PMID- 28877306 TI - A Violaceous, Photodistributed Cutaneous Eruption and Leg Ulcer in a Woman With Essential Thrombocytosis. PMID- 28877307 TI - A Reconfigurable Multiplanar In Vitro Simulator for Real-Time Absolute Motion With External and Musculotendon Forces. AB - Advancements in computational musculoskeletal biomechanics are constrained by a lack of experimental measurement under real-time physiological loading conditions. This paper presents the design, configuration, capabilities, accuracy, and repeatability of The University of Texas at El Paso Joint Load Simulator (UTJLS) by testing four cadaver knee specimens with 47 real-time tests including heel and toe squat maneuvers with and without musculotendon forces. The UTJLS is a musculoskeletal simulator consisting of two robotic manipulators and eight musculotendon actuators. Sensors include eight tension load cells, two force/torque systems, nine absolute encoders, and eight incremental encoders. A custom control system determines command output for position, force, and hybrid control and collects data at 2000 Hz. Controller configuration performed forward dynamic control for all knee degrees-of-freedom (DOFs) except knee flexion. Actuator placement and specimen potting techniques uniquely replicate muscle paths. Accuracy and repeatability standard deviations across specimen during squat simulations were equal or less than 8 N and 5 N for musculotendon actuators, 30 N and 13 N for ground reaction forces (GRFs), and 4.4 N.m and 1.9 N.m for ground reaction moments. The UTJLS is the first of its design type. Controller flexibility and physical design support axis constraints to match traditional testing rigs, absolute motion, and synchronous real-time simulation of multiplanar kinematics, GRFs, and musculotendon forces. System DOFs, range of motion, and speed support future testing of faster maneuvers, various joints, and kinetic chains of two connected joints. PMID- 28877308 TI - Incidence of Myocardial Infarction After High-Risk Vascular Operations in Adults. AB - Importance: Advances in perioperative cardiac management and an increase in the number of endovascular procedures have made significant contributions to patients and postoperative myocardial infarction (POMI) risk following high-risk vascular procedures. Whether these changes have translated into real-world improvements in POMI incidence remain unknown. Objective: To examine the temporal trends of myocardial infarction (MI) following high-risk vascular procedures. Design, Setting, and Participants: A retrospective cohort study was performed using data collected from January 1, 2005, to December 31, 2013, in the American College of Surgeons National Surgery Quality Improvement Program database, to which participating hospitals across the United States report their preoperative, operative, and 30-day outcome data. A total of 90 303 adults who underwent a high risk vascular procedure-open aortic surgery or infrainguinal bypass-during the study period were identified. Patients were divided into cohorts based on their year of operation, and their baseline cardiac risk factors and incidence of POMI were compared. Cases from 2005 to 2014 in the database were eligible for inclusion if one of their Current Procedural Terminology codes matched any of the operations identified as a high-risk vascular procedure. Data analysis took place from August 1, 2016, to November 15, 2016. Exposures: The main exposure was the year of the operation. Other variables of interest included demographics, comorbidities, and other risk factors for MI. Main Outcomes and Measures: Primary outcome of interest was the incidence of POMI. Results: Of the 90 303 patients included in the study, 22 836 (25.3%) had undergone open aortic surgery and 67 467 (74.7%) had had infrainguinal bypass. The open aortic cohort comprised 16 391 men (71.9%), had a mean (SD) age of 69.1 (11.5) years, and was predominantly white (18 440 patients [80.8%] self-identified as white race/ethnicity). The infrainguinal bypass cohort included 41 845 men (62.1%), had a mean (SD) age of 66.7 (11.7) years, and had 51 043 patients (75.7%) who self-identified as white race/ethnicity. During the study period, patients who underwent open aortic procedures were more likely to be classified as American Society of Anesthesiologists class IV (7426 patients [32.6%] vs 15 683 [23.3%] for the infrainguinal bypass cohort) or class V (1131 [5.0%] vs 206 [0.3%]; P < .001) and to undergo emergency procedures (4852 [21.3%] vs 4954 [7.3%]; P < .001). The open aortic procedure cohort also experienced significantly higher actual incidence of POMI (464 [3.0%] vs 1270 [1.9%]; P < .001). From 2009 to 2014, the incidence of POMI demonstrated no substantial temporal change (2.7% in 2009 to 3.1% in 2014; P = .64 for trend). Postoperative MI was consistently associated with poor prognosis, with a 3.62-fold (95% CI, 2.25-5.82) to 11.77-fold (95% CI, 6.10 22.72) increased odds of cardiac arrest and a 3.01-fold (95% CI, 2.08-4.36) to 6.66-fold (95% CI, 4.66-9.52) increased odds of mortality. Conclusions and Relevance: The incidence of MI did not significantly decrease in the past decade and has been consistently associated with worse clinical outcomes. Further inquiry into why advanced perioperative care did not reduce cardiac complications is important to quality improvement efforts. PMID- 28877309 TI - A Finite Element Model of a Midsize Male for Simulating Pedestrian Accidents. AB - Pedestrians represent one of the most vulnerable road users and comprise nearly 22% the road crash-related fatalities in the world. Therefore, protection of pedestrians in car-to-pedestrian collisions (CPC) has recently generated increased attention with regulations involving three subsystem tests. The development of a finite element (FE) pedestrian model could provide a complementary component that characterizes the whole-body response of vehicle pedestrian interactions and assesses the pedestrian injuries. The main goal of this study was to develop and to validate a simplified full body FE model corresponding to a 50th male pedestrian in standing posture (M50-PS). The FE model mesh and defined material properties are based on a 50th percentile male occupant model. The lower limb-pelvis and lumbar spine regions of the human model were validated against the postmortem human surrogate (PMHS) test data recorded in four-point lateral knee bending tests, pelvic?abdomen?shoulder?thoracic impact tests, and lumbar spine bending tests. Then, a pedestrian-to-vehicle impact simulation was performed using the whole pedestrian model, and the results were compared to corresponding PMHS tests. Overall, the simulation results showed that lower leg response is mostly within the boundaries of PMHS corridors. In addition, the model shows the capability to predict the most common lower extremity injuries observed in pedestrian accidents. Generally, the validated pedestrian model may be used by safety researchers in the design of front ends of new vehicles in order to increase pedestrian protection. PMID- 28877311 TI - Restricted Mean Survival Time as a Measure to Interpret Clinical Trial Results. PMID- 28877310 TI - Consumer Preferences, Product Characteristics, and Potentially Allergenic Ingredients in Best-selling Moisturizers. AB - Importance: Because moisturizer use is critical for the prevention and treatment of numerous dermatological conditions, patients frequently request product recommendations from dermatologists. Objective: To determine the product performance characteristics and ingredients of best-selling moisturizers. Design and Setting: This cohort study involved publicly available data of the top 100 best-selling whole-body moisturizing products at 3 major online retailers (Amazon, Target, and Walmart). Products marketed for use on a specific body part (eg, face, hands, eyelids) were excluded. Main Outcomes and Measures: Pairwise comparisons of median price per ounce on the basis of marketing claims (eg, dermatologist recommended, fragrance free, hypoallergenic) and presence of ingredients represented in the North American Contact Dermatitis Group (NACDG) series were conducted using Wilcoxon rank sum tests. The effect of vehicle type (eg, ointment, lotion, cream, butter) was assessed using the Kruskal-Wallis test. Cross-reactors and botanicals for fragrances were derived from the American Contact Dermatitis Society's Contact Allergen Management Program database. Results: A total of 174 unique best-selling moisturizer products were identified, constituting 109 713 reviews as of August 2016. The median price per ounce was $0.59 (range, $0.10-$9.51 per ounce) with a wide range (9400%). The most popular vehicles were lotions (102 [59%]), followed by creams (22 [13%]), oils (21 [12%]), butters (14 [8%]), and ointments (3 [2%]). Only 12% (n = 21) of best selling moisturizer products were free of NACDG allergens. The 3 most common allergens were fragrance mix (n = 87), paraben mix (n = 75), and tocopherol (n = 74). Products with the claim "dermatologist recommended" had higher median price per ounce ($0.79; interquartile range [IQR], $0.56-$1.27) than products without the claim ($0.59; IQR, $0.34-$0.92). Products with the claim "phthalate free" had higher median price per ounce ($1.38; IQR, $0.86-$1.63) than products without the claim ($0.59; IQR, $0.35-$0.91). Lotions (median, $0.49; IQR, $0.31-0.68) were statistically less expensive per ounce than butters (median, $1.20; IQR, $0.76 $1.63), creams (median, $0.80; IQR, $0.69-$1.25) and oils (median, $1.30; IQR, $0.64-$2.43). For products with a claim of "fragrance free," 18 (45%) had at least 1 fragrance cross-reactor or botanical ingredient. Products without any ingredients in the NACDG (median, $0.83; IQR, $0.47-$1.69) were not statistically more expensive per ounce than products with 1 or more allergens (median, $0.60; IQR, $0.35-$1.06). Conclusions and Relevance: Best-selling moisturizers vary widely by price and product characteristics. Given the lack of readily available comparison data on moisturizer efficacy, dermatologists should balance consumer preference, price, and allergenicity in their recommendations. PMID- 28877313 TI - Nonoperative Management of Pancreatic Fistula-Reply. PMID- 28877314 TI - Correction of Misspelled Author Name. PMID- 28877315 TI - Incorrect P Value in Table 3. PMID- 28877312 TI - Effect of Topical Fluorouracil Cream on Photodamage: Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Photoaging, which is premature skin aging caused by long-term UV exposure, is of aesthetic concern to many patients. Objective: To investigate the effect of topical fluorouracil, 5%, cream on photoaging using validated photonumeric scales. Design, Setting, and Participants: The Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial was a randomized clinical trial of 932 US veterans with a recent history of 2 or more keratinocyte carcinomas performed from September 30, 2011, through June 30, 2014, to assess the chemopreventive effects of a standard course of topical fluorouracil. Photographs were taken at baseline and at numerous time points for up to 4 years. In our secondary analysis, 2 independent dermatologists graded these photographs using 4 validated photonumeric scales. A total of 3042 photographs from 281 participants randomized to apply topical fluorouracil or placebo were evaluated at baseline, 6 months, 12 months, and 18 months using 4 photonumeric scales (Griffiths scale, Allergan forehead lines scale, melomental folds scale, and crow's feet scale). Data analysis was performed from November 1, 2016, to January 1, 2017. Interventions: Participants were randomized to apply topical fluorouracil, 5%, cream or a vehicle control cream to the face and ears twice daily for 2 to 4 weeks for a total of 28 to 56 doses. Main Outcomes and Measures: Effect of a standard course of fluorouracil on the extent of photodamage as measured using 4 photonumeric scales. Results: The study population was predominantly male (274 [97.5%]) and white (281 [100%]), with a mean (SD) age of 71.5 (0.57) years. No statistically significant changes were found in photodamage between baseline and 6 months (Griffiths scale: chi2 = 0.01, P = .93; Allergan forehead lines scale: chi2 = 0.18, P = .67; melomental fold scale: chi2 = 0.03, P = .87; crow's feet scale: chi2 = 2.41, P = .12), 12 months (Griffiths scale: chi2 = 1.39, P = .24; Allergan forehead lines scale: chi2 = 0.64, P = .43; melomental fold scale: chi2 = 0.12, P = .73; crow's feet scale: chi2 = 1.07, P = .30), and 18 months (Griffiths scale: chi2 = 3.11, P = .08; Allergan forehead lines scale: chi2 = 0.89, P = .34; melomental fold scale: chi2 = 1.64, P = .20; crow's feet scale: chi2 = 0.46, P = .50). Conclusions and Relevance: This study did not demonstrate improvement in photoaging with a standard course of topical fluorouracil, 5%, cream, a finding that may be attributable to a true lack of effect in photodamage or limitations of the photonumeric scales in capturing the effect. The development of photonumeric scales that include manifestations of photoaging other than rhytids, such as lentigines, hyperpigmentation, and telangiectasias, should be considered. Trial Registration: clinicaltrials.gov Identifier: NCT00847912. PMID- 28877316 TI - Effectiveness of Psychological and/or Educational Interventions in the Prevention of Anxiety: A Systematic Review, Meta-analysis, and Meta-regression. AB - Importance: To our knowledge, no systematic reviews or meta-analyses have been conducted to assess the effectiveness of preventive psychological and/or educational interventions for anxiety in varied populations. Objective: To evaluate the effectiveness of preventive psychological and/or educational interventions for anxiety in varied population types. Data Sources: A systematic review and meta-analysis was conducted based on literature searches of MEDLINE, PsycINFO, Web of Science, EMBASE, OpenGrey, Cochrane Central Register of Controlled Trials, and other sources from inception to March 7, 2017. Study Selection: A search was performed of randomized clinical trials assessing the effectiveness of preventive psychological and/or educational interventions for anxiety in varying populations free of anxiety at baseline as measured using validated instruments. There was no setting or language restriction. Eligibility criteria assessment was conducted by 2 of us. Data Extraction and Synthesis: Data extraction and assessment of risk of bias (Cochrane Collaboration's tool) were performed by 2 of us. Pooled standardized mean differences (SMDs) were calculated using random-effect models. Heterogeneity was explored by random-effects meta regression. Main Outcomes and Measures: Incidence of new cases of anxiety disorders or reduction of anxiety symptoms as measured by validated instruments. Results: Of the 3273 abstracts reviewed, 131 were selected for full-text review, and 29 met the inclusion criteria, representing 10 430 patients from 11 countries on 4 continents. Meta-analysis calculations were based on 36 comparisons. The pooled SMD was -0.31 (95% CI, -0.40 to -0.21; P < .001) and heterogeneity was substantial (I2 = 61.1%; 95% CI, 44% to 73%). There was evidence of publication bias, but the effect size barely varied after adjustment (SMD, -0.27; 95% CI, 0.37 to -0.17; P < .001). Sensitivity analyses confirmed the robustness of effect size results. A meta-regression including 5 variables explained 99.6% of between study variability, revealing an association between higher SMD, waiting list (comparator) (beta = -0.33 [95% CI, -0.55 to -0.11]; P = .005) and a lower sample size (lg) (beta = 0.15 [95% CI, 0.06 to 0.23]; P = .001). No association was observed with risk of bias, family physician providing intervention, and use of standardized interviews as outcomes. Conclusions and Relevance: Psychological and/or educational interventions had a small but statistically significant benefit for anxiety prevention in all populations evaluated. Although more studies with larger samples and active comparators are needed, these findings suggest that anxiety prevention programs should be further developed and implemented. PMID- 28877317 TI - Association of White Matter Structure With Autism Spectrum Disorder and Attention Deficit/Hyperactivity Disorder. AB - Importance: Clinical overlap between autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is increasingly appreciated, but the underlying brain mechanisms remain unknown to date. Objective: To examine associations between white matter organization and 2 commonly co-occurring neurodevelopmental conditions, ASD and ADHD, through both categorical and dimensional approaches. Design, Setting, and Participants: This investigation was a cross-sectional diffusion tensor imaging (DTI) study at an outpatient academic clinical and research center, the Department of Child and Adolescent Psychiatry at New York University Langone Medical Center. Participants were children with ASD, children with ADHD, or typically developing children. Data collection was ongoing from December 2008 to October 2015. Main Outcomes and Measures: The primary measure was voxelwise fractional anisotropy (FA) analyzed via tract-based spatial statistics. Additional voxelwise DTI metrics included radial diffusivity (RD), mean diffusivity (MD), axial diffusivity (AD), and mode of anisotropy (MA). Results: This cross-sectional DTI study analyzed data from 174 children (age range, 6.0-12.9 years), selected from a larger sample after quality assurance to be group matched on age and sex. After quality control, the study analyzed data from 69 children with ASD (mean [SD] age, 8.9 [1.7] years; 62 male), 55 children with ADHD (mean [SD] age, 9.5 [1.5] years; 41 male), and 50 typically developing children (mean [SD] age, 9.4 [1.5] years; 38 male). Categorical analyses revealed a significant influence of ASD diagnosis on several DTI metrics (FA, MD, RD, and AD), primarily in the corpus callosum. For example, FA analyses identified a cluster of 4179 voxels (TFCE FEW corrected P < .05) in posterior portions of the corpus callosum. Dimensional analyses revealed associations between ASD severity and FA, RD, and MD in more extended portions of the corpus callosum and beyond (eg, corona radiata and inferior longitudinal fasciculus) across all individuals, regardless of diagnosis. For example, FA analyses revealed clusters overall encompassing 12121 voxels (TFCE FWE corrected P < .05) with a significant association with parent ratings in the social responsiveness scale. Similar results were evident using an independent measure of ASD traits (ie, children communication checklist, second edition). Total severity of ADHD-traits was not significantly related to DTI metrics but inattention scores were related to AD in corpus callosum in a cluster sized 716 voxels. All these findings were robust to algorithmic correction of motion artifacts with the DTIPrep software. Conclusions and Relevance: Dimensional analyses provided a more complete picture of associations between ASD traits and inattention and indexes of white matter organization, particularly in the corpus callosum. This transdiagnostic approach can reveal dimensional relationships linking white matter structure to neurodevelopmental symptoms. PMID- 28877318 TI - Peripheral Vascular Endothelial Dysfunction in Central Serous Chorioretinopathy. AB - Purpose: To explore the pathophysiology of central serous chorioretinopathy (CSC) by comparing peripheral vascular endothelium function in patients with CSC and control subjects. Methods: This study included 34 patients with CSC who attended the Department of Ophthalmology and 34 healthy age- and sex-matched healthy control subjects from a routine physical check-up population. Endothelium dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerine-mediated vasodilation (NMD) were measured using high-resolution, two-dimensional ultrasonographic imaging of the brachial artery. Blood samples were taken to test serum glucose, cholesterol, triglyceride, alanine aminotransferase, uric acid, and high-sensitivity C-reactive protein (hs-CRP) levels. Results: The mean age of patients with CSC was 44.0 years (SD +/-8.1) and that of controls 46.1 years (+/-9.9) (P = 0.352). There were no significant differences between groups in serum biochemical data, including serum glucose, alanine aminotransferase, uric acid, cholesterol, triglyceride, and hs-CRP. FMD was significantly impaired in patients with CSC compared with control subjects (CSC: 4.62 +/- 1.96, control: 7.52 +/- 2.63, P < 0.001), whereas NMD did not differ significantly between the two groups (CSC: 16.31 +/- 5.60, control: 16.22 +/- 5.56, P = 0.950). Conclusions: This study demonstrated impaired FMD in patients with CSC and the results have provided evidence of peripheral endothelium dysfunction associated with CSC in patients. PMID- 28877321 TI - Errors in Abstract and Discussion. PMID- 28877320 TI - The Properties of Outer Retinal Band Three Investigated With Adaptive-Optics Optical Coherence Tomography. AB - Purpose: Optical coherence tomography's (OCT) third outer retinal band has been attributed to the zone of interdigitation between RPE cells and cone outer segments. The purpose of this paper is to investigate the structure of this band with adaptive optics (AO)-OCT. Methods: Using AO-OCT, images were obtained from two subjects. Axial structure was characterized by measuring band 3 thickness and separation between bands 2 and 3 in segmented cones. Lateral structure was characterized by correlation of band 3 with band 2 and comparison of their power spectra. Band thickness and separation were also measured in a clinical OCT image of one subject. Results: Band 3 thickness ranged from 4.3 to 6.4 MUm. Band 2 correlations ranged between 0.35 and 0.41 and power spectra of both bands confirmed peak frequencies that agree with histologic density measurements. In clinical images, band 3 thickness was between 14 and 19 MUm. Measurements of AO OCT of interband distance were lower than our corresponding clinical OCT measurements. Conclusions: Band 3 originates from a structure with axial extent similar to a single surface. Correlation with band 2 suggests an origin within the cone photoreceptor. These two observations indicate that band 3 corresponds predominantly to cone outer segment tips (COST). Conventional OCT may overestimate both the thickness of band 3 and outer segment length. PMID- 28877324 TI - T786C Mutation in the Endothelial Nitric Oxide Synthase Gene in Patients With Primary Osteonecrosis. AB - Mutations in the T786C endothelial nitric oxide synthase gene (eNOS) are associated with osteonecrosis and Prinzmetal's angina. Nitric oxide is necessary for bone health and ameliorates Prinzmetal's angina. This study compared mutations of T786C eNOS in 146 patients with primary osteonecrosis, 114 patients with Prinzmetal's angina, and 83 normal control subjects. Patients with osteonecrosis had more mutant eNOS alleles than control subjects (42% vs 22%, respectively; P<.0001) but had the same number of mutant alleles as patients with Prinzmetal's angina (42% vs 41%, respectively; P=.7), who in turn had more mutant eNOS alleles than control subjects (41% vs 22%, respectively; P=.0001). Of 146 patients with primary osteonecrosis, 65 (45%) had none of the 5 thrombophilias (Factor V Leiden heterozygosity, high levels of Factors VIII and XI, anticardiolipin antibody immunoglobulin M, and homocysteine) that otherwise distinguished patients with osteonecrosis from control subjects (P<.05). No associations were found between eNOS hetero-homozygosity and the 5 major thrombophilias in primary osteonecrosis. Of the 65 patients who had osteonecrosis but no major thrombophilias, for 41 (28% of the total sample of 146), eNOS hetero homozygosity was the only abnormality. Normalization of nitric oxide levels with l-arginine 9 g/d or l-citrulline 800 mg/d, both of which relieve vasospastic angina in Prinzmetal's angina, which has the same eNOS genotype as primary osteonecrosis, may slow or stop the progression of osteonecrosis. Placebo controlled trials of patients with primary osteonecrosis who are hetero homozygous for the T786C eNOS mutation and have no major thrombophilias are needed to assess the safety and efficacy of this treatment. [Orthopedics. 2017; 40(5):e898-e903.]. PMID- 28877319 TI - Absence of Sigma 1 Receptor Accelerates Photoreceptor Cell Death in a Murine Model of Retinitis Pigmentosa. AB - Purpose: Sigma 1 Receptor (Sig1R) is a novel therapeutic target in neurodegenerative diseases, including retinal disease. Sig1R-/- mice have late onset retinal degeneration with ganglion cell loss that worsens under stress. Whether Sig1R plays a role in maintaining other retinal neurons is unknown, but was investigated here using rd10 mice, a model of severe photoreceptor degeneration. Methods: Wild-type, rd10, and rd10/Sig1R-/- mice were subjected to ERG and spectral-domain optical coherence tomography (SD-OCT) to assess visual function/structure in situ. Retinas imaged microscopically were subjected to morphometric analysis, immunodetection of cones, and analysis of gliosis. Oxidative and endoplasmic reticulum (ER) stress was evaluated at mRNA/protein levels. Results: Photopic ERG responses were reduced significantly in rd10/Sig1R /- versus rd10 mice at P28 (31 +/- 6 vs. 56 +/- 7 MUV), indicating accelerated cone loss when Sig1R was absent. At P28, SD-OCT revealed reduced retinal thickness in rd10/Sig1R-/- mice (60% of WT) versus rd10 (80% of WT). Morphometric analysis disclosed profound photoreceptor nuclei loss in rd10/Sig1R-/- versus rd10 mice. rd10/Sig1R-/- mice had 35% and 60% fewer photoreceptors, respectively, at P28 and P35, than rd10. Peanut agglutinin cone labeling decreased significantly; gliosis increased significantly in rd10/Sig1R-/- versus rd10 mice. At P21, NRF2 levels increased in rd10/Sig1R-/- mice versus rd10 and downstream antioxidants increased indicating oxidative stress. At P28, ER stress genes/proteins, especially XBP1, a potent transcriptional activator of the unfolded protein response and CHOP, a proapoptotic transcription factor, increased significantly in rd10/Sig1R-/- mice versus rd10. Conclusions: Photoreceptor cell degeneration accelerates and cone function diminishes much earlier in rd10/Sig1R-/- than rd10 mice emphasizing the importance of Sig1R as a modulator of retinal cell survival. PMID- 28877325 TI - Perioperative Blood Loss During Total Hip Arthroplasty Among Patients With Ankylosing Spondylitis. AB - Intraoperative blood loss is frequently an overarching concern during total hip arthroplasty (THA) for patients who have ankylosing spondylitis with hip involvement. However, the factors that affect blood loss have not been identified. The goal of this study was to investigate these factors among patients with ankylosing spondylitis. Patients in the authors' department who had ankylosing spondylitis and underwent unilateral THA from 2011 to 2016 were studied retrospectively. Demographic characteristics, perioperative laboratory values, intraoperative data, transfusion rate, transfusion volume, and data on hemostatic use were collected and analyzed statistically. Multiple and univariate linear regression analyses were performed. As a result, 44 patients were eligible for inclusion in the study. Mean age was 31.7+/-10.6 years, and mean disease duration was 9.7+/-5.8 years. Mean body mass index was 21.30+/-3.01 kg/m2. Mean volume of blood loss during THA was 1735.19+/-756.04 mL. Multiple linear regression analysis showed that perioperative blood loss was positively associated with Ankylosing Spondylitis Disease Activity Score (ASDAS), fibrinogen concentration, and surgical time. Further evaluation with univariate linear regression analysis suggested that ASDAS, red blood cell transfusion, and change of hematocrit concentration from preoperatively to postoperatively were correlated with blood loss. Disease activity, allogeneic blood transfusion volume, and change of hematocrit concentration from preoperatively to postoperatively appeared to be positively associated with perioperative blood loss during THA for patients with ankylosing spondylitis. For these patients, disease activity and the potential for allogeneic transfusion should be considered carefully before surgery. [Orthopedics. 2017; 40(5):e904-e910.]. PMID- 28877326 TI - Upper Extremity Deep Venous Thrombosis Prophylaxis After Elective Upper Extremity Surgery. AB - Historically, upper extremity deep venous thromboses (DVTs) have been rare; however, their incidence has increased as awareness has increased. Patients who develop upper extremity DVTs often have multiple comorbidities. However, in the past decade, studies have found a small risk of upper extremity DVTs associated with orthopedic procedures involving the upper extremity. The risk of complications following a DVT, including postthrombotic syndrome and pulmonary embolism, is substantially higher with a DVT of the upper extremity compared with a DVT of the lower extremity. Furthermore, there is no consensus regarding the role and efficacy of prophylactic measures in preventing upper extremity DVT after upper extremity surgery. This article discusses the use of prophylactic agents after elective upper extremity surgery, with an emphasis on the efficacy of commonly used interventions. [Orthopedics. 2018; 41(1):21-27.]. PMID- 28877327 TI - Advances in Computer-Aided Technology for Total Knee Arthroplasty. AB - Technology such as computer-assisted navigation systems, robotic-assisted systems, and patient-specific instrumentation has been increasingly explored during the past decade in an effort to optimize component alignment and improve clinical outcomes. Computer-assisted navigation accurately restores mechanical axis alignment, but clinical outcome data are inconsistent. Computer-assisted navigation gap balancing has shown early promise in establishing mechanical-axis alignment with improved functional outcomes. Robotic-assisted systems more accurately restore component alignment when compared with computer-assisted navigation, but clinical outcomes have yet to be determined. Patient-specific instrumentation does not consistently improve alignment, accuracy, or patient outcomes. Studies demonstrating implant survivorship, cost-efficiency, and improved clinical outcomes and patient satisfaction are needed. [Orthopedics. 2017; 40(6):338-352.]. PMID- 28877328 TI - Procedural Sedation With Ketamine Versus Propofol for Closed Reduction of Pediatric Both Bone Forearm Fractures. AB - Effective treatment of pediatric both bone forearm fractures consists of timely restoration of anatomic alignment with manipulation and immobilization, often accomplished with the aid of procedural sedation in the emergency department setting. The current lack of consensus regarding a safe and optimal regimen may result in inadequate sedation, compromised quality of reduction, or patient harm. The current study was conducted to answer the following questions for pediatric both bone forearm fractures treated with closed reduction with either ketamine or propofol procedural sedation: (1) Is there a difference in the rate of unacceptable alignment 4 weeks after reduction? (2) Is there a difference in the rates of major sedation-related complications? Medical records, data on procedural sedation, and radiographs of 74 skeletally immature patients with diaphyseal or distal metaphyseal both bone forearm fractures treated with manipulation were reviewed (ketamine sedation, 26; propofol sedation, 48). Rates of unacceptable alignment for the 2 cohorts were similar both immediately after reduction and at 4 weeks. Rates of complications of procedural sedation did not differ between cohorts. The duration of procedural sedation was longer and the padding index was greater with ketamine. Malalignment after reduction was more likely in older patients and those with a higher padding index. Although no difference was found in the rates of malalignment or sedation-related complications between fractures reduced with ketamine or propofol sedation, the sedation regimens differ in both procedural duration and padding index. Careful consideration of the risks and benefits of procedural sedation for closed reduction of pediatric forearm fractures is warranted. [Orthopedics. 2017; 40(5):288-294.]. PMID- 28877329 TI - Comparison of Knee Stability and Synovial Fluid Alterations in Anterior Cruciate Ligament Reconstruction With a Hamstring Autograft or an Allograft. AB - This study compared knee stability and alterations in the composition of synovial fluid among patients who underwent arthroscopic anterior cruciate ligament (ACL) reconstruction with either a hamstring autograft or a hamstring allograft. This prospective cohort study enrolled 175 patients. Of these patients, 90 underwent hamstring tendon autograft ACL reconstruction. The remaining patients (n=85) underwent hamstring tendon allograft ACL reconstruction. All of the patients had a minimum of 1 year of follow-up (mean, 2.5 years). Side-to-side differences and the proportion of mononuclear cells in knee joint synovial fluid were measured at 5 time points (preoperatively and at postoperative weeks 1, 3, 6, and 12). During the early postoperative phase, side-to-side knee laxity was greater among the allograft group compared with the autograft group (P<.001). Additionally, among the allograft group, the proportion of mononuclear cells remained high at weeks 6 and 12 (mean, 90.0% and 88.9%, respectively) compared with a normal level in the autograft group (mean, 45.1% and 65.7%, separately). However, no significant difference was found between the 2 groups at final follow-up for range of motion, results of the Lachman test, results of the anterior drawer test, results of the pivot shift test, Lysholm score, bone tunnel enlargement, and graft failure rate (P>.05). These findings showed that, in the early postoperative phase, ACL reconstruction with a hamstring allograft resulted in greater knee laxity and immunologic response compared with the hamstring autograft group. However, at relatively long-term follow-up, both grafts achieved similar objective and subjective outcomes. [Orthopedics. 2017; 40(5):e892-e897.]. PMID- 28877330 TI - Terrestrial biosphere models underestimate photosynthetic capacity and CO2 assimilation in the Arctic. AB - Terrestrial biosphere models (TBMs) are highly sensitive to model representation of photosynthesis, in particular the parameters maximum carboxylation rate and maximum electron transport rate at 25 degrees C (Vc,max.25 and Jmax.25 , respectively). Many TBMs do not include representation of Arctic plants, and those that do rely on understanding and parameterization from temperate species. We measured photosynthetic CO2 response curves and leaf nitrogen (N) content in species representing the dominant vascular plant functional types found on the coastal tundra near Barrow, Alaska. The activation energies associated with the temperature response functions of Vc,max and Jmax were 17% lower than commonly used values. When scaled to 25 degrees C, Vc,max.25 and Jmax.25 were two- to five fold higher than the values used to parameterize current TBMs. This high photosynthetic capacity was attributable to a high leaf N content and the high fraction of N invested in Rubisco. Leaf-level modeling demonstrated that current parameterization of TBMs resulted in a two-fold underestimation of the capacity for leaf-level CO2 assimilation in Arctic vegetation. This study highlights the poor representation of Arctic photosynthesis in TBMs, and provides the critical data necessary to improve our ability to project the response of the Arctic to global environmental change. PMID- 28877331 TI - Lactic Acid Bacteria Combinations for Wheat Sourdough Preparation and Their Influence on Wheat Bread Quality and Acrylamide Formation. AB - : Different lactic acid bacteria (LAB) from spontaneous wheat sourdough were isolated, identified, and characterized by their growth, acidification rate, and carbohydrate metabolism. The combinations of isolated LAB (Pediococcus pentosaceus LUHS183 and Leuconostoc mesenteroides LUHS242, P. pentosaceus LUHS183 and Lactobacillus brevis LUHS173, P. pentosaceus LUHS183 and Enterococcus pseudoavium LUHS 234, P. pentosaceus LUHS183 and Lactobacillus curvatus LUHS51, Lactobacillus plantarum LUHS135 and L. curvatus LUHS51, L. plantarum LUHS135 and P. pentosaceus LUHS183) were used for wheat sourdough production, and the effects of LAB fermentation in sourdoughs on wheat bread quality parameters and acrylamide formation were evaluated. All of the tested strains (except E. pseudoavium LUHS 234) were able to ferment l-arabinose, d-ribose, d-galactose, d fructose, and d-maltose and showed high tolerance to acidic conditions. The highest overall acceptability (135.8 +/- 5.5 mm) was found in the bread produced with L. plantarum and P. pentosaceus sourdough. This group of bread also showed the highest shape coefficient (2.59 +/- 0.02), the highest specific volume (3.40 +/- 0.03 cm3 /g), the highest porosity (76.6 +/- 0.3%), and the highest moisture content (33.7%). Selected sourdoughs reduced acrylamide content in bread samples by 29.5% (sourdough prepared with P. pentosaceus and L. mesenteroides) to 67.2% (sourdough prepared with P. pentosaceus and L. curvatus). These cultures potentially can be used to reduce acrylamide in breads. PRACTICAL APPLICATION: The data of this study have practical applications. L. plantarum and P. pentosaceus sourdoughs increases overall acceptability, specific volume, and porosity of wheat bread. Besides the fact that sourdoughs produced by using combinations of selected LAB strains improved the quality parameters of bread, fermentation with prepared sourdoughs also reduced the acrylamide content in wheat bread samples by 29.5% (sourdough prepared with P. pentosaceus and L. mesenteroides) to 67.2% (sourdough prepared with P. pentosaceus and L. curvatus). PMID- 28877332 TI - Socioeconomic position, population density and site-specific cancer mortality: A multilevel analysis of Belgian adults, 2001-2011. AB - Our study explores the association between individual and neighborhood socioeconomic position (SEP) and all-cancer and site-specific cancer mortality. Data on all Belgian residents are retrieved from a population-based dataset constructed from the 2001 census linked to register data on emigration and mortality for 2001-2011. The study population contains all men and women aged 40 years or older during follow-up. Individual SEP is measured using education, employment status and housing conditions. Neighborhood SEP is measured by a deprivation index (in quintiles). Directly age-standardized mortality rates and multilevel Poisson models are used to estimate the association between individual SEP and neighborhood deprivation and mortality from all-cancer and cancer of the lung, colon and rectum, pancreas, prostate and female breast. The potential confounding role of population density is assessed using multilevel models as well. Our findings show an increase in mortality from all-cancer and site specific cancer by decreasing level of individual SEP for both men and women. In addition, individuals living in highly deprived neighborhoods experience significantly higher mortality from all-cancer, lung cancer, pancreatic cancer and female colorectal cancer after controlling for individual SEP. Male colorectal and prostate cancer and female breast cancer are not associated with neighborhood deprivation. Population density acts as a confounder for female lung cancer only. Our study indicates that deprivation at both the individual and neighborhood level is associated with all-cancer mortality and mortality from several cancer sites. More research into the role of life-style related and clinical factors is necessary to gain more insight into causal pathway. PMID- 28877333 TI - OCTOPUS-LIKE 2, a novel player in Arabidopsis root and vascular development, reveals a key role for OCTOPUS family genes in root metaphloem sieve tube differentiation. AB - Protophloem and metaphloem sieve tubes are essential for transporting carbohydrates and signalling molecules towards sink tissues. OCTOPUS (OPS) was previously identified as an important regulator of protophloem differentiation in Arabidopsis roots. Here, we investigated the role of OCTOPUS-LIKE 2 (OPL2), a gene homologous to OPS. OPL2 expression patterns were analysed, and functional equivalence of OPS and OPL2 was tested. Mutant and double mutant phenotypes were investigated. OPS and OPL2 displayed overlapping expression patterns and a high degree of functional overlap. A mutation in OPL2 revealed redundant functions of OPS and OPL2 in developmental processes in which OPS was known to play a role, notably cotyledon vascular patterning and protophloem development. Moreover, we also uncovered redundant roles for OPS and OPL2 in leaf vascular patterning and, most interestingly, metaphloem sieve tube differentiation. Our results reveal a novel OPS-like protein that, together with OPS, is an important regulator of vascular patterning, root growth and phloem development. OPS and OPL2 are the first genes identified that play a role in metaphloem sieve tube differentiation. PMID- 28877334 TI - Personality correlates of individual differences in the recruitment of cognitive mechanisms when rewards are at stake. AB - Individuals differ greatly in their sensitivity to rewards and punishments. In the extreme, these differences are implicated in a range of psychiatric disorders from addiction to depression. However, it is unclear how these differences influence the recruitment of attention, working memory, and long-term memory when responding to potential rewards. Here, we used a rewarded memory-guided visual search task and ERPs to examine the influence of individual differences in self reported reward/punishment sensitivity, as measured by the Behavioral Inhibition System (BIS)/Behavioral Activation System (BAS) scales, on the recruitment of cognitive mechanisms in conditions of potential reward. Select subscales of the BAS, including the fun seeking and reward responsiveness scales, showed unique relationships with context updating to reward cues and working memory maintenance of potentially rewarded stimuli. In contrast, BIS scores showed unique relationships with deployment of attention at different points in the task. These results suggest that sensitivity to rewards (i.e., BAS) and to punishment (i.e., BIS) may play an important role in the recruitment of specific and distinct cognitive mechanisms in conditions of potential rewards. PMID- 28877336 TI - Identification of omega- or (omega-1)-Hydroxylated Medium-Chain Acylcarnitines as Novel Urinary Biomarkers for CYP3A Activity. AB - Quantitative models of endogenous metabolites are useful in predicting CYP3A mediated drug-drug interactions. This study aimed to identify novel predictive markers for the magnitude of CYP3A induction and inhibition in male and female subjects using an untargeted metabolomics approach. Here we report five omega- or (omega-1)-hydroxylated medium-chain acylcarnitines as novel CYP3A4 markers. As CYP4 catalyzes the omega- or (omega-1)-hydroxylation of various medium-chain fatty acids (MCFAs), recombinant enzyme assays were used to determine the omega- and (omega-1)-hydroxylation activities of CYP3A4, CYP4A11, and CYP4F2. CYP3A4 catalyzed omega- and (omega-1)-hydroxylated MCFAs with the lowest Km and highest Vmax /Km values. Finally, we derived a model to predict midazolam clearance using these markers and demonstrated that the predictive model including three omega- or (omega-1)-hydroxylated medium-chain acylcarnitines, 6beta-OH cortisol, and gender as covariates shows reliable predictability (r2 = 0.894). PMID- 28877335 TI - Cranial sexual dimorphism in the Kinda baboon (Papio hamadryas kindae). AB - OBJECTIVES: The smallest extant member of genus Papio, the Kinda baboon exhibits low sexual dimorphism and a distinctive cranial shape. Ontogenetic scaling accounts for most cranial-shape differences within Papio, but studies have shown that the Kinda follows a separate ontogenetic trajectory. If so, its cranial dimorphism pattern should differ from other subspecies. To evaluate this hypothesis, morphometric analysis was used to investigate cranial dimorphism in Papio. MATERIALS AND METHODS: Three-dimensional landmarks were digitized on 434 adult crania representing six Papio subspecies. Size- and shape-dimorphism magnitudes were quantified using centroid size and Procrustes distances. Patterns of sex- and size-related variation were explored using MAN(C)OVA, multivariate regression, and form-space PCA. Canine dimorphism was investigated using dental metrics. RESULTS: Kinda size and shape dimorphism are significantly lower than in other Papio subspecies. The relative magnitude of Kinda shape dimorphism is similar to other southern baboons; Kinda canine dimorphism is unremarkable. MAN(C)OVA results support subspecies differences in cranial dimorphism and scaling. Allometric and dimorphism vectors differ significantly in some subspecies, and their vector-angle matrices are strongly correlated. The Kinda's allometric vector angles are divergent. Form-space PC3, summarizing size independent dimorphism, separates the Kinda from other subspecies. DISCUSSION: The Kinda baboon exhibits significantly lower size and shape dimorphism than other baboons, but its relative dimorphism levels are unexceptional. The Kinda differs from other subspecies in patterns of allometry, size-related shape dimorphism, and residual shape dimorphism. Kinda facial shape is "masculinized" relative to size, especially in females, suggesting female sexual selection contributed to the evolution of Kinda dimorphism. PMID- 28877337 TI - Parent-reported indicators for detecting feeding and swallowing difficulties and undernutrition in preschool-aged children with cerebral palsy. AB - AIM: To determine the most accurate parent-reported indicators for detecting (1) feeding/swallowing difficulties and (2) undernutrition in preschool-aged children with cerebral palsy (CP). METHOD: This was a longitudinal, population-based study, involving 179 children with CP, aged 18 to 60 months (mean 34.1mo [SD 11.9] at entry, 111 males, 68 females [Gross Motor Function Classification System level I, 84; II, 23; III, 28; IV, 18; V, 26], 423 data points). Feeding/swallowing difficulties were determined by the Dysphagia Disorders Survey and 16 signs suggestive of pharyngeal phase impairment. Undernutrition was indicated by height-weight and skinfold composite z-scores less than -2. Primary parent-reported indicators included mealtime duration, mealtime stress, concern about growth, and respiratory problems. Other indicators were derived from a parent feeding questionnaire, including 'significant difficulty eating and drinking'. Data were analysed using multilevel mixed-effects regression and diagnostic statistics. RESULTS: Primary parent-reported indicators associated with feeding/swallowing were 'moderate-severe parent stress' (odds ratio [OR]=3.2 [95% confidence interval {CI} 1.3-7.8]; p<0.01), 'moderate-severe concern regarding growth' (OR=4.5 [95% CI 1.7-11.9]; p<0.01), and 'any respiratory condition' (OR=1.8 [95% CI 1.4-5.8]; p<0.01). The indicator associated with undernutrition was 'moderate-severe concern regarding growth' (height-weight OR=13.5 [95% CI 3.0-61.3]; p<0.01; skinfold OR=19.1 [95% CI 3.7-98.9]; p<0.01). 'Significant difficulty eating and drinking' was most sensitive/specific for feeding outcome (sensitivity=58.6%, specificity=100.0%), and 'parent concern regarding growth' for undernutrition (sensitivity=77.8%, specificity=77.0%). INTERPRETATION: Parent-reported indicators are feasible for detecting feeding and swallowing difficulties and undernutrition in children with CP, but need formal validation. WHAT THIS PAPER ADDS: Parent-reported indicators can detect feeding/swallowing difficulties and undernutrition in children with cerebral palsy. Most accurate screening questions were 0-10 scales for 'difficulty eating' and 'difficulty drinking'. Supplementation of these scales with additional indicators would improve detection. PMID- 28877338 TI - A Switchable Linker-Based Immunoassay for Ultrasensitive Visible Detection of Salmonella in Tomatoes. AB - : On-site detection for sensitive identification of foodborne pathogens on fresh produce with minimal use of specialized instrumentation is crucial to the food industry. A switchable linker (SL)-based immunoassay was designed for ultrasensitive on-site detection of Salmonella in tomato samples. The assay is based on large-scale aggregation of gold nanoparticles (GNPs), induced by a quantitative relationship among the biotinylated Salmonella polyclonal antibody (b-Ab) used as the SL, the functionalized GNPs, and Salmonella. Important factors such as the concentration of SLs, time required for large-scale aggregation, and selectivity of b-Ab were optimized to minimize the detection time (within 45 min with gentle agitation) and achieve the lowest limit of detection (LOD; 10 CFU/g in tomato samples) possible. This SL-based immunoassay with its relatively low LOD and short detection time may meet the need for rapid, simple, on-site analysis of pathogens in fresh produce. PRACTICAL APPLICATION: The novel switchable linker-based immunoassay is a rapid, specific, and sensitive method that has potential applications for routine diagnostics of Salmonella in tomato products. These advantages make it a practical approach for general use in the processing industry to detect Salmonella rapidly and to implement appropriate regulatory procedures. Furthermore, it could be applied to other fresh products including cantaloupe, strawberry, and cucumbers. PMID- 28877339 TI - Cognitive functioning over 2 years after intracerebral hemorrhage in school-aged children. AB - AIM: Previous research investigating outcomes after pediatric intracerebral hemorrhage (ICH) has generally been limited to global and sensorimotor outcomes. This study examined cognitive outcomes after spontaneous ICH in school-aged children with serial assessments over 2 years after stroke. METHOD: Seven children (age range 6-16y, median 13; six males, one female; 57% white, 43% black) presenting with spontaneous ICH (six arteriovenous malformations) were assessed at 3 months, 12 months, and 24 months after stroke. The Pediatric Stroke Outcome Measure (PSOM) quantified neurological outcome and Wechsler Intelligence Scales measured cognitive outcomes: verbal comprehension, perceptual reasoning, working memory, and processing speed. RESULTS: PSOM scales showed improved neurological function over the first 12 months, with mild to no sensorimotor deficits and moderate overall deficits at 1- and 2-year follow-ups (median 2-year sensorimotor PSOM=0.5, total PSOM=1.5). Changes in cognitive function indicated a different trajectory; verbal comprehension and perceptual reasoning improved over 24 months; low performance was sustained in processing speed and working memory. Age-normed centile scores decreased between 1- and 2-year follow-ups for working memory, suggesting emerging deficits compared with peers. INTERPRETATION: Early and serial cognitive testing in children with ICH is needed to assess cognitive functioning and support children in school as they age and cognitive deficits become more apparent and important for function. WHAT THIS PAPER ADDS: In children with intracerebral hemorrhage (ICH), motor function improved between 3 months and 24 months. Improvements in cognitive function were variable between 3 months and 24 months. Working memory centiles declined, suggesting emerging deficits compared with peers. Processing speed improved but remained significantly below the 50th centile. Cognitive impact of ICH may increase with age in children. PMID- 28877341 TI - Fine-tuning the 'plant domestication-reduced defense' hypothesis: specialist vs generalist herbivores. AB - Domesticated plants are assumed to have weakened chemical defenses. We argue, however, that artificial selection will have maintained defense traits against specialized herbivores that have coexisted with the crops throughout their domestication. We assessed the performance of eight species of insect herbivores from three feeding guilds on six European maize lines and six populations of their wild ancestor, teosinte. A metabolomics approach was used in an attempt to identify compounds responsible for observed differences in insect performance. Insects consistently performed better on maize than on teosinte. As hypothesized, this difference was greater for generalist herbivores that are normally not found on teosinte. We also found clear differences in defense metabolites among the different genotypes, but none that consistently correlated with differences in performance. Concentrations of benzoxazinoids, the main chemical defense in maize, tended to be higher in leaves of teosinte, but the reverse was true for the roots. It appears that chemical defenses that target specialized insects are still present at higher concentrations in cultivated maize than compounds that are more effective against generalists. These weakened broad-spectrum defenses in crops may explain the successes of novel pests. PMID- 28877340 TI - The miR156-SPL4 module predominantly regulates aerial axillary bud formation and controls shoot architecture. AB - Grasses possess basal and aerial axillary buds. Previous studies have largely focused on basal bud (tiller) formation but scarcely touched on aerial buds, which may lead to aerial branch development. Genotypes with and without aerial buds were identified in switchgrass (Panicum virgatum), a dedicated bioenergy crop. Bud development was characterized using scanning electron microscopy. Microarray, RNA-seq and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to identify regulators of bud formation. Gene function was characterized by down-regulation and overexpression. Overexpression of miR156 induced aerial bud formation in switchgrass. Various analyses revealed that SQUAMOSA PROMOTER BINDING PROTEIN LIKE4 (SPL4), one of the miR156 targets, directly regulated aerial axillary bud initiation. Down-regulation of SPL4 promoted aerial bud formation and increased basal buds, while overexpression of SPL4 seriously suppressed bud formation and tillering. RNA-seq and RT-qPCR identified potential downstream genes of SPL4. Unlike all previously reported genes acting as activators of basal bud initiation, SPL4 acts as a suppressor for the formation of both aerial and basal buds. The miR156-SPL4 module predominantly regulates aerial bud initiation and partially controls basal bud formation. Genetic manipulation of SPL4 led to altered plant architecture with increased branching, enhanced regrowth after cutting and improved biomass yield. PMID- 28877342 TI - Synergistic effects of long-wavelength ultraviolet A1 and visible light on pigmentation and erythema. AB - BACKGROUND: Visible light (VL) induces multiple cutaneous effects. Sunscreen testing protocols recommended by regulatory bodies throughout the world require the use of solar simulators with spectral output in the ultraviolet (UV) domain only. However, sunlight contains VL and infrared radiation also. OBJECTIVES: This study aimed to evaluate the contributions of VL and UVA on pigmentation and erythema, and optimize parameters for in vivo testing. METHODS: Ten subjects with Fitzpatrick skin phototype IV-VI were enrolled. Subjects were irradiated on their back with VL using two light sources: one containing pure VL and one containing VL with less than 0.5% UVA1 (VL+UVA1). Four different irradiances were administered to investigate reciprocity behaviour. Assessments, including photography, Investigator's Global Assessment, colorimetry and spectroscopy, were performed immediately, 24 h, 7 days and 14 days post-irradiation. RESULTS: Pigmentation was observed with both light sources; however, pigment intensity was greater with VL+UVA1 than with pure VL. Reciprocity was observed in pure VL sites, but not VL+UVA1. Variation in spectral output had greater impact on pigment intensity than irradiance. Clinical erythema was observed on the VL+UVA1 side, but not on the pure VL side. A protocol for testing photoprotection product efficacy against VL-induced effects has been proposed. CONCLUSIONS: The findings suggest a synergistic relationship between VL and UVA1 and emphasize the need for developing means of photoprotection against VL. PMID- 28877343 TI - Transition to agriculture in South-Eastern Arabia: Insights from oral conditions. AB - OBJECTIVES: In Southeast (SE) Arabia, agriculture is supposed to expand around 3000 BC, but its tempo and its actual role in populations' subsistence is still debated by archaeologists. Here, we compare dental health conditions of 11 skeletal samples from coastal and inland sites, dated from the Late Neolithic (ca. 4500-3100 BC) to the Early Bronze Age (EBA), conventionally divided into Hafit (ca. 3100-2700 BC) and Umm an-Nar period (ca. 2700-2000 BC). The goal is to assess long-term trends in subsistence patterns and regional variability during the local transition to agriculture. METHODS: Seven indicators of oral health and childhood stress were analyzed, including dental wear, calculus, caries, alveolar resorption, periapical lesions, ante-mortem tooth loss (AMTL), and linear enamel hypoplasia (LEH). RESULTS: Neolithic coastal populations are globally characterized by high dental wear, high calculus frequency, high LEH frequency, and frequent periodontal disease, whereas they exhibit low abscesses and AMTL frequencies and a total absence of carious lesions. Samples from the Hafit period present high dental wear, low rates of calculus and LEH, frequent periodontal disease, combined with low abscess and AMTL frequencies and absence of caries. By contrast, samples from the Umm an-Nar period exhibit much lower dental wear, calculus and LEH rates, whereas caries, periapical lesions and AMTL frequencies increase significantly. Marked differences were observed between coastal and inland Umm an-Nar groups, the latter presenting significantly higher frequencies of caries, periapical lesions, alveolar resorption and AMTL. DISCUSSION/CONCLUSION: Oral conditions from the Neolithic coastal populations denote a diet mainly composed of unprocessed and abrasive food, with high protein and low carbohydrate intakes, and frequent stress episodes. Although Hafit populations display some changes in oral pathologies, which indicate modifications in their lifestyle and a diversification of the diet, no markers of high carbohydrate intakes were observed in our samples. The impact of agriculture on oral health appears clearly only from the Umm an-Nar period, and is more intense inland than on the coast, where marine resources are still a main component of the diet. PMID- 28877344 TI - Development of a 3D remote dosimetry protocol compatible with MRgIMRT. AB - PURPOSE: To develop a novel remote 3D dosimetry protocol to verify Magnetic Resonance-guided Radiation Therapy (MRgRT) treatments. The protocol was applied to investigate the accuracy of TG-119 IMRT irradiations delivered by the MRIdian(r) system (ViewRay(r) , Oakwood Village, OH, USA) allowing for a 48-hour delay between irradiation at a field institution and subsequent readout at a base institution. METHODS: The 3D dosimetry protocol utilizes a novel formulation of PRESAGE(r) radiochromic dosimeters developed for high postirradiation stability and compatibility with optical-CT readout. Optical-CT readout was performed with an in-house system utilizing telecentric lenses affording high-resolution scanning. The protocol was developed from preparatory experiments to characterize PRESAGE(r) response in relevant conditions. First, linearity and sensitivity of PRESAGE(r) dose-response in the presence of a magnetic field was evaluated in a small volume study (4 ml cuvettes) conducted under MRgRT conditions and irradiated with doses 0-15 Gy. Temporal and spatial stability of the dose response were investigated in large volume studies utilizing large field-of-view (FOV) 2 kg cylindrical PRESAGE(r) dosimeters. Dosimeters were imaged at t = 1 hr and t = 48 hrs enabling the development of correction terms to model any observed spatial and temporal changes postirradiation. Polynomial correction factors for temporal and spatial changes in PRESAGE(r) dosimeters (CT and CR respectively) were obtained by numerical fitting to time-point data acquired in six irradiated dosimeters. A remote dosimetry protocol was developed where PRESAGE(r) change in optical-density (DeltaOD) readings at time t = X (the irradiation to return shipment time interval) were corrected back to a convenient standard time t = 1 hr using the CT and CR corrections. This refined protocol was then applied to TG 119 (American Association of Physicists in Medicine, Task Group 119) plan deliveries on the MRIdian(r) system to evaluate the accuracy of MRgRT in these conditions. RESULTS: In the small volume study, in the presence of a 0.35 T magnetic field, PRESAGE(r) was observed to respond linearly (R2 = 0.9996) to Co 60 irradiation at t = 48 hrs postirradiation, within the dose ranges of 0 to 15 Gy, with a sensitivity of 0.0305(+/-0.003) DeltaOD cm-1 Gy-1 . In the large volume studies, at t = 1 hr postirradiation, consistent linear response was observed, with average sensitivity of 0.0930 +/- 0.002 DeltaOD cm-1 Gy-1 . However, dosimeters gradually darkened with time (OD< 5% per day). A small radial dependence to the dosimeter sensitivity was measured (< 3% of maximum dose), which is attributed to a spherically symmetric dosimeter artifact arising from exothermic heating legacy in the PRESAGE(r) polyurethane substrate during curing. When applied to the TG-119 IMRT irradiations, the remote dosimetry protocol (including correction terms) yielded excellent line-profile and 3D gamma agreement for 3%/3 mm, 10% threshold (mean passing rate = 96.6% +/- 4.0%). CONCLUSION: A novel 3D remote dosimetry protocol is introduced for validating off site dosimetrically complex radiotherapy systems, including MRgRT. The protocol involves correcting for temporal and spatially dependent changes in PRESAGE(r) radiochromic dosimeters readout by optical-CT. Application of the protocol to TG 119 irradiations enabled verification of MRgRT dose distributions with high resolution. PMID- 28877345 TI - Solute Transfer in Osmotic Dehydration of Vegetable Foods: A Review. AB - While various mechanisms have been proposed for the water transfer during osmotic dehydration (OD), little progress has been made to understand the mechanisms of solute transfer during osmotic dehydration. The transfer of solutes has been often described only by the diffusion mechanism; however, numerous evidences suggest the participation of a variety of mechanisms. This review deals with the main issues of solute transfer in the OD of vegetables. In this context, several studies suggest that during OD of fruits and vegetables, the migration of solutes is not influenced by diffusion. Thus, new theories that may explain the solute transport are analyzed, considering the influence of the plant microstructure and its interaction with the physicochemical properties of osmotic liquid media. In particular, the surface adhesion phenomenon is analyzed and discussed, as a possible mechanism present during the transfer of solutes in OD. PMID- 28877346 TI - Comparable Outcome of Out-of-Hospital Cardiac Arrest and In-Hospital Cardiac Arrest Treated With Extracorporeal Life Support. AB - Extracorporeal life support (ECLS) has shown benefits in the management of refractory in-hospital cardiac arrest (IHCA) by improving survival. Nonetheless, the results concerning out-of-hospital refractory cardiac arrests (OHCA) remain uncertain. The aim of our investigation was to compare survival between the two groups. We realized a single-center retrospective, observational study of all patients who presented IHCA or OHCA treated with ECLS between 2011 and 2015. Multivariate analysis was realized to determine independent factors associated with mortality. Over the 4-year period, 65 patients were included, 43 in the IHCA group (66.2%), and 22 (33.8%) in the OHCA group. The duration of low flow was significantly longer in the OHCA group (60 vs. 90 min, P = 0.004). Survival to discharge from the hospital was identical in the two groups (27% in the OHCA group vs. 23% in the IHCA group, P = 0.77). All surviving patients in the OHCA group had a cerebral performance categories score of 1-2. In multivariate analysis, we found that the initial lactate level and baseline blood creatinine were independently associated with mortality. We found comparable survival and neurological score in patients who presented IHCA and OHCA treated with ECLS. We believe that appropriate selection of patients and optimization of organ perfusion during resuscitation can lead to good results in patients with OHCA treated with ECLS. PMID- 28877347 TI - Sex differences in the role of phospholipase A2 -dependent arachidonic acid pathway in the perivascular adipose tissue function in pigs. AB - KEY POINTS: The fat surrounding blood vessels (perivascular adipose tissue or PVAT) releases vasoactive compounds that regulate vascular smooth muscle tone. There are sex differences in the regulation of vascular tone, but, to date, no study has investigated whether there are sex differences in the regulation of blood vessel tone by PVAT. This study has identified that the cyclooxygenase products thromboxane and PGF2alpha are released from coronary artery PVAT from pigs. Thromboxane appears to mediate the PVAT-induced contraction in arteries from females, whereas PGF2alpha appears to mediate the contraction in arteries from males. These sex differences in the role of these prostanoids in the PVAT induced contraction can be explained by a greater release of thromboxane from PVAT from female animals and greater sensitivity to PGF2alpha in the porcine coronary artery from males. ABSTRACT: Previous studies have demonstrated that perivascular adipose tissue (PVAT) causes vasoconstriction. In this present study, we determined the role of cyclooxygenase-derived prostanoids in this contractile response and determined whether there were any sex differences in the regulation of vascular tone by PVAT. Contractions in isolated segments of coronary arteries were determined using isolated tissue baths and isometric tension recording. Segments were initially cleaned of PVAT, which was then re added to the tissue bath and changes in tone measured over 1 h. Levels of PGF2alpha and thromboxane B2 (TXB2 ) were quantified by ELISA, and PGF2alpha (FP) and thromboxane A2 (TP) receptor expression determined by Western blotting. In arteries from both male and female pigs, re-addition of PVAT caused a contraction, which was partially inhibited by the cyclooxygenase inhibitors indomethacin and flurbiprofen. The FP receptor antagonist AL8810 attenuated the PVAT-induced contraction in arteries from males, whereas the TP receptor antagonist GR32191B inhibited the PVAT-induced contraction in arteries from females. Although there was no difference in PGF2alpha levels in PVAT between females and males, PGF2alpha produced a larger contraction in arteries from males, correlating with a higher FP receptor expression. In contrast, release of TXB2 from PVAT from females was greater than from males, but there was no difference in the contraction by the TXA2 agonist U46619, or TP receptor expression in arteries from different sexes. These findings demonstrate clear sex differences in PVAT function in which PGF2alpha and TXA2 antagonists can inhibit the PVAT-induced vasoconstriction in male and female PCAs, respectively. PMID- 28877348 TI - Superparamagnetic iron oxide nanoparticles as the sole method for sentinel node biopsy detection in patients with breast cancer. AB - BACKGROUND: Sentinel node biopsy (SNB) using superparamagnetic iron oxide (SPIO) nanoparticles is a novel method in breast cancer. Several studies have verified the non-inferiority of SPIO compared with the standard use of radioisotope 99m Tc with or without blue dye. The aim of the MONOS study presented here was to evaluate the use of SPIO as a sole tracer and the efficacy of tracer injection in the preoperative setting. METHODS: This prospective cohort study was carried out in two hospitals, one using 99m Tc and the other SPIO. 99m Tc was injected in the morning of the day of surgery or the day before. SPIO was either injected before surgery in the outpatient clinic or 1 h before the operation. RESULTS: A total of 338 consecutive patients with breast cancer underwent 343 procedures; SPIO nanoparticles were used in 184 procedures and 99m Tc-labelled tracer in 159. Detection rates for SPIO and 99m Tc were 95.6 and 96.9 per cent respectively (P = 0.537). All nodes with SPIO uptake were coloured brown. Fewer nodes were retrieved with SPIO (mean 1.35 versus 1.89), regardless of whether blue dye was used (P < 0.001). Preoperative SPIO injection (58.7 per cent of procedures), a median of 16 (range 2-27) days before the procedure, was associated with a better tracer-specific detection rate (95.3 versus 86 per cent; P = 0.031) and retrieval of more nodes (mean 1.43 versus 1.03; P < 0.001) than perioperative administration. Skin staining was present in 39.9 per cent of patients, and was related to breast-conserving surgery and periareolar injection. CONCLUSION: The use of SPIO alone is a safe alternative, with results comparable to those of the standard dual technique using 99m Tc and blue dye. The efficacy of injection in the preoperative setting simplifies logistics and improves performance. Skin staining can be prevented by a deeper peritumoral injection. PMID- 28877350 TI - Oxidative Stress Increases Erythrocyte Sensitivity to Shear-Mediated Damage. AB - Patients receiving mechanical circulatory support often present with heightened inflammation and free radical production associated with pre-existing conditions in addition to that which is due to blood interactions with nonbiological surfaces. The aim of this experimental laboratory study was to assess the deformability of red blood cells (RBC) previously exposed to oxygen free radicals and determine the susceptibility of these cells to mechanical forces. In the present study, RBC from 15 healthy donors were washed and incubated for 60 min at 37 degrees C with 50 uM phenazine methosulfate (PMS; an agent that generates superoxide within RBC). Incubated RBC and negative controls were assessed for their deformability and susceptibility to mechanical damage (using ektacytometry) prior to the application of shear stress, and also following exposure to 25 different shear conditions of varied magnitudes (shear stress 1, 4, 16, 32, 64 Pa) and durations (1, 4, 16, 32, 64 s). The salient findings demonstrate that incubation with PMS impaired important indices of RBC deformability indicating altered cell mechanics by ~19% in all conditions (pre- and postexposure to shear stress). The typical trends in shear-mediated changes in RBC susceptibility to mechanical damage, following conditioning shear stresses, were maintained for PMS incubated and control conditions. We demonstrated that free radicals hinder the ability of RBC to deform; however, RBC retained their typical mechanical response to shear stress, albeit at a decreased level compared with control following exposure to PMS. Our findings also indicate that low shear exposure may decrease cell sensitivity to mechanical damage upon subsequent shear stress exposures. As patients receiving mechanical circulatory support have elevated exposure to free radicals (which limits RBC deformability), concomitant exposure to high shear environments needs to be minimized. PMID- 28877349 TI - Development of the quality of reaching in infants with cerebral palsy: a kinematic study. AB - AIM: To assess development of reaching and head stability in infants at very high risk (VHR-infants) of cerebral palsy (CP) who did and did not develop CP. METHOD: This explorative longitudinal study assessed the kinematics of reaching and head sway in sitting in 37 VHR-infants (18 CP) one to four times between 4.7 months and 22.6 months corrected age. Developmental trajectories were calculated using linear mixed effect models. Motor function was evaluated with the Infant Motor Profile (IMP) around 13 months corrected age. RESULTS: Throughout infancy, VHR infants with CP had a worse reaching quality than infants without CP, reflected for example by more movement units (factor 1.52, 95% CI 1.16-1.99) and smaller transport movement units (factor 1.86, 95% CI 1.20-2.90). Total head sway of infants with and without CP was similar, but infants with CP used more head movement units to achieve stability. The rate of developmental change in infants with and without CP was similar. Around 13 months, head control and reaching quality were interrelated; both were associated with IMP-scores. INTERPRETATION: Infants with CP showed a worse kinematic reaching quality and head stability throughout infancy from early age onwards than VHR-infants without CP, implying that kinematically they do not grow into a deficit, but exhibit deficits from early infancy on. WHAT THIS PAPER ADDS: Reaching quality improves throughout infancy in all infants at high risk (VHR-infants). Infants with cerebral palsy (CP) show a worse reaching quality than VHR-infants without CP. Infants with CP achieve head stability differently from infants without CP. Infants with CP exhibit kinematic reaching problems from early age onwards. PMID- 28877351 TI - Evaluation of a novel collimator for molecular breast tomosynthesis. AB - PURPOSE: This study investigated a novel gamma camera for molecular breast tomosynthesis (MBT), which is a nuclear breast imaging method that uses limited angle tomography. The camera is equipped with a variable angle, slant-hole (VASH) collimator that allows the camera to remain close to the breast throughout the acquisition. The goal of this study was to evaluate the spatial resolution and count sensitivity of this camera and to compare contrast and contrast-to-noise ratio (CNR) with conventional planar imaging using an experimental breast phantom. METHODS: The VASH collimator mounts to a commercial gamma camera for breast imaging that uses a pixelated (3.2 mm), 15 * 20 cm NaI crystal. Spatial resolution was measured in planar images over a range of distances from the collimator (30-100 mm) and a range of slant angles (-25 degrees to 25 degrees ) using 99m Tc line sources. Spatial resolution was also measured in reconstructed MBT images including in the depth dimension. The images were reconstructed from data acquired over the -25 degrees to 25 degrees angular range using an iterative algorithm adapted to the slant-hole geometry. Sensitivity was measured over the range of slant angles using a disk source. Measured spatial resolution and sensitivity were compared to theoretical values. Contrast and CNR were measured using a breast phantom containing spherical lesions (6.2 mm and 7.8 mm diameter) and positioned over a range of depths in the phantom. The MBT and planar methods had equal scan time, and the count density in the breast phantom data was similar to that in clinical nuclear breast imaging. The MBT method used an iterative reconstruction algorithm combined with a postreconstruction Metz filter. RESULTS: The measured spatial resolution in planar images agreed well with theoretical calculations over the range of distances and slant angles. The measured FWHM was 9.7 mm at 50 mm distance. In reconstructed MBT images, the spatial resolution in the depth dimension was approximately 2.2 mm greater than the other two dimensions due to the limited angle data. The measured count sensitivity agreed closely with theory over all slant angles when using a wide energy window. At 0 degrees slant angle, measured sensitivity was 19.7 counts sec-1 MUCi-1 with the open energy window and 11.2 counts sec-1 MUCi-1 with a 20% wide photopeak window (126 to 154 keV). The measured CNR in the MBT images was significantly greater than in the planar images for all but the lowest CNR cases where the lesion detectability was extremely low for both MBT and planar. The 7.8 mm lesion at 37 mm depth was marginally detectable in the planar image but easily visible in the MBT image. The improved CNR with MBT was due to a large improvement in contrast, which out-weighed the increase in image noise. CONCLUSION: The spatial resolution and count sensitivity measurements with the prototype MBT system matched theoretical calculations, and the measured CNR in breast phantom images was generally greater with the MBT system compared to conventional planar imaging. These results demonstrate the potential of the proposed MBT system to improve lesion detection in nuclear breast imaging. PMID- 28877353 TI - Adolescence transitional care in neurogenic detrusor overactivity and the use of OnabotulinumtoxinA: A clinical algorithm from an Italian consensus statement. AB - AIMS: OnabotulinumtoxinA (onaBNTa) for treating neurogenic detrusor overactivity (NDO) is widely used after its regulatory approval in adults. Although the administration of onaBNTa is still considered off-label in children, data have already been reported on its efficacy and safety. Nowadays, there is a lack of standardized protocols for treatment of NDO with onaBNTa in adolescent patients in their transition from the childhood to the adult age. With the aim to address this issue a consensus panel was obtained. METHODS: A panel of leading urologists and urogynaecologists skilled in functional urology, neuro-urology, urogynaecology, and pediatric urology participated in a consensus-forming project using a Delphi method to reach national consensus on NDO-onaBNTa treatment in adolescence transitional care. RESULTS: In total, 11 experts participated. All panelists participated in the four phases of the consensus process. Consensus was reached if >=70% of the experts agreed on recommendations. To facilitate a common understanding among all experts, a face-to-face consensus meeting was held in Rome in march 2015 and then with a follow-up teleconference in march 2017. By the end of the Delphi process, formal consensus was achieved for 100% of the items and an algorithm was then developed. CONCLUSIONS: This manuscript represents the first report on the onaBNTa in adolescents. Young adults should be treated as a distinct sub-population in policy, planning, programming, and research, as strongly sustained by national public health care. This consensus and the algorithm could support multidisciplinary communication, reduce the extent of variations in clinical practice and optimize clinical decision making. PMID- 28877352 TI - Incidence, Risk Factors, and Outcomes of Hyperbilirubinemia in Adult Cardiac Patients Supported by Veno-Arterial ECMO. AB - The aims of this study were to evaluate the incidence, risk factors, and outcomes of hyperbilirubinemia in cardiac patients with veno-arterial (VA) ECMO. Data on 89 adult patients with cardiac diseases who received VA ECMO implantation in our hospital were retrospectively reviewed. All patients were divided into the following three groups: 24 in normal group (N, total bilirubin [TBIL] <=3 mg/dL), 30 in high bilirubin group (HB, 6 mg/dL >= TBIL > 3 mg/dL), and 35 in severe high bilirubin group (SHB, TBIL > 6 mg/dL). lg(variables + 1) was performed for nonnormally distributed variables. The incidence of hyperbilirubinemia (>3 mg/dL) was 73%. In a multiple linear regression analysis, lg(peak TBIL + 1) was significantly associated with lg(peak AST + 1) (b-coefficient 0.188, P = 0.001), lg(peak pFHb + 1) (b-coefficient 0.201, P = 0.003), and basic TBIL (b-coefficient 0.006, P = 0.009). Repeated measurement analysis of variance revealed that the main effect for three groups in pFHb and lg(AST + 1) was significant at first 3 days during ECMO. The patients in SHB had low platelets during ECMO and low in hospital survival rate. Hyperbilirubinemia remains common in patients with VA ECMO and is associated with low platelets and high in-hospital mortality. Hemolysis and liver dysfunction during ECMO and basic high bilirubin levels are risk factors of hyperbilirubinemia. PMID- 28877354 TI - Lung Ultrasonography in Patients With Idiopathic Pulmonary Fibrosis: Evaluation of a Simplified Protocol With High-Resolution Computed Tomographic Correlation. AB - OBJECTIVES: To compare a simplified ultrasonographic (US) protocol in 2 patient positions with the same-positioned comprehensive US assessments and high resolution computed tomographic (CT) findings in patients with idiopathic pulmonary fibrosis. METHODS: Twenty-five consecutive patients with idiopathic pulmonary fibrosis were prospectively enrolled and examined in 2 sessions. During session 1, patients were examined with a US protocol including 56 lung intercostal spaces in supine/sitting (supine/sitting comprehensive protocol) and lateral decubitus (decubitus comprehensive protocol) positions. During session 2, patients were evaluated with a 16-intercostal space US protocol in sitting (sitting simplified protocol) and left/right decubitus (decubitus simplified protocol) positions. The 16 intercostal spaces were chosen according to the prevalence of idiopathic pulmonary fibrosis-related changes on high-resolution CT. The sum of B-lines counted in each intercostal space formed the US scores for all 4 US protocols: supine/sitting and decubitus comprehensive US scores and sitting and decubitus simplified US scores. High-resolution CT-related Warrick scores (J Rheumatol 1991; 18:1520-1528) were compared to US scores. The duration of each protocol was recorded. RESULTS: A significant correlation was found between all US scores and Warrick scores and between simplified and corresponding comprehensive scores (P < .0001). Decubitus simplified US scores showed a slightly higher correlation with Warrick scores compared to sitting simplified US scores. Mean durations of decubitus and sitting simplified protocols were 4.76 and 6.20 minutes, respectively (P < .005). CONCLUSIONS: Simplified 16-intercostal space protocols correlated with comprehensive protocols and high-resolution CT findings in patients with idiopathic pulmonary fibrosis. The 16-intercostal space simplified protocol in the lateral decubitus position correlated better with high resolution CT findings and was less time-consuming compared to the sitting position. PMID- 28877355 TI - Sonographic Evaluation of Complications of Extracranial Carotid Artery Interventions. AB - Carotid endarterectomy and carotid artery stenting are among the most common peripheral vascular procedures performed worldwide. Sonography is the initial and often only imaging modality used in the evaluation of iatrogenic carotid arterial injuries. This pictorial essay provides an overview of the clinical and sonographic findings of complications after interventions in the extracranial carotid arteries, including dissection, fluid collections, pseudoaneurysm, thrombosis, thromboembolism, restenosis, and stent deformation. Grayscale, color, and pulsed Doppler imaging findings are reviewed, and correlations with computed tomography, magnetic resonance imaging, and angiography are provided. PMID- 28877356 TI - Analysis of Contrast-Enhanced Ultrasound Perfusion Patterns and Time-Intensity Curves for Metastatic Lymph Nodes From Lung Cancer: Preliminary Results. AB - OBJECTIVES: To retrospectively summarize the similarities and differences in contrast-enhanced ultrasound (US) findings for lymph node metastasis from adenocarcinoma, squamous carcinoma, and small cell lung cancer. METHODS: Patients who had received contrast-enhanced US examinations and had a histologic diagnosis of supraclavicular lymph node metastasis from lung cancer were included. The perfusion patterns on contrast-enhanced US images and time-intensity curve parameters were analyzed for the different pathologic types. The microvascular density and microvascular diameter were evaluated. RESULTS: Totally, 61 patients were enrolled in this study, including 26 cases with lung squamous carcinoma, 26 with lung adenocarcinoma, and 9 with small cell lung cancer. Contrast-enhanced US perfusion showed no significant differences in enhancement uniformity during the arterial phase and in the presence of unenhanced areas of metastatic lymph nodes with the 3 different pathologic origins (P > .05), but fewer unenhanced areas could be seen in metastatic lymph nodes from adenocarcinoma. The analysis of the time-intensity curve parameters showed that there were significant differences in the peak intensity between metastatic lymph nodes from lung squamous carcinoma and lung adenocarcinoma (P < .05). The microvascular density of metastatic lymph nodes from adenocarcinoma was significantly higher than that of metastatic lymph nodes from squamous carcinoma and small cell lung cancer (P < .001; P = .0444), whereas the microvascular diameter of metastatic lymph nodes from adenocarcinoma was significantly smaller than that from squamous carcinoma and small cell lung cancer (P = .0277; P < .001). CONCLUSIONS: Effects of the pathologic diagnosis should be considered when analyzing quantitative parameters of metastatic lymph nodes during contrast-enhanced US examinations, even in the same organ. PMID- 28877357 TI - Assessment of the Fetal Cerebral Artery: Importance of Doppler Preset Settings. AB - OBJECTIVES: The Doppler assessment of the middle cerebral artery (MCA) has a central role in the monitoring of high-risk pregnancies. The objective of this study was to investigate the importance of Doppler preset settings for measurement of the peak systolic velocity (PSV) and pulsatility index (PI) of the MCA. METHODS: The PI and PSV of the MCA were determined prospectively in 350 healthy fetuses between 19 and 42 weeks of pregnancy. The first measurement of the MCA (MCA.S) was performed with the conventional settings and the second (MCA.O) with an optimized setting of the maximum achievable frame rate. For the MCA.O measurement, the width of the B-mode image and the color Doppler window were adjusted as narrowly as possible. In addition, the MCA was shown in optimized high-definition zoom. Resulting values were compared with commonly used reference values. RESULTS: The PSV and PI values and frame rates of the MCA.O setting were noticeably greater than those of the MCA.S setting (P < .001 for all). For both settings, the PSV and PI values were increased compared to common reference values. CONCLUSIONS: The assessment of the MCA with the optimized Doppler default setting yielded increased PSV and PI values compared to the commonly used measurement technique. Moreover, the resulting median curves differed from the established median reference curves. Therefore, an updated standardization for measuring the MCA should be set out, and current reference values should be adjusted. PMID- 28877358 TI - Utility of Transfacial Dental Ultrasonography in Evaluation of Cystic Jaw Lesions. AB - OBJECTIVES: Plain radiography has been widely used in dentistry. Because of the variability of the quality of equipment, radiographic technique, accuracy of interpretation, and radiation risk to the patients, the field is ripe for the introduction of other newer diagnostic modalities. In this report, we demonstrate the utility of ultrasonography in the diagnostic workup of cystic or cystlike lesions of the jaw. METHODS: We used a transfacial ultrasonographic scanning approach to examine 32 patients with clinical or radiographic presentation of a jaw cyst. Computed tomography and histopathologic analysis were used as the reference standards to confirm the findings. RESULTS: Ultrasonography could establish the presence or absence of a lesion, erosion of the buccal cortical plate, and identification of associated soft tissue involvement in all cases (sensitivity and specificity, 100% and 100%, respectively; area under the receiver operating characteristic curve, 1.0; P < .001). CONCLUSIONS: Our observations revealed the usefulness of ultrasonography and demonstrated its potential value when introduced as a routine office-based imaging method for dentistry. PMID- 28877359 TI - Food elimination diets are effective for long-term treatment of adults with eosinophilic oesophagitis. AB - BACKGROUND: Limited data describe the long-term efficacy of dietary elimination in eosinophilic oesophagitis (EoE). AIM: To assess the long-term outcomes of food elimination diets for treatment of adults with EoE. METHODS: We conducted a retrospective cohort study at our centre analysing all EoE patients receiving a food elimination diet without concomitant steroids. Baseline data were abstracted using standardised collection forms. Follow-up data from a mean 24.9-month period were collected for patients with a histological response to a food elimination diet during and after food reintroduction. The main outcomes were symptomatic, endoscopic and histological responses. RESULTS: Of 52 patients, 18 received a 6 food food elimination diet, 32 received targeted diet, and two received a 6-food food elimination diet with targeted elimination. There were 21 (40%) patients with an initial histological response. Responders reported less dysphagia after treatment (95% baseline vs 11%; P = .001) and at the end of follow-up (95% baseline vs 33%; P = .008). Significant and durable endoscopic improvements were recorded at the same time points: Endoscopic reference score: 3.2 vs 0.7; P = .001; and 3.2 vs 1.7; P = .06. Histological findings improved after the most restrictive diet in responders (49.8 vs 4.1 eosinophils per high-power field; P = .001) and remained suppressed in the 10 initial responders maintaining compliance at the end of follow-up (5.2 eosinophils per high-power field). CONCLUSIONS: Among EoE patients responding to a food elimination diet and remaining adherent, maintenance dietary therapy produced durable long-term symptomatic, endoscopic and histological disease control. These long-term data confirm that a food elimination diet is an effective maintenance treatment option in select adults with EoE. PMID- 28877360 TI - Improvement of the efficacy of vascularized lymph node transfer for lower extremity lymphedema via a prefabricated lympho-venous shunt through lymphaticovenular anastomosis between the efferent lymphatic vessel and small vein in the elevated vascularized lymph node. AB - BACKGROUND: Following vascularized lymph node (VLN) transfer (VLNT), the VLN may be at a risk for sclerosis because of efferent lymphatic vessel obstruction. We developed a new technique to prevent VLN sclerosis via a prefabricated lympho venous (LV) shunt. This study compared the treatment outcomes of single VLNT with prefabricated LV shunt, conventional multiple VLNTs, and conventional single VLNT. METHODS: Overall, 47 limbs of 45 patients that underwent VLNT for lower extremity lymphedema (LEL) in late clinical stage II/III were divided into 3 groups: conventional single VLNT group (control; 21 limbs where 4 had primary LEL), multiple VLNTs group (13 limbs where 3 had primary LEL), and prefabricated LV shunt group (13 limbs where 4 had primary LEL). In the prefabricated LV shunt group, lymphaticovenular anastomosis between the efferent lymphatic vessel and small vein in the elevated VLN were performed simultaneously with VLNT. RESULTS: Although venous thrombosis at the anastomosis site was observed in 1 case, it was salvaged by re-anastomosis, and all VLNs survived. No other complications were observed. The LEL index significantly improved in the prefabricated LV shunt group compared with that in the control group (28.0 +/- 1.7 vs 20.9 +/- 1.5, P = 0.02). In the prefabricated LV shunt group, all VLNs survived functionally, and the average size of the transferred lymph nodes was significantly larger than that of the control group (5.7 +/- 0.1 vs 4.3 +/- 0.2 mm, P < 0.01). CONCLUSIONS: Prefabricated LV shunt may improve the efficacy of VLNT. PMID- 28877361 TI - "Enticing case study" or "celebrated anomaly"? Policy learning from the Cuban health system. AB - Cuba is regarded as having achieved very good health outcomes for its level of economic development. It has adopted policies and programs that focus on prevention, universal access to healthcare, a strong primary care system, the integration of health in all policies, and public participation in health. It has also established a strong and accessible system of medical education and provides substantial medical aid and support to other countries. Why then, it may be asked, has the Cuban experience not had greater influence on health policies and reforms elsewhere? This article, based on a literature review and new primary sources, analyzes various factors highlighted in the policy transfer literature to explain this. It also notes other factors that have created greater awareness of Cuban health achievements in some countries and which provide a basis for learning lessons from its policies. PMID- 28877362 TI - Trends in urodynamic testing prior to midurethral sling placement-What was the value of the VALUE trial? AB - BACKGROUND: Many urologists use urodynamic testing (UDS) to assist clinical decision-making. The VALUE study, a multi-institutional, randomized controlled trial published in 2012, demonstrated that UDS prior to midurethral sling placement for uncomplicated stress urinary incontinence (SUI) did not change management. We sought to determine whether use of UDS for evaluation of SUI diminished thereafter. METHODS: Records of patients who underwent isolated mid urethral sling surgery at our tertiary-care referral center from 2008 to 2009 (pre-VALUE) and 2014 to 2016 (post-VALUE) were reviewed. Comorbidities, presenting symptoms, surgeon specialty, use of UDS, UDS results and sling type were recorded. Patients with neurologic comorbidities or prior anti-incontinence procedures were excluded. Descriptive statistics were calculated and multivariable logistic regression analyses performed. RESULTS: Three hundred and eighty-seven patients met inclusion criteria. Median age was 54 years. Patients most frequently presented with stress urinary incontinence (56% pre, 50% post), followed by stress predominant mixed urinary incontinence (40% pre, 48% post, P = 0.09). Before VALUE, UDS was performed in 70% of patients prior to primary sling; in the later cohort, this decreased to 41% (P < 0.0001). On multivariable analysis, provider specialty (P < 0.0001) and belonging to the pre-VALUE cohort (P = < 0.0001) predicted use of UDS prior to sling. CONCLUSION: It is paramount that new data be incorporated into diagnostic and treatment algorithms. We found that the rate of preoperative urodynamic testing decreased after publication of a randomized-controlled trial demonstrating that these studies did not change procedural decision-making. Future studies that identify instances of over testing may have the ability to positively impact patient care and contain costs. PMID- 28877363 TI - Establishing an Ultrasound Curriculum in Undergraduate Medical Education: How Much Time Does It Take? AB - OBJECTIVES: Over the years, the use of ultrasound in the medical profession has become a common occurrence. As a result, many medical schools are considering an ultrasound curriculum for first- and second-year medical students. The question posed by many of these programs is how much time and effort are required to establish such a curriculum. We at the University of Colorado School of Medicine sought to quantify the resources and time required. METHODS: We conducted a cohort study that analyzed the time spent teaching, as well as the types of instructors (eg, faculty, resident, and peer student) that contributed to our ultrasound curriculum. The study population consisted of instructors who participated in the curriculum during the 2014-2015 academic year. We analyzed the amount of time that facilitators spent teaching and tabulated these data using their specialty. RESULTS: Our data revealed that within an academic year, a combined total of 484 hours were spent teaching ultrasound to first- and second year medical students combined. A total of 6 days were required to teach ultrasound to first-year medical students, and a total of 5 days were required for second-year medical students. It required 1 instructor for every 8 students, and most the faculty who volunteered time were from the field of emergency medicine, followed by family medicine and radiology. CONCLUSIONS: We describe the number of hours and instructors required to implement an ultrasound curriculum for undergraduate medical education. PMID- 28877364 TI - Are great apes able to reason from multi-item samples to populations of food items? AB - Inductive learning from limited observations is a cognitive capacity of fundamental importance. In humans, it is underwritten by our intuitive statistics, the ability to draw systematic inferences from populations to randomly drawn samples and vice versa. According to recent research in cognitive development, human intuitive statistics develops early in infancy. Recent work in comparative psychology has produced first evidence for analogous cognitive capacities in great apes who flexibly drew inferences from populations to samples. In the present study, we investigated whether great apes (Pongo abelii, Pan troglodytes, Pan paniscus, Gorilla gorilla) also draw inductive inferences in the opposite direction, from samples to populations. In two experiments, apes saw an experimenter randomly drawing one multi-item sample from each of two populations of food items. The populations differed in their proportion of preferred to neutral items (24:6 vs. 6:24) but apes saw only the distribution of food items in the samples that reflected the distribution of the respective populations (e.g., 4:1 vs. 1:4). Based on this observation they were then allowed to choose between the two populations. Results show that apes seemed to make inferences from samples to populations and thus chose the population from which the more favorable (4:1) sample was drawn in Experiment 1. In this experiment, the more attractive sample not only contained proportionally but also absolutely more preferred food items than the less attractive sample. Experiment 2, however, revealed that when absolute and relative frequencies were disentangled, apes performed at chance level. Whether these limitations in apes' performance reflect true limits of cognitive competence or merely performance limitations due to accessory task demands is still an open question. PMID- 28877366 TI - Melanocortin receptor subtypes are expressed on cells in the oligodendroglial lineage and signal ACTH protection. AB - ACTH, a melanocortin peptide used to treat multiple sclerosis (MS) relapses, acts by stimulating adrenal corticosteroid (CS) production via melanocortin receptor 2 (MC2R), but it may also exert a therapeutic effect independent of CS by stimulating other melanocortin receptors (MCR) distributed in many tissues, including the brain. We reported that oligodendroglia (OL) and oligodendroglial precursor cells (OPC) express MC4R, and that ACTH 1-39 protects OL and OPC in vitro from cell death induced by mechanisms likely involved in white matter damage in MS. This study investigates expression of MC1R, MC2R, MC3R and MC5R in OL and MC4R in OPC using immunocytochemistry with MCR subtype specific antibodies. OL express surface MC1R, MC3R and MC5R, in addition to MC4R. To investigate whether these receptors are functional, we asked if signaling through MCR is involved in ACTH protection of cultured rat OL from apoptosis (staurosporine), or cell death induced by excitotoxicity (glutamate), reactive oxygen species (ROS), or an inflammatory mediator (quinolinic acid). Like ACTH 1 39, MCR subtype specific agonists for MC1R, MC3R, MC4R and MC5R all protected OL from these insults. Conversely, antagonists for MC3R and MC4R blocked ACTH protection of OL. We then investigated the role of MC4R, as a prototype MCR, in protection and proliferation of OPC; MC4R agonists protected OPC and increased their proliferation, while antagonists blocked these effects. Our results demonstrate that MCR on OL and OPC are functional and activate signaling pathways that protect against mechanisms involved in OL damage in MS, suggesting potential beneficial effects in neurologic diseases. PMID- 28877365 TI - Molecular cloning, characterization and expression of immunoglobulin D on pathogen challenge and pathogen associated molecular patterns stimulation in freshwater carp, Catla catla. AB - The primordial immunoglobulin class, IgD, was the first non-IgM isotype discovered in teleosts. The crucial roles of IgM and IgZ in imparting systemic and mucosal immunity, respectively, in various fish species have been widely established. However, the putative function of a unique IgD isotype during pathogenic invasions has not been well explored. The present study reports the existence of an IgD ortholog in freshwater carp, Catla catla, and further evaluates its differential expression profile in response to bacterial, parasitic and viral antigenic exposure and pathogen associated molecular patterns (PAMPs) stimulation. The IgD of C. catla (CcIgD) cDNA sequence was found to encode 226 amino acids and confirmed homology with heavy chain delta region of Cyprinidae family members. Phylogenetic analysis of CcIgD exhibited greatest similarity with Ctenopharyngodon idella. qRT-PCR analysis revealed significant upregulation (P < 0.001) of IgD gene expression in kidney with respect to other tissues at 24 hr post-Aeromonas hydrophila challenge. CcIgD gene expression in skin was enhanced following Streptococcus uberis infection and in blood following Argulus infection and inactivated rhabdoviral antigen stimulation. Further, the treatment of bacterial and viral products (PAMPs) also triggered significant (P < 0.05) increases in CcIgD mRNA expression in kidney. These findings indicate the functional importance of teleost IgD in orchestrating tissue specific neutralization of antigens on stimulation with different pathogens and PAMPs. PMID- 28877367 TI - sigma-holes and pi-holes: Similarities and differences. AB - sigma-Holes and pi-holes are regions of molecules with electronic densities lower than their surroundings. There are often positive electrostatic potentials associated with them. Through these potentials, the molecule can interact attractively with negative sites, such as lone pairs, pi electrons, and anions. Such noncovalent interactions, "sigma-hole bonding" and "pi-hole bonding," are increasingly recognized as being important in a number of different areas. In this article, we discuss and compare the natures and characteristics of sigma holes and pi-holes, and factors that influence the strengths and locations of the resulting electrostatic potentials. (c) 2017 Wiley Periodicals, Inc. PMID- 28877368 TI - Trends in pelvic organ prolapse management in Latin America. AB - AIMS: To describe practice patterns and perspectives regarding pelvic organ prolapse (POP) management among urologists, gynecologists, and urogynecologists in Latin America (LATAM). METHODS: A cross-sectional study was conducted from April to September 2016 using a 37-item internet-based survey applied to members of urologic and gynecologic associations from 18 countries. Participants were asked about their background and practice patterns. Descriptive statistics were employed. RESULTS: A total of 673 responses were obtained. Most came from Colombia (33.6%) and Brazil (24.7%). The number of practitioners who perform at least one POP procedure per month and were eligible to finish the survey was 529 (78.6%), out of which 323 (61.0%) were urologists, 156 (29.5%) gynecologists, and 50 (9.5%) urogynecologists. Mesh-based POP repairs were used by 57.1% of participants. Out of non-mesh users, the most frequent vaginal procedures were sacrospinous fixation (30%), colporrhaphy (25%), and uterosacral fixation (12%). Regarding the impact of FDA warnings, 75.2% participants indicated that the use of mesh has declined, and 41.9% considered this has had a negative effect in the use of incontinence tapes as well. Only two physicians reported legal disputes related to mesh procedures, and 75.8% said they would still indicate mesh repairs in certain cases. CONCLUSIONS: This is the first report on POP practice patterns in LATAM. Preferences regarding surgical management of POP are not very different from international trends. Despite intense scrutiny and media exposure, mesh based procedures are still largely used in LATAM. PMID- 28877369 TI - Diet and feeding behavior of a group of 42 Phayre's langurs in a seasonal habitat in Mt. Gaoligong, Yunnan, China. AB - In habitats such as temperate evergreen forests, fruit, and seed productivity is reported to exhibit marked changes in seasonal availability, such that fruit is most available in summer and seeds are most available in autumn. Primates living in these habitats, therefore, are expected to adjust their diets in response to the spatial and temporal variation in these food resources. We studied the diet and feeding behavior of a group of 42 Phayre's langurs (Trachypithecus phayrei) living in a northern (24 degrees 48'N) montane habitat (1,700-2,350 m) in Mt. Gaoligong, Yunnan, China from August 2012 to July 2013. The langurs were found to forage on 50 plant species, of which 28 species each accounted for more than 1% of their annual feeding time. Castanopsis echidnocarpa, the most abundant species in their habitat, accounted for 17.5% of the total forest trees, and contributed to the largest proportion of the annual langur diet. The primary component of the langur diet was composed of fruits (22.2%), seeds (18.7%), and buds and young leaves (41.5%). Mature leaves accounted for only 4.1% of their diet. Based on DBH and the percent of the crown containing edible food items, we found that the langurs changed their monthly diet according to the availability of fruits and seeds (Spearman rank correlation: r = 0.609, p = 0.035), and buds and young leaves (Spearman rank correlation: r = 0.837, p = 0.001). The seeds of C. echidnocarpa accounted for 12.5% of langur feeding time. A single tree produced a large seed and fruit crop, which likely reduced opportunities for within-group feeding competition. We argue that the resource productivity of this northern montane enables Phayre's langurs to live in stable groups that are 3.6 times larger than reported for Phayre's langurs living in other habitats. PMID- 28877370 TI - On the Existence of He?He Bond in the Endohedral Fullerene He2 @C60. AB - Twenty years have already been passed since the endohedral fullerene's void ceaselessly attracts attention of both, experimentalists and theoreticians, computational chemists and physicists in particular, who direct their efforts on computer simulations of encapsulating atoms and molecules into fullerene void and on unraveling the arising bonding patterns. We review recent developments on the endohedral He2 @C60 fullerene, on its experimental observation and on related computational works. The two latter are the main concerns in the present work: on the one hand, there experimentally exists the He dimer embedded into C60 void. On the other, computational side, each He atom exhibits a negligible charge transfer to C60 resulting in that altogether, the He dimer exists as a fractionally charged (He+delta )2 . Whether there exists a bond between these two helium atoms is the key question of the present work. Since a bond is a two-body creature, we assert that it suffices to define the bond on the basis of Lowdin's postulate of a molecule which we invoke to investigate such formation of the He dimer in a given C60 void in terms of the He?He potential energy well. It is analytically demonstrated that this well enables to maintain at least one bound (ground) state, and therefore, according to Lowdin's postulate which is naturally anticipated within quantum theory, we infer that (He+delta )2 is a molecule, a diatomic, where two heliums are bonded to each other. Using these arguments, we also propose to extend the concept of stability of endohedral fullerenes. (c) 2017 Wiley Periodicals, Inc. PMID- 28877371 TI - Association Between Increased Concavity of Maxillary Labial Alveolar Bone and Decreased Labial Cortical Bone Thickness: A Cone Beam Computed Tomography Aided Retrospective Cohort Study. AB - PURPOSE: To assess whether an increased concavity of maxillary labial alveolar bone is related to labial thickness of cortical bone in that area and to the presence of extraoral manifestations in the philtrum. MATERIALS AND METHODS: Cone beam computed tomography images along with intra- and extraoral photographic images of 50 Caucasian female patients, age range 18 to 65 years (mean: 37 years), previously evaluated for implant treatment were assessed by three experienced prosthodontists. Patients were divided into two groups (A and B), according to the presence or absence of a horizontal groove at the philtrum area. Mann-Whitney U test (alpha = 0.05) was performed to reveal any statistical differences regarding the angle of the maxillary labial concavity and the labial thickness of the alveolar cortical bone between the two groups. RESULTS: The mean angle of the maxillary concavity in group A was 127.76 degrees while in group B it was 137.12 degrees . The mean thickness of the labial cortical wall of the dental, interdental, and edentulous areas of the 8 anterior teeth for group A were: 0.41 mm, 0.61 mm, and 0.46 mm, respectively; and for group B were: 0.52 mm, 0.72 mm, and 0.56 mm, respectively. The Mann-Whitney U test (alpha = 0.05) revealed a statistically significant difference for both the angle (p = 0.008) but not for the thickness of the bone (p = 0.062). CONCLUSIONS: According to the results of this study an increased maxillary labial concavity was associated with reduced thickness of the labial cortical wall and the presence of a horizontal groove at the philtrum area. PMID- 28877372 TI - Desquamation takes center stage at the origin of proliferative inflammatory atrophy, epithelial-mesenchymal transition, and stromal growth in benign prostate hyperplasia. AB - In this commentary, we propose a relationship between desquamation, initially described as the collective detachment and deletion of epithelial cell in the prostate gland after castration, and proliferative inflammatory atrophy (PIA) and stromal growth in benign prostate hyperplasia (BPH). First, in response to diverse stimuli, including inflammatory mediators, epithelial cells desquamate and leave a large surface of the luminal side of the basement membrane (BM) exposed. Basal cells are activated into intermediate-type cells, which change morphology to cover and remodel the exposed BM (simple atrophy) to a new physiological demand (such as in the hypoandrogen environment, simulated by surgical and/or chemical castration) and/or to support re-epithelialization (under normal androgen levels). In the presence of inflammation (that might be the cause of desquamation), the intermediate-type cells proliferate and characterize PIA. Second, in other circumstances, desquamation is an early step of epithelial-to-mesenchymal transition (EMT), which contributes to stromal growth, as suggested by some experimental models of BPH. The proposed associations correlate unexplored cell behaviors and reveal the remarkable plasticity of the prostate epithelium that might be at the origin of prostate diseases. PMID- 28877374 TI - Role of oral nystatin prophylaxis in cardiac surgery with prolongedextracorporeal circulation. AB - Duration >120 minutes of extracorporeal circulation (ECC) during cardiopulmonary bypass procedure was associated to an increased risk of candidemia in the intensive care unit (ICU). To evaluate oral nystatin prophylaxis in cardiac surgery considering its exclusive effect on Candida, in the absence of systemic effects and selection of resistant strains to polyene. We conducted an observational study in the postcardiac surgery ICU of Policlinico "Umberto I" of Rome. From January 2014, all patients with a prolonged ECC >120 minutes were systematically treated with oral nystatin (Prophylaxis group). This group was compared with all patients hospitalised in the same ICU, who have not received oral nystatin after ECC >120 minutes (No prophylaxis group). Overall, 672 consecutive patients were analyzed: 318 (47.3%) patients belonged to the no prophylaxis group, and 354 (52.7%) patients to the prophylaxis group. Diagnosis of candidemia was confirmed in 7 (2.2%) patients, all belonged to the no prophylaxis group. At multivariate analysis, oral nystatin prophylaxis showed a protective effect for development of candidemia after cardiac surgery. Oral nystatin prophylaxis, in patients who underwent a ECC >120 minutes, seems to reduce development of candidemia; however, the real efficacy of such prophylaxis approach requires further investigation. PMID- 28877375 TI - Polyacrylamide gel augmentation mammoplasty: Breast Images. PMID- 28877373 TI - Prevalence of onychomycosis among patients with nail psoriasis who are not receiving immunosuppressive agents: Results of a pilot study. AB - Nail psoriasis and onychomycosis can often be hard to differentiate clinically and may coexist, complicating each other's course. The aim of this study was to determine the prevalence of onychomycosis among patients with nail psoriasis not being treated with immunosuppressive agents, which constitute an independent risk factor for fungal infections. A cross-sectional study was performed. All adult patients with nail psoriasis who were not receiving antifungal and/or immunosuppressive treatment were recruited at the 2nd University Dermatology Department of Aristotle University of Thessaloniki from 10/2016 till 02/2017. If onychomycosis was clinically suspected, nail samples were collected and direct microscopy with 15% KOH solution and culture were performed. Target-NAPSI and DLQI score were also calculated. Of the 23 patients recruited, 20 were men and 3 were women, with a mean age of 53.43 years (48.25, 58.62), a mean target-NAPSI score of 10.72 (9.62, 11.77) and a mean DLQI score of 10.17 (7.46, 12.89). A total of 34.78% of patients tested positive for onychomycosis. Yeast were isolated in 37.50% of cases, non-dermatophyte filamentous fungi in 37.50% and T. rubrum in 12.50%. The prevalence of onychomycosis among nail psoriasis patients is higher than that among the general population of Greece (15%-20%). Yeast and moulds predominate in infection cases of nail psoriasis patients. PMID- 28877376 TI - Solitary fibrous tumor of the breast: A rare neoplasm. PMID- 28877377 TI - Membrane cholesterol effect on the 5-HT2A receptor: Insights into the lipid induced modulation of an antipsychotic drug target. AB - The serotonin 5-hydroxytryptamine 2A (5-HT2A ) receptor is a G-protein-coupled receptor (GPCR) relevant for the treatment of CNS disorders. In this regard, neuronal membrane composition in the brain plays a crucial role in the modulation of the receptor functioning. Since cholesterol is an essential component of neuronal membranes, we have studied its effect on the 5-HT2A receptor dynamics through all-atom MD simulations. We find that the presence of cholesterol in the membrane increases receptor conformational variability in most receptor segments. Importantly, detailed structural analysis indicates that conformational variability goes along with the destabilization of hydrogen bonding networks not only within the receptor but also between receptor and lipids. In addition to increased conformational variability, we also find receptor segments with reduced variability. Our analysis suggests that this increased stabilization is the result of stabilizing effects of tightly bound cholesterol molecules to the receptor surface. Our finding contributes to a better understanding of membrane induced alterations of receptor dynamics and points to cholesterol-induced stabilizing and destabilizing effects on the conformational variability of GPCRs. PMID- 28877378 TI - The Spatial Distribution of Alkaloids in Psychotria prunifolia (Kunth) Steyerm and Palicourea coriacea (Cham.) K. Schum Leaves Analysed by Desorption Electrospray Ionisation Mass Spectrometry Imaging. AB - INTRODUCTION: Species of the genera Psychotria and Palicourea are sources of indole alkaloids, however, the distribution of alkaloids within the plants is not known. Analysing the spatial distribution using desorption electrospray ionisation mass spectrometry imaging (DESI-MSI) has become attractive due to its simplicity and high selectivity compared to traditional histochemical techniques. OBJECTIVES: To apply DESI-MSI to visualise the alkaloid distribution on the leaf surface of Psychotria prunifolia and Palicourea coriacea and to compare the distributions with HPLC-MS and histochemical analyses. METHODOLOGY: Based upon previous structure elucidation studies, four alkaloids targeted in this study were identified using high resolution mass spectrometry by direct infusion of plant extracts, and their distributions were imaged by DESI-MSI via tissue imprints on a porous Teflon surface. Relative quantitation of the four alkaloids was obtained by HPLC-MS/MS analysis performed using multiple-reaction monitoring (MRM) mode on a triple quadrupole mass spectrometer. RESULTS: Alkaloids showed distinct distributions on the leaf surfaces. Prunifoleine was mainly present in the midrib, while 10-hydroxyisodeppeaninol was concentrated close to the petiole; a uniform distribution of 10-hydroxyantirhine was observed in the whole leaf of Psychotria prunifolia. The imprinted image from the Palicourea coriacea leaf also showed a homogeneous distribution of calycanthine throughout the leaf surface. CONCLUSION: Different distributions were found for three alkaloids in Psychotria prunifolia, and the distributions found by MSI were in complete accordance with HPLC-MS analysis and histochemical results. The DESI-MSI technique was therefore demonstrated to provide reliable information about the spatial distribution of metabolites in plants. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28877379 TI - Short-term safety and efficacy of left atrial appendage closure with the WATCHMAN device in patients with small left atrial appendage ostia. AB - INTRODUCTION: Left atrial appendage (LAA) closure with the WATCHMAN device, according to FDA labelling, is recommended in patients with a maximal LAA ostial width between 17 and 31 mm. The safety and efficacy of LAA closure in patients with a maximal LAA ostial width < 17 mm has not been evaluated. The goal of this study was to determine the acute and short-term safety and efficacy of LAA closure with the WATCHMAN device in patients with a maximal LAA ostial width < 17 mm. METHODS AND RESULTS: Thirty-two consecutive patients with a maximal LAA ostial width < 17 mm as determined by a screening transesophageal echocardiogram (TEE) underwent LAA closure with the WATCHMAN device between March 2015 and November 2016 at five medical centers, and were included in this study. Mean age, body mass index (BMI), and CHA2 DS2 -VASC score were 70.8 +/- 8.6 years, 29.3 +/- 6.5 kg/m2 , and 3.9 +/-1.2, respectively. At the screening TEE, mean maximal LAA ostial width and depth were 15.6 +/- 0.6 mm (range 14-16) and 23.2 +/- 4.5 mm (range 13-31), respectively. Successful LAA closure with the WATCHMAN device was achieved in 31 of 32 patients (97%), with no major complications. TEE performed 45 days after LAA closure demonstrated no peridevice leak > 5 mm and no device related thrombi. Warfarin was discontinued in all 31 patients 45 days after LAA closure. CONCLUSIONS: LAA closure with the WATCHMAN device can be successfully and safely achieved in patients with a maximal LAA ostial width < 17 mm. PMID- 28877380 TI - Axillary lymphangioma in an asymptomatic adult female. PMID- 28877381 TI - Caffeine and glucosamine mobility shifts by adduction with 2-butanol depended on interaction energy, charge delocalization, and steric hindrance in ion mobility spectrometry. AB - Ion mobility spectrometry (IMS) is an analytical technique that separates gas phase ions drifting under an electric field according to their size to charge ratio. We used electrospray ionization-drift tube IMS coupled to quadrupole mass spectrometry to measure the mobilities of glucosamine (GH+ ) and caffeine (CH+ ) ions in pure nitrogen or when the shift reagent (SR) 2-butanol was introduced in the drift gas at 6.9 mmol m-3 . Binding energies of 2-butanol-ion adducts were calculated using Gaussian 09 at the CAMB3LYP/6-311++G(d,p) level of theory. The mobility shifts with the introduction of 2-butanol in the drift gas were -2.4% (GH+ ) and -1.7% (CH+ ) and were due to clustering of GH+ and CH+ with 2-butanol. The formation of GBH+ was favored over that of CBH+ because GBH+ formed more stable hydrogen bonds (83.3 kJ/mol) than CBH+ (81.7 kJ/mol) for the reason that the positive charge on CH+ is less sterically available than on GH+ and the charge is stabilized by resonance in CH+ . These results are a confirmation of the arguments used to explain the drift behavior of these ions when ethyl lactate SR was used (Bull Kor Chem Soc 2014, 1023-1028). This study is a step forward to predict IMS separations of overlapping peaks in IMS spectra, simplifying a procedure that is trial and error by now. PMID- 28877382 TI - Incorporating fragmentation and non-native species into distribution models to inform fluvial fish conservation. AB - Fluvial fishes face increased imperilment from anthropogenic activities, but the specific factors contributing most to range declines are often poorly understood. For example, the range of the fluvial-specialist shoal bass (Micropterus cataractae) continues to decrease, yet how perceived threats have contributed to range loss is largely unknown. We used species distribution models to determine which factors contributed most to shoal bass range loss. We estimated a potential distribution based on natural abiotic factors and a series of currently occupied distributions that incorporated variables characterizing land cover, non-native species, and river fragmentation intensity (no fragmentation, dams only, and dams and large impoundments). We allowed interspecific relationships between non native congeners and shoal bass to vary across fragmentation intensities. Results from the potential distribution model estimated shoal bass presence throughout much of their native basin, whereas models of currently occupied distribution showed that range loss increased as fragmentation intensified. Response curves from models of currently occupied distribution indicated a potential interaction between fragmentation intensity and the relationship between shoal bass and non native congeners, wherein non-natives may be favored at the highest fragmentation intensity. Response curves also suggested that >100 km of interconnected, free flowing stream fragments were necessary to support shoal bass presence. Model evaluation, including an independent validation, suggested that models had favorable predictive and discriminative abilities. Similar approaches that use readily available, diverse, geospatial data sets may deliver insights into the biology and conservation needs of other fluvial species facing similar threats. PMID- 28877383 TI - Levels of interleukin (IL)-6 and IL-8 are elevated in serum and bronchoalveolar lavage fluid of haematological patients with invasive pulmonary aspergillosis. AB - Aspergillus spp. have been shown to induce T-helper cell (Th) 1 and Th17 subsets resulting in elevated levels of several cytokines. The objective of this study was to analyse a bundle of cytokines in serum and bronchoalveolar lavage fluid (BALF) in patients with and without invasive pulmonary aspergillosis (IPA). This nested case-control analysis included 10 patients with probable/proven IPA and 20 matched controls without evidence of IPA, out of a pool of prospectively enrolled (2014-2017) adult cases with underlying haematological malignancies and suspected pulmonary infection. Serum samples were collected within 24 hours of BALF sampling. All samples were stored at -70 degrees C for retrospective determination of cytokines. IL-6 and IL-8 were significantly associated with IPA in both serum (P = .011 and P = .028) and BALF (P = .006 and P = .012, respectively), and a trend was observed for serum IL-10 (P = .059). In multivariate conditional logistic regression analysis, IL-10 remained a significant predictor of IPA in serum and IL-8 among BALF cytokines. In conclusion, levels of IL-6 and IL-8 were significantly associated with probable/proven IPA, and a similar trend was observed for serum IL-10. Future cohort studies should determine the diagnostic potential of these cytokines for IPA, and evaluate combinations with other IPA biomarkers/diagnostic tests. PMID- 28877385 TI - Is the R3 Si Moiety in Metal-Silyl Complexes a Z ligand? An Answer from the Interaction Energy. AB - The computation of metal-silyl interaction energies indicates the existence of situations in which the silyl group behaves as a Z-type ligand according to the Green method of covalent-bond classification. There is a scale of relative intrinsic silylicity Pi, defined as the ratio of the intrinsic silyl-to-triflate interaction energy of a silyltriflate as a reference compound relative to the silyl-to-metal interaction of given complex, that can reveal in a straightforward manner the propensity of SiR3 groups to behave chemically as metal-bound "silylium" ions, namely, [SiR3 ]+ . Emblematic cases, either taken from the Cambridge Structural Database (CSD) or constructed for the purpose of this study, were also investigated from the viewpoints of extended transition-state natural orbitals for chemical valence (ETS-NOCV) and quantum theory of atoms in molecules (QTAIM) analyses. It is shown in the case of POBMUP-which is the iridium 1,3 bis[(di-tert-butylphosphino)oxy]benzene (POCOP) complex isolated by Brookhart et al.-how slight variations of molecular charge and structure can drastically affect the relative intrinsic silylicity of the SiEt3 group that is weakly bonded to the hydrido-iridium motif. PMID- 28877384 TI - Exosomes secreted from mutant-HIF-1alpha-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit. AB - Mesenchymal stem cells (MSCs)-derived exosomes exhibit protective effects on damaged or diseased tissues. Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a critical role in bone development. However, HIF-1alpha is easily biodegradable under normoxic conditions. The bone-marrow-derived mesenchymal stem cells (BMSCs) were transfected with adenovirus carrying triple point-mutations (amino acids 402, 564, and 803) in the HIF-1alpha coding sequence (CDS). The mutant HIF-1alpha can efficiently express functional proteins under normoxic conditions. To date, no study has reported the role of exosomes secreted by mutant HIF-1alpha modified BMSCs in the recovery of the early steroid-induced avascular necrosis of femoral head (SANFH). In this study, we firstly analyzed exosomes derived from BMSCs modified by mutant (BMSC-ExosMU ) or wild-type HIF-1alpha (BMSC-ExosWT ). In vitro, we investigated the osteogenic differentiation capacity of BMSCs modified by BMSC-ExosMU or BMSC-ExosWT , and the angiogenesis effects of BMSC-ExosMU and BMSC-ExosWT on human umbilical vein endothelial cells (HUVECs). Besides, the healing of the femoral head was also assessed in vivo. We found that the potential of osteogenic differentiation of BMSCs treated with BMSC-ExosMU was higher than the wild-type group in vitro. In addition, BMSC-ExosMU stimulated the proliferation, migration, and tube formation of HUVECs in a dose-dependent manner. Compared with the BMSC-ExosWT or PBS control group, the injection of BMSC ExosMU into the necrosis region markedly accelerated the bone regeneration and angiogenesis, which were indicated by the increased trabecular reconstruction and microvascular density. Taken together, our data suggest that BMSC-ExosMU facilitates the repair of SANFH by enhancing osteogenesis and angiogenesis. PMID- 28877386 TI - Oral mucormycosis in patients with haematologic malignancies in a bone marrow transplant unit. AB - Mucormycosis is an aggressive and life-threatening opportunistic fungal infection, which predominantly affects immunocompromised patients. It typically manifests in rhinocerebral, pulmonary or disseminated forms in patients with immunosuppressive conditions. Mucormycosis limited to the oral cavity is rare, and to the best of our knowledge only seven cases have previously been reported in English literature. We present five consecutive cases of oral mucormycosis in patients with leukaemia, and provide a literature review. PMID- 28877387 TI - Recommendations for Low-Grade Carotid Stenosis Follow-up Based on a Single Institution Database. AB - OBJECTIVES: The purpose of this study was to determine the incidences and rates of progression of varying degrees of carotid stenosis that do not require intervention according to the Asymptomatic Carotid Atherosclerosis Study, the European Carotid Surgery Trial, and the North American Symptomatic Carotid Endarterectomy Trial, and from this information, to provide evidence-based recommendations for follow-up imaging. METHODS: A retrospective review was performed of all carotid ultrasound examinations performed at a single institution from January 1995 through April 2015. Examinations following endarterectomy or stenting were excluded. Stenoses were classified by a modification of the criteria of Bluth et al (Radiographics 1988; 8:487-506). A Kaplan-Meier survival analysis was performed for stenosis progression and to provide information for follow-up recommendations. RESULTS: Most of the carotid arteries (91.6%) reviewed for this study showed 1% to 39% stenosis. However, only 6.8% of carotid arteries with 1% to 39% stenosis progressed compared to 38.9% of carotid arteries with 40% to 59% stenosis. A table of evidence-based follow-up recommendations is provided for patients with varying levels of stenosis. CONCLUSIONS: We provide evidence-based follow-up recommendations for patients who have low degrees of carotid stenosis. Different degrees of carotid stenosis progress at different rates and therefore should be followed at different intervals. Additionally, the most patients in our database showed 1% to 39% stenosis and did not have any follow-up imaging, suggesting that carotid ultrasound may not be overused for low degrees of stenosis. PMID- 28877388 TI - Motivation of the nurses in pre-hospital emergency and educational hospitals emergency in the southeast of Iran. AB - INTRODUCTION: Nurses, as the largest human resource element of health care systems, have a major role in providing ongoing, high-quality care to patients. Therefore, due to the importance of this issue, this study aimed to determine job motivation of the nurses in pre-hospital and educational hospitals emergency in the southeast of Iran. METHODS: In this study, a cross-sectional method was used, and it was conducted in educational hospitals and pre-hospital emergencies under supervision of the Kerman University of Medical Sciences in 2017. Using a valid and reliable questionnaire, we assessed job motivation of the nurses using a census method (N = 275). Data were analyzed by implementing descriptive statistics including mean and standard deviation (SD), and analytical statistics such as Kolmogorov-Smirnov, ANOVA, t-test, X2, Pearson, and multivariate regression tests using SPSS 16 and P <= 0.05. RESULTS: Among the pre-hospital emergency nurses, the average of the educational factors was 25.33, financial factors was 6.34, psychological factors was 20.07, welfare factors was 0.63, and administrative factors was 8.16. Among the nurses of the educational hospitals emergency, these factors were 25.33, 6.51, 20.34, 16.55, and 8.39, respectively. Two group's nurses were at the intermediate level of the job motivation. CONCLUSION: Dynamic and predetermined goals of emergency include providing services as soon as possible and stabilizing patient's condition during the golden and vital time of rescue. Findings suggest that national and local policies in Iran may need to examine factors that contribute to the promotion of the motivation as well as focusing on how to improve them. PMID- 28877389 TI - Abstracts from the IVECCS & EVECC Annual Congresses and the ACVECC VetCOT Veterinary Trauma & Critical Care Conference 2017. PMID- 28877390 TI - Terminal Molybdenum Phosphides with d Electrons: Radical Character Promotes Coupling Chemistry. AB - A terminal Mo phosphide was prepared through the group transfer of both P and Cl atoms from chloro-substituted dibenzo-7lambda3 -phosphanorbornadiene. This compound represents the first structurally characterized terminal transition metal phosphide with valence d electrons. In the tetragonal ligand field, these electrons populate an orbital of dxy parentage, an electronic configuration that accommodates both metal d electrons and a formal M=P triple bond. Single-electron oxidation affords a transient open-shell terminal phosphide cation with significant spin density on P, as corroborated by continuous wave (CW) and pulse electron paramagnetic resonance (EPR) characterization. Facile P-P bond formation occurs from this species through intermolecular phosphide coupling. PMID- 28877391 TI - An NMR Method To Pinpoint Supramolecular Ligand Binding to Basic Residues on Proteins. AB - Targeting protein surfaces involved in protein-protein interactions by using supramolecular chemistry is a rapidly growing field. NMR spectroscopy is the method of choice to map ligand-binding sites with single-residue resolution by amide chemical shift perturbation and line broadening. However, large aromatic ligands affect NMR signals over a greater distance, and the binding site cannot be determined unambiguously by relying on backbone signals only. We herein employed Lys- and Arg-specific H2(C)N NMR experiments to directly observe the side-chain atoms in close contact with the ligand, for which the largest changes in the NMR signals are expected. The binding of Lys- and Arg-specific supramolecular tweezers and a calixarene to two model proteins was studied. The H2(C)N spectra track the terminal CH2 groups of all Lys and Arg residues, revealing significant differences in their binding kinetics and chemical shift perturbation, and can be used to clearly pinpoint the order of ligand binding. PMID- 28877392 TI - Prevalence of pruritus in patients with chronic liver disease: A multicenter study. AB - AIM: Pruritus is a common comorbidity in chronic liver disease. The aim of this study was to clarify the prevalence of pruritus and its characteristics in patients with chronic liver disease. METHODS: A total of 1631 patients with chronic liver disease who attended one of nine joint-research facilities from January to June 2016 were enrolled. We investigated the prevalence of pruritus, itch location, itch duration, daily itch fluctuation, seasonal itch exacerbation, treatment drugs, and therapeutic effects using a medical interview questionnaire. RESULTS: The median age was 66 years and 890 (54.6%) patients were women. The prevalence of pruritus was 40.3% (658/1631), and it differed according to the underlying liver disease. The most frequent body location for pruritus was on the back (63.1%). Pruritus duration was more than 6 months in 252 (38.3%) patients. The severity of pruritus, assessed using a visual analog scale, was higher during the day than at night (median, 4 vs. 3, P < 0.001). Seasonal exacerbation was observed in 296 (45.0%) patients. Although 301 (45.7%) patients were treated with antipruritic agents, 57.8% (174/301) patients reported an insufficient effect. Active hepatitis B virus infection (odds ratio [OR], 2.51; P = 0.043), primary biliary cholangitis (OR, 3.69; P = 0.018), diabetes (OR, 1.57; P = 0.010), and aspartate aminotransferase >=60 U/L (OR, 2.06; P = 0.011) were independent factors associated with pruritus. CONCLUSION: The prevalence of pruritus varies according to the chronic liver disease etiology. Underlying liver disease, aspartate aminotransferase >=60 U/L, and comorbid diabetes are factors associated with pruritus in patients with chronic liver disease. PMID- 28877394 TI - HER2+ breast cancer cells undergo apoptosis upon exposure to tannic acid released from remodeled cross-linked collagen type I. AB - Tannic acid (TA) is a naturally occurring polyphenol that cross-links collagen type I and possesses anticancer potential. In previous studies, we demonstrated the increased sensitivity of estrogen receptor-positive (ER+ ) breast cancer cells to TA as opposed to triple negative breast cancer cells and normal human breast epithelial cells. In the current study, human pre-adipocytes and HER2+ breast cancer cells were grown on TA cross-linked collagen type I beads. Cell attachment, growth, and proliferation of the cells result in remodeling of the collagen matrix and release of the cross-linking TA. TA concentrations in the conditioned media were determined. Induced apoptosis of cells grown on the TA cross-linked collagen type I beads was imaged and quantified. Viability of HER2+ breast cancer cells and normal breast epithelial cells after exposure TA released from bead remodeling was quantified. Caspase gene expression and protein expression were evaluated. HER2+ breast cancer cells underwent caspase-mediated apoptosis in response to TA exposure. TA-induced apoptosis in a concentration- and time-dependent manner, with HER2+ breast cancer cells demonstrating an increased sensitivity to the TA effects. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 26-32, 2018. PMID- 28877395 TI - Optimal Lead Positioning in Sacral Neuromodulation: Which Factors Are Related to Treatment Outcome? AB - OBJECTIVES: Sacral neuromodulation (SNM) is a well-established treatment for overactive bladder (OAB) and non-obstructive urinary retention (NOR). During test stimulation, the lead is positioned along the third sacral nerve, which ideally results in a response in all four contact points (active electrodes). However, it is unclear whether the position of the lead (depth, angle, deflection) and the number of active electrodes is related to the outcome of SNM. METHODS: All patients who underwent test stimulation using the tined lead between January 2011 and September 2016 were included in this retrospective study. Success was defined as >50% improvement in voiding diary parameters compared to baseline. The correlation between lead position and outcome of test stimulation was evaluated. The lead position was determined by evaluating the depth, angle and deflection with respect to the sacral foramen. Binary logistic regression was used in order to determine the predictive value of these factors. RESULTS: We included 189 patients of whom 105 were diagnosed with OAB and 84 with NOR. After a SNM test period of 4 weeks, 111 patients (59%) were successful and received a permanent implant. The position of the lead and the number of active electrodes did not predict success of test stimulation in neither the OAB group nor the NOR. However, lateral deflection of the lead was associated with finding more active electrodes (p = 0.01). CONCLUSION: In our study, the position of the lead or the number of active electrodes did not predict the outcome of SNM test stimulation. However, the impact of lead positioning and number of active electrodes on long term outcome remains to be proven. PMID- 28877393 TI - Polyester vascular patches acquire arterial or venous identity depending on their environment. AB - Polyester is commonly used in vascular surgery for patch angioplasty and grafts. We hypothesized that polyester patches heal by infiltration of arterial or venous progenitor cells depending on the site of implantation. Polyester patches were implanted into the Wistar rat aorta or inferior vena cava and explanted on day 7 or 30. Neointima that formed on polyester patches was thicker in the venous environment compared to the amount that formed on patches in the arterial environment. Venous patches had more cell proliferation and greater numbers of VCAM-positive and CD68-positive cells, whereas arterial patches had greater numbers of vimentin-positive and alpha-actin-positive cells. Although there were similar numbers of endothelial progenitor cells in the neointimal endothelium, cells in the arterial patch were Ephrin-B2- and notch-4-positive while those in the venous patch were Eph-B4- and COUP-TFII-positive. Venous patches treated with an arteriovenous fistula had decreased neointimal thickness; neointimal endothelial cells expressed Ephrin-B2 and notch-4 in addition to Eph-B4 and COUP TFII. Polyester patches in the venous environment acquire venous identity, whereas patches in the arterial environment acquire arterial identity; patches in the fistula environment acquire dual arterial-venous identity. These data suggest that synthetic patches heal by acquisition of identity of their environment. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3422-3431, 2017. PMID- 28877396 TI - Neurotensin in the posterior thalamic paraventricular nucleus: inhibitor of pharmacologically relevant ethanol drinking. AB - Individuals prone to ethanol overconsumption may have preexisting neurochemical disturbances that contribute to their vulnerability. This study examined the paraventricular nucleus of the thalamus (PVT), a limbic structure recently shown to participate in ethanol intake. To identify individuals prone to ethanol overconsumption, we tested Long-Evans rats in behavioral paradigms and found high levels of vertical time (rearing behavior) in a novel activity chamber to be a consistent predictor of subsequent excessive 20 percent ethanol drinking under the intermittent access model. Examining neurochemicals in the PVT, we found before ethanol exposure that prone rats with high rearing, compared with non prone rats, had significantly lower levels of neurotensin (NTS) mRNA and peptide in the posterior (pPVT) but not anterior (aPVT) subregion of the PVT. Our additional finding that ethanol intake has no significant impact on either rearing or NTS levels indicates that these measures, which are different in prone rats before ethanol consumption, remain stable after ethanol consumption. The possibility that NTS directly controls ethanol drinking is supported by our finding that NTS administration specifically suppresses ethanol drinking when injected into the pPVT but not aPVT, with this effect occurring exclusively in higher drinkers that presumably have lower endogenous levels of NTS. Further, an NTS antagonist in the pPVT augments intake in lower drinkers with presumably more endogenous NTS, while NTS in the pPVT inhibits novelty-induced rearing that predicts excessive drinking. Together, these results provide strong evidence that low endogenous levels of NTS in the pPVT contribute to an increased propensity toward excessive ethanol drinking. PMID- 28877397 TI - meta-Selective C-H Borylation of Benzylamine-, Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled by a Single Anionic Ligand. AB - Selective functionalization at the meta position of arenes remains a significant challenge. In this work, we demonstrate that a single anionic bipyridine ligand bearing a remote sulfonate group enables selective iridium-catalyzed borylation of a range of common amine-containing aromatic molecules at the arene meta position. We propose that this selectivity is the result of a key hydrogen bonding interaction between the substrate and catalyst. The scope of this meta selective borylation is demonstrated on amides derived from benzylamines, phenethylamines and phenylpropylamines; amine-containing building blocks of great utility in many applications. PMID- 28877398 TI - Spectral Identification in the Attogram Regime through Laser-Induced Emission of Single Optically Trapped Nanoparticles in Air. AB - Current trends in nanoengineering are bringing along new structures of diverse chemical compositions that need to be meticulously defined in order to ensure their correct operation. Few methods can provide the sensitivity required to carry out measurements on individual nano-objects without tedious sample pre treatment or data analysis. In the present study, we introduce a pathway for the elemental identification of single nanoparticles (NPs) that avoids suspension in liquid media by means of optical trapping and laser-induced plasma spectroscopy. We demonstrate spectroscopic detection and identification of individual 25(+/ 3.7) to 70(+/-10.5) nm in diameter Cu NPs stably trapped in air featuring masses down to 73+/-35 attograms. We found an increase in the absolute number of photons produced as size of the particles decreased; pointing towards a more efficient excitation of ensembles of only ca. 7*105 Cu atoms in the onset plasma. PMID- 28877399 TI - Cops and docs: The challenges for ED physicians balancing the police, state laws, and EMTALA. AB - State laws are awash with discord concerning whether a police officer's request or court order necessarily obligates physicians to perform a body fluid analysis of an arrested, conscious, nonconsenting suspect. Police typically bring arrestees directly to the emergency department (ED), and federal courts have begun to wrestle with the implications of the Emergency Medical Treatment and Labor Act (EMTALA), which requires that anyone presenting to the ED be screened for treatment. Some state laws require health care providers to comply with any police request for lab analysis, while other states offer more leeway to physicians. Recent trends in federal case law interpreting EMTALA suggest that a medical screening exam is not required for patients brought by police specifically for a blood or urine sample unless either the arrestee requests medical care or a prudent observer would believe medical care was indicated. This article answers two questions: What happens when a police officer presents to the ED requesting service on behalf of an arrestee? What does EMTLA require of physicians in response? We survey current state statutes, review recent state and federal case law, describe example policies from various hospitals, and conclude with recommendations for hospital risk managers. PMID- 28877401 TI - Overcoming the Incompatibility Challenge in Chemoenzymatic and Multi-Catalytic Cascade Reactions. AB - Multi-catalytic cascade reactions bear a great potential to minimize downstream and purification steps, leading to a drastic reduction of the produced waste. In many examples, the compatibility of chemo- and biocatalytic steps could be easily achieved. Problems associated with the incompatibility of the catalysts and their reactions, however, are very frequent. Cascade-like reactions can hardly occur in this way. One possible solution to combine, in principle, incompatible chemo- and biocatalytic reactions is the defined control of the microenvironment by compartmentalization or scaffolding. Current methods for the control of the microenvironment of biocatalysts go far beyond classical enzyme immobilization and are thus believed to be very promising tools to overcome incompatibility issues and to facilitate the synthetic application of cascade reactions. In this Minireview, we will summarize recent synthetic examples of (chemo)enzymatic cascade reactions and outline promising methods for their spatial control either by using bio-derived or synthetic systems. PMID- 28877400 TI - Glucocorticoid receptor is involved in the differential expression of hepatic 3beta-hydroxysteroid dehydrogenase between barrows and boars at finishing stage. AB - The enzyme 3beta-hydroxysteroid dehydrogenase (3beta-HSD) plays an important role in androstenone metabolism in pig liver, and its defective expression is related to the development of boar taint. Early age castration is a common practice in many countries to avoid boar taint, yet whether and how castration affects porcine hepatic 3beta-HSD expression are still poorly understood. In this study, we aimed to compare the expression of 3beta-HSD between intact (boars) and castrated (barrows) male pigs, and to explore the potential factors regulating 3beta-HSD transcription. Compared to barrows, boars showed worse carcass quality. Boars had significantly higher levels of serum androstenone (P < 0.01), testosterone (P < 0.01) and hepatic cortisol (P < 0.05), which were contrary to significantly lower expression of 3beta-HSD messenger RNA (P < 0.01) and protein (P < 0.01) in the liver. Significant differences were detected for the hepatic expression of androgen receptor (AR) and CCAAT/enhancer binding protein beta (C/EBPbeta). Chromatin immunoprecipitation (ChIP) assay demonstrated reduced histone H3 acetylation (P < 0.05) but increased glucocorticoid receptor (GR) binding to 3beta-HSD gene promoter in boars (P < 0.05). These results indicate that GR binding to 3beta-HSD promoter is involved in the differential hepatic 3beta-HSD expression between boars and barrows. PMID- 28877403 TI - Comparison of HER2 status of breast cancer between Chinese women in China and Chinese-American women in the US. PMID- 28877402 TI - Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats. AB - BACKGROUND: Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists. METHODS: The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin. RESULTS: While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by alpha2 adrenoreceptors desensitization in the locus coeruleus. CONCLUSIONS: These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain. SIGNIFICANCE: S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by alpha2 receptors desensitization in the locus coeruleus. PMID- 28877404 TI - Benefits of Well-Being Training in Healthy Older Adults. AB - INTRODUCTION: Several studies have shown that psychological well-being (PWB) can be promoted through positive psychological interventions (PPIs). Although these interventions have shown promising results in clinical settings, only a few studies have investigated their effectiveness in older adults, and they have rarely considered an active control group. In addition, generalisation effects of the PWB training to quality of life (QoL) and to untrained cognitive abilities have never been considered. OBJECTIVE: In this study, we evaluated the effectiveness of a six-session PWB intervention aiming specifically to improve PWB, and sought any transfer effects on an aspect related to PWB, QoL. Transfer effects on a high-level cognitive process, working memory (WM), were also investigated. METHODS: Thirty-two older adults (61-82 years old) volunteered to take part in the study and were randomly assigned to either a training group or an active control group. RESULTS: Only the trained group, once controlled for variability, reported larger gains in PWB and in WM performance after the training. CONCLUSIONS: This pilot study suggests that PWB training can be effective in older adults, with a positive generalisation effect on cognition (WM). The discussion focuses on the need to develop PPIs tailored to older adults' needs and resources. PMID- 28877405 TI - EGFR Targeting and Shielding of pDNA Lipopolyplexes via Bivalent Attachment of a Sequence-Defined PEG Agent. AB - For successful nonviral gene delivery, cationic polymers are promising DNA carrier, which need to comprise several functionalities. The current work focuses on the postincorporation of epidermal growth factor receptor (EGFR) targeted PEGylation agents onto lipopolyplexes for pDNA delivery. T-shaped lipo-oligomers are previously found to be effective sequence-defined carriers for pDNA and siRNA. Here, the bis-oleoyl-oligoaminoethanamide 454 containing tyrosine trimer cysteine ends is applied for complex formation with pDNA coding for luciferase or sodium iodide symporter (NIS). In a second step, the lipopolyplexes are modified via disulfide formation with sequence-defined monovalent or bivalent PEGylation agents containing one or two 3-nitro-2-pyridinesulfenyl (NPys)-activated cysteines, respectively. For targeting, the polyethylene glycol (PEG) agents comprise the EGFR targeting peptide GE11. In comparison of all transfection complexes, 454 lipopolyplexes modified with the bidentate PEG-GE11 agent show the best, EGFR-dependent uptake as well as luciferase and NIS gene expression into receptor-positive tumor cells. PMID- 28877406 TI - Integration of Bromine and Cyanogen Bromide Generators for the Continuous-Flow Synthesis of Cyclic Guanidines. AB - A continuous-flow process for the in situ on-demand generation of cyanogen bromide (BrCN) from bromine and potassium cyanide that makes use of membrane separation technology is described. In order to circumvent the handling, storage, and transportation of elemental bromine, a continuous bromine generator using bromate-bromide synproportionation can optionally be attached upstream. Monitoring and quantification of BrCN generation was enabled through the implementation of in-line FTIR technology. With the Br2 and BrCN generators connected in series, 0.2 mmol BrCN per minute was produced, which corresponds to a 0.8 m solution of BrCN in dichloromethane. The modular Br2 /BrCN generator was employed for the synthesis of a diverse set of biologically relevant five- and six-membered cyclic amidines and guanidines. The set-up can either be operated in a fully integrated continuous format or, where reactive crystallization is beneficial, in semi-batch mode. PMID- 28877408 TI - Application of dispersive liquid-liquid microextraction for the preconcentration of eight parabens in real samples and their determination by high-performance liquid chromatography. AB - A simple and sensitive method for the simultaneous determination of eight parabens in human plasma and urine samples was developed. The samples were preconcentrated using dispersive liquid-liquid microextraction based on the solidification of floating organic drops and determined by high-performance liquid chromatography with ultraviolet detection. The influence of variables affecting the extraction efficiency was investigated and optimized using Placket Burman design and Box-Behnken design. The optimized values were: 58 MUL of 1 decanol (as extraction solvent), 0.65 mL methanol (as disperser solvent), 1.5% w/v NaCl in 5.0 mL of sample solution, pH 10.6, and 4.0 min centrifugation at 4000 rpm. The extract was injected into the high-performance liquid chromatography system for analysis. Under the optimum conditions, the linear ranges for eight parabens in plasma and urine were 1.0-1000 ng/mL, with correlation coefficients above 0.994. The limit of detection was 0.2-0.4 and 0.1 0.4 ng/mL for plasma and urine samples, respectively. Relative recoveries were between 80.3 and 110.7%, while relative standard deviations were less than 5.4%. Finally, the method was applied to analyze the parabens in 98 patients of primary breast cancer. Results showed that parabens existed widely, at least one paraben detected in 96.9% (95/98) of plasma samples and 98.0% (96/98) of urine samples. PMID- 28877407 TI - Size makes a difference: Chiral recognition in complexes of fenchone with cyclodextrins studied by means of NMR titration. AB - Gibbs energies of complex formation between enantiomers of bicyclic terpenoid, fenchone, and naturally occurring cyclodextrins, betaCD and gammaCD, were determined by means of 13 C and 1 H nuclear magnetic resonance (NMR) titration data. These results were compared with the corresponding data obtained previously for the diastereomeric fenchone/alphaCD complexes. The size of the inner cavity of host molecules significantly influences stoichiometry, association constants, and enantiomeric differentiation of the studied complexes. These complementary data allow us to discuss qualitatively the influence of the host size on the guest-host interactions. A method of the simultaneous use of titration data collected for several resonances of different isotopes in the determination of association constants was worked out and thoroughly analyzed. Comparison of the results of global data analyses with weighted means of individual ones revealed that both these approaches are equally trustworthy. PMID- 28877409 TI - Hydrophilic interaction liquid chromatography tandem mass spectrometry analysis of malonyl-coenzyme A in breast cancer cell cultures applying online solid-phase extraction. AB - Cofactors such as coenzyme A and its derivatives acetyl-coenzyme A and malonyl coenzyme A are involved in many metabolic pathways. Due to trace level concentrations in biological samples and the high reactivity of cofactors, a fast, sensitive, and selective method for quantification is mandatory. In this study, online solid-phase extraction was coupled successfully to hydrophilic interaction liquid chromatography with tandem mass spectrometry for isolation of analytes in complex matrix and quantification by external calibration. Online solid-phase extraction was carried out by application of a weak anion-exchange column, whereas hydrophilic interaction liquid chromatography separation was performed on an amide modified stationary phase. Sample preparation of the extracts before the analysis was reduced to a centrifugation and dilution step. Moreover, the applied online solid-phase extraction significantly reduced matrix effects and increased the signal-to-noise ratio. The limit of detection and the limit of quantification were in the lower nanomolar range. Finally, the applicability of this method was demonstrated on MCF-7 breast cancer cell cultures, a commonly used model system, where acetyl-coenzyme A and malonyl coenzyme A were determined using standard addition procedure in concentrations of 1.98 MUM and 41 nM, respectively. PMID- 28877411 TI - New Cytotoxic Triterpenoid Saponins from the Roots of Albizia gummifera (J.F.Gmel.) C.A.Sm. AB - As part of our search for new bioactive saponins from Cameroonian medicinal plants, two new oleanane-type saponins, named gummiferaosides D and E (1 and 2), along with one known saponin, julibroside J8 (3), were isolated from the roots of Albizia gummifera. Their structures were established on the basis of extensive 1D and 2D-NMR (1 H- and 13 C-NMR, DEPT, COSY, TOCSY, NOESY, HSQC, HSQC-TOCSY, and HMBC) and HR-ESI-MS studies, and by chemical evidence. The apoptotic effect of saponins 1 - 3 was evaluated on the A431 human epidermoid cancer cell. Flow cytometric analyses showed that saponins 1 - 3 induced apoptosis of human epidermoid cancer cell (A431) in a dose-dependent manner. PMID- 28877410 TI - Neural correlates of tobacco cue reactivity predict duration to lapse and continuous abstinence in smoking cessation treatment. AB - It has been hypothesized that neural reactivity to drug cues in certain limbic/paralimbic regions of the brain is an indicator of addiction severity and a marker for likelihood of success in treatment. To address this question, in the current study, 32 participants (44 percent female) completed a functional magnetic resonance imaging cigarette cue exposure paradigm 2 hours after smoking, and then enrolled in a 9-week smoking cessation treatment program. Neural activation to smoking cues was measured in five a priori defined limbic/paralimbic regions previously implicated with cue reactivity across substances. These included regions of the ventral striatum, anterior cingulate cortex and amygdala. Cox proportional hazard modeling was conducted to predict the number of days to first smoking lapse by using neural activation in these regions. Greater neural activation during pre-treatment exposure to smoking cues in the right ventral striatum, the left amygdala, and the anterior cingulate was associated with longer periods of abstinence following cessation. A similar pattern was present for continuous abstinence for the full duration of treatment. While baseline levels of nicotine dependence were strongly associated with treatment outcome, activation in the right ventral striatum predicted duration of abstinence beyond level of nicotine dependence. These results suggest that pre treatment reactivity to smoking cues in areas associated with cue reactivity may be associated with successfully maintaining abstinence during treatment. This is consistent with models that propose that as addiction becomes more severe, motivational processing shifts from regions that subserve reward salience and learning to regions responsible motor behavior and habit learning. PMID- 28877412 TI - Neuronal differentiation of human mesenchymal stem cells in response to the domain size of graphene substrates. AB - Graphene is a noncytotoxic monolayer platform with unique physical, chemical, and biological properties. It has been demonstrated that graphene substrate may provide a promising biocompatible scaffold for stem cell therapy. Because chemical vapor deposited graphene has a two dimensional polycrystalline structure, it is important to control the individual domain size to obtain desirable properties for nano-material. However, the biological effects mediated by differences in domain size of graphene have not yet been reported. On the basis of the control of graphene domain achieved by one-step growth (1step-G, small domain) and two-step growth (2step-G, large domain) process, we found that the neuronal differentiation of bone marrow-derived human mesenchymal stem cells (hMSCs) highly depended on the graphene domain size. The defects at the domain boundaries in 1step-G graphene was higher (*8.5) and had a relatively low (13% lower) contact angle of water droplet than 2step-G graphene, leading to enhanced cell-substrate adhesion and upregulated neuronal differentiation of hMSCs. We confirmed that the strong interactions between cells and defects at the domain boundaries in 1step-G graphene can be obtained due to their relatively high surface energy, which is stronger than interactions between cells and graphene surfaces. Our results may provide valuable information on the development of graphene-based scaffold by understanding which properties of graphene domain influence cell adhesion efficacy and stem cell differentiation. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 43-51, 2018. PMID- 28877414 TI - Evaluation of the analgesic and pharmacokinetic properties of transdermally administered fentanyl in goats. AB - OBJECTIVE: Evaluate the analgesic properties and pharmacokinetics of transdermal fentanyl patches (TFPs) in goats. DESIGN: Prospective, randomized study. SETTING: Preclinical Testing Facility at a University Teaching Hospital. ANIMALS: Thirty four adult female Boer-cross goats. INTERVENTIONS: Goats underwent surgery as part of a concurrent orthopedic research study. Twelve hours prior to surgery, each goat received a TFP (target dosage of 2.5 MUg/kg/h), or a placebo patch with analgesia provided by buprenorphine (0.01 mg/kg, IM, q 6 h). Patches were removed after 72 hours. Blood was sampled at specified intervals, up to 84 hours following TFP placement. Plasma concentrations of fentanyl (FEN) were determined using liquid chromatography-mass spectrometry. Postoperative pain assessments were performed by two independent blinded observers. MEASUREMENTS AND MAIN RESULTS: TFPs were applied at a mean (+/- standard deviation, SD) dose of 2.54 +/ 0.36 MUg/kg/h. No adverse events occurred. Pain scores between TFP and BUP groups were not significantly different at any time point. Mean plasma FEN concentration (+/- SD) 2 hours following patch application was 1.06 +/- 0.85 ng/mL, and remained above 0.5 ng/mL for 40 hours. Maximum mean plasma FEN concentration (Cmax ) was 1.84 (ranging from 0.81 to 3.35) ng/mL with average time to maximum concentration (Tmax ) of 12 hours after patch application. CONCLUSIONS: TFP resulted in consistent FEN absorption and plasma concentrations within the human and ovine therapeutic ranges. Pain scores for goats administered TFP were not different than those administered buprenorphine. Ease of administration, duration of analgesia, and decreased dosing frequency make TFPs an attractive option for pain management in goats. PMID- 28877418 TI - ECVECC News. PMID- 28877422 TI - Ultrathin Composite Polymeric Membranes for CO2 /N2 Separation with Minimum Thickness and High CO2 Permeance. AB - The use of ultrathin films as selective layers in composite membranes offers significant advantages in gas separation for increasing productivity while reducing the membrane size and energy costs. In this contribution, composite membranes have been obtained by the successive deposition of approximately 1 nm thick monolayers of a polymer of intrinsic microporosity (PIM) on top of dense membranes of the ultra-permeable poly[1-(trimethylsilyl)-1-propyne] (PTMSP). The ultrathin PIM films (30 nm in thickness) demonstrate CO2 permeance up to seven times higher than dense PIM membranes using only 0.04 % of the mass of PIM without a significant decrease in CO2 /N2 selectivity. PMID- 28877423 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 38/2017. PMID- 28877425 TI - Peer review week 2017. PMID- 28877426 TI - AANP News. PMID- 28877428 TI - What has GWAS done for HLA and disease associations? AB - The major histocompatibility complex (MHC) is located in chromosome 6p21 and contains crucial regulators of immune response, including human leucocyte antigen (HLA) genes, alongside other genes with nonimmunological roles. More recently, a repertoire of noncoding RNA genes, including expressed pseudogenes, has also been identified. The MHC is the most gene dense and most polymorphic part of the human genome. The region exhibits haplotype-specific linkage disequilibrium patterns, contains the strongest cis- and trans-eQTLs/meQTLs in the genome and is known as a hot spot for disease associations. Another layer of complexity is provided to the region by the extreme structural variation and copy number variations. While the HLA-B gene has the highest number of alleles, the HLA-DR/DQ subregion is structurally most variable and shows the highest number of disease associations. Reliance on a single reference sequence has complicated the design, execution and analysis of GWAS for the MHC region and not infrequently, the MHC region has even been excluded from the analysis of GWAS data. Here, we contrast features of the MHC region with the rest of the genome and highlight its complexities, including its functional polymorphisms beyond those determined by single nucleotide polymorphisms or single amino acid residues. One of the several issues with customary GWAS analysis is that it does not address this additional layer of polymorphisms unique to the MHC region. We highlight alternative approaches that may assist with the analysis of GWAS data from the MHC region and unravel associations with all functional polymorphisms beyond single SNPs. We suggest that despite already showing the highest number of disease associations, the true extent of the involvement of the MHC region in disease genetics may not have been uncovered. PMID- 28877430 TI - Nontarget Screening with High Resolution Mass Spectrometry in the Environment: Ready to Go? AB - The vast, diverse universe of organic pollutants is a formidable challenge for environmental sciences, engineering, and regulation. Nontarget screening (NTS) based on high resolution mass spectrometry (HRMS) has enormous potential to help characterize this universe, but is it ready to go for real world applications? In this Feature article we argue that development of mass spectrometers with increasingly high resolution and novel couplings to both liquid and gas chromatography, combined with the integration of high performance computing, have significantly widened our analytical window and have enabled increasingly sophisticated data processing strategies, indicating a bright future for NTS. NTS has great potential for treatment assessment and pollutant prioritization within regulatory applications, as highlighted here by the case of real-time pollutant monitoring on the River Rhine. We discuss challenges for the future, including the transition from research toward solution-centered and robust, harmonized applications. PMID- 28877429 TI - Computational Simulations of DNA Polymerases: Detailed Insights on Structure/Function/Mechanism from Native Proteins to Cancer Variants. AB - Genetic information is vital in the cell cycle of DNA-based organisms. DNA polymerases (DNA Pols) are crucial players in transactions dealing with these processes. Therefore, the detailed understanding of the structure, function, and mechanism of these proteins has been the focus of significant effort. Computational simulations have been applied to investigate various facets of DNA polymerase structure and function. These simulations have provided significant insights over the years. This perspective presents the results of various computational studies that have been employed to research different aspects of DNA polymerases including detailed reaction mechanism investigation, mutagenicity of different metal cations, possible factors for fidelity synthesis, and discovery/functional characterization of cancer-related mutations on DNA polymerases. PMID- 28877432 TI - Distinguishing Biologically Relevant Hexoses by Water Adduction to the Lithium Cationized Molecule. AB - A method to distinguish the four most common biologically relevant underivatized hexoses, d-glucose, d-galactose, d-mannose, and d-fructose, using only mass spectrometry with no prior separation/derivatization step has been developed. Electrospray of a solution containing hexose and a lithium salt generates [Hexose+Li]+. The lithium-cationized hexoses adduct water in a quadrupole ion trap. The rate of this water adduction reaction can be used to distinguish the four hexoses. Additionally, for each hexose, multiple lithiation sites are possible, allowing for multiple structures of [Hexose+Li]+. Electrospray produces at least one structure that reacts with water and at least one that does not. The ratio of unreactive lithium-cationized hexose to total lithium-cationized hexose is unique for the four hexoses studied, providing a second method for distinguishing the isomers. Use of the water adduction reaction rate or the unreactive ratio provides two separate methods for confidently (p <= 0.02) distinguishing the most common biologically relevant hexoses using only femtomoles of hexose. Additionally, binary mixtures of glucose and fructose were studied. A calibration curve was created by measuring the reaction rate of various samples with different ratios of fructose and glucose. The calibration curve was used to accurately measure the percentage of fructose in three samples of high fructose corn syrup (<4% error). PMID- 28877431 TI - In Situ Imaging of Tissue Remodeling with Collagen Hybridizing Peptides. AB - Collagen, the major structural component of nearly all mammalian tissues, undergoes extensive proteolytic remodeling during developmental states and a variety of life-threatening diseases such as cancer, myocardial infarction, and fibrosis. While degraded collagen could be an important marker of tissue damage, it is difficult to detect and target using conventional tools. Here, we show that a designed peptide (collagen hybridizing peptide: CHP), which specifically hybridizes to the degraded, unfolded collagen chains, can be used to image degraded collagen and inform tissue remodeling activity in various tissues: labeled with 5-carboxyfluorescein and biotin, CHPs enabled direct localization and quantification of collagen degradation in isolated tissues within pathologic states ranging from osteoarthritis and myocardial infarction to glomerulonephritis and pulmonary fibrosis, as well as in normal tissues during developmental programs associated with embryonic bone formation and skin aging. The results indicate the general correlation between the level of collagen remodeling and the amount of denatured collagen in tissue and show that the CHP probes can be used across species and collagen types, providing a versatile tool for not only pathology and developmental biology research but also histology based disease diagnosis, staging, and therapeutic screening. This study lays the foundation for further testing CHP as a targeting moiety for theranostic delivery in various animal models. PMID- 28877433 TI - Detection of Chemical Warfare Agent-Related Phenylarsenic Compounds in Marine Biota Samples by LC-HESI/MS/MS. AB - A new method has been developed to determine oxidation products of three chemical warfare agent (CWA) related phenylarsenic compounds from marine biota samples by a liquid chromatography-heated electrospray ionization/tandem mass spectrometry (LC-HESI/MS/MS). The target chemicals were oxidation products of Adamsite (DM[ox]), Clark I (DPA[ox]), and triphenylarsine (TPA[ox]). Method was validated within the concentration range of 1-5, 0.2-5, and 0.2-5 ng/g for DM[ox], DPA[ox], and TPA[ox], respectively. The method was linear, precise and accurate. Limits of quantification (LOQ) were 2.0, 1.3, and 2.1 ng/g for DM[ox], DPA[ox], and TPA[ox], respectively. A total of ten fish samples and one lobster sample collected from near Swedish coast, Maseskar dumpsite were analyzed. Trace concentrations below LOQ values were detected in three samples and the elemental composition of oxidized form of Clark I and/or II was confirmed by LC-HESI/HRMS. To our knowledge, this is the first study that provides the presence of CWA related chemicals in marine biota samples. PMID- 28877434 TI - Reduction-Responsive Polypeptide Micelles for Intracellular Delivery of Antineoplastic Agent. AB - Reduction-responsive methoxy poly(ethylene glycol)-block-poly(S-tert butylmercapto-L-cysteine) copolymers (i.e., mPEG113-b-PBMLC4 and mPEG113-b PBMLC9) were facilely synthesized through primary amino-initiated ring-opening polymerization (ROP) of disulfide-containing N-carboxyanhydride monomer. The reduction-responsive block copolymers were then investigated for intracellular delivery of antitumor drug after forming smart micelles in vitro and in vivo. The micelles were denoted as P4M and P9M, respectively. Doxorubicin (DOX) was selected as a model chemotherapeutic agent, which was loaded into micelles via hydrophobic interaction. The drug loading efficiency (DLE) were detected to be 55.4 and 61.7 wt % for P4M and P9M, respectively. The loaded micelles, referred as P4M/DOX and P9M/DOX, exhibited spherical morphologies with hydrodynamic radii of 92.3 +/- 2.3 and 80.2 +/- 2.8 nm, respectively. Compared to P4M/DOX, P9M/DOX with a smaller size exhibited upregulated cell endocytosis and higher cytotoxicity to human breast cancer MCF-7 cells. Furthermore, the loading micelles, especially P9M/DOX, demonstrated improved antitumor efficacy toward an MCF-7 breast tumor-bearing BALB/c nude mouse model compared with free doxorubicin hydrochloride (DOX.HCl). This was also confirmed by the histopathological and immunohistochemical results. The above results demonstrated that the facially prepared smart polypeptide micelles exhibited a potent prospect in intracellular drug delivery in vitro and in vivo. PMID- 28877435 TI - Diasteroselective and Enantioselective Ir-Catalyzed Allylic Substitutions of 1 Substituted 1-Fluoro-1-(arenesulfonyl)methylene Derivatives. AB - diasteroselective and enantioselective Ir-catalyzed allylic substitutions of 1 substituted 1-fluoro-1-(arenesulfonyl)methylene derivatives are presented, which afford the fluorinated allyl products with two chirality centers. The steric demand of 1-substituted 1-fluoro-1-(arenesulfonyl)methylene derivatives and allylic substrates has a great influence on the dr values of these reactions. The transformation of the branched allyl product into the fluorinated 3,4-dihydro-2H pyrrole 1-oxide was discussed, as well. PMID- 28877436 TI - Comparative Study of Nonhybrid Density Functional Approximations for the Prediction of 3d Transition Metal Thermochemistry. AB - The utility of several nonhybrid density functional approximations (DFAs) is considered for the prediction of gas phase enthalpies of formation for a large set of 3d transition metal-containing molecules. Nonhybrid DFAs can model thermochemical values for 3d transition metal-containing molecules with accuracy comparable to that of hybrid functionals. The GAM-generalized gradient approximation (GGA); the TPSS, M06-L, and MN15-L meta-GGAs; and the Rung 3.5 PBE+PiLDA(s) DFAs all give root-mean-square deviations below that of the widely used B3LYP hybrid. Modern nonhybrid DFAs continue to show utility for transition metal thermochemistry. PMID- 28877437 TI - Solvent Effect on the Third-Order Nonlinear Optical Properties of alpha- and beta Tertbutyl Phenoxy-Substituted Tin(IV) Chloride Phthalocyanines. AB - This paper investigates the third-order nonlinear optical properties of 4alpha-(4 tert-butylphenoxy) phthalocyaninato dichlorotin(IV) (alpha-SnOtBpPc) and 4beta-(4 tert-butylphenoxy) phthalocyaninato dichlorotin(IV) (beta-SnOtBpPc) in different organic solvents. The third-order susceptibilities of alpha-SnOtBpPc and beta SnOtBpPc are reported in different solvents, using Z-scan techniques with 10 ns laser pulses at 532 nm. Their nonlinear absorption coefficient and absorption cross sections were also determined. The molecular imaginary components of the second-order hyperpolarizability Im[gamma] of alpha-SnOtBpPc and beta-SnOtBpPc were found to be 2.60 * 10-31 and 2.94 * 10-31 esu (tetrahydrofuran), 2.12 * 10 31 and 2.54 * 10-31 esu (chloroform), 3.06 * 10-31 and 2.54 * 10-31 esu (dichloromethane), and 1.27 * 10-31 and 1.50 * 10-31 esu (toluene), respectively. This study found that substitution at the alpha position has an effect of lowering the two-photon (2PA) cross section value for alpha-SnOtBpPc compared to that for beta-SnOtBpPc, with values of 64.30 and 456.65 GM, respectively. The large 2PA cross section observed in beta-SnOtBpPc is attributed to the decreased energy difference between the virtual state and the LUMO. PMID- 28877438 TI - Integrated Three-Dimensional Microanalysis Combining X-Ray Microtomography and X Ray Fluorescence Methodologies. AB - A novel 3D elemental and morphological analysis approach is presented combining X ray computed tomography (MUCT), X-ray fluorescence (XRF) tomography, and confocal XRF analysis in a single laboratory instrument (Herakles). Each end station of Herakles (MUCT, XRF-CT, and confocal XRF) represents the state-of-the-art of currently available laboratory techniques. The integration of these techniques enables linking the (quantitative) spatial distribution of chemical elements within the investigated materials to their three-dimensional (3D) internal morphology/structure down to 1-10 MUm resolution level, which has not been achieved so-far using laboratory X-ray techniques. The concept of Herakles relies strongly on its high precision (around 100 nm) air-bearing motor system that connects the different end-stations, allowing combined measurements based on the above X-ray techniques while retaining the coordinate system. In-house developed control and analysis software further ensures a smooth integration of the techniques. Case studies on a Cu test pattern, a Daphnia magna model organism and a perlite biocatalyst support material demonstrate the attainable resolution, elemental sensitivity of the instrument, and the strength of combining these three complementary methodologies. PMID- 28877439 TI - 2D Stokesian Approach to Modeling Flow Induced Deformation of Particle Laden Interfaces. AB - A Stokesian dynamics simulation of the effect of surface Couette flow on the microstructure of particles irreversibly adsorbed to an interface is presented. Rather than modeling both bulk phases, the interface, and particles in a full 3D simulation, known interfacial interactions between adsorbed particles are used to create a 2D model from a top down perspective. This novel methodology is easy to implement and computationally inexpensive, which makes it favorable to simulate behavior of particles under applied flow at fluid-fluid interfaces. The methodology is used to examine microstructure deformation of monodisperse, rigid spherical colloids with repulsive interactions when a surface Couette flow is imposed. Simulation results compare favorably to experimental results taken from literature, showing that interparticle forces must be 1 order of magnitude greater than viscous drag for microstructure to transition from aligned particle strings to rotation of local hexagonal domains. Additionally, it is demonstrated that hydrodynamic interactions between particles play a significant role in the magnitude of these microstructure deformations. PMID- 28877440 TI - Bimodal Grain-Size Scaling of Thermal Transport in Polycrystalline Graphene from Large-Scale Molecular Dynamics Simulations. AB - Grain boundaries in graphene are inherent in wafer-scale samples prepared by chemical vapor deposition. They can strongly influence the mechanical properties and electronic and heat transport in graphene. In this work, we employ extensive molecular dynamics simulations to study thermal transport in large suspended polycrystalline graphene samples. Samples of different controlled grain sizes are prepared by a recently developed efficient multiscale approach based on the phase field crystal model. In contrast to previous works, our results show that the scaling of the thermal conductivity with the grain size implies bimodal behavior with two effective Kapitza lengths. The scaling is dominated by the out-of-plane (flexural) phonons with a Kapitza length that is an order of magnitude larger than that of the in-plane phonons. We also show that, to get quantitative agreement with the most recent experiments, quantum corrections need to be applied to both the Kapitza conductance of grain boundaries and the thermal conductivity of pristine graphene, and the corresponding Kapitza lengths must be renormalized accordingly. PMID- 28877442 TI - Interactions on External MOF Surfaces: Desorption of Water and Ethanol from CuBDC Nanosheets. AB - The external surfaces of metal-organic framework (MOF) materials are difficult to experimentally isolate due to the high porosities of these materials. MOF surface surrogates in the form of copper benzenedicarboxylate (CuBDC) nanosheets were synthesized using a bottom-up approach, and the surface interactions of water and ethanol were investigated by temperature-programmed desorption (TPD). A method of analysis of diffusion-influenced TPD was developed to measure the desorption properties of these porous materials. This approach also allows the extraction of diffusion coefficients from TPD data. The transmission Fourier transform infrared spectra, powder X-ray diffraction patterns, and TPD data indicate that water desorbs from CuBDC nanosheets with activation energies of 44 +/- 2 kJ/mol at edge sites and 58 +/- 1 kJ/mol at external surface and internal and pore sites. Ethanol desorbs with activation energies of 58 +/- 1 kJ/mol at internal pore sites and 66 +/- 0.4 kJ/mol at external surface sites. Co-adsorption of water and ethanol was also investigated. The presence of ethanol was found to inhibit the desorption of water, resulting in a water desorption process with an activation energy of 68 +/- 0.7 kJ/mol. PMID- 28877441 TI - Development of the Large-Scale Synthesis of Tetrahydropyran Glycine, a Precursor to the HCV NS5A Inhibitor BMS-986097. AB - An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of t-butyl 2 ((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but 2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API BMS-986097 for toxicology studies. PMID- 28877443 TI - Characterization of Bifunctional Spin Labels for Investigating the Structural and Dynamic Properties of Membrane Proteins Using EPR Spectroscopy. AB - Site-directed spin labeling (SDSL) coupled with electron paramagnetic resonance (EPR) spectroscopy is a very powerful technique to study structural and dynamic properties of membrane proteins. The most widely used spin label is methanthiosulfonate (MTSL). However, the flexibility of this spin label introduces greater uncertainties in EPR measurements obtained for determining structures, side-chain dynamics, and backbone motion of membrane protein systems. Recently, a newer bifunctional spin label (BSL), 3,4 bis(methanethiosulfonylmethyl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yloxy, has been introduced to overcome the dynamic limitations associated with the MTSL spin label and has been invaluable in determining protein backbone dynamics and inter-residue distances due to its restricted internal motion and fewer size restrictions. While BSL has been successful in providing more accurate information about the structure and dynamics of several proteins, a detailed characterization of the spin label is still lacking. In this study, we characterized BSLs by performing CW-EPR spectral line shape analysis as a function of temperature on spin-labeled sites inside and outside of the membrane for the integral membrane protein KCNE1 in POPC/POPG lipid bilayers and POPC/POPG lipodisq nanoparticles. The experimental data revealed a powder pattern spectral line shape for all of the KCNE1-BSL samples at 296 K, suggesting the motion of BSLs approaches the rigid limit regime for these series of samples. BSLs were further utilized to report for the first time the distance measurement between two BSLs attached on an integral membrane protein KCNE1 in POPC/POPG lipid bilayers at room temperature using dipolar line broadening CW-EPR spectroscopy. The CW dipolar line broadening EPR data revealed a 15 +/- 2 A distance between doubly attached BSLs on KCNE1 (53/57-63/67) which is consistent with molecular dynamics modeling and the solution NMR structure of KCNE1 which yielded a distance of 17 A. This study demonstrates the utility of investigating the structural and dynamic properties of membrane proteins in physiologically relevant membrane mimetics using BSLs. PMID- 28877444 TI - New Tethered Phospholipid Bilayers Integrating Functional G-Protein-Coupled Receptor Membrane Proteins. AB - Membrane proteins exhibiting extra- and intracellular domains require an adequate near-native lipid platform for their functional reconstitution. With this aim, we developed a new technology enabling the formation of a peptide-tethered bilayer lipid membrane (pep-tBLM), a lipid bilayer grafted onto peptide spacers, by way of a metal-chelate interaction. To this end, we designed an original peptide spacer derived from the natural alpha-laminin thiopeptide (P19) possessing a cysteine residue in the N-terminal extremity for grafting onto gold and a C terminal extremity modified by four histidine residues (P19-4H). In the presence of nickel, the use of this anchor allowed us to bind liposomes of variable compositions containing a 2% molar ratio of a chelating lipid, 1,2-dioleoyl-sn glycero-3-[(N-(5-amino-1-carboxypentyl)iminodiacetic acid)succinyl] so-called DOGS-NTA, and to form the planar bilayer by triggering liposome fusion by an alpha-helical (AH) peptide derived from the N-terminus of the hepatitis C virus NS5A protein. The formation of pep-tBLMs was characterized by surface plasmon resonance imaging (SPRi), and their continuity, fluidity, and homogeneity were demonstrated by fluorescence recovery after photobleaching (FRAP), with a diffusion coefficient of 2.5 * 10-7 cm2/s, and atomic force microscopy (AFM). By using variable lipid compositions including phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol 4,5 bisphosphate (PIP2), sphingomyelin (SM), phosphatidic acid (PA), and cholesterol (Chol) in various ratios, we show that the membrane can be formed independently from the lipid composition. We made the most of this advantage to reincorporate a transmembrane protein in an adapted complex lipid composition to ensure its functional reinsertion. For this purpose, a cell-free expression system was used to produce proteoliposomes expressing the functional C-X-C motif chemokine receptor 4 (CXCR4), a seven-transmembrane protein belonging to the large superfamily of G-protein-coupled receptors (GPCRs). We succeeded in reinserting CXCR4 in pep-tBLMs formed on P19-4H by the fusion of tethered proteoliposomes. AFM and FRAP characterization allowed us to show that pep-tBLMs inserting CXCR4 remained fluid, homogeneous, and continuous. The value of the diffusion coefficient determined in the presence of reinserted CXCR4 was 2 * 10-7 cm2/s. Ligand binding assays using a synthetic CXCR4 antagonist, T22 ([Tyr5,12, Lys7] polyphemusin II), revealed that CXCR4 can be reinserted in pep-tBLMs with functional folding and orientation. This new approach represents a method of choice for investigating membrane protein reincorporation and a promising way of creating a new generation of membrane biochips adapted for screening agonists or antagonists of transmembrane proteins. PMID- 28877445 TI - Anti-fibrosis effect of nanoparticle-mediated delivery of plasminogen kringle 5. AB - Retinal fibrosis, including epiretinal membrane (ERM) and proliferative vitreoretinopathy (PVR), is an ocular disease that can lead to blindness. An efficacious therapy remains an unmet medical challenge. In this study, we intended to explore the inhibitory effects of the nanoparticle-mediated delivery of plasminogen kringle 5 (K5-NPs) on laser-induced ERM and to identify the potential anti-fibrosis targets of K5-NPs. A rat model of laser-induced ERM was used. Control-NPs or K5-NPs were intravitreally injected. ERM formation was observed in vivo. The expression of fibrosis-associated factors including TGF beta, CTGF, and alpha-SMA was detected by qRT-PCR, Western blot, or immunohistochemistry. Our results showed that K5-NPs effectively inhibit laser induced ERM formation. The expression of alpha-SMA, the marker of myofibroblast, apparently decreased in immunostained ERMs in the K5-NPs group. The expression of CTGF, a pro-fibrotic factor, in our ERM rat model was significantly downregulated by K5-NPs. Meanwhile, the expression of TGF-beta, the upstream regulator of CTGF, was found to be suppressed by K5-NPs as well. The anti-fibrosis effect of K5-NPs might be achieved by interfering with TGF-beta expression, thus abrogating the TGF-beta-induced upregulation of CTGF and alpha-SMA. Our study has an important clinical relevance, demonstrating that K5-NPs might offer an additional efficacious clinical option for treating fibrosis-related diseases. PMID- 28877446 TI - Role of ion channels in natural killer cell function towards cancer. AB - Progression of cancer to advanced states is associated with treatment resistance and metastatic spread -- features that are linked to poor prognosis and patient mortality. Investigations into potential new treatments to reduce cancer spread are ongoing, with immunotherapy generating much interest. Natural killer (NK) cells are part of the body's innate immune system and are known for their ability to target and lyse cancer cells. Ion channels have previously been linked to the growth and development of tumors, but recent research suggests that these channels may also serve to alter immune cell functioning. This review examines the current understanding as to the role of ion channels in NK cells and how manipulation of these channels may increase NK effectiveness in targeting and removing cancer cells. With a large number of existing FDA-approved drugs targeting ion channels, potential exists for drug repurposing in order to improve immunotherapy and thus patient outcomes. PMID- 28877447 TI - Limiting oxidative stress following neurotrauma with a combination of ion channel inhibitors. AB - Following injury to the central nervous system, secondary degeneration is mediated by Ca2+ imbalances and overproduction of reactive oxygen species from mitochondria, and is associated with myelin deficits and loss of function. Preventing intracellular Ca2+ influx at the acute phase of injury is a potential strategy for limiting these deficits and preserving function. The use of single ion channel inhibitors has had little success in attenuating morphological and functional deficits, potentially due to the many pathways by which calcium can traverse the cell membrane. Focus has shifted to the simultaneous administration of a combination of ion channel inhibitors: lomerizine, oxATP, and YM872. The combination has resulted in reductions in oxidative damage, as well as preservation of function and myelin ultrastructure, potentially due to the protection of oligodendrocytes and their progenitors. The use of multiple ion channel inhibitors is promising and suggests a reduction in total intracellular Ca2+ influx is necessary and sufficient for the protection of neurons and glia following neurotrauma. Optimization of treatment timing, inhibitor choice, and method of delivery will be required for translation of this strategy to the clinic. PMID- 28877448 TI - Gene therapy for heart failure: status quo and quo vadis. AB - Gene therapy is recently attracting increased attention and cardiac gene therapy is not an exception. Advances in gene transfer vectors, development of new vector delivery methods, and discovery of new gene targets continue to fuel our motivation to use this approach in routine bedside care. In the past two years, we have witnessed important advances in the field, as the results of three recently completed cardiac gene therapy programs have been published. Unfortunately, none of the trials have met their primary efficacy endpoints, but sub-analysis demonstrated potential efficacy. Careful review and interpretation of these trial results will provide important insights and direct us to improve the future trial design. In this review, we update our previous overview with a specific focus on recent clinical trial results. We then contemplate future strategies towards successful application of gene therapy for treating clinical heart failure. PMID- 28877449 TI - Surgical management of metastatic renal cell carcinoma. AB - Despite advances in systemic therapy for metastatic renal cell carcinoma, durable responses remain rare and surgical management remains a mainstay of treatment for many patients with metastatic disease. Management of the primary tumor in metastatic patients can occur as 1) palliative nephrectomy for symptomatic patients in whom cure is not achievable, 2) cytoreductive nephrectomy before systemic therapy, or 3) consolidative nephrectomy after systemic therapy. Palliative nephrectomy is rarely performed in centers where angioembolization is available. The evidence for cytoreductive nephrectomy is based on randomized trials in the cytokine era and retrospective studies in the more recent targeted therapy era. Consolidative nephrectomy is utilized after systemic therapy for intermediate- and poor-risk patients or in patients with potentially unresectable disease based on retrospective evidence. Resection of metastatic lesions, or metastasectomy, is utilized in select patients, with efficacy predicated on the organs involved and the extent of resection that is achievable, based on retrospective data. Herein, the evidence for surgical management of both the primary tumor and metastatic lesions in patients with metastatic renal cell carcinoma is reviewed. PMID- 28877450 TI - Women in Metabolism: The Next Generation. AB - The "Rosies" of Cell Metabolism persist as a new generation enters the stage. With inspiration from this issue's cover art, we celebrate young and diverse scientists and the mentorship that has guided them throughout. Their stories come from different corners of the world but are tied together by a common thread of tenacity and perseverance. PMID- 28877451 TI - The Liver as a Hub in Thermogenesis. AB - Manipulating thermogenesis could increase energy expenditure and improve metabolism. Brown fat is a major site of nonshivering thermogenesis, but other tissues, notably muscle and liver, can contribute to cold adaptation. In this issue, Simcox et al. (2017) demonstrate in cold-exposed mice that liver-generated acylcarnitines are required to fuel thermogenesis. PMID- 28877452 TI - Meds Modify Microbiome, Mediating Their Effects. AB - The mechanisms of action of some common medications remain unknown but, in some cases, may involve the microorganisms within us. A new study by Wu et al. (2017) provides evidence that the type 2 diabetes drug metformin alters the gut microbiota, which in turn may mediate some of the drug's effects. PMID- 28877453 TI - Disentangling High Fat, Low Carb, and Healthy Aging. AB - Dietary interventions are simple, non-invasive tools that can be utilized to improve health and lifespan. In this issue, Roberts et al. (2017) and Newman et al. (2017) reveal the physiological benefits of feeding mice ketogenic diets and suggest different underlying mechanisms that may promote healthy aging. PMID- 28877454 TI - A Stat6/Pten Axis Links Regulatory T Cells with Adipose Tissue Function. AB - Obesity and type 2 diabetes are associated with metabolic defects and adipose tissue inflammation. Foxp3+ regulatory T cells (Tregs) control tissue homeostasis by counteracting local inflammation. However, if and how T cells interlink environmental influences with adipocyte function remains unknown. Here, we report that enhancing sympathetic tone by cold exposure, beta3-adrenergic receptor (ADRB3) stimulation or a short-term high-calorie diet enhances Treg induction in vitro and in vivo. CD4+ T cell proteomes revealed higher expression of Foxp3 regulatory networks in response to cold or ADRB3 stimulation in vivo reflecting Treg induction. Specifically, Ragulator-interacting protein C17orf59, which limits mTORC1 activity, was upregulated in CD4+ T cells by either ADRB3 stimulation or cold exposure, suggesting contribution to Treg induction. By loss- and gain-of-function studies, including Treg depletion and transfers in vivo, we demonstrated that a T cell-specific Stat6/Pten axis links cold exposure or ADRB3 stimulation with Foxp3+ Treg induction and adipose tissue function. Our findings offer a new mechanistic model in which tissue-specific Tregs maintain adipose tissue function. PMID- 28877456 TI - Distinct Circadian Signatures in Liver and Gut Clocks Revealed by Ketogenic Diet. AB - The circadian clock orchestrates rhythms in physiology and behavior, allowing organismal adaptation to daily environmental changes. While food intake profoundly influences diurnal rhythms in the liver, how nutritional challenges are differentially interpreted by distinct tissue-specific clocks remains poorly explored. Ketogenic diet (KD) is considered to have metabolic and therapeutic value, though its impact on circadian homeostasis is virtually unknown. We show that KD has profound and differential effects on liver and intestine clocks. Specifically, the amplitude of clock-controlled genes and BMAL1 chromatin recruitment are drastically altered by KD in the liver, but not in the intestine. KD induces nuclear accumulation of PPARalpha in both tissues but with different circadian phase. Also, gut and liver clocks respond differently to carbohydrate supplementation to KD. Importantly, KD induces serum and intestinal beta-hydroxyl butyrate levels to robustly oscillate in a circadian manner, an event coupled to tissue-specific cyclic histone deacetylase (HDAC) activity and histone acetylation. PMID- 28877455 TI - Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis. AB - Cold-induced thermogenesis is an energy-demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted liquid chromatography-mass spectrometry-based lipidomics, we identified elevated levels of plasma acylcarnitines in response to the cold. We found that the liver undergoes a metabolic switch to provide fuel for brown fat thermogenesis by producing acylcarnitines. Cold stimulates white adipocytes to release free fatty acids that activate the nuclear receptor HNF4alpha, which is required for acylcarnitine production in the liver and adaptive thermogenesis. Once in circulation, acylcarnitines are transported to brown adipose tissue, while uptake into white adipose tissue and liver is blocked. Finally, a bolus of L-carnitine or palmitoylcarnitine rescues the cold sensitivity seen with aging. Our data highlight an elegant mechanism whereby white adipose tissue provides long-chain fatty acids for hepatic carnitilation to generate plasma acylcarnitines as a fuel source for peripheral tissues in mice. PMID- 28877458 TI - Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. AB - Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies downregulation of insulin, protein synthesis, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, upregulation of PPARalpha target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice. PMID- 28877457 TI - A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. AB - Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD extends longevity and healthspan in mice. PMID- 28877459 TI - Cell-Intrinsic Glycogen Metabolism Supports Early Glycolytic Reprogramming Required for Dendritic Cell Immune Responses. AB - Dendritic cell (DC) activation by Toll-like receptor (TLR) agonists causes rapid glycolytic reprogramming that is required to meet the metabolic demands of their immune activation. Recent efforts in the field have identified an important role for extracellular glucose sourcing to support DC activation. However, the contributions of intracellular glucose stores to these processes have not been well characterized. We demonstrate that DCs possess intracellular glycogen stores and that cell-intrinsic glycogen metabolism supports the early effector functions of TLR-activated DCs. Inhibition of glycogenolysis significantly attenuates TLR mediated DC maturation and impairs their ability to initiate lymphocyte activation. We further report that DCs exhibit functional compartmentalization of glucose- and glycogen-derived carbons, where these substrates preferentially contribute to distinct metabolic pathways. This work provides novel insights into nutrient homeostasis in DCs, demonstrating that differential utilization of glycogen and glucose metabolism regulates their optimal immune function. PMID- 28877461 TI - Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. PMID- 28877460 TI - Persistence of Pancreatic Insulin mRNA Expression and Proinsulin Protein in Type 1 Diabetes Pancreata. AB - The canonical notion that type 1 diabetes (T1D) results following a complete destruction of beta cells has recently been questioned as small amounts of C peptide are detectable in patients with long-standing disease. We analyzed protein and gene expression levels for proinsulin, insulin, C-peptide, and islet amyloid polypeptide within pancreatic tissues from T1D, autoantibody positive (Ab+), and control organs. Insulin and C-peptide levels were low to undetectable in extracts from the T1D cohort; however, proinsulin and INS mRNA were detected in the majority of T1D pancreata. Interestingly, heterogeneous nuclear RNA (hnRNA) for insulin and INS-IGF2, both originating from the INS promoter, were essentially undetectable in T1D pancreata, arguing for a silent INS promoter. Expression of PCSK1, a convertase responsible for proinsulin processing, was reduced in T1D pancreata, supportive of persistent proinsulin. These data implicate the existence of beta cells enriched for inefficient insulin/C-peptide production in T1D patients, potentially less susceptible to autoimmune destruction. PMID- 28877462 TI - A Hypothalamic Phosphatase Switch Coordinates Energy Expenditure with Feeding. PMID- 28877463 TI - Mpp6 Incorporation in the Nuclear Exosome Contributes to RNA Channeling through the Mtr4 Helicase. AB - The RNA-degrading exosome mediates the processing and decay of many cellular transcripts. In the yeast nucleus, the ubiquitous 10-subunit exosome core complex (Exo-9-Rrp44) functions with four conserved cofactors (Rrp6, Rrp47, Mtr4, and Mpp6). Biochemical and structural studies to date have shed insights into the mechanisms of the exosome core and its nuclear cofactors, with the exception of Mpp6. We report the 3.2-A resolution crystal structure of a S. cerevisiae Exo-9 Mpp6 complex, revealing how linear motifs in the Mpp6 middle domain bind Rrp40 via evolutionary conserved residues. In particular, Mpp6 binds near a tryptophan residue of Rrp40 that is mutated in human patients suffering from pontocerebellar hypoplasia. Using biochemical assays, we show that Mpp6 is required for the ability of Mtr4 to extend the trajectory of an RNA entering the exosome core, suggesting that it promotes the channeling of substrates from the nuclear helicase to the processive RNase. PMID- 28877464 TI - Tail-Anchored Protein Insertion by a Single Get1/2 Heterodimer. AB - The Get1/2 transmembrane complex drives the insertion of tail-anchored (TA) proteins from the cytosolic chaperone Get3 into the endoplasmic reticulum membrane. Mechanistic insight into how Get1/2 coordinates this process is confounded by a lack of understanding of the basic architecture of the complex. Here, we define the oligomeric state of full-length Get1/2 in reconstituted lipid bilayers by combining single-molecule and bulk fluorescence measurements with quantitative in vitro insertion analysis. We show that a single Get1/2 heterodimer is sufficient for insertion and demonstrate that the conserved cytosolic regions of Get1 and Get2 bind asymmetrically to opposing subunits of the Get3 homodimer. Altogether, our results define a simplified model for how Get1/2 and Get3 coordinate TA protein insertion. PMID- 28877465 TI - Dynamics of Presynaptic Diacylglycerol in a Sensory Neuron Encode Differences between Past and Current Stimulus Intensity. AB - Memorizing the intensity of sensory stimuli enables animals to successfully deal with changing environmental conditions and contributes to cognitive functions such as auditory and visual working memory. However, how nervous systems process past and current stimulus intensity is largely unknown at the molecular level. Here, we employ in vivo diacylglycerol (DAG) imaging in the ASER taste neuron of Caenorhabditis elegans and demonstrate that associative learning between ambient salt concentrations and food can be explained by changes in presynaptic DAG. The abundance of DAG is regulated in response to external salt concentration changes via sensory transduction in ASER and can encode differences between past and current salt concentrations. The DAG dynamics are modulated downstream of the synaptic insulin/phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which regulates the behavioral plasticity induced by starvation. These results provide insights into how a single neuron stores past input intensity and generates appropriate behavioral responses. PMID- 28877466 TI - Local Nucleation of Microtubule Bundles through Tubulin Concentration into a Condensed Tau Phase. AB - Non-centrosomal microtubule bundles play important roles in cellular organization and function. Although many diverse proteins are known that can bundle microtubules, biochemical mechanisms by which cells could locally control the nucleation and formation of microtubule bundles are understudied. Here, we demonstrate that the concentration of tubulin into a condensed, liquid-like compartment composed of the unstructured neuronal protein tau is sufficient to nucleate microtubule bundles. We show that, under conditions of macro-molecular crowding, tau forms liquid-like drops. Tubulin partitions into these drops, efficiently increasing tubulin concentration and driving the nucleation of microtubules. These growing microtubules form bundles, which deform the drops while remaining enclosed by diffusible tau molecules exhibiting a liquid-like behavior. Our data suggest that condensed compartments of microtubule bundling proteins could promote the local formation of microtubule bundles in neurons by acting as non-centrosomal microtubule nucleation centers and that liquid-like tau encapsulation could provide both stability and plasticity to long axonal microtubule bundles. PMID- 28877468 TI - Cbln1 and Cbln4 Are Structurally Similar but Differ in GluD2 Binding Interactions. AB - Unlike cerebellin 1 (Cbln1), which bridges neurexin (Nrxn) receptors and delta type glutamate receptors in a trans-synaptic triad, Cbln4 was reported to have no or weak binding for the receptors despite sharing ~70% sequence identity with Cbln1. Here, we report crystal structures of the homotrimers of the C1q domain of Cbln1 and Cbln4 at 2.2 and 2.3 A resolution, respectively. Comparison of the structures suggests that the difference between Cbln1 and Cbln4 in GluD2 binding might be because of their sequence and structural divergence in loop CD. Surprisingly, we show that Cbln4 binds to Nrxn1beta and forms a stable complex with the laminin, nectin, sex-hormone binding globulin (LNS) domain of Nrxn1beta. Furthermore, the negative-stain electron microscopy reconstruction of hexameric full-length Cbln1 at 13 A resolution and that of the Cbln4/Nrxn1beta complex at 19 A resolution suggest that Nrxn1beta binds to the N-terminal region of Cbln4, probably through strand beta10 of the S4 insert. PMID- 28877467 TI - The SET1 Complex Selects Actively Transcribed Target Genes via Multivalent Interaction with CpG Island Chromatin. AB - Chromatin modifications and the promoter-associated epigenome are important for the regulation of gene expression. However, the mechanisms by which chromatin modifying complexes are targeted to the appropriate gene promoters in vertebrates and how they influence gene expression have remained poorly defined. Here, using a combination of live-cell imaging and functional genomics, we discover that the vertebrate SET1 complex is targeted to actively transcribed gene promoters through CFP1, which engages in a form of multivalent chromatin reading that involves recognition of non-methylated DNA and histone H3 lysine 4 trimethylation (H3K4me3). CFP1 defines SET1 complex occupancy on chromatin, and its multivalent interactions are required for the SET1 complex to place H3K4me3. In the absence of CFP1, gene expression is perturbed, suggesting that normal targeting and function of the SET1 complex are central to creating an appropriately functioning vertebrate promoter-associated epigenome. PMID- 28877469 TI - Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9. AB - Iron is vital for many homeostatic processes, and its liberation from ferritin nanocages occurs in the lysosome. Studies indicate that ferritin and its binding partner nuclear receptor coactivator-4 (NCOA4) are targeted to lysosomes by a form of selective autophagy. By using genome-scale functional screening, we identify an alternative lysosomal transport pathway for ferritin that requires FIP200, ATG9A, VPS34, and TAX1BP1 but lacks involvement of the ATG8 lipidation machinery that constitutes classical macroautophagy. TAX1BP1 binds directly to NCOA4 and is required for lysosomal trafficking of ferritin under basal and iron depleted conditions. Under basal conditions ULK1/2-FIP200 controls ferritin turnover, but its deletion leads to TAX1BP1-dependent activation of TBK1 that regulates redistribution of ATG9A to the Golgi enabling continued trafficking of ferritin. Cells expressing an amyotrophic lateral sclerosis (ALS)-associated TBK1 allele are incapable of degrading ferritin suggesting a molecular mechanism that explains the presence of iron deposits in patient brain biopsies. PMID- 28877470 TI - Strong Clonal Relatedness between Serum and Gut IgA despite Different Plasma Cell Origins. AB - Mucosal antigens induce generation of lamina propria plasma cells (PCs) that secrete dimeric immunoglobulin A (IgA) destined for transport across the epithelium. In addition, blood contains monomeric IgA. To study the relationship between mucosal and systemic antibody responses, we took advantage of celiac disease patient samples for isolation of gut PCs as well as serum IgA and IgG reactive with a gluten-derived peptide or the autoantigen transglutaminase 2. Proteomic analysis of serum IgA revealed antigen-specific V-gene preferences, which matched those found in gut PCs. Further, gut PC CDR-H3 sequences were abundant in serum IgA but also detectable in serum IgG. Our data indicate that the same B cell clones that give rise to gut PCs also contribute to the serum antibody pool. However, serum IgA antibodies had a molecular composition distinct from that of IgA antibodies secreted in the gut, suggesting that individual B cell clones give rise to different PC populations. PMID- 28877471 TI - KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub. AB - Gene fusions are increasingly recognized as important cancer drivers. The KIF5B RET gene has been identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation, including hyperproliferation, epithelial-to mesenchymal transition, invasion, and extension of striking invadopodia-like processes. The KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation, including invadopodia-like processes. Through a combination of genetic and biochemical studies, we demonstrate that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB-vesicle-dependent RET-SRC-EGFR-FGFR signaling hub. We demonstrate that drugs designed to inhibit RET alone work poorly in KIF5B-RET-transformed cells. However, combining the RET inhibitor sorafenib with drugs that target EGFR, microtubules, or FGFR led to strong efficacy in both Drosophila and human cell line KIF5B-RET models. This work demonstrates the utility of exploring the full biology of fusions to identify rational therapeutic strategies. PMID- 28877472 TI - ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System. AB - Activation of transcription factor NF-kappaB is a hallmark of infection with the gastric pathogen Helicobacter pylori, associated with inflammation and carcinogenesis. Genome-wide RNAi screening revealed numerous host factors involved in H. pylori-, but not IL-1beta- and TNF-alpha-dependent NF-kappaB regulation. Pathway analysis including CRISPR/Cas9-knockout and recombinant protein technology, immunofluorescence microscopy, immunoblotting, mass spectrometry, and mutant H. pylori strains identified the H. pylori metabolite D glycero-beta-D-manno-heptose 1,7-bisphosphate (betaHBP) as a cagPAI type IV secretion system (T4SS)-dependent effector of NF-kappaB activation in infected cells. Upon pathogen-host cell contact, TIFA forms large complexes (TIFAsomes) including interacting host factors, such as TRAF2. NF-kappaB activation, TIFA phosphorylation, and TIFAsome formation depend on a functional ALPK1 kinase, highlighting the ALPK1-TIFA axis as a core innate immune pathway. ALPK1-TIFA mediated NF-kappaB activation was independent of CagA protein translocation, indicating that CagA translocation and HBP delivery to host cells are distinct features of the pathogen's T4SS. PMID- 28877473 TI - Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease. AB - Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines. PMID- 28877475 TI - A Single TCF Transcription Factor, Regardless of Its Activation Capacity, Is Sufficient for Effective Trilineage Differentiation of ESCs. AB - Co-expression and cross-regulation of the four TCF/LEFs render their redundant and unique functions ambiguous. Here, we describe quadruple-knockout (QKO) mouse ESCs lacking all full-length TCF/LEFs and cell lines rescued with TCF7 or TCF7L1. QKO cells self-renew, despite gene expression patterns that differ significantly from WT, and display delayed, neurectoderm-biased, embryoid body (EB) differentiation. QKO EBs have no contracting cardiomyocytes and differentiate poorly into mesendoderm but readily generate neuronal cells. QKO cells and TCF7L1 rescued cells cannot efficiently activate TCF reporters, whereas TCF7-rescued cells exhibit significant reporter responsiveness. Surprisingly, despite dramatically different transactivation capacities, re-expression of TCF7L1 or TCF7 in QKO cells restores their tri-lineage differentiation ability, with similar lineage marker expression patterns and beating cardiomyocyte frequencies observed in EBs. Both factors also similarly affect the transcriptome of QKO cells. Our data reveal that a single TCF, regardless of its activation capacity, is sufficient for effective trilineage differentiation of ESCs. PMID- 28877474 TI - Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer. AB - Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels. PMID- 28877476 TI - mTORC2 Signaling Selectively Regulates the Generation and Function of Tissue Resident Peritoneal Macrophages. AB - Tissue-resident macrophages play critical roles in sentinel and homeostatic functions as well as in promoting inflammation and immunity. It has become clear that the generation of these cells is highly dependent upon tissue-specific cues derived from the microenvironment that, in turn, regulate unique differentiation programs. Recently, a role for GATA6 has emerged in the differentiation programming of resident peritoneal macrophages. We identify a critical role for mTOR in integrating cues from the tissue microenvironment in regulating differentiation and metabolic reprogramming. Specifically, inhibition of mTORC2 leads to enhanced GATA6 expression in a FOXO1 dependent fashion. Functionally, inhibition of mTORC2 promotes peritoneal resident macrophage generation in the resolution phase during zymosan-induced peritonitis. Also, mTORC2-deficient peritoneal resident macrophages displayed increased functionality and metabolic reprogramming. Notably, mTORC2 activation distinguishes tissue-resident macrophage proliferation and differentiation from that of M2 macrophages. Overall, our data implicate a selective role for mTORC2 in the differentiation of tissue-resident macrophages. PMID- 28877477 TI - Heparin Increases Food Intake through AgRP Neurons. AB - Although the widely used anticoagulant drug heparin has been shown to have many other biological functions independent of its anticoagulant role, its effects on energy homeostasis are unknown. Here, we demonstrate that heparin level is negatively associated with nutritional states and that heparin treatment increases food intake and body weight gain. By using electrophysiological, pharmacological, molecular biological, and chemogenetic approaches, we provide evidence that heparin increases food intake by stimulating AgRP neurons and increasing AgRP release. Our results support a model whereby heparin competes with insulin for insulin receptor binding on AgRP neurons, and by doing so it inhibits FoxO1 activity to promote AgRP release and feeding. Heparin may be a potential drug target for food intake regulation and body weight control. PMID- 28877478 TI - The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI. AB - The connection between signaling pathways activating cancer-associated fibroblasts (CAFs) remains to be determined. Metabolic alterations linked to autophagy have also been implicated in CAF activation. CSL/RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses the gene expression program(s), leading to stromal senescence and CAF activation. Deregulated GLI signaling can also contribute to CAF conversion. Here, we report that compromised CSL function depends on GLI activation for conversion of human dermal fibroblasts into CAFs, separately from cellular senescence. Decreased CSL upregulates the expression of the ULK3 kinase, which binds and activates GLI2. Increased ULK3 also induces autophagy, which is unlinked from GLI and CAF activation. ULK3 upregulation occurs in the CAFs of several tumor types, and ULK3 silencing suppresses the tumor-enhancing properties of these cells. Thus, ULK3 links two key signaling pathways involved in CAF conversion and is an attractive target for stroma-focused anti-cancer intervention. PMID- 28877479 TI - The Prohormone VGF Regulates beta Cell Function via Insulin Secretory Granule Biogenesis. AB - The prohormone VGF is expressed in neuroendocrine and endocrine tissues and regulates nutrient and energy status both centrally and peripherally. We and others have shown that VGF-derived peptides have direct action on the islet beta cell as secretagogues and cytoprotective agents; however, the endogenous function of VGF in the beta cell has not been described. Here, we demonstrate that VGF regulates secretory granule formation. VGF loss-of-function studies in both isolated islets and conditional knockout mice reveal a profound decrease in stimulus-coupled insulin secretion. Moreover, VGF is necessary to facilitate efficient exit of granule cargo from the trans-Golgi network and proinsulin processing. It also functions to replenish insulin granule stores following nutrient stimulation. Our data support a model in which VGF operates at a critical node of granule biogenesis in the islet beta cell to coordinate insulin biosynthesis with beta cell secretory capacity. PMID- 28877480 TI - A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA)n Repeats Associated with Friedreich's Ataxia. AB - Expansions of microsatellite repeats are responsible for numerous hereditary diseases in humans, including myotonic dystrophy and Friedreich's ataxia. Whereas the length of an expandable repeat is the main factor determining disease inheritance, recent data point to genomic trans modifiers that can impact the likelihood of expansions and disease progression. Detection of these modifiers may lead to understanding and treating repeat expansion diseases. Here, we describe a method for the rapid, genome-wide identification of trans modifiers for repeat expansion in a yeast experimental system. Using this method, we found that missense mutations in the endoribonuclease subunit (Ysh1) of the mRNA cleavage and polyadenylation complex dramatically increase the rate of (GAA)n repeat expansions but only when they are actively transcribed. These expansions correlate with slower transcription elongation caused by the ysh1 mutation. These results reveal an interplay between RNA processing and repeat-mediated genome instability, confirming the validity of our approach. PMID- 28877481 TI - An Intestine-Derived Neuropeptide Controls Avoidance Behavior in Caenorhabditis elegans. AB - Adjusting to a continuously changing environment is a key feature of life. For metazoans, environmental changes include alterations in the gut microbiota, which can affect both memory and behavior. The bacteriovorous nematode Caenorhabditis elegans discriminates between pathogenic and non-pathogenic food sources, avoiding the consumption of pathogens. Here, we demonstrate the role of the intestine in regulating C. elegans avoidance to Pseudomonas aeruginosa by an insulin-like neuropeptide encoded by ins-11. The transcriptional expression of ins-11 is controlled through transcription factor hlh-30 and the p38 mitogen activated protein kinase (MAPK) pathway. ins-11 negatively controls signal pathways in neurons that regulate aversive learning behavior. Attenuation of ins 11 increased avoidance behavior and survival on pathogenic bacteria but decreased opportunities to find a food source as well as lowered energy storage and the number of viable progeny. Our findings support a role for the intestine in avoidance and identify an advantageous role for negative feedback that allows C. elegans to actively balance noxious and favorable environments. PMID- 28877483 TI - Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. PMID- 28877482 TI - High-Yield Methods for Accurate Two-Alternative Visual Psychophysics in Head Fixed Mice. AB - Research in neuroscience increasingly relies on the mouse, a mammalian species that affords unparalleled genetic tractability and brain atlases. Here, we introduce high-yield methods for probing mouse visual decisions. Mice are head fixed, facilitating repeatable visual stimulation, eye tracking, and brain access. They turn a steering wheel to make two alternative choices, forced or unforced. Learning is rapid thanks to intuitive coupling of stimuli to wheel position. The mouse decisions deliver high-quality psychometric curves for detection and discrimination and conform to the predictions of a simple probabilistic observer model. The task is readily paired with two-photon imaging of cortical activity. Optogenetic inactivation reveals that the task requires mice to use their visual cortex. Mice are motivated to perform the task by fluid reward or optogenetic stimulation of dopamine neurons. This stimulation elicits a larger number of trials and faster learning. These methods provide a platform to accurately probe mouse vision and its neural basis. PMID- 28877484 TI - Effect of a Paramagnetic Spin Label on the Intrinsically Disordered Peptide Ensemble of Amyloid-beta. AB - Paramagnetic relaxation enhancement is an NMR technique that has yielded important insight into the structure of folded proteins, although the perturbation introduced by the large spin probe might be thought to diminish its usefulness when applied to characterizing the structural ensembles of intrinsically disordered proteins (IDPs). We compare the computationally generated structural ensembles of the IDP amyloid-beta42 (Abeta42) to an alternative sequence in which a nitroxide spin label attached to cysteine has been introduced at its N-terminus. Based on this internally consistent computational comparison, we find that the spin label does not perturb the signature population of the beta-hairpin formed by residues 16-21 and 29-36 that is dominant in the Abeta42 reference ensemble. However, the presence of the tag induces a strong population shift in a subset of the original Abeta42 structural sub-populations, including a sevenfold enhancement of the beta-hairpin formed by residues 27-31 and 33-38. Through back-calculation of NMR observables from the computational structural ensembles, we show that the structural differences between the labeled and unlabeled peptide would be evident in local residual dipolar couplings, and possibly differences in homonuclear 1H-1H nuclear Overhauser effects (NOEs) and heteronuclear 1H-15N NOEs if the paramagnetic contribution to the longitudinal relaxation does not suppress the NOE intensities in the real experiment. This work shows that molecular simulation provides a complementary approach to resolving the potential structural perturbations introduced by reporter tags that can aid in the interpretation of paramagnetic relaxation enhancement, double electron-electron resonance, and fluorescence resonance energy transfer experiments applied to IDPs. PMID- 28877485 TI - Conformational Heterogeneity and FRET Data Interpretation for Dimensions of Unfolded Proteins. AB - A mathematico-physically valid formulation is required to infer properties of disordered protein conformations from single-molecule Forster resonance energy transfer (smFRET). Conformational dimensions inferred by conventional approaches that presume a homogeneous conformational ensemble can be unphysical. When all possible-heterogeneous as well as homogeneous-conformational distributions are taken into account without prejudgment, a single value of average transfer efficiency between dyes at two chain ends is generally consistent with highly diverse, multiple values of the average radius of gyration . Here we utilize unbiased conformational statistics from a coarse-grained explicit-chain model to establish a general logical framework to quantify this fundamental ambiguity in smFRET inference. As an application, we address the long-standing controversy regarding the denaturant dependence of of unfolded proteins, focusing on Protein L as an example. Conventional smFRET inference concluded that of unfolded Protein L is highly sensitive to [GuHCl], but data from SAXS suggested a near-constant irrespective of [GuHCl]. Strikingly, our analysis indicates that although the reported values for Protein L at [GuHCl] = 1 and 7 M are very different at 0.75 and 0.45, respectively, the Bayesian Rg2 distributions consistent with these two values overlap by as much as 75%. Our findings suggest, in general, that the smFRET-SAXS discrepancy regarding unfolded protein dimensions likely arise from highly heterogeneous conformational ensembles at low or zero denaturant, and that additional experimental probes are needed to ascertain the nature of this heterogeneity. PMID- 28877486 TI - Two Cl Ions and a Glu Compete for a Helix Cage in the CLC Proton/Cl- Antiporter. AB - The ubiquitously expressed CLC chloride transporters are involved in a great variety of physiological functions. The CLC protein fold is shared by Cl- channels and 2Cl-:1H+ antiporters. The antiporters pump three charges per cycle across the membrane with two Cl ions moving in the opposite direction of one proton. Multiconformational continuum electrostatics was used to calculate the coupled thermodynamics of the protonation of the extracellular-facing gating Glu (Ex) and Cl- binding to the external (Sx) and central (Sc) sites in CLC-ec1, the Escherichia coli exchanger. Sx, Sc, and Ex are buried within the protein where the intersection of two helix N-termini creates a region with a strong, localized positive potential for anion binding. Our chemical potential titrations describe the thermodynamic linkage for binding the Cl- to each site and protons to Ex. We find that the 2Cl-:1H+ binding stoichiometry is a result of Cl- binding to Sx requiring H+ binding to Ex, whereas Cl- binding to Sc does not lead to proton uptake. When Sx binds a Cl-, the protonated Ex moves upward, out of the positive helix cage. The increasing Ex proton affinity on binding the first Cl- reduces the cost of binding the second Cl- at either Sx or Sc. Despite the repulsion among the anions, the lowest energy states have two anions bound in the helix cage. The state with no Cl- is not favored electrostatically, but relies on Ex blocking Sx and on the central residues Y445 and S107 blocking Sc. PMID- 28877487 TI - Microparticle Assembly Pathways on Lipid Membranes. AB - Understanding interactions between microparticles and lipid membranes is of increasing importance, especially for unraveling the influence of microplastics on our health and environment. Here, we study how a short-ranged adhesive force between microparticles and model lipid membranes causes membrane-mediated particle assembly. Using confocal microscopy, we observe the initial particle attachment to the membrane, then particle wrapping, and in rare cases spontaneous membrane tubulation. In the attached state, we measure that the particle mobility decreases by 26%. If multiple particles adhere to the same vesicle, their initial single-particle state determines their interactions and subsequent assembly pathways: 1) attached particles only aggregate when small adhesive vesicles are present in solution, 2) wrapped particles reversibly attract one another by membrane deformation, and 3) a combination of wrapped and attached particles form membrane-mediated dimers, which further assemble into a variety of complex structures. The experimental observation of distinct assembly pathways, induced only by a short-ranged membrane-particle adhesion, shows that a cytoskeleton or other active components are not required for microparticle aggregation. We suggest that this membrane-mediated microparticle aggregation is a reason behind reported long retention times of polymer microparticles in organisms. PMID- 28877488 TI - Caveolae in Rabbit Ventricular Myocytes: Distribution and Dynamic Diminution after Cell Isolation. AB - Caveolae are signal transduction centers, yet their subcellular distribution and preservation in cardiac myocytes after cell isolation are not well documented. Here, we quantify caveolae located within 100 nm of the outer cell surface membrane in rabbit single-ventricular cardiomyocytes over 8 h post-isolation and relate this to the presence of caveolae in intact tissue. Hearts from New Zealand white rabbits were either chemically fixed by coronary perfusion or enzymatically digested to isolate ventricular myocytes, which were subsequently fixed at 0, 3, and 8 h post-isolation. In live cells, the patch-clamp technique was used to measure whole-cell plasma membrane capacitance, and in fixed cells, caveolae were quantified by transmission electron microscopy. Changes in cell-surface topology were assessed using scanning electron microscopy. In fixed ventricular myocardium, dual-axis electron tomography was used for three-dimensional reconstruction and analysis of caveolae in situ. The presence and distribution of surface-sarcolemmal caveolae in freshly isolated cells matches that of intact myocardium. With time, the number of surface-sarcolemmal caveolae decreases in isolated cardiomyocytes. This is associated with a gradual increase in whole-cell membrane capacitance. Concurrently, there is a significant increase in area, diameter, and circularity of sub-sarcolemmal mitochondria, indicative of swelling. In addition, electron tomography data from intact heart illustrate the regular presence of caveolae not only at the surface sarcolemma, but also on transverse-tubular membranes in ventricular myocardium. Thus, caveolae are dynamic structures, present both at surface-sarcolemmal and transverse-tubular membranes. After cell isolation, the number of surface-sarcolemmal caveolae decreases significantly within a time frame relevant for single-cell research. The concurrent increase in cell capacitance suggests that membrane incorporation of surface-sarcolemmal caveolae underlies this, but internalization and/or micro vesicle loss to the extracellular space may also contribute. Given that much of the research into cardiac caveolae-dependent signaling utilizes isolated cells, and since caveolae-dependent pathways matter for a wide range of other study targets, analysis of isolated cell data should take the time post-isolation into account. PMID- 28877489 TI - Rupture Dynamics and Chromatin Herniation in Deformed Nuclei. AB - During migration of cells in vivo, in both pathological processes such as cancer metastasis or physiological events such as immune cell migration through tissue, the cells must move through narrow interstitial spaces that can be smaller than the nucleus. This can induce deformation of the nucleus which, according to recent experiments, may result in rupture of the nuclear envelope that can lead to cell death, if not prevented or healed within an appropriate time. The nuclear envelope, which can be modeled as a double lipid bilayer attached to a viscoelastic gel (lamina) whose elasticity and viscosity primarily depend on the lamin composition, may utilize mechanically induced, self-healing mechanisms that allow the hole to be closed after the deformation-induced strains are reduced by leakage of the internal fluid. Here, we present a viscoelastic model of the evolution of a hole nucleated by deformations of the nuclear lamina and estimate the herniation of chromatin through the hole and its relation to the lamin expression levels in the nuclear envelope. PMID- 28877490 TI - Adaptive Response of Actin Bundles under Mechanical Stress. AB - Actin is one of the main components of the architecture of cells. Actin filaments form different polymer networks with versatile mechanical properties that depend on their spatial organization and the presence of cross-linkers. Here, we investigate the mechanical properties of actin bundles in the absence of cross linkers. Bundles are polymerized from the surface of mDia1-coated latex beads, and deformed by manipulating both ends through attached beads held by optical tweezers, allowing us to record the applied force. Bundle properties are strikingly different from the ones of a homogeneous isotropic beam. Successive compression and extension leads to a decrease in the buckling force that we attribute to the bundle remaining slightly curved after the first deformation. Furthermore, we find that the bundle is solid, and stiff to bending, along the long axis, whereas it has a liquid and viscous behavior in the transverse direction. Interpretation of the force curves using a Maxwell visco-elastic model allows us to extract the bundle mechanical parameters and confirms that the bundle is composed of weakly coupled filaments. At short times, the bundle behaves as an elastic material, whereas at long times, filaments flow in the longitudinal direction, leading to bundle restructuring. Deviations from the model reveal a complex adaptive rheological behavior of bundles. Indeed, when allowed to anneal between phases of compression and extension, the bundle reinforces. Moreover, we find that the characteristic visco-elastic time is inversely proportional to the compression speed. Actin bundles are therefore not simple force transmitters, but instead, complex mechano-transducers that adjust their mechanics to external stimulation. In cells, where actin bundles are mechanical sensors, this property could contribute to their adaptability. PMID- 28877491 TI - beta1-Integrin-Mediated Adhesion Is Lipid-Bilayer Dependent. AB - Integrin-mediated adhesion is a central feature of cellular adhesion, locomotion, and endothelial cell mechanobiology. Although integrins are known to be transmembrane proteins, little is known about the role of membrane biophysics and dynamics in integrin adhesion. We treated human aortic endothelial cells with exogenous amphiphiles, shown previously in model membranes, and computationally, to affect bilayer thickness and lipid phase separation, and subsequently measured single-integrin-molecule adhesion kinetics using an optical trap, and diffusion using fluorescence correlation spectroscopy. Benzyl alcohol (BA) partitions to liquid-disordered (Ld) domains, thins them, and causes the greatest increase in hydrophobic mismatch between liquid-ordered (Lo) and Ld domains among the three amphiphiles, leading to domain separation. In human aortic endothelial cells, BA increased beta1-integrin-Arg-Gly-Asp-peptide affinity by 18% with a transition from single to double valency, consistent with a doubling of the molecular brightness of mCherry-tagged beta1-integrins measured using fluorescence correlation spectroscopy. Accordingly, BA caused an increase in the size of focal adhesion-kinase/paxillin-positive peripheral adhesions and reduced migration speeds as measured using wound-healing assays. Vitamin E, which thickens Lo domains and disperses them by lowering edge energy on domain boundaries, left integrin affinity unchanged but reduced binding probability, leading to smaller focal adhesions and equivalent migration speed relative to untreated cells. Vitamin E reversed the BA-induced decrease in migration speed. Triton X-100 also thickens Lo domains, but partitions to both lipid phases and left unchanged binding kinetics, focal adhesion sizes, and migration speed. These results demonstrate that only the amphiphile that thinned Ld lipid domains increased beta1-integrin-Arg-Gly-Asp-peptide affinity and valency, thus implicating Ld domains in modulation of integrin adhesion, nascent adhesion formation, and cell migration. PMID- 28877492 TI - Spatially Organized beta-Cell Subpopulations Control Electrical Dynamics across Islets of Langerhans. AB - Understanding how heterogeneous cells within a multicellular system interact and affect overall function is difficult without a means of perturbing individual cells or subpopulations. Here we apply optogenetics to understand how subpopulations of beta-cells control the overall [Ca2+]i response and insulin secretion dynamics of the islets of Langerhans. We spatiotemporally perturbed electrical activity in beta-cells of channelrhodopsin2-expressing islets, mapped the [Ca2+]i response, and correlated this with the cellular metabolic activity and an in silico electrophysiology model. We discovered organized regions of metabolic activity across the islet, and these affect the way in which beta-cells electrically interact. Specific regions acted as pacemakers by initiating calcium wave propagation. Our findings reveal the functional architecture of the islet, and show how distinct subpopulations of cells can disproportionality affect function. These results also suggest ways in which other neuroendocrine systems can be regulated, and demonstrate how optogenetic tools can discern their functional architecture. PMID- 28877493 TI - Spatially Different Tissue-Scale Diffusivity Shapes ANGUSTIFOLIA3 Gradient in Growing Leaves. AB - The spatial gradient of signaling molecules is pivotal for establishing developmental patterns of multicellular organisms. It has long been proposed that these gradients could arise from the pure diffusion process of signaling molecules between cells, but whether this simplest mechanism establishes the formation of the tissue-scale gradient remains unclear. Plasmodesmata are unique channel structures in plants that connect neighboring cells for molecular transport. In this study, we measured cellular- and tissue-scale kinetics of molecular transport through plasmodesmata in Arabidopsis thaliana developing leaf primordia by fluorescence recovery assays. These trans-scale measurements revealed biophysical properties of diffusive molecular transport through plasmodesmata and revealed that the tissue-scale diffusivity, but not the cellular-scale diffusivity, is spatially different along the leaf proximal-to distal axis. We found that the gradient in cell size along the developmental axis underlies this spatially different tissue-scale diffusivity. We then asked how this diffusion-based framework functions in establishing a signaling gradient of endogenous molecules. ANGUSTIFOLIA3 (AN3) is a transcriptional co-activator, and as we have shown here, it forms a long-range signaling gradient along the leaf proximal-to-distal axis to determine a cell-proliferation domain. By genetically engineering AN3 mobility, we assessed each contribution of cell-to-cell movement and tissue growth to the distribution of the AN3 gradient. We constructed a diffusion-based theoretical model using these quantitative data to analyze the AN3 gradient formation and demonstrated that it could be achieved solely by the diffusive molecular transport in a growing tissue. Our results indicate that the spatially different tissue-scale diffusivity is a core mechanism for AN3 gradient formation. This provides evidence that the pure diffusion process establishes the formation of the long-range signaling gradient in leaf development. PMID- 28877494 TI - Enhanced Dynamics of Confined Cytoskeletal Filaments Driven by Asymmetric Motors. AB - Cytoskeletal filaments and molecular motors facilitate the micron-scale force generation necessary for the distribution of organelles and the restructuring of the cytoskeleton within eukaryotic cells. Although the mesoscopic structure and the dynamics of such filaments have been studied in vitro and in vivo, their connection with filament polarity-dependent motor-mediated force generation is not well understood. Using 2D Brownian dynamics simulations, we study a dense, confined mixture of rigid microtubules (MTs) and active springs that have arms that cross-link neighboring MT pairs and move unidirectionally on the attached MT. We simulate depletion interactions between MTs using an attractive potential. We show that dimeric motors, with a motile arm on only one of the two MTs, produce large polarity-sorted MT clusters, whereas tetrameric motors, with motile arms on both microtubules, produce bundles. Furthermore, dimeric motors induce, on average, higher velocities between antialigned MTs than tetrameric motors. Our results, where MTs move faster near the confining wall, are consistent with experimental observations in Drosophila oocytes where enhanced microtubule activity is found close to the confining plasma membrane. PMID- 28877495 TI - Wave Mechanics of the Vestibular Semicircular Canals. AB - The semicircular canals are biomechanical sensors responsible for detecting and encoding angular motion of the head in 3D space. Canal afferent neurons provide essential inputs to neural circuits responsible for representation of self position/orientation in space, and to compensatory circuits including the vestibulo-ocular and vestibulo-collic reflex arcs. In this work we derive, to our knowledge, a new 1D mathematical model quantifying canal biomechanics based on the morphology, dynamics of the inner ear fluids, and membranous labyrinth deformability. The model takes the form of a dispersive wave equation and predicts canal responses to angular motion, sound, and mechanical stimulation. Numerical simulations were carried out for the morphology of the human lateral canal using known physical properties of the endolymph and perilymph in three diverse conditions: surgical plugging, rotation, and mechanical indentation. The model reproduces frequency-dependent attenuation and phase shift in cases of canal plugging. During rotation, duct deformability extends the frequency bandwidth and enhances the high frequency gain. Mechanical indentation of the membranous duct at high frequencies evokes traveling waves that move away from the location of indentation and at low frequencies compels endolymph displacement along the canal. These results demonstrate the importance of the conformal perilymph-filled bony labyrinth to pressure changes and to high frequency sound and vibration. PMID- 28877496 TI - Acceleration Strategies to Enhance Metabolic Ensemble Modeling Performance. AB - Developing reliable, predictive kinetic models of metabolism is a difficult, yet necessary, priority toward understanding and deliberately altering cellular behavior. Constraint-based modeling has enabled the fields of metabolic engineering and systems biology to make great strides in interrogating cellular metabolism but does not provide sufficient insight into regulation or kinetic limitations of metabolic pathways. Moreover, the growth-optimized assumptions that constraint-based models often rely on do not hold when studying stationary or persistor cell populations. However, developing kinetic models provides many unique challenges, as many of the kinetic parameters and rate laws governing individual enzymes are unknown. Ensemble modeling (EM) was developed to circumnavigate this challenge and effectively sample the large kinetic parameter solution space using consistent experimental datasets. Unfortunately, EM, in its base form, requires long solve times to complete and often leads to unstable kinetic model predictions. Furthermore, these limitations scale prohibitively with increasing model size. As larger metabolic models are developed with increasing genetic information and experimental validation, the demand to incorporate kinetic information increases. Therefore, in this work, we have begun to tackle the challenges of EM by introducing additional steps to the existing method framework specifically through reducing computation time and optimizing parameter sampling. We first reduce the structural complexity of the network by removing dependent species, and second, we sample locally stable parameter sets to reflect realistic biological states of cells. Lastly, we presort the screening data to eliminate the most incorrect predictions in the earliest screening stages, saving further calculations in later stages. Our complementary improvements to this EM framework are easily incorporated into concurrent EM efforts and broaden the application opportunities and accessibility of kinetic modeling across the field. PMID- 28877498 TI - Disentangling Random Motion and Flow in a Complex Medium. PMID- 28877497 TI - Factors Diminishing Cytoadhesion of Red Blood Cells Infected by Plasmodium falciparum in Arterioles. AB - Cytoadhesion of red blood cells infected by Plasmodium falciparum (Pf-IRBCs) is predominantly found in postcapillary venules, rather than in arterioles. However, factors influencing this phenomenon remain unclear. Here, we conduct a systematic study using a numerical model coupling the fluid and solid mechanics of the cells and cellular environment with the biochemical ligand-receptor interaction. Our results show that, once a Pf-IRBC adheres to the vascular wall, the Pf-IRBC can withstand even arteriole shear stresses, and exhibits either rolling or firm adhesion. We also perform a simulation of the multistep process of cytoadhesion, consisting of flow, margination, capture, and rolling or firm adhesion. This multistep simulation suggests that a lower probability of contact with the vascular wall at high shear rates may diminish adherent Pf-IRBCs in the arterioles. PMID- 28877499 TI - H4 Tails Potentially Produce the Diversity in the Orientation of Two Nucleosomes. AB - Histone tails play an important role in internucleosomal interaction and chromatin compaction. To understand how the H4 tails are involved in the internucleosomal interaction, an adaptively biased molecular dynamics simulation of 63 models of two stacked nucleosomes, each with the H4 tails in different locations, was carried out. This simulation generated a variety of orientations of the separated nucleosomes depending on the formation of the H4 tail bridge between the H4 tails and the DNA of the neighboring nucleosomes. For the models that showed distinctive orientations of the two nucleosomes, the free energies of the separation of the nucleosomes were further investigated using umbrella sampling simulations. The attractive force between the nucleosomes was estimated from the free energies; the force when two H4 tail bridges formed varied from 36 to 63 pN, depending on the formation of the H4 tail-bridge and the interfacial interaction, whereas the force reduced to 15-18 pN after either one of the H4 tail bridges had broken, regardless of the conformation of the H4 tail. Additional simulations of the nucleosomes show that when the H4 tail was truncated, the force between the nucleosomes became repulsive (from-3 to -7 pN). We concluded that the H4 tails potentially produce the diversity in the orientation of the two nucleosomes, which would contribute to the polymorphism of the chromatin structure. PMID- 28877501 TI - PDB-Dev: a Prototype System for Depositing Integrative/Hybrid Structural Models. AB - Burley et al. (leadership of the Worldwide PDB [wwPDB] Partnership [wwpdb.org] and the wwPDB Integrative/Hybrid Methods Task Force) announce public release of a prototype system for depositing integrative/hybrid structural models, PDB Development (PDB-Dev; https://pdb-dev.wwpdb.org). PMID- 28877500 TI - sw ApoMb Amyloid Aggregation under Nondenaturing Conditions: The Role of Native Structure Stability. AB - Investigation of the molecular mechanisms underlying amyloid-related human diseases attracts close attention. These diseases, the number of which currently is above 40, are characterized by formation of peptide or protein aggregates containing a cross-beta structure. Most of the amyloidogenesis mechanisms described so far are based on experimental studies of aggregation of short peptides, intrinsically disordered proteins, or proteins under denaturing conditions, and studies of amyloid aggregate formations by structured globular proteins under conditions close to physiological ones are still in the initial stage. We investigated the effect of amino acid substitutions on propensity of the completely helical protein sperm whale apomyoglobin (sw ApoMb) for amyloid formation from its structured state in the absence of denaturing agents. Stability and aggregation of mutated sw ApoMb were studied using circular dichroism, Fourier transform infrared spectroscopy, x-ray diffraction, native electrophoresis, and electron microscopy techniques. Here, we demonstrate that stability of the protein native state determines both protein aggregation propensity and structural peculiarities of formed aggregates. Specifically, structurally stable mutants show low aggregation propensity and moderately destabilized sw ApoMb variants form amyloids, whereas their strongly destabilized mutants form both amyloids and nonamyloid aggregates. PMID- 28877502 TI - How a Glycoside Hydrolase Recognizes a Helical Polyglucan. AB - Similarly to other biopolymers, linear polysaccharides can form double- or triple helical structures. How enzymes recognize and manage this quaternary structure is an unresolved question. In this issue of Structure, Pluvinage et al. (2017) shed light on the structural complementarity between family GH81 glycoside hydrolase and the quaternary structure of their polysaccharide substrates. PMID- 28877503 TI - One Ring, Two Membranes: IM30 Ring Complex and the Thylakoid Membrane Fusion. AB - Direct membrane fusion in chloroplasts and cyanobacteria is triggered by IM30 protein oligomers, but so far the exact mechanism of membrane binding has remained obscure. In this issue of Structure, Saur et al. (2017) describe the detailed structure of Janus-faced IM30 rings crucial for thylakoid membrane fusion and membrane layer architecture. PMID- 28877504 TI - Remodeling KRAS. AB - Mutations in members of the RAS family of small GTPases have been associated with numerous human cancers. However, RAS family members are notoriously difficult to target. In this issue of Structure, Lu et al. (2017) examine the effects of two compounds with distinct chemical scaffolds on the structure and dynamics of an oncogenic KRAS mutant, thus highlighting the usefulness of HDX-MS for drug development. PMID- 28877505 TI - Mapping the ER Interactome: The P Domains of Calnexin and Calreticulin as Plurivalent Adapters for Foldases and Chaperones. AB - The lectin chaperones calreticulin (CRT) and calnexin (CNX) contribute to the folding of glycoproteins in the ER by recruiting foldases such as the protein disulfide isomerase ERp57 and the peptidyl prolyl cis-trans isomerase CypB. Recently, CRT was shown to interact with the chaperone ERp29. Here, we show that ERp29 directly binds to the P domain of CNX. Crystal structures of the D domain of ERp29 in complex with the P domains from CRT and calmegin, a tissue-specific CNX homolog, reveal a commonality in the mechanism of binding whereby the tip of the P domain functions as a plurivalent adapter to bind a variety of folding factors. We show that mutation of a single residue, D348 in CNX, abrogates binding to ERp29 as well as ERp57 and CypB. The structural diversity of the accessory factors suggests that these chaperones became specialized for glycoprotein folding through convergent evolution of their P-domain binding sites. PMID- 28877506 TI - Cryoelectron Microscopy Reconstructions of the Pseudomonas aeruginosa and Neisseria gonorrhoeae Type IV Pili at Sub-nanometer Resolution. AB - We report here cryoelectron microscopy reconstructions of type IV pili (T4P) from two important human pathogens, Pseudomonas aeruginosa and Neisseria gonorrhoeae, at ~ 8 and 5 A resolution, respectively. The two structures reveal distinct arrangements of the pilin globular domains on the pilus surfaces, which impart different helical parameters, but similar packing of the conserved N-terminal alpha helices, alpha1, in the filament core. In contrast to the continuous alpha helix seen in the X-ray crystal structures of the P. aeruginosa and N. gonorrhoeae pilin subunits, alpha1 in the pilus filaments has a melted segment located between conserved helix-breaking residues Gly14 and Pro22, as seen for the Neisseria meningitidis T4P. Using mutagenesis we show that Pro22 is critical for pilus assembly, as are Thr2 and Glu5, which are positioned to interact in the hydrophobic filament core. These structures provide a framework for understanding T4P assembly, function, and biophysical properties. PMID- 28877507 TI - Crystal Structure of a Plant Multidrug and Toxic Compound Extrusion Family Protein. AB - The multidrug and toxic compound extrusion (MATE) family of proteins consists of transporters responsible for multidrug resistance in prokaryotes. In plants, a number of MATE proteins were identified by recent genomic and functional studies, which imply that the proteins have substrate-specific transport functions instead of multidrug extrusion. The three-dimensional structure of eukaryotic MATE proteins, including those of plants, has not been reported, preventing a better understanding of the molecular mechanism of these proteins. Here, we describe the crystal structure of a MATE protein from the plant Camelina sativa at 2.9 A resolution. Two sets of six transmembrane alpha helices, assembled pseudo symmetrically, possess a negatively charged internal pocket with an outward facing shape. The crystal structure provides insight into the diversity of plant MATE proteins and their substrate recognition and transport through the membrane. PMID- 28877508 TI - The NO-heme signaling hypothesis. AB - While the biological role of nitric oxide (NO) synthase (NOS) is appreciated, several fundamental aspects of the NOS/NO-related signaling pathway(s) remain incompletely understood. Canonically, the NOS-derived NO diffuses through the (inter)cellular milieu to bind the prosthetic ferro(Fe2+)-heme group of the soluble guanylyl cyclase (sGC). The formation of ternary NO-ferroheme-sGC complex results in the enzyme activation and accelerated production of the second messenger, cyclic GMP. This paper argues that cells dynamically generate mobile/exchangeable NO-ferroheme species, which activate sGC and regulate the function of some other biomolecules. In contrast to free NO, the mobile NO ferroheme may ensure safe, efficient and coordinated delivery of the signal within and between cells. The NO-heme signaling may contribute to a number of NOS/NO-related phenomena (e.g. nitrite bioactivity, selective protein S-(N )nitrosation, endothelium and erythrocyte-dependent vasodilation, some neural and immune NOS functions) and predicts new NO-related discoveries, diagnostics and therapeutics. PMID- 28877509 TI - Botulinum toxin for chronic migraine: Clinical trials and technical aspects. AB - OnabotulinumtoxinA has been approved for the prophylaxis of chronic migraine following the demonstration of efficacy in two large controlled trials. Data collected from pragmatic studies in the real-life setting have contributed important additional information useful for the management of this group of extremely disabled and challenging patients. The main findings from these studies are presented and discussed. PMID- 28877510 TI - Heart Rate Variability modifications induced by high doses of incobotulinumtoxinA and onabotulinumtoxinA in hemiplegic chronic stroke patients: A single blind randomized controlled, crossover pilot study. AB - BACKGROUND: Botulinum toxin type A is a valid and safe treatment for focal spasticity, with documented effects on both sympathetic and parasympathetic systems. Heart rate variability can provide detailed information about the control of the autonomic nervous system on cardiovascular activities. Previous studies in literature showed no significant changes in Heart Rate Variability with doses >600 U of incobotulinumtoxinA in chronic post stroke spastic patients; however, at present time, these results have not been confirmed with doses >600 U of onabotulinumtoxinA. AIM: To evaluate changes in Heart Rate Variability induced by high doses (>600 U) of incobotulinumtoxinA or onabotulinumtoxinA in spastic stroke patients over a 1-year period. DESIGN: single blind randomized controlled crossover study design. SETTING: Rehabilitation Unit of the University Hospital in Novara. POPULATION: 10 stroke survivors with spastic hemiplegia (Modified Ashworth Scale >= 2) were recruited and randomly divided in two groups (A and B). METHODS: In the first part of the study, patients in Group A were injected with incobotulinumtoxinA while patients in Group B with onabotulinumtoxinA; after 6 months, a crossover intervention was performed. All patients were blinded to Botulinum toxin type A type, and performed an ECG registration in the 24 h before injection (t0) and 10 days after treatment (t1), both in the first and in the second part of the study. Functional status was evaluated with Barthel Index, Motricity Index and Functional Ambulation Category scores. RESULTS: Heart Rate Variability analysis showed no significant changes after each Botulinum toxin type A injection in both groups at any evaluation time. Moreover, no statistically significant differences were found regarding each variable between the two groups. CONCLUSIONS: Our data show that high doses (>600 U) of incobotulinumtoxinA and onabotulinumtoxinA do not influence the cardiovascular activity of the autonomic nervous system in chronic hemiplegic spastic stroke survivors. PMID- 28877511 TI - Severe neurotoxicity requiring mechanical ventilation in a dog envenomed by a red bellied black snake (Pseudechis porphyriacus) and successful treatment with an experimental bivalent whole equine IgG antivenom. AB - Snakebite in dogs from Pseudechis porphyriacus (red-bellied black snake; RBBS) is a common envenomation treated by veterinarians in Australia where this snake occurs. This case report describes the successful treatment of a clinically severe RBBS envenomation in a dog with an experimental bivalent equine whole IgG antivenom and mechanical ventilation, following its presentation in a cyanotic state. The cause of the cyanosis and respiratory distress was considered due to paralysis from neurotoxins in RBBS venom. The dog was treated with two vials of bivalent antivenom, each containing sufficient antivenom to neutralise the lethal effects of 40 mg of tiger snake (Notechis sp) and 40 mg of brown snake (Pseudonaja sp) venom. Hypoxaemia (Sp02 of 75%) and hypercapnia (PaCO2 of 61 mmHg) indicated the need for mechanical ventilation (MV) to prevent imminent death. The dog was anaesthetised using total intravenous anaesthesia and MV used for 18 h. Following discontinuation of MV, it resumed spontaneous breathing thereafter and made a complete recovery. Serum biochemistry revealed a significant myopathy with elevated CK and AST levels, peaking approximately 48 h post-treatment. Elevated liver enzymes, suggestive of hypoxic liver injury, were detected during the period of hospitalisation. The dog represented approximately one week after hospital discharge because of inappetence and mild hepatopathy, which resolved spontaneously by 30 d post-treatment. A mild coagulopathy was initially present which resolved within 24 h following antivenom treatment. At initial presentation, RBBS venom antigen was detected by sandwich ELISA in urine and serum. Free RBBS venom antigen was not detected post-antivenom treatment. Human cases of RBBS requiring ventilatory support are rare. This unusual case of RBBS envenomation in a dog highlights its potential clinical severity in dogs, and the need for early, aggressive, MV to achieve a successful outcome in cyanosed and clinically severe cases. PMID- 28877512 TI - Sex-dependent neural effect of oxytocin during subliminal processing of negative emotion faces. AB - In line with animal models indicating sexually dimorphic effects of oxytocin (OXT) on social-emotional processing, a growing number of OXT-administration studies in humans have also reported sex-dependent effects during social information processing. To explore whether sex-dependent effects already occur during early, subliminal, processing stages the present pharmacological fMRI study combined the intranasal-application of either OXT or placebo (n = 86-43 males) with a backward-masking emotional face paradigm. Results showed that while OXT suppressed inferior frontal gyrus, dorsal anterior cingulate and anterior insula responses to threatening face stimuli in men it increased them in women. In women increased anterior cingulate reactivity during subliminal threat processing was also positively associated with trait anxiety. On the network level, sex-dependent effects were observed on amygdala, anterior cingulate and inferior frontal gyrus functional connectivity that were mainly driven by reduced coupling in women following OXT. Our findings demonstrate that OXT produces sex dependent effects even at the early stages of social-emotional processing, and suggest that while it attenuates neural responses to threatening social stimuli in men it increases them in women. Thus in a therapeutic context OXT may potentially produce different effects on anxiety disorders in men and women. PMID- 28877513 TI - Predicting functional neuroanatomical maps from fusing brain networks with genetic information. AB - Functional neuroanatomical maps provide a mesoscale reference framework for studies from molecular to systems neuroscience and psychiatry. The underlying structure-function relationships are typically derived from functional manipulations or imaging approaches. Although highly informative, these are experimentally costly. The increasing amount of publicly available brain and genetic data offers a rich source that could be mined to address this problem computationally. Here, we developed an algorithm that fuses gene expression and connectivity data with functional genetic meta data and exploits cumulative effects to derive neuroanatomical maps related to multi-genic functions. We validated the approach by using public available mouse and human data. The generated neuroanatomical maps recapture known functional anatomical annotations from literature and functional MRI data. When applied to multi-genic meta data from mouse quantitative trait loci (QTL) studies and human neuropsychiatric databases, this method predicted known functional maps underlying behavioral or psychiatric traits. Taken together, genetically weighted connectivity analysis (GWCA) allows for high throughput functional exploration of brain anatomy in silico. It maps functional genetic associations onto brain circuitry for refining functional neuroanatomy, or identifying trait-associated brain circuitry, from genetic data. PMID- 28877514 TI - Fast Gaussian Naive Bayes for searchlight classification analysis. AB - The searchlight technique is a variant of multivariate pattern analysis (MVPA) that examines neural activity across large sets of small regions, exhaustively covering the whole brain. This usually involves application of classifier algorithms across all searchlights, which entails large computational costs especially when testing the statistical significance of the accuracies with permutation methods. In this article, a new implementation of the Gaussian Naive Bayes classifier is presented (henceforth massive-GNB). This approach allows classification in all searchlights simultaneously, and is faster than previously published searchlight GNB implementations, as well as other more complex classifiers including support vector machines (SVM). To ensure that the gain in speed for GNB would be useful in searchlight analysis, we compared the accuracies of massive-GNB and SVM in detecting the lateral occipital complex (LOC) in an fMRI localizer experiment (26 subjects). Moreover, this region as defined in a meta-analysis of many activation studies was used as a gold standard to compare error rates for both classifiers. In individual searchlights, SVM was somewhat more accurate than massive-GNB and more selective in detecting the meta-analytic LOC. However, with multiple comparison correction at the cluster-level the two classifiers performed equivalently. Thus for cluster-level analysis, massive-GNB produces an accuracy similar to more sophisticated classifiers but with a substantial gain in speed. Massive-GNB (available as a public Matlab toolbox) could facilitate the more widespread use of searchlight analysis. PMID- 28877516 TI - BAX and BCL2 Gene Polymorphisms in Rhegmatogenous Retinal Detachment. AB - PURPOSE: The purpose of this study was to investigate the potential association between rhegmatogenous retinal detachment (RRD) and BAX and BCL2 polymorphisms. METHODS: This is a case control study of 99 patients with RRD and 120 healthy control subjects of Greek origin, surveyed for BAX and BCL2 polymorphisms (rs2279115 and rs4645878) and a potential correlation to RRD. RESULTS: The rs4645878 AA genotype was found to be significantly associated with RRD (p = 0.003; OR: 6.89, 95% CI: 1.76-26.93), while the rs2279115 CC genotype as well as the C allele was not found in patients with RRD. CONCLUSIONS: This is the first study evaluating the potential relationship between BCL2 and BAX gene polymorphisms and RRD in a Greek population, showing a significant association between BAX rs4645878 polymorphism and RRD susceptibility. This finding suggests that an apoptotic mechanism is implicated in the pathogenesis of RRD. PMID- 28877515 TI - Neural congruence between intertemporal and interpersonal self-control: Evidence from delay and social discounting. AB - Behavioral studies using delay and social discounting as indices of self-control and altruism, respectively, have revealed functional similarities between farsighted and social decisions. However, neural evidence for this functional link is lacking. Twenty-five young adults completed a delay and social discounting task during fMRI scanning. A spatiotemporal partial least squares analysis revealed that both forms of discounting were well characterized by a pattern of brain activity in areas comprising frontoparietal control, default, and mesolimbic reward networks. Both forms of discounting appear to draw on common neurocognitive mechanisms, regardless of whether choices involve intertemporal or interpersonal outcomes. We also observed neural profiles differentiating between high and low discounters. High discounters were well characterized by increased medial temporal lobe and limbic activity. In contrast, low discount rates were associated with activity in the medial prefrontal cortex and right temporoparietal junction. This pattern may reflect biological mechanisms underlying behavioral heterogeneity in discount rates. PMID- 28877517 TI - The Histopathological Characteristics Caused by Trionyx sinensis Hemorrhagic Syndrome Virus (TSHSV) and Comparative Proteomic Analysis of Liver Tissue in TSHSV-Infected Chinese Soft-Shelled Turtles (Pelodiscus sinensis). AB - Trionyx sinensis hemorrhagic syndrome virus (TSHSV) is a pathogen that causes severe hemorrhagic syndrome and irreversible damage to different infected tissues of Pelodis cus sinensis, ending in the death of affected organisms. In the present study, the histopathological characteristics of TSHSV-infected P. sinensis were analyzed and compared by HE staining. Relative and absolute quantification (iTRAQ)-based proteomic analysis was employed to explore the molecular pathology of liver injury. Anatomical features indicated that TSHSV caused obvious congestion in the liver, kidney, intestine, and other tissues of P. sinensis. The typical clinical symptoms included hepatomegaly, fragility, spotty and severe congestion in liver tissue, and also obvious intestinal bleeding. The histopathological studies corroborated such lesions in the liver and kidney, etc. iTRAQ-based proteomic analysis revealed that there were 252 differentially expressed proteins in the liver tissue between healthy and infected P. sinensis, of which 118 proteins were upregulated and 134 proteins were downregulated. GO enrichment analysis and KEGG pathway analysis initially revealed the molecular mechanism of pathological changes in P. sinensis by TSHSV infection. The expression of some differentially expressed proteins was further confirmed by qRT-PCR. These results provided important information for the pathological diagnosis of TSHSV-caused disease, as well as the mechanism underlying TSHSV-caused disease. PMID- 28877518 TI - Naltrexone in the Treatment of Broadly Defined Behavioral Addictions: A Review and Meta-Analysis of Randomized Controlled Trials. AB - INTRODUCTION: Broadly defined behavioral addiction is a conceptual framework including behaviors characterized by loss of control and continuation despite significant negative consequences. Broadly defined behavioral addictions share many similarities with substance use disorders. As naltrexone is one of the most studied treatment for substance use disorders, we conducted a meta-analysis of randomized placebo-controlled trials (RCT) assessing the effectiveness of naltrexone in the treatment of broadly defined behavioral addictions. METHOD: We conducted a literature search and selection, up to January 1, 2017, according to previously set inclusion criteria. The selected trials underwent a quality assessment before data extraction and statistical analysis, which used fixed and random effects models. Standardized mean differences (SMD) were calculated using Hedge's adjusted g. RESULTS: A total of 6 RCTs (n = 356) were included. Of these, 3 assessed naltrexone effectiveness in the treatment of pathological gambling, and 3 tested its benefits in broadly defined behavioral addictions other than pathological gambling (kleptomania, trichotillomania, and impulsive compulsive disorders). The meta-analysis of the whole sample resulted in a statistically significant score improvement under naltrexone versus placebo (fixed effect model: SMD = -0.27, 95% CI [-0.51 to -0.03], z = 2.23; p = 0.025). CONCLUSION: The results of our meta-analysis suggest a beneficial effect of naltrexone in the treatment of broadly defined behavioral addictions. PMID- 28877519 TI - Applying a Successful New Protocol for Storing a Tissue Plasminogen Activator for Locking Dysfunctional Permcath: A Single-Center Study. PMID- 28877520 TI - Protective Effect of Ginger (Zingiber officinale Roscoe) Extract against Oxidative Stress and Mitochondrial Apoptosis Induced by Interleukin-1beta in Cultured Chondrocytes. AB - AIMS: The protective effects of ginger (Zingiber officinale Roscoe) extract on IL 1beta-mediated oxidative stress and mitochondrial apoptosis were investigated in C28I2 human chondrocytes. METHODS: The effects of various concentrations of ginger extract on C28I2 human chondrocyte viability were evaluated in order to obtain noncytotoxic concentrations of the drug by methylthiotetrazole assay. The cells were pretreated with 5 and 25 MUg/mL ginger extract for 24 h, followed by incubation with IL-1beta (10 ng/mL) for 24 h. The effects of ginger extract on IL 1beta-induced intracellular reactive oxygen species (ROS) production and lipid peroxidation were examined. The mRNA expressions of antioxidant enzymes including catalase, superoxide dismutase-1, glutathione peroxidase-1, glutathione peroxidase-3, and glutathione peroxidase-4 were evaluated by reverse transcription polymerase chain reaction. The protein expressions of Bax, Bcl-2, and caspase-3 were analyzed by Western blotting. RESULTS: No cytotoxicity was observed at any concentration of ginger extract in C28I2 cells. Ginger extract pretreatment remarkably increased the gene expression of antioxidant enzymes and reduced the IL-1beta-induced elevation of ROS, lipid peroxidation, the Bax/Bcl-2 ratio, and caspase-3 activity. CONCLUSIONS: Ginger extract could considerably reduce IL-1beta-induced oxidative stress and consequent mitochondrial apoptosis as the major mechanisms of chondrocyte cell death. These beneficial effects of ginger extract may be due to its antioxidant properties. It may be considered as a natural herbal product to prevent OA-induced cartilage destruction in the clinical setting. PMID- 28877521 TI - Case Report: Pulmonary Tumor Thrombotic Microangiopathy in a Cervical Cancer Patient. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a rapidly progressive and often fatal pulmonary disease induced by tumor emboli within the small pulmonary arteries. PTTM presents clinically as progressive hypoxia and pulmonary hypertension. Most cases of PTTM are caused by an adenocarcinoma of the stomach. We present the first case report of PTTM caused by cervical squamous cell carcinoma. An 82-year-old woman presented with vaginal bleeding and exertional dyspnea. A cervical mass biopsy showed squamous cell carcinoma. Computed tomography revealed ground glass opacity of the bilateral peripheral lung fields. Hypoxia and pulmonary hypertension gradually worsened after admission. Treatment for acute heart failure was started, but was ineffective. She died of respiratory failure 31 days after admission. She was diagnosed at autopsy as having PTTM induced by cervical squamous cell carcinoma. PTTM needs to be considered in any patient with advanced cancer and lung-related issues to rule out metastatic disease, even in the absence of imaging findings. PMID- 28877523 TI - 11th Congress of the International Society of Nutrigenetics/Nutrigenomics (ISNN) : Abstracts. PMID- 28877522 TI - Ganglion Cell-Inner Plexiform Layer Thickness in Different Glaucoma Stages Measured by Optical Coherence Tomography. AB - AIM: To compare ganglion cell (GCL) and inner plexiform layer (IPL) thickness in patients at different stages of primary open-angle glaucoma (POAG), determine their sensitivity and specificity values, and correlate thickness values with mean deviations (MD). METHODS: This prospective, cross- sectional study was conducted in a group of patients with confirmed POAG who were compared to an age- and gender-matched control group. Glaucomatous damage was classified according to the Hodapp-Parrish-Anderson scale: glaucoma stage 1 (early), glaucoma stage 2 (moderate), and glaucoma stage 3 (severe). The average, minimum, and all 6 sectoral (superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal) GCL + IPL thicknesses were measured and compared between groups. RESULTS: The average GCL + IPL thickness of 154 eyes of 93 patients in glaucoma stages 1, 2, 3, and 94 eyes of 47 persons in the control group were 76.79 +/- 8.05, 65.90 +/- 7.92, 57.38 +/- 10.00, and 86.01 +/- 3.68 MUm, respectively. There were statistically significant differences in the average, minimum, and all 6 sectoral GCL + IPL values among the groups. The areas under the receiver operating characteristic curve for average and minimum GCL + IPL thickness values were 0.93 and 0.94, respectively, sensitivity 91.5 and 88.3%, and specificity 98.9 and 100%, respectively. Both thickness values showed significant correlations with MD. Each micrometer decrease in the average GCL + IPL thickness was associated with a 0.54-dB loss in MD. CONCLUSION: GCL + IPL layer thickness is a highly specific and sensitive parameter in differentiating glaucomatous from healthy eyes showing progressive damage as glaucoma worsens. Loss of this layer is highly correlated with overall loss of visual field sensitivity. PMID- 28877524 TI - Selection Paradigms for Large Vessel Occlusion Acute Ischemic Stroke Endovascular Therapy. AB - BACKGROUND: Optimal patient selection methods for thrombectomy in large vessel occlusion stroke (LVOS) are yet to be established. We sought to evaluate the ability of different selection paradigms to predict favorable outcomes. METHODS: Review of a prospectively collected database of endovascular patients with anterior circulation LVOS, adequate CT perfusion (CTP), National Institutes of Health Stroke Scale (NIHSS) >=10 from September 2010 to March 2016. Patients were retrospectively assessed for thrombectomy eligibility by 4 mismatch criteria: Perfusion-Imaging Mismatch (PIM): between CTP-derived perfusion defect and ischemic core volumes; Clinical-Core Mismatch (CCM): between age-adjusted NIHSS and CTP core; Clinical-ASPECTS Mismatch (CAM-1): between age-adjusted NIHSS and ASPECTS; Clinical-ASPECTS Mismatch (CAM-2): between NIHSS and ASPECTS. Outcome measures were inclusion rates for each paradigm and their ability to predict good outcomes (90-day modified Rankin Scale 0-2). RESULTS: Three hundred eighty-four patients qualified. CAM-2 and CCM had higher inclusion (89.3 and 82.3%) vs. CAM-1 (67.7%) and PIM (63.3%). Proportions of selected patients were statistically different except for PIM and CAM-1 (p = 0.19), with PIM having the highest disagreement. There were no differences in good outcome rates between PIM(+)/PIM( ) (52.2 vs. 48.5%; p = 0.51) and CAM-2(+)/CAM-2(-) (52.4 vs. 38.5%; p = 0.12). CCM(+) and CAM-1(+) had higher rates compared to nonselected counterparts (53.4 vs. 38.7%, p = 0.03; 56.6 vs. 38.6%; p = 0.002). The abilities of PIM, CCM, CAM 1, and CAM-2 to predict outcomes were similar according to the c-statistic, Akaike and Bayesian information criterion. CONCLUSIONS: For patients with NIHSS >=10, PIM appears to disqualify more patients without improving outcomes. CCM may improve selection, combining a high inclusion rate with optimal outcome discrimination across (+) and (-) patients. Future studies are warranted. PMID- 28877525 TI - Development of a Thai Parkinson's Disease Screening Tool and the Prevalence of Parkinsonism and Parkinson's Disease, Based on a Community Survey in Bangkok. AB - INTRODUCTION: Few epidemiological data of parkinsonism and Parkinson's disease (PD) exist in Southeast Asia. We aimed to develop and validate a screening tool, and investigate the prevalence of parkinsonism and PD via a community survey. METHODS: A PD-screening tool comprising 11 "yes/no" items was developed in a clinical setting and validated in the community. The prevalence of PD and parkinsonism was investigated in a survey that included PD screening tools, face to-face interviews, and physical examinations. Receiver operating characteristic curves were constructed for a range of cutoff points to explore the screening tool's sensitivity and specificity. RESULTS: Of 1,846 participants surveyed, the mean age was 64.4 +/- 8.0 years. The age-standardized prevalence of parkinsonism was 1,954 per 100,000 people, and that of PD was 706. Of 36 parkinsonism cases, 13 were PD, 13 were vascular parkinsonism, 8 were drug-induced parkinsonism, and 2 were head-injury related. Three cases were previously diagnosed with PD. A cutoff score of 5 on the screening tool showed a sensitivity of 98%, a specificity of 94%, and positive and negative likelihood ratios of 16.33 and 0.02, respectively. The area under the curve was 0.985. CONCLUSIONS: The prevalence of parkinsonism and PD in Thailand is similar to that in Western countries but slightly higher than that for other Asian countries. Differing methodologies, diagnostic criteria, and case identification strategies may contribute to variations in the reported prevalence of PD. Widespread use of the Thai PD-screening tool should be implemented to facilitate early detection of new cases and, in turn, better healthcare. PMID- 28877526 TI - [Einstellung von Arzten gegenuber Komplementarmedizin in einer landlichen Region der Schweiz: Ergebnisse einer Umfrage]. AB - Fragestellung: Im Zusammenhang mit der Einfuhrung ambulanter KM-Sprechstunden am Regionalspital Burgdorf wurde die arztliche Einstellung zu Komplementarmedizin (KM) untersucht. Weiterhin wurden der Anteil der Arzte mit KM-Angeboten im Versorgungsgebiet des Regionalspitals, deren KM-Erfahrungen sowie der Einfluss dieser Erfahrungen auf die Einstellung gegenuber KM untersucht. Material und Methoden: Alle Arzte jeglicher Fachrichtung (n = 170) im Versorgungsgebiet wurden 2011 und 2012 schriftlich zu ihrer Einstellung gegenuber KM (Befurwortung/Ablehnung und Ambivalenz), ihrem KM-Angebot und ihren KM Erfahrungen befragt (Rucklaufquote 45% bzw. 36%). Ergebnisse: Die Einstellung gegenuber KM war im Durchschnitt neutral (M = 2,47, Standardabweichung (SD) = 0,61; Befurwortung von KM von 1 = "stimme vollig zu" bis 4 = "stimme uberhaupt nicht zu") und klar (M = 1,59, SD = 0,46; Einstellungsambivalenz von 1 = "habe klare Meinung" bis 4 = "bin mir sehr unsicher in meiner Meinung"). Die hochste Zustimmung erhielten die Forderungen nach wissenschaftlicher Untersuchung der KM (M = 2,10, SD = 0,95) und nach zertifizierter arztlicher KM in der Grundversicherung (M = 2,53, SD = 1,15). Knapp ein Drittel der Arzte bot KM an, und 77% bzw. 69% uberwiesen Patienten zu KM-Behandlungen. Die wichtigsten Pradiktoren der KM-Befurwortung waren eine zertifizierte KM-Ausbildung und unerwartete positive bzw. negative Verlaufe unter einer KM-Behandlung (R22011 = 0,44, p < 0,001). 25% der Arzte hatten Erfahrungen mit der neuen KM-Sprechstunde, die uberwiegend positiv waren. Schlussfolgerung: Die teilnehmenden Arzte aus einer landlichen Region der Schweiz zeigten im Durchschnitt eine neutrale und klare Einstellung zur KM, die sich im eigenen KM-Angebot bzw. in der Uberweisungspraxis spiegelte. PMID- 28877527 TI - Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway. AB - Recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (PRRs) is the first step in the initiation of a host innate immune response. As a PRR, RIG-I detects either viral RNA or replication transcripts. Avoiding RIG-I recognition is a strategy employed by viruses for immune evasion. Epstein-Barr virus (EBV) infects the majority of the human population worldwide. During the latent infection period there are only a few EBV proteins expressed, whereas EBV-encoded microRNAs, such as BART microRNAs, are highly expressed. BART microRNAs regulate both EBV and the host's gene expression, modulating virus proliferation and the immune response. Here, through gene expression profiling, we found that EBV miR-BART6-3ps inhibited genes of RIG I-like receptor signaling and the type I interferon (IFN) response. We demonstrated that miR-BART6-3p rather than other BARTs specifically suppressed RIG-I-like receptor signaling-mediated IFN-beta production. RNA-seq was used to analyze the global transcriptome change upon EBV infection and miR-BART6-3p mimics transfection, which revealed that EBV infection-triggered immune response signaling can be repressed by miR-BART6-3p overexpression. Furthermore, miR-BART6 3p inhibited the EBV-triggered IFN-beta response and facilitated EBV infection through targeting the 3'UTR of RIG-I mRNA. These findings provide new insights into the mechanism underlying the strategies employed by EBV to evade immune surveillance. PMID- 28877528 TI - X-Linked Hypohidrotic Ectodermal Dysplasia: New Features and a Novel EDA Gene Mutation. AB - We described a 5-year-old male with hypodontia, hypohidrosis, and facial dysmorphisms characterized by a depressed nasal bridge, maxillary hypoplasia, and protuberant lips. Chromosomal analysis revealed a normal 46,XY male karyotype. Due to the presence of clinical features of hypohidrotic ectodermal dysplasia (HED), the EDA gene, located at Xq12q13.1, of the patient and his family was sequenced. Analysis of the proband's sequence revealed a missense mutation (T to A transversion) in hemizygosity state at nucleotide position 158 in exon 1 of the EDA gene, which changes codon 53 from leucine to histidine, while heterozygosity at this position was detected in the slightly affected mother; moreover, this mutation was not found in the publically available Human Gene Mutation Database. To date, our findings indicate that a novel mutation in EDA is associated with X linked HED, adding it to the repertoire of EDA mutations. PMID- 28877529 TI - Retinal Nerve Fiber Layer Thickness Changes in the Pseudoexfoliation Syndrome: A Meta-Analysis of Case-Control Studies. AB - PURPOSE: To evaluate and compare changes in retinal nerve fiber layer (RNFL) thickness in patients with the pseudoexfoliation syndrome (PXS) and healthy controls. METHODS: Case-control studies were selected through an electronic search of the Cochrane Controlled Trials Register, PubMed, and Embase. Results were reviewed to ensure that the included studies met prespecified inclusion/exclusion criteria, and the quality of each study was assessed using the Newcastle-Ottawa Scale. All included studies measured average and 4-quadrant (temporal, superior, nasal, and inferior) RNFL thickness using optical coherence tomography (OCT). For the continuous outcomes, we calculated the weighted mean difference (WMD) and 95% confidence intervals (CIs). RESULTS: Eight case-control studies were included in this meta-analysis involving 225 eyes of PXS patients and 208 eyes of healthy controls in total. Statistical analysis revealed that the average RNFL thickness in PXS patients was significantly reduced compared to healthy controls (WMD = -6.91, 95% CI: -9.99 to -3.82, p < 0.0001). Additionally, differences in RNFL thickness in the superior quadrant (WMD = -10.68, 95% CI: 16.40 to -4.95, p = 0.0003), inferior quadrant (WMD = -8.20, 95% CI: -10.85 to 5.55, p < 0.00001), nasal quadrant (WMD = -3.05, 95% CI: -5.21 to -0.90, p = 0.005), and temporal quadrant (WMD = -6.39, 95% CI: -9.98 to -2.80, p = 0.0005) were all significant between the two groups. CONCLUSIONS: These results suggest that it is important to evaluate RNFL thickness and the optic nerve head through OCT in patients with PXS in order to determine early glaucomatous damage and start timely intervention prior to visual field loss. PMID- 28877530 TI - Black and Blue. PMID- 28877531 TI - Towards Individualized Tracheobronchial Stents: Technical, Practical and Legal Considerations. AB - Stent placement has been established as a standard procedure for treating airway obstructions. Other indications are localized malacias and fistulas. Though many different stents with various diameters and lengths are available, the shapes are hardly ever ideal because of the distorted anatomy in patients with diseased airways. There are technical and legal limitations for customizing purchased airway stents. Individually tailored stents would be preferable. New techniques of additive manufacturing such as 3D printing make it possible to produce optimized stents for a particular patient. Using CT data and bronchoscopic images, stents can be constructed that match a particular anatomical situation and apply the optimized expansion force. We give an overview of the currently available manufacturing techniques for polymeric stents and report about our own experience. Direct on-site printing of polyurethane stents in a hospital and printing individual extrusion molds for silicone stents in a certified cleanroom are both feasible. Furthermore, there are promising attempts of combining mechanically customized stents with surface modifications, drug-eluting features, biodegradability, and time-dependent adaptation (4D printing). Truly optimized airway stents with the potential of solving the well-known stent problems such as granulation tissue formation, remodeling, mucostasis, and infections are in reach. The technical hurdles are probably easier to overcome than the legal constraints. The legal situations are discussed from a physician's and a manufacturer's perspective. PMID- 28877532 TI - Stereotype Knowledge and Endorsement in Schizophrenia. AB - BACKGROUND: Social cognition is severely impaired in schizophrenia. Emotion processing, attributional biases, and theory of mind are often impaired, as well as the understanding of shared social knowledge. So far, little is known about stereotype knowledge and endorsement in schizophrenia. SAMPLING AND METHODS: White patients with schizophrenia and matched healthy respondents reported both their personal beliefs and the predicted beliefs of other people toward Black (study 1) and Gypsy individuals (study 2). RESULTS: Results showed that respondents in the clinical sample displayed less stereotype endorsement as compared to the matched healthy respondents. Most importantly, the contents of the responses provided by the 2 samples were strongly overlapped. CONCLUSIONS: Findings indicate that individuals with schizophrenia tend to hold less negative attitudes toward stigmatized outgroups and, most notably, that knowledge about culturally transmitted stereotypes is relatively preserved in schizophrenia. Future research should address the generalizability of the findings in relation to the perception of other stigmatized social groups. PMID- 28877534 TI - Open Abdomen Improves Survival in Patients With Peritonitis Secondary to Acute Superior Mesenteric Artery Occlusion. AB - BACKGROUND: Damage control surgery and open abdomen (OA) have been extensively used in the severe traumatic patients. However, there was little information when extended to a nontrauma setting. The purpose of this study was to evaluate whether the liberal use of OA as a damage control surgery adjunct improved the clinical outcome in acute superior mesenteric artery occlusion patients. STUDY DESIGN: A single-center, retrospective cohort review was performed in a national tertiary surgical referral center. RESULTS: Forty-four patients received OA (OA group) and 65 patients had a primary fascial closure (non-OA group) after diagnosed as peritonitis secondary to acute superior mesenteric artery occlusion from January, 2005 to June, 2016. Revascularization was achieved through endovascular aspiration embolectomy, open embolectomy, or percutaneous stent. No difference of bowel resection length was found between groups in the first emergency surgery. However, more non-OA patients (35.4%) required a second-look enterectomy to remove the residual bowel ischemia than OA patients (13.6%, P<0.05). OA was closed within a median of 7 days (4 to 15 d). There was a mean of 134 cm residual alive bowel in OA, whereas 96 cm in non-OA. More non-OA patients suffered from intra-abdominal sepsis (23.1% vs. 6.8%, P<0.01), intra-abdominal hypertension (31% vs. 0, P<0.01), and acute renal failure (53.8% vs. 31.8%, P<0.05) than OA group after surgery. Short-bowel syndrome occurred infrequently in OA than non-OA patients (9.1% vs. 36.9%, P<0.01). OA significantly decreased the 30-day (27.3% vs. 52.3%, P<0.01) and 1-year mortality rate (31.8 % vs. 61.5%, P<0.01) compared with non-OA group. CONCLUSIONS: Liberal use of OA, as a damage control adjunct avoided the development of intra-abdominal hypertension, reduced sepsis-related complication, and improved the clinical outcomes in peritonitis secondary to acute SMA occlusion. PMID- 28877533 TI - Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment. AB - OBJECTIVES: Tamoxifen bioactivation to endoxifen is mediated primarily by CYP2D6; however, considerable variability remains unexplained. Our aim was to perform a comprehensive assessment of the effect of genetic variation in tamoxifen-relevant enzymes and transporters on steady-state endoxifen concentrations. PATIENTS AND METHODS: Comprehensive genotyping of CYP enzymes and transporters was performed using the iPLEX ADME PGx Pro Panel in 302 tamoxifen-treated breast cancer patients. Predicted activity phenotype for 19 enzymes and transporters were analyzed for univariate association with endoxifen concentration, and then adjusted for CYP2D6 and clinical covariates. RESULTS: In univariate analysis, higher activity of CYP2C8 (regression beta=0.22, P=0.020) and CYP2C9 (beta=0.20, P=0.04), lower body weight (beta=-0.014, P<0.0001), and endoxifen measurement during winter (each beta<-0.39, P=0.002) were associated with higher endoxifen concentrations. After adjustment for the CYP2D6 diplotype, weight, and season, CYP2C9 remained significantly associated with higher concentrations (P=0.02), but only increased the overall model R by 1.3%. CONCLUSION: Our results further support a minor contribution of CYP2C9 genetic variability toward steady-state endoxifen concentrations. Integration of clinician and genetic variables into individualized tamoxifen dosing algorithms would marginally improve their accuracy and potentially enhance tamoxifen treatment outcomes. PMID- 28877536 TI - Trial-dependent psychometric functions accounting for perceptual learning in 2 AFC discrimination tasks. AB - The majority of theoretical models of learning consider learning to be a continuous function of experience. However, most perceptual learning studies use thresholds estimated by fitting psychometric functions to independent blocks, sometimes then fitting a parametric function to these block-wise estimated thresholds. Critically, such approaches tend to violate the basic principle that learning is continuous through time (e.g., by aggregating trials into large "blocks" for analysis that each assume stationarity, then fitting learning functions to these aggregated blocks). To address this discrepancy between base theory and analysis practice, here we instead propose fitting a parametric function to thresholds from each individual trial. In particular, we implemented a dynamic psychometric function whose parameters were allowed to change continuously with each trial, thus parameterizing nonstationarity. We fit the resulting continuous time parametric model to data from two different perceptual learning tasks. In nearly every case, the quality of the fits derived from the continuous time parametric model outperformed the fits derived from a nonparametric approach wherein separate psychometric functions were fit to blocks of trials. Because such a continuous trial-dependent model of perceptual learning also offers a number of additional advantages (e.g., the ability to extrapolate beyond the observed data; the ability to estimate performance on individual critical trials), we suggest that this technique would be a useful addition to each psychophysicist's analysis toolkit. PMID- 28877535 TI - Monkeys and humans take local uncertainty into account when localizing a change. AB - Since sensory measurements are noisy, an observer is rarely certain about the identity of a stimulus. In visual perception tasks, observers generally take their uncertainty about a stimulus into account when doing so helps task performance. Whether the same holds in visual working memory tasks is largely unknown. Ten human and two monkey subjects localized a single change in orientation between a sample display containing three ellipses and a test display containing two ellipses. To manipulate uncertainty, we varied the reliability of orientation information by making each ellipse more or less elongated (two levels); reliability was independent across the stimuli. In both species, a variable-precision encoding model equipped with an "uncertainty-indifferent" decision rule, which uses only the noisy memories, fitted the data poorly. In both species, a much better fit was provided by a model in which the observer also takes the levels of reliability-driven uncertainty associated with the memories into account. In particular, a measured change in a low-reliability stimulus was given lower weight than the same change in a high-reliability stimulus. We did not find strong evidence that observers took reliability independent variations in uncertainty into account. Our results illustrate the importance of studying the decision stage in comparison tasks and provide further evidence for evolutionary continuity of working memory systems between monkeys and humans. PMID- 28877537 TI - Sutureless Microvascular Anastomosis using Intravascular Stenting and Cyanoacrylate Adhesive. AB - BACKGROUND: Microvascular anastomosis using cyanoacrylate adhesive has a reputation among researchers as an alternative to conventional sutures. However, a degree of ingenuity is required to avoid the collapse of the vascular lumen for the duration of the anastomosis. The aim of this study was to determine the feasibility of intravascular stenting (IVaS) as a temporary stent during sutureless microvascular anastomosis with cyanoacrylate adhesive. METHODS: Sixty male Fisher 344 rats were evenly divided into two groups. The right superficial femoral arteries (RSFAs) were transected in each group. Microvascular anastomoses were then performed with the sutureless (SL) method in one group and conventional sutures (CS) in the other group. The diameter of the RSFA, duration of microvascular anastomosis, and the patency of the RSFA were evaluated immediately after anastomosis and 7 days after the surgery. Tissue samples were obtained for pathological consideration. RESULTS: There was no significant difference in the diameter of the RSFAs between the SL and the CS groups. There was no significant difference in the patency rates of the groups. The anastomosis time of the SL group was significantly shorter than that of the CS group, regardless of the experience of the surgeons. A histological analysis showed a comparable level of foreign body reactions in each group. CONCLUSION: IVaS plays a supportive role in sutureless microvascular anastomosis with cyanoacrylate adhesive. The short term safety of this technique has now been confirmed at the experimental stage. PMID- 28877538 TI - Nikolaus Rudinger (1832-1896), His Description of Joint Innervation in 1857, and the History of Surgical Joint Denervation. AB - BACKGROUND: Selective joint denervation has become a reliable palliative treatment, especially for painful joints in the upper and lower extremity. METHODS: This article highlights the life and work of Nikolaus Rudinger (1832 1896) who first described joint innervation which became the basis of later techniques of surgical joint denervation. The historical evolution of this method is outlined. RESULTS: Rudinger made a unique career from apprentice barber to military surgeon and anatomy professor in Munich, Germany. His first description of articular innervation of temporomandibular, shoulder, elbow, wrist, finger, sacroiliac, hip, knee, ankle, foot, and toe joints in 1857 stimulated the subsequent history of surgical joint denervation. Comparing his investigations with modern joint denervation methods, developed by pioneers like Albrecht Wilhelm or A. Lee Dellon, shows his great exactitude and anatomical correspondence despite different current terminology. Clinical series of modern surgical joint denervations reveal success rates of up to 80% with reliable long term results. CONCLUSION: The history of joint denervation with Rudinger as its important protagonist offers inspiring insights into the evolution of surgical techniques and exemplifies the value of descriptive functional anatomy, even if surgical application may not have been realized until a century later. PMID- 28877539 TI - Liquid and Vapor-Phase Activity of Artemisia annua Essential Oil against Pathogenic Malassezia spp. AB - Artemisia annua essential oil has given us many encouraging results for its numerous antimicrobial properties. In this study, the essential oil, both in liquid and in vapor phases, was tested against various Malassezia species closely related to many skin disorders in humans and animals. Malassezia treatment and eradication are mainly based on old azole drugs, which are characterized by poor compliance, unpredictable clinical efficacy, emerging resistance, and several side effects. Monoterpenes (ca. 88%) represent the most abundant group of compounds in the essential oil, mainly the oxygenated derivatives (ca. 74%) with camphor (25.2%), 1,8-cineole (20%), and artemisia ketone (12.5%). In vapor phase, monoterpenes represent more than 98% of the constituents, alpha-pinene being the main constituent (22.8%), followed by 1,8-cineole (22.1%) and camphene (12.9%). Essential oil of A. annua, both in vapor phase and liquid, showed strong antimicrobial activity towards almost the tested twenty strains of Malassezia analyzed. The minimum fungicidal concentrations from most of the strains tested were from 0.78 uL/mL to 1.56 uL/mL, and only three strains of Malassezia sympodialis required a higher concentration of 3.125 uL/mL. Overall, the minimal inhibitor concentrations obtained by vapor diffusion assay were lower than those obtained by the liquid method. The average values of minimal inhibitor concentrations obtained by the two methods at 72 h are 1.3 - 8.0 times higher in liquid compared to those in the vapor phase. PMID- 28877540 TI - Evidence for the Use of Tranexamic Acid in Subarachnoid and Subdural Hemorrhage: A Systematic Review. PMID- 28877541 TI - Ischemic Conditioning as a Hemostatic Intervention in Surgery and Cardiac Procedures: A Systematic Review. PMID- 28877544 TI - An Editorial on Editorials. PMID- 28877542 TI - A Systematic Review and Meta-analysis Comparing Anticoagulation versus No Anticoagulation and Shorter versus Longer duration of Anticoagulation for Treatment of Isolated Distal Deep Vein Thrombosis. PMID- 28877545 TI - In vivo assessment of muscle membrane properties in the sodium channel myotonias. AB - INTRODUCTION: The gain-of-function mutations that underlie sodium channel myotonia (SCM) and paramyotonia congenital (PMC) produce differing clinical phenotypes. We used muscle velocity recovery cycles (MVRCs) to investigate membrane properties. METHODS: MVRCs and responses to trains of stimuli were compared in patients with SCM (n = 9), PMC (n = 8), and normal controls (n = 26). RESULTS: The muscle relative refractory period was reduced in SCM, consistent with faster recovery of the mutant sodium channels from inactivation. Both SCM and PMC showed an increased early supernormality and increased mean supernormality following multiple conditioning stimuli, consistent with slowed sodium channel inactivation. Trains of fast impulses caused a loss of amplitude in PMC, after which only half of the muscle fibers recovered, suggesting that the remainder stayed depolarized by persistent sodium currents. DISCUSSION: The differing effects of mutations on sodium channel function can be demonstrated in human subjects in vivo using this technique. Muscle Nerve 57: 586-594, 2018. PMID- 28877547 TI - Comparing excitability at 37 degrees C versus at 20 degrees C: Differences between motor and sensory axons. AB - INTRODUCTION: In some peripheral nervous system disorders, cold induces symptoms of muscle weakness without loss of sensation. To understand this selective effect on motor function, it is first essential to delineate the effects of cooling in motor and sensory axons of healthy subjects. METHODS: In 17 healthy volunteers, we performed excitability and clinical tests of median nerve motor and sensory axons at 37 degrees C and at 20 degrees C. Clinical tests consisted of assessing thenar muscle strength, 2-point discrimination, and joint position sense of the third finger. RESULTS: Excitability tests showed that cooling induced opposite changes to hyperpolarizing current in threshold electrotonus (motor, decreased threshold change; sensory, increased threshold change) and current-voltage relation slopes (motor, steepening; sensory, less steep). Clinical tests showed worsening in motor function but no consistent changes in sensory function. DISCUSSION: Cooling induces changes in motor axons consistent with depolarization and more complicated changes in sensory axons, possibly related to differences in hyperpolarization-activated cyclic nucleotide-gated channel expression. Muscle Nerve 57: 574-580, 2018. PMID- 28877546 TI - Clinical features and evolution of juvenile myasthenia gravis in a French cohort. AB - INTRODUCTION: In this study we determined the clinical, paraclinical, and treatment-related features of juvenile myasthenia gravis (JMG) as well as the clinical course in a cohort of French children. METHODS: We conducted a retrospective study of 40 patients with JMG at 2 French pediatric neurology departments from April 2004 to April 2014. RESULTS: Among the patients, 70% had generalized JMG, 52% had positive acetylcholine receptor antibodies, 8% had muscle-specific kinase antibodies, and 40% were seronegative. Treatment with acetylcholinesterase inhibitors was effective and sufficient in 47% of patients. The 6 patients with generalized JMG treated with rituximab and/or immunoadsorption showed improvement. Thirty percent of the patients required hospitalization in an intensive care unit during follow-up (mean 4.7 years). Remission without treatment occurred in 18% of patients. DISCUSSION: As with adults, JMG has high morbidity, particularly among children with generalized symptoms, and rituximab should be considered early in the course of the disease as a second-line treatment. Muscle Nerve 57: 603-609, 2018. PMID- 28877548 TI - Sonoanatomy of sensory branches of the ulnar nerve below the elbow in healthy subjects. AB - INTRODUCTION: We identify sensory branches of the ulnar nerve-palmar ulnar cutaneous nerve (PUCN), dorsal ulnar cutaneous nerve (DUCN), and superficial sensory branch-using ultrasonography. METHODS: In 60 forearms of 30 healthy adult volunteers, the origin and size of the PUCN, DUCN, and superficial sensory branch were measured by ultrasonography. The relative pathway of the DUCN to the ulnar styloid process was also investigated. RESULTS: The PUCN was observed in 47 forearms (78%), and the DUCN was observed in all forearms. Average distances from the pisiform to the origin of the PUCN and DUCN were 11.9 +/- 1.4 and 7.0 +/- 1.0 cm, respectively. Superficial and deep divisions split 0.9 +/- 0.3 cm distal to the pisiform. Cross-sectional areas of the PUCN, DUCN, and superficial sensory branch were 0.3 +/- 0.1, 1.5 +/- 0.5, and 3.9 +/- 1.0 mm2 , respectively. DISCUSSION: Sensory branches of the ulnar nerve can be visualized by ultrasonography, helping to differentiate ulnar nerve injury originating at either wrist or elbow. Muscle Nerve 57: 569-573, 2018. PMID- 28877550 TI - Organization of the motor-unit pool for different directions of isometric contraction of the first dorsal interosseous muscle. AB - INTRODUCTION: Muscle force generation involves recruitment and firing rate modulation of motor units (MUs). The control of MUs in producing multidirectional forces remains unclear. METHODS: We studied MU recruitment and firing properties, recorded from the first dorsal interosseous muscle, for 3 different directions of contraction: abduction; abduction/flexion combination; and flexion. RESULTS: MUs were recruited systematically at higher threshold force during flexion. Larger MUs were recruited and firing rates of MUs were lower during abduction. There was an orderly recruitment of MUs according to MU size regardless of contraction direction, obeying the "size principle." Firing rates of earlier-recruited MUs were consistently higher than later-recruited MUs, affirming the "onion-skin" property. DISCUSSION: Our findings suggest that the size principle and onion-skin organization together provide a general description of MU recruitment patterns and firing properties. The directional alternations of MU control properties likely reflect changes in neural drive to the muscle. Muscle Nerve 57: E85-E93, 2018. PMID- 28877551 TI - President's Message: Establishing partnerships to foster nursing research. PMID- 28877549 TI - A research agenda for curing chronic hepatitis B virus infection. PMID- 28877553 TI - A novel phenotype Of Zika virus-related neurological disease: Sensory neuronopathy. PMID- 28877552 TI - Diabetes affects everything: Type 2 diabetes self-management among Spanish speaking hispanic immigrants. AB - This article is a report of qualitative findings of a mixed-methods study of the relationships among knowledge, self-efficacy, health promoting behaviors, and type 2 diabetes mellitus (T2DM) self-management among limited-english-proficient recent Hispanic immigrants, a population with increased incidence of T2DM and barriers to successful T2DM management. Semi-structured interviews were conducted with 30 participants, and physiological and demographic data also were collected. The participants generally attributed developing the disease to strong emotions and viewed T2DM as a serious disease. Although a majority understood the importance of exercise and diet in T2DM self-management, other aspects such as medication adherence were not well-understood. Obstacles to effective T2DM self management were negative interactions and communications with health care providers and other personnel, cultural stigma related to the disease, financial constraints, immigration status, and the complexity of the disease. Suggested interventions to improve the care and self-management of this at-risk population are discussed. PMID- 28877555 TI - Cutaneous silent period in myofascial pain syndrome. AB - INTRODUCTION: An increased response to painful stimuli without spontaneous pain suggests a role of central hyperexcitability of pain pathways in the pathogenesis of myofascial pain syndrome (MPS). In this study we aimed to test the hypothesis that spinal pain pathways are affected in MPS. We used cutaneous silent period (CSP) parameters to demonstrate the hyperexcitability of spinal pain pathways in MPS. METHODS: Twenty-nine patients diagnosed with MPS and 30 healthy volunteers were included in the study. The CSP recordings were performed in the right upper and left lower extremities. RESULTS: In both upper and lower extremities, patients had prolonged CSP latencies (P = 0.034 and P = 0.049 respectively) and shortened CSP durations (P = 0.009 and P = 0.008, respectively). DISCUSSION: Delayed and shortened CSP in MPS patients implies dysfunction in the inhibitory mechanism of the spinal/supraspinal pain pathways, suggesting central sensitization in the pathogenesis of MPS and supporting our research hypothesis. Muscle Nerve 57: E24-E28, 2018. PMID- 28877556 TI - Patient-identified impact of symptoms in spinal and bulbar muscular atrophy. AB - INTRODUCTION: The effects of spinal bulbar muscular atrophy (SBMA) on quality of life (QoL) are not well understood. This study describes symptoms from the patient's perspective and the impact these symptoms have on QoL. METHODS: We conducted open-ended interviews with 21 adult men with genetically confirmed SBMA. Using a qualitative framework technique, we coded and analyzed interviews to identify symptoms and resulting themes. RESULTS: From these interviews, 729 quotations were extracted. We identified 200 SBMA-specific symptoms and 20 symptomatic themes. Weakness was mentioned by all interviewees. Symptoms within the domain of mental health and the specific themes of emotional issues and psychological impact were also frequently mentioned. DISCUSSION: Numerous symptoms affect QoL for patients with SBMA. We identified previously unrecognized symptoms that are important to address in enhancing clinical care for patients with SBMA and in developing tools to evaluate efficacy in future clinical trials. Muscle Nerve 57: 40-44, 2018. PMID- 28877554 TI - The role of sociodemographic factors in maternal psychological distress and mother-preterm infant interactions. AB - Preterm birth has been associated with greater psychological distress and less positive mother infant interactions than were experienced by mothers of full-term infants. Maternal and infant sociodemographic factors have also shown a strong association with psychological distress and the mother-infant relationship. However, findings on their effects over time are limited. In this longitudinal analysis, we explored the relationship of maternal and infant sociodemographic variables (maternal age, maternal education, marital status, being on social assistance, maternal race, infant birth weight, and infant gender) to maternal psychological distress (depressive, posttraumatic stress, anxiety, parenting stress symptoms, and maternal worry about child's health) through 12 months corrected age for prematurity, and on the home environment, and mother-infant interactions through 6 months corrected age for prematurity. We also explored differences related to maternal obstetrical characteristics (gestational age at birth, parity, mode of delivery, and multiple birth) and severity of infant conditions (Apgar scores, need for mechanical ventilation, and infant medical complications). Although the relationship of maternal and infant characteristics with these outcomes did not change over time, psychological distress differed based on marital status, maternal education, infant gender, and infant medical complications. Older mothers provided more a positive home environment. Mother infant interactions differed by maternal age, being on public assistance, maternal race, infant gender, and infant medical complications. More longitudinal research is needed to better understand these effects over time in order to identify and support at-risk mothers. PMID- 28877557 TI - Can we reconcile 'the obesity paradox' with recent cardiovascular outcome trials in diabetes? PMID- 28877558 TI - Social status and energy intake: a randomized controlled experiment. AB - While the inverse association between socioeconomic status (SES) and obesity in high gross domestic product countries is well established using observational data, the extent to which the association is due to a true causal effect of SES and, if so, the mechanisms of this effect remain incompletely known. To assess the influence of social status on obesity via energy intake, we randomized individuals to a higher or lower social status and observed subsequent energy intake. College students between the ages of 18 and 25 were randomized to social status and were operationalized as being a leader or follower in a partner activity as purportedly determined by a (bogus) test of leadership ability. Investigators were blinded to treatment assignment. Immediately after being told their leadership assignment, paired participants were provided with platters of food. Energy intake was objectively measured in kilocalories (kcal) consumed, and paired t-tests were used to test for significant differences in intake between leaders and followers. A total of 60 participants were included in the final analysis (males = 28, females = 32). Overall, no difference in energy intake was observed between leaders and followers, consuming an average of 575.3 and 579.8 kcal, respectively (diff = 4.5 kcal, P = 0.94). The null hypothesis of no effect of social status, operationalized as assignment to a leadership position in a small-group activity, on energy intake was not rejected. PMID- 28877559 TI - An instrumented timed up and go in facioscapulohumeral muscular dystrophy. AB - INTRODUCTION: Instrumenting timed functional motor tasks may reveal a continuum of motor disability that predicts future motor dysfunction. METHODS: We performed a prospective study of the instrumented timed up and go (iTUG) test in genetically confirmed facioscapulohumeral muscular dystrophy (FSHD) participants using a commercially available system of wireless motion sensors. Patients returned within 2 weeks to determine test-retest reliability. Gait parameters in FSHD participants were compared with a normative database, FSHD clinical severity score, manual muscle testing, and patient-reported functional disability. RESULTS: Gait parameters in FSHD participants were significantly (P < 0.05) altered compared with normative values, and reliability was excellent (intraclass correlation coefficient 0.84-0.99). Stride velocity and trunk sagittal range of motion had moderate to strong correlations to other FSHD disease measures. DISCUSSION: The iTUG was reliable, abnormal in FSHD, and could distinguish between participants with differing disease severities. Instrumenting timed functional tasks may prove to be useful in FSHD clinical trials. Muscle Nerve 57: 503-506, 2018. PMID- 28877561 TI - A severe phenotype of Kennedy disease associated with a very large CAG repeat expansion. PMID- 28877562 TI - Rate of Stroke Mimics over Telestroke. PMID- 28877560 TI - Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies. AB - Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57: 6-15, 2018. PMID- 28877563 TI - Intravenous Thrombolysis in Patients with Stroke Taking Rivaroxaban Using Drug Specific Plasma Levels: Experience with a Standard Operation Procedure in Clinical Practice. AB - BACKGROUND AND PURPOSE: Standard operating procedures (SOP) incorporating plasma levels of rivaroxaban might be helpful in selecting patients with acute ischemic stroke taking rivaroxaban suitable for IVthrombolysis (IVT) or endovascular treatment (EVT). METHODS: This was a single-center explorative analysis using data from the Novel-Oral-Anticoagulants-in-Stroke-Patients-registry (clinicaltrials.gov:NCT02353585) including acute stroke patients taking rivaroxaban (September 2012 to November 2016). The SOP included recommendation, consideration, and avoidance of IVT if rivaroxaban plasma levels were <20 ng/mL, 20-100 ng/mL, and >100 ng/mL, respectively, measured with a calibrated anti factor Xa assay. Patients with intracranial artery occlusion were recommended IVT+EVT or EVT alone if plasma levels were <=100 ng/mL or >100 ng/mL, respectively. We evaluated the frequency of IVT/EVT, door-to-needle-time (DNT), and symptomatic intracranial or major extracranial hemorrhage. RESULTS: Among 114 acute stroke patients taking rivaroxaban, 68 were otherwise eligible for IVT/EVT of whom 63 had plasma levels measured (median age 81 years, median baseline National Institutes of Health Stroke Scale 6). Median rivaroxaban plasma level was 96 ng/mL (inter quartile range [IQR] 18-259 ng/mL) and time since last intake 11 hours (IQR 4.5-18.5 hours). Twenty-two patients (35%) received IVT/EVT (IVT n=15, IVT+EVT n=3, EVT n=4) based on SOP. Median DNT was 37 (IQR 30-60) minutes. None of the 31 patients with plasma levels >100 ng/mL received IVT. Among 14 patients with plasma levels <=100 ng/mL, the main reason to withhold IVT was minor stroke (n=10). No symptomatic intracranial or major extracranial bleeding occurred after treatment. CONCLUSIONS: Determination of rivaroxaban plasma levels enabled IVT or EVT in one-third of patients taking rivaroxaban who would otherwise be ineligible for acute treatment. The absence of major bleeding in our pilot series justifies future studies of this approach. PMID- 28877564 TI - Intracranial Atherosclerosis: From Microscopy to High-Resolution Magnetic Resonance Imaging. AB - Intracranial atherosclerosis is one of the leading causes of ischemic stroke and occurs more commonly in patients of Asian, African or Hispanic origin than in Caucasians. Although the histopathology of intracranial atherosclerotic disease resembles extracranial atherosclerosis, there are some notable differences in the onset and severity of atherosclerosis. Current understanding of intracranial atherosclerotic disease has been advanced by the high-resolution magnetic resonance imaging (HRMRI), a novel emerging imaging technique that can directly visualize the vessel wall pathology. However, the pathological validation of HRMRI signal characteristics remains a key step to depict the plaque components and vulnerability in intracranial atherosclerotic lesions. The purpose of this review is to describe the histological features of intracranial atherosclerosis and to state current evidences regarding the validation of MR vessel wall imaging with histopathology. PMID- 28877565 TI - Prognostic Significance of Troponin Elevation for Long-Term Mortality after Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Troponin, a marker of myocardial injury, frequently increases and is related with poor outcome in ischemic stroke patients. However, the long-term outcome of this elevation remains uncertain. We, therefore, investigated the prognostic significance of troponin elevation for long-term mortality, and explored factors affecting troponin elevation after ischemic stroke. METHODS: We retrospectively analyzed the medical data of stroke patients who were admitted within 24 hours of symptom onset and underwent a serum cardiac troponin I test at admission during a five-year period. Information on mortality as the outcome was obtained from the National Death Certificate system. RESULTS: A total of 1,692 patients were eligible for inclusion with 33 months of median follow-up. Troponin elevation that exceeded the 99th percentile (>0.04 ng/mL) of values was detected in 166 patients (9.8%). After adjusting for baseline characteristics, troponin elevation was associated with previous ischemic heart disease and congestive heart failure, comorbid atrial fibrillation and active cancer, and increased National Institutes of Health Stroke Scale score. Patients with troponin elevation had a high risk of overall death (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.40-2.40), including stroke-related (HR 1.71, 95% CI 1.14-2.55), cardiac-related (HR 3.17, 95% CI 1.49-6.74), and cancer-related (HR 1.98, 95% CI 1.14-3.45) death than those without troponin elevation. CONCLUSIONS: Troponin elevation in the acute stage of ischemic stroke was associated with long-term mortality, mainly due to increased stroke- and cancer related death in the first year and cardiacrelated death in the later period. PMID- 28877566 TI - Is Ginger Effective in Reducing Post-tonsillectomy Morbidity? A Prospective Randomised Clinical Trial. AB - OBJECTIVES: An assessment of the effects of ginger on pain, nausea, vomiting, bleeding, and wound site healing that occur after tonsillectomy. METHODS: This prospective clinical study was participated by 49 patients aged 18-45 years out of 56 patients that underwent tonsillectomy and regularly attended follow-up visits. The patients were randomly divided into two groups. Group 1 consisted of 23 patients that used ginger capsules and group 2 consisted of 26 patients that did not use ginger capsules in addition to the routine antibiotic and paracetamol treatment following tonsillectomy. The pain, nausea, vomiting, and bleeding scores of patients were assessed on days 1, 4, 7, and 10 by using the visual analogue scale. Similarly, the epithelialization degrees of tonsillar bed were assessed on postoperative days 1, 4, 7, and 10 and regular oral intake times of patients were recorded. RESULTS: There were no differences between groups in terms of age and sex. On the postoperative days 1, 4, 7, and 10, the pain scores were lower in the group 1 (all P<0.001) and there were no differences between the two groups in terms of postoperative nausea, vomiting, and bleeding scores (P=0.35 and P=0.53). On the postoperative days 7 and 10, epithelialization in the tonsil bed was quicker in the group 1 (P=0.041 and P=0.026) and the regular oral intake time was earlier in group 1 (P<0.001). CONCLUSION: In this study, ginger relieved pain, accelerated wound site epithelialization, and decreased duration of oral intake following tonsillectomy. It did not result in postoperative bleeding or any other complications. Ginger can be recommended as an adjunct to routine medical treatment for decreasing morbidity following tonsillectomy. PMID- 28877567 TI - Genetic Diversity and Phylogenetic Analysis of the Iranian Leishmania Parasites Based on HSP70 Gene PCR-RFLP and Sequence Analysis. AB - Despite the broad distribution of leishmaniasis among Iranians and animals across the country, little is known about the genetic characteristics of the causative agents. Applying both HSP70 PCR-RFLP and sequence analyses, this study aimed to evaluate the genetic diversity and phylogenetic relationships among Leishmania spp. isolated from Iranian endemic foci and available reference strains. A total of 36 Leishmania isolates from almost all districts across the country were genetically analyzed for the HSP70 gene using both PCR-RFLP and sequence analysis. The original HSP70 gene sequences were aligned along with homologous Leishmania sequences retrieved from NCBI, and subjected to the phylogenetic analysis. Basic parameters of genetic diversity were also estimated. The HSP70 PCR-RFLP presented 3 different electrophoretic patterns, with no further intraspecific variation, corresponding to 3 Leishmania species available in the country, L. tropica, L. major, and L. infantum. Phylogenetic analyses presented 5 major clades, corresponding to 5 species complexes. Iranian lineages, including L. major, L. tropica, and L. infantum, were distributed among 3 complexes L. major, L. tropica, and L. donovani. However, within the L. major and L. donovani species complexes, the HSP70 phylogeny was not able to distinguish clearly between the L. major and L. turanica isolates, and between the L. infantum, L. donovani, and L. chagasi isolates, respectively. Our results indicated that both HSP70 PCR-RFLP and sequence analyses are medically applicable tools for identification of Leishmania species in Iranian patients. However, the reduced genetic diversity of the target gene makes it inevitable that its phylogeny only resolves the major groups, namely, the species complexes. PMID- 28877568 TI - Trichomonas vaginalis alpha-Actinin 2 Modulates Host Immune Responses by Inducing Tolerogenic Dendritic Cells via IL-10 Production from Regulatory T Cells. AB - Trichomonas vaginalis is a pathogen that triggers severe immune responses in hosts. T. vaginalis alpha-actinin 2, Tvalpha-actinin 2, has been used to diagnose trichomoniasis. This study was undertaken to examine the role of Tvalpha-actinin 2 as an antigenic molecule to induce immune responses from humans. Western blot analysis using anti-Tvalpha-actinin 2 antibodies indicated its presence in the secreted proteins of T. vaginalis. ELISA was employed to measure cytokine production by vaginal epithelial cells, prostate cells, mouse dendritic cells (DCs), or T cells stimulated with T. vaginalis or Tvalpha-actinin 2 protein. Both T. vaginalis and rTvalpha-actinin 2 induced cytokine production from epithelial cell lines, including IL-10. Moreover, CD4+CD25- regulatory T cells (Treg cells) incubated with rTvalpha-actinin 2-treated DCs produced high levels of IL-10. These data indicate that Tvalpha-actinin 2 modulates immune responses via IL-10 production by Treg cells. PMID- 28877569 TI - Seroprevalence of Toxoplasmosis Detected by RDT in Residents near the DMZ (demilitarized zone) of Cheorwon-gun, Gangwon-do, Korea. AB - Seroprevalence of Toxoplasma gondii infection among the residents of Cheorwon gun, Gangwon-do, Korea, which partly includes the demilitarized zone (DMZ), were surveyed for 4 years and evaluated by RDT using recombinant fragment of major surface antigen (SAG1A). Sera from 1336, 583, 526, and 583 adult residents were collected on a yearly basis from 2010 to 2013, respectively. The total positive seroprevalence was 19.3, 21.9, 23.4, and 26.8% from 2010 to 2013, respectively. The positive seroprevalence in men (23.6, 27.5, 29.5, 34.6%) was far higher than women (14.1, 18.3, 19.4, 21.4%), from 2010 to 2013, respectively. This high seroprevalence of toxoplasmosis in Cheorwon-gun may have been influenced in part by its geographical locality of the area as it includes the DMZ, where civilian access is strictly limited, thus creating a relatively isolated area that is a well-preserved habitat. Further research is necessary to study the epidemiology of toxoplasmosis in this area. PMID- 28877570 TI - Hookworm Infection: A Neglected Cause of Overt Obscure Gastrointestinal Bleeding. AB - Hookworm infections are widely prevalent in tropical and subtropical areas, especially in low income regions. In the body, hookworms parasitize the proximal small intestine, leading to chronic intestinal hemorrhage and iron deficiency anemia. Occasionally, hookworms can cause overt gastrointestinal bleeding, but this is often ignored in heavily burdened individuals from endemic infectious areas. A total of 424 patients with overt obscure gastrointestinal bleeding were diagnosed by numerous blood tests or stool examinations as well as esophagogastroduodenoscopy, colonoscopy, capsule endoscopy or double-balloon enteroscopy. All of the patients lived in hookworm endemic areas and were not screened for hookworm infection using sensitive tests before the final diagnosis. The patients recovered after albendazole treatment, blood transfusion, and iron replacement, and none of the patients experienced recurrent bleeding in the follow-up. All the 31 patients were diagnosed with hookworm infections without other concomitant bleeding lesions, a rate of 7.3% (31/424). Seventeen out of 227 patients were diagnosed with hookworm infections in the capsule endoscopy (CE), and 14 out of 197 patients were diagnosed with hookworm infections in the double balloon enteroscopy (DBE). Hookworm infections can cause overt gastrointestinal bleeding and should be screened in patients with overt obscure gastrointestinal bleeding (OGIB) in endemic infectious areas with sensitive methods. Specifically, the examination of stool specimens is clinically warranted for most patients, and the proper examination for stool eggs relies on staff's communication. PMID- 28877571 TI - Prevalence and Density of Digenetic Trematode Metacercariae in Clams and Oysters from Western Coastal Regions of the Republic of Korea. AB - A survey was performed to know the recent infection status of digenetic trematode metacercariae in clams and oysters from 4 sites in western coastal regions of the Republic of Korea (=Korea). Four species of clams (Mactra veneriformis, Ruditapes philippinarum, Cyclina sinensis, and Saxidomus purpuratus) were collected from Taean-gun, Chungcheongnam-do (Province), Buan-gun (County) and Gochang-gun, Jeollabuk-do, and oysters, Crassostrea gigas, from Shinan-gun, Jeollanam-do were transferred to our laboratory on ice and examined by the artificial digestion method. The metacercariae of Himasthla alincia were detected in 3 species of clams, M. veneriformis, R. philippinarum, and C. sinensis from the 3 surveyed areas. The positive rate and the mean density per clam infected were 98.9% (30.8 metacercariae) in M. veneriformis, 60.0% (5.0) in R. philippinarum, and 96.0% (28.4) in C. sinensis. The positive rate (mean density) of Acanthoparyphium tyosenense metacercariae in M. veneriformis was 50.0% (2.1) from Taean-gun and 70.0% (2.8) from Gochang-gun. The metacercariae of Parvatrema spp. were detected in M. veneriformis and R. philippinarum from Taean-gun and Gochang-gun; the positive rate (mean density) was 63.3% (4,123) and 50.0% (19) in M. veneriformis, and 6.7% (126) and 100% (238) in R. philippinarum from the 2 regions, respectively. The metacercariae of Gymnophalloides seoi were detected in all 30 oysters from Shinan-gun, and their average density per oyster was 646. From the above results, it has been confirmed that more than 3 species of metacercariae are prevalent in clams from the western coastal regions, and G. seoi metacercariae are still prevalent in oysters from Shinan-gun, Jeollanam-do, Korea. PMID- 28877572 TI - Safety, Efficacy, and Physicochemical Characterization of Tinospora crispa Ointment: A Community-Based Formulation against Pediculus humanus capitis. AB - The high prevalence of pediculosis capitis, commonly known as head lice (Pediculus humanus capitis) infestation, has led to the preparation of a community-based pediculicidal ointment, which is made of common household items and the extract of Tinospora crispa stem. The present study aimed to evaluate the safety, efficacy, and physicochemical characteristics of the T. crispa pediculicidal ointment. The physicochemical properties of the ointment were characterized, and safety was determined using acute dermal irritation test (OECD 404), while the efficacy was assessed using an in vitro pediculicidal assay. Furthermore, the chemical compounds present in T. crispa were identified using liquid-liquid extraction followed by ultra-performance liquid chromatography quadruple time-of-flight mass spectrometric (UPLC-qTOF/MS) analysis. The community-based ointment formulation was light yellow in color, homogeneous, smooth, with distinct aromatic odor and pH of 6.92+/-0.09. It has spreadability value of 15.04+/-0.98 g.cm/sec and has thixotropic behavior. It was also found to be non-irritant, with a primary irritation index value of 0.15. Moreover, it was comparable to the pediculicidal activity of the positive control Kwell(r), a commercially available 1% permethrin shampoo (P>0.05), and was significantly different to the activity of the negative control ointment, a mixture of palm oil and candle wax (P<0.05). These findings suggested that the community-based T. crispa pediculicidal ointment is safe and effective, having acceptable physicochemical characteristics. Its activity can be attributed to the presence of compounds moupinamide and physalin I. PMID- 28877573 TI - Hookworm Infection Caused Acute Intestinal Bleeding Diagnosed by Capsule: A Case Report and Literature Review. AB - Hookworm infections are rare causes of acute gastrointestinal bleeding. We report a middle aged man with primary nephrotic syndrome and pulmonary embolism. During the treatment with steroids and anticoagulants, the patient presented acute massive hemorrhage of the gastrointestinal tract. The results of gastroscopy showed red worms in the duodenum. Colonoscopy and CT angiogram of abdomen were unremarkable. Capsule endoscopy revealed fresh blood and multiple hookworms in the jejunum and ileum. Hookworms caused the acute intestinal bleeding. The patient responded well to albendazole. Hematochezia was markedly ameliorated after eliminating the parasites. Hence, hookworm infection should be considered in the differential diagnosis of a patient with obscure gastrointestinal bleeding. Capsule endoscopy may offer a better means of diagnosis for intestinal hookworm infections. PMID- 28877574 TI - Sparganosis of the Unilateral Breast: A Case Report. AB - Sparganosis is a parasitic infection caused by the sparganum, the plercercoid of the genus Spirometra. The preoperative diagnosis of breast sparganosis is difficult in most cases because it is a rare parasitic infection less than 2% of all cases. We report a 62-year-old woman case of breast sparganosis that were confirmed by surgical removal of worms from the right breast. The radiologic images of the patient also revealed characteristic features of breast sparganosis. The patient described the migrating palpable breast mass, which strongly suggested the possibility of breast sparganosis. The treatment of choice and confirmative diagnosis for sparganosis are complete surgical extraction of the sparganum irrespective of infected site. Inspection of the mass site with detailed medical history and radiological examinations are important for preoperative diagnosis of sparganosis patients. PMID- 28877575 TI - Molecular Identification of Diphyllobothrium latum from a Pediatric Case in Taiwan. AB - Human diphyllobothriasis is a parasitic disease caused by ingestion of larvae (plerocercoids) in raw or undercooked fish and commonly found in temperate areas. Rare cases were reported in tropical or subtropical areas especially in children. The first documented case of pediatric diphyllobothriasis in Taiwan had been reported 11 years ago. Here, we report another 8-year-old girl case who presented with a live noodle-like worm hanging down from her anus, with no other detectable symptoms. We pulled the worm out and found the strobila being 260 cm in length. Examination of gravid proglottids showed that they were wider than their lengths, containing an ovoid cirrus sac in the anterior side and the rosette-shaped uterus. Eggs extracted from the uterus were ovoid and operculated. Diphyllobothrium latum was confirmed by molecular analysis of the mitochondrial DNA cytochrome c oxidase subunit 1 (cox1) gene. The girl was treated with a single oral dose of praziquantel, and no eggs or proglottids were observed from her stool in the subsequent 3 months. The reemergence of human diphyllobothriasis in non-endemic countries is probably due to prevalent habit of eating imported raw fish from endemic areas. This pediatric case raised our concern that human diphyllobothriasis is likely underestimated because of unremarkable symptoms. PMID- 28877576 TI - Unusual Location of Hydatid Cysts: Report of Two Cases in the Heart and Hip Joint of Romanian Patients. AB - Hydatid cyst is usually located in the liver and lungs, rare cases showing localization in other organs or tissues. In the unusual location, echinococcosis is an excluding diagnosis that is established only after microscopic evaluation. Our first case occurred in a 67-year-old female previously diagnosed with pulmonary tuberculosis and hospitalized with persistent pain in the hip joint. The clinical diagnosis was tuberculosis of the joint, but the presence of the specific acellular membrane indicated a hydatid cyst of the synovial membrane, without bone involvement. Fewer than 25 cases of joint hydatidosis have been reported in literature to date. In the second case, the intramural hydatid cyst was incidentally discovered at autopsy, in the left heart ventricle of a 52-year old male hospitalized for a fatal brain hemorrhage, as a result of rupture of an anterior communicating artery aneurysm. The conclusion of our paper is that echinococcosis should be taken into account for the differential diagnosis of cystic lesions, independently from their location. PMID- 28877577 TI - A Case of Pentastomiasis at the Left Maxilla Bone in a Patient with Thyroid Cancer. AB - Pentastomiasis, a zoonotic parasite infection, is typically found in the respiratory tract and viscera of the host, including humans. Here, we report for the first time an extremely rare case of intraosseous pentastomiasis in the human maxilla suffering from medication related osteonecrosis of the jaw (MRONJ). A 55 year-old male had continuously visited the hospital for MRONJ which had primarily developed after bisphosphonate and anti-neoplastic administration for previous bone metastasis of medullary thyroid cancer. Pain, bone exposure, and pus discharge in the right mandible and left maxilla were seen. Osteolysis with maxillary cortical bone perforation at the left buccal vestibule, palate, nasal cavity, and maxillary sinus was observed by radiologic images. A biopsy was done at the left maxilla and through pathological evaluation, a parasite with features of pentastome was revealed within the necrotic bone tissue. Further history taking and laboratory evaluation was done. The parasite was suspected to be infected through maxillary open wounds caused by MRONJ. Awareness of intraosseous pentastomiasis should be emphasized not to be missed behind the MRONJ. Proper evaluation and interpretation for past medical history may lead to correct differential diagnosis and therapeutic intervention for parasite infections. PMID- 28877578 TI - Syphacia obvelata: A New Hope to Induction of Intestinal Immunological Tolerance in C57BL/6 Mice. AB - The ability of nematodes to manipulate the immune system of their host towards a Th2 and T regulatory responses has been proposed to suppress the inflammatory response. Clinical trials have proposed a useful effect of helminth infections on improvement of inflammatory disorders. In this study, we investigated the immunomodulatory effect of Syphacia obvelata infection to induce intestinal tolerance in C57BL/6 mice. Mice were infected through the cagemates with self infected BALB/c mice. Four weeks post-infection, expression levels of IFN-gamma, TNF-alpha, IL-17, and IL-10 were assessed in the supernatant of mesenteric lymph node (MLN) culture. Foxp3+Treg were measured in MLN cells by flow cytometry. In the S. obvelata-infected group, the percentage of Tregs (5.2+/-0.4) was significantly higher than the control (3.6+/-0.5) (P<0.05). The levels of IL-10 (55.3+/-2.2 vs 35.2+/-3.2), IL-17 (52.9+/-3.8 vs 41+/-1.8), IFN-gamma (44.8+/-4.8 vs 22.3+/-2.3) and TNF-alpha (71.1+/-5.8 vs 60.1+/-3.3) were significantly increased in infected mice compared to the control group (P<0.05). The above results showed the potential effects of S. obvelata to induce intestinal tolerance. Therefore, it seems that S. obvelata may increase the immunological suppressive function in the intestinal tract. PMID- 28877580 TI - Characterization of Echinostoma cinetorchis endoribonuclease, RNase H. AB - Echinostoma cinetorchis is an oriental intestinal fluke causing significant pathological damage to the small intestine. The aim of this study was to determine a full-length cDNA sequence of E. cinetorchis endoribonuclease (RNase H; EcRNH) and to elucidate its molecular biological characters. EcRNH consisted of 308 amino acids and showed low similarity to endoribonucleases of other parasites (<40%). EcRNH had an active site centered on a putative DDEED motif instead of DEDD conserved in other species. A recombinant EcRNH produced as a soluble form in Escherichia coli showed enzymatic activity to cleave the 3'-O-P bond of RNA in a DNA-RNA duplex, producing 3'-hydroxyl and 5'-phosphate. These findings may contribute to develop antisense oligonucleotides which could damage echinostomes and other flukes. PMID- 28877579 TI - Prevalence of Centrocestus formosanus Metacercariae in Ornamental Fish from Chiang Mai, Thailand, with Molecular Approach Using ITS2. AB - The prevalence of Centrocestus formosanus metacercariae was investigated in ornamental fish purchased from a pet shop in Chiang Mai, Thailand, including Carassius auratus (goldfish), Cyprinus carpio (Koi), Poecilia latipinna (Sailfin Molly), Danio rerio (Zebrafish), and Puntigrus tetrazona (Tiger barb). The parasite species was identified by the morphology of worms as well as by a molecular approach using ITS2. The results showed that 50 (33.3%) of 150 fish examined were infected with the metacercariae. The highest prevalence was found in C. auratus (83.3%), and the highest intensity was noted in C. carpio (70.8 metacercariae/fish). The most important morphological character was the presence of 32-34 circumoral spines on the oral sucker. The phylogenetic studies using the rRNA ITS2 region revealed that all the specimens of C. formosanus in this study were grouped together with C. formosanus in GenBank database. This is the first report on ornamental fish, C. carpio, P. latipinna, D. rerio, and P. tetrazona, taking the role of second intermediate hosts of C. formosanus in Thailand. Prevention and control of metacercarial infection in ornamental fish is urgently needed. PMID- 28877582 TI - Active Thermochemical Tables: The Adiabatic Ionization Energy of Hydrogen Peroxide. AB - The adiabatic ionization energy of hydrogen peroxide (HOOH) is investigated, both by means of theoretical calculations and theoretically assisted reanalysis of previous experimental data. Values obtained by three different approaches: 10.638 +/- 0.012 eV (purely theoretical determination), 10.649 +/- 0.005 eV (reanalysis of photoelectron spectrum), and 10.645 +/- 0.010 eV (reanalysis of photoionization spectrum) are in excellent mutual agreement. Further refinement of the latter two values to account for asymmetry of the rotational profile of the photoionization origin band leads to a reduction of 0.007 +/- 0.006 eV, which tends to bring them into even closer alignment with the purely theoretical value. Detailed analysis of this fundamental quantity by the Active Thermochemical Tables approach, using the present results and extant literature, gives a final estimate of 10.641 +/- 0.006 eV. PMID- 28877581 TI - Historical Details about the Meat Consumption and Taeniases in Joseon Period of Korea. AB - Previous paleoparasitological studies of Joseon specimens established that the prevalence of Taenia infection was not much different from that of the early 20th century Korean population. As many of taeniases originally diagnosed as Taenia saginata in South Korea were revealed to be actually Taenia asiatica, which share a common intermediate host with T. solium (the pig), Joseon people must have ingested raw pork frequently. However, the current examination of extant Joseon documents revealed that the population ate significant amounts of beef even if the beef ban was enforced; and pork was not consumed as much as we thought. Considering the meat consumption pattern at that time, Joseon people should have been infected by T. saginata more frequently than T. asiatica. This may suggest a low prevalence of T. saginata metacestodes in cattle compared to that of T. asiatica metacestodes in pigs, possibly due to the traditional way of rearing pigs (using human feces). This letter gives us a chance to reconsider the existing preconception about parasitic infections in Korean history though we are still hard to accurately estimate the historical patterns of taeniases at this stage. PMID- 28877583 TI - Leaf LIMS: A Flexible Laboratory Information Management System with a Synthetic Biology Focus. AB - This paper presents Leaf LIMS, a flexible laboratory information management system (LIMS) designed to address the complexity of synthetic biology workflows. At the project's inception there was a lack of a LIMS designed specifically to address synthetic biology processes, with most systems focused on either next generation sequencing or biobanks and clinical sample handling. Leaf LIMS implements integrated project, item, and laboratory stock tracking, offering complete sample and construct genealogy, materials and lot tracking, and modular assay data capture. Hence, it enables highly configurable task-based workflows and supports data capture from project inception to completion. As such, in addition to it supporting synthetic biology it is ideal for many laboratory environments with multiple projects and users. The system is deployed as a web application through Docker and is provided under a permissive MIT license. It is freely available for download at https://leaflims.github.io . PMID- 28877585 TI - Spotlights: Volume 8, Issue 17. PMID- 28877584 TI - Influence of a Modified Atmosphere on the Induction and Activity of Respiratory Enzymes in Broccoli Florets during the Early Stage of Postharvest Storage. AB - Modified atmosphere packaging and controlled atmosphere storage (hypoxia conditions) extend shelf lives of horticultural products by depressing the O2 uptake rate. We investigated the relationship between atmospheres and alternative oxidase (AOX) to cytochrome c oxidase (COX) activities (on the basis of oxygen isotope discrimination) and the relative amounts of two respiratory enzymes, AOX and COX, during the early stage of storage. Broccoli florets, with high O2 uptake rates, were stored under hypoxia and normoxia at 25 degrees C. O2 uptake rates, weight loss, and yellowing of broccoli florets were significantly lower when stored under hypoxia than when stored under normoxia. Significantly more AOX proteins were produced during storage under normoxia, but COX proteins were more consistent than those of AOX proteins. Hypoxia may depress the expression of AOX and prolong the shelf life. Oxygen isotope discrimination was elevated under hypoxia after 50.5 h. AOX production in broccoli was controlled more by changing atmospheres than by COX. PMID- 28877587 TI - Gene therapy renews hope to lower the global rural sickle cell disease burden. PMID- 28877588 TI - What do evaluations tell us about implementing new models in rural and remote primary health care? Findings from a narrative analysis of seven service evaluations conducted by an Australian Centre of Research Excellence. AB - INTRODUCTION: A Centre of Research Excellence (CRE) in Rural and Remote Primary Healthcare was established in 2012 with the goal of providing evidence to inform policy development to increase equity of access to quality health care and the identification of services that should be available to the diverse communities characterising Australia. This article reports on the key findings from seven CRE service evaluations to better understand what made these primary health care (PHC) models work where they worked, and why. METHODS: We conducted a narrative synthesis of 15 articles reporting on seven CRE service evaluations of different PHC models published between 2012 and 2015. RESULTS: Three different contexts for PHC reform were evaluated: community, regional and clinic based. Themes identified were factors that enabled changes to PHC delivery, processes that supported services to improve access to PHC and requirements for service adaptation to promote sustainability. In both Indigenous and mainstream community settings, the active engagement with local communities, and their participation in, or leadership of, shared decision-making was reported across the three themes. In addition, local governance processes, informed by service activity and impact data, enabled these service changes to be sustained over time. The considerations were different for the outreach, regional and clinic services that relied on internal processes to drive change because they did not require the cooperation of multiple organisations to succeed. CONCLUSIONS: The review highlighted that shared decision-making, negotiation and consultation with communities is important and should be used to promote feasible strategies that improve access to community-based PHC services. There is a growing need for service evaluations to report on the feasibility, acceptability and fit of successful service models within context, in addition to reach and effectiveness in order to provide evidence for local dissemination, adaption and implementation strategies. PMID- 28877590 TI - Improved latrine cleanliness through behaviour change and changes in quality of latrine construction: a longitudinal intervention study in rural Burundi. AB - Latrine cleanliness increased in the intervention group compared to the control group (increase from 21 to 31 % of latrines classified as clean in intervention [N = 198] and decrease from 37 to 27 % in control [N = 91]). Improved habitual latrine cleaning lead to latrines being 3.5 times more likely to improve in observed latrine cleanliness (chi2 = 16.36, p < .001) and so did improvements in quality of latrine construction, eg households that had installed a lid were 7.39 times more likely to have a cleaner latrine (chi2 = 4.46, p < .05). Changes in psychosocial factors, namely forgetting, personal norm, satisfaction with cleanliness, explained much of the change in habitual latrine cleaning (adj. r2 = .46). Behaviour change interventions targeting psychosocial factors and quality of latrine construction seem promising to ensure clean and hygienic latrines. PMID- 28877589 TI - Questionnaire-Based Anti-Inflammatory Diet Index as a Predictor of Low-Grade Systemic Inflammation. AB - There is accumulating evidence that diet may be associated with markers of inflammation. We have evaluated if an empirically developed questionnaire-based Anti-Inflammatory Diet Index (AIDI) may predict low-grade systemic chronic inflammation in a Nordic population. The AIDI was developed using a 123-item food frequency questionnaire among 3503 women (56-74 years old) with high-sensitivity C-reactive protein (hsCRP) plasma concentration <20 mg/L. Using Spearman correlations, we identified 20 foods (AIDI-20) statistically significantly related to hsCRP. The median (range) of AIDI-20 was 8 (0-17) scores, and the median concentration of hsCRP in the lowest versus the highest quintile of AIDI 20 (<=6 vs. >=11 scores) varied by 80% (1.8 vs. 1.0 mg/L, respectively). In a multivariable-adjusted linear regression model, women in the highest quintile of AIDI-20 compared with those in the lowest had a 26% (95% confidence interval [CI] 18-33%; p-trend <0.001) lower hsCRP concentration; each 1-score increment in the AIDI-20 was associated with a 0.06 (95% CI 0.04-0.08) mg/L lower hsCRP. The observed association between the AIDI-20 and hsCRP was robust by all hsCRP levels and in subgroups defined by inflammatory-related factors. Our results lead to the hypothesis that the empirically developed questionnaire-based dietary anti inflammatory index may predict low-grade systemic inflammation. Antioxid. Redox Signal. 28, 78-84. PMID- 28877591 TI - Positive correlation between pesticide sales and central nervous system and cardiovascular congenital abnormalities in Brazil. AB - BACKGROUND: This study investigated the association between pesticide exposure in Brazil (2005-2013) with rates of central nervous system (CNS) and cardiovascular system (CVS) congenital abnormalities in 2014. METHOD: An exposure variable was established from data on production and sales of pesticides (kg) per crop area (ha) for 2012 and 2013 years. The Brazilian states were divided into three categories: high, medium, and low pesticide use and rate ratios were estimated for each group of states (CI: 95 %). RESULTS: In 2013 and 2014, the high use group presented a 100 and a 75 % increase, and the medium group a 65 and 23 % increase, respectively, in the risk of CNS and CVS congenital abnormalities at birth, compared to the low use group. CONCLUSION: These findings suggest that pesticide exposure could be associated with increased risk of congenital malformations at birth in Brazil. PMID- 28877592 TI - The Optimal Location to Measure Scapholunate Diastasis on Screening Radiographs. AB - BACKGROUND: Lack of a universally accepted location and normal value limits the utility of measuring scapholunate diastasis. The primary purpose of this study was to define the optimal location to measure the scapholunate gap throughout sequential ligament transections. Secondary purposes were to compare plain radiographs with fluoroscopy and to evaluate interrater reliability in measuring scapholunate diastasis. METHODS: Five cadaver forearms were imaged with intact carpal ligaments and after sequentially transecting the scapholunate, radioscaphocapitate, and scaphotrapezium-trapezoid ligaments. Plain radiographs and static fluoroscopic images were obtained with wrists in neutral and 30 degrees ulnar deviation for each stage. Multiple reviewers performed measurements of the scapholunate interval at 3 separate locations. Mean distances were calculated and pairwise comparisons between groups were made. Intraclass correlation was calculated to determine interrater reliability. RESULTS: Overall, measurements made in the middle of the scapholunate joint had the smallest margins of error for all imaging modalities, ligament disruptions, and wrist positions. For normal wrists, the mean scapholunate measurements were all less than 2.0 mm at the middle of the joint, regardless of imaging modality or wrist position. Fluoroscopy detected significance between more stages of instability than plain radiographs at the middle of the joint. CONCLUSIONS: Measurements in the middle of the scapholunate joint in neutral and 30 degrees of ulnar deviation under fluoroscopic imaging best capture all stages of ligamentous disruptions. Measurements less than 2.0 mm at the middle of the scapholunate interval may be considered within normal range. PMID- 28877593 TI - Is There a Role for MRI in Plantar Heel Pain. AB - INTRODUCTION: There is an increasing trend to investigate plantar heel pain with magnetic resonance imaging (MRI) scan though plantar fasciitis is the most common cause. The purpose of our study was to evaluate the role of MRI in patients presenting with plantar heel pain. METHODS: Case notes and MRI scans of 141 patients with a clinical diagnosis of plantar fasciitis were reviewed retrospectively. There were 98 females and 43 males patients. Fourteen patients had bilateral symptoms. Average age for male patients was 51 years (range = 26-78 years), and for female patients the average age was 52 years (range = 29-76 years). RESULTS: A total of 121 feet had MRI features suggestive of plantar fasciitis. MRI was normal in 32 feet. There was one case of stress fracture of calcaneus and another of a heel fibroma diagnosed on MRI scan. CONCLUSIONS: In our study, MRI scan was normal in 20.7% of the cases; 1.3% had a diagnosis other than plantar fasciitis but no sinister pathology. We therefore conclude that MRI scan is not routinely indicated and key is careful clinical assessment. LEVELS OF EVIDENCE: Therapeutic, Level IV: Retrospective, Case series. PMID- 28877594 TI - A Medial Malleolar "Fleck Sign" May Predict Ankle Instability in Ligamentous Supination External Rotation Ankle Fractures. AB - BACKGROUND: Ankle joint stability dictates treatment in ligamentous supination external rotation ankle injuries (LSERAI). Investigation of the medial structures that support the ankle mortise is critical, and a small avulsion fracture, or "fleck", of the medial malleolus is occasionally encountered. This study aimed to assess the utility of this medial malleolus fleck sign (MMFS) in diagnosing instability requiring surgery in LSERAI. METHODS: This retrospective observational study examined 166 LSERAI at a single level I trauma center. A standardized diagnostic and treatment protocol for ankle fractures was followed. LSERAI at presentation were reported as having a normal, dynamically wide, or statically wide medial clear space. Patient demographics, MMFS characteristics, and the use of operative management were recorded. RESULTS: MMFS incidence in the cohort was 16 (10%) of 166 and was present in 25% of patients with unstable LSERAI. Fifteen (94%) of 16 patients with a MMFS were deemed to have an unstable LSERAI (P < .005). MMFS had a 25% sensitivity and 99% specificity in diagnosing an unstable LSERAI. For the subgroup of patients without a statically wide medial clear space, MMFS had a 50% sensitivity and 99% specificity in determining instability. CONCLUSION: A MMFS may be indicative of an unstable LSERAI. With previous MRI studies demonstrating complete deltoid disruption in unstable LSERAI, we deduce the MMFS may be associated with extensive deltoid incompetence. The MMFS may help to diagnose a complete deltoid injury in LSERAI with a normal medial clear space, which could influence treatment and reduce patient morbidity, radiation exposure, and healthcare costs. LEVELS OF EVIDENCE: Level III: Retrospective Cohort Study. PMID- 28877595 TI - Predicting Coronary Atherosclerotic Plaque Burden From Clinical Parameters: Bringing Old Knowledge in the Game. PMID- 28877596 TI - What the human sperm methylome tells us. AB - AIM: To characterize the sperm methylome in semen samples from 19 donors with proven fertility. MATERIALS & METHODS: Bisulfite-converted sperm DNA was hybridized on the HumanMethylation450 Infinium BeadChip platform. CpG fluorescence intensities were extracted and converted to beta-values. RESULTS: The sperm methylome is highly homogeneous and hypomethylated. Genes with hypomethylated promoters are ontologically associated to biological functions related to spermatogenesis and embryogenesis. Sex chromosomes are the most hypomethylated chromosomes, supporting data that indicated their essential role in spermatogenesis. A total of 94 genes are resistant to demethylation, being strong candidates for transgenerational inheritance. CONCLUSION: Spermatozoa carry a homogeneous methylation profile that is a footprint of past events (spermatogenesis), is designed to facilitate future events (embryogenesis) and has a possible influence in the adult life (transgenerational effects). PMID- 28877597 TI - Acute Onset of Bilateral Lower Extremity Weakness and Unsteady Gait in a Toddler. PMID- 28877598 TI - Resident Documentation of Social Determinants of Health: Effects of a Teaching Tool in the Outpatient Setting. AB - Social determinants of health (SDH) significantly affect the health of children and thus, screening is important in pediatric primary care. We assessed the use of a formal social history taking tool after a 2-phase intervention. The first phase (P1) was a teaching module describing SDH and community resources and the second phase (P2) consisted of visual reminders to use the tool. Patient charts (n = 322) were reviewed pre- and postintervention. Residents had higher documentation rates of Women, Infants, and Children (WIC) program use and housing subsidies at post-P1 and at post-P(1 + 2) (WIC, P = .01 and P = .03, respectively; housing, P = .02 and P = .04, respectively), and higher documentation rates of food stamp utilization at post-P(1 + 2) ( P = .04), as compared with baseline. Implementation of a simple teaching tool in the outpatient setting enabled residents to document income benefits and housing. Further studies should be done to evaluate effective teaching methods to elicit other important SDH. PMID- 28877599 TI - Acceptability of a Salon-Based Intervention to Promote Colonoscopy Screening Among African American Women. AB - African American women have the highest colorectal cancer incidence and mortality rates among women of any race/ethnicity in the United States. Colonoscopy screening is an efficacious procedure for the prevention and early detection of colorectal cancer, making it a promising tool in the effort to eliminate colorectal cancer disparities. Toward that end, the present qualitative study sought to assess acceptability of and preferences for a beauty salon-based intervention to promote colonoscopy screening among African American women. A total of 11 focus groups were conducted: 6 with staff from African American serving salons ( n = 3 with salon owners, n = 3 with salon stylists) and 5 with African American salon clients. Theory-guided focus group questions were used to explore participants' beliefs, interests, and preferences associated with the proposed intervention. Results indicated that, across all subgroups, participants were highly supportive of the idea of a salon-based intervention to promote colonoscopy screening among African American women, citing reasons such as the commonplace nature of health discussions in salons and the belief that, with proper training, stylists could effectively deliver colorectal cancer-related health information to their clients. The greatest differences between salon staff and clients were found with respect to the specifics of the intervention. Staff focused more heavily on content-related issues, such as the specific information that should be stressed in the intervention, whereas clients focused largely on process-related issues, such as the preferred intervention formats and how stylists should present themselves to clients. The findings from this study offer both encouragement and important groundwork for the development of a salon-based, stylist-delivered intervention to promote colonoscopy screening among African American women. PMID- 28877600 TI - Technique for Intramedullary Stabilization of Ulnar Neck Fractures. AB - BACKGROUND: Distal ulna fractures at the ulnar neck can be seen in association with distal radius fractures, and multiple techniques have been described to address the ulnar neck component of these injuries. We have found that treatment of ulnar neck fractures can be challenging in terms of anatomy and fracture fixation. We present a new percutaneous fixation technique for ulnar neck fractures commonly seen with distal radius fractures. TECHNIQUE: Fixation of the ulnar neck fracture is performed after fixation of the distal radius fracture. Our technique uses anterograde intramedullary fixation to stabilize the fracture with a 1.6-mm (0.062 inch) Kirschner wire or a commercially available metacarpal fixation intramedullary nail. The fixation is introduced into the intramedullary space of the ulnar shaft 4 to 6 cm proximal to the fracture at a separate surgical site along the subcutaneous border of the ulna. The fixation is also supported with a sugar-tong splint for the first few weeks after surgery and requires removal of the ulnar implant approximately 10 weeks after implantation. CONCLUSION: Our technique utilizes a percutaneous approach with minimal fracture exposure. It provides a relatively simple and reproducible method to address ulnar neck fractures commonly seen in association with distal radial fractures. PMID- 28877601 TI - Partner unmitigated communion moderates communal coping benefits in type 2 diabetes. AB - The study goal was to determine whether partner's level of unmitigated communion moderated the relation of partner communal coping to patient health. Couples in which one person was recently diagnosed with type 2 diabetes ( n = 123) were interviewed separately and asked to discuss a diabetes-related problem. Communal coping behavior (from videotaped discussions) interacted with partner communal coping, such that partner communal coping was related to lower patient distress, higher patient self-efficacy, and higher patient medication adherence only when partners scored lower on unmitigated communion. The extent to which perceived emotional responsiveness and overprotective behavior mediated these relations was explored. PMID- 28877602 TI - "Hi Mommy": Parental Preferences of Greetings by Medical Staff. AB - The therapeutic alliance between pediatricians and parents begins at the initial encounter. The manner in which pediatricians greet family members influences this relationship. This study evaluated whether parents are addressed using generic titles and investigated perceptions of parents regarding how they are addressed by medical staff. Written surveys of 137 parents of pediatric inpatients collected opinions about greetings during medical encounters. Parents were asked if they have been addressed as Mom/Dad/Mommy/Daddy during past medical encounters and which generic titles they would prefer. Using a Likert-type scale, the parents' perceptions of various salutations were assessed and compared. In this sample, 86% of parents were previously called Mom/Dad/Mommy/Daddy. Parents preferred to be addressed as Mom or Dad over other generic titles. Many disliked being addressed as Mommy/Daddy, Ma'am/Sir, or without a name, suggesting that providers should avoid the use of these salutations. PMID- 28877603 TI - The Use of Psychosocial Services Post Hand and Upper Limb Injury and Trauma: A Pilot Study. AB - BACKGROUND: Research demonstrates that hand injuries may cause psychological difficulties. To enhance recovery, therapists must provide appropriate referrals. The purpose of this study was to explore the use of psychosocial services by occupational therapists (OTs) and certified hand therapists (CHTs) post hand and upper limb injury or trauma. METHODS: A quantitative survey design was implemented using a self-made questionnaire, which consisted of questions regarding demographic information, types and frequency of hand and upper limb injuries, psychiatric diagnoses, frequency of psychosocial service referrals, frames of references used, types of psychosocial assessments and interventions employed, and barriers to psychosocial services. The questionnaire was randomly distributed to 29 therapists. RESULTS: The most frequently recorded frame of reference was the Biomechanical. Only 17.2% participants implemented psychosocial assessments. Sixteen of the 29 participants referred to 9 possible psychosocial services; however, majority of referrals were "occasionally." OTs specialized in mental health, behavioral specialists, and social workers were recorded with the least amount of referrals. A Spearman rank correlation found a weak, but significant inverse relationship between referrals by therapists and years of experience as an OT or CHT (-0.322 and -0.351, P < .05, respectively). CONCLUSIONS: Therapists appear to be biomechanically oriented which may impact outcomes. An inverse correlation was found where the less experience participants had, the more likely they were to refer to psychosocial services. The results emphasized the lack of psychosocial assessments, interventions, and referral services being used by therapists. Further education to therapists, third parties, and other health professionals is warranted. PMID- 28877604 TI - The Relative Contribution to Small Finger Abduction of the Ulnar Versus Radial Slip of the EDM: Implications for Tendon Transfers. AB - BACKGROUND: The extensor digiti minimi (EDM) tendon is commonly divided into a radial slip (EDM-R) and an ulnar slip (EDM-U). To our knowledge, the degree to which each EDM slip concomitantly abducts the small finger with active extension has not been formally tested. This study sought to characterize the comparative contributions of finger abduction inherent to each slip of the EDM to observe the sequelae of active small finger extension following transfer of the contralateral slip. METHODS: Eighteen fresh-frozen cadaveric hands were used in this study. Starting with the hand in resting position, a controlled traction of 10 N was applied to each slip of the EDM tendon. The range of small finger abduction with respect to the fixed ring finger was recorded utilizing infrared reflective markers tracked through the range of motion using a digital video camera. RESULTS: The mean abduction of the small finger when the radial slip of the EDM tendon was tested was 13.33 degrees (95% confidence interval [CI]: 10.10 degrees -16.55 degrees ), which was significantly different ( P <= .001) than small finger abduction produced by the ulnar slip of the EDM, with a mean of 23.72 degrees (95% CI: 19.40 degrees -28.04 degrees ). CONCLUSIONS: Given the fact that the ulnar slip of the EDM tendon is shown to be the major contributor of aberrant abduction with active small finger extension, as traction on this slip produces almost twice as much abduction as the radial slip, the EDM-U is the ideal donor graft with respect to tendon transfers of the EDM. PMID- 28877605 TI - Obesity Paradox in Patients With Deep Venous Thrombosis. AB - We aimed to investigate the association between obesity and deep venous thrombosis (DVT) in a country with a high prevalence of obesity. This is a retrospective cohort study of patients who presented with DVT between 2008 and 2012. Data were analyzed and compared based on body mass index (BMI), and patients were classified into normal (<25), overweight (>=25 to <30), obese I (30 to <35), obese II (35 to <40), and obese III (>=40). Among 662 patients with DVT, 28% were overweight and 49% were obese. The mean age was 50.3 (16.5) years, and 51% were females. Diabetes mellitus and prior venous thromboembolism were significantly higher among obese patients. History of malignancy was more common in nonobese patients. Protein S and antithrombin III deficiency and hyperhomocysteinemia were more prevalent among morbid obese patients. Also, obese patients had higher incidence of thrombosis in the distal veins ( P = .03). Warfarin use and long-term therapy were more frequent in obese than nonobese. Postthrombotic syndrome was comparable in obese and nonobese groups. Recurrent DVT was higher in obese I ( P < .01), whereas mortality rates were greater in nonobese groups ( P = .001). Malignancy, diabetes mellitus, and common femoral vein involvement were predictors of mortality, whereas BMI >=30 was the predictor of survival. Cox regression models showed that after adjusting for age, sex, pulmonary embolism, and duration of warfarin treatment, BMI >=40 had better survival (hazard ratio: 0.177, 95% confidence interval: 0.045-0.691, P = .013). There is a significant association between obesity and DVT. Obese patients have characteristic risk factors and better survival. This obesity paradox needs further studies to assess its clinical and pharmacotherapeutic implications. PMID- 28877606 TI - Discordance Between VASP Phosphorylation and Platelet Aggregation in Defining High On-Clopidogrel Platelet Reactivity After ST-Segment Elevation Myocardial Infarction. AB - To investigate potential clinical characteristics associated with discordance between platelet vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) flow cytometry (FCM) assay and light transmission aggregometry (LTA) in defining high on-clopidogrel platelet reactivity (HPR) after ST-segment elevation myocardial infarction (STEMI). In this study, platelet responsiveness was measured by the above 2 methods simultaneously on day 1 and on day 6 of STEMI onset in 90 consecutive patients who underwent primary percutaneous coronary intervention. The FCM-derived platelet reactivity index and LTA-derived platelet aggregation rate were both significantly reduced after dual antiplatelet therapy on day 6. Multiple variable-adjusted logistic regression analysis revealed that smoking (odds ratio [OR]: 4.507, 95% confidence interval [CI]: 1.123-18.09, P = .034) and onset-to-admission time (per 1 hour increase, OR: 1.196, 95% CI: 1.023 1.398, P = .025) both were independent predictors for the discordance between the 2 methods. Additionally, improved correlation and concordance was observed in nonsmokers compared with smokers. Our data show that smoking and prolonged onset to-admission time are associated with discordance between platelet VASP-P and LTA in defining HPR after STEMI, which should be considered when planning personalized antiplatelet therapy. PMID- 28877607 TI - Levels of Matrix-Degrading Enzymes and Lubricin in Patients With Degenerative Joint Disease Requiring Arthroplasty. AB - Total joint arthroplasty (TJA) of the hip or knee (THA and TKA) is the primary surgical intervention for individuals with degenerative joint disease (DJD). Although it is commonly thought that shear force on the joint causes the degradation of articular cartilage, it is possible that there are other factors that contribute to the progression of DJD. It is plausible that specific enzymes that degrade the joint are upregulated, or conversely, there is downregulation of enzymes critical for joint lubrication. The aim of this study is to profile collagenase-1, elastase, heparanase, and lubricin levels in patients undergoing TJA in order to determine potential preexisting dysregulation that contributes to the pathogenesis of DJD. Deidentified blood samples were obtained from patients undergoing TJA 1 day pre- and 1 day postoperatively. Plasma samples were analyzed using enzyme-linked immunosorbent assay kits for elastase, collagenase-1, heparanase, and lubricin. In comparison to healthy controls, there were significant increases in circulating collagenase-1, elastase, and lubricin levels in both the preoperative and postoperative samples. There were no significant differences in heparanase levels in the preoperative or postoperative samples. Comparing the preoperative versus postoperative patient samples, only lubricin demonstrated a significant change. The results of this study confirm that patients undergoing TJA have preexisting alterations in the levels of matrix degrading enzymes and lubricin. The alterations observed in this study may provide insight into the pathogenesis of DJD. PMID- 28877608 TI - Genome-wide integrative analysis identified SNP-miRNA-mRNA interaction networks in peripheral blood mononuclear cells. AB - AIM: To detect SNP-miRNA-mRNA interaction networks and to elucidate miRNA mediated regulation effects on mRNA expression. MATERIALS & METHODS: In human peripheral blood mononuclear cells of 43 females, SNP-miRNA-mRNA interaction networks were established through an integrative analysis. Then causal inference test was followed to detect miRNA-mediated effects on mRNA expressions. RESULTS: About 167 trios corresponding to 56 SNPs, 20 miRNAs and 47 target-mRNAs have the SNP-miRNA-mRNA interactions, but only 22 trios have miRNA-mediated effects between SNP and mRNA. For the three miRNAs (hsa-miR-222-3p, hsa-miR-181b-5p and hsa-miR-106b-5p), each mediates at least four correlations between SNP and mRNA. The mRNAs in interaction play an important role in energy metabolism, cellular and tissue homeostasis. CONCLUSION: This study represents the first effort of constructing an integrative interaction network of SNP-miRNA-mRNA and miRNA mediated regulatory effects that provide helpful clues for future investigations of peripheral blood mononuclear cell-related physiological process and immunological diseases. PMID- 28877609 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of advanced epithelial and recurrent ovarian carcinoma: a single center experience. AB - BACKGROUND: With standard treatment of epithelial ovarian cancer (EOC), prognosis is very poor. The aim of this study is to show early and late results in patients who underwent cytoreductive surgery and intraperitoneal chemotherapy. PATIENTS AND METHODS: This was a retrospective single centre study. All patients with advanced and recurrent ovarian cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) or modified early postoperative intraperitoneal chemotherapy (EPIC) were included in the study. RESULTS: In the period 1995-2014, 116 patients were treated, 55 with primary EOC and 61 with recurrent EOC. The mean age was 59 years (26-74). Statistically, median survival time was significantly longer in the group with primary advanced cancer of the ovary (41.3 months) compared to relapsed ovarian cancer (27.3 months). Survival for the primary EOC was 65 and 24% at 3 and 5 years, respectively. Survival for recurrent EOC was 33 and 16% at 3 and 5 years, respectively. Mortality was 1/116 (0.8%). Morbidity was 11/116 (9.5%). Peritoneal cancer index (PCI) was <=20 in 59 (51%) patients and statistically, their average survival was significantly longer than in the group of 57 (49%) patients with PCI >20 (p = 0.014). CONCLUSIONS: In advanced or recurrent EOC, a curative therapeutic approach was pursued that combined optimal cytoreductive surgery and intraperitoneal chemotherapy. PCI and timing of the intervention (primary or recurrent) were the strongest independent prognostic factors. PMID- 28877610 TI - The tumor suppressive role of inhibin betaA in diffuse large B-cell lymphoma. AB - INHBA (inhibin betaA), a subunit of a ligand of the transforming growth factor beta superfamily, is known to play diverse roles in various solid tumors. However, its role in hematologic malignancies remains unexplored. Here, we investigated the function of INHBA in diffuse large B-cell lymphoma (DLBCL). Both mRNA and protein levels of INHBA were significantly downregulated in primary DLBCL tissues, irrespective of germinal center B-cell-like (GCB) or non-GCB subtype, compared to those in benign tonsils. The low level of INHBA in patients with de novo DLBCL was correlated with reduced overall and progression-free survival. Ectopic expression of INHBA in DLBCL cell lines (OCI-Ly01 and SUDHL-10) resulted in reduced cell proliferation, increased spontaneous apoptosis and arrested cell cycle in vitro and suppressed xenograft tumor growth in vivo. Moreover, INHBA enhanced the chemosensitivity of DLBCL cells. Thus, our results provide novel evidence that INHBA functions as a tumor suppressor in DLBCL. PMID- 28877611 TI - An update on behavioral treatments in migraine - current knowledge and future options. AB - INTRODUCTION: Besides pharmacological and interventional treatments a variety of non-medical therapeutic options exist for migraine, which has largely been derived from behavioral therapy. Areas covered: For our update we collected available studies via PubMed searches. This review highlights that already consulting of the patient is able to reduce the frequency of migraine attacks. Relaxation techniques, especially progressive muscle relaxation, and various types of biofeedback are effective, as is the implementation of cognitive behavioral therapy. However, recent reviews also point to some existing inconsistencies and methodological limitations. The advent of modern information technology based approaches (e.g. online therapy, smartphone applications) further advanced the arsenal of behavioral treatment regimes. The combination of behavioral treatment options and the combination with pharmacotherapy lead to additive effects. In modern multidisciplinary treatment approaches, behavioral therapy is an indispensable component. Expert commentary: Behavioral treatment in prophylaxis of migraine is as effective as pharmacological treatment with additional effects when pharmacological and behavioral treatment is applied in combination. Novel treatment approaches using online technology and electronic devices offer interesting options that will spread more in the future. PMID- 28877612 TI - The role of MRI in the early evaluation of lung microwave ablation. AB - PURPOSE: To retrospectively investigate the role of a contrast enhanced MRI (ceMRI) performed 24 h after a microwave ablation (MWA) of the lung, in predicting local tumour progression (LTP) and detecting complications compared to an unenhanced CT. MATERIAL AND METHODS: Forty-nine patients who underwent MWA of 77 lung metastases between 2008 and 2015 were included. All patients received an unenhanced chest CT and a ceMRI (including T2 and ceT1) 24 h after MWA. The conspicuities of the peripheral rim and the ablated tumour were scored using 1-3 scales and compared between examinations. The safety margin was measured directly (both scores >=2) and indirectly using a subtraction method. The ability of each imaging modality to predict LTP based on safety margin width was analysed using receiver operating characteristic curves. The MRI ability to detect a pneumothorax was compared to CT. RESULTS: The peripheral rim was best visualised on T2 followed by T1 and CT. The tumour was best visualised on CT, followed by T1 and T2. Direct safety margin measurement was possible on CT, ceT1 and T2 in 68.8%, 64.9% and 27.3% of cases, respectively. Direct CT (AUC = 0.77) and ceT1 (AUC = 0.76) measurements had better diagnostic performance than indirect CT (AUC = 0.72), ceT1 (AUC = 0.70) and T2 (AUC = 0.69) measurements. The MRI sensitivity and specificity for pneumothorax were 60.8% and 87.0%, respectively. Only one pneumothorax >1 cm was missed. CONCLUSIONS: A ceMRI performed 24 h after MWA of lung tumours has a similar ability to predict LTP and detect important complications as a CT has. PMID- 28877614 TI - Recovery from depression: a systematic review of perceptions and associated factors. AB - BACKGROUND: Despite extensive literature examining perceptions of recovery from severe mental illness, literature focusing on recovery from depression in adults is limited. AIM: Systematically review the existing literature investigating patients' and clinicians' perceptions of, and factors associated with, recovery from depression. METHOD: Studies investigating perceptions of, and factors associated with, recovery from depression in adults were identified through database searches. Studies were assessed against inclusion criteria and quality rating checklists. RESULTS: Fourteen studies met the inclusion criteria. Recovery from depression is perceived as a complex, personal journey. The concept of normalised, biomedical definitions of recovery is not supported, with the construction of self and societal gender expectations identified by women as central to recovery. Recovery from depression was associated with higher levels of perceived social support and group memberships. A range of factors are identified as influencing recovery. However, physicians and patients prioritise different factors assessing what is important in being "cured" from depression. CONCLUSIONS: Recovery from depression is perceived by patients as a complex, personal process, influenced by a range of factors. However, greater understanding of clinicians' perceptions of client recovery from depression is essential to inform clinical practice and influence future research. PMID- 28877613 TI - Odontogenic sinusitis: a comprehensive review. AB - Odontogenic sinusitis (OS) is a highly prevalent, underappreciated and underdiagnosed disease that has been known for over 100 years. Apical periodontitis, periodontal disease and iatrogenic extrusion of foreign bodies into the sinus are the main causes of OS. Although the prevalence of sinus pathosis of dental origin is still controversial, otolaryngologists recognize that in the presence of recalcitrant sinusitis, a dental origin should be considered and properly treated. Currently, cone-beam computed tomography is the gold-standard imaging technique to assess the relationship between dental conditions, especially apical periodontitis and sinus diseases, and whenever this association is detected, patients should be seen by both a dentist and an otolaryngologist in order to achieve complete recovery. This article reviews the current concepts regarding the definitions, diagnosis and management of OS from a clinical point of view. PMID- 28877615 TI - Clinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, with a focus on regression. AB - Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein-Barr virus (EBV) infection (p = .00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors. PMID- 28877616 TI - Metabolic effects of breastfeeding in women with previous gestational diabetes diagnosed according to the IADPSG criteria. AB - BACKGROUND: Some studies have already investigated about the short-term favorable metabolic effects of breastfeeding in women with previous gestational diabetes mellitus (GDM). AIM: The aim of our study is to confirm whether the positive effects reported are maintained in the larger cohorts of patients with mild form of gestational diabetes mellitus (GDM) because recently diagnosed according to IADPSG criteria. MATERIALS AND METHODS: This retrospective study includes 97 evaluable consecutive women with prior GDM who have the follow-up oral glucose tolerance test at least 3 months after delivery. Fasting and 2-h plasma glucose values, homeostasis model assessment (HOMA-IR), total cholesterol, and triglycerides were obtained in pregnancy and during the post-partum control. RESULTS: These patients were divided in 81 (83.5%) who lactate until 3 months and 16 (16.5%) who did not lactate. During pregnancy, there are no significant differences between the two groups for age, BMI, fasting and 2-h plasma glucose values, HOMA-IR, total cholesterol and triglycerides. At the postpartum control, we have at univariate analysis significant differences for all these parameters except total cholesterol. After adjustment for confounders we still have, in the breastfeeding group, HOMA-IR reduction (OR 0.370; 95% CI 0.170-0.805; p < .01) as significant independent variable, whose improvement is the most acknowledged important factor for the prevention of abnormal glucose tolerance later in life. CONCLUSION: These encouraging results confirm our determination to warmly advice the women affected by GDM to breastfeeding at least for 3 months. PMID- 28877617 TI - Workforce flexibility - in defence of professional healthcare work. AB - Purpose The desirability of having a more flexible workforce is emphasised across many health systems yet this goal is as ambiguous as it is ubiquitous. In the absence of empirical studies in healthcare that have defined flexibility as an outcome, the purpose of this paper is to draw on classic management and sociological theory to reduce this ambiguity. Design/methodology/approach The paper uses the Weberian tool of "ideal types". Key workforce reforms are held against Atkinson's model of functional flexibility which aims to increase responsiveness and adaptability through multiskilling, autonomy and teams; and Taylorism which seeks stability and reduced costs through specialisation, fragmentation and management control. Findings Appeals to an amorphous goal of increasing workforce flexibility make an assumption that any reform will increase flexibility. However, this paper finds that the work of healthcare professionals already displays most of the essential features of functional flexibility but many widespread reforms are shifting healthcare work in a Taylorist direction. This contradiction is symptomatic of a failure to confront inevitable trade-offs in reform: between the benefits of specialisation and the costs of fragmentation; and between management control and professional autonomy. Originality/value The paper questions the conventional conception of "the problem" of workforce reform as primarily one of professional control over tasks. Holding reforms against the ideal types of Taylorism and functional flexibility is a simple, effective way the costs and benefits of workforce reform can be revealed. PMID- 28877618 TI - A value-based taxonomy of improvement approaches in healthcare. AB - Purpose The concept of value is becoming increasingly fashionable in healthcare and various improvement approaches (IAs) have been introduced with the aim of increasing value. The purpose of this paper is to construct a taxonomy that supports the management of parallel IAs in healthcare. Design/methodology/approach Based on previous research, this paper proposes a taxonomy that includes the dimensions of view on value and organizational focus; three contemporary IAs - lean, value-based healthcare, and patient-centered care are related to the taxonomy. An illustrative qualitative case study in the context of psychiatric (psychosis) care is then presented that contains data from 23 interviews and focuses on the value concept, IAs, and the proposed taxonomy. Findings Respondents recognized the dimensions of the proposed taxonomy and indicated its usefulness as support for choosing and combining different IAs into a coherent management model, and for facilitating dialog about IAs. The findings also suggested that the view of value as "health outcomes" is widespread, but healthcare professionals are less likely than managers to also view value as a process. Originality/value The conceptual contribution of this paper is to delineate some important characteristics of IAs in relation to the emerging "value era". It also highlights the coexistence of different IAs in healthcare management practice. A taxonomy is proposed that can help managers choose, adapt, and combine IAs in local management models. PMID- 28877619 TI - "That was a good shift". AB - Purpose The purpose of this paper is to investigate a boundary spanning, interprofessional collaboration between advanced practice nurses (APNs) and junior doctors to support junior doctors' learning and improve patient management during the overtime shift. Design/methodology/approach A mixed methods evaluation of an intervention in an adult tertiary referral hospital, to enhance interprofessional collaboration on overtime shifts. Phase 1 compared tasks and ward rounds on 86 intervention shifts with 106 "regular" shifts, and examined the effect on junior doctor patient management testing a model using regression techniques. Phase 2 explored the experience of the intervention for stakeholders. 91 junior doctors participated (89 percent response rate) on 192 overtime shifts. Junior doctors, APNs and senior medical professionals/administrators participated in interviews. Findings The intervention was associated with an increase in self initiated ward rounds by junior doctors, partially explained by junior doctors completing fewer tasks skilled nurses could also complete. The intervention significantly reduced doctors' engagement in tasks carried over from day shifts as well as first year (but not more experienced) junior doctors' total tasks. Interviews suggested the initiative reduced junior doctors' work pressure and promoted a safe team climate, situation awareness, skills, confidence, and well being. Originality/value Junior doctors overtime shifts (5 p.m. to 11 p.m.) are important, both for hospitals to maintain patient care after hours and for junior doctors to learn and develop independent clinical decision making skills. However, junior doctors frequently report finding overtime shifts challenging and stressful. Redesigning overtime shifts to facilitate interprofessional collaboration can improve patient management and junior doctors' learning and well-being. PMID- 28877620 TI - They did not start the fire: reviewing and resolving the issue of physician stress and burnout. AB - Purpose Physician stress and burnout is a serious and common concern in healthcare, with over half of physicians in the USA meeting at least one criterion for burnout. The paper aims to discuss these issues. Design/methodology/approach A review on current state of physician stress and burnout research, from 2008 to 2016, was undertaken. A subsequent perspective paper was shaped around these reviews. Findings Findings reveal research strength in prevalence and incidence with opportunities for stronger intervention studies. While descriptive studies on causes and consequences of physician burnout are available, studies on interventions and prevention of physician burnout are lacking. Future research on physician stress and burnout should incorporate intervention studies and take care to avoid limitations found in current research. Accountability and prevention of physician burnout is the responsibility of the healthcare industry as a whole, and organizational strategies must be emphasized in future research. Originality/value The value of this research comes in the original comprehensive review, international inclusion and succinct summary of physician burnout research and strategies. PMID- 28877621 TI - Emerging hybridity: comparing UK healthcare regulatory arrangements. AB - Purpose Healthcare regulation is one means to address quality challenges in healthcare systems and is carried out using compliance, deterrence and/or improvement approaches. The four countries of the UK provide an opportunity to explore and compare different regulatory architecture and models. The purpose of this paper is to understand emerging regulatory models and associated tensions. Design/methodology/approach This paper uses qualitative methods to compare the regulatory architecture and models. Data were collected from documents, including board papers, inspection guidelines and from 48 interviewees representing a cross section of roles from six organisational regulatory agencies. The data were analysed thematically using an a priori coding framework developed from the literature. Findings The findings show that regulatory agencies in the four countries of the UK have different approaches and methods of delivering their missions. This study finds that new hybrid regulatory models are developing which use improvement support interventions in parallel with deterrence and compliance approaches. The analysis highlights that effective regulatory oversight of quality is contingent on the ability of regulatory agencies to balance their requirements to assure and improve care. Nevertheless, they face common tensions in sustaining the balance in their requirements connected to their roles, relationships and resources. Originality/value The paper shows through its comparison of UK regulatory agencies that the development and implementation of hybrid models is complex. The paper contributes to research by identifying three tensions related to hybrid regulatory models; roles, resources and relationships which need to be managed to sustain hybrid regulatory models. PMID- 28877622 TI - Are we nearly there yet? A study of the English National Health Service as professional bureaucracies. AB - Purpose The purpose of this paper is to explore issues of medical engagement in the management and leadership of health services in the English National Health Service (NHS). The literature suggests that this is an important component of high performing health systems, although the NHS has traditionally struggled to engage doctors and has been characterised as a professional bureaucracy. This study explored the ways in which health care organisations structure and operate medical leadership processes to assess the degree to which professional bureaucracies still exist in the English NHS. Design/methodology/approach Drawing on the qualitative component of a research into medical leadership in nine case study sites, this paper reports on findings from over 150 interviews with doctors, general managers and nurses. In doing so, the authors focus specifically on the operation of medical leadership in nine different NHS hospitals. Findings Concerted attention has been focussed on medical leadership and this has led to significant changes to organisational structures and the recruitment and training processes of doctors for leadership roles. There is a cadre of doctors that are substantially more engaged in the leadership of their organisations than previous research has found. Yet, this engagement has tended to only involve a small section of the overall medical workforce in practice, raising questions about the nature of medical engagement more broadly. Originality/value There are only a limited number of studies that have sought to explore issues of medical leadership on this scale in the English context. This represents the first significant study of this kind in over a decade. PMID- 28877623 TI - Management challenges in British Columbia's healthcare system. AB - Purpose The purpose of this paper is to identify the operational and management challenges in a globally budgeted, regionalized healthcare system and their implications for public service. Design/methodology/approach Concentrating on British Columbia's regional health authorities (RHAs) and hospitals, this study utilized data from interviews of key informants, documents (histories, legislation, agreements between RHAs and provincial government, and RHA organizational charts), news reports, and participant observation at board meetings. Findings Challenges encountered by the managers include accommodating powerful stakeholders (elected officials, providers, and organized publics), adhering to fixed budgets, obtaining capital from public sources, and adjusting to government turnover. In response, the managers engage in balancing priorities of stakeholders, shifting of resources within and across sites and operating units, and working strategically with the capital allocation process. Responses of managers to these challenges have promoted stability but raise concerns about attaining the system's goals. Practical implications Management challenges and potential patterns of response should be considered in assessing the options for health system reforms. Many countries periodically reorganize their healthcare systems, and recognition of potential management challenges can contribute to the achievement of objectives sought in these reforms. Originality/value Although studies have demonstrated that management affects the implementation of public programs in several areas, little research has focused on the relationships between features of health systems, management responses, and potential outcomes. PMID- 28877624 TI - Work motivation among healthcare professionals. AB - Purpose The purpose of this paper is to explore work motivation among professionals at well-functioning primary healthcare centers subject to a national healthcare reform which include financial incentives. Design/methodology/approach Five primary healthcare centers in Sweden were purposively selected for being well-operated and representing public/private and small/large units. In total, 43 interviews were completed with different medical professions and qualitative deductive content analysis was conducted. Findings Work motivation exists for professionals when their individual goals are aligned with the organizational goals and the design of the reform. The centers' positive management was due to a unique combination of factors, such as clear direction of goals, a culture of non-hierarchical collaboration, and systematic quality improvement work. The financial incentives need to be translated in terms of quality patient care to provide clear direction for the professionals. Social processes where professionals work together as cohesive groups, and provided space for quality improvement work is pivotal in addressing how alignment is created. Practical implications Leaders need to consistently translate and integrate reforms with the professionals' drives and values. This is done by encouraging participation through teamwork, time for structured reflection, and quality improvement work. Social implications The design of the reforms and leadership are essential preconditions for work motivation. Originality/value The study offers a more complete picture of how reforms are managed at primary healthcare centers, as different medical professionals are included. The value also consists of showing how a range of aspects combine for primary healthcare professionals to successfully manage external reforms. PMID- 28877625 TI - Bricks-and-mortar and patient safety culture. AB - Purpose Building a new hospital requires a major investment in capital infrastructure. The purpose of this paper is to investigate the impact of bricks and-mortar on patient safety culture before and two years after the move of a large tertiary hospital to a greenfield site. The difference in patient safety perceptions between clinical and non-clinical staff is also explored. Design/methodology/approach This research uses data collected from the same workforce across two time periods (2013 and 2015) in a large Australian healthcare service. Validated surveys of patient safety culture ( n=306 and 246) were analysed using descriptive and inferential statistics. Findings Using two way analysis of variance, the authors found that perceived patient safety culture remains unchanged for staff despite a major relocation and upgrade of services and different perceptions of patient safety culture between staff groups remains the same throughout change. Practical implications A dramatic change in physical context, such as moving an entire hospital, made no measurable impact on perceived patient safety culture by major groups of staff. Improving patient safety culture requires more than investment in buildings and infrastructure. Understanding differences in professional perspectives of patient safety culture may inform organisational management approaches, and enhance the targeting of specific strategies. Originality/value The authors believe this to be the first empirically based paper that investigates the impact of a large investment into hospital capital and a subsequent relocation of services on clinical and non clinical staff perceptions of patient safety culture. PMID- 28877626 TI - Tumor-associated macrophages, nanomedicine and imaging: the axis of success in the future of cancer immunotherapy. AB - The success of any given cancer immunotherapy relies on several key factors. In particular, success hinges on the ability to stimulate the immune system in a controlled and precise fashion, select the best treatment options and appropriate therapeutic agents, and use highly effective tools to accurately and efficiently assess the outcome of the immunotherapeutic intervention. Furthermore, a deep understanding and effective utilization of tumor-associated macrophages (TAMs), nanomedicine and biomedical imaging must be harmonized to improve treatment efficacy. Additionally, a keen appreciation of the dynamic interplay that occurs between immune cells and the tumor microenvironment (TME) is also essential. New advances toward the modulation of the immune TME have led to many novel translational research approaches focusing on the targeting of TAMs, enhanced drug and nucleic acid delivery, and the development of theranostic probes and nanoparticles for clinical trials. In this review, we discuss the key cogitations that influence TME, TAM modulations and immunotherapy in solid tumors as well as the methods and resources of tracking the tumor response. The vast array of current nanomedicine technologies can be readily modified to modulate immune function, target specific cell types, deliver therapeutic payloads and be monitored using several different imaging modalities. This allows for the development of more effective treatments, which can be specifically designed for particular types of cancer or on an individual basis. Our current capacities have allowed for greater use of theranostic probes and multimodal imaging strategies that have led to better image contrast, real-time imaging capabilities leveraging targeting moieties, tracer kinetics and enabling more detailed response profiles at the cellular and molecular levels. These novel capabilities along with new discoveries in cancer biology should drive innovation for improved biomarkers for efficient and individualized cancer therapy. PMID- 28877628 TI - Corrigendum. PMID- 28877627 TI - Five new therapies or just one new treatment? A critical look at immune checkpoint inhibition in urothelial cancer. PMID- 28877629 TI - Application of chimeric antigen receptor-engineered T cells in ovarian cancer therapy. AB - Due to the critical role of T cells in the immune surveillance of ovarian cancer, adoptive T-cell therapies are receiving increased attention as an immunotherapeutic approach for ovarian cancer. Chimeric antigen receptors (CARs), constructed by incorporating the single-chain Fv fragment to a T-cell signaling domain such as CD3 zeta or Fc receptor gamma chain, endow T cell with nonmajor histocompatibility complex-restricted specificity. Dual specificity, trans signaling CARs and affinity-tuned single-chain Fv fragment have broadened the applicability of CAR-engineered T-cell therapy and may be considered preferential to T cell receptor T-cell therapy in clinical care. As new insights into the CAR engineered T cells have emerged over the last decade, we review the development of CAR T-cell therapy and discuss the progress and safety concerns regarding its translation from basic research into clinical care of ovarian cancer. PMID- 28877630 TI - FOCIS goes south: advances in translational and clinical immunology. AB - FOCIS goes South: Advances in Translational and Clinical Immunology was the first Federation of Clinical Immunology Societies (FOCIS) ( www.focisnet.org ) meeting held in Latin America (May 15-17, 2017, Santiago de Chile, Chile). The meeting was organized as a 3-day workshop and was fostered by the Millennium Institute on Immunology and Immunotherapy, a recently nominated FOCIS Center of Excellence. The workshop brought together FOCIS associates, such as members of the FOCIS Board of Directors, Directors of different Centers of Excellence, regional speakers and 350 attendees. The Meeting covered aspects of immune regulation and modulation, as well as immunotherapy in areas of autoimmunity, transplantation, cancer and infectious diseases, among others. The activity also had a full-day immunology course and a day-long flow cytometry course. PMID- 28877631 TI - PM01183 inhibits myeloid-derived suppressor cells in vitro and in vivo. AB - AIM: To evaluate the ability of PM01183 to eliminate myeloid-derived suppressor cells (MDSCs). MATERIALS & METHODS: The effect of PM01183 on MDSCs, NK cells and CD8+ T cells was examined in vitro and in vivo. The mechanism by which PM01183 depletes MDSCs was also investigated. RESULTS: PM01183 reduced the number of MDSCs by inducing apoptosis and attenuated the MDSC-mediated suppression of CD8+ T cells by inhibiting arginase-1 production, whereas no significant effect on CD8+ T or NK cells was noted. The inhibitory effect of PM01183 on MDSC was mediated by the attenuation of STAT3 phosphorylation. The inhibitory effect of PM01183 on MDSCs was greater than those of existing anticancer agents. CONCLUSION: PM01183 exhibits strong inhibitory effects on MDSCs. PMID- 28877632 TI - Case report: pembrolizumab-induced Type 1 diabetes in a patient with metastatic cholangiocarcinoma. AB - BACKGROUND: Immune checkpoint inhibitors are novel cancer therapies associated with numerous autoimmune toxicities, some of which are only now being appreciated. CASE PRESENTATION: A 67-year old female with metastatic cholangiocarcinoma and no prior history of diabetes was treated with leucovorin, fluorouracil, oxaliplatin and pembrolizumab. After eight cycles, she developed new onset type 1 diabetes mellitus with positive glutamic acid decarboxylase antibody titers. Conclusions: To our knowledge, this is the first reported case of PD-1 inhibitor associated Type 1 diabetes mellitus in a patient with cholangiocarcinoma and supports others' experiences that PD-1 inhibition can cause a spectrum of autoimmune adverse events that require clinical monitoring and periodic screenings. PMID- 28877633 TI - Targeting the PSGL-1 pathway for immune modulation. PMID- 28877634 TI - Certolizumab, an anti-TNF safe during pregancy? The CRIB Study results: an interview with Professor Xavier Mariette. AB - Professor Xavier Mariette, MD, PhD, has served as the Head of the Rheumatology Department of Bicetre Hospital, Paris-Sud University since 1999, a role he took following 10 years of practice of clinical immunology. Professor Mariette has initiated a number of clinical research studies on biotherapies in autoimmune diseases. He is the head of the French RATIO (Research Axed on Tolerance of Biotherapy) observatory, collecting specific rare serious adverse events in patients treated with anti-TNF. He initiated the French AIR (Autoimmunity and Rituximab) and ORA (Orencia and Rheumatoid arthritis) registries of patients with autoimmune diseases treated with rituximab and abatacept. He initiated clinical trials in Sjogren's syndrome with infliximab, hydroxychloroquine and belimumab. Professor Mariette is involved in basic research, leading a group working on pathogeny of Sjogren's syndrome, relationships between innate immunity and B-cell activation in autoimmunity and the relationships between autoimmunity and lymphoma. Professor Mariette is also very interested in new ways of teaching. In 2007, he participated with other European Experts in the creation of the EULAR Web Course of Rheumatology in 2007. Professor Mariette has been the President of the Scientific Committee of the EULAR meeting, which took place in Berlin in 2012 and is in 2016 the elect Chair of the EULAR standing committee on investigative rheumatology. Professor Mariette is co-author of more than 430 publications referenced in PubMed with an H-index of 61. PMID- 28877635 TI - Two is better than one: advances in pathogen-boosted immunotherapy and adoptive T cell therapy. AB - The recent tremendous successes in clinical trials take cancer immunotherapy into a new era and have attracted major attention from both academia and industry. Among the variety of immunotherapy strategies developed to boost patients' own immune systems to fight against malignant cells, the pathogen-based and adoptive cell transfer therapies have shown the most promise for treating multiple types of cancer. Pathogen-based therapies could either break the immune tolerance to enhance the effectiveness of cancer vaccines or directly infect and kill cancer cells. Adoptive cell transfer can induce a strong durable antitumor response, with recent advances including engineering dual specificity into T cells to recognize multiple antigens and improving the metabolic fitness of transferred cells. In this review, we focus on the recent prospects in these two areas and summarize some ongoing studies that represent potential advancements for anticancer immunotherapy, including testing combinations of these two strategies. PMID- 28877637 TI - Ghost probiotics with a combined regimen: a novel therapeutic approach against the Zika virus, an emerging world threat. AB - The Zika virus (ZIKV) used to be an obscure flavivirus closely related to dengue virus (DENV). Transmission of this epidemic pathogen occurs mainly via mosquitoes, but it is also capable of placental and sexual transmission. Although the characteristics of these viruses are well defined, infections are unpredictable in terms of disease severity, unusual clinical manifestations, unexpected methods of transmission, long-term persistence, and the development of new strains. Recently, ZIKV has gained huge medical attention following the large scale epidemics around the world, and reported cases of congenital abnormalities associated with Zika virus infections which have created a public health emergency of international concern. Despite continuous research on ZIKV, no specific treatment or vaccine has been developed, excepting a preventive strategy for congenital ZIKV infection. Probiotics, known as GRAS, are bacteria that confer various health beneficial effects, and have been shown to be effective at curing a number of viral diseases by modulating the immune system. Furthermore, probiotic preparations consisting of dead cells and cellular metabolites, so called "Ghost probiotics", can also act as biological response modifiers. Here, we review available information on the epidemiology, transmission, and clinical features of ZIKV, and on treatment and prevention strategies. In addition, we emphasize the use of probiotics and plant-based natural remedies and describe their action mechanisms, and the green technologies for microbial conversion, which could contribute to the development of novel therapies that may reduce the pathogenicity of ZIKV. Accordingly, we draw attention to new findings, unanswered questions, unresolved issues, and controversies regarding ZIKV. PMID- 28877638 TI - Spinocerebellar ataxia: a critical review of cognitive and socio-cognitive deficits. AB - PURPOSE: The primary aim of this contribution is to provide a critical discussion on cognitive and sociocognitive implications of spinocerebellar ataxias (SCAs) subtypes. The term SCA refers to a group of neurodegenerative disorders that have been increasingly investigated in the last years, sharing the characteristic of progressive ataxia resulting from degeneration of cerebellum and its connections. In past decades only involvement of cerebellum in behaviour and timing has been investigated, bringing to the belief about its central role in timing of movement and sensation, particularly for short intervals of time. Only very recently the cerebellum has been considered as a potentially important centre for cognitive processing and related spheres of social cognition, so that several studies with SCA patients have been carried out on these topics: as a consequence a section of this review will be dedicated to this important aspect. RESULTS: After a brief discussion on most commonly used methods to assess cognitive and socio-cognitive abilities in SCAs, cognitive and socio-cognitive profiles of principal SCA subtypes have been thoroughly reviewed and critically discussed. Due to the very poor literature in this field the most common SCA variants have been fully included (i.e. SCA1, SCA2, SCA3, SCA6 and SCA7). CONCLUSIONS: A comparative summary of the main characteristics of cognitive and social cognition deficit in SCA subtypes has been proposed together with a research agenda for future investigation in this field principally aimed at using measures of cognition and/or social cognition as potential predictors of the extent and progression of disease. PMID- 28877636 TI - Is the Newest Vital Sign a Useful Measure of Health Literacy in HIV Disease? AB - BACKGROUND: Limited health literacy is common among persons infected with HIV and has been linked to poor mental and physical health outcomes, but there are no well-validated screening measures of health literacy in this vulnerable clinical population. The present study evaluates the usefulness of the Newest Vital Sign (NVS) as a brief measure of health literacy in HIV disease. METHODS: Seventy eight HIV+ adults were administered the NVS, Rapid Estimate of Adult Literacy in Medicine (REALM), and Single Item Literacy Screener (SILS). Main criterion variables included plasma HIV viral load, medication management capacity, self efficacy for medication management, and perceived relationships with healthcare providers. RESULTS: The NVS showed good internal consistency and moderate correlations with the REALM and SILS. Rates of limited health literacy were highest on the NVS (30.3%) as compared to SILS (6.6%) and REALM (9.2%). A series of regressions controlling for education showed that the NVS was incrementally predictive of viral load, medication management capacity and self-efficacy, and relationships with healthcare providers, above and beyond the REALM and SILS. CONCLUSION: The NVS shows evidence of reliability, convergent validity, and incremental criterion-related validity and thus may serve as useful screening tool for assessing health literacy in HIV disease. PMID- 28877639 TI - Novel solidified reverse micellar solution-based mucoadhesive nano lipid gels encapsulating miconazole nitrate-loaded nanoparticles for improved treatment of oropharyngeal candidiasis. AB - OBJECTIVE: To develop and evaluate solidified-reverse-micellar-solution (SRMS) based oromucosal nano lipid gels for improved localised delivery of miconazole nitrate (MN). METHODS: Phospholipon(r) 90G and Softisan(r) 154 (3:7) were used to prepare SRMS by fusion. Solid lipid nanoparticles (SLNs, 0.25-1.0% w/w MN) formulated with the SRMS by high shear homogenisation were employed to prepare mucoadhesive nano lipid gels. Physicochemical characterisation, drug release in simulated salivary fluid (SSF) (pH 6.8) and anti-candidal activity were carried out. RESULTS: The SLNs were spherical nanoparticles, had mean size of 133.8 +/- 6.4 to 393.2 +/- 14.5 nm, low polydispersity indices, good encapsulation efficiency (EE) (51.96 +/- 2.33-67.12 +/- 1.65%) and drug loading (DL) (19.05 +/- 2.44-24.93 +/- 1.98%). The nano lipid gels were stable, spreadable, pseudoplastic viscoelastic mucoadhesive systems that exhibited better prolonged release and anti-candidal properties than marketed formulation (Daktarin(r) oral gel) (p < 0.05). CONCLUSION: This study has shown that SRMS-based nano lipid gels could be employed to prolong localised oromucosal delivery of MN. PMID- 28877640 TI - Development and conceptual validation of a questionnaire to help contraceptive choice: CHLOE (Contraception: HeLping for wOmen's choicE). AB - OBJECTIVE: The aim of this research was to develop a questionnaire to facilitate choice of the most appropriate contraceptive method for individual women. METHODS: A literature review was conducted to identify key aspects influencing contraceptive choice and inform development of a questionnaire for online completion. Questionnaire development was overseen by a steering committee consisting of eight gynaecologists from across Europe. The initial draft underwent conceptual validation through cognitive debriefing interviews with six native English-speaking women. A qualitative content analysis was conducted to accurately identify potential issues and areas for questionnaire improvement. A revised version of the questionnaire then underwent face-to-face and online evaluation by 115 international gynaecologists/obstetricians with expertise in contraception, prior to development of a final version. RESULTS: The final conceptually validated Contraception: HeLping for wOmen's choicE (CHLOE) questionnaire takes <=10 min to complete and includes three sections to elicit general information about the individual, the health conditions that might influence contraceptive choice, and the woman's needs and preferences that might influence contraceptive choice. The questionnaire captures the core aspects of personalisation, efficacy and safety, identified as key attributes influencing contraceptive choice, and consists of 24 closed-ended questions for online completion prior to a health care provider (HCP) consultation. The HCP receives a summary of the responses. CONCLUSION: The CHLOE questionnaire has been developed to help women choose the contraception that best suits their needs and situation while optimising the HCP's time. PMID- 28877642 TI - To Assess the Success of Computerized Order Sets and Pharmacy Education Modules in Improving Antiretroviral Prescribing. AB - PURPOSE: To assess the success of order set and pharmacist training improvement (OSPTI) in improving prescription of antiretroviral therapy (ART) in a tertiary care, public, teaching hospital. METHODS: In this pre-OSPTI (January 2012 through June 2013) and post-OSPTI study (July 2013 through September 2014), an infectious disease pharmacist reviewed all patients on ART. A review of intervention data in July 2013 led to order-set changes in the hospital's computerized order entry system for frequently intervened on antiretrovirals: ritonavir, tenofovir, emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and lamivudine. Concurrently, case-based education modules were conducted to help pharmacists identify ART errors. The number of patients on ART, number of interventions, and types of ritonavir interventions were compared between pre- and post-OSPTI periods. RESULTS: In the pre-OSPTI period, an average of 239 patients were reviewed per quarter compared to an average of 216 per quarter in the post-OSPTI period. After implementing enhanced order sets, the number of interventions decreased by approximately 34% ( P < .0001). The number of ritonavir interventions decreased on average by 45% ( P < .0001), although the types of ritonavir interventions were similar. CONCLUSION: Enhanced antiretroviral order sets and pharmacy education modules improved ART prescription by reducing the overall number of antiretroviral interventions required per quarter. This modality was effective in improving prescribing of ART and reducing the need for pharmacist interventions. PMID- 28877643 TI - A Case Series of 18 Patients Receiving Ticagrelor After Carotid Stenting. AB - PURPOSE: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist is often used to prevent thrombotic complications after endovascular stent placement. Most of the published experience surrounding DAPT after carotid stenting is with clopidogrel. Ticagrelor may be a promising alternative, especially in patients who may be considered nonresponders to clopidogrel. However, clinical outcomes utilizing DAPT with ticagrelor in a cohort with carotid stenting is lacking. In this case series, we describe our experience with systematic prescribing of ticagrelor after carotid stent placement in 18 patients. METHODS: A retrospective review of 18 patients prescribed ticagrelor who underwent carotid stenting between November 2015 and January 2017 was performed. All eligible patients were included in the review. The primary end point of interest was any ischemic stroke or death within 30 days following the procedure. Intracranial hemorrhage was a secondary end point. RESULTS AND CONCLUSIONS: No patients experienced the primary end point of ischemic stroke or death within 30 days. No intracranial hemorrhages were observed. The use of ticagrelor after carotid stenting may be a reasonable alternative to clopidogrel after carotid stent placement. Randomized trials to support our findings are needed. PMID- 28877641 TI - Collagen and Hydroxyapatite Scaffolds Activate Distinct Osteogenesis Signaling Pathways in Adult Adipose-Derived Multipotent Stromal Cells. AB - Osteogenic cell signaling pathway disruption varies among bone diseases. This investigation was designed to identify adipose-derived multipotent stromal cell (ASC) and bone graft scaffold combinations for local, targeted restoration of gene expression and extracellular matrix (ECM) deposition. Human ASC osteogenesis on bone graft materials was quantified following culture in stromal (S), osteogenic (O), or osteogenic for 48 h followed by stromal medium (OS) to test the two-part hypothesis: (1) identical ASC isolates on distinct bone graft scaffolds demonstrate unique viability, differentiation, ECM production, and gene expression in the same culture conditions; (2) identical ASC-bone graft scaffold combinations have different cell viability, differentiation, ECM production, and gene expression when cultured in S, O, or OS medium. Three commercially available bone graft scaffold materials, type I bovine collagen (C), hydroxyapatite + beta tricalcium phosphate + type I bovine collagen (HT), and beta-tricalcium phosphate + type I bovine collagen (CT) were evaluated. Passage 3 ASCs were loaded onto scaffold blocks with a spinner flask bioreactor, and constructs were cultured up to 28 days. Cell viability, gene expression (alkaline phosphatase [ALPL], osteoprotegerin [TNFRSF11B], osteocalcin [BGLAP], cannabinoid receptors type I [CNR1] and II [CNR2], receptor activator of nuclear factor kappa beta ligand [TNFSF11]), as well as ECM DNA, collagen, sulfated glycosaminoglycan, and protein content were quantified. Matrix organization was evaluated with scanning electron microscopy. Effects of scaffold, medium, or culture duration on cell viability were minimal. Significantly higher initial ALPL expression decreased with time, while BGLAP expression increased in HT constructs in O medium, and the constructs had the most abundant ECM components and ultrastructural organization. There was a similar, although delayed, pattern of gene expression and greater ECM collagen with less organization in C constructs in O medium. Higher CNR1 expression in C versus higher TNFRSF11B/TNFSF11 expression in HT constructs throughout the study support stimulation of unique osteogenic signaling pathways by identical cell isolates. These results suggest that bone scaffold composition may be used to selectively target specific osteogenic cell signaling pathways in ASC constructs to stimulate ECM deposition based on therapeutic needs. PMID- 28877644 TI - A Time Course of Bevacizumab (Anti-VEGF) Effect on Rat Peritoneum: Relations Between Antiadhesive Action and Fibrin Regulation Enzymes. AB - BACKGROUND: To investigate the early and late antiadhesive effect and any changes of fibrin matrix regulation enzymes on rat peritoneum, after local administration of bevacizumab. METHODS: Rats were subjected to cecal abrasion. Bevacizumab (5 mg/kg) against placebo was given intraperitoneally. On the 2nd, 14th, and 28th postoperative days adhesions were scored, and tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), degree of fibrosis, and angiogenesis were measured in abrased cecum and in intact parietal peritoneum. RESULTS: Bevacizumab significantly reduced adhesions up to 15% on the 2nd, 52.5% on the 14th, and 55% on the 28th postoperative day, and significantly increased tPA concentrations in peritoneum. PAI-1 was decreased, and a significantly higher tPA/PAI-1 ratio along with an increase of MMP-9 was measured at all time points. Fibrosis and angiogenesis were significantly lower on the 14th and 28th postoperative days. CONCLUSIONS: Local bevacizumab administration has a strong early and late antiadhesive action on rat peritoneum, mediated by changes in the tPA/PAI-1 and MMP balance in favor of fibrinolysis up to 28 days after operations. PMID- 28877645 TI - Bone marrow cavity segmentation using graph-cuts with wavelet-based texture feature. AB - Emerging bioimaging technologies enable us to capture various dynamic cellular activities [Formula: see text]. As large amounts of data are obtained these days and it is becoming unrealistic to manually process massive number of images, automatic analysis methods are required. One of the issues for automatic image segmentation is that image-taking conditions are variable. Thus, commonly, many manual inputs are required according to each image. In this paper, we propose a bone marrow cavity (BMC) segmentation method for bone images as BMC is considered to be related to the mechanism of bone remodeling, osteoporosis, and so on. To reduce manual inputs to segment BMC, we classified the texture pattern using wavelet transformation and support vector machine. We also integrated the result of texture pattern classification into the graph-cuts-based image segmentation method because texture analysis does not consider spatial continuity. Our method is applicable to a particular frame in an image sequence in which the condition of fluorescent material is variable. In the experiment, we evaluated our method with nine types of mother wavelets and several sets of scale parameters. The proposed method with graph-cuts and texture pattern classification performs well without manual inputs by a user. PMID- 28877646 TI - Comparison of Canadian firefighters and healthy controls based on submaximal fitness testing and strength considering age and gender. AB - INTRODUCTION: Few studies have addressed whether firefighters are fitter than the general population and possess sufficient levels of aerobic capacity and muscle strength to perform on-duty tasks in a safe and efficient manner, considering age and gender. We aimed to evaluate the fitness levels of Hamilton firefighters, and to determine the effects of age and gender. METHODS: In total, 89 participants were recruited. The modified Canadian aerobic fitness test was used to determine participants' estimated maximal oxygen consumption (VO2max) levels. For upper and lower body strength levels, a calibrated J-Tech hand-held dynamometer and a National Institute for Occupational Safety and Health (NIOSH) lifting device was used respectively. RESULTS: Firefighters' mean (SD) VO2max level was 40.30 +/- 6.25 ml.kg-1.min-1. Age proved to have a statistically significant impact on VO2max (p < 0.001). Gender displayed statistically significant effects on strength levels. Firefighters' age was the only statistically significant independent variable, and accounted for 61.00% of the variance in firefighters' aerobic capacity levels. CONCLUSIONS: Firefighters possessed somewhat similar aerobic capacities but much higher levels of body strength when compared with the general population. With age, firefighters' aerobic capacities decreased; however, their upper and lower body strength levels remained the same. PMID- 28877647 TI - Improvement of In Vivo Expression of Genes Delivered by Self-Amplifying RNA Using Vaccinia Virus Immune Evasion Proteins. AB - Among nucleic acid-based delivery platforms, self-amplifying RNA (saRNA) vectors are of increasing interest for applications such as transient expression of recombinant proteins and vaccination. saRNA is safe and, due to its capability to amplify intracellularly, high protein levels can be produced from even minute amounts of transfected templates. However, it is an obstacle to full exploitation of this platform that saRNA induces a strong innate host immune response. In transfected cells, pattern recognition receptors sense double-stranded RNA intermediates and via activation of protein kinase R (PKR) and interferon signaling initiate host defense measures including a translational shutdown. To reduce pattern recognition receptor stimulation and unleash suppressed saRNA translation, this study co-delivered non-replicating mRNA encoding vaccinia virus immune evasion proteins E3, K3, and B18. It was shown that E3 is far superior to K3 or B18 as a highly potent blocker of PKR activation and of interferon (IFN) beta upregulation. B18, in contrast, is superior in controlling OAS1, a key IFN inducible gene involved in viral RNA degradation. By combining all three vaccinia proteins, the study achieved significant suppression of PKR and IFN pathway activation in vitro and enhanced expression of saRNA-encoded genes of interest both in vitro and in vivo. This approach promises to overcome key hurdles of saRNA gene delivery. Its application may improve the bioavailability of the encoded protein, and reduce the effective dose and correspondingly the cost of goods of manufacture in the various fields where saRNA utilization is envisioned. PMID- 28877648 TI - * The Chorioallantoic Membrane Assay for Biomaterial Testing in Tissue Engineering: A Short-Term In Vivo Preclinical Model. AB - The fields of regenerative medicine and tissue engineering offer significant promise to address the urgent unmet need for therapeutic strategies in a number of debilitating conditions, diseases, and tissue needs of an aging population. Critically, the safety and efficacy of these pioneering strategies need to be assessed before clinical application, often necessitating animal research as a prerequisite. The growing number of newly developed potential treatments, together with the ethical concerns involved in the application of in vivo studies, requires the implementation of alternative models to facilitate such screening of new treatments. The present review examines the current in vitro and in vivo models of preclinical research with particular emphasis on the chorioallantoic membrane (CAM) assay as a minimally invasive, short-term in vivo alternative. Traditionally used as an angiogenic assay, the CAM of the developing chick embryo provides a noninnervated rapidly growing vascular bed, which can serve as a surrogate blood supply for organ culture, and hence a platform for biomaterial testing. This review offers an overview of the CAM assay and its applications in biomedicine as an in vivo model for organ culture and angiogenesis. Moreover, the application of imaging techniques (magnetic resonance imaging, microcomputed tomography, fluorescence labeling for tracking) will be discussed for the evaluation of biomaterials cultured on the CAM. Finally, an overview of the CAM assay methodology will be provided to facilitate the adoption of this technique across laboratories and the regenerative medicine community, and thus aid the reduction, replacement, and refinement of animal experiments in research. PMID- 28877650 TI - Understanding allied health practitioners' use of evidence-based assessments for children with cerebral palsy: a mixed methods study. AB - PURPOSE: Evidence-based assessments for children with cerebral palsy are not widely used by healthcare professionals in day-to-day practice. This study aimed to examine allied health practitioner experiences, perceptions, and use of assessments for children with cerebral palsy. METHOD: A mixed methods study was conducted in two rehabilitation organisations. Three focus group interviews explored therapists' assessment experiences with data analysed using interpretive description. Assessment practices of therapists (n = 55) were assessed through self-report questionnaire and case-file audit of children with cerebral palsy (n = 44). RESULTS: Emergent themes described therapists' motivation to use evidence based assessments on a behavioural continuum - I don't; I can't; I try; I do; We do; influenced by assessment satisfaction, child and family collaboration, organisational expectation, research fit, and time dedication. Only two of fifteen audited assessments were documented in more than 50% of files. Use was higher where assessments positively connected therapists, children and parents, and use was organisationally endorsed. The Cultural Cone for evidence-based assessment behaviour was conceptualised. CONCLUSIONS: "Engagement in" assessment appears to require a conceptual shift by therapists and organisations to understanding assessment as part of, not an adjunct to, therapy. The Cultural Cone framework may assist therapists and services in designing strategies to promote evidence-based assessment behaviours. Implications for rehabilitation Therapists' can reflect on where they are positioned on the "use continuum" in the Cultural Cone framework, and consider the contextual influences contained in this framework to understand their motivation to use evidence-based assessments. Routine use of evidenced-based assessments for children with cerebral palsy by allied health practitioners remains generally low and therapists and service organisations need to consider ways to increase use. Where possible, therapists' should choose assessment tools that fully engage children and families and themselves in the assessment process. The Cultural Cone framework may be used to assist therapists and organisations identify and design site specific strategies to increase evidence-based assessment use in day-to-day practice. PMID- 28877649 TI - The Effect of Hypothermic and Cryogenic Preservation on Engineered Neural Tissue. AB - This study explored different approaches to preserve engineered neural tissue (EngNT), a stabilized, cellular collagen hydrogel containing columns of aligned Schwann cells for nervous system repair. The ability to preserve EngNT without disrupting cellular and extracellular components and structures is important for clinical translation and commercialization. Stabilized cellular gels and EngNT constructs were preserved under various conditions and cell survival assessed using live/dead microscopy and metabolic assay. Optimal survival was recorded in hypothermic (4 degrees C) conditions for 2-3 days using Hibernate(r)-A media and, for longer-term cryogenic storage (liquid nitrogen), using a mixture of 60% Dulbecco's modified Eagle's medium, 30% fetal bovine serum, and 10% dimethyl sulfoxide. Functionality and structure of preserved EngNT were assessed in coculture with dorsal root ganglion neurons, which indicated that alignment of Schwann cells and the ability of EngNT to support and guide neuronal regeneration were not disrupted. The identification of conditions that preserve EngNT will inform development of storage and transport methodologies to support clinical and commercial translation of this technology and other therapies based on cellular hydrogels. PMID- 28877651 TI - Production of a bioflocculant from Klebsiella sp. OS-1 using brewery wastewater as a source. AB - This study evaluated the potential of bioflocculant production from a Klebsiella strain using brewery wastewater as nutrients. The bioflocculant named OS-1B produced by Klebsiella sp. OS-1 exhibited a good flocculating activity to kaolin clay suspension (around 95%), when the diluted brewery wastewater with 7.2 mg/L total nitrogen and 1013 mg/L CODCr was used as a nitrogen source. Glucose (15 g/L) is the most favorable carbon source for Klebsiella sp. OS-1 in bioflocculant production from brewery wastewater. The yielded bioflocculant is pH tolerant and thermally stable, suggesting its good industrial potential. OS-1B mainly comprises polysaccharide (69.4%) and protein (24.5%). Fourier-transform infrared spectra indicate the presence of hydroxyl, carboxyl, esters and amino groups in the bioflocculant molecules. Combined with the results of zeta potential measurements, bridging is suggested as the main flocculation mechanism for OS-1B flocculation with kaolin. Overall, brewery wastewater can be used as a substrate to produce bioflocculants. PMID- 28877653 TI - Why do older adults have difficulty with semantic fluency? AB - Aging involves many cognitive declines, particularly in fluid intelligence, with relative maintenance of crystallized intelligence. This paradox is evident in the language domain: lexical retrieval becomes slower and less accurate, despite well preserved vocabularies. Verbal fluency assesses both crystallized and fluid aspects of language. Semantic fluency hypothetically reflects semantic knowledge, while letter fluency putatively reflects executive functioning, which would predict a greater impact of aging on the latter. However, the opposite is typically observed. To investigate factors contributing to such asymmetries, we examined verbal fluency in 86 adults (30-89 years). Multiple regression analyses indicated that semantic fluency depends largely on lexical retrieval speed, as well as visualization strategies to support controlled retrieval, skills which may disproportionately decline with age. By contrast, letter fluency relies heavily on vocabulary knowledge, providing some protection against age-related declines. These findings contribute to our understanding of the mechanisms of typical age-related declines in word retrieval. PMID- 28877652 TI - Angiotensin-(1-7) attenuates atrial tachycardia-induced sympathetic nerve remodeling. AB - INTRODUCTION: The effect of Angiotensin-(1-7) (Ang-(1-7)) on atrial autonomic remodeling is still unknown. We hypothesized that Ang-(1-7) could inhibit sympathetic nerve remodeling in a canine model of chronic atrial tachycardia. MATERIALS AND METHODS: Eighteen dogs were randomly assigned to sham group, pacing group and Ang-(1-7) group. Rapid atrial pacing was maintained for 14 days in the pacing and Ang-(1-7) groups. Ang-(1-7) was administered intravenously in the Ang (1-7) group. The atrial effective refractory period and atrial fibrillation inducibility level were measured at baseline and under sympathetic nerve stimulation after 14 days of measurement. The atrial sympathetic nerves labeled with tyrosine hydroxylase were detected using immunohistochemistry and Western blotting, and tyrosine hydroxylase and nerve growth factor mRNA levels were measured by reverse transcription polymerase chain reaction. RESULTS: Pacing shortened the atrial effective refractory period and increased the atrial fibrillation inducibility level at baseline and under sympathetic nerve stimulation. Ang-(1-7) treatment attenuated the shortening of the atrial effective refractory period and the increase in the atrial fibrillation inducibility level. Immunohistochemistry and Western blotting showed sympathetic nerve hyperinnervation in the pacing group, while Ang-(1-7) attenuated sympathetic nerve proliferation. Ang-(1-7) alleviated the pacing-induced increases in tyrosine hydroxylase and nerve growth factor mRNA expression levels. CONCLUSION: Ang-(1-7) can attenuate pacing-induced atrial sympathetic hyperinnervation. PMID- 28877654 TI - NUCKS nuclear elevated expression indicates progression and prognosis of ovarian cancer. AB - NUCKS (nuclear, casein kinase, and cyclin-dependent kinase substrate) is implicated in the tumorigenesis of several human malignancies, but its role in ovarian cancer remains unknown. We aim to investigate NUCKS expression and its clinical significance in ovarian cancer. The messenger RNA expression of NUCKS was determined in normal and malignant ovarian tissues using quantitative polymerase chain reaction assay. Immunohistochemistry was applied to detect the status of NUCKS protein expression in 121 ovarian cancer tissues. NUCKS protein high expression was detected in 52 (43.0%) of 121 patients. NUCKS messenger RNA expression was gradually upregulated in non-metastatic ovarian cancers ( n = 20), metastatic ovarian cancers ( n = 20), and its matched metastatic lesions ( n = 20) in comparison with that in normal ovarian tissues ( n = 10; p < 0.05). Elevated expression of NUCKS in ovarian cancer was associated significantly with the Federation of Gynecology and Obstetrics stage ( p = 0.037), histological grade ( p = 0.003), residual disease ( p = 0.013), lymph node metastasis ( p = 0.002), response to chemotherapy ( p < 0.001), and recurrence ( p = 0.013). In the multivariate Cox analysis, NUCKS expression was an independent prognostic marker for overall survival and disease-free survival in ovarian cancer with p values of <0.001 for both. Especially, NUCKS overexpression had prognostic potential for overall survival and disease-free survival ( p < 0.001 for both) in advanced ovarian cancers and only for disease-free survival in early ovarian cancers ( p = 0.017). Our data suggest that NUCKS overexpression may contribute to progression and poor prognosis in ovarian cancer especially in advanced ovarian cancer. PMID- 28877655 TI - Developing a Strategy for Interventional Molecular Imaging of Oxidized Low Density Lipoprotein in Atherosclerosis. AB - The identification of vulnerable coronary artery atherosclerotic plaques offers the prospect of either localized or systematic therapeutic targeting in order to prevent myocardial infarction. Molecular imaging of atherosclerosis adds to morphological imaging by focusing on the immunobiology hidden in and behind the endothelium and therefore may be able to improve the identification of prospective culprit lesions. Our focus has been on identifying arterial accumulation of oxidized low-density lipoprotein (oxLDL) by exploiting advances in knowledge of vascular pathobiology. Here, we reflect on our work developing near-infrared fluorescence imaging of oxLDL using LO1, a monoclonal autoantibody generated in our laboratory. We detail progress to date and discuss our vision on taking the work through the early translational pipeline toward a multitargeted approach in imaging rupture-prone atherosclerotic plaques. Ultimately, molecular imaging of coronary arteries should be able to assess the regional risk that is specific to a lesion, which can then be used in concert with global risk factors to personalize the therapeutic strategy for patients in a way that goes beyond generalized population-based therapies. PMID- 28877657 TI - Retained binding mode of various DNA-binding molecules under molecular crowding condition. AB - Meso-tetrakis(N-methyl pyridinium-4-yl)porphyrin (TMPyP) intercalates between the base-pairs of DNA at a low [TMPyP]/[DNA base] ratio in aqueous solutions and molecular crowding conditions, which is induced by the addition of Poly(ethylene glycol) (PEG). Studied DNA-binding drugs, including TMPyP, 9-aminoacridine, ethidium bromide, and DAPI (4',6-diamidino-2-phenylindole) showed similar binding properties in the presence or absence of PEG molecules which is examined by circular and linear dichroism. According to the LDr (reduced linear dichroism) results of the binding drugs examined in this work, PEG molecules induced no significant change compared to their binding properties in aqueous buffering systems. These results suggest that the transition moments are not expected to be perturbed significantly by PEG molecules. In this study, the experimental conditions of PEG 8000 were maintained at 35% (v/v) of total reaction volume, which is equal to the optimal molar concentration (0.0536 M as final concentration for PEG 8000) to maintain suitable cell-like conditions. Therefore, there was no need to focus on the conformational changes of the DNA helical structure, such as forming irregular aggregate structures, induced by large quantities of molecular crowding media itself at this stage. PMID- 28877658 TI - Long-term Tai Chi exercise increases body stability of the elderly during stair ascent under high and low illumination. AB - The effects of long-term Tai Chi exercise on body stability of the elderly during stair ascent under high and low illumination were investigated. Forty-five healthy elderly women were divided into three groups, namely, Tai Chi exercise group, brisk walking group and no-exercise control group. All the participants ascended a staircase, during which force platforms and a motion capture system collected the data. Under the high illumination, Tai Chi exercise participants exhibited higher loading rate and anteroposterior centre of pressure (COPap) displacement as well as a lower braking impulse than no-exercise group. Under the low illumination, Tai Chi exercise participants demonstrated higher COPap and mediolateral centre of pressure (COPml) displacements as well as lower braking and lateral impulses compared with no-exercise participants. The centre of mass (COM)ml sway in Tai Chi and no exercise participants were higher, the loading rates in Tai Chi and walking participants were higher, and the lateral impulse in no exercise participants was higher under low illumination than under high illumination. Thus, low illumination increases the risk of falling. Tai Chi participants increased their foot clearance, head inclination angle and COPap displacement under low illumination to increase their stability during stair ascent. PMID- 28877656 TI - Longitudinal Evaluation of Myocardial Fatty Acid and Glucose Metabolism in Fasted and Nonfasted Spontaneously Hypertensive Rats Using MicroPET/CT. AB - Using longitudinal micro positron emission tomography (microPET)/computed tomography (CT) studies, we quantified changes in myocardial metabolism and perfusion in spontaneously hypertensive rats (SHRs), a model of left ventricular hypertrophy (LVH). Fatty acid and glucose metabolism were quantified in the hearts of SHRs and Wistar-Kyoto (WKY) normotensive rats using long-chain fatty acid analog 18F-fluoro-6-thia heptadecanoic acid (18F-FTHA) and glucose analog 18F-fluorodeoxyglucose (18F-FDG) under normal or fasting conditions. We also used 18F-fluorodihydrorotenol (18F-FDHROL) to investigate perfusion in their hearts without fasting. Rats were imaged at 4 or 5 times over their life cycle. Compartment modeling was used to estimate the rate constants for the radiotracers. Blood samples were obtained and analyzed for glucose and free fatty acid concentrations. SHRs demonstrated no significant difference in 18F-FDHROL wash-in rate constant ( P = .1) and distribution volume ( P = .1), significantly higher 18F-FDG myocardial influx rate constant ( P = 4*10-8), and significantly lower 18F-FTHA myocardial influx rate constant ( P = .007) than WKYs during the 2009-2010 study without fasting. SHRs demonstrated a significantly higher 18F FDHROL wash-in rate constant ( P = 5*10-6) and distribution volume ( P = 3*10-8), significantly higher 18F-FDG myocardial influx rate constant ( P = 3*10-8), and a higher trend of 18F-FTHA myocardial influx rate constant (not significant, P = .1) than WKYs during the 2011-2012 study with fasting. Changes in glucose plasma concentrations were generally negatively correlated with corresponding radiotracer influx rate constant changes. The study indicates a switch from preferred fatty acid metabolism to increased glucose metabolism with hypertrophy. Increased perfusion during the 2011-2012 study may be indicative of increased aerobic metabolism in the SHR model of LVH. PMID- 28877659 TI - Editorial: Theoretical Studies of the Metabolism in Drug Discovery. PMID- 28877660 TI - Editorial. PMID- 28877661 TI - Editorial: Natural Products as the Integral Part of the Therapy? PMID- 28877662 TI - Genome-wide characterization of non-reference transposable element insertion polymorphisms reveals genetic diversity in tropical and temperate maize. AB - BACKGROUND: Maize was originally domesticated in a tropical environment but is now widely cultivated at temperate latitudes. Temperate and tropical maize populations have diverged both genotypically and phenotypically. Tropical maize lines grown in temperate environments usually exhibit delayed flowering, pollination, and seed set, which reduces their grain yield relative to temperate adapted maize lines. One potential mechanism by which temperate maize may have adapted to a new environment is novel transposable element insertions, which can influence gene regulation. Recent advances in sequencing technology have made it possible to study variation in transposon content and insertion location in large sets of maize lines. RESULTS: In total, 274,408 non-redundant TEs (NRTEs) were identified using resequencing data generated from 83 maize inbred lines. The locations of DNA TEs and copia-superfamily retrotransposons showed significant positive correlations with gene density and genetic recombination rates, whereas gypsy-superfamily retrotransposons showed a negative correlation with these two parameters. Compared to tropical maize, temperate maize had fewer unique NRTEs but higher insertion frequency, lower background recombination rates, and higher linkage disequilibrium, with more NRTEs close to flowering and stress-related genes in the genome. Association mapping demonstrated that the presence/absence of 48 NRTEs was associated with flowering time and that expression of neighboring genes differed between haplotypes where a NRTE was present or absent. CONCLUSIONS: This study suggests that NRTEs may have played an important role in creating the variation in gene regulation that enabled the rapid adaptation of maize to diverse environments. PMID- 28877663 TI - High-throughput PCR assay design for targeted resequencing using primerXL. AB - BACKGROUND: Although the sequencing landscape is rapidly evolving and sequencing costs are continuously decreasing, whole genome sequencing is still too expensive for use on a routine basis. Targeted resequencing of only the regions of interest decreases both costs and the complexity of the downstream data-analysis. Various target enrichment strategies are available, but none of them obtain the degree of coverage uniformity, flexibility and specificity of PCR-based enrichment. On the other hand, the biggest limitation of target enrichment by PCR is the need to design large numbers of partially overlapping assays to cover the target. RESULTS: To overcome the aforementioned hurdles, we have developed primerXL, a state-of-the-art PCR primer design pipeline for targeted resequencing. It uses an optimized design criteria relaxation cascade and a thorough downstream in silico evaluation process to generate high quality singleplex PCR assays, reducing the need for amplicon normalization, and outperforming other target enrichment strategies and similar primer design tools when considering assay quality, coverage uniformity and target coverage. Results of four different sequencing projects with 2348 amplicons in total covering 470 kb are presented. PrimerXL can be accessed at www.primerxl.org . CONCLUSION: PrimerXL is an state-of-the-art, easy to use primer design webtool capable of generating high-quality targeted resequencing assays. The workflow is fully customizable to suit every researchers' needs, while an innovative relaxation cascade ensures maximal target coverage. PMID- 28877664 TI - Adherence, satisfaction and functional health status among patients with multiple sclerosis using the BETACONNECT(r) autoinjector: a prospective observational cohort study. AB - BACKGROUND: Maintaining patient adherence to disease modifying drugs in multiple sclerosis is a challenge, which can be improved by autoinjectors. The BETACONNECT(r) is a fully electronic autoinjector for the injection of interferon beta-1b (IFN beta-1b) automatically recording injections. METHODS: The BETAEVAL study was a prospective, observational, cohort study over 24 weeks among patients with relapsing remitting multiple sclerosis or clinically isolated syndrome treated with IFN beta-1b in Germany using the BETACONNECT(r). The primary aim was to investigate treatment adherence, secondary aims included assessing satisfaction and functional health status. Adherence was evaluated from injection data recorded by the device. Patient-related data were obtained from clinical examinations and patient questionnaires. RESULTS: Of the 151 patients enrolled, 143 were available for analysis. Thirty-four patients discontinued the study prematurely. 107/143 (74.8%) patients still used the BETACONNECT(r) at the end of the study. Injection data from the device at any visit was available for 107 patients. Among those, the percentage of adherent patients injecting >=80% of doses and still participating in the study was 57.9% at week 24. 29% of patients prematurely stopped the study, 13.1% injected <80%. Among patients with BETACONNECT(r) data at the respective visit, the proportion of adherent patients was high over the entire study period (week 4: 81.1% [N = 95], week 12: 86.7% [N = 83], week 24: 80.5% [N = 77]). Participants (N = 143) indicated high satisfaction with the BETACONNECT(r). At week 24, 98.0% of patients who completed the corresponding questionnaire (strongly) agreed that it was user-friendly, 81.2% felt confident in using it compared to their previous way and 85.5% preferred it to their previous way of injection. Injection-related pain was rated as mild to moderate at all follow-up visits. Whereas 17.2% of patients with corresponding questionnaire indicated using analgesics prior to injection at week 4, only 9.1% did at week 24. Outcomes from questionnaires assessing functional health status, depression, fatigue and cognitive function were very similar throughout the study course. CONCLUSIONS: The majority of patients continued using the BETACONNECT(r) for IFN beta-1b treatment during the 24-week study period. Adherence was high among participants still using the BETACONNECT(r) and patients were highly satisfied with the device. Ongoing studies will evaluate long-term adherence and treatment outcomes in patients using the BETACONNECT(r). TRIAL REGISTRATION: clinicaltrails.gov NCT02121444 (registered April 22, 2014). PMID- 28877665 TI - Lack of 14-3-3 proteins in Saccharomyces cerevisiae results in cell-to-cell heterogeneity in the expression of Pho4-regulated genes SPL2 and PHO84. AB - BACKGROUND: Ion homeostasis is an essential property of living organisms. The yeast Saccharomyces cerevisiae is an ideal model organism to investigate ion homeostasis at all levels. In this yeast genes involved in high-affinity phosphate uptake (PHO genes) are strongly induced during both phosphate and potassium starvation, indicating a link between phosphate and potassium homeostasis. However, the signal transduction processes involved are not completely understood. As 14-3-3 proteins are key regulators of signal transduction processes, we investigated the effect of deletion of the 14-3-3 genes BMH1 or BMH2 on gene expression during potassium starvation and focused especially on the expression of genes involved in phosphate uptake. RESULTS: Genome-wide analysis of the effect of disruption of either BMH1 or BMH2 revealed that the mRNA levels of the PHO genes PHO84 and SPL2 are greatly reduced in the mutant strains compared to the levels in wild type strains. This was especially apparent at standard potassium and phosphate concentrations. Furthermore the promoter of these genes is less active after deletion of BMH1. Microscopic and flow cytometric analysis of cells with GFP-tagged SPL2 showed that disruption of BMH1 resulted in two populations of genetically identical cells, cells expressing the protein and the majority of cells with no detectible expression. Heterogeneity was also observed for the expression of GFP under control of the PHO84 promoter. Upon deletion of PHO80 encoding a regulator of the transcription factor Pho4, the effect of the BMH1 deletion on SPL2 and PHO84 promoter was lost, suggesting that the BMH1 deletion mainly influences processes upstream of the Pho4 transcription factor. CONCLUSION: Our data indicate that that yeast cells can be in either of two states, expressing or not expressing genes required for high-affinity phosphate uptake and that 14-3-3 proteins are involved in the process(es) that establish the activation state of the PHO regulon. PMID- 28877666 TI - Multiple imputation for handling missing outcome data when estimating the relative risk. AB - BACKGROUND: Multiple imputation is a popular approach to handling missing data in medical research, yet little is known about its applicability for estimating the relative risk. Standard methods for imputing incomplete binary outcomes involve logistic regression or an assumption of multivariate normality, whereas relative risks are typically estimated using log binomial models. It is unclear whether misspecification of the imputation model in this setting could lead to biased parameter estimates. METHODS: Using simulated data, we evaluated the performance of multiple imputation for handling missing data prior to estimating adjusted relative risks from a correctly specified multivariable log binomial model. We considered an arbitrary pattern of missing data in both outcome and exposure variables, with missing data induced under missing at random mechanisms. Focusing on standard model-based methods of multiple imputation, missing data were imputed using multivariate normal imputation or fully conditional specification with a logistic imputation model for the outcome. RESULTS: Multivariate normal imputation performed poorly in the simulation study, consistently producing estimates of the relative risk that were biased towards the null. Despite outperforming multivariate normal imputation, fully conditional specification also produced somewhat biased estimates, with greater bias observed for higher outcome prevalences and larger relative risks. Deleting imputed outcomes from analysis datasets did not improve the performance of fully conditional specification. CONCLUSIONS: Both multivariate normal imputation and fully conditional specification produced biased estimates of the relative risk, presumably since both use a misspecified imputation model. Based on simulation results, we recommend researchers use fully conditional specification rather than multivariate normal imputation and retain imputed outcomes in the analysis when estimating relative risks. However fully conditional specification is not without its shortcomings, and so further research is needed to identify optimal approaches for relative risk estimation within the multiple imputation framework. PMID- 28877667 TI - Vaginal delivery: how does early hospital discharge affect mother and child outcomes? A systematic literature review. PMID- 28877668 TI - De novo assembly of Phlomis purpurea after challenging with Phytophthora cinnamomi. AB - BACKGROUND: Phlomis plants are a source of biological active substances with potential applications in the control of phytopathogens. Phlomis purpurea (Lamiaceae) is autochthonous of southern Iberian Peninsula and Morocco and was found to be resistant to Phytophthora cinnamomi. Phlomis purpurea has revealed antagonistic effect in the rhizosphere of Quercus suber and Q. ilex against P. cinnamomi. Phlomis purpurea roots produce bioactive compounds exhibiting antitumor and anti-Phytophthora activities with potential to protect susceptible plants. Although these important capacities of P. purpurea have been demonstrated, there is no transcriptomic or genomic information available in public databases that could bring insights on the genes underlying this anti oomycete activity. RESULTS: Using Illumina technology we obtained a de novo assembly of P. purpurea transcriptome and differential transcript abundance to identify putative defence related genes in challenged versus non-challenged plants. A total of 1,272,600,000 reads from 18 cDNA libraries were merged and assembled into 215,739 transcript contigs. BLASTX alignment to Nr NCBI database identified 124,386 unique annotated transcripts (57.7%) with significant hits. Functional annotation identified 83,550 out of 124,386 unique transcripts, which were mapped to 141 pathways. 39% of unigenes were assigned GO terms. Their functions cover biological processes, cellular component and molecular functions. Genes associated with response to stimuli, cellular and primary metabolic processes, catalytic and transporter functions were among those identified. Differential transcript abundance analysis using DESeq revealed significant differences among libraries depending on post-challenge times. Comparative cyto histological studies of P. purpurea roots challenged with P. cinnamomi zoospores and controls revealed specific morphological features (exodermal strips and epi cuticular layer), that may provide a constitutive efficient barrier against pathogen penetration. Genes involved in cutin biosynthesis and in exodermal Casparian strips formation were up-regulated. CONCLUSIONS: The de novo assembly of transcriptome using short reads for a non-model plant, P. purpurea, revealed many unique transcripts useful for further gene expression, biological function, genomics and functional genomics studies. The data presented suggest a combination of a constitutive resistance and an increased transcriptional response from P. purpurea when challenged with the pathogen. This knowledge opens new perspectives for the understanding of defence responses underlying pathogenic oomycete/plant interaction upon challenge with P. cinnamomi. PMID- 28877669 TI - Evaluating the role of Pleistocene refugia, rivers and environmental variation in the diversification of central African duikers (genera Cephalophus and Philantomba). AB - BACKGROUND: This study aims to assess the role that Pleistocene refugia, rivers and local habitat conditions may have played in the evolutionary diversification of three central African duiker species (Cephalophus dorsalis, C. callipygus and Philantomba monticola). Genetic data from geo-referenced feces were collected from a wide range of sites across Central Africa. Historical patterns of population genetic structure were assessed using a ~ 650 bp fragment of the mitochondrial control region and contemporary patterns of genetic differentiation were evaluated using 12 polymorphic microsatellite loci. RESULTS: Mitochondrial analyses revealed that populations of C. callipygus and P. monticola in the Gulf of Guinea refugium are distinct from other populations in west central Africa. All three species exhibit signatures of past population expansion across much of the study area consistent with a history of postglacial expansion. There was no strong evidence for a riverine barrier effect in any of the three species, suggesting that duikers can readily cross major rivers. Generalized dissimilarity models (GDM) showed that environmental variation explains most of the nuclear genetic differentiation in both C. callipygus and P. monticola. The forest savanna transition across central Cameroon and the Plateaux Bateke region in southeastern Gabon show the highest environmentally-associated turnover in genetic variability. A pattern of genetic differentiation was also evident between the coast and forest interior that may reflect differences in precipitation and/or vegetation. CONCLUSIONS: Findings from this study highlight the historical impact of Pleistocene fragmentation and current influence of environmental variation on genetic structure in duikers. Conservation efforts should therefore target areas that harbor as much environmentally-associated genetic variation as possible in order to maximize species' capacity to adapt to environmental change. PMID- 28877670 TI - Indoleamine 2, 3-dioxygenase (IDO) increases during renal fibrogenesis and its inhibition potentiates TGF-beta 1-induced epithelial to mesenchymal transition. AB - BACKGROUND: Indoleamine 2, 3-dioxygenase (IDO) is an immunomodulatory molecule that has been implicated in several biological processes. Although IDO has been linked with some renal diseases, its role in renal fibrosis is still unclear. Because IDO may be modulated by TGF-beta1, a potent fibrogenic molecule, we hypothesized that IDO could be involved in renal fibrosis, especially acting in the TGF-beta1-induced tubular epithelial-mesenchymal transition (EMT). We analyzed the IDO expression and activity in a model of renal fibrogenesis, and the effect of the IDO inhibitor 1-methyl-tryptophan (MT) on TGF-beta1-induced EMT using tubular cell culture. METHODS: Male Wistar rats where submited to 7 days of UUO. Non-obstructed kidneys (CL) and kidneys from SHAM rats were used as controls. Masson's Tricrome and macrophages counting were used to chatacterize the tissue fibrosis. The EMT was analysed though immunohistochemistry and qRT PCR. Immunohistochemestry in tissue has used to show IDO expression. MDCK cells were incubated with TGF- beta1 to analyse IDO expression. Additionally, effects of TGF- beta1 and the inhibition of IDO over the EMT process was acessed by immunoessays and scrath wound essay. RESULTS: IDO was markedly expressed in cortical and medular tubules of the UUO kidneys. Similarly to the immunolocalizaton of TGF- beta1, accompanied by loss of e-cadherin expression and an increase of mesenchymal markers. Results in vitro with MDCK cells, showed that IDO was increased after stimulus with TGF-beta1, and treatment with MT potentiated its expression. MDCK stimulated with TGF-beta1 had higher migratory activity (scratch-wound assay), which was exacerbated by MT treatment. CONCLUSIONS: IDO is constitutively expressed in tubular cells and increases during renal fibrogenesis. Although IDO is induced by TGF-beta1 in tubular cells, its chemical inhibitor acts as a profibrotic agent. PMID- 28877671 TI - Surveillance of device associated infections and mortality in a major intensive care unit in the Republic of Cyprus. AB - BACKGROUND: Device-associated health care-associated infections (DA-HAI) pose a threat to patient safety, particularly in the intensive care unit. The aim of this study was to assess the incidence of DA-HAIs, mortality and crude excess mortality at a General Hospital's Intensive Care Unit (ICU) in the Republic of Cyprus for 1 year period. METHODS: A prospective cohort, active DA-HAIs surveillance study with the use of Health Acquired Infections (HAIs) ICU Protocol (v1.01 standard edition) as provided by ECDC/NHSN for the active DA-HAIs surveillance study was conducted. The study sample included 198 ICU patients admitted during the research period and hospitalized for over 48 h. The Ventilator-Associated Pneumonia (VAP), Central Line-Associated Bloodstream Infection (CLABSI), and Catheter-Associated Urinary Tract Infection (CAUTI) rates, length of stay (LOS), mortality, and crude excess mortality were calculated. RESULTS: CLABSI was the most frequent DA-HAI with 15.9 incidence rate per 1000 Central Venus Catheter (CVC) days. The VAP rate, was 10.1 per 1000 ventilator days and the CAUTI rate was 2.7 per 1000 urinary catheter days. Device associated infections were found to be significantly associated with the length of ICU stay (p < 0.001), the CVC days (p < 0.001), ventilator days (p < 0.001), and urinary catheter days (p < 0.001). The excess mortality was 22.1% for those who acquired a DA-HAI (95% CI, 2-42.2%) compared to the patients who remained DA HAI free. Mortality of patients with VAP infection was 2.3 times higher (RR = 2.33 95% CI, 1.07-5.05) than those patients admitted without a HAI and subsequently did not acquire a DA-HAI. The most frequently isolated pathogen was Staphylococcus epidermidis (13.9%) and Candida albicans (13.9%). CONCLUSIONS: Higher DA-HAIs rates and device utilization than the international benchmarks were found in this study, calling into question the safety of preventative practices employed in this unit. PMID- 28877672 TI - Chronic lower extremity wound infection due to Kerstersia gyiorum in a patient with Buerger's disease: a case report. AB - BACKGROUND: Kerstersia gyiorum is an extremely rare pathogen of human infection. It can cause chronic infection in patients with underlying conditions. It can easily be misdiagnosed if proper diagnostic methods are not used. CASE PRESENTATION: A 47-year-old male patient with a history of Buerger's Disease for 28 years presented to our hospital with an infected chronic wound on foot. The wound was debrided, and the specimen was sent to Microbiology laboratory. Gram staining of the specimen showed abundant polymorphonuclear leukocytes and gram negative bacilli. Four types of colonies were isolated on blood agar. These were identified as Kerstersia gyiorum, Proteus vulgaris, Enterobacter cloacae, Morganella morganii by Maldi Biotyper (Bruker Daltonics, Germany). The identification of K. gyiorum was confirmed by 16S ribosomal RNA gene sequencing. The patient was successfully recovered with antimicrobial therapy, surgical debridement, and skin grafting. CONCLUSIONS: This is the first case of wound infection due to K. gyiorum in a patient with Buerger's Disease. We made a brief review of K. gyiorum cases up to date. Also, this case is presented to draw attention to the use of new and advanced methods like MALDI-TOF MS and 16S rRNA gene sequencing for identification of rarely isolated species from clinical specimens of patients with chronic infections and with chronic underlying conditions. PMID- 28877673 TI - LAIT: a local ancestry inference toolkit. AB - BACKGROUND: Inferring local ancestry in individuals of mixed ancestry has many applications, most notably in identifying disease-susceptible loci that vary among different ethnic groups. Many software packages are available for inferring local ancestry in admixed individuals. However, most of these existing software packages require specific formatted input files and generate output files in various types, yielding practical inconvenience. RESULTS: We developed a tool set, Local Ancestry Inference Toolkit (LAIT), which can convert standardized files into software-specific input file formats as well as standardize and summarize inference results for four popular local ancestry inference software: HAPMIX, LAMP, LAMP-LD, and ELAI. We tested LAIT using both simulated and real data sets and demonstrated that LAIT provides convenience to run multiple local ancestry inference software. In addition, we evaluated the performance of local ancestry software among different supported software packages, mainly focusing on inference accuracy and computational resources used. CONCLUSION: We provided a toolkit to facilitate the use of local ancestry inference software, especially for users with limited bioinformatics background. PMID- 28877674 TI - Health professional's knowledge and use of the partograph in public health institutions in eastern Ethiopia: a cross-sectional study. AB - BACKGROUND: The partograph is a vital tool for health professionals who need to be able to identify pathological labor. It is used to recognize complications in childbirth on time and to take appropriate actions. We aimed to assess the knowledge and utilization of the partograph and associated factors among health professionals at public health institutions in eastern Ethiopia. METHODS: An institution based cross-sectional quantitative study was carried out among health professionals who were working in public health institutions. Multistage sampling with proportional to size allocation was used to recruit a total of 441 study participants. Self-administered questionnaire was used to collect data in this study. Eight midwives were recruited and trained to facilitate the data collection activities. Data were entered into Epi data software and exported into SPSS (22.0) for analysis. Descriptive statistics, bivariate and multiple logistic regression were computed to determine proportions and significant association with knowledge and use of the partograph among health professionals. RESULTS: More than half of health professionals, 232(53.7%) had a good level of knowledge about the partograph. However, only 196(45.4%) of health professionals had fair knowledge of partograph. Nevertheless, the proportion of the partograph utilization to follow labor progress by health professionals was 92.6%. Working in the health center [AOR = 0.31, 95% CI: 0.20, 0.48], being a midwife [AOR = 2.80, 95% CI: 1.60, 5.60] and in-service training [AOR = 2.0, 95% CI: 1.22, 3.42] were significantly associated with good level of knowledge. Health professionals who had in-service training about the partograph [AOR = 3.10, 95% CI: 1.35, 4.98] and who had positive attitude about the partograph [AOR = 2.90, 95% CI: 1.30, 6.30] were significantly associated with utilization of the partograph. CONCLUSION: Only less than half of health professionals had fair knowledge about the partograph. Having in-service obstetric care training, type of health institutions and profession were significantly associated with knowledge of the partograph. Health professionals who had positive attitude towards use of the partograph were significantly associated with the partograph utilization. We suggest regular in-service training of health professionals can enhance their knowledge and utilization of the partograph. PMID- 28877675 TI - Signal functions for emergency obstetric care as an intervention for reducing maternal mortality: a survey of public and private health facilities in Lusaka District, Zambia. AB - BACKGROUND: Zambia's maternal mortality ratio was estimated at 398/100,000 live births in 2014. Successful aversion of deaths is dependent on availability and usability of signal functions for emergency obstetric and neonatal care. Evidence of availability, usability and quality of signal functions in urban settings in Zambia is minimal as previous research has evaluated their distribution in rural settings. This survey evaluated the availability and usability of signal functions in private and public health facilities in Lusaka District of Zambia. METHODS: A descriptive cross sectional study was conducted between November 2014 and February 2015 at 35 public and private health facilities. The Service Availability and Readiness Assessment tool was adapted and administered to overall in-charges, hospital administrators or maternity ward supervisors at health facilities providing maternal and newborn health services. The survey quantified infrastructure, human resources, equipment, essential drugs and supplies and used the UN process indicators to determine availability, accessibility and quality of signal functions. Data on deliveries and complications were collected from registers for periods between June 2013 and May 2014. RESULTS: Of the 35 (25.7% private and 74.2% public) health facilities assessed, only 22 (62.8%) were staffed 24 h a day, 7 days a week and had provided obstetric care 3 months prior to the survey. Pre-eclampsia/ eclampsia and obstructed labor accounted for most direct complications while postpartum hemorrhage was the leading cause of maternal deaths. Overall, 3 (8.6%) and 5 (14.3%) of the health facilities had provided Basic and Comprehensive EmONC services, respectively. All facilities obtained blood products from the only blood bank at a government referral hospital. CONCLUSION: The UN process indicators can be adequately used to monitor progress towards maternal mortality reduction. Lusaka district had an unmet need for BEmONC as health facilities fell below the minimum UN standard. Public health facilities with capacity to perform signal functions should be upgraded to Basic EmONC status. Efforts must focus on enhancing human resource capacity in EmONC and improving infrastructure and supply chain. Obstetric health needs and international trends must drive policy change. PMID- 28877676 TI - Long-term outcomes of coronary artery bypass grafting versus stent-PCI for unprotected left main disease: a meta-analysis. AB - BACKGROUND: Coronary artery bypass graft (CABG) surgery has traditionally represented the standard of care for left main coronary artery (LMCA) disease. However, percutaneous coronary intervention with stent implantation (PCI) has more recently emerged as a valuable alternative. The long-time awaited results of the largest randomized trials on the long-term impact of PCI versus CABG in LMCA disease, the newly published NOBLE and EXCEL studies, revealed contrasting results. Thus, aim of the present meta-analysis was to review the most robust evidence from randomized comparisons of CABG versus PCI for revascularization of LMCA. METHODS: Randomized studies comparing long-term clinical outcomes of CABG or Stent-PCI for the treatment of LMCA disease were searched for in PubMed, the Chochrane Library and Scopus electronic databases. A total of 5 randomized studies were selected, including 4499 patients. RESULTS: No significant difference between CABG and PCI was found in the primary analysis on the composite endpoint of death, stroke and myocardial infarction (OR = 1.06 95% CI 0.80-1.40; p = 0.70). Similarly, no differences were observed between CABG and PCI for all-cause death (OR = 1.03 95% CI 0.81-1.32; p = 0.81). Although not statistically significant, a lower rate of stroke was registered in the PCI arm (OR = 0.86; p = 0.67), while a lower rate of myocardial infarction was found in the CABG arm (OR = 1.43; p = 0.17). On the contrary, a significantly higher rate of repeat revascularization was registered in the PCI arm (OR = 1.76 95% CI 1.45 2.13; p < 0.001). CONCLUSIONS: The present meta-analysis, the most comprehensive and updated to date, including 5 randomized studies and 4499 patients, demonstrates no difference between Stent-PCI and CABG for the treatment of LMCA disease in the composite endpoint of death, stroke and myocardial infarction. Hence, a large part of patients with unprotected left main coronary artery disease can be managed equally well by means of both these revascularization strategies. PMID- 28877677 TI - Maternal body mass index and access to antenatal care: a retrospective analysis of 619,502 births in England. AB - BACKGROUND: Late access to antenatal care increases risks of adverse outcomes including maternal and perinatal mortality. There is evidence that BMI influences patient engagement with health services, such as cancer screening services and delayed access to treatment; this association has not been fully explored in the context of antenatal care. This study investigated the association between the stage of pregnancy women access antenatal care, BMI, and other socio-demographic factors. METHODS: Retrospective analysis of routine hospital data from 34 NHS maternity units in England, UK, including 619,502 singleton births between 1989 and 2007. Analyses used logistic regression to investigate the association between maternal BMI categories and stage of pregnancy women accessed antenatal care. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were used to estimate associations, adjusting for maternal age, ethnic group, parity, Index of Multiple Deprivation score and employment status. The primary outcome was late access to antenatal care (>13+6 weeks). Secondary outcomes were trimester of access, and the association between late access and other socio-demographic variables. RESULTS: Women with an overweight or obese BMI accessed antenatal care later than women with a recommended BMI (aOR 1.11, 95%CI 1.09-1.12; aOR 1.04, 95%CI 1.02-1.06 respectively), and underweight women accessed care earlier (aOR 0.77, 95%CI 0.74-0.81). Women with obesity were 42% more likely to access care in the third trimester compared with women with a recommended BMI. Additional significant socio-demographic associations with late access included women from minority ethnic groups, teenagers, unemployment and deprivation. The greatest association was observed among Black/Black British women accessing care in the third trimester (aOR 5.07, 95% CI 4.76, 5.40). CONCLUSIONS: There are significant and complex socio-demographic inequalities associated with the stage of pregnancy women access maternity care, particularly for women with obesity accessing care very late in their pregnancy, and among BME groups, teenagers, deprived and unemployed women. These populations are at increased risk of adverse maternal and fetal outcomes and require support to address inequalities in access to antenatal care. Interventions to facilitate earlier access to care should address the complex and inter-related nature of these inequalities to improve pregnancy outcomes among high-risk groups. PMID- 28877678 TI - Extranodal natural killer/T-cell lymphoma in Malawi: a report of three cases. AB - BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTCL) reports from sub-Saharan Africa (SSA) are remarkably rare, despite early childhood acquisition and high prevalence of the causative infectious agent, Epstein-Barr virus (EBV), and frequent occurrence of other lymphoproliferative disorders causally associated with EBV. CASE PRESENTATIONS: At a national teaching hospital in Malawi, three patients of African descent were seen with ENKTCL between 2013 and 2014. Patients were aged between 29 and 60 years, two with craniofacial involvement and one with a primary abdominal tumor, and all were HIV-negative. All had systemic B symptoms, and two severely impaired performance status. On histologic review, morphology and immunophenotyping demonstrated classical ENKTCL features in all cases, including diffuse proliferations of intermediate-to-large atypical lymphocytes with high mitotic activity and extensive background necrosis, positivity for CD3 and CD56, and negativity for CD20. By in situ hybridization, all three tumors were positive for EBV-encoded RNA (EBER). Baseline plasma EBV DNA was also markedly elevated for all three patients. Due to radiotherapy and chemotherapy limitations, patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with rapid disease progression. All three patients died from progressive lymphoma within 3 months of initial diagnosis. CONCLUSIONS: Our experience with these three patients in Malawi can highlight that ENKTCL does indeed occur in SSA, increase familiarity with ENKTCL among clinicians and pathologists throughout the region, and emphasize the need for better diagnosis and treatment for this neglected population. PMID- 28877679 TI - microRNAs participate in gene expression regulation and phytohormone cross-talk in barley embryo during seed development and germination. AB - BACKGROUND: Small RNA and degradome sequencing have identified a large number of miRNA-target pairs in plant seeds. However, detailed spatial and temporal studies of miRNA-mediated regulation, which can reflect links between seed development and germination are still lacking. RESULTS: In this study, we extended our investigation on miRNAs-involved gene regulation by a combined analysis of seed maturation and germination in barley. Through bioinformatics analysis of small RNA sequencing data, a total of 1324 known miRNA families and 448 novel miRNA candidates were identified. Of those, 16 known miRNAs with 40 target genes, and three novel miRNAs with four target genes were confirmed based on degradome sequencing data. Conserved miRNA families such as miR156, miR168, miR166, miR167, and miR894 were highly expressed in embryos of developing and germinating seeds. A barley-specific miRNA, miR5071, which was predicted to target an OsMLA10-like gene, accumulated at a high level, suggesting its involvement in defence response during these two developmental stages. Based on target prediction and Kyoto Encyclopedia of Genes and Genomes analysis of putative targets, nine highly expressed miRNAs were found to be related to phytohormone signalling and hormone cross-talk. Northern blot and qRT-PCR analysis showed that these miRNAs displayed differential expression patterns during seed development and germination, indicating their different roles in hormone signalling pathways. In addition, we showed that miR393 affected seed development through targeting two genes encoding the auxin receptors TIR1/AFBs in barley, as over-expression of miR393 led to an increased length-width ratio of seeds, whereas target mimic (MIM393)-mediated inhibition of its activity decreased the 1000-grain weight of seeds. Furthermore, the expression of auxin-responsive genes, abscisic acid- and gibberellic acid related genes was altered in miR393 misexpression lines during germination and early seedling growth. CONCLUSIONS: Our work indicates that miRNA-target pairs participate in gene expression regulation and hormone interaction in barley embryo and provides evidence that miR393-mediated auxin response regulation affects grain development and influences gibberellic acid and abscisic acid homeostasis during germination. PMID- 28877680 TI - Longitudinal studies that use data collected as part of usual care risk reporting biased results: a systematic review. AB - BACKGROUND: Longitudinal studies using data collected as part of usual care risk providing biased results if visit times are related to the outcome of interest. Statistical methods for mitigating this bias are available but rarely used. This lack of use could be attributed to a lack of need or to a lack of awareness of the issue. METHODS: We performed a systematic review of longitudinal studies that used data collected as part of patients' usual care and were published in MEDLINE or EMBASE databases between January 2005 through May 13th 2015. We asked whether the extent of and reasons for variability in visit times were reported on, and in cases where there was a need to account for informativeness of visit times, whether an appropriate method was used. RESULTS: Of 44 eligible articles, 57% (n = 25) reported on the total follow-up time, 7% (n = 3) on the gaps between visits, and 57% (n = 25) on the number of visits per patient; 78% (n = 34) reported on at least one of these. Two studies assessed predictors of visit times, and 86% of studies did not report enough information to assess whether there was a need to account for informative follow-up. Only one study used a method designed to account for informative visit times. CONCLUSIONS: The low proportion of studies reporting on whether there were important predictors of visit times suggests that researchers are unaware of the potential for bias when data is collected as part of usual care and visit times are irregular. Guidance on the potential for bias and on the reporting of longitudinal studies subject to irregular follow-up is needed. PMID- 28877681 TI - Fibronectin glomerulopathy complicated with persistent cloaca and congenital esophageal atresia: a case report and literature review. AB - BACKGROUND: Fibronectin glomerulopathy is a rare, inherited, autosomal dominant, glomerular disease characterized by proteinuria, microscopic hematuria, hypertension, massive glomerular deposits of fibronectin, and slow progression to end-stage renal failure. Because the incident of fibronectin glomerulopathy is extremely low, the pathophysiology, genetic abnormalities, epidemiology, and mechanisms remain to be elucidated. CASE PRESENTATION: We report a 21-year-old woman with fibronectin glomerulopathy, who had been diagnosed with persistent cloaca and congenital esophageal atresia at birth. She developed proteinuria and hematuria 7 months before admission. Urinary protein and serum creatinine levels were 3.38 g/gCr and 0.73 mg/dL. Renal biopsy showed severe mesangial widening due to massive deposits, which was positive periodic acid-Schiff and negative methenamine silver. Immunostaining was negative for immunoglobulin but positive for fibronectin. Electron microscopy showed diffuse mesangial granular deposits. Thus she was diagnosed with fibronectin glomerulopathy, despite a negative family history of kidney disease and lack of any known missense mutations of fibronectin 1 gene. CONCLUSION: We report a patient who developed fibronectin glomerulopathy during the clinical course of extremely rare congenital malformations, including persistent cloaca and congenital esophageal atresia. We describe a case of this condition in detail and summarize the 75 case reports of fibronectin glomerulopathy. PMID- 28877682 TI - Epidemiologic and clinical parameters of West Nile virus infections in humans: a scoping review. AB - BACKGROUND: Clinical syndromes associated with West Nile virus (WNV) infection range from fever to neuroinvasive disease. Understanding WNV epidemiology and disease history is important for guiding patient care and healthcare decision making. The objective of this review was to characterize the existing body of peer-reviewed and surveillance literature on WNV syndromes and summarize epidemiologic and clinical parameters. METHODS: We followed scoping review methodology described by the Joanna Briggs Institute. Terms related to WNV epidemiology, hospitalization, and surveillance were searched in four bibliographic databases (MEDLINE, EMBASE, Scopus, and CINAHL) for literature published from January 1999 to December 2015. RESULTS: In total, 2334 non duplicated titles and abstracts were screened; 92 primary studies were included in the review. Publications included one randomized controlled trial and 91 observational studies. Sample sizes ranged from under 25 patients (n = 19) to over 400 patients (n = 28). Eight studies were from Canada, seven from Israel, and the remaining (n = 77) from the United States. N = 17 studies were classified as outbreak case investigations following epidemics; n = 37 with results of regional/national surveillance and monitoring programs. Mean patient ages were > 40 years old; three studies (3%) focused on the pediatric population. Patients with encephalitis fared worse than patients with meningitis and fever, considering hospitalization, length of stay, discharge, recovery, and case fatality. Several studies examined risk factors; however, age was the only risk factor for neuroinvasive disease/death consistently identified. Overall, patients with acute flaccid paralysis or encephalitis fared worse than patients with meningitis and West Nile fever in terms of hospitalization and mortality. Among the included studies, proportion hospitalized, length of stay, proportion discharged home and case-fatality ranged considerably. CONCLUSION: Our review highlights the heterogeneity among reporting clinical WNV syndromes and epidemiologic parameters of WNV-related illness. Presently, there is potential for further synthesis of the risk factors of WNV-illness and mortality; undertaking further analysis through a systematic review and meta-analysis may benefit our understanding of risk factors for emerging mosquito-borne diseases. Future research on the burden of WNV can build on existing evidence summarized in this review, not only to support our understanding of endemic WNV, but also to strengthen research on emerging arboviruses with similar clinical manifestations. PMID- 28877683 TI - Genome-wide association study reveals putative role of gga-miR-15a in controlling feed conversion ratio in layer chickens. AB - BACKGROUND: Efficient use of feed resources for farm animals is a critical concern in animal husbandry. Numerous genetic and nutritional studies have been conducted to investigate feed efficiency during the regular laying cycle of chickens. However, by prolonging the laying period of layers, the performance of feed utilization in the late-laying period becomes increasingly important. In the present study, we measured daily feed intake (FI), residual feed intake (RFI) and feed conversion ratio (FCR) of 808 hens during 81-82 weeks of age to evaluate genetic properties and then used a genome-wide association study (GWAS) to reveal the genetic determinants. RESULTS: The heritability estimates for the investigated traits were medium and between 0.15 and 0.28 in both pedigree- and genomic-based estimates, whereas the genetic correlations among these traits were high and ranged from 0.49 to 0.90. Three genome-wide significant SNPs located on chromosome 1 (GGA1) were detected for FCR. Linkage disequilibrium (LD) and conditional GWA analysis indicated that these 3 SNPs were highly correlated with one another, located at 13.55-45.16 Kb upstream of gga-miR-15a. Results of quantitative real-time polymerase chain reaction (qRT-PCR) analysis in liver tissue showed that the expression of gga-miR-15a was significantly higher in the high FCR birds than that in the medium or low FCR birds. Bioinformatics analysis further revealed that gga-mir-15a could act on many target genes, such as forkhead box O1 (FOXO1) that is involved in the insulin-signaling pathway, which influences nutrient metabolism in many organisms. Additionally, some suggestively significant variants, located on GGA3 and GGA9, were identified to associate with FI and RFI. CONCLUSIONS: This GWA analysis was conducted on feed intake and efficiency traits for chickens and was innovative for application in the late laying period. Our findings can be used as a reference in the genomic breeding programs for increasing the efficiency performance of old hens and to improve our understanding of the molecular determinants for feed efficiency. PMID- 28877684 TI - Medical and sociodemographic factors predict persistent smoking after coronary events. AB - BACKGROUND: Understanding the determinants of persistent smoking after a coronary event constitutes the basis of modelling interventions of smoking cessation in secondary prevention programs. We aim to identify the potentially modifiable medical, sociodemographic and psychosocial factors, comprising the study factors, associated with unfavourable risk factor control after CHD events. METHODS: A cross-sectional explorative study used logistic regression analysis to investigate the association between study factors and smoking status in 1083 patients hospitalized with myocardial infarction and/or coronary revascularization. Hospital record data, a self-report questionnaire, clinical examination and blood samples were applied. RESULTS: At the index hospitalization, 390 patients were smoking and at follow-up after 2-36 months 167 (43%) of these had quit, while 230 reported persistent smoking. In adjusted analyses, unemployed or disability benefits (Odds ratio (OR) 4.1), low education (OR 3.5), longer smoking duration (OR 2.3) and not having ST-elevation myocardial infarction (STEMI) as index event (OR 2.3) were significantly associated with persistent smoking. Psychosocial factors at follow-up were not associated with persistent smoking. Smokers reported high motivation for cessation, with 68% wanting help to quit. Only 42% had been offered nicotine replacement therapy or other cessation aids. Smokers rated use of tobacco as the most important cause of their coronary disease (6.8 on a 1-10 Likert scale). CONCLUSIONS: Low socioeconomic status, prior duration of smoking, and not having STEMI as index event were associated with persisting smoking. Persistent smokers in this study seem to have an acceptable risk perception and were motivated to cease smoking, but needed assistance through cessation programs including prescription of pharmacological aids. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT02309255 , registered retrospectively. PMID- 28877685 TI - Positive regulation of prostate cancer cell growth by lipid droplet forming and processing enzymes DGAT1 and ABHD5. AB - BACKGROUND: Neoplastic cells proliferate rapidly and obtain requisite building blocks by reprogramming metabolic pathways that favor growth. Previously, we observed that prostate cancer cells uptake and store lipids in the form of lipid droplets, providing building blocks for membrane synthesis, to facilitate proliferation and growth. Mechanisms of lipid uptake, lipid droplet dynamics and their contribution to cancer growth have yet to be defined. This work is focused on elucidating the prostate cancer-specific modifications in lipid storage pathways so that these modified gene products can be identified and therapeutically targeted. METHODS: To identify genes that promote lipid droplet formation and storage, the expression profiles of candidate genes were assessed and compared between peripheral blood mononuclear cells and prostate cancer cells. Subsequently, differentially expressed genes were inhibited and growth assays performed to elucidate their role in the growth of the cancer cells. Cell cycle, apoptosis and autophagy assays were performed to ascertain the mechanism of growth inhibition. RESULTS: Our results indicate that DGAT1, ABHD5, ACAT1 and ATGL are overexpressed in prostate cancer cells compared to PBMCs and of these overexpressed genes, DGAT1 and ABHD5 aid in the growth of the prostate cancer cells. Blocking the expression of both DGAT1 and ABHD5 results in inhibition of growth, cell cycle block and cell death. DGAT1 siRNA treatment inhibits lipid droplet formation and leads to autophagy where as ABHD5 siRNA treatment promotes accumulation of lipid droplets and leads to apoptosis. Both the siRNA treatments reduce AMPK phosphorylation, a key regulator of lipid metabolism. While DGAT1 siRNA reduces phosphorylation of ACC, the rate limiting enzyme in de novo fat synthesis and triggers phosphorylation of raptor and ULK-1 inducing autophagy and cell death, ABHD5 siRNA decreases P70S6 phosphorylation, leading to PARP cleavage, apoptosis and cell death. Interestingly, DGAT-1 is involved in the synthesis of triacylglycerol where as ABHD5 is a hydrolase and participates in the fatty acid oxidation process, yet inhibition of both enzymes similarly promotes prostate cancer cell death. CONCLUSION: Inhibition of either DGAT1 or ABHD5 leads to prostate cancer cell death. Both DGAT1 and ABHD5 can be selectively targeted to block prostate cancer cell growth. PMID- 28877686 TI - Disease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia - identification of responders by gene expression profiling of pretreatment leukemic cells. AB - BACKGROUND: Acute myeloid leukemia (AML) is an aggressive malignancy only cured by intensive therapy. However, many elderly and unfit patients cannot receive such treatment due to an unacceptable risk of treatment-related morbidity and mortality. Disease-stabilizing therapy is then the only possible strategy, one alternative being treatment based on all-trans retinoic acid (ATRA) combined with the histone deacetylase inhibitor valproic acid and possibly low-toxicity conventional chemotherapy. METHODS: Primary AML cells were derived from 43 patients included in two clinical studies of treatment based on ATRA, valproic acid and theophyllamine; low toxicity chemotherapy (low-dose cytarabine, hydroxyurea, 6-mercaptopurin) was also allowed. Pretreatment leukemic cells were analyzed by mutation profiling of 54 genes frequently mutated in myeloid malignancies and by global gene expression profiling before and during in vivo treatment. RESULTS: Patients were classified as responders and non-responders to the treatment, however response to treatment showed no significant associations with karyotype or mutational profiles. Significance analysis of microarray (SAM) showed that responders and non-responders significantly differed with regard to the expression of 179 different genes. The differentially expressed genes encoding proteins with a known function were further classified based on the PANTHER (protein annotation through evolutionary relationship) classification system. The identified genes encoded proteins that are involved in several important biological functions, but a main subset of the genes were important for transcriptional regulation. These pretherapy differences in gene expression were largely maintained during treatment. Our analyses of primary AML cells during in vivo treatment suggest that ATRA modulates HOX activity (i.e. decreased expression of HOXA3, HOXA4 and HOXA5 and their regulator PBX3), but altered function of DNA methyl transferase 3A (DNMT3A) and G-protein coupled receptor signaling may also contribute to the effect of the overall treatment. CONCLUSIONS: Responders and non-responders to AML stabilizing treatment based on ATRA and valproic acid differ in the pretreatment transcriptional regulation of their leukemic cells, and these differences may be important for the clinical effect of this treatment. TRIAL REGISTRATIONS: ClinicalTrials.gov no. NCT00175812 ; EudraCT no. 2004-001663-22, registered September 9, 2005 and ClinicalTrials.gov no. NCT00995332 ; EudraCT no. 2007-2007-001995-36, registered October 14, 2009. PMID- 28877687 TI - Factors associated with utilization of long-acting and permanent contraceptive methods among women who have decided not to have more children in Gondar city. AB - BACKGROUND: Despite the fact that long acting family planning methods reduce population growth and improve maternal health, their utilization remains poor. Therefore, this study assessed the prevalence of long acting and permanent family planning method utilization and associated factors among women in reproductive age groups who have decided not to have more children in Gondar city, northwest Ethiopia. METHOD: An institution based cross-sectional study was conducted from August to October, 2015. Three hundred seventeen women who have decided not to have more children were selected consecutively into the study. A structured and pretested questionnaire was used to collect data. Both bivariate and multi variable logistic regressions analyses were used to identify factors associated with utilization of long acting and permanent family planning methods. The multi variable logistic regression analysis was used to investigate factors associated with the utilization of long acting and permanent family planning methods. The Adjusted Odds Ratio (AOR) with the corresponding 95% Confidence Interval (CI) was used to show the strength of associations, and variables with a P-value of <0.05 were considered statistically significant. RESULTS: In this study, the overall prevalence of long acting and permanent contraceptive (LAPCM) method utilization was 34.7% (95% CI: 29.5-39.9). According to the multi-variable logistic regression analysis, utilization of long acting and permanent contraceptive methods was significantly associated with women who had secondary school, (AOR: 2279, 95% CI: 1.17, 4.44), college, and above education (AOR: 2.91, 95% CI: 1.36, 6.24), history of previous utilization (AOR: 3.02, 95% CI: 1.69, 5.38), and information about LAPCM (AOR: 8.85, 95% CI: 2.04, 38.41). CONCLUSION: In this study the prevalence of long acting and permanent family planning method utilization among women who have decided not to have more children was high compared with previous studies conducted elsewhere. Advanced educational status, previous utilization of LAPCM, and information on LAPCM were significantly associated with the utilization of LAPCM. As a result, strengthening behavioral change communication channels to make information accessible is highly recommended. PMID- 28877689 TI - A national survey of Chinese medicine doctors and clinical practice guidelines in China. AB - BACKGROUND: Clinical practice guidelines (CPGs) for Chinese medicine (CM) are being developed to assist doctors with appropriate decisions concerning CM care. To date, there has been little investigation on the perspectives of those to whom the guidelines are directed. METHODS: A self-administered questionnaire was sent to 4503 doctors in 28 provinces of China in the latter half of 2012. Questions were organized around the topics of knowledge, application, practice changes, beliefs and outcomes of implementation. Basic classificatory data on specialties and years of qualification were also collected. RESULTS: Replies were received from 4495 CM doctors (99.82%). Of these, 85.56% of CM doctors reported being familiar with CPG recommendations, but the overall adherence rate was only 50.39%. The length of time practicing CM may influence the rate of adherence, since 709 doctors (51.90%) with less than 5 years of experience reported never having followed CPGs. Doctors in nine specialties showed a modest degree of homogeneity in their attitudes towards CM diagnosis and treatment, which were generally positive. Most doctors regarded CPG-recommended therapies as safe (92%), economic (84%), and effective (76%). Approximately four-fifths of those questioned selected 'acceptable' (60.84%) and 'acceptable after revision' (19.23%) regarding their comprehensive assessment of the CPGs. CONCLUSIONS: An encouraging result from this survey is that the majority of CM doctors support the concept of CPGs for the practice of CM. However, the results of this survey also suggest that improving the adherence of CM doctors to the guidelines remains a major challenge to improving the practice standards for CM. PMID- 28877688 TI - Effects of hyaluronic acid combined with anti-inflammatory drugs compared with hyaluronic acid alone, in clinical trials and experiments in osteoarthritis: a systematic review and meta-analysis. AB - BACKGROUND: The objectives are to compare the efficacy of intra-articular hyaluronic acid (IA-HA) alone and in combination with anti-inflammatory drugs (IA HA + AI), corticosteroids (CS) or non-steroidal anti-inflammatory drugs (NSAIDs) in clinical trials and in vivo and in vitro studies of osteoarthritis (OA). METHODS: Data in the BIOSIS, CINAHL, Cochrane Library, EMBASE and Medline databases were collected and analyzed. Random effects models were used to compute the effect size (ES) of the mean difference in pain reduction scores from baseline and the relative risk (RR) of adverse events. The ES of histological scores in vivo and cartilage metabolism in vitro were also calculated. We conducted sensitivity analysis of blinding and intention-to-treat (ITT), compared IA-HA combined with CS vs. IA-HA alone in trials, and compared the effects of HA + AI vs. AI alone in vitro, including anabolic and catabolic gene expression. RESULTS: Thirteen out of 382 papers were included for data analysis. In clinical trials, the ES of pain reduction scores within the 1st month was -4.24 (-6.19, 2.29); 2nd-12th month, -1.39 (-1.95, -0.82); and within one year, -1.63 (-2.19, 1.08), favoring IA-HA + AI (P < 0.001). The ES of RR was 1.08 (0.59, 1.98), and histological scores was 1.38 (-0.55, 3.31). The ES of anabolic gene expression was 1.22 (0.18, 2.25), favoring HA alone (P < 0.05); catabolic gene expression was 0.74 (-0.44, 1.53), favoring HA alone; and glycosaminoglycans remaining was 2.45 (-5.94, 1.03). CONCLUSIONS: IA-HA + AI had greater efficacy for pain relief than IA-HA alone within a one-year period. However, HA + AI down-regulated the ACAN gene when compared with HA alone in vitro. PMID- 28877690 TI - Gypenosides ameliorate memory deficits in MPTP-lesioned mouse model of Parkinson's disease treated with L-DOPA. AB - BACKGROUND: Previous studies have revealed that gypenosides (GPS) improve the symptoms of anxiety disorders in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rat model of Parkinson's disease (PD). The present study aimed to investigate the effects of GPS on memory deficits in an MPTP-lesioned mouse model of PD treated with L-3,4-dihydroxyphenylalanine (L-DOPA). METHODS: MPTP (30 mg/kg/day, 5 days)-lesioned mice were treated with GPS (50 mg/kg) and/or L-DOPA (10 and 25 mg/kg) for 21 days. After the final treatments, behavioral changes were assessed in all mice using passive avoidance and elevated plus-maze tests. We then evaluated the biochemical influences of GPS treatment on levels of tyrosine hydroxylase (TH), dopamine, N-methyl-D-aspartate (NMDA) receptors, extracellular signal-regulated kinase (ERK1/2), and cyclic AMP-response element binding protein (CREB) phosphorylation. RESULTS: MPTP-lesioned mice exhibited deficits associated with habit learning and spatial memory, which were further aggravated by treatment with L-DOPA (25 mg/kg). However, treatment with GPS (50 mg/kg) ameliorated memory deficits. Treatment with GPS (50 mg/kg) also improved L DOPA (25 mg/kg)-treated MPTP lesion-induced decreases in retention latency on the passive avoidance test, as well as levels of TH-immunopositive cells and dopamine in the substantia nigra and striatum. GPS treatment also attenuated increases in retention transfer latency on the elevated plus-maze test and in NMDA receptor expression, as well as decreases in the phosphorylation of ERK1/2 and CREB in the hippocampus. Treatment with L-DOPA (10 mg/kg) also ameliorated deficits in habit learning and spatial memory in MPTP-lesioned mice, and this effect was further enhanced by treatment with GPS (50 mg/kg). CONCLUSION: GPS ameliorate deficits in habit learning and spatial memory by modulating the dopaminergic neuronal and N methyl-D-aspartate receptor-mediated signaling systems in MPTP-lesioned mice treated with L-DOPA. GPS may serve as an adjuvant therapeutic agent for memory deficits in patients with PD receiving L-DOPA. PMID- 28877691 TI - Alternative moth-eye nanostructures: antireflective properties and composition of dimpled corneal nanocoatings in silk-moth ancestors. AB - Moth-eye nanostructures are a well-known example of biological antireflective surfaces formed by pseudoregular arrays of nipples and are often used as a template for biomimetic materials. Here, we provide morphological characterization of corneal nanostructures of moths from the Bombycidae family, including strains of domesticated Bombyx mori silk-moth, its wild ancestor Bombyx mandarina, and a more distantly related Apatelodes torrefacta. We find high diversification of the nanostructures and strong antireflective properties they provide. Curiously, the nano-dimple pattern of B. mandarina is found to reduce reflectance as efficiently as the nanopillars of A. torrefacta. Access to genome sequence of Bombyx further permitted us to pinpoint corneal proteins, likely contributing to formation of the antireflective nanocoatings. These findings open the door to bioengineering of nanostructures with novel properties, as well as invite industry to expand traditional moth-eye nanocoatings with the alternative ones described here. PMID- 28877693 TI - Comparison of radiofrequency ablation and partial nephrectomy for tumor in a solitary kidney. AB - BACKGROUND: To estimate oncologic and functional outcomes for radiofrequency ablation (RFA) versus partial nephrectomy (PN) for tumors in a solitary kidney. METHODS: Nineteen patients with sporadic renal cell carcinoma in a solitary kidney were treated with RFA, and 21 patients were treated with PN between November 2008 and September 2015. Basic demographic information including age, gender, operative and pathological data, complications, renal function, oncological outcomes, was obtained for each patient. Statistical analysis was done to test for the correlation of clinical and pathological features, renal function outcomes, as well as oncological outcomes of RFA and PN. All statistical tests were 2-sided, and p-value < 0.05 was considered significant. Statistical analyses were performed using SPSS 19.0. RESULTS: No significant differences were indicated between the RFA and PN with respect to mean patient age, tumor size, as well as intraoperative or postoperative complications. The mean length of hospitalization (P = 0.019) and mean operative time (P = 0.036) was significantly shorter in RFA, with the median estimated blood loss being greater in PN (P = 0.001). The mean serum creatinine level 24 h following operation were significantly higher than preoperative creatinine in PN (P = 0.009), but did not reach statistical significance in RFA. Local recurrence were detected in only 1 patient (5%) in PN and 3 patients (18.75%) in RFA (P = 0.4). One patient developed pulmonary metastasis and one exhibited tumor persistence in RFA, none were present in PN. CONCLUSIONS: Radiofrequency Ablation and Partial Nephrectomy for Tumors in a Solitary Kidney were all safe and effective, with each method having distinct advantages. It is the decision of the patient and urologist to pick the best approach. PMID- 28877694 TI - Assembling and validating data from multiple sources to study care for Veterans with bladder cancer. AB - BACKGROUND: Despite the high prevalence of bladder cancer, research on optimal bladder cancer care is limited. One way to advance observational research on care is to use linked data from multiple sources. Such big data research can provide real-world details of care and outcomes across a large number of patients. We assembled and validated such data including (1) administrative data from the Department of Veterans Affairs (VA), (2) Medicare claims, (3) data abstracted by tumor registrars, (4) data abstracted via chart review from the national electronic health record, and (5) full text pathology reports. METHODS: Based on these combined data, we used administrative data to identify patients with newly diagnosed bladder cancer who received care in the VA. To validate these data, we first compared the diagnosis date from the administrative data to that from the tumor registry. Second, we measured accuracy of identifying bladder cancer care in VA administrative data, using a random chart review (n = 100) as gold standard. Lastly, we compared the proportion of patients who received bladder cancer care among those who did versus did not have full text bladder pathology reports available, expecting that those with reports are significantly more likely to receive care in VA. RESULTS: Out of 26,675 patients, 11,323 (42%) had tumor registry data available. 90% of these patients had a difference of 90 days or less between the diagnosis dates from administrative and registry data. Among 100 patients selected for chart review, 59 received bladder cancer care in VA, 58 of which were correctly identified using administrative data (sensitivity 98%, specificity 90%). Receipt of bladder cancer care was substantially more common among those who did versus did not have bladder pathology available (96% vs. 43%, p < 0.001). CONCLUSION: Merging administrative with electronic health record and pathology data offers new possibilities to validate the use of administrative data in bladder cancer research. PMID- 28877692 TI - The use of a P. falciparum specific coiled-coil domain to construct a self assembling protein nanoparticle vaccine to prevent malaria. AB - BACKGROUND: The parasitic disease malaria remains a major global public health concern and no truly effective vaccine exists. One approach to the development of a malaria vaccine is to target the asexual blood stage that results in clinical symptoms. Most attempts have failed. New antigens such as P27A and P27 have emerged as potential new vaccine candidates. Multiple studies have demonstrated that antigens are more immunogenic and are better correlated with protection when presented on particulate delivery systems. One such particulate delivery system is the self-assembling protein nanoparticle (SAPN) that relies on coiled-coil domains of proteins to form stable nanoparticles. In the past we have used de novo designed amino acid domains to drive the formation of the coiled-coil scaffolds which present the antigenic epitopes on the particle surface. RESULTS: Here we use naturally occurring domains found in the tex1 protein to form the coiled-coil scaffolding of the nanoparticle. Thus, by engineering P27A and a new extended form of the coiled-coil domain P27 onto the N and C terminus of the SAPN protein monomer we have developed a particulate delivery system that effectively displays both antigens on a single particle that uses malaria tex1 sequences to form the nanoparticle scaffold. These particles are immunogenic in a murine model and induce immune responses similar to the ones observed in seropositive individuals in malaria endemic regions. CONCLUSIONS: We demonstrate that our P27/P27A-SAPNs induce an immune response akin to the one in seropositive individuals in Burkina Faso. Since P27 is highly conserved among different Plasmodium species, these novel SAPNs may even provide cross-protection between Plasmodium falciparum and Plasmodium vivax the two major human malaria pathogens. As the SAPNs are also easy to manufacture and store they can be delivered to the population in need without complication thus providing a low cost malaria vaccine. PMID- 28877695 TI - Methodological barriers to studying the association between the economic crisis and suicide in Spain. AB - BACKGROUND: The hypothetical relationship between economic recession and the increase in suicides in Spain is subject to various arguments. In addition to the inherent complexity of capturing and explaining the underlining mechanisms that could describe this causal link, different points of contention have been be identified. The period of this association and its possible starting points, the socioeconomic determinants that may explain the variation in suicide rate, and the data sources available are the main focus of controversy. The present study aims to identify the phases of association between different periods of economic recession and suicide rates, and compare the effect of different social determinants of health that have been mentioned in previous studies. METHODS: We have used interrupted time series analyses to assess the impact of economic recession on national rates of suicide mortality provided by the Spanish Statistical Office (1980-2014). In an attempt to consider the factors that have affected the study of suicide in Spain, different data sources/periods, predictors, and regions in Spain were analysed. RESULTS: The analysis revealed a positive and significant relationship between the Great Recession and suicide rates during the second period of economic recession (2011-2014), while appeared to decrease during the first recession period. However, the first decreasing trend was not statistically significant in the global analysis of the evolution of monthly suicide rates for the entire country. Both unemployment and per capita GDP were positively related to suicide trends. Finally, the regional analysis demonstrates a similar pattern in different Spanish areas. CONCLUSION: Although previous studies have mentioned the double-dip in the suicide rate associated with the corresponding period of double recession, our study only identify a positive relationship during the second recession period. These results points out that the major impact of economic problems might have had a delayed effect due to initial protection policies. PMID- 28877697 TI - Enhancing the get healthy information and coaching service for Aboriginal adults: evaluation of the process and impact of the program. AB - BACKGROUND: Non-communicable chronic diseases in Australia contribute to approximately 85% of the total burden of disease; this proportion is greater for Aboriginal communities. The Get Healthy Service (GHS) is effective at reducing lifestyle-based chronic disease risk factors among adults and was enhanced to facilitate accessibility and ensure Aboriginal cultural appropriateness. The purpose of this study is to detail how formative research with Aboriginal communities was applied to guide the development and refinement of the GHS and referral pathways; and to assess the reach and impact of the GHS (and the Aboriginal specific program) on the lifestyle risk factors of Aboriginal participants. METHODS: Formative research included interviews with Aboriginal participants, leaders and community members, healthcare professionals and service providers to examine acceptability of the GHS; and contributed to the redesign of the GHS Aboriginal program. A quantitative analysis employing a pre-post evaluation design examined anthropometric measures, physical activity and fruit and vegetable consumption of Aboriginal participants using descriptive and chi square analyses, t-tests and Wilcoxon signed-rank tests. RESULTS: Whilst feedback from the formative research was positive, Aboriginal people identified areas for service enhancement, including improving program content, delivery and service promotion as well as ensuring culturally appropriate referral pathways. Once these changes were implemented, the proportion of Aboriginal participants increased significantly (3.2 to 6.4%). There were significant improvements across a number of risk factors assessed after six months (average weight loss: 3.3 kg and waist circumference reduction: 6.2 cm) for Aboriginal participants completing the program. CONCLUSIONS: Working in partnership with Aboriginal people, Elders, communities and peak bodies to enhance the GHS for Aboriginal people resulted in an enhanced culturally acceptable and tailored program which significantly reduced chronic disease risk factors for Aboriginal participants. Mainstream telephone based services can be modified and enhanced to meet the needs of Aboriginal communities through a process of consultation, community engagement, partnership and governance. PMID- 28877696 TI - Oral administration of taheebo (Tabebuia avellanedae Lorentz ex Griseb.) water extract prevents DSS-induced colitis in mice by up-regulating type II T helper immune responses. AB - BACKGROUND: Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders that are mediated by pathogenic Th1 and Th17 cells. Previous studies have demonstrated that taheebo water extract (TWE) derived from Tabebuia avellanedae Lorentz ex Griseb., as folk remedy, has been used to treat various inflammatory diseases. Although TWE has been previously shown to display anti-inflammatory activities, the in vivo effects of TWE on mucosal immune responses remain unclear. METHODS: We examined the anti-inflammatory effects of TWE on innate immune cells such as dendritic cells (DCs) and macrophages and also on the differentiation of T helper cells. Lastly, adopting a method for dextran sulfate sodium (DSS)-induced colitis, we investigated whether the oral administration of TWE can modulate mucosal inflammatory responses. RESULTS: We found that TWE could activate DCs to produce immunosuppressive IL10 and polarize macrophages toward an anti-inflammatory phenotype in the mesenteric lymph node (MLN). Such alterations in DCs and macrophages resulted in a significant increase in anti-inflammatory Th2 and Foxp3+ Treg cells and a dramatic decrease in pro-inflammatory Th1 and Th17 cells in the MLN. Upon induction of colitis with DSS treatment, TWE significantly reduced the clinical symptoms, including body weight loss and colonic tissue inflammation, by up-regulating type II T helper immune responses. CONCLUSIONS: Taken together, these data suggest that TWE is an excellent natural product with therapeutic effects to help improve inflammatory disorders such as colitis. PMID- 28877698 TI - Subchronic toxicity of herbal compound "Jiedu Huayu" granules in rats. AB - BACKGROUND: "Jiedu Huayu" (JDHY) granules are traditional Chinese herbal compounds that have been used to treat severe liver injury for many years. The purpose of the current study is to evaluate the safety of JDHY granules. METHODS: Subchronic toxicity was tested in male and female rats that were orally administered three different doses (80, 100, and 130 g/kg/d) of JDHY for 13 weeks. Clinical signs, bodyweight, food consumption, hematological and biochemical parameters, organ coefficients, and histological changes were observed during the study. RESULTS: There were no significant changes in toxicity observed in either sex at any dose of JDHY granules treatment. CONCLUSIONS: These results suggest that repeated oral administration of JDHY granules at dosage levels of <=130 g/kg/d can be considered safe. PMID- 28877699 TI - Honoring the voices of bereaved caregivers: a Metasummary of qualitative research. AB - BACKGROUND: Family caregiving in the context of advanced disease in particular, can be physically and emotionally taxing. Caregivers can subsequently face bereavement exhausted with few supports, limited resources and a significant proportion will develop negative psychological and social outcomes. Although some research has attended to the bereavement experiences of family caregivers who had cared for a person requiring palliative care, a comprehensive qualitative understanding of the impact of caregiving on bereavement has not been articulated. The purpose of this study was to conduct a qualitative metasummary to explore the experiences of bereaved family caregivers of people who received palliative care services, regardless of their underlying disease. METHODS: Sandelowski and Barroso's qualitative metasummary method was utilized: 1287 articles were identified through extensive database searches (i.e. - MEDLINE, PsychINFO, and CINAHL) and reviewed to determine if they fit the criteria. Those included in the review were assessed for study quality. Findings from each study were then thematically coded and a frequency of themes was calculated. RESULTS: The sample consisted of 47 qualitative studies. A total of 15 themes emerged. In descending order of frequency, the 15 themes were: the individual emotions of serenity, sadness, guilt, uncertainty, trauma, escape, and anger; post-loss experiences that helped the caregiver in bereavement; post-loss experiences that hindered; practical life changes; caregiver role identity; pre-loss experiences that helped; pre-loss experiences that hindered; caregiver context; and a need for different kinds of supports. Three key findings emerged from the themes: (1) many different aspects of the caregiving experience impact the bereavement experience, (2) every bereavement experience is unique, and (3) a variety of supports must be developed and made available to caregivers to meet these unique needs. CONCLUSIONS: Based on the metasummary findings, changes are needed in practice and policy to ensure the health and well-being of the family caregiver is maintained by offering support both during caregiving and bereavement. PMID- 28877700 TI - Testosterone inhibits the growth of prostate cancer xenografts in nude mice. AB - BACKGROUND: Traditional beliefs of androgen's stimulating effects on the growth of prostate cancer (PCa) have been challenged in recent years. Our previous in vitro study indicated that physiological normal levels of androgens inhibited the proliferation of PCa cells. In this in vivo study, the ability of testosterone (T) to inhibit PCa growth was assessed by testing the tumor incidence rate and tumor growth rate of PCa xenografts on nude mice. METHODS: Different serum testosterone levels were manipulated in male nude/nude athymic mice by orchiectomy or inserting different dosages of T pellets subcutaneously. PCa cells were injected subcutaneously to nude mice and tumor incidence rate and tumor growth rate of PCa xenografts were tested. RESULTS: The data demonstrated that low levels of serum T resulted in the highest PCa incidence rate (50%). This PCa incidence rate in mice with low T levels was significantly higher than that in mice treated with higher doses of T (24%, P < 0.01) and mice that underwent orchiectomy (8%, P < 0.001). Mice that had low serum T levels had the shortest tumor volume doubling time (112 h). This doubling time was significantly shorter than that in the high dose 5 mg T arm (158 h, P < 0.001) and in the orchiectomy arm (468 h, P < 0.001). CONCLUSION: These results indicated that low T levels are optimal for PCa cell growth. Castrate T levels, as seen after orchiectomy, are not sufficient to support PCa cell growth. Higher levels of serum T inhibited PCa cell growth. PMID- 28877701 TI - The prevalence of disrespect and abuse during facility-based maternity care in Malawi: evidence from direct observations of labor and delivery. AB - BACKGROUND: There is increasing evidence throughout the world that the negative treatment of pregnant women during labor and delivery can be a barrier to seeking skilled maternity care. At this time, there has been little quantitative evidence published on disrespect and abuse (D&A) in Malawi. The objective of this research is to describe the prevalence of disrespect and abuse during labor and delivery through the secondary analysis of direct clinical observations and to describe the association between the observation of D&A items with the place of delivery and client background characteristics. METHODS: As part of the evaluation of the Helping Babies Breathe intervention, direct observations of labor and delivery were conducted in August 2013 from 27 out of the 28 districts in Malawi. Frequencies of disrespect and abuse items organized around the Bowser and Hill categories of disrespect and abuse and presented in the White Ribbon Alliance's Universal Rights of Childbearing Women Framework were calculated. Bivariate analysis was done to assess the association between selected client background characteristics and the place of delivery with the disrespect and use during childbirth. RESULTS: A total of 2109 observations were made across 40 facilities (12 health centers and 28 hospitals) in Malawi. The results showed that while women were frequently greeted respectfully (13.9% were not), they were often not encouraged to ask the health provider questions (73.1%), were not given privacy (58.2%) and were not encouraged to have a support person present with them (83.2%). Results from the bivariate analysis did not show a consistent relationship between place of delivery and D&A items, where the odds of being shouted at was lower in a health center when compared to a hospital (OR: 0.19; CI: 0.59-0.62) while there was a higher odds of clients not being asked if they have any concerns if they were in a health center when compared to a hospital (OR: 2.40; CI: 1.06-5.44). Women who were HIV+ had significantly lower odds of not having audio and visual privacy (OR: 0.34, CI: 0.12-0.97), of not being asked about her preferred delivery position (OR: 0.17, CI: 0.05-0.65) and of not being asked if she has any other problems she is concerned about (OR 0.38, CI:0.15 0.96). CONCLUSION: This study is among the first to quantify the prevalence of disrespect and abuse during labor and delivery in Malawi through direct clinical observations. Measurement of the poor treatment of women during childbirth is essential for understanding the scope of the problem and how to address this issue. PMID- 28877702 TI - Psychosocial risk and protective factors for the health and well-being of professionals working in emergency and non-emergency medical transport services, identified via questionnaires. AB - BACKGROUND: Medical transport (MT) professionals are subject to considerable emotional demands due to their involvement in life-or-death situations and their exposure to the serious health problems of their clients. An increase in the demand for MT services has, in turn, increased interest in the study of the psychosocial risk factors affecting the health of workers in this sector. However, research thus far has not distinguished between emergency (EMT) and non emergency (non-EMT) services, nor between the sexes. Furthermore, little emphasis has been placed on the protective factors involved. The main objective of the present study is to identify any existing differential exposure - for reasons of work setting (EMT and non-EMT) or of gender - to the various psychosocial risk and protective factors affecting the health of MT workers. METHODS: Descriptive and transversal research with responses from 201 professionals. RESULTS: The scores obtained on the various psychosocial scales in our study - as indicators of future health problems - were more unfavourable for non-EMT workers than they were for EMT workers. Work setting, but not gender, was able to account for these differences. DISCUSSION: The scores obtained for the different psychosocial factors are generally more favourable for the professionals we surveyed than those obtained in previous samples. CONCLUSION: The significant differences observed between EMT and non-EMT personnel raise important questions regarding the organization of work in companies that carry out both services at the same time in the same territory. The relationships among the set of risk/protective factors suggests a need for further investigation into working conditions as well as a consideration of the workers' sense of coherence and subjective well-being as protective factors against occupational burnout syndrome. PMID- 28877703 TI - Influence of growth hormone treatment on radiographic indices of the spine: propensity-matched analysis. AB - BACKGROUND: We performed this study to investigate the influence of recombinant human growth hormone (rhGH) therapy on radiographic indices of the spine using propensity-matched analysis. METHODS: Patients with idiopathic short stature who had undergone both growth hormone therapy and whole-spine radiographs more than twice prior to 15 years of age were included in the patient group. Other patients who had undergone whole-spine radiographs more than twice prior to the same age during regular checkups for idiopathic scoliosis formed the control group. Propensity-matched analysis was performed to reduce the selection bias. The scoliosis Cobb angle, coronal balance, apical vertebral translation, apical rotation, and pelvic obliquity were measured from the radiographs taken at the periodic follow-ups. The rate of progression of the measurements was adjusted by multiple factors using a linear mixed model with sex as the fixed effect and age and each subject as the random effects. RESULTS: Using a propensity-matched analysis, 48 patients were finally included in both groups. The scoliosis Cobb angle increased by 1.0 degrees (p < 0.001) per year in the patient group, whereas there was no significant annual change in the control group (p = 0.496). Female patients showed a greater scoliosis Cobb angle (1.8 degrees , p = 0.039) compared with male patients. There was no significant difference between the patient and control groups in coronal balance (p = 0.264). Apical vertebral translation per year was increased by 1.2 mm (p < 0.001) in the patient group and 0.5 mm in the control group (p = 0.003). CONCLUSION: Radiographic examination revealed that growth hormone therapy for idiopathic short stature affected the progression of the scoliosis Cobb angle and apical vertebral translation on the coronal plane. Physicians should be aware that annual follow-up is required to evaluate the change in the curvature of the spine in patients undergoing rhGH treatment. PMID- 28877704 TI - Coproscopy and molecular screening for detection of intestinal protozoa. AB - BACKGROUND: Intestinal parasitosis is one of several health concerns about immigrants who travel from endemic to non-endemic regions. Reliable rapid sensitive diagnostic tools, for use in non-endemic regions, are urgently required to enable frequent assessment of immigrant workers in jobs where risk of local transmission is a particular concern (e.g. food-handlers). We assessed the burden of intestinal protozoa in newly arrived immigrants and those applying for renewal of work permits in Qatar (n = 735), by both microscopic examination of stool samples and by Real Time PCR methodology. RESULTS: Prevalence was considerably higher using RT-PCR compared with coproscopy (Blastocystis hominis: 65.2 vs 7.6%; Giardia duodenalis: 14.3 vs 2.9%; Entamoeba histolytica: 1.6 vs 1.2%). Dientamoeba fragilis was sought only by RT-PCR (prevalence of 25.4%). Prevalence of G. duodenalis was significantly higher in male subjects, associated with blue collar workers and declined over time. Prevalence of B. hominis varied significantly with region of origin of subjects with highest values recorded among African immigrants. Prevalence of D. fragilis also varied with region of origin of subjects, and was lower in young female subjects and in renewal applicants compared with first-time applicants for work permits. CONCLUSIONS: We strongly recommend that, henceforth, intestinal protozoa should be screened by RT PCR, with a particular focus on frequent assessment of immigrant food-handlers. PMID- 28877705 TI - Loxapine to control agitation during weaning from mechanical ventilation. AB - BACKGROUND: Weaning from mechanical ventilation (MV) may be impeded by the occurrence of agitation. Loxapine has the ability to control agitation without affecting spontaneous ventilation. The aim of this study was to establish whether loxapine would reduce MV weaning duration in agitated patients. METHODS: We performed a multicentre, double-blind, placebo-controlled, parallel group, randomised trial. Patients who were potential candidates for weaning but exhibited agitation (Richmond Agitation-Sedation Scale score >= 2) after sedation withdrawal were randomly assigned to receive either loxapine or placebo. In case of severe agitation, conventional sedation was immediately resumed. The primary endpoint was the time between first administration of loxapine or placebo and successful extubation. RESULTS: The trial was discontinued after 102 patients were enrolled because of an insufficient inclusion rate. Median times to successful extubation were 3.2 days in the loxapine group and 5 days in the placebo group (relative risk 1.2, 95% CI 0.75-1.88, p = 0.45). During the first 24 h, sedation was more frequently resumed in the placebo group (44% vs 17%, p = 0.01). CONCLUSIONS: In this prematurely stopped trial, loxapine did not significantly shorten weaning from MV. However, loxapine reduced the need for resuming sedation. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01193816 . Registered on 26 August 2010. PMID- 28877706 TI - Does exposure to the food environment differ by socioeconomic position? Comparing area-based and person-centred metrics in the Fenland Study, UK. AB - BACKGROUND: Retail food environments (foodscapes) are a recognised determinant of eating behaviours and may contribute to inequalities in diet. However, findings from studies measuring socioeconomic inequality in the foodscape have been mixed, which may be due to methodological differences. The aim of this cross-sectional study was to compare exposure to the foodscape by socioeconomic position using different measures, to test whether the presence, direction or amplitude of differences was sensitive to the choice of foodscape metric or socioeconomic indicator. METHODS: A sample of 10,429 adults aged 30-64 years with valid home address data were obtained from the Fenland Study, UK. Of this sample, 7270 participants also had valid work location data. The sample was linked to data on food outlets obtained from local government records. Foodscape metrics included count, density and proximity of takeaway outlets and supermarkets, and the percentage of takeaway outlets relative to all food outlets. Exposure metrics were area-based (lower super output areas), and person-centred (proximity to nearest; Euclidean and Network buffers at 800 m, 1 km, and 1 mile). Person centred buffers were constructed using home and work locations. Socioeconomic status was measured at the area-level (2010 Index of Multiple Deprivation) and the individual-level (highest educational attainment; equivalised household income). Participants were classified into socioeconomic groups and average exposures estimated. Results were analysed using the statistical and percent differences between the highest and lowest socioeconomic groups. RESULTS: In area based measures, the most deprived areas contained higher takeaway outlet densities (p < 0.001). However, in person-centred metrics lower socioeconomic status was associated with lower exposure to takeaway outlets and supermarkets (all home-based exposures p < 0.001) and socioeconomic differences were greatest at the smallest buffer sizes. Socioeconomic differences in exposure was similar for home and combined home and work measures. Measuring takeaway exposure as a percentage of all outlets reversed the socioeconomic differences; the lowest socioeconomic groups had a higher percentage of takeaway outlets compared to the middle and highest groups (p < 0.001). CONCLUSIONS: We compared approaches to measuring socioeconomic variation in the foodscape and found that the association was sensitive to the metric used. In particular, the direction of association varied between area- and person-centred measures and between absolute and relative outlet measures. Studies need to consider the most appropriate measure for the research question, and may need to consider multiple measures as a single measure may be context dependent. PMID- 28877707 TI - Semi-high-throughput detection of Plasmodium falciparum and Plasmodium vivax oocysts in mosquitoes using bead-beating followed by circumsporozoite ELISA and quantitative PCR. AB - BACKGROUND: The malaria infection status of mosquitoes is commonly determined by microscopic detection of oocysts on the dissected mosquito midgut. This method is labour-intensive, does not allow processing of large numbers of mosquitoes and can be challenging in terms of objective classification of oocysts. Here, a semi high-throughput bead-beating ELISA method is proposed for detection of the circumsporozoite protein (CSP) followed by confirmation by quantitative PCR (qPCR). METHODS: Cultured Plasmodium falciparum gametocytes were offered to Anopheles stephensi mosquitoes and examined by microscopy. After bead-beating, mosquito homogenate was examined by CSP-ELISA and 18S qPCR. As negative controls, mosquitoes that were offered a heat-inactivated gametocyte blood meal were used. The CSP-ELISA/qPCR methodology was applied to high and low-intensity infections of cultured P. falciparum gametocytes. A similar methodology optimized for P. vivax was used on mosquitoes that were offered blood from Ethiopian donors who were naturally infected with P. vivax. RESULTS: There was considerable variation in CSP-ELISA signal and qPCR values in mosquitoes with low oocyst intensities. There was a strong agreement mosquito positivity by CSP-ELISA and by qPCR in mosquitoes that fed on cultured P. falciparum material (agreement 96.9%; kappa = 0.97) and naturally infected P. vivax parasite carriers [agreement 92.4% (kappa = 0.83)]. CONCLUSIONS: The proposed bead-beating CSP-ELISA/qPCR methodology considerably increases throughput for the detection of mosquito infection. qPCR remains necessary to confirm infections in mosquitoes with low CSP-ELISA signal. This methodology may prove particularly useful for studies where very low mosquito infection prevalence is expected and study sites where experience with oocyst detection is limited. PMID- 28877708 TI - Fabry disease and incidence of cancer. AB - BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by deficient activity of alpha-galactosidase A and the resulting accumulation of the glycosphingolipid globotriaosylceramide (Gb3) and its derivatives, including globotriaosylsphingosine (Lyso-Gb3). Increased cellular and plasma levels of Gb3 and Lyso-Gb3 affect multiple organs, with specific clinical consequences for the kidneys, heart and brain. There is growing evidence that alterations in glycosphingolipids may have an oncogenic role and this prompted a review of cases of cancer and benign lesions in a large single centre cohort of Fabry patients. We also explored whether there is a difference in the risk of cancer in Fabry patients compared to the general population. RESULTS: Our results suggest that Fabry patients may have a marginally reduced rate of all cancer (incidence rate ratio 0.61, 95% confidence interval 0.37 to 0.99) but possibly increased rates of melanoma, urological malignancies and meningiomas. CONCLUSION: Greater knowledge and awareness of cancer in patients with Fabry disease may help identify at-risk individuals and elucidate cancer mechanisms in this rare inherited disease, which may potentially be relevant to the wider cancer population. PMID- 28877709 TI - Prevalence of Amyloidosis in Korea. AB - BACKGROUND: The aim of this study was to assess in amyloidosis prevalence in Korea between 2006 and 2015. METHODS: Primary diagnoses related to amyloidosis, regardless of subtype, were collected from the Korean National Health Insurance Service from 2006 through 2015. RESULTS: Overall, the age-standardized prevalence of amyloidosis was 0.93 (95% confidence interval (CI) 0.81, 1.04) persons per 100,000 persons in 2006 and 1.91 (95% CI 1.78, 2.05) persons per 100,000 persons in 2015. This included an increase from 0.43 (95% CI 0.35, 0.51) to 1.04 (95% CI 0.94, 1.14) persons per 100,000 persons in men and from 0.49 (95% CI 0.40, 0.57) to 0.87 (95% CI 0.77, 0.96) persons per 100,000 persons in women. In particular, the age-standardized prevalence of amyloidosis showed a greater increase in patients aged 65 years or older and in patients aged 45-64 years than in patients aged 20-44 years, for both men and women. CONCLUSIONS: The overall age standardized prevalence of amyloidosis was approximately 2 persons per 100,000 persons in 2015. The overall age-standardized prevalence of amyloidosis increased between 2006 and 2015, especially in individuals aged 45-64 and older than 65 years. PMID- 28877710 TI - Zinc-finger domains in metazoans: evolution gone wild. PMID- 28877711 TI - Pulmonary challenge with carbon nanoparticles induces a dose-dependent increase in circulating leukocytes in healthy males. AB - BACKGROUND: Inhalation of particulate matter, as part of air pollution, is associated with increased morbidity and mortality. Nanoparticles (< 100 nm) are likely candidates for triggering inflammatory responses and activation of coagulation pathways because of their ability to enter lung cells and pass bronchial mucosa. We tested the hypothesis that bronchial segmental instillation of carbon nanoparticles causes inflammation and activation of coagulation pathways in healthy humans in vivo. METHODS: This was an investigator-initiated, randomized controlled, dose-escalation study in 26 healthy males. Participants received saline (control) in one lung segment and saline (placebo) or carbon nanoparticles 10 MUg, 50 MUg, or 100 MUg in the contra-lateral lung. Six hours later, blood and bronchoalveolar lavage fluid (BALF) was collected for inflammation and coagulation parameters. RESULTS: There was a significant dose dependent increase in blood neutrophils (p = 0.046) after challenge with carbon nanoparticles. The individual top-dose of 100 MUg showed a significant (p = 0.05) increase in terms of percentage neutrophils in blood as compared to placebo. CONCLUSIONS: This study shows a dose-dependent effect of bronchial segmental challenge with carbon nanoparticles on circulating neutrophils of healthy volunteers. This suggests that nanoparticles in the respiratory tract induce systemic inflammation. TRIAL REGISTRATION: Dutch Trial Register no. 2976. 11 July 2011. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2976. PMID- 28877712 TI - Ten years analysis of stillbirth in a tertiary hospital in sub-Sahara Africa: a case control study. AB - OBJECTIVE: Stillbirth measures provide means to assess adequacy of maternal and perinatal care in a given population. The aim of this study was to describe the determinants of stillbirth in Douala general hospital, Cameroon. RESULTS: Determinants of stillbirth in this hospital are: maternal age >=35 years (OR 1.79, 95% CI 1.26-2.54, p = 0.001), pre-eclampsia/eclampsia (OR 2.97, 95% CI 0.87 8.89, p value of 0.03), diabetes in pregnancy (OR 9.97, 95% CI 1.15-86.86, p = 0.03), stillbirth in previous pregnancies (OR 3.94, CI 2.02-7.7, p < 0.0001), inter-pregnancy interval >2 years (OR 2, 06 CI 1.22-3.49; p = 0,006), referral from another hospital (OR 14.16, 95% CI 7.08-28.3, p < 0.0001), gestational age <37 (OR 19.9, 95% CI 12.3-32.2, p < 0.0001) and >42 (OR 6.27, 95% CI = 0.86-45.2, p = 0.096), congenital malformation (OR 11.09, 95% CI 3.2-38,5, p < 0.0001) and birth weight <2500 g (p < 0.0001). PMID- 28877713 TI - Breast Tissue Organisation and its Association with Breast Cancer Risk. AB - BACKGROUND: Mammographic percentage density is an established and important risk factor for breast cancer. In this paper, we investigate the role of the spatial organisation of (dense vs. fatty) regions of the breast defined from mammographic images in terms of breast cancer risk. METHODS: We present a novel approach that provides a thorough description of the spatial organisation of different types of tissue in the breast. Each mammogram is first segmented into four regions (fatty, semi-fatty, semi-dense and dense tissue). The spatial relations between each pair of regions is described using so-called forces histograms (FHs) and summarised using functional principal component analysis. In our main analysis, association with case-control status is assessed using a Swedish population-based case control study (1,170 cases and 1283 controls), for which digitised mammograms were available. We also carried out a small validation study based on digital images. RESULTS: For our main analysis, we obtained a global p value of 2*10-7 indicating a significant association between the spatial relations of the four segmented regions and breast cancer status after adjustment for percentage density and other important breast cancer risk factors. Our (spatial relations) score had a per standard deviation odds ratio 1.29, after accounting for overfitting (percentage density had a per standard deviation odds ratio of 1.34). The spatial relations between the fatty and semi-fatty tissue and the spatial relations between the fatty and dense tissue were the most significant. The spatial relations between the fatty and semi-fatty tissue were associated with parity and age at first birth (p=6*10-4). Using digital images, we were able to verify that the same characteristics of tissue organisation can be identified and we validated the association for the spatial relations between the fatty and semi fatty tissue. CONCLUSIONS: Our findings are consistent with the notion that fibroglandular and adipose tissue plays a role in breast cancer risk and, more specifically, they suggest that fatty tissue in the lower quadrants and the absence of density in the retromammary space, as shown in mediolateral oblique images, are protective against breast cancer. PMID- 28877714 TI - Successful medical management of a case of Austrian syndrome-an uncommon entity in the modern antibiotic era: a case report. AB - BACKGROUND: Austrian syndrome-the combination of meningitis, pneumonia and infective endocarditis due to Streptococcus pneumoniae infection, is a rare entity. In literature only a few hundreds of cases are reported but surprisingly we did not find any report on Austrian syndrome in or from Bangladesh. CASE PRESENTATION: We report the case history of a middle aged Bangladeshi diabetic man, who had fever, cough, shortness of breath and altered mentation. He had tachycardia, bi-basal lung crepitations, new cardiac murmurs and meningism. Diagnostic work-up revealed Austrian syndrome. Because of the rarity of the condition, this case is reported. CONCLUSION: A case of pneumococcal pneumonia or meningitis should raise suspicion of concomitant endocarditis and Austrian syndrome, specially if there is heart failure, as early recognition and treatment may appear life-saving. PMID- 28877715 TI - Exploring efficacy and safety of oral Pirfenidone for progressive, non-IPF lung fibrosis (RELIEF) - a randomized, double-blind, placebo-controlled, parallel group, multi-center, phase II trial. AB - BACKGROUND: Pirfenidone is currently approved in the EU for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) and offers a beneficial risk benefit profile. However, there are several other, progressive fibrotic lung diseases, in which conventional anti-inflammatory therapy is not sufficiently effective and antifibrotic therapies may offer a novel treatment option. METHODS/DESIGN: We designed a study protocol for inclusion of patients with progressive fibrotic lung disease despite conventional anti-inflammatory therapy (EudraCT 2014-000861-32). The study population comprises patients with collagen vascular disease-associated lung fibrosis (CVD-LF), fibrotic non-specific interstitial pneumonia (fNSIP), chronic hypersensitivity pneumonitis (cHP), and asbestos-related lung fibrosis (ALF). Disease progression needs to be proven by slope calculation of at least three Forced Vital Capacity (FVC) values obtained within 6-24 months prior to inclusion, documenting an annualized decline in percent predicted FVC of 5% (absolute) or more despite appropriate conventional therapy. Absolute change in percent predicted FVC from baseline - analyzed using a rank analysis of covariance (ANCOVA) model - will serve as efficacy-related primary study endpoint. DISCUSSION: There is an urgent unmet clinical need for effective therapies for patients with a progressive fibrotic lung disease other than IPF. The current study protocol is unique with respect to selecting patients with different disease entities of lung fibrosis which have, however, essential pathophysiological characteristics in common. Moreover, by selecting patients with evidence of disease progression despite conventional therapy, the protocol ensures that a cohort of interstitial lung disease (ILD) patients with a high unmet medical need is targeted and it may allow a sufficiently high event rate for evaluation of treatment responses. TRIAL REGISTRATION: DRKS00009822 (registration date: January 13th 2016). PMID- 28877716 TI - Assessing the quality of reports about randomized controlled trials of scalp acupuncture combined with another treatment for stroke. AB - BACKGROUND: This study was designed to assess the quality of reporting on randomized controlled trials (RCTs) of scalp acupuncture for the treatment of stroke. METHODS: The following 8 databases were systematically investigated from their inception to December 2015: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, National Institute of Informatics Scholarly and Academic Information Navigator, National Digital Science Library, Korean Traditional Knowledge Portal, and Korean Studies Information Service System. RCTs utilizing scalp acupuncture as an intervention for stroke were selected, and the quality of reports was assessed based on the Consolidated Standards of Reporting Trials 2010 statement (CONSORT) and Standards for Reporting Interventions in Controlled Trials of Acupuncture 2010 (STRICTA). For each study, the overall quality score (OQS) of 13 CONSORT items, a combined key methodological index score (MIS) of 5 CONSORT items, and the OQS of 17 STRICTA items were measured. RESULTS: The original reports of 63 RCTs were ultimately obtained, and the median CONSORT OQS was 7 (minimum 2, maximum 11). Particularly, the items 'trial design', 'sample size', 'ancillary analyses', and 'harms' had a positive rate of less than 10%. The median MIS was 1 (minimum 0, maximum 5), with 'allocation concealment and implementation' and 'intent-to-treat analysis (ITT) analysis' having a positive rate of less than 10%. The median STRICTA OQS was 11 (minimum 6, maximum 14), and only the items 'sample size' and 'intent-to-treat analysis' were reported, with a positive rate of less than 10%. The mean CONSORT OQS increased by approximately 0.81 for each 5-year period in which manuscripts were published (95% confidence interval: 0.43 to 1.19; p < 0.001). No variable was significantly associated with MIS in the ordinal regression model. CONCLUSION: The quality of reports on RCTs investigating scalp acupuncture treatment for stroke was moderate to low. Furthermore, reporting of some items was either insufficient or inadequate in the majority of studies. In order to improve and standardize the quality of RCTs investigating scalp acupuncture for stroke, CONSORT and STRICTA guidelines should be utilized more frequently. PMID- 28877717 TI - Cardiovascular health effects following exposure of human volunteers during fire extinction exercises. AB - BACKGROUND: Firefighters have increased risk of cardiovascular disease and of sudden death from coronary heart disease on duty while suppressing fires. This study investigated the effect of firefighting activities, using appropriate personal protective equipment (PPE), on biomarkers of cardiovascular effects in young conscripts training to become firefighters. METHODS: Healthy conscripts (n = 43) who participated in a rescue educational course for firefighting were enrolled in the study. The exposure period consisted of a three-day training course where the conscripts participated in various firefighting exercises in a constructed firehouse and flashover container. The subjects were instructed to extinguish fires of either wood or wood with electrical cords and mattresses. The exposure to particulate matter (PM) was assessed at various locations and personal exposure was assessed by portable PM samplers and urinary excretion of 1 hydroxypyrene. Cardiovascular measurements included microvascular function and heart rate variability (HRV). RESULTS: The subjects were primarily exposed to PM in bystander positions, whereas self-contained breathing apparatus effectively abolished pulmonary exposure. Firefighting training was associated with elevated urinary excretion of 1-hydroxypyrene (105%, 95% CI: 52; 157%), increased body temperature, decreased microvascular function (-18%, 95% CI: -26; -9%) and altered HRV. There was no difference in cardiovascular measurements for the two types of fires. CONCLUSION: Observations from this fire extinction training show that PM exposure mainly occurs in situations where firefighters removed the self contained breathing apparatus. Altered cardiovascular disease endpoints after the firefighting exercise period were most likely due to complex effects from PM exposure, physical exhaustion and increased core body temperature. PMID- 28877718 TI - Aortic atheroma as a source of stroke - assessment of embolization risk using 3D CMR in stroke patients and controls. AB - BACKGROUND: It was our purpose to identify vulnerable plaques in the thoracic aorta using 3D multi-contrast CMR and estimate the risk of cerebral embolization using 4D flow CMR in cryptogenic stroke patients and controls. METHODS: One hundred patients (40 with cryptogenic stroke, 60 ophthalmologic controls matched for age, sex and presence of hypertension) underwent a novel 3D multi-contrast (T1w, T2w, PDw) CMR protocol at 3 Tesla for plaque detection and characterization within the thoracic aorta, which was combined with 4D flow CMR for mapping potential embolization pathways. Plaque morphology was assessed in consensus reading by two investigators and classified according to the modified American Heart-Association (AHA) classification of atherosclerotic plaques. RESULTS: In the thoracic aorta, plaques <4 mm thickness were found in a similar number of stroke patients and controls [23 (57.5%) versus 33 (55.0%); p = 0.81]. However, plaques >=4 mm were more frequent in stroke patients [22 (55.0%) versus 10 (16.7%); p < 0.001]. Of those patients with plaques >=4 mm, seven (17.5%) stroke patients and two (3.3%) controls (p < 0.001) had potentially vulnerable AHA type VI plaques. Six stroke patients with vulnerable AHA t ype VI plaques >=4 mm had potential embolization pathways connecting the plaque, located in the aortic arch (n = 3) and proximal descending aorta (n = 3), with the individual territory of stroke, which made them the most likely source of stroke in those patients. CONCLUSIONS: Our findings underline the significance of >=4 mm thick and vulnerable plaques in the aortic arch and descending aorta as a relevant etiology of stroke. CLINICAL TRIAL REGISTRATION: Unique identifier: DRKS00006234 ; date of registration: 11/06/2014. PMID- 28877719 TI - Absolute quantification of microparticles by flow cytometry in ascites of patients with decompensated cirrhosis: a cohort study. AB - BACKGROUND: Microparticles (MPs) are small (<1 MUm) cell membrane-derived vesicles that are formed in response to cellular activation or early stages of apoptosis. Increased plasma MP levels have been associated with liver disease severity. Here we investigated the clinical impact of ascites MPs in patients with decompensated liver cirrhosis. METHODS: Ascites and blood samples of 163 patients with cirrhosis (ascites n = 163, blood n = 31) were collected between February 2011 and December 2012. MPs were obtained from ascites and from blood by two-step ultracentrifugation and quantified by flow cytometry. Quantitative absolute MP levels were correlated with clinical and laboratory baseline parameters as well as patient outcomes. Ascites microparticles were stained with antibodies against CD66b (neutrophils) and CD3 (lymphocytes) in a subgroup of 60 matched patients. RESULTS: MPs were detected in all ascites and blood samples. Absolute ascites MP levels correlated with blood levels (r = 0.444, p = 0.011). Low ascites MP levels (<488.4 MP/MUL) were associated with a poor 30-day survival probability (<488.4 MP/MUL 71.1% vs. >488.4 MP/MUL 94.7%, log rank p = 0.001) and such patients had a higher relative amount of ascites microparticles derived from neutrophils and lymphocytes. Low levels of ascites MPs, high MELD score and antibiotic treatment were independent risk factors for death within 30 days. CONCLUSIONS: Ascites MP levels predict short-term survival along with the liver function in patients with decompensated cirrhosis. Further studies which evaluate ascites MPs as disease specific biomarker with a validation cohort and which investigate its underlying mechanisms are needed. Neutrophils and lymphocytes contributed more frequently to the release of microparticles in patients with low ascites levels, possibly indicating an immune activation in this cohort. PMID- 28877720 TI - Reduced ovarian reserve in young early breast cancer patients: preliminary data from a prospective cohort trial. AB - BACKGROUND: The numerous side effects of chemotherapy in patients with breast cancer are well known. However, the precise effects of chemotherapy on ovarian function in premenopausal women are poorly investigated. The patients are at risk of developing sexual hormone deficiency and impaired fertility. This prospective cohort study addresses predictive parameters of ovarian reserve after chemotherapy. METHODS: Fifty-one premenopausal women (28-46 years) with primary breast cancer were included in the trial. All of them received anthracycline based chemotherapy (n = 18), or combinations with taxanes (n = 30), or anthracycline-free chemotherapy (n = 3). Changes in hormone levels (LH, FSH, E2 and Anti-Mullerian hormone (AMH)), antral follicle count (AFC), and amenorrhea were determined before (V1), and 6, 12 and 24 months after the initiation of chemotherapy (V2-V4). Quality of life parameters were evaluated. The additional impact of parity, BMI, and smoking on ovarian reserve was also assessed. RESULTS: AFC and AMH fell very markedly after chemotherapy and did not return to pre treatment levels until V4. A significant positive correlation was noted in AFC before and 1 year after chemotherapy. AMH levels at V2-V4 were significantly correlated with those registered at V1. AFC and AMH were negatively correlated with age. Continued smoking had a significant detrimental effect on AFC after 24 months. LH and FSH levels increased between V1 and V2 and fell at V3 and V4, but stayed above pre-chemotherapy values. Two years after the start of chemotherapy 31/51 patients were amenorrhoic while 17 resumed their menstrual cycle; this was not influenced by the type of chemotherapy or age. Non-smokers were 13 times more likely to resume their menstruation than smokers. Quality of life (QL) was significantly lower 6 months after the initiation of chemotherapy. QL at one and 2 years after chemotherapy did not differ significantly from pre-chemotherapy scores. CONCLUSIONS: Our study contributes to a better understanding and prediction of ovarian reserve in young early breast cancer patients undergoing chemotherapy. The data suggest that personal counseling in regard of the preservation of fertility should be offered especially to patients of a higher age, with low AMH levels or low follicle counts. Patients should be advised to stop smoking in order to enhance the likelihood of preserving their fertility. PMID- 28877721 TI - A case of Adrenocoricotrophic hormone -independent bilateral adrenocortical macronodular hyperplasia concomitant with primary aldosteronism. AB - BACKGROUND: Adrenocoricotrophic hormone (ACTH) - independent bilateral adrenocortical macronodular hyperplasia (AIMAH) is a rare cause of Cushing's syndrome, and is characterized by bilateral adrenal hyperplasia. However, Primary aldosteronism (PA) is a relatively common adrenal disease. CASE PRESENTATION: A 56-year-old man who has been treated hypertension and diabetes mellitus was detected low plasma potassium level with an elevated level of plasma aldosterone concentration and bilateral adrenal swelling. Endocrinological examinations showed autonomous secretion of cortisol and aldosterone, with suppression of plasma ACTH level and renin activity. A selective adrenal venous sampling demonstrated that left adrenal gland was responsible for aldosterone hypersecretion. He was diagnosed preclinical Cushing's syndrome due to ACTH - independent bilateral adrenocortical macronodular hyperplasia (AIMAH) associated with aldosterone producing adenoma of the left adrenal gland. A laparoscopic left adrenalectomy was performed. CONCLUSION: The resected adrenal specimen histologically consisted with a diagnosis of AIMAH. Moreover, tiny cell clusters positive immunostaining for aldosterone synthase was revealed. This is a rare case of AIMAH accompanied by preclinical Cushing's syndrome and primary aldosteronism. PMID- 28877722 TI - Tissue microarray analysis indicates hedgehog signaling as a potential prognostic factor in intermediate-risk prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) is a heterogeneous disease with a variable natural history, genetics, and treatment outcome. The Hedgehog (Hh) signaling pathway is increasingly recognized as being potentially important for the development and progression of PCa. In this retrospective study, we compared the activation status of the Hh signaling pathway between benign and tumor tissue, and evaluated the clinical significance of Hh signaling in PCa. METHODS: In this tissue microarray (TMA) study, the protein expression of several Hh signaling components and Hh target proteins, along with microvessel density, were compared between benign (n = 64) and malignant (n = 170) prostate tissue, and correlated with PCa clinicopathological characteristics and biochemical recurrence (BCR). RESULTS: The Hh signaling pathway appeared to be more active in PCa than in benign prostate tissue, as demonstrated by lower expression of the negative regulators PTCH1 and GLI3 in the tumor tissue compared to benign. In addition, high epithelial GLI2 expression correlated with higher pathological Gleason score. Overall, higher epithelial GLI3 expression in the tumor was shown to be an independent marker of a favorable prognosis. CONCLUSION: Hh signaling activation might reflect aggressive tumoral behavior, since high epithelial GLI2 expression positively correlates with a higher pathological Gleason score. Moreover, higher epithelial GLI3 expression is an independent marker of a more favorable prognosis. PMID- 28877723 TI - Conditioned place preference training prevents hippocampal depotentiation in an orexin-dependent manner. AB - BACKGROUND: Long-term potentiation (LTP) is well recognized as a cellular correlated synaptic plasticity of learning and memory. However, its reversal forms of synaptic plasticity, depotentiation, is less studied and its association with behaviors is also far from clear. Previously, we have shown that nanomolar orexin A can prevent the depotentiation induced by low frequency stimulation (LFS) following theta burst stimulation-induced LTP, namely inducing re potentiation, at hippocampal CA1 synapses in vitro. Here, we explored the functional correlate of this orexin-mediated hippocampal re-potentiation. METHODS AND RESULTS: We found that intraperitoneal (i.p.) injection process-paired contextual exposures during the conditioned place preference (CPP) task in mice resulted in re-potentiation at CA1 synapses of hippocampal slices, regardless of whether the CPP behavior is expressed or not. Simply exposing the mouse in the CPP apparatus, or giving the mouse consecutive i.p. injections of saline in its home cage or a novel cage did not lead to hippocampal re-potentiation. Besides, this CPP training process-induced hippocampal re-potentiation was prevented when mice were pretreated with TCS1102, a dual orexin receptor antagonist. These results suggest that the expression of hippocampal re-potentiation is orexin dependent and requires the association of differential spatial contexts and i.p. injections in the CPP apparatus. CONCLUSIONS: Together, we reveal an unprecedentedly orexin-mediated modulation on hippocampal depotentiation by the training process in the CPP paradigm. PMID- 28877724 TI - Characteristics of lipid metabolism including serum apolipoprotein M levels in patients with primary nephrotic syndrome. AB - BACKGROUND: Apolipoprotein M (apoM) is a 26-kD apolipoprotein that is mainly expressed in specific cell types, such as human liver parenchymal cells and kidney proximal renal tubular epithelial cells. ApoM can regulate the formation of pre-beta-HDL and the reverse cholesterol transport and thus plays an important role in the metabolism of lipids and lipoproteins, meaning that it can affect the development of lipid metabolism disorders. Significantly elevated serum apoM levels are detected in patients with hyperlipidemia. However, few studies have shown how apoM is expressed in primary nephrotic syndrome (PNS), which is often accompanied with hyperlipidemia, and the underlying mechanism is poorly understood. This study was aimed at examining the apoM levels in patients with PNS and at determining the effects of PNS on serum apoM levels in these patients. METHODS: This study included patients with hyperlipidemia (n = 37), the PNS with hyperlipidemia group (n = 62), PNS without hyperlipidemia group (n = 33), and healthy controls (n = 73). The age and body-mass index (BMI) matched among the groups of participants. Their serum apoM concentrations were measured by an enzyme-linked immunosorbent assay. Serum levels of conventional lipids and renal function indices were assessed using an automatic biochemical analyzer. The data were analyzed by means of Pearson's correlation coefficient (continuous variables) or Student's t test (mean differences). RESULTS: The average serum apoM concentrations were higher in the hyperlipidemia group (61.1 +/- 23.2 mg/L, P = 0.004) than in the healthy controls (31.6 +/- 18.92 mg/L). The serum apoM concentrations were lower in the PNS with hyperlipidemia group (25.1 +/- 16.31 mg/L, P = 0.007) and in the PNS without hyperlipidemia group (21.00 +/- 17.62 mg/L, P = 0.003) than in the healthy controls. The serum apoM concentrations in the PNS with hyperlipidemia group did not differ significantly from those in the PNS without hyperlipidemia group (P = 0.083). Moreover, serum apoM levels positively correlated with serum high-density lipoprotein cholesterol (HDL-C) and apoA1 levels and negatively correlated with proteinuria in PNS patients (r = 0.458, P = 0.003; r = 0.254, P = 0.022; r = -0.414, P = 0.028). CONCLUSION: Serum apoM concentrations are higher in patients with hyperlipidemia than in healthy controls. Low serum apoM levels in patients with PNS are likely caused by PNS. PMID- 28877725 TI - Over-expression of BAG-1 in head and neck squamous cell carcinomas (HNSCC) is associated with cisplatin-resistance. AB - BACKGROUND: In order to improve therapy for head and neck squamous cell carcinoma (HNSCC), biomarkers associated with local and/or distant tumor relapses and cancer drug resistance are urgently needed. This study identified a potential biomarker, Bcl-2 associated athanogene-1 (BAG-1), that is implicated in HNSCC insensitive to cisplatin and tumor progression. METHODS: Primary and advanced (relapsed from parental) University of Michigan squamous cell carcinoma cell lines were tested for sensitivity to cisplatin and gene expression profiles were compared between primary (cisplatin sensitive) and the relapsed (cisplatin resistant) cell lines by using Agilent microarrays. Additionally, differentially expressed genes phosphorylated AKT, and BAG-1, and BCL-xL were evaluated for expression using HNSCC tissue arrays. RESULTS: Advanced HNSCC cells revealed resistant to cisplatin accompanied by increased expression of BAG-1 protein. siRNA knockdown of BAG-1 expression resulted in significant improvement of HNSCC sensitivity to cisplatin. BAG-1 expression enhanced stability of BCL-xL and conferred cisplatin resistant to the HNSCC cells. In addition, high levels of expression of phosphorylated AKT, BAG-1, and BCL-xL were observed in advanced HNSCC compared to in that of primary HNSCC. CONCLUSION: Increased expression of BAG-1 was associated with cisplatin resistance and tumor progression in HNSCC patients and warrants further validation in larger independent studies. Over expression of BAG-1 may be a biomarker for cisplatin resistance in patients with primary or recurrent HNSCCs and targeting BAG-1 could be helpful in overcoming cisplatin resistance. PMID- 28877727 TI - Zonnic(r): a new player in an old field. AB - The tobacco industry is continually evolving to adapt to increasing tobacco control pressure and regulation, and to cater to consumer preferences. Recently, RJ Reynolds rolled-out a nicotine-containing gum, Zonnic(r), which is marketed as a smoking cessation and reduction product and is sold at convenience stores at a lower price and in a smaller quantity than existing brands sold at pharmacies. The introduction of Zonnic(r) products is a critical first step in tobacco industry's involvement in the NRT market and a serious indication of the evolving tobacco and nicotine-delivery industry and environment. It is likely that this trend will continue and spread, and as such, have a significant impact at multiple dimensions, including consumer perceptions and behavior, tobacco and NRT industry business strategy, and regulation and policy. In this special communication, we present an overview of the current marketing strategy for Zonnic(r), discuss its potential impacts at the market level and at the level of the individual consumer, and suggest research and policy priorities based on the magnitude and urgency of the impacts. PMID- 28877726 TI - The effect of bovine BST2A1 on the release and cell-to-cell transmission of retroviruses. AB - BACKGROUND: Human BST2 (hBST2, also called Tetherin) is a host restriction factor that blocks the release of various enveloped viruses. BST2s from different mammals also possess antiviral activity. Bovine BST2s (bBST2s), bBST2A1 and bBST2A2, reduce production of cell-free bovine leukemia virus (BLV) and vesicular stomatitis virus (VSV). However, the effect of bBST2 on other retroviruses remains unstudied. RESULTS: Here, we studied the antiviral activity of wildtype and mutant bBST2A1 proteins on retroviruses including human immunodeficiency virus type 1 (HIV-1), prototypic foamy virus (PFV), bovine foamy virus (BFV) and bovine immunodeficiency virus (BIV). The results showed that wildtype bBST2A1 suppressed the release of HIV-1, PFV and BFV. We also generated bBST2A1 mutants, and found that GPI anchor and dimerization, but not glycosylation, are essential for antiviral activity of bBST2A1. Moreover, unlike hBST2, bBST2A1 displayed no inhibitory effect on cell-to-cell transmission of PFV, BFV and BIV. CONCLUSIONS: Our data suggested that bBST2A1 inhibited retrovirus release, however, had no effect on cell-to-cell transmission of retroviruses. PMID- 28877728 TI - We need support! A Delphi study about desirable support during the first year in the emergency medical service. AB - BACKGROUND: New and inexperienced emergency medical service (EMS) professionals lack important experience. To prevent medical errors and improve retention there is an urgent need to identify ways to support new professionals during their first year in the EMS. METHODS: A purposeful sample and snowball technique was used and generated a panel of 32 registered nurses with 12-48 months of EMS experience. A Delphi technique in four rounds was used. Telephone interviews were undertaken in round one to identify what desirable support professionals new to the EMS desire during their first year. Content analysis of the transcribed interviews yielded items which were developed into a questionnaire. The experts graded each item in terms of perceived importance on a 5-graded likert scale. Consensus level was set at 75%. Items which reached consensus were removed from questionnaires used in subsequent rounds. RESULTS: Desirable support was categorized into eight areas: Support from practical skills exercises, support from theoretical knowledge, support from experiences based knowledge, theoretical support, support from an introduction period, support from colleagues and work environment, support from management and organization and other support. The experts agree on the level of importance on 64 of a total of 70 items regarding desirable support. One item was considered not important, graded 1 or 2, 63 items were considered important, graded 4 or 5. CONCLUSION: Even with extensive formal competence the EMS context poses challenges where a wide variety of desirable forms of support is needed. Support structures should address both personal and professional levels and be EMS context oriented. PMID- 28877729 TI - Effect of enhanced feedback to hospitals that are part of an emerging clinical information network on uptake of revised childhood pneumonia treatment policy: study protocol for a cluster randomized trial. AB - BACKGROUND: The national pneumonia treatment guidelines in Kenya changed in February 2016 but such guideline changes are often characterized by prolonged delays in affecting practice. We designed an enhanced feedback intervention, delivered within an ongoing clinical network that provides a general form of feedback, aimed at improving and sustaining uptake of the revised pneumonia treatment policy. The objective was to determine whether an enhanced feedback intervention will improve correctness of classification and treatment of childhood pneumonia, compared to an existing approach to feedback, after nationwide treatment policy change and within an existing hospital network. METHODS/DESIGN: A pragmatic, cluster randomized trial conducted within a clinical network of 12 Kenyan county referral hospitals providing inpatient pediatric care to children (aged 2-59 months) with acute medical conditions between March and November 2016. The intervention comprised enhanced feedback (monthly written feedback incorporating goal setting, and action planning delivered by a senior clinical coordinator for selected pneumonia indicators) and this was compared to standard feedback (2-monthly written feedback on multiple quality of pediatric care indicators) both delivered within a clinical network promoting clinical leadership linked to mentorship and peer-to-peer support, and improved use of health information on service delivery. The 12 hospitals were randomized to receive either enhanced feedback (n = 6) or standard feedback (n = 6) delivered over a 9-month period following nationwide pneumonia treatment policy change. The primary outcome is the proportion of all admitted patients with pneumonia (fulfilling criteria for treatment with orally administered amoxicillin) who are correctly classified and treated in the first 24 h. The secondary outcome will be measured over the course of the admission as any change in treatment for pneumonia after the first 24 h. DISCUSSION: This trial protocol employs a pragmatic trial design during a period of nationwide change in treatment guidelines to address two high-priority areas within implementation research: promoting adoption of health policies and optimizing effectiveness of feedback. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02817971 . Registered retrospectively on 27 June 2016. PMID- 28877730 TI - Pancreas herniation into the mediastinum: a case report. AB - BACKGROUND: Pancreatic tissue found in the mediastinum (both true ectopic and herniated pancreas) is rare. It becomes even more challenging when there are complications associated with this entity. CASE PRESENTATION: We report an unusual case of pancreatic herniation into the mediastinum in a 90-year-old Caucasian female. This patient initially presented with nausea and vomiting associated with abdominal pain. Serum lipase and amylase both were elevated. Computed tomography scan of the chest, abdomen and pelvis revealed a large hiatal hernia with pancreas herniation into the mediastinum, with superimposed acute pancreatitis likely due to gallstone. Because of its unusual location, the patient also developed acute mediastinitis. The patient was management conservatively and did well. On the day of discharge; she was tolerating a diet, had no pain or nausea and was back to her baseline health. CONCLUSION: Acute pancreatitis can be managed conservatively even if it is in the mediastinum. Also, ectopic or herniated pancreatic tissue is extremely rare and leads to unique clinical presentations, along with diagnostic and therapeutic challenges. Clinicians should not only be vigilant to the presence of ectopic or herniated pancreatic tissue, but also be mindful of the resulting complications. PMID- 28877731 TI - Hypoluteoidism in a dog associated with recurrent mammary fibroadenoma stimulated by progestin therapy. AB - BACKGROUND: Hypoluteoidism in the bitch is characterized by insufficient production and secretion of progesterone by the corpora lutea. It is a rare pathologic condition and during pregnancy, it leads to embryonic resorption or fetal abortion. Supplementary therapy with progestins is indicated during pregnancy to obtain delivery of vital puppies but unwarranted side effects of such treatment are poorly documented. CASE PRESENTATION: A 4-year-old, nulliparous, female Istrian Shorthaired Hound dog had been mated repeatedly in six heats with different dogs of proven fertility but signs of pregnancy did not develop. Estrous cycles, mating and pregnancies were monitored as hypoluteoidism or genital disease was suspected. During the first monitored estrus, the bitch was mated and on day 18 [day 0, day of estimated peak of luteinizing hormone (LH)], ultrasound examination showed three amniotic vesicles that were however found to be resorbed between day 20 and 23. Progesterone concentrations, measured by ELISA, were >8 ng/mL until day 12 and 1-2.5 ng/mL on days 20, 23 and 26. Primary hypoluteoidism was therefore suspected. In the second monitored estrus, the bitch was mated and during pregnancy, progesterone concentrations were >8 ng/mL until day 17 and 1-2.5 ng/mL on day 19. On days 20 and 22, two out of three embryonic vesicles had been resorbed. The bitch was treated with progesterone in oil from day 19 to day 58. Increase in the size of 2nd left thoracic mammary gland (T2-L) was observed and on day 46, ultrasound evaluation and biopsy were performed revealing a low-cellularity fibroadenoma. Parturition started spontaneously at day 65 but due to dystocia caused by fetal macrosomia, a Caesarean section was performed. During the next (third) monitored estrus, the bitch was bred again and during pregnancy, early decrease in progesterone concentration confirmed the diagnosis of primary hypoluteoidism. The bitch was treated with synthetic progestin (altrenogest) from day 8 to day 57. Five amniotic vesicles were detected by ultrasonography. Recurrence of swelling of T2 L was observed. On day 60, the bitch whelped five pups, two males and three females. As reported later by the owner, the latter did not show any sign of heat over the past 3 years. In one of them, clitoral hypertrophy and a blind ending vagina were diagnosed. CONCLUSIONS: This is the first description of early hypoluteoidism in a pregnant bitch developing a mammary fibroadenoma under progestin treatment. PMID- 28877732 TI - Ontology-based specification, identification and analysis of perioperative risks. AB - BACKGROUND: Medical personnel in hospitals often works under great physical and mental strain. In medical decision-making, errors can never be completely ruled out. Several studies have shown that between 50 and 60% of adverse events could have been avoided through better organization, more attention or more effective security procedures. Critical situations especially arise during interdisciplinary collaboration and the use of complex medical technology, for example during surgical interventions and in perioperative settings (the period of time before, during and after surgical intervention). METHODS: In this paper, we present an ontology and an ontology-based software system, which can identify risks across medical processes and supports the avoidance of errors in particular in the perioperative setting. We developed a practicable definition of the risk notion, which is easily understandable by the medical staff and is usable for the software tools. Based on this definition, we developed a Risk Identification Ontology (RIO) and used it for the specification and the identification of perioperative risks. RESULTS: An agent system was developed, which gathers risk relevant data during the whole perioperative treatment process from various sources and provides it for risk identification and analysis in a centralized fashion. The results of such an analysis are provided to the medical personnel in form of context-sensitive hints and alerts. For the identification of the ontologically specified risks, we developed an ontology-based software module, called Ontology-based Risk Detector (OntoRiDe). CONCLUSIONS: About 20 risks relating to cochlear implantation (CI) have already been implemented. Comprehensive testing has indicated the correctness of the data acquisition, risk identification and analysis components, as well as the web-based visualization of results. PMID- 28877733 TI - Insecticide use pattern and phenotypic susceptibility of Anopheles gambiae sensu lato to commonly used insecticides in Lower Moshi, northern Tanzania. AB - BACKGROUND: Evidence of insecticide resistance has been documented in different malaria endemic areas. Surveillance studies to allow prompt investigation of associated factors to enable effective insecticide resistance management are needed. The objective of this study was to assess insecticide use pattern and phenotypic susceptibility level of Anopheles gambiae sensu lato to insecticides commonly used in malaria control in Moshi, northern Tanzania. METHODS: A cross sectional survey was conducted to assess insecticide usage pattern. Data was collected was through closed and open ended questionnaires The WHO diagnostic standard kit with doses of 0.1% bendiocarb, 0.05% deltamethrin, 0.75% permethrin and 4% DDT were used to detect knockdown time, mortality and resistance ratio of wild A. gambiae sensu lato. The questionnaire survey data was analyzed using descriptive statistics and one-way analysis of variance while susceptibility data was analysed by logistic regression with probit analysis using SPSS program. The WHO criteria was used to evaluate the resistance status of the tested mosquito populations. RESULTS: A large proportion of respondents (80.8%) reported to have used insecticide mainly for farming purposes (77.3%). Moreover, 93.3% of household reported usage of long lasting insecticidal nets. The frequently used class of insecticide was organophosphate with chloropyrifos as the main active ingredients and dursban was the brand constantly reported. Very few respondents (24.1%) applied integrated vector control approaches of and this significantly associated with level of knowledge of insecticide use (P < 0.001). Overall knockdown time for A. gambiae s.l was highest in DDT, followed by Pyrethroids (Permethrin and deltamethrin) and lowest in bendiocarb. Anopheles gambiae s.l showed susceptibility to bendiocarb, increased tolerance to permethrin and resistant to deltamethrin. The most effective insecticide against the population from tested was bendiocarb, with a resistance ratio ranging between 0.93-2.81. CONCLUSION: Education on integrated vector management should be instituted and a policy change on insecticide of choice for malaria vector control from pyrethroids to carbamates (bendiocarb) is recommended. Furthermore, studies to detect cross resistance between pyrethroids and organophosphates should be carried out. PMID- 28877734 TI - Local relapse of nasopharyngeal cancer and Voxel-based analysis of FMISO uptake using PET with semiconductor detectors. AB - BACKGROUND: Hypoxic cancer cells are thought to be radioresistant and could impact local recurrence after radiotherapy (RT). One of the major hypoxic imaging modalities is [18F]fluoromisonidazole positron emission tomography (FMISO-PET). High FMISO uptake before RT could indicate radioresistant sites and might be associated with future local recurrence. The predictive value of FMISO-PET for intra-tumoral recurrence regions was evaluated using high-resolution semiconductor detectors in patients with nasopharyngeal carcinoma after intensity modulated radiotherapy (IMRT). METHODS: Nine patients with local recurrence and 12 patients without local recurrence for more than 3 years were included in this study. These patients received homogeneous and standard doses of radiation to the primary tumor irrespective of FMISO uptake. The FMISO-PET image before RT was examined via a voxel-based analysis, which focused on the relationship between the degree of FMISO uptake and recurrence region. RESULTS: In the pretreatment FMISO-PET images, the tumor-to-muscle ratio (TMR) of FMISO in the voxels of the tumor recurrence region was significantly higher than that of the non-recurrence region (p < 0.0001). In the recurrent patient group, a TMR value of 1.37 (95% CI: 1.36-1.39) corresponded to a recurrence rate of 30%, the odds ratio was 5.18 (4.87-5.51), and the area under the curve (AUC) of the receiver operating characteristic curve was 0.613. In all 21 patients, a TMR value of 2.42 (2.36 2.49) corresponded to an estimated recurrence rate of 30%, and the AUC was only 0.591. CONCLUSIONS: The uptake of FMISO in the recurrent region was significantly higher than that in the non-recurrent region. However, the predictive value of FMISO-PET before IMRT is not sufficient for up-front dose escalation for the intra-tumoral high-uptake region of FMISO. Because of the higher mean TMR of the recurrence region, a new hypoxic imaging method is needed to improve the sensitivity and specificity for hypoxia. PMID- 28877736 TI - Prevalence and determinants of risky sexual practice in Ethiopia: Systematic review and Meta-analysis. AB - BACKGROUND: Risky sexual practice is a major public health problem in Ethiopia. There are various studies on the prevalence and determinants of risky sexual practice in different regions of the country but there is no study which shows the national estimate of risky sexual practices in Ethiopia. Therefore, this review was conducted to estimate the national pooled prevalence of risky sexual practice and its risk factors in Ethiopia. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was followed to review published and unpublished studies in Ethiopia. The databases used were; PubMed, Google Scholar, CINAHL and African Journals Online. Search terms were; risky sexual behavior, risky sexual practice, unprotected sex, multiple sexual partner, early sexual initiation, and/or Ethiopia. Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument was used for critical appraisal. The meta-analysis was conducted using Review Manager software. Descriptive information of studies was presented in narrative form and quantitative results were presented in forest plots. The Cochran Q test and I 2 test statistics were used to test heterogeneity across studies. The pooled estimate prevalence and the odd ratios with 95% confidence intervals were computed by a random effect model. RESULTS: A total of 31 studies with 43,695 participants were included in the meta analysis. The pooled prevalence of risky sexual practice was 42.80% (95% CI: 35.64%, 49.96%). Being male (OR: 1.69; 95% CI: 1.21, 2.37), substance use (OR: 3.42; 95% CI: 1.41, 8.31), peer pressure (OR: 3.41; 95% CI: 1.69, 6.87) and watching pornography (OR: 3.6; 95% CI: 2.21, 5.86) were factors associated with an increase in risky sexual practices. CONCLUSIONS: The prevalence of risky sexual practices is high in Ethiopia. Being male, substance use, peer pressure and viewing pornographic materials were found to be associated with risky sexual practices. Therefore, life skills training is recommended to reduce peer pressure among individuals. Interventions should be designed to reduce substance use and viewing pornography. PMID- 28877735 TI - Priming astrocytes with TNF enhances their susceptibility to Trypanosoma cruzi infection and creates a self-sustaining inflammatory milieu. AB - BACKGROUND: In conditions of immunosuppression, the central nervous sty 5ystem (CNS) is the main target tissue for the reactivation of infection by Trypanosoma cruzi, the causative agent of Chagas disease. In experimental T. cruzi infection, interferon gamma (IFNgamma)+ microglial cells surround astrocytes harboring amastigote parasites. In vitro, IFNgamma fuels astrocyte infection by T. cruzi, and IFNgamma-stimulated infected astrocytes are implicated as potential sources of tumor necrosis factor (TNF). Pro-inflammatory cytokines trigger behavioral alterations. In T. cruzi-infected mice, administration of anti-TNF antibody hampers depressive-like behavior. Herein, we investigated the effects of TNF on astrocyte susceptibility to T. cruzi infection and the regulation of cytokine production. METHODS: Primary astrocyte cultures of neonatal C57BL/6 and C3H/He mice and the human U-87 MG astrocyte lineage were infected with the Colombian T. cruzi strain. Cytokine production, particularly TNF, and TNF receptor 1 (TNFR1/p55) expression were analyzed. Recombinant cytokines (rIFNgamma and rTNF), the anti-TNF antibody infliximab, and the TNFR1 modulator pentoxifylline were used to assess the in vitro effects of TNF on astrocyte susceptibility to T. cruzi infection. To investigate the role of TNF on CNS colonization by T. cruzi, infected mice were submitted to anti-TNF therapy. RESULTS: rTNF priming of mouse and human astrocytes enhanced parasite/astrocyte interaction (i.e., the percentage of astrocytes invaded by trypomastigote parasites and the number of intracellular parasite forms/astrocyte). Furthermore, T. cruzi infection drove astrocytes to a pro-inflammatory profile with TNF and interleukin-6 production, which was amplified by rTNF treatment. Adding rTNF prior to infection fueled parasite growth and trypomastigote egression, in parallel with increased TNFR1 expression. Importantly, pentoxifylline inhibited the TNF-induced increase in astrocyte susceptibility to T. cruzi invasion. In T. cruzi-infected mice, anti TNF therapy reduced the number of amastigote nests in the brain. CONCLUSIONS: Our data implicate TNF as a promoter of T. cruzi invasion of mouse and human astrocytes. Moreover, the TNF-enriched inflammatory milieu and enhanced TNFR1 expression may favor TNF signaling, astrocyte colonization by T. cruzi and egression of trypomastigotes. Therefore, in T. cruzi infection, a self-sustaining TNF-induced inflammatory circuit may perpetuate the parasite cycle in the CNS and ultimately promote cytokine-driven behavioral alterations. PMID- 28877737 TI - Erratum to: A manual-based vocational rehabilitation program for patients with an acquired brain injury: study protocol of a pragmatic randomized controlled trial (RCT). PMID- 28877738 TI - Sclerosing thymoma-like thymic amyloidoma with nephrotic syndrome: a case report. AB - BACKGROUND: Primary localized amyloidosis presenting as an isolated mediastinal mass is extremely rare, especially in the thymus. Sclerosing thymoma is also an extremely rare anterior mediastinal tumor, pathologically characterized by extensive sclerotic lesions with hyalinization and calcification. Only 14 cases of sclerosing thymoma and five cases of thymic amyloidosis have been reported to date. CASE PRESENTATION: A 78-year-old Japanese woman was diagnosed as having sclerosing thymoma (Masaoka stage IVa pericardial dissemination)-like thymic amyloidoma. She was diagnosed as having either lung cancer or mediastinal tumor with pericardial dissemination, and received palliative treatment. Three years later, she was readmitted with a complaint of general malaise. Since minimal change nephrotic syndrome was suspected based on the disease onset and selectivity index of urinary protein, steroid pulse therapy was started. Subsequently, because a marked reduction in tumor size was observed during maintenance treatment with prednisolone, a thoracoscopic needle biopsy was performed for a definitive diagnosis. According to the pathological findings and clinical investigations, a final diagnosis of sclerosing thymoma (Masaoka stage IVa pericardial dissemination)-like thymic amyloidoma was made. CONCLUSIONS: This is a case report of sclerosing thymoma-like thymic amyloidoma. Both sclerosing thymoma and thymic amyloidoma are extremely rare diseases: only 14 cases of sclerosing thymoma and five cases of thymic amyloidosis have been reported to date. In either diagnosis, our case is the first case in which marked reduction in tumor size was observed with steroid therapy. All reported cases of sclerosing thymomas underwent surgical resection, but steroid therapy to sclerosing thymoma has not been reported. It is still unknown whether steroid therapy is effective or not. The hyalinized components of sclerosing thymoma possibly contain amyloid deposits. The marked reduction in tumor size with steroid therapy may result in amyloid deposits. The association between sclerosing thymoma and thymic amyloidoma remains uncertain. Sclerosing thymoma should be stained with Congo red. PMID- 28877739 TI - Estrogen and soy isoflavonoids decrease sensitivity of medulloblastoma and central nervous system primitive neuroectodermal tumor cells to chemotherapeutic cytotoxicity. AB - BACKGROUND: Our previous studies demonstrated that growth and migration of medulloblastoma (MB), the most common malignant brain tumor in children, are stimulated by 17beta-estradiol. The growth stimulating effects of estrogens are mediated through ERbeta and insulin-like growth factor 1 signaling to inhibit caspase 3 activity and reduce tumor cell apoptosis. The objective of this study was to determine whether estrogens decreased sensitivity of MB cells to cytotoxic actions of chemotherapeutic drugs. METHODS: Using in vitro cell viability and clonogenic survival assays, concentration response analysis was used to determine whether the cytoprotective effects of estradiol protected human D283 Med MB cells from the cytotoxic actions of the MB chemotherapeutic drugs cisplatin, vincristine, or lomustine. Additional experiments were done to determine whether the ER antagonist fulvestrant or the selective ER modulator tamoxifen blocked the cytoprotective actions of estradiol. ER-selective agonists and antagonists were used to define receptor specificity, and the impacts of the soy-derived phytoestrogens genistein, daidzein, and s-equol on chemosensitivity were evaluated. RESULTS: In D283 Med cells the presence of 10 nM estradiol increased the IC50 for cisplatin-induced inhibition of viability 2-fold from ~5 MUM to >10 MUM. In clonogenic survival assays estradiol decreased the chemosensitivity of D283 Med cells exposed to cisplatin, lomustine and vincristine. The ERbeta selective agonist DPN and low physiological concentrations of the soy-derived phytoestrogens genistein, daidzein, and s-equol also decreased sensitivity of D283 Med cells to cisplatin. The protective effects of estradiol were blocked by the antiestrogens 4-hydroxytamoxifen, fulvestrant (ICI 182,780) and the ERbeta selective antagonist PPHTP. Whereas estradiol also decreased chemosensitivity of PFSK-1 cells, estradiol increased sensitivity of Daoy cell to cisplatin, suggesting that ERbeta mediated effects may vary in different MB celltypes. CONCLUSIONS: These findings demonstrate that E2 and environmental estrogens decrease sensitivity of MB to cytotoxic chemotherapeutics, and that ERbeta selective and non-selective inhibition of estrogen receptor activity blocks these cytoprotective actions. These findings support the therapeutic potential of antiestrogen adjuvant therapies for MB, and findings that soy phytoestrogens also decrease sensitivity of MB cells to cytotoxic chemotherapeutics suggest that decreased exposure to environmental estrogens may benefit MB patient responses to chemotherapy. PMID- 28877740 TI - Non-base-contacting residues enable kaleidoscopic evolution of metazoan C2H2 zinc finger DNA binding. AB - BACKGROUND: The C2H2 zinc finger (C2H2-ZF) is the most numerous protein domain in many metazoans, but is not as frequent or diverse in other eukaryotes. The biochemical and evolutionary mechanisms that underlie the diversity of this DNA binding domain exclusively in metazoans are, however, mostly unknown. RESULTS: Here, we show that the C2H2-ZF expansion in metazoans is facilitated by contribution of non-base-contacting residues to DNA binding energy, allowing base contacting specificity residues to mutate without catastrophic loss of DNA binding. In contrast, C2H2-ZF DNA binding in fungi, plants, and other lineages is constrained by reliance on base-contacting residues for DNA-binding functionality. Reconstructions indicate that virtually every DNA triplet was recognized by at least one C2H2-ZF domain in the common progenitor of placental mammals, but that extant C2H2-ZF domains typically bind different sequences from these ancestral domains, with changes facilitated by non-base-contacting residues. CONCLUSIONS: Our results suggest that the evolution of C2H2-ZFs in metazoans was expedited by the interaction of non-base-contacting residues with the DNA backbone. We term this phenomenon "kaleidoscopic evolution," to reflect the diversity of both binding motifs and binding motif transitions and the facilitation of their diversification. PMID- 28877741 TI - Morphometric variability among the species of the Sordida subcomplex (Hemiptera: Reduviidae: Triatominae): evidence for differentiation across the distribution range of Triatoma sordida. AB - BACKGROUND: The Sordida subcomplex (Triatominae) comprises four species, Triatoma garciabesi, T. guasayana, T. patagonica and T. sordida, which differ in epidemiological importance and adaptations to human environments. Some morphological similarities among species make taxonomic identification, population differentiation and species delimitation controversial. Triatoma garciabesi and T. sordida are the most similar species, having been considered alternatively two and a single species until T. garciabesi was re-validated, mostly based on the morphology of male genitalia. More recently, T. sordida from Argentina has been proposed as a new cryptic species distinguishable from T. sordida from Brazil, Bolivia and Paraguay by cytogenetics. We studied linear and geometric morphometry of the head, wings and pronotum in populations of these species aiming to find phenotypic markers for their discrimination, especially between T. sordida and T. garciabesi, and if any set of variables that validates T. sordida from Argentina as a new species. RESULTS: Head width and pronotum length were the linear variables that best differentiated species. Geometric morphometry revealed significant Mahalanobis distances in wing shape between all pairwise comparisons. Triatoma patagonica exhibited the best discrimination and T. garciabesi overlapped the distribution of the other species in the morphometric space of the first two DFA axes. Head shape showed differentiation between all pairs of species except for T. garciabesi and T. sordida. Pronotum shape did not differentiate T. garciabesi from T. guasayana. The comparison between T. garciabesi and T. sordida from Argentina and T. sordida from Brazil and Bolivia revealed low differentiation based on head and pronotum linear measurements. Pronotum and wing shape were different between T. garciabesi and T. sordida from Brazil and Bolivia and T. sordida from Argentina. Head shape did not differentiate T. garciabesi from T. sordida from Argentina. CONCLUSIONS: Wing shape best delimited the four species phenotypically. The proposed cryptic species, T. sordida from Argentina, differed from T. sordida from Brazil and Bolivia in all measured shape traits, suggesting that the putative new species may not be cryptic. Additional studies integrating cytogenetic, phenotypic and molecular markers, as well as cross-breeding experiments are needed to confirm if these three entities represent true biological species. PMID- 28877742 TI - A comparative study of the impacts of unbalanced sample sizes on the four synthesized methods of meta-analytic structural equation modeling. AB - BACKGROUND: In the first stage of meta-analytic structural equation modeling (MASEM), researchers synthesized studies using univariate meta-analysis (UM) and multivariate meta-analysis (MM) approaches. The MM approaches are known to be of better performance than the UM approaches in the meta-analysis with equal sized studies. However in real situations, where the studies might be of different sizes, the empirical performance of these approaches is yet to be studied in the first and second stages of MASEM. The present study aimed to evaluate the performance of the UM and MM methods, having unequal sample sizes in different primary studies. Testing the homogeneity of correlation matrices and the empirical power, estimating the pooled correlation matrix and also, estimating parameters of a path model were investigated using these approaches by simulation. RESULTS: The results of the first stage showed that Type I error rate was well under control at 0.05 level when the average sample sizes were 200 or more, irrespective of the types of the methods or the sample sizes used. Moreover, the relative percentage biases of the pooled correlation matrices were also lower than 2.5% for all methods. There was a dramatic decrease in the empirical power for all synthesis methods when the inequality of the sample sizes was increased. In fitting the path model at the second stage, MM methods provided better estimation of the parameters. CONCLUSIONS: This study showed the different performance of the four methods in the statistical power, especially when the sample sizes of primary studies were highly unequal. Moreover, in fitting the path model, the MM approaches provided better estimation of the parameters. PMID- 28877743 TI - Evaluation of the efficacy of sarolaner (Simparica(r)) in the prevention of babesiosis in dogs. AB - BACKGROUND: Canine babesiosis is a clinically significant emerging vector-borne disease caused among others by the protozoan Babesia canis. The efficacy of sarolaner (Simparica(r); Zoetis; at the minimum recommended label dose of 2.0 mg per kg bodyweight) in the prevention of babesiosis was evaluated in twenty-four dogs randomly allocated to either a placebo-treated group or one of two sarolaner treated groups. At 21 or 28 days after treatment administration, dogs were infested with 50 +/- 4 Dermacentor reticulatus ticks of which 25% were confirmed to be infected with Babesia canis. Blood samples were collected from each dog prior to tick infestation and weekly thereafter until 49 days after infestation. The blood was assayed for B. canis antibodies using an indirect immunofluorescence test (IFAT) and for B. canis DNA by PCR assay. A dog was a priori defined as B. canis-positive if it tested positive by both IFAT and PCR at any time during the study. RESULTS: No treatment-related adverse reactions were recorded during the study. All placebo-treated animals displayed clinical signs due to babesiosis and tested positive on both IFAT and PCR. None of the sarolaner treated animals displayed any clinical symptoms or tested positive on both IFAT and PCR, resulting in a 100% efficacy in the prevention of canine babesiosis (P = 0.0002). CONCLUSION: When given 21 or 28 days before tick infestation, a single treatment with sarolaner at the minimum recommended label dose of 2.0 mg per kg body weight prevented the transmission of B. canis by D. reticulatus to dogs. PMID- 28877745 TI - Erythrocytosis caused by giant chromophobe renal cell carcinoma: a case report indicating a 9-year misdiagnosis of polycythemia vera. AB - BACKGROUND: Erythrocytosis, a rare paraneoplastic syndrome, generally occurs in patients with clear cell renal cell carcinoma and has never been reported in patients with chromophobe renal cell carcinoma. CASE PRESENTATION: We report a case of a young man suffering from a giant (22-cm) mass on his left kidney. Because of a history of polycythemia vera, the patient had been treated for the condition for 9 years. Radical nephrectomy was successfully performed, and the postoperative pathologic examination confirmed a diagnosis of chromophobe renal cell carcinoma. Unexpectedly, the symptom of erythrocytosis disappeared after the surgery. Further examination and analysis were performed, and we finally attributed his erythrocytosis to chromophobe renal cell carcinoma. CONCLUSIONS: Chromophobe renal cell carcinoma could cause erythrocytosis, but the clear-cut mechanism needs further research. Secondary erythrocytosis such as those related with renal tumors should be taken into consideration during the diagnosis of polycythemia vera. PMID- 28877744 TI - Exome sequences versus sequential gene testing in the UK highly specialised Service for Limb Girdle Muscular Dystrophy. AB - BACKGROUND: Limb girdle muscular dystrophies are a group of rare and genetically heterogeneous diseases that share proximal weakness as a common feature; however they are often lacking very specific phenotypic features to allow an accurate differential diagnosis based on the clinical signs only, limiting the diagnostic rate using phenotype driven genetic testing. Next generation sequencing provides an opportunity to obtain molecular diagnoses for undiagnosed patients, as well as identifying novel genetic causes of muscle diseases. We performed whole exome sequencing (WES) on 104 affected individuals from 75 families in who standard gene by gene testing had not yielded a diagnosis. For comparison we also evaluated the diagnostic rate using sequential gene by gene testing for 91 affected individuals from 84 families over a 2 year period. RESULTS: Patients selected for WES had undergone more extensive prior testing than those undergoing standard genetic testing and on average had had 8 genes screened already. In this extensively investigated cohort WES identified the genetic diagnosis in 28 families (28/75, 37%), including the identification of the novel gene ZAK and two unpublished genes. WES of a single affected individual with sporadic disease yielded a diagnosis in 13/38 (34%) of cases. In comparison, conventional gene by gene testing provided a genetic diagnosis in 28/84 (33%) families. Titinopathies and collagen VI related dystrophy were the most frequent diagnoses made by WES. Reasons why mutations in known genes were not identified previously included atypical phenotypes, reassignment of pathogenicity of variants, and in one individual mosaicism for a COL6A1 mutation which was undetected by prior direct sequencing. CONCLUSION: WES was able to overcome many limitations of standard testing and achieved a higher rate of diagnosis than standard testing even in this cohort of extensively investigated patients. Earlier application of WES is therefore likely to yield an even higher diagnostic rate. We obtained a high diagnosis rate in simplex cases and therefore such individuals should be included in exome or genome sequencing projects. Disease due to somatic mosaicism may be increasingly recognised due to the increased sensitivity of next generation sequencing techniques to detect low level mosaicism. PMID- 28877747 TI - The value of one versus three sputum smear examinations for diagnosis of pulmonary tuberculosis in Asella hospital, South-East Ethiopia. AB - OBJECTIVE: The aim of the study is to compare the value of a single with three sputum smear examinations in the detection of smear-positive pulmonary tuberculosis. RESULTS: There were a total of 7012 patients studied out of which 3599 (51.3%) were males and the rest females. In 637 (9.1%) of the patients, two or more smears were positive for AFB. 616 (96.7%) of the sputum smear positive patients had positive smears on the first spot sputum exams as compared to 635 (99.7%) who were positive on the morning sputum, (P = 0.000064). 598/637 (93.9%) of sputum smear positive patients had positive smears in all three smears regardless of the smear grading. A single morning smear examination is as sensitive as doing three sputum smear examinations in the diagnosis of sputum smear positive TB. The incidence of sputum smear positivity differed significantly across age groups, but did not differ between genders. PMID- 28877746 TI - "Scaling-out" evidence-based interventions to new populations or new health care delivery systems. AB - BACKGROUND: Implementing treatments and interventions with demonstrated effectiveness is critical for improving patient health outcomes at a reduced cost. When an evidence-based intervention (EBI) is implemented with fidelity in a setting that is very similar to the setting wherein it was previously found to be effective, it is reasonable to anticipate similar benefits of that EBI. However, one goal of implementation science is to expand the use of EBIs as broadly as is feasible and appropriate in order to foster the greatest public health impact. When implementing an EBI in a novel setting, or targeting novel populations, one must consider whether there is sufficient justification that the EBI would have similar benefits to those found in earlier trials. DISCUSSION: In this paper, we introduce a new concept for implementation called "scaling-out" when EBIs are adapted either to new populations or new delivery systems, or both. Using existing external validity theories and multilevel mediation modeling, we provide a logical framework for determining what new empirical evidence is required for an intervention to retain its evidence-based standard in this new context. The motivating questions are whether scale-out can reasonably be expected to produce population-level effectiveness as found in previous studies, and what additional empirical evaluations would be necessary to test for this short of an entirely new effectiveness trial. We present evaluation options for assessing whether scaling-out results in the ultimate health outcome of interest. CONCLUSION: In scaling to health or service delivery systems or population/community contexts that are different from the setting where the EBI was originally tested, there are situations where a shorter timeframe of translation is possible. We argue that implementation of an EBI in a moderately different setting or with a different population can sometimes "borrow strength" from evidence of impact in a prior effectiveness trial. The collection of additional empirical data is deemed necessary by the nature and degree of adaptations to the EBI and the context. Our argument in this paper is conceptual, and we propose formal empirical tests of mediational equivalence in a follow-up paper. PMID- 28877749 TI - Women's determinant factors for preferred place of delivery in Dodoma region Tanzania: a cross sectional study. AB - BACKGROUND: Skilled birth attendance is one of the key factors in improving maternal health but less than 50% of women in sub-Saharan African countries do not have the opportunity to be attended to by skilled personnel during childbirth. The aim of the study was to assess the factors determining women's preference for a place to give birth in Dodoma Region, Tanzania. METHODS: This study employed a cross-sectional survey design using quantitative data collection and analysis methods. Data were collected using structured questionnaire administered to 800 women obtained through multistage random sampling. Multivariable logistic regression model was applied to determine the predictors of place of delivery. RESULTS: More than three quarters 629(78.6%) respondents had their last delivery in the health facilities while 171(21.4%) had their last delivery at home/on the way to hospital. Reasons for delivering at home include: abrupt occurrence of labour pain, long distance to the health facilities, lack of money to pay for transport and unfriendly experience with the health care providers. Simple logistic regression model indicate that mothers' education level, number of children, cost of transport the estimated distance to the nearby health facility and occupation were strong predictors of the preferred place of delivery. However, after controlling the potential confounder, the multivariable logistic regression model demonstrated a significant association between delivery at the health facility and the number of children and transport cost. CONCLUSION: Our findings suggest a need for health care providers to enhance health education to women and their spouses about birth preparedness and the importance of delivering at the health facility. There is also a need for the government to increase the number of health facilities including maternity waiting homes and well trained health workers in both rural and urban areas. PMID- 28877748 TI - A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. AB - BACKGROUND: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. METHODS: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow up. RESULTS: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. CONCLUSIONS: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012. PMID- 28877750 TI - MIT-Skywalker: considerations on the Design of a Body Weight Support System. AB - BACKGROUND: To provide body weight support during walking and balance training, one can employ two distinct embodiments: support through a harness hanging from an overhead system or support through a saddle/seat type. This paper presents a comparison of these two approaches. Ultimately, this comparison determined our selection of the body weight support system employed in the MIT-Skywalker, a robotic device developed for the rehabilitation/habilitation of gait and balance after a neurological injury. METHOD: Here we will summarize our results with eight healthy subjects walking on the treadmill without any support, with 30% unloading supported by a harness hanging from an overhead system, and with a saddle/seat-like support system. We compared the center of mass as well as vertical and mediolateral trunk displacements across different walking speeds and support. RESULTS: The bicycle/saddle system had the highest values for the mediolateral inclination, while the overhead harness body weight support showed the lowest values at all speeds. The differences were statistically significant. CONCLUSION: We selected the bicycle/saddle system for the MIT-Skywalker. It allows faster don-and-doff, better centers the patient to the split treadmill, and allows all forms of training. The overhead harness body weight support might be adequate for rhythmic walking training but limits any potential for balance training. PMID- 28877751 TI - Inguinal canal angioleiomyoma: case report of a rare disease entity within inguinal canal. AB - BACKGROUND: Angioleiomyoma is an uncommon benign soft tissue tumor and originates from the vascular smooth muscle. It often causes pain and is rarely found in inguinal region. We present a rare case of inguinal canal angioleiomyoma of a female patient who suffered from right groin pain for 4 years and mimicking inguinal hernia clinically. PRESENTATION OF CASE: A 53-year-old Chinese female patient presented with 4-year history of right groin pain which was exacerbated by movement. Magnetic resonance imaging was performed in view of atypical presentation and absence of cough impulse. Inguinal canal was subsequently explored by open approach and the mass was found arising from the posterior wall of the inguinal canal and measured 5.2 cm * 3.8 cm. The posterior wall was repaired by Bassini approach after the mass was resected en-bloc. Inguinal pain was resolved and no hernia was found during follow-up. Pathology of the resected specimen confirmed angioleiomyoma with clear resection margins. CONCLUSION: This is the first report of a case of angioleiomyoma of the inguinal canal, which presents as a painful mass. Magnetic resonance imaging should be considered when presenting history and physical examination does not confirm with the diagnosis of inguinal hernia. After inguinal canal exploration, suture or mesh repair should be performed to prevent weakening of posterior wall leading to inguinal hernia. PMID- 28877752 TI - SPEN, a new player in primary cilia formation and cell migration in breast cancer. AB - BACKGROUND: The primary cilium is a microtubule-based and nonmotile organelle functioning as a cellular antenna that is involved in the regulation of cell proliferation, differentiation, and migration. In breast cancer cells, the primary cilium is a structure that decreases in incidence with increasing degrees of transformation and may be biologically more important in estrogen receptor (ERalpha)-negative breast cancer cells. Split ends (SPEN) is an ERalpha corepressor that we have identified as a tumor suppressor protein in ERalpha positive breast cancer cells whose hormone-independent roles in breast cancer have never been explored. METHODS: We determined the hormone-independent transcriptional program regulated by the ERalpha cofactor SPEN in breast cancer using DNA microarrays. The biological functions regulated by SPEN independently of hormones were studied in vitro in ERalpha-positive and ERalpha-negative breast cancer cells. Finally, we examined the clinical relevance of SPEN expression in cohorts of breast cancer samples with outcome data. RESULTS: We found that SPEN is coexpressed with a number of genes involved in ciliary biology, including the ciliogenic transcription factor RFX3, in a hormone-independent manner. SPEN reexpression in T47D cells containing a nonsense mutation in SPEN restored the primary cilium, whereas its knockdown in MCF10A and Hs578T cells considerably decreased primary cilia levels. We also report that SPEN regulates migration in breast cells, but only in those harboring primary cilia, and that KIF3A silencing, a critical factor in primary cilia, partially reverses SPEN's effects, suggesting that SPEN may coordinate cellular movement through primary cilia dependent mechanisms. Finally, we found that high SPEN RNA levels were predictive of early metastasis in two independent cohorts of 77 (HR 2.25, P = 0.03) and 170 (HR = 2.23, P = 0.004) patients with ERalpha-negative breast cancer. CONCLUSIONS: Together, our data demonstrate a role for SPEN in the regulation of primary cilia formation and cell migration in breast cancer cells, which may collectively explain why its expression is associated with time to metastasis in cohorts of patients with ERalpha-negative breast cancers. PMID- 28877754 TI - Association between suspected Zika virus disease during pregnancy and giving birth to a newborn with congenital microcephaly: a matched case-control study. AB - OBJECTIVE: In early 2015, an outbreak of an acute exanthematous illness with dengue-like symptoms occurred in northeastern Brazil. By the end of the same year, an unexpected increase in the number of cases of microcephaly was observed in the region. The microcephaly outbreak cause was unknown and rumors pointing to various potential causes arose. Since we were unaware at the time if this scenario would attract the interest of the broader scientific community, due to the neglected regions associated and as often happens with many others health conditions related to infectious diseases in Latin America. This coupled with the fact that diagnostic testing for Zika virus was not available, prompted us to design a study that could demonstrate the correlation between the development of an exanthematous illness with Zika-like symptoms during pregnancy and the delivery of a newborn with congenital microcephaly. RESULTS: Mothers who experienced symptoms associated with the Zika virus during pregnancy had 10 times higher odds of delivering newborns with congenital microcephaly when compared with mothers who did not exhibit Zika-like symptoms. Thus, the acute exanthematous illness outbreak could be associated with the congenital microcephaly outbreak. We could not distinguish which virus caused the acute exanthematous illness in the study subjects (Zika, dengue or chikungunya), but these results could help to reduce the misquided speculation in regards to the cause of the microcephaly and could have expedited public health policies intended for controlling the mosquito vector. In addition to the lower head circumference, microcephalic neonates also had lower thoracic circumference, lower height and lower weight compared to non-microcephalic babies suggesting intrauterine growth restriction. Additionally, we found borderline association between mothers classified as homemakers and, who had past dengue infections with microcephaly. Prior contraction of dengue virus seems to play a role in the risk for the condition reflecting the domestication of the Aedes Aegypti and the enhancement of the Zika virus infection by dengue antibodies, respectively. The limitations of this study are: (a) participants recall bias, (b) absence of laboratory test results for Zika virus and other arboviruses and (c) incomplete test results for other pathogens that could lead to microcephaly. The study protocol was registered at ClinicalTrial.gov under the identifier NCT02741882. Registered on April 13th, 2016. PMID- 28877753 TI - Weekends affect mortality risk and chance of discharge in critically ill patients: a retrospective study in the Austrian registry for intensive care. AB - BACKGROUND: In this study, we primarily investigated whether ICU admission or ICU stay at weekends (Saturday and Sunday) is associated with a different risk of ICU mortality or chance of ICU discharge than ICU admission or ICU stay on weekdays (Monday to Friday). Secondarily, we analysed whether weekend ICU admission or ICU stay influences risk of hospital mortality or chance of hospital discharge. METHODS: A retrospective study was performed for all adult patients admitted to 119 ICUs participating in the benchmarking project of the Austrian Centre for Documentation and Quality Assurance in Intensive Care (ASDI) between 2012 and 2015. Readmissions to the ICU during the same hospital stay were excluded. RESULTS: In a multivariable competing risk analysis, a strong weekend effect was observed. Patients admitted to ICUs on Saturday or Sunday had a higher mortality risk after adjustment for severity of illness by Simplified Acute Physiology Score (SAPS) 3, year, month of the year, type of admission, ICU, and weekday of death or discharge. Hazard ratios (95% confidence interval) for death in the ICU following admission on a Saturday or Sunday compared with Wednesday were 1.15 (1.08-1.23) and 1.11 (1.03-1.18), respectively. Lower hazard ratios were observed for dying on a Saturday (0.93 (0.87-1.00)) or Sunday (0.85 (0.80-0.91)) compared with Wednesday. This is probably related to the reduced chance of being discharged from the ICU at the weekend (0.63 (0.62-064) for Saturday and 0.56 (0.55-0.57) for Sunday). Similar results were found for hospital mortality and hospital discharge following ICU admission. CONCLUSIONS: Patients admitted to ICUs at weekends are at increased risk of death in both the ICU and the hospital even after rigorous adjustment for severity of illness. Conversely, death in the ICU and discharge from the ICU are significantly less likely at weekends. PMID- 28877755 TI - Uric acid, an important screening tool to detect inborn errors of metabolism: a case series. AB - BACKGROUND: Uric acid is the metabolic end product of purine metabolism in humans. Altered serum and urine uric acid level (both above and below the reference ranges) is an indispensable marker in detecting rare inborn errors of metabolism. We describe different case scenarios of 4 Sri Lankan patients related to abnormal uric acid levels in blood and urine. CASE 1: A one-and-half-year-old boy was investigated for haematuria and a calculus in the bladder. Xanthine crystals were seen in microscopic examination of urine sediment. Low uric acid concentrations in serum and low urinary fractional excretion of uric acid associated with high urinary excretion of xanthine and hypoxanthine were compatible with xanthine oxidase deficiency. CASE 2: An 8-month-old boy presented with intractable seizures, feeding difficulties, screaming episodes, microcephaly, facial dysmorphism and severe neuro developmental delay. Low uric acid level in serum, low fractional excretion of uric acid and radiological findings were consistent with possible molybdenum cofactor deficiency. Diagnosis was confirmed by elevated levels of xanthine, hypoxanthine and sulfocysteine levels in urine. CASE 3: A 3-year-10-month-old boy presented with global developmental delay, failure to thrive, dystonia and self-destructive behaviour. High uric acid levels in serum, increased fractional excretion of uric acid and absent hypoxanthine-guanine phosphoribosyltransferase enzyme level confirmed the diagnosis of Lesch-Nyhan syndrome. CASE 4: A 9-year-old boy was investigated for lower abdominal pain, gross haematuria and right renal calculus. Low uric acid level in serum and increased fractional excretion of uric acid pointed towards hereditary renal hypouricaemia which was confirmed by genetic studies. CONCLUSION: Abnormal uric acid level in blood and urine is a valuable tool in screening for clinical conditions related to derangement of the nucleic acid metabolic pathway. PMID- 28877756 TI - Jigsaw Puzzles As Cognitive Enrichment (PACE) - the effect of solving jigsaw puzzles on global visuospatial cognition in adults 50 years of age and older: study protocol for a randomized controlled trial. AB - BACKGROUND: Neurocognitive disorders are an important societal challenge and the need for early prevention is increasingly recognized. Meta-analyses show beneficial effects of cognitive activities on cognition. However, high financial costs, low intrinsic motivation, logistic challenges of group-based activities, or the need to operate digital devices prevent their widespread application in clinical practice. Solving jigsaw puzzles is a cognitive activity without these hindering characteristics, but cognitive effects have not been investigated yet. With this study, we aim to evaluate the effect of solving jigsaw puzzles on visuospatial cognition, daily functioning, and psychological outcomes. METHODS: The pre-posttest, assessor-blinded study will include 100 cognitively healthy adults 50 years of age or older, who will be randomly assigned to a jigsaw puzzle group or a cognitive health counseling group. Within the 5-week intervention period, participants in the jigsaw puzzle group will engage in 30 days of solving jigsaw puzzles for at least 1 h per day and additionally receive cognitive health counseling. The cognitive health counseling group will receive the same counseling intervention but no jigsaw puzzles. The primary outcome, global visuospatial cognition, will depict the average of the z-standardized performance scores in visuospatial tests of perception, constructional praxis, mental rotation, processing speed, flexibility, working memory, reasoning, and episodic memory. As secondary outcomes, we will assess the eight cognitive abilities, objective and subjective visuospatial daily functioning, psychological well being, general self-efficacy, and perceived stress. The primary data analysis will be based on mixed-effects models in an intention-to-treat approach. DISCUSSION: Solving jigsaw puzzles is a low-cost, intrinsically motivating, cognitive leisure activity, which can be executed alone or with others and without the need to operate a digital device. In the case of positive results, these characteristics allow an easy implementation of solving jigsaw puzzles in clinical practice as a way to improve visuospatial functioning. Whether cognitive impairment and loss of independence in everyday functioning might be prevented or delayed in the long run has to be examined in future studies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02667314 . Registered on 27 January 2016. PMID- 28877757 TI - Whole genome sequencing of ESBL-producing Escherichia coli isolated from patients, farm waste and canals in Thailand. AB - BACKGROUND: Tackling multidrug-resistant Escherichia coli requires evidence from One Health studies that capture numerous potential reservoirs in circumscribed geographic areas. METHODS: We conducted a survey of extended beta-lactamase (ESBL)-producing E. coli isolated from patients, canals and livestock wastewater in eastern Thailand between 2014 and 2015, and analyzed isolates using whole genome sequencing. RESULTS: The bacterial collection of 149 isolates consisted of 84 isolates from a single hospital and 65 from the hospital sewer, canals and farm wastewater within a 20 km radius. E. coli ST131 predominated the clinical collection (28.6%), but was uncommon in the environment. Genome-based comparison of E. coli from infected patients and their immediate environment indicated low genetic similarity overall between the two, although three clinical-environmental isolate pairs differed by <= 5 single nucleotide polymorphisms. Thai E. coli isolates were dispersed throughout a phylogenetic tree containing a global E. coli collection. All Thai ESBL-positive E. coli isolates were multidrug resistant, including high rates of resistance to tobramycin (77.2%), gentamicin (77.2%), ciprofloxacin (67.8%) and trimethoprim (68.5%). ESBL was encoded by six different CTX-M elements and SHV-12. Three isolates from clinical samples (n = 2) or a hospital sewer (n = 1) were resistant to the carbapenem drugs (encoded by NDM-1, NDM-5 or GES-5), and three isolates (clinical (n = 1) and canal water (n = 2)) were resistant to colistin (encoded by mcr-1); no isolates were resistant to both carbapenems and colistin. CONCLUSIONS: Tackling ESBL-producing E. coli in this setting will be challenging based on widespread distribution, but the low prevalence of resistance to carbapenems and colistin suggests that efforts are now required to prevent these from becoming ubiquitous. PMID- 28877758 TI - Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration. AB - Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is associated with the accumulation of pathological neuronal and glial intracytoplasmic inclusions as well as accompanying neuron loss. We explored if cortical neurons detected by NeuN decreased with increasing TDP-43 inclusion pathology in the postmortem brains of 63 patients with sporadic and familial FTLD-TDP. Semi automated quantitative algorithms to quantify histology in tissue sections stained with antibodies specific for pathological or phosphorylated TDP-43 (pTDP 43) and NeuN were developed and validated in affected (cerebral cortex) and minimally affected (cerebellar cortex) brain regions of FTLD-TDP cases. Immunohistochemistry (IHC) for NeuN and other neuronal markers found numerous neurons lacking reactivity, suggesting NeuN may reflect neuron health rather than neuron loss in FTLD. We found three patterns of NeuN and pTDP-43 reactivity in our sample of cortical tissue representing three intracortical region-specific stages of FTLD-TDP progression: Group 1 showed low levels of pathological pTDP-43 and high levels NeuN, while Group 2 showed increased levels of pTDP-43, and Group 3 tissues were characterized by reduced staining for both pTDP-43 and NeuN. Comparison of non-C9orf72/GRN FTLD-TDP with cases linked to both GRN mutations and C9orf72 expansions showed a significantly increased frequency of Group 3 histopathology in the latter cases, suggesting more advanced cortical disease. Hence, we propose that IHC profiles of pTDP-43 and NeuN reflect the burden of pTDP-43 and its deleterious effects on neuron health. PMID- 28877760 TI - SBMLPkgSpec: a LaTeX style file for SBML package specification documents. AB - OBJECTIVE: The Systems Biology Markup Language (SBML) is a popular open format for storing and exchanging computational models in biology. The definition of SBML is captured in formal specification documents. SBMLPkgSpec is a LaTeX document style intended to fill the need for a standard format for writing such specification documents. RESULTS: Specification documents for SBML Level 3 extensions (known as packages in SBML) are made more uniform with the use of a standard template. SBMLPkgSpec is a LaTeX class that provides a document framework for SBML Level 3 package specifications, to simplify the work of document authors while improving the overall quality of the family of SBML specifications. PMID- 28877761 TI - Phenotypic prevalence of extended spectrum beta-lactamases among enterobacteriaceae isolated at Mulago National Referral Hospital: Uganda. AB - OBJECTIVE: Enterobacteriaceae, common causes of health care associated and community acquired infections are mainly treated with beta-lactam agents. Our study objective was to determine the prevalence and common enterobacteriaceae pathogen producing extended spectrum beta lactamases (ESBLs). The isolates were recovered from various clinical specimens. This was cross sectional study conducted between July 2016 and September 2016 at Mulago National Referral Hospital, Uganda. We used ChromIDTM ESBL agar (Biomerieux SA, Lyon, France) and Vitek2 compact system GN83 card (BioMerieux Inc, Hazelwood, Missouri, USA) to detect and confirm presence of phenotypic extended spectrum beta lactamases producing pathogens respectively. RESULTS: Of the 261 tested clinical isolates, 35 (13.4%) were identified as ESBLs producing bacteria. Escherichia coli predominated in the samples [18 (51.4%)], presenting the highest frequency of ESBLs producing, followed by Klebsiella pneumonia [10 (28.5%)], Proteus mirabilis [4 (11.4%)], Enterobacter sp. [2 (5.7%)] and least among Acinetobacter baumanii [1 (2.8%)]. PMID- 28877759 TI - The effects of 17 alpha-estradiol to inhibit inflammation in vitro. AB - BACKGROUND: 17 Alpha-estradiol (17 alpha-E2) is a natural, non-feminizing stereoisomer of 17 beta-estradiol (17 beta-E2). Whereas much is known about the physiological effects of 17 beta-E2, much less is known about 17 alpha-E2. For example, 17 beta-E2 exerts anti-inflammatory effects in neurons and adipocytes through binding and activation of estrogen receptor alpha (ERalpha); however, if 17 alpha-E2 has similar effects on inflammation is currently unknown. METHODS: To begin to address this, we analyzed the ability of 17 alpha-E2 and 17 beta-E2 to suppress lipopolysaccharide (LPS)-induced inflammation in vitro using embryonic fibroblast cells (MEF) from wild type and total body ERalpha (ERKO) male and female mice. Additionally, we further probed if there were sex differences with respect to the effects of E2s using primary pre-adipocyte cells from C57BL/6J male and female mice. Also, we probed mechanistically the effects of E2s in fully differentiated 3T3-L1 cells. RESULTS: Both E2s decreased LPS-induced markers of inflammation Tnf-alpha and Il-6, and increased the anti-inflammatory markers Il-4 and IL-6 receptor (Il-6ra) in MEF cells. To begin to understand the mechanisms by which both E2's mediate their anti-inflammatory effects, we probed the role of ERalpha using two methods. First, we used MEF cells from ERKO mice and found reductions in ERalpha diminished the ability of 17 alpha-E2 to suppress Tnf-alpha in female but not in male cells, demonstrating a sexual dimorphism in regard to the role of ERalpha to mediate 17 alpha-E2's effects. Second, we selectively reduced the expression of ERalpha in 3T3-L1 cells using siRNA and found reductions in ERalpha diminished the ability of both E2s to suppress Tnf-alpha and Il-6 expression. Lastly, to determine the mechanisms by which E2s reduce inflammation, we explored the role of NFkappaB-p65 and found both E2s decreased NFkappaB-p65 expression. CONCLUSIONS: In conclusion, we demonstrate for the first time that 17 alpha-E2, as well as 17 beta-E2, suppresses inflammation through their effects on ERalpha and NFkappaB-p65. PMID- 28877762 TI - Larvicidal effect of Endod (Phytolacca dodecandra) seed products against Anopheles arabiensis (Diptera: Culicidae) in Ethiopia. AB - OBJECTIVE: The purpose of the present study was to determine the larvicidal effect of 'Endod' (Phytolacca dodecandra) seed products on Anopheles arabiensis, in Ethiopia. RESULTS: Experimental study was conducted using a total of 2400 third instars larvae of A. arabiensis. The seed products P. dodecandra showed larvicidal activity against 3rd-stage larvae of both the laboratory and field population of A. arabiensis. The LC99 values for P. dodecandra's seed powder and its extract form against the laboratory reared larvae were 121.07, and 616.46 mg/l, respectively. The LC50 and LC95 values were also determined. PMID- 28877763 TI - Alzheimer's disease pathological lesions activate the spleen tyrosine kinase. AB - The pathology of Alzheimer's disease (AD) is characterized by dystrophic neurites (DNs) surrounding extracellular Abeta-plaques, microgliosis, astrogliosis, intraneuronal tau hyperphosphorylation and aggregation. We have previously shown that inhibition of the spleen tyrosine kinase (Syk) lowers Abeta production and tau hyperphosphorylation in vitro and in vivo. Here, we demonstrate that Abeta overexpressing Tg PS1/APPsw, Tg APPsw mice, and tau overexpressing Tg Tau P301S mice exhibit a pathological activation of Syk compared to wild-type littermates. Syk activation is occurring in a subset of microglia and is age-dependently increased in Abeta-plaque-associated dystrophic neurites of Tg PS1/APPsw and Tg APPsw mice. In Tg Tau P301S mice, a pure model of tauopathy, activated Syk occurs in neurons that show an accumulation of misfolded and hyperphosphorylated tau in the cortex and hippocampus. Interestingly, the tau pathology is exacerbated in neurons that display high levels of Syk activation supporting a role of Syk in the formation of tau pathological species in vivo. Importantly, human AD brain sections show both pathological Syk activation in DNs around Abeta deposits and in neurons immunopositive for pathological tau species recapitulating the data obtained in transgenic mouse models of AD. Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Abeta deposition and the formation of tau pathological species. Given that we have previously shown that Syk activation also promotes Abeta formation and tau hyperphosphorylation, our data suggest that AD pathological lesions may be self propagating via a Syk dependent mechanism highlighting Syk as an attractive therapeutic target for the treatment of AD. PMID- 28877765 TI - A comparative assessment of the glucose monitor (SD Codefree) and auto analyzer (BT-3000) in measuring blood glucose concentration among diabetic patients. AB - OBJECTIVE: The aim of this study was to determine how well the measurements from a glucometer (SD Codefree) correlated with those from a standard auto analyser (BT-3000) using blood samples from diabetic and non-diabetic patients at the Bolgatanga Regional Hospital in Ghana. A cross-sectional study was conducted with a total of 150 randomly selected patients; 100 diabetic patients (4 type 1 and 96 type II) and 50 non diabetic patients. Ante-cubital venous and finger pricked blood samples were obtained from the patients following standard procedures, and blood glucose concentrations were determined using the two methods respectively. RESULTS: Data generated was entered and analysed using SPSS version 20. The mean glucose concentration for the diabetic patients (n = 100) using the glucometer were not significantly different from that of the auto analyser (10.16 +/- 3.708 mmol/L vs. 9.458 +/- 3.204 mmol/L, p = 0.154), though the glucometer generally overestimated the glucose concentration. Similarly, readings for non-diabetics were comparable between the two methods (5.286 +/- 0.477 mmol/L vs. 5.092 +/- 0.525 mmol/L, p = 0.057). The correlation between the two methods was good and highly significant (r = 0.862, p < 0.001) with both methods depicting high sensitivity and specificity in measuring blood glucose levels among diabetics as indicated by the ROC curve. PMID- 28877766 TI - Tardive dyskinesia: motor system impairments, cognition and everyday functioning. AB - The recent approval of treatments for tardive dyskinesia (TD) has rekindled interest in this chronic and previously recalcitrant condition. A large proportion of patients with chronic mental illness suffer from various degrees of TD. Even the newer antipsychotics constitute a liability for TD, and their liberal prescription might lead to emergence of new TD in patient populations previously less exposed to antipsychotics, such as those with depression, bipolar disorder, autism, or even attention deficit hyperactivity disorder. The association of TD with activity limitations remains poorly understood. We review potential new avenues of assessing the functional sequelae of TD, such as the performance of instrumental activities of daily living, residential status, and employment outcomes. We identify several mediating aspects, including physical performance measures and cognition, that may represent links between TD and everyday performance, as well as potential treatment targets. PMID- 28877764 TI - Perilipin-2 modulates dietary fat-induced microbial global gene expression profiles in the mouse intestine. AB - BACKGROUND: Intestinal microbiota are critical determinants of obesity and metabolic disease risk. In previous work, we showed that deletion of the cytoplasmic lipid droplet (CLD) protein perilipin-2 (Plin2) modulates gut microbial community structure and abrogates long-term deleterious effects of a high-fat (HF) diet in mice. However, the impact of Plin2 on microbiome function is unknown. RESULTS: Here, we used metatranscriptomics to identify differences in microbiome transcript expression in WT and Plin2-null mice following acute exposure to high-fat/low-carbohydrate (HF) or low-fat/high-carbohydrate (LF) diets. Consistent with previous studies, dietary changes resulted in significant taxonomic shifts. Unexpectedly, when fed a HF diet, the microbiota of Plin2-null and WT mice exhibited dramatic shifts in transcript expression despite no discernible shift in community structure. For Plin2-null mice, these changes included the coordinated upregulation of metabolic enzymes directing flux towards the production of growth metabolites such as fatty acids, nucleotides, and amino acids. In contrast, the LF diet did not appear to induce the same dramatic changes in transcript or pathway expression between the two genotypes. CONCLUSIONS: Our data shows that a host genotype can modulate microbiome function without impacting community structure and identify Plin2 as a specific host determinant of diet effects on microbial function. Along with uncovering potential mechanisms for integrating how diet modulates host and microbial metabolism, our findings demonstrate the limits of 16S rRNA surveys to inform on community functional activities and the need to prioritize metatranscriptomic studies to gain more meaningful insights into microbiome function. PMID- 28877767 TI - Feeding broilers with dry whey powder and whey protein concentrate affected productive performance, ileal digestibility of nutrients and cecal microbiota community. AB - Dietary interventions are a common practice in the poultry industry to promote optimal performance and health of animals. Here, we aim at assessing the influence of supplementing broiler diets with dry whey powder (DWP) and whey protein concentrate (WPC) on nutrient coefficient of apparent ileal digestibility (CAID) and productive performance. Cecal microbiota composition was also determined using Illumina amplicon sequencing. Dietary treatments were control diet (no supplementation of DWP or WPC), 60-DWP (60 g/kg of DWP), and 80-WPC (80 g/kg of WPC). One-day-old male broilers were randomly assigned to one of three treatments, and housed in floor pens. In Trial 1, 90 1-day-old chicks were allocated to three pens/treatment, with 10 birds/pen, during 21 days for CAID evaluation. Diet 60-DWP increased Ca CAID (P=0.041), while diet 80-WPC improved Ca and P CAID (P<0.001 and 0.002, respectively) when compared with control diet. In Trial 2, 810 one-day-old chicks were allocated to nine pens/treatment, with 30 birds/pen, during 42 days. Feeding chickens with 60-DWP and 80-WPC increased their BW, average daily gain (ADG) and feed intake (FI) during the starter (P<0.001 for all variables) and grower-finisher periods (P<0.001 for BW and FI, and P=0.048 for ADG), and during the entire feeding period (P<0.05), when compared with control diet. Diets 60-DWP and 80-WPC reduced the feed conversion ratio of chickens during the starter period (P<0.001 and 0.003, respectively), while 60-DWP reduced this parameter during the entire feeding period (P=0.048), when compared to control diet. At day 42, cecal microbial communities of chickens that were fed with 60-DWP and 80-WPC differed from those fed with control diet (R=0.776, P=0.008; and R=0.740, P=0.008, respectively). The abundance of Bacteroides fragilis, Bacteroides spp., Escherichia coli/Shigella flexneri and Megamonas furniformis increased when 60-DWP and 80-WPC diets were offered, while the presence of Helicobacter pullorum decreased. Lactobacillus salivarius consistently increased in chickens with better feed conversion ratio, which were those fed with 60-DWP. The results obtained in the present study indicate that growth of chickens is improved by DWP and WPC supplementation because of a higher mineral digestibility, increased feed intake and modulation of cecal microbiota communities. PMID- 28877768 TI - Are questionnaires reliable in diagnosing sleep-disordered breathing in university students? AB - OBJECTIVE: This study aimed to screen young adults for sleep-disordered breathing, and compare those with high and low risk for sleep-disordered breathing. METHODS: A survey based on the Berlin questionnaire was completed by 330 university students, and the results were used to divide them into sleep disordered breathing positive and sleep-disordered breathing negative groups. A representative group was selected from each cohort (positive group, n = 16; negative group, n = 21), and assessed with sleep study, ENT examination, the Nose Obstruction Symptom Evaluation scale, and the Epworth Sleepiness Scale. RESULTS: Sleep-disordered breathing prevalence was 11.2 per cent in the questionnaire and 24 per cent according to the sleep study. The sleep-disordered breathing positive and negative groups significantly differed in terms of coexisting sleep disordered breathing symptoms. There were no significant differences between the positive and negative groups with regard to sleep study parameters (apnoea/hypopnoea index, respiratory disturbance index, oxygen desaturation index, snoring intensity) and the Epworth Sleepiness Scale. CONCLUSION: Subjective and objective diagnostic tools revealed that sleep-disordered breathing is a common problem among young adults. PMID- 28877769 TI - Anti-Ma2-Associated Encephalitis Secondary to Hodgkin's Lymphoma. PMID- 28877770 TI - First trimester antenatal depression and anxiety: prevalence and associated factors in an urban population in Soweto, South Africa. AB - Depression and anxiety in the antenatal period are of public health concern given potential adverse effects for both mother and infant. Both are under-researched in the first trimester of pregnancy, especially in Africa. We examine the prevalence of first trimester antenatal depression and anxiety in a cohort of South African women and investigate associated risk factors. Data were collected from 946 women (2014-2016) in the Soweto First 1000 Days Cohort, a prospective pregnancy cohort in Soweto, South Africa. Antenatal depression was assessed using the Edinburgh Postnatal Depression Scale with a score of ?13 indicating probable depression. Anxiety was assessed using the short form of the State-Trait Anxiety Index with a score ?12 indicating probable anxiety. Prevalence of antenatal depression was 27% [95% confidence interval (CI) 24.2-29.8] and anxiety 15.2% (95% CI 12.9-17.5). Factors associated with antenatal depression and anxiety were predominantly relationship- and family-centred. Women who perceived that their partner made life harder for them had three-fold increased odds for depression [(odds ratio (OR) 3.33 [2.28-4.85] P<0.001], whereas those with family stressors had almost double the odds for depression (OR 1.78 [1.22-2.59] P=0.003) and anxiety (OR 1.75 [1.44-2.69] P=0.0011). Antenatal depression and anxiety are common in the first trimester of pregnancy, and partner and family relationship stressors are central. Longitudinal analysis is needed to determine if this is a phase of adjustment to pregnancy or onset of persistent symptomology. Early intervention may have secondary preventative effects and should involve the partner and family. PMID- 28877771 TI - Stability, fatty acid composition and sensory properties of the M. Longissimus muscle from beef steers grazing either chicory/ryegrass or ryegrass. AB - Research has shown both production and health benefits for the use of chicory (Cichorium intybus) within ruminant diets. Despite this, little was known about the effects of this forage, containing differing fatty acid profiles and secondary plant compounds compared with ryegrass, on beef stability, fatty acid composition or sensory properties. An experiment was conducted to investigate whether the inclusion of chicory in the diet of grazing beef steers would alter these three properties in the M. Longissimus muscle when compared with beef steers grazing perennial ryegrass (Lolium perenne). Triplicate 2 ha plots were established with a chicory (cv. Puna II)/perennial ryegrass mix or a perennial ryegrass control. A core group of 36 Belgian Blue - cross steers were used within a 2-year beef finishing experiment (n=6/replicate plot). In the 2nd grazing year, steers were slaughtered as they reached a target fat class of 3. Muscle pH was checked 2 and 48 h post-slaughter. A section of the hindloin joint containing the M. Longissimus lumborum muscle was removed and a 20 mm-thick steak was cut and muscle samples were taken for analysis of vitamin E and fatty acid analysis. The remaining section of the loin was vacuum packed in modified atmosphere packs and subjected to simulated retail display. A section of the conditioned loin was used for sensory analysis. Data on pH, vitamin E concentration and colour stability in a simulated retail display showed there were no effects of including chicory in the diet of grazing beef steers on meat stability. There were also no differences found in the fatty acid composition or the overall eating quality of the steaks from the two treatments. In conclusion, there were no substantive effects of including chicory in the swards of grazing beef cattle on meat stability, fatty acid composition or sensory properties of the M. Longissimus muscle when compared with beef steers grazing ryegrass-only swards. PMID- 28877772 TI - Toward Theoretical and Experimental Synergies in Neuroscience: A Personal View. PMID- 28877773 TI - Mothers' self-reported grocery shopping behaviours with their 2- to 7-year-old children: relationship between feeding practices and mothers' willingness to purchase child-requested nutrient-poor, marketed foods, and fruits and vegetables. AB - OBJECTIVE: To assess relationships between mothers' feeding practices (food as a reward, food for emotion regulation, modelling of healthy eating) and mothers' willingness to purchase child-marketed foods and fruits/vegetables (F&V) requested by their children during grocery co-shopping. DESIGN: Cross-sectional. Mothers completed an online survey that included questions about feeding practices and willingness (i.e. intentions) to purchase child-requested foods during grocery co-shopping. Feeding practices scores were dichotomized at the median. Foods were grouped as nutrient-poor or nutrient-dense (F&V) based on national nutrition guidelines. Regression models compared mothers with above-the median v. at-or-below-the-median feeding practices scores on their willingness to purchase child-requested food groupings, adjusting for demographic covariates. SETTING: Participants completed an online survey generated at a public university in the USA. SUBJECTS: Mothers (n 318) of 2- to 7-year-old children. RESULTS: Mothers who scored above-the-median on using food as a reward were more willing to purchase nutrient-poor foods (beta=0.60, P<0.0001), mothers who scored above the-median on use of food for emotion regulation were more willing to purchase nutrient-poor foods (beta=0.29, P<0.0031) and mothers who scored above-the-median on modelling of healthy eating were more willing to purchase nutrient-dense foods (beta=0.22, P<0.001) than were mothers with at-or-below-the-median scores, adjusting for demographic covariates. CONCLUSIONS: Mothers who reported using food to control children's behaviour were more willing to purchase child requested, nutrient-poor foods. Parental feeding practices may facilitate or limit children's foods requested in grocery stores. Parent-child food consumer behaviours should be investigated as a route that may contribute to children's eating patterns. PMID- 28877774 TI - Complete mitochondrial genome of bamboo grasshopper, Ceracris fasciata, and the phylogenetic analyses and divergence time estimation of Caelifera (Orthoptera). AB - The bamboo grasshopper Ceracris fasciata is regarded as a major pest species because of the damage it causes to bamboo, and its classification within the families and subfamilies of the suborder Caelifera remains unclear. Thus, we attempted to resolve these questions using molecular biology methods and analyses. Our results are as follows: (1) the complete mitochondrial genome of C. fasciata is 15,569 bp in length. The mitochondrial genome contains a standard set of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and an A + T-rich region in the same order as those of the other analysed Caeliferan species. The putative start codon for the COX1 gene in C. fasciata is ACC, although it is not defined in other genes. The presence of tandem repeats of different sizes in the A + T-rich region may lead to size differences in other mitochondrial genomes. The mitochondrial genome of C. fasciata harbours the typical 37 genes and an A + T-rich region, and it shows similar characteristics to those of other grasshopper species. Characterization of the mitochondrial genome has enriched our knowledge of the mitochondrial genomes of Orthoptera around the world. Therefore, the phylogenetic relationships in Orthoptera can be re-examined. (2) In phylogenetic analyses, the monophyly of Orthoptera and its two suborders (Caelifera and Ensifera) has been consistently recovered based on most of the datasets selected, regardless of the optimal criteria. Our results do not support the monophyly of the subfamily Oedipodinae of Caelifera. We found that Phlaeoba albonema of the Acridinae is sorted into a clade with Ceracris in all our phylogenetic trees, and field experiments show that Phlaeoba always lives with Ceracris in the same ecotopes. Therefore, we suggest that Phlaeoba should be classified as a member of the Oedipodinae. We found that C. fasciata always clustered with Ceracris kiangsu, and both were sisters to Ceracris versicolor. Therefore, the genetic relationship between C. fasciata and C. kiangsu is closer than that between C. fasciata and C. versicolor. (3) The oldest estimated time of divergence of Ensifera in this context was determined to be 146.16 million years ago (Mya), or around the late Jurassic or early Cretaceous. We estimated that katydids (Grylloidea) likely diverged from other groups in the early Cretaceous. According to our divergence time analyses, we concluded that the ancestral Acrididae probably originated in the early Paleogene, and it is likely that the major diversification events happened at the middle Paleogene, well into the next geologic time. We estimated that crickets (Tettigoniidae) likely diverged from other groups in the early Cretaceous. Acrididae and Romaleinae group, Pyrgacrididae and Ommexechidae group, the youngest two clades we observed, were estimated to have diverged 58.79 Mya, between the middle and early Paleogene. C. versicolor is a sister to the group containing C. kiangsu and C. fasciata. First, C. versicolor diverged from the sister group (C. kiangsu + C. fasciata) around 44.81 Mya, and then the C. kiangsu and C. fasciata group separated at 43.04 Mya. PMID- 28877775 TI - Legal advocacy as a tool to advance Roma Health. AB - Roma in central Europe face many violations of their rights, including those that impede their access to high-quality health care. Legal frameworks have the potential to address these violations, whereas legal advocacy services offer a means for enforcement of rights. We undertook key informant interviews with Roma civil society organisations and selected knowledgeable individuals in Macedonia, Romania and Serbia to identify lessons from the development of these services. Achievements were reported in four areas. Legal empowerment, with employment of Roma paralegals was especially effective, increasing awareness of the ability to challenge violations. Documentation of human rights violations is an important basis for advocacy, but does not guarantee redress, and may work best in combination with legal empowerment or international pressure. Strategic litigation can play a key role in removing bureaucratic obstacles that prevent Roma from exercising their right to access to health care. Progress in changing the narrative on Roma in the mainstream media has been limited but examples of good practice exist. Although much remains to be done, Roma groups report that legal advocacy has strengthened their ability to challenge rights violations, thereby enhancing their ability to access effective and responsive care. PMID- 28877776 TI - Maternal body weight trajectories across the life course and risk of preterm delivery. AB - We examined the association between life course body weight percentile trajectories and risk for preterm delivery (PTD). Data about women's weight at birth, age 18, and before pregnancy were obtained by retrospective self-report in a cohort of 1410 black women in metropolitan Detroit. Growth mixture models were used to categorize women with similar weight percentile trajectories across these time points. Log-Poisson models were used to examine the association between the trajectory groups and PTD. Four trajectory groups with different beginning and endpoints of their weight percentiles (high-high, high-low, low-high and low-low) best fit the data. The groups with the highest prevalence of PTD were those that started low (low-high, 21%; low-low, 18%). The low-high group had a higher prevalence of PTD than the high-high trajectory group in unadjusted models (prevalence ratio=1.49 [95% confidence interval (CI) 1.11, 2.00]). The association became not significant after adjusting for maternal age at delivery, income, diabetes and hypertension. When compared with the high-high trajectory group, the low-low trajectory seemed to also have a higher prevalence of PTD after adjusting for maternal age at delivery, income, diabetes and hypertension (prevalence ratio=1.35 [95% CI 1.00, 1.83]). Results suggest that a woman's risk for PTD is influenced by her body weight trajectory across the life course. PMID- 28877778 TI - Sow level risk factors for early piglet mortality and crushing in organic outdoor production. AB - Piglet mortality is a major problem in organic pig production affecting both farm economy and animal welfare. Knowledge is scarce on the risk factors of piglet mortality in Danish commercial organic pig production. The objectives of this study were to evaluate season, litter size, parity, sow body condition and stillborn littermates as risk factors for early piglet mortality and crushing of liveborn piglets from parturition until castration at day 3 to 5 postpartum (pp). The study was conducted over a 1-year period in nine commercial Danish organic pig herds practicing outdoor farrowing all year round. Data included recordings on 3393 farrowings with 50 284 liveborn piglets of which 14.8% died before castration. A subset of the dead piglets were collected and necropsied to identify crushed piglets. The average number of liveborn piglets per litter was 14.8 (SD=3.7) and the average time from parturition until castration was 4.1 (SD=1.7) days. A negative binomial regression analysis was used to model the effect of the predictive variables on the early piglet mortality accounting for different time periods from parturition to castration. An increase in maternal body condition score (BCS) and parity significantly increased the risk of dying between parturition and castration. Early mortality was found to be lowest during spring (March to May) and highest during summer (June to August). Being born into a litter with one or more stillborn littermates increased the risk of early mortality. The risk factors for crushing of piglets were evaluated using a logistic analysis. A significant effect of parity and litter size was found where the odds of at least one piglet in a litter with mortality was diagnosed as crushed increased with increasing parity and litter size. In conclusion, being born during summer (June to August), high parity and maternal BCS and stillborn littermates were found to be risk factors for piglet mortality between parturition and castration. In addition, parity and increasing litter size were found to be risk factors for crushing of piglets in litters with mortality. PMID- 28877777 TI - Metabolomics reveals the mechanism of (-)-hydroxycitric acid promotion of protein synthesis and inhibition of fatty acid synthesis in broiler chickens. AB - (-)-Hydroxycitric acid (HCA), a major component of Garcinia cambogia extracts, has been shown to suppress BW gain and fat accumulation in animals and humans. However, the mechanism remains unknown. In this study, gas chromatography-mass spectrometry was used to analyse serum metabolites, and principal component analysis and partial least-squares-discriminant analysis models were generated to analyse serum metabolite changes in broiler chickens after the administration of (-)-HCA at 0, 1000, 2000 and 3000 mg/kg diets for 28 days. Metabolites showing significant changes were screened by 'variable importance in the projection' plots. The results showed that 20 metabolites in the 1000 mg/kg (-)-HCA treatment group and 16 metabolites in 3000 mg/kg (-)-HCA treatment group were significantly altered. Metabolites pathway enrichment analysis indicated that these metabolites were mainly associated with metabolism of amino acids, protein synthesis, citric acid cycle, and uric acid and fatty acid synthesis. The data indicated that (-) HCA promoted protein synthesis by regulating the metabolic directions of amino acids. At the same time, (-)-HCA treatment inhibited fatty acid synthesis by promoting the citric acid cycle, resulting in reduced cytosolic acetyl-CoA content in broiler chickens. The present study identified global changes in metabolites and analysed the main canonical metabolic pathways in broiler chickens supplemented with (-)-HCA. These results will deepen our understanding of the mechanism of (-)-HCA's effects in animals. PMID- 28877780 TI - MicroRNA-384 Inhibits the Growth and Invasion of Renal Cell Carcinoma Cells by Targeting Astrocyte Elevated Gene 1. AB - MicroRNAs (miRNAs) are emerging as pivotal regulators in the development and progression of various cancers, including renal cell carcinoma (RCC). MicroRNA 384 (miR-384) has been found to be an important cancer-related miRNA in several types of cancers. However, the role of miR-384 in RCC remains unclear. In this study, we aimed to investigate the potential function of miR-384 in regulating tumorigenesis in RCC. Here we found that miR-384 was significantly downregulated in RCC tissues and cell lines. Overexpression of miR-384 significantly inhibited the growth and invasion of RCC cells, whereas inhibition of miR-384 had the opposite effects. Bioinformatic analysis and luciferase reporter assay showed that miR-384 directly targeted the 3'-untranslated region of astrocyte elevated gene 1 (AEG-1). Further data showed that miR-384 could negatively regulate the expression of AEG-1 in RCC cells. Importantly, miR-384 expression was inversely correlated with AEG-1 expression in clinical RCC specimens. Moreover, miR-384 regulates the activation of Wnt signaling. Overexpression of AEG-1 significantly reversed the antitumor effects of miR-384. Overall, these findings suggest that miR-384 suppresses the growth and invasion of RCC cells via downregulation of AEG 1, providing a potential therapeutic target for the treatment of RCC. PMID- 28877779 TI - Adverse Health Complaints of Adults Exposed to Benzene After a Flaring Disaster at the BP Refinery Facility in Texas City, Texas. AB - OBJECTIVE: The objective of this study was to assess the adverse health symptoms experienced by adult subjects who were exposed to benzene after a flaring disaster at the BP refinery in Texas City, Texas. METHODS: A total of 2162 adults aged 18 years or older and exposed to benzene were included. Using the patients' medical charts, we collected and analyzed data on health complaints as well as the patients' serum levels of beta-2-microglobulin and urinary excretion of phenol. RESULTS: A total of 11,368 health symptom complaints were reported in 2162 adults exposed to benzene. Neurological symptoms occurred most frequently (174%), followed upper respiratory symptoms (115%), cough (31%), painful joints (30%), cardiac symptoms (28%), dermatological symptoms (28%), gastrointestinal symptoms (27%), diarrhea (25%), vision symptoms (21%), and nausea/vomiting (19%). Logistic regression analysis indicated that urinary symptoms (R2=0.65) and painful joints (R2=0.44) were positively associated with increasing age in benzene-exposed subjects. CONCLUSION: Adult subjects exposed to benzene experience a range of adverse health symptoms and an altered profile of urinary phenol, thus indicating they are at high risk of developing serious future health complications. (Disaster Med Public Health Preparedness. 2018;12:232-240). PMID- 28877781 TI - Letters to the Editor. PMID- 28877783 TI - G-Protein-Coupled Estrogen Receptor Antagonist G15 Decreases Estrogen-Induced Development of Non-Small Cell Lung Cancer. AB - G-protein-coupled estrogen receptor (GPER) was found to promote Non-small cell lung cancer (NSCLC) by estrogen, indicating the potential necessity of inhibiting GPER by selective antagonist. This study was performed to elucidate the function of GPER selective inhibitor G15 in NSCLC development. Cytoplasmic GPER (cGPER) and nuclear GPER (nGPER) were detected by immunohistochemical analysis in NSCLC samples. The relation of GPER and estrogen receptor beta (ERbeta) expression and correlation between GPER, ERbeta and clinical factors were analyzed. The effects of activating GPER and function of G15 were analyzed in proliferation of A549, H1793 cell lines and development of urethane-induced adenocarcinoma. Overexpression of cGPER and nGPER was detected in 80.49% (120/150) and 52.00% (78/150) of the NSCLC samples. High expression of GPER related with higher stages, poorer differentiation and high expression of ERbeta. Protein level of GPER in A549 and H1793 cell lines increased by treatment of E2, G1 (GPER agonist) or Ful (fulvestrant, ERbeta antagonist), and decreased by G15. Administration with G15 reversed the E2- or G1-induced cell growth by inhibiting GPER. In urethane-induced adenocarcinoma mice, number of tumor nodules and tumor index increased in E2 or G1 group and decreased by treatment of G15. These findings deomonstrate that using of G15 to block GPER signaling may be considered as a new therapeutic target in NSCLC. PMID- 28877782 TI - Chemometric-Assisted Spectrophotometric Method for the Simultaneous Quantitative Determination of Ezetimibe and Simvastatin in Their Combined Dosage Forms. AB - The multivariate method, partial least-squares (PLS), was used as a calibration procedure for the simultaneous UV spectrophotometric determination of ezetimibe and simvastatin in their pharmaceutical forms. The method was developed and satisfactorily validated according to International Conference on Harmonization guidelines with respect to specificity, linearity, precision, accuracy, and robustness. In this study, the PLS algorithms are based on the absorption spectra of 25 different mixtures of drugs obtained by a multilevel factorial design. The method was linear in the concentration range of 2-8 MUg/mL for ezetimibe and 4-16 MUg/mL for simvastatin (r2 > 0.99; n = 7) at wavelengths of 238 and 247 nm, respectively. The LOD and LOQ were 0.28 and 0.93 MUg/mL for ezetimibe and 0.16 and 0.53 MUg/mL for simvastatin, respectively. Precision and accuracy data, evaluated by RSD, were lower than 2%. The method, which proved to be robust, was performed with a 2n full-factorial design. The validated method is simple and low cost, has a low use of polluting reagents, and is environmental friendly. Therefore, the proposed method was successfully applied for the simultaneous quantitative analysis of ezetimibe and simvastatin in commercial formulations. PMID- 28877784 TI - Lung Metastasis Presenting as Rectal Mass. PMID- 28877785 TI - Pediatric Four-Wheel Type Vehicle Injuries: Outcomes and Injury Patterns. PMID- 28877786 TI - A Newly Developed Mask Facilitates Management During Percutaneous Endoscopic Gastrostomy Introduction in Patients with Respiratory Compromise. PMID- 28877787 TI - Acute Sigmoid Diverticulitis Presenting as Necrotizing Fasciitis of the Thigh and Retroperitoneum. PMID- 28877788 TI - Cecal Herniation and Volvulus through the Foramen of Winslow. PMID- 28877789 TI - Y-type Anovulvar Fistula Complicating Inflammatory Bowel Disease. PMID- 28877790 TI - Abdominal Cocoon-An Unusual Case of Bowel Obstruction. PMID- 28877791 TI - Splenic Abscess Requiring Early Splenectomy Following Angioembolization for Blunt Splenic Injury in an Immunocompromised Host: Implications for Management. PMID- 28877792 TI - Empowering Surgical Residents as Mentors: A Pilot Program for Female Medical Students. PMID- 28877793 TI - Thoracic Endovascular Aortic Repair for Blunt Traumatic Rupture of a Penetrating Atherosclerotic Ulcer. PMID- 28877794 TI - Morgagni Hernia: Is It Just a Congenital Hernia or a Cause of Emergency Surgery? PMID- 28877795 TI - Perforated Transverse Colon Cancer Presenting as an Incarcerated Inguinal Hernia. PMID- 28877796 TI - Perils in the Pelvis: Laparoscopic Management of Bilateral Pouch of Douglas Hernial Defects. PMID- 28877797 TI - Liver Metastases 10 Years after Resection of a "Benign" Insulinoma. PMID- 28877798 TI - Omental Pedicle Flap Does Not Decrease the Incidence of Bowel Obstruction after Abdominoperineal Resection. PMID- 28877799 TI - Remembering Dr. Henry W. Gray (1827-1861) and His Timeless Contribution to Modern Medical Education. PMID- 28877800 TI - Disparities in Mangement of Patients with Benign Colorectal Disease: Impact of Urbanization and Specialized Care. AB - : Disparities in the management of patients with various medical conditions are well established. Colorectal diseases continue to remain one of the most common causes for surgical intervention. The aim of this study was to assess disparities (rural versus urban) in the surgical management of patients with noncancerous benign colorectal diseases. We hypothesized that there is no difference among rural versus urban centers (UC) in the surgical management for noncancerous benign colorectal diseases. The national estimates of surgical procedures for benign colorectal diseases from the National Inpatient Sample database 2011 representing 20 per cent of all in-patient admissions were abstracted. Patients undergoing procedures (abscess drainage, hemmoroidectomy, fistulectomy, and bowel resections) were included. Patients with colon cancer and those who underwent emergency surgery were excluded. The population was divided into two groups: urban and rural, based on the location of treatment. Outcome measures were in hospital complications, mortality, and hospital costs. Subanalysis of UC was preformed: centers with colorectal surgeons and centers without colorectal surgeons. Regression analysis was performed. A total of 20,617 patients who underwent surgical intervention for benign colorectal diseases across 496 (urban: 342, rural: 154) centers, were included. Of the UC, 38.3 per cent centers had colorectal surgeons. Patients managed in UC had lower complication rate (7.6% vs 10.2%, P < 0.001), shorter hospital length of stay (4.7 +/- 3.1 vs 5.9 +/- 3.6 days, P < 0.001), and higher hospital costs ($56,820 +/- $27,691 vs $49,341 +/- $2,598, P < 0.001) compared with rural centers. On subanalysis, patients managed in UC with colorectal surgeons had 11 per cent lower incidence of in-hospital complications [odds ratio: 0.89 (95% confidence interval: 0.76-0.94)] and a shorter hospital length of stay [Beta: -0.72 (95% confidence interval: -0.81 to 0.65)] when compared with patients managed in UC without colorectal specialization. Disparities exit in outcomes of the patients with noncancerous benign colorectal diseases managed surgically in urban versus rural centers. Specialized care with colorectal surgeons at UC helps reduce adverse patient outcomes. Steps to provide effective and safe surgical care in a cost-effective manner across rural as well as UC are warranted. LEVEL OF EVIDENCE: Level III, retrospective cohort analysis. PMID- 28877801 TI - Using Electromagnetic Navigation Bronchoscopy and Dye Injection to Aid in Video Assisted Lung Resection. AB - Small (2 cm) peripheral lung lesions and ground glass opacities remain a difficult subset of lung lesions for the diagnosis and management of lung cancer. Surgical biopsy is more difficult for these lesions because intraoperative localization has to be made without the aid of direct visualization or manual palpation. Electromagnetic navigation bronchoscopy can be used in the operating room to identify a small peripheral lesion and marked using an injection of methylene blue, which can be seen on the visceral pleura of the lung. We present our initial experience using this technique. The sample was eight patients who had peripheral lesions with an average size of 19 mm. Surgical wedge biopsy was diagnostic in all cases, with an average procedure time of 28 minutes. There were no complications from this procedure. In conclusion, these data suggest that electromagnetic navigation bronchoscopy can be performed safely with high diagnostic accuracy by the operating thoracic surgeon, but further data are needed to establish its utility and safety. PMID- 28877802 TI - A Comprehensive Investigation of Comorbidities, Mechanisms, Injury Patterns, and Outcomes in Geriatric Blunt Trauma Patients. AB - The geriatric population is growing and trauma providers are often tasked with caring for injuries in the elderly. There is limited information regarding injury patterns in geriatric trauma patients stratified by mechanism of injury. This study intends to investigate the comorbidities, mechanisms, injury patterns, and outcomes in geriatric blunt trauma patients. A retrospective study of the 2012 National Trauma Databank was performed. Adult blunt trauma patients were identified; geriatric (>/=65) patients were compared with younger (<65) patients regarding admission demographics and vital signs, mechanism and severity of injury, and comorbidities. The primary outcome was injuries sustained and secondary outcomes included mortality, length of stay in the intensive care unit and hospital, and ventilator days. There were 589,830 blunt trauma patients who met the inclusion criteria, including 183,209 (31%) geriatric and 406,621 (69%) nongeriatric patients. Falls were more common in geriatric patients (79 vs 29%, P < 0.0001). Geriatric patients less often had an Injury Severity Score >/=16 (18 vs 20%, P < 0.0001) but more often a head Abbreviated Injury Scale >/=3 (24 vs 18%, P < 0.0001) and lower extremity Abbreviated Injury Scale >/=3 (24% vs 8%, P < 0.0001). After logistic regression older age was an independent risk factor for mortality for the overall population and across all mechanisms. Falls are the most common mechanism for geriatric trauma patients. Geriatric patients overall present with a lower Injury Severity Score, but more often sustain severe injuries to the head and lower extremities. Injury patterns vary significantly between older and younger patients when stratified by mechanism. Mortality is significantly higher for geriatric trauma patients and older age is independently associated with mortality across all mechanisms. PMID- 28877803 TI - Surgical Aspects of Recurrent Inguinal Hernia in Adults. AB - Surgeons occasionally encounter a case of recurrent hernia in adult patients after the primary repair, and these cases are challenging to manage appropriately. This study was conducted to describe the clinical nature of recurrent inguinal hernia, compare the results of management, and identify the relationship between the specific risk factors and the occurrence of recurrent hernia. Retrospectively reviewed 58 patients who underwent the inguinal herniorrhaphy for recurrent hernia in a single institution. Analyzed clinical characteristics of recurrent hernia and tried to verify the relationship between smoking, obesity, and occurrence of recurrent hernia. Recurrent inguinal hernia was 13.5 per cent of all hernia repairs in the study period. Most of the recurrence was the first event (74.1%) and showed an interval to recurrence with a mean duration of 40.7 months. There was no significant difference in procedure time, development of postoperative complications, and duration of hospital stay according to the procedure. Compromise of smoker and overweight was significantly higher in the recurrent group (P < 0.05). Surgeons should be aware of the increased risk for recurrence in adult inguinal hernia patients when they smoke or are overweight (body mass index >= 25 kg/m2), also it needs to follow-up during the adequate period. PMID- 28877805 TI - Increased Age Predicts Failure to Rescue. AB - Failure to rescue (FTR), defined as any death after the development of in hospital complications, is an important quality measure, but the relationship with age after a traumatic injury, has not been well defined. We sought to examine whether older trauma patients are at higher risk for FTR. The National Trauma Databank (NTDB) research datasets 2007 to 2011 were queried for patients >=16 years who had any reported complication. Those who survived (non-FTR) were compared with those who did not (FTR) using a forward logistic regression model. Overall, 218,986 subjects met inclusion criteria of those, 201,358 (91.2%) survived their complication (non-FTR) and 17,628 (8.8%) died (FTR). A forward logistic regression identified age 65 to 89 years as the strongest predictor of FTR [adjusted odds ratio (AOR) 95% confidence interval (CI): 6.58 (6.11, 7.08), P < 0.001]. Using age group 16 to 45 years as the reference group, the adjusted risk for FTR increased with increasing age in a stepwise fashion [AOR (95 % CI): 1.94 (1.80, 2.09) for age 46 to 65 years, 6.78 (6.19, 7.42) for age 66 to 89 years and 27.58 [21.81, 34.87] for age >=90 years]. The adjusted risk of FTR also increased in a stepwise fashion with increasing number of complications, reaching AOR (95 per cent CI) of 2.25 (2.07, 2.45), P < 0.001 for >=4 complications. The risk of failure to rescue increases with age and number of complications. Strategies which track this quality measure to encourage early recognition and treatment of complications in the elderly are necessary. PMID- 28877804 TI - Use of Antibiotic-Impregnated Absorbable Beads and Tissue Coverage of Complex Wounds. AB - The treatment of complex wounds is commonplace for plastic surgeons. Standard management is debridement of infected and devitalized tissue and systemic antibiotic therapy. In cases where vital structures are exposed within the wound, coverage is obtained with the use of vascularized tissue using both muscle and fasciocutaneous flaps. The use of nondissolving polymethylmethacrylate and absorbable antibiotic-impregnated beads has been shown to deliver high concentrations of antibiotics with low systemic levels of the same antibiotic. We present a multicenter retrospective review of all cases that used absorbable antibiotic-impregnated beads for complex wound management from 2003 to 2013. A total of 104 cases were investigated, flap coverage was used in 97 cases (93.3%). Overall, 15 patients (14.4%) required reoperation with the highest groups involving orthopedic wounds and sternal wounds. The advantages of using absorbable antibiotic-impregnated beads in complex infected wounds have been demonstrated with minimal disadvantages. The utilization of these beads is expanding to a variety of complex infectious wounds requiring high concentrations of local antibiotics. PMID- 28877806 TI - National Disparities in Surgical Approach to T1 Rectal Cancer and Impact on Outcomes. AB - This study investigated disparities between patients who had local excision versus radical resection for T1 rectal cancer. A retrospective analysis was performed using the National Cancer Data Base, 2004 to 2011. Inclusion criteria consisted of patients with T1, N0 rectal adenocarcinoma that were <3 cm, well or moderately differentiated without perineural invasion. Patients were stratified based on local excision and radical surgery. The primary outcome was overall survival (OS). Secondary outcomes included 30-day mortality, unplanned readmission rates, and postoperative length of stay. A total of 2235 patients were identified; 1335 (59.7%) underwent local excision and 900 (40.3%) had radical surgery. Overall, radical surgery was associated with an improved 5-year OS rate compared to local excision (0.86 vs 0.78, P = 0.009), increased unplanned readmission (6.5% vs 2.7%, P < 0.001), and longer postoperative length of stay (6.9 days vs 3.1 days, P < 0.001). For patients who had local excision, insurance status was an independent predictor of OS. Compared to patients with private insurance, those with government plans or no insurance had poorer OS (hazard ratio = 1.77 and 17.45, respectively, P = 0.006). Further study is warranted to understand the reasons accounting for this disparity in surgical approach to T1 rectal cancer. PMID- 28877807 TI - Independent Preoperative Predictors of Prolonged Length of Stay after Laparoscopic Appendectomy in Patients Over 30 Years of Age: Experience from a Single Institution. AB - Prompt discharge after laparoscopic appendectomy (LA) is a marker of quality of care, fiscally desirable and feasible in select patients. Patients over 30 comprise a more heterogeneous cohort known to experience worse outcomes after LA. We aimed to identify easily available preoperative risk factors portending a postoperative length of stay >=2 days among patients above age 30. In this investigation, 296 included patients from a single institution who underwent LA for acute appendicitis from 2010 to 2014 were retrospectively reviewed for preoperative demographics, laboratory studies, comorbidities, presentation characteristics, radiographic finding, and other rationally selected factors for association with postoperative length of stay >=2 days. Bivariate and multivariate analysis was conducted to determine independent risk factors, which were subsequently modeled via receiver-operating characteristic curve generation and Kaplan-Meier analysis. "Classic" presentation [odds ratio (OR) = 0.5, P = .02], elevated red cell distribution width (RDW; OR = 1.5/% increase, P = 0.004) as well as evidence of rupture on CT (OR = 6.9, P < 0.001) were independently associated with postoperative length of stay >= 2 days. Modeling length of stay using these factors generated an area under the curve of 0.713 +/- 0.037. Kaplan Meier analysis of "classic" presentation, elevated RDW, and evidence of rupture on CT through the fifth postoperative day generated log-rank P values of 0.02, 0.05, and <= 0.001, respectively. In summary, lack of "classic" presentation, elevated RDW, and CT evidence of rupture are novel risk factors for prolonged postoperative length of stay in LA patients over 30. These findings may help target patients most appropriate for prompt discharge. PMID- 28877808 TI - Percutaneous Treatment of Superficial Femoral Artery Stenosis Secondary to Radiation Arteritis. AB - Radiation arteritis is a rare cause of lower extremity peripheral arterial occlusive disease, and has been traditionally treated with open interventions. There have been only a few reported cases of endovascular interventions for this disease. Previous reports described endovascular treatment in the iliac and common femoral regions, but intervention in the superficial femoral artery have not been described. Described here is a case of acute lower extremity ischemia caused by remote radiation arteritis of the superficial femoral artery, which was successfully treated by percutaneous endovascular technique. PMID- 28877809 TI - A Review of Sleeve Gastrectomy Specimen Histopathology. AB - With the increasing popularity of sleeve gastrectomy, many stomach specimens are being evaluated. Understanding the significance and treatment for unexpected pathology is important. This study examines the incidence of relevant histopathology of sleeve gastrectomy specimens. It evaluates previous data for each histopathology and provides recommendations for treatment. In this study, a retrospective review was performed for 241 patients who underwent sleeve gastrectomy from 2009 to 2014 at a single institution. Of the specimens, 122 had no significant histopathology, 91 had gastritis, 13 had lymphoid aggregates, 5 had hyperplasia, 3 had intestinal metaplasia, 3 had gastrointestinal stromal tumors (GISTs), and 3 had gastric polyps. Of the GISTs all had a low mitotic rate and the size of the tumor ranged from 1.5 to 4.5 cm. The findings of metaplasia may be a marker for increased risk of malignancy and may require additional surveillance. The findings of GIST may warrant interval imaging to survey for recurrence, though the likelihood of recurrence for the tumors in this study is less than 2 per cent based on previous studies. PMID- 28877810 TI - The Ferguson Operating Anoscope for Resection of T1 Rectal Cancer. AB - The Ferguson Operating Anoscope (FOA) is a surgical instrument, which can facilitate transanal excision of appropriate rectal tumors within 15 cm of the anal verge. Previous work showed low recurrence (4.3%) for favorable T1 tumors (no lymphovascular invasion, well/moderate differentiation, negative margins). This follow-up study evaluates outcomes in rectal cancer excised with FOA at a tertiary care center. T1 rectal cancer patients were identified in a prospectively maintained database. Tumor pathology and patient characteristics were reviewed. Primary outcomes include tumor recurrence and patient and disease free survival. Secondary outcomes are quality of excision (intact specimen). Twenty-eight patients had pathologic stage T1 rectal cancer (average 8 +/- 2.6 cm from the anal verge). Final path demonstrated 14 per cent to be well differentiated, 82 per cent moderately differentiated, and 93 per cent without angiolymphatic invasion. All specimens removed were intact. One patient had a true local recurrence and underwent a salvage operation 24 months after her index operation. Patient survival was 96.4 per cent (n = one death from primary lung cancer) at median follow-up 64 +/- 35 months. With appropriate tumor selection and quality of initial resection, FOA has demonstrated utility in achieving optimal oncologic resection of T1 rectal tumors. PMID- 28877811 TI - Resection of Gastrointestinal Metastases in Stage IV Melanoma: Correlation with Outcomes. AB - The prognosis of patients with gastrointestinal (GI) melanoma metastases is poor. Surgery renders select patients disease free and/or palliates symptoms. We reviewed our single-institution experience of resection with GI melanoma metastases. A retrospective review was performed on patients who underwent surgery for GI melanoma metastases from 2007 to 2013. Fifty-four patients were identified and separated based on completeness of resection into curative 13 (24%) and palliative 41 (75.9%) groups. Thiry-six (63.2%) were symptomatic preoperatively with bleeding and/or obstruction/pain with 91.7 per cent achieving objective symptom relief. Thirty-day operative mortality was 0 per cent. The most common complication was wound infection (n = 5); major complications like anastomotic leak (n = 1) were uncommon. With a median follow-up of 9.5 months (range 0.2-75.8), median overall survival was not reached (curative) versus 9.53 months (palliative group). Median recurrence-free and progression-free survival after resection were 18.89 and 1.97 months in the curative versus palliative groups, respectively. On multivariate analysis, resection to no clinical evidence of disease (P = 0.012) and presence of single metastases (P = 0.031) were associated with improved overall survival. Surgery for GI metastases from melanoma provides symptomatic relief without major morbidity. Fewer metastases and curative resection were associated with improved survival. PMID- 28877812 TI - Spontaneous Hepatic Hemorrhage: A Single Institution's 16-Year Experience. AB - Spontaneous hemorrhage from hepatic tumors is an uncommon but serious complication. Recently, interventional radiologic (IR) techniques are being used increasingly in the management of these patients. We report our 16-year experience in managing spontaneous hemorrhage from liver tumors. Twenty-six consecutive patients were diagnosed with spontaneous liver hemorrhage between 1995 and 2011. Initial management was operative in eight, IR in six, and supportive in 12 patients. Of those managed operatively, five were segmentectomies; one hemihepatectomy; one wedge resection; and one packing who later died from coagulopathy. In the IR patients, seven had an angiographic embolization; two required reembolization; one underwent resection of a hepatic adenoma 21 days after angiographic embolization. The malignant lesions included hepatocellular carcinoma (n = 6), angiosarcoma (n = 1), metastatic squamous cell carcinoma (n = 1), metastatic leiomyosarcoma (n = 1), nonsquamous cell carcinoma (n = 1), or metastatic angiosarcoma (n = 1). Benign diseases included hepatic adenoma (n = 5), end-stage liver disease (n = 1), and polycystic liver (n = 1). Spontaneous hemorrhage from the liver occurs evenly from benign or malignant causes, one-third of which are primary liver disease. If the patients presents emergently, angiographic embolization may control the bleeding and allow for elective resection once the sequelae of bleeding have resolved. PMID- 28877813 TI - Mixed Hepatocellular Carcinoma, Neuroendocrine Carcinoma of the Liver. AB - We present the case of a 76-year-old male found to have a large tumor involving the left lateral lobe of the liver, presumed to be hepatocellular carcinoma (HCC). After resection, pathologic features demonstrated both high-grade HCC and high-grade neuroendocrine carcinoma (NEC). Areas of NEC stained strongly for synaptophysin, which was not present in HCC component. The HCC component stained strongly for Hep-Par 1, which was not present in the NEC component. The patient underwent genetic analysis for biomarkers common to both tumor cell types. Both tumor components contained gene mutations in CTNNB1 gene (S33F located in exon 3). They also shared mutations in PD-1, PGP, and SMO. Mixed HCC/NEC tumors have been rarely reported in the literature with generally poor outcomes. This patient has been referred for adjuvant platinum-based chemotherapy; genetic biomarker analysis may provide some insight to guide targeted chemotherapy. PMID- 28877814 TI - Limited Resection of the Duodenum for Nonampullary Duodenal Tumors, with Review of the Literature. AB - The surgical management of duodenal pathology is challenging because of its retroperitoneal position and shared blood supply with the pancreas. We present three types of limited resection of the duodenum for the removal of superficial or small nonampullary duodenal (NADL) lesions, and also a review of the English literature regarding management, such as endoscopic resection and limited duodenal resection. Ten cases underwent limited resections of the duodenum for superficial or small NADL lesions from 2011 to 2015. Pancreas-preserving segmental duodenectomy was performed in three cases, local full-thickness resection was performed in three and transduodenal submucosal dissection was performed in four. One patient experienced pancreatic fistula as a postoperative complication. Postoperative pathological diagnosis were adenoma (n = 2), mucosal adenocarcinomas (n = 5), and neuroendocrine tumor (n = 3). Surgical margin was negative in all cases, and no patient has experienced postoperative recurrence or metastasis. Limited resections of the duodenum were feasible and safe procedures for patients with superficial or small NADL lesions. Laparoscopic surgery may be considered in treatment for these tumors. However, the optimal surgical management for superficial or small nonampullary duodenal lesions remains controversial. PMID- 28877815 TI - Improved Postoperative Survival for Intraductal-Growth Subtype of Intrahepatic Cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is classified according to the following subtypes: massforming (MF), periductal infiltrating (PI), and intraductal growth (IG). The aim of this study is to measure the association between ICC subtypes and patient survival after surgical resection. Data were abstracted on all patients treated with definitive resections of ICC at a single institution between 2000 and 2011 with at least three years follow-up. Survival estimates were quantified using Kaplan-Meier curves and compared using the log-rank test. There were 37 patients with ICC treated with definitive partial hepatectomies with a median survival of 33.5 months. Tumor stage (P < 0.0001), satellitosis (P < 0.001), lymphovascular space invasion (P = 0.003), and macroscopic subtype (P = 0.003) were predictive of postoperative survival. Disease-free survivals for MF, PI, and IG subtypes, respectively, were 30 per cent, 0 per cent, and 57 per cent (P = 0.017). Overall survivals among ICC macroscopic subtypes were as follows: MF 37 per cent, PI 0 per cent, and IG 71 per cent (P = 0.003). Although limited by the small sample size of this rare cancer, this study demonstrates significant differences among macroscopic subtypes of ICC in both disease-free survivals and overall survivals after definitive partial hepatectomy. PMID- 28877816 TI - Synchronous Acute Appendicitis and Acute Cholecystitis: A Discussion of a Century's Worth of Epidemiologic, Basic Science, and Clinical Research, Explicating the Pathophysiology of a Likely Underrecognized Historical Condition. PMID- 28877817 TI - Defining Outpatient Surgery: Perspectives of Surgical Staff in the Veterans Health Administration. PMID- 28877818 TI - Neuroendocrine Tumor of the Minor Duodenal Papilla: An Unusual Cause of Pancreaticoduodenectomy. PMID- 28877819 TI - Primary Pelvic Papillary Thyroid Carcinoma with Metastases to Peritoneal Surfaces. PMID- 28877820 TI - American Academy of Sleep Medicine Position Paper for the Use of a Home Sleep Apnea Test for the Diagnosis of OSA in Children. AB - INTRODUCTION: The purpose of this position paper is to establish the American Academy of Sleep Medicine's (AASM) position on the use of a home sleep apnea test (HSAT) for the diagnosis of obstructive sleep apnea (OSA) in children (birth to 18 years of age). METHODS: The AASM commissioned a task force of 8 experts in sleep medicine to review the available literature on the use of an HSAT to diagnose OSA in children. The task force developed the position statement based on a thorough review of these studies and their clinical expertise. The AASM Board of Directors approved the final position statement. POSITION STATEMENT: Use of a home sleep apnea test is not recommended for the diagnosis of obstructive sleep apnea in children. The ultimate judgment regarding propriety of any specific care must be made by the clinician, in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options, and resources. PMID- 28877821 TI - Association of Body Composition and Other Clinical Factors with Incomplete Immune Response after Highly Active Antiretroviral Therapy. AB - Objective To explore whether baseline body composition and other clinical factors are associated with incomplete immune response after highly active antiretroviral therapy(HAART)in Chinese men with human immunodeficiency virus(HIV)or acquired immunodeficiency syndrome(AIDS).Methods A retrospective study was conducted among HIV/AIDS male patients who achieved viral suppression(maintained HIV-1 RNA levels<400 copies/ml)after a year of HAART between 2007 and 2015.Clinical,immunological,and virological data were collected from patients' files,including weight,height,and whole body composition measured within one month prior to staring HAART.Body mass index(BMI),lean mass index(LMI),fat mass index(FMI),and body bone mineral content/height were adjusted by height.According to whether the patients experienced incomplete immune responses(CD4 cell count<350 cells/MUl)after a year of HAART,the patients were divided into two groups:the complete immune response(CD4 cell count>=350 cells/MUl)and the incomplete immune response(CD4 cell count<350 cells/MUl),respectively.Student's t test,chi-square test,and Wilcoxon rank test were used to assess differences between these two groups.Multiple Logistic regression analysis was used to assess factors associated with an incomplete immune response in patients with sustained viral suppression.Results Totally 84 HIV/AIDS male patients with viral suppression were included in this study.There were statistical differences between these two groups in terms of age(Z=-2.479,P=0.013),baseline BMI(t=2.030,P=0.045),LMI(t=2.200,P=0.029),and CD4 cell count(Z=6.416,P=0.000).However,there was no statistical differences in viral load,FMI,body bone mineral content/height,HAART duration,and HAART regimen(all P>0.05).BMI[OR=0.742,95% confidence interval(CI)=0.554 0.993,P=0.044],LMI(OR=0.459,95% CI=0.249-0.844,P=0.012),HAART duration(OR=10.161,95% CI=1.110-93.052,P=0.040),baseline CD4 cell count(OR=80.051,95% CI=8.396-762.563,P=0.000)were significantly associated with incomplete immune response.Age(OR=1.497,95% CI=0.213-10.505,P=0.685),viral load(OR=0.333,95% CI=0.071-1.572,P=0.164),FMI(OR=0.797,95% CI=0.546 1.164,P=0.240),body bone mineral content/height(OR=1.145,95% CI=0.037 35.676,P=0.938)and HAART regimen(OR=0.430,95% CI=0.159-1.159,P=0.095)were not associated with incomplete immune response.Conclusions Baseline CD4 cell count and HAART duration may affect immune response.Patients with higher baseline BMI or higher LMI may be less likely to develop incomplete immune response.Baseline FMI and body bone mineral content/height ratio are not associated with incomplete immune response. PMID- 28877822 TI - Effect of Intravenous Dexmedetomidine Injection(1 MUg/kg)on the Intubating Conditions without Muscle Relaxants in Children after Inhalation Induction with Sevoflurane. AB - Objective To investigate the effect of intravenous dexmedetomidine injection(1 MUg/kg)on the intubating conditions after inhalation induction with sevoflurane 8% and nitrous oxide(N2O)50% in children. Methods Totally 122 patients aged 4-10 years with an American Society of Anesthesiologists physical statusI undergoing elective plastic surgery under general anesthesia were randomly divided to dexmedetomidine group(intraveneously injected with dexmedetomidine 1MUg/kg)and control group(injected with normal saline)by using the random sampling table.On arrival of the operating room,anesthesia was induced with sevoflurane 8% and N2O 50% in oxygen 50%.When the patient became unconscious,the intravenous cannula 24# was inserted on the dorsum of hand.One minute later,laryngoscopy and tracheal intubation were performed.The intubating conditions were assessed by the scoring system in the previous study. Results The rates of acceptable conditions were 97% and 90% in dexmedetomidine group and in control group(P=0.143),and the rates of excellent conditions were 82% and 67%(P=0.04),respectively.In dexmedetomidine group,there were no signifi-cant differences of mean arterial presser and heart rate between the time-point of before intubation and the time-point of immediately after intubation.Conclusion Intravenous bolus of dexmedetomidine(1 MUg/kg)can effectively improve the intubating conditions after inhalation induction of sevoflurane 8% and N2O 50% in children and make the hemodynamics more stable during tracheal intubation. PMID- 28877823 TI - Clinical and Magnetic Resonance Imaging Features of Solid Pseudopapillary Tumor of the Pancreas in Male Patients. AB - Objective To analyze the clinical and magnetic resonance imaging(MRI)findings of solid pseudopapillary tumor(SPT)of the pancreas in male patients. Methods Clinical and MRI features of 51 patients with pathologically-proved SPT were retrospectively analyzed.The following MRI features of the lesions were analyzed:location,maximal diameter,shape,margin,capsule,solid and cystic components,signal intensity characteristics,and enhancement patterns.Results The average maximal diameter of the SPT in male patients was significantly smaller [(3.9+/-1.6)cm vs.(6.3+/-3.9)cm,P=0.035]than that of SPT in female patients.Pure solid tumors were signiciantly more common in male patients(8/14)than in female patients(9/37)(P=0.037).T1-weighted images of SPT showed mainly homogenous hypo intensity in male patients(11/14)and heterogeneous hypo-intensity in female patients(23/37)(P=0.001).Hemorrhage was more prevalent in female patients(22/37)than in male patients(2/14)(P=0.005).There were no significant differences between male and female patients regarding clinical features and other magnetic resonance features(P>0.05).Conclusions On MRI,SPT in male patients is small and shows mainly pure solid component with rare hemorrhage.The clinical and other MRI features of SPT are not different between males and females. PMID- 28877824 TI - Quantifying the Cerebral Hemodynamic Changes in Hypertensive Patients Using 3D Pseudo-continuous Arterial Spin Labeling. AB - Objective To investigate the cerebral hemodynamic changes in hypertensive patients using 3D pseudo-continuous arterial spin labeling(3D pCASL).Methods Fifty-eight hypertensive subjects and thirty-four age-matched healthy volunteers were recruited and scanned using the 3D whole-brain pCASL sequence.The regional cerebral blood flow(CBF)values were achieved based on 3D pCASL with SPM8 technique and were manually drawn. Results Compared with healthy volunteers,hypertensive patients had significantly lower CBF values in various regions,with statistical difference at the bilateral centrum semiovale(P=0.000,P=0.000),periventricular white matter(P=0.001,P=0.002),splenium of corpus callosum(P=0.003),frontal lobe(P=0.003),parietal lobe(P=0.014),occipital lobe(P=0.002),temporal lobe(P=0.006),medulla(P=0.012),pons(P=0.016),midbrain(P=0.034),cerebellum(P=0.000 ,and gray matter(P=0.001).Nevertheless,the CBF values in the thalami,globus pallidus,putamen,and genu of corpus callosum demonstrated no significant inter group difference(all P>0.05).Conclusions 3D pCASL can be used to detect the subtle hemodynamic abnormalities even at the early stage of hypertension.The observed decrease in CBF in these regions may suggest an increased risk of cerebral small vessel diseases. PMID- 28877826 TI - Clinical Analysis of Unicentric Castleman's Disease with Paraneoplastic Pemphigus and Bronchiolitis Obliterans. AB - Objective To investigate the clinical features of unicentric Castleman's disease(UCD)with paraneoplastic pemphigus(PNP)and bronchiolitis obliterans(BO).Method Data of UCD patients with PNP and BO from Peking Union Medical College Hospital were retrospectively analyzed,along with literatures review. Results Totally 23 cases(11 males and 12 females)were enrolled.The median age was 31 years(13-56 years).The most common pathological type was hyaline vascular variant(91.4%),and most tumors located in abdominopelvic cavity(69.6%).Considerable cases presented bulky masses(26.3%).Most cases were first diagnosed on presentation with the symtoms of PNP(90.0%).BO was characterized by progressive dyspnea after excision of CD lesions.The average follow-up duration was 27.5 months(1-135 months).The median overall survival time was 36.0 months(95% CI=13.9-58.1).Respiratory failure was the dominant cause of death(91.7%).Conclusions PNP should be considered among those patients with specific oral or cutaneous lesions.Earlier diagnosis and treatment of latent UCD are important for reducing complications and deaths. PMID- 28877825 TI - Effectiveness of Peritoneal Dialysis in Treating Adult End Stage Renal Disease Patients with Polycystic Kidney Disease. AB - Objective To observe the clinical characteristics,dialysis modalities,and outcomes of end stage renal disease(ESRD)patients with polycystic kidney disease(PKD)and to evaluate the feasibility of peritoneal dialysis in these population. Methods The clinical data of ESRD patient whose primary diagnosis was PKD in Peking Union Medical College Hospital were retrospectively collected from January 1993 to December 2015.PKD patients were divided into two groups according to dialysis modality,namely peritoneal dialysis group(PKD-PD)group and hemodialysis(PKD-HD)group.In addition,we randomly chose non-PKD patients from 622 peritoneal dialysis patients who were matched with PKD-PD patients in age,gender and dialysis time.The primary end point was death.The survival rate was calculated by Kaplan-Meier analysis and the risk factors for suivival were analyzed by Cox regression model. Results Totally 47 PKD patients were enrolled,including 33 patients in PKD-PD group and 14 patients in PKD-HD group,and 42 non-PKD patients as the control group.The average age of PKD patients was(53+/-11)years,of which 38.3% were women.When compared with PKD-HD group,no significant difference in age,gender,comorbidities,kidney size,and residual glomerular filtration rate were observed in PKD-PD patients at baseline(all P>0.05).The average time on dialysis of PKD-PD patients was(36.2+/ 33.1)months.The weekly urea clearance index(Kt/V)and weekly creatinine clearance were similar to non-PKD-PD group at 3 months,1 year,3 years,and 5 years(all P>0.05).The peritonitis rate was 1 episode/84.5 months.The survival rates at 1 year,3 years,and 5 years of PKD-PD group were 85.7%,78.6%,and 78.6%,which were similar to non-PKD-PD group and PKD-HD group respectively(all P>0.05).Multivariate Cox regression analysis showed that neither PKD nor PD independently predicted the mortality. Conclusion PD can be an option for ESRD patients with PKD. PMID- 28877827 TI - Influences of Gender and Age on the Prevalence and Complications of Nonalcoholic Fatty Liver Disease. AB - Objective To investigate the effects of gender and age on the prevalence and complications of nonalcoholic fatty liver disease(NAFLD). Methods A total of 8429 NAFLD patients were selected from the Health Check-up Center and Outpatient Departments of Qilu Hospital of Shandong University(Qingdao).The questionnaire based survey,physical examinations,biochemical tests,and liver ultrasonography were performed for all cases.Patients were divided into young group(<45 years),middle aged group(45 years<=age<60 years),and old group(>=60 years)according to age,and the clinical features and laboratory findings were analyzed. Results The proportion of male patients gradually decreased with age,while the proportion of female patients increased(P<0.01);The incidences of metabolic diseases showed significant difference among young group,middle aged group,and old group(P<0.01).Except for hyperlipidemia,the proportion of male patients with NAFLD-accompanied metabolic symdrome was significantly higher than that of female patients in all three age groups(all P<0.01). Conclusions The prevalence of NAFLD-accompanied metabolic syndrome disease is associated with age and gender.This finding is useful for the prevention and treatment of NAFLD. PMID- 28877828 TI - Infection Modes and Subtypes of Human Papilloma Virus in Patients. AB - Objective To investigate the prevalence of human papilloma virus(HPV)subtypes in patients and to provide an evidence for the prevention and treatment of HPV infection and the development of HPV vaccine. Methods Multiplex PCR was used to detect HPV DNA in 6917 patients in Peking Union Medical College Hospital from January 1,2013 to June 30,2015.Totally 5586 patients entered the final analysis after the repeat samples were deleted.The total positive rate of HPV subtypes(including high-risk subtypes including HPV 16,18,31,33,35,39,45,51,52,56,58,59,and 68 and low-risk subtypes including HPV-6 and 11)and the infection status of different age were analyzed. Results The total positive rate of HPV was 36.29%(2027/5586).The positive rate of high-risk subtype was 24.92%(1392/5586)and low-risk subtype was 1.66%(93/5586).The positive rate of multiple was 9.70%(542/5586)and multiple high-risk subtype was 7.75%(433/5586).The positive rate of high-risk subtype and multiple were 25.52%(1366/5353)and 11.16%(26/233)in female and 9.99%(535/5353)and 3.00%(7/233)in male,there were significantly difference(chi2=24.61,chi2=12.45,all P<0.001).The positive rate of low-risk subtypes(3.86%,9/233)in males was significantly higher than that in females(1.57%,84/5353)(chi2=5.84,P=0.007).The high-risk HPV subtype infection mainly was seen in patients aged 31-50 years and the low-risk HPV subtype infection mainly in patients aged 21-40 years.The age of multiple HPV infections from 31-40 years.The lowest turn negative rates of subtype were HPV52 and HPV58.The top three HPV subtypes with the highest positive rates were HPV52,HPV16,and HPV58.Conclusions The positive rates of HPV type are different between male and female patients.The males are mainly infected with low risk subtypes,whereas the females with high-risk subtypes and the multiple HPV subtypes.The top three high-risk subtypes are HPV-52,16,and 58.HPV subtypes with the lowest secondary negative rates are HPV-52 and 58.HPV infection is mainly seen in young individuals. PMID- 28877829 TI - Major Metabolite Levels of Preoperative Proton Magnetic Resonance Sectroscopy and Intraoperative Fluorescence Intensity in Glioblastoma. AB - Objective To compare the intraoperative major metabolite level of preoperative proton magnetic resonance spectroscopy(1H-MRS)and fluorescence intensity marked with fluorescein sodium(FLs)in glioblastoma(GBM)and thus provide an objective basis for fluorescence surgical treatment of GBM. Methods All newly diagnosed patients by plain and enhanced magnetic resonance imaging from the April 1,2014 to December 31,2015 were enrolled in this study.All of them received 1H-MRS and marked with FLs.The expression of Ki67 in tumor boundary were confirmed by postoperative pathology and determined by immunostaining assay.The relationship between 1H-MRS metabolite levels and tumor fluorescence intensity was analyzed. Results Totally 33 patients were included in the study.Preoperative 1H-MRS revealed high-grade gliomas in 25 cases.The N-acetylaspartate(NAA)decreased significantly and choline(Cho)increased significantly in high-grade gliomas.The ratios of Cho/NAA,NAA/creatine(Cr),and Cho/Cr significantly differed in different tumor regions(P=0.02,P=0.01,and P=0.00,respectively).Surgical results were marked with FLs intraoperatively.Tissue fluorescence were clearly seen.There were 29 patients undergoing total resection and 4 cases undergoing subtotal resection.No acute encephalocele occured after operation,while 2 patients suffered from epilepsy.Postoperative pathology results included:28 cases were diagnosed as GBM(22 cases consistent with 1H-MRS diagnosis).The results of GBM fluorescence imaging included:the level of fluorescence intensity in tumor parenchyma was significantly higher than that in tumor boundary and peritumoral edema(P=0.01).The result of 1H-MRS metabolite analysis included:The kurtosis of NAA and of Cho and the ratio of Cho/NAA were significantly different according the fluorescence intensity in tumor parenchyma(P=0.01,P=0.02,and P=0.01).While there was no difference in the kurtosis of NAA,the kurtosis of Cho and the ratio of Cho/NAA were significantly different according the fluorescence intensity in tumor boundary(P=0.02, P=0.00).In peritumoral edema,there was no significant different in kurtosis of NAA and of Cho and in the ratio of Cho/NAA(P=0.23,P=0.09,P=0.14).Immunohistochemistry in GBM tumor boundary showed different Ki67 expressions according to different fluorescence imaging(P=0.03). Conclusions The fluorescence intensity in GBM parenchyma is higher than that in other tumor regions,and there are different metabolic levels in different fluorescence intensity.The metabolic information marked by FLs and provided by 1H MRS before operationis are important,and the correlation between them should be further investigated. PMID- 28877830 TI - Construction of A New Random Short Hairpin RNA Library Based on microRNA Context. AB - Objective To build an efficient random short hairpin RNA(shRNA)library. Methods shRNA expression vector was constructed with enhanced green fluorescent protein(EGFP)in the upstream of shRNA,driven by pol II promoter(CMV).After the constructs were transfected into cells,the proteins were collected.The inhibition efficiency of shRNA was determined by Western blot and dual luciferase reporter system.After the shRNA expression vector was constructed with EGFP in the upstream of shRNA,driven by pol II promoter(CMV),shRNA was further embedded into microRNA(miRNA)context.The constructs were transfected into cells,and then the inhibition efficiency of shRNA against target genes was evaluated by quantificational real-time polymerase chain reaction.According to the result of quantificational real-time polymerase chain reaction,a new random shRNA library was constructed based on miRNA context. Results shRNA downstream of a large transcript was transcripted efficiently by pol II promoter(CMV).The efficiency of shRNA interference on target gene was improved when shRNA was embedded into miRNA context.Thus,we constructed a new random shRNA library sized 1.8*107 based on miRNA context.Conclusion We successfully constructed a new large random shRNA library. PMID- 28877831 TI - Comparing Different Weights to Construct Composite Indicators of Maternal and Child's Basic Health Services from the Prospective of Continuum of Care:Based on Data from the National Health Services Survey 2008 and 2013 in Jilin Province. AB - Objective To construct composite indicators of maternal and child's basic health services using different weights from the prospective of continuum of care and to compare them based on data from the National Health Services Survey 2008 and 2013 in Jilin Province. Methods The study selected indicators based on the countdown and the Lives Saved Tool(LiST),considering the data availability from the 2008 and 2013 National Health Surveys in Jilin.Equal weights,equal weights for different areas,epidemiology weights,and principal component weights were used to construct different composite indicators.Cronbach's alpha reliability coefficient was used to test the internal consistency.Analysis of variance of randomized block design was used to test the differences.The Spearman's correlation coefficient was calculated to compare the rank correlation.The maternal mortality,children under 5 years old mortality rate,and children under 5 years old stunting incidence were used as the outcome indicators to test the validity using correlation analysis. Results Finally 13 indicators were selected,with the Cronbach's alpha reliability coefficient value exceeding 0.7,which means acceptable internal consistency of these indicators.Analysis of variance showed that the scores were not significantly the same(F=8.14,P<0.01).The rank correlations among equal weights,principal component weights,and equal weights for different areas composite indicators were quite strong,and the Spearman's correlation coefficient between either two were all above 0.9,while the epidemiology weights composite indicator got smaller Spearman's correlation coefficient with equal weights,principal component weights,and equal weights for different areas composite indicators(0.697,0.671,and 0.818,respectively).The composite indicator using epidemiology weights showed significant negative correlation with children under 5 years old mortality rate and children under 5 years old stunting incidence(R2=0.168,P<0.05;R2=0.398,P<0.01,respectively).The composite indicators using equal weights,equal weights for different areas and principal component weights only showed significant negative correlation with children under 5 years old stunting incidence(R2=0.238,R2=0.304,R2=0.232,P<0.01 for all,respectively).Conclusion The composite indicator using epidemiology objective weights has some predictive value for maternal and child health outcomes. PMID- 28877832 TI - Mechanism of Non-receptor Tyrosine Kinase Src Regulating Neuroinflammation Through Phosphatase and Tensin Homology Protein in Microglia. AB - Objective To investigate the mechanism of non-receptor tyrosine kinase Src regulating neuroinflammation through phosphatase and tensin homology protein(PTEN)in microglia. Methods BV2 cells were incubated with PTEN inhibitor bpv(HOpic)for 2 hours,and then added with lipopolysaccharide(LPS)to induce neuroinflammation,Western blot was performed to determine the expression of phosphorylated protein kinase B(Akt)to investigate the activity of PTEN. Enzyme linked immunosorben assay(ELISA)was used to determine the release of tumor necrosis factor alpha(TNF-alpha)to assess neuroinflammation.After PTEN inhibitor or Src specific small interfering RNA was added,the change of neuroinflammation was evaluated to study the mechanism of Src regulating neuroinflammation. Results LPS induced significant neuroinflammation in BV2 cells,as indicated by significantly increased expression of p-Akt and release of TNF-alpha(P<0.001).The PTEN inhibitor signficantly increased Akt phosphorylation(P<0.05)and TNF-alpha release(P<0.001)in LPS-induced BV2 cells compared to simply LPS-induced cells.The Src small interfering RNA significantly decreased the release of TNF alpha(P<0.001)and inhibited PTEN(P<0.001)and Akt(P<0.001)phosphorylation. Conclusion Src kinase may regulate neuroinflammtion response in BV2 cells by regulating the phosphorylation of PTEN. PMID- 28877833 TI - Effect of Lymph Node Metastasis on Change of Positive Thyroglobulin Antibody in Differentiated Thyroid Carcinoma after Initial Treatment. AB - Objective To investigate the influence of lymph node metastasis on the change of positive thyroglobulin antibody(TgAb)in differentiated thyroid carcinoma after initial treatment.Methods We retrospectively analyzed the clinical data of 98 differentiated thyroid carcinoma patients with positive TgAb(>=115 IU/ml)before radioiodine(RAI)therapy.All of whom underwent total or near total thyroidectomy,neck lymph node dissection,and subsequent RAI therapy.Patients were divided into negative group(n=83)and non-negative group(n=15)according to the disappearance of positive TgAb or not after a mean follow-up of 21.0 months.Analysis of variance,chi2 test,and Mann-Whitney rank-sum test were applied to compare the basic clinical features including number of metastatic lymph nodes,lymph node metastasis rate and node stage,and dose of RAI ablation.The receiver operating characteristic curves were employed to evaluate the predictive values of TgAb levels(negative or positive)and optimal cut-off points.Multivariate analyses were further performed to explore the independent indicators for persistent positive TgAb. Results Compared with the negative group,the proportions of N1a and N1b in the non-negative group were significantly higher,with no N0 in the non-negative group(Fisher's Exact Test,P=0.032).The median metastatic lymph node rate was also significantly higher in the non negative group(Mann-Whitney U=-3.498,P=0.000).The cut-off value for metastatic lymph node rate to predicting disappearance of positive TgAb was 24%,and its sensitivity was 71.4%.The multivariate analysis showed that only lymph node stage(OR=3.183,P=0.038)was the independent indicator for persistent positive TgAb. Conclusions Lymph node stage was an independent indicator for the disappearance of positive TgAb.A metastatic lymph node rate of higher than 24% may be predictive for the disappearance of positive TgAb. PMID- 28877834 TI - Clinicopathological Features of Idiopathic Membranous Nephropathy in 33 Adolescents. AB - Objective To investigate the clinicopathological features and prognosis of idiopathic membranous nephropathy(IMN)in adolescents. Methods This was a retrospective study on IMN patients hospitalized between June 2012 and December 2014,and a total of 33 IMN patients aged between 13 and 24 years old were enrolled in the study.Meanwhile,33 IMN patients aged more than 24 years old were selected randomly as control group during the same period.Diagnosis was confirmed by renal biopsy,and the secondary causes of membranous nephropathy were ruled out.Data collected from medical record and biopsy were analyzed. Results In the adolescent IMN group,the mean age at renal biopsy was(20+/-3)years old,and the male/female ratio was 22/11.Twenty-three cases presented as nephrotic syndrome.Systolic and diastolic pressures were(127+/-13)mmHg and(77+/ 9)mmHg,respectively.The median 24-hour urine protein was 5.14(3.39,9.31)g/d,and the median serum creatinine was 62(52,73)MUmol/L.The positive rate of serum anti phospholipase A2 receptor in adolescent group was 54%.Compared with control group,the adolescent patients had lower incidence of hypertension and higher baseline estimated glomerular filtration rate level [15.2% vs.39.3%,chi2=4.889,P=0.03;125 ml/(min.1.73m2)vs.100 ml/(min.1.73m2),U=137.5,P<0.001].According to IMN staging criteria in electron microscopy,adolescent patients were classified as one case in stage I,21 in stage II,and 11 in stage III or higher.The positive rates of IgG1,IgG2,IgG3 and IgG4 subclass staining in glomeruli were 46.9%,3.1%,56.3%,and 87.5%,respectively.Compared with control group,the adolescent patients had lower incidence of renal interstitial fibrosis and arteriolar lesions(6.1% vs.66.7%,chi2=26.19,P<0.001;15.2% vs.66.7%,chi2=18.11,P<0.001).Three patients lost to follow-up while others started steroid combined with cyclosporine A(n=20),cyclophosphamide(n=7),or mycophenolate(n=1)or solely(n=2).After a median follow-up of 18(12,24)months,the median proteinuria decreased to 0.20(0.10,0.42)g/d,whereas serum creatinine level remained stable [69(56.8,81.3)MUmol/L].Seventeen patients(56.7%)achieved complete remission(CR),and the remaining 13 patients(43.4%)achieved partial remission(PR).The median time of CR and PR were three and six months,respectively.Only one patient relapsed during the follow-up.Also,21 cases received maintenance therapy including cyclosporine A(n=18),azathioprine(n=2)and mycophenolate(n=1).Conclusions The immunofluorescence IgG subclass in glomeruli and distribution of serum anti-phospholipase A2 receptor in adolescent IMN patients are similar to those in older IMN patients.IMN patients in adolescents responded well to immunosuppressive therapy.Cyclosporine A in low dose as maintenance therapy is effective after achieving remission,and will not increase risk of nephrotoxicity. PMID- 28877835 TI - Pathological Changes in APP/PS-1 Transgenic Mouse Models of Alzheimer's Disease Treated with Ganoderma Lucidum Preparation. AB - Objective To explore the efficacy of ganoderma lucidum preparation(Ling Zhi) in treating APP/PS-1 transgenic mouse models of Alzheimer's disease(AD).Methods APP/PS-1 transgenic mice of 4 months were randomly divided into model group,ganoderma lucidum treatment groups,including high [2250 mg/(kg.d)] and middle [750 mg/(kg.d)] dose groups,i.e.LZ-H and LZ-M groups,and the positive control group(treated with donepezil hydrochloride [2 mg/(kg.d)]).In addition,C57BL/6J wild mice were selected as normal group.The animals were administered for 4 months.Histopathological examinations including hematoxylin eosin(HE) staining,immunohistochemistry,special staining,and electron microscopy were applied,and then the pathological morphology and structures in different groups were compared. Results The senile plaques and neurofibrillar tangles in the cerebrum and cerebellum were dissolved or disappeared in LZ-H and LZ-M groups.Decrease of amyloid angiopathy was found in LZ-H and LZ-M groups.The immature neurons appeared more in hippocampus and dentate nucleus of LZ-H and LZ M groups than those in AD model and donepezil hydrochloride groups(hippcampus:F=1.738,P=0.016;dentate nucleus:F=1.924,P=0.026),and these immature neurons differentiated to be neurons.More Purkinje cells loss occurred in AD model mice than that in LZ-H and LZ-M groups(F=9.46,P=0.007;F=9.46,P=0.010).The LZ-H and LZ-M groups had more new neuron stem cells grown up in cerebellum.Electromicroscopic examination showed the hippocampal neurons in LZ-H and LZ-M group were integrated,the nuclear membrane was intact,and the mitochondria in the cytoplasm,endoplasmic reticulum,Golgi bodies,microtubules,and synapses were also complete.The microglial cell showed no abnormality.No toxicity appeared in the pathological specimens of mice treated with ganoderma lucidum preparation.Conclusion The ganoderma lucidum preparation can dissolve and decline or dismiss the senile plaques and neurofibrillar tangles in the brain of AD mice and also reduce the amyloid angiopathy. PMID- 28877836 TI - Efficacy of Gemcitabine and S-1 for Patients with Advanced Pancreatic Cancer. AB - Objective To explore the efficacy and toxicities of gemcitabine combined with S-1 in treating locally advanced and metastatic pancreatic ductal adenocarcinoma and prognostic factors. Methods We retrospectively analyzed the clinical data of patients with locally advanced and metastatic pancreatic cancer receiving gemcitabine and S-1 as first-line therapy in the Department of Medical Oncology,Peking Union Medical College Hospital from January 2014 to January 2017.Gemcitabine was administered at a dose of 1000 mg/m2 over 30 min-utes on days 1 and 8,and oral S-1 at a dose of 40-60 mg twice daily from days 1 to 14,repeated every 3 weeks.All patients received at least two cycles of chemotherapy. Results A total of 60 patients were included,13(22%) achieved partial remission,37(61%) had stable disease,and 10(17%) experienced progressive disease.The median progression-free survival was 7 months(95% CI=6-10 months) and the median overall survival was 12 months(95% CI=9-20 months).Both univariate and multivariate analyses of prognostic factors showed primary resection was significant in predicting shorter progression-free survival and lung metastasis was significant for shorter overall survival.The most common grade 3-4 toxicities were neutropenia(27%) and leukopenia(18%). Conclusion Gemcitabine combined with S 1 is an effective regimen with manageable toxicities in the treatment of advanced pancreatic cancer and can be used as first-line therapy. PMID- 28877838 TI - Advances in Mechanisms for Prevention and Treatment of Pathological Scars with Mesenchymal Stem Cells. AB - Pathological scars,including keloids and hypertrophic scars,result from aberrations in the process of physiologic wound healing.An exaggerated inflammatory process is one of the main pathophysiological contributors.Pathological scars may cause pain and pruritis,limit joint mobility,and cause a range of cosmetic deformities that affect the patient's quality of life.However,the effectiveness of currently available prevention and treatment measures remains unsatisfactory.Mesenchymal stem cells,among their multifunctional roles,have the functions of immunomodulation and promotion of angiogenesis.Thus,they have been proposed to be a major candidate for cell therapy to treat or prevent pathologicalscars.This article reviews the mechanism and potentials of stem cell therapy in the prevention and treatment of pathological scars. PMID- 28877837 TI - Clinical Diagnosis and Treatment of Male Breast Cancer:Analysis of 24 Cases. AB - Objective To summarize our experiences in the clinical diagnosis and treatment of male breast cancer(MBC).Methods The clinical date of 24 MBC patients treated in our hospital from January 2006 to December 2012 were retrospective analyzed.Results The average age of these 24 patients was(55.7+/-2.1) years.All the patients received surgical treatment,and the surgical procedures were simple excision of breast lesion in 6 patients,breast resection alone in 5 patients,and modified radical mastectomy in 13 patients(bilateral in 1 case).The pathological diagnoses included invasive ductal carcinoma in 18 cases,papillary carcinoma in 4 cases,mucinous adenocarcinoma in 1 case,and malignant solitary fibrous tumor in 1 case.Twenty patients received chemotherapy,7 received radiotherapy,and 15 received endocrine therapy after operation.The 5-year survival rate was 54.2%.Conclusions The incidence of MBC is low.This malignancy is mainly seen in elderly individuals,with relatively long disease course,poor prognosis,and high risk of metastasis.MBC is mainly treated by surgery,and adjuvant chemotherapy,radiotherapy,and endocrine therapy may be applied,if appropriate,after the operation. PMID- 28877839 TI - Significances of MYD88L265P and CXCR4WHIM Mutations in Waldenstrom Macroglobulinemia. AB - Waldenstrom macroglobulinemia(WM) is a lymphoplasmacytic lymphoma characterized by serum monoclonal IgM immunoglobulin.Recently,the high mutation rates of MYD88L265P and CXCR4WHIM have been documented in WM.Furthermore,MYD88L265P and CXCR4WHIM are related to the response to target drugs.This article reviews the significances of MYD88L265P and CXCR4WHIM in the diagnosis and treatment of WM. PMID- 28877840 TI - Application of Intravoxel Incoherent Motion Model-based Diffusion Weighted Imaging in the Diagnosis and Therapy of Breast Cancer. AB - Intravoxel incoherent motion model-based diffusion weighted imaging can distinguish the microcirculation reperfusion and true diffusion of water molecules,which can quantitatively or semi-quantitatively reflect the functional state and microstructure features of tissues.Thus,this technique has increasingly been used in breast tumor,especially in the differential diagnosis,pathological classification,and curative effect monitoring of breast cancer. PMID- 28877841 TI - Cognitive-behaviour therapy for health anxiety in medical patients (CHAMP): a randomised controlled trial with outcomes to 5 years. AB - BACKGROUND: Health anxiety is an under-recognised but frequent cause of distress that is potentially treatable, but there are few studies in secondary care. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of a modified form of cognitive-behaviour therapy (CBT) for health anxiety (CBT-HA) compared with standard care in medical outpatients. DESIGN: Randomised controlled trial. SETTING: Five general hospitals in London, Middlesex and Nottinghamshire. PARTICIPANTS: A total of 444 patients aged 16-75 years seen in cardiology, endocrinology, gastroenterology, neurology and respiratory medicine clinics who scored >= 20 points on the Health Anxiety Inventory (HAI) and satisfied diagnostic requirements for hypochondriasis. Those with current psychiatric disorders were excluded, but those with concurrent medical illnesses were not. INTERVENTIONS: Cognitive-behaviour therapy for health anxiety - between 4 and 10 1-hour sessions of CBT-HA from a health professional or psychologist trained in the treatment. Standard care was normal practice in primary and secondary care. MAIN OUTCOME MEASURES: Primary - researchers masked to allocation assessed patients at baseline, 3, 6, 12, 24 months and 5 years. The primary outcome was change in the HAI score between baseline and 12 months. Main secondary outcomes - costs of care in the two groups after 24 and 60 months, change in health anxiety (HAI), generalised anxiety and depression [Hospital Anxiety and Depression Scale (HADS)] scores, social functioning using the Social Functioning Questionnaire and quality of life using the EuroQol-5 Dimensions (EQ-5D), at 6, 12, 24 and 60 months, and deaths over 5 years. RESULTS: Of the 28,991 patients screened over 21 months, 5769 had HAI scores of >= 20 points. Improvement in HAI scores at 3 months was significantly greater in the CBT-HA group (mean number of sessions = 6) than in the standard care, and this was maintained over the 5-year period (overall p < 0.0001), with no loss of efficacy between 2 and 5 years. Differences in the generalised anxiety (p = 0.0018) and depression scores (p = 0.0065) on the HADS were similar in both groups over the 5-year period. Gastroenterology and cardiology patients showed the greatest CBT gains. The outcomes for nurses were superior to those of other therapists. Deaths (n = 24) were similar in both groups; those in standard care died earlier than those in CBT-HA. Patients with mild personality disturbance and higher dependence levels had the best outcome with CBT-HA. Total costs were similar in both groups over the 5-year period (L12,590.58 for CBT-HA; L13,334.94 for standard care). CBT-HA was not cost effective in terms of quality-adjusted life-years, as measured using the EQ-5D, but was cost-effective in terms of HAI outcomes, and offset the cost of treatment. LIMITATIONS: Many eligible patients were not randomised and the population treated may not be representative. CONCLUSIONS: CBT-HA is a highly effective treatment for pathological health anxiety with lasting benefit over 5 years. It also improves generalised anxiety and depressive symptoms more than standard care. The presence of personality abnormality is not a bar to successful outcome. CBT-HA may also be cost-effective, but the high costs of concurrent medical illnesses obscure potential savings. This treatment deserves further research in medical settings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14565822. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 50. See the NIHR Journals Library website for further project information. PMID- 28877842 TI - Improving health literacy about dementia among older Chinese and Vietnamese Australians. AB - The number of older people in the population is increasing faster than for any other age group. This population growth, while positive, is associated with increasing incidence of chronic and progressive diseases such as dementia. This requires older people to navigate services that may not be designed to meet their needs. This issue can be further amplified in culturally and linguistically diverse populations who often have limited English language proficiency and limited knowledge of diseases such as dementia. Health literacy, a person's ability to access, understand, appraise and apply information about their health and health care, including navigating health services, is low among older people and even lower among older people born overseas. This paper describes findings from a recent research study which developed and used the Cultural Exchange Model. The model is based on a process of collaboration, whereby researchers, service providers and community members work together to build evidence about a particular topic, in this case dementia. The study demonstrated that the Cultural Exchange Model facilitates opportunities for researchers, health professionals, community workers and carers to improve their knowledge of conditions such as dementia and rapidly translate evidence into practice. It also showed that it is possible to recruit, engage and generate new knowledge within populations that are traditionally excluded from research but have high prevalence of dementia. This study shows health literacy is an evolving process. Access to ongoing education for professionals, not only of the clinical condition and the service system, but also the cultural elements of the communities they are working with, requires consideration. PMID- 28877843 TI - Ongoing mumps outbreak in Israel, January to August 2017. AB - In Israel, 262 mumps cases were registered between 1 January and 28 August 2017 despite a vaccine coverage of >= 96%. The majority (56.5%) of cases were adolescents and young adults between 10 and 24 years of age. Nearly twice as many cases were reported in males than in females. Sequence information identified genotype G and suggested specific transmission chains in different religious communities, with the Muslim population in Jerusalem being most severely affected. PMID- 28877844 TI - The spatiotemporal characteristics of influenza A and B in the WHO European Region: can one define influenza transmission zones in Europe? AB - We aimed to assess the epidemiology and spatiotemporal patterns of influenza in the World Health Organization (WHO) European Region and evaluate the validity of partitioning the Region into five influenza transmission zones (ITZs) as proposed by the WHO. We used the FluNet database and included over 650,000 influenza cases from 2000 to 2015. We analysed the data by country and season (from July to the following June). We calculated the median proportion of cases caused by each virus type in a season, compared the timing of the primary peak between countries and used a range of cluster analysis methods to assess the degree of overlap between the WHO-defined and data-driven ITZs. Influenza A and B caused, respectively, a median of 83% and 17% cases in a season. There was a significant west-to-east and non-significant (p = 0.10) south-to-north gradient in the timing of influenza activity. Typically, influenza peaked in February and March; influenza A earlier than influenza B. Most countries in the WHO European Region would fit into two ITZs: 'Western Europe' and 'Eastern Europe'; countries bordering Asia may be better placed into extra-European ITZs. Our findings have implications for the presentation of surveillance data and prevention and control measures in this large WHO Region. PMID- 28877845 TI - Letter to the Editor: Surveillance of mcr-1 and mcr-2 genes in Carbapenem resistant Klebsiella pneumoniae strains from an Italian Hospital. PMID- 28877846 TI - Environmental surveillance during an outbreak of tularaemia in hares, the Netherlands, 2015. AB - Tularaemia, a disease caused by the bacterium Francisella tularensis, is a re emerging zoonosis in the Netherlands. After sporadic human and hare cases occurred in the period 2011 to 2014, a cluster of F. tularensis-infected hares was recognised in a region in the north of the Netherlands from February to May 2015. No human cases were identified, including after active case finding. Presence of F. tularensis was investigated in potential reservoirs and transmission routes, including common voles, arthropod vectors and surface waters. F. tularensis was not detected in common voles, mosquito larvae or adults, tabanids or ticks. However, the bacterium was detected in water and sediment samples collected in a limited geographical area where infected hares had also been found. These results demonstrate that water monitoring could provide valuable information regarding F. tularensis spread and persistence, and should be used in addition to disease surveillance in wildlife. PMID- 28877847 TI - Are infections of gastrostomies not leaks? PMID- 28877848 TI - Temporal artery biopsy in the diagnosis of giant cell arteritis: Bigger is not always better. AB - OBJECTIVE: Accurate early giant cell arteritis (GCA) diagnosis can be established through temporal artery biopsy (TAB). We herein investigate the relationship between specimen length and positive TAB result in a tertiary-care hospital in Germany during a 8-year period. Secondarily, we studied the relationships of specific epidemiological and laboratory parameters with positive TABs. METHOD: We retrospectively reviewed the medical records of all patients with suspected GCA, who underwent TAB in our institution. RESULTS: The total sample consisted of 116 patients with a mean age of 76.1 (SD 7.7) years. Mean specimen length post fixation was 0.94 cm (SD 0.49). The TAB(+) group consisted of 64 patients (55.2%). The specimen length was comparable in the two groups (0.96 cm vs 0.91 cm, p = 0.581). Twenty six TAB(+) patients (41%) had a post-fixation specimen longer than 1 cm, comparable with the respective percentage in the TAB(-) group (42%, p = 1). All laboratory tests performed were statistically significantly different in the two groups. CONCLUSION: We conclude that TAB length is not associated with the TAB diagnostic yield in patients with clinical suspicion of GCA. PMID- 28877849 TI - Not All Is CFTR - Neutrophils and Cholesterol in Cystic Fibrosis. PMID- 28877850 TI - Gabapentin regulates expression of FGF2 and FGFR1 in dorsal root ganglia via microRNA-15a in the arthritis rat model. AB - BACKGROUND: Arthritis is an inflammatory disease with a prevalence rate of approximately 10% in China, which commonly manifests as pain. The aim of the current study was to investigate the function of gabapentin in the dorsal root ganglion in an arthritis rat model, and assess the effect of gabapentin on the expression of fibroblast growth factor 2 (FGF2) and FGF receptor 1 (FGFR1). METHODS: A total of 30 healthy male Sprague-Dawley rats were randomly divided into the following three groups: Untreated group, control group and gabapentin group. Rats in the control and the gabapentin groups were injected with Freund's complete adjuvant to induce arthritis. A total of 7 days subsequent to model establishment, the gabapentin group was administered intraperitoneally gabapentin for 8 days. The alterations in thickness of paw pad and paw withdrawal mechanical threshold (PWMT) were detected, which indicated that the rats in the control and gabapentin groups presented with the symptoms of arthritis. RESULTS: In the control group, the PWMT value was significantly reduced (P < 0.05), whereas the PWMT value was significantly increased in the gabapentin group. Immunohistochemistry demonstrated that the expression levels of FGF2 and FGFR1 were increased in the control group compared with the untreated group, while the expression levels of FGF2 and FGFR1 were reduced in the gabapentin group. Moreover, the FGF2 antagonist PD173074 partially improved the plantar thickness and PWMT of the arthritic rats. Bioinformatics analysis predicted microRNA-15a binding sites in the 3'untranslated regions (UTR) of FGF2 and FGFR1. Furthermore, the expression of microRNA-15a was reduced in the control group compared with untreated rats, whereas microRNA-15a in the gabapentin group was upregulated compared with the control. Additionally, the luciferase reporter assay confirmed that microRNA-15a could inhibit the protein expression through pairing with the 3'UTR of FGF2 and FGFR1 mRNAs. CONCLUSION: Gabapentin may relieve arthritis pain and reduce the expression of FGF2 and FGFR1 in dorsal root ganglia. Furthermore, microRNA-15a may be involved in the regulatory process. PMID- 28877852 TI - Detangling and detailing sexual health in the SDG era. PMID- 28877851 TI - Platform construction of molecular breeding for utilization of brown macroalgae. AB - Brown macroalgae are characterized by a large size and high productivity without requiring arable land, fresh water, and fertilizer. Furthermore, since brown macroalgae contain little or no lignin, simple biorefinery processing can efficiently produce sugars from this material. Therefore, brown macroalgae have attracted attention as an alternative feedstock for bioethanol production. However, the utilization of biotechnologies previously developed for terrestrial biomass processing results in difficulties in the bioconversion of brown macroalgae. Recently, several studies have developed biotechnologies for using major carbohydrates of brown macroalgae, such as laminarin, mannitol, and alginate. This review focuses on these fermentation biotechnologies using natural or engineered microorganisms. PMID- 28877853 TI - Vitamins supplementation affects the onset of preeclampsia. AB - Preeclampsia may affect between 2-8% of all pregnancies. It seriously affects maternal health after pregnancy. This meta-analysis was performed to define the efficacy of vitamins supplementation on the risk of preeclampsia. Potential articles were systematically searched on the databases of Pubmed, Embase and Web of Science up to May 2016. Relative risk (RR) and 95% confidence intervals (95%CIs) were used to analyze the relationship of vitamins supplementation with risk of preeclampsia. Cochran Q test was used to test inter-study heterogeneity. Begg's funnel plot was adopted to assess the potential publication bias. 28 eligible studies were selected. Pooled results indicated that vitamins supplementation could reduce the risk of preeclampsia (RR = 0.74, 95%CI = 0.64 0.86). The studies with non-randomized controlled trial (RCT) analysis also suggested the significant relationship of vitamins supplementation with risk of preeclampsia (RR = 0.60, 95%CI = 0.42-0.85). However, negative results were observed in studies with RCT analysis. Subgroup analysis by vitamin type was performed among the studies with RCT analysis. The results indicated that vitamin D supplementation could significantly reduce the risk of preeclampsia (RR = 0.41, 95%CI = 0.22-0.78). Similar results were observed in the studies with multivitamins supplementation (RR = 0.69, 95%CI = 0.51-0.93). Vitamins supplementation could reduce the onset of preeclampsia. PMID- 28877854 TI - Letter to the editor regarding the paper by Loquai C et al. 'Use of complementary and alternative medicine: a multicenter cross-sectional study in 1089 melanoma patients'. PMID- 28877855 TI - Introduction to "Pathology of Infections of the Lung". PMID- 28877856 TI - Geriatric cancer trends in the Middle-East: Findings from Lebanese cancer projections until 2025. AB - OBJECTIVE: By 2020, 70% of all cancers will occur in patients aged 65years and older, causing an increase in related morbidity, mortality, and cost. This study projects cancer trends in the elderly population in Lebanon, a country experiencing accelerating aging trends. Findings will guide future policy decisions regarding geriatric oncology in Lebanon and the surrounding Arab world. MATERIALS AND METHODS: Cancer incidence rates were derived for men and women 65years and above, divided into three age groups: 65-69years, 70-74years, and 75years and above. Raw data were obtained from the National Cancer Registry reports 2003-2010. The eight consecutive year data were used to project the incidence until 2025 using a logarithmic model. The Average Annual Percent Change in incidence rates was calculated to determine whether it would significantly increase, decrease, or remain stable over time. RESULTS: Incidence rates are projected to increase significantly in all age groups of both genders until 2025. In men, the fastest rise is expected in prostate cancer, followed by bladder, lung, colorectal, and NHL. In women, the rise will be fastest in breast, followed by colorectal, lung, NHL, and ovary. Projected rates increase faster in the "younger" age group 65-69 compared to the "oldest" >=75, both in men and women. Only kidney and liver cancers continue to rise significantly after 75. CONCLUSIONS: Cancer incidence is projected to increase in individuals between 65 and 74years of age. Lebanese and Middle Eastern physicians must implement adapted therapeutic strategies in the management of the increasing caseload among frail, elderly patients. PMID- 28877857 TI - Reduced mind wandering in patients with Parkinson's disease. AB - BACKGROUND: Mind Wandering (MW) refers to the process of disengaging from the immediate external environment and participating in internally driven mentation. This process has been suggested to be supported by a distributed set of brain regions, collectively referred to as the Default Mode Network (DMN). Recently, reduced recruitment and connectivity of the DMN has been described in Parkinson's disease (PD) patients compared to healthy controls. We thus aimed to explore whether PD patients with normal cognitive test scores show differential MW capabilities compared to healthy controls. METHODS: Thirty PD patients and thirty age-matched controls, all with a Montreal cognitive assessment (MoCA) score of 26 or above, performed a novel yet validated thought-sampling paradigm used to assess the frequency and extent of MW irrespective of cognitive load in which participants were asked to observe a series of geometric shapes and describe their thoughts after watching them. Shapes were presented one at a time for varying durations across nine trials. RESULTS: PD patients showed significantly less MW compared to the control. ANCOVA revealed a significant interaction indicating that the difference in MW scores was driven by trials with short stimulus presentation times. CONCLUSIONS: These findings provide evidence for decreased MW in PD patients. We propose that this is due to difficulties in performing MW within short time frames. PMID- 28877858 TI - Effects of surgical treatment of hypertrophic turbinates on the nasal obstruction and the quality of life. AB - PURPOSE: Chronic hyperplasia of the inferior nasal concha is accompanied by a nasal obstruction; however, there is no standardised surgical treatment for this condition. Here, we compared the outcome of three surgical techniques frequently used to treat the hyperplasia of inferior turbinates: turbinectomy with lateralization, submucosal electrocautery and laser cautery additional to septoplasty. MATERIALS AND METHODS: One hundred and nine patients participated in this prospective randomized study upon signing written consent. The subjects were randomly assigned to one of three intervention groups: 1) submucosal turbinectomy with lateralization, 2) submucosal electrocautery or 3) laser cautery. All groups were followed-up for up to 6months after surgical intervention. During the four follow-up appointments, the outcomes were measured with the modified German version of Sino-Nasal Outcome Test 20 questionnaire. In addition, the nasal breathing and the absolute nasal flow rates and respective mucosal component were determined by the anterior rhinomanometry. RESULTS: Following surgery, the subjective and objective nasal obstruction decreased significantly in all three groups. Moreover, the subjective symptoms measured by modified Sino-Nasal Outcome Test 20 improved significantly, although there were some temporal differences between groups regarding subjective nasal obstruction, ear pressure, nasal discomfort, daytime fatigue, cough and dry mouth. The mucosal component of nasal congestion decreased significantly after surgery. CONCLUSIONS: All surgical techniques used to reduce the conchae mucosa led to a significant improvement in the objective and subjective nasal breathing and the quality of life. Septoplastic reduction proved to be of additional benefit. PMID- 28877859 TI - Adjuvant radiation and survival following surgical resection of sinonasal melanoma. AB - BACKGROUND: Surgery remains the mainstay of treatment for sinonasal melanoma, but it is often difficult to obtain clear, negative margins. Therefore, patients often receive adjuvant radiation therapy (RT), however its impact on overall survival (OS) is not well understood. METHODS: Patients with surgically resected sinonasal melanoma were identified from the National Cancer Data Base (NCDB, n=696). Kaplan-Meier curves and parametric survival regression were used to analyze the impact of adjuvant RT on OS from surgery. Adjusted time ratios (aTRs) were computed, with values >1 corresponding to improved survival. RESULTS: 399 (57.3%) patients received adjuvant RT. Those receiving RT tended to be younger but with more advanced disease and greater likelihood of positive margins, compared to those receiving no adjuvant therapy. Median survival was 25.0months for those treated with surgery alone, compared to 28.3months for those receiving adjuvant RT (log-rank P=0.408). When adjusting for potential confounders, there was a trend towards greater survival with adjuvant RT (aTR 1.16, 95%CI 0.98 1.37). RT appeared beneficial in those with stage IVB disease (aTR 2.58, 95%CI 1.40-4.75) but not stage IVA (aTR 1.19, 95%CI 0.88-1.61) or III (aTR 0.85, 95%CI 0.65-1.13) disease. In contrast, there were no differences in impact of RT according to margin status (aTR 1.16 for both positive and negative margins). CONCLUSIONS: Adjuvant therapy does not appear to provide a significant survival benefit in resected sinonasal melanomas regardless of margin status, except those with stage IVB disease. Practitioners should carefully consider the added benefit of adjuvant therapy in these patients. PMID- 28877860 TI - Accelerometer-assessed light-intensity physical activity and mortality among those with mobility limitations. AB - BACKGROUND: Emerging research demonstrates that light-intensity physical activity is favorably associated with numerous health outcomes among the general population, even independent of high-intensity physical activity. OBJECTIVE: To examine the association between accelerometer-assessed light-intensity physical activity and mortality in a national sample of American adults with mobility limitations. METHODS: Data from the 2003-2006 National Health and Nutrition Examination Survey were utilized. Participants were followed through 2011. Based on self-report, analyzed participants included those with mobility limitations (N = 1369). Light-intensity physical activity was assessed via waist-mounted accelerometry. RESULTS: For the sample, 108,010 person-months occurred with an all-cause mortality rate of 2.07 per 1000 person-months. After adjustments, for every 60 min/day increase in light-intensity physical activity, participants with mobility limitations had a 14% reduced risk of all-cause mortality (HR = 0.86; 95% CI: 0.75-0.98; P = 0.03). CONCLUSION: These findings underscore the importance of promoting light-intensity physical activity to those with mobility limitations. PMID- 28877861 TI - Assessing the Equivalence of Paper, Mobile Phone, and Tablet Survey Responses at a Community Mental Health Center Using Equivalent Halves of a 'Gold-Standard' Depression Item Bank. AB - BACKGROUND: The computerized administration of self-report psychiatric diagnostic and outcomes assessments has risen in popularity. If results are similar enough across different administration modalities, then new administration technologies can be used interchangeably and the choice of technology can be based on other factors, such as convenience in the study design. An assessment based on item response theory (IRT), such as the Patient-Reported Outcomes Measurement Information System (PROMIS) depression item bank, offers new possibilities for assessing the effect of technology choice upon results. OBJECTIVE: To create equivalent halves of the PROMIS depression item bank and to use these halves to compare survey responses and user satisfaction among administration modalities paper, mobile phone, or tablet-with a community mental health care population. METHODS: The 28 PROMIS depression items were divided into 2 halves based on content and simulations with an established PROMIS response data set. A total of 129 participants were recruited from an outpatient public sector mental health clinic based in Memphis. All participants took both nonoverlapping halves of the PROMIS IRT-based depression items (Part A and Part B): once using paper and pencil, and once using either a mobile phone or tablet. An 8-cell randomization was done on technology used, order of technologies used, and order of PROMIS Parts A and B. Both Parts A and B were administered as fixed-length assessments and both were scored using published PROMIS IRT parameters and algorithms. RESULTS: All 129 participants received either Part A or B via paper assessment. Participants were also administered the opposite assessment, 63 using a mobile phone and 66 using a tablet. There was no significant difference in item response scores for Part A versus B. All 3 of the technologies yielded essentially identical assessment results and equivalent satisfaction levels. CONCLUSIONS: Our findings show that the PROMIS depression assessment can be divided into 2 equivalent halves, with the potential to simplify future experimental methodologies. Among community mental health care recipients, the PROMIS items function similarly whether administered via paper, tablet, or mobile phone. User satisfaction across modalities was also similar. Because paper, tablet, and mobile phone administrations yielded similar results, the choice of technology should be based on factors such as convenience and can even be changed during a study without adversely affecting the comparability of results. PMID- 28877862 TI - Effectiveness of a Web-Based Tailored Intervention With Virtual Assistants Promoting the Acceptability of HPV Vaccination Among Mothers of Invited Girls: Randomized Controlled Trial. AB - BACKGROUND: In 2010, the human papillomavirus (HPV) vaccination was introduced in the Dutch National Immunization Program for 12-year-old girls, aiming to reduce the incidence of cervical cancer in women. HPV vaccination uptake turned out to be lower than expected: 61% versus 70%, respectively. Mothers were shown to play the most important role in the immunization decision about this vaccination. They had also expressed their need for interactive personal information about the HPV vaccination over and above the existing universal general information. To improve the effectiveness of the existing education about the HPV vaccination, we systematically developed a Web-based tailored intervention with virtual assistants providing mothers of girls to be invited with tailored feedback on their decision making about the HPV vaccination. OBJECTIVE: The aim of this study was to evaluate the effectiveness of the Web-based tailored intervention for promoting HPV vaccination acceptance by means of a randomized controlled trial (RCT). METHODS: Mothers were recruited via the Dutch vaccination register (Praeventis) (n=36,000) and three Web-based panels (n=2483). Those who gave informed consent (N=8062) were randomly assigned to the control (n=4067) or intervention condition (n=3995). HPV vaccination uptake, as registered by Praeventis once the HPV vaccination round was completed, was used as the primary outcome. Secondary outcomes were differential scores across conditions between baseline (before the provided access to the new tailored intervention) and follow up (just before the first vaccination) regarding the mothers' degree of informed decision making (IDM), decisional conflict, and critical determinants of HPV vaccination uptake among which are intention, attitude, risk perception, and outcome beliefs. RESULTS: Intention-to-treat analysis (N=8062) showed a significant positive effect of the intervention on IDM, decisional conflict, and nearly all determinants of HPV vaccination uptake (P<.001). No effect was found on uptake (P=.60). This may be attributed to the overall high uptake rates in both conditions. Mothers evaluated the intervention as highly positive, including the website as well as the virtual assistants that were used to deliver the tailored feedback. CONCLUSIONS: This computer-tailored intervention has the potential to improve HPV vaccination acceptability and IDM and to decrease decisional conflict among mothers of invited girls. Implications for future research are discussed. TRIAL REGISTRATION: Trialregister.nl NTR4935; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4935 (Archived by WebCite at http://www.webcitation.org/6srT7l9EM). PMID- 28877863 TI - The Paget Trial: A Multicenter, Observational Cohort Intervention Study for the Clinical Efficacy, Safety, and Immunological Response of Topical 5% Imiquimod Cream for Vulvar Paget Disease. AB - BACKGROUND: Vulvar Paget disease is a rare skin disorder, which is most common in postmenopausal Caucasian women. They usually present with an erythematous plaque that may show fine or typical "cake icing" scaling or ulceration that may cause itching, pain, irritation, or a burning sensation. Although most cases are noninvasive, vulvar Paget disease may be invasive or associated with an underlying vulvar or distant adenocarcinoma. The histological evidence of so called "Paget cells" with abundant pale cytoplasm in the epithelium confirms the diagnosis. The origin of these Paget cells is still unclear. Treatment of choice is wide local excision with negative margins. Obtaining clear surgical margins is challenging and may lead to extensive and mutilating surgery. Even then, recurrence rates are high, ranging from 15% to 70%, which emphasizes the need for new treatment options. A number of case reports, retrospective case series, and one observational study have shown promising results using the topical immune response modifier imiquimod. OBJECTIVE: This study aims to investigate the efficacy, safety, and immunological response in patients with noninvasive vulvar Paget disease using a standardized treatment schedule with 5% imiquimod cream. METHODS: Topical 5% imiquimod cream might be an effective and safe treatment alternative for vulvar Paget disease. The Paget Trial is a multicenter observational cohort study including eight tertiary referral hospitals in the Netherlands. It is ethically approved by the Medical-Ethical Committee of Arnhem Nijmegen and registered in the Central Committee on Research Involving Human Subjects (CCMO) Register by as NL51648.091.14. Twenty patients with (recurrent) noninvasive vulvar Paget disease will be treated with topical 5% imiquimod cream three times a week for 16 weeks. The primary efficacy outcome is the reduction in lesion size at 12 weeks after end of treatment. Secondary outcomes are safety, immunological response, and quality of life. Safety will be assessed by evaluation of adverse events and tolerability of treatment. To evaluate the immunological response, various immunological markers will be tested on biopsy specimens taken before, during, and after treatment. Quality of life will be assessed with three questionnaires taken before, during, and after treatment. RESULTS: First results are expected in the summer of 2018. TRIAL REGISTRATION: ClinicalTrials.gov NCT02385188; https://clinicaltrials.gov/ct2/show/NCT02385188 (Archived by WebCite at http://www.webcitation.org/6sXygHuhP). PMID- 28877864 TI - Internet Searches and Their Relationship to Cognitive Function in Older Adults: Cross-Sectional Analysis. AB - BACKGROUND: Alzheimer disease (AD) is a very challenging experience for all those affected. Unfortunately, detection of Alzheimer disease in its early stages when clinical treatments may be most effective is challenging, as the clinical evaluations are time-consuming and costly. Recent studies have demonstrated a close relationship between cognitive function and everyday behavior, an avenue of research that holds great promise for the early detection of cognitive decline. One area of behavior that changes with cognitive decline is language use. Multiple groups have demonstrated a close relationship between cognitive function and vocabulary size, verbal fluency, and semantic ability, using conventional in person cognitive testing. An alternative to this approach which is inherently ecologically valid may be to take advantage of automated computer monitoring software to continually capture and analyze language use while on the computer. OBJECTIVE: The aim of this study was to understand the relationship between Internet searches as a measure of language and cognitive function in older adults. We hypothesize that individuals with poorer cognitive function will search using fewer unique terms, employ shorter words, and use less obscure words in their searches. METHODS: Computer monitoring software (WorkTime, Nestersoft Inc) was used to continuously track the terms people entered while conducting searches in Google, Yahoo, Bing, and Ask.com. For all searches, punctuation, accents, and non-ASCII characters were removed, and the resulting search terms were spell-checked before any analysis. Cognitive function was evaluated as a z normalized summary score capturing five unique cognitive domains. Linear regression was used to determine the relationship between cognitive function and Internet searches by controlling for variables such as age, sex, and education. RESULTS: Over a 6-month monitoring period, 42 participants (mean age 81 years [SD 10.5], 83% [35/42] female) conducted 2915 searches using these top search engines. Participants averaged 3.08 words per search (SD 1.6) and 5.77 letters per word (SD 2.2). Individuals with higher cognitive function used more unique terms per search (beta=.39, P=.002) and employed less common terms in their searches (beta=1.39, P=.02). Cognitive function was not significantly associated with the length of the words used in the searches. CONCLUSIONS: These results suggest that early decline in cognitive function may be detected from the terms people search for when they use the Internet. By continuously tracking basic aspects of Internet search terms, it may be possible to detect cognitive decline earlier than currently possible, thereby enabling proactive treatment and intervention. PMID- 28877865 TI - Developing a Web-Based Geolocated Directory of HIV Pre-Exposure Prophylaxis Providing Clinics: The PrEP Locator Protocol and Operating Procedures. AB - BACKGROUND: Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV transmission, yet patients interested in learning more about PrEP or in getting a PrEP prescription may not be able to find local medical providers willing to prescribe PrEP. OBJECTIVE: We sought to create a national database of PrEP-providing clinics to allow for patients to have access to a unified, vetted source of PrEP providers in an easily accessible database. METHODS: To develop the protocol and operating procedures for the PrEP Locator, we conducted a series of 7 key informant interviews with experts who had organized PrEP or other HIV service directories. We convened an external advisory committee and a collaborators board to gain expert and community-situated perspectives. RESULTS: At its public release in September 2016, the database included 1,272 PrEP-providing clinics, including clinics in all 50 states and in Puerto Rico. Web searches, referrals, and outreach to state health departments identified 58 unique lists of PrEP-providing clinics, with 33 from state health departments, 6 from government localities, 2 from professional medical organizations, and 19 from nongovernmental organizations. Out of the 2,420 clinics identified from the lists and Web searches, we removed 798 as duplicate entries, and we determined that 350 were ineligible for listing. The most common reasons for ineligibility were not having the appropriate medical licensure to prescribe PrEP (67/350) or not prescribing PrEP, based on self-report (192/350). Key informant interviews shaped important protocol decisions, such as listing clinics instead of individual clinicians as the primary data element and streamlining data collection to facilitate scalability. We developed a Web interface to provide public access to the data, with geolocated data display, search filter functionality, a webform for public suggestions of new clinics, and a publicly available directory Web tool that can be embedded in websites. In the 6 months following release, preplocator.org and hosting websites had received over 35,000 unique views and 300 clinic additions, and 5 websites had initiated hosting of the widget. CONCLUSIONS: Directories exist for many preventive and treatment services. As new medical applications become available, there will be a corresponding need to develop new directories for service provision. Geolocated directories can assist patients in accessing care and have the potential to increase demand for and access to newer, more efficacious medical interventions. Early choices in the development of service directories have long-lasting impact, because once data collection begins, it can be challenging to reverse course. The PrEP Locator protocol may inform early decisions in the development of future service directories. Additionally, the case study on developing the PrEP Locator demonstrates the importance of formative work in identifying service-specific factors that can guide decisions on directory development. PMID- 28877867 TI - Different glucosamine sulfate products generate different outcomes on osteoarthritis symptoms. PMID- 28877866 TI - European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative. AB - Lupus nephritis (LN) occurs in 50%-60% of patients with childhood-onset systemic lupus erythematosus (cSLE), leading to significant morbidity. Timely recognition of renal involvement and appropriate treatment are essential to prevent renal damage. The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative aimed to generate diagnostic and management regimens for children and adolescents with rheumatic diseases including cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of childhood LN. Recommendations were developed using the European League Against Rheumatism standard operating procedures. A European-wide expert committee including paediatric nephrology representation formulated recommendations using a nominal group technique. Six recommendations regarding diagnosis and 20 recommendations covering treatment choices and goals were accepted, including each class of LN, described in the International Society of Nephrology/Renal Pathology Society 2003 classification system. Treatment goal should be complete renal response. Treatment of class I LN should mainly be guided by other symptoms. Class II LN should be treated initially with low-dose prednisone, only adding a disease modifying antirheumatic drug after 3 months of persistent proteinuria or prednisone dependency. Induction treatment of class III/IV LN should be mycophenolate mofetil (MMF) or intravenous cyclophosphamide combined with corticosteroids; maintenance treatment should be MMF or azathioprine for at least 3 years. In pure class V LN, MMF with low-dose prednisone can be used as induction and MMF as maintenance treatment. The SHARE recommendations for diagnosis and treatment of LN have been generated to support uniform and high quality care for all children with SLE. PMID- 28877869 TI - Hemoglobin polymerization via disulfide bond formation in the hypoxia-tolerant turtle Trachemys scripta: implications for antioxidant defense and O2 transport. AB - The ability of many reptilian hemoglobins (Hbs) to form high-molecular weight polymers, albeit known for decades, has not been investigated in detail. Given that turtle Hbs often contain a high number of cysteine (Cys), potentially contributing to the red blood cell defense against reactive oxygen species, we have examined whether polymerization of Hb could occur via intermolecular disulfide bonds in red blood cells of freshwater turtle Trachemys scripta, a species that is highly tolerant of hypoxia and oxidative stress. We find that one of the two Hb isoforms of the hemolysate HbA is prone to polymerization in vitro into linear flexible chains of different size that are visible by electron microscopy but not the HbD isoform. Polymerization of purified HbA is favored by hydrogen peroxide, a main cellular reactive oxygen species and a thiol oxidant, and inhibited by thiol reduction and alkylation, indicating that HbA polymerization is due to disulfide bonds. By using mass spectrometry, we identify Cys5 of the alphaA-subunit of HbA as specifically responsible for forming disulfide bonds between adjacent HbA tetramers. Polymerization of HbA does not affect oxygen affinity, cooperativity, and sensitivity to the allosteric cofactor ATP, indicating that HbA is still fully functional. Polymers also form in T. scripta blood after exposure to anoxia but not normoxia, indicating that they are of physiological relevance. Taken together, these results show that HbA polymers may form during oxidative stress and that Cys5alphaA of HbA is a key element of the antioxidant capacity of turtle red blood cells. PMID- 28877868 TI - Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis. AB - OBJECTIVES: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. METHODS: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. RESULTS: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). CONCLUSIONS: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA. PMID- 28877870 TI - Circadian variability of body temperature responses to methamphetamine. AB - Vital parameters of living organisms exhibit circadian rhythmicity. Although rats are nocturnal animals, most of the studies involving rats are performed during the day. The objective of this study was to examine the circadian variability of the body temperature responses to methamphetamine. Body temperature was recorded in male Sprague-Dawley rats that received intraperitoneal injections of methamphetamine (Meth, 1 or 5 mg/kg) or saline at 10 AM or at 10 PM. The baseline body temperature at night was 0.8 degrees C higher than during the day. Both during the day and at night, 1 mg/kg of Meth induced monophasic hyperthermia. However, the maximal temperature increase at night was 50% smaller than during the daytime. Injection of 5 mg/kg of Meth during the daytime caused a delayed hyperthermic response. In contrast, the same dose at night produced responses with a tendency toward a decrease of body temperature. Using mathematical modeling, we previously showed that the complex dose dependence of the daytime temperature responses to Meth results from an interplay between inhibitory and excitatory drives. In this study, using our model, we explain the suppression of the hyperthermia in response to Meth at night. First, we found that the baseline activity of the excitatory drive is greater at night. It appears partially saturated and thus is additionally activated by Meth to a lesser extent. Therefore, the excitatory component causes less hyperthermia or becomes overpowered by the inhibitory drive in response to the higher dose. Second, at night the injection of Meth results in reduction of the equilibrium body temperature, leading to gradual cooling counteracting hyperthermia. PMID- 28877872 TI - Insulin sensitivity, leptin, adiponectin, resistin, and testosterone in adult male and female rats after maternal-neonatal separation and environmental stress. AB - Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics. PMID- 28877871 TI - Comparative NMR and NIRS analysis of oxygen-dependent metabolism in exercising finger flexor muscles. AB - Muscle contraction requires the physiology to adapt rapidly to meet the surge in energy demand. To investigate the shift in metabolic control, especially between oxygen and metabolism, researchers often depend on near-infrared spectroscopy (NIRS) to measure noninvasively the tissue O2 Because NIRS detects the overlapping myoglobin (Mb) and hemoglobin (Hb) signals in muscle, interpreting the data as an index of cellular or vascular O2 requires deconvoluting the relative contribution. Currently, many in the NIRS field ascribe the signal to Hb. In contrast, 1H NMR has only detected the Mb signal in contracting muscle, and comparative NIRS and NMR experiments indicate a predominant Mb contribution. The present study has examined the question of the NIRS signal origin by measuring simultaneously the 1H NMR, 31P NMR, and NIRS signals in finger flexor muscles during the transition from rest to contraction, recovery, ischemia, and reperfusion. The experiment results confirm a predominant Mb contribution to the NIRS signal from muscle. Given the NMR and NIRS corroborated changes in the intracellular O2, the analysis shows that at the onset of muscle contraction, O2 declines immediately and reaches new steady states as contraction intensity rises. Moreover, lactate formation increases even under quite aerobic condition. PMID- 28877874 TI - Fostering research into antimicrobial resistance in India. PMID- 28877873 TI - The in vitro zebrafish heart as a model to investigate the chronotropic effects of vapor anesthetics. AB - In addition to their intended clinical actions, all general anesthetic agents in common use have detrimental intrasurgical and postsurgical side effects on organs and systems, including the heart. The major cardiac side effect of anesthesia is bradycardia, which increases the probability of insufficient systemic perfusion during surgery. These side effects also occur in all vertebrate species so far examined, but the underlying mechanisms are not clear. The zebrafish heart is a powerful model for studying cardiac electrophysiology, employing the same pacemaker system and neural control as do mammalian hearts. In this study, isolated zebrafish hearts were significantly bradycardic during exposure to the vapor anesthetics sevoflurane (SEVO), desflurane (DES), and isoflurane (ISO). Bradycardia induced by DES and ISO continued during pharmacological blockade of the intracardiac portion of the autonomic nervous system, but the chronotropic effect of SEVO was eliminated during blockade. Bradycardia evoked by vagosympathetic nerve stimulation was augmented during DES and ISO exposure; nerve stimulation during SEVO exposure had no effect. Together, these results support the hypothesis that the cardiac chronotropic effect of SEVO occurs via a neurally mediated mechanism, while DES and ISO act directly upon cardiac pacemaker cells via an as yet unknown mechanism. PMID- 28877876 TI - Sex Differences in Percutaneous Coronary Intervention-Insights From the Coronary Angiography and PCI Registry of the German Society of Cardiology. PMID- 28877875 TI - Metabolic Syndrome Risks Following the Great Recession in Rural Black Young Adults. AB - BACKGROUND: Some of the country's highest rates of morbidity and mortality from cardiovascular disease are found in lower-income black communities in the rural Southeast. Research suggests these disparities originate in the early decades of life, and partly reflect the influence of broader socioeconomic forces acting on behavioral and biological processes that accelerate cardiovascular disease progression. However, this hypothesis has not been tested explicitly. Here, we examine metabolic syndrome (MetS) in rural black young adults as a function of their family's economic conditions before and after the Great Recession. METHODS AND RESULTS: In an ongoing prospective study, we followed 328 black youth from rural Georgia, who were 16 to 17 years old when the Great Recession began. When youth were 25, we assessed MetS prevalence using the International Diabetes Federation's guidelines. The sample's overall MetS prevalence was 18.6%, but rates varied depending on family economic trajectory from before to after the Great Recession. MetS prevalence was lowest (10.4%) among youth whose families maintained stable low-income conditions across the Recession. It was intermediate (21.8%) among downwardly mobile youth (ie, those whose families were lower income before the Recession, but slipped into poverty). The highest MetS rates (27.5%) were among youth whose families began the Recession in poverty, and sank into more meager conditions afterwards. The same patterns were observed with 3 alternative MetS definitions. CONCLUSIONS: These patterns suggest that broader economic forces shape cardiometabolic risk in young blacks, and may exacerbate disparities already present in this community. PMID- 28877877 TI - Acute blood loss stimulates fibroblast growth factor 23 production. AB - Fibroblast growth factor 23 (FGF23) production is upregulated by iron deficiency and hypoxia. However, the influence of acute blood loss, and the resulting increases in circulating erythropoietin, on FGF23 production is unknown. Using wild-type C57BL/6 mice, we show that acute loss of 10% total blood volume leads to an increase in plasma C-terminal FGF23 (cFGF23) levels within 6 h, while plasma levels of intact FGF23, phosphate, calcium, parathyroid hormone, iron, and ferritin remain similar to control mice without acute blood loss. Volume resuscitation with PBS did not significantly alter these findings. The increase in plasma cFGF23 levels in bled animals was accompanied by increased plasma erythropoietin levels at 6 h. Administration of erythropoietin led to an acute increase in plasma cFGF23 levels similar to that observed in acute blood loss. Fgf23 mRNA expression was increased 20-fold in bone marrow, but not in bone, of bled vs. control mice, suggesting bone marrow as a key source of elevated plasma FGF23 levels following acute blood loss. To extend these findings to humans, we measured plasma cFGF23 levels in 131 critically ill patients admitted to the intensive care unit. In univariate and multivariate models, we found a positive association between number of red blood cell transfusions, an indirect indicator of acute blood loss, and plasma cFGF23 levels. We conclude that FGF23 production is rapidly increased after acute blood loss and that erythropoietin may be the mediator of this increase. Thus erythropoietin may represent a novel physiological regulator of FGF23 production. PMID- 28877878 TI - Angiotensin II type 1a receptor-deficient mice develop angiotensin II-induced oxidative stress and DNA damage without blood pressure increase. AB - Hypertensive patients have an increased risk of developing kidney cancer. We have shown in vivo that besides elevating blood pressure, angiotensin II causes DNA damage dose dependently. Here, the role of blood pressure in the formation of DNA damage is studied. Mice lacking one of the two murine angiotensin II type 1 receptor (AT1R) subtypes, AT1aR, were equipped with osmotic minipumps, delivering angiotensin II during 28 days. Parameters of oxidative stress and DNA damage of kidneys and hearts of AT1aR-knockout mice were compared with wild-type (C57BL/6) mice receiving angiotensin II, and additionally, with wild-type mice treated with candesartan, an antagonist of both AT1R subtypes. In wild-type mice, angiotensin II induced hypertension, reduced kidney function, and led to a significant formation of reactive oxygen species (ROS). Furthermore, genomic damage was markedly increased in this group. All these responses to angiotensin II could be attenuated by concurrent administration of candesartan. In AT1aR-deficient mice treated with angiotensin II, systolic pressure was not increased, and renal function was not affected. However, angiotensin II still led to an increase of ROS in kidneys and hearts of these animals. Additionally, genomic damage in the form of double-strand breaks was significantly induced in kidneys of AT1aR deficient mice. Our results show that angiotensin II induced ROS production and DNA damage even without the presence of AT1aR and independently of blood pressure changes. PMID- 28877879 TI - Uninephrectomy and apical fluid shear stress decrease ENaC abundance in collecting duct principal cells. AB - Acute nephron reduction such as after living kidney donation may increase the risk of hypertension. Uninephrectomy induces major hemodynamic changes in the remaining kidney, resulting in rapid increase of single-nephron glomerular filtration rate (GFR) and fluid delivery in the distal nephron. Decreased sodium (Na) fractional reabsorption after the distal tubule has been reported after uninephrectomy in animals preserving volume homeostasis. In the present study, we thought to specifically explore the effect of unilateral nephrectomy on epithelial Na channel (ENaC) subunit expression in mice. We show that gamma-ENaC subunit surface expression was specifically downregulated after uninephrectomy, whereas the expression of the aldosterone-sensitive alpha-ENaC and alpha1-Na-K ATPase subunits as well as of kidney-specific Na-K-Cl cotransporter isoform and Na-Cl cotransporter were not significantly altered. Because acute nephron reduction induces a rapid increase of single-nephron GFR, resulting in a higher tubular fluid flow, we speculated that local mechanical factors such as fluid shear stress (FSS) were involved in Na reabsorption regulation after uninephrectomy. We further explore such hypothesis in an in vitro model of FSS applied on highly differentiated collecting duct principal cells. We found that FSS specifically downregulates beta-ENaC and gamma-ENaC subunits at the transcriptional level through an unidentified heat-insensitive paracrine basolateral factor. The primary cilium as a potential mechanosensor was not required. In contrast, protein kinase A and calcium-sensitive cytosolic phospholipase A2 were involved, but we could not demonstrate a role for cyclooxygenase or epoxygenase metabolites. PMID- 28877880 TI - Altered vasopressin and natriuretic peptide levels in a rat model of spinal cord injury: implications for the development of polyuria. AB - Urinary dysfunction is a common complaint following spinal cord injury (SCI) and is a leading issue for individuals with SCI that impacts their quality of life. One urinary complication that has received little attention is SCI-induced polyuria, even though individuals with SCI will significantly restrict their fluid intake to decrease urine production, leading to sequelae of medical complications. Understanding the mechanisms instigating the development of polyuria will allow us to target interventions that may alleviate polyuria symptoms, leading to significant improvements in the quality of life and urinary health of individuals with SCI. In a rat SCI contusion model, an increase in the amount of urine excreted over a 24-h period ( P <= 0.001) was found at 2 wk postinjury. The urine excreted was more dilute with decreased urinary creatinine and specific gravity ( P <= 0.001). Several factors important in fluid balance regulation, vasopressin (AVP), natriuretic peptides, and corticosterone (CORT), also changed significantly postinjury. AVP levels decreased ( P = 0.042), whereas atrial natriuretic peptide (ANP) and CORT increased ( P = 0.005 and P = 0.031, respectively) at 2 wk postinjury. There was also a positive correlation between the increase in ANP and urine volume postinjury ( P = 0.033). The changes in AVP, ANP, and CORT are conducive to producing polyuria, and the timing of these changes coincides with the development of SCI-induced polyuria. This study identifies several therapeutic targets that could be used to ameliorate polyuria symptoms and improve quality of life in individuals with SCI. PMID- 28877883 TI - Versatility of NaCl transport mechanisms in the cortical collecting duct. AB - The cortical collecting duct (CCD) forms part of the aldosterone-sensitive distal nephron and plays an essential role in maintaining the NaCl balance and acid-base status. The CCD epithelium comprises principal cells as well as different types of intercalated cells. Until recently, transcellular Na+ transport was thought to be restricted to principal cells, whereas (acid-secreting) type A and (bicarbonate-secreting) type B intercalated cells were associated with the regulation of acid-base homeostasis. This review describes how this traditional view has been upended by several discoveries in the past decade. A series of studies has shown that type B intercalated cells can mediate electroneutral NaCl reabsorption by a mechanism involving Na+-dependent and Na+-independent Cl /[Formula: see text] exchange, and that is energetically driven by basolateral vacuolar H+-ATPase pumps. Other research indicates that type A intercalated cells can mediate NaCl secretion, through a bumetanide-sensitive pathway that is energized by apical H+,K+-ATPase type 2 pumps operating as Na+/K+ exchangers. We also review recent findings on the contribution of the paracellular route to NaCl transport in the CCD. Last, we describe cross-talk processes, by which one CCD cell type impacts Na+/Cl- transport in another cell type. The mechanisms that have been identified to date demonstrate clearly the interdependence of NaCl and acid-base transport systems in the CCD. They also highlight the remarkable versatility of this nephron segment. PMID- 28877882 TI - Mechanotransduction signaling in podocytes from fluid flow shear stress. AB - Recently, we and others have found that hyperfiltration-associated increase in biomechanical forces, namely, tensile stress and fluid flow shear stress (FFSS), can directly and distinctly alter podocyte structure and function. The ultrafiltrate flow over the major processes and cell body generates FFSS to podocytes. Our previous work suggests that the cyclooxygenase-2 (COX-2)-PGE2-PGE2 receptor 2 (EP2) axis plays an important role in mechanoperception of FFSS in podocytes. To address mechanotransduction of the perceived stimulus through EP2, cultured podocytes were exposed to FFSS (2 dyn/cm2) for 2 h. Total RNA from cells at the end of FFSS treatment, 2-h post-FFSS, and 24-h post-FFSS was used for whole exon array analysis. Differentially regulated genes ( P < 0.01) were analyzed using bioinformatics tools Enrichr and Ingenuity Pathway Analysis to predict pathways/molecules. Candidate pathways were validated using Western blot analysis and then further confirmed to be resulting from a direct effect of PGE2 on podocytes. Results show that FFSS-induced mechanotransduction as well as exogenous PGE2 activate the Akt-GSK3beta-beta-catenin (Ser552) and MAPK/ERK but not the cAMP-PKA signal transduction cascades. These pathways are reportedly associated with FFSS-induced and EP2-mediated signaling in other epithelial cells as well. The current regimen for treating hyperfiltration-mediated injury largely depends on targeting the renin-angiotensin-aldosterone system. The present study identifies specific transduction mechanisms and provides novel information on the direct effect of FFSS on podocytes. These results suggest that targeting EP2 mediated signaling pathways holds therapeutic significance for delaying progression of chronic kidney disease secondary to hyperfiltration. PMID- 28877885 TI - Bicuspid Aortic Valve: What to Image in Patients Considered for Transcatheter Aortic Valve Replacement? PMID- 28877884 TI - Aberrant Smad3 phosphoisoforms in cyst-lining epithelial cells in the cpk mouse, a model of autosomal recessive polycystic kidney disease. AB - Cystic epithelia acquire mesenchymal-like features in polycystic kidney disease (PKD). In this phenotypic alteration, it is well known that transforming growth factor (TGF)-beta/Smad3 signaling is involved; however, there is emerging new data on Smad3 phosphoisoforms: Smad3 phosphorylated at linker regions (pSmad3L), COOH-terminal regions (pSmad3C), and both (pSmad3L/C). pSmad3L/C has a pathological role in colorectal cancer. Mesenchymal phenotype-specific cell responses in the TGF-beta/Smad3 pathway are implicated in carcinomas. In this study, we confirmed mesenchymal features and examined Smad3 phosphoisoforms in the cpk mouse, a model of autosomal recessive PKD. Kidney sections were stained with antibodies against mesenchymal markers and domain-specific phospho-Smad3. TGF-beta, pSmad3L, pSmad3C, JNK, cyclin-dependent kinase (CDK) 4, and c-Myc were evaluated by Western blotting. Cophosphorylation of pSmad3L/C was assessed by immunoprecipitation. alpha-Smooth muscle actin, which indicates mesenchymal features, was expressed higher in cpk mice. pSmad3L expression was increased in cpk mice and was predominantly localized in the nuclei of tubular epithelial cells in cysts; however, pSmad3C was equally expressed in both cpk and control mice. Levels of pSmad3L, JNK, CDK4, and c-Myc protein in nuclei were significantly higher in cpk mice than in controls. Immunoprecipitation showed that Smad3 was cophosphorylated (pSmad3L/C) in cpk mice. Smad3 knockout/cpk double-mutant mice revealed amelioration of cpk abnormalities. These findings suggest that upregulating c-Myc through the JNK/CDK4-dependent pSmad3L pathway may be key to the pathophysiology in cpk mice. In conclusion, a qualitative rather than a quantitative abnormality of the TGF-beta/Smad3 pathway is involved in PKD and may be a target for disease-specific intervention. PMID- 28877881 TI - Regulatory T cells in acute and chronic kidney diseases. AB - Foxp3-expressing CD4+ regulatory T cells (Tregs) make up one subset of the helper T cells (Th) and are one of the major mechanisms of peripheral tolerance. Tregs prevent abnormal activation of the immune system throughout the lifespan, thus protecting from autoimmune and inflammatory diseases. Recent studies have elucidated the role of Tregs beyond autoimmunity. Tregs play important functions in controlling not only innate and adaptive immune cell activation, but also regulate nonimmune cell function during insults and injury. Inflammation contributes to a multitude of acute and chronic diseases affecting the kidneys. This review examines the role of Tregs in pathogenesis of renal inflammatory diseases and explores the approaches for enhancing Tregs for prevention and therapy of renal inflammation. PMID- 28877886 TI - Pulmonary Right Ventricular Resynchronization in Congenital Heart Disease: Acute Improvement in Right Ventricular Mechanics and Contraction Efficiency. AB - BACKGROUND: Electromechanical discoordination may contribute to long-term pulmonary right ventricular (RV) dysfunction in patients after surgery for congenital heart disease. We sought to evaluate changes in RV function after temporary RV cardiac resynchronization therapy. METHODS AND RESULTS: Twenty-five patients aged median 12.0 years after repair of tetralogy of Fallot and similar lesions were studied echocardiographically (n=23) and by cardiac catheterization (n=5) after primary repair (n=4) or after surgical RV revalvulation for significant pulmonary regurgitation (n=21). Temporary RV cardiac resynchronization therapy was applied in the presence of complete right bundle branch block by atrial-synchronized RV free wall pacing in complete fusion with spontaneous ventricular depolarization using temporary electrodes. The q-RV interval at the RV free wall pacing site (mean 77.2% of baseline QRS duration) confirmed pacing from a late activated RV area. RV cardiac resynchronization therapy carried significant decrease in QRS duration (P<0.001) along with elimination of the right bundle branch block QRS morphology, increase in RV filling time (P=0.002), pulmonary artery velocity time integral (P=0.006), and RV maximum +dP/dt (P<0.001), and decrease in RV index of myocardial performance (P=0.006). RV mechanical synchrony improved: septal-to-lateral RV mechanical delay decreased (P<0.001) and signs of RV dyssynchrony pattern were significantly abolished. RV systolic stretch fraction reflecting the ratio of myocardial stretching and contraction during systole diminished (P=0.001). CONCLUSIONS: In patients with congenital heart disease and right bundle branch block, RV cardiac resynchronization therapy carried multiple positive effects on RV mechanics, synchrony, and contraction efficiency. PMID- 28877887 TI - Another Step in the Right Direction: Resynchronizing the Dyssynchronous Right Ventricle Improves Its Efficiency and Function. PMID- 28877888 TI - A Novel 18-Marker Panel Predicting Clinical Outcome in Breast Cancer. AB - Background: Gene expression profiling has made considerable contributions to our understanding of cancer biology and clinical care. This study describes a novel gene expression signature for breast cancer-specific survival that was validated using external datasets.Methods: Gene expression signatures for invasive breast carcinomas (mainly luminal B subtype) corresponding to 136 patients were analyzed using Cox regression, and the effect of each gene on disease-specific survival (DSS) was estimated. Iterative Bayesian model averaging was applied on multivariable Cox regression models resulting in an 18-marker panel, which was validated using three external validation datasets. The 18 genes were analyzed for common pathways and functions using the Ingenuity Pathway Analysis software. This study complied with the REMARK criteria.Results: The 18-gene multivariable model showed a high predictive power for DSS in the training and validation cohort and a clear stratification between high- and low-risk patients. The differentially expressed genes were predominantly involved in biological processes such as cell cycle, DNA replication, recombination, and repair. Furthermore, the majority of the 18 genes were found to play a pivotal role in cancer.Conclusions: Our findings demonstrated that the 18 molecular markers were strong predictors of breast cancer-specific mortality. The stable time-dependent area under the ROC curve function (AUC(t)) and high C-indices in the training and validation cohorts were further improved by fitting a combined model consisting of the 18-marker panel and established clinical markers.Impact: Our work supports the applicability of this 18-marker panel to improve clinical outcome prediction for breast cancer patients. Cancer Epidemiol Biomarkers Prev; 26(11); 1619-28. (c)2017 AACR. PMID- 28877889 TI - Alcohol, Physical Activity, Smoking, and Breast Cancer Subtypes in a Large, Nested Case-Control Study from the Norwegian Breast Cancer Screening Program. AB - Background: To what extent alcohol, smoking, and physical activity are associated with the various subtypes of breast cancer is not clear. We took advantage of a large population-based screening cohort to determine whether these risk factors also increase the risk of the poor prognosis subtypes.Methods: We conducted a matched case-control study nested within the Norwegian Breast Cancer Screening Program during 2006-2014. A total of 4,402 breast cancer cases with risk factor and receptor data were identified. Five controls were matched to each case on year of birth and year of screening. Conditional logistic regression was used to estimate ORs of breast cancer subtypes adjusted for potential confounders.Results: There were 2,761 luminal A-like, 709 luminal B-like HER2 negative, 367 luminal B-like HER2-positive, 204 HER2-positive, and 361 triple negative cancers. Current alcohol consumption was associated with breast cancer risk overall [OR 1.26; 95% confidence interval (CI), 1.09-1.45] comparing 6+ glasses a week to never drinkers. However, this risk increase was found only for luminal A-like breast cancer. Smoking 20+ cigarettes a day was associated with an OR of 1.41 (95% CI, 1.06-1.89) overall, with significant trends for luminal A like and luminal B-like HER2-negative cancer. Current physical activity (4+ hours/week compared with none) was associated with 15% decreased risk of luminal A-like cancer, but not clearly with other subtypes.Conclusions: In this large study, alcohol, smoking, and physical activity were predominantly associated with luminal A-like breast cancer.Impact: Alcohol, smoking, and physical activity were associated with luminal A-like breast cancer subtype. Cancer Epidemiol Biomarkers Prev; 26(12); 1736-44. (c)2017 AACR. PMID- 28877890 TI - Tackling iron deficiency in infants: galacto-oligosaccharides may be up to the task. PMID- 28877892 TI - Supplementing a normal diet with protein yields a moderate improvement in the robust gains in muscle mass and strength induced by resistance training in older individuals. PMID- 28877891 TI - Investigating predictors of eating: is resting metabolic rate really the strongest proxy of energy intake? AB - Background: Evidence suggests that fat-free mass and resting metabolic rate (RMR), but not fat mass, are strong predictors of energy intake (EI). However, body composition and RMR do not explain the entire variance in EI, suggesting that other factors may contribute to this variance.Objective: We aimed to investigate the associations between body mass index (in kg/m2), fat mass, fat free mass, and RMR with acute (1 meal) and daily (24-h) EI and between fasting appetite ratings and certain eating behavior traits with daily EI. We also evaluated whether RMR is a predictor of the error variance in acute and daily EI.Design: Data collected during the control condition of 7 studies conducted in Ottawa, Ontario, Canada, were included in these analyses (n = 191 and 55 for acute and daily EI, respectively). These data include RMR (indirect calorimetry), body composition (dual-energy X-ray absorptiometry), fasting appetite ratings (visual analog scales), eating behavior traits (Three-Factor Eating Questionnaire), and EI (food buffet or menu).Results: Fat-free mass was the best predictor of acute EI (R2 = 0.46; P < 0.0001). The combination of fasting prospective food consumption ratings and RMR was the best predictor of daily EI (R2 = 0.44; P < 0.0001). RMR was a statistically significant positive predictor of the error variance for acute (R2 = 0.20; P < 0.0001) and daily (R2 = 0.23; P < 0.0001) EI. RMR did, however, remain a statistically significant predictor of acute (R2 = 0.32; P < 0.0001) and daily (R2 = 0.30; P < 0.0001) EI after controlling for this error variance.Conclusions: Our findings suggest that combined measurements of appetite ratings and RMR could be used to estimate EI in weight-stable individuals. However, greater error variance in acute and daily EI with increasing RMR values was observed. Future studies are needed to identify whether greater fluctuations in daily EI over time occur with increasing RMR values. This trial was registered at clinicaltrials.gov as NCT02653378. PMID- 28877893 TI - Randomized controlled trial on the impact of early-life intervention with bifidobacteria on the healthy infant fecal microbiota and metabolome. AB - Background: Early-life colonization of the intestinal tract is a dynamic process influenced by numerous factors. The impact of probiotic-supplemented infant formula on the composition and function of the infant gut microbiota is not well defined.Objective: We sought to determine the effects of a bifidobacteria containing formula on the healthy human intestinal microbiome during the first year of life.Design: A double-blind, randomized, placebo-controlled study of newborn infants assigned to a standard whey-based formula containing a total of 107 colony-forming units (CFU)/g of Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, B. longum subspecies infantis (intervention), or to a control formula without bifidobacteria (placebo). Breastfed controls were included. Diversity and composition of fecal microbiota were determined by 16S ribosomal RNA gene amplicon sequencing, and metabolite profiles were analyzed by ultrahigh-performance liquid chromatography-mass spectrometry over a period of 2 y.Results: Infants (n = 106) were randomly assigned to either the interventional (n = 48) or placebo (n = 49) group; 9 infants were exclusively breastfed throughout the entire intervention period of 12 mo. Infants exposed to bifidobacteria-supplemented formula showed decreased occurrence of Bacteroides and Blautia spp. associated with changes in lipids and unknown metabolites at month 1. Microbiota and metabolite profiles of intervention and placebo groups converged during the study period, and long-term colonization (24 mo) of the supplemented Bifidobacterium strains was not detected. Significant differences in microbiota and metabolites were detected between infants fed breast milk and those fed formula (P < 0.005) and between infants birthed vaginally and those birthed by cesarean delivery (P < 0.005). No significant differences were observed between infant feeding groups regarding growth, antibiotic uptake, or other health variables (P > 0.05).Conclusion: The supplementation of bifidobacteria to infant diet can modulate the occurrence of specific bacteria and metabolites during early life with no detectable long-term effects. This trial was registered at germanctr.de as DRKS00003660. PMID- 28877894 TI - Later circadian timing of food intake is associated with increased body fat. AB - Background: Weight gain and obesity have reached alarming levels. Eating at a later clock hour is a newly described risk factor for adverse metabolic health; yet, how eating at a later circadian time influences body composition is unknown. Using clock hour to document eating times may be misleading owing to individual differences in circadian timing relative to clock hour.Objective: This study examined the relations between the timing of food consumption relative to clock hour and endogenous circadian time, content of food intake, and body composition.Design: We enrolled 110 participants, aged 18-22 y, in a 30-d cross sectional study to document sleep and circadian behaviors within their regular daily routines. We used a time-stamped-picture mobile phone application to record all food intake across 7 consecutive days during a participant's regular daily routines and assessed their body composition and timing of melatonin release during an in-laboratory assessment.Results: Nonlean individuals (high body fat) consumed most of their calories 1.1 h closer to melatonin onset, which heralds the beginning of the biological night, than did lean individuals (low body fat) (log-rank P = 0.009). In contrast, there were no differences between lean and nonlean individuals in the clock hour of food consumption (P = 0.72). Multiple regression analysis showed that the timing of food intake relative to melatonin onset was significantly associated with the percentage of body fat and body mass index (both P < 0.05) while controlling for sex, whereas no relations were found between the clock hour of food intake, caloric amount, meal macronutrient composition, activity or exercise level, or sleep duration and either of these body composition measures (all P > 0.72).Conclusions: These results provide evidence that the consumption of food during the circadian evening and/or night, independent of more traditional risk factors such as amount or content of food intake and activity level, plays an important role in body composition. This trial was registered at clinicaltrials.gov as NCT02846077. PMID- 28877895 TI - Trajectories of maternal weight from before pregnancy through postpartum and associations with childhood obesity. AB - Background: Prepregnancy body mass index [BMI (in kg/m2)], gestational weight gain, and postpartum weight retention may have distinct effects on the development of child obesity, but their combined effect is currently unknown.Objective: We described longitudinal trajectories of maternal weight from before pregnancy through the postpartum period and assessed the relations between maternal weight trajectories and offspring obesity in childhood.Design: We analyzed data from 4436 pairs of mothers and their children in the National Longitudinal Survey of Youth 1979 (1981-2014). We used latent-class growth modeling in addition to national recommendations for prepregnancy BMI, gestational weight gain, and postpartum weight retention to create maternal weight trajectory groups. We used modified Poisson regression models to assess the associations between maternal weight trajectory group and offspring obesity at 3 age periods (2-5, 6-11, and 12-19 y).Results: Our analysis using maternal weight trajectories based on either latent-class results or recommendations showed that the risk of child obesity was lowest in the lowest maternal weight trajectory group. The differences in obesity risk were largest after 5 y of age and persisted into adolescence. In the latent-class analysis, the highest-order maternal weight trajectory group consisted almost entirely of women who were obese before pregnancy and was associated with a >2-fold increase in the risk of offspring obesity at ages 6-11 y (adjusted RR: 2.39; 95% CI: 1.97, 2.89) and 12 19 y (adjusted RR: 2.74; 95% CI: 2.13, 3.52). In the analysis with maternal weight trajectory groups based on recommendations, the risk of child obesity was consistently highest for women who were overweight or obese at the beginning of pregnancy.Conclusion: These findings suggest that high maternal weight across the childbearing period increases the risk of obesity in offspring during childhood, but high prepregnancy BMI has a stronger influence than either gestational weight gain or postpartum weight retention. PMID- 28877897 TI - Sensitivity and specificity are not appropriate for diagnostic reasoning. PMID- 28877896 TI - Intake of potassium- and magnesium-enriched salt improves functional outcome after stroke: a randomized, multicenter, double-blind controlled trial. AB - Background: Stroke is one of the leading causes of mortality and neurologic deficits. Management measures to improve neurologic outcomes are in great need. Our previous intervention trial in elderly subjects successfully used salt as a carrier for potassium, demonstrating a 41% reduction in cardiovascular mortality by switching to potassium-enriched salt. Dietary magnesium has been associated with lowered diabetes and/or stroke risk in humans and with neuroprotection in animals.Objective: Because a large proportion of Taiwanese individuals are in marginal deficiency states for potassium and for magnesium and salt is a good carrier for minerals, it is justifiable to study whether further enriching salt with magnesium at an amount near the Dietary Reference Intake (DRI) amount may provide additional benefit for stroke recovery.Design: This was a double-blind, randomized controlled trial comprising 291 discharged stroke patients with modified Rankin scale (mRS) <=4. There were 3 arms: 1) regular salt (Na salt) (n = 99), 2) potassium-enriched salt (K salt) (n = 97), and 3) potassium- and magnesium-enriched salt (K/Mg salt) (n = 95). The NIH Stroke Scale (NIHSS), Barthel Index (BI), and mRS were evaluated at discharge, at 3 mo, and at 6 mo. A good neurologic performance was defined by NIHSS = 0, BI = 100, and mRS <=1.Results: After the 6-mo intervention, the proportion of patients with good neurologic performance increased in a greater magnitude in the K/Mg salt group than in the K salt group and the Na salt group, in that order. The K/Mg salt group had a significantly increased OR (2.25; 95% CI: 1.09, 4.67) of achieving good neurologic performance compared with the Na salt group. But the effect of K salt alone (OR: 1.58; 95% CI: 0.77, 3.22) was not significant.Conclusions: This study suggests that providing the DRI amount of magnesium and potassium together long term is beneficial for stroke patient recovery from neurologic deficits. This trial was registered at clinicaltrials.gov as NCT02910427. PMID- 28877899 TI - Equipping NK Cells with CARs. AB - Adding a chimeric antigen receptor (CAR) to natural killer (NK) cells is garnering interest as a therapeutic strategy because this immune cell type doesn't cause graft-versus-host disease, making its widespread, off-the-shelf use feasible. Based on promising preclinical data, a phase I/II trial of one such CAR NK-cell therapy is under way, targeting CD19 in hematologic malignancies. PMID- 28877898 TI - Diagnosis and management of endometriosis: summary of NICE guidance. PMID- 28877900 TI - Gilead Buying Kite for $11.9 Billion. AB - Gilead Sciences will buy Kite Pharma-and its autologous CAR T-cell technology-for $11.9 billion. The acquisition will help Gilead build its oncology portfolio and boost its revenues. PMID- 28877901 TI - Margaret McCartney: Nuclear weapons do harm, even if never used. PMID- 28877902 TI - Sixty seconds on . . . the private finance initiative. PMID- 28877903 TI - David Sanders: Privileged to serve patients. PMID- 28877904 TI - The impact of the junior doctor contract-one year on. PMID- 28877906 TI - Conference organisers swimming against the tide of Twitter. PMID- 28877905 TI - Perioperative tobacco use treatments: putting them into practice. AB - Treatment for tobacco use is efficacious and beneficial to health. Although guidelines recommend that all patients who use tobacco are offered treatment as a part of their clinical care, implementing treatment has proven challenging. In the case of surgical patients, this lack of treatment is particularly unfortunate, as the benefits of abstinence from tobacco are immediate in terms of reducing the risk of surgical complications, including cardiovascular, respiratory, and wound related complications. Surgery also presents an opportunity for patients to quit for good and reduce the long term health risk. This review examines the principles of tobacco use treatment, the rationale for tobacco use treatment in the perioperative period, and how treatment can be incorporated into the routine care of surgical patients. The discipline of implementation science helps to frame these efforts by seeking to better understand how changes in clinical practice occur, and it has the potential to guide an evidence based approach to embedding tobacco treatment into the routine clinical care of surgical patients. This review uses the consolidated framework for implementation research, which includes five major domains, as a representative conceptual framework. A basic understanding of factors potentially important to successful implementation can help to guide clinicians who accept the challenge of implementing tobacco use treatment in surgical care. PMID- 28877908 TI - Capitation based funding of general practice is not fit for purpose. PMID- 28877907 TI - Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study. AB - Objective To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders.Design Population based cohort study.Setting Danish national registers.Participants 905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1*106 person years at risk.Exposures for observational studies Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy).Main outcome measure First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models.Results Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group.Conclusions In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive. PMID- 28877909 TI - Scottish government must act to fill consultant vacancies, says BMA. PMID- 28877910 TI - Prenatal exposure to antidepressants and increased risk of psychiatric disorders. PMID- 28877911 TI - Hepatic GALE Regulates Whole-Body Glucose Homeostasis by Modulating Tff3 Expression. AB - Transcripts of key enzymes in the Leloir pathway of galactose metabolism in mouse livers are significantly increased after chronic high-fat/high-sucrose feeding. UDP-galactose-4-epimerase (GALE) is the last enzyme in this pathway that converts UDP-galactose to UDP-glucose and was previously identified as a downstream target of the endoplasmic reticulum (ER) stress effector spliced X-box binding protein 1, suggesting an interesting cross talk between galactose and glucose metabolism in the context of hepatic ER stress and whole-body metabolic fitness. However, its specific role in glucose metabolism is not established. Using an inducible and tissue-specific mouse model, we report that hepatic overexpression of Gale increases gluconeogenesis from pyruvate and impairs glucose tolerance. Conversely, genetic reduction of Gale in liver improves glucose tolerance. Transcriptional profiling identifies trefoil factor 3 (Tff3) as one of the downstream targets of GALE. Restoration of Tff3 expression corrects glucose intolerance in Gale-overexpressing mice. These studies reveal a new link between hepatic GALE activity and whole-body glucose homeostasis via regulation of hepatic Tff3 expression. PMID- 28877913 TI - Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above: Analyses From the WOSCOPS (West of Scotland Coronary Prevention Study) 5-Year Randomized Trial and 20-Year Observational Follow-Up. AB - BACKGROUND: Patients with primary elevations of low-density lipoprotein cholesterol (LDL-C) >=190 mg/dL are at a higher risk of atherosclerotic cardiovascular disease as a result of long-term exposure to markedly elevated LDL C levels. Therefore, initiation of statin therapy is recommended for these individuals. However, there is a lack of randomized trial evidence supporting these recommendations in primary prevention. In the present analysis, we provide hitherto unpublished data on the cardiovascular effects of LDL-C lowering among a primary prevention population with LDL-C >=190 mg/dL. METHODS: We aimed to assess the benefits of LDL-C lowering on cardiovascular outcomes among individuals with primary elevations of LDL-C >=190 mg/dL without preexisting vascular disease at baseline. We performed post hoc analyses from the WOSCOPS (West of Scotland Coronary Prevention Study) randomized, placebo-controlled trial, and observational posttrial long-term follow-up, after excluding individuals with evidence of vascular disease at baseline. WOSCOPS enrolled 6595 men aged 45 to 64 years, who were randomly assigned to pravastatin 40 mg/d or placebo. In the present analyses, 5529 participants without evidence of vascular disease were included, stratified by LDL-C levels into those with LDL-C <190 mg/dL (n=2969; mean LDL-C 178+/-6 mg/dL) and those with LDL-C >=190 mg/dL (n=2560; mean LDL-C 206+/-12 mg/dL). The effect of pravastatin versus placebo on coronary heart disease and major adverse cardiovascular events were assessed over the 4.9-year randomized controlled trial phase and on mortality outcomes over a total of 20 years of follow-up. RESULTS: Among 5529 individuals without vascular disease, pravastatin reduced the risk of coronary heart disease by 27% (P=0.002) and major adverse cardiovascular events by 25% (P=0.004) consistently among those with and without LDL-C >=190 mg/dL (P-interaction >0.9). Among individuals with LDL-C >=190 mg/dL, pravastatin reduced the risk of coronary heart disease by 27% (P=0.033) and major adverse cardiovascular events by 25% (P=0.037) during the initial trial phase and the risk of coronary heart disease death, cardiovascular death, and all-cause mortality by 28% (P=0.020), 25% (P=0.009), and 18% (P=0.004), respectively, over a total of 20 years of follow-up. CONCLUSIONS: The present analyses provide robust novel evidence for the short- and long-term benefits of lowering LDL-C for the primary prevention of cardiovascular disease among individuals with primary elevations of LDL-C >=190 mg/dL. PMID- 28877912 TI - Type 1 Interferons Potentiate Human CD8+ T-Cell Cytotoxicity Through a STAT4- and Granzyme B-Dependent Pathway. AB - Events defining the progression to human type 1 diabetes (T1D) have remained elusive owing to the complex interaction between genetics, the immune system, and the environment. Type 1 interferons (T1-IFN) are known to be a constituent of the autoinflammatory milieu within the pancreas of patients with T1D. However, the capacity of IFNalpha/beta to modulate human activated autoreactive CD8+ T-cell (cytotoxic T lymphocyte) responses within the islets of patients with T1D has not been investigated. Here, we engineer human beta-cell-specific cytotoxic T lymphocytes and demonstrate that T1-IFN augments cytotoxicity by inducing rapid phosphorylation of STAT4, resulting in direct binding at the granzyme B promoter within 2 h of exposure. The current findings provide novel insights concerning the regulation of effector function by T1-IFN in human antigen-experienced CD8+ T cells and provide a mechanism by which the presence of T1-IFN potentiates diabetogenicity within the autoimmune islet. PMID- 28877917 TI - Vitamin D and adolescents: a forgotten 'at risk' group? PMID- 28877914 TI - Age and Outcomes of Primary Prevention Implantable Cardioverter-Defibrillators in Patients With Nonischemic Systolic Heart Failure. AB - BACKGROUND: The DANISH study (Danish Study to Assess the Efficacy of ICDs [Implantable Cardioverter Defibrillators] in Patients With Non-Ischemic Systolic Heart Failure on Mortality) did not demonstrate an overall effect on all-cause mortality with ICD implantation. However, the prespecified subgroup analysis suggested a possible age-dependent association between ICD implantation and mortality with survival benefit seen only in the youngest patients. The nature of this relationship between age and outcome of a primary prevention ICD in patients with nonischemic systolic heart failure warrants further investigation. METHODS: All 1116 patients from the DANISH study were included in this prespecified subgroup analysis. We assessed the relationship between ICD implantation and mortality by age, and an optimal age cutoff was estimated nonparametrically with selection impact curves. Modes of death were divided into sudden cardiac death and nonsudden death and compared between patients younger and older than this age cutoff with the use of chi2 analysis. RESULTS: Median age of the study population was 63 years (range, 21-84 years). There was a linearly decreasing relationship between ICD and mortality with age (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.003-1.06; P=0.03). An optimal age cutoff for ICD implantation was present at <=70 years. There was an association between reduced all-cause mortality and ICD in patients <=70 years of age (HR, 0.70; 95% CI, 0.51-0.96; P=0.03) but not in patients >70 years of age (HR, 1.05; 95% CI, 0.68-1.62; P=0.84). For patients <=70 years old, the sudden cardiac death rate was 1.8 (95% CI, 1.3-2.5) and nonsudden death rate was 2.7 (95% CI, 2.1-3.5) events per 100 patient-years, whereas for patients >70 years old, the sudden cardiac death rate was 1.6 (95% CI, 0.8-3.2) and nonsudden death rate was 5.4 (95% CI, 3.7-7.8) events per 100 patient-years. This difference in modes of death between the 2 age groups was statistically significant (P=0.01). CONCLUSIONS: In patients with systolic heart failure not caused by ischemic heart disease, the association between the ICD and survival decreased linearly with increasing age. In this study population, an age cutoff for ICD implantation at <=70 years yielded the highest survival for the population as a whole. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00542945. PMID- 28877916 TI - Temporal trends in the association between socioeconomic status and cancer survival in Ontario: a population-based retrospective study. AB - BACKGROUND: Cancer survival is known to be associated with socioeconomic status. The income gap between the richer and poorer segments of the population has widened over the last 20 years in Canada. The purpose of this study was to investigate temporal trends in disparities in cancer-specific survival related to socioeconomic status in Ontario. METHODS: There were 920 334 cancer cases between 1993 and 2009 in the Ontario Cancer Registry. We linked median household income from the Canadian census to the registry. We calculated 5-year cancer-specific survival rates for all cancers combined and for specific cancer sites by socioeconomic status quintile and year of diagnosis, and modelled time to death using Cox regression. RESULTS: Between 1993 and 2009, for all cancers combined, the hazard of death decreased by 3.1% (hazard ratio [HR] 0.969 [95% confidence interval (CI) 0.967-0.971]) per year in the richest quintile and by 1.2% (HR 0.988 [95% CI 0.987-0.990]) per year in the poorest quintile. The corresponding values for breast cancer were 4.3% (HR 0.957 [95% CI 0.951-0.964]) and 2.0% (HR 0.980 [95% CI 0.975-0.986]); for lung cancer, 1.4% (HR 0.986 [95% CI 0.982 0.990]) and 0.3% (HR 0.997 [95% CI 0.995-1.000]); for colorectal cancer, 3.7% (HR 0.963 [95% CI 0.958-0.968]) and 1.8% (HR 0.982 [95% CI 0.978-0.985]); and for head and neck cancer, 3.1% (HR 0.969 [95% CI 0.958-0.979]) and 1.0% (HR 0.990 [95% CI 0.983-0.996]). INTERPRETATION: Between 1993 and 2009, cancer-specific survival in Ontario improved more among patients from affluent communities than among those from poorer communities. This phenomenon cannot be explained by increased disparity in income. PMID- 28877915 TI - Plasma Concentrations of Afamin Are Associated With Prevalent and Incident Type 2 Diabetes: A Pooled Analysis in More Than 20,000 Individuals. AB - OBJECTIVE: The human vitamin E-binding glycoprotein afamin is primarily expressed in the liver and has been associated with prevalent and incident metabolic syndrome. These data were in line with observations in transgenic mice. We thus investigated whether afamin concentrations are associated with prediabetes, type 2 diabetes, and insulin resistance (IR). RESEARCH DESIGN AND METHODS: Individual level baseline (n = 20,136) and follow-up data (n = 14,017) of eight prospective cohort studies were investigated. Study-level data were combined using random effects meta-analyses. Main outcomes were prevalent and incident type 2 diabetes, prediabetes, and IR. Discrimination and reclassification of participants was analyzed for incident type 2 diabetes. RESULTS: Mean afamin concentrations between studies ranged from 61 to 73 mg/L. The eight studies included 1,398 prevalent and 585 incident cases of type 2 diabetes. Each increase of afamin by 10 mg/L was associated with prevalent type 2 diabetes (odds ratio [OR] 1.19 [95% CI 1.12-1.26], P = 5.96 * 10-8). Afamin was positively associated with IR assessed by HOMA-IR (beta 0.110 [95% CI 0.089-0.132], P = 1.37 * 10-23). Most importantly, afamin measured at baseline was an independent predictor for 585 incident cases of type 2 diabetes (OR 1.30 [95% CI 1.23-1.38], P = 3.53 * 10-19) and showed a significant and valuable gain in risk classification accuracy when added to this extended adjustment model. CONCLUSIONS: This pooled analysis in >20,000 individuals showed that afamin is strongly associated with IR, prevalence, and incidence of type 2 diabetes independent of major metabolic risk factors or parameters. Afamin might be a promising novel marker for the identification of individuals at high risk for the development of type 2 diabetes. PMID- 28877918 TI - Very Deep Convolutional Neural Networks for Morphologic Classification of Erythrocytes. AB - BACKGROUND: Morphologic profiling of the erythrocyte population is a widely used and clinically valuable diagnostic modality, but one that relies on a slow manual process associated with significant labor cost and limited reproducibility. Automated profiling of erythrocytes from digital images by capable machine learning approaches would augment the throughput and value of morphologic analysis. To this end, we sought to evaluate the performance of leading implementation strategies for convolutional neural networks (CNNs) when applied to classification of erythrocytes based on morphology. METHODS: Erythrocytes were manually classified into 1 of 10 classes using a custom-developed Web application. Using recent literature to guide architectural considerations for neural network design, we implemented a "very deep" CNN, consisting of >150 layers, with dense shortcut connections. RESULTS: The final database comprised 3737 labeled cells. Ensemble model predictions on unseen data demonstrated a harmonic mean of recall and precision metrics of 92.70% and 89.39%, respectively. Of the 748 cells in the test set, 23 misclassification errors were made, with a correct classification frequency of 90.60%, represented as a harmonic mean across the 10 morphologic classes. CONCLUSIONS: These findings indicate that erythrocyte morphology profiles could be measured with a high degree of accuracy with "very deep" CNNs. Further, these data support future efforts to expand classes and optimize practical performance in a clinical environment as a prelude to full implementation as a clinical tool. PMID- 28877919 TI - High Lipoprotein(a) and Low Risk of Major Bleeding in Brain and Airways in the General Population: a Mendelian Randomization Study. AB - BACKGROUND: The physiological role of lipoprotein(a) is unclear; however, lipoprotein(a) may play a role in hemostasis and wound healing. We tested the hypothesis that high lipoprotein(a) concentrations are associated with low risk of major bleeding in the brain and airways both observationally and causally (from human genetics). METHODS: We examined 109169 individuals from the Copenhagen City Heart Study and the Copenhagen General Population study, 2 similar prospective studies conducted in the Danish general population. Individuals had information on plasma lipoprotein(a) concentrations (n = 59980), LPA kringle-IV type 2 (KIV-2) number of repeats (n = 98965), and/or LPA single nucleotide polymorphism rs10455872 associated with high lipoprotein(a) concentrations (n = 109 169), and information on hospital contacts or death due to major bleeding in brain and airways from registers. RESULTS: Using extreme phenotypes or genotypes, the multifactorially adjusted hazard ratio for major bleeding in the brain and airways was 0.84 (95%CI: 0.71-0.99) for lipoprotein(a), >800 mg/L vs <110 mg/L; 0.83 (0.73-0.96) for KIV-2, <24 vs >35 number of repeats; and 0.89 (0.81-0.97) for rs10455872 carriers (heterozygotes + homozygotes) vs noncarriers. The corresponding hazard ratios were 0.89 (0.82-0.98) for heterozygotes and 0.59 (0.36-0.98) for homozygotes separately vs rs10455872 noncarriers. Also, for a 1 standard deviation higher lipoprotein(a) (= 310 mg/L), the hazard ratio for major bleeding in the brain and airways was 0.95 (95%CI: 0.91-1.00) observationally, 0.89 (0.80-0.98) causally based on LPA KIV-2 number of repeats, and 0.94 (0.87-1.02) causally based on LPA rs10455872. CONCLUSIONS: High lipoprotein(a) concentrations were associated with lower risk of major bleeding in the brain and airways observationally and causally. This indicates that lipoprotein(a) may play a role in hemostasis and wound healing. PMID- 28877920 TI - N-Acetylaspartate and 2-Hydroxyglutarate Assessed in Human Brain Tissue by Mass Spectrometry as Neuronal Markers of Oncogenesis. PMID- 28877921 TI - Author's reply to Shepherd and Beerstecher. PMID- 28877922 TI - Plausible link between circa'bi'dian activity rhythms and circadian clock systems in the large black chafer Holotrichia parallela. AB - Two-day rhythms, referred to as circa'bi'dian rhythms, have been reported in humans and mosquitos. However, these rhythms only appear under constant conditions, and the functional mechanisms of 2-day rhythms were unknown. Here, we report clear circabidian rhythms of large black chafers (Holotrichia parallela, Coleoptera: Scarabaeidae) in both the laboratory and field. Under 12 h:12 h light:dark (L:D) conditions at 25 degrees C, H. parallela appeared on the ground at the beginning of the dark phase every 2 days. Under constant darkness, H. parallela exhibited free-running with a period of 47.9+/-0.3 h, suggesting the existence of a clear circabidian rhythm entrained to two 12 h:12 h L:D cycles. Phase responses of the circabidian rhythm to light pulses occurred under constant darkness in a phase-dependent manner. Phase responses suggest that there are two circadian cycles, each consisting of a less-responsive and more-responsive period, in a circabidian oscillation, and the circabidian rhythm is driven by the circadian clock. A mark-recapture study showed that beetles repeatedly appeared on the same tree approximately every 2 days. However, the periodicity was not as rigid as that observed under laboratory conditions in that individuals often switched appearance days. For instance, a large precipitation made the 2-day rhythm shift phase by half a cycle of the rhythm at a time. We propose a novel function of the circadian clock characterized by the release of an output signal every two cycles to produce the 2-day rhythm. PMID- 28877923 TI - Natural epigenetic variation within and among six subspecies of the house sparrow, Passer domesticus. AB - Epigenetic modifications can respond rapidly to environmental changes and can shape phenotypic variation in accordance with environmental stimuli. One of the most studied epigenetic marks is DNA methylation. In the present study, we used the methylation-sensitive amplified polymorphism (MSAP) technique to investigate the natural variation in DNA methylation within and among subspecies of the house sparrow, Passer domesticus We focused on five subspecies from the Middle East because they show great variation in many ecological traits and because this region is the probable origin for the house sparrow's commensal relationship with humans. We analysed house sparrows from Spain as an outgroup. The level of variation in DNA methylation was similar among the five house sparrow subspecies from the Middle East despite high phenotypic and environmental variation, but the non-commensal subspecies was differentiated from the other four (commensal) Middle Eastern subspecies. Further, the European subspecies was differentiated from all other subspecies in DNA methylation. Our results indicate that variation in DNA methylation does not strictly follow subspecies designations. We detected a correlation between methylation level and some morphological traits, such as standardized bill length, and we suggest that part of the high morphological variation in the native populations of the house sparrow is influenced by differentially methylated regions in specific loci throughout the genome. We also detected 10 differentially methylated loci among subspecies and three loci that differentiated between commensal or non-commensal status. Therefore, the MSAP technique detected larger scale differences among the European and non-commensal subspecies, but did not detect finer scale differences among the other Middle Eastern subspecies. PMID- 28877924 TI - GP shortage is a mismatch problem. PMID- 28877925 TI - The impact of vitamin D status on hungry bone syndrome after surgery for primary hyperparathyroidism. AB - OBJECTIVE: Prolonged hypocalcemia but normal intact parathyroid hormone (iPTH) levels after surgery for primary hyperparathyroidism (PHPT) are referred to as 'hungry bone syndrome' (HBS). The aim was to evaluate preoperative risk factors for HBS with a focus on the impact of 25-hydroxyvitamin D (25(OH)D) deficiency. DESIGN: Patients having undergone initial successful surgery for sporadic PHPT within 6 years were considered for retrospective analysis. METHODS: A total of 385 patients were evaluated, of whom 33 (8.6%) developed HBS influencing negatively the postoperative bone metabolism. All patients underwent biochemical evaluations two days before parathyroid surgery and were followed biochemically on a daily basis in the first postoperative week and thereafter at 8 weeks and 6 months. CONCLUSIONS: No relationship was established between preoperative 25(OH)D deficiency and HBS. The only significant risk factor for HBS in multivariable analysis was high levels of preoperative iPTH. As HBS therefore cannot be predicted preoperatively, we recommend a consistent postoperative calcium and vitamin D supplementation to improve the bone metabolism. PMID- 28877926 TI - Effectiveness of Quality Improvement Strategies for the Management of CKD: A Meta Analysis. AB - BACKGROUND AND OBJECTIVES: Quality improvement interventions have enhanced care for other chronic illnesses, but their effectiveness for patients with CKD is unknown. We sought to determine the effects of quality improvement strategies on clinical outcomes in adult patients with nondialysis-requiring CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a systematic review of randomized trials, searching Medline and the Cochrane Effective Practice and Organization of Care database from January of 2003 to April of 2015. Eligible studies evaluated one or more of 11 prespecified quality improvement strategies, and prespecified study outcomes included at least one process of care measure, surrogate outcome, or hard clinical outcome. We used a random effects model to estimate the pooled risk ratio (RR; dichotomous data) or the mean difference (continuous data). RESULTS: We reviewed 15 patient-level randomized trials (n=3298 patients), and six cluster-randomized trials (n=30,042 patients). Quality improvement strategies reduced dialysis incidence (seven trials; RR, 0.85; 95% confidence interval [95% CI], 0.74 to 0.97) and LDL cholesterol concentrations (four trials; mean difference, -17.6 mg/dl; 95% CI, -28.7 to -6.5), and increased the likelihood that patients received renin-angiotensin-aldosterone system inhibitors (nine trials; RR, 1.16; 95% CI, 1.06 to 1.27). We did not observe statistically significant effects on mortality, cardiovascular events, eGFR, glycated hemoglobin, and systolic or diastolic BP. CONCLUSIONS: Quality improvement interventions yielded significant beneficial effects on three elements of CKD care. Estimates of the effectiveness of quality improvement strategies were limited by study number and adherence to quality improvement principles. PODCAST: This article contains a podcast at https://www.asn online.org/media/podcast/CJASN/2017_09_06_CJASNPodcast_17_10.mp3. PMID- 28877927 TI - Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice. AB - The aim of this study was to evaluate the protective efficacy of MTBK_24820, a complete form of PPE39 protein derived from a predominant Beijing/K strain of Mycobacterium tuberculosis in South Korea. Mice were immunized with MTKB_24820, M. bovis Bacilli Calmette-Guerin (BCG), or adjuvant prior to a high-dosed Beijing/K strain aerosol infection. After 4 and 9 weeks, bacterial loads were determined and histopathologic and immunologic features in the lungs and spleens of the M. tuberculosis-infected mice were analyzed. Putative immunogenic T-cell epitopes were examined using synthetic overlapping peptides. Successful immunization of MTBK_24820 in mice was confirmed by increased IgG responses (P < 0.05) and recalled gamma interferon (IFN-gamma), interleukin-2 (IL-2), IL-6, and IL-17 responses (P < 0.05 or P < 0.01) to MTBK_24820. After challenge with the Beijing/K strain, an approximately 0.5 to 1.0 log10 reduction in CFU in lungs and fewer lung inflammation lesions were observed in MTBK_24820-immunized mice compared to those for control mice. Moreover, MTBK_24820 immunization elicited significantly higher numbers of CD4+ T cells producing protective cytokines, such as IFN-gamma and IL-17, in lungs and spleens (P < 0.01) and CD4+ multifunctional T cells producing IFN-gamma, tumor necrosis factor alpha (TNF-alpha), and/or IL 17 (P < 0.01) than in control mice, suggesting protection comparable to that of BCG against the hypervirulent Beijing/K strain. The dominant immunogenic T-cell epitopes that induced IFN-gamma production were at the N terminus (amino acids 85 to 102 and 217 to 234). Its vaccine potential, along with protective immune responses in vivo, may be informative for vaccine development, particularly in regions where the M. tuberculosis Beijing/K-strain is frequently isolated from TB patients. PMID- 28877928 TI - Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor Specific Antibodies in Human Recipients. AB - Edema toxin (ET), composed of edema factor (EF) and protective antigen (PA), is a virulence factor of Bacillus anthracis that alters host immune cell function and contributes to anthrax disease. Anthrax vaccine precipitated (AVP) contains low but detectable levels of EF and can elicit EF-specific antibodies in human recipients of AVP. Active and passive vaccination of mice with EF can contribute to protection from challenge with Bacillus anthracis spores or ET. This study compared humoral responses to ET in recipients of AVP (n = 33) versus anthrax vaccine adsorbed (AVA; n = 66), matched for number of vaccinations and time postvaccination, and further determined whether EF antibodies elicited by AVP contribute to ET neutralization. AVP induced higher incidence (77.8%) and titer (229.8 +/- 58.6) of EF antibodies than AVA (4.2% and 7.8 +/- 8.3, respectively), reflecting the reported low but detectable presence of EF in AVP. In contrast, PA IgG levels and ET neutralization measured using a luciferase-based cyclic AMP reporter assay were robust and did not differ between the two vaccine groups. Multiple regression analysis failed to detect an independent contribution of EF antibodies to ET neutralization in AVP recipients; however, EF antibodies purified from AVP sera neutralized ET. Serum samples from at least half of EF IgG positive AVP recipients bound to nine decapeptides located in EF domains II and III. Although PA antibodies are primarily responsible for ET neutralization in recipients of AVP, increased amounts of an EF component should be investigated for the capacity to enhance next-generation, PA-based vaccines. PMID- 28877930 TI - Viral taxonomy: The effect of metagenomics on understanding the diversity and evolution of viruses. PMID- 28877929 TI - Merozoite Surface Protein 1 from Plasmodium falciparum Is a Major Target of Opsonizing Antibodies in Individuals with Acquired Immunity against Malaria. AB - Naturally acquired immunity against malaria is largely mediated by serum antibodies controlling levels of blood-stage parasites. A limited understanding of the antigenic targets and functional mechanisms of protective antibodies has hampered the development of efficient malaria vaccines. Besides directly inhibiting the growth of Plasmodium parasites, antibodies can opsonize merozoites and recruit immune effector cells such as monocytes and neutrophils. Antibodies against the vaccine candidate merozoite surface protein 1 (MSP-1) are acquired during natural infections and have been associated with protection against malaria in several epidemiological studies. Here we analyzed serum antibodies from semi-immune individuals from Burkina Faso for their potential (i) to directly inhibit the growth of P. falciparum blood stages in vitro and (ii) to opsonize merozoites and to induce the antibody-dependent respiratory burst (ADRB) activity of neutrophils. While a few sera that directly inhibited the growth of P. falciparum blood stages were identified, immunoglobulin G (IgG) from all individuals clearly mediated the activation of neutrophils. The level of neutrophil activation correlated with levels of antibodies to MSP-1, and affinity purified MSP-1-specific antibodies elicited ADRB activity. Furthermore, immunization of nonhuman primates with recombinant full-size MSP-1 induced antibodies that efficiently opsonized P. falciparum merozoites. Reversing the function by preincubation with recombinant antigens allowed us to quantify the contribution of MSP-1 to the antiparasitic effect of serum antibodies. Our data suggest that MSP-1, especially the partially conserved subunit MSP-183, is a major target of opsonizing antibodies acquired during natural exposure to malaria. Induction of opsonizing antibodies might be a crucial effector mechanism for MSP-1-based malaria vaccines. PMID- 28877931 TI - Prostaglandin E2 Inhibits Histamine-Evoked Ca2+ Release in Human Aortic Smooth Muscle Cells through Hyperactive cAMP Signaling Junctions and Protein Kinase A. AB - In human aortic smooth muscle cells, prostaglandin E2 (PGE2) stimulates adenylyl cyclase (AC) and attenuates the increase in intracellular free Ca2+ concentration evoked by activation of histamine H1 receptors. The mechanisms are not resolved. We show that cAMP mediates inhibition of histamine-evoked Ca2+ signals by PGE2 Exchange proteins activated by cAMP were not required, but the effects were attenuated by inhibition of cAMP-dependent protein kinase (PKA). PGE2 had no effect on the Ca2+ signals evoked by protease-activated receptors, heterologously expressed muscarinic M3 receptors, or by direct activation of inositol 1,4,5 trisphosphate (IP3) receptors by photolysis of caged IP3 The rate of Ca2+ removal from the cytosol was unaffected by PGE2, but PGE2 attenuated histamine-evoked IP3 accumulation. Substantial inhibition of AC had no effect on the concentration dependent inhibition of Ca2+ signals by PGE2 or butaprost (to activate EP2 receptors selectively), but it modestly attenuated responses to EP4 receptors, activation of which generated less cAMP than EP2 receptors. We conclude that inhibition of histamine-evoked Ca2+ signals by PGE2 occurs through "hyperactive signaling junctions," wherein cAMP is locally delivered to PKA at supersaturating concentrations to cause uncoupling of H1 receptors from phospholipase C. This sequence allows digital signaling from PGE2 receptors, through cAMP and PKA, to histamine-evoked Ca2+ signals. PMID- 28877932 TI - Detection and genomic characterization of a mammary-like adenocarcinoma. AB - Whole-genome and transcriptome sequencing were performed to identify potential therapeutic strategies in the absence of viable treatment options for a patient initially diagnosed with vulvar adenocarcinoma. Genomic events were prioritized by comparison against variant distributions in the TCGA pan-cancer data set and complemented with detailed transcriptome sequencing and copy-number analysis. These findings were considered against published scientific literature in order to evaluate the functional effects of potentially relevant genomic events. Analysis of the transcriptome against a background of 27 TCGA cancer types led to reclassification of the tumor as a primary HER2+ mammary-like adenocarcinoma of the vulva. This revised diagnosis was subsequently confirmed by follow-up immunohistochemistry for a mammary-like adenocarcinoma. The patient was treated with chemotherapy and targeted therapies for HER2+ breast cancer. The detailed pathology and genomic findings of this case are presented herein. PMID- 28877933 TI - Upgrading Supply Chain Management Systems to Improve Availability of Medicines in Tanzania: Evaluation of Performance and Cost Effects. AB - BACKGROUND: To address challenges in public health supply chain performance, Tanzania invested in a national logistics management unit (LMU) and a national electronic logistics management information system (eLMIS). This evaluation examined the impact of those 2 key management upgrades approximately 1 year after they were introduced. METHODS: We used a nonexperimental pre-post study design to compare the previous system with the upgraded management system. We collected baseline data from August to November 2013. We conducted round 1 of post implementation data collection during April and May 2015, about 1 year after implementation of the upgrades. We evaluated key indicators of data use and reporting; supply chain management practices such as storage and supervision; supply chain performance including stock-out and expiry rates; and supply chain cost and savings. We analyzed the data using a range of techniques including statistical testing of baseline and round-1 results, and cost, cost effectiveness, and return on investment analysis. RESULTS: The upgrades were associated with improvements in data use, accessibility, visibility, and transparency; planning, control, and monitoring; support for quantification; stock-out rates; stock-out duration; commodity expiry; and forecast error. The upgraded system was more costly, but it was also more efficient, particularly when adjusting for the performance improvements. The upgrades also generated substantial savings that defrayed some, but not all, of the investment costs. CONCLUSION: Upgrades to Tanzania's supply chain management systems created multiple and complex pathways to impact. One year after implementation, the LMU and eLMIS brought about performance improvements through better data use and through improvements in some, but not all, management practices. Furthermore, the upgrades-while not inexpensive-contributed to greater system efficiency and modest savings. PMID- 28877934 TI - Identification of senescent cell surface targetable protein DPP4. AB - Senescent cell accumulation in aging tissues is linked to age-associated diseases and declining function, prompting efforts to eliminate them. Mass spectrometry analysis revealed that DPP4 (dipeptidyl peptidase 4) was selectively expressed on the surface of senescent, but not proliferating, human diploid fibroblasts. Importantly, the differential presence of DPP4 allowed flow cytometry-mediated isolation of senescent cells using anti-DPP4 antibodies. Moreover, antibody dependent cell-mediated cytotoxicity (ADCC) assays revealed that the cell surface DPP4 preferentially sensitized senescent, but not dividing, fibroblasts to cytotoxicity by natural killer cells. In sum, the selective expression of DPP4 on the surface of senescent cells enables their preferential elimination. PMID- 28877935 TI - Targeting Aberrant p70S6K Activation for Estrogen Receptor-Negative Breast Cancer Prevention. AB - The prevention of estrogen receptor-negative (ER-) breast cancer remains a major challenge in the cancer prevention field, although antiestrogen and aromatase inhibitors have shown adequate efficacy in preventing estrogen receptor-positive (ER+) breast cancer. Lack of commonly expressed, druggable targets is a major obstacle for meeting this challenge. Previously, we detected the activation of Akt signaling pathway in atypical hyperplasic early-stage lesions of patients. In the current study, we found that Akt and the downstream 70 kDa ribosomal protein S6 kinase (p70S6K) signaling pathway was highly activated in ER- premalignant breast lesions and ER- breast cancer. In addition, p70S6K activation induced transformation of ER- human mammary epithelial cells (hMEC). Therefore, we explored the potential of targeting Akt/p70S6K in the p70S6K activated, ER- hMEC models and mouse mammary tumor models for the prevention of ER- breast cancer. We found that a clinically applicable Akt/p70S6K dual inhibitor, LY2780301, drastically decreased proliferation of hMECs with ErbB2-induced p70S6K activation via Cyclin B1 inhibition and cell-cycle blockade at G0-G1 phase, while it did not significantly reverse the abnormal acinar morphology of these hMECs. In addition, a brief treatment of LY2780301 in MMTV-neu mice that developed atypical hyperplasia (ADH) and mammary intraepithelial neoplasia (MIN) lesions with activated p70S6K was sufficient to suppress S6 phosphorylation and decrease cell proliferation in hyperplasic MECs. In summary, targeting the aberrant Akt/p70S6K activation in ER- hMEC models in vitro and in the MMTV-neu transgenic mouse model in vivo effectively inhibited Akt/S6K signaling and reduced proliferation of hMECs in vitro and ADH/MIN lesions in vivo, indicating its potential in prevention of p70S6K activated ER- breast cancer. Cancer Prev Res; 10(11); 641 50. (c)2017 AACR. PMID- 28877937 TI - An Essential Role of Maspin in Embryogenesis and Tumor Suppression-Letter. PMID- 28877936 TI - Alterations in Bronchial Airway miRNA Expression for Lung Cancer Detection. AB - We have previously shown that gene expression alterations in normal-appearing bronchial epithelial cells can serve as a lung cancer detection biomarker in smokers. Given that miRNAs regulate airway gene expression responses to smoking, we evaluated whether miRNA expression is also altered in the bronchial epithelium of smokers with lung cancer. Using epithelial brushings from the mainstem bronchus of patients undergoing bronchoscopy for suspected lung cancer (as part of the AEGIS-1/2 clinical trials), we profiled miRNA expression via small-RNA sequencing from 347 current and former smokers for which gene expression data were also available. Patients were followed for one year postbronchoscopy until a final diagnosis of lung cancer (n = 194) or benign disease (n = 153) was made. Following removal of 6 low-quality samples, we used 138 patients (AEGIS-1) as a discovery set to identify four miRNAs (miR-146a-5p, miR-324-5p, miR-223-3p, and miR-223-5p) that were downregulated in the bronchial airway of lung cancer patients (ANOVA P < 0.002, FDR < 0.2). The expression of these miRNAs is significantly more negatively correlated with the expression of their mRNA targets than with the expression of other nontarget genes (K-S P < 0.05). Furthermore, these mRNA targets are enriched among genes whose expression is elevated in cancer patients (GSEA FDR < 0.001). Finally, we found that the addition of miR-146a-5p to an existing mRNA biomarker for lung cancer significantly improves its performance (AUC) in the 203 samples (AEGIS-1/2) serving an independent test set (DeLong P < 0.05). Our findings suggest that there are miRNAs whose expression is altered in the cytologically normal bronchial epithelium of smokers with lung cancer, and that they may regulate cancer-associated gene expression differences. Cancer Prev Res; 10(11); 651-9. (c)2017 AACR. PMID- 28877938 TI - An Essential Role of Maspin in Embryogenesis and Tumor Suppression-Response. PMID- 28877939 TI - Daycare attendance and respiratory tract infections: a prospective birth cohort study. AB - OBJECTIVE: We explored the burden of respiratory tract infections (RTIs) in young children with regard to day-care initiation. DESIGN: Longitudinal prospective birth cohort study. SETTING AND METHODS: We recruited 1827 children for follow-up until the age of 24 months collecting diary data on RTIs and daycare. Children with continuous daycare type and complete data were divided into groups of centre based daycare (n=299), family day care (FDC) (n=245) and home care (n=350). Using repeated measures variance analyses, we analysed days per month with symptoms of respiratory tract infection, antibiotic treatments and parental absence from work for a period of 6 months prior to and 9 months after the start of daycare. RESULTS: We documented a significant effect of time and type of daycare, as well as a significant interaction between them for all outcome measures. There was a rise in mean days with symptoms from 3.79 (95% CI 3.04 to 4.53) during the month preceding centre-based daycare to 10.57 (95% CI 9.35 to 11.79) at 2 months after the start of centre-based daycare, with a subsequent decrease within the following 9 months. Similar patterns with a rise and decline were observed in the use of antibiotics and parental absences. The start of FDC had weaker effects. Our findings were not changed when taking into account confounding factors. CONCLUSIONS: Our study shows the rapid increase in respiratory infections after start of daycare and a relatively fast decline in the course of time with continued daycare. It is important to support families around the beginning of daycare. PMID- 28877940 TI - Qualitative meta-synthesis of barriers and facilitators that influence the implementation of community pharmacy services: perspectives of patients, nurses and general medical practitioners. AB - OBJECTIVES: The integration of community pharmacy services (CPSs) into primary care practice can be enhanced by assessing (and further addressing) the elements that enable (ie, facilitators) or hinder (ie, barriers) the implementation of such CPSs. These elements have been widely researched from the perspective of pharmacists but not from the perspectives of other stakeholders who can interact with and influence the implementation of CPSs. The aim of this study was to synthesise the literature on patients', general practitioners' (GPs) and nurses' perspectives of CPSs to identify barriers and facilitators to their implementation in Australia. METHODS: A meta-synthesis of qualitative studies was performed. A systematic search in PubMed, Scopus and Informit was conducted to identify studies that explored patients', GPs' or nurses' views about CPSs in Australia. Thematic synthesis was performed to identify elements influencing CPS implementation, which were further classified using an ecological approach. RESULTS: Twenty-nine articles were included in the review, addressing 63 elements influencing CPS implementation. Elements were identified as a barrier, facilitator or both and were related to four ecological levels: individual patient (n=14), interpersonal (n=24), organisational (n=16) and community and healthcare system (n=9). It was found that patients, nurses and GPs identified elements reported in previous pharmacist-informed studies, such as pharmacist's training/education or financial remuneration, but also new elements, such as patients' capability to follow service's procedures, the relationships between GP and pharmacy professional bodies or the availability of multidisciplinary training/education. CONCLUSIONS: Patients, GPs and nurses can describe a large number of elements influencing CPS implementation. These elements can be combined with previous findings in pharmacists-informed studies to produce a comprehensive framework to assess barriers and facilitators to CPS implementation. This framework can be used by pharmacy service planners and policy makers to improve the analysis of the contexts in which CPSs are implemented. PMID- 28877941 TI - What treatments work for anxiety in children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)? Systematic review. AB - OBJECTIVES: Anxiety is more prevalent in children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) than in the general population. A systematic review was carried out to identify which treatment methods are most effective for children with CFS and anxiety. DESIGN: Systematic review using search terms entered into the Cochrane library and Ovid to search the databases Medline, Embase and psychINFO. PARTICIPANTS: Studies were selected if participants were <18 years old, diagnosed with CFS/ME (using US Centers for Disease Control and Prevention, the National Institute for Health and Care Excellence or Oxford criteria) and had a valid assessment of anxiety. INTERVENTIONS: We included observational studies and randomised controlled trials. COMPARISON: Any or none. OUTCOMES: Change in anxiety diagnostic status and/or change in anxiety severity on a validated measure of anxiety from pretreatment to post-treatment. RESULTS: The review identified nine papers from eight studies that met the inclusion criteria. None of the studies specifically targeted anxiety but six studies tested an intervention and measured anxiety as a secondary outcome. Of these studies, four used a cognitive behavioural therapy (CBT)-type approach to treat CFS/ME, one used a behavioural approach and one compared a drug treatment, gammaglobulin with a placebo. Three of the CBT-type studies described an improvement in anxiety as did the trial of gammaglobulin. As none of the studies stratified outcomes according to anxiety diagnostic status or severity, we were unable to determine whether anxiety changed prognosis or whether treatments were equally effective in those with comorbid anxiety compared with those without. CONCLUSION: We do not know what treatment should be offered for children with both anxiety and CFS/ME. Further research is therefore required to answer this question. TRIAL REGISTRATION NUMBER: This review was registered on Prospective Register of Systematic Review Protocols (PROSPERO) and the protocol is available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016043488. PMID- 28877942 TI - Changes in mortality inequalities across occupations in Japan: a national register based study of absolute and relative measures, 1980-2010. AB - OBJECTIVE: Changes in mortality inequalities across socioeconomic groups have been a substantial public health concern worldwide. We investigated changes in absolute/relative mortality inequalities across occupations, and the contribution of different diseases to inequalities in tandem with the restructuring of the Japanese economy. METHODS: Using complete Japanese national death registries from 5 year intervals (1980-2010), all cause and cause specific age standardised mortality rates (ASMR per 100 000 people standardised using the Japanese standard population in 1985, aged 30-59 years) across 12 occupations were computed. Absolute and relative inequalities were measured in ASMR differences (RDs) and ASMR ratios (RRs) among occupations in comparison with manufacturing workers (reference). We also estimated the changing contribution of different diseases by calculating the differences in ASMR change between 1995 and 2010 for occupations and reference. RESULTS: All cause ASMRs tended to decrease in both sexes over the three decades except for male managers (increased by 71% points, 1995-2010). RDs across occupations were reduced for both sexes (civil servants 233.5 to -1.9 for men; sales workers 63.3 to 4.5 for women) but RRs increased for some occupations (professional workers 1.38 to 1.70; service workers 2.35 to 3.73) for men and decreased for women from 1980 to 2010. Male relative inequalities widened among farmer, fishery and service workers, because the percentage declines were smaller in these occupations. Cerebrovascular disease and cancer were the main causes of the decrease in mortality inequalities among sexes but the incidence of suicide increased among men, thereby increasing sex related inequalities. CONCLUSIONS: Absolute inequality trends in mortality across occupations decreased in both sexes, while relative inequality trends were heterogeneous in Japan. The main drivers of narrowing and widening mortality inequalities were cerebrovascular disease and suicide, respectively. Future public health efforts will benefit from eliminating residual inequalities in mortality by considering the contribution of the causes of death and socioeconomic status stratification. PMID- 28877944 TI - Effects of external inspection on sepsis detection and treatment: a study protocol for a quasiexperimental study with a stepped-wedge design. AB - INTRODUCTION: Inspections are widely used in health care as a means to improve the health services delivered to patients. Despite their widespread use, there is little evidence of their effect. The mechanisms for how inspections can promote change are poorly understood. In this study, we use a national inspection campaign of sepsis detection and initial treatment in hospitals as case to: (1) Explore how inspections affect the involved organizations. (2) Evaluate what effect external inspections have on the process of delivering care to patients, measured by change in indicators reflecting how sepsis detection and treatment is carried out. (3) Evaluate whether external inspections affect patient outcomes, measured as change in the 30-day mortality rate and length of hospital stay. METHODS AND ANALYSIS: The intervention that we study is inspections of sepsis detection and treatment in hospitals. The intervention will be rolled out sequentially during 12 months to 24 hospitals. Our effect measures are change on indicators related to the detection and treatment of sepsis, the 30-day mortality rate and length of hospital stay. We collect data from patient records at baseline, before the inspections, and at 8 and 14 months after the inspections. We use logistic regression models and linear regression models to compare the various effect measurements between the intervention and control periods. All the models will include time as a covariate to adjust for potential secular changes in the effect measurements during the study period. We collect qualitative data before and after the inspections, and we will conduct a thematic content analysis to explore how inspections affect the involved organisations. ETHICS AND DISSEMINATION: The study has obtained ethical approval by the Regional Ethics Committee of Norway Nord and the Norwegian Data Protection Authority. It is registered at www.clinicaltrials.gov (Identifier: NCT02747121). Results will be reported in international peer-reviewed journals. TRIAL REGISTRATION: NCT02747121; Pre-results. PMID- 28877943 TI - Systematic review of the evidence on orthotic devices for the management of knee instability related to neuromuscular and central nervous system disorders. AB - OBJECTIVES: To assess the effectiveness of orthotic devices for the management of instability of the knee in adults with a neuromuscular disorder or central nervous system disorder. DESIGN: A systematic review of primary studies. SETTING: Community. PARTICIPANTS: Adults with a neuromuscular disorder or central nervous system disorder and impaired walking ability due to instability of the knee. INTERVENTIONS: Orthoses with the clinical aim of controlling knee instability, for example, knee-ankle-foot orthoses, ankle-foot orthoses and knee orthoses or mixed design with no restrictions in design or material. PRIMARY AND SECONDARY OUTCOME MEASURES: Condition-specific or generic patient-reported outcome measures assessing function, disability, independence, activities of daily living, quality of life or psychosocial outcomes; pain; walking ability; functional assessments; biomechanical analysis; adverse effects; usage; patient satisfaction and the acceptability of a device; and resource utilisation data. RESULTS: Twenty-one studies including 478 patients were included. Orthotic devices were evaluated in patients with postpolio syndrome, poststroke syndrome, inclusion body myositis and spinal cord injury. The review included 2 randomised controlled trials (RCTs), 3 non-randomised controlled studies and 16 case series. Most were small, single-centre studies with only 6 of 21 following patients for 1 year or longer. They met between one and five of nine quality criteria and reported methods and results poorly. They mainly assessed outcomes related to gait analysis and energy consumption with limited use of standardised, validated, patient-reported outcome measures. There was an absence of evidence on outcomes of direct importance to patients such as reduction in pain and falls. CONCLUSIONS: There is a need for high-quality research, particularly RCTs, of orthotic devices for knee instability related to neuromuscular and central nervous system conditions. This research should address outcomes important to patients. There may also be value in developing a national registry. REGISTRATION NUMBER SYSTEMATIC REVIEW: PROSPERO (CRD42014010180). PMID- 28877945 TI - Qualitative study to develop processes and tools for the assessment and tracking of African institutions' capacity for operational health research. AB - OBJECTIVES: Research is key to achieving global development goals. Our objectives were to develop and test an evidence-informed process for assessing health research management and support systems (RMSS) in four African universities and for tracking interventions to address capacity gaps. SETTING: Four African universities. PARTICIPANTS: 83 university staff and students from 11 cadres. INTERVENTION/METHODS: A literature-informed 'benchmark' was developed and used to itemise all components of a university's health RMSS. Data on all components were collected during site visits to four African universities using interview guides, document reviews and facilities observation guides. Gaps in RMSS capacity were identified against the benchmark and institutional action plans developed to remedy gaps. Progress against indicators was tracked over 15 months and common challenges and successes identified. RESULTS: Common gaps in operational health research capacity included no accessible research strategy, a lack of research e tracking capability and inadequate quality checks for proposal submissions and contracts. Feedback indicated that the capacity assessment was comprehensive and generated practical actions, several of which were no-cost. Regular follow-up helped to maintain focus on activities to strengthen health research capacity in the face of challenges. CONCLUSIONS: Identification of each institutions' strengths and weaknesses against an evidence-informed benchmark enabled them to identify gaps in in their operational health research systems, to develop prioritised action plans, to justify resource requests to fulfil the plans and to track progress in strengthening RMSS. Use of a standard benchmark, approach and tools enabled comparisons across institutions which has accelerated production of evidence about the science of research capacity strengthening. The tools could be used by institutions seeking to understand their strengths and to address gaps in research capacity. Research capacity gaps that were common to several institutions could be a 'smart' investment for governments and health research funders. PMID- 28877946 TI - Cohort profile: maternal lifestyle and diet in relation to pregnancy, postpartum and infant health outcomes in Vietnam: A multicentre prospective cohort study. AB - PURPOSE: To determine modifiable maternal risk factors for adverse pregnancy, postpartum maternal and child health outcomes in Vietnam. PARTICIPANTS: This prospective cohort study included pregnant women seeking prenatal care at six hospitals in three large cities in Vietnam. After enrolment, eligible participants who gave their consent to participate in the study were interviewed at 24-28 weeks' gestation. Glucose testing was conducted and blood pressure was measured during this period. Each participant will be assessed prospectively during their postnatal visits at delivery, 1, 3, 6, 12, 18 and 24 months, and will be followed up for 5 years. FINDINGS TO DATE: Of 2248 eligible pregnant women, 2030 were recruited (participation rate 90.3%) between August 2015 and July 2016. All participants completed the baseline assessment. Their mean (SD) age was 27.6 (5.3) years. The mean pre-pregnancy body mass index (BMI) was 20.2 (SD 2.6) kg/m2, with nearly two-thirds of participants having a normal pre pregnancy BMI (18.5 to <23.0 kg/m2) and one-quarter being underweight (pre pregnancy BMI <18.5 kg/m2). Overweight or obese mothers (pre-pregnancy BMI >=23.0 kg/m2) accounted for 12.8%. No pregnant women reported smoking during their pregnancy while 13.4% of them had continued drinking. 22.8% of participants had hyperglycaemia. Their mean systolic blood pressure was 105.6 (SD 8.2) mm Hg, and diastolic blood pressure was 67.4 (SD 7.5) mm Hg. FUTURE PLANS: The relationships of maternal lifestyle and nutritional status with the health outcomes of pregnancy, postpartum maternity and infants will be analysed. Meanwhile, participants will be closely tracked to minimise loss to follow-up. PMID- 28877947 TI - Influence of hospital volume on nephrectomy mortality and complications: a systematic review and meta-analysis stratified by surgical type. AB - OBJECTIVES: The provision of complex surgery is increasingly centralised to high volume (HV) specialist hospitals. Evidence to support nephrectomy centralisation however has been inconsistent. We conducted a systematic review and meta-analysis to determine the association between hospital case volumes and perioperative outcomes in radical nephrectomy, partial nephrectomy and nephrectomy with venous thrombectomy. METHODS: Medline, Embase and the Cochrane Library were searched for relevant studies published between 1990 and 2016. Pooled effect estimates for nephrectomy mortality and complications were calculated for each nephrectomy type using the DerSimonian and Laird random-effects model. Sensitivity analyses were performed to examine the effects of heterogeneity on the pooled effect estimates by excluding studies with the heaviest weighting, lowest methodological score and most likely to introduce bias from misclassification of standardised hospital volume. RESULTS: Some 226 372 patients from 16 publications were included in our review and meta-analysis. Considerable between-study heterogeneity was noted and only a few reported volume-outcome relationships specifically in partial nephrectomy or nephrectomy with venous thrombectomy.HV hospitals were correlated with a 26% and 52% reduction in mortality for radical nephrectomy (OR 0.74, 95% CI 0.61 to 0.90, p<0.01) and nephrectomy with venous thrombectomy (OR 0.48, 95% CI 0.29 to 0.81, p<0.01), respectively. In addition, radical nephrectomy in HV hospitals was associated with an 18% reduction in complications (OR 0.82, 95% CI 0.73 to 0.92, p<0.01). No significant volume-outcome relationship in mortality (OR 0.84, 95% CI 0.31 to 2.26, p=0.73) or complications (OR 0.85, 95% CI 0.55 to 1.30, p=0.44) was observed for partial nephrectomy. CONCLUSIONS: Our findings suggest that patients undergoing radical nephrectomy have improved outcomes when treated by HV hospitals. Evidence of this in partial nephrectomy and nephrectomy with venous thrombectomy is however not yet clear and could be secondary to the low number of studies included and the small patient number in our analyses. Further investigation is warranted to establish the full potential of nephrectomy centralisation particularly as existing evidence is of low quality with significant heterogeneity. PMID- 28877948 TI - APpropriAteness of percutaneous Coronary interventions in patients with ischaemic HEart disease in Italy: the APACHE pilot study. AB - OBJECTIVES: To first explore in Italy appropriateness of indication, adherence to guideline recommendations and mode of selection for coronary revascularisation. DESIGN: Retrospective, pilot study. SETTING: 22 percutaneous coronary intervention (PCI)-performing hospitals (20 patients per site), 13 (59%) with on site cardiac surgery. PARTICIPANTS: 440 patients who received PCI for stable coronary artery disease (CAD) or non-ST elevation acute coronary syndrome were independently selected in a 4:1 ratio with half diabetics. PRIMARY AND SECONDARY OUTCOME MEASURES: Proportion of patients who received appropriate PCI using validated appropriate use scores (ie, AUS>=7). Also, in patients with stable CAD, we examined adherence to the following European Society of Cardiology recommendations: (A) per cent of patients with complex coronary anatomy treated after heart team discussion; (B) per cent of fractional flow reserve-guided PCI for borderline stenoses in patients without documented ischaemia; (C) per cent of patients receiving guideline-directed medical therapy at the time of PCI as well as use of provocative test of ischaemia according to pretest probability (PTP) of CAD. RESULTS: Of the 401 mappable PCIs (91%), 38.7% (95% CI 33.9 to 43.6) were classified as appropriate, 47.6% (95% CI 42.7 to 52.6) as uncertain and 13.7% (95% CI 10.5% to 17.5%) as inappropriate. Median PTP in patients with stable CAD without known coronary anatomy was 69% (78% intermediate PTP, 22% high PTP). Ischaemia testing use was similar (p=0.71) in patients with intermediate (n=140, 63%) and with high PTP (n=40, 66%). In patients with stable CAD (n=352) guideline adherence to the three recommendations explored was: (A) 11%; (B) 25%; (C) 23%. AUS was higher in patients evaluated by the heart team as compared with patients who were not (7 (6.8) vs 5 (4.7); p=0.001). CONCLUSIONS: Use of heart team approaches and adherence to guideline recommendations on coronary revascularisation in a real-world setting is limited. This pilot study documents the feasibility of measuring appropriateness and guideline adherence in clinical practice and identifies substantial opportunities for quality improvement. TRIAL REGISTRATION NUMBER: NCT02748603. PMID- 28877949 TI - Feasibility randomised multicentre, double-blind, double-dummy controlled trial of anakinra, an interleukin-1 receptor antagonist versus intramuscular methylprednisolone for acute gout attacks in patients with chronic kidney disease (ASGARD): protocol study. AB - INTRODUCTION: Acute gout occurs in people with chronic kidney disease, who are commonly older people with comorbidities such as hypertension, heart disease and diabetes. Potentially harmful treatments are administered to these vulnerable patients due to a lack of clear evidence. Newly available treatment that targets a key inflammatory pathway in acute gout attacks provides an opportunity to undertake the first-ever trial specifically looking treating people with kidney disease. This paper describes the protocol for a feasibility randomised controlled trial (RCT) comparing anakinra, a novel interleukin-1 antagonist versus steroids in people with chronic kidney disease (ASGARD). METHODS AND ANALYSIS: ASGARD is a two-parallel group double-blind, double-dummy multicentre RCT comparing anakinra 100 mg, an interleukin-1 antagonist, subcutaneous for 5 days against intramuscular methylprednisolone 120 mg. The primary objective is to assess the feasibility of the trial design and procedures for a definitive RCT. The specific aims are: (1) test recruitment and retention rates and willingness to be randomised; (2) test eligibility criteria; (3) collect and analyse outcome data to inform sample and power calculations for a trial of efficacy; (4) collect economic data to inform a future economic evaluation estimating costs of treatment and (5) assess capacity of the project to scale up to a national multicentre trial. We will also gather qualitative insights from participants. It aims to recruit 32 patients with a 1:1 randomisation. Information from this feasibility study will help design a definitive trial and provide general information in designing acute gout studies. ETHICS AND DISSEMINATION: The London Central Ethics Committee approved the protocol. The results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: EudraCT No. 2015-001787-19, NCT/Clinicalstrials.gov No. NCT02578394, pre results, WHO Universal Trials Reference No. U1111-1175-1977. NIHR Grant PB-PG 0614-34090. PMID- 28877950 TI - Effects of complex interventions in 'skin cancer prevention and treatment': protocol for a mixed-method systematic review with qualitative comparative analysis. AB - INTRODUCTION: Occurring from ultraviolet radiation combined with impairing ozone levels, uncritical sun exposure and use of tanning beds an increasing number of people are affected by different types of skin cancer. But preventive interventions like skin cancer screening are still missing the evidence for effectiveness and therefore are criticised. Fundamental for an appropriate course of action is to approach the defined parameters as measures for effectiveness critically. A prerequisite should be the critical application of used parameter that are defined as measures for effectiveness. This research seeks to establish, through the available literature, the effects and conditions that prove the effectiveness of prevention strategies in skin cancer. METHOD AND ANALYSIS: A mixed-method approach is employed to combine quantitative to qualitative methods and answer what effects can display effectiveness considering time horizon, perspective and organisational level and what are essential and sufficient conditions to prove effectiveness and cost-effectiveness in skin cancer prevention strategies. A systematic review will be performed to spot studies from any design and assess the data quantitatively and qualitatively. Included studies from each key question will be summarised by characteristics like population, intervention, comparison, outcomes, study design, endpoints, effect estimator and so on. Beside statistical relevancies for a systematic review the qualitative method of qualitative comparative analysis (QCA) will be performed. The estimated outcomes from this review and QCA are the accomplishment and absence of effects that are appropriate for application in effectiveness assessments and further cost-effectiveness assessment. ETHICS AND DISSEMINATION: Formal ethical approval is not required as primary data will not be collected. TRIAL REGISTRATION NUMBER: International Prospective Register for Systematic Reviews number CRD42017053859. PMID- 28877951 TI - Psychological distress following a motor vehicle crash: evidence from a statewide retrospective study examining settlement times and costs of compensation claims. AB - OBJECTIVE: To determine whether psychological distress associated with musculoskeletal injuries sustained in a motor vehicle crash (MVC), regardless of time of onset, impacts compensation outcomes such as claim settlement times and costs. Second, to identify factors routinely collected by insurance companies that contribute to psychological distress during the compensation process. DESIGN: Statewide retrospective study. DATA SOURCE: Analysis of the New South Wales statewide (Australia) injury register for MVC survivors who lodged a compensation claim from 2011 to 2013. PARTICIPANTS: 6341 adults who sustained a musculoskeletal injury and who settled a claim for injury after an MVC. Participants included those diagnosed with psychological distress (n=607) versus those not (n=5734). MAIN OUTCOME MEASURES: Time to settlement and total costs of claims, as well as socio-demographic and injury characteristics that may contribute to elevated psychological distress, such as socio-economic disadvantage, and injury severity. RESULTS: Psychological distress in those with a musculoskeletal injury was associated with significantly longer settlement times (an additional 17 weeks) and considerably higher costs (an additional $A41 575.00 or 4.3 times more expensive). Multivariate logistic regression analysis identified risk factors for psychological distress including being female, social disadvantage, unemployment prior to the claim, not being at fault in the MVC, requiring ambulance transportation and rehabilitation as part of recovery. CONCLUSIONS: Results provide compelling evidence that psychological distress has an adverse impact on people with musculoskeletal injury as they progress through compensation. Findings suggest that additional resources should be directed toward claimants who are at risk (eg, the socially disadvantaged or those unemployed prior to the claim), the major aim being to reduce risk of psychological distress, such as post-traumatic stress disorder, and associated risk of increased settlement times and claim costs. Prospective studies are now required that investigate treatment strategies for those at risk of psychological distress associated with an MVC. PMID- 28877952 TI - Effectiveness and cost-effectiveness of a cardiovascular risk prediction algorithm for people with severe mental illness (PRIMROSE). AB - OBJECTIVES: To determine the cost-effectiveness of two bespoke severe mental illness (SMI)-specific risk algorithms compared with standard risk algorithms for primary cardiovascular disease (CVD) prevention in those with SMI. SETTING: Primary care setting in the UK. The analysis was from the National Health Service perspective. PARTICIPANTS: 1000 individuals with SMI from The Health Improvement Network Database, aged 30-74 years and without existing CVD, populated the model. INTERVENTIONS: Four cardiovascular risk algorithms were assessed: (1) general population lipid, (2) general population body mass index (BMI), (3) SMI-specific lipid and (4) SMI-specific BMI, compared against no algorithm. At baseline, each cardiovascular risk algorithm was applied and those considered high risk (> 10%) were assumed to be prescribed statin therapy while others received usual care. PRIMARY AND SECONDARY OUTCOME MEASURES: Quality-adjusted life years (QALYs) and costs were accrued for each algorithm including no algorithm, and cost effectiveness was calculated using the net monetary benefit (NMB) approach. Deterministic and probabilistic sensitivity analyses were performed to test assumptions made and uncertainty around parameter estimates. RESULTS: The SMI specific BMI algorithm had the highest NMB resulting in 15 additional QALYs and a cost saving of approximately L53 000 per 1000 patients with SMI over 10 years, followed by the general population lipid algorithm (13 additional QALYs and a cost saving of L46 000). CONCLUSIONS: The general population lipid and SMI specific BMI algorithms performed equally well. The ease and acceptability of use of an SMI-specific BMI algorithm (blood tests not required) makes it an attractive algorithm to implement in clinical settings. PMID- 28877953 TI - Anti-inflammatory roles of p38alpha MAPK in macrophages are context dependent and require IL-10. AB - The p38 MAPK pathway was originally identified as a master regulator of proinflammatory cytokine production by myeloid cells. Numerous drugs targeting this kinase showed promise in preclinical models of inflammatory disease, but so far, none have shown efficacy in clinical trials. The reasons behind this are unclear, but may, in part, be explained by emerging anti-inflammatory functions of this kinase or overly refined selectivity of second-generation pharmacologic inhibitors. Here, we show that p38alpha signaling in macrophages plays pro- and anti-inflammatory functions in vivo and in vitro, with the outcome depending on the stimulus, output, kinetics, or mode of kinase inhibition (genetic vs. pharmacologic). Different pharmacologic inhibitors of p38 exhibit opposing effects, with second-generation inhibitors acting more specifically but inhibiting anti-inflammatory functions. Functionally, we show that the anti inflammatory functions of p38alpha in macrophages are critically dependent on production of IL-10. Accordingly, in the absence of IL-10, inhibition of p38alpha signaling in macrophages is protective in a spontaneous model of colitis. Taken together, our results shed light on the limited clinical efficacy of drugs targeting p38 and suggest that their therapeutic efficacy can be significantly enhanced by simultaneous modulation of p38-dependent anti-inflammatory mediators, such as IL-10. PMID- 28877955 TI - New perspectives in ocean acidification research: editor's introduction to the special feature on ocean acidification. AB - Ocean acidification, caused by the uptake of additional carbon dioxide (CO2) from the atmosphere, will have far-reaching impacts on marine ecosystems (Gattuso & Hansson 2011 Ocean acidification Oxford University Press). The predicted changes in ocean chemistry will affect whole biological communities and will occur within the context of global warming and other anthropogenic stressors; yet much of the biological research conducted to date has tested the short-term responses of single species to ocean acidification conditions alone. While an important starting point, these studies may have limited predictive power because they do not account for possible interactive effects of multiple climate change drivers or for ecological interactions with other species. Furthermore, few studies have considered variation in responses among populations or the evolutionary potential within populations. Therefore, our knowledge about the potential for marine organisms to adapt to ocean acidification is extremely limited. In 2015, two of the pioneers in the field, Ulf Riebesell and Jean-Pierre Gattuso, noted that to move forward as a field of study, future research needed to address critical knowledge gaps in three major areas: (i) multiple environmental drivers, (ii) ecological interactions and (iii) acclimation and adaptation (Riebesell and Gattuso 2015 Nat. Clim. Change5, 12-14 (doi:10.1038/nclimate2456)). In May 2016, more than 350 researchers, students and stakeholders met at the 4th International Symposium on the Ocean in a High-CO2 World in Hobart, Tasmania, to discuss the latest advances in understanding ocean acidification and its biological consequences. Many of the papers presented at the symposium reflected this shift in focus from short-term, single species and single stressor experiments towards multi-stressor and multispecies experiments that address knowledge gaps about the ecological impacts of ocean acidification on marine communities. The nine papers in this Special Feature are from authors who attended the symposium and address cutting-edge questions and emerging topics in ocean acidification research, across the taxonomic spectrum from plankton to top predators. They cover the three streams of research identified as crucial to understanding the biological impacts of ocean acidification: (i) the relationship with other environmental drivers, (ii) the effects on ecological process and species interactions, and (iii) the role that individual variation, phenotypic plasticity and adaptation will have in shaping the impacts of ocean acidification and warming on marine ecosystems. PMID- 28877954 TI - Suppression of Toll-like receptor 2-mediated proinflammatory responses by Mycobacterium tuberculosis protein Rv3529c. AB - Microorganisms are known to devise various strategies to thwart protective responses by the host. One such strategy is to incorporate sequences and domains in their genes/proteins that have similarity to various domains of the host proteins. In this study, we report that Mycobacterium tuberculosis protein Rv3529c exhibits significant similarity to the death domain of the TLR pathway adaptor protein MyD88. Incubation of macrophages with Rv3529c specifically inhibited TLR2-mediated proinflammatory responses. This included attenuated oxidative burst, reduced phosphorylation of MAPK-ERK, reduced activation of transcription factor NF-kappaB and reduced secretion of proinflammatory cytokines IFN-gamma, IL-6, and IL-17A with a concomitant increased secretion of suppressor cytokines IL-10 and TGF-beta. Importantly, Rv3529c significantly inhibited TLR2 induced association of MyD88 with IRAK1 by competitively binding with IRAK1. Further, Rv3529c mediated inhibition of apoptosis and phagosome-lysosome fusion. Lastly, incubation of macrophages with Rv3529c increased bacterial burden inside macrophages. The data presented show another strategy evolved by M. tuberculosis toward immune evasion that centers on incorporating sequences in proteins that are similar to crucial proteins in the innate immune system of the host. PMID- 28877956 TI - Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage. AB - Severe brain injury significantly influences immune responses; however, the levels at which this influence occurs and which neurogenic pathways are involved are not well defined. Here, we used MRI to measure spleen volume and tissue diffusion changes in patients with intracerebral hemorrhage (ICH). We observed increased capillary exchange and spleen shrinkage by d 3 post-ICH, with recovery by d 14. The extent of spleen shrinkage was associated with brain hematoma size, and a reduced progression of perihematomal edema was observed in the presence of severe spleen shrinkage. At the cellular level, lymphopenia was present in patients with ICH at admission and persisted up to 14 d. Lymphopenia did not parallel the observed spleen alteration. In addition, patients with ICH with infection had significant deficiencies of T and NK cells and poor functional outcomes. Finally, in mouse models of ICH, spleen shrinkage could be related to innervations from adrenergic input and the hypothalamus-pituitary-adrenal (HPA) axis. In sum, the profound impact of ICH on the immune system involves the coordinated actions of sympathetic innervation and the HPA axis, which modulate spleen shrinkage and cellular immunity.-Zhang, J., Shi, K., Li, Z., Li, M., Han, Y., Wang, L., Zhang, Z., Yu, C., Zhang, F., Song, L., Dong, J.-F., La Cava, A., Sheth, K. N., Shi, F.-D. Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage. PMID- 28877957 TI - Identification of a new adtrp1-tfpi regulatory axis for the specification of primitive myelopoiesis and definitive hematopoiesis. AB - A genomic variant in the human ADTRP [androgen-dependent tissue factor (TF) pathway inhibitor (TFPI) regulating protein] gene increases the risk of coronary artery disease, the leading cause of death worldwide. TFPI is the TF pathway inhibitor that is involved in coagulation. Here, we report that adtrp and tfpi form a regulatory axis that specifies primitive myelopoiesis and definitive hematopoiesis, but not primitive erythropoiesis or vasculogenesis. In zebrafish, there are 2 paralogues for adtrp (i.e., adtrp1 and adtrp2). Knockdown of adtrp1 expression inhibits the specification of hemangioblasts, as shown by decreased expression of the hemangioblast markers, etsrp, fli1a, and scl; blocks primitive hematopoiesis, as shown by decreased expression of pu.1, mpo, and l-plastin; and disrupts the specification of hematopoietic stem cells (definitive hematopoiesis), as shown by decreased expression of runx1 and c-myb However, adtrp1 knockdown does not affect erythropoiesis during primitive hematopoiesis (no effect on gata1 or h-bae1) or vasculogenesis (no effect on kdrl, ephb2a, notch3, dab2, or flt4). Knockdown of adtrp2 expression does not have apparent effects on all markers tested. Knockdown of adtrp1 reduced the expression of tfpi, and hematopoietic defects in adtrp1 morphants were rescued by tfpi overexpression. These data suggest that the regulation of tfpi expression is one potential mechanism by which adtrp1 regulates primitive myelopoiesis and definitive hematopoiesis.-Wang, L., Wang, X., Wang, L., Yousaf, M., Li, J., Zuo, M., Yang, Z., Gou, D., Bao, B., Li, L., Xiang, N., Jia, H., Xu, C., Chen, Q., Wang, Q. K. Identification of a new adtrp1-tfpi regulatory axis for the specification of primitive myelopoiesis and definitive hematopoiesis. PMID- 28877958 TI - Proline-dependent and basophilic kinases phosphorylate human TRPC6 at serine 14 to control channel activity through increased membrane expression. AB - Signaling via the transient receptor potential (TRP) ion channel C6 plays a pivotal role in hereditary and sporadic glomerular kidney disease. Several studies have identified gain-of-function mutations of TRPC6 and report induced expression and enhanced channel activity of TRPC6 in association with glomerular diseases. Interfering with TRPC6 activity may open novel therapeutic pathways. TRPC6 channel activity is controlled by protein expression and stability as well as intracellular trafficking. Identification of regulatory phosphorylation sites in TRPC6 and corresponding protein kinases is essential to understand the regulation of TRPC6 activity and may result in future therapeutic strategies. In this study, an unbiased phosphoproteomic screen of human TRPC6 identified several novel serine phosphorylation sites. The phosphorylation site at serine 14 of TRPC6 is embedded in a basophilic kinase motif that is highly conserved across species. We confirmed serine 14 as a target of MAPKs and proline-directed kinases like cyclin-dependent kinase 5 (Cdk5) in cell-based as well as in vitro kinase assays and quantitative phosphoproteomic analysis of TRPC6. Phosphorylation of TRPC6 at serine 14 enhances channel conductance by boosting membrane expression of TRPC6, whereas protein stability and multimerization of TRPC6 are not altered, making serine 14 phosphorylation a potential drug target to interfere with TRPC6 channel activity.-Hagmann, H., Mangold, N., Rinschen, M. M., Koenig, T., Kunzelmann, K., Schermer, B., Benzing, T., Brinkkoetter, P. T. Proline-dependent and basophilic kinases phosphorylate human TRPC6 at serine 14 to control channel activity through increased membrane expression. PMID- 28877959 TI - Prognostic role of tumour-associated macrophages and regulatory T cells in EBV positive and EBV-negative nasopharyngeal carcinoma. AB - AIMS: Tumour-associated macrophages (TAMs) and regulatory T cells (Tregs) form a special niche supporting tumour progression, and both correlate with worse survival in head and neck cancers. However, the prognostic role of TAM and Tregs in nasopharyngeal carcinoma (NPC) is still unknown. Therefore, we determined differences in TAMs and Tregs in different NPC subtypes, and their prognostic significance. METHODS: Tissue of 91 NPCs was assessed for TAMs and Tregs by determination of CD68, CD163, CD206 and FOXP3 expression in the tumour microenvironment. Clinicopathological correlations were assessed using Pearson X2 test, Fisher's exact test, analysis of variance and Mann-Whitney U test. Survival was analysed using Kaplan-Meier curves and Cox regression. RESULTS: CD68 and FOXP3 counts were higher in Epstein-Barr virus (EBV)-positive NPC, while CD68 /FOXP3-, CD163+/FOXP3- and CD206+/FOXP3- infiltrates were more common in EBV negative NPC. In the whole NPC group, CD68-/FOXP3- correlated with worse overall survival (OS), and after multivariate analysis high FOXP3 count showed better OS (HR 0.352, 95% CI 0.128 to 0.968). No difference in M2 counts existed between EBV positive and negative NPC. CONCLUSIONS: FOXP3, a Treg marker, seems to be an independent prognostic factor for better OS in the whole NPC group. Therefore, immune-based therapies targeting Tregs should be carefully evaluated. M2 spectrum macrophages are probably more prominent in EBV-negative NPC with also functional differences compared with EBV-positive NPC. PMID- 28877960 TI - RT-PCR for the diagnosis of Clostridium difficile infection: the final answer has yet to come. PMID- 28877961 TI - Adrenal insufficiency is seen in more than one-third of patients during ongoing low-dose prednisolone treatment for rheumatoid arthritis. AB - OBJECTIVE: Patients receiving long-term glucocorticoid treatment are at risk of developing adrenal insufficiency during treatment. We investigated the prevalence of prednisolone-induced adrenal insufficiency in the particular clinical situation where patients receive ongoing low-dose (5 mg/day) prednisolone treatment, a dose by itself too low to cover glucocorticoid needs during stress. DESIGN AND METHODS: Cross-sectional study in 42 patients with rheumatoid arthritis (29 women, aged 36-86 years) treated with 5 mg prednisolone/day, who had received prednisolone for >=6 months (median: 66, range: 6-444 months). Adrenal function was evaluated by a 250 MUg Synacthen test performed after mean 48.7 h prednisolone pause. Local assay-specific cut-off for normal adrenal function was P-cortisol >=420 nmol/L 30 min after Synacthen injection. RESULTS: Overall, 20 of the 42 patients (48%, 95% CI: 33-62%) had an insufficient adrenal response to the Synacthen test. Including only patients who had not received concomitant treatment with any other glucocorticoid formulas within the last 3 months, 13 of 33 patients (39%, 95% CI: 25-56%) had an insufficient response. Adrenocorticotrophic hormone (ACTH) concentrations were generally low and anti adrenal antibodies were negative indicating secondary adrenal insufficiency as the most likely diagnosis. There was no correlation between duration of treatment and 30 min P-cortisol (P = 0.62). Adrenal function did not depend on sex or seropositivity of rheumatoid arthritis. CONCLUSION: We demonstrate a high prevalence of adrenal insufficiency during ongoing low-dose prednisolone treatment. The results urge to increase focus on the condition to ensure identification and correct management of insufficient patients during stress and withdrawal. Strategies for adrenal function evaluation during ongoing low-dose glucocorticoid treatment need to be established. PMID- 28877963 TI - The effect of prior knowledge and intelligibility on the cortical entrainment response to speech. AB - It has been suggested that cortical entrainment plays an important role in speech perception by helping to parse the acoustic stimulus into discrete linguistic units. However, the question of whether the entrainment response to speech depends on the intelligibility of the stimulus remains open. Studies addressing this question of intelligibility have, for the most part, significantly distorted the acoustic properties of the stimulus to degrade the intelligibility of the speech stimulus, making it difficult to compare across "intelligible" and "unintelligible" conditions. To avoid these acoustic confounds, we used priming to manipulate the intelligibility of vocoded speech. We used EEG to measure the entrainment response to vocoded target sentences that are preceded by natural speech (nonvocoded) prime sentences that are either valid (match the target) or invalid (do not match the target). For unintelligible speech, valid primes have the effect of restoring intelligibility. We compared the effect of priming on the entrainment response for both 3-channel (unintelligible) and 16-channel (intelligible) speech. We observed a main effect of priming, suggesting that the entrainment response depends on prior knowledge, but not a main effect of vocoding (16 channels vs. 3 channels). Furthermore, we found no difference in the effect of priming on the entrainment response to 3-channel and 16-channel vocoded speech, suggesting that for vocoded speech, entrainment response does not depend on intelligibility.NEW & NOTEWORTHY Neural oscillations have been implicated in the parsing of speech into discrete, hierarchically organized units. Our data suggest that these oscillations track the acoustic envelope rather than more abstract linguistic properties of the speech stimulus. Our data also suggest that prior experience with the stimulus allows these oscillations to better track the stimulus envelope. PMID- 28877964 TI - Constitutive activity of 5-HT2C receptors is present after incomplete spinal cord injury but is not modified after chronic SSRI or baclofen treatment. AB - After spinal cord injury (SCI), reflexes become hyperexcitable, leading to debilitating muscle spasms and compromised motor function. Previous work has described adaptations in spinal systems that might underlie this hyperexcitability, including an increase in constitutively active 5-HT2C receptors in spinal motoneurons. That work, however, examined adaptations following complete transection SCI, whereas SCI in humans is usually anatomically and functionally incomplete. We therefore evaluated whether constitutive activity of 5-HT2C receptors contributes to reflex hyperexcitability in an incomplete compression model of SCI and to spasms in vitro and in vivo. Our results confirm that 5-HT2C receptor constitutive activity contributes to reflex excitability after incomplete SCI. We also evaluated whether constitutive activity could be altered by manipulation of neural activity levels after SCI, testing the hypothesis that it reflects homeostatic processes acting to maintain spinal excitability. We decreased neural activity after SCI by administering baclofen and increased activity by administering the selective serotonin reuptake inhibitor (SSRI) fluoxetine. We found that drug administration produced minimal alterations in in vivo locomotor function or reflex excitability. Similarly, we found that neither baclofen nor fluoxetine altered the contribution of constitutively active 5-HT2C receptors to reflexes after SCI, although the contribution of 5-HT2C receptors to reflex activity was altered after SSRIs. These results confirm the importance of constitutive activity in 5-HT2C receptors to spinal hyperexcitability following SCI in the clinically relevant case of incomplete SCI but suggest that this activity is not driven by homeostatic processes that act to maintain overall levels of spinal excitability.NEW & NOTEWORTHY After spinal cord injury (SCI), most people will develop muscle spasms below their level of injury that can severely impact function. In this work, we examine the adaptations that occur within the spinal cord after SCI that contribute to these motor dysfunctions. We also evaluate one hypothesis about how these adaptations develop, which will potentially lead to intervention strategies to improve functional outcomes in persons with SCI. PMID- 28877962 TI - Toward the human cellular microRNAome. AB - MicroRNAs are short RNAs that serve as regulators of gene expression and are essential components of normal development as well as modulators of disease. MicroRNAs generally act cell-autonomously, and thus their localization to specific cell types is needed to guide our understanding of microRNA activity. Current tissue-level data have caused considerable confusion, and comprehensive cell-level data do not yet exist. Here, we establish the landscape of human cell specific microRNA expression. This project evaluated 8 billion small RNA-seq reads from 46 primary cell types, 42 cancer or immortalized cell lines, and 26 tissues. It identified both specific and ubiquitous patterns of expression that strongly correlate with adjacent superenhancer activity. Analysis of unaligned RNA reads uncovered 207 unknown minor strand (passenger) microRNAs of known microRNA loci and 495 novel putative microRNA loci. Although cancer cell lines generally recapitulated the expression patterns of matched primary cells, their isomiR sequence families exhibited increased disorder, suggesting DROSHA- and DICER1-dependent microRNA processing variability. Cell-specific patterns of microRNA expression were used to de-convolute variable cellular composition of colon and adipose tissue samples, highlighting one use of these cell-specific microRNA expression data. Characterization of cellular microRNA expression across a wide variety of cell types provides a new understanding of this critical regulatory RNA species. PMID- 28877965 TI - Tests of the sorption and olfactory "fovea" hypotheses in the mouse. AB - The spatial distribution of receptors within sensory epithelia (e.g., retina and skin) is often markedly nonuniform to gain efficiency in information capture and neural processing. By contrast, odors, unlike visual and tactile stimuli, have no obvious spatial dimension. What need then could there be for either nearest neighbor relationships or nonuniform distributions of receptor cells in the olfactory epithelium (OE)? Adrian (Adrian ED. J Physiol 100: 459-473, 1942; Adrian ED. Br Med Bull 6: 330-332, 1950) provided the only widely debated answer to this question when he posited that the physical properties of odors, such as volatility and water solubility, determine a spatial pattern of stimulation across the OE that could aid odor discrimination. Unfortunately, despite its longevity, few critical tests of the "sorption hypothesis" exist. Here we test the predictions of this hypothesis by mapping mouse OE responses using the electroolfactogram (EOG) and comparing these response "maps" to computational fluid dynamics (CFD) simulations of airflow and odorant sorption patterns in the nasal cavity. CFD simulations were performed for airflow rates corresponding to quiet breathing and sniffing. Consistent with predictions of the sorption hypothesis, water-soluble odorants tended to evoke larger EOG responses in the central portion of the OE than the peripheral portion. However, sorption simulation patterns along individual nasal turbinates for particular odorants did not correlate with their EOG response gradients. Indeed, the most consistent finding was a rostral-greater to caudal-lesser response gradient for all the odorants tested that is unexplained by sorption patterns. The viability of the sorption and related olfactory "fovea" hypotheses are discussed in light of these findings.NEW & NOTEWORTHY Two classical ideas concerning olfaction's receptor surface two-dimensional organization-the sorption and olfactory fovea hypotheses were found wanting in this study that afforded unprecedented comparisons between electrophysiological recordings in the mouse olfactory epithelium and computational fluid dynamic simulations of nasal airflow. Alternatively, it is proposed that the olfactory receptor layouts in macrosmatic mammals may be an evolutionary contingent state devoid of the functional significance found in other sensory epithelia like the cochlea and retina. PMID- 28877966 TI - T-Cell Mediation of Pregnancy Analgesia Affecting Chronic Pain in Mice. AB - It has been reported consistently that many female chronic pain sufferers have an attenuation of symptoms during pregnancy. Rats display increased pain tolerance during pregnancy due to an increase in opioid receptors in the spinal cord. Past studies did not consider the role of non-neuronal cells, which are now known to play an important role in chronic pain processing. Using an inflammatory (complete Freund's adjuvant) or neuropathic (spared nerve injury) model of persistent pain, we observed that young adult female mice in early pregnancy switch from a microglia-independent to a microglia-dependent pain hypersensitivity mechanism. During late pregnancy, female mice show no evidence of chronic pain whatsoever. This pregnancy-related analgesia is reversible by intrathecal administration of naloxone, suggesting an opioid-mediated mechanism; pharmacological and genetic data suggest the importance of delta-opioid receptors. We also observe that T-cell-deficient (nude and Rag1-null mutant) pregnant mice do not exhibit pregnancy analgesia, which can be rescued with the adoptive transfer of CD4+ or CD8+ T cells from late-pregnant wild-type mice. These results suggest that T cells are a mediator of the opioid analgesia exhibited during pregnancy.SIGNIFICANCE STATEMENT Chronic pain symptoms often subside during pregnancy. This pregnancy-related analgesia has been demonstrated for acute pain in rats. Here, we show that pregnancy analgesia can produce a complete cessation of chronic pain behaviors in mice. We show that the phenomenon is dependent on pregnancy hormones (estrogen and progesterone), delta-opioid receptors, and T cells of the adaptive immune system. These findings add to the recent but growing evidence of sex-specific T-cell involvement in chronic pain processing. PMID- 28877967 TI - Memantine and Ketamine Differentially Alter NMDA Receptor Desensitization. AB - Memantine and ketamine are clinically useful NMDA receptor (NMDAR) open channel blockers that inhibit NMDARs with similar potency and kinetics, but display vastly different clinical profiles. This discrepancy has been hypothesized to result from inhibition by memantine and ketamine of overlapping but distinct NMDAR subpopulations. For example, memantine but not ketamine may inhibit extrasynaptic NMDARs more effectively than synaptic NMDARs. However, the basis for preferential NMDAR inhibition depending on subcellular location has not been investigated systematically. We integrated recordings from heterologously expressed single NMDAR subtypes, kinetic modeling, and recordings of synaptically evoked NMDAR responses in acute brain slices to investigate mechanisms by which channel blockers may distinguish NMDAR subpopulations. We found that memantine and ketamine differentially alter NMDAR desensitization and that memantine stabilizes a Ca2+-dependent desensitized state. As a result, inhibition by memantine of GluN1/2A receptors in tsA201 cells and of native synaptic NMDARs in cortical pyramidal neurons from mice of either sex increased in conditions that enhanced intracellular Ca2+ accumulation. Therefore, differential inhibition by memantine and ketamine based on NMDAR location is likely to result from location dependence of the intensity and duration of NMDAR activation. Modulation of Ca2+ dependent NMDAR desensitization is an unexplored mechanism of inhibitory action with the potential to endow drugs with NMDAR selectivity that leads to superior clinical profiles. Our results suggest that designing compounds to target specific receptor states, rather than specific receptor types, may be a viable strategy for future drug development.SIGNIFICANCE STATEMENT Memantine and ketamine are NMDA receptor (NMDAR) channel-blocking drugs with divergent clinical effects. Understanding mechanistically their differential actions may advance our understanding of nervous system disorders and suggest strategies for the design of more effective drugs. Here, we show that memantine and ketamine have contrasting effects on NMDAR desensitization. Ketamine binding decreases occupancy of desensitized states of the GluN1/2B NMDAR subtype. In contrast, memantine binding increases occupancy of GluN1/2A and native NMDAR desensitized states entered after accumulation of intracellular Ca2+, a novel inhibitory mechanism. These properties may contribute to inhibition of distinct NMDAR subpopulations by memantine and ketamine and help to explain their differential clinical effects. Our results suggest stabilization of Ca2+-dependent desensitized states as a new strategy for pharmaceutical neuroprotection. PMID- 28877968 TI - Action Potential Broadening in Capsaicin-Sensitive DRG Neurons from Frequency Dependent Reduction of Kv3 Current. AB - Action potential (AP) shape is a key determinant of cellular electrophysiological behavior. We found that in small-diameter, capsaicin-sensitive dorsal root ganglia neurons corresponding to nociceptors (from rats of either sex), stimulation at frequencies as low as 1 Hz produced progressive broadening of the APs. Stimulation at 10 Hz for 3 s resulted in an increase in AP width by an average of 76 +/- 7% at 22 degrees C and by 38 +/- 3% at 35 degrees C. AP clamp experiments showed that spike broadening results from frequency-dependent reduction of potassium current during spike repolarization. The major current responsible for frequency-dependent reduction of overall spike-repolarizing potassium current was identified as Kv3 current by its sensitivity to low concentrations of 4-aminopyridine (IC50 <100 MUm) and block by the peptide inhibitor blood depressing substance I (BDS-I). There was a small component of Kv1-mediated current during AP repolarization, but this current did not show frequency-dependent reduction. In a small fraction of cells, there was a component of calcium-dependent potassium current that showed frequency-dependent reduction, but the contribution to overall potassium current reduction was almost always much smaller than that of Kv3-mediated current. These results show that Kv3 channels make a major contribution to spike repolarization in small-diameter DRG neurons and undergo frequency-dependent reduction, leading to spike broadening at moderate firing frequencies. Spike broadening from frequency dependent reduction in Kv3 current could mitigate the frequency-dependent decreases in conduction velocity typical of C-fiber axons.SIGNIFICANCE STATEMENT Small-diameter dorsal root ganglia (DRG) neurons mediating nociception and other sensory modalities express many types of potassium channels, but how they combine to control firing patterns and conduction is not well understood. We found that action potentials of small-diameter rat DRG neurons showed spike broadening at frequencies as low as 1 Hz and that spike broadening resulted predominantly from frequency-dependent inactivation of Kv3 channels. Spike width helps to control transmitter release, conduction velocity, and firing patterns and understanding the role of particular potassium channels can help to guide new pharmacological strategies for targeting pain-sensing neurons selectively. PMID- 28877970 TI - The Transcriptional Response of Candida albicans to Weak Organic Acids, Carbon Source, and MIG1 Inactivation Unveils a Role for HGT16 in Mediating the Fungistatic Effect of Acetic Acid. AB - Candida albicans is a resident fungus of the human intestinal microflora. Commonly isolated at low abundance in healthy people, C. albicans outcompetes local microbiota during candidiasis episodes. Under normal conditions, members of the human gastrointestinal (GI) microbiota were shown to keep C. albicans colonization under control. By releasing weak organic acids (WOAs), bacteria are able to moderate yeast growth. This mechanism displays a synergistic effect in vitro with the absence of glucose in medium of culture, which underlines the complex interactions that C. albicans faces in its natural environment. Inactivation of the transcriptional regulator MIG1 in C. albicans results in a lack of sensitivity to this synergistic outcome. To decipher C. albicans transcriptional responses to glucose, WOAs, and the role of MIG1, we performed RNA sequencing (RNA-seq) on four biological replicates exposed to combinations of these three parameters. We were able to characterize the (i) glucose response, (ii) response to acetic and butyric acid, (iii) MIG1 regulation of C. albicans, and (iv) genes responsible for WOA resistance. We identified a group of six genes linked to WOA sensitivity in a glucose-MIG1-dependent manner and inactivated one of these genes, the putative glucose transporter HGT16, in a SC5314 wild-type background. As expected, the mutant displayed a partial complementation to WOA resistance in the absence of glucose. This result points toward a mechanism of WOA sensitivity in C. albicans involving membrane transporters, which could be exploited to control yeast colonization in human body niches. PMID- 28877972 TI - Clinical care for primary ciliary dyskinesia: current challenges and future directions. AB - Primary ciliary dyskinesia (PCD) is a rare genetic disease that affects the motility of cilia, leading to impaired mucociliary clearance. It is estimated that the vast majority of patients with PCD have not been diagnosed as such, providing a major obstacle to delivering appropriate care. Challenges in diagnosing PCD include lack of disease-specific symptoms and absence of a single, "gold standard", diagnostic test. Management of patients is currently not based on high-level evidence because research findings are mostly derived from small observational studies with limited follow-up period. In this review, we provide a critical overview of the available literature on clinical care for PCD patients, including recent advances. We identify barriers to PCD research and make suggestions for overcoming challenges. PMID- 28877969 TI - Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control. AB - The nicotinic system plays an important role in cognitive control and is implicated in several neuropsychiatric conditions. However, the contributions of genetic variability in this system to individuals' cognitive control abilities are poorly understood and the brain processes that mediate such genetic contributions remain largely unidentified. In this first large-scale neuroimaging genetics study of the human nicotinic receptor system (two cohorts, males and females, fMRI total N = 1586, behavioral total N = 3650), we investigated a common polymorphism of the high-affinity nicotinic receptor alpha4beta2 (rs1044396 on the CHRNA4 gene) previously implicated in behavioral and nicotine related studies (albeit with inconsistent major/minor allele impacts). Based on our prior neuroimaging findings, we expected this polymorphism to affect neural activity in the cingulo-opercular (CO) network involved in core cognitive control processes including maintenance of alertness. Consistent across the cohorts, all cortical areas of the CO network showed higher activity in heterozygotes compared with both types of homozygotes during cognitive engagement. This inverted U shaped relation reflects an overdominant effect; that is, allelic interaction (cumulative evidence p = 1.33 * 10-5). Furthermore, heterozygotes performed more accurately in behavioral tasks that primarily depend on sustained alertness. No effects were observed for haplotypes of the surrounding CHRNA4 region, supporting a true overdominant effect at rs1044396. As a possible mechanism, we observed that this polymorphism is an expression quantitative trait locus modulating CHRNA4 expression levels. This is the first report of overdominance in the nicotinic system. These findings connect CHRNA4 genotype, CO network activation, and sustained alertness, providing insights into how genetics shapes individuals' cognitive control abilities.SIGNIFICANCE STATEMENT The nicotinic acetylcholine system plays a central role in neuromodulatory regulation of cognitive control processes and is dysregulated in several neuropsychiatric disorders. Despite this functional importance, no large-scale neuroimaging genetics studies have targeted the contributions of genetic variability in this system to human brain activity. Here, we show the impact of a common polymorphism of the high-affinity nicotinic receptor alpha4beta2 that is consistent across brain activity and behavior in two large human cohorts. We report a hitherto unknown overdominant effect (allelic interaction) at this locus, where the heterozygotes show higher activity in the cingulo-opercular network underlying alertness maintenance and higher behavioral alertness performance than both homozygous groups. This gene-brain-behavior relationship informs about the biological basis of interindividual differences in cognitive control. PMID- 28877971 TI - Genome-Wide Analysis of DNA Methylation During Ovule Development of Female Sterile Rice fsv1. AB - The regulation of female fertility is an important field of rice sexual reproduction research. DNA methylation is an essential epigenetic modification that dynamically regulates gene expression during development processes. However, few reports have described the methylation profiles of female-sterile rice during ovule development. In this study, ovules were continuously acquired from the beginning of megaspore mother cell meiosis until the mature female gametophyte formation period, and global DNA methylation patterns were compared in the ovules of a high-frequency female-sterile line (fsv1) and a wild-type rice line (Gui99) using whole-genome bisulfite sequencing (WGBS). Profiling of the global DNA methylation revealed hypo-methylation, and 3471 significantly differentially methylated regions (DMRs) were observed in fsv1 ovules compared with Gui99. Based on functional annotation and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis of differentially methylated genes (DMGs), we observed more DMGs enriched in cellular component, reproduction regulation, metabolic pathway, and other pathways. In particular, many ovule development genes and plant hormone related genes showed significantly different methylation patterns in the two rice lines, and these differences may provide important clues for revealing the mechanism of female gametophyte abortion. PMID- 28877973 TI - Heritable pulmonary hypertension: from bench to bedside. AB - Mutations in the BMPR2 gene, and more rarely in ACVRL1, endoglin, caveolin-1, KCNK3 and TBX4 genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance. Bi-allelic mutations in the EIF2AK4 gene predispose to heritable pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis, an autosomal recessive disease with an unknown penetrance.In France, the national pulmonary hypertension referral centre offers genetic counselling and testing to adults and children. Predictive testing is also proposed to adult relatives at risk of carrying a predisposing mutation. In that context, we offer all asymptomatic BMPR2 mutation carriers a programme to detect pulmonary arterial hypertension at an early phase, as recommended by the 2015 European Society Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Finally, pre-implantation genetic diagnosis has been conducted on five embryos from two couples in which the fathers were carriers of a pathogenic BMPR2 mutation. PMID- 28877974 TI - Exertional dyspnoea in pulmonary arterial hypertension. AB - Dyspnoea is a principal presenting symptom in pulmonary arterial hypertension (PAH), and often the most distressing. The pathophysiology of PAH is relatively well understood, with the primary abnormality of pulmonary vascular disease resulting in a combination of impaired cardiac output on exercise and abnormal gas exchange, both contributing to increased ventilatory drive. However, increased ventilatory drive is not the sole explanation for the complex neurophysiological and neuropsychological symptom of dyspnoea, with other significant contributions from skeletal muscle reflexes, respiratory muscle function, and psychological and emotional status. In this review, we explore the physiological aspects of dyspnoea in PAH, both in terms of the central cardiopulmonary abnormalities of PAH and the wider, systemic impact of PAH, and how these interact with common comorbidities. Finally, we discuss its relationship with disease severity. PMID- 28877975 TI - The lung in amyloidosis. AB - Amyloidosis is a disorder caused by misfolding of autologous protein and its extracellular deposition as fibrils, resulting in vital organ dysfunction and eventually death. Pulmonary amyloidosis may be localised or part of systemic amyloidosis.Pulmonary interstitial amyloidosis is symptomatic only if the amyloid deposits severely affect gas exchange alveolar structure, thus resulting in serious respiratory impairment. Localised parenchymal involvement may be present as nodular amyloidosis or as amyloid deposits associated with localised lymphomas. Finally, tracheobronchial amyloidosis, which is usually not associated with evident clonal proliferation, may result in airway stenosis.Because the treatment options for amyloidosis are dependent on the fibril protein type, the workup of all new cases should include accurate determination of the amyloid protein. Most cases are asymptomatic and need only a careful follow-up. Diffuse alveolar-septal amyloidosis is treated according to the underlying systemic amyloidosis. Nodular pulmonary amyloidosis is usually localised, conservative excision is usually curative and the long-term prognosis is excellent. Tracheobronchial amyloidosis is usually treated with bronchoscopic interventions or external beam radiation therapy. PMID- 28877976 TI - Evaluating disease severity in idiopathic pulmonary fibrosis. AB - Accurate assessment of idiopathic pulmonary fibrosis (IPF) disease severity is integral to the care provided to patients with IPF. However, to date, there are no generally accepted or validated staging systems. There is an abundance of data on using information acquired from physiological, radiological and pathological parameters, in isolation or in combination, to assess disease severity in IPF. Recently, there has been interest in using serum biomarkers and computed tomography-derived quantitative lung fibrosis measures to stage disease severity in IPF. This review will focus on the suggested methods for staging IPF, at baseline and on serial assessment, their strengths and limitations, as well as future developments. PMID- 28877977 TI - Rare pulmonary diseases: a common fight. PMID- 28877978 TI - How I manage pulmonary Langerhans cell histiocytosis. AB - Pulmonary Langerhans cell histiocytosis (PLCH) is a rare sporadic cystic lung disease of unknown aetiology that is characterised by the infiltration and destruction of the wall of distal bronchioles by CD1a+ Langerhans-like cells. In adults, PLCH is frequently isolated and affects young smokers of both sexes. Recent multicentre studies have led to the more standardised management of patients in clinical practice. Smoking cessation is essential and is occasionally the only suitable intervention. Serial lung function testing is important because a significant proportion of patients may experience an early decline in forced expiratory volume in 1 s and develop airflow obstruction. Cladribine was reported to dramatically improve progressive PLCH in some patients. Its efficacy and tolerance are currently being evaluated. Patients who complain of unexplained dyspnoea with decreased diffusing capacity of the lung for carbon monoxide should be screened for pulmonary hypertension by Doppler echocardiography, which must be confirmed by right heart catheterisation. Lung transplantation is a therapeutic option for patients with advanced PLCH.The identification of the BRAFV600E mutation in approximately half of Langerhans cell histiocytosis lesions, including PLCH, and other mutations of the mitogen-activated protein kinase (MAPK) pathway in a subset of lesions has led to targeted treatments (BRAF and MEK (MAPK kinase) inhibitors). These treatments need to be rigorously evaluated because of their potentially severe side-effects. PMID- 28877979 TI - Fatty acids promote fatty liver disease via the dysregulation of 3 mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway. AB - OBJECTIVE: Accumulation of free fatty acids (FFAs) in hepatocytes induces lipotoxicity, leading to non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the underlying mechanisms by which FFA contributes to the pathogenesis of NAFLD via the regulation of 3-mercaptopyruvate sulfurtransferase (MPST), a key enzyme that regulates endogenous hydrogen sulfide (H2S) biosynthesis. DESIGN: Hepatic MPST expression was evaluated in mice and patients with NAFLD. A variety of molecular approaches were used to study the effects of MPST regulation on hepatic steatosis in vivo and in vitro. RESULTS: In vitro treatment of hepatocytes with FFAs upregulated MPST expression, which was partially dependent on NF-kappaB/p65. Hepatic MPST expression was markedly increased in high fat diet (HFD)-fed mice and patients with NAFLD. Partial knockdown of MPST via adenovirus delivery of MPST short hairpin RNA or heterozygous deletion of the Mpst gene significantly ameliorated hepatic steatosis in HFD-fed mice. Consistently, inhibition of MPST also reduced FFA induced fat accumulation in L02 cells. Intriguingly, inhibition of MPST significantly enhanced rather than decreased H2S production, whereas MPST overexpression markedly inhibited H2S production. Co-immunoprecipitation experiments showed that MPST directly interacted with and negatively regulated cystathionine gamma-lyase (CSE), a major source of H2S production in the liver. Mechanistically, MPST promoted steatosis via inhibition of CSE/H2S and subsequent upregulation of the sterol regulatory element-binding protein 1c pathway, C-Jun N terminal kinase phosphorylation and hepatic oxidative stress. CONCLUSIONS: FFAs upregulate hepatic expression of MPST and subsequently inhibit the CSE/H2S pathway, leading to NAFLD. MPST may be a potential therapeutic target for NAFLD. PMID- 28877981 TI - Prospective study on the incidence, prevalence and 5-year pancreatic-related mortality of pancreatic cysts in a population-based study. AB - OBJECTIVE: To analyse the prevalence, incidence and clinical relevance of pancreatic cysts detected as incidental finding in a population-based longitudinal study. DESIGN: A total of 1077 participants (521 men, mean age 55.8+/-12.8 years) of 2333 participants from the population-based Study of Health in Pomerania (SHIP) underwent magnetic resonance cholangiopancreaticography (MRCP) at baseline (2008-2012). MRCP was analysed for pancreatic cysts with a diameter >=2 mm. 676/1077 subjects received a 5-year follow-up (2014-2016). The prevalence and incidence of pancreatic cysts (weighted for study participation) were assessed in association to age, gender and suspected epidemiological risk factors. Mortality follow-up was performed in 2015 for all SHIP participants (mean follow-up period 5.9 years, range 3.2-7.5 years). RESULTS: At baseline pancreatic cysts had a weighted prevalence of 49.1%, with an average number of 3.9 (95% CI 3.2 to 4.5) cysts per subject in the subgroup harbouring cysts. Cyst size ranged from 2 to 29 mm. Prevalence (p<0.001), number (p=0.001) and maximum size (p<0.001) increased significantly with age. The 5-year follow-up revealed a weighted incidence of 12.9% newly detected pancreatic cysts. 57.1% of the subjects initially harbouring pancreatic cysts showed an increase in number and/or maximum cyst size. Of all subjects undergoing MRCP, no participant died of pancreatic diseases within mortality follow-up. CONCLUSION: The prevalence of pancreatic cysts in the general population is unexpectedly high, and their number and size increase with age. Overall, no pancreatic cancer was observed in this collective during a 5-year follow-up. Nevertheless, prospective follow-up imaging showed minimal progress in more than 50%. Only about 6% of cysts and 2.5% of the study group initially presented with cysts of more than 1 cm and thus might be clinically meaningful. PMID- 28877980 TI - NAD metabolism fuels human and mouse intestinal inflammation. AB - OBJECTIVE: Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism. DESIGN: We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD. RESULTS: FK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1-/- mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10. CONCLUSION: Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation. PMID- 28877982 TI - Noncanonical regulation of insulin-mediated ERK activation by phosphoinositide 3 kinase gamma. AB - Classically Class IB phosphoinositide 3-kinase (PI3Kgamma) plays a role in extracellular signal-regulated kinase (ERK) activation following G-protein coupled receptor (GPCR) activation. Knock-down of PI3Kgamma unexpectedly resulted in loss of ERK activation to receptor tyrosine kinase agonists such as epidermal growth factor or insulin. Mouse embryonic fibroblasts (MEFs) or primary adult cardiac fibroblasts isolated from PI3Kgamma knock-out mice (PI3KgammaKO) showed decreased insulin-stimulated ERK activation. However, expression of kinase-dead PI3Kgamma resulted in rescue of insulin-stimulated ERK activation. Mechanistically, PI3Kgamma sequesters protein phosphatase 2A (PP2A), disrupting ERK-PP2A interaction, as evidenced by increased ERK-PP2A interaction and associated PP2A activity in PI3KgammaKO MEFs, resulting in decreased ERK activation. Furthermore, beta-blocker carvedilol-mediated beta-arrestin-dependent ERK activation is significantly reduced in PI3KgammaKO MEF, suggesting accelerated dephosphorylation. Thus, instead of classically mediating the kinase arm, PI3Kgamma inhibits PP2A by scaffolding and sequestering, playing a key parallel synergistic step in sustaining the function of ERK, a nodal enzyme in multiple cellular processes. PMID- 28877983 TI - General and specific promotion of flagellar assembly by a flagellar nucleoside diphosphate kinase. AB - Nucleoside diphosphate kinases (NDKs) play a central role in diverse cellular processes using the canonical NDK activity or alternative mechanisms that remain poorly defined. Our study of dimeric NDK5 in a flagellar motility control complex, the radial spoke (RS), has revealed new modalities. The flagella in Chlamydomonas ndk5 mutant were paralyzed, albeit only deficient in three RS subunits. RS morphology appeared severely changed in averaged cryo-electron tomograms, suggesting that NDK5 is crucial for the intact spokehead formation as well as RS structural stability. Intriguingly, ndk5's flagella were also short, resembling those of an allelic spoke-less mutant. All ndk5's phenotypes were rescued by expressions of NDK5 or a mutated NDK5 lacking the canonical kinase activity. Importantly, the mutated NDK5 that appeared fully functional in ndk5 cells elicited a dominant-negative effect in wild-type cells, causing paralyzed short flagella with hypophosphorylated, less abundant, but intact RSs, and accumulated hypophosphorylated NDK5 in the cell body. We propose that NDK5 dimer is an RS structural subunit with an additional mechanism that uses cross-talk between the two NDK monomers to accelerate phosphorylation-related assembly of RSs and entire flagella. PMID- 28877985 TI - MTBP, the partner of Treslin, contains a novel DNA-binding domain that is essential for proper initiation of DNA replication. AB - Treslin, which is essential for incorporation of Cdc45 into the replicative helicase, possesses a partner called MTBP (Mdm2-binding protein). We have analyzed Xenopus and human MTBP to assess its role in DNA replication. Depletion of MTBP from Xenopus egg extracts, which also removes Treslin, abolishes DNA replication. These extracts be can rescued with recombinant Treslin-MTBP but not Treslin or MTBP alone. Thus, Treslin-MTBP is collectively necessary for replication. We have identified a C-terminal region of MTBP (the CTM domain) that binds efficiently to both double-stranded DNA and G-quadruplex (G4) DNA. This domain also exhibits homology with budding yeast Sld7. Mutants of MTBP without a functional CTM domain are defective for DNA replication in Xenopus egg extracts. These mutants display an impaired localization to chromatin and the inability to support loading of Cdc45. Human cells harboring such a mutant also display severe S-phase defects. Thus, the CTM domain of MTBP plays a critical role in localizing Treslin-MTBP to the replication apparatus for initiation. PMID- 28877984 TI - alpha5beta1-Integrin promotes tension-dependent mammary epithelial cell invasion by engaging the fibronectin synergy site. AB - Tumors are fibrotic and characterized by abundant, remodeled, and cross-linked collagen that stiffens the extracellular matrix stroma. The stiffened collagenous stroma fosters malignant transformation of the tissue by increasing tumor cell tension to promote focal adhesion formation and potentiate growth factor receptor signaling through kinase. Importantly, collagen cross-linking requires fibronectin (FN). Fibrotic tumors contain abundant FN, and tumor cells frequently up-regulate the FN receptor alpha5beta1 integrin. Using transgenic and xenograft models and tunable two- and three-dimensional substrates, we show that FN-bound alpha5beta1 integrin promotes tension-dependent malignant transformation through engagement of the synergy site that enhances integrin adhesion force. We determined that ligation of the synergy site of FN permits tumor cells to engage a zyxin-stabilized, vinculin-linked scaffold that facilitates nucleation of phosphatidylinositol (3,4,5)-triphosphate at the plasma membrane to enhance phosphoinositide 3-kinase (PI3K)-dependent tumor cell invasion. The data explain why rigid collagen fibrils potentiate PI3K activation to promote malignancy and offer a perspective regarding the consistent up-regulation of alpha5beta1 integrin and FN in many tumors and their correlation with cancer aggression. PMID- 28877986 TI - Phosphorylation and nuclear transit modulate the balance between normal function and terminal aggregation of the yeast RNA-binding protein Ssd1. AB - Yeast Ssd1 is an RNA-binding protein that shuttles between the nucleus and cytoplasm. Ssd1 interacts with its target mRNAs initially during transcription by binding through its N-terminal prion-like domain (PLD) to the C-terminal domain of RNA polymerase II. Ssd1 subsequently targets mRNAs acquired in the nucleus either to daughter cells for translation or to stress granules (SGs) and P-bodies (PBs) for mRNA storage or decay. Here we show that PB components assist in the nuclear export of Ssd1and subsequent targeting of Ssd1 to PB sites in the cytoplasm. In the absence of import into the nucleus, Ssd1 fails to associate with PBs in the cytoplasm but rather is targeted to cytosolic insoluble protein deposits (IPODs). The association of Ssd1 either with IPOD sites or with PB/SG requires the PLD, whose activity is differentially regulated by the Ndr/LATS family kinase, Cbk1: phosphorylation suppresses PB/SG association but enhances IPOD formation. This regulation likely accrues from a phosphorylation-sensitive nuclear localization sequence located in the PLD. The results presented here may inform our understanding of aggregate formation by RBP in certain neurological diseases. PMID- 28877989 TI - Regulatory T Cell-Mediated Suppression of Inflammation Induced by DR3 Signaling Is Dependent on Galectin-9. AB - Stimulation of several TNF receptor family proteins has been shown to dampen inflammatory disease in murine models through augmenting the number and/or activity of regulatory T cells (Tregs). We recently found that one molecule, 4 1BB, used binding to Galectin-9 to exert its immunosuppressive effects and drive expansion of CD8+Foxp3- Tregs. We now show that ligation of another TNFR family molecule, DR3, which has previously been found to strongly expand CD4+Foxp3+ Tregs and suppress inflammation, also requires Galectin-9. We found that the extracellular region of DR3 directly binds to Galectin-9, and that Galectin-9 associates with DR3 in Tregs. From studies in vitro with Galectin-9-/- CD4+ T cells and Tregs, we found that stimulatory activity induced by ligating DR3 was in part dependent on Galectin-9. In vivo, in a model of experimental autoimmune encephalomyelitis, we show that an agonist of DR3 suppressed disease, correlating with expansion of CD4+Foxp3+ Tregs, and this protective effect was lost in Galectin-9-/- mice. Similar results were seen in an allergic lung inflammation model. Thus, we demonstrate a novel function of Galectin-9 in facilitating activity of DR3 related to Treg-mediated suppression. PMID- 28877987 TI - Adhesion to the host cell surface is sufficient to mediate Listeria monocytogenes entry into epithelial cells. AB - The intestinal epithelium is the first physiological barrier breached by the Gram positive facultative pathogen Listeria monocytogenes during an in vivo infection. Listeria monocytogenes binds to the epithelial host cell receptor E-cadherin, which mediates a physical link between the bacterium and filamentous actin (F actin). However, the importance of anchoring the bacterium to F-actin through E cadherin for bacterial invasion has not been tested directly in epithelial cells. Here we demonstrate that depleting alphaE-catenin, which indirectly links E cadherin to F-actin, did not decrease L. monocytogenes invasion of epithelial cells in tissue culture. Instead, invasion increased due to increased bacterial adhesion to epithelial monolayers with compromised cell-cell junctions. Furthermore, expression of a mutant E-cadherin lacking the intracellular domain was sufficient for efficient L. monocytogenes invasion of epithelial cells. Importantly, direct biotin-mediated binding of bacteria to surface lipids in the plasma membrane of host epithelial cells was sufficient for uptake. Our results indicate that the only requirement for L. monocytogenes invasion of epithelial cells is adhesion to the host cell surface, and that E-cadherin-mediated coupling of the bacterium to F-actin is not required. PMID- 28877990 TI - Grb2-Mediated Recruitment of USP9X to LAT Enhances Themis Stability following Thymic Selection. AB - Themis is a new component of the TCR signaling machinery that plays a critical role during T cell development. The positive selection of immature CD4+CD8+ double-positive thymocytes and their commitment to the CD4+CD8- single-positive stage are impaired in Themis-/- mice, suggesting that Themis might be important to sustain TCR signals during these key developmental processes. However, the analysis of Themis mRNA levels revealed that Themis gene expression is rapidly extinguished during positive selection. We show in this article that Themis protein expression is increased in double-positive thymocytes undergoing positive selection and is sustained in immature single-positive thymocytes, despite the strong decrease in Themis mRNA levels in these subsets. We found that Themis stability is controlled by the ubiquitin-specific protease USP9X, which removes ubiquitin K48-linked chains on Themis following TCR engagement. Biochemical analyses indicate that USP9X binds directly to the N-terminal CABIT domain of Themis and indirectly to the adaptor protein Grb2, with the latter interaction enabling recruitment of Themis/USP9X complexes to LAT, thereby sustaining Themis expression following positive selection. Together, these data suggest that TCR mediated signals enhance Themis stability upon T cell development and identify USP9X as a key regulator of Themis protein turnover. PMID- 28877988 TI - IL-17A Produced by Innate Lymphoid Cells Is Essential for Intestinal Ischemia Reperfusion Injury. AB - Ischemia-reperfusion (IR) injury to the small intestine following clamping of the superior mesenteric artery results in an intense local inflammatory response that is characterized by villous damage and neutrophil infiltration. IL-17A, a cytokine produced by a variety of cells in response to inflammatory cytokines released following tissue injury, has been implicated in IR injury. Using Il17a-/ , Il23r-/- , and Rorc-/- mice and administration of anti-IL-17A and anti-IL-23 neutralizing Abs to wild-type mice, we demonstrate that intestinal IR injury depends on IL-17A and that IL-17A is downstream of the binding of autoantibody to ischemia-conditioned tissues and subsequent complement activation. Using bone marrow chimeras, we demonstrate that the IL-17A required for intestinal IR injury is derived from hematopoietic cells. Finally, by transferring autoantibody-rich sera into Rag2gammac-/- and Rag2-/- mice, we demonstrate that innate lymphoid cells are the main producers of IL-17A in intestinal IR injury. We propose that local production of IL-17A by innate lymphoid cells is crucial for the development of intestinal IR injury and may provide a therapeutic target for clinical exploitation. PMID- 28877991 TI - Activated Protein C Attenuates Severe Inflammation by Targeting VLA-3high Neutrophil Subpopulation in Mice. AB - The host injury involved in multiorgan system failure during severe inflammation is mediated, in part, by massive infiltration and sequestration of hyperactive neutrophils in the visceral organ. A recombinant form of human activated protein C (rhAPC) has shown cytoprotective and anti-inflammatory functions in some clinical and animal studies, but the direct mechanism is not fully understood. Recently, we reported that, during endotoxemia and severe polymicrobial peritonitis, integrin VLA-3 (CD49c/CD29) is specifically upregulated on hyperinflammatory neutrophils and that targeting the VLA-3high neutrophil subpopulation improved survival in mice. In this article, we report that rhAPC binds to human neutrophils via integrin VLA-3 (CD49c/CD29) with a higher affinity compared with other Arg-Gly-Asp binding integrins. Similarly, there is preferential binding of activated protein C (PC) to Gr1highCD11bhighVLA-3high cells isolated from the bone marrow of septic mice. Furthermore, specific binding of rhAPC to human neutrophils via VLA-3 was inhibited by an antagonistic peptide (LXY2). In addition, genetically modified mutant activated PC, with a high affinity for VLA-3, shows significantly improved binding to neutrophils compared with wild-type activated PC and significantly reduced neutrophil infiltration into the lungs of septic mice. These data indicate that variants of activated PC have a stronger affinity for integrin VLA-3, which reveals novel therapeutic possibilities. PMID- 28877992 TI - Activation of Human Mucosal-Associated Invariant T Cells Induces CD40L-Dependent Maturation of Monocyte-Derived and Primary Dendritic Cells. AB - Mucosal-associated invariant T (MAIT) cells are innate T cells that recognize intermediates of the vitamin B2 biosynthetic pathway presented by the monomorphic MR1 molecule. It remains unclear whether, in addition to their cytolytic activity that is important in antimicrobial defense, MAIT cells have immune-modulatory functions that could enhance dendritic cell (DC) maturation. In this study, we investigated the molecular mechanisms dictating the interactions between human MAIT cells and DCs and demonstrate that human MAIT cells mature monocyte-derived and primary DCs in an MR1- and CD40L-dependent manner. Furthermore, we show that MAIT cell-derived signals synergize with microbial stimuli to induce secretion of bioactive IL-12 by DCs. Activation of human MAIT cells in whole blood leads to MR1- and cytokine-dependent NK cell transactivation. Our results underscore an important property of MAIT cells, which can be of translational relevance to rapidly orchestrate adaptive immunity through DC maturation. PMID- 28877993 TI - Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Abeta1-42 synaptotoxicity. AB - Oligomeric Amyloid beta1-42 (Abeta) plays a crucial synaptotoxic role in Alzheimer's disease, and hyperphosphorylated tau facilitates Abeta toxicity. The link between Abeta and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Abeta acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Abeta. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Abeta-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau mediated neuronal damage. PMID- 28877994 TI - Cadherin complexes recruit mRNAs and RISC to regulate epithelial cell signaling. AB - Cumulative evidence demonstrates that most RNAs exhibit specific subcellular distribution. However, the mechanisms regulating this phenomenon and its functional consequences are still under investigation. Here, we reveal that cadherin complexes at the apical zonula adherens (ZA) of epithelial adherens junctions recruit the core components of the RNA-induced silencing complex (RISC) Ago2, GW182, and PABPC1, as well as a set of 522 messenger RNAs (mRNAs) and 28 mature microRNAs (miRNAs or miRs), via PLEKHA7. Top canonical pathways represented by these mRNAs include Wnt/beta-catenin, TGF-beta, and stem cell signaling. We specifically demonstrate the presence and silencing of MYC, JUN, and SOX2 mRNAs by miR-24 and miR-200c at the ZA. PLEKHA7 knockdown dissociates RISC from the ZA, decreases loading of the ZA-associated mRNAs and miRNAs to Ago2, and results in a corresponding increase of MYC, JUN, and SOX2 protein expression. The present work reveals a mechanism that directly links junction integrity to the silencing of a set of mRNAs that critically affect epithelial homeostasis. PMID- 28877995 TI - A neuroprotective agent that inactivates prodegenerative TrkA and preserves mitochondria. AB - Axon degeneration is an early event and pathological in neurodegenerative conditions and nerve injuries. To discover agents that suppress neuronal death and axonal degeneration, we performed drug screens on primary rodent neurons and identified the pan-kinase inhibitor foretinib, which potently rescued sympathetic, sensory, and motor wt and SOD1 mutant neurons from trophic factor withdrawal-induced degeneration. By using primary sympathetic neurons grown in mass cultures and Campenot chambers, we show that foretinib protected neurons by suppressing both known degenerative pathways and a new pathway involving unliganded TrkA and transcriptional regulation of the proapoptotic BH3 family members BimEL, Harakiri,and Puma, culminating in preservation of mitochondria in the degenerative setting. Foretinib delayed chemotherapy-induced and Wallerian axonal degeneration in culture by preventing axotomy-induced local energy deficit and preserving mitochondria, and peripheral Wallerian degeneration in vivo. These findings identify a new axon degeneration pathway and a potentially clinically useful therapeutic drug. PMID- 28877996 TI - BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres. AB - Alternative lengthening of telomeres (ALT) is a telomere lengthening pathway that predominates in aggressive tumors of mesenchymal origin; however, the underlying mechanism of telomere synthesis is not fully understood. Here, we show that the BLM-TOP3A-RMI (BTR) dissolvase complex is required for ALT-mediated telomere synthesis. We propose that recombination intermediates formed during strand invasion are processed by the BTR complex, initiating rapid and extensive POLD3 dependent telomere synthesis followed by dissolution, with no overall exchange of telomeric DNA. This process is counteracted by the SLX4-SLX1-ERCC4 complex, which promotes resolution of the recombination intermediate, resulting in telomere exchange in the absence of telomere extension. Our data are consistent with ALT being a conservative DNA replication process, analogous to break-induced replication, which is dependent on BTR and counteracted by SLX4 complex-mediated resolution events. PMID- 28877998 TI - Respiratory Infections and the Risk of Celiac Disease. AB - BACKGROUND AND OBJECTIVES: The increasing incidence of celiac disease (CD) suggests that common infections before the onset of autoimmune diseases could be an important factor in switching the immune response. We aimed to explore the relationship between early clinical events and the development of CD in genetically predisposed infants. METHODS: In this study, 373 newborns from families with at least 1 relative with CD were recruited, and human leukocyte antigen DQ2- or DQ8-positive infants were followed up with clinical and serological evaluations. Cross tabulation and odds ratios were used to explore the risk associated with single variables, and logistic regression analysis was performed to determine the variables that contributed to the risk of developing CD. Stepwise discriminant analysis was used to determine which variables could distinguish case patients from controls before diagnosis. RESULTS: The cumulative incidence of CD in this cohort was 6% at 3 years and 13.5% at 5 years of age, and l34 children (14%) developed CD before the sixth year of life. An analysis of adverse events showed a higher frequency of respiratory tract infections among CD patients during the first 24 months of life. In a stepwise discriminant analysis, which included sex and human leukocyte antigen risk class, only respiratory infections in the second and first years of life significantly contributed to discrimination of case patients versus controls. CONCLUSIONS: A multivariate model of discriminant analysis showed that the frequency of respiratory infections in the first 2 years of life could distinguish children who developed CD from those who did not. PMID- 28877997 TI - The Pumilio-domain protein PUF6 contributes to SIDER2 retroposon-mediated mRNA decay in Leishmania. AB - Leishmania and other trypanosomatid protozoa lack control at the level of transcription initiation and regulate gene expression exclusively post transcriptionally. We have reported previously that Leishmania harbors a unique class of short interspersed degenerate retroposons (SIDERs) that are predominantly located within 3'UTRs and play a major role in post-transcriptional control. We have shown that members of the SIDER2 subfamily initiate mRNA decay through endonucleolytic cleavage within the second conserved 79-nt signature sequence of SIDER2 retroposons. Here, we have developed an optimized MS2 coat protein tethering system to capture trans-acting factor(s) regulating SIDER2 mediated mRNA decay. Tethering of the MS2 coat protein to a reporter RNA harboring two MS2 stem-loop aptamers and the cognate SIDER2-containing 3'UTR in combination with immunoprecipitation and mass spectrometry analysis led to the identification of RNA-binding proteins with known functions in mRNA decay. Among the candidate SIDER2-interacting proteins that were individually tethered to a SIDER2 reporter RNA, the Pumilio-domain protein PUF6 was shown to enhance degradation and reduce transcript half-life. Furthermore, we showed that PUF6 binds to SIDER2 sequences that include the regulatory 79-nt signature motif, hence contributing to the mRNA decay process. Consistent with a role of PUF6 in SIDER2-mediated decay, genetic inactivation of PUF6 resulted in increased accumulation and higher stability of endogenous SIDER2-bearing transcripts. Overall, these studies provide new insights into regulated mRNA decay pathways in Leishmania controlled by SIDER2 retroposons and propose a broader role for PUF proteins in mRNA decay within the eukaryotic kingdom. PMID- 28877999 TI - Sudden Cardiac Arrest While Eating a Hot Dog: A Rare Presentation of Brugada Syndrome in a Child. AB - Patients who are diagnosed with Brugada syndrome (BS) usually experience sudden cardiac arrest (SCA) and arrhythmia when they have a high fever, consume alcohol, and, more frequently, during their night sleep. In some rare cases, an SCA can be seen depending on a possible vagal stimulus, such as eating a large bite of food. We describe a 9-year-old patient who had a sudden cardiac attack while he was eating a large hot dog. After successful resuscitation, a suspicious ST elevation in V2 was seen in his electrocardiographic evaluation. He was diagnosed with BS after the ajmaline test and an implantable cardioverter defibrillator was implanted. Vagal stimulus-dependent SCA after eating a large bite of food may be the first symptom of BS. For this reason, the electrocardiographic results of the children who had a cardiac arrest after eating a large meal with big bites should be evaluated in detail. PMID- 28878000 TI - Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing. AB - Recent advances in single-cell, transcriptomic profiling have provided unprecedented access to investigate cell heterogeneity during tissue and organ development. In this study, we used massively parallel, single-cell RNA sequencing to define cell heterogeneity within the zebrafish kidney marrow, constructing a comprehensive molecular atlas of definitive hematopoiesis and functionally distinct renal cells found in adult zebrafish. Because our method analyzed blood and kidney cells in an unbiased manner, our approach was useful in characterizing immune-cell deficiencies within DNA-protein kinase catalytic subunit (prkdc), interleukin-2 receptor gamma a (il2rga), and double-homozygous mutant fish, identifying blood cell losses in T, B, and natural killer cells within specific genetic mutants. Our analysis also uncovered novel cell types, including two classes of natural killer immune cells, classically defined and erythroid-primed hematopoietic stem and progenitor cells, mucin-secreting kidney cells, and kidney stem/progenitor cells. In total, our work provides the first, comprehensive, single-cell, transcriptomic analysis of kidney and marrow cells in the adult zebrafish. PMID- 28878001 TI - NLR Nod1 signaling promotes survival of BCR-engaged mature B cells through up regulated Nod1 as a positive outcome. AB - Although B cell development requires expression of the B cell antigen receptor (BCR), it remains unclear whether engagement of self-antigen provides a positive impact for most B cells. Here, we show that BCR engagement by self-ligand during development in vivo results in up-regulation of the Nod-like receptor member Nod1, which recognizes the products of intestinal commensal bacteria. In anti thymocyte/Thy-1 autoreactive BCR knock-in mice lacking self-Thy-1 ligand, immunoglobulin light chain editing occurred, generating B cells with up-regulated Nod1, including follicular and marginal zone B cells with natural autoreactivity. This BCR editing with increased Nod1 resulted in preferential survival. In normal adult mice, most mature B cells are enriched for Nod1 up-regulated cells, and signaling through Nod1 promotes competitive survival of mature B cells. These findings demonstrate a role for microbial products in promoting survival of mature B cells through up-regulated Nod1, providing a positive effect of BCR engagement on development of most B cells. PMID- 28878002 TI - COMBAT: A Combined Association Test for Genes Using Summary Statistics. AB - Genome-wide association studies (GWAS) have been widely used for identifying common variants associated with complex diseases. Traditional analysis of GWAS typically examines one marker at a time, usually single nucleotide polymorphisms (SNPs), to identify individual variants associated with a disease. However, due to the small effect sizes of common variants, the power to detect individual risk variants is generally low. As a complementary approach to SNP-level analysis, a variety of gene-based association tests have been proposed. However, the power of existing gene-based tests is often dependent on the underlying genetic models, and it is not known a priori which test is optimal. Here we propose a combined association test (COMBAT) for genes, which incorporates strengths from existing gene-based tests and shows higher overall performance than any individual test. Our method does not require raw genotype or phenotype data, but needs only SNP level P-values and correlations between SNPs from ancestry-matched samples. Extensive simulations showed that COMBAT has an appropriate type I error rate, maintains higher power across a wide range of genetic models, and is more robust than any individual gene-based test. We further demonstrated the superior performance of COMBAT over several other gene-based tests through reanalysis of the meta-analytic results of GWAS for bipolar disorder. Our method allows for the more powerful application of gene-based analysis to complex diseases, which will have broad use given that GWAS summary results are increasingly publicly available. PMID- 28878004 TI - Mycoplasma genitalium Macrolide and Fluoroquinolone Resistance Detection and Clinical Implications in a Selected Cohort in New Zealand. AB - Mycoplasma genitalium has been associated with infections of the genitourinary tract, and prevalence is secondary to Chlamydia trachomatis The clinical observation of increasing treatment failure indicating antibiotic resistance, especially in cases of recurrent urethritis, has been confirmed by molecular testing. Mutations in the 23S rRNA gene can cause macrolide resistance, and topoisomerase/gyrase mutations can cause fluoroquinolone resistance. In this study, 115 M. genitalium DNA-positive samples were analyzed. Eighty-nine (77.4%) samples had a 23S rRNA mutation present, and 26 (22.6%) were wild type (no resistance mutation). Fluoroquinolone mutation screening was performed on 86 (74.8%) of the 115 samples, of which 20 (23.3%) samples had a mutation or mutations associated with increased resistance. This study shows the increasing antibiotic resistance in New Zealand and the need for appropriate guidelines to treat at-risk patients. PMID- 28878003 TI - Evaluation of the Lumipulse G TP-N Chemiluminescent Immunoassay as a Syphilis Screening Test. AB - A syphilis diagnosis is often aided by the detection of treponemal and nontreponemal antibodies. Automated treponemal antibody detection systems enable high-volume clinical laboratories to perform syphilis screening at a faster pace with lower labor costs. The Lumipulse G TP-N chemiluminescent immunoassay is an automated system that qualitatively detects IgG and IgM antibodies against Treponema pallidum antigens in human serum and plasma. To assess performance characteristics and workflow efficiency, the Lumipulse G TP-N assay was compared to the Bioplex 2200 Syphilis IgG multiplex flow immunoassay. Among the 4,134 routine and HIV samples tested by the two automated assays, the percentage of agreement was excellent at 99.0% (95% confidence interval [CI], 98.6% to 99.2%; kappa, 0.89), with the Lumipulse G TP-N having a shorter time to first and subsequent results. All specimens with reactive syphilis screening results were further tested by rapid plasma reagin (RPR) and Treponema pallidum particle agglutination (TP.PA) testing (n = 231). The results from the RPR-reactive samples (n = 82) showed complete concordance with the two automated assays, while the TP.PA assay displayed some discrepancies. The positive percent agreement (PPA) and negative percent agreement (NPA) between the TP.PA test and the Lumipulse G TP-N test were 98.9% and 77.3%, respectively. The Bioplex 2200 Syphilis IgG immunoassay displayed a similar PPA (100%) but a substantially lower NPA (15.9%). Patient chart reviews of discrepant results suggested that the Lumipulse G TP-N assay produced 27 fewer falsely reactive results and can reduce the amount of additional confirmatory RPR and TP.PA testing needed. The analogous performance characteristics of the two automated systems indicate that the Lumipulse G TP-N assay is suitable for high-throughput syphilis screening. PMID- 28878005 TI - Citrate Anticoagulant Improves the Sensitivity of Borreliella (Borrelia) burgdorferi Plasma Culture. PMID- 28878006 TI - Evaluation of GenoType MTBDRplus by Use of Extracted DNA from Formalin-Fixed Paraffin-Embedded Specimens. PMID- 28878007 TI - Development of Serotype-Specific PCR Assays for Typing of Haemophilus parasuis Isolates Circulating in Southern China. AB - The bacterium Haemophilus parasuis is the specific pathogenic cause of Glasser's disease in swine. Fifteen serotypes of H. parasuis have been reported. A method to serotype H. parasuis isolates accurately would help to prevent and control Glasser's disease outbreaks through appropriate vaccination and to understand the epidemiology in specific geographic areas. However, according to traditional serotyping, the rate of nontypeable (NT) strains is 10 to 40%, which gives low accuracy. In the present study, we developed a set of PCR assays that are able to identify all the currently known H. parasuis serotypes, with a detection limit of 5 CFU. This PCR method is particularly useful to distinguish serotype 5 from serotype 12. We then surveyed the serotype prevalence of H. parasuis isolates from southern China using both the traditional indirect hemagglutination (IHA) and current PCR methods. Of the 298 isolates tested, 228 (76.51%) and 281 (94.30%) were serotyped by the IHA and PCR tests, respectively, with a concordance rate of 80.87% (241/298). The most prevalent serotypes obtained by PCR were 4, 5, 12, 13, NT, and 2, and the most prevalent obtained by IHA were NT, 5, 4, 12, 13, and 2. In conclusion, the PCR assays developed in this study provide a rapid and specific method for the molecular serotyping of H. parasuis. PMID- 28878008 TI - Biographical Feature: William Michael Dunne, Jr., Ph.D. PMID- 28878009 TI - Multisite Evaluation of the BD Max Extended Enteric Bacterial Panel for Detection of Yersinia enterocolitica, Enterotoxigenic Escherichia coli, Vibrio, and Plesiomonas shigelloides from Stool Specimens. AB - The purpose of this study was to perform a multisite evaluation to establish the performance characteristics of the BD Max extended enteric bacterial panel (xEBP) assay directly from unpreserved or Cary-Blair-preserved stool specimens for the detection of Yersinia enterocolitica, enterotoxigenic Escherichia coli (ETEC), Vibrio, and Plesiomonas shigelloides The study included prospective, retrospective, and prepared contrived specimens from 6 clinical sites. BD Max xEBP results were compared to the reference method, which included standard culture techniques coupled with alternate PCR and sequencing, except for ETEC, for which the reference method was two alternate PCRs and sequencing. Alternate PCR was also used to confirm the historical results for the retrospective specimens and for discrepant result analysis. A total of 2,410 unformed, deidentified stool specimens were collected. The prevalence in the prospective samples as defined by the reference method was 1.2% ETEC, 0.1% Vibrio, 0% Y. enterocolitica, and 0% P. shigelloides Compared to the reference method, the positive percent agreement (PPA) (95% confidence interval [CI]), negative percent agreement (NPA) (95% CI), and kappa coefficient (95% CI) for the BD Max xEBP assay for all specimens combined were as follows: ETEC, 97.6% (87.4 to 99.6), 99.8% (99.5 to 99.9), and 0.93 (0.87 to 0.99); Vibrio, 100% (96.4 to 100), 99.7% (99.4 to 99.8), and 0.96 (0.93 to 0.99); Y. enterocolitica, 99.0% (94.8 to 99.8), 99.9% (99.8 to 99.9), and 0.99 (0.98 to 1); P. shigelloides, 100% (96.4 to 100), 99.8% (99.5 to 99.9), and 0.98 (0.95 to 1), respectively. In this multicenter study, the BD Max xEBP showed a high correlation (kappa, 0.97; 95% CI, 0.95 to 0.98) with the conventional methods for the detection of ETEC, Vibrio, Y. enterocolitica, and P. shigelloides in stool specimens from patients suspected of acute gastroenteritis, enteritis, or colitis. PMID- 28878010 TI - Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge. AB - Neutralizing antibodies to the V2 apex antigenic region of the HIV-1 envelope (Env) trimer are among the most prevalent cross-reactive antibodies elicited by natural infection. Two recently described V2-specific antibodies, PGDM1400 and CAP256-VRC26.25, have demonstrated exquisite potency and neutralization breadth against HIV-1. However, little data exist on the protective efficacy of V2 specific neutralizing antibodies. We created a novel SHIV-325c viral stock that included a clade C HIV-1 envelope and was susceptible to neutralization by both of these antibodies. Rhesus macaques received a single infusion of either antibody at three different concentrations (2, 0.4, and 0.08 mg/kg) before challenge with SHIV-325c. PGDM1400 was fully protective at the 0.4 mg/kg dose, whereas CAP256-VRC26.25-LS was fully protective even at the 0.08 mg/kg dose, which correlated with its greater in vitro neutralization potency against the challenge virus. Serum antibody concentrations required for protection were <0.75 MUg/ml for CAP256-VRC26.25-LS. These data demonstrate unprecedented potency and protective efficacy of V2-specific neutralizing antibodies in nonhuman primates and validate V2 as a potential target for the prevention of HIV-1 infection in passive immunization strategies in humans. PMID- 28878011 TI - Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. AB - Conventional methods for histopathologic tissue diagnosis are labor- and time intensive and can delay decision-making during diagnostic and therapeutic procedures. We report the development of an automated and biocompatible handheld mass spectrometry device for rapid and nondestructive diagnosis of human cancer tissues. The device, named MasSpec Pen, enables controlled and automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules. We used the MasSpec Pen for ex vivo molecular analysis of 20 human cancer thin tissue sections and 253 human patient tissue samples including normal and cancerous tissues from breast, lung, thyroid, and ovary. The mass spectra obtained presented rich molecular profiles characterized by a variety of potential cancer biomarkers identified as metabolites, lipids, and proteins. Statistical classifiers built from the histologically validated molecular database allowed cancer prediction with high sensitivity (96.4%), specificity (96.2%), and overall accuracy (96.3%), as well as prediction of benign and malignant thyroid tumors and different histologic subtypes of lung cancer. Notably, our classifier allowed accurate diagnosis of cancer in marginal tumor regions presenting mixed histologic composition. Last, we demonstrate that the MasSpec Pen is suited for in vivo cancer diagnosis during surgery performed in tumor-bearing mouse models, without causing any observable tissue harm or stress to the animal. Our results provide evidence that the MasSpec Pen could potentially be used as a clinical and intraoperative technology for ex vivo and in vivo cancer diagnosis. PMID- 28878012 TI - Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins. AB - Low-molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12 mers could be reversed using protamine. One of these, labeled as 12-mer-1, reduced the size of blood clots in the mouse model of deep vein thrombosis and attenuated circulating procoagulant markers in the mouse model of sickle cell disease. An ex vivo experiment demonstrates that the anticoagulant activity of 12 mer-1 could be reversed by protamine. 12-mer-1 was also examined in a nonhuman primate model to determine its pharmacodynamic parameters. A 7-day toxicity study in a rat model showed no toxic effects. The data suggest that a synthetic homogeneous oligosaccharide can replace animal-sourced LMWHs. PMID- 28878013 TI - New class of precision antimicrobials redefines role of Clostridium difficile S layer in virulence and viability. AB - There is a medical need for antibacterial agents that do not damage the resident gut microbiota or promote the spread of antibiotic resistance. We recently described a prototypic precision bactericidal agent, Av-CD291.2, which selectively kills specific Clostridium difficile strains and prevents them from colonizing mice. We have since selected two Av-CD291.2-resistant mutants that have a surface (S)-layer-null phenotype due to distinct point mutations in the slpA gene. Using newly identified bacteriophage receptor binding proteins for targeting, we constructed a panel of Avidocin-CDs that kills diverse C. difficile isolates in an S-layer sequence-dependent manner. In addition to bacteriophage receptor recognition, characterization of the mutants also uncovered important roles for S-layer protein A (SlpA) in sporulation, resistance to innate immunity effectors, and toxin production. Surprisingly, S-layer-null mutants were found to persist in the hamster gut despite a complete attenuation of virulence. These findings suggest antimicrobials targeting virulence factors dispensable for fitness in the host force pathogens to trade virulence for viability and would have clear clinical advantages should resistance emerge. Given their exquisite specificity for the pathogen, Avidocin-CDs have substantial therapeutic potential for the treatment and prevention of C. difficile infections. PMID- 28878014 TI - Identification of a 35S U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complex intermediate in spliceosome assembly. AB - The de novo assembly and post-splicing reassembly of the U4/U6.U5 tri-snRNP remain to be investigated. We report here that ZIP, a protein containing a CCCH type zinc finger and a G-patch domain, as characterized by us previously, regulates pre-mRNA splicing independent of RNA binding. We found that ZIP physically associates with the U4/U6.U5 tri-small nuclear ribonucleoprotein (tri snRNP). Remarkably, the ZIP-containing tri-snRNP, which has a sedimentation coefficient of ~35S, is a tri-snRNP that has not been described previously. We also found that the 35S tri-snRNP contains hPrp24, indicative of a state in which the U4/U6 di-snRNP is integrating with the U5 snRNP. We found that the 35S tri snRNP is enriched in the Cajal body, indicating that it is an assembly intermediate during 25S tri-snRNP maturation. We showed that the 35S tri-snRNP also contains hPrp43, in which ATPase/RNA helicase activities are stimulated by ZIP. Our study identified, for the first time, a tri-snRNP intermediate, shedding new light on the de novo assembly and recycling of the U4/U6.U5 tri-snRNP. PMID- 28878015 TI - Thioredoxin-1 actively maintains the pseudokinase MLKL in a reduced state to suppress disulfide bond-dependent MLKL polymer formation and necroptosis. AB - Necroptosis is an immunogenic cell death program that is associated with a host of human diseases, including inflammation, infections, and cancer. Receptor interacting protein kinase 3 (RIPK3) and its substrate mixed lineage kinase domain-like protein (MLKL) are required for necroptosis activation. Specifically, RIPK3-dependent MLKL phosphorylation promotes the assembly of disulfide bond dependent MLKL polymers that drive the execution of necroptosis. However, how MLKL disulfide bond formation is regulated is not clear. In this study we discovered that the MLKL-modifying compound necrosulfonamide cross-links cysteine 86 of human MLKL to cysteine 32 of the thiol oxidoreductase thioredoxin-1 (Trx1). Recombinant Trx1 preferentially binds to monomeric MLKL and blocks MLKL disulfide bond formation and polymerization in vitro Inhibition of MLKL polymer formation requires the reducing activity of Trx1. Importantly, shRNA-mediated knockdown of Trx1 promotes MLKL polymerization and sensitizes cells to necroptosis. Furthermore, pharmacological inhibition of Trx1 with compound PX-12 induces necroptosis in multiple cancer cell lines. Altogether, these findings demonstrate that Trx1 is a critical regulator of necroptosis that suppresses cell death by maintaining MLKL in a reduced inactive state. Our results further suggest new directions for targeted cancer therapy in which thioredoxin inhibitors like PX-12 could potentially be used to specifically target cancers expressing high levels of MLKL or MLKL short isoforms. PMID- 28878016 TI - Enantiomeric barbiturates bind distinct inter- and intrasubunit binding sites in a nicotinic acetylcholine receptor (nAChR). AB - Nicotinic acetylcholine receptors (nAChRs) and gamma-aminobutyric acid type A receptors (GABAARs) are members of the pentameric ligand-gated ion channel superfamily. Drugs acting as positive allosteric modulators of muscle-type alpha2betagammadelta nAChRs, of use in treatment of neuromuscular disorders, have been hard to identify. However, identification of nAChR allosteric modulator binding sites has been facilitated by using drugs developed as photoreactive GABAAR modulators. Recently, R-1-methyl-5-allyl-5-(m-trifluoromethyl diazirinylphenyl) barbituric acid (R-mTFD-MPAB), an anesthetic and GABAAR potentiator, has been shown to inhibit Torpedo alpha2betagammadelta nAChRs, binding in the ion channel and to a gamma+-alpha- subunit interface site similar to its GABAAR intersubunit binding site. In contrast, S-1-methyl-5-propyl-5-(m trifluoromethyl-diazirinylphenyl) barbituric acid (S-mTFD-MPPB) acts as a convulsant and GABAAR inhibitor. Photolabeling studies established that S-mTFD MPPB binds to the same GABAAR intersubunit binding site as R-mTFD-MPAB, but with negative rather than positive energetic coupling to GABA binding. We now show that S-mTFD-MPPB binds with the same state (agonist) dependence as R-mTFD-MPAB within the nAChR ion channel, but it does not bind to the intersubunit binding site. Rather, S-mTFD-MPPB binds to intrasubunit sites within the alpha and delta subunits, photolabeling alphaVal-218 (alphaM1), deltaPhe-232 (deltaM1), deltaThr 274 (deltaM2), and deltaIle-288 (deltaM3). Propofol, a general anesthetic that binds to GABAAR intersubunit sites, inhibited [3H]S-mTFD-MPPB photolabeling of these nAChR intrasubunit binding sites. These results demonstrate that in an nAChR, the subtle difference in structure between S-mTFD-MPPB and R-mTFD-MPAB (chirality; 5-propyl versus 5-allyl) determines selectivity for intra- versus intersubunit sites, in contrast to GABAARs, where this difference affects state dependence of binding to a common site. PMID- 28878017 TI - Structural basis for pH-insensitive inhibition of immunoglobulin G recycling by an anti-neonatal Fc receptor antibody. AB - The neonatal Fc receptor FcRn plays a critical role in the trafficking of IgGs across tissue barriers and in retaining high circulating concentrations of both IgG and albumin. Although generally beneficial from an immunological perspective in maintaining IgG populations, FcRn can contribute to the pathogenesis of autoimmune disorders when an abnormal immune response targets normal biological components. We previously described a monoclonal antibody (DX-2507) that binds to FcRn with high affinity at both neutral and acidic pH, prevents the simultaneous binding of IgG, and reduces circulating IgG levels in preclinical animal models. Here, we report a 2.5 A resolution X-ray crystal structure of an FcRn-DX-2507 Fab complex, revealing a nearly complete overlap of the IgG-Fc binding site in FcRn by complementarity-determining regions in DX-2507. This overlap explains how DX 2507 blocks IgG binding to FcRn and thereby shortens IgG half-life by preventing IgGs from recycling back into circulation. Moreover, the complex structure explains how the DX-2507 interaction is pH-insensitive unlike normal Fc interactions and how serum albumin levels are unaffected by DX-2507 binding. These structural studies could inform antibody-based therapeutic approaches for limiting the effects of IgG-mediated autoimmune disease. PMID- 28878018 TI - A rational approach to enhancing antibody Fc homodimer formation for robust production of antibody mixture in a single cell line. AB - Combinations of different antibodies have been shown to be more effective for managing certain diseases than monotherapy. Co-expression of the antibody mixture in a single cell line is key to reducing complexity during antibody development and manufacturing. However, co-transfection of multiple light and heavy chains into cells often leads to production of mismatched, heterodimeric by-products that are inactive, making the development of co-expression systems that robustly and efficiently produce highly active antibody mixtures a high priority. In this study, we modified the CH3 domain interface of the antibody fragment crystallizable (Fc) region by changing several charge pairs to create electrostatic interactions favoring Fc homodimer formation and disfavoring Fc heterodimer formation. When co-expressed, these modified antibodies with altered charge polarity across the Fc dimer interface preferentially formed homodimers that fully preserved the functions of each component, rather than inactive heterodimers whose formation was reduced because of rationally designed repulsive interactions. We designed eight different combinations and experimentally screened the best one, which enabled us to produce a binary antibody mixture against the EGF receptor with a minimal heterodimer contaminant. We further determined the crystal structure of a triple-mutated Fc variant in the best combination, and we elucidated the molecular interactions favoring Fc homodimer over heterodimer formation, which provided a structural basis for further optimization. The approach presented here demonstrates the feasibility of rational antibody modification for efficient and consistent production of monoclonal antibody mixtures in a single cell line and thus broadens our options for manufacturing more effective antibody-based therapeutic agents. PMID- 28878019 TI - The lipopolysaccharide transport (Lpt) machinery: A nonconventional transporter for lipopolysaccharide assembly at the outer membrane of Gram-negative bacteria. AB - The outer membrane (OM) of Gram-negative is a unique lipid bilayer containing LPS in its outer leaflet. Because of the presence of amphipathic LPS molecules, the OM behaves as an effective permeability barrier that makes Gram-negative bacteria inherently resistant to many antibiotics. This review focuses on LPS biogenesis and discusses recent advances that have contributed to our understanding of how this complex molecule is transported across the cellular envelope and is assembled at the OM outer leaflet. Clearly, this knowledge represents an important platform for the development of novel therapeutic options to manage Gram-negative infections. PMID- 28878020 TI - Lipid stress inhibits endocytosis of melanocortin-4 receptor from modified clathrin-enriched sites and impairs receptor desensitization. AB - Melanocortin-4 receptor (MC4R) is a G-protein-coupled receptor expressed in the brain's hypothalamus where it regulates energy homeostasis. MC4R agonists function to lower food intake and weight. In this respect, although obesity promotes hyperlipidemia and hypothalamic injury, MC4R agonists are nevertheless more effective to reduce food intake within hours of administration in overweight, rather than lean, mice. MC4R undergoes constitutive internalization and recycling to the plasma membrane with agonist binding inducing receptor retention along the intracellular route and, under prolonged exposure, desensitization. Here, we found that, in neuronal cells, lipid stress by exposure to elevated palmitate leaves unchanged the rate by which MC4R and transferrin receptor are constitutively excluded from the cell surface. However, lipid stress disrupted later steps of MC4R and transferrin receptor internalization to endosomes as well as traffic of agonist-occupied MC4R to lysosomes and MC4R desensitization. In the lipid-stressed cells, MC4R and clathrin were redistributed to the plasma membrane where they colocalized to sites that appeared by super-resolution microscopy to be modified and to have higher clathrin content than those of cells not exposed to elevated palmitate. The data suggest that lipid stress disrupts steps of endocytosis following MC4R localization to clathrin-coated sites and exclusion of the receptor from the extracellular medium. We conclude that increased effectiveness of MC4R agonists in obesity may be an unexpected outcome of neuronal injury with disrupted clathrin-dependent endocytosis and impaired receptor desensitization. PMID- 28878021 TI - CK1alpha ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation. AB - Casein kinase 1alpha (CK1alpha), a component of the beta-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1alpha (encoded by Csnk1a1) in skin physiology, we crossed mice harboring floxed Csnk1a1 with mice expressing K14-Cre-ERT2 to generate mice in which tamoxifen induces the deletion of Csnk1a1 exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1alpha loss was accompanied by beta-catenin and p53 stabilization, with the preferential induction of p53 target genes, but phenotypically most striking was hyperpigmentation of the skin, importantly without tumorigenesis, for at least 9 mo after Csnk1a1 ablation. The number of epidermal melanocytes and eumelanin levels were dramatically increased in SKO mice. To clarify the putative role of p53 in epidermal hyperpigmentation, we established K14-Cre-ERT2 CK1alpha/p53 double-knockout (DKO) mice and found that coablation failed to induce epidermal hyperpigmentation, demonstrating that it was p53-dependent. Transcriptome analysis of the epidermis revealed p53-dependent up-regulation of Kit ligand (KitL). SKO mice treated with ACK2 (a Kit-neutralizing antibody) or imatinib (a Kit inhibitor) abrogated the CK1alpha ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of alpha-melanocyte-stimulating hormone (alpha-MSH), was not activated in the CK1alpha ablation-induced hyperpigmentation, which is in contrast to the mechanism of p53-dependent UV tanning. Nevertheless, acute sunburn effects were successfully prevented in the hyperpigmented skin of SKO mice. CK1alpha inhibition induces skin-protective eumelanin but no carcinogenic pheomelanin and may therefore constitute an effective strategy for safely increasing eumelanin via UV-independent pathways, protecting against acute sunburn. PMID- 28878023 TI - Maximal aggregation of polynomial dynamical systems. AB - Ordinary differential equations (ODEs) with polynomial derivatives are a fundamental tool for understanding the dynamics of systems across many branches of science, but our ability to gain mechanistic insight and effectively conduct numerical evaluations is critically hindered when dealing with large models. Here we propose an aggregation technique that rests on two notions of equivalence relating ODE variables whenever they have the same solution (backward criterion) or if a self-consistent system can be written for describing the evolution of sums of variables in the same equivalence class (forward criterion). A key feature of our proposal is to encode a polynomial ODE system into a finitary structure akin to a formal chemical reaction network. This enables the development of a discrete algorithm to efficiently compute the largest equivalence, building on approaches rooted in computer science to minimize basic models of computation through iterative partition refinements. The physical interpretability of the aggregation is shown on polynomial ODE systems for biochemical reaction networks, gene regulatory networks, and evolutionary game theory. PMID- 28878024 TI - Molecular mechanism of substrate recognition and transport by the AtSWEET13 sugar transporter. AB - Sugar Will Eventually be Exported Transporters (SWEETs) are recently identified sugar transporters that can discriminate and transport di- or monosaccharides across a membrane following the concentration gradient. SWEETs play key roles in plant biological processes, such as pollen nutrition, nectar secretion, seed filling, and phloem loading. SWEET13 from Arabidopsis thaliana (AtSWEET13) is an important sucrose transporter in pollen development. Here, we report the 2.8-A resolution crystal structure of AtSWEET13 in the inward-facing conformation with a substrate analog, 2'-deoxycytidine 5'-monophosphate, bound in the central cavity. In addition, based on the results of an in-cell transport activity assay and single-molecule Forster resonance energy transfer analysis, we suggest a mechanism for substrate selectivity based on the size of the substrate-binding pocket. Furthermore, AtSWEET13 appears to form a higher order structure presumably related to its function. PMID- 28878022 TI - Drusen in patient-derived hiPSC-RPE models of macular dystrophies. AB - Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, the mechanisms underlying their progression remain ill-defined. This is partly due to the lack of disease models recapitulating the human pathology. Furthermore, in vivo studies have yielded limited understanding of the role of specific cell types in the eye vs. systemic influences (e.g., serum) on the disease pathology. Here, we use human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) derived from patients with three dominant MDs, Sorsby's fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy/malattia Leventinese (DHRD), and autosomal dominant radial drusen (ADRD), and demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases. Consistent with clinical studies, sub-RPE basal deposits were present beneath both control (unaffected) and patient hiPSC-RPE cells. Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid- and protein-rich "drusen-like" composition. Furthermore, increased accumulation of COL4 was observed in ECM isolated from control vs. patient hiPSC-RPE cultures. Interestingly, RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD). Finally, although serum exposure was not necessary for drusen formation, COL4 accumulation in ECM, and complement pathway gene alteration, it impacted the composition of drusen-like deposits in patient hiPSC-RPE cultures. Together, the drusen model(s) of MDs described here provide fundamental insights into the unique biology of maculopathies affecting the RPE-ECM interface. PMID- 28878025 TI - Gallbladder-derived surfactant protein D regulates gut commensal bacteria for maintaining intestinal homeostasis. AB - The commensal microbiota within the gastrointestinal tract is essential in maintaining homeostasis. Indeed, dysregulation in the repertoire of microbiota can result in the development of intestinal immune-inflammatory diseases. Further, this immune regulation by gut microbiota is important systemically, impacting health and disease of organ systems beyond the local environment of the gut. What has not been explored is how distant organs might in turn shape the microbiota via microbe-targeted molecules. Here, we provide evidence that surfactant protein D (SP-D) synthesized in the gallbladder and delivered into intestinal lumen binds selectively to species of gut commensal bacteria. SP-D deficient mice manifest intestinal dysbiosis and show a susceptibility to dextran sulfate sodium-induced colitis. Further, fecal transfer from SP-D-deficient mice to wild-type, germ-free mice conveyed colitis susceptibility. Interestingly, colitis caused a notable increase in Sftpd gene expression in the gallbladder, but not in the lung, via the activity of glucocorticoids produced in the liver. These findings describe a unique mechanism of interorgan regulation of intestinal immune homeostasis by SP-D with potential clinical implications such as cholecystectomy. PMID- 28878027 TI - Death by HDAC Inhibition in Synovial Sarcoma Cells. AB - Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell-cycle arrest, neuronal differentiation, and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb group targets were reactivated, including tumor suppressor CDKN2A, and proapoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and proapoptotic factors BIK, BIM, and BMF were important to apoptosis induction following HDAC inhibition in synovial sarcoma. HDAC inhibitor pathway activation results in apoptosis and decreased tumor burden following a 7-day quisinostat treatment in the Ptenfl/fl;hSS2 mouse model of synovial sarcoma. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of clinical treatment. Mol Cancer Ther; 16(12); 2656-67. (c)2017 AACR. PMID- 28878028 TI - Basal-A Triple-Negative Breast Cancer Cells Selectively Rely on RNA Splicing for Survival. AB - Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of 1 TNBC line. Thirty common dependency genes were identified, including multiple proteasome and RNA splicing genes, especially those associated with the U4/U6.U5 tri-snRNP complex (e.g., PRPF8, PRPF38A). PRPF8 or PRPF38A knockdown or the splicing modulator E7107 led to widespread intronic retention and altered splicing of transcripts involved in multiple basal-like TNBC dependencies, including protein homeostasis, mitosis, and apoptosis. E7107 treatment suppressed the growth of basal-A TNBC cell line and patient-derived basal-like TNBC xenografts at a well-tolerated dose. The antitumor response was enhanced by adding the proteasome inhibitor bortezomib. Thus, inhibiting both splicing and the proteasome might be an effective approach for treating basal-like TNBC. Mol Cancer Ther; 16(12); 2849-61. (c)2017 AACR. PMID- 28878026 TI - The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma. AB - Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375-86. (c)2017 AACR. PMID- 28878029 TI - IL4 Receptor-Targeted Proapoptotic Peptide Blocks Tumor Growth and Metastasis by Enhancing Antitumor Immunity. AB - Cellular cross-talk between tumors and M2-polarized tumor-associated macrophages (TAM) favors tumor progression. Upregulation of IL4 receptor (IL4R) is observed in diverse tumors and TAMs. We tested whether an IL4R-targeted proapoptotic peptide could inhibit tumor progression. The IL4R-binding peptide (IL4RPep-1) preferentially bound to IL4R-expressing tumor cells and M2-polarized macrophages both in vitro and in 4T1 breast tumors in vivo To selectively kill IL4R expressing cells, we designed an IL4R-targeted proapoptotic peptide, IL4RPep-1-K, by adding the proapoptotic peptide (KLAKLAK)2 to the end of IL4RPep-1. IL4RPep-1 K exerted selective cytotoxicity against diverse IL4R-expressing tumor cells and M2-polarized macrophages. Systemic administration of IL4RPep-1-K inhibited tumor growth and metastasis in 4T1 breast tumor-bearing mice. Interestingly, IL4RPep-1 K treatment increased the number of activated cytotoxic CD8+ T cells while reducing the numbers of immunosuppressive regulatory T cells and M2-polarized TAMs. No significant systemic side effects were observed. These results suggest that IL4R-targeted proapoptotic peptide has potential for treating diverse IL4R expressing cancers. Mol Cancer Ther; 16(12); 2803-16. (c)2017 AACR. PMID- 28878030 TI - The Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels. AB - Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are important members of the voltage-gated pore loop channels family. They show unique features: they open at hyperpolarizing potential, carry a mixed Na/K current, and are regulated by cyclic nucleotides. Four different isoforms have been cloned (HCN1-4) that can assemble to form homo- or heterotetramers, characterized by different biophysical properties. These proteins are widely distributed throughout the body and involved in different physiologic processes, the most important being the generation of spontaneous electrical activity in the heart and the regulation of synaptic transmission in the brain. Their role in heart rate, neuronal pacemaking, dendritic integration, learning and memory, and visual and pain perceptions has been extensively studied; these channels have been found also in some peripheral tissues, where their functions still need to be fully elucidated. Genetic defects and altered expression of HCN channels are linked to several pathologies, which makes these proteins attractive targets for translational research; at the moment only one drug (ivabradine), which specifically blocks the hyperpolarization-activated current, is clinically available. This review discusses current knowledge about HCN channels, starting from their biophysical properties, origin, and developmental features, to (patho)physiologic role in different tissues and pharmacological modulation, ending with their present and future relevance as drug targets. PMID- 28878031 TI - Collective memory in primate conflict implied by temporal scaling collapse. AB - In biological systems, prolonged conflict is costly, whereas contained conflict permits strategic innovation and refinement. Causes of variation in conflict size and duration are not well understood. We use a well-studied primate society model system to study how conflicts grow. We find conflict duration is a 'first to fight' growth process that scales superlinearly, with the number of possible pairwise interactions. This is in contrast with a 'first to fail' process that characterizes peaceful durations. Rescaling conflict distributions reveals a universal curve, showing that the typical time scale of correlated interactions exceeds nearly all individual fights. This temporal correlation implies collective memory across pairwise interactions beyond those assumed in standard models of contagion growth or iterated evolutionary games. By accounting for memory, we make quantitative predictions for interventions that mitigate or enhance the spread of conflict. Managing conflict involves balancing the efficient use of limited resources with an intervention strategy that allows for conflict while keeping it contained and controlled. PMID- 28878032 TI - Effect of aspirin on tumour cell colony formation and evolution. AB - Aspirin is known to reduce the risk of colorectal cancer (CRC) incidence, but the underlying mechanisms are not fully understood. In a previous study, we quantified the in vitro growth kinetics of different CRC tumour cell lines treated with varying doses of aspirin, measuring the rate of cell division and cell death. Here, we use these measured parameters to calculate the chances of successful clonal expansion and to determine the evolutionary potential of the tumour cell lines in the presence and absence of aspirin. The calculations indicate that aspirin increases the probability that a single tumour cell fails to clonally expand. Further, calculations suggest that aspirin increases the evolutionary potential of an expanding tumour cell colony. An aspirin-treated tumour cell population is predicted to result in the accumulation of more mutations (and is thus more virulent and more difficult to treat) than a cell population of the same size that grew without aspirin. This indicates a potential trade-off between delaying the onset of cancer and increasing its evolutionary potential through chemoprevention. Further work needs to investigate to what extent these findings apply to in vivo settings, and to what degree they contribute to the epidemiologically documented aspirin-mediated protection. PMID- 28878033 TI - A light-dependent magnetoreception mechanism insensitive to light intensity and polarization. AB - Billions of migratory birds navigate thousands of kilometres every year aided by a magnetic compass sense, the biophysical mechanism of which is unclear. One leading hypothesis is that absorption of light by specialized photoreceptors in the retina produces short-lived chemical intermediates known as radical pairs whose chemistry is sensitive to tiny magnetic interactions. A potentially serious but largely ignored obstacle to this theory is how directional information derived from the Earth's magnetic field can be separated from the much stronger variations in the intensity and polarization of the incident light. Here we propose a simple solution in which these extraneous effects are cancelled by taking the ratio of the signals from two neighbouring populations of magnetoreceptors. Geometric and biological arguments are used to derive a set of conditions that make this possible. We argue that one likely location of the magnetoreceptor molecules would be in association with ordered opsin dimers in the membrane discs of the outer segments of double-cone photoreceptor cells. PMID- 28878034 TI - Validation Testing Demonstrates Efficacy of a 7-Day Fluid Record to Estimate Daily Water Intake in Adult Men and Women When Compared with Total Body Water Turnover Measurement. AB - Background: Mean daily water intake from fluids (WATER-FL) has proven to be difficult to measure because of a range of nonvalidated data collection techniques. Few questionnaires have been validated to estimate WATER-FL against self-reported diaries or urinary hydration markers, which may limit their objectivity.Objectives: The goals of this investigation were 1) to assess the validity of a 7-d fluid record (7dFLR) to measure WATER-FL (WATER-FL-7dFLR) through comparison with WATER-FL as calculated by measuring deuterium oxide (D2O) disappearance (WATER-FL-D2O), and 2) to evaluate the reliability of the 7dFLR in measuring WATER-FL.Methods: Participants [n = 96; 51% female; mean +/- SD age: 41 +/- 14 y; mean +/- SD body mass index (in kg/m2): 26.2 +/- 5.1] completed body water turnover analysis over 3 consecutive weeks. They completed the 7dFLR and food diaries during weeks 2 and 4 of the observation. The records were entered into nutritional software to determine the water content of all foods and fluids consumed. WATER-FL-D2O was calculated from water turnover (via the D2O dilution method), minus water from food and metabolic water. The agreement between the 2 methods of determining WATER-FL were compared according to a Bland-Altman plot at week 2. The test-retest reliability of 7dFLR between weeks 2 and 4 was assessed via intraclass correlation (ICC).Results: The mean +/- SD difference between WATER-FL-7dFLR and WATER-FL-D2O was -131 +/- 845 mL/d. In addition, no bias was observed (F[1,94] = 0.484; R2 = 0.006; P = 0.488). When comparing WATER-FL-7dFLR from weeks 2 and 4, no significant difference (mean +/- SD difference: 71 +/- 75 mL/d; t[79] = 0.954; P = 0.343) and an ICC of 0.85 (95% CI: 0.77, 0.90) was observed.Conclusions: The main findings of this study were that the use of the 7dFLR is an effective and reliable method to estimate WATER-FL in adults. This style of questionnaire may be extremely helpful for collecting water intake data for large-scale epidemiologic studies. PMID- 28878035 TI - A Simplified Regimen Compared with WHO Guidelines Decreases Antenatal Calcium Supplement Intake for Prevention of Preeclampsia in a Cluster-Randomized Noninferiority Trial in Rural Kenya. AB - Background: To prevent preeclampsia, the WHO recommends antenatal calcium supplementation in populations with inadequate habitual intake. The WHO recommends 1500-2000 mg Ca/d with iron-folic acid (IFA) taken separately, a complex pill-taking regimen. Objective: The objective of this study was to test the hypothesis that simpler regimens with lower daily dosages would lead to higher adherence and similar supplement intake.Methods: In the Micronutrient Initiative Calcium Supplementation study, we compared the mean daily supplement intake associated with 2 dosing regimens with the use of a parallel, cluster randomized noninferiority trial implemented in 16 primary health care facilities in rural Kenya. The standard regimen was 3 * 500 mg Ca/d in 3 pill-taking events, and the low-dose regimen was 2 * 500 mg Ca/d in 2 pill-taking events; both regimens included a 200 IU cholecalciferol and calcium pill and a separate IFA pill. We enrolled 990 pregnant women between 16 and 30 wk of gestation. The primary outcome was supplemental calcium intake measured by pill counts 4 and 8 wk after recruitment. We carried out intention-to-treat analyses with the use of mixed-effect models, with regimen as the fixed effect and health care facilities as a random effect, by using a noninferiority margin of 125 mg Ca/d.Results: Women in facilities assigned to the standard regimen consumed a mean of 1198 mg Ca/d, whereas those assigned to the low-dose regimen consumed 810 mg Ca/d. The difference in intake was 388 mg Ca/d (95% CI = 341, 434 mg Ca/d), exceeding the prespecified margin of 125 mg Ca/d. The overall adherence rate was 80% and did not differ between study arms.Conclusions: Contrary to our expectation, a simpler, lower-dose regimen led to significantly lower supplement intake than the regimen recommended by the WHO. Further studies are needed to precisely characterize the dose-response relation of calcium supplementation and preeclampsia risk and to examine cost effectiveness of lower and simpler regimens in program settings. This trial was registered at clinicaltrials.gov as NCT02238704. PMID- 28878037 TI - Silencing CAFFEOYL SHIKIMATE ESTERASE Affects Lignification and Improves Saccharification in Poplar. AB - Caffeoyl shikimate esterase (CSE) was recently shown to play an essential role in lignin biosynthesis in Arabidopsis (Arabidopsis thaliana) and later in Medicago truncatula However, the general function of this enzyme was recently questioned by the apparent lack of CSE activity in lignifying tissues of different plant species. Here, we show that down-regulation of CSE in hybrid poplar (Populus tremula * Populus alba) resulted in up to 25% reduced lignin deposition, increased levels of p-hydroxyphenyl units in the lignin polymer, and a relatively higher cellulose content. The transgenic trees were morphologically indistinguishable from the wild type. Ultra-high-performance liquid chromatography-mass spectrometry-based phenolic profiling revealed a reduced abundance of several oligolignols containing guaiacyl and syringyl units and their corresponding hydroxycinnamaldehyde units, in agreement with the reduced flux toward coniferyl and sinapyl alcohol. These trees accumulated the CSE substrate caffeoyl shikimate along with other compounds belonging to the metabolic classes of benzenoids and hydroxycinnamates. Furthermore, the reduced lignin amount combined with the relative increase in cellulose content in the CSE down-regulated lines resulted in up to 62% more glucose released per plant upon limited saccharification when no pretreatment was applied and by up to 86% and 91% when acid and alkaline pretreatments were used. Our results show that CSE is not only important for the lignification process in poplar but is also a promising target for the development of improved lignocellulosic biomass crops for sugar platform biorefineries. PMID- 28878038 TI - The requirement of Mettl3-promoted MyoD mRNA maintenance in proliferative myoblasts for skeletal muscle differentiation. AB - Myogenic progenitor/stem cells retain their skeletal muscle differentiation potential by maintaining myogenic transcription factors such as MyoD. However, the mechanism of how MyoD expression is maintained in proliferative progenitor cells has not been elucidated. Here, we found that MyoD expression was reduced at the mRNA level by cell cycle arrest in S and G2 phases, which in turn led to the absence of skeletal muscle differentiation. The reduction of MyoD mRNA was correlated with the reduced expression of factors regulating RNA metabolism, including methyltransferase like 3 (Mettl3), which induces N6-methyladenosine (m6A) modifications of RNA. Knockdown of Mettl3 revealed that MyoD RNA was specifically downregulated and that this was caused by a decrease in processed, but not unprocessed, mRNA. Potential m6A modification sites were profiled by m6A sequencing and identified within the 5' untranslated region (UTR) of MyoD mRNA. Deletion of the 5' UTR revealed that it has a role in MyoD mRNA processing. These data showed that Mettl3 is required for MyoD mRNA expression in proliferative myoblasts. PMID- 28878036 TI - Different Routes for Conifer- and Sinapaldehyde and Higher Saccharification upon Deficiency in the Dehydrogenase CAD1. AB - In the search for renewable energy sources, genetic engineering is a promising strategy to improve plant cell wall composition for biofuel and bioproducts generation. Lignin is a major factor determining saccharification efficiency and, therefore, is a prime target to engineer. Here, lignin content and composition were modified in poplar (Populus tremula * Populus alba) by specifically down regulating CINNAMYL ALCOHOL DEHYDROGENASE1 (CAD1) by a hairpin-RNA-mediated silencing approach, which resulted in only 5% residual CAD1 transcript abundance. These transgenic lines showed no biomass penalty despite a 10% reduction in Klason lignin content and severe shifts in lignin composition. Nuclear magnetic resonance spectroscopy and thioacidolysis revealed a strong increase (up to 20 fold) in sinapaldehyde incorporation into lignin, whereas coniferaldehyde was not increased markedly. Accordingly, ultra-high-performance liquid chromatography mass spectrometry-based phenolic profiling revealed a more than 24,000-fold accumulation of a newly identified compound made from 8-8 coupling of two sinapaldehyde radicals. However, no additional cinnamaldehyde coupling products could be detected in the CAD1-deficient poplars. Instead, the transgenic lines accumulated a range of hydroxycinnamate-derived metabolites, of which the most prominent accumulation (over 8,500-fold) was observed for a compound that was identified by purification and nuclear magnetic resonance as syringyl lactic acid hexoside. Our data suggest that, upon down-regulation of CAD1, coniferaldehyde is converted into ferulic acid and derivatives, whereas sinapaldehyde is either oxidatively coupled into S'(8-8)S' and lignin or converted to sinapic acid and derivatives. The most prominent sink of the increased flux to hydroxycinnamates is syringyl lactic acid hexoside. Furthermore, low-extent saccharification assays, under different pretreatment conditions, showed strongly increased glucose (up to +81%) and xylose (up to +153%) release, suggesting that down regulating CAD1 is a promising strategy for improving lignocellulosic biomass for the sugar platform industry. PMID- 28878040 TI - Glareosin: a novel sexually dimorphic urinary lipocalin in the bank vole, Myodes glareolus. AB - The urine of bank voles (Myodes glareolus) contains substantial quantities of a small protein that is expressed at much higher levels in males than females, and at higher levels in males in the breeding season. This protein was purified and completely sequenced at the protein level by mass spectrometry. Leucine/isoleucine ambiguity was completely resolved by metabolic labelling, monitoring the incorporation of dietary deuterated leucine into specific sites in the protein. The predicted mass of the sequenced protein was exactly consonant with the mass of the protein measured in bank vole urine samples, correcting for the formation of two disulfide bonds. The sequence of the protein revealed that it was a lipocalin related to aphrodisin and other odorant-binding proteins (OBPs), but differed from all OBPs previously described. The pattern of secretion in urine used for scent marking by male bank voles, and the similarity to other lipocalins used as chemical signals in rodents, suggest that this protein plays a role in male sexual and/or competitive communication. We propose the name glareosin for this novel protein to reflect the origin of the protein and to emphasize the distinction from known OBPs. PMID- 28878039 TI - Discovery of novel representatives of bilaterian neuropeptide families and reconstruction of neuropeptide precursor evolution in ophiuroid echinoderms. AB - Neuropeptides are a diverse class of intercellular signalling molecules that mediate neuronal regulation of many physiological and behavioural processes. Recent advances in genome/transcriptome sequencing are enabling identification of neuropeptide precursor proteins in species from a growing variety of animal taxa, providing new insights into the evolution of neuropeptide signalling. Here, detailed analysis of transcriptome sequence data from three brittle star species, Ophionotus victoriae, Amphiura filiformis and Ophiopsila aranea, has enabled the first comprehensive identification of neuropeptide precursors in the class Ophiuroidea of the phylum Echinodermata. Representatives of over 30 bilaterian neuropeptide precursor families were identified, some of which occur as paralogues. Furthermore, homologues of endothelin/CCHamide, eclosion hormone, neuropeptide-F/Y and nucleobinin/nesfatin were discovered here in a deuterostome/echinoderm for the first time. The majority of ophiuroid neuropeptide precursors contain a single copy of a neuropeptide, but several precursors comprise multiple copies of identical or non-identical, but structurally related, neuropeptides. Here, we performed an unprecedented investigation of the evolution of neuropeptide copy number over a period of approximately 270 Myr by analysing sequence data from over 50 ophiuroid species, with reference to a robust phylogeny. Our analysis indicates that the composition of neuropeptide 'cocktails' is functionally important, but with plasticity over long evolutionary time scales. PMID- 28878041 TI - Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co expression. AB - Solute carriers (SLCs) are vital as they are responsible for a major part of the molecular transport over lipid bilayers. At present, there are 430 identified SLCs, of which 28 are called atypical SLCs of major facilitator superfamily (MFS) type. These are MFSD1, 2A, 2B, 3, 4A, 4B, 5, 6, 6 L, 7, 8, 9, 10, 11, 12, 13A, 14A and 14B; SV2A, SV2B and SV2C; SVOP and SVOPL; SPNS1, SPNS2 and SPNS3; and UNC93A and UNC93B1. We studied their fundamental properties, and we also included CLN3, an atypical SLC not yet belonging to any protein family (Pfam) clan, because its involvement in the same neuronal degenerative disorders as MFSD8. With phylogenetic analyses and bioinformatic sequence comparisons, the proteins were divided into 15 families, denoted atypical MFS transporter families (AMTF1 15). Hidden Markov models were used to identify orthologues from human to Drosophila melanogaster and Caenorhabditis elegans Topology predictions revealed 12 transmembrane segments (for all except CLN3), corresponding to the common MFS structure. With single-cell RNA sequencing and in situ proximity ligation assay on brain cells, co-expressions of several atypical SLCs were identified. Finally, the transcription levels of all genes were analysed in the hypothalamic N25/2 cell line after complete amino acid starvation, showing altered expression levels for several atypical SLCs. PMID- 28878042 TI - Interactions of the Bacillus subtilis DnaE polymerase with replisomal proteins modulate its activity and fidelity. AB - During Bacillus subtilis replication two replicative polymerases function at the replisome to collectively carry out genome replication. In a reconstituted in vitro replication assay, PolC is the main polymerase while the lagging strand DnaE polymerase briefly extends RNA primers synthesized by the primase DnaG prior to handing-off DNA synthesis to PolC. Here, we show in vivo that (i) the polymerase activity of DnaE is essential for both the initiation and elongation stages of DNA replication, (ii) its error rate varies inversely with PolC concentration, and (iii) its misincorporations are corrected by the mismatch repair system post-replication. We also found that the error rates in cells encoding mutator forms of both PolC and DnaE are significantly higher (up to 15 fold) than in PolC mutants. In vitro, we showed that (i) the polymerase activity of DnaE is considerably stimulated by DnaN, SSB and PolC, (ii) its error-prone activity is strongly inhibited by DnaN, and (iii) its errors are proofread by the 3' > 5' exonuclease activity of PolC in a stable template-DnaE-PolC complex. Collectively our data show that protein-protein interactions within the replisome modulate the activity and fidelity of DnaE, and confirm the prominent role of DnaE during B. subtilis replication. PMID- 28878043 TI - The rapid in vivo evolution of Pseudomonas aeruginosa in ventilator-associated pneumonia patients leads to attenuated virulence. AB - Pseudomonas aeruginosa is an opportunistic pathogen that causes severe airway infections in humans. These infections are usually difficult to treat and associated with high mortality rates. While colonizing the human airways, P. aeruginosa could accumulate genetic mutations that often lead to its better adaptability to the host environment. Understanding these evolutionary traits may provide important clues for the development of effective therapies to treat P. aeruginosa infections. In this study, 25 P. aeruginosa isolates were longitudinally sampled from the airways of four ventilator-associated pneumonia (VAP) patients. Pacbio and Illumina sequencing were used to analyse the in vivo evolutionary trajectories of these isolates. Our analysis showed that positive selection dominantly shaped P. aeruginosa genomes during VAP infections and led to three convergent evolution events, including loss-of-function mutations of lasR and mpl, and a pyoverdine-deficient phenotype. Specifically, lasR encodes one of the major transcriptional regulators in quorum sensing, whereas mpl encodes an enzyme responsible for recycling cell wall peptidoglycan. We also found that P. aeruginosa isolated at late stages of VAP infections produce less elastase and are less virulent in vivo than their earlier isolated counterparts, suggesting the short-term in vivo evolution of P. aeruginosa leads to attenuated virulence. PMID- 28878045 TI - A case of heart failure and diarrhoea. PMID- 28878044 TI - Progress and prospects of early detection in lung cancer. AB - Lung cancer is the leading cause of cancer-related death in the world. It is broadly divided into small cell (SCLC, approx. 15% cases) and non-small cell lung cancer (NSCLC, approx. 85% cases). The main histological subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma, with the presence of specific DNA mutations allowing further molecular stratification. If identified at an early stage, surgical resection of NSCLC offers a favourable prognosis, with published case series reporting 5-year survival rates of up to 70% for small, localized tumours (stage I). However, most patients (approx. 75%) have advanced disease at the time of diagnosis (stage III/IV) and despite significant developments in the oncological management of late stage lung cancer over recent years, survival remains poor. In 2014, the UK Office for National Statistics reported that patients diagnosed with distant metastatic disease (stage IV) had a 1-year survival rate of just 15-19% compared with 81-85% for stage I. PMID- 28878046 TI - Nonlinear temporal dynamics of cerebral small vessel disease: The RUN DMC study. AB - OBJECTIVE: To investigate the temporal dynamics of cerebral small vessel disease (SVD) by 3 consecutive assessments over a period of 9 years, distinguishing progression from regression. METHODS: Changes in SVD markers of 276 participants of the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC) cohort were assessed at 3 time points over 9 years. We assessed white matter hyperintensities (WMH) volume by semiautomatic segmentation and rated lacunes and microbleeds manually. We categorized baseline WMH severity as mild, moderate, or severe according to the modified Fazekas scale. We performed mixed-effects regression analysis including a quadratic term for increasing age. RESULTS: Mean WMH progression over 9 years was 4.7 mL (0.54 mL/y; interquartile range 0.95-5.5 mL), 20.3% of patients had incident lacunes (2.3%/y), and 18.9% had incident microbleeds (2.2%/y). WMH volume declined in 9.4% of the participants during the first follow-up interval, but only for 1 participant (0.4%) throughout the whole follow-up. Lacunes disappeared in 3.6% and microbleeds in 5.7% of the participants. WMH progression accelerated over time: including a quadratic term for increasing age during follow-up significantly improved the model (p < 0.001). SVD progression was predominantly seen in participants with moderate to severe WMH at baseline compared to those with mild WMH (odds ratio [OR] 35.5, 95% confidence interval [CI] 15.8-80.0, p < 0.001 for WMH progression; OR 5.7, 95% CI 2.8-11.2, p < 0.001 for incident lacunes; and OR 2.9, 95% CI 1.4-5.9, p = 0.003 for incident microbleeds). CONCLUSIONS: SVD progression is nonlinear, accelerating over time, and a highly dynamic process, with progression interrupted by reduction in some, in a population that on average shows progression. PMID- 28878047 TI - Long-term risk of seizures in adult survivors of sepsis. AB - OBJECTIVE: To examine the association between sepsis and the long-term risk of seizures. METHODS: We conducted a retrospective population-based cohort study using administrative claims data from all emergency department visits and hospitalizations at nonfederal acute care hospitals in California, Florida, and New York from 2005 to 2013. Using previously validated diagnosis codes, we identified all adult patients hospitalized with sepsis. Our outcome was any emergency department visit or hospitalization for seizure. Poisson regression and demographic data were used to calculate age-, sex-, and race-standardized incidence rate ratios (IRR). To confirm our findings, we used a matched cohort of hospitalized patients without sepsis for comparison and additionally assessed claims data from a nationally representative 5% sample of Medicare beneficiaries. RESULTS: We identified 842,735 patients with sepsis. The annual incidence of seizure was 1.29% (95% confidence interval [CI] 1.27%-1.30%) in patients with sepsis vs 0.16% (95% CI 0.16%-0.16%) in the general population (IRR 4.98; 95% CI 4.92-5.04). A secondary analysis using matched hospitalized patients confirmed these findings (IRR 4.33; 95% CI 4.13-4.55), as did a separate analysis of Medicare beneficiaries, in whom we found a similar strength of association (IRR 2.72; 95% CI 2.60-2.83), as we did in patients >=65 years of age in our primary statewide data (IRR 2.83; 95% CI 2.78-2.88). CONCLUSIONS: We found that survivors of sepsis faced a significantly higher long-term risk of seizures than both the general population and other hospitalized patients. Our findings suggest that sepsis is associated with pathways that lead to permanent neurologic sequelae. PMID- 28878049 TI - Reducing placebo exposure in trials: Considerations from the Research Roundtable in Epilepsy. AB - The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically ~6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19-20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3- to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here. PMID- 28878050 TI - Antibody-associated CNS syndromes without signs of inflammation in the elderly. AB - OBJECTIVE: To report the CNS syndromes of patients >=60 years of age with antibodies against neuronal surface antigens but no evidence of brain MRI and CSF inflammatory changes. METHODS: This was a retrospective clinical analysis of patients with antibodies against neuronal surface antigens who fulfilled 3 criteria: age >=60 years, no inflammatory abnormalities in brain MRI, and no CSF pleocytosis. Antibodies were determined with reported techniques. RESULTS: Among 155 patients >=60 years of age with neurologic syndromes related to antibodies against neuronal surface antigens, 35 (22.6%) fulfilled the indicated criteria. The median age of these 35 patients was 68 years (range 60-88 years). Clinical manifestations included faciobrachial dystonic seizures (FBDS) in 11 of 35 (31.4%) patients, all with LGI1 antibodies; a combination of gait instability, brainstem dysfunction, and sleep disorder associated with IgLON5 antibodies in 10 (28.6%); acute confusion, memory loss, and behavioral changes suggesting autoimmune encephalitis (AE) in 9 (25.7%; 2 patients with AMPAR, 2 with NMDAR, 2 with GABAbR, 2 with LGI1, and 1 with CASPR2 antibodies); and rapidly progressive cognitive deterioration in 5 (14.3%; 3 patients with IgLON5 antibodies, 1 with chorea; 1 with DPPX antibody-associated cerebellar ataxia and arm rigidity; and 1 with CASPR2 antibodies). CONCLUSIONS: In patients >=60 years of age, the correct identification of characteristic CNS syndromes (FBDS, anti-IgLON5 syndrome, AE) should prompt antibody testing even without evidence of inflammation in MRI and CSF studies. Up to 15% of the patients developed rapidly progressive cognitive deterioration, which further complicated the differential diagnosis with a neurodegenerative disorder. PMID- 28878051 TI - Olfaction and incident Parkinson disease in US white and black older adults. AB - OBJECTIVE: To investigate olfaction in relation to incident Parkinson disease (PD) in US white and black older adults. METHODS: The study included 1,510 white (mean age 75.6 years) and 952 black (75.4 years) participants of the Health, Aging, and Body Composition study. We evaluated the olfaction of study participants with the Brief Smell Identification Test (BSIT) in 1999-2000. We retrospectively adjudicated PD cases identified through August 31, 2012, using multiple data sources. We used multivariable Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During an average of 9.8 years of follow-up, we identified a total of 42 incident PD cases, including 30 white and 12 black participants. Overall, poor sense of smell, as indicated by a lower BSIT score, was associated with higher risk of PD. Compared with the highest tertile of BSIT (t3), the HR was 1.3 (95% CI 0.5-3.6) for the second tertile (t2) and 4.8 (95% CI 2.0-11.2) for the lowest tertile (t1) (ptrend < 0.00001). Further analyses revealed significant associations for incident PD in both the first 5 years of follow-up (HRt1/[t2+t3] 4.2, 95% CI 1.7-10.8) and thereafter (HRt1/[t2+t3] 4.1, 95% CI 1.7-9.8). This association appeared to be stronger in white (HRt1/[t2+t3] 4.9, 95% CI 2.3-10.5) than in black participants (HRt1/[t2+t3] 2.5, 95% CI 0.8-8.1), and in men (HRt1/[t2+t3] 5.4, 95% CI 2.3 12.9) than in women (HRt1/[t2+t3] 2.9, 95% CI 1.1-7.8). CONCLUSIONS: Poor olfaction predicts PD in short and intermediate terms; the possibility of stronger associations among men and white participants warrants further investigation. PMID- 28878052 TI - Biomarkers for early detection of Parkinson disease: A scent of consistency with olfactory dysfunction. PMID- 28878048 TI - Functional impairments for outcomes in a randomized trial of unruptured brain AVMs. AB - OBJECTIVE: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). METHODS: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults >=18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score >=2. ARUBA closed recruitment on April 15, 2013. RESULTS: After a median of 33.3 months of follow-up (interquartile range 16.3-49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score >=2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11-0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04-0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001). CONCLUSION: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. CLINICALTRIALSGOV IDENTIFIER: NCT00389181. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ~3 years. PMID- 28878053 TI - Subjective memory complaints in preclinical autosomal dominant Alzheimer disease. AB - OBJECTIVE: To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). METHODS: We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. RESULTS: Self-reported SMC were greater in carriers than noncarriers (p = 0.02). Study partner-based SMC did not differ between groups (p = 0.21), but in carriers increased with age (r = 0.66, p < 0.001) and decreased with hippocampal volume (r = -0.35, p = 0.08). CONCLUSIONS: Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. PMID- 28878054 TI - Sneeze to leave: African wild dogs (Lycaon pictus) use variable quorum thresholds facilitated by sneezes in collective decisions. AB - In despotically driven animal societies, one or a few individuals tend to have a disproportionate influence on group decision-making and actions. However, global communication allows each group member to assess the relative strength of preferences for different options among their group-mates. Here, we investigate collective decisions by free-ranging African wild dog packs in Botswana. African wild dogs exhibit dominant-directed group living and take part in stereotyped social rallies: high energy greeting ceremonies that occur before collective movements. Not all rallies result in collective movements, for reasons that are not well understood. We show that the probability of rally success (i.e. group departure) is predicted by a minimum number of audible rapid nasal exhalations (sneezes), within the rally. Moreover, the number of sneezes needed for the group to depart (i.e. the quorum) was reduced whenever dominant individuals initiated rallies, suggesting that dominant participation increases the likelihood of a rally's success, but is not a prerequisite. As such, the 'will of the group' may override dominant preferences when the consensus of subordinates is sufficiently great. Our findings illustrate how specific behavioural mechanisms (here, sneezing) allow for negotiation (in effect, voting) that shapes decision-making in a wild, socially complex animal society. PMID- 28878055 TI - Interacting effects of wildlife loss and climate on ticks and tick-borne disease. AB - Both large-wildlife loss and climatic changes can independently influence the prevalence and distribution of zoonotic disease. Given growing evidence that wildlife loss often has stronger community-level effects in low-productivity areas, we hypothesized that these perturbations would have interactive effects on disease risk. We experimentally tested this hypothesis by measuring tick abundance and the prevalence of tick-borne pathogens (Coxiella burnetii and Rickettsia spp.) within long-term, size-selective, large-herbivore exclosures replicated across a precipitation gradient in East Africa. Total wildlife exclusion increased total tick abundance by 130% (mesic sites) to 225% (dry, low productivity sites), demonstrating a significant interaction of defaunation and aridity on tick abundance. When differing degrees of exclusion were tested for a subset of months, total tick abundance increased from 170% (only mega-herbivores excluded) to 360% (all large wildlife excluded). Wildlife exclusion differentially affected the abundance of the three dominant tick species, and this effect varied strongly over time, likely due to differences among species in their host associations, seasonality, and other ecological characteristics. Pathogen prevalence did not differ across wildlife exclusion treatments, rainfall levels, or tick species, suggesting that exposure risk will respond to defaunation and climate change in proportion to total tick abundance. These findings demonstrate interacting effects of defaunation and aridity that increase disease risk, and they highlight the need to incorporate ecological context when predicting effects of wildlife loss on zoonotic disease dynamics. PMID- 28878056 TI - Community responses to seawater warming are conserved across diverse biological groupings and taxonomic resolutions. AB - Temperature variability is a major driver of ecological pattern, with recent changes in average and extreme temperatures having significant impacts on populations, communities and ecosystems. In the marine realm, very few experiments have manipulated temperature in situ, and current understanding of temperature effects on community dynamics is limited. We developed new technology for precise seawater temperature control to examine warming effects on communities of bacteria, microbial eukaryotes (protists) and metazoans. Despite highly contrasting phylogenies, size spectra and diversity levels, the three community types responded similarly to seawater warming treatments of +3 degrees C and +5 degrees C, highlighting the critical and overarching importance of temperature in structuring communities. Temperature effects were detectable at coarse taxonomic resolutions and many taxa responded positively to warming, leading to increased abundances at the community-level. Novel field-based experimental approaches are essential to improve mechanistic understanding of how ocean warming will alter the structure and functioning of diverse marine communities. PMID- 28878057 TI - Exceptional preservation and the fossil record of tetrapod integument. AB - The fossil record of exceptionally preserved soft tissues in Konservat Lagerstatten provides rare yet significant insight into past behaviours and ecologies. Such deposits are known to occur in bursts rather than evenly through time, but reasons for this pattern and implications for the origins of novel structures remain unclear. Previous assessments of these records focused on marine environments preserving chemically heterogeneous tissues from across animals. Here, we investigate the preservation of skin and keratinous integumentary structures in land-dwelling vertebrates (tetrapods) through time, and in distinct terrestrial and marine depositional environments. We also evaluate previously proposed biotic and abiotic controls on the distribution of 143 tetrapod Konservat-Lagerstatten from the Permian to the Pleistocene in a multivariate framework. Gap analyses taking into account sampling intensity and distribution indicate that feathers probably evolved close to their first appearance in the fossil record. By contrast, hair and archosaur filaments are weakly sampled (five times less common than feathers), and their origins may significantly pre-date earliest known occurrences in the fossil record. This work suggests that among-integument variation in preservation can bias the reconstructed first origins of integumentary novelties and has implications for predicting where, and in what depositional environments, to expect further discoveries of exquisitely preserved tetrapod integument. PMID- 28878058 TI - A vertebrate retina with segregated colour and polarization sensitivity. AB - Besides colour and intensity, some invertebrates are able to independently detect the polarization of light. Among vertebrates, such separation of visual modalities has only been hypothesized for some species of anchovies whose cone photoreceptors have unusual ultrastructure that varies with retinal location. Here, I tested this hypothesis by performing physiological experiments of colour and polarization discrimination using the northern anchovy, Engraulis mordax Optic nerve recordings showed that the ventro-temporal (VT), but not the ventro nasal (VN), retina was polarization sensitive, and this coincided with the exclusive presence of polarization-sensitive photoreceptors in the VT retina. Spectral (colour) sensitivity recordings from the VN retina indicated the contribution of two spectral cone mechanisms to the optic nerve response, whereas only one contributed to the VT retina. This was supported by the presence of only one visual pigment in the VT retina and two in the VN retina, suggesting that only the VN retina was associated with colour sensitivity. Behavioural tests further demonstrated that anchovies could discriminate colour and the polarization of light using the ventral retina. Thus, in analogy with the visual system of some invertebrates, the northern anchovy has a retina with segregated retinal pathways for colour and polarization vision. PMID- 28878059 TI - Can hook-bending be let off the hook? Bending/unbending of pliant tools by cockatoos. AB - The spontaneous crafting of hook-tools from bendable material to lift a basket out of a vertical tube in corvids has widely been used as one of the prime examples of animal tool innovation. However, it was recently suggested that the animals' solution was hardly innovative but strongly influenced by predispositions from habitual tool use and nest building. We tested Goffin's cockatoo, which is neither a specialized tool user nor a nest builder, on a similar task set-up. Three birds individually learned to bend hook tools from straight wire to retrieve food from vertical tubes and four subjects unbent wire to retrieve food from horizontal tubes. Pre-experience with ready-made hooks had some effect but was not necessary for success. Our results indicate that the ability to represent and manufacture tools according to a current need does not require genetically hardwired behavioural routines, but can indeed arise innovatively from domain general cognitive processing. PMID- 28878061 TI - Predictable invasion dynamics in North American populations of the Eurasian collared dove Streptopelia decaocto. AB - Species invasions represent a significant dimension of global change yet the dynamics of invasions remain poorly understood and are considered rather unpredictable. We explored interannual dynamics of the invasion process in the Eurasian collared dove (Streptopelia decaocto) and tested whether the advance of the invasion front of the species in North America relates to centrality (versus peripherality) within its estimated fundamental ecological niche. We used ecological niche modelling approaches to estimate the dimensions of the fundamental ecological niche on the Old World distribution of the species, and then transferred that model to the New World as measures of centrality versus peripherality within the niche for the species. Although our hypothesis was that the invasion front would advance faster over more favourable (i.e. more central) conditions, the reverse was the case: the invasion expanded faster in areas presenting less favourable (i.e. more peripheral) conditions for the species as it advanced across North America. This result offers a first view of a predictive approach to the dynamics of species' invasions, and thereby has relevant implications for the management of invasive species, as such a predictive understanding would allow better anticipation of coming steps and advances in the progress of invasions, important to designing and guiding effective remediation and mitigation efforts. PMID- 28878062 TI - Plant defences limit herbivore population growth by changing predator-prey interactions. AB - Plant quality and predators are important factors affecting herbivore population growth, but how they interact to regulate herbivore populations is not well understood. We manipulated jasmonate-induced plant resistance, exposure to the natural predator community and herbivore density to test how these factors jointly and independently affect herbivore population growth. On low-resistance plants, the predator community was diverse and abundant, promoting high predator consumption rates. On high-resistance plants, the predator community was less diverse and abundant, resulting in low predator consumption rate. Plant resistance only directly regulated aphid population growth on predator-excluded plants. When predators were present, plant resistance indirectly regulated herbivore population growth by changing the impact of predators on the herbivorous prey. A possible mechanism for the interaction between plant resistance and predation is that methyl salicylate, a herbivore-induced plant volatile attractive to predators, was more strongly induced in low-resistance plants. Increased plant resistance reduced predator attractant lures, preventing predators from locating their prey. Low-resistance plants may regulate herbivore populations via predators by providing reliable information on prey availability and increasing the effectiveness of predators. PMID- 28878060 TI - Fearful but not happy expressions boost face detection in human infants. AB - Human adults show an attentional bias towards fearful faces, an adaptive behaviour that relies on amygdala function. This attentional bias emerges in infancy between 5 and 7 months, but the underlying developmental mechanism is unknown. To examine possible precursors, we investigated whether 3.5-, 6- and 12 month-old infants show facilitated detection of fearful faces in noise, compared to happy faces. Happy or fearful faces, mixed with noise, were presented to infants (N = 192), paired with pure noise. We applied multivariate pattern analyses to several measures of infant looking behaviour to derive a criterion free, continuous measure of face detection evidence in each trial. Analyses of the resulting psychometric curves supported the hypothesis of a detection advantage for fearful faces compared to happy faces, from 3.5 months of age and across all age groups. Overall, our data show a readiness to detect fearful faces (compared to happy faces) in younger infants that developmentally precedes the previously documented attentional bias to fearful faces in older infants and adults. PMID- 28878063 TI - Mitochondrial phylogenomics of Hemiptera reveals adaptive innovations driving the diversification of true bugs. AB - Hemiptera, the largest non-holometabolous order of insects, represents approximately 7% of metazoan diversity. With extraordinary life histories and highly specialized morphological adaptations, hemipterans have exploited diverse habitats and food sources through approximately 300 Myr of evolution. To elucidate the phylogeny and evolutionary history of Hemiptera, we carried out the most comprehensive mitogenomics analysis on the richest taxon sampling to date covering all the suborders and infraorders, including 34 newly sequenced and 94 published mitogenomes. With optimized branch length and sequence heterogeneity, Bayesian analyses using a site-heterogeneous mixture model resolved the higher level hemipteran phylogeny as (Sternorrhyncha, (Auchenorrhyncha, (Coleorrhyncha, Heteroptera))). Ancestral character state reconstruction and divergence time estimation suggest that the success of true bugs (Heteroptera) is probably due to angiosperm coevolution, but key adaptive innovations (e.g. prognathous mouthpart, predatory behaviour, and haemelytron) facilitated multiple independent shifts among diverse feeding habits and multiple independent colonizations of aquatic habitats. PMID- 28878064 TI - Adaptation to a novel family environment involves both apparent and cryptic phenotypic changes. AB - Cryptic evolution occurs when evolutionary change is masked by concurrent environmental change. In most cases, evolutionary changes in the phenotype are masked by changing abiotic factors. However, evolutionary change in one trait might also be masked by evolutionary change in another trait, a phenomenon referred to as evolutionary environmental deterioration. Nevertheless, detecting this second type of cryptic evolution is challenging and there are few compelling examples. Here, we describe a likely case of evolutionary environmental deterioration occurring in experimental burying beetle (Nicrophorus vespilloides) populations that are adapting to a novel social environment that lacks post hatching parental care. We found that populations rapidly adapted to the removal of post-hatching parental care. This adaptation involved clear increases in breeding success and larval density (number of dispersing larvae produced per gram of breeding carcass), which in turn masked a concurrent increase in the mean larval mass across generations. This cryptic increase in larval mass was accomplished through a change in the reaction norm that relates mean larval mass to larval density. Our results suggest that cryptic evolution might be commonplace in animal families, because evolving trophic and social interactions can potentially mask evolutionary change in other traits, like body size. PMID- 28878065 TI - Selective disappearance of great tits with short telomeres in urban areas. AB - Urban environments pose novel challenges, as well as opportunities, for urban dwelling wildlife. Although differences have been reported in several phenotypic traits (e.g. morphology, physiology and behaviour) between urban and rural populations, it is poorly understood whether this affects individual fitness. Telomere dynamics are posited as one possible mechanism underlying senescence and mortality. It was recently shown that telomere shortening is accelerated when growing up in an urban, compared with a rural, environment. However, the implications of accelerated telomere attrition for fitness are still unclear. Here, we examine the relationship between telomere length (TL) and survival in a bird common to urban and rural environments, and during both early and later life. The results reveal that TL is a strong predictor of post-fledging survival and recruitment in both habitats but, crucially, selective disappearance of individuals with short telomeres early in life is more pronounced in the urban environment, resulting in a longer average TL among the adult population. However, following recruitment, we found no difference in the relationship between TL and survival between the urban and rural environments. This indicates that the urban environment has negative effects in early life, while during later life the benefits could potentially outweigh the costs. PMID- 28878066 TI - Cytological analysis of cytoplasmic incompatibility induced by Cardinium suggests convergent evolution with its distant cousin Wolbachia. AB - Cytoplasmic incompatibility (CI) is a conditional sterility in numerous arthropods that is caused by inherited, intracellular bacteria such as Wolbachia Matings between males carrying CI-inducing Wolbachia and uninfected females, or between males and females infected with different Wolbachia strains, result in progeny that die during very early embryogenesis. Multiple studies in diploid (Drosophila) and haplodiploid (Nasonia) insects have shown that CI-Wolbachia cause a failure of the paternally derived chromatin from resolving into distinct chromosomes. This leads to the formation of chromatin bridges and other mitotic defects as early as the first mitotic division, and to early mitotic arrest. It is currently unknown if CI-inducing symbionts other than Wolbachia affect similar cellular processes. Here, we investigated CI caused by an unrelated bacterium, Cardinium, which naturally infects a parasitic wasp, Encarsia suzannae CI crosses in this host-symbiont system resulted in early mitotic defects including asynchrony of paternal and maternal chromosome sets as they enter mitosis, chromatin bridges and improper chromosome segregation that spanned across multiple mitotic divisions, triggering embryonic death through accumulated aneuploidy. We highlight small differences with CI-Wolbachia, which could be due to the underlying CI mechanism or host-specific effects. Our results suggest a convergence of CI-related cellular phenotypes between these two unrelated symbionts. PMID- 28878067 TI - Tree species richness attenuates the positive relationship between mutualistic ant-hemipteran interactions and leaf chewer herbivory. AB - Interactions across trophic levels influence plant diversity effects on ecosystem functions, but the complexity of these interactions remains poorly explored. For example, the interplay between different interactions (e.g. mutualism, predation) might be an important moderator of biodiversity-ecosystem function relationships. We tested for relationships between trophobioses (facultative ant-hemipteran mutualism) and leaf chewer herbivory in a subtropical forest biodiversity experiment. We analysed trophobiosis and herbivory data of more than 10 000 trees along a tree species richness gradient. Against expectations, chewing damage was higher on trees with trophobioses. However, the net positive relationship between trophobioses and overall herbivory depended on tree species richness, being most pronounced at low richness. Our results point to indirect, positive effects of ant-tended sap suckers on leaf chewers, potentially by altering plant defences. Direct antagonistic relationships of trophobiotic ants and leaf-chewing herbivores-frequently reported to drive community-wide effects of trophobioses in other ecosystems-seemed less relevant. However, antagonistic interactions likely contributed to the attenuating effect of tree species richness, because trophobiotic ant and herbivore communities changed from monocultures to species rich mixtures. Our findings, therefore, suggest that biodiversity loss might lead to complex changes in higher trophic level effects on ecosystem functions, mediated by both trophic and non-trophic interactions. PMID- 28878068 TI - A metacognitive illusion in monkeys. AB - Like humans, monkeys can make accurate judgements about their own memory by reporting their confidence during cognitive tasks. Some have suggested that animals use associative learning to make accurate confidence judgements, while others have suggested animals directly access and estimate the strength of their memories. Here we test a third, non-exclusive possibility: perhaps monkeys, like humans, base metacognitive inferences on heuristic cues. Humans are known to use cues like perceptual fluency (e.g. how easy something is to see) when making metacognitive judgements. We tested monkeys using a match-to-sample task in which the perceptual fluency of the stimuli was manipulated. The monkeys made confidence wagers on their accuracy before or after each trial. We found that monkeys' wagers were affected by perceptual fluency even when their accuracy was not. This is novel evidence that animals are susceptible to metacognitive illusions similar to those experienced by humans. PMID- 28878069 TI - Filling Knowledge Gaps for Mimivirus Entry, Uncoating, and Morphogenesis. AB - Since the discovery of mimivirus, its unusual structural and genomic features have raised great interest in the study of its biology; however, many aspects concerning its replication cycle remain uncertain. In this study, extensive analyses of electron microscope images, as well as biological assay results, shed light on unclear points concerning the mimivirus replication cycle. We found that treatment with cytochalasin, a phagocytosis inhibitor, negatively impacted the incorporation of mimivirus particles by Acanthamoeba castellanii, causing a negative effect on viral growth in amoeba monolayers. Treatment of amoebas with bafilomicin significantly impacted mimivirus uncoating and replication. In conjunction with microscopic analyses, these data suggest that mimiviruses indeed depend on phagocytosis for entry into amoebas, and particle uncoating (and stargate opening) appears to be dependent on phagosome acidification. In-depth analyses of particle morphogenesis suggest that the mimivirus capsids are assembled from growing lamellar structures. Despite proposals from previous studies that genome acquisition occurs before the acquisition of fibrils, our results clearly demonstrate that the genome and fibrils can be acquired simultaneously. Our data suggest the existence of a specific area surrounding the core of the viral factory where particles acquire the surface fibrils. Furthermore, we reinforce the concept that defective particles can be formed even in the absence of virophages. Our work provides new information about unexplored steps in the life cycle of mimivirus.IMPORTANCE Investigating the viral life cycle is essential to a better understanding of virus biology. The combination of biological assays and microscopic images allows a clear view of the biological features of viruses. Since the discovery of mimivirus, many studies have been conducted to characterize its replication cycle, but many knowledge gaps remain to be filled. In this study, we conducted a new examination of the replication cycle of mimivirus and provide new evidence concerning some stages of the cycle which were previously unclear, mainly entry, uncoating, and morphogenesis. Furthermore, we demonstrate that atypical virion morphologies can occur even in the absence of virophages. Our results, along with previous data, allow us to present an ultimate model for the mimivirus replication cycle. PMID- 28878070 TI - Effect of Phosphorylation of CM2 Protein on Influenza C Virus Replication. AB - CM2 is the second membrane protein of the influenza C virus and has been demonstrated to play a role in the uncoating and genome packaging processes in influenza C virus replication. Although the effects of N-linked glycosylation, disulfide-linked oligomerization, and palmitoylation of CM2 on virus replication have been analyzed, the effect of the phosphorylation of CM2 on virus replication remains to be determined. In this study, a phosphorylation site(s) at residue 78 and/or 103 of CM2 was replaced with an alanine residue(s), and the effects of the loss of phosphorylation on influenza C virus replication were analyzed. No significant differences were observed in the packaging of the reporter gene between influenza C virus-like particles (VLPs) produced from 293T cells expressing wild-type CM2 and those from the cells expressing the CM2 mutants lacking the phosphorylation site(s). Reporter gene expression in HMV-II cells infected with VLPs containing the CM2 mutants was inhibited in comparison with that in cells infected with wild-type VLPs. The virus production of the recombinant influenza C virus possessing CM2 mutants containing a serine-to alanine change at residue 78 was significantly lower than that of wild-type recombinant influenza C virus. Furthermore, the virus growth of the recombinant viruses possessing CM2 with a serine-to-aspartic acid change at position 78, to mimic constitutive phosphorylation, was virtually identical to that of the wild type virus. These results suggest that phosphorylation of CM2 plays a role in efficient virus replication, probably through the addition of a negative charge to the Ser78 phosphorylation site.IMPORTANCE It is well-known that many host and viral proteins are posttranslationally modified by phosphorylation, which plays a role in the functions of these proteins. In influenza A and B viruses, phosphorylation of viral proteins NP, M1, NS1, and the nuclear export protein (NEP), which are not integrated into the membranes, affects the functions of these proteins, thereby affecting virus replication. However, it was reported that phosphorylation of the influenza A virus M2 ion channel protein, which is integrated into the membrane, has no effect on virus replication in vitro or in vivo We previously demonstrated that the influenza C virus CM2 ion channel protein is modified by N-glycosylation, oligomerization, palmitoylation, and phosphorylation and have analyzed the effects of these modifications, except phosphorylation, on virus replication. This is the first report demonstrating that phosphorylation of the influenza C virus CM2 ion channel protein, unlike that of the influenza A virus M2 protein, plays a role in virus replication. PMID- 28878071 TI - Zika Virus Escapes NK Cell Detection by Upregulating Major Histocompatibility Complex Class I Molecules. AB - NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-beta). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus.IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus infection is largely unknown. Here we demonstrate that Zika virus infection is almost undetected by NK cells, as evidenced by the fact that the expression of activating ligands for NK cells is not induced following Zika infection. We identified a mechanism whereby Zika virus sensing via the RIGI-IRF3 pathway resulted in IFN-beta-mediated upregulation of MHC-I molecules and inhibition of NK cell activity. Countering MHC class I upregulation and boosting NK cell activity may be employed as prophylactic measures to combat Zika virus infection. PMID- 28878072 TI - High-Throughput Protein Engineering Improves the Antigenicity and Stability of Soluble HIV-1 Envelope Glycoprotein SOSIP Trimers. AB - Soluble envelope glycoprotein (Env) trimers (SOSIP.664 gp140) are attractive HIV 1 vaccine candidates, with structures that mimic the native membrane-bound Env spike (gp160). Since engineering trimers can be limited by the difficulty of rationally predicting beneficial mutations, here we used a more comprehensive mutagenesis approach with the goal of identifying trimer variants with improved antigenic and stability properties. We created 341 cysteine pairs at predicted points of stabilization throughout gp140, 149 proline residue substitutions at every residue of the gp41 ectodomain, and 362 space-filling residue substitutions at every hydrophobic and aromatic residue in gp140. The parental protein target, the clade B strain B41 SOSIP.664 gp140, does not bind the broadly neutralizing antibody PGT151 and so was used here to identify improved variants that also provide insight into the structural basis for Env antigenicity. Each of the 852 mutants was expressed in human cells and screened for antigenicity using four different monoclonal antibodies (MAbs), including PGT151. We identified 29 trimer variants with antigenic improvements derived from each of the three mutagenesis strategies. We selected four variants (Q203F, T538F, I548F, and M629P) for more comprehensive biochemical, structural, and antigenicity analyses. The T538F substitution had the most beneficial effect overall, including restoration of the PGT151 epitope. The improved B41 SOSIP.664 trimer variants identified here may be useful for vaccine and structural studies.IMPORTANCE Soluble Env trimers have become attractive HIV-1 vaccine candidates, but the prototype designs are capable of further improvement through protein engineering. Using a high-throughput screening technology (shotgun mutagenesis) to create and evaluate 852 variants, we were able to identify sequence changes that were beneficial to the antigenicity and stability of soluble trimers based on the clade B B41 env gene. The strategies described here may be useful for identifying a wider range of antigenically and structurally improved soluble trimers based on multiple genotypes for use in programs intended to create a broadly protective HIV-1 vaccine. PMID- 28878073 TI - Characterization of a Replicating Mammalian Orthoreovirus with Tetracysteine Tagged MUNS for Live-Cell Visualization of Viral Factories. AB - Within infected host cells, mammalian orthoreovirus (MRV) forms viral factories (VFs), which are sites of viral transcription, translation, assembly, and replication. The MRV nonstructural protein MUNS comprises the structural matrix of VFs and is involved in recruiting other viral proteins to VF structures. Previous attempts have been made to visualize VF dynamics in live cells, but due to current limitations in recovery of replicating reoviruses carrying large fluorescent protein tags, researchers have been unable to directly assess VF dynamics from virus-produced MUNS. We set out to develop a method to overcome this obstacle by utilizing the 6-amino-acid (CCPGCC) tetracysteine (TC) tag and FlAsH-EDT2 reagent. The TC tag was introduced into eight sites throughout MUNS, and the capacity of the TC-MUNS fusion proteins to form virus factory-like (VFL) structures and colocalize with virus proteins was characterized. Insertion of the TC tag interfered with recombinant virus rescue in six of the eight mutants, likely as a result of loss of VF formation or important virus protein interactions. However, two recombinant (r)TC-MUNS viruses were rescued and VF formation, colocalization with associating virus proteins, and characterization of virus replication were subsequently examined. Furthermore, the rTC-MUNS viruses were utilized to infect cells and examine VF dynamics using live-cell microscopy. These experiments demonstrate active VF movement with fusion events as well as transient interactions between individual VFs and demonstrate the importance of microtubule stability for VF fusion during MRV infection. This work provides important groundwork for future in-depth studies of VF dynamics and host cell interactions.IMPORTANCE MRV has historically been used as a model to study the double-stranded RNA (dsRNA) Reoviridae family, the members of which infect and cause disease in humans, animals, and plants. During infection, MRV forms VFs that play a critical role in virus infection but remain to be fully characterized. To study VFs, researchers have focused on visualizing the nonstructural protein MUNS, which forms the VF matrix. This work provides the first evidence of recovery of replicating reoviruses in which VFs can be labeled in live cells via introduction of a TC tag into the MUNS open reading frame. Characterization of each recombinant reovirus sheds light on MUNS interactions with viral proteins. Moreover, utilizing the TC-labeling FlAsH-EDT2 biarsenical reagent to visualize VFs, evidence is provided of dynamic VF movement and interactions at least partially dependent on intact microtubules. PMID- 28878074 TI - Cooperation of the Ebola Virus Proteins VP40 and GP1,2 with BST2 To Activate NF kappaB Independently of Virus-Like Particle Trapping. AB - BST2 is a host protein with dual functions in response to viral infections: it traps newly assembled enveloped virions at the plasma membrane in infected cells, and it induces NF-kappaB activity, especially in the context of retroviral assembly. In this study, we examined whether Ebola virus proteins affect BST2 mediated induction of NF-kappaB. We found that the Ebola virus matrix protein, VP40, and envelope glycoprotein, GP, each cooperate with BST2 to induce NF-kappaB activity, with maximal activity when all three proteins are expressed. Unlike human immunodeficiency virus type 1 Vpu protein, which antagonizes both virion entrapment and the activation of NF-kappaB by BST2, Ebola virus GP does not inhibit NF-kappaB signaling even while it antagonizes the entrapment of virus like particles. GP from Reston ebolavirus, a nonpathogenic species in humans, showed a phenotype similar to that of GP from Zaire ebolavirus, a highly pathogenic species, in terms of both the activation of NF-kappaB and the antagonism of virion entrapment. Although Ebola virus VP40 and GP both activate NF-kappaB independently of BST2, VP40 is the more potent activator. Activation of NF-kappaB by the Ebola virus proteins either alone or together with BST2 requires the canonical NF-kappaB signaling pathway. Mechanistically, the maximal NF-kappaB activation by GP, VP40, and BST2 together requires the ectodomain cysteines needed for BST2 dimerization, the putative BST2 tetramerization residue L70, and Y6 of a potential hemi-ITAM motif in BST2's cytoplasmic domain. BST2 with a glycosylphosphatidylinositol (GPI) anchor signal deletion, which is not expressed at the plasma membrane and is unable to entrap virions, activated NF-kappaB in concert with the Ebola virus proteins at least as effectively as wild-type BST2. Signaling by the GPI anchor mutant also depended on Y6 of BST2. Overall, our data show that activation of NF-kappaB by BST2 is independent of virion entrapment in the case of Ebola virus. Nonetheless, BST2 may induce or amplify proinflammatory signaling during Ebola virus infection, potentially contributing to the dysregulated cytokine response that is a hallmark of Ebola virus disease.IMPORTANCE Understanding how the host responds to viral infections informs the development of therapeutics and vaccines. We asked how proinflammatory signaling by the host protein BST2/tetherin, which is mediated by the transcription factor NF-kappaB, responds to Ebola virus proteins. Although the Ebola virus envelope glycoprotein (GP1,2) antagonizes the trapping of newly formed virions at the plasma membrane by BST2, we found that it does not inhibit BST2's ability to induce NF-kappaB activity. This distinguishes GP1,2 from the HIV-1 protein Vpu, the prototype BST2 antagonist, which inhibits both virion entrapment and the induction of NF-kappaB activity. Ebola virus GP1,2, the Ebola virus matrix protein VP40, and BST2 are at least additive with respect to the induction of NF-kappaB activity. The effects of these proteins converge on an intracellular signaling pathway that depends on a protein modification termed neddylation. Better mechanistic understanding of these phenomena could provide targets for therapies that modulate the inflammatory response during Ebola virus disease. PMID- 28878075 TI - Characterization of the Quasi-Enveloped Hepatitis E Virus Particles Released by the Cellular Exosomal Pathway. AB - Our previous studies demonstrated that membrane-associated hepatitis E virus (HEV) particles-now considered "quasi-enveloped particles"-are present in the multivesicular body with intraluminal vesicles (exosomes) in infected cells and that the release of HEV virions is related to the exosomal pathway. In this study, we characterized exosomes purified from the culture supernatants of HEV infected PLC/PRF/5 cells. Purified CD63-, CD9-, or CD81-positive exosomes derived from the culture supernatants of HEV-infected cells that had been cultivated in serum-free medium were found to contain HEV RNA and the viral capsid (ORF2) and ORF3 proteins, as determined by reverse transcription-PCR (RT-PCR) and Western blotting, respectively. Furthermore, immunoelectron microscopy, with or without prior detergent and protease treatment, revealed the presence of virus-like particles in the exosome fraction. These particles were 39.6 +/- 1.0 nm in diameter and were covered with a lipid membrane. After treatment with detergent and protease, the diameter of these virus-like particles was 26.9 +/- 0.9 nm, and the treated particles became accessible with an anti-HEV ORF2 monoclonal antibody (MAb). The HEV particles in the exosome fraction were capable of infecting naive PLC/PRF/5 cells but were not neutralized by an anti-HEV ORF2 MAb which efficiently neutralizes nonenveloped HEV particles in cell culture. These results indicate that the membrane-wrapped HEV particles released by the exosomal pathway are copurified with the exosomes in the exosome fraction and suggest that the capsids of HEV particles are individually covered by lipid membranes resembling those of exosomes, similar to enveloped viruses.IMPORTANCE Hepatitis E, caused by HEV, is an important infectious disease that is spreading worldwide. HEV infection can cause acute or fulminant hepatitis and can become chronic in immunocompromised hosts, including patients after organ transplantation. The HEV particles present in feces and bile are nonenveloped, while those in circulating blood and culture supernatants are covered with a cellular membrane, similar to enveloped viruses. Furthermore, these membrane-associated and -unassociated HEV particles can be propagated in cultured cells. The significance of our research is that the capsids of HEV particles are individually covered by a lipid membrane that resembles the membrane of exosomes, similar to enveloped viruses, and are released from infected cells via the exosomal pathway. These data will help to elucidate the entry mechanisms and receptors for HEV infection in the future. This is the first report to characterize the detailed morphological features of membrane-associated HEV particles. PMID- 28878076 TI - Zika Virus Infects Human Sertoli Cells and Modulates the Integrity of the In Vitro Blood-Testis Barrier Model. AB - Confirmed reports of Zika virus (ZIKV) in human seminal fluid for months after the clearance of viremia suggest the ability of ZIKV to establish persistent infection in the seminiferous tubules, an immune-privileged site in the testis protected by the blood-testis barrier, also called the Sertoli cell (SC) barrier (SCB). However, cellular targets of ZIKV in human testis and mechanisms by which the virus enters seminiferous tubules remain unclear. We demonstrate that primary human SCs were highly susceptible to ZIKV compared to the closely related dengue virus and induced the expression of alpha interferon (IFN-alpha), key cytokines, and cell adhesion molecules (vascular cell adhesion molecule 1 [VCAM-1] and intracellular adhesion molecule 1 [ICAM-1]). Furthermore, using an in vitro SCB model, we show that ZIKV was released on the adluminal side of the SCB model with a higher efficiency than in the blood-brain barrier model. ZIKV-infected SCs exhibited enhanced adhesion of leukocytes that correlated with decreases in SCB integrity. ZIKV infection did not affect the expression of tight and adherens junction proteins such as ZO-1, claudin, and JAM-A; however, exposure of SCs to inflammatory mediators derived from ZIKV-infected macrophages led to the degradation of the ZO-1 protein, which correlated with increased SCB permeability. Taken together, our data suggest that infection of SCs may be one of the crucial steps by which ZIKV gains access to the site of spermatozoon development and identify SCs as a therapeutic target to clear testicular infections. The SCB model opens up opportunities to assess interactions of SCs with other testicular cells and to test the ability of anti-ZIKV drugs to cross the barrier.IMPORTANCE Recent outbreaks of ZIKV, a neglected mosquito-borne flavivirus, have identified sexual transmission as a new route of disease spread, which has not been reported for other flaviviruses. To be able to sexually transmit for months after the clearance of viremia, ZIKV must establish infection in the seminiferous tubules, the site of spermatozoon development. However, little is known about the cell types that support ZIKV infection in the human testis. Currently, there are no models to study mechanisms of virus persistence in the seminiferous tubules. We provide evidence that ZIKV infection of human Sertoli cells, which are an important component of the seminiferous tubules, is robust and induces a strong antiviral response. The use of an in vitro Sertoli cell barrier to describe how ZIKV or inflammatory mediators derived from ZIKV infected macrophages compromise barrier integrity will enable studies to explore the interactions of other testicular cells with Sertoli cells and to test novel antivirals for clearing testicular ZIKV infection. PMID- 28878077 TI - IRF9 Prevents CD8+ T Cell Exhaustion in an Extrinsic Manner during Acute Lymphocytic Choriomeningitis Virus Infection. AB - Effective CD8+ T cell responses play an important role in determining the course of a viral infection. Overwhelming antigen exposure can result in suboptimal CD8+ T cell responses, leading to chronic infection. This altered CD8+ T cell differentiation state, termed exhaustion, is characterized by reduced effector function, upregulation of inhibitory receptors, and altered expression of transcription factors. Prevention of overwhelming antigen exposure to limit CD8+ T cell exhaustion is of significant interest for the control of chronic infection. The transcription factor interferon regulatory factor 9 (IRF9) is a component of type I interferon (IFN-I) signaling downstream of the IFN-I receptor (IFNAR). Using acute infection of mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong, we show here that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and IFN-I and by controlling levels of IRF7, a transcription factor essential for IFN-I production. Infection of IRF9- or IFNAR-deficient mice led to a loss of early restriction of viral replication and impaired antiviral responses in dendritic cells, resulting in CD8+ T cell exhaustion and chronic infection. Differences in the antiviral activities of IRF9- and IFNAR-deficient mice and dendritic cells provided further evidence of IRF9-independent IFN-I signaling. Thus, our findings illustrate a CD8+ T cell-extrinsic function for IRF9, as a signaling factor downstream of IFNAR, in preventing overwhelming antigen exposure resulting in CD8+ T cell exhaustion and, ultimately, chronic infection.IMPORTANCE During early viral infection, overwhelming antigen exposure can cause functional exhaustion of CD8+ T cells and lead to chronic infection. Here we show that the transcription factor interferon regulatory factor 9 (IRF9) plays a decisive role in preventing CD8+ T cell exhaustion. Using acute infection of mice with LCMV strain Armstrong, we found that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and Irf7, encoding a transcription factor crucial for type I interferon (IFN-I) production, as well as by controlling the levels of IFN I. Infection of IRF9-deficient mice led to a chronic infection that was accompanied by CD8+ T cell exhaustion due to defects extrinsic to T cells. Our findings illustrate an essential role for IRF9, as a mediator downstream of IFNAR, in preventing overwhelming antigen exposure causing CD8+ T cell exhaustion and leading to chronic viral infection. PMID- 28878078 TI - Potent Plasmablast-Derived Antibodies Elicited by the National Institutes of Health Dengue Vaccine. AB - Exposure to dengue virus (DENV) is thought to elicit lifelong immunity, mediated by DENV-neutralizing antibodies (nAbs). However, Abs generated by primary infections confer serotype-specific protection, and immunity against other serotypes develops only after subsequent infections. Accordingly, the induction of these nAb responses acquired after serial DENV infections has been a long sought-after goal for vaccination. Nonetheless, it is still unclear if tetravalent vaccines can elicit or recall nAbs. In this study, we have characterized the responses from a volunteer who had been previously exposed to DENV and was immunized with the live attenuated tetravalent vaccine Butantan-DV, developed by the NIH and Butantan Institute. Eleven days after vaccination, we observed an ~70-fold expansion of the plasmablast population. We generated 21 monoclonal Abs (MAbs) from singly sorted plasmablasts. These MAbs were the result of clonal expansions and had significant levels of somatic hypermutation (SHM). Nineteen MAbs (90.5%) neutralized at least one DENV serotype at concentrations of 1 MUg/ml or less; 6 of the 21 MAbs neutralized three or more serotypes. Despite the tetravalent composition of the vaccine, we observed a neutralization bias in the induced repertoire: DENV3 was targeted by 18 of the 19 neutralizing MAbs (nMAbs). Furthermore, the P3D05 nMAb neutralized DENV3 with extraordinary potency (concentration to achieve half-maximal neutralization [Neut50] = 0.03 MUg/ml). Thus, the Butantan-DV vaccine engendered a mature, antigen-selected B cell repertoire. Our results suggest that preexisting responses elicited by a previous DENV3 infection were recalled by immunization.IMPORTANCE The dengue epidemic presents a global public health challenge that causes widespread economic burden and remains largely unchecked by existing control strategies. Successful control of the dengue epidemic will require effective prophylactic and therapeutic interventions. Several vaccine clinical efficacy trials are approaching completion, and the chances that one or more live attenuated tetravalent vaccines (LATVs) will be introduced worldwide is higher than ever. While it is widely accepted that dengue virus (DENV)-neutralizing antibody (nAb) titers are associated with protection, the Ab repertoire induced by LATVs remain uncharacterized. Here, we describe the isolation of potent (Neut50 < 0.1 MUg/ml) nAbs from a DENV-seropositive volunteer immunized with the tetravalent vaccine Butantan-DV, which is currently in phase III trials. PMID- 28878079 TI - Minocycline Has Anti-inflammatory Effects and Reduces Cytotoxicity in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection. AB - West Nile virus (WNV) is a neurotropic flavivirus that can cause significant neurological disease. Mouse models of WNV infection demonstrate that a proinflammatory environment is induced within the central nervous system (CNS) after WNV infection, leading to entry of activated peripheral immune cells. We utilized ex vivo spinal cord slice cultures (SCSC) to demonstrate that anti inflammatory mechanisms may also play a role in WNV-induced pathology and/or recovery. Microglia are a type of macrophage that function as resident CNS immune cells. Similar to mouse models, infection of SCSC with WNV induces the upregulation of proinflammatory genes and proteins that are associated with microglial activation, including the microglial activation marker Iba1 and CC motif chemokines CCL2, CCL3, and CCL5. This suggests that microglia assume a proinflammatory phenotype in response to WNV infection similar to the proinflammatory (M1) activation that can be displayed by other macrophages. We now show that the WNV-induced expression of these and other proinflammatory genes was significantly decreased in the presence of minocycline, which has antineuroinflammatory properties, including the ability to inhibit proinflammatory microglial responses. Minocycline also caused a significant increase in the expression of anti-inflammatory genes associated with alternative anti-inflammatory (M2) macrophage activation, including interleukin 4 (IL-4), IL 13, and FIZZ1. Minocycline-dependent alterations to M1/M2 gene expression were associated with a significant increase in survival of neurons, microglia, and astrocytes in WNV-infected slices and markedly decreased levels of inducible nitric oxide synthase (iNOS). These results demonstrate that an anti-inflammatory environment induced by minocycline reduces viral cytotoxicity during WNV infection in ex vivo CNS tissue.IMPORTANCE West Nile virus (WNV) causes substantial morbidity and mortality, with no specific therapeutic treatments available. Antiviral inflammatory responses are a crucial component of WNV pathology, and understanding how they are regulated is important for tailoring effective treatments. Proinflammatory responses during WNV infection have been extensively studied, but anti-inflammatory responses (and their potential protective and reparative capabilities) following WNV infection have not been investigated. Minocycline induced the expression of genes associated with the anti-inflammatory (M2) activation of CNS macrophages (microglia) in WNV-infected SCSC while inhibiting the expression of genes associated with proinflammatory (M1) macrophage activation and was protective for multiple CNS cell types, indicating its potential use as a therapeutic reagent. This ex vivo culture system can uniquely address the ability of CNS parenchymal cells (neurons, astrocytes, and microglia) to respond to minocycline and to modulate the inflammatory environment and cytotoxicity in response to WNV infection without peripheral immune cell involvement. PMID- 28878080 TI - Mechanical Barriers Restrict Invasion of Herpes Simplex Virus 1 into Human Oral Mucosa. AB - Oral mucosa is one of the main target tissues of the human pathogen herpes simplex virus 1 (HSV-1). How the virus overcomes the protective epithelial barriers and penetrates the tissue to reach its receptors and initiate infection is still unclear. Here, we established an ex vivo infection assay with human oral mucosa that allows viral entry studies in a natural target tissue. The focus was on the susceptibility of keratinocytes in the epithelium and the characterization of cellular receptors that mediate viral entry. Upon ex vivo infection of gingiva or vestibular mucosa, we observed that intact human mucosa samples were protected from viral invasion. In contrast, the basal layer of the oral epithelium was efficiently invaded once the connective tissue and the basement membrane were removed. Later during infection, HSV-1 spread from basal keratinocytes to upper layers, demonstrating the susceptibility of the stratified squamous epithelium to HSV-1. The analysis of potential receptors revealed nectin-1 on most mucosal keratinocytes, whereas herpesvirus entry mediator (HVEM) was found only on a subpopulation of cells, suggesting that nectin-1 acts as primary receptor for HSV 1 in human oral mucosa. To mimic the supposed entry route of HSV-1 via microlesions in vivo, we mechanically wounded the mucosa prior to infection. While we observed a limited number of infected keratinocytes in some wounded mucosa samples, other samples showed no infected cells. Thus, we conclude that mechanical wounding of mucosa is insufficient for the virus to efficiently overcome epithelial barriers and to make entry-mediating receptors accessible.IMPORTANCE To invade the target tissue of its human host during primary infection, herpes simplex virus (HSV) must overcome the epithelial barriers of mucosa, skin, or cornea. For most viruses, the mechanisms underlying the invasion into the target tissues of their host organism are still open. Here, we established an ex vivo infection model of human oral mucosa to explore how HSV can enter its target tissue. Our results demonstrate that intact mucosa samples and even compromised tissue allow only very limited access of HSV to keratinocytes. Detailed understanding of barrier functions is an essential precondition to unravel how HSV bypasses the barriers and approaches its receptors in tissue and why it is beneficial for the virus to use a cell-cell adhesion molecule, such as nectin-1, as a receptor. PMID- 28878081 TI - Foot-and-Mouth Disease (FMD) Virus 3C Protease Mutant L127P: Implications for FMD Vaccine Development. AB - The foot-and-mouth disease virus (FMDV) afflicts livestock in more than 80 countries, limiting food production and global trade. Production of foot-and mouth disease (FMD) vaccines requires cytosolic expression of the FMDV 3C protease to cleave the P1 polyprotein into mature capsid proteins, but the FMDV 3C protease is toxic to host cells. To identify less-toxic isoforms of the FMDV 3C protease, we screened 3C mutants for increased transgene output in comparison to wild-type 3C using a Gaussia luciferase reporter system. The novel point mutation 3C(L127P) increased yields of recombinant FMDV subunit proteins in mammalian and bacterial cells expressing P1-3C transgenes and retained the ability to process P1 polyproteins from multiple FMDV serotypes. The 3C(L127P) mutant produced crystalline arrays of FMDV-like particles in mammalian and bacterial cells, potentially providing a practical method of rapid, inexpensive FMD vaccine production in bacteria.IMPORTANCE The mutant FMDV 3C protease L127P significantly increased yields of recombinant FMDV subunit antigens and produced virus-like particles in mammalian and bacterial cells. The L127P mutation represents a novel advancement for economical FMD vaccine production. PMID- 28878082 TI - Lysine 242 within helix 10 of the pseudorabies virus nuclear egress complex pUL31 component is critical for primary envelopment of nucleocapsids. AB - Newly assembled herpesvirus nucleocapsids are translocated from the nucleus to the cytosol by a vesicle-mediated process engaging the nuclear membranes. This transport is governed by the conserved nuclear egress complex (NEC), consisting of the alphaherpesviral pUL34 and pUL31 homologs. The NEC is not only required for efficient nuclear egress but also sufficient for vesicle formation from the inner nuclear membrane (INM) as well as from synthetic lipid bilayers. The recently solved crystal structures for the NECs from different herpesviruses revealed molecular details of this membrane deformation and scission machinery uncovering the interfaces involved in complex and coat formation. However, the interaction domain with the nucleocapsid remained undefined. Since the NEC assembles a curved hexagonal coat on the nucleoplasmic side of the INM consisting of tightly interwoven pUL31/pUL34 heterodimers arranged in hexamers, only the membrane-distal end of the NEC formed by pUL31 residues appears accessible for interaction with the nucleocapsid cargo. To identify the amino acids involved in capsid incorporation we mutated the corresponding regions in the alphaherpesvirus pseudorabies virus (PrV). Site-specifically mutated pUL31 were tested for localization, interaction with pUL34 and complementation of PrV-DeltaUL31. Here, we identify a conserved lysine residue at amino acid position 242 in PrV pUL31 located in the alpha-helical domain H10 exposed on the membrane-distal end of the NEC as a key residue for nucleocapsid incorporation into the nascent primary particle.IMPORTANCE Vesicular transport through the nuclear envelope is a focus of research but still not well understood. Herpesviruses pioneered this mechanism for translocation of the newly assembled nucleocapsid from the nucleus into the cytosol via vesicles derived from the inner nuclear membrane which fuse in a well tuned process with the outer nuclear membrane to release their content. The structure of the viral nuclear membrane budding and scission machinery has been solved recently providing in-depth molecular details. However, how cargo is incorporated remained unclear. Here, we identified a conserved lysine residue in the membrane-distal portion of the nuclear egress complex required for capsid uptake into inner nuclear membrane-derived vesicles. PMID- 28878084 TI - Human Herpesvirus 8 Interleukin-6 Interacts with Calnexin Cycle Components and Promotes Protein Folding. AB - Viral interleukin-6 (vIL-6) encoded by human herpesvirus 8 (HHV-8) is believed to contribute via mitogenic, survival, and angiogenic activities to HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease through autocrine or paracrine mechanisms during latency or productive replication. There is direct evidence that vIL-6 promotes latently infected PEL cell viability and proliferation and also viral productive replication in PEL and endothelial cells. These activities are mediated largely through endoplasmic reticulum (ER)-localized vIL-6, which can induce signal transduction via the gp130 signaling receptor, activating mitogen-activated protein kinase and signal transducer and activator of transcription signaling, and interactions of vIL-6 with the ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2). The latter functional axis involves suppression of proapoptotic lysosomal protein cathepsin D by promotion of the ER-associated degradation of ER-transiting, preproteolytically processed procathepsin D. Other interactions of VKORC1v2 and activities of vIL-6 via the receptor have not been reported. We show here that both vIL-6 and VKORC1v2 interact with calnexin cycle proteins UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), which catalyzes monoglucosylation of N-glycans, and oppositely acting glucosidase II (GlucII), and that vIL-6 can promote protein folding. This activity was found to require VKORC1v2 and UGGT1, to involve vIL-6 associations with VKORC1v2, UGGT1, and GlucII, and to operate in the context of productively infected cells. These findings document new VKORC1v2-associated interactions and activities of vIL-6, revealing novel mechanisms of vIL-6 function within the ER compartment.IMPORTANCE HHV-8 vIL-6 prosurvival (latent) and proreplication functions are mediated from the ER compartment through both gp130 receptor-mediated signal transduction and interaction of vIL-6 with the ER membrane protein VKORC1v2. This report identifies interactions of vIL-6 and VKORC1v2 with calnexin cycle enzymes GlucII and UGGT1, which are involved in glycan processing and nascent protein folding. The presented data show that vIL-6 and VKORC1v2 can cocomplex with GlucII and UGGT1, that vIL-6 promotes protein folding, and that VKORC1v2, UGGT1, and vIL-6 interactions with GlucII and UGGT1 are important for the profolding activity of vIL-6, which can be detected in the context of infected cells. This newly identified ER activity of vIL-6 involving VKORC1v2 may promote viral latency (in PEL cells) and productive replication by limiting the damaging effects of unfolded protein response signaling in addition to enhancing viral protein folding. This is the first report of such a function for a cytokine. PMID- 28878083 TI - How germinal centers evolve broadly neutralizing antibodies: the breadth of the follicular helper T cell response. AB - Many HIV-1 infected patients evolve broadly neutralizing antibodies (bnAbs). This evolutionary process typically takes several years, and is poorly understood as selection taking place in germinal centers occurs on the basis of antibody affinity. B cells with the highest affinity receptors tend to acquire the most antigen from the FDC network, and present the highest density of cognate peptides to follicular helper T cells (Tfh), which provide survival signals to the B cell. BnAbs are therefore only expected to evolve when the B cell lineage evolving breadth is consistently capturing and presenting more peptides to Tfh cells than other lineages of more specific B cells. Here we develop mathematical models of Tfh in germinal centers to explicitly define the mechanisms of selection in this complex evolutionary process.Our results suggest that broadly reactive B cells presenting a high density of pMHC are readily outcompeted by B cells responding to lineages of HIV-1 that transiently dominate the within host viral population. Conversely, if broadly reactive B cells acquire a large variety of several HIV-1 proteins from the FDC network and present a high diversity of several pMHC, they be rescued by a large fraction of the Tfh repertoire in the germinal center. Under such circumstances the evolution of bnAbs is much more consistent. Increasing the magnitude of the Tfh response, or the breadth of the Tfh repertoire, both markedly facilitate the evolution of bnAbs. Because both can be increased by vaccination with several HIV-1 proteins, this calls for experiments testing.Importance Many HIV-infected patients slowly evolve antibodies that can neutralize a large variety of viruses. Such "broadly neutralizing antibodies" (bnAbs) could in the future become therapeutic agents. BnAbs appear very late and patients are typically not protected by them. At the moment we fail to understand why this takes so long, and how the immune system selects for broadly neutralizing capacity. Typically antibodies are selected based on affinity and not on breadth. We develop mathematical models to study two different mechanisms by which the immune system can select for broadly neutralizing capacity. One of these is based upon the repertoire of different follicular helper T cells (Tfh) in germinal centers. We suggest that broadly reactive B cells may interact with a larger fraction of this repertoire, and demonstrate that this would select for bnAbs. Intriguingly, this suggest that broadening the Tfh repertoire by vaccination may speed up the evolution of bnAbs. PMID- 28878085 TI - Human Cytomegalovirus Particles Treated with Specific Antibodies Induce Intrinsic and Adaptive but Not Innate Immune Responses. AB - Human cytomegalovirus (HCMV) persistently infects 40% to 100% of the human population worldwide. Experimental and clinical evidence indicates that humoral immunity to HCMV plays an important role in restricting virus dissemination and protecting the infected host from disease. Specific immunoglobulin preparations from pooled plasma of adults selected for high titers of HCMV antibodies have been used for the prevention of CMV disease in transplant recipients and pregnant women. Even though incubation of HCMV particles with these preparations leads to the neutralization of viral infectivity, it is still unclear whether the antibody treated HCMV particles (referred to here as HCMV-Ab) enter the cells and modulate antiviral immune responses. Here we demonstrate that HCMV-Ab did enter macrophages. HCMV-Ab did not initiate the expression of immediate early antigens (IEAs) in macrophages, but they induced an antiviral state and rendered the cells less susceptible to HCMV infection upon challenge. Resistance to HCMV infection seemed to be due to the activation of intrinsic restriction factors and was independent of interferons. In contrast to actively infected cells, autologous NK cells did not degranulate against HCMV-Ab-treated macrophages, suggesting that these cells may not be eliminated by innate effector cells. Interestingly, HCMV Ab-treated macrophages stimulated the proliferation of autologous adaptive CD4+ and CD8+ T cells. Our findings not only expand the current knowledge on virus antibody immunity but may also be relevant for future vaccination strategies.IMPORTANCE Human cytomegalovirus (HCMV), a common herpesvirus, establishes benign but persistent infections in immunocompetent hosts. However, in subjects with an immature or dysfunctional immune system, HCMV is a major cause of morbidity and mortality. Passive immunization has been used in different clinical settings with variable clinical results. Intravenous hyperimmune globulin preparations (IVIg) are obtained from pooled adult human plasma selected for high anti-CMV antibody titers. While HCMV neutralization can be shown in vitro using different systems, data are lacking regarding the cross-influence of IVIg administration on the cellular immune responses. The aim of this study was to evaluate the effects of IVIg on distinct components of the immune response against HCMV, including antigen presentation by macrophages, degranulation of innate natural killer cells, and proliferation of adaptive CD4+ and CD8+ T cells. PMID- 28878087 TI - Novel Stable Ebola Virus Minigenome Replicon Reveals Remarkable Stability of the Viral Genome. AB - Ebola virus (EBOV) causes severe hemorrhagic fever in humans and other primates with a high case fatality rate. No approved drug or vaccine of EBOV is available, which necessitates better understanding of the virus life cycle. Studies on EBOV have been hampered because experimentations involving live virus are restricted to biosafety level 4 (BSL-4) laboratories. EBOV minigenome system has provided researchers with the opportunity to study EBOV under BSL-2 conditions. Here, we developed a novel EBOV minigenome replicon which, to our knowledge, is the first EBOV cell culture system that can stably replicate and transcribe EBOV minigenome. The minigenomic RNA harboring a Gaussia Luciferase and hygromycin resistant marker can replicate for months in a helper cell stably expressing viral NP, VP35, VP30 and L proteins. Quantification of vRNA, cRNA and mRNA levels of EBOV minigenome demonstrated that the stable EBOV replicon had much more active minigenome replication than previously developed transient transfection based EBOV minigenome systems which recapitulate viral primary transcription more than genome replication. Interestingly, minigenome replication in the stable EBOV replicon cells was insensitive to interferon treatment or RNA interference. Moreover, RNase digestion of the replicon cell lysates revealed the remarkably stable nature of EBOV minigenomic vRNA ribonucleoprotein complex, which may help understand EBOV persistence in convalescent patients.IMPORTANCE The scope and severity of the recent Ebola outbreak in the Western Africa justified more comprehensive investigation of the causative Risk Group 4 agent Ebola virus (EBOV). Study of EBOV replication and antiviral development can be facilitated by developing a cell culture system that allows for experimentations in the biosafety level 2 conditions. Here, we developed a novel stable EBOV minigenome replicon which, to our knowledge, is the first EBOV cell culture system that can stably replicate and transcribe EBOV minigenome. Compared to previously developed transient transfection-based EBOV minigenome systems, the replicon system had more active genome replication, providing a convenient surrogate system to study EBOV replication. Furthermore, self-replicating minigenomic vRNA in the replicon cells displayed strong stability in response to interferon treatment, RNA silencing and RNase digestion, which may provide an explanation for the persistence of EBOV in survivors. PMID- 28878086 TI - Methanosarcina Spherical Virus, a Novel Archaeal Lytic Virus Targeting Methanosarcina Strains. AB - A novel archaeal lytic virus targeting species of the genus Methanosarcina was isolated using Methanosarcina mazei strain Go1 as the host. Due to its spherical morphology, the virus was designated Methanosarcina spherical virus (MetSV). Molecular analysis demonstrated that MetSV contains double-stranded linear DNA with a genome size of 10,567 bp containing 22 open reading frames (ORFs), all oriented in the same direction. Functions were predicted for some of these ORFs, i.e., such as DNA polymerase, ATPase, and DNA-binding protein as well as envelope (structural) protein. MetSV-derived spacers in CRISPR loci were detected in several published Methanosarcina draft genomes using bioinformatic tools, revealing a potential protospacer-adjacent motif (PAM) motif (TTA/T). Transcription and expression of several predicted viral ORFs were validated by reverse transcription-PCR (RT-PCR), PAGE analysis, and liquid chromatography-mass spectrometry (LC-MS)-based proteomics. Analysis of core lipids by atmospheric pressure chemical ionization (APCI) mass spectrometry showed that MetSV and Methanosarcina mazei both contain archaeol and glycerol dialkyl glycerol tetraether without a cyclopentane moiety (GDGT-0). The MetSV host range is limited to Methanosarcina strains growing as single cells (M. mazei, Methanosarcina barkeri and Methanosarcina soligelidi). In contrast, strains growing as sarcina-like aggregates were apparently protected from infection. Heterogeneity related to morphology phases in M. mazei cultures allowed acquisition of resistance to MetSV after challenge by growing cultures as sarcina like aggregates. CRISPR/Cas-mediated resistance was excluded since neither of the two CRISPR arrays showed MetSV-derived spacer acquisition. Based on these findings, we propose that changing the morphology from single cells to sarcina like aggregates upon rearrangement of the envelope structure prevents infection and subsequent lysis by MetSV.IMPORTANCE Methanoarchaea are among the most abundant organisms on the planet since they are present in high numbers in major anaerobic environments. They convert various carbon sources, e.g., acetate, methylamines, or methanol, to methane and carbon dioxide; thus, they have a significant impact on the emission of major greenhouse gases. Today, very little is known about viruses specifically infecting methanoarchaea that most probably impact the abundance of methanoarchaea in microbial consortia. Here, we characterize the first identified Methanosarcina-infecting virus (MetSV) and show a mechanism for acquiring resistance against MetSV. Based on our results, we propose that growth as sarcina-like aggregates prevents infection and subsequent lysis. These findings allow new insights into the virus-host relationship in methanogenic community structures, their dynamics, and their phase heterogeneity. Moreover, the availability of a specific virus provides new possibilities to deepen our knowledge of the defense mechanisms of potential hosts and offers tools for genetic manipulation. PMID- 28878088 TI - Effect of Polymorphisms at Codon 146 of the Goat PRNP Gene on Susceptibility to Challenge with Classical Scrapie by Different Routes. AB - This report presents the results of experimental challenges of goats with scrapie by both the intracerebral (i.c.) and oral routes, exploring the effects of polymorphisms at codon 146 of the goat PRNP gene on resistance to disease. The results of these studies illustrate that while goats of all genotypes can be infected by i.c. challenge, the survival distribution of the animals homozygous for asparagine at codon 146 was significantly shorter than those of animals of all other genotypes (chi-square value, 10.8; P = 0.001). In contrast, only those animals homozygous for asparagine at codon 146 (NN animals) succumbed to oral challenge. The results also indicate that any cases of infection in non-NN animals can be detected by the current confirmatory test (immunohistochemistry), although successful detection with the rapid enzyme-linked immunosorbent assay (ELISA) was more variable and dependent on the polymorphism. Together with data from previous studies of goats exposed to infection in the field, these data support the previously reported observations that polymorphisms at this codon have a profound effect on susceptibility to disease. It is concluded that only animals homozygous for asparagine at codon 146 succumb to scrapie under natural conditions.IMPORTANCE In goats, like in sheep, there are PRNP polymorphisms that are associated with susceptibility or resistance to scrapie. However, in contrast to the polymorphisms in sheep, they are more numerous in goats and may be restricted to certain breeds or geographical regions. Therefore, eradication programs must be specifically designed depending on the identification of suitable polymorphisms. An initial analysis of surveillance data suggested that such a polymorphism in Cypriot goats may lie in codon 146. In this study, we demonstrate experimentally that NN animals are highly susceptible after i.c. inoculation. The presence of a D or S residue prolonged incubation periods significantly, and prions were detected in peripheral tissues only in NN animals. In oral challenges, prions were detected only in NN animals, and the presence of a D or S residue at this position conferred resistance to the disease. This study provides an experimental transmission model for assessing the genetic susceptibility of goats to scrapie. PMID- 28878090 TI - Histone 3 lysine 9 acetylation is a biomarker of the effects of culture on zygotes. AB - Acetylation of histone proteins is a major determinant of chromatin structure and function. Fertilisation triggers a round of chromatin remodelling that prepares the genome for the first round of transcription from the new embryonic genome. In this study we confirm that fertilisation leads to a marked progressive increase in the level of histone 3 lysine 9 acetylation in both the paternally and maternally derived genomes. The culture of zygotes in simple defined media caused a marked increase in the global level of acetylation and this affected the male pronucleus more than the female. The culture created a marked asymmetry in staining between the two pronuclei that was not readily detected in zygotes collected directly from the reproductive tract and was ameliorated to some extent by optimized culture media. The increased acetylation caused by culture resulted in increased transcription of Hspa1b, a marker of embryonic genome activation. Pharmacological analyses showed the hyperacetylation of H3K9 and the increased expression of Hspa1b caused by culture were due to the altered net activity of a range of histone acetylases and deacetylases. The marked hyperacetylation of histone 3 lysine 9 caused by culture of zygotes may serve as an early biomarker for the effects of culture on the normal function of the embryo. The results also provide further evidence for an effect of the stresses associated with assisted reproductive technologies on the normal patterns of epigenetic reprogramming in the early embryo. PMID- 28878091 TI - Kisspeptin regulates steroidogenesis and spermiation in anuran amphibian. AB - Kisspeptin (Kp) system has a recognized role in the control of gonadotropic axis, at multiple levels. Recently, a major focus of research has been to assess any direct activity of this system on testis physiology. Using the amphibian anuran, Pelophylax esculentus, as animal model, we demonstrate - for the first time in non-mammalian vertebrate - that testis expresses both Kiss-1 and Gpr54 proteins during the annual sexual cycle and that ex vivo 17B-estradiol (E2, 10-6 M) increases both proteins over control group. Since the interstitium is the main site of localization of both ligand and receptor, its possible involvement in the regulation of steroidogenesis has been evaluated by ex vivo treatment of testis pieces with increasing doses of Kp-10 (10-9-10-6 M). Treatments have been carried out in February - when a new wave of spermatogenesis occurs - and affect the expression of key enzymes of steroidogenesis inducing opposite effects on testosterone and estradiol intratesticular levels. Morphological analysis of Kp treated testes reveals higher number of tubules with spermatozoa detached from Sertoli cells than control group and the expression of connexin 43, the main junctional protein in testis, is deeply affected by the treatment. In spite of the effects on spermatozoa observed ex vivo, in vivo administration of Kp-10 has been unable to induce sperm release in cloacal fluid. In conclusion, we demonstrate Kp-10 effects on steroidogenesis with possible involvement in the balance between testosterone and estradiol levels, and report new Kp-10 activities on spermatozoa-Sertoli cell interaction. PMID- 28878092 TI - Equine fetal adrenal, gonadal and placental steroidogenesis. AB - Equine fetuses have substantial circulating pregnenolone concentrations and thus have been postulated to provide significant substrate for placental 5alpha reduced pregnane production, but the fetal site of pregnenolone synthesis remains unclear. The current studies investigated steroid concentrations in blood, adrenal glands, gonads and placenta from fetuses (4, 6, 9 and 10 months of gestational age (GA)), as well as tissue steroidogenic enzyme transcript levels. Pregnenolone and dehydroepiandrosterone (DHEA) were the most abundant steroids in fetal blood, pregnenolone was consistently higher but decreased progressively with GA. Tissue steroid concentrations generally paralleled those in serum with time. Adrenal and gonadal tissue pregnenolone concentrations were similar and 100 fold higher than those in allantochorion. DHEA was far higher in gonads than adrenals and progesterone was higher in adrenals than gonads. Androstenedione decreased with GA in adrenals but not in gonads. Transcript analysis generally supported these data. CYP17A1 was higher in fetal gonads than adrenals or allantochorion, and HSD3B1 was higher in fetal adrenals and allantochorion than gonads. CYP11A1 transcript was also significantly higher in adrenals and gonads than allantochorion and CYP19 and SRD5A1 transcripts were higher in allantochorion than either fetal adrenals or gonads. Given these data, and their much greater size, the fetal gonads are the source of DHEA and likely contribute more than fetal adrenal glands to circulating fetal pregnenolone concentrations. Low CYP11A1 but high HSD3B1 and SRD5A1 transcript abundance in allantochorion, and low tissue pregnenolone, suggests that endogenous placental pregnenolone synthesis is low and likely contributes little to equine placental 5alpha-reduced pregnane secretion. PMID- 28878089 TI - HLA-B*14:02-Restricted Env-Specific CD8+ T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection. AB - Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B*14-EL9). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, HLA-B*14-DA9). Using HLA-B*14/peptide-saporin-conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype specific, applying only to HLA B*14:02 and not to HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.IMPORTANCE In HIV infection, although cytotoxic T lymphocytes (CTL) play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B*14, unique among HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. We demonstrate that Env-specific HLA-B*14-restricted activity is substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV are observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*14:02. Finally, we show that HLA-B*14:02 is significantly more strongly associated with viremic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV. PMID- 28878093 TI - Implications of microRNA dysregulation in the development of prostate cancer. AB - MicroRNAs (miRNAs) are non-coding small RNAs that target mRNA to reduce protein expression. They play fundamental roles in several diseases, including prostate cancer (PCa). A single miRNA can target hundreds of mRNAs and coordinately regulate them, which implicates them in nearly every biological pathway. Hence, miRNAs modulate proliferation, cell cycle, apoptosis, adhesion, migration, invasion and metastasis, most of them constituting crucial hallmarks of cancer. Due to these properties, miRNAs emerged as promising tools for diagnostic, prognosis and management of cancer patients. Moreover, they come out as potential targets for cancer treatment, and several efforts are being made to progress in the field of miRNA-based cancer therapy. In this review, we will summarize the recent information about miRNAs in PCa. We will recapitulate all the miRNAs involved in the androgen pathway and the biology of PCa, focusing in PCa initiation and progression. In particular, we will describe the miRNAs associated with cell proliferation, cell cycle and apoptosis in PCa, as well as invasion, adhesion and metastatic miRNAs. We will revise the recent progress made understanding the role of circulating miRNAs identified in PCa that might be useful for PCa patient stratification. Another key aspect to be discussed in this review is miRNAs' role in PCa therapy, including the miRNAs delivery. PMID- 28878095 TI - Celebrating Peer Review Week 2017: Transparency in the Review Process. PMID- 28878096 TI - Effects of Astroglia on Motor Neurons in Spinal Muscular Atrophy. PMID- 28878094 TI - Male genital tract immune response against Chlamydia trachomatis infection. AB - Chlamydia trachomatis is the most commonly reported agent of sexually transmitted bacterial infections worldwide. This pathogen frequently leads to persistent, long-term, subclinical infections, which in turn may cause severe pathology in susceptible hosts. This is in part due to the strategies that Chlamydia trachomatis uses to survive within epithelial cells and to evade the host immune response, such as subverting intracellular trafficking, interfering signaling pathways and preventing apoptosis. Innate immune receptors such as toll-like receptors expressed on epithelial and immune cells in the genital tract mediate the recognition of chlamydial molecular patterns. After bacterial recognition, a subset of pro-inflammatory cytokines and chemokines are continuously released by epithelial cells. The innate immune response is followed by the initiation of the adaptive response against Chlamydia trachomatis, which in turn may result in T helper 1-mediated protection or in T helper 2-mediated immunopathology. Understanding the molecular mechanisms developed by Chlamydia trachomatis to avoid killing and host immune response would be crucial for designing new therapeutic approaches and developing protective vaccines. In this review, we focus on chlamydial survival strategies and the elicited immune responses in male genital tract infections. PMID- 28878097 TI - Laughter as a Neurochemical Mechanism Aimed at Reinforcing Social Bonds: Integrating Evidence from Opioidergic Activity and Brain Stimulation. PMID- 28878099 TI - Distal Cuff Occlusion: A Novel, Simple Approach for Distal Embolic Protection in Peripheral Vascular Intervention. AB - AIM: To evaluate the feasibility, effectiveness, and safety of the cuff-occlusion method for distal embolic protection in peripheral artery disease. METHODS AND RESULTS: We evaluated 61 patients who underwent peripheral vascular intervention (PVI) for infrainguinal lesion at a single center where a blood pressure cuff occlusion method for distal embolic protection was utilized during the procedure. Primary endpoint included incidence of distal embolization, acute limb ischemia, or emergency limb amputation. Safety endpoints were freedom from bleeding, vessel perforation, or dissection. Lesion location was in the superficial femoral artery in 39% of cases and popliteal and infrapopliteal in 61% of patients. Procedural success was achieved in 98.4% of patients and 1 patient had distal embolization. There was no bleeding or perforation or major flow-limiting vessel dissection. CONCLUSION: Our study demonstrated that the cuff-occlusion strategy was feasible and safe for protection form distal embolization in PVI. Further study is required to evaluate the efficacy and safety of this novel method compared with existing devices for distal protection. PMID- 28878098 TI - Loss of Protein Arginine Methyltransferase 8 Alters Synapse Composition and Function, Resulting in Behavioral Defects. AB - Diverse molecular mechanisms regulate synaptic composition and function in the mammalian nervous system. The multifunctional protein arginine methyltransferase 8 (PRMT8) possesses both methyltransferase and phospholipase activities. Here we examine the role of this neuron-specific protein in hippocampal plasticity and cognitive function. PRMT8 protein localizes to synaptic sites, and conditional whole-brain Prmt8 deletion results in altered levels of multiple synaptic proteins in the hippocampus, using both male and female mice. Interestingly, these altered protein levels are due to post-transcriptional mechanisms as the corresponding mRNA levels are unaffected. Strikingly, electrophysiological recordings from hippocampal slices of mice lacking PRMT8 reveal multiple defects in excitatory synaptic function and plasticity. Furthermore, behavioral analyses show that PRMT8 conditional knock-out mice exhibit impaired hippocampal-dependent fear learning. Together, these findings establish PRMT8 as an important component of the molecular machinery required for hippocampal neuronal function.SIGNIFICANCE STATEMENT Numerous molecular processes are critically required for normal brain function. Here we use mice lacking protein arginine methyltransferase 8 (PRMT8) in the brain to examine how loss of this protein affects the structure and function of neurons in the hippocampus. We find that PRMT8 localizes to the sites of communication between neurons. Hippocampal neurons from mice lacking PRMT8 have no detectable structural differences compared with controls; however, multiple aspects of their function are altered. Consistently, we find that mice lacking PRMT8 also exhibit reduced hippocampus dependent memory. Together, our findings establish important roles for PRMT8 in regulating neuron function and cognition in the mammalian brain. PMID- 28878100 TI - A Time to Act and a Time to Watch: Severe Guide-Catheter Induced Proximal Coronary Dissection With Extensive Ascending Aorta and Arch Dissection, Managed by Immediate Coronary Stenting and Watchful Waiting. AB - In this case, prompt stenting of the dissection entry flap allowed for stabilization and eventual healing of a severe catheter-induced aortic dissection, without resort to surgical intervention. PMID- 28878101 TI - Percutaneous Closure of Two Acquired Aorto-Right Ventricular Fistulae Following Right Ventricular Outflow Tract Surgery. AB - The present case illustrates the successful transcatheter closure of an unusual double aortic root-to-right ventricular outflow tract fistula utilizing two Amplatzer duct occluders II. PMID- 28878102 TI - Coronary Intervention Complicated by Pressure Wires Caught Within Stent Struts. AB - Coronary guidewire fracture or entrapment is a recognized complication of percutaneous coronary intervention that can result in abrupt vessel closure, thrombosis, or stent deformation. Developments in pressure-wire (PW) design have enabled their use for coronary intervention. We describe two cases where the pressure sensor became trapped against stent struts during PW removal. PMID- 28878103 TI - Multimodality Imaging of Anomalous Origin of Right Coronary Artery From Pulmonary Artery (ARCAPA). AB - Computed tomography angiogram confirmed the anomalous right coronary artery from pulmonary artery (ARCAPA) in a patient who presented with altered mental status and hypoxia due to opiate drug abuse. ARCAPA is exceedingly rare, with reported incidence of 0.002% in the literature. We present clinical images and describe the case management. PMID- 28878104 TI - Treatment of Severe Native Left Pulmonary Artery Stenosis With Coronary Stent Implantation in a 2.4 kg Neonate. AB - A 1-month-old, 2.4 kg infant, previously born at 32 weeks gestation, was found to have a murmur while in the neonatal intensive care unit. The patient had ongoing feeding intolerance and required supplemental oxygen via nasal cannula. Cardiac computed tomography showed discrete stenosis of the proximal left pulmonary artery (LPA) with a normal-sized distal LPA. We describe the treatment course with transcatheter coronary stent implantation. PMID- 28878105 TI - Percutaneous Balloon Dilation of Discrete Subaortic Stenosis: A Futile Exercise. AB - Discrete subaortic stenosis (DSS) is a progressive obstruction of left ventricular outflow tract (LVOT) resulting in the development of aortic regurgitation in its natural course. Hence, early intervention is recommended. Percutaneous balloon dilation of DSS has been reported and can substantially reduce LVOT pressure gradient. The response to balloon dilation of DSS is transient and may complicate with chordal or papillary muscle rupture. Hence, balloon dilation of DSS should be discouraged. PMID- 28878106 TI - A Statistical Study of Serum Cholesterol Level by Gender and Race. AB - BACKGROUND: Cholesterol level (CL) is growing concerned as health issue in human health since it is considered one of the causes in heart diseases. A study of cholesterol level can provide insight about its nature and characteristics. STUDY DESIGN: A cross-sectional study. METHODS: National Health and Nutrition Examination Survey (NHANS) II was conducted on a probability sample of approximately 28,000 persons in the USA and cholesterol level is obtained from laboratory results. Samples were selected so that certain population groups thought to be at high risk of malnutrition. Study included 11,864 persons for CL cases with 9,602 males and 2,262 females with races: whites, blacks, and others. Non-parametric statistical tests and goodness of fit test have been used to identify probability distributions. RESULTS: The study concludes that the cholesterol level exhibits significant racial and gender differences in terms of probability distributions. The study has concluded that white people are relatively higher at risk than black people to have risk line and high risk cholesterol. The study clearly indicates that black males normally have higher cholesterol. Females have lower variation in cholesterol than males. CONCLUSIONS: There exists gender and racial discrepancies in cholesterol which has been identified as lognormal and gamma probability distributions. White individuals seem to be at a higher risk of having high risk cholesterol level than blacks. Females tend to have higher variation in cholesterol level than males. PMID- 28878107 TI - Predicting Factors for Retailers' Sale of Cigarettes to Adolescents in the Lower Part of Northern Region of Thailand. AB - BACKGROUND: Thailand is one of the members of WHO FCTC and has paid so much attention to preventing adolescents' access to tobacco. However, Thai adolescents still have access to tobacco with ease. The aim of this research was to investigate the predicting factors for the cigarettes sale to adolescents by the retailers in Thailand. STUDY DESIGN: A cross-sectional study. METHODS: This cross sectional survey was conducted after a careful desk review of the relevant literature. Multistage random sampling technique was used to sample the survey participants (n = 675) who were retailers of tobacco in the lower northern region of Thailand. Data were collected by validated questionnaires and analyzed by descriptive analytic, chi-square test and binary logistic regression. RESULTS: More than half (58.7%) of the participants sell cigarettes to adolescents. Factors such as open display of cigarette at the point of sale, selling cigarettes in sticks, selling cigarettes by self-service, and reluctant disregard of buyers' age by the seller significantly correlated with and predicted, at 95% level of confidence, the behavior of retailers selling cigarettes to adolescents. CONCLUSIONS: Thai adolescent's access to tobacco continues to be a serious public health problem. Therefore, the Ministry of Public Health and other relevant stakeholders saddled with the responsibility of interventions to scale up measures that would reinforce the law of Tobacco Control Act. PMID- 28878108 TI - Influence Factors on Birth Spacing and Childbearing Rates using Survival Recurrent Events Model and Parity Progression Ratios. AB - BACKGROUND: Reproduction rates are declining in Hamadan, western Iran. This study identified the influence factors associated with reproduction rate and birth spacing in Hamadan as an area of low population growth in Iran. STUDY DESIGN: A cross sectional study. METHODS: The study considered reproductive status of 812 women referred to health care centers of Hamadan, western Iran in 2015. Data were obtained through frequency and percentage. PWP-GT model was used to determine the influence factors on women's reproductive by R software (version 3.3.2). The parity progression ratios were determined based on Yadava and Kumar. RESULTS: The median time for the second, the third and the fourth birth was 4.53, 4.65 and 5.27 yr, respectively. PWP-GT model showed that women age at marriage (P=0.001), women's (P=0.005) and their husband's (P=0.039) employment had significant effect on time birth of first child. The women's education (P=0.001) was the only variable that had a significant effect on the birth time from the first to the second child as well as from the third to the fourth child. Education of women (P=0.001) and their husbands (P=0.034) had significant effect on the time interval from the second to the third child. The birth probability from marriage to the first birth (0 to 1st child) was high (0.91), while the probability had been fallen from the third birth and more (0.31). CONCLUSIONS: Birth spacing in Hamadan is more than WHO recommended. In addition, reducing of the population growth and childbearing has started in the past few decades in Hamadan the same as Iran. The chance of fertility has dramatically declined from the third child and then. PMID- 28878109 TI - Socioeconomic Inequality in Childhood Obesity. AB - BACKGROUND: The aim of this study was to assess the socioeconomic inequalities in obesity and overweight in children aged 10 to 12 yr old. STUDY DESIGN: A cross sectional study. METHODS: This study was conducted on 2506 children aged 10 to 12 yr old in the city of Sanandaj, western Iran in 2015. Body mass index (BMI) was calculated. Considering household situation and assets, socioeconomic status (SES) of the subjects was determined using Principal Component Analysis (PCA). Concentration Index was used to measure inequality and Oaxaca decomposition was used to determine the share of different determinants of inequality. RESULTS: The prevalence of overweight was 24.1% (95% CI: 22.4, 25.7). 11.5% (95% CI: 10.0, 12.0) were obese. The concentration index for overweight and obesity, respectively, was 0.10 (95% CI: 0.05, 0.15), and 0.07 (95% CI:0.00, 0.14) which indicated inequality and a higher prevalence of obesity and overweight in higher SES. The results of Oaxaca decomposition suggested that socioeconomic factors accounted for 75.8% of existing inequalities. Residential area and mother education were the most important causes of inequality. CONCLUSIONS: To reduce inequalities in childhood obesity, mother education must be promoted and special attention must be paid to residential areas and children gender. PMID- 28878110 TI - Estimation of Intravenous Drug Users' Population in Kermanshah City, West of Iran in 2016 using Capture-recapture Method. AB - BACKGROUND: Drug abuse, particularly intravenous drug use, is one of the most common challenges in human communities so that its negative impact on economic and cultural conditions of society and physical as well as mental health of individuals is evident. We aimed to estimate the IDUs' population in Kermanshah City, West of Iran using Capture-recapture method. STUDY DESIGN: A Cross sectional study. METHODS: The data in this study were collected from three different sources: Drop in Centers (DICs), Out Reach Teams (ORTs) and Methadone Maintenance Treatment centers (MMTs) in Kermanshah City from Mar 2015 until Mar 2016, and then indirect Capture-recapture was used to estimate the IDUs' population. RESULTS: The number of IDUs registered in DICs, ORTs, and MMTs were 694, 731, and 156 cases, respectively. Having determined the commonalities and removing duplicates, the number of drug users registered were 1,375 cases, after analysis of data, the number of drug users not registered in any center was estimated as 2,042 (95% CI: 1708, 2444). By counting 1,375 cases recorded in these sources, the total number of injection drug users in the Kermanshah City was about 3,417 people, (95% CI: (3083, 3819). CONCLUSIONS: The prevalence of IDUs in Kermanshah City is high, which could cause severe economic and social problems in the society. To reduce the negative effects of drug use, awareness and measuring of the drug users population, seem to be necessary overtime. PMID- 28878111 TI - Reasons for Inconsistent Condom Use Found as Answers to a Multiple Response Question: A National Survey of Iranian Adults, 2013. AB - BACKGROUND: The use of condoms is important for preventing Sexually Transmitted Infections (STIs). However, the prevalence of condom use is not satisfactory. The aim of this study was to assess the reasons for inconsistent condom use in Iranian adults. STUDY DESIGN: Cross-sectional study. METHODS: Data were gathered through multi-stage sampling. Participants were enrolled from 13 provinces in Iran aged between 19 and 29 years. They had ever-extramarital sex and did not use condoms regularly in their sexual contacts, asked the reasons for inconsistent condom use. RESULTS: We had 3,246 adults, from which 635 (19.5%) had ever extramarital sex. Among them, 495 (77.96%) did not use condoms with regularity. The reason frequently chosen for inconsistent condom use was 'that it is not accessible' (49.3%). The differences between the categories of some variables, according to the choice of reasons for inconsistent condom use, were significant (P<0.05): age, gender, knowledge of HIV, attitude towards HIV, knowing infected HIV person and alcohol or stimulant(s) used before sexual contact. According to multivariate multilevel logistic, the effect of gender was significant on most of reasons for inconsistent condom use (P <0.05). CONCLUSIONS: Most of the reasons that were selected for inconsistent condom use were inaccessibility and not knowing that its use is essential. Hence, it is important to improve the knowledge of adults regarding STI/HIV and extend the locations of condom distribution. We should try to promote the culture of condom use as a routine. PMID- 28878112 TI - Artificial Neural Network to Modeling Zero-inflated Count Data: Application to Predicting Number of Return to Blood Donation. AB - BACKGROUND: Traditional statistical models often are based on certain presuppositions and limitations that may not presence in actual data and lead to turbulence in estimation or prediction. In these situations, artificial neural networks (ANNs) could be suitable alternative rather than classical statistical methods. STUDY DESIGN: A prospective cohort study. METHODS: The study was conducted in Shahrekord Blood Transfusion Center, Shahrekord, central Iran, on blood donors from 2008-2009. The accuracy of the proposed model to prediction of number of return to blood donations was compared with classical statistical models. A number of 864 donors who had a first-time successful donation were followed for five years. Number of return for blood donation was considered as response variable. Poisson regression (PR), negative binomial regression (NBR), zero-inflated Poisson regression (ZIPR) and zero-inflated negative binomial regression (ZINBR) as well as ANN model were fitted to data. MSE criterion was used to compare models. To fitting the models, STATISTICA 10 and, R 3.2.2 was used RESULTS: The MSE of PR, NBR, ZIPR, ZINBR and ANN models was obtained 2.71, 1.01, 1.54, 0.094 and 0.056 for the training and 4.05, 9.89, 3.99, 2.53 and 0.27 for the test data, respectively. CONCLUSIONS: The ANN model had the least MSE in both training, and test data set and has a better performance than classic models. ANN could be a suitable alternative for modeling such data because of fewer restrictions. PMID- 28878113 TI - Documentation of Measles Elimination in Iran: Evidences from 2012 to 2014. AB - BACKGROUND: Documentation of achieving the goal of measles elimination to justify to international organizations including the WHO is a priority for public health authorities. This study aimed to address the status of Iran in the achievement of the measles elimination goal from 2012-2014. STUDY DESIGN: A descriptive study METHODS: Data on the measles outbreaks were extracted from the national notifiable measles surveillance system in Iran from 2012 to 2014. The required documents regarding the achievement of measles elimination, including Effective Reproduction Number (R) and the distribution of outbreak size, was addressed. The R was calculated using the proportion of imported cases as 1 - P, where P is equal to the proportion of cases that were imported. The distribution of the measles outbreaks size was described using descriptive statistics to show their magnitudes. The proportion of large outbreaks with more than 10 cases was considered as a proxy of the R value. RESULTS: The total number of measles cases was 232 cases (including 186 outbreak related cases) in 2012 and 142 cases in 2014, including108 outbreak related cases. The distribution of the measles outbreak size of occurred outbreaks from that period indicated that there were 37 outbreaks with three or more than three cases. The R value in 2012 was 0.87 and the corresponding value for 2014 was 0.76. CONCLUSIONS: According to the magnitude of effective reproduction number and distribution of outbreaks' size, measles has been eliminated in Iran. However, it is necessary to consider the potential endemic activity of measles because of no authorized immigration. PMID- 28878114 TI - Strategies to Reduce HIV Transmission amongst Prisoners; Lessons Learned From Iran. AB - . PMID- 28878115 TI - IL-23R-activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity. AB - The factors that promote the differentiation of pathogenic T cells in autoimmune diseases are poorly defined. Use of genetically modified mice has provided insight into molecules necessary for the development of autoimmunity, but the sum of the data has led to contradictory observations based on what is currently known about specific molecules in specific signaling pathways. To define the minimum signals required for development of encephalitogenic T cells that cause CNS autoimmunity, myelin-specific T cells were differentiated with various cytokine cocktails, and pathogenicity was determined by transfer into mice. IL 6+IL-23 or IL-12+IL-23 generated encephalitogenic T cells and recapitulated the essential cytokine signals provided by antigen-presenting cells, and both IL-6 and IL-12 induced IL-23 receptor expression on both mouse and human naive T cells. IL-23 signaled through both STAT3 and STAT4, and disruption in STAT4 signaling impaired CNS autoimmunity independent of IL-12. These data explain why IL-12-deficient mice develop CNS autoimmunity, while STAT4-deficient mice are resistant. CD4+ memory T cells from multiple sclerosis patients had significantly higher levels of p-STAT3/p-STAT4, and p-STAT3/p-STAT4 heterodimers were observed upon IL-23 signaling, suggesting that p-STAT3/p-STAT4 induced by IL-23 signaling orchestrate the generation of pathogenic T cells in CNS autoimmunity, regardless of Th1 or Th17 phenotype. PMID- 28878116 TI - Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function. AB - Cardiomyopathy frequently complicates sepsis and is associated with increased mortality. Increased cardiac oxidative stress and mitochondrial dysfunction have been observed during sepsis, but the mechanisms responsible for these abnormalities have not been determined. We hypothesized that NADPH oxidase 2 (NOX2) activation could be responsible for sepsis-induced oxidative stress and cardiomyopathy. Treatment of isolated adult mouse cardiomyocytes with low concentrations of the endotoxin lipopolysaccharide (LPS) increased total cellular reactive oxygen species (ROS) and mitochondrial superoxide. Elevated mitochondrial superoxide was accompanied by depolarization of the mitochondrial inner membrane potential, an indication of mitochondrial dysfunction, and mitochondrial calcium overload. NOX2 inhibition decreased LPS-induced superoxide and prevented mitochondrial dysfunction. Further, cardiomyocytes from mice with genetic ablation of NOX2 did not have LPS-induced superoxide or mitochondrial dysfunction. LPS decreased contractility and calcium transient amplitude in isolated cardiomyocytes, and these abnormalities were prevented by inhibition of NOX2. LPS decreased systolic function in mice, measured by echocardiography. NOX2 inhibition was cardioprotective in 2 mouse models of sepsis, preserving systolic function after LPS injection or cecal ligation and puncture (CLP). These data show that inhibition of NOX2 decreases oxidative stress, preserves intracellular calcium handling and mitochondrial function, and alleviates sepsis-induced systolic dysfunction in vivo. Thus, NOX2 is a potential target for pharmacotherapy of sepsis-induced cardiomyopathy. PMID- 28878117 TI - Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy. AB - Heart disease remains the leading cause of death worldwide, highlighting a pressing need to identify novel regulators of cardiomyocyte (CM) function that could be therapeutically targeted. The mammalian Hippo/Tead pathway is critical in embryonic cardiac development and perinatal CM proliferation. However, the requirement of Tead1, the transcriptional effector of this pathway, in the adult heart is unknown. Here, we show that tamoxifen-inducible adult CM-specific Tead1 ablation led to lethal acute-onset dilated cardiomyopathy, associated with impairment in excitation-contraction coupling. Mechanistically, we demonstrate Tead1 is a cell-autonomous, direct transcriptional activator of SERCA2a and SR associated protein phosphatase 1 regulatory subunit, Inhibitor-1 (I-1). Thus, Tead1 deletion led to a decrease in SERCA2a and I-1 transcripts and protein, with a consequent increase in PP1-activity, resulting in accumulation of dephosphorylated phospholamban (Pln) and decreased SERCA2a activity. Global transcriptomal analysis in Tead1-deleted hearts revealed significant changes in mitochondrial and sarcomere-related pathways. Additional studies demonstrated there was a trend for correlation between protein levels of TEAD1 and I-1, and phosphorylation of PLN, in human nonfailing and failing hearts. Furthermore, TEAD1 activity was required to maintain PLN phosphorylation and expression of SERCA2a and I-1 in human induced pluripotent stem cell-derived (iPS-derived) CMs. To our knowledge, taken together, this demonstrates a nonredundant, novel role of Tead1 in maintaining normal adult heart function. PMID- 28878118 TI - Podoplanin is a negative regulator of Th17 inflammation. AB - Recent data indicate that there are different subpopulations of Th17 cells that can express a regulatory as opposed to an inflammatory gene signature. The transmembrane glycoprotein PDPN is critical in the development of multiple organs including the lymphatic system and has been described on T cells in mouse models of autoimmune Th17 inflammation. Here, we demonstrate that unlike in mice, PDPN+ T cells induced under classic Th17-polarizing conditions express transcription factors associated with Th17 cells but do not produce IL-17. Moreover, these cells express a transcriptional profile enriched for immunosuppressive and regulatory pathways and express a distinct cytokine profile compared with potentially pathogenic PDPN- Th17 cells. Ligation of PDPN by its ligand CLEC-2 ameliorates the Th17 inflammatory response. IL-17 secretion is restored with shRNA gene silencing of PDPN. Furthermore, PDPN expression is reduced via an Sgk1 mediated pathway under proinflammatory, high sodium chloride conditions. Finally, CD3+PDPN+ T cells are devoid of IL-17 in skin biopsies from patients with candidiasis, a prototypical Th17-driven skin disease. Thus, our data support the hypothesis that PDPN may serve as a marker of a nonpathogenic Th17 cell subset and may also functionally regulate pathogenic Th17 inflammation. PMID- 28878119 TI - Pharmacologic HIV-1 Nef blockade promotes CD8 T cell-mediated elimination of latently HIV-1-infected cells in vitro. AB - Eradication of the HIV-1 latent reservoir represents the current paradigm to developing a cure for AIDS. HIV-1 has evolved multiple mechanisms to evade CD8 T cell responses, including HIV-1 Nef-mediated downregulation of MHC-I from the surface of infected cells. Nef transcripts and protein are detectable in samples from aviremic donors, suggesting that Nef expression in latently HIV-1-infected CD4 T cells protects them from immune-mediated clearance. Here, we tested 4 small molecule inhibitors of HIV-1 Nef in an in vitro primary CD4 T cell latency model and measured the ability of autologous ex vivo or HIV-1 peptide-expanded CD8 T cells to recognize and kill latently infected cells as a function of inhibitor treatment. Nef inhibition enhanced cytokine secretion by autologous CD8 T cells against latently HIV-1-infected targets in an IFN-gamma release assay. Additionally, CD8 T cell-mediated elimination of latently HIV-1-infected cells was significantly enhanced following Nef blockade, measured as a reduction in the frequency of infected cells and Gag protein in cultures following viral outgrowth assays. We demonstrate for the first time to our knowledge that Nef blockade, in combination with HIV-specific CD8 T cell expansion, might be a feasible strategy to target the HIV-1 latent reservoir that should be tested further in vivo. PMID- 28878121 TI - A TCRalpha framework-centered codon shapes a biased T cell repertoire through direct MHC and CDR3beta interactions. AB - Selection of biased T cell receptor (TCR) repertoires across individuals is seen in both infectious diseases and autoimmunity, but the underlying molecular basis leading to these shared repertoires remains unclear. Celiac disease (CD) occurs primarily in HLA-DQ2.5+ individuals and is characterized by a CD4+ T cell response against gluten epitopes dominated by DQ2.5-glia-alpha1a and DQ2.5-glia alpha2. The DQ2.5-glia-alpha2 response recruits a highly biased TCR repertoire composed of TRAV26-1 paired with TRBV7-2 harboring a semipublic CDR3beta loop. We aimed to unravel the molecular basis for this signature. By variable gene segment exchange, directed mutagenesis, and cellular T cell activation studies, we found that TRBV7-3 can substitute for TRBV7-2, as both can contain the canonical CDR3beta loop. Furthermore, we identified a pivotal germline-encoded MHC recognition motif centered on framework residue Y40 in TRAV26-1 engaging both DQB1*02 and the canonical CDR3beta. This allowed prediction of expanded DQ2.5 glia-alpha2-reactive TCR repertoires, which were confirmed by single-cell sorting and TCR sequencing from CD patient samples. Our data refine our understanding of how HLA-dependent biased TCR repertoires are selected in the periphery due to germline-encoded residues. PMID- 28878120 TI - Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of beta-adrenergic receptor signaling. AB - The oncoprotein Mdm2 is a RING domain-containing E3 ubiquitin ligase that ubiquitinates G protein-coupled receptor kinase 2 (GRK2) and beta-arrestin2, thereby regulating beta-adrenergic receptor (betaAR) signaling and endocytosis. Previous studies showed that cardiac Mdm2 expression is critical for controlling p53-dependent apoptosis during early embryonic development, but the role of Mdm2 in the developed adult heart is unknown. We aimed to identify if Mdm2 affects betaAR signaling and cardiac function in adult mice. Using Mdm2/p53-KO mice, which survive for 9-12 months, we identified a critical and potentially novel role for Mdm2 in the adult mouse heart through its regulation of cardiac beta1AR signaling. While baseline cardiac function was mostly similar in both Mdm2/p53-KO and wild-type (WT) mice, isoproterenol-induced cardiac contractility in Mdm2/p53 KO was significantly blunted compared with WT mice. Isoproterenol increased cAMP in left ventricles of WT but not of Mdm2/p53-KO mice. Additionally, while basal and forskolin-induced calcium handling in isolated Mdm2/p53-KO and WT cardiomyocytes were equivalent, isoproterenol-induced calcium handling in Mdm2/p53-KO was impaired. Mdm2/p53-KO hearts expressed 2-fold more GRK2 than WT. GRK2 polyubiquitination via lysine-48 linkages was significantly reduced in Mdm2/p53-KO hearts. Tamoxifen-inducible cardiomyocyte-specific deletion of Mdm2 in adult mice also led to a significant increase in GRK2, and resulted in severely impaired cardiac function, high mortality, and no detectable betaAR responsiveness. Gene delivery of either Mdm2 or GRK2-CT in vivo using adeno associated virus 9 (AAV9) effectively rescued beta1AR-induced cardiac contractility in Mdm2/p53-KO. These findings reveal a critical p53-independent physiological role of Mdm2 in adult hearts, namely, regulation of GRK2-mediated desensitization of betaAR signaling. PMID- 28878122 TI - Wnt11 regulates cardiac chamber development and disease during perinatal maturation. AB - Ventricular chamber growth and development during perinatal circulatory transition is critical for functional adaptation of the heart. However, the chamber-specific programs of neonatal heart growth are poorly understood. We used integrated systems genomic and functional biology analyses of the perinatal chamber specific transcriptome and we identified Wnt11 as a prominent regulator of chamber-specific proliferation. Importantly, downregulation of Wnt11 expression was associated with cyanotic congenital heart defect (CHD) phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Perinatal hypoxia treatment in mice suppressed Wnt11 expression and induced myocyte proliferation more robustly in the right ventricle, modulating Rb1 protein activity. Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse hearts and reduced Rb1 protein and phosphorylation in neonatal cardiomyocytes. Finally, downregulated Wnt11 in hypoxemic TOF infantile hearts was associated with Rb1 suppression and induction of proliferation markers. This study revealed a previously uncharacterized function of Wnt11-mediated signaling as an important player in programming the chamber-specific growth of the neonatal heart. This function influences the chamber-specific development and pathogenesis in response to hypoxia and cyanotic CHDs. Defining the underlying regulatory mechanism may yield chamber-specific therapies for infants born with CHDs. PMID- 28878123 TI - The R213G polymorphism in SOD3 protects against allergic airway inflammation. AB - Oxidative stress is important in the pathogenesis of allergic asthma. Extracellular superoxide dismutase (EC-SOD; SOD3) is the major antioxidant in lungs, but its role in allergic asthma is unknown. Here we report that asthmatics have increased SOD3 transcript levels in sputum and that a single nucleotide polymorphism (SNP) in SOD3 (R213G; rs1799895) changes lung distribution of EC SOD, and decreases likelihood of asthma-related symptoms. Knockin mice analogous to the human R213G SNP had lower airway hyperresponsiveness, inflammation, and mucus hypersecretion with decreased interleukin-33 (IL-33) in bronchoalveolar lavage fluid and reduced type II innate lymphoid cells (ILC2s) in lungs. SOD mimetic (Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin) attenuated Alternaria-induced expression of IL-33 and IL-8 release in BEAS-2B cells. These results suggest that R213G SNP potentially benefits its carriers by resulting in high EC-SOD in airway-lining fluid, which ameliorates allergic airway inflammation by dampening the innate immune response, including IL-33/ST2 mediated changes in ILC2s. PMID- 28878124 TI - Reversal of pathological cardiac hypertrophy via the MEF2-coregulator interface. AB - Cardiac hypertrophy, as a response to hemodynamic stress, is associated with cardiac dysfunction and death, but whether hypertrophy itself represents a pathological process remains unclear. Hypertrophy is driven by changes in myocardial gene expression that require the MEF2 family of DNA-binding transcription factors, as well as the nuclear lysine acetyltransferase p300. Here we used genetic and small-molecule probes to determine the effects of preventing MEF2 acetylation on cardiac adaptation to stress. Both nonacetylatable MEF2 mutants and 8MI, a molecule designed to interfere with MEF2-coregulator binding, prevented hypertrophy in cultured cardiac myocytes. 8MI prevented cardiac hypertrophy in 3 distinct stress models, and reversed established hypertrophy in vivo, associated with normalization of myocardial structure and function. The effects of 8MI were reversible, and did not prevent training effects of swimming. Mechanistically, 8MI blocked stress-induced MEF2 acetylation, nuclear export of class II histone deacetylases HDAC4 and -5, and p300 induction, without impeding HDAC4 phosphorylation. Correspondingly, 8MI transformed the transcriptional response to pressure overload, normalizing almost all 232 genes dysregulated by hemodynamic stress. We conclude that MEF2 acetylation is required for development and maintenance of pathological cardiac hypertrophy, and that blocking MEF2 acetylation can permit recovery from hypertrophy without impairing physiologic adaptation. PMID- 28878125 TI - Human hepatic organoids for the analysis of human genetic diseases. AB - We developed an in vitro model system where induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional human hepatic organoids (HOs) through stages that resemble human liver during its embryonic development. The HOs consist of hepatocytes, and cholangiocytes, which are organized into epithelia that surround the lumina of bile duct-like structures. The organoids provide a potentially new model for liver regenerative processes, and were used to characterize the effect of different JAG1 mutations that cause: (a) Alagille syndrome (ALGS), a genetic disorder where NOTCH signaling pathway mutations impair bile duct formation, which has substantial variability in its associated clinical features; and (b) Tetralogy of Fallot (TOF), which is the most common form of a complex congenital heart disease, and is associated with several different heritable disorders. Our results demonstrate how an iPSC-based organoid system can be used with genome editing technologies to characterize the pathogenetic effect of human genetic disease-causing mutations. PMID- 28878126 TI - Endothelium-derived extracellular vesicles promote splenic monocyte mobilization in myocardial infarction. AB - Transcriptionally activated monocytes are recruited to the heart after acute myocardial infarction (AMI). After AMI in mice and humans, the number of extracellular vesicles (EVs) increased acutely. In humans, EV number correlated closely with the extent of myocardial injury. We hypothesized that EVs mediate splenic monocyte mobilization and program transcription following AMI. Some plasma EVs bear endothelial cell (EC) integrins, and both proinflammatory stimulation of ECs and AMI significantly increased VCAM-1-positive EV release. Injected EC-EVs localized to the spleen and interacted with, and mobilized, splenic monocytes in otherwise naive, healthy animals. Analysis of human plasma EV-associated miRNA showed 12 markedly enriched miRNAs after AMI; functional enrichment analyses identified 1,869 putative mRNA targets, which regulate relevant cellular functions (e.g., proliferation and cell movement). Furthermore, gene ontology termed positive chemotaxis as the most enriched pathway for the miRNA-mRNA targets. Among the identified EV miRNAs, EC-associated miRNA-126-3p and -5p were highly regulated after AMI. miRNA-126-3p and -5p regulate cell adhesion- and chemotaxis-associated genes, including the negative regulator of cell motility, plexin-B2. EC-EV exposure significantly downregulated plexin-B2 mRNA in monocytes and upregulated motility integrin ITGB2. These findings identify EVs as a possible novel signaling pathway by linking ischemic myocardium with monocyte mobilization and transcriptional activation following AMI. PMID- 28878127 TI - Autoantibody-producing plasmablasts after B cell depletion identified in muscle specific kinase myasthenia gravis. AB - Myasthenia gravis (MG) is a B cell-mediated autoimmune disorder of neuromuscular transmission. Pathogenic autoantibodies to muscle-specific tyrosine kinase (MuSK) can be found in patients with MG who do not have detectable antibodies to the acetylcholine receptor (AChR). MuSK MG includes immunological and clinical features that are generally distinct from AChR MG, particularly regarding responsiveness to therapy. B cell depletion has been shown to affect a decline in serum autoantibodies and to induce sustained clinical improvement in the majority of MuSK MG patients. However, the duration of this benefit may be limited, as we observed disease relapse in MuSK MG patients who had achieved rituximab-induced remission. We investigated the mechanisms of such relapses by exploring autoantibody production in the reemerging B cell compartment. Autoantibody expressing CD27+ B cells were observed within the reconstituted repertoire during relapse but not during remission or in controls. Using two complementary approaches, which included production of 108 unique human monoclonal recombinant immunoglobulins, we demonstrated that antibody-secreting CD27hiCD38hi B cells (plasmablasts) contribute to the production of MuSK autoantibodies during relapse. The autoantibodies displayed hallmarks of antigen-driven affinity maturation. These collective findings introduce potential mechanisms for understanding both MuSK autoantibody production and disease relapse following B cell depletion. PMID- 28878128 TI - Respiratory syncytial virus infection of newborn CX3CR1-deficent mice induces a pathogenic pulmonary innate immune response. AB - Respiratory syncytial virus (RSV) infects almost all infants by 2 years of age, and severe bronchiolitis resulting from RSV infection is the primary cause of hospitalization in the first year of life. Among infants hospitalized due to RSV induced bronchiolitis, those with a specific mutation in the chemokine receptor CX3CR1, which severely compromises binding of its ligand CX3CL1, were at a higher risk for more severe viral bronchiolitis than those without the mutation. Here, we show that RSV infection of newborn mice deficient in CX3CR1 leads to significantly greater neutrophilic inflammation in the lungs, accompanied by an increase in mucus production compared with that induced in WT mice. Analysis of innate and adaptive immune responses revealed an early increase in the number of IL-17+ gammadelta T cells in CX3CR1-deficient mice that outnumbered IFN-gamma+ gammadelta T cells as well as IFN-gamma+ NK cells, IFN-gamma being host protective in the context of RSV infection. This bias toward IL-17+ gammadelta T cells persisted at a later time. The lungs of CX3CR1-deficient mice expressed higher levels of IL-1beta mRNA and protein, and blockade of IL-1beta signaling using IL-1 receptor antagonist significantly reduced the number of IL-17+ gammadelta T cells in the lungs of infected mice. Blockade of IL-17RC abolished RSV-induced lung pathology in infected CX3CR1-deficient mice. We propose that, in infants harboring mutant CX3CR1, targeting the IL-17R may minimize disease severity and hospitalization in early life. PMID- 28878129 TI - Correction of intermittent hypoxia reduces inflammation in obese subjects with obstructive sleep apnea. AB - BACKGROUND: In obese subjects with obstructive sleep apnea (OSA), chronic intermittent hypoxia (CIH) may be linked to systemic and adipose tissue inflammation. METHODS: We obtained abdominal subcutaneous adipose tissue biopsies from OSA and non-OSA obese (BMI > 35) subjects at baseline and after 24 weeks (T1) of weight-loss intervention plus continuous positive airway pressure (c-PAP) or weight-loss intervention alone, respectively. OSA subjects were grouped according to good (therapeutic) or poor (subtherapeutic) adherence to c-PAP. RESULTS: At baseline, anthropometric and metabolic parameters, serum cytokines, and adipose tissue mRNA levels of obesity-associated chemokines and inflammatory markers were not different in OSA and non-OSA subjects. At T1, body weight was significantly reduced in all groups. Serum concentrations of IL-2, IL-4, IL-6, MCP-1, PDGFbeta, and VEGFalpha were reduced by therapeutic c-PAP in OSA subjects and remained unaltered in non-OSA and subtherapeutic c-PAP groups. Similarly, adipose tissue mRNA levels of macrophage-specific (CD68, CD36) and ER stress (ATF4, CHOP, ERO-1) gene markers, as well as of IL-6, PDGFbeta, and VEGFalpha, were decreased only in the therapeutic c-PAP group. CONCLUSION: CIH does not represent an additional factor increasing systemic and adipose tissue inflammation in morbid obesity. However, in subjects with OSA, an effective c-PAP therapy improves systemic and obesity-associated inflammatory markers. FUNDING: Ministero dell'Universita e della Ricerca and Progetti di Rilevante Interesse Nazionale. PMID- 28878130 TI - An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes. AB - Human endogenous retroviruses (HERVs), remnants of ancestral viral genomic insertions, are known to represent 8% of the human genome and are associated with several pathologies. In particular, the envelope protein of HERV-W family (HERV-W Env) has been involved in multiple sclerosis pathogenesis. Investigations to detect HERV-W-Env in a few other autoimmune diseases were negative, except in type-1 diabetes (T1D). In patients suffering from T1D, HERV-W-Env protein was detected in 70% of sera, and its corresponding RNA was detected in 57% of peripheral blood mononuclear cells. While studies on human Langerhans islets evidenced the inhibition of insulin secretion by HERV-W-Env, this endogenous protein was found to be expressed by acinar cells in 75% of human T1D pancreata. An extensive immunohistological analysis further revealed a significant correlation between HERV-W-Env expression and macrophage infiltrates in the exocrine part of human pancreata. Such findings were corroborated by in vivo studies on transgenic mice expressing HERV-W-env gene, which displayed hyperglycemia and decreased levels of insulin, along with immune cell infiltrates in their pancreas. Altogether, these results strongly suggest an involvement of HERV-W-Env in T1D pathogenesis. They also provide potentially novel therapeutic perspectives, since unveiling a pathogenic target in T1D. PMID- 28878131 TI - Physiological adaptations to resistance exercise as a function of age. AB - BACKGROUND: The impact of resistance exercise training (RE-T) across the life span is poorly defined. METHODS: To resolve this, we recruited three distinct age cohorts of young (18-28 years; n = 11), middle-aged (45-55 years; n = 20), and older (nonsarcopenic; 65-75 years; n = 17) individuals to a cross-sectional intervention study. All subjects participated in 20 weeks of fully supervised whole-body progressive RE-T, undergoing assessment of body composition, muscle and vascular function, and metabolic health biomarkers before and after RE-T. Individuals also received stable isotope tracer infusions to ascertain muscle protein synthesis (MPS). RESULTS: There was an age-related increase in adiposity, but only young and middle-age groups demonstrated reductions following RE-T. Increases in blood pressure with age were attenuated by RE-T in middle-aged, but not older, individuals, while age-related increases in leg vascular conductance were unaffected by RE-T. The index of insulin sensitivity was reduced by RE-T in older age. Despite being matched at baseline, only younger individuals increased muscle mass in response to RE-T, and there existed a negative correlation between age and muscle growth; in contrast, increases in mechanical quality were preserved across ages. Acute increases in MPS (upon feeding plus acute RE-T) were enhanced only in younger individuals, perhaps explaining greater hypertrophy. CONCLUSION: Our data indicate that RE-T offsets some, but not all, negative characteristics of ageing - some of which are apparent in midlife. FUNDING: Biotechnology and Biological Sciences Research Council (BB/C516779/1). PMID- 28878133 TI - Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases. AB - Bone metastases (BoM) are a significant cause of morbidity in patients with estrogen receptor-positive (ER-positive) breast cancer; yet, characterizations of human specimens are limited. In this study, exome-capture RNA sequencing (ecRNA seq) on aged (8-12 years), formalin-fixed, paraffin-embedded (FFPE), and decalcified cancer specimens was evaluated. Gene expression values and ecRNA-seq quality metrics from FFPE or decalcified tumor RNA showed minimal differences when compared with matched flash-frozen or nondecalcified tumors. ecRNA-seq was then applied on a longitudinal collection of 11 primary breast cancers and patient-matched synchronous or recurrent BoMs. Overtime, BoMs exhibited gene expression shifts to more Her2 and LumB PAM50 subtype profiles, temporally influenced expression evolution, recurrently dysregulated prognostic gene sets, and longitudinal expression alterations of clinically actionable genes, particularly in the CDK/Rb/E2F and FGFR signaling pathways. Taken together, this study demonstrates the use of ecRNA-seq on decade-old and decalcified specimens and defines recurrent longitudinal transcriptional remodeling events in estrogen deprived breast cancers. PMID- 28878132 TI - Therapeutic opportunities for alcoholic steatohepatitis and nonalcoholic steatohepatitis: exploiting similarities and differences in pathogenesis. AB - Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are among the most frequent causes of chronic liver disease in the United States. Although the two entities are triggered by different etiologies - chronic alcohol consumption (ASH) and obesity-associated lipotoxicity (NASH) - they share overlapping histological and clinical features owing to common pathogenic mechanisms. These pathogenic processes include altered hepatocyte lipid metabolism, organelle dysfunction (i.e., ER stress), hepatocyte apoptosis, innate immune system activation, and hepatic stellate cell activation. Nonetheless, there are several disease-specific molecular signaling pathways, such as differential pathway activation downstream of TLR4 (MyD88-dependence in NASH versus MyD88-independence in ASH), inflammasome activation and IL-1beta signaling in ASH, insulin resistance and lipotoxicity in NASH, and dysregulation of different microRNAs, which clearly highlight that ASH and NASH are two distinct biological entities. Both pathogenic similarities and differences have therapeutic implications. In this Review, we discuss these pathogenic mechanisms and their therapeutic implications for each disease, focusing on both shared and distinct targets. PMID- 28878135 TI - REV-ERBalpha ameliorates heart failure through transcription repression. AB - A cure for heart failure remains a major unmet clinical need, and current therapies targeting neurohomonal and hemodynamic regulation have limited efficacy. The pathological remodeling of the myocardium has been associated with a stereotypical gene expression program, which had long been viewed as the consequence and not the driver of the disease until very recently. Despite the advance, there is no therapy available to reverse the already committed gene program. Here, we demonstrate that transcriptional repressor REV-ERB binds near driver transcription factors across the genome. Pharmacological activation of REV ERB selectively suppresses aberrant pathologic gene expression and prevents cardiomyocyte hypertrophy. In vivo, REV-ERBalpha activation prevents development of cardiac hypertrophy, reduces fibrosis, and halts progression of advanced heart failure in mouse models. Thus, to our knowledge, modulation of gene networks by targeting REV-ERBalpha represents a novel approach to heart failure therapy. PMID- 28878134 TI - Prevention of breast cancer skeletal metastases with parathyroid hormone. AB - Advanced breast cancer is frequently associated with skeletal metastases and accelerated bone loss. Recombinant parathyroid hormone [teriparatide, PTH(1-34)] is the first anabolic agent approved in the US for treatment of osteoporosis. While signaling through the PTH receptor in the osteoblast lineage regulates bone marrow hematopoietic niches, the effects of anabolic PTH on the skeletal metastatic niche are unknown. Here, we demonstrate, using orthotopic and intratibial models of 4T1 murine and MDA-MB-231 human breast cancer tumors, that anabolic PTH decreases both tumor engraftment and the incidence of spontaneous skeletal metastasis in mice. Microcomputed tomography and histomorphometric analyses revealed that PTH increases bone volume and reduces tumor engraftment and volume. Transwell migration assays with murine and human breast cancer cells revealed that PTH alters the gene expression profile of the metastatic niche, in particular VCAM-1, to inhibit recruitment of cancer cells. While PTH did not affect growth or migration of the primary tumor, it elicited several changes in the tumor gene expression profile resulting in a less metastatic phenotype. In conclusion, PTH treatment in mice alters the bone microenvironment, resulting in decreased cancer cell engraftment, reduced incidence of metastases, preservation of bone microarchitecture and prolonged survival. PMID- 28878136 TI - Old age causes de novo intracortical bone remodeling and porosity in mice. AB - Decreased cortical thickness and increased cortical porosity are the key anatomic changes responsible for osteoporotic fractures in elderly women and men. The cellular basis of these changes is unbalanced endosteal and intracortical osteonal remodeling by the osteoclasts and osteoblasts that comprise the basic multicellular units (BMUs). Like humans, mice lose cortical bone with age, but unlike humans, this loss occurs in the face of sex steroid sufficiency. Mice are therefore an ideal model to dissect age-specific osteoporotic mechanisms. Nevertheless, lack of evidence for endosteal or intracortical remodeling in mice has raised questions about their translational relevance. We show herein that administration of the antiosteoclastogenic cytokine osteoprotegerin to Swiss Webster mice ablated not only osteoclasts, but also endosteal bone formation, demonstrating the occurrence of BMU-based endosteal remodeling. Femoral cortical thickness decreased in aged male and female C57BL/6J mice, as well as F1 hybrids of C57BL/6J and BALB/cBy mice. This decrease was greater in C57BL/6J mice, indicating a genetic influence. Moreover, endosteal remodeling became unbalanced because of increased osteoclast and decreased osteoblast numbers. The porosity of the femoral cortex increased with age but was much higher in females of both strains. Notably, the increased cortical porosity resulted from de novo intracortical remodeling by osteon-like structures. Age-dependent cortical bone loss was associated with increased osteocyte DNA damage, cellular senescence, the senescence-associated secretory phenotype, and increased levels of RANKL. The demonstration of unbalanced endosteal and intracortical remodeling in old mice validates the relevance of this animal model to involutional osteoporosis in humans. PMID- 28878137 TI - CF airway smooth muscle transcriptome reveals a role for PYK2. AB - Abnormal airway smooth muscle function can contribute to cystic fibrosis (CF) airway disease. We previously found that airway smooth muscle from newborn CF pigs had increased basal tone, an increased bronchodilator response, and abnormal calcium handling. Since CF pigs lack airway infection and inflammation at birth, these findings suggest intrinsic airway smooth muscle dysfunction in CF. In this study, we tested the hypothesis that CFTR loss in airway smooth muscle would produce a distinct set of changes in the airway smooth muscle transcriptome that we could use to develop novel therapeutic targets. Total RNA sequencing of newborn wild-type and CF airway smooth muscle revealed changes in muscle contraction-related genes, ontologies, and pathways. Using connectivity mapping, we identified several small molecules that elicit transcriptional signatures opposite of CF airway smooth muscle, including NVP-TAE684, an inhibitor of proline-rich tyrosine kinase 2 (PYK2). In CF airway smooth muscle tissue, PYK2 phosphorylation was increased and PYK2 inhibition decreased smooth muscle contraction. In vivo NVP-TAE684 treatment of wild-type mice reduced methacholine induced airway smooth muscle contraction. These findings suggest that studies in the newborn CF pig may provide an important approach to enhance our understanding of airway smooth muscle biology and for discovery of novel airway smooth muscle therapeutics for CF and other diseases of airway hyperreactivity. PMID- 28878138 TI - Stereotyped antibody responses target posttranslationally modified gluten in celiac disease. AB - The role of B cells and posttranslational modifications in pathogenesis of organ specific immune diseases is increasingly envisioned but remains poorly understood, particularly in human disorders. In celiac disease, transglutaminase 2-modified (TG2-modified; deamidated) gluten peptides drive disease-specific T cell and B cell responses, and antibodies to deamidated gluten peptides are excellent diagnostic markers. Here, we substantiate by high-throughput sequencing of IGHV genes that antibodies to a disease-specific, deamidated, and immunodominant B cell epitope of gluten (PLQPEQPFP) have biased and stereotyped usage of IGHV3-23 and IGHV3-15 gene segments with modest somatic mutations. X-ray crystal structures of 2 prototype IGHV3-15/IGKV4-1 and IGHV3-23/IGLV4-69 antibodies reveal peptide interaction mainly via germline-encoded residues. In depth mutational analysis showed restricted selection and substitution patterns at positions involved in antigen binding. While the IGHV3-15/IGKV4-1 antibody interacts with Glu5 and Gln6, the IGHV3-23/IGLV4-69 antibody interacts with Gln3, Pro4, Pro7, and Phe8 - residues involved in substrate recognition by TG2. Hence, both antibodies, despite different interaction with the epitope, recognize signatures of TG2 processing that facilitates B cell presentation of deamidated gluten peptides to T cells, thereby providing a molecular framework for the generation of these clinically important antibodies. The study provides essential insight into the pathogenic mechanism of celiac disease. PMID- 28878141 TI - Intestinal and Circulating MicroRNAs in Coeliac Disease. AB - MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression at the post-transcriptional level and play a key role in the pathogenesis of autoimmune and gastrointestinal diseases. Previous studies have revealed that miRNAs are dysregulated in intestinal biopsies of patients affected by coeliac disease (CD). Combined bioinformatics analyses of miRNA expression profiles and mRNA target genes as classified by Gene Ontology, are powerful tools to investigate the functional role of miRNAs in coeliac disease. However, little is still known about the function of circulating miRNAs, their expression level compared to tissue miRNAs, and whether the mechanisms of post-transcriptional regulation are the same of tissue miRNAs. In any case, if we assume that a cell-cell communication process has to occur, and that circulating miRNAs are delivered to recipient cells, we can derive useful information by performing target predictions. Interestingly, all of the mRNA targets of dysregulated miRNAs reported in the literature (i.e., miR-31-5p, miR-192, miR-194, miR-449a and miR 638) belong to several important biological processes, such as Wnt signaling, cell proliferation and differentiation, and adherens junction pathways. Although we think that these predictions have to be necessarily confirmed by "wet-lab" data, the miRNAs dysregulated during the development of CD could be potentially involved in the pathogenesis of coeliac disease and their correlation with circulating miRNAs offers new possibilities to use them as disease biomarkers. PMID- 28878140 TI - The Supramolecular Buildup of Eumelanin: Structures, Mechanisms, Controllability. AB - Research on the supramolecular buildup of eumelanin has gained high momentum in the last years. Several new aspects regarding the involved structures and mechanisms have been established, which has led to a better understanding of the entire process. This review intends to provide a clearly laid-out summary of previous and new findings regarding structures, mechanisms, and controllability. With respect to materials applications, the aspect of controllability is of supreme importance. A focus of this review is therefore set on a novel method with high potential for specific synthesis of various, isolated particle morphologies. Finally, open questions and possibilities for their elucidation are discussed. PMID- 28878139 TI - Overview of β-Glucans from Laminaria spp.: Immunomodulation Properties and Applications on Biologic Models. AB - Glucans are a group of glucose polymers that are found in bacteria, algae, fungi, and plants. While their properties are well known, their biochemical and solubility characteristics vary considerably, and glucans obtained from different sources can have different applications. Research has described the bioactivity of β-glucans extracted from the algae of the Laminaria genus, including in vivo and in vitro studies assessing pro- and anti-inflammatory cytokines, vaccine production, inhibition of cell proliferation, and anti- and pro-oxidant activity. Thus, the objective of this article was to review the potential application of β-glucans from Laminaria spp. in terms of their immunomodulatory properties, microorganism host interaction, anti-cancer activity and vaccine development. PMID- 28878142 TI - Dietary Phenethyl Isothiocyanate Protects Mice from Colitis Associated Colon Cancer. AB - We have previously reported alleviation of dextran sodium sulfate (DSS)-induced ulcerative colitis signs in phenethyl isothiocyanate (PEITC)-treated mice. Here we investigated chemoprotective activities of PEITC in mice with Azoxymethane-DSS induced colitis associated colon carcinogenesis. We also examined the molecular mediators associated with the PEITC effects using relevant cell lines. A 0.12% PEITC-enriched mouse-diet reduced mucosal and submucosal inflammation as well as glandular atypia by 12% and the frequency of adenocarcinoma by 17% with a concomitant improvement in overall disease activity indices compared to the diseased control group. Lipopolysaccharide-induced in vitro up-regulation of key mediators of inflammation, immune response, apoptosis, and cell proliferation were attenuated by 10 μM PEITC. Three of these mediators showed concentration-dependent reduction in respective mRNAs. Furthermore, PEITC inhibited Nuclear factor kappa B1 (NFκB1) proteins in a concentration dependent manner. The NFκB1 mRNA expression inversely correlated ( r = −0.940, p = 0.013) with tri-methylation of lysine 27 on histone 3 near its promoter region in a time-dependent manner. These results indicate that PEITC may slow down the development of colon carcinogenesis in an inflammatory intestinal setting which is potentially associated with epigenetic modulation of NFκB1 signaling. PMID- 28878143 TI - Cobra Venom Factor and Ketoprofen Abolish the Antitumor Effect of Nerve Growth Factor from Cobra Venom. AB - We showed recently that nerve growth factor (NGF) from cobra venom inhibited the growth of Ehrlich ascites carcinoma (EAC) inoculated subcutaneously in mice. Here, we studied the influence of anti-complementary cobra venom factor (CVF) and the non-steroidal anti-inflammatory drug ketoprofen on the antitumor NGF effect, as well as on NGF-induced changes in EAC histological patterns, the activity of lactate and succinate dehydrogenases in tumor cells and the serum level of some cytokines. NGF, CVF and ketoprofen reduced the tumor volume by approximately 72%, 68% and 30%, respectively. The antitumor effect of NGF was accompanied by an increase in the lymphocytic infiltration of the tumor tissue, the level of interleukin 1β and tumor necrosis factor α in the serum, as well as the activity of lactate and succinate dehydrogenases in tumor cells. Simultaneous administration of NGF with either CVF or ketoprofen abolished the antitumor effect and reduced all other effects of NGF, whereas NGF itself significantly decreased the antitumor action of both CVF and ketoprofen. Thus, the antitumor effect of NGF critically depended on the status of the immune system and was abolished by the disturbance of the complement system; the disturbance of the inflammatory response canceled the antitumor effect as well. PMID- 28878144 TI - Event-Based Sensing and Control for Remote Robot Guidance: An Experimental Case. AB - This paper describes the theoretical and practical foundations for remote control of a mobile robot for nonlinear trajectory tracking using an external localisation sensor. It constitutes a classical networked control system, whereby event-based techniques for both control and state estimation contribute to efficient use of communications and reduce sensor activity. Measurement requests are dictated by an event-based state estimator by setting an upper bound to the estimation error covariance matrix. The rest of the time, state prediction is carried out with the Unscented transformation. This prediction method makes it possible to select the appropriate instants at which to perform actuations on the robot so that guidance performance does not degrade below a certain threshold. Ultimately, we obtained a combined event-based control and estimation solution that drastically reduces communication accesses. The magnitude of this reduction is set according to the tracking error margin of a P3-DX robot following a nonlinear trajectory, remotely controlled with a mini PC and whose pose is detected by a camera sensor. PMID- 28878145 TI - Transdermal Permeation of Drugs in Various Animal Species. AB - Excised human skin is utilized for in vitro permeation experiments to evaluate the safety and effect of topically-applied drugs by measuring its skin permeation and concentration. However, ethical considerations are the major problem for using human skin to evaluate percutaneous absorption. Moreover, large variations have been found among human skin specimens as a result of differences in age, race, and anatomical donor site. Animal skins are used to predict the in vivo human penetration/permeation of topically-applied chemicals. In the present review, skin characteristics, such as thickness of skin, lipid content, hair follicle density, and enzyme activity in each model are compared to human skin. In addition, intra- and inter-individual variation in animal models, permeation parameter correlation between animal models and human skin, and utilization of cultured human skin models are also descried. Pig, guinea pig, and hairless rat are generally selected for this purpose. Each animal model has advantages and weaknesses for utilization in in vitro skin permeation experiments. Understanding of skin permeation characteristics such as permeability coefficient ( P ), diffusivity ( D ), and partition coefficient ( K ) for each skin model would be necessary to obtain better correlations for animal models to human skin permeation. PMID- 28878146 TI - Computer versus Compensatory Calendar Training in Individuals with Mild Cognitive Impairment: Functional Impact in a Pilot Study. AB - This pilot study examined the functional impact of computerized versus compensatory calendar training in cognitive rehabilitation participants with mild cognitive impairment (MCI). Fifty-seven participants with amnestic MCI completed randomly assigned calendar or computer training. A standard care control group was used for comparison. Measures of adherence, memory-based activities of daily living (mADLs), and self-efficacy were completed. The calendar training group demonstrated significant improvement in mADLs compared to controls, while the computer training group did not. Calendar training may be more effective in improving mADLs than computerized intervention. However, this study highlights how behavioral trials with fewer than 30-50 participants per arm are likely underpowered, resulting in seemingly null findings. PMID- 28878147 TI - Extraction of Rice Heavy Metal Stress Signal Features Based on Long Time Series Leaf Area Index Data Using Ensemble Empirical Mode Decomposition. AB - The use of remote sensing technology to diagnose heavy metal stress in crops is of great significance for environmental protection and food security. However, in the natural farmland ecosystem, various stressors could have a similar influence on crop growth, therefore making heavy metal stress difficult to identify accurately, so this is still not a well resolved scientific problem and a hot topic in the field of agricultural remote sensing. This study proposes a method that uses Ensemble Empirical Mode Decomposition (EEMD) to obtain the heavy metal stress signal features on a long time scale. The method operates based on the Leaf Area Index (LAI) simulated by the Enhanced World Food Studies (WOFOST) model, assimilated with remotely sensed data. The following results were obtained: (i) the use of EEMD was effective in the extraction of heavy metal stress signals by eliminating the intra-annual and annual components; (ii) LAI df (The first derivative of the sum of the interannual component and residual) can preferably reflect the stable feature responses to rice heavy metal stress. LAI df showed stability with an R² of greater than 0.9 in three growing stages, and the stability is optimal in June. This study combines the spectral characteristics of the stress effect with the time characteristics, and confirms the potential of long-term remotely sensed data for improving the accuracy of crop heavy metal stress identification. PMID- 28878148 TI - A Geometric Analysis of the Regulation of Inorganic Nutrient Intake by the Subterranean Termite Reticulitermes flavipes Kollar. AB - Most studies on termite food selection have focused on a single nutrient per choice, however, termites, like all animals, must balance multiple nutrients in their diet. While most studies that use multi-nutrient approaches focus on macromolecules, the ability to balance the intake of inorganic nutrients is also vital to organisms. In this study, we used the geometric framework to test the effects of multiple inorganic nutrients on termite feeding. We presented the subsets of Reticulitermes flavipes colonies with food enriched with varying in levels of KCl, MgSO₄, and FePO₄. Each trial varied two of the three nutrients while the third nutrient was kept constant. The amount of food consumed was measured over two weeks. The termites' feeding patterns during the study suggested that they fed until they reached a limit for MgSO₄. This result suggests that the termites were using the rule of compromise such that the termites would over consume KCl or FePO₄ in order to avoid overeating MgSO₄. Thus, the termite colonies are able to regulate the intake of inorganic nutrients, and by doing so, adjust their intake from multiple resources in order to maintain an intake target. PMID- 28878149 TI - Biomass Waste Inspired Highly Porous Carbon for High Performance Lithium/Sulfur Batteries. AB - The synthesis of highly porous carbon (HPC) materials from poplar catkin by KOH chemical activation and hydrothermal carbonization as a conductive additive to a lithium-sulfur cathode is reported. Elemental sulfur was composited with as prepared HPC through a melt diffusion method to form a S/HPC nanocomposite. Structure and morphology characterization revealed a hierarchically sponge-like structure of HPC with high pore volume (0.62 cm³?g −1 ) and large specific surface area (1261.7 m²?g −1 ). When tested in Li/S batteries, the resulting compound demonstrated excellent cycling stability, delivering a second-specific capacity of 1154 mAh?g −1 as well as presenting 74% retention of value after 100 cycles at 0.1 C. Therefore, the porous structure of HPC plays an important role in enhancing electrochemical properties, which provides conditions for effective charge transfer and effective trapping of soluble polysulfide intermediates, and remarkably improves the electrochemical performance of S/HPC composite cathodes. PMID- 28878150 TI - Multimorbidity in Chronic Conditions: Public Primary Care Patients in Four Greater Mekong Countries. AB - The aim of this study was to explore the prevalence, pattern, and social determinants of chronic conditions multimorbidity among chronic disease primary care patients in four Greater Mekong countries (Cambodia, Myanmar, Thailand, and Vietnam). In a cross-sectional survey, chronic disease patients accessing primary care were recruited if they had been diagnosed with any of 21 chronic conditions in the past 12 months, and were interviewed with a structured questionnaire on anxiety, depression, alcohol use, tobacco use, dietary behaviour, physical activity, and quality of life. The sample included 6236 public primary care patients (32.8% men and 67.2% women), with a mean age of 53.0 years (SD = 16.8). From 21 chronic conditions, the three most common were hypertension (37.4%), depression (34.4%), and digestive diseases (32.0%). In all, 27.4% had one chronic condition, 28.6% had two, 22.4% had three, and 21.6% had four or more chronic conditions. The percentage with the highest comorbidity was depression (47.3%), hypertension (43.4%), and digestive diseases (34.1%). The highest mean multimorbidity reported was for mental illness (4.44), kidney disease (4.11), and Parkinson's disease (4.10), and the lowest multimorbidity for epilepsy (2.43) and cancer (2.80). Compared to those who had only one chronic condition, being male, older age, lower education, and lower quality of life were associated with having two and three or more chronic conditions. Multimorbidity is a prevalent problem among chronic condition primary care patients-a finding with implications for health care delivery, management, and research. PMID- 28878151 TI - Simultaneous Voltammetric Detection of Carbaryl and Paraquat Pesticides on Graphene-Modified Boron-Doped Diamond Electrode. AB - Monitoring of pesticide residues in food, beverages, and the environment requires fast, versatile, and sensitive analyzing methods. Direct electrochemical detection of pesticides could represent an efficient solution. Adequate electrode material, electrochemical technique, and optimal operation parameters define the detection method for practical application. In this study, cyclic voltammetric and differential pulse voltammetric techniques were used in order to individually and simultaneously detect two pesticides, i.e., carbaryl (CR) and paraquat (PQ), from an acetate buffer solution and also from natural apple juice. A graphene modified boron-doped diamond electrode, denoted BDDGR, was obtained and successfully applied in the simultaneous detection of CR and PQ pesticides, using the differential pulse voltammetric technique with remarkable electroanalytical parameters in terms of sensitivity: 33.27 μA μM −1 cm −2 for CR and 31.83 μA μM −1 cm −2 for PQ. These outstanding results obtained in the acetate buffer supporting electrolyte allowed us to simultaneously detect the targeted pesticides in natural apple juice. PMID- 28878152 TI - Comments to Article by Willetts A. et al., Microorganisms 2016, 4, 38. AB - We would like to comment on recent work published in your journal in October 2016 by Willetts A. et al. [1].[...]. PMID- 28878153 TI - High-Throughput Study of the Effects of Celastrol on Activated Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis. AB - Celastrol, a natural triterpene, exhibits potential anti-inflammatory activity in a variety of inflammatory diseases. The present study aimed to investigate its biological effect on activated fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA). The primary FLSs of the synovial tissues were obtained from synovial biopsies of patients with RA. The normal human FLS line (HFLS) was used as a control. After the RA-FLSs and HFLSs were treated with or without celastrol, various approaches, including the WST-1 assay, transwell assay, real-time PCR and ELISA analysis, were performed to estimate proliferation, invasion and expression of pro-inflammatory cytokines of the RA FLSs. Microarray analysis was performed to screen for differentially expressed genes in RA-FLSs before and after celastrol treatment. The results showed that treatment of celastrol attenuated both the proliferation and invasion of the RA FLSs. The expression of several chemokine genes, including CCL2 , CXCL10 , CXCL12 , CCR2 and CXCR4 , was significantly changed after celastrol treatment. The genes involved in the NF-κB signaling pathway appeared to be regulated by celastrol. PMID- 28878154 TI - Effects of Various Surfactants on the Dispersion of MWCNTs-OH in Aqueous Solution. AB - Dispersion of carbon nanotubes (CNTs) is a challenge for their application in the resulting matrixes. The present study conducted a comparison investigation of the effect of four surfactants: Alkylphenol polyoxyethylene ether (APEO), Silane modified polycarboxylate (Silane-PCE), I-Cationic polycarboxylate (I-C-PCE), and II-Cationic polycarboxylate (II-C-PCE) on the dispersion of hydroxyl functionalized multi-walled carbon nanotubes (MWCNTs-OH). Among the four surfactants, APEO and II-C-PCE provide the best and the worst dispersion effect of CNTs in water, respectively. Dispersion effect of MWCNTs-OH has been characterized by optical microscope (OM), field emission-scanning electron microscope (FE-SEM), and Ultraviolet-visible spectroscopy (UV-Vis).The OM images are well consistent with the UV-Vis results. Based on the chemical molecular structures of the four surfactants, the mechanism of MWCNTs-OH dispersion in water was investigated. For each kind of surfactant, an optimum surfactant/MWCNTs OH ratio has been determined. This ratio showed a significant influence on the dispersion of MWCNTs-OH. Surfactant concentration higher or lower than this value can weaken the dispersion quality of MWCNTs-OH. PMID- 28878156 TI - Honey Mitigates Radiation-Induced Oral Mucositis in Head and Neck Cancer Patients without Affecting the Tumor Response. AB - Radiation-induced mucositis is a dose-limiting factor in the effective treatment of head and neck (H & N) cancers. The objective of this study was to understand the efficacy of honey in mitigating radiation-induced mucositis and whether it would interfere with tumor control. This was a single-blinded, randomized, controlled study and was carried out in patients with H & N cancer requiring curative radiotherapy (>62 Gy (Gray)). The patients meeting the inclusion criteria were randomly assigned to receive either honey ( n = 25) or povidone iodine (active comparator) ( n = 25) during radiotherapy. Oral mucositis was assessed using the RTOG (Radiation Therapy Oncology Group) grading system before the start, during, and at the end of the treatment by an investigator unaware of the treatment. The results indicate that when compared with the active comparator, honey reduced the radiation-induced oral mucositis, decreased the incidence of intolerable mucositis, treatment breaks, loss of treatment days ( p < 0.0001 and < 0.0003) and did not affect the radiation-induced tumor response. The clinical observations indicate that honey mitigates the radiation-induced mucositis and does not interfere with tumor cell killing. PMID- 28878157 TI - Modeling the Effect of Optical Signal Multipath. AB - Here, we propose a model to determine the effect of multipath in indoor environments when the shape and characteristics of the environment are known. The main paper goal is to model the multipath signal formation to solve, as much as possible, the negative effects in light communications, as well as the indoor positioning errors due to this phenomenon when using optical signals. The methodology followed was: analyze the multipath phenomenon, establish a theoretical approach and propose different models to characterize the behavior of the channel, emitter and receiver. The channel impulse response and received signal strength are obtained from different proposed algorithms. We also propose steps for implementing a numerical procedure to calculate the effects of these multipaths using information that characterizes the environment, transmitter and receiver and their corresponding positions. In addition, the results of an empirical test in a controlled environment are compared with those obtained using the model, in order to validate the latter. The results may largely vary with respect to the cell size used to discretize the environment. We have concluded that a cell size whose side is 20-times smaller than the minimum distance between emitter and receiver (i.e., 10 cm × 10 cm for a 2-m distance) provides almost identical results between the empirical tests and the proposed model, with an affordable computational load. PMID- 28878155 TI - Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA Related Health Hazards Using Pathway Studio. AB - Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive biological cell model systems in determining BPA health risk are lacking. Here, we determined suitable cell model systems and potential biomarkers for predicting BPA-mediated disease using the bioinformatics tool Pathway Studio. We compiled known BPA-mediated diseases in humans, which were categorized into five major types. Subsequently, we investigated the differentially expressed proteins following BPA exposure in several cell types, and analyzed the efficacy of altered proteins to investigate their associations with BPA-mediated diseases. Our results demonstrated that colon cancer cells (SW480), mammary gland, and Sertoli cells were highly sensitive biological model systems, because of the efficacy of predicting the majority of BPA-mediated diseases. We selected glucose 6-phosphate dehydrogenase (G6PD), cytochrome b-c1 complex subunit 1 (UQCRC1), and voltage-dependent anion-selective channel protein 2 (VDAC2) as highly sensitive biomarkers to predict BPA-mediated diseases. Furthermore, we summarized proteomic studies in spermatozoa following BPA exposure, which have recently been considered as another suitable cell type for predicting BPA-mediated diseases. PMID- 28878158 TI - Optimizing Melamine Resin Microspheres with Excess Formaldehyde for the SERS Substrate. AB - Influence of the excess monomer within the synthetic reaction solution of melamine resin microspheres (MFMSs) on the surface-enhanced Raman spectroscopy (SERS) enhancement from Rhodamine 6G (R6G) was investigated, where the R6G was adsorbed on the silver nanoparticles (AgNPs) that were loaded on the MFMSs. Surface characteristics of the MFMSs were modified by the excess monomer (i.e., the excessive melamine or formaldehyde) through its terminal overreaction, which can be simply controlled by some of the synthetic reaction conditions, thus further allowing us to optimize the assembly of the loaded AgNPs for the SERS detection. These SERS substrates incorporating the optimized MFMSs with the excess formaldehyde can also be used for tracing analyses of more environmental and food contaminants. PMID- 28878159 TI - Connecting the Dots between Schizotypal Symptoms and Social Anxiety in Youth with an Extra X Chromosome: A Mediating Role for Catastrophizing. AB - Youth with an extra X chromosome (47, XXY & 47, XXX) display higher levels of schizotypal symptoms and social anxiety as compared to typically developing youth. It is likely that the extra X chromosome group is at-risk for clinical levels of schizotypy and social anxiety. Hence, this study investigated how schizotypal and social anxiety symptoms are related and mechanisms that may explain their association in a group of 38 children and adolescents with an extra X chromosome and a comparison group of 109 typically developing peers (8-19 years). Three cognitive coping strategies were investigated as potential mediators, rumination, catastrophizing, and other-blame. Moderated mediation analyses revealed that the relationship between schizotypal symptoms and social anxiety was mediated by catastrophizing coping in the extra X chromosome group but not in the comparison group. The results suggest that youth with an extra X chromosome with schizotypal symptoms could benefit from an intervention to weaken the tendency to catastrophize life events as a way of reducing the likelihood of social anxiety symptoms. PMID- 28878161 TI - Tapered Optical Fiber Functionalized with Palladium Nanoparticles by Drop Casting and Laser Radiation for H₂ and Volatile Organic Compounds Sensing Purposes. AB - A comparative study on the sensing properties of a tapered optical fiber pristine and functionalized with the palladium nanoparticles to hydrogen and volatile organic compounds (VOCs), is presented. The sensor response and, response/recovery times were extracted from the measurements of the transient response of the device. The tapered optical fiber sensor was fabricated using a single-mode optical fiber by the flame-brushing technique. Functionalization of the optical fiber was performed using an aqueous solution of palladium chloride by drop-casting technique assisted for laser radiation. The detection principle of the sensor is based on the changes in the optical properties of palladium nanoparticles when exposed to reducing gases, which causes a variation in the absorption of evanescent waves. A continuous wave laser diode operating at 1550 nm is used for the sensor characterization. The sensor functionalized with palladium nanoparticles by this technique is viable for the sensing of hydrogen and VOCs, since it shows an enhancement in sensor response and response time compared to the sensor based on the pristine optical microfiber. The results show that the fabricated sensor is competitive with other fiber optic sensors functionalized with palladium nanoparticles to the hydrogen. PMID- 28878162 TI - Tribological Properties of AlSi12-Al₂O₃ Interpenetrating Composite Layers in Comparison with Unreinforced Matrix Alloy. AB - Alumina-Aluminum composites with interpenetrating network structures are a new class of advanced materials with potentially better properties than composites reinforced by particles or fibers. Local casting reinforcement was proposed to take into account problems with the machinability of this type of materials and the shaping of the finished products. The centrifugal infiltration process fabricated composite castings in the form of locally reinforced shafts. The main objective of the research presented in this work was to compare the tribological properties (friction coefficient, wear resistance) of AlSi12/Al₂O₃ interpenetrating composite layers with unreinforced AlSi12 matrix areas. Profilometric tests enabled both quantitative and qualitative analyses of the wear trace that formed on investigated surfaces. It has been shown that interpenetrating composite layers are characterized by lower and more stable coefficients of friction (μ), as well as higher wear resistance than unreinforced matrix areas. At the present stage, the study confirmed that the tribological properties of the composite layers depend on the spatial structure of the ceramic reinforcement, and primarily the volume and size of alumina foam cells. PMID- 28878160 TI - Diuretic Activity of Compatible Triterpene Components of Alismatis rhizoma. AB - Alismatis rhizoma (AR), the dried rhizoma of Alisma orientale Juzepzuk (Alismataceae), is a traditional Chinese medicine. AR is an important part of many prescriptions and is commonly used as a diuretic agent in Asia. This study aimed to evaluate the diuretic effects of total triterpene extract (TTE) and triterpene component compatibility (TCC, the mixture of alisol B 23-acetate, alisol B, alisol A 24-acetate, alisol A, and alisol C 23-acetate) of AR in saline loaded rats. The optimal diuretic TCC of AR was optimized using a uniform design. Different doses (5, 20, and 40 mg/kg) of TTE and TCC groups (N1-N8) were orally administered to rats. Urinary excretion rate, pH, and electrolyte excretion were measured in the urine of saline-loaded rats. Results showed that TTE doses increased urine volume and electrolyte excretion compared with the control group. All uniformly designed groups of TCC also increased urine excretion. In addition, optimal diuretic TCC was calculated (alisol B 23-acetate: alisol B: alisol A 24 acetate: alisol A: alisol C 23-acetate 7.2:0.6:2.8:3.0:6.4) and further validated by saline-loaded rats. This study demonstrated that TTE presented a notable diuretic effect by increasing Na⁺, K⁺, and Cl − displacements. The most suitable TTC compatible proportion of alisol B 23-acetate: alisol B: alisol A 24-acetate: alisol A: alisol C 23-acetate for diuretic activity was validated, and triterpenes were the material basis for the diuretic activity of AR. PMID- 28878164 TI - Erratum: Xu, Y., et al. Computational Studies on Acetylcholinesterases. Molecules 2017, 22, 1324. PMID- 28878163 TI - RECQ1 Helicase Silencing Decreases the Tumour Growth Rate of U87 Glioblastoma Cell Xenografts in Zebrafish Embryos. AB - RECQ1 helicase has multiple roles in DNA replication, including restoration of the replication fork and DNA repair, and plays an important role in tumour progression. Its expression is highly elevated in glioblastoma as compared to healthy brain tissue. We studied the effects of small hairpin RNA (shRNA)-induced silencing of RECQ1 helicase on the increase in cell number and the invasion of U87 glioblastoma cells. RECQ1 silencing reduced the rate of increase in the number of U87 cells by 30%. This corresponded with a 40% reduction of the percentage of cells in the G2 phase of the cell cycle, and an accumulation of cells in the G1 phase. These effects were confirmed in vivo, in the brain of zebrafish ( Daniorerio ) embryos, by implanting DsRed-labelled RECQ1 helicase silenced and control U87 cells. The growth of resulting tumours was quantified by monitoring the increase in xenograft fluorescence intensity during a three-day period with fluorescence microscopy. The reduced rate of tumour growth, by approximately 30% in RECQ1 helicase-silenced cells, was in line with in vitro measurements of the increase in cell number upon RECQ1 helicase silencing. However, RECQ1 helicase silencing did not affect invasive behaviour of U87 cells in the zebrafish brain. This is the first in vivo confirmation that RECQ1 helicase is a promising molecular target in the treatment of glioblastoma. PMID- 28878165 TI - Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase. AB - The liver toxicity of valproic acid (VPA) is an established side effect of this widely used antiepileptic drug, which is extremely problematic for patients with metabolic epilepsy and particularly epilepsy due to mitochondrial dysfunction. In the present report, we investigated the reason for liver mitochondrial toxicity of VPA and several acid and amide VPA analogues. While the pyruvate and 2 oxoglutarate oxidation rates of rat brain mitochondria were nearly unaffected by VPA, rat liver mitochondrial pyruvate and 2-oxoglutarate oxidation was severely impaired by VPA concentrations above 100 uM. Among the reactions involved in pyruvate oxidation, pyruvate transport and dehydrogenation steps were not affected by VPA, while α-lipoamide dehydrogenase was strongly inhibited. Strong inhibition of α-lipoamide dehydrogenase was also noted for the VPA one-carbon homolog sec -butylpropylacetic acid (SPA) and to a lesser extent for the VPA constitutional isomer valnoctic acid (VCA), while the corresponding amides of the above three acids valpromide (VPD), sec -butylpropylacetamide (SPD) and valnoctamide (VCD) showed only small effects. We conclude that the active inhibitors of pyruvate and 2-oxoglutarate oxidation are the CoA conjugates of VPA and its acid analogues affecting selectively α-lipoamide dehydrogenase in liver. Amide analogues of VPA, like VCD, show low inhibitory effects on mitochondrial oxidative phosphorylation in the liver, which might be relevant for treatment of patients with mitochondrial epilepsy. PMID- 28878166 TI - Simultaneous Detection of Displacement, Rotation Angle, and Contact Pressure Using Sandpaper Molded Elastomer Based Triple Electrode Sensor. AB - In this article, we report on a flexible sensor based on a sandpaper molded elastomer that simultaneously detects planar displacement, rotation angle, and vertical contact pressure. When displacement, rotation, and contact pressure are applied, the contact area between the translating top elastomer electrode and the stationary three bottom electrodes change characteristically depending on the movement, making it possible to distinguish between them. The sandpaper molded undulating surface of the elastomer reduces friction at the contact allowing the sensor not to affect the movement during measurement. The sensor showed a 0.25 mm −1 displacement sensitivity with a ±33 μm accuracy, a 0.027 degree −1 of rotation sensitivity with ~0.95 degree accuracy, and a 4.96 kP −1 of pressure sensitivity. For possible application to joint movement detection, we demonstrated that our sensor effectively detected the up-and-down motion of a human forefinger and the bending and straightening motion of a human arm. PMID- 28878167 TI - Functionalizing a Tapered Microcavity as a Gas Cell for On-Chip Mid-Infrared Absorption Spectroscopy. AB - Increasing demand for field instruments designed to measure gas composition has strongly promoted the development of robust, miniaturized and low-cost handheld absorption spectrometers in the mid-infrared. Efforts thus far have focused on miniaturizing individual components. However, the optical absorption path that the light beam travels through the sample defines the length of the gas cell and has so far limited miniaturization. Here, we present a functionally integrated linear variable optical filter and gas cell, where the sample to be measured is fed through the resonator cavity of the filter. By using multiple reflections from the mirrors on each side of the cavity, the optical absorption path is elongated from the physical m m -level to the effective m m -level. The device is batch-fabricated at the wafer level in a CMOS-compatible approach. The optical performance is analyzed using the Fizeau interferometer model and demonstrated with actual gas measurements. PMID- 28878168 TI - Metabolomics Analysis of Urine Samples from Children after Acetaminophen Overdose. AB - Acetaminophen (APAP), a commonly used over-the-counter analgesic, accounts for approximately fifty percent of the cases of acute liver failure (ALF) in the United States due to overdose, with over half of those unintentional. Current clinical approaches for assessing APAP overdose rely on identifying the precise time of overdose and quantitating acetaminophen alanine aminotransferase (ALT) levels in peripheral blood. Novel specific and sensitive biomarkers may provide additional information regarding patient status post overdose. Previous non clinical metabolomics studies identified potential urinary biomarkers of APAP induced hepatotoxicity and metabolites involved pathways of tricarboxylic acid cycle, ketone metabolism, and tryptophan metabolism. In this study, biomarkers identified in the previous non-clinical study were evaluated in urine samples collected from healthy subjects ( N = 6, median age 14.08 years) and overdose patients ( N = 13, median age 13.91 years) as part of an IRB-approved multicenter study of APAP toxicity in children. The clinical results identified metabolites from pathways previously noted, and pathway analysis indicated analogous pathways were significantly altered in both the rats and humans after APAP overdose. The results suggest a metabolomics approach may enable the discovery of specific, translational biomarkers of drug-induced hepatotoxicity that may aid in the assessment of patients. PMID- 28878169 TI - Enhancement of Antioxidant Systems and Storability of Two Plum Cultivars by Preharvest Treatments with Salicylates. AB - In this research the effect of salicylic acid (SA), acetylsalicylic acid (ASA), and methylsalicylate (MeSA) treatments, applied as a foliar spray during on-tree plum development, on fruit quality attributes, bioactive compounds, antioxidant activity, and the activity of the antioxidant enzymes at harvest and after long term cold storage was evaluated in two plum cultivars ("Black Splendor", BS, and "Royal Rosa", RR). At harvest, plum quality parameters, such as weight, total phenolics (including anthocyanins, in BS), total carotenoids, and antioxidant activity, in both hydrophilic and lipophilic compounds were found at higher levels in plums from SA-, ASA-, and MeSA-treated trees than in those from control trees. During storage, fruit firmness, total acidity, and antioxidant compounds were at higher levels in treated, than in control, plums, which show an effect of salicylate treatments on delaying the plum postharvest ripening process. In addition, the activity of the antioxidant enzymes catalase (CAT), peroxidase (POX), superoxide dismutase (SOD), and ascorbate peroxidase (APX) were also enhanced at the time of harvest in salicylate-treated plums as compared with plums from control trees. The activity of these antioxidant enzymes was also found at higher levels in salicylate-treated plums during storage. Thus, preharvest treatment with salicylates could be a safe, eco-friendly, and new tool to improve and maintain plum quality attributes, and especially their content of antioxidant compounds, with an additional effect on delaying the postharvest ripening process through increasing the levels of antioxidant compounds and the activity of the antioxidant enzymes. PMID- 28878170 TI - Nanosilver-Silica Composite: Prolonged Antibacterial Effects and Bacterial Interaction Mechanisms for Wound Dressings. AB - Infected superficial wounds were traditionally controlled by topical antibiotics until the emergence of antibiotic-resistant bacteria. Silver (Ag) is a kernel for alternative antibacterial agents to fight this resistance quandary. The present study demonstrates a method for immobilizing small-sized (~5 nm) silver nanoparticles on silica matrix to form a nanosilver-silica (Ag-SiO₂) composite and shows the prolonged antibacterial effects of the composite in vitro. The composite exhibited a rapid initial Ag release after 24 h and a slower leaching after 48 and 72 h and was effective against both methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli ( E . coli ). Ultraviolet (UV) irradiation was superior to filter-sterilization in retaining the antibacterial effects of the composite, through the higher remaining Ag concentration. A gauze, impregnated with the Ag-SiO₂ composite, showed higher antibacterial effects against MRSA and E . coli than a commercial Ag-containing dressing, indicating a potential for the management and infection control of superficial wounds. Transmission and scanning transmission electron microscope analyses of the composite-treated MRSA revealed an interaction of the released silver ions with the bacterial cytoplasmic constituents, causing ultimately the loss of bacterial membranes. The present results indicate that the Ag-SiO₂ composite, with prolonged antibacterial effects, is a promising candidate for wound dressing applications. PMID- 28878171 TI - Lactobacillus sakei: A Starter for Sausage Fermentation, a Protective Culture for Meat Products. AB - Among lactic acid bacteria of meat products, Lactobacillus sakei is certainly the most studied species due to its role in the fermentation of sausage and its prevalence during cold storage of raw meat products. Consequently, the physiology of this bacterium regarding functions involved in growth, survival, and metabolism during meat storage and processing are well known. This species exhibits a wide genomic diversity that can be observed when studying different strains and on which probably rely its multiple facets in meat products: starter, spoiler, or protective culture. The emerging exploration of the microbial ecology of meat products also revealed the multiplicity of bacterial interactions L. sakei has to face and their various consequences on microbial quality and safety at the end of storage. PMID- 28878173 TI - Reply to the Comment by Littlechild and Isupov. AB - I thank Drs. Littlechild and Isupov for their recent comments, which are considered below. Before addressing these specifically, their correspondence raises two more general issues which require initial clarification.[...]. PMID- 28878174 TI - Anti-Sweep Jamming Design and Implementation Using Multi-Channel Harmonic Timing Sequence Detection for Short-Range FMCW Proximity Sensors. AB - Currently, frequency-modulated continuous-wave (FMCW) proximity sensors are widely used. However, they suffer from a serious sweep jamming problem, which significantly reduces the ranging performance. To improve its anti-jamming capability, this paper analyzed the response mechanism of a proximity sensor with the existence of real target echo signals and sweep jamming, respectively. Then, a multi-channel harmonic timing sequence detection method, using the spectrum components' distribution difference between the real echo signals and sweep jamming, is proposed. Moreover, a novel fast Fourier transform (FFT)-based implementation was employed to extract multi-channel harmonic information. Compared with the traditional band-pass filter (BPF) implementation, this novel realization scheme only computes FFT once, in each transmission cycle, which significantly reduced hardware resource consumption and improved the real-time performance of the proximity sensors. The proposed method was implemented and proved to be feasible through the numerical simulations and prototype experiments. The results showed that the proximity sensor utilizing the proposed method had better anti-sweep jamming capability and ranging performance. PMID- 28878172 TI - Dietary Protein Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis of Cohort Studies. AB - Recently, some studies have focused on the relationship between dietary protein intake and the risk of type 2 diabetes mellitus (T2DM), but the conclusions have been inconsistent. Therefore, in this paper, a systematic review and meta analysis of cohort studies regarding protein consumption and T2DM risk are conducted in order to present the association between them. We searched the PubMed and Embase databases for cohort studies on dietary protein, high-protein food consumption and risk of T2DM, up to July 2017. A summary of relative risks was compiled by the fixed-effect model or random-effect model. Eleven cohort studies regarded protein intake and T2DM (52,637 cases among 483,174 participants). The summary RR and 95% CI (Confidence Interval) of T2DM was 1.12 (1.08-1.17) in all subjects, 1.13 (1.04-1.24) in men, and 1.09 (1.04-1.15) in women for total protein;1.14 (1.09-1.19) in all subjects, 1.23 (1.09-1.38) in men, and 1.11 (1.03-1.19) in women for animal protein; 0.96 (0.88-1.06) in all subjects, 0.98 (0.72-1.34) in men, and 0.92 (0.86-0.98) in women for plant protein. We also compared the association between different food sources of protein and the risk of T2DM. The summary RR (Relative Risk) and 95% CI of T2DM was 1.22 (1.09-1.36) for red meat, 1.39 (1.29-1.49) for processed meat, 1.03 (0.89-1.17) for fish, 1.03 (0.64-1.67) for egg, 0.89 (0.84-0.94) for total dairy products, 0.87 (0.78-0.96) for whole milk, 0.83 (0.70-0.98) for yogurt, 0.74 (0.59-0.93) in women for soy. This meta-analysis shows that total protein and animal protein could increase the risk of T2DM in both males and females, and plant protein decreases the risk of T2DM in females. The association between high protein food types and T2DM are also different. Red meat and processed meat are risk factors of T2DM, and soy, dairy and dairy products are the protective factors of T2DM. Egg and fish intake are not associated with a decreased risk of T2DM. This research indicates the type of dietary protein and food sources of protein that should be considered for the prevention of diabetes. PMID- 28878175 TI - Modelled Cost-Effectiveness of a Package Size Cap and a Kilojoule Reduction Intervention to Reduce Energy Intake from Sugar-Sweetened Beverages in Australia. AB - Interventions targeting portion size and energy density of food and beverage products have been identified as a promising approach for obesity prevention. This study modelled the potential cost-effectiveness of: a package size cap on single-serve sugar sweetened beverages (SSBs) >375 mL ( package size cap ), and product reformulation to reduce energy content of packaged SSBs ( energy reduction ). The cost-effectiveness of each intervention was modelled for the 2010 Australia population using a multi-state life table Markov model with a lifetime time horizon. Long-term health outcomes were modelled from calculated changes in body mass index to their impact on Health-Adjusted Life Years (HALYs). Intervention costs were estimated from a limited societal perspective. Cost and health outcomes were discounted at 3%. Total intervention costs estimated in AUD 2010 were AUD 210 million. Both interventions resulted in reduced mean body weight ( package size cap : 0.12 kg; energy reduction : 0.23 kg); and HALYs gained ( package size cap : 73,883; energy reduction : 144,621). Cost offsets were estimated at AUD 750.8 million ( package size cap ) and AUD 1.4 billion ( energy reduction ). Cost-effectiveness analyses showed that both interventions were "dominant", and likely to result in long term cost savings and health benefits. A package size cap and kJ reduction of SSBs are likely to offer excellent "value for money" as obesity prevention measures in Australia. PMID- 28878176 TI - Non-Polar Natural Products from Bromelia laciniosa, Neoglaziovia variegata and Encholirium spectabile (Bromeliaceae). AB - Extensive regional droughts are already a major problem on all inhabited continents and severe regional droughts are expected to become an increasing and extended problem in the future. Consequently, extended use of available drought resistant food plants should be encouraged. Bromelia laciniosa , Neoglaziovia variegata and Encholirium spectabile are excellent candidates in that respect because they are established drought resistant edible plants from the semi-arid Caatinga region. From a food safety perspective, increased utilization of these plants would necessitate detailed knowledge about their chemical constituents. However, their chemical compositions have previously not been determined. For the first time, the non-polar constituents of B. laciniosa , N. variegata and E. spectabile have been identified. This is the first thorough report on natural products from N. variegata , E. spectabile , and B. laciniosa . Altogether, 20 non-polar natural products were characterized. The identifications were based on hyphenated gas chromatography-high resolution mass spectrometry (GC-HRMS) and supported by 1D and 2D Nuclear Magnetic Resonance (NMR) plant metabolomics. PMID- 28878177 TI - Authentication of Smartphone Users Based on Activity Recognition and Mobile Sensing. AB - Smartphones are context-aware devices that provide a compelling platform for ubiquitous computing and assist users in accomplishing many of their routine tasks anytime and anywhere, such as sending and receiving emails. The nature of tasks conducted with these devices has evolved with the exponential increase in the sensing and computing capabilities of a smartphone. Due to the ease of use and convenience, many users tend to store their private data, such as personal identifiers and bank account details, on their smartphone. However, this sensitive data can be vulnerable if the device gets stolen or lost. A traditional approach for protecting this type of data on mobile devices is to authenticate users with mechanisms such as PINs, passwords, and fingerprint recognition. However, these techniques are vulnerable to user compliance and a plethora of attacks, such as smudge attacks. The work in this paper addresses these challenges by proposing a novel authentication framework, which is based on recognizing the behavioral traits of smartphone users using the embedded sensors of smartphone, such as Accelerometer, Gyroscope and Magnetometer. The proposed framework also provides a platform for carrying out multi-class smart user authentication, which provides different levels of access to a wide range of smartphone users. This work has been validated with a series of experiments, which demonstrate the effectiveness of the proposed framework. PMID- 28878178 TI - Microwave-Assisted Extraction of Natural Antioxidants from the Exotic Gordonia axillaris Fruit: Optimization and Identification of Phenolic Compounds. AB - Our previous study reported that the fruit of Gordonia axillaris , an edible wild fruit, possessed strong antioxidant activity. In this study, a microwave-assisted extraction (MAE) method was established to extract antioxidants from the fruit of Gordonia axillaris . The influence of five parameters, including ethanol concentration, solvent/material ratio, extraction time, extraction temperature and microwave power, was investigated by single-factor experiments. Three factors, namely ethanol concentration, solvent/material ratio, extraction time, were found to exert a major influence on extraction efficacy, and were further studied by response surface methodology to investigate their interactions. Ethanol concentration of 36.89%, solvent/material ratio of 29.56 mL/g, extraction time of 71.04 min, temperature of 40 °C, and microwave power of 400 W were found to be the optimal condition. The TEAC value was 198.16 ± 5.47 umol Trolox/g DW under the optimal conditions, which was in conformity to the predicted value (200.28 umol Trolox/g DW). In addition, the MAE method was compared with two conventional methods (Soxhlet extraction and maceration extraction). Results showed that the antioxidant capacity of the extract obtained by MAE method was stronger than that obtained by maceration (168.67 ± 3.88 umol Trolox/g DW) or Soxhlet extraction (114.09 ± 2.01 umol Trolox/g DW). Finally, several phenolic compounds in the extract were identified and quantified by UPLC-MS/MS, which were rutin, gallic acid, protocatechuic acid, epicatechin, epicatechin gallate, 2-hydrocinnamic acid, p -coumaric acid, quercetin, chlorogenic acid and ferulic acid. PMID- 28878179 TI - Masticadienonic and 3α-OH Masticadienoic Acids Induce Apoptosis and Inhibit Cell Proliferation and Tumor Growth in Prostate Cancer Xenografts in Vivo. AB - The triterpenes have been constituted as a group of interesting molecules as possible antitumor agents. Despite several of them not presenting a potent cytotoxic activity in vitro against cancer cells, in vivo in xenotransplant tumors studies, they show promising results. Based on the above considerations, we investigated the antitumor activity of both masticadienonic (MDA) and 3α OH masticadienoic (3α-OH MDA) acids in a mouse prostate cancer xenograft model. Immunohistochemical assays were used to evaluate the decrease in the expression of the Proliferating Cell Nuclear Antigen (PCNA) and the Ki-67 induced by MDA and 3α-OH MDA. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to demonstrate the fragmentation of DNA. Our results showed that the two triterpenes inhibited tumor growth, had anti proliferative effect in vivo and induced cell death by apoptosis. Collectively, our data suggested that the antitumor mechanism of MDA and 3α-OH MDA involves several molecular targets related to cell proliferation and apoptosis. PMID- 28878181 TI - Developmental Outcomes at 24 Months of Age in Toddlers Supplemented with Arachidonic Acid and Docosahexaenoic Acid: Results of a Double Blind Randomized, Controlled Trial. AB - Little is known about arachidonic acid (ARA) and docosahexaenoic acid (DHA) requirements in toddlers. A longitudinal, double blind, controlled trial in toddlers ( n = 133) age 13.4 ± 0.9 months (mean ± standard deviation), randomized to receive a DHA (200 mg/day) and ARA (200 mg/day) supplement (supplement) or a corn oil supplement (control) until age 24 months determined effects on neurodevelopment. We found no effect of the supplement on the Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) cognitive and language composites and Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) at age 24 months. Supplemented toddlers had higher RBC phosphatidylcholine (PC), phosphatidylethanolamine (PE), and plasma DHA and ARA compared to placebo toddlers at age 24 months. A positive relationship between RBC PE ARA and Bayley III Cognitive composite (4.55 (0.21-9.00), B (95% CI), p = 0.045) in supplemented boys, but not in control boys, was observed in models adjusted for baseline fatty acid, maternal non-verbal intelligence, and BMI z score at age 24 months. A similar positive relationship between RBC PE ARA and Bayley III Language composite was observed for supplemented boys (11.52 (5.10 17.94), p < 0.001) and girls (11.19 (4.69-17.68), p = 0.001). These findings suggest that increasing the ARA status in toddlers is associated with better neurodevelopment at age 24 months. PMID- 28878182 TI - RuO₂ pH Sensor with Super-Glue-Inspired Reference Electrode. AB - A pH-sensitive RuO₂ electrode coated in a commercial cyanoacrylate adhesive typically exhibits very low pH sensitivity, and could be paired with a RuO₂ working electrode as a differential type pH sensor. However, such sensors display poor performance in real sample matrices. A pH sensor employing a RuO₂ pH sensitive working electrode and a SiO₂-PVB junction-modified RuO₂ reference electrode is developed as an alternative high-performance solution. This sensor exhibits a performance similar to that of a commercial glass pH sensor in some common sample matrices, particularly, an excellent pH sensitivity of 55.7 mV/pH, a hysteresis as low as 2.7 mV, and a drift below 2.2 mV/h. The developed sensor structure opens the way towards the development of a simple, cost effective, and robust pH sensor for pH analysis in various sample matrices. PMID- 28878180 TI - Bariatric Surgery and Precision Nutrition. AB - This review provides a literature overview of new findings relating nutritional genomics and bariatric surgery. It also describes the importance of nutritional genomics concepts in personalized bariatric management. It includes a discussion of the potential role bariatric surgery plays in altering the three pillars of nutritional genomics: nutrigenetics, nutrigenomics, and epigenetics. We present studies that show the effect of each patient's genetic and epigenetic variables on the response to surgical weight loss treatment. We include investigations that demonstrate the association of single nucleotide polymorphisms with obesity phenotypes and their influence on weight loss after bariatric surgery. We also present reports on how significant weight loss induced by bariatric surgery impacts telomere length, and we discuss studies on the existence of an epigenetic signature associated with surgery outcomes and specific gene methylation profile, which may help to predict weight loss after a surgical procedure. Finally, we show articles which evidence that bariatric surgery may affect expression of numerous genes involved in different metabolic pathways and consequently induce functional and taxonomic changes in gut microbial communities. The role nutritional genomics plays in responses to weight loss after bariatric surgery is evident. Better understanding of the molecular pathways involved in this process is necessary for successful weight management and maintenance. PMID- 28878184 TI - Simplified Models for the Material Characterization of Cold-Formed RHS. AB - It is well known that the cold-forming process used to manufacture tubes causes an increase in both the yielding stress and the ultimate strength of the corner material in rectangular steel hollow sections. This may have a significant effect on the resistance of any structure built with those profiles. However, the mentioned material hardening can be difficult to take into account in the calculations for member design or to evaluate the connection resistance through the design formulation or when using numerical simulation models. As an attempt to face the above-mentioned problem, the present paper presents a comparison among simplified approaches that consider homogeneous material properties for the whole section. It has been carried out by comparing the results obtained from the finite element modelling of stub column tests in which the material properties based on the flat faces were considered for the whole profile. PMID- 28878183 TI - A Novel Combination of Wheat Peptides and Fucoidan Attenuates Ethanol-Induced Gastric Mucosal Damage through Anti-Oxidant, Anti-Inflammatory, and Pro-Survival Mechanisms. AB - Gastritis or peptic ulcer is believed to affect about half of people worldwide. Traditional medications can lead to adverse effects, therefore, alternative nutritional strategies are needed to prevent the development of gastric mucosal damage. A novel combination of two food-grade ingredients, wheat peptides and fucoidan (WPF), was prepared to treat male Sprague Dawley rats for 30 days before gastric mucosal damage was induced by oral administration of ethanol. The serum levels of biomarkers were determined by enzyme-linked immunosorbent assay. Biomarkers in stomach tissue were analyzed using immunohistochemistry. In addition, human gastric epithelial cell line (GES-1) was used to investigate protein expression by Western blot. WPF could attenuate ethanol-induced gastric mucosal damage in an inverse dose-dependent manner, with both ulcer index and pathological index improved. WPF increased superoxide dismutase level and decreased malondialdehyde level. WPF also decreased the levels of interleukin-8, platelet-activating factor, and Caspase 3, while increasing the levels of prostaglandin E-2, epidermal growth factor (EGF), and EGF receptor (EGFR). Furthermore, phosphorylation of EGFR and extracellular signal-regulated kinases was induced by WPF in GES-1 cells. In conclusion, the novel combination of wheat peptides and fucoidan attenuated ethanol-induced gastric mucosal damage in rats through anti-oxidant, anti-inflammatory, and pro-survival mechanisms. PMID- 28878185 TI - Effects of Hyporheic Water Fluxes and Sediment Grain Size on the Concentration and Diffusive Flux of Heavy Metals in the Streambed. AB - The hyporheic zone regulates physicochemical processes in surface-groundwater systems and can be an important source of heavy metals in fluvial systems. This study assesses the pore water concentrations and diffusive fluxes of heavy metals with respect to the vertical water exchange flux (VWEF) and sediment grain size. Water and sediment samples were collected on August 2016 from upstream Site 1 and downstream Site 2 along the Juehe River in Shaanxi Province, China. Streambed vertical hydraulic conductivity (Kv) and the VWEF were estimated via the standpipe permeameter test method and Darcy's law. The heavy metal concentrations in the pore water were measured and the diffusive fluxes were calculated using Fick's first law. The VWEF patterns were dominated by upward flow, and Site 1 featured higher values of Kv and VWEF. Higher Cu and Zn concentrations occurred near the channel centre with coarse sand and gravel and greater upward VWEFs because coarser sediment and greater upward VWEFs cause stronger metal desorption capacity. Additionally, Cu and Zn at the two sites generally diffused from pore water to surface water, potentially due to the upward VWEF. The VWEF and sediment grain size are likely crucial factors influencing the heavy metal concentrations and diffusive fluxes. PMID- 28878186 TI - Monitoring Ion Track Formation Using In Situ RBS/c, ToF-ERDA, and HR-PIXE. AB - The aim of this work is to investigate the feasibility of ion beam analysis techniques for monitoring swift heavy ion track formation. First, the use of the in situ Rutherford backscattering spectrometry in channeling mode to observe damage build-up in quartz SiO₂ after MeV heavy ion irradiation is demonstrated. Second, new results of the in situ grazing incidence time-of-flight elastic recoil detection analysis used for monitoring the surface elemental composition during ion tracks formation in various materials are presented. Ion tracks were found on SrTiO₃, quartz SiO₂, a-SiO₂, and muscovite mica surfaces by atomic force microscopy, but in contrast to our previous studies on GaN and TiO₂, surface stoichiometry remained unchanged. Third, the usability of high resolution particle induced X-ray spectroscopy for observation of electronic dynamics during early stages of ion track formation is shown. PMID- 28878187 TI - Composite Fibers from Recycled Plastics Using Melt Centrifugal Spinning. AB - New methods are being developed to enable the production of value-added materials from high-volume, low-cost feedstocks arising from domestic recycling streams. In this work, recycled bottle-grade polyethylene terephthalate, polystyrene, and polypropylene were spun into fibers from the melt using a centrifugal spinning technique. Mono-component fibers and 50/50 blends of each polymer and a 33/33/33 blend of all three polymers were evaluated. Fiber morphology, chemistry, thermal, and mechanical properties were probed. Fiber diameters ranged from ca. 1 to over 12 um, with polypropylene fibers having the smallest fiber diameters. Mono component fibers were generally defect-free, while composite fibers containing polypropylene were beady. Fibers made from polyethylene terephthalate had the highest tensile strength, and the addition of polyethylene terephthalate to the other polymers improved the mechanical properties of the blends. Nano- and micro fibers from both pure and mixed waste streams are expected to have applications in myriad areas such as ultra/micro-filtration, composites, and insulation. PMID- 28878188 TI - MTLD, a Database of Multiple Target Ligands, the Updated Version. AB - Polypharmacology plays an important role in drug discovery and polypharmacology drug strategies provide a novel path in drug design. However, to develop a polypharmacology drug with the desired profile remains a challenge. Previously, we developed a free web-accessible database called Multiple Target Ligand Database (MTLD, www.mtdcadd.com). Herein, the MTLD database has been updated, containing 2444 Multiple Target Ligands (MTLs) that bind with 21,424 binding sites from 18,231 crystal structures. Of the MTLs, 304 entries are approved drugs, and 1911 entries are drug-like compounds. Also, we added new functions such as multiple conditional search and linkage visualization. Through querying the updated database, extremely useful information for the development of polypharmacology drugs may be provided. PMID- 28878189 TI - Synthesis and Biological Activity of Novel O-Alkyl Derivatives of Naringenin and Their Oximes. AB - O -Alkyl derivatives of naringenin ( 1a - 10a ) were prepared from naringenin using the corresponding alkyl iodides and anhydrous potassium carbonate. The resulting products were used to obtain oximes ( 1b - 10b ). All compounds were tested for antimicrobial activity against Escherichia coli ATCC10536, Staphylococcus aureus DSM799, Candida albicans DSM1386, Alternaria alternata CBS1526, Fusarium linii KB-F1, and Aspergillus niger DSM1957. The resulting biological activity was expressed as the increase in optical density (ΔOD). The highest inhibitory effect against E. coli ATCC10536 was observed for 7,4'-di- O -pentylnaringenin ( 8a ), 7- O -dodecylnaringenin ( 9a ), naringenin oxime ( NG OX ), 7,4'-di- O -pentylnaringenin oxime ( 8b ), and 7- O -dodecylnaringenin oxime ( 9b ) (ΔOD = 0). 7- O -dodecylnaringenin oxime ( 9b ) also inhibited the growth of S. aureus DSM799 (ΔOD = 0.35) and C. albicans DSM1386 (ΔOD = 0.22). The growth of A. alternata CBS1526 was inhibited as a result of the action of 7,4'-di- O -methylnaringenin ( 2a ), 7- O -ethylnaringenin ( 4a ), 7,4'-di- O -ethylnaringenin ( 5a ), 5,7,4'-tri- O -ethylnaringenin ( 6a ), 7,4'-di- O -pentylnaringenin ( 8a ), and 7- O -dodecylnaringenin ( 9a ) (ΔOD in the range of 0.49-0.42) in comparison to that of the control culture (ΔOD = 1.87). In the case of F. linii KB-F1, naringenin ( NG ), 7,4'-di- O dodecylnaringenin ( 10a ), 7- O -dodecylnaringenin oxime ( 9b ), and 7,4'-di- O dodecylnaringenin oxime ( 10b ) showed the strongest effect (ΔOD = 0). 7,4' Di- O -pentylnaringenin ( 8a ) and naringenin oxime ( NG-OX ) hindered the growth of A. niger DSM1957 (ΔOD = 0). PMID- 28878190 TI - Effect of Mo on Microstructures and Wear Properties of In Situ Synthesized Ti(C,N)/Ni-Based Composite Coatings by Laser Cladding. AB - Using Ni60 alloy, C, TiN and Mo mixed powders as the precursor materials, in situ synthesized Ti(C,N) particles reinforcing Ni-based composite coatings are produced on Ti6Al4V alloys by laser cladding. Phase constituents, microstructures and wear properties of the composite coatings with 0 wt % Mo, 4 wt % Mo and 8 wt % Mo additions are studied comparatively. Results indicate that Ti(C,N) is formed by the in situ metallurgical reaction, the (Ti,Mo)(C,N) rim phase surrounding the Ti(C,N) ceramic particle is synthesized with the addition of Mo, and the increase of Mo content is beneficial to improve the wear properties of the cladding coatings. Because of the effect of Mo, the grains are remarkably refined and a unique core-rim structure that is uniformly dispersed in the matrix appears; meanwhile, the composite coatings with Mo addition exhibit high hardness and excellent wear resistance due to the comprehensive action of dispersion strengthening, fine grain strengthening and solid solution strengthening. PMID- 28878192 TI - Improving the Mechanical Properties of Cu-15Ni-8Sn Alloys by Addition of Titanium. AB - The effect of Ti addition on the microstructure and mechanical properties of Cu 15Ni-8Sn alloys was investigated. Optical microscopy (OM), scanning electronic microscopy (SEM), and transmission electron microscopy (TEM) were used to determine grain size and distribution of the second phases in the alloys. The results indicate that the tensile properties of Cu-15Ni-8Sn alloys are improved significantly with Ti addition. Tensile elongation increased from 2.7% for the alloy without Ti to 17.9% for the alloy with 0.3% Ti, while tensile strength was maintained and even increased from 935 MPa to 1024 MPa. The improvement of the mechanical properties of Cu-15Ni-8Sn alloys by the addition of Ti is attributed to the grain refinement and suppression of discontinuous precipitation during heat treatment. PMID- 28878193 TI - Time-Frequency Analysis of Mu Rhythm Activity during Picture and Video Action Naming Tasks. AB - This study used whole-head 64 channel electroencephalography to measure changes in sensorimotor activity-as indexed by the mu rhythm-in neurologically-healthy adults, during subvocal confrontation naming tasks. Independent component analyses revealed sensorimotor mu component clusters in the right and left hemispheres. Event related spectral perturbation analyses indicated significantly stronger patterns of mu rhythm activity ( p FDR < 0.05) during the video condition as compared to the picture condition, specifically in the left hemisphere. Mu activity is hypothesized to reflect typical patterns of sensorimotor activation during action verb naming tasks. These results support further investigation into sensorimotor cortical activity during action verb naming in clinical populations. PMID- 28878194 TI - A Rationally Designed Reversible 'Turn-Off' Sensor for Glutathione. AB - γ-Glutamyl-cysteinyl-glycine (GSH) plays a critical role in maintaining redox homeostasis in biological systems and a decrease in its cellular levels is associated with diseases. Existing fluorescence-based chemosensors for GSH acts as irreversible reaction-based probes that exhibit a maximum fluorescence ('turn on') once the reaction is complete, regardless of the actual concentration of GSH. A reversible, reaction-based 'turn-off' probe ( 1 ) is reported here to sense the decreasing levels of GSH, a situation known to occur at the onset of various diseases. The more fluorescent merocyanine (MC) isomer of 1 exists in aqueous solution and this reacts with GSH to induce formation of the ring-closed spiropyran (SP) isomer, with a measurable decrease in absorbance and fluorescence ('turn-off'). Sensor 1 has good aqueous solubility and shows an excellent selectivity for GSH over other biologically relevant metal ions and aminothiol analytes. The sensor permeates HEK 293 cells and an increase in fluorescence is observed on adding buthionine sulfoximine, an inhibitor of GSH synthesis. PMID- 28878195 TI - 1α,25-dihydroxyvitamin D3 Attenuates TGF-β-Induced Pro-Fibrotic Effects in Human Lung Epithelial Cells through Inhibition of Epithelial-Mesenchymal Transition. AB - Pulmonary fibrosis is a progressive fibrotic lung disease of persisting lung injury and ineffective wound repair, with poor prognosis. Epithelial-mesenchymal transition (EMT) of alveolar epithelia cells is an early event in the development of pulmonary fibrosis, and transforming growth factor β (TGF-β) is an acknowledged inducer of EMT. Epidemiological studies demonstrated that serum levels of 25-hydroxy-vitamin D were associated with the presence of fibrosis diseases. We investigated whether vitamin D attenuated TGF-β-induced pro fibrotic effects through inhibiting EMT in human alveolar epithelia A549 cells. A549 cells were cultured with TGF-β alone or in combination with 1α,25 dihydroxyvitamin D3 (1α,25(OH)₂D₃). TGF-β increased the expression of the mesenchymal markers (N-cadherin and Vimentin), and decreased the expression of epithelial markers (E-cadherin). 1α,25(OH)₂D₃ attenuated these TGF-β-induced alterations. Furthermore, the EMT-related transcription factors (Snail and β-catenin) and the extracellular matrix genes (Collagen I and fibronectin) were inhibited by 1α,25(OH)₂D₃, while the expression of vitamin D receptor (VDR) was elevated. In addition, 1α,25(OH)₂D₃ alleviated the cell migration and the invasion abilities in TGF-β-stimulated A549 cells, determined by the scratch wound healing and transwell assays. Our findings suggested that 1α,25(OH)₂D₃ inhibited the pro-fibrotic phenotype of lung epithelial cells under TGF-β stimulation and provided new clues in the clinical management of pulmonary fibrosis. PMID- 28878191 TI - Melatonin and Hippo Pathway: Is There Existing Cross-Talk? AB - Melatonin is an indolic hormone that regulates a plethora of functions ranging from the regulation of circadian rhythms and antioxidant properties to the induction and maintenance of tumor suppressor pathways. It binds to specific receptors as well as to some cytosolic proteins, leading to several cellular signaling cascades. Recently, the involvement of melatonin in cancer insurgence and progression has clearly been demonstrated. In this review, we will first describe the structure and functions of melatonin and its receptors, and then discuss both molecular and epidemiological evidence on melatonin anticancer effects. Finally, we will shed light on potential cross-talk between melatonin signaling and the Hippo signaling pathway, along with the possible implications for cancer therapy. PMID- 28878196 TI - Metasurfaces Based on Phase-Change Material as a Reconfigurable Platform for Multifunctional Devices. AB - Integration of phase-change materials (PCMs) into electrical/optical circuits has initiated extensive innovation for applications of metamaterials (MMs) including rewritable optical data storage, metasurfaces, and optoelectronic devices. PCMs have been studied deeply due to their reversible phase transition, high endurance, switching speed, and data retention. Germanium-antimony-tellurium (GST) is a PCM that has amorphous and crystalline phases with distinct properties, is bistable and nonvolatile, and undergoes a reliable and reproducible phase transition in response to an optical or electrical stimulus; GST may therefore have applications in tunable photonic devices and optoelectronic circuits. In this progress article, we outline recent studies of GST and discuss its advantages and possible applications in reconfigurable metadevices. We also discuss outlooks for integration of GST in active nanophotonic metadevices. PMID- 28878198 TI - Endocrine Disruptors and Pregnancy: Knowledge, Attitudes and Prevention Behaviors of French Women. AB - Endocrine disrupting chemicals (EDC) are environmental exposure factors that are rarely reported in clinical practice, particularly during pregnancy. This study aimed to describe women's knowledge, attitudes and behaviors towards EDC exposure. A study was conducted in the French Department of Vienne between 2014 and 2016 and comprised semi-structured interviews with pregnant women, a focus group of professionals in perinatology and environmental health, and the administration of a psychosocial questionnaire comprising scores in 300 pregnant or in postpartum period women. The mean score of knowledge was 42.9 +/- 9.8 out of 100 (from 13.5 to 75.7). Exposure attitude was determined by risk perception. Mean level of cues to action to reduce their EDC exposure was estimated at 56.9 +/- 22.5 out of 100 (from 0 to 100). Anxiety was significantly increased after the questionnaire. Anxiety about EDC was associated with a high score of knowledge (OR = 2.30, 95% CI (1.12-4.71)) and with no pregnancy anxiety (OR = 0.57, 95% CI (0.34-0.95)). Our findings suggest that healthcare providers should consider pregnant women's knowledge and perceptions, possibilities of action, and be careful not to increase their anxiety when advising them about EDC and environmental exposure. PMID- 28878197 TI - Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease. AB - Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and de novo lipogenesis (DNL). Fructose-derived precursors also act as nutritional regulators of the transcription factors, including ChREBP and SREBP1c, that regulate the expression of hepatic gluconeogenesis and DNL genes. In support of these mechanisms, fructose intake increases hepatic gluconeogenesis and DNL and raises plasma glucose and triglyceride levels in humans. However, epidemiological and fructose-intervention studies have had inconclusive results with respect to liver fat, and there is currently no good human evidence that fructose, when consumed in isocaloric amounts, causes more liver fat accumulation than other energy-dense nutrients. In this review, we aim to provide an overview of the seemingly contradicting literature on fructose and NAFLD. We outline fructose physiology, the mechanisms that link fructose to NAFLD, and the available evidence from human studies. From this framework, we conclude that the cellular mechanisms underlying hepatic fructose metabolism will likely reveal novel targets for the treatment of NAFLD, dyslipidemia, and hepatic insulin resistance. Finally, fructose-containing sugars are a major source of excess calories, suggesting that a reduction of their intake has potential for the prevention of NAFLD and other obesity-related diseases. PMID- 28878199 TI - Microfluidic-Based Measurement Method of Red Blood Cell Aggregation under Hematocrit Variations. AB - Red blood cell (RBC) aggregation and erythrocyte sedimentation rate (ESR) are considered to be promising biomarkers for effectively monitoring blood rheology at extremely low shear rates. In this study, a microfluidic-based measurement technique is suggested to evaluate RBC aggregation under hematocrit variations due to the continuous ESR. After the pipette tip is tightly fitted into an inlet port, a disposable suction pump is connected to the outlet port through a polyethylene tube. After dropping blood (approximately 0.2 mL) into the pipette tip, the blood flow can be started and stopped by periodically operating a pinch valve. To evaluate variations in RBC aggregation due to the continuous ESR, an EAI (Erythrocyte-sedimentation-rate Aggregation Index) is newly suggested, which uses temporal variations of image intensity. To demonstrate the proposed method, the dynamic characterization of the disposable suction pump is first quantitatively measured by varying the hematocrit levels and cavity volume of the suction pump. Next, variations in RBC aggregation and ESR are quantified by varying the hematocrit levels. The conventional aggregation index (AI) is maintained constant, unrelated to the hematocrit values. However, the EAI significantly decreased with respect to the hematocrit values. Thus, the EAI is more effective than the AI for monitoring variations in RBC aggregation due to the ESR. Lastly, the proposed method is employed to detect aggregated blood and thermally-induced blood. The EAI gradually increased as the concentration of a dextran solution increased. In addition, the EAI significantly decreased for thermally-induced blood. From this experimental demonstration, the proposed method is able to effectively measure variations in RBC aggregation due to continuous hematocrit variations, especially by quantifying the EAI. PMID- 28878200 TI - A Protocol for Generating and Exchanging (Genome-Scale) Metabolic Resource Allocation Models. AB - In this article, we present a protocol for generating a complete (genome-scale) metabolic resource allocation model, as well as a proposal for how to represent such models in the systems biology markup language (SBML). Such models are used to investigate enzyme levels and achievable growth rates in large-scale metabolic networks. Although the idea of metabolic resource allocation studies has been present in the field of systems biology for some years, no guidelines for generating such a model have been published up to now. This paper presents step by-step instructions for building a (dynamic) resource allocation model, starting with prerequisites such as a genome-scale metabolic reconstruction, through building protein and noncatalytic biomass synthesis reactions and assigning turnover rates for each reaction. In addition, we explain how one can use SBML level 3 in combination with the flux balance constraints and our resource allocation modeling annotation to represent such models. PMID- 28878201 TI - Protein Complexes Prediction Method Based on Core-Attachment Structure and Functional Annotations. AB - Recent advances in high-throughput laboratory techniques captured large-scale protein-protein interaction (PPI) data, making it possible to create a detailed map of protein interaction networks, and thus enable us to detect protein complexes from these PPI networks. However, most of the current state-of-the-art studies still have some problems, for instance, incapability of identifying overlapping clusters, without considering the inherent organization within protein complexes, and overlooking the biological meaning of complexes. Therefore, we present a novel overlapping protein complexes prediction method based on core-attachment structure and function annotations (CFOCM), which performs in two stages: first, it detects protein complex cores with the maximum value of our defined cluster closeness function, in which the proteins are also closely related to at least one common function. Then it appends attach proteins into these detected cores to form the returned complexes. For performance evaluation, CFOCM and six classical methods have been used to identify protein complexes on three different yeast PPI networks, and three sets of real complexes including the Munich Information Center for Protein Sequences (MIPS), the Saccharomyces Genome Database (SGD) and the Catalogues of Yeast protein Complexes (CYC2008) are selected as benchmark sets, and the results show that CFOCM is indeed effective and robust for achieving the highest F-measure values in all tests. PMID- 28878202 TI - Predicting Organ-Specific Risk Interactions between Radiation and Chemotherapy in Secondary Cancer Survivors. AB - Several studies have shown that pediatric patients have an increased risk of developing a secondary malignancy several decades after treatment with radiotherapy and chemotherapy. In this work, we use a biologically motivated mathematical formalism to estimate the relative risks of breast, lung and thyroid cancers in childhood cancer survivors due to concurrent therapy regimen. This model specifically includes possible organ-specific interaction between radiotherapy and chemotherapy. The model predicts relative risks for developing secondary cancers after chemotherapy in breast, lung and thyroid tissues, and compared with the epidemiological data. For a concurrent therapy protocol, our model predicted relative risks of 3.2, 9.3, 4.5 as compared to the clinical data, i.e., 1.4, 8.0, 2.3 for secondary breast, lung and thyroid cancer risks, respectively. The extracted chemotherapy mutation induction rates for breast, lung and thyroid are 10 −9 , 0.5 × 10 −6 , 0.9 × 10 −7 respectively. We found that there exists no synergistic interaction between radiation and chemotherapy for neither mutation induction nor cell kill in lung tissue, but there is an interaction in cell kill for the breast and thyroid organs. These findings help understand the risks of current clinical protocols and might provide rational guidance to develop future multi-modality treatment protocols to minimize secondary cancer risks. PMID- 28878203 TI - Biventricular Cardiac Hypertrophy in a Patient with Primary Aldosteronism and Atrial Septal Defect. AB - BACKGROUND Primary aldosteronism can be caused by adrenocortical adenoma and is usually associated with left ventricular hypertrophy. Biventricular cardiac hypertrophy and heart failure in the presence of a pre-existing atrial septal defect (ASD) are a rare association of primary aldosteronism. CASE REPORT A 33 year-old woman with resistant hypertension and refractory hypokalemia presented with signs and symptoms of heart failure. She had previously been diagnosed having a right adrenal tumor and ostium secundum type ASD. Transthoracic echocardiography confirmed the location of the ASD, with a left-to-right cardiac shunt, moderate to severe tricuspid insufficiency, moderate pulmonary hypertension (60 mm Hg), four chamber dilatation and biventricular hypertrophy. The left ventricular ejection fraction was 17%. Endocrine function tests showed a raised plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio, which supported a diagnosis of primary aldosteronism. A captopril suppression test failed to suppress the patient's PAC, which confirmed the diagnosis. The patient underwent a right adrenalectomy with subsequent normalization of hypokalemia, PAC, and PAC to PRA ratio and her hypertension was managed successfully with monotherapy. Surgical pathology examination of the tumor revealed an adrenocortical adenoma. At follow-up at 18 months, the patient had a normal potassium level, and her cardiac function and ventricular geometries were improved. CONCLUSIONS Reversible cardiac hypertrophy is rarely associated with primary aldosteronism, however, it should be recognized. Present findings suggest that aldosteronism contributes to cardiac remodelling and biventricular hypertrophic changes. Administering appropriate treatment in a timely manner, can reverse cardiac changes along with the other symptoms of primary aldosteronism. PMID- 28878205 TI - Tunneling anisotropic magnetoresistance driven by magnetic phase transition. AB - The independent control of two magnetic electrodes and spin-coherent transport in magnetic tunnel junctions are strictly required for tunneling magnetoresistance, while junctions with only one ferromagnetic electrode exhibit tunneling anisotropic magnetoresistance dependent on the anisotropic density of states with no room temperature performance so far. Here, we report an alternative approach to obtaining tunneling anisotropic magnetoresistance in alpha'-FeRh-based junctions driven by the magnetic phase transition of alpha'-FeRh and resultantly large variation of the density of states in the vicinity of MgO tunneling barrier, referred to as phase transition tunneling anisotropic magnetoresistance. The junctions with only one alpha'-FeRh magnetic electrode show a magnetoresistance ratio up to 20% at room temperature. Both the polarity and magnitude of the phase transition tunneling anisotropic magnetoresistance can be modulated by interfacial engineering at the alpha'-FeRh/MgO interface. Besides the fundamental significance, our finding might add a different dimension to magnetic random access memory and antiferromagnet spintronics.Tunneling anisotropic magnetoresistance is promising for next generation memory devices but limited by the low efficiency and functioning temperature. Here the authors achieved 20% tunneling anisotropic magnetoresistance at room temperature in magnetic tunnel junctions with one alpha'-FeRh magnetic electrode. PMID- 28878204 TI - Analysis of Antineutrophil Cytoplasm Antibody from 118 730 Patients in Tertiary Hospitals in Jiangxi Province, China. AB - BACKGROUND The discovery of antineutrophil cytoplasm antibody (ANCA) makes the early diagnosis of primary vasculitis possible, and also has important guiding significance for the diagnosis and treatment of secondary vasculitis. This study aimed to investigate the clinical significance of ANCA. MATERIAL AND METHODS ANCA was detected by indirect immunofluorescence assay (IIF), and anti-myeloperoxidase (MPO) antibody, and anti-proteinase 3 (PR3) antibody were detected by ELISA. The results were analyzed retrospectively. RESULTS Among 118 730 patients, a total of 5853 (4.93%) were positive for ANCA. In the positive cases, 3.98% were male and 6.33% were female, with significant differences (chi2=123.38, P<0.01). For ANCA, the department with the highest positive rate (15.06%) was the Department of Rheumatology, followed by 7.78% in the Department of Dermatology, 6.79% in the Department of Nephrology, and 5.72% in the Department of Traditional Chinese Medicine (TCM). Anti-PR3 and cANCA were highly specific in primary vasculitis (P<0.01). Anti-MPO and pANCA had high specificity for other autoimmune diseases (P<0.01). CONCLUSIONS ANCA has important guiding significance for vasculitis related diseases. Therefore, it is important in the diagnosis and treatment of this disease and has value in clinical practice. PMID- 28878207 TI - Silicon quantum processor with robust long-distance qubit couplings. AB - Practical quantum computers require a large network of highly coherent qubits, interconnected in a design robust against errors. Donor spins in silicon provide state-of-the-art coherence and quantum gate fidelities, in a platform adapted from industrial semiconductor processing. Here we present a scalable design for a silicon quantum processor that does not require precise donor placement and leaves ample space for the routing of interconnects and readout devices. We introduce the flip-flop qubit, a combination of the electron-nuclear spin states of a phosphorus donor that can be controlled by microwave electric fields. Two qubit gates exploit a second-order electric dipole-dipole interaction, allowing selective coupling beyond the nearest-neighbor, at separations of hundreds of nanometers, while microwave resonators can extend the entanglement to macroscopic distances. We predict gate fidelities within fault-tolerance thresholds using realistic noise models. This design provides a realizable blueprint for scalable spin-based quantum computers in silicon.Quantum computers will require a large network of coherent qubits, connected in a noise-resilient way. Tosi et al. present a design for a quantum processor based on electron-nuclear spins in silicon, with electrical control and coupling schemes that simplify qubit fabrication and operation. PMID- 28878206 TI - Towards designer organelles by subverting the peroxisomal import pathway. AB - The development of 'designer' organelles could be a key strategy to enable foreign pathways to be efficiently controlled within eukaryotic biotechnology. A fundamental component of any such system will be the implementation of a bespoke protein import pathway that can selectively deliver constituent proteins to the new compartment in the presence of existing endogenous trafficking systems. Here we show that the protein-protein interactions that control the peroxisomal protein import pathway can be manipulated to create a pair of interacting partners that still support protein import in moss cells, but are orthogonal to the naturally occurring pathways. In addition to providing a valuable experimental tool to give new insights into peroxisomal protein import, the variant receptor-signal sequence pair forms the basis of a system in which normal peroxisomal function is downregulated and replaced with an alternative pathway, an essential first step in the creation of a designer organelle.Designer organelles could allow the isolation of synthetic biological pathways from endogenous components of the host cell. Here the authors engineer a peroxisomal protein import pathway orthogonal to the naturally occurring system. PMID- 28878208 TI - HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. AB - T-cell-based immunotherapies are promising treatments for cancer patients. Although durable responses can be achieved in some patients, many patients fail to respond to these therapies, underscoring the need for improvement with combination therapies. From a screen of 850 bioactive compounds, we identify HSP90 inhibitors as candidates for combination with immunotherapy. We show that inhibition of HSP90 with ganetespib enhances T-cell-mediated killing of patient derived human melanoma cells by their autologous T cells in vitro and potentiates responses to anti-CTLA4 and anti-PD1 therapy in vivo. Mechanistic studies reveal that HSP90 inhibition results in upregulation of interferon response genes, which are essential for the enhanced killing of ganetespib treated melanoma cells by T cells. Taken together, these findings provide evidence that HSP90 inhibition can potentiate T-cell-mediated anti-tumor immune responses, and rationale to explore the combination of immunotherapy and HSP90 inhibitors.Many patients fail to respond to T cell based immunotherapies. Here, the authors, through a high throughput screening, identify HSP90 inhibitors as a class of preferred drugs for treatment combination with immunotherapy. PMID- 28878209 TI - Community-like genome in single cells of the sulfur bacterium Achromatium oxaliferum. AB - Polyploid bacteria are common, but the genetic and functional diversity resulting from polyploidy is unknown. Here we use single-cell genomics, metagenomics, single-cell amplicon sequencing, and fluorescence in situ hybridization, to show that individual cells of Achromatium oxaliferum, the world's biggest known freshwater bacterium, harbor genetic diversity typical of whole bacterial communities. The cells contain tens of transposable elements, which likely cause the unprecedented diversity that we observe in the sequence and synteny of genes. Given the high within-cell diversity of the usually conserved 16S ribosomal RNA gene, we suggest that gene conversion occurs in multiple, separated genomic hotspots. The ribosomal RNA distribution inside the cells hints to spatially differential gene expression. We also suggest that intracellular gene transfer may lead to extensive gene reshuffling and increased diversity.The cells of Achromatium bacteria are remarkably large and contain multiple chromosome copies. Here, Ionescu et al. show that chromosome copies within individual cells display high diversity, similar to that of bacterial communities, and contain tens of transposable elements. PMID- 28878210 TI - Alkaline earth metal vanadates as sodium-ion battery anodes. AB - The abundance of sodium resources indicates the potential of sodium-ion batteries as emerging energy storage devices. However, the practical application of sodium ion batteries is hindered by the limited electrochemical performance of electrode materials, especially at the anode side. Here, we identify alkaline earth metal vanadates as promising anodes for sodium-ion batteries. The prepared calcium vanadate nanowires possess intrinsically high electronic conductivity (> 100 S cm 1), small volume change (< 10%), and a self-preserving effect, which results in a superior cycling and rate performance and an applicable reversible capacity (> 300 mAh g-1), with an average voltage of ~1.0 V. The specific sodium-storage mechanism, beyond the conventional intercalation or conversion reaction, is demonstrated through in situ and ex situ characterizations and theoretical calculations. This work explores alkaline earth metal vanadates for sodium-ion battery anodes and may open a direction for energy storage.The development of suitable anode materials is essential to advance sodium-ion battery technologies. Here the authors report that alkaline earth metal vanadates are promising candidates due to the favorable electrochemical properties and interesting sodium storage mechanism. PMID- 28878211 TI - Assay to visualize specific protein oxidation reveals spatio-temporal regulation of SHP2. AB - Reactive oxygen species are produced transiently in response to cell stimuli, and function as second messengers that oxidize target proteins. Protein-tyrosine phosphatases are important reactive oxygen species targets, whose oxidation results in rapid, reversible, catalytic inactivation. Despite increasing evidence for the importance of protein-tyrosine phosphatase oxidation in signal transduction, the cell biological details of reactive oxygen species-catalyzed protein-tyrosine phosphatase inactivation have remained largely unclear, due to our inability to visualize protein-tyrosine phosphatase oxidation in cells. By combining proximity ligation assay with chemical labeling of cysteine residues in the sulfenic acid state, we visualize oxidized Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2). We find that platelet-derived growth factor evokes transient oxidation on or close to RAB5+/ early endosome antigen 1- endosomes. SHP2 oxidation requires NADPH oxidases (NOXs), and oxidized SHP2 co localizes with platelet-derived growth factor receptor and NOX1/4. Our data demonstrate spatially and temporally limited protein oxidation within cells, and suggest that platelet-derived growth factor-dependent "redoxosomes," contribute to proper signal transduction.Protein-tyrosine phosphatases (PTPs) are thought to be major targets of receptor-activated reactive oxygen species (ROS). Here the authors describe a method that allows the localized visualization of oxidized intermediates of PTPs inside cells during signaling, and provide support for the "redoxosome" model. PMID- 28878212 TI - Reconstructing cell cycle and disease progression using deep learning. AB - We show that deep convolutional neural networks combined with nonlinear dimension reduction enable reconstructing biological processes based on raw image data. We demonstrate this by reconstructing the cell cycle of Jurkat cells and disease progression in diabetic retinopathy. In further analysis of Jurkat cells, we detect and separate a subpopulation of dead cells in an unsupervised manner and, in classifying discrete cell cycle stages, we reach a sixfold reduction in error rate compared to a recent approach based on boosting on image features. In contrast to previous methods, deep learning based predictions are fast enough for on-the-fly analysis in an imaging flow cytometer.The interpretation of information-rich, high-throughput single-cell data is a challenge requiring sophisticated computational tools. Here the authors demonstrate a deep convolutional neural network that can classify cell cycle status on-the-fly. PMID- 28878213 TI - Contactless graphene conductivity mapping on a wide range of substrates with terahertz time-domain reflection spectroscopy. AB - We demonstrate how terahertz time-domain spectroscopy (THz-TDS) operating in reflection geometry can be used for quantitative conductivity mapping of large area chemical vapour deposited graphene films on sapphire, silicon dioxide/silicon and germanium. We validate the technique against measurements performed with previously established conventional transmission based THz-TDS and are able to resolve conductivity changes in response to induced back-gate voltages. Compared to the transmission geometry, measurement in reflection mode requires careful alignment and complex analysis, but circumvents the need of a terahertz transparent substrate, potentially enabling fast, contactless, in-line characterisation of graphene films on non-insulating substrates such as germanium. PMID- 28878214 TI - Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression. AB - Ovarian cancer have a poor overall survival rate in patients, and late disease presentation and chemoresistance are the main factors that lead to the mortality of ovarian cancer. Cancer stem cells (CSCs), a small subpopulation of cancer cells, have been associated with resistance to chemo- and radio-therapy in cancer treatment. Hypoxia is a common characteristic of many malignant tumors, and increased HIF-1alpha expression predicts the poor prognosis of ovarian cancer. In this study, we reported the relationship between hypoxia and cancer stem cells like properties in human ovarian cancer cell lines SKOV3 and HO8910, we found that hypoxia induced cancer stem cells-like properties in ovarian cancer cells. Moreover, SIRT1 was found to be the downstream target gene of HIF-1alpha, which was involved in the promotion of cancer stem cells-like features in ovarian cancer cells by hypoxia, and NF-kappaB signaling pathway was involved in hypoxia induced SIRT1 up-regulation. Our results hinted that HIF1alpha and SIRT1 might serve as potential therapeutic targets for ovarian cancer. PMID- 28878215 TI - Respiratory oscillations in alveolar oxygen tension measured in arterial blood. AB - Arterial oxygen partial pressure can increase during inspiration and decrease during expiration in the presence of a variable shunt fraction, such as with cyclical atelectasis, but it is generally presumed to remain constant within a respiratory cycle in the healthy lung. We measured arterial oxygen partial pressure continuously with a fast intra-vascular sensor in the carotid artery of anaesthetized, mechanically ventilated pigs, without lung injury. Here we demonstrate that arterial oxygen partial pressure shows respiratory oscillations in the uninjured pig lung, in the absence of cyclical atelectasis (as determined with dynamic computed tomography), with oscillation amplitudes that exceeded 50 mmHg, depending on the conditions of mechanical ventilation. These arterial oxygen partial pressure respiratory oscillations can be modelled from a single alveolar compartment and a constant oxygen uptake, without the requirement for an increased shunt fraction during expiration. Our results are likely to contribute to the interpretation of arterial oxygen respiratory oscillations observed during mechanical ventilation in the acute respiratory distress syndrome. PMID- 28878216 TI - Environmental stress is the major cause of transcriptomic and proteomic changes in GM and non-GM plants. AB - The approval of genetically modified (GM) crops is preceded by years of intensive research to demonstrate safety to humans and environment. We recently showed that in vitro culture stress is the major factor influencing proteomic differences of GM vs. non-GM plants. This made us question the number of generations needed to erase such "memory". We also wondered about the relevance of alterations promoted by transgenesis as compared to environment-induced ones. Here we followed three rice lines (1-control, 1-transgenic and 1-negative segregant) throughout eight generations after transgenesis combining proteomics and transcriptomics, and further analyzed their response to salinity stress on the F6 generation. Our results show that: (a) differences promoted during genetic modification are mainly short-term physiological changes, attenuating throughout generations, and (b) environmental stress may cause far more proteomic/transcriptomic alterations than transgenesis. Based on our data, we question what is really relevant in risk assessment design for GM food crops. PMID- 28878217 TI - In Vivo Confocal Microscopy Evaluation of Ocular Surface with Graft-Versus-Host Disease-Related Dry Eye Disease. AB - Dry eye disease (DED) is often elicited by graft-versus-host disease (GVHD), an extensive complication of hematopoietic stem cell transplantation (HSCT). To unravel the mechanism of this type of DED, in vivo confocal microscopy (IVCM) was used to investigate alterations in the state of the sub-basal nerves, dendritic cells (DCs) and globular immune cells (GICs) in the central cornea and limbal epithelia. In this study, we examined 12 HSCT recipients with GVHD-caused DED and 10 HSCT recipients without GVHD-associated DED and evaluated the clinical parameters in the 2 groups. Analysis of the central cornea and limbal epithelia using IVCM was conducted to investigate the density of the corneal sub-basal nerves, DCs and GICs as well as the tortuosity and branching of the sub-basal nerves. As suggested by our data, the clinical variables in the GVHD group were significantly different from those in the non-GVHD group. Additionally, GVHD triggered DED conceivably increased the density of DCs and GICs in the central cornea and the density of DCs in limbal epithelia and altered the morphology of the sub-basal nerves. These phenomena are presumably correlated with the degree of inflammation. Thus, our findings may be translated into non-invasive diagnostic methods that indicate the severity of inflammation on the ocular surface in HSCT recipients. PMID- 28878218 TI - Lack of Evidence for Vasoactive and Inflammatory Mediators in the Promotion of Macular Edema Associated with Epiretinal Membranes. AB - The development of symptoms in patients with epiretinal membranes (ERMs) often corresponds with the accumulation of interstitial fluid in the retina [i.e., the development of macular edema, (ME)]. To explore the potential value of pharmacologic therapeutic options to treat ME in patients with ERMs, we examine here the expression of vasoactive and inflammatory mediators in the vitreous of patients with idiopathic ERMs. We observed that vitreous concentrations of classic vasoactive factors (e.g., vascular endothelial growth factor) were similar in ERM patients with ME compared to controls. Using an array assessing the expression of 102 inflammatory cytokines we similarly did not observe a marked difference in cytokine expression in the vitreous of most ERM patients with ME compared to control patients. While the array data did implicate a group of inflammatory cytokines that were elevated in a subset of ERM patients who had severe ME (central subfield thickness >=450 MUm on spectral domain optical coherence tomography), expression of 3 of these inflammatory cytokines, all previously implicated in the promotion of ME in ischemic retinal disease, were not elevated by quantitative enzyme-linked immunosorbent assay. We conclude that therapies modulating vasoactive mediators or inflammatory cytokines may not affect ME in ERM patients. PMID- 28878219 TI - Carnot efficiency is reachable in an irreversible process. AB - In thermodynamics, there exists a conventional belief that "the Carnot efficiency is reachable only in the reversible (zero entropy production) limit of nearly reversible processes." However, there is no theorem proving that the Carnot efficiency is unattainable in an irreversible process. Here, we show that the Carnot efficiency is reachable in an irreversible process through investigation of the Feynman-Smoluchowski ratchet (FSR). We also show that it is possible to enhance the efficiency by increasing the irreversibility. Our result opens a new possibility of designing an efficient heat engine in a highly irreversible process and also answers the long-standing question of whether the FSR can operate with the Carnot efficiency. PMID- 28878221 TI - Combining Positive Matrix Factorization and Radiocarbon Measurements for Source Apportionment of PM2.5 from a National Background Site in North China. AB - To explore the utility of combining positive matrix factorization (PMF) with radiocarbon (14C) measurements for source apportionment, we applied PM2.5 data collected for 14 months at a national background station in North China to PMF models. The solutions were compared to 14C results of four seasonally averaged samples and three outlier samples. Comparing the most readily interpretable PMF solutions and 14C results revealed that PMF modeling was well able to capture the source patterns of PM2.5 with two and three irrelevant source classifications for the seasonal and outlier samples. The contribution of sources that could not be classified as either fossil or non-fossil sources in the PMF solution, and the errors between the modeled and measured concentrations weakened the effectiveness of the comparison. Based on these two factors, we developed an index for selecting the most suitable 14C measurement samples for combining with the PMF model. Then we examined the potential for coupling PMF modeling and 14C data with a constrained PMF run using the 14C data as a priori information. The restricted run could provide a more reliable solution; however, the PMF model must provide a flexible dialog to input the priori restrictions for executing the constraint simulation. PMID- 28878220 TI - Lactoferrin-derived Peptides Active towards Influenza: Identification of Three Potent Tetrapeptide Inhibitors. AB - Bovine lactoferrin is a biglobular multifunctional iron binding glycoprotein that plays an important role in innate immunity against infections. We have previously demonstrated that selected peptides from bovine lactoferrin C-lobe are able to prevent both Influenza virus hemagglutination and cell infection. To deeper investigate the ability of lactoferrin derived peptides to inhibit Influenza virus infection, in this study we identified new bovine lactoferrin C-lobe derived sequences and corresponding synthetic peptides were synthesized and assayed to check their ability to prevent viral hemagglutination and infection. We identified three tetrapeptides endowed with broad anti-Influenza activity and able to inhibit viral infection in a concentration range femto- to picomolar. Our data indicate that these peptides may constitute a non-toxic tool for potential applications as anti-Influenza therapeutics. PMID- 28878222 TI - Angiotensin II induces cholesterol accumulation and injury in podocytes. AB - Angiotensin II (Ang II) is a risk factor for the initiation and progression of chronic kidney disease (CKD), as elevated Ang II levels can lead to podocyte injury. However, there have been no studies on the role of Ang II in lipid metabolism or on podocyte injury caused by lipid dysfunction. Our study showed that Ang II induced lipid droplet (LD) accumulation and expression of the LD marker adipose differentiation-related protein (ADRP) in podocytes, and the extent of lipid deposition could be alleviated by losartan. Our study also demonstrated that Ang II increased the content of cholesterol in podocytes, which is an LD component, and this change was accompanied by decreased expression of the cholesterol efflux-related molecule ATP-binding cassette transporter-1 (ABCA1) and increased expression of the cholesterol uptake-related molecule LDL receptor (LDLR) and the cholesterol synthesis-related molecules sterol regulatory element-binding protein (SREBP1 and SREBP2) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR). Pretreating podocytes with methyl-beta-cyclodextrin (CD), which induces cholesterol efflux, decreased Ang II-mediated cholesterol accumulation and Ang II-induced podocyte apoptosis and maintained the podocyte cytoskeleton and spreading. These results suggested that Ang II induced podocyte cholesterol accumulation by regulating the expression of cholesterol metabolism related molecules and that the subsequent cholesterol metabolism dysfunction resulted in podocyte injury. PMID- 28878223 TI - Process design of microdomains with quantum mechanics for giant pulse lasers. AB - The power scaling of laser devices can contribute to the future of humanity. Giant microphotonics have been advocated as a solution to this issue. Among various technologies in giant microphotonics, process control of microdomains with quantum mechanical calculations is expected to increase the optical power extracted per unit volume in gain media. Design of extensive variables influencing the Gibbs energy of controlled microdomains in materials can realize desired properties. Here we estimate the angular momentum quantum number of rare earth ions in microdomains. Using this process control, we generate kilowatt level laser output from orientation-controlled microdomains in a laser gain medium. We also consider the limitations of current samples, and discuss the prospects of power scaling and applications of our technology. This work overturns at least three common viewpoints in current advanced technologies, including material processing based on magnetohydrodynamics, grain-size control of transparent polycrystals in fine ceramics, and the crystallographic symmetry of laser ceramics in photonics. PMID- 28878224 TI - Mild intracellular acidification by dexamethasone attenuates mitochondrial dysfunction in a human inflammatory proximal tubule epithelial cell model. AB - Septic acute kidney injury (AKI) associates with poor survival rates and often requires renal replacement therapy. Glucocorticoids may pose renal protective effects in sepsis via stimulation of mitochondrial function. Therefore, we studied the mitochondrial effects of dexamethasone in an experimental inflammatory proximal tubule epithelial cell model. Treatment of human proximal tubule epithelial cells with lipopolysaccharide (LPS) closely resembles pathophysiological processes during endotoxaemia, and led to increased cytokine excretion rates and cellular reactive oxygen species levels, combined with a reduced mitochondrial membrane potential and respiratory capacity. These effects were attenuated by dexamethasone. Dexamethasone specifically increased the expression and activity of mitochondrial complex V (CV), which could not be explained by an increase in mitochondrial mass. Finally, we demonstrated that dexamethasone acidified the intracellular milieu and consequently reversed LPS induced alkalisation, leading to restoration of the mitochondrial function. This acidification also provides an explanation for the increase in CV expression, which is expected to compensate for the inhibitory effect of the acidified environment on this complex. Besides the mechanistic insights into the beneficial effects of dexamethasone during renal cellular inflammation, our work also supports a key role for mitochondria in this process and, hence, provides novel therapeutic avenues for the treatment of AKI. PMID- 28878226 TI - Ultrafast isomerization in acetylene dication after carbon K-shell ionization. AB - Ultrafast proton migration and isomerization are key processes for acetylene and its ions. However, the mechanism for ultrafast isomerization of acetylene [HCCH]2+ to vinylidene [H2CC]2+ dication remains nebulous. Theoretical studies show a large potential barrier ( > 2 eV) for isomerization on low-lying dicationic states, implying picosecond or longer isomerization timescales. However, a recent experiment at a femtosecond X-ray free-electron laser suggests sub-100 fs isomerization. Here we address this contradiction with a complete theoretical study of the dynamics of acetylene dication produced by Auger decay after X-ray photoionization of the carbon atom K shell. We find no sub-100 fs isomerization, while reproducing the salient features of the time-resolved Coulomb imaging experiment. This work resolves the seeming contradiction between experiment and theory and also calls for careful interpretation of structural information from the widely applied Coulomb momentum imaging method.The timescale of isomerization in molecules involving ultrafast migration of constituent atoms is difficult to measure. Here the authors report that sub-100 fs isomerization time on acetylene dication in lower electronic states is not possible and point to misinterpretation of recent experimental results. PMID- 28878227 TI - Intermittent muscle activity in the feedback loop of postural control system during natural quiet standing. AB - The origin of continual body oscillation during quiet standing is a neural muscular-skeletal closed feedback loop system that includes insufficient joint stiffness and a time delay. Thus, muscle activity and joint oscillations are nonlinear during quiet standing, making it difficult to demonstrate the muscular skeletal relationship experimentally. Here we experimentally revealed this relationship using intermittent control theory, in which non-actuation works to stabilize the skeletal system towards equilibrium. We found that leg muscles were activated/inactivated when the state point was located in the opposite/same direction as the direction of anatomical action, which was associated with joint torque actuating the body towards equilibrium. The derivative values of stability index defined in the phase space approximately 200 ms before muscle inactivation were also larger than those before activation for some muscles. These results indicate that bipedal standing might be achieved by monitoring the rate of change of stability/instability components and generating joint torque to stabilize the body. In conclusion, muscles are likely to activate in an event-driven manner during quiet standing and a possible metric for on/off switching is SI dot, and our methodology of EMG processing could allows us to extract such event-driven intermittent muscle activities. PMID- 28878225 TI - The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway. AB - Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides. Thus, DCA was used in the 70 s to treat diabetes mellitus, hyperlipoproteinemia and hypercholesterolemia with satisfactory results. However, the mechanism of action remained unknown and we describe it here. DCA increases LDLR mRNA and protein levels as well as LDL intake in several cell lines, primary human hepatocytes and two different mouse models. This effect is mediated by transcriptional activation as evidenced by H3 acetylation on lysine 27 on the LDLR promoter. DCA induces expression of the MAPK ERK5 that turns on the transcription factor MEF2. Inhibition of this ERK5/MEF2 pathway by genetic or pharmacological means decreases LDLR expression and LDL intake. In summary, our results indicate that DCA, by inducing OXPHOS, promotes ERK5/MEF2 activation leading to LDLR expression. The ERK5/MEF2 pathway offers an interesting pharmacological target for drug development. PMID- 28878228 TI - In-line balanced detection stimulated Raman scattering microscopy. AB - We introduce a novel configuration for stimulated Raman scattering (SRS) microscopy, called In-line Balanced Detection (IBD), which employs a birefringent plate to generate a time-delayed polarization-multiplexed collinear replica of the probe, acting as a reference. Probe and reference cross the sample at the same position, thus maintaining their balance during image acquisition. IBD can be implemented in any conventional SRS setup, by adding a few simple elements, bringing its sensitivity close to the shot-noise limit even with a noisy laser. We tested IBD with a fiber-format laser system and observed signal-to-noise ratio improvement by up to 30 dB. PMID- 28878230 TI - Halotolerant aminopeptidase M29 from Mesorhizobium SEMIA 3007 with biotechnological potential and its impact on biofilm synthesis. AB - The aminopeptidase gene from Mesorhizobium SEMIA3007 was cloned and overexpressed in Escherichia coli. The enzyme called MesoAmp exhibited optimum activity at pH 8.5 and 45 degrees C and was strongly activated by Co2+ and Mn2+. Under these reaction conditions, the enzyme displayed Km and kcat values of 0.2364 +/- 0.018 mM and 712.1 +/- 88.12 s-1, respectively. Additionally, the enzyme showed remarkable stability in organic solvents and was active at high concentrations of NaCl, suggesting that the enzyme might be suitable for use in biotechnology. MesoAmp is responsible for 40% of the organism's aminopeptidase activity. However, the enzyme's absence does not affect bacterial growth in synthetic broth, although it interfered with biofilm synthesis and osmoregulation. To the best of our knowledge, this report describes the first detailed characterization of aminopeptidase from Mesorhizobium and suggests its importance in biofilm formation and osmotic stress tolerance. In summary, this work lays the foundation for potential biotechnological applications and/or the development of environmentally friendly technologies and describes the first solvent- and halo tolerant aminopeptidases identified from the Mesorhizobium genus and its importance in bacterial metabolism. PMID- 28878229 TI - Hydrogen bond based smart polymer for highly selective and tunable capture of multiply phosphorylated peptides. AB - Multisite phosphorylation is an important and common mechanism for finely regulating protein functions and subsequent cellular responses. However, this study is largely restricted by the difficulty to capture low-abundance multiply phosphorylated peptides (MPPs) from complex biosamples owing to the limitation of enrichment materials and their interactions with phosphates. Here we show that smart polymer can serve as an ideal platform to resolve this challenge. Driven by specific but tunable hydrogen bonding interactions, the smart polymer displays differential complexation with MPPs, singly phosphorylated and non-modified peptides. Importantly, MPP binding can be modulated conveniently and precisely by solution conditions, resulting in highly controllable MPP adsorption on material surface. This facilitates excellent performance in MPP enrichment and separation from model proteins and real biosamples. High enrichment selectivity and coverage, extraordinary adsorption capacities and recovery towards MPPs, as well as high discovery rates of unique phosphorylation sites, suggest its great potential in phosphoproteomics studies.Capture of low-abundance multiply phosphorylated peptides (MPPs) is difficult due to limitation of enrichment materials and their interactions with phosphates. Here the authors show, a smart polymer driven by specific but tunable hydrogen bonding interactions can differentially complex with MPPs, singly phosphorylated and non-modified peptides. PMID- 28878232 TI - Holographic Writing of Ink-Based Phase Conjugate Nanostructures via Laser Ablation. AB - The optical phase conjugation (OPC) through photonic nanostructures in coherent optics involves the utilization of a nonlinear optical mechanism through real time processing of electromagnetic fields. Their applications include spectroscopy, optical tomography, wavefront sensing, and imaging. The development of functional and personalized holographic devices in the visible and near infrared spectrum can be improved by introducing cost-effective, rapid, and high throughput fabrication techniques and low-cost recording media. Here, we develop flat and thin phase-conjugate nanostructures on low-cost ink coated glass substrates through a facile and flexible single pulsed nanosecond laser based reflection holography and a cornercube retroreflector (CCR). Fabricated one/two dimensional (1D/2D) nanostructures exhibited far-field phase-conjugated patterns through wavefront reconstruction by means of diffraction. The optical phase conjugation property had correlation with the laser light (energy) and structural parameters (width, height and exposure angle) variation. The phase conjugated diffraction property from the recorded nanostructures was verified through spectral measurements, far-field diffraction experiments, and thermal imaging. Furthermore, a comparison between the conventional and phase-conjugated nanostructures showed two-fold increase in diffracted light intensity under monochromatic light illumination. It is anticipated that low-cost ink based holographic phase-conjugate nanostructures may have applications in flexible and printable displays, polarization-selective flat waveplates, and adaptive diffraction optics. PMID- 28878231 TI - Dietary iron restriction alleviates renal tubulointerstitial injury induced by protein overload in mice. AB - Increased proteinuria causes tubulointerstitial injury due to inflammation in chronic kidney disease (CKD). Iron restriction exhibits protective effects against renal dysfunction; however, its effects against protein overload-induced tubulointerstitial damage remain unclear. Here, we investigated dietary iron restriction effect on tubulointerstitial damage in mice with protein-overload tubulointerstitial injury. Renal tubulointerstitial injury in animal model was induced by intraperitoneal injection of an overdose of bovine serum albumin (BSA). We divided mice into three groups: normal saline + normal diet (ND), BSA + ND, and BSA + iron-restricted diet (IRD). BSA overload induced renal tubulointerstitial injury in the ND mice, which was ameliorated in the IRD mice. Inflammatory cytokines and extracellular matrix mRNA expression was upregulated in BSA + ND mice kidneys and was inhibited by IRD. BSA-induced increase in renal superoxide production, NADPH oxidase activity, and p22phox expression was diminished in the IRD mice. IRD suppression increased BSA-induced renal macrophage infiltration. Moreover, BSA mice exhibited nucleotide-binding oligomerisation domain-like receptor pyrin domain-containing protein (NLRP) inflammasome activation, which was inhibited by IRD. Ferrous iron increased in kidneys with BSA overload and was inhibited by IRD. Thus, iron restriction inhibited oxidative stress and inflammatory changes, contributing to the protective effect against BSA overload-induced tubulointerstitial injury. PMID- 28878233 TI - A chalcone derivative reactivates latent HIV-1 transcription through activating P TEFb and promoting Tat-SEC interaction on viral promoter. AB - The principal barrier to the eradication of HIV/AIDS is the existence of latent viral reservoirs. One strategy to overcome this barrier is to use latency reversing agents (LRAs) to reactivate the latent proviruses, which can then be eliminated by effective anti-retroviral therapy. Although a number of LRAs have been found to reactivate latent HIV, they have not been used clinically due to high toxicity and poor efficacy. In this study, we report the identification of a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV provirses and act synergistically with known LRAs such as prostratin and JQ1 to reverse latency. Amt-87 works by activating the human transcriptional elongation factor P-TEFb, a CDK9-cyclin T1 heterodimer that is part of the super elongation complex (SEC) used by the viral encoded Tat protein to activate HIV transcription. Amt-87 does so by promoting the phosphorylation of CDK9 at the T-loop, liberating P-TEFb from the inactive 7SK snRNP, and inducing the formation of the Tat-SEC complex at the viral promoter. Together, our data reveal chalcones as a promising category of compounds that should be further explored to identify effective LRAs for targeted reversal of HIV latency. PMID- 28878234 TI - Immunoregulation by IL-7R-targeting antibody-drug conjugates: overcoming steroid resistance in cancer and autoimmune disease. AB - Steroid-resistance is a common complication in the treatment of malignancies and autoimmune diseases. IL-7/IL-7R signaling, which regulates lymphocyte growth and survival, has been implicated in the development of malignancies and autoimmune diseases. However, the biological significance of IL-7/IL-7R signaling in steroid treatment is poorly understood. Here, we identified a novel relationship between IL-7R signaling and steroid-resistance, and showed that an anti-IL-7R antibody conjugated with SN-38 (A7R-ADC-SN-38) has strong anti-tumor effects against both parental and steroid-resistant malignant cells. Furthermore, inflammation in the mouse autoimmune arthritis model was suppressed to greater extent by A7R-ADC conjugated to MMAE than by A7R-ADC-SN-38. Given that an increased proportion of IL-7R-positive cells is a common mechanism underlying the pathogenesis of autoimmunity, we found that specific depletion of this cell population abrogated the progression of disease. This suggests that the cytotoxicity and immunosuppressive capacity of A7R-ADC could be modulated to treat specific malignancies or autoimmune diseases through the introduction of different payloads, and represents a novel alternative to steroid therapy. PMID- 28878235 TI - Seasonal and geographical impact on human resting periods. AB - We study the influence of seasonally and geographically related daily dynamics of daylight and ambient temperature on human resting or sleeping patterns using mobile phone data of a large number of individuals. We observe two daily inactivity periods in the people's aggregated mobile phone calling patterns and infer these to represent the resting times of the population. We find that the nocturnal resting period is strongly influenced by the length of daylight, and that its seasonal variation depends on the latitude, such that for people living in two different cities separated by eight latitudinal degrees, the difference in the resting periods of people between the summer and winter in southern cities is almost twice that in the northern cities. We also observe that the duration of the afternoon resting period is influenced by the temperature, and that there is a threshold from which this influence sets in. Finally, we observe that the yearly dynamics of the afternoon and nocturnal resting periods appear to be counterbalancing each other. This also lends support to the notion that the total daily resting time of people is more or less conserved across the year. PMID- 28878236 TI - Sponge bioerosion on changing reefs: ocean warming poses physiological constraints to the success of a photosymbiotic excavating sponge. AB - Excavating sponges are prominent bioeroders on coral reefs that in comparison to other benthic organisms may suffer less or may even benefit from warmer, more acidic and more eutrophic waters. Here, the photosymbiotic excavating sponge Cliona orientalis from the Great Barrier Reef was subjected to a prolonged simulation of both global and local environmental change: future seawater temperature, partial pressure of carbon dioxide (as for 2100 summer conditions under "business-as-usual" emissions), and diet supplementation with particulate organics. The individual and combined effects of the three factors on the bioerosion rates, metabolic oxygen and carbon flux, biomass change and survival of the sponge were monitored over the height of summer. Diet supplementation accelerated bioerosion rates. Acidification alone did not have a strong effect on total bioerosion or survival rates, yet it co-occurred with reduced heterotrophy. Warming above 30 degrees C (+2.7 degrees C above the local maximum monthly mean) caused extensive bleaching, lower bioerosion, and prevailing mortality, overriding the other factors and suggesting a strong metabolic dependence of the sponge on its resident symbionts. The growth, bioerosion capacity and likelihood of survival of C. orientalis and similar photosymbiotic excavating sponges could be substantially reduced rather than increased on end-of-the-century reefs under "business-as-usual" emission profiles. PMID- 28878237 TI - Two-dimensional photonic crystal Bragg lasers with triangular lattice for monolithic coherent beam combining. AB - We demonstrate an electrically pumped, single-mode, large area, edge-emitting InGaAsP/InP two-dimensional photonic crystal (PC) Bragg laser with triangular lattice. The laser operates in the single transverse and longitudinal modes with a single lobe, near-diffraction-limited far field. We compare the performance of the triangular-lattice PC Bragg laser with the rectangular-lattice PC Bragg laser fabricated from the same wafer and find that their performances are comparable. Then, we combine two single triangular-lattice PC Bragg lasers that tilt to opposite directions by taking advantage of the symmetry of the single emitter cavity mode. The measurement results show that the combined PC Bragg lasers provide the near-diffraction-limited output beam, and the single wavelength operation is also maintained in the coherently combined broad-area PC Bragg lasers. PMID- 28878239 TI - Mutation E87Q of the beta1-subunit impairs the maturation of the cardiac voltage dependent sodium channel. AB - Voltage-dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These membrane integral proteins are composed by a pore-forming alpha-subunit, and one or more auxiliary beta subunits. Mutation E87Q of the beta1 subunit is correlated with Brugada syndrome, a genetic disease characterised by ventricular fibrillation, right precordial ST segment elevation on ECG and sudden cardiac death. Heterologous expression of E87Q-beta1 subunit in CHO cells determines a reduced sodium channel functional expression. The effect the E87Q mutation of the beta1 subunit on sodium currents and alpha protein expression is correlated with a reduced availability of the mature form of the alpha subunit in the plasma membrane. This finding offers a new target for the treatment of the Brugada syndrome, based on protein maturation management. This work highlights the role played by the beta1 subunit in the maturation and expression of the entire sodium channel complex and underlines how the defective interaction between the sodium channel constituents could lead to a disabling pathological condition. PMID- 28878240 TI - Electron paramagnetic resonance microscopy using spins in diamond under ambient conditions. AB - Magnetic resonance spectroscopy is one of the most important tools in chemical and bio-medical research. However, sensitivity limitations typically restrict imaging resolution to ~ 10 um. Here we bring quantum control to the detection of chemical systems to demonstrate high-resolution electron spin imaging using the quantum properties of an array of nitrogen-vacancy centres in diamond. Our electron paramagnetic resonance microscope selectively images electronic spin species by precisely tuning a magnetic field to bring the quantum probes into resonance with the external target spins. This provides diffraction limited spatial resolution of the target spin species over a field of view of 50 * 50 um2 with a spin sensitivity of 104 spins per voxel or ~100 zmol. The ability to perform spectroscopy and dynamically monitor spin-dependent redox reactions at these scales enables the development of electron spin resonance and zepto chemistry in the physical and life sciences.Electron paramagnetic resonance spectroscopy has important scientific and medical uses but improving the resolution of conventional methods requires cryogenic, vacuum environments. Simpson et al. show nitrogen vacancy centres can be used for sub-micronmetre imaging with improved sensitivity in ambient conditions. PMID- 28878238 TI - APOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism. AB - Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n = 188; p = 0.004). The frequency of APOBEC3B-deletion alleles is ~50% in 143 genotyped oral squamous cell carcinoma -Taiwan samples (27A3B -/-:89A3B +/-:27A3B +/+), compared to the 5.8% found in 314 OSCC-TCGA samples. We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance. Our finding might be recapitulated by genomic studies in other cancer types.Oral squamous cell carcinoma is a prevalent malignancy in Taiwan. Here, the authors show that OSCC in Taiwanese show a frequent deletion polymorphism in the cytidine deaminases gene cluster APOBEC3 resulting in increased expression of A3A, which is shown to be of clinical prognostic relevance. PMID- 28878241 TI - Switching the unidirectional reflectionlessness by polarization in non-ideal PT metamaterial based on the phase coupling. AB - An effective scheme on switching the exceptional point(EP) where unidirectional reflectionlessness occurs is firstly proposed in non-ideal PT metamaterial via the polarization of incident light. The unidirectional reflectionlessness could be effectively controlled only by adjusting the phase coupling of the two resonators which are consisted of two identical but vertically placed crosses and are excited by incident light as an effective gain. Besides, the unidirectional perfect absorber occurs in the vicinity of EP. PMID- 28878242 TI - Increased PD-L1 expression and IL-6 secretion characterize human lung tumor derived perivascular-like cells that promote vascular leakage in a perfusable microvasculature model. AB - Pericytes represent important support cells surrounding microvessels found in solid organs. Emerging evidence points to their involvement in tumor progression and metastasis. Although reported to be present in the human lung, their specific presence and functional orientation within the tumor microenvironment in non small cell lung cancer (NSCLC) has not yet been adequately studied. Using a multiparameter approach, we prospectively identified, sorted and expanded mesenchymal cells from human primary NSCLC samples based on co-expression of CD73 and CD90 while lacking hematopoietic and endothelial lineage markers (CD45, CD31, CD14 and Gly-A) and the epithelial marker EpCAM. Compared to their normal counterpart, tumor-derived Lineage-EpCAM-CD73+CD90+ cells showed enhanced expression of the immunosuppressive ligand PD-L1, a higher constitutive secretion of IL-6 and increased basal alphaSMA levels. In an in vitro model of 3D microvessels, both tumor-derived and matched normal Lineage-EpCAM-CD73+CD90+ cells supported the assembly of perfusable vessels. However, tumor-derived Lineage-EpCAM-CD73+CD90+ cells led to the formation of vessels with significantly increased permeability. Together, our data show that perivascular-like cells present in NSCLC retain functional abnormalities in vitro. Perivascular-like cells as an eventual target in NSCLC warrants further investigation. PMID- 28878243 TI - The environmental impacts of one of the largest tailing dam failures worldwide. AB - The impacts of the SAMARCO iron tailing spill along more than 650 km, between the dam and the plume of the Doce River in the Atlantic, were assessed by the determination of toxic metals. The tailing spill caused a substantial increase in suspended sediment loads (up to 33,000 mg L-1), in addition to large depositions of waste along the Doce basin. The highest estimated transport of dissolved metals was observed for Fe (58.8 MUg s-1), Ba (37.9 MUg s-1) and Al (25.0 MUg s 1). Sediments reached the highest enrichment factors (EFs) for Hg (4,234), Co (133), Fe (43), and Ni (16), whereas As (55), Ba (64), Cr (16), Cu (17), Mn (41), Pb (38) and Zn (82) highest EFs were observed for suspended particulate matter (SPM). Iron, As, Hg, Mn exceeded sediment quality guidelines. Therefore, the risk of occurrence of adverse effects is highly possible, not only due to the dam failure, but also due to the Fe mining and the artisan Au mining. Heavy rain episodes will likely cause enhanced erosion, remobilization, and transport of contaminated particles, sustaining high inputs of SPM and metals for the years to come and threatening the ecosystem services. PMID- 28878244 TI - The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan. AB - In Saccharomyces cerevisiae, deletion of large ribosomal subunit protein-encoding genes increases the replicative lifespan in a Gcn4-dependent manner. However, how Gcn4, a key transcriptional activator of amino acid biosynthesis genes, increases lifespan, is unknown. Here we show that Gcn4 acts as a repressor of protein synthesis. By analyzing the messenger RNA and protein abundance, ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that Gcn4 is sufficient to reduce protein synthesis and increase yeast lifespan. Chromatin immunoprecipitation reveals Gcn4 binding not only at genes that are activated, but also at genes, some encoding ribosomal proteins, that are repressed upon Gcn4 overexpression. The promoters of repressed genes contain Rap1 binding motifs. Our data suggest that Gcn4 is a central regulator of protein synthesis under multiple perturbations, including ribosomal protein gene deletions, calorie restriction, and rapamycin treatment, and provide an explanation for its role in longevity and stress response.The transcription factor Gcn4 is known to regulate yeast amino acid synthesis. Here, the authors show that Gcn4 also acts as a repressor of protein biosynthesis in a range of conditions that enhance yeast lifespan, such as ribosomal protein knockout, calorie restriction or mTOR inhibition. PMID- 28878245 TI - Effects of Centella asiatica (L.) Urb. on cognitive function and mood related outcomes: A Systematic Review and Meta-analysis. AB - Centella asiatica (L.) Urb. has been used as an herbal brain tonic for mental disorders and enhancing memory, but no review of the overall evidence of C. asiatica and cognitive function has been conducted. This study aims to determine the effects of C. asiatica on cognitive function and its related properties. The current systematic review includes five randomized controlled trials (RCTs) conducted to determine the effect of C. asiatica alone and six RCTs conducted to determine the effect of C. asiatica-containing products. Meta-analysis indicated that there are no significant differences in all cognitive function domains of C. asiatica when compared to placebo. However, it could improve mood by increasing alert scores [SMD: 0.71 (95% CI; 0.01 to 1.41); I2 = 30.5%] and decreasing anger scores at 1 hour after treatment [SMD: -0.81 (95%CI; -1.51 to -0.09); I2 = 36.6%]. None of the studies reported adverse effects of C. asiatica. In conclusion, there is not strong evidence to support the use of C. asiatica for cognitive function improvement in each cognitive domain. C. asiatica could improve alertness and relieve anger. However, some limitations should be aware including dose regimen, plant preparation, standardization, and product variation. Future well-designed clinical trials using suitable doses of standardized C. asiatica are still needed. PMID- 28878246 TI - Loss of NR2E3 represses AHR by LSD1 reprogramming, is associated with poor prognosis in liver cancer. AB - The aryl hydrocarbon receptor (AHR) plays crucial roles in inflammation, metabolic disorder, and cancer. However, the molecular mechanisms regulating AHR expression remain unknown. Here, we found that an orphan nuclear NR2E3 maintains AHR expression, and forms an active transcriptional complex with transcription factor Sp1 and coactivator GRIP1 in MCF-7 human breast and HepG2 liver cancer cell lines. NR2E3 loss promotes the recruitment of LSD1, a histone demethylase of histone 3 lysine 4 di-methylation (H3K4me2), to the AHR gene promoter region, resulting in repression of AHR expression. AHR expression and responsiveness along with H3K4me2 were significantly reduced in the livers of Nr2e3rd7 (Rd7) mice that express low NR2E3 relative to the livers of wild-type mice. SP2509, an LSD1 inhibitor, fully restored AHR expression and H3K4me2 levels in Rd7 mice. Lastly, we demonstrated that both AHR and NR2E3 are significantly associated with good clinical outcomes in liver cancer. Together, our results reveal a novel link between NR2E3, AHR, and liver cancer via LSD1-mediated H3K4me2 histone modification in liver cancer development. PMID- 28878247 TI - A novel role of the soybean clock gene LUX ARRHYTHMO in male reproductive development. AB - The evening complex of ELF4-ELF3-LUX proteins is an integral component of a plant circadian clock. LUX ARRHYTHMO (LUX) is one of the key components of the evening complex, and that play a key role in circadian rhythms and flowering. Here, we report that diverged soybean LUX has the additional role in male reproductive development. We studied diurnal and circadian rhythms of soybean LUX (GmLUXa, GmLUXb, and GmLUXc) using qRT-PCR, and show its nuclear localisation by particle bombardment. Yeast-two hybrid (Y2H) studies indicate that both GmLUXb and GmLUXc form an evening complex with GmELF4b and GmELF3a, respectively. Ectopic expression of GmLUXb in Arabidopsis lux mutants can complement functions of AtLUX, whereas GmLUXc generates novel phenotypes of serrated leaves, stunted plants, shortened anther filament, and low seed set. Overall, our results suggest that the LUX gene has diverged in soybean where GmLUXb and GmLUXc share the role to control flowering time, but GmLUXc has evolved to regulate anther filament growth and seed set by regulating the Gibberellin hormone biosynthesis pathway. PMID- 28878248 TI - Mechanisms of charge transfer and electronic properties of Cu2ZnGeS4 from investigations of the high-field magnetotransport. AB - Recent development of the thin film solar cells, based on quaternary compounds, has been focused on the Ge contain compounds and their solid solutions. However, for effective utilization of Cu2ZnGeS4, deeper investigations of its transport properties are required. In the present manuscript, we investigate resistivity, rho (T), magnetoresistance and Hall effect in p-type Cu2ZnGeS4 single crystals in pulsed magnetic fields up to 20 T. The dependence of rho (T) in zero magnetic field is described by the Mott type of the variable-range hopping (VRH) charge transfer mechanism within a broad temperature interval of ~100-200 K. Magnetoresistance contains the positive and negative components, which are interpreted by the common reasons of doped semiconductors. On the other hand, a joint analysis of the resistivity and magnetoresistance data has yielded series of important electronic parameters and permitted specification of the Cu2ZnGeS4 conductivity mechanisms outside the temperature intervals of the Mott VRH conduction. The Hall coefficient is negative, exhibiting an exponential dependence on temperature, which is quite close to that of rho(T). This is typical of the Hall effect in the domain of the VRH charge transfer. PMID- 28878249 TI - Erratum: Localization of Laplacian eigenvectors on random networks. AB - A correction to this Article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 28878250 TI - Improving understanding of the functional diversity of fisheries by exploring the influence of global catch reconstruction. AB - Functional diversity is thought to enhance ecosystem resilience, driving research focused on trends in the functional composition of fisheries, most recently with new reconstructions of global catch data. However, there is currently little understanding of how accounting for unreported catches (e.g. small-scale and illegal fisheries, bycatch and discards) influences functional diversity trends in global fisheries. We explored how diversity estimates varied among reported and unreported components of catch in 2010, and found these components had distinct functional fingerprints. Incorporating unreported catches had little impact on global-scale functional diversity patterns. However, at smaller, management-relevant scales, the effects of incorporating unreported catches were large (changes in functional diversity of up to 46%). Our results suggest there is greater uncertainty about the risks to ecosystem integrity and resilience from current fishing patterns than previously recognized. We provide recommendations and suggest a research agenda to improve future assessments of functional diversity of global fisheries. PMID- 28878251 TI - Effects of biochar, waste water irrigation and fertilization on soil properties in West African urban agriculture. AB - In large areas of sub-Saharan Africa crop production must cope with low soil fertility. To increase soil fertility, the application of biochar (charred biomass) has been suggested. In urban areas, untreated waste water is widely used for irrigation because it is a nutrient-rich year-round water source. Uncertainty exists regarding the interactions between soil properties, biochar, waste water and fertilization over time. The aims of this study were to determine these interactions in two typical sandy, soil organic carbon (SOC) and nutrient depleted soils under urban vegetable production in Tamale (Ghana) and Ouagadougou (Burkina Faso) over two years. The addition of biochar at 2 kg m-2 made from rice husks and corn cobs initially doubled SOC stocks but SOC losses of 35% occurred thereafter. Both biochar types had no effect on soil pH, phosphorous availability and effective cation exchange capacity (CEC) but rice husk biochar retained nitrogen (N). Irrigation with domestic waste water increased soil pH and exchangeable sodium over time. Inorganic fertilization alone acidified soils, increased available phosphorous and decreased base saturation. Organic fertilization increased SOC, N and CEC. The results from both locations demonstrate that the effects of biochar and waste water were less pronounced than reported elsewhere. PMID- 28878252 TI - Efficient Bioimaging with Diaminodicyanoquinodimethanes: Selective Imaging of Epidermal and Stomatal Cells and Insight into the Molecular Level Interactions. AB - The enhanced fluorescence emission of diaminodicyanoquinodimethanes (DADQs) in rigid and aggregated states holds great promise for bioimaging applications. This is demonstrated through their efficient application in epidermal and stomatal imaging with selective staining of cell walls and nuclei. Major advantages include the small quantities (a few nmols) of the fluorophore required, choice of DADQs soluble in water and organic solvents, and quick staining of the specimen in buffer-free state and in buffer medium. The molecular level interactions that enable staining are unraveled through isothermal calorimetry, infra-red spectroscopy and microscopy with energy dispersive X-ray spectroscopy analysis. It is proposed that DADQs with ionic or H-bonding functionalities bind to the polygalacturonic acid moieties in the epidermal layer; the former can bind also to nucleic acid polyanions. Fluorescence experiments explain the emission enhancement that enables the efficient imaging. DADQs are easy to synthesize, non cytotoxic, and thermally, chemically and photo-stable, requiring no special storage conditions; preliminary experiments point to their potential utility in imaging different classes of cells. PMID- 28878253 TI - Erratum: Solitonic conduction of electrotonic signals in neuronal branchlets with polarized microstructure. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28878254 TI - Germline Mutations in Cancer Predisposition Genes are Frequent in Sporadic Sarcomas. AB - Associations of sarcoma with inherited cancer syndromes implicate genetic predisposition in sarcoma development. However, due to the apparently sporadic nature of sarcomas, little attention has been paid to the role genetic susceptibility in sporadic sarcoma. To address this, we performed targeted genomic sequencing to investigate the prevalence of germline mutations in known cancer-associated genes within an Asian cohort of sporadic sarcoma patients younger than 50 years old. We observed 13.6% (n = 9) amongst 66 patients harbour at least one predicted pathogenic germline mutation in 10 cancer-associated genes including ATM, BRCA2, ERCC4, FANCC, FANCE, FANCI, MSH6, POLE, SDHA and TP53. The most frequently affected genes are involved in the DNA damage repair pathway, with a germline mutation prevalence of 10.6%. Our findings suggests that genetic predisposition plays a larger role than expected in our Asian cohort of sporadic sarcoma, therefore clinicians should be aware of the possibility that young sarcoma patients may be carriers of inherited mutations in cancer genes and should be considered for genetic testing, regardless of family history. The prevalence of germline mutations in DNA damage repair genes imply that therapeutic strategies exploiting the vulnerabilities resulting from impaired DNA repair may be promising areas for translational research. PMID- 28878255 TI - Adaptive aggregation by spider mites under predation risk. AB - Grouping together is a commonly observed anti-predator strategy. Possible anti predator benefits of aggregation include the encounter/avoidance effect for visually hunting predators and the dilution effect, together dubbed attack abatement. Possible costs opposing the dilution effect are easier detection of aggregated than scattered individuals. The benefits of attack abatement, and opposing costs after group detection, are poorly understood for chemosensory predator-prey interactions. We tackled this issue by assessing the aggregation behavior of spider mites Tetranychus urticae under predation risk emanating from predatory mites Phytoseiulus persimilis. We examined whether adult spider mite females aggregate more tightly when perceiving predator cues (traces left and eggs), representing graded risk levels, and whether grouping enhances survival in physical predator presence. The spider mites aggregated more tightly and were more active in presence than absence of predator cues. Grouped spider mites were less likely and later detected and attacked than scattered spider mites. Moreover, encounter and attack of one group member did not increase the risk of other members to be attacked, as compared to scattered spider mites. To the best of our knowledge, our study is the first rigorous documentation of the adaptive benefit of tightened prey aggregation towards a purely chemosensorily hunting predator. PMID- 28878256 TI - Non-parametric genetic prediction of complex traits with latent Dirichlet process regression models. AB - Using genotype data to perform accurate genetic prediction of complex traits can facilitate genomic selection in animal and plant breeding programs, and can aid in the development of personalized medicine in humans. Because most complex traits have a polygenic architecture, accurate genetic prediction often requires modeling all genetic variants together via polygenic methods. Here, we develop such a polygenic method, which we refer to as the latent Dirichlet process regression model. Dirichlet process regression is non-parametric in nature, relies on the Dirichlet process to flexibly and adaptively model the effect size distribution, and thus enjoys robust prediction performance across a broad spectrum of genetic architectures. We compare Dirichlet process regression with several commonly used prediction methods with simulations. We further apply Dirichlet process regression to predict gene expressions, to conduct PrediXcan based gene set test, to perform genomic selection of four traits in two species, and to predict eight complex traits in a human cohort.Genetic prediction of complex traits with polygenic architecture has wide application from animal breeding to disease prevention. Here, Zeng and Zhou develop a non-parametric genetic prediction method based on latent Dirichlet Process regression models. PMID- 28878257 TI - Molecular mechanisms governing microRNA-125a expression in human hepatocellular carcinoma cells. AB - MicroRNA-125a-5p (miR-125a) is a vertebrate homolog of lin-4, the first discovered microRNA, and plays a fundamental role in embryo development by downregulating Lin-28 protein. MiR-125a is also expressed in differentiated cells where it generally acts as an antiproliferative factor by targeting membrane receptors or intracellular transductors of mitogenic signals. MiR-125a expression is downregulated in several tumors, including hepatocellular carcinoma (HCC) where it targets sirtuin-7, matrix metalloproteinase-11, VEGF-A, Zbtb7a, and c Raf. In this study, we have isolated the transcription promoter of human miR-125a and characterized its activity in HCC cells. It is a TATA-less Pol II promoter provided with an initiator element and a downstream promoter element, located 3939 bp upstream the genomic sequence of the miRNA. The activity of the promoter is increased by the transcription factor NF-kB, a master regulator of inflammatory response, and miR-125a itself was found to strengthen this activation through inhibition of TNFAIP3, a negative regulator of NF-kB. This finding contributes to explain the increased levels of miR-125a observed in the liver of patients with chronic hepatitis B. PMID- 28878258 TI - Oxidative damage and impairment of protein quality control systems in keratinocytes exposed to a volatile organic compounds cocktail. AB - Compelling evidence suggests that volatile organic compounds (VOCs) have potentially harmful effects to the skin. However, knowledge about cellular signaling events and toxicity subsequent to VOC exposure to human skin cells is still poorly documented. The aim of this study was to focus on the interaction between 5 different VOCs (hexane, toluene, acetaldehyde, formaldehyde and acetone) at doses mimicking chronic low level environmental exposure and the effect on human keratinocytes to get better insight into VOC-cell interactions. We provide evidence that the proteasome, a major intracellular proteolytic system which is involved in a broad array of processes such as cell cycle, apoptosis, transcription, DNA repair, protein quality control and antigen presentation, is a VOC target. Proteasome inactivation after VOC exposure is accompanied by apoptosis, DNA damage and protein oxidation. Lon protease, which degrades oxidized, dysfunctional, and misfolded proteins in the mitochondria is also a VOC target. Using human skin explants we found that VOCs prevent cell proliferation and also inhibit proteasome activity in vivo. Taken together, our findings provide insight into potential mechanisms of VOC-induced proteasome inactivation and the cellular consequences of these events. PMID- 28878260 TI - alpha7 nicotinic acetylcholine receptor signaling modulates the inflammatory phenotype of fetal brain microglia: first evidence of interference by iron homeostasis. AB - Neuroinflammation in utero may result in life-long neurological disabilities. Microglia play a pivotal role, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of microglia. We hypothesized that agonism on alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of alpha7nAChR will achieve the opposite. Using an in vivo - in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep microglia cultures re-exposed to LPS in presence of a selective alpha7nAChR agonist or antagonist. Our RNAseq and protein level findings show that a pro-inflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with alpha7nAChR agonistic stimulation. Conversely, antagonistic alpha7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated alpha7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of alpha7nAChR agonists in early re-programming of microglia in neonates exposed to in utero inflammation via an endogenous cerebral cholinergic anti-inflammatory pathway. Future studies will assess the role of interactions between inflammation triggered microglial iron sequestering and alpha7nAChR signaling in neurodevelopment. PMID- 28878261 TI - Accelerated oral wound healing using a pre-vascularized mucosal cell sheet. AB - Cell sheets with pre-vascularization have recently been developed but remain relatively untested in oral wound healing. Therefore, we examined the potential utility of our newly developed pre-vascularized mucosal cell sheets in oral wound healing. Mucosal keratinocytes, fibroblasts, and endothelial progenitor cells were primarily cultured for in vitro cell expansion from mucosa and blood of Sprague-Dawley rats. Mucosal cell sheets were generated using cultured keratinocytes and plasma fibrin (K sheet) or keratinocytes and a mixture of fibrin, fibroblasts, and endothelial cells (PV sheet). Autologous sheets were transplanted on deep wounds in the buccal region of rats. The gross and histological characteristics of wound healing were compared among control wound, K sheet, and PV sheet groups. We successfully cultured and expanded keratinocytes, fibroblasts, and endothelial progenitor cells in vitro for generating mucosal cell sheets with or without pre-vascularization. In the in vivo oral wound model, compared with the control wound, the PV sheet group exhibited rapid wound closure more prominently than the K sheet group. The histological healing in the PV sheet group was similar to that in rat normal buccal mucosa without fibrosis. The pre-vascularized mucosal cell sheet exhibited in vivo efficacy in oral wound healing by promoting accelerated healing. PMID- 28878262 TI - Hyper-O-GlcNAcylation induces cisplatin resistance via regulation of p53 and c Myc in human lung carcinoma. AB - Aberrant metabolism in hexosamine biosynthetic pathway (HBP) has been observed in several cancers, affecting cellular signaling and tumor progression. However, the role of O-GlcNAcylation, a post-translational modification through HBP flux, in apoptosis remains unclear. Here, we found that hyper-O-GlcNAcylation in lung carcinoma cells by O-GlcNAcase inhibition renders the cells to apoptosis resistance to cisplatin (CDDP). Profiling of various key regulatory proteins revealed an implication of either p53 or c-Myc in the apoptosis regulation by O GlcNAcylation, independent of p53 status. Using co-immunoprecipitation and correlation analyses, we found that O-GlcNAcylation of p53 under certain cellular contexts, i.e. high p53 activation, promotes its ubiquitin-mediated proteasomal degradation, resulting in a gain of oncogenic and anti-apoptotic functions. By contrast, O-GlcNAcylation of c-Myc inhibits its ubiquitination and subsequent proteasomal degradation. Gene manipulation studies revealed that O-GlcNAcylation of p53/c-Myc is in part a regulator of CDDP-induced apoptosis. Accordingly, we classified CDDP resistance by hyper-O-GlcNAcylation in lung carcinoma cells as either p53 or c-Myc dependence based on their molecular targets. Together, our findings provide novel mechanisms for the regulation of lung cancer cell apoptosis that could be important in understanding clinical drug resistance and suggest O-GlcNAcylation as a potential target for cancer therapy. PMID- 28878259 TI - Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster. AB - The accumulation of dysfunctional mitochondria has been implicated in aging, but a deeper understanding of mitochondrial dynamics and mitophagy during aging is missing. Here, we show that upregulating Drp1-a Dynamin-related protein that promotes mitochondrial fission-in midlife, prolongs Drosophila lifespan and healthspan. We find that short-term induction of Drp1, in midlife, is sufficient to improve organismal health and prolong lifespan, and observe a midlife shift toward a more elongated mitochondrial morphology, which is linked to the accumulation of dysfunctional mitochondria in aged flight muscle. Promoting Drp1 mediated mitochondrial fission, in midlife, facilitates mitophagy and improves both mitochondrial respiratory function and proteostasis in aged flies. Finally, we show that autophagy is required for the anti-aging effects of midlife Drp1 mediated mitochondrial fission. Our findings indicate that interventions that promote mitochondrial fission could delay the onset of pathology and mortality in mammals when applied in midlife.Mitochondrial fission and fusion are important mechanisms to maintain mitochondrial function. Here, the authors report that middle-aged flies have more elongated, or 'hyper-fused' mitochondria, and show that induction of mitochondrial fission in midlife, but not in early life, extends the health and life of flies. PMID- 28878263 TI - A progesterone-brown fat axis is involved in regulating fetal growth. AB - Pregnancy is associated with profound maternal metabolic changes, necessary for the growth and development of the fetus, mediated by reproductive signals acting on metabolic organs. However, the role of brown adipose tissue (BAT) in regulating gestational metabolism is unknown. We show that BAT phenotype is lost in murine pregnancy, while there is a gain of white adipose tissue (WAT)-like features. This is characterised by reduced thermogenic capacity and mitochondrial content, accompanied by increased levels of markers of WAT and lipid accumulation. Surgical ablation of BAT prior to conception caused maternal and fetal hyperlipidemia, and consequently larger fetuses. We show that BAT phenotype is altered from day 5 of gestation, implicating early pregnancy factors, which was confirmed by reduced expression of BAT markers in progesterone challenged oophorectomised mice. Moreover, in vitro data using primary BAT cultures show a direct impact of progesterone on expression of Ucp1. These data demonstrate that progesterone mediates a phenotypic change in BAT, which contributes to the gestational metabolic environment, and thus overall fetal size. PMID- 28878264 TI - Manipulation of acoustic wavefront by gradient metasurface based on Helmholtz Resonators. AB - We designed a gradient acoustic metasurface to manipulate acoustic wavefront freely. The broad bandwidth and high efficiency transmission are achieved by the acoustic metasurface which is constructed with a series of unit cells to provide desired discrete acoustic velocity distribution. Each unit cell is composed of a decorated metal plate with four periodically arrayed Helmholtz resonators (HRs) and a single slit. The design employs a gradient velocity to redirect refracted wave and the impedance matching between the metasurface and the background medium can be realized by adjusting the slit width of unit cell. The theoretical and numerical results show that some excellent wavefront manipulations are demonstrated by anomalous refraction, non-diffracting Bessel beam, sub-wavelength flat focusing, and effective tunable acoustic negative refraction. Our designed structure may offer potential applications for the imaging system, beam steering and acoustic lens. PMID- 28878266 TI - Transglutaminase 2 regulates osteoclast differentiation via a Blimp1-dependent pathway. AB - Transglutaminase 2 (TG2) performs multiple reactions, including transamidation, and also plays a role in signal transduction as a GTP-binding protein. In this study, we reveal that TG2 controls osteoclast differentiation and bone homeostasis in mice. Osteoclasts specifically expressed the TG2 isoform among eight TG family members. Suppression in TG2 expression with siRNA led to increased osteoclast formation from primary mouse precursor cells in response to receptor activator of nuclear factor kappaB ligand (RANKL). This osteoclastogenic effect of TG2 knockdown was associated with enhanced induction of c-Fos and NFATc1 by RANKL. Moreover, TG2 knockdown up-regulated B lymphocyte-induced maturation protein 1 (Blimp1), which represses anti-osteoclastogenic genes, in a manner dependent on the NF-kappaB signaling pathway. To the contrary, TG2 overexpression inhibited osteoclast formation and the expression of osteoclastogenic genes. Consistent with these in vitro results, TG2 knockout mice exhibited lower trabecular bone mass and increased number of osteoclasts compared with wild-type mice. Taken together, our results provide strong evidence that TG2 plays an important role in bone metabolism by suppressing excessive osteoclastogenesis via the regulation of the NF-kappaB-Blimp1 signaling pathway. PMID- 28878265 TI - O-GlcNAcylation Reduces Ischemia-Reperfusion-Induced Brain Injury. AB - O-GlcNAcylation is a common posttranslational modification of nucleocytoplasmic proteins with beta-N-acetylglucosamine (GlcNAc) and regulates numerous biological processes. By using mouse models of cerebral ischemia induced by permanent and transient middle cerebral artery occlusion (MCAO), we observed an initial elevation (~1.7-fold, 1-4 hours after ischemia) and then decline of O GlcNAcylation during cerebral ischemia. We found that moderate increase (<3-fold) of brain O-GlcNAcylation by pharmacological means ameliorated cerebral ischemia reperfusion injury and the consequent motor and neurological deficits. Interference of the transient elevation of O-GlcNAcylation pharmacologically or genetically aggravates the ischemia-induced brain damage, motor deficits and mortality. The alteration of O-GlcNAcylation was also seen in the ischemic areas of postmortem human brains. This study reveals an important regulation of cerebral ischemia-reperfusion injury by O-GlcNAcylation and also provides a possible therapeutic strategy, i.e., by increasing O-GlcNAcylation, to reduce the cerebral damage and improve the clinical outcome of ischemic stroke. PMID- 28878268 TI - Different spatial patterns of nitrogen and phosphorus resorption efficiencies in China's forests. AB - Nutrient resorption is an important internal-strategy for plant to retain nutrients. However, the spatial patterns of nitrogen and phosphorus resorption efficiencies (NRE, PRE) in national scales are still unexplored. In this study, we first estimated the magnitudes of NRE and PRE, and explored their spatial patterns across China's forests based on the dataset from a nation-wide field campaign from 2011 to 2015. Mean NRE was estimated to be 35.64% and higher than mean PRE (43.72%). The main effects of forest type and the interactions between climatic zone and land use were significant for both NRE and PRE. In addition, NRE and PRE exhibited different patterns along climatic gradients and nutrient status. Our results can shed light on the nutrient strategies of China's forests under future environmental changes and the results could be used in global biogeochemical models. PMID- 28878267 TI - Carbonyl reductase 1 catalyzes 20beta-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity. AB - Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH- dependent production of 20beta-dihydrocortisol (20beta-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20beta-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20beta dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity. PMID- 28878269 TI - Caveolin-1 Protects Retinal Ganglion Cells against Acute Ocular Hypertension Injury via Modulating Microglial Phenotypes and Distribution and Activating AKT pathway. AB - Glaucoma, a group of eye diseases, causes gradual loss of retinal ganglion cells (RGCs) and ultimately results in irreversible blindness. Studies of the underlying mechanisms of glaucoma and clinical trial are far from satisfactory. Results from a genome-wide association study have suggested that the CAV1/CAV2 locus is associated with glaucoma, but this association and its potential underlying mechanisms need to be confirmed and further explored. Here, we studied the function of caveolin-1 (Cav1) in an acute ocular hypertension glaucoma model. Cav1 deficiency caused an aggregated lesion in the retina. In addition, treatment with cavtratin, a membrane permeable Cav1 scaffolding domain peptide, enhanced RGC survival. After cavtratin treatment, microglial numbers decreased significantly, and the majority of them migrated from the inner retinal layer to the outer retinal layers. Furthermore, cavtratin promoted a change in the microglia phenotype from the neurotoxic pro-inflammatory M1 to the neuroprotective anti-inflammatory M2. In a molecular mechanism experiment, we found that cavtratin activated the phosphorylation of both AKT and PTEN in cultured N9 cells. Our data highlights the neuroprotective effect of Cav1 on acute ocular hypertension and suggests that Cav1 may serve as a novel therapeutic target for the treatment of glaucoma. We further propose that cavtratin is a therapeutic candidate for glaucoma clinical trials. PMID- 28878271 TI - Closing the bandgap for III-V nitrides toward mid-infrared and THz applications. AB - A theoretical study of InNBi alloy by using density functional theory is presented. The results show non-linear dependence of the lattice parameters and bulk modulus on Bi composition. The formation energy and thermodynamic stability analysis indicate that the InNBi alloy possesses a stable phase over a wide range of intermediate compositions at a normal growth temperature. The bandgap of InNBi alloy in Wurtzite (WZ) phase closes for Bi composition higher than 1.5625% while that in zinc-blende (ZB) phase decreases significantly at around 356 meV/%Bi. The Bi centered ZB InNBi alloy presents a change from a direct bandgap to an indirect bandgap up to 1.5625% Bi and then an oscillates between indirect bandgap and semi metallic for 1.5625% to 25% Bi and finally to metallic for higher Bi compositions. For the same Bi composition, its presence in cluster or uniform distribution has a salient effect on band structures and can convert between direct and indirect bandgap or open the bandgap from the metallic gap. These interesting electronic properties enable III-nitride closing the bandgap and make this material a good candidate for future photonic device applications in the mid infrared to THz energy regime. PMID- 28878270 TI - Membrane association of the bacterial riboregulator Hfq and functional perspectives. AB - Hfq is a bacterial RNA binding protein that carries out several roles in genetic expression regulation, mainly at the post-transcriptional level. Previous studies have shown its importance in growth and virulence of bacteria. Here, we provide the direct observation of its ability to interact with membranes. This was established by co-sedimentation assay, cryo-transmission electron (cryo-TEM) and atomic force (AFM) microscopies. Furthermore, our results suggest a role for its C-terminus amyloidogenic domain in membrane disruption. Precisely, AFM images of lipid bilayers in contact with Hfq C-terminus fibrils show the emergence of holes with a size dependent on the time of interaction. Cryo-TEM observations also show that liposomes are in contact with clusters of fibrils, with occasional deformation of the vesicles and afterward the apparition of a multitude of tiny vesicles in the proximity of the fibrils, suggesting peptide-induced breakage of the liposomes. Finally, circular dichroism spectroscopy demonstrated a change in the secondary structure of Hfq C-terminus upon interaction with liposomes. Altogether, these results show an unexpected property of Hfq and suggest a possible new role for the protein, exporting sRNA outside of the bacterial cell. PMID- 28878272 TI - Enhancement of the productivity of the potent bacteriocin avicin A and improvement of its stability using nanotechnology approaches. AB - Herein, enhancements of the yield and antimicrobial activity duration of the bacteriocin avicin A were accomplished using fractional factorial design (FFD) and layered double hydroxide (LDH) nanoparticles. Firstly, potential factors affecting bacteriocin production were selected for preliminary study. By a 25-1 FFD, high pH was shown to have a positive effect on avicin A yield, while temperature and duration of incubation, as well as peptone nitrogen sources all had negative effects. The highest bacteriocin production and activity (2560 BU/ml) were observed after 30 h of incubation at 30 degrees C, with pH adjustment at 7, and in the presence of 2 g mannitol as carbon source and 2.2 g peptone as nitrogen source. Secondly, avicin A nanocomposites with different LDH precursors were tested. Only avicin A-ZnAl-CO3 LDH demonstrated a potent antimicrobial activity against Lactobacillus sakei LMGT 2313 that lasted for at least 24 days, as compared to the values of 6 and 15 days observed with the free avicin A that has been stored at room temperature and at 4 degrees C, respectively. In conclusion, avicin A production and stability can be improved by manipulating the growth conditions and media composition, together with conjugation to LDHs. PMID- 28878273 TI - Reactivation of dead sulfide species in lithium polysulfide flow battery for grid scale energy storage. AB - Lithium polysulfide batteries possess several favorable attributes including low cost and high energy density for grid energy storage. However, the precipitation of insoluble and irreversible sulfide species on the surface of carbon and lithium (called "dead" sulfide species) leads to continuous capacity degradation in high mass loading cells, which represents a great challenge. To address this problem, herein we propose a strategy to reactivate dead sulfide species by reacting them with sulfur powder with stirring and heating (70 degrees C) to recover the cell capacity, and further demonstrate a flow battery system based on the reactivation approach. As a result, ultrahigh mass loading (0.125 g cm-3, 2 g sulfur in a single cell), high volumetric energy density (135 Wh L-1), good cycle life, and high single-cell capacity are achieved. The high volumetric energy density indicates its promising application for future grid energy storage.Lithium polysulfide batteries suffer from the precipitation of insoluble and irreversible sulfide species on the surface of carbon and lithium. Here the authors show a reactivation strategy by a reaction with cheap sulfur powder under stirring and heating to recover the cell capacity. PMID- 28878274 TI - Development of oriC-plasmids for use in Mycoplasma hyorhinis. AB - Mycoplasma hyorhinis (M. hyorhinis) is an opportunistic pig pathogen, belonging to the class Mollicutes. It causes polyserositis, arthritis and cancers in vitro, increasing attention of the researchers. Currently, there is no available genetic tool to manipulate its genome. This study describes a development of oriC plasmids harboring either large (pGEMT-LoriC) or minimum (pGEMT-MoriC) origin of replication (oriC) of M. hyorhinis along with tetracycline resistance marker.These plasmids were successfully transformed into M. hyorhinis with average transformation frequency of 1.5 * 10-4 and 2.0 * 10-5 transformants/CFU for pGEMT-LoriC and pGEMT-MoriC respectively, and were integrated at the chromosomal oriC as well as remained freely replicating. We also constructed a Mini-oriC-HT1 targeting plasmid by inclusion of hlyC arms and was used to inactivate hlyC at average frequency of 50%. The efficiency of hlyC inactivation was further improved (by 90%) when Mini-oriC-HT2 that contains E. coli recA was used. In both cases, hemolysin mutant bacteria diminished the ability to lyse mouse RBCs compared to wild-type (P < 0.001). OriC-plasmids described in this study may, therefore open the way for functional genomics in M. hyorhinis. Furthermore, this is a first study demonstrated the gene associated with a hemolytic phenotype in mycoplasmas. PMID- 28878276 TI - Non-autonomous multi-rogue waves for spin-1 coupled nonlinear Gross-Pitaevskii equation and management by external potentials. AB - We investigate non-autonomous multi-rogue wave solutions in a three component(spin-1) coupled nonlinear Gross-Pitaevskii(GP) equation with varying dispersions, higher nonlinearities, gain/loss and external potentials. The similarity transformation allows us to relate certain class of multi-rogue wave solutions of the spin-1 coupled nonlinear GP equation to the solutions of integrable coupled nonlinear Schrodinger(CNLS) equation. We study the effect of time-dependent quadratic potential on the profile and dynamic of non-autonomous rogue waves. With certain requirement on the backgrounds, some non-autonomous multi-rogue wave solutions exhibit the different shapes with two peaks and dip in bright-dark rogue waves. Then, the managements with external potential and dynamic behaviors of these solutions are investigated analytically. The results could be of interest in such diverse fields as Bose-Einstein condensates, nonlinear fibers and super-fluids. PMID- 28878275 TI - A fluorescence-based reporter for monitoring expression of mycobacterial cytochrome bd in response to antibacterials and during infection. AB - Cytochrome bd is a component of the oxidative phosphorylation pathway in many Gram-positive and Gram-negative bacteria. Next to its role as a terminal oxidase in the respiratory chain this enzyme plays an important role as a survival factor in the bacterial stress response. In Mycobacterium tuberculosis and related mycobacterial strains, cytochrome bd is an important component of the defense system against antibacterial drugs. In this report we describe and evaluate an mCherry-based fluorescent reporter for detection of cytochrome bd expression in Mycobacterium marinum. Cytochrome bd was induced by mycolic acid biosynthesis inhibitors such as isoniazid and most prominently by drugs targeting oxidative phosphorylation. We observed no induction by inhibitors of protein-, DNA- or RNA synthesis. The constructed expression reporter was suitable for monitoring mycobacterial cytochrome bd expression during mouse macrophage infection and in a zebrafish embryo infection model when using Mycobacterium marinum. Interestingly, in both these infection models cytochrome bd levels were considerably higher than during in vitro culturing of M. marinum. The expression reporter described here can be a valuable tool for elucidating the role of cytochrome bd as a survival factor. PMID- 28878278 TI - Surface reconstruction of InAs (001) depending on the pressure and temperature examined by density functional thermodynamics. AB - A detailed understanding of the atomic configuration of the compound semiconductor surface, especially after reconstruction, is very important for the device fabrication and performance. While there have been numerous experimental studies using the scanning probe techniques, further theoretical studies on surface reconstruction are necessary to promote the clear understanding of the origins and development of such subtle surface structures. In this work, therefore, a pressure-temperature surface reconstruction diagram was constructed for the model case of the InAs (001) surface considering both the vibrational entropy and configurational entropy based on the density functional theory. Notably, the equilibrium fraction of various reconstructions was determined as a function of the pressure and temperature, not as a function of the chemical potential, which largely facilitated the direct comparison with the experiments. By taking into account the entropy effects, the coexistence of the multiple reconstructions and the fractional change of each reconstruction by the thermodynamic condition were predicted and were in agreement with the previous experimental observations. This work provides the community with a useful framework for such type of theoretical studies. PMID- 28878277 TI - Increased TCR signal strength in DN thymocytes promotes development of gut TCRalphabeta(+)CD8alphaalpha(+) intraepithelial lymphocytes. AB - CD4(+)CD8(+) "double positive" (DP) thymocytes differentiate into diverse alphabeta T cell sub-types using mechanistically distinct programs. For example, conventional alphabeta T cells develop from DP cells after partial-agonist T cell receptor (TCR) interactions with self-peptide/MHC, whereas unconventional alphabeta T cells, such as TCRalphabeta(+)CD8alphaalpha(+) intraepithelial lymphocytes (IELs), require full-agonist TCR interactions. Despite this, DP cells appear homogeneous, and it remains unclear how distinct TCR signalling instructs distinct developmental outcomes. Moreover, whether TCR signals at earlier stages of development, for example in CD4(-)CD8(-) double negative (DN) cells, impact on later fate decisions is presently unknown. Here, we assess four strains of mice that display altered TCR signal strength in DN cells, which correlates with altered generation of unconventional TCRalphabeta(+)CD8alphaalpha(+) IELs. FVB/n mice (compared to C57BL/6 animals) and mice with altered preTCRalpha (pTalpha) expression, both displayed weaker TCR signalling in DN cells, an inefficient DN to-DP transition, and reduced contribution of TCRalphabeta(+)CD8alphaalpha(+) IELs to gut epithelium. Conversely, TCRalphabeta(+)CD8alphaalpha(+) IEL development was favoured in mice with increased TCR signal strength in DN cells. Collectively, these data suggest TCR signal strength in DN cells directly impacts on subsequent DP cell differentiation, fundamentally altering the potential of thymocyte progenitors to adopt conventional versus unconventional T cell fates. PMID- 28878279 TI - Changes in Resting-State Cerebral Activity in Patients with Hyperthyroidism: A Short-Term Follow-Up Functional MR Imaging Study. AB - To investigate the brain functional abnormality of hyperthyroid patients before and after treatment for one month using resting-state functional magnetic resonance imaging (rs-fMRI). Amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) analysis were performed in 27 new-onset untreated hyperthyroid patients relative to 30 healthy controls. In addition, follow-up data were available for 19 patients treated with methimazole for one month. Compared with healthy controls, patients exhibited lower ALFF in the right posterior cingulate cortex (PCC); increased FC in the bilateral anterior insula (AI), bilateral posterior insula (PI) and left anterior lobe of the cerebellum (ALC); and decreased FC in the bilateral lateral prefrontal cortex (LPFC), the right medial temporal gyrus (MTG) and the bilateral PCC. Compared with the hyperthyroid status, patients with improved thyroid function showed increased FC in the right LPFC and right dorsolateral prefrontal cortex (DLPFC). Subsequently, Pearson's correlation analyses were performed between abnormal ALFF, FC, neuropsychological assessment and serum free triiodothyronine (FT3) levels. The results indicated that the alterations in regional and network-level brain functions, which might underlie different psychiatric complications were dynamic and interactional processes in hyperthyroidism. Moreover, the improvement in regional brain FC was correlated with the efficacy of anti-thyroid medication. PMID- 28878280 TI - Tilt-less 3-D electron imaging and reconstruction of complex curvilinear structures. AB - The ability to obtain three-dimensional (3-D) information about morphologies of nanostructures elucidates many interesting properties of materials in both physical and biological sciences. Here we demonstrate a novel method in scanning transmission electron microscopy (STEM) that gives a fast and reliable assessment of the 3-D configuration of curvilinear nano structures, all without needing to tilt the sample through an arc. Using one-dimensional crystalline defects known as dislocations as a prototypical example of a complex curvilinear object, we demonstrate their 3-D reconstruction two orders of magnitude faster than by standard tilt-arc TEM tomographic techniques, from data recorded by selecting different ray paths of the convergent STEM probe. Due to its speed and immunity to problems associated with a tilt arc, the tilt-less 3-D imaging offers important advantages for investigations of radiation-sensitive, polycrystalline, or magnetic materials. Further, by using a segmented detector, the total electron dose is reduced to a single STEM raster scan acquisition; our tilt-less approach will therefore open new avenues for real-time 3-D electron imaging of dynamic processes. PMID- 28878281 TI - Synthesis, structure, and luminescent properties of a family of lanthanide functionalized peroxoniobiophosphates. AB - Eight new lanthanide derivatives containing 6-peroxoniobio-4-phosphate building block, [LnIII(H2O)6]2[H4(NbO2)6P4O24].nH2O [Ln = Eu (1), Gd (2), Tb (3), Dy (4), Ho (5), Er (6), Tm (7), Yb (8), 1-5, 7, 8 n = 12; 6 n = 9], have been successfully obtained using an in-situ strategy and fully characterized in the solid state by single-crystal X-ray diffraction, IR spectra, TG-MS, PXRD. Structural analyses indicate that these isostructural polyanions 1-8 consist of one [P4(NbO2)6O24]10- (P 4 (NbO 2 ) 6 ) clusters and two pendant Ln3+ cations. In these compounds, P 4 (NbO 2 ) 6 clusters are connected by lanthanide cations to form extended two-dimensional architectures. The approach takes advantage of the ability of in-situ formed P 4 (NbO 2 ) 6 cluster to build frameworks by using it as ligands to lanthanide ions. The photoluminescence (PL) and lifetime decay behaviors of 1, 3 and 4 in solid state have been performed at room temperature. The PL emission of 1, 3 and 4 is mainly derived from the characteristic 5D0->7FJ (J = 1, 2, 3, 4), 5D4->7FJ (J = 6, 5, 4, 3) and 4F9/2->6H J (J = 15/2, 13/2, 11/2) transitions of the EuIII, TbIII and DyIII cations, respectively. PMID- 28878282 TI - A Novel Benzocoumarin-Stilbene Hybrid as a DNA ligase I inhibitor with in vitro and in vivo anti-tumor activity in breast cancer models. AB - Existing cancer therapies are often associated with drug resistance and toxicity, which results in poor prognosis and recurrence of cancer. This necessitates the identification and development of novel therapeutics against existing as well as novel cellular targets. In this study, a novel class of Benzocoumarin-Stilbene hybrid molecules were synthesized and evaluated for their antiproliferative activity against various cancer cell lines followed by in vivo antitumor activity in a mouse model of cancer. The most promising molecule among the series, i.e. compound (E)-4-(3,5-dimethoxystyryl)-2H-benzo[h]chromen-2-one (19) showed maximum antiproliferative activity in breast cancer cell lines (MDA-MB-231 and 4T1) and decreased the tumor size in the in-vivo 4T1 cell-induced orthotopic syngeneic mouse breast cancer model. The mechanistic studies of compound 19 by various biochemical, cell biology and biophysical approaches suggest that the compound binds to and inhibits the human DNA ligase I enzyme activity that might be the cause for significant reduction in tumor growth and may constitute a promising next-generation therapy against breast cancers. PMID- 28878283 TI - Rate-limiting steps in transcription dictate sensitivity to variability in cellular components. AB - Cell-to-cell variability in cellular components generates cell-to-cell diversity in RNA and protein production dynamics. As these components are inherited, this should also cause lineage-to-lineage variability in these dynamics. We conjectured that these effects on transcription are promoter initiation kinetics dependent. To test this, first we used stochastic models to predict that variability in the numbers of molecules involved in upstream processes, such as the intake of inducers from the environment, acts only as a transient source of variability in RNA production numbers, while variability in the numbers of a molecular species controlling transcription of an active promoter acts as a constant source. Next, from single-cell, single-RNA level time-lapse microscopy of independent lineages of Escherichia coli cells, we demonstrate the existence of lineage-to-lineage variability in gene activation times and mean RNA production rates, and that these variabilities differ between promoters and inducers used. Finally, we provide evidence that this can be explained by differences in the kinetics of the rate-limiting steps in transcription between promoters and induction schemes. We conclude that cell-to-cell and consequent lineage-to-lineage variability in RNA and protein numbers are both promoter sequence-dependent and subject to regulation. PMID- 28878284 TI - MicroRNA-449a deficiency promotes colon carcinogenesis. AB - MicroRNAs have broad roles in tumorigenesis and cell differentiation through regulation of target genes. Notch signaling also controls cell differentiation and tumorigenesis. However, the mechanisms through which Notch mediates microRNA expression are still unclear. In this study, we aimed to identify microRNAs regulated by Notch signaling. Our analysis found that microRNA-449a (miR-449a) was indirectly regulated by Notch signaling. Although miR-449a-deficient mice did not show any Notch-dependent defects in immune cell development, treatment of miR 449a-deficient mice with azoxymethane (AOM) or dextran sodium sulfate (DSS) increased the numbers and sizes of colon tumors. These effects were associated with an increase in intestinal epithelial cell proliferation following AOM/DSS treatment. In patients with colon cancer, miR-449a expression was inversely correlated with disease-free survival and histological scores and was positively correlated with the expression of MLH1 for which loss-of function mutations have been shown to be involved in colon cancer. Colon tissues of miR-449a-deficient mice showed reduced Mlh1 expression compared with those of wild-type mice. Thus, these data suggested that miR-449a acted as a key regulator of colon tumorigenesis by controlling the proliferation of intestinal epithelial cells. Additionally, activation of miR-449a may represent an effective therapeutic strategy and prognostic marker in colon cancer. PMID- 28878285 TI - Interleukin-33 promotes inflammation-induced lymphangiogenesis via ST2/TRAF6 mediated Akt/eNOS/NO signalling pathway. AB - The interplay between inflammation and lymphangiogenesis is mediated by various cytokines. However, most of these molecules and their associated mechanism are yet to be defined. Here, we explored the role of IL-33 in modulating inflammation induced lymphangiogenesis (ILA) and its underlying mechanisms using an ILA mouse model and a lymphatic endothelial cell (LEC) line. Our results show that IL-33 promoted the proliferation, migration and tube formation of LECs and ILA in vivo. The pro-lymphangiogenic activity of IL-33 was abolished by ST2 blockage. In mechanisms, IL-33 induced the phosphorylation of Akt/eNOS to produce NO in LECs. The IL-33-induced Akt/eNOS activation was suppressed by the PI3K-specific inhibitor wortmannin, and NO-production was inhibited by both wortmannin and the NO synthase-inhibitor NMA. Knock-down of ST2 or TRAF6 suppressed Akt/eNOS phosphorylation and NO production. The reduction of NO treated with wortmannin or NMA abolished the promoting effects of IL-33 on the chemotactic motility and tube formation of HDLECs. In vivo, IL-33-induced ILA was also impaired in eNOS-/- mice. In conclusion, our study is the first to show that IL-33 promotes inflammation-induced lymphangiogenesis via a ST2/TRAF6-mediated Akt/eNOS/NO signalling pathway. This findings may provide us more opportunities to treat inflammation and lymphangiogenesis associated diseases. PMID- 28878286 TI - Proteomic analysis on roots of Oenothera glazioviana under copper-stress conditions. AB - Proteomic studies were performed to identify proteins involved in the response of Oenothera glazioviana seedlings under Cu stress. Exposure of 28-d-old seedlings to 50 MUM CuSO4 for 3 d led to inhibition of shoot and root growth as well as a considerable increase in the level of lipid peroxidation in the roots. Cu absorbed by O. glazioviana accumulated more easily in the root than in the shoot. Label-free proteomic analysis indicated 58 differentially abundant proteins (DAPs) of the total 3,149 proteins in the roots of O. glazioviana seedlings, of which 36 were upregulated and 22 were downregulated under Cu stress conditions. Gene Ontology analysis showed that most of the identified proteins could be annotated to signal transduction, detoxification, stress defence, carbohydrate, energy, and protein metabolism, development, and oxidoreduction. We also retrieved 13 proteins from the enriched Kyoto Encyclopaedia of Genes and Genomes and the protein-protein interaction databases related to various pathways, including the citric acid (CA) cycle. Application of exogenous CA to O. glazioviana seedlings exposed to Cu alleviated the stress symptoms. Overall, this study provided new insights into the molecular mechanisms of plant response to Cu at the protein level in relation to soil properties. PMID- 28878288 TI - Abnormal Electroretinogram after Kir7.1 Channel Suppression Suggests Role in Retinal Electrophysiology. AB - The KCNJ13 gene encodes the inwardly rectifying potassium channel, Kir7.1. Mutations in this gene cause childhood blindness, in which the a- and b-wave responses of electroretinogram (ERG) are abolished. The ERG a-wave is the light induced hyperpolarization of retinal photoreceptors, and the b-wave is the depolarization of ON-bipolar cells. The Kir7.1 channel is localized to the apical aspects of retinal pigment epithelium (RPE) cells and contributes to a delayed c wave response. We sought to understand why a defect in an RPE ion-channel result in abnormal electrophysiology at the level of the retinal neurons. We have established the expression of Kir7.1 channels in the mouse RPE. ERGs recorded after mice Kir7.1 suppression by shRNA, or by blocking with VU590, showed reduced a-, b- and c-wave amplitudes. In contrast, the Kir7.1 blocker had no effect on the ex-vivo isolated mouse retina ERG where the RPE is not attached to the isolated retina preparation. Finally, we confirmed the specificity of VU590 action by inhibition of native mouse RPE Kir7.1 current in patch-clamp experiment. We propose that mutant RPE Kir7.1 channels contribute directly to the abnormal ERG associated with blindness via alterations in sub-retinal space K+ homeostasis in the vicinity of the photoreceptor outer segment. PMID- 28878287 TI - Metabolomic Profiling of Serum Retinol in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. AB - The role of retinol in the prevention of multifactorial chronic diseases remains uncertain, and there is sparse evidence regarding biological actions and pathways implicated in its effects on various outcomes. The aim is to investigate whether serum retinol in an un-supplemented state is associated with low molecular weight circulating metabolites. We performed a metabolomic analysis of 1,282 male smoker participants based on pre-supplementation fasting serum in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We examined the association between 947 metabolites measured by ultra-high performance LC-MS/GC-MS and retinol concentration (from HPLC) using linear regression that estimated the difference in metabolite concentrations per unit difference in retinol concentration as standardized beta-coefficients and standard errors (SE). We identified 63 metabolites associated with serum retinol below the Bonferroni-corrected P-value (p < 5.3 * 10-5). The strongest signals were for N-acetyltryptophan (beta = 0.27; SE = 0.032; p = 9.8 * 10-17), myo-inositol (beta = 0.23; SE = 0.032; p = 9.8 * 10 13), and 1-palmitoylglycerophosphoethanolamine (beta = 0.22; SE = 0.032; p = 3.2 * 10-12). Several chemical class pathways were strongly associated with retinol, including amino acids (p = 1.6 * 10-10), lipids (p = 3.3 * 10-7), and cofactor/vitamin metabolites (3.3 * 10-7). The strongest sub-pathway association was for inositol metabolism (p = 2.0 * 10-14). Serum retinol concentration is associated with circulating metabolites in various metabolic pathways, particularly lipids, amino acids, and cofactors/vitamins. These interrelationships may have relevance to the biological actions of retinol, including its role in carcinogenesis. PMID- 28878289 TI - Persistence within dendritic cells marks an antifungal evasion and dissemination strategy of Aspergillus terreus. AB - Aspergillus terreus is an airborne human fungal pathogen causing life-threatening invasive aspergillosis in immunocompromised patients. In contrast to Aspergillus fumigatus, A. terreus infections are associated with high dissemination rates and poor response to antifungal treatment. Here, we compared the interaction of conidia from both fungal species with MUTZ-3-derived dendritic cells (DCs). After phagocytosis, A. fumigatus conidia rapidly escaped from DCs, whereas A. terreus conidia remained persisting with long-term survival. Escape from DCs was independent from DHN-melanin, as A. terreus conidia expressing wA showed no increased intracellular germination. Within DCs A. terreus conidia were protected from antifungals, whereas A. fumigatus conidia were efficiently cleared. Furthermore, while A. fumigatus conidia triggered expression of DC activation markers such as CD80, CD83, CD54, MHCII and CCR7, persistent A. terreus conidia were significantly less immunogenic. Moreover, DCs confronted with A. terreus conidia neither produced pro-inflammatory nor T-cell stimulating cytokines. However, TNF-alpha addition resulted in activation of DCs and provoked the expression of migration markers without inactivating intracellular A. terreus conidia. Therefore, persistence within DCs and possibly within other immune cells might contribute to the low response of A. terreus infections to antifungal treatment and could be responsible for its high dissemination rates. PMID- 28878290 TI - Enhanced tensile strength and thermal conductivity in copper diamond composites with B4C coating. AB - Boron carbide (B4C) coating on diamond particle is synthesized by heating diamond particles in a powder mix of H3BO3 and B in Ar atmosphere. The composition, bond state and coverage fraction of boron carbide coating on diamond particles are investigated. The boron carbide coating favors to grow on diamond (100) surface rather than on diamond (111) surface. Cu matrix composites reinforced with B4C coated diamond particles were made by powder metallurgy. The addition of B4C coating gave rise to a dense composite. The influence of B4C coating on both tensile strength and thermal conductivity of the composite were investigated. When the B4C fully covered on diamond particles, the composite exhibited a greatly increase in tensile strength (115 MPa) which was much higher than that for uncoated-diamond/Cu (60 MPa) composites. Meanwhile, a high thermal conductivity of 687 W/mK was achieved in the B4C-coated-diamond/Cu composites. PMID- 28878291 TI - MAP kinase-interacting serine/threonine kinase 2 promotes proliferation, metastasis, and predicts poor prognosis in non-small cell lung cancer. AB - We hypothesized that MAP kinase-interacting serine/threonine kinase 2 (MNK2) may contribute to non-small cell lung cancer (NSCLC) development, and serve as a new therapeutic target. Immunohistochemical staining evaluated the correlation between MNK2 expression and clinicopathological features in 367 NSCLC cancer tissues. We determined the effects of MNK2 silencing in NSCLC cell lines in vitro and in vivo. RT-PCR and western blotting was used to examine the impact of MNK2 on ERK and AKT pathways. MNK2 was overexpressed in NSCLC cell lines and tumor tissues. Patients with MNK2 overexpression had lower OS rates (P < 0.001). High expression of MNK2 was correlated with lymph node metastasis (P = 0.008). MNK2 functioned as an independent prognostic factor for poor survival in patients with NSCLC (P = 0.003). MNK2 down-regulation inhibited proliferation, migration and invasion in vitro (P < 0.001), and reduced tumor growth and invasion in nude mice (P < 0.05). MNK2 enhanced phosphorylation of eIF4E, a downstream target of ERK and AKT pathways, which promoted NSCLC proliferation and invasion. We conclude that MNK2 overexpression in NSCLC is associated with proliferation, migration, invasion, and lower survival rates in patients via the phosphorylated eIF4E mediated signaling pathway. PMID- 28878292 TI - Supercurrent switch in pi topological junctions based upon a narrow quantum spin Hall insulator. AB - The narrow quantum spin Hall (QSH) insulator is characterized by interedge coupling, which could feature exotic transport phenomena, and thus serves as the key element for topological superconducting electronic devices. Herein, we theoretically explore possible Josephson pi states in a QSH insulator strip touching on two s-wave superconductors in the presence of the interedge coupling. It is shown that the interedge coupling could give rise to a 0 - pi transition modulated by the gate voltage, originating from an additional pi phase difference caused by the interedge backscattering. The 0 - pi transition in turn can manifest the helical spin texture of the edge states. A considerable residual value of the supercurrent at the 0 - pi transition point is always exhibited, suggesting a very efficient performance of the device as a supercurrent switch. Moreover, the region of coexisting 0 and pi states is found fairly large, which can be used to improve accuracy in the design of a pi superconducting quantum interference device. PMID- 28878293 TI - An improved statistical iterative algorithm for sparse-view and limited-angle CT image reconstruction. AB - Because radiation is harmful to patients, it is important to reduce X-ray exposure in the clinic. For CT, reconstructions from sparse views or limited angle tomography are being used more frequently for low dose imaging. However, insufficient sampling data causes severe streak artifacts in images reconstructed using conventional methods. To solve this issue, various methods have recently been developed. In this paper, we improve a statistical iterative algorithm based on the minimization of the image total variation (TV) for sparse or limited projection views during CT image reconstruction. Considering the statistical nature of the projection data, the TV is performed under a penalized weighted least-squares (PWLS-TV) criterion. During implementation of the proposed method, the image reconstructed using the filtered back-projection (FBP) method is used as the initial value of the first iteration. Next, the feature refinement (FR) step is performed after each PWLS-TV iteration to extract the fine features lost in the TV minimization, which we refer to as 'PWLS-TV-FR'. PMID- 28878294 TI - Spectral control of elastic dynamics in metallic nano-cavities. AB - We show how the elastic response of metallic nano-cavities can be tailored by tuning the interplay with an underlying phononic superlattice. In particular, we exploit ultrafast optical excitation in order to address a resonance mode in a tungsten thin film, grown on top of a periodic MgO/ZrO2 multilayer. Setting up a simple theoretical model, we can explain our findings by the coupling of the resonance in the tungsten to an evanescent surface mode of the superlattice. To demonstrate a second potential benefit of our findings besides characterization of elastic properties of multilayer samples, we show by micromagnetic simulation how a similar structure can be utilized for magneto-elastic excitation of exchange-dominated spin waves. PMID- 28878295 TI - Garcinone E induces apoptosis and inhibits migration and invasion in ovarian cancer cells. AB - Ovarian cancer remains the most lethal gynecological malignant tumor. In this study, 24 xanthones were isolated and identified from the pericarps of mangosteen (Garcinia mangostana), and their anti-proliferative activities were tested in ovarian cancer cells. Garcinone E (GE) was found to exhibit excellent anti proliferative effects among the tested xanthones. It significantly inhibited the proliferation in HEY, A2780, and A2780/Taxol cells as evidenced by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release assay, Hoechst 33342 staining, annexin V/PI staining, and JC-1 staining. It induced endoplasmic reticulum (ER) stress and activated the protective inositol-requiring kinase (IRE)-1alpha pathway. Knocking down IRE 1alpha further activated the caspase cascade and caused an increase in cell death. Moreover, GE eliminated the migratory ability of HEY cells by reducing the expression of RhoA and Rac. It also blocked the invasion, which might be related to downregulation of matrix metalloproteinases (MMPs), i.e., MMP-9 and MMP-2, and upregulation of tissue inhibitors of metalloproteinase (TIMP) -1 and TIMP-2. In summary, GE exerts anticancer activities by inducing apoptosis and suppressing migration and invasion in ovarian cancer cells, which indicates its therapeutic potential for ovarian cancer. PMID- 28878296 TI - Genetic variants in ERCC1 and XPC predict survival outcome of non-small cell lung cancer patients treated with platinum-based therapy. AB - Nucleotide excision repair (NER) plays a vital role in platinum-induced DNA damage during chemotherapy. We hypothesize that regulatory single nucleotide polymorphisms (rSNPs) of the core NER genes modulate clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy (PBS). We investigated associations of 25 rSNPs in eight NER genes with progression free survival (PFS) and overall survival (OS) in 710 NSCLC patients. We found that ERCC1 rs3212924 AG/GG and XPC rs2229090 GC/CC genotypes were associated with patients' PFS (HRadj = 1.21, 95% CI = 1.03-1.43, P adj = 0.021 for ERCC1 and HRadj = 0.80, 95% CI = 0.68-0.94, P adj = 0.007 for XPC), compared with the AA and GG genotypes, respectively. The association of XPC rs2229090 was more apparent in adenocarcinoma than in squamous cell carcinoma patients. Additionally, ERCC4 rs1799798 GA/AA genotypes were associated with poorer OS (HRadj = 1.32, 95% CI = 1.04-1.69, P adj = 0.026), compared with the GG genotype. The expression quantitative trait loci analysis revealed that ERCC1 rs3212924 and XPC rs2229090 might regulate transcription of their genes, which is consistent with their associations with survival. Larger studies are needed to validate our findings with further functional studies to elucidate the mechanisms underlying these observed associations. PMID- 28878297 TI - Role of NF-kappaB/GATA3 in the inhibition of lysyl oxidase by IL-1beta in human amnion fibroblasts. AB - Preterm premature rupture of membranes (pPROMs) account for one-third of preterm births, a leading cause of neonatal death. Understanding the mechanism of membrane rupture is thus of clinical significance in the prevention of preterm birth. Parturition at both term and preterm is associated with increased abundance of proinflammatory cytokines in the fetal membranes regardless of the presence of infection, which is believed to induce rupture of membranes through activation of the matrix metalloproteinases. It remains unknown whether there are any alternative mechanisms underpinning proinflammatory cytokine-induced rupture of membranes. Here we showed that there were reciprocal increases in interleukin 1beta (IL-1beta) and decreases in lysyl oxidase (LOX), a collagen crosslinking enzyme, in the human amnion tissue following spontaneous rupture of membrane at term and pPROM. Studies using human amnion tissue explants revealed that IL-1beta inhibited the expression of LOX, which can be reproduced in cultured human amnion fibroblasts. Mechanistic study revealed that IL-1beta inhibited LOX expression through activation of p38 and Erk1/2 mitogen-activated protein kinase pathways, which resulted in the phosphorylation of the nuclear factor kappa light-chain enhancer of activated B (NF-kappaB) cell subunit p65 as well as GATA binding protein 3 (GATA3). Subsequently, activated NF-kappaB interacted with GATA3 at the NF-kappaB binding site of LOX promoter to inhibit its expression. Conclusively, this study has revealed an alternative mechanism that IL-1beta may contribute to the rupture of membranes by attenuating collagen crosslinking through downregulation of LOX expression in amnion fibroblasts. PMID- 28878298 TI - Upregulation of cathepsin C expression contributes to endothelial chymase activation in preeclampsia. AB - Chymase is an ACE (angiotensin-converting enzyme)-independent angiotensin II forming enzyme whose expression is increased in the maternal vascular endothelium in preeclampsia. However, mechanisms underlying chymase activation in preeclampsia remain unclear. Cathepsin C is a key enzyme in the activation of several serine proteases including chymase. In this study, we determined whether increased cathepsin C expression/activity might be responsible for the upregulation of chymase expression in preeclampsia. Maternal vascular cathepsin C, chymase and ACE expression were examined through immunohistochemical staining of subcutaneous fat tissue sections of normal and preeclamptic pregnant women. The role of cathepsin C in endothelial chymase and ACE expression was determined in cells treated with cathepsin C. Consequences of chymase activation were then determined by measurement of angiotensin II production in cells treated with the ACE inhibitor captopril and the chymase inhibitor chymostatin, separately and in combination. Expression of both cathepsin C and chymase, but not ACE expression, was markedly increased in the maternal vascular endothelium in subjects with preeclampsia compared with normal pregnant controls. Exogenous cathepsin C induced a dose-dependent increase in expression of mature cathepsin C and chymase, but not ACE, in endothelial cells. Moreover, angiotensin II production was significantly inhibited in cells treated with captopril or chymostatin alone and was further inhibited in cells treated with both inhibitors. These results suggest that cathepsin C upregulation induces chymase activation and subsequently promotes angiotensin II generation in endothelial cells. These data also provide evidence of upregulation of the cathepsin C-chymase-angiotensin signaling axis in maternal vasculature in preeclampsia. PMID- 28878299 TI - A study on clinicoradiological characteristics and pregnancy outcomes of reversible posterior leukoencephalopathy syndrome in preeclampsia or eclampsia. AB - Reversible posterior leukoencephalopathy syndrome (RPLS) is a critical maternal complication in preeclampsia or eclampsia during pregnancy. However, studies regarding the clinicoradiological and outcome differences between RPLS and non RPLS pregnancies are scarce. We aimed to explore the incidence of RPLS, and summarize the clinicoradiological characteristics and pregnancy outcomes. We consecutively collected a total of 100 patients who were diagnosed with preeclampsia or eclampsia, and examined via magnetic resonance imaging (MRI) among 21 872 women between 2013 and 2016. All patients were grouped into RPLS (n=49) and non-RPLS (n=51) groups according to their MRI results. Information about clinicoradiological features and pregnancy outcomes was collected retrospectively to explore the differences between the groups. The incidence of RPLS in pregnant women was 0.22% (49/21 872). The frequency of clinical symptoms, such as headache, vision change, seizure and consciousness disorders, and blood pressure conditions, such as severely elevated hypertension, systolic and diastolic pressure and mean arterial pressure levels, was increased in the RPLS group compared with that in the non-RPLS group (P<0.05). The occipital lobe was the most frequently affected area (93.88%) in RPLS patients. The cesarean section rate in RPLS group was higher than the non-RPLS group (P<0.05), whereas the 1 min Apgar score was lower (P<0.05). These results suggest that the incidence of RPLS was high. Information about clinical symptoms and blood pressure was useful in predicting RPLS. In addition, RPLS was significantly associated with the delivery mode and pregnancy outcomes. The most frequently affected area was the occipital lobe. PMID- 28878300 TI - White-coat and masked hypertension are associated with albuminuria in a general population: the Hisayama Study. AB - Epidemiological and clinical studies have investigated the influence of hypertension on chronic kidney disease (CKD), but limited data are available for the associations of white-coat hypertension (WCHT), masked hypertension (MHT) and sustained hypertension (SHT) with kidney dysfunction in general populations. We examined the associations of these types of hypertension with CKD (albuminuria and reduction in estimated glomerular filtration rate (eGFR)) in a cross sectional survey of 2974 community-dwelling Japanese aged ?40 years. The types of hypertension were defined based on combined measurements of clinic and home blood pressures. Albuminuria was determined as urinary albumin-creatinine ratio (UACR) levels ?30.0 mg g-1. The eGFR was calculated using the Japanese equation. The age and sex-adjusted geometric mean of the UACR values was significantly higher in the subjects with WCHT (20.2 mg g-1), MHT (19.6 mg g-1) and SHT (31.6 mg g-1) than in those with normotension (NT) (12.5 mg g-1) (all P<0.001). Compared with NT, all types of hypertension were significantly associated with an increased likelihood of albuminuria (the age- and sex-adjusted prevalence of albuminuria; NT 14.1%, WCHT 26.3%, MHT 26.4% and SHT 43.3%; all P<0.001). These associations remained significant even after adjustment for other risk factors. However, the age- and sex-adjusted mean of eGFR and the prevalence of low eGFR (<60 ml min-1 per 1.73 m2) did not differ between NT and the three hypertension types. The associations of the types of hypertension with the likelihood of CKD were similar to those for albuminuria. Our findings suggest that WCHT, MHT and SHT are associated with albuminuria in the general Japanese population. PMID- 28878301 TI - EPA:DHA 6:1 prevents angiotensin II-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase- and COX-derived oxidative stress. AB - Eicosapentaenoic acid:docosahexaenoic acid (EPA:DHA) 6:1, an omega-3 polyunsaturated fatty acid formulation, has been shown to induce a sustained formation of endothelial nitric oxide (NO) synthase-derived NO, a major vasoprotective factor. This study examined whether chronic intake of EPA:DHA 6:1 prevents hypertension and endothelial dysfunction induced by angiotensin II (Ang II) in rats. Male Wister rats received orally corn oil or EPA:DHA 6:1 (500 mg kg 1 per day) before chronic infusion of Ang II (0.4 mg kg-1 per day). Systolic blood pressure was determined by tail cuff sphingomanometry, vascular reactivity using a myograph, oxidative stress using dihydroethidium and protein expression by immunofluorescence and western blot analysis. Ang II-induced hypertension was associated with reduced acetylcholine-induced relaxations of secondary branch mesenteric artery rings affecting the endothelium-dependent hyperpolarization (EDH)- and the NO-mediated relaxations, both of which were improved by the NADPH oxidase inhibitor VAS-2870. The Ang II treatment induced also endothelium dependent contractile responses (EDCFs), which were abolished by the cyclooxygenase (COX) inhibitor indomethacin. An increased level of vascular oxidative stress and expression of NADPH oxidase subunits (p47phox and p22phox), COX-1 and COX-2, endothelial NO synthase and Ang II type 1 receptors were observed in the Ang II group, whereas SKCa and connexin 37 were downregulated. Intake of EPA:DHA 6:1 prevented the Ang II-induced hypertension and endothelial dysfunction by improving both the NO- and EDH-mediated relaxations, and by reducing EDCFs and the expression of target proteins. The present findings indicate that chronic intake of EPA:DHA 6:1 prevented the Ang II-induced hypertension and endothelial dysfunction in rats, most likely by preventing NADPH oxidase- and COX-derived oxidative stress. PMID- 28878302 TI - Oxygen Mapping of Melanoma Spheroids using Small Molecule Platinum Probe and Phosphorescence Lifetime Imaging Microscopy. AB - Solid tumours display varied oxygen levels and this characteristic can be exploited to develop new diagnostic tools to determine and exploit these variations. Oxygen is an efficient quencher of emission of many phosphorescent compounds, thus oxygen concentration could in many cases be derived directly from relative emission intensity and lifetime. In this study, we extend our previous work on phosphorescent, low molecular weight platinum(II) complex as an oxygen sensing probe to study the variation in oxygen concentration in a viable multicellular 3D human tumour model. The data shows one of the first examples of non-invasive, real-time oxygen mapping across a melanoma tumour spheroid using one-photon phosphorescence lifetime imaging microscopy (PLIM) and a small molecule oxygen sensitive probe. These measurements were quantitative and enabled real time oxygen mapping with high spatial resolution. This combination presents as a valuable tool for optical detection of both physiological and pathological oxygen levels in a live tissue mass and we suggest has the potential for broader clinical application. PMID- 28878303 TI - Typewriter tinnitus revisited: The typical symptoms and the initial response to carbamazepine are the most reliable diagnostic clues. AB - Although neurovascular compression of the cochlear nerve (NVC-C) presenting as typewriter tinnitus is a discrete disease category, verified diagnostic criteria are lacking. We sought to refine the diagnostic criteria for NVC-C by reference to a relatively large case series. The medical records of 22 NVC-C patients were retrospectively reviewed. Psychoacoustic characteristics, the results of diagnostic work-up (including audiovestibular neurophysiological tests and radiological evaluations), and the initial treatment response to carbamazepine were investigated. All subjects described their tinnitus as a typical "typewriter" or "staccato" sound. Of the 22 subjects, 11 (50%) had histories of vertiginous spells, but none had ipsilesional hearing loss. Vestibular function tests in 11 subjects tested revealed only 2 (18.2%) isolated cervical vestibular evoked myogenic potential abnormalities. Radiological comparisons of the symptomatic and asymptomatic sides, regarding the type of the vascular loop and neurovascular contact, revealed no significant differences. However, all 22 subjects exhibited immediate and marked responses to short-term carbamazepine treatment. Meticulous history-taking in terms of the psychoacoustic characteristics and the response to initial carbamazepine, are more reliable diagnostic clues than are radiological or neurophysiological data in NVC-C subjects. Therefore, the typical psychoacoustic characteristics and the response to initial carbamazepine should be included in the diagnostic criteria. PMID- 28878304 TI - Maximum extent and decay of the Laurentide Ice Sheet in Western Baffin Bay during the Last glacial episode. AB - Reconstructing the extent, flow and decay of the Laurentide Ice Sheet (LIS) on the continental shelves of North America during the last glaciation provides paleoglaciological analogues that are essential for understanding and predicting how modern marine-based ice-sheets will respond to future climate change and sea level fluctuations. The geometry of the LIS during Marine isotope stage 2 (MIS-2; 29-14 ka BP) is one key element for ice-sheet modelling. The maximum extent of the LIS during this stage is well constrained for most sectors of the ice sheet, but major uncertainties remain, especially along the continental shelves of Arctic Canada. Despite a series of recent papers, the extent of the LIS in Western Baffin Bay, an area draining large volumes of glacial ice through multiple ice streams and likely characterized by ice shelves, remains highly speculative. Here we present unequivocal marine geophysical evidence that during the MIS-2 the LIS extended to the edge of the continental shelf, seaward of the previously proposed limits and subsequently retreated episodically westward during deglaciation. These data support interpretations of deep glacial ice grounding in Western Baffin Bay. PMID- 28878305 TI - Effects of Intensive Blood Pressure Reduction on Acute Intracerebral Hemorrhage: A Systematic Review and Meta-analysis. AB - Current opinions about the effect of intensive blood pressure (BP) reduction for acute intracerebral hemorrhage (ICH) are inconsistent. We performed a meta analysis to evaluate the efficacy and safety of intensive BP reduction for acute ICH by analyzing data from several recent randomized controlled trials (RCTs). There were six eligible studies that met the inclusion criteria, for a total of 4,385 acute ICH patients in this meta-analysis. After analyzing these data, we found differences between intensive and standard BP lowering treatment groups in total mortality rates, unfavorable outcomes, hematoma expansion, neurologic deterioration, and severe hypotension were not significant. Moreover, compared with the standard treatment, the rate of renal adverse event in intensive treatment group was significantly higher. The intensive treatment approach was recommended in the following situations: (1) longer prehospital duration; (2) lower National Institute of Health stroke scale (NIHSS) score; (3) no hypertension history. PMID- 28878306 TI - Culture-independent metagenomics supports discovery of uncultivable bacteria within the genus Chlamydia. AB - Advances in culture-independent methods have meant that we can more readily detect and diagnose emerging infectious disease threats in humans and animals. Metagenomics is fast becoming a popular tool for detection and characterisation of novel bacterial pathogens in their environment, and is particularly useful for obligate intracellular bacteria such as Chlamydiae that require labour-intensive culturing. We have used this tool to investigate the microbial metagenomes of Chlamydia-positive cloaca and choana samples from snakes. The microbial complexity within these anatomical sites meant that despite previous detection of chlamydial 16S rRNA sequences by single-gene broad-range PCR, only a chlamydial plasmid could be detected in all samples, and a chlamydial chromosome in one sample. Comparative genomic analysis of the latter revealed it represented a novel taxon, Ca. Chlamydia corallus, with genetic differences in regards to purine and pyrimidine metabolism. Utilising statistical methods to relate plasmid phylogeny to the phylogeny of chromosomal sequences showed that the samples also contain additional novel strains of Ca. C. corallus and two putative novel species in the genus Chlamydia. This study highlights the value of metagenomics methods for rapid novel bacterial discovery and the insights it can provide into the biology of uncultivable intracellular bacteria such as Chlamydiae. PMID- 28878307 TI - A Method for Combined Retinal Vascular and Tissue Oxygen Tension Imaging. AB - The retina requires adequate oxygenation to maintain cellular metabolism and visual function. Inner retinal oxygen metabolism is directly related to retinal vascular oxygen tension (PO2) and inner retinal oxygen extraction fraction (OEF), whereas outer retinal oxygen consumption (QO2) relies on oxygen availability by the choroid and is contingent upon retinal tissue oxygen tension (tPO2) gradients across the retinal depth. Thus far, these oxygenation and metabolic parameters have been measured independently by different techniques in separate animals, precluding a comprehensive and correlative assessment of retinal oxygenation and metabolism dynamics. The purpose of the current study is to report an innovative optical system for dual oxyphor phosphorescence lifetime imaging to near simultaneously measure retinal vascular PO2 and tPO2 in rats. The use of a new oxyphor with different spectral characteristics allowed differentiation of phosphorescence signals from the retinal vasculature and tissue. Concurrent measurements of retinal arterial and venous PO 2 , tPO2 through the retinal depth, inner retinal OEF, and outer retinal QO 2 were demonstrated, permitting a correlative assessment of retinal oxygenation and metabolism. Future application of this method can be used to investigate the relations among retinal oxygen content, extraction and metabolism under pathologic conditions and thus advance knowledge of retinal hypoxia pathophysiology. PMID- 28878308 TI - Iron-dependent reconfiguration of the proteome underlies the intracellular lifestyle of Brucella abortus. AB - Brucella ssp. is a facultative intracellular pathogen that causes brucellosis, a worldwide zoonosis that affects a wide range of mammals including humans. A critical step for the establishment of a successful Brucella infection is its ability to survive within macrophages. To further understand the mechanisms that Brucella utilizes to adapt to an intracellular lifestyle, a differential proteomic study was performed for the identification of intracellular modulated proteins. Our results demonstrated that at 48 hours post-infection Brucella adjusts its metabolism in order to survive intracellularly by modulating central carbon metabolism. Remarkably, low iron concentration is likely the dominant trigger for reprogramming the protein expression profile. Up-regulation of proteins dedicated to reduce the concentration of reactive oxygen species, protein chaperones that prevent misfolding of proteins, and proteases that degrade toxic protein aggregates, suggest that Brucella protects itself from damage likely due to oxidative burst. This proteomic analysis of B. abortus provides novel insights into the mechanisms utilized by Brucella to establish an intracellular persistent infection and will aid in the development of new control strategies and novel targets for antimicrobial therapy. PMID- 28878309 TI - Identification of oriT and a recombination hot spot in the IncA/C plasmid backbone. AB - Dissemination of multiresistance has been accelerating among pathogenic bacteria in recent decades. The broad host-range conjugative plasmids of the IncA/C family are effective vehicles of resistance determinants in Gram-negative bacteria. Although more than 150 family members have been sequenced to date, their conjugation system and other functions encoded by the conserved plasmid backbone have been poorly characterized. The key cis-acting locus, the origin of transfer (oriT), has not yet been unambiguously identified. We present evidence that IncA/C plasmids have a single oriT locus immediately upstream of the mobI gene encoding an indispensable transfer factor. The fully active oriT spans ca. 150-bp AT-rich region overlapping the promoters of mobI and contains multiple inverted and direct repeats. Within this region, the core domain of oriT with reduced but detectable transfer activity was confined to a 70-bp segment containing two inverted repeats and one copy of a 14-bp direct repeat. In addition to oriT, a second locus consisting of a 14-bp imperfect inverted repeat was also identified, which mimicked the function of oriT but which was found to be a recombination site. Recombination between two identical copies of these sites is RecA independent, requires a plasmid-encoded recombinase and resembles the functioning of dimer-resolution systems. PMID- 28878310 TI - Large-scale production of recombinant human lactoferrin from high-expression, marker-free transgenic cloned cows. AB - Human lactoferrin (hLF) is a valuable protein for pharmaceutical products and functional foods, and worldwide demand for this protein has steadily increased. However, large-scale recombinant human lactoferrin (rhLF) production using current animal bioreactor techniques is limited by the low expression of foreign proteins, the use of antibiotic resistance genes and the down-regulation of endogenous milk proteins. Here, we generated a herd of marker-free, hLF bacterial artificial chromosome (BAC) transgenic cloned cows, as confirmed by Polymerase chain reaction, Southern blot and Western blot analyses. These transgenic cloned cows produced rhLF in milk at concentrations of 4.5-13.6 g/L. Moreover, the total protein content of the milk was increased. Over two hundred transgenic cloned cows were propagated by multiple ovulation and embryo transfer (MOET). A total of 400-450 g of rhLF protein, which shows similar enzymatic activity to natural hLF in iron binding and release, can be purified on a large scale from >100 L of milk per day. Our results suggested that transgenic bovine mammary bioreactors have the potential for large-scale protein production. PMID- 28878311 TI - High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions. AB - An early and accurate in vivo diagnosis of rapidly progressive dementia remains challenging, despite its critical importance for the outcome of treatable forms, and the formulation of prognosis. Real-Time Quaking-Induced Conversion (RT-QuIC) is an in vitro assay that, for the first time, specifically discriminates patients with prion disease. Here, using cerebrospinal fluid (CSF) samples from 239 patients with definite or probable prion disease and 100 patients with a definite alternative diagnosis, we compared the performance of the first (PQ-CSF) and second generation (IQ-CSF) RT-QuIC assays, and investigated the diagnostic value of IQ-CSF across the broad spectrum of human prions. Our results confirm the high sensitivity of IQ-CSF for detecting human prions with a sub-optimal sensitivity for the sporadic CJD subtypes MM2C and MM2T, and a low sensitivity limited to variant CJD, Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia. While we found no difference in specificity between PQ-CSF and IQ-CSF, the latter showed a significant improvement in sensitivity, allowing prion detection in about 80% of PQ-CSF negative CJD samples. Our results strongly support the implementation of IQ-CSF in clinical practice. By rapidly confirming or excluding CJD with high accuracy the assay is expected to improve the outcome for patients and their enrollment in therapeutic trials. PMID- 28878312 TI - SERS-based Immunoassay in a Microfluidic System for the Multiplexed Recognition of Interleukins from Blood Plasma: Towards Picogram Detection. AB - SERS-active nanostructures incorporated into a microfluidic device have been developed for rapid and multiplex monitoring of selected Type 1 cytokine (interleukins: IL-6, IL-8, IL-18) levels in blood plasma. Multiple analyses have been performed by using nanoparticles, each coated with different Raman reporter molecules: 5,5'-dithio-bis(2-nitro-benzoic acid) (DTNB), fuchsin (FC), and p mercatpobenzoic acid (p-MBA) and with specific antibodies. The multivariate statistical method, principal component analysis (PCA), was applied for segregation of three different antigen-antibody complexes encoded by three Raman reporters (FC, p-MBA, and DTNB) during simultaneous multiplexed detection approach. To the best of our knowledge, we have also presented, for the first time, a possibility for multiplexed quantification of three interleukins: IL-6, IL-8, and IL-18 in blood plasma samples using SERS technique. Our method improves the detection limit in comparison to standard ELISA methods. The low detection limits were estimated to be 2.3 pg.ml-1, 6.5 pg.ml-1, and 4.2 pg.ml-1 in a parallel approach, and 3.8 pg.ml-1, 7.5 pg.ml-1, and 5.2 pg.ml-1 in a simultaneous multiplexed method for IL-6, IL-8, and IL-18, respectively. This demonstrated the sensitivity and reproducibility desirable for analytical examinations. PMID- 28878313 TI - Atomic-scale engineering of ferroelectric-ferromagnetic interfaces of epitaxial perovskite films for functional properties. AB - Besides epitaxial mismatch that can be accommodated by lattice distortions and/or octahedral rotations, ferroelectric-ferromagnetic interfaces are affected by symmetry mismatch and subsequent magnetic ordering. Here, we have investigated La0.67 Sr0.33 MnO3 (LSMO) samples with varying underlying unit cells (uc) of BaTiO3 (BTO) layer on (001) and (110) oriented substrates in order to elucidate the role of symmetry mismatch. Lattice mismatch for 3 uc of BTO and symmetry mismatch for 10 uc of BTO, both associated with local MnO6 octahedral distortions of the (001) LSMO within the first few uc, are revealed by scanning transmission electron microscopy. Interestingly, we find exchange bias along the in-plane [110]/[100] directions only for the (001) oriented samples. Polarized neutron reflectivity measurements confirm the existence of a layer with zero net moment only within (001) oriented samples. First principle density functional calculations show that even though the bulk ground state of LSMO is ferromagnetic, a large lattice constant together with an excess of La can stabilize an antiferromagnetic LaMnO3-type phase at the interface region and explain the experimentally observed exchange bias. Atomic scale tuning of MnO6 octahedra can thus be made possible via symmetry mismatch at heteroepitaxial interfaces. This aspect can act as a vital parameter for structure-driven control of physical properties. PMID- 28878314 TI - Limited locomotive ability relaxed selective constraints on molluscs mitochondrial genomes. AB - Mollusca are the second largest phylum in the animal kingdom with different types of locomotion. Some molluscs are poor-migrating, while others are free-moving or fast-swimming. Most of the energy required for locomotion is provided by mitochondria via oxidative phosphorylation. Here, we conduct a comparative genomic analysis of 256 molluscs complete mitochondrial genomes and evaluate the role of energetic functional constraints on the protein-coding genes, providing a new insight into mitochondrial DNA (mtDNA) evolution. The weakly locomotive molluscs, compared to strongly locomotive molluscs, show significantly higher Ka/Ks ratio, which suggest they accumulated more nonsynonymous mutations in mtDNA and have experienced more relaxed evolutionary constraints. Eleven protein-coding genes (CoxI, CoxII, ATP6, Cytb, ND1-6, ND4L) show significant difference for Ka/Ks ratios between the strongly and weakly locomotive groups. The relaxation of selective constraints on Atp8 arise in the common ancestor of bivalves, and the further relaxation occurred in marine bivalves lineage. Our study thus demonstrates that selective constraints relevant to locomotive ability play an essential role in evolution of molluscs mtDNA. PMID- 28878315 TI - Cholesterol-modified Hydroxychloroquine-loaded Nanocarriers in Bleomycin-induced Pulmonary Fibrosis. AB - An increasing number of reports have suggested the use of hydroxychloroquine (HCQ) as an adjunct anti-cancer treatment to enhance the chemotherapeutic response, as well as for the treatment of several fibrotic skin diseases and cystic fibrosis. In this study, we synthesized a cholesterol-modified HCQ (Chol HCQ) and hypothesized that a systemic delivery system with Chol-HCQ nanocarriers could be effective for the treatment of bleomycin-induced pulmonary fibrosis. Chol-HCQ significantly inhibits the proliferation of rat lung fibroblasts, regulates inflammation and ameliorates bleomycin-induced pulmonary fibrosis in rats. It regulates the expression of pro-inflammatory cytokines, such as TNF alpha; reduces the infiltration of inflammatory neutrophils; and inhibits the phosphorylation of NF-kappaB. Chol-HCQ also reduces the expression of connective tissue growth factor (CTGF) and phosphorylation of extracellular regulated protein kinase (p-ERK) in rats with bleomycin-induced pulmonary fibrosis. Chol HCQ nanocarriers reduce early pulmonary inflammation and inhibit the CTGF/ERK signalling pathway in bleomycin-induced pulmonary fibrosis. These results demonstrate that Chol-HCQ liposomes suppress pulmonary inflammation and reduce pulmonary fibrosis induced by bleomycin. The systemic administration safety of Chol-HCQ liposomes was confirmed after intravenous administration for 28 days in rats. The present study provides evidence that Chol-HCQ liposomes may be a potential therapeutic agent for inflammation associated with pulmonary fibrosis. PMID- 28878316 TI - Diagnostic accuracy of standardised qualitative sensory test in the detection of lumbar lateral stenosis involving the L5 nerve root. AB - Misdiagnosis of symptomatic lumbar lateral stenosis (LS) may result in an unfavourable prognosis after surgical treatment. This study investigated the diagnostic accuracy of a standardised qualitative sensory test (SQST) in the detection of symptomatic LS in patients who had degenerative spinal disorders involving the L5 spinal nerve. We prospectively identified 75 patients, of which 60 met the inclusion criteria. Lateral recess stenosis at the L5 level or foraminal stenosis at the L5/S1 level on MRI was identified and graded by a neurosurgeon blinded to any clinical information. The reference criteria for the diagnosis of symptomatic LS were grade III LS on MRI and relevant clinical symptoms. Cutaneous sensory functions of the L5 dermatome on the symptomatic side were evaluated using the SQST. Each item of the SQST showed a satisfactory performance in the diagnosis of LS (sensitivity = 0.455-0.727, specificity = 0.868-1.0). A stepwise selection model identified low-strength von-Frey, high strength von-Frey, and vibration as the most accurate predictors of symptomatic LS with an area under the receiver operating characteristic curve of 0.9563 (95% confidence interval = 0.9003-1.0). In combination with MRI, the SQST is a promising diagnostic tool for detecting symptomatic LS involving L5 nerve roots. PMID- 28878317 TI - Harnessing no-photon exciton generation chemistry to engineer semiconductor nanostructures. AB - Production of semiconductor nanostructures with high yield and tight control of shape and size distribution is an immediate quest in diverse areas of science and technology. Electroless wet chemical etching or stain etching can produce semiconductor nanoparticles with high yield but is limited to a few materials because of the lack of understanding the physical-chemical processes behind. Here we report a no-photon exciton generation chemistry (NPEGEC) process, playing a key role in stain etching of semiconductors. We demonstrate NPEGEC on silicon carbide polymorphs as model materials. Specifically, size control of cubic silicon carbide nanoparticles of diameter below ten nanometers was achieved by engineering hexagonal inclusions in microcrystalline cubic silicon carbide. Our finding provides a recipe to engineer patterned semiconductor nanostructures for a broad class of materials. PMID- 28878318 TI - A complete investigation of monocular and binocular functions in clinically treated amblyopia. AB - The gold standard of a successful amblyopia treatment is full recovery of visual acuity (VA) in the amblyopic eye, but there has been no systematic study on both monocular and binocular visual functions. In this research, we aimed to quantify visual qualities with a variety of perceptual tasks in subjects with treated amblyopia. We found near stereoacuity and pAE dominance in binocular rivalry in "treated" amblyopia were largely comparable to those of normal subjects. CSF of the pAE remained deficient in high spatial frequencies. The binocular contrast summation ratio is significantly lower than normal standard. The interocular balance point is 34%, indicating that contrast in pAE is much less effective as the same contrast in pFE in binocular phase combination. Although VA, stereoacuity and binocular rivalry at low spatial frequency in treated amblyopes were normal or nearly normal, the pAE remained "lazy" in high frequency domain, binocular contrast summation, and interocular phase combination. Our results suggest that structured monocular and binocular training are necessary to fully recover deficient functions in amblyopia. PMID- 28878319 TI - Revisiting myocardial necrosis biomarkers: assessment of the effect of conditioning therapies on infarct size by kinetic modelling. AB - Infarct size is a major predictor of subsequent cardiovascular events following ST-segment elevation myocardial infarction (STEMI) and is frequently used in clinical trials focused on cardioprotection. Approximately assessed through serial blood sampling, it can be accurately measured by imaging techniques, e.g. cardiac magnetic resonance imaging, which is the actual gold standard for infarct size determination but with limited availability in daily practice. We developed a mathematical biomarker kinetic model based on pharmacokinetic compartment models to easily and accurately estimate infarct size using individual data from five clinical trials evaluating the impact of conditioning therapies in STEMI between 2005 and 2013. Serial blood sampling was available in all studies with data regarding creatine kinase (CK), CK specific of cardiomyocytes (CK-MB) and cardiac troponin I. Our model allowed an accurate estimation of biomarker release as a surrogate marker of infarct size and a powerful assessment of conditioning treatments. This biomarker kinetic modelling approach identified CK-MB as the most accurate biomarker in determining infarct size and supports the development of limited sampling strategies that estimate total biomarker amount released with a lower number of samples. It will certainly be a useful add-on to future studies in the field of STEMI and cardioprotection. PMID- 28878320 TI - A new mass spectrometry-based method for the quantification of histones in plasma from septic shock patients. AB - The aim of this study was to develop a novel method to detect circulating histones H3 and H2B in plasma based on multiple reaction monitoring targeted mass spectrometry and a multiple reaction monitoring approach (MRM-MS) for its clinical application in critical bacteriaemic septic shock patients. Plasma samples from 17 septic shock patients with confirmed bacteraemia and 10 healthy controls were analysed by an MRM-MS method, which specifically detects presence of histones H3 and H2B. By an internal standard, it was possible to quantify the concentration of circulating histones in plasma, which were significantly higher in patients, and thus confirmed their potential as biomarkers for diagnosing septic shock. After comparing surviving patients and non-survivors, a correlation was found between higher levels of circulating histones and unfavourable outcome. Indeed, histone H3 proved a more efficient and sensitive biomarker for septic shock prognosis. In conclusion, these findings suggest the accuracy of the MRM-MS technique and stable isotope labelled peptides to detect and quantify circulating plasma histones H2B and H3. This method may be used for early septic shock diagnoses and for the prognosis of fatal outcomes. PMID- 28878321 TI - A natural chalcone induces apoptosis in lung cancer cells: 3D-QSAR, docking and an in vivo/vitro assay. AB - This study was to study the antitumor effect of lonchocarpin (34) from traditional herbal medicine Pongamia pinnata (L.) Pierre and to reveal the underlying mechanism. The cytotoxic activities of lonchocarpin were evaluated in 10 lung cancer cell lines and it exhibited 97.5% activity at a dose of 100 MUM in the H292 cell line. A field-based quantitative structure-activity relationship (3D-QSAR) study of 37 flavonoids from P. pinnata was also performed, and the results obtained showed that the hydrophobic interaction could be the crucial factor for the antitumor activity of lonchocarpin. Molecular docking studies revealed that lonchocarpin bound stably to the BH3-binding groove of the Bcl-2 protein with hydrophobic interactions with ALA146. Also, lonchocarpin significantly reduced cell proliferation via modulating Bax/Caspase-9/Caspase-3 pathway. An apoptotic test using flow cytometry showed that lonchocarpin produced about 41.1% and 47.9% apoptosis after treatment for 24 h and 48 h, respectively. Moreover, lonchocarpin inhibited tumor growth in S180-bearing mice with an inhibition rate of 57.94, 63.40 and 72.51%, respectively at a dose of 25, 50 and 100 mg/kg. These results suggest that lonchocarpin is a potentially useful natural agent for cancer treatment. PMID- 28878322 TI - Altered topology of structural brain networks in patients with Gilles de la Tourette syndrome. AB - Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by tics. Abnormal neuronal circuits in a wide-spread structural and functional network involved in planning, execution and control of motor functions are thought to represent the underlying pathology. We therefore studied changes of structural brain networks in 13 adult GTS patients reconstructed by diffusion tensor imaging and probabilistic tractography. Structural connectivity and network topology were characterized by graph theoretical measures and compared to 13 age-matched controls. In GTS patients, significantly reduced connectivity was detected in right hemispheric networks. These were furthermore characterized by significantly reduced local graph parameters (local clustering, efficiency and strength) indicating decreased structural segregation of local subnetworks. Contrasting these results, whole brain and right hemispheric networks of GTS patients showed significantly increased normalized global efficiency indicating an overall increase of structural integration among distributed areas. Higher global efficiency was associated with tic severity (R = 0.63, p = 0.022) suggesting the clinical relevance of altered network topology. Our findings reflect an imbalance between structural integration and segregation in right hemispheric structural connectome of patients with GTS. These changes might be related to an underlying pathology of impaired neuronal development, but could also indicate potential adaptive plasticity. PMID- 28878323 TI - Permanent modifications in silica produced by ion-induced high electronic excitation: experiments and atomistic simulations. AB - The irradiation of silica with ions of specific energy larger than ~0.1 MeV/u produces very high electronic excitations that induce permanent changes in the physical, chemical and structural properties and give rise to defects (colour centres), responsible for the loss of sample transparency at specific bands. This type of irradiation leads to the generation of nanometer-sized tracks around the ion trajectory. In situ optical reflection measurements during systematic irradiation of silica samples allowed us to monitor the irradiation-induced compaction, whereas ex situ optical absorption measurements provide information on colour centre generation. In order to analyse the results, we have developed and validated an atomistic model able to quantitatively explain the experimental results. Thus, we are able to provide a consistent explanation for the size of the nanotracks, the velocity and thresholding effects for track formation, as well as, the colour centre yield per ion and the colour centre saturation density. In this work we will discuss the different processes involved in the permanent modification of silica: collective atomic motion, bond breaking, pressure-driven atom rearrangement and ultra-fast cooling. Despite the sudden lattice energy rise is the triggering and dominant step, all these processes are important for the final atomic configuration. PMID- 28878324 TI - Regional genetic diversity for NNV grouper viruses across the Indo-Asian region - implications for selecting virus resistance in farmed groupers. AB - Grouper aquaculture around Asia is impacted by the nervous necrosis virus (NNV) and, in response, host resistance to this infection is being considered as a trait for selection. However efficient selection may be confounded if there are different genetic strains of NNV within and between regions and over years. This study uses statistical approaches and assessment of "characteristic attributes" (i.e. nucleotide positions that discriminate among strains) to assess whether published and new NNV RNA2 cds sequences show genetic differentiation over geography, host species and years. Rather clear evidence was found for regional strains of NNV. Interestingly, most of the geographic defining "characteristic attributes" were in codon position three, and not translated into differences for the protein capsid (i.e. they were synonymous variations), suggesting that while NNV strains were geographically isolated and had diverged in different regions for RNA sequences, selection had largely conserved the protein sequences among regions. The apparent selection constraint on the capsid protein may mitigate the risk that despite geographic subdivision, NNV strain variability will confound genetic selection for host resistance. The existence of regional Asian NNV strains may suggest that hatcheries are at risk from NNV not only from imported material but also from endemic reservoirs. PMID- 28878325 TI - The influence of the mating type on virulence of Mucor irregularis. AB - Mucor irregularis is an emerging fungal pathogen that cause cutaneous infection and could cause death. However, little is known about its mechanism of pathogenesis. There is evidence suggesting virulence vary with mating types in fungi, including the Mucorales. Here, we characterized the mating type locus of M. irregularis and the mating type ratio of 17 clinical isolates in China. Genomic data indicated M. irregularis is heterothallic having two mating types - bearing either SexP or SexM allele. Also, we employed a mice model to study the inflammation and pathological effects of different mating types. The comparison of the inflammatory response, cytokine profiles and Th-1, Th-2 and Th-17 cells numbers in each mating type treated mice showed that the severity and disease progress were enhanced in (+) mating type treated mice. One (+/0) mutant strain, with multiple mutations at the mating locus, had defects in sexual mating ability but appeared to be more virulent than the (-) mating type. Although (+) mating type appeared to be more virulent, most of our clinical isolates presented belonged to (-) mating type. Our findings support the involvement of MAT genes in sexual fertility, and the influence of mating type on the severity of cutaneous infection. PMID- 28878326 TI - Swapping of transmembrane domains in the epithelial calcium channel TRPV6. AB - Tetrameric ion channels have either swapped or non-swapped arrangements of the S1 S4 and pore domains. Here we show that mutations in the transmembrane domain of TRPV6 can result in conversion from a domain-swapped to non-swapped fold. These results reveal structural determinants of domain swapping and raise the possibility that a single ion channel subtype can fold into either arrangement in vivo, affecting its function in normal or disease states. PMID- 28878327 TI - Accelerated Healing of Diabetic Wounds Treated with L-Glutamic acid Loaded Hydrogels Through Enhanced Collagen Deposition and Angiogenesis: An In Vivo Study. AB - We have developed L-glutamic acid (LG) loaded chitosan (CS) hydrogels to treat diabetic wounds. Although literature reports wound healing effects of poly(glutamic acid)-based materials, there are no studies on the potential of L glutamic acid in treating diabetic wounds. As LG is a direct precursor for proline synthesis, which is crucial for collagen synthesis, we have prepared CS + LG hydrogels to accelerate diabetic wound healing. Physiochemical properties of the CS + LG hydrogels showed good swelling, thermal stability, smooth surface morphology, and controlled biodegradation. The addition of LG to CS hydrogels did not alter their biocompatibility significantly. CS + LG hydrogel treatment showed rapid wound contraction compared to control and chitosan hydrogel. Period of epithelialization is significantly reduced in CS + LG hydrogel treated wounds (16 days) compared to CS hydrogel (20 days), and control (26 days). Collagen synthesis and crosslinking are also significantly improved in CS + LG hydrogel treated diabetic rats. Histopathology and immunohistochemistry results revealed that the CS + LG hydrogel dressing accelerated vascularization and macrophage recruitment to enhance diabetic wound healing. These results demonstrate that incorporation of LG can improve collagen deposition, and vascularization, and aid in faster tissue regeneration. Therefore, CS + LG hydrogels could be an effective wound dressing used to treat diabetic wounds. PMID- 28878328 TI - CLEC14a-HSP70-1A interaction regulates HSP70-1A-induced angiogenesis. AB - CLEC14a (C-type lectin domain family 14 member) is a tumor endothelial cell marker protein that is known to play an important role in tumor angiogenesis, but the basic molecular mechanisms underlying this function have not yet been clearly elucidated. In this study, using various proteomic tools, we isolated a 70-kDa protein that interacts with the C-type lectin-like domain of CLEC14a (CLEC14a CTLD) and identified it as heat shock protein 70-1A (HSP70-1A). Co immunoprecipitation showed that HSP70-1A and CLEC14a interact on endothelial cells. In vitro binding analyses identified that HSP70-1A specifically associates with the region between amino acids 43 and 69 of CLEC14a-CTLD. Competitive blocking experiments indicated that this interacting region of CLEC14a-CTLD significantly inhibits HSP70-1A-induced extracellular signal-regulated kinase (ERK) phosphorylation and endothelial tube formation by directly inhibiting CLEC14a-CTLD-mediated endothelial cell-cell contacts. Our data suggest that the specific interaction of HSP70-1A with CLEC14a may play a critical role in HSP70 1A-induced angiogenesis and that the HSP70-1A-interacting region of CLEC14a-CTLD may be a useful tool for inhibiting HSP70-1A-induced angiogenesis. PMID- 28878330 TI - The impact of wavelengths of LED light-therapy on endothelial cells. AB - Low level light therapy receives increasing interest in the fields of tissue regeneration and wound healing. Several in vivo studies demonstrated the positive effects of LLLT on angiogenesis. This study aimed to investigate the underlying properties in vitro by comparing the effects of light therapy by light emitting diodes of different wavelengths on endothelial cells in vitro. Human umbilical vein endothelial cells were treated with either 475 nm, 516 nm or 635 nm light. Control cells were not illuminated. 2D proliferation was quantified by manual counting. HUVEC migration was analyzed by performing a 2D wound scratch assay and a 3D bead assay. The influence of LLLT on early vasculogenic events was determined in a 3D fibrin co-culture model with adipose-derived stem cells. Stimulation with both red and green pulsed LED light significantly increased HUVEC proliferation and 3D migration. Moreover, HUVEC showed increased 2D migration potential with green light stimulation. The treatment with blue light was ineffective. Several parameters showed that green light was even more potent to stimulate proliferation and migration of endothelial cells than clinically well-established red light therapy. Further studies have to focus on intracellular mechanisms induced by different wavelengths in order to optimize this promising therapy in tissue regeneration. PMID- 28878329 TI - RNA Sequencing and Co-expressed Long Non-coding RNA in Modern and Wild Wheats. AB - There is an urgent need for the improvement of drought-tolerant bread and durum wheat. The huge and complex genome of bread wheat (BBAADD genome) stands as a vital obstruction for understanding the molecular mechanism underlying drought tolerance. However, tetraploid wheat (Triticum turgidum ssp., BBAA genome) is an ancestor of modern bread wheat and offers an important model for studying the drought response due to its less complex genome. Additionally, several wild relatives of tetraploid wheat have already shown a significant drought tolerance. We sequenced root transcriptome of three tetraploid wheat varieties with varying stress tolerance profiles, and built differential expression library of their transcripts under control and drought conditions. More than 5,000 differentially expressed transcripts were identified from each genotype. Functional characterization of transcripts specific to drought-tolerant genotype, revealed their association with osmolytes production and secondary metabolite pathways. Comparative analysis of differentially expressed genes and their non-coding RNA partners, long noncoding RNAs and microRNAs, provided valuable insight to gene expression regulation in response to drought stress. LncRNAs as well as coding transcripts share similar structural features in different tetraploid species; yet, lncRNAs slightly differ from coding transcripts. Several miRNA-lncRNA target pairs were detected as differentially expressed in drought stress. Overall, this study suggested an important pool of transcripts where their manipulations confer a better performance of wheat varieties under drought stress. PMID- 28878331 TI - The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant. AB - Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naive CD4 T cells. Treatment with Salp15 results in the inhibition of early signaling events and the production of the autocrine growth factor, interleukin-2. The fate of the CD4 T cells activated in the presence of Salp15 or its long-term effects are, however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished cross-antigenic antibody production even after interruption of the treatment with the protein. Transcriptionally, the salivary protein provokes an acute effect that includes known activation markers, such as Il2 or Cd44, and that fades over time. The long-term effects exerted by Salp15 do not involve the induction of either anergy traits nor increased populations of regulatory T cells. Similarly, the treatment with Salp15 does not result in B cell anergy or the generation of myeloid suppressor cells. However, Salp15 induces the increased expression of the ectoenzyme, CD73, in regulatory T cells and increased production of adenosine. Our study provides a profound characterization of the immunomodulatory activity of Salp15 and suggests that its long-term effects are due to the specific regulation of CD73. PMID- 28878332 TI - Broadband angle- and permittivity-insensitive nondispersive optical activity based on planar chiral metamaterials. AB - Because of the strong inherent resonances, the giant optical activity obtained via chiral metamaterials generally suffers from high dispersion, which has been a big stumbling block to broadband applications. In this paper, we propose a type of planar chiral metamaterial consisting of interconnected metal helix slat structures with four-fold symmetry, which exhibits nonresonant Drude-like response and can therefore avoid the highly dispersive optical activity resulting from resonances. It shows that the well-designed chiral metamaterial can achieve nondispersive and pure optical activity with high transmittance in a broadband frequency range. And the optical activity of multi-layer chiral metamaterials is proportional to the layer numbers of single-layer chiral metamaterial. Most remarkably, the broadband behaviors of nondispersive optical activity and high transmission are insensitive to the incident angles of electromagnetic waves and permittivity of dielectric substrate, thereby enabling more flexibility in polarization manipulation. PMID- 28878333 TI - Ligand activation induces different conformational changes in CXCR3 receptor isoforms as evidenced by plasmon waveguide resonance (PWR). AB - The chemokine receptor CXCR3 plays important roles in angiogenesis, inflammation and cancer. Activation studies and biological functions of CXCR3 are complex due to the presence of spliced isoforms. CXCR3-A is known as a pro-tumor receptor whereas CXCR3-B exhibits anti-tumor properties. Here, we focused on the conformational change of CXCR3-A and CXCR3-B after agonist or antagonist binding using Plasmon Waveguide Resonance (PWR). Agonist stimulation induced an anisotropic response with very distinct conformational changes for the two isoforms. The CXCR3 agonist bound CXCR3-A with higher affinity than CXCR3-B. Using various concentrations of SCH546738, a CXCR3 specific inhibitor, we demonstrated that low SCH546738 concentrations (<=1 nM) efficiently inhibited CXCR3-A but not CXCR3-B's conformational change and activation. This was confirmed by both, biophysical and biological methods. Taken together, our study demonstrates differences in the behavior of CXCR3-A and CXCR3-B upon ligand activation and antagonist inhibition which may be of relevance for further studies aimed at specifically inhibiting the CXCR3A isoform. PMID- 28878335 TI - Systemic lupus erythematosus: OX40L-expressing B cells promote SLE. PMID- 28878334 TI - Vasculitis syndromes: Tocilizumab - a new frontier for GCA therapy. PMID- 28878336 TI - Effect of GnRHR polymorphisms on in vitro fertilization and embryo transfer in patients with polycystic ovary syndrome. AB - We investigated the relationship between gonadotropin-releasing hormone receptor (GnRHR) gene polymorphisms and outcome of patients with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization and embryo transfer (IVF-ET). PCOS patients undergoing IVF-ET were selected, and infertile patients due to dysfunctional oviducts served as controls. GnRHR gene polymorphisms were detected using the polymerase chain reaction-restriction fragment length polymorphism assay. Gene-gene interaction and linkage disequilibrium tests were performed using the SHEsis software. Logistic regression analysis was performed to evaluate factors affecting outcome of patients undergoing IVF-ET. The PCOS group showed more patients with CC+CT genotypes rs12644822, rs3756159 and rs13138607 than the control group, and CC+CT genotypes and C alleles from three positions enhanced risk of PCOS. Patients with CC+CT genotypes from three positions exhibited increased serum luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH), testosterone (T) and follicles than those with TT genotypes. The haplotype analysis indicated that CCC, CCT and TCC haplotypes increased the risk of PCOS, while TCT, TTC and TTT haplotypes lowered the risk. After IVF-ET treatment, patients with CC+CT genotypes of three positions in the GnRHR gene had a lower pregnancy rate than patients with TT genotypes. Logistic regression analysis indicated that CC+CT genotypes rs12644822, rs3756159 and rs13138607 were risk factor for patients undergoing IVF-ET. In conclusion, these findings demonstrate that CC+CT genotypes rs12644822C>T, rs3756159C>T and rs13138607C>T in the GnRHR gene may contribute to a decreased pregnancy rate for PCOS patients after IVF-ET. PMID- 28878337 TI - Precise mapping of 17 deletion breakpoints within the central hotspot deletion region (introns 50 and 51) of the DMD gene. AB - Exon deletions in the human DMD gene, which encodes the dystrophin protein, are the molecular defect in 50-70% of cases of Duchenne/Becker muscular dystrophies. Deletions are preferentially clustered in the 5' (exons 2-20) and the central (exons 45-53) region of DMD, likely because local DNA structure predisposes to specific breakage or recombination events. Notably, innovative therapeutic strategies may rescue dystrophin function by homology-based specific targeting of sequences within the central DMD hot spot deletion region. To further study molecular mechanisms that generate such frequent genome variations and to identify residual intronic sequences, we sequenced 17 deletion breakpoints within introns 50 and 51 of DMD and analyzed the surrounding genomic architecture. There was no breakpoint clustering within the introns nor extensive homology between sequences adjacent to each junction. However, at or near the breakpoint, we found microhomology, short tandem repeats, interspersed repeat elements and short sequence stretches that predispose to DNA deletion or bending. Identification of such structural elements contributes to elucidate general mechanisms generating deletion within the DMD gene. Moreover, precise mapping of deletion breakpoints and localization of repeated elements are of interest, because residual intronic sequences may be targeted by therapeutic strategies based on genome editing correction. PMID- 28878338 TI - The clinical characteristics of Asian patients with classical-type Hutchinson Gilford progeria syndrome. AB - Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that shows a characteristic progeria phenotype. We conducted a questionnaire survey of 1173 tertiary hospitals in Japan and reviewed the academic reports, to identify the characteristics of Asian patients with classical HGPS. As a result, four Japanese patients were identified; this was estimated to account for approximately two-third of the prevalence in Japan. Three Asian patients who had definitively been diagnosed with classical HGPS were identified in the literature; in total, the clinical characteristics of seven patients were evaluated. Most of the clinical phenotypes of Asian patients were essentially similar to those of patients of other ethnicities, such as sclerodermatous skin, growth failure, loss of scalp hair or severe complications of cardiovascular and cerebral ischemic disease. In conclusion, to circumvent or minimalize severe vascular complication, an early diagnosis, careful observation and, promisingly, new intervention with farnesylation inhibitors may improve the prognosis of classical HGPS patients. PMID- 28878339 TI - Pathogen lineage-based genome-wide association study identified CD53 as susceptible locus in tuberculosis. AB - Tuberculosis (TB) is known to be affected by host genetic factors. We reported a specific genetic risk factor through a genome-wide association study (GWAS) that focused on young age onset TB. In this study, we further focused on the heterogeneity of Mycobacterium tuberculosis (M. tb) lineages and assessed its possible interaction with age at onset on host genetic factors. We identified the pathogen lineage in 686 Thai TB cases and GWAS stratified by both infected pathogen lineage information and age at onset revealed a genome-wide significant association of one single-nucleotide polymorphism (SNP) on chromosome 1p13, which was specifically associated with non-Beijing lineage-infected old age onset cases (P=2.54E-08, OR=1.74 (95% CI=1.43-2.12)), when we compared them to the population matched healthy controls. This SNP locates near the CD53 gene, which encodes a leukocyte surface glycoprotein. Interestingly, the expression of CD53 was also correlated with the patients' active TB status. This is the first report of a pathogen lineage-based genome-wide association study. The results suggested that host genetic risk in TB is depended upon the pathogen genetic background and demonstrate the importance of analyzing the interaction between host and pathogen genomes in TB. PMID- 28878340 TI - The pharmacogenomics of valproic acid. AB - Valproic acid is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. Adverse effects of valproic acid are rare, but hepatotoxicity is severe in particular in those younger than 2 years old and polytherapy. During valproic acid treatment, it is difficult for prescribers to predict its individual response. Recent advances in the field of pharmacogenomics have indicated variants of candidate genes that affect valproic acid efficacy and safety. In this review, a large number of candidate genes that influence valproic acid pharmacokinetics and pharmacodynamics are discussed, including metabolic enzymes, drug transporters, neurotransmitters and drug targets. Furthermore, pharmacogenomics is an important tool not only in further understanding of interindividual variability but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization. PMID- 28878341 TI - A Botrytis cinerea KLP-7 Kinesin acts as a Virulence Determinant during Plant Infection. AB - Botrytis cinerea is a necrotrophic pathogen that infects many important crops. In an attempt to unravel some novel factors that govern pathogenicity in B. cinerea, Agrobacterium tumefaciens mediated transformation (ATMT) was deployed, and a number of tagged transformants were generated. Among these, a mutant, BCM-29 exhibited slower growth rate, reduced conidia size, conidiation and penetration. The mutant was also defective in secretion of oxalic acid (OA) and exhibited reduced activities of polygalacturonase (PG) and pectin methyl esterases (PME). TAIL-PCR followed by BLAST search identified the tagged gene as KLP-7 that encodes for kinesin. Targeted deletion of KLP-7 resulted in several folds decrease in virulence of mutants as compared to WT, while complementation of the gene helped in rescue of virulence traits. This is the first time when a unique kinesin KLP-7 that is mainly found in the phylum Pezizomycotina has been linked to virulence in B. cinerea. PMID- 28878343 TI - Plasmid transfection influences the readout of nonsense-mediated mRNA decay reporter assays in human cells. AB - Messenger RNA (mRNA) turnover is a crucial and highly regulated step of gene expression in mammalian cells. This includes mRNA surveillance pathways such as nonsense-mediated mRNA decay (NMD), which assesses the fidelity of transcripts and eliminates mRNAs containing a premature translation termination codon (PTC). When studying mRNA degradation pathways, reporter mRNAs are commonly expressed in cultivated cells. Traditionally, the molecular mechanism of NMD has been characterized using pairs of reporter constructs that express the same mRNA with ("PTC-containing mRNA") or without ("wild-type mRNA") a PTC. Cell lines stably expressing an NMD reporter have been reported to yield very robust and highly reproducible results, but establishing the cell lines can be very time-consuming. Therefore, transient transfection of such reporter constructs is frequently used and allows analysis of many samples within a short period of time. However, the behavior of transiently and stably transfected NMD constructs has not been systematically compared so far. Here, we report that not all commonly used human cell lines degrade NMD targets following transient transfection. Furthermore, the degradation efficiency of NMD substrates can depend on the manner of transfection within the same cell line. This has substantial implications for the interpretation of NMD assays based on transient transfections. PMID- 28878344 TI - Compensated Row-Column Ultrasound Imaging System Using Multilayered Edge Guided Stochastically Fully Connected Random Fields. AB - The row-column method received a lot of attention for 3-D ultrasound imaging. By reducing the number of connections required to address the 2-D array and therefore reducing the amount of data to handle, this addressing method allows for real time 3-D imaging. Row-column still has its limitations: the issues of sparsity, speckle noise inherent to ultrasound, the spatially varying point spread function, and the ghosting artifacts inherent to the row-column method must all be taken into account when building a reconstruction framework. In this research, we build on a previously published system and propose an edge-guided, compensated row-column ultrasound imaging system that incorporates multilayered edge-guided stochastically fully connected conditional random fields to address the limitations of the row-column method. Tests carried out on simulated and real row-column ultrasound images show the effectiveness of our proposed system over other published systems. Visual assessment show our proposed system's potential at preserving edges and reducing speckle. Quantitative analysis shows that our proposed system outperforms previously published systems when evaluated with metrics such as Peak Signal-to-Noise Ratio, Coefficient of Correlation, and Effective Number of Looks. These results show the potential of our proposed system as an effective tool for enhancing 3-D row-column imaging. PMID- 28878342 TI - Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis. AB - Lack of CD2-associated protein (CD2AP) in mice increases podocyte apoptosis and leads to glomerulosclerosis and renal failure. We showed previously that SHIP2, a negative regulator of the PI3K/AKT signalling pathway, interacts with CD2AP. Here, we found that the expression level and activity of SHIP2 and production of reactive oxygen species (ROS) are increased in cultured CD2AP knockout (CD2AP-/-) mouse podocytes. Oxidative stress was also increased in CD2AP-/- mouse glomeruli in vivo. We found that puromycin aminonucleoside (PA), known to increase ROS production and apoptosis, increases SHIP2 activity and reduces CD2AP expression in cultured human podocytes. PDK1 and CDK2, central regulators of AKT, were downregulated in CD2AP-/- or PA-treated podocytes. Downregulation of PDK1 and CDK2, ROS generation and apoptosis were prevented by CD2AP overexpression in both models. Notably, inhibition of SHIP2 activity with a small molecule inhibitor AS1949490 ameliorated ROS production in CD2AP-/- podocytes, but, surprisingly, further reduced PDK1 expression and aggravated apoptosis. AKT- and ERK-mediated signalling was diminished and remained reduced after AS1949490 treatment in the absence of CD2AP. The data suggest that inhibition of the catalytic activity of SHIP2 is beneficial in reducing oxidative stress, but leads to deleterious increase in apoptosis in podocytes with reduced expression of CD2AP. PMID- 28878345 TI - Duration of farming is an indicator of natural restoration potential of sedge meadows. AB - Soil seed banks can be important components of ecological restoration, particularly if the species remain viable in the soil for long periods of time. A germination experiment was conducted in the greenhouse to determine seed bank viability based on length of time farmed. Soils from sedge meadows farmed between 0 and 50 years were collected in Sanjiang Plain, China. Most dominant sedges (e.g., Carex schmidtii, C. lasiocarpa) and grasses (e.g. Calamagrostis angustifolia) survived as seeds if farmed for less than 5 years, therefore fields farmed for short periods of time are the best candidates for wetland restoration. Certain important structural components (tussock-forming Carex spp.) are not retained in seed banks when farmed for 6-15 years, but the seed banks still contained viable seeds of other important sedge meadow species, which could contribute to the restoration of wetland communities. However, most sedge meadow species were missing in fields farmed for more than 16 years, which make these fields difficult to restore via natural recolonization. We conclude that the duration of farming can be used as a general indicator of the potential of natural restoration for sedge meadows. This information could be used to determine which wetlands might be targeted for restoration. PMID- 28878346 TI - Impact of phenolic compounds in the acyl homoserine lactone-mediated quorum sensing regulatory pathways. AB - Quorum sensing (QS) is a cell density-dependent regulation of virulent bacterial gene expression by autoinducers that potentially pertains in the epidemic of bacterial virulence. This study was initially designed to evaluate the effect of 5 phenolic compounds in the modulation of QS and virulence factors of Chromobacterium violaceum and Pseudomonas aeruginosa, and to determine the mechanisms of their effects. Biosensor strains were used to assess antibacterial and anti-QS effect of these compounds. Only methyl gallate (MG) among these compounds demonstrated profound anti-QS effect in the preliminary study, and thus only MG was utilized further to evaluate the effects on the synthesis and activity of acyl homoserine lactone (AHL) in C. violaceum and on the modulation of biofilm, motility, proteolytic, elastase, pyocyanin, and rhamnolipid activity in P. aeruginosa. Finally, the effect of MG on the expression of QS-regulated genes of P. aeruginosa was verified. MG suppressed both the synthesis and activity of AHL in C. violaceum. It also restricted the biofilm formation and other QS-associated virulence factor of P. aeruginosa. MG concentration dependently suppressed the expression of lasI/R, rhlI/R, and pqsA of P. aeruginosa and was non-toxic in in vitro study. This is the first report of the anti-QS mechanism of MG. PMID- 28878347 TI - Targeting Bacterial Cardiolipin Enriched Microdomains: An Antimicrobial Strategy Used by Amphiphilic Aminoglycoside Antibiotics. AB - Some bacterial proteins involved in cell division and oxidative phosphorylation are tightly bound to cardiolipin. Cardiolipin is a non-bilayer anionic phospholipid found in bacterial inner membrane. It forms lipid microdomains located at the cell poles and division plane. Mechanisms by which microdomains are affected by membrane-acting antibiotics and the impact of these alterations on membrane properties and protein functions remain unclear. In this study, we demonstrated cardiolipin relocation and clustering as a result of exposure to a cardiolipin-acting amphiphilic aminoglycoside antibiotic, the 3',6-dinonyl neamine. Changes in the biophysical properties of the bacterial membrane of P. aeruginosa, including decreased fluidity and increased permeability, were observed. Cardiolipin-interacting proteins and functions regulated by cardiolipin were impacted by the amphiphilic aminoglycoside as we demonstrated an inhibition of respiratory chain and changes in bacterial shape. The latter effect was characterized by the loss of bacterial rod shape through a decrease in length and increase in curvature. It resulted from the effect on MreB, a cardiolipin dependent cytoskeleton protein as well as a direct effect of 3',6-dinonyl neamine on cardiolipin. These results shed light on how targeting cardiolipin microdomains may be of great interest for developing new antibacterial therapies. PMID- 28878348 TI - FOXF1 transcription factor promotes lung regeneration after partial pneumonectomy. AB - FOXF1, a member of the forkhead box family of transcription factors, has been previously shown to be critical for lung development, homeostasis, and injury responses. However, the role of FOXF1 in lung regeneration is unknown. Herein, we performed partial pneumonectomy, a model of lung regeneration, in mice lacking one Foxf1 allele in endothelial cells (PDGFb-iCre/Foxf1 fl/+ mice). Endothelial cell proliferation was significantly reduced in regenerating lungs from mice deficient for endothelial Foxf1. Decreased endothelial proliferation was associated with delayed lung regeneration as shown by reduced respiratory volume in Foxf1-deficient lungs. FACS-sorted endothelial cells isolated from regenerating PDGFb-iCre/Foxf1 fl/+ and control lungs were used for RNAseq analysis to identify FOXF1 target genes. Foxf1 deficiency altered expression of numerous genes including those regulating extracellular matrix remodeling (Timp3, Adamts9) and cell cycle progression (Cdkn1a, Cdkn2b, Cenpj, Tubb4a), which are critical for lung regeneration. Deletion of Foxf1 increased Timp3 mRNA and protein, decreasing MMP14 activity in regenerating lungs. ChIPseq analysis for FOXF1 and histone methylation marks identified DNA regulatory regions within the Cd44, Cdkn1a, and Cdkn2b genes, indicating they are direct FOXF1 targets. Thus FOXF1 stimulates lung regeneration following partial pneumonectomy via direct transcriptional regulation of genes critical for extracellular matrix remodeling and cell cycle progression. PMID- 28878349 TI - Peptide-mediated delivery of donor mitochondria improves mitochondrial function and cell viability in human cybrid cells with the MELAS A3243G mutation. AB - The cell penetrating peptide, Pep-1, has been shown to facilitate cellular uptake of foreign mitochondria but further research is required to evaluate the use of Pep-1-mediated mitochondrial delivery (PMD) in treating mitochondrial defects. Presently, we sought to determine whether mitochondrial transplantation rescue mitochondrial function in a cybrid cell model of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) disease. Following PMD, recipient cells had internalized donor mitochondria after 1 h, and expressed higher levels of normal mitochondrial DNA, particularly at the end of the treatment and 11 days later. After 4 days, mitochondrial respiratory function had recovered and biogenesis was evident in the Pep-1 and PMD groups, compared to the untreated MELAS group. However, only PMD was able to reverse the fusion-to fission ratio of mitochondrial morphology, and mitochondria shaping proteins resembled the normal pattern seen in the control group. Cell survival following hydrogen peroxide-induced oxidative stress was also improved in the PMD group. Finally, we observed that PMD partially normalized cytokine expression, including that of interleukin (IL)-7, granulocyte macrophage-colony-stimulating factor (GM CSF), and vascular endothelial growth factor (VEGF), in the MELAS cells. Presently, our data further confirm the protective effects of PMD as well in MELAS disease. PMID- 28878350 TI - Functional association of cellular microtubules with viral capsid assembly supports efficient hepatitis B virus replication. AB - Viruses exploit host factors and environment for their efficient replication. The virus-host interaction mechanisms for achieving an optimal hepatitis B virus (HBV) replication have been largely unknown. Here, a single cell cloning revealed that HepAD38 cells, a widely-used HBV-inducible cell line, contain cell clones with diverse permissiveness to HBV replication. The HBV permissiveness was impaired upon treatment with microtubule inhibitor nocodazole, which was identified as an HBV replication inhibitor from a pharmacological screening. In the microtubule-disrupted cells, the efficiency of HBV capsid assembly was remarkably decreased without significant change in pre-assembly process. We further found that HBV core interacted with tubulin and co-localized with microtubule-like fibriforms, but this association was abrogated upon microtubule disassembly agents, resulting in attenuation of capsid formation. Our data thus suggest a significant role of microtubules in the efficient capsid formation during HBV replication. In line with this, a highly HBV permissive cell clone of HepAD38 cells showed a prominent association of core-microtubule and thus a high capacity to support the capsid formation. These findings provide a new aspect of virus-cell interaction for rendering efficient HBV replication. PMID- 28878351 TI - Tillage and nitrogen fertilization enhanced belowground carbon allocation and plant nitrogen uptake in a semi-arid canola crop-soil system. AB - Carbon (C) and nitrogen (N) allocation and assimilation are coupled processes, likely influencing C accumulation, N use efficiency and plant productivity in agro-ecosystems. However, dynamics and responses of these processes to management practices in semi-arid agro-ecosystems are poorly understood. A field-based 13CO2 and urea-15N pulse labelling experiment was conducted to track how C and N allocation and assimilation during canola growth from flowering to maturity were affected by short-term (2-year) tillage (T) and no-till (NT) with or without 100 kg urea-N ha-1 (T-0, T-100, NT-0, NT-100) on a Luvisol in an Australian semi-arid region. The T-100 caused greater (P < 0.05) belowground C allocation and higher (P < 0.05) translocation of soil N to shoots and seeds, compared to other treatments. Microbial N uptake was rapid and greatest in the fertilized (cf. non fertilized) treatments, followed by a rapid release of microbial immobilized N, thus increasing N availability for plant uptake. In contrast, management practices had insignificant impact on soil C and N stocks, aggregate stability, microbial biomass, and 13C retention in aggregate-size fractions. In conclusion, tillage and N fertilization increased belowground C allocation and crop N uptake and yield, possibly via enhancing root-microbial interactions, with minimal impact on soil properties. PMID- 28878353 TI - Interactive effect of gibberellic acid and NPK fertilizer combinations on ramie yield and bast fibre quality. AB - Understanding the effects of different combinations of nitrogen (N), phosphorus (P) and potassium (K) fertilizers and the effects of GA3 (gibberellic acid) foliar spray on the fiber quality and yield of ramie are important for maximizing the economic value of these plants. Three pot experiments were conducted using low NPK (140:70:140 kg/ha), normal NPK (280:140:280 kg/ha), and low NPK + GA3 (10 mg/L) treatments. In each experiment, following fertilizers were applied: no fertilizer (control), N, P, K, NP, NK, PK, and NPK. Ramie was harvested three times from each plant; ramie grown without fertilizers had significantly lower biomass and yield than plants grown with fertilizers. At both normal and low fertilization rates, application of NPK resulted in greater growth and yield than application of N, P, K, NP, NK, or PK. Unfertilized plants produced the thinnest fibres (22-24 um), with lowest elongation rate (3.0-3.1%) and breaking strength (22.7-23.3 cN). Fibre yield and fibre quality were improved by application of GA3 + fertilizers. Maximum fibre yield was obtained at low NPK + GA3 treatment, resulting in 65-81% more yield than low NPK alone. GA3 with low NPK treatment significantly improved fibre diameter, fibre elongation, and breaking strength compared to both NPK alone and control treatment. PMID- 28878352 TI - S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells. AB - The Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL. PMID- 28878354 TI - Japanese Food Data Challenge the Claimed Link between Fukushima's Releases and Recently Observed Thyroid Cancer Increase in Japan. AB - Internal, high-dose exposure with radioiodine is known to increase the risk for thyroid cancer in children and adolescents. Ingestion of contaminated food is generally regarded a dominant route of internal exposure. We analyzed the huge data set of the post-Fukushima food monitoring campaign and deployed a conservative model for the estimation of the doses to the general public in a worst-case scenario. Our data suggest that the committed equivalent ingestion doses to the thyroids of the affected Japanese public, even in the utmost conservative approach, remained below the limit on ingestion of radioiodine in foodstuffs and beverages of 50 mSv (as thyroid equivalent dose). This level of 50 mSv is also the intervention level for the administration of stable iodine, mainly after inhalation. Our study hence suggests that, based on the food data, the internal exposure of Japanese residents was too low to cause a statistically discernible increase in thyroid cancer, even if the contribution from inhalation is taken into account. The data also indicate that the governmental efforts in the food monitoring campaign were successful and cut the thyroid doses to the public by a factor of approximately 3 compared to a scenario without any monitoring. PMID- 28878355 TI - Comparative study on cellular entry of incinerated ancient gold particles (Swarna Bhasma) and chemically synthesized gold particles. AB - Gold nanoparticles (AuNPs) are used for a number of imaging and therapeutic applications in east and western part of the world. For thousands of years, the traditional Indian Ayurvedic approach to healing involves the use of incinerated gold ash, prepared with a variety of plant extracts and minerals depending on the region. Here, we describe the characterization of incinerated gold particles (IAuPs) in HeLa (human cells derived from cervical cancer) and HFF-1 (human foreskin fibroblast cells) in comparison to synthesized citrate-capped gold nanoparticles (AuNPs). We found that while individual IAuP crystallites are around 60 nm in size, they form large aggregates with a mean diameter of 4711.7 nm, some of which can enter cells. Fewer cells appeared to have IAuPs compared to AuNPs, although neither type of particle was toxic to cells. Imaging studies revealed that IAuPs were in vesicles, cytosol, or in the nucleus. We found that their nuclear accumulation likely occurred after nuclear envelope breakdown during cell division. We also found that larger IAuPs entered cells via macropinocytosis, while smaller particles entered via clathrin-dependent receptor mediated endocytosis. PMID- 28878356 TI - Selection of reference genes suitable for normalization of qPCR data under abiotic stresses in bioenergy crop Arundo donax L. AB - Suitable reference gene selection in qRT-PCR is a key pre-requisite to produce reliable data in gene expression analyses. In this study, novel primers for six commonly used reference genes (AC1, TLF, Act2, TUB alpha, EF-1alpha and GAPDH) plus two new candidates (pDUF221 and RPN6) were designed and comparatively tested for expression stability under abiotic stresses (osmotic, heavy metal and heat shock) in shoot, root and their combination of Arundo donax L., a raising non food energy crop. Expression stability rankings from the most to the least stable gene in each condition and in two tissues (young shoots and roots) were generated with geNorm, NormFinder and BestKeeper programs. All programs provided similar rankings and, strikingly, in most cases identified one of the new candidates, RPN6, as the most suitable reference gene. This novel set of reliable references allows to choose either the best combination of reference genes across multiple stress/organ conditions or to select condition-specific genes that can improve the quality of qRT-PCR analysis. This work provides a solid basis for the functional characterization of A. donax, by enabling accurate quantification of the transcriptional responsiveness under a series of common stress conditions of any gene of interest in this promising biomass/bioenergy species. PMID- 28878357 TI - Semi-transparent Perovskite Solar Cells Developed by Considering Human Luminosity Function. AB - Semi-transparent solar cells draw a great deal of attention because their applications include, for instance, photovoltaic windows. General approach to semi-transparent cells is using thin active layers or island-type structures. Here we take human luminosity function into account, and develop solar cells that harvest photons in the wavelength regions in which human eyes are less sensitive to light. We used an organic-inorganic hybrid perovskite, which is sensitive to light particularly in the blue and deep-blue regions, and plasmonic silver nanocubes that enhance light harvesting in the red and deep-red ranges. In order to tune the plasmonic wavelength to that range, we took advantage of electrode coupled plasmons (ECPs). We prepared non-plasmonic semi-transparent solar cells, and reduced the active layer thickness and introduced ECPs, so that the visual transparency index and power conversion efficiency of the cell were improved by 28% and 6%, respectively, of the initial values. PMID- 28878359 TI - Directed Differentiation of Human Induced Pluripotent Stem Cells into Fallopian Tube Epithelium. AB - The fallopian tube epithelium (FTE) has been recognized as a site of origin of high-grade serous ovarian cancer (HGSC). However, the absence of relevant in vitro human models that can recapitulate tissue-specific architecture has hindered our understanding of FTE transformation and initiation of HGSC. Here, induced pluripotent stem cells (iPSCs) were used to establish a novel 3 dimensional (3D) human FTE organoid in vitro model containing the relevant cell types of the human fallopian tube as well as a luminal architecture that closely reflects the organization of fallopian tissues in vivo. Modulation of Wnt and BMP signaling directed iPSC differentiation into Mullerian cells and subsequent use of pro-Mullerian growth factors promoted FTE precursors. The expression and localization of Mullerian markers verified correct cellular differentiation. An innovative 3D growth platform, which enabled the FTE organoid to self-organize into a convoluted luminal structure, permitted matured differentiation to a FTE lineage. This powerful human-derived FTE organoid model can be used to study the earliest stages of HGSC development and to identify novel and specific biomarkers of early fallopian tube epithelial cell transformation. PMID- 28878360 TI - Spatial inhomogeneity and temporal dynamics of a 2D electron gas in interaction with a 2D adatom gas. AB - Fundamental interest for 2D electron gas (2DEG) systems has been recently renewed with the advent of 2D materials and their potential high-impact applications in optoelectronics. Here, we investigate a 2DEG created by the electron transfer from a Ag adatom gas deposited on a Si(111) [Formula: see text]-Ag surface to an electronic surface state. Using low-energy electron microscopy (LEEM), we measure the Ag adatom gas concentration and the 2DEG-induced charge transfer. We demonstrate a linear dependence of the surface work function change on the Ag adatom gas concentration. A breakdown of the linear relationship is induced by the occurrence of the Ag adatom gas superstructure identified as Si(111) [Formula: see text]-Ag only observed below room temperature. We evidence below room temperature a confinement of the 2DEG on atomic terraces characterised by spatial inhomogeneities of the 2DEG-induced charge transfer along with temporal fluctuations. These variations mirror the Ag adatom gas concentration changes induced by the growth of 3D Ag islands and the occurrence of an Ehrlich-Schwoebel diffusion barrier of 155 +/- 10 meV. PMID- 28878361 TI - Scatter-plate microscope for lensless microscopy with diffraction limited resolution. AB - Scattering media have always been looked upon as an obstacle in imaging. Various methods, ranging from holography to phase compensation as well as to correlation techniques, have been proposed to cope with this obstacle. We, on the other hand, have a different understanding about the role of the diffusing media. In this paper we propose and demonstrate a 'scatter-plate microscope' that utilizes the diffusing property of the random medium for imaging micro structures with diffraction-limited resolution. The ubiquitous property of the speckle patterns permits to exploit the scattering medium as an ultra-thin lensless microscope objective with a variable focal length and a large working distance. The method provides a light, flexible and cost effective imaging device as an alternative to conventional microscope objectives. In principle, the technique is also applicable to lensless imaging in UV and X-ray microscopy. Experiments were performed with visible light to demonstrate the microscopic imaging of USAF resolution test target and a biological sample with varying numerical aperture (NA) and magnifications. PMID- 28878362 TI - Highly Efficient Colored Perovskite Solar Cells Integrated with Ultrathin Subwavelength Plasmonic Nanoresonators. AB - Highly efficient colored perovskite solar cells that exploit localized surface plasmon resonances in ultrathin subwavelength plasmonic nanoresonators are demonstrated. Localized resonances in ultrathin metal nano-strip optical resonators consisting of an array of metallic subwavelength nanowires on a transparent substrate, fabricated by using low-cost nanoimprint lithography over a large area, lead to a sharp peak in a reflection spectrum for distinctive color generation with angle-insensitive property up to 60 degrees , and simultaneously transmit the complementary spectrum of visible light that can be efficiently harvested by the perovskite solar cells for electric power generation. The plasmonic color filter-integrated perovskite solar cells provide 10.12%, 8.17% and 7.72% of power conversion efficiencies with capabilities of creating vivid reflective red, green and blue colors. The scheme described in this work could be applied to a variety of applications such as power-generating decorations, tandem cells, power-saving wearable devices and energy-efficient reflective display technologies. PMID- 28878358 TI - Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients. AB - The oncogenic mechanisms of overnutrition, a confirmed independent cancer risk factor, remain poorly understood. Herein, we report that enoyl-CoA hydratase-1 (ECHS1), the enzyme involved in the oxidation of fatty acids (FAs) and branched chain amino acids (BCAAs), senses nutrients and promotes mTOR activation and apoptotic resistance. Nutrients-promoted acetylation of lys101 of ECHS1 impedes ECHS1 activity by impairing enoyl-CoA binding, promoting ECHS1 degradation and blocking its mitochondrial translocation through inducing ubiquitination. As a result, nutrients induce the accumulation of BCAAs and FAs that activate mTOR signaling and stimulate apoptosis, respectively. The latter was overcome by selection of BCL-2 overexpressing cells under overnutrition conditions. The oncogenic effects of nutrients were reversed by SIRT3, which deacetylates lys101 acetylation. Severely decreased ECHS1, accumulation of BCAAs and FAs, activation of mTOR and overexpression of BCL-2 were observed in cancer tissues from metabolic organs. Our results identified ECHS1, a nutrients-sensing protein that transforms nutrient signals into oncogenic signals.Overnutrition has been linked to increased risk of cancer. Here, the authors show that exceeding nutrients suppress Enoyl-CoA hydratase-1 (ECHS1) activity by inducing its acetylation resulting in accumulation of fatty acids and branched-chain amino acids and oncogenic mTOR activation. PMID- 28878363 TI - A TCR-based Chimeric Antigen Receptor. AB - Effector T cells equipped with engineered antigen receptors specific for cancer targets have proven to be very efficient. Two methods have emerged: the Chimeric Antigen Receptors (CARs) and T-cell Receptor (TCR) redirection. Although very potent, CAR recognition is limited to membrane antigens which represent around 1% of the total proteins expressed, whereas TCRs have the advantage of targeting any peptide resulting from cellular protein degradation. However, TCRs depend on heavy signalling machinery only present in T cells which restricts the type of eligible therapeutic cells. Hence, an introduced therapeutic TCR will compete with the endogenous TCR for the signalling proteins and carries the potential risk of mixed dimer formation giving rise to a new TCR with unpredictable specificity. We have fused a soluble TCR construct to a CAR-signalling tail and named the final product TCR-CAR. We here show that, if expressed, the TCR-CAR conserved the specificity and the functionality of the original TCR. In addition, we demonstrate that TCR-CAR redirection was not restricted to T cells. Indeed, after transduction, the NK cell line NK-92 became TCR positive and reacted against pMHC target. This opens therapeutic avenues combing the killing efficiency of NK cells with the diversified target recognition of TCRs. PMID- 28878364 TI - Analysis and imaging of biocidal agrochemicals using ToF-SIMS. AB - ToF-SIMS has been increasingly widely used in recent years to look at biological matrices, in particular for biomedical research, although there is still a lot of development needed to maximise the value of this technique in the life sciences. The main issue for biological matrices is the complexity of the mass spectra and therefore the difficulty to specifically and precisely detect analytes in the biological sample. Here we evaluated the use of ToF-SIMS in the agrochemical field, which remains a largely unexplored area for this technique. We profiled a large number of biocidal active ingredients (herbicides, fungicides, and insecticides); we then selected fludioxonil, a halogenated fungicide, as a model compound for more detailed study, including the effect of co-occurring biomolecules on detection limits. There was a wide range of sensitivity of the ToF-SIMS for the different active ingredient compounds, but fludioxonil was readily detected in real-world samples (wheat seeds coated with a commercial formulation). Fludioxonil did not penetrate the seed to any great depth, but was largely restricted to a layer coating the seed surface. ToF-SIMS has clear potential as a tool for not only detecting biocides in biological samples, but also mapping their distribution. PMID- 28878365 TI - Impact of biology knowledge on the conservation and management of large pelagic sharks. AB - Population growth rate, which depends on several biological parameters, is valuable information for the conservation and management of pelagic sharks, such as blue and shortfin mako sharks. However, reported biological parameters for estimating the population growth rates of these sharks differ by sex and display large variability. To estimate the appropriate population growth rate and clarify relationships between growth rate and relevant biological parameters, we developed a two-sex age-structured matrix population model and estimated the population growth rate using combinations of biological parameters. We addressed elasticity analysis and clarified the population growth rate sensitivity. For the blue shark, the estimated median population growth rate was 0.384 with a range of minimum and maximum values of 0.195-0.533, whereas those values of the shortfin mako shark were 0.102 and 0.007-0.318, respectively. The maturity age of male sharks had the largest impact for blue sharks, whereas that of female sharks had the largest impact for shortfin mako sharks. Hypotheses for the survival process of sharks also had a large impact on the population growth rate estimation. Both shark maturity age and survival rate were based on ageing validation data, indicating the importance of validating the quality of these data for the conservation and management of large pelagic sharks. PMID- 28878366 TI - The utility of neutrophil to lymphocyte ratio and fluid sequestration as an early predictor of severe acute pancreatitis. AB - It is important to identify the patients with high-risk progression to develop severe acute pancreatitis (SAP). The study was to assess whether neutrophil to lymphocyte ratio (NLR) and fluid sequestration (FS) could represent useful markers for predicting the severity. A total of 1639 patients who underwent clinical diagnosis of AP was performed. Various serologic and clinical parameters on admission were investigated. Chronologic change in NLR and FS were analyzed, and theirs utility for predicting severity of AP was evaluated by receiver operator characteristic (ROC) curve analysis. Correlation analysis was assessed by Spearman's rank test. NLR and FS levels were both increased significantly in SAP and positively correlated with Ranson score and hospital stays. The ROC curve analyses showed the optimal cut-off values of NLR for admission with day0, day1, day2 were 9.64, 6.66 and 6.50, giving sensitivity of 77-82%. The optimal cut-off values of FS for admission with day1, day2, day3 were 1375 ml, 2345 ml and 3424 ml, giving sensitivity of 62-75%. Moreover, measurement of NLR and FS together exhibited a similar area under curve (AUC) and sensitivity for SAP prediction compared with the those of Ranson score. Increase of NLR and FS are correlated with severity and can be suggested as a predictive factor in an early stage of AP. PMID- 28878367 TI - FUT2 non-secretor status is associated with altered susceptibility to symptomatic enterotoxigenic Escherichia coli infection in Bangladeshis. AB - Polymorphisms of the FUT2 gene alters glycan ABO(H) blood group and Lewis antigen expression (commonly known as non-secretor status) in the small intestinal mucosa. Whilst non-secretor status affects 20% of the population worldwide, it has been reported to be present in up to 40% of all Bangladeshis. Furthermore, Bangladeshi children are reportedly more susceptible to symptomatic enterotoxigenic Escherichia coli (ETEC) infection if they are non-secretors. Therefore, in an attempt to identify a non-secretor status genotypic biomarker of altered susceptibility to ETEC infection, we used the 1000 Genomes Project to identify three population related non-synonymous FUT2 single nucleotide polymorphisms (SNPs). We then assessed the genotypic frequency of these SNPs in Bangladeshi children who had been clinically monitored for ETEC infection. One novel missense FUT2 SNP, rs200157007-TT and the earlier established rs601338-AA SNP were shown to be causing non-secretor status, with these SNPs being associated with symptomatic but not asymptomatic ETEC infection. Moreover, rs200157007-TT and rs601338-AA were associated with symptomatic but not asymptomatic ETEC infection irrespective of the child's Lewis secretor status, suggesting FUT2, the regulator of Lewis and ABO(H) antigens in the intestinal mucosa, could be a host genotypic feature affecting susceptibility to ETEC infection. PMID- 28878368 TI - Cryo-EM Studies of Drp1 Reveal Cardiolipin Interactions that Activate the Helical Oligomer. AB - Dynamins are mechano-chemical GTPases involved in the remodeling of cellular membranes. In this study, we have investigated the mechanism of dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission. To date, it is unclear how Drp1 assembles on the mitochondrial outer membrane in response to different lipid signals to induce membrane fission. Here, we present cryo-EM structures of Drp1 helices on nanotubes with distinct lipid compositions to mimic membrane interactions with the fission machinery. These Drp1 polymers assemble exclusively through stalk and G-domain dimerizations, which generates an expanded helical symmetry when compared to other dynamins. Interestingly, we found the characteristic gap between Drp1 and the lipid bilayer was lost when the mitochondrial specific lipid cardiolipin was present, as Drp1 directly interacted with the membrane. Moreover, this interaction leads to a change in the helical structure, which alters G-domain interactions to enhance GTPase activity. These results demonstrate how lipid cues at the mitochondrial outer membrane (MOM) can alter Drp1 structure to activate the fission machinery. PMID- 28878369 TI - Peroxisome Proliferator-Activated Receptor Gamma in Obesity and Colorectal Cancer: the Role of Epigenetics. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that is deregulated in obesity. PPARgamma exerts diverse antineoplastic effects. Attempting to determine the clinical relevance of the epigenetic mechanisms controlling the expression PPARgamma and susceptibility to colorectal cancer (CRC) in obese subjects, this study investigated the role of some microRNAs and DNA methylation on the deregulation of PPARgamma. Seventy CRC patients (34 obese and 36 lean), 22 obese and 24 lean healthy controls were included. MicroRNA levels were measured in serum. PPARgamma promoter methylation was evaluated in peripheral blood mononuclear cells (PBMC). PPARgamma level was evaluated by measuring mRNA level in PBMC and protein level in serum. The tested microRNAs (miR-27b, 130b and 138) were significantly upregulated in obese and CRC patients. Obese and CRC patients had significantly low levels of PPARgamma. A significant negative correlation was found between PPARgamma levels and the studied microRNAs. There was a significant PPARgamma promoter hypermethylation in CRC patients that correlated to low PPARgamma levels. Our results suggest that upregulation of microRNAs 27b, 130b and 138 is associated with susceptibility to CRC in obese subjects through PPARgamma downregulation. Hypermethylation of PPARgamma gene promoter is associated with CRC through suppression of PPARgamma regardless of BMI. PMID- 28878370 TI - Reward: Restraint from risky reward. PMID- 28878371 TI - Reward: Eating goes down a treat. PMID- 28878373 TI - Decision making: Making hasty decisions. PMID- 28878372 TI - The use of brain organoids to investigate neural development and disease. AB - Understanding the development and dysfunction of the human brain is a major goal of neurobiology. Much of our current understanding of human brain development has been derived from the examination of post-mortem and pathological specimens, bolstered by observations of developing non-human primates and experimental studies focused largely on mouse models. However, these tissue specimens and model systems cannot fully capture the unique and dynamic features of human brain development. Recent advances in stem cell technologies that enable the generation of human brain organoids from pluripotent stem cells (PSCs) promise to profoundly change our understanding of the development of the human brain and enable a detailed study of the pathogenesis of inherited and acquired brain diseases. PMID- 28878374 TI - Above-threshold scattering about a Feshbach resonance for ultracold atoms in an optical collider. AB - Ultracold atomic gases have realized numerous paradigms of condensed matter physics, where control over interactions has crucially been afforded by tunable Feshbach resonances. So far, the characterization of these Feshbach resonances has almost exclusively relied on experiments in the threshold regime near zero energy. Here, we use a laser-based collider to probe a narrow magnetic Feshbach resonance of rubidium above threshold. By measuring the overall atomic loss from colliding clouds as a function of magnetic field, we track the energy-dependent resonance position. At higher energy, our collider scheme broadens the loss feature, making the identification of the narrow resonance challenging. However, we observe that the collisions give rise to shifts in the center-of-mass positions of outgoing clouds. The shifts cross zero at the resonance and this allows us to accurately determine its location well above threshold. Our inferred resonance positions are in excellent agreement with theory.Studies on energy dependent scattering of ultracold atoms were previously carried out near zero collision energies. Here, the authors observe a magnetic Feshbach resonance in ultracold Rb collisions for above-threshold energies and their method can also be used to detect higher partial wave resonances. PMID- 28878375 TI - Fasting glucose and body mass index as predictors of activity in breast cancer patients treated with everolimus-exemestane: The EverExt study. AB - Evidence on everolimus in breast cancer has placed hyperglycemia among the most common high grade adverse events. Anthropometrics and biomarkers of glucose metabolism were investigated in a observational study of 102 postmenopausal, HR + HER2- metastatic breast cancer patients treated with everolimus-exemestane in first and subsequent lines. Best overall response (BR) and clinical benefit rate (CBR) were assessed across subgroups defined upon fasting glucose (FG) and body mass index (BMI). Survival was estimated by Kaplan-Meier method and log-rank test. Survival predictors were tested in Cox models. Median follow up was 12.4 months (1.0-41.0). The overall cohort showed increasing levels of FG and decreasing BMI (p < 0.001). Lower FG fasting glucose at BR was more commonly associated with C/PR or SD compared with PD (p < 0.001). We also observed a somewhat higher BMI associated with better response (p = 0.052). More patients in the lowest FG category achieved clinical benefit compared to the highest (p < 0.001), while no relevant differences emerged for BMI. Fasting glucose at re assessment was also predictive of PFS (p = 0.037), as confirmed in models including BMI and line of therapy (p = 0.049). Treatment discontinuation was significantly associated with changes in FG (p = 0.014). Further research is warranted to corroborate these findings and clarify the underlying mechanisms. PMID- 28878377 TI - Calcium ion regulation by BAPTA-AM and ruthenium red improved the fertilisation capacity and developmental ability of vitrified bovine oocytes. AB - Vitrification reduces the fertilisation capacity and developmental ability of mammalian oocytes; this effect is closely associated with an abnormal increase of cytoplasmic free calcium ions ([Ca2+]i). However, little information about the mechanism by which vitrification increases [Ca2+]i levels or a procedure to regulate [Ca2+]i levels in these oocytes is available. Vitrified bovine oocytes were used to analyse the effect of vitrification on [Ca2+]i, endoplasmic reticulum Ca2+ (ER Ca2+), and mitochondrial Ca2+ (mCa2+) levels. Our results showed that vitrification, especially with dimethyl sulfoxide (DMSO), can induce ER Ca2+ release into the cytoplasm, consequently increasing the [Ca2+]i and mCa2+ levels. Supplementing the cells with 10 MUM 1,2-bis (o-aminophenoxy)ethane N,N,N',N'-tetraacetic acid (BAPTA-AM or BAPTA) significantly decreased the [Ca2+]i level and maintained the normal distribution of cortical granules in the vitrified bovine oocytes, increasing their fertilisation ability and cleavage rate after in vitro fertilisation (IVF). Treating vitrified bovine oocytes with 1 MUM ruthenium red (RR) significantly inhibited the Ca2+ flux from the cytoplasm into mitochondria; maintained normal mCa2+ levels, mitochondrial membrane potential, and ATP content; and inhibited apoptosis. Treating vitrified oocytes with a combination of BAPTA and RR significantly improved embryo development and quality after IVF. PMID- 28878376 TI - Impulsivity influences betting under stress in laboratory gambling. AB - Although recent research suggests that acute stress influences subsequent decision-making under ambiguity, less is known about the role of personality variables in this relationship. This study tested whether impulsivity traits and acute stress differentially influence the way in which a prior feedback is incorporated into further decisions involving ambiguity. Sixty college students (50% male; aged 18-25 years) were randomly assigned to a stress versus a non stress condition before completing a laboratory gambling task. The results revealed that independently of the stress condition, subjects behaved as if the odds of winning increase after a single loss. Additionally, stress effects varied as a function of impulsivity traits. Individuals who lacked perseverance (i.e., had difficulty focusing on a difficult or boring task) gambled more after experiencing a loss in the stress condition than did those in the control condition. The present study supports that impulsivity traits can explain the differential effect of stress on the relationship between prior feedback and choices made under ambiguity. PMID- 28878378 TI - Prokaryotic and Highly-Repetitive WD40 Proteins: A Systematic Study. AB - As an ancient protein family, the WD40 repeat proteins often play essential roles in fundamental cellular processes in eukaryotes. Although investigations of eukaryotic WD40 proteins have been frequently reported, prokaryotic ones remain largely uncharacterized. In this paper, we report a systematic analysis of prokaryotic WD40 proteins and detailed comparisons with eukaryotic ones. About 4,000 prokaryotic WD40 proteins have been identified, accounting for 6.5% of all WD40s. While their abundances are less than 0.1% in most prokaryotes, they are enriched in certain species from Cyanobacteria and Planctomycetes, and participate in various functions such as prokaryotic signal transduction and nutrient synthesis. Comparisons show that a higher proportion of prokaryotic WD40s tend to contain multiple WD40 domains and a large number of hydrogen bond networks. The observation that prokaryotic WD40 proteins tend to show high internal sequence identity suggests that a substantial proportion of them (~20%) should be formed by recent or young repeat duplication events. Further studies demonstrate that the very young WD40 proteins, i.e., Highly-Repetitive WD40s, should be of higher stability. Our results have presented a catalogue of prokaryotic WD40 proteins, and have shed light on their evolutionary origins. PMID- 28878379 TI - Novel oscillator model with damping factor for plasmon induced transparency in waveguide systems. AB - We introduce a novel two-oscillator model with damping factor to describe the plasmon induced transparency (PIT) in a bright-dark model plasmonic waveguide system. The damping factor gamma in the model can be calculated from metal conductor damping factor gamma c and dielectric damping factor gamma d . We investigate the influence of geometry parameters and damping factor gamma on transmission spectra as well as slow-light effects in the plasmonic waveguide system. We can find an obvious PIT phenomenon and realize a considerable slow light effect in the double-cavities system. This work may provide guidance for optical switching and plasmon-based information processing. PMID- 28878380 TI - An in-silico approach to predict and exploit synthetic lethality in cancer metabolism. AB - Synthetic lethality is a promising concept in cancer research, potentially opening new possibilities for the development of more effective and selective treatments. Here, we present a computational method to predict and exploit synthetic lethality in cancer metabolism. Our approach relies on the concept of genetic minimal cut sets and gene expression data, demonstrating a superior performance to previous approaches predicting metabolic vulnerabilities in cancer. Our genetic minimal cut set computational framework is applied to evaluate the lethality of ribonucleotide reductase catalytic subunit M1 (RRM1) inhibition in multiple myeloma. We present a computational and experimental study of the effect of RRM1 inhibition in four multiple myeloma cell lines. In addition, using publicly available genome-scale loss-of-function screens, a possible mechanism by which the inhibition of RRM1 is effective in cancer is established. Overall, our approach shows promising results and lays the foundation to build a novel family of algorithms to target metabolism in cancer.Exploiting synthetic lethality is a promising approach for cancer therapy. Here, the authors present an approach to identifying such interactions by finding genetic minimal cut sets (gMCSs) that block cancer proliferation, and apply it to study the lethality of RRM1 inhibition in multiple myeloma. PMID- 28878381 TI - Large order fluctuations, switching, and control in complex networks. AB - We propose an analytical technique to study large fluctuations and switching from internal noise in complex networks. Using order-disorder kinetics as a generic example, we construct and analyze the most probable, or optimal path of fluctuations from one ordered state to another in real and synthetic networks. The method allows us to compute the distribution of large fluctuations and the time scale associated with switching between ordered states for networks consistent with mean-field assumptions. In general, we quantify how network heterogeneity influences the scaling patterns and probabilities of fluctuations. For instance, we find that the probability of a large fluctuation near an order disorder transition decreases exponentially with the participation ratio of a network's principle eigenvector - measuring how many nodes effectively contribute to an ordered state. Finally, the proposed theory is used to answer how and where a network should be targeted in order to optimize the time needed to observe a switch. PMID- 28878382 TI - Pleomorphic bacteria-like structures in human blood represent non-living membrane vesicles and protein particles. AB - Although human blood is believed to be a sterile environment, recent studies suggest that pleomorphic bacteria exist in the blood of healthy humans. These studies have led to the development of "live-blood analysis," a technique used by alternative medicine practitioners to diagnose various human conditions, including allergies, cancer, cardiovascular disease and septicemia. We show here that bacteria-like vesicles and refringent particles form in healthy human blood observed under dark-field microscopy. These structures gradually increase in number during incubation and show morphologies reminiscent of cells undergoing division. Based on lipid analysis and Western blotting, we show that the bacteria like entities consist of membrane vesicles containing serum and exosome proteins, including albumin, fetuin-A, apolipoprotein-A1, alkaline phosphatase, TNFR1 and CD63. In contrast, the refringent particles represent protein aggregates that contain several blood proteins. 16S rDNA PCR analysis reveals the presence of bacterial DNA in incubated blood samples but also in negative controls, indicating that the amplified sequences represent contaminants. These results suggest that the bacteria-like vesicles and refringent particles observed in human blood represent non-living membrane vesicles and protein aggregates derived from blood. The phenomena observed during live-blood analysis are therefore consistent with time-dependent decay of cells and body fluids during incubation ex vivo. PMID- 28878383 TI - Avascular Necrosis of Femoral Head: A Metabolomic, Biophysical, Biochemical, Electron Microscopic and Histopathological Characterization. AB - Avascular necrosis of the femur head (AVNFH) is a debilitating disease caused due to the use of alcohol, steroids, following trauma or unclear (idiopathic) etiology, affecting mostly the middle aged population. Clinically AVNFH is associated with impaired blood supply to the femoral head resulting in bone necrosis and collapse. Although Homocysteine (HC) has been implicated in AVNFH, levels of homocysteine and its associated pathway metabolites have not been characterized. We demonstrate elevated levels of homocysteine and concomitantly reduced levels of vitamins B6 and B12, in plasma of AVNFH patients. AVNFH patients also had elevated blood levels of sodium and creatinine, and reduced levels of random glucose and haemoglobin. Biophysical and ultrastructural analysis of AVNFH bone revealed increased remodelling and reduced bone mineral density portrayed by increased carbonate to phosphate ratio and decreased Phosphate to amide ratio together with disrupted trabeculae, loss of osteocytes, presence of calcified marrow, and elevated expression of osteocalcin in the osteoblasts localized in necrotic regions. Taken together, our studies for the first time characterize the metabolomic, pathophysiological and morphometric changes associated with AVNFH providing insights for development of new markers and therapeutic strategies for this debilitating disorder. PMID- 28878384 TI - Combination of optical coherence tomography and near infrared spectroscopy enhances determination of articular cartilage composition and structure. AB - Conventional arthroscopic evaluation of articular cartilage is subjective and poorly reproducible. Therefore, implementation of quantitative diagnostic techniques, such as near infrared spectroscopy (NIRS) and optical coherence tomography (OCT), is essential. Locations (n = 44) with various cartilage conditions were selected from mature equine fetlock joints (n = 5). These locations and their surroundings were measured with NIRS and OCT (n = 530). As a reference, cartilage proteoglycan (PG) and collagen contents, and collagen network organization were determined using quantitative microscopy. Additionally, lesion severity visualized in OCT images was graded with an automatic algorithm according to International Cartilage Research Society (ICRS) scoring system. Artificial neural network with variable selection was then employed to predict cartilage composition in the superficial and deep zones from NIRS data, and the performance of two models, generalized (including all samples) and condition specific models (based on ICRS-grades), was compared. Spectral data correlated significantly (p < 0.002) with PG and collagen contents, and collagen orientation in the superficial and deep zones. The combination of NIRS and OCT provided the most reliable outcome, with condition-specific models having lower prediction errors (9.2%) compared to generalized models (10.4%). Therefore, the results highlight the potential of combining both modalities for comprehensive evaluation of cartilage during arthroscopy. PMID- 28878385 TI - A Universal Isotherm Model to Capture Adsorption Uptake and Energy Distribution of Porous Heterogeneous Surface. AB - The adsorbate-adsorbent thermodynamics are complex as it is influenced by the pore size distributions, surface heterogeneity and site energy distribution, as well as the adsorbate properties. Together, these parameters defined the adsorbate uptake forming the state diagrams, known as the adsorption isotherms, when the sorption site energy on the pore surfaces are favorable. The available adsorption models for describing the vapor uptake or isotherms, hitherto, are individually defined to correlate to a certain type of isotherm patterns. There is yet a universal approach in developing these isotherm models. In this paper, we demonstrate that the characteristics of all sorption isotherm types can be succinctly unified by a revised Langmuir model when merged with the concepts of Homotattic Patch Approximation (HPA) and the availability of multiple sets of site energy accompanied by their respective fractional probability factors. The total uptake (q/q*) at assorted pressure ratios (P/P s ) are inextricably traced to the manner the site energies are spread, either naturally or engineered by scientists, over and across the heterogeneous surfaces. An insight to the porous heterogeneous surface characteristics, in terms of adsorption site availability has been presented, describing the unique behavior of each isotherm type. PMID- 28878386 TI - Creation of a multi-segmented optical needle with prescribed length and spacing using the radiation pattern from a sectional-uniform line source. AB - This paper presents a method to generate a multi-segmented optical needle with a strong longitudinally polarized field, uniform intensity along the optical axis, and a transverse size (~0.36lambda). The length of each segment in the optical needle and the spacing between adjacent segments are controllable by reversing and focusing the radiation pattern from a sectional-uniform line source antenna to the focal volume of a 4Pi focusing system. By solving the inverse problem, we can obtain the required incident field distribution at the pupil plane to create the multi-segmented optical needle. Numerical examples demonstrate that a multi segmented optical needle with variable focal depth, adjustable interval, narrow lateral width, homogeneous intensity, and high longitudinal polarization purity can be formed using the proposed approach. The length of each needle segment is approximately equal to the length of the corresponding sectional uniform line source. The multi-segmented optical needle may be employed in applications such as multi-particle acceleration, multi-particle trapping and manipulation, laser machining, and laser material processing. PMID- 28878387 TI - Erratum: Noncanonical cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGFbeta-activated kinase 1. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28878388 TI - Promotion effect of extracts from plastrum testudinis on alendronate against glucocorticoid-induced osteoporosis in rat spine. AB - Alendronate (ALN) is a key therapeutic used to treat glucocorticoid-induced osteoporosis (GIOP), but may induce severe side effects. We showed earlier that plastrum testudinis extracts (PTE) prevented and treated GIOP in vivo. However, clinically, PTE is seldom used alone. Herein, we reveal the synergistic effect of ALN and PTE can treat GIOP of the rat spine and define the mechanism. Sprague Dawley rats were randomly assigned to four groups: a vehicle group, a GIOP group, an ALN group, and an ALN+PTE group. Each group was further divided into two experimental phases, including dexamethasone (DXM) intervention and withdrawal. Bone mass, microarchitecture, biomechanics, bone-turnover markers, and histomorphology were evaluated. The mRNA and protein expression levels of CTSK and Runx2 were detemined. We found that ALN+PTE improved bone quantity and quality, bone strength, bone turnover; and mitigated histological damage during glucocorticoid intervention and withdrawal. The therapeutic effect was better than that afforded by ALN alone. ALN+PTE reduced CTSK protein expression, promoted Runx2 mRNA and protein expression to varying extents, and more strongly inhibited bone resorption than did ALN alone. Overall, the synergistic effect mediated by ALN+PTE reversed GIOP during DXM intervention and withdrawal via affecting CTSK and Runx2 expression at mRNA and protein levels. PMID- 28878389 TI - Gas6 derived from cancer-associated fibroblasts promotes migration of Axl expressing lung cancer cells during chemotherapy. AB - Alterations to the tumor stromal microenvironment induced by chemotherapy could influence the behavior of cancer cells. In the tumor stromal microenvironment, cancer-associated fibroblasts (CAFs) play an important role. Because the receptor tyrosine kinase Axl and its ligand Gas6 could be involved in promoting non-small cell lung cancer (NSCLC), we investigated the role of Gas6 secreted by CAFs during chemotherapy in NSCLC. In a murine model, we found that Gas6 expression by CAFs was upregulated following cisplatin treatment. Gas6 expression might be influenced by intratumoral hypoperfusion during chemotherapy, and it increased after serum starvation in a human lung CAF line, LCAFhTERT. Gas6 is associated with LCAFhTERT cell growth. Recombinant Gas6 promoted H1299 migration, and conditioned medium (CM) from LCAFhTERT cells activated Axl in H1299 cells and promoted migration. Silencing Gas6 in LCAFhTERT reduced the Axl activation and H1299 cell migration induced by CM from LCAFhTERT. In clinical samples, stromal Gas6 expression increased after chemotherapy. Five-year disease-free survival rates for patients with tumor Axl- and stromal Gas6-positive tumors (n = 37) was significantly worse than for the double negative group (n = 12) (21.9% vs 51.3%, p = 0.04). Based on these findings, it is presumed that Gas6 derived from CAFs promotes migration of Axl-expressing lung cancer cells during chemotherapy and is involved in poor clinical outcome. PMID- 28878390 TI - Impact of nutritional supplements on cognitive development of children in developing countries: A meta-analysis. AB - Nutritional supplements may be important on cognition but the evidence is heterogeneous. This meta-analysis aimed (1) to determine whether nutritional supplements provided to pregnant women or young children could improve cognitive development of children in developing countries, and (2) to explore how supplementation characteristics could improve children's cognitive outcomes. This meta-analysis examined nutritional supplementation studies in 9 electronic databases and 13 specialist websites. Experimental studies were included if they were published from 1992 to 2016, were conducted in developing countries, had nutritional supplementation for pregnant women or children aged <=8, and reported effect sizes on cognitive outcomes. Interventions with confounded components, such as stimulation and parenting, were excluded. 67 interventions (48 studies) for 29814 children from 20 developing countries were evaluated. Childhood nutritional supplementation could improve children's cognitive development (d 0.08, 95% CI 0.03-0.13) and those with >=5 nutrients was particularly beneficial (0.15, 0.08-0.22). Antenatal supplementation did not improve cognitive development (0.02, -0.01 to 0.06) except for those implemented in the first trimester (0.15, 0.03-0.28). In conclusion, childhood nutritional supplementation was beneficial to cognitive development but could be optimised by providing multiple nutrients; antenatal supplementation should target pregnancy women in the first trimester for better cognitive benefits. PMID- 28878393 TI - All-optical tunable buffering with coupled ultra-high Q whispering gallery mode microcavities. AB - All-optical tunable buffering was recently achieved on a chip by using dynamically tuned coupled mode induced transparency, which is an optical analogue of electromagnetically induced transparency. However, the small Q s of about 105 used in those systems were limiting the maximum buffering time to a few hundred ps. Although employing an ultra-high Q whispering gallery mode (WGM) microcavity can significantly improve the maximum buffering time, the dynamic tuning of the WGM has remained challenging because thermo-optic and pressure tunings, which are widely used for WGM microcavities, have a very slow response. Here we demonstrate all-optical tunable buffering utilizing coupled ultra-high Q WGM cavities and the Kerr effect. The Kerr effect can change the refractive index instantaneously, and this allowed us to tune the WGM cavity very quickly. In addition, from among the various WGM cavities we employed a silica toroid microcavity for our experiments because it has an ultra-high Q factor (>2 * 107) and a small mode volume, and can be fabricated on a chip. Use of the Kerr effect and the silica toroid microcavity enabled us to observe an on-chip all-optical tunable buffering operation and achieve a maximum buffering time of 20 ns. PMID- 28878391 TI - Identification of a p53 target, CD137L, that mediates growth suppression and immune response of osteosarcoma cells. AB - p53 encodes a transcription factor that transactivates downstream target genes involved in tumour suppression. Although osteosarcoma frequently has p53 mutations, the role of p53 in osteosarcomagenesis is not fully understood. To explore p53-target genes comprehensively in calvarial bone and find out novel druggable p53 target genes for osteosarcoma, we performed RNA sequencing using the calvarial bone and 23 other tissues from p53 +/+ and p53 -/- mice after radiation exposure. Of 23,813 genes, 69 genes were induced more than two-fold in irradiated p53 +/+ calvarial bone, and 127 genes were repressed. Pathway analysis of the p53-induced genes showed that genes associated with cytokine-cytokine receptor interactions were enriched. Three genes, CD137L, CDC42 binding protein kinase gamma and Follistatin, were identified as novel direct p53 target genes that exhibited growth-suppressive effects on osteosarcoma cell lines. Of the three genes, costimulatory molecule Cd137l was induced only in calvarial bone among the 24 tissues tested. CD137L-expressing cells exhibited growth-suppressive effects in vivo. In addition, recombinant Fc-fusion Cd137l protein activated the immune response in vitro and suppressed osteosarcoma cell growth in vivo. We clarified the role of CD137L in osteosarcomagenesis and its potential therapeutic application. Our transcriptome analysis also indicated the regulation of the immune response through p53. PMID- 28878392 TI - Multivariate discovery and replication of five novel loci associated with Immunoglobulin G N-glycosylation. AB - Joint modeling of a number of phenotypes using multivariate methods has often been neglected in genome-wide association studies and if used, replication has not been sought. Modern omics technologies allow characterization of functional phenomena using a large number of related phenotype measures, which can benefit from such joint analysis. Here, we report a multivariate genome-wide association studies of 23 immunoglobulin G (IgG) N-glycosylation phenotypes. In the discovery cohort, our multi-phenotype method uncovers ten genome-wide significant loci, of which five are novel (IGH, ELL2, HLA-B-C, AZI1, FUT6-FUT3). We convincingly replicate all novel loci via multivariate tests. We show that IgG N-glycosylation loci are strongly enriched for genes expressed in the immune system, in particular antibody-producing cells and B lymphocytes. We empirically demonstrate the efficacy of multivariate methods to discover novel, reproducible pleiotropic effects.Multivariate analysis methods can uncover the relationship between phenotypic measures characterised by modern omic techniques. Here the authors conduct a multivariate GWAS on IgG N-glycosylation phenotypes and identify 5 novel loci enriched in immune system genes. PMID- 28878394 TI - An efficient algorithm for finding all possible input nodes for controlling complex networks. AB - Understanding structural controllability of a complex network requires to identify a Minimum Input nodes Set (MIS) of the network. Finding an MIS is known to be equivalent to computing a maximum matching of the network, where the unmatched nodes constitute an MIS. However, maximum matching is often not unique for a network, and finding all possible input nodes, the union of all MISs, may provide deep insights to the controllability of the network. Here we present an efficient enumerative algorithm for the problem. The main idea is to modify a maximum matching algorithm to make it efficient for finding all possible input nodes by computing only one MIS. The algorithm can also output a set of substituting nodes for each input node in the MIS, so that any node in the set can replace the latter. We rigorously proved the correctness of the new algorithm and evaluated its performance on synthetic and large real networks. The experimental results showed that the new algorithm ran several orders of magnitude faster than an existing method on large real networks. PMID- 28878395 TI - Recovery of woody plant species richness in secondary forests in China: a meta analysis. AB - There is considerable uncertainty concerning changes in plant diversity of Chinese secondary forests, particularly with respect to diversity recovery following anthropogenic disturbance. Here we present a meta-analysis of the recovery of woody plant species richness in secondary forests in China, with nearby primary forests as a reference. A total of 125 pairs of secondary-primary forest data reported in 55 publications were identified across China. We analyzed the data by region and logging history to examine their influences on secondary forest recovery. Our results indicated that the woody plant richness of secondary forests in China was close to fully recovered when compared to the primary forest, with the recovery ratio being 85-103%. Higher recovery ratios were observed in central, northeast and southwest China, with lower recovery ratios seen in east, south and northwest China, and the recovery in central China significantly reached the primary forests (reference) level. Concerning logging histories, the recovery ratios showed two peak values, with one at 21-40 years after clear cutting and the other at 61-80 years. We reveal the fundamental recovery patterns of woody plant species richness in secondary forests in China. These patterns provide information for the sustainable management of secondary forest resources. PMID- 28878397 TI - Physical and Pharmacokinetic Characterizations of trans-Resveratrol (t-Rev) Encapsulated with Self-Assembling Lecithin-based Mixed Polymeric Micelles (saLMPMs). AB - This study involved physical and pharmacokinetic characterizations of trans resveratrol (t-Rev)-loaded saLMPMs which attempted to improve t-Rev's pharmacokinetic profiles and bioavailability resolving hurdles limiting its potential health benefits. The optimal formulation consisted of t-Rev, lecithin, and Pluronic(r) P123 at 5:2:20 (t-Rev-loaded PP123 saLMPMs) provided mean particle size <200 nm, encapsulation efficiency >90%, and drug loading >15%. Compared to t-Rev solubilized with HP-beta-CD, t-Rev-loaded PP123 saLMPMs enhanced t-Rev's stability in PBS at RT, 4 degrees C, and 37 degrees C and in FBS at 37 degrees C, and retarded the in vitro release. Intravenous administration of t-Rev-loaded PP123 saLMPMs was able to enhance 40% absolute bioavailability and a greater portion of t-Rev was found to preferably distribute into peripheral compartment potentially establishing a therapeutic level at the targeted site. With oral administration, t-Rev-loaded LMPMs increases 2.17-fold absolute bioavailability and furnished a 3-h period of time in which the plasma concentration maintained above the desirable concentration for chemoprevention and accomplished a higher value of the dose-normalized area under the curve for potentially establishing an effective level at the target site. Therefore, intravenous and oral pharmacokinetic characteristics of t-Rev encapsulated with PP123 saLMPMs indicate that t-Rev can be translated into a clinically useful therapeutic agent. PMID- 28878398 TI - Erratum: ETS Related Gene mediated Androgen Receptor Aggregation and Endoplasmic Reticulum Stress in Prostate Cancer Development. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 28878396 TI - RhoA-ROCK Inhibition Reverses Synaptic Remodeling and Motor and Cognitive Deficits Caused by Traumatic Brain Injury. AB - Traumatic brain injury (TBI) causes extensive neural damage, often resulting in long-term cognitive impairments. Unfortunately, effective treatments for TBI remain elusive. The RhoA-ROCK signaling pathway is a potential therapeutic target since it is activated by TBI and can promote the retraction of dendritic spines/synapses, which are critical for information processing and memory storage. To test this hypothesis, RhoA-ROCK signaling was blocked by RhoA deletion from postnatal neurons or treatment with the ROCK inhibitor fasudil. We found that TBI impairs both motor and cognitive performance and inhibiting RhoA ROCK signaling alleviates these deficits. Moreover, RhoA-ROCK inhibition prevents TBI-induced spine remodeling and mature spine loss. These data argue that TBI elicits pathological spine remodeling that contributes to behavioral deficits by altering synaptic connections, and RhoA-ROCK inhibition enhances functional recovery by blocking this detrimental effect. As fasudil has been safely used in humans, our results suggest that it could be repurposed to treat TBI. PMID- 28878399 TI - Structural and molecular comparison of bacterial and eukaryotic trigger factors. AB - A considerably small fraction of approximately 60-100 proteins of all chloroplast proteins are encoded by the plastid genome. Many of these proteins are major subunits of complexes with central functions within plastids. In comparison with other subcellular compartments and bacteria, many steps of chloroplast protein biogenesis are not well understood. We report here on the first study of chloroplast-localised trigger factor. In bacteria, this molecular chaperone is known to associate with translating ribosomes to facilitate the folding of newly synthesized proteins. Chloroplast trigger factors of the unicellular green algae Chlamydomonas reinhardtii and the vascular land plant Arabidopsis thaliana were characterized by biophysical and structural methods and compared to the Escherichia coli isoform. We show that chloroplast trigger factor is mainly monomeric and displays only moderate stability against thermal unfolding even under mild heat-stress conditions. The global shape and conformation of these proteins were determined in solution by small-angle X-ray scattering and subsequent ab initio modelling. As observed for bacteria, plastidic trigger factors have a dragon-like structure, albeit with slightly altered domain arrangement and flexibility. This structural conservation despite low amino acid sequence homology illustrates a remarkable evolutionary robustness of chaperone conformations across various kingdoms of life. PMID- 28878400 TI - Thiamine antagonists trigger p53-dependent apoptosis in differentiated SH-SY5Y cells. AB - Accumulating evidences suggest that p53 is a key coordinator of cellular events triggered by oxidative stress often associated with the impairment in thiamine metabolism and its functions. However, there are limited data regarding the pursuant feedback between p53 transactivation and thiamine homeostasis. Impairment in thiamine metabolism can be induced experimentally via interference with the thiamine uptake and/or inhibition of the thiamin pyrophosphate-dependent enzymes using thiamine antagonists - amprolium (AM), oxythiamine (OT) or pyrithiamine (PT). We found that exposure of neuronally differentiated SH-SY5Y cells to AM, OT and PT triggered upregulation of p53 gene expression, post translational modification of p53 via phosphorylation and activation of p53 DNA binding activity. Phosphorylation of p53 at Ser20 was equally efficient in upregulation of thiamine transporter 1 (THTR1) by all antagonists. However, induction of the expressions of the pyruvate dehydrogenase E1 component subunit beta (PDHB) and oxoglutarate dehydrogenase (OGDH) required dual phosphorylation of p53 at Ser9 and Ser20, seen in cells treated with PT and OT. Moreover, pretreatment of the cells with a decoy oligonucleotide carrying wild-type p53 response element markedly attenuated OT-induced THTR1, PDHB and OGDH gene expression suggesting an important role of p53 in transactivation of these genes. Finally, analysis of gene and metabolic networks showed that OT triggers cell apoptosis through the p53-dependent intrinsic pathway. PMID- 28878401 TI - Structural basis for CRMP2-induced axonal microtubule formation. AB - Microtubule associated protein Collapsin response mediator protein 2 (CRMP2) regulates neuronal polarity in developing neurons through interactions with tubulins or microtubules. However, how CRMP2 promotes axonal formation by affecting microtubule behavior remains unknown. This study aimed to obtain the structural basis for CRMP2-tubulin/microtubule interaction in the course of axonogenesis. The X-ray structural studies indicated that the main interface to the soluble tubulin-dimer is the last helix H19 of CRMP2 that is distinct from the known C-terminal tail-mediated interaction with assembled microtubules. In vitro structural and functional studies also suggested that the H19-mediated interaction promoted the rapid formation of GTP-state microtubules directly, which is an important feature of the axon. Consistently, the H19 mutants disturbed axon elongation in chick neurons, and failed to authorize the structural features for axonal microtubules in Caenorhabditis elegans. Thus, CRMP2 induces effective axonal microtubule formation through H19-mediated interactions with a soluble tubulin-dimer allowing axonogenesis to proceed. PMID- 28878403 TI - Growth of the northeastern margin of the Tibetan Plateau by squeezing up of the crust at the boundaries. AB - In classic orogenic models, the mountain range is underlain by a deep crustal root. Here we present the crustal and upper mantle structures along two receiver function profiles across Qilian, an orogen experiencing recent growth at the northern margin of the Tibetan plateau. Opposite to an expected crustal root beneath the orogen, the Moho beneath Qilian is arch-like, shallower beneath the center and deepens by up to 10 km beneath its southern and northern boundaries. Additional velocity interfaces sub-parallel to the Moho are observed in the lower crust of the basins south of Qilian, which we interpret as the top of a mechanically strong lower crust thrusting several tens of kilometers underneath Qilian. In the north, the small lateral offset between the surface and mantle traces of the thrust system reveals a steep boundary, indicating that the North China cratonic crust acts as a strong resistance to the northward growth of the plateau, forcing the development of the left-lateral strike-slip Haiyuan fault south of the northern Qilian suture. The young Qilian orogen thus has been rising and growing progressively from the boundaries to the center, squeezed up by more rigid tectonic blocks in the north and south. PMID- 28878402 TI - Genetic Mechanisms Contribute to the Development of Heart Failure in Patients with Atrioventricular Block and Right Ventricular Apical Pacing. AB - Right ventricular apical (RVA) pacing can lead to progressive left ventricular dysfunction and heart failure (HF), even in patients with normal cardiac structure and function. Our study conducted candidate gene screening and lentivirus transfected neonatal rat cardiomyocytes (NRCMs) to explore the genetic and pathogenic mechanisms of RVA pacing induced cardiomyopathy in third degree atrioventricular block (III AVB) patients. We followed 887 III AVB patients with baseline normal cardiac function and RVA pacing. After a median follow-up of 2.5 years, 10 patients (four males, mean age 47.6 +/- 10.0 years) were diagnosed with RVA pacing induced HF with left ventricular ejection fraction (LVEF) reducing dramatically to 37.8 +/- 7.1% (P < 0.05). Candidate genes sequencing found cardiomyopathy associated genetic variations in all ten HF patients and six SCN5A variations in 6 of 20 control patients. Transfected NRCMs of Lamin A/C mutations (R216C and L379F) disrupted Lamin A/C location on nucleus membrane and finally resulted in increased apoptotic rate after serum starvation. In conclusion, cardiomyopathy associated genetic variations play an essential role in occurrence of newly onset HF in the III AVB patients with RVA pacing. RVA pacing, serving as extra stimulator, might accelerate the deterioration of cardiac structure and function. PMID- 28878404 TI - Tunable and high-sensitivity sensing based on Fano resonance with coupled plasmonic cavities. AB - Tunable and high-sensitivity sensing based on Fano resonance is analytically and numerically investigated in coupled plasmonic cavities structure. To analyze and manipulate the Fano line shape, the coupled cavities are taken as a composite cavity that supports at least two resonance modes. A theoretical model is newly established, and its results agree well with the finite difference time domain (FDTD) simulations for the plasmonic stub-pair structure. The detection sensitivity factor in coupled cavities approaches 6.541 * 107 m-1, which is an order of magnitude larger than single stub case. In addition, the wavelengths of resonant modes in the plasmonic stub-pair structure can be adjusted independently, which paves a new way for improving detection sensitivity. These discoveries hold potential applications for realizing tunable and highly integrated photonic devices. PMID- 28878405 TI - Some sustained improvements in pneumonia case management four and five years following implementation of paediatric hospital guidelines in Lao PDR. AB - In 2010, WHO paediatric hospital guidelines were implemented in Lao PDR, along with training workshops and feedback audits, achieving significant improvements in pneumonia case management when assessed one-year post-intervention. The sustainability of these improvements is hereby assessed, four and five years post intervention. Medical records of children aged 1-59 months, diagnosed with pneumonia in 2010, 2011, 2014 and 2015 from a central Lao hospital were reviewed. Information relating to clinical steps in pneumonia case management was extracted and a scoring system applied based on the documentation of each clinical step, producing a pneumonia assessment score for each case. Comparisons of clinical steps and mean assessment score across study years were performed using Pearson's chi-squared and t-tests, respectively. Of 231 pneumonia cases, the mean assessment scores in 2010, 2011, 2014 and 2015 were 57%, 96%, 69% and 69% respectively, showing a significant reduction from the immediate post intervention period (2011) to 2015 (p < 0.01). Mean assessment score in 2014/2015 was significantly higher than in 2010 (p < 0.01). The high standards of pneumonia case management in 2011 were not observed in 2014/2015 in the absence of ongoing intervention but overall quality of care remained higher than pre-intervention levels, suggesting some degree of sustainability in the long-term. PMID- 28878406 TI - High temperature in-situ synchrotron-based XRD study on the crystal structure evolution of C/C composite impregnated by FLiNaK molten salt. AB - An in-situ real-time synchrotron-based grazing incidence X-ray diffraction was systematically used to investigate the crystal structural evolution of carbon fiber reinforced carbon matrix (C/C) composite impregnated with FLiNaK molten salt during the heat-treatment process. It was found that the crystallographic thermal expansion and contraction rate of interlayer spacing d 002 in C/C composite with FLiNaK salt impregnation is smaller than that in the virgin sample, indicating the suppression on interlayer spacing from FLiNaK salt impregnated. Meanwhile the crystallite size L C002 of C/C composite with FLiNaK salt impregnation is larger than the virgin one after whole heat treatment process, indicating that FLiNaK salt impregnation could facilitate the crystallization of C/C composite after heat treatment process. This improved crystallization in C/C composite with FLiNaK salt impregnation suggests the synthetic action of the salt squeeze effect on crooked carbon layer and the release of internal residual stress after heating-cooling process. Thus, the present study not only contribute to reveal the interaction mechanism between C/C composite and FLiNaK salt in high temperature environment, but also promote the design of safer and more reliable C/C composite materials for the next generation molten salt reactor. PMID- 28878408 TI - Erratum. AB - [This corrects the article on p. 690 in vol. 58.]. PMID- 28878407 TI - Simultaneous measurement of transverse load and temperature using hybrid structured fiber-optic Fabry-Perot interferometer. AB - We experimentally demonstrated a novel fiber-optic hybrid structured Fabry-Perot interferometer with special air-cavity for simultaneous measurement of transverse load and temperature. By the linear phase finite impulse response filters, the transverse load sensitivities of the air-cavity and the silica-cavity are 1272.71 pm/N and -53.07 pm/N, respectively, and temperature sensitivities of the air cavity and silica-cavity are 1.1 pm/ degrees C and 14 pm/ degrees C. Thus, the different sensitivities of silica-cavity and air-cavity to transverse load and temperature indicate that such a structure can be used to simultaneously measure transverse load and temperature. PMID- 28878410 TI - Best profession ever! PMID- 28878409 TI - Lessons learned from the evolution of terrestrial animal health surveillance in Canada and options for creating a new collaborative national structure - Second opinion. PMID- 28878411 TI - Veterinary Medical Ethics. PMID- 28878412 TI - Putative contact ketoconazole shampoo-triggered pemphigus foliaceus in a dog. AB - A 10-year-old spayed female cocker spaniel dog was referred for an evaluation of acute-onset generalized pustular cutaneous lesions following application of ketoconazole shampoo. Cytologic and histopathologic examinations of the lesions revealed intra-epidermal pustules with predominantly neutrophils and acantholytic cells. This is the first description of putative contact ketoconazole shampoo triggered pemphigus foliaceus in a dog. PMID- 28878413 TI - Retinal astrocytoma in a dog. AB - A miniature schnauzer dog presenting with hyphema and glaucoma of the right eye had a retinal neoplasm. Neoplastic cells stained positively for glial fibrillary acidic protein, vimentin, and S-100 and largely negatively for oligodendrocyte transcription factor 2 by immunohistochemistry. The clinical and histopathological features of canine retinal astrocytomas are discussed. PMID- 28878414 TI - Atlanto-axial malformation in an adult Quarter horse gelding. AB - An adult gelding was evaluated for bilateral intermittent forelimb lameness of approximately 2 years duration. The horse was found to have grade 2/5 upper motor neuron-general proprioception ataxia with no cranial nerve deficits. During radiographic and gross necropsy examinations a novel atlanto-axial malformation of possible congenital etiology was found. PMID- 28878415 TI - Surgical removal of a gastric trichophytobezoar in a foal. AB - This report describes a rare case of gastric impaction caused by a trichophytobezoar in a foal. This case highlights the difficulty in diagnosing this condition and reports surgical removal via a gastrotomy after failure of medical treatment. PMID- 28878416 TI - Intramuscular mast cell tumors in 7 dogs. AB - Mast cell tumors (MCTs) are commonly encountered in dogs and have been reported in cutaneous, conjunctival, oral mucosal, and gastrointestinal locations, but not in an intramuscular location. Medical records at 2 referral centers in the UK were examined to find cases of MCTs in this location. Seven dogs were identified as having an intramuscular MCT by a combination of fine-needle aspirate cytology and computed tomography or ultrasound. None of the dogs had evidence of local lymph node metastasis. Six dogs had no evidence of distant metastasis and surgery was carried out as the primary treatment option. Three of those dogs also had adjunctive chemotherapy due to a high Ki67 value or high mitotic index. All 6 dogs that had had surgery were alive at follow-up with a minimum elapsed time of 7 months. One dog had a course of chemotherapy due to the location, size, and evidence of biological activity of the tumor and died 23 days afterwards. The prognosis of intramuscular mast cell tumors appears to be favorable in most cases. PMID- 28878417 TI - Post-operative Salmonella surgical site infection in a dog. AB - Following decompressive surgery for degenerative lumbosacral stenosis, a 6-year old German shepherd dog developed a subcutaneous infection at the surgical site and discospondylitis at the lumbosacral intervertebral disc. Salmonella enterica subsp. enterica, serotype Dublin was recovered from the surgical site. Salmonella of a different serovar was isolated from a sample of the raw meat-based diet that the owner fed the dog. PMID- 28878418 TI - Effect of acupuncture on pain and quality of life in canine neurological and musculoskeletal diseases. AB - This prospective study investigated the effects of acupuncture alone or combined with analgesics in chronic pain and quality of life assessed by owners for up to 24 weeks in 181 dogs with neurological and musculoskeletal diseases. The scores before and after the onset of treatment were evaluated using the Wilcoxon test and the evolution of success was evaluated by Kaplan-Meier curves. Differences were considered significant at P < 0.05. The success rates for Helsinki chronic pain index (HCPI), quality of life assessment, and visual analog scales (VAS) for pain and locomotion were 79%, 84%, 78%, and 78% of the animals, respectively, when both diseases and groups of treatment were combined. Dogs with musculoskeletal disorders had greater improvement in HCPI (P = 0.003) and VAS locomotion (P = 0.045) than those with neurological disorders. Use of acupuncture alone or in combination with analgesics reduced pain and improved quality of life in dogs with neurological and musculoskeletal diseases. PMID- 28878419 TI - ? AB - Convenience euthanasia in companion animals: Dilemma among veterinarians in Quebec. Many veterinarians working in the field of companion animal medicine have to deal with requests for convenience euthanasia in their practices. As it is the case in other medical fields, veterinarians are trained to treat their patients. It is thus easy to understand that veterinarians consider convenience euthanasia as one of the most difficult ethical dilemmas they have to deal with in their practice. Regulatory boundaries concerning the practice of euthanasia are limited to the method use to induce the death of the animal but do not give any indication as to what should be the proper circumstances surrounding the request. To date, there are few articles on this matter and the perspective of veterinarians on the subject was rarely addressed. This article reports results obtained following a study conducted upon Quebec's veterinarians on the topic of convenience euthanasia. The data was obtained via an online survey created by the research team to evaluate the perspective of veterinarians on the topic, how they perceived consequences of convenience euthanasia and what were the solutions they would take into consideration in order to help the profession on resolving their dilemma. The data collected sheds light on the existing duality between double allegiance regarding the duties emerging from the relation with the patient (animal) and the client (pet owner) veterinarian are facing in their daily practice. On one hand veterinarians recognized that 'convenience euthanasia' is contrary to animal welfare. On the other hand they also recognized the pet owner's right to ask for 'convenience euthanasia' when he can no longer care for its pet.(Translated by Dr. Rathwell-Deault). PMID- 28878420 TI - Comparison of methicillin-resistant Staphylococcus pseudintermedius adherence to 2 canine limb salvage endoprosthesis implants. AB - The objective of our study was to compare adhesion of methicillin-resistant Staphylococcus pseudintermedius (MRSP) to stainless steel (SS) and to tantalum (TA) canine limb salvage endoprosthesis implants in an in vitro experimental study. The median of the mean log10 colony forming units/mL for adherent MRSP was 4.96 (range: 4.63 to 6.33) for the TA endoprosthesis and 4.31 (range: 3.86 to 5.05) for the SS endoprosthesis (P = 0.009). Although the trabecular and porous design of the TA endoprosthesis provides mechanical benefits over the SS endoprosthesis, it may increase the risk of developing infection due to higher levels of bacterial adherence. PMID- 28878421 TI - Prevalence of obesity in the equine population of Saskatoon and surrounding area. AB - A retrospective study determined the prevalence of obesity and over-conditioning in horses in Saskatoon, Saskatchewan. Body condition score (BSC) was assessed for 290 horses from the Field Service practice at the Western College of Veterinary Medicine. The median BSC of horses was 6; however, 59 (20.3%) horses were classified as over-conditioned, and 24 (8.3%) as obese. PMID- 28878422 TI - Intrahepatic cholelithiasis in dogs and cats: A case series. AB - A retrospective study of intrahepatic cholelithiasis (IC) in 9 dogs and 2 cats was conducted. Only 1 dog showed clinical signs related to hepatobiliary disease before referral and during the follow-up period. Intrahepatic cholelithiasis might be a subclinical finding in both dogs and cats. PMID- 28878423 TI - Single incision laparoscopic-assisted ovariohysterectomy for an ovarian tumor in a dog. AB - This report describes a single-incision, laparoscopic-assisted ovariohysterectomy in a 6-year-old, intact female Keeshond dog for the staging and treatment of a left-sided ovarian tumor. Abdominal access was obtained using a modified-Hasson technique allowing for placement of a multi-channel, single incision laparoscopic surgery port. Following carbon dioxide insufflation, superficial laparoscopic exploration of the abdominal cavity was performed and then both ovarian pedicles were sealed and divided using a vessel-sealing device. Laparoscopic-assisted ovariohysterectomy was performed with the aid of a wound retractor for exteriorization of the mass. There were no perioperative complications and the patient was discharged 1 day after surgery. Histopathology of the mass revealed an ovarian teratoma. Telephone follow-up 608 days after surgery revealed a good clinical outcome. Single-incision, laparoscopic-assisted ovariohysterectomy is technically feasible for the treatment of selected ovarian tumors in the dog. PMID- 28878424 TI - The CVMA MyVetStore: Delivering dietary convenience and compliance. PMID- 28878425 TI - Diagnostic Ophthalmology. PMID- 28878426 TI - Temporomandibular joint luxation in the cat: Diagnosis and management. PMID- 28878427 TI - Mortality and Disability-Adjusted Life-Years (Dalys) for Common Neglected Tropical Diseases in Ethiopia, 1990-2015: Evidence from the Global Burden of Disease Study 2015. AB - INTRODUCTION: Neglected tropical diseases (NTDs) are important public health problems in Ethiopia. In 2013, the Federal Ministry of Health (FMOH) has launched a national NTD master plan to eliminate major NTDs of public health importance by 2020. Benchmarking the current status of NTDs in the country is important to monitor and evaluate the progress in the implementation of interventions and their impacts. Therefore, this study aims to assess the trends of mortality and Disability-adjusted Life-Years (DALY) for the priority NTDs over the last 25 years. METHODS: We used the Global Burden of Disease (GBD) 2015 estimates for this study. The GBD 2015 data source for cause of death and DALY estimation included verbal autopsy (VA), Demographic and Health Surveys (DHS), and other disease specific surveys, Ministry of Health reports submitted to United Nations (UN) agencies and published scientific articles. Cause of Death Ensemble modeling (CODEm) and/or natural history models were used to estimate NTDs mortality rates. DALY were estimated as the sum of Years of Life Lost (YLL) due to premature mortality and Years Lived with Disability (YLD). RESULTS: All NTDs caused an estimated of 6,293 deaths (95% uncertainty interval (UI): 3699-10,080) in 1990 and 3,593 deaths (95% UI: 2051 - 6178) in 2015, a 43% reduction over the 25 years. Age-standardized mortality rates due to schistosomiasis, STH and leshmaniasis have declined by 91.3%, 73.5% and 21.6% respectively between 1990 to 2015. The number of DALYs due to all NTDs has declined from 814.4 thousand (95% UI: 548 thousand-1.2million) in 1990 to 579.5 thousand (95%UI: 309.4 thousand-1.3 million) in 2015. Age-standardized DALY rates due to all NTDs declined by 30.7%, from 17.6 per 1000(95%UI: 12.5-26.5) in 1990 to 12.2 per 1000(95%UI: 6.5 - 27.4) in 2015. Age-standardized DALY rate for trachoma declined from 92.7 per 100,000(95% UI: 63.2 - 128.4) in 1990 to 41.2 per 100,000(95%UI: 27.4-59.2) in 2015, a 55.6% reduction between 1990 and 2015. Age-standardized DALY rates for onchocerciasis, schistosomiasis and lymphiaticfilariasis decreased by 66.2%, 29.4% and 12.5% respectively between 1990 and 2015. DALY rate for ascariasis fell by 56.8% over the past 25 years. CONCLUSIONS: Ethiopia has made a remarkable progress in reducing the DALY rates for most of the NTDs over the last 25 years. The rapid scale of interventions and broader system strengthening may have a lasting impact on achieving the 2020 goal of elimination of most of NTDs. Ethiopia should strengthen the coverage of integrated interventions of NTD through proper coordination with other health programs and sectors and community participation to eliminate NTDs by 2020. PMID- 28878428 TI - Elimination of Guinea Worm Disease in Ethiopia; Current Status of the Disease's, Eradication Strategies and Challenges to the End Game. AB - Dracunculiasis, also named Guinea Worm Disease (GWD), is one of the Neglected Tropical Diseases (NTDs) caused by a parasitic nematode known as Dracunculus medinensis and has been known since antiquity as 'fiery serpent' from Israelites. It is transmitted to humans via drinking contaminated water containing infective copepods. Given, its feasibility for eradication, the Guinea Worm Eradication Program (GWEP) was launched in 1980 with the aim of eradicating the disease. Since its inception, GWEP has made an extraordinary progress in interrupting transmission. Globally, the number of reported cases reduced from 3.5 million in 20 countries in 1986 to only 22 cases in 2015 from only four countries namely South Sudan, Mali, Chad and Ethiopia. Since Mali has interrupted transmission of GWD in 2016, currently, the disease remains endemic in only three sub-Saharan African countries namely, South Sudan, Chad and Ethiopia. Each endemic country has its own national Guinea Worm Eradication Program. In Ethiopia, the Ethiopian Dracunculiasis Eradication Program (EDEP) which was established in 1993 has made remarkable move towards interruption of disease transmission and now the endgame is fast approaching. The EDEP with support mainly from The Carter Center, WHO, and UNICEF has reduced GWD by more than 99% from 1994 to 2015. In 2015, only 3 indigenous cases in humans and 14 in animals (13 in dogs and 1 in baboon) were reported. In 2016, 3 human cases, 14 dogs and 2 baboon infections were reported.. Refugee influx from the Republic of South Sudan (RSS), increased animal infections with unknown role in transmission of Dracunculiasis, the presence of hard to reach communities and lack of safe water sources in remote non-village areas remain among important challenges at this final stage of GWD eradication in Ethiopia. This paper reviews progress made towards Guinea Worm Eradication with a focus on the experience of the Ethiopian Dracunculiasis Eradication Program (EDEP), and intervention strategies that need further intensification to realize the endgame. Eradication strategies encompassing community education for behavioral change including raising awareness towards cash reward for reporting Guniea Worm Disease (GWD) and animal infection, case containment, surveillance systems, provision of safe water supply, and ABATE chemical application are discussed. It also summarizes challenges the end game faces and recommendations to strengthen the eradication effort. PMID- 28878429 TI - The National Programme to Eliminate Lymphatic Filariasis from Ethiopia. AB - Lymphatic filariasis (LF) is one of the most debilitating and disfiguring diseases common in Ethiopia and is caused by Wuchereria bancrofti. Mapping for LF has shown that 70 woredas (districts) are endemic and 5.9 million people are estimated to be at risk. The national government's LF elimination programme commenced in 2009 in 5 districts integrated with the onchocerciasis programme. The programme developed gradually and has shown significant progress over the past 6 years, reaching 100% geographical coverage for mass drug administration (MDA) by 2016. To comply with the global LF elimination goals an integrated morbidity management and disability prevention (MMDP) guideline and a burden assessment programme has also been developed; MMDP protocols and a hydrocoele surgical handbook produced for country-wide use. In Ethiopia, almost all LF endemic districts are co-endemic with malaria and vector control aspects of the activities are conducted in the context of malaria programme as the vectors for both diseases are mosquitoes. In order to monitor the elimination, 11 sentinel and spot-check sites have been established and baseline information has been collected. Although significant achievements have been achieved in the scale up of the LF elimination programme, there is still a need to strengthen operational research to generate programme-relevant evidence, to increase access to morbidity management services, and to improve monitoring and evaluation of the LF programme. However, the current status of implementation of the LF national programme indicates that Ethiopia is poised to achieve the 2020 goal of elimination of LF. Nevertheless, to achieve this goal, high and sustained treatment coverage and strong monitoring and evaluation of the programme are essential. PMID- 28878430 TI - Review of Ethiopian Onchocerciasis Elimination Programme. AB - Onchocerciasis is a severe parasitic infection which causes disabling skin and subcutaneous tissue changes. The disease is endemic in many African countries including Ethiopia. In 2013, Ethiopia launched Onchocerciasis elimination program with the goal of attaining interruption of onchocerciasis transmission nationwide by 2020. The country has successfully scaled up interventions and achieved 100% geographic coverage in all known endemic districts. The main strategy for interrupting the disease is mass drug administration (MDA) delivered two times per year. The treatment coverage for the last five years has been maintained at more than 80%. Despite many years of ivermectin MDA the transmission of onchocerciasis in many districts remained unabated. To achieve the 2020 goal, sustained high geographic and therapeutic coverage is required which is validated by coverage surveys. The programme should aim to improve the knowledge and attitude of the community towards the programme in order to improve drug compliance. The partnership between the relevant stakeholders should be strengthened to facilitate open discussions regarding the programme implementation and any challenges that may arise in the control and elimination of the disease. It is also important to consider intensified vector control. PMID- 28878431 TI - Podoconiosis in Ethiopia: From Neglect to Priority Public Health Problem. AB - Podoconiosis is a geochemical disease occurring in individuals exposed to red clay soil of volcanic origin. This Neglected Tropical Disease (NTD) is highly prevalent in Ethiopia. According to the nationwide mapping in 2013, the disease is endemic in 345 districts, where an estimated 35 million people live. The government of Ethiopia prioritized podoconiosis as one of eight priority NTDs and included it in the national integrated master plan for NTDs. An integrated lymphoedema management guideline has been developed. Service expansion has continued in the last few years and lymphoedema management services have been expanded to over one hundred endemic districts. The last few years have been critical in generating evidence about the distribution, burden and effective interventions for podoconiosis in Ethiopia. Although the extent of the problem within Ethiopia is considerable, the country is well positioned to now scale-up elimination efforts. Given the extraordinary progress of the past ten years and the current commitment of government, private and third sectors, Ethiopia seems to be on course for the elimination of podoconiosis in our lifetime. We need continued strong partner commitment, evidence-building, and scale-up of activities to accomplish this. PMID- 28878432 TI - Ethiopia Schistosomiasis and Soil-Transmitted Helminthes Control Programme: Progress and Prospects. AB - Schistosomiasis and soil-transmitted helminthes are among seventeen WHO prioritized neglected tropical diseases that infect humans. These parasitic infections can be treated using single-dose and safe drugs. Ethiopia successfully mapped the distribution of these infections nationwide. According to the mapping there are an estimated 37.3 million people living in schistosomiasis endemic areas, and 79 million in schistosomiasis and soil-transmitted helminthes endemic areas. The Federal Ministry of Health successfully scaled up Schistosomiasis and schistosomiasis and soil-transmitted helminthes intervention in endemic areas and treated over 19 million individuals in 2015. The Ministry of Health has made a huge effort to establish neglected tropical diseases, including schistosomiasis and soil-transmitted helminthes program in the health system which helped to map majority of the woredas and initiate nationwide intervention. The National control programme is designed to achieve elimination for those diseases as a major public health problem by 2020 and aim to attain transmission break by 2025. The programme focuses on reaching those school-aged children who are not attending school, integration between neglected tropical diseases programme, and further collaboration with the WASH actors. PMID- 28878433 TI - Sasa veitchii extract reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. AB - The aim of this study was to investigate the therapeutic effect of Sasa veitchii leaf extract (SE) on features of obesity induced by a high-fat diet (HFD), such as hyperglycemia, insulin resistance, and inflammatory response. Four-week-old male ddY mice were freely fed HFD or control normal diet for 12 weeks; half was given SE in addition twice per day in weeks 8-12. Glucose and insulin intolerance were estimated, and body weight measured, weekly throughout the study. Following the experiment, the mice were fasted for 16 h, euthanized, and plasma was collected. Liver and epididymal adipose tissue was collected and weighed. Treatment with SE significantly decreased body weight, adipose tissue weight, plasma glucose, insulin, leptin, and tumor necrosis factor alpha compared with HFD groups, and markedly reduced the impairment of glucose and insulin tolerance in obese mice. Furthermore, hepatic steatosis and hepatic insulin receptor substrate were improved by treatment with SE. Our findings demonstrate that SE may reduce obesity-induced glucose and insulin tolerance, not only by suppressing inflammatory responses but also by improving insulin signaling. PMID- 28878434 TI - Incidence and characteristics of accidental falls in hospitalizations. AB - Aging of the patient population has led to increased occurrence of accidental falls in acute care settings. The aim of this study is to survey the annual occurrence of falls in a university hospital, and to examine procedures to prevent fall. A total of 49,059 inpatients were admitted to our hospital from April 2015 to March 2016. A fall assessment scale was developed to estimate the risk of fall at admission. Data on falls were obtained from the hospital incident reporting system. There were fall-related incidents in 826 patients (1.7%). Most falls occurred in hospital rooms (67%). Adverse events occurred in 101 patients who fell (12%) and were significantly more frequent in patients aged >=80 years old and in those wearing slippers. The incidence of falls was also significantly higher in patients in the highest risk group. These results support the validity of the risk assessment scale for predicting accidental falls in an acute treatment setting. The findings also clarify the demographic and environmental factors and consequences associated with fall. These results of the study could provide important information for designing effective interventions to prevent fall in elderly patients. PMID- 28878435 TI - Assessment of knowledge about snakebite management amongst healthcare providers in the provincial and two district hospitals in Savannakhet Province, Lao PDR. AB - Snakebite is a neglected condition and a common public health problem in Lao People's Democratic Republic (Lao PDR), with a high incidence of up to 1,105 cases per 100,000 persons per year. Snakebite patients with systemic envenoming do not receive effective treatment at local health facilities. Healthcare providers have only limited knowledge in assessing and providing the correct treatment for venomous snakebites. A cross-sectional study was conducted among 119 healthcare providers in Savannakhet Province, Lao PDR, with respect to their socio-demographic characteristics, knowledge of snake identification, and management of snakebite. Data was analyzed using SPSS. Logistic regression was performed to estimate the odds ratios (OR) and 95% confidence intervals (CI) of adequate knowledge for treating snakebites among the healthcare providers. Among 119 participants, 27.7% and 45.4% had an adequate knowledge of snake identification and management of snakebites, respectively. Approximately 59% could correctly identify symptoms of envenomation, and 19.3% expressed confidence in treating snakebites. Study participants who had received training achieved significantly better snake identification results compared to those without training, with an OR of 2.54 (95% CI: 1.02-6.28). In particular, physicians achieved significantly better results compared to nurses in knowing how to manage snakebites, with an OR of 2.31 (95% CI: 1.04-5.12). Given the level of inadequate knowledge of snakebite management among healthcare providers in the province, more training in snakebite management is needed. University and Health Science Colleges should include snakebite management into the curriculum, to ensure that medical graduates have the appropriate knowledge and skills to treat snakebites. PMID- 28878436 TI - Effect of text messages to improve health literacy on medication adherence in patients with type 2 diabetes mellitus: A randomized controlled pilot trial. AB - It has been suggested that low health literacy (HL) is associated with poor medication adherence. This study aimed to examine the effect of a text message based HL intervention to promote medication adherence, compared with text messages that only sent medication reminders, in patients with type 2 diabetes. This was a single-center, open-label, randomized (1:1) controlled pilot study. The study period was 6 months. Intervention group was sent HL related text messages, compared to the reminder messages that were sent to the control group. The primary outcome was the difference in the change rate of scores on the Morisky Eight-Item Medication Adherence Scale (MMAS-8). Forty-one participants were randomized into the intervention (n = 21) and control (n = 20) groups and completed the 6-month follow-up. Although almost participants read and understood the information provided in the messages, no significant difference was observed between groups for the primary outcome (p = 0.78). Our results suggested that medication adherence at 6 months after discharge in patients with type 2 diabetes did not significantly change by text messages, which aimed to improve their HL levels. PMID- 28878437 TI - Randomized controlled trial for assessment of Internet of Things system to guide intensive glucose control in diabetes outpatients: Nagoya Health Navigator Study protocol. AB - The Internet of Things (IoT) allows collecting vast amounts of health-relevant data such as daily activity, body weight (BW), and blood pressure (BP) automatically. The use of IoT devices to monitor diabetic patients has been studied, but could not evaluate IoT-dependent effects because health data were not measured in control groups. This multicenter, open-label, randomized, parallel group study will compare the impact of intensive health guidance using IoT and conventional medical guidance on glucose control. It will be conducted in outpatients with type 2 diabetes for a period of 6 months. IoT devices to measure amount of daily activity, BW, and BP will be provided to IoT group patients. Healthcare professionals (HCPs) will provide appropriate feedback according to the data. Non-IoT control, patients will be given measurement devices that do not have a feedback function. The primary outcome is glycated hemoglobin at 6 months. The study has already enrolled 101 patients, 50 in the IoT group and 51 in the non-IoT group, at the two participating outpatient clinics. The baseline characteristics of two groups did not differ, except for triglycerides. This will be the first randomized, controlled study to evaluate IoT-dependent effects of intensive feedback from HCPs. The results will validate a new method of health data collection and provision of feedback suitable for diabetes support with increased effectiveness and low cost. PMID- 28878438 TI - Optimized treatment strategy of radiotherapy for early glottic squamous cell carcinomas: An initial analysis. AB - The purpose of this study was to evaluate the clinical outcomes of radiotherapy for patients with T1/T2 glottic carcinoma. Patients with T1/T2 glottic carcinoma histopathologically diagnosed with squamous cell carcinoma and treated at our hospital between 2007 and 2015 were analyzed retrospectively. Our strategy for T1/T2 glottic carcinoma was as follows: radiotherapy alone with 2.25 Gy per fraction to a total of 25-28 fractions for patients with non-bulky T1 glottic carcinoma; concurrent chemoradiotherapy with oral S-1 and radiotherapy with 2 Gy per fraction to a total of 30 fractions for patients with T1 bulky/T2 favorable glottic carcinoma; or chemoradiotherapy with high-dose cisplatin and radiotherapy with 2 Gy per fraction to a total of 35 fractions for T2 unfavorable glottic carcinoma. Forty-eight patients were eligible. The median follow-up period among surviving patients was 38 months (range, 11-107). The disease was T1a in 23%, T1b in 13%, and T2 in 65% of patients. The 3-year local control rate in all patients, T1a, T1b, and T2 was 96.7%, 100%, 100%, and 96.0%, respectively. Of the 46 patients, one with T2 glottic carcinoma developed recurrent disease at the primary site, and one with T2 glottic carcinoma had lymph node recurrences in the neck. Acute Grade 3 dermatitis occurred in 8 (17%) patients and late Grade 2 hypothyroidism occurred in 2 (4%) patients. This retrospective study shows that our optimized treatment strategy of radiotherapy depending on the stage of early glottic carcinoma is not only effective but also well-tolerated. PMID- 28878439 TI - Impact of self-efficacy and parenting practice on physical activity among school children. AB - As insufficient engagement in physical activity (PA) is becoming a major health concern in Thailand, we aimed to investigate the impact of parenting practices and children's self-efficacy on a child's PA level and further in the subgroups, stratified by the child's sex and weight status. A total of 609 primary school children recruited by cluster sampling in two schools were asked to complete questionnaires, and general familial factors and parenting practice related to activities were completed by parents. Multivariate linear regressions were conducted to calculate the standardized beta-coefficients (beta). Children's PA level was positively related to greater support seeking self-efficacy (beta=0.281) for engaging in PA, and parenting practices, including less limit setting (beta=-0.124) and more discipline (beta=0.147) in the total sample. In the analyses of subgroups by a child's sex and weight status, parenting practice, such as less limit setting and discipline played a more important role in children's PA in normal weight children and girls as taking account of around 10% of variance of the child's PA, while only seeking support self-efficacy showed great impact in overweight children and boys. In conclusion, impacts of children's self-efficacy and parenting practices on children's PA were different by child's sex and weight status. This can suggest that future interventions to increase children's PA might need to consider different strategies to increase children's self-efficacy as well as parenting strategies when targeting different groups of children. PMID- 28878440 TI - Yokukansankachimpihange increased body weight but not food-incentive motivation in wild-type mice. AB - Yokukansankachimpihange (YKSCH), a traditional Japanese medicine, is widely used for the amelioration of the behavioral and psychological symptoms of dementia with digestive dysfunction. Regardless of its successful use for digestive dysfunction, the effect of YKSCH on body weight was unknown. Furthermore, if YKSCH increased body weight, it might increase motivation according to Kampo medicine theory. Therefore, we investigated whether YKSCH had the potential to increase body weight and enhance motivation in mice. To address this, C57BL/6J mice were used to evaluate the long-term effect of YKSCH on body weight and food incentive motivation. As part of the evaluation, we optimized an operant test for use over the long-term. We found that feeding mice YKSCH-containing chow increased body weight, but did not increase their motivation to food reward. We propose that YKSCH may be a good treatment option for preventing decrease in body weight in patients with dementia. PMID- 28878441 TI - Development and validation of an educational program to enhance sense of coherence in patients with diabetes mellitus type 2. AB - This study aimed to develop a group education program that facilitates a sense of coherence among patients with type 2 diabetes mellitus, which was provided four times, and to validate the effect of the program among the patients. Researchers allocated 40 patients with type 2 diabetes, who had been admitted to a general hospital in Japan for diabetes education for two weeks. Twenty-one patients were allocated to the intervention group and 19 to the control group. The control group undertook a lecture-based educational program that the facility offered. The intervention group received the program, in addition to the facility's educational program. The sense of coherence scale and the Problem Areas in Diabetes Survey were used as evaluation indices. The average age of the intervention group was 59.1 years and that of the control group was 59.5 years. The intervention group showed a between-group effect of improvement in the sense of coherence score. Additionally, the intervention group showed a within-group effect of improvement in the sense of coherence score, as well as the comprehensibility and manageability scores, which are subdomains, and the Problem Areas in Diabetes Survey score. The within-group comparison showed a significant decrease in the early-morning FPG at both groups by an effect of treatment. The program suggested the possibility of improving the sense of coherence and the Problem Areas in Diabetes Survey. In order to enhance general use of the program, it is necessary to reach out to participating facilities and verify the effect of the program. PMID- 28878442 TI - The poor quality and reliability of information on periacetabular osteotomy on the internet in Japan. AB - Although many patients use the internet to access health-related information, the quality and the reliability of the information is highly inconsistent. Periacetabular osteotomy (PAO) is one of the surgical procedures for hip dysplasia. However, medical information on PAO is limited on the internet. This study aims to evaluate the quality and reliability of information available on PAO on the internet in Japan. A web search was conducted on two search engines for the following terms: "hip osteotomy," "pelvic osteotomy," and "osteotomy for hip preservation" in Japanese. In total, we found 120 websites. To determine the quality and reliability of information on each website, we used the Health on the Net Foundation (HON) score, the Brief DISCERN score, and an osteotomy-specific content (OSC) score. After eliminating duplicate websites, we reviewed 49 unique websites. Only three websites (6.1%) had good reliability, as indicated by their HON scores. Twelve websites (24.4%) had good-quality information, as measured by their Brief DISCERN scores. As evaluated by their OSC scores, physician websites were found to be biased toward etiology and surgical indication and did not provide information on the complications of procedures. Non-physician websites were generally insufficient. The information about PAO on the internet is, therefore, unreliable and of poor-quality for Japanese patients. PMID- 28878443 TI - Diagnostic performance of 11C-choline PET/CT and bone scintigraphy in the detection of bone metastases in patients with prostate cancer. AB - The aim of this study was to compare 11C-choline PET/CT and bone scintigraphy (BS) for detection of bone metastases in patients with prostate cancer. Twenty one patients with histologically proven prostate cancer underwent 11C-choline PET/CT and BS before (n = 4) or after (n = 17) treatment. Patient-, region-, and lesion-based diagnostic performances of bone metastasis of both 11C-choline PET/CT and BS were evaluated using a five-point scale by two experienced readers. Bone metastases were present in 11 (52.4%) of 21 patients and 48 (32.7%) of 147 regions; 111 lesions were found to have bone metastases. Region-based analysis showed that the sensitivity, specificity, accuracy, and area under the receiver operating-characteristic curves (AUC) of 11C-choline PET/CT were 97.9%, 99.0%, 98.6%, and 0.9989, respectively; those of BS were 72.9%, 99.0%, 90.5%, and 0.8386, respectively. Sensitivity, accuracy, and AUC significantly differed between the two methods (McNemar test, p = 0.0015, p = 0.0015, and p < 0.0001, respectively). 11C-choline PET/CT detected 110/111 metastatic lesions (99.1%); BS detected 85 (76.6%) (p < 0.0001). According to the CT morphological type, the visualization rates of 11C-choline-PET/BS were 100%/90.3% for the blastic type, 91.7%/8.3% for the lytic type, 100%/100% for the mixed type, and 100%/53.3% for the invisible type, respectively. Significant differences in blastic, lytic, and invisible types were observed between the two methods (p = 0.013, p = 0.0044, and p = 0.023, respectively). In conclusion, 11C-choline PET/CT had greater sensitivity and accuracy than BS for detection of bone involvement in patients with prostate cancer. PMID- 28878444 TI - Experimental evaluation and training of stent clot retrieval: the confront clot scrambling method. AB - The introduction of stent retrievers has changed the methods used for acute intracranial thrombectomy, but the training approach has not been discussed enough. We, therefore, aimed to establish a simple skill up method which can be used to train anytime and anywhere with low costs. Also, we introduce our experimental confront clot scrambling method (CCSM) which makes a profitable visualization in how the stent retriever works. The CCSM involved a sham clot set in the middle of a polyvinyl chloride tube, after which two stent retrievers were navigated from each side before being simultaneously withdrawn with the same force. The stent that removes the sham clot is determined to have stronger clot retrieval ability. Several adjunctive techniques were also compared. The push and fluff adjunctive technique was the most effective among all the stents. Generally, the former deployed stent was stronger than later one. Therefore, the later deployed stent with the push and fluff technique lets us know whether the physician's maneuver worked well or not. CCSM could directly evaluate the ability of adjunctive techniques with each stent retriever and demonstrate the physicians' skills. Because the actual endovascular clot retrieval requires extreme fine maneuvers against invisible vessels, repeat training is very important especially in beginners. PMID- 28878445 TI - Phase II trial of CH5424802 (alectinib hydrochloride) for recurrent or refractory ALK-positive anaplastic large cell lymphoma: study protocol for a non-randomized non-controlled trial. AB - Currently, a standard therapy has not been established for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. While there are many treatment options, such as hematopoietic stem cell transplantation, patients with resistant disease to conventional chemotherapies have particularly poor prognosis. There is urgent need to develop new drugs because of the lack of a standard therapy and poor prognoses. This phase II trial is designed for evaluating the efficacy and safety of alectinib hydrochloride for patients with recurrent or refractory anaplastic lymphoma kinase -positive anaplastic large cell lymphoma. The primary endpoint is the response rate according to the Revised Response Criteria for Malignant Lymphoma. The secondary endpoints are pharmacokinetics, safety in children, complete response rate, response duration, progression-free survival, event-free survival, overall survival, and adverse events. The results of this trial will be the pivotal data for the drug approval of alectinib hydrochloride for recurrent or refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. PMID- 28878446 TI - Review of redo-Kasai portoenterostomy for biliary atresia in the transition to the liver transplantation era. AB - Portoenterostomy (PE) is the standard therapy for biliary atresia (BA). PE offers the chance of survival to children with BA. PE was the ultimate therapeutic modality for BA before liver transplantation (LT) was available. Failure of biliary drainage with PE was almost invariably fatal in children with BA. In such cases, redo-PE was performed to salvage patients following PE failure. PE remains the standard first treatment for BA despite the availability of LT. Further, redo PE is also performed in a limited number of cases despite the development of LT as an alternative means of PE. However, there is concern that redo-PE increases morbidity at the time of subsequent LT. Laparoscopic redo-PE has recently been described. Laparoscopic redo-PE is expected to reduce complications of LT by preventing abdominal adhesion associated with repetitive surgery. In the present article, the future utility of redo-PE and the history of its changing roles are reviewed. PMID- 28878447 TI - Anterior interosseous nerve palsy mimicking rupture of the index flexor digitorum profundus after volar locking plate fixation of a distal radius fracture. AB - We describe the case of a patient with distal radius fracture who became unable to flex the distal interphalangeal joint of the index finger after internal fixation using a volar locking plate. There was palpable crepitus with active thumb motion, and wrist radiographs showed prominence of the volar plate at the watershed line. Therefore, our initial diagnosis was plate-induced closed rupture of the flexor digitorum profundus tendon of the index finger. However, upon surgical removal of the plate, no tendon rupture was found. Magnetic resonance imaging after plate removal showed diffuse increased signal intensity in the index flexor digitorum profundus on T2-weighted fat-suppressed images, which indicated muscle denervation. Based on the above findings, we changed the diagnosis to anterior interosseous nerve palsy with isolated paralysis of the flexor digitorum profundus of the index finger. Finger flexion disability following volar plate fixation of distal radius fracture should always be investigated carefully.. PMID- 28878448 TI - The effect of virtual reality program on the cognitive function and balance of the people with mild cognitive impairment. AB - [Purpose] The purpose of this study was to investigate the effects of a virtual reality (VR) program on cognitive function and balance in the elderly with mild cognitive impairment (MCI) attending G welfare center in Gurye. [Subjects and Methods] Twenty-four patients with MCI were studied. The patients were exposed to the VR program for 30 min per experiment, which was conducted 20 times for four weeks. [Results] The cognitive function and balancing ability of the experimental group, when compared to the control group, showed a statistically significant increase in Visual Span Test (VST), Word Color Test (WCT), and Limit of Stability (LOS), which are the sub-categories of CNT 4.0, after the exposure to the program. In all test categories, the experimental group exhibited statistically significant differences compared to the control group. [Conclusion] Thus, the VR program is an effective intervention for the elderly with MCI. PMID- 28878449 TI - Ingenuity for enabling the habituation of pelvic floor muscle training. AB - [Purpose] To clarify factors contributing to habituation of pelvic floor muscle training (PFMT) for urinary incontinence. [Subjects and Methods] We included 13 healthy females and examined diurnal and nocturnal urination frequency at initial program participation and at 3 months. The survey used the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), a 10-level self assessment of anxiety associated with urinary incontinence, and a 10-level self evaluation of PFMT understanding and skill acquisition. We evaluated PFMT practice at home and postures that facilitated PFMT. The practice of PFMT at home was surveyed during a 3-month period. [Results] Compared to baseline, the level of skill acquisition assessed by the ICIQ-SF and PFMT according to the 10-level self-evaluation improved significantly at 3 months. The rate of PFMT sessions performed at home per week was high. The number of times PFMT was performed per day was positively correlated with level of understanding and acquisition of skills pertaining to PFMT, according to the 10-level self-assessment. [Conclusion] By incorporating behavior modification techniques appropriate for urinary incontinence and by increasing the level of understanding regarding incontinence and PFMT, as well as the level of skill acquisition, self-efficacy increased. This may have motivated habituation of PFMT. PMID- 28878450 TI - The effects of aroma massage and foot bath on psychophysiological response in stroke patients. AB - [Purpose] This research aimed to examine the effects of back massage and foot bath with blended essential oil on psychophysiological response in stroke patients. [Subjects and Methods] The subjects were 14 adult stroke patients randomly divided into the experimental group (7 patients) and the control group (7 patients). Physical and psychological stress, mood state and sleep satisfaction was measured using evaluation instruments and body temperature was measured with infrared thermography (T-1000). [Results] Measurements included physical and psychological stress, and mood state of the experiment group became significantly lower than that of the control group. The body temperature and sleeping satisfaction of the experimental group became significantly higher than that of the control group. [Conclusion] The present study suggested that aroma therapy and foot bath that can be used as alternative physical therapy that offers an overall beneficial effect on psychophysiological response such as reduced stress, mood state and increased body temperature, sleeping satisfaction of stroke patients. PMID- 28878451 TI - Effect of complex training on carbon monoxide, cardiorespiratory function, and body mass among college students at the initial stage of stopping smoking. AB - [Purpose] This study aimed to analyze the effects of complex training on carbon monoxide, cardiorespiratory function, and body mass among college students with the highest smoking rate among all age group. [Subjects and Methods] A total of 40 college students voluntarily participated in this study. All subjects smoked and were randomly divided into two groups: the experimental group (N=20) and the control group (N=20). The experimental group underwent complex training (30 min of training five times a week for 12 weeks) while the control group did not participate in such training. The complex training consisted of two parts: aerobic exercise (walking and running) and resistance exercise (weight training). [Results] Two-way ANOVA with repeated measures revealed significant interactions among CO, VO2max, HRmax, VEmax, body fat, and skeletal muscle mass, indicating that the changes were significantly different among groups. [Conclusion] A 12 week of complex physical exercise program would be an effective way to support a stop-smoking campaign as it quickly eliminates CO from the body and improves cardiorespiratory function and body condition. PMID- 28878452 TI - The effects of spinal support device on pain and extensibility of the hamstrings in patients with non-specific low back pain. AB - [Purpose] The objective of this study was to investigate the effects of spinal support device (SSD) on pain and hamstring extensibility in patients with non specific low back pain (NSLBP). [Subjects and Methods] 20 patients with NSLBP were recruited and randomly assigned to either the SSD group or the control group. In the SSD group, SSD was applied; in the control group, bed rest in supine position was performed. Both groups underwent treatment 20 min/day, 3 times a week, for a duration of 4 weeks. To assess the hamstring extensibility, sit and reach test (SRT) was performed. To assess pain pressure threshold (PPT) of the sacroiliac joint, a pressure algometer was used. Visual analog scale (VAS) was used to quantify pain. [Results] The SSD group showed a significant improvement in sacroiliac joint pain with increased VAS, and the control group showed a significantly increased VAS after intervention. In the SSD group, VAS was significantly increased, but SRT was not changed compared with the control group. [Conclusion] These results demonstrated that an application of SSD effectively attenuates low back pain. Therefore, SSD may be a suitable intervention for pain control in patients with NSLBP. PMID- 28878453 TI - Pulsed electromagnetic field with or without exercise therapy in the treatment of benign prostatic hyperplasia. AB - [Purpose] To investigate the effect of pulsed electromagnetic field with or without exercise therapy in the treatment of benign prostatic hyperplasia. [Subjects and Methods] Sixty male patients aged 55-65 years with benign prostatic hyperplasia were invited to participate in this study. Patients were randomly assigned to Group A (n=20; patients who received pulsed electromagnetic field in addition to pelvic floor and aerobic exercises), Group B (n=20; patients who received pulsed electromagnetic field), and Group C (n=20; patients who received placebo electromagnetic field). The assessments included post-void residual urine, urine flow rate, prostate specific antigen, white blood cells count, and International Prostate Symptom Score were weighed, before and after a 4-week intervention. [Results] There were significant differences in Group A and B in all parameters. Group C showed non-significant differences in all measured variables except for International Prostate Symptom Score. Among groups, all parameters showed highly significant differences in favor of Group A. There were non-significant differences between Group A and B and significant difference between Groups A and C and between Groups B and C. [Conclusion] The present study demonstrated that electromagnetic field had a significant impact on the treatment of benign prostatic hyperplasia. Accordingly, electromagnetic field can be utilized alone or in combination with other physiotherapy modalities. Moreover, clinicians should have the capacity to perceive the advantages accomplished using extra treatment alternatives. Electromagnetic field is a safe, noninvasive method and can be used for the treatment of benign prostatic hyperplasia. PMID- 28878454 TI - Effects of pelvic compression belts on the kinematics and kinetics of the lower extremities during sit-to-stand maneuvers. AB - [Purpose] To investigate the effects of a pelvic compression belt (PCB) and chair height on the kinematics and kinetics of the lower extremity during sit-to-stand (STS) maneuvers in healthy people. [Subjects and Methods] Twenty-two people participated in this study. They were required to perform STS maneuvers under four conditions. Hip joint moment and angular displacement of the hip, knee, and ankle were measured. A PCB was also applied below the anterior superior iliac spine. [Results] The angular displacement of the ankle joint increased while performing STS maneuvers from a normal chair with a PCB in phase 1, and decreased during phase 2 when performing STS maneuvers from a high chair. The overall angular displacement in phase 3 was decreased while rising from a chair with a PCB and rising from a high chair. When performed STS maneuvers from a high chair, the angular displacement of the hip, knee, and ankle joint decreased considerably in phase 3. This decreased lower extremity motion in phase 3 indicated that participants required less momentum to complete the maneuver. [Conclusion] The results of this study suggest that a PCB might be appropriate for patients with pelvic girdle pain and lower back pain related to pregnancy. PMID- 28878455 TI - Relationship of visual dependence to age, balance, attention, and vertigo. AB - [Purpose] The aim of this study was to investigate the relationship of increased visual dependence to age, balance, attention, and vertigo. [Subjects and Methods] Twelve younger, 12 visually independent (VI) older and 12 visually dependent (VD) older adults were assessed for levels of visual dependence using Subjective Visual Vertical (SVV) tilt values, balance ability using the Clinical Test of Sensory Integration for Balance (CTSIB), and attentional requirements through the dual-task paradigm and experience of vertigo by completing the Situational Vertigo Questionnaire (SVQ). [Results] VD older adults had higher SVV tilt values, greater postural sway in a scenario where visual and proprioceptive inputs were simultaneously altered, similar dual-task cost and lower SVQ scores compared with younger and VI older adults. No difference was observed between the latter two. [Conclusion] Visual dependence may not necessarily increase with age but affect balance in a sensory condition involving visual-proprioceptive conflict. There is a non-significant trend for elevated visual dependence with increased attentional demands. Greater visual dependence is not accompanied by more frequent symptoms of vertigo in visually complex environments. PMID- 28878457 TI - Effects of chronic ankle instability and induced mediolateral muscular fatigue of the ankle on competitive taekwondo athletes. AB - [Purpose] The purpose of this study was to investigate the effects of chronic ankle instability and induced mediolateral muscular fatigue of the ankle on competitive Taekwondo athletes during single-leg drop landing. [Subjects and Methods] Fourteen competitive taekwondo athletes with chronic ankle instability and 14 healthy adults participated, and they performed three single-leg drop landings from a 40-cm height before and after induced fatigue. Ankle angular position, peak vertical ground reaction force, loading rate, eccentric work, and contribution were calculated and analyzed. [Results] Athletes had lower ankle eversion and abduction angle than the controls did at maximum knee flexion both pre- and post-fatigue. Furthermore, athletes had lower eccentric work of the hip than the controls did post-fatigue, and they had lower eccentric work of the knee than controls at both pre- and post-fatigue. The eccentric work of the knee increased while, peak vertical ground reaction force decreased in both, athletes as well as controls post-fatigue. [Conclusion] Taekwondo athletes with chronic ankle instability who participate in a high-intensity training program are continuously exposed to potential injuries of their ankle or knee joints. Therefore, competitive taekwondo athletes with chronic ankle instability should limit their participation in regular training until they complete the rehabilitation process. PMID- 28878456 TI - Daily physical activity affects exercise capacity in patients with idiopathic pulmonary fibrosis. AB - [Purpose] The aim of this study was to determine which factors, including pulmonary, physical, and mental functions; dyspnea; and daily physical activity (PA) affect the 6-minute walk distance (6MWD) in IPF patients. [Subjects and Methods] The pulmonary, physical, and mental functions; dyspnea; PA; and 6MWD were assessed in 38 outpatients with IPF. PA was represented by the mean number of steps per day. [Results] The mean 6MWD was 443.8 m (SD, 98.5), and the mean number of steps per day showing PA was 5148.4 (SD, 3295.7). The 6MWD was correlated with age, base dyspnea index, vital capacity (VC), diffusion capacity of carbon monoxide, quadriceps force (QF), dyspnea during the 6-minute walk test, and PA. Stepwise multiple regression analysis revealed that VC (beta=0.382), QF (beta=0.272), and PA (beta=0.574) were contributing factors of the 6MWD. [Conclusion] In patients with IPF, PA has a greater effect on the 6MWD than VC and QF. The evaluation of daily PA, in addition to physiological and muscle functions, is important in patients with IPF. PMID- 28878458 TI - Evaluation of bilateral force deficit in shoulder flexion using a handheld dynamometer in healthy subjects. AB - [Purpose] This study aimed to develop a simple, inexpensive, and accurate method for measuring the strength of shoulder flexion (Experiment 1) and evaluate the bilateral force deficit in shoulder flexion (Experiment 2) in healthy subjects. [Subjects and Methods] In Experiment 1, maximal voluntary contractions (MVCs) in isometric shoulder flexion were measured on both sides using an isometric dynamometer (ID) and a hand-grip dynamometer (HGD), as an alternative dynamometer, in six subjects. In Experiment 2, bilateral force deficit was evaluated using HGD in 21 subjects who performed unilateral and bilateral MVCs in isometric flexions of the shoulder. The peak value of electromyography (PVE) in the lateral head of the biceps brachii and anterior deltoid was measured during MVCs. [Results] In Experiment 1, ID and HGD showed almost similar coefficients of variation. A strong positive correlation was found between the values obtained using the two methods. In Experiment 2, the bilateral force deficit in shoulder flexion associated with a reduced PVE (-10.9%) was found in 85.7% of subjects. [Conclusion] The reproducibility of measurements was similar between ID and HGD. HGD could evaluate the bilateral force deficit in shoulder flexion and is a practical tool for measuring shoulder strength. PMID- 28878459 TI - Carryover effect of hip and knee exercises program on functional performance in individuals with patellofemoral pain syndrome. AB - [Purpose] This study was carried out to investigate the carryover effect of hip and knee exercises program on functional performance (single legged hop test as functional performance test and Kujala score for functional activities). [Subjects and Methods] Thirty patients with patellofemoral pain syndrome were randomly assigned into two equal groups. Group (A) consisted of 15 patients undergoing hip strengthening exercises for four weeks then measuring all variables followed by additional four weeks of knee exercises program then measuring all variables again. Group (B): consisted of 15 patients undergoing knee exercises program for four weeks then measuring all variables followed by additional four weeks of hip strengthening exercises then measuring all variables. Functional abilities and knee muscles performance were assessed using Kujala questionnaire and single legged hop test respectively pre and after the completion of the first 4 weeks then after 8 weeks for both groups. [Results] Significantly increase in Kujala questionnaire in group A compared with group B was observed. While, there were significant increase in single legged hop performance test in group B compared with group A. [Conclusion] Starting with hip exercises improve the performance of subjects more than functional activities while starting with knee exercises improve the functional activities of subjects more than performance. PMID- 28878460 TI - The effects of dance music jump rope exercise on pulmonary function and body mass index after music jump rope exercise in overweight adults in 20's. AB - [Purpose] The purpose of this study was to examine the effect of a dance music jump rope exercise on changes Pulmonary Function and body mass index in female overweight subjects in their 20's. [Subjects and Methods] The subjects were randomly assigned to the dance music jump rope exercise group and the stationary cycle exercise group. All subjects have conducted the exercises three times a week for four weeks. Pulmonary function was evaluated using a spirometer, and body mass index was evaluated using an InBody 3.0. [Results] The findings of this study showed significant improvements in the voluntary capacity and body mass index of the experimental groups. Vital capacity was higher in the music jump rope exercise group than the stationary cycle exercise group, and body mass index was lower in the music jump rope exercise group than the stationary cycle exercise group. [Conclusion] This study showed that the dance music jump rope exercise can be used to improve vital capacity and body mass index. PMID- 28878461 TI - Comparison of physical activities of female football players in junior high school and high school. AB - [Purpose] This study aimed to compare physical activities between junior high school and high school female football players in order to explain the factors that predispose to a higher incidence of sports injuries in high school female football players. [Subjects and Methods] Twenty-nine female football players participated. Finger floor distance, the center of pressure during single limb stance with eyes open and closed, the 40-m linear sprint time, hip abduction and extension muscle strength and isokinetic knee flexion and extension peak torque were measured. The modified Star Excursion Balance Test, the three-steps bounding test and three-steps hopping tests, agility test 1 (Step 50), agility test 2 (Forward run), curl-up test for 30 seconds and the Yo-Yo intermittent recovery test were performed. [Results] The high school group was only significantly faster than the junior high school group in the 40-m linear sprint time and in the agility tests. The distance of the bounding test in the high school group was longer than that in the junior high school group. [Conclusion] Agility and speed increase with growth; however, muscle strength and balance do not develop alongside. This unbalanced development may cause a higher incidence of sports injuries in high school football players. PMID- 28878462 TI - Effect of task-oriented activities on hand functions, cognitive functions and self-expression of elderly patients with dementia. AB - [Purpose] This study investigates the effects of task-oriented activities on hand function, cognitive function, and self-expression of the elderly with dementia, and then identify the influencing factors on self-expression in sub-factors of dependent variables. [Subjects and Methods] Forty elderly persons were divided into two groups: intervention group (n=20) and control group (n=20). The interventions were applied to the subjects 3 times a week, 50 minutes per each time, for a total of five weeks. We measured the jamar hand dynamometer test for grip strength, the jamar hydraulic pinch gauge test for prehension test, nine hole pegboard test for coordination test, and Loewenstein Occupational Therapy Cognitive Assessment-Geriatric Population for cognitive function, and self expression rating scale for self-expression test. [Results] The task-oriented activities promoted hand function, cognitive function (visual perception, spatial perception, visuomotor organization, attention & concentration) and self expression of the elderly with early dementia, and the factors influencing the self-expression were cognitive function (visual perception) and hand function (coordination). The study showed that the task-oriented program enabled self expression by improving hand function and cognitive function. [Conclusion] This study suggested that there should be provided the task-oriented program for prevention and treatment of the elderly with early dementia in the clinical settings and it was considered that results have a value as basic data that can be verified relationship of hand function, cognitive function, and self expression. PMID- 28878463 TI - Associations between ankle dorsiflexion range of motion and foot and ankle strength in young adults. AB - [Purpose] This study assessed the relationships between the ankle dorsiflexion range of motion and foot and ankle strength. [Subjects and Methods] Twenty-nine healthy (young adults) volunteers participated in this study. Each participant completed tests for ankle dorsiflexion range of motion, hallux flexor strength, and ankle plantar and dorsiflexor strength. [Results] The results showed (1) a moderate correlation between ankle dorsiflexor strength and dorsiflexion range of motion and (2) a moderate correlation between ankle dorsiflexor strength and first toe flexor muscle strength. Ankle dorsiflexor strength is the main contributor ankle dorsiflexion range of motion to and first toe flexor muscle strength. [Conclusion] Ankle dorsiflexion range of motion can play an important role in determining ankle dorsiflexor strength in young adults. PMID- 28878464 TI - Effects of sling exercise on postural sway in post-stroke patients. AB - [Purpose] To examine the effects of sling exercise on the balance of post-stroke patients. [Subjects and Methods] A total of 18 post-stroke patients (13 men; mean age, 55.3 years) were recruited, and randomly assigned them into sling exercise (n=10) and control exercise (n=8) groups. The Good Balance System was used for measurement of velocity (anteroposterior and mediolateral, mm/s), velocity moment (mm2/s) of the movement of the center of pressure, and distance (anteroposterior and mediolateral, mm) between the center of pressure and the center point. The changes in mediolateral velocity, anteroposterior velocity, and velocity moment were compared between two groups in addition to the comparison of distance between the center of pressure and the center point of postural sway. [Results] The sling exercise group showed more significant improvements in anteroposterior velocity, mediolateral velocity, velocity moment, anteroposterior distance, and mediolateral distance than the control exercise group. [Conclusion] Sling exercise improved post-stroke balance performance and could be used as a therapeutic strategy to improve post-stroke functional recovery. PMID- 28878465 TI - Patellar movement perception related to a backward-leaning standing position. AB - [Purpose] To investigate the patellar movement perception related to backward leaning standing. [Subjects and Methods] Both the patellar range of motion during backward-leaning standing and perception related to patellar movement were analyzed using television-x irradiation images in 12 randomly selected healthy young individuals. [Results] Starting in a relaxed condition, two types of patellar movements were confirmed: those where the patella moves (patellar movement trials) and those where the patella does not move (patellar non-movement trials) during backward-leaning standing. The rate of the perceived patellar motion in the patellar movement trials was significantly higher (90.9%) than that in the patellar non-movement trials (66.7%). When starting in a quadriceps contracted condition, the rate of perceived trials (77.0%) was significantly lower than that of the trials started in a relaxed condition. [Conclusion] The perception of patellar movement while backward-leaning standing may contribute to the perception of a backward standing position especially when the patella really moves. PMID- 28878466 TI - A comparison of the function, activity and participation and quality of life between down syndrome children and typically developing children. AB - [Purpose] To compare function, activity, participation, and quality of life of Down syndrome children and typically developing children according to age. [Subjects and Methods] A total of 16 Down syndrome children and 20 children with typical development were included as subjects for this study. International Classification of Functioning, Disability, and Health (ICF) Child and Youth version (CY) developed by the World Health Organization (WHO) and a questionnaire were used to measure children's functioning, activity, and participation. To measure quality of life, KIDSCREEN 52-HRQOL questionnaire was used in this study. [Results] ICF-CY function, activity, participation, and quality of life showed statistically significant differences between Down syndrome children and typically developing children. Down syndrome children with higher functions showed higher activities and participation. Higher function, activity and participation features were correlated with better quality of life. Higher function resulted in better quality of life. [Conclusion] Function, activity, participation, quality of life, and several common factors of Down syndrome children depend on the ability of children. Function of Down syndrome children affects their activity, participation, and quality of life. Activities and participations also affect quality of life. Therefore, children's functional aspect is the foundation for quality of life. PMID- 28878467 TI - Key function for obstacle crossing in hemiplegic persons with varied degrees of spasticity. AB - [Purpose] To evaluate various key functions related to obstacle crossing motions in hemiplegic people based on the paralysis degree. [Subjects and Methods] Thirty seven patients with maintenance-stage hemiplegia who could independently ambulate outdoors were included. Subjects' crossing movements were measured using obstacles with heights of 10%, 20%, and 30% of the trochanter length. The relationship among maximal crossing height and isometric knee extension muscle strength, one leg standing time, Trunk Impairment Scale score, disease duration, and subject age was examined, as was the target variable of maximum crossing height and the top four measurement items, to determine the explanatory variables. The participants were grouped based on Brunnstrom Recovery Stages III IV (severe spasticity) and V-VI (mild spasticity). [Results] The explanatory variables were the Trunk Impairment Scale in the severe spasticity group and unaffected side-knee extension muscle strength in the mild spasticity group (contribution rates: 75.6% and 21.0%, respectively). [Conclusion] Trunk function in the severe spasticity group majorly contributed to crossing obstacles. Furthermore, knee extension muscle strength on the unaffected side in the mild spasticity group moderately contributed to crossing obstacles. Selecting and implementing a physical therapy routine that is aimed at improving function, depending on the severity of paralysis, is necessary. PMID- 28878468 TI - The effect of changing condition of walking speed on the knee angle of rats with osteoarthritis. AB - [Purpose] The purpose of this study was to investigate the positive effect of exercise on knee osteoarthritis in rats with osteoarthritis induced by applying effective walking speed when changing speed conditions during walking. [Subjects and Methods] The rats used in this study were male Sprague-Dawley rats weighing 300 g and 7 weeks old, and 20 rats were used. The Osteoarthritis (OA) rats model was induced by MIA (monoiodoacetate). The rats was randomly divided into experimental group (MIA injection group) and control group (normal cell line injection group). Treadmill exercise was provided two groups for 2 weeks, 4 days per week. The knee joint angle of the stance was divided into pre-test and post test, and each group was subjected to paired sample test. Independent sample t test was conducted to examine the difference between experimental group and control group. [Results] There were statistically significant changes in the control and experimental groups. The knee angle was changed from 99.70 +/- 2.40 to 85.60 +/- 2.67 in the control group. The knee angle was changed from 100.96 +/ 1.36 to 87.71 +/- 1.57 in the experimental group. [Conclusion] In conclusion, the angle of the knee gradually decreases. It is considered a characteristic of progressive osteoarthritis. The change of knee angle was less in the experimental group than in the control group. This means that the stiffness of the joints during the walking exercise was less progressed in the experimental group than in the control group. PMID- 28878469 TI - Effects of kinetic chain exercise using EMG-biofeedback on balance and lower extremity muscle activation in stroke patients. AB - [Purpose] The purpose of this study was to examine the effect of kinetic chain exercise using EMG-biofeedback on balance and lower extremity muscle activation. [Subjects and Methods] For this study, 30 stroke patients participated in this study and they were divided into closed kinetic chain exercise using EMG biofeedback group (CKCE+EB) and open kinetic chain exercise using EMG-biofeedback group (OKCE+EB), each group consisting of 15 patients. The kinetic chain exercise using EMG-biofeedback was performed by the patients for 20 minutes once a day, 5 days a week, for 6 weeks using an Myo-Ex. BioRescue was used to measure balance ability, while surface EMG was used to measure the lower extremity muscle activation. [Results] According to the results of the comparison within the groups, after the intervention, both groups showed significant increases in the balance ability and lower extremity muscle activation. In the comparisons between the groups, after the intervention, balance ability and lower extremity muscle activation were significantly higher in the CKCE+BE than in the OKCE+EB. [Conclusion] This study showed that closed kinetic chain exercise using EMG biofeedback is effective for improving balance ability and lower extremity muscle activation in stroke patients. PMID- 28878470 TI - Reliability of musculoskeletal ultrasound imaging to measure supraspinatus tendon thickness in healthy subjects. AB - [Purpose] The purpose of this study was to assess intra-rater and inter-rater reliability of musculoskeletal ultrasound (MSKUS) as a tool to measure supraspinatus tendon thickness in healthy subjects. [Subjects and Methods] Twenty healthy subjects were assessed in similar sitting position. Two experienced musculoskeletal ultrasound specialists measured supraspinatus tendon thickness. Tendon was measured twice in one day by each of two raters with an interval of one hour for within day reliability and was re-measured following one week for between days reliability. Data analysis was performed using the intraclass correlation coefficient (ICC) and standard error of measurement (SEM). [Results] Results reflected excellent within day intra-rater and inter-rater reliability with Mean +/- standard deviation (SD)=5.14 +/- 0.83 and 5.17 +/- 0.78, ICC (2,1)=0.89-0.93 and ICC (2,2)=0.98 (0.95-0.99) and SEM=0.18-0.18 and 0.17 while between days intra-rater rater and inter-rater reliability with Mean +/- SD=5.14 +/- 0.83 and 5.17 +/- 0.78, ICC(2,1)=0.88-0.90 and ICC(2,2)=0.95 (0.88-0.98), SEM=0.17-0.38 and 0.17 [Conclusion] The results of the current study indicate that MSKUS is a reliable tool for measuring supraspinatus tendon thickness in healthy subjects. PMID- 28878471 TI - Test-retest reliability of static postural control in people with multiple sclerosis. AB - [Purpose] The purpose of this study was to analyse the intraday test-retest reliability of stabilometric measurements on the Centre of Pressure (CoP) in persons with Multiple Sclerosis. [Subjects and Methods] The measurements were taken with the subject standing on the force platform with both feet together, in four different conditions: eyes open and closed whilst standing on both a rigid surface and then on foam. The measurements were taken on three occasions with intervals of 20 minutes between them. 18 persons with confirmed Multiple Sclerosis (MS), (aged 44.4 +/- 13.3 years and 3.5 +/- 1.5 EDSS) participated in the study. Relative reliability was measured using the intraclass correlation coefficient (ICC) and the 95% confidence interval (95% CI); and the absolute reliability using the coefficient of variation (CV) and standard error of measurement (SEM). [Results] The measurements of the CoP in all of the variables in each of the four conditions, showed a reliability of good to excellent (ICC=0.69-0.92) in the intraday test-retest. The variables which showed greatest consistency with repetition were X Speed, Y Speed and Side Length. [Conclusion] Given the results it would seem that the best variables for monitoring postural control in persons with MS are Speed on X and Y along with Side Length. PMID- 28878472 TI - Effects of the centrifugal contraction exercise of the rectus abdominis accompanied with the isometric exercise of the transversus abdominis on pain and balance of lower back pain patients. AB - [Purpose] The current study attempted to examine the effects of centrifugal contraction exercise of the rectus abdominis during the isometric contraction of the transversus abdominis on pain and balance of patients with chronic back pain. [Subjects and Methods] The subjects included thirty patients who were diagnosed with back pain due to causes other than neurological by a specialist after conducting a medical precision diagnosis. The experiment was performed after evenly dividing the subjects into two groups, namely, control and experimental, using a random method. This study measured pain by using the visual analog scale. To determine the patients' balancing ability using the Multifunktionale trainsgerate balance measurer. [Results] All groups showed a statistically significant within-group difference in visual analog scale and balance change. However, no significant between-group difference was observed in the comparison of therapy effects. [Conclusion] Strengthening the rectus abdominis can be an important factor for increasing the stability and reducing the pain of the lumbar area among patients with back pain. PMID- 28878473 TI - Cross-cultural adaptation of the 12-item Orebro musculoskeletal screening questionnaire to Japanese (OMSQ-12-J), reliability and clinicians' impressions for practicality. AB - [Purpose] To translate and culturally adapt the Orebro Musculoskeletal Screening Questionnaire (OMSQ-12) into Japanese (OMSQ-12-J), and to preliminarily investigate practicality from the clinicians' perspectives, and determine inter session reliability. [Subjects and Methods] This study included four phases: cross-cultural adaptation (Phases 1-2); survey among 14 clinicians (two medical doctors and 12 physiotherapists) about the practicality of using the questionnaire in six perspectives (speed of evaluation/treatment; capacity to detect patients with yellow flags; attitude towards management with bio-psycho social perspectives; quality of evaluation/treatment; considerations of communications with patients at history-taking, physical assessments and interventions; and general clinical usefulness) based on their experiences with patients (Phase 3); and investigation of inter-session reliability among 50 patients with musculoskeletal disorders (Phase 4). [Results] The OMSQ-12-J was developed in Phases 1-2 using the recommended international guidelines for cultural adaptation and translation. In Phase 3, most responses were in the 3 positive options (35.7-78.6%). In Phase 4, the Intraclass Correlation Coefficient for each item ranged from 0.71-0.99 and 0.92 for the total score. [Conclusion] This study developed the OMSQ-12-J, which has preliminary evidence of good practicality and moderate-strong inter-session reliability. Further investigation is required to determine the predictive and prognostic capacity within a problematic musculoskeletal Japanese population. PMID- 28878475 TI - Factors related to coping strategies during Japanese physical therapy students' clinical practice. AB - [Purpose] This study aimed to identify social skills and support that are related to the coping strategies Janpanese physical therapy students use during their clinical practice. [Subjects and Methods] Third-year students who were finished with their clinical practice participated. Self-administered questionnaires were used, including the daily life skill scale, social support scale, and tri-axial coping scale. Spearman's partial correlation coefficients were calculated between social skills, support of daily living, and coping strategies used during the clinical practice, while controlling for gender. [Results] A total of 56 completed questionnaires (median of age: 21 years; 27 males). Social skills during personal situations-knowledge summarization, self-esteem, and positive thinking-were significantly, positively correlated with planning and affirmative interpreting strategies to approach stressors regarding clinical practice, and negatively related to giving up strategies to avoid stressors. Intimacy, leadership, and empathy (social skills during interpersonal situations) were significantly, positively correlated with the following responses to approach stressors: catharsis, information gathering, and affirmative interpreting. Moreover, emotional/companionship social support was significantly, positively correlated with all avoidant coping strategies. [Conclusion] Japanese physical therapy students who had low personal and interpersonal social skills and excess emotional/companionship support in daily life tend to select avoidance, not approach, coping strategies during clinical practice. PMID- 28878474 TI - Acupressure for chronic low back pain: a single system study. AB - [Purpose] Low back pain (LBP) is the leading cause of global disability. Acupressure is a manual approach that can be used for self-management of LBP. The purpose of the study was to determine the effectiveness of acupressure in treating chronic LBP. [Subjects and Methods] The research design was a single system study utilizing an AB design. The subject was recruited using convenience sampling. During phase A, the subject received traditional physical therapy interventions. During phase B, the subject received acupressure in addition to traditional physical therapy interventions. Outcomes included the Visual Analog Scale (VAS), the Patient Specific Functional Scale (PSFS), and the Oswestry Disability Index (ODI). [Results] For the VAS, the pain was 38.8 mm at baseline, decreased to 11.3 mm after phase A, and decreased to 2.5 mm after phase B. For the PSFS, the subject's function was 5/10 at baseline, remained the same after phase A, and increased to 9/10 after phase B. For the ODI, the subject's disability was moderate (30%) at the baseline, decreased to minimal (14%) after phase A, and completely resolved (0%) after phase B. [Conclusion] The data indicated that integrating acupressure in physical therapy could reduce pain, increase function, and decrease disability. PMID- 28878476 TI - Center of mass with the use of smartphone during walking in healthy individuals. AB - [Purpose] The purpose of this study was to measure the center of mass using a smartphone application during walking in healthy. [Subjects and Methods] Forty eight healthy participants volunteered for this study. Measurements of center of mass were obtained by gait analysis application using smartphone while subjects performed 6 meter walking test. The measured data were automatically calculated by the application, subjects performed three trial walks to get a more accurate data analysis. [Results] There were no significant differences among subjects or between genders during the three trials in the vertical and lateral displacement of COM, and the results of the Kolmogorov-Simirnov test showed no differences in vertical and lateral displacement of COM in all subjects or between genders. However, the vertical displacement of COM significantly varied in male subjects than in female subjects, but the lateral displacement of COM did not significantly differ between the male and female subjects. [Conclusion] We can use the Smartphone application to measure the COM for walking; however more studies comparing advanced technological instruments with the smartphone application are needed. PMID- 28878477 TI - Near-infrared spectroscopy can reveal increases in brain activity related to animal-assisted therapy. AB - [Purpose] Previous studies have indicated that animal-assisted therapy can promote recovery of psychological, social, and physiological function in mental disorders. This study was designed as a pilot evaluation of the use of near infrared spectroscopy to objectively identify changes in brain activity that could mediate the effect of animal-assisted therapy. [Subjects and Methods] The participants were 20 healthy students (10 males and 10 females; age 19-21 years) of the Faculty of Agriculture, Saga University. Participants were shown a picture of a Tokara goat or shack (control) while prefrontal cortical oxygenated haemoglobin levels (representing neural activity) were measured by near-infrared spectroscopy. [Results] The prefrontal cortical near-infrared spectroscopy signal was significantly higher during viewing of the animal picture than during a rest condition or during viewing of the control picture. [Conclusion] Our results suggest that near-infrared spectroscopy can be used to objectively identify brain activity changes during human mentation regarding animals; furthermore, these preliminary results suggest the efficacy of animal-assisted therapy could be related to increased activation of the prefrontal cortex. PMID- 28878478 TI - Clinical features of patients diagnosed with degenerative rotator cuff tendon disease: a 6-month prospective-definitive clinical study from turkey. AB - [Purpose] In rotator cuff tendon disease (RCTD), anamnesis is as important as clinical findings and anatomic/radio diagnostic examination. This study aimed to investigate the clinical features of patients diagnosed with RCTD using clinical and radiological methods between March 2015 and August 2015 at Malatya Research and Training Hospital Physical Medicine and Rehabilitation department. [Subjects and Methods] The study included 178 patients who were diagnosed with RCTD (128 females and 50 males). A questionnaire comprising 33 questions was given to each patient. [Results] Eighty-eight of the patients (49.9%) had an involvement on their right side, eighty-four (47.1%) had an involvement on their left side, and 6 had bilateral involvement. Mean visual analog scale (VAS) score was found to be statistically significant in favor of female patients. A statistically significant correlation was found between educational status and VAS. The body mass index (BMI) of the female patients was found to be higher than that of the male patients. Statistically significant correlation between doing risky work and gender showed that males were at a higher risk. [Conclusion] RCDT is more seen in people who have high BMI and are at their 50s. Pain complaint and BMI were found higher in female patients. DM, thyroid and cardiac diseases were seen more in the patients who are diagnosed with RCTD relative to the healthy population. PMID- 28878479 TI - Prediction of prognosis of upper-extremity function following stroke-related paralysis using brain imaging. AB - [Purpose] Diffusion tensor imaging (DTI) has attracted attention as a method for determining prognosis following paralysis after stroke. However, DTI can assess the degree of damage to the corticospinal tract but cannot evaluate other brain regions. In this study, we examined in detail the prognosis of upper-limb function of the paralyzed side following stroke, using DTI and voxel-based morphometry (VBM). [Subjects and Methods] We studied 17 consecutive patients diagnosed with stroke, including hemorrhagic and ischemic types, who exhibited hemiparesis and were treated in our hospital. DTI and VBM were performed 14 days after admission. Outcome measurements that assessed upper limb function were Fugl Meyer Assessment (FMA) and Motor Activity Log (MAL), which were applied after 3 months. [Results] The fractional anisotropy ratio of the bilateral cerebral peduncles (rFA) was significantly correlated with FMA, amount of use, and quality of movement 3 months after stroke. The precentral gyrus significantly degenerated as compared with the control group for a case with notable motor paralysis, for which rFA was high. [Conclusion] We suggest it may be possible to predict recovery of upper limb function following stroke by combining DTI and VBM visualization methods. PMID- 28878480 TI - Anti-gravity treadmill can promote aerobic exercise for lower limb osteoarthritis patients. AB - [Purpose] The anti-gravity treadmill (Alter-G(r)) allows the load on the lower limbs to be adjusted, which is considered useful for patients with lower limb osteoarthritis. The aim of the present study was to examine the effects of aerobic exercise using an anti-gravity treadmill in patients with lower limb osteoarthritis by using a cardiopulmonary exercise load monitoring system. [Subjects and Methods] The subjects were 20 patients with lower limb osteoarthritis. These subjects walked naturally for 8 minutes and then walked on the Alter-G for 8 minutes at their fastest speed at a load where lower limb pain was alleviated. [Results] Subjective and objective exercise intensity did not differ significantly between level ground walking and Alter-G walking neither before nor after walking. Pain before walking did not differ significantly between level ground walking and Alter-G walking, but pain after walking was significantly greater with level ground walking than with Alter-G walking. [Conclusion] Exercise therapy using an anti-gravity treadmill was useful for patients with lower limb osteoarthritis in terms of cardiopulmonary function, which suggested that this could become a new form of exercise therapy. PMID- 28878481 TI - Effects of high-intensity pulse irradiation with linear polarized near-infrared rays and stretching on muscle tone in patients with cerebrovascular disease: a randomized controlled trial. AB - [Purpose] The purpose of this study was to clarify the influence of high intensity pulse irradiation with linear polarized near-infrared rays (HI-LPNR) and stretching on hypertonia in cerebrovascular disease patients. [Subjects and Methods] The subjects were 40 cerebrovascular disease patients with hypertonia of the ankle joint plantar flexor muscle. The subjects were randomly allocated to groups undergoing treatment with HI-LPNR irradiation (HI-LPNR group), stretching (stretching group), HI-LPNR irradiation followed by stretching (combination group), and control group (10 subjects each). In all groups, the passive range of motion of ankle dorsiflexion and passive resistive joint torque of ankle dorsiflexion were measured before and after the specified intervention. [Results] The changes in passive range of motion, significant increase in the stretching and combination groups compared with that in the control group. The changes in passive resistive joint torque, significant decrease in HI-LPNR, stretching, and combination groups compared with that in the control group. [Conclusion] HI-LPNR irradiation and stretching has effect of decrease muscle tone. However, combination of HI-LPNR irradiation and stretching has no multiplier effect. PMID- 28878482 TI - Effects of high intensity aerobic exercise on treadmill on maximum-expiratory lung capacity of elderly women. AB - [Purpose] The aim of this study was to examine whether a systematic high intensity aerobic exercise on treadmill was effective in improving pulmonary function. [Subjects and Methods] The subjects of this study were 22 healthy elderly women over 65 years of age who were attending the Senior Welfare Center and Social Welfare Center programs in B city. For the pulmonary function test, a spirometry (Pony FX, COSMED Inc., Italy) was used. The item for measurement of pulmonary function in elderly women was maximum-effort expiratory spirogram (MES). The pulmonary function test was performed 3 times, and its mean value was used for analysis. After a 15 minute warm-up stretching, high intensity aerobic exercise was performed for 20 minutes as a main exercise, followed by 15 minutes of cool-down stretching. Exercise was performed three days a week for 12 weeks. [Results] Among items of maximum-effort expiratory spirogram, a significant difference after exercise was demonstrated in forced vital capacity, forced expiratory volume in 1 second. Two factors were improved after exercise. [Conclusion] The results demonstrated that high intensity aerobic exercise on the treadmill has a positive effect on the pulmonary function of elderly women. PMID- 28878483 TI - Factors affecting dyspnea after the 6-minute walk test in idiopathic pulmonary fibrosis patients presenting with exercise-induced hypoxemia. AB - [Purpose] The current study aimed to investigate factors affecting dyspnea after the 6-minute walk test (6MWT) in idiopathic pulmonary fibrosis (IPF) patients presenting with hypoxemia. [Subjects and Methods] The subjects were IPF out patients with stable symptoms whose percutaneous arterial oxygen saturation fell to 88% during the 6MWT test. Quadriceps force, 6-minute walk distance (6MWD), dyspnea after the 6MWT, and leg fatigue (LF) were evaluated as exercise-related variables. [Results] The subjects were 14 patients (mean age 73.6 +/- 6.3 years) classed based on the modified Medical Research Council dyspnea scale as 0 for 2 patients, 1 for 6 patients, and 2 for 6 patients, indicating that the patients were comparatively mild cases. Mean 6MWD was 408.9 +/- 102.4 m, and dyspnea after the 6MWT and LF were 3.0 +/- 1.4 and 1.5 +/- 1.5, respectively. Dyspnea after the 6MWT was correlated with vital capacity (VC), forced vital capacity, and LF. Stepwise multiple regression analysis identified VC and LF as factors significantly affecting dyspnea after the 6MWT. [Conclusion] The results of this study demonstrated that it is necessary to evaluate both pulmonary function and LF in IPF patients presenting with exercise-induced hypoxemia and exertional dyspnea. PMID- 28878484 TI - Direct access to physical therapy for the patient with musculoskeletal disorders, a literature review. AB - [Purpose] To present legislation comparing direct and referred access-or other measures-to physical therapy. The focus is on the management of the most burdensome musculoskeletal disorders in terms of regulations, costs, effectiveness, safety and cost-effectiveness. [Methods] Main biomedical databases and gray literature were searched ranging from a global scenario to the analysis of targeted geographical areas and specifically Italy and the Region Piedmont. [Results] legislation on Direct Access highlights inconsistencies among the countries belonging to World Confederation for Physical Therapy. Direct Access could be an effective, safe and efficient organization model for the management of patients with musculoskeletal diseases and seems to be more effective safer and cost effective. [Conclusion] Direct Access is a virtuous model which can help improve the global quality of physical therapy services. Further studies are required to confirm this approach and determine whether the findings of the present overview can be replicated in different countries and healthcare systems. PMID- 28878485 TI - Non-surgical relief of cervical radiculopathy through reduction of forward head posture and restoration of cervical lordosis: a case report. AB - [Purpose] To present a case demonstrating the relief of cervical radiculopathy following the dramatic reduction of forward head posture and restoration of the cervical lordosis by use of a multi-modal rehabilitation program incorporating cervical extension traction. [Subject and Methods] A 31-year-old male patient presented with severe cervical radiculopathy and muscle weakness as well as neck pain. The patient had limited neck range of motion, and multiple positive orthopedic tests. Radiography revealed excessive forward head posture with a cervical kyphosis. [Results] The patient received a multi-modal rehabilitation protocol including mirror image extension exercises, cervical extension traction, and spinal manipulative therapy. After forty treatments over 17 weeks, the patient reported a complete resolution of radiculopathy and significant improvement in neck pain level. Post radiography demonstrated correction of the spine and posture alignment. The patient remained well and maintained corrected posture with limited treatment one year later. [Conclusion] Our case demonstrates the relief of cervical radiculopathy resulting from the non-surgical correction of forward head posture and cervical kyphosis. PMID- 28878486 TI - Treating 'slouchy' (hyperkyphosis) posture with chiropractic biophysics(r): a case report utilizing a multimodal mirror image(r) rehabilitation program. AB - [Purpose] To present a case of the non-surgical reduction of 'slouchy' hyperkyphosis posture utilizing the multimodal Chiropractic BioPhysics(r) rehabilitation program emphasizing the mirror image(r) concept. [Subject and Methods] A 27-year-old female presented suffering from neck and back pains, headaches and gait dysfunction. The patient was treated 30 times over a period of 6-months. Treatment consisted of anterior thoracic translation, thoracic extension, and head retraction exercises as well as spinal traction and spinal manipulation. [Results] After 6-months of treatment the patient displayed a total correction of the posterior thoracic translation with a significant reduction in thoracic hyperkyphosis. The dramatic correction of her overall posture and spine alignment corresponded to the significant relief of neck and back pains, headaches and improvement of various other health issues as demonstrated by self report and SF-36. [Conclusion] Poor postures corresponding to poor health can be changed for the better with multimodal rehabilitation programs that are now showing consistent postural improvements corresponding with improvements in various health conditions. We suggest that the postural correction of those with various pain symptoms be considered as a first line non-pharmalogical, non surgical rehabilitation approach for those presenting with poor posture. PMID- 28878487 TI - Effect of a combined thoracic and backward lifting exercise on the thoracic kyphosis angle and intercostal muscle pain. AB - [Purpose] This study developed a combined thoracic and backward lifting exercise for thoracic kyphosis angle and intercostal muscle pain. [Subject and Methods] The subject was a 41-year-old man who complained of upper thoracic and intercostal pain. He performed the combined thoracic and backward lifting exercise for 15 days. [Results] The initial VAS score for the intercostal area was 4/10. The VAS score decreased to 1/10 after the thoracic exercise combined with backward lifting. The initial thoracic kyphosis angle was 38 degrees and it decreased to 32 degrees after the exercise period. [Conclusion] Therefore, backward lifting and thoracic extension is a good posture for activating the different layers of muscle that are attached to the ribs. The kyphosis angle is also reduced by providing sufficient resistance during the thoracic exercise. PMID- 28878488 TI - Research progress on the autonomous flowering time pathway in Arabidopsis. AB - The transition from vegetative to reproductive growth phase is a pivotal and complicated process in the life cycle of flowering plants which requires a comprehensive response to multiple environmental aspects and endogenous signals. In Arabidopsis, six regulatory flowering time pathways have been defined by their response to distinct cues, namely photoperiod, vernalization, gibberellin, temperature, autonomous and age pathways, respectively. Among these pathways, the autonomous flowering pathway accelerates flowering independently of day length by inhibiting the central flowering repressor FLC. FCA, FLD, FLK, FPA, FVE, FY and LD have been widely known to play crucial roles in this pathway. Recently, AGL28, CK2, DBP1, DRM1, DRM2, ESD4, HDA5, HDA6, PCFS4, PEP, PP2A-B'gamma, PRMT5, PRMT10, PRP39-1, REF6, and SYP22 have also been shown to be involved in the autonomous flowering time pathway. This review mainly focuses on FLC RNA processing, chromatin modification of FLC, post-translational modification of FLC and other molecular mechanisms in the autonomous flowering pathway of Arabidopsis. PMID- 28878490 TI - Identification and expression analysis under abiotic stress of the R2R3-MYB genes in Ginkgo biloba L. AB - The R2R3-MYB gene family is the largest MYB subfamily in plants and is involved in the regulation of plant secondary metabolism and specific morphogenesis, as well as the response to biotic and abiotic stress. However, a systematic identification and characterization of this gene family has not been carried out in Ginkgo biloba. In this study, we performed a transcriptome-wide survey from four tissues of G. biloba to determine the genetic variation and expression pattern of the R2R3-MYB genes. We analyzed 45 GbMYBs and identified 42 with a complete coding sequence via conserved motif searches. The MYB domain and other motifs in GbMYBs are highly conserved with Arabidopsis thaliana AtMYBs. Phylogenetic analysis of the GbMYBs and AtMYBs categorized the R2R3-MYBs into 26 subgroups, of which 11 subgroups included proteins from both G. biloba and Arabidopsis, and 1 subgroup was specific to G. biloba. Moreover, the GbMYBs expression patterns were analyzed in different tissues and abiotic stress conditions. The results revealed that GbMYBs were differentially expressed in various tissues and following abiotic stresses and phytohormone treatments, indicating their possible roles in biological processes and abiotic stress tolerance and adaptation. Our study demonstrated the functional diversity of the GbMYBs and will provide a foundation for future research into their biological and molecular functions. PMID- 28878491 TI - Salt stress reveals differential physiological, biochemical and molecular responses in T. monococcum and T. durum wheat genotypes. AB - Salt stress responses implicate a complex mechanism and differ from plant species to another. In this study, we analyzed the physiological, biochemical and molecular responses to salt stress of the diploid wheat (T. monococcum) and compared to the tetraploid wheat (T. durum). Our results showed that the diploid wheat cultivar (cv. Turkey) is relatively tolerant to different salt stress conditions than the tetraploid wheat cultivar (cv. Om Rabia3). This tolerance was manifested by significant germination, plant growth and uptake of water generating cell turgor and development. Moreover, total chlorophyll content was higher in the diploid wheat than that in the tetraploid wheat. The Na+ content in leaf blade of the cv. Om Rabia3 was significantly higher than that of the cv. Turkey, suggesting that the diploid cultivar accumulates less toxic sodium in the photosynthetic tissues. This mechanism could be explained by the recirculation of the toxic ions Na+ into the xylem sap by SOS1 protein, which coordinates with HKT like proteins to reduce the accumulation of Na+ ions in leaf blade. Interestingly, the expression of the three genes SOS1, HKT and NHX was enhanced under salinity especially in leaf blade of the cv. Turkey. Moreover, this wheat cultivar induced the antioxidative enzymes CAT and SOD activity more efficiently than the other cultivar. PMID- 28878489 TI - RNAi technology: a new platform for crop pest control. AB - The insect pests are big threat in meeting the food demands for future generation. The present pest control strategies, including the existing transgenic approaches show certain limitations and are not completely successful in limiting the insect pests. However, the sequence-specific gene silencing via RNA interference (RNAi) holds a great promise for effective management of agricultural pests. RNAi is naturally occurring conserved process responsible for gene regulation and defense against pathogens. The efficacy of RNAi varies among different insect orders and also depends upon various factors, including the target gene selection, method of dsRNAs delivery, expression of dsRNAs and presence of off-target effects. RNAi-mediated silencing of different insect genes involved in various physiological processes was found to be detrimental to insects growth, development and survival. In this article, we have reviewed the potential of RNAi-based strategies for effective management of insect pests. We have also discussed the various parameters, which are to be considered for host induced RNAi-mediated control of insect pests without producing any effect on non target organisms and environment. PMID- 28878493 TI - Improvement of drought tolerance of soybean plants by using methyl jasmonate. AB - Methyl jasmonate (MeJA) is a naturally occurring plant growth regulator and play vital roles in plant defense and many developmental processes such as root growth and seed germination. This study was undertaken to study the possible role of using methyl jasmonate to alleviate the adverse effect of water stress on soybean genotypes (Giza 22 and 35). The results showed that water stress reduced shoot length, fresh and dry weights of shoot and root, photosynthetic pigments, relative water content and oil content in the shoots of all soybean genotypes. On the other hand, there was a considerable increase in cell wall fractionation, saturated and unsaturated fatty acids, flavonoids, phenolic acid and sugar fraction content in the shoots of the soybean genotypes in response to the water stress. Foliar spray with methyl jasmonate increased all the above parameters as compared to stressed plants. The results investigate the important role of MeJA in alleviation of water stress in soybean plants and suggest that MeJA could be used for improving plant growth under water stress as a potential growth regulator. The soybean genotypes Giza 22 was found to be more resistant to water stress than Giza 35. PMID- 28878492 TI - Biochemical, physiological and molecular evaluation of rice cultivars differing in salt tolerance at the seedling stage. AB - Changes in the antioxidant enzymes, lipid peroxidation, sodium and potassium, chlorophyll, H2O2 and proline content were monitored in the leaves of 42 rice varieties which were not yet well-documented for the salinity tolerance under different salinity levels. The tolerant varieties (FL478, Hassani, Shahpasand, Gharib and Nemat) showed signs of tolerance (lower Na+/K+ ratio, high proline accumulation, less membrane damage, lower H2O2 production, and higher superoxide dismutase and catalase activity) very well. The positive relationship between the level of salt tolerance and the amount of proline accumulation in the rice varieties support the important role of proline under the salt stress. The varieties were genotyped for 12 microsatellite markers that were closely linked to SalTol QTL. The results of association analysis indicated that RM1287, RM8094, RM3412 and AP3206 markers had the high value of R2 for the regression models of the studied traits. It shows the important role of SalTol in controlling physio biochemical traits. The results can be used in the future marker assisted selection (MAS) directly, if the results are confirmed. PMID- 28878494 TI - Responses of wheat plants to interactions of 24-epibrassinolide and Glomus mosseae in saline condition. AB - This study was designed to investigate the possible effects of 24-Epibrassinolide (BR), arbuscular mycorrhizal (AM) fungus, Glomus mosseae, singularly and collectively under salt stress in wheat (Triticum aestivum L.) plants. After foliar spraying of mycorrhizal and non-mycorrhizal plants by 5 uM epibrassinolide (24-Epi), they were treated with 0 and 150 mM NaCl for 2 weeks and then harvested. The results showed interactions of G. mosseae and 24-Epi could alleviate the adverse effects of salinity by improving relative water content (RWC) of leaves (62%), relative growth rate (40.74%), shoot fresh weights (39.83%) and shoot phosphorous content (63.93%), stimulating leaf enzymatic antioxidant activities including catalase (2.24 fold) and ascorbate peroxidase (2.18 fold) as well as malondialdehyde (36.17%) and H2O2 concentrations (49.74%) as compared to those of NaCl treatments. Moreover, mycorrhizal dependency of root dry weight (2%) and phosphorus concentration (0.4%) increased with AM infection and 24-Epi application under saline condition. Leaf RWC, also, negatively correlated with membrane electrolyte leakage. Furthermore, the greatest mitigating effects were observed in mycorrhizal plants subjected to NaCl and 24 Epi. This study indicated that 24-Epi application and AM fungi may synergistically mitigate harmful impacts of salinity in wheat plants. PMID- 28878495 TI - The expression of a candidate cucumber fruit sugar starvation marker gene CsSEF1 is enhanced in malformed fruit induced by salinity. AB - The cucumber (Cucumis sativus L.) gene Cucumis sativus Somatic Embryogenesis Zinc Finger 1 (CsSEF1) was suggested to be a good marker gene for sugar starvation in fruit. The expression of this gene in fruits is dramatically upregulated in plants that have suffered either complete defoliation or prolonged darkness. CsSEF1 was initially discovered as a gene that was upregulated during somatic embryogenesis. We examined the difference in fruit parts and the effect of pollination on the upregulation of CsSEF1 induced by defoliation treatment. The results indicated that the upregulation of CsSEF1 in fruit by defoliation is not dependent on the presence of developing embryos. The expression of CsSEF1 was upregulated in malformed fruit induced by salinity in which the development of placenta was arrested. Partial cutting of the distal part of the fruit showed that if placenta tissue remained there was no upregulation of CsSEF1, whereas when placenta tissue did not remain there was a marked upregulation of CsSEF1. These results could be consistently interpreted as showing that placenta tissue induced the transport of photoassimilates to the fruit and that without developing placenta tissue, pericarp tissue suffers from severe sugar starvation. This interpretation, in turn, enforces the view that CsSEF1 is a good marker gene of fruit sugar starvation. PMID- 28878496 TI - Plant growth promoting effect of Bacillus amyloliquefaciens H-2-5 on crop plants and influence on physiological changes in soybean under soil salinity. AB - This study was aimed to identify plant growth-promoting bacterial isolates from soil samples and to investigate their ability to improve plant growth and salt tolerance by analysing phytohormones production and phosphate solubilisation. Among the four tested bacterial isolates (I-2-1, H-1-4, H-2-3, and H-2-5), H-2-5 was able to enhance the growth of Chinese cabbage, radish, tomato, and mustard plants. The isolated bacterium H-2-5 was identified as Bacillus amyloliquefaciens H-2-5 based on 16S rDNA sequence and phylogenetic analysis. The secretion of gibberellins (GA4, GA8, GA9, GA19, and GA20) from B. amyloliquefaciens H-2-5 and their phosphate solubilisation ability may contribute to enhance plant growth. In addition, the H-2-5-mediated mitigation of short term salt stress was tested on soybean plants that were affected by sodium chloride. Abscisic acid (ABA) produced by the H-2-5 bacterium suppressed the NaCl-induced stress effects in soybean by enhancing plant growth and GA4 content, and by lowering the concentration of ABA, salicylic acid, jasmonic acid, and proline. These results suggest that GAs, ABA production, and the phosphate solubilisation capacity of B. amyloliquefaciens H-2-5 are important stimulators that promote plant growth through their interaction and also to improve plant growth by physiological changes in soybean at saline soil. PMID- 28878497 TI - Biochemical basis of improvement of defense in tomato plant against Fusarium wilt by CaCl2. AB - The objective of this study was to investigate the effectiveness of calcium chloride (CaCl2), as potential elicitor, on tomato plants against Fusarium oxysporum f. sp. lycopersici. Foliar application of CaCl2 showed significant reduction of wilt incidence after challenge inoculation. Increased production of defense and antioxidant enzymes was observed in elicitor treated sets over control. Simultaneously, altered amount of phenolic acids were analyzed spectrophotometrically and by using high performance liquid chromatography. Significant induction of defense-related genes expressions was measured by semi quantitative RT-PCR. Greater lignifications by microscopic analysis were also recorded in elicitor treated plants. Simultaneously, generation of nitric oxide (NO) in elicitor treated plants was confirmed by spectrophotometrically and microscopically by using membrane permeable fluorescent dye. Furthermore, plants treated with potential NO donor and NO modulators showed significant alteration of all those aforesaid defense molecules. Transcript analysis of nitrate reductase and calmodulin gene showed positive correlation with elicitor treatment. Furthermore, CaCl2 treatment showed greater seedling vigor index, mean trichome density etc. The result suggests that CaCl2 have tremendous potential to elicit defense responses as well as plant growth in co-relation with NO, which ultimately leads to resistance against the wilt pathogen. PMID- 28878498 TI - Improved tolerance against Helicoverpa armigera in transgenic tomato over expressing multi-domain proteinase inhibitor gene from Capsicum annuum. AB - Plant proteinase inhibitors (PIs) are plant defense proteins and considered as potential candidates for engineering plant resistances against herbivores. Capsicum annuum proteinase inhibitor (CanPI7) is a multi-domain potato type II inhibitor (Pin-II) containing four inhibitory repeat domains (IRD), which target major classes of digestive enzymes in the gut of Helicoverpa armigera larvae. Stable integration and expression of the transgene in T1 transgenic generation, were confirmed by established molecular techniques. Protein extract of transgenic tomato lines showed increased inhibitory activity against H. armigera gut proteinases, supporting those domains of CanPI7 protein to be effective and active. When T1 generation plants were analyzed, they exhibited antibiosis effect against first instar larvae of H. armigera. Further, larvae fed on transgenic tomato leaves showed delayed growth relative to larvae fed on control plants, but did not change mortality rates significantly. Thus, better crop protection can be achieved in transgenic tomato by overexpression of multi-domain proteinase inhibitor CanPI7 gene against H. armigera larvae. PMID- 28878499 TI - Comparative proteomic analysis of autotetraploid and diploid Paulownia tomentosa reveals proteins associated with superior photosynthetic characteristics and stress adaptability in autotetraploid Paulownia. AB - To enlarge the germplasm resource of Paulownia plants, we used colchicine to induce autotetraploid Paulownia tomentosa, as reported previously. Compared with its diploid progenitor, autotetraploid P. tomentosa exhibits better photosynthetic characteristics and higher stress resistance. However, the underlying mechanism for its predominant characteristics has not been determined at the proteome level. In this study, isobaric tag for relative and absolute quantitation coupled with liquid chromatography-tandem mass spectrometry was employed to compare proteomic changes between autotetraploid and diploid P. tomentosa. A total of 1427 proteins were identified in our study, of which 130 proteins were differentially expressed between autotetraploid and diploid P. tomentosa. Functional analysis of differentially expressed proteins revealed that photosynthesis-related proteins and stress-responsive proteins were significantly enriched among the differentially expressed proteins, suggesting they may be responsible for the photosynthetic characteristics and stress adaptability of autotetraploid P. tomentosa. The correlation analysis between transcriptome and proteome data revealed that only 15 (11.5%) of the differentially expressed proteins had corresponding differentially expressed unigenes between diploid and autotetraploid P. tomentosa. These results indicated that there was a limited correlation between the differentially expressed proteins and the previously reported differentially expressed unigenes. This work provides new clues to better understand the superior traits in autotetraploid P. tomentosa and lays a theoretical foundation for developing Paulownia breeding strategies in the future. PMID- 28878500 TI - Genome-wide identification of SAUR genes in watermelon (Citrullus lanatus). AB - The early auxin responsive SAUR family is an important gene family in auxin signal transduction. We here present the first report of a genome-wide identification of SAUR genes in watermelon genome. We successfully identified 65 ClaSAURs and provide a genomic framework for future study on these genes. Phylogenetic result revealed a Cucurbitaceae-specific SAUR subfamily and contribute to understanding of the evolutionary pattern of SAUR genes in plants. Quantitative RT-PCR analysis demonstrates the existed expression of 11 randomly selected SAUR genes in watermelon tissues. ClaSAUR36 was highly expressed in fruit, for which further study might bring a new prospective for watermelon fruit development. Moreover, correlation analysis revealed the similar expression profiles of SAUR genes between watermelon and Arabidopsis during shoot organogenesis. This work gives us a new support for the conserved auxin machinery in plants. PMID- 28878501 TI - Genome-wide identification, phylogeny and expression analyses of SCARECROW LIKE(SCL) genes in millet (Setaria italica). AB - As a member of the GRAS gene family, SCARECROW-LIKE (SCL) genes encode transcriptional regulators that are involved in plant information transmission and signal transduction. In this study, 44 SCL genes including two SCARECROW genes in millet were identified to be distributed on eight chromosomes, except chromosome 6. All the millet genes contain motifs 6-8, indicating that these motifs are conserved during the evolution. SCL genes of millet were divided into eight groups based on the phylogenetic relationship and classification of Arabidopsis SCL genes. Several putative millet orthologous genes in Arabidopsis, maize and rice were identified. High throughput RNA sequencing revealed that the expressions of millet SCL genes in root, stem, leaf, spica, and along leaf gradient varied greatly. Analyses combining the gene expression patterns, gene structures, motif compositions, promoter cis-elements identification, alternative splicing of transcripts and phylogenetic relationship of SCL genes indicate that the these genes may play diverse functions. Functionally characterized SCL genes in maize, rice and Arabidopsis would provide us some clues for future characterization of their homologues in millet. To the best of our knowledge, this is the first study of millet SCL genes at the genome wide level. Our work provides a useful platform for functional analysis of SCL genes in millet, a model crop for C4 photosynthesis and bioenergy studies. PMID- 28878502 TI - Cytogenetic and molecular evidences revealing genomic changes after autopolyploidization: a case study of synthetic autotetraploid Phlox drummondii Hook. AB - Polyploidy is known to be common in plants; indeed most of the world's economically important crop plants are polyploids. Recent studies revealed extensive genomic changes in synthetic polyploids after genome doubling, although most of the information available is with regards to allopolyploids and little information have been generated in autopolyploids. In the present study, we used Phlox drummondii Hooker (2n = 2x = 14) as a model plant to observe genomic changes, if any, in synthetic autopolyploids. Colchitetraploids were produced and followed through different generations (C0, C1, C2 and C3). Male meiosis analysis showed differences between the frequency of both quadrivalents and bivalents from C0 to C2 generations. RAPD analysis revealed 2.8, 1.6, 2.1 and 3.2% polymorphism in C0, C1, C2 and C3 colchitetraploids respectively. The polymorphic fragments were further characterized after cloning. Dot blot assay was performed to confirm high copy/low copy nature of fragments showing variation. The analysis revealed changes in both repetitive and non-repetitive regions. Out of the six fragments only one fragment T01 was found to be of high copy, while four fragments were of the moderate copy and one fragment of the low copy nature. PMID- 28878503 TI - Assessment of genetic diversity and population structure of an endemic Moroccan tree (Argania spinosa L.) based in IRAP and ISSR markers and implications for conservation. AB - Argan Tree is well known for its precious oil extracted from its seeds particularly used for the nutritional and cosmetic benefits. Because of the high international demand, the argan tree suffers from overexploitation and its cultivation is rare. Thus, the assessment of the genetic variation of this endemic tree is critically important for designing conservation strategies. In the present study and for the first time, genetic diversity of the global natural distribution of argan tree (Argania spinosa L.) in Morocco was assessed. Four IRAP (inter-retrotransposon amplified polymorphism) primer combinations and seven ISSR (inter-simple sequence repeat) primers amplified 164 and 248 scorable polymorphic bands respectively. Polymorphic information content (PIC = 0.27), resolving power (Rp = 15) and marker index (MI = 10.81) generated by IRAP primer combinations were almost identical to those generated by ISSR primers (PIC = 0.27, Rp = 9.16 and MI = 12). AMOVA analysis showed that 49% of the genetic variation was partitioned within populations which is supported by Nei's genetic differentiation (Gst = 0.5391) and the overall estimate of gene flow (Nm) being 0.4274. The STRUCTURE analysis, PCoA (principal coordinate analysis) and UPGMA (unweighted pair-group method with arithmetic mean) based on the combined data matrices of IRAP and ISSR divided the 240 argan genotypes into two groups. The strong differentiation observed might be due to the geographical distribution of argan tree. Our results provide crucial insight for genetic conservation programs of this genetic resource. PMID- 28878504 TI - Analysis of spatial distribution of genetic diversity and validation of Indian foxtail millet core collection. AB - Foxtail millet [Setaria italica (L.) P. Beauv.] is an important small millet, grown as a short duration, drought tolerant crop across the world. This crop can be grown on wide ranges of soil conditions and has an immense potential for food and fodder in rainfed and arid regions of the India. In the present study, 31 primer pairs (27 SSR and 4 EST-SSR) were used to analyse the genetic diversity in 223 core collection accessions. Analysis resulted in detection of a total of 136 alleles with an average of 4.38 alleles per locus. Among these 136 alleles, 22 were rare, 70 were common and 44 were frequent. The PIC value ranged from 0.01 to 0.86 with an average of 0.31. The average number of observed alleles ranged from 2.0 (northern hills of India accessions) to 4.06 (exotic) with an average of 2.72. The mean Shannon's Information Index ranged from 0.44 (northern hills of India) to 0.69 (exotic) with an average of 0.52. Pair-wise Fst values indicated little to moderate genetic differentiation among the group of accessions. UPGMA clustering grouped the accessions into two major groups while analysis for population substructure indicated presence of four subpopulations. However there was no statistically well supported grouping of the accessions based on eco geographic specificities. The core collection designated here represented substantial genetic diversity at molecular level, hence may be a good source of diversity for use in foxtail improvement programs in the region. PMID- 28878505 TI - Analysis of an intraspecific RIL population uncovers genomic segments harbouring multiple QTL for seed relevant traits in lentil (Lens culinaris L.). AB - Improving seed related traits remains key objective in lentil breeding. In recent years, genomic resources have shown great promise to accelerate crop improvement. However, limited genomic resources in lentil greatly restrict the use of genomics assisted breeding. The present investigation aims to build an intraspecific genetic linkage map and identify the QTL associated with important seed relevant traits using 94 recombinant inbreds (WA 8649090 * Precoz). A total of 288 polymorphic DNA markers including simple sequence repeat (SSR), inter simple sequence repeat (ISSR) and random amplified polymorphic DNA (RAPD) were assayed on mapping population. The resultant genetic linkage map comprised 220 loci spanning 604.2 cM of the lentil genome, with average inter-marker distance of 2.74 cM. QTL mapping in this RIL population uncovered a total of 18 QTL encompassing nine major and nine minor QTL. All major QTL were detected for seed related traits viz., seed diameter (SD), seed thickness (ST), seed weight (SW) and seed plumpness (SP) across two locations. A considerable proportion of the phenotypic variation (PV) was accounted to these QTL. For instance, one major QTL on LG5 controlling SW (QTL 15) explained 50% PV in one location, while the same QTL accounted for 34.18% PV in other location. Importantly, the genomic region containing multiple QTL for different seed traits was mapped to a 17-cM region on LG5. The genomic region harbouring QTL for multiple traits opens up exciting opportunities for genomics assisted improvement of lentil. PMID- 28878506 TI - Analysis of tandem repeat units of the promoter of capsanthin/capsorubin synthase (Ccs) gene in pepper fruit. AB - Capsanthin/capsorubin synthase (Ccs) gene is a key gene that regulates the synthesis of capsanthin and the development of red coloration in pepper fruits. There are three tandem repeat units in the promoter region of Ccs, but the potential effects of the number of repetitive units on the transcriptional regulation of Ccs has been unclear. In the present study, expression vectors carrying different numbers of repeat units of the Ccs promoter were constructed, and the transient expression of the beta-glucuronidase (GUS) gene was used to detect differences in expression levels associated with the promoter fragments. These repeat fragments and the plant expression vector PBI121 containing the 35s CaMV promoter were ligated to form recombinant vectors that were transfected into Agrobacterium tumefaciens GV3101. A fluorescence spectrophotometer was used to analyze the expression associated with the various repeat units. It was concluded that the constructs containing at least one repeat were associated with GUS expression, though they did not differ from one another. This repeating unit likely plays a role in transcription and regulation of Ccs expression. PMID- 28878507 TI - Improvement of yield and quality of two Spinacia oleracea L. varieties by using different fertilizing approaches. AB - The effects of different fertilizers [the control with no fertilizer (C), inorganic fertilization (I), combined inorganic and organic fertilizer (IOHumax1) and (IOHumax2)] on yield and nutrients contents of two spinach varieties ("Balady and Virofly") were investigated. Significant effects of variety were observed on vegetative growth and nutrients contents. While Virofly had significantly higher leaf area (236.96 cm2), stem diameter (7.43 mm) and fresh weight of vegetative and radical parts (15.05 and 0.96 g, respectively), Balady had significantly higher chlorophyll and carotene contents (0.0023 and 0.0018 g/g fw, respectively). No significant impacts of variety on vitamin C, nitrite, nitrate and oxalates contents were observed. IOHumax2 treatment (4 g/l of Humax + 100 mg/l of NH4NO3 per plant fertigation-1) enhanced stem diameter and root growth and significantly improved the yield by produced plants with higher stem length, leaf number and surface area. This treatment improved the quality of plant by increasing vitamin C content and reducing nitrite and oxalates contents. No significant effects of different fertilizers were observed on NO3- content. A fairly balanced yield/NO3- and oxalates content can be achieved with combined inorganic and organic fertilizer (IOHumax1) and (IOHumax2). PMID- 28878508 TI - Assessment of sucrose transporters, metabolites and sucrose phosphate synthase in different sugarcane tissues. AB - The expression of sucrose-phosphate synthase II (SPSII) and sucrose transporters ShSUT1A and ShSUT4 were determined by RT-PCR and qRT-PCR in the sink and source leaves and in rind and pith of mature internodes of four high-yielding Hawaiian sugarcane cultivars. Expression of SPSII, ShSUT1A, and ShSUT4 was lower in pith than in rind, except in one cultivar, but else quite similar in the cultivars. The strong expression of transporter ShSUT4 in the rind of the internodes may hint to a special role of ShSUT4 in the rind. ShSUT4-expression in the sink and source leaves was similar in all four cultivars, whereas large differences were found for the expression of ShSUT1A and SPSII between the source and sink leaves and between the cultivars. The levels of sucrose precursors were doubled in source leaves compared to sink leaves, whereas they were higher in immature internode compared to mature internode. The role of sucrose transporters and SPSII in leaves and internodes is discussed, but the large differences, which were observed in the transcript levels of SPSII and sucrose transporters between some cultivars, although all the cultivars were similarly high-yielding cultivars, show that SPSII and SUT transcript levels cannot be used as indicators of high-yield cultivars. PMID- 28878509 TI - An improved micropropagation system, ex vitro rooting and validation of genetic homogeneity in wild female Momordica dioica: an underutilized nutraceutical vegetable crop. AB - Momordica dioica Roxb. ex Willd., is a perennial and dioecious (2n = 28) plant of family Cucurbitaceae. Conventional methods of propagation through seeds, stem cuttings and rhizomatous/tuberous roots are inadequate for its mass cultivation as a vegetable crop. This paper reports an improved and efficient micropropagation method for wild female M. dioica using nodal explants. Shoot amplification was achieved using subculturing of in vitro raised shoots on MS medium supplemented with various concentrations of 6-benzylaminopurine (BAP) alone or in combination with indole-3-acetic acid (IAA). The maximum number of shoots (45.30 +/- 3.83) with an average length 6.52 +/- 0.89 cm were differentiated on MS medium containing 0.5 mg L-1 BAP, 0.1 mg L-1 IAA and additives (50 mg L-1 ascorbic acid, 25 mg L-1 each of adenine sulphate, citric acid and l-arginine). The cloned shoots were rooted ex vitro. Each shoot treated with 250 mg L-1 IBA for 5 min produced 12.3 +/- 1.33 with a mean length 5.4 +/- 0.73 cm. More than 85% (46 plants) of ex vitro rooted plantlets were successfully hardened in a greenhouse with normal growth characteristics. In order to evaluate the genetic stability of micropropagated plants, the two PCR-based techniques, Random Amplified Polymorphic DNA (RAPD) and Inter Simple Sequence Repeats (ISSR) were used. The amplification patterns of the micropropagated and mother plant were monomorphic thus depicting genetic stability of the micropropagation system. This protocol could be effectively employed for the mass multiplication of wild female M. dioica, a popular summer vegetable crop. PMID- 28878510 TI - Antimicrobial activity of essential oil and aqueous and ethanol extracts of Teucrium polium L. subsp. gabesianum (L.H.) from Tunisia. AB - The antimicrobial effects of essential oil, ethanol and aqueous extracts of Teucrium polium L. were investigated against 13 microorganisms. Extracts and essential oil were obtained from maceration, decoction and hydrodistillation respectively. Samples were tested for their antimicrobial activity using the disk diffusion, the agar dilution and the agar incorporation method. Essential oil was analysed using GC/MS, results showed that beta-pinene (35.97%) and alpha-pinene (13.32%) were the main components. Furthermore, essential oil exhibited the highest antimicrobial activity, it was most effective against Proteus mirabilis, Staphylococcus aureus and Citrobacter freundei where inhibition zone ranged between 15 and 25 mm, and with the microbial inhibitory concentration (MIC) values of 0.078-0.156 mg/ml. The oil and ethanol extract showed the best antifungal activity against Microsporum canis, Scopulariopsis brevicaulis, and Trichophyton rubrum with the inhibition percentage (I%) ranging from 18.94 to 100%. However, none of the samples exhibited antifungal activity against Aspergillus fumigatus. In this study, the obtained results showed significant effects of essential oils and ethanol extracts of T. polium which may used as a substitute to the synthetic drugs against certain microbial diseases. PMID- 28878511 TI - Management of the open book APC II pelvis: Survey results from pelvic and acetabular surgeons in the United Kingdom. AB - The results of this questionnaire show that the opinion of pelvic and acetabular surgeons in the UK and Republic of Ireland vary as to the best method of fixation for APC II pelvic injuries. A single anterior plate and single sacroiliac joint (SIJ) screw was the most popular fixation method, chosen by 34%. 74% favour a single, opposed to two orthogonal anterior plates. Posterior fixation supplementing anterior plating is preferred by 63% of surgeons, 58% use a single versus 42% two SIJ screws. Case by case assessment and intraoperative screening to assess stability is essential when considering whether to stabilise the SIJ. PMID- 28878512 TI - Comparison of postoperative complications after total hip arthroplasty among patients receiving aspirin, enoxaparin, warfarin, and factor Xa inhibitors. AB - Optimal prophylaxis for prevention of venous thromboembolism (VTE) after total joint arthroplasty (TJA) remains debated. The purpose of this study was to compare postoperative complications in patients receiving different VTE chemoprophylactic regimens. Using a nationwide healthcare database, 72,670 THA patients without a history of VTE were identified. Study cohorts received VTE prophylaxis within 30 days postoperatively. Odds ratios and 95% confidence intervals were used to assess 30-day and 90-day postoperative complications (hematoma, hemorrhage, transfusion, pulmonary embolism (PE), VTE, prosthetic joint infection (PJI), and incision/drainage (I&D)). Of the 72,670 THA patients, 25,966 received single medication VTE prophylaxis; 551 (2.12%) aspirin, 6791 (26.15%) enoxaparin, 12,008 (46.25%) warfarin, 5403 (20.81%) rivaroxaban, 876 (3.37%) fondaparinux and 337 (1.30%) apixaban. 30-day complications included; aspirin: I&D; warfarin: I&D, hematoma, hemorrhage, transfusion, PJI, PE and DVT; apixaban: hematoma and hemorrhage. 90-day complications included; aspirin: I&D; warfarin: I&D, hematoma, hemorrhage, transfusion, PJI, PE and DVT. Warfarin was the only anticoagulant associated with a higher risk for DVT, and the highest risk for 30-day and 90-day complications. Aspirin had the highest risk for I&D. Despite three times increased 30-day risk for bleeding, apixaban was effective in preventing VTE during the high-risk 3-month-period. Enoxaparin had the lowest risk for PE and DVT while rivaroxaban had the lowest risk for PJI, hematoma, I&D, hemorrhage and transfusion. PMID- 28878513 TI - Fibromas arising from the posterior cruciate ligament tendon sheath in the bilateral knee joints: Case report. AB - Fibroma of tendon sheath in the intra-knee joint is a very rare and benign soft tissue tumour which has been reported unilaterally in the various aged people. To help distinguish it from other similar kinds of lesions and symptoms including osteoarthritis, we report the oldest case of fibromas arising from the posterior cruciate ligament tendon sheath in the bilateral knee joints within one year of each other confirmed with magnetic resonance imaging (MRI) features, operative findings and histological examination. PMID- 28878514 TI - Traumatic cervical epidural hematoma due to fusion mass fracture following elective rod removal. AB - Many studies have examined complications associated with spinal instrumentation, however, few have analyzed complications associated with removal. In this case report, we outline the course of a patient who presented with cervical epidural hematoma secondary to fusion mass fracture five years after removal of spinal hardware. PMID- 28878515 TI - Review: Medial collateral ligament injuries. AB - The medial collateral ligament (MCL) is a major stabilizer of the knee joint. It is the most common ligament injured in the knee, particularly in athletes, and has been reported to be torn in 7.9% of all knee injuries.2 The MCL has a complex, layered anatomy with multiple insertions and functions. Minor trauma can cause tearing of the superficial portion whereas higher energy mechanisms can disrupt both the deep and superficial layers. History and physical are often adequate, but the gold standard for diagnosis is MRI. Lesser injuries to the MCL can often be treated conservatively with early rehabilitation, but more significant tears often necessitate surgery. A thorough understanding of the MCL and associated injuries is essential for proper diagnosis and treatment. PMID- 28878516 TI - Enhanced recovery principles applied to revision hip and knee arthroplasty reduces length of stay and blood transfusion. AB - INTRODUCTION: This is the first study reporting the application of Enhanced Recovery Principles (ERP) to revision arthroplasty. METHOD: Retrospective series of 132 revision hip and knee replacements treated with ERP. RESULTS: Infiltration was associated with reduced LOS in knees (6 vs 8.5 days), lower PCA usage and incidence of transfusion in knees (2 vs 3 days) and hips (1 vs 6 days). Revisions for infection had a longer LOS (5.4 vs 11.5 days p = 0.001), a greater use of PCA and a higher incidence of transfusion (5 vs 0) in both knees and hips. DISCUSSION: The application of ERPs to revision arthroplasty is safe. Infiltration appears to be an important factor in improving outcome measures. PMID- 28878517 TI - Comparison of metal ion levels in patients with hip resurfacing versus total hip arthroplasty. AB - Mechanical wear at the articular surface and corrosive processes at modular junctions, such as the trunnion, are responsible for metal ions production. We retrospectively reviewed 64 patients who underwent THA with a metal on metal bearing surface and 34 patients with hip Resurfacing. Metal ion measurements, six week post-op radiographs, and functional scores were included in the analysis. Cobalt ion levels were significantly elevated in THA patients, 2.95 MUg/L as compared to resurfacing patients, (2.95 versus 1.30 MUg/L, p < 0.0005). Chromium levels were not significantly different between THA patients and resurfacing patients (1.05 versus 1.00 MUg/L, p = 0.529). PMID- 28878518 TI - On-demand antibiotic-eluting microchip for implanted spinal screws. AB - OBJECTIVE: Surgical instrumentation of the spine is susceptible to infection. Intravenous antibiotics is a current mainstay of treating infection; however penetrating the bacterial biofilm and directly targeting the source of the infection is challenging. METHODS: Using multiple reservoirs of discrete drug doses, microchips represent a new technology capable of on-demand drug release over long periods of time. RESULTS: A novel solution of integrating vancomycin eluting microchips into pedicle screws in order directly target and treat spinal infections is proposed. CONCLUSION: This drug-releasing implant has the potential to provide the particular benefit to high-infection-risk patients in order to avoid reoperation. PMID- 28878519 TI - State of Globe: Biofilm Formation in Staphylococcus aureus Isolates. PMID- 28878520 TI - Standardization and Classification of In vitro Biofilm Formation by Clinical Isolates of Staphylococcus aureus. AB - BACKGROUND: Staphylococcus aureus is Gram-positive bacterium commonly associated with nosocomial infections. The development of biofilm exhibiting drug resistance especially in foreign body associated infections has enabled the bacterium to draw considerable attention. However, till date, consensus guidelines for in vitro biofilm quantitation and categorization criterion for the bacterial isolates based on biofilm-forming capacity are lacking. Therefore, it was intended to standardize in vitro biofilm formation by clinical isolates of S. aureus and then to classify them on the basis of their biofilm-forming capacity. MATERIALS AND METHODS: A study was conducted for biofilm quantitation by tissue culture plate (TCP) assay employing 61 strains of S. aureus isolated from clinical samples during May 2015- December 2015 wherein several factors influencing the biofilm formation were optimized. Therefore, it was intended to propose a biofilm classification criteria based on the standard deviation multiples of the control differentiating them into non, low, medium, and high biofilm formers. RESULTS: Brain-heart infusion broth was found to be more effective in biofilm formation compared to trypticase soy broth. Heat fixation was more effective than chemical fixation. Although, individually, glucose, sucrose, and sodium chloride (NaCl) had no significant effect on biofilm formation, a statistically significant increase in absorbance was observed after using the supplement mix consisting of 222.2 mM glucose, 116.9 mM sucrose, and 1000 mM NaCl (P= 0.037). CONCLUSIONS: The present study puts forth a standardized in vitro TCP assay for biofilm biomass quantitation and categorization criteria for clinical isolates of S. aureus based on their biofilm-forming capacity. The proposed in vitro technique may be further evaluated for its usefulness in the management of persistent infections caused by the bacterium. PMID- 28878521 TI - Time to Positivity and Antibiotic Sensitivity of Neonatal Blood Cultures. AB - BACKGROUND: Sepsis is a commonly encountered and potentially life-threatening problem in neonatal intensive care units, blood culture of neonatal sepsis helps in either optimizing treatment or terminating antibiotics. MATERIALS AND METHODS: We determined the causative agent, time to positivity (TTP), and antibiogram of neonatal blood cultures collected in a tertiary care center, to investigate difference between early- and late-onset neonatal sepsis and to establish the time at which a blood culture could safely be considered negative, using the BacT/ALERT(r) 3D 60. A total of 826 clinically suspected neonates suffering from sepsis and admitted to a neonatal intensive care unit of a tertiary care hospital, Alexandria, Egypt were included in this study. RESULTS: Eighty-five (10.29%) showed positive results. The overall TTP median was 21.1 h. Out of the 85 positive cultures, 57 (67.06%) were Gram-positive, 15 (17.65%) were Gram negative, and 13 (15.29%) were fungi (all Candida). Coagulase-negative staphylococci were the predominant organism (41.18%). All the Gram-positive pathogenic isolates were sensitive to vancomycin and tigecycline. Among the Gram negative isolates, maximum antibiotic sensitivity was observed for levofloxacin. CONCLUSION: We conclude that more than 3 days of incubation may not be required when using the BacT/ALERT(r) 3D 60 system. PMID- 28878522 TI - Validation of Geno-Sen's Scrub Typhus Real Time Polymerase Chain Reaction Kit by its Comparison with a Serological ELISA Test. AB - BACKGROUND: In the recent past, scrub typhus (ST) has been reported from different parts of India, based on Weil-Felix/enzyme-linked immunosorbent assay (ELISA)/indirect immunofluorescence assay (IFA). Molecular tests are applied only by a few researchers. AIMS: Evaluation of a new commercial real time polymerase chain reaction (PCR) kit for molecular diagnosis of ST by comparing it with the commonly used IgM ELISA is our aim. SETTINGS AND DESIGN: ST has been reported all over India including Puducherry and surrounding Tamil Nadu and identified as endemic for ST. This study was designed to correlate antibody detection by IgM ELISA and Orientia tsutsugamushi DNA in real time PCR. MATERIALS AND METHODS: ST IgM ELISA (InBios Inc., USA) was carried out for 170 consecutive patients who presented with the symptoms of acute ST during 11 months (November, 2015- September, 2016). All 77 of these patients with IgM ELISA positivity and 49 of 93 IgM ELISA negative patients were subjected to real time PCR (Geno-Sen's ST real time PCR, Himachal Pradesh, India). STATISTICAL ANALYSIS: Statistical analysis for clinical and laboratory results was performed using IBM SPSS Statistics 17 for Windows (SPSS Inc., Chicago, USA). Chi-square test with Yates correction (Fisher's test) was employed for a small number of samples. RESULTS AND CONCLUSION: Among 77 suspected cases of acute ST with IgM ELISA positivity and 49 IgM negative patients, 42 and 7 were positive, respectively, for O. tsutsugamushi 56-kDa type-specific gene in real time PCR kit. Until ST IFA, the gold standard diagnostic test, is properly validated in India, diagnosis of acute ST will depend on both ELISA and quantitative PCR. PMID- 28878524 TI - A Microbial Old Friend with a New Face: A Rare Case of Pyrexia of Unknown Origin and Leukemoid Reaction. AB - We present a case of a young male, who presented to us with high-grade fever for more than four weeks, refractory seizures, multiple subcutaneous palpable lumps, and evidence of leukocytosis with predominant left shift on the peripheral smear. The classic "starry-sky" appearance on imaging, generalized muscular uptake on positron emission tomography-computerized tomography scan, and positive serology led to a diagnosis of disseminated cysticercosis. He responded to oral steroids. To the best of our knowledge, disseminated cysticercosis presenting as pyrexia of unknown origin and with a leukemoid reaction has never been reported in literature. PMID- 28878523 TI - Transcultural Adaptation and Validation of the Korean Version of the Brief Illness Perception Questionnaire for Patients with Pulmonary Tuberculosis. AB - BACKGROUND AND AIM: The brief illness perception questionnaire (BIPQ) has been used in many populations for both adults and children, and it provides a rapid assessment of illness perception. This study was performed to create a translated version of the BIPQ to fit the Korean society and to test its validity through pulmonary tuberculosis (TB) patients. METHODS: Translation and transcultural adaptation of BIPQ, applicable to the Korean society, was performed in accordance with the international guidelines. Internal consistency, test-retest reliability, concurrent validity, and discrimination validity were evaluated. To assess the discrimination validity, the BIPQ scores were compared between pulmonary TB and chronic obstructive pulmonary disease (COPD). RESULTS: Sixty-eight patients with pulmonary TB participated in this study. Cronbach's alpha coefficient was 0.753, which indicated satisfactory internal consistency. The concurrent validity showed significant correlations (Pearson's correlation of 0.753). The test-retest reliability was confirmed with an intraclass correlation coefficient of 0.892. The total score of BIPQ in patients with COPD was significantly higher than that in those with pulmonary TB (37.67 vs. 30.85; P = 0.005), which supported the discrimination validity. CONCLUSIONS: The Korean version of BIPQ was found to be a reliable and valid questionnaire for patients with pulmonary TB. PMID- 28878526 TI - Splenic and Kidney Infarct: Sequelae of Subacute Streptococcus mitis Bacterial Endocarditis. AB - Infective endocarditis (IE) is caused due to the vegetation on the heart valves, myocardium wall, or the pacemaker leads. Vegetation is a lesion that appears as a consequence of successive deposition of platelets and fibrin on the endothelial surface of the heart. Colonies of microbes can be usually found under the vegetation. Heart valves are involved more frequently as compared to other places. Streptococcus mitis, formerly known as S. mitior, is a commensal of the oral flora, however, if there of loss of integrity of the mucous membrane, the infection may disseminate to the blood flow. We describe here a rare presentation of S. mitis, causing IE and its complications in an immunocompetent patient. PMID- 28878525 TI - Association of Three H - Hookworm, Hemosuccus Pancreaticus, and Hypertension (Portal) in a Patient with Melena. AB - Hookworm infestations, endemic in India, are a common cause of iron deficiency anemia. Hemosuccus pancreaticus, a rare clinical condition, is due to passage of blood into the pancreatic duct possibly through a route between an aneurysm of an artery close to the pancreas and/or pancreatic duct, leading to gastrointestinal (GI) bleeding. Portal hypertensive upper GI bleed is also known since long. We report a case of a 38-year-old male with a history of alcoholism who was being investigated for GI bleeding who had concomitant hookworm infestation, hemosuccus pancreaticus as well as portal hypertension. To the best of our knowledge, this is the first report of common occurrence of hemosuccus pancreaticus and portal hypertension with hookworm infection. This case signifies the importance of infectious causes of GI bleeding to be considered even in cases where anatomic malformations or pathophysiological alterations are predominant. PMID- 28878527 TI - Cutaneous Larva Migrans. PMID- 28878528 TI - Acute Osteomyelitis: It is Still Here. PMID- 28878529 TI - Geotrichum candidum in Infective Endocarditis. PMID- 28878530 TI - Oldest epiphyseal osteochondroma in a subadult from Ancient Egypt. AB - Benign bone tumours are pathologies frequently encountered in archaeological human remains, with the most common being osteoma and osteochondroma. We present the case of a juvenile individual recovered from the Necropolis of Sharuna, Middle Egypt and dated to the end of Old Kingdom and First Intermediate Period of Ancient Egypt (circa 2150 BC), showing an osteochondroma arising from the proximal epiphysis of the right tibia which, in all likelihood, affected the patellar tendon in life. Osteochondromas are usually discovered during childhood and adolescence. These lesions are commonly located at the metaphysis and diaphysis of long bones and directed away from the joint, with the epiphysis being a rare location. To our knowledge, there have been no similar cases published to date from ancient times and we conclude that this is the oldest case of epiphyseal osteochondroma reported. PMID- 28878531 TI - Neglected acetabular fracture: Fix or replace? AB - INTRODUCTION: Operative treatment of acute acetabular fractures has shown better results than the non-operative approach. There is, however, limited data regarding the operative treatment of neglected acetabular fracture. METHODS: We present six subjects with neglected fracture of the acetabulum in Cipto Mangunkusumo National Hospital, Jakarta, Indonesia. One had only open reduction and internal fixation, three had open reduction and internal fixation first before we performed arthroplasty later, one had both open reduction and internal fixation with arthroplasty, and another had immediate arthroplasty. RESULTS: Our subjects were 4 males and 2 females with the average age of 41.1 years and the average neglect period was 18 months. In four of our subjects, the fractures had posterior wall involvement, one had an anterior column-posterior hemitransverse fracture, and the last one had transverse fracture. All fractures were classified to either Elementary or Associated type according to the Letournel classification. We observed all subjects up to eighteen months post-operatively. One subject had poor outcome, four subjects had fair outcome, and one subject had excellent outcome according to the Harris Hip Score. CONCLUSION: Even in neglected acetabular fracture, open reduction and internal fixation where possible should be attempted to restore the anatomical relationship to facilitate immediate or late total hip arthroplasty. Surgical treatment of such fractures should be based on individual case characteristics, which includes age, associated comorbidity, neglect period, as well as the type and union state of the fracture for a better outcome. Neglected Associated acetabular fracture types are more difficult to reduce and have poorer outcome compared to Elementary types. Likewise, malunited acetabular fractures are more difficult to operate on than non-united neglected acetabular fractures, where reduction is relatively easier. PMID- 28878532 TI - Bladder incarceration following anterior pelvic infix of a traumatic pubic symphysis diastasis treated with immediate open reduction and internal fixation. AB - Stabilization after a pelvic fracture can be accomplished using multiple techniques. The anterior external fixator has been traditionally used in variety of unstable pelvis either singly or in combination of posterior screws. These devices are cumbersome and restrict side turning and sitting particularly in obese patients. An alternative, anterior subcutaneous pelvic internal fixation technique (ASPIF) was developed which is well tolerated by patients for mobility and comfort and biomechanically more stable construct Complications of this construct included irritation of the lateral femoral cutaneous nerve, femoral nerve palsy &heterotypic ossification with reduced rates of infections and aseptic loosening as compared to external fixator. Bladder incarceration following treatment has never been reported and we encountered such a problem during management which we want to highlight. PMID- 28878533 TI - The importance of pelvic ring stabilization as a life-saving measure in pre hospital - A case report commented by autopsy. AB - Hip fractures with unstable pelvic ring have great morbidity and mortality rates. These fractures result from high energy trauma such as falls from heights, road accidents and collapsing structures or other similar mechanisms of action. We report the case of a 63 years old man, construction worker, who stood inside a ditch during a wall construction when he was surprised by this collapse, which resulted in direct trauma to the right thigh and pelvis. The autopsy revealed diaphysis fracture of the right femur with an open book pelvic fracture with severe hemorrhagic infiltration and hematoma of the pelvic muscles without arterial injury. Bone bleeding and the vascular damage associated with disruption of the sacroiliac ligaments promote a very significant bleeding. Simple maneuvers such as sheet circumferential compression to promote pelvic ring closure are effective on stabilizing and closure of the sacroiliac joint. Hip manipulation of the fracture was performed during the necropsy to demonstrate and prove how a simple sheet contention can promote stabilization of the pelvic ring by closing the sacroiliac joints in open book fractures. PMID- 28878534 TI - Endoscopic management of posterior ankle impingement syndrome-A case report. AB - Posterior ankle impingement syndrome (PAIS) is a clinical condition characterized by pain in the posterior aspect of ankle on performing activities requiring extreme plantar flexion. The impinging lesion could be bony and/or soft tissue. The operative treatment aims at removing the impinging lesion either by open or endoscopic surgery. The later has been shown to have benefits of early return to sports, better cosmesis, less wound complications. We report a case of a 19 year old footballer with PAIS secondary to Os Trigonum. The patient complained of pain on performing running and on kicking football. Conservative treatment in form of NSAIDS, rest, physiotherapy modality use could not ensure pain free return to sports.The patient was managed using endoscopic excision of the Os Trigonum followed by aggressive rehabilitation. The patient returned to competitive football at the end of 14 weeks after surgery. There were no wound complications. AAFOS score had changed from 73 to 100 and NPS scale showed pain score reduce from 7/10 to 1/10. We concluded that endoscopic management of PAIS to remove the impinging lesion is a minimally invasive technique that ensures early return to sports, good cosmesis, less risk of wound complications and good patient satisfaction. PMID- 28878535 TI - Atraumatic sequential bilateral locking of the knee joints secondary to dislocation of non-discoid lateral menisci without radiological abnormality. AB - Lateral meniscus dislocation, as a cause of atraumatic knee locking, is often attributed to a discoid meniscus which can be readily diagnosed on MRI. In the absence of radiological abnormality, a dislocated lateral meniscus is a rare occurrence. We present a case of a 14 year old male who presented with atraumatic sequential locking of bilateral knees 6 months apart. Although on both occasions, MRI was normal, arthroscopy demonstrated dislocating lateral menisci that were subsequently surgically stabilised. To date, there have been no reports describing this phenomenon bilaterally in the same patient. A high index of suspicion is needed to evaluate a locked knee in an adolescent in the absence of trauma or a radiological abnormality. Furthermore there is a probability of a similar occurrence in the opposite knee. PMID- 28878536 TI - Osteochondral autograft transplants for femoral head impaction fracture: A case report with arthroscopic findings. PMID- 28878537 TI - Arthroscopically assisted surgical fixation of a juvenile Tillaux fracture and implant removal: A case report. AB - Juvenile Tillaux fractures are Salter-Hallis III fractures of the distal tibial epiphysis that occur only when the tibial epiphyses are closing. Theoretically, arthroscopically assisted reduction and fixation of a juvenile Tillaux fracture can facilitate the accurate reconstruction of the articular surface, using arthroscopic visualization. We treated a girl aged 14 years who had a juvenile Tillaux fracture by using arthroscopically assisted reduction and fixation. In order to obtain articular congruency, the screw was inserted under arthroscopic visualization. Although the screw was placed through the epiphysis, the patient had no symptoms of discomfort and the functional results were excellent. We performed a second operation to remove the implant 9 months later. During this procedure, arthroscopy indicated the healing of the fracture site and an intact articular surface. At the 1.5 year follow-up, the radiograph indicated that the epiphysis was closed normally and that the patient had no symptoms. The American Orthopaedic Foot and Ankle Society (AOFAS) score was 100, or excellent. Although screw insertion into the epiphysis should be avoided, reconstructing the congruency of the joint surface is of higher priority in repairing the epiphysis. PMID- 28878538 TI - Triceps tendon reconstruction using autologous semitendinosis graft in professional kabaddi player-A rare case report. AB - Triceps tendon rupture is a rare injury occurs due to sudden forceful contraction of triceps against flexed elbow. Though there are case reports describing various treatment options for this injury, including primary repair as well as reconstruction using different technique, no standardised technique has been defined. We present, for the first time, a case of five month old neglected triceps tendon rupture in a professional kabaddi player. Ruptured tendon was reconstructed using free autologous semitendinous graft with good functional outcome. PMID- 28878539 TI - Unusual association of elbow dislocation with humeral biepicondylar fracture in a child: A case report and review of literature. AB - Humeral biepicondylar fracture with elbow dislocation is an unusual pattern of injury encountered in paediatric population. We reported a case of humeral biepicondylar fracture-dislocation of elbow in a 11-year-old boy, who presented with tender, swollen, and deformed left elbow following fall on his outstretched hand. Roentgenographic and CT evaluation confirmed the diagnosis, and also showed incarcerated medial epicondylar fragment. Closed reduction was unsuccessful; open reduction and internal fixation was performed with headless screws. Avulsed medial collateral ligament was repaired with suture anchor. Following 4 weeks of immobilization, physiotherapy was started. The child regained satisfactory range of-motion of the elbow with complete bony union within 3 months. Two years following operation, the child is asymptomatic, with pain free stable elbow. High index of suspicion and astute clinical and radiological assessment is utilitarian for timely diagnosis and appropriate management. Open reduction and internal fixation is believed to be pivotal to restore elbow stability and functionality. PMID- 28878540 TI - Bare medial epicondyle physeal fracture of the humerus: A case report. AB - We identified an unusual case of the medial epiondyle physeal fracture, which has been caused by a direct blow, accompanied with complete stripping of soft tissue. Surgery was performed for open reduction and internal fixation of the medial epicondyle and reattachment of the anterior oblique bundle of medial collateral ligament and flexor muscle origin. Six months after the surgery, strength of wrist flexion and forearm pronation, range of motion and valgus stability of the left elbow had recovered. One year after the injury, radiographs showed atrophy and sclerosis of the medial epicondylar apophysis. In this type of injury, revascularization of medial epicondyle fracture is not essential for recovery of elbow function when reattachment of the medial collateral ligament and flexor pronator muscle origin to the distal medial humerus successfully restores stability of the elbow joint. PMID- 28878541 TI - An unusual localization of chondroblastoma: The triradiate cartilage; from a case report a reconstructive technique proposal with imaging evolution. AB - INTRODUCTION: Chondroblastoma (also known as Codman tumor) is a rare intermediate grade cartilaginous neoplasm, representing less than 1% of all primary bone tumors; it characteristically arises in the epiphysis or apophysis of a long bone in young patients, predominantly males. The most frequent location of chondroblastoma is the humerus (70% incidence rate) and more rarely it is located in the pelvis. When it affects the hip, the triradiate cartilage is the most common site. MATERIALS AND METHODS: An unusual case of Chondroblastoma located in the triradiate cartilage is reported. The surgical technique and the imaging are emphasized: a homoplastic fascia latae was used to reconstruct the cartilage layer then a layer of engineered homoplastic bone was superiorly positioned to reconstruct the subchondral bone; the residual cavity was filled with a homoplastic hemi-femoral head concavity molded to best correspond to the acetabular roof and morcelized bone. RESULTS: At four years of follow-up the patient is pain free and able to walk without crutches; the imaging showed a rearrangement of the trabecula distribution following the lines of force. CONCLUSIONS: The suggested technique could be a valid option in reconstructing acetabular roof in benign lesions. A correct radiological assessment could be helpful for diagnosis and an early detection of local recurrence. PMID- 28878542 TI - Ewings sarcoma of ilium: Resection and reconstruction with femoral head allograft. AB - Ewing's sarcoma is a common malignant bone tumor seen in 5-15 years age group. It often arises from diaphysis of long bones. Ewing's sarcoma arising from the ilium is very rare, and it has an unfavourable prognosis. We present a rare case report of Ewings sarcoma of ilium with no metastasis in a two and a half year old boy, who was treated with neoadjuvant chemotherapy followed by surgical excision of the tumor and reconstruction using allograft from the femoral head fixed with multiple k-wires and screw. The patient is disease free at one year follow up and the allograft has taken the shape of growing ilium and excellent functionality and gait with minimal limp. Through this report, we emphasize on the occurrence of Ewings sarcoma in unusual site and resection and reconstruction of the tumor utilizing the allograft. PMID- 28878543 TI - Reproducible transient asystolic arrest during intramedullary reaming of the femoral canal: A case report. AB - The utilization of intramedullary devices in the surgical fixation of hip fractures is increasing. Although intramedullary devices offer many advantages in the treatment of these injuries, they are also associated with a unique set of potential complications, particularly during preparation of the femoral canal. Cardiac dysrhythmia resulting from reaming the femoral canal is rare and has not been previously described in detail in the literature. We present the case of a 69-year-old male with an infected right cephalomedullary femoral nail who underwent removal of hardware and experienced reproducible, transient asystolic cardiac arrest during reaming of the femoral canal and offer potential explanations for this event. PMID- 28878544 TI - Proximal humerus fracture dislocation leading to axillary artery injury in an young adult: Case report of an unusual presentation. AB - Proximal humerus fractures constitute five percent of all fracture cases. Though rare, severely comminuted proximal humerus fractures can cause injury to neurovascular structure. Majority of these injuries reported in literature were in elderly age group from low velocity injury owing to loss of elasticity of vessel wall. We report a case of proximal humerus fracture dislocation associated with axillary artery injury in a young male due to fall of heavy iron object. Timely exploration and removal of impinging bone fragment restored the blood supply. The purpose of this report is to heighten the clinical suspicion of the vascular injury in patients with proximal humerus fracture dislocations in all age groups. PMID- 28878545 TI - Atraumatic segmental atypical femur fracture secondary to bisphosphonate use: A case report. AB - Atypical femur fractures as a result of long term bisphosphonate use are characterized by several unique radiographic features. We describe an atypical femur fracture treated by cephalomedullary nail with a previously undescribed segmental fracture pattern. Other than 1.5 years of bisphosphonate use the patient did not have any other risk factors known to cause atypical femur fractures. Judicious bisphosphonate use as well as increased awareness of the associated complications may help reduce the rate of bisphosphonate associated atypical femur fractures. PMID- 28878546 TI - A case of rapidly destructive osteoarthritis of the hip with onset of less than six weeks. AB - INTRODUCTION: Rapidly destructive osteoarthritis is characterized by a severe destruction of the hip joint developing over short periods of time. However, to date, there is no agreement on the biological process that triggers this condition. The aim of this report is to present a case of rapidly destructive osteoarthritis. CASE REPORT: We report a case of a 76 year-old female who presented with hip pain of sudden onset and normal X-rays. Six weeks later she presented with increased pain intensity, functional limitation and evidence of a collapse of the femoral head in the X-rays. DISCUSSION: Rapidly destructive osteoarthritis of the hip is a complex entity that might be more frequent than previously described and which clinical course could vary between few weeks and several months. In order to make an accurate diagnosis, other causes of massive destruction of the joint should be excluded. PMID- 28878547 TI - Bilateral simultaneous total hip replacement in Achondroplasia. AB - We present a case of bilateral simultaneous total hip replacement in a very short statured (height 112 cm) 45 years old male patient with Achondroplasia and disabling osteoarthritis of both the hips. We describe the difficulties encountered and provide a methodical approach for such cases. PMID- 28878548 TI - Arthroscopic diagnosis and treatment of shoulder ochronotic arthropathy - A case report. AB - Alkaptonuria is a rare inherited metabolic disorder, caused by the deficiency of homogentisate 1,2 dioxygenase enzyme. The three major features of alkaptonuria are the presence of homogentisic acid in urine, ochronosis (bluish-black pigmentation in connective tissue) and arthritis of the spine and large joints. We present a 48 years old female presented with pain, restriction of movements of right shoulder. Arthroscopy was suggestive of ochronotic arthropathy. The definitive diagnosis of ochronosis was subsequently confirmed by laboratory and pathologic evaluation. PMID- 28878550 TI - Whitham modulation theory for the Kadomtsev- Petviashvili equation. AB - The genus-1 Kadomtsev-Petviashvili (KP)-Whitham system is derived for both variants of the KP equation; namely the KPI and KPII equations. The basic properties of the KP-Whitham system, including symmetries, exact reductions and its possible complete integrability, together with the appropriate generalization of the one-dimensional Riemann problem for the Korteweg-de Vries equation are discussed. Finally, the KP-Whitham system is used to study the linear stability properties of the genus-1 solutions of the KPI and KPII equations; it is shown that all genus-1 solutions of KPI are linearly unstable, while all genus-1 solutions of KPII are linearly stable within the context of Whitham theory. PMID- 28878549 TI - Risk perceptions, attitudes, and knowledge of chikungunya among the public and health professionals: a systematic review. AB - BACKGROUND: Recently, attention to chikungunya has increased due to its spread into previously non-endemic areas. Since there is no available treatment or vaccine, most intervention strategies focus on mosquito bite prevention and mosquito control, which require community involvement to be successful. Thus, our objective was to systematically review the global primary literature on the risk perceptions, attitudes, and knowledge of chikungunya among the public and health professionals to inform future research and improve our understanding on which intervention strategies are likely to be successful. METHODS: Potentially relevant articles were identified through a standardized systematic review (SR) process consisting of the following steps: comprehensive search strategy in seven databases (Scopus, PubMed, CINAHL, CAB, LILACS, Agricola, and Cochrane) and a grey literature search of public health organizations, relevance screening, risk of bias assessment, and data extraction. Two independent reviewers performed each step. Reporting of this SR follows PRISMA reporting guidelines. RESULTS: Thirty seven relevant articles were identified. The majority of the articles were published since 2011 (83.8%) and reported on studies conducted in Asia (48.7%) and the Indian Ocean Islands (24.3%). The results were separated into four categories: general knowledge and perceptions on chikungunya; perceptions on the risk and severity of chikungunya; knowledge of chikungunya-harboring vectors and transmission; and knowledge, perceptions, and attitudes on mitigation practices. Overall, the systematic review found that risk perceptions, attitudes, and knowledge of chikungunya among the public and health professionals vary across populations and countries and knowledge is higher in areas that have experienced an outbreak. CONCLUSION: The results suggest that most of the affected populations in this study do not understand mosquito borne diseases or chikungunya and are therefore less likely to protect themselves from mosquito bites. While more research is required to improve the generalizability of this dataset, it appears that a lack of knowledge is an important barrier for motivating community level interventions and personal protection against mosquitoes. PMID- 28878551 TI - A variation on the Donsker-Varadhan inequality for the principal eigenvalue. AB - The purpose of this short paper is to give a variation on the classical Donsker Varadhan inequality, which bounds the first eigenvalue of a second-order elliptic operator on a bounded domain Omega by the largest mean first exit time of the associated drift-diffusion process via [Formula: see text]Instead of looking at the mean of the first exit time, we study quantiles: let [Formula: see text] be the smallest time t such that the likelihood of exiting within that time is p, then [Formula: see text]Moreover, as [Formula: see text], this lower bound converges to lambda1. PMID- 28878552 TI - Recursive modular modelling methodology for lumped-parameter dynamic systems. AB - This paper proposes a novel approach to the modelling of lumped-parameter dynamic systems, based on representing them by hierarchies of mathematical models of increasing complexity instead of a single (complex) model. Exploring the multilevel modularity that these systems typically exhibit, a general recursive modelling methodology is proposed, in order to conciliate the use of the already existing modelling techniques. The general algorithm is based on a fundamental theorem that states the conditions for computing projection operators recursively. Three procedures for these computations are discussed: orthonormalization, use of orthogonal complements and use of generalized inverses. The novel methodology is also applied for the development of a recursive algorithm based on the Udwadia-Kalaba equation, which proves to be identical to the one of a Kalman filter for estimating the state of a static process, given a sequence of noiseless measurements representing the constraints that must be satisfied by the system. PMID- 28878553 TI - Rebound mechanics of micrometre-scale, spherical particles in high-velocity impacts. AB - The impact mechanics of micrometre-scale metal particles with flat metal surfaces is investigated for high-velocity impacts ranging from 50 m s-1 to more than 1 km s-1, where impact causes predominantly plastic deformation. A material model that includes high strain rate and temperature effects on the yield stress, heat generation due to plasticity, material damage due to excessive plastic strain and heat transfer is used in the numerical analysis. The coefficient of restitution e is predicted by the classical work using elastic-plastic deformation analysis with quasi-static impact mechanics to be proportional to [Formula: see text] and [Formula: see text] for the low and moderate impact velocities that span the ranges of 0-10 and 10-100 m s-1, respectively. In the elastic-plastic and fully plastic deformation regimes the particle rebound is attributed to the elastic spring-back that initiates at the particle-substrate interface. At higher impact velocities (0.1-1 km s-1) e is shown to be proportional to approximately [Formula: see text]. In this deeply plastic deformation regime various deformation modes that depend on plastic flow of the material including the time lag between the rebound instances of the top and bottom points of particle and the lateral spreading of the particle are identified. In this deformation regime, the elastic spring-back initiates subsurface, in the substrate. PMID- 28878554 TI - Model selection for dynamical systems via sparse regression and information criteria. AB - We develop an algorithm for model selection which allows for the consideration of a combinatorially large number of candidate models governing a dynamical system. The innovation circumvents a disadvantage of standard model selection which typically limits the number of candidate models considered due to the intractability of computing information criteria. Using a recently developed sparse identification of nonlinear dynamics algorithm, the sub-selection of candidate models near the Pareto frontier allows feasible computation of Akaike information criteria (AIC) or Bayes information criteria scores for the remaining candidate models. The information criteria hierarchically ranks the most informative models, enabling the automatic and principled selection of the model with the strongest support in relation to the time-series data. Specifically, we show that AIC scores place each candidate model in the strong support, weak support or no support category. The method correctly recovers several canonical dynamical systems, including a susceptible-exposed-infectious-recovered disease model, Burgers' equation and the Lorenz equations, identifying the correct dynamical system as the only candidate model with strong support. PMID- 28878555 TI - Organic molecule fluorescence as an experimental test-bed for quantum jumps in thermodynamics. AB - We demonstrate with an experiment how molecules are a natural test bed for probing fundamental quantum thermodynamics. Single-molecule spectroscopy has undergone transformative change in the past decade with the advent of techniques permitting individual molecules to be distinguished and probed. We demonstrate that the quantum Jarzynski equality for heat is satisfied in this set-up by considering the time-resolved emission spectrum of organic molecules as arising from quantum jumps between states. This relates the heat dissipated into the environment to the free energy difference between the initial and final state. We demonstrate also how utilizing the quantum Jarzynski equality allows for the detection of energy shifts within a molecule, beyond the relative shift. PMID- 28878556 TI - Initial boundary-value problem for the spherically symmetric Einstein equations with fluids with tangential pressure. AB - We prove that, for a given spherically symmetric fluid distribution with tangential pressure on an initial space-like hypersurface with a time-like boundary, there exists a unique, local in time solution to the Einstein equations in a neighbourhood of the boundary. As an application, we consider a particular elastic fluid interior matched to a vacuum exterior. PMID- 28878557 TI - Designing the optimal bit: balancing energetic cost, speed and reliability. AB - We consider the challenge of operating a reliable bit that can be rapidly erased. We find that both erasing and reliability times are non-monotonic in the underlying friction, leading to a trade-off between erasing speed and bit reliability. Fast erasure is possible at the expense of low reliability at moderate friction, and high reliability comes at the expense of slow erasure in the underdamped and overdamped limits. Within a given class of bit parameters and control strategies, we define 'optimal' designs of bits that meet the desired reliability and erasing time requirements with the lowest operational work cost. We find that optimal designs always saturate the bound on the erasing time requirement, but can exceed the required reliability time if critically damped. The non-trivial geometry of the reliability and erasing time scales allows us to exclude large regions of parameter space as suboptimal. We find that optimal designs are either critically damped or close to critical damping under the erasing procedure. PMID- 28878559 TI - Effective potentials in nonlinear polycrystals and quadrature formulae. AB - This study presents a family of estimates for effective potentials in nonlinear polycrystals. Noting that these potentials are given as averages, several quadrature formulae are investigated to express these integrals of nonlinear functions of local fields in terms of the moments of these fields. Two of these quadrature formulae reduce to known schemes, including a recent proposition (Ponte Castaneda 2015 Proc. R. Soc. A471, 20150665 (doi:10.1098/rspa.2015.0665)) obtained by completely different means. Other formulae are also reviewed that make use of statistical information on the fields beyond their first and second moments. These quadrature formulae are applied to the estimation of effective potentials in polycrystals governed by two potentials, by means of a reduced order model proposed by the authors (non-uniform transformation field analysis). It is shown how the quadrature formulae improve on the tangent second-order approximation in porous crystals at high stress triaxiality. It is found that, in order to retrieve a satisfactory accuracy for highly nonlinear porous crystals under high stress triaxiality, a quadrature formula of higher order is required. PMID- 28878558 TI - Characterization of columnar inertial modes in rapidly rotating spheres and spheroids. AB - We consider fluid-filled spheres and spheroidal containers of eccentricity epsilon in rapid rotation, as a proxy for the interior dynamics of stars and planets. The fluid motion is assumed to be quasi-geostrophic (QG): horizontal motions are invariant parallel to the rotation axis z, a characteristic which is handled by use of a stream function formulation which additionally enforces mass conservation and non-penetration at the boundary. By linearizing about a quiescent background state, we investigate a variety of methods to study the QG inviscid inertial wave modes which are compared with fully three-dimensional (3D) calculations. We consider the recently proposed weak formulation of the inviscid system valid in spheroids of arbitrary eccentricity, to which we present novel closed-form polynomial solutions. Our modal solutions accurately represent, in both spatial structure and frequency, the most z-invariant of the inertial wave modes in a spheroid, and constitute a simple basis set for the analysis of rotationally dominated fluids. We further show that these new solutions are more accurate than those of the classical axial-vorticity equation, which is independent of epsilon and thus fails to properly encode the container geometry. We also consider the effects of viscosity for the cases of both no-slip and stress-free boundary conditions for a spherical container. Calculations performed under the columnar approximation are compared with 3D solutions and excellent agreement has been found despite fundamental differences in the two formulations. PMID- 28878560 TI - Numerical simulations of drumlin formation. AB - We summarize the present form of the instability theory for drumlin formation, which describes the coupled subglacial flow of ice, water and sediment. This model has evolved over the last 20 years, and is now at the point where it can predict instabilities corresponding to ribbed moraine, drumlins and mega-scale glacial lineations, but efforts to provide numerical solutions of the model have been limited. The present summary adds some slight nuances to previously published versions of the theory, notably concerning the constitutive description of the subglacial water film and its flow. A new numerical method is devised to solve the model, and we show that it can be solved for realistic values of most of the parameters, with the exception of that corresponding to the water film thickness. We show that evolved bedforms can be three-dimensional and of the correct sizes, and we explore to some extent the variation of the solutions with the model's parameters. PMID- 28878561 TI - Temperature profile in a liquid-vapour interface near the critical point. AB - Thanks to an expansion with respect to densities of energy, mass and entropy, we discuss the concept of thermocapillary fluid for inhomogeneous fluids. The non convex state law valid for homogeneous fluids is modified by adding terms taking account of the gradients of these densities. This seems more realistic than Cahn and Hilliard's model which uses a density expansion in mass-density gradient only. Indeed, through liquid-vapour interfaces, realistic potentials in molecular theories show that entropy density and temperature do not vary with the mass density as it would do in bulk phases. In this paper, we prove using a rescaling process near the critical point, that liquid-vapour interfaces behave essentially in the same way as in Cahn and Hilliard's model. PMID- 28878563 TI - The structure of turbulence in a rapid tidal flow. AB - The structure of turbulence in a rapid tidal flow is characterized through new observations of fundamental statistical properties at a site in the UK which has a simple geometry and sedate surface wave action. The mean flow at the Sound of Islay exceeded 2.5 m s-1 and the turbulent boundary layer occupied the majority of the water column, with an approximately logarithmic mean velocity profile identifiable close to the seabed. The anisotropic ratios, spectral scales and higher-order statistics of the turbulence generally agree well with values reported for two-dimensional open channels in the laboratory and other tidal channels, therefore providing further support for the application of universal models. The results of the study can assist in developing numerical models of turbulence in rapid tidal flows such as those proposed for tidal energy generation. PMID- 28878562 TI - Flexural edge waves generated by steady-state propagation of a loaded rectilinear crack in an elastically supported thin plate. AB - The problem of a rectilinear crack propagating at constant speed in an elastically supported thin plate and acted upon by an equally moving load is considered. The full-field solution is obtained and the spotlight is set on flexural edge wave generation. Below the critical speed for the appearance of travelling waves, a threshold speed is met which marks the transformation of decaying edge waves into edge waves propagating along the crack and dying away from it. Yet, besides these, and for any propagation speed, a pair of localized edge waves, which rapidly decay behind the crack tip, is also shown to exist. These waves are characterized by a novel dispersion relation and fade off from the crack line in an oscillatory manner, whence they play an important role in the far field behaviour. Dynamic stress intensity factors are obtained and, for speed close to the critical speed, they show a resonant behaviour which expresses the most efficient way to channel external work into the crack. Indeed, this behaviour is justified through energy considerations regarding the work of the applied load and the energy release rate. Results might be useful in a wide array of applications, ranging from fracturing and machining to acoustic emission and defect detection. PMID- 28878564 TI - Nonlinear electroelasticity: material properties, continuum theory and applications. AB - In the last few years, it has been recognized that the large deformation capacity of elastomeric materials that are sensitive to electric fields can be harnessed for use in transducer devices such as actuators and sensors. This has led to the reassessment of the mathematical theory that is needed for the description of the electromechanical (in particular, electroelastic) interactions for purposes of material characterization and prediction. After a review of the key experiments concerned with determining the nature of the electromechanical interactions and a discussion of the range of applications to devices, we provide a short account of the history of developments in the nonlinear theory. This is followed by a succinct modern treatment of electroelastic theory, including the governing equations and constitutive laws needed for both material characterization and the analysis of general electroelastic coupling problems. For illustration, the theory is then applied to two simple representative boundary-value problems that are relevant to the geometries of activation devices; in particular, (a) a rectangular plate and (b) a circular cylindrical tube, in each case with compliant electrodes on the major surfaces and a potential difference between them. In (a), an electric field is generated normal to the major surfaces and in (b), a radial electric field is present. This is followed by a short section in which other problems addressed on the basis of the general theory are described briefly. PMID- 28878565 TI - Mittag-Leffler synchronization of delayed fractional-order bidirectional associative memory neural networks with discontinuous activations: state feedback control and impulsive control schemes. AB - This paper is concerned with the drive-response synchronization for a class of fractional-order bidirectional associative memory neural networks with time delays, as well as in the presence of discontinuous activation functions. The global existence of solution under the framework of Filippov for such networks is firstly obtained based on the fixed-point theorem for condensing map. Then the state feedback and impulsive controllers are, respectively, designed to ensure the Mittag-Leffler synchronization of these neural networks and two new synchronization criteria are obtained, which are expressed in terms of a fractional comparison principle and Razumikhin techniques. Numerical simulations are presented to validate the proposed methodologies. PMID- 28878566 TI - Elastic deformation of twinned microstructures. AB - Many crystalline materials exhibit twinned microstructures, where well-defined orientation relationships define the special symmetry between different, elastically anisotropic twin variants. When such twins are subjected to external loading, additional internal stresses necessarily occur at the twin boundaries in order to maintain compatibility. These compatibility stresses are constant inside each variant in repeating stacks of twins and considerably affect the local stress state. In this paper, we use anisotropic linear elasticity to derive general analytical solutions for compatibility stresses in a stack of twin variants in arbitrary materials, for arbitrary variant volume fractions and twin types, subjected to arbitrary applied stresses. By considering two examples, growth twins in electrodeposited Cu and B19' martensite twins in the shape memory alloy NiTi, we further demonstrate that compatibility stresses can considerably alter the preferred slip systems for dislocation plasticity as well as the effective macroscopic behaviour of twinned microstructures. PMID- 28878567 TI - Adaptive compliant structures for flow regulation. AB - This paper introduces conceptual design principles for a novel class of adaptive structures that provide both flow regulation and control. While of general applicability, these design principles, which revolve around the idea of using the instabilities and elastically nonlinear behaviour of post-buckled panels, are exemplified through a case study: the design of a shape-adaptive air inlet. The inlet comprises a deformable post-buckled member that changes shape depending on the pressure field applied by the surrounding fluid, thereby regulating the inlet aperture. By tailoring the stress field in the post-buckled state and the geometry of the initial, stress-free configuration, the deformable section can snap through to close or open the inlet completely. Owing to its inherent ability to change shape in response to external stimuli-i.e. the aerodynamic loads imposed by different operating conditions-the inlet does not have to rely on linkages and mechanisms for actuation, unlike conventional flow-controlling devices. PMID- 28878568 TI - Spectral derivation of the classic laws of wall-bounded turbulent flows. AB - We show that the classic laws of the mean-velocity profiles (MVPs) of wall bounded turbulent flows-the 'law of the wall,' the 'defect law' and the 'log law' can be predicated on a sufficient condition with no manifest ties to the MVPs, namely that viscosity and finite turbulent domains have a depressive effect on the spectrum of turbulent energy. We also show that this sufficient condition is consistent with empirical data on the spectrum and may be deemed a general property of the energetics of wall turbulence. Our findings shed new light on the physical origin of the classic laws and their immediate offshoot, Prandtl's theory of turbulent friction. PMID- 28878569 TI - Multi-parameter actuation of a neutrally stable shell: a flexible gear-less motor. AB - We have designed and tested experimentally a morphing structure consisting of a neutrally stable thin cylindrical shell driven by a multi-parameter piezoelectric actuation. The shell is obtained by plastically deforming an initially flat copper disc, so as to induce large isotropic and almost uniform inelastic curvatures. Following the plastic deformation, in a perfectly isotropic system, the shell is theoretically neutrally stable, having a continuous set of stable cylindrical shapes corresponding to the rotation of the axis of maximal curvature. Small imperfections render the actual structure bistable, giving preferred orientations. A three-parameter piezoelectric actuation, exerted through micro-fibre-composite actuators, allows us to add a small perturbation to the plastic inelastic curvature and to control the direction of maximal curvature. This actuation law is designed through a geometrical analogy based on a fully nonlinear inextensible uniform-curvature shell model. We report on the fabrication, identification and experimental testing of a prototype and demonstrate the effectiveness of the piezoelectric actuators in controlling its shape. The resulting motion is an apparent rotation of the shell, controlled by the voltages as in a 'gear-less motor', which is, in reality, a precession of the axis of principal curvature. PMID- 28878570 TI - Some applications of mathematics in golf. AB - At its core, like many other sports, golf is a game of integers. The minimization of the number of strokes played is generally what determines the winner, whether each of these are associated with the shortest of putts or the longest of drives. The outcomes of these shots are influenced by very slight changes, but hopefully in a deterministic sense. Understanding the mechanics of golf necessitates the development of models and this is coupled more often than not to the use of statistics. In essence, the individual aspects of the sport can be modelled adequately via fairly simplistic models, but the presence of a human at one end of the kinematic chain has a significant impact on the variability of the entire process. In this paper, we will review some of the ways that mathematics has been used to develop the understanding of the physical processes involved in the sport, including some of the analysis which is exploited within the Equipment Rules. We will also discuss some of the future challenges. PMID- 28878572 TI - Dabigatran reversal with idarucizumab in a patient undergoing heart transplantation: first European report. AB - BACKGROUND: Dabigatran is a direct thrombin inhibitor with a favorable effectiveness and safety profile when compared to vitamin K antagonists, both in randomized trials and real world registries of atrial fibrillation patients. Yet, physicians' fear of high bleeding risk scenarios in daily clinical practice still precludes a more widespread use of oral anticoagulation. We hereby report a successful case of dabigatran reversal with the novel monoclonal antibody fragment idarucizumab in a patient undergoing heart transplantation. CASE PRESENTATION: A 45-year old male patient on dabigatran for atrial fibrillation thromboprophylaxis was enlisted for heart transplantation due to end-stage ischemic heart failure. Upon donor availability and suitability and following the last intake of the drug 12 h previously, activated partial thromboplastin time was measured and found to be elevated. After general anesthesia and before extracorporeal circulation, idarucizumab was administered as two boluses of 2.5 g. Orthotopic heart transplantation ensued under full heparinization and cardiopulmonary bypass. Total chest tube output was 1125 mL after 3 days and 4 units of fresh frozen plasma and one platelet pool were administered in the operating room without further need for blood products. The post-operative period was uneventful. CONCLUSIONS: Idarucizumab was associated with an effective hemostasis in the setting of heart transplantation. Dabigatran may be considered as an alternative to vitamin K antagonists in heart transplant candidates with an indication for oral anticoagulation. PMID- 28878571 TI - Ribonucleic acid interference knockdown of IL-6 enhances the efficacy of cisplatin in laryngeal cancer stem cells by down-regulating the IL-6/STAT3/HIF1 pathway. AB - BACKGROUND: Cisplatin has been used in the treatment of many cancers, including laryngeal cancer; however, its efficacy can be reduced due to the development of drug resistance. This study aimed to investigate whether interleukin-6 (IL-6) knockdown may enhance the efficacy of cisplatin in laryngeal cancer stem cells (CSC) and the potential involvement of the signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1 (HIF1) in this effect. METHODS: The ALDH+ and CD44+ CSC in Hep2 human laryngeal squamous cancer cells were identified by the fluorescence-activated cell sorting technique. IL-6, STAT3 and HIF1 mRNA and protein expressions were examined with quantitative real-time polymerase chain reaction and Western blot, respectively. Cell proliferation was measured by MTT assay. Tumorigenicity was measured by a colony formation assay and invasion was determined by a cell invasion assay. Apoptotic cells were counted by flow cytometry. Immunohistochemistry was performed to detect immunoreactive IL-6, STAT3 and HIF1 cells in xenografts. RESULTS: The mRNA and protein levels of IL-6, STAT3 and HIF1 were significantly increased in Hep2-CSC as compared with those from Hep2 cells. Application of siRNA-IL-6 to knockdown IL 6 resulted in significantly decreased IL-6, STAT3 and HIF1 mRNA and protein levels. IL-6 knockdown reduced cell proliferation, tumorigenicity and invasion and increased apoptosis within CSC. Enhanced degrees of suppression in these parameters were observed when IL-6 knockdown was combined with cisplatin in these CSC. Results from the xenograft study showed that the combination of IL-6 knockdown and cisplatin further inhibited the growth of xenografts as compared with that obtained in the cisplatin-injected group alone. Immunoreactive IL-6, STAT3 and HIF1 cell numbers were markedly reduced in IL-6 knockdown tumor tissues. IL-6, STAT3 and HIF1 immunoreactive cell counts were further reduced in tissue where IL-6 knockdown was combined with cisplatin treatment as compared with tissue receiving cisplatin alone. CONCLUSIONS: IL-6 knockdown can increase chemo-drug efficacy of cisplatin, inhibit tumor growth and reduce the potential for tumor recurrence and metastasis in laryngeal cancer. The IL-6/STAT3/HIF1 pathway may represent an important target for investigating therapeutic strategies for the treatment of laryngeal cancer. PMID- 28878573 TI - Cost-effectiveness of human papillomavirus vaccination in Germany. AB - BACKGROUND: The aim of this study was to assess the cost-effectiveness of human papillomavirus (HPV) vaccination in addition to the current cervical cancer screening programme in Germany using a dynamic transmission model. METHODS: Based on a mathematical model simulating the transmission dynamics and the natural history of HPV infection and associated diseases (cervical intraepithelial neoplasia, cervical cancer, and genital warts), we estimated the epidemiological and economic consequences of HPV vaccination with both the quadrivalent and bivalent vaccines. In our base case analysis, we assessed the cost-effectiveness of vaccinating 12-year-old girls with a 3-dose schedule. In sensitivity analysis, we also evaluated the use of a 2-dose schedule and assessed the impact of vaccinating boys. RESULTS: From a health care payer perspective, incremental cost effectiveness ratios (ICERs) of a 3-dose schedule were ?34,249 per quality adjusted life year (QALY) for the bivalent and ?14,711 per QALY for the quadrivalent vaccine. Inclusion of indirect costs decreased ICERs by up to 40%. When adopting a health care payer perspective, ICERs of a 2-dose approach decreased to ?19,450 per QALY for the bivalent and to ?3645 per QALY for the quadrivalent vaccine. From a societal perspective, a 2-dose approach using the quadrivalent vaccine was a cost-saving strategy while using the bivalent vaccine resulted in an ICER of ?13,248 per QALY. Irrespective of the perspective adopted, additional vaccination of boys resulted in ICERs exceeding ?50,000 per QALY, except for scenarios with low coverage (20%) in girls. CONCLUSIONS: Our model results suggest that routine HPV vaccination of 12-year-old girls with three doses is likely to be cost-effective in Germany. Due to the additional impact on genital warts, the quadrivalent vaccine appeared to be more cost-effective than the bivalent vaccine. A 2-dose schedule of the quadrivalent vaccine might even lead to cost savings when adopting a societal perspective. The cost-effectiveness of additional vaccination of boys was highly dependent on the coverage in girls. PMID- 28878575 TI - My Time in Jail. PMID- 28878574 TI - Skin Necrosis Induced by Coumarin Congeners. PMID- 28878576 TI - Comparison of 3 Predictive Clinical Risk Scores in 603 Patients with Stable Coronary Artery Disease. AB - No clinical risk score is universally accepted for coronary artery disease. In 603 patients (mean age, 61.2 +/- 12.3 yr) with stable coronary artery disease, we investigated the predictive power of clinical risk scores derived from the Framingham, the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), and the Vienna and Ludwigshafen Coronary Artery Disease (VILCAD) studies. Secondary outcomes were the recurrence of an acute thrombotic event (coronary events, strokes, or transient ischemic attacks), or heart failure or death. The primary outcome was the combination of secondary outcomes. During follow-up (duration, 2.08 +/- 0.97 yr), 42 patients had an acute thrombotic event; 22, heart failure or death; and 60, the primary outcome. The Framingham score predicted acute thrombotic events: hazard ratio (HR)=1.05; 95% confidence interval (CI), 1.01-1.08; P=0.03; net reclassification index (NRI, calculated to evaluate improvement in prediction gained by adding different risk scores to models constructed with variables excluded from the calculation of that score)=9.7% (95% CI, 9.6-9.8). The LIPID (HR=1.13; 95% CI, 1.04-1.22; P=0.005) and VILCAD scores (HR=1.99; 95% CI, 1.48-2.67; P <0.001) predicted heart failure or death with NRIs of 5.8% (95% CI, 5.7-5.9) and 18.6% (95% CI, 18.3-18.9), respectively. The primary outcome was predicted by the LIPID (HR=1.1; 95% CI, 1.03-1.17; P=0.005) and VILCAD scores (HR=1.39; 95% CI, 1.13-1.70; P=0.003). The NRIs (95% CIs) were 3.4% (3.3-3.5) and 19.4% (19.3-19.6), respectively. We conclude that the accuracy of these risk scores varies in accordance with the outcome studied. PMID- 28878577 TI - Echocardiographic Classification and Surgical Approaches to Double-Outlet Right Ventricle for Great Arteries Arising Almost Exclusively from the Right Ventricle. AB - Selecting an appropriate surgical approach for double-outlet right ventricle (DORV), a complex congenital cardiac malformation with many anatomic variations, is difficult. Therefore, we determined the feasibility of using an echocardiographic classification system, which describes the anatomic variations in more precise terms than the current system does, to determine whether it could help direct surgical plans. Our system includes 8 DORV subtypes, categorized according to 3 factors: the relative positions of the great arteries (normal or abnormal), the relationship between the great arteries and the ventricular septal defect (committed or noncommitted), and the presence or absence of right ventricular outflow tract obstruction (RVOTO). Surgical approaches in 407 patients were based on their DORV subtype, as determined by echocardiography. We found that the optimal surgical management of patients classified as normal/committed/no RVOTO, normal/committed/RVOTO, and abnormal/committed/no RVOTO was, respectively, like that for patients with large ventricular septal defects, tetralogy of Fallot, and transposition of the great arteries without RVOTO. Patients with abnormal/committed/RVOTO anatomy and those with abnormal/noncommitted/RVOTO anatomy underwent intraventricular repair and double root translocation. For patients with other types of DORV, choosing the appropriate surgical approach and biventricular repair techniques was more complex. We think that our classification system accurately groups DORV patients and enables surgeons to select the best approach for each patient's cardiac anatomy. PMID- 28878578 TI - Single-Breath-Hold Evaluation of Cardiac Function with Use of Time-Resolved Parallel Cardiac Magnetic Resonance. AB - Using cardiac magnetic resonance, we tested whether a single-breath-hold approach to cardiac functional evaluation was equivalent to the established multiple breath-hold method. We examined 39 healthy volunteers (mean age, 31.9 +/- 11.4 yr; 22 men) by using 1.5 T with multiple breath-holds and our proposed single breath-hold. Left ventricular and right ventricular ejection fractions (LVEF and RVEF), LV and RV end-diastolic volumes (LVEDV and RVEDV), and LV myocardial mass (LVMM) were compared by using Bland-Altman plots; LVEF and RVEF were tested for equivalence by inclusion of 95% confidence intervals (CIs). Equivalence of the methods was assumed within the range of -5% to 5%. In the multiple- versus the single-breath-hold method, LVEF was 0.62 +/- 0.05 versus 0.62 +/- 0.04, and RVEF was 0.59 +/- 0.06 versus 0.59 +/- 0.07. The mean difference in both methods was 0.2% (95% CI, -1 to 0.6) for LVEF and 0.3% (95% CI, -0.8 to 1.5) for RVEF. The mean differences between methods fit within the predetermined range of equivalence, including the 95% CI. The mean relative differences between the methods were 3.8% for LVEDV, 4.5% for RVEDV, and 1.6% for LVMM. Results of our single-breath-hold method to evaluate LVEF and RVEF were equivalent to those of the multiple-breath-hold technique. In addition, LVEDV, RVEDV, and LVMM showed low bias between methods. PMID- 28878579 TI - Left Ventricular Noncompaction Cardiomyopathy Presenting with Heart Failure in a 35-Year-Old Man. AB - Isolated ventricular noncompaction, a rare genetic cardiomyopathy, is thought to be caused by the arrest of normal myocardial morphogenesis. It is characterized by prominent, excessive trabeculation in a ventricular wall segment and deep intertrabecular recesses perfused from the ventricular cavity. The condition can present with heart failure, systematic embolic events, and ventricular arrhythmias. Two-dimensional echocardiography is the typical diagnostic method. We report a case of heart failure in a 35-year-old man who presented with palpitations. Two-dimensional echocardiograms revealed left ventricular noncompaction, which markedly improved after standard heart failure therapy. PMID- 28878580 TI - Can Left Ventricular Noncompaction Be Acquired, and Can It Disappear? PMID- 28878581 TI - Optical Coherence Tomographic Evaluation of Hyperacute Bivalirudin-Induced Coronary Stent Thrombosis. AB - Thrombus formation after stent deployment has been linked to the use of heparin and of antithrombotic agents, such as bivalirudin, during percutaneous coronary intervention. Fluoroscopy has been used to identify stent thrombosis, typically after patients become symptomatic. We describe our use of optical coherence tomography to diagnose and evaluate intraprocedural stent thrombosis in a 68-year old man who was given bivalirudin just before a percutaneous coronary procedure. This imaging method enabled immediate therapeutic intervention. PMID- 28878582 TI - Transcatheter Mitral Valve Replacement with the Edwards Sapien 3 Valve. AB - We describe the case of a 57-year-old man who had severe mitral valve stenosis and regurgitation without significant annular calcification. He was not a candidate for surgical valve replacement or repair because of his substantial comorbid conditions, overall frailty, and elevated surgical risk. He underwent successful transcatheter mitral valve replacement of his native mitral valve with compassionate, off-label use of an Edwards Sapien 3 valve. A search of the literature produced no other cases like ours, which represents a further evolution of the transcatheter valve implantation concept. Further studies are needed to help define accurate valve sizing, intraprocedural positioning, and long-term device stability, as well as to determine which patients might benefit from this commercially available valve. In the meantime, our findings could present a means of treating patients who have no other options. PMID- 28878583 TI - Balloon Repositioning of Transcatheter Aortic Valve after Migration into the Left Ventricular Outflow Tract, Followed by Valve-in-Valve Procedure. AB - Transcatheter aortic valve replacement is an established option for treating patients with symptomatic aortic stenosis; however, severe, life-threatening complications, such as valve migration, are possible. We report the case of an 82 year-old woman whose Edwards Sapien XT valve migrated into the left ventricular outflow tract one day after transcatheter aortic valve replacement. We used an inflated balloon to adjust the position of the migrated valve before performing a valve-in-valve procedure via a transapical approach, which resulted in a good valve implantation. PMID- 28878584 TI - Healthy Adolescent with a Mycotic Aortic Aneurysm from Community-Acquired Methicillin-Resistant Staphylococcus aureus. AB - Mycotic aneurysm after bacteremia is a rare diagnosis in children and adolescents. We report the case of a previously healthy adolescent who presented with chest pain and fever and who developed a mycotic aneurysm of the aorta after contracting community-acquired, methicillin-resistant Staphylococcus aureus. Early recognition of widening of the patient's superior mediastinum, noted during a comparison of the patient's initial and follow-up chest radiographs, prompted computed tomographic angiography of the chest and led to a timely diagnosis, rapid surgical intervention, and a good clinical outcome. To our knowledge, this is the first reported case of mycotic aortic aneurysm from community-acquired methicillin-resistant S. aureus in a healthy adolescent who had no predisposing cardiac or aortic anomalies. PMID- 28878585 TI - Selective Upper-Body Perfusion Technique for Removal of Renal Cell Carcinoma Extending into the Inferior Vena Cava and Right Atrium. AB - Invasion of a renal cell carcinoma thrombus into the inferior vena cava and right atrium is infrequent. Reaching and completely excising a tumor from the inferior vena cava is particularly challenging because the liver covers the surgical field. We report the case of a 61-year-old man who underwent surgery for a renal cell carcinoma of the right kidney that extended into the inferior vena cava and right atrium. During dissection of the liver to expose the inferior vena cava, transesophageal echocardiograms revealed right atrial mass migration into the tricuspid valve. On emergency sternotomy, the tumor embolized into the main pulmonary artery. We used a selective upper-body perfusion technique involving moderately hypothermic cardiopulmonary bypass, cardioplegic arrest, and clamping of the descending aorta, which provided a bloodless surgical field for precise removal of the mass and resulted in minimal blood loss. Our technique might be useful in other patients with tumor thrombus extending into the right atrium because it reduces the need for transfusion and avoids the deleterious effects of deep hypothermic circulatory arrest. Our case also illustrates the importance of continuous transesophageal echocardiographic monitoring to detect thrombus embolization. PMID- 28878586 TI - Isolated Diffuse Supravalvular Aortic Stenosis with Severe Aortic Narrowing in a 41-Year-Old Man. AB - Isolated supravalvular aortic stenosis in adults is a rare form of left ventricular outflow tract obstruction. We describe a case in a 41-year-old man in whom the supravalvular aorta had narrowed to approximately the size of the left anterior descending coronary artery. The patient underwent aortic surgery with replacement of the ascending aorta and repair of supravalvular aortic stenosis with a pantaloon graft. A postoperative echocardiogram showed substantial improvement: the mean gradient across the aorta had fallen from 48 to 8 mmHg. Surgery is the definitive treatment in symptomatic patients with supravalvular aortic stenosis. PMID- 28878588 TI - Bigeminy and a Pacemaker. PMID- 28878587 TI - Arrhythmogenic Right Ventricular Cardiomyopathy in an Endurance Athlete Presenting with Ventricular Tachycardia and Normal Right Ventricular Function. AB - Arrhythmogenic right ventricular cardiomyopathy, a genetically inherited disease that results in fibrofatty replacement of normal cardiac myocytes, has been associated with sudden cardiac death in athletes. Long-term participation in endurance exercise hastens the development of both the arrhythmic and structural arrhythmogenic right ventricular cardiomyopathy phenotypes. We describe the unusual case of a 34-year-old, symptomatic, female endurance athlete who had arrhythmogenic right ventricular cardiomyopathy in the presence of a structurally normal right ventricle. Clinicians should be aware of this infrequent presentation when evaluating athletic patients who have ventricular arrhythmias and normal findings on cardiac imaging studies. PMID- 28878589 TI - Diagnostic Imaging and Treatment of a Left Atrial Paraganglioma. PMID- 28878590 TI - Enzymatically modified isoquercitrin supplementation intensifies plantaris muscle fiber hypertrophy in functionally overloaded mice. AB - BACKGROUND: Enzymatically modified isoquercitrin (EMIQ) is produced from rutin using enzymatic hydrolysis followed by treatment with glycosyltransferase in the presence of dextrin to add glucose residues. EMIQ is absorbed in the same way as quercetin, a powerful antioxidant reported to prevent disused muscle atrophy by targeting mitochondria and to have ergogenic effects. The present study investigated the effect of EMIQ on skeletal muscle hypertrophy induced by functional overload. METHODS: In Study 1, 6-week-old ICR male mice were divided into 4 groups: sham-operated control, sham-operated EMIQ, overload-operated control, and overload-operated EMIQ groups. In Study 2, mice were divided into 3 groups: overload-operated whey control, overload-operated whey/EMIQ (low dose), and overload-operated whey/EMIQ (high dose) groups. The functional overload of the plantaris muscle was induced by ablation of the synergist (gastrocnemius and soleus) muscles. EMIQ and whey protein were administered with food. Three weeks after the operation, the cross-sectional area and minimal fiber diameter of the plantaris muscle fibers were measured. RESULTS: In Study 1, functional overload increased the cross-sectional area and minimal fiber diameter of the plantaris muscle. EMIQ supplementation significantly increased the cross-sectional area and minimal fiber diameter of the plantaris muscle in both the sham-operated and overload-operated groups. In Study 2, EMIQ supplementation combined with whey protein administration significantly increased the cross-sectional area and minimal fiber diameter of the plantaris muscle. CONCLUSION: EMIQ, even when administered as an addition to whey protein supplementation, significantly intensified the fiber hypertrophy of the plantaris muscle in functionally overloaded mice. EMIQ supplementation also induced fiber hypertrophy of the plantaris in sham-operated mice. PMID- 28878592 TI - The Management of Unplanned Erection during Endoscopic Urological Surgery. AB - Penile erection at the time of urological surgery is a rare but problematic event which can delay, complicate or even lead to the cancellation of planned surgery. Erection may occur irrespective of the type of anesthetic method employed. Several techniques for treatment of this troublesome complication have been described in the literature, all with varying levels of success and potential adverse effects. In our experience over the last 25 years, we have found that intracavernous injection of ephedrine into the penis has a 100% success rate in safely producing detumescence with minimum side effects and should therefore be considered early among the treatment options for this condition. PMID- 28878591 TI - Mutations in the gene of the Galpha subunit of the heterotrimeric G protein are the cause for the brachytic1 semi-dwarf phenotype in barley and applicable for practical breeding. AB - BACKGROUND: Short-culm mutants have been widely used in breeding programs to increase lodging resistance. In barley (Hordeum vulgare L.), several hundreds of short-culm mutants have been isolated over the years. The objective of the present study was to identify the Brachytic1 (Brh1) semi-dwarfing gene and to test its effect on yield and malting quality. RESULTS: Double-haploid lines generated through a cross between a brh1.a mutant and the European elite malting cultivar Quench, showed good malting quality but a decrease in yield. Especially the activities of the starch degrading enzymes beta-amylase and free limit dextrinase were high. A syntenic approach comparing markers in barley to those in rice (Oryza sativa L.), sorghum (Sorghum bicolor Moench) and brachypodium (Brachypodium distachyon P. Beauv) helped us to identify Brh1 as an orthologue of rice D1 encoding the Galpha subunit of a heterotrimeric G protein. We demonstrated that Brh1 is allelic to Ari-m. Sixteen different mutant alleles were described at the DNA level. CONCLUSIONS: Mutants in the Brh1 locus are deficient in the Galpha subunit of a heterotrimeric G protein, which shows that heterotrimeric G proteins are important regulators of culm length in barley. Mutant alleles do not have any major negative effects on malting quality. PMID- 28878594 TI - Outcomes of Ureteral Stent Placement for Hydronephrosis in Patients with Gynecological Malignancies. AB - OBJECTIVE: We examined the outcomes of patients undergoing ureteral stent placement for hydronephrosis that occurred during treatment for gynecological malignancies. MATERIALS AND METHODS: From January 2004 to December 2009, we enrolled 33 patients with 45 ureters undergoing ureteral stent placement for hydronephrosis which occurred during treatment for gynecological malignancies. We examined the outcomes of the patients after stent placement. RESULTS: The causes of hydronephrosis were obstruction of the urinary tract by a tumor (n = 22), obstruction due to lymph node swelling (n = 6), ureteral stenosis after radiation therapy (n = 4), and others (n = 1). The ureteral stent was inserted into both ureters in 12 cases, and into one ureter in 21 cases. Ureteral stents were replaced 1-26 times during the observation period (median 3 times). Eighteen (40%) ureteral stents were removed. The reasons for ureteral stent removal were hydronephrosis improvement (11 ureters, 24.4%), a change to nephrostomy (cystectomy: 1 ureter, progression of ureteral stenosis: 2 ureters), renal atrophy (3 ureters), and ureteral dilatation (1 ureter). All of the cases in which ureteral stent withdrawal due to hydronephrosis improvement were cases in which the ureter was compressed by a tumor and were lower ureteral obstructions. Twenty-one patients (64%) died due to cancer after stent placement. The periods from the first stent placement to death ranged from 1 to 58 months (median 18 months). CONCLUSION: Ureteral stent placement was associated with a poor prognosis in patients with gynecological malignancies. There were a few cases in which stent withdrawal became possible due to the improvement of hydronephrosis. In such cases, the withdrawal rate varied according to the cause and obstructive level. PMID- 28878593 TI - Low-Risk Prostate Cancer and Tumor Upgrading in the Surgical Specimen: Analysis of Clinical Factors Predicting Tumor Upgrading in a Contemporary Series of Patients Who were Evaluated According to the Modified Gleason Score Grading System. AB - OBJECTIVE: To identify significant clinical factors associated with prostate cancer (PCa) upgrading the low-risk PCa patients graded according to the modified Gleason score system. MATERIALS AND METHODS: The logistic regression model was used to evaluate the records of 438 patients. RESULTS: There were 170 cases (38.8%) of low-risk PCa and tumors were upgraded in 111 patients (65.3%). Only prostate specific antigen (PSA) and the proportion of positive cores (P+) were independent predictors of tumor upgrading. Further exploration was investigated by categorizing and regressing PSA (<= 5.0 vs. > 5.0 ng/ml) and P+ (<= 0.20 vs. > 0.20). The odds ratio of PSA > 5 ng/ml was 1.32 and of P+ > 0.20 was 2.71. The population was stratified into very low-risk with PSA <= 5 ng/ml and P+ <= 0.20 (class A), low-risk with PSA > 5 ng/ml and P+ <= 0.20 (class B), intermediate risk with PSA <= 5 ng/ml and P+ > 0.20 (class C), and high risk with PSA > 5 ng/ml and P+ 0.20 (class D). Upgrading rates were extremely low in class A (9%), extremely high in D (50.5%), and moderate (20%) in B and C. CONCLUSION: Patients diagnosed with low-risk PCa at biopsy are a heterogeneous population because they include subsets with undetected high-grade disease. Significant clinical predictors of upgrading include the PSA value and P+. In low-risk PCa, we identified a high-risk upgrading subgroup that needed repeat biopsies in order to reclassify the tumor grade and to reassess the clinical risk category. PMID- 28878595 TI - Neoadjuvant Platinum-Based Chemotherapy is an Independent Predictor for Preoperative Thromboembolic Events in Bladder Cancer Patients Undergoing Radical Cystectomy. AB - INTRODUCTION: Neoadjuvant chemotherapy (NAC) confers a significant survival benefit in patients with muscle invasive bladder cancer. Platinum-based chemotherapy increases the risk of thromboembolic events (TEE). We determined the effect of cisplatin-based NAC on the incidence of preoperative TEEs in radical cystectomy patients. MATERIALS AND METHODS: A retrospective matched case-control study was performed on 55 patients undergoing radical cystectomy for muscle invasive bladder cancer. Group 1 (n = 20) included patients that received NAC prior to radical cystectomy and Group 2 (n = 35) included patients that underwent radical cystectomy without NAC. Logistic regression analyses tested potential predictors for TEEs in both groups (age, American Society of Anesthesiologists grade, use of NAC, histological subtype, pathological stage). RESULTS: In total, 6 patients of 55 developed a TEE. Five patients of 20 (25%) treated with NAC prior to radical cystectomy developed TEEs, while 1 of 35 (2.9%) treated with radical cystectomy alone developed a TEE. On univariate and multivariate regression analysis, NAC prior to radical cystectomy was an independent predictor for TEE prior to radical cystectomy (p = 0.033 and p = 0.043, respectively). The effect of perioperative anticoagulation on operative blood loss and postoperative hemoglobin level was not statistically significant between both groups (p = 0.22 and p = 0.08, respectively). CONCLUSION: Neoadjuvant cisplatin-based chemotherapy is a significant predictor for preoperative TEE in patients undergoing radical cystectomy. PMID- 28878596 TI - Nucleotide Transition 390C-T in the Wilms' Tumor 1 Gene: A Risk Factor of Hypospadias? AB - INTRODUCTION: The gene Wilms' tumor 1 (WT1) encodes a unique transcription factor. Its defects are known to cause a wide range of complex genitourinary malformations and may contribute to non-syndromic forms of hypospadias. MATERIALS AND METHODS: We performed WT1 mutation analysis and copy number analysis of WT1 interacting protein in 13 Hungarian patients diagnosed with isolated hypospadias. RESULTS: Sequencing of WT1 revealed a high frequency of heterozygosity for transition 390C-T (5 heterozygotes out of 13 patients, including 2 brothers). WT1 interacting protein had a normal copy number in all patients. CONCLUSION: Nucleotide substitution 390C-T may play a role in the pathogenesis of non syndromic hypospadias. The genotype-phenotype correlation should be confirmed by a larger-scale analysis. PMID- 28878597 TI - The Advantages of Transurethral Resection of the Prostate in Patients with an Elevated or Rising Prostate Specific Antigen, Mild or Moderate Lower Urinary Tract Symptoms, Bladder Outlet Obstruction and Negative Prostate Cancer Imaging or Prostate Biopsies: A Prospective Analysis in 105 Consecutive Patients. AB - OBJECTIVE: To investigate elevated or rising prostate specific antigen (PSA) as a marker for bladder outlet obstruction (BOO) in patients with minor lower urinary tract symptoms (LUTS) and without prostate cancer. MATERIALS AND METHODS: One hundred and five consecutive patients were prospectively analyzed between 2005 and 2013. All patients were referred to the principal investigator by their general practitioner as a result of an elevated and/or rising PSA. Only patients with minor LUTS [International Prostate Symptom Score (I-PSS) 0-19] and without suspicion for prostate cancer were included. All patients had BOO, shown by full urodynamics, and underwent transurethral resection of the prostate. The resected tissue was histologically examined and PSA and I-PSS were evaluated after 3, 6 and 12 months and later on yearly. RESULTS: Mean pre-operative PSA and I-PSS values were 8.8 ng/ml and 11.1, respectively. The mean detrusor pressure at maximum flow was 93.6 cmH2O. The mean resected volume was 52 g and the mean prostate biopsy rate was 1.8. Eighty-three of 105 patients (79%) had no malignancy and were diagnosed with BOO due to benign prostate hyperplasia (subgroup 1). Their mean PSA decreased from 9.2 to 0.7 ng/ml and 0.9 ng/ml after 6 and 12 months post-operation, respectively. The mean I-PSS declined from 11 to 3 after 6 and 12 months. Sixteen of 105 patients (15%) were treated for prostate cancer (subgroup 2). Radical prostatectomy was performed in 11 patients, brachytherapy in 3 patients and external beam radiotherapy in 2 patients. Six of 105 patients (5.7%) had active surveillance (subgroup 3). CONCLUSION: BOO can cause an elevated or rising PSA in patients with minor LUTS and negative screening for prostate cancer. Transurethral resection of the prostate is an adequate treatment for these patients. PMID- 28878598 TI - Bladder Neck Contracture Following Radical Retropubic versus Robotic-Assisted Laparoscopic Prostatectomy. AB - INTRODUCTION: Radical retropubic prostatectomy (RRP) and robotic-assisted laparoscopic prostatectomy (RALP) are co-standard surgical therapies for localized prostatic adenocarcinoma. These surgical modalities offer similar outcomes; however, lower rate of bladder neck contracture (BNC) is amongst the touted benefits of RALP. The differences between approaches are largely elucidated through multiple-surgeon comparisons, which can be biased by differential experience and practice patterns. We aimed to eliminate inter surgeon bias through this single-surgeon comparison of BNC rates following RRP and RALP. MATERIALS AND METHODS: We retrospectively reviewed all RRPs and RALPs performed by one surgeon over 4 years. We compared clinical characteristics, intraoperative and postoperative outcomes. RESULTS: RRP patients had more advanced cancer and a higher biochemical recurrence rate. No significant differences were noted between groups in rates of anastomotic leakage, BNC, or 12 month postoperative pad-free continence. CONCLUSION: RRP offers similar outcomes to RALP with regard to postoperative urinary extravasation, urinary continence, and BNC. PMID- 28878599 TI - Clinical Importance of Histopathological Inflammation in Patients with Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: A Prospective Study of 222 Patients. AB - OBJECTIVE: To investigate the relationship between the severity of histopathological prostatic inflammation with lower urinary tract symptoms and prostate specific antigen (PSA) levels. METHODS: We prospectively included 222 consecutive patients eligible for transurethral resection of the prostate in a non-academic referral center by a single surgeon. Patients with proven urinary tract infection or prostate cancer were excluded. Preoperative assessment included PSA levels, International Prostate Symptom Score (IPSS), mean peak flow, mean resected prostate weight and post-residual volume. Finally, the presence and severity of inflammation was determined histopathologically. RESULTS: Mean patient age was 69.1 +/- 8.6 years with mean preoperative PSA levels of 4.7 +/- 5.4 ng/mL and IPSS of 15.7 +/- 6.9. Mean peak flow was 10.7 +/- 6.5 ml/s and the mean resected prostate weight 39.4 +/- 27.3 g. Positive correlations between PSA (log) and prostate weight (r = 0.54, p < 0.001) and between PSA (log) and active (r = 0.30, p < 0.0001) and chronic inflammation (r = 0.19, p = 0.005) were observed. No correlations were found between IPSS and PSA (log) (r = -0.14, p = 0.040) or between IPSS and active inflammation (p = 0.659) or chronic inflammation (p = 0.125). CONCLUSION: The study showed a weak correlation between PSA and the active or chronic inflammation. It also showed that there was no correlation between the active or chronic histopathological inflammation and IPSS. PMID- 28878600 TI - Kenalog Injection into Hunner's Lesions as a Treatment for Interstitial Cystitis/Bladder Pain Syndrome. AB - INTRODUCTION: This study aims to evaluate the effectiveness of kenalog injection into Hunner's lesions. MATERIALS AND METHODS: All patients had cystoscopy and bladder hydrodistention with corticosteroid injection into Hunner's lesions over a 2.5-year period. Data include patient characteristics and pre- and post operative validated questionnaires. Spearman Correlation and Wilcoxon t-tests were used for analysis. RESULTS: One hundred patients were reviewed retrospectively. There was a 1.1 point decrease in pain at 12 weeks post operation (p = 0.435). Urinary frequency decreased from a mean of 11.7 to 9.1 daily episodes (p = 0.05), and nocturia from a mean of 3 to 1.6 nightly episodes (p = 0.008). CONCLUSION: The use of a corticosteroid may be beneficial to symptom control and improvement in the quality of life of interstitial cystitis/painful bladder syndrome patients. Patients had improved frequency and nocturia 12 weeks post injection. PMID- 28878601 TI - An Atypical Presentation of Retroperitoneal Fibrosis. AB - A 69-year-old man with a psoriatic arthritis treated with infliximab for 1 month presented to the urology clinic for lower urinary tract symptoms. He was found to have a new diagnosis of elevated creatinine. Computed tomography of the abdomen and pelvis revealed bilateral severe hydronephrosis with abnormal soft tissue thickening of the right renal pelvis and proximal ureter. Bilateral stents were placed after ureteroscopy demonstrated no abnormalities. A computed tomography guided biopsy of the peri-ureteral lesions revealed fibroadipose tissue with sclerosis and extensive chronic inflammation consistent with retroperitoneal fibrosis. Infliximab was discontinued and the patient was started on corticosteroids. Follow-up magnetic resonance imaging of the abdomen and pelvis at 2 months revealed total resolution of soft tissue and inflammation along the proximal ureter bilaterally. Repeat imaging demonstrated no hydronephrosis after stents removal, and the patient's creatinine remains normal at 12 months follow up. PMID- 28878602 TI - Post Traumatic Isolated Ureteropelvic Junction Avulsion in a Child. AB - Isolated ureteropelvic junction injuries due to blunt trauma are very rare and are missed at initial presentation in more than 50% patients. Hence they need high index of suspicion for diagnosis which is the main aim of reporting this case. PMID- 28878603 TI - Abdominal Mass After Robotic Assisted Laparoscopic Prostatectomy: Spigelian Type Trocar Hernia. AB - Prostate cancer is the most common cancer in men. Men are diagnosed at early stages of prostate cancer with the use of prostate specific antigen. Surgical removal of the prostate is the standard treatment in localized prostate cancer. Complications after surgical procedures are inevitable. Although robotic prostatectomy has resulted in decreased complications compared to open surgery, complications occur. After an uneventful robotic assisted laparoscopic prostatectomy in a 71-year-old gentleman, with history of chronic cough and continued low dose glucocorticoid use, the patient returned to hospital with complain of a tender abdominal mass in right lower quadrant. After performing a computed tomography of the contrast, a Spigelian type trocar hernia was noted. The patient underwent a laparoscopic diagnostic surgery followed by small bowel resection and abdominal wall defect repair. The patient was discharged home with no other complains. PMID- 28878605 TI - Adding Insult to Injury, Complexity to Intricacy. PMID- 28878604 TI - The Effects of Different Doses and Patterns of Docetaxel Chemotherapy in Japanese Patients with Castration-Resistant Prostate Cancer. PMID- 28878606 TI - Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test. AB - Congenital heart disease (CHD) is the most common congenital disorder among live births. When associated with extracardiac abnormalities, it is characterized as a syndromic heart disease (syndromic CHD) and corresponds to 25% of all liveborn infants with a heart defect. The etiology in about 65% of the cases still remains unknown, and in about 35% of the patients, it is associated with genetic factors. In the present study, MLPA and SNP-array techniques were used to investigate a group of 47 patients with syndromic CHD. In total, 16 defects (34%) were identified, of which 12 (25.5%) were classified as pathogenic or probably pathogenic. The most frequent abnormalities were 22q11.2 deletion (22q11.2 deletion syndrome) and 7q11.23 deletion (Williams-Beuren syndrome). We also show that rarer malformations may be associated with syndromic CHD, such as 14q32.33 deletion as well as 17q25.3, 15q11.2 (BP1-BP2), 22q13.31, and 12p13.31 (SLC2A3) duplications. The present study demonstrates that CNVs are important causal factors and should be studied in patients with syndromic CHD. Furthermore, the use of MLPA as a first screening test was appropriate, as this less expensive technology detected 11 of the 12 pathogenic abnormalities (91.6%). PMID- 28878607 TI - Genetic Testing in a Cohort of Complex Esophageal Atresia. AB - The objective of the present study is to describe a cohort of complex esophageal atresia and the yield of genetic tests performed for such patients. We selected 45 patients with complex esophageal atresia (EA), namely those having at least one associated anomaly. We reviewed their medical records to assess clinical features, other diagnoses, and genetic investigations. Most of the patients had a diagnosis of VACTERL association (56%) with no genetic variant identified. Interestingly, 5 patients in the cohort (11%) had a right pulmonary hypoplasia or agenesis. A majority of our cohort (73%) had genetic testing; 60% were karyotyped (abnormal in 4 of the 27 patients tested), 31% had aCGH (abnormal in 1 of the 14 patients tested), and 31% had diepoxybutane (DEB) testing for Fanconi anemia (abnormal in 2 of the 14 patients tested). One patient had exome sequencing studies, but no candidate gene was identified. Various anomalies were associated with EA, and overall a genetic variant could be identified in 7 of the 33 patients tested. Chromosomal studies such as aCGH and chromosomal breakage studies should be considered, and their yield varied between 7 and 14%. Other genetic investigations such as exome sequencing could possibly have even higher yields but will need to be assessed in a large cohort. Improved genetic diagnoses in EA may improve the management of these patients by directing specific surveillance and management schemes. PMID- 28878608 TI - Diagnostic Approach to Microdeletion Syndromes Based on 22q11.2 Investigation: Challenges in Four Cases. AB - In the last few decades, different methods for the detection of genomic imbalances, such as the microdeletion syndromes, were developed. The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome and presents wide clinical heterogeneity. The aim of this study was to describe 4 unusual cases of genomic imbalances found in individuals with suspected microdeletion syndromes. Different methods were necessary to complete the diagnosis and to obtain information for genetic counseling. The study was retrospective and descriptive. From August 2014 to December 2015, 39 individuals were assessed using FISH and/or MLPA; in 15 cases, chromosomal microarray (CMA) analysis was carried out. Of 39 registered individuals, we found deletions in the 22q11.2 region in 10 individuals (8 individuals with 22q11.2DS and 2 individuals presenting with atypical deletions in the 22q11.2 region: 1 distal deletion and 1 central deletion). In one case with a typical 22q11.2 deletion, a familial balanced translocation was detected. In another case without a 22q11.2 deletion, a 6p duplication concomitant with a 9p deletion was detected by CMA. Clinical data are reported and diagnostic investigations are discussed. Essential aspects for the understanding of different diagnostic techniques of genomic imbalances are considered, and the 4 cases described underline the complexity and the difficulties involved in the diagnostic process. The approach is informative for clinical practice and may be applied in other contexts of genomic imbalance investigation in microdeletion syndromes. PMID- 28878610 TI - A Novel Loss-of-Function Mutation in HOXB1 Associated with Autosomal Recessive Hereditary Congenital Facial Palsy in a Large Iranian Family. AB - Hereditary congenital facial palsy (HCFP) is a rare congenital cranial dysinnervation disorder, recognisable by non-progressive isolated facial nerve palsy (cranial nerve VII). It is caused by developmental abnormalities of the facial nerve nucleus and its nerve. So far, 4 homozygous mutations have been identified in 5 unrelated families (12 patients) with HCFP worldwide. In this study, a large Iranian consanguineous kindred with 5 members affected by HCFP underwent thorough clinical and genetic evaluation. The candidate gene HOXB1 was screened and analysed by Sanger sequencing. As in previous cases, the most remarkable findings in the affected members of the family were mask-like faces, bilateral facial palsy with variable sensorineural hearing loss, and some dysmorphic features. Direct sequencing of the candidate gene HOXB1 identified a novel homozygous frameshift mutation (c.296_302del; p.Y99Wfs*20) which co segregated with the disease phenotype within the extended family. Our findings expand the mutational spectrum of HOXB1 involved in HCFP and consolidate the role of the gene in the development of autosomal recessive HCFP. Moreover, the truncating mutation identified in this family leads to a broadly similar presentation and severity observed in previous patients with nonsense and missense mutations. This study characterises and defines the phenotypic features of this rare syndrome in a larger family than has previously been reported. PMID- 28878609 TI - Novel Mutation of the RUNX2 Gene in Patients with Cleidocranial Dysplasia. AB - Cleidocranial dysplasia (CCD) is an autosomal dominant disorder linked to mutations in the Runt-related transcription factor 2, encoded by the RUNX2 gene, which is essential for osteoblast differentiation and skeletal development. Here, we describe a novel nonsense mutation (c.532C>T; p.Q178X) in RUNX2 identified in 3 affected members of a Polish family with CCD. The localization and transcriptional transactivation studies show that the mutated form of the protein has altered the subcellular localization and significantly decreased transactivation properties, respectively. Consequently, our data show that the c.532C>T mutation generates a defective RUNX2 protein and is genetically linked to the CCD phenotype. PMID- 28878611 TI - Low-Level Chromosomal Mosaicism in Neurodevelopmental Disorders. AB - Chromosomal mosaicism, which represents a diagnostic challenge for detection and interpretation, has been described in several genetic conditions. It can contribute to a large phenotypic variation in diseases. At analysis of a well characterized cohort of 714 patients with neurodevelopmental disorders (NDDs) of unknown etiology using a high-resolution chromosomal microarray platform, we found 2 cases (0.28%) of low-level mosaicism and defined a previously detected extra chromosome in a third patient. Two of the cases were mosaics for segmental imbalances (a partial trisomy 3q26.1q27.3 and a partial monosomy 18q21.2qter with 14.6 and 20% mosaic ratios in lymphocytes, respectively), and 1 was a mosaic for an entire chromosome (trisomy 14, mosaic ratio 20%). Our diagnostic yield is in line with the ratios previously published in patients with intellectual disability. Notably, the partial trisomy 3q26.1q27.3 case is an example of a rare and unusual class of a rearranged neocentric ring chromosome, which can neither be categorized in class I, nor in class II of such rearrangements. Our cases further elucidate the phenotypes related to the aberrations of the specific chromosome segments observed and underline the important role of low-level mosaics in the pathogenesis of NDDs of unknown etiology even in the absence of clinical signs of mosaicism. PMID- 28878612 TI - Whole-Exome Sequencing Reveals FAT4 Mutations in a Clinically Unrecognizable Patient with Syndromic CAKUT: A Case Report. AB - We present the case of a patient of Macedonian origin with unilateral renal agenesis and ureterovesical junction obstruction in combination with further abnormalities including midface hypoplasia, scoliosis as well as camptodactyly of one toe. Whole-exome sequencing analysis revealed compound heterozygous variants in the FAT4 gene. Recessive variants in FAT4 are a known cause of van Maldergem syndrome (VMS) in which congenital anomalies of the kidney and urinary tract are a less characteristic but common feature. The initial presentation of our patient was not clinically recognizable. However, in view of the molecular findings, the most likely diagnosis is a mild manifestation of VMS. Only very few publications have reported patients with VMS and mutations in FAT4 to date. With this case, we hope to provide further insight into the phenotypic variability of this syndrome. PMID- 28878613 TI - Mixed Adenocarcinoma and Squamous Cell Carcinoma of Duodenum: A Case Report and Review of the Literature. AB - Despite being the largest part of the human gastrointestinal (GI) tract, the small intestine accounts for only 1-1.4% of all GI malignancies. Adenocarcinoma is the most common primary small bowel malignancy, with the most common site being the duodenum. On the other hand, squamous cell carcinoma (SCC) of the duodenum is extremely uncommon. We report the first case of mixed adenocarcinoma and SCC occurring in the third part of duodenum (D3). Our patient, a 64-year-old female with history of GERD, hypertension, and IDDM presented with 4 weeks of nausea, vomiting, and abdominal pain. Tomographic imaging of her abdomen demonstrated a distended stomach and a proximal duodenum with narrow caliber changes at the level of D3. An EGD revealed a tight stricture at D3 that could not be traversed. Stricture biopsies revealed duodenal mucosa with two small foci of SCC (positive for p63 and CK5/6) and adenocarcinoma (positive for CK7 and Moc31). Peritoneal metastases were detected on exploratory laparotomy, making the tumor surgically incurable. As she progressively declined and with worsening liver enzymes and general debility, she was not a candidate for chemotherapy and was eventually discharged on home hospice. Small bowel SCC/adenocarcinoma is an exceedingly uncommon cancer, making further case reports such as ours important to understand the nature of this entity and establish management guidelines. PMID- 28878614 TI - Fatal Gastrointestinal Hemorrhage in a Patient with Brunner's Gland Hyperplasia. AB - Brunner's gland hyperplasia is a rare cause of duodenal mass and gastrointestinal hemorrhage. Imaging and esophagoduodenoscopic evaluation of this condition are frequently consistent with a duodenal malignancy often resulting in surgical resection. However, the malignant potential of these lesions is still unknown, and most are benign. We report the case of a 74-year-old man who presented with fatal gastrointestinal bleeding and esophagoduodenoscopy findings consistent with a duodenal mass and mucosal ulceration. At autopsy, histologic examination of the mass revealed Brunner's gland hyperplasia with associated ulcer formation. In this report, we review the findings associated with this case as well the literature regarding presentation, clinical associations, and treatment of Brunner's gland hyperplasia. PMID- 28878615 TI - Clinically Silent Intracardiac Metastasis with Extremely Poor Prognosis in a Patient with Hepatocellular Carcinoma. AB - Intracavitary cardiac extension remains an unusual site of extrahepatic metastasis in patients with hepatocellular carcinoma. While patients can present with signs and symptoms suggestive of right-sided heart failure, it may be totally asymptomatic, which is very rare with only a few cases reported so far. Also, cardiac metastasis is of great prognostic importance as patients with intracardiac metastasis can have an extremely poor prognosis. Here, we present the case of a 52-year-old male patient with advanced hepatocellular carcinoma, with an incidentally found tumor thrombus extending from the inferior vena cava to the right atrium, protruding through the tricuspid valve into the right ventricle, on routine echocardiography. The patient did not have any signs or symptoms of heart involvement and unfortunately died on the 18th day of the hospital stay. PMID- 28878616 TI - Interim Results of a Multicenter Trial with the New Electronic Subretinal Implant Alpha AMS in 15 Patients Blind from Inherited Retinal Degenerations. AB - Purpose: We assessed the safety and efficacy of a technically advanced subretinal electronic implant, RETINA IMPLANT Alpha AMS, in end stage retinal degeneration in an interim analysis of two ongoing prospective clinical trials. The purpose of this article is to describe the interim functional results (efficacy). Methods: The subretinal visual prosthesis RETINA IMPLANT Alpha AMS (Retina Implant AG, Reutlingen, Germany) was implanted in 15 blind patients with hereditary retinal degenerations at four study sites with a follow-up period of 12 months (www.clinicaltrials.gov NCT01024803 and NCT02720640). Functional outcome measures included (1) screen-based standardized 2- or 4-alternative forced-choice (AFC) tests of light perception, light localization, grating detection (basic grating acuity (BaGA) test), and Landolt C-rings; (2) gray level discrimination; (3) performance during activities of daily living (ADL-table tasks). Results: Implant mediated light perception was observed in 13/15 patients. During the observation period implant mediated localization of visual targets was possible in 13/15 patients. Correct grating detection was achieved for spatial frequencies of 0.1 cpd (cycles per degree) in 4/15; 0.33 cpd in 3/15; 0.66 cpd in 2/15; 1.0 cpd in 2/15 and 3.3 cpd in 1/15 patients. In two patients visual acuity (VA) assessed with Landolt C- rings was 20/546 and 20/1111. Of 6 possible gray levels on average 4.6 +/- 0.8 (mean +/- SD, n = 10) were discerned. Improvements (power ON vs. OFF) of ADL table tasks were measured in 13/15 patients. Overall, results were stable during the observation period. Serious adverse events (SAEs) were reported in 4 patients: 2 movements of the implant, readjusted in a second surgery; 4 conjunctival erosion/dehiscence, successfully treated; 1 pain event around the coil, successfully treated; 1 partial reduction of silicone oil tamponade leading to distorted vision (silicon oil successfully refilled). The majority of adverse events (AEs) were transient and mostly of mild to moderate intensity. Conclusions: Psychophysical and subjective data show that RETINA IMPLANT Alpha AMS is reliable, well tolerated and can restore limited visual functions in blind patients with degenerations of the outer retina. Compared with the previous implant Alpha IMS, longevity of the new implant Alpha AMS has been considerably improved. Alpha AMS has meanwhile been certified as a commercially available medical device, reimbursed in Germany by the public health system. PMID- 28878617 TI - Corrigendum: Spiking Neural Networks Based on OxRAM Synapses for Real-Time Unsupervised Spike Sorting. AB - [This corrects the article on p. 474 in vol. 10, PMID: 27857680.]. PMID- 28878619 TI - miRNA Enriched in Human Neuroblast Nuclei Bind the MAZ Transcription Factor and Their Precursors Contain the MAZ Consensus Motif. AB - While the cytoplasmic function of microRNA (miRNA) as post-transcriptional regulators of mRNA has been the subject of significant research effort, their activity in the nucleus is less well characterized. Here we use a human neuronal cell model to show that some mature miRNA are preferentially enriched in the nucleus. These molecules were predominantly primate-specific and contained a sequence motif with homology to the consensus MAZ transcription factor binding element. Precursor miRNA containing this motif were shown to have affinity for MAZ protein in nuclear extract. We then used Ago1/2 RIP-Seq to explore nuclear miRNA-associated mRNA targets. Interestingly, the genes for Ago2-associated transcripts were also significantly enriched with MAZ binding sites and neural function, whereas Ago1-transcripts were associated with general metabolic processes and localized with SC35 spliceosomes. These findings suggest the MAZ transcription factor is associated with miRNA in the nucleus and may influence the regulation of neuronal development through Ago2-associated miRNA induced silencing complexes. The MAZ transcription factor may therefore be important for organizing higher order integration of transcriptional and post-transcriptional processes in primate neurons. PMID- 28878618 TI - The Non-Survival Effects of Glial Cell Line-Derived Neurotrophic Factor on Neural Cells. AB - Glial cell line-derived neurotrophic factor (GDNF) was first characterized as a survival-promoting molecule for dopaminergic neurons (DANs). Afterwards, other cells were also discovered to respond to GDNF not only as a survival factor but also as a protein supporting other cellular functions, such as proliferation, differentiation, maturation, neurite outgrowth and other phenomena that have been less studied than survival and are now more extendedly described here in this review article. During development, GDNF favors the commitment of neural precursors towards dopaminergic, motor, enteric and adrenal neurons; in addition, it enhances the axonal growth of some of these neurons. GDNF also induces the acquisition of a dopaminergic phenotype by increasing the expression of Tyrosine Hydroxylase (TH), Nurr1 and other proteins that confer this identity and promote further dendritic and electrical maturation. In motor neurons (MNs), GDNF not only promotes proliferation and maturation but also participates in regenerating damaged axons and modulates the neuromuscular junction (NMJ) at both presynaptic and postsynaptic levels. Moreover, GDNF modulates the rate of neuroblastoma (NB) and glioblastoma cancer cell proliferation. Additionally, the presence or absence of GDNF has been correlated with conditions such as depression, pain, muscular soreness, etc. Although, the precise role of GDNF is unknown, it extends beyond a survival effect. The understanding of the complete range of properties of this trophic molecule will allow us to investigate its broad mechanisms of action to accelerate and/or improve therapies for the aforementioned pathological conditions. PMID- 28878621 TI - The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells. AB - CLN1 disease (OMIM #256730) is an early childhood ceroid-lipofuscinosis associated with mutated CLN1, whose product Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S acylated proteins. In neurons, PPT1 expression is also linked to synaptic compartments. The aim of this study was to unravel molecular signatures connected to CLN1. We utilized SH-SY5Y neuroblastoma cells overexpressing wild type CLN1 (SH-p.wtCLN1) and five selected CLN1 patients' mutations. The cellular distribution of wtPPT1 was consistent with regular processing of endogenous protein, partially detected inside Lysosomal Associated Membrane Protein 2 (LAMP2) positive vesicles, while the mutants displayed more diffuse cytoplasmic pattern. Transcriptomic profiling revealed 802 differentially expressed genes (DEGs) in SH-p.wtCLN1 (as compared to empty-vector transfected cells), whereas the number of DEGs detected in the two mutants (p.L222P and p.M57Nfs*45) was significantly lower. Bioinformatic scrutiny linked DEGs with neurite formation and neuronal transmission. Specifically, neuritogenesis and proliferation of neuronal processes were predicted to be hampered in the wtCLN1 overexpressing cell line, and these findings were corroborated by morphological investigations. Palmitoylation survey identified 113 palmitoylated protein-encoding genes in SH p.wtCLN1, including 25 ones simultaneously assigned to axonal growth and synaptic compartments. A remarkable decrease in the expression of palmitoylated proteins, functionally related to axonal elongation (GAP43, CRMP1 and NEFM) and of the synaptic marker SNAP25, specifically in SH-p.wtCLN1 cells was confirmed by immunoblotting. Subsequent, bioinformatic network survey of DEGs assigned to the synaptic annotations linked 81 DEGs, including 23 ones encoding for palmitoylated proteins. Results obtained in this experimental setting outlined two affected functional modules (connected to the axonal and synaptic compartments), which can be associated with an altered gene dosage of wtCLN1. Moreover, these modules were interrelated with the pathological effects associated with loss of PPT1 function, similarly as observed in the Ppt1 knockout mice and patients with CLN1 disease. PMID- 28878620 TI - Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that results from the loss of upper and lower motor neurons. One of the key pathological hallmarks in diseased neurons is the mislocalization of disease-associated proteins and the formation of cytoplasmic aggregates of these proteins and their interactors due to defective protein quality control. This apparent imbalance in the cellular protein homeostasis could be a crucial factor in causing motor neuron death in the later stages of the disease in patients. Autophagy is a major protein degradation pathway that is involved in the clearance of protein aggregates and damaged organelles. Abnormalities in autophagy have been observed in numerous neurodegenerative disorders, including ALS. In this review, we discuss the contribution of autophagy dysfunction in various in vitro and in vivo models of ALS. Furthermore, we examine the crosstalk between autophagy and other cellular stresses implicated in ALS pathogenesis and the therapeutic implications of regulating autophagy in ALS. PMID- 28878622 TI - Ganaxolone: A New Treatment for Neonatal Seizures. AB - Neonatal seizures are amongst the most common neurologic conditions managed by a neonatal care service. Seizures can exacerbate existing brain injury, induce "de novo" injury, and are associated with neurodevelopmental disabilities in post neonatal life. In this mini-review, we present evidence in support of the use of ganaxolone, a GABAA agonist neurosteroid, as a novel neonatal therapy. We discuss evidence that ganaxolone can provide both seizure control and neuroprotection with a high safety profile when administered early following birth-related hypoxia, and show evidence that it is likely to prevent or reduce the incidence of the enduring disabilities associated with preterm birth, cerebral palsy, and epilepsy. We suggest that ganaxolone is an ideal anti-seizure treatment because it can be safely used prospectively, with minimal or no adverse effects on the neonatal brain. PMID- 28878623 TI - Mechanisms of Spontaneous Climbing Fiber Discharge-Evoked Pauses and Output Modulation of Cerebellar Purkinje Cell in Mice. AB - Climbing fiber (CF) afferents modulate the frequency and patterns of cerebellar Purkinje cell (PC) simple spike (SS) activity, but its mechanism is unclear. In the present study, we investigated the mechanisms of spontaneous CF discharge evoked pauses and the output modulation of cerebellar PCs in urethane anesthetized mice using in vivo whole-cell recording techniques and pharmacological methods. Under voltage-clamp recording conditions, spontaneous CF discharge evoked strong inward currents followed by small conductance calcium activated potassium (SK) channels that mediated outward currents. The application of a GABAA receptor antagonist did not significantly alter the spontaneous SS firing rate, although an AMPA receptor blocker abolished complex spike (CS) activity and induced significantly increased SS firing rates and a decreased coefficient of variation (CV) SS value. Either removal of extracellular calcium or chelated intracellular calcium induced a decrease in amplitude of CS-evoked after-hyperpolarization (AHP) potential accompanied by an increase in SS firing rate. In addition, blocking SK channels activity with a selective antagonist, dequalinium decreased the amplitude of AHP and increased SS firing rate. Moreover, we found repeated CF stimulation at 1 Hz induced a significant decrease in the spontaneous firing rate of SS, and accompanied with an increase in CV of SS in cerebellar slices, which was also abolished by dequalinium. These results indicated that the spontaneous CF discharge contributed to decreasing SS firing rate via activation of SK channels in the cerebellar PCs in vivo in mice. PMID- 28878626 TI - MAP Kinase Phosphatase 3 (MKP3) Preserves Norepinephrine Transporter Activity by Modulating ERK1/2 Kinase-Mediated Gene Expression. AB - The norepinephrine transporter (NET) mediates the clearance of norepinephrine (NE) from the extracellular space and is a target of therapeutic antidepressants and psychostimulants. Previously we identified a MAP kinase phosphatase 3 (MKP3), as an important modulator of protein kinase C (PKC) mediated internalization of the related dopamine transporter (DAT). Here we show that MKP3 decreases PKC mediated down regulation of NET expressed in PC12 cells. We demonstrate that this process involves a PKC-stimulated decrease of NET surface expression that is dependent on dynamin. Surprisingly, MAP kinase inhibitors have no effect on the PKC-mediated regulation of NET activity, suggesting that, like PKC-mediated regulation of the DAT, the acute activation of MAP kinases is not likely to be involved. To elucidate potential mechanisms we used a substrate trap-based assay to identify extracellular-signal-regulated kinase (ERK)1/2 as the predominant substrate of MKP3. Furthermore we also established that brief chemical stabilization of a modified destabilized MKP3 does not alter PKC-mediated down regulation of NET. Finally, the expression of a dominant negative version of H Ras, an upstream activator of ERK1/2, abolishes phorbol 12-myristate 13-acetate (PMA)-mediated down regulation of NET in a manner similar to MKP3. Taken together we propose that chronic MKP3 expression regulates surface NET through the sustained inhibition of ERK1/2 MAP kinase signaling that alters gene expression in PC12 cells. This is supported by gene expression data from naive and MKP3 expressing PC12 cells that reveal robust decreases in gene expression of several genes in the MKP3-tranfected cells. Interestingly, caveolin-1, a protein with a critical role in membrane protein trafficking is down regulated by MKP3 expression. We further show that selective silencing of the caveolin-1 gene in naive PC12 cells attenuates PKC-mediated downregulation of NET activity, consistent with a potential role for caveolins in regulating NET surface expression. In summary, these results suggest that chronic MKP3 expression alters the expression of genes in PC12 cells that are involved in the regulation of NET surface expression. PMID- 28878625 TI - Non-autonomous Cellular Responses to Ototoxic Drug-Induced Stress and Death. AB - The first major recognition of drug-induced hearing loss can be traced back more than seven decades to the development of streptomycin as an antimicrobial agent. Since then at least 130 therapeutic drugs have been recognized as having ototoxic side-effects. Two important classes of ototoxic drugs are the aminoglycoside antibiotics and the platinum-based antineoplastic agents. These drugs save the lives of millions of people worldwide, but they also cause irreparable hearing loss. In the inner ear, sensory hair cells (HCs) and spiral ganglion neurons (SGNs) are important cellular targets of these drugs, and most mechanistic studies have focused on the cell-autonomous responses of these cell types in response to ototoxic stress. Despite several decades of studies on ototoxicity, important unanswered questions remain, including the cellular and molecular mechanisms that determine whether HCs and SGNs will live or die when confronted with ototoxic challenge. Emerging evidence indicates that other cell types in the inner ear can act as mediators of survival or death of sensory cells and SGNs. For example, glia-like supporting cells (SCs) can promote survival of both HCs and SGNs. Alternatively, SCs can act to promote HC death and inhibit neural fiber expansion. Similarly, tissue resident macrophages activate either pro-survival or pro-death signaling that can influence HC survival after exposure to ototoxic agents. Together these data indicate that autonomous responses that occur within a stressed HC or SGN are not the only (and possibly not the primary) determinants of whether the stressed cell ultimately lives or dies. Instead non-cell autonomous responses are emerging as significant determinants of HC and SGN survival vs. death in the face of ototoxic stress. The goal of this review is to summarize the current evidence on non-cell-autonomous responses to ototoxic stress and to discuss ways in which this knowledge may advance the development of therapies to reduce hearing loss caused by these drugs. PMID- 28878627 TI - Optic Nerve Degeneration after Retinal Ischemia/Reperfusion in a Rodent Model. AB - Retinal ischemia is a common pathomechanism in many ocular disorders such as age related macular degeneration (AMD), diabetic retinopathy, glaucoma or retinal vascular occlusion. Several studies demonstrated that ischemia/reperfusion (I/R) leads to morphological and functional changes of different retinal cell types. However, little is known about the ischemic effects on the optic nerve. The goal of this study was to evaluate these effects. Ischemia was induced by raising the intraocular pressure (IOP) in one eye of rats to 140 mmHg for 1 h followed by natural reperfusion. After 21 days, histological as well as quantitative real time PCR (qRT-PCR) analyses of optic nerves were performed. Ischemic optic nerves showed an infiltration of cells and also degeneration with signs of demyelination. Furthermore, a migration and an activation of microglia could be observed histologically as well as on mRNA level. In regard to macroglia, a trend toward gliosis could be noted after ischemia induction by vimentin staining. Additionally, an up-regulation of glial fibrillary acidic protein (GFAP) mRNA was found in ischemic optic nerves. Counting of oligodendrocyte transcription factor 2 positive (Olig2+) cells revealed a decrease of oligodendrocytes in the ischemic group. Also, myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) mRNA expression was down-regulated after induction of I/R. On immunohistological level, a decrease of MOG was detectable in ischemic optic nerves as well. In addition, SMI-32 stained neurofilaments of longitudinal optic nerve sections showed a strong structural damage of the ischemic optic nerves in comparison to controls. Consequently, retinal ischemia impacts optic nerve degeneration. These findings could help to better understand the course of destruction in the optic nerve after an ischemic insult. Especially for therapeutic studies, the optic nerve is important because of its susceptibility to be damaged as a result to retinal ischemic injury and also its connecting function between the eye and the brain. So, future drug screenings should target not only the retina, but also the functionality and structure of the optic nerve. In the future, these results could lead to the development of new therapeutic strategies for treatment of ischemic injury. PMID- 28878628 TI - Early Correlated Network Activity in the Hippocampus: Its Putative Role in Shaping Neuronal Circuits. AB - Synchronized neuronal activity occurring at different developmental stages in various brain structures represents a hallmark of developmental circuits. This activity, which differs in its specific patterns among animal species may play a crucial role in de novo formation and in shaping neuronal networks. In the rodent hippocampus in vitro, the so-called giant depolarizing potentials (GDPs) constitute a primordial form of neuronal synchrony preceding more organized forms of activity such as oscillations in the theta and gamma frequency range. GDPs are generated at the network level by the interaction of the neurotransmitters glutamate and GABA which, immediately after birth, exert both a depolarizing and excitatory action on their targets. GDPs are triggered by GABAergic interneurons, which in virtue of their extensive axonal branching operate as functional hubs to synchronize large ensembles of cells. Intrinsic bursting activity, driven by a persistent sodium conductance and facilitated by the low expression of Kv7.2 and Kv7.3 channel subunits, responsible for IM, exerts a permissive role in GDP generation. Here, we discuss how GDPs are generated in a probabilistic way when neuronal excitability within a local circuit reaches a certain threshold and how GDP-associated calcium transients act as coincident detectors for enhancing synaptic strength at emerging GABAergic and glutamatergic synapses. We discuss the possible in vivo correlate of this activity. Finally, we debate recent data showing how, in several animal models of neuropsychiatric disorders including autism, a GDPs dysfunction is associated to morphological alterations of neuronal circuits and behavioral deficits reminiscent of those observed in patients. PMID- 28878629 TI - Higher Arc Nucleus-to-Cytoplasm Ratio during Sleep in the Superficial Layers of the Mouse Cortex. AB - The activity-regulated cytoskeleton associated protein Arc is strongly and quickly upregulated by neuronal activity, synaptic potentiation and learning. Arc entry in the synapse is followed by the endocytosis of glutamatergic AMPA receptors (AMPARs), and its nuclear accumulation has been shown in vitro to result in a small decline in the transcription of the GluA1 subunit of AMPARs. Since these effects result in a decline in synaptic strength, we asked whether a change in Arc dynamics may temporally correlate with sleep-dependent GluA1 down regulation. We measured the ratio of nuclear to cytoplasmic Arc expression (Arc Nuc/Cyto) in the cerebral cortex of EGFP-Arc transgenic mice that were awake most of the night and then perfused immediately before lights on (W mice), or were awake most of the night and then allowed to sleep (S mice) or sleep deprived (SD mice) for the first 2 h of the light phase. In primary motor cortex (M1), neurons with high levels of nuclear Arc (High Arc cells) were present in all mice, but in these cells Arc Nuc/Cyto was higher in S mice than in W mice and, importantly, ~15% higher in S mice than in SD mice collected at the same time of day, ruling out circadian effects. Greater Arc Nuc/Cyto with sleep was observed in the superficial layers of M1, but not in the deep layers. In High Arc cells, Arc Nuc/Cyto was also ~15%-30% higher in S mice than in W and SD mice in the superficial layers of primary somatosensory cortex (S1) and cingulate cortex area 1 (Cg1). In High Arc Cells of Cg1, Arc Nuc/Cyto and cytoplasmic levels of GluA1 immunoreactivities in the soma were also negatively correlated, independent of behavioral state. Thus, Arc moves to the nucleus during both sleep and wake, but its nuclear to cytoplasmic ratio increases with sleep in the superficial layers of several cortical areas. It remains to be determined whether the relative increase in nuclear Arc contributes significantly to the overall decline in the strength of excitatory synapses that occurs during sleep. Similarly, it remains to be determined whether the entry of Arc into specific synapses is gated by sleep. PMID- 28878630 TI - Temporal Expression of Wnt1 Defines the Competency State and Terminal Identity of Progenitors in the Developing Cochlear Nucleus and Inferior Colliculus. AB - The auditory system contains a diverse array of interconnected anatomical structures that mediate the perception of sound. The cochlear nucleus of the hindbrain serves as the initial site of convergence for auditory stimuli, while the inferior colliculus of the midbrain serves as an integration and relay station for all ascending auditory information. We used Genetic Inducible Fate Mapping (GIFM) to determine how the timing of Wnt1 expression is related to the competency states of auditory neuron progenitors. We demonstrate that the Wnt1 lineage defines progenitor pools of auditory neurons in the developing midbrain and hindbrain. The timing of Wnt1 expression specifies unique cell types during embryogenesis and follows a mixed model encompassing a brief epoch of de novo expression followed by rapid and progressive lineage restriction to shape the inferior colliculus. In contrast, Wnt1 fate mapping of the embryonic hindbrain revealed de novo induction of Wnt1 in auditory hindbrain progenitors, which is related to the development of biochemically distinct neurons in the cochlear nucleus. Thus, we uncovered two modes of lineage allocation that explain the relationship between the timing of Wnt1 expression and the development of the cochlear nucleus and the inferior colliculus. Finally, our analysis of Wnt1sw/sw mutant mice demonstrated a functional requirement of Wnt1 for the development of auditory midbrain and hindbrain neurons. Collectively, our study provides a deeper understanding of Wnt1 lineage allocation and function in mammalian brain development. PMID- 28878624 TI - Cell Death in the Developing Brain after Hypoxia-Ischemia. AB - Perinatal insults such as hypoxia-ischemia induces secondary brain injury. In order to develop the next generation of neuroprotective therapies, we urgently need to understand the underlying molecular mechanisms leading to cell death. The cell death mechanisms have been shown to be quite different in the developing brain compared to that in the adult. The aim of this review is update on what cell death mechanisms that are operating particularly in the setting of the developing CNS. In response to mild stress stimuli a number of compensatory mechanisms will be activated, most often leading to cell survival. Moderate-to severe insults trigger regulated cell death. Depending on several factors such as the metabolic situation, cell type, nature of the stress stimulus, and which intracellular organelle(s) are affected, the cell undergoes apoptosis (caspase activation) triggered by BAX dependent mitochondrial permeabilzation, necroptosis (mixed lineage kinase domain-like activation), necrosis (via opening of the mitochondrial permeability transition pore), autophagic cell death (autophagy/Na+, K+-ATPase), or parthanatos (poly(ADP-ribose) polymerase 1, apoptosis-inducing factor). Severe insults cause accidental cell death that cannot be modulated genetically or by pharmacologic means. However, accidental cell death leads to the release of factors (damage-associated molecular patterns) that initiate systemic effects, as well as inflammation and (regulated) secondary brain injury in neighboring tissue. Furthermore, if one mode of cell death is inhibited, another route may step in at least in a scenario when upstream damaging factors predominate over protective responses. The provision of alternative routes through which the cell undergoes death has to be taken into account in the hunt for novel brain protective strategies. PMID- 28878633 TI - The Role of Monoaminergic Neurotransmission for Metabolic Control in the Fruit Fly Drosophila Melanogaster. AB - Hormones control various metabolic traits comprising fat deposition or starvation resistance. Here we show that two invertebrate neurohormones, octopamine (OA) and tyramine (TA) as well as their associated receptors, had a major impact on these metabolic traits. Animals devoid of the monoamine OA develop a severe obesity phenotype. Using flies defective in the expression of receptors for OA and TA, we aimed to decipher the contributions of single receptors for these metabolic phenotypes. Whereas those animals impaired in octbeta1r, octbeta2r and tar1 share the obesity phenotype of OA-deficient (tbetah-deficient) animals, the octbeta1r, octbeta2r deficient flies showed reduced insulin release, which is opposed to the situation found in tbetah-deficient animals. On the other hand, OAMB deficient flies were leaner than controls, implying that the regulation of this phenotype is more complex than anticipated. Other phenotypes seen in tbetah-deficient animals, such as the reduced ability to perform complex movements tasks can mainly be attributed to the octbeta2r. Tissue-specific RNAi experiments revealed a very complex interorgan communication leading to the different metabolic phenotypes observed in OA or OA and TA-deficient flies. PMID- 28878632 TI - The Influence of Regional Distribution and Pharmacologic Specificity of GABAAR Subtype Expression on Anesthesia and Emergence. AB - Anesthetics produce unconsciousness by modulating ion channels that control neuronal excitability. Research has shown that specific GABAA receptor (GABAAR) subtypes in particular regions of the central nervous system contribute to different hyperpolarizing conductances, and behaviorally to distinct components of the anesthetized state. The expression of these receptors on the neuron cell surface, and thus the strength of inhibitory neurotransmission, is dynamically regulated by intracellular trafficking mechanisms. Pharmacologic or activity based perturbations to these regulatory systems have been implicated in pathology of several neurological conditions, and can alter the individual response to anesthesia. Furthermore, studies are beginning to uncover how anesthetic exposure itself elicits enduring changes in subcellular physiology, including the processes that regulate ion channel trafficking. Here, we review the mechanisms that determine GABAAR surface expression, and elaborate on influences germane to anesthesia and emergence. We address known trafficking differences between the intrasynaptic receptors that mediate phasic current and the extra-synaptic receptors mediating tonic current. We also describe neurophysiologic consequences and network-level abnormalities in brain function that result from receptor trafficking aberrations. We hypothesize that the relationship between commonly used anesthetic agents and GABAAR surface expression has direct consequences on mature functioning neural networks and by extension ultimately influence the outcome of patients that undergo general anesthesia. Rational design of new anesthetics, anesthetic techniques, EEG-based monitoring strategies, or emergence treatments will need to take these effects into consideration. PMID- 28878631 TI - A Laminar Organization for Selective Cortico-Cortical Communication. AB - The neocortex is central to mammalian cognitive ability, playing critical roles in sensory perception, motor skills and executive function. This thin, layered structure comprises distinct, functionally specialized areas that communicate with each other through the axons of pyramidal neurons. For the hundreds of such cortico-cortical pathways to underlie diverse functions, their cellular and synaptic architectures must differ so that they result in distinct computations at the target projection neurons. In what ways do these pathways differ? By originating and terminating in different laminae, and by selectively targeting specific populations of excitatory and inhibitory neurons, these "interareal" pathways can differentially control the timing and strength of synaptic inputs onto individual neurons, resulting in layer-specific computations. Due to the rapid development in transgenic techniques, the mouse has emerged as a powerful mammalian model for understanding the rules by which cortical circuits organize and function. Here we review our understanding of how cortical lamination constrains long-range communication in the mammalian brain, with an emphasis on the mouse visual cortical network. We discuss the laminar architecture underlying interareal communication, the role of neocortical layers in organizing the balance of excitatory and inhibitory actions, and highlight the structure and function of layer 1 in mouse visual cortex. PMID- 28878634 TI - Localized vs. Systematic Neurodegeneration: A Paradigm Shift in Understanding Neurodegenerative Diseases. PMID- 28878635 TI - Alcohol Intake Increases in Adolescent C57BL/6J Mice during Intermittent Cycles of Phase-Delayed, Long-Light Conditions. AB - : Adolescents naturally go to bed and awaken late, but are forced to awaken early for school and work. This leads to "social jetlag", a state of circadian desynchrony (CD), in which internal biological rhythms are out of sync with behavioral rhythms. CD is associated with increased alcohol intake in adults, but has been less well-studied in adolescents. The goal of this study was to model adolescent alcohol intake during similar CD conditions in male C57BL/6J mice. Free access alcohol intake, water intake and wheel-running activity were measured during a normal 12HR photoperiod or during alternating photoperiod (Experiment 1: 12 h light for 4 days followed by 18 h light for 3 days, with dark (activity onset) delayed 9 h during the 18HR photoperiod; Experiment 2: 12 h light for 4 days followed by 6 h light for 3 days, with dark onset delayed 3 h during the 6HR photoperiod). In Experiment 1, CD produced a small but significant increase in the total alcohol intake per day as well as in intake in bouts, with the greatest increase over controls in the hours following the 6HR dark period. Additionally, the pattern of alcohol intake in bouts shifted to increase alcohol intake during the shorter dark period. In Experiment 2, the opposite effect occurred-the longer dark cycle led to lower alcohol drinking in the second half of the dark period. However, in Experiment 2, CD produced no significant changes in either total alcohol intake or alcohol intake in bouts. CONCLUSION: shifts in the light cycle that disrupt the regular pattern of day and night, and increase the length of the night phase, are sufficient to increase both drinking in bouts and restricted drinking in adolescent mice, modeling increased alcohol intake in adolescents during CD. PMID- 28878636 TI - Do Insects Have Emotions? Some Insights from Bumble Bees. AB - While our conceptual understanding of emotions is largely based on human subjective experiences, research in comparative cognition has shown growing interest in the existence and identification of "emotion-like" states in non human animals. There is still ongoing debate about the nature of emotions in animals (especially invertebrates), and certainly their existence and the existence of certain expressive behaviors displaying internal emotional states raise a number of exciting and challenging questions. Interestingly, at least superficially, insects (bees and flies) seem to fulfill the basic requirements of emotional behavior. Yet, recent works go a step further by adopting terminologies and interpretational frameworks that could have been considered as crude anthropocentrism and that now seem acceptable in the scientific literature on invertebrate behavior and cognition. This change in paradigm requires, therefore, that the question of emotions in invertebrates is reconsidered from a cautious perspective and with parsimonious explanations. Here we review and discuss this controversial topic based on the recent finding that bumblebees experience positive emotions while experiencing unexpected sucrose rewards, but also incorporating a broader survey of recent literature in which similar claims have been done for other invertebrates. We maintain that caution is warranted before attributing emotion-like states to honey bees and bumble bees as some experimental caveats may undermine definitive conclusions. We suggest that interpreting many of these findings in terms of motivational drives may be less anthropocentrically biased and more cautious, at least until more careful experiments warrant the use of an emotion-related terminology. PMID- 28878637 TI - Corrigendum: The Australian Bogong Moth Agrotis infusa: A Long-Distance Nocturnal Navigator. AB - [This corrects the article on p. 77 in vol. 10, PMID: 27147998.]. PMID- 28878638 TI - Evolutionary and Modern Image Content Differentially Influence the Processing of Emotional Pictures. AB - From an evolutionary perspective, environmental threats relevant for survival constantly challenged human beings. Current research suggests the evolution of a fear processing module in the brain to cope with these threats. Recently, humans increasingly encountered modern threats (e.g., guns or car accidents) in addition to evolutionary threats (e.g., snakes or predators) which presumably required an adaptation of perception and behavior. However, the neural processes underlying the perception of these different threats remain to be elucidated. We investigated the effect of image content (i.e., evolutionary vs. modern threats) on the activation of neural networks of emotion processing. During functional magnetic resonance imaging (fMRI) 41 participants watched affective pictures displaying evolutionary-threatening, modern-threatening, evolutionary-neutral and modern-neutral content. Evolutionary-threatening stimuli evoked stronger activations than modern-threatening stimuli in left inferior frontal gyrus and thalamus, right middle frontal gyrus and parietal regions as well as bilaterally in parietal regions, fusiform gyrus and bilateral amygdala. We observed the opposite effect, i.e., higher activity for modern-threatening than for evolutionary-threatening stimuli, bilaterally in the posterior cingulate and the parahippocampal gyrus. We found no differences in subjective arousal ratings between the two threatening conditions. On the valence scale though, subjects rated modern-threatening pictures significantly more negative than evolutionary threatening pictures, indicating a higher level of perceived threat. The majority of previous studies show a positive relationship between arousal rating and amygdala activity. However, comparing fMRI results with behavioral findings we provide evidence that neural activity in fear processing areas is not only driven by arousal or valence, but presumably also by the evolutionary content of the stimulus. This has also fundamental methodological implications, in the sense to suggest a more elaborate classification of stimulus content to improve the validity of experimental designs. PMID- 28878639 TI - Differential Associations between Cortical Thickness and Striatal Dopamine in Treatment-Naive Adults with ADHD vs. Healthy Controls. AB - Alterations in catecholamine signaling and cortical morphology have both been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, possible links between the two remain unstudied. Here, we report exploratory analyses of cortical thickness and its relation to striatal dopamine transmission in treatment-naive adults with ADHD and matched healthy controls. All participants had one magnetic resonance imaging (MRI) and two [11C]raclopride positron emission tomography scans. Associations between frontal cortical thickness and the magnitude of d-amphetamine-induced [11C]raclopride binding changes were observed that were divergent in the two groups. In the healthy controls, a thicker cortex was associated with less dopamine release; in the ADHD participants the converse was seen. The same divergence was seen for baseline D2/3 receptor availability. In healthy volunteers, lower D2/3 receptor availability was associated with a thicker cortex, while in the ADHD group lower baseline D2/3 receptor availability was associated with a thinner cortex. Individual differences in cortical thickness in these regions correlated with ADHD symptom severity. Together, these findings add to the evidence of associations between dopamine transmission and cortical morphology, and suggest that these relationships are altered in treatment-naive adults with ADHD. PMID- 28878640 TI - Neural Pattern Similarity in the Left IFG and Fusiform Is Associated with Novel Word Learning. AB - Previous studies have revealed that greater neural pattern similarity across repetitions is associated with better subsequent memory. In this study, we used an artificial language training paradigm and representational similarity analysis to examine whether neural pattern similarity across repetitions before training was associated with post-training behavioral performance. Twenty-four native Chinese speakers were trained to learn a logographic artificial language for 12 days and behavioral performance was recorded using the word naming and picture naming tasks. Participants were scanned while performing a passive viewing task before training, after 4-day training and after 12-day training. Results showed that pattern similarity in the left pars opercularis (PO) and fusiform gyrus (FG) before training was negatively associated with reaction time (RT) in both word naming and picture naming tasks after training. These results suggest that neural pattern similarity is an effective neurofunctional predictor of novel word learning in addition to word memory. PMID- 28878641 TI - The Emergence of Language in the Hominin Lineage: Perspectives from Fossil Endocasts. PMID- 28878642 TI - Binary Associative Memories as a Benchmark for Spiking Neuromorphic Hardware. AB - Large-scale neuromorphic hardware platforms, specialized computer systems for energy efficient simulation of spiking neural networks, are being developed around the world, for example as part of the European Human Brain Project (HBP). Due to conceptual differences, a universal performance analysis of these systems in terms of runtime, accuracy and energy efficiency is non-trivial, yet indispensable for further hard- and software development. In this paper we describe a scalable benchmark based on a spiking neural network implementation of the binary neural associative memory. We treat neuromorphic hardware and software simulators as black-boxes and execute exactly the same network description across all devices. Experiments on the HBP platforms under varying configurations of the associative memory show that the presented method allows to test the quality of the neuron model implementation, and to explain significant deviations from the expected reference output. PMID- 28878643 TI - Homologous Basal Ganglia Network Models in Physiological and Parkinsonian Conditions. AB - The classical model of basal ganglia has been refined in recent years with discoveries of subpopulations within a nucleus and previously unknown projections. One such discovery is the presence of subpopulations of arkypallidal and prototypical neurons in external globus pallidus, which was previously considered to be a primarily homogeneous nucleus. Developing a computational model of these multiple interconnected nuclei is challenging, because the strengths of the connections are largely unknown. We therefore use a genetic algorithm to search for the unknown connectivity parameters in a firing rate model. We apply a binary cost function derived from empirical firing rate and phase relationship data for the physiological and Parkinsonian conditions. Our approach generates ensembles of over 1,000 configurations, or homologies, for each condition, with broad distributions for many of the parameter values and overlap between the two conditions. However, the resulting effective weights of connections from or to prototypical and arkypallidal neurons are consistent with the experimental data. We investigate the significance of the weight variability by manipulating the parameters individually and cumulatively, and conclude that the correlation observed between the parameters is necessary for generating the dynamics of the two conditions. We then investigate the response of the networks to a transient cortical stimulus, and demonstrate that networks classified as physiological effectively suppress activity in the internal globus pallidus, and are not susceptible to oscillations, whereas parkinsonian networks show the opposite tendency. Thus, we conclude that the rates and phase relationships observed in the globus pallidus are predictive of experimentally observed higher level dynamical features of the physiological and parkinsonian basal ganglia, and that the multiplicity of solutions generated by our method may well be indicative of a natural diversity in basal ganglia networks. We propose that our approach of generating and analyzing an ensemble of multiple solutions to an underdetermined network model provides greater confidence in its predictions than those derived from a unique solution, and that projecting such homologous networks on a lower dimensional space of sensibly chosen dynamical features gives a better chance than a purely structural analysis at understanding complex pathologies such as Parkinson's disease. PMID- 28878644 TI - Coexisting Behaviors of Asymmetric Attractors in Hyperbolic-Type Memristor based Hopfield Neural Network. AB - A new hyperbolic-type memristor emulator is presented and its frequency-dependent pinched hysteresis loops are analyzed by numerical simulations and confirmed by hardware experiments. Based on the emulator, a novel hyperbolic-type memristor based 3-neuron Hopfield neural network (HNN) is proposed, which is achieved through substituting one coupling-connection weight with a memristive synaptic weight. It is numerically shown that the memristive HNN has a dynamical transition from chaotic, to periodic, and further to stable point behaviors with the variations of the memristor inner parameter, implying the stabilization effect of the hyperbolic-type memristor on the chaotic HNN. Of particular interest, it should be highly stressed that for different memristor inner parameters, different coexisting behaviors of asymmetric attractors are emerged under different initial conditions, leading to the existence of multistable oscillation states in the memristive HNN. Furthermore, by using commercial discrete components, a nonlinear circuit is designed and PSPICE circuit simulations and hardware experiments are performed. The results simulated and captured from the realization circuit are consistent with numerical simulations, which well verify the facticity of coexisting asymmetric attractors' behaviors. PMID- 28878646 TI - Continuous Timescale Long-Short Term Memory Neural Network for Human Intent Understanding. AB - Understanding of human intention by observing a series of human actions has been a challenging task. In order to do so, we need to analyze longer sequences of human actions related with intentions and extract the context from the dynamic features. The multiple timescales recurrent neural network (MTRNN) model, which is believed to be a kind of solution, is a useful tool for recording and regenerating a continuous signal for dynamic tasks. However, the conventional MTRNN suffers from the vanishing gradient problem which renders it impossible to be used for longer sequence understanding. To address this problem, we propose a new model named Continuous Timescale Long-Short Term Memory (CTLSTM) in which we inherit the multiple timescales concept into the Long-Short Term Memory (LSTM) recurrent neural network (RNN) that addresses the vanishing gradient problem. We design an additional recurrent connection in the LSTM cell outputs to produce a time-delay in order to capture the slow context. Our experiments show that the proposed model exhibits better context modeling ability and captures the dynamic features on multiple large dataset classification tasks. The results illustrate that the multiple timescales concept enhances the ability of our model to handle longer sequences related with human intentions and hence proving to be more suitable for complex tasks, such as intention recognition. PMID- 28878645 TI - Adaptive Control Strategies for Interlimb Coordination in Legged Robots: A Review. AB - Walking animals produce adaptive interlimb coordination during locomotion in accordance with their situation. Interlimb coordination is generated through the dynamic interactions of the neural system, the musculoskeletal system, and the environment, although the underlying mechanisms remain unclear. Recently, investigations of the adaptation mechanisms of living beings have attracted attention, and bio-inspired control systems based on neurophysiological findings regarding sensorimotor interactions are being developed for legged robots. In this review, we introduce adaptive interlimb coordination for legged robots induced by various factors (locomotion speed, environmental situation, body properties, and task). In addition, we show characteristic properties of adaptive interlimb coordination, such as gait hysteresis and different time-scale adaptations. We also discuss the underlying mechanisms and control strategies to achieve adaptive interlimb coordination and the design principle for the control system of legged robots. PMID- 28878647 TI - Adenocarcinoma of the Lung Acquiring Resistance to Afatinib by Transformation to Small Cell Carcinoma: A Case Report. AB - A 65-year-old woman visited our hospital due to right chest pain and dyspnea on exertion. Chest radiography revealed decreased permeability of the right lung. Computed tomography demonstrated a huge mass in the right upper lobe and right pleural effusion. Right pleural effusion cytology yielded a diagnosis of adenocarcinoma and was positive for mutation of epidermal growth factor receptor (EGFR; exon 21 L858R). Afatinib was selected for the initial treatment. Multiple tumors regressed remarkably, but then rapidly progressed 3 months later. We performed re-biopsy to detect the mechanism of resistance to afatinib. Histopathology revealed a mixture of small cell carcinoma (SCC) and adenocarcinoma harboring same EGFR mutation. To the best of our knowledge, this is the first report of transformation to SCC after treatment with afatinib. PMID- 28878648 TI - Acquired Pulmonary Arteriovenous Fistula within Metastasis from Choriocarcinoma: A Case Report. AB - Choriocarcinoma is a highly malignant neoplasm arising from the trophoblast of a human pregnancy, which may have distant spread to multiple organs, particularly to the lung. We report a case of a pulmonary arteriovenous fistula that developed after chemotherapy within a choriocarcinoma metastasis. A 24-year-old female with a history of uterine choriocarcinoma presented with multiple hypervascular pulmonary nodules on the initial chest computed tomography (CT) scan, consistent with lung metastases. Four months after chemotherapy, follow-up chest CT revealed a decrease in the size and vascularity of the lung metastases, except for 1 nodule that persisted with marked contrast enhancement and developed a communication with a pulmonary artery and vein. These findings were consistent with an acquired arteriovenous fistula. Physicians should be aware of the risk of acquired arteriovenous fistula in pulmonary metastases after chemotherapy because it can lead to a right-to-left shunt, pulmonary hemorrhage, and paradoxical emboli. It is also important for the definition of therapeutic planning, in order to avoid it being misdiagnosed as a site of disease progression. PMID- 28878649 TI - A Symptomatic Case of Adenomatous Ductal Proliferation/Hyperplasia with a Large Cystic Lesion. AB - Adenomatous ductal proliferation/hyperplasia (ADP/H) of the salivary gland, a rare asymptomatic nonneoplastic lesion that histopathologically resembles basal cell adenoma, is typically incidentally identified in resected specimens of other salivary diseases such as tumors and chronic sialadenitis. A 70-year-old male was referred to our hospital with a 9-month history of continuous swelling in the left parotid region. A physical examination revealed a soft mass in the left parotid gland, which was identified as a cystic mass by computed tomography. A parotid tumor with cystic components was suspected, and partial parotidectomy was performed under general anesthesia. The histopathological findings were consistent with the diagnosis of ADP/H of the salivary gland. This case report emphasizes the necessity for a proper diagnosis of ADP/H of the salivary gland. Further large case series are required for a modification of the definition of ADP/H for its correct diagnosis. PMID- 28878650 TI - Interstitial Lung Disease Following Single-Agent Nanoparticle Albumin-Bound Paclitaxel Treatment in Patients with Advanced Non-Small Cell Lung Cancer. AB - Interstitial lung disease (ILD) is a serious and potentially fatal adverse event in lung cancer therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a novel, solvent-free formulation of paclitaxel (PTX). Although the incidence of nab-PTX-induced ILD is not clear, it is generally considered that this formulation presents a similar risk of developing ILD as PTX. Here, we report 3 patients who developed severe ILD following treatment with nab-PTX. We draw attention to the risk of developing drug-induced ILD following nab-PTX treatment, and highlight that this novel formulation might therefore not be as safe as PTX with respect to the development of ILD. PMID- 28878652 TI - Solitary Skeletal Muscle Metastasis as First Site of Recurrence of Cervical Cancer: A Case Report. AB - Cervical cancer is the fourth most common cancer in women worldwide, with a large majority of prevalence (85%) in developing countries. As of 2012, it accounts for 7.5% of all female cancer deaths. Despite its high prevalence, skeletal muscle metastasis from cervical cancer is extremely uncommon. In our extensive literature search, we were able to find only 8 cases where skeletal muscle metastasis was the only site of recurrence. We report a case of a 52-year-old African-American woman with a past medical history of cervical cancer (stage IIIB) who presented with pain and swelling in her left upper arm over the preceding 2 months. MRI of the left upper arm showed a solid well-circumscribed mass measuring 7.0 * 2.8 * 2.5 cm, deep to the biceps. Biopsy of the mass revealed a metastatic squamous cell carcinoma that was p16-positive. PET scan showed that the lesion was the sole site of metastasis. She received local radiation with concurrent chemotherapy. Follow-up MRI 6 months after the completion of therapy showed resolution of the mass. She has remained disease free for the last 24 months as evidenced by a PET/CT scan in May 2016. In this case report, we discuss the role of imaging and pathology in the diagnosis of a solitary metastatic lesion. This case also emphasizes the importance of a close follow-up which aids in early intervention, increasing overall survival. PMID- 28878651 TI - Ischemic Colitis Associated with Paclitaxel and Carboplatin Combination. AB - A 62-year-old white female with a history of early-stage triple-negative breast cancer on a combination of carboplatin and paclitaxel in the adjuvant setting presented with lower gastrointestinal bleeding. She tolerated 4 cycles of dose dense adriamycin/cyclophosphamide with no major symptoms. After 6 cycles of weekly paclitaxel in combination with carboplatin every 3 weeks, she presented with diarrhea and lower gastrointestinal bleeding. Colonosopic examination showed erythema and inflammation in the splenic flexure, descending colon, and sigmoid colon consistent with ischemic colitis. Pathology favored the same diagnosis. She was treated conservatively with intravenous fluids and bowel rest. Chemotherapy was held for 2 weeks and resumed after recovery without carboplatin. She was able to tolerate the remaining 6 cycles of paclitaxel with no recurrence of her symptoms. PMID- 28878653 TI - Correlation between Tumor-Infiltrating Lymphocytes and Pathological Response in Locally Advanced Breast Cancer Patients Who Received Neoadjuvant Chemotherapy in H. Adam Malik General Hospital. AB - BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are emerging as biomarkers mediating tumor response to treatments. Earlier studies have provided evidence that the level of TILs has prognostic value, particularly in triple-negative and human epidermal growth factor receptor-2-positive breast cancer. Moreover, the level of TILs has been associated with treatment outcome in patients undergoing neoadjuvant chemotherapy, and there is a strong correlation with pathologically complete response. In this study, we analyzed whether changes in TILs take place after neoadjuvant therapy and if they correlate with pathological response to treatment. PATIENTS AND METHODS: We retrospectively analyzed the specimen slides from the Department of Anatomic Pathology of H. Adam Malik General Hospital during 2011-2015. We identified 51 patients fulfilling the inclusion criteria of this study. The histological sections had already been evaluated by hematoxylin and eosin slides. They were reassessed by our pathologist for the percentage of intratumoral and stromal TILs. The correlation with pathological response of the tumor after neoadjuvant therapy was also studied in these patients. Each case was also defined as high- or low-TIL breast cancer adopting previously validated cutoffs. RESULTS: The mean age of the 51 patients was 49.22 years. The most frequent type of breast cancer histology was invasive ductal breast carcinoma in 49 (96%) patients, and there were 2 (4%) patients with lobular carcinoma. The histopathological grading for high TILs was grade 1 in 5 patients, grade 2 in 15 patients, and grade 3 in 3 patients. High TILs that had a pathologically complete response were found in 47.8% of patients, and low TILs were found in 28.8%. There was no significant correlation between TILs and pathological response in patients with neoadjuvant chemotherapy (p = 0.157). CONCLUSIONS: This research has not been able to demonstrate a significant correlation between TILs and pathological response in patients with locally advanced breast cancer who received neoadjuvant chemotherapy, but high TILs were more likely to have a complete response. Further information may prove useful for future biomarker trials. PMID- 28878655 TI - Dedifferentiated Liposarcoma in the Spermatic Cord Finally Diagnosed at 7th Resection of Recurrence: A Case Report and Bibliographic Consideration. AB - Liposarcoma in the spermatic cord is infrequent, and accurate diagnosis of histopathological subtype is often difficult in spite of the importance of differential diagnosis for adequate treatment. A 54-year-old man underwent left sided high orchiectomy with inguinal lymphadenectomy for a spermatic cord tumor in July 2006. The initial histopathological report diagnosed leiomyosarcoma in the spermatic cord. He then underwent surgeries for repeated recurrences a further 6 times between July 2008 and May 2014. Pathological finding at the 7th resection of the recurrent tumor was osteosarcoma, which was uncommon in the spermatic cord. With a thorough overview of all specimens, the histopathological diagnosis was finally confirmed as dedifferentiated liposarcoma because of a biphasic pattern in the specimen of high orchiectomy at the first resection. A biphasic pattern represents high-grade sarcoma like osteosarcoma and well differentiated liposarcoma, and is characteristic of dedifferentiated liposarcoma. Although the dedifferentiated type is one of poor prognosis, the diagnosing of liposarcoma histopathologically was found to be difficult throughout this case. In this report we discuss the accurate histopathological diagnosis of liposarcoma in the spermatic cord in order to prevent repeated recurrences based on a review of the literature, as well as the difficulty in recognizing dedifferentiated liposarcoma macroscopically and morphologically. Our experience suggests that, after much difficulty, accurate histopathological diagnosis of liposarcoma in the spermatic cord is still clinically challenging. PMID- 28878654 TI - Advanced Tracheal Adenoid Cystic Carcinoma with Thyroid Invasion Mimicking Thyroid Cancer Treated with Definitive Radiation: Case Report and Review of the Literature. AB - A 54-year-old female patient, a breast cancer survivor and a case of unresectable adenoid cystic carcinoma of the trachea, with thyroid invasion, presented with suprasternal neck swelling mimicking thyroid primary. A literature search was undertaken to highlight this rare presentation. There have been few reports in the literature describing tracheal adenoid cystic carcinoma involving the thyroid. PMID- 28878656 TI - Dramatic Response of a Metastatic Primary Small-Cell Carcinoma of the Pancreas to a Trial of Immunotherapy with Nivolumab: A Case Report. AB - Extrapulmonary small-cell neuroendocrine cancers are rare in clinical practice. They are frequently metastatic at the time of diagnosis with survival in months even with the most intensive treatment. So far, treatment recommendations for this group rely on data from the similar but more common small-cell carcinoma of the lungs. Immune checkpoint inhibitors are being investigated for the treatment of metastatic small-cell lung cancer with positive outcome. We applied the experience from these studies to a case of metastatic small-cell neuroendocrine cancer of the pancreas using nivolumab as a treatment of last resort. We noted a favorable and durable response suggesting that this may be superior to all currently available options for palliative treatment in a similar scenario. PMID- 28878657 TI - Targeted Approaches Applied to Uncommon Diseases: A Case of Salivary Duct Carcinoma Metastatic to the Brain Treated with the Multikinase Inhibitor Neratinib. AB - Salivary duct carcinoma is a rare malignancy associated with hormone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. Local surgical control is the cornerstone of therapy, but a subset of patients develops metastatic disease portending a poor prognosis and limited management options. Intracranial metastases are an uncommon manifestation and present a therapeutic challenge. We report the case of a 31-year-old male who presented with facial pain and swelling subsequently diagnosed with salivary duct carcinoma. Our patient underwent extensive locoregional resection and analysis of the tumor tissue demonstrated evidence of androgen receptor expression and HER2 overexpression. His course was complicated by metastatic extra- and intracranial recurrence despite combined modality treatment with radiation and chemotherapy followed by anti-HER2 monoclonal antibody therapy and androgen deprivation therapy. After exhausting standard treatment options, he received experimental therapy with a new small-molecule tyrosine kinase inhibitor, neratinib, with evidence of a transient clinical response and no significant adverse effects. This case exemplifies the potential and limitations of targeted therapy, particularly when applied to patients with rare diseases and presentations. PMID- 28878658 TI - Synchronous Endometrial and Ovarian Carcinoma: A Case Series. AB - Synchronous ovarian and endometrial cancer (SEOC) is a rare instance but it accounts for 50-70% of all synchronous female genital tract tumors. We report three cases of women who were diagnosed with SEOC and underwent surgical staging. All cases were of the endometrioid subtype, grade 1, both in the ovarian and endometrial component. Two of them were stage Ia/Ia, and the third was stage Ib/Ib. More than 2 years after the diagnosis, all patients were alive and recurrence-free. The present report critically discusses the main characteristics, risk factors, and management of patients with SEOCs. PMID- 28878659 TI - A Case of Cervical Carcinoid and Review of the Literature. AB - Uterine cervix carcinoids are distinct neuroendocrine cervical tumors, representing a comparatively small percentage of them. These well-differentiated neoplasms are far less prevalent than small- and large-cell carcinomas, characterized by a more favorable biological course. We report a case of a 43 year-old woman with a nonmetastatic cervical carcinoid, managed with radical hysterectomy. She still remains free of disease. Scant reports in the literature prohibit any reliable prediction of cervical carcinoid prognosis. Thus, prompt identification of the disease and subsequent therapeutic intervention could alter the final outcome. PMID- 28878660 TI - Long-Term Progression of Sensorineural Hearing Loss and Tinnitus after Combined Intensity-Modulated Radiation Therapy and Cisplatin-Based Chemotherapy for Nasopharyngeal Carcinoma: A Case Report. AB - Sensorineural hearing loss (SNHL) is a common adverse effect for nasopharyngeal carcinoma (NPC) patients treated with chemoradiotherapy. We report a case of 12 year follow-up from a patient with stage IIB NPC, treated in 2004 with intensity modulated radiotherapy and cisplatin-based chemotherapy. Pure-tone audiograms were conducted before treatment and at two other points in the 12-year period after treatment. Analysis of the patient's audiograms reveals that the development of high-frequency SNHL started after treatment and reached a plateau accompanied by tinnitus approximately 32 months after treatment conclusion. After the plateau, high-frequency SNHL continued to develop slowly in the next 10 years, possibly a long-term effect from radiation-induced microvascular change of the hearing apparatus. The continuous high-frequency hearing decline is associated with increased tinnitus pitch in the patient. With experience learned from this case, we recommend hearing tests at regular intervals for at least 3-5 years for NPC patients treated with chemoradiotherapy. Patients need to be educated about tinnitus and counseling can be offered when they begin to feel inconvenienced by tinnitus. These patients also need to be advised against exposure to noise that can aggravate the already compromised hearing apparatus, leading to further hearing loss and worsening tinnitus. Limiting the peak dose and total cumulative dose of cisplatin should be considered based on the patients' risk factors to achieve a balance between treatment efficacy and long term adverse effects. PMID- 28878661 TI - The Successful Treatment of Pulmonary Pleomorphic Carcinoma with Pembrolizumab: A Case Report. AB - Pulmonary pleomorphic carcinomas are rare malignant tumors, and no standard treatments have been established. We herein report the successful treatment of a patient with pulmonary pleomorphic carcinoma with pembrolizumab. A 51-year-old man who was a current smoker presented to our hospital due to dyspnea and hemosputum. Chest X-ray showed right-sided pneumothorax with pleural effusion; chest tube drainage was therefore performed. Computed tomography after chest tube drainage showed a cavitary nodule in the right upper lobe and right hilar and bilateral mediastinal lymphadenopathy. Surgery was performed for the diagnosis and treatment. He was eventually diagnosed with pulmonary pleomorphic carcinoma corresponding to clinical stage IVB (cT2aN2M1c [PLE, ADR, HEP]). The giant cells strongly expressed programmed death ligand-1, and the tumor proportion score was more than 50%. Therefore, pembrolizumab was introduced as the first-line therapy. After 3 cycles of pembrolizumab, his right hilar and bilateral mediastinal lymphadenopathy and pleural dissemination notably decreased. Pembrolizumab might be an effective therapy for pulmonary pleomorphic carcinoma. PMID- 28878662 TI - Epulis-Like Presentation of Gingival Renal Cancer Metastasis. AB - Mouth metastatic cancers are very rare and they usually represent the evidence of a widespread disease. Common primary tumors are lung carcinoma in men and breast carcinoma in women, followed by kidney cancer. In the oral soft tissues, the gingiva is the most common site, suggesting a possible role of inflammation in the attraction of circulating tumor cells. Oral metastasis has a serious prognosis. In this work, we describe the case of a 58-year-old man affected by renal cancer, who was brought to our attention for the appearance of a gingival swelling. Initially, the lesion was excised through a provisional clinical diagnosis of epulis. Subsequently, anatomopathological analysis showed a metastasis compatible with clear-cell carcinoma and specifically its renal origin was confirmed by immunohistochemical techniques. PMID- 28878663 TI - Subacute Cerebellar Degeneration due to a Paraneoplastic Phenomenon Associated with Metastatic Merkel Cell Carcinoma: A Case Report. AB - PURPOSE: The aim of this article is to illustrate the diagnostic challenges and management of paraneoplastic neurological syndromes in Merkel cell carcinoma. MATERIALS AND METHODS: We describe a previously functionally independent 85-year old woman who presented with subacute onset of dizziness and gait ataxia in the setting of metastatic Merkel cell carcinoma. RESULTS: Diagnosis was made on biopsy after positron emission tomography imaging revealed increased metabolic activity in 2 left inguinofemoral lymph nodes. Cerebrospinal fluid analysis was positive for anti-Hu on subsequent admission. Her functional status improved with methylprednisolone treatment and radiotherapy. CONCLUSION: The case highlights the challenge of the evaluation of patients who present with progressive cerebellar signs and the need to consider a paraneoplastic syndrome, especially in the setting of previous malignancy. PMID- 28878664 TI - A Novel PRKAR1A Mutation Identified in a Patient with Isolated Primary Pigmented Nodular Adrenocortical Disease. AB - Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing syndrome, especially the isolated form without Carney complex, associated with germline mutations in PRKAR1A, the protein kinase A regulatory subunit type 1 alpha gene. We report a 31-year-old female who presented with secondary amenorrhea, cushingoid appearance, and hypertension without Carney complex. Biochemical laboratory examinations confirmed the ACTH-independent adrenal Cushing syndrome with negative Liddle test. A small right adrenal adenoma of 0.8 cm was shown on computed tomography while magnetic resonance imaging revealed nodularity of both adrenal glands. The histological report confirmed PPNAD using laparoscopic right adrenalectomy, and subsequent left adrenalectomy was performed 6 months later. She had inherited heterozygosity of a novel germline mutation of the PRKAR1A gene (g.114213T>=G or c.709-5T>=G). This splice site mutation results in exon 8 skipping. Her father carrying the same mutation had no clinical features of either PPNAD or Carney complex. This novel PRKAR1A gene mutation, c.709-5T>=G, is reported here for the first time manifesting as an incomplete clinical expression of the isolated form of PPNAD and being inherited with low penetrance unlike other inherited mutations of the Carney complex which have a penetrance of almost 100%. PMID- 28878665 TI - Memory Alteration Test to Detect Amnestic Mild Cognitive Impairment and Early Alzheimer's Dementia in Population with Low Educational Level. AB - Background/Aims: Short tests to early detection of the cognitive impairment are necessary in primary care setting, particularly in populations with low educational level. The aim of this study was to assess the performance of Memory Alteration Test (M@T) to discriminate controls, patients with amnestic Mild Cognitive Impairment (aMCI) and patients with early Alzheimer's Dementia (AD) in a sample of individuals with low level of education. Methods: Cross-sectional study to assess the performance of the M@T (study test), compared to the neuropsychological evaluation (gold standard test) scores in 247 elderly subjects with low education level from Lima-Peru. The cognitive evaluation included three sequential stages: (1) screening (to detect cases with cognitive impairment); (2) nosological diagnosis (to determinate specific disease); and (3) classification (to differentiate disease subtypes). The subjects with negative results for all stages were considered as cognitively normal (controls). The test performance was assessed by means of area under the receiver operating characteristic (ROC) curve. We calculated validity measures (sensitivity, specificity and correctly classified percentage), the internal consistency (Cronbach's alpha coefficient), and concurrent validity (Pearson's ratio coefficient between the M@T and Clinical Dementia Rating (CDR) scores). Results: The Cronbach's alpha coefficient was 0.79 and Pearson's ratio coefficient was 0.79 (p < 0.01). The AUC of M@T to discriminate between early AD and aMCI was 99.60% (sensitivity = 100.00%, specificity = 97.53% and correctly classified = 98.41%) and to discriminate between aMCI and controls was 99.56% (sensitivity = 99.17%, specificity = 91.11%, and correctly classified = 96.99%). Conclusions: The M@T is a short test with a good performance to discriminate controls, aMCI and early AD in individuals with low level of education from urban settings. PMID- 28878666 TI - Weight Rich-Club Analysis in the White Matter Network of Late-Life Depression with Memory Deficits. AB - Patients with late-life depression (LLD) have a higher incident of developing dementia, especially individuals with memory deficits. However, little is known about the white matter characteristics of LLD with memory deficits (LLD-MD) in the human connectome, especially for the rich-club coefficient, which is an indicator that describes the organization pattern of hub in the network. To address this question, diffusion tensor imaging of 69 participants [15 LLD-MD patients; 24 patients with LLD with intact memory (LLD-IM); and 30 healthy controls (HC)] was applied to construct a brain network for each individual. A full-scale battery of neuropsychological tests were used for grouping, and evaluating executive function, processing speed and memory. Rich-club analysis and global network properties were utilized to describe the topological features in each group. Network-based statistics (NBS) were calculated to identify the impaired subnetwork in the LLD-MD group relative to that in the LLD-IM group. We found that compared with HC participants, patients with LLD (LLD-MD and LLD-IM) had relatively impaired rich-club organizations and rich-club connectivity. In addition, LLD-MD group exhibited lower feeder and local connective average strength than LLD-IM group. Furthermore, global network properties, such as the shortest path length, connective strength, efficiency and fault tolerant efficiency, were significantly decreased in the LLD-MD group relative to those in the LLD-IM and HC groups. According to NBS analysis, a subnetwork, including right cognitive control network (CCN) and corticostriatal circuits, were disrupted in LLD-MD patients. In conclusion, the disease effects of LLD were prevalent in rich-club organization. Feeder and local connections, especially in the subnetwork including right CCN and corticostriatal circuits, were further impaired in those with memory deficits. Global network properties were disrupted in LLD-MD patients relative to those in LLD-IM patients. PMID- 28878668 TI - Analysis of Regional Variation in the Scope of Eligibility Defined by Ages in Children's Medical Expense Subsidy Program in Japan. AB - Children's medical expense subsidy programs are programs run by local governments that use public monies to reduce or eliminate the copayments for children's medical treatment including pharmaceutical cost (typically 20% for preschoolers and 30% thereafter). Currently, all prefectures and municipalities in Japan provide subsidies for infants' and children's medical expenses, but scope on ages of eligibility, income limits, and copayment requirements vary. The fact that these programs are run by local governments has given rise to differences in the costs borne by households with children, depending on the jurisdiction in which they live. Therefore, although it would be desirable to gain society's understanding of such variation, the factors have not been fully studied. This analysis investigates what factors could impact such variation. In it, we looked at 219 municipalities in the prefectures in the Kanto region, focusing on the gap from the average age eligibility of municipalities, which reflects the scope of eligibility. Neither a regression analysis using the instrumental variable method to account for simultaneous decision bias nor an ordered logit analysis with rank of coverage as an order variable revealed that differences in copayments by locale had any impact on the scope of age eligibility. Residents' income and the number of children tended to narrow scope of eligibility for subsidies, but the strength of local government finances were not a significant factor of influence. In designing these programs, local government bodies take into account the local population's ability to pay and the number of eligible people, but their awareness of the local government's financial condition seems to be scant. Local governments are currently moving to expand their children's medical expense subsidy programs, but in the future they will need to pay more attention to balancing an expanded scope of eligibility by ages with the maintenance of local government fiscal discipline. In addition, copayments have not been adequately linked to the expansion of eligibility, so it would be advisable to clearly demonstrate the reason for this limit in order to eliminate perceptions of unfairness. PMID- 28878667 TI - Adaptive Pathways: Possible Next Steps for Payers in Preparation for Their Potential Implementation. AB - Medicines receiving a conditional marketing authorization through Medicines Adaptive Pathways to Patients (MAPPs) will be a challenge for payers. The "introduction" of MAPPs is already seen by the European Medicines Agency (EMA) as a fait accompli, with payers not consulted or involved. However, once medicines are approved through MAPPs, they will be evaluated for funding by payers through different activities. These include Health Technology Assessment (HTA) with often immature clinical data and high uncertainty, financial considerations, and negotiations through different types of agreements, which can require monitoring post launch. Payers have experience with new medicines approved through conditional approval, and the fact that MAPPs present additional challenges is a concern from their perspective. There may be some activities where payers can collaborate. The final decisions on whether to reimburse a new medicine via MAPPs will have more variation than for medicines licensed via conventional processes. This is due not only to increasing uncertainty associated with medicines authorized through MAPPs but also differences in legal frameworks between member states. Moreover, if the financial and side-effect burden from the period of conditional approval until granting full marketing authorization is shifted to the post-authorization phase, payers may have to bear such burdens. Collection of robust data during routine clinical use is challenging along with high prices for new medicines during data collection. This paper presents the concept of MAPPs and possible challenges. Concerns and potential ways forward are discussed and a number of recommendations are presented from the perspective of payers. PMID- 28878669 TI - Picrorhiza kurroa Enhances beta-Cell Mass Proliferation and Insulin Secretion in Streptozotocin Evoked beta-Cell Damage in Rats. AB - Autoimmune destruction of insulin producing pancreatic beta-cells leads to insulin insufficiency and hyperglycemia in type 1 diabetes mellitus. Regeneration of beta-cells is one of the proposed treatment for type 1 diabetes and insulin insufficiency. Picrorhiza kurroa is a medicinal herb and is traditionally being used for the treatment of various diseases. Previous studies reported the hypoglycemic potential of P. kurroa. However, its potential role in beta-cell induction in insulin secretion have not been fully investigated. Here, we characterized the hydro alcoholic extract of P. kurroa rhizome (PKRE) and further studied its beta-cell regeneration and induction of insulin secretion potential in streptozotocin (STZ) induced diabetic rats as well as in insulin producing Rin5f cells. 1H-NMR revealed the presence of more than thirty metabolites including picroside I and II in PKRE. Further, we found that PKRE treatment (100 and 200 mg/kg dose for 30 days) significantly (p <= 0.05) protected the pancreatic beta-cells against streptozotocin (STZ) evoked damage and inhibited the glucagon receptor expression (Gcgr) in hepatic and renal tissues. It significantly (p <= 0.05) enhanced the insulin expression and aids in proliferation of insulin producing Rin5f cells with elevated insulin secretion. Furthermore it significantly (p <= 0.05) increased insulin mediated glucose uptake in 3T3L1 and L6 cells. On the contrary, in diabetic rats, PKRE significantly (p <= 0.05) decreased high blood glucose and restored the normal levels of serum biochemicals. Altogether, our results showed that PKRE displayed beta-cell regeneration with enhanced insulin production and antihyperglycemic effects. PKRE also improves hepatic and renal functions against oxidative damage. PMID- 28878671 TI - A Pilot Study Evaluating the Safety of Intravenously Administered Human Amnion Epithelial Cells for the Treatment of Hepatic Fibrosis. AB - Liver cirrhosis is the 6th leading cause of death in adults aged 15-59 years in high-income countries. For many who progress to cirrhosis, the only prospect for survival is liver transplantation. While there is some indication that mesenchymal stem cells may be useful in reversing established liver fibrosis, there are limitations to their widespread use - namely their rarity, the need for extensive serial passaging and the associated potential for genomic instability and cellular senescence. To this end, we propose the use of allogeneic amnion epithelial cells. This clinical trial will assess the safety of intravenously delivered allogeneic human amnion epithelial cells (hAECs) in patients with compensated liver cirrhosis. This will also provide clinical data that will inform phases 2 and 3 clinical trials with the ultimate goal of developing hAECs as a therapeutic option for patients with cirrhosis who are at significant risk of disease progression. We will recruit 12 patients with compensated cirrhosis, based on their hepatic venous pressure gradient, for a dose escalation study. Patients will be closely monitored in the first 24 h post-infusion, then via daily telephone interviews until clinical assessment on day 5. Long term follow up will include standard liver tests, transient elastography and hepatic ultrasound. Ethics approval was obtained from Monash Health for this trial 16052A, "A Pilot Study Evaluating the Safety of Intravenously Administered Human Amnion Epithelial Cells for the Treatment of Liver Fibrosis, A First in Adult Human Study." The trial will be conducted in accordance to Monash Health Human Ethics guidelines. Outcomes from this study will be disseminated in the form of conference presentations and submission to a peer reviewed journal. This trial has been registered on the Australian and New Zealand Clinical Trials Registry ACTRN12616000437460. PMID- 28878670 TI - DAF-16/FOXO Transcription Factor in Aging and Longevity. AB - Aging is associated with age-related diseases and an increase susceptibility of cancer. Dissecting the molecular mechanisms that underlie aging and longevity would contribute to implications for preventing and treating the age-dependent diseases or cancers. Multiple signaling pathways such as the insulin/IGF-1 signaling pathway, TOR signaling, AMPK pathway, JNK pathway and germline signaling have been found to be involved in aging and longevity. And DAF-16/FOXO, as a key transcription factor, could integrate different signals from these pathways to modulate aging, and longevity via shuttling from cytoplasm to nucleus. Hence, understanding how DAF-16/FOXO functions will be pivotal to illustrate the processes of aging and longevity. Here, we summarized how DAF 16/FOXO receives signals from these pathways to affect aging and longevity. We also briefly discussed the transcriptional regulation and posttranslational modifications of DAF-16/FOXO, its co-factors as well as its potential downstream targets participating in lifespan according to the published data in C. elegans and in mammals, and in most cases, we may focus on the studies in C. elegans which has been considered to be a very good animal model for longevity research. PMID- 28878672 TI - Differences in Spatial Memory Recognition Due to Cognitive Style. AB - Field independence refers to the ability to perceive details from the surrounding context as a whole and to represent the environment by relying on an internal reference frame. Conversely, field dependence individuals tend to focus their attention on single environmental features analysing them individually. This cognitive style affects several visuo-spatial abilities including spatial memory. This study assesses both the effect of field independence and field dependence on performance displayed on virtual environments of different complexity. Forty young healthy individuals took part in this study. Participants performed the Embedded Figures Test for field independence or dependence assessment and a new spatial memory recognition test. The spatial memory recognition test demanded to memorize a green box location in a virtual room picture. Thereafter, during ten trials participants had to decide if a green box was located in the same position as in the sample picture. Five of the pictures were correct. The information available in the virtual room was manipulated. Hence, two different experimental conditions were tested: a virtual room containing all landmarks and a virtual room with only two cues. Accuracy and reaction time were registered. Analyses demonstrated that higher field independent individuals were related to better spatial memory performance in two landmarks condition and were faster in all landmark condition. In addition, men and women did not differ in their performance. These results suggested that cognitive style affects spatial memory performance and this phenomenon is modulated by environment complexity. This does not affect accuracy but time spent. Moreover, field dependent individuals are unable to organize the navigational field by relying on internal reference frames when few landmarks are available, and this causes them to commit more errors. PMID- 28878673 TI - Review of the Reported Measures of Clinical Validity and Clinical Utility as Arguments for the Implementation of Pharmacogenetic Testing: A Case Study of Statin-Induced Muscle Toxicity. AB - Advances from pharmacogenetics (PGx) have not been implemented into health care to the expected extent. One gap that will be addressed in this study is a lack of reporting on clinical validity and clinical utility of PGx-tests. A systematic review of current reporting in scientific literature was conducted on publications addressing PGx in the context of statins and muscle toxicity. Eighty nine publications were included and information was selected on reported measures of effect, arguments, and accompanying conclusions. Most authors report associations to quantify the relationship between a genetic variation an outcome, such as adverse drug responses. Conclusions on the implementation of a PGx-test are generally based on these associations, without explicit mention of other measures relevant to evaluate the test's clinical validity and clinical utility. To gain insight in the clinical impact and select useful tests, additional outcomes are needed to estimate the clinical validity and utility, such as cost effectiveness. PMID- 28878675 TI - Inhibition of Collagen-Induced Platelet Aggregation by the Secobutanolide Secolincomolide A from Lindera obtusiloba Blume. AB - Atherothrombosis is one of the main underlying cause of cardiovascular diseases. In addition to treating atherothrombosis with antithrombotic agents, there is growing interest in the role of natural food products and biologically active ingredients for the prevention and treatment of cardiovascular diseases. This study aimed to investigate the effect of secolincomolide A (3) isolated from Lindera obtusiloba Blume on platelet activity and identify possible signaling pathways. In our study, the antiplatelet activities of 3 were measured by collagen-induced platelet aggregation and serotonin secretion in freshly isolated rabbit platelets. Interestingly, 3 effectively inhibited the collagen-induced platelet aggregation and serotonin secretion via decreased production of diacylglycerol, arachidonic acid, and cyclooxygenase-mediated metabolites such as thromboxane B2 (TXB2), and prostaglandin D2 (PGD2). In accordance with the antiplatelet activities, 3 prolonged bleeding time and attenuated FeCl3-induced thrombus formation in arterial thrombosis model. Notably, 3 abolished the phosphorylation of phospholipase Cgamma2 (PLCgamma2), spleen tyrosine kinase (Syk), p47, extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase B (Akt) by inhibiting the activation of the collagen receptor, glycoprotein VI (GPVI). Taken together, our results indicate the therapeutic potential of 3 in antiplatelet action through inhibition of the GPVI-mediated signaling pathway and the COX-1-mediated AA metabolic pathways. PMID- 28878676 TI - PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. AB - Several cancers are highly refractory to conventional chemotherapy. The survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Check point antibody inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. These checkpoint blockers are rapidly becoming a highly promising cancer therapeutic approach that yields remarkable antitumor responses with limited side effects. In recent times, more than four check point antibody inhibitors have been commercialized for targeting PD-1, PDL-1, and CTLA 4. Despite the huge success and efficacy of the anti-PD therapy response, it is limited to specific types of cancers, which attributes to the insufficient and heterogeneous expression of PD-1 in the tumor microenvironment. Herein, we review the current landscape of the PD-1/PD-L1 mechanistic role in tumor immune evasion and therapeutic outcome for cancer treatment. We also review the current progress in clinical trials, combination of drug therapy with immunotherapy, safety, and future of check point inhibitors for multiple types of cancer. PMID- 28878674 TI - Sphingosine Kinases and Sphingosine 1-Phosphate Receptors: Signaling and Actions in the Cardiovascular System. AB - The sphingosine kinases 1 and 2 (SphK1 and 2) catalyze the phosphorylation of the lipid, sphingosine, generating the signal transmitter, sphingosine 1-phosphate (S1P). The activation of such kinases and the subsequent S1P generation and secretion in the blood serum of mammals represent a major checkpoint in many cellular signaling cascades. In fact, activating the SphK/S1P system is critical for cell motility and proliferation, cytoskeletal organization, cell growth, survival, and response to stress. In the cardiovascular system, the physiological effects of S1P intervene through the binding and activation of a family of five highly selective G protein-coupled receptors, called S1PR1-5. Importantly, SphK/S1P signal is present on both vascular and myocardial cells. S1P is a well recognized survival factor in many tissues. Therefore, it is not surprising that the last two decades have seen a flourishing of interest and investigative efforts directed to obtain additional mechanistic insights into the signaling, as well as the biological activity of this phospholipid, and of its receptors, especially in the cardiovascular system. Here, we will provide an up-to-date account on the structure and function of sphingosine kinases, discussing the generation, release, and function of S1P. Keeping the bull's eye on the cardiovascular system, we will review the structure and signaling cascades and biological actions emanating from the stimulation of different S1P receptors. We will end this article with a summary of the most recent, experimental and clinical observations targeting S1PRs and SphKs as possible new therapeutic avenues for cardiovascular disorders, such as heart failure. PMID- 28878677 TI - Teuvincenone F Suppresses LPS-Induced Inflammation and NLRP3 Inflammasome Activation by Attenuating NEMO Ubiquitination. AB - Inflammation causes many diseases that are serious threats to human health. However, the molecular mechanisms underlying regulation of inflammation and inflammasome activation are not fully understood which has delayed the discovery of new anti-inflammatory drugs of urgent clinic need. Here, we found that the natural compound Teuvincenone F, which was isolated and purified from the stems and leaves of Premna szemaoensis, could significantly inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokines production and NLRP3 inflammasome activation. Our results showed that Teuvincenone F attenuated K63-linked ubiquitination of NF-kappaB-essential modulator (NEMO, also known as IKKgamma) to suppress LPS-induced phosphorylation of NF-kappaB, and inhibited mRNA expression of IL-1beta, IL-6, TNF-alpha, and NLRP3. In addition, we found that decreased NLRP3 expression by Teuvincenone F suppressed NLRP3 inflammasome activation and IL-1beta/IL-18 maturation. In vivo, we revealed that Teuvincenone F treatment relieved LPS-induced inflammation. In conclusion, Teuvincenone F is a highly effective natural compound to suppress LPS-induced inflammation by attenuating K63-linked ubiquitination of NEMO, highlighting that Teuvincenone F may be a potential new anti-inflammatory drug for the treatment of inflammatory and NLRP3 inflammasome-driven diseases. PMID- 28878679 TI - Time Investment in Drug Supply Problems by Flemish Community Pharmacies. AB - Introduction: Drug supply problems are a known problem for pharmacies. Community and hospital pharmacies do everything they can to minimize impact on patients. This study aims to quantify the time spent by Flemish community pharmacies on drug supply problems. Materials and Methods: During 18 weeks, employees of 25 community pharmacies filled in a template with the total time spent on drug supply problems. The template stated all the steps community pharmacies could undertake to manage drug supply problems. Results: Considering the median over the study period, the median time spent on drug supply problems was 25 min per week, with a minimum of 14 min per week and a maximum of 38 min per week. After calculating the median of each pharmacy, large differences were observed between pharmacies: about 25% spent less than 15 min per week and one-fifth spent more than 1 h per week. The steps on which community pharmacists spent most time are: (i) "check missing products from orders," (ii) "contact wholesaler/manufacturers regarding potential drug shortages," and (iii) "communicating to patients." These three steps account for about 50% of the total time spent on drug supply problems during the study period. Conclusion: Community pharmacies spend about half an hour per week on drug supply problems. Although 25 min per week does not seem that much, the time spent is not delineated and community pharmacists are constantly confronted with drug supply problems. PMID- 28878678 TI - Verapamil Blocks Scopolamine Enhancement Effect on Memory Consolidation in Passive Avoidance Task in Rats. AB - Our recent data have indicated that scopolamine, a non-selective muscarinic receptor antagonist, improves memory consolidation, in a passive avoidance task, tested in rats. It has been found that verapamil, a phenylalkylamine class of the L-type voltage-dependent calcium channel antagonist, inhibits [3H] N-methyl scopolamine binding to M1 muscarinic receptors. However, there are no data about the effect of verapamil on memory consolidation in the passive avoidance task, in rats. The purpose of the present study was to examine the effects of verapamil (0.5, 1.0, 2.5, 5.0, 10, or 20 mg/kg i.p.) as well as the interaction between scopolamine and verapamil on memory consolidation in the step-through passive avoidance task, in Wistar rats. Our results showed that verapamil (1.0 and 2.5 mg/kg) administered immediately after the acquisition task significantly increased the latency of the passive avoidance response, on the 48 h retested trial, improving memory consolidation. On the other hand, verapamil in a dose of 5 mg/kg, that per se does not affect memory consolidation, significantly reversed the memory consolidation improvement induced by scopolamine (1 mg/kg, i.p., administered immediately after verapamil treatment) but did not change the passive avoidance response in rats treated by an ineffective dose of scopolamine (30 mg/kg). In conclusion, the present data suggest that (1) the post-training administration of verapamil, dose-dependently, improves the passive avoidance response; (2) verapamil, in ineffective dose, abolished the improvement of memory consolidation effect of scopolamine; and (3) exists interaction between cholinergic muscarinic receptors and calcium homeostasis-related mechanisms in the consolidation of emotional memory. PMID- 28878680 TI - Andrographolide, a New Hope in the Prevention and Treatment of Metabolic Syndrome. AB - Recently, the use of plant-derived medicines is increasing interest in the prevention and treatment of a variety of disorders including metabolic syndromes. Metabolic syndrome is one of the major risk factors for cardiovascular diseases (CVDs) and incidence of mortality worldwide. Scientific evidence suggests that Andrographis paniculata and its derived components, especially andrographolide (AGL) and its analogs/derivatives have a broad spectrum of biological activities. This review aims to sketch the activity of AGL and its analogs/derivatives against the components of metabolic syndromes such as diabetes, hyperlipidemia, hypertension, and obesity. Additionally, AGL activity against CVDs is also summarized. The finding suggests that AGL and its analogs/derivatives have a potential role in the management of metabolic syndrome; however, more studies should be conducted to evaluate their effectiveness. PMID- 28878681 TI - Alpha5 Nicotinic Acetylcholine Receptor Contributes to Nicotine-Induced Lung Cancer Development and Progression. AB - Nicotine and nicotinic acetylcholine receptors (nAChRs) are considered to be involved in lung cancer risk, onset and progression, but their precise physiological roles in these contexts remain unclear. Our previous studies suggested that alpha5-nAChR mediates nicotine-induced lung cancer cell proliferation, migration, and invasion in vitro. In this study, we aimed to determine the role of alpha5-nAChR in the development and progression of non small cell lung cancer (NSCLC). Our microarray results reveal that knockdown of the CHRNA5 gene encoding alpha5-nAChR significantly modulates key pathways including the cell cycle, DNA replication, pathway in cancer. alpha5-nAChR knockdown in cultured A549 cells affected cell cycle distribution, apoptosis, and cyclin expression. In vivo, alpha5-nAChR silencing inhibited the growth of lung tumors, especially in the context of nicotine exposure. Importantly, alpha5-nAChR expression in patient tumors correlated with the primary T stage, N stage, and reduced survival time. These results reveal that alpha5-nAChR silencing inhibits the progression of nicotine-related NSCLC, making this receptor a potential pharmacological target for the treatment of nicotine-related lung carcinogenesis. PMID- 28878682 TI - Experience-Related Changes in Place Cell Responses to New Sensory Configuration That Does Not Occur in the Natural Environment in the Rat Hippocampus. AB - The hippocampal formation (HF) is implicated in a comparator that detects sensory conflict (mismatch) among convergent inputs. This suggests that new place cells encoding the new configuration with sensory mismatch develop after the HF learns to accept the new configuration as a match. To investigate this issue, HF CA1 place cell activity in rats was analyzed after the adaptation of the rats to the same sensory mismatch condition. The rats were placed on a treadmill on a stage that was translocated in a figure 8-shaped pathway. We recorded HF neuronal activities under three conditions; (1) an initial control session, in which both the stage and the treadmill moved forward, (2) a backward (mismatch) session, in which the stage was translocated backward while the rats locomoted forward on the treadmill, and (3) the second control session. Of the 161 HF neurons, 56 place differential activities were recorded from the HF CA1 subfield. These place differential activities were categorized into four types; forward-related, backward-related, both-translocation-related, and session-dependent. Forward related activities showed predominant spatial firings in the forward sessions, while backward-related activities showed predominant spatial firings in the backward sessions. Both-translocation-related activities showed consistent spatial firings in both the forward and backward conditions. On the other hand, session-dependent activities showed different spatial firings across the sessions. Detailed analyses of the place fields indicated that mean place field sizes were larger in the forward-related, backward-related, and both translocation-related activities than in the session-dependent activities. Furthermore, firing rate distributions in the place fields were negatively skewed and asymmetric, which is similar to place field changes that occur after repeated experience. These results demonstrate that the HF encodes a naturally impossible new configuration of sensory inputs after adaptation, suggesting that the HF is capable of updating its stored memory to accept a new configuration as a match by repeated experience. PMID- 28878683 TI - Association between Diastolic Dysfunction with Inflammation and Oxidative Stress in Females ob/ob Mice. AB - Objective: To evaluate autonomic and cardiovascular function, as well as inflammatory and oxidative stress markers in ob/ob female mice. Methods: Metabolic parameters, cardiac function, arterial pressure (AP), autonomic, hormonal, inflammatory, and oxidative stress markers were evaluated in 12-weeks female wild-type (WT group) and ob/ob mice (OB group). Results: OB animals showed increased body weight, blood glucose, and triglyceride levels, along with glucose intolerance, when compared to WT animals. Ejection fraction (EF) and AP were similar between groups; however, the OB group presented diastolic dysfunction, as well as an impairment on myocardial performance index. Moreover, the OB group exhibited important autonomic dysfunction and baroreflex sensitivity impairment, when compared to WT group. OB group showed increased Angiotensin II levels in heart and renal tissues; decreased adiponectin and increased inflammatory markers in adipose tissue and spleen. Additionally, OB mice presented a higher damage to proteins and lipoperoxidation and lower activity of antioxidant enzymes in kidney and heart. Correlations were found between autonomic dysfunction with angiotensin II and inflammatory mediators, as well as between inflammation and oxidative stress. Conclusions: Our results showed that female adult ob/ob mice presented discrete diastolic dysfunction accompanied by autonomic disorder, which is associated with inflammation and oxidative stress in these animals. PMID- 28878684 TI - Ecdysis Triggering Hormone Signaling (ETH/ETHR-A) Is Required for the Larva-Larva Ecdysis in Bactrocera dorsalis (Diptera: Tephritidae). AB - Insects must undergo ecdysis for successful development and growth, and the ecdysis triggering hormone (ETH), released by the Inka cells, is a master hormone in this process. In this study, we determined the sequence of the ETH precursor and receptors in an agriculturally important pest insect, the oriental fruit fly Bactrocera dorsalis (Hendel). We identified two functionally distinct splice receptor isoforms: BdETH-R-A and BdETH-R-B, and when expressed in Chinese hamster ovary (CHO-WTA11) cells, they exhibited a high sensitivity to the two mature peptides BdETH1 and BdETH2. The BdETH transcript was detected in the tracheal tissue of the larvae. Inka cells were identified with immunohistochemical antibody staining against Drosophila melanogaster ETH1, and in situ hybridization with specific DNA probes. Selective RNA silencing of BdETH or BdETH-R-A, but not of BdETH-R-B, caused developmental failure at ecdysis. The dsRNA-treated larvae displayed tracheal defects and could not shed the old cuticle followed by death. Our results demonstrated that BdETH, via activation of BdETH-R-A but not ETH-R-B, plays an essential role in regulating the process of larva-larva ecdysis in B. dorsalis. PMID- 28878686 TI - Comparative Analysis of 3D Bladder Tumor Spheroids Obtained by Forced Floating and Hanging Drop Methods for Drug Screening. AB - Introduction: Cell-based assays using three-dimensional (3D) cell cultures may reflect the antitumor activity of compounds more accurately, since these models reproduce the tumor microenvironment better. Methods: Here, we report a comparative analysis of cell behavior in the two most widely employed methods for 3D spheroid culture, forced floating (Ultra-low Attachment, ULA, plates), and hanging drop (HD) methods, using the RT4 human bladder cancer cell line as a model. The morphology parameters and growth/metabolism of the spheroids generated were first characterized, using four different cell-seeding concentrations (0.5, 1.25, 2.5, and 3.75 * 104 cells/mL), and then, subjected to drug resistance evaluation. Results: Both methods generated spheroids with a smooth surface and round shape in a spheroidization time of about 48 h, regardless of the cell seeding concentration used. Reduced cell growth and metabolism was observed in 3D cultures compared to two-dimensional (2D) cultures. The optimal range of spheroid diameter (300-500 MUm) was obtained using cultures initiated with 0.5 and 1.25 * 104 cells/mL for the ULA method and 2.5 and 3.75 * 104 cells/mL for the HD method. RT4 cells cultured under 3D conditions also exhibited a higher resistance to doxorubicin (IC50 of 1.00 and 0.83 MUg/mL for the ULA and HD methods, respectively) compared to 2D cultures (IC50 ranging from 0.39 to 0.43). Conclusions: Comparing the results, we concluded that the forced floating method using ULA plates was considered more suitable and straightforward to generate RT4 spheroids for drug screening/cytotoxicity assays. The results presented here also contribute to the improvement in the standardization of the 3D cultures required for widespread application. PMID- 28878688 TI - Dynamics of Stride Interval Characteristics during Continuous Stairmill Climbing. AB - It has been shown that statistical persistence in stride intervals characteristics exist during walking, running and cycling and were speed dependent among healthy young adults. The purpose of this study was to determine if such statistical persistence in stride time interval, stride length and stride speed also exists during self-paced continuous stairmill climbing and if the strength is dependent on stepping rate. Stride time, stride length, and stride speed were collected from nine healthy participants during 3 min of stairmill climbing at 100, 110, and 120% of their preferred stepping rate (PSR) and 5 min of treadmill walking at preferred walking speed (PWS). The amount of variability (assessed by standard deviation and coefficient of variation) and dynamics (assessed by detrended fluctuation analysis and sample entropy) of the stride time, stride length, and stride speed time series were investigated. The amounts of variability were significantly higher during stairmill climbing for the stride time, stride length, and stride speed and did only change with increased stepping rate for stride speed. In addition to a more irregular pattern during stairmill climbing, the detrended fluctuation analysis (DFA) revealed that the stride length fluctuations were statistical anti-persistent for all subjects. On a group level both stride time and stride speed fluctuations were characterized by an uncorrelated pattern which was more irregular compared to that during treadmill walking. However, large inter-participant differences were observed for these two variables. In addition, the dynamics did not change with increase in stepping rate. PMID- 28878685 TI - Oxidative Stress-Mediated Atherosclerosis: Mechanisms and Therapies. AB - Atherogenesis, the formation of atherosclerotic plaques, is a complex process that involves several mechanisms, including endothelial dysfunction, neovascularization, vascular proliferation, apoptosis, matrix degradation, inflammation, and thrombosis. The pathogenesis and progression of atherosclerosis are explained differently by different scholars. One of the most common theories is the destruction of well-balanced homeostatic mechanisms, which incurs the oxidative stress. And oxidative stress is widely regarded as the redox status realized when an imbalance exists between antioxidant capability and activity species including reactive oxygen (ROS), nitrogen (RNS) and halogen species, non radical as well as free radical species. This occurrence results in cell injury due to direct oxidation of cellular protein, lipid, and DNA or via cell death signaling pathways responsible for accelerating atherogenesis. This paper discusses inflammation, mitochondria, autophagy, apoptosis, and epigenetics as they induce oxidative stress in atherosclerosis, as well as various treatments for antioxidative stress that may prevent atherosclerosis. PMID- 28878687 TI - NO-sGC Pathway Modulates Ca2+ Release and Muscle Contraction in Zebrafish Skeletal Muscle. AB - Vertebrate skeletal muscle contraction and relaxation is a complex process that depends on Ca2+ ions to promote the interaction of actin and myosin. This process can be modulated by nitric oxide (NO), a gas molecule synthesized endogenously by (nitric oxide synthase) NOS isoforms. At nanomolar concentrations NO activates soluble guanylate cyclase (sGC), which in turn activates protein kinase G via conversion of GTP into cyclic GMP. Alternatively, NO post-translationally modifies proteins via S-nitrosylation of the thiol group of cysteine. However, the mechanisms of action of NO on Ca2+ homeostasis during muscle contraction are not fully understood and we hypothesize that NO exerts its effects on Ca2+ homeostasis in skeletal muscles mainly through negative modulation of Ca2+ release and Ca2+ uptake via the NO-sGC-PKG pathway. To address this, we used 5-7 days-post fecundation-larvae of zebrafish, a well-established animal model for physiological and pathophysiological muscle activity. We evaluated the response of muscle contraction and Ca2+ transients in presence of SNAP, a NO-donor, or L NAME, an unspecific NOS blocker in combination with specific blockers of key proteins of Ca2+ homeostasis. We also evaluate the expression of NOS in combination with dihydropteridine receptor, ryanodine receptor and sarco/endoplasmic reticulum Ca2+ ATPase. We concluded that endogenous NO reduced force production through negative modulation of Ca2+ transients via the NO-sGC pathway. This effect could be reversed using an unspecific NOS blocker or sGC blocker. PMID- 28878689 TI - A20/TNFAIP3 Discriminates Tumor Necrosis Factor (TNF)-Induced NF-kappaB from JNK Pathway Activation in Hepatocytes. AB - In the liver tumor necrosis factor (TNF)-induced signaling critically regulates the immune response of non-parenchymal cells as well as proliferation and apoptosis of hepatocytes via activation of the NF-kappaB and JNK pathways. Especially, the induction of negative feedback regulators, such as IkappaBalpha and A20 is responsible for the dynamic and time-restricted response of these important pathways. However, the precise mechanisms responsible for different TNF induced phenotypes under physiological stimulation conditions are not completely understood so far. In addition, it is not known if varying TNF concentrations may differentially affect the desensitization properties of both pathways. By using computational modeling, we first showed that TNF-induced activation and downstream signaling is qualitatively comparable between primary mouse hepatocytes and immortalized hepatocellular carcinoma (HCC) cells. In order to define physiologically relevant TNF levels, which allow for an adjustable and dynamic NF-kappaB/JNK pathway response in parenchymal liver cells, a range of cytokine concentrations was defined that led to gradual pathway responses in HCC cells (1-5 ng/ml). Repeated stimulations with low (1 ng/ml), medium (2.5 ng/ml) and high (5 ng/ml) TNF amounts demonstrated that JNK signaling was still active at cytokine concentrations, which led to dampened NF-kappaB signaling illustrating differential pathway responsiveness depending on TNF input dynamics. SiRNA-mediated inhibition of the negative feedback regulator A20 (syn. TNFAIP3) or its overexpression did not significantly affect the NF-kappaB response. In contrast, A20 silencing increased the JNK response, while its overexpression dampened JNK phosphorylation. In addition, the A20 knockdown sensitized hepatocellular cells to TNF-induced cleavage and activity of the effector caspase 3. In conclusion, a mathematical model-based approach shows that the TNF-induced pathway responses are qualitatively comparable in primary and immortalized mouse hepatocytes. The cytokine amount defines the pathway responsiveness under repeated treatment conditions with NF-kappaB signaling being dampened 'earlier' than JNK. A20 appears to be the molecular switch discriminating between NF-kappaB and JNK signaling when stimulating with varying physiological cytokine concentrations. PMID- 28878690 TI - Regulation of Pulmonary Vascular Smooth Muscle Contractility in Pulmonary Arterial Hypertension: Implications for Therapy. AB - There are two primary components that produce pulmonary arterial hypertension (PAH); aberrant structural changes (smooth muscle cell proliferation, smooth muscle cell hypertrophy, and the deposition of matrix proteins within the media of pulmonary arterial vessels), and excess vasoconstriction. However, in PAH, the target and aim of all current therapeutic agents is to reduce the contractility of the pulmonary vasculature; prostaglandins, phosphodiesterase inhibitors, guanylate cyclase stimulators, endothelin antagonists, NO inhalation and Rho kinase inhibitors all influence signaling pathways in the pulmonary vascular smooth muscle to decrease vasoconstriction, and hence, pulmonary vascular resistance (PVR). This review will therefore primarily focus on discussing the signaling pathways regulating contractility in pulmonary vascular smooth muscle, the mechanism for current treatments, as well as highlighting potential targets for the development of novel therapies. PMID- 28878691 TI - Spontaneous Preterm Birth Is Associated with Differential Expression of Vaginal Metabolites by Lactobacilli-Dominated Microflora. AB - A major challenge in preventing preterm birth (PTB) is identifying women at greatest risk. This pilot study prospectively examined the differences in vaginal microbiota and metabolite profiles of women who delivered prematurely compared to their term counterparts in a cohort of asymptomatic (studied at 20-22, n = 80; and 26-28 weeks, n = 41) and symptomatic women (studied at 24-36 weeks, n = 37). Using 16S rRNA sequencing, the vaginal microbiota from cervicovaginal fluid samples was characterized into five Community State Types (CST) dominated by Lactobacillus spp.: CSTI (Lactobacillus crispatus), CSTII (Lactobacillus gasseri), CSTIII (Lactobacillus iners), CSTV (Lactobacillus jensenii); and mixed anaerobes-CSTIV. This was then related to the vaginal metabolite profile and pH determined by 1H-Nuclear Magnetic Resonance spectroscopy and pH indicator paper, respectively. At 20-22 weeks, the term-delivered women (TDW) indicated a proportion of CSTI-dominated microbiota >2-fold higher compared to the preterm delivered women (PTDW) (40.3 vs. 16.7%, P = 0.0002), and a slightly higher proportion at 26-28 weeks (20.7 vs. 16.7%, P = 0.03). CSTV was >2-fold higher in the PTDW compared to TDW at 20-22 (22.2 vs. 9.7%, P = 0.0002) and 26-28 weeks (25.0 vs. 10.3%, P = 0.03). Furthermore, at 26-28 weeks no PTDW had a CSTII dominated microbiome, in contrast to 28% of TDW (P < 0.0001). CSTI-dominated samples showed higher lactate levels than CSTV at 20-22 weeks (P < 0.01), and 26 28 weeks (P < 0.05), while CSTII-dominated samples indicated raised succinate levels over CSTV at 26-28 weeks (P < 0.05). These were supported by Principal coordinates analysis, which revealed strong clustering of metabolites according to CST. In addition, the CSTI-dominated samples had an average pH of 3.8, which was lower than those of CSTII-4.4, and CSTV-4.2 (P < 0.05). Elevated vaginal lactate and succinate were associated with predominance of CSTI and II over CSTV in women who delivered at term compared with their preterm counterparts. This suggests that L. jensenii-dominance and decreased lactate and/or succinate could increase the risk of PTB, while L. crispatus/gasseri may confer some protection against inflammation-associated PTB and highlight the need for further study in this area. PMID- 28878692 TI - Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment. AB - Drug-induced Torsade-de-Pointes (TdP) has been responsible for the withdrawal of many drugs from the market and is therefore of major concern to global regulatory agencies and the pharmaceutical industry. The Comprehensive in vitro Proarrhythmia Assay (CiPA) was proposed to improve prediction of TdP risk, using in silico models and in vitro multi-channel pharmacology data as integral parts of this initiative. Previously, we reported that combining dynamic interactions between drugs and the rapid delayed rectifier potassium current (IKr) with multi channel pharmacology is important for TdP risk classification, and we modified the original O'Hara Rudy ventricular cell mathematical model to include a Markov model of IKr to represent dynamic drug-IKr interactions (IKr-dynamic ORd model). We also developed a novel metric that could separate drugs with different TdP liabilities at high concentrations based on total electronic charge carried by the major inward ionic currents during the action potential. In this study, we further optimized the IKr-dynamic ORd model by refining model parameters using published human cardiomyocyte experimental data under control and drug block conditions. Using this optimized model and manual patch clamp data, we developed an updated version of the metric that quantifies the net electronic charge carried by major inward and outward ionic currents during the steady state action potential, which could classify the level of drug-induced TdP risk across a wide range of concentrations and pacing rates. We also established a framework to quantitatively evaluate a system's robustness against the induction of early afterdepolarizations (EADs), and demonstrated that the new metric is correlated with the cell's robustness to the pro-EAD perturbation of IKr conductance reduction. In summary, in this work we present an optimized model that is more consistent with experimental data, an improved metric that can classify drugs at concentrations both near and higher than clinical exposure, and a physiological framework to check the relationship between a metric and EAD. These findings provide a solid foundation for using in silico models for the regulatory assessment of TdP risk under the CiPA paradigm. PMID- 28878693 TI - Brain Activation during Perception and Anticipation of Dyspnea in Chronic Obstructive Pulmonary Disease. AB - Background: Dyspnea is the impairing cardinal symptom in COPD, but the underlying brain mechanisms and their relationships to clinical patient characteristics are widely unknown. This study compared neural responses to the perception and anticipation of dyspnea between patients with stable moderate-to-severe COPD and healthy controls. Moreover, associations between COPD-specific brain activation and clinical patient characteristics were examined. Methods: During functional magnetic resonance imaging, dyspnea was induced in patients with stable moderate to-severe COPD (n = 17) and healthy control subjects (n = 21) by resistive-loaded breathing. Blocks of severe and mild dyspnea were alternating, with each block being preceded by visually cued anticipation phases. Results: During the perception of increased dyspnea, both patients and controls showed comparable brain activation in common dyspnea-relevant sensorimotor and cortico-limbic brain regions. During the anticipation of increased dyspnea, patients showed higher activation in hippocampus and amygdala than controls which was significantly correlated with reduced exercise capacity, reduced health-related quality of life, and higher levels of dyspnea and anxiety. Conclusions: This study suggests that patients with stable moderate-to-severe COPD show higher activation in emotion-related brain areas than healthy controls during the anticipation, but not during the actual perception of experimentally induced dyspnea. These brain activations were related to important clinical characteristics and might contribute to an unfavorable course of the disease via maladaptive psychological and behavioral mechanisms. PMID- 28878694 TI - Physiological Responses to Firefighting in Extreme Temperatures Do Not Compare to Firefighting in Temperate Conditions. AB - Purpose: The aim of this study was to examine physiological responses to two different simulated firefighting exercises: a firefighting exercise with flashovers, smoke, poor visibility and extreme temperatures (300 degrees ) in a burning container and a standard firefighting exercise in temperate conditions. Furthermore, a second purpose of the study was to find out if the contribution of strength and endurance capacities to firefighting performance changes when the demands of the firefighting exercise change. Methods: Sixteen professional firefighters performed a maximum treadmill test, strength testing, a standard simulated firefighting exercise (SFE) without heat and flashovers and a firefighting exercise with a simulation of the flashover phenomenon in a burning container (FOT). The treadmill testing was used to determine peak oxygen uptake (VO2peak), ventilatory threshold (VT1) and respiratory compensation point (RCP). Three intensity zones were identified according to heart rate (HR) values corresponding to VT1 and RCP: zone 1-HR below VT1, zone 2-HR between VT1 and RCP, zone 3-HR above RCP. Firefighting performance was determined by a simple time strain-air depletion model (TSA) taking the sum of z-transformed parameters of time to finish the exercise, strain in terms of mean heart rate, and air depletion from the breathing apparatus. Correlations were then established between TSA based firefighting performance parameters and fitness variables representing strength and endurance. Results: HR was significantly lower during SFE (79.9 +/- 6.9%HRmax) compared to FOT (85.4 +/- 5.2%HRmax). During SFE subjects spent 24.6 +/- 30.2% of time in zone 1, 65.8 +/- 28.1% in zone 2 and 9.7 +/- 16.6% in zone 3. During FOT subjects spent 16.3 +/- 12.8% in zone 1, 50.4 +/- 13.2% in zone 2 and 33.3 +/- 16.6% in zone 3. Out of all correlations, relative VO2peak showed the highest relation to mean HR during SFE (-0.593) as well as FOT (-0.693). Conclusions: Endurance in terms of VO2peak is an important prerequisite for both firefighting exercises. However, for standard simulated firefighting exercises it is important to work below VT1. For firefighting exercises in extreme temperatures with smoke, poor visibility and unexpected flashovers a high fitness level is required in order to keep the time spent above RCP as short as possible. PMID- 28878695 TI - Erratum: Vitamin A Affects Flatfish Development in a Thyroid Hormone Signaling and Metamorphic Stage Dependent Manner. AB - [This corrects the article on p. 458 in vol. 8, PMID: 28713287.]. PMID- 28878696 TI - "I Am I and My Bacterial Circumstances": Linking Gut Microbiome, Neurodevelopment, and Depression. AB - Recently, there has been renewed interest in the role played by microbiome in both human health and human disease. A correct equilibrium between the human host and their microorganisms is important for an appropriate physiological function. Extensive research has shown that microbes that inhabit the gastrointestinal tract-or gut microbiota-are involved not only in both nutritive and digestive activities but also in immunological processes. Moreover, the gut microbiome influences both central nervous system and energy homeostasis. An altered gut microbiome has been associated with the pathophysiology of different diseases, including neuropsychiatric disorders. Apparently, both environmental-diet, exposition to antibiotics, and infections-and host-genetic factors have a strong influence on gut microbiome, modulating the risk for neuropsychiatric illness. Also, early life disruption of the microbiome-gut-brain (MGB) axis has been associated with an increased risk of developing depression later in life, suggesting a link between gut microbiome, neurodevelopment, and depression. This review aims to contribute to this growing area of research by exploring the role played by the gut microbiome in neurodevelopment and in the etiology of the depressive syndrome, including nutritional, immunological, and energy homeostasis approaches. PMID- 28878697 TI - Dietary Supplement for Core Symptoms of Autism Spectrum Disorder: Where Are We Now and Where Should We Go? AB - Autism spectrum disorders (ASDs) are a class of severe and chronic conditions and core symptoms are deficits in social interaction, language communication impairments, and repetitive/stereotyped behavior. Given the limitations of available treatments and substantially increased prevalence of the disease, additional interventions are needed. Since the use of dietary supplements for ASD is of high prevalence, up-to-date information about those supplements are required for both parents and clinicians. Relevant articles were identified through a systematic search of PubMed, EMBASE, Cochrane library, and PsychINFO databases (through May 2017). Current best evidences of 22 randomized controlled trials on 8 different dietary supplements for core symptoms of ASD were reviewed. For each supplement, this report focuses on the definition and potential therapeutic mechanisms, the latest advances, and discussion of study limitations and future directions. Most studies were small and short term, and there is little evidence to support effectiveness of dietary supplements for children with ASD. PMID- 28878699 TI - Bodily Reactions to Emotional Words Referring to Own versus Other People's Emotions. AB - According to embodiment theories, language and emotion affect each other. In line with this, several previous studies investigated changes in bodily responses including facial expressions, heart rate or skin conductance during affective evaluation of emotional words and sentences. This study investigates the embodiment of emotional word processing from a social perspective by experimentally manipulating the emotional valence of a word and its personal reference. Stimuli consisted of pronoun-noun pairs, i.e., positive, negative, and neutral nouns paired with possessive pronouns of the first or the third person ("my," "his") or the non-referential negation term ("no") as controls. Participants had to quickly evaluate the word pairs by key presses as either positive, negative, or neutral, depending on the subjective feelings they elicit. Hereafter, they elaborated the intensity of the feeling on a non-verbal scale from 1 (very unpleasant) to 9 (very pleasant). Facial expressions (M. Zygomaticus, M. Corrugator), heart rate, and, for exploratory purposes, skin conductance were recorded continuously during the spontaneous and elaborate evaluation tasks. Positive pronoun-noun phrases were responded to the quickest and judged more often as positive when they were self-related, i.e., related to the reader's self (e.g., "my happiness," "my joy") than when related to the self of a virtual other (e.g., "his happiness," "his joy"), suggesting a self positivity bias in the emotional evaluation of word stimuli. Physiologically, evaluation of emotional, unlike neutral pronoun-noun pairs initially elicited an increase in mean heart rate irrespective of stimulus reference. Changes in facial muscle activity, M. Zygomaticus in particular, were most pronounced during spontaneous evaluation of positive other-related pronoun-noun phrases in line with theoretical assumptions that facial expressions are socially embedded even in situation where no real communication partner is present. Taken together, the present results confirm and extend the embodiment hypothesis of language by showing that bodily signals can be differently pronounced during emotional evaluation of self- and other-related emotional words. PMID- 28878698 TI - Synthetic Cathinone and Cannabinoid Designer Drugs Pose a Major Risk for Public Health. AB - As part of an increasing worldwide use of designer drugs, recent use of compounds containing cathinones and synthetic cannabinoids is especially prevalent. Here, we reviewed current literature on the prevalence, epidemiology, bio-behavioral effects, and detection of these compounds. Gender differences and clinical effects will also be examined. Chronic use of synthetic cathinone compounds can have major effects on the central nervous system and can induce acute psychosis, hypomania, paranoid ideation, and delusions, similar to the effects of other better-known amphetamine-type stimulants. Synthetic cannabinoid products have effects that are somewhat similar to those of natural cannabis but more potent and long-lasting than THC. Some of these compounds are potent and dangerous, having been linked to psychosis, mania, and suicidal ideation. Novel compounds are developed rapidly and new screening techniques are needed to detect them as well as a rigorous regulation and legislation reinforcement to prevent their distribution and use. Given the rapid increase in the use of synthetic cathinones and cannabinoid designer drugs, their potential for dependence and abuse, and harmful medical and psychiatric effects, there is a need for research and education in the areas of prevention and treatment. PMID- 28878700 TI - Growth Mixture Modeling of Depression Symptoms Following Traumatic Brain Injury. AB - Growth Mixture Modeling (GMM) was used to investigate the longitudinal trajectory of groups (classes) of depression symptoms, and how these groups were predicted by the covariates of age, sex, severity, and length of hospitalization following Traumatic Brain Injury (TBI) in a group of 1074 individuals (696 males, and 378 females) from the Royal Hobart Hospital, who sustained a TBI. The study began in late December 2003 and recruitment continued until early 2007. Ages ranged from 14 to 90 years, with a mean of 35.96 years (SD = 16.61). The study also examined the associations between the groups and causes of TBI. Symptoms of depression were assessed using the Hospital Anxiety and Depression Scale within 3 weeks of injury, and at 1, 3, 6, 12, and 24 months post-injury. The results revealed three groups: low, high, and delayed depression. In the low group depression scores remained below the clinical cut-off at all assessment points during the 24-months post-TBI, and in the high group, depression scores were above the clinical cut off at all assessment points. The delayed group showed an increase in depression symptoms to 12 months after injury, followed by a return to initial assessment level during the following 12 months. Covariates were found to be differentially associated with the three groups. For example, relative to the low group, the high depression group was associated with more severe TBI, being female, and a shorter period of hospitalization. The delayed group also had a shorter period of hospitalization, were younger, and sustained less severe TBI. Our findings show considerable fluctuation of depression over time, and that a non-clinical level of depression at any one point in time does not necessarily mean that the person will continue to have non-clinical levels in the future. As we used GMM, we were able to show new findings and also bring clarity to contradictory past findings on depression and TBI. Consequently, we recommend the use of this approach in future studies in this area. PMID- 28878702 TI - Stigma-Stop: A Serious Game against the Stigma toward Mental Health in Educational Settings. AB - This paper presents the results from the application of a serious game called Stigma-Stop among a group of high school students with the aim of reducing the stigma toward mental illnesses. The video game features characters with various mental disorders (schizophrenia, depression, bipolar disorder, and panic disorder with agoraphobia) and provides information about these problems. Additionally, the game asks players about whether they have ever felt the same as the characters, if they believe the characters are psychologically well, and if they think they could help these individuals. Similarly, a variety of reactions are provided for players to choose from when they encounter the characters with these problems. A total of 552 students between the ages of 14 and 18 participated in the study, and they were randomly assigned to either the experimental group, which used Stigma-Stop, or the control group, which utilized a video game completely unrelated to mental health. Both video games were used for similar lengths of time. Following the application of Stigma-Stop, a statistically significant decrease was obtained in levels of stigma toward schizophrenia, both in terms of stereotypes and, to a greater extent, its potential dangerousness. However, this was not the case in the control group. Results thus demonstrate the video game's usefulness toward eradicating erroneous notions about serious mental disorders like schizophrenia. PMID- 28878701 TI - Working Memory Capacity Limits Motor Learning When Implementing Multiple Instructions. AB - Although it is generally accepted that certain practice conditions can place large demands on working memory (WM) when performing and learning a motor skill, the influence that WM capacity has on the acquisition of motor skills remains unsubstantiated. This study examined the role of WM capacity in a motor skill practice context that promoted WM involvement through the provision of explicit instructions. A cohort of 90 children aged 8 to 10 years were assessed on measures of WM capacity and attention. Children who scored in the lowest and highest thirds on the WM tasks were allocated to lower WM capacity (n = 24) and higher WM capacity (n = 24) groups, respectively. The remaining 42 participants did not participate in the motor task. The motor task required children to practice basketball shooting for 240 trials in blocks of 20 shots, with pre- and post-tests occurring before and after the intervention. A retention test was administered 1 week after the post-test. Prior to every practice block, children were provided with five explicit instructions that were specific to the technique of shooting a basketball. Results revealed that the higher WM capacity group displayed consistent improvements from pre- to post-test and through to the retention test, while the opposite effect occurred in the lower WM capacity group. This implies that the explicit instructions had a negative influence on learning by the lower WM capacity children. Results are discussed in relation to strategy selection for dealing with instructions and the role of attention control. PMID- 28878703 TI - You Look Human, But Act Like a Machine: Agent Appearance and Behavior Modulate Different Aspects of Human-Robot Interaction. AB - Gaze following occurs automatically in social interactions, but the degree to which gaze is followed depends on whether an agent is perceived to have a mind, making its behavior socially more relevant for the interaction. Mind perception also modulates the attitudes we have toward others, and determines the degree of empathy, prosociality, and morality invested in social interactions. Seeing mind in others is not exclusive to human agents, but mind can also be ascribed to non human agents like robots, as long as their appearance and/or behavior allows them to be perceived as intentional beings. Previous studies have shown that human appearance and reliable behavior induce mind perception to robot agents, and positively affect attitudes and performance in human-robot interaction. What has not been investigated so far is whether different triggers of mind perception have an independent or interactive effect on attitudes and performance in human robot interaction. We examine this question by manipulating agent appearance (human vs. robot) and behavior (reliable vs. random) within the same paradigm and examine how congruent (human/reliable vs. robot/random) versus incongruent (human/random vs. robot/reliable) combinations of these triggers affect performance (i.e., gaze following) and attitudes (i.e., agent ratings) in human robot interaction. The results show that both appearance and behavior affect human-robot interaction but that the two triggers seem to operate in isolation, with appearance more strongly impacting attitudes, and behavior more strongly affecting performance. The implications of these findings for human-robot interaction are discussed. PMID- 28878704 TI - The Reporting Quality of Systematic Reviews and Meta-Analyses in Industrial and Organizational Psychology: A Systematic Review. AB - Objective: The goal of this systematic review was to examine the reporting quality of the method section of quantitative systematic reviews and meta analyses from 2009 to 2016 in the field of industrial and organizational psychology with the help of the Meta-Analysis Reporting Standards (MARS), and to update previous research, such as the study of Aytug et al. (2012) and Dieckmann et al. (2009). Methods: A systematic search for quantitative systematic reviews and meta-analyses was conducted in the top 10 journals in the field of industrial and organizational psychology between January 2009 and April 2016. Data were extracted on study characteristics and items of the method section of MARS. A cross-classified multilevel model was analyzed, to test whether publication year and journal impact factor (JIF) were associated with the reporting quality scores of articles. Results: Compliance with MARS in the method section was generally inadequate in the random sample of 120 articles. Variation existed in the reporting of items. There were no significant effects of publication year and journal impact factor (JIF) on the reporting quality scores of articles. Conclusions: The reporting quality in the method section of systematic reviews and meta-analyses was still insufficient, therefore we recommend researchers to improve the reporting in their articles by using reporting standards like MARS. PMID- 28878705 TI - Children Affected by War and Armed Conflict: Parental Protective Factors and Resistance to Mental Health Symptoms. AB - This study examined the role of parenting styles and parental warmth in moderating relations between exposure to political life events and mental health symptoms among 277 Israeli adolescents aged 12-14 and their parents, who had been exposed to protracted periods of war, missile bombardments, and terrorism. Adolescents completed the Political Life Events (PLE) scale, Brief Symptom Inventory and questionnaires regarding parenting style and parental warmth. The primary caregiver completed the Child Behavior Checklist for assessment of the child's internalizing and externalizing symptoms. Results confirmed that severity of PLE exposure was positively correlated with psychological distress and with internalizing and externalizing symptoms. Maternal authoritativeness and warmth functioned as protective factors and had moderating effects on the relation between PLE exposure and mental health symptoms. In contrast, maternal authoritarianism exacerbated the relation between PLE exposure and children's externalizing symptoms. Fathers' parenting style and warmth had no significant relationship with children's mental health outcomes. These findings have important clinical and practical implications for parental guidance and support during periods of war and armed conflict. PMID- 28878706 TI - Does More Respect from Leaders Postpone the Desire to Retire? Understanding the Mechanisms of Retirement Decision-Making. AB - The demographic trends (i.e., low birth rates and increasing longevity) pose challenges with regard to the increase of the average employee age along with a lack of skilled personnel on the labor market. Society, organizations, and individuals are confronted with the question on how to prolong working lives in the future. Based on socioemotional selectivity theory, the purpose of this study was to investigate the relationship between respectful leadership and older workers' desired retirement age. In particular, we took a closer look at job satisfaction, subjective health, and work-to-private life conflict as underlying mechanisms. Further, we tested for the moderating role of occupational self efficacy as an auxiliary condition for the assumed relationships of respectful leadership. We tested our hypothesized model using data from 1,130 blue- and white-collar workers aged 45-65 years. The results of structural equation modeling indicated that respectful leadership was positively related to older workers' desired retirement age and that this relationship was mediated by subjective health and work-to-private life conflict but not by job satisfaction. The findings add to the literature on resources in retirement decision-making; notably, they highlight the importance of leadership behavior for older workers' motivation and socioemotional needs. PMID- 28878707 TI - Secondary Students' Writing Achievement Goals: Assessing the Mediating Effects of Mastery and Performance Goals on Writing Self-Efficacy, Affect, and Writing Achievement. AB - The two studies reported here explored the factor structure of the newly constructed Writing Achievement Goal Scale (WAGS), and examined relationships among secondary students' writing achievement goals, writing self-efficacy, affect for writing, and writing achievement. In the first study, 697 middle school students completed the WAGS. A confirmatory factor analysis revealed a good fit for this data with a three-factor model that corresponds with mastery, performance approach, and performance avoidance goals. The results of Study 1 were an indication for the researchers to move forward with Study 2, which included 563 high school students. The secondary students completed the WAGS, as well as the Self-efficacy for Writing Scale, and the Liking Writing Scale. Students also self-reported grades for writing and for language arts courses. Approximately 6 weeks later, students completed a statewide writing assessment. We tested a theoretical model representing relationships among Study 2 variables using structural equation modeling including students' responses to the study scales and students' scores on the statewide assessment. Results from Study 2 revealed a good fit between a model depicting proposed relationships among the constructs and the data. Findings are discussed relative to achievement goal theory and writing. PMID- 28878708 TI - Inferential Costs of Trait Centrality in Impression Formation: Organization in Memory and Misremembering. AB - An extension of the DRM paradigm was used to study the impact of central traits (Asch, 1946) in impression formation. Traits corresponding to the four clusters of the implicit theory of personality-intellectual, positive and negative; and social, positive and negative (Rosenberg et al., 1968)-were used to develop lists containing several traits of one cluster and one central trait prototypical of the opposite cluster. Participants engaging in impression formation relative to participants engaging in memorization not only produced higher levels of false memories corresponding to the same cluster of the list traits but, under response time pressure at retrieval, also produced more false memories of the cluster corresponding to the central trait. We argue that the importance of central traits stems from their ability to activate their corresponding semantic space within a specialized associative memory structure underlying the implicit theory of personality. PMID- 28878709 TI - Why Is 10 Past 10 the Default Setting for Clocks and Watches in Advertisements? A Psychological Experiment. AB - Have you ever noticed that in watch advertisements the time is usually set at 10:10? The reasons and psychological effects of this default time setting are elusive. In Experiment 1, we hypothesized that watches showing a time setting resembling a smiling face (10:10) would enhance emotional valence and intention to buy compared to a neutral time setting (11:30), whereas a time setting resembling a sad face (8:20) would have the opposite effect. Moreover, we investigated a possible interaction effect with the gender of the participants. In Experiment 2, we directly tested the hypotheses that watches set at 10:10 resemble a smiling face, whereas watches set at 8:20 resemble a sad face. The data of the first experiment reveal that watches set at 10:10 showed a significant positive effect on the emotion of the observer and the intention to buy. However, watches set at 8:20 did not show any effect on the emotion or the intention to buy. Moreover, watches set at 10:10 induced in women significantly stronger ratings of pleasure than in men. The data of the second experiment show that participants consistently perceive high resemblance between watches set at 10:10 and a smiling face as well as high resemblance between watches set at 8:20 and a sad face. This study provides for the first time empirical evidence for the notion that using watches with a time setting resembling a smiling face (like 10:10) can positively affect the emotional response of the observers and their evaluation of a seen watch, even though they are not aware of the fact that the shown time setting is inducing this effect. Practical implications of the observed findings and alternative explanations are discussed. PMID- 28878710 TI - Examining Depressive Symptoms and Their Predictors in Malaysia: Stress, Locus of Control, and Occupation. AB - The 2015 National Health and Morbidity Survey estimated that over 29% of the adult population of Malaysia suffers from mental distress, a nearly 3-fold increase from the 10.7% estimated by the NHMS in 1996 pointing to the potential beginnings of a public health crisis. This study aimed to better understand this trend by assessing depressive symptoms and their correlates in a cross-section of Malaysians. Specifically, it assesses stress, perceived locus of control, and various socio-demographic variables as possible predictors of depressive symptoms in the Malaysian context. A total of 728 adults from three Malaysian states (Selangor, Penang, Terengganu) completed Beck's depression inventory as well as several other measures: 10% of respondents reported experiencing severe levels of depressive symptoms, 11% reported moderate and 15% reported mild depressive symptoms indicating that Malaysians are experiencing high levels of emotional distress. When controlling for the influence of other variables, depressive symptoms were predictably related to higher levels of stress and lower levels of internal locus of control. Ethnic Chinese Malaysians, housewives and those engaged in professional-type occupations reported less depressive symptoms. Business owners reported more depressive symptoms. Further research should look more into Malaysians' subjective experience of stress and depression as well as explore environmental factors that may be contributing to mental health issues. It is argued that future policies can be designed to better balance individual mental health needs with economic growth. PMID- 28878711 TI - Parental Factors Associated with Child Post-traumatic Stress Following Injury: A Consideration of Intervention Targets. AB - Post-traumatic stress disorder (PTSD) symptoms are relatively common following pediatric traumatic injury and are related to poor long-term child outcomes. However, due to concerns regarding the efficacy of early child preventive interventions, and difficulty intervening with injured and medicated children soon after the event, it is not feasible to provide early psychological interventions to children exposed to traumatic injury. Parental PTSD symptoms and reactions to the child's traumatic injury impact child outcomes and provide potential targets for early intervention to reduce child symptom development without involving the child. The authors conducted a review of the literature using Psycinfo and Pubmed research databases (publication years = 1990-2017) and identified 65 published studies relevant to the topic of the review. The present review considers parent factors [parenting styles, parental post-traumatic pathology (PTS), adaptive and maladaptive coping strategies, and communication regarding the traumatic injury] and their impact on child PTS. We focus specifically on factors amenable to intervention. We further review moderators of these relationships (e.g., child age and gender, parent gender) and conclude that it is unlikely that a one-size-fits-all approach to treatment will be successful. Rather, it is necessary to consider the age and gender of parent child dyads in designing and providing targeted interventions to families following the traumatic injury of a child. PMID- 28878712 TI - How Game Location Affects Soccer Performance: T-Pattern Analysis of Attack Actions in Home and Away Matches. AB - The influence of game location on performance has been widely examined in sport contexts. Concerning soccer, game-location affects positively the secondary and tertiary level of performance; however, there are fewer evidences about its effect on game structure (primary level of performance). This study aimed to detect the effect of game location on a primary level of performance in soccer. In particular, the objective was to reveal the hidden structures underlying the attack actions, in both home and away matches played by a top club (Serie A 2012/2013-First Leg). The methodological approach was based on systematic observation, supported by digital recordings and T-pattern analysis. Data were analyzed with THEME 6.0 software. A quantitative analysis, with nonparametric Mann-Whitney test and descriptive statistics, was carried out to test the hypotheses. A qualitative analysis on complex patterns was performed to get in depth information on the game structure. This study showed that game tactics were significantly different, with home matches characterized by a more structured and varied game than away matches. In particular, a higher number of different patterns, with a higher level of complexity and including more unique behaviors was detected in home matches than in the away ones. No significant differences were found in the number of events coded per game between the two conditions. THEME software, and the corresponding T-pattern detection algorithm, enhance research opportunities by going further than frequency-based analyses, making this method an effective tool in supporting sport performance analysis and training. PMID- 28878713 TI - Human-Animal Interaction and Older Adults: An Overview. AB - Both pet ownership and animal-assisted therapy are becoming increasingly popular in the United States, and the science of human-animal interaction (HAI) seeks to explore how these relationships with animals can impact health and well-being. In particular, one burgeoning area of research is the role of HAI in healthy aging, given the potential for HAI as an important feature of health and well-being in older adults. The purpose of this review is to summarize and evaluate existing research in this innovative area of scholarship, identifying the potential benefits and risks of both pet ownership and animals in therapeutic settings for older adults. We will also identify recommendations for future research and applications in this developing area of scholarship. PMID- 28878714 TI - Modulating the Activity of the DLPFC and OFC Has Distinct Effects on Risk and Ambiguity Decision-Making: A tDCS Study. AB - Human beings are constantly exposed to two types of uncertainty situations, risk and ambiguity. Neuroscientific studies suggest that the dorsolateral prefrontal cortex (DLPFC) and the orbital frontal cortex (OFC) play significant roles in human decision making under uncertainty. We applied the transcranial direct current stimulation (tDCS) device to modulate the activity of participants' DLPFC and OFC separately, comparing the causal relationships between people's behaviors and the activity of the corresponding brain cortex when confronted with situations of risk and ambiguity. Our experiment employed a pre-post design and a risk/ambiguity decision-making task, from which we could calculate the preferences via an estimation model. We found evidences that modulating the activity of the DLPFC using right anodal/left cathodal tDCS significantly enhanced the participants' preferences for risk, whereas modulating the activity of the OFC with right anodal/left cathodal tDCS significantly decreased the participants' preferences for ambiguity. The reverse effects were also observed in the reversed tDCS treatments on the two areas. Our results suggest that decision-making processes under risk and ambiguity are complicated and may be encoded in two distinct circuits in our brains as the DLPFC primarily impacts decisions under risk whereas the OFC affects ambiguity. PMID- 28878715 TI - Commentary: Task-Switching in Pigeons: Associative Learning or Executive Control? PMID- 28878717 TI - Understanding the Self in Individuals with Autism Spectrum Disorders (ASD): A Review of Literature. AB - When the system of self is explored in individuals with Autism Spectrum Disorders (ASDs), it is important to measure it via both their own perceptions of the self and their understanding of others' perceptions on themselves at a multidimensional level. This paper reviews existing research in this area using a three-dimension approach. Researchers have found that impairments in the self system are usually correlated with these individuals' social and cognitive functioning levels: high functioning individuals with ASD who have higher IQ are found to have better awareness of their limitations in social and communication domains than those with lower IQ. Many researchers believe that there are impairments in the psychological (but not physical) self in individuals with ASD, such as theory of mind deficits due to social and communicative impairments. On the other hand, some researchers argue that individuals with ASD have selective rather than global impairments in the self. In other words, the impairment usually lies in a specific aspect of functioning in individuals with ASD. Insights from the review of existing literature on this topic may be able to shed some lights on the development of effective intervention programs to improve social communication deficits in this population. PMID- 28878718 TI - Errors in the 2017 APA Clinical Practice Guideline for the Treatment of PTSD: What the Data Actually Says. AB - The American Psychological Association (APA) Practice Guidelines for the Treatment of Posttraumatic Stress Disorder (PTSD) concluded that there was strong evidence for cognitive behavioral therapy (CBT), cognitive processing therapy (CPT), cognitive therapy (CT), and exposure therapy yet weak evidence for eye movement desensitization and reprocessing (EMDR). This is despite the findings from an associated systematic review which concluded that EMDR leads to loss of PTSD diagnosis and symptom reduction. Depression symptoms were also found to improve more with EMDR than control conditions. In that review, EMDR was marked down on strength of evidence (SOE) for symptom reduction for PTSD. However, there were several problems with the conclusions of that review. Firstly, in assessing the evidence in one of the studies, the reviewers chose an incorrect measure that skewed the data. We recalculated a meta-analysis with a more appropriate measure and found the SOE improved. The resulting effect size for EMDR on PTSD symptom reduction compared to a control condition was large for studies that meet the APA inclusion criteria (SMD = 1.28) and the heterogeneity was low (I2= 43%). Secondly, even if the original measure was chosen, we highlight inconsistencies with the way SOE was assessed for EMDR, CT, and CPT. Thirdly, we highlight two papers that were omitted from the analysis. One of these was omitted without any apparent reason. It found EMDR superior to a placebo control. The other study was published in 2015 and should have been part of APA guidelines since they were published in 2017. The inclusion of either study would have resulted in an improvement in SOE. Including both studies results in standard mean difference and confidence intervals that were better for EMDR than for CPT or CT. Therefore, the SOE should have been rated as moderate and EMDR assessed as at least equivalent to these CBT approaches in the APA guidelines. This would bring the APA guidelines in line with other recent practice guidelines from other countries. Less critical but also important, were several inaccuracies in assessing the risk of bias and the failure to consider studies supporting strong gains of EMDR at follow-up. PMID- 28878716 TI - Cognitive Mechanisms Underlying Directional and Non-directional Spatial-Numerical Associations across the Lifespan. AB - There is accumulating evidence suggesting an association of numbers with physical space. However, the origin of such spatial-numerical associations (SNAs) is still debated. In the present study we investigated the development of two SNAs in a cross-sectional study involving children, young and middle-aged adults as well as the elderly: (1) the SNARC (spatial-numerical association of response codes) effect, reflecting a directional SNA; and (2) the numerical bisection bias in a line bisection task with numerical flankers. Results revealed a consistent SNARC effect in all age groups that continuously increased with age. In contrast, a numerical bisection bias was only observed for children and elderly participants, implying an U-shaped distribution of this bias across age groups. Additionally, individual SNARC effects and numerical bisection biases did not correlate significantly. We argue that the SNARC effect seems to be influenced by longer lasting experiences of cultural constraints such as reading and writing direction and may thus reflect embodied representations. Contrarily, the numerical bisection bias may originate from insufficient inhibition of the semantic influence of irrelevant numerical flankers, which should be more pronounced in children and elderly people due to development and decline of cognitive control, respectively. As there is an ongoing debate on the origins of SNAs in general and the SNARC effect in particular, the present results are discussed in light of these differing accounts in an integrative approach. However, taken together, the present pattern of results suggests that different cognitive mechanisms underlie the SNARC effect and the numerical bisection bias. PMID- 28878719 TI - Different and Similar at the Same Time. Cultural Competence through the Leans of Healthcare Providers. AB - Cultural competence (CC) for professionals and organizations has been recognized as a key strategy to reduce health care inequalities for migrants and to promote responsiveness to diversity. For decades its main aim has been matching health services to the cultural needs of migrant users. Otherwise literature highlighted the need to find a pragmatic middle way between the 'static' and the 'dynamic' views of culture that are recognizable in CC approaches. A pragmatic middle way to CC will be proposed as the way to respect diversity, even responding to cultural issues, without stereotyping or discriminating. To understand conditions that favor this pragmatic middle way this study aims to explore: (1) perceptions of healthcare providers in managing diversity; (2) strategies used to meet health needs at a professional and organizational level. A qualitative case study was conducted in a healthcare service renowned for its engagement in migrant sensitive care. Four different professional figures involved in CC strategies at different levels, both managerial and non-managerial, were interviewed. Data were analyzed using thematic analysis. Findings indicated that dealing with diversity poses challenges for healthcare providers, by confronting them with multilevel barriers to quality of care. A pragmatic middle way to CC seems to rely on complex understanding of the interaction between patients social conditions and the capacity of the institutional system to promote equity. Professional and organizational strategies, such as inter-professional and intersectional collaboration, cultural food adaptation and professional training can enhance quality of care, patient compliance responding to social and cultural needs. PMID- 28878720 TI - Cross-Cultural Investigation of Male Gait Perception in Relation to Physical Strength and Speed. AB - Previous research documents that men and women can accurately judge male physical strength from gait, but also that the sexes differ in attractiveness judgments of strong and weak male walkers. Women's (but not men's) attractiveness assessments of strong male walkers are higher than for weak male walkers. Here, we extend this research to assessments of strong and weak male walkers in Chile, Germany, and Russia. Men and women judged videos of virtual characters, animated with the walk movements of motion-captured men, on strength and attractiveness. In two countries (Germany and Russia), these videos were additionally presented at 70% (slower) and 130% (faster) of their original speed. Stronger walkers were judged to be stronger and more attractive than weak walkers, and this effect was independent of country (but not sex). Women tended to provide higher attractiveness judgments to strong walkers, and men tended to provide higher attractiveness judgments to weak walkers. In addition, German and Russian participants rated strong walkers most attractive at slow and fast speed. Thus, across countries men and women can assess male strength from gait, although they tended to differ in attractiveness assessments of strong and weak male walkers. Attractiveness assessments of male gait may be influenced by society-specific emphasis on male physical strength. PMID- 28878721 TI - Guiding Framework for Driver Assessment Using Driving Simulators. PMID- 28878722 TI - Prenatal Internal Locus of Control Is Positively Associated with Offspring IQ, Mediated through Parenting Behavior, Prenatal Lifestyle and Social Circumstances. AB - Locus of control (LOC) is a measure that identifies the likelihood as to whether an individual considers what happens to him is largely a matter of luck or fate (known as externally oriented) or whether it is something that the individual can influence (internality). Here we have used data collected as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine the associations between the mothers' LOC orientation before the birth of the child and her child's cognition measured at age 8. Using results from 6801 children we show that maternal internal LOC is associated with increased ability in offspring IQ, as measured using the WISC, with children of internally oriented mothers having an advantage of approximately 7 IQ points at age 8. As a sensitivity analysis we used the IQ test results of a sample of 986 preschool children tested using the WPSSI at age 4. A similar advantage was found among the offspring of the internally oriented mothers. We investigated mechanistic explanations for these results firstly by determining the extent to which three separate sets of factors known to be influenced by the LOC orientation might explain these findings. We showed that (a) perinatal life-style exposures, (b) parenting attitudes and strategies and (c) socio-economic circumstances, largely explain the mechanism through which the internality of the mother influences the cognition of the child. Similar effects were found using the smaller sample tested at age 4. The results indicate that efforts made to foster internality in adolescents and young adults prior to parenthood may result in improvements in the cognitive development of the next generation. Intervention studies are urgently needed. PMID- 28878723 TI - Fitting the Fractional Polynomial Model to Non-Gaussian Longitudinal Data. AB - As in cross sectional studies, longitudinal studies involve non-Gaussian data such as binomial, Poisson, gamma, and inverse-Gaussian distributions, and multivariate exponential families. A number of statistical tools have thus been developed to deal with non-Gaussian longitudinal data, including analytic techniques to estimate parameters in both fixed and random effects models. However, as yet growth modeling with non-Gaussian data is somewhat limited when considering the transformed expectation of the response via a linear predictor as a functional form of explanatory variables. In this study, we introduce a fractional polynomial model (FPM) that can be applied to model non-linear growth with non-Gaussian longitudinal data and demonstrate its use by fitting two empirical binary and count data models. The results clearly show the efficiency and flexibility of the FPM for such applications. PMID- 28878724 TI - Commentary: The Need for Bayesian Hypothesis Testing in Psychological Science. PMID- 28878725 TI - The Logic of Appearance: Dennett, Phenomenology and Psychoanalysis. AB - In the present essay, we aim to develop and contrast three different positions toward Sellars' distinction between the manifest and scientific images of man: Dennett's philosophical reconstruction of neurocognitive science, contemporary phenomenology and psychoanalysis. We will suggest that these respective traditions and the substantial differences between them can be understood in terms of a 'logic of appearance.' Related to this are differing ideas about the rights and limits of the first-person perspective, the relation between conscious experience and belief, and the issue of naturalization. In the final part, we will try to specify, on the basis of a detailed reading of the disagreement between Dennett and phenomenology, in what way psychoanalytic theory could respond to these different issues. PMID- 28878726 TI - The Family Alliance Model: A Way to Study and Characterize Early Family Interactions. AB - The aim of this paper is to present the family alliance (FA) model, which is designed to conceptualize the relational dynamics in the early family. FA is defined as the coordination a family can reach when fulfilling a task, such as playing a game or having a meal. According to the model, being coordinated as a family depends on four interactive functions: participation (all members are included), organization (members assume differentiated roles), focalization (family shares a common theme of activity), affect sharing (there is empathy between members). The functions are operationalized through the spatiotemporal characteristics of non-verbal interactions: for example, distance between the partners, orientation of their bodies, congruence within body segments, signals of readiness to interact, joint attention, facial expressions. Several standardized observational situations have been designed to assess FA: The Lausanne Trilogue Play (with its different versions), in which mother, father, and baby interact in all possible configurations of a triad, and the PicNic Game for families with several children. Studies in samples of non-referred and referred families (for infant or parental psychopathology) have highlighted different types of FA: disorganized, conflicted, and cooperative. The type of FA in a given family is stable through the first years and is predictive of developmental outcomes in children, such as psychofunctional symptoms, understanding of complex emotions, and Theory of Mind development. PMID- 28878727 TI - Exploring Memories of the Self: 2412 Self-image Norms for Adults Aged 17 to 88. PMID- 28878728 TI - Patient Affected by Beta-Propeller Protein-Associated Neurodegeneration: A Therapeutic Attempt with Iron Chelation Therapy. AB - Here, we report the case of a 36-year-old patient with a diagnosis of de novo mutation of the WDR45 gene, responsible for beta-propeller protein-associated neurodegeneration, a phenotypically distinct, X-linked dominant form of Neurodegeneration with Brain Iron Accumulation. The clinical history is characterized by a relatively stable intellectual disability and a hypo bradykinetic and hypertonic syndrome with juvenile onset. Genetic investigations and T1 and T2-weighted MR images align with what is described in literature. The patient was also subjected to PET with 18-FDG investigation and DaT-Scan study. In reporting relevant clinical data, we want to emphasize the fact that the patient received a chelation therapy with deferiprone (treatment already used in other forms of NBIA with encouraging results), which, however, had to be interrupted because the parkinsonian symptoms worsened. Conversely, the patient has benefited from non-drug therapies and, in particular, from an adapted motor activity with assisted pedaling (method in the process of validation in treatments of parkinsonian syndromes), which started before the treatment with deferiprone and still continues. PMID- 28878729 TI - Structural, Functional, and Metabolic Brain Markers Differentiate Collision versus Contact and Non-Contact Athletes. AB - There is growing concern about how participation in contact sports affects the brain. Retrospective evidence suggests that contact sports are associated with long-term negative health outcomes. However, much of the research to date has focused on former athletes with significant health problems. Less is known about the health of current athletes in contact and collision sports who have not reported significant medical issues. In this cross-sectional study, advanced magnetic resonance imaging (MRI) was used to evaluate multiple aspects of brain physiology in three groups of athletes participating in non-contact sports (N = 20), contact sports (N = 22), and collision sports (N = 23). Diffusion tensor imaging was used to assess white matter microstructure based on measures of fractional anisotropy (FA) and mean diffusivity (MD); resting-state functional MRI was used to evaluate global functional connectivity; single-voxel spectroscopy was used to compare ratios of neural metabolites, including N-acetyl aspartate (NAA), creatine (Cr), choline, and myo-inositol. Multivariate analysis revealed structural, functional, and metabolic measures that reliably differentiated between sport groups. The collision group had significantly elevated FA and reduced MD in white matter, compared to both contact and non contact groups. In contrast, the collision group showed significant reductions in functional connectivity and the NAA/Cr metabolite ratio, relative to only the non contact group, while the contact group overlapped with both non-contact and collision groups. For brain regions associated with contact sport participation, athletes with a history of concussion also showed greater alterations in FA and functional connectivity, indicating a potential cumulative effect of both contact exposure and concussion history on brain physiology. These findings indicate persistent differences in brain physiology for athletes participating in contact and collision sports, which should be considered in future studies of concussion and subconcussive impacts. PMID- 28878730 TI - Stepping to the Beat: Feasibility and Potential Efficacy of a Home-Based Auditory Cued Step Training Program in Chronic Stroke. AB - BACKGROUND: Hemiparesis after stroke typically results in a reduced walking speed, an asymmetrical gait pattern and a reduced ability to make gait adjustments. The purpose of this pilot study was to investigate the feasibility and preliminary efficacy of home-based training involving auditory cueing of stepping in place. METHODS: Twelve community-dwelling participants with chronic hemiparesis completed two 3-week blocks of home-based stepping to music overlaid with an auditory metronome. Tempo of the metronome was increased 5% each week. One 3-week block used a regular metronome, whereas the other 3-week block had phase shift perturbations randomly inserted to cue stepping adjustments. RESULTS: All participants reported that they enjoyed training, with 75% completing all training blocks. No adverse events were reported. Walking speed, Timed Up and Go (TUG) time and Dynamic Gait Index (DGI) scores (median [inter-quartile range]) significantly improved between baseline (speed = 0.61 [0.32, 0.85] m?s-1; TUG = 20.0 [16.0, 39.9] s; DGI = 14.5 [11.3, 15.8]) and post stepping training (speed = 0.76 [0.39, 1.03] m?s-1; TUG = 16.3 [13.3, 35.1] s; DGI = 16.0 [14.0, 19.0]) and was maintained at follow-up (speed = 0.75 [0.41, 1.03] m?s-1; TUG = 16.5 [12.9, 34.1] s; DGI = 16.5 [13.5, 19.8]). CONCLUSION: This pilot study suggests that auditory-cued stepping conducted at home was feasible and well-tolerated by participants post-stroke, with improvements in walking and functional mobility. No differences were detected between regular and phase-shift training with the metronome at each assessment point. PMID- 28878731 TI - Head-Eye Vestibular Motion Therapy Affects the Mental and Physical Health of Severe Chronic Postconcussion Patients. AB - CONTEXT: Approximately 1.8-3.6 million annual traumatic brain injuries occur in the United States. An evidence-based treatment for concussions that is reliable and effective has not been available. OBJECTIVE: The objective of this study is to test whether head-eye vestibular motion (HEVM) therapy is associated with decreased symptoms and increased function in postconcussive syndrome (PCS) patients that have been severely impaired for greater than 6 months after a mild traumatic brain injury. DESIGN: Retrospective clinical chart review. SETTING AND PARTICIPANTS: Tertiary Specialist Brain Rehabilitation Center. INTERVENTIONS: All subjects underwent comprehensive neurological examinations including measurement of eye and head movement. The seven modules of the C3 Logix Comprehensive Concussion Management System were used for pre- and postmeasurements of outcome of HEVM therapy. MATERIALS AND METHODS: We utilized an objective validated measurement of physical and mental health characteristics of our patients before and after a 1-week HEVM rehabilitation program. We included only PCS patients that were disabled from work or school for a period of time exceeding 6 months after suffering a sports concussion. These subjects all were enrolled in a 5-day HEVM rehabilitation program at our Institutional Brain Center with pre- and post C3 Logix testing outcomes. RESULTS: There were statistical and substantive significant decreases in PCS symptom severity after treatment and statistical and substantive significant increases in standardized assessment of concussion scores. The outcomes were associated with positive changes in mental and physical health issues. This is a retrospective review and no control group has been included in this study. These are major limitations with retrospective reviews and further investigations with prospective designs including a randomized controlled study are necessary to further our understanding. CONCLUSION: Head-eye vestibular motion therapy of 5 days duration is associated with statistical and substantive significant decreases of symptom severity associated with chronic PCS. PMID- 28878732 TI - Multiple Sclerosis Treatments Affect Monocyte-Derived Microvesicle Production. AB - Microvesicles (MVs) are released by immune cells especially of the myeloid lineage upon stimulation with ATP on its cognate receptor P2X7, both in physiological and pathological conditions. In multiple sclerosis (MS) the role of MVs remains little investigated. We aimed to compare the release of MVs in peripheral blood monocytes from MS patients with healthy donors (HDs) and to see how current MS treatment may affect such a production. We also assessed the treatment effect on M1 and M2 monocyte polarization and on the inflammasome components. Spectrophotometric quantification was performed to compare monocyte derived MVs from 20 untreated relapsing-remitting MS patients and 20 HDs and to evaluate the effect of different treatments. Subgroups of nine interferon-beta and of five teriflunomide-treated MS patients were evaluated at baseline and after 2, 6, and 12 months of treatment. Six MS patients taking Fingolimod, after switching from a first-line therapy, were included in the study and analyzed only at 12 months of treatment. MVs analysis revealed that monocytes from MS patients produced vesicles in higher amounts than controls. All treatments reduced vesicle production but only teriflunomide was associated with a downregulation of purinergic P2X7 receptor and inflammasome components expression. The therapies modulated mRNA expression of both M1 and M2 monocyte markers. Our results, suggesting new molecular targets for drugs currently used in MS, may potentially provide useful novel evidence to approach the disease. PMID- 28878733 TI - Clinical Approach to Supranuclear Brainstem Saccadic Gaze Palsies. AB - Failure of brainstem supranuclear centers for saccadic eye movements results in the clinical presence of a brainstem-mediated supranuclear saccadic gaze palsy (SGP), which is manifested as slowing of saccades with or without range of motion limitation of eye movements and as loss of quick phases of optokinetic nystagmus. Limitation in the range of motion of eye movements is typically worse with saccades than with smooth pursuit and is overcome with vestibular-ocular reflexive eye movements. The differential diagnosis of SGPs is broad, although acute-onset SGP is most often from brainstem infarction and chronic vertical SGP is most commonly caused by the neurodegenerative condition progressive supranuclear palsy. In this review, we discuss the brainstem anatomy and physiology of the brainstem saccade-generating network; we discuss the clinical features of SGPs, with an emphasis on insights from quantitative ocular motor recordings; and we consider the broad differential diagnosis of SGPs. PMID- 28878735 TI - MicroRNA Regulation of Brown Adipogenesis and Thermogenic Energy Expenditure. AB - Obesity, diabetes, and associated metabolic diseases have become global epidemics. Obesity results from excess accumulation of white fat, while brown and its related beige fat function to dissipate energy as heat, thus counteracting obesity and its related metabolic disorders. Understanding the regulatory mechanisms for both white and brown adipogenesis provides new insights for prevention and treatment of these metabolic diseases. In addition to traditional gene transcription and translation, microRNA (miRNA) represents a new layer of regulatory mechanism in many biological processes and has attracted a great deal of research interests in exploring their roles in physiological and pathophysiological conditions. This review focuses on the recent advances of regulating brown adipogenesis and energy metabolism by miRNAs, aiming to delineate the regulatory principles of miRNAs on this unique aspect of energy homeostasis. PMID- 28878736 TI - Commentary: Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut From Gut to Brain? PMID- 28878734 TI - Speech and Voice Response to a Levodopa Challenge in Late-Stage Parkinson's Disease. AB - BACKGROUND: Parkinson's disease (PD) patients are affected by hypokinetic dysarthria, characterized by hypophonia and dysprosody, which worsens with disease progression. Levodopa's (l-dopa) effect on quality of speech is inconclusive; no data are currently available for late-stage PD (LSPD). OBJECTIVE: To assess the modifications of speech and voice in LSPD following an acute l-dopa challenge. METHOD: LSPD patients [Schwab and England score <50/Hoehn and Yahr stage >3 (MED ON)] performed several vocal tasks before and after an acute l-dopa challenge. The following was assessed: respiratory support for speech, voice quality, stability and variability, speech rate, and motor performance (MDS-UPDRS-III). All voice samples were recorded and analyzed by a speech and language therapist blinded to patients' therapeutic condition using Praat 5.1 software. RESULTS: 24/27 (14 men) LSPD patients succeeded in performing voice tasks. Median age and disease duration of patients were 79 [IQR: 71.5-81.7] and 14.5 [IQR: 11-15.7] years, respectively. In MED OFF, respiratory breath support and pitch break time of LSPD patients were worse than the normative values of non-parkinsonian. A correlation was found between disease duration and voice quality (R = 0.51; p = 0.013) and speech rate (R = -0.55; p = 0.008). l Dopa significantly improved MDS-UPDRS-III score (20%), with no effect on speech as assessed by clinical rating scales and automated analysis. CONCLUSION: Speech is severely affected in LSPD. Although l-dopa had some effect on motor performance, including axial signs, speech and voice did not improve. The applicability and efficacy of non-pharmacological treatment for speech impairment should be considered for speech disorder management in PD. PMID- 28878737 TI - Conservation of Three-Dimensional Helix-Loop-Helix Structure through the Vertebrate Lineage Reopens the Cold Case of Gonadotropin-Releasing Hormone Associated Peptide. AB - GnRH-associated peptide (GAP) is the C-terminal portion of the gonadotropin releasing hormone (GnRH) preprohormone. Although it was reported in mammals that GAP may act as a prolactin-inhibiting factor and can be co-secreted with GnRH into the hypophyseal portal blood, GAP has been practically out of the research circuit for about 20 years. Comparative studies highlighted the low conservation of GAP primary amino acid sequences among vertebrates, contributing to consider that this peptide only participates in the folding or carrying process of GnRH. Considering that the three-dimensional (3D) structure of a protein may define its function, the aim of this study was to evaluate if GAP sequences and 3D structures are conserved in the vertebrate lineage. GAP sequences from various vertebrates were retrieved from databases. Analysis of primary amino acid sequence identity and similarity, molecular phylogeny, and prediction of 3D structures were performed. Amino acid sequence comparison and phylogeny analyses confirmed the large variation of GAP sequences throughout vertebrate radiation. In contrast, prediction of the 3D structure revealed a striking conservation of the 3D structure of GAP1 (GAP associated with the hypophysiotropic type 1 GnRH), despite low amino acid sequence conservation. This GAP1 peptide presented a typical helix-loop-helix (HLH) structure in all the vertebrate species analyzed. This HLH structure could also be predicted for GAP2 in some but not all vertebrate species and in none of the GAP3 analyzed. These results allowed us to infer that selective pressures have maintained GAP1 HLH structure throughout the vertebrate lineage. The conservation of the HLH motif, known to confer biological activity to various proteins, suggests that GAP1 peptides may exert some hypophysiotropic biological functions across vertebrate radiation. PMID- 28878739 TI - Precocious Puberty or Premature Thelarche: Analysis of a Large Patient Series in a Single Tertiary Center with Special Emphasis on 6- to 8-Year-Old Girls. AB - INTRODUCTION: We describe the etiology, MRI findings, and growth patterns in girls who had presented with signs of precocious puberty (PP), i.e., premature breast development or early menarche. Special attention was paid to the diagnostic findings in 6- to 8-year-olds. MATERIALS AND METHODS: We reviewed the medical records of 149 girls (aged 0.7-10.3 years) who had been evaluated for PP in the Helsinki University Hospital between 2001 and 2014. RESULTS: In 6- to 8 year-old girls, PP was most frequently caused by idiopathic gonadotropin releasing hormone (GnRH)-dependent PP (60%) and premature thelarche (PT; 39%). The former subgroup grew faster (8.7 +/- 2.0 cm/year, n = 58) than the girls with PT (7.0 +/- 1.1 cm/year, n = 32) (P < 0.001), and the best discrimination for GnRH-dependent PP was achieved with a growth velocity cut-off value of 7.0 cm/year (sensitivity 92% and specificity 58%) [area under the curve 0.82, 95% confidence interval (CI) 0.73-0.91, P < 0.001]. Among asymptomatic and previously healthy 6- to 8-year-old girls with GnRH-dependent PP, one (1.7%, 95% CI 0.3 9.7%) had a pathological brain MRI finding requiring surgical intervention (craniopharyngioma). In girls younger than 3 years, the most frequent cause of breast development was PT, and, in 3- to 6-year-olds, GnRH-dependent PP. CONCLUSION: In 6- to 8-year-old girls, analysis of growth velocity is helpful in differentiating between PT and GnRH-dependent PP. Although the frequency of clinically relevant intracranial findings in previously healthy, asymptomatic 6- to 8-year-old girls was low, they can present without any signs or symptoms, which favors routine MRI imaging also in this age group. PMID- 28878738 TI - Overlooked Mechanisms in Type 1 Diabetes Etiology: How Unique Costimulatory Molecules Contribute to Diabetogenesis. AB - Type 1 Diabetes (T1D) develops when immune cells invade the pancreatic islets resulting in loss of insulin production in beta cells. T cells have been proven to be central players in that process. What is surprising, however, is that classic mechanisms of tolerance cannot explain diabetogenesis; alternate mechanisms must now be considered. T cell receptor (TCR) revision is the process whereby T cells in the periphery alter TCR expression, outside the safety-net of thymic selection pressures. This process results in an expanded T cell repertoire, capable of responding to a universe of pathogens, but limitations are that increased risk for autoimmune disease development occurs. Classic T cell costimulators including the CD28 family have long been thought to be the major drivers for full T cell activation. In actuality, CD28 and its family member counterparts, ICOS and CTLA-4, all drive regulatory responses. Inflammation is driven by CD40, not CD28. CD40 as a costimulus has been largely overlooked. When naive T cells interact with antigen presenting cell CD154, the major ligand for CD40, is induced. This creates a milieu for T cell (CD40)-T cell (CD154) interaction, leading to inflammation. Finally, defined pathogenic effector cells including TH40 (CD4+CD40+) cells can express FOXP3 but are not Tregs. The cells loose FOXP3 to become pathogenic effector cells. Each of these mechanisms creates novel options to better understand diabetogenesis and create new therapeutic targets for T1D. PMID- 28878740 TI - DNA Delivery and Genomic Integration into Mammalian Target Cells through Type IV A and B Secretion Systems of Human Pathogens. AB - We explore the potential of bacterial secretion systems as tools for genomic modification of human cells. We previously showed that foreign DNA can be introduced into human cells through the Type IV A secretion system of the human pathogen Bartonella henselae. Moreover, the DNA is delivered covalently attached to the conjugative relaxase TrwC, which promotes its integration into the recipient genome. In this work, we report that this tool can be adapted to other target cells by using different relaxases and secretion systems. The promiscuous relaxase MobA from plasmid RSF1010 can be used to deliver DNA into human cells with higher efficiency than TrwC. MobA also promotes DNA integration, albeit at lower rates than TrwC. Notably, we report that DNA transfer to human cells can also take place through the Type IV secretion system of two intracellular human pathogens, Legionella pneumophila and Coxiella burnetii, which code for a distantly related Dot/Icm Type IV B secretion system. This suggests that DNA transfer could be an intrinsic ability of this family of secretion systems, expanding the range of target human cells. Further analysis of the DNA transfer process showed that recruitment of MobA by Dot/Icm was dependent on the IcmSW chaperone, which may explain the higher DNA transfer rates obtained. Finally, we observed that the presence of MobA negatively affected the intracellular replication of C. burnetii, suggesting an interference with Dot/Icm translocation of virulence factors. PMID- 28878741 TI - Heat Stress Dictates Microbial Lipid Composition along a Thermal Gradient in Marine Sediments. AB - Temperature exerts a first-order control on microbial populations, which constantly adjust the fluidity and permeability of their cell membrane lipids to minimize loss of energy by ion diffusion across the membrane. Analytical advances in liquid chromatography coupled to mass spectrometry have allowed the detection of a stunning diversity of bacterial and archaeal lipids in extreme environments such as hot springs, hydrothermal vents and deep subsurface marine sediments. Here, we investigated a thermal gradient from 18 to 101 degrees C across a marine sediment field and tested the hypothesis that cell membrane lipids provide a major biochemical basis for the bioenergetics of archaea and bacteria under heat stress. This paper features a detailed lipidomics approach with the focus on membrane lipid structure-function. Membrane lipids analyzed here include polar lipids of bacteria and polar and core lipids of archaea. Reflecting the low permeability of their ether-linked isoprenoids, we found that archaeal polar lipids generally dominate over bacterial lipids in deep layers of the sediments influenced by hydrothermal fluids. A close examination of archaeal and bacterial lipids revealed a membrane quandary: not only low permeability, but also increased fluidity of membranes are required as a unified property of microbial membranes for energy conservation under heat stress. For instance, bacterial fatty acids were composed of longer chain lengths in concert with higher degree of unsaturation while archaea modified their tetraethers by incorporation of additional methyl groups at elevated sediment temperatures. It is possible that these configurations toward a more fluidized membrane at elevated temperatures are counterbalanced by the high abundance of archaeal glycolipids and bacterial sphingolipids, which could reduce membrane permeability through strong intermolecular hydrogen bonding. Our results provide a new angle for interpreting membrane lipid structure-function enabling archaea and bacteria to survive and grow in hydrothermal systems. PMID- 28878743 TI - Characterization of the Copy Number and Variants of Deformed Wing Virus (DWV) in the Pairs of Honey Bee Pupa and Infesting Varroa destructor or Tropilaelaps mercedesae. AB - Recent honey bee colony losses, particularly during the winter, have been shown to be associated with the presence of both ectoparasitic mites and Deformed Wing Virus (DWV). Whilst the role of Varroa destructor mites as a viral vector is well established, the role of Tropilaelaps mercedesae mites in viral transmission has not been fully investigated. In this study, we tested the effects that V. destructor and T. mercedesae infestation have on fluctuation of the DWV copy number and alteration of the virus variants in honey bees by characterizing individual pupae and their infesting mites. We observed that both mite species were associated with increased viral copy number in honey bee pupae. We found a positive correlation between DWV copy number in pupae and copy number in infesting mites, and the same DWV type A variant was present in either low or high copy number in both honey bee pupae and infesting V. destructor. These data also suggest that variant diversity is similar between honey bee pupae and the mites that infest them. These results support a previously proposed hypothesis that DWV suppresses the honey bee immune system when virus copy number reaches a specific threshold, promoting greater replication. PMID- 28878744 TI - Guanidine N-methylation by BlsL Is Dependent on Acylation of Beta-amine Arginine in the Biosynthesis of Blasticidin S. AB - The peptidyl nucleoside blasticidin S (BS) produced by Streptomyces griseochromogenes was the first non-mercurial fungicide used to prevent rice blast and increasingly used as a selection reagent in transgenic study. Acylation by addition of a leucine residue at the beta amine group of arginine side chain of demethylblasticidin S (DBS) has been proposed as a novel self-resistance to the cytotoxic biosynthetic intermediate. But the resultant product leucyldemethylblasticidin S (LDBS) has not been isolated as a metabolite, and LDBS synthetase activity remained to be demonstrated in S. griseochromogenes. In this study, we isolated LDBS in a BS heterologous producer S. lividans WJ2 upon the deletion of blsL, which encodes a S-Adenosyl methionine-dependent methyltransferase. Purified BlsL efficiently methylated LDBS at the delta N of beta-arginine to generate the ultimate intermediate LBS, but nearly didn't methylate DBS to final product BS. Above experiments demonstrated that LDBS is indeed an intermediate in BS biosynthetic pathway, and acylation of beta-amino group of arginine side chain is prerequisite for efficient guanidine N methylation in addition to being a self-resistance mechanism. PMID- 28878742 TI - Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic? AB - Zika is a viral disease transmitted mainly by mosquitoes of the genus Aedes. In recent years, it has expanded geographically, changing from an endemic mosquito borne disease across equatorial Asia and Africa, to an epidemic disease causing large outbreaks in several areas of the world. With the recent Zika virus (ZIKV) outbreaks in the Americas, the disease has become a focus of attention of public health agencies and of the international research community, especially due to an association with neurological disorders in adults and to the severe neurological and ophthalmological abnormalities found in fetuses and newborns of mothers exposed to ZIKV during pregnancy. A large number of studies have been published in the last 3 years, revealing the structure of the virus, how it is transmitted and how it affects human cells. Many different animal models have been developed, which recapitulate several features of ZIKV disease and its neurological consequences. Moreover, several vaccine candidates are now in active preclinical development, and three of them have already entered phase I clinical trials. Likewise, many different compounds targeting viral and cellular components are being tested in in vitro and in experimental animal models. This review aims to discuss the current state of this rapidly growing literature from a multidisciplinary perspective, as well as to present an overview of the public health response to Zika and of the perspectives for the prevention and treatment of this disease. PMID- 28878745 TI - Coordination of Chromosome Segregation and Cell Division in Staphylococcus aureus. AB - Productive bacterial cell division and survival of progeny requires tight coordination between chromosome segregation and cell division to ensure equal partitioning of DNA. Unlike rod-shaped bacteria that undergo division in one plane, the coccoid human pathogen Staphylococcus aureus divides in three successive orthogonal planes, which requires a different spatial control compared to rod-shaped cells. To gain a better understanding of how this coordination between chromosome segregation and cell division is regulated in S. aureus, we investigated proteins that associate with FtsZ and the divisome. We found that DnaK, a well-known chaperone, interacts with FtsZ, EzrA and DivIVA, and is required for DivIVA stability. Unlike in several rod shaped organisms, DivIVA in S. aureus associates with several components of the divisome, as well as the chromosome segregation protein, SMC. This data, combined with phenotypic analysis of mutants, suggests a novel role for S. aureus DivIVA in ensuring cell division and chromosome segregation are coordinated. PMID- 28878746 TI - Inhibition of New Delhi Metallo-beta-Lactamase 1 (NDM-1) Producing Escherichia coli IR-6 by Selected Plant Extracts and Their Synergistic Actions with Antibiotics. AB - Improper use of antibiotics has led to a great concern in the development of pathogenic microbial resistance. New Delhi metallo-beta-lactamase 1 (NDM-1) producing bacteria are resistant to most of the beta-lactam antibiotics, and so far, no new compounds have been clinically tested against these bacteria. In this study, ethanol extracts from the leaves of 240 medicinal plant species were screened for antibacterial activity against an NDM-1 Escherichia coli strain. The extracts that showed antibacterial activity were then tested for minimum inhibitory concentrations (MICs) and zones of inhibition. The extract from Combretum albidum G. Don, Hibiscus acetosella Welw. ex Hiern, Hibiscus cannabinus L., Hibiscus furcatus Willd., Punica granatum L., and Tamarindus indica L. showed bactericidal activity between 5 and 15 mg/ml and the MIC was between 2.56 and 5.12 mg/ml. All six plant extracts inhibited activity of the NDM-1 enzyme in vitro, and the IC50 value ranged between 0.50 and 1.2 ng/MUl. Disruption of bacterial cell wall integrity by the plant extracts was clearly visible with scanning electron microscopy. Increases in membrane permeability caused 79.4 89.7% bacterial cell deaths as investigated by fluorescence-activated cell sorting. All the plant extracts showed synergistic effects when combined with colistin [fractional inhibitory concentration (SigmaFIC) = 0.125-0.375], meropenem (SigmaFIC = 0.09-0.313), and tetracycline (SigmaFIC = 0.125-0.313). Thus, the plant extracts can be fractionated for the identification of active compounds, which could be used as new antibacterial compounds for the development of drugs against NDM-1 E. coli in addition to their use in combination therapy. PMID- 28878747 TI - In Vitro Antibacterial Activity of Unconjugated and Conjugated Bile Salts on Staphylococcus aureus. AB - Bile salts are potent antimicrobial agents and are an important component of innate defenses in the intestine, giving protection against invasive organisms. They play an important role in determining microbial ecology of the intestine and alterations in their levels can lead to increased colonization by pathogens. We have previously demonstrated survival of the opportunistic pathogen Staphylococcus aureus in the human colonic model. Thus investigating the interaction between S. aureus and bile salts is an important factor in understanding its ability to colonize in the host intestine. Harnessing bile salts may also give a new avenue to explore in the development of therapeutic strategies to control drug resistant bacteria. Despite this importance, the antibacterial activity of bile salts on S. aureus is poorly understood. In this study, we investigated the antibacterial effects of the major unconjugated and conjugated bile salts on S. aureus. Several concentration-dependent antibacterial mechanisms were found. Unconjugated bile salts at their minimum inhibitory concentration (cholic and deoxycholic acid at 20 and 1 mM, respectively) killed S. aureus, and this was associated with increased membrane disruption and leakage of cellular contents. Unconjugated bile salts (cholic and deoxycholic acid at 8 and 0.4 mM, respectively) and conjugated bile salts (glycocholic and taurocholic acid at 20 mM) at their sub inhibitory concentrations were still able to inhibit growth through disruption of the proton motive force and increased membrane permeability. We also demonstrated that unconjugated bile salts possess more potent antibacterial action on S. aureus than conjugated bile salts. PMID- 28878748 TI - Transcriptomic Analysis of Oenococcus oeni SD-2a Response to Acid Shock by RNA Seq. AB - Oenococcus oeni can be applied to conduct malolactic fermentation (MLF), but also is the main species growing naturally in wine. Due to the high stress tolerance, it is an interesting model for investigating acid response mechanisms. In this study, the changes in the transcriptome of O.oeni SD-2a during the adaptation period have been studied. RNA-seq was introduced for the transcriptomic analysis of O. oeni samples treated with pH 4.8 and pH 3.0 at 0 and 1 h, respectively. Gene ontology (GO) and Kyoto encyclopedia of genes and genome (KEGG) were performed to compare the transcriptome data between different treatments. From GO analysis, the majority of differentially expressed genes (DEGs) (pH 3.0_1 h-VS-pH 4.8_1 h, pH 3.0_1 h-VS-pH 4.8_0 h, and pH 4.8_1 h-VS-pH 4.8_0 h) were found to be involved in the metabolic process, catalytic activity, cellular process, and binding. KEGG analysis reveals that the most functional gene categories affected by acid are membrane transport, amino acid metabolism and carbohydrate metabolism. Some genes, like the heat shock protein Hsp20, malate transporter and malate permease, were also over-expressed in response to acid stress. In addition, a considerable proportion of gene indicate a significantly different expression in this study, are novel, which needs to be investigated further. These results provide a new viewpoint and crucial resource on the acid stress response in O. oeni. PMID- 28878749 TI - In Vitro Evaluation of the Impact of the Probiotic E. coli Nissle 1917 on Campylobacter jejuni's Invasion and Intracellular Survival in Human Colonic Cells. AB - Campylobacter jejuni is a leading cause of bacterial food poisoning in humans. Due to the rise in antibiotic-resistant Campylobacter, there exists a need to develop antibiotic-independent interventions to control infections in humans. Here, we evaluated the impact of Escherichia coli Nissle 1917 (EcN), a probiotic strain, on C. jejuni's invasion and intracellular survival in polarized human colonic cells (HT-29). To further understand how EcN mediates its impact, the expression of 84 genes associated with tight junctions and cell adhesion was profiled in HT-29 cells after treatment with EcN and challenge with C. jejuni. The pre-treatment of polarized HT-29 cells with EcN for 4 h showed a significant effect on C. jejuni's invasion (~2 log reduction) of the colonic cells. Furthermore, no intracellular C. jejuni were recovered from EcN pre-treated HT-29 cells at 24 h post-infection. Other probiotic strains tested had no significant impact on C. jejuni invasion and intracellular survival. C. jejuni decreased the expression of genes associated with epithelial cells permeability and barrier function in untreated HT-29 cells. However, EcN positively affected the expression of genes that are involved in enhanced intestinal barrier function, decreased cell permeability, and increased tight junction integrity. The results suggest that EcN impedes C. jejuni invasion and subsequent intracellular survival by affecting HT-29 cells barrier function and tight junction integrity. We conclude that EcN might be a viable alternative for controlling C. jejuni infections. PMID- 28878750 TI - Identification of the Tolfenamic Acid Binding Pocket in PrbP from Liberibacter asiaticus. AB - In Liberibacter asiaticus, PrbP is an important transcriptional accessory protein that was found to regulate gene expression through interactions with the RNA polymerase beta-subunit and a specific sequence on the promoter region. It was found that inactivation of PrbP, using the inhibitor tolfenamic acid, resulted in a significant decrease in the overall transcriptional activity of L. asiaticus, and the suppression of L. asiaticus infection in HLB symptomatic citrus seedlings. The molecular interactions between PrbP and tolfenamic acid, however, were yet to be elucidated. In this study, we modeled the structure of PrbP and identified a ligand binding pocket, TaP, located at the interface of the predicted RNA polymerase interaction domain (N-terminus) and the DNA binding domain (C-terminus). The molecular interactions of PrbP with tolfenamic acid were predicted using in silico docking. Site-directed mutagenesis of specific amino acids was followed by electrophoresis mobility shift assays and in vitro transcription assays, where residues N107, G109, and E148 were identified as the primary amino acids involved in interactions with tolfenamic acid. These results provide insight into the binding mechanism of PrbP to a small inhibitory molecule, and a starting scaffold for the identification and development of therapeutics targeting PrbP and other homologs in the CarD_CdnL_TRCF family. PMID- 28878752 TI - Myxobacteria Are Able to Prey Broadly upon Clinically-Relevant Pathogens, Exhibiting a Prey Range Which Cannot Be Explained by Phylogeny. AB - Myxobacteria are natural predators of microorganisms and the subjects of concerted efforts to identify novel antimicrobial compounds. Myxobacterial predatory activity seems to require more than just the possession of specific antimicrobial metabolites. Thus a holistic approach to studying predation promises novel insights into antimicrobial action. Here, we report the isolation of 113 myxobacteria from samples of soil taken from a range of habitats in mid Wales. Predatory activity of each isolate was quantified against a panel of clinically important prey organisms, including Klebsiella pneumoniae, Proteus mirabilis, Candida albicans, Enterococcus faecalis, and three species of Staphylococcus. Myxobacterial isolates exhibited a wide range of predation activity profiles against the panel of prey. Efficient predation of all prey by isolates within the collection was observed, with K. pneumoniae and C. albicans proving particularly susceptible to myxobacterial predation. Notably efficient predators tended to be proficient at predating multiple prey organisms, suggesting they possess gene(s) encoding a broad range killing activity. However, predatory activity was not congruent with phylogeny, suggesting prey range is subject to relatively rapid specialization, potentially involving lateral gene transfer. The broad but patchy prey ranges observed for natural myxobacterial isolates also implies multiple (potentially overlapping) genetic determinants are responsible for dictating predatory activity. PMID- 28878753 TI - Conserved TRAM Domain Functions as an Archaeal Cold Shock Protein via RNA Chaperone Activity. AB - Cold shock proteins (Csps) enable organisms to acclimate to and survive in cold environments and the bacterial CspA family exerts the cold protection via its RNA chaperone activity. However, most Archaea do not contain orthologs to the bacterial csp. TRAM, a conserved domain among RNA modification proteins ubiquitously distributed in organisms, occurs as an individual protein in most archaeal phyla and has a structural similarity to Csp proteins, yet its biological functions remain unknown. Through physiological and biochemical studies on four TRAM proteins from a cold adaptive archaeon Methanolobus psychrophilus R15, this work demonstrated that TRAM is an archaeal Csp and exhibits RNA chaperone activity. Three TRAM encoding genes (Mpsy_0643, Mpsy_3043, and Mpsy_3066) exhibited remarkable cold-shock induced transcription and were preferentially translated at lower temperature (18 degrees C), while the fourth (Mpsy_2002) was constitutively expressed. They were all able to complement the cspABGE mutant of Escherichia coli BX04 that does not grow in cold temperatures and showed transcriptional antitermination. TRAM3066 (gene product of Mpsy_3066) and TRAM2002 (gene product of Mpsy_2002) displayed sequence-non-specific RNA but not DNA binding activity, and TRAM3066 assisted RNases in degradation of structured RNA, thus validating the RNA chaperone activity of TRAMs. Given the chaperone activity, TRAM is predicted to function beyond a Csp. PMID- 28878755 TI - Fermentation Process and Metabolic Flux of Ethanol Production from the Detoxified Hydrolyzate of Cassava Residue. AB - With the growth of the world population, energy problems are becoming increasingly severe; therefore, sustainable energy sources have gained enormous importance. With respect to ethanol fuel production, biomass is gradually replacing grain as the main raw material. In this study, we explored the fermentation of five- and six-carbon sugars, the main biomass degradation products, into alcohol. We conducted mutagenic screening specifically for Candida tropicalis CICC1779 to obtain a strain that effectively used xylose (Candida tropicalis CICC1779-Dyd). By subsequently studying fermentation conditions under different initial liquid volume oxygen transfer coefficients (kLalpha), and coupling control of the aeration rate and agitation speed under optimal conditions, the optimal dissolved oxygen change curve was obtained. In addition, we constructed metabolic flow charts and equations to obtain a better understanding of the fermentation mechanism and to improve the ethanol yield. In our experiment, the ethanol production of the wild type stain was 17.58 g.L-1 at a kLalpha of 120. The highest ethanol yield of the mutagenic strains was 24.85 g.L-1. The ethanol yield increased to 26.56 g.L-1 when the dissolved oxygen content was optimized, and the conversion of sugar into alcohol reached 0.447 g.g 1 glucose (the theoretical titer of yeast-metabolized xylose was 0.46 g ethanol/g xylose and the glucose ethanol fermentation titer was 0.51 g ethanol/g glucose). Finally, the detected activity of xylose reductase and xylose dehydrogenase was higher in the mutant strain than in the original, which indicated that the mutant strain (CICC1779-Dyd) could effectively utilize xylose for metabolism. PMID- 28878751 TI - Burkholderia cenocepacia Infections in Cystic Fibrosis Patients: Drug Resistance and Therapeutic Approaches. AB - Burkholderia cenocepacia is an opportunistic pathogen particularly dangerous for cystic fibrosis (CF) patients. It can cause a severe decline in CF lung function possibly developing into a life-threatening systemic infection known as cepacia syndrome. Antibiotic resistance and presence of numerous virulence determinants in the genome make B. cenocepacia extremely difficult to treat. Better understanding of its resistance profiles and mechanisms is crucial to improve management of these infections. Here, we present the clinical distribution of B. cenocepacia described in the last 6 years and methods for identification and classification of epidemic strains. We also detail new antibiotics, clinical trials, and alternative approaches reported in the literature in the last 5 years to tackle B. cenocepacia resistance issue. All together these findings point out the urgent need of new and alternative therapies to improve CF patients' life expectancy. PMID- 28878754 TI - Marine Microbial Gene Abundance and Community Composition in Response to Ocean Acidification and Elevated Temperature in Two Contrasting Coastal Marine Sediments. AB - Marine ecosystems are exposed to a range of human-induced climate stressors, in particular changing carbonate chemistry and elevated sea surface temperatures as a consequence of climate change. More research effort is needed to reduce uncertainties about the effects of global-scale warming and acidification for benthic microbial communities, which drive sedimentary biogeochemical cycles. In this research, mesocosm experiments were set up using muddy and sandy coastal sediments to investigate the independent and interactive effects of elevated carbon dioxide concentrations (750 ppm CO2) and elevated temperature (ambient +4 degrees C) on the abundance of taxonomic and functional microbial genes. Specific quantitative PCR primers were used to target archaeal, bacterial, and cyanobacterial/chloroplast 16S rRNA in both sediment types. Nitrogen cycling genes archaeal and bacterial ammonia monooxygenase (amoA) and bacterial nitrite reductase (nirS) were specifically targeted to identify changes in microbial gene abundance and potential impacts on nitrogen cycling. In muddy sediment, microbial gene abundance, including amoA and nirS genes, increased under elevated temperature and reduced under elevated CO2 after 28 days, accompanied by shifts in community composition. In contrast, the combined stressor treatment showed a non-additive effect with lower microbial gene abundance throughout the experiment. The response of microbial communities in the sandy sediment was less pronounced, with the most noticeable response seen in the archaeal gene abundances in response to environmental stressors over time. 16S rRNA genes (amoA and nirS) were lower in abundance in the combined stressor treatments in sandy sediments. Our results indicated that marine benthic microorganisms, especially in muddy sediments, are susceptible to changes in ocean carbonate chemistry and seawater temperature, which ultimately may have an impact upon key benthic biogeochemical cycles. PMID- 28878757 TI - Different Origins of Newcastle Disease Virus Hemagglutinin-Neuraminidase Protein Modulate the Replication Efficiency and Pathogenicity of the Virus. AB - To investigate the exact effects of different origins of Newcastle disease virus (NDV) hemagglutinin-neuraminidase (HN) protein to the biological characteristics of the virus, we systematically studied the correlation between the HN protein and NDV virulence by exchanging the HN of velogenic or lentogenic NDV strains with the HN from other strains of different virulence. The results revealed that the rSG10 or rLaSota derivatives bearing the HN gene of other viruses exhibited decreased or increased hemadsorption (HAd), neuraminidase and fusion promotion activities. In vitro and in vivo tests further showed that changes in replication level, tissue tropism and virulence of the chimeric viruses were also consistent with these biological activities. These findings demonstrated that the balance among three biological activities caused variation in replication and pathogenicity of the virus, which was closely related to the origin of the HN protein. Our study highlights the importance of the HN glycoprotein in modulating the virulence of NDV and contributes to a more complete understanding of the virulence of NDV. PMID- 28878758 TI - Differences in Growth Properties among Two Human Cytomegalovirus Glycoprotein O Genotypes. AB - Glycoprotein O (gO) of the human cytomegalovirus (HCMV) is the critical subunit of the envelope trimer gH/gL/gO as it interacts with platelet-derived growth factor alpha receptor upon fibroblast entry, and triggers gB-mediated fusion for fibroblast and epithelial cell infection. Eight genotypes (GT) of the highly polymorphic gO gene are described, yet it is unclear whether the distinct GTs differ in their function. Thus, we aimed to elucidate potential functional differences between two highly diverse gO GTs in an otherwise genomically identical HCMV strain. Therefore, resident gO GT1c sequence of strain TB40-BAC4 luc was entirely replaced by gO GT4 of strain Towne and both, GT1c and GT4 viruses, were investigated for their growth properties in fibroblasts and epithelial cells. In addition, two conserved gO cysteines involved in gH/gL/gO stabilization were mutated to serine either in GT1c (C218S and C343S) or GT4 (C216S and C336S) and their effects on cell-free infectivity were assessed. GT4 viruses displayed a significantly enhanced epithelial cell tropism and this resulted in higher virus release upon replication in epithelial cells when compared to GT1c viruses. Further, when the two cysteines were individually mutated in gO GT1c no impairment in cell-free infectivity was observed. This, however, was in sharp contrast to gO GT4, in which both of the corresponding cysteine mutations led to a substantial reduction in cell-free infectivity which was even more pronounced upon mutation of GT4-C336 than of GT4-C216. In conclusion, these findings provide evidence that the two highly diverse gO genotypes, GT1c and GT4, differ in their functional properties as revealed by their different infection capacities for epithelial cells and by their different responsiveness to mutation of strictly conserved cysteine residues. Thus, it is likely that the gO heterogeneity influences cell-free infectivity of HCMV also in vivo which may have important implications for virus host transmission. PMID- 28878759 TI - Editorial: Microbial Food Safety along the Dairy Chain. PMID- 28878756 TI - Analysis of Microbial Functions in the Rhizosphere Using a Metabolic-Network Based Framework for Metagenomics Interpretation. AB - Advances in metagenomics enable high resolution description of complex bacterial communities in their natural environments. Consequently, conceptual approaches for community level functional analysis are in high need. Here, we introduce a framework for a metagenomics-based analysis of community functions. Environment specific gene catalogs, derived from metagenomes, are processed into metabolic network representation. By applying established ecological conventions, network edges (metabolic functions) are assigned with taxonomic annotations according to the dominance level of specific groups. Once a function-taxonomy link is established, prediction of the impact of dominant taxa on the overall community performances is assessed by simulating removal or addition of edges (taxa associated functions). This approach is demonstrated on metagenomic data describing the microbial communities from the root environment of two crop plants - wheat and cucumber. Predictions for environment-dependent effects revealed differences between treatments (root vs. soil), corresponding to documented observations. Metabolism of specific plant exudates (e.g., organic acids, flavonoids) was linked with distinct taxonomic groups in simulated root, but not soil, environments. These dependencies point to the impact of these metabolite families as determinants of community structure. Simulations of the activity of pairwise combinations of taxonomic groups (order level) predicted the possible production of complementary metabolites. Complementation profiles allow formulating a possible metabolic role for observed co-occurrence patterns. For example, production of tryptophan-associated metabolites through complementary interactions is unique to the tryptophan-deficient cucumber root environment. Our approach enables formulation of testable predictions for species contribution to community activity and exploration of the functional outcome of structural shifts in complex bacterial communities. Understanding community-level metabolism is an essential step toward the manipulation and optimization of microbial function. Here, we introduce an analysis framework addressing three key challenges of such data: producing quantified links between taxonomy and function; contextualizing discrete functions into communal networks; and simulating environmental impact on community performances. New technologies will soon provide a high-coverage description of biotic and a-biotic aspects of complex microbial communities such as these found in gut and soil. This framework was designed to allow the integration of high-throughput metabolomic and metagenomic data toward tackling the intricate associations between community structure, community function, and metabolic inputs. PMID- 28878760 TI - Respiratory Commensal Bacteria Corynebacterium pseudodiphtheriticum Improves Resistance of Infant Mice to Respiratory Syncytial Virus and Streptococcus pneumoniae Superinfection. AB - Corynebacterium pseudodiphtheriticum is a Gram-positive bacterium found as a member of the normal microbiota of the upper respiratory tract. It was suggested that C. pseudodiphtheriticum may be potentially used as a next-generation probiotic for nasal application, although no deep studies were performed in this regard. We hypothesized that human isolate C. pseudodiphtheriticum strain 090104 is able to modulate the respiratory innate immune response and beneficially influence the resistance to viral and bacterial infections. Therefore, in the present study we investigated how the exposure of infant mice to nasal priming with viable or non-viable C. pseudodiphtheriticum 090104 influences the respiratory innate immune response triggered by Toll-like receptor (TLR)-3 activation, the susceptibility to primary Respiratory Synsytial Virus (RSV) infection, and the resistance to secondary Streptococcus pneumoniae pneumonia. We demonstrated that the nasal priming with viable C. pseudodiphtheriticum 090104 differentially modulated TLR3-mediated innate antiviral immune response in the respiratory tract of infant mice, improving their resistance to primary RSV infection, and secondary pneumococcal pneumonia. In association with the protection against RSV-pneumococcal superinfection, we found that viable C. pseudodiphtheriticum improved lung CD3+CD4+IFN-gamma+, and CD3+CD4+IL-10+ T cells as well as CD11c+SiglecF+IFN-beta+ alveolar macrophages. Of interest, non-viable bacteria did not have the same protective effect, suggesting that C. pseudodiphtheriticum colonization is needed for achieving its protective effect. In conclusion, we present evidence that nasal application of viable C. pseudodiphtheriticum could be thought as an alternative to boost defenses against RSV and secondary pneumococcal pneumonia, which should be further studied and validated in clinical trials. Due to the absence of a long-lasting immunity, re infection with RSV throughout life is common. Thus, a possible perspective use could be a seasonal application of a nasal probiotic spray to boost respiratory innate immunity in immunocompetent subjects. PMID- 28878761 TI - Effect of Different Antibiotic Chemotherapies on Pseudomonas aeruginosa Infection In Vitro of Primary Human Corneal Fibroblast Cells. AB - Pseudomonas aeruginosa is a major cause of bacterial keratitis (BK) worldwide. Inappropriate or non-optimal antibiotic chemotherapy can lead to corneal perforation and rapid sight loss. In this study, we tested the hypothesis that P. aeruginosa strain PAO1 invades primary human corneal fibroblasts (hCFs) in vitro and persists intracellularly, despite chemotherapy with antibiotics used commonly to treat BK. In rank order, ciprofloxacin, levofloxacin and polymyxin B showed the highest activity against planktonic PAO1 growth (100% inhibitory concentration <=10 MUg/mL; 50% inhibitory concentration <=1 MUg/mL), followed by gentamicin and ofloxacin (100% inhibitory concentration <=50 MUg/mL; 50% inhibitory concentration <=10 MUg/mL). These bactericidal antibiotics (50-200 MUg/mL concentrations) all killed PAO1 in the extracellular environment of infected hCF monolayers. By contrast, the bactericidal antibiotic cefuroxime and the bacteriostatic antibiotic chloramphenicol failed to sterilize both PAO1 broth cultures, even at a concentration of >=200 MUg/mL) and infected hCF monolayers. Statistically, all antibiotics were able to prevent LDH release from PAO1 infected hCF monolayers at both concentrations tested. Intracellular Pseudomonas were significantly reduced (>99%, P < 0.05) following treatment with ciprofloxacin, levofloxacin and ofloxacin, whereas gentamicin, polymyxin B and cefuroxime failed to clear intracellular bacteria over 24 h. Intracellular Pseudomonas infection was resistant to chloramphenicol, with hCF death observed by 9 h. Eventual growth of remaining intracellular Pseudomonas was observed in hCF after removal of all antibiotics, resulting in re-infection cycles and cell death by 48 h. All of the antibiotics reduced significantly (P < 0.05) IL-1beta secretion by hCF infected with a Multiplicity Of Infection (MOI) = 1 of PAO1. With higher MOI, no pro-inflammatory effects were observed with antibiotic treatment, expect with polymyxin B and ofloxacin, which induced significant increased IL-1beta secretion (P < 0.001). The findings from our study demonstrated that bactericidal and bacteriostatic antibiotics, routinely used to treat BK, failed to eradicate Pseudomonas infection of hCFs in vitro and that their bactericidal efficacies were influenced by the cellular location of the organism. PMID- 28878762 TI - The C-terminal Six Amino Acids of the FNT Channel FocA Are Required for Formate Translocation But Not Homopentamer Integrity. AB - FocA is the archetype of the pentameric formate-nitrite transporter (FNT) superfamily of channels, members of which translocate small organic and inorganic anions across the cytoplasmic membrane of microorganisms. The N- and C-termini of each protomer are cytoplasmically oriented. A Y-L-R motif is found immediately after transmembrane helix 6 at the C-terminus of FNT proteins related to FocA, or those with a role in formate translocation. Previous in vivo studies had revealed that formate translocation through FocA was controlled by interaction with the formate-producing glycyl-radical enzyme pyruvate formate-lyase (PflB) or its structural and functional homolog, TdcE. In this study we analyzed the effect on in vivo formate export and import, as well as on the stability of the homopentamer in the membrane, of successively removing amino acid residues from the C-terminus of FocA. Removal of up to five amino acids was without consequence for either formate translocation or oligomer stability. Removal of a sixth residue (R280) prevented formate uptake by FocA in a strain lacking PflB and significantly reduced, but did not prevent, formate export. Sensitivity to the toxic formate analog hypophosphite, which is also transported into the cell by FocA, was also relieved. Circular dichroism spectroscopy and blue-native PAGE analysis revealed, however, that this variant had near identical secondary and quaternary structural properties to those of native FocA. Interaction with the glycyl radical enzyme, TdcE, was also unaffected by removal of the C-terminal 6 amino acid residues, indicating that impaired interaction with TdcE was not the reason for impaired formate translocation. Removal of a further residue (L279) severely restricted formate export, the stability of the protein and its ability to form homopentamers. Together, these studies revealed that the Y278-L279-R280 motif at the C-terminus is essential for bidirectional formate translocation by FocA, but that L279 is both necessary and sufficient for homopentamer integrity. PMID- 28878763 TI - Experimental Hyalohyphomycosis by Purpureocillium lilacinum: Outcome of the Infection in C57BL/6 Murine Models. AB - Purpureocillium lilacinum is a filamentous, hyaline fungus considered an emerging pathogen in humans. The aim of our study was to evaluate the outcome of hyalohyphomycosis in C57BL/6 murine models inoculated with two clinical P. lilacinum isolates (S1 and S2). Each isolate was inoculated in mice randomly distributed in immunocompetent (CPT) and immunosuppressed (SPS) groups. Mice were evaluated at day 7, 21, and 45 after inoculation for histopathological analysis, recovery of fungal cells, and immunological studies. Histological analysis showed scarce conidia-like structures in lung tissue from CPT mice and a lot of fungal cells in SPS mice inoculated with S2 compared to mice inoculated with S1. The maximum recovery of fungal cells was seen in CPT mice inoculated with both isolates at day 7, but with mean significantly higher in those inoculated with S2 isolate. Phenotypical characterization of T cells showed TCD8+ lymphocytes predominance over TCD4+ in immunosuppressed mice infected and control groups. We also observed higher percentages of the central and effector memory/effector phenotype in CPT mice infected with S2 strain, especially in TCD8+ in the initial period of infection. Regulatory T cells showed higher percentages in immunosuppressed, predominantly after the acute phase. Our results showed that the P. lilacinum is a fungus capable to cause damages in competent and immunosuppressed experimental hosts. Furthermore, S2 isolate seems to cause more damage to the experimental host and it was possible to identify different cellular subsets involved in the mice immune response. PMID- 28878764 TI - Molecular Cloning, Characterization, and Anti-avian Pathogenic Escherichia coli Innate Immune Response of the Cherry Valley Duck CIITA Gene. AB - Class II major histocompatibility complex (MHC-II) transactivator (CIITA) is a member of the pattern recognition receptor in cytoplasm, which is involved in host innate immune responses. In this study, the full-length cDNA of Cherry Valley duck CIITA (duCIITA) was cloned from the spleen of healthy Cherry Valley ducks for the first time. The CDs of duCIITA have 3648 bp and encode 1215 amino acids. The homology analysis of CIITAs amino acid sequence showed that the duCIITA has the highest identity with the Anas platyrhynchos (94.9%), followed by Gallus gallus and Meleagris gallopavo. Quantitative real-time PCR analysis indicated that duCIITA mRNA has a broad expression level in healthy Cherry Valley duck tissues. It was highly expressed in the lung and cerebellum, and lowly expressed in the rectum and esophagus. After the avian pathogenic Escherichia coli (APEC) O1K1 infection, the ducks exhibited the typical clinical symptoms, and a severe fibrinous exudate in the heart and liver surface was observed. Meanwhile, a significant up-regulation of duCIITA was detected in the infected liver. The inflammatory cytokines IL-1beta, IL-6, and IL-8 have a significant up regulation in the infected liver, spleen and brain. In addition, knockdown of the duCIITA reduces antibacterial activity and inflammatory cytokine production of the duck embryo fibroblast cells. Our research is the first study of the cloning, tissue distribution, and antibacterial immune responses of duCIITA, and these findings imply that duCIITA was an important receptor, which was involved in the early stage of the antibacterial innate immune response to APEC O1K1 infection of Cherry Valley duck. PMID- 28878765 TI - Dyslipidemic Diet-Induced Monocyte "Priming" and Dysfunction in Non-Human Primates Is Triggered by Elevated Plasma Cholesterol and Accompanied by Altered Histone Acetylation. AB - Monocytes and the recruitment of monocyte-derived macrophages into sites of inflammation play a key role in atherogenesis and other chronic inflammatory diseases linked to cardiometabolic syndrome and obesity. Previous studies from our group have shown that metabolic stress promotes monocyte priming, i.e., enhanced adhesion and accelerated chemotaxis of monocytes in response to chemokines, both in vitro and in dyslipidemic LDLR-/- mice. We also showed that metabolic stress-induced monocyte dysfunction is, at least to a large extent caused by the S-glutathionylation, inactivation, and subsequent degradation of mitogen-activated protein kinase phosphatase 1. Here, we analyzed the effects of a Western-style, dyslipidemic diet (DD), which was composed of high levels of saturated fat, cholesterol, and simple sugars, on monocyte (dys)function in non human primates (NHPs). We found that similar to mice, a DD enhances monocyte chemotaxis in NHP within 4 weeks, occurring concordantly with the onset of hypercholesterolemia but prior to changes in triglycerides, blood glucose, monocytosis, or changes in monocyte subset composition. In addition, we identified transitory decreases in the acetylation of histone H3 at the lysine residues 18 and 23 in metabolically primed monocytes, and we found that monocyte priming was correlated with the acetylation of histone H3 at lysine 27 after an 8 week DD regimen. Our data show that metabolic stress promotes monocyte priming and hyper-chemotactic responses in NHP. The histone modifications accompanying monocyte priming in primates suggest a reprogramming of the epigenetic landscape, which may lead to dysregulated responses and functionalities in macrophages derived from primed monocytes that are recruited to sites of inflammation. PMID- 28878766 TI - Chronic Exposure to Malaria Is Associated with Inhibitory and Activation Markers on Atypical Memory B Cells and Marginal Zone-Like B Cells. AB - In persistent infections that are accompanied by chronic immune activation, such as human immunodeficiency virus, hepatitis C virus, and malaria, there is an increased frequency of a phenotypically distinct subset of memory B cells lacking the classic memory marker CD27 and showing a reduced capacity to produce antibodies. However, critical knowledge gaps remain on specific B cell changes and immune adaptation in chronic infections. We hypothesized that expansion of atypical memory B cells (aMBCs) and reduction of activated peripheral marginal zone (MZ)-like B cells in constantly exposed individuals might be accompanied by phenotypic changes that would confer a tolerogenic profile, helping to establish tolerance to infections. To better understand malaria-associated phenotypic abnormalities on B cells, we analyzed peripheral blood mononuclear cells from 55 pregnant women living in a malaria-endemic area of Papua Nueva Guinea and 9 Spanish malaria-naive individuals using four 11-color flow cytometry panels. We assessed the expression of markers of B cell specificity (IgG and IgM), activation (CD40, CD80, CD86, b220, TACI, and CD150), inhibition (PD1, CD95, and CD71), and migration (CCR3, CXCR3, and CD62l). We found higher frequencies of active and resting aMBC and marked reduction of MZ-like B cells, although changes in absolute cell counts could not be assessed. Highly exposed women had higher PD1+-, CD95+-, CD40+-, CD71+-, and CD80+-activated aMBC frequencies than non exposed subjects. Malaria exposure increased frequencies of b220 and proapoptotic markers PD1 and CD95, and decreased expression of the activation marker TACI on MZ-like B cells. The increased frequencies of inhibitory and apoptotic markers on activated aMBCs and MZ-like B cells in malaria-exposed adults suggest an immune homeostatic mechanism for maintaining B cell development and function while simultaneously downregulating hyperreactive B cells. This mechanism would keep the B cell activation threshold high enough to control infection but impaired enough to tolerate it, preventing systemic inflammation. PMID- 28878767 TI - Human Blood CD1c+ Dendritic Cells Promote Th1 and Th17 Effector Function in Memory CD4+ T Cells. AB - Dendritic cells (DC) initiate the differentiation of CD4+ helper T cells into effector cells including Th1 and Th17 responses that play an important role in inflammation and autoimmune disease pathogenesis. In mice, Th1 and Th17 responses are regulated by different conventional (c) DC subsets, with cDC1 being the main producers of IL-12p70 and inducers of Th1 responses, while cDC2 produce IL-23 to promote Th17 responses. The role that human DC subsets play in memory CD4+ T cell activation is not known. This study investigated production of Th1 promoting cytokine IL-12p70, and Th17 promoting cytokines, IL-1beta, IL-6, and IL-23, by human blood monocytes, CD1c+ DC, CD141+ DC, and plasmacytoid DC and examined their ability to induce Th1 and Th17 responses in memory CD4+ T cells. Human CD1c+ DC produced IL-12p70, IL-1beta, IL-6, and IL-23 in response to R848 combined with LPS or poly I:C. CD141+ DC were also capable of producing IL-12p70 and IL-23 but were not as proficient as CD1c+ DC. Activated CD1c+ DC were endowed with the capacity to promote both Th1 and Th17 effector function in memory CD4+ T cells, characterized by high production of interferon-gamma, IL-17A, IL-17F, IL 21, and IL-22. These findings support a role for CD1c+ DC in autoimmune inflammation where Th1/Th17 responses play an important role in disease pathogenesis. PMID- 28878768 TI - Natural IgM and TLR Agonists Switch Murine Splenic Pan-B to "Regulatory" Cells That Suppress Ischemia-Induced Innate Inflammation via Regulating NKT-1 Cells. AB - Natural IgM anti-leukocyte autoantibodies (IgM-ALAs) inhibit inflammation by several mechanisms. Here, we show that pan-B cells and bone marrow-derived dendritic cells (BMDCs) are switched to regulatory cells when pretreated ex vivo with IgM. B cells are also switched to regulatory cells when pretreated ex vivo with CpG but not with LPS. Pre-emptive infusion of such ex vivo induced regulatory cells protects C57BL/6 mice from ischemia-induced acute kidney injury (AKI) via regulation of in vivo NKT-1 cells, which normally amplify the innate inflammatory response to DAMPS released after reperfusion of the ischemic kidney. Such ex vivo induced regulatory pan-B cells and BMDC express low CD1d and inhibit inflammation by regulating in vivo NKT-1 in the context of low-lipid antigen presentation and by a mechanism that requires costimulatory molecules, CD1d, PDL1/PD1, and IL10. Second, LPS and CpG have opposite effects on induction of regulatory activity in BMDC and B cells. LPS enhances regulatory activity of IgM pretreated BMDC but negates the IgM-induced regulatory activity in B cells, while CpG, with or without IgM pretreatment, induces regulatory activity in B cells but not in BMDC. Differences in the response of pan-B and dendritic cells to LPS and CpG, especially in the presence of IgM-ALA, may have relevance during infections and inflammatory disorders where there is an increased IgM-ALA and release of TLRs 4 and 9 ligands. Ex vivo induced regulatory pan-B cells could have therapeutic relevance as these easily available cells can be pre-emptively infused to prevent AKI that can occur during open heart surgery or in transplant recipients receiving deceased donor organs. PMID- 28878769 TI - Protective Role of Mast Cells in Primary Systemic Vasculitis: A Perspective. AB - Mast cells are important cells of the immune system. Although traditionally considered as key players in allergic and hypersensitivity reactions, emerging evidence suggests that mast cells have many complex roles in vascular disease. These include regulation of vasodilation, angiogenesis, activation of matrix metalloproteinases, apoptosis of smooth muscle cells, and activation of the renin angiotensin system. Mast cells are also known to play an immunomodulatory role via modulation of regulatory T-cell (Treg), macrophage and endothelial cell functions. This dual role of the mast cells is evident in myeloperoxidase anti neutrophil cytoplasmic antibodies-mouse model of glomerulonephritis in which mast cell deficiency worsens glomerulonephritis, whereas inhibition of mast cell degranulation is effective in abrogating the development of glomerulonephritis. Our previous work demonstrated that mast cell degranulation inhibits lipopolysaccharide-induced interleukin 6 (IL-6) production in mice. This effect was not seen in histamine-1-receptor knockout (H1R-/-) mice suggesting a role for histamine in IL-6 homeostasis. In addition, mast cell degranulation-mediated decrease in IL-6 production was associated with an upregulation of suppressor of cytokine signaling-1 protein in the aorta. We propose that mast cells regulate large artery inflammation through T-cells, shifting a primarily Th1 and Th17 toward a Th2 response and leading to enhanced IL-10 production, activation Treg cells, and the inhibition of macrophage functions. PMID- 28878770 TI - Changes in Reactivity In Vitro of CD4+CD25+ and CD4+CD25- T Cell Subsets in Transplant Tolerance. AB - Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4+CD25+ T cells, yet in many models, proliferation of CD4+ T cells from hosts tolerant to specific-alloantigen in vitro is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4+, CD4+CD25+, and CD4+CD25- T cells from DA rats tolerant to Piebald Virol Glaxo rat strain (PVG) cardiac allografts and from naive DA rats were examined. Proliferation of CD4+ T cells from both naive and tolerant hosts was similar to both PVG and Lewis stimulator cells. In mixed lymphocyte culture to PVG, proliferation of naive CD4+CD25- T cells was greater than naive CD4+ T cells. In contrast, proliferation of CD4+CD25- T cells from tolerant hosts to specific donor PVG was not greater than CD4+ T cells, whereas their response to Lewis and self-DA was greater than CD4+ T cells. Paradoxically, CD4+CD25+ T cells from tolerant hosts did not proliferate to PVG, but did to Lewis, whereas naive CD4+CD25+ T cells proliferate to both PVG and Lewis but not to self-DA. CD4+CD25+ T cells from tolerant, but not naive hosts, expressed receptors for interferon (IFN)-gamma and IL-5 and these cytokines promoted their proliferation to specific alloantigen PVG but not to Lewis or self-DA. We identified several differences in the patterns of proliferation to specific-donor alloantigen between cells from tolerant and naive hosts. Most relevant is that CD4+CD25+ T cells from tolerant hosts failed to proliferate or suppress to specific donor in the absence of either IFN-gamma or IL-5. The proliferation to third-party and self of each cell population from tolerant and naive hosts was similar and not affected by IFN gamma or IL-5. Our findings suggest CD4+CD25+ T cells that mediate transplant tolerance depend on IFN-gamma or IL-5 from alloactivated Th1 and Th2 cells. PMID- 28878771 TI - Coordinated Role of Toll-Like Receptor-3 and Retinoic Acid-Inducible Gene-I in the Innate Response of Bovine Endometrial Cells to Virus. AB - Bovine herpesvirus-4 (BoHV-4) and bovine viral diarrhea virus (BVDV) infect the uterus of cattle, often resulting in reduced fertility, or abortion of the fetus, respectively. Here, exposure of primary bovine endometrial cells to BoHV-4 or BVDV modulated the production of inflammatory mediators. Viral pathogen associated molecular patterns (PAMPs) are detected via pattern-recognition receptors (PRRs). However, the relative contribution of specific PRRs to innate immunity, during viral infection of the uterus, is unclear. Endometrial epithelial and stromal cells constitutively express the PRR Toll-like receptor (TLR)-3, but, the status of retinoic acid-inducible gene I (RIG-I), a sensor of cytosolic nucleic acids, is unknown. Primary endometrial epithelial and stromal cells had low expression of RIG-I, which was increased in stromal cells after 12 h transfection with the TLR3 ligand Poly(I:C), a synthetic analog of double stranded RNA. Furthermore, short interfering RNA targeting TLR3, or interferon (IFN) regulatory transcription factor 3, an inducer of type I IFN transcription, reduced Poly(I:C)-induced RIG-I protein expression and reduced inflammatory mediator secretion from stromal cells. We conclude that antiviral defense of endometrial stromal cells requires coordinated recognition of PAMPs, initially via TLR3 and later via inducible RIG-I. PMID- 28878773 TI - Response: Commentary: The Scavenger Receptor SSc5D Physically Interacts with Bacteria through the SRCR-Containing N-Terminal Domain. PMID- 28878772 TI - Lactobacillus plantarum Strains Can Enhance Human Mucosal and Systemic Immunity and Prevent Non-steroidal Anti-inflammatory Drug Induced Reduction in T Regulatory Cells. AB - Orally ingested bacteria interact with intestinal mucosa and may impact immunity. However, insights in mechanisms involved are limited. In this randomized placebo controlled cross-over trial, healthy human subjects were given Lactobacillus plantarum supplementation (strain TIFN101, CIP104448, or WCFS1) or placebo for 7 days. To determine whether L. plantarum can enhance immune response, we compared the effects of three stains on systemic and gut mucosal immunity, by among others assessing memory responses against tetanus toxoid (TT)-antigen, and mucosal gene transcription, in human volunteers during induction of mild immune stressor in the intestine, by giving a commonly used enteropathic drug, indomethacin [non steroidal anti-inflammatory drug (NSAID)]. Systemic effects of the interventions were studies in peripheral blood samples. NSAID was found to induce a reduction in serum CD4+/Foxp3 regulatory cells, which was prevented by L. plantarum TIFN101. T-cell polarization experiments showed L. plantarum TIFN101 to enhance responses against TT-antigen, which indicates stimulation of memory responses by this strain. Cell extracts of the specific L. plantarum strains provoked responses after WCFS1 and TIFN101 consumption, indicating stimulation of immune responses against the specific bacteria. Mucosal immunomodulatory effects were studied in duodenal biopsies. In small intestinal mucosa, TIFN101 upregulated genes associated with maintenance of T- and B-cell function and antigen presentation. Furthermore, L. plantarum TIFN101 and WCFS1 downregulated immunological pathways involved in antigen presentation and shared downregulation of snoRNAs, which may suggest cellular destabilization, but may also be an indicator of tissue repair. Full sequencing of the L. plantarum strains revealed possible gene clusters that might be responsible for the differential biological effects of the bacteria on host immunity. In conclusion, the impact of oral consumption L. plantarum on host immunity is strain dependent and involves responses against bacterial cell components. Some strains may enhance specific responses against pathogens by enhancing antigen presentation and leukocyte maintenance in mucosa. In future studies and clinical settings, caution should be taken in selecting beneficial bacteria as closely related strains can have different effects. Our data show that specific bacterial strains can prevent immune stress induced by commonly consumed painkillers such as NSAID and can have enhancing beneficial effects on immunity of consumers by stimulating antigen presentation and memory responses. PMID- 28878774 TI - Goose Mx and OASL Play Vital Roles in the Antiviral Effects of Type I, II, and III Interferon against Newly Emerging Avian Flavivirus. AB - Duck Tembusu virus (TMUV), an emerging avian flavivirus, is highly pathogenic to birds and has the potential to become a zoonotic pathogen. Here, the molecular antiviral mechanism of goose type I, II, and III interferon (goIFNalpha, goIFNgamma, and goIFNlambda), the key components of the innate immune pathway, against TMUV was studied. We found that the transcription of goIFNs was obviously driven by TMUV infection in vivo and in vitro, and the titers and copies of TMUV were significantly reduced following treatment with goIFNs. The results of RNA sequencing (RNA-seq) revealed that goIFN stimulation triggered a set of differentially expressed genes at different levels and a positive regulatory feedback loop of IFN release against infection. Two important interferon stimulated genes, goMx and goOASL, were identified as workhorse IFNs in the inhibition of TMUV replication. The antiviral effects of goMx and goOASL were confirmed by transient overexpression and knockdown assay in vitro. Overall, our findings defined that goose Mx and OASL play key roles in the antiviral effects of type I, II, and III interferon against the TMUV. These results extend our understanding of the transcriptional profile of the goose IFN-mediated signaling pathway and provide insight into the antiviral mechanism of goIFNs against flavivirus infection. PMID- 28878775 TI - RTS,S/AS01E Malaria Vaccine Induces Memory and Polyfunctional T Cell Responses in a Pediatric African Phase III Trial. AB - Comprehensive assessment of cellular responses to the RTS,S/AS01E vaccine is needed to understand potential correlates and ultimately mechanisms of protection against malaria disease. Cellular responses recognizing the RTS,S/AS01E containing circumsporozoite protein (CSP) and Hepatitis B surface antigen (HBsAg) were assessed before and 1 month after primary vaccination by intracellular cytokine staining and 16-color flow cytometry in 105 RTS,S/AS01-vaccinated and 74 rabies-vaccinated participants (controls) in a pediatric phase III trial in Africa. RTS,S/AS01E-vaccinated children had significantly higher frequencies of CSP- and HBsAg-specific CD4+ T cells producing IL-2, TNF-alpha, and CD40L and HBsAg-specific CD4+ T producing IFN-gamma and IL-17 than baseline and the control group. Vaccine-induced responses were identified in both central and effector memory (EM) compartments. EM CD4+ T cells expressing IL-4 and IL-21 were detected recognizing both vaccine antigens. Consistently higher response rates to both antigens in RTS,S/AS01E-vaccinated than comparator-vaccinated children were observed. RTS,S/AS01E induced polyfunctional CSP- and HBsAg-specific CD4+ T cells, with a greater degree of polyfunctionality in HBsAg responses. In conclusion, RTS,S/AS01E vaccine induces T cells of higher functional heterogeneity and polyfunctionality than previously characterized. Responses detected in memory CD4+ T cell compartments may provide correlates of RTS,S/AS01 induced immunity and duration of protection in future correlates of immunity studies. PMID- 28878776 TI - Interferon-lambdas and Plasmacytoid Dendritic Cells: A Close Relationship. AB - Interferon lambdas (IFNlambdas) are recently discovered cytokines acting not only at the first line of defense against viral infections but also at the mucosal barriers. In fact, a peculiar feature of the IFNlambda system is the restricted expression of the functional IFNlambdaR, which is known to be limited to epithelial cells and discrete leukocyte subsets, including the plasmacytoid dendritic cells (pDCs). In the latter case, current data, discussed in this minireview, indicate that IFNlambdas positively regulate various pDC functions, including pDC expression of interferon-dependent gene (ISG) mRNAs, production of cytokines, survival, and phenotype. Although the knowledge of the effects on pDCs by IFNlambdas is still incomplete, we speculate that the peculiar pDC responsiveness to IFNlambdas provide unique advantages for these innate immune cells, not only for viral infections but also during autoimmune disorders and/or tumors, in which pDC involvement and activation variably contribute to their pathogenesis. PMID- 28878777 TI - Zika Virus Promotes Neuronal Cell Death in a Non-Cell Autonomous Manner by Triggering the Release of Neurotoxic Factors. AB - Zika virus (ZIKV) has recently caused a worldwide outbreak of infections associated with severe neurological complications, including microcephaly in infants born from infected mothers. ZIKV exhibits high neurotropism and promotes neuroinflammation and neuronal cell death. We have recently demonstrated that N methyl-d-aspartate receptor (NMDAR) blockade by memantine prevents ZIKV-induced neuronal cell death. Here, we show that ZIKV induces apoptosis in a non-cell autonomous manner, triggering cell death of uninfected neurons by releasing cytotoxic factors. Neuronal cultures infected with ZIKV exhibit increased levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and glutamate. Moreover, infected neurons exhibit increased expression of GluN2B and augmented intracellular Ca2+ concentration. Blockade of GluN2B-containing NMDAR by ifenprodil normalizes Ca2+ levels and rescues neuronal cell death. Notably, TNF-alpha and IL-1beta blockade decreases ZIKV-induced Ca2+ flux through GluN2B containing NMDARs and reduces neuronal cell death, indicating that these cytokines might contribute to NMDAR sensitization and neurotoxicity. In addition, ZIKV-infected cultures treated with ifenprodil exhibits increased activation of the neuroprotective pathway including extracellular signal-regulated kinase and cAMP response element-binding protein, which may underlie ifenprodil-mediated neuroprotection. Together, our data shed some light on the neurotoxic mechanisms triggered by ZIKV and begin to elucidate how GluN2B-containing NMDAR blockade can prevent neurotoxicity. PMID- 28878778 TI - Multivariate Analysis As a Support for Diagnostic Flowcharts in Allergic Bronchopulmonary Aspergillosis: A Proof-of-Concept Study. AB - Molecular-based allergy diagnosis yields multiple biomarker datasets. The classical diagnostic score for allergic bronchopulmonary aspergillosis (ABPA), a severe disease usually occurring in asthmatic patients and people with cystic fibrosis, comprises succinct immunological criteria formulated in 1977: total IgE, anti-Aspergillus fumigatus (Af) IgE, anti-Af "precipitins," and anti-Af IgG. Progress achieved over the last four decades led to multiple IgE and IgG(4) Af biomarkers available with quantitative, standardized, molecular-level reports. These newly available biomarkers have not been included in the current diagnostic criteria, either individually or in algorithms, despite persistent underdiagnosis of ABPA. Large numbers of individual biomarkers may hinder their use in clinical practice. Conversely, multivariate analysis using new tools may bring about a better chance of less diagnostic mistakes. We report here a proof-of-concept work consisting of a three-step multivariate analysis of Af IgE, IgG, and IgG4 biomarkers through a combination of principal component analysis, hierarchical ascendant classification, and classification and regression tree multivariate analysis. The resulting diagnostic algorithms might show the way for novel criteria and improved diagnostic efficiency in Af-sensitized patients at risk for ABPA. PMID- 28878779 TI - Wip1 Deficiency Promotes Neutrophil Recruitment to the Infection Site and Improves Sepsis Outcome. AB - Sepsis is defined as an uncontrolled host response to infection, and no specific therapy or drugs have been used in clinical trials currently. Discovering new therapeutic targets for sepsis treatment has always been a central problem in the field of sepsis research. Neutrophils stand at the first line in controlling infection and have been identified to be dysregulated with impaired migration and antimicrobial function during sepsis. Based on our previous results on demonstrating wild-type p53-induced phosphatase 1 in controlling neutrophil development, we explored the possible relationship among Wip1, neutrophils, and sepsis in the present study. Wip1-deficient mice exhibited improved outcomes in cecal ligation and puncture (CLP)-induced sepsis model with enhanced bacterial clearance and less multi-organ damage. The protection seen in Wip1 KO mice was mainly due to an increased accumulation of neutrophils in the primary infectious locus mediated by the decreased internalization of CXCR2, as well as by an increased antimicrobial function. Additionally, we also identified a negative correlation between CXCR2 and Wip1 in human neutrophils during sepsis. Pharmacological inhibition of Wip1 with its inhibitor can also prevent the internalization of CXCR2 on human neutrophils treated with lipopolysaccharides in vitro and significantly improve the outcome in CLP-induced sepsis model. Taken together, our results demonstrate that Wip1 can negatively regulate neutrophil migration and antimicrobial immunity during sepsis and inhibition of Wip1 can be a potential therapeutic target for sepsis treatment. PMID- 28878780 TI - P2Y6 Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL) cells derived from IPF patients as well as in animals following bleomycin administration. Furthermore, BAL fluid levels of the P2Y6R agonist uridine-5'-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2Y6R-deficient compared to wild-type animals confirming the pathophysiological relevance of P2Y6R subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2Y6R expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2Y6R antagonist MRS2578. In vitro studies demonstrated that proliferation and secretion of the pro inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2Y6R-mediated processes. In summary, our results clearly demonstrate the involvement of P2Y6R subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y6 receptors might be a new target for the treatment of IPF. PMID- 28878781 TI - Calreticulin Release at an Early Stage of Death Modulates the Clearance by Macrophages of Apoptotic Cells. AB - Calreticulin (CRT) is a well-known "eat-me" signal harbored by dying cells participating in their recognition by phagocytes. CRT is also recognized to deeply impact the immune response to altered self-cells. In this study, we focus on the role of the newly exposed CRT following cell death induction. We show that if CRT increases at the outer face of the plasma membrane and is well recognized by C1q even when phosphatidylserine is not yet detected, CRT is also released in the surrounding milieu and is able to interact with phagocytes. We observed that exogenous CRT is endocytosed by THP1 macrophages through macropinocytosis and that internalization is associated with a particular phenotype characterized by an increase of cell spreading and migration, an upregulation of CD14, an increase of interleukin-8 release, and a decrease of early apoptotic cell uptake. Importantly, CRT-induced pro-inflammatory phenotype was confirmed on human monocytes-derived macrophages by the overexpression of CD40 and CD274, and we found that monocyte-derived macrophages exposed to CRT display a peculiar polarization notably associated with a downregulation of the histocompatibility complex of class II molecules hampering its description through the classical M1/M2 dichotomy. Altogether our results highlight the role of soluble CRT with strong possible consequences on the macrophage-mediated immune response to dying cell. PMID- 28878782 TI - In Planta Synthesis of Designer-Length Tobacco Mosaic Virus-Based Nano-Rods That Can Be Used to Fabricate Nano-Wires. AB - We have utilized plant-based transient expression to produce tobacco mosaic virus (TMV)-based nano-rods of predetermined lengths. This is achieved by expressing RNAs containing the TMV origin of assembly sequence (OAS) and the sequence of the TMV coat protein either on the same RNA molecule or on two separate constructs. We show that the length of the resulting nano-rods is dependent upon the length of the RNA that possesses the OAS element. By expressing a version of the TMV coat protein that incorporates a metal-binding peptide at its C-terminus in the presence of RNA containing the OAS we have been able to produce nano-rods of predetermined length that are coated with cobalt-platinum. These nano-rods have the properties of defined-length nano-wires that make them ideal for many developing bionanotechnological processes. PMID- 28878785 TI - Phenotypic Stability of Zea mays Grain Yield and Its Attributing Traits under Drought Stress. AB - Phenotypic stability under stress environment facilitate the fitness of genotype and opens new horizons to explore the cryptic genetic variation. Variation in tolerance to drought stress, a major grain yield constraint to global maize production, was identified, at the phenotypic and genotypic level. Here we found a prominent hybrid H9 that showed fitness over four growing seasons for grain yield under water stress conditions. Genotypic and phenotypic correlation of yield attributing traits over four seasons demonstrated that cobs per plant, 100 seed weight, number of grains rows per cob, total dry matter, cob diameter had positive association (r2 = 0.3-0.9) to grain yield. The perturbation was found for chlorophyll content as it showed moderate to strong association (P < 0.01) over four seasons, might be due to environment or genotype dependent. Highest heritability (95%) and genetic advance (79%) for grain yield was found in H9 over four consecutive crop growing seasons. Combined analysis over four seasons showed that studied variables together explained 85% of total variation in dependent structure (grain yield) obtained by Principal component analysis. This significant finding is the best example of phenotypic stability of grain yield in H9 and made it best fitted for grain yield under drought stress scenario. Detailed genetic analysis of H9 will help us to identify significant loci and alleles that made H9 the best fitted and it could serve as a potential source to generate novel transgressive levels of tolerance for drought stress in arid/semiarid regions. PMID- 28878784 TI - Quantitative Disease Resistance under Elevated Temperature: Genetic Basis of New Resistance Mechanisms to Ralstonia solanacearum. AB - In the context of climate warming, plants will be facing an increased risk of epidemics as well as the emergence of new highly aggressive pathogen species. Although a permanent increase of temperature strongly affects plant immunity, the underlying molecular mechanisms involved are still poorly characterized. In this study, we aimed to uncover the genetic bases of resistance mechanisms that are efficient at elevated temperature to the Ralstonia solanacearum species complex (RSSC), one of the most harmful phytobacteria causing bacterial wilt. To start the identification of quantitative trait loci (QTLs) associated with natural variation of response to R. solanacearum, we adopted a genome wide association (GWA) mapping approach using 176 worldwide natural accessions of Arabidopsis thaliana inoculated with the R. solanacearum GMI1000 strain. Following two different procedures of root-inoculation (root apparatus cut vs. uncut), plants were grown either at 27 or 30 degrees C, with the latter temperature mimicking a permanent increase in temperature. At 27 degrees C, the RPS4/RRS1-R locus was the main QTL of resistance detected regardless of the method of inoculation used. This highlights the power of GWA mapping to identify functionally important loci for resistance to the GMI1000 strain. At 30 degrees C, although most of the accessions developed wilting symptoms, we identified several QTLs that were specific to the inoculation method used. We focused on a QTL region associated with response to the GMI1000 strain in the early stages of infection and, by adopting a reverse genetic approach, we functionally validated the involvement of a strictosidine synthase-like 4 (SSL4) protein that shares structural similarities with animal proteins known to play a role in animal immunity. PMID- 28878783 TI - Extra-Cellular But Extra-Ordinarily Important for Cells: Apoplastic Reactive Oxygen Species Metabolism. AB - Reactive oxygen species (ROS), by their very nature, are highly reactive, and it is no surprise that they can cause damage to organic molecules. In cells, ROS are produced as byproducts of many metabolic reactions, but plants are prepared for this ROS output. Even though extracellular ROS generation constitutes only a minor part of a cell's total ROS level, this fraction is of extraordinary importance. In an active apoplastic ROS burst, it is mainly the respiratory burst oxidases and peroxidases that are engaged, and defects of these enzymes can affect plant development and stress responses. It must be highlighted that there are also other less well-known enzymatic or non-enzymatic ROS sources. There is a need for ROS detoxification in the apoplast, and almost all cellular antioxidants are present in this space, but the activity of antioxidant enzymes and the concentration of low-mass antioxidants is very low. The low antioxidant efficiency in the apoplast allows ROS to accumulate easily, which is a condition for ROS signaling. Therefore, the apoplastic ROS/antioxidant homeostasis is actively engaged in the reception and reaction to many biotic and abiotic stresses. PMID- 28878786 TI - Functional Analysis of the Pepper Ethylene-Responsive Transcription Factor, CaAIEF1, in Enhanced ABA Sensitivity and Drought Tolerance. AB - Abscisic acid (ABA) is a plant hormone that plays a critical role in the response to environmental stress conditions, especially regulation of the stomatal aperture under water-deficit conditions. The signal transduction occurring during the stress response is initiated by transcription of defense-related genes. Here, we isolated the pepper ethylene-responsive transcription factor CaAIEF1 (Capsicum annuum ABA Induced ERF 1). The CaAIEF1 gene was significantly induced after exposure to ABA, drought, and high salinity. Fusion of the acidic domain in the C terminal region of CaAIEF1 to the GAL4 DNA-binding domain had a transactivation effect on the reporter gene in yeast. Further, the CaAIEF1-GFP fusion constructs localized in the nucleus. We used CaAIEF1-silenced plants and CaAIEF1 overexpressing (OX) plants to elucidate the biological function of CaAIEF1 in response to ABA and drought stress. CaAIEF1-silenced pepper plants and CaAIEF1-OX Arabidopsis plants displayed drought-sensitive and -tolerant phenotypes, respectively, which were characterized by regulation of transpirational water loss and stomatal aperture. In drought stress condition, quantitative RT-PCR analyses revealed that the expression levels of pepper stress-related genes were higher in CaAIEF1-silenced pepper plants than control plants. Moreover, expression levels of Arabidopsis stress-related genes were significantly reduced in CaAIEF1-OX plants compared with control plants in drought stress condition. Our findings suggest that CaAIEF1 positively regulates the drought stress response and the ABA signaling. PMID- 28878787 TI - Planting Patterns and Deficit Irrigation Strategies to Improve Wheat Production and Water Use Efficiency under Simulated Rainfall Conditions. AB - The ridge furrow (RF) rainwater harvesting system is an efficient way to enhance rainwater accessibility for crops and increase winter wheat productivity in semi arid regions. However, the RF system has not been promoted widely in the semi arid regions, which primarily exist in remote hilly areas. To exploit its efficiency on a large-scale, the RF system needs to be tested at different amounts of simulated precipitation combined with deficit irrigation. Therefore, in during the 2015-16 and 2016-17 winter wheat growing seasons, we examined the effects of two planting patterns: (1) the RF system and (2) traditional flat planting (TF) with three deficit irrigation levels (150, 75, 0 mm) under three simulated rainfall intensity (1: 275, 2: 200, 3: 125 mm), and determined soil water storage profile, evapotranspiration rate, grain filling rate, biomass, grain yield, and net economic return. Over the two study years, the RF treatment with 200 mm simulated rainfall and 150 mm deficit irrigation (RF2150) significantly (P < 0.05) increased soil water storage in the depth of (200 cm); reduced ET at the field scale by 33%; increased total dry matter accumulation per plant; increased the grain-filling rate; and improved biomass (11%) and grain (19%) yields. The RF2150 treatment thus achieved a higher WUE (76%) and RIWP (21%) compared to TF. Grain-filling rates, grain weight of superior and inferior grains, and net economic profit of winter wheat responded positively to simulated rainfall and deficit irrigation under both planting patterns. The 200 mm simulated rainfall amount was more economical than other precipitation amounts, and led to slight increases in soil water storage, total dry matter per plant, and grain yield; there were no significant differences when the simulated rainfall was increased beyond 200 mm. The highest (12,593 Yuan ha-1) net income profit was attained using the RF system at 200 mm rainfall and 150 mm deficit irrigation, which also led to significantly higher grain yield, WUE, and RIWP than all other treatments. Thus, we recommend the RF2150 treatment for higher productivity, income profit, and improve WUE in the dry-land farming system of China. PMID- 28878788 TI - Transcriptomic Analysis Reveals Candidate Genes for Female Sterility in Pomegranate Flowers. AB - Pomegranate has two types of flowers on the same plant: functional male flowers (FMF) and bisexual flowers (BF). BF are female-fertile flowers that can set fruits. FMF are female-sterile flowers that fail to set fruit and that eventually drop. The putative cause of pomegranate FMF female sterility is abnormal ovule development. However, the key stage at which the FMF pomegranate ovules become abnormal and the mechanism of regulation of pomegranate female sterility remain unknown. Here, we studied ovule development in FMF and BF, using scanning electron microscopy to explore the key stage at which ovule development was terminated and then analyzed genes differentially expressed (differentially expressed genes - DEGs) between FMF and BF to investigate the mechanism responsible for pomegranate female sterility. Ovule development in FMF ceased following the formation of the inner integument primordium. The key stage for the termination of FMF ovule development was when the bud vertical diameter was 5.0 13.0 mm. Candidate genes influencing ovule development may be crucial factors in pomegranate female sterility. INNER OUTER (INO/YABBY4) (Gglean016270) and AINTEGUMENTA (ANT) homolog genes (Gglean003340 and Gglean011480), which regulate the development of the integument, showed down-regulation in FMF at the key stage of ovule development cessation (ATNSII). Their upstream regulator genes, such as AGAMOUS-like (AG-like) (Gglean028014, Gglean026618, and Gglean028632) and SPOROCYTELESS (SPL) homolog genes (Gglean005812), also showed differential expression pattern between BF and FMF at this key stage. The differential expression of the ethylene response signal genes, ETR (ethylene-resistant) (Gglean022853) and ERF1/2 (ethylene-responsive factor) (Gglean022880), between FMF and BF indicated that ethylene signaling may also be an important factor in the development of pomegranate female sterility. The increase in BF observed after spraying with ethephon supported this interpretation. Results from qRT-PCR confirmed the findings of the transcriptomic analysis. PMID- 28878790 TI - Optimum Temperatures for Net Primary Productivity of Three Tropical Seagrass Species. AB - Rising sea water temperature will play a significant role in responses of the world's seagrass meadows to climate change. In this study, we investigated seasonal and latitudinal variation (spanning more than 1,500 km) in seagrass productivity, and the optimum temperatures at which maximum photosynthesis and net productivity (for the leaf and the whole plant) occurs, for three seagrass species (Cymodocea serrulata, Halodule uninervis, and Zostera muelleri). To obtain whole plant net production, photosynthesis, and respiration rates of leaves and the root/rhizome complex were measured using oxygen-sensitive optodes in closed incubation chambers at temperatures ranging from 15 to 43 degrees C. The temperature-dependence of photosynthesis and respiration was fitted to empirical models to obtain maximum metabolic rates and thermal optima. The thermal optimum (Topt) for gross photosynthesis of Z. muelleri, which is more commonly distributed in sub-tropical to temperate regions, was 31 degrees C. The Topt for photosynthesis of the tropical species, H. uninervis and C. serrulata, was considerably higher (35 degrees C on average). This suggests that seagrass species are adapted to water temperature within their distributional range; however, when comparing among latitudes and seasons, thermal optima within a species showed limited acclimation to ambient water temperature (Topt varied by 1 degrees C in C. serrulata and 2 degrees C in H. uninervis, and the variation did not follow changes in ambient water temperature). The Topt for gross photosynthesis were higher than Topt calculated from plant net productivity, which includes above- and below-ground respiration for Z. muelleri (24 degrees C) and H. uninervis (33 degrees C), but remained unchanged at 35 degrees C in C. serrulata. Both estimated plant net productivity and Topt are sensitive to the proportion of below-ground biomass, highlighting the need for consideration of below- to above-ground biomass ratios when applying thermal optima to other meadows. The thermal optimum for plant net productivity was lower than ambient summer water temperature in Z. muelleri, indicating likely contemporary heat stress. In contrast, thermal optima of H. uninervis and C. serrulata exceeded ambient water temperature. This study found limited capacity to acclimate: thus the thermal optima can forewarn of both the present and future vulnerability to ocean warming during periods of elevated water temperature. PMID- 28878789 TI - Effect of Co-segregating Markers on High-Density Genetic Maps and Prediction of Map Expansion Using Machine Learning Algorithms. AB - Advances in sequencing and genotyping methods have enable cost-effective production of high throughput single nucleotide polymorphism (SNP) markers, making them the choice for linkage mapping. As a result, many laboratories have developed high-throughput SNP assays and built high-density genetic maps. However, the number of markers may, by orders of magnitude, exceed the resolution of recombination for a given population size so that only a minority of markers can accurately be ordered. Another issue attached to the so-called 'large p, small n' problem is that high-density genetic maps inevitably result in many markers clustering at the same position (co-segregating markers). While there are a number of related papers, none have addressed the impact of co-segregating markers on genetic maps. In the present study, we investigated the effects of co segregating markers on high-density genetic map length and marker order using empirical data from two populations of wheat, Mohawk * Cocorit (durum wheat) and Norstar * Cappelle Desprez (bread wheat). The maps of both populations consisted of 85% co-segregating markers. Our study clearly showed that excess of co segregating markers can lead to map expansion, but has little effect on markers order. To estimate the inflation factor (IF), we generated a total of 24,473 linkage maps (8,203 maps for Mohawk * Cocorit and 16,270 maps for Norstar * Cappelle Desprez). Using seven machine learning algorithms, we were able to predict with an accuracy of 0.7 the map expansion due to the proportion of co segregating markers. For example in Mohawk * Cocorit, with 10 and 80% co segregating markers the length of the map inflated by 4.5 and 16.6%, respectively. Similarly, the map of Norstar * Cappelle Desprez expanded by 3.8 and 11.7% with 10 and 80% co-segregating markers. With the increasing number of markers on SNP-chips, the proportion of co-segregating markers in high-density maps will continue to increase making map expansion unavoidable. Therefore, we suggest developers improve linkage mapping algorithms for efficient analysis of high-throughput data. This study outlines a practical strategy to estimate the IF due to the proportion of co-segregating markers and outlines a method to scale the length of the map accordingly. PMID- 28878791 TI - Characterization and Mapping of Leaf Rust and Stripe Rust Resistance Loci in Hexaploid Wheat Lines UC1110 and PI610750 under Mexican Environments. AB - Growing resistant wheat varieties is a key method of minimizing the extent of yield losses caused by the globally important wheat leaf rust (LR) and stripe rust (YR) diseases. In this study, a population of 186 F8 recombinant inbred lines (RILs) derived from a cross between a synthetic wheat derivative (PI610750) and an adapted common wheat line (cv. "UC1110") were phenotyped for LR and YR response at both seedling and adult plant stages over multiple seasons. Using a genetic linkage map consisting of single sequence repeats and diversity arrays technology markers, in combination with inclusive composite interval mapping analysis, we detected a new LR adult plant resistance (APR) locus, QLr.cim-2DS, contributed by UC1110. One co-located resistance locus to both rusts, QLr.cim 3DC/QYr.cim-3DC, and the known seedling resistance gene Lr26 were also mapped. QLr.cim-2DS and QLr.cim-3DC showed a marginally significant interaction for LR resistance in the adult plant stage. In addition, two previously reported YR APR loci, QYr.ucw-3BS and Yr48, were found to exhibit stable performances in rust environments in both Mexico and the United States and showed a highly significant interaction in the field. Yr48 was also observed to confer intermediate seedling resistance against Mexican YR races, thus suggesting it should be re-classified as an all-stage resistance gene. We also identified 5 and 2 RILs that possessed all detected YR and LR resistance loci, respectively. With the closely linked molecular markers reported here, these RILs could be used as donors for multiple resistance loci to both rusts in wheat breeding programs. PMID- 28878792 TI - UV Screening in Native and Non-native Plant Species in the Tropical Alpine: Implications for Climate Change-Driven Migration of Species to Higher Elevations. AB - Ongoing changes in Earth's climate are shifting the elevation ranges of many plant species with non-native species often experiencing greater expansion into higher elevations than native species. These climate change-induced shifts in distributions inevitably expose plants to novel biotic and abiotic environments, including altered solar ultraviolet (UV)-B (280-315 nm) radiation regimes. Do the greater migration potentials of non-native species into higher elevations imply that they have more effective UV-protective mechanisms than native species? In this study, we surveyed leaf epidermal UV-A transmittance (TUV A) in a diversity of plant species representing different growth forms to test whether native and non-native species growing above 2800 m elevation on Mauna Kea, Hawaii differed in their UV screening capabilities. We further compared the degree to which TUV A varied along an elevation gradient in the native shrub Vaccinium reticulatum and the introduced forb Verbascum thapsus to evaluate whether these species differed in their abilities to adjust their levels of UV screening in response to elevation changes in UV-B. For plants growing in the Mauna Kea alpine/upper subalpine, we found that adaxial TUV A, measured with a UVA-PAM fluorometer, varied significantly among species but did not differ between native (mean = 6.0%; n = 8) and non-native (mean = 5.8%; n = 11) species. When data were pooled across native and non-native taxa, we also found no significant effect of growth form on TUV A, though woody plants (shrubs and trees) were represented solely by native species whereas herbaceous growth forms (grasses and forbs) were dominated by non-native species. Along an elevation gradient spanning 2600-3800 m, TUV A was variable (mean range = 6.0-11.2%) and strongly correlated with elevation and relative biologically effective UV-B in the exotic V. thapsus; however, TUV A was consistently low (3%) and did not vary with elevation in the native V. reticulatum. Results indicate that high levels of UV protection occur in both native and non-native species in this high UV-B tropical alpine environment, and that flexibility in UV screening is a mechanism employed by some, but not all species to cope with varying solar UV-B exposures along elevation gradients. PMID- 28878793 TI - Activation of ABA Receptors Gene GhPYL9-11A Is Positively Correlated with Cotton Drought Tolerance in Transgenic Arabidopsis. AB - The sensitivity to abscisic acid (ABA) by its receptors, pyrabactin resistance like proteins (PYLs), is considered a most important factor in activating the ABA signal pathway in response to abiotic stress. However, it is still unknown which PYL is the crucial ABA receptor mediating response to drought stress in cotton (Gossypium hirsutum L.). Here, we reported the identification and characterization of highly induced ABA receptor GhPYL9-11A in response to drought in cotton. It is observed that GhPYL9-11A was highly induced by ABA treatment. GhPYL9-11A binds to protein phosphatase 2Cs (PP2Cs) in an ABA-independent manner. Moreover, the GhPYL-11A-PP2C interactions are partially disrupted by mutations, proline (P84) and histidine (H111), in the gate-latch region. Transgenic Arabidopsis overexpressing GhPYL9-11A plants were hypersensitive to ABA during seed germination and early seedling stage. Further, the increased in root growth and up regulation of drought stress-related genes in transgenic Arabidopsis as compared to wild type confirmed the potential role of GhPYL9-11A in abiotic stress tolerance. Consistently, the expression level of GhPYL9-11A is on average higher in drought-tolerant cotton cultivars than in drought-sensitive cottons under drought treatment. In conclusion, the manipulation of GhPYL9-11A expression could be a useful strategy for developing drought-tolerant cotton cultivars. PMID- 28878794 TI - A Tau Class Glutathione-S-Transferase is Involved in Trans-Resveratrol Transport Out of Grapevine Cells. AB - Vitis vinifera cell cultures respond to pathogens and elicitors by synthesizing and extracellularly accumulating stilbenoid phytoalexins. Large amounts of trans resveratrol (t-R) are produced when a cell culture is elicited with methylated cyclodextrins (MBCD), either alone or combined with methyl jasmonate (MeJA). t-R transport to the extracellular medium, which represents the apoplastic space, would place this antifungal defense right in the battlefield to efficiently fight against pathogen attack. Yet despite their physiological relevance, these transport pathways are mostly unknown. A broad hypothesis-free DIGE-based proteomic experiment of a temporal series of elicited grapevine cell cultures was performed to explore the expression profiles of t-R biosynthetic proteins and other co-expressing proteins potentially involved in such a cell response. A correlation between two tau class glutathione-S-transferases (GSTs) with several stilbene synthase and phenylalanine ammonia-lyase isoforms, and with the t-R metabolite itself, was found and further assessed by a qRT-PCR gene expression analysis. The best candidate, GSTU-2, was cloned from the cDNA of the MBCD + MeJA elicited grapevine cells and used for Agrobacterium-mediated grapevine cell transformation. The non-elicited lines that overexpressed GSTU-2 displayed an extracellular t-R accumulating phenotype, but stabilization of t-R required the addition to culture medium of adsorbent compounds, e.g., PVP or beta cyclodextrin. The wild-type cell cultures accumulated no t-R, not even in the presence of adsorbents. The transient expression of the GSTU-2-GFP fusion proteins in grapevine cells showed localisation in the plasma membrane, and the immunoprecipitation of HA-tagged GSTU-2 revealed its interaction with HIR, a plasma membrane-bound protein. These findings are consistent with a functional role in transport. This is the first report providing several pieces of experimental evidence for the involvement of a specific tau class GST in t-R transport to the extracellular medium. PMID- 28878795 TI - Organization and Regulation of Soybean SUMOylation System under Abiotic Stress Conditions. AB - Covalent attachment of the small ubiquitin-related modifier, SUMO, to substrate proteins plays a significant role in plants under stress conditions, which can alter target proteins' function, location, and protein-protein interactions. Despite this importance, information about SUMOylation in the major legume crop, soybean, remains obscure. In this study, we performed a bioinformatics analysis of the entire soybean genome and identified 40 genes belonged to six families involved in a cascade of enzymatic reactions in soybean SUMOylation system. The cis-acting elements analysis revealed that promoters of SUMO pathway genes contained different combinations of stress and development-related cis-regulatory elements. RNA-seq data analysis showed that SUMO pathway components exhibited versatile tissue-specific expression patterns, indicating coordinated functioning during plant growth and development. qRT-PCR analysis of 13 SUMO pathway members indicated that majority of the SUMO pathway members were transcriptionally up regulated by NaCl, heat and ABA stimuli during the 24 h period of treatment. Furthermore, SUMOylation dynamics in soybean roots under abiotic stress treatment were analyzed by western blot, which were characterized by regulation of SUMOylated proteins. Collectively, this study defined the organization of the soybean SUMOylation system and implied an essential function for SUMOylation in soybean abiotic stress responses. PMID- 28878796 TI - Autophagy Is Rapidly Induced by Salt Stress and Is Required for Salt Tolerance in Arabidopsis. AB - Salinity stress challenges agriculture and food security globally. Upon salt stress, plant growth slows down, nutrients are recycled, osmolytes are produced, and reallocation of Na+ takes place. Since autophagy is a high-throughput degradation pathway that contributes to nutrient remobilization in plants, we explored the involvement of autophagic flux in salt stress response of Arabidopsis with various approaches. Confocal microscopy of GFP-ATG8a in transgenic Arabidopsis showed that autophagosome formation is induced shortly after salt treatment. Immunoblotting of ATG8s and the autophagy receptor NBR1 confirmed that the level of autophagy peaks within 30 min of salt stress, and then settles to a new homeostasis in Arabidopsis. Such an induction is absent in mutants defective in autophagy. Within 3 h of salt treatment, accumulation of oxidized proteins is alleviated in the wild-type; however, such a reduction is not seen in atg2 or atg7. Consistently, the Arabidopsis atg mutants are hypersensitive to both salt and osmotic stresses, and plants overexpressing ATG8 perform better than the wild-type in germination assays. Quantification of compatible osmolytes further confirmed that the autophagic flux contributes to salt stress adaptation. Imaging of intracellular Na+ revealed that autophagy is required for Na+ sequestration in the central vacuole of root cortex cells following salt treatment. These data suggest that rapid protein turnover through autophagy is a prerequisite for salt stress tolerance in Arabidopsis. PMID- 28878797 TI - Overexpression of Hevea brasiliensis HbICE1 Enhances Cold Tolerance in Arabidopsis. AB - Rubber trees (Hevea brasiliensis) were successfully introduced to south China in the 1950s on a large-scale; however, due to the climate, are prone to cold injury during the winter season. Increased cold tolerance is therefore an important goal, yet the mechanism underlying rubber tree responses to cold stress remains unclear. This study carried out functional characterization of HbICE1 (Inducer of CBF Expression 1) from H. brasiliensis. A nucleic protein with typical features of ICEs, HbICE1 was able to bind to MYC recognition sites and had strong transactivation activity. HbICE1 was constitutively expressed in all tested tissues, with highest levels in the bark, and was up-regulated when subjected to various stresses including cold, dehydration, salinity and wounding. When overexpressed in Arabidopsis, 35S::HbICE1 plants showed enhanced cold resistance with increased proline content, reduced malondialdehyde (MDA) metabolism and electrolyte leakage, and decreased reactive oxygen species (ROS) accumulation. Expression of the cold responsive genes (COR15A, COR47, RD29A, and KIN1) was also significantly promoted in 35S::HbICE1 compared to wild-type plants under cold stress. Differentially expressed genes (DEGs) analysis showed that cold treatment changed genes expression profiles involved in many biological processes and phytohormones perception and transduction. Ethylene, JA, ABA, as well as ICE-CBF signaling pathways might work synergistically to cope with cold tolerance in rubber tree. Taken together, these findings suggest that HbICE1 is a member of the ICE gene family and a positive regulator of cold tolerance in H. brasiliensis. PMID- 28878798 TI - Characterization of Genetic Basis on Synergistic Interactions between Root Architecture and Biological Nitrogen Fixation in Soybean. AB - Soybean [Glycine max (L.) Merr] is an important legume crop and its yield largely depends on root architecture (RA) and biological nitrogen fixation (BNF). However, the relationship between RA and BNF, and its genetics behind remain unclear. Here, two soybean genotypes contrasting in RA and their 175 F9:11 recombinant inbred lines (RILs) were evaluated in field. The shallow-root parent, JD12, had better nodulation and higher yield than the deep-root parent, NF58. Strong correlations between shoot dry weight (SDW) and RA or BNF traits existed in the RILs, and the shallow-root group had more and heavier nodules, as well as higher SDW. After inoculating with rhizobia, roots became shallower and bigger, showing strong synergistic interactions between RA and BNF. In total, 70 QTLs were identified for the 21 tested traits. Among them, qBNF-RA-C2, qBNF-RA-O, and qBNF-RA-B1, were newly identified QTLs for BNF and/or RA traits in soybean, which co-located with the QTLs for SDW detected presently, and with the QTLs for yield identified previously. The results together suggest that there are synergistic interactions between RA and BNF, and the QTLs identified here could be used for breeding new soybean varieties with higher yields through optimization of RA traits and BNF capacity. PMID- 28878799 TI - Integration of Physical, Genetic, and Cytogenetic Mapping Data for Cellulose Synthase (CesA) Genes in Flax (Linum usitatissimum L.). AB - Flax, Linum usitatissimum L., is a valuable multi-purpose plant, and currently, its genome is being extensively investigated. Nevertheless, mapping of genes in flax genome is still remaining a challenging task. The cellulose synthase (CesA) multigene family involving in the process of cellulose synthesis is especially important for metabolism of this fiber crop. For the first time, fluorescent in situ hybridization (FISH)-based chromosomal localization of the CesA conserved fragment (KF011584.1), 5S, and 26S rRNA genes was performed in landrace, oilseed, and fiber varieties of L. usitatissimum. Intraspecific polymorphism in chromosomal distribution of KF011584.1 and 5S DNA loci was revealed, and the generalized chromosome ideogram was constructed. Using BLAST analysis, available data on physical/genetic mapping and also whole-genome sequencing of flax, localization of KF011584.1, 45S, and 5S rRNA sequences on genomic scaffolds, and their anchoring to the genetic map were conducted. The alignment of the results of FISH and BLAST analyses indicated that KF011584.1 fragment revealed on chromosome 3 could be anchored to linkage group (LG) 11. The common LG for 45S and 5S rDNA was not found probably due to the polymorphic localization of 5S rDNA on chromosome 1. Our findings indicate the complexity of integration of physical, genetic, and cytogenetic mapping data for multicopy gene families in plants. Nevertheless, the obtained results can be useful for future progress in constructing of integrated physical/genetic/cytological maps in L. usitatissimum which are essential for flax breeding. PMID- 28878800 TI - Transcriptome Assembly and Systematic Identification of Novel Cytochrome P450s in Taxus chinensis. AB - Taxus spp. is a highly valuable medicinal plant with multiple pharmacological effects on various cancers. Cytochrome P450s (CYP450s) play important roles in the biosynthesis of active compounds in Taxus spp., such as the famous diterpenoid, Taxol. However, some specific CYP450 enzymes involved in the biosynthesis of Taxol remain unknown, and the systematic identification of CYP450s in Taxus has not been reported. In this study, 118 full-length and 175 partial CYP450 genes were identified in Taxus chinensis transcriptomes. The 118 full-length genes were divided into 8 clans and 29 families. The CYP71 clan included all A-type genes (52) belonging to 11 families. The other seven clans possessed 18 families containing 66 non-A-type genes. Two new gymnosperm-specific families were discovered, and were named CYP864 and CYP947 respectively. Protein sequence alignments revealed that all of the T. chinensis CYP450s hold distinct conserved domains. The expression patterns of all 118 CYP450 genes during the long-time subculture and MeJA elicitation were analyzed. Additionally, the expression levels of 15 novel CYP725 genes in different Taxus species were explored. Considering all the evidence, 6 CYP725s were identified to be candidates for Taxol biosynthesis. The cis-regulatory elements involved in the transcriptional regulation were also identified in the promoter regions of CYP725s. This study presents a comprehensive overview of the CYP450 gene family in T. chinensis and can provide important insights into the functional gene studies of Taxol biosynthesis. PMID- 28878802 TI - Development of Highly Informative Genome-Wide Single Sequence Repeat Markers for Breeding Applications in Sesame and Construction of a Web Resource: SisatBase. AB - The sequencing of the full nuclear genome of sesame (Sesamum indicum L.) provides the platform for functional analyses of genome components and their application in breeding programs. Although the importance of microsatellites markers or simple sequence repeats (SSR) in crop genotyping, genetics, and breeding applications is well established, only a little information exist concerning SSRs at the whole genome level in sesame. In addition, SSRs represent a suitable marker type for sesame molecular breeding in developing countries where it is mainly grown. In this study, we identified 138,194 genome-wide SSRs of which 76.5% were physically mapped onto the 13 pseudo-chromosomes. Among these SSRs, up to three primers pairs were supplied for 101,930 SSRs and used to in silico amplify the reference genome together with two newly sequenced sesame accessions. A total of 79,957 SSRs (78%) were polymorphic between the three genomes thereby suggesting their promising use in different genomics-assisted breeding applications. From these polymorphic SSRs, 23 were selected and validated to have high polymorphic potential in 48 sesame accessions from different growing areas of Africa. Furthermore, we have developed an online user-friendly database, SisatBase (http://www.sesame-bioinfo.org/SisatBase/), which provides free access to SSRs data as well as an integrated platform for functional analyses. Altogether, the reference SSR and SisatBase would serve as useful resources for genetic assessment, genomic studies, and breeding advancement in sesame, especially in developing countries. PMID- 28878801 TI - CRISPR/Cas9: A Practical Approach in Date Palm Genome Editing. AB - The genetic modifications through breeding of crop plants have long been used to improve the yield and quality. However, precise genome editing (GE) could be a very useful supplementary tool for improvement of crop plants by targeted genome modifications. Various GE techniques including ZFNs (zinc finger nucleases), TALENs (transcription activator-like effector nucleases), and most recently clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR associated protein 9)-based approaches have been successfully employed for various crop plants including fruit trees. CRISPR/Cas9-based approaches hold great potential in GE due to their simplicity, competency, and versatility over other GE techniques. However, to the best of our knowledge no such genetic improvement has ever been developed in date palm-an important fruit crop in Oasis agriculture. The applications of CRISPR/Cas9 can be a challenging task in date palm GE due to its large and complex genome, high rate of heterozygosity and outcrossing, in vitro regeneration and screening of mutants, high frequency of single-nucleotide polymorphism in the genome and ultimately genetic instability. In this review, we addressed the potential application of CRISPR/Cas9-based approaches in date palm GE to improve the sustainable date palm production. The availability of the date palm whole genome sequence has made it feasible to use CRISPR/Cas9 GE approach for genetic improvement in this species. Moreover, the future prospects of GE application in date palm are also addressed in this review. PMID- 28878803 TI - Purification of Maize Nucleotide Pyrophosphatase/Phosphodiesterase Casts Doubt on the Existence of Zeatin Cis-Trans Isomerase in Plants. AB - Almost 25 years ago, an enzyme named zeatin cis-trans isomerase from common bean has been described by Bassil et al. (1993). The partially purified enzyme required an external addition of FAD and dithiothreitol for the conversion of cis zeatin to its trans- isomer that occurred only under light. Although an existence of this important enzyme involved in the metabolism of plant hormones cytokinins was generally accepted by plant biologists, the corresponding protein and encoding gene have not been identified to date. Based on the original paper, we purified and identified an enzyme from maize, which shows the described zeatin cis-trans isomerase activity. The enzyme belongs to nucleotide pyrophosphatase/phosphodiesterase family, which is well characterized in mammals, but less known in plants. Further experiments with the recombinant maize enzyme obtained from yeast expression system showed that rather than the catalytic activity of the enzyme itself, a non-enzymatic flavin induced photoisomerization is responsible for the observed zeatin cis-trans interconversion in vitro. An overexpression of the maize nucleotide pyrophosphatase/phosphodiesterase gene led to decreased FAD and increased FMN and riboflavin contents in transgenic Arabidopsis plants. However, neither contents nor the ratio of zeatin isomers was altered suggesting that the enzyme is unlikely to catalyze the interconversion of zeatin isomers in vivo. Using enhanced expression of a homologous gene, functional nucleotide pyrophosphatase/phosphodiesterase was also identified in rice. PMID- 28878804 TI - The Latex Protein MLX56 from Mulberry (Morus multicaulis) Protects Plants against Insect Pests and Pathogens. AB - Biotic stresses are major constraints limiting the leaf quality and productivity of mulberry. MLX56 is a unique chitin-binding protein isolated from Shin-Ichinose (Morus alba) latex that displays toxicity against lepidopteran caterpillars. In this study, the full-length cDNA encoding MLX56 was isolated from Husang 32 (M. multicaulis) and designated HMLX56. Amino acid sequence analysis and protein modeling of three MLX56 proteins showed that they were highly conserved among Morus species. Tissue expression pattern analysis showed that the HMLX56 gene was strongly expressed in mulberry bark and leaves but only slightly expressed in fruits. In addition, analysis of GUS expression indicated that the promoter of HMLX56 showed higher transcriptional activity along the vascular strands, and its activity can be regulated by various environmental factors. Like the MLX56 protein from M. alba, the HMLX56 protein showed toxicity to Plutella xylostella. Moreover, when the HMLX56 gene was ectopically expressed in Arabidopsis, the transgenic plants showed enhanced resistance to aphids, the fungal pathogen Botrytis cinerea and the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. Our data suggest that the HMLX56 protein has a lectin-like molecular structure consisting of two hevein-like chitin-binding domains which provide not only chitin-binding activities but also other mechanisms of defense. The information provided here improves our understanding of the potential functions and defense mechanisms of MLX56 proteins, enabling in-depth functional analysis of latex exudates and perhaps facilitating mulberry genetic improvement in the future. PMID- 28878805 TI - Corrigendum: Transcriptomic Identification of Drought-Related Genes and SSR Markers in Sudan Grass Based on RNA-Seq. AB - [This corrects the article on p. 687 in vol. 8, PMID: 28523007.]. PMID- 28878806 TI - Measuring Animal Age with DNA Methylation: From Humans to Wild Animals. AB - DNA methylation (DNAm) is a key mechanism for regulating gene expression in animals and levels are known to change with age. Recent studies have used DNAm changes as a biomarker to estimate chronological age in humans and these techniques are now also being applied to domestic and wild animals. Animal age is widely used to track ongoing changes in ecosystems, however chronological age information is often unavailable for wild animals. An ability to estimate age would lead to improved monitoring of (i) population trends and status and (ii) demographic properties such as age structure and reproductive performance. Recent studies have revealed new examples of DNAm age association in several new species increasing the potential for developing DNAm age biomarkers for a broad range of wild animals. Emerging technologies for measuring DNAm will also enhance our ability to study age-related DNAm changes and to develop new molecular age biomarkers. PMID- 28878808 TI - Luteolin, quercetin, genistein and quercetagetin inhibit the effects of lipopolysaccharide obtained from Porphyromonas gingivalis in H9c2 cardiomyoblasts. AB - BACKGROUND: One of the microorganisms from dental plaque associated with severe inflammatory responses in infectious endocarditis is Porphyromonas gingivalis. It is a Gram-negative bacteria harvested from chronic periodontitis patients. Lipopolysaccharide (LPS) obtained from P. gingivalis promotes the expressions of interleukin-1 (IL-1), IL-6 and tumor necrosis factor alpha (TNF-alpha). Flavonoids are thought to participate in processes that control inflammation, such as the expression of cyclooxygenase-2 (COX-2). METHODS: We investigated the effects of luteolin, quercetin, genistein and quercetagetin on cardiomyoblasts treated with LPS alone or in combination with following inhibitors p38 (SB203580), ERK (PD98059), JNK (SP600125) and PKC (Calphostin C) for 1 h. The kinase activation and COX-2 expression levels were determined at the gene and protein levels. RESULTS: These flavonoids are considered to inhibit the activation of mitogen-activated protein kinase (MAPK) and the degradation of inhibitor of kappa B-alpha (IkappaB-alpha). They also play a role in COX-2 expression. CONCLUSION: We conclude that the tested flavonoids inhibit inflammatory responses induced by LPS in H9c2 cells. PMID- 28878807 TI - Distribution and Functionality of Copy Number Variation across European Cattle Populations. AB - Copy number variation (CNV), which is characterized by large-scale losses or gains of DNA fragments, contributes significantly to genetic and phenotypic variation. Assessing CNV across different European cattle populations might reveal genetic changes responsible for phenotypic differences, which have accumulated throughout the domestication history of cattle as consequences of evolutionary forces that act upon them. To explore pattern of CNVs across European cattle, we genotyped 149 individuals, that represent different European regions, using the Illumina Bovine HD Genotyping array. A total of 9,944 autosomal CNVs were identified in 149 samples using a Hidden Markov Model (HMM) as employed in PennCNV. Animals originating from several breeds of British Isles, and Balkan and Italian regions, on average, displayed higher abundance of CNV counts than Dutch or Alpine animals. A total of 923 CNV regions (CNVRs) were identified by aggregating CNVs overlapping in at least two animals. The hierarchical clustering of CNVRs indicated low differentiation and sharing of high-frequency CNVRs between European cattle populations. Various CNVRs identified in the present study overlapped with olfactory receptor genes and genes related to immune system. In addition, we also detected a CNV overlapping the Kit gene in English longhorn cattle which has previously been associated with color-sidedness. To conclude, we provide a comprehensive overview of CNV distribution in genome of European cattle. Our results indicate an important role of purifying selection and genomic drift in shaping CNV diversity that exists between different European cattle populations. PMID- 28878810 TI - Prevalence and clinical features of adverse food reactions in Portuguese children. AB - BACKGROUND: The prevalence of adverse food reactions (AFR) has been increasing in the western world. Clinical manifestations are diversified and it may not be possible to clinically discriminate between IgE and non-IgE mediated AFR. In Portugal, the prevalence of AFR and food allergies in children is not known. Thus, the objectives of this study were to determine the prevalence of AFR in central Portugal. METHODS: Point prevalence study in 3-11 year-old schoolchildren from Central Portugal. Food-related questionnaires, skin prick tests (SPT) with foods and determination of food-specific IgE levels were performed. RESULTS: Of 4045 schoolchildren, 2474 (61.2%) accepted to be included in the study. Global prevalence of AFR was 7.1% (95% CI 6.2-8.1), based upon the initial questionnaire, 4.6% (95% CI 3.9-5.5), based upon a confirmatory questionnaire and the prevalence of probable food allergy (IgE-associated AFR: positive history + positive SPT and/or positive specific IgE) was 1.4% (95% CI 0.9-1.9). Most frequently implicated foods were fresh fruits, fish and egg. A first episode at an earlier age, mucocutaneous and anaphylactic reactions were more frequent in IgE-associated AFR. CONCLUSIONS: The prevalence of probable food allergy in 3-11 year old Portuguese children from central Portugal is low and parents over-report its frequency. Most frequently implicated foods were fresh fruit and fish. Immediate type, polysymptomatic, and more severe reactions may commence at an earlier age and be more frequent in IgE-associated than in non-IgE associated reactions. PMID- 28878809 TI - Are online prediction tools a valid alternative to genomic profiling in the context of systemic treatment of ER-positive breast cancer? AB - BACKGROUND: Clinicians use clinical and pathological parameters, such as tumour size, grade and nodal status, to make decisions on adjuvant treatments for breast cancer. However, therapeutic decisions based on these features tend to vary due to their subjectivity. Computational and mathematical algorithms were developed using clinical outcome data from breast cancer registries, such as Adjuvant! Online and NHS PREDICT. More recently, assessments of molecular profiles have been applied in the development of better prognostic tools. METHODS: Based on the available literature on online registry-based tools and genomic assays, we evaluated whether these online tools could be valid and accurate alternatives to genomic and molecular profiling of the individual breast tumour in aiding therapeutic decisions, particularly in patients with early ER-positive breast cancer. RESULTS AND CONCLUSIONS: Early breast cancer is currently considered a systemic disease and a complex ecosystem with behaviour determined by the complex genetic and molecular signatures of the tumour cells, mammary stem cells, microenvironment and host immune system. We anticipate that molecular profiling will continue to evolve, expanding beyond the primary tumour to include the tumour microenvironment, cancer stem cells and host immune system. This should further refine therapeutic decisions and optimise clinical outcome. This article was specially invited by the editors and represents work by leading researchers. PMID- 28878811 TI - Serum metabolites in non-alcoholic fatty-liver disease development or reversion; a targeted metabolomic approach within the PREDIMED trial. AB - BACKGROUND: Limited prospective studies have examined changes in non-alcoholic fatty-liver disease (NAFLD) related serum-metabolites and none the effects of NAFLD-reversion. We aimed to evaluate whether perturbations in metabolites indicate predisposition to NAFLD development and to assess the effects of NAFLD reversion on metabolite profiles. METHODS: A targeted liquid-chromatography tandem mass-spectrometry metabolic profiling (n = 453 metabolites) approach was applied, using serum from 45 subjects of the PREDIMED study, at baseline and after a median 3.8-year follow-up. NAFLD was determined using the hepatic steatosis index; with three groups classified and studied: Group 1, not characterized as NAFLD cases during the follow-up (n = 15); Group 2, characterized as NAFLD during the follow-up (n = 15); Group 3, characterized as NAFLD-reversion during the follow-up (n = 15). RESULTS: At baseline, significantly lower storage and transport lipids (triacylglycerols and cholesteryl esters), several monoetherglycerophosphocholines, acylglycerophosphocholines, ceramides and ceramide to sphingomyelin ratio (P < 0.05), were found; whereas a higher L-cystine to L-glutamate ratio (P < 0.05) was observed, in group 2 as compared to group 1.P-ether acylglycerophosphocholines, ceramides and sphingolipids were significantly different betweengroup 3 and group 1 (P < 0.05). Higher 16:1n-7 to 16:0, and 18:0 to16:0 ratio (P < 0.05), while lower 18:1n-9 to 18:0, 16:0 to 18:2n-6, and 18:3n-6 to 18:2n-6 ratio (P < 0.05) were observed in the final, compared to baseline values, in groups 2 and 3. CONCLUSION: The rearrangement of lipid biosynthesis and serum transport may indicate predisposition to NAFLD development. Despite an expected reduction of hepatic lipotoxicity and improved hepatic function in the participants of the study characterized as NAFLD-reversing, the side effects of NAFLD in serum metabolic profiles remained present. TRIAL REGISTRATION: The trial is registered at ISRCTN35739639. Registration date: 5th October 2005. PMID- 28878812 TI - An arabic translation, reliability, and validation of Patient Health Questionnaire in a Saudi sample. AB - BACKGROUND: Psychological disorders including depression and anxiety are not rare in primary care clinics. The Patient Health Questionnaire (PHQ) is a clinical diagnostic tool that is widely utilized by primary health care physicians worldwide because it provides a practical in-clinic tool to screen for psychological disorders. This study evaluated the validity of the Arabic version of the PHQ in all six modules including depression, anxiety, somatic, panic, eating, and alcohol abuse disorders. METHODS: This is a quantitative observational cross-sectional study that was conducted by administrating the translated Arabic version of PHQ to a sample of King Saud University students in Riyadh, Saudi Arabia. RESULTS: The sample was 731 university students who participated in this study including 376 (51.6%) females and 354 (48.4%) males with a mean age of 21.30 years. Eight mental health experts carried out the face validation process of the PHQ Arabic version. The internal consistency reliability was measured using Cronbach's alpha for the PHQ9, GAD7, PHQ15, and panic disorder modules. The results were 0.857, 0.763, 0.826, and 0.696, respectively. In comparison, the eating disorders and alcohol abuse modules demonstrated poor internal consistency due to small number of participants in these modules. CONCLUSION: This study demonstrates that the Arabic version of the PHQ is a valid and reliable tool to screen for depression, anxiety, somatic, and panic disorders in a Saudi sample. PMID- 28878813 TI - Health utilities for chronic low back pain. AB - BACKGROUND: Chronic low back pain (LBP) is a common health problem, with a large potential for primary prevention. Health utilities (HU) reflect which proportion of their expected remaining life time individuals would hypothetically trade to be alleviated of a health condition of interest. A value of 0 means "prefer to die immediately", a value of 1 means "not willing to trade any life time". The aim of this cross-sectional study was to assess HU for LBP patients and for healthy participants and to examine whether HU for LBP are useful indicators to substantiate preventive and therapeutic decision making. METHODS: Healthy participants (n = 126) and LBP patients (n = 32) were recruited mainly among the employees of a tertiary care hospital in Germany. Standardized LBP scenarios were presented to all participants and HU values were assessed using the time-trade off method. RESULTS: Median HU for LBP were 0.90 (IQR 0.31) for participants and 0.93 (IQR 0.10) for LBP patients. Measurements were consistent across illness severity ratings with HU and with a visual analogue scale (VAS); in the healthy sample the intraclass correlation coefficient (ICC) was 0.61 (95% CI 0.23-1.00, F(1125) = 190, p < .001), in the patient sample the ICC was 0.66 (95% CI = 0.24 1.00, F(1,31) = 62, p < .001). 8% of participants reported HU of 1. There was no statistically significant relation between HU and age, income, or gender. CONCLUSION: On average, participants chose a 7 to 10% shorter life expectancy to avoid LBP, but almost 1 in 10 participants were not willing to trade any life years. The results indicate a certain stability of HU due to the comparability of HU ratings across patients and healthy participants, the measurement consistency when comparing VAS and HU ratings, and the lack of association between demographic variables and HU. This underlines the usefulness of HU for measuring illness severity in comparative health economics evaluations of preventive and therapeutic measures that address chronic LBP or other pain-characterized diseases. Future studies should focus on different LBP intensities and derive stratified HU that reflect the distribution of pain intensity in the population. PMID- 28878814 TI - Thoracic trauma severity contributes to differences in intensive care therapy and mortality of severely injured patients: analysis based on the TraumaRegister DGU(r). AB - BACKGROUND: Thoracic trauma is a relevant source of comorbidity throughout multiply-injured patient care. We aim to determine a measurable influence of chest trauma's severity on early resuscitation, intensive care therapy, and mortality in severely injured patients. METHODS: Patients documented between 2002 and 2012 in the TraumaRegister DGU(r), aged >= 16 years, injury severity score (ISS) >= 16 are analyzed. Isolated brain injury and severe head injury led to exclusion. Subgroups are formed using the Abbreviated Injury ScaleThorax. RESULTS: Twenty-two thousand five hundred sixty-five patients were predominantly male (74%) with mean age of 45.7 years (SD 19.3), blunt trauma (95%), mean ISS 25.6 (SD 9.6). Overall mean intubation period was 5.6 days (SD 10.7). Surviving patients were discharged from the ICU after a mean of about 5 days following extubation. Thoracic trauma severity (AISThorax >= 4) and fractures to the thoracic cage significantly prolonged the ventilation period. Additionally, fractures extended the ICU stay significantly. Suffering from more than one thoracic injury was associated with a mean of 1-2 days longer intubation period and longer ICU stay. Highest rates of sepsis, respiratory, and multiple organ failure occurred in patients with critical compared to lesser thoracic trauma severity. CONCLUSION: Thoracic trauma severity in multiply-injured patients has a measurable impact on rates of respiratory and multiple organ failure, sepsis, mortality, time of mechanical ventilation, and ICU stay. PMID- 28878816 TI - A child with anorexia nervosa presenting with severe infection with cytopenia and hemophagocytosis: a case report. AB - BACKGROUND: Patients with anorexia nervosa in the acute phase have physical complications, such as infectious disease. Although hemophagocytic syndrome due to infection is a rare complication in anorexia nervosa, early identification for hemophagocytosis is important for avoiding a life-threatening condition. CASE PRESENTATION: We report a case of a 12-year-old girl with anorexia nervosa presenting with infection with cytopenia and hemophagocytosis during initial nutritional therapy. She developed pyrexia, abdominal pain, and diarrhea during inpatient treatment. Although intravenous antibiotics were administered, the symptoms persisted. Acinetobacter baumannii was detected in blood culture. Hemophagocytosis was present in the bone marrow. Gamma globulin therapy was effective, with improvement in symptoms and cytopenia. CONCLUSIONS: Although our case did not fulfill the criteria of hemophagocytic syndrome, clinicians should consider severe infection in anorexia nervosa with cytopenia and hemophagocytosis. PMID- 28878815 TI - Efficacy of Chinese herbal medicine for stroke modifiable risk factors: a systematic review. AB - BACKGROUND: The vast majority of stroke burden is attributable to its modifiable risk factors. This paper aimed to systematically summarise the evidence of Chinese herbal medicine (CHM) interventions on stroke modifiable risk factors for stroke prevention. METHODS: A literature search was conducted via the MEDLINE, CINAHL/EBSCO, SCOPUS, and Cochrane Database from 1996 to 2016. Randomised controlled trials or cross-over studies were included. Risk of bias was assessed according to the Cochrane Risk of Bias tool. RESULTS: A total of 46 trials (6895 participants) were identified regarding the use of CHM interventions in the management of stroke risk factors, including 12 trials for hypertension, 10 trials for diabetes, eight trials for hyperlipidemia, seven trials for impaired glucose tolerance, three trials for obesity, and six trials for combined risk factors. Amongst the included trials with diverse study design, an intervention of CHM as a supplement to biomedicine and/or a lifestyle intervention was found to be more effective in lowering blood pressure, decreasing blood glucose level, helping impaired glucose tolerance reverse to normal, and/or reducing body weight compared to CHM monotherapy. While no trial reported deaths amongst the CHM groups, some papers do report moderate adverse effects associated with CHM use. However, the findings of such beneficial effects of CHM should be interpreted with caution due to the heterogeneous set of complex CHM studied, the various control interventions employed, the use of different participants' inclusion criteria, and low methodological quality across the published studies. The risk of bias of trials identified was largely unclear in the domains of selection bias and detection bias across the included studies. CONCLUSION: This study showed substantial evidence of varied CHM interventions improving the stroke modifiable risk factors. More rigorous research examining the use of CHM products for sole or multiple major stroke risk factors are warranted. PMID- 28878817 TI - Children's mental health problems and their relation to parental stress in foster mothers and fathers. AB - BACKGROUND: This study focuses on children living in foster families with a history of maltreatment or neglect. These children often show adverse mental health outcomes reflected in increased externalizing and internalizing problems. It is expected that these adverse outcomes are associated with increased parental stress levels experienced by foster mothers as well as foster fathers. METHODS: The study sample included 79 children living in foster families and 140 children living in biological families as comparison group. The age of the children ranged from 2 to 7 years. Mental health problems were assessed with the Child Behavior Checklist, while parenting stress was measured with a parenting stress questionnaire including subscales on the amount of experienced stress and the amount of perceived support. The Child Behavior Checklist assessments were based mainly on maternal reports, while the parental stress assessments were based on maternal as well as paternal reports. RESULTS: As expected the results showed increased externalizing and internalizing scores for the foster children accompanied by increased parental stress experiences in the foster family sample (however only in the maternal, but not in the paternal stress reports). The stress differences between the foster and biological family groups disappeared, when the children's mental health problem scores were included as covariates. Moreover, especially the externalizing scores were strong predictors of parental stress in both, the groups of foster and biological parents. The amount of perceived social support was associated with reduced parental stress, but only in the group of biological fathers. CONCLUSION: The emergence of parental stress in biological as well as foster parents is closely related to child characteristics (mainly externalizing child problems). Possible implications for the reduction of parental stress are discussed as a consequence of the present results. PMID- 28878818 TI - Socioeconomic position and self-harm among adolescents: a population-based cohort study in Stockholm, Sweden. AB - BACKGROUND: Understanding the association between parental socioeconomic position and self-harm in adolescence is crucial due to its substantial magnitude and associated inequality. Most previous studies have been either of cross-sectional nature or based solely on self-reports or hospital treated self-harm. The aim of this study is to determine the association between parental socioeconomic position and self-harm among adolescents with a specific focus on gender and severity of self-harm. METHODS: A total of 165,932 adolescents born 1988-1994 who lived in Stockholm at the age of 13 were followed in registers until they turned 18. Self-harm was defined as first time self-harm and severity of self-harm was defined as hospitalized or not. Socioeconomic position was defined by parental education and household income. Cox proportional hazards regression were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Analyses showed an association between parental socioeconomic position and self-harm. Among adolescents with parents with primary and secondary education compared to tertiary parental education the HR were 1.10 (95% CI 0.97-1.24) and 1.16 (95% CI 1.08-1.25) respectively. Compared to the highest income category, adolescents from the lower income categories were 1.08 (95% CI 0.97-1.22) to 1.19 (95% CI 1.07-1.33) times more likely to self-harm. In gender-stratified analyses, an association was found only among girls. Further, restriction to severe cases eliminated the association. CONCLUSIONS: This study suggested that low parental socioeconomic position is associated with self-harm in adolescence, predominantly among girls. The desertion of an association among severe cases may be explained by differences in suicidal intent and underlying psychiatric diagnosis. Efforts to prevent self-harm should consider children with low parental socioeconomic position as a potential target group. PMID- 28878820 TI - Saccharomyces cerevisiae strain comparison in glucose-xylose fermentations on defined substrates and in high-gravity SSCF: convergence in strain performance despite differences in genetic and evolutionary engineering history. AB - BACKGROUND: The most advanced strains of xylose-fermenting Saccharomyces cerevisiae still utilize xylose far less efficiently than glucose, despite the extensive metabolic and evolutionary engineering applied in their development. Systematic comparison of strains across literature is difficult due to widely varying conditions used for determining key physiological parameters. Here, we evaluate an industrial and a laboratory S. cerevisiae strain, which has the assimilation of xylose via xylitol in common, but differ fundamentally in the history of their adaptive laboratory evolution development, and in the cofactor specificity of the xylose reductase (XR) and xylitol dehydrogenase (XDH). RESULTS: In xylose and mixed glucose-xylose shaken bottle fermentations, with and without addition of inhibitor-rich wheat straw hydrolyzate, the specific xylose uptake rate of KE6-12.A (0.27-1.08 g gCDW-1 h-1) was 1.1 to twofold higher than that of IBB10B05 (0.10-0.82 g gCDW-1 h-1). KE6-12.A further showed a 1.1 to ninefold higher glycerol yield (0.08-0.15 g g-1) than IBB10B05 (0.01-0.09 g g-1). However, the ethanol yield (0.30-0.40 g g-1), xylitol yield (0.08-0.26 g g-1), and maximum specific growth rate (0.04-0.27 h-1) were in close range for both strains. The robustness of flocculating variants of KE6-12.A (KE-Flow) and IBB10B05 (B-Flow) was analyzed in high-gravity simultaneous saccharification and co-fermentation. As in shaken bottles, KE-Flow showed faster xylose conversion and higher glycerol formation than B-Flow, but final ethanol titres (61 g L-1) and cell viability were again comparable for both strains. CONCLUSIONS: Individual specific traits, elicited by the engineering strategy, can affect global physiological parameters of S. cerevisiae in different and, sometimes, unpredictable ways. The industrial strain background and prolonged evolution history in KE6-12.A improved the specific xylose uptake rate more substantially than the superior XR, XDH, and xylulokinase activities were able to elicit in IBB10B05. Use of an engineered XR/XDH pathway in IBB10B05 resulted in a lower glycerol rather than a lower xylitol yield. However, the strain development programs were remarkably convergent in terms of the achieved overall strain performance. This highlights the importance of comparative strain evaluation to advance the engineering strategies for next-generation S. cerevisiae strain development. PMID- 28878819 TI - Construction of an easy-to-use CRISPR-Cas9 system by patching a newly designed EXIT circuit. AB - BACKGROUND: Plasmid-borne genetic editing tools, including the widely used CRISPR Cas9 system, have greatly facilitated bacterial programming to obtain novel functionalities. However, the lack of effective post-editing plasmid elimination methods impedes follow-up genetic manipulation or application. Conventional strategies including exposure to physical and chemical treatments, or exploiting temperature-sensitive replication origins have several drawbacks (e.g., they are limited for efficiency and are time-consuming). Therefore, the demand is apparent for easy and rapid elimination of the tool plasmids from their bacterial hosts after genetic manipulation. RESULTS: To bridge this gap, we designed a novel EXIT circuit with the homing endonuclease, which can be exploited for rapid and efficient elimination of various plasmids with diverse replication origins. As a proof of concept, we validated the EXIT circuit in Escherichia coli by harnessing homing endonuclease I-SceI and its cleavage site. When integrated into multiple plasmids with different origins, the EXIT circuit allowed them to be eliminated from the host cells, simultaneously. By combining the widely used plasmid-borne CRISPR-Cas9 system and the EXIT circuit, we constructed an easy-to-use CRISPR Cas9 system that eliminated the Cas9- and the single-guide RNA (sgRNA)-encoding plasmids in one-step. Within 3 days, we successfully constructed an atrazine degrading E. coli strain, thus further demonstrating the advantage of this new CRISPR-Cas9 system for bacterial genome editing. CONCLUSIONS: Our novel EXIT circuit, which exploits the homing endonuclease I-SceI, enables plasmid(s) with different replication origins to be eliminated from their host cells rapidly and efficiently. We also developed an easy-to-use CRISPR-Cas9 system with the EXIT circuit, and this new system can be widely applied to bacterial genome editing. PMID- 28878821 TI - High-throughput analysis of chemical components and theoretical ethanol yield of dedicated bioenergy sorghum using dual-optimized partial least squares calibration models. AB - BACKGROUND: Due to its chemical composition and abundance, lignocellulosic biomass is an attractive feedstock source for global bioenergy production. However, chemical composition variations interfere with the success of any single methodology for efficient bioenergy extraction from diverse lignocellulosic biomass sources. Although chemical component distributions could guide process design, they are difficult to obtain and vary widely among lignocellulosic biomass types. Therefore, expensive and laborious "one-size-fits-all" processes are still widely used. Here, a non-destructive and rapid analytical technology, near-infrared spectroscopy (NIRS) coupled with multivariate calibration, shows promise for addressing these challenges. Recent advances in molecular spectroscopy analysis have led to methodologies for dual-optimized NIRS using sample subset partitioning and variable selection, which could significantly enhance the robustness and accuracy of partial least squares (PLS) calibration models. Using this methodology, chemical components and theoretical ethanol yield (TEY) values were determined for 70 sweet and 77 biomass sorghum samples from six sweet and six biomass sorghum varieties grown in 2013 and 2014 at two study sites in northern China. RESULTS: Chemical components and TEY of the 147 bioenergy sorghum samples were initially analyzed and compared using wet chemistry methods. Based on linear discriminant analysis, a correct classification assignment rate (either sweet or biomass type) of 99.3% was obtained using 20 principal components. Next, detailed statistical analysis demonstrated that partial optimization using sample set partitioning based on joint X-Y distances (SPXY) for sample subset partitioning enhanced the robustness and accuracy of PLS calibration models. Finally, comparisons between five dual-optimized strategies indicated that competitive adaptive reweighted sampling coupled with the SPXY (CARS-SPXY) was the most efficient and effective method for improving predictive performance of PLS multivariate calibrations. CONCLUSIONS: As a dual-optimized methodology, sample subset partitioning combined with variable selection is an efficient and straightforward strategy to enhance the accuracy and robustness of NIRS models. This knowledge should facilitate generation of improved lignocellulosic biomass feedstocks for bioethanol production. Moreover, methods described here should have wider applicability for use with feedstocks incorporating multispecies biomass resource streams. PMID- 28878822 TI - Coexistence and competition of sulfate-reducing and methanogenic populations in an anaerobic hexadecane-degrading culture. AB - BACKGROUND: Over three-fifths of the world's known crude oil cannot be recovered using state-of-the-art techniques, but microbial conversion of petroleum hydrocarbons trapped in oil reservoirs to methane is one promising path to increase the recovery of fossil fuels. The process requires cooperation between syntrophic bacteria and methanogenic archaea, which can be affected by sulfate reducing prokaryotes (SRPs). However, the effects of sulfate on hydrocarbon degradation and methane production remain elusive, and the microbial communities involved are not well understood. RESULTS: In this study, a methanogenic hexadecane-degrading enrichment culture was treated with six different concentrations of sulfate ranging from 0.5 to 25 mM. Methane production and maximum specific methane production rate gradually decreased to 44 and 56% with sulfate concentrations up to 25 mM, respectively. There was a significant positive linear correlation between the sulfate reduction/methane production ratio and initial sulfate concentration, which remained constant during the methane production phase. The apparent methanogenesis fractionation factor (alphaapp) gradually increased during the methane production phase in each treatment, the alphaapp for the treatments with lower sulfate (0.5-4 mM) eventually plateaued at ~1.047, but that for the treatment with 10-25 mM sulfate only reached ~1.029. The relative abundance levels of Smithella and Methanoculleus increased almost in parallel with the increasing sulfate concentrations. Furthermore, the predominant sulfate reducer communities shifted from Desulfobacteraceae in the low-sulfate cultures to Desulfomonile in the high sulfate cultures. CONCLUSION: The distribution of hexadecane carbon between methane-producing and sulfate-reducing populations is dependent on the initial sulfate added, and not affected during the methane production period. There was a relative increase in hydrogenotrophic methanogenesis activity over time for all sulfate treatments, whereas the total activity was inhibited by sulfate addition. Both Smithella and Methanoculleus, the key alkane degraders and methane producers, can adapt to sulfate stress. Specifically, different SRP populations were stimulated at various sulfate concentrations. These results could help to evaluate interactions between sulfate-reducing and methanogenic populations during anaerobic hydrocarbon degradation in oil reservoirs. PMID- 28878824 TI - CMA analysis identifies homozygous deletion of MCPH1 in 2 brothers with primary Microcephaly-1. AB - BACKGROUND: Homozygous mutations and deletions of the microcephalin gene (MCPH1; OMIM *607117) have been identified as a cause of autosomal recessive primary microcephaly and intellectual disability (MIM #251200). Previous studies in families of Asian descent suggest that the severity of the phenotype may vary based on the extent of the genomic alteration. We report chromosome microarray (CMA) findings and the first described family study of a patient with primary microcephaly in a consanguineous Hispanic family. CASE PRESENTATION: The proband, a boy born at full-term to consanguineous parents from Mexico, presented at 35 months of age with microcephaly, abnormal brain MRI findings, underdeveloped right lung, almond-shaped eyes, epicanthal folds, bilateral esotropia, low hairline, large ears, smooth philtrum, thin upper lip, and developmental delay. MRI of the brain showed a small dermoid or lipoma (without mass effect) within the interpeduncular cistern and prominent arachnoid granulation. The underdeveloped right lung was managed with long-acting inhaled corticosteroids. Otherwise the proband did not have any other significant medical history. The proband had 2 older brothers, ages 14 and 16, from the same consanguineous parents. The 14-year-old brother had a phenotype similar to that of the proband, while both parents and the oldest brother did not have the same phenotypic findings as the proband. The SNP-based CMA analysis of the proband detected a homozygous 250-kb microdeletion at 8p23.2p23.1, extending from 6,061,169 to 6,310,738 bp [hg19]. This genomic alteration encompasses the first 8 exons of MCPH1. Follow-up studies detected the same homozygous deletion in the affected brother, segregating with microcephaly and intellectual disability. Regions of homozygosity (ROHs) were also observed in the affected brother. Since ROHs are associated with an increased risk for recessive disorders, presence of ROH may also contribute to the phenotype of the affected brothers. The parents were both hemizygous for the deletion. CONCLUSION: Here we report a homozygous deletion of multiple exons of the MCPH1 gene that was associated with primary microcephaly and intellectual disability in a Hispanic family. In the context of previous studies, our results support the idea that deletions involving multiple exons cause a more severe phenotype than point mutations. PMID- 28878823 TI - A de novo complex chromosome rearrangement associated with multisystematic abnormalities, a case report. AB - BACKGROUND: Complex chromosomal rearrangements (CCRs) are constitutional structural rearrangements that involve three or more chromosomes or that have more than two breakpoints. CASE PRESENTATION: Here, we describe a four-way CCR involving chromosomes 4, 5, 6 and 8. The patient had mild multisystematic abnormalities during his development, including defects in his eyes and teeth, exomphalos and asthenozoospermia. His wife had two spontaneous abortions during the first trimester. The translocations in 4q27, 5q22, 6q22.3, and 8p11.2 were diagnosed by conventional cytogenetic analysis and confirmed by fluorescence in situ hybridization(FISH). After analysis using a SNP array, we defined three microdeletions, including 0.89 Mb on chromosome 4, 5.39 Mb on chromosome 5 and 0.43 Mb on chromosome 8. His mother had a chimera karyotype of 47, XXX[5]/45, X[4]/46, XX[91]; the other chromosomes were normal. After one cycle of in vitro fertility (IVF) treatment followed by preimplantation genetic diagnosis (PGD), they obtained two embryos, but neither was balanced. CONCLUSIONS: The patient's phenotype resulted from the CCR and microdeletion of chromosomes 4, 5 and 8. The couple decided to use artificial insemination by donor (AID) technology. PMID- 28878825 TI - RNA-sequence data normalization through in silico prediction of reference genes: the bacterial response to DNA damage as case study. AB - BACKGROUND: Measuring how gene expression changes in the course of an experiment assesses how an organism responds on a molecular level. Sequencing of RNA molecules, and their subsequent quantification, aims to assess global gene expression changes on the RNA level (transcriptome). While advances in high throughput RNA-sequencing (RNA-seq) technologies allow for inexpensive data generation, accurate post-processing and normalization across samples is required to eliminate any systematic noise introduced by the biochemical and/or technical processes. Existing methods thus either normalize on selected known reference genes that are invariant in expression across the experiment, assume that the majority of genes are invariant, or that the effects of up- and down-regulated genes cancel each other out during the normalization. RESULTS: Here, we present a novel method, moose2 , which predicts invariant genes in silico through a dynamic programming (DP) scheme and applies a quadratic normalization based on this subset. The method allows for specifying a set of known or experimentally validated invariant genes, which guides the DP. We experimentally verified the predictions of this method in the bacterium Escherichia coli, and show how moose2 is able to (i) estimate the expression value distances between RNA-seq samples, (ii) reduce the variation of expression values across all samples, and (iii) to subsequently reveal new functional groups of genes during the late stages of DNA damage. We further applied the method to three eukaryotic data sets, on which its performance compares favourably to other methods. The software is implemented in C++ and is publicly available from http://grabherr.github.io/moose2/. CONCLUSIONS: The proposed RNA-seq normalization method, moose2 , is a valuable alternative to existing methods, with two major advantages: (i) in silico prediction of invariant genes provides a list of potential reference genes for downstream analyses, and (ii) non-linear artefacts in RNA-seq data are handled adequately to minimize variations between replicates. PMID- 28878826 TI - Analysis of factors influencing glucose tolerance in Japanese patients with non alcoholic fatty liver disease. AB - BACKGROUND: While the association of the prevalence of non-alcoholic fatty liver disease (NAFLD) with impaired glucose metabolism has been reported, the factors influencing glucose tolerance in NAFLD remain to be clarified. METHODS: Glucose tolerance of 131 Japanese patients diagnosed as NAFLD by histological findings of liver biopsy specimen was examined using 75 g-OGTT. According to Matteoni's classification, patients were divided to 4 groups [M1 ~ 4, M1, 2: non-alcoholic fatty liver (NAFL); and M3, 4: non-alcoholic steatohepatitis (NASH)]. Based on the OGTT data, insulinogenic index (IGI) and QUICKI were calculated as indices of insulin secretion and insulin sensitivity, respectively. Plasma glucose 120 min after glucose loading (G120) was used as the index for glucose intolerance. RESULTS: Stepwise multiple regression analysis using G120 as a dependent variable and loge-IGI, QUICKI, sex, BMI, age, NAFL/NASH as independent variables revealed that loge-IGI (beta = -0.595) and QUICKI (beta = -0.323) are significant factors predicting glucose intolerance (R2 = 0.403), indicating an important role of insulin secretion in glucose tolerance. These findings accord with glucose intolerance as high as 89.7% in patients with impaired insulin secretion defined by <=43.2 pmol/mmol (40 MUU/mg) IGI. Stepwise multiple regression analysis using QUICKI as a dependent variable and NAFL/NAFLD, sex, BMI, and age as independent variables revealed that BMI (beta = -0.469) and NAFL/NAFLD (beta = -0.204) are significant factors predicting insulin sensitivity (R2 = 0.248). CONCLUSION: Impairment of insulin secretion is the most important factor to predict glucose intolerance in NAFLD; severity of histological findings is associated with insulin sensitivity independent of adiposity in NAFLD. PMID- 28878827 TI - Association of the leptin-to-adiponectin ratio with metabolic syndrome in a sub Saharan African population. AB - BACKGROUND: Worldwide there is an increased prevalence of metabolic syndrome mainly due to life-style modifications, and Africans are not saved of this situation. Many markers have been studied to predict the risk of this syndrome but the most used are leptin and adiponectin. Data on these metabolic markers are scare in Africa and this study aimed to assess the association between the leptin to-adiponectin ratio (LAR) with metabolic syndrome in a Cameroonian population. METHODS: This was a cross-sectional study that included 476 adults among a general population of Cameroon. Data collected concerned the body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose, plasma lipids, adiponectin, leptin, insulin and homeostasis model for assessment of insulin resistance (HOMA-IR). To assess correlations we used Spearman's analyses and association of the studied variables with metabolic syndrome were done using binary logistic regression analysis. RESULTS: The leptin to adiponectin ratio was significantly and positively correlated with the body mass index (r = 0.669, p < 0.0001), waist circumference (r = 0.595, p < 0.0001), triglycerides (r = 0.190, p = 0.001), insulin levels (r = 0.333, p < 0.0001) and HOMA-IR (r = 0.306, p < 0.0001). Binary logistic regression analysis revealed that leptin, adiponectin and LAR were significantly associated with metabolic syndrome with respective unadjusted OR of 1.429, 0.468 and 1.502. After adjustment, for age and sex, the associations remained significative; LAR was also found to be significantly associated with metabolic syndrome (OR = 1.573, p value =0.000) as well as lower levels of adiponectin (OR = 0.359, p value =0.000) and higher levels of leptin (OR = 1.469, p value =0.001). CONCLUSION: This study revealed that LAR is significantly associated with metabolic syndrome in sub Saharan African population, independently to age and sex. PMID- 28878829 TI - The Antibodies: What a Universe! PMID- 28878828 TI - Elevated serum interleukin-6 is predictive of coronary artery disease in intermediate risk overweight patients referred for coronary angiography. AB - BACKGROUND: Interleukin-6 (IL-6) plays a central role in atherosclerosis and inflammation. It may improve risk prediction in patients at intermediate cardiovascular risk. OBJECTIVE: To analyze the impact of serum IL-6 in predicting early angiographic coronary artery disease in patients at intermediate cardiovascular risk with chest pain. METHODS: In a cross-sectional study, patients referred for coronary angiography due to suspected coronary artery disease (CAD) were included. Coronary artery disease was defined as the presence of at least 30% stenosis in one or more coronary artery. Severity of CAD was classified by the anatomic burden score. Performance of serum IL-6 assay was compared with ACC/AHA atherosclerotic cardiovascular disease (ASCVD) risk score and hs-CRP through receiver operating characteristic (ROC) curves. RESULTS: We have included 48 patients with a mean 10-year ASCVD risk of 10.0 +/- 6.8%. The prevalence of CAD was 72.9%. The presence of CAD was associated with higher mean levels of IL-6 (p = 0.025). Patients with CAD had significantly more overweight than subjects without CAD. In 27% of patients, IL-6 was >1.0 pg/mL and 100% of these patients had CAD, while only 64% in those with IL-6 <1.0 pg/mL, corresponding to a positive predictive value of 100% (p = 0.015). The area under the receiver operating characteristic (ROC) curve of IL-6, hs-CRP and ASCVD were respectively 0.72, 0.60 and 0.54. Intermediate risk patients with IL-6 >1.0 pg/mL were further reclassified into ASCVD high risk due to the presence of coronary lesions. CONCLUSION: In intermediate risk patients referred for coronary angiography, a serum IL-6 level above 1 pg/mL is predictive of significant CAD. IL-6 determination may be useful to reclassify ASCVD intermediate risk patients into higher risk categories. PMID- 28878830 TI - Caesarean Birth in Romania: Safe Motherhood Between Ethical, Medical and Statistical Arguments. AB - The number of caesarean sections increased significantly in Romania. In 2012, caesarean sections accounted for 41.2% of total births, according to a study of the Romanian National School for Public Health. This estimation is in agreement with the statistical data on caesarean sections recorded in one of the most important hospitals in Bucharest, Romania, Filantropia Hospital. Many factors have influenced the large number and sharply increasing trend of caesarean sections, from the historical ones, with roots in the communist regime, when abortions were outlawed, to current day doctors' medical practices and mothers' beliefs and fears related to the process of labor and the newborn's health. This paper aims to examine the pros and cons for caesarean birth. The analysis is presented from three perspectives: expressed by the doctor/medical caregiver, the patient/mother and some of the third parties indirectly involved in the medical decision: the foetus/newborn, the hospital/medical unit and the society as a whole, knowing that ethics is beyond the legal, economic or administrative frames. PMID- 28878831 TI - The Mirage of Long Term Vital Benefice - Risk for the Beginning of Life? AB - INTRODUCTION: Cord blood is the "life" of the fetus until birth. After delivery, the newborn is "single" and forced to adapt to live using the latest resources provided by the mother. Those who believe that a newborn is just a miniature independent adult are just trusting one of the illusions of secular medicine. Cord blood contains precious cells, stem, red and white blood cells. T cells as a part of white blood cells prevent infections and other illnesses. Cochrane Database 2013 published a study reporting the role of delayed umbilical cord clamping for the benefit of infants. Harvesting of stem cells increases early clamping. So, is prevention better than treatment, speaking about possible pathologies that can occur throughout life? MATERIAL AND METHODS: prospective study of newborns in "Alessandrescu-Rusescu" National Institute for Mother and Child Health, Bucharest, Romania, was monitored by their adaptation to extrauterine life, depending on time and technique of clamping. The impact of harvesting stem cells after birth was explored. RESULTS: Of all babies, 8.23% were premature. Maternal pathology (arterial hypertension, diabetes mellitus, infections, thrombophilia) was present in 31.76% of cases. Of the 85 newborns with harvested stem cells, 47% needed assistance in the neonatal intensive care unit (NICU). Birth asphyxia (SA.7) was present in 10.58% of cases. CONCLUSIONS: Two protocols with strong recommendations about umbilical cord clamping and harvesting stem cells, respectively, are necessary. PMID- 28878832 TI - Concomitant Lung and Liver Hydatid Cyst Managed as One-Stage Surgery. AB - OBJECTIVE: Over the world, hydatidosis is endemic in many countries. It is more prevalent in Turkey. We came across with concomitant hydatidosis of the lung and liver and reviewed the management. MATERIAL AND METHODS: This is a prospective study that was carried out in the Government Medical College and Hospital, sector 32, Chandigarh, India, between 2004 and 2010, in the Department of Surgery. A total of five patients diagnosed with concomitant liver and pulmonary hydatid disease underwent surgery. They were operated by thoracotomy and laparotomy in the same sitting. RESULTS: Hydatid cysts located in the lungs were managed by means of cystotomy and capitonnage. For liver cysts, cystotomy and inversion of the cavity with sutures was the surgical method of choice, and a drain was left in place. Excessive biliary drainage occurred in one patient who was managed successfully. CONCLUSIONS: We believe that simultaneous management of pulmonary and hepatic cysts through the thoracic route and by laparotomy is convenient and should be encouraged in patients because this approach decreased morbidity and mortality by deferring second operation. Needle aspiration can be applied only for liver cysts but it is absolutely contraindicated in lung hydatid cysts. PMID- 28878833 TI - Unusual Entities of Appendix Mimicking Appendicitis Clinically - Emphasis on Diagnosis and Treatment. AB - BACKGROUND: Abdomen is considered a magic box or a Pandora box where you will get different, unexpected pathologies along with rare entities. Appendicitis is the commonest emergency in surgery which presents challenges to surgeons because of a myriad list of differential diagnosis including both medical and gynaecological pathologies. Preoperative imaging plays an important role in diagnosis and management. AIMS AND OBJECTIVES: To study the rare atypical anatomical and surgical presentations of appendix in patients with clinical features of appendicitis. We focus on the clinical features and the role of investigations for the radiological part and management. MATERIAL AND METHODS: This study was done in M.M. Institute of Medical Sciences and Research, Mullana, Ambala, from November 2014 to July 2016. This was a retrospective study. We found 168 cases with the diagnosis of appendicitis, out of which 19 were with rare entities. RESULTS: Subjects of both genders were aged between 20 and 60 years. Out of 19, 15 were males and 4 females. Four patients were operated for inguinal hernia but incidentally we found appendix in the hernial sac termed as Amyand's hernia. Another patient presented with obstruction and appendix was forming a band diagnosed as torsion of appendix. Two most interesting cases were diagnosed as appendicular neuralgia and relieved by appendectomy. Out of 19 cases, 7 cases were operated for appendicitis diagnosed as appendicolith. In all the cases appendectomy was done without encountering any complications. Symptom free patients were operated for appendicular neuralgia. No malignancy was found in mucocele appendix at follow up. There were no complications by the 6-month follow up. CONCLUSION: As we came across with different entities of appendix presented with appendicitis, patients should be investigated before proceeding for surgery. In our study, there were incidental findings for which surgeons were not aware of the diagnosis and even for the patient. In inguinal hernia, ultrasonography was not done, diagnosis being made on clinical basis. Clinical and radiological investigations play an important part in early diagnosis and management. PMID- 28878834 TI - Combined Anatomic Anterior Cruciate Ligament and Anterolateral Ligament Reconstruction. AB - PURPOSE: The purpose of the current paper was to report the surgical technique of combined anatomic anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction as well as the short term clinical results after this surgical procedure. MATERIAL AND METHODS: The current prospective study included 32 patients (5 females and 27 males) with combined ACL and ALL reconstruction performed between December 2015 and July 2016. The patients were included in the study taking into consideration the following criteria: chronic ACL lesion, high grade rotational instability (pivot shift grade II and III) and participation in high grade pivoting sports. Patient evaluation followed an established clinical and imaging protocol both preoperatively and at 6 and 12 weeks postoperatively. This included clinical knee stability testing (Lachman test, Pivot shift test), Rolimeter differential laxity testing, subjective and objective IKDC scores and Lysholm score and Tegner score. RESULTS: Postoperative stability at 6 weeks and 12 weeks as tested with Lachman test (p=0.02 and 0.01, respectively), pivot shift test (p=0.03 and 0.01, respectively) and the Rolimeter arthrometer (p=0.008 and 0.006, respectively) showed a statistically significant difference as compared to preoperative values. Postoperative scores at 6 weeks and 12 weeks as measured using objective IKDC form (p=0.008 and 0.006, respectively), subjective IKDC form (p=0.04 and 0.03, respectively) and Lysholm form (p=0.02 and 0.01, respectively) were statistically significant improved as compared to preoperative values. All patients had a negative Lachman test at 6 and 12 weeks postoperatively. One patient had a positive grade I pivot shift test at 6 weeks postoperatively and two patients had a positive grade I pivot shift test at 12 weeks postoperatively. Differential anteroposterior laxity as measured with the Rolimeter arthrometer improved from 7.19+/-1.96 mm preoperatively to 0.28+/-0.45 mm and 0.13+/-0.34 mm, at 6 weeks and 12 weeks postoperatively, respectively. According to the objective IKDC form, 29 patients were normal or nearly normal (grade A and B) at 6 weeks postoperatively and 31 patients were normal or nearly normal at 12 weeks postoperatively. Subjective IKDC score improved from 47.72+/-17.18 preoperatively to 56.52+/-11.74 and 73.38+/-14.28 at 6 and 12 weeks postoperatively, respectively. Lysholm score improved from 63.44+/-23.01 preoperatively to 80.41+/ 11.94 and 90.47+/-8.22 at 6 and 12 weeks postoperatively, respectively. Improved Tegner activity scores were present at 12 weeks postoperatively as compared with 6 weeks postoperatively, but still lower as compared to pre-traumatic scores. No significant complications were present in the current study group. CONCLUSIONS: Combined ACL and ALL reconstruction is an effective surgical procedure, with improved postoperative clinical results and no significant short term complications. Longer follow-up is necessary in order to better evaluate the results of this procedure. PMID- 28878835 TI - Uterine Artery Doppler Flow Indices in Pregnant Women During the 11 Weeks + 0 Days and 13 Weeks + 6 Days Gestational Ages: a Study of 168 Patients. AB - OBJECTIVES: Uterine artery Doppler flow studies during the 11th and 14th week of pregnancy are important in the prediction of preeclampsia and intrauterine growth restriction in pregnant women as well as in the prevention thereof. METHODS: Our study on Doppler flow indices of the uterine arteries involved 168 patients examined in our clinic, with pregnancies ranging from 11 weeks + 0 days to 13 weeks + 6 days. RESULTS: There were 72 patients from 11 weeks + 0 days to 11 weeks + 6 days (42.86%), 43 from 12 weeks + 0 days to 12 weeks + 6 days (25.60%), and 53 from 13 weeks + 0 days to 13 weeks + 6 days (31.55%). The mean values of the Doppler indices were PI 1.75+/-0.79, 1.88+/- 0.81, 1.71+/-0.81, and 1.58+/ 0.72 and RI 0.72+/-0.14, 0.75+/-0.14, 0.71+/-0.14, and 0.70+/-0.14 for the entire group and for the three intervals, respectively. There were 71 (42.26%), 33 (19.64%, with 18 cases or 54.55% on the right side), and 64 (38.10%) patients with bilateral, unilateral and absent uterine artery notching, respectively. The mean Doppler indices for the three aforementioned groups were 2.18+/-0.79, 1.63+/ 0.72, and 1.33+/-0.57 for the PI, and 0.79+/-0.11, 0.71+/-0.14, and 0.66+/-0.14 for the RI, respectively. The indices for the 175 arteries with and 161 without notching, taken separately, in all patients, as well as for the uterine arteries with and without notching in patients with unilateral notching only were 2.16+/ 0.76, 1.30+/-0.54, 2.08+/-0.66, and 1.17+/-0.43 for the PI, and 0.79+/-0.11, 0.65+/-0.14, 0.79+/-0.11, and 0.63+/-0.12 for the RI, respectively. CONCLUSIONS: The mean uterine artery PI and RI decrease from 11 weeks + 0 days-11 weeks + 6 days to 13 weeks + 0 days-13 weeks + 6 days. They also decrease from patients with bilateral uterine artery notching to those without notching. The frequency of uterine artery notching decreases with increasing gestational age. Our results are similar to those in literature. PMID- 28878836 TI - Newborn Skin: Common Skin Problems. AB - The newborn skin can be separated from adult's skin in several ways. In dermatologic examination it can be easily observed that it is thinner, less hairy and has less sweat and sebaceous gland secretions. These differentiations present especially in preterm newborns. Their skin is exposed to mechanical trauma, bacteria and weather, heat alterations. At birth, newborn skin is protected by the coverage of vernix caseosa, which has lubricating and antibacterial features and its pH ranges from 6.7 to 7.4. Beneath the vernix caseosa the skin has a pH of 5.5-6.0. In newborn dermatologic examination it is very important to distinguish transient benign dermatoses and severe diseases, make early diagnosis and treat congenital skin disorders. Although the benign cases are common in this life period, clinical presentations can be much more exaggerated, dramatic and cause a great deal of anxiety to parents. Therefore, as a doctor, knowing the dermatological, pathological and non-pathological common skin rashes guides the family in the right direction, offers advice to reduce uncertainty and time for the treatment of severe conditions and builds a confidential doctor-patient relationship. In this review, our aim is to provide a general overview to common skin rashes in newborn period. PMID- 28878837 TI - Cutaneous Toxicities of Molecular Targeted Therapies. AB - Antineoplastic targeted therapies, such as EGFR inhibitors, tyrosine kinase inhibitors and BRAF inhibitors, frequently lead to systemic and cutaneous side effects, significantly affecting patient's quality of life. Patients with new targeted therapies have an increased risk of developing skin reactions. The new molecular target therapies developed in the last decades can induce severe skin reactions, which may require dose reduction or discontinuation of treatment and consequently, a decrease in patient's quality of life. The present paper describes toxic cutaneous reactions associated with the most frequently used molecular therapies (epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, BRAF-inhibitors), frequency of occurrence and methods of diagnosis and treatment, in order to offer a clinically efficient management for maintaining a good quality of life, with compliance to treatment and good therapeutic efficacy. Knowledge of cutaneous adverse reactions in new therapies is mandatory in order to have a proper management of oncologic patients. Recognizing target therapy toxicities by both oncologists and dermatologists, understanding therapeutic mechanisms and choosing optimum treatments for oncologic patients are critical. A correct evaluation of skin toxicity can allow for an adequate decision regarding treatment dose or discontinuation, impacting therapy response and patient survival. PMID- 28878838 TI - Correlation Between Idiopathic Nephrotic Syndrome and Atopy in Children - Short Review. AB - The idiopathic nephrotic syndrome is a common chronic kidney diseases in children defined by the association of massive proteinuria and hypoalbuminemia in a relapsing/remission course, with histological aspect of minimal changes (also called minimal change disease) in the majority of the cases, but its pathogenesis remains not very well known. Clinical and immunological studies have consistently shown a relationship between atopic diathesis, immunoglobulin E and cytokines involved in immunoglobulin E synthesis and idiopathic nephrotic syndrome. Additional research is necessary to clarify this relationship and to explore the contribution of allergic disease to the development of nephrotic syndrome and to identify potential new strategies of diagnosis and treatment. PMID- 28878839 TI - A Case Report of 9p Deletion Syndrome Associated with Partial Trisomy of 1q42. AB - We report a case of partial deletion of 9p with partial trisomy of 1q42 syndrome, which is a rare clinical and cytogenetic report. The dysmorphic features of the patient include microcephaly, plagiocephaly, trigonocephaly with metopic ridge, arched eyebrows, hypertelorism, down-slanting palpebral fissure, ptosis, blepharophimosis, unilateral left epicanthic fold, long eyelashes, low-set and posteriorly rotated ears, long philtrum, anteverted nares, retrognathia and unilateral undescended testis. Chromosomal analysis revealed partial monosomy of 9p24 associated with partial trisomy of 1q42q>ter. PMID- 28878840 TI - Chronic Venous Insufficiency: a Frequently Underdiagnosed and Undertreated Pathology. AB - The article describes the medical approach of a frequent pathology, chronic venous insufficiency. Chronic venous insufficiency requires early diagnosis as well as an evaluation of the associated risk factors; also, patients need to understand the disease and its treatment, and to become compliant with all their physician's recommendations. Importantly, the physician should correctly evaluate the disease and decide the best option for the patient. These days, it is crucial that the patient benefits from optimal treatment choice in order to prevent complications. CVI is a potentially severe pathology that has been underdiagnosed and undertreated for a long time and requires patience from the patient as well as care from the physician. PMID- 28878841 TI - Thyroid Association Ophthalmopathy in Hashimoto's Thyroiditis: a Case Report. AB - Thyroid associated ophthalmopathy is a constellation of symptoms caused by an autoimmune process involving the orbital tissue. It is common in hyperthyroid patients due to Graves' disease and also reported in euthyroid and hypothyroid Graves' patients with positive thyroid receptor antibodies. But in Hashimoto's thyroiditis, thyroid associated ophthalmopathy is a rarely reported and poorly understood entity. Here we report thyroid associated ophthalmopathy in a patient with hypothyroidism and negative thyroid receptor antibodies who showed heterogeneously hypoechoic thyroid gland on ultrasonography, diffuse lymphocytic infiltrate on fine needle aspiration citology and reduced 99m Tc radioisotope uptake, supporting the diagnosis of Hashimoto's thyroiditis. The patient was treated with levothyroxine and artificial tear drops. PMID- 28878844 TI - Message from the Editor-in-Chief. PMID- 28878842 TI - Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with rates of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) dramatically increasing. The overexpression of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for the trimethylation at lysine 27 of histone 3 (H3K27me3), is associated with a poor clinical prognosis and aggressive HPV-positive phenotypes. METHODS: We utilized three EZH2 pathway inhibitors, GSK-343, DZNeP, and EPZ-5687, and tested their efficacy in two HPV-positive and two HPV-negative OPSCC cell lines. RESULTS: Treatment with GSK-343 decreased H3K27me3 in all cell lines and treatment with DZNeP decreased H3K27me3 in only HPV-negative cell lines as determined by Western blot. Cells treated with EPZ-5687 displayed no appreciable change in H3K27me3. Epigenetic effect on gene expression was measured via ddPCR utilizing 11 target probes. Cells treated with DZNeP showed the most dramatic expressional changes, with decreased EGFR in HPV-positive cell lines and an overall increase in proliferation markers in HPV-negative cell lines. GSK-343-treated cells displayed moderate expressional changes, with CCND1 increased in HPV-positive cell lines and decreased TP53 in HPV-negative SCC-1. EPZ-5687-treated cell lines displayed few expressional changes overall. Only DZNeP-treated cells displayed anti proliferative characteristics shown in wound-healing assays. CONCLUSIONS: Our findings suggest that EZH2 inhibitors are a viable therapeutic option for the role of epigenetic effect, potentially sensitizing tumors to current chemotherapies or limiting cell differentiation. PMID- 28878843 TI - Prognostic relevance of an epigenetic biomarker panel in sentinel lymph nodes from colon cancer patients. AB - BACKGROUND: Patients with early colorectal cancer (stages I-II) generally have a good prognosis, but a subgroup of 15-20% experiences relapse and eventually die of disease. Occult metastases have been suggested as a marker for increased risk of recurrence in patients with node-negative disease. Using a previously identified, highly accurate epigenetic biomarker panel for early detection of colorectal tumors, we aimed at evaluating the prognostic value of occult metastases in sentinel lymph nodes of colon cancer patients. RESULTS: The biomarker panel was analyzed by quantitative methylation-specific PCR in primary tumors and 783 sentinel lymph nodes from 201 patients. The panel status in sentinel lymph nodes showed a strong association with lymph node stage (P = 8.2E 17). Compared with routine lymph node diagnostics, the biomarker panel had a sensitivity of 79% (31/39). Interestingly, among 162 patients with negative lymph nodes from routine diagnostics, 13 (8%) were positive for the biomarker panel. Colon cancer patients with high sentinel lymph node methylation had an inferior prognosis (5-year overall survival P = 3.0E-4; time to recurrence P = 3.1E-4), although not significant. The same trend was observed in multivariate analyses (P = 1.4E-1 and P = 6.7E-2, respectively). Occult sentinel lymph node metastases were not detected in early stage (I-II) colon cancer patients who experienced relapse. CONCLUSIONS: Colon cancer patients with high sentinel lymph node methylation of the analyzed epigenetic biomarker panel had an inferior prognosis, although not significant in multivariate analyses. Occult metastases in TNM stage II patients that experienced relapse were not detected. PMID- 28878845 TI - Influence of Androgen Deprivation Therapy on the Uptake of PSMA-Targeted Agents: Emerging Opportunities and Challenges. AB - Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgen-deprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA targeted methods for pre-targeting of prostate cancer. PMID- 28878846 TI - What Do We Measure in Oncology PET? AB - Positron emission tomography (PET) has come to the practice of oncology. It is known that 18F-fluorodeoxyglucose (FDG) PET is more sensitive for the assessment of treatment response than conventional imaging. In addition, PET has an advantage in the use of quantitative analysis of the study. Nowadays, various PET parameters are adopted in clinical settings. In addition, a wide range of factors has been known to be associated with FDG uptake. Therefore, there has been a need for standardization and harmonization of protocols and PET parameters. We will introduce PET parameters and discuss major issues in this review. PMID- 28878847 TI - Potential Clinical Applications of 18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Mammography in Breast Cancer. AB - The whole-body positron emission tomography (PET)/magnetic resonance (MR) scan is a cutting edge technology providing comprehensive structural information from MR imaging and functional features from PET in a single session. Recent research findings and clinical experience have shown that 18F-fluorodeoxyglucose (FDG) whole-body PET/MR imaging has a diagnostic performance comparable with or superior to that of PET/CT in the field of oncology, including for breast cancer. In particular, FDG PET/MR mammography in the prone position with the breast hanging in a pendant manner can provide more comprehensive information about the metabolism, anatomy, and functional features of a breast lesion than a whole-body PET/MR scan. This article reports on current state-of-the-art PET/MR mammography in patients with breast cancer and the prospects for potential application in the future. PMID- 28878848 TI - Quantification of Contraction Synchronicity and Contraction Work in Coronary Artery Disease. AB - PURPOSE: This study quantified the contraction synchronicity (CS; with 100% representing full synchrony and -100% dyssynchrony) and contraction work (CW, millijoules per centimeter squared; representing myocardial area) in patients with reduced left ventricular ejection fraction (LVEF) associated with coronary artery disease (CAD). METHODS: CS, CW and LVEF in 104 subjects (54 CAD patients and 50 control subjects without CAD) were measured using rest electrocardiography gated single-photon emission computed tomography (ECG SPECT). Contraction amplitude (CA), synchronous contraction index (SCI), and CW were evaluated using the program Quantification of Segmental Function by Solving the Poisson Equation (QSFP) developed in-house. RESULTS: The mean CA, SCI and CW of 17 segments in the control subjects were 33.8 +/- 4.1% (+/-SD), 96.6 +/- 1.4%, and 6.9 +/- 1.0 mJ/cm2, respectively. In the patients with CAD, the respective values were 26.1 +/- 7.3%, 82.1 +/- 16.8%, and 5.4 +/- 1.6 mJ/cm2. In the CAD patients with LVEF <40% (n = 14), the mean CA, SCI,and CW were 17.9 +/- 4.0%, 63.0 +/- 18.4%, and 3.5 +/- 1.1 mJ/cm2, respectively. These values were significantly lower than in the control subjects (p < 0.005). Using receiver operating characteristic analysis, values for the area under the curve showing the performance of CA, CS, CW and LVEF in the diagnosis of CAD were 0.81, 0.86, 0.78, and 0.84, respectively. CONCLUSION: Asynchrony shown using the QSFP is useful for CAD detection. PMID- 28878850 TI - Difference in F-18 FDG Uptake After Esophagogastroduodenoscopy and Colonoscopy in Healthy Sedated Subjects. AB - PURPOSE: We aimed to evaluate the difference in fluorodeoxyglucose (FDG) uptake in sedated healthy subjects after they underwent esophagogastroduodenoscopy (EGD) and colonoscopy procedures. METHODS: The endoscopy group (n = 29) included healthy subjects who underwent screening via F-18 FDG positron emission tomography/computed tomography (PET/CT) after an EGD and/or colonoscopy under sedation on the same day. The control group (n = 35) included healthy subjects who underwent screening via PET/CT only. FDG uptake in the tongue, uvula, epiglottis, vocal cords, esophagus, stomach, duodenum, liver, cecum, colon, anus, and muscle were compared between the two groups. RESULTS: Maximum standardized uptake value (SUVmax) in the tongue, pharynx, larynx, and esophagus did not significantly differ between the endoscopy and control groups. In contrast, mean SUVmax in the whole stomach was 18 % higher in the endoscopy group than in the control group (SUVmax: 2.96 vs. 2.51, P = 0.010). In the lower gastrointestinal track, SUVmax from the cecum to the rectum was not significantly different between the two groups, whereas SUVmax in the anus was 20 % higher in the endoscopy group than in the control group (SUVmax: 4.21 vs. 3.50, P = 0.002). SUVmax in the liver and muscle was not significantly different between the two groups. Mean volume of the stomach and mean cross section of the colon was significantly higher in the endoscopy group than in the control group (stomach: 313.28 cm3 vs. 209.93 cm3, P < 0.001, colon: 8.82 cm2 vs. 5.98 cm2, P = 0.001). CONCLUSIONS: EGD and colonoscopy under sedation does not lead to significant differences in SUVmax in most parts of the body. Only gastric FDG uptake in the EGD subjects and anal FDG uptake in the colonoscopy subjects was higher than uptake in those regions in the control subjects. PMID- 28878849 TI - Prognostic Value of Tumor-to-Blood Standardized Uptake Ratio in Patients with Resectable Non-Small-Cell Lung Cancer. AB - OBJECTIVES: Previously published studies showed that the standard tumor-to-blood standardized uptake value (SUV) ratio (SUR) was a more accurate prognostic method than tumor maximum standardized uptake value (SUVmax). This study evaluated and compared prognostic value of positron emission tomography (PET) parameters and normalized value of PET parameters by blood pool SUV in non-small-cell lung cancer (NSCLC) patients who received curative surgery. METHODS: Seventy-seven patients who underwent curative resection for NSCLC between January 2010 to December 2013 were enrolled in this study. 18Fluorine-fluorodeoxyglucose (18F FDG) positron emission tomography/computed tomography (PET/CT) was performed before surgery. The mean standardized uptake value (SUVmean), SUVmax, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of each lesion was measured, on the workstation. SURmean, SURmax, and TLGSUR were calculated by dividing each of them by descending aorta SUVmean. Cox proportional hazards regression was used to analyze the effect of age, sex, pathological parameters, and PET parameters on recurrence and death. RESULTS: In Cox regression analysis, N stage predicted for both recurrence (p < 0.0001) and death (p < 0.0001). SURmax predicted recurrence (p = 0.0014), not death. Area under the receiver operating characteristic curve of SURmax was 0.759 with cutoff value 4.004. However, SUVmax, SUVmean, MTV, TLG, SURmean, and TLGSUR predicted neither recurrence nor death. CONCLUSIONS: Among PET parameters, SURmax was the independent predictor of recurrence in NSCLC patients who received curative surgery. N stage was the independent prognostic factor for both recurrence and death. Both parameters could be used to stratify the risk of NSCLC patients. PMID- 28878851 TI - Clinical Significance of Incidental Focal 18F-FDG Uptake in the Spinal Cord of Patients with Cancer. AB - PURPOSE: We investigated the incidence, location, and clinical significance of focal 18F-FDG uptake of the spinal cord in patients with cancer. METHODS: We reviewed the medical records of 22,937 consecutive adult patients with known or suspicious malignancy who underwent 18F-FDG PET/CT. PET/CT scans with incidental focal spinal cord uptake were selected and retrospectively reviewed to determine the presence, location, number, and maximum standardized uptake value (SUVmax) of any focal hypermetabolic lesions of the spinal cord. In subjects with focal spinal uptake, clinical characteristics and clinical follow-up results, including follow-up PET/CT, were reviewed. RESULTS: Incidental focal spinal cord uptake was observed in 69 of 22,937 adult patients (incidence = 0.3%; M:F = 31:38; age, 55.8 +/- 14.7 years). Seventy-eight focal hypermetabolic lesions on spinal cord in the PET/CT scans of the 69 study subjects were analyzed. The most common sites of focal spinal cord uptake were the T12 vertebra (47/78; 60.3%) and L1 vertebra (20/78; 25.6%). Multifocal cord uptake was found in 8 of 69 patients (11.6%). The average SUVmax for cord uptake was 2.5 +/- 0.5 (range, 1.4~3.9). There was no clinical or imaging evidence of abnormalities in the spinal cord, both at the time of PET/CT and during clinical follow-up. CONCLUSIONS: Although incidental focal 18F-FDG uptake of the spinal cord is rare in patients with cancer, it may be physiological or benign, but it should not be considered as malignant involvement. Common sites for the uptake were in the T12 and L1 spine levels. PMID- 28878852 TI - Potential Adjunctive Role of Radiosynovectomy in Primary Synovial Osteochondromatosis of the Knee: A Case Report. AB - Primary synovial osteochondromatosis (PSOC) is a rare but clinically significant cause of morbidity especially in the male population. Surgery is the primary treatment of choice, but the recurrence rate is reported to be high. Moreover, the presence of widespread loose bodies makes it a cumbersome procedure. The complete removal of the disease is tough at times and results in early recurrence. Radiosynovectomy is an established technique for treating various joint arthropathies. The role of radiosynovectomy in case of PSOC has not yet been explored. This case report described the case of a young male with PSOC of the knee joint who was treated with radiosynovectomy for pain relief. The patient reported complete relief from the pain along with significant improvement in joint mobility. The post-therapy three-phase bone scan also validated the reduction in joint inflammation. The patient was taken for surgical removal of the redundant loose bodies after a significant improvement in the pain and reduction in inflammation. Post-therapy radiation fibrosis of the synovium also helped in the en bloc removal of the disease. The role of radiosynovectomy in PSOC needs to be further explored concerning its potential role as an adjuvant to surgical procedures. PMID- 28878853 TI - Bilateral Renal Metastasis of Hurthle Cell Thyroid Cancer with Discordant Uptake Between I-131 Sodium Iodide and F-18 FDG. AB - Renal metastasis of thyroid cancer is extremely rare. We report the case of a 62 year-old woman with Hurthle cell thyroid cancer (HCTC) with lungs, bones, and bilateral kidneys metastases. The renal metastatic lesions were clearly demonstrated by 131I whole body scan (WBS) with SPECT/CT. However, they exhibited false-negative results in 18F-FDG PET/CT, kidney ultrasonography, and contrast enhanced CT scan. The findings imply that tumors have low glucose metabolism and are able to accumulate radioiodine, which is not commonly found in the relatively aggressive nature of HCTC. The patient received two sessions of 200 mCi 131I therapy within 6 months duration. There was complete treatment response as evaluated by the second post-therapeutic 131I SPECT/CT and serum thyroglobulin. To our knowledge, renal metastasis from HCTC with positive 131I but negative 18F FDG uptake has not been reported in the literature. This case suggests that 131I SPECT/CT is useful for lesion localization and prediction of 131I therapy response. PMID- 28878854 TI - Composite Cutaneous Lymphoma (Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder) in a Patient with Rheumatoid Arthritis Treated with Methotrexate: Staging and Evaluation of Response to Therapy with 18F-FDG PET/CT. AB - A 67 year old woman with a 10 year history of rheumatoid arthritis (RA) treated with methotrexate and prednisone, presented with a 2 year history of worsening multiple cutaneous plaques of variable appearance. Two distinct skin lesions were biopsied to reveal a composite cutaneous lymphoma, possibly caused by long term methotrexate therapy. An [18F] fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed to stage the malignancy, and was later repeated to evaluate response to chemotherapy, which guided subsequent management. We present the PET/CT imaging findings of this very rare iatrogenic (methotrexate induced) immunodeficiency-associated lymphoproliferative disorder. PMID- 28878855 TI - Incidentally Detected Small Intestine Intussusception Caused by Primary Small Intestine Carcinoma on 18F-FDG PET/CT. AB - Small intestine intussusception in adults is a rare condition mainly caused by primary or metastatic small intestine malignancy. Here, we present a 72-year-old male patient who was diagnosed with small intestine cancer that was presented as small intestine intussusception on hybrid 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). The patient was initially referred for an abnormality on a chest radiography and severe anemia. FDG PET/CT showed the lung lesion in the right upper lobe of lung as a high FDG uptake mass. Accidentally, FDG PET demonstrated another intense hypermetabolic intraluminal lesion in the small intestine accompanied with intussusception shown as a circumferential hypermetabolic wall. By pathologic examination, the patient was diagnosed as primary small intestine cancer with lung metastasis. This case highlights usefulness of hybrid FDG PET/CT to identify unexpected malignancy. PMID- 28878856 TI - 68Gallium-Arginine-Glycine-Aspartic Acid and 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Chondroblastic Osteosarcoma of the Skull. AB - We report the case of a 32 year-old male with Chondroblastic Osteosarcoma of the skull, which was imaged with both 18[F]fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and 68Gallium-arginine-glycine aspartic acid (68Ga-RGD) PET/CT. The 18F-FDG PET/CT did not demonstrate the tumour, whereas the 68Ga-RGD PET/CT clearly depicted a left-sided frontal tumour. 68Ga-RGD PET/CT may be a clinically useful imaging modality for early detection of recurrent osteosarcoma, considering the limitations of 18F-FDG PET in a setting of low glycolytic activity. PMID- 28878857 TI - Unusual Soft Tissue Uptake of F-18 Sodium Fluoride in Three Patients Undergoing F 18 NaF PET/CT Bone Scans for Prostate Cancer. AB - Three males aged 71 to 80 years with known stage IV metastatic prostate cancer underwent F-18 sodium fluoride (NaF) PET/CT to assess osseous metastatic disease burden and stability. In addition to F-18 NaF avid known osseous metastases, each patient also exhibited increased F-18 NaF activity in soft tissues. The first patient exhibited multiple F-18 NaF avid enlarged retroperitoneal and pelvic lymph nodes on consecutive PET/CT scans. The second patient demonstrated an F-18 NaF avid thyroid nodule on consecutive PET/CT scans. The third patient exhibited increased F-18 NaF activity in a hepatic metastasis. PMID- 28878858 TI - 18F-FDG PET/CT Imaging of Pulmonary Mucinous Cystadenocarcinoma with Signet Ring Cells. AB - A 63-year-old male with a recently diagnosed right lung lesion was referred for staging. F-FDG PET/CT scan revealed a hypodense, cystic-like mass in the right upper lung lobe, which demonstrated low, diffuse 18F-FDG uptake, likely due to the presence of mucus, as well as intensely hypermetabolic right hilar and right paratracheal lymph nodes. Transbronchial biopsy revealed a primary pulmonary mucinous cystadenocarcinoma with the presence of signet ring cell carcinoma, a co existence of two rare variants of lung adenocarcinoma. This case report demonstrates the metabolic phenotype along with the radiographic characteristics of this rare tumor and its metastases. PMID- 28878859 TI - Radioprotective activity of blackcurrant extract evaluated by in vitro micronucleus and gene mutation assays in TK6 human lymphoblastoid cells. AB - INTRODUCTION: Blackcurrant (Ribs nigrum L.) is a classical fruit that has long been used to prepare juice, jam, liqueur, and sometimes medicines in Europe. Previously, we reported a genome defense effect by the antioxidative activity of several types of blackcurrant extracts (BCEs) in yeast and human cell gene mutation assays. In this study, we determined if BCE exerted radioprotective activity against DNA damage, chromosomal aberration, and gene mutations in the TK6 human lymphoblastoid cell line. We prepared aqueous BCE extracted from mature fruits cultivated in the Aomori Prefecture, Japan. FINDINGS: In the micronucleus test and TK gene mutation assay, TK6 cells were irradiated with 0, 0.125, 0.250, 0.500, and 1.000 Gy with or without 1.0 mg/mL BCE. Intracellular hydrogen peroxide (H2O2) was measured using the fluorescent probe BES-H2O2-Ac. Induction of micronuclei and gene mutations by gamma-irradiation exposure was suppressed in combination with BCE. In addition, BCE reduced intracellular H2O2 levels caused by gamma-irradiation. CONCLUSIONS: Our findings clearly support the genome defense potential of blackcurrant against gamma-induced DNA damage. We postulate that these genome defense activities are related to the antioxidant compounds in blackcurrant. PMID- 28878860 TI - Draft genome sequences of two opportunistic pathogenic strains of Staphylococcus cohnii isolated from human patients. AB - Herein, we report the draft-genome sequences and annotation of two opportunistic pathogenic strains of Staphylococcus cohnii isolated from humans. One strain (SC 57) was isolated from blood from a male patient in May 2006 and the other (SC 532) from a catheter from a male patient in June 2006. Similar to other genomes of Staphylococcus species, most genes (42%) of both strains are involved in metabolism of amino acids and derivatives, carbohydrates and proteins. Eighty (4%) genes are involved in virulence, disease, and defense and both species show phenotypic low biofilm production and evidence of increased antibiotic resistance associated to biofilm production. From both isolates, a new Staphylococcal Cassette Chromosome mec was detected: mec class A, ccr type 1. This is the first report of whole genome sequences of opportunistic S. cohnii isolated from human patients. PMID- 28878861 TI - Genome sequence of the sulfur-oxidizing Bathymodiolus thermophilus gill endosymbiont. AB - Bathymodiolus thermophilus, a mytilid mussel inhabiting the deep-sea hydrothermal vents of the East Pacific Rise, lives in symbiosis with chemosynthetic Gammaproteobacteria within its gills. The intracellular symbiont population synthesizes nutrients for the bivalve host using the reduced sulfur compounds emanating from the vents as energy source. As the symbiont is uncultured, comprehensive and detailed insights into its metabolism and its interactions with the host can only be obtained from culture-independent approaches such as genomics and proteomics. In this study, we report the first draft genome sequence of the sulfur-oxidizing symbiont of B. thermophilus, here tentatively named Candidatus Thioglobus thermophilus. The draft genome (3.1 Mb) harbors 3045 protein-coding genes. It revealed pathways for the use of sulfide and thiosulfate as energy sources and encodes the Calvin-Benson-Bassham cycle for CO2 fixation. Enzymes required for the synthesis of the tricarboxylic acid cycle intermediates oxaloacetate and succinate were absent, suggesting that these intermediates may be substituted by metabolites from external sources. We also detected a repertoire of genes associated with cell surface adhesion, bacteriotoxicity and phage immunity, which may perform symbiosis-specific roles in the B. thermophilus symbiosis. PMID- 28878862 TI - Permanent draft genome sequence of Frankia sp. NRRL B-16219 reveals the presence of canonical nod genes, which are highly homologous to those detected in Candidatus Frankia Dg1 genome. AB - Frankia sp. NRRL B-16219 was directly isolated from a soil sample obtained from the rhizosphere of Ceanothus jepsonii growing in the USA. Its host plant range includes members of Elaeagnaceae species. Phylogenetically, strain NRRL B-16219 is closely related to "Frankia discariae" with a 16S rRNA gene similarity of 99.78%. Because of the lack of genetic tools for Frankia, our understanding of the bacterial signals involved during the plant infection process and the development of actinorhizal root nodules is very limited. Since the first three Frankia genomes were sequenced, additional genome sequences covering more diverse strains have helped provide insight into the depth of the pangenome and attempts to identify bacterial signaling molecules like the rhizobial canonical nod genes. The genome sequence of Frankia sp. strain NRRL B-16219 was generated and assembled into 289 contigs containing 8,032,739 bp with 71.7% GC content. Annotation of the genome identified 6211 protein-coding genes, 561 pseudogenes, 1758 hypothetical proteins and 53 RNA genes including 4 rRNA genes. The NRRL B 16219 draft genome contained genes homologous to the rhizobial common nodulation genes clustered in two areas. The first cluster contains nodACIJH genes whereas the second has nodAB and nodH genes in the upstream region. Phylogenetic analysis shows that Frankia nod genes are more deeply rooted than their sister groups from rhizobia. PCR-sequencing suggested the widespread occurrence of highly homologous nodA and nodB genes in microsymbionts of field collected Ceanothus americanus. PMID- 28878863 TI - Innate lymphoid cells in tissue homeostasis and diseases. AB - Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells. They are a part of the innate immune system, but develop from the lymphoid lineage. They lack pattern-recognition receptors and rearranged receptors, and therefore cannot directly mediate antigen specific responses. The progenitors specifically associated with the ILCs lineage have been uncovered, enabling the distinction between ILCs and natural killer cells. Based on the requirement of specific transcription factors and their patterns of cytokine production, ILCs are categorized into three subsets (ILC1, ILC2 and ILC3). First observed in mucosal surfaces, these cell populations interact with hematopoietic and non-hematopoietic cells throughout the body during homeostasis and diseases, promoting immunity, commensal microbiota tolerance, tissue repair and inflammation. Over the last 8 years, ILCs came into the spotlight as an essential cell type able to integrate diverse host immune responses. Recently, it became known that ILC subsets play a key role in immune responses at barrier surfaces, interacting with the microbiota, nutrients and metabolites. Since the liver receives the venous blood directly from the intestinal vein, the intestine and liver are essential to maintain tolerance and can rapidly respond to infections or tissue damage. Therefore, in this review, we discuss recent findings regarding ILC functions in homeostasis and disease, with a focus on the intestine and liver. PMID- 28878865 TI - MicroRNAs and clinical implications in hepatocellular carcinoma. AB - AIM: To assess the role of some circulating miRNAs (miR-23a, miR-203, miR338, miR 34, and miR-16) as tumor markers for diagnosis of hepatocellular carcinoma (HCC). METHODS: One hundred and seventy-one subjects were enrolled, 57 patients with HCC, 57 patients with liver cirrhosis (LC) and 57 healthy subjects as control group. Severity of liver disease was assessed by Child Pugh score. Tumor staging was done using Okuda staging system. Quantification of Micro RNA (miR-23a, miR 203, miR338, miR-34, and miR-16) was performed. RESULTS: All studied miRNA showed significant difference between HCC and cirrhotic patients in comparison to healthy control. miR-23a showed statistically significant difference between HCC and cirrhotic patients being higher in HCC group than cirrhotic. miR-23a is significantly higher in HCC patients with focal lesion size equal or more than 5 cm, patients with multiple focal lesions and Okuda stage III. At cutoff value >= 210, miR-23a showed accuracy 79.3% to diagnose HCC patients with sensitivity 89.47% and specificity about 64.91%. At cut off level >= 200 ng/mL, serum alpha fetoprotein had 73.68% sensitivity, 52.63% specificity, 43.75% PPV, 80% NPV for diagnosis of HCC. CONCLUSION: MicroRNA 23a can be used as a screening test for early detection of HCC. Also, it is related to larger size of tumour, late Okuda staging and multiple hepatic focal lesions, so it might be a prognostic biomarker. PMID- 28878866 TI - Association of autoimmune hepatitis type 1 in a child with Evans syndrome. AB - Autoimmune hepatitis (AIH) is a progressive liver disease that is often associated with extrahepatic autoimmune disorders. Evans syndrome (ES) is a rare autoimmune disorder, which is characterized by immune thrombocytopenia and autoimmune hemolytic anemia. Association of AIH with ES is rare, especially in children. We report a 3-year-old female with a past medical history of ES who presented with jaundice and significant transaminitis due to AIH type 1. She required multiple treatments with steroids as well as azathioprine, intravenous immunoglobulin and a course of rituximab. PMID- 28878864 TI - Use of everolimus in liver transplantation. AB - In recent years, the use of mammalian target of rapamycin inhibitors has gained traction in their use as alternative or adjunct immunosuppressants in the post liver transplantation (LT) setting. The efficacy of everolimus (EVR) in de novo LT is established and a reasonable time to initiate EVR is 30 d from LT surgery. Initiating EVR early post-LT allows for calcineurin inhibitor (CNI) reduction, thus reducing nephrotoxicity in LT recipients. However, data is inadequate on the appropriate timing for conversion from CNI to EVR maintenance in order to achieve optimal renoprotective effect without compromising drug efficacy. Adverse effects of proteinuria, hypercholesterolemia and hyperlipidemia are significantly higher as compared to standard CNI and long-term implications on graft and patient survival in LT is still unclear. Future research to explore strategies to minimise EVR adverse effects will be crucial for the success of EVR as an important alternative or adjunct immunosuppressive therapy in LT. PMID- 28878867 TI - Prevalence of Squamous Cell Carcinoma of the Esophagus in a Single Tertiary Center of South Africa: A Cross Sectional Analytic Study. AB - The incidence of esophageal cancer varies widely in the world. In the Middle East, Africa, and Asia and parts of Europe, squamous cell carcinoma of the esophagus dominates the esophageal cancer landscape. Worldwide the rates are highest in Northern China, South Africa, Turkey and Iran. In the United States, the black population has a five-fold higher incidence of esophageal squamous cell carcinoma than the white population. To determine the prevalence of squamous cell carcinoma of the esophagus in a single tertiary center in South Africa. Patients referred to Gastroenterology Division of Steve Biko Academic Hospital for upper gastrointestinal endoscopy were recruited. Those with a known diagnoses of squamous cell carcinoma of the esophagus were recorded and those with suspicious lesions had biopsies done. These were then evaluated by an experienced histopathologist. 6118 patients were recruited. Squamous cell carcinoma was found in 59 patients giving us a prevalence of 0.96% 95%CI. The cancer was found mainly in back elderly males. The prevalence of squamous cell carcinoma of the esophagus in this single center study is 0.96%, 95% confidence interval and is a disease of black elderly males as seen elsewhere. Bigger multicenter studies are needed to further clarify this findings. PMID- 28878868 TI - HIV Testing and Risk Perceptions: A Qualitative Analysis of Secondary School Students in Kampala, Uganda. AB - The purpose of this paper is to explore the perceptions of self-reported HIV testing and risk behavior among sexually active adolescents and youth in secondary schools in Kampala Uganda. This was a cross-sectional survey conducted between June and October 2010 among secondary school students in Kampala, Uganda. Forty eight (48) students across the 54 schools were purposively selected for the qualitative sub-study based on their responses to particular questions. We thematically analyzed 28 interviews for our qualitative study using Nvivo software. Drug and alcohol use coupled with peers pressure impaired students' perceptions towards HIV risk and therefore increased their susceptibility to HIV risk behaviors. Of the 28 scripts analyzed, 82% (23/28) had ever had sexual partners, 79% (22/28) were currently sexually active, and 57% (16/28) had ever been tested for HIV. In conclusion, most adolescents interviewed did not perceive HIV testing to be important to HIV prevention and reported low perception of susceptibility to HIV infection. Development of an adolescent HIV prevention model is important in improving uptake of HIV services. PMID- 28878869 TI - The Mortality of Ill Infants with False Tooth Extraction in a Rural Ugandan Emergency Department. AB - False tooth extraction (FTE), a cultural practice in East Africa used to treat fever and diarrhea in infants, has been thought to increase infant mortality. The mortality of clinically similar infants with and without false tooth extraction has not previously been examined. The objective of our retrospective cohort study was to examine the mortality, clinical presentation, and treatment of infants with and without false tooth extraction. We conducted a retrospective chart review of records of infants with diarrhea, sepsis, dehydration, and fever in a rural Ugandan emergency department. Univariate analysis was used to test statistical significance. We found the mortality of infants with false tooth extraction (FTE+) was 18% and without false tooth extraction (FTE-) was 14% (P=0.22). The FTE+ study group, and FTE- comparison group, had similar proportions of infants with abnormal heart rate and with hypoxia. There was a significant difference in the portion of infants that received antibiotics (P=0.001), and fluid bolus (P=0.002). Although FTE+ infants had clinically similar ED presentations to FTE- infants, the FTE+ infants were significantly more likely to receive emergency department interventions, and had a higher mortality than FTE- infants. PMID- 28878870 TI - Determinants of Knowledge and Safety Practices of Occupational Hazards of Textile Dye Workers in Sokoto, Nigeria: A Descriptive Analytic Study. AB - Textile dye workers are subject to occupational hazards on a daily basis due to exposure to precarious conditions in the workplace. This study aimed to assess the knowledge, attitude and safety practices and its determinants among textile dye workers in Sokoto metropolis, Nigeria. This is a descriptive cross-sectional study conducted among 200 textile dye workers and the respondents were selected by multi stage sampling technique. Data was collected using an interviewer administered questionnaire. Data was processed using SPSS IBM version 20 and analyzed using descriptive and inferential statistics. Majority of the respondents (74.0%) had good knowledge of workplace hazards; (81.0%) had positive attitude and only 20% observed all the safety practices. Formal education (P=0.047); working less than 5 days a week (P=0.001) and permanent employment (P=0.013) were found to be determinants of respondents' knowledge and attitude towards workplace hazards. Although the respondents had good knowledge and positive attitude, their lack of observance of safety practices brings to fore the need for direct safety instruction and training and retraining of textile dye workers on workplace hazards and safety practices. PMID- 28878871 TI - A Behavioral and Serological Survey on HIV Prevalence Among Prisoners in Benin. AB - Cases of HIV are common in Benin, with infection rates varying according to socioeconomic and cultural factors, and by region. Certain segments of the population, such as prison inmates, sex worker clients and truck drivers are at high risk for HIV/AIDS. The aim of this study is to identify which behavioral and serological indicators contribute to the spread of HIV among prisoners. A total of 496 inmates from prisons located in all major cities in Benin were surveyed. Data was collected through interview sessions carried out using a questionnaire and through blood samples. The results show that most inmates are Beninese (83.5%), and the average age is 33 years (range: 14-80 years). No prisoner reported using a condom the last time they engaged in sexual intercourse. Blood exposure was found in 14.6% of inmates and HIV was detected in 1.4% of cases. Our analysis indicates that the length of detention and gender are factors that influence HIV status. However, age, education, nationality and HIV awareness had no significant effect on HIV prevalence among inmates. The results highlight the need to raise awareness in prisons about HIV. This can be achieved by strengthening communication strategies and by organizing HIV and sexually transmitted diseases information sessions for both prison officers and inmates. PMID- 28878872 TI - Quantum crystallography. AB - Approximate wavefunctions can be improved by constraining them to reproduce observations derived from diffraction and scattering experiments. Conversely, charge density models, incorporating electron-density distributions, atomic positions and atomic motion, can be improved by supplementing diffraction experiments with quantum chemically calculated, tailor-made electron densities (form factors). In both cases quantum chemistry and diffraction/scattering experiments are combined into a single, integrated tool. The development of quantum crystallographic research is reviewed. Some results obtained by quantum crystallography illustrate the potential and limitations of this field. PMID- 28878876 TI - An unusual case of disappearing bone disease in the mandible and literature review. AB - Disappearing bone disease is a rare disorder that causes spontaneous and progressive osteolysis and proliferation of lymphatic tissue and blood vessels. It is debilitating and there is evidence of mortality in reported cases including those affecting mandible. A 38-year-old man was diagnosed with disappearing bone disease of the mandible in 2013. This had progressed from being in the right ramus only, and now extends to the lower right first molar and affects the left coronoid process and ramus. Mandibular involvement has shown to be high-risk. In older patients, misdiagnosis can occur without thorough investigation, and education of clinicians needs to be paramount to provide the appropriate treatment for this rare condition. The disease can be debilitating and as such education and support of patients is essential. PMID- 28878874 TI - PaxA, but not PaxC, is required for cnidocyte development in the sea anemone Nematostella vectensis. AB - BACKGROUND: Pax genes are a family of conserved transcription factors that regulate many aspects of developmental morphogenesis, notably the development of ectodermal sensory structures including eyes. Nematostella vectensis, the starlet sea anemone, has numerous Pax orthologs, many of which are expressed early during embryogenesis. The function of Pax genes in this eyeless cnidarian is unknown. RESULTS: Here, we show that PaxA, but not PaxC, plays a critical role in the development of cnidocytes in N. vectensis. Knockdown of PaxA results in a loss of developing cnidocytes and downregulation of numerous cnidocyte-specific genes, including a variant of the transcription factor Mef2. We also demonstrate that the co-expression of Mef2 in a subset of the PaxA-expressing cells is associated with the development with a second lineage of cnidocytes and show that knockdown of the neural progenitor gene SoxB2 results in downregulation of expression of PaxA, Mef2, and several cnidocyte-specific genes. Because PaxA is not co expressed with SoxB2 at any time during cnidocyte development, we propose a simple model for cnidogenesis whereby a SoxB2-expressing progenitor cell population undergoes division to give rise to PaxA-expressing cnidocytes, some of which also express Mef2. DISCUSSION: The role of PaxA in cnidocyte development among hydrozoans has not been studied, but the conserved role of SoxB2 in regulating the fate of a progenitor cell that gives rise to neurons and cnidocytes in Nematostella and Hydractinia echinata suggests that this SoxB2/PaxA pathway may well be conserved across cnidarians. PMID- 28878873 TI - Hypoxia inducible factor (HIF) as a model for studying inhibition of protein protein interactions. AB - The modulation of protein-protein interactions (PPIs) represents a major challenge in modern chemical biology. Current approaches (e.g. high-throughput screening, computer aided ligand design) are recognised as having limitations in terms of identification of hit matter. Considerable success has been achieved in terms of developing new approaches to PPI modulator discovery using the p53/hDM2 and Bcl-2 family of PPIs. However these important targets in oncology might be considered as "low-hanging-fruit". Hypoxia inducible factor (HIF) is an emerging, but not yet fully validated target for cancer chemotherapy. Its role is to regulate the hypoxic response and it does so through a plethora of protein protein interactions of varying topology, topography and complexity: its modulation represents an attractive approach to prevent development of new vasculature by hypoxic tumours. PMID- 28878877 TI - Multiple small intestinal perforations in a patient with Hepatitis B Virus associated Polyarteritis Nodosa. AB - We present the case of a 38-year-old patient with a history of Hepatitis B Virus associated Polyarteritis Nodosa, who presented with acute abdomen and septic shock. The patient initially had three perforations of the small intestine that were treated with segmental enterectomy and anastomosis at two sites. During his postoperative course he continued to develop new perforations and necrotic lesions along the whole length of the small intestine, that mandated repetitive laparotomies and the technique of the open abdomen was employed. Despite the aggressive surgical treatment and the medical treatment with corticosteroids, cyclophosphamide and plasma exchanges, the patient died 15 days after the first operation due to septic shock and multiple organ failure. PMID- 28878878 TI - Successful treatment of aortic root dissection complicated with extensive myocardial infarction using the total artificial heart. AB - Acute Type A aortic dissection is a surgical emergency. Urgent repair is indicated to avoid complications such as acute aortic insufficiency, coronary ischemia and aortic rupture with cardiac tamponade. This report details the management of a patient with acute Type A aortic dissection complicated by an extensive anterolateral myocardial infarction and cardiogenic shock who was successfully bridged to transplantation with a total artificial heart. PMID- 28878879 TI - If I had a hammer. AB - We present the case of a 64-year-old man who was referred to our service after sustaining a self-inflicted nail-gun injury to his chest. He received three nails penetrated into his chest. Computer tomography revealed no massive haemorrhage or damage to major vessels. He underwent an emergency sternotomy, two nails caused pericardial perforation and myocardial injury were noted easily and removed easily via sternotomy. Myocardial injury showed a trajectory near the junction of the left anterior descending artery and the diagonal artery with no significant bleeding appreciated. The third nail was deep in the lung parenchyma at the hilum. A pacemaker magnet was used to locate the third nail, which was subsequently removed. Our case demonstrates the use of magnets in emergency surgery, to locate and remove metallic foreign bodies. PMID- 28878880 TI - Greater saphenous vein anomaly and aneurysm with subsequent pulmonary embolism. AB - Venous aneurysms often present as painful masses. They can present either in the deep or superficial venous system. Deep venous system aneurysms have a greater risk of thromboembolism. Though rare, there have been case reports of superficial aneurysms and thrombus causing significant morbidity such as pulmonary embolism. We present a case of an anomalous greater saphenous vein connection with an aneurysm and thrombus resulting in a pulmonary embolism. This is the only reported case of an anomalous greater saphenous vein connection with aneurysm and thrombus, which eventually led to a pulmonary embolism. Recognition of the morbidity and mortality associated with superficial venous aneurysms can help prevent catastrophic outcomes such as pulmonary embolism. Surgical intervention on large symptomatic superficial venous aneurysms may be the optimal treatment in preventing unwanted complications compared to anticoagulation alone. PMID- 28878881 TI - Tracking low back pain in adolescent idiopathic scoliosis: a prospective cohort study protocol. AB - BACKGROUND: Numerous methodological limitations have constrained the findings of previous studies that have examined the prevalence of low back pain in adolescents with idiopathic scoliosis. This article presents a study protocol that has been designed to address the shortcomings of prior research in this area. In addition, it will establish the level of disease burden associated with acute, recurrent, and chronic low back pain in adolescents with idiopathic scoliosis. METHODS: This study will involve a prospective cohort of adolescents with idiopathic scoliosis presenting to an outpatient department in a paediatric hospital. Potential participants will be eligible for inclusion if they are aged 10-17 years, experience adolescent idiopathic scoliosis, own a mobile phone, and are able to communicate in either French or English adequately. The primary outcome measure is the presence of low back pain. The secondary outcome will be measures with the Brief Pain Questionnaire and the PedsQL questionnaire. Participants will be followed over a 12-month period reporting weekly, via SMS tracking. DISCUSSION: Previous studies frequently established the prevalence of low back pain through asking participants to recall whether they experienced low back pain over certain periods. These periods often extended beyond many months, and hence were subject to recall bias. Our study addresses such bias through gathering data on a weekly basis using SMS-tracking providing detailed information about the progression of low back pain, which allows researchers to establish the prevalence of acute, recurrent, and chronic low back pain with a better certainty. Furthermore, the previous studies failed to use a standardised definition of low back pain. As such, it is not possible to determine whether the reported low back pain was experienced at the following standardised defined location: "pain in the space between the lower posterior margin of the rib cage and the horizontal gluteal fold". CONCLUSION: This research protocol will be the first study to determine the proportion of adolescents with idiopathic scoliosis who experience acute, recurrent, and chronic low back pain, and establish the level of the burden associated with these subgroups of low back pain. PMID- 25901276 TI - Long read nanopore sequencing for detection of HLA and CYP2D6 variants and haplotypes. AB - Haplotypes are often critical for the interpretation of genetic laboratory observations into medically actionable findings. Current massively parallel DNA sequencing technologies produce short sequence reads that are often unable to resolve haplotype information. Phasing short read data typically requires supplemental statistical phasing based on known haplotype structure in the population or parental genotypic data. Here we demonstrate that the MinION nanopore sequencer is capable of producing very long reads to resolve both variants and haplotypes of HLA-A, HLA-B and CYP2D6 genes important in determining patient drug response in sample NA12878 of CEPH/UTAH pedigree 1463, without the need for statistical phasing. Long read data from a single 24-hour nanopore sequencing run was used to reconstruct haplotypes, which were confirmed by HapMap data and statistically phased Complete Genomics and Sequenom genotypes. Our results demonstrate that nanopore sequencing is an emerging standalone technology with potential utility in a clinical environment to aid in medical decision making. PMID- 26478812 TI - Ligand uptake in Mycobacterium tuberculosis truncated hemoglobins is controlled by both internal tunnels and active site water molecules. AB - Mycobacterium tuberculosis, the causative agent of human tuberculosis, has two proteins belonging to the truncated hemoglobin (trHb) family. Mt-trHbN presents well-defined internal hydrophobic tunnels that allow O 2 and *NO to migrate easily from the solvent to the active site, whereas Mt-trHbO possesses tunnels interrupted by a few bulky residues, particularly a tryptophan at position G8. Differential ligand migration rates allow Mt-trHbN to detoxify *NO, a crucial step for pathogen survival once under attack by the immune system, much more efficiently than Mt-trHbO. In order to investigate the differences between these proteins, we performed experimental kinetic measurements, *NO decomposition, as well as molecular dynamics simulations of the wild type Mt-trHbN and two mutants, VG8F and VG8W. These mutations affect both the tunnels accessibility as well as the affinity of distal site water molecules, thus modifying the ligand access to the iron. We found that a single mutation allows Mt-trHbN to acquire ligand migration rates comparable to those observed for Mt-trHbO, confirming that ligand migration is regulated by the internal tunnel architecture as well as by water molecules stabilized in the active site. PMID- 26448859 TI - Theoretical modelling of epigenetically modified DNA sequences. AB - We report herein a set of calculations designed to examine the effects of epigenetic modifications on the structure of DNA. The incorporation of methyl, hydroxymethyl, formyl and carboxy substituents at the 5-position of cytosine is shown to hardly affect the geometry of CG base pairs, but to result in rather larger changes to hydrogen-bond and stacking binding energies, as predicted by dispersion-corrected density functional theory (DFT) methods. The same modifications within double-stranded GCG and ACA trimers exhibit rather larger structural effects, when including the sugar-phosphate backbone as well as sodium counterions and implicit aqueous solvation. In particular, changes are observed in the buckle and propeller angles within base pairs and the slide and roll values of base pair steps, but these leave the overall helical shape of DNA essentially intact. The structures so obtained are useful as a benchmark of faster methods, including molecular mechanics (MM) and hybrid quantum mechanics/molecular mechanics (QM/MM) methods. We show that previously developed MM parameters satisfactorily reproduce the trimer structures, as do QM/MM calculations which treat bases with dispersion-corrected DFT and the sugar phosphate backbone with AMBER. The latter are improved by inclusion of all six bases in the QM region, since a truncated model including only the central CG base pair in the QM region is considerably further from the DFT structure. This QM/MM method is then applied to a set of double-stranded DNA heptamers derived from a recent X-ray crystallographic study, whose size puts a DFT study beyond our current computational resources. These data show that still larger structural changes are observed than in base pairs or trimers, leading us to conclude that it is important to model epigenetic modifications within realistic molecular contexts. PMID- 26167275 TI - Longitudinal variations of brain functional connectivity: A case report study based on a mouse model of epilepsy. AB - Brain Functional Connectivity (FC) quantifies statistical dependencies between areas of the brain. FC has been widely used to address altered function of brain circuits in control conditions compared to different pathological states, including epilepsy, a major neurological disorder. However, FC also has the as yet unexplored potential to help us understand the pathological transformation of the brain circuitry. Our hypothesis is that FC can differentiate global brain interactions across a time-scale of days. To this end, we present a case report study based on a mouse model for epilepsy and analyze longitudinal intracranial electroencephalography data of epilepsy to calculate FC changes from the initial insult (status epilepticus) and over the latent period, when epileptogenic networks emerge, and at chronic epilepsy, when unprovoked seizures occur as spontaneous events. We found that the overall network FC at low frequency bands decreased immediately after status epilepticus was provoked, and increased monotonously later on during the latent period. Overall, our results demonstrate the capacity of FC to address longitudinal variations of brain connectivity across the establishment of pathological states. PMID- 26339477 TI - Intracellular Dynamics of the Ubiquitin-Proteasome-System. AB - The ubiquitin-proteasome system is the major degradation pathway for short-lived proteins in eukaryotic cells. Targets of the ubiquitin-proteasome-system are proteins regulating a broad range of cellular processes including cell cycle progression, gene expression, the quality control of proteostasis and the response to geno- and proteotoxic stress. Prior to degradation, the proteasomal substrate is marked with a poly-ubiquitin chain. The key protease of the ubiquitin system is the proteasome. In dividing cells, proteasomes exist as holo enzymes composed of regulatory and core particles. The regulatory complex confers ubiquitin-recognition and ATP dependence on proteasomal protein degradation. The catalytic sites are located in the proteasome core particle. Proteasome holo enzymes are predominantly nuclear suggesting a major requirement for proteasomal proteolysis in the nucleus. In cell cycle arrested mammalian or quiescent yeast cells, proteasomes deplete from the nucleus and accumulate in granules at the nuclear envelope (NE) / endoplasmic reticulum ( ER) membranes. In prolonged quiescence, proteasome granules drop off the nuclear envelopeNE / ER membranes and migrate as droplet-like entitiesstable organelles throughout the cytoplasm, as thoroughly investigated in yeast. When quiescence yeast cells are allowed to resume growth, proteasome granules clear and proteasomes are rapidly imported into the nucleus. Here, we summarize our knowledge about the enigmatic structure of proteasome storage granules and the trafficking of proteasomes and their substrates between the cyto- and nucleoplasm. Most of our current knowledge is based on studies in yeast. Their translation to mammalian cells promises to provide keen insight into protein degradation in non-dividing cells, which comprise the majority of our body's cells. PMID- 26594347 TI - Impact of a structured review session on medical student psychiatry subject examination performance. AB - Introduction: The National Board of Medical Examiners (NBME) subject examinations are used as a standardized metric for performance in required clerkships for third-year medical students. While several medical schools have implemented a review session to help consolidate knowledge acquired during the clerkship, the effects of such an intervention are not yet well-established. An improvement in NBME psychiatry examination scores has previously been reported with a single end of-clerkship review session, but this was limited by a small sample size and the fact that attendance at the review session was optional, leading to likely selection bias. Methods: A 1.5-hour structured review session was conducted for medical students in the last week of each 4-week psychiatry clerkship between September 2014 and July 2015. Students were required to attend unless excused due to scheduling conflicts. Scores on the NBME psychiatry subject exam were compared with those of students taking the examination in the corresponding time period in each of the previous two academic years. Results: 83 students took the exam during the experimental period, while 176 took the exam during the control period. Statistically significant improvements were found in mean score (p=0.03), mean for the two lowest scores in each group (p<0.0007), and percentage of students scoring 70 or less (p=0.03). Percentage of students achieving the maximum possible score (99) was higher in the experimental group, but did not reach significance (p=0.06). Conclusions: An end-of-clerkship review session led to increased mean scores on the NBME psychiatry subject examination, particularly for students at the lower end of the score range. Future research should investigate the impact of such an intervention in other specialties and other institutions. PMID- 28878888 TI - Cardiovascular and thermal strain during 3-4 days of a metabolically demanding cold-weather military operation. AB - BACKGROUND: Cardiovascular (CV) and thermal responses to metabolically demanding multi-day military operations in extreme cold-weather environments are not well described. Characterization of these operations will provide greater insights into possible performance capabilities and cold injury risk. METHODS: Soldiers from two cold-weather field training exercises (FTX) were studied during 3-day (study 1, n = 18, age: 20 +/- 1 year, height: 182 +/- 7 cm, mass: 82 +/- 9 kg) and 4-day (study 2, n = 10, age: 20 +/- 1 year, height: 182 +/- 6 cm, mass: 80.7 +/- 8.3 kg) ski marches in the Arctic. Ambient temperature ranged from -18 to -4 degrees C during both studies. Total daily energy expenditure (TDEE, from doubly labeled water), heart rate (HR), deep body (Tpill), and torso (Ttorso) skin temperature (obtained in studies 1 and 2) as well as finger (Tfing), toe (Ttoe), wrist, and calf temperatures (study 2) were measured. RESULTS: TDEE was 6821 +/- 578 kcal day-1 and 6394 +/- 544 for study 1 and study 2, respectively. Mean HR ranged from 120 to 140 bpm and mean Tpill ranged between 37.5 and 38.0 degrees C during skiing in both studies. At rest, mean Tpill ranged from 36.0 to 36.5 degrees C, (lowest value recorded was 35.5 degrees C). Mean Tfing ranged from 32 to 35 degrees C during exercise and dropped to 15 degrees C during rest, with some Tfing values as low as 6-10 degrees C. Ttoe was above 30 degrees C during skiing but dropped to 15-20 degrees C during rest. CONCLUSIONS: Daily energy expenditures were among the highest observed for a military training exercise, with moderate exercise intensity levels (~65% age-predicted maximal HR) observed. The short-term cold-weather training did not elicit high CV and Tpill strain. Tfing and Ttoe were also well maintained while skiing, but decreased to values associated with thermal discomfort at rest. PMID- 28878889 TI - Preoperative fluid retention increases blood loss during major open abdominal surgery. AB - BACKGROUND: Quantification of renal fluid conservation is possible by urine analysis, and the results can indicate dehydration. The present report sought to determine whether this fluid retention correlates with fluid requirements during major abdominal surgeries that have estimated operating times >= 2 h. METHODS: Urine colour, specific weight, osmolality and creatinine concentration were used to calculate a composite "fluid retention index" (FRI) in 97 patients prior to major abdominal surgery. Goal-directed fluid volume optimization, with hydroxyethyl starch supplemented with a background administration of crystalloid fluid, was used. RESULTS: The median preoperative FRI was 3.0. Fluid retention, considered as present when FRI >= 3.5, was found in 37% of the patients. Fluid retention was followed by a significantly larger blood loss (+ 125%; 450 vs. 200 ml), higher haemorrhage rate (+ 41%; 123 vs. 87 ml/h) and greater need for both colloid (+ 43%; 1.43 vs. 1.00 l) and crystalloid (+ 18%; 1.28 vs. 1.08 l) fluids. Despite the larger blood loss, the total fluid balance was more positive after surgery in the dehydrated patients (+ 26%; 1.91 vs. 1.51 l; P < 0.02). CONCLUSIONS: Preoperative fluid retention, as detected in a urine sample, was associated with a greater blood loss and a more positive fluid balance during major abdominal surgery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01458678. PMID- 28878890 TI - Key features of mcr-1-bearing plasmids from Escherichia coli isolated from humans and food. AB - BACKGROUND: Mcr-1-harboring Enterobacteriaceae are reported worldwide since their first discovery in 2015. However, a limited number of studies are available that compared full-length plasmid sequences of human and animal origins. METHODS: In this study, mcr-1-bearing plasmids from seven Escherichia coli isolates recovered from patients (n = 3), poultry meat (n = 2) and turkey meat (n = 2) in Switzerland were further analyzed and compared. Isolates were characterized by multilocus sequence typing (MLST). The mcr-1-bearing plasmids were transferred by transformation into reference strain E. coli DH5alpha and MCR-1-producing transformants were selected on LB-agar supplemented with 2 mg/L colistin. Purified plasmids were then sequenced and compared. RESULTS: MLST revealed six distinct STs, illustrating the high clonal diversity among mcr-1-positive E. coli isolates of different origins. Two different mcr-1-positive plasmids were identified from a single E. coli ST48 human isolate. All other isolates possessed a single mcr-1 harboring plasmid. Transferable IncI2 (size ca. 60-61 kb) and IncX4 (size ca. 33-35 kb) type plasmids each bearing mcr-1 were found associated with human and food isolates. None of the mcr-1-positive IncI2 and IncX4 plasmids possessed any additional resistance determinants. Surprisingly, all but one of the sequenced mcr-1-positive plasmids lacked the ISApl1 element, which is a key element mediating acquisition of mcr-1 into various plasmid backbones. CONCLUSIONS: There is strong evidence that the food chain may be an important transmission route for mcr-1-bearing plasmids. Our data suggest that some "epidemic" plasmids rather than specific E. coli clones might be responsible for the spread of the mcr-1 gene along the food chain. PMID- 28878892 TI - Laparoscopic and open inguinal hernia repair: Patient reported outcomes in the elderly from a single centre - A prospective cohort study. AB - BACKGROUND: With those over 65 making up over 16% of the UK's population, surgeons are counselling increasing numbers of elderly patients for hernia repair. Data is currently lacking comparing different repair methods of inguinal hernias in the elderly population with regards to patient reported outcomes. AIM: To compare open and laparoscopic hernia repair in patients >65 years old and those <65 years old with respect to patient reported outcomes. METHOD: As part of a quality assurance process patients receive a telephone consultation day 2 post procedure. This includes an optional survey with questions to quantify pain, general feeling, nausea, dizziness, drowsiness, satisfaction and vomiting since the operation. Patients were then classified into age >= 65 years or <65 years and subclassified into totally extraperitoneal (TEP) or open inguinal hernia repair (IHR). RESULTS: Data is presented from patients treated between January 2009 and August 2016, totalling those included 1167 of 2522 (55.5%). Only five patients (4.42%) reported moderate pain; in the >65 TEP group this was significantly lower (10.2% open IHR <65; 6.7% TEP <65; 12.8% open IHR >65). Patient satisfaction with the surgery was satisfied or very satisfied in all patients in all groups. CONCLUSION: Time off work is not an absolute appropriate measure of return to premorbid status with respect to the elderly as a substantial number of >65 year olds have retired. We therefore present this interesting insight into patient perceptions following hernia repair by age group. Overall patients over 65 can expect the same high levels of satisfaction and low levels of pain following either technique for inguinal hernia repair as younger patients. PMID- 28878891 TI - Epidemic characterization and molecular genotyping of Shigella flexneri isolated from calves with diarrhea in Northwest China. AB - BACKGROUND: The widespread presence of antibiotics resistance genes in pathogenic bacteria can cause enormous problems. Food animals are one of the main reservoirs of intestinal pathogens that pose a potential risk to human. Analyzing the epidemiological characteristics and resistance patterns of Shigella flexneri in calves is necessary for animal and human health. METHODS AND RESULTS: A total of 54 Shigella flexneri isolates, including six serotypes (1a, 2a, 2b, 4a, 6 and Xv), were collected from 837 fecal samples obtained from 2014 to 2016. We performed pulsed-field gel electrophoresis (PFGE) and applied the restriction enzyme NotI to analyze the genetic relatedness among the 54 isolates and to categorize them into 31 reproducible and unique PFGE patterns. According to the results of antimicrobial susceptibility tests, all 26 Shigella flexneri 2a serotypes were resistant to cephalosporin and/or fluoroquinolones. The genes blaTEM-1 , blaOXA-1 , and blaCTX-M-14 were detected in 19 cephalosporin-resistant S. flexneri 2a isolates. Among 14 fluoroquinolone-resistant isolates, the aac(6') Ib-cr gene was largely present in each strain, followed by qnrS (5). Only one ciprofloxacin-resistant isolate harbored the qepA gene. Sequencing the quinolone resistance determining regions (QRDRs) of the fluoroquinolone-resistant isolates revealed two point mutations in gyrA (S83 L, D87N/Y) and a single point mutation in parC (S80I). Interestingly, two gyrA (D87N/Y) strains were resistant to ciprofloxacin. CONCLUSIONS: The current study enhances our knowledge of Shigella in cattle, although continual surveillance is necessary for the control of shigellosis. The high level of cephalosporin and/or fluoroquinolone resistance in Shigella warns us of a potential risk to human and animal health. PMID- 28878893 TI - S-shaped versus conventional straight skin incision: Impact on primary functional maturation, stenosis and thrombosis of autogenous radiocephalic arteriovenous fistula: Impact of incision on maturation, stenosis & failure of RCAVF. Study design: Prospective observational comparative. AB - INTRODUCTION: The objective of this study is to test the null hypothesis that an S-shaped surgical incision versus conventional (straight) skin incision in the creation of autogenous radiocephalic arteriovenous fistulas (RCAVFs) have no impact on the primary end-point of primary functional maturation and secondary end points of stenosis and thrombosis. METHODS: A prospective observational comparative consecutive study with intention-to-treat on individuals undergoing only radiocephalic arteriovenous fistula (RCAVFs) over a period of 12 months was conducted. Variables on patient's demographics, comorbidities, anesthesia type, mean arterial blood pressure, thrill, laterality, cephalic vein and radial artery diameter were collated. The test of probability was assessed through Chi-Square, Kaplan-Meier survival estimator and Log-Rank analysis. RESULTS: Total of n = 83 individuals with median age of 67 years (IQR, 20-89) and male predominance 83% during this period were subjected to RCAVF formation. Total of n = 45 patients in straight skin incision were compared to n = 38 individuals in S-shaped group. Despite equal prevalence of demographics, comorbidities, anesthesia type, mean arterial blood pressure (MAP), thrill, laterality, cephalic vein and radial artery diameter (p > 0.05) higher incidence of juxta-anastomotic stenosis was noted in the straight skin incision group (p = 0.029) in comparative and survival analysis (Log-Rank, p = 0.036). The maturation of the entire cohort was 69% (S shaped 76% vs. straight group 62%) (p > 0.05). CONCLUSION: The outcome of this study demonstrates that S-shaped surgical skin incision is associated with a lower incidence of stenosis in comparison to straight incision type in RCAVF formation. PMID- 28878895 TI - Social determinants and risk behaviors associated with prevalent Hepatitis C and HIV/HCV co-infection among male injection drug users in Nepal. AB - BACKGROUND: Nepal is facing double burden of injecting drug use and HIV, yet the problem of Hepatitis C Virus (HCV) has not been so well addressed, where there is large population known to be at risk for HCV. This study assessed the prevalence of HCV infection and HIV/HCV co-infection among male injection drug users (IDUs) in Nepal and identified factors associated with infection. METHODS: Cross sectional surveys in 2015 aimed to sample 1045 male IDUs in the Kathmandu valley, Pokhara Valley and Eastern Terai districts of Nepal. Information about socio demographic characteristics, injecting and sexual risk behaviours were obtained, and biological specimens tested for HCV and HIV. The logistic regression model was used to identify the determinants associated with HCV and HIV/HCV co infection. RESULTS: HCV prevalence was 28.8% and HIV/HCV co-infection was 4%. Among the 6% of HIV positive male IDUs, 65% were found to be co-infected. The multivariate logistic analysis revealed that HCV prevalence was higher in Eastern Terai districts, longer duration of drug use and injecting drugs and presence of HIV. Similarly, HIV/HCV co-infection was associated with Eastern highway districts, older age and longer duration of injecting drugs. CONCLUSION: The factors strongly contributing to HCV and HIV/HCV co-infection was longer duration of injecting drugs. Highest HCV and HIV/HCV co-infection was found in Eastern Terai districts. Target health interventions need to be focused in Eastern Terai districts and IDUs with longer duration of injecting drugs for the prevention of HCV and HIV/HCV transmission. PMID- 28878894 TI - Genomic regions and pathways associated with gastrointestinal parasites resistance in Santa Ines breed adapted to tropical climate. AB - BACKGROUND: The aim of this study was to estimate variance components and to identify genomic regions and pathways associated with resistance to gastrointestinal parasites, particularly Haemonchus contortus, in a breed of sheep adapted to tropical climate. Phenotypes evaluations were performed to verify resistance to gastrointestinal parasites, and were divided into two categories: i) farm phenotypes, assessing body condition score (BCS), degree of anemia assessed by the famacha chart (FAM), fur score (FS) and feces consistency (FC); and ii) lab phenotypes, comprising blood analyses for hematocrit (HCT), white blood cell count (WBC), red blood cell count (RBC), hemoglobin (HGB), platelets (PLT) and transformed (log10) egg per gram of feces (EPGlog). A total of 576 animals were genotyped with the Ovine SNP12k BeadChip (Illumina, Inc.), that contains 12,785 bialleleic SNP markers. The variance components were estimated using a single trait model by single step genomic BLUP procedure. RESULTS: The overall linkage disequilibrium (LD) mean between pairs of markers measured by r2 was 0.23. The overall LD mean between markers considering windows up to 10 Mb was 0.07. The mean LD between adjacent SNPs across autosomes ranged from 0.02 to 0.10. Heritability estimates were low for EPGlog (0.11), moderate for RBC (0.18), PLT (0.17) HCT (0.20), HGB (0.16) and WBC (0.22), and high for FAM (0.35). A total of 22, 21, 23, 20, 26, 25 and 23 windows for EPGlog for FAM, WBC, RBC, PLT, HCT and HGB traits were identified, respectively. Among the associated windows, 10 were shown to be common to HCT and HGB traits on OAR1, OAR2, OAR3, OAR5, OAR8 and OAR15. CONCLUSION: The traits indicating gastrointestinal parasites resistance presented an adequate genetic variability to respond to selection in Santa Ines breed, and it is expected a higher genetic gain for FAM trait when compared to the others. The level of LD estimated for markers separated by less than 1 Mb indicated that the Ovine SNP12k BeadChip might be a suitable tool for identifying genomic regions associated with traits related to gastrointestinal parasite resistance. Several candidate genes related to immune system development and activation, inflammatory response, regulation of lymphocytes and leukocytes proliferation were found. These genes may help in the selection of animals with higher resistance to parasites. PMID- 28878897 TI - Severe phenotype of X-linked dominant chondrodysplasia punctata. AB - A prenatally ascertained case representing the more severe end of the X-linked dominant chondrodysplasia punctata (CDPX2). PMID- 28878896 TI - Oral manifestations of a rare variant of Marfan syndrome. AB - This article reports the oral manifestations of an unusual presentation of Marfan syndrome (MFS) and provides an evidence to the importance of recognizing the oral features in confirming the diagnosis of MFS. Dentists have a vital role in confirming the diagnosis of developmental disorders that involve the craniofacial compendium. PMID- 28878898 TI - Tourniquet-induced common peroneal nerve injury in a pediatric patient after knee arthroscopy - raising the red flag. AB - Peripheral nerve injury following the use of arterial tourniquets is a rare but potentially debilitating complication. Further education on the safe and appropriate practice of tourniquets is imperative to reduce the incidence of tourniquet-related complications. PMID- 28878899 TI - Left ventricular blood cyst in an adult case. AB - We present a 57-year-old man with a 1.5-cm-diameter blood cyst in the left ventricle, which was incidentally detected by conventional diagnostic echocardiography before colon surgery. The cyst originated from the papillary muscle, and the pathological findings were compatible with a cardiac blood cyst. PMID- 28878900 TI - Intravascular large B-cell lymphoma presenting as Richter's syndrome with cerebral involvement in a patient with chronic lymphocytic leukemia. AB - Intravascular large B-cell lymphoma (IVLBCL) is an aggressive non-Hodgkin's lymphoma which can present with B symptoms, rash, and neurological deterioration. Up to 10% of cases of IVLBCL are associated with other hematological neoplasms, including this extremely rare presentation of IVLBCL as Richter's transformation in chronic lymphocytic leukemia. PMID- 28878901 TI - Breast reconstruction in pregnancy: a case report of multidisciplinary team approach in immediate autologous flap reconstruction for pregnancy-associated breast cancer. AB - This report presents the results of immediate breast reconstruction with autologous flap in Pregnancy-associated breast cancer (PABC). There was no obstetrics and surgical complications in our report. Immediate breast reconstruction can be performed in PABC after a careful selection. Multidisciplinary team approach is the key in managing these groups of patients. PMID- 28878903 TI - Combined LASER and femoral approach to remove a previous failure of Riata lead extraction. AB - Transvenous extraction of Riata lead could be a challenging procedure due to insulation failure and conductor cables' externalization through the eroded outer insulation. In this case, a complete lead extraction was achieved through a combined LASER and femoral approach because of the massive conductors' externalization. PMID- 28878902 TI - Primary cardiac lymphoma with central nervous system relapse. AB - Primary cardiac lymphoma (PCL), a rare disease, often presents with symptoms resembling other cardiac diseases. The correct diagnosis is crucial, as cardiac lymphoma can be cured with immuno-chemotherapy. PCL has a high risk of central nervous system recurrence (CNS); therefore, screening for CNS involvement and even prophylaxis may be necessary. PMID- 28878904 TI - A case of choledochoduodenal fistula - an unusual case report. AB - Choledochoduodenal fistula (CDF) is an abnormal communication between the choledochus and the duodenum, accounts for 5-25% of all internal biliary fistulas. Here, we report a case of CDF secondary to chronic duodenal ulcer who presented with cholangitis. CDF is suspected in case of pneumobilia, and surgery is recommended for refractory cases. PMID- 28878906 TI - First patient with hereditary spastic paraplegia type 8 in Poland. AB - SPG 8 is an autosomal dominant HSP, which phenotype results from KIAA0196 gene mutations. There have been twelve types of KIAA0196 mutations described in HGMD, which are located in conservative region of gene encoding strumpellin. We describe first patient in Poland, simultaneously second in the world with KIAA0196 mutation - p.V620A. PMID- 28878905 TI - Severe obstructive sleep apnea: first screening with an implanted pacemaker. AB - Sleep apnea syndrome (SAS) is a chronic condition associated with cardiovascular disease. In some pacemakers, an advanced algorithm using transthoracic impedance may be used to identify SAS. This algorithm may be also a useful tool for a long term monitoring helping physicians to optimize therapy, reducing risk factors, and improving therapeutic compliance. PMID- 28878907 TI - Salvage of an osteocutaneous thermonecrosis secondary to tibial reaming by the induced membrane procedure. AB - Osteocutaneous thermonecrosis is a rare but devastating complication of tibial reaming, which can cause large and infected bone and cutaneous defects. The case presented here illustrates that the induced membrane technique described by Masquelet is a valuable option in treating this complication. PMID- 28878908 TI - A case report of spontaneous rupture of the quadriceps tendon. AB - Spontaneous quadriceps tendon rupture is a rare occurrence in patients with primary hyperparathyroidism (PHPT), which is less common in adolescents. We first reported a spontaneous unilateral rupture in a young patient with PHPT. PMID- 28878909 TI - A rare case of Epstein-Barr virus-related plasmacytoma involving maxillary sinus mucosa. AB - Extramedullary plasmacytomas, Epstein-Bar virus (EBV) associated, are rarely encountered and usually have a fairly good clinical outcome. EBV+ plasmacytoma may cause a diagnostic dilemma as it phenotypically resembles an aggressive plasmablastic lymphoma (PBL). Herein, we report a unique case with maxillary EBV+ plasmacytoma from a 76-year-old immunocompetent individual. PMID- 28878910 TI - Hemophagocytosis lymphocytosis presenting as pulmonary-renal syndrome: a case report and literature review. AB - Hemophagocytosis Lymphocytosis (HLH) is a rare and life-threatening illness that is more commonly seen in infants; however, its incidence in adults is becoming more common. Recognizing HLH in a complicated clinical scenario is key to early recognition, treatment, as well as improved morbidity and mortality. PMID- 28878911 TI - Severe autoimmune hemolytic anemia during pegylated interferon plus ribavirin treatment for chronic hepatitis C: a case report. AB - We report a rare case of severe autoimmune hemolytic anemia triggered by pegylated interferon during combination therapy for chronic HCV. This case demonstrated that interferon can de novo induce autoimmune hemolytic anemia during therapy for chronic hepatitis C in a previously healthy patient. PMID- 28878912 TI - Multiple myeloma presenting in association with gastric phytobezoar. AB - We present a rare case of a patient with delayed gastric emptying, gastric phytobezoar formation, and osteosclerotic bone lesions as an atypical association with multiple myeloma. Associated gastric features in myeloma, which include diffuse infiltration, gastric plasmacytomas, or delayed gastric emptying, are rare and have a poor prognosis. PMID- 28878913 TI - Induction treatment of acute myeloid leukemia in an elderly patient with intramarrow injection/administration of cytarabine. Second case report. AB - We show for the second time that intramarrow injection/administration of chemotherapeutic agents such as cytarabine (Ara-C) can be used safely and effectively and is associated with no toxicity, promising antileukemic activity and possible improved survival. PMID- 28878914 TI - A novel keratin 13 variant in a four-generation family with white sponge nevus. AB - We report a novel KRT13 germ line variant that causes white sponge nevus (WSN) with mucosal dysplasia. Genital, vaginal, and cervical WSN were observed in four female patients, of whom two had premalignant cervical lesions at young age. Two of the 12 patients with oral WSN developed oral squamous cell carcinoma. PMID- 28878915 TI - Ethanol injection into the Marshall vein provoking a pericardial effusion resulting in a fatal complication in a patient with persistent atrial fibrillation. AB - An EIM (ethanol infusion into the vein of Marshall [VOM]) provoked a fatal complication in a chronic hemodialysis patient. Autopsy revealed a lacerated VOM covered with thrombi as the only potential cause. The EIM caused vascular damage and clots resulting in myocardial necrosis and interstitial bleeding around the lacerated VOM. PMID- 28878916 TI - What is the cause of this synchronous palpable abdominal mass in a woman recently diagnosed with lung cancer as demonstrated in Figure 1? AB - Colonic metastases from lung cancer are rare [1, 2]. Presentation of an abdominal mass in the setting of a new lung cancer diagnosis should prompt complete evaluation including endoscopic and CT imaging. This case also highlights the need for immunohistochemical analysis of unusual tumor deposits facilitating appropriate treatment. PMID- 28878917 TI - Management of a patient with Opalski's syndrome in intensive care unit. AB - Opalski syndrome is a rare vascular brainstem syndrome which is accepted as a variant of Wallenberg syndrome. Opalski syndrome should be considered in acute conditions in which typical symptoms of lateral medullary infarct are accompanied by ipsilateral hemiparesis. Other brain stem syndromes are distinguished from Opalski syndrome by the presence of contralateral hemiparesis. PMID- 28878918 TI - Development of Harlequin Syndrome following placement of thoracic epidural anesthesia in a pediatric patient undergoing Nuss procedure. AB - We report the development of Harlequin Syndrome following thoracic epidural placement in a pediatric patient. Unilateral facial flushing with contralateral pallor and anhidrosis is the clinical presentation. This syndrome is typically benign. When related to regional anesthesia, treatment involves reducing the local anesthetic infusion or stopping it altogether. PMID- 28878919 TI - From anemia to polycythemia in 4 weeks. AB - Primary polycythemia (PCV) may coexist in otherwise asymptomatic patients particularly in the presence of unsuspecting conditions such as Thrombotic thrombocytopenic purpura (TTP). In presumed "idiopathic TTP," autoimmune conditions such as rheumatoid arthritis (RA) should be investigated as a possible etiology for TTP. Standardization of targeted therapy with immunomodulatory agents may be recommended for this subset of patients. PMID- 28878920 TI - Full mouth rehabilitation with retrievable metal-ceramic implant-supported fixed prostheses for a young patient with atrophic jaws: a clinical report. AB - Treatment of atrophic edentulous jaws with implant-supported fixed prostheses is one of the most complicated challenges in dentistry. This clinical report describes the prosthesis which consists of screw retained frameworks with individual cement retained crowns which combines the advantages of the screw retained restoration with the advantage of cement retained. PMID- 28878921 TI - T-cell prolymphocytic leukemia and tuberculosis: a puzzling association. AB - T-cell prolymphocytic leukemia can result in severe immune T-cell deficiency. Clinicians should be aware of this complication in this rare lymphoid malignancy, and opportunistic infections should be ruled out before the use of usual immunosuppressive procedures such as alemtuzumab and hematopoietic stem cell transplantation. PMID- 28878922 TI - Visualization of poikilothermia using handheld thermography. AB - Poikilothermia is a fundamental symptom of acute limb ischemia (ALI) and is known as "6Ps". Herein, we present the visualization of poikilothermia caused by ALI using handheld thermography. We believe that handheld thermography could be useful to assess poikilothermia objectively as a supplementary method to physical examination. PMID- 28878923 TI - A 31-year-old with idiopathic reversible cerebral vasoconstriction syndrome. AB - In our patient with reversible cerebral vasoconstriction syndrome (RCVS) syndrome, presenting with thunderclap-like headache, there is a possibility to be readily confused with migraine. Initiating treatment with selective serotonin reuptake inhibitors (SSRIs) and triptans can further aggravate the condition. Therefore, it is essential to understand the nature and type of headache and correlate the clinical findings with imaging studies. PMID- 28878924 TI - Serpentine supravenous hyperpigmentation. AB - Serpentine supravenous hyperpigmentation is a peculiar cutaneous eruption that follows the path of vein after intravenous injection of the chemotherapeutic agent. The lesions gradually resolve spontaneously if administration of the offending agent is stopped through the affected limb. Drugs such as 5 fluorouracil, docetaxel, vinorelbine, hydroxychloroquine, fotemustine, and minocycline are implicated. PMID- 28878925 TI - Severe Japanese Mamushi (Gloydius blomhoffii) bite. AB - Venomous snake bites can be life threatening, occasionally requiring intensive care. For Mamushi bites, conservative treatment may be possible in mild cases but for severe cases or in cases where symptoms do not improve, a horse-derived antivenom is indicated. PMID- 28878926 TI - What is this very big skin lesion? AB - This clinical image shows the importance of the early diagnosis and treatment of any suspicious skin lesion. PMID- 28878927 TI - Themes arising in clinical consultation for therapists implementing family-based treatment for adolescents with anorexia nervosa: a qualitative study. AB - BACKGROUND: Our study aims to explore and describe themes arising in sessions of clinical consultation with therapists implementing Family-Based Treatment (FBT) for adolescents with Anorexia Nervosa (AN). There is currently no literature describing the content of clinical consultation for FBT. Thus, this knowledge will add to the evidence-base on what therapists need from consultants in ongoing clinical consultation. METHODS: Eight therapists at four sites participated in this study, which spanned a two-year period. Following a two-day training workshop, each therapist treated at least one adolescent patient presenting with a restrictive eating disorder with FBT, focusing on adherence to the treatment manual. Clinical consultation sessions occurred monthly and were led by an external FBT expert. Thirty-five (average per site = 9) audio recorded group clinical consultation sessions were transcribed verbatim and coded for themes. Twenty percent of the transcripts were double-coded to ensure consistency. Fundamental qualitative description guided the sampling and data collection. RESULTS: Thematic content analysis revealed ten common themes relating to the provision of clinical consultation to therapists implementing FBT in clinical practice: encouraging parental meal time supervision,discussing the role of mothers, how to align parents, ensuring parental buy-in, when to transition to Phase 2, weighing the patient and the patients' knowledge of their weight, the role of siblings in FBT sessions, how best to manage patient co-morbidities, the role of the father in FBT and how best to manage the family meal. CONCLUSIONS: In conclusion, clinical consultation themes aligned with many of the central tenets of FBT, including how to help parents align their supportive approach during the refeeding process, and how to help parents assume control of eating disordered behaviours. This knowledge helps to guide consultants to anticipate common issues brought forward by therapists attempting to implement FBT. PMID- 28878928 TI - Evaluation of a guided continuous quality improvement program in community pharmacies. AB - BACKGROUND: The importance of creating and sustaining a strong culture of patient safety has been recognized as a critical component of safe medication use. This study aims to assess changes in attitudes toward patient safety culture and frequency of quality-related event (QRE) reporting after guided implementation of a continuous quality improvement (CQI) program in a panel of community pharmacies in the United States (U.S.). METHODS: Twenty-one community pharmacies volunteered to participate in the project and were randomly assigned to intervention or control groups. Pharmacy staff in the intervention group received guided training to ensure full implementation of a CQI program while those in the control group partially implemented the program. Pharmacy staff in both groups completed retrospective pre-post safety culture questionnaires and reported medication errors and near misses that occurred in their practices. Rasch analysis was applied to assess questionnaire validity and reliability and to confirm if the ordinal level data approximated interval level measures. Paired t-tests and repeated measure analysis of covariance tests were subsequently used to compare observed changes in the attitudes of subjects and frequency of QREs reporting in intervention and control groups. RESULTS: Sixty-nine employees completed the questionnaire, a 43.9% response rate. Improvement in attitudes toward patient safety was statistically significant in the intervention group in six domains: staff, training, and skill (p = 0.017); patient counseling (p = 0.043); communication about mistakes (p < 0.001); response to mistakes (p < 0.001); organizational learning - continuous improvement (p < 0.001); and overall patient safety perceptions (p = 0.033). No significant differences were observed in QRE reporting rates between intervention and control groups. However, differences were observed in the types of QREs reported (e.g., incorrect safety cap) and the point in the prescription processing workflow where a QRE was detected (e.g., partner check station, and drug utilization review station) in the intervention group (p < 0.001). CONCLUSION: Guided CQI program implementation increased the self-reported patient safety culture attitudes among staff. PMID- 28878929 TI - Antimicrobial resistance in India. PMID- 28878930 TI - Non-adherence to eye care in people with diabetes. AB - OBJECTIVE: Evaluate individual factors that impact adherence to eye care follow up in patients with diabetes. DESIGN AND METHODS: A 4-year retrospective chart review was conducted for 1968 patients with diabetes over age 40 from an urban academic center. Data collected included demographics, insurance, visual acuity, smoking status, medications, dates of dilated fundus examinations (DFE), and reported hemoglobin A1C and blood glucose levels. The primary outcome was timely DFE follow-up adherence following the initial eye exam visit. RESULTS: Overall, 41.6% of patients adhered to initial follow-up eye care recommendations. Multivariable analysis demonstrated that patients with severe diabetic retinopathy (DR) were more adherent than patients with mild DR (OR 1.86). Other variables associated with increased adherence were visual impairment and reported A1C or blood glucose. Smoking was associated with decreased adherence. Ethnicity and insurance were also significantly associated with adherence. Longitudinal follow-up rates were influenced by additional factors, including ethnicity and neighborhood deprivation index. CONCLUSIONS: Patients with moderate to severe DR and/or visual impairment were more likely to adhere to timely DFE follow-up. This could relate to the presence of visual symptoms and/or other systemic manifestations of diabetes. Smokers were less likely to adhere to timely DFE follow-up. One hypothesis is patients who smoke have other symptomatic health problems which patients prioritize over asymptomatic ocular disorders. In order to reduce vision loss from DR, practitioners should be aware that patients with mild and moderate DR, patients with normal vision, and smokers are at greater risk for poor follow-up eye care adherence. PMID- 28878931 TI - Comorbid depression and risk of lower extremity amputation in people with diabetes: systematic review and meta-analysis. AB - OBJECTIVE: To compare the risk of lower extremity amputation (LEA) in people with diabetes with and without comorbid depression. RESEARCH DESIGN AND METHODS: A systematic review of the published literature was conducted. Six databases were searched including PubMed, CINAHL, EMBASE, Medline, the Cochrane Library and PsycARTICLES from inception to 22 June 2016, using a detailed search strategy and cross-checking of reference lists for potentially eligible studies published in English. No date restrictions were employed. All studies were reviewed independently for inclusion by two review authors. Data extraction was performed using a standardized data abstraction form, and study quality was assessed independently by two reviewers. A meta-analysis was performed reporting pooled hazard ratios (HRs) and 95% CIs in Review Manager software. RESULTS: In total, seven studies were eligible for inclusion in the systematic review. Data on 767 997 patients from five studies were included in the meta-analysis. Pooled estimates across the studies were obtained using a random-effects model due to significant heterogeneity (I2=87%). People with diabetes and depression had an increased hazard of LEA (HR 1.76, 95% CI 1.19 to 2.60) compared to people with diabetes and no depression. CONCLUSIONS: Based on the available evidence, comorbid depression appears to increase the risk of LEA in people with diabetes. Limited data were available, however, with significant heterogeneity between studies. Further research is needed to inform intervention and clinical practice development in the management of diabetes. PMID- 28878932 TI - Individuals at high risk for type 2 diabetes invited to a lifestyle program: characteristics of participants versus non-participants (the HUNT Study) and 24 month follow-up of participants (the VEND-RISK Study). AB - OBJECTIVE: Prevention of type 2 diabetes mellitus is possible through lifestyle programs, but the effect depends on the program's content, resources, and setting. Lifestyle programs are often confronted with high rates of non participation and attrition. This study invited individuals at high risk for type 2 diabetes to a lifestyle program in the Norwegian primary healthcare setting. The aims were to investigate possible differences in characteristics between participants and non-participants and to study the effect of the lifestyle program at 24-month follow-up for participants. RESEARCH DESIGN AND METHODS: Individuals identified at high risk for type 2 diabetes during the third survey of the Nord-Trondelag Health Study (HUNT3) from two municipalities (n=332) were invited to a lifestyle program (the VEND-RISK Study). A cross-sectional design was used to explore if the participants' characteristics differed from non participants. A non-randomized, single-arm, pre-post examination was used to examine the effect of the lifestyle program on participants' characteristics at 24-month follow-up. RESULTS: Of all individuals at high risk for type 2 diabetes invited to the lifestyle program, 86% (287/332) declined to participate. Non participating women had fewer years of education (p<0.001), compared with participating women. For men, no differences were seen between non-participants and participants. Among all participants (n=45) at 24-month follow-up, none had developed type 2 diabetes, and HbA1c (p<0.001) had decreased significantly. There was a small reduction in mean body mass index from baseline to 24 months that was not statistically significant. For women, waist circumference (-4.0 cm, p<0.001) decreased significantly. CONCLUSIONS: Future research regarding individuals at high risk for type 2 diabetes in the primary healthcare lifestyle program should focus on how to promote recruitment of women with low education. Participants attending this study's lifestyle program improved their cardiometabolic markers. CLINICAL TRIALS REGISTRATION: NCT01135901; Results. PMID- 28878933 TI - Comparison of a 'two-bag system' versus conventional treatment protocol ('one-bag system') in the management of diabetic ketoacidosis. AB - OBJECTIVE: We compared the conventional 'one-bag protocol' of management of diabetic ketoacidosis (DKA) with the 'two-bag protocol' which utilizes two bags of fluids, one containing saline and supplemental electrolytes and the other containing the same solution with the addition of 10% dextrose. RESEARCH DESIGN AND METHODS: A retrospective chart review and analysis was done on adult patients admitted for DKA to the Riverside University Health System Medical Center from 2008 to 2015. There were 249 cases of DKA managed by the one-bag system and 134 cases managed by the two-bag system. RESULTS: The baseline patient characteristics were similar in both groups. The anion gap closed in 13.56 hours in the one-bag group versus 10.94 hours in the two-bag group (p value <0.0002). None of the individual factors significantly influenced the anion gap closure time; only the two-bag system favored earlier closure of the anion gap. Plasma glucose levels improved to <250 mg/dL earlier with two-bag protocol (9.14 vs 7.82 hours, p=0.0241). The incidence of hypoglycemic events was significantly less frequent with the two-bag protocol compared with the standard one-bag system (1.49% vs 8.43%, p=0.0064). Neither the time to improve serum HCO3 level >18 mg/dL nor the hospital length of stay differed between the two groups. CONCLUSIONS: Our study indicates that the two-bag protocol closes the anion gap earlier than the one-bag protocol in adult patients with DKA. Blood glucose levels improved faster with the two-bag protocol compared with the one-bag protocol with fewer associated episodes of hypoglycemia. Prospective studies are needed to evaluate the clinical significance of these findings. PMID- 28878934 TI - Postauthorization safety study of the DPP-4 inhibitor saxagliptin: a large-scale multinational family of cohort studies of five outcomes. AB - OBJECTIVE: To evaluate the risk of serious adverse events among patients with type 2 diabetes mellitus initiating saxagliptin compared with oral antidiabetic drugs (OADs) in classes other than dipeptidyl peptidase-4 (DPP-4) inhibitors. RESEARCH DESIGN AND METHODS: Cohort studies using 2009-2014 data from two UK medical record data sources (Clinical Practice Research Datalink, The Health Improvement Network) and two USA claims-based data sources (HealthCore Integrated Research Database, Medicare). All eligible adult patients newly prescribed saxagliptin (n=110 740) and random samples of up to 10 matched initiators of non DPP-4 inhibitor OADs within each data source were selected (n=913 384). Outcomes were hospitalized major adverse cardiovascular events (MACE), acute kidney injury (AKI), acute liver failure (ALF), infections, and severe hypersensitivity events, evaluated using diagnostic coding algorithms and medical records. Cox regression was used to determine HRs with 95% CIs for each outcome. Meta-analyses across data sources were performed for each outcome as feasible. RESULTS: There were no increased incidence rates or risk of MACE, AKI, ALF, infection, or severe hypersensitivity reactions among saxagliptin initiators compared with other OAD initiators within any data source. Meta-analyses demonstrated a reduced risk of hospitalization/death from MACE (HR 0.91, 95% CI 0.85 to 0.97) and no increased risk of hospitalization for infection (HR 0.97, 95% CI 0.93 to 1.02) or AKI (HR 0.99, 95% CI 0.88 to 1.11) associated with saxagliptin initiation. ALF and hypersensitivity events were too rare to permit meta-analysis. CONCLUSIONS: Saxagliptin initiation was not associated with increased risk of MACE, infection, AKI, ALF, or severe hypersensitivity reactions in clinical practice settings. TRIAL REGISTRATION NUMBER: NCT01086280, NCT01086293, NCT01086319, NCT01086306, and NCT01377935; Results. PMID- 28878936 TI - Primary care physicians' utilization of type 2 diabetes screening guidelines and referrals to behavioral interventions: a survey-linked retrospective study. AB - OBJECTIVE: To assess primary care physicians' (PCPs) knowledge of type 2 diabetes screening guidelines (American Diabetes Association (ADA) and 2008 US Preventive Services Task Force (USPSTF)), the alignment between their self-reported adherence and actual practice, and how often PCPs recommended diabetes prevention and self-management education programs (DPP/DSME). RESEARCH DESIGN AND METHODS: An online survey of PCPs to understand knowledge and adherence toward use of USPSTF/ADA guidelines and recommendation of DPP/DSME. Patient data from electronic medical records (EMRs) for each PCP were used to identify rates of screening in eligible patients as per guidelines and the two sources were compared to assess concordance. RESULTS: Of 305 surveyed physicians, 38% reported use of both guidelines (33% use ADA only, 25% USPSTF only). Approximately one third of physicians who reported use of USPSTF/ADA guidelines had non-concordant EMR data. Similarly, while most PCPs reported they are 'very likely' to screen patients with risk factors listed in guidelines, for each criterion at least one fourth (24%) of PCPs survey responses were non-concordant with EMRs. PCPs reported they provide referral to DPP and DSME on average to 45% and 67% of their newly diagnosed patients with pre-diabetes and diabetes, respectively. CONCLUSION: Findings show disconnect between PCPs' perceptions of adherence to screening guidelines and actual practice, and highlight limited referrals to DPP/DSME programs. More research is needed to understand barriers to guideline consistent screening and uptake of DPP/DSME, particularly in light of recent policy changes such as the linking USPSTF criteria to reimbursement and expected Medicare DPP reimbursement in 2018. PMID- 28878935 TI - Elevated incidence rates of diabetes in Peru: report from PERUDIAB, a national urban population-based longitudinal study. AB - OBJECTIVE: A recent report from a non-nationally representative, geographically diverse sample in four separate communities in Peru suggests an unusually high diabetes incidence. We aimed to estimate the national diabetes incidence rate using PERUDIAB, a probabilistic, national urban population-based longitudinal study. RESEARCH DESIGN AND METHODS: 662 subjects without diabetes, selected by multistage, cluster, random sampling of households, representing the 24 administrative and the 3 (coast, highlands and jungle) natural regions across the country, from both sexes, aged 25+ years at baseline, enrolled in 2010-2012, were followed for 3.8 years. New diabetes cases were defined as fasting blood glucose >=126 mg/dL or on medical diabetes treatment. RESULTS: There were 49 cases of diabetes in 2408 person-years follow-up. The weighted cumulative incidence of diabetes was 7.2% while the weighted incidence rate was estimated at 19.5 (95% CI 13.9 to 28.3) new cases per 1000 person-years. Older age, obesity and technical or higher education were statistically associated with the incidence of diabetes. CONCLUSION: Our results confirm that the incidence of diabetes in Peru is among the highest reported globally. The fast economic growth in the last 20 years, high overweight and obesity rates may have triggered this phenomenon. PMID- 28878937 TI - Contrast sensitivity to spatial gratings in moderate and dim light conditions in patients with diabetes in the absence of diabetic retinopathy. AB - OBJECTIVE: To evaluate the ability of contrast sensitivity (CS) to discriminate loss of visual function in diabetic subjects with no clinical signs of retinopathy relative to that of normal subjects. RESEARCH DESIGN AND METHODS: In this prospective cross-sectional study, we measured CS in 46 diabetic subjects with a mean age of 48+/-6 years, a best-corrected visual acuity of 20/20 and no signs of diabetic retinopathy. The CS in these subjects was compared with CS measurements in 46 normal control subjects at four spatial frequencies (3, 6, 12, 18 cycles per degree) under moderate (500 lux) and dim (less than 2 lux) background light conditions. RESULTS: CS was approximately 0.16 log units lower in patients with diabetes relative to controls both in moderate and in dim background light conditions. Logistic regression classification and receiver operating characteristic curve analysis indicated that CS analysis using two light conditions was more accurate (0.78) overall compared with CS analysis using only a single illumination condition (accuracy values were 0.67 and 0.70 in moderate and dim light conditions, respectively). CONCLUSIONS: Our results showed that patients with diabetes without clinical signs of retinopathy exhibit a uniform loss in CS at all spatial frequencies tested. Measuring the loss in CS at two spatial frequencies (3 and 6 cycles per degree) and two light conditions (moderate and dim) is sufficiently robust to classify diabetic subjects with no retinopathy versus control subjects. PMID- 28878939 TI - Insulin-sensitive and insulin-resistant obese and non-obese phenotypes: role in prediction of incident pre-diabetes in a longitudinal biracial cohort. AB - OBJECTIVE: We measured insulin sensitivity with euglycemic clamp (Si-clamp) in initially normoglycemic African Americans (AA) and European Americans (EA), to probe the existence of subphenotypes of obesity and leanness, and their impact on incident dysglycemia during longitudinal follow-up. RESEARCH DESIGN AND METHODS: 320 healthy subjects (176 AA, 144 EA; mean age 44.2+/-10.6 years) underwent baseline assessments, including Si-clamp and homeostasis model of insulin resistance (HOMA-IR) and were stratified into: insulin-resistant obese (IRO) (body mass index (BMI) >30 kg/m2, Si-clamp <0.1, HOMA-IR >2.5); insulin-sensitive obesity (ISO) (BMI >30 kg/m2, Si-clamp >0.1, HOMA-IR <2.5); insulin-resistant non obese (IRN) (BMI <28 kg/m2, Si-clamp <0.1, HOMA-IR >2.5); insulin-sensitive non obese (ISN) (BMI <28 kg/m2, Si-clamp >0.1, HOMA-IR <2.5). Outcome measures were cardiometabolic risks and incident pre-diabetes/type 2 diabetes (T2D) during 5.5 years. RESULTS: Compared with IRO, subjects with ISO had lower abdominal fat, triglycerides and high-sensitivity C reactive protein and higher adiponectin (p=0.015 to <0.0001). IRN subjects had higher cardiometabolic risk markers than ISN (p=0.03 to <0.0001). During 5.5-year follow-up, incident pre-diabetes/T2D was lower in ISO (31.3% vs 48.7%) among obese subjects and higher in IRN (47.1% vs. 26.0%) among non-obese subjects (p=0.0024). Kaplan-Meier analysis showed significantly different pre-diabetes/T2D survival probabilities across insulin sensitivity/adiposity phenotypes (p=0.0001). CONCLUSIONS: Insulin sensitivity predicts ~40% decrease in the relative risk of incident pre-diabetes/T2D among obese persons, whereas insulin resistance predicts ~80% increased risk among non obese persons. This is the first documentation of healthy and unhealthy phenotypes of obesity and leanness in a prospective biracial cohort, using rigorous measurement of insulin sensitivity. PMID- 28878938 TI - Presentation, pathology and prognosis of renal disease in type 2 diabetes. AB - OBJECTIVE: Non-diabetic renal disease (NDRD) is common in patients with type 2 diabetes (T2D), but the relationship between its presentation and prognosis is unknown. RESEARCH DESIGN AND METHODS: In a retrospective cohort study, we compared renal and patient survival among 263 patients with T2D who had native renal biopsies between 2002 and 2008 from three Auckland hospitals in New Zealand. The presence of diabetic nephropathy (DN), NDRD or mixed (DN and NDRD) was determined from biopsy. We examined clinical associations according to NDRD etiologies and mode of presentation-acute (defined by acute kidney injury (AKI)) or non-acute. Patients were followed until end-stage renal disease, death or December 2015. Survival was compared using Log-rank test. RESULTS: 94 (36%) patients had DN, 72 (27%) had NDRD, and 97 (37%) had mixed pathologies. Obesity related focal segmental glomerulosclerosis was the most common NDRD (46%) in patients with non-acute presentations, whereas interstitial nephritis or immune complex glomerulonephritides were the most prevalent in those with acute presentations (60%). DN was commonly associated with AKI (p<0.001). The prevalence of DN increased with diabetes duration (p<0.001), but NDRD was still found in 55% of subjects with >=14 years T2D. NDRD was strongly associated with the absence of retinopathy (p<0.001). Renal survival was best in the NDRD group (p<0.001). Among those with DN, renal prognosis was worse in those with more advanced DN lesions and those with an acute presentation (p<0.001). The proportion of all-cause mortality was similar in all three groups, but overall survival was poorest in the DN group (p=0.025). CONCLUSIONS: Renal disease in patients with T2D is heterogeneous. The renal prognosis differs markedly according to histopathological diagnosis and mode of presentation. PMID- 28878940 TI - Ethnic differences in early glycemic control in childhood-onset type 1 diabetes. AB - : Some ethnic minorities with type 1 diabetes (T1D) have worse glycemic control (higher glycated hemoglobin (HbA1c)) and increased risk for vascular complications. There is limited evidence on the impact of ethnicity on early glycemic control when most patients experience transient remission postdiagnosis. We examined associations between ethnicity and longitudinal HbA1c trajectories during the first 6 months postdiagnosis in a multiethnic cohort in East London. RESEARCH DESIGN AND METHODS: Data on 443 (50% female) children <19 years of age, with T1D and attending one of three clinics in East London between January 2005 and December 2015 were included. Linear mixed-effects modeling was used to assess ethnic differences in longitudinal HbA1c trajectories during the first 6 months postdiagnosis (1,028 HbA1c data points), adjusting for sex, age at diagnosis, socioeconomic status and pH at diagnosis. Growth curve modeling was used to plot discrete HbA1c trajectories by ethnicity. RESULTS: Longitudinal modeling revealed that all ethnic minorities had higher mean HbA1c at diagnosis compared with White children and highest in Bangladeshi (9.7 mmol/mol, 95% CI 5.1 to 14.3), Asian Other (5.8 mmol/mol, 95% CI 2.2 to 9.3) and Somali (5.2 mmol/mol, 95% CI 0.1 to 10.2) children, and these differences persisted over the 6-month period after diagnosis. During the first month, HbA1c decreased on average by 19.6 mmol/mol (95% CI -21 to -18) for all children. Population averaged HbA1c decreased between diagnosis and 4 months, followed by a gradual increase in HbA1c levels (mean difference of -30 mmol/mol between diagnosis and 6 months). CONCLUSIONS: Ethnic minorities present with higher HbA1c at diagnosis, with the largest mean differences observed in Bangladeshi, Asian-Other and Somali children. These higher levels (indicating poorer glycemic control) track into the first 6 months postdiagnosis. PMID- 28878941 TI - Clinical profiles, comorbidities and complications of type 2 diabetes mellitus in patients from United Arab Emirates. AB - OBJECTIVE: To assess clinical profiles of patients with type 2 diabetes in the United Arab Emirates (UAE), including patterns, frequencies, and risk factors of microvascular and macrovascular complications. RESEARCH DESIGN AND METHODS: Four hundred and ninety patients with type 2 diabetes were enrolled from two major hospitals in Abu Dhabi. The presence of microvascular and macrovascular complications was assessed using logistic regression, and demographic, clinical and laboratory data were collected. Significance was set at p<0.05. RESULTS: Hypertension (83.40%), obesity (90.49%) and dyslipidemia (93.43%) were common type 2 diabetes comorbidities. Most of the patients had relatively poor glycemic control and presented with multiple complications (83.47% of patients had one or more complication), with frequent renal involvement. The most frequent complication was retinopathy (13.26%). However, the pattern of complications varied based on age, where in patients <65 years, a single pattern presented, usually retinopathy, while multiple complications was typically seen in patients >65 years old. Low estimated glomerular filtration rate in combination with disease duration was the most significant risk factor in the development of a diabetic-associated complication especially for coronary artery disease, whereas age, lipid values and waist circumference were significantly associated with the development of diabetic retinopathy. CONCLUSIONS: Patients with type 2 diabetes mellitus in the UAE frequently present with comorbidities and complications. Renal disease was found to be the most common comorbidity, while retinopathy was noted as the most common diabetic complication. This emphasizes the need for screening and prevention program toward early, asymptomatic identification of comorbidities and commence treatment, especially for longer disease duration. PMID- 28878942 TI - Medication adherence and glycemic control among newly diagnosed diabetes patients. AB - BACKGROUND: Poor medication adherence can have negative consequences for the patients, the provider, the physician, and the sustainability of the healthcare system. To our knowledge, the association between medication adherence and glycemic control among newly diagnosed diabetes patients has not been studied. This study aims to bridge the gap. METHOD: This is a retrospective cohort study of 2463 patients managed in the National Healthcare Group in Singapore with newly diagnosed diabetes. Patients were followed up for the first two years from their first medication dispensed for measuring medication adherence, proportion of days covered (PDC); and for another three years for investigating outcomes of glycemic control, emergency department visit, and hospitalization. Multivariable regressions were performed to study the association between medication adherence and the outcomes as well as the risk factors of poor adherence. RESULTS: The prevalence of medication adherence (PDC>=80%) was 65.0% (95% CI 63.1% to 66.9%) among newly diagnosed diabetes patients in Singapore. Male, Indian, or patients without hypertension or dyslipidemia were associated with poorer medication adherence. The HbA1c level of poor adherent patients (PDC <40%) increased by 0.4 (95% CI 0.2 to 0.5) over the two years, and they were also more likely to have hospitalization (OR 2.6,95% CI 1.7 to 3.8) or emergency department visit (OR 2.4,95% CI 1.7 to 3.4) compared with the fully adherent patients (PDC=100%). CONCLUSIONS: The medication adherence in the early stage of diabetes is important for maximizing the effectiveness of pharmaceutical therapy. Health policies or interventions targeting the improvement of medication adherence among newly diagnosed diabetes patients are in need. PMID- 28878943 TI - Obstructive sleep apnea in adults with type 1 and type 2 diabetes: perspectives from a quality improvement initiative in a university-based diabetes center. AB - OBJECTIVE: Obstructive sleep apnea (OSA) and diabetes are frequent comorbid conditions. Screening for OSA in patients with diabetes is recommended but the frequency with which this is done in clinical practice is unknown. The objectives of this quality improvement initiative were to identify clinician and patient perceptions regarding OSA and to identify the prevalence of patients at high risk for OSA (HROSA). METHODS: A quality improvement initiative was conducted to query clinicians and patients attending a specialty diabetes clinic regarding attitudes and beliefs related to OSA. The Berlin Questionnaire was embedded in patient questionnaires to identify patients as low risk for OSA (LROSA) or HROSA. RESULTS: 35 clinicians completed questionnaires with >80% agreement that OSA contributed to blood pressure (BP), glycemic control, and diabetes complications and that screening is a shared responsibility with other physicians; but only 17% indicated regular screening due predominantly to insufficient time. Of 107 patients (26 type 1 diabetes mellitus (T1DM) and 81 type 2 diabetes mellitus (T2DM)), 30% were aware that OSA could affect diabetes outcomes. The prevalence of known OSA, LROSA, and HROSA was similar in T1DM (15%, 50%, 35%) and T2DM (36%, 33%, 31%, respectively) (p=0.21). 59% of all HROSA patients indicated that OSA screening had never been discussed with them. CONCLUSIONS: These results demonstrate that providers, but not patients, are knowledgeable about the importance of OSA screening, but insufficient time is a major barrier to wider screening. Approximately, 30% of patients with T1DM and T2DM were identified as HROSA supporting the need for procedures that improve detection and treatment. PMID- 28878944 TI - Development and validation of a clinical risk score to predict mortality after percutaneous coronary intervention. AB - OBJECTIVE: To develop and validate a contemporary clinical risk score to predict mortality after percutaneous coronary intervention (PCI). METHODS: Using data collected from patients undergoing PCI at the South Yorkshire Cardiothoracic Centre, Sheffield, UK, between January 2007 and September 2013, a risk score was developed to predict mortality. Logistic regression was used to evaluate the effect of each variable upon 30-day mortality. A backwards stepwise logistic regression model was then used to build a predictive model. The results were validated both internally and externally with data from Manchester Royal Infirmary, UK. 30-Day mortality status was determined from the UK Office of National Statistics. RESULTS: The development data set comprised 6522 patients from Sheffield. Five risk factors, including cardiogenic shock, procedural urgency, history of renal disease, diabetes mellitus and age, were statistically significant to predict 30-day mortality. The risk score was validated internally on a further 3290 patients from Sheffield and externally on 3230 patients from Manchester. The discrimination of the model was high in the development (C statistic=0.82, 95% CI 0.79 to 0.85), internal (C-statistic=0.81, 95% CI 0.76 to 0.86) and external (C statistics=0.90, 95% CI 0.87 to 0.93) cohorts. There was no significant difference between observed and predicted mortality in any group. CONCLUSION: This contemporary risk score reliably predicts 30-day mortality after PCI using a small number of clinical variables obtainable prior to the procedure, without knowledge of the coronary anatomy. PMID- 28878945 TI - Gated metabolic myocardial imaging, a surrogate for dual perfusion-metabolism imaging by positron emission tomography. AB - OBJECTIVE: Perfusion-metabolism mismatch pattern on positron emission tomography (PET) predicts hibernating myocardium. We assess the ECG-gated metabolic PET as a surrogate for the perfusion-metabolism mismatch pattern on PET imaging. METHODS: 13N-Ammonia (NH3) and 18F-fluorodeoxyglucose (FDG) are respectively perfusion and metabolism PET tracers. We used ECG gating to acquire FDG-PET to collect wall thickening (mechanical) data. These allow detection of metabolic activity in regions with reduced contraction (metabolism-mechanical mismatch pattern). We had two data sets on each patient: perfusion-metabolism and metabolism-mechanical data sets. We tested the hypothesis that metabolism-mechanical pattern on PET could predict perfusion-metabolism mismatch pattern. RESULTS: We studied 55 patients (48 males), mean age 62 years. All were in sinus rhythm, and had impaired left ventricular contraction. Perfusion-metabolism mismatch pattern was found in 26 patients. Metabolism-mechanical mismatch pattern was found in 25 patients. The results were concordant in 52 patients (95%). As a surrogate for perfusion-metabolism mismatch pattern, demonstration of metabolism-mechanical mismatch pattern is highly sensitive (92%) and specific (97%). In this cohort, the positive and negative predictive accuracy of the new method are 96% and 93%, respectively. CONCLUSION: Metabolism-mechanical mismatch pattern could predict perfusion-metabolism mismatch pattern in patients with myocardial viability criteria on PET. Prospective validation against the gold standard of improved myocardial contraction after revascularisation is needed. PMID- 28878947 TI - The importance of early life family factors in the association between cardiovascular risk factors and early cardiovascular mortality. AB - OBJECTIVE: To explore the importance of early life factors shared by siblings, such as parental socioeconomic position, parental practices, housing and neighbourhood, for the association between cardiovascular disease (CVD) risk factors and mortality from CVD, ischaemic heart disease (IHD) and cerebrovascular disease. METHODS: Norwegian health surveys (1974-2003) were linked with data from the Norwegian Family Based Life Course Study and the Cause of Death Registry. Participants with at least one full sibling among survey participants (n=2 71 643) were included. Data on CVD risk factors, body mass index (BMI), height, systolic blood pressure (SBP) and total cholesterol (TC) were stratified into 'low', 'medium' and 'high' risk, and smoking to 'daily smoking' and 'not daily smoking'. RESULTS: Mean age of participants was 41 years, mean follow-up time was 19 years and during follow-up 2512 died from CVD. For each category of increased risk factor level, the per step HR of CVD mortality was increased by 1.91 (95% CI 1.78 to 2.05) for SBP, 1.67 (1.58 to 1.76) for TC, 1.44 (1.36 to 1.53) for BMI, 1.26 (1.18 to 1.35) for height and 2.89 (2.66 to 3.14) for smoking. In analyses where each sibship (groups of full siblings) had a group-specific baseline hazard, these associations were attenuated to 1.74, 1.51, 1.29, 1.18 and 2.63, respectively. The associations between risk factors and IHD mortality followed the same pattern. CONCLUSION: Early life family factors explained a small part of the association between risk factors and mortality from CVD and IHD in a relatively young sample. PMID- 28878946 TI - Supplemental N-acetylcysteine and other measures that boost intracellular glutathione can downregulate interleukin-1beta signalling: a potential strategy for preventing cardiovascular events? PMID- 28878948 TI - The impact of passive and active smoking on inflammation, lipid profile and the risk of myocardial infarction. AB - OBJECTIVE: To investigate the effect of passive smoking, active smoking and smoking cessation on inflammation, lipid profile and the risk of myocardial infarction (MI). METHODS: A total of 423 cases with a first MI and 465 population controls from the Maltese Acute Myocardial Infarction (MAMI) Study were analysed. Data were collected through an interviewer-led questionnaire, and morning fasting blood samples were obtained. ORs adjusted for the conventional risk factors of MI (aORs) were calculated as an estimate of the relative risk of MI. The influence of smoking on biochemical parameters was determined among controls. RESULTS: Current smokers had a 2.7-fold (95% CI 1.7 to 4.2) and ex-smokers a 1.6-fold (95% CI 1.0 to 2.4) increased risk of MI. Risk increased with increasing pack-years and was accompanied by an increase in high-sensitivity C reactive protein levels and an abnormal lipid profile. Smoking cessation was associated with lower triglyceride levels. Exposure to passive smoking increased the risk of MI (aOR 3.2 (95% CI 1.7 to 6.3)), with the OR being higher for individuals exposed to passive smoking in a home rather than in a public setting (aOR 2.0 (95% CI 0.7 to 5.6) vs aOR 1.2 (95% CI 0.7 to 2.0)). Passive smoke exposure was associated with higher levels of total cholesterol, triglycerides and total cholesterol:high density lipoprotein cholesterol ratio compared with individuals not exposed to passive smoking. CONCLUSIONS: Both active and passive smoking are strong risk factors for MI. This risk increased with increasing pack-years and decreased with smoking cessation. Such effects may be partly mediated through the influence of smoking on inflammation and lipid metabolism. PMID- 28878949 TI - Association of Life's Simple 7 and presence of cardiovascular disease in general Australians. AB - OBJECTIVE: The American Heart Association developed Life's Simple 7 to define and monitor cardiovascular health (CVH), but their contributions to cardiovascular disease (CVD) in general Australians are still unclear. Our study aimed to evaluate the separate and combined effects of Life's Simple 7 on CVD among Australians. METHODS: We performed a cross-sectional study based on 7499 adults (>=18 years) who have been tested for total cholesterol and fasting plasma glucose as part of the 2011-2012 Australian Health Survey. Poisson regression analyses were used to estimate the incidence rate ratios and population attributable fractions of those metrics to CVD prevalence. Participants were classified into three CVH status groups based on the number of ideal metrics: inadequate (0-2), average (3-4) and optimal (5-7). Logistic regression analyses were performed to illustrate the relationships between overall CVH and CVD prevalence. RESULTS: 2100 (21.0%) participants were having CVD. Smoking, elevated body mass index, blood pressure, total cholesterol, fasting plasma glucose and physical inactivity were observed as significant indicators of CVD. Compared with the inadequate category, participants in the optimal and average category have a 66% (adjusted OR, 0.34; 95% CI 0.22 to 0.54) and a 33% (adjusted OR, 0.67; 95% CI 0.56 to 0.81) lower CVD risk. One more ideal metric was associated with a 21% reduced CVD risk (adjusted OR, 0.79; 95% CI 0.73 to 0.84). CONCLUSIONS: We have identified several modifiable risk factors and contributors of CVD in general Australians. The improvement of overall CVH may also reduce CVD risk. PMID- 28878950 TI - Exercise dose and all-cause mortality within extended cardiac rehabilitation: a cohort study. AB - AIMS: To investigate the relationship between exercise participation, exercise 'dose' expressed as metabolic equivalent (MET) hours (h) per week, and prognosis in individuals attending an extended, community-based exercise rehabilitation programme. METHODS: Cohort study of 435 participants undertaking exercise-based cardiac rehabilitation (CR) in Leeds, West Yorkshire, UK between 1994 and 2006, followed up to 1 November 2013. MET intensity of supervised exercise was estimated utilising serial submaximal exercise test results and corresponding exercise prescriptions. Programme participation was routinely monitored. Cox regression analysis including time-varying and propensity score adjustment was applied to identify predictors of long-term, all-cause mortality across exercise dose and programme duration groups. RESULTS: There were 133 events (31%) during a median follow-up of 14 years (range, 1.2 to 18.9 years). The significant univariate association between exercise dose and all-cause mortality was attenuated following multivariable adjustment for other predictors, including duration in the programme. Longer-term adherence to supervised exercise training (>36 months) was associated with a 33% lower mortality risk (multivariate adjusted HR: 0.67; 95% CI: 0.47 to 0.97; p=0.033) compared with all lesser durations of CR (3, 12, 36 months), even after adjustment for baseline fitness, comorbidities and survivor bias. CONCLUSION: Exercise dose (MET-h per week) appears less important than long-term adherence to supervised exercise for the reduction of long-term mortality risk. Extended, supervised CR programmes within the community may play a key role in promoting long-term exercise maintenance and other secondary prevention therapies for survival benefit. PMID- 28878951 TI - High-pitch versus conventional cardiovascular CT in patients being assessed for transcatheter aortic valve implantation: a real-world appraisal. AB - OBJECTIVE: High-pitch protocols are increasingly used in cardiovascular CT assessment for transcatheter aortic valve implantation (TAVI), but the impact on diagnostic image quality is not known. METHODS: We reviewed 95 consecutive TAVI studies: 44 (46%) high-pitch and 51 (54%) standard-pitch. Single high-pitch scans were performed regardless of heart rate. For standard-pitch acquisitions, a separate CT-aortogram and CT-coronary angiogram were performed with prospective gating, unless heart rate was >=70 beats/min, when retrospective gating was used. The aortic root and coronary arteries were assessed for artefact (significant artefact=1; artefact not limiting diagnosis=2; no artefact=3). Aortic scans were considered diagnostic if the score was >1; the coronaries, if all three epicardial arteries scored >1. RESULTS: There was no significant difference in diagnostic image quality for either the aorta (artefact-free high-pitch: 31 (73%) scans vs standard-pitch: 40 (79%), p=0.340) or the coronary tree as a whole (10 (23%) vs 15 (29%), p=0.493). However, proximal coronary arteries were less well visualised using high-pitch acquisitions (16 (36%) vs 30 (59%), p=0.04). The median (IQR) radiation dose was significantly lower in the high-pitch cohort (dose-length product: 347 (318-476) vs 1227 (1150-1474) mGy cm, respectively, p<0.001), and the protocol required almost half the amount of contrast. CONCLUSIONS: The high-pitch protocol significantly reduces radiation and contrast doses and is non-inferior to standard-pitch acquisitions for aortic assessment. For aortic root assessment, the high-pitch protocol is recommended. However, if coronary assessment is critical, this should be followed by a conventional standard-pitch, low-dose, prospectively gated CT-coronary angiogram if the high pitch scan is non-diagnostic. PMID- 28878952 TI - Pathophysiology of exercise intolerance in chronic diseases: the role of diminished cardiac performance in mitochondrial and heart failure patients. AB - OBJECTIVE: Exercise intolerance is a clinical hallmark of chronic conditions. The present study determined pathophysiological mechanisms of exercise intolerance in cardiovascular, neuromuscular, and metabolic disorders. METHODS: In a prospective cross-sectional observational study 152 patients (heart failure reduced ejection fraction, n=32; stroke, n=34; mitochondrial disease, n=28; type two diabetes, n=28; and healthy controls, n=30) performed cardiopulmonary exercise testing with metabolic and haemodynamic measurements. Peak exercise O2 consumption and cardiac power output were measures of exercise tolerance and cardiac performance. RESULTS: Exercise tolerance was significantly diminished in patients compared with controls (ie, by 45% stroke, 39% mitochondria disease, and 33% diabetes and heart failure, p<0.05). Cardiac performance was only significantly reduced in heart failure (due to reduced heart rate, stroke volume, and blood pressure) and mitochondrial patients (due reduced stroke volume) compared with controls (ie, by 53% and 26%, p<0.05). Ability of skeletal muscles to extract oxygen (ie, arterial venous O2 difference) was diminished in mitochondrial, stroke, and diabetes patients (by 24%, 22%, and 18%, p<0.05), but increased by 21% in heart failure (p<0.05) compared with controls. Cardiac output explained 65% and 51% of the variance in peak O2 consumption (p<0.01) in heart failure and mitochondrial patients, whereas arterial-venous O2 difference explained 69% (p<0.01) of variance in peak O2 consumption in diabetes, and 65% and 48% in stroke and mitochondrial patients (p<0.01). CONCLUSIONS: Different mechanisms explain exercise intolerance in patients with heart failure, mitochondrial dysfunction, stroke and diabetes. Their better understanding may improve management of patients, their stress tolerance and quality of life. PMID- 28878953 TI - Extracellular cardiac matrix biomarkers in patients with reduced ejection fraction heart failure as predictors of response to cardiac resynchronisation therapy: a systematic review. AB - OBJECTIVE: Cardiac resynchronisation therapy (CRT) is an effective therapy for selected patients with heart failure (HF); however, a significant non-response rate exists. We examined current evidence on extracellular cardiac matrix (ECM) biomarkers in predicting response following CRT. METHODS: Complete literature review of PubMed, Ovid SP MEDLINE, Cochrane Library and TRIP, reference lists, international cardiology conferences and ongoing studies between December 1999 and December 2015 conducted according to prospectively registered study selection and analysis criteria (PROSPERO:CRD42016025864) was performed. All observational and randomised control trials (RCT) were included if they tested prespecified ECM biomarkers' ability to predict CRT response. Risk of bias assessment and data extraction determined pooling of included studies was not feasible due to heterogeneity of the selected studies. RESULTS: A total of 217 studies were screened; six (five prospective cohort and one RCT substudy) were included in analysis with 415 participants in total. Study sizes varied (n=55-260), cohort characteristics contrasted (male: 67.8%-83.6%, ischaemic aetiology: 40.2%-70.3%) and CRT response definitions differed (three clinical/functional, three echocardiographic). Consistent observation in all ECM biomarker behaviour before and after CRT implantation was not observed between studies. Lower type I and type III collagen synthesis biomarkers (N-terminal propeptides of type I and III procollagens) expression demonstrated replicated ability to predict reverse left ventricular remodelling. CONCLUSION: Collagen synthesis biomarkers offer the most potential as ECM biomarkers for predicting CRT response. Heterogeneity between these studies was large and limited the ability to pool and compare results numerically. Use of different response definitions was one of the biggest challenges. PMID- 28878954 TI - Brainstem dermoid cyst rupture with hydrocephalus in a child. AB - Intracranial dermoid cysts are ectodermal lesions of embryological origin. They are of slow progression and symptoms associated with unruptured cysts are most commonly due to mass effect. However, a potential rupture in the ventricular system is rare and can cause meningitis, seizures and hydrocephalus. Hereby, we report a case of a 12-year-old boy presenting with obstructive hydrocephalus due to brainstem dermoid cyst rupture. PMID- 28878955 TI - Chimpanzees recognize their own delayed self-image. AB - Unlike mirror self-recognition, recognizing one's own image in delayed video footage may indicate the presence of a concept of self that extends across time and space. While humans typically show this ability around 4 years of age, it is unknown whether this capacity is found in non-human animals. In this study, chimpanzees performed a modified version of the mark test to investigate whether chimpanzees could remove stickers placed on the face and head while watching live and delayed video images. The results showed that three of five chimpanzees consistently removed the mark in delayed-viewing conditions, while they removed the stickers much less frequently in control video conditions which lacked a link to their current state. These findings suggest that chimpanzees, like human children at the age of 4 years and more, can comprehend temporal dissociation in their concept of self. PMID- 28878956 TI - Object recognition and localization from 3D point clouds by maximum-likelihood estimation. AB - We present an algorithm based on maximum-likelihood analysis for the automated recognition of objects, and estimation of their pose, from 3D point clouds. Surfaces segmented from depth images are used as the features, unlike 'interest point'-based algorithms which normally discard such data. Compared to the 6D Hough transform, it has negligible memory requirements, and is computationally efficient compared to iterative closest point algorithms. The same method is applicable to both the initial recognition/pose estimation problem as well as subsequent pose refinement through appropriate choice of the dispersion of the probability density functions. This single unified approach therefore avoids the usual requirement for different algorithms for these two tasks. In addition to the theoretical description, a simple 2 degrees of freedom (d.f.) example is given, followed by a full 6 d.f. analysis of 3D point cloud data from a cluttered scene acquired by a projected fringe-based scanner, which demonstrated an RMS alignment error as low as 0.3 mm. PMID- 28878957 TI - Control mechanisms for stochastic biochemical systems via computation of reachable sets. AB - Controlling the behaviour of cells by rationally guiding molecular processes is an overarching aim of much of synthetic biology. Molecular processes, however, are notoriously noisy and frequently nonlinear. We present an approach to studying the impact of control measures on motifs of molecular interactions that addresses the problems faced in many biological systems: stochasticity, parameter uncertainty and nonlinearity. We show that our reachability analysis formalism can describe the potential behaviour of biological (naturally evolved as well as engineered) systems, and provides a set of bounds on their dynamics at the level of population statistics: for example, we can obtain the possible ranges of means and variances of mRNA and protein expression levels, even in the presence of uncertainty about model parameters. PMID- 28878959 TI - Influence of tangential displacement on the adhesion strength of a contact between a parabolic profile and an elastic half-space. AB - The adhesion strength of a contact between a rotationally symmetric indenter and an elastic half-space is analysed analytically and numerically using an extension of the method of dimensionality reduction for superimposed normal/tangential adhesive contacts. In particular, the dependence of the critical adhesion force on the simultaneously applied tangential force is obtained and the relevant dimensionless parameters of the problem are identified. The fracture criterion used coincides with that suggested by Johnson. In this paper, it is used to develop a method that is applicable straightforwardly to adhesive contacts of arbitrary bodies of revolution with compact contact area. PMID- 28878958 TI - Tumour heterogeneity promotes collective invasion and cancer metastatic dissemination. AB - Heterogeneity within tumour cell populations is commonly observed in most cancers. However, its impact on metastatic dissemination, one of the primary determinants of the disease prognosis, remains poorly understood. Working with a simplified numerical model of tumour spheroids, we investigated the impact of mechanical heterogeneity on the onset of tumour invasion into surrounding tissues. Our work establishes a positive link between tumour heterogeneity and metastatic dissemination, and recapitulates a number of invasion patterns identified in vivo, such as multicellular finger-like protrusions. Two complementary mechanisms are at play in heterogeneous tumours. A small proportion of stronger cells are able to initiate and lead the escape of cells, while collective effects in the bulk of the tumour provide the coordination required to sustain the invasive process through multicellular streaming. This suggests that the multicellular dynamics observed during metastasis is a generic feature of mechanically heterogeneous cell populations and might rely on a limited and generic set of attributes. PMID- 28878960 TI - Eversion and withdrawal of an intromittent organ before sexual maturation prepares male beetles for copulation. AB - Some species of criocerine beetles have a hyper-elongated part of the intromittent organ called a flagellum. In resting position, the flagellum is stored in a specialized internal sac in the intromittent organ. This specialized state of the flagellum and internal sac is indispensable during copulation for flagellar insertion into the female spermathecal duct for sperm transfer. However, the morphogenesis of the flagellum does not generate the active state of the flagellum; rather, the flagellum is generated in an inactive and completely coiled state. After eclosion, males of Lema coronata evert and withdraw the internal sac multiple times before sexual maturation, without mounting a female. This behaviour serves to uncoil the flagellum and guide it into the active state with the aid of surface structures on the internal sac. A closely related species, Lema dilecta, also has a long flagellum and undergoes the same behaviour to place the flagellum in the active position. However, some other species of criocerine beetles with much shorter flagella can attain the active state without exhibiting this behaviour. Based on a previously proposed phylogenetic tree, we discuss the evolutionary history of the hyper-elongation of the flagellum and associated behaviour. PMID- 28878961 TI - Utterance-final position and pitch marking aid word learning in school-age children. AB - We investigated the effects of word order and prosody on word learning in school age children. Third graders viewed photographs belonging to one of three semantic categories while hearing four-word nonsense utterances containing a target word. In the control condition, all words had the same pitch and, across trials, the position of the target word was varied systematically within each utterance. The only cue to word-meaning mapping was the co-occurrence of target words and referents. This cue was present in all conditions. In the Utterance-final condition, the target word always occurred in utterance-final position, and at the same fundamental frequency as all the other words of the utterance. In the Pitch peak condition, the position of the target word was varied systematically within each utterance across trials, and produced with pitch contrasts typical of infant-directed speech (IDS). In the Pitch peak + Utterance-final condition, the target word always occurred in utterance-final position, and was marked with a pitch contrast typical of IDS. Word learning occurred in all conditions except the control condition. Moreover, learning performance was significantly higher than that observed with simple co-occurrence (control condition) only for the Pitch peak + Utterance-final condition. We conclude that, for school-age children, the combination of words' utterance-final alignment and pitch enhancement boosts word learning. PMID- 28878962 TI - Age of enlightenment: long-term effects of outdoor aesthetic lights on bats in churches. AB - We surveyed 110 country churches in south-western Sweden for presence of brown long-eared bats Plecotus auritus in summer 2016 by visual inspection and/or evening emergence counts. Each church was also classified according to the presence and amount of aesthetic directional lights (flood-lights) aimed on its walls and tower from the outside. Sixty-one of the churches had previously been surveyed by one of us (J.R.) between 1980 and 1990, before lights were installed on Swedish churches, using the same methods. Churches with bat colonies had decreased significantly in frequency from 61% in 1980s to 38% by 2016. All abandoned churches had been fitted with flood-lights in the period between the two surveys. The loss of bat colonies from lit churches was highly significant and most obvious when lights were applied from all directions, leaving no dark corridor for the bats to leave and return to the roost. In contrast, in churches that were not lit, all of 13 bat colonies remained after 25+ years between the surveys. Lighting of churches and other historical buildings is a serious threat to the long-term survival and reproduction of light-averse bats such as Plecotus spp. and other slow-flying species. Bat roosts are strictly protected according to the EU Habitats Directive and the EUROBATS agreement. Lighting of buildings for aesthetic purposes is becoming a serious environmental issue, because important bat roosts are destroyed in large numbers, and the problem should be handled accordingly. As a start, installation of flood-lights on historical buildings should at least require an environmental impact assessment (EIA). PMID- 28878963 TI - The impact of weather and storm water management ponds on the transmission of West Nile virus. AB - West Nile virus (WNV) is the most widely distributed arbovirus in the world and the spread is influenced by complex factors including weather conditions and urban environmental settings like storm water management ponds (SWMP). The purpose of this work was to develop an ordinary differential equation model to explore the impacts of SWMP, temperature and precipitation on WNV vector abundance and the transmission of WNV between mosquito and bird populations. The model was used to analyse how weather conditions and SWMP can influence the basic reproduction number. The results found that an excess of precipitation and fiercer intraspecific competition will reduce vector population and the peak value of infectious vectors and birds. This information can be used to identify measures that would be useful to control larval abundance in SWMP and the transmission of WNV. PMID- 28878964 TI - The role of climatic and geological events in generating diversity in Ethiopian grass frogs (genus Ptychadena). AB - Ethiopia is a world biodiversity hotspot and harbours levels of biotic endemism unmatched in the Horn of Africa, largely due to topographic-and thus habitat complexity, which results from a very active geological and climatic history. Among Ethiopian vertebrate fauna, amphibians harbour the highest levels of endemism, making amphibians a compelling system for the exploration of the impacts of Ethiopia's complex abiotic history on biotic diversification. Grass frogs of the genus Ptychadena are notably diverse in Ethiopia, where they have undergone an evolutionary radiation. We used molecular data and expanded taxon sampling to test for cryptic diversity and to explore diversification patterns in both the highland radiation and two widespread lowland Ptychadena. Species delimitation results support the presence of nine highland species and four lowland species in our dataset, and divergence dating suggests that both geologic events and climatic fluctuations played a complex and confounded role in the diversification of Ptychadena in Ethiopia. We rectify the taxonomy of the endemic P. neumanni species complex, elevating one formally synonymized name and describing three novel taxa. Finally, we describe two novel lowland Ptychadena species that occur in Ethiopia and may be more broadly distributed. PMID- 28878965 TI - Social seeking declines in young adolescents. AB - The desire to engage with others is an important motivational force throughout our lifespan. It is known that social behaviour and preferences change from childhood to adulthood, but whether this change is linked with any changes in social motivation is not known. We evaluated 255 typically developing participants from ages 4-20 years on a behavioural paradigm 'Choose a Movie' (CAM). On every trial, participants had a choice between viewing social or non social movies presented with different levels of effort (key presses/screen touch required). Hence, participants chose not only the movie they would watch but also how much effort they would make. The difference between the effort levels of the chosen and not chosen stimuli helps in quantifying the motivation to seek it. This task could be used with all the age groups with minimal adaptations, allowing comparison between the groups. Results showed that children (4-8 years), older adolescents (12-16 years) and young adults (17-20 years) made more effort to look at social movies. Counterintuitively, this preference was not seen in young adolescents (around 9-12 years), giving a U-shaped developmental trajectory over the population. We present the first evidence for non-monotonic developmental change in social motivation in typical participants. PMID- 28878966 TI - Assessment and analysis of human laterality for manipulation and communication using the Rennes Laterality Questionnaire. AB - Despite significant scientific advances, the nature of the left-hemispheric systems involved in language (speech and gesture) and manual actions is still unclear. To date, investigations of human laterality focused mainly on non communication functions. Although gestural laterality data have been published for infants and children, relatively little is known about laterality of human gestural communication. This study investigated human laterality in depth considering non-communication manipulation actions and various gesture types involving hands, feet, face and ears. We constructed an online laterality questionnaire including 60 items related to daily activities. We collected 317 594 item responses by 5904 randomly selected participants. The highest percentages of strong left-lateralized (6.76%) and strong right-lateralized participants (75.19%) were for manipulation actions. The highest percentages of mixed left-lateralized (12.30%) and ambidextrous (50.23%) participants were found for head-related gestures. The highest percentage of mixed right-lateralized participants (55.33%) was found for auditory gestures. Every behavioural category showed a significant population-level right-side bias. More precisely, participants were predominantly right-lateralized for non-communication manual actions, for visual iconic, visual symbolic, visual deictic (with and without speech), tactile and auditory manual gestures as well as for podial and head related gestures. Our findings support previous studies reporting that humans have left-brain predominance for gestures and complex motor activities such as tool-use. Our study shows that the Rennes Laterality Questionnaire is a useful research instrument to assess and analyse human laterality for both manipulation and communication functions. PMID- 28878967 TI - Resisting the urge to smoke: inhibitory control training in cigarette smokers. AB - Impaired response inhibition is an important factor in tobacco dependence. We examined the effects of inhibitory control training (ICT) on inhibition, smoking resistance and cigarette use. Smokers (n = 55) abstained from smoking for 12 h prior to testing. On the test day, participants recorded cigarette use and completed pre-training measures of global and cue-specific (smoking-related) response inhibition. Participants were randomized to either an active or a control ICT group. The active group was required to repeatedly inhibit a response towards smoking cues (100%), while the control group was required to inhibit a response towards smoking and neutral cues with equal frequency (50%). Participants performed post-training measures of response inhibition, smoking resistance and cigarette use. Inhibition data did not indicate time (pre training, post-training) * group (active training, control training) or time * group * cue (smoking, neutral) interactions. There was weak evidence that smokers in the active group were more likely to resist smoking than those in the control group. Cigarette use data did not indicate a time * group interaction. Our data suggest that ICT may enhance the ability to resist smoking, indicating that training may be a promising adjunct to smoking pharmacotherapy. PMID- 28878968 TI - The leading-edge vortex of swift wing-shaped delta wings. AB - Recent investigations on the aerodynamics of natural fliers have illuminated the significance of the leading-edge vortex (LEV) for lift generation in a variety of flight conditions. A well-documented example of an LEV is that generated by aircraft with highly swept, delta-shaped wings. While the wing aerodynamics of a manoeuvring aircraft, a bird gliding and a bird in flapping flight vary significantly, it is believed that this existing knowledge can serve to add understanding to the complex aerodynamics of natural fliers. In this investigation, a model non-slender delta-shaped wing with a sharp leading edge is tested at low Reynolds number, along with a delta wing of the same design, but with a modified trailing edge inspired by the wing of a common swift Apus apus. The effect of the tapering swift wing on LEV development and stability is compared with the flow structure over the unmodified delta wing model through particle image velocimetry. For the first time, a leading-edge vortex system consisting of a dual or triple LEV is recorded on a swift wing-shaped delta wing, where such a system is found across all tested conditions. It is shown that the spanwise location of LEV breakdown is governed by the local chord rather than Reynolds number or angle of attack. These findings suggest that the trailing-edge geometry of the swift wing alone does not prevent the common swift from generating an LEV system comparable with that of a delta-shaped wing. PMID- 28878970 TI - Building information modelling review with potential applications in tunnel engineering of China. AB - Building information modelling (BIM) can be applied to tunnel engineering to address a number of problems, including complex structure, extensive design, long construction cycle and increased security risks. To promote the development of tunnel engineering in China, this paper combines actual cases, including the Xingu mountain tunnel and the Shigu Mountain tunnel, to systematically analyse BIM applications in tunnel engineering in China. The results indicate that BIM technology in tunnel engineering is currently mainly applied during the design stage rather than during construction and operation stages. The application of BIM technology in tunnel engineering covers many problems, such as a lack of standards, incompatibility of different software, disorganized management, complex combination with GIS (Geographic Information System), low utilization rate and poor awareness. In this study, through summary of related research results and engineering cases, suggestions are introduced and an outlook for the BIM application in tunnel engineering in China is presented, which provides guidance for design optimization, construction standards and later operation maintenance. PMID- 28878969 TI - Natal foraging philopatry in eastern Pacific hawksbill turtles. AB - The complex processes involved with animal migration have long been a subject of biological interest, and broad-scale movement patterns of many marine turtle populations still remain unresolved. While it is widely accepted that once marine turtles reach sexual maturity they home to natal areas for nesting or reproduction, the role of philopatry to natal areas during other life stages has received less scrutiny, despite widespread evidence across the taxa. Here we report on genetic research that indicates that juvenile hawksbill turtles (Eretmochelys imbricata) in the eastern Pacific Ocean use foraging grounds in the region of their natal beaches, a pattern we term natal foraging philopatry. Our findings confirm that traditional views of natal homing solely for reproduction are incomplete and that many marine turtle species exhibit philopatry to natal areas to forage. Our results have important implications for life-history research and conservation of marine turtles and may extend to other wide-ranging marine vertebrates that demonstrate natal philopatry. PMID- 28878972 TI - Chemical element transport in stellar evolution models. AB - Stellar evolution computations provide the foundation of several methods applied to study the evolutionary properties of stars and stellar populations, both Galactic and extragalactic. The accuracy of the results obtained with these techniques is linked to the accuracy of the stellar models, and in this context the correct treatment of the transport of chemical elements is crucial. Unfortunately, in many respects calculations of the evolution of the chemical abundance profiles in stars are still affected by sometimes sizable uncertainties. Here, we review the various mechanisms of element transport included in the current generation of stellar evolution calculations, how they are implemented, the free parameters and uncertainties involved, the impact on the models and the observational constraints. PMID- 28878971 TI - Hovering hummingbird wing aerodynamics during the annual cycle. I. Complete wing. AB - The diverse hummingbird family (Trochilidae) has unique adaptations for nectarivory, among which is the ability to sustain hover-feeding. As hummingbirds mainly feed while hovering, it is crucial to maintain this ability throughout the annual cycle-especially during flight-feather moult, in which wing area is reduced. To quantify the aerodynamic characteristics and flow mechanisms of a hummingbird wing throughout the annual cycle, time-accurate aerodynamic loads and flow field measurements were correlated over a dynamically scaled wing model of Anna's hummingbird (Calypte anna). We present measurements recorded over a model of a complete wing to evaluate the baseline aerodynamic characteristics and flow mechanisms. We found that the vorticity concentration that had developed from the wing's leading-edge differs from the attached vorticity structure that was typically found over insects' wings; firstly, it is more elongated along the wing chord, and secondly, it encounters high levels of fluctuations rather than a steady vortex. Lift characteristics resemble those of insects; however, a 20% increase in the lift-to-torque ratio was obtained for the hummingbird wing model. Time-accurate aerodynamic loads were also used to evaluate the time-evolution of the specific power required from the flight muscles, and the overall wingbeat power requirements nicely matched previous studies. PMID- 28878974 TI - Multilevel and quasi-Monte Carlo methods for uncertainty quantification in particle travel times through random heterogeneous porous media. AB - In this study, we apply four Monte Carlo simulation methods, namely, Monte Carlo, quasi-Monte Carlo, multilevel Monte Carlo and multilevel quasi-Monte Carlo to the problem of uncertainty quantification in the estimation of the average travel time during the transport of particles through random heterogeneous porous media. We apply the four methodologies to a model problem where the only input parameter, the hydraulic conductivity, is modelled as a log-Gaussian random field by using direct Karhunen-Loeve decompositions. The random terms in such expansions represent the coefficients in the equations. Numerical calculations demonstrating the effectiveness of each of the methods are presented. A comparison of the computational cost incurred by each of the methods for three different tolerances is provided. The accuracy of the approaches is quantified via the mean square error. PMID- 28878973 TI - Making better decisions in groups. AB - We review the literature to identify common problems of decision-making in individuals and groups. We are guided by a Bayesian framework to explain the interplay between past experience and new evidence, and the problem of exploring the space of hypotheses about all the possible states that the world could be in and all the possible actions that one could take. There are strong biases, hidden from awareness, that enter into these psychological processes. While biases increase the efficiency of information processing, they often do not lead to the most appropriate action. We highlight the advantages of group decision-making in overcoming biases and searching the hypothesis space for good models of the world and good solutions to problems. Diversity of group members can facilitate these achievements, but diverse groups also face their own problems. We discuss means of managing these pitfalls and make some recommendations on how to make better group decisions. PMID- 28878975 TI - Export of ice nucleating particles from a watershed. AB - Ice nucleating particles (INP) active at a few degrees below 0 degrees C are produced by a range of organisms and released into the environment. They may affect cloud properties and precipitation when becoming airborne. So far, our knowledge about sources of biological INP is based on grab samples of vegetation, soil or water studied in the laboratory. By combining measurements of INP concentrations in river water with river water discharge rates over the course of 16 months, we obtained a lower limit for the production rate of INP in a watershed covering most of Switzerland (4 * 105 INP-8 m-2 d-1). Coincidentally, we found that INP-8 are likely to retain their potential for catalysing ice formation in the natural environment for at least several months before they are mobilized by an intensive rainfall, washed into the river and exported from the watershed. PMID- 28878976 TI - The nature and distribution of affiliative behaviour during exposure to mild threat. AB - Individual reactions to danger in humans are often characterized as antisocial and self-preservative. Yet, more than 50 years of research have shown that humans often seek social partners and behave prosocially when confronted by danger. This research has relied on post hoc verbal reports, which fall short of capturing the more spontaneous reactions to danger and determine their social nature. Real world responses to danger are difficult to observe, due to their evanescent nature. Here, we took advantage of a series of photographs freely accessible online and provided by a haunted house attraction, which enabled us to examine the more immediate reactions to mild threat. Regarding the nature and structure of affiliative behaviour and their motivational correlates, we were able to analyse the distribution of gripping, a behaviour that could either be linked to self- or other-oriented protection. We found that gripping, an affiliative behaviour, was common, suggestive of the social nature of human immediate reactions to danger. We also found that, while gripping behaviour is quite stable across group sizes, mutual gripping dropped dramatically as group size increases. The fact that mutual gripping disappears when the number of available partners increases suggests that gripping behaviour most probably reflects a self preservative motivation. We also found age class differences, with younger individuals showing more gripping but receiving little reciprocation. Also, the most exposed individuals received little mutual gripping. Altogether, these results suggest that primary reactions to threat in humans are driven by affiliative tendencies serving self-preservative motives. PMID- 28878977 TI - How effective is incidental learning of the shape of probability distributions? AB - The idea that people learn detailed probabilistic generative models of the environments they interact with is intuitively appealing, and has received support from recent studies of implicit knowledge acquired in daily life. The goal of this study was to see whether people efficiently induce a probability distribution based upon incidental exposure to an unknown generative process. Subjects played a 'whack-a-mole' game in which they attempted to click on objects appearing briefly, one at a time on the screen. Horizontal positions of the objects were generated from a bimodal distribution. After 180 plays of the game, subjects were unexpectedly asked to generate another 180 target positions of their own from the same distribution. Their responses did not even show a bimodal distribution, much less an accurate one (Experiment 1). The same was true for a pre-announced test (Experiment 2). On the other hand, a more extreme bimodality with zero density in a middle region did produce some distributional learning (Experiment 3), perhaps reflecting conscious hypothesis testing. We discuss the challenge this poses to the idea of efficient accurate distributional learning. PMID- 28878978 TI - Error rate on the director's task is influenced by the need to take another's perspective but not the type of perspective. AB - Adults are prone to responding erroneously to another's instructions based on what they themselves see and not what the other person sees. Previous studies have indicated that in instruction-following tasks participants make more errors when required to infer another's perspective than when following a rule. These inference-induced errors may occur because the inference process itself is error prone or because they are a side effect of the inference process. Crucially, if the inference process is error-prone, then higher error rates should be found when the perspective to be inferred is more complex. Here, we found that participants were no more error-prone when they had to judge how an item appeared (Level 2 perspective-taking) than when they had to judge whether an item could or could not be seen (Level 1 perspective-taking). However, participants were more error-prone in the perspective-taking variants of the task than in a version that only required them to follow a rule. These results suggest that having to represent another's perspective induces errors when following their instructions but that error rates are not directly linked to errors in inferring another's perspective. PMID- 28878979 TI - Oriented, molecularly imprinted cavities with dual binding sites for highly sensitive and selective recognition of cortisol. AB - Novel, molecularly imprinted polymers (MIPs) were developed for the highly sensitive and selective recognition of the stress marker cortisol. Oriented, homogeneous cavities with two binding sites for cortisol were fabricated by surface-initiated atom transfer radical polymerization, using a cortisol motif template molecule (TM1) which consists of a polymerizable moiety attached at the 3-carbonyl group of cortisol via an oxime linkage and an adamantane carboxylate moiety coupled with the 21-hydroxyl group. TM1 was orientationally immobilized on a beta-cyclodextrin (beta-CD)-grafted gold-coated sensor chip by inclusion of the adamantane moiety of TM1, followed by copolymerization of a hydrophilic comonomer, 2-methacryloyloxyethyl phosphorylcholine, with or without a cross linker, N,N'-methylenebisacrylamide. Subsequent cleavage of the oxime linkage leaves the imprinted cavities that contain dual binding sites-namely, the aminooxy group and beta-CD-capable of oxime formation and hydrophobic interaction, respectively. As an application, MIP-based picomolar level detection of cortisol was demonstrated by a competitive binding assay using a fluorescent competitor. Cross-linking of the MIP imparts rigidity to the binding cavities, and improves the selectivity and sensitivity significantly, reducing the limit of detection to 4.8 pM. In addition, detection of cortisol in saliva samples was demonstrated as a feasibility study. PMID- 28878980 TI - The origins of babytalk: smiling, teaching or social convergence? AB - When addressing their young infants, parents systematically modify their speech. Such infant-directed speech (IDS) contains exaggerated vowel formants, which have been proposed to foster language development via articulation of more distinct speech sounds. Here, this assumption is rigorously tested using both acoustic and, for the first time, fine-grained articulatory measures. Mothers were recorded speaking to their infant and to another adult, and measures were taken of their acoustic vowel space, their tongue and lip movements and the length of their vocal tract. Results showed that infant- but not adult-directed speech contains acoustically exaggerated vowels, and these are not the product of adjustments to tongue or to lip movements. Rather, they are the product of a shortened vocal tract due to a raised larynx, which can be ascribed to speakers' unconscious effort to appear smaller and more non-threatening to the young infant. This adjustment in IDS may be a vestige of early mother-infant interactions, which had as its primary purpose the transmission of non aggressiveness and/or a primitive manifestation of pre-linguistic vocal social convergence of the mother to her infant. With the advent of human language, this vestige then acquired a secondary purpose-facilitating language acquisition via the serendipitously exaggerated vowels. PMID- 28878981 TI - Taxonomy assignment approach determines the efficiency of identification of OTUs in marine nematodes. AB - Precision and reliability of barcode-based biodiversity assessment can be affected at several steps during acquisition and analysis of data. Identification of operational taxonomic units (OTUs) is one of the crucial steps in the process and can be accomplished using several different approaches, namely, alignment based, probabilistic, tree-based and phylogeny-based. The number of identified sequences in the reference databases affects the precision of identification. This paper compares the identification of marine nematode OTUs using alignment based, tree-based and phylogeny-based approaches. Because the nematode reference dataset is limited in its taxonomic scope, OTUs can only be assigned to higher taxonomic categories, families. The phylogeny-based approach using the evolutionary placement algorithm provided the largest number of positively assigned OTUs and was least affected by erroneous sequences and limitations of reference data, compared to alignment-based and tree-based approaches. PMID- 28878982 TI - Biophysical properties of the human finger for touch comprehension: influences of ageing and gender. AB - The human finger plays an extremely important role in tactile perception, but little is known about how age and gender affect its biophysical properties and their role in tactile perception. We combined studies on contact characteristics, mechanical properties and surface topography to understand age and gender effects on the human finger. The values obtained regarding contact characteristics (i.e. adhesive force) were significantly higher for women than for men. As for mechanical properties (i.e. Young's modulus E), a significant and positive correlation with age was observed and found to be higher for women. A positive correlation was observed between age and the arithmetic mean of surface roughness for men. However, an inverse age effect was highlighted for women. The age and gender effects obtained have never been reported previously in the literature. These results open new perspectives for understanding the weakening of tactile perception across ages and how it differs between men and women. PMID- 28878983 TI - Development of a novel and cost-effective redox sensor for voltammetric determination of pantoprazole sodium during pharmacokinetic studies. AB - A pencil graphite electrode modified with poly (bromocresol green (BCG)) was prepared by electro-polymerization process for the determination of pantoprazole sodium. The surface morphology and structure of poly (BCG) film were characterized by scanning electron microscopy and Fourier transform infrared spectroscopy. The determination of pantoprazole sodium in Britton-Robinson buffer (pH 7.0) was carried out by square wave adsorptive stripping voltammetric technique. Under optimum conditions, the linear response of the peak with concentration of the cited drug was in the range of 6.6-360 * 10-8 M with limit of detection of 2.2 * 10-8 M. Moreover, the poly (BCG)-modified electrode has been successfully applied to determine pantoprazole sodium in tablets, vials and during pharmacokinetic studies. PMID- 28878984 TI - A mix-and-click method to measure amyloid-beta concentration with sub-micromolar sensitivity. AB - Aggregation of amyloid-beta (Abeta) protein plays a central role in Alzheimer's disease. Because protein aggregation is a concentration-dependent process, rigorous investigations require accurate concentration measurements. Owing to the high aggregation propensity of Abeta protein, working solutions of Abeta are typically in the low micromolar range. Therefore, an ideal Abeta quantification method requires high sensitivity without sacrificing speed and accuracy. Absorbance at 280 nm is frequently used to measure Abeta concentration, but the sensitivity is low with only one tyrosine and no tryptophan residues in the Abeta sequence. Here we present a fluorescence method for Abeta quantification using fluorescamine, which gives high fluorescence upon reaction with primary amines. We show that, using hen egg white lysozyme as a standard, fluorescence correlates linearly with primary amine concentration across a wide range of fluorescamine concentrations, from 62.5 to 1000 uM. The maximal sensitivity of detection is achieved at a fluorescamine concentration of 250 uM or higher. The fluorescamine method is compatible with the presence of dimethyl sulfoxide, which is commonly used in the preparation of Abeta oligomers, and limits the use of absorbance at 280 nm due to its high background reading. Using aggregation kinetics, we show that the fluorescamine method gives accurate concentration measurements at low micromolar range and leads to highly consistent aggregation data. We recommend the fluorescamine assay to be used for routine and on-the-fly concentration determination in Abeta oligomerization and fibrillization experiments. PMID- 28878985 TI - Task allocation and site fidelity jointly influence foraging regulation in honeybee colonies. AB - Variation in behaviour among group members often impacts collective outcomes. Individuals may vary both in the task that they perform and in the persistence with which they perform each task. Although both the distribution of individuals among tasks and differences among individuals in behavioural persistence can each impact collective behaviour, we do not know if and how they jointly affect collective outcomes. Here, we use a detailed computational model to examine the joint impact of colony-level distribution among tasks and behavioural persistence of individuals, specifically their fidelity to particular resource sites, on the collective trade-off between exploring for new resources and exploiting familiar ones. We developed an agent-based model of foraging honeybees, parametrized by data from five colonies, in which we simulated scouts, who search the environment for new resources, and individuals who are recruited by the scouts to the newly found resources, i.e. recruits. We varied the persistence of returning to a particular food source of both scouts and recruits and found that, for each value of persistence, there is a different optimal ratio of scouts to recruits that maximizes resource collection by the colony. Furthermore, changes to the persistence of scouts induced opposite effects from changes to the persistence of recruits on the collective foraging of the colony. The proportion of scouts that resulted in the most resources collected by the colony decreased as the persistence of recruits increased. However, this optimal proportion of scouts increased as the persistence of scouts increased. Thus, behavioural persistence and task participation can interact to impact a colony's collective behaviour in orthogonal directions. Our work provides new insights and generates new hypotheses into how variations in behaviour at both the individual and colony levels jointly impact the trade-off between exploring for new resources and exploiting familiar ones. PMID- 28878986 TI - The in situ synthesis of PbS nanocrystals from lead(II) n-octylxanthate within a 1,3-diisopropenylbenzene-bisphenol A dimethacrylate sulfur copolymer. AB - The synthesis of lead sulfide nanocrystals within a solution processable sulfur 'inverse vulcanization' polymer thin film matrix was achieved from the in situ thermal decomposition of lead(II) n-octylxanthate, [Pb(S2COOct)2]. The growth of nanocrystals within polymer thin films from single-source precursors offers a faster route to networks of nanocrystals within polymers when compared with ex situ routes. The 'inverse vulcanization' sulfur polymer described herein contains a hybrid linker system which demonstrates high solubility in organic solvents, allowing solution processing of the sulfur-based polymer, ideal for the formation of thin films. The process of nanocrystal synthesis within sulfur films was optimized by observing nanocrystal formation by X-ray photoelectron spectroscopy and X-ray diffraction. Examination of the film morphology by scanning electron microscopy showed that beyond a certain precursor concentration the nanocrystals formed were not only within the film but also on the surface suggesting a loading limit within the polymer. We envisage this material could be used as the basis of a new generation of materials where solution processed sulfur polymers act as an alternative to traditional polymers. PMID- 28878987 TI - Effects of the distant population density on spatial patterns of demographic dynamics. AB - Spatio-temporal patterns of population changes within and across countries have various implications. Different geographical, demographic and econo-societal factors seem to contribute to migratory decisions made by individual inhabitants. Focusing on internal (i.e. domestic) migration, we ask whether individuals may take into account the information on the population density in distant locations to make migratory decisions. We analyse population census data in Japan recorded with a high spatial resolution (i.e. cells of size 500*500 m) for the entirety of the country, and simulate demographic dynamics induced by the gravity model and its variants. We show that, in the census data, the population growth rate in a cell is positively correlated with the population density in nearby cells up to a distance of 20 km as well as that of the focal cell. The ordinary gravity model does not capture this empirical observation. We then show that the empirical observation is better accounted for by extensions of the gravity model such that individuals are assumed to perceive the attractiveness, approximated by the population density, of the source or destination cell of migration as the spatial average over a circle of radius ~1 km. PMID- 28878988 TI - Bias associated with the detectability of the coral-eating pest crown-of-thorns seastar and implications for reef management. AB - Outbreaks of the predator crown-of-thorns seastar (COTS) Acanthaster planci cause widespread coral mortality across the Indo-Pacific. Like many marine invertebrates, COTS is a nocturnal species whose cryptic behaviour during the day can affect its detectability, particularly in structurally complex reef habitats that provide many refuges for benthic creatures. We performed extensive day and night surveys of COTS populations in coral reef habitats showing differing levels of structural complexity and COTS abundance. We tested whether estimations of COTS density varied between day and night observations, and if the differences were related to changes in COTS abundance, reef structural complexity and the spatial scale of observation. Estimations of COTS density were on average 27% higher at night than during the day. Differences in COTS detection varied with changing seastar abundance but not reef structural complexity or scale of observation. Underestimation of COTS abundance in daytime was significant for a broad seastar density range, thus potentially affecting most outbreak events. Our study suggests that portions of COTS populations can be undetected during conventional surveys and control campaigns, which are exclusively conducted by day, and significantly affect the trajectory of coral reefs. Accounting for bias in COTS detection can strengthen coral reef management broadly. PMID- 28878989 TI - Expansion of the known distribution of Asiatic mouflon (Ovis orientalis) in the Late Pleistocene of the Southern Levant. AB - Wild sheep (Ovis orientalis) bones recovered from the Natufian site of Shubayqa 1 demonstrate a wider distribution of mouflon in the Late Pleistocene of the Southern Levant than previously known. Early Epipalaeolithic sites are common in the limestone steppe region of eastern Jordan but have yielded only a handful of caprine bones that cannot be identified to species level and few faunal remains from excavated Late Epipalaeolithic sites have been reported. Analysis of animal bone from Shubayqa 1 suggests a significant population of wild sheep could be found concentrated in the basalt desert environment of eastern Jordan during the Late Pleistocene, especially where higher rainfall over the Jebel Druze provided more water. A population of wild sheep was still present in the Pre-Pottery Neolithic A when the nearby site of Shubayqa 6 was occupied. Hunting of diverse, locally available resources including wild sheep at the end of the Pleistocene illustrates the flexible and adaptive exploitation strategies that hunter-forager groups engaged in. This provides further evidence to the increasing body of data showing the creative and opportunistic approach of terminal Pleistocene groups allowing continued occupation even in more marginal environments in a period of environmental change. PMID- 28878990 TI - Human altruism, evolution and moral philosophy. AB - This paper has two central aims. The first is to explore philosophical complications that arise when we move from (i) explaining the evolutionary origins of genetically influenced traits associated with human cooperation and altruism, to (ii) explaining present manifestations of human thought, feeling and behaviour involving cooperation and altruism. While the former need only appeal to causal factors accessible to scientific inquiry, the latter must engage also with a distinctive form of explanation, i.e. reason-giving explanation, which in turn raises important philosophical questions, the answers to which will affect the nature of the ultimate explanations of our moral beliefs and related actions. On one possibility I will explore, this explanatory project cannot avoid engaging with first-order ethical theory. The second aim is to apply lessons from these explanatory complications to the critique of 'evolutionary debunking arguments', which seek to debunk morality, or at least objective construals of it (i.e. moral realism), by appeal to allegedly scientific debunking explanations of our moral beliefs that would defeat our justification for them. The explanatory complications brought out in the first half raise difficulties for such debunking arguments. If we avoid begging central philosophical questions then such debunking arguments pose little threat of saddling us with moral scepticism or subjectivism, though they do pose an important challenge for those developing a moral realist view. PMID- 28878991 TI - Synthesis of isopropyl-substituted anthraquinones via Friedel-Crafts acylations: migration of isopropyl groups. AB - Friedel-Crafts reactions of isopropyl-substituted benzenes with phthalic anhydride in the presence of aluminium trichloride, followed by cyclization of the products with strong sulfuric acid give, as expected, anthraquinones. The syntheses, however, often afford more than one anthraquinone. In some cases the isopropyl groups migrate cleanly to other ring positions; in other cases they are lost. PMID- 28878992 TI - One step at a time in investigating relationships between self-directed behaviours and parasitological, social and environmental variables. PMID- 28878993 TI - Differential metal-binding properties of dynamic acylhydrazone polymers and their sensing applications. AB - As one of common dynamic covalent bonds, acylhydrazone bond plays an important role in developing intelligent responsive materials. In this report, we present acylhydrazone-based dynamic polymers with multi-stimuli responsiveness, particularly metal recognition behaviours and their modulation. A series of polyacylhydrazones with different metal-binding sites were designed and prepared in a modular fashion. Titration of these receptors with a diverse set of metal ions, including Cu2+, Zn2+ and La3+, resulted in unique optical changes, and both the sensitivity and selectivity profiles can be regulated. Moreover, the metal binding feature was facilely modulated by changing the solvent. The addition of weakly basic anions was employed to further fine-tune the responsiveness of the polymers by taking advantage of the cooperative effect with metal coordination. Finally, the sensitive detection of 6-mercaptopurine and pyrophosphate was achieved to demonstrate the application potential of these systems. PMID- 28878994 TI - Stochastic phase segregation on surfaces. AB - Phase separation and coarsening is a phenomenon commonly seen in binary physical and chemical systems that occur in nature. Often, thermal fluctuations, modelled as stochastic noise, are present in the system and the phase segregation process occurs on a surface. In this work, the segregation process is modelled via the Cahn-Hilliard-Cook model, which is a fourth-order parabolic stochastic system. Coarsening is analysed on two sample surfaces: a unit sphere and a dumbbell. On both surfaces, a statistical analysis of the growth rate is performed, and the influence of noise level and mobility is also investigated. For the spherical interface, it is also shown that a lognormal distribution fits the growth rate well. PMID- 28878995 TI - A generalized solution procedure for in-plane free vibration of rectangular plates and annular sectorial plates. AB - A generalized solution procedure is developed for in-plane free vibration of rectangular and annular sectorial plates with general boundary conditions. For the annular sectorial plate, the introduction of a logarithmic radial variable simplifies the basic theory and the expression of the total energy. The coordinates, geometric parameters and potential energy for the two different shapes are organized in a unified framework such that a generalized solving procedure becomes feasible. By using the improved Fourier-Ritz approach, the admissible functions are formulated in trigonometric form, which allows the explicit assembly of global mass and stiffness matrices for both rectangular and annular sectorial plates, thereby making the method computationally effective, especially when analysing annular sectorial plates. Moreover, the improved Fourier expansion eliminates the potential discontinuity of the original normal and tangential displacement functions and their derivatives in the entire domain, and accelerates the convergence. The generalized Fourier-Ritz approach for both shapes has the characteristics of generality, accuracy and efficiency. These features are demonstrated via a few numerical examples. PMID- 28878996 TI - Stable, metastable and unstable cellulose solutions. AB - We have characterized the dissolution state of microcrystalline cellulose (MCC) in aqueous tetrabutylammonium hydroxide, TBAH(aq), at different concentrations of TBAH, by means of turbidity and small-angle X-ray scattering. The solubility of cellulose increases with increasing TBAH concentration, which is consistent with solubilization driven by neutralization. When comparing the two polymorphs, the solubility of cellulose I is higher than that of cellulose II. This has the consequence that the dissolution of MCC (cellulose I) may create a supersaturated solution with respect to cellulose II. As for the dissolution state of cellulose, we identify three different regimes. (i) In the stable regime, corresponding to concentrations below the solubility of cellulose II, cellulose is molecularly dissolved and the solutions are thermodynamically stable. (ii) In the metastable regime, corresponding to lower supersaturations with respect to cellulose II, a minor aggregation of cellulose occurs and the solutions are kinetically stable. (iii) In the unstable regime, corresponding to larger supersaturations, there is macroscopic precipitation of cellulose II from solution. Finally, we also discuss strong alkali solvents in general and compare TBAH(aq) with the classical NaOH(aq) solvent. PMID- 28878997 TI - Social learning in otters. AB - The use of information provided by others to tackle life's challenges is widespread, but should not be employed indiscriminately if it is to be adaptive. Evidence is accumulating that animals are indeed selective and adopt 'social learning strategies'. However, studies have generally focused on fish, bird and primate species. Here we extend research on social learning strategies to a taxonomic group that has been neglected until now: otters (subfamily Lutrinae). We collected social association data on captive groups of two gregarious species: smooth-coated otters (Lutrogale perspicillata), known to hunt fish cooperatively in the wild, and Asian short-clawed otters (Aonyx cinereus), which feed individually on prey requiring extractive foraging behaviours. We then presented otter groups with a series of novel foraging tasks, and inferred social transmission of task solutions with network-based diffusion analysis. We show that smooth-coated otters can socially learn how to exploit novel food sources and may adopt a 'copy when young' strategy. We found no evidence for social learning in the Asian short-clawed otters. Otters are thus a promising model system for comparative research into social learning strategies, while conservation reintroduction programmes may benefit from facilitating the social transmission of survival skills in these vulnerable species. PMID- 28878998 TI - Flame-retardant polyvinyl alcohol membrane with high transparency based on a reactive phosphorus-containing compound. AB - Flame-retardant polyvinyl alcohol (PVA) membranes with high transparency and flexibility were prepared by mixing an aqueous solution of a phosphorus containing acrylic acid (AOPA) with PVA. The reaction between AOPA and PVA, the transparency, the crystallinity and the flexibility of the membrane were investigated with Fourier transform infrared spectrometry (FTIR), UV-vis light transmittance, X-ray diffraction and tensile tests, respectively. The limited oxygen index (LOI) and vertical flame (UL 94 VTM), microscale combustion calorimetry, thermogravimetric analysis (TGA) and TGA-FTIR were employed to evaluate the flame retardancy as well as to reveal the corresponding mechanisms. Results showed that PVA containing 30 wt% of AOPA can reach the UL 94 VTM V0 rating with an LOI of 27.3% and retain 95% of the original transparency of pure PVA. Adding AOPA reduces crystallinity of PVA, while the flexibility is increased. AOPA depresses the thermal degradation of PVA and promotes char formation during combustion. The proposed decomposition mechanism indicates that AOPA acts mainly in the condensed phase. PMID- 28879000 TI - An investigation into the unusual linkage isomerization and nitrite reduction activity of a novel tris(2-pyridyl) copper complex. AB - The copper-containing nitrite reductases (CuNIRs) are a class of enzymes that mediate the reduction of nitrite to nitric oxide in biological systems. Metal ligand complexes that reproduce the salient features of the active site of CuNIRs are therefore of fundamental interest, both for elucidating the possible mode of action of the enzymes and for developing biomimetic catalysts for nitrite reduction. Herein, we describe the synthesis and characterization of a new tris(2 pyridyl) copper complex ([Cu1(NO2)2]) that binds two molecules of nitrite, and displays all three of the common binding modes for [Formula: see text], with one nitrite bound in an asymmetric quasi-bidentate kappa2-ONO manner and the other bound in a monodentate fashion with a linkage isomerism between the kappa1-ONO and kappa1-NO2 binding modes. We use density functional theory to help rationalize the presence of all three of these linkage isomers in one compound, before assessing the redox activity of [Cu1(NO2)2]. These latter studies show that the complex is not a competent nitrite reduction electrocatalyst in non aqueous solvent, even in the presence of additional proton donors, a finding which may have implications for the design of biomimetic catalysts for nitrite reduction. PMID- 28879001 TI - Booming far: the long-range vocal strategy of a lekking bird. AB - The pressures of selection acting on transmission of information by acoustic signals are particularly high in long-distance communication networks. Males of the North African houbara bustard (Chlamydotis undulata undulata) produce extremely low-frequency vocalizations called 'booms' as a component of their courtship displays. These displays are performed on sites separated by a distance of on average 550 m, constituting exploded leks. Here, we investigate the acoustic features of booms involved in species-specific identity. We first assessed the modifications of acoustic parameters during boom transmission at long range within the natural habitat of the species, finding that the frequency content of booms was reliably transmitted up to 600 m. Additionally, by testing males' behavioural responses to playbacks of modified signals, we found that the presence of the second harmonic and the frequency modulation are the key parameters for species identification, and also that a sequence of booms elicited stronger responses than a single boom. Thus, the coding-decoding process relies on redundant and propagation-resistant features, making the booms particularly well adapted for the long-range transmission of information between males. Moreover, by experimentally disentangling the presentation of visual and acoustic signals, we showed that during the booming phase of courtship, the two sensory modalities act in synergy. The acoustic component is dominant in the context of intra-sexual competition. While the visual component is not necessary to induce agonistic response, it acts as an amplifier and reduces the time of detection of the signaller. The utilization of these adaptive strategies allows houbara males to maximize the active space of vocalizations emitted in exploded leks. PMID- 28878999 TI - Gamete compatibility genes in mammals: candidates, applications and a potential path forward. AB - Fertilization represents a critical stage in biology, where successful alleles of a previous generation are shuffled into new arrangements and subjected to the forces of selection in the next generation. Although much research has been conducted on how variation in morphological and behavioural traits lead to variation in fertilization patterns, surprisingly little is known about fertilization at a molecular level, and specifically about how genes expressed on the sperm and egg themselves influence fertilization patterns. In mammals, several genes have been identified whose products are expressed on either the sperm or the egg, and which influence the fertilization process, but the specific mechanisms are not yet known. Additionally, in 2014 an interacting pair of proteins was identified: 'Izumo' on the sperm, and 'Juno' on the egg. With the identification of these genes comes the first opportunity to understand the molecular aspects of fertilization in mammals, and to identify how the genetic characteristics of these genes influence fertilization patterns. Here, we review recent progress in our understanding of fertilization and gamete compatibility in mammals, which should provide a helpful guide to researchers interested in untangling the molecular mechanisms of fertilization and the resulting impacts on population biology and evolutionary processes. PMID- 28879002 TI - Polarized light use in the nocturnal bull ant, Myrmecia midas. AB - Solitary foraging ants have a navigational toolkit, which includes the use of both terrestrial and celestial visual cues, allowing individuals to successfully pilot between food sources and their nest. One such celestial cue is the polarization pattern in the overhead sky. Here, we explore the use of polarized light during outbound and inbound journeys and with different home vectors in the nocturnal bull ant, Myrmecia midas. We tested foragers on both portions of the foraging trip by rotating the overhead polarization pattern by +/-45 degrees . Both outbound and inbound foragers responded to the polarized light change, but the extent to which they responded to the rotation varied. Outbound ants, both close to and further from the nest, compensated for the change in the overhead e vector by about half of the manipulation, suggesting that outbound ants choose a compromise heading between the celestial and terrestrial compass cues. However, ants returning home compensated for the change in the e-vector by about half of the manipulation when the remaining home vector was short (1-2 m) and by more than half of the manipulation when the remaining vector was long (more than 4 m). We report these findings and discuss why weighting on polarization cues change in different contexts. PMID- 28879003 TI - Non-contact incipient fault diagnosis method of fixed-axis gearbox based on CEEMDAN. AB - Gearbox plays most essential role in the modern machinery for transmitting the required torque along with motion and contributes to wide range of applications. Any failure in gearbox components affects the productivity and efficiency of the system. Most machine breakdowns related to gears are a result of improper operating conditions and loading, hence lead to failure of the whole mechanism. Ensemble Empirical Mode Decomposition (EEMD) comprises advancement and valuable addition in Empirical Mode Decomposition (EMD) and has been widely used in fault detection of rotating machines. However, intrinsic mode functions (IMFs) produced by EEMD often carry the residual noise. Also, the produced IMFs are different in number due to addition of white Gaussian noise, which leads to final averaging problem. To alleviate these drawbacks, Complete Ensemble Empirical Mode Decomposition with Adaptive Noise (CEEMDAN) was previously presented. This paper describes and presents the implementation of CEEMDAN for fault diagnosis of simulated local defects using sound signals in a fixed-axis gearbox. Statistical parameters are extracted from decomposed sound signals for different simulated faults. Results show the effectiveness of CEEMDAN over EEMD in order to obtain more accurate IMFs and fault severity. PMID- 28879004 TI - Diving behaviour of Cuvier's beaked whales exposed to two types of military sonar. AB - Cuvier's beaked whales (Ziphius cavirostris) have stranded in association with mid-frequency active sonar (MFAS) use, and though the causative mechanism linking these events remains unclear, it is believed to be behaviourally mediated. To determine whether MFAS use was associated with behavioural changes in this species, satellite tags were used to record the diving and movements of 16 Cuvier's beaked whales for up to 88 days in a region of frequent MFAS training off the coast of Southern California. Tag data were combined with summarized records of concurrent bouts of high-power, surface-ship and mid-power, helicopter deployed MFAS use, along with other potential covariates, in generalized additive mixed-effects models. Deep dives, shallow dives and surface intervals tended to become longer during MFAS use, with some variation associated with the total amount of overlapping MFAS during the behaviour. These changes in dives and surface intervals contributed to a longer interval between deep dives, a proxy for foraging disruption in this species. Most responses intensified with proximity and were more pronounced during mid-power than high-power MFAS use at comparable distances within approximately 50 km, despite the significantly lower source level of mid-power MFAS. However, distance-mediated responses to high power MFAS, and increased deep dive intervals during mid-power MFAS, were evident up to approximately 100 km away. PMID- 28879005 TI - Starvation effects on nitrogen and carbon stable isotopes of animals: an insight from meta-analysis of fasting experiments. AB - Nitrogen and carbon stable isotopic compositions (delta15N and delta13C) of consumers have been used for physiological and food web studies. Previous studies have shown delta15N and delta13C values are affected by several biological and environmental factors during starvation, but the generality of the effect of starvation on delta15N and delta13C values has not yet been tested. Here, we performed a meta-analysis to evaluate the effects of starvation on delta15N and delta13C values of consumers, and the underlying factors that may explain the observed variation. The delta15N and delta13C values were calculated as the differences between the final delta15N and delta13C values of consumers (post starvation) and the pre-starvation values on each experiment. Our meta-analysis showed a large variation in the delta15N and delta13C values of consumers (delta15N range: -0.82 to 4.300/00; mean: 0.470/00 and delta13C range: -1.92 to 2.620/00; mean: 0.010/00). The delta15N values of most consumers increased along the length of the starvation period and were influenced by nitrogen excretion and thermoregulation types, probably because differences in nitrogen metabolism and thermoregulation affect nitrogen processing and excretion rates. None of our predictor variables accounted for the variation in delta13C values, which showed both increases and decreases due to fasting. Our findings suggest that starvation results in changes in consumer delta15N values which are mainly explained by the length of the fasting period and by nitrogen and energy metabolism, but the underlying mechanisms of the starvation effects on delta13C values seem to be more complex than previously thought. PMID- 28879006 TI - A framework for the identification of long-term social avoidance in longitudinal datasets. AB - Animal sociality is of significant interest to evolutionary and behavioural ecologists, with efforts focused on the patterns, causes and fitness outcomes of social preference. However, individual social patterns are the consequence of both attraction to (preference for) and avoidance of conspecifics. Despite this, social avoidance has received far less attention than social preference. Here, we detail the necessary steps to generate a spatially explicit, iterative null model which can be used to identify non-random social avoidance in longitudinal studies of social animals. We specifically identify and detail parameters which will influence the validity of the model. To test the usability of this model, we applied it to two longitudinal studies of social animals (Eastern water dragons (Intellegama lesueurii) and bottlenose dolphins (Tursiops aduncus)) to identify the presence of social avoidances. Using this model allowed us to identify the presence of social avoidances in both species. We hope that the framework presented here inspires interest in addressing this critical gap in our understanding of animal sociality, in turn allowing for a more holistic understanding of social interactions, relationships and structure. PMID- 28879007 TI - Investigating the impact of feedback update interval on the efficacy of restorative brain-computer interfaces. AB - Restorative brain-computer interfaces (BCIs) have been proposed to enhance stroke rehabilitation. Restorative BCIs are able to close the sensorimotor loop by rewarding motor imagery (MI) with sensory feedback. Despite the promising results from early studies, reaching clinically significant outcomes in a timely fashion is yet to be achieved. This lack of efficacy may be due to suboptimal feedback provision. To the best of our knowledge, the optimal feedback update interval (FUI) during MI remains unexplored. There is evidence that sensory feedback disinhibits the motor cortex. Thus, in this study, we explore how shorter than usual FUIs affect behavioural and neurophysiological measures following BCI training for stroke patients using a single-case proof-of-principle study design. The action research arm test was used as the primary behavioural measure and showed a clinically significant increase (36%) over the course of training. The neurophysiological measures including motor evoked potentials and maximum voluntary contraction showed distinctive changes in early and late phases of BCI training. Thus, this preliminary study may pave the way for running larger studies to further investigate the effect of FUI magnitude on the efficacy of restorative BCIs. It may also elucidate the role of early and late phases of motor learning along the course of BCI training. PMID- 28879008 TI - The effects of geometric uncertainties on computational modelling of knee biomechanics. AB - The geometry of the articular components of the knee is an important factor in predicting joint mechanics in computational models. There are a number of uncertainties in the definition of the geometry of cartilage and meniscus, and evaluating the effects of these uncertainties is fundamental to understanding the level of reliability of the models. In this study, the sensitivity of knee mechanics to geometric uncertainties was investigated by comparing polynomial based and image-based knee models and varying the size of meniscus. The results suggested that the geometric uncertainties in cartilage and meniscus resulting from the resolution of MRI and the accuracy of segmentation caused considerable effects on the predicted knee mechanics. Moreover, even if the mathematical geometric descriptors can be very close to the imaged-based articular surfaces, the detailed contact pressure distribution produced by the mathematical geometric descriptors was not the same as that of the image-based model. However, the trends predicted by the models based on mathematical geometric descriptors were similar to those of the imaged-based models. PMID- 28879010 TI - Modelling radicalization: how small violent fringe sects develop into large indoctrinated societies. AB - We model radicalization in a society consisting of two competing religious, ethnic or political groups. Each of the 'sects' is divided into moderate and radical factions, with intra-group transitions occurring either spontaneously or through indoctrination. We also include the possibility of one group violently attacking the other. The intra-group transition rates of one group are modelled to explicitly depend on the actions and characteristics of the other, including violent episodes, effectively coupling the dynamics of the two sects. We use a game theoretic framework and assume that radical factions may tune 'strategic' parameters to optimize given utility functions aimed at maximizing their ranks while minimizing the damage inflicted by their rivals. Constraints include limited overall resources that must be optimally allocated between indoctrination and external attacks on the other group. Various scenarios are considered, from symmetric sects whose behaviours mirror each other, to totally asymmetric ones where one sect may have a larger population or a superior resource availability. We discuss under what conditions sects preferentially employ indoctrination or violence, and how allowing sects to readjust their strategies allows for small, violent sects to grow into large, indoctrinated communities. PMID- 28879009 TI - Iron-based magnetic molecular imprinted polymers and their application in removal and determination of di-n-pentyl phthalate in aqueous media. AB - Iron-based magnetic molecular imprinted polymers (Fe@SiO2@MIP) were synthesized for highly selective removal and recognition of di-n-pentyl phthalate (DnPP) from water. Well-defined core-shell Fe@SiO2 nanoparticles (less than 70 nm) were decorated on MIPs reticular layers to endow DnPP-MIPs with magnetic property for the first time. Five other phthalic acid esters including dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di-n-butyl phthalate and di-iso-octyl phthalate were used to investigate the adsorptive selectivity to DnPP. The designed experiments were carried out to explore the adsorption kinetics, isotherms and thermodynamics and the results demonstrated that the adsorption was a spontaneous, exothermal and physical adsorption process. The materials were proved to be excellent adsorbents in removal of DnPP with an adsorption capacity as high as 194.15 mg g-1 in optimal condition. Furthermore, a magnetic solid phase extraction with Fe@SiO2@MIP coupled to high-performance liquid chromatography method was successfully developed for the determination of DnPP, and the proposed method achieved a good linear range of 0.5-250 ug l-1 with a correlation coefficient (R2) of 0.999 and low limit of detection (LOD) of 0.31 ug l-1. These materials exhibited excellent capacity in removal and highly sensitive identification of DnPP from aqueous environment samples, and opened a valuable direction for developing new adsorbents for the removal and enrichment of important pollutants. PMID- 28879011 TI - The morphology of the inner ear of squamate reptiles and its bearing on the origin of snakes. AB - The inner ear morphology of 80 snake and lizard species, representative of a range of ecologies, is here analysed and compared to that of the fossil stem snake Dinilysia patagonica, using three-dimensional geometric morphometrics. Inner ear morphology is linked to phylogeny (we find here a strong phylogenetic signal in the data that can complicate ecological correlations), but also correlated with ecology, with Dinilysia resembling certain semi-fossorial forms (Xenopeltis and Cylindrophis), consistent with previous reports. We here also find striking resemblances between Dinilysia and some semi-aquatic snakes, such as Myron (Caenophidia, Homalopsidae). Therefore, the inner ear morphology of Dinilysia is consistent with semi-aquatic as well as semi-fossorial habits: the most similar forms are either semi-fossorial burrowers with a strong affinity to water (Xenopeltis and Cylindrophis) or amphibious, intertidal forms which shelter in burrows (Myron). Notably, Dinilysia does not cluster as closely with snakes with exclusively terrestrial or obligate burrowing habits (e.g. scolecophidians and uropeltids). Moreover, despite the above similarities, Dinilysia also occupies a totally unique morphospace, raising issues with linking it with any particular ecological category. PMID- 28879012 TI - Essential oil optimizes the susceptibility of Callosobruchus maculatus and enhances the nutritional qualities of stored cowpea Vigna unguiculata. AB - The intensive use of synthetic pesticides in cowpea storage has led to the development of resistance by Callosobruchus maculatus and subsequent degradation of grain quality. In an attempt to circumvent these constraints, the susceptibility of C. maculatus to 2,2-dichlorovinyldimethyl phosphate (DDVP) and Lippia adoensis essential oil (EO) was investigated and variations in the proportions of nutritional values of treated grains 150 days after storage were assessed. The survival rate was recorded after five generations. The resistance index and biochemical parameters of grains were determined. The results from this study revealed that the survival rate and resistance index significantly increased proportionally with damage in DDVP treatments (r = 0.889; p = 0.018) while in EO treatments, those values remained low without significant variations (p = 0.0764) throughout the generations. DDVP stored grains yielded higher crude protein values, but lower carbohydrates, tannins, phenolics and minerals compared to EO. Eighteen amino acids were detected in EO treated grains and 14 in DDVP which was devoid of albumin and prolamin. Lippia adoensis EO could therefore represent a safe alternative bio-pesticide to cope with insect resistance and enhance the nutritional qualities of stored cowpea seeds. PMID- 28879013 TI - The dual impact of ecology and management on social incentives in marine common pool resource systems. AB - Understanding how and when cooperative human behaviour forms in common-pool resource systems is critical to illuminating social-ecological systems and designing governance institutions that promote sustainable resource use. Before assessing the full complexity of social dynamics, it is essential to understand, concretely and mechanistically, how resource dynamics and human actions interact to create incentives and pay-offs for social behaviours. Here, we investigated how such incentives for information sharing are affected by spatial dynamics and management in a common-pool resource system. Using interviews with fishermen to inform an agent-based model, we reveal generic mechanisms through which, for a given ecological setting characterized by the spatial dynamics of the resource, the two 'human factors' of information sharing and management may heterogeneously impact various members of a group for whom theory would otherwise predict the same strategy. When users can deplete the resource, these interactions are further affected by the management approach. Finally, we discuss the implications of alternative motivations, such as equity among fishermen and consistency of the fleet's output. Our results indicate that resource spatial dynamics, form of management and level of depletion can interact to alter the sociality of people in common-pool resource systems, providing necessary insight for future study of strategic decision processes. PMID- 28879014 TI - Annulus fibrosus functional extrafibrillar and fibrous mechanical behaviour: experimental and computational characterisation. AB - The development of current surgical treatments for intervertebral disc damage could benefit from virtual environment accounting for population variations. For such models to be reliable, a relevant description of the mechanical properties of the different tissues and their role in the functional mechanics of the disc is of major importance. The aims of this work were first to assess the physiological hoop strain in the annulus fibrosus in fresh conditions (n = 5) in order to extract a functional behaviour of the extrafibrillar matrix; then to reverse-engineer the annulus fibrosus fibrillar behaviour (n = 6). This was achieved by performing both direct and global controlled calibration of material parameters, accounting for the whole process of experimental design and in silico model methodology. Direct-controlled models are specimen-specific models representing controlled experimental conditions that can be replicated and directly comparing measurements. Validation was performed on another six specimens and a sensitivity study was performed. Hoop strains were measured as 17 +/- 3% after 10 min relaxation and 21 +/- 4% after 20-25 min relaxation, with no significant difference between the two measurements. The extrafibrillar matrix functional moduli were measured as 1.5 +/- 0.7 MPa. Fibre-related material parameters showed large variability, with a variance above 0.28. Direct controlled calibration and validation provides confidence that the model development methodology can capture the measurable variation within the population of tested specimens. PMID- 28879016 TI - Correction to 'Fossil skulls reveal that blood flow rate to the brain increased faster than brain volume during human evolution'. AB - [This corrects the article DOI: 10.1098/rsos.160305.]. PMID- 28879015 TI - Connecting the dots across time: reconstruction of single-cell signalling trajectories using time-stamped data. AB - Single-cell responses are shaped by the geometry of signalling kinetic trajectories carved in a multidimensional space spanned by signalling protein abundances. It is, however, challenging to assay a large number (more than 3) of signalling species in live-cell imaging, which makes it difficult to probe single cell signalling kinetic trajectories in large dimensions. Flow and mass cytometry techniques can measure a large number (4 to more than 40) of signalling species but are unable to track single cells. Thus, cytometry experiments provide detailed time-stamped snapshots of single-cell signalling kinetics. Is it possible to use the time-stamped cytometry data to reconstruct single-cell signalling trajectories? Borrowing concepts of conserved and slow variables from non-equilibrium statistical physics we develop an approach to reconstruct signalling trajectories using snapshot data by creating new variables that remain invariant or vary slowly during the signalling kinetics. We apply this approach to reconstruct trajectories using snapshot data obtained from in silico simulations, live-cell imaging measurements, and, synthetic flow cytometry datasets. The application of invariants and slow variables to reconstruct trajectories provides a radically different way to track objects using snapshot data. The approach is likely to have implications for solving matching problems in a wide range of disciplines. PMID- 28879017 TI - Correction to 'RNA sequencing reveals a complete but an unconventional type of dosage compensation in the domestic silkworm Bombyx mori'. AB - [This corrects the article DOI: 10.1098/rsos.170261.]. PMID- 28879018 TI - Are we missing non-motor seizures in Parkinson's disease? Two case reports. AB - BACKGROUND: Parkinson's disease (PD) is predominantly recognized for its motor symptoms, but patients struggle from a morbid and heterogeneous collection of non motor symptoms (NMS-PD) that can affect their quality of life even more. NMS-PD is a rather generalized term and the heterogeneity and non-specific nature of many symptoms poses a clinical challenge when a PD patient presents with non motor complaints that may not be NMS-PD. CASE PRESENTATION: We report two patients with idiopathic PD who presented with acute episodes of cognitive changes. Structural brain images, cardiovascular and laboratory assessment were unremarkable. Both patients experienced a considerable delay before receiving an epilepsy-evaluation, at which point electroencephalogram abnormalities supported the diagnosis of focal non-motor seizures with alteration of awareness. Antiepileptic therapy was implemented and was effective in both cases. CONCLUSIONS: Diagnosing non-motor seizures can be challenging. However, PD patients pose an even greater challenge given their eclectic non-motor clinical manifestations and other disease-related complications that could confound and mislead adequate clinical interpretation. Our two cases provide examples of non motor seizures that may mimic non-motor symptoms of PD. Treating physicians should always consider other possible causes of non-motor symptoms that may coexist in PD patients. Epilepsy work-up should be contemplated in the differential of acute changes in cognition, behavior, or alertness. PMID- 28879019 TI - Contraception and fertility transition in AMHARA National Regional State of ETHIOPIA: an application of BONGAARTS' model. AB - BACKGROUND: The overall decline of fertility in Amhara National Regional State between 2000 and 2011 was the highest in Ethiopia. The aim of the present study was to determine the most significant proximate determinant of fertility change during the last decade in the region using Bongaarts' model. METHODS: The sources of data were the 2000, 2005, and 2011 Ethiopia Demographic and Health Surveys. The model indices were calculated for each survey. Decomposition of fertility change into components of proximal determinants was also carried out. An index value close to 1 is a negligible inhibiting effect while a large inhibiting effect when the value very closes to 0. RESULTS: The fertility-constraining effect of contraception increased from 0.93 in 2000 to 0.65 in 2011; however, it was lower than the effect of postpartum insusceptibility at all given times. The index of marriage remained unchanged in constraining fertility over the period (0.71 in 2000 and 0.70 in 2011) while the influence of postpartum insusceptibility slightly declined from 0.49 in 2000 to 0.54 in 2011 but was stronger than contraception and marriage. The contribution of contraception was most important in urban areas (0.46 in 2011 from 0.52 in 2005 and 0.64 in 2000); however, in rural areas, it became an important determinant over the period (0.95 in 2000 and 0.69 in 2011). The effect of postpartum insusceptibility in rural areas showed a decreasing trend (0.48 in 2000 and 0.53 in 2011). The index of marriage in rural areas was stable overtime (0.75 in 2000 and 0.73 in 2011) while in urban areas the effect declined from 0.42 in 2000 to 0.65 in 2011. Marriage was the most important proximate determinant of fertility among women with secondary and above education but the impact declined during the period (0.41 in 2000 and 0.61 in 2011). The importance of postpartum insusceptibility in limiting fertility among women with secondary and above education declined overtime (0.77 in 2000 and 0.87 in 2011) whereas the contribution of contraception became more important (0.44 in 2000 and 0.35 in 2011). CONCLUSIONS: An increase in the level of contraceptive use and effectiveness overtime was the single most important contributing factor for the recent fertility decline in the region. PMID- 28879020 TI - Surgical castration with pain relief affects the health and productive performance of pigs in the suckling period. AB - BACKGROUND: Surgical castration is still practiced in many EU countries to avoid undesirable aggressive behavior and boar taint in male pigs. However, evidence shows that castration is painful and has a detrimental influence on pig health. This study investigated the clinical and productive effects of surgical castration in the suckling period. A total of 3696 male pigs, 3 to 6 days old, comprising of 721 litters from two different farms were included in the study. Within each litter, half of the males were kept as intact males (IM) and half were surgically castrated (CM). Surgical castration was conducted by a trained farmer. Average daily gain (ADG), body weight at weaning (BWW), percentage of pre weaning mortality (PWM) and antibiotic usage were measured. Pig major acute phase protein (PigMAP) serum concentrations were analyzed prior to castration, and on days 1 and 10 after castration. Productive performance data were analyzed using a linear mixed model. Mortality and percentage of pigs treated with antibiotics were analyzed using the Fisher's exact test. RESULTS: No overall differences in BWW and ADG were observed between the two groups. However, differences were observed when the same effects were analyzed in the 25% lightest, 50% medium and 25% heaviest pigs at birth. PWM was higher in CM than in IM groups (6.3% vs 3.6%; p < 0.001), especially in the light (12.2% vs 6.2%; p = 0.02) and in the medium (5.5% vs 2.7%; p = 0.04) weight groups. In the heaviest pigs group PWM was not affected by castration, but IM tended to show higher ADG (p = 0.06) and showed higher BWW (8.0 kg vs 7.8 kg; p = 0.05) than CM. There were no differences in percentage of pigs treated with antibiotics between the two groups (5.8% vs 5.8%; p = 0.98) in this study. Furthermore, PigMAP was increased in CM the day after castration (0.944 mg/ml vs 0.847 mg/ml; p = 0.025), but there was no difference between CM and IM groups at day 10. CONCLUSIONS: Surgical castration has a negative impact on production in the suckling period because it causes an increase in PWM, especially in pigs in the three lower quartiles for body weight, and negatively affects the BWW in pigs born in the highest quartile for body weight. PMID- 28879021 TI - DIAMOND (DIgital Alcohol Management ON Demand): a mixed methods feasibility RCT and embedded process evaluation of a digital health intervention to reduce hazardous and harmful alcohol use. AB - BACKGROUND: Alcohol is a major risk factor for preventable illness, with huge cost to healthcare economies. There is a role for alcohol-specific digital health interventions (DHI), but there have been few randomised controlled trials (RCT) comparing DHI with face-to-face treatment. Such trials are complex and face obstacles in recruitment and retention. METHODS: Mixed-methods feasibility RCT of an alcohol DHI, testing recruitment, online data-collection and randomisation processes, with an embedded process evaluation. Recruitment ran from October 2014 for 9 months. Participants were adults drinking at hazardous and harmful levels, attending four community drug and alcohol services (CDAS) in London. Participants completed baseline demographic, alcohol-related and other psychological questionnaires online and were randomised to HeLP-Alcohol, a six-module DHI with weekly reminder prompts (phone, email or text message), which mirrors face-to face treatment, or to face-to-face treatment at CDAS. Alcohol counsellors took part in qualitative interviews at the end of the study. RESULTS: Alcohol counsellors screened 1253 patients. One thousand one hundred eighty-nine did not meet inclusion criteria so were excluded: 579 were dependent drinkers, 548 had health conditions that made them ineligible to take part and 62 were ineligible for other reasons including homelessness. Of the 64 patients who were eligible to take part, 54 declined to participate, with 36 stating a preference for face-to face treatment, 13 gave no reason, and 5 gave other reasons including not wanting to use a computer. Ten consented but then 3 changed their minds, so we were able to randomise 7 participants to the study (11% of eligible). Five alcohol counsellors agreed to be interviewed for the process evaluation and provided the following feedback: Although most of their colleagues were enthusiastic about the trial, some were not at equipoise in recruiting; potential participants also declared strong preference to intervention arm from the outset. These factors affected recruitment. Counsellors also lacked time to undertake the data inputting and follow-up of participants in addition to their everyday work. CONCLUSIONS: This feasibility study aimed to test recruitment, randomisation, retention and data collection methods but recruited only 7 participants so these aims were not fully achieved. This illustrates to all researchers of complex interventions the importance of conducting feasibility studies and is generalisable to areas other than alcohol research. CDAS were seeing larger numbers of non-dependent drinkers with complex additional problems than alcohol commissioners expected. CDAS clients and some counsellors were not at equipoise for recruitment. Alternative settings for recruitment need to be explored in future trials. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number: ISRCTN31789096, DOI 10.1186/ISRCTN31789096. PMID- 28879022 TI - Pitch-side management of acute shoulder dislocations: a conceptual review. AB - The shoulder, specifically the glenohumeral joint, by virtue of its anatomical characteristics and biomechanics confers a large range of movement, which ultimately results in a joint that is inherently prone to becoming unstable. The incidence of acute traumatic shoulder dislocation varies within the sporting environment, commonly occurring following direct trauma. Anterior dislocations account for nearly 90% of all dislocations. While most are referred and managed in the emergency department, pitch-side relocation by experienced clinicians does occur prior to referral. The aim of this study was to delineate a guideline specifically for the pitch-side management of this common injury. A literature search of PubMed and Medline using the keywords 'prehospital', 'pitch-side', 'shoulder dislocation' and 'reduction' or 'relocation technique' was performed, and the available literature was reviewed and collated. Articles focusing on reduction techniques were then reviewed, with particular consideration on their applicability to a pitch-side setting. While studies exist that compare and contrast examination and reduction techniques, most are based in a hospital setting. To date, there is no standardised management protocol published for the initial management of an anterior dislocated shoulder in a pitch-side setting. This article addresses this discrepancy and proposes a structured, algorithmic approach to the pitch-side management of a shoulder dislocation. The article addresses factors to consider in a pitch-side setting, suitable techniques and postreduction care. While a systematic approach has been delineated in this article, we recommend those pitch-side medical practitioners who provide this form of support should have attended appropriate training and ensure adequate malpractice cover. PMID- 28879023 TI - Sports injuries and illnesses during the Granada Winter Universiade 2015. AB - OBJECTIVE: To analyse the incidence of diseases and injuries suffered by athletes participating in the 27th Winter Sports Universiade held in Granada, Spain. METHODS: The daily occurrence of injuries and diseases was registered at the point of first aid (Borreguiles, 2665 metres above sea level (masl)) and in the clinic of Pradollano (2017 masl), both in Sierra Nevada, as well as in medical services provided by the organising committee of Granada 2015 Universiade and located in sport pavilions in which indoor competitions are held. RESULTS: A total of 1109 athletes (650 men, 58.61%; 459 women, 41.39%). Nine diseases and 68 injuries were recorded. In total, the rate of injury was 6.13% (7.07% for men and 4.79% for women). The percentage of injury was highest in alpine skiing (10.34%) followed by freestyle skiing (8.62%). In relation to the time of exposure, freestyle skiing showed the shortest time of exposure (0.31 hours) before suffering an injury. Short track speed skating showed the longest exposure (9.80 hours), before suffering an injury. The most common anatomical areas of injury were the head, shoulder and knee (13.23%). Only nine diseases were suffered (four women and five men) of which six were infections, one was a friction burn, one was a lipothymy and one a cluster headache due to height. CONCLUSION: In general, 6.13% of the athletes sustained at least one injury and 0.81% a disease, which is a much lower percentage than that recorded in similar events. The incidence of injuries and diseases varied among sport specialities. PMID- 28879024 TI - Randomised, prospective, non-blinded pilot study comparing the effect of intramuscular steroid injections and intralesional steroid injections in the management of tennis elbow. AB - BACKGROUND: Tennis elbow is an overuse injury affecting people performing repetitive forearm movements. It is a soft tissue disorder that causes significant disability and pain. The aim of the study was to establish that an intramuscular steroid injection is effective in the short-term pain relief and functional improvement of tennis elbow. The severity of pain at the injection site was monitored to determine whether the intramuscular injection is better tolerated than the intralesional injection. METHODS AND RESULTS: 19 patients, who had no treatment for tennis elbow in the preceding 3 months, were recruited from Whipps Cross University Hospital, London, and were randomised to receive either 80 mg of intramuscular Depo-Medrone or 40 mg of intralesional Depo-Medrone injection. Blinding proved difficult as the injection sites differed and placebo arms were not included in the study. A Patient-Rated Tennis Elbow Evaluation (PRTEE) Questionnaire and a 10-point Likert scale were used to assess primary outcome. Six weeks after the treatment, there was a reduction in pain, improvement in function and total PRTEE scores in both intramuscular and intralesional groups (p=0.008) using a 95% CI for mean treatment difference of 26 to +16 points. A statistically significant result (p=0.001) in favour of intramuscular causing less pain at the injection site was noted. CONCLUSION: Non inferiority of intramuscular to intralesional injections was not confirmed; however, the intramuscular injection proved to be effective in reducing tennis elbow-related symptoms and was found less painful at the site of injection at the time of administration. TRIAL REGISTRATION NUMBER: EUDRACT Number: 2010-022131 11. REC Number: 10/H0718/76 (NRES, Central London REC 1). PMID- 28879025 TI - Are parents' motivations to exercise and intention to engage in regular family based activity associated with both adult and child physical activity? AB - BACKGROUND/AIM: To examine the associations between parents' motivation to exercise and intention to engage in family-based activity with their own and their child's physical activity. METHODS: Cross-sectional data from 1067 parent child pairs (76.1% mother-child); children were aged 5-6 years. Parents reported their exercise motivation (ie, intrinsic motivation, identified regulation, introjected regulation, external regulation and amotivation) as described in self determination theory and their intention to engage in family-based activity. Parents' and children's mean minutes of moderate-to-vigorous-intensity physical activity (MVPA) and mean counts per minute were derived from ActiGraph accelerometers worn for 3 to 5 days (including a mixture of weekdays and weekend days). Multivariable linear regression models, adjusted for parent sex, number of children, indices of multiple deprivation and clustering of children in schools were used to examine associations (total of 24 associations tested). RESULTS: In fully adjusted models, each unit increase in identified regulation was associated with a 6.08 (95% CI 3.27 to 8.89, p<0.001) min-per-day increase in parents' MVPA. Parents' external regulation was associated with children performing 2.93 (95% CI -5.83 to -0.03, p=0.05) fewer minutes of MVPA per day and a 29.3 (95% CI -53.8 to -4.7, p=0.02) accelerometer count-per-minute reduction. There was no evidence of association for the other 21 associations tested. CONCLUSIONS: Future family based physical activity interventions may benefit from helping parents identify personal value in exercise while avoiding the use of external control or coercion to motivate behaviour. PMID- 28879027 TI - Movement and physical demands of school and university rugby union match-play in England. AB - BACKGROUND: In England, rugby union is a popular sport and is widely played within schools. Despite the large participation numbers, the movement and physical demands of the sport and how they progress by age have not been explored. METHOD: Ninety-six male rugby union players wore microtechnology devices during six rugby union matches within the education pathway to investigate the movement and physical demands of match-play. To quantify the positional differences and progression by age, data were obtained for participants at the under 16 (U16) (n=31 participants), under 18 (U18) (n=34 participants) and university (n=31 participants) levels. Players were further divided in forwards and backs. Data were analysed using magnitude-based inferences. RESULTS: For the movement demands, U16 total distance and 'striding' was likely higher for forwards than backs, whereas at U18, unclear differences were observed and from university players the inverse was observed (very likely). In all age groups sprint distance was likely to very likely greater for backs than forwards. Forwards had greater physical demands than backs at all age groups. For consecutive age groups, U16 had a likely higher relative distance than U18, and U18 had a likely lower relative distance than university players. Physical demands were similar across age groups for forwards, and greater for backs at older age groups. CONCLUSION: The movement and physical demands of rugby union players participating in schools (U16 and U18), may not be as expected, however, the findings from university players show a similar pattern to the senior game. PMID- 28879026 TI - Update on the effects of physical activity on insulin sensitivity in humans. AB - PURPOSE AND METHODS: This review presents established knowledge on the effects of physical activity (PA) on whole-body insulin sensitivity (SI) and summarises the findings of recent (2013-2016) studies. DISCUSSION AND CONCLUSIONS: Recent studies provide further evidence to support the notion that regular PA reduces the risk of insulin resistance, metabolic syndrome and type 2 diabetes, and SI improves when individuals comply with exercise and/or PA guidelines. Many studies indicate a dose response, with higher energy expenditures and higher exercise intensities, including high intensity interval training (HIIT), producing greater benefits on whole-body SI, although these findings are not unanimous. Aerobic exercise interventions can improve SI without an associated increase in cardiorespiratory fitness as measured by maximal or peak oxygen consumption. Both aerobic and resistance exercise can induce improvements in glycaemic regulation, with some suggestions that exercise regimens including both may be more efficacious than either exercise mode alone. Some studies report exercise-induced benefits to SI that are independent of habitual diet and weight loss, while others indicate an association with fat reduction, hence the debate over the relative importance of PA and weight loss continues. During exercise, muscle contraction stimulated improvements in SI are associated with increases in AMPK activity, which deactivates TCB1D1, promoting GLUT4 translocation to the cell membrane and thereby increasing glucose uptake. Postexercise, increases in Akt deactivate TCB1D4 and thereby increase GLUT4 translocation to the cell membrane. The reduction in intramuscular saturated fatty acids and concomitant reductions in ceramides, but not diacylglycerols, provide a potential link between intramuscular lipid content and SI. Increased skeletal muscle capillarisation provides another independent adaptation through which SI is improved, as does enhanced beta cell activity. Recent studies are combining exercise interventions with dietary and feeding manipulations to investigate the potential for augmenting the exercise-induced improvements in SI and glycaemic control. PMID- 28879028 TI - Reduced muscular fatigue after a 12-week leucine-rich amino acid supplementation combined with moderate training in elderly: a randomised, placebo-controlled, double-blind trial. AB - BACKGROUND: Age-related muscle loss is characterised by a progressing decrease in muscle mass, strength and function. Besides resistance training and physical activity, appropriate nutrition that is rich in protein, especially branched chain amino acids, is very important to support training effects and positively influence the protein synthesis to degradation ratio. AIM: The purpose of this study was to evaluate the effect of a 12-week leucine-rich amino acid supplementation in combination with moderate training. METHODS: Forty-eight healthy subjects exercised for 30 min three times per week and received either a leucine-rich amino acid supplementation or a placebo. Before and after supplementation, volunteers performed an exhaustive eccentric exercise protocol. Maximal concentric strength, muscle soreness, creatine kinase (CK), type II collagen collagenase cleavage neoepitope (C2C), C propeptide of type II procollagen (CP2) and safety assessments were performed before exercise and after 3, 24, 48 and 72 hours. RESULTS: The supplementation with leucine resulted in reduced loss of strength at 0 and 3 hours after downhill walking compared with the placebo (p=0.0439). The reduction of C2C/CP2 ratio deflection was significantly increased (p=0.038) due to leucine compared with the placebo. The same tendency could be observed for the recovery phase. No significant supplement effects for muscle soreness and CK could be observed. CONCLUSION: The principle findings show that leucine-rich amino acid supplementation can counteract the negative effects of eccentric exercise. The treatment resulted in a reduction of exercise-induced strength loss. PMID- 28879029 TI - Prevalence of FAI radiographic hip abnormalities in elite soccer players: are there differences related to skeletal maturity? AB - BACKGROUND: Femoroacetabular impingement (FAI) can be a source of hip pain in young adults. Some reports have revealed that participation in high-impact sports may play a role in the development of cam deformity, and there is a higher prevalence of signs of cam impingement in asymptomatic adolescents who participate in soccer and basketball than in non-athlete controls; however, current evidence is scarce regarding the initiation and development of deformities. PURPOSE: The aim of this study was to evaluate the prevalence of radiographic hip abnormalities related to FAI in young elite soccer players and compare this with findings in a group of adult elite soccer players. SUBJECTS AND METHODS: Anteroposterior pelvic and cross-table hip radiographs were obtained for 75 young elite soccer players with skeletal immaturity (group 1) and for 75 adult elite soccer players (group 2), all of whom were previously asymptomatic and had no history of hip disease. After exclusion, group 1 included 72 patients, and group 2 included 70 patients. Radiological signs of FAI were evaluated. RESULTS: 34 subjects in groups 1 and 2 demonstrated cam morphology. The prevalence of pincer morphology was 30 in group 1 and 36 in group 2. However, these differences were not statistically significant. CONCLUSION: We found no differences in the prevalence of FAI radiological signs between soccer players in their late adolescence and adult soccer players. PMID- 28879030 TI - Metabolic equivalents fail to indicate metabolic load in post-myocardial infarction patients during the modified Bruce treadmill walking test. AB - AIM: To investigate the suitability of metabolic equivalents (METs) for determining exercise intensity in phase-IV post-myocardial infarction (MI) men during the modified Bruce treadmill walking test (MBWT). METHODS: Twenty phase-IV post-MI men (mean+/-SD, aged 64.4+/-5.8 years) and 20 healthy non-cardiac male controls (59.8+/-7.6 years) participated. Participants performed a MBWT. Throughout the participants' heart rate (HR), heart rhythm, expired air parameters and ratings of perceived exertion (RPEs) were measured. MET values were compared between groups and those currently ascribed to each stage of the MBWT. RESULTS: General linear model analysis found no significant differences between groups during the MBWT for VO2, VCO2, HR, METs or RPEs (Borg 6-20 scale). Ascribed METs did not differ from mean METs of post-MIs or controls other than at stage 5 where post-MI METs were significantly lower. Irrespective, the post-MI group worked at a higher percentage of their anaerobic threshold (AT) (respiratory exchange ratio, RER=1.0) (F(2,5)=7.22, p<0.008), higher RER (F(2,5)=11.25, p<0.001) with increased breathing frequency (F(2,5)=7.22, p<0.001). Regression analysis revealed AT to be VO2 25.6 (mL/kg/min) for post-MI versus VO2 31.1 (mL/kg/min) for controls. Gross energy expenditure (kcal/min) was greater for the post-MI group compared with controls (F(2,5)=11.22, p<0.001). Throughout the MBWT, post-MI group worked at a higher %AT/MET than controls (F(2,196)=211.76, p<0.01). Body composition did not strongly influence %AT/MET, parameters of VO2, METs or RPE. CONCLUSION: During the MBWT, post-MI men worked more anaerobically per MET (%AT/MET) than controls. Therefore, current METs based on non-cardiac individuals appear unsuitable in determining the full metabolic load of the exercise intensity for cardiac patients during the MBWT. PMID- 28879031 TI - Descriptive analysis of objectively assessed physical activity among talented soccer players: a study of three Norwegian professional football clubs. AB - BACKGROUND: Talented football players are expected to overcome large training and match loads, indicating a high weekly level of physical activity (PA). AIMS: With the use of accelerometers, the aim of this study was to objectively describe the players' total time spent in moderate-to-vigorous PA (MVPA), vigorous PA (VPA) and very vigorous PA (VVPA) per day in 1 week. Since high-intensity PA has been highlighted as important in terms of overall PA load, we also included 2 and 4 min bouts of VPA. METHODS: Data were collected in three junior teams in professional football clubs in March (club 1: 2014, club 2: 2012 and club 3: 2011). A one-way analysis of variance was applied to analyse differences between the three respective clubs. RESULTS: The players averaged 77.2-86.2 min in MVPA, 14.9-18.5 min in VPA and 1.0-3.1 in VVPA per day. While there were no differences in total time spent in MVPA and VPA per day, VVPA was significantly higher in club 1 (p<0.01) compared with clubs 2 and 3. Moreover, when using the VPA bouts, club 3 (p<0.01) achieved significantly more time in this intensity compared with clubs 1 and 2. CONCLUSION: This study acknowledges the importance of including both club-related and non-club-related PA when analysing talented football players' PA level. We suggest that future studies examining players' PA with accelerometers should emphasise time spent in high-intensity PA and how this is associated with physical overload, psychological burnout and risk of injury. PMID- 28879032 TI - Epidemiology of injuries in the Spanish national futsal male team: a five-season retrospective study. AB - BACKGROUND: Futsal started being played in 1930 and the number of futsal players has increased all over the world ever since. Nonetheless, despite the fact that Spain is one of the most relevant national teams worldwide, information on the incidence of injuries and their anthropometric characteristics is sparse in this country. AIM: To analyse medical assistance provided to players in their prematch concentration camps with the Spanish national team over five seasons, from 2010 2011 to 2014-2015, and also to collect data regarding anthropometric characteristics. MATERIALS AND METHODS: This is a retrospective and detailed study of injuries players suffered over these five seasons. All variables were registered on an Excel spreadsheet and later analysed statistically. RESULTS: 411 injuries were studied in total. The dominant somatotype was mesomorph and the injured pivots were both the most endomorphic and the most mesomorphic. The most injured body structure was the hamstring muscles, occurring due to training and intrinsic mechanisms, where fatigue was the most frequent diagnosis. Only a few complementary examinations were carried out and prematch withdrawal was rare. DISCUSSION: The skinfold test total sum was lower than that of the Spanish 11-a side players or than that in the lower category futsal Spanish players. In various research studies analysing exclusively injuries occurring in matches, the most frequent injury is ligament injury by extrinsic mechanism. The body mass index was not a useful parameter when assessing players' appropriate weight. Most injuries occurred in training sessions, mostly by intrinsic mechanism; the highest percentage of traumatic injuries occurred in official matches. PMID- 28879033 TI - Effects of a systemic enzyme therapy in healthy active adults after exhaustive eccentric exercise: a randomised, two-stage, double-blinded, placebo-controlled trial. AB - BACKGROUND: Systemic enzyme therapy may improve symptoms of exhaustive eccentric exercise due to anti-inflammatory properties. METHODS: In a randomised, placebo controlled, two-stage clinical trial, systemic enzyme therapy (Wobenzym) was administered for 72 hours before and 72 hours following a day on which subjects performed an exhaustive eccentric exercise (isokinetic loading of the quadriceps). Efficacy criteria (maximal strength and pain) and time points were selected to account for the multidimensional nature of exercise-induced muscle damage symptoms. Subjects were randomised in a crossover (stage I, n=28) and parallel group design (stage II, n=44). RESULTS: Analysis of stage I data demonstrated a significant superiority (Mann-Whitney=0.6153; p=0.0332; one sided) for systemic enzyme therapy compared with placebo. Stage II was designed as a randomised controlled parallel group comparison. Heterogeneity (I2>0.5) between stages led to separate analyses of stage I (endurance-trained subjects) and stage II (strength-trained subjects). Combined analysis resulted in no evidence for corresponding treatment effects. Analysis of pooled biomarker data, however, demonstrated significant favourable effects for systemic enzyme therapy in both stages. CONCLUSION: Systemic enzyme therapy before and after exhaustive eccentric exercise resulted in higher maximal concentric strength in the less strength trained subjects (stage I) and in significant favourable effects on biomarkers (inflammatory, metabolic and immune) in all subjects. The application of these findings needs further evaluation. PMID- 28879034 TI - Unloading knee brace is a cost-effective method to bridge and delay surgery in unicompartmental knee arthritis. AB - BACKGROUND: Unloading knee braces can provide good short-term pain relief for some patients with unicompartmental osteoarthritis (UOA). Their cost is relatively small compared with surgical interventions. However, no previous studies have reported their use over a duration of 5 years or more. METHODS: Up to 8 years of prospective data were collected from 63 patients who presented with UOA. After conservative management with analgesia and physiotherapy, patients were offered an unloading brace. EQ-5D (EuroQol five dimensions) questionnaires were collected at baseline and after wearing the brace. Cost and quality-adjusted life years (QALYs) were compared with a total knee replacement (TKR) with an 8 month waiting duration and 8 years of results. RESULTS: Patients experienced a mean increase in EQ-5D of 0.42 with an average duration of wear of 26.1 months resulting in an increase of 0.44 in QALYs with a mean cost of L625. The adoption of an unloader knee brace was found to be a short-term cost-effective treatment option with an 8-month incremental cost effectiveness ratio of L9599. Compared with no treatment, the unloader knee brace can be considered cost effective at 4 months or more. At 8 years follow-up, the unloader knee brace demonstrated QALYs gain of 0.43 and with an incremental cost-effectiveness ratio of -L6467 compared with TKR. CONCLUSION: Unloading knee braces are cost effective for the management of UOA. These findings strongly support the undertaking of further research into the long-term impact of unloading knee brace. The unloader knee brace has benefits to the National Health Service for capacity, budget, waiting list duration, frequency of surgery and reducing the required severity of surgical intervention. PMID- 28879035 TI - Objective functional results in patients with knee osteoarthritis submitted to a 2-day educational programme: a prospective randomised clinical trial. AB - BACKGROUND: Although education is recommended for the treatment of knee osteoarthritis (KOA), its effectiveness in osteoarthritis (OA) remains low according to subjective questionnaires. The timed-up-and-go (TUG) and five-times sit-to-stand tests (FTSST) reflect muscle strength and balance and could be used as objective measures of effectiveness. AIM: To measure the effect of an educational programme in patients with KOA by TUG and FTSST and correlate these results to those of subjective questionnaires. METHODS: Prospective randomised controlled trial of patients with KOA. Participants (n=198) were allocated into four groups. Three groups participated in 2 days of lectures with 1 (group 1), 2 (group 2) and 3-month (group 3) intervals between classes. Group 4 had no classes. Participants were asked to exercise at least three times a week. Half of the patients from all groups received bimonthly telephone calls reinforcing diet and exercise instructions. All four groups received the printed and video material presented in the classes. At baseline and at 1 year after initial assessment, patients performed the FTSST and TUG and answered WOMAC, Lequesne, SF 36 and Visual Analogue Scale questionnaires. RESULTS: The TUG results did not change at 1 year follow-up, whereas FTSST improved (average difference of 4.66, p<0.001) irrespective of the implementation of classes or telephone calls. Both baseline and 1 year TUG and FTSST results correlated weakly (r<0.3) to the subjective functional, pain and quality of life results (p<0.001). CONCLUSIONS: This educational programme improved function as determined by lower limb muscle strength (FTSST) irrespective of the patients' subjective non-improvement. TRIAL REGISTRATION NUMBER: Clinical trials registration number: NCT01572051. LEVEL OF EVIDENCE: Level 1A. PMID- 28879036 TI - Evaluation of determinants of walking fitness in patients attending cardiac rehabilitation. AB - AIM: This study aims to investigate the ability of patients' baseline characteristics to predict the distance walked during the incremental shuttle walk test (ISWT) in the cardiac rehabilitation (CR) population and to produce reference values to guide practice. METHODS: Secondary analysis was conducted on National Audit Cardiac Rehabilitation data collected between 2010 and 2015. Patients (n=8863) were included if they were aged >=18 years and had a recorded ISWT score assessed before starting CR. Stepwise regression was used to identify factors predicting the ISWT distance. Age, gender, body mass index, height, weight; presence of hypertension, dyslipidemia or diabetes; smoking and physical activity were independent variables. ISWT distance was the dependent variable. The 25th, 50th and 75th percentiles of the ISWT distance were used as reference values. RESULTS: Age and gender explained 27% of the variance of the distance covered in the ISWT (R2=0.27, adjusted R2=0.27,Standard Error of the Estimate (SEE) = 148.7, p<0.001). Reference values using age and gender categories were developed. CONCLUSION: Age and gender were the significant factors for predicting the walking fitness in the CR population, with age being the best predictor. The age and gender reference values produced represent a potentially valuable tool to be used in the clinical setting. PMID- 28879037 TI - Outcomes in patients with glenoid labral lesions: a cohort study. AB - BACKGROUND/AIM: For patients presenting with glenoid labral pathologies, there is little information on how operative interventions affect long-term outcomes and health-related quality of life (HRQoL). This study evaluated outcomes in operative and non-operative patients presenting with labral tears versus labral degenerations. METHODS: Participants completed a pain Visual Analogue Scale (VAS), the Veterans RAND 12-item Health Survey, Western Ontario Rotator Cuff Index, American Shoulder and Elbow Surgeons instrument, Scapular Assistance Test (SAT), Shoulder Activity Level, and Single Assessment Numeric Evaluation at baseline and at 6-month, 12-month and 2-year follow-ups. chi2and Student's t-test were used to test the differences between categorical and continuous variables. Analysis of variance investigated the differences between groups, and linear regression analyses explored the relationship of baseline characteristics with outcome scores. RESULTS: After 2 years, the operative cohort (n=68) significantly improved in all measures. The non-operative cohort (n=55) showed significant improvements in all scores except the mental component summary (MCS) and pain VAS. Labral tear patients (n=52) within the operative group (n=28) significantly improved in all measures except MCS. Non-operative labral tear patients (n=24) indicated significant improvements in all measures except MCS, VAS and SAT. Labral degeneration patients (n=71) within the operative group (n=27) significantly improved in all measures except MCS and SAT. Non-operative labral degeneration patients (n=44) indicated significant improvements in all measures except the physical component summary, MCS, VAS and SAT. CONCLUSION: Patients who were surgically treated for labral tears or degenerations had significantly improved outcomes and HRQoL scores after 2 years compared with the non-operative cohort. PMID- 28879038 TI - No effects of functional exercise therapy on walking biomechanics in patients with knee osteoarthritis: exploratory outcome analyses from a randomised trial. AB - AIM: To assess the effects of a functional and individualised exercise programme on gait biomechanics during walking in people with knee OA. METHODS: Sixty participants were randomised to 12 weeks of facility-based functional and individualised neuromuscular exercise therapy (ET), 3 sessions per week supervised by trained physical therapists, or a no attention control group (CG). Three-dimensional gait analyses were used, from which a comprehensive list of conventional gait variables were extracted (totally 52 kinematic, kinetic and spatiotemporal variables). According to the protocol, the analyses were based on the 'Per-Protocol' population (defined as participants following the protocol with complete and valid gait analyses). Analysis of covariance adjusting for the level at baseline was used to determine differences between groups (95% CIs) in the changes from baseline at follow-up. RESULTS: The per-protocol population included 46 participants (24 ET/22 CG). There were no group differences in the analysed gait variables, except for a significant group difference in the second peak knee flexor moment and second peak vertical ground reaction force. CONCLUSION: While plausible we have limited confidence in the findings due to multiple statistical tests and lack of biomechanical logics. Therefore we conclude that a 12-week supervised individualised neuromuscular exercise programme has no effects on gait biomechanics. Future studies should focus on exercise programmes specifically designed to alter gait patterns, or include other measures of mobility, such as walking on stairs or inclined surfaces. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01545258. PMID- 28879039 TI - The tymbal muscle of cicada has flight muscle-type sarcomeric architecture and protein expression. AB - BACKGROUND: The structural and biochemical features of the tymbal (sound producing) muscle of cicadas were studied by X-ray diffraction and immunochemistry, and compared with those of flight muscles from the same species. RESULTS: The X-ray diffraction pattern of the tymbal muscle was very similar to that of the dorsal longitudinal flight muscle: In both muscles, the 2,0 equatorial reflection is much more intense than the 1,1, indicating that both muscles have a flight muscle-type myofilament lattice. In rigor, the first myosin/actin layer line reflection was finely lattice-sampled, indicating that the contractile proteins are arranged with a crystalline regularity as in asynchronous flight muscles. In contrast, the diffraction pattern from the tensor muscle, which modulates the sound by stressing the tymbal, did not show signs of such high regularity or flight muscle-type filament lattice. Electrophoretic patterns of myofibrillar proteins were also very similar in the tymbal muscle and flight muscles, but distinct from those from the tensor or leg muscles. The antibody raised against the flight muscle-specific troponin-I isoform reacted with an 80-kDa band from both tymbal and flight muscles, but with none of the bands from the tensor or leg muscles. CONCLUSION: The close similarities of the structural and biochemical profiles between the tymbal and the flight muscles suggest the possibility that a set of flight muscle-specific proteins is diverted to the tymbal muscle to meet its demand for fast, repetitive contractions. PMID- 28879040 TI - Comparison of effects between calcium channel blocker and diuretics in combination with angiotensin II receptor blocker on 24-h central blood pressure and vascular hemodynamic parameters in hypertensive patients: study design for a multicenter, double-blinded, active-controlled, phase 4, randomized trial. AB - BACKGROUND: Hypertension is a risk factor for coronary heart disease and stroke, and is one of the leading causes of death. Although over a billion people are affected worldwide, only half of them receive adequate treatment. Current guidelines on antihypertensive treatment recommend combination therapy for patients not responding to monotherapy, but as the number of pills increase, patient compliance tends to decrease. As a result, fixed-dose combination drugs with different antihypertensive agents have been developed and widely used in recent years. CCBs have been shown to be better at reducing central blood pressure and arterial stiffness than diuretics. Recent studies have reported that central blood pressure and arterial stiffness are associated with cardiovascular outcomes. This trial aims to compare the efficacy of combination of calcium channel blocker (CCB) or thiazide diuretic with an angiotensin receptor blocker (ARB). METHODS: This is a multicenter, double-blinded, active-controlled, phase 4, randomized trial, comparing the antihypertensive effects of losartan/amlodipine and losartan/hydrochlorothiazide in patients unresponsive to treatment with losartan. The primary endpoint is changes in mean sitting systolic blood pressure (msSBP) after 4 weeks of treatment. Secondary endpoints are changes in msSBP, mean 24-h ambulatory mobile blood pressure, mean 24-h ambulatory mobile central SBP, mean 24-h ambulatory carotid-femoral pulse wave velocity, ambulatory augmentation index, and microalbuminuria/proteinuria after 20 weeks of treatment. The sample size will be 119 patients for each group in order to confer enough power to test for non-inferiority regarding the primary outcome. CONCLUSION: The investigators aim to prove that combination of a CCB with ARB shows non-inferiority in lowering blood pressure compared with a combination of thiazide diuretic and ARB. We also hope to distinguish the subset of patients that are more responsive to certain types of combination drugs. The results of this study should aid physicians in selecting appropriate combination regimens to treat hypertension in certain populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT02294539. Registered 12 November 2014. PMID- 28879041 TI - Pulmonary arterial hypertension, a novelty in idiopathic inflammatory myopathies: insights and first experiences with vasoactive therapy. AB - To characterise the different types of pulmonary hypertension (PH) among idiopathic inflammatory myopathy (IIM). A retrospective case series with assessment of PH by right heart catheterisation, extent of interstitial lung disease (ILD) and outcome of vasoactive therapy.The group of patients with IIM with PH (n=9) showed a median age at PH diagnosis of 62 years (IQR 48-71 years; eight women), seven diagnosed with polymyositis and two with dermatomyositis; median disease duration of 5.7 years and five patients with a positive anti-Jo1 antibody. We found one patient to be classified in PH WHO group 2 (left heart disease), five patients in WHO group 3 (lung disease) and three patients in WHO group 1 (pulmonary arterial hypertension (PAH)). During median observed follow-up of 24 months, mortality for the total group was 44%. Surprisingly, we found a relevant group (33%) of patients with IIM who suffered from non-ILD-PH, which reflects the presence of PAH phenotype. This result should lead to more awareness among treating physicians that complaints of dyspnoea among patient with IIM could be related to PAH and not only ILD. The role of vasoactive therapy remains to be defined in patients with IIM suffering from PAH or PH-ILD. PMID- 28879043 TI - Fully automated joint space width measurement and digital X-ray radiogrammetry in early RA. AB - OBJECTIVES: To study fully automated digital joint space width (JSW) and bone mineral density (BMD) in relation to a conventional radiographic scoring method in early rheumatoid arthritis (eRA). METHODS: Radiographs scored by the modified Sharp van der Heijde score (SHS) in patients with eRA were acquired from the SWEdish FarmacOTherapy study. Fully automated JSW measurements of bilateral metacarpals 2, 3 and 4 were compared with the joint space narrowing (JSN) score in SHS. Multilevel mixed model statistics were applied to calculate the significance of the association between DeltaJSW and DeltaBMD over 1 year, and the JSW differences between damaged and undamaged joints as evaluated by the JSN. RESULTS: Based on 576 joints of 96 patients with eRA, a significant reduction from baseline to 1 year was observed in the JSW from 1.69 (+/-0.19) mm to 1.66 (+/-0.19) mm (p<0.01), and BMD from 0.583 (+/-0.068) g/cm2 to 0.566 (+/-0.074) g/cm2 (p<0.01). A significant positive association was observed between DeltaJSW and DeltaBMD over 1 year (p<0.0001). On an individual joint level, JSWs of undamaged (JSN=0) joints were wider than damaged (JSN>0) joints: 1.68 mm (95% CI 1.70 to 1.67) vs 1.54 mm (95% CI 1.63 to 1.46). Similarly the unadjusted multilevel model showed significant differences in JSW between undamaged (1.68 mm (95% CI 1.72 to 1.64)) and damaged joints (1.63 mm (95% CI 1.68 to 1.58)) (p=0.0048). This difference remained significant in the adjusted model: 1.66 mm (95% CI 1.70 to 1.61) vs 1.62 mm (95% CI 1.68 to 1.56) (p=0.042). CONCLUSIONS: To measure the JSW with this fully automated digital tool may be useful as a quick and observer-independent application for evaluating cartilage damage in eRA. TRIAL REGISTRATION NUMBER: NCT00764725. PMID- 28879042 TI - Salivary gland ultrasound abnormalities in primary Sjogren's syndrome: consensual US-SG core items definition and reliability. AB - OBJECTIVES: Ultrasonography (US) is sensitive for detecting echostructural abnormalities of the major salivary glands (SGs) in primary Sjogren's syndrome (pSS). Our objectives were to define selected US-SG echostructural abnormalities in pSS, set up a preliminary atlas of these definitions and evaluate the consensual definitions reliability in both static and acquisition US-SG images. METHODS: International experts in SG US in pSS participated in consensus meetings to select and define echostructural abnormalities in pSS. The US reliability of detecting these abnormalities was assessed using a two-step method. First 12 experts used a web-based standardised form to evaluate 60 static US-SG images. Intra observer and interobserver reliabilities were expressed in kappa values. Second, five experts, who participated all throughout the study, evaluated US-SG acquisition interobserver reliability in pSS patients. RESULTS: Parotid glands (PGs) and submandibular glands (SMGs) intra observer US reliability on static images was substantial (kappa > 0.60) for the two main reliable items (echogenicity and homogeneity) and for the advised pSS diagnosis. PG inter observer reliability was substantial for homogeneity. SMGs interobserver reliability was moderate for homogeneity (kappa = 0.46) and fair for echogenicity (kappa = 0.38). On acquisition images, PGs interobserver reliability was substantial (kappa = 0.62) for echogenicity and moderate (kappa = 0.52) for homogeneity. The advised pSS diagnosis reliability was substantial (kappa = 0.66). SMGs interobserver reliability was fair (0.20< kappa <= 0.40) for echogenicity and homogeneity and either slight or poor for all other US core items. CONCLUSION: This work identified two most reliable US-SG items (echogenicity and homogeneity) to be used by US-SG trained experts. US-PG interobserver reliability result for echogenicity is in line with diagnosis of pSS. PMID- 28879044 TI - Evaluating quality of care in rheumatoid arthritis: the patient perspective. PMID- 28879045 TI - Functional limitations in the phase of clinically suspect arthralgia are as serious as in early clinical arthritis; a longitudinal study. AB - INTRODUCTION: A phase of arthralgia may precede the emergence of rheumatoid arthritis (RA). Although several studies have focused on biomarkers, the relevance of this phase for patients is less studied. It is unknown if patients already have functional limitations and if this is correlated to the extent of subclinical inflammation. Therefore, we assessed functional disability in patients with clinically suspect arthralgia (CSA), its association with MRI detected subclinical inflammation and its course during progression to clinical arthritis. METHODS: From April 2012 to March 2015, 241 patients had arthralgia for <1 year and were, based on clinical presentation, considered at risk for RA by their rheumatologists. At baseline, Health Assessment Questionnaire (HAQ) scores were determined and unilateral 1.5 T MRI of metacarpophalangeal, wrist and metatarsophalangeal joints were made. Presence of MRI-detected subclinical inflammation was assessed by summing synovitis, tenosynovitis and bone marrow oedema scores (range 0-189). Patients were followed on arthritis development and HAQ scores were repeated when clinical arthritis had developed. RESULTS: The median HAQ score at presentation with CSA was 0.50. Higher MRI-inflammation scores were associated with higher HAQ scores (beta=0.017, 95% CI=0.004 to 0.030). During median 103 weeks follow-up, 44 patients progressed to clinical arthritis. HAQ scores >=1.0 were associated with arthritis development (HR=2.50, 95% CI=1.03 to 6.10). Within converters, median HAQ scores did not increase from presentation with CSA to arthritis development (0.88 and 0.75, p=0.36). CONCLUSIONS: HAQ scores >=1.0 at presentation were associated with the development of clinical arthritis. Functional limitations in the prearthritis phase of CSA were as serious as in the early clinical phase, demonstrating the relevance of CSA from patients' perspectives. PMID- 28879046 TI - Flares assessed weekly in patients with rheumatoid arthritis or axial spondyloarthritis and relationship with physical activity measured using a connected activity tracker: a 3-month study. AB - BACKGROUND: The evolution of rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA) is marked by flares, although their frequency is unclear. Flares may impact physical activity. Activity can be assessed objectively using activity trackers. The objective was to assess longitudinally the frequency of flares and the association between flares and objective physical activity. METHODS: This prospective observational study (ActConnect) included patients with definite clinician-confirmed RA or axSpA, owning a smartphone. During 3 months, physical activity was assessed continuously by number of steps/day, using an activity tracker, and disease flares were self-assessed weekly using a specific flare question and, if relevant, the duration of the flare. The relationship between flares and physical activity for each week (time point) was assessed by linear mixed models. RESULTS: In all, 170/178 patients (91 patients with RA and 79 patients with axSpA; 1553 time points) were analysed: mean age was 45.5+/-12.4 years, mean disease duration was 10.3+/-8.7 years, 60 (35.3%) were men and 90 (52.9%) received biologics. The disease was well controlled (mean Disease Activity Score 28: 2.3+/-1.2; mean Bath Ankylosing Spondylitis Disease Activity Index score: 3.3+/-2.1). Patients self-reported flares in 28.2%+/-28.1% of the weekly assessments. Most flares (78.9%+/-31.4%) lasted <=3 days. Persistent flares lasting more than 3 days were independently associated with less weekly physical activity (p=0.03), leading to a relative decrease of 12%-21% and an absolute decrease ranging from 836 to 1462 steps/day. CONCLUSION: Flares were frequent but usually of short duration in these stable patients with RA and axSpA. Persistent flares were related to a moderate decrease in physical activity, confirming objectively the functional impact of patient reported flares. PMID- 28879047 TI - Treatment of polyarteritis nodosa with tocilizumab: a new therapeutic approach? AB - We describe the effect of interleukin 6 (IL-6) blockade using tocilizumab (TCZ) for inducing and maintaining remission of refractory polyarteritis nodosa (PAN). Three patients with refractory PAN defined according to the American College of Rheumatology criteria were treated with TCZ infusions (8 mg/kg) on a monthly basis. All of them had severe cutaneous and articular involvement with elevated biological inflammatory markers. One suffered from a neuritis multiplex and one from renal and digestive damage. All three patients were dependent on high doses of glucocorticoids (above 0.5 mg/kg) and two of them were resistant to immunosuppressive drugs. All patients achieved and maintained clinical response and normalisation of the inflammation acute-phase proteins after a few weeks of treatment with TCZ. Prednisolone could be reduced by an average of 41-13 mg/day. These first case reports suggest that IL-6 blockade using TCZ could be a therapeutic alternative to induce remission in patients with polyarteritis nodosa resistant or intolerant to the reference treatment. PMID- 28879048 TI - No evidence for a direct role of HLA-B27 in pathological bone formation in axial SpA. AB - OBJECTIVE: The strong genetic association between HLA-B27 and ankylosing spondylitis has been known for over 40 years. HLA-B27 positivity is possibly associated with severity of ankylosis. We studied the in vitro and in vivo impact of HLA-B27 in models of chondrogenesis and osteogenesis. METHODS: Different in vitro differentiation systems were used to mimic endochondral and direct bone formation. ATDC5 cells and primary human periosteum-derived cells (hPDCs) were transduced with lentiviral vectors expressing HLA-B27 or HLA-B7. These cells and limb bud cells (from HLA-B27 transgenic and wild-type (WT) mice) were cultured in micromasses. To study direct osteogenesis in hPDCs, cells were cultured as monolayers and stimulated with osteogenic media. Chondrogenesis (COL2, ACAN, COL10) and osteogenesis (OSC, ALP, RUNX2) marker expression was studied by quantitative RT-PCR. Colorimetric tests were performed to measure proteoglycans, mineralization and collagens. Collagen antibody-induced arthritis (CAIA) was induced in HLA-B27 transgenic and WT mice. Clinical scoring and uCTs were performed. Statistical analyses were performed by two-way ANOVA. RESULTS: There was no difference in chondrogenesis markers or in colorimetric tests between HLA B27+ and HLA-B7+ micromasses. Expression of osteogenesis markers and Alizarin red staining was comparable in the HLA-B27+ and the HLA-B7+ hPDCs in monolayers. HLA B27 transgenic mice showed more severe arthritis compared with WT mice in the CAIA model. uCT analysis showed no increased bone formation in HLA-B27 transgenic mice. CONCLUSION: HLA-B27 seems to enhance joint inflammation in the CAIA model. We could not document a direct effect of HLA-B27 on chondrogenesis or osteogenesis. PMID- 28879049 TI - Rituximab in early systemic sclerosis. AB - OBJECTIVES: (1) Hypothesis testing of the potency of rituximab (RTX) in preventing fibrotic complications and (2) assessing acceptability and feasibility of RTX in early systemic sclerosis (SSc). METHODS: A small, 24-month, randomised, double-blind, placebo-controlled, single-centre trial in patients with SSc diagnosed <2 years was conducted. Patients received RTX or placebo infusions at t=0, t=15 days and t=6 months. Patients were clinically evaluated every 3 months, with lung function tests and high-resolution CT every other visit. Skin biopsies were taken at baseline and month 3. Immunophenotyping of peripheral blood mononuclear cells was performed at every visit, except at months 9 and 18. Adverse events, course of skin and pulmonary involvement and B cell populations in skin and peripheral blood were evaluated. RESULTS: In total 16, patients (rituximab n=8, placebo n=8) were included. Twelve patients had diffuse cutaneous SSc. Eighty-eight adverse events (RTX n=53, placebo n=35, p=0.22) and 11 serious adverse events (RTX n=7, placebo n=4, p=0.36) occurred. No unexpected RTX-related events were observed. Mean skin score over time did not differ between the groups. Over time, forced vital capacity and extent of lung involvement slightly improved with RTX, but this difference was insignificant. In peripheral blood B cells depletion was demonstrated. CONCLUSIONS: No unexpected safety issues were observed with RTX in early SSc. Although this small trial could not confirm or reject potential efficacy of RTX in these patients, future placebo-controlled trials are warranted, specifically in the subgroup of patients with pulmonary involvement. TRIAL REGISTRATION NUMBER: EudraCT 2008-07180-16; Results. PMID- 28879050 TI - Relationship between the gut and the spine: a pilot study of first-degree relatives of patients with ankylosing spondylitis. PMID- 28879051 TI - Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis. AB - OBJECTIVES: To seek evidence of the danger molecule, high-mobility group protein B1 (HMGB1) expression in human tendinopathy and thereafter, to explore mechanisms where HMGB1 may regulate inflammatory mediators and matrix regulation in human tendinopathy. METHODS: Torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing 'early pathology') biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from patients undergoing arthroscopic stabilisation surgery. Markers of inflammation and HMGB1 were quantified by reverse transcriptase PCR (RT-PCR) and immunohistochemistry. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon anterior cruciate ligament reconstruction and used through passage 3. In vitro effects of recombinant HMGB1 on tenocyte matrix and inflammatory potential were measured using quantitative RT-PCR, ELISA and immunohistochemistry staining. RESULTS: Tendinopathic tissues demonstrated significantly increased levels of the danger molecule HMGB1 compared with control tissues with early tendinopathy tissue showing the greatest expression. The addition of recombinant human HMGB1 to tenocytes led to significant increase in expression of a number of inflammatory mediators, including interleukin 1 beta (IL-1beta), IL-6, IL-33, CCL2 and CXCL12, in vitro. Further analysis demonstrated rhHMGB1 treatment resulted in increased expression of genes involved in matrix remodelling. Significant increases were observed in Col3, Tenascin-C and Decorin. Moreover, blocking HMGB1 signalling via toll-like receptor 4 (TLR4) silencing reversed these key inflammatory and matrix changes. CONCLUSION: HMGB1 is present in human tendinopathy and can regulate inflammatory cytokines and matrix changes. We propose HMGB1 as a mediator driving the inflammatory/matrix crosstalk and manipulation of the HMGB1/TLR4 axis may offer novel therapeutic approaches targeting inflammatory mechanisms in the management of human tendon disorders. PMID- 28879052 TI - Obesity is a strong predictor of worse clinical outcomes and treatment responses in early rheumatoid arthritis: results from the SWEFOT trial. AB - OBJECTIVES: The aim of this paper was to analyse the impact of obesity, in addition to known predictors, on disease outcome in early rheumatoid arthritis (RA). METHODS: Body mass index (BMI) was available in 260 patients from the Swedish pharmacotherapy trial (SWEFOT). Differences in disease activity (DAS28), functional impairment (HAQ), pain (Visual Analogue Scale, VAS-pain) and radiographic damage were evaluated over 24 months between BMI categories (obese BMI >30, n=43; overweight BMI=25-29.9, n=74; normal BMI <25, n=143) using non parametric testing. Predictors of European League Against Rheumatism non remission (DAS28 >=2.6) at 24 months of follow-up were evaluated using binary univariate and multivariate logistic regression. RESULTS: Obesity at baseline was associated with worse continuous-scale clinical outcomes over 24 months (DAS28, HAQ and VAS-pain at last visit: obese vs normal: p<0.001; obese vs overweight: p<0.05). Furthermore, obese patients compared with non-obese patients had significantly greater odds of non-remission at 24 months (adjusted OR (aOR) 5.2; 95% CI 1.8 to 15.2). Other independent predictors were female sex (aOR 2.6; 95% CI 1.1 to 5.8), current smoking (aOR 2.6; 95% CI 1.1 to 6.3) and HAQ (per-unit increase, aOR 1.9; 95% CI 1.1 to 3.4). The pattern was similar among seropositive and seronegative patients; and in the subgroups of methotrexate responders and patients randomised at 3 months to add-on of sulfasalazine+hydroxychloroquine, although not significant with add-on of infliximab. Obesity had no independent association to radiographic progression. CONCLUSIONS: In this early RA trial reflecting today's standard treatment, obesity, in addition to sex, smoking and functional impairment strongly lowered the chance of attaining good clinical outcomes, including remission, today's treatment goal. This highlights the importance of considering lifestyle modification as one of the cornerstones of RA care. TRIAL REGISTRATION NUMBER: NCT00764725; Post-results. WHO database at the Karolinska University Hospital: CT20080004. PMID- 28879053 TI - Efficacy of embedded nurse-led versus conventional physician-led follow-up in rheumatoid arthritis: a systematic review and meta-analysis. AB - OBJECTIVE: To compare the efficacy of embedded nurse-led versus conventional physician-led follow-up on disease activity in patients with rheumatoid arthritis (RA). METHODS: In a systematic literature search, we identified randomised controlled trials (RCTs) reporting on the efficacy of nurse-led follow-up on disease control in patients with RA compared with physician-led follow-up. Primary outcome was disease activity indicated by Disease Activity Score (DAS) 28. Secondary outcomes were: patient satisfaction, physical disability, fatigue, self-efficacy and quality of life. Outcomes were assessed after 1-year and 2 year follow-ups. RESULTS: Seven studies representing five RCTs, including a total of 723 participants, were included. All but one study included stable patients in low disease activity or remission at baseline. No difference in DAS-28 was found after 1 year (mean difference (MD) -0.07 (95% CI -0.23 to 0.09)). After 2 years, a statistically significant difference was seen in favour of nurse-led follow-up (MD -0.28 (95% CI -0.53 to -0.04)). However, the difference did not reach a clinically relevant level. No difference was found in patient satisfaction after 1 year (standard mean difference (SMD) -0.17 (95 % CI -1.0 to 0.67), whereas a statistical significant difference in favour of nurse-led follow-up was seen after 2 years (SMD: 0.6 (95% CI -0.00 to 1.20)). CONCLUSION: After 1 year no difference in disease activity, indicated by DAS-28, were found between embedded nurse-led follow-up compared with conventional physician-led follow-up, in RA patients with low disease activity or remission. PMID- 28879054 TI - Achilles enthesitis defined by ultrasound is not associated with clinical enthesitis in patients with psoriatic arthritis. AB - OBJECTIVE: To compare clinical and ultrasonographic (US) evaluation of Achilles enthesitis in patients with psoriatic arthritis (PsA). METHODS: The Achilles insertion of outpatients with PsA was examined by clinical assessment of tenderness and US evaluation of (1) inflammatory activity (defined as the presence of power Doppler signal, tendon thickening and/or hypoechogenicity) and (2) structural damage (defined as the presence of erosions, calcifications and/or enthesophytes). Univariate and multivariate logistic regression analyses were performed0.4 to explore the associations between clinical characteristics and US scores. RESULTS: 282 Achilles tendons in 141 patients with PsA were assessed. Mean (SD) age was 52.4 (10.2) years, disease duration 9.5 (6.6) years and 50.4% were females. Palpatory tenderness was found in 88 (31.2%), US-verified inflammatory activity in 46 (16.3%) and structural damage in 148 (52.5%) of the Achilles. Total US scores, as well as their components, were similar for patients with and without palpatory tenderness. None of the clinical characteristics were associated with inflammatory activity. Age, body mass index (BMI), regular physical exercise and current use of biological disease-modifying antirheumatic drugs (bDMARDs) were associated with structural damage. CONCLUSION: There appears to be a lack of association between clinical and US signs of Achilles enthesitis in PsA. Age, BMI, regular physical exercise and current use of bDMARDs were associated with structural damage on US. PMID- 28879055 TI - Working in cold environment and risk of developing rheumatoid arthritis: results from the Swedish EIRA case-control study. AB - OBJECTIVES: To investigate (1) whether working in cold environment (WCE) is associated with an increased risk of developing rheumatoid arthritis (RA) (overall), anticitrullinated protein antibody (ACPA)-positive RA and ACPA negative RA and (2) whether WCE interacts with occupational physical workload in conferring RA risk. METHODS: Data from the Swedish population-based case-control study Epidemiological Investigation of Rheumatoid Arthritis involving 3659 incident cases and 5925 controls were analysed. Study participants were asked whether they had ever worked in cold/outdoor environment along with their exposure duration and frequency. Occurrence of RA among exposed and unexposed subjects were compared by calculating ORs with 95% CI using logistic regression. Additive interactions between WCE and six types of physical workload were assessed using the principle of departure from additivity by calculating attributable proportion due to interaction (AP). RESULTS: The OR associated with having ever worked in cold environment was 1.5 (95% CI 1.4 to 1.7) for RA (overall), 1.6 (95% CI 1.4 to 1.8) for ACPA-positive RA and 1.4 (95% CI 1.2 to 1.6) for ACPA-negative RA. The risk of developing RA increased with increasing cumulative dose of working in cold indoor environment (p value <0.001), but not working in cold outdoor environment. Positive additive interaction was observed between WCE and repetitive hand/finger movements (AP 0.3 (95% CI 0.1 to 0.5)). CONCLUSIONS: WCE is associated with increased risk of developing both ACPA positive and ACPA-negative RA. A dose-response relationship was found between working in cold indoor environment and risk of developing RA. Moderate additive interaction was observed between exposure to cold environment and exposure to repetitive hand/finger movements. PMID- 28879057 TI - Erratum: Clinical responses to ERK inhibition in BRAFV600E-mutant colorectal cancer predicted using a computational model. AB - [This corrects the article DOI: 10.1038/s41540-017-0016-1.]. PMID- 28879056 TI - Ultrasound-detected osteophytes predict the development of radiographic and clinical features of hand osteoarthritis in the same finger joints 5 years later. AB - BACKGROUND: Structural pathology may be present in joints without radiographic evidence of osteoarthritis (OA). Ultrasound is a sensitive tool for early detection of osteophytes. Our aim was to explore whether ultrasound-detected osteophytes (in radiographically and clinically normal finger joints) predicted the development of radiographic and clinical hand OA 5 years later. METHODS: We included finger joints without radiographic OA (Kellgren-Lawrence grade (KLG)=0; n=301) or no clinical bony enlargements (n=717) at baseline and examined whether ultrasound-detected osteophytes predicted incident radiographic OA (KLG >=1, osteophytes or joint space narrowing (JSN)) or incident clinical bony enlargement (dependent variables) in the same joints 5 years later. We applied logistic regression with generalised estimating equations adjusted for age, sex, body mass index and follow-up time. RESULTS: Ultrasound demonstrated osteophytes in 86/301 (28.6%) joints without radiographic OA and 392/717 (54.7%) joints without clinical bony enlargement. These osteophytes were confirmed in the majority of joints where MRI assessment was available. Significant associations were found between ultrasound-detected osteophytes and development of both radiographic OA (OR=4.1, 95% CI 2.0 to 8.1) and clinical bony enlargement (OR=3.5, 95% CI 2.4 to 5.1) and also incident radiographic osteophytes (OR=4.2, 95% CI 2.1 to 8.5) and JSN (OR=5.3, 95% CI 2.1 to 13.4). CONCLUSION: Ultrasound-detected osteophytes predicted incident radiographic and clinical hand OA 5 years later. These results support the use of ultrasound for early detection of OA. PMID- 28879059 TI - Pulmonary hypertension and cardiac hypertrophy in children recipients of orthotopic living related liver transplantation. AB - Surgical stress, liberation of cytokines associated with re-perfusion injury, and long standing use of immune suppressive medications in children recipients of orthotopic living related liver transplantation (OLRLT) pose cardiovascular risk. Reported cardiovascular adverse effects vary from left ventricular wall thickening, hypertrophic cardiomyopathy to resting ECG abnormalities, asymptomatic ST depression following increased heart rate and ventricular arrhythmias. Twenty-five consecutive children recipients of OLRLT were assessed by conventional 2-D, M-mode echocardiography and Doppler. The mean age +/- SD at transplantation and at enrollment in study was 6.3 +/- 4.5 and 13.5 +/- 5.6 years respectively. All children were on immunosuppressive medications, with tacrolimus being constant among all. Long-term post-transplant echocardiography revealed statistically significant interventricular septal hypertrophy among all (mean thickness 0.89 +/- 0.16 cm), (P = 0.0001) in comparison to reference range for age, 24 had pulmonary hypertension (mean mPAP 36.43 +/- 5.60 mm Hg, P = 0.0001), and early diastolic dysfunction with a mean Tei index of 0.40 +/- 0.10. However cardiac function was generally preserved. Children recipients of OLRLT have cardiac structural and functional abnormalities that can be asymptomatic. Pulmonary hypertension, increased cardiac mass, de novo aortic stenosis and diastolic heart failure were among abnormalities encountered in the studied population. Echocardiography is indispensible in follow-up of children recipients of OLRLT. PMID- 28879060 TI - Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface. AB - BACKGROUND: Preterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, research of the preterm birth is hindered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. Here we comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor in tissues comprising the pregnancy using precisely phenotyped samples. The four complementary phenotypes together provide comprehensive insight into preterm and term parturition. METHODS: Samples of maternal blood, chorion, amnion, placenta, decidua, fetal blood, and myometrium from the uterine fundus and lower segment (n = 183) were obtained during cesarean delivery from women with four complementary phenotypes: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). Enrolled were 35 pregnant women with four precisely and prospectively defined phenotypes: PL (n = 8), PNL (n = 10), TL (n = 7) and TNL (n = 10). Gene expression data were analyzed using shrunken centroid analysis to identify a minimal set of genes that uniquely characterizes each of the four phenotypes. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified each of the four phenotypes. The shrunken centroid analysis and 10 times 10-fold cross-validation was also used to minimize false positive finings and overfitting. Identified were the pathways and molecular processes associated with and the cis-regulatory elements in gene's 5' promoter or 3'-UTR regions of the set of genes which expression uniquely characterized the four phenotypes. RESULTS: The largest differences in gene expression among the four groups occurred at maternal fetal interface in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 5'and 3' UTR regions. CONCLUSIONS: The results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection. PMID- 28879061 TI - A practical guide to build de-novo assemblies for single tissues of non-model organisms: the example of a Neotropical frog. AB - Whole genome sequencing (WGS) is a very valuable resource to understand the evolutionary history of poorly known species. However, in organisms with large genomes, as most amphibians, WGS is still excessively challenging and transcriptome sequencing (RNA-seq) represents a cost-effective tool to explore genome-wide variability. Non-model organisms do not usually have a reference genome and the transcriptome must be assembled de-novo. We used RNA-seq to obtain the transcriptomic profile for Oreobates cruralis, a poorly known South American direct-developing frog. In total, 550,871 transcripts were assembled, corresponding to 422,999 putative genes. Of those, we identified 23,500, 37,349, 38,120 and 45,885 genes present in the Pfam, EggNOG, KEGG and GO databases, respectively. Interestingly, our results suggested that genes related to immune system and defense mechanisms are abundant in the transcriptome of O. cruralis. We also present a pipeline to assist with pre-processing, assembling, evaluating and functionally annotating a de-novo transcriptome from RNA-seq data of non model organisms. Our pipeline guides the inexperienced user in an intuitive way through all the necessary steps to build de-novo transcriptome assemblies using readily available software and is freely available at: https://github.com/biomendi/TRANSCRIPTOME-ASSEMBLY-PIPELINE/wiki. PMID- 28879062 TI - A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes. AB - BACKGROUND: Heterocyclic aromatic amines (HAA) are environmental and food contaminants that are potentially carcinogenic for humans. 2-Amino-3,8 dimethylimidazo[4,5-f]quinoxaline (MeIQx) is one of the most abundant HAA formed in cooked meat. MeIQx is metabolized by cytochrome P450 1A2 in the human liver into detoxificated and bioactivated products. Once bioactivated, MeIQx metabolites can lead to DNA adduct formation responsible for further genome instability. METHODS: Using a computational approach, we developed a numerical model for MeIQx metabolism in the liver that predicts the MeIQx biotransformation into detoxification or bioactivation pathways according to the concentration of MeIQx. RESULTS: Our results demonstrate that (1) the detoxification pathway predominates, (2) the ratio between detoxification and bioactivation pathways is not linear and shows a maximum at 10 uM of MeIQx in hepatocyte cell models, and (3) CYP1A2 is a key enzyme in the system that regulates the balance between bioactivation and detoxification. Our analysis suggests that such a ratio could be considered as an indicator of MeIQx genotoxicity at a low concentration of MeIQx. CONCLUSIONS: Our model permits the investigation of the balance between bioactivation (i.e., DNA adduct formation pathway through the prediction of potential genotoxic compounds) and detoxification of MeIQx in order to predict the behaviour of this environmental contaminant in the human liver. It highlights the importance of complex regulations of enzyme competitions that should be taken into account in any further multi-organ models. PMID- 28879063 TI - The influence of fundamental frequency on perceived duration in spectrally comparable sounds. AB - The perceived duration of a sound is affected by its fundamental frequency and intensity: higher sounds are judged to be longer, as are sounds with greater intensity. Since increasing intensity lengthens the perceived duration of the auditory object, and increasing the fundamental frequency increases the sound's perceived loudness (up to ca. 3 kHz), frequency modulation of duration could be potentially explained by a confounding effect where the primary cause of the modulation would be variations in intensity. Here, a series of experiments are described that were designed to disentangle the contributions of fundamental frequency, intensity, and duration to perceived loudness and duration. In two forced-choice tasks, participants judged duration and intensity differences between two sounds varying simultaneously in intensity, fundamental frequency, fundamental frequency gliding range, and duration. The results suggest that fundamental frequency and intensity each have an impact on duration judgments, while frequency gliding range did not influence the present results. We also demonstrate that the modulation of perceived duration by sound fundamental frequency cannot be fully explained by the confounding relationship between frequency and intensity. PMID- 28879064 TI - Measuring coral calcification under ocean acidification: methodological considerations for the 45Ca-uptake and total alkalinity anomaly technique. AB - As the oceans become less alkaline due to rising CO2 levels, deleterious consequences are expected for calcifying corals. Predicting how coral calcification will be affected by on-going ocean acidification (OA) requires an accurate assessment of CaCO3 deposition and an understanding of the relative importance that decreasing calcification and/or increasing dissolution play for the overall calcification budget of individual corals. Here, we assessed the compatibility of the 45Ca-uptake and total alkalinity (TA) anomaly techniques as measures of gross and net calcification (GC, NC), respectively, to determine coral calcification at pHT 8.1 and 7.5. Considering the differing buffering capacity of seawater at both pH values, we were also interested in how strongly coral calcification alters the seawater carbonate chemistry under prolonged incubation in sealed chambers, potentially interfering with physiological functioning. Our data indicate that NC estimates by TA are erroneously ~5% and ~21% higher than GC estimates from 45Ca for ambient and reduced pH, respectively. Considering also previous data, we show that the consistent discrepancy between both techniques across studies is not constant, but largely depends on the absolute value of CaCO3 deposition. Deriving rates of coral dissolution from the difference between NC and GC was not possible and we advocate a more direct approach for the future by simultaneously measuring skeletal calcium influx and efflux. Substantial changes in carbonate system parameters for incubation times beyond two hours in our experiment demonstrate the necessity to test and optimize experimental incubation setups when measuring coral calcification in closed systems, especially under OA conditions. PMID- 28879065 TI - Pharmacologic inhibition of MEK1/2 reduces lung inflammation without impairing bacterial clearance in experimental Pseudomonas aeruginosa pneumonia. AB - This study was designed to test the therapeutic potential of a MEK1/2 inhibitor (MEKi) in an experimental model of Pseudomonas aeruginosa pneumonia. The study found that treatment with MEKi reduced alveolar neutrophilic inflammation and led to faster recovery of weight compared to carrier-treated mice, without impairing bacterial clearance. Alveolar macrophages isolated from MEKi-treated mice also had increased M2 gene and protein expression, supporting the concept that MEKi modulates in vivo macrophage inflammatory responses. In summary, this report demonstrates the potential of MEKi to promote the resolution of inflammation in vivo during a primary lung infection without impairing bacterial clearance. PMID- 28879066 TI - Obstetricians and gynecologists' opinions about the Affordable Care Act and their expectations about how it will impact their practice. AB - As the primary healthcare providers for women, obstetrician-gynecologists' (OB/GYNs) experiences with and opinions about the Affordable Care Act (ACA) are important to understand. An online survey was sent to 1000 randomly selected OB/GYNs who were members of the American College of Obstetricians and Gynecologists (ACOG) in 2014. Of those, 523 opened the email and 163 responded (31% participation rate). Data were collected August 2014-October 2014 and analyzed in 2015-2016. Support for the ACA was widely distributed, with the largest subset of the sample (about 21%) in the "very supportive" category. Opinions of the ACA were more supportive than they were in a previous study conducted in 2011. When given a list of possible positive and negative impacts of the ACA on their practice, roughly 1 in 5 reported that the ACA increased work related stress (28%), decreased total profits (22%), and lowered career satisfaction (22%), whereas 8.6% reported that the ACA increased quality of care. Around half of the providers thought that their newly insured patients would have the same level of education (42%) and numeric ability (55%) as their current patients. Almost all respondents (87%) indicated that it is at least slightly important for patients to understand their numeric likelihood of risk (such as numeric risk information from medications, treatments, and other procedures you might prescribe) -31% think it is extremely important and 44% think it is moderately important. PMID- 28879067 TI - Sedentary time, physical activity and compliance with IOM recommendations in young children at childcare. AB - The aim of this study was to report patterns of sitting, standing and physical activity (PA) and compliance with Institute of Medicine (IOM) recommendations for sedentary behavior (SB) and PA among children aged 1 to 5 years at childcare, and examine sociodemographic variations. Sitting, standing and PA time was assessed using an activPAL inclinometer over a period of 1 to 5 days in 301 children (49% boys; mean age = 3.7 +/- 1.0 years) across 11 childcare services in Illawarra, NSW, Australia. Breaks and bouts of sitting and standing were calculated and categorized. Height and weight were assessed and parents completed a demographic survey. Differences by sex, age category (< 3 vs >= 3 years), weight status and SES were examined. Children spent 48.4% of their time at childcare sitting, 32.5% standing, and 19.1% in PA. Boys spent significantly more time in PA compared to girls (20.8% vs 17.7%; P = 0.003). Toddlers (< 3 years) spent significantly more time in PA compared to preschoolers (>= 3 years) (22.2% vs 18.3%; P < 0.001). Children who were underweight spent significantly more time sitting compared with their overweight peers (52.4% vs 46.8%; P = 0.003). 56% and 16% of children met the IOM SB and PA recommendations, respectively. Girls (odds ratio [OR]; 95%CI = 0.26; 0.13 to 0.55) and preschoolers (0.16; 0.07 to 0.38) were less likely to meet the IOM PA recommendation compared to boys and toddlers. Young children spent ~ 50% of their time at childcare sitting. Girls and preschoolers sit more and are less likely to meet PA recommendations, making them important groups to target in future interventions. PMID- 28879068 TI - Self-collected vaginal swabs for HPV screening: An exploratory study of rural Black Mississippi women. AB - OBJECTIVES: To determine the post-procedure acceptability of self-collecting a vaginal swab for HPV testing among a highly impoverished and geographically isolated population of medically underserved Black women residing in the Mississippi Delta. Further, to test correlates of reporting that self-collection is preferred over Pap testing. Finally, to determine the prevalence of any of 13 high-risk HPV types among this population and the correlates of testing positive. METHODS: Eighty-eight women were recruited from two churches located in different towns of the Mississippi Delta. After completing a survey, women were provided instructions for self-collecting a cervico-vaginal swab and completing a post collection survey. Specimens were tested for 13 oncogenic HPV types. Due to the exploratory nature of the study, significance was defined by a 0.15 alpha-level. RESULTS: Comfort levels with self-collection were high: 78.4% indicated a preference for self-collecting a specimen compared to Pap testing. Overall, 24 women (28.7%) tested positive for one or more of the 13 HPV types. Significant associations with testing positive were found for women having sex with females (P = 0.09), those never having an abnormal Pap (P = 0.06), younger women (P = 0.10), those with greater fatalism scores (P = 0.006), and those having less trust in doctors (P = 0.001). CONCLUSIONS: Black rural women from the deep-south are generally comfortable self-collecting cervico-vaginal swabs for HPV testing. Given that nearly 30% tested positive for oncogenic HPV, and that fatalism as well a lack of trust in doctors predicted prevalence, a reasonable screening alternative to Pap testing may be community-based testing for HPV using self collected vaginal swabs. PMID- 28879069 TI - Biking practices and preferences in a lower income, primarily minority neighborhood: Learning what residents want. AB - This paper examines if, in a lower-income minority neighborhood, bicycling practices and bicycle-environment preferences of Blacks and Hispanics were different from Whites. During the summer of 2014, surveys were mailed to 1537 households near a proposed cycle track on Malcolm X Boulevard in Roxbury, MA. On the Boulevard, intercept surveys were distributed to cyclists and observations noted about passing cyclist's characteristics. Data were analyzed from 252 returned-mailed surveys, 120 intercept surveys, and 709 bicyclists. White (100%), Hispanic (79%), and Black (76%) bicyclists shown pictures of 6 bicycle facility types in intercept surveys perceived the cycle track as safest. More White mailed survey respondents thought bikes would not be stolen which may explain why more Hispanics (52%) and Blacks (47%) preferred to park their bikes inside their home compared with Whites (28%), with H/W B/W differences statistically significant (p < 0.05). More Hispanic (81%) and Black (54%) mailed-survey respondents thought they would bicycle more if they could bicycle with family and friends compared with Whites (40%). Bicyclists observed commuting morning and evening included Blacks (55%), Whites (36%) and Hispanics (9%). More Whites (68%) wore helmets compared with Hispanics (21%) and Blacks (17%) (p < 0.001). More Blacks (94%) and Hispanics (94%) rode a mountain bike compared with Whites (75%). Minority populations are biking on roads but prefer cycle tracks. They also prefer to park bikes inside their homes and bicycle with family and friends. Wide cycle tracks (bicycling with family/friends) and home bike parking should be targeted as capital investments in lower-income minority neighborhoods. PMID- 28879070 TI - Trends in breast and colorectal cancer screening among U.S. adults by race, healthcare coverage, and SES before, during, and after the great recession. AB - The aim of this study is examine trends in breast and colorectal cancer screening in the U.S. by race, healthcare coverage, and socio-economic status (SES) before the Great Recession (2003-2005), during the recession (2007-2009), and post recession/Affordable Care Act (ACA) period (2010 - 2012). Data on a representative sample of U.S. adults was obtained from the Behavioral Risk Factor Surveillance System (BRFSS). Breast and colorectal cancer screening were defined in line with U.S. Preventative Services Task Force guidelines, and survey weighted statistical methods were utilized to analyze trends in cancer screening among 1,858,572 BRFSS participants. Overall, 83% of women received mammograms in the past 2 years, while 95% of adults received colorectal cancer screening in the past 10 years. Compared with the pre-recession period, the odds of colorectal screening within 5 years were slightly higher during the recession (OR: 1.05, 95% CI: 1.03-1.08) but significantly lower in the post-recession/ACA period (OR: 0.73, 95% CI: 0.72-0.75). Odds of mammography screening were lower during (OR: 0.94,95% CI: 0.91-0.96) and post-recession/ACA period (OR: 0.80, 95% CI: 0.78 0.82). Breast cancer screening rates declined in the recession and post recession, while colorectal cancer screening rates increased during the recession and decreased post-recession. Low SES adults and those without healthcare coverage were the least likely to receive screening. PMID- 28879071 TI - An examination of compensation effects in accelerometer-measured occupational and non-occupational physical activity. AB - Self-report data suggests a large proportion of total physical activity (PA) occurs at work. However, adults with higher levels of occupational PA may compensate by engaging in less non-occupational PA. The study aims were to 1) estimate the intensity, volume, and duration of PA in American adults that occurs at work, and 2) determine if those more active at work are less active outside of work. A cross-sectional sample of full-time employed adults (N = 510) was recruited from Georgia city and county governments in 2013-2015. Participants wore an Actigraph GT3X + accelerometer for two weeks. In 2016, for 442 participants with complete data including work schedules and self-reported job titles, accelerometer wear minutes were classified as either occupational or non occupational, and as sedentary, LPA (light-intensity PA), or MVPA (moderate-to vigorous intensity PA). The proportion of daily PA that occurred during work was 41.2% for total PA, 41.0% for LPA, and 39.5% for MVPA. Higher levels of occupational LPA were associated with lower levels of non-occupational LPA (r = - 0.38, P < 0.0001). However, higher levels of occupational MVPA were associated with higher levels of non-occupational MVPA (r = 0.17, P < 0.0001). These associations remained significant in a MANOVA adjusting for labor sector and other covariates. On average, employed adults get more LPA and MVPA outside of work. Adults who do more occupational MVPA do not compensate by doing less non occupational MVPA. In contrast, adults who do more occupational LPA do compensate by doing less non-occupational LPA. Evaluations of interventions to reduce sedentary behavior should be designed to detect compensation effects. PMID- 28879072 TI - Association between screen time and depression among US adults. AB - Epidemiological surveys conducted in general populations have found that the prevalence of depression is about 9% in the United States. World Health Organization has projected that depression will be leading cause of disease burden by the year 2030. Growing evidence suggests that sedentary lifestyle is an important risk factor of depression among adults. The relationship between television watching/computer use and depression in US adults is still unknown. The objective of this study was to assess the relationship between television watching/computer use and depression. This is a cross-sectional study that used the secondary data from the National Health and Nutritional Examination Survey (NHANES) (2011/2012). Participants were 3201 US adults who were 20 years or more. Self-reported Patient Health Questionnaire-9 [PHQ-9] was used to classify depression level; self-reported hours of watching TV and use of computer/day, and demographic information were obtained from NHANES data set. SAS(r)9.4was used to perform all statistical analyses and final model selection procedure. Depression was found to be significantly higher among female. Results showed that moderate or severe depression level was associated with higher time spent on TV watching and use of computer (> 6 h/day) (adjusted odds ratio: 2.3, 95% CI: 1.602-3.442). Duration of screen time was significantly associated when all covariates were adjusted. TV watching and computer use can predict the depression level among adults. Prospective studies and measurement of factors such as: work place sitting, social relationship, and family history of depression are warranted. PMID- 28879073 TI - Process evaluation of a culturally-tailored physical activity intervention in African-American mother-daughter dyads. AB - The purpose of this study was to describe process evaluation data including intervention fidelity, dosage, quality, participant responsiveness, and program reach for the Mothers And dauGhters daNcing togEther Trial (MAGNET) in Springfield, MA, in Spring 2013 and 2014. Seventy-six mother-daughter dyads were randomized to the mother-daughter group (CH-M, n = 28), the child-only group (CH, n = 25), or the health education group (CON, n = 23). CH-M consisted of 60 min of moderate-to-vigorous culturally-tailored dance classes for dyads. CH consisted of dance classes for the child. All groups received homework tutoring and weekly health newsletters. Process evaluation data were assessed at each intervention session (three days/week, 6-months) with semi-structured questionnaires by researchers. CH dance classes were slightly longer (58.2 +/- 3.5 min) than CH-M (54.4 +/- 5.5 min). In both groups, participants spent the majority of the dance intervention in light intensity physical activity (PA). Participants in the CH-M group enjoyed participating in MAGNET > 90% of the time. Mothers (92%) indicated that they wanted to continue dance as a form of PA. Mothers expressed that transportation, time commitment, and assessments were barriers to participation. Participants suggested future interventions should include longer intervention length and more communications between research staff and mothers. The MAGNET intervention matched the originally intended program in most aspects. A lower intervention dose was delivered to the CH-M group potentially due to barriers described by mothers. Because mother-daughter interventions have shown minimal effects on increasing PA, it is imperative that researchers utilize process evaluation data to shape future studies. PMID- 28879074 TI - A case report of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR tyrosine kinase inhibitors with T790M mutation and epithelial-to-mesenchymal transition. AB - Although a secondary mutation and the epithelial-to-mesenchymal transition (EMT) are encountered very often in patients received the EGFR-TKI targeted treatment. The entire detrimental morphological change of the cancer entity was rare reported. Herein we report a case that acquired resistance to EGFR-TKI with T790M mutation and complete EMT morphological change of the tumor tissue. The primary lung tumor from a 52-year-old woman was diagnosed with moderate differentiated adenocarcinoma, with intensively positiveTTF-1 and E-cadherin in differentiated glandular structure but not the budding cancer cell cluster which with an intensive Vimentin staining. Molecular analysis revealed an EGFR exon 19 deletion and with an excellent response to Gefitinib treatment. Microscopic examination of recurred tumor specimens revealed a diffuse poorer differentiated proliferation of atypical cells. Immunostaining showed intensive Vimentin but almost completely negative for E-cadherin and TTF-1. Genetic analyses revealed T790M mutation. It is worth noting that rare clinical studies have been reported that acquired EGFR TKI resistant lung adenocarcinoma underwent T790M mutation and almost complete EMT together. More significantly, the similarity of poorly differentiated cancer cell cluster in the primary lesions to recurred tumor lesions, which may pre harbor drug resistance mutation should not be neglected underneath the predominant morphologic patterns. PMID- 28879075 TI - Endobronchial ultrasound convex probe for lymphoma, sarcoidosis, lung cancer and other thoracic entities. A case series. AB - Endobronchial ultrasound endoscopy is a state of the art diagnostic endoscopic procedure for the thorax. Firstly it was designed mainly for the staging of lung cancer and of course for the diagnosis of suspicious findings in large central airways. The main limitation of the equipment is the diameter of the instrument and therefore it can only be guided through large airways. However; the diameter of the working channel also provides a large tissue sample nowadays with the 19G biopsy needle. We will provide our experience with the 22G needle of the endobronchial convex-probe in several medical situations of the thorax. PMID- 28879076 TI - Immunotherapy "Shock" a case series of PD-L1 100% and pembrolizumab first-line treatment. AB - In this decade a "bloom" of novel therapies has been observed for non-small cell lung cancer. We have new tools for the diagnosis of lung cancer and also we can re-biospy easier than before in different lesions and obtain tissue samples in order to investigate whether a patient can receive new targeted therapies. Immunotherapy has been well established previously for other forms of cancer, and nowadays it is also available for lung cancer. There are two immunotherapies for now nivolumab and pembrolizumab which can be administered as second line treatment, the second can also be administered as first-line if there is a programmed death-ligand 1 >=50% expression. PMID- 28879077 TI - A rare case of Actinomyces meyeri empyema: Still a challenging entity to manage. AB - Actinomyces meyeri is a rare pathogen and an infrequent cause of human actinomycosis. Less than ten cases were reported in the English-literature to date concerning A. meyeri empyema. We herein report a case to promote the awareness and adequate management of the disease. A 44-year-old immunocompetent male with known pulmonary disease was diagnosed with an A. meyeri empyema. He underwent chest tube drainage and a short-term treatment with clindamycin for 4 months. This is the first report of a patient with structural pulmonary disease with an A. meyeri empyema treated with 4-month of clindamycin and chest tube drainage. In comparison to previous reports, our case was diagnosed early, empyema was effectively drained with one chest tube and symptoms and radiological findings were rapidly improved. Short-term antibiotic treatment can be well succeeded if an early diagnosis is made, there is no evidence of dissemination and adequate management is promptly instituted. PMID- 28879078 TI - Left ventricle and systemic air embolism after percutaneous lung biopsy. AB - BACKGROUND: Systemic arterial air embolism following a percutaneous transthoracic lung biopsy is a rare but known complication, with current literature reporting an incidence of 0.01-0.45%. A prompt diagnosis of arterial air embolism is important as complications resulting from migration of air to the systemic circulation with correspondent complications. CASE REPORT: A 60-year-old female who presented for an elective percutaneous lung biopsy of an incidentally found pulmonary nodule. The procedure was performed, following the completion of the procedure the patient experiment syncopal symptoms and was diagnosed by CT scan with Left ventricular air embolism, subsequently transferred to Intensive care unit for medical attention, she was placed on right lateral decubitus Trendelenburg for 24 hours and administer 100% oxygen via a nonrebreather mask. Repeat chest CT the following day revealed complete resolution of her intracardiac free air. CONCLUSION: Although systemic arterial air embolism remains a rare complication of percutaneous lung biopsies, recognition prevents potential mortality which can develop due to neurological and cardiac complications. Close vigilance in the intensive care unit is recommended and hyperbaric chamber when appropriate. PMID- 28879079 TI - Intrathoracic ganglioneuroma presenting as an endobronchial mass. AB - : Peripheral nerve sheath tumors (PNST) are exceedingly rare, especially outside of the posterior mediastinum. These tumors represent less than 1% of pulmonary tumors. Very few pulmonary PNSTs are ganglioneuromas. We present a case of a ganglioneuroma presenting as an endobronchial mass. CASE PRESENTATION: An 80 year old male was seen in pulmonary clinic for routine cancer screening. He had a 60 pack year smoking history. CT evaluation noted a 1cm right lower lobe endobronchial lesion. This lesion was present since 2012 and had slightly increased in size since that time from 8mm (Figure 1). The lesion was further assessed using virtual bronchoscopy (Figure 2). Bronchoscopy revealed an obstructing lesion, which was completely excised with the snare (Figure 3). Pathology revealed well-circumscribed tumor consisting of nests and trabeculae of round/polygonal cells with granular eosinophilic and basophilic cytoplasm. The tumor was chromogranin, synaptophysin, S-100, pancytokeratin, SOX10, and TTF-1 positive, consistent with a ganglioneuroma. DISCUSSION: Aside from a solitary article regarding 75 patient samples (which included only one ganglioneuroma) only a small number of intrathoracic PNSTs have been reported. Only a single case report of an endobronchial ganglioneuroma has been reported. Each of these lesions were benign, and detected on routine imaging evaluations. CONCLUSIONS: An intrapulmonary endobronchial location for a PNST is an exceedingly rare presentation of an already uncommon pathology. PMID- 28879080 TI - Diffuse parenchymal lung disease with micro aspirations in presence of hiatal hernia. AB - There has been controversy regarding the relationship between gastroesophageal reflux, microaspiration, and idiopathic pulmonary fibrosis (IPF). In the last decade, there is increasing evidence supporting a relationship between gastroesophageal reflux, microaspiration, and IPF. The presence of hiatal hernia further propagates microaspirations. Surgical management of hiatal hernia plays a vital role in the treatment. PMID- 28879081 TI - Validity and reliability of four language mapping paradigms. AB - Language areas of the brain can be mapped in individual participants with functional MRI. We investigated the validity and reliability of four language mapping paradigms that may be appropriate for individuals with acquired aphasia: sentence completion, picture naming, naturalistic comprehension, and narrative comprehension. Five neurologically normal older adults were scanned on each of the four paradigms on four separate occasions. Validity was assessed in terms of whether activation patterns reflected the known typical organization of language regions, that is, lateralization to the left hemisphere, and involvement of the left inferior frontal gyrus and the left middle and/or superior temporal gyri. Reliability (test-retest reproducibility) was quantified in terms of the Dice coefficient of similarity, which measures overlap of activations across time points. We explored the impact of different absolute and relative voxelwise thresholds, a range of cluster size cutoffs, and limitation of analyses to a priori potential language regions. We found that the narrative comprehension and sentence completion paradigms offered the best balance of validity and reliability. However, even with optimal combinations of analysis parameters, there were many scans on which known features of typical language organization were not demonstrated, and test-retest reproducibility was only moderate for realistic parameter choices. These limitations in terms of validity and reliability may constitute significant limitations for many clinical or research applications that depend on identifying language regions in individual participants. PMID- 28879082 TI - Hemodynamic variability in soldiers with trauma: Implications for functional MRI connectivity studies. AB - Functional MRI (fMRI) is an indirect measure of neural activity as a result of the convolution of the hemodynamic response function (HRF) and latent (unmeasured) neural activity. Recent studies have shown variability of HRF across brain regions (intra-subject spatial variability) and between subjects (inter subject variability). Ignoring this HRF variability during data analysis could impair the reliability of such fMRI results. Using whole-brain resting-state fMRI (rs-fMRI), we employed hemodynamic deconvolution to estimate voxel-wise HRF. Studying the impact of mental disorders on HRF variability, we identified HRF aberrations in soldiers (N = 87) with posttraumatic stress disorder (PTSD) and mild-traumatic brain injury (mTBI) compared to combat controls. Certain subcortical and default-mode regions were found to have significant HRF aberrations in the clinical groups. These brain regions have been previously associated with neurochemical alterations in PTSD, which are known to impact the shape of the HRF. We followed-up these findings with seed-based functional connectivity (FC) analysis using regions-of-interest (ROIs) whose HRFs differed between the groups. We found that part of the connectivity group differences reported from traditional FC analysis (no deconvolution) were attributable to HRF variability. These findings raise the question of the degree of reliability of findings from conventional rs-fMRI studies (especially in psychiatric populations like PTSD and mTBI), which are corrupted by HRF variability. We also report and discus, for the first time, voxel-level HRF alterations in PTSD and mTBI. To the best of our knowledge, this is the first study to report evidence for the impact of HRF variability on connectivity group differences. Our work has implications for rs-fMRI connectivity studies. We encourage researchers to incorporate hemodynamic deconvolution during pre-processing to minimize the impact of HRF variability. PMID- 28879083 TI - Monitoring disease progression in mild cognitive impairment: Associations between atrophy patterns, cognition, APOE and amyloid. AB - BACKGROUND: A disease severity index (SI) for Alzheimer's disease (AD) has been proposed that summarizes MRI-derived structural measures into a single score using multivariate data analysis. OBJECTIVES: To longitudinally evaluate the use of the SI to monitor disease progression and predict future progression to AD in mild cognitive impairment (MCI). Further, to investigate the association between longitudinal change in the SI and cognitive impairment, Apolipoprotein E (APOE) genotype as well as the levels of cerebrospinal fluid amyloid-beta 1-42 (Abeta) peptide. METHODS: The dataset included 195 AD, 145 MCI and 228 control subjects with annual follow-up for three years, where 70 MCI subjects progressed to AD (MCI-p). For each subject the SI was generated at baseline and follow-ups using 55 regional cortical thickness and subcortical volumes measures that extracted by the FreeSurfer longitudinal stream. RESULTS: MCI-p subjects had a faster increase of the SI over time (p < 0.001). A higher SI at baseline in MCI-p was related to progression to AD at earlier follow-ups (p < 0.001) and worse cognitive impairment (p < 0.001). AD-like MCI patients with the APOE epsilon4 allele and abnormal Abeta levels had a faster increase of the SI, independently (p = 0.003 and p = 0.004). CONCLUSIONS: Longitudinal changes in the SI reflect structural brain changes and can identify MCI patients at risk of progression to AD. Disease related brain structural changes are influenced independently by APOE genotype and amyloid pathology. The SI has the potential to be used as a sensitive tool to predict future dementia, monitor disease progression as well as an outcome measure for clinical trials. PMID- 28879084 TI - Quantitative susceptibility mapping to evaluate the early stage of Alzheimer's disease. AB - The objective of this study was to evaluate susceptibility changes caused by iron accumulation in cognitive normal (CN) elderly, those with amnestic mild cognitive impairment (aMCI), and those with early state AD, and to compare the findings with gray matter volume (GMV) changes caused by neuronal loss. The participants included 19 elderly CN, 19 aMCI, and 19 AD subjects. The voxel-based quantitative susceptibility map (QSM) and GMV in the brain were calculated and the differences of those insides were compared among the three groups. The differences of the QSM data and GMVs among the three groups were investigated by voxel-based and region of interest (ROI)-based comparisons using a one-way analysis of covariance (ANCOVA) test with the gender and age as covariates. Finally, a receiver operating-characteristic (ROC) curve analysis was performed. The voxel-based results showed that QSM demonstrated more areas with significant difference between the CN and AD groups compared to GMV. GMVs were decreased, but QSM values were increased in aMCI and AD groups compared with the CN group. QSM better differentiated aMCI from CN than GMV in the precuneus and allocortex regions. In the accumulation regions of iron and amyloid beta, QSM can be used to differentiate between CN and aMCI groups, indicating a useful an auxiliary imaging for early diagnosis of AD. PMID- 28879085 TI - Progressive medial temporal lobe atrophy during preclinical Alzheimer's disease. AB - This study examined whether longitudinal MRI trajectories in medial temporal lobe (MTL) brain regions differed among groups of cognitively normal individuals defined by their cerebrospinal fluid (CSF) levels when they were first enrolled (N = 207; mean clinical follow-up = 13.3 years (max = 20 years), mean MRI follow up = 2.4 years (max = 8 years)). We first compared atrophy rates among groups defined by CSF amyloid and phosphorylated-tau (p-tau) vs. CSF amyloid and total tau (t-tau). We also examined whether, in the presence of amyloid or tau/p-tau, the atrophy rates differed based on whether the subjects ultimately progressed to a diagnosis of mild cognitive impairment (MCI), as well as whether apolipoprotein epsilon4 (Apoepsilon4) status had an impact on the longitudinal MRI trajectories. The primary finding was that when the groups were defined using CSF amyloid and p tau, individuals with low levels of CSF amyloid and high levels of CSF p-tau (referred to as Stage 2) showed a significantly greater rate of atrophy in a composite measure of MTL volumes compared to groups defined by evidence of abnormal CSF levels in only one of the brain proteins (but not both), or no evidence of CSF abnormality. In contrast, there were no differences in rate of MTL atrophy when the groups were defined by levels of CSF amyloid and t-tau (instead of p-tau). Additionally, the rate of MTL atrophy did not differ between subjects who progressed to MCI at follow-up vs. those who remained cognitively normal when CSF levels of amyloid, t-tau, or p-tau were covaried. Lastly, the presence of an APOE epsilon4 genotype did not modulate the degree of MTL atrophy once baseline levels of CSF amyloid, p-tau or t-tau were accounted for. These results suggest that abnormal levels of CSF amyloid and CSF p-tau (but not t-tau) maximize the likelihood of observing significant MTL atrophy over time among individuals with normal cognition at baseline, and emphasize the importance of differentiating biomarkers that primarily reflect neurofibrillary tangle pathology (CSF p-tau) compared with biomarkers of neuronal injury (CSF t-tau). PMID- 28879088 TI - Editorial. PMID- 28879086 TI - Emotion detection deficits and changes in personality traits linked to loss of white matter integrity in primary progressive aphasia. AB - Non-cognitive features including personality changes are increasingly recognized in the three PPA variants (semantic-svPPA, non fluent-nfvPPA, and logopenic lvPPA). However, differences in emotion processing among the PPA variants and its association with white matter tracts are unknown. We compared emotion detection across the three PPA variants and healthy controls (HC), and related them to white matter tract integrity and cortical degeneration. Personality traits in the PPA group were also examined in relation to white matter tracts. Thirty-three patients with svPPA, nfvPPA, lvPPA, and 32 HC underwent neuropsychological assessment, emotion evaluation task (EET), and MRI scan. Patients' study partners were interviewed on the Clinical Dementia Rating Scale (CDR) and completed an interpersonal traits assessment, the Interpersonal Adjective Scale (IAS). Diffusion tensor imaging of uncinate fasciculus (UF), superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF), and voxel-based morphometry to derive gray matter volumes for orbitofrontal cortex (OFC), anterior temporal lobe (ATL) regions were performed. In addition, gray matter volumes of white matter tract-associated regions were also calculated: inferior frontal gyrus (IFG), posterior temporal lobe (PTL), inferior parietal lobe (IPL) and occipital lobe (OL). ANCOVA was used to compare EET performance. Partial correlation and multivariate linear regression were conducted to examine association between EET and neuroanatomical regions affected in PPA. All three variants of PPA performed significantly worse than HC on EET, and the svPPA group was least accurate at recognizing emotions. Performance on EET was related to the right UF, SLF, and ILF integrity. Regression analysis revealed EET performance primarily relates to the right UF integrity. The IAS subdomain, cold-hearted, was also associated with right UF integrity. Disease-specific emotion recognition and personality changes occur in the three PPA variants and are likely associated with disease-specific neuroanatomical changes. Loss of white matter integrity contributes as significantly as focal atrophy in behavioral changes in PPA. PMID- 28879087 TI - Chronic exposure to dopamine agonists affects the integrity of striatal D2 receptors in Parkinson's patients. AB - We aimed to investigate the integrity and clinical relevance of striatal dopamine receptor type-2 (D2R) availability in Parkinson's disease (PD) patients. We studied 68 PD patients, spanning from early to advanced disease stages, and 12 healthy controls. All participants received one [11C]raclopride PET scan in an OFF medication condition for quantification of striatal D2R availability in vivo. Parametric images of [11C]raclopride non-displaceable binding potential were generated from the dynamic [11C]raclopride scans using implementation of the simplified reference tissue model with cerebellum as the reference tissue. PET data were interrogated for correlations with clinical data related to disease burden and dopaminergic treatment. PD patients showed a mean 16.7% decrease in caudate D2R and a mean 3.5% increase in putaminal D2R availability compared to healthy controls. Lower caudate [11C]raclopride BPND correlated with longer PD duration. PD patients on dopamine agonist treatment had 9.2% reduced D2R availability in the caudate and 12.8% in the putamen compared to PD patients who never received treatment with dopamine agonists. Higher amounts of lifetime dopamine agonist therapy correlated with reduced D2Rs availability in both caudate and putamen. No associations between striatal D2R availability and levodopa treatment and dyskinesias were found. In advancing PD the caudate and putamen D2R availability are differentially affected. Chronic exposure to treatment with dopamine agonists, but no levodopa, suppresses striatal D2R availability, which may have relevance to output signaling to frontal lobes and the occurrence of executive deficits, but not dyskinesias. PMID- 28879089 TI - Pathology, clinical signs, and tissue distribution of Toxoplasma gondii in experimentally infected reindeer (Rangifer tarandus). AB - Toxoplasma gondii is a zoonotic parasite found in vertebrates worldwide for which felids serve as definitive hosts. Despite low densities of felids in northern Canada, Inuit people in some regions show unexpectedly high levels of exposure, possibly through handling and consumption of Arctic wildlife. Free-ranging caribou (Rangifer tarandus) are widely harvested for food across the Canadian North, show evidence of seroexposure to T. gondii, and are currently declining in numbers throughout the Arctic. We experimentally infected three captive reindeer (conspecific with caribou) with 1000, 5000 or 10,000 oocysts of T. gondii via stomach intubation to assess clinical signs of infection, pathology, and tissue distribution. An unexposed reindeer served as a negative control. Signs of stress, aggression, and depression were noted for the first two weeks following infection. By 4 weeks post infection, all infected reindeer were positive on a modified agglutination test at the highest titer tested (1:200) for antibodies to T. gondii. At 20 weeks post infection, no gross abnormalities were observed on necropsy. Following histopathology and immunohistochemistry, tissue cysts were visualized in the reindeer given the highest and lowest dose of oocysts. Focal pleuritis and alveolitis were associated with respiratory problems in reindeer given the middle dose. DNA of T. gondii was detected following traditional DNA extraction and conventional PCR on 25 mg samples from 17/33 muscles and organs, and by magnetic capture DNA extraction from 100 g samples from all 26 tissues examined. This research demonstrated that reindeer/caribou can serve as intermediate hosts for T. gondii, and that the parasite may be associated with health effects in wildlife. The presence of T. gondii in all tissues tested, many of which are commonly consumed raw, smoked, or dried in northern communities, suggests that caribou may serve as a source of human exposure to T. gondii. PMID- 28879090 TI - Faciobrachial dystonic seizures result from fronto-temporo-basalganglial network involvement. AB - *Faciobrachial dystonic seizures (FBDS) are caused by autoantibodies to leucine rich glioma-inactivated1 proteins, a component of the voltage-gated potassium channel complex (VGKC-complex) and precede the clinical presentation of limbic encephalitis.*The exact pathophysiology of FBDS is not known and whether they are seizures or movement disorder is still debated.*We suggest the fronto-temporo basal ganglia network involving the medial frontal and temporal regions along with the corpus striatum and substantia nigra being responsible for the clinical phenomenon of FBDS.*The varied clinical, electrical and imaging features of FBDS in our cases and in the literature are best explained by involvement of this network.*Entrainment from any part of this network will result in similar clinical expression of FBDS, whereas other electro-clinical associations and duration depends on the extent of involvement of the network. PMID- 28879091 TI - Desensitization of stimulation-induced weight loss: A secondary finding in a patient with vagal nerve stimulator for drug-resistant epilepsy. PMID- 28879092 TI - Scabies. PMID- 28879093 TI - Refractory acute respiratory failure due to Pneumocystis jiroveci (PCP) and Cytomegalovirus (CMV) pneumonitis: A case report and review of literature. AB - BACKGROUND: Opportunistic infections with Pneumocystis jiroveci pneumonia (PCP) are common in patients with HIV (human immunodeficiency virus) and are encountered once the CD4 count decreases below 200 cells/mm3. Cytomegalovirus (CMV) tends to cause disease once the CD4 count drops below 50 cells/mm3. CMV pneumonitis is not common in this population. However, detecting its presence in broncho-alveolar lavage (BAL) fluid has been associated with increased morbidity and mortality. The role of antiviral therapy against CMV remains unclear. CASE PRESENTATION: We report a newly diagnosed HIV patient with a CD4 count of 44 cells/mm3 presenting with acute respiratory failure secondary to PCP that failed to respond to 3 weeks of standard therapy with trimethoprim-sulfamethoxazole and corticosteroids. He was later diagnosed to have a CMV co-infection causing pneumonitis with BAL cytology findings showing CMV cytopathic effects and PCP. Plasma CMV DNA PCR was 17,424 copies/mL. He responded well after introduction of intravenous ganciclovir. CONCLUSION: The presence of histopathologic changes demonstrating viral cytopathic effects on BAL cytology along with a high plasma CMV DNA PCR should raise the specificity for diagnosing CMV pneumonitis. True PCP and CMV pneumonitis can occur, and the addition of antiviral therapy with ganciclovir may benefit such patients in the right clinical scenario. PMID- 28879094 TI - Vertebral osteomyelitis as a rare manifestation of Lemierre's syndrome. PMID- 28879095 TI - Unilateral Complete Agenesis of Mesonephric Duct Derivatives in an 82-year-Old Male Cadaver: Embryology, Anatomy and Clinical Considerations. AB - Development of urogenital anatomy in the human fetus is the result of a complex interplay between multiple different tissues. The time course of development is well documented and the morphologic outcomes of insults at various time points during development are predictable. We present a cadaveric case of unilateral agenesis of the left kidney, ureter, bladder hemitrigone, ureteric opening, seminal vesicle, vas deferens, and epididymis. Failure of development of the mesonephric duct early during embryogenesis, likely between the third and fifth week, caused ipsilateral urogenital organ agenesis. PMID- 28879096 TI - Spontaneous miscarriage in first trimester pregnancy is associated with altered urinary metabolite profile. AB - Threatened miscarriage is the most common gynecological emergency, occurring in about 20% of pregnant women. Approximately one in four of these patients go on to have spontaneous miscarriage and the etiology of miscarriage still remains elusive. In a bid to identify possible biomarkers and novel treatment targets, many studies have been undertaken to elucidate the pathways that lead to a miscarriage. Luteal phase deficiency has been shown to contribute to miscarriages, and the measurement of serum progesterone as a prognostic marker and the prescription of progesterone supplementation has been proposed as possible diagnostic and treatment methods. However, luteal phase deficiency only accounts for 35% of miscarriages. In order to understand the other causes of spontaneous miscarriage and possible novel urine biomarkers for miscarriage, we looked at the changes in urinary metabolites in women with threatened miscarriage. To this end, we performed a case-control study of eighty patients who presented with threatened miscarriage between 6 and 10 weeks gestation. Urine metabolomics analyses of forty patients with spontaneous miscarriages and forty patients with ongoing pregnancies at 16 weeks gestation point to an impaired placental mitochondrial beta-oxidation of fatty acids as the possible cause of spontaneous miscarriage. This study also highlighted the potential of urine metabolites as a non-invasive screening tool for the risk stratification of women presenting with threatened miscarriage. PMID- 28879097 TI - Signatures derived from increase in SHARPIN gene copy number are associated with poor prognosis in patients with breast cancer. AB - We report three signatures produced from SHARPIN gene copy number increase (GCN Increase) and their effects on patients with breast cancer (BC). In the Metabric dataset (n = 2059, cBioPortal), SHARPIN GCN-Increase occurs preferentially or mutual exclusively with mutations in TP53, PIK3CA, and CDH1. These genomic alterations constitute a signature (SigMut) that significantly correlates with reductions in overall survival (OS) in BC patients (n = 1980; p = 1.081e - 6). Additionally, SHARPIN GCN-Increase is associated with 4220 differentially expressed genes (DEGs). These DEGs are enriched in activation of the pathways regulating cell cycle progression, RNA transport, ribosome biosynthesis, DNA replication, and in downregulation of the pathways related to extracellular matrix. These DEGs are thus likely to facilitate the proliferation and metastasis of BC cells. Additionally, through forward (FWD) and backward (BWD) stepwise variate selections among the top 160 downregulated and top 200 upregulated DEGs using the Cox regression model, a 6-gene (SigFWD) and a 50-gene (SigBWD) signature were derived. Both signatures robustly associate with decreases in OS in BC patients within the Curtis (n = 1980; p = 6.16e - 11 for SigFWD; p = 1.06e 10, for SigBWD) and TCGA cohort (n = 817; p = 4.53e - 4 for SigFWD and p = 0.00525 for SigBWD). After adjusting for known clinical factors, SigMut (HR 1.21, p = 0.0297), SigBWD (HR 1.25, p = 0.0263), and likely SigFWD (HR 1.17, p = 0.062) remain independent risk factors of BC deaths. Furthermore, the proportion of patients positive for these signatures is significantly increased in ER -, Her2 enriched, basal-like, and claudin-low BCs compared to ER + and luminal BCs. Collectively, these SHARPIN GCN-Increase-derived signatures may have clinical applications in management of patients with BC. PMID- 28879098 TI - Red cell allo- and autoimmunisation in transfused sickle cell and cancer patients in Kenyatta National Hospital, Nairobi, Kenya. AB - BACKGROUND: Currently, no data are available on the prevalence of red blood cell (RBC) antibody formation amongst Kenyan patients with multiple transfusion needs, such as patients with sickle cell disease (SCD) or haematological malignancies (HM) and solid (SM) malignancies. OBJECTIVES: We determined the prevalence and specificities of RBC alloantibodies and autoantibodies in two patient groups with recurrent transfusion demands at Kenyatta National Hospital, Nairobi, Kenya. METHOD: Between February and August 2014, 300 samples from SCD, HM and SM patients were collected and screened for alloantibodies. Samples from 51 healthy blood donors were screened for irregular antibodies and phenotyped. RESULTS: Amongst the 228 patients with viable samples (SCD, n = 137; HM, n = 48; SM, n = 43), the median transfusion frequency was two to three events per group, 38 (16.7%) were RBC immunised and 32 (14.0%) had a positive direct antiglobulin test. We identified specific alloantibodies in six patients (2.6%). Four of these six were SCD patients (2.9%) who had specific RBC alloantibodies (anti-Cw, anti M, anti-Cob, anti-S); amongst HM patients one had anti-K and one had anti-Lea. RBC autoantibody prevalence was 3.1% (7/228). Amongst the healthy blood donors, the Ror, ccD.ee and R2r, ccD.Ee phenotypes accounted for 82% of the Rhesus phenotypes and all were Kell negative. CONCLUSION: The numbers of transfusions and the rates of RBC alloantibodies are low and the most important RBC alloantibody-inducing blood group antigens are relatively homogeneously distributed in this population. A general change in the Kenyatta National Hospital pre-transfusion test regimen is thus not necessary. The current transfusion practice should be reconsidered if transfusion frequencies increase in the future. PMID- 28879099 TI - ISO 15189:2012: What changes for African laboratories? PMID- 28879100 TI - Development of immunohistochemistry services for cancer care in western Kenya: Implications for low- and middle-income countries. AB - BACKGROUND: Cancer is becoming a major cause of mortality in low- and middle income countries. Unlike infectious disease, malignancy and other chronic conditions require significant supportive infrastructure for diagnostics, staging and treatment. In addition to morphologic diagnosis, diagnostic pathways in oncology frequently require immunohistochemistry (IHC) for confirmation. We present the experience of a tertiary-care hospital serving rural western Kenya, which developed and validated an IHC laboratory in support of a growing cancer care service. OBJECTIVES METHODS AND OUTCOMES: Over the past decade, in an academic North-South collaboration, cancer services were developed for the catchment area of Moi Teaching and Referral Hospital in western Kenya. A major hurdle to treatment of cancer in a resource-limited setting has been the lack of adequate diagnostic services. Building upon the foundations of a histology laboratory, strategic investment and training were used to develop IHC services. Key elements of success in this endeavour included: translation of resource-rich practices to a resource-limited setting, such as using manual, small-batch IHC instead of disposable- and maintenance-intensive automated machinery, engagement of outside expertise to develop reagent-efficient protocols and supporting all levels of staff to meet the requirements of an external quality assurance programme. CONCLUSION: Development of low- and middle-income country models of services, such as the IHC laboratory presented in this paper, is critical for the infrastructure in resource-limited settings to address the growing cancer burden. We provide a low-cost model that effectively develops these necessary services in a challenging laboratory environment. PMID- 28879101 TI - Real-time polymerase chain reaction optimised for hepatitis C virus detection in dried blood spots from HIV-exposed infants, KwaZulu-Natal, South Africa. AB - BACKGROUND: There is a paucity of data on the prevalence of hepatitis C virus (HCV) in children, particularly in sub-Saharan Africa. A major obstacle in resource-limited settings for polymerase chain reaction (PCR) testing is the necessity for specimen transportation and storage at low temperatures. There are numerous recent studies of using real-time HCV PCR for diagnosis and screening of plasma and serum, but few have looked at using dried blood spot (DBS) specimens. OBJECTIVES: The aim of this study was to optimise a real-time HCV PCR method to detect HCV RNA from infant DBS specimens for use as a tool for HCV surveillance in KwaZulu-Natal, South Africa. METHOD: The LightCycler(r) 2.0 instrument was used for the HCV PCR using the LightCycler(r) RNA Master SYBR Green I kit. Template volume, primer concentration and primer annealing temperatures were optimised and the method was used on 179 DBS specimens from HIV-exposed infants in KwaZulu-Natal. RESULTS: Primer concentrations adjusted to 0.25 uM and a template volume of 10 uL improved the PCR amplification. Primer annealing temperatures lowered from 65 degrees C to 58 degrees C resulted in higher quantities of amplified PCR product. The limit of detection of the optimised HCV PCR assay was between 1200 IU/mL and 3580 IU/mL of HCV RNA. HCV was not detected in any of the 179 DBS specimens. CONCLUSION: The optimised real-time HCV PCR on infant DBS specimens performed well, but HCV was not found in this surveillance study. HIV infection may have little impact on the vertical transmission of HCV in this region. PMID- 28879102 TI - Performance of the Cellslide(r) automated liquid-based cytology system amongst HIV-positive women. AB - BACKGROUND: Many women undergoing cervical screening as part of a national South African screening programme may be positive for HIV. The performance of liquid based cytology (LBC) on samples from HIV-positive women needs to be determined. OBJECTIVES: The performance of the Cellslide(r) automated LBC system was evaluated as a possible alternative to conventional cytology in a national cervical cancer screening programme. METHODS: Split samples from 348 HIV-positive women attending an HIV treatment clinic in Johannesburg, South Africa were examined by conventional cytology and monolayer LBC methods. All samples were stained, examined and reported in the same manner. Cytotechnologists were blinded to the conventional smear diagnosis if the LBC smear was screened and vice versa. RESULTS: The same percentage of inadequate smears (1.4%) was obtained by conventional cytology and LBC. Atypical squamous cells of undetermined significance were observed in 5.2% of conventional smears and 4.0% of LBC smears. Low-grade squamous intraepithelial lesions were found in 35.6% of conventional smears and 32.7% of LBC smears. Only one conventional smear was categorised as atypical squamous cells - cannot exclude a high-grade lesion, whereas five such cases were identified on LBC. High-grade squamous intraepithelial lesions were seen in 21.6% of conventional smears and 23.3% LBC smears. No invasive carcinoma was identified. CONCLUSION: The performance of the Cellslide(r) LBC system was similar to that of conventional cytology in this population of high-risk HIV positive women, indicating that it may be introduced successfully as part of a cervical cancer screening programme. PMID- 28879103 TI - Implementation of the World Health Organization Regional Office for Africa Stepwise Laboratory Quality Improvement Process Towards Accreditation. AB - BACKGROUND: The increase in disease burden has continued to weigh upon health systems in Africa. The role of the laboratory has become increasingly critical in the improvement of health for diagnosis, management and treatment of diseases. In response, the World Health Organization Regional Office for Africa (WHO AFRO) and its partners created the WHO AFRO Stepwise Laboratory (Quality) Improvement Process Towards Accreditation (SLIPTA) program. SLIPTA IMPLEMENTATION PROCESS: WHO AFRO defined a governance structure with roles and responsibilities for six main stakeholders. Laboratories were evaluated by auditors trained and certified by the African Society for Laboratory Medicine. Laboratory performance was measured using the WHO AFRO SLIPTA scoring checklist and recognition certificates rated with 1-5 stars were issued. PRELIMINARY RESULTS: By March 2015, 27 of the 47 (57%) WHO AFRO member states had appointed a SLIPTA focal point and 14 Ministers of Health had endorsed SLIPTA as the desired programme for continuous quality improvement. Ninety-eight auditors from 17 African countries, competent in the Portuguese (3), French (12) and English (83) languages, were trained and certified. The mean score for the 159 laboratories audited between May 2013 and March 2015 was 69% (median 70%; SD 11.5; interquartile range 62-77). Of these audited laboratories, 70% achieved 55% compliance or higher (2 or more stars) and 1% scored at least 95% (5 stars). The lowest scoring sections of the WHO AFRO SLIPTA checklist were sections 6 (Internal Audit) and 10 (Corrective Action), which both had mean scores below 50%. CONCLUSION: The WHO AFRO SLIPTA is a process that countries with limited resources can adopt for effective implementation of quality management systems. Political commitment, ownership and investment in continuous quality improvement are integral components of the process. PMID- 28879104 TI - The prevalence of hepatitis B virus infection in HIV-positive and HIV-negative infants: KwaZulu-Natal, South Africa. AB - BACKGROUND: The prevalence of hepatitis B virus (HBV) amongst South African infants and children has been reported in the pre-HIV era. Despite the reported high prevalence of HIV in the general population of South Africa, the rate of HIV/HBV co-infection amongst infants and children remains poorly reported. OBJECTIVES: We describe the prevalence of HBV infection amongst HIV-positive and HIV-negative infants by molecular methods of diagnosis using dried blood spot samples. METHODS: This retrospective cross-sectional study was conducted between July 2011 and December 2011 in an academic referral laboratory offering viral diagnostic services to the entire KwaZulu-Natal province of South Africa. A total of 322 study samples were collected from discarded residual dried blood spot samples following routine infant diagnosis of HIV. Equal proportions of HIV positive and HIV-negative infant specimens were studied. Statistical differences in the prevalence of HBV between the HIV-positive and HIV-negative samples were calculated using the Pearson chi-square test, and a p-value < 0.05 was considered statistically significant. Further testing for HBV DNA using a nested polymerase chain reaction method was performed. RESULTS: The overall prevalence of HBV was 10%. In the HIV-positive group, 21 of 161 infants tested positive for HBV compared with 12 of 161 HIV-negative infants who tested positive for HBV. The proportion of infants infected with HBV was marginally higher amongst HIV positive infants (13.0%; 95% CI 6.8-19.9) compared with HIV-negative infants (7.5%; 95% CI 2.5-13.7; P = 0.098), though not statistically significant. CONCLUSION: The finding of a 10% HBV prevalence in this infant cohort is clinically significant. The non-statistically significant difference in HBV prevalence between the HIV-positive and HIV-negative infants suggests that high prevalence of HBV infection in children may be a problem independent of HIV. PMID- 28879105 TI - Molecular confirmation of Lassa fever imported into Ghana. AB - BACKGROUND: Recent reports have shown an expansion of Lassa virus from the area where it was first isolated in Nigeria to other areas of West Africa. Two Ghanaian soldiers on a United Nations peacekeeping mission in Liberia were taken ill with viral haemorrhagic fever syndrome following the death of a sick colleague and were referred to a military hospital in Accra, Ghana, in May 2013. Blood samples from the soldiers and five asymptomatic close contacts were subjected to laboratory investigations. OBJECTIVE: We report the results of these investigations to highlight the importance of molecular diagnostic applications and the need for heightened awareness about Lassa fever in West Africa. METHODS: We used molecular assays on sera from the two patients to identify the causative organism. Upon detection of positive signals for Lassa virus ribonucleic material by two different polymerase chain reaction assays, sequencing and phylogenetic analyses were performed. RESULTS: The presence of Lassa virus in the soldiers' blood samples was shown by L-gene segment homology to be the Macenta and las803792 strains previously isolated in Liberia, with close relationships then confirmed by phylogenetic tree construction. The five asymptomatic close contacts were negative for Lassa virus. CONCLUSIONS: The Lassa virus strains identified in the two Ghanaian soldiers had molecular epidemiological links to strains from Liberia. Lassa virus was probably responsible for the outbreak of viral haemorrhagic fever in the military camp. These data confirm Lassa fever endemicity in West Africa. PMID- 28879106 TI - Evaluation of the accuracy of the CellaVisionTM DM96 in a high HIV-prevalence population in South Africa. AB - INTRODUCTION: The CellaVisionTM DM96 (DM96) is a digital microscopy system which performs well in developed countries. However, to date it has not been evaluated in Africa, where the pathology spectrum encountered is very different. In particular, its utility in a setting with high HIV prevalence has not been assessed, which is of interest because of the morphological aberrations often seen in HIV-positive patients. OBJECTIVES: This study aimed to evaluate the accuracy of the DM96 in a South African laboratory, with emphasis on its performance in samples collected from HIV-positive patients. METHODS: A total of 149 samples submitted for a routine differential white cell count in 2012 and 2013 at the Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa were included, of which 79 (53.0%) were collected from HIV-positive patients. Results of DM96 analysis pre- and post-classification were compared with a manual differential white cell count and the impact of HIV infection and other variables of interest were assessed. RESULTS: Pre- and post-classification accuracies were similar to those reported in developed countries. Reclassification was required in 16% of cells, with particularly high misclassification rates for eosinophils (31.7%), blasts (33.7%) and basophils (93.5%). Multivariate analysis revealed a significant relationship between the number of misclassified cells and both the white cell count (p = 0.035) and the presence of malignant cells in the blood (p = 0.049), but not with any other variables analysed, including HIV status. CONCLUSION: The DM96 exhibited acceptable accuracy in this South African laboratory, which was not impacted by HIV infection. However, as it does not eliminate the need for experienced morphologists, its cost may be unjustifiable in a resource-constrained setting. PMID- 28879107 TI - Implications of the introduction of laboratory demand management at primary care clinics in South Africa on laboratory expenditure. AB - BACKGROUND: Diagnostic health laboratory services are regarded as an integral part of the national health infrastructure across all countries. Clinical laboratory tests contribute substantially to health system goals of increasing quality of care and improving patient outcomes. OBJECTIVES: This study aimed to analyse current laboratory expenditures at the primary healthcare (PHC) level in South Africa as processed by the National Health Laboratory Service and to determine the potential cost savings of introducing laboratory demand management. METHODS: A retrospective cross-sectional analysis of laboratory expenditures for the 2013/2014 financial year across 11 pilot National Health Insurance health districts was conducted. Laboratory expenditure tariff codes were cross-tabulated to the PHC essential laboratory tests list (ELL) to determine inappropriate testing. Data were analysed using a Microsoft Access database and Excel software. RESULTS: Approximately R35 million South African Rand (10%) of the estimated R339 million in expenditures was for tests that were not listed within the ELL. Approximately 47% of expenditure was for laboratory tests that were indicated in the algorithmic management of patients on antiretroviral treatment. The other main cost drivers for non-ELL testing included full blood count and urea, as well as electrolyte profiles usually requested to support management of patients on antiretroviral treatment. CONCLUSIONS: Considerable annual savings of up to 10% in laboratory expenditure are possible at the PHC level by implementing laboratory demand management. In addition, to achieve these savings, a standardised PHC laboratory request form and some form of electronic gatekeeping system that must be supported by an educational component should be implemented. PMID- 28879108 TI - Dried blood spot specimen quality and validation of a new pre-analytical processing method for qualitative HIV-1 PCR, KwaZulu-Natal, South Africa. AB - BACKGROUND: Poor quality dried blood spot (DBS) specimens are usually rejected by virology laboratories, affecting early infant diagnosis of HIV. The practice of combining two incompletely-filled DBS in one specimen preparation tube during pre analytical specimen processing (i.e., the two-spot method) has been implemented to reduce the number of specimens being rejected for insufficient volume. OBJECTIVES: This study analysed laboratory data to describe the quality of DBS specimens and the use of the two-spot method over a one-year period, then validated the two-spot method against the standard (one-spot) method. METHODS: Data on HIV-1 PCR test requests submitted in 2014 to the Department of Virology at Inkosi Albert Luthuli Central Hospital in KwaZulu-Natal province, South Africa were analysed to describe reasons for specimen rejection, as well as results of the two-spot method. The accuracy, lower limit of detection and precision of the two-spot method were assessed. RESULTS: Of the 88 481 specimens received, 3.7% were rejected for pre-analytical problems. Of those, 48.9% were rejected as a result of insufficient specimen volume. Two health facilities had significantly more specimen rejections than other facilities. The two-spot method prevented 10 504 specimen rejections. The Pearson correlation coefficient comparing the standard to the two-spot method was 0.997. CONCLUSIONS: The two-spot method was comparable with the standard method of pre-analytical specimen processing. Two health facilities were identified for targeted retraining on specimen quality. The two-spot method of DBS specimen processing can be used as an adjunct to retraining, to reduce the number of specimens rejected and improve linkage to care. PMID- 28879109 TI - Whole blood pathogen reduction technology and blood safety in sub-Saharan Africa: A systematic review with regional discussion. AB - BACKGROUND: Despite vast improvements in transfusion services in sub-Saharan Africa over the last decade, there remain serious concerns on the safety and adequacy of the blood supply across the region. OBJECTIVE: This review paper ascertains the role of pathogen reduction technology (PRT) in improving blood safety and supply adequacy in the region. METHOD: The state of blood safety in sub-Saharan Africa was reviewed. Meetings, seminars and correspondence were undertaken with key clinicians, scientists and professional bodies in the region, including the World Health Organization's Regional Office for Africa, to examine the suitability of PRT for improving the safety of whole blood transfusion, a prevalent transfusion format in the region. RESULTS: Existing literature suggests that combining PRT with current blood safety measures (such as serology) would improve the safety and adequacy of the blood supply for transfusions in sub Saharan Africa. This was echoed by the findings of the stakeholder meetings. CONCLUSION: Following a detailed appraisal of two leading PRT systems, the Mirasol(r) PRT System and the Cerus S-303 System, we suggest that companies conduct comprehensive toxicological evaluation of the agents used for PRT and publish this in the scientific literature. We also recommend that the safety and efficacy of these technologies should be established in a randomised clinical trial conducted in sub-Saharan Africa. PMID- 28879110 TI - The viable but non-culturable state in pathogenic Escherichia coli: A general review. AB - BACKGROUND: The persistence and pathogenicity of pathogenic bacteria are dependent on the ability of the species to survive in adverse conditions. During the infectious process, the organism may need to pass through certain hostile anatomical sites, such as the stomach. Under various environmental stresses, many bacteria enter into the viable but non-culturable (VBNC) state, where they are 'alive' or metabolically active, but will not grow on conventional media. Escherichia coli bacteria encounter several diverse stress factors during their growth, survival and infection and thus may enter into the VBNC state. OBJECTIVES: This review discusses various general aspects of the VBNC state, the mechanisms and possible public health impact of indicator and pathogenic E. coli entering into the VBNC state. METHOD: A literature review was conducted to ascertain the possible impact of E. coli entering into the VBNC state. RESULTS: Escherichia coli enter into the VBNC state by means of several induction mechanisms. Various authors have found that E. coli can be resuscitated post VBNC. Certain strains of pathogenic E. coli are still able to produce toxins in the VBNC state, whilst others are avirulent during the VBNC state but are able to regain virulence after resuscitation. CONCLUSION: Pathogenic and indicator E. coli entering into the VBNC state could have an adverse effect on public health if conventional detection methods are used, where the number of viable cells could be underestimated and the VBNC cells still produce toxins or could, at any time, be resuscitated and become virulent again. PMID- 28879111 TI - Evaluating laboratory request forms submitted to haematology and blood transfusion departments at a hospital in Northwest Nigeria. AB - BACKGROUND: The laboratory request form (LRF) is a communication link between laboratories, requesting physicians and users of laboratory services. Inadequate information or errors arising from the process of filling out LRFs can significantly impact the quality of laboratory results and, ultimately, patient outcomes. OBJECTIVE: We assessed routinely-submitted LRFs to determine the degree of correctness, completeness and consistency. METHODS: LRFs submitted to the Department of Haematology (DH) and Blood Transfusion Services (BTS) of Aminu Kano Teaching Hospital in Kano, Nigeria, between October 2014 and December 2014, were evaluated for completion of all items on the forms. Performance in four quality indicator domains, including patient identifiers, test request details, laboratory details and physician details, was derived as a composite percentage. RESULTS: Of the 2084 LRFs evaluated, 999 were from DH and 1085 from BTS. Overall, LRF completeness was 89.5% for DH and 81.2% for BTS. Information on patient name, patient location and laboratory number were 100% complete for DH, whereas only patient name was 100% complete for BTS. Incomplete information was mostly encountered on BTS forms for physician's signature (60.8%) and signature of laboratory receiver (63.5%). None of the DH and only 9.4% of BTS LRFs met all quality indicator indices. CONCLUSION: The level of completion of LRFs from these two departments was suboptimal. This underscores the need to review and redesign the LRF, improve on training and communication between laboratory and clinical staff and review specimen rejection practices. PMID- 28879112 TI - Verification of chemistry reference ranges using a simple method in sub-Saharan Africa. AB - BACKGROUND: Chemistry safety assessments are interpreted by using chemistry reference ranges (CRRs). Verification of CRRs is time consuming and often requires a statistical background. OBJECTIVES: We report on an easy and cost saving method to verify CRRs. METHODS: Using a former method introduced by Sigma Diagnostics, three study sites in sub-Saharan Africa, Bondo, Kenya, and Pretoria and Bloemfontein, South Africa, verified the CRRs for hepatic and renal biochemistry assays performed during a clinical trial of HIV antiretroviral pre exposure prophylaxis. The aspartate aminotransferase/alanine aminotransferase, creatinine and phosphorus results from 10 clinically-healthy participants at the screening visit were used. In the event the CRRs did not pass the verification, new CRRs had to be calculated based on 40 clinically-healthy participants. RESULTS: Within a few weeks, the study sites accomplished verification of the CRRs without additional costs. The aspartate aminotransferase reference ranges for the Bondo, Kenya site and the alanine aminotransferase reference ranges for the Pretoria, South Africa site required adjustment. The phosphorus CRR passed verification and the creatinine CRR required adjustment at every site. The newly established CRR intervals were narrower than the CRRs used previously at these study sites due to decreases in the upper limits of the reference ranges. As a result, more toxicities were detected. CONCLUSION: To ensure the safety of clinical trial participants, verification of CRRs should be standard practice in clinical trials conducted in settings where the CRR has not been validated for the local population. This verification method is simple, inexpensive, and can be performed by any medical laboratory. PMID- 28879113 TI - Evaluation of the BioFire(r) FilmArray(r) Blood Culture Identification Panel on positive blood cultures in a regional hospital laboratory in KwaZulu-Natal. AB - BACKGROUND: There are presently many non-culture-based methods commercially available to identify organisms and antimicrobial susceptibility from blood culture bottles. Each platform has its benefits and limitations. However, there is a need for an improved system with minimal hands-on requirements and short run times. OBJECTIVES: In this study, the performance characteristics of the FilmArray(r) BCID Panel kit were evaluated to assess the efficiency of the kit against an existing system used for identification and antimicrobial susceptibility of organisms from blood cultures. METHODS: Positive blood cultures that had initially been received from hospitalised patients of a large quaternary referral hospital in Durban, South Africa were processed as per routine protocol at its Medical Microbiology Laboratory. Positive blood cultures were processed on the FilmArray BCID Panel kit in parallel with the routine sample processing. Inferences were then drawn from results obtained. RESULTS: Organism detection by the FilmArray BCID panel was accurate at 92.6% when organisms that were on the repertoire of the kit were considered, compared to the combination methods (reference method used in the study laboratory). Detection of the antimicrobial resistance markers provided by the panel and reference method demonstrated 100% consistency. Blood cultures with a single organism were accurately identified at 93.8% by FilmArray, while blood cultures with more than one organism were identified at 85.7%. CONCLUSION: The FilmArray BCID Panel kit is valuable for detection of organisms and markers of antibiotic resistance for an extensive range of organisms. PMID- 28879114 TI - A review of antimicrobial resistance in East Africa. AB - BACKGROUND AND OBJECTIVES: Knowledge of local and regional antimicrobial resistance (AMR) is important for clinical decision making. However, surveillance capacity for AMR is lacking throughout East Africa, and current AMR data are sparse. We sought to address this gap by summarising all available high-quality data on AMR in the East Africa region. METHOD: We searched the PubMed database and African Journals Online archives in April and May 2015 using the search term 'antimicrobial resistance AND sub-Saharan Africa' to find articles published from 2005 onwards. Only full-text articles in English were included. RESULTS: We included 12 published articles in our analysis. Most articles were on bloodstream infections, hospital-based and cross-sectional in design; a majority described either community- or hospital-acquired infections. High levels of AMR to commonly used antibiotics were reported, including 50% - 100% resistance to ampicillin and cotrimoxazole infections, emerging resistance to gentamicin (20% - 47%) and relatively high levels of resistance to ceftriaxone (46% - 69%) among Gram negative infections. Much of the resistance was reported to be in Klebsiella species and Escherichia coli. Among Gram-positive infections, extensive resistance was reported to ampicillin (100%), gentamicin and ceftriaxone (50% - 100%), with methicillin-resistant Staphylococcus aureus prevalence ranging from 2.6% - 4.0%. CONCLUSION: Overall, bacterial resistance was reported among commonly-used antibiotics (ampicillin, gentamicin and ceftriaxone), raising concern that these antibiotics may no longer be useful for treating moderate or severe bacterial infections in East Africa. Thus, empirical treatment of bacterial infections needs to be reconsidered and guided by local assessment of AMR. Improvements in the limited amount of quality data and lack of harmonisation in assessing the burden of AMR are also needed. PMID- 28879115 TI - Laboratory evaluation of the Chembio Dual Path Platform HIV-Syphilis Assay. AB - BACKGROUND: Use of rapid diagnostic tests for HIV and syphilis has increased remarkably in the last decade. As new rapid diagnostic tests become available, there is a continuous need to assess their performance and operational characteristics prior to use in clinical settings. OBJECTIVES: In this study, we evaluated the performance of the Chembio Dual Path Platform (DPP(r)) HIV-Syphilis Assay to accurately diagnose HIV, syphilis, and HIV/syphilis co-infection. METHOD: In 2013, 990 serum samples from the Georgia Public Health Laboratory in Atlanta, Georgia, United States were characterised for HIV and syphilis and used to evaluate the platform. HIV reference testing combined third-generation Enzyme Immunoassay and Western Blot, whereas reference testing for syphilis was conducted by the Treponema pallidum passive particle agglutination method and the TrepSure assay. We assessed the sensitivity and specificity of the DPP assay on this panel by comparing results with the HIV and syphilis reference testing algorithms. RESULTS: For HIV, sensitivity was 99.8% and specificity was 98.4%; for syphilis, sensitivity was 98.8% and specificity was 99.4%. Of the 348 co infected sera, 344 (98.9%) were detected accurately by the DPP assay, but 11 specimens had false-positive results (9 HIV and 2 syphilis) due to weak reactivity. CONCLUSION: In this evaluation, the Chembio DPP HIV-Syphilis Assay had high sensitivity and specificity for detecting both HIV and treponemal antibodies. Our results indicate that this assay could have a significant impact on the simultaneous screening of HIV and syphilis using a single test device for high-risk populations or pregnant women needing timely care and treatment. PMID- 28879116 TI - Experimental phage therapy against haematogenous multi-drug resistant Staphylococcus aureus pneumonia in mice. AB - BACKGROUND: Community-acquired haematogenous Staphylococcus aureus pneumonia is a rare infection, though it can be acquired nosocomially. Currently, antibiotics used against S. aureus pneumonia have shown reduced efficacy. Thus, there is need for an alternative therapy against multidrug-resistant S. aureus (MDRSA) strains in the community. OBJECTIVE: We sought to determine the efficacy of environmentally-obtained S. aureus lytic phage against haematogenous MDRSA pneumonia in mice. METHODS: Phages and MDRSA were isolated from sewage samples collected within Nairobi County, Kenya. Isolated S. aureus bacteria were screened for resistance against ceftazidime, oxacillin, vancomycin, netilmicin, gentamicin, erythromycin, trimethroprim-sulfamethoxazole and cefuroxime. Thirty BALB/c mice aged six to eight weeks were randomly assigned into three groups: the MDRSA-infection group (n = 20), the phage-infection group (n = 5) and the non infection group (n = 5). Mice were infected with either MDRSA or phage (108 CFU/mL) and treated after 72 hours with a single dose of clindamycin (8 mg/kg/bwt) or 108 PFU/mL of phage or a combination therapy (clindamycin and phage). The efficacy of phage, clindamycin or clindamycin with phage combination was determined using resolution of lung pathology and bacterial load in lung homogenates. RESULTS: The viable MDRSA count was 0.5 +/- 0.2 log10 CFU/gm in the phage-treated group, 4.4 +/- 0.2 log10 CFU/gm in the clindamycin-treated group and 4.0 +/- 0.2 log10 CFU/gm in the combination-treated group. The efficacy of phage therapy was significantly different from other therapeutic modes (p = 0 < 0.0001). Histology showed that the mice treated with phage did not develop pneumonia. CONCLUSION: Phage therapy is effective against haematogenous MDRSA infection. Thus, it can be explored as an alternative treatment method. PMID- 28879117 TI - Experiential Bloom's Taxonomy learning framework for point-of-care diagnostics training of primary healthcare workers. PMID- 28879119 TI - The diagnostic-clinical chasm: Work in progress? PMID- 28879118 TI - Biosafety level-2 laboratory diagnosis of Zaire Ebola virus disease imported from Liberia to Nigeria. AB - INTRODUCTION: Global travel is an efficient route of transmission for highly infectious pathogens and increases the chances of such pathogens moving from high disease-endemic areas to new regions. We describe the rapid and safe identification of the first imported case of Ebola virus disease in a traveler to Lagos, Nigeria, using conventional reverse transcription polymerase chain reaction (RT-PCR) in a biosafety level (BSL)-2 facility. CASE PRESENTATION: On 20 July 2014, a traveler arrived from Liberia at Lagos International Airport and was admitted to a private hospital in Lagos, with clinical suspicion of Ebola virus disease. METHODOLOGY AND OUTCOME: Blood and urine specimens were collected, transported to the Virology Unit Laboratory at the College of Medicine, University of Lagos, and processed under stringent biosafety conditions for viral RNA extraction. RT-PCR was set-up to query the Ebola, Lassa and Dengue fever viruses. Amplicons for pan-filoviruses were detected as 300 bp bands on a 1.5% agarose gel image; there were no detectable bands for Lassa and Dengue viral RNA. Nucleotide BLAST and phylogenetic analysis of sequence data of the RNA-dependent RNA polymerase (L) gene confirmed the sequence to be Zaire ebolavirus (EBOV/Hsap/NGA/2014/LIB-NIG 01072014; Genbank: KM251803.1). CONCLUSION: Our BSL-2 facility in Lagos, Nigeria, was able to safely detect Ebola virus disease using molecular techniques, supporting the reliability of molecular detection of highly infectious viral pathogens under stringent safety guidelines in BSL-2 laboratories. This is a significant lesson for the many under-facilitated laboratories in resource-limited settings, as is predominantly found in sub Saharan Africa. PMID- 28879120 TI - South Africa's experience with provision of quality HIV diagnostic services. PMID- 28879121 TI - Experience from a pilot point-of-care CD4 enumeration programme in Kenya. PMID- 28879122 TI - Establishing a national laboratory quality system for HIV diagnosis and monitoring in resource-limited settings: Experience from Senegal. PMID- 28879123 TI - QASI: A collaboration for implementation of an independent quality assessment programme in India. AB - OBJECTIVE: The HIV pandemic remains a significant global health concern. Accurate determination of CD4+ T-cells in patient samples relies on reliable CD4 enumeration. The Quality Assessment and Standardization programme for Immunological measures relevant to HIV/AIDS (QASI) programme of the Public Health Agency of Canada provides clinical laboratories from resource-limited countries with a mechanism to evaluate the quality of CD4 testing and develop the implementation of an independent national External Quality Assessment (EQA) programme. This study describes how QASI helped develop the capacity for managing a sustainable national CD4 EQA programme in India. DESIGN: Supported by the Public Health Agency of Canada and Clinton Foundation HIV/AIDS Initiative, QASI engaged with the National AIDS Control Organization and the Indian National AIDS Research Institute to assist in technology transfer in preparation for the implementation/management of an independent CD4 EQA programme. Technology transfer training was provided to support corrective actions and to improve the quality of CD4 testing. Inter-laboratory variation of EQA surveys between pre- and post-skill development was compared. RESULTS: Prior to training, coefficient of variation values were 14.7% (mid-level CD4 count controls) and 39.0% (low level). Following training, variation was reduced to 10.3% for mid-level controls and 20.0% for low-level controls. CONCLUSION: This training assisted the National AIDS Control Organization and the Indian National AIDS Research Institute in identifying the information necessary for management of an EQA programme, and developed the foundation for India to provide corrective actions for sites with challenges in achieving reliable results for CD4 enumeration. This led to a demonstrable improvement in CD4 testing quality and illustrates how country specific training significantly improved CD4 enumeration performance for better clinical management of HIV care in India. PMID- 28879124 TI - Quality assurance for point-of-care testing in Mozambique's National Health Service. PMID- 28879125 TI - Quality assurance as an integral component of diagnostic testing in clinical laboratories and point-of-care testing: The Uganda experience. PMID- 28879126 TI - Quality assurance for point-of-care testing in Zimbabwe. PMID- 28879127 TI - Quality assurance for point-of-care testing: Ethiopia's experience. PMID- 28879128 TI - Implementing quality assurance for laboratory-based and point-of-care HIV testing in Nigeria. PMID- 28879129 TI - Data connectivity: A critical tool for external quality assessment. AB - Point-of-care (POC) tests have been useful in increasing access to testing and treatment monitoring for HIV. Decentralising testing from laboratories to hundreds of sites around a country presents tremendous challenges in training and quality assurance. In order to address these concerns, companies are now either embedding connectivity in their new POC diagnostic instruments or providing some form of channel for electronic result exchange. These will allow automated key performance and operational metrics from devices in the field to a central database. Setting up connectivity between these POC devices and a central database at the Ministries of Health will allow automated data transmission, creating an opportunity for real-time information on diagnostic instrument performance as well as the competency of the operator through external quality assessment. A pilot programme in Zimbabwe shows that connectivity has significantly improve the turn-around time of external quality assessment result submissions and allow corrective actions to be provided in a timely manner. Furthermore, by linking the data to existing supply chain management software, stock-outs can be minimised. As countries are looking forward to achieving the 90 90-90 targets for HIV, such innovative technologies can automate disease surveillance, improve the quality of testing and strengthen the efficiency of health systems. PMID- 28879130 TI - A national quality assurance programme for point-of-care testing in Malawi. PMID- 28879131 TI - Quality assurance for point-of-care diagnostic testing: It is not negotiable. PMID- 28879132 TI - External quality assurance for HIV point-of-care testing in Africa: A collaborative country-partner approach to strengthen diagnostic services. AB - It is important to consider the role of diagnostics and the critical need for quality diagnostics services in resource-limited settings. Accurate diagnostic tests play a key role in patient management and the prevention and control of most infectious diseases. As countries plan for implementation of HIV early infant diagnosis and viral load point-of-care testing, the London School of Hygiene & Tropical Medicine has worked with countries and partners with an interest in external quality assurance to support quality point-of-care testing on the continent. Through a series of collaborative consultations and workshops, the London School of Hygiene & Tropical Medicine has gathered lessons learned, tools, and resources and developed quality assurance models that will support point-of-care testing. The London School of Hygiene & Tropical Medicine is committed to the continued advancement of laboratory diagnostics in Africa and quality laboratory services and point-of-care testing. PMID- 28879134 TI - Assuring the quality of diagnostic testing: The future is now. PMID- 28879133 TI - Quality assurance for HIV point-of-care testing and treatment monitoring assays. AB - In 2015, UNAIDS launched the 90-90-90 targets aimed at increasing the number of people infected with HIV to become aware of their status, access antiretroviral therapies and ultimately be virally suppressed. To achieve these goals, countries may need to scale up point-of-care (POC) testing in addition to strengthening central laboratory services. While decentralising testing increases patient access to diagnostics, it presents many challenges with regard to training and assuring the quality of tests and testing. To ensure synergies, the London School of Hygiene & Tropical Medicine held a series of consultations with countries with an interest in quality assurance and their implementing partners, and agreed on an external quality assessment (EQA) programme to ensure reliable results so that the results lead to the best possible care for HIV patients. As a result of the consultations, EQA International was established, bringing together EQA providers and implementers to develop a strategic plan for countries to establish national POC EQA programmes and to estimate the cost of setting up and maintaining the programme. With the dramatic increase in the number of proficiency testing panels required for thousands of POC testing sites across Africa, it is important to facilitate technology transfer from global EQA providers to a network of regional EQA centres in Africa for regional proficiency testing panel production. EQA International will continue to identify robust and cost-effective EQA technologies for quality POC testing, integrating novel technologies to support sustainable country-owned EQA programmes in Africa. PMID- 28879135 TI - The WHO AFRO external quality assessment programme (EQAP): Linking laboratory networks through EQA programmes. AB - External Quality Assessment (EQA) surveys performed by the World Health Organization Regional Office for Africa (WHO AFRO) revealed the need for the strengthening of public health microbiology laboratories, particularly for testing of epidemic-prone diseases in the African Region. These surveys revealed common issues such as supply chain management, skilled personnel, logistical support and overall lack of quality standards. For sustainable improvements to health systems as well as global health security, deficiencies identified need to be actively corrected through robust quality assurance programmes and implementation of laboratory quality management systems. Given all the pathogens of public health importance, an external quality assessment programme with a focus on vaccine-preventable diseases and emerging and re-emerging dangerous pathogens is important, and should not be stand-alone, but integrated within laboratory networks as seen in polio, measles, yellow fever and rubella. In 2015, WHO AFRO collaborated with the US Centers for Disease Control and Prevention, the London School of Hygiene & Tropical Medicine and partners in a series of consultations with countries and national and regional EQA providers for the development of quality assurance models to support HIV point-of-care testing and monitoring. These consultations revealed similar challenges as seen in the WHO AFRO surveys. WHO AFRO brought forth its experience in implementing quality standards for health programmes, and also opened discussions on how lessons learned through such established programmes can be utilised to supporting and strengthening the introduction of early infant diagnosis of HIV and viral load point-of-care testing. An optimised external quality assessment programme will impact the ability of countries to meet core capacities, providing improved quality management systems, improving the confidence of diagnostic network services in Africa, and including capacities to detect events of international public health importance. PMID- 28879136 TI - Integrating laboratory networks, surveillance systems and public health institutes in Africa. AB - The Ebola outbreak in West Africa underlined the urgent need for integration of public health systems, including the establishment of national laboratory networks, surveillance systems, and health research institutions at all levels of service delivery. The integration schema presented here would assist in driving the immediate steps needed for integration of public health systems, particularly laboratory networks, in support of the implementation of International Health Regulations and the Global Health Security Agenda in the African region. Increased funding, political willingness from countries, and coordination through enhanced technical assistance from international partners, are critical in achieving this objective. PMID- 28879137 TI - Practical recommendations for strengthening national and regional laboratory networks in Africa in the Global Health Security era. AB - The role of national health laboratories in support of public health response has expanded beyond laboratory testing to include a number of other core functions such as emergency response, training and outreach, communications, laboratory based surveillance and data management. These functions can only be accomplished by an efficient and resilient national laboratory network that includes public health, reference, clinical and other laboratories. It is a primary responsibility of the national health laboratory in the Ministry of Health to develop and maintain the national laboratory network in the country. In this article, we present practical recommendations based on 17 years of network development experience for the development of effective national laboratory networks. These recommendations and examples of current laboratory networks, are provided to facilitate laboratory network development in other states. The development of resilient, integrated laboratory networks will enhance each state's public health system and is critical to the development of a robust national laboratory response network to meet global health security threats. PMID- 28879138 TI - Stepwise approach for implementation of antimicrobial resistance surveillance in Africa. AB - BACKGROUND: Antimicrobial resistance (AMR) has reached an end point, prompting a worldwide scare as no new antibiotics are in the pipeline, particularly for treatment of Gram-negative bacteria. To prevent further development and spread of AMR and to inform empirical treatment guidelines, surveillance of AMR is necessary. OBJECTIVE: We aim to provide a framework for a stepwise approach toward implementation of laboratory-based surveillance for AMR in African countries. METHODS AND RESULTS: Building up a surveillance system is a robust process that begins with a gap analysis in each participating country. This framework provides practical guidance on how to set up surveillance, identify responsibilities and set timelines in sustainable manner for African countries. It addresses sampling strategies, human resources, procurement and maintenance issues for AMR testing at routine clinical and national reference and public health laboratories involved in AMR surveillance. Key issues such as laboratory capacity building, training and continuous education, quality and diagnostic stewardship are discussed in detail. DISCUSSION: There are several priorities for AMR surveillance that need to be addressed in a comprehensive manner at regional and national levels, whilst keeping in line with current and proposed initiatives for laboratory capacity building, in order for African countries to achieve goals for combatting the real and current threat of AMR. PMID- 28879139 TI - A framework for the assessment and implementation of diagnostics in outbreak situations. AB - OBSERVATION: Outbreak situations require in vitro diagnostics (IVDs) to identify those who are infected and to track the infectious agent in the population. However, such IVDs are typically not available and must be developed. In addition, the process of IVD development, assessment, and implementation are very time and resource intensive. Recognising the extraordinary public health need for IVDs in an outbreak situation, streamlined processes are needed to provide tests that meet the standard of a reasonable assurance of safety and effectiveness in the shortest amount of time. These IVDs are designated for outbreak use. ADDRESSING ISSUES: This paper presents a pathway to the outbreak use of IVDs that can be considered by countries experiencing an outbreak situation. It takes into account recognition of the outbreak, product development, regulatory evaluation, implementation, and monitoring of the outbreak-use test. Streamlined assessment programmes for emergency-use tests have been established by the US Food and Drug Administration and the World Health Organization. These programmes take into account test requirements for the country in which the outbreak exists. Therefore, countries can consider adopting these tests without the need to conduct expensive and time consuming assessments, such as performance studies. Key responsible parties are identified for each step of the pathway, recognising that transparency and communication among all parties are critical. PMID- 28879140 TI - Laboratory systems as an antibacterial resistance containment tool in Africa. AB - INTRODUCTION: As crucial as clinical laboratories are to preventing, identifying and managing resistance problems, laboratory scientists are among the most overlooked stakeholders. This review outlines the contributions that diagnostic laboratory systems should make toward all five of the World Health Organization's 2015 strategic objectives for antimicrobial resistance containment. LABORATORY SYSTEMS IN RESISTANCE CONTAINMENT: Antimicrobial susceptibility testing and surveillance are central to antibacterial resistance management and control and need to be implemented more commonly and closer to sick patients. However, the scope of tests that promote judicious antimicrobial use extend beyond susceptibility testing. Laboratory tests for pathogens or their associated biomarkers confirm or rule out specific causes of signs and symptoms associated with infection. Laboratory systems also provide critical support to infection control programmes. All of these functions promote rational antimicrobial use and contain the spread of resistance. Routine laboratory data supports the development of vaccines and other technologies that could ease the pressure placed by antimicrobials. Laboratories are also a rich source of information for health professionals, policymakers and the general public about the urgency of the resistance problem and progress in containing it. CONCLUSION: Laboratory systems are integral to antimicrobial resistance containment and contributions from African laboratories to addressing resistance need to be enhanced. PMID- 28879141 TI - A new matrix for scoring the functionality of national laboratory networks in Africa: introducing the LABNET scorecard. AB - BACKGROUND: Functional national laboratory networks and systems are indispensable to the achievement of global health security targets according to the International Health Regulations. The lack of indicators to measure the functionality of national laboratory network has limited the efficiency of past and current interventions to enhance laboratory capacity in resource-limited settings. SCORECARD FOR LABORATORY NETWORKS: We have developed a matrix for the assessment of national laboratory network functionality and progress thereof, with support from the African Society of Laboratory Medicine and the Association of Public Health Laboratories. The laboratory network (LABNET) scorecard was designed to: (1) Measure the status of nine overarching core capabilities of laboratory network required to achieve global health security targets, as recommended by the main normative standards; (2) Complement the World Health Organization joint external evaluation tool for the assessment of health system preparedness to International Health Regulations (2005) by providing detailed information on laboratory systems; and (3) Serve as a clear roadmap to guide the stepwise implementation of laboratory capability to prevent, detect and act upon infectious threats. CONCLUSIONS: The application of the LABNET scorecard under the coordination of the African Society of Laboratory Medicine and the Association of Public Health Laboratories could contribute to the design, monitoring and evaluation of upcoming Global Health Security Agenda-supported laboratory capacity building programmes in sub Saharan-Africa and other resource limited settings, and inform the development of national laboratory policies and strategic plans. Endorsement by the World Health Organization Regional Office for Africa is foreseen. PMID- 28879142 TI - Pre-Ebola virus disease laboratory system and related challenges in Liberia. AB - Prior to the Ebola virus disease outbreak in Liberia, the laboratory system was duplicative, fragmented and minimally coordinated. The National Reference Laboratory was conceptualised to address the existing challenges by promoting the implementation of effective and sustainable laboratory services in Liberia. However, in a resource-limited environment such as Liberia, progress regarding the rebuilding of the health system can be relatively slow, while efforts to sustain the transient gains remain a key challenge for the Ministry of Health. In this paper, we describe the pre-Ebola virus disease laboratory system in Liberia and its prevailing efforts to address future emerging infectious diseases, as well as current Infectious diseases, all of which are exacerbated by poverty. We conclude that laboratory and diagnostic services in Liberia have encountered numerous challenges regarding its efforts to strengthen the healthcare delivery system. These challenges include limited trained human resource capacity, inadequate infrastructure, and a lack of coordination. As with most countries in sub-Saharan Africa, when comparing urban and rural settings, diagnostic and clinical services are generally skewed toward urban health facilities and private, faith-based health facilities. We recommend that structured policy be directed at these challenges for national institutions to develop guidelines to improve, strengthen and sustain diagnostic and curative laboratory services to effectively address current infectious diseases and prepare for future emerging and re-emerging infectious diseases. PMID- 28879143 TI - The laboratory health system and its response to the Ebola virus disease outbreak in Liberia. AB - The laboratory system in Liberia has generally been fragmented and uncoordinated. Accordingly, the country's Ministry of Health established the National Reference Laboratory to strengthen and sustain laboratory services. However, diagnostic testing services were often limited to clinical tests performed in health facilities, with the functionality of the National Reference Laboratory restricted to performing testing services for a limited number of epidemic-prone diseases. The lack of testing capacity in-country for Lassa fever and other haemorrhagic fevers affected the response of the country's health system during the onset of the Ebola virus disease (EVD) outbreak. Based on the experiences of the EVD outbreak, efforts were initiated to strengthen the laboratory system and infrastructure, enhance human resource capacity, and invest in diagnostic services and public health surveillance to inform admittance, treatment, and discharge decisions. In this article, we briefly describe the pre-EVD laboratory capability in Liberia, and extensively explore the post-EVD strengthening initiatives to enhance capacity, mobilise resources and coordinate disaster response with international partners to rebuild the laboratory infrastructure in the country. Now that the EVD outbreak has ended, additional initiatives are needed to revise the laboratory strategic and operational plan for post-EVD relevance, promote continual human resource capacity, institute accreditation and validation programmes, and coordinate the investment strategy to strengthen and sustain the preparedness of the laboratory sector to mitigate future emerging and re-emerging infectious diseases. PMID- 28879144 TI - Sierra Leone laboratory systems - now and future. PMID- 28879145 TI - Building laboratory capacity to combat disease outbreaks in Africa. PMID- 28879146 TI - Trends in leprosy case detection in Rwanda, 1995-2011: analysis of 17 years of laboratory data. AB - BACKGROUND: Leprosy, or Hansen's disease, is a chronic, infectious disease caused by Mycobacterium leprae. It remains one of the leading causes of deformity and physical disability. OBJECTIVE: We analysed laboratory records to assess trends in prevalence rates and case detection rates (CDRs) in Rwanda. METHODS: A retrospective review of detected leprosy cases from the records of the Rwanda National Reference Laboratory over a 17-year period (1995-2011) was conducted. Skin biopsy samples were analysed microscopically using Ziehl-Neelsen staining technique to identify M. leprae. RESULTS: Cumulatively, 266 suspected cases were reported between 1995 and 2011. Of the suspected cases, 77 (28.9%) were laboratory confirmed as having leprosy. Among detected cases, 59 (76.6%) were men and 18 (23.4%) women. The male:female ratio was 3:1. There were 77 registered leprosy cases over the 17-year period of the study, and the prevalence rate was 0.005 per 10 000 population. A gradual decrease in the prevalence rate was observed from 0.015 per 10 000 population in 2003 to 0.003 per 10 000 population in 2010. From 1995 to 2011, the CDR did not exceed one per 10 000 population. CONCLUSION: This laboratory review demonstrates a declining trend in prevalence rates and CDR during the period of the study. Early case detection and a sustainable leprosy control programme remain the cornerstones of reducing the physical and socio-economic burden of leprosy in Rwanda. PMID- 28879147 TI - Laboratory test result interpretation for primary care doctors in South Africa. AB - BACKGROUND: Challenges and uncertainties with test result interpretation can lead to diagnostic errors. Primary care doctors are at a higher risk than specialists of making these errors, due to the range in complexity and severity of conditions that they encounter. OBJECTIVES: This study aimed to investigate the challenges that primary care doctors face with test result interpretation, and to identify potential countermeasures to address these. METHODS: A survey was sent out to 7800 primary care doctors in South Africa. Questionnaire themes included doctors' uncertainty with interpreting test results, mechanisms used to overcome this uncertainty, challenges with appropriate result interpretation, and perceived solutions for interpreting results. RESULTS: Of the 552 responses received, the prevalence of challenges with result interpretation was estimated in an average of 17% of diagnostic encounters. The most commonly-reported challenges were not receiving test results in a timely manner (51% of respondents) and previous results not being easily available (37%). When faced with diagnostic uncertainty, 84% of respondents would either follow-up and reassess the patient or discuss the case with a specialist, and 67% would contact a laboratory professional. The most useful test utilisation enablers were found to be: interpretive comments (78% of respondents), published guidelines (74%), and a dedicated laboratory phone line (72%). CONCLUSION: Primary care doctors acknowledge uncertainty with test result interpretation. Potential countermeasures include the addition of patient specific interpretive comments, the availability of guidelines or algorithms, and a dedicated laboratory phone line. The benefit of enhanced test result interpretation would reduce diagnostic error rates. PMID- 28879148 TI - Implementation of broad screening with Ebola rapid diagnostic tests in Forecariah, Guinea. AB - BACKGROUND: Laboratory-enhanced surveillance is critical for rapidly detecting the potential re-emergence of Ebola virus disease. Rapid diagnostic tests (RDT) for Ebola antigens could expand diagnostic capacity for Ebola virus disease. OBJECTIVES: The Guinean National Coordination for Ebola Response conducted a pilot implementation to determine the feasibility of broad screening of patients and corpses with the OraQuick(r) Ebola RDT. METHODS: The implementation team developed protocols and trained healthcare workers to screen patients and corpses in Forecariah prefecture, Guinea, from 15 October to 30 November 2015. Data collected included number of consultations, number of fevers reported or measured, number of tests performed for patients or corpses and results of confirmatory RT-PCR testing. Data on malaria RDT results were collected for comparison. Feedback from Ebola RDT users was collected informally during supervision visits and forums. RESULTS: There were 3738 consultations at the 15 selected healthcare facilities; 74.6% of consultations were for febrile illness. Among 2787 eligible febrile patients, 2633 were tested for malaria and 1628 OraQuick(r) Ebola RDTs were performed. A total of 322 OraQuick(r) Ebola RDTs were conducted on corpses. All Ebola tests on eligible patients were negative. CONCLUSIONS: Access to Ebola testing was expanded by the implementation of RDTs in an emergency situation. Feedback from Ebola RDT users and lessons learned will contribute to improving quality for RDT expansion. PMID- 28879149 TI - Development and implementation of the Caribbean Laboratory Quality Management Systems Stepwise Improvement Process (LQMS-SIP) Towards Accreditation. AB - BACKGROUND: Implementing quality management systems and accrediting laboratories in the Caribbean has been a challenge. OBJECTIVES: We report the development of a stepwise process for quality systems improvement in the Caribbean Region. METHODS: The Caribbean Laboratory Stakeholders met under a joint Pan American Health Organization/US Centers for Disease Control and Prevention initiative and developed a user-friendly framework called 'Laboratory Quality Management System Stepwise Improvement Process (LQMS-SIP) Towards Accreditation' to support countries in strengthening laboratory services through a stepwise approach toward fulfilling the ISO 15189: 2012 requirements. RESULTS: This approach consists of a three-tiered framework. Tier 1 represents the minimum requirements corresponding to the mandatory criteria for obtaining a licence from the Ministry of Health of the participating country. The next two tiers are quality improvement milestones that are achieved through the implementation of specific quality management system requirements. Laboratories that meet the requirements of the three tiers will be encouraged to apply for accreditation. The Caribbean Regional Organisation for Standards and Quality hosts the LQMS-SIP Secretariat and will work with countries, including the Ministry of Health and stakeholders, including laboratory staff, to coordinate and implement LQMS-SIP activities. The Caribbean Public Health Agency will coordinate and advocate for the LQMS-SIP implementation. CONCLUSION: This article presents the Caribbean LQMS-SIP framework and describes how it will be implemented among various countries in the region to achieve quality improvement. PMID- 28879150 TI - Failure of BACTECTM MGIT 960TM to detect Mycobacterium tuberculosis complex within a 42-day incubation period. AB - For the optimal recovery of Mycobacterium tuberculosis from the BACTECTM Mycobacterium Growth Indicator Tube 960TM system, an incubation period of 42-56 days is recommended by the manufacturer. Due to logistical reasons, it is common practice to follow an incubation period of 42 days. We undertook a retrospective study to document positive Mycobacterium Growth Indicator Tube cultures beyond the 42-day incubation period. In total, 98/110 (89%) were positive for M. tuberculosis complex. This alerted us to M. tuberculosis growth detection failure at 42 days. PMID- 28879151 TI - Programmatic implications of implementing the relational algebraic capacitated location (RACL) algorithm outcomes on the allocation of laboratory sites, test volumes, platform distribution and space requirements. AB - INTRODUCTION: CD4 testing in South Africa is based on an integrated tiered service delivery model that matches testing demand with capacity. The National Health Laboratory Service has predominantly implemented laboratory-based CD4 testing. Coverage gaps, over-/under-capacitation and optimal placement of point of-care (POC) testing sites need investigation. OBJECTIVES: We assessed the impact of relational algebraic capacitated location (RACL) algorithm outcomes on the allocation of laboratory and POC testing sites. METHODS: The RACL algorithm was developed to allocate laboratories and POC sites to ensure coverage using a set coverage approach for a defined travel time (T). The algorithm was repeated for three scenarios (A: T = 4; B: T = 3; C: T = 2 hours). Drive times for a representative sample of health facility clusters were used to approximate T. Outcomes included allocation of testing sites, Euclidian distances and test volumes. Additional analysis included platform distribution and space requirement assessment. Scenarios were reported as fusion table maps. RESULTS: Scenario A would offer a fully-centralised approach with 15 CD4 laboratories without any POC testing. A significant increase in volumes would result in a four-fold increase at busier laboratories. CD4 laboratories would increase to 41 in scenario B and 61 in scenario C. POC testing would be offered at two sites in scenario B and 20 sites in scenario C. CONCLUSION: The RACL algorithm provides an objective methodology to address coverage gaps through the allocation of CD4 laboratories and POC sites for a given T. The algorithm outcomes need to be assessed in the context of local conditions. PMID- 28879152 TI - National laboratory policies and plans in sub-Saharan African countries: gaps and opportunities. AB - BACKGROUND: The 2008 Maputo Declaration calls for the development of dedicated national laboratory policies and strategic plans supporting the enhancement of laboratory services in response to the long-lasting relegation of medical laboratory systems in sub-Saharan Africa. OBJECTIVES: This study describes the extent to which laboratories are addressed in the national health policies and plans created directly following the 2008 momentum for laboratory strengthening. METHOD: National health policies and plans from 39 sub-Saharan African countries, valid throughout and beyond 31 December 2010 were collected in March 2012 and analysed during 2013. RESULTS: Laboratories were addressed by all countries. Human resources were the most addressed topic (38/39) and finances and budget were the least addressed (< 5/39). Countries lagging behind in national laboratory strategic planning at the end of 2013 (17/39) were more likely to be francophone countries located in West-Central Africa (13/17) and have historically low HIV prevalence. The most common gaps anticipated to compromise the implementation of the policies and plans were the disconnect between policies and plans, under-developed finance sections and monitoring and evaluating frameworks, absence of points of reference to define gaps and shortages, and inappropriate governance structure. CONCLUSION: The availability of laboratory policy and plan implementation can be improved by strictly applying a more standardised methodology for policy development, using harmonised norms to set targets for improvement and intensifying the establishment of directorates of laboratory services directly under the authority of Ministries of Health. Horizontal programmes such as the Global Health Security Agenda could provide the necessary impulse to take the least advanced countries on board. PMID- 28879153 TI - Implementing SLMTA in the Kenya National Blood Transfusion Service: lessons learned. AB - BACKGROUND: The Kenya National Blood Transfusion Service (KNBTS) is mandated to provide safe and sufficient blood and blood components for the country. In 2013, the KNBTS National Testing Laboratory and the six regional blood transfusion centres were enrolled in the Strengthening Laboratory Management Toward Accreditation (SLMTA) programme. The process was supported by Global Communities with funding from the United States Centers for Disease Control and Prevention. METHODS: The SLMTA implementation at KNBTS followed the standard three-workshop series, on-site mentorships and audits. Baseline, midterm and exit audits were conducted at the seven facilities, using a standard checklist to measure progress. Given that SLMTA was designed for clinical and public health laboratories, key stakeholders, guided by Global Communities, tailored SLMTA materials to address blood transfusion services, and oriented trainers, auditors and mentors on the same. RESULTS: The seven facilities moved from an average of zero stars at baseline to an average of three stars at the exit audit. The average baseline audit score was 38% (97 points), midterm 71% (183 points) and exit audit 79% (205 points). The Occurrence Management and Process Improvement quality system essential had the largest improvement (at 67 percentage points), from baseline to exit, whereas Facilities and Safety had the smallest improvement (at 31 percentage points). CONCLUSION: SLMTA can be an effective tool for preparing a blood transfusion service for accreditation. Key success factors included customising SLMTA to blood transfusion activities; sensitising trainers, mentors and auditors on operations of blood transfusion service; creating SLMTA champions in key departments; and integrating other blood transfusion-specific accreditation standards into SLMTA. PMID- 28879154 TI - Performance evaluation of tuberculosis smear microscopists working at rechecking laboratories in Ethiopia. AB - BACKGROUND: Tuberculosis is an infectious disease caused by the bacillus Mycobacterium tuberculosis. According to the Ethiopian Federal Ministry of Health's 2013-2014 report, the tuberculosis case detection rate was 53.7%, which was below the target of 81% set for that year. OBJECTIVE: This study assessed the performance of tuberculosis smear microscopists at external quality assessment rechecking laboratories in Ethiopia. METHODS: A cross-sectional study was conducted at 81 laboratories from April to July 2015. Panel slides were prepared and validated at the National Tuberculosis Reference Laboratory. The validated panel slides were used to evaluate the performance of microscopists at these laboratories compared with readers from the reference laboratory. RESULTS: A total of 389 external quality assessment rechecking laboratory microscopists participated in the study, of which 268 (68.9%) worked at hospitals, 241 (62%) had more than five years of work experience, 201 (51.7%) held Bachelors degrees, and 319 (82%) reported tuberculosis smear microscopy training. Overall, 324 (83.3%) participants scored >= 80%. Sensitivity for detecting tuberculosis bacilli was 84.5% and specificity was 93.1%. The overall percent agreement between participants and reference readers was 87.1 (kappa=0.72). All 10 slides were correctly read (i.e., scored 100%) by 80 (20.6%) participants, 156 (40.1%) scored 90% - 95%, 88 (22.6%) scored 80% - 85% and 65 (16.7%) scored below 80%. There were 806 (20.7%) total errors, with 143 (3.7%) major and 663 (17%) minor errors. CONCLUSION: The overall performance of participants in reading the slides showed good agreement with the reference readers. Most errors were minor, and the ability to detect tuberculosis bacilli can be improved through building the capacity of professionals. PMID- 28879155 TI - Cylindrocarpon lichenicola keratomycosis in Nigeria: the challenge of limited access to effective antimicrobials. AB - INTRODUCTION: We report a rare cause of keratitis, due to Cylindrocarpon lichenicola, in a farmer with keratomycosis. Despite the acknowledged virulence of this fungus, a suitable antifungal for its management was not accessible. CASE PRESENTATION: A 67-year-old farmer presented with a two-week history of pain, mucopurulent discharge, redness and a corneal ulcer with a visual acuity of hand movement in the right eye. With a working diagnosis of infective keratitis, corneal scrapings were taken under a slit lamp biomicroscope for microbiological testing. Direct lactophenol cotton blue mounts revealed septate fungal hyphae, while fungal culture on Sabouraud dextrose agar at room temperature grew woolly mould phenotypically consistent with C. lichenicola. MANAGEMENT AND OUTCOME: The patient was started on hourly topical natamycin (5%), ciprofloxacin (0.3%), two hourly instillation of tobramycin (0.3%) and atropine (1%) twice daily for three months following the isolation of the fungus. The eye healed with a corneal scar and no improvements in visual acuity. DISCUSSION: This infection was difficult to manage due to the inaccessibility of a suitable antifungal, namely, voriconazole in our setting. Hence, there is a need for prompt identification and early institution of suitable antifungals in any patient with suspected keratomycosis. PMID- 28879156 TI - Africa CDC: Establishing Integrated Surveillance and Laboratory Networks for Rapid Disease Detection and Response, Control, Prevention, and Clinical Care in Africa. PMID- 28879157 TI - Evaluation of the SD Bioline TB Ag MPT64 test for identification of Mycobacterium tuberculosis complex from liquid cultures in Southwestern Uganda. AB - BACKGROUND: To confirm presence of Mycobacterium tuberculosis complex, some tuberculosis culture laboratories still rely on para-nitrobenzoic acid (PNB), a traditional technique that requires sub-culturing of clinical isolates and two to three weeks to give results. Rapid identification tests have improved turnaround times for mycobacterial culture results. Considering the challenges of the PNB method, we assessed the performance of the SD Bioline TB Ag MPT64 assay by using PNB as gold standard to detect M. tuberculosis complex from acid-fast bacilli (AFB) positive cultures. OBJECTIVES: The aim of this study was to determine the sensitivity, specificity and turnaround time of the SD MPT64 assay for identification of M. tuberculosis complex, in a setting with high prevalence of tuberculosis and HIV. METHODS: A convenience sample of 690 patients, with tuberculosis symptoms, was enrolled at Epicentre Mbarara Research Centre between April 2010 and June 2011. The samples were decontaminated using NALC-NaOH and re suspended sediments inoculated in Mycobacterium Growth Indicator Tubes (MGIT) media, then incubated at 37 degrees C for a maximum of eight weeks. A random sample of 50 known negative cultures and 50 non-tuberculous mycobacteria isolates were tested for specificity, while sensitivity was based on AFB positivity. The time required from positive culture to reporting of results was also assessed with PNB used as the gold standard. RESULTS: Of the 138 cultures that were AFB positive, the sensitivity of the SD MPT64 assay was 100.0% [95% CI: 97.3 - 100] and specificity was 100.0% (95% CI, 96.4 - 100). The median time from a specimen receipt to confirmation of strain was 10 days [IQR: 8-12] with SD MPT64 and 24 days [IQR: 22-26] with PNB. CONCLUSION: The SD MPT64 assay is comparable to PNB for identification of M. tuberculosis complex and reduces the time to detection. PMID- 28879158 TI - Tuberculosis diagnostic technology: an African solution ... think rats. PMID- 28879159 TI - Molecular characterisation of rifampicin-resistant Mycobacterium tuberculosis strains from Malawi. AB - BACKGROUND: Availability and access to the detection of resistance to anti tuberculosis drugs remains a significant challenge in Malawi due to limited diagnostic services. The Xpert(r) MTB/RIF can detect Mycobacterium tuberculosis and resistance to rifampicin in a single, rapid assay. Rifampicin-resistant M. tuberculosis has not been well studied in Malawi. OBJECTIVES: We aimed to determine mutations in the rifampicin resistance determining region (RRDR) of the rpoB gene of M. tuberculosis strains which were defined as resistant to rifampicin by the Xpert MTB/RIF assay. METHODS: Rifampicin-resistant isolates from 43 adult patients (>= 18 years) from various districts of Malawi were characterised for mutations in the RRDR (codons 507-533) of the rpoB gene by DNA sequencing. RESULTS: Mutations were found in 37/43 (86%) of the resistant isolates in codons 511, 512, 513, 516, 522, 526 and 531. The most common mutations were in codons 526 (38%), 531 (29.7%) and 516 (16.2%). Mutations were not found in 6/43 (14%) of the resistant isolates. No novel rpoB mutations other than those previously described were found among the rifampicin-resistant M. tuberculosis complex strains. CONCLUSION: This study is the first to characterise rifampicin resistance in Malawi. The chain-termination DNA sequencing employed in this study is a standard method for the determination of nucleotide sequences and can be used to confirm rifampicin resistance obtained using other assays, including the Xpert MTB/RIF. Further molecular cluster analysis, such as spoligotyping and DNA finger printing, is still required to determine transmission dynamics and the epidemiological link of the mutated strains. PMID- 28879160 TI - Performance of Xpert(r) MTB/RIF among tuberculosis outpatients in Lilongwe, Malawi. AB - BACKGROUND: Xpert(r) MTB/RIF is a molecular test for the detection of Mycobacterium tuberculosis and rifampicin resistance. It is considered to be a great advance over smear microscopy and culture. However, there is very little information regarding the performance characteristics of Xpert MTB/RIF in Malawi. OBJECTIVE: We aimed to evaluate the performance of Xpert MTB/RIF in a Malawian setting. METHODS: Stored sputum pellets were processed on Xpert MTB/RIF between June 2012 and May 2014. Results were compared to mycobacteria growth indicator tube and Lowenstein-Jensen cultures, LED fluorescent microscopy and GenoType(r) MTBDRplus assay. Rifampicin resistance was confirmed by DNA sequencing. RESULTS: Of the 348 specimens with valid Xpert MTB/RIF results, 129/348 (37%) were smear positive and 198/348 (57%) were culture-positive. Xpert MTB/RIF demonstrated a sensitivity of 93.8% (95% CI 89.4% - 96.8%) and specificity of 97.4% (95% CI 93.5% - 99.3%), with a positive predictive value of 97.8% (95% CI 94.6% - 99.4%) and a negative predictive value of 92.6% (95% CI 87.4% - 96.1%). Xpert MTB/RIF correctly identified 185/186 (99.5%) rifampicin-sensitive and 2/2 (100%) rifampicin-resistant M. tuberculosis strains. Mutations were not detected by sequencing in one isolate which was rifampicin resistant on Xpert MTB/RIF but sensitive on MTBDRplus. Four non-tuberculous mycobacteria grew from four smear negative specimens, namely, M. avium (n = 1) and M. intracellulare (n = 3). No cross-reactivity was observed with any of the non-tuberculous mycobacteria when using Xpert MTB/RIF. CONCLUSION: When fully implemented, Xpert MTB/RIF may have an impact on patient care in Malawi. The increased diagnostic yield of Xpert MTB/RIF over smear microscopy can increase laboratory-confirmed tuberculosis detection and ensure that treatment is given to appropriate individuals or groups. PMID- 28879161 TI - Implementation of quality management systems and progress towards accreditation of National Tuberculosis Reference Laboratories in Africa. AB - BACKGROUND: Laboratory services are essential at all stages of the tuberculosis care cascade, from diagnosis and drug resistance testing to monitoring response to treatment. Enabling access to quality services is a challenge in low-resource settings. Implementation of a strong quality management system (QMS) and laboratory accreditation are key to improving patient care. OBJECTIVES: The study objective was to determine the status of QMS implementation and progress towards accreditation of National Tuberculosis Reference Laboratories (NTRLs) in the African Region. METHOD: An online questionnaire was administered to NTRL managers in 47 World Health Organization Regional Office for Africa member states in the region, between February and April 2015, regarding the knowledge of QMS tools and progress toward implementation to inform strategies for tuberculosis diagnostic services strengthening in the region. RESULTS: A total of 21 laboratories (43.0%) had received SLMTA/TB-SLMTA training, of which 10 had also used the Global Laboratory Initiative accreditation tool. However, only 36.7% of NTRLs had received a laboratory audit, a first step in quality improvement. Most NTRLs participated in acid-fast bacilli microscopy external quality assurance (95.8%), although external quality assurance for other techniques was lower (60.4% for first-line drug susceptibility testing, 25.0% for second-line drug susceptibility testing, and 22.9% for molecular testing). Barriers to accreditation included lack of training and accreditation programmes. Only 28.6% of NTRLs had developed strategic plans and budgets which included accreditation. CONCLUSION: Good foundations are in place on the continent from which to scale up accreditation efforts. Laboratory audits should be conducted as a first step in developing quality improvement action plans. Political commitment and strong leadership are needed to drive accreditation efforts; advocacy will require clear evidence of patient impact and cost-benefit. PMID- 28879162 TI - Mozambique's journey toward accreditation of the National Tuberculosis Reference Laboratory. AB - BACKGROUND: Internationally-accredited laboratories are recognised for their superior test reliability, operational performance, quality management and competence. In a bid to meet international quality standards, the Mozambique National Institute of Health enrolled the National Tuberculosis Reference Laboratory (NTRL) in a continuous quality improvement process towards ISO 15189 accreditation. Here, we describe the road map taken by the NTRL to achieve international accreditation. METHODS: The NTRL adopted the Strengthening Laboratory Management Toward Accreditation (SLMTA) programme as a strategy to implement a quality management system. After SLMTA, the Mozambique National Institute of Health committed to accelerate the NTRL's process toward accreditation. An action plan was designed to streamline the process. Quality indicators were defined to benchmark progress. Staff were trained to improve performance. Mentorship from an experienced assessor was provided. Fulfilment of accreditation standards was assessed by the Portuguese Accreditation Board. RESULTS: Of the eight laboratories participating in SLMTA, the NTRL was the best performing laboratory, achieving a 53.6% improvement over the SLMTA baseline conducted in February 2011 to the Stepwise Laboratory Quality Improvement Process Towards Accreditation (SLIPTA) assessment in June 2013. During the accreditation assessment in September 2014, 25 minor nonconformities were identified and addressed. In March 2015, the NTRL received Portuguese Accreditation Board recognition of technical competency for fluorescence smear microscopy, and solid and liquid culture. The NTRL is the first laboratory in Mozambique to achieve ISO 15189 accreditation. CONCLUSIONS: From our experience, accreditation was made possible by institutional commitment, strong laboratory leadership, staff motivation, adequate infrastructure and a comprehensive action plan. PMID- 28879163 TI - Diagnostic system strengthening for drug resistant tuberculosis in Nigeria: impact and challenges. AB - BACKGROUND: The increasing prevalence of drug-resistant tuberculosis and the threat of extensively-drug-resistant tuberculosis in HIV hotspots have made the detection and treatment of drug-resistant tuberculosis in the sub-Saharan Africa setting a global public health priority. OBJECTIVE: We sought to examine the impact and challenges of tuberculosis diagnostic capacity development for the detection of drug-resistant tuberculosis and bio-surveillance using a modular biosafety level 3 (BSL-3) laboratory in Nigeria. METHOD: In 2010, the United States President's Emergency Plan for AIDS Relief (PEPFAR) programme, through the Institute of Human Virology at the University of Maryland in Baltimore, Maryland, United States, deployed a modular, BSL-3 laboratory to support the national tuberculosis programme in drug-resistant tuberculosis detection and bio surveillance for effective tuberculosis prevention and control. RESULTS: From 2010 until present, sputum samples from 11 606 suspected cases in 33 states were screened for drug-resistant tuberculosis. Of those, 1500 (12.9%) had mono resistant tuberculosis strains, and 459 (4.0%) cases had multidrug-resistant tuberculosis. Over the last four years, 133 scientists were trained in a train the-trainer programme on advanced tuberculosis culture, drug susceptibility testing, line-probe assays and Xpert(r) MTB/RIF, in addition to safety operations for biosafety facilities. Power instability, running cost and seasonal dust are notable challenges to optimal performance and scale up. CONCLUSION: Movable BSL-3 containment laboratories can be deployed to improve diagnostic capacity for drug resistant tuberculosis and bio-surveillance in settings with limited resources. PMID- 28879164 TI - Stronger tuberculosis laboratory networks and services in Africa essential to ending tuberculosis. PMID- 28879165 TI - Developing a customised approach for strengthening tuberculosis laboratory quality management systems toward accreditation. AB - BACKGROUND: Quality-assured tuberculosis laboratory services are critical to achieve global and national goals for tuberculosis prevention and care. Implementation of a quality management system (QMS) in laboratories leads to improved quality of diagnostic tests and better patient care. The Strengthening Laboratory Management Toward Accreditation (SLMTA) programme has led to measurable improvements in the QMS of clinical laboratories. However, progress in tuberculosis laboratories has been slower, which may be attributed to the need for a structured tuberculosis-specific approach to implementing QMS. We describe the development and early implementation of the Strengthening Tuberculosis Laboratory Management Toward Accreditation (TB SLMTA) programme. DEVELOPMENT: The TB SLMTA curriculum was developed by customizing the SLMTA curriculum to include specific tools, job aids and supplementary materials specific to the tuberculosis laboratory. The TB SLMTA Harmonized Checklist was developed from the World Health Organisation Regional Office for Africa Stepwise Laboratory Quality Improvement Process Towards Accreditation checklist, and incorporated tuberculosis-specific requirements from the Global Laboratory Initiative Stepwise Process Towards Tuberculosis Laboratory Accreditation online tool. IMPLEMENTATION: Four regional training-of-trainers workshops have been conducted since 2013. The TB SLMTA programme has been rolled out in 37 tuberculosis laboratories in 10 countries using the Workshop approach in 32 laboratories in five countries and the Facility based approach in five tuberculosis laboratories in five countries. CONCLUSION: Lessons learnt from early implementation of TB SLMTA suggest that a structured training and mentoring programme can build a foundation towards further quality improvement in tuberculosis laboratories. Structured mentoring, and institutionalisation of QMS into country programmes, is needed to support tuberculosis laboratories to achieve accreditation. PMID- 28879166 TI - Tuberculosis diagnostic networks: Moving beyond the laboratory to end tuberculosis in Africa. PMID- 28879167 TI - Vascular Endothelial Growth Factor, Irradiation, and Axitinib Have Diverse Effects on Motility and Proliferation of Glioblastoma Multiforme Cells. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor. It is highly aggressive with an unfavorable prognosis for the patients despite therapies including surgery, irradiation, and chemotherapy. One important characteristic of highly vascularized GBM is the strong expression of vascular endothelial growth factor (VEGF). VEGF has become a new target in the treatment of GBM, and targeted therapies such as the VEGF-receptor blocker axitinib are in clinical trials. Most studies focus on VEGF-induced angiogenesis, but only very few investigations analyze autocrine or paracrine effects of VEGF on the tumor cells. In this study, we examined the impact of VEGF, irradiation, and axitinib on cell proliferation and cell motility in human GBM cell lines U-251 and U-373. VEGF receptor 2 was shown to be expressed within both cell lines by using PCR and immunochemistry. Moreover, we performed 24-h videography to analyze motility, and a viability assay for cell proliferation. We observed increasing effects of VEGF and irradiation on cell motility in both cell lines, as well as strong inhibiting effects on cellular motility by VEGF-receptor blockade using axitinib. Moreover, axitinib diminished irradiation induced accelerating effects. While VEGF stimulation or irradiation did not affect cell proliferation, axitinib significantly decreased cell proliferation in both cell lines. Therefore, the impairment of VEGF signaling might have a crucial role in the treatment of GBM. PMID- 28879168 TI - The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform. AB - Despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. More than 8.2 million deaths were attributed to cancer in 2012, and it is anticipated that cancer incidence will continue to rise, with 19.3 million cases expected by 2025. The development and investigation of new diagnostic modalities and innovative therapeutic tools is critical for reducing the global cancer burden. Toward this end, transitional animal models serve a crucial role in bridging the gap between fundamental diagnostic and therapeutic discoveries and human clinical trials. Such animal models offer insights into all aspects of the basic science-clinical translational cancer research continuum (screening, detection, oncogenesis, tumor biology, immunogenicity, therapeutics, and outcomes). To date, however, cancer research progress has been markedly hampered by lack of a genotypically, anatomically, and physiologically relevant large animal model. Without progressive cancer models, discoveries are hindered and cures are improbable. Herein, we describe a transgenic porcine model-the Oncopig Cancer Model (OCM)-as a next-generation large animal platform for the study of hematologic and solid tumor oncology. With mutations in key tumor suppressor and oncogenes, TP53R167H and KRASG12D , the OCM recapitulates transcriptional hallmarks of human disease while also exhibiting clinically relevant histologic and genotypic tumor phenotypes. Moreover, as obesity rates increase across the global population, cancer patients commonly present clinically with multiple comorbid conditions. Due to the effects of these comorbidities on patient management, therapeutic strategies, and clinical outcomes, an ideal animal model should develop cancer on the background of representative comorbid conditions (tumor macro- and microenvironments). As observed in clinical practice, liver cirrhosis frequently precedes development of primary liver cancer or hepatocellular carcinoma. The OCM has the capacity to develop tumors in combination with such relevant comorbidities. Furthermore, studies on the tumor microenvironment demonstrate similarities between OCM and human cancer genomic landscapes. This review highlights the potential of this and other large animal platforms as transitional models to bridge the gap between basic research and clinical practice. PMID- 28879169 TI - Herpes Simplex Virus Type 1 Neuronal Infection Perturbs Golgi Apparatus Integrity through Activation of Src Tyrosine Kinase and Dyn-2 GTPase. AB - Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen that establishes a latent persistent neuronal infection in humans. The pathogenic effects of repeated viral reactivation in infected neurons are still unknown. Several studies have reported that during HSV-1 epithelial infection, the virus could modulate diverse cell signaling pathways remodeling the Golgi apparatus (GA) membranes, but the molecular mechanisms implicated, and the functional consequences to neurons is currently unknown. Here we report that infection of primary neuronal cultures with HSV-1 triggers Src tyrosine kinase activation and subsequent phosphorylation of Dynamin 2 GTPase, two players with a role in GA integrity maintenance. Immunofluorescence analyses showed that HSV-1 productive neuronal infection caused a scattered and fragmented distribution of the GA through the cytoplasm, contrasting with the uniform perinuclear distribution pattern observed in control cells. In addition, transmission electron microscopy revealed swollen cisternae and disorganized stacks in HSV-1 infected neurons compared to control cells. Interestingly, PP2, a selective inhibitor for Src family kinases markedly reduced these morphological alterations of the GA induced by HSV-1 infection strongly supporting the possible involvement of Src tyrosine kinase. Finally, we showed that HSV-1 tegument protein VP11/12 is necessary but not sufficient to induce Dyn2 phosphorylation. Altogether, these results show that HSV-1 neuronal infection triggers activation of Src tyrosine kinase, phosphorylation of Dynamin 2 GTPase, and perturbation of GA integrity. These findings suggest a possible neuropathogenic mechanism triggered by HSV-1 infection, which could involve dysfunction of the secretory system in neurons and central nervous system. PMID- 28879171 TI - The Genomics of Neonatal Abstinence Syndrome. AB - Significant variability has been observed in the development and severity of neonatal abstinence syndrome (NAS) among neonates exposed to prenatal opioids. Since maternal opioid dose does not appear to correlate directly with neonatal outcome, maternal, placental, and fetal genomic variants may play important roles in NAS. Previous studies in small cohorts have demonstrated associations of variants in maternal and infant genes that encode the MU-opioid receptor (OPRM1), catechol-O-methyltransferase (COMT), and prepronociceptin (PNOC) with a shorter length of hospital stay and less need for treatment in neonates exposed to opioids in utero. Consistently falling genomic sequencing costs and computational approaches to predict variant function will permit unbiased discovery of genomic variants and gene pathways associated with differences in maternal and fetal opioid pharmacokinetics and pharmacodynamics and with placental opioid transport and metabolism. Discovery of pathogenic variants should permit better delineation of the risk of developing more severe forms of NAS. This review provides a summary of the current role of genomic factors in the development of NAS and suggests strategies for further genomic discovery. PMID- 28879170 TI - Helicobacter pylori cagA+ Is Associated with Milder Duodenal Histological Changes in Chilean Celiac Patients. AB - HIGHLIGHTS What is already known about this subject?Celiac disease (CD) has a high clinical and histological diversity and the mechanisms underlying this phenomenon remain elusive.H. pylori is a bacterium that chronically infect gastric and duodenal mucosa activating both a Th1/Th17 and T-reg pathways.The role of H. pylori (and the effect of their virulence factors) in CD have not yet completely elucidated.What are the new findings?cagA+ H. pylori strains are associated to milder histological damage in infected CD patients.In active-CD patients the presence of cagA+ H. pylori is associated to an increase in T-reg markers, contrasting with a downregulation in cagA+ infected potential-CD individuals.How might it impact on clinical practice in the foreseeable future?The identification of microbiological factors that could modulate inflammation and clinical expression of CD may be used in the future as preventive strategies or as supplementary treatment in patients that cannot achieve complete remission, contributing to the better care of these patients. Background: Mechanisms underlying the high clinical and histological diversity of celiac disease (CD) remain elusive. Helicobacter pylori (Hp) chronically infects gastric and duodenal mucosa and has been associated with protection against some immune-mediated conditions, but its role (specifically of cagA+ strains) in CD is unclear. Objective: To assess the relationship between gastric Hp infection (cagA+ strains) and duodenal histological damage in patients with CD. Design: Case-control study including patients with active-CD, potential-CD and non-celiac individuals. Clinical presentation, HLA genotype, Hp/cagA gene detection in gastric mucosa, duodenal histology, Foxp3 positive cells and TGF-beta expression in duodenal lamina propria were analyzed. Results: We recruited 116 patients, 29 active-CD, 37 potential-CD, and 50 non-CD controls. Hp detection was similar in the three groups (~30-40%), but cagA+ strains were more common in infected potential-CD than in active-CD (10/11 vs. 4/10; p = 0.020) and non-CD (10/20; p = 0.025). Among active-CD patients, Foxp3 positivity was significantly higher in subjects with cagA+ Hp+ compared to cagA- Hp+ (p < 0.01) and Hp- (p < 0.01). In cagA+ Hp+ individuals, Foxp3 positivity was also higher comparing active- to potential-CD (p < 0.01). TGF-beta expression in duodenum was similar in active-CD with cagA+ Hp+ compared to Hp- and was significantly downregulated in cagA+ potential-CD subjects compared to other groups. Conclusion: Hp infection rates were similar among individuals with/without CD, but infection with cagA+ strains was associated with milder histological damage in celiac patients infected by Hp, and in active-CD cases with higher expression of T-reg markers. Results suggest that infection by cagA+ Hp may be protective for CD progression, or conversely, that these strains are prone to colonize intestinal mucosa with less severe damage. PMID- 28879173 TI - Integrating Public Health and Health Promotion Practice in the Medical Curriculum: A Self-Directed Team-Based Project Approach. AB - Preparing health professionals in health promotion (HP) and disease prevention is essential for improvement of population health, community HP, and better health care for individuals. The aim of this article is to describe an HP project in the form of a major self-directed project-based learning task integrated within the curriculum in the second year of the medical degree program at United Arab Emirates University. The project introduces students to public health and HP practice and develops students' literature searching, writing, presentation skills, and team work. Students learn the principles underlying behavioral change, and the design of HP programs and materials, through a lecture format. Small groups of students each choose a specific health topic for their project. Over 11 weeks, students obtain information about their topic from appropriate sources (library, PubMed, Google Scholar, credible health sources such as World Health Organization). Using the principles learned in the lectures, they develop appropriate materials for their target audience: for example, posters, a pamphlet, social media content, or a video or radio message. Students seek advice from specialist faculty as needed. In week 12, each team presents their project background, rationale, and materials to their colleagues in a seminar format open to all faculty. They then submit the materials they developed for assessment. Group marks are assigned for presentations and materials. Key concepts are assessed by multiple choice questions in comprehensive course examinations. By participation in the HP project, many students develop a solid background in prevention. The information retrieval, writing, and presentation skills, as well as experience of team work, are valuable both for the remaining years of their training and their future careers. PMID- 28879174 TI - Mobile Technology to Increase HIV/HCV Testing and Overdose Prevention/Response among People Who Inject Drugs. AB - The United States faces dramatically increasing rates of opioid overdose deaths, as well as persistent ongoing problems of undiagnosed HIV and HCV infection. These problems commonly occur together in substance using populations that have limited, if any, access to primary care and other routine health services. To collectively address all three issues, we developed the Mobile Intervention Kit (MIK), a tablet computer-based intervention designed to provide overdose prevention and response training and to facilitate HIV/HCV testing in community settings. Intervention content was produced in collaboration with experienced street outreach workers who appear onscreen in a series of educational videos. A preliminary pilot test of the MIK in a Bronx, NY street outreach syringe exchange program found the MIK is feasible and highly acceptable to a population of people who inject drugs. Participants accepted HIV and HCV testing post-intervention, as well as naloxone training to reverse overdose events. Pre-post tests also showed significant increases in knowledge of overdose prevention, HIV testing procedures, and asymptomatic HCV infection. Future iterations of the MIK can be optimized for use in community as well as clinical settings nationwide, and perhaps globally, with a focus on underserved urban populations. PMID- 28879175 TI - Computer Vision Malaria Diagnostic Systems-Progress and Prospects. AB - Accurate malaria diagnosis is critical to prevent malaria fatalities, curb overuse of antimalarial drugs, and promote appropriate management of other causes of fever. While several diagnostic tests exist, the need for a rapid and highly accurate malaria assay remains. Microscopy and rapid diagnostic tests are the main diagnostic modalities available, yet they can demonstrate poor performance and accuracy. Automated microscopy platforms have the potential to significantly improve and standardize malaria diagnosis. Based on image recognition and machine learning algorithms, these systems maintain the benefits of light microscopy and provide improvements such as quicker scanning time, greater scanning area, and increased consistency brought by automation. While these applications have been in development for over a decade, recently several commercial platforms have emerged. In this review, we discuss the most advanced computer vision malaria diagnostic technologies and investigate several of their features which are central to field use. Additionally, we discuss the technological and policy barriers to implementing these technologies in low-resource settings world-wide. PMID- 28879172 TI - Epigenetic Matters: The Link between Early Nutrition, Microbiome, and Long-term Health Development. AB - Epigenetic modifications are among the most important mechanisms by which environmental factors can influence early cellular differentiation and create new phenotypic traits during pregnancy and within the neonatal period without altering the deoxyribonucleic acid sequence. A number of antenatal and postnatal factors, such as maternal and neonatal nutrition, pollutant exposure, and the composition of microbiota, contribute to the establishment of epigenetic changes that can not only modulate the individual adaptation to the environment but also have an influence on lifelong health and disease by modifying inflammatory molecular pathways and the immune response. Postnatal intestinal colonization, in turn determined by maternal flora, mode of delivery, early skin-to-skin contact and neonatal diet, leads to specific epigenetic signatures that can affect the barrier properties of gut mucosa and their protective role against later insults, thus potentially predisposing to the development of late-onset inflammatory diseases. The aim of this review is to outline the epigenetic mechanisms of programming and development acting within early-life stages and to examine in detail the role of maternal and neonatal nutrition, microbiota composition, and other environmental factors in determining epigenetic changes and their short- and long-term effects. PMID- 28879176 TI - Nature, Eco, and Adventure Therapies for Mental Health and Chronic Disease. PMID- 28879177 TI - Comparison of Orthodontic Medicaid Funding in the United States 2006 to 2015. AB - INTRODUCTION: Orthodontic treatment is reimbursed by Medicaid based on orthodontic and financial need with qualifiers determined by individual states. Changes in Medicaid-funded orthodontic treatment following the "Great Recession" in 2007 and the enactment of the Affordable Care Act in 2010 were compared for the 50 United States and the District of Columbia to better understand disparities in access to care. The results from this 2015 survey were compared to data gathered in 2006 (1). MATERIALS AND METHODS: Medicaid officials were contacted by email, telephone, or postal mail regarding the age limit for treatment, practitioner type who can determine eligibility and provide treatment, records required for case review, and rate and frequency of reimbursement. When not attained by direct contact, the information was gleaned from online websites, provider manuals, and state orthodontists. RESULTS: Information gathered from 50 states and the District of Columbia documents that Medicaid program characteristics and expenditures continue to vary by state. Expenditures and reimbursement rates have decreased since 2006 and vary widely by geographic region. Some states have tightened restrictions on qualifiers and increased submission requirements by providers. CONCLUSION: The variation and lack of uniformity that still exists among Medicaid orthodontic programs in different states creates disparities in orthodontic care for US citizens. Barriers to care for Medicaid-funded orthodontic treatment have increased since 2006. PMID- 28879178 TI - Identification of Delivery Models for the Provision of Predictive Genetic Testing in Europe: Protocol for a Multicentre Qualitative Study and a Systematic Review of the Literature. AB - INTRODUCTION: The appropriate application of genomic technologies in healthcare is surrounded by many concerns. In particular, there is a lack of evidence on what constitutes an optimal genetic service delivery model, which depends on the type of genetic test and healthcare context considered. The present project aims to identify, classify, and evaluate delivery models for the provision of predictive genetic testing in Europe and in selected Anglophone extra-European countries (the USA, Canada, Australia, and New Zealand). It also sets out to survey the European public health community's readiness to incorporate public health genomics into their practice. MATERIALS AND EQUIPMENT: The project consists of (i) a systematic review of published literature and selected country websites, (ii) structured interviews with health experts on the genetic service delivery models in their respective countries, and (iii) a survey of European Public Health Association (EUPHA) members' knowledge and attitudes toward genomics applications in clinical practice. The inclusion criteria for the systematic review are that articles be published in the period 2000-2015; be in English or Italian; and be from European countries or from Canada, the USA, Australia, or New Zealand. Additional policy documents will be retrieved from represented countries' government-affiliated websites. The results of the research will be disseminated through the EUPHA network, the Italian Network for Genomics in Public Health (GENISAP), and seminars and workshops. EXPECTED IMPACT OF THE STUDY ON PUBLIC HEALTH: The transfer of genomic technologies from research to clinical application is influenced not only by several factors inherent to research goals and delivery of healthcare but also by external and commercial interests that may cause the premature introduction of genetic tests in the public and private sectors. Furthermore, current genetic services are delivered without a standardized set of process and outcome measures, which makes the evaluation of healthcare services difficult. The present study will identify and classify delivery models and, subsequently, establish which are appropriate for the provision of predictive genetic testing in Europe by comparing sets of process and outcome measures. In this way, the study will provide a basis for future recommendations to decision makers involved in the financing, delivery, and consumption of genetic services. PMID- 28879180 TI - Gene Expression Patterns in Brachiopod Larvae Refute the "Brachiopod-Fold" Hypothesis. PMID- 28879179 TI - Capturing the Cranio-Caudal Signature of a Turn with Inertial Measurement Systems: Methods, Parameters Robustness and Reliability. AB - BACKGROUND: Turning is a challenging mobility task requiring coordination and postural stability. Optimal turning involves a cranio-caudal sequence (i.e., the head initiates the motion, followed by the trunk and the pelvis), which has been shown to be altered in patients with neurodegenerative diseases, such as Parkinson's disease as well as in fallers and frails. Previous studies have suggested that the cranio-caudal sequence exhibits a specific signature corresponding to the adopted turn strategy. Currently, the assessment of cranio caudal sequence is limited to biomechanical labs which use camera-based systems; however, there is a growing trend to assess human kinematics with wearable sensors, such as attitude and heading reference systems (AHRS), which enable recording of raw inertial signals (acceleration and angular velocity) from which the orientation of the platform is estimated. In order to enhance the comprehension of complex processes, such as turning, signal modeling can be performed. AIM: The current study investigates the use of a kinematic-based model, the sigma-lognormal model, to characterize the turn cranio-caudal signature as assessed with AHRS. METHODS: Sixteen asymptomatic adults (mean age = 69.1 +/- 7.5 years old) performed repeated 10-m Timed-Up-and-Go (TUG) with 180 degrees turns, at varying speed. Head and trunk kinematics were assessed with AHRS positioned on each segments. Relative orientation of the head to the trunk was then computed for each trial and relative angular velocity profile was derived for the turn phase. Peak relative angle (variable) and relative velocity profiles modeled using a sigma-lognormal approach (variables: Neuromuscular command amplitudes and timing parameters) were used to extract and characterize the cranio-caudal signature of each individual during the turn phase. RESULTS: The methodology has shown good ability to reconstruct the cranio-caudal signature (signal-to-noise median of 17.7). All variables were robust to speed variations (p > 0.124). Peak relative angle and commanded amplitudes demonstrated moderate to strong reliability (ICC between 0.640 and 0.808). CONCLUSION: The cranio caudal signature assessed with the sigma-lognormal model appears to be a promising avenue to assess the efficiency of turns. PMID- 28879181 TI - Regulation of the Sar1 GTPase Cycle Is Necessary for Large Cargo Secretion from the Endoplasmic Reticulum. AB - Proteins synthesized within the endoplasmic reticulum (ER) are transported to the Golgi via coat protein complex II (COPII)-coated vesicles. The formation of COPII coated vesicles is regulated by the GTPase cycle of Sar1. Activated Sar1 is recruited to ER membranes and forms a pre-budding complex with cargoes and the inner-coat complex. The outer-coat complex then stimulates Sar1 inactivation and completes vesicle formation. The mechanisms of forming transport carriers are well-conserved among species; however, in mammalian cells, several cargo molecules such as collagen, and chylomicrons are too large to be accommodated in conventional COPII-coated vesicles. Thus, special cargo-receptor complexes are required for their export from the ER. cTAGE5/TANGO1 complexes and their isoforms have been identified as cargo receptors for these macromolecules. Recent reports suggest that the cTAGE5/TANGO1 complex interacts with the GEF and the GAP of Sar1 and tightly regulates its GTPase cycle to accomplish large cargo secretion. PMID- 28879182 TI - Vasopressin Receptor Antagonists in Hyponatremia: Uses and Misuses. AB - Decreases in the concentration of sodium in plasma constitute hyponatremia, the commonest electrolyte disorder in clinical medicine. It is now well established that its presence conveys an increased mortality risk even when the decrement is mild. In addition, recent evidence suggests that chronic and apparently asymptomatic hyponatremia is associated with increased morbidity including neurocognitive deficits and bone fractures. Furthermore, hyponatremia is associated with higher health care-related expenses. Consequently, exploring new therapeutic strategies that increase plasma sodium in a safe and effective manner is of paramount importance. In this regard, there are scant data to support the use of traditional management strategies for hyponatremia (fluid restriction, salt tablets, loop diuretics, and normal saline). Furthermore, data from a large hyponatremia registry reveal the limited efficacy of these therapies. More recently vasopressin receptor antagonists provide a promising treatment for hyponatremia by targeting its most common mechanism, namely, increased vasopressin activity. However, uncertainty still lingers as to the optimal indications for the use of vasopressin receptor antagonists in hyponatremia and a few reports have described complications resulting from their misuse. This review summarizes the appropriate and inappropriate uses of vasopressin receptor antagonists in the treatment of hyponatremia. PMID- 28879183 TI - Deep Sequencing Transcriptome Analysis of Murine Wound Healing: Effects of a Multicomponent, Multitarget Natural Product Therapy-Tr14. AB - Wound healing involves an orchestrated response that engages multiple processes, such as hemostasis, cellular migration, extracellular matrix synthesis, and in particular, inflammation. Using a murine model of cutaneous wound repair, the transcriptome was mapped from 12 h to 8 days post-injury, and in response to a multicomponent, multi-target natural product, Tr14. Using single-molecule RNA sequencing (RNA-seq), there were clear temporal changes in known transcripts related to wound healing pathways, and additional novel transcripts of both coding and non-coding genes. Tr14 treatment modulated >100 transcripts related to key wound repair pathways, such as response to wounding, wound contraction, and cytokine response. The results provide the most precise and comprehensive characterization to date of the transcriptome's response to skin damage, repair, and multicomponent natural product therapy. By understanding the wound repair process, and the effects of natural products, it should be possible to intervene more effectively in diseases involving aberrant repair. PMID- 28879184 TI - Hsp78 (78 kDa Heat Shock Protein), a Representative AAA Family Member Found in the Mitochondrial Matrix of Saccharomyces cerevisiae. AB - ATPases associated with diverse cellular activities (AAA+) form a superfamily of proteins involved in a variety of functions and are characterized by the presence of an ATPase module containing two conserved motifs known as Walker A and Walker B. ClpB and Hsp104, chaperones that have disaggregase activities, are members of a subset of this superfamily, known as the AAA family, and are characterized by the presence of a second highly conserved motif, known as the second region of homology (SRH). Hsp104 and its homolog Hsp78 (78 kDa heat shock protein) are representatives of the Clp family in yeast. The structure and function of Hsp78 is reviewed and the possible existence of other homologs in metazoans is discussed. PMID- 28879186 TI - Bullying and Quality of Life in Pediatric Alopecia Areata. AB - Alopecia areata (AA) is a clinically heterogeneous disease that is characterized by nonscarring hair loss, nail changes, and increased risk of other autoimmune disease. During clinical visits, children with AA often report bullying. We report survey results that highlight the prevalence of bullying and surrounding emotional impact of AA in pediatric patients. We found that bullying was common overall and additional psychological impact, including impairment of social and home life, was even more common. Children of all ages experienced bullying. Boys reported increased physical bullying. Interestingly, those with more severe disease and longer duration of disease experienced less bullying than those with less severe disease. PMID- 28879185 TI - Increased Potency of a Bi-specific TL1A-ADAM17 (TACE) Inhibitor by Cell Surface Targeting. AB - Inflammatory bowel disease (IBD) is a multifactorial disease characterized by the dysregulated activity of many pro-inflammatory factors. Thus, bi-specific inhibitors for the simultaneous inhibition of two pro-inflammatory factors can exhibit high therapeutic potential. Here, we developed a novel bi-specific inhibitor targeting the TL1A cytokine and ADAM17/TACE metalloprotease. Biochemical analysis of the bi-specific inhibitor revealed high TL1A binding and TACE inhibition that is similar to the two respective mono-specific inhibitors. Interestingly, cell based assays for TL1A inhibition revealed strong synergism between the inhibitory domains showing an up to 80-fold increase in potency of the bi-specific inhibitor. The dramatic increase in potency is associated with binding to cell membranes through the TACE inhibitory domain leading to increased concentration of the inhibitor on the cell surface. Our study highlights the high potential of the simultaneous targeting of cell surface metalloprotease (TACE) and soluble pro-inflammatory cytokine (TL1A) as a potential therapeutic approach in IBD. PMID- 28879187 TI - Clinical and Dermoscopic Features of the Scalp in 31 Patients with Dermatomyositis. AB - BACKGROUND: Scalp involvement is not directly evaluated in patients with dermatomyositis (DM). Therefore, the exact frequency of scalp dermatomyositis (SDM) and its clinical and trichoscopic characteristics have been poorly described. OBJECTIVE: The aim of this study was to determine the frequency and clinical and dermoscopic features of SDM in patients diagnosed with DM. METHODS: We performed a descriptive prospective, cross-sectional observational study that included all patients diagnosed with DM at a Mexican academic institute over the course of a year. RESULTS: Twenty-four out of 31 patients with DM had scalp involvement at clinical examination, with a prevalence of 77.4%. SDM was clinically characterized by erythema in all cases, scales in 20 (83.3%) patients, nonscarring alopecia in 21 (87.5%) patients, pruritus in 17 (70.8%) patients, and poikiloderma of the scalp in 16 (51.6%) patients. Twenty-eight patients were evaluated by trichoscopy. The most consistent finding was the presence of enlarged capillaries, found in 20 (71.4%) cases, followed by peripilar casts (57.1%) and tufting and interfollicular scales in 14 (50%) cases. Twenty-two patients also had positive nail fold capillaroscopic features similar to those observed by trichoscopy. LIMITATIONS: The simple size was limited. CONCLUSIONS: Scalp involvement and alopecia are common in patients with DM, and trichoscopy shows features similar to those found at capillaroscopy. Trichoscopy is a very important tool for diagnosis of scalp involvement in patients with DM. PMID- 28879188 TI - The Use of Direct Immunofluorescence in Frontal Fibrosing Alopecia. AB - BACKGROUND: Frontal fibrosing alopecia (FFA) differs from lichen planopilaris (LPP) in many clinical aspects, but histology fails to distinguish between these entities. Direct immunofluorescence (DIF) is a diagnostic technique used for autoimmune diseases, including those affecting skin and hair. OBJECTIVE: To characterize DIF patterns in patients with FFA. METHOD: Data was collected retrospectively from FFA cases presenting to the Centre de Sante Sabouraud Hair Clinic in Paris from November 2013 to November 2014. RESULTS: Of 149 patients with FFA, 44 cases underwent DIF. Thirteen cases showed positive results with DIF. Patterns characteristic of LPP and lupus erythematosus were observed, with nearly half showing nonspecific staining. CONCLUSION: DIF patterns in patients with FFA were variable. This diagnostic technique should be used with caution in cases of cicatricial alopecia, particularly FFA. PMID- 28879189 TI - An Unusual Periungual Lesion. PMID- 28879190 TI - Primary Scarring Alopecia: Clinical-Pathological Review of 72 Cases and Review of the Literature. AB - PURPOSE OF THE STUDY: To analyze the epidemiologic, demographic, clinical, and histological characteristics of primary scarring alopecia (PSA) cases diagnosed over a 7-year period at the Department of Dermatology, Hospital Clinic, Barcelona, Spain. PROCEDURES: Seventy-two patients diagnosed with PSA between 2006 and 2012 were included. Age, sex, ethnic group, clinical pattern, predominant histological infiltrate, final clinical diagnosis, time of onset, treatments used, and clinical evolution were evaluated and correlated. RESULTS: The ethnic groups were distributed as follows: 93% European-Caucasian, 5% Mestizo American, 1% oriental, and 1% Afro-American. Most cases were females (71%), and mean age was 51 +/- 6 years. The follicular pattern was the most common, and the predominant inflammatory infiltrate was lymphocytic. Lichen planopilaris and frontal fibrosing alopecia were the main diagnoses. When correlating clinical aspects and histopathology, lymphocytic PSAs had a subacute onset and resulted in a nonchanging, more stable form, while neutrophilic PSAs had a more acute onset with an evolution of acute outbreaks. PSAs in a late stage with an absent/mild infiltrate had a subclinical onset and a slowly progressive or stable evolution. CONCLUSIONS: The PSAs are severe trichological conditions. Their high clinical and histopathological variability make them a diagnostic and therapeutic challenge. MESSAGE OF THE PAPER: Knowing the clinical and histopathological aspects of PSAs should be of crucial importance to the dermatologist. PMID- 28879191 TI - Patient-Reported Outcomes in Onychomycosis: A Review of Psychometrically Evaluated Instruments in Assessing Treatment Effectiveness. AB - PURPOSE: Onychomycosis is the most common nail disorder and causes morbidity and impaired quality of life (QOL). Patient-reported outcomes (PRO) are patients' assessment of their health status or treatment response. PROs help assess what is most bothersome to patients to identify targets for intervention. We sought to review the PRO instruments currently used to assess QOL and treatment response in onychomycosis patients. PROCEDURES: A systematic review was performed by searching PubMed, Embase, CINAHL, and PsycINFO databases through December 31, 2016, to identify all English language literature on onychomycosis, PRO, and QOL. RESULTS: Currently, 5 validated PRO instruments exist specifically for onychomycosis. Oral therapies were most extensively studied using PRO instruments. QOL data generally correlated with clinical change, although patients sometimes reported improvement without any clinically significant nail clearance. The only psychometrically validated PRO instrument used to evaluate treatment response is the OnyCOE-tTM. CONCLUSIONS: Clinicians may underestimate the impact of onychomycosis on patients. With recent initiatives from health-care management organizations to improve patient experience and the recent approval of expensive and nonsuperior topical antifungal medications, PROs will be increasingly important in onychomycosis to assess patient priorities and optimize treatment. Future research should evaluate these instruments in special populations and fingernail disease. PMID- 28879192 TI - Unsuccessful Treatment of Alopecia Areata with Simvastatin/Ezetimibe: Experience in 12 Patients. AB - BACKGROUND/AIMS: Alopecia areata is a common immune-mediated hair condition with limited treatment options and success rates. There is evidence that statins, which are used for reducing atherogenesis and cardiovascular disease, have immunomodulatory activities and therefore may also be used for treatment of selected dermatologic conditions, including alopecia areata. Among treatments evaluated for alopecia areata, oral simvastatin/ezetimibe therapy is currently under the scrutiny of expert opinion. METHODS: Prospective observational study of the efficacy and tolerability of simvastatin/ezetimibe 40/10 mg (Inegy; MSD Merck Sharp & Dohme AG, Lucerne, Switzerland) over a treatment period of 6 months in alopecia totalis, universalis, multipatch involvement of the scalp >30%, ophiasis, or diffuse alopecia areata. RESULTS: Of the 12 patients included in the study, 67% had no hair regrowth, 24% transient diffuse or patchy hair regrowth, and 24% patchy regrowth of pigmented hair which was not considered cosmetically satisfactory. Adverse effects were observed in 24% of patients, who reported myalgia. One patient showed elevation of creatine phosphokinase. CONCLUSION: Simvastatin/ezetimibe is not effective for treatment of alopecia areata, at least in severe and/or cases refractory to other treatments, either as monotherapy or as adjuvant. Ultimately, in choosing such a treatment with questionable benefit, one must take the risk of serious adverse effects into careful consideration. PMID- 28879193 TI - Minocycline-Induced Blue-Gray Discoloration. PMID- 28879194 TI - An Unusual Case of Contact Dermatitis. AB - We report a case of acute psoriasiform contact dermatitis of the forehead and scalp related to the use of a low-laser light cap. The patient had a positive patch test to dimethylol dihydroxyethyleneurea (DMDE), methylisothiazolinone, kathon CG, and cobalt. We believe that DMDE in the fabric of the cap was responsible for the allergic contact dermatitis in this case as the lesions resolved with cessation of cap use. PMID- 28879195 TI - A Review of the Use of Biotin for Hair Loss. AB - BACKGROUND: Biotin has gained commercial popularity for its claimed benefits on healthy hair and nail growth. Despite its reputation, there is limited research to support the utility of biotin in healthy individuals. OBJECTIVE: To systematically review the literature on biotin efficacy in hair and nail growth. METHODS: We conducted a PubMed search of all case reports and randomized clinical trials (RCTs) using the following terms: (biotin and hair); (biotin and supplementation and hair); (biotin supplementation); (biotin and alopecia); (biotin and nails); (biotin and dermatology), and (biotin recommendations). RESULTS: We found 18 reported cases of biotin use for hair and nail changes. In all cases, patients receiving biotin supplementation had an underlying pathology for poor hair or nail growth. All cases showed evidence of clinical improvement after receiving biotin. CONCLUSIONS: Though its use as a hair and nail growth supplement is prevalent, research demonstrating the efficacy of biotin is limited. In cases of acquired and inherited causes of biotin deficiency as well as pathologies, such as brittle nail syndrome or uncombable hair, biotin supplementation may be of benefit. However, we propose these cases are uncommon and that there is lack of sufficient evidence for supplementation in healthy individuals. PMID- 28879196 TI - Assessment of Whole-Exome Sequence Data in Attempted Suicide within a Bipolar Disorder Cohort. AB - Suicidal behavior is a complex and devastating phenotype with a heritable component that has not been fully explained by existing common genetic variant analyses. This study represents the first large-scale DNA sequencing project designed to assess the role of rare functional genetic variation in suicidal behavior risk. To accomplish this, whole-exome sequencing data for ~19,000 genes were generated for 387 bipolar disorder subjects with a history of suicide attempt and 631 bipolar disorder subjects with no prior suicide attempts. Rare functional variants were assessed in all exome genes as well as pathways hypothesized to contribute to suicidal behavior risk. No result survived conservative Bonferroni correction, though many suggestive findings have arisen that merit additional attention. In addition, nominal support for past associations in genes, such as BDNF, and pathways, such as the hypothalamic pituitary-adrenal axis, was also observed. Finally, a novel pathway was identified that is driven by aldehyde dehydrogenase genes. Ultimately, this investigation explores variation left largely untouched by existing efforts in suicidal behavior, providing a wealth of novel information to add to future investigations, such as meta-analyses. PMID- 28879197 TI - A Preliminary Study of the Opioid System and Personality Traits Using Positron Emission Tomography. AB - BACKGROUND: Personality traits, such as Neuroticism and Extraversion, have been implicated in the processing of emotion. The neural correlates most often associated with Neuroticism and Extraversion are the insular cortex, orbitofrontal cortex, amygdala, and ventral striatum. OBJECTIVE: The aim of the current study was to explore neurotransmitter systems underlying those neural correlates and investigate the relationship between personality traits and opioid receptor binding potential. METHOD: Twelve healthy participants completed an [11C]diprenorphine positron emission tomography scan at rest. Endogenous opioid levels as indicated by opioid receptor binding potential was examined in relation to personality phenotype. RESULTS: A high score of Neuroticism, a personality trait characterized by negative affect, was found to be associated with high opioid receptor binding in the right anterior insula. Conversely, a high score of Extraversion, a personality trait characterized by positive affect, was found to be associated with low opioid receptor binding in the left posterior insula. CONCLUSIONS: While preliminary, the results of this study suggest that the expression of Neuroticism and Extraversion is related to baseline function of the opioid neurotransmitter system in the insular cortex. These findings may help elucidate the neural mechanisms underlying the expression of personality traits, particularly those implicated in affective processing. PMID- 28879198 TI - Complement C3 Expression Is Decreased in Autism Spectrum Disorder Subjects and Contributes to Behavioral Deficits in Rodents. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder with hallmark symptoms including social deficits, communication deficits and repetitive behaviors. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of ASD. The complement system represents one of the major effector mechanisms of the innate immune system, and regulates inflammation, and orchestrates defense against pathogens. However, the role of CNS complement system in ASD is not well understood. In the present study, we found a significant increase in C2, C5, and MASP1, but a decrease in C1q, C3, and C4 mRNA levels in the middle frontal gyrus of ASD subjects compared to controls. Significant decreases in the mRNA levels of 2 key proinflammatory cytokines, IL 17 and IL-23 were observed in ASD subjects. Our study further demonstrated a strong association of complement genes with IL-17 and IL-23, suggesting a possible role of the complement system in immune dysregulation in ASD. We observed significant associations between complement components and abnormality of development scores in subjects with ASD. In rodents, C3 knockdown in the prefrontal cortex induced social interaction deficits and repetitive behavior in mice. Together, these studies suggest a potential role of C3 in the pathophysiology of ASD. PMID- 28879199 TI - Low-Density Neuronal Cultures from Human Induced Pluripotent Stem Cells. AB - Induced pluripotent stem cell (iPSC)-based technologies offer an unprecedented possibility to investigate defects occurring during neuronal differentiation in neuropsychiatric and neurodevelopmental disorders, but the density and intricacy of intercellular connections in neuronal cultures challenge currently available analytic methods. Low-density neuronal cultures facilitate the morphometric and functional analysis of neurons. We describe a differentiation protocol to generate low-density neuronal cultures (~2,500 neurons/cm2) from human iPSC derived neural stem cells/early neural progenitor cells. We generated low-density cultures using cells from 3 individuals. We also evaluated the morphometric features of neurons derived from 2 of these individuals, one harboring a microdeletion on chromosome 15q11.2 and the other without the microdeletion. An approximately 7.5-fold increase in the density of dendritic filopodia was observed in the neurons with the microdeletion, consistent with previous reports. Low-density neuronal cultures enable facile and unbiased comparisons of iPSC derived neurons from different individuals or clones. PMID- 28879200 TI - The Nuclear Proteome of White and Gray Matter from Schizophrenia Postmortem Brains. AB - Schizophrenia (SCZ) is a serious neuropsychiatric disorder that manifests through several symptoms from early adulthood. Numerous studies over the last decades have led to significant advances in increasing our understanding of the factors involved in SCZ. For example, mass spectrometry-based proteomic analysis has provided important insights by uncovering protein dysfunctions inherent to SCZ. Here, we present a comprehensive analysis of the nuclear proteome of postmortem brain tissues from corpus callosum (CC) and anterior temporal lobe (ATL). We show an overview of the role of deregulated nuclear proteins in these two main regions of the brain: the first, mostly composed of glial cells and axons of neurons, and the second, represented mainly by neuronal cell bodies. These samples were collected from SCZ patients in an attempt to characterize the role of the nucleus in the disease process. With the ATL nucleus enrichment, we found 224 proteins present at different levels, and 76 of these were nuclear proteins. In the CC analysis, we identified 119 present at different levels, and 24 of these were nuclear proteins. The differentially expressed nuclear proteins of ATL are mainly associated with the spliceosome, whereas those of the CC region are associated with calcium/calmodulin signaling. PMID- 28879202 TI - Roadmap to the Digital Transformation of Animal Health Data. PMID- 28879201 TI - WNT/beta-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4. AB - Genetic variation within the transcription factor TCF4 locus can cause the intellectual disability and developmental disorder Pitt-Hopkins syndrome (PTHS), whereas single-nucleotide polymorphisms within noncoding regions are associated with schizophrenia. These genetic findings position TCF4 as a link between transcription and cognition; however, the neurobiology of TCF4 remains poorly understood. Here, we quantitated multiple distinct TCF4 transcript levels in human induced pluripotent stem cell-derived neural progenitors and differentiated neurons, and PTHS patient fibroblasts. We identify two classes of pharmacological treatments that regulate TCF4 expression: WNT pathway activation and inhibition of class I histone deacetylases. In PTHS fibroblasts, both of these perturbations upregulate a subset of TCF4 transcripts. Finally, using chromatin immunoprecipitation sequencing in conjunction with genome-wide transcriptome analysis, we identified TCF4 target genes that may mediate the effect of TCF4 loss on neuroplasticity. Our studies identify new pharmacological assays, tools, and targets for the development of therapeutics for cognitive disorders. PMID- 28879203 TI - A Stakeholder Survey on Live Bird Market Closures Policy for Controlling Highly Pathogenic Avian Influenza in Vietnam. AB - Extensive research in Vietnam and elsewhere has shown that live bird markets (LBMs) play a significant role in the ecology and zoonotic transmission of avian influenzas (AIs) including H5N1 and H7N9. Vietnam has a large number of LBMs reflecting the consumer preferences for live poultry. Under pressure to mitigate risks for H7N9 and other zoonotic AIs, Vietnam is considering, among other mitigation measures, temporary closures of LBMs as a policy to reduce risk of AI outbreaks. However, the efficacy of market closure is debated, particularly because little is known about how poultry traders may react, and whether trading may emerge outside formal marketplaces. Combining efforts of anthropologists, economists, sociologists, and veterinarians can be useful to elucidate the drivers behind poultry traders' reactions and better understanding the barriers to implementing risk mitigation measures. In this paper, we present results from a stakeholder survey of LBM stakeholders in Vietnam. Our qualitative data show that trading outside formal markets is very likely to occur in the event of a temporary LBM market closure. Our data show that the poultry value chain in Vietnam remains highly flexible, with traders willing and able to trade poultry in many possible locations. Our results indicate that simplification of the poultry value chain along with strict enforcement, engagement of stakeholders, and adequate communication would be a necessary prerequisite before market closure could be an effective policy. PMID- 28879204 TI - Dynamic Susceptibility Contrast Perfusion Magnetic Resonance Imaging Demonstrates Reduced Periventricular Cerebral Blood Flow in Dogs with Ventriculomegaly. AB - The nature of ventriculomegaly in dogs is still a matter of debate. Signs of increased intraventricular pressure and atrophy of the cerebral white matter have been found in dogs with ventriculomegaly, which would imply increased intraventricular pressure and, therefore, a pathological condition, i.e., to some extent. Reduced periventricular blood flow was found in people with high elevated intraventricular pressure. The aim of this study was to compare periventricular brain perfusion in dogs with and without ventriculomegaly using perfusion weighted-magnetic-resonance-imaging to clarify as to whether ventriculomegaly might be associated with an increase in intraventricular pressure. Perfusion was measured in 32 Cavalier King Charles spaniels (CKCS) with ventriculomegaly, 10 CKCSs were examined as a control group. Cerebral blood flow (CBF) was measured using free-hand regions of interest (ROI) in five brain regions: periventricular white matter, caudate nucleus, parietal cortex, hippocampus, and thalamus. CBF was significantly lower in the periventricular white matter of the dogs with ventriculomegaly (p = 0.0029) but not in the other ROIs. Reduction of periventricular CBF might imply increase of intraventricular pressure in ventriculomegaly. PMID- 28879206 TI - Endoscopic Ultrasound-Guided Management of Bleeding Rectal Varices. AB - Rectal variceal bleeding, though rare, can pose significant morbidity and mortality in the wake of treatment failure. Conventional treatment utilizing endoscopic glue injection might not be feasible in all cases due to poor visualization and inadvertent missing of variceal source of bleed. Endoscopic ultrasound (EUS)-guided rectal variceal management is a promising and effective modality. We provide real-time images and a video of EUS-guided precision management of rectal variceal bleed using coiling and glue in a cirrhotic. PMID- 28879205 TI - Pediatric burn resuscitation: past, present, and future. AB - Burn injury is a leading cause of unintentional death and injury in children, with the majority being minor (less than 10%). However, a significant number of children sustain burns greater than 15% total body surface area (TBSA), leading to the initiation of the systemic inflammatory response syndrome. These patients require IV fluid resuscitation to prevent burn shock and death. Prompt resuscitation is critical in pediatric patients due to their small circulating blood volumes. Delays in resuscitation can result in increased complications and increased mortality. The basic principles of resuscitation are the same in adults and children, with several key differences. The unique physiologic needs of children must be adequately addressed during resuscitation to optimize outcomes. In this review, we will discuss the history of fluid resuscitation, current resuscitation practices, and future directions of resuscitation for the pediatric burn population. PMID- 28879207 TI - Delayed Spontaneous Passage of Gallstones via Cholecystocutaneous Fistula. PMID- 28879208 TI - Tumor Necrosis Factor Alpha Inhibitor-Induced Acute Pancreatitis. AB - Treatment of acute pancreatitis remains a challenge, with therapy focused on supportive care and treating the inciting etiology. Tumor necrosis factor-alpha (TNFalpha) inhibitors have shown promising results treating acute pancreatitis in animal models, but they have not been evaluated in human trials yet. A 25-year old woman presented with ulcerative colitis. She was unresponsive to immunomodulators and developed acute pancreatitis shortly after initiation of a TNFalpha inhibitor. Her symptoms subsided after discontinuation of the medication, but reemerged when a different TNFalpha inhibitor was introduced to control her ulcerative colitis. Other potential etiologies were investigated and clinically excluded by laboratory and imaging studies. PMID- 28879209 TI - Colorectal Cancer Associated with Strongyloides stercoralis Colitis. AB - Strongyloides stercoralis colitis is a severe but easily curable disease with a high mortality rate if left untreated. Strongyloidiasis can persist up to several decades and may lead to a chronic colitis similar to that seen in inflammatory bowel disease (IBD), and the two are often confused. Chronic colitis from IBD is associated with an increased risk of colorectal cancer, so it is plausible that chronic colitis from strongyloidiasis may carry a similar risk. Our case report associates chronic Strongyloides colitis and colorectal cancer. PMID- 28879210 TI - Gastroduodenal Artery Psuedoaneurysm Bleed through a Spontaneous Pancreaticoduodenal Fistula as a Result of Acute Necrotizing Pancreatitis. AB - Spontaneous pancreaticoduodenal fistulization and arterial psuedoaneurysm formation are both complications of acute pancreatitis. We present a 27-year-old man with hematemesis who was found to be bleeding from a gastroduodenal artery psuedoaneurysm through a spontaneous pancreaticoduodenal fistula as a result of severe alcohol-related necrotizing pancreatitis. This is the first reported case in the literature to describe this occurrence. PMID- 28879211 TI - Common Variable Immunodeficiency with Several Gastrointestinal Manifestations. AB - Common variable immunodeficiency (CVID) is an immunodeficiency disorder with a high incidence of gastrointestinal (GI) manifestations and an increased risk of gastric malignancy. We report a case of a CVID with mild anemia presenting with multiple GI manifestations: gastric low-grade dysplasia (LGD), enteropathy with villous atrophy, refractory Giardia infection, nodular lymphoid hyperplasia, and inflammatory bowel-like disease. The differential diagnosis with celiac sprue could be challenging because of CVID enteropathy with villous flattening. Gastric LGD in a patient with an increased risk for gastric malignancy makes the appropriate surveillance of gastric cancer in CVID challenging. PMID- 28879212 TI - Safety and Efficacy of the Complement Inhibitor AMY-101 in a Natural Model of Periodontitis in Non-human Primates. AB - Periodontitis is a chronic inflammatory disease associated with overactivation of the complement system. Recent preclinical studies suggest that host-modulation therapies may contribute to effective treatment of human periodontitis, which may lead to loss of teeth and function if untreated. We previously showed that locally administered AMY-101 (Cp40), a peptidic inhibitor of the central complement component C3, can inhibit naturally occurring periodontitis in non human primates (NHPs) when given once a week. This study was undertaken to determine the local safety of increasing doses of the drug as well as its efficacy when given at a reduced frequency or after systemic administration. Our findings have determined a local dose of AMY-101 (0.1 mg/site) that is free of local irritation and effective when given once every 3 weeks. Moreover, a daily subcutaneous dose of AMY-101 (4 mg/kg bodyweight) was protective against NHP periodontitis, suggesting that patients treated for systemic disorders (e.g., paroxysmal nocturnal hemoglobinuria) can additionally benefit in terms of improved periodontal condition. In summary, AMY-101 appears to be a promising candidate drug for the adjunctive treatment of human periodontitis, a notion that merits investigation in human clinical trials. PMID- 28879213 TI - DNA-Loaded Cationic Liposomes Efficiently Function as a Vaccine against Malarial Proteins. AB - The delivery of antigens as DNA vaccines is an efficient alternative to induce immune responses against antigens, which are difficult to produce in recombinant form. However, the delivery of naked DNA is ineffective or relies on sophisticated ballistic devices. Here, we show a combination of liposome application and naked DNA vaccine that successfully overcomes these problems. Upon entrapment of plasmids encoding different antigens in cationic particles, transfection efficiencies similar to commercial kits were achieved in in vitro cell cultures. The liposome-based approach provided strong humoral responses against three malarial antigens, namely the Circumsporozoite protein and the C terminus of merozoite surface protein 1 from Plasmodium vivax (titers 104 or 103 104, respectively) and P. falciparum Rhoptry antigen 5 from Plasmodium falciparum (titers 103-104). When employed in P. falciparum growth-inhibition assays, antibodies demonstrated consistent reinvasion-blocking activities that were dose dependent. Liposome-formulated DNA vaccines may prove useful when targets cannot be produced as recombinant proteins and when conformation-dependent and highly specific antibodies are mandatory. PMID- 28879215 TI - Synthesis of adsorbent from Tamarix hispida and modified by lanthanum metal for fluoride ions removal from wastewater: Adsorbent characteristics and real wastewater treatment data. AB - This data article describes a facile method for production of an adsorbent from Tamarix hispida wasted wood and modified by lanthanum metal for fluoride ions removal from wastewater. The main characteristics of the adsorbent consist of BET surface area, functional groups, and elemental analysis is presented. The data for attenuating the pollutants from a real wastewater treatment which was provided from a glass factory is also represented. More than 90% of fluoride content of the real wastewater was treated by the adsorbent. Generally, these data would be informative for extend research aim to industrial wastewater treatment and those who work in the wastewater treatment plants. PMID- 28879214 TI - Chicken domestication changes expression of stress-related genes in brain, pituitary and adrenals. AB - Domesticated species have an attenuated behavioral and physiological stress response compared to their wild counterparts, but the genetic mechanisms underlying this change are not fully understood. We investigated gene expression of a panel of stress response-related genes in five tissues known for their involvement in the stress response: hippocampus, hypothalamus, pituitary, adrenal glands and liver of domesticated White Leghorn chickens and compared it with the wild ancestor of all domesticated breeds, the Red Junglefowl. Gene expression was measured both at baseline and after 45 min of restraint stress. Most of the changes in gene expression related to stress were similar to mammals, with an upregulation of genes such as FKBP5, C-FOS and EGR1 in hippocampus and hypothalamus and StAR, MC2R and TH in adrenal glands. We also found a decrease in the expression of CRHR1 in the pituitary of chickens after stress, which could be involved in negative feedback regulation of the stress response. Furthermore, we observed a downregulation of EGR1 and C-FOS in the pituitary following stress, which could be a potential link between stress and its effects on reproduction and growth in chickens. We also found changes in the expression of important genes between breeds such as GR in the hypothalamus, POMC and PC1 in the pituitary and CYP11A1 and HSD3B2 in the adrenal glands. These results suggest that the domesticated White Leghorn may have a higher capacity for negative feedback of the HPA axis, a lower capacity for synthesis of ACTH in the pituitary and a reduced synthesis rate of corticosterone in the adrenal glands compared to Red Junglefowl. All of these findings could explain the attenuated stress response in the domesticated birds. PMID- 28879216 TI - Data on the construction of a recombinant HEK293 cell line overexpressing hERG potassium channel and examining the presence of hERG mRNA and protein expression. AB - The data presented in this article are related to the research article entitled "The effects of deoxyelephantopin on the cardiac delayed rectifier potassium channel current (IKr) and human ether-a-go-go-related gene (hERG) expression" (Y.F. Teah, M.A. Abduraman, A. Amanah, M.I. Adenan, S.F. Sulaiman, M.L. Tan) [1], which the possible hERG blocking properties of deoxyelephantopin were investigated. This article describes the construction of human embryonic kidney 293 (HEK293) cells overexpressing HERG potassium channel and verification of the presence of hERG mRNA and protein expression in this recombinant cell line. PMID- 28879217 TI - Data on SEM, TEM and Raman Spectra of doped, and wool carbon nanotubes made directly from CO2 by molten electrolysis. AB - This SEM, TEM and Raman Spectra and economic calculations data provides a benchmark for carbon nanotubes synthesized via molten electrolyte via the carbon dioxide to carbon nanotube (C2CNT) process useful for comparison to other data on longer length C2CNT wools; specifically: (I) C2CNT electrosynthesis with bare (uncoated) cathodes and without pre-electrolysis low current activation. (II) C2CNT Intermediate length CNTs with intermediate integrated electrolysis charge transfer. (III) C2CNT Admixing of sulfur, nitrogen and phosphorous (in addition to boron) to carbon nanotubes, and (IV) Scalability of the C2CNT process. This data presented in this article are related to the research article entitled "Carbon Nanotube Wools Made Directly from CO2 by Molten Electrolysis: Value Driven Pathways to Carbon Dioxide Greenhouse Gas Mitigation" (Johnson et al., 2017) [1]. PMID- 28879218 TI - Identification of epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3''Me) and amino acid profiles in various tea (Camellia sinensis L.) cultivars. AB - This article includes experimental data on the identification of epigallocatechin 3-O-(3-O-methyl)-gallate (EGCG3''Me) by 2-dimensional (2D) proton (1H) NMR analysis and on the information of amino acid and catechin compound profiles by HPLC analysis in leaf extracts of various tea cultivars. These data are related to the research article "Metabolic phenotyping of various tea (Camellia sinensis L.) cultivars and understanding of their intrinsic metabolism" (Ji et al., 2017) [1]. The assignment for EGCG3x''Me by 1H NMR analysis was also confirmed with spiking experiment of its pure chemical. PMID- 28879219 TI - Delayed-onset vemurafenib-induced panniculitis. PMID- 28879220 TI - Pyoderma gangrenosum in pregnancy successfully treated with infliximab and prednisone. PMID- 28879221 TI - Delusional parasitosis secondary to severe iron deficiency anemia. PMID- 28879222 TI - Multiple fixed drug eruption to minocycline at sites of healed burn and zoster: An interesting case of locus minoris resistentiae. PMID- 28879223 TI - Blinatumomab-associated vasculitis. PMID- 28879224 TI - Amicrobial pustulosis of the folds and palmoplantar pustulosis simultaneously induced by different tumor necrosis factor-alpha inhibitors: Demonstration of a shared pathophysiology. PMID- 28879225 TI - Preoperative biliary drainage by plastic or self-expandable metal stents in patients with periampullary tumors: results of a randomized clinical study. AB - BACKGROUND AND STUDY AIMS : Preoperative biliary drainage in patients with periampullary tumors and jaundice has been popularized to improve the quality of life and minimize the risks associated with subsequent radical surgery. The aim of this study was to investigate the possible superiority of self-expandable metal stents (SEMS) over plastic stents, by comparing the amount of bacteria in intraoperatively collected bile and using this variable as a proxy for the efficacy of the respective biliary drainage modalities. PATIENTS AND METHODS : In this randomized clinical trial, 92 patients with obstructive jaundice were enrolled; 45 were allocated to the plastic stent group and 47 to the SEMS group. The primary outcome was the extent and magnitude of biliary bacterial growth at the time of surgical exploration. Secondary outcomes were: macroscopic grading of inflammation of the stented bile ducts, occurrence of adverse events after stenting, stent dysfunction, recognized surgical complexities, and incidence of postoperative complications. RESULTS: The patients were well matched regarding clinical and disease-specific characteristics. At surgery, there were no group differences in the bacterial amount and composition of the bile cultures or the perceived difficulty of surgical dissection. During the preoperative biliary drainage period, more instances of stent dysfunction requiring stent replacement were recorded in the plastic stent group (19 % vs. 0 %; P = 0.03). Postoperative complications in patients who underwent curative surgery were more common in patients with plastic stents (72 % vs. 52 %), among which clinically significant leakage from the pancreatic anastomoses seemed to predominate (12 % vs. 3.7 %); however, none of these differences in postoperative adverse events reached statistical significance. CONCLUSION: This randomized clinical study was unable to demonstrate any superiority of SEMS in the efficacy of preoperative bile drainage, as assessed by the amount of bacteria in the intraoperatively collected bile. However, some data in favor of SEMS were observed among the clinical secondary outcomes variables (preoperative stent exchange rates) without increases in local inflammatory reactions. PMID- 28879226 TI - Increased risk and severity of ERCP-related complications associated with asymptomatic common bile duct stones. AB - BACKGROUND AND STUDY AIMS: Endoscopic removal of asymptomatic common bile duct stones (CBDS) is generally recommended. Although many reports have described the risk of complications in endoscopic retrograde cholangiopancreatography (ERCP), no studies have addressed this problem in the context of asymptomatic CBDS. This study examines the risk of complications arising in ERCP for asymptomatic CBDS. PATIENTS AND METHODS: This retrospective study included 425 patients with naive papilla who underwent therapeutic ERCP for choledocholithiasis at 2 institutions in Japan for 2 years. The risk of complications was examined in patients who were divided into the asymptomatic and symptomatic CBDS groups. We used propensity score analysis to adjust for confounding effects. RESULTS: Complications were observed in 32 (7.5 %) of the 425 patients. Of the 358 patients with symptomatic CBDS, 14 patients (3.9 %) had complications. In contrast, of the 67 patients with asymptomatic CBDS, 18 patients (26.9 %) had complications. Propensity score analysis revealed that asymptomatic CBDS was a significant risk factor, with a significantly higher incidence of complications compared with symptomatic CBDS (odds ratio, 5.3). Moderate to severe complications were observed in 15 of 18 patients (83.3 %) in the asymptomatic CBDS group, with significantly more moderate to severe complications than those in the symptomatic CBDS (odds ratio, 6.7). CONCLUSIONS: Asymptomatic CBDS carried a high risk of ERCP-related complications, and these were often more severe. In asymptomatic CBDS, endoscopic treatment should be carefully performed after considering the patient's background, and detailed explanation of its possible complications should be given to patients in advance. PMID- 28879227 TI - Assessment of quality indicators among nurse practitioners performing upper endoscopy. AB - BACKGROUND AND STUDY AIMS: Limited international data have shown that non physicians can safely perform upper endoscopy, but no such study has been performed in the United States. Our aim was to assess the quality of outpatient upper endoscopies performed by nurse practitioners (NPs). PATIENTS AND METHODS: Retrospective chart review of upper endoscopies performed by 3 NPs between 2010 and 2013 was performed. Comparisons among all NPs performing upper endoscopy and assessment of individual NP performance over time with respect to quality indicators were performed. RESULTS : Three NPs performed 333 upper endoscopies (distribution of 166, 44, and 123, respectively). Of the cases, 98.2 %s were successfully completed to the second portion of the duodenum. In most cases, photo-documentation of required anatomical landmarks was performed: GE junction (84.2 %), GE junction in retroflexed view (84.2 %), antrum (82.1 %) and duodenum (80.9 %). Photo-documentation improved with increasing experience. NPs appropriately performed biopsies for specific medical conditions: 10/11 (90.9 %) gastric ulcers were biopsied and 63/66 (95.5) of patients with iron deficiency had duodenal biopsies performed for celiac disease. A physician endoscopist was required during the procedure 22.5 % of the time. Important parameters such as documenting informed consent (100 %) and documenting a discharge plan (99.4 %) in the procedure reports were overwhelming present. There was a single adverse event during the study period. CONCLUSION: In the first US study of NPs performing upper endoscopy, they were able to perform high-quality and safe upper endoscopies. These findings support incorporation of non-physicians alongside physicians to help meet the growing demand for endoscopic services across the United States. PMID- 28879228 TI - Thermodiffusion in multicomponent n-alkane mixtures. AB - Compositional grading within a mixture has a strong impact on the evaluation of the pre-exploitation distribution of hydrocarbons in underground layers and sediments. Thermodiffusion, which leads to a partial diffusive separation of species in a mixture due to the geothermal gradient, is thought to play an important role in determining the distribution of species in a reservoir. However, despite recent progress, thermodiffusion is still difficult to measure and model in multicomponent mixtures. In this work, we report on experimental investigations of the thermodiffusion of multicomponent n-alkane mixtures at pressure above 30 MPa. The experiments have been conducted in space onboard the Shi Jian 10 spacecraft so as to isolate the studied phenomena from convection. For the two exploitable cells, containing a ternary liquid mixture and a condensate gas, measurements have shown that the lightest and heaviest species had a tendency to migrate, relatively to the rest of the species, to the hot and cold region, respectively. These trends have been confirmed by molecular dynamics simulations. The measured condensate gas data have been used to quantify the influence of thermodiffusion on the initial fluid distribution of an idealised one dimension reservoir. The results obtained indicate that thermodiffusion tends to noticeably counteract the influence of gravitational segregation on the vertical distribution of species, which could result in an unstable fluid column. This confirms that, in oil and gas reservoirs, the availability of thermodiffusion data for multicomponent mixtures is crucial for a correct evaluation of the initial state fluid distribution. PMID- 28879229 TI - Erratum: A cubesat centrifuge for long duration milligravity research. AB - [This corrects the article DOI: 10.1038/s41526-017-0021-0.]. PMID- 28879230 TI - Polarization recovery through scattering media. AB - The control and use of light polarization in optical sciences and engineering are widespread. Despite remarkable developments in polarization-resolved imaging for life sciences, their transposition to strongly scattering media is currently not possible, because of the inherent depolarization effects arising from multiple scattering. We show an unprecedented phenomenon that opens new possibilities for polarization-resolved microscopy in strongly scattering media: polarization recovery via broadband wavefront shaping. We demonstrate focusing and recovery of the original injected polarization state without using any polarizing optics at the detection. To enable molecular-level structural imaging, an arbitrary rotation of the input polarization does not degrade the quality of the focus. We further exploit the robustness of polarization recovery for structural imaging of biological tissues through scattering media. We retrieve molecular-level organization information of collagen fibers by polarization-resolved second harmonic generation, a topic of wide interest for diagnosis in biomedical optics. Ultimately, the observation of this new phenomenon paves the way for extending current polarization-based methods to strongly scattering environments. PMID- 28879231 TI - Homeodomain-like DNA binding proteins control the haploid-to-diploid transition in Dictyostelium. AB - Homeodomain proteins control the developmental transition between the haploid and diploid phases in several eukaryotic lineages, but it is not known whether this regulatory mechanism reflects the ancestral condition or, instead, convergent evolution. We have characterized the mating-type locus of the amoebozoan Dictyostelium discoideum, which encodes two pairs of small proteins that determine the three mating types of this species; none of these proteins display recognizable homology to known families. We report that the nuclear magnetic resonance structures of two of them, MatA and MatB, contain helix-turn-helix folds flanked by largely disordered amino- and carboxyl-terminal tails. This fold closely resembles that of homeodomain transcription factors, and, like those proteins, MatA and MatB each bind DNA characteristically using the third helix of their folded domains. By constructing chimeric versions containing parts of MatA and MatB, we demonstrate that the carboxyl-terminal tail, not the central DNA binding motif, confers mating specificity, providing mechanistic insight into how a third mating type might have originated. Finally, we show that these homeodomain-like proteins specify zygote function: Hemizygous diploids, formed in crosses between a wild-type strain and a mat null mutant, grow and differentiate identically to haploids. We propose that Dictyostelium MatA and MatB are divergent homeodomain proteins with a conserved function in triggering the haploid-to-diploid transition that can be traced back to the last common ancestor of eukaryotes. PMID- 28879232 TI - Intracellular spectral recompositioning of light enhances algal photosynthetic efficiency. AB - Diatoms, considered as one of the most diverse and largest groups of algae, can provide the means to reach a sustainable production of petrochemical substitutes and bioactive compounds. However, a prerequisite to achieving this goal is to increase the solar-to-biomass conversion efficiency of photosynthesis, which generally remains less than 5% for most photosynthetic organisms. We have developed and implemented a rapid and effective approach, herein referred to as intracellular spectral recompositioning (ISR) of light, which, through absorption of excess blue light and its intracellular emission in the green spectral band, can improve light utilization. We demonstrate that ISR can be used chemogenically, by using lipophilic fluorophores, or biogenically, through the expression of an enhanced green fluorescent protein (eGFP) in the model diatom Phaeodactylum tricornutum. Engineered P. tricornutum cells expressing eGFP achieved 28% higher efficiency in photosynthesis than the parental strain, along with an increased effective quantum yield and reduced nonphotochemical quenching (NPQ) induction levels under high-light conditions. Further, pond simulator experiments demonstrated that eGFP transformants could outperform their wild-type parental strain by 50% in biomass production rate under simulated outdoor sunlight conditions. Transcriptome analysis identified up-regulation of major photosynthesis genes in the engineered strain in comparison with the wild type, along with down-regulation of NPQ genes involved in light stress response. Our findings provide a proof of concept for a strategy of developing more efficient photosynthetic cell factories to produce algae-based biofuels and bioactive products. PMID- 28879233 TI - Low-energy transmission electron diffraction and imaging of large-area graphene. AB - Two-dimensional (2D) materials have attracted interest because of their excellent properties and potential applications. A key step in realizing industrial applications is to synthesize wafer-scale single-crystal samples. Until now, single-crystal samples, such as graphene domains up to the centimeter scale, have been synthesized. However, a new challenge is to efficiently characterize large area samples. Currently, the crystalline characterization of these samples still relies on selected-area electron diffraction (SAED) or low-energy electron diffraction (LEED), which is more suitable for characterizing very small local regions. This paper presents a highly efficient characterization technique that adopts a low-energy electrostatically focused electron gun and a super-aligned carbon nanotube (SACNT) film sample support. It allows rapid crystalline characterization of large-area graphene through a single photograph of a transmission-diffracted image at a large beam size. Additionally, the low-energy electron beam enables the observation of a unique diffraction pattern of adsorbates on the suspended graphene at room temperature. This work presents a simple and convenient method for characterizing the macroscopic structures of 2D materials, and the instrument we constructed allows the study of the weak interaction with 2D materials. PMID- 28879234 TI - Significant and stable drag reduction with air rings confined by alternated superhydrophobic and hydrophilic strips. AB - Superhydrophobic surfaces have the potential to reduce the viscous drag of liquids by significantly decreasing friction at a solid-liquid interface due to the formation of air layers between solid walls and interacting liquids. However, the trapped air usually becomes unstable due to the finite nature of the domain over which it forms. We demonstrate for the first time that a large surface energy barrier can be formed to strongly pin the three-phase contact line of air/water/solid by covering the inner rotor of a Taylor-Couette flow apparatus with alternating superhydrophobic and hydrophilic circumferential strips. This prevents the disruption of the air layer, which forms stable and continuous air rings. The drag reduction measured at the inner rotor could be as much as 77.2%. Moreover, the air layers not only significantly reduce the strength of Taylor vortexes but also influence the number and position of the Taylor vortex pairs. This has strong implications in terms of energy efficiency maximization for marine applications and reduction of drag losses in, for example, fluid transport in pipelines and carriers. PMID- 28879235 TI - Spectral purity and tunability of terahertz quantum cascade laser sources based on intracavity difference-frequency generation. AB - Terahertz sources based on intracavity difference-frequency generation in mid infrared quantum cascade lasers (THz DFG-QCLs) have recently emerged as the first monolithic electrically pumped semiconductor sources capable of operating at room temperature across the 1- to 6-THz range. Despite tremendous progress in power output, which now exceeds 1 mW in pulsed and 10 MUW in continuous-wave regimes at room temperature, knowledge of the major figure of merits of these devices for high-precision spectroscopy, such as spectral purity and absolute frequency tunability, is still lacking. By exploiting a metrological grade system comprising a terahertz frequency comb synthesizer, we measure, for the first time, the free-running emission linewidth (LW), the tuning characteristics, and the absolute center frequency of individual emission lines of these sources with an uncertainty of 4 * 10-10. The unveiled emission LW (400 kHz at 1-ms integration time) indicates that DFG-QCLs are well suited to operate as local oscillators and to be used for a variety of metrological, spectroscopic, communication, and imaging applications that require narrow-LW THz sources. PMID- 28879237 TI - Moisture-triggered physically transient electronics. AB - Physically transient electronics, a form of electronics that can physically disappear in a controllable manner, is very promising for emerging applications. Most of the transient processes reported so far only occur in aqueous solutions or biofluids, offering limited control over the triggering and degradation processes. We report novel moisture-triggered physically transient electronics, which exempt the needs of resorption solutions and can completely disappear within well-controlled time frames. The triggered transient process starts with the hydrolysis of the polyanhydride substrate in the presence of trace amounts of moisture in the air, a process that can generate products of corrosive organic acids to digest various inorganic electronic materials and components. Polyanhydride is the only example of polymer that undergoes surface erosion, a distinct feature that enables stable operation of the functional devices over a predefined time frame. Clear advantages of this novel triggered transience mode include that the lifetime of the devices can be precisely controlled by varying the moisture levels and changing the composition of the polymer substrate. The transience time scale can be tuned from days to weeks. Various transient devices, ranging from passive electronics (such as antenna, resistor, and capacitor) to active electronics (such as transistor, diodes, optoelectronics, and memories), and an integrated system as a platform demonstration have been developed to illustrate the concept and verify the feasibility of this design strategy. PMID- 28879236 TI - Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50. AB - The phospholipid cardiolipin mediates the functional interactions of proteins that reside within energy-conserving biological membranes. However, the molecular basis by which this lipid performs this essential cellular role is not well understood. We address this role of cardiolipin using the multisubunit mitochondrial TIM23 protein transport complex as a model system. The early stages of protein import by this complex require specific interactions between the polypeptide substrate receptor, Tim50, and the membrane-bound channel-forming subunit, Tim23. Using analyses performed in vivo, in isolated mitochondria, and in reductionist nanoscale model membrane systems, we show that the soluble receptor domain of Tim50 interacts with membranes and with specific sites on the Tim23 channel in a manner that is directly modulated by cardiolipin. To obtain structural insights into the nature of these interactions, we obtained the first small-angle x-ray scattering-based structure of the soluble Tim50 receptor in its entirety. Using these structural insights, molecular dynamics simulations combined with a range of biophysical measurements confirmed the role of cardiolipin in driving the association of the Tim50 receptor with lipid bilayers with concomitant structural changes, highlighting the role of key structural elements in mediating this interaction. Together, these results show that cardiolipin is required to mediate specific receptor-channel associations in the TIM23 complex. Our results support a new working model for the dynamic structural changes that occur within the complex during transport. More broadly, this work strongly advances our understanding of how cardiolipin mediates interactions among membrane-associated proteins. PMID- 28879238 TI - Mechanistic basis for the recognition of laminin-511 by alpha6beta1 integrin. AB - Laminins regulate diverse cellular functions through interaction with integrins. Two regions of laminins-three laminin globular domains of the alpha chain (LG1-3) and the carboxyl-terminal tail of the gamma chain (gamma-tail)-are required for integrin binding, but it remains unclear how the gamma-tail contributes to the binding. We determined the crystal structure of the integrin binding fragment of laminin-511, showing that the gamma-tail extends to the bottom face of LG1-3. Electron microscopic imaging combined with biochemical analyses showed that integrin binds to the bottom face of LG1-3 with the gamma1-tail apposed to the metal ion-dependent adhesion site (MIDAS) of integrin beta1. These findings are consistent with a model in which the gamma-tail coordinates the metal ion in the MIDAS through its Glu residue. PMID- 28879239 TI - Understanding Pediatric Dentists' Dental Caries Management Treatment Decisions: A Conjoint Experiment. AB - When traditional ranking and rating surveys are used to assess dentists' treatment decisions, the patient's source of payment appears to be of little importance. Therefore, this study used the marketing research tool conjoint analysis to investigate the relative impact of source of payment along with the child's age and cooperativeness on pediatric dentists' willingness to use Atraumatic Restorative Treatment (ART) to restore posterior primary teeth. A conjoint survey was completed by 707 pediatric dentists. Three factors (age of the child, cooperativeness, type of insurance) were varied across 3 levels to create 9 patient scenarios. The relative weights that dentists placed on these factors in the restorative treatment decision process were determined by conjoint analysis. "Cooperativeness" (52%) was the most important factor, "age of the child" (26%) the second-most important factor, followed by "insurance status of the child" (22%). For the third factor, insurance, pediatric dentists were least willing to use ART with publicly insured children (-0.082), and this was significantly different from their willingness to use ART with uninsured children (0.010) but not significantly different than their willingness to use ART for children with private insurance (0.073). Unlike traditional ranking and rating tools, conjoint analysis found that the insurance status of the patient appeared to be an important factor in dentists' decisions about different restorative treatment options. When pediatric dentists were forced to make tradeoffs among different patients' factors, they were most willing to use ART technique with young, uncooperative patients when they had no insurance. Knowledge Transfer Statement: The present study suggests the feasibility of using techniques borrowed from marketing research, such as conjoint analysis, to understand dentists' restorative treatment decisions. Results of this study demonstrate pediatric dentists' willingness to use a particular restorative treatment option (Atraumatic Restorative Treatment in this application) when forced to make tradeoffs in a "conjoined," or holistic, context among different factors presented in real-life patient scenarios. A deeper understanding of dentists' treatment decisions is vital to develop valid practice guidelines and interventions that encourage the use of appropriate restorative treatment modalities. PMID- 28879240 TI - Early Childhood Caries: Future Perspectives in Risk Assessment. PMID- 28879241 TI - Parents' Experiences of Toothbrushing with Children: A Qualitative Study. AB - Globally, dental caries is one of the most prevalent diseases and is more common in children living in deprived areas. Dental caries is preventable, and guidance in the United Kingdom recommends parental supervised brushing (PSB): a collection of behaviors-including twice-daily toothbrushing with fluoridated toothpaste-that should begin upon eruption of the first tooth (approximately 6 to 12 mo of age) and for which children need to be helped or supervised by an adult until at least 7 y of age. The aim of this study was to explore parents' experiences of toothbrushing with their young children and to establish barriers and facilitators to PSB at individual, interpersonal, and environmental levels according to the theoretical domains framework. Qualitative semistructured interviews guided by the framework were conducted with 27 parents of young children (<7 y) in 2 deprived areas of the United Kingdom. Framework analysis was used. Parents were not aware of national guidance concerning their active involvement in toothbrushing; however, they did have detailed knowledge of toothbrushing practices for children, and their intentions were to brush their children's teeth themselves twice every day as part of a family routine. Nonetheless, parents' difficulties experienced in managing their children's challenging behavior and the environmental context of their stressful lives meant that many parents adopted a role of simply reminding their children to brush or watching them brush. As such, the main barriers to PSB among parents living in deprived areas were skills in managing their children's behavior and environmental influences on family life. The results of our study have clear implications for the development of appropriate interventions to address the modifiable barriers to improve parental adoption of PSB. Knowledge Transfer Statement: The results of this study will be used to develop a behavior change intervention to encourage parental supervised brushing. The intervention-which is likely to be delivered through health practitioners rather than dental teams-will be developed to reduce dental caries among young children and will require evaluation in terms of its clinical and cost effectiveness. PMID- 28879242 TI - Disparities in Emergency Department Pain Treatment for Toothache. AB - Racial disparities in how pain is treated in the emergency department (ED) for toothache have not been reported. Due to increasing reliance on EDs for dental care, the authors investigated whether race/ethnicity and insurance type are associated with treatment for toothache pain. The authors conducted a nationally representative cross-sectional study of ED toothache visits by adults (19 to 64 y old), using the 2008-2010 National Hospital Ambulatory Medical Care Survey. Multinomial regression models accounted for the complex survey design. Outcomes were pain medicines received: none, nonopioid only, or opioids. After adjusting for sociodemographic factors, black patients had 1.99 greater odds (P < 0.005) than white patients of receiving only a nonopioid pain medicine for toothache. Visits made by patients on Medicare, Medicaid, uninsured, or "other" insurance status had greater odds than the privately insured of receiving only a nonopioid pain medicine rather than an opioid (odds ratios, respectively: 4.8, P < 0.001; 2.1, P <= 0.001; 2.3, P < 0.01; and 4.1, P < 0.001). Blacks are less likely than whites to receive opioids in the ED for a toothache, even with similar levels of pain. Nonprivately insured patients have lower odds than the privately insured to receive opioids for toothache pain. A better understanding of the etiology of these disparities could lead to directed interventions. Knowledge Transfer Statement: This study presents findings novel to the body of pain and oral health care literature. Because there is an increasing reliance on the emergency department to address dental pain, disparities in how toothache pain is treated will be of great interest to a growing number of Americans, clinicians, and policy makers. PMID- 28879243 TI - Development and Testing of a Cognitive Behavioral Therapy Resource for Children's Dental Anxiety. AB - Cognitive Behavioral Therapy (CBT) is an evidence-based treatment for dental anxiety; however, access to therapy is limited. The current study aimed to develop a self-help CBT resource for reducing dental anxiety in children, and to assess the feasibility of conducting a trial to evaluate the treatment efficacy and cost-effectiveness of such an intervention. A mixed methods design was employed. Within phase 1, a qualitative "person-based" approach informed the development of the self-help CBT resource. This also employed guidelines for the development and evaluation of complex interventions. Within phase 2, children, aged between 9 and 16 y, who had elevated self-reported dental anxiety and were attending a community dental service or dental hospital, were invited to use the CBT resource. Children completed questionnaires, which assessed their dental anxiety and health-related quality of life (HRQoL) prior to and following their use of the resource. Recruitment and completion rates were recorded. Acceptability of the CBT resource was explored using interviews and focus groups with children, parents/carers and dental professionals. For this analysis, the authors adhered to the Mixed Methods Appraisal Tool criteria. There were 24 families and 25 dental professionals participating in the development and qualitative evaluation of the CBT resource for children with dental anxiety. A total of 56 children agreed to trial the CBT resource (66% response rate) and 48 of these children completed the study (86% completion rate). There was a significant reduction in dental anxiety (mean score difference = 7.7, t = 7.9, df = 45, P < 0.001, Cohen's d ES = 1.2) and an increase in HRQoL following the use of the CBT resource (mean score difference = -0.03, t = 2.14, df = 46, P < 0.05, Cohen's d ES = 0.3). The self-help approach had high levels of acceptability to stakeholders. These findings provide preliminary evidence for the effectiveness and acceptability of the resource in reducing dental anxiety in children and support the further evaluation of this approach in a randomized control trial. Knowledge Transfer Statement: This study details the development of a guided self help Cognitive Behavioral Therapy resource for the management of dental anxiety in children and provides preliminary evidence for the feasibility and acceptability of this approach with children aged between 9 and 16 y. The results of this study will inform the design of a definitive trial to examine the treatment- and cost-effectiveness of the resource for reducing dental anxiety in children. PMID- 28879244 TI - Care Pathways in Persistent Orofacial Pain: Qualitative Evidence from the DEEP Study. AB - Persistent orofacial pain is relatively common and known to have an adverse effect on quality of life. Previous studies suggest that the current care pathway may be problematic, but it is not well understood which health services patients access and what their experience is. The aim of this study was to explore care pathways and their impact from the perspective of patients. Qualitative interviews were conducted with a maximum variation sample of patients recruited from primary (community based) and secondary (specialist hospital based) care in the United Kingdom. Questions focused on the stages in their pathway and the impact of the care that they had received. Interviews were digitally recorded and transcribed verbatim, and analysis followed principles of the constant comparative method. NVivo 10 was used to help organize and analyze data. Twenty two patients were interviewed at baseline, and 18 took part in a second interview at 12 mo. Three main themes emerged from the data: the "fluidity of the care pathway," in which patients described moving among health care providers in attempts to have their pain diagnosed and managed, occurring alongside a "failure to progress," where despite multiple appointments, patients described frustration at delays in obtaining a diagnosis and effective treatment for their pain. Throughout their care pathways, patients described the "effects of unmanaged pain," where the longer the pain went unmanaged, the greater its potential to negatively affect their lives. Findings of this study suggest that the current care pathway is inefficient and fails to meet patient needs. Future work needs to focus on working with stakeholder groups to redesign patient-centered care pathways. Knowledge Transfer Statement: Data from qualitative interviews conducted with patients with persistent orofacial pain suggest significant problems with the existing care pathway, consisting of delays to diagnosis, treatment, and referral. Patients describing their struggle to progress through the current care pathway highlighted the difficulties occurring while living with orofacial pain. This study suggests a need for a revised care pathway, which better meets the needs of people with persistent orofacial pain. PMID- 28879245 TI - Effects of High-Dose Capsaicin on TMD Subjects: A Randomized Clinical Study. AB - Temporomandibular joint disorder (TMD) is a complex musculoskeletal disorder that presents with pain, limited jaw opening, and abnormal noises in the temporomandibular joint. Despite the significant impact that TMD has in terms of suffering and financial burden, relatively few new treatments have emerged; therefore, development of novel treatments to treat TMD pain remains a high priority. The rationale of this study was to use a double-blind, vehicle controlled clinical trial to evaluate the effects of a high-concentration (8%) capsaicin cream on TMD. This is based on the hypothesis that targeting TRP vanilloid subfamily member 1 (TRPV1) for pain control may provide a novel method for pain relief in TMD patients. TRPV1 is primarily expressed on a population of nociceptive-specific neurons and provides a candidate target for the development of pain treatments. Capsaicin is the primary agonist for TRPV1 and has been used previously in relatively low doses (0.025% to 0.075%) as a therapeutic for a variety of pain disorders, including postherpetic neuralgia and osteoarthritis; however, analgesic efficacy remains equivocal. TMD and healthy control subjects were assigned to either an active capsaicin or vehicle control group. The treatments were applied for 2 h and then removed. Quantitative sensory testing (QST) was completed prior to drug application (baseline), 2 h after drug application, and 1 wk later. Perceived pain intensity was measured using a visual analog scale (VAS) following capsaicin or vehicle cream application. Significantly lower pain was reported in the week after application in the capsaicin-treated TMD subjects. For QST measures, there was a decreased thermal pain threshold 2 h after capsaicin application for both the control and TMD groups, but this resolved within a week. Capsaicin had no effect on pressure pain threshold or mechanical sensitivity in both TMD and healthy individuals. This study demonstrates that 8% topical capsaicin therapy is a relatively safe, simple, and effective treatment for patients with TMD. Knowledge Transfer Statement: This study evaluated a novel topical capsaicin therapy for reducing orofacial pain. The results of this study can be used to provide another treatment option for patients with TMD. PMID- 28879246 TI - Opioid Analgesic Prescribing Practices of Dental Professionals in the United States. AB - The prescription of opioid analgesics by dental professionals is widespread in the United States. Policy makers, government agencies, and professional organizations consider this phenomenon a growing public health concern. This study examined trends in the prescription of opioid analgesics for adults by dental professionals and associated factors in the United States. Data from the Medical Expenditure Panel Survey (1996-2013) were analyzed. Descriptive statistics were calculated separately for each year. Logistic regression analyses were conducted to estimate the overall trend during the period with and without adjusting for dental procedures and personal characteristics. Survey weights were incorporated to handle the sampling design. The prescription of opioid analgesics following dental care increased over time. After adjusting for sociodemographic factors, source of payment, and type of dental procedure, the odds ratio (OR) of prescribing opioid analgesics following a dental visit per each decade difference was 1.28 (95% confidence interval [CI], 1.19-1.38). Surgical, root canal, and implant procedures had the highest rates of opioid prescriptions and the greatest increases in rates over the study period. After adjusting for personal characteristics and type of dental procedure, the OR of receiving a prescription for opioids comparing blacks, Asians, and Hispanics to whites was 1.29 (95% CI, 1.17-1.41), 0.57 (95% CI, 0.47-0.70), and 0.84 (95% CI, 0.75-0.95), respectively. Opioid analgesic prescriptions following dental visits increased over time after adjusting for personal characteristics and type of dental procedure. The odds of receiving a prescription for opioids were higher for certain racial/ethnic minority groups. Knowledge Transfer Statement: This study highlights dental professionals prescribing practices of opioid analgesics by following dental treatments in the United States. With this knowledge, appropriate guidelines, protocols, and policies can be developed and implemented to address any inappropriate prescribing practices of opioid analgesics. In addition, this information could lead to an improvement in the prescribing practices of dental professionals and to evidence-based therapeutic decision making. PMID- 28879247 TI - Aggregatibacter actinomycetemcomitans in African Americans with Localized Aggressive Periodontitis. AB - This study aims to investigate the prevalence of the highly leukotoxic JP2 sequence versus the minimally leukotoxic non-JP2 sequence of Aggregatibacter actinomycetemcomitans within a cohort of 180 young African Americans, with and without localized aggressive periodontitis (LAP), in north Florida. The study included patients aged 5 to 25 y: 60 LAP patients, 60 healthy siblings (HS), and 60 unrelated healthy controls (HC). Subgingival plaque was collected from LAP sites-diseased (PD >=5 mm with bleeding on probing) and healthy (PD <=3 mm with no bleeding on probing)-and from healthy sites of HS and HC. Plaque DNA was extracted and analyzed by polymerase chain reaction for the detection of the JP2 and non-JP2 sequences of A. actinomycetemcomitans. Overall, 90 (50%) subjects tested positive for the JP2 sequence. Fifty (83.33%) LAP subjects were carriers of the highly leukotoxic JP2 sequence, detected in 45 (75%) diseased sites and 34 (56.67%) healthy sites. Additionally, JP2 carriage was found in 16 HS (26.67%) and 24 HC (40%; P < 0.0001, among groups). The non-JP2 sequence was detected in 26 (14.44%) total subjects: 17 (28.33%) LAP patients detected in equal amounts of diseased and healthy sites (n = 11, 18.33%), 6 (10%) HS sites, and 3 (5%) HC sites (P < 0.05, among groups). The JP2 sequence was strongly associated with LAP diseased sites in young African Americans, significantly more so than the non-JP2 (ClinicalTrials.gov NCT01330719). Knowledge Transfer Statement: Clinicians may use the results of this study to identify susceptible individuals to aggressive periodontitis, potentially leading to more appropriate selection of therapeutic choices. PMID- 28879248 TI - Local and Plasma Biomarker Profiles in Localized Aggressive Periodontitis. AB - Localized aggressive periodontitis (LAP) patients possess a systemic hyperinflammatory response after lipopolysaccharide stimulation. However, the levels of inflammatory and bone biomarkers in plasma, as well as possible associations between local and plasma biomarkers, are unknown in LAP. This cross sectional study aimed to characterize gingival crevicular fluid (GCF) and plasma biomarker profiles in LAP patients, their healthy siblings (HS), and healthy unrelated controls (HC). Fifty-eight LAP subjects, 33 HS, and 49 HC (African Americans, aged 5 to 25 y) were included. Following collection of clinical parameters with GCF and plasma samples, levels of 16 inflammatory and bone resorption biomarkers were determined with Milliplex. Univariate and correlation analyses were performed among all clinical and laboratorial parameters. Discriminant analyses were used to investigate groups of biomarkers discriminating LAP from HS and HC in GCF and plasma. GCF levels of multiple cytokines and chemokines and RANKL:OPG ratio (receptor activator of nuclear factor kappa-B ligand:osteoprotegerin) were higher in LAP disease, most of which positively correlated with probing depth and attachment loss of sampled sites. A group of IL-12p40, IL-6, IL-12p70, IL-2, and MIP-1alpha discriminated LAP diseased sites from twheir healthy sites, as well as from HS and HC healthy sites. In plasma, only RANKL levels were increased in LAP versus controls, which positively correlated with the percentage of affected sites and deep/bleeding sites. A plasma inflammatory profile including MIP-1alpha, IL-8, IL-10, and INF gamma could significantly discriminate LAP patients from HS and HC. No correlations were found between GCF and plasma levels of biomarkers. In conclusion, an inflammatory profile including groups of specific biomarkers in GCF and plasma may significantly discriminate LAP from healthy individuals. The hyperinflammatory response previously found in the peripheral blood of LAP patients is dependent on lipopolysaccharide stimulation, apparently resulting mostly in local tissue destruction and changes in biomarker profile, with a slight influence in the systemic inflammatory profile (ClinicalTrials.gov NCT01330719). Knowledge Transfer Statement: The results of this study can be possibly used by clinicians in the future as diagnostic tools for localized aggressive periodontitis. Thus, in the future, with proper consideration of cost, patient preference, chair-side feasibility and ultimately further studies validating the role of GCF markers for disease progression and response to treatment, this information could lead to more appropriate therapeutic decisions and the development of preventive approaches for susceptible patients. PMID- 28879249 TI - Gingival Fluid Inflammatory Biomarkers and Hypertension in African Americans. AB - Hypertension and periodontitis are highly prevalent among African Americans. This cross-sectional study investigated the relationships among inflammatory biomarkers in the gingival fluid, periodontitis, and blood pressure in these individuals. Twenty-one subjects who reported a diagnosis of hypertension and a comparison group of 26 nonhypertensive participants were enrolled. All were African Americans, non-cigarette smoking, and free from other systemic illness. Blood pressure and body mass index were assessed. A comprehensive periodontal examination was performed. Gingival fluid was collected from 3 healthy sites and 3 diseased sites when available. Samples were assessed for 8-isoprostane, interleukin 1beta, monocyte chemoattractant protein 1, tumor necrosis factor alpha (TNFalpha), C-reactive protein (CRP), and matrix metalloproteinase 8. Regardless of hypertension status, diseased sites were associated with increased levels of these biomarkers. CRP and TNFalpha levels were also significantly higher in hypertensive than nonhypertensive individuals without diseased sites. After adjusting for demographics and body mass index, periodontal attachment loss was higher among hypertensive than nonhypertensive subjects. TNFalpha and CRP levels and hypertension were in the same association pathway with attachment loss. Elevated blood pressure may increase the risk of periodontitis through a localized inflammatory mechanism. Knowledge Transfer Statement: The results of this study can be used by clinicians to better understand the etiology and pathogenesis of periodontitis in hypertensive individuals in general and African Americans in particular. The information could lead to better management of periodontal disease. PMID- 28879250 TI - Dental Care-Related Fear and Anxiety: Distress Tolerance as a Possible Mechanism. AB - Distress tolerance, the degree to which one is able to cope with and endure negative emotional states, has been broadly applied to understand and treat a variety of health (including behavioral) problems, but little is known about its role in oral health care and specifically dental care-related fear and anxiety, making it a novel construct in the oral health care literature. This cross sectional study examined distress tolerance as a possible predictor of dental fear and anxiety among a sample of adults with and without diagnoses of dental phobia, investigated possible differences in levels of distress tolerance between adults with and without dental phobia, and determined possible associations between distress tolerance and fear of pain, anxiety sensitivity, and depression. Using 52 volunteers (n = 31, dental phobia group; n = 21, healthy comparison group), this investigation used self-report measures of distress tolerance, fear of pain, anxiety sensitivity, dental fear, and depression. The Anxiety Disorders Interview Schedule, a semi-structured interview, was used to assess for dental phobia and other psychological disorders. Distress tolerance significantly predicted dental fear and anxiety, even after controlling for age, sex, fear of pain, anxiety sensitivity, and depression. In addition, the dental phobia group had lower distress tolerance than the healthy comparison group. Distress tolerance was significantly associated with fear of pain, anxiety sensitivity, and depression. Findings indicate that low distress tolerance plays a unique and distinct role as a possible mechanism in the genesis of dental care-related fear and anxiety and phobia and may exacerbate the experience of other states, including fear of pain and anxiety sensitivity. Knowledge Transfer Statement: Results indicate that patients who have a lower ability to tolerate emotional and physical distress may have higher levels of dental care-related fear and anxiety and even dental phobia, as well as associated sequelae (e.g., avoidance of dental care). Treatment of highly fearful dental patients may helpfully include a focus on increasing distress tolerance. PMID- 28879251 TI - The alternative of oral sedation for pediatric dental care. AB - In pediatric dentistry, chloral hydrate is habitually selected for sedation of uncooperative children. Although chloral hydrate has been used for decades, various adverse effects are reported and necessity for new alternative drugs has increased. Dexmedetomidine was approved by FDA for sedation at intensive care units (ICU) in 1999. Compared to conventional sedative drugs, dexmedetomidine has not only analgesic and sedative effects but also it barely suppresses the respiratory system. Due to these characteristics, dexmedetomidine is known as safe sedative drug for children and elderly patients. Furthermore, approved by KFDA in 2010 in Korea, the frequency of sedation using dexmedetomidine is increasing. However, due to its intravenous administration method, it was difficult to apply in pediatric dentistry. Recently, intranasal administration method was introduced which might be a new possible alternative of oral sedation. In this study, we compare the mechanisms, pros and cons of chloral hydrate and dexmedetomidine, introducing new possibilities. PMID- 28879252 TI - Telephone follow-up care for disabled patients discharged after receiving dental treatment under outpatient general anesthesia. AB - BACKGROUND: Patients were subjected to post-discharge follow-up (by telephone) in order to investigate the potential complications of outpatient general anesthesia or deep sedation that could develop in disabled dental patients discharged from the hospital. The ultimate aim of this study was to establish an appropriate response measure for such complications. METHODS: The caregivers of 79 disabled patients who underwent dental procedures under general anesthesia at our outpatient clinic were interviewed over telephone. Necessary care instructions were provided during the phone calls when required. The patient satisfaction level regarding the telephonic follow-up care was surveyed by additional telephone calls. RESULTS: Most of the patients did not suffer any serious complications; however, some reported fever and bleeding. The data obtained in this study can be utilized towards the development of caregiver education pertaining to the ambulatory general anesthesia of dental patients with disabilities. CONCLUSIONS: Additionally, we hope that the findings of this study will help minimize the effects of complications experienced by disabled dental patients undergoing ambulatory general anesthesia, as well as increase the overall patient satisfaction level. PMID- 28879253 TI - Using nasal cannula for sevoflurane deep sedation in emergency dental treatment. AB - BACKGROUND: Emergency room doctors run into difficulties in treating injured pediatric patients because usually they fell into panic after trauma. In these situation, deep sedation with sevoflurane is fully recommendable method. The conventional way can interrupt common dental treatment procedure. METHODS: In the present study, nasal cannula was used for sevoflurane deep sedation in 11 dental emergency treatment. Age ranged from 0 to 3 years old (average of 1.8 years). RESULTS: Treatment duration was from 10 to 35 minutes (average of 16.7 minutes). Average duration of sedation was 25.5 minutes ranging from 15 to 45 minutes. CONCLUSIONS: It has advantages to use nasal cannula for sevoflurane deep sedation rather than conventional intubation; saves time and secures good operation field. PMID- 28879254 TI - Protective dental splint for oroendotracheal intubation: experience of 202 cases. AB - BACKGROUND: Dental injury as a result of oroendotracheal intubation during general anesthesia is very common. We report our experiences of using mouthguard to prevent dental injury during intubation based on our protocol. METHODS: This retrospective study enrolled patients referred for preanesthetic evaluation, those patients with a history of any of the dental treatments to their anterior teeth listed on our fabrication protocol from January 1, 2009 to June 30, 2010. RESULTS: No cases of dental trauma during oroendotracheal intubation were reported among the 202 patients who used a protective device. 66% of the patients had risk factors for hard tissue damage aged 10-40 years. At the ages of 40-70 years, the incidence of risk group for periodontal damage was higher. CONCLUSIONS: Preanesthetic consultation was effective for preventing dental injury, so preanesthetic questionnaire and proper dental consultation would be helpful. PMID- 28879255 TI - Factor XI deficiency and orthognathic surgery: a case report on anesthesia management. AB - Factor XI deficiency (Hemophilia C) is a very rare autosomal recessive bleeding disorder. Patients with factor XI deficiency do not typically show any spontaneous bleeding or specific symptoms. Sometimes those who have this disorder are identified during special situations such as trauma or surgery. Orthognathic surgery is particularly associated with a high bleeding risk. Therefore, great care must be taken when treating patients with bleeding disorders such as factor XI deficiency. There are a few reports that address the management of patients with bleeding disorders during orthognathic surgery. The current report describes a patient with factor XI deficiency who underwent Le Fort I osteotomy together with bilateral sagittal split osteotomy. The patient's condition was assessed using both rotation thromboelastometry (ROTEMTM) and noninvasive measurements of total hemoglobin (SpHb) using Masimo Radical 7 (Masimo Co. CA, USA). PMID- 28879256 TI - Acute mediastinitis secondary to delayed vascular injury by a central venous catheter and total parenteral nutrition. AB - Vascular injury caused by a central venous catheter (CVC) has been reported to be a rare complication, especially delayed vascular injury due to CVC has a few cases and it can be fatal because of delayed recognition and more serious complications. A 59-year-old woman with no available medical history was admitted for treatment of ovarian cancer. For the surgery, a triple-lumen CVC was placed through the left subclavian vein. Parenteral nutrition through the CVC was used for postoperative nutritional management in the first postoperative day. On the sixth postoperative day (POD), the patient suddenly complained of dyspnea. The CT revealed bilateral pleural effusion and irregular soft tissue density and air bubble in anterior mediastinum suggesting migration of the distal portion of the CVC into the anterior mediastium. In the intensive care unit (ICU) bilateral thoracentesis and percutaneous drainage were performed. She was discharged from the ICU in 3 days later and transferred to the general ward. This case emphasizes the possibility of the delayed vascular injury related to CVC and some strategies for prevention of vascular injury. PMID- 28879257 TI - The effect of stellate ganglion block on the atypical facial pain. AB - Atypical facial pain (AFP) is a type of facial pain which does not fulfill any other diagnosis. It has several features such as no objective signs, no obvious explanation of the cause and poor response to treatments. We report a case of a female patient with AFP on the left maxillary area. The pain was increased by cold innocuous stimulation and thermography showed that the temperature on the painful area was significantly decreased. The pain was successfully alleviated by stellate ganglion block (SGB). Therefore, SGB can be effectively used to treat AFP. PMID- 28879258 TI - Considerations for submucosal midazolam administration in combination with oral and inhaled medications for sedation of pediatric dental patients. AB - Sedation allows patients to maintain their airway independently and respond appropriately to physical stimulation and verbal command while maintaining a minimum depressed level of consciousness. Drugs commonly used for sedation of pediatric dental patients include a combination of chloral hydrate, hydroxyzine, and nitrous oxide-oxygen. Midazolam is a benzodiazepine and currently one of the most commonly used intravenous sedative agents. It can be easily titrated to provide a wide range of sedation, from conscious sedation to deep sedation, and exhibits a wide safety margin without severe respiratory and circulatory depression. At an appropriate dose, it also decreases patient anxiety and induces amnesia. We found that the submucosal administration of midazolam combined with chloral hydrate provided increased sedative effects and decreased the postoperative vomiting response compared with conventional chloral hydrate administration, with no significant difference in physiological responses. The depth of sedation can be titrated using this technique. PMID- 28879260 TI - Advantages of anterior inferior alveolar nerve block with felypressin propitocaine over conventional epinephrine-lidocaine: an efficacy and safety study. AB - BACKGROUND: Conventional anesthetic nerve block injections into the mandibular foramen risk causing nerve damage. This study aimed to compare the efficacy and safety of the anterior technique (AT) of inferior alveolar nerve block using felypressin-propitocaine with a conventional nerve block technique (CT) using epinephrine and lidocaine for anesthesia via the mandibular foramen. METHODS: Forty healthy university students with no recent dental work were recruited as subjects and assigned to two groups: right side CT or right side AT. Anesthesia was evaluated in terms of success rate, duration of action, and injection pain. These parameters were assessed at the first incisor, premolar, and molar, 60 min after injection. Chi-square and unpaired t-tests were used for statistical comparisons, with a P value of < 0.05 designating significance. RESULTS: The two nerve block techniques generated comparable success rates for the right mandible, with rates of 65% (CT) and 60% (AT) at both the first molar and premolar, and rates of 60% (CT) and 50% (AT) at the lateral incisor. The duration of anesthesia using the CT was 233 +/- 37 min, which was approximately 40 min shorter than using the AT. This difference was statistically significant (P < 0.05). Injection pain using the AT was rated as milder compared with the CT. This difference was also statistically significant (P < 0.05). CONCLUSIONS: The AT is no less successful than the CT for inducing anesthesia, and has the added benefits of a significantly longer duration of action and significantly less pain. PMID- 28879259 TI - Dental fear & anxiety and dental pain in children and adolescents; a systemic review. AB - BACKGROUND: There are few previous studies investigating the relationship of dental fear and anxiety (DFA) with dental pain among children and adolescents. To address this issue, we examined the literature published between November 1873 and May 2015 to evaluate the prevalence of DFA and dental pain among children and adolescents, and their relationships with age and sex. METHODS: We performed a broad search of the PubMed database using 3 combinations of the search terms dental fear, anxiety, and dental pain and prevalence. A large proportion of the identified articles could not be used for the review due to inadequate end points or measures, or because of poor study design. Thirty-two papers of acceptable quality were identified and reviewed. RESULTS: We found that the prevalence of DFA was estimated to be 10%, with a decrease in prevalence with age. It was more frequently seen in girls, and was related to dental pain. CONCLUSIONS: We concluded that dental fear, anxiety, and pain are common, and several psychological factors are associated with their development. In order to better understand these relationships, further clinical evaluations and studies are required. PMID- 28879261 TI - The efficacy of an elevated concentration of lidocaine HCl in impacted lower third molar surgery. AB - BACKGROUND: There have been few studies on the effect of an elevated concentration of lidocaine hydrochloride in the surgical removal of an impacted lower third molar. This study aimed to examine the efficacy of 4% lidocaine along with 1:100,000 epinephrine compared to 2% lidocaine along with 1:100,000 epinephrine as inferior alveolar nerve block for the removal of an impacted lower third molar. METHODS: This single-blind study involved 31 healthy patients (mean age: 23 y; range: 19-33 y) with symmetrically impacted lower third molars as observed on panoramic radiographs. Volunteers required 2 surgical interventions by the same surgeon with a 3-week washout period. The volunteers were assigned either 4% lidocaine with 1:100,000 epinephrine or 2% lidocaine with 1:100,000 epinephrine as local anesthetic during each operation. RESULTS: We recorded the time of administration, need for additional anesthetic administration, total volume of anesthetic used. We found that the patient's preference for either of the 2 types of local anesthetic were significantly different (P < 0.05). However, the extent of pulpal anesthesia, surgical duration, and duration of soft tissue anesthesia were not significantly different. CONCLUSIONS: Our study suggested that inferior alveolar nerve block using 4% lidocaine HCl with 1:100,000 epinephrine as a local anesthetic was clinically more effective than that using 2% lidocaine HCl with 1:100,000 epinephrine; the surgical duration was not affected, and no clinically adverse effects were encountered. PMID- 28879262 TI - Emergency response team activation in the outpatient clinic of a single dental teaching hospital in Korea: a retrospective study of 10 years' records. AB - BACKGROUND: To prepare for possible emergency situations during dental treatment, it is helpful to know how often and what kinds of emergencies may arise. This study set out to evaluate the incidences, causes, treatments, and outcomes of emergency situations in the outpatient clinic of a dental teaching hospital in Korea. METHODS: We retrospectively reviewed the records of patients who had experienced an emergency situation and emergency response team activated in a selected outpatient clinic between November 2004 and November 2013. Specific information about the emergency cases was collected, including the patient characteristics and the frequency, types, treatments, and outcomes of the emergency situations. RESULTS: We identified 35 instances of emergency situations in 2,890,424 patients (incidence = 0.012 per 10,000 outpatients). The number of cases was as follows: 10 (28.6%) in the Department of Periodontics, 10 (28.6%) in the Department of Oral and Maxillofacial Surgery, 6 (17.1%) in the Department of Oral and Maxillofacial Radiology, 4 (11.4%) in the Department of Prosthodontics, 2 (5.7%) in the Department of Conservative Dentistry, 2 (5.7%) in the Department of Pediatric Dentistry, and 1 (2.9%) in the Department of Orthodontics. Three (8.6%) of the emergency situations arose before treatment, 22 (62.9%) during treatment, 7 (20.0%) after treatment, and 2 (5.7%) in a patient's guardian. CONCLUSIONS: In accordance with the growing elderly population and more aggressive dental procedures, the number of emergency situations may increase in the future. We recommend that clinicians keep in mind airway management and the active control of emergency situations. PMID- 28879263 TI - Reliability and validity of the Korean version of the Dental Fear Survey. AB - BACKGROUND: Many people experience varying levels of discomfort when confronted with the prospect of dental treatment. Dental treatment can be a traumatic experience, especially for children and adolescents with dental anxiety. In this age group, dental fear causes a significant problem in dental management and has been related to severe dental caries and dental pain. The Dental Fear Survey ( DFS ) is the most widely used measure of dental fear. This study was undertaken to develop the Korean version of the DFS ( K-DFS ) and test its reliability and validity. METHODS: The K-DFS, which uses projective techniques to measure children's and adolescents' dental fear, was developed. The DFS was translated into Korean and participants were selected via convenience sampling. Reliability and validity were tested using data from a sample of 813 middle school students in Gyeonggi Province, selected from the Self questionnaire survey. The K-DFS was administered twice to 102 adolescents aged 12-15 years. RESULTS: The K-DFS had high internal consistency reliability (99.1%) but low test-retest reliability. CONCLUSIONS: The results indicate that the Korean versions of the DFS have good internal consistency reliabilities and test-retest validities. However, we need to further examine the test-retest reliability of the K-DFS and replicate the current study in different samples covering various age groups. PMID- 28879264 TI - Diplopia after inferior alveolar nerve block: case report and related physiology. AB - Although inferior alveolar nerve block is one of the most common procedures performed at dental clinics, complications or adverse effects can still occur. On rare occasions, ocular disturbances, such as diplopia, blurred vision, amaurosis, mydriasis, abnormal pupillary light reflex, retrobulbar pain, miosis, and enophthalmos, have also been reported after maxillary and mandibular anesthesia. Generally, these symptoms are temporary but they can be rather distressing to both patients and dental practitioners. Herein, we describe a case of diplopia caused by routine inferior alveolar nerve anesthesia, its related physiology, and management. PMID- 28879265 TI - The surgical retrieval of a broken dental needle: A case report. AB - One complication related to local anesthesia in the dental clinic is a broken needle. Although rare, a broken needle may be difficult to retrieve. Dental radiographs and 3D CT have been used in the past to confirm the location of a broken needle. We present the case of a broken needle, which was successfully removed using a careful, microscopic approach. PMID- 28879266 TI - Damage to the pilot balloon of the nasotracheal tube during orthognathic double jaw surgery: A case report. AB - In oral and maxillofacial surgery, many complications associated with nasotracheal tube can be caused. In this case, we reported ballooning tube damage of nasotracheal tube during orthognathic double-jaw surgery and replacement of tube through cut down of tube and tube exchange using airway exchange catheter. The patient scheduled for high Le Fort I osteotomy and bilateral sagittal split osteotomy was intubated nasotracheally with nasal endotracheal tube. During maxilla osteotomy, air bubble was detected in the oral blood. In spite of our repeated ballooning, the results were the same so we changed damaged tube using airway exchange catheter aseptically. Tiny and superficial cutting site was detected in the middle of pilot tube. As we know in our case, tiny injury impeded a normal airway management and prevention is important. PMID- 28879267 TI - The influence of mandibular skeletal characteristics on inferior alveolar nerve block anesthesia. AB - BACKGROUND: The inferior alveolar nerve block (IANB) is the most common anesthetic techniques in dentistry; however, its success rate is low. The purpose of this study was to determine the correlation between IANB failure and mandibular skeletal characteristics. METHODS: In total, 693 cases of lower third molar extraction (n = 575 patients) were examined in this study. The ratio of the condylar and coronoid distances from the mandibular foramen (condyle-coronoid ratio [CC ratio]) was calculated, and the mandibular skeleton was then classified as normal, retrognathic, or prognathic. The correlation between IANB failure and sex, treatment side, and the CC ratio was assessed. RESULTS: The IANB failure rates for normal, retrognathic, and prognathic mandibles were 7.3%, 14.5%, and 9.5%, respectively, and the failure rate was highest among those with a CC ratio < 0.8 (severe retrognathic mandible). The failure rate was significantly higher in the retrognathic group than in normal group (P = 0.019), and there was no statistically significant difference between the other two groups. CONCLUSIONS: IANB failure could be attributable, in part, to the skeletal characteristics of the mandible. In addition, the failure rate was found to be significantly higher in the retrognathic group. PMID- 28879268 TI - Hemodynamic changes associated with a novel concentration of lidocaine HCl for impacted lower third molar surgery. AB - BACKGROUND: The authors studied the hemodynamic effect influent by using the novel high concentration of lidocaine HCl for surgical removal impacted lower third molar. The objective of this study was to evaluate the hemodynamic change when using different concentrations of lidocaine in impacted lower third molar surgery. METHODS: Split mouth single blind study comprising 31 healthy patients with a mean age of 23 years (range 19-33 years). Subjects had symmetrically impacted lower third molars as observed on panoramic radiograph. Each participant required 2 surgical interventions by the same surgeon with a 3-week washout period washout period. The participants were alternately assigned one of two types of local anesthetic (left or right) for the first surgery, then the other type of anesthetic for the second surgery. One solution was 4% lidocaine with 1:100,000 epinephrine and the other was 2% lidocaine with 1:100,000 epinephrine. A standard IANB with 1.8 ml volume was used. Any requirement for additional anesthetic and patient pain intra-operation was recorded. Post-operatively, patient was instructed to fill in the patient report form for any adverse effect and local anesthetic preference in terms of intra-operative pain. This form was collected at the seven day follow up appointment. RESULTS: In the 4% lidocaine group, the heart rate increased during the first minute post-injection (P < 0.05). However, there was no significant change in arterial blood pressure during the operation. In the 2% lidocaine group, there was a significant increase in arterial blood pressure and heart rate in the first minute following injection for every procedure. When the hemodynamic changes in each group were compared, the 4% lidocaine group had significantly lower arterial blood pressure compared to the 2% lidocaine group following injection. Post-operatively, no adverse effects were observed by the operator and patient in either local anesthetic group. Patients reported less pain intra-operation in the 4% lidocaine group compared with the 2% lidocaine group (P < .05). CONCLUSIONS: Our results suggest that a 4% concentration of lidocaine HCl with 1:100,000 epinephrine has better clinical efficacy than 2% lidocaine HCl with 1:100,000 epinephrine when used for surgical extraction of lower third molars. Neither drug had any clinical adverse effects. PMID- 28879269 TI - Comparison of the hemodynamic effects of propofol and ketamine as anesthetic induction agents during high-dose remifentanil administration: a single-center retrospective comparative study. AB - BACKGROUND: We hypothesized that ketamine, when administered as the anesthetic induction agent, may prevent cardiovascular depression during high-dose remifentanil administration, unlike propofol. To test our hypothesis, we retrospectively compared the hemodynamic effects of ketamine, during high-dose remifentanil administration, with those of propofol. METHODS: Thirty-eight patients who underwent oral surgery at the Nagasaki University Hospital between April 2014 and June 2015 were included in this study. Anesthesia was induced by the following procedure: First, high-dose remifentanil (0.3-0.5 ug/kg/min) was administered 2-3 min before anesthesia induction; next, the anesthetic induction agent, either propofol (Group P) or ketamine (Group K), was administered. Mean arterial pressure (MAP) and the heart rate were recorded by the automated anesthesia recording system at four time points: immediately before the administration of high-dose remifentanil (T1); immediately before the administration of propofol or ketamine (T2); 2.5 min (T3), and 5 min (T4) after the administration of the anesthetic induction agent. RESULTS: In Group P, the MAP at T3 (75.7 +/- 15.5 mmHg, P = 0.0015) and T4 (68.3 +/- 12.5 mmHg, P < 0.001) were significantly lower than those at T1 (94.0 +/- 12.4 mmHg). However, the MAP values in the K group were very similar (P = 0.133) at all time points. The heart rates in both Groups P (P = 0.254) and K (P = 0.859) remained unchanged over time. CONCLUSIONS: We showed that ketamine, when administered as the anesthetic induction agent during high-dose remifentanil administration, prevents cardiovascular depression. PMID- 28879270 TI - Diagnostic value of procalcitonin and CRP in critically ill patients admitted with suspected sepsis. AB - BACKGROUND: Identifying early markers of septic complications can aid in the diagnosis and therapeutic management of hospitalized patients. In this study, the utility of procalcitonin (PCT) vs. C-reactive protein (CRP) as early markers of sepsis was compared. METHODS: A series of 2,697 consecutive blood samples was collected from hospitalized patients and serum PCT and CRP levels were measured. Patients were categorized by PCT level as follows: < 0.05 ng/ml, 0.05-0.49 ng/ml, 0.5-1.99 ng/ml, 2-9.99 ng/ml, and > 10 ng/ml. Diagnostic utility was analyzed by receiver operating characteristic (ROC) curves. RESULTS: Mean CRP levels varied among the five PCT categories at 0.31 +/- 2.87, 5.65 +/- 6.26, 13.78 +/- 8.01, 12.15 +/- 10.16, and 17.77 +/- 10.59, respectively (P < 0.05). PCT and CRP differed between positive and negative blood culture groups (PCT: 15.9 vs. 4.78 mg/dl; CRP: 11.5 ng/ml vs. 9.57 ng/ml; P < 0.05). The areas under the ROC curves (PCT, 95% confidence interval [CI]: 0.743, range: 0.698-0.789 at a threshold of 0.5 ng/ml; CRP, 95% CI: 0.540, range: 0.478-0.602 at a threshold of 8 mg/l) differed for PCT and CRP (P < 0.05). CONCLUSIONS: Therefore, PCT is a reliable marker for sepsis diagnosis and is more relevant than CRP in patients with a positive blood culture. These findings can be useful for the treatment of critically ill sepsis patients. PMID- 28879271 TI - Circadian variation of IV PCA use in patients after orthognathic surgery - a retrospective comparative study. AB - BACKGROUND: An understanding of the features of postoperative pain is essential for optimal analgesic dosing strategies. Using a visual analogue scale (VAS) score and patient controlled analgesia (PCA) infusion pattern analysis, an anesthesiologist can estimate when and how severely patients suffer from pain. Several reports have been published about circadian changes in the pain threshold. Postoperative pain was analyzed retrospectively in 250 patients who underwent orthognathic surgery. METHODS: A total of 250 patients were allocated into two groups according to the time of recovery from anesthesia. Patients in the early group (group E) recovered from anesthesia before 06:00 p.m. Patients in the late group (group L) recovered from anesthesia after 06:00 p.m. All patients received intravenous patient controlled analgesia (IV PCA) at the end of the operation. The VAS score of pain intensity was measured. Self-administration of bolus analgesic from the IV PCA device was also analyzed according to actual time and elapsed time. RESULTS: VAS scores showed no difference between the two groups except 36 hours after recovery from anesthesia. On POD1, there were two peaks for self-administration of bolus analgesics in group L and one peak in the morning for group E. Two peaks each in the morning and in the afternoon were shown in both groups on POD2. CONCLUSIONS: Diurnal variance in pain should be considered for effective dosing strategies. PMID- 28879272 TI - Immediate implant placement for schizophrenic patient with outpatient general anesthesia. AB - The difficult oral healthcare in intellectually disabled patients with poor behavioral control has led to debate over the cost-effectiveness and validity of implant treatment in these patients. The patient in the present report had schizophrenia that had led to poor oral care and severe dental caries in the full mouth. Tooth extraction and a removable prosthesis were planned, but the guardian wanted an implant procedure. Since the guardian showed strong will and cooperation with regard to the patient's oral healthcare, extraction followed by immediate implant placement was performed across two rounds of general anesthesia. Since the outcome appears successful, we present this case report. Immediate implant placement after tooth extraction requires fewer surgeries and rounds of general anesthesia, reduces horizontal bone resorption, and can achieve better esthetic results. Therefore, as long as a certain degree of oral care is possible, this can be a positive option for restoration of a partially edentulous mouth, even in intellectually disabled patients. PMID- 28879273 TI - Difficult airway management in a patient with a parapharyngeal tumor. AB - A 47-year-old man was referred to the operating room to treat a dentigenous cyst of the mandibular bone. Initial assessment of the airway was considered normal. However, after the induction of anesthesia, we could not intubate the patient due to severe distortion of the glottis. Fiberoptic bronchoscopy and video laryngoscopy were not effective. Intubation using a retrograde wire technique was successful. After the conclusion of surgery, the patient recovered without any complications. Subsequent magnetic resonance imaging of the patient's neck showed a 6 * 4 * 8.6 cm heterogeneous T2 hyperintense, T1 isointense well-enhancing mass in the prestyloid parapharyngeal space. The patient was scheduled for excision of the mass. We planned awake intubation with fiberoptic bronchoscopy. The procedure was successful and the patient recovered without complications. Anesthetic induction can decrease the muscle tone of the airway and increase airway distortion. Therefore, careful airway assessment is necessary. PMID- 28879274 TI - Takotsubo cardiomyopathy in a patient with oral cancer. AB - A patient with squamous cell carcinoma on the left mandible presented with symptoms similar to acute coronary syndrome just after surgery. The exact etiology was unclear, but following transthoracic echocardiogram, takotsubo cardiomyopathy was diagnosed. This is a rare, acute, and reversible form of heart failure, and the patient recovered completely within weeks. Related risk factors are believed to include extended surgery times and extended time under general anesthesia. Early recognition, followed by postoperative control of pain and anxiety are crucial to patient recovery. PMID- 28879275 TI - Dental treatment of a patient with long QT syndrome under moderate sedation with target-controlled infusion of propofol. AB - Long QT syndrome (LQTs) is a rare congenital disorder of the heart's electrical activity. Patients with LQTs are at increased risk of developing fatal ventricular arrhythmias. Elevated levels of sympathetic stimulation can exacerbate this risk. Successful behavior management is indispensable in the treatment of patients with LQTs. However, many drugs involved in pharmacologic behavior management are known to adversely affect the QT interval. Therefore, careful selection of a sedative drug is essential in avoiding such incidences. A 10-year-old boy with a known diagnosis of LQTs required restorative treatment due to dental caries at the permanent molar. He required sedation since treatment was painful and dental phobia can trigger sympathetic stimulation, creating a dangerous situation for patients with LQTs. Therefore, the treatment was performed over two sessions under moderate sedation involving propofol combined with nitrous oxide. Restorative treatment was successful without any complications under sedation with a target-controlled infusion (TCI) of propofol. There was no significant QT prolongation during pulpal treatment. Propofol TCI may be a good candidate for sedation in patients with LQTs. PMID- 28879277 TI - Full mouth rehabilitation of a patient with Sturge-Weber syndrome using a mixture of general and sedative anesthesia. AB - Issues related to the control of seizures and bleeding, as well as behavioral management due to mental retardation, render dental treatment less accessible or impossible for patients with Sturge-Weber syndrome (SWS). A 41-year-old man with SWS visited a dental clinic for rehabilitation of missing dentition. A bilateral port-wine facial nevus and intraoral hemangiomatous swollen lesion of the left maxillary and mandibular gingivae, mucosa, and lips were noted. The patient exhibited extreme anxiety immediately after injection of a local anesthetic and required various dental treatments to be performed over multiple visits. Therefore, full-mouth rehabilitation over two visits with general anesthesia and two visits with target-controlled intravenous infusion of a sedative anesthesia were planned. Despite concerns regarding seizure control, bleeding control, and airway management, no specific complications occurred during the treatments, and the patient was satisfied with the results. PMID- 28879276 TI - Difficult intubation using intubating laryngeal mask airway in conjunction with a fiber optic bronchoscope. AB - When anesthesiologists encounter conditions in which intubation is not possible using a conventional direct laryngoscope, they can consider using other available techniques and devices such as fiber optic bronchoscope (FOB)-guided intubation, a laryngeal mask airway (LMA), intubating LMA (ILMA), a light wand, and the Combitube. FOB-guided intubation is frequently utilized in predicted difficult airway cases and is generally performed when the patient is awake to enable easier access to the trachea. An LMA can be introduced to ventilate the patient with relative ease, while an ILMA can be used for definite endotracheal intubation. However, occasionally, an endotracheal tube (ETT) cannot pass through the larynx, despite successful introduction of a FOB into the trachea and placement of an ILMA by the anesthesiologist. Therefore, we initially introduced an ILMA for emergent ventilation, followed by successful insertion of an ETT under FOB guidance. In this report, we describe three cases of difficult intubation using a FOB and ILMA combination approach. PMID- 28879278 TI - Blind nasal intubation as an alternative to difficult intubation approaches. AB - Airway difficulties are a major concern for anesthesiologists. Even though fiberoptic intubation is the generally accepted method for management of difficult airways, it is not without disadvantages-requires patient cooperation, and cannot be performed on soiled airway or upper airways with pre-existing narrowing pathology. Additionally, fiberoptic bronchoscopy is not available at every medical institution. In this case, we encountered difficult airway management in a 71-year-old man with a high Mallampati grade and a thick neck who had undergone urologic surgery. Several attempts, including a bronchoscope-guided intubation, were unsuccessful. Finally, blind nasal intubation was successful while the patient's neck was flexed and the tracheal cartilage was gently pressed down. We suggest that blind nasal intubation is a helpful alternative in difficult airway management and it can be a lifesaving technique in emergencies. Additionally, its simplicity makes it a less expensive option when advanced airway technology (fiberoptic bronchoscopy) is unavailable. PMID- 28879279 TI - Clinical considerations in the use of forced-air warming blankets during orthognathic surgery to avoid postanesthetic shivering. AB - BACKGROUND: During head and neck surgery including orthognathic surgery, mild intraoperative hypothermia occurs frequently. Hypothermia is associated with postanesthetic shivering, which may increase the risk of other postoperative complications. To improve intraoperative thermoregulation, devices such as forced air warming blankets can be applied. This study aimed to evaluate the effect of supplemental forced-air warming blankets in preventing postanesthetic shivering. METHODS: This retrospective study included 113 patients who underwent orthognathic surgery between March and September 2015. According to the active warming method utilized during surgery, patients were divided into two groups: Group W (n = 55), circulating-water mattress; and Group F (n = 58), circulating water mattress and forced-air warming blanket. Surgical notes and anesthesia and recovery room records were evaluated. RESULTS: Initial axillary temperatures did not significantly differ between groups (Group W = 35.9 +/- 0.7C, Group F = 35.8 +/- 0.6C). However, at the end of surgery, the temperatures in Group W were significantly lower than those in Group F (35.2 +/- 0.5C and 36.2 +/- 0.5C, respectively, P = 0.04). The average body temperatures in Groups W and F were, respectively, 35.9 +/- 0.5C and 36.2 +/- 0.5C (P = 0.0001). In Group W, 24 patients (43.6%) experienced postanesthetic shivering, while in Group F, only 12 (20.7%) patients required treatment for postanesthetic shivering (P = 0.009, odds ratio = 0.333, 95% confidence interval: 0.147-0.772). CONCLUSIONS: Additional use of forced-air warming blankets in orthognathic surgery was superior in maintaining normothermia and reduced the incidence of postanesthetic shivering. PMID- 28879280 TI - Articaine (4%) with epinephrine (1:100,000 or 1:200,000) in inferior alveolar nerve block: Effects on the vital signs and onset, and duration of anesthesia. AB - BACKGROUND: This prospective, randomized, double-blind, clinical study was conducted to compare the effects of 4% articaine with 1:100,000 epinephrine (A100) and 4% articaine with 1:200,000 epinephrine (A200) on the vital signs and onset and duration of anesthesia in an inferior alveolar nerve block (IANB). METHODS: In the first appointment, an IANB was performed by injecting A100 or A200 in 1 side of the mouth (right or left) randomly in patients referred for extraction of both their first mandibular molars. In the second appointment, the protocol was repeated and the other anesthetic solution was injected in the side that had not received the block in the previous session. Systolic and diastolic blood pressures (SBP and DBP) and pulse rate were measured during and 5 min after the injection. The onset and duration of anesthesia were also evaluated. Data were analyzed using t-test and Mann-Whitney U-test, and p-value was set at 0.05. RESULTS: SBP and pulse rate changes were slightly more with A100; however, DBP changes were more with A200, although the differences were not significant (P > 0.05). There were no statistically significant differences in the parameters evaluated in this study. The onset and duration of anesthesia, and the changes in SBP, DBP, and pulse rate during and 5 min after the injection were the same in both the groups. CONCLUSIONS: For an IANB, A200 and A100 were equally efficient and successful in producing the block. Epinephrine concentration did not influence the effects of 4% articaine. PMID- 28879281 TI - Endotracheal intubation by inexperienced trainees using the Clarus Video System: learning curve and orodental trauma perspectives. AB - BACKGROUND: The ideal alternative airway device should be intuitive to use, yielding proficiency after only a few trials. The Clarus Video System (CVS) is a novel optical stylet with a semi-rigid tip; however, the learning curve and associated orodental trauma are poorly understood. METHODS: Two novice practitioners with no CVS experience performed 30 intubations each. Each trial was divided into learning (first 10 intubations) and standard phases (remaining 20 intubations). Total time to achieve successful intubation, number of intubation attempts, ease of use, and orodental trauma were recorded. RESULTS: Intubation was successful in all patients. In 51 patients (85%), intubation was accomplished in the first attempt. Nine patients required two or three intubation attempts; six were with the first 10 patients. Learning and standard phases differed significantly in terms of success at first attempt, number of attempts, and intubation time (70% vs. 93%, 1.4 +/- 0.7 vs. 1.1 +/- 0.3, and 71.4 +/- 92.3 s vs. 24.6 +/- 21.9 s, respectively). The first five patients required longer intubation times than the subsequent five patients (106.8 +/- 120.3 s vs. 36.0 +/ 26.8 s); however, the number of attempts was similar. Sequential subgroups of five patients in the standard phase did not differ in the number of attempts or intubation time. Dental trauma, lip laceration, or mucosal bleeding were absent. CONCLUSIONS: Ten intubations are sufficient to learn CVS utilization properly without causing any orodental trauma. A relatively small number of experiences are required in the learning curve compared with other devices. PMID- 28879282 TI - A retrospective study of deep sedation with concomitant administration of sedative agents in children undergoing surgical removal of a mesiodens. AB - BACKGROUND: Pediatric dentists face challenges when young patients require a mesiodens extraction. General anesthesia may be a burden to the child as well as the parent due to dental fears and costs. The aim of this study was to evaluate oral and intravenous sedation in the outpatient setting as a safe and effective means of managing patients who require a mesiodens extraction. METHODS: Records were reviewed retrospectively to find patients who underwent a mesiodens removal procedure from January 2013 to September 2014 in the Department of Pediatric Dentistry at Ajou University Hospital (Suwon, Gyeonggi-do, Republic of Korea). A total of 81 patients (62 male and 19 female) between 4 and 11 years of age (mean [+/- SD] 81.6 +/- 14.1 months) were studied, with a mean weight of 22.9 +/- 3.3 kg (16 kg to 30 kg). Vital signs, sedation drug dosage, and sedation time were studied. RESULTS: Mean doses of 63.7 +/- 2.5 mg/kg chloral hydrate and 1.36 +/- 0.22 mg/kg hydroxyzine were used for oral sedation. Nitrous oxide/oxygen was administrated for 40.0 +/- 2.1 min. The mean dose of midazolam administered intravenously was 0.14 +/- 0.06 mg/kg (2.38 +/- 0.97 times). In all cases, the mesiodens was removed successfully. CONCLUSIONS: Intravenous sedation combined with oral sedation and nitrous oxide/oxygen inhalation can be an alternative to general anesthesia when administrated and monitored properly. PMID- 28879283 TI - Optimal effect-site concentration of remifentanil for minimizing cardiovascular changes caused by fiberoptic nasotracheal intubation. AB - BACKGROUND: Endotracheal intubation induces clinically adverse cardiovascular changes. Various pharmacological strategies for controlling these responses have been suggested with opioids being widely administered. In this study, the optimal effect-site concentration (Ce) of remifentanil for minimizing hemodynamic responses to fiberoptic nasotracheal intubation was evaluated. METHODS: Thirty patients, aged 18-63 years, scheduled for elective surgery were included. Anesthesia was induced with a propofol and remifentanil infusion via target controlled infusion (TCI). Remifentanil infusion was initiated at 3.0 ng/mL, and the response of each patient determined the Ce of remifentanil for the next patient by the Dixon up-and-down method at an interval of 0.5 ng/mL. Rocuronium was administered after propofol and remifentanil reached their preset Ce; 90 seconds later fiberoptic nasotracheal intubation was initiated. Non-invasive blood pressure and heart rate (HR) were measured at pre-induction, the time Ce was reached, immediately before and after intubation, and at 1 and 3 minutes after intubation. The up-and-down criteria comprised a 20% change in mean blood pressure and HR between just prior to intubation and 1 minute after intubation. RESULTS: The median effective effect-site concentration (EC50) of remifentanil was 3.11 +/- 0.38 ng/mL by the Dixon's up-and-down method. From the probit analysis, the EC50 of remifentanil was 3.43 ng/mL (95% confidence interval, 2.90 4.06 ng/mL). In PAVA, the EC50 and EC95 of remifentanil were 3.57 ng/mL (95% CI, 2.95-3.89) and 4.35 ng/mL (95% CI, 3.93-4.45). No remifentanil-related complications were observed. CONCLUSIONS: The EC50 of remifentanil for minimizing the cardiovascular changes and side effects associated with fiberoptic nasotracheal intubation was 3.11-3.43 ng/mL during propofol TCI anesthesia with a Ce of 4 ug/mL. PMID- 28879284 TI - Hemolysis of irradiated leukoreduced red blood cells during rapid warming: An in vitro experimental study. AB - BACKGROUND: Although water chambers are often used as surrogate blood-warming devices to facilitate rapid warming of red blood cells (RBCs), these cells may be damaged if overheated. Moreover, filtered and irradiated RBCs may be damaged during the warming process, resulting in excessive hemolysis and extracellular potassium release. METHODS: Using hand-held syringes, each unit of irradiated and leukocyte-filtered RBCs was rapidly passed through a water chamber set to different temperatures (baseline before blood warming, 50C, 60C, and 70C). The resulting plasma potassium and free hemoglobin levels were then measured. RESULTS: Warming RBCs to 60C and 70C induced significant increases in free hemoglobin (median [interquartile ranges] = 60.5 mg/dl [34.9-101.4] and 570.2 mg/dl [115.6-2289.7], respectively). Potassium levels after warming to 70C (31.4 +/- 7.6 mEq/L) were significantly higher compared with baseline (29.7 +/- 7.1 mEq/L; P = 0.029). Potassium levels were significantly correlated with storage duration after warming to 50C and 60C (r = 0.450 and P = 0.001; r = 0.351 and P = 0.015, respectively). CONCLUSIONS: Rapid warming of irradiated leukoreduced RBCs to 50C may not further increase the extracellular release of hemoglobin or potassium. However, irradiated leukoreduced RBCs that have been in storage for long periods of time and contain higher levels of potassium should be infused with caution. PMID- 28879285 TI - Combitube insertion in the situation of acute airway obstruction after extubation in patients underwent two-jaw surgery. AB - The Combitube is an emergency airway-maintaining device, which can supply oxygen to dyspneic patients in emergency situations following two-jaw surgery. These patients experience difficulty in opening the mouth or have a partially obstructed airway caused by edema or hematoma in the oral cavity. As such, they cannot maintain the normal airway. The use of a Combitube may be favorable compared to the laryngeal mask airway because it is a thin and relatively resilient tube. A healthy 24-year-old man was dyspneic after extubation. Oxygen saturation fell below 90% despite untying the bimaxillary fixation and ambubagging. The opening of the mouth was narrow; thus, emergency airway maintenance was gained by insertion of a Combitube. The following day, a facial computer tomography revealed that the airway space narrowing was severe compared to its pre-operational state. After the swelling subsided, the patient was successfully extubated without complications. PMID- 28879286 TI - Management of traumatic neuralgia in a patient with the extracted teeth and alveoloplasty: a case report. AB - A majority of patients who sustain injuries to the peripheral sensory nerves of the face and jaws experience a slow but gradual return of sensation that is functional and tolerable, if not the same as before the injuries. However, long term effects of such injuries are aggravating for many patients, and a few patients experience significant suffering. In some of these patients, posttraumatic symptoms become pathological and are painful. The predominant painful components are (1) numbing anesthesia dolorosa pain, (2) triggered neuralgiaform pain, (3) burning and aching causalgiaform pain, and (4) phantom pain. This is a case report of conservative management of traumatic neuralgia and neuritis as part of posttraumatic pain syndromes in geriatric patients who have undergone the teeth extraction and alveoloplasty. PMID- 28879287 TI - Treatment of herpes zoster with ultrasound-guided superficial cervical plexus block. AB - Herpes zoster most commonly occurs in elderly patients, and usually affects sensory neurons. Therefore, its characteristic symptoms are segmental pain, itching, and sensory changes in the affected areas. A 71-yr-old woman experienced painful herpetic rash on the right cervical 2-4 dermatomes for 16 days. Two days after the onset of the rash, she was diagnosed with herpes zoster, and prescribed 250 mg famciclovir three times a day for 7 days, pregabalin 150 mg twice a day, and tramadol 150 mg once a day for 14 days, by a dermatologist. Despite medication, her pain was rated at an intensity of 6/10 on the numeric rating scale. In addition, she complained of severe itching sensation on the affected dermatomes. Superficial cervical plexus block (SCPB) was performed at the right C4 level with 15 ml 0.5% lidocaine plus triamcinolone 30 mg. Five days after the procedure, pain and itching completely disappeared. SCPB may be an effective option for the treatment of acute pain and itching arising from herpes zoster, and for the prevention of postherpetic neuralgia. PMID- 28879288 TI - An 18-year-old patient with Prader-Willi syndrome: a case report on dental management under sedation and general anesthesia. AB - Prader-Willi syndrome (PWS) is a rare genetic disorder reported rarely in dentistry. Dental practitioners should know the features of PWS because affected patients have a variety of dental symptoms. The current report describes a case of PWS. An 18-year-old male patient presented with traumatic injuries. Initial emergency treatments were performed under sedation, and further treatments were conducted under general anesthesia. After adequate healing, periodic follow-up and dietary management according to the patient's age and nutritional phase were recommended. Dental management of PWS patients consists of active preventive measures in addition to dietary consultation according to age and nutritional phase. PMID- 28879289 TI - Diagnosis and treatment of abnormal dental pain. AB - Most dental pain is caused by an organic problem such as dental caries, periodontitis, pulpitis, or trauma. Diagnosis and treatment of these symptoms are relatively straightforward. However, patients often also complain of abnormal dental pain that has a non-dental origin, whose diagnosis is challenging. Such abnormal dental pain can be categorized on the basis of its cause as referred pain, neuromodulatory pain, and neuropathic pain. When it is difficult to diagnose a patient's dental pain, these potential alternate causes should be considered. In this clinical review, we have presented a case of referred pain from the digastric muscle (Patient 1), of pulpectomized (Patient 2), and of pulpectomized pain (Patient 3) to illustrate referred, neuromodulatory, and neuropathic pain, respectively. The Patient 1 was advised muscle stretching and gentle massage of the trigger points, as well as pain relief using a nonsteroidal anti-inflammatory and the tricyclic antidepressant amitriptyline. The pain in Patient 2 was relieved completely by the tricyclic antidepressant amitriptyline. In Patient 3, the pain was controlled using either a continuous drip infusion of adenosine triphosphate or intravenous Mg2+ and lidocaine administered every 2 weeks. In each case of abnormal dental pain, the patient's diagnostic chart was used (Fig.2 and 3). Pain was satisfactorily relieved in all cases. PMID- 28879290 TI - Pediatric advanced life support and sedation of pediatric dental patients. AB - Programs provided by the Korea Association of Cardiopulmonary Resuscitation include Basic Life Support (BLS), Advanced Cardiac Life Support (ACLS), Pediatric Advanced Life Support (PALS), and Korean Advanced Life Support (KALS). However, programs pertinent to dental care are lacking. Since 2015, related organizations have been attempting to develop a Dental Advanced Life Support (DALS) program, which can meet the needs of the dental environment. Generally, for initial management of emergency situations, basic life support is most important. However, emergencies in young children mostly involve breathing. Therefore, physicians who treat pediatric dental patients should learn PALS. It is necessary for the physician to regularly renew training every two years to be able to immediately implement professional skills in emergency situations. In order to manage emergency situations in the pediatric dental clinic, respiratory support is most important. Therefore, mastering professional PALS, which includes respiratory care and core cases, particularly upper airway obstruction and respiratory depression caused by a respiratory control problem, would be highly desirable for a physician who treats pediatric dental patients. Regular training and renewal training every two years is absolutely necessary to be able to immediately implement professional skills in emergency situations. PMID- 28879291 TI - Antimicrobial effect of topical local anesthetic spray on oral microflora. AB - BACKGROUND: To evaluate the antimicrobial activity of lidocaine (LD) topical anesthetic spray against oral microflora. METHODS: Antimicrobial effects of 10% LD spray were assessed against six bacterial cultures obtained from volunteers: Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Streptococcus salivarius, Streptococcus pyogenes, and Streptococcus sanguinis. The filter papers contained 50-ul LD, brain heart infusion (BHI) broth, or 0.2% chlorhexidine. Papers were placed on the cultured blood plates for 1-3 min. After the papers were removed, plates were incubated for 24 h. Bacterial growth on the contact areas was recorded as the antimicrobial score. The split mouth technique was use in for sample collection in clinical study. Filter papers soaked with either BHI broth or LD were placed on the right or left buccal mucosa for 1 min, and replaced with other papers to imprint biofilms onto the contact areas. Papers were placed on blood plates, incubated for 24 h, and antimicrobial scores were determined. Experiments were conducted for 2- and 3-min exposure times with a 1 day washout period. RESULTS: LD exhibited bactericidal effects against E. coli, S. sanguinis, and S. salivarius within 1 min but displayed no effect against S. aureus, E. faecalis, and S. pyogenes. The antimicrobial effect of LD on oral microflora depended upon exposure time, similar to the results obtained from the clinical study (P < 0.05). LD showed 60-95% biofilm reduction on buccal mucosa. CONCLUSIONS: Antimicrobial activity of 10% LD topical anesthetic spray was increased by exposure time. The 3 min application reduced oral microflora in the buccal mucosa. PMID- 28879292 TI - Intranasal administration of dexmedetomidine (DEX) as a premedication for pediatric patients undergoing general anesthesia for dental treatment. AB - BACKGROUND: The most important reason for pre-operative administration of medication is to reduce anxiety. Alleviation of fear and anxiety about surgery enables patients to remain comfortable during treatment. Dexmedetomidine (DEX) is a fast-acting drug that is used as a premedication in different circumstances because it has sedative and anti-anxiolytic effects, and stable hemodynamics. It also has the advantage of intranasal administration. The aim of this study was to investigate the effects and hemodynamic stability of DEX by retrospectively analyzing cases in which DEX was administered nasally as a premedication. METHODS: Ten patients treated at Dankook University Dental Hospital, recruited between February and April 2015, received intranasal delivery of 2 ug/kg DEX, 30 minutes prior to general anesthesia. Anesthesia records of anxiety, blood pressure, respiration, pulse, estimated arterial oxygen saturation (SpO2), and partial pressure, or maximum concentration, of carbon dioxide (ETCO2) were analyzed. RESULTS: Administration of DEX prior to a general anesthetic effectively relieved anxiety. Respiratory depression, the most severe adverse effect of other sedatives, was not observed. Hemodynamic stability under general anesthesia was maintained during treatment and a reduction in emergence delirium was observed upon completion of treatment. CONCLUSIONS: Premedication administration of DEX is safe for pediatric patients undergoing dental treatment under general anesthesia. PMID- 28879293 TI - Study on the trends in Korean clinical practice guidelines development. AB - BACKGROUND: The definition of evidence-based clinical practice guidelines (CPGs) is "statements that are systematically developed to assist in the doctors' and patients' decision-making in certain situations." This study aims to establish the concept of evidence-based CPGs and investigate the development status to seek measures to apply evidence-based methods to CPG development for dental sedation in Korea. METHODS: The study conducted systematic searching methods based on evidence-based CPGs. Articles published between 1995 to 2015 were searched on a Korean database and the international database PubMed. The search was based on keywords related to four subjects (dentistry, clinical practice, guideline, recommendation). Two authors independently reviewed the searched articles to determine their analysis inclusion and the convergence stages, and to arrive at a conclusion through discussion. RESULTS: A total of 65 Korean CPGs were included. There were 51 medical guidelines, of which seven were dental and seven were Oriental medicine. CONCLUSIONS: As a basic direction for the development of evidence-based CPGs, this work suggests the following: increased awareness; consensus on the need to supply evidence-based development methods; education, computerization, and systematic observation of evidence-based CPG development methods; continuous research development and distribution of CPGs; and creation of a database for Korean clinical dentistry practice outcomes. PMID- 28879294 TI - Effects of propofol-induced autophagy against oxidative stress in human osteoblasts. AB - BACKGROUND: Oxidative stress occurs during the aging process and other conditions such as bone fracture, bone diseases, and osteoporosis, but the role of oxidative stress in bone remodeling is unknown. Propofol exerts antioxidant effects, but the mechanisms of propofol preconditioning on oxidative stress have not been fully explained. Therefore, the aim of this study was to evaluate the protective effects of propofol against H2O2-induced oxidative stress on a human fetal osteoblast (hFOB) cell line via activation of autophagy. METHODS: Cells were randomly divided into the following groups: control cells were incubated in normoxia (5% CO2, 21% O2, and 74% N2) without propofol. Hydrogen peroxide (H2O2) group cells were exposed to H2O2 (200 uM) for 2 h, propofol preconditioning (PPC)/H2O2 group cells were pretreated with propofol then exposed to H2O2, 3 methyladenine (3-MA)/PPC/H2O2 cells were pretreated with 3-MA (1 mM) and propofol, then were exposed to H2O2. Cell viability and apoptosis were evaluated. Osteoblast maturation was determined by assaying bone nodular mineralization. Expression levels of bone related proteins were determined by western blot. RESULTS: Cell viability and bone nodular mineralization were decreased significantly by H2O2, and this effect was rescued by propofol preconditioning. Propofol preconditioning effectively decreased H2O2-induced hFOB cell apoptosis. However, pretreatment with 3-MA inhibited the protective effect of propofol. In western blot analysis, propofol preconditioning increased protein levels of collagen type I, BMP-2, osterix, and TGF-beta1. CONCLUSIONS: This study suggests that propofol preconditioning has a protective effect on H2O2-induced hFOB cell death, which is mediated by autophagy activation. PMID- 28879295 TI - The use of laryngeal mask airway in dental treatment during sevoflurane deep sedation. AB - BACKGROUND: General anesthesia is frequently considered for pediatric patients, as they often find it difficult to cooperate and stay calm during administration of potentially painful treatments. Sedation can overcome these adversities; however, this is challenging while maintaining unobstructed airways. METHODS: The study involved 11 pediatric dental patients treated with LMA under deep sedation with sevoflurane, from 2011 through 2015. LMA size, sevoflurane concentration, and the vital signs of patients were assessed through a chart review. RESULTS: The age distribution of the patients ranged from 6 to 10 years old. A total of 3 patients underwent mesiodens extraction, while the remaining 8 underwent an surgically assisted orthodontic forced tooth eruption The average sedation period was approximately 45 minutes and the LMA size was 21/2. The sevoflurane concentration was maintained at 2% on average, and overall, the measurements of vital signs were within the normal range; the patients had an average blood pressure of 98/49 mmHg, breathing rate of 26 times/min, pulse frequency of 95 times/min, SpO2s level of 99 mmHg, and ETCO2 level of 41.2 mmHg. CONCLUSIONS: Deep sedation with sevoflurane coupled with LMA may be applied successfully in pediatric patients who undergo mesiodens extraction or a surgically assisted orthodontic forced tooth eruption. PMID- 28879296 TI - Dexmedetomidine intravenous sedation using a patient-controlled sedation infusion pump: a case report. AB - Dental treatment under sedation requires various sedation depths depending on the invasiveness of the procedure and patient drug sensitivity. Inappropriate sedation depth may cause patient discomfort or endangerment. For these reasons, patient-controlled sedation (PCS) pumps are commonly used. Patients are able to control the sedation depths themselves by pushing the demand button after the practitioner sets up the bolus dose and lock-out time. Dexmedetomidine is an alpha-2 adrenoreceptor agonist with sedative, analgesic, and anxiolytic properties. It has been widely used for sedation for its minimal respiratory depression; however, there are few studies on PCS using dexmedetomidine. This study assessed the applicability of dexmedetomidine to PCS. PMID- 28879297 TI - Displacement of deciduous tooth into hypopharynx due to endotracheal intubation. AB - Intubation may lead to several dental complications. Furthermore, a tooth damaged during intubation may be subsequently dislocated. In the present case, the upper primary incisor was avulsed during intubation and, unbeknownst to the anesthesiologist, displaced to the larynx. We report here on the findings and indicate appropriate treatment. Intubation for general anesthesia in children can result in tooth damage and/or dislocation of primary teeth with subsequent root resorption. Prevention is key, and thus it is critical to evaluate the patient's dental status before and after intubation. Furthermore, anesthesiologists and dentists should pay close attention to this risk to prevent any avulsed, dislocated, or otherwise displaced teeth from remaining undetected and subsequently causing serious complications. PMID- 28879298 TI - Deep sedation for dental treatment in a Down syndrome patient with Eisenmenger syndrome: A case report. AB - Eisenmenger syndrome (ES) is characterized by pulmonary arterial hypertension and right-to-left shunting. The signs and symptoms of ES include cyanosis, shortness of breath, fatigue, hemoptysis, and sudden death. In patients with ES, it is important that the systemic and pulmonary circulations be properly distributed and maintained. General dental treatment is not known to be particularly dangerous. To control pain and anxiety, local anesthetics without epinephrine are usually recommended. However, in cases of difficulty of cooperation, general anesthesia for dental treatment makes the condition worse. In the present case, intravenous deep sedation with propofol and remifentanil was administered for behavioral management during dental treatment successfully. PMID- 28879299 TI - Computer-controlled local anesthetic delivery for painless anesthesia: a literature review. AB - Local anesthesia is administered to reduce pain during dental treatments, but may itself cause pain and contribute to increased dental fear. Computer-controlled local anesthetic delivery (CCLAD) is one the method to reduce patient pain during local anesthesia; it is a device that slowly administers anesthetics by using a computerized device to control the injection speed. This literature review aims to provide an objective assessment of the usefulness of CCLAD for controlling pain by reviewing papers published to date that have used CCLAD. PMID- 28879300 TI - Current trends in intravenous sedative drugs for dental procedures. AB - Anxiety and phobia in dental procedures are common deterrents for patients visiting the dental care unit. For these individuals, procedural sedation may aid in completion of dental treatments. In most cases, the patients are conscious during sedation, thereby allowing spontaneous ventilation. Intravenous sedation (IVS) is widely used during dental treatment to relieve patient anxiety. IVS is the most effective route of administration to achieve this goal, but it requires advanced training, more than that provided during undergraduate education. During IVS, rapid onset, repetitive drug administration, easy titration, and rapid recovery from sedation can be achieved. However, conscious sedation during IVS can result in deep sedation that can cause respiratory and cardiovascular depression. Therefore, the characteristics of intravenous sedatives should be known. The purpose of this review is to discuss the characteristics and usage of intravenous sedatives currently used for dental procedures. PMID- 28879301 TI - The efficacy of dexamethasone injection on postoperative pain in lower third molar surgery. AB - BACKGROUND: Surgery on the lower impacted third molar usually involves trauma in the highly vascularized loose connective tissue area, leading to inflammatory sequelae including postoperative pain, swelling, and general oral dysfunction during the immediate post-operative phase. This study aimed to investigate the effectiveness of preoperative injection of a single dose of 8 mg dexamethasone for postoperative pain control in lower third molar surgery. METHODS: A controlled, randomized, split-mouth, prospective study involving lower third molar surgery was performed in 31 patients. The randomized sampling group was preoperatively injected, after local anesthesia, with a single dose of dexamethasone (8 mg in 2 ml) through the pterygomandibular space; 2 ml of normal saline (with no dexamethasone) was injected as a placebo. RESULTS: The pain VAS score was significantly different on the day of the operation compared to the first post-operative day (P = 0.00 and 0.01, respectively), but it was not significantly different on the third and seventh postoperative day between the control and study groups. There was a significant reduction in swelling on the second postoperative day, and a difference between the second postoperative day and baseline value in the study group (P < 0.05). Trismus was highly significantly different on the second postoperative day and between baseline and second postoperative day between the groups (P = 0.04 and 0.02, respectively). Descriptive statistics and independent-samples t- test were used to assess the significance of differences. CONCLUSIONS: Injection of 8 mg dexamethasone into the pterygomandibular space effectively reduced the postoperative pain and other postoperative sequalae. PMID- 28879302 TI - Identifying the more suitable nostril for nasotracheal intubation using radiographs. AB - BACKGROUND: One nostril must be selected for nasotracheal intubation. In some cases, structural anomalies within the nasal cavity hinder the insertion of the tube or complications, such as epistaxis, develop. This study examined the possibility of using radiography to select the nostril that would induce fewer complications. METHODS: Four hundred and five patients who underwent nasotracheal intubation under general anesthesia were studied. A 7.0-mm internal diameter nasal right angle endotracheal (RAE) tube and 6.5-mm internal diameter nasal RAE tube were inserted into men and women, respectively. Complications were considered to have developed in cases in which insertion of the tube into the nasal cavity failed or epistaxis occurred. The tube was inserted into the other nostril for insertion failures and hemostasis was performed in cases of epistaxis. The degree of nasal septal deviation was determined from posteroanterior skull radiographs or panoramic radiographs; the incidence of complications was compared depending on the direction of the septal deviation and the intubated nostril. RESULTS: The radiographs of 390 patients were readable; 94 had nasal septum deviation. The incidence of complications for cases without nasal septum deviation was 16.9%, that for cases in which the tube was inserted into the nostril on the opposite side of the deviation was 18.5%, and that for cases in which the tube was inserted into the nostril with the deviation was 35.0%, showing a high incidence of complications when intubation is performed through the nostril with septum deviation (chi-square test, P < 0.05 ). CONCLUSIONS: Although there were no differences in the incidence rates of complications between intubation through the left nostril and that through the right nostril, radiological findings indicated that incidence of complications significantly increased when the tube was inserted into the nostril with the septum deviation. PMID- 28879303 TI - Success rates of the first inferior alveolar nerve block administered by dental practitioners. AB - BACKGROUND: Inferior alveolar nerve block (IANB) of the mandible is commonly used in the oral cavity as an anesthetic technique for dental procedures. This study evaluated the success rate of the first IANB administered by dental practitioners. METHODS: Volunteer dental practitioners at Mahidol University who had never performed an INAB carried out 106 INAB procedures. The practitioners were divided into 12 groups with their advisors by randomized control trials. We recorded the success rate via pain visual analog scale (VAS) scores. RESULTS: A large percentage of the dental practitioners (85.26%) used the standard method to locate the anatomical landmarks, injecting the local anesthetic at the correct position, with the barrel of the syringe parallel to the occlusal plane of the mandibular teeth. Further, 68.42% of the dental practitioners injected the local anesthetic on the right side by using the left index finger for retraction. The onset time was approximately 0-5 mins for nearly half of the dental practitioners (47.37% for subjective onset and 43.16% for objective onset), while the duration of the IANB was approximately 240-300 minutes (36.84%) after the initiation of numbness. Moreover, the VAS pain scores were 2.5 +/- 1.85 and 2.1 +/- 1.8 while injecting and delivering local anesthesia, respectively. CONCLUSIONS: The only recorded factor that affected the success of the local anesthetic was the administering practitioner. This reinforces the notion that local anesthesia administration is a technique-sensitive procedure. PMID- 28879304 TI - Comparative study of analgesia with bupivacaine 0.25% versus 0.5% for third molar removal under general anesthesia. AB - BACKGROUND: The aim of this study was to compare the effectiveness and duration of action of two concentrations of bupivacaine with adrenaline for postoperative pain in patients undergoing surgical removal of four third molars under general anesthesia. METHODS: Sixty patients undergoing surgical removal of four wisdom teeth received bupivacaine 0.5% (n = 30) or 0.25% (n = 30). The severity of pain in the immediate recovery period and at 2 and 24 h after surgery was recorded using the visual analogue scale. Differences were assessed by box and whisper plot and the Student's t-test. RESULTS: The analgesic effects of the 0.25% and 0.5% doses were significantly different (P = 0.022) at 30 min after surgery but not after 2 and 24 h. The difference of mean of 0.25% and 0.5% was much higher after 0.5 h but less after 2 and 24 h. CONCLUSIONS: Bupivacaine 0.5% was statistically better for pain control during the immediate postoperative period, but there was no significant difference in pain control between the two dose strengths at 2 and 24 h after surgery. PMID- 28879305 TI - A survey of the intravenous sedation status in one provincial dental clinic center for the disabled in Korea. AB - BACKGROUND: The objective of the present study was to examine the status of patients who had received dental treatment under intravenous (IV) sedation at Chungnam Dental Clinic for the Disabled in Korea from its inception to the present time, and to review the analysis results. METHODS: Retrospective analysis was performed on 305 cases of patients who had received dental treatments under IV sedation between January 2011 and May 2016. The analysis examined the patient's sex, age, primary reason for IV sedation, duration of anesthesia and dental treatment, type of dental treatment performed, number of clinical departments involved in the dental treatment and level of multidisciplinary cooperation, and annual trends. RESULTS: Most dental treatments using intravenous sedation were performed on medically disabled patients or dentally disabled patients with an extreme gag reflex or dental phobia. The mean duration of IV sedation was 72.5 min, while the mean duration of treatment was 58.0 min. The types of dental treatments included surgical treatment (n = 209), periodontal treatment (n = 28), prosthodontic treatment (n = 28), restorative treatment (n = 23), implant surgery (n = 22), endodontic treatment (n = 9), reduction of temporomandibular joint dislocation (n = 1), and treatment of traumatic injuries (n = 1), with treatments mostly performed on adult patients. CONCLUSIONS: With increasing demand for minimally painful treatment, cases using IV sedation are on an upward trend and are expected to continue to increase. PMID- 28879306 TI - Pain and quality of life related to suture removal after 3 or 7 days at the extraction sites of impacted lower third molars. AB - BACKGROUND: This study aimed to evaluate the patient's pain and quality of life after suture removal at either 3 or 7 days following the bilateral surgical extraction of impacted lower third molars. METHODS: This study was a prospective, randomized controlled clinical trial carried out in 30 patients, who acted as their own control. Each patient required the bilaterally impacted mandibular third molars to be extracted. The impacted teeth were removed and the wound margins were approximated and sutured with black braided silk. The suture material was removed on day 3 on one side and on day 7 on the other. Each participant was asked to complete a questionnaire after the removal of the suture material on each designated day. RESULTS: Regarding overall clinical symptoms, the mean VAS scores of male and female participants on day 3 were not significantly different from those on day 7. A significant difference was found in female participants, in that overall daily activity was better on day 7. There were significant differences in the ability to smile and laugh in both sexes and the ability to chew in the male participants was better on day 7. CONCLUSIONS: There were no significant differences in the patient's pain and quality of life between suture removal on day 3 or on day 7 following surgery to remove impacted lower third molars. PMID- 28879307 TI - Local anesthesia of the temporomandibular joint to reduce pain during mouth opening for dental treatment in a patient with spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is an autosomal recessive, severe neuromuscular disorder in which degeneration of alpha motor neurons in the spine progressively weakens and ultimately paralyzes the proximal muscles. It occurs in one per 6,000 10,000 infants, and is a genetic disorder with the second-highest mortality rate worldwide. An 18-year-old male patient with SMA was referred for general anesthesia for difficulty in performing dental treatment due to limited mouth opening caused by temporomandibular joint (TMJ) pain. However, the patient had a high risk of general anesthesia complications, so TMJ pain during mouth opening was reduced through local anesthesia of the TMJ. Fortunately, the anesthesia was successful in reducing pain during mouth opening, enabling the patient to receive dental treatment with an adequate mouth opening. PMID- 28879308 TI - Occurrence of bilateral pneumothorax during tracheostomy in a patient with deep neck infection. AB - Infection that progresses to deep areas of the neck requires appropriate assessment of the airway, and securing of the airway is critical in patients with deep neck infection. In the patient in our case report, bilateral pneumothorax occurred while performing tracheostomy to the airways of a patient with deep neck infection, and therefore, this paper details the method used to secure the airway of patients with deep neck infection. PMID- 28879309 TI - Management of hyperthyroid patients in dental emergencies: a case report. AB - The prevalence of thyroid disease, particularly hyperthyroidism, has rapidly increased in Korea in the past 10 years. Therefore, it is important to consider the complete medical history including thyroid disease in patients under dental treatment. Both the drugs used for dental treatment and psychological symptoms associated with treatment can induce emergencies in hyperthyroid patients. This case report considers emergency situations during dental treatment for hyperthyroid patients, and discusses risk factors and related concerns. PMID- 28879310 TI - Education that allows South Korean Colleges of Dentistry to teach Emergency Care. AB - As the medical environment and dental services change, the importance of educating dentists in responses to systemic emergencies is increasing. The current student-oriented education paradigm is moving towards training students in the abilities required to address the daily crises they will face, while also providing them with the ability to deliver knowledge. Before addressing a patient's situation, emergency physicians begin by diagnosing symptoms. As they must decide on the tests and treatments that are immediately required and must solve problems through interdisciplinary treatment, emergency physicians require additional skills and communication abilities besides clinical knowledge. Since dentistry colleges provide education that emphasizes the skills dentists require to treat oral diseases, they do not have sufficient time to teach emergency care. Additionally, because their professors lack expertise in pedagogy, dental students also have insufficient motivation to study the pathophysiology of systemic diseases. This review proposes a direction of teaching that can help dental students recognize problems and situations in emergency cases and that can help them develop their capability to immediately make a decision and resolve the problem. To do this, the author surveyed the educational philosophy and knowledge provided in the instructional design of clinical professors who give lectures on emergency care, and also examined the teaching methods of the learner-oriented education paradigm. PMID- 28879311 TI - Recent advances in topical anesthesia. AB - Topical anesthetics act on the peripheral nerves and reduce the sensation of pain at the site of application. In dentistry, they are used to control local pain caused by needling, placement of orthodontic bands, the vomiting reflex, oral mucositis, and rubber-dam clamp placement. Traditional topical anesthetics contain lidocaine or benzocaine as active ingredients and are used in the form of solutions, creams, gels, and sprays. Eutectic mixtures of local anesthesia cream, a mixture of various topical anesthetics, has been reported to be more potent than other anesthetics. Recently, new products with modified ingredients and application methods have been introduced into the market. These products may be used for mild pain during periodontal treatment, such as scaling. Dentists should be aware that topical anesthetics, although rare, might induce allergic reactions or side effects as a result of an overdose. Topical anesthetics are useful aids during dental treatment, as they reduce dental phobia, especially in children, by mitigating discomfort and pain. PMID- 28879312 TI - Regional anesthesia for maxillofacial surgery in developing countries. AB - Regional anesthesia in the maxillofacial region is safer and more efficient than general anesthesia when its indications are carefully considered. In addition, the majority of medical institutions in developing countries are not well equipped for proper anesthesia and elective surgery. In this review, we describe regional anesthesia and cutaneous nerve divisions in the maxillofacial region. In addition, we summarize detailed regional anesthetic techniques adapted for representative cleft lip cases in developing countries. PMID- 28879313 TI - Developmental procedures for the clinical practice guidelines for conscious sedation in dentistry for the Korean Academy of Dental Sciences. AB - BACKGROUND: Evidence-based clinical practice guidelines (CPGs) are defined as "statements that are scientifically reviewed about evidence and systematically developed to assist in the doctors' and patients' decision making in certain clinical situations." This recommendation aims to promote good clinical practice for the provision of safe and effective practices of conscious sedation in dentistry. METHODS: The development of this clinical practice guideline was conducted by performing a systematic search of the literature for evidence-based CPGs. Existing guidelines, relevant systematic reviews, policy documents, legislation, or other recommendations were reviewed and appraised. To supplement this information, key questions were formulated by the Guideline Development Group and used as the basis for designing systematic literature search strategies to identify literature that may address these questions. Guideline documents were evaluated through a review of domestic and international databases for the development of a renewing of existing conscious sedation guidelines for dentistry. Clinical practice guidelines were critically appraised for their methodologies using Appraisal of guidelines for research and evaluation (AGREE) II. RESULTS: A total of 12 existing CPGs were included and 13 recommendations were made in a range of general, adult, and pediatric areas. CONCLUSION: The clinical practice guidelines for conscious sedation will be reviewed in 5 years' time for further updates to reflect significant changes in the field. PMID- 28879314 TI - Protective effects of remifentanil against H2O2-induced oxidative stress in human osteoblasts. AB - BACKGROUND: Bone injury is common in many clinical situations, such as surgery or trauma. During surgery, excessive reactive oxygen species (ROS) production decreases the quality and quantity of osteoblasts. Remifentanil decreases ROS production, reducing oxidative stress and the inflammatory response. We investigated remifentanil's protective effects against H2O2-induced oxidative stress in osteoblasts. METHODS: To investigate the effect of remifentanil on human fetal osteoblast (hFOB) cells, the cells were incubated with 1 ng/ml of remifentanil for 2 h before exposure to H2O2. For induction of oxidative stress, hFOB cells were then treated with 200 uM H2O2 for 2 h. To evaluate the effect on autophagy, a separate group of cells were incubated with 1 mM 3-methyladenine (3 MA) before treatment with remifentanil and H2O2. Cell viability and apoptotic cell death were determined via MTT assay and Hoechst staining, respectively. Mineralized matrix formation was visualized using alizarin red S staining. Western blot analysis was used to determine the expression levels of bone-related genes. RESULTS: Cell viability and mineralized matrix formation increased on remifentanil pretreatment before exposure to H2O2-induced oxidative stress. As determined via western blot analysis, remifentanil pretreatment increased the expression of bone-related genes (Col I, BMP-2, osterix, and TGF-beta). However , pretreatment with 3-MA before exposure to remifentanil and H2O2 inhibited remifentanil's protective effects on hFOB cells during oxidative stress. CONCLUSIONS: We showed that remifentanil prevents oxidative damage in hFOB cells via a mechanism that may be highly related to autophagy. Further clinical studies are required to investigate its potential as a therapeutic agent. PMID- 28879315 TI - Postoperative nausea and vomiting after general anesthesia for oral and maxillofacial surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is one of the most common postoperative complications. Despite this, few papers have reported the incidence and independent risk factors associated with PONV in the context of oral and maxillofacial surgery (OMFS). Therefore, we sought to determine the incidence of PONV, as well as to identify risk factors for the condition in patients who had undergone OMFS under general anesthesia. METHODS: A total of 372 patients' charts were reviewed, and the following potential risk factors for PONV were analyzed: age, sex, body mass index, smoking status, history of PONV and/or motion sickness, duration of anesthesia, amount of blood loss, nasogastric tube insertion and retention and postoperative opioid used. Univariate analysis was performed, and variables with a P-value less than 0.1 were entered into a multiple logistic regression analysis, wherein P-values < 0.05 were considered significant. RESULTS: The overall incidence of PONV was 25.26%. In the multiple logistic regression analysis, the following variables were independent predictors of PONV: age < 30 years, history of PONV and/or motion sickness, and anesthesia duration > 4 h. Furthermore, the number of risk factors was proportional to the incidence of PONV. CONCLUSIONS: The incidence of PONV in patients who have undergone OMFS varies from center to center depending on patient characteristics, as well as on anesthetic and surgical practice. Identifying the independent risk factors for PONV will allow physicians to optimize prophylactic, antiemetic regimens. PMID- 28879316 TI - Survey of the sevoflurane sedation status in one provincial dental clinic center for the disabled. AB - BACKGROUND: Sevoflurane sedation in pediatric and disabled patients has the advantage of faster induction and recovery compared to general anesthesia, as well as minimum influence on the respiratory and cardiovascular functions, and airway protective reflexes. This study aimed to evaluate the clinical efficacy of sevoflurane sedation used in dental treatment at one provincial dental clinic center for the disabled. METHODS: We investigated patients' gender, age, reasons for undergoing sedation, medication history prior to treatment, duration of anesthesia, treatment length, type of treatment, and yearly patterns, for 387 cases of dental treatment performed using sevoflurane sedation from January 2013 to October 2016. RESULTS: We analyzed 387 cases (215 male patients, 172 female patients). Male patients aged 20 year or older accounted for 39.0% of all patients, marking the highest proportion. Patient's lack of cooperation was the most common reason for performing dental sedation. Prosthetic treatment was the most frequently practiced, accounting for 174 treatment cases. The mean lengths of the entire treatment and of the dental procedure were 55.2 min and 39.8 min, respectively. CONCLUSIONS: Sevoflurane sedation has the advantage of fast anesthesia induction and recovery compared to general anesthesia; therefore, it can be used efficiently to induce anesthesia in pediatric and disabled patients during short dental procedures, enabling stable treatment of these patients. PMID- 28879317 TI - The evaluation of implementing smart patient controlled analgesic pump with a different infusion rate for different time duration on postoperative pain management. AB - BACKGROUND: Control of postoperative pain is an important aspect of postoperative patient management. Among the methods of postoperative pain control, patient controlled analgesia (PCA) has been the most commonly used. This study tested the convenience and safety of a PCA method in which the dose adjusted according to time. METHODS: This study included 100 patients who had previously undergone orthognathic surgery, discectomy, or total hip arthroplasty, and wished to control their postoperative pain through PCA. In the test group (n = 50), the rate of infusion was changed over time, while in the control group (n = 50), drugs were administered at a fixed rate. Patients' pain scores on the visual analogue scale, number of rescue analgesic infusions, side effects, and patients' satisfaction with analgesia were compared between the two groups. RESULTS: The patients and controls were matched for age, gender, height, weight, and body mass index. No significant difference in the mount of drug administered was found between the test and control groups at 0-24 h after the operation; however, a significant difference was observed at 24-48 h after the operation between the two groups. No difference was found in the postoperative pain score, number of side effects, and patient satisfaction between the two groups. CONCLUSIONS: Patient-controlled anesthesia administered at changing rates of infusion has similar numbers of side effects as infusion performed at a fixed rate; however, the former allows for efficient and safe management of postoperative pain even in small doses. PMID- 28879318 TI - Dexmedetomidine attenuates H2O2-induced cell death in human osteoblasts. AB - BACKGROUND: Reactive oxygen species play critical roles in homeostasis and cell signaling. Dexmedetomidine, a specific agonist of the alpha2-adrenoceptor, has been commonly used for sedation, and it has been reported to have a protective effect against oxidative stress. In this study, we investigated whether dexmedetomidine has a protective effect against H2O2-induced oxidative stress and the mechanism of H2O2-induced cell death in normal human fetal osteoblast (hFOB) cells. METHODS: Cells were divided into three groups: control group-cells were incubated in normoxia without dexmedetomidine, hydrogen peroxide (H2O2) group cells were exposed to H2O2 (200 uM) for 2 h, and Dex/H2O2 group-cells were pretreated with dexmedetomidine (5 uM) for 2 h then exposed to H2O2 (200 uM) for 2 h. Cell viability and apoptosis were evaluated. Osteoblast maturation was determined by assaying bone nodular mineralization. Expression levels of bone related proteins were determined by western blot. RESULTS: Cell viability was significantly decreased in the H2O2 group compared with the control group, and this effect was improved by dexmedetomidine. The Hoechst 33342 and Annexin-V FITC/PI staining revealed that dexmedetomidine effectively decreased H2O2-induced hFOB cell apoptosis. Dexmedetomidine enhanced the mineralization of hFOB cells when compared to the H2O2 group. In western blot analysis, bone-related protein was increased in the Dex/H2O2 group. CONCLUSIONS: We demonstrated the potential therapeutic value of dexmedetomidine in H2O2-induced oxidative stress by inhibiting apoptosis and enhancing osteoblast activity. Additionally, the current investigation could be evidence to support the antioxidant potential of dexmedetomidine in vitro. PMID- 28879319 TI - Efficacy evaluation of syringe pump developed for continuous drug infusion. AB - BACKGROUND: In dental intravenous sedation, continuous intravenous infusion of a low-dose drug requires an infusion pump such as a syringe pump. To develop a new syringe pump for clinical use, the functions of the pump must meet certain international standards. Various safety and efficacy tests must be performed on the syringe pump, as stipulated by these standards, and an approval must be received from the approving agency based on such test results. METHODS: The authors of the present study developed a novel syringe pump and performed efficacy evaluation by testing its infusion speed at 1 and 25 ml/h, and infusion performance testing at 2 and 24 h. Moreover, performance evaluation was conducted by comparing the novel pump to an existing pump with the infusion speed varied from 1 to 5 ml/h. RESULTS: In the efficacy testing on the newly developed syringe pump, infusion with the infusion speed initially set to 1 ml/h resulted in infusion speeds of 1.00 and 0.99 ml/h in the 2- and 24-h assessment, respectively. Changing the infusion speed setting to 25 ml/h resulted in an infusion speed of 25.09 and 23.92 ml/h in the 2- and 24-h assessment, respectively. These results show no significant differences when compared with other commercially available pumps. CONCLUSIONS: The efficacy testing of the newly developed syringe pump showed the accuracy to be within tolerance. Based on these findings, we believe that the newly developed syringe pump is suitable for clinical use. PMID- 28879320 TI - Pharyngeal flap damage caused by nasotracheal intubation in a patient who underwent palatoplasty and pharyngoplasty. AB - Patients with cleft lip and palate (CLP) must undergo corrective surgeries during infancy and early childhood. Many patients with CLP undergo orthognathic surgery during their childhood for correction of skeletal asymmetries or pharyngoplasty with a pharyngeal flap to improve the quality of speech and velopharyngeal function. During orthognathic surgeries, nasotracheal intubation is performed under general anesthesia. In our case report, the patient had undergone palatoplasty and pharygoplasty previously. During the orthognathic surgery, a flexible fiberoptic bronchoscope-guided nasotracheal tube was inserted through the pharyngeal flap ostium; however, active bleeding occurred in the nasopharynx. Bleeding occurred because the flap was torn. After achieving hemostasis, the surgery was completed successfully. Thus, if a patient may show the potential for velopharyngeal port obstruction, nasotracheal intubation should be performed with utmost care. PMID- 28879321 TI - Perioperative airway management of a patient with Beckwith-Wiedemann syndrome. AB - Airway obstruction in pediatric patients always poses a challenge for anesthesiologists. Beckwith-Wiedemann syndrome causes various abnormalities such as macroglossia and omphalocele. Patients with these abnormalities often need corrective surgeries. Management of difficult airway caused by conditions such as macroglossia in patients with this syndrome could be challenging. We encountered a case of difficult airway in an infant with Beckwith-Wiedemann syndrome. It was predicted that macroglossia might cause difficult ventilation, intubation, and extubation. Preoperative assessment and preparations for difficult airway should be considered. PMID- 28879322 TI - Difficult airway management in a patient with a thin mandible. AB - A 47-year-old woman was referred for surgical treatment of osteomyelitis of the mandible. She had already undergone three previous surgeries. Pre-anesthetic airway evaluation predicted a difficult airway, due to the thin, retro-positioned mandible, tongue, and atrophic changes in the lips and soft tissue. We inserted packing gauzes in the buccal mucosa for easier mask fitting and ventilation. During direct laryngoscopic intubation with a nasotracheal tube (NTT), fracture of a thin mandible can easily occur. Therefore, we used a fiberoptic bronchoscope to insert the NTT. After surgery, we performed a tongue-tie to protect against airway obstruction caused by the backward movement of the tongue during recovery. The patient recovered without any complications. We determined the status of the patient precisely and consequently performed thorough preparations for the surgery, allowing the patient to be anesthetized safely and recover after surgery. Careful assessment of the patient and airway prior to surgery is necessary. PMID- 28879324 TI - Cause analysis, prevention, and treatment of postoperative restlessness after general anesthesia in children with cleft palate. AB - Cleft palate is one of the most common congenital malformations of the oral and maxillofacial region, with an incidence rate of around 0.1%. Early surgical repair is the only method for treatment of a cleft lip and palate. However, because of the use of inhalation anesthesia in children and the physiological characteristics of the cleft palate itself combined with the particularities of cleft palate surgery, the incidence rate of postoperative emergence agitation (EA) in cleft palate surgery is significantly higher than in other types of interventions. The exact mechanism of EA is still unclear. Although restlessness after general anesthesia in children with cleft palate is self-limiting, its effects should be considered by clinicians. In this paper, the related literature on restlessness after surgery involving general anesthesia in recent years is summarized. This paper focuses on induction factors as well as prevention and treatment of postoperative restlessness in children with cleft palate after general anesthesia. The corresponding countermeasures to guide clinical practice are also presented in this paper. PMID- 28879323 TI - Pneumonitis and pneumonia after aspiration. AB - Aspiration pneumonitis and aspiration pneumonia are clinical syndromes caused by aspiration. These conditions are clinically significant due to their high morbidity and mortality. However, aspiration as a preceding event are often unwitnessed, particularly in cases of asymptomatic or silent aspiration. Furthermore, despite the difference in treatment approaches for managing aspiration pneumonitis and aspiration pneumonia, these two disease entities are often difficult to discriminate from one another, resulting in inappropriate treatment. The use of unclear terminologies hinders the comparability among different studies, making it difficult to produce evidence-based conclusions and practical guidelines. We reviewed the most recent studies to define aspiration, aspiration pneumonitis, and aspiration pneumonia, and to further assess these conditions in terms of incidence and epidemiology, pathophysiology, risk factors, diagnosis, management and treatment, and prevention. PMID- 28879325 TI - Propofol protects human keratinocytes from oxidative stress via autophagy expression. AB - BACKGROUND: The skin consists of tightly connected keratinocytes, and prevents extensive water loss while simultaneously protecting against the entry of microbial pathogens. Excessive cellular levels of reactive oxygen species can induce cell apoptosis and also damage skin integrity. Propofol (2,6 diisopropylphenol) has antioxidant properties. In this study, we investigated how propofol influences intracellular autophagy and apoptotic cell death induced by oxidative stress in human keratinocytes. METHOD: The following groups were used for experimentation: control, cells were incubated under normoxia (5% CO2, 21% O2, and 74% N2) without propofol; hydrogen peroxide (H2O2), cells were exposed to H2O2 (300 uM) for 2 h; propofol preconditioning (PPC)/H2O2, cells pretreated with propofol (100 uM) for 2 h were exposed to H2O2; and 3-methyladenine (3 MA)/PPC/H2O2, cells pretreated with 3-MA (1 mM) for 1 h and propofol were exposed to H2O2. Cell viability, apoptosis, and migration capability were evaluated. Relation to autophagy was detected by western blot analysis. RESULTS: Cell viability decreased significantly in the H2O2 group compared to that in the control group and was improved by propofol preconditioning. Propofol preconditioning effectively decreased H2O2-induced cell apoptosis and increased cell migration. However, pretreatment with 3-MA inhibited the protective effect of propofol on cell apoptosis. Autophagy was activated in the PPC/H2O2 group compared to that in the H2O2 group as demonstrated by western blot analysis and autophagosome staining. CONCLUSION: The results suggest that propofol preconditioning induces an endogenous cellular protective effect in human keratinocytes against oxidative stress through the activation of signaling pathways related to autophagy. PMID- 28879326 TI - 4% lidocaine versus 4% articaine for inferior alveolar nerve block in impacted lower third molar surgery. AB - BACKGROUND: No study has compared lidocaine with articaine, each at a concentration of 4% and combined with epinephrine. The purpose of this study was to compare the effectiveness of 4% lidocaine with that of 4% articaine, with a concentration of 1:100,000 epinephrine added to each, in an inferior alveolar nerve block for surgery on impacted lower third molars. METHOD: This study was conducted at the Faculty of Dentistry, Mahidol University in Bangkok, Thailand. The randomized, single-blind, comparative split-mouth study was carried out in patients with symmetrically impacted lower third molars, as identified on panoramic radiographs. Each patient underwent surgery for the removal of the lower third molars by the same surgeon under local anesthesia at two separate visits, 3 weeks apart. The onset and duration of local anesthesia, intra operative pain, surgical duration, and number of additional anesthetics administered were recorded. RESULTS: The subjective and objective onset of action for the local anesthetics showed statistically significant differences (P < 0.05). However, the intra-operative pain, surgical duration, duration of local anesthesia, and number of additional anesthetics administered did not show statistically significant differences. CONCLUSION: The use of 4% articaine for the inferior alveolar nerve block was clinically more effective in the onset of subjective and objective anesthesia as compared with the use of 4% lidocaine. Based on the pain scores from the visual analogue scale, 4% lidocaine provided more analgesia during the procedure, and patients noted less intra-operative pain than with 4% articaine; however, the difference was not clinically significant. PMID- 28879327 TI - Propofol protects against oxidative-stress-induced COS-7 cell apoptosis by inducing autophagy. AB - BACKGROUND: In oxidative stress, reactive oxygen species (ROS) production contributes to cellular dysfunction and initiates the apoptotic cascade. Autophagy is considered the mechanism that decreases ROS concentration and oxidative damage. Propofol shows antioxidant properties, but the mechanisms underlying the effect of propofol preconditioning (PPC) on oxidative injury remain unclear. Therefore, we investigated whether PPC protects against cell damage from hydrogen peroxide (H2O2)-induced oxidative stress and influences cellular autophagy. METHOD: COS-7 cells were randomly divided into the following groups: control, cells were incubated in normoxia (5% CO2, 21% O2, and 74% N2) for 24 h without propofol; H2O2, cells were exposed to H2O2 (400 uM) for 2 h; PPC + H2O2, cells pretreated with propofol were exposed to H2O2; and 3-methyladenine (3-MA) + PPC + H2O2, cells pretreated with 3-MA (1 mM) for 1 h and propofol were exposed to H2O2. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide thiazolyl blue (MTT) reduction. Apoptosis was determined using Hoechst 33342 staining and fluorescence microscopy. The relationship between PPC and autophagy was detected using western blot analysis. RESULTS: Cell viability decreased more significantly in the H2O2 group than in the control group, but it was improved by PPC (100 uM). Pretreatment with propofol effectively decreased H2O2-induced COS-7 cell apoptosis. However, pretreatment with 3-MA inhibited the protective effect of propofol during apoptosis. Western blot analysis showed that the level of autophagy-related proteins was higher in the PPC + H2O2 group than that in the H2O2 group. CONCLUSION: PPC has a protective effect on H2O2-induced COS-7 cell apoptosis, which is mediated by autophagy activation. PMID- 28879328 TI - Decreased post-operative pain using a sublingual injection of dexamethasone (8 mg) in lower third molar surgery. AB - BACKGROUND: Every patient who undergoes mandibular third molar surgery is concerned about post-operative pain. Indeed, previous researchers have used various methods to treat such pain. This study aimed to assess the effectiveness of sublingual injection of dexamethasone (8 mg) to treat post-operative pain after mandibular third molar surgery. METHOD: This was a randomized, double blind, split-mouth, clinical trial, involving 48 healthy patients who required surgical removal of two mandibular third molars with similar bilateral positions. All operations were performed by the same experienced surgeon. The patients were randomized into a study group (8 mg dexamethasone injection) and a placebo group (normal saline injection). Both interventions were injected into the sublingual space immediately after local anesthesia, 30 min before the first incision. The study group received an 8 mg dexamethasone injection, while the placebo group received a normal saline injection. The wash period between the patients' two operations was 3 to 4 weeks. Pain was assessed by recording the number of analgesic tablets (rescue drug) consumed, as well as by noting the patients' responses to the visual analog scale (VAS) on the first, second, and third days after surgery. RESULTS: The study group differed significantly from the placebo group in terms of VAS score and analgesic consumption. CONCLUSION: Dexamethasone (8 mg), injected sublingually, significantly eased post-operative pain after surgical removal of the mandibular third molar. PMID- 28879329 TI - Creating protective appliances for preventing dental injury during endotracheal intubation using intraoral scanning and 3D printing: a technical note. AB - Digital dentistry has influenced many dental procedures, such as three dimensional (3D) diagnosis and treatment planning, surgical splints, and prosthetic treatments. Patient-specific protective appliances (PSPAs) prevent dental injury during endotracheal intubation. However, the required laboratory work takes time, and there is the possibility of tooth extraction while obtaining the dental impression. In this technical report, we utilized new digital technology for creating PSPAs, using direct intraoral scanners and 3D printers for dental cast fabrication. PMID- 28879330 TI - Flexible laryngeal mask airway management for dental treatment cases associated with difficult intubation. AB - Nasotracheal intubation is generally a useful maxillofacial surgery that provides good surgical access for intraoral procedures. When nasotracheal intubation is difficult, laryngeal mask airway (LMA) insertion can be performed, and the flexible LMATM (FLMA) is also useful for anesthetic management. However, the FLMA provides limited access to the mouth, which restricts the insertion of instrumentation and confines the surgical field available. Here, we present our experience using the FLMA airway management for dental treatment cases involving difficulty with intubation. PMID- 28879331 TI - Dental treatment in patients with severe gag reflex using propofol-remifentanil intravenous sedation. AB - Patients with severe gag reflex (SGR) have difficulty getting the treatment they require in local clinics, and many tend to postpone the start of their treatment. To address this problem, dentists have used behavioral techniques and/or pharmacological techniques for treatment. Among the pharmacological methods available, propofol IV sedation is preferred over general anesthesia because it is a simpler procedure. Propofol in combination with remifentanil is characterized by stable sedative effects and quick recovery, leading to a deep sedation. Remifentanil acts to reduce the pain caused by lipid-soluble propofol on injection. The synergistic effects of propofol-remifentanil include reduction in the total amount of drug required to achieve a desired sedation level and anti emetic effects. In this case report, we outline how the use of propofol remifentanil IV sedation enabled us to successfully complete a wide range of dental treatments in a patient with SGR. PMID- 28879332 TI - Anesthetic management for simultaneous drug-induced sleep endoscopy and maxillomandibular advancement in a patient with obstructive sleep apnea. AB - Drug-induced sleep endoscopy (DISE) is used to identify areas of upper airway obstruction, which occurs when patients with obstructive sleep apnea (OSA) snore. DISE enables effective diagnosis and appropriate treatment of the obstruction site. Among surgical treatment methods for OSA, maxillomandibular advancement surgery (MMA) is performed to move a jaw forward; the surgery has a high success rate for OSA treatment. In DISE, anesthetics such as propofol and midazolam must be administered to induce snoring while the patient is deeply sedated for an accurate diagnosis to be made. When inducing deep sedation in a patient with OSA, airway obstruction may increase, causing oxygen saturation to drop; airway interventions are necessary in such cases. Effective DISE and MMA surgery can be performed by administering propofol through target-controlled infusion while monitoring the bispectral index (BIS). PMID- 28879333 TI - Letter to the Editor: Effects of airway evaluation parameters on the laryngeal view grade in mandibular prognathism and retrognathism patients. PMID- 28879334 TI - Authors' Reply to Letter to the Editor "Effects of airway evaluation parameters on the laryngeal view grade in mandibular prognathism and retrognathism patients". PMID- 28879335 TI - Use of local anesthetics for dental treatment during pregnancy; safety for parturient. AB - Pregnancy induces significant anatomical and physiological changes in the mother. Many pregnant women need dental treatment due to poor oral hygiene related to pregnancy. However, most dentists are reluctant to provide, and most pregnant women are reluctant to receive, dental treatment during pregnancy. Theoretically, maternally administered drugs are transferred to the fetus. Depending on the types of drugs and the stage of pregnancy, the effects of drugs on the mother, as well as the fetus, may vary. Local anesthetics are the most widely used in dental treatment. It is, therefore, important to understand the potential effects of local anesthetics during pregnancy. In this review, we will focus on the maternal and fetal effects of local anesthetics widely used in dental treatment with consideration of the use of local anesthetics during pregnancy. PMID- 28879336 TI - The use of general anesthesia to facilitate dental treatment in adult patients with special needs. AB - General anesthesia is commonly used to facilitate dental treatment in patients with anxiety or challenging behavior, many of whom are children or patients with special needs. When performing procedures under general anesthesia, dental surgeons must perform a thorough pre-operative assessment, as well as ensure that the patients are aware of the potential risks and that informed consent has been obtained. Such precautions ensure optimal patient management and reduce the frequency of morbidities associated with this form of sedation. Most guidelines address the management of pediatric patients under general anesthesia. However, little has been published regarding this method in patients with special needs. This article constitutes a review of the current literature regarding management of patients with special needs under general anesthesia. PMID- 28879337 TI - Hemodynamic changes and pain perception-related anxiety after experiencing an impacted-tooth removal: clinical practice outcome. AB - BACKGROUND: Dental fear is usually associated with hemodynamic changes. Fear of pain during the surgical removal of a lower impacted third molar might cause patients anxiety, thereby leading to avoidance of any future dental therapy. This study aimed to determine the effect of experiencing a surgical impacted-tooth removal on the pain perception-related anxiety and hemodynamic status. METHODS: Twenty-seven healthy patients aged 15-30 years (mean age, 24 years), for whom surgical removal of bilateral lower third molars was advised, were included. This prospective, randomized, controlled, split-mouth study involved operations on both sides of the mandibular arch, with a 1-month washout period in between. Blood pressure and heart rate were measured before the surgical procedure, during and after the injection, preoperatively, and postoperatively. Pain perception was evaluated using a 100-mm visual analog scale during the injection, preoperatively, and postoperatively after the numbness disappeared. Differences in the blood pressure, heart rate, and pain perception between the two appointments were analyzed using the paired t-test. For all statistical analyses, SPSS version 11.5 was used. RESULTS: The mean pain perception values during the injection and preoperatively showed no significant differences between the two appointments (P > 0.05); however, significant differences in the blood pressure and heart rate were noted before the surgical procedure; preoperatively, the blood pressure alone showed a significant difference (P < 0.05). CONCLUSIONS: There was a significant decrease in the blood pressure and heart rate preoperatively; hence, experiencing a surgical impacted-tooth removal can reduce the subsequent preoperative anxiety in healthy patients. PMID- 28879338 TI - Distribution of medical status and medications in elderly patients treated with dental implant surgery covered by national healthcare insurance in Korea. AB - BACKGROUND: The purpose of this study was to investigate the distribution of systemic diseases and medications in patients older than 65 years of age who visited the hospital for implant treatment, as well as to investigate basic information about surgical complications that may occur after insured implant treatment. METHODS: A total of 126 patients over 65 years of age were treated for implant surgery from October 1, 2013 to October 30, 2016. Electronic chart review was conducted to obtain medical records, which included sex, age, systemic diseases, medication(s) being taken, and control of the medications. Five patients were excluded due to lack of medical records giving information about systemic disease. RESULTS: Of the 126 patients, 112 (88.9%) were taking medication due to systemic disease and 9 patients (7.1%) were not. The sex distribution was 71 women and 55 men and the highest proportion of patients were between 65 and 69 years old. The most common diseases were, from most to least frequent, hypertension, cardiovascular disease, diabetes, and osteoporosis. The drug groups that can cause major complications after dental treatment were classified as hemorrhagic, osteoporotic, and immunosuppressive agents, and were taken by 45 (35.7%), 22 (17.5%) and 4 (3.2%) patients, respectively. CONCLUSION: Given that 88.9% of the elderly patients who were eligible for insurance implant treatment had systemic disease, it is necessary to carefully evaluate patients' medical histories and their general conditions in order to prevent emergencies during implant surgery. PMID- 28879339 TI - Double versus single cartridge of 4% articaine infiltration into the retro-molar area for lower third molar surgery. AB - BACKGROUND: There are no studies regarding 4% articaine infiltration injection into the retro-molar area for an impacted lower third molar (LITM) surgery. This study aimed to evaluate the efficacy of infiltration using 1.7 ml (single cartridge: SC) of 4% articaine versus 3.4 ml (double cartridges: DC) of 4% articaine with 1:100,000 epinephrine in LITM surgery. METHOD: This study involved 30 healthy patients with symmetrical LITM. The patients were assigned to receive either a DC or SC of 4% articaine with 1:100,000 epinephrine as a local anesthetic for each operation. Onset, duration, profoundness, need for additional anesthetic administration, total volume of anesthetic used, vitality of the tooth, and pain score during operation were recorded. RESULTS: The DC of 4 % articaine had a significantly higher success rate (83.3%) than did the SC (53.3%; P < 0.05). The duration of soft tissue anesthesia was longer in the DC group. The intra-operative pain was higher in the SC group with a significant (P < 0.05) requirement for a supplementary local anesthetic. CONCLUSION: We concluded that using DC for the infiltration injection had a higher success rate, longer duration of anesthesia, less intra-operative pain, and a lower amount of additional anesthesia than SC in the surgical removal of LITM. We recommend that a DC of 4% articaine and a 1:100,000 epinephrine infiltration in the retro-molar region can be an alternative anesthetic for LITM surgery. PMID- 28879340 TI - Application of augmented reality for inferior alveolar nerve block anesthesia: A technical note. AB - Efforts to apply augmented reality (AR) technology in the medical field include the introduction of AR techniques into dental practice. The present report introduces a simple method of applying AR during an inferior alveolar nerve block, a procedure commonly performed in dental clinics. PMID- 28879341 TI - Airway obstruction by dissection of the inner layer of a reinforced endotracheal tube in a patient with Ludwig's angina: A case report. AB - Intraoperative airway obstruction is perplexing to anesthesiologists because the patient may fall into danger rapidly. A 74-year-old woman underwent an emergency incision and drainage for a deep neck infection of dental origin. She was orally intubated with a 6. 0 mm internal diameter reinforced endotracheal tube by video laryngoscope using volatile induction and maintenance anesthesia (VIMA) with sevoflurane, fentanyl (100 ug), and succinylcholine (75 mg). During surgery, peak inspiratory pressure increased from 22 to 38 cmH2O and plateau pressure increased from 20 to 28 cmH2O. We maintained anesthesia because we were unable to access the airway, which was covered with surgical drapes, and tidal volume was delivered. At the end of surgery, we found a longitudinal fold inside the tube with a fiberoptic bronchoscope. The patient was reintubated with another tube and ventilation immediately improved. We recognized that the tube was obstructed due to dissection of the inner layer. PMID- 28879342 TI - Anesthetic management of a patient with chromosome 6p duplication: a case report. AB - Chromosome 6p duplication is very rare and clinically characterized by short stature, mental retardation, and congenital heart diseases. Patients with mental retardation may present with poor oral health conditions. Dental treatment may need to be performed under general anesthesia in such patients. Our case report deals with induction of general anesthesia to a patient with chromosome 6p duplication, for dental treatment. The selection of a nasotracheal tube of an appropriate size, because of the patient's short stature, was especially important for airway management. In the present case, the patient with chromosome 6p duplication was intubated with a nasotracheal tube, which was not age-matched but adapted to the height and physique of the patient. PMID- 28879343 TI - Delayed bleeding after implant surgery in patients taking novel oral anticoagulants: a case report. AB - The use of novel oral anticoagulants (NOACs) has increased in recent times in an effort to overcome the shortcomings of warfarin. They are being used primarily for the prevention of thrombosis caused by atrial fibrillation and offer the advantages of having fewer drug interactions than warfarin, no dietary restrictions, and no requirement for regular blood tests. Although there is reportedly less postoperative bleeding even if the drug is not discontinued during procedures that can cause local bleeding, such as dental procedures, no well-designed clinical studies have assessed postoperative bleeding associated with the use of these drugs. This article reports a case of a 74-year-old male patient who was taking rivaroxaban. The patient underwent a dental implant procedure after discontinuing rivaroxaban for one day and subsequently suffered delayed bleeding on postoperative day 6. Accordingly, this article also reports that the use of NOACs may also lead to delayed bleeding. PMID- 28879344 TI - Prognosis after treatment with multiple dental implants under general anesthesia and sedation in a cerebral palsy patient with mental retardation: A case report. AB - Cerebral palsy is a non-progressive disorder resulting from central nervous system damage caused by multiple factors. Almost all cerebral palsy patients have a movement disorder that makes dental treatment difficult. Oral hygiene management is difficult and the risks for periodontitis, dental caries and loss of multiple teeth are high. Placement of dental implants for multiple missing teeth in cerebral palsy patients needs multiple rounds of general anesthesia, and the prognosis is poor despite the expense. Therefore, making the decision to perform multiple dental implant treatments on cerebral palsy patients is difficult. A 33-year-old female patient with cerebral palsy and mental retardation was scheduled for multiple implant treatments. She underwent computed tomography (CT) under sedation and the operation of nine dental implants under general anesthesia. Implant-supported fixed prosthesis treatment was completed. During follow-up, she had the anterior incisors extracted and underwent the surgery of 3 additional dental implants, completing the prosthetic treatment. Although oral parafunctions existed due to cerebral palsy, no implant failure was observed 9 years after the first implant surgery. PMID- 28879345 TI - Managing the behavior of a patient with autism by sedation via submucosal route during dental treatment. AB - In sedation via the submucosal route, the drug is administered through the maxillary buccal submucosa. It is time saving, effective, and safe. Patients with autism, a mental disorder, often find it hard to make relationships with other people. These patients display a strong resistance to dental treatment and sedation. This study reports a successful case of behavioral management during dental treatment, using sedation via the submucosal route. The patient was strongly resistant to sedation via the oral, intramuscular, and intravenous routes. The drug used was 9 mg (0.1 mg/kg) of midazolam. Through this case report, we reaffirm the significance of sedation via the submucosal route, and expect that it will be used more frequently for patients with autism, who display behaviors that are difficult to manage, patients with other disabilities, and children. PMID- 28879346 TI - Can Cut-Off-Values for Tumor Size or Patient Age in Breast Ultrasound Reduce Unnecessary Biopsies or is it all About Bi-rads?- A Retrospective Analysis of 763 Biopsied T1-Sized Lesions. AB - AIMS AND OBJECTIVES: To assess whether it is possible to establish a size cut-off value for sonographically visible breast lesions in a screening situation, under which it is justifiable to obviate a biopsy and to evaluate the grayscale characteristics of the identified lesions. MATERIALS AND METHODS: Images of sonographically visible and biopsied breast lesions of 684 patients were retrospectively reviewed and assessed for the following parameters: size, shape, margin, lesion boundary, vascularity, patient's age, side of breast, histological result, and initial BI-RADS category. Statistical analyses (t-test for independent variables, ROC analyses, binary logistic regression models, cross tabulations, positive/negative predictive values) were performed using IBM SPSS (Version 21.0). RESULTS: Of all 763 biopsied lesions, 223 (29.2%) showed a malignant histologic result, while 540 (70.8%) were benign. Although we did find a statistically significant correlation of malignancy and lesion size (p=0.031), it was not possible to define a cut-off value, under which it would be justifiable to obviate a biopsy in terms of sensitivity and specificity (AUC: 0.558) at any age. Lesions showing the characteristics of a round or oval shape, a sharp delineation and no echogenic rim (n=112) were benign with an NPV of 99.1%. CONCLUSION: It is not possible to define a cut-off value for size or age, under which a biopsy of a sonographically visible breast lesion can be obviated in the screening situation. The combination of the 3 grayscale characteristics, shape (round or oval), margin (circumscribed) and no echogenic-rim sign, showed an NPV of 99.1%. Therefore, it seems appropriate to classify such lesions as BI RADS 2. PMID- 28879347 TI - Towards ionic liquids with tailored magnetic properties: bmim+ salts of ferro- and antiferromagnetic Cu triangles. AB - Complexes (bmim)2[Cu3(MU3-Cl)2(MU-pz)3Cl3] (1), (bmim)[Cu3(MU3-OH)(MU-pz)3Cl3] (2) and (bmim)2[Cu3(MU3-OH)(MU-Cl)(MU-pz)3Cl3] (3) were synthesized (bmim+ = 1 butyl-3-methylimidazolium, pz- = pyrazolato anion). Dianionic complexes 1 and 3 were obtained as crystalline solids, whereas the monoanionic complex 2 was obtained as a viscous paste. Magnetic susceptibility and X-band EPR studies revealed intramolecular ferromagnetic interactions for 1 with small magnetoanisotropy in its ground state (D3/2~ 10-3 cm-1) and intramolecular antiferromagnetic interactions for 2 and 3 (-285 and -98 cm-1 average J, respectively) with important magnetic anisotropy in their ground states stemming from a combination of low magnetic symmetry and antisymmetric exchange interactions. Thermal studies revealed a clear melting point of 140 degrees C for 1, which is lower than that of its PPN+ and Bu4N+ analogues (1PPN and 1Bu4N, respectively, PPN+ = bis(triphenylphosphine)iminium). Upon cooling, 1 remains molten down to 70 degrees C. Mixtures of the salts 1, 1PPN and 1Bu4N, exhibited modified melting behaviours, with the mixtures exhibiting lower melting points than those of either of their pure components. PMID- 28879348 TI - The elemental role of iron in DNA synthesis and repair. AB - Iron is an essential redox element that functions as a cofactor in many metabolic pathways. Critical enzymes in DNA metabolism, including multiple DNA repair enzymes (helicases, nucleases, glycosylases, demethylases) and ribonucleotide reductase, use iron as an indispensable cofactor to function. Recent striking results have revealed that the catalytic subunit of DNA polymerases also contains conserved cysteine-rich motifs that bind iron-sulfur (Fe/S) clusters that are essential for the formation of stable and active complexes. In line with this, mitochondrial and cytoplasmic defects in Fe/S cluster biogenesis and insertion into the nuclear iron-requiring enzymes involved in DNA synthesis and repair lead to DNA damage and genome instability. Recent studies have shown that yeast cells possess multi-layered mechanisms that regulate the ribonucleotide reductase function in response to fluctuations in iron bioavailability to maintain optimal deoxyribonucleotide concentrations. Finally, a fascinating DNA charge transport model indicates how the redox active Fe/S centers present in DNA repair machinery components are critical for detecting and repairing DNA mismatches along the genome by long-range charge transfers through double-stranded DNA. These unexpected connections between iron and DNA replication and repair have to be considered to properly understand cancer, aging and other DNA-related diseases. PMID- 28879349 TI - The necessity of bioanalytical tools for advancing water and sediment quality assessment. PMID- 28879350 TI - Mechanisms of molecular water oxidation in solution and on oxide surfaces. AB - Initial experiments on water oxidation by well-defined molecular catalysts were initiated with the goal of finding solutions to solar energy conversion. This account is a summary of research in this area by the T. J. Meyer research group. It begins with the design and characterization of the first catalyst, the blue Ru dimer, to current applications with surface-bound complexes on photoanodes for water oxidation in Dye Sensitized Photoelectrosynthesis Cells. PMID- 28879351 TI - Design and construction of a bifunctional magnetically recyclable 3D CoMn2O4/CF hybrid as an adsorptive photocatalyst for the effective removal of contaminants. AB - Herein, a magnetic microsphere CoMn2O4 (MS-CoMn2O4) with a 3D architecture was constructed directly on cellulose fiber (CF) substrates from wastepaper by a solvothermal synthesis method with further calcination treatment. The designed hybrid shows excellent dual functions including rapid catalytic oxidation of tetracycline (TC)/methylene blue (MB) and a high adsorption capacity. What's more, the hybrid is easily recycled using an external magnetic field. In comparison with that of pure MS-CoMn2O4, the enhanced adsorption ability and photocatalytic activity of MS-CoMn2O4/CFs can mainly be attributed to the introduced cellulose fiber supporter in the hybrid system. MS-CoMn2O4 incorporated CFs can improve the efficient separation of photogenerated electron hole pairs and the transport pathway of electrons. More importantly, introduction of CFs can help to enrich and further improve the degradation efficiency of organic contaminants. The possible mechanism for the enhancement of the photocatalytic activity has been elucidated in detail. The reusability analysis revealed that the MS-CoMn2O4/CF hybrid exhibited superb cycling stability after 5 cycles. This study provides novel insights into the design and construction of high capacity sorbents as strongly adsorptive photocatalysts to perform catalytic degradation of organic contaminants. PMID- 28879352 TI - A new family of clusters containing a silver-centered tetracapped [Ag@Ag4(MU3 P)4] tetrahedron, inscribed within a N12 icosahedron. AB - An unprecedented silver-centered P-tetracapped [Ag@Ag4(MU3-P)4] tetrahedron inscribed within a N12 icosahedral cage has been discovered in the novel family of luminescent clusters. The latter are easily self-assembled by reacting AgI salts with tris(2-pyridyl)phosphine (Py3P). PMID- 28879353 TI - Correction: The effect of wall depletion and hydrodynamic interactions on stress gradient-induced polymer migration. AB - Correction for 'The effect of wall depletion and hydrodynamic interactions on stress-gradient-induced polymer migration' by Hossein Rezvantalab et al., Soft Matter, 2016, 12, 5883-5897. PMID- 28879354 TI - Bio-based chemicals: general discussion. PMID- 28879355 TI - Rare earth elements in freshwater, marine, and terrestrial ecosystems in the eastern Canadian Arctic. AB - Few ecotoxicological studies exist for rare earth elements (REEs), particularly field-based studies on their bioaccumulation and food web dynamics. REE mining has led to significant environmental impacts in several countries (China, Brazil, U.S.), yet little is known about the fate and transport of these contaminants of emerging concern. Northern ecosystems are potentially vulnerable to REE enrichment from prospective mining projects at high latitudes. To understand how REEs behave in remote northern food webs, we measured REE concentrations and carbon and nitrogen stable isotope ratios (?15N, ?13C) in biota from marine, freshwater, and terrestrial ecosystems of the eastern Canadian Arctic (N = 339). Wildlife harvesting and tissue sampling was partly conducted by local hunters through a community-based monitoring project. Results show that REEs generally follow a coherent bioaccumulation pattern for sample tissues, with some anomalies for redox-sensitive elements (Ce, Eu). Highest REE concentrations were found at low trophic levels, especially in vegetation and aquatic invertebrates. Terrestrial herbivores, ringed seal, and fish had low total REE levels in muscle tissue (?REE for 15 elements <0.1 nmol g-1), yet accumulation was an order of magnitude higher in liver tissues. Age- and length-dependent REE accumulation also suggest that REE uptake is faster than elimination for some species. Overall, REE bioaccumulation patterns appear to be species- and tissue-specific, with limited potential for biomagnification. This study provides novel data on the behaviour of REEs in ecosystems and will be useful for environmental impact assessment of REE enrichment in northern regions. PMID- 28879356 TI - Feedstocks and analysis: general discussion. PMID- 28879357 TI - Fluorescent mesogenic boron difluoride complexes derived from heterocyclic benzoxazoles. AB - One new series of boron difluoride complexes 1 derived from heterocyclic benzoxazoles 2 was reported, and their mesomorphic and optical properties were also investigated. One single crystal of the mesogenic BF2 complex 1a (m = 12, n = 8) was obtained, and its single crystal and molecular structure were resolved. The geometry coordination at the central boron atom is tetrahedral. It crystallizes in a triclinic space group P1[combining macron] with Z = 4. The overall molecular shape was described as slightly bent Z-shapes, and the molecular length was ca. 34.06 A. Weak intramolecular and intermolecular H-bonds observed in the crystal lattice were attributed to the formation of mesophases. The results indicated that benzoxazoles 2a (n = 6, 8, 12) formed monotropic SmA phases, while boron difluoride complexes 1a (n = 6, 8, 12, 16) exhibited monotropic SmC mesophases. In contrast, all compounds of 2b and 1b (m = 1, n = 12 for all) were not mesogenic. Boron complexes 1 emitted a pronounced violet emission at lambdamax = 399 nm in solution at room temperature. PMID- 28879358 TI - Conversion technologies: general discussion. PMID- 28879359 TI - Enantioselective synthesis of sulfoxide using an SBA-15 supported vanadia catalyst: a computational elucidation using a QM/MM approach. AB - Metal catalyzed asymmetric oxidation of prochiral sulfides is one of the prevailing strategies to produce enantiopure sulfoxides. Keeping in view the reported reactivity of peroxo vanadium complexes towards asymmetric oxidation reactions, this study explores the reactivity of vanadia represented as a VO4 cluster with CH3-S-Ph through DFT computations. The mechanism of the oxidation of sulfides to sulfoxides with unsupported VO4 is thoroughly investigated. The chiral centre in the VO4 cluster is introduced by grafting it on an SBA-15 support and two conformers of the supported cluster are thus obtained. The study was extended to locate transition states for the reaction of each conformer with CH3-S-Ph. The large enantiomeric excess obtained from the energy difference of the transition states confirms the formation of enantiopure sulfoxide. Analysis of the computational results provides a rational explanation for the observed enantioselectivity, which is remarkable. The optical stability as well as asymmetry of chiral sulfoxides obtained by the current approach has been further confirmed by locating the planar transition state, through which conversion from one enantiomer to another takes place. The calculations suggest that transition between the two enantiomers of sulfoxide is hampered by sufficiently high inversion barriers. PMID- 28879360 TI - Target-induced cyclic DNAzyme formation for colorimetric and chemiluminescence imaging assay of protein biomarkers. AB - A target-induced cyclic strategy for DNAzyme formation was proposed to achieve simple, sensitive and universal detection of protein biomarkers with convenient colorimetric or chemiluminescence imaging readout. In the assay, the target protein was recognized by a pair of DNA-labeled antibodies (Ab1-DNA1 and Ab2 DNA2) to form a proximate complex, which could hybridize with the conjugate DNA3/DNA4 to release the guanine-rich DNA4 and thus formed G-quadruplex/hemin horseradish peroxidase-mimicking DNAzyme. The process could be further recycled with Exonuclease III by cleaving DNA3 to free the proximate complex, resulting in the cyclic formation of DNAzyme. The G-quadruplex/hemin DNAzyme could catalyze the H2O2-mediated oxidation of 3,3,5,5-tetramethylbenzidine to produce the color change from colorless to blue or enhance the chemiluminescence of a luminol-H2O2 system. Thus the signal could be read out with the naked eye, and by colorimetry and chemiluminescence imaging. Using a carcinoembryonic antigen as a model target, the proposed assay showed a detection range of 4 orders of magnitude along with detection limits of 170 and 16 pg mL-1 for colorimetric and chemiluminescence imaging assays respectively. This assay had the advantages of easy operation, sensitive detection, target flexibility and diversified signal readout, providing a great opportunity for commercial application. PMID- 28879361 TI - Development of lithium attachment mass spectrometry - knudsen effusion and chemical ionisation mass spectrometry (KEMS, CIMS). AB - Lithium ion attachment mass spectrometry provides a non-specific, non fragmenting, sensitive and robust method for the detection of volatile species in the gas phase. The design, manufacture and results of lithium based ion attachment ionisation sources for two different mass spectrometry systems are presented. In this study trace gas analysis is investigated using a modified Chemical Ionization Mass Spectrometer (CIMS) and vapour pressure measurements are made using a modified Knudsen Effusion Mass Spectrometer (KEMS). In the Li+ CIMS, where the Li+ ionization acts a soft and unselective ionization source, limits of detection of 0.2 ppt for formic acid, 15 ppt for nitric acid and 120 ppt for ammonia were achieved, allowing for ambient measurements of such species at atmospherically relevant concentrations. In the first application of Lithium ion attachment in ultra-high vacuum (UHV), vapor pressures of various atmospherically relevant species were measured with the adapted KEMS, giving measured values equivalent to previous results from electron impact KEMS. In the Li+ KEMS vapour pressures <10-3 mbar can be measured without any fragmentation, as is seen with the initial electron impact (EI) set up, allowing the vapor pressure of individual components within mixtures to be determined. PMID- 28879362 TI - Self-assembly and rheology of dipolar colloids in simple shear studied using multi-particle collision dynamics. AB - Magnetic nanoparticles in a colloidal solution self-assemble in various aligned structures, which has a profound influence on the flow behavior. However, the precise role of the microstructure in the development of the rheological response has not been reliably quantified. We investigate the self-assembly of dipolar colloids in simple shear using hybrid molecular dynamics and multi-particle collision dynamics simulations with explicit coarse-grained hydrodynamics, conduct simulated rheometric studies and apply micromechanical models to produce master curves, showing evidence of the universality of the structural behavior governed by the competition between the bonding (dipolar) and erosive (thermal and/or hydrodynamic) stresses. The simulations display viscosity changes across several orders of magnitude in fair quantitative agreement with various literature sources, substantiating the universality of the approach, which seems to apply generally across vastly different length scales and a broad range of physical systems. PMID- 28879363 TI - Bio-based materials: general discussion. PMID- 28879364 TI - A novel supramolecular magnesoborate framework with snowflake-like channels built by unprecedented huge B69 cluster cages. AB - A novel magnesoborate, Mg7@[B69O108(OH)18], with a 3D supramolecular framework has been made under solvothermal conditions, and features wonderful snowflake like channels assembled from unprecedented [B69O108(OH)18] clusters. Notably, unique triple-helical ribbons reside in the middle of the B69 cluster. Up to now, the discovery of a B69 cluster sets a new record in cluster sizes among borates. PMID- 28879365 TI - Plasmonic response and SERS modulation in electrochemical applied potentials. AB - We study the optical response of individual nm-wide plasmonic nanocavities using a nanoparticle-on-mirror design utilised as an electrode in an electrochemical cell. In this geometry Au nanoparticles are separated from a bulk Au film by an ultrathin molecular spacer, giving intense and stable Raman amplification of 100 molecules. Modulation of the plasmonic spectra and the SERS response is observed with an applied voltage under a variety of electrolytes. Different scenarios are discussed to untangle the various mechanisms that can be involved in the electronic interaction between NPs and electrode surfaces. PMID- 28879366 TI - Phase diagrams of the LiBH4-NaBH4-KBH4 system. AB - A combination of experimental and computational techniques has been used to fully describe the thermodynamic properties and phase diagrams of the LiBH4-NaBH4-KBH4 system. The Calphad method was used to assess the thermodynamic properties of LiBH4-NaBH4, LiBH4-KBH4, and NaBH4-KBH4 binary systems and to extend the investigation to the LiBH4-NaBH4-KBH4 ternary system. Samples with various compositions in the ternary system were synthesised, both by ball milling and manual mixing of the parent borohydrides, and their thermal stability has been studied using in situ synchrotron radiation X-ray diffraction as a function of temperature and using differential scanning calorimetry. From collected experimental and literature data, a thermodynamic assessment of the ternary system led to the determination of the phase diagrams. In all cases, the solid solutions can be described in the frame of the regular solution model, with interaction parameters positive or equal to zero (i.e. ideal solution). In contrast, the liquid phase was described using negative interaction parameters. A new ternary eutectic composition was estimated and it was confirmed experimentally to be equal to a molar fraction of 0.66LiBH4-0.11NaBH4-0.23KBH4 with a melting temperature of 102 degrees C. PMID- 28879367 TI - Conducting redox polymers with non-activated charge transport properties. AB - Non-activated charge transport has been demonstrated in terephthalate functionalized conducting redox polymers. The transition from a temperature activated conduction mechanism to a residual scattering mechanism was dependent on the doping level. The latter mechanism is associated with apparent negative activation barriers to charge transport and is generally found in polymer materials with a high degree of order. Crystallographic data, however, suggested a low degree of order in this polymer, indicating the existence of interconnected crystal domains in the predominantly amorphous polymer matrix through which the charge was transported. We have thus shown that the addition of bulky pendant groups to conducting polymers does not prevent efficient charge transport via the residual scattering mechanism with low barriers to charge transport. PMID- 28879368 TI - Shift work and the incidence of prostate cancer: a 10-year follow-up of a German population-based cohort study. AB - Objectives We investigated the association of shift and night work with the incidence of prostate cancer using data of the population-based prospective Heinz Nixdorf Recall Study from the highly industrialized Ruhr area in Germany. Methods Participants of the baseline survey were recruited between 2000-2003. A follow-up survey including, a detailed interview on shift and night work, was conducted from 2011-2014. We included 1757 men who did not report a history of prostate cancer at baseline. We assessed shift- and night-work exposure up to time of the baseline interview. Incident prostate cancers were recorded from baseline through September 2014. We calculated hazard ratios (HR) of shift- and night-work exposure using Cox proportional hazards regression with age at event as timescale, adjusting for smoking status, family history of prostate cancer, education (<=13, 14-17, >=18 years), and equivalent income (low, medium, high). Results We observed a twofold increased HR for prostate cancer among shift and night workers. Ever employment in shift work was associated with HR 2.29, 95% confidence interval (CI) 1.43-3.67 and night work with HR 2.27, 95% CI 1.42-3.64. HR increased steadily with duration of employment in shift or night work. Stratifying analyses by preferred midpoint of sleep, yielded strongly elevated HR among subjects with early sleep preference, although these analyses were limited by small number of cases. Conclusions We identified increased risks for prostate cancer among men with employment in shift or night work. HR were strongly elevated among long-term employed shift workers and men with early preferred midpoint of sleep. PMID- 28879369 TI - Surgical tricks for open lumbar discectomy. PMID- 28879370 TI - Radiofrequency facet joint denervation in the lumbar spine. PMID- 28879371 TI - Transforaminal lumbar interbody fusion. PMID- 28879372 TI - PLIF and modified TLIF using the PLIF approach. PMID- 28879373 TI - Single level anterior cervical discectomy and interbody fusion. PMID- 28879374 TI - Lumbar and cervical injection techniques. PMID- 28879375 TI - Comment on: International Hernia Collaboration Consensus on Nomenclature of Abdominal Wall Hernia Repair: Reply. PMID- 28879377 TI - Erratum to: Extended diffusion weighted magnetic resonance imaging with two compartment and anomalous diffusion models for differentiation of low-grade and high-grade brain tumors in pediatric patients. PMID- 28879378 TI - Erratum to: Determinants of bone mineral density in young Australian women; results from the Safe-D study. PMID- 28879380 TI - [Report on the dermatopathology working group meeting : 101st anniversary of the DGP, Erlangen 24.06.2017]. PMID- 28879381 TI - Erratum to: Cementless total hip arthroplasty in the treatment after acetabular fractures. PMID- 28879383 TI - Pediatric head injury-an opportunity to make a difference in the global burden of disease. PMID- 28879384 TI - Eulogy for Prof. Mami Yamasaki. PMID- 28879382 TI - The dawn of neurosurgery in pre-conquest Mesoamerican territories. PMID- 28879387 TI - ? PMID- 28879390 TI - Erratum to: Highlight report: co-cultures of hepatocytes and macrophages for hepatotoxicity testing. PMID- 28879392 TI - ? PMID- 28879391 TI - Response to comments on "Effect of high-intensity aerobic exercise on aerobic fitness and HbA1c in patients with type 2 diabetes". PMID- 28879393 TI - [Basic therapeutics : What are the features of modern personal care products to protect and regenerate the skin barrier?] AB - It is international consensus that the daily use of properly selected products for the maintenance therapy is a must in the adjuvant treatment of most chronic skin diseases. In a first step, the selection of an adequate product can be guided by the classical triangle of the dermal vehicles. However, modern skin care products use diverse excipients, e. g. emulsifiers and viscosity enhancers, to improve the galenical and haptic properties of the formulations. It is thus no longer sufficient to simply have knowledge about the oil and water content of a cream in order to make a proper selection. A very positive effect on the skin barrier can be achieved using biomimetic lipids which can be incorporated into the epidermal lipid barrier. The application of such products as a foam cream is the most convenient way especially favorable when inflamed or hardly accessible skin areas have to be treated. PMID- 28879394 TI - Measurement uncertainty and clinical impact of target-to-background ratios derived by interim FDG-PET/CT in Hodgkin lymphoma: reply to Laffon and Martan. PMID- 28879395 TI - A comparison of laparoscopic and open D3 lymphadenectomy for transverse colon cancer. AB - PURPOSE: The type of surgery or surgical approach for transverse colon cancer treatment largely depends on the tumor location or surgeon's preference. However, extensive lymphadenectomy appears to improve the long-term outcomes of locally advanced colon cancers. This study was designed to compare the short- and long term outcomes after surgery via the laparoscopic or open approach with radical D3 lymph node dissection in patients with stage II and III transverse colon cancer. METHODS: Patients were treated for stage II and III transverse colon cancer between May 2006 and December 2014. This retrospective study evaluated data collected prospectively at a tertiary teaching hospital. Radical D3 lymphadenectomy included the principal middle colic artery nodes. RESULTS: The study included 144 patients among whom 118 (81.9%) underwent laparoscopic surgery. Significantly more patients in the laparoscopic group underwent extended right hemicolectomy compared with the open group (90.7 vs. 65.4%, p = 0.005). The operative time was longer in the laparoscopic group (151.3 vs. 131.2 min, p = 0.021), and the open group had a greater estimated blood loss volume (160.8 vs. 289.3 ml, p = 0.011). Although the groups differed in terms of tumor size (5.8 vs 7.9 cm, p = 0.007), other pathologic outcomes did not differ. The groups did not differ regarding postoperative parameters or disease-free, overall, and cancer specific survivals. CONCLUSION: Despite differences in surgical methods and related factors, no long-term differences in outcomes were observed between laparoscopic and open approaches to radical D3 lymphadenectomy in patients with stage II and III transverse colon cancer. PMID- 28879397 TI - Detection and tissue distribution of potato spindle tuberviroid in infected tomato plants by tissue print hybridization. AB - Potato spindle tuber viroid (PSTVd) was detected in two cultivars of tomato (Lycopersicon esculentum Mill.) by tissue print hybridization of cross-sections of stem and rhachis, using a 35S-labeled PSTVd RNA probe. PSTVd was detectable in the viroid-sensitive and symptom-developping cv "Rutgers" 2 weeks p.i., and in the viroid-tolerant and practically symptomless cv "Goldkugel" 3 weeks p.i. In both tomato cultivars, PSTVd accumulated in the upper parts of the plants newly grown after inoculation. It was predominantly found in association with the ring formed by the vascular tissue. The final accumulation of PSTVd as well as its spatial distribution were similar in the sensitive and in the tolerant tomato cultivar, as estimated from the tissue print autoradiographs. Thus, tissue print hybridization provides a rapid and sensitive means for viroid diagnosis and for the assessment of tissue-specific localization of the viroid RNA. PMID- 28879396 TI - Vestibulo-ocular reflex deficits with medial longitudinal fasciculus lesions. AB - The medial longitudinal fasciculus (MLF) is the final common pathway for all conjugate adducting horizontal eye movements, as well as for the vertical torsional vestibulo-ocular reflex (VOR). MLF lesion causes adduction paresis of ipsilesional (adducting) eye with dissociated nystagmus of contralesional (abducting) eye-the well-known clinical syndrome of internuclear ophthalmoplegia (INO). We measured the VOR stimulation and also any catch-up saccades, from individual semicircular canal (SCC) evoked by the head impulse test (HIT), using head and binocular 3-dimensional scleral search coils in 27 multiple sclerosis (MS) patients, 8 with unilateral, 19 with bilateral INO. In unilateral INO, VOR gain (normal >0.90) from ipsilesional lateral SCC stimulation was 0.48 for the adducting eye and 0.81 for the abducting eye; 0.61 from contralesional anterior SCC stimulation and only 0.29 from contralesional posterior SCC stimulation. In bilateral INO, there were VOR gain deficits from all six SCCs: lateral SCC gains were asymmetrically reduced to 0.45 in the adducting eye and 0.66 in the abducting eye; anterior SCC gain was 0.48 and posterior SCC gain was only 0.19. Horizontal VOR versional dysconjugacy between adducting and abducting eyes at 0.66 was less severe than horizontal catch-up saccade versional dysconjugacy (0.44); normal >0.80. Unexpected partial preservation of horizontal VOR with greater catch-up saccade impairment from the adducting than abducting eye suggests that the ascending tract of Deiters (ATD), an extra-MLF pathway, also mediates the horizontal VOR, but not adducting horizontal saccades. Vertical VOR deficits will produce vertical oscillopsia with any vertical head movement and measurement of the vertical VOR could help with the diagnosis and quantitative evaluation of MLF lesions in suspected MS. Horizontal VOR deficits and catch-up saccade versional dysconjugacy in INO will cause gaze instability and horizontal oscillopsia during active horizontal head movements. PMID- 28879398 TI - A novel synthetic reversible inhibitor of sialidase efficiently blocks secondary but not primary influenza virus infection of MDCK cells in culture. AB - The sodium salts of 2-difluoromethyl-phenyl-alpha-ketoside of N-acetyl-neuraminic acid (compound 1) and of 4-difluoromethyl-2-methoxy-phenyl-alpha-ketoside of N acetylneuraminic acid (compound 2) were designed as potential mechanism-based inhibitors of sialidase. In vitro both of these compounds competitively inhibited the sialidases of Clostridium perfringens and of influenza virus A/HK/1/68. Inhibition was irreversible with the sialidase of Clostridium perfringens whereas it was reversible with that of A/HK/1/68. Compound 2 did not inhibit the hemagglutinin of the virus but exhibited significant anti-influenza activity when added to the medium of Madin-Darby canine kidney (MDCK) cells infected by influenza virus. In non-infected MDCK cells no inhibition of cellular sialidase was observed. Compound 2 did not block primary infection, but inhibited the release of progeny virus from infected cells. Even after 8 passages in its presence, no resistant strains were detected. Because of its high Ki (8 * 10-5M) compared to the low Ki (1 * 1-10 M) of 4 guanidino-Neu 5 Ac 2en and its reversible inhibition of viral sialidase, its development as an anti-influenza agent is no longer envisaged. Nevertheless, as a mechanism-based irreversible inhibitor of the bacterial enzyme, it could at least be useful for investigating the intrinsic role of sialidase in infections caused by this strain. PMID- 28879399 TI - Taxonomic changes in tailed phages of enterobacteria. AB - Out of 136 new phages, 80 (59%) are classified into 23 species according to morphology and physicochemical properties. Six new species are described and species b4, from a previous classification scheme, is renamed T1. The morphology of 36 phage species is schematically represented. PMID- 28879400 TI - Human T-lymphotropic Virus Type II Infection inVietnamese Thalassemic Patients. AB - Anti-human T-lymphotropic virus type I/II (HTLV-I/II) antibodies were screened by particle agglutination test in a total of 66 patients with thalassemia major who received multiple transfusion from paid donors at the Blood Transfusion Hematology Center of Ho Chi Minh City in South Vietnam. HTLV-II infection was confirmed in 6 patients (9.1%) by Western blot analysis and/or polymerase chain reaction. Phylogenetic analysis revealed that long terminal repeat sequences of HTLV-II proviruses from 5 thalassemic patients in Vietnam belonged to the same phylogenetic subgroup of HTLV-IIb as those from intravenous drug abusers in North America and Europe. These data shed light on the route of introducing HTLV-II into Vietnam. PMID- 28879401 TI - Phylogenetic analysis of feline immunodeficiency virus isolated from cats in Taiwan. AB - Feline immunodeficiency virus was isolated from four cats from Taiwan. The isolates were designated TI-1, TI-2, TI-3 and TI-4. Each was isolated from PBMCs following co-cultivation of PBMCs with a feline T-lymphoblastoid cell line (MYA-1 cells). However, the Taiwanese isolates did not grow in a feline kidney cell line (CRFK cells). The nucleotide sequences of the V3-V5 region of the envelope gene of the Taiwanese isolates were determined and compared with those of previously described isolates. Phylogenetic analysis of this region indicates that Taiwanese isolates belong to subtype C. PMID- 28879402 TI - Genetic Variation in the VP7 Gene of Human Rotavirus Serotype 3 (G3 Type) Isolated in China and Japan. AB - Sequence analysis of the VP7 gene was performed on twenty-one human isolates of serotype 3 related-rotavirus in China and Japan. The five Chinese isolates were found to be not similar to the 16 Japanese isolates and to SAff11 (simian rotavirus). The Chinese isolates, especially CHW2 and CH-32, were different from the major serotype 3 human isolates. AU-1 and 02/92 which previously showed a wider spacing between RNA segments 10 and 11 by RNA polyacrylamide gel electrophoretic analysis, were more closely related to each other and could be differentiated from the other Chinese and Japanese isolates. For these reasons, serotype 3 viruses were considered to be intra-serotypically more heterologous than serotype 1, 2 and 4 viruses. PMID- 28879403 TI - Detection and Characterization of a Distinct Type of Beet Necrotic Yellow Vein Virus RNA 5 in a Sugarbeet Growing Area in Europe. AB - A fifth beet necrotic yellow vein virus (BNYVV) RNA species has been detected in Europe in sugarbeet infected with P-type BNYVV. Very little sequence variation was found between two European sources of this RNA 5*, but considerable differences were detected between these two European sources on the one hand and the four Japanese sources recently analysed by Kiguchi et al. on the other. The BNYVV RNA 5-encoded 26K proteins share a stretch of six amino acids (FRGPGN) with the BNYVV RNA 3-encoded 25K protein which may be of interest in view of the reported interactions between the two RNAs in pathogenicity. PMID- 28879404 TI - Guidelines to the demarcation of virus species. PMID- 28879405 TI - Infection control interventions affected by resource shortages: impact on the incidence of bacteremias caused by carbapenem-resistant pathogens. AB - We evaluated an infection control (IC) program influenced by personnel and material resource shortages on the incidence of bloodstream infections (BSI) due to carbapenem-resistant Klebsiella pneumoniae (CRKP), Acinetobacter baumannii (CRAB), and Pseudomonas aeruginosa (CRPA) in an endemic region. Between January 2010 and December 2015, all BSI episodes caused by CRKP, CRAB, and CRPA were recorded. An IC bundle was implemented in January 2012. We evaluated the effect of the interventions on BSI rates between the pre-intervention (2010-2011) and intervention (2012-2013) periods, using an interrupted time-series model. From 2014, when interventions were still applied, BSI incidence was gradually increased. For this reason, we evaluated with a linear mixed effects model several factors possibly contributing to this increase for the years 2012-2015, which was considered as the intervention/follow-up period. During the study period, 351 patients with BSI were recorded, with a total of 538 episodes; the majority (83.6%) occurred in the intensive care unit (ICU). The BSI incidence rate per year during 2010-2015 for ICU patients was 21.03/19.63/17.32/14.45/22.85/25.02 per 1000 patient-days, respectively, with the reduction in BSI levels after the start of intervention marginal (p = 0.054). During the follow-up period (2014-2015), the most influential factors for the increased BSI incidence were the reduced participation in educational courses and compliance with hand hygiene. The implementation of IC interventions reduced the BSI incidence rates, particularly for ICU patients. However, factors possibly related to the restrictions of human and material resources apparently contributed to the observed expansion of BSI in our endemic setting. PMID- 28879406 TI - Whole-tumor histogram analysis of the cerebral blood volume map: tumor volume defined by 11C-methionine positron emission tomography image improves the diagnostic accuracy of cerebral glioma grading. AB - PURPOSE: This study aimed to compare the tumor volume definition using conventional magnetic resonance (MR) and 11C-methionine positron emission tomography (MET/PET) images in the differentiation of the pre-operative glioma grade by using whole-tumor histogram analysis of normalized cerebral blood volume (nCBV) maps. MATERIALS AND METHODS: Thirty-four patients with histopathologically proven primary brain low-grade gliomas (n = 15) and high-grade gliomas (n = 19) underwent pre-operative or pre-biopsy MET/PET, fluid-attenuated inversion recovery, dynamic susceptibility contrast perfusion-weighted magnetic resonance imaging, and contrast-enhanced T1-weighted at 3.0 T. The histogram distribution derived from the nCBV maps was obtained by co-registering the whole tumor volume delineated on conventional MR or MET/PET images, and eight histogram parameters were assessed. RESULTS: The mean nCBV value had the highest AUC value (0.906) based on MET/PET images. Diagnostic accuracy significantly improved when the tumor volume was measured from MET/PET images compared with conventional MR images for the parameters of mean, 50th, and 75th percentile nCBV value (p = 0.0246, 0.0223, and 0.0150, respectively). CONCLUSION: Whole-tumor histogram analysis of CBV map provides more valuable histogram parameters and increases diagnostic accuracy in the differentiation of pre-operative cerebral gliomas when the tumor volume is derived from MET/PET images. PMID- 28879407 TI - MicroRNA Profiling in Aging Brain of PSEN1/PSEN2 Double Knockout Mice. AB - MicroRNAs are small non-coding RNAs that function as regulators of gene expression. The altered expression of microRNAs influences the pathogenesis of Alzheimer's disease. Many researchers have focused on studies based on the relatively distinctive etiology of familial Alzheimer's disease due to the absence of risk factors in the pathogenesis of sporadic Alzheimer's disease. Although there is a limitation in Alzheimer's disease studies, both Alzheimer's disease types have a common risk factor-aging. No study to date has examined the aging factor in Alzheimer's disease animal models with microRNAs. To investigate the effect of aging on the changes in microRNA expressions in the Alzheimer's disease animal model, we selected 37 hippocampal microRNAs whose expression in 12 and 18-month aged mice changed significantly using microRNA microarray. On the basis of bioinformatics databases, 30 hippocampal microRNAs and their putative targets of PSEN1/PSEN2 double knockout mice were included in 28 pathways such as the wnt signaling pathway and ubiquitin-mediated proteolysis pathway. Cortical microRNAs and its putative targets involved in pathological aging were included in only four pathways such as the heparin sulfate biosynthesis. The altered expressions of these hippocampal microRNAs were associated to the imbalance between neurotoxic and neuroprotective functions and seemed to affect neurodegeneration in PSEN1/PSEN2 double knockout mice more severely than in wild type mice. This microRNA profiling suggests that microRNAs play potential roles in the normal aging process, as well as in the Alzheimer's disease process. PMID- 28879408 TI - Neuromelanin in Parkinson's Disease: from Fenton Reaction to Calcium Signaling. AB - Neuromelanin is supposed to play a key role in the pathogenesis of Parkinson's disease. A common theory is the formation of reactive oxygen species through the Fenton reaction catalyzed by neuromelanin-bound iron ions and subsequent death of the dopaminergic cells in the substantia nigra. From a physicochemical point of view, this pathway is rather implausible: a highly reactive radical built within a powerful radical scavenger would more promptly be inactivated before it might diffuse within the cell to reach a target to exert its deleterious potential. This review of the literature provides evidence for an interaction of neuromelanin with the calcium signaling pathway in Parkinson's disease and expands the view of the pathophysiological contribution of neuromelanin towards a cytoprotective involvement of this macromolecule in the calcium signaling system. More probably than being directly involved in the production of reactive oxygen species, neuromelanin may act as a calcium reservoir and thus protect dopaminergic cells from cell death. A loss of neuromelanin, as observed in the substantia nigra of Parkinson patients, would lead to enhanced calcium messaging through the loss of an important calcium reservoir and thus finally via the formation of reactive oxygen species to cell death within the substantia nigra. PMID- 28879409 TI - Erratum to: Minimum-Norm Estimation of Motor Representations in Navigated TMS Mappings. PMID- 28879410 TI - Vesicovaginal reflux and urocolpos with bilateral pelviureteric junction obstruction. PMID- 28879411 TI - Serial changes in anatomy and ventricular function on dual-source cardiac computed tomography after the Norwood procedure for hypoplastic left heart syndrome. AB - BACKGROUND: Accurate evaluation of anatomy and ventricular function after the Norwood procedure in hypoplastic left heart syndrome is important for treatment planning and prognostication, but echocardiography and cardiac MRI have limitations. OBJECTIVE: To assess serial changes in anatomy and ventricular function on dual-source cardiac CT after the Norwood procedure for hypoplastic left heart syndrome. MATERIALS AND METHODS: In 14 consecutive patients with hypoplastic left heart syndrome, end-systolic and end-diastolic phase cardiac dual-source CT was performed before and early (average: 1 month) after the Norwood procedure, and repeated late (median: 4.5 months) after the Norwood procedure in six patients. Ventricular functional parameters and indexed morphological measurements including pulmonary artery size, right ventricular free wall thickness, and ascending aorta size on cardiac CT were compared between different time points. Moreover, morphological features including ventricular septal defect, endocardial fibroelastosis and coronary ventricular communication were evaluated on cardiac CT. RESULTS: Right ventricular function and volumes remained unchanged (indexed end-systolic and end-diastolic volumes: 38.9+/-14.0 vs. 41.1+/-21.5 ml/m2, P=0.7 and 99.5+/-30.5 vs. 105.1+/-33.0 ml/m2, P=0.6; ejection fraction: 60.1+/-7.3 vs. 63.8+/-7.0%, P=0.1, and indexed stroke volume: 60.7+/-18.0 vs. 64.0+/-15.6 ml/m2, P=0.5) early after the Norwood procedure, but function was decreased (ejection fraction: 64.2+/-2.6 vs. 58.1+/-7.1%, P=0.01) and volume was increased (indexed end-systolic and end-diastolic volumes: 39.2+/ 14.9 vs. 68.9+/-20.6 ml/m2, P<0.003 and 107.8+/-36.5 vs. 162.9+/-36.2 ml/m2, P<0.006, and indexed stroke volume: 68.6+/-21.7 vs. 94.0+/-21.3 ml/m2, P=0.02) later. Branch pulmonary artery size showed a gradual decrease without asymmetry after the Norwood procedure. Right and left pulmonary artery stenoses were identified in 21.4% (3/14) of the patients. Indexed right ventricular free wall thickness showed a significant increase early after the Norwood procedure (25.5+/ 3.5 vs. 34.8+/-5.1 mm/m2, P=0.01) and then a significant decrease late after the Norwood procedure (34.8+/-5.1 vs. 27.2+/-4.2 mm/m2, P<0.0001). The hypoplastic ascending aorta smaller than 2 mm in diameter was identified in 21.4% (3/14) of the patients. Ventricular septal defect (n=3), endocardial fibroelastosis (n=2) and coronary ventricular communication (n=1) were detected on cardiac CT. CONCLUSION: Cardiac CT can be used to assess serial changes in anatomy and ventricular function after the Norwood procedure in patients with hypoplastic left heart syndrome. PMID- 28879414 TI - Language Skills in Classical Chinese Text Comprehension. AB - This study used both quantitative and qualitative methods to explore the role of lower- and higher-level language skills in classical Chinese (CC) text comprehension. A CC word and sentence translation test, text comprehension test, and questionnaire were administered to 393 Secondary Four students; and 12 of these were randomly selected to participate in retrospective interviews. The findings revealed that students' CC reading performance was unsatisfactory with respect to both lower- and text-level comprehension. Among the different factors examined, the most crucial to CC reading comprehension was lower-level reading skill. Owing to students' weak lower-level reading skills, participants relied heavily on contextual clues when reading in CC. The implications of these findings for understanding factors that contribute to CC reading comprehension, and for planning effective instruction to enhance students' CC reading competence are discussed. PMID- 28879413 TI - Predictors of patient decision to discontinue anti-rheumatic medication in patients with rheumatoid arthritis: results from the Ontario best practices research initiative. AB - Despite the availability of treatment guidelines and effective treatments, real world effectiveness remains suboptimal partly due to poor patient medication adherence. We evaluated a comprehensive set of sociodemographic, health insurance, and disease-related factors for association with patient decision to discontinue anti-rheumatic medications (ARMs) in a large observational RA cohort in Ontario, Canada. Patients from the Ontario Best Practices Research Initiative registry were included. The following predictors of ARM discontinuation were evaluated with cox-regression: patient age, gender, education, income, smoking, health insurance type/coverage, RA duration, erosion presence, RF positivity, DAS28-ESR, physician global, HAQ-DI, comorbidity number, ARM types, and physician characteristics (gender, academic position, urban vs. rural, distance from patient's residence). Patients (1762) were included with a mean (SD) age of 57.4 years (13.0). Approximately 80% were female, 29% had early (<= 1 year) RA, and 70% were RF-positive. Mean (SD) baseline DAS28-ESR and HAQ-DI were 4.5 (1.5) and 1.2 (0.76), respectively. In multivariate analysis, married status (HR [95%CI] 0.73 [0.56-0.96]), RF positivity (0.73 [0.56-0.96]), and higher comorbidity number (0.92 [0.85-0.99]) were significant predictors of ARMs continuation while higher physician global (1.10 [1.04-1.15]), NSAID use (1.75 [1.29-2.38]), and number of ARMs (1.23 [1.07-1.40]) were associated with ARMs discontinuation. In a subset analysis assessing conventional or biologic DMARD discontinuation, higher HAQ-DI and biologic use over time were associated with lower hazard for discontinuation. Several sociodemographic, disease, and treatment parameters were identified as independent predictors of patient discontinuation of ARMs. These results should be considered when developing patient adherence support programs and in the choice of treatment regimens. PMID- 28879412 TI - The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations. AB - The treatment landscape for relapsing forms of multiple sclerosis (RMS) has expanded considerably over the last 10 years with the approval of multiple new disease-modifying therapies (DMTs), and others in late-stage clinical development. All DMTs for RMS are believed to reduce central nervous system immune-mediated inflammatory processes, which translate into demonstrable improvement in clinical and radiologic outcomes. However, some DMTs are associated with long-lasting effects on the immune system and/or serious adverse events, both of which may complicate the use of subsequent therapies. When customizing a treatment program, a benefit-risk assessment must consider multiple factors, including the efficacy of the DMT to reduce disease activity, the short- and long-term safety and immunologic profiles of each DMT, the criteria used to define switching treatment, and the risk tolerance of each patient. A comprehensive benefit-risk assessment can only be achieved by evaluating the immunologic, safety, and efficacy data for DMTs in the controlled clinical trial environment and the postmarketing clinical practice setting. This review is intended to help neurologists make informed decisions when treating RMS by summarizing the known data for each DMT and raising awareness of the multiple considerations involved in treating people with RMS throughout the entire course of their disease. PMID- 28879415 TI - Development of metabolic syndrome in high-sucrose diet fed rats is not associated with decrease in adiponectin levels. AB - PURPOSE: Association of circulating adiponectin levels with metabolic syndrome has been controversial, with studies reporting low as well as high circulating adiponectin levels in metabolic syndrome. Present study aims to examine prospectively the course of circulating adiponectin levels during development of metabolic syndrome in a diet-induced rat model of metabolic syndrome. METHODS: In a prospective study, eight-week-old male wistar rats were randomized into two groups (n = 24 each). Group A: standard chow diet and group B: high sucrose diet. Body weight, total and high molecular weight (HMW) adiponectin and insulin levels were measured during the study. Oral fat and glucose tolerance tests were done during the study at various time points from weeks 2 to 26. Visceral fat, subcutaneous fat, and adiponectin levels were also measured at week 48 in some of the rats. RESULTS: Significantly higher total adiponectin levels were found from week 2 to 26 in group B compared to group A (P = <0.05), whereas HMW adiponectin levels were similar in both the groups. Postprandial triglycerides, obesity, insulin resistance, and glucose intolerance were also found to be significantly higher in group B compared to group A during this period (P = <0.05). Total adiponectin levels of week 26 showed significant positive correlation with preceding postprandial triglyceride burden in group B (r = 0.60, P = 0.002). CONCLUSION: In conclusion, the present study finds that development of metabolic syndrome in high-sucrose diet fed rats is not associated with decrease in circulating adiponectin levels. PMID- 28879416 TI - Patient Age and Tumor Subtype Predict the Extent of Axillary Surgery Among Breast Cancer Patients Eligible for the American College of Surgeons Oncology Group Trial Z0011. AB - BACKGROUND: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial established the safety of omitting axillary lymph node dissection (ALND) for early-stage breast cancer patients with limited nodal disease undergoing lumpectomy. We examined the extent of axillary surgery among women eligible for Z0011 based on patient age and tumor subtype. METHODS: Patients with cT1-2, cN0 breast cancers and one or two positive nodes diagnosed from 2009 to 2014 and treated with lumpectomy were identified in the National Cancer Data Base. Sentinel lymph node biopsy (SLNB) was defined as the removal of 1-5 nodes and ALND as the removal of 10 nodes or more. Tumor subtype was categorized as luminal, human epidermal growth factor 2-positive (HER2+), or triple-negative. Logistic regression was used to estimate the odds of receiving SLNB alone versus ALND. RESULTS: The inclusion criteria were met by 28,631 patients (21,029 SLNB alone and 7602 ALND patients). Patients 70 years of age or older were more likely to undergo SLNB alone than ALND (27.0% vs 20.1%; p < 0.001). The radiation therapy use rate was 89.4% after SLNB alone and 89.7% after ALND. In the multivariate analysis, the uptake of Z0011 recommendations increased over time (2014 vs 2009: odds ratio [OR] 13.02; p < 0.001). Younger patients were less likely to undergo SLNB alone than older patients (age <40 vs >=70: OR 0.59; p < 0.001). Patients with HER2+ (OR 0.89) or triple-negative disease (OR 0.79) (p < 0.001) were less likely to undergo SLNB alone than those with luminal subtypes. CONCLUSIONS: Among women potentially eligible for ACOSOG Z0011, the use of SLNB alone increased over time in all groups, but the extent of axillary surgery differed by patient age and tumor subtype. PMID- 28879417 TI - Potential for aerobic NO2- reduction and corresponding key enzyme genes involved in Alcaligenes faecalis strain NR. AB - The potential for aerobic NO2- removal by Alcaligenes faecalis strain NR was investigated. 35 mg/L of NO2--N was removed by strain NR under aerobic conditions in the presence of NH4+. 15N-labeling experiment demonstrated that N2O and N2 were possible products during the aerobic nitrite removal process by strain NR. The key enzyme genes of nirK, norB and nosZ, which regulate the aerobic nitrite denitrification process, were successfully amplified from strain NR. The gene sequence analysis indicates that copper-containing nitrite reductase (NIRK) and periplasmic nitrous oxide reductase (NOSZ) were both hydrophilic protein and the transmembrane structures were absent, while nitric oxide reductase large subunit (NORB) was a hydrophobic and transmembrane protein. According to the three dimensional structure and binding site analysis, the bulky and hydrophobic methionine residue proximity to the nitrite binding sites of NIRK was speculated to be related to the oxygen tolerance of NIRK from strain NR. PMID- 28879418 TI - Thread like calcifications in mesenteric phlebosclerosis. PMID- 28879420 TI - Estimated incidence of high altitude retinal hemorrhages. PMID- 28879419 TI - Experience and dissection device are more relevant than patient-related factors for operation time in laparoscopic sigmoid resection-a retrospective 8-year observational study. AB - PURPOSE: Surgical outcome is influenced by multiple patient-specific factors and operative expertise of the surgeon. Clinical relevance of medical technical innovations often remains unclear even though laparoscopic surgical procedures are characterized by continual advancement of various devices. Lately, in dissection and sealing technology, fast-cutting ultrasonic scissors are combined with simultaneous bipolar coagulation (bimodal dissection device (BDD)). We investigated how this new technology, operative expertise, and patient-specific factors (body mass index, age) influence operation time in laparoscopic-assisted sigmoid resection. METHODS: Between 2008 and 2016, 161 laparoscopic sigmoid resections (52% conventional dissection device (CDD); 48% BDD) performed in a single center were retrospectively evaluated. Biometric patient data, complication rates, and surgery duration, reflecting the learning curve, were analyzed. Operations were performed by experienced surgeons (n = 3) and trainees (n = 4). RESULTS: Minor postoperative complications (e.g., impaired wound healing, non-revisional secondary bleeding) occurred in 11 cases (6.8%). Major complications (e.g., bleeding requiring revision, anastomotic leakage) were observed in 3.7%. No heat-related coagulation damage was observed. BDD reduced operation time for both experienced (CDD 150 min, BDD 125 min; p < 0.001) and trainee surgeons (CDD 169 min, BDD 135 min; p = 0.036). Reduction of operation time (indicative of a learning curve in progress) was observed for all surgeons. The curve was steeper using BDD. CONCLUSIONS: Patient-specific factors did not have a significant effect on operation time. Even taking the learning curve into account, a combination of ultrasonic dissection and simultaneous bipolar coagulation reduces operation time of laparoscopic-assisted sigmoid resection, regardless of surgeon's expertise. PMID- 28879421 TI - The history of Rhoton's Lab. AB - The work performed in Dr. Rhoton's Lab, represented by over 500 publications on microneurosurgical anatomy, greatly contributed to improving the level of neurosurgical treatment throughout the world. The authors reviewed the development and activities of the Lab over 40 years. Dr. Albert L. Rhoton Jr., the founder of, and leader in, this field, displayed great creativity and ingenuity during his life. He devoted himself to perfecting his study methodology, employing high-definition photos and slides to enhance the quality of his published papers. He dedicated his life to the education of neurosurgeons. His "lab team," which included microneuroanatomy research fellows, medical illustrators, lab directors, and secretaries, worked together under his leadership to develop the methods and techniques of anatomical study to complete over 160 microneurosurgical anatomy projects. The medical illustrators adapted computer technologies and integrated art and science in the field of microneurosurgical anatomy. Dr. Rhoton's fellows established methods of injecting colors and pursued a series of projects to innovate surgical approaches and instruments over a 40-year period. They also continued to help Dr. Rhoton to conduct international educational activities after returning to their home countries. Rhoton's Lab became a world-renowned anatomical lab as well as a microsurgical training center and generated the knowledge necessary to perform accurate, gentle, and safe surgery for the sake of patients. PMID- 28879422 TI - Differentiating primary hepatic angiosarcomas from hemangiomatosis and epithelioid hemangioendotheliomas using gadoxetic acid-enhanced and diffusion weighted MR imaging. AB - OBJECTIVES: To assess the value of gadoxetic acid-enhanced and diffusion-weighted (DW) magnetic resonance (MR) imaging for differentiating primary hepatic angiosarcomas from hemangiomatosis and epithelioid hemangioendotheliomas (EHEs). METHODS: We reviewed MR images of seven patients with pathologically determined hepatic angiosarcomas, 11 patients with hemangiomatosis, and five patients with EHEs. Two radiologists assessed morphologic features, signal intensity (SI), enhancement patterns, and the presence of diffusion restriction by consensus and compared between angiosarcoma vs hemangiomatosis and angiosarcoma vs EHEs. RESULTS: Angiosarcomas more frequently showed mixed well- and ill-defined margins (6, 85.7%), mixed strong and intermediate-high SI (5, 71.4%) on T2-weighted images, mixed peripheral and/or central nodular and rim and/or target enhancement (5, 71.4%), and mixed presence and absence of diffusion restriction (7, 100%) compared with hemangiomatosis and EHEs (P < 0.05). The overall survival rate in patients with angiosarcomas was 42.9% at 3 months and 14.3% at 14 months, whereas all patients with EHEs were alive during the follow-up period from 4 to 43 months (P = 0.002). CONCLUSION: Gadoxetic acid-enhanced and DW MR imaging may help differentiate primary hepatic angiosarcomas with hemangioma-like appearance, EHE like appearance, or both; and poor prognosis from hemangiomatosis and EHEs. PMID- 28879424 TI - Increasing the involvement of diverse populations in genomics-based health care lessons from haemoglobinopathies. AB - Integrating genomic medicine into health care delivery poses significant challenges to health professionals. To draw clinical benefit from genomic information, there is a need to build an evidence-based relationship between genotype and the physical expression of that genomic information. The work presented here uses preliminary work in the field of haemoglobinopathies to address two important challenges: to ensure that health care professionals in low and middle-income countries are actively involved in the processes that will support genomic medicine, and that equity and diversity concerns are met so that clinical services can have relevance across all population and sub-population groups. Haemoglobinopathies provide an opportunity for gaining a better understanding of how long-standing genetic knowledge can be leveraged to determine if genomic-based services can be beneficial in low-resource settings. The Global Globin 2020 Challenge (GG2020) is an international initiative that uses haemoglobinopathies as an entry point to achieving growth in the quality and quantity of curated inputs into internationally recognised databases, harmonising the sharing of variant information within and between countries for better health care delivery and ensuring that storing, curation and sharing of variant information become an integral part of health care. Early findings from GG2020 indicate that paying attention to population diversity is an integral part of prevention and control of haemoglobinopathies. PMID- 28879425 TI - Erratum to: Non-coding RNA: It's Not Junk. PMID- 28879426 TI - Cerebral amyloid angiopathy: subtypes, treatment and role in cognitive impairment. PMID- 28879423 TI - Transcriptional Effects of ApoE4: Relevance to Alzheimer's Disease. AB - The major genetic risk factor for sporadic Alzheimer's disease (AD) is the lipid binding and transporting carrier protein apolipoprotein E, epsilon 4 allele (ApoE4). One of the unsolved mysteries of AD is how the presence of ApoE4 elicits this age-associated, currently incurable neurodegenerative disease. Recently, we showed that ApoE4 acts as a transcription factor and binds to the promoters of genes involved in a range of processes linked to aging and AD disease pathogenesis. These findings point to novel therapeutic strategies for AD and aging, resulting in an extension of human healthspan, the disease-free and functional period of life. Here, we review the effects and implications of the putative transcriptional role of ApoE4 and propose a model of Alzheimer's disease that focuses on the transcriptional nature of ApoE4 and its downstream effects, with the aim that this knowledge will help to define the role ApoE4 plays as a risk factor for AD, aging, and other processes such as inflammation and cardiovascular disease. PMID- 28879427 TI - Relapsed subcutaneous panniculitis-like T cell lymphoma: role of haploidentical hematopoietic stem cell transplant. PMID- 28879428 TI - Difficult-to-treat idiopathic nephrotic syndrome: established drugs, open questions and future options. AB - The idiopathic nephrotic syndrome in childhood can be classified according to the International Study of Kidney Disease in Children (ISKDC) based on the response to steroids. Typically, steroid-sensitive nephrotic syndrome (SSNS) is characterised by minimal changes in disease (MCD) histology, whereas in steroid resistant nephrotic syndrome (SRNS) focal segmental glomerulosclerosis (FSGS) is the most prevalent lesion. Patients with SSNS may develop frequent relapses and/or steroid dependency, which can be difficult to treat. New studies confirm the value of calcineurin inhibitors (CNIs) and mycophenolic acid in preventing relapses of SSNS. Rituximab also plays an important role, but many questions regarding initial dosing, repetitions of courses, and long-term side effects remain unclear. SRNS, especially when unresponsive to treatment, can lead to chronic kidney disease. In particular, treatment with CNIs has improved the prognosis and recent data indicate that treatment can even be discontinued in many patients with full remission. In CNI-unresponsive SRNS, rituximab is less effective than in SSNS and the role of other biologicals (such as ofatumumab, abatacept, and others) remains unclear. A significant proportion of children with FSGS have genetic causes and most patients do not respond to immunosuppression, although individual patients with partial and even complete response have been documented. Future studies should evaluate treatments leading to long-term remission without maintenance immunosuppression in SSNS; in both genetic and immune-mediated SRNS, novel options to decrease the number of treatment unresponsive patients seem mandatory, as they are at a high risk of developing end-stage renal disease. PMID- 28879429 TI - An observational study investigating failure of primary endocrine therapy for operable breast cancer in the elderly. AB - BACKGROUND: Elderly patients are more likely to have oestrogen receptor positive cancers that can be treated without surgery with primary endocrine therapy (PET). Few studies have sought to identify predictors of failure of PET and so the aim of this study was to evaluate treatment failures in elderly breast cancer patients treated with PET and to determine predictors of failure. METHODS: A retrospective observational study was performed on consecutive patients with ER positive early stage breast cancer treated with PET between 2005 and 2015 in the three breast units in the North East of England. The primary outcome measure was treatment failure and secondary outcome measure was disease progression. RESULTS: 488 patients were included with mean follow-up 31 months (SD 23). Overall, 206 patients were still alive with their disease controlled at the end of follow-up, 219 had died with their disease controlled and 63 (12%) experienced treatment failure. Younger age [SHR 0.96 (95% CI 0.94-0.99) p 0.013], larger tumours [SHR 1.03 (1.01-1.06) p 0.015], grade 3 cancers [SHR 3.58 (1.93-6.63) p < 0.001] and axillary lymph node metastases [SHR 1.93 (1.06-3.52) p 0.030] were all independent predictors of treatment failure. Disease progression was reported in 86 (17.6%) of patients. CONCLUSIONS: This is the largest retrospective series evaluating PET treatment failure. Clear predictors of failure have been identified, which can be used to facilitate treatment decision making. These results support previous analyses, further validating our results. PMID- 28879430 TI - High mobility group box 1 enhances hyperthermia-induced seizures and secondary epilepsy associated with prolonged hyperthermia-induced seizures in developing rats. AB - Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1's role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14-15-day-old male rats were divided into four groups: high dose HMGB1 (100 MUg), moderate-dose (10 MUg), low-dose (1 MUg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10-11-day-old rats were divided into four groups: pHS + HMGB1 (10 MUg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS. PMID- 28879431 TI - Bootstrap-Calibrated Interval Estimates for Latent Variable Scores in Item Response Theory. AB - In most item response theory applications, model parameters need to be first calibrated from sample data. Latent variable (LV) scores calculated using estimated parameters are thus subject to sampling error inherited from the calibration stage. In this article, we propose a resampling-based method, namely bootstrap calibration (BC), to reduce the impact of the carryover sampling error on the interval estimates of LV scores. BC modifies the quantile of the plug-in posterior, i.e., the posterior distribution of the LV evaluated at the estimated model parameters, to better match the corresponding quantile of the true posterior, i.e., the posterior distribution evaluated at the true model parameters, over repeated sampling of calibration data. Furthermore, to achieve better coverage of the fixed true LV score, we explore the use of BC in conjunction with Jeffreys' prior. We investigate the finite-sample performance of BC via Monte Carlo simulations and apply it to two empirical data examples. PMID- 28879432 TI - Opportunistic Environmental Sensing with Smartphones: a Critical Review of Current Literature and Applications. AB - PURPOSE OF REVIEW: This review sought to summarize recent literature and applications of passive, or opportunistic, mobile sensing in the fields of exposure science in built environment settings; highlight innovative opportunistic sensing systems; and analyze their functionality, significant features, and limitations. RECENT FINDINGS: Fifty-two papers related to opportunistic environmental sensing from 2009 or later were related to this review, of which 27 were included. An array of applications have emerged in environmental monitoring, employing anywhere from one to six of the phone's on board sensors. The viability of an application is determined by several key factors: the number and quality of sensors on-board the smartphone; power and processing demand; algorithm complexity; data security; mobile network coverage; reliance on external data sources; minimum number of users required; and degree of user burden when using the application. Some factors are universal, while others are more context-specific. Future research should assess sensing applications based on these factors. PMID- 28879434 TI - Sedentary behaviour and bone health in children, adolescents and young adults: a systematic review-supplementary presentation. AB - BACKGROUND: Sedentary behaviour (SB) is a potential risk factor for suboptimal bone deposition in youth. RESULTS: Total SB was negatively associated with lower extremity bone outcomes, while no association was observed with total body bone outcomes. Insufficient evidence was found for an association between total SB and lumbar spine bone outcomes. CONCLUSION: This review highlights the heterogeneity of the available evidence and emphasizes the need for well-designed studies. PMID- 28879433 TI - CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN. AB - The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN. Importantly, SMN acetylation enhances its cytoplasmic localization, causes depletion of CBs, and reduces the accumulation of snRNPs in nuclear speckles. In contrast, the acetylation-deficient SMNK119R mutant promotes formation of CBs and a novel category of promyelocytic leukemia (PML) bodies enriched in this protein. Acetylation increases the half-life of SMN protein, reduces its cytoplasmic diffusion rate and modifies its interactome. Hence, SMN acetylation leads to its dysfunction, which explains the ineffectiveness of HDAC (histone deacetylases) inhibitors in SMA therapy despite their potential to increase SMN levels. PMID- 28879435 TI - Anti-herpes simplex virus 1 and immunomodulatory activities of a poly-gamma- glutamic acid from Bacillus horneckiae strain APA of shallow vent origin. AB - Herpes simplex virus type 1 (HSV-1) is responsible of common and widespread viral infections in humans through the world, and of rare, but extremely severe, clinical syndromes in the central nervous system. The emergence of resistant strains to drugs actually in use encourages the searching for novel antiviral compounds, including those of natural origin. In this study, the recently described poly-gamma-glutamic acid (gamma-PGA-APA), produced by the marine thermotolerant Bacillus horneckiae strain APA, and previously shown to possess biological and antiviral activity, was evaluated for its anti-HSV-1 and immunomodulatory properties. The biopolymer hindered the HSV-1 infection in the very early phase of virus replication. In addition, the gamma-PGA-APA was shown to exert low cytotoxicity and noticeable immunomodulatory activities towards TNF alpha and IL-1beta gene expression. Moreover, the capacity to positively modulate the transcriptional activity of the cytokine genes was paired with increased level of activation of the transcription factor NF-kB by gamma-PGA-APA. Overall, as non-cytotoxic biopolymer able to contribute in the antiviral defense against HSV-1, gamma-PGA-APA could lead to the development of novel natural drugs for alternative therapies. PMID- 28879436 TI - Dynamic morphological changes of thrombosed lateral sinus pericranii revealed by serial magnetic resonance images. AB - BACKGROUND: Sinus pericranii (SP) is a rare venous anomaly involving an abnormal connection of the intracranial dural sinuses with the extracranial veins. Magnetic resonance (MR) imaging (MRI) with MR venography can detect the typically congested intra- and extracranial venous components of SP. CLINICAL PRESENTATION: We report a rare case of lateral SP associated with the superior sagittal sinus, which might had already developed almost total thrombosis of the SP at the first MRI. As this patient had not presented with classical manifestations of SP on clinical or neuroradiological findings, the initial diagnosis of SP was difficult. Repeated MRI revealed dynamic morphological changes associated with reperfusion of the thrombosed SP via the cortical vein. CONCLUSION: MR venography combined with gadolinium enhancement was useful for diagnosis of the SP with an extremely slow flow status. PMID- 28879437 TI - Major underestimation and overestimation of visual blood loss during cesarean deliveries: can they be predicted? AB - PURPOSE: The surgeons' visual estimation is the most widely used method for estimating blood loss (BL) while performing cesarean deliveries (CDs). Major BL underestimation may adversely influence obstetric decision making, and result in delaying interventions. Major BL overestimation may result in unnecessary costly interventions. Therefore, we aimed to identify independent predictors for major BL underestimation and overestimation during CDs. METHODS: All CDs performed between 11/2008 and 6/2016, in a university-affiliated hospital, were reviewed for demographic and surgical data, including the surgeons' reported estimated BL (EBL). Calculated BL (CBL) was calculated by multiplying the calculated maternal blood volume by the percent of hematocrit decrease. Multivariate logistic regressions were performed to identify independent risk factors for major BL underestimation (CBL-EBL >= 400 ml) and overestimation (EBL-CBL >= 400 ml). RESULTS: During the study period, 3655 CDs were analyzed, of which 420 met the criterion for major BL underestimation and 1214 for major BL overestimation. Urgent surgery (aOR = 2.83; 95% CI 2.06-3.89), general anesthesia (aOR = 2.39; 95% CI 1.71-3.33), and higher surgeon experience (aOR = 1.03; 95% CI 1.01-1.06) were found to be independent risk factors for major BL underestimation, while any previous CD (aOR = 0.47; 95% CI 0.33-0.67) decreased the risk of underestimation. Any previous CD (aOR = 1.29; 95% CI 1.05-1.58) and intra-abdominal adhesions (aOR = 1.37; 95% CI 1.11-1.70) were found to be independent risk factors for major BL overestimation, while urgent CD (aOR = 0.50; 95% CI 0.41-0.60) decreased the risk of overestimation. CONCLUSION: Various factors can predict major underestimation and overestimation of BL during CDs. Recognizing these factors can assist in the interpretation of visual EBL and improve obstetric decision making. PMID- 28879438 TI - Do cognition and other non-motor symptoms decline similarly among patients with Parkinson's disease motor subtypes? Findings from a 5-year prospective study. AB - Among patients with Parkinson's disease (PD), a wide range of motor and non-motor symptoms (NMS) are evident. PD is often divided into tremor dominant (TD) and postural instability gait difficulty (PIGD) motor subtypes. We evaluated the effect of disease duration and aimed to characterize whether there are differences in the deterioration of cognitive function and other NMS between the PIGD and TD subtypes. Sixty-three subjects were re-evaluated at the follow-up visit about 5 years after baseline examination. Cognitive function and other NMS were assessed. At follow-up, the PIGD and TD groups were similar with respect to medications, comorbidities and disease-related symptoms. There was a significant time effect for all measures, indicating deterioration and worsening in both groups. However, cognitive scores, particularly those related to executive function, became significantly worse in the PIGD with a more moderate decrease in the TD group. For example, the computerized global cognitive score declined in the PIGD group from 94.21 +/- 11.88 to 83.91 +/- 13.76, p < 0.001. This decline was significantly larger (p = 0.03) than the decrease observed in the TD group (96.56 +/- 10.29 to 92.21 +/- 14.20, p = 0.047). A significant group * time interaction effect was found for the change in global cognitive score (p = 0.047), the executive function index (p = 0.002) and accuracy on a motor cognitive catch game (p = 0.008). In contrast, several NMS including depression, health-related quality of life and fear of falling deteriorated in parallel in both subtypes, with no interaction effect. The present findings highlight the difference in the natural history of the disease between the two PD "motor" subtypes. While the PIGD group demonstrated a significant cognitive decline, especially in executive functions, a more favorable course was observed in the TD subtype. This behavior was not seen in regards to the other NMS. PMID- 28879439 TI - Mannose-binding lectin (MBL) deficiency and tuberculosis infection in patients with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) patients may have higher prevalence of mannose binding lectin (MBL) deficiency than normal individuals. MBL deficiency may influence susceptibility to infections. The aim of the study was to verify if MBL deficiency in patients with AS predisposes to infections. We studied 60 patients with AS diagnosed according to the Assessment of SpondyloArthritis international Society (ASAS) criteria. These patients had their MBL serum levels determinated. Twenty-five individuals were identified as MBL deficient (serum values 100 ng/mL). These patients were paired with 35 "sufficient" MBL producers (median serum level = 700 ng/mL; range 150-4100 ng/mL) for gender, age, use of medications, and tobacco exposure. Medical records of all patients were retrospectively investigated for the period of 5 years and the rate of infection occurrence was compared in the two groups. AS patients with MBL deficiency had higher number of urinary tract infections (p = 0.03; IRR = 2.33; 95% CI = 0.95 6.04) and tuberculosis (p = 0.008; IRR = 9.8; 95% CI = 1.2-441.6) than controls. Regarding tuberculosis infection, one patient (2.8%) in the MBL-sufficient group and six (24.0%) from the deficient group had this infection. The MBL-sufficient patient and five from the deficient group have had latent infections, detected in the screening tests done previous to anti-TNF drug use. The other, in the deficient group, had lung infection while not on anti-TNF treatment. Another patient, from the deficient group, has had tuberculosis skeletal infection in the past. We found a significant association between MBL deficiency and higher risk of tuberculosis and urinary tract infection in patients with AS. More studies with higher number of patients are needed to confirm this finding. PMID- 28879440 TI - Neighborhood Influences on Vehicle-Pedestrian Crash Severity. AB - Socioeconomic factors are known to be contributing factors for vehicle-pedestrian crashes. Although several studies have examined the socioeconomic factors related to the location of the crashes, limited studies have considered the socioeconomic factors of the neighborhood where the road users live in vehicle-pedestrian crash modelling. This research aims to identify the socioeconomic factors related to both the neighborhoods where the road users live and where crashes occur that have an influence on vehicle-pedestrian crash severity. Data on vehicle pedestrian crashes that occurred at mid-blocks in Melbourne, Australia, was analyzed. Neighborhood factors associated with road users' residents and location of crash were investigated using boosted regression tree (BRT). Furthermore, partial dependence plots were applied to illustrate the interactions between these factors. We found that socioeconomic factors accounted for 60% of the 20 top contributing factors to vehicle-pedestrian crashes. This research reveals that socioeconomic factors of the neighborhoods where the road users live and where the crashes occur are important in determining the severity of the crashes, with the former having a greater influence. Hence, road safety countermeasures, especially those focussing on the road users, should be targeted at these high risk neighborhoods. PMID- 28879442 TI - Comparing eye trackers by correlating their eye-metric data. AB - Up to now, the potential of eye tracking in science as well as in everyday life has not been fully realized because of the high acquisition cost of trackers. Recently, manufacturers have introduced low-cost devices, preparing the way for wider use of this underutilized technology. As soon as scientists show independently of the manufacturers that low-cost devices are accurate enough for application and research, the real advent of eye trackers will have arrived. To facilitate this development, we propose a simple approach for comparing two eye trackers by adopting a method that psychologists have been practicing in diagnostics for decades: correlating constructs to show reliability and validity. In a laboratory study, we ran the newer, low-cost EyeTribe eye tracker and an established SensoMotoric Instruments eye tracker at the same time, positioning one above the other. This design allowed us to directly correlate the eye tracking metrics of the two devices over time. The experiment was embedded in a research project on memory where 26 participants viewed pictures or words and had to make cognitive judgments afterwards. The outputs of both trackers, that is, the pupil size and point of regard, were highly correlated, as estimated in a mixed effects model. Furthermore, calibration quality explained a substantial amount of individual differences for gaze, but not pupil size. Since data quality is not compromised, we conclude that low-cost eye trackers, in many cases, may be reliable alternatives to established devices. PMID- 28879441 TI - EGFR and KRAS mutations do not enrich for the activation of IL-6, JAK1 or phosphorylated STAT3 in resected lung adenocarcinoma. AB - Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against EGFR mutant lung adenocarcinoma develops after a median of nine to thirteen months. Upregulation of the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway may be a potential source of resistance to EGFR TKIs. We undertook a detailed assessment of the IL-6/JAK1/phosphorylated STAT3 (pSTAT3) pathway in resected lung adenocarcinoma specimens, with special interest in whether the presence of an EGFR mutation enriched for pSTAT3 positivity. Tumours from 143 patients with resected lung adenocarcinoma were assessed. EGFR and KRAS mutation status were scanned for with high-resolution melting and confirmed by polymerase chain reaction. Immunohistochemisty (IHC) was performed for IL-6, gp130, JAK1 and pSTAT3. Two methods for assigning IHC positivity were assessed (the presence of any positivity, and the presence of positivity at an H score >40). We found statistically significant associations between IL-6, JAK1 and pSTAT3 measured by IHC, consistent with the activation of the pathway in clinical specimens. No relationship was demonstrated between members of this pathway and oncogenic mutations in EGFR or KRAS. However, a proportion of tumours with EGFR mutations showed staining for IL-6, JAK1 and pSTAT3. No correlations with clinicopathologic features or survival outcomes were found for IL-6, JAK1 or pSTAT3 staining. The presence of EGFR or KRAS mutations did not enrich for the activation of IL-6, JAK1 or pSTAT3. pSTAT3 may still play a role in resistance to EGFR TKIs in clinical practice. PMID- 28879443 TI - Surgery vs. radiotherapy in patients with uveal melanoma : Analysis of the SEER database using propensity score matching and weighting. AB - BACKGROUND: The treatment modalities for uveal melanoma (UM) include surgery and radiotherapy (RT). The utilization of RT as a strategy for organ preservation has been increasing, but the survival difference between the two aforementioned treatment modalities has not been reported. METHODS: An observational and cohort study was performed using a propensity score with an already existing public database. Patients diagnosed with UM within the period from 2004-2013 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. One-to-one matching and inverse probability of treatment weighting (IPTW) using the propensity score were used to estimate and compare survival rates. RESULTS: Overall, 3291 patients were treated: 2503 received RT only (RT group) and 788 received surgical resection only (surgery group). The RT group had an improved crude 5-year overall survival (OS) rate compared with the surgery group (76% vs. 60%, P < 0.001), and an improved 5-year melanoma-specific survival (MSS) rate (89% vs. 73%, P < 0.001). Compared to the surgery group, the RT group was associated with improved OS (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.38-0.73, P < 0.001) and MSS (HR 0.48, 95% CI 0.35-0.65, P < 0.001) in the matched cohort. The survival benefit of the RT group maintained after adjustment with IPTW, both in OS and MSS. CONCLUSIONS: To our knowledge, the present study was the first to demonstrate the survival difference between the two treatment modalities for UM using both the propensity score matching and weighting methods with the SEER database. The current study suggests that RT may provide a survival advantage over surgery in the treatment of UM. PMID- 28879444 TI - Comparative Study on Whole Genome Sequences of Aspergillus terreus (Soil Fungus) and Diaporthe ampelina (Endophytic Fungus) with Reference to Lovastatin Production. AB - Lovastatin is a competitive inhibitor of the enzyme hydroxymethyl glutaryl coenzyme A reductase (HMGR) in cholesterol biosynthetic pathway and hence used in the treatment of hyperlipidemia. In a previous study, we report a tropical soil isolate, Aspergillus terreus (KM017963), which produces ample amount of lovastatin than its counterpart that are endophytic in origin. Bioinformatic analysis of whole genome sequence of A. terreus (AH007774.1), a soil isolate revealed the presence of gene cluster (AF141924.1 & AF141925.1) responsible for lovastatin production, whereas endophytic fungi including a strain of A. terreus showed no homology with the lovastatin gene cluster. The molecular study was also carried out targeting PCR amplification of the two important genes, lovE (a regulatory gene) and lovF (transcriptional regulatory factor) in genomic and c DNA of soil and endophytic fungi. Expression of the two genes was successful in A. terreus (KM017963), whereas the same was not achieved in endophytic fungi. To further validate our above findings, in the present study, the whole genome sequencing of A. terreus and a selected endophytic fungus, Diaporthe ampelina (Phomopsis) was performed. Lovastatin gene cluster, when aligned on the consensus sequence of both genomes, the entire lovastatin gene cluster was detected in a single scaffold (1.16) of A.terreus genome. On the contrary, there was a complete absence of lovastatin gene cluster in the genome of D. ampelina (an endophyte). The probable reasons for the absence of lovastatin gene cluster in endophytic fungi are discussed. PMID- 28879445 TI - Validity, reliability, and responsiveness to change of the "Osteoporosis and You" knowledge scale. AB - : We studied the Osteoporosis and You knowledge scale in 7749 participants enrolled in a clinical trial. Results confirmed its psychometric properties in a diverse audience. Baseline scores were associated with better recall of bone mineral density test results at follow-up; however, the scale was not responsive to knowledge change. INTRODUCTION: The goal of this study was to confirm the measurement properties of the Osteoporosis and You (O&Y) knowledge scale using classic test theory methods in the 7749 men and women participating in the Patient Activation After DXA Result Notification (PAADRN) randomized controlled trial. We hypothesized a simple factor structure that would reflect the four factor model previously published. METHODS: We conducted psychometric analyses which included item analysis, internal consistency reliability, construct validity using exploratory and confirmatory factor analysis (EFA and CFA), comparing knowledge levels across pre-specified groups, and responsiveness to change. RESULTS: PAADRN participants were predominantly college educated, White females with low bone density, and a moderate level of 10-year fracture risk. EFA revealed four domains closely matching those in two previous reports. While overall scale reliability was minimally acceptable at 0.68, the reliabilities of the domain subscales were unacceptably low (0.59, 0.64, 0.45, and 0.36 for the Biological, Lifestyle, Consequences, and Prevention and Treatment subscales). CFA revealed the data fit the hypothesized model reasonably well with the items loading on their expected latent variable. The scale was not responsive to change, but although not significant, improved knowledge indicated better DXA result recall at 12 and 52 weeks. CONCLUSIONS: In the PAADRN population, the O&Y knowledge scale had psychometric properties similar to those previously reported. Over 12 and 52 weeks, participants did not demonstrate significant changes in knowledge, but those with higher knowledge at baseline were more likely to accurately recall their baseline DXA result. PMID- 28879446 TI - Parkinsonian symptoms in normal pressure hydrocephalus: a population-based study. AB - It may be challenging to differentiate normal pressure hydrocephalus (NPH) from neurodegenerative disorders such as Parkinson's disease. In this population-based study, we wanted to describe the frequency of parkinsonian symptoms among individuals with and without NPH, and whether the motor examination part of the Unified Parkinson's Disease Rating Scale (UPDRS-m) score differs between these groups. Furthermore, we wanted to find out whether there was a relationship between UPDRS-m score, NPH symptoms, and radiological signs of NPH. A sample of 168 individuals over the age of 65 with and without self-reported symptoms of NPH underwent a computerized tomography of the brain and clinical examination, including UPDRS-m to grade parkinsonian symptoms. According to diagnostic guidelines, 38 fulfilled criteria for NPH, whereas 130 had unlikely NPH. Bradykinesia was significantly more common among those with NPH (79%) compared to those with unlikely NPH (32%) (p < 0.001). The corresponding figures for rigidity were 43 vs. 15% (p < 0.001), for postural instability 71 vs. 22% (p < 0.001), and for tremor at rest 5 vs. 6% (not significant). The total UPDRS-m score was significantly higher among individuals with NPH (median = 12) than without (median = 1) and correlated significantly with the degree of NPH symptoms (r = 0.72) and ventriculomegaly (r = 0.31). In this study, parkinsonian symptoms, except resting tremor, were frequent in individuals with NPH and correlated with the severity of NPH symptoms. Asymmetric symptoms were uncommon. We recommend a liberal use of neuroradiological imaging when investigating a patient with parkinsonian features. PMID- 28879447 TI - Lactic acid bacteria isolated from yak milk show probiotic potential. AB - Probiotic industries strive for new, efficient and promising probiotic strains that impart a positive impact on consumer health. Challenges are persisting in isolation, screening, and selection of the new indigenous probiotic strains. In the present research, we explored the probiotic potential of 17 lactic acid bacteria isolated from Yak milk in a series of in vitro tests. We also demonstrated their health benefits, i.e., cholesterol degradation, lactose digestion, antimicrobial activity, antioxidant, and anticancer activities. Principal component analysis revealed that more than 50% of the strains fulfilled the examined criteria, e.g., survival in acidic pH, bile concentrations, and adherent property. Approximately all the strains produced antimicrobial substances against the maximum number of tested strains including clinical strains. Most strains degraded cholesterol in comparison to the reference probiotic strain whereas strain Yc showed 1.5 times higher the degradation efficiency of the control strain. Lan4 strain exhibited remarkable anticancer activity and induced the maximum apoptosis (87%) in the Hela cells and was non toxic to the non-cancerous HEK293 cells. Around ten strains showed positive lactose digestion. Overall, this can be concluded that selected lactic acid bacteria revealed excellent probiotic properties along with desirable health benefits. These strains need to be further investigated in details for their application in the development of novel probiotic preparations for the improvement of public health. PMID- 28879448 TI - Pre-decannulation flexible bronchoscopy in tracheostomized children. AB - OBJECTIVES: This study was aimed to evaluate the utility and benefits of flexible fiberoptic bronchoscopy (FFB) prior to tracheostomy decannulation. METHODS: Besides demographic data, initial cause of tracheostomy, primary diagnosis, pre tracheostomy and pre-decannulation bronchoscopic findings and duration of tracheostomy were collected from medical charts. The type of active intervention following bronchoscopy and outcome after decannulation were recorded. Departmental decannulation policy and procedure were used in all patients. RESULTS: Forty-nine tracheostomized patients who underwent decannulation attempt were included. The median age of the children at the time of decannulation was 3 years (range 4 months-16 years). The median duration of tracheostomy was 8 months (range 1-86 months). Prolonged mechanical ventilation was the commonest indication for tracheostomy. There were 45 abnormal findings on FFB in 36 patients. Airway granulation was the commonest abnormality (23/45, 51%). Successful decannulation without any intervention was possible in 23 (46.9%) cases. 12 of these had normal bronchoscopy. Fifteen (30.6%) patients required surgical interventions before attempting decannulation. In five patients decannulation failed, while in six children decannulation was not attempted after FFB. CONCLUSION: Pre-decannulation flexible fiberoptic bronchoscopy in children with tracheostomy helps in identifying the possible causes of decannulation failure and helps in deciding the appropriate intervention. PMID- 28879449 TI - Prognostic factors of mortality in Iranian patients with systemic lupus erythematosus admitted to intensive care unit. AB - The aim was to determine the course, outcome, and determinants of mortality in patients with systemic lupus erythematosus (SLE) in intensive care unit (ICU). SLE patients admitted to ICU from 2004 to 2015 were recruited retrospectively. Demographic data, disease characteristics, causes of admission, baseline SLE disease activity index-2K (SLEDAI-2K) and Acute Physiologic and Chronic Health Evaluation II (APACHE) score, the outcome, and the causes of death were recorded. Predictors of mortality were compared between alive and dead patients by Cox regression analysis. Ninety-four patients with SLE were enrolled. Mean age at the time of ICU admission was 29.6 years. Average scores of SLEDAI and APACHE II were 11.3 and 19.8, respectively. The most common causes of ICU admission were pneumonia, diffuse alveolar hemorrhage (DAH), and seizure. Forty-seven patients (50%) died in ICU. The principal causes of death were septic shock (25.5%), multi organ failure (12.5%), DAH (10.6%), and pneumonia (10.6%). After multivariate analysis, high APACHE II, septic shock, and duration of mechanical ventilation were indicators of survival outcome. Mean (95% CI) survival days in ICU in patients with and without respiratory failure were 14.6 (10.4-18.9) and 28.7 (17.9-39.5) days, respectively (P = 0.001). This figure for those with and without septic shock was 13.5 (4.9-11.1) and 22.3 (9.3-24.7) days, respectively (P = 0.016). High APACHE II, septic shock, and duration of mechanical ventilation were the main predictors of death in patients with SLE in ICU. Multicenter studies are needed to draw a fine picture of SLE behavior in ICU. PMID- 28879450 TI - Estimation of neonatal outcome artery pH value according to CTG interpretation of the last 60 min before delivery: a retrospective study. Can the outcome pH value be predicted? AB - PURPOSE: The aim of this study was to analyze whether the umbilical artery pH value can be estimated throughout CTG assessment 60 min prior to delivery and if the estimated umbilical artery pH value correlates with the actual one. This includes analysis of correlation between CTG trace classification and actual umbilical artery pH value. Intra-and interobserver agreement and the impact of professional experience on visual analysis of fetal heart rate tracing were evaluated. METHODS: This was a retrospective study. 300 CTG records of the last 60 min before delivery were picked randomly from the computer database with the following inclusion criteria; singleton pregnancy >37 weeks, no fetal anomalies, vaginal delivery either spontaneous or instrumental-assisted. Five obstetricians and two midwives of different professional experience classified 300 CTG traces according to the FIGO criteria and estimated the postnatal umbilical artery pH. RESULTS: The results showed a significant difference (p < 0.05) in estimated and actual pH value, independent of professional experience. Analysis and correlation of CTG assessment and actual umbilical artery pH value showed significantly (p < 0.05) diverging results. Intra- and interobserver variability was high. Intraobserver variability was significantly higher for the resident (p = 0.001). No significant differences were detected regarding interobserver variability. CONCLUSION: An estimation of the pH value and consequently of neonatal outcome on the basis of a present CTG seems to be difficult. Therefore, not only CTG training but also clinical experience and the collaboration and consultation within the whole team is important. PMID- 28879451 TI - Prognostic factors and disease course in aquaporin-4 antibody-positive Chinese patients with acute optic neuritis. AB - The objective is to assess the frequency of AQP4-Ab in Chinese patients with optic neuritis (ON) and to investigate the prognostic implications of AQP4-Ab seropositivity in such patients. The presence of aquaporin-4 (AQP4) antibodies in human AQP4-transfected cells was determined by indirect immunofluorescence, and the diagnostic and prognostic relevance of AQP4 antibodies in 215 Chinese patients with optic neuritis was evaluated. The patients were enrolled from the Chinese People's Liberation Army General Hospital (PLAGH) and followed up to 1 228 months. Kaplan-Meier survival analysis was used to investigate the visual outcomes and prognostic characteristics of 70 patients who were aquaporin-4 antibody seropositive, and altogether 115 eyes were involved. AQP4-Ab was detectable in 70/215 (32.6%) patients with acute monosymptomatic optic neuritis. These AQP4-Ab seropositive patients were diagnosed as sufferers of neuromyelitis optica (NMO) (n = 10), NMO spectrum disease (NMOSD) (n = 41), multiple sclerosis (MS) (n = 1), and acute optic neuritis (AON) (n = 18). Moreover, AQP4-Ab levels did not vary between seropositive AON and NMO-ON and did not correlate with disease severity. Finally, the male gender, older age at onset, number of relapses, concomitant autoimmune antibodies, and optic lesions in magnetic resonance imaging (MRI) were associated with the AQP4-Ab seropositive status and the risk of developing permanent visual disability. Acute optic neuritis has a higher incidence of anti-aquaporin-4 antibody in China than in Western countries, and AQP4 antibody is a sensitive and specific biomarker for discriminating NMO-ON from other types of optic neuritis during the early stage of the disease course. PMID- 28879452 TI - Methylprednisolone plus diazepam i.v. as bridge therapy for medication overuse headache. AB - Management of medication overuse headache (MOH) requires abrupt suspension of overused drugs either alone or in association with a detoxification protocol to prevent withdrawal. However, there is no consensus about which suspension strategy is the most effective. Moreover, reliable data about the possible mid term effect of detoxification are not available. The objective of this study was to evaluate whether a bridge therapy consisting of a 5-day i.v. infusion of methylprednisolone and diazepam determines a significant reduction in headache frequency and drug assumption during the detoxification protocol (day 5) and in the first 3 months in patients with MOH. We conducted a retrospective non randomized before-and-after study comparing patients with MOH undergoing a bridge therapy protocol (5-day infusion of methylprednisolone, diazepam) with those who refused the treatment and were only recommended to suspend overused painkillers. Both groups started a prophylactic treatment and were followed-up for 3 months. At day 5, 82% of our patients were headache-free; moreover, 48% of the patients did not take any painkiller during the 5-day treatment. Three months after, the intervention group showed a greater reduction of monthly headache days (9.4 vs 3.0) and drugs (19.7 vs 6.5), a greater rate of patients with a >= 50% reduction of monthly headaches (p = 0.019) and symptomatic drug consumption (p = 0.000), than the control group. The methylprednisolone and diazepam detoxification protocol reduced headache attacks and drug assumption immediately and in the first 3 months after the intervention, concurring to improve the effect of a new prophylactic therapy. PMID- 28879453 TI - Fecal Calprotectin Rise in Chronic Granulomatous Disease-Associated Colitis. PMID- 28879454 TI - [Acute skin disorders in children]. PMID- 28879455 TI - Suicide in children and adolescents: a Tunisian perspective from 2009 to 2015. AB - This study presents the characteristics of child and adolescent suicides which occurred in Kairouan, Tunisia. Data were collected from autopsy records of the Forensic Department of the University Hospital Ibn El Jazzar of Kairouan. General characteristics of suicides among children and adolescents (under the age of 18) between 2009 and 2015 were retrospectively reviewed. A total of 49 cases, with a female predominance (61.2%) and a mean age of 15.4 +/- 2.1, were registered. Most of the victims were from rural areas (93.1%). In most cases, suicide occurred in the victim's home or the surrounding area (73.4%). The identified precipitating factors were family problems in 55.1%, and school issues in 12.2%. The most common suicide method was hanging (69.38%) for both genders, followed by self immolation for males and poisoning for females, the majority using pesticides. This study offers useful information to understand the risk factors in Tunisian child and adolescent suicides and provides a basis for the development of urgently needed preventive strategies. PMID- 28879456 TI - Experimental and kinetic study for lead removal via photosynthetic consortia using genetic algorithms to parameter estimation. AB - This work presents an experimental-theoretical strategy for a batch process for lead removal by photosynthetic consortium, conformed by algae and bacteria. Photosynthetic consortium, isolated from a treatment plant wastewater of Tecamac (Mexico), was used as inoculum in bubble column photobioreactors. The consortium was used to evaluate the kinetics of lead removal at different initial concentrations of metal (15, 30, 40, 50, and 60 mgL-1), carried out in batch culture with a hydraulic residence time of 14 days using Bold's Basal mineral medium. The photobioreactor was operated under the following conditions: aeration of 0.5 vvm, 80 MUmol m-2 s-1 of photon flux density and a photoperiod light/dark 12:12. After determining the best growth kinetics of biomass and metal removal, they were tested under different ratios (30 and 60%) of wastewater-culture medium. Additionally, the biomass growth (X), nitrogen consumption (N), chemical oxygen demand (COD), and metal removal (Pb) were quantified. Achieved lead removal was 97.4% when the initial lead concentration was up to 50 mgL-1 using 60% of wastewater. Additionally, an unstructured-type mathematical model was developed to simulate COD, X, N, and lead removal. Furthermore, a comparison between the Levenberg-Marquardt (L-M) optimization approach and Genetic Algorithms (GA) was carried out for parameter estimation. Also, it was concluded that GA has a slightly better performance and possesses better convergence and computational time than L-M. Hence, the proposed method might be applied for parameter estimation of biological models and be used for the monitoring and control process. PMID- 28879457 TI - Combining local and global cues to motion. AB - A spinning, moving object, such as a football with a surface texture, combines motion signals from rotation and translation. The interaction between these two kinds of signal was studied psychophysically with moving, circular clouds of dots, which also could move within the cloud. If the cloud moved near-vertically downwards but the dots within it moved obliquely, the apparent path of the cloud was attracted to that of the dots, as previously demonstrated with moving Gabor patches (Tse & Hseih Vision Research, 46, 3881-3885, 2006; Lisi & Cavanagh Current Biology, 25, 2535-40, 2015). This attractive effect was enhanced in parafoveal viewing and by not presenting a frame around the dots. A larger effect in the opposite direction (repulsion) was found for the perceived direction of the dots when they moved near-vertically and the cloud containing them moved obliquely. These results are discussed in relation to Gestalt principles of perceived relative motion and, more recently, Bayes-inspired accounts of the interaction between local and global motion. PMID- 28879458 TI - Magnetic Carbon Microspheres as a Reusable Adsorbent for Sulfonamide Removal from Water. AB - Novel reusable magnetic carbon microspheres (MCMs) were prepared by hydrothermal method with glucose as carbon source and Fe3O4 nanoparticles as magnetic raw materials. And adsorption performance of MCMs for sulfonamide removal from water was investigated in detail. The results indicated that the calcination temperature and calcination time had significant effects on the surface area and its volume porous of MCMs. When MCMs were calcined in 600 degrees C for 1 h, the surface area and volume porous of MCMs were 1228 m2/g and 0.448 m3/g, respectively. The adsorption results showed that the adsorption data fitted well with the Langmuir isotherm model and followed pseudo-second-order kinetics. When the pH value was changed from 4.0 to 10.0, the adsorption capacity of MCMs for sulfonamide was decreased from 24.6 to 19.2 mg/g. The adsorption capacity of as synthesized MCMs achieved 18.31 mg/g after it was reused four times, which exhibited a desirable adsorption capacity and reusability. PMID- 28879459 TI - Hypofractionated radiotherapy with simultaneous integrated boost (SIB) plus temozolomide in good prognosis patients with glioblastoma: a multicenter phase II study by the Brain Study Group of the Italian Association of Radiation Oncology (AIRO). AB - INTRODUCTION: A multicenter phase II study for assessing the efficacy and the toxicity of hypofractionated radiotherapy with SIB plus temozolomide in patients with glioblastoma was carried out by the Brain Study Group of the Italian Association of Radiation Oncology. METHODS: Twenty-four patients with newly diagnosed glioblastoma belonging to Recursive Partitioning Analysis classes III and IV were enrolled. The prescribed dose was 52.5 Gy in 15 fractions of 3.5 Gy and 67.5 in 15 fractions of 4.5 Gy to the SIB volume. Dose constraints for the hypofractionated schedule were provided. Radiotherapy was associated with concomitant and sequential temozolomide. RESULTS: Median overall survival (OS) was 15.1 months, while median progression-free survival (PFS) was 8.6 months. Actuarial OS at 12 months was 65.6% +/- 0.09, whereas actuarial PFS at 12 months was 41.2% +/- 0.10. Status of methylation of MGMT promoter resulted to be a significant prognostic factor for OS. Radiotherapy-related acute toxicity was not relevant. Three patients (12.5%) had G3 myelotoxicity that required temozolomide temporary interruption or dose reduction during the chemotherapy. However, chemotherapy was not definitely discontinued for toxicity in any case. One patient out of 24 (4.2%) developed radionecrosis that required surgical resection with no evidence of disease in the surgical specimen. CONCLUSIONS: This trial confirms that hypofractionated radiotherapy with SIB and association with temozolomide may be a reasonable and feasible option for good prognosis patients with GBM. PMID- 28879462 TI - Abstracts of Scientific Oral and Poster Presentations at the 19th Meeting of the Biofeedback Federation of Europe. PMID- 28879460 TI - Vitamin B6 Reduces Neurochemical and Long-Term Cognitive Alterations After Polymicrobial Sepsis: Involvement of the Kynurenine Pathway Modulation. AB - Neurological dysfunction as a result of neuroinflammation has been reported in sepsis and cause high mortality. High levels of cytokines stimulate the formation of neurotoxic metabolites by kynurenine (KYN) pathway. Vitamin B6 (vit B6) has anti-inflammatory and antioxidant properties and also acts as a cofactor for enzymes of the KYN pathway. Thus, by using a relevant animal model of polymicrobial sepsis, we studied the effect of vit B6 on the KYN pathway, acute neurochemical and neuroinflammatory parameters, and cognitive dysfunction in rats. Male Wistar rats (250-300 g) were submitted to cecal ligation and perforation (CLP) and divided into sham + saline, sham + vit B6, CLP + saline, and CLP + vit B6 (600 mg/kg, s.c.) groups. Twenty-four hours later, the prefrontal cortex and hippocampus were removed for neurochemical and neuroinflammatory analyses. Animals were followed for 10 days to determine survival rate, when cognitive function was assessed by behavioral tests. Vitamin B6 interfered in the activation of kynurenine pathway, which led to an improvement in neurochemical and neuroinflammatory parameters and, consequently, in the cognitive functions of septic animals. Thus, the results indicate that vit B6 exerts neuroprotective effects in acute and late consequences after sepsis. PMID- 28879463 TI - Predictors of complications of snake envenomation in Cayenne, French Guiana, 2007 2015. PMID- 28879461 TI - Perinatal Exposure to the Cyanotoxin beta-N-Methylamino-L-Alanine (BMAA) Results in Long-Lasting Behavioral Changes in Offspring-Potential Involvement of DNA Damage and Oxidative Stress. AB - We recently demonstrated that perinatal exposure to the glutamate-related herbicide, glufosinate ammonium, has deleterious effects on neural stem cell (NSC) homeostasis within the sub-ventricular zone (SVZ), probably leading to ASD like symptoms in offspring later in life. In the present study, we aimed to investigate whether perinatal exposure to another glutamate-related toxicant, the cyanobacterial amino acid beta-N-methylamino-L-alanine (BMAA), might also trigger neurodevelopmental disturbances. With this aim, female mice were intranasally exposed to low doses of BMAA, 50 mg kg-1 three times a week from embryonic days 7 10 to postnatal day 21. Behavioral analyses were performed during the offspring's early life and during adulthood. Developmental analyses revealed that perinatal exposure to BMAA hastened the appearance of some reflexes and communicative skills. BMAA-exposed offspring displayed sex-dependent changes in emotional cognition shortly after exposure. Later in life, the female offspring continued to express emotional defects and to display abnormal sociability, while males were less affected. To assess whether early exposure to BMAA had deleterious effects on NSC homeostasis, we exposed mice NSCs to 1 and 3 mM BMAA during 24 h. We found that BMAA-exposed NSCs produced high levels of ROS, highlighting the ability of BMAA to induce oxidative stress. We also showed that BMAA exposure increased the number of gammaH2AX/53BP1 foci per nucleus, suggesting that BMAA induced DNA damage in NSCs. Collectively, this data strongly suggests that perinatal exposure to the cyanobacteria BMAA, even at low doses, results in neurobehavioral disturbances during both the postnatal period and adulthood. This is considered to be underpinned at the cellular level through dysregulation of NSC homeostasis in the developing brain. PMID- 28879465 TI - [Nodular lymphocyte-dominant Hodgkin's lymphoma : LP cells show recurrent mutations in DUSP2, SGK1 and JUNB]. PMID- 28879464 TI - Prevalence of Subclinical Enteric Alpha-1-Antitrypsin Loss in Children with Univentricular Circulation Following Total Cavopulmonary Connection. AB - Protein-Losing Enteropathy post Fontan palliation is associated with significant morbidity and mortality. To date, very little research has been carried out to improve early identification of enteric protein loss in these patients. We hypothesise that subclinical enteric protein loss may occur in patients post Fontan surgery. A cross-sectional study was performed on 43 patients post Fontan surgery. We collected specimens of stool and blood from patients with no symptoms of protein-losing enteropathy post Fontan. Stool samples were assessed for alpha one antitrypsin. The stool samples of two patients were discarded, leaving 41 stool samples. Blood samples were also collected to review albumin, C-reactive protein, liver and renal function. Twenty-eight (65%) of those enrolled were male. The median (IQR) age between Fontan and collection of study specimens was 3.5 (2-7) years. Two (5%) patients had elevated levels of alpha-1-antitrypsin. There was no correlation between blood biochemistry and elevated stool alpha-1 antitrypsin. Subclinical protein loss is rare in asymptomatic children after Fontan procedure with only 5% of patients having elevated stool alpha-1 antitrypsin but no other symptoms. These findings may relate to our small cohort size and the time to testing post cardiac surgery. Future longitudinal follow-up studies should assess the ability of alpha-1-antitrypsin to provide earlier detection of protein-losing enteropathy in asymptomatic patients post Fontan. Given the serious prognosis of protein-losing enteropathy in this patient group, further work is warranted. PMID- 28879467 TI - Relieving the Bottleneck: An Investigation of Barriers to Expansion of Supervision Networks at Genetic Counseling Training Programs. AB - Rapid growth in the demand for genetic counselors has led to a workforce shortage. There is a prevailing assumption that the number of training slots for genetic counseling students is linked to the availability of clinical supervisors. This study aimed to determine and compare barriers to expansion of supervision networks at genetic counseling training programs as perceived by supervisors, non-supervisors, and Program Directors. Genetic counselors were recruited via National Society of Genetic Counselors e-blast; Program Directors received personal emails. Online surveys were completed by 216 supervisors, 98 non-supervisors, and 23 Program Directors. Respondents rated impact of 35 barriers; comparisons were made using Kruskal-Wallis and Wilcoxon ranked sum tests. Half of supervisors (51%) indicated willingness to increase supervision. All non-supervisors were willing to supervise. However, all agreed that being too busy impacted ability to supervise, highlighted by supervisors' most impactful barriers: lack of time, other responsibilities, intensive nature of supervision, desire for breaks, and unfilled positions. Non-supervisors noted unique barriers: distance, institutional barriers, and non-clinical roles. Program Directors' perceptions were congruent with those of genetic counselors with three exceptions they rated as impactful: lack of money, prefer not to supervise, and never been asked. In order to expand supervision networks and provide comprehensive student experiences, the profession must examine service delivery models to increase workplace efficiency, reconsider the supervision paradigm, and redefine what constitutes a countable case or place value on non-direct patient care experiences. PMID- 28879466 TI - Involvement of metabolic components, volatile compounds, PR proteins, and mechanical strengthening in multilayer protection of cucumber plants against Rhizoctonia solani activated by Trichoderma atroviride TRS25. AB - In the present study, the spread of Rhizoctonia solani-induced disease was limited when cucumber plants were pretreated with Trichoderma atroviride TRS25. The systemic disease suppression was related to TRS25-induced resistance (TISR) induction with simultaneous plant growth promotion. Protection of cucumber was related to enhanced activity of defense enzymes, e.g., guaiacol peroxidase (GPX), syringaldazine peroxidase (SPX), phenylalanine ammonia lyase (PAL), and polyphenol oxidase (PPO) as well as phenolic (PC) concentration increases in the conditions of hydrogen peroxide (H2O2) accumulation, resulting in thiobarbituric acid reactive substance (TBARS) decrease. Moreover, the obtained results indicated that TISR might depend on accumulation of salicylic acid derivatives, that is methyl salicylate (MeSA), ethylhexyl salicylate (EHS), salicylic acid glucosylated conjugates (SAGC), and beta-cyclocitral as well as volatile organic compounds (VOC) such as Z-3-hexanal, Z-3-hexenol, and E-2-hexenal. The results point to important, not previously documented, roles of these VOC in TISR signaling with up-regulation of PR1 and PR5 gene characteristic of systemic acquired resistance (SAR) and of PR4 gene, marker of induced systemic resistance (ISR). The study established that TRS25 enhanced deposition of callose and lignin in specialized plant cells, which protected vascular system in cucumber shoots and roots as well as assimilation cells and dermal tissues in shoots and leaves. These compounds protected cucumber organs against R. solani influence and made them more flexible and resilient, which contributed to better nutrition and hydration of plants. The growth promotion coupled with systemic mobilization of biochemical and mechanical strengthening might be involved in multilayer protection of cucumber against R. solani activated by TRS25. PMID- 28879468 TI - Source contributions to total concentrations and carcinogenic potencies of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in ambient air: a case study in Suzhou City, China. AB - The potential source categories and source contributions of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in ambient air from Suzhou City, China, were performed by principal component analysis-multiple linear regression (PCA-MLR) and positive matrix factorization (PMF). The carcinogenic potencies of PCDD/Fs were quantitatively apportioned based on the positive matrix factorization-toxic equivalent concentration (PMF-TEQ) method. The results of the present study were summarized as follows. (1) The total concentrations and toxic equivalent concentrations of PCDD/Fs (?PCDD/Fs and TEQ) in ambient air from Suzhou City were 1.34-42.80 pg N m-3 and 0.081-1.22 pg I-TEQ N m-3, respectively. (2) PCA-MLR suggested that industrial combustion (IC), electric arc furnaces (EAFs) and secondary aluminum smelters (ALSs), unleaded gas fueled vehicle sources (UGFVs), ALSs, and hazardous solid waste incinerators (HSWIs) could be the primary PCDD/F contributors, accounting for 13.2, 16.7, 35.5, 19.4, and 15.2% of ?PCDD/Fs, respectively. (3) PMF and PMF-TEQ indicated that EAFs (carbon steel), UGFVs, IC, ALSs, municipal solid waste incinerators (MSWIs) and hospital waste incinerators (HWIs), and HSWIs contributed 10.9, 10.9, 42.8, 11.3, 10.7, and 13.4% to ?PCDD/Fs, but contributed 8.3, 12.3, 50.3, 12.7, 6.0, and 10.4% to carcinogenic potencies of PCDD/Fs. This study was the first attempt to quantitatively apportion the source-specific carcinogenic potencies of PCDD/Fs in ambient air. PMID- 28879469 TI - Pancreatic Cancer Screening. AB - PURPOSE OF REVIEW: This review describes the rationale for pancreatic cancer screening, outlines groups that are at elevated risk for pancreatic cancer, and summarizes the relative risk in each setting. We also review the methods available for performing pancreatic cancer screening and the recommended screening intervals. RECENT FINDINGS: Several genetic mutations have been identified that increase the risk for pancreatic cancer. Most are rare, however, and at-risk individuals are most often those with a strong family history of pancreatic cancer (with multiple family members affected) but no identifiable genetic mutation. Known genetic syndromes that increase the risk for pancreatic cancer include hereditary pancreatitis, familial atypical mole and multiple melanoma, Peutz-Jeghers syndrome, Lynch syndrome, BRCA mutations, and Li-Fraumeni syndrome. Genetic testing should be performed in conjunction with genetic counseling, and testing of an affected family member is preferred if possible.The goal of pancreatic cancer screening is to identify pancreatic cancer at an early, curable stage or, ideally, to identify precancerous lesions that can be resected to prevent the development of cancer. Imaging can be performed with either endoscopic ultrasound (EUS) or magnetic resonance cholangiopancreatography (MRCP). These techniques are generally considered to be complementary, although an advantage of EUS is that cysts or solid lesions can be sampled at the time of the procedure. Published results of small cohorts of high-risk patients in pancreatic cancer screening programs have demonstrated a high prevalence of small cystic lesions identified on EUS or MRCP, which often represent side-branch intraductal papillary mucinous neoplasms (IPMN). Knowledge of conditions and syndromes that increase pancreatic cancer risk allows one to identify those patients that may benefit from pancreatic cancer screening. As we gather evidence from large, international, multicenter cohorts of patients at high-risk for pancreatic cancer who are undergoing screening and as our understanding of the genetic underpinnings of pancreatic cancer improve, recommendations on screening will continue to be refined. PMID- 28879471 TI - ? PMID- 28879470 TI - Childhood maltreatment and the medical morbidity in bipolar disorder: a case control study. AB - BACKGROUND: Childhood maltreatment (abuse and neglect) can have long-term deleterious consequences, including increased risk for medical and psychiatric illnesses, such as bipolar disorder in adulthood. Emerging evidence suggests that a history of childhood maltreatment is linked to the comorbidity between medical illnesses and mood disorders. However, existing studies on bipolar disorder have not yet explored the specific influence of child neglect and have not included comparisons with individuals without mood disorders (controls). This study aimed to extend the existing literature by examining the differential influence of child abuse and child neglect on medical morbidity in a sample of bipolar cases and controls. METHODS: The study included 72 participants with bipolar disorder and 354 psychiatrically healthy controls (average age of both groups was 48 years), who completed the Childhood Trauma Questionnaire, and were interviewed regarding various medical disorders. RESULTS: A history of any type of childhood maltreatment was significantly associated with a diagnosis of any medical illness (adjusted OR = 6.28, 95% confidence intervals 1.70-23.12, p = 0.006) and an increased number of medical illnesses (adjusted OR = 3.77, 95% confidence intervals 1.34-10.57, p = 0.012) among adults with bipolar disorder. Exposure to child abuse was more strongly associated with medical disorders than child neglect. No association between childhood maltreatment and medical morbidity was detected among controls. CONCLUSIONS: To summarise, individuals with bipolar disorder who reported experiencing maltreatment during childhood, especially abuse, were at increased risk of suffering from medical illnesses and warrant greater clinical attention. PMID- 28879475 TI - Comparing analyses of corticosteroids and transition to delirium in critically ill patients. PMID- 28879474 TI - Pregnancy-related fractures: a retrospective study of a French cohort of 52 patients and review of the literature. AB - : A retrospective, multicentre study involving 52 patients was carried out to define the causes and characteristics of pregnancy-related osteoporosis. The mean number of vertebral fractures occurring during the last trimester of pregnancy or at the time of delivery was 3.8. This is often promoted by risk factors before or during pregnancy. INTRODUCTION: In order to define the causes or predisposing factors of pregnancy-related osteoporosis and its clinical, radiological and bone density characteristics, laboratory findings, course and outcome, we carried out a retrospective multicentre study. METHODS: The records of 52 women hospitalised over the last 10 years in the rheumatology departments of six French university hospitals and with a diagnosis of pregnancy-related osteoporosis were examined. RESULTS: The patients' mean age at time of fracture was 32.1 years. In 10 patients, the fractures had occurred during the last trimester of pregnancy, and in 36 at the time of delivery or during the first 2 months post-partum. The mean number of vertebral fractures was 3.8 +/- 2.0. Thirty three of the 52 patients had a risk factor of low bone mass before pregnancy. Twelve had disorders or treatments (heparin) that might promote osteoporosis during pregnancy, while 14 had no trigger factors before or during pregnancy. Overall, phosphate and calcium levels were normal, except for hyperphosphoraemia in lactating women (90%). On DXA scan, osteoporosis predominated in the trabecular bone (spinal T-score - 3.4, hip T-score - 2). Only 10 patients had a repeat fracture, and the increase in bone mineral density during follow-up was considerable, and improved by bisphosphonates (annual gain + 10% in the spine) or teriparatide (+ 15%). CONCLUSIONS: Pregnancy-related osteoporosis gives rise to multiple vertebral fractures. It is often promoted by risk factors before or during pregnancy. Its mechanism is still unknown. Treatment with bisphosphonates or teriparatide appears to improve the recovery of bone mineral density. PMID- 28879476 TI - Impact Assessment of Atmospheric Dust on Foliage Pigments and Pollution Resistances of Plants Grown Nearby Coal Based Thermal Power Plants. AB - Plant species grown in the vicinity of thermal power plants (TPP) are one of the immobile substrates to sink most of the pollutants emitted from their stacks. The continuous exposure of toxic pollutants to these plants may affect their resistances and essential biochemical's concentrations. In the present study, we estimated the impact of dust load generated by a TPPs to plant's dust retention capacity and pollution resistances (APTI and API). The observed ambient air quality index (AQI) showed that the surroundings of TPPs are in the severe air pollution category. Observed AQI was greater than 100 in the surrounding area of TPP. The mean dust load on plant foliage was significantly greater in the polluted site compared with the control site: 4.45 +/- 1.96 versus 1.38 +/- 0.41 mg cm-2. Nearby, TPP highest and lowest dust load were founded in F. benghalensis (7.58 +/- 0.74) and F. religiosa (2.25 +/- 0.12 mg cm-2) respectively. Analysis revealed the strong negative correlation between dust load and essential pigments of foliage, such as chlorophyll content, carotenoids, pH of foliage extract, and relative water content. Conversely, strong positive correlation was observed with the ascorbic acid content of plant species. Correlation and percentage change analysis in ascorbic acid content for the polluted site against the control site showed the adverse impact on plants due to dust load. Based on their responses to dust pollution, A. scholaris, P. longifolia, and M. indica were observed as most suitable plant species. Estimation of DRC, chlorophyll a/b ratio, APTI and API revealed the A. scholaris, F. benghalensis, P. longifolia, and M. indica as the most suitable plant species for green belt formation. The high gradation was obtained in A. scholaris, F. benghalensis, P. longifolia, and M. indica for opted parameters and showed their most suitability for green belt formation. Salient features of the present study provide useful evidences to estimate the combined effect of DRC and pollution resistances of plant species on green belt establishment for long-term environmental management around industries. PMID- 28879477 TI - Sex-specific inhibition and stimulation of worker-reproductive transition in a termite. AB - In social insects, the postembryonic development of individuals exhibits strong phenotypic plasticity in response to the environment, thus generating the caste system. Different from eusocial Hymenoptera, in which queens dominate reproduction and inhibit worker fertility, the primary reproductive caste in termites (kings and queens) can be replaced by neotenic reproductives derived from functionally sterile individuals. Feedback regulation of nestmate differentiation into reproductives has been suggested, but the sex specificity remains inconclusive. In the eastern subterranean termite, Reticulitermes flavipes, we tested the hypothesis that neotenic reproductives regulate worker reproductive transition in a sex-specific manner. With this R. flavipes system, we demonstrate a sex-specific regulatory mechanism with both inhibitory and stimulatory functions. Neotenics inhibit workers of the same sex from differentiating into additional reproductives but stimulate workers of the opposite sex to undergo this transition. Furthermore, this process is not affected by the presence of soldiers. Our results highlight the reproductive plasticity of termites in response to social cues and provide insights into the regulation of reproductive division of labor in a hemimetabolous social insect. PMID- 28879478 TI - Influence of oxygen availability on the metabolism and morphology of Yarrowia lipolytica: insights into the impact of glucose levels on dimorphism. AB - Dynamic behavior of Yarrowia lipolytica W29 strain under conditions of fluctuating, low, and limited oxygen supply was characterized in batch and glucose-limited chemostat cultures. In batch cultures, transient oscillations between oxygen-rich and -deprived environments induced a slight citric acid accumulation (lower than 29 mg L-1). By contrast, no citric acid was detected in continuous fermentations for all stress conditions: full anoxia (zero pO2 value, 100% N2), limited (zero pO2 value, 75% of cell needs), and low (pO2 close to 2%) dissolved oxygen (DO) levels. The macroscopic behavior (kinetic parameters, yields, viability) of Y. lipolytica was not significantly affected by the exposure to DO fluctuations under both modes of culture. Nevertheless, conditions of oxygen limitation resulted in the destabilization of the glucose-limited growth during the continuous cultivations. Morphological responses of Y. lipolytica to DO oscillations were different between batch and chemostat runs. Indeed, a yeast-to-mycelium transition was induced and progressively intensified during the batch fermentations (filamentous subpopulation reaching 74% (v/v)). While, in chemostat bioreactors, the culture consisted mainly of yeast-like cells (mean diameter not exceeding 5.7 MUm) with a normal size distribution. During the continuous cultures, growth at low DO concentration did not induce any changes in Y. lipolytica morphology. Dimorphism (up to 80.5% (v/v) of filaments) was only detected under conditions of oxygen limitation in the presence of a residual glucose excess (more than 0.75 g L-1). These data suggest an impact of glucose levels on the signaling pathways regulating dimorphic responses in Y. lipolytica. PMID- 28879479 TI - The Italian master Leonardo da Vinci and his early understanding of the brachial plexus. PMID- 28879480 TI - Mortality in Patients with Splenic Injuries: The Role of Multi-Organ Failure. PMID- 28879481 TI - Association between the number of oocytes retrieved and cumulative live birth rate in women aged 35-40 years undergoing long GnRH agonist IVF/ICSI cycles. AB - PURPOSE: To study the association between the numbers of oocytes retrieved and the cumulative live birth rates (LBR) in women aged 35-40 years undergoing long GnRH agonist IVF/ICSI cycles. METHODS: A total of 931 women aged 35-40 years who underwent their first cycle of IVF/ICSI treatment between January 2010 and December 2013 at Nanjing Drum Tower Hospital were identified and reviewed. The main endpoint of this study was the cumulative LBR after one complete oocyte retrieval, which included fresh and all subsequent frozen-thaw embryo transfer cycles. Odds ratios (OR) and 95% confidence interval (CI) for live birth were estimated by multivariate logistic regression analysis. Furthermore, all the women were divided into four groups based on the number of oocytes retrieved: 0 4, 5-9, 10-14 or >=15 oocytes group. Variables were then compared among groups. RESULTS: We found that 634 out of the 931 patients (68.1%) achieved at least one live birth. The number of oocytes retrieved was an independent predictive factor for live birth, with OR 1.20 (95% CI 1.15-1.26) when adjusted for age (years), duration of infertility and Gn (gonadotrophin) doses. The cumulative LBR in the four different oocyte groups was 35.6, 68.8, 83.4 and 89.2%, respectively. When the 1-4 oocytes group was issued as a reference, the ORs for cumulative LBR gradually increased to 3.66, 6.74 and 11.77 in other three oocytes groups, respectively. The moderate-severe ovarian hyperstimulation syndrome (OHSS) rate was dramatically increased in the >=15 oocytes group (6.9%) when compared to that in the 10-14 oocytes group (0.8%), while the cumulative LBR only increased 5.8% (from 83.4 to 89.2%). CONCLUSIONS: The ideal number of oocytes retrieved in women aged 35-40 years is 10-14 oocytes, which achieves a high cumulative LBR while maintaining an acceptable low OHSS rate. PMID- 28879482 TI - Pristane-induced lupus: considerations on this experimental model. AB - Systemic lupus erythematosus (SLE) is a multifactorial, autoimmune inflammatory disease with pleomorphic clinical manifestations involving different organs and tissues. The etiology of this disease has been associated with a dysfunctional response of B and T lymphocytes against environmental stimuli in individuals genetically susceptible to SLE, which determines an immune response against different autoantigens and, consequently, tissue damage. The study of different murine models has provided a better understanding of these autoimmune phenomena. This review primarily focuses on that has been learned from the pristane-induced lupus (PIL) model and how this model can be used to supplement recent advances in understanding the pathogenesis of SLE. We also consider both current and future therapies for this disease. The PubMed, SciELO, and Embase databases were searched for relevant articles published from 1950 to 2016. PIL has been shown to be a useful tool for understanding the multiple mechanisms involved in systemic autoimmunity. In addition, it can be considered an efficient model to evaluate the environmental contributions and interferon signatures present in patients with SLE. PMID- 28879483 TI - Molecular characterization of Acanthamoeba strains isolated from the oral cavity of hemodialysis patients in Iran. AB - Free-living amoebae (FLA) of the genus Acanthamoeba are opportunistic pathogenic agents able to cause life-threatening infections in immunosuppressed patients. Chronic kidney disease impairs adaptive and innate immunity. Thus, patients with chronic kidney disease are prone to opportunistic infections by potentially pathogenic FLA. Therefore, in the present study, the investigation of Acanthamoeba genotypes isolated from the oral cavity of hemodialysis patients of reference hospitals in Iran was aimed, using both morphology and molecular (sequence-based analysis) tools. Furthermore, classification of the strains at the genotype level was performed on the basis of differences in the diagnostic fraction 3 (DF3) region of the 18S rRNA gene. The pathogenic potential of the isolated amoebae was also determined using thermotolerance and osmotolerance assays. Out of the 187 oral cavity samples investigated, nine (4.8%) were positive for FLA. DNA sequencing of the ASA.A1 region of the 18S rRNA gene revealed that the isolated strains belonged to the Acanthamoeba T1 and T4 genotypes. Genotype T1 was isolated for the first time from a patient in Iran. Interestingly, the T1 strain (AN2 strain) exhibits a high pathogenic potential in tolerance assays. The pathogenicity assay revealed that five strains were able to grow at high temperatures (37-40 degrees C) and high osmolarity (0.5 and 1 M D mannitol) conditions; thus, they were considered as potentially pathogenic strains. Moreover, two of the patients were positive for Vermamoeba genus. The present study is the first report of genotype T1 isolation in Iran and the first to identify the occurrence of Acanthamoeba and Vermamoeba genera in patients undergoing hemodialysis worldwide. Monitoring hemodialysis and renal failure patients should be a priority for possible control of Acanthamoeba and other FLA related diseases. PMID- 28879484 TI - ACEt: An R Package for Estimating Dynamic Heritability and Comparing Twin Models. AB - Estimating dynamic effects of age on the genetic and environmental variance components in twin studies may contribute to the investigation of gene environment interactions, and may provide more insights into more accurate and powerful estimation of heritability. Existing parametric models for estimating dynamic variance components suffer from various drawbacks such as limitation of predefined functions. We present ACEt, an R package for fast estimating dynamic variance components and heritability that may change with respect to age or other moderators. Building on the twin models using penalized splines, ACEt provides a unified framework to incorporate a class of ACE models, in which each component can be modeled independently and is not limited by a linear or quadratic function. We demonstrate that ACEt is robust against misspecification of the number of spline knots, and offers a refined resolution of dynamic behavior of the genetic and environmental components and thus a detailed estimation of age specific heritability. Moreover, we develop resampling methods for testing twin models with different variance functions including splines, log-linearity and constancy, which can be easily employed to verify various model assumptions. We evaluated the type I error rate and statistical power of the proposed hypothesis testing procedures under various scenarios using simulated datasets. Potential numerical issues and computational cost were also assessed through simulations. We applied the ACEt package to a Finnish twin cohort to investigate age-specific heritability of body mass index and height. Our results show that the age specific variance components of these two traits exhibited substantially different patterns despite of comparable estimates of heritability. In summary, the ACEt R package offers a useful tool for the exploration of age-dependent heritability and model comparison in twin studies. PMID- 28879485 TI - Sensitivity ranking for freshwater invertebrates towards hydrocarbon contaminants. AB - Hydrocarbons have an utmost economical importance but may also cause substantial ecological impacts due to accidents or inadequate transportation and use. Currently, freshwater biomonitoring methods lack an indicator that can unequivocally reflect the impacts caused by hydrocarbons while being independent from effects of other stressors. The aim of the present study was to develop a sensitivity ranking for freshwater invertebrates towards hydrocarbon contaminants, which can be used in hydrocarbon-specific bioindicators. We employed the Relative Sensitivity method and developed the sensitivity ranking S hydrocarbons based on literature ecotoxicological data supplemented with rapid and mesocosm test results. A first validation of the sensitivity ranking based on an earlier field study has been conducted and revealed the S hydrocarbons ranking to be promising for application in sensitivity based indicators. Thus, the first results indicate that the ranking can serve as the core component of future hydrocarbon-specific and sensitivity trait based bioindicators. PMID- 28879486 TI - Forster Resonance Energy Transfer Study of Cytochrome c-Lipid Interactions. AB - Specific interactions between a mitochondrial hemoprotein cytochrome c (cyt c) and cardiolipin, a lipid component of mitochondrial membrane, are crucial to electron shuttling and apoptotic activities of this protein. In the present study the Forster resonance energy transfer (FRET) between anthrylvinyl-labeled phosphatidylcholine as a donor and heme moiety of cyt c as an acceptor was employed to give a quantitative characterization of the protein binding to the model membranes from the mixtures of phosphatidylcholine (PC) with phosphatidylglycerol (PG), phosphatidylserine (PS) or cardiolipin (CL) in different molar ratios. The multiple arrays of the FRET data were globally analyzed in terms of the model of energy transfer in two-dimensional systems combined with the scaled particle adsorption model. The arguments in favor of the specificity of cyt c interactions with CL were obtained, including the higher adsorption potential and the deeper protein insertion in the lipid bilayer. PMID- 28879487 TI - Effects of supplement with sanitary landfill leachate in gas exchange of sunflower (Helianthus annuus L.) seedlings under drought stress. AB - Sanitary landfill leachate is one of the major problems arising from disposal of urban waste. Sanitary landfill leachate may, however, have use in agriculture. This study, therefore, aimed to analyze initial plant growth and gas exchange in sunflower seedlings supplemented with sanitary landfill leachate and subjected to drought stress through variables of root fresh mass (RFM), shoot fresh mass (SFM), total fresh mass (TFM), relative chlorophyll content (CL), stomatal conductance (g s ), transpiration rate (E), net photosynthetic rate (A), ratio of internal to external CO2 concentration (Ci/Ca),water use efficiency (EUA), instantaneous carboxylation efficiency (A/Ci), and electron transport rate (ETR). The experimental design was a completely randomized 2 (irrigated and non irrigated) * 4 (sand, sand + 100 kg N ha-1 organic fertilizer, sand + 100 kg N ha 1 sanitary landfill leachate, and sand + 150 kg N ha-1 sanitary landfill leachate) factorial with five replicates. Under drought stress conditions, leachate treatment supplemented with 100 kg N ha-1 exhibited higher plant fresh weights than those of the treatment containing 150 kg N ha-1. Increases in fresh mass in plant treatments supplemented with 100 and 150 kg N ha-1 sanitary landfill leachate were related to higher photosynthetic rates. PMID- 28879488 TI - Diabetes and the Stomach. AB - OPINION STATEMENT: Longstanding diabetes mellitus (both type 1 and type 2) can impair gastric motor function and cause significant upper gastrointestinal symptoms which significantly degrade quality of life, cause nutritional deficits, and degrade healthcare resource use. The most commonly considered gut complication of diabetes, diabetic gastroparesis, is a syndrome of delayed gastric emptying in the absence of mechanical obstruction which leads to symptoms of nausea, vomiting, postprandial fullness, early satiation, bloating, and upper abdominal pain. Gastroparesis also can lead to loss of glycemic control. A diagnosis of gastroparesis is made by documenting delayed gastric emptying and excluding mechanical obstruction. Gastric emptying scintigraphy is the most commonly utilized test for the diagnosis of gastroparesis but novel tests of gastric function have recently been introduced including the gastric emptying breath test and wireless motility capsule. Management most often is aimed at controlling symptoms, which includes dietary modification, optimization of glycemic control, and medication therapy with prokinetics, antiemetics, and neuromodulatory agents. Endoscopic and/or surgical therapies may be considered for refractory cases of gastroparesis. Recent research has provided new insights into the pathophysiology of this disease and is characterizing potential benefits of novel therapeutic agents which show promise in the treatment of this condition. This article will review the pathophysiology, new insights into disease mechanism, and treatment options for diabetic gastroparesis. PMID- 28879489 TI - Place Still Matters: Racial/Ethnic and Geographic Disparities in HIV Transmission and Disease Burden. AB - Neighborhood-level structural interventions are needed to address HIV/AIDS in highly affected areas. To develop these interventions, we need a better understanding of contextual factors that drive the pandemic. We used multinomial logistic regression models to examine the relationship between census tract of current residence and mode of HIV transmission among HIV-positive cases. Compared to the predominantly white high HIV prevalence tract, both the predominantly black high and low HIV prevalence tracts had greater odds of transmission via injection drug use and heterosexual contact than male-to-male sexual contact. After adjusting for current age, gender, race/ethnicity, insurance status, and most recently recorded CD4 count, there was no statistically significant difference in mode of HIV transmission by census tract. However, heterosexual transmission and injection drug use remain key concerns for underserved populations. Blacks were seven times more likely than whites to have heterosexual versus male-to-male sexual contact. Those who had Medicaid or were uninsured (versus private insurance) were 23 and 14 times more likely, respectively, to have injection drug use than male-to-male sexual contact and 10 times more likely to have heterosexual contact than male-to-male sexual contact. These findings can inform larger studies for the development of neighborhood-level structural interventions. PMID- 28879490 TI - Homogeneous Subgroups of Young Children with Autism Improve Phenotypic Characterization in the Study to Explore Early Development. AB - The objective of this study was to identify homogenous classes of young children with autism spectrum disorder (ASD) to improve phenotypic characterization. Children were enrolled in the Study to Explore Early Development between 2 and 5 years of age. 707 children were classified with ASD after a comprehensive evaluation with strict diagnostic algorithms. Four classes of children with ASD were identified from latent class analysis: mild language delay with cognitive rigidity, mild language and motor delay with dysregulation, general developmental delay, and significant developmental delay with repetitive motor behaviors. We conclude that a four-class phenotypic model of children with ASD best describes our data and improves phenotypic characterization of young children with ASD. Implications for screening, diagnosis, and research are discussed. PMID- 28879491 TI - Profiling of cardio-metabolic risk factors and medication utilisation among Type II diabetes patients in Ghana: a prospective cohort study. AB - BACKGROUND: Type II diabetes mellitus (T2DM) is complicated by multiple cardio metabolic risk factors. Controlling these factors requires lifestyle modifications alongside utilisation of anti-diabetic medications. Different glucose lowering [(biguanides (BIGs), sulfonylureas (SUAs), thiazolidinediones (TNZ)], lipid lowering (statins), and anti-hypertensive medicines [angiotensin converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs) and central acting drugs (CADs)] have been approved for controlling hyperglycaemia, dyslipidaemia and hypertension respectively. Here, we examined factors that characterise T2DM and explored the response to medication therapy among T2DM patients. METHODS: This prospective cohort study recruited 241 T2DM patients reporting at a clinic in Ghana, from January through to August, 2016. Each patient's demographic, medications and anthropometric data was obtained while information on medication adherence was captured using Morisky adherence scale-8 (MMAS-8). Fasting blood samples were collected for biochemical analysis. RESULTS: The mean age of participants was 57.82 years for baseline and six-month follow-up. Physical activity differed at baseline and follow up (p < 0.05) but not body mass index (BMI). BIG alone, or in combination with SUA and TNZ did not improve glycaemic status at follow up (p > 0.05). Many participants using either ACEI or ARB were able to control their blood pressures. Among dyslipidaemia patients under statin treatment, there was an improved lipid profile at follow-up. CONCLUSIONS: Statin medications are effective for reducing dyslipidaemia in T2DM patients. However, control of modifiable risk factors, particularly blood glucose and to a lesser degree blood pressure is suboptimal. Addressing these will require concomitant interventions including education on medication adherence and correct dietary plans, lifestyle modifications and physical activity. PMID- 28879492 TI - Molecular modeling and structure-based drug discovery approach reveals protein kinases as off-targets for novel anticancer drug RH1. AB - Potential drug target identification and mechanism of action is an important step in drug discovery process, which can be achieved by biochemical methods, genetic interactions or computational conjectures. Sometimes more than one approach is implemented to mine out the potential drug target and characterize the on-target or off-target effects. A novel anticancer agent RH1 is designed as pro-drug to be activated by NQO1, an enzyme overexpressed in many types of tumors. However, increasing data show that RH1 can affect cells in NQO1-independent fashion. Here, we implemented the bioinformatics approach of modeling and molecular docking for search of RH1 targets among protein kinase species. We have examined 129 protein kinases in total where 96 protein kinases are in complexes with their inhibitor, 11 kinases were in the unbound state with any ligand and for 22 protein kinases 3D structure were modeled. Comparison of calculated free energy of binding of RH1 with indigenous kinase inhibitors binding efficiency as well as alignment of their pharmacophoric maps let us predict and ranked protein kinases such as KIT, CDK2, CDK6, MAPK1, NEK2 and others as the most prominent off-targets of RH1. Our finding opens new avenues in search of protein targets that might be responsible for curing cancer by new promising drug RH1 in NQO1-independent way. PMID- 28879493 TI - Neural Progenitor Cells Undergoing Yap/Tead-Mediated Enhanced Self-Renewal Form Heterotopias More Easily in the Diencephalon than in the Telencephalon. AB - Spatiotemporally ordered production of cells is essential for brain development. Normally, most undifferentiated neural progenitor cells (NPCs) face the apical (ventricular) surface of embryonic brain walls. Pathological detachment of NPCs from the apical surface and their invasion of outer neuronal territories, i.e., formation of NPC heterotopias, can disrupt the overall structure of the brain. Although NPC heterotopias have previously been observed in a variety of experimental contexts, the underlying mechanisms remain largely unknown. Yes associated protein 1 (Yap1) and the TEA domain (Tead) proteins, which act downstream of Hippo signaling, enhance the stem-like characteristics of NPCs. Elevated expression of Yap1 or Tead in the neural tube (future spinal cord) induces massive NPC heterotopias, but Yap/Tead-induced expansion of NPCs in the developing brain has not been previously reported to produce NPC heterotopias. To determine whether NPC heterotopias occur in a regionally characteristic manner, we introduced the Yap1-S112A or Tead-VP16 into NPCs of the telencephalon and diencephalon, two neighboring but distinct forebrain regions, of embryonic day 10 mice by in utero electroporation, and compared NPC heterotopia formation. Although NPCs in both regions exhibited enhanced stem-like behaviors, heterotopias were larger and more frequent in the diencephalon than in the telencephalon. This result, the first example of Yap/Tead-induced NPC heterotopia in the forebrain, reveals that Yap/Tead-induced NPC heterotopia is not specific to the neural tube, and also suggests that this phenomenon depends on regional factors such as the three-dimensional geometry and assembly of these cells. PMID- 28879494 TI - Regeneration of sciatic nerve crush injury by a hydroxyapatite nanoparticle containing collagen type I hydrogel. AB - The current study aimed to enhance the efficacy of peripheral nerve regeneration using a hydroxyapatite nanoparticle-containing collagen type I hydrogel. A solution of type I collagen, extracted from the rat tails, was incorporated with hydroxyapatite nanoparticles (with the average diameter of ~212 nm) and crosslinked with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) to prepare the hydrogel. The Schwann cell cultivation on the prepared hydrogel demonstrated a significantly higher cell proliferation than the tissue culture plate, as positive control, after 48 h (n = 3, P < 0.005) and 72 h (n = 3, P < 0.01). For in vivo evaluation, the prepared hydrogel was administrated on the sciatic nerve crush injury in Wistar rats. Four groups were studied: negative control (with injury but without interventions), positive control (without injury), collagen hydrogel and hydroxyapatite nanoparticle-containing collagen hydrogel. After 12 weeks, the administration of hydroxyapatite nanoparticle-containing collagen significantly (n = 4, P < 0.005) enhanced the functional behavior of the rats compared with the collagen hydrogel and negative control groups as evidenced by the sciatic functional index, hot plate latency and compound muscle action potential amplitude measurements. The overall results demonstrated the applicability of the produced hydrogel for the regeneration of peripheral nerve injuries. PMID- 28879495 TI - A quantum theory account of order effects and conjunction fallacies in political judgments. AB - Are our everyday judgments about the world around us normative? Decades of research in the judgment and decision-making literature suggest the answer is no. If people's judgments do not follow normative rules, then what rules if any do they follow? Quantum probability theory is a promising new approach to modeling human behavior that is at odds with normative, classical rules. One key advantage of using quantum theory is that it explains multiple types of judgment errors using the same basic machinery, unifying what have previously been thought of as disparate phenomena. In this article, we test predictions from quantum theory related to the co-occurrence of two classic judgment phenomena, order effects and conjunction fallacies, using judgments about real-world events (related to the U.S. presidential primaries). We also show that our data obeys two a priori and parameter free constraints derived from quantum theory. Further, we examine two factors that moderate the effects, cognitive thinking style (as measured by the Cognitive Reflection Test) and political ideology. PMID- 28879497 TI - Does Time Difference in CT Scan Causes More Mortality? PMID- 28879496 TI - Tinea corporis caused by Trichophyton equinum in a rider and review of the literature. AB - BACKGROUND: Trichophyton equinum is a zoophilic dermatophyte usually causing ringworm in horses. Cases of skin infections in humans are very rare. CASE REPORT : We describe a case of tinea corporis caused by T. equinum on a buttock of a rider who often rode bareback with short trousers. CONCLUSION: Although T. equinum was considered in the past as a strict zoophilic dermatophyte, our case report confirms that it can cause dermatophytoses also in humans. A review of epidemiological and clinical features of human infections caused by T. equinum is presented. PMID- 28879498 TI - Locating QTLs controlling overwintering trait in Chinese perennial Dongxiang wild rice. AB - Overwintering (OW) is the process by which rice passes through the winter season and germinates in the following spring. OW is also a typical quantitative inheritance trait. Currently, the molecular genetic basis of OW trait in Chinese perennial Dongxiang wild rice (DXWR) still remains to be known. In this study, a linkage map consisting of 139 simple sequence repeat (SSR) markers was constructed using an F2 population derived from a cross between DXWR and 93-11. This map covered the rice genome by approximately 1778.72 cM with approximately 12.80 cM average interval. The phenotype data of OW trait were investigated for QTL analysis in the following spring of 2017. The gene ontology (GO) annotation of the M-QTL was performed through the rice genome annotation project system. A major QTL-qOW6 was flanked by RM20069 (16,542,428 bp) and RM3498 (20,982,059 bp) on chromosome 6 and detected repeatedly by both inclusive composite interval and single-marker analysis mapping with an LOD score of 9.45 and explained 22.22% of phenotypic variance. In addition, two small QTLs (qOW2 and qOW3) controlling OW trait were detected on the second and third chromosomes, respectively. No epistatic interaction was detected between these QTLs, suggesting their unique genetic model. A total of 183 candidate genes at qOW6 locus were involved in 887 GO terms. Among them, 52 candidate genes were involved in response to stress. The other 28 candidate genes were related to cell membrane, which might affect the OW trait in perennial DXWR. These results may establish the foundation for understanding the genetic mechanism about OW trait and provide a novel gene resource for OW rice variety improvement. PMID- 28879499 TI - Impaired Dopamine-Dependent Locomotory Behavior of C. elegans Neuroligin Mutants Depends on the Catechol-O-Methyltransferase COMT-4. AB - Neurexins and neuroligins are neuronal membrane adhesion molecules that have been involved in neuropsychiatric and neurodevelopmental disorders. The nrx-1 and nlg 1 genes of Caenorhabditis elegans encode NRX-1 and NLG-1, orthologue proteins of human neurexins and neuroligins, respectively. Dopaminergic and serotoninergic signalling control the locomotory rate of the nematode. When well-fed animals are transferred to a plate with food (bacterial lawn), they reduce the locomotory rate. This behavior, which depends on dopamine, is known as basal slowing response (BSR). Alternatively, when food-deprived animals are moved to a plate with a bacterial lawn, further decrease their locomotory rate. This behavior, known as enhanced slowing response (ESR), is serotonin dependent. C. elegans nlg 1-deficient mutants are impaired in BSR and ESR. Here we report that nrx-1 deficient mutants were defective in ESR, but not in BSR. The nrx-1;nlg-1 double mutant was impaired in both behaviors. Interestingly, the nlg-1 mutants upregulate the expression of comt-4 which encodes an enzyme with putative catechol-O-methyltransferase activity involved in dopamine degradation. Our study also shows that comt-4(RNAi) in nlg-1-deficient mutants rescues the wild type phenotypes of BSR and ESR. On the other hand, comt-4(RNAi) in nlg-1-deficient mutants also recovers, at least partially, the gentle touch response and the pharyngeal pumping rate that were impaired in these mutants. These latter behaviors are dopamine and serotonin dependent, respectively. Based on these results we propose a model for the neuroligin function in modulating the dopamine dependent locomotory behavior in the nematode. PMID- 28879500 TI - In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level. AB - ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a histone lysine methyltransferase (HKMT) and it preferentially tri-methylates lysine 9 of histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington's disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation. PMID- 28879502 TI - Role of macrophages in depot-dependent browning of white adipose tissue. AB - Sympathetic stimulation induces beige adipocytes in white adipose tissue (WAT), known as browning of WAT. In this study, exposure of mice to cold ambient temperature (10 degrees C) for 24 h induced the mRNA expression of uncoupling protein 1 (UCP1), a marker for beige adipocytes, in inguinal WAT, but not in perigonadal WAT. Thus, we examined the role of macrophages in depot-dependent WAT browning in mice. Flowcytometric analysis showed that total number of macrophages was higher in perigonadal WAT than in inguinal WAT. Cold exposure failed to change the expression of macrophage marker genes in inguinal WAT; however, it increased the mRNA expression of CD11c and tumor necrosis factor-alpha in perigonadal WAT, indicating that proinflammatory M1 macrophage is activated. The removal of macrophages using clodronate significantly enhanced cold-induced UCP1 mRNA expression in perigonadal WAT. These results suggest that M1 macrophages are involved in the phenotype of perigonadal WAT that hardly undergo browning. PMID- 28879503 TI - Asthma Phenotypes and Endotypes: Implications for Personalised Therapy. AB - Asthma is increasingly recognised as a heterogeneous group of diseases with similar clinical presentations rather than a singular disease entity. Asthma was historically categorised by clinical symptoms; however, newer methods of subgrouping, describing and categorising the disease have sub-defined asthma. These sub-definitions are intermittently called phenotypes or endotypes, but the real meanings of these words are poorly understood. Novel treatments are currently and increasingly available, partly in the monoclonal antibody environment, and also some physical therapies (bronchial thermoplasty), but additionally small molecules are not far away from clinical practice. Understanding the disease pathogenesis and the mechanism of action more completely may enable identification of treatable traits, biomarkers, mediators and modifiable therapeutic targets. However, there remains a danger that clinicians become preoccupied with the concept of endotypes and biomarkers, ignoring therapies that are hugely effective but have no companion biomarker. This review discusses our understanding of the concept of phenotypes and endotypes in appreciating and managing the heterogeneous condition that is asthma. We consider the role of functional imaging, physiology, blood-, sputum- and breath-based biomarkers and clinical manifestations that could be used to produce a personalised asthma profile, with implications on prognosis, pathophysiology and most importantly specific therapeutic responses. With the advent of increasing numbers of biological therapies and other interventional options such as bronchial thermoplasty, the importance of targeting expensive therapies to patients with the best chance of clinical response has huge health economic importance. PMID- 28879501 TI - Child and adolescent self-report symptom measurement in pediatric oncology research: a systematic literature review. AB - OBJECTIVE: Previous work in pediatric oncology has found that clinicians and parents tend to under-report the frequency and severity of treatment-related symptoms compared to child self-report. As such, there is a need to identify high quality self-report instruments to be used in pediatric oncology research studies. This study's objective was to conduct a systematic literature review of existing English language instruments used to measure self-reported symptoms in children and adolescents undergoing cancer treatment. METHODS: A comprehensive literature search was conducted in MEDLINE/PubMed, EMBASE, CINAHL, and PsycINFO to identify relevant articles published through November 10, 2016. Using pre specified inclusion/exclusion criteria, six trained reviewers carefully screened abstracts and full-text articles for eligibility. RESULTS: There were 7738 non duplicate articles identified in the literature search. Forty articles met our eligibility criteria, and within these articles, there were 38 self-report English symptom instruments. Most studies evaluated only cross-sectional psychometric properties, such as reliability or validity. Ten studies assessed an instrument's responsiveness or ability to detect changes in symptoms over time. Eight instruments met our criteria for use in future longitudinal pediatric oncology studies. CONCLUSIONS: This systematic review aids pediatric oncology researchers in identifying and selecting appropriate symptom measures with strong psychometric evidence for their studies. Enhancing the child's voice in pediatric oncology research studies allows us to better understand the impact of cancer and its treatment on the lives of children. PMID- 28879504 TI - [TKI 2.0 - changes in the medical treatment of renal cell carcinoma]. AB - Only for renal cell carcinoma (RCC) in a local stage curative treatment option by surgical resection exists. For metastatic disease the 5-year survival rate decreases radically. A factor that contributes to this is the low sensibility to radiation and chemotherapeutics. Since the approval of the tyrosine kinase inhibitors in 2006 effective drugs for the treatment of mRCC is available. The specific inhibition of the vascular-endothelial-growth (VEGF)-receptor and the "mammalian Target of Rapamycin" (mTOR) leads to a prolongation of the progression free survival as well as the overall survival rate. For a long time, the current target therapy with TKI appeared to be exhausted, but since recently research has gone a step further. Thus, Cabozantinib and Lenvatinib in the combination with Everolimus have been approved for second-line therapy in mRCC. For the first time a clinical study demonstrated positive results for an adjuvant treatment with sunitinib in patients with a high-risk RCC. Furthermore, in april 2016 the immune checkpoint inhibitor Nivolumab was approved for second-line therapy in mRCC in Germany. The following report examines briefly the current therapeutic recommendations, new findings and drug approvals and ongoing clinical trials. PMID- 28879505 TI - Recovery of oculomotor nerve palsy after endovascular treatment of ruptured posterior communicating artery aneurysm. AB - PURPOSE: Oculomotor nerve palsy (ONP) may result from Posterior communicating artery (Pcom) aneurysms. Endovascular treatment of ruptured Pcom aneurysms generally is a safe procedure, but the effect of this therapy on ONP is incompletely elucidated. This retrospective study evaluates outcomes of ONP after endovascular treatment for ruptured Pcom aneurysm and with the intention to clarify predictors of recovery. METHODS: From May 2010 to October 2015, 210 patients with Pcom aneurysms underwent endovascular treatment at our institution. Among them, 34 patients with ruptured aneurysms and either complete or incomplete ONP were identified. The outcomes and predictors of ONP recovery were analyzed. RESULTS: At the last available clinical follow-up, ONP resolution was complete in 21 (61.8%) patients and incomplete in 8 (23.5%) patients. The mean resolution time after embolization was 24.5 days. Five patients showed no signs of ONP recovery. In no case was an initial incomplete ONP observed to worsen. There was a statistically insignificant trend toward complete recovery among patients with initial incomplete ONP (OR = 4.17; 95% CI, 0.75-23.18; P = 0.103). CONCLUSION: Endovascular treatment appears to be an effective treatment modality for ruptured Pcom aneurysm and related ONP. The initial incomplete ONP might encourage complete ONP recovery after endovascular treatment. PMID- 28879506 TI - Proton Induced Modulation of ICT and PET Processes in an Imidazo-phenanthroline Based BODIPY Fluorophores. AB - BODIPY fluorophores linked with an imidazo-phenanthroline donor at alpha and beta positions have been synthesized. Intriguing intramolecular charge transfer phenomenon is observed in both the dyes which has been extensively investigated using UV-vis absorption, steady-state and time-resolved fluorescence measurements. H-bonding and intrinsic polarity of the solvents has modulated the absorption and emission bands of these fluorophores strongly causing significant increase in the Stokes shifts. In spite of having difference only in terms of the position of donor subunit, the photophysics of these dyes are not only significantly different from each other, but contradictory too. Interestingly, acidochromic studies revealed the shuttling mechanism between ICT and PET processes for BDP 2. Quantum chemical calculations have been employed further to support experimental findings. DFT and TD-DFT method of analysis have been used to optimize ground and excited state geometries of the synthesized dyes. PMID- 28879508 TI - Response to letter re: Carotid atherosclerotic plaques standardized uptake values: methodological issues on reproducibility and accuracy. PMID- 28879507 TI - Methanethiol generation potential from anaerobic degradation of municipal solid waste in landfills. AB - Volatile sulfur compounds are the main odorants at landfills. In this study, methanethiol (CH3SH) was chosen as a typical volatile organic sulfur compound, and its generation potential was investigated during the anaerobic degradation of the organic fractions of municipal solid waste (MSW) including rice, flour food, vegetable, fish and pork, paper, cellulose textile, and yard wastes. Among the experimental wastes, gas generation was the highest in the fish and pork waste with a high CH3SH concentration of up to 2.5% (v/v). Sulfur reduction in the solid phase was mostly converted into gaseous sulfur compounds. During the whole experiment, the cumulative CH3SH generation from the fish and pork waste was 0.139 L kgdw-1, which was about 2 and 6 orders of magnitude higher than that from the other experimental wastes. The ratio of CH3SH-S to TS reduction was 31.56% in the fish and pork waste. These results would be helpful to understand the generation of volatile sulfur compounds during the anaerobic degradation of MSW and develop techniques to control odor pollution at landfills. PMID- 28879509 TI - IL26 modulates cytokine response and anti-TNF consumption in Crohn's disease patients with bacterial DNA. AB - : Interleukin IL26 supports killing of microbes and the innate sensing of bacterial-derived DNA (bactDNA). We evaluated the relationship between IL26 serum levels and bactDNA translocation in Crohn's disease (CD). We ran a prospective study on CD patients in remission. IL26 common polymorphisms, serum cytokines and complement protein, amplified-bactDNA, and anti-TNF-alpha were evaluated. In vitro PBMC analysis was performed. Three hundred and thirteen patients were included (mean CDAI: 83.6 +/- 32.8; mean fecal calprotectin: 55.4 +/- 35.3 MUg/g). A total of 106 patients (33.8%) showed bactDNA and 223 patients (71%) had a varIL26 genotype. BactDNA significantly correlated with increased IL26 levels compared with bactDNA-negative patients. PBMCs from varIL26 patients significantly reduced E. coli killing capacity compared with wtIL26-genotyped patients. The stimulation with a recombinant IL26 protein reduced pro inflammatory cytokines in response to E. coli in the varIL26 cell supernatants. Serum anti-TNF-alpha levels in varIL26 vs wtIL26-genotyped patients on biologics were significantly lower in the presence of bactDNA. Cells from varIL26 vs wtIL26 genotyped patients cultured with E. coli DNA and infliximab showed a significant decrease in free anti-TNF-alpha concentration. A varIL26 genotype was associated with the initiation of anti-TNF-alpha in CD patients during the 6-month follow up. IL26 polymorphisms may prevent bactDNA clearance and identify CD patients with a worse inflammatory evolution and response to therapy. KEY MESSAGES: BactDNA translocation in CD is associated with an increased risk of relapse. IL26 is sensitive to bactDNA and modulates the inflammatory response in CD patients. The varIL26 genotype is associated with reduced PMN capacity to kill bacteria. A varIL26 genotype is associated with decreased levels of anti-TNF-alpha in CD patients. IL26 may help explain the role of bactDNA as a risk factor of flare in CD patients. PMID- 28879510 TI - Examining impairment of adaptive compensation for stabilizing motor repetitions in stroke survivors. AB - The hand, one of the most versatile but mechanically redundant parts of the human body, suffers more and longer than other body parts after stroke. One of the rehabilitation paradigms, task-oriented rehabilitation, encourages motor repeatability, the ability to produce similar motor performance over repetitions through compensatory strategies while taking advantage of the motor system's redundancy. The previous studies showed that stroke survivors inconsistently performed a given motor task with limited motor solutions. We hypothesized that stroke survivors would exhibit deficits in motor repeatability and adaptive compensation compared to healthy controls in during repetitive force-pulse (RFP) production tasks using multiple fingers. Seventeen hemiparetic stroke survivors and seven healthy controls were asked to repeatedly press force sensors as fast as possible using the four fingers of each hand. The hierarchical variability decomposition model was employed to compute motor repeatability and adaptive compensation across finger-force impulses, respectively. Stroke survivors showed decreased repeatability and adaptive compensation of force impulses between individual fingers as compared to the control (p < 0.05). The stroke survivors also showed decreased pulse frequency and greater peak-to-peak time variance than the control (p < 0.05). Force-related variables, such as mean peak force and peak force interval variability, demonstrated no significant difference between groups. Our findings indicate that stroke-induced brain injury negatively affects their ability to exploit their redundant or abundant motor system in an RFP task. PMID- 28879511 TI - Risk Factors for Unresectable Recurrence After Up-Front Surgery for Colorectal Liver Metastasis. AB - BACKGROUND: There is no clear evidence that preoperative chemotherapy for resectable colorectal liver metastasis (CRLM) is superior to up-front surgery (UFS). The aim of this study was to identify the risk factors associated with poor prognosis after UFS for CRLM. METHODS: Data about consecutive patients with CRLM who underwent liver resection at Nara Medical University Hospital between January 2000 and December 2015 were retrieved from a prospective database. Recurrence that developed within 2 years after liver resection and could not be surgically resected was defined as unresectable recurrence (UR). Preoperative risk factors associated with UR after UFS were analyzed. Among the patients with the identified risk factors, the patients who were treated with UFS were compared with those who received preoperative chemotherapy via propensity score-matching analysis. RESULTS: There were 167 patients treated with UFS, and 71 of them developed UR (the UR group). The overall survival (OS) rate of the UR group was significantly worse than that of the non-UR group (5-year survival rate: 3.8 vs. 66.8%, p < 0.001). Multivariate analysis identified a primary colorectal cancer N factor of N2-3 as a risk factor for UR (hazard ratio 2.72, p = 0.004). Propensity score-matching analysis demonstrated that among patients with N2-3 primary colorectal cancer the post-initial treatment OS of the patients treated with UFS was significantly worse than that of the patients who received preoperative chemotherapy (5-year survival rate: 11.1 vs. 30.0%, p = 0.046). CONCLUSIONS: Patients with CRLM with a primary colorectal cancer N factor of N2-3 should be considered for preoperative chemotherapy. PMID- 28879512 TI - Feasibility of Intraoperative Navigation for Liver Resection Using Real-time Virtual Sonography With Novel Automatic Registration System. AB - BACKGROUND: The clinical feasibility and usability of intraoperative ultrasonography (IOUS) tracked by computed tomography (CT) images have been proposed; however, it requires technically demanding manual registration procedure. STUDY DESIGN: A prospective study using real-time virtual sonography (RVS) with novel automatic registration system was conducted in four high-volume centers of liver resection from 2015 to 2016. The requiring time for registration of IOUS and CT images and positional error of confluence of middle hepatic venous tributaries (V8-MHV, V5-MHV) were measured in patients undergoing laparotomy. RESULTS: Automatic registration was successful in 43 of 52 enrolled patients (83%), with error ranges of 11.4 (3.1-69.4) mm for V8-MHV and 16.2 (4.3-66.8) mm for V5-MHV. Time required for total registration process was 36 (27-74) s. CONCLUSIONS: The RVS with novel automatic registration system can provide quick and easy registration and acceptable accuracy, which can promote the usage of IOUS. PMID- 28879513 TI - High contrast sensitivity for visually guided flight control in bumblebees. AB - Many insects rely on vision to find food, to return to their nest and to carefully control their flight between these two locations. The amount of information available to support these tasks is, in part, dictated by the spatial resolution and contrast sensitivity of their visual systems. Here, we investigate the absolute limits of these visual properties for visually guided position and speed control in Bombus terrestris. Our results indicate that the limit of spatial vision in the translational motion detection system of B. terrestris lies at 0.21 cycles deg-1 with a peak contrast sensitivity of at least 33. In the perspective of earlier findings, these results indicate that bumblebees have higher contrast sensitivity in the motion detection system underlying position control than in their object discrimination system. This suggests that bumblebees, and most likely also other insects, have different visual thresholds depending on the behavioral context. PMID- 28879514 TI - Maternal doubled haploid production in interploidy hybridization between Brassica napus and Brassica allooctaploids. AB - MAIN CONCLUSION: We found a new in vivo route to produce maternal doubled haploid of Brassica napus . The pollen donor, an allooctaploid rapeseed, acts as a DH inducer. Inbred line has a powerful advantage in cultivar breeding and genetic analysis. Compared to the traditional breeding methods, doubled haploid production can save years off the breeding process. Though genotype-dependent tissue culture methods are widely used in the Brassica crops, seed-based in vivo doubled haploid developing systems are rare in nature and in the laboratory. As interspecific cross and interploid hybridization play an important role in genome evolution and plant speciation, we created a new Brassica artificial hybrid, a Brassica allooctaploid (AAAACCCC, 2n = 8* = 76), by interspecific crossing and genome doubling. A homozygous line was observed at the third self-generation of a synthesized Brassica allohexaploid (AAAACC, 2n = 6* = 58). Crosses between B. napus as female and Brassica allooctaploid as pollen donor were conducted, which yielded maternal doubled haploid B. napus that were identified based on phenotype, ploidy, and molecular analysis. The Brassica octaploid acted as a maternal doubled haploid inducer and had a relatively high induction rate. Our research provides a new insight for generation of homozygous lines in vivo using a single-step approach, as well as promotes the understanding in breeding programs and genetic studies involving the Brassicas. PMID- 28879515 TI - Testicular adrenal rest tumors in congenital adrenal hyperplasia-cross-sectional study of 51 Croatian male patients. AB - : Testicular adrenal rest tumors (TARTs) are common cause of infertility in males with congenital adrenal hyperplasia (CAH). We studied the role of genotype and disease regulation on TART development, their impact on gonadal function, and frequency in 47 21-hydroxylase deficiency (21-OHD) and four 11-hydroxylase deficiency (11-OHD) male patients. Testicular ultrasound (TU), genotype, hormonal measurement in 51, and spermiogram in five patients were performed. TARTs were detected in 14 SW21-OHD and one 11-OHD patient: 1/8 patients aged <7 years (1.8 years old is the youngest), 1/8 patients aged <12 years, 5/17 patients aged <18 years, and in 8/18 adults. All 21-OHD TART patients had exclusively severe mutations of CYP21A2 gene. Poor hormonal control in 8/15 patients with and 12/36 patients without TART indicates correlation of tumor development with poor disease control. None of the TART patients fathered a child. Low inhibin-B was found in 7/15 TART patients. Azoospermia was found in four and oligoasthenozoospermia in one patient. CONCLUSION: TART was detected exclusively in patients with severe CYP21A2 mutations. Disease regulation plays a role in development of TART that impairs testicular function and increases the risk of infertility. Screening for TART by TU is indicated from early childhood. What is Known: * Due to improved diagnostic and therapeutic possibilities, majority of the male patients with congenital adrenal hyperplasia nowadays reach adulthood and screening for long-term complications is becoming more important. * Testicular adrenal rest tumors (TARTs) are common cause of infertility and impaired gonadal function in males with CAH. What is New: * A 1.8-year-old boy described in this paper is the youngest reported patient with TART. * Screening for TART by testicular ultrasound from early childhood, especially in patients with severe CYP21A mutations, is recommended. PMID- 28879516 TI - The Influence of Temperature on Chytridiomycosis In Vivo. AB - Chytridiomycosis, an amphibian disease caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), is an ideal system for studying the influence of temperature on host-pathogen relationships because both host and pathogen are ectothermic. Studies of Bd in culture suggest that optimal growth occurs between 17 and 23 degrees C, and death of the fungus occurs above 29 or below 0 degrees C. Amphibian immune systems, however, are also temperature dependent and often more effective at higher temperatures. We therefore hypothesized that pathogen load, probability of infection and mortality in Bd exposed frogs would peak at a lower temperature than that at which Bd grows best in vitro. To test this, we conducted a study where Bd- and sham-exposed Northern cricket frogs (Acris crepitans) were incubated at six temperatures between 11 and 26 degrees C. While probability of infection did not differ across temperatures, pathogen load and mortality were inversely related to temperature. Survival of infected hosts was greatest between 20 and 26 degrees C, temperatures where Bd grows well in culture. These results demonstrate that the conditions under which a pathogen grows best in culture do not necessarily reflect patterns of pathogenicity, an important consideration for predicting the threat of this and other wildlife pathogens. PMID- 28879518 TI - Virginity Requirement Versus Sexually-Active Young People: What Girls and Boys Think About Virginity in South Kivu, Democratic Republic of Congo. AB - This article aims to explore Congolese male and female high school students' cultural attitudes concerning virginity. The study employed a qualitative approach to collect data from 56 boys and girls aged 16-20 years old. Eight focus group discussions and 40 individual interviews were conducted among participants from two urban and two rural high schools in South Kivu province. Findings indicate that men are disappointed when they marry non-virgin girls. In fact, most male and female participants perceived girls who were virgins as trustworthy individuals. They believe that the girl's virginity loss brings shame to her family. However, some female participants clearly dissociate from societal views or norms about virginity, and remark that virginity itself is not the key to a successful household nor a guarantee for remaining faithful after marriage. Such traditional norms-in the context of high levels of rape-place enormous pressure on young women and cause them to lie about virginity because they fear losing their fiances. They indicated that they would lie about it regardless of any consequences they may encounter. In fact, some traditional beliefs need to be challenged and modified. PMID- 28879517 TI - Glioma targeting peptide in combination with the P53 C terminus inhibits glioma cell proliferation in vitro. AB - Glioma is a prevalent malignant primary brain tumor in adults, the treatment for which remains a challenge due to its high infiltration and recurrence. Hence, treatments that lead to the suppression of glioma cell migration and invasion may be used in addition to surgery to increase the therapeutic outcome. In this study, we aimed to construct a multifunctional protein that would exert an effect on glioma cell proliferation and migration. The protein is named GL1-P53C-11R and it consists of the glioma-targeting peptide GL1 (G), the P53 C terminus (Pc) and the cell-penetrating peptide arginine (R). GL1-P53C-R was expressed with the fusion protein ZZ and immunofluorescence analysis showed effective delivery of the fused ZZ-GL1-P53C-R protein represented as ZZ-GPcR. The ZZ-GPcR exhibited an inhibitory effect on the proliferation, migration and invasion of U87DeltaEGFR cells. Western blotting results indicated that it caused significant changes in the expression levels of cell cycle and apoptotic proteins. Flow cytometric analysis showed increase apoptosis. Our findings suggest that the P53C in the fusion protein ZZ-GPcR can enter into glioma cells to exert its inhibitory effect. PMID- 28879519 TI - Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF V600 mutation-positive solid tumors: a phase 1 study. AB - Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF V600E mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF V600 mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma. PMID- 28879520 TI - Transnasal Snare Technique for Retrograde Primary Jejunostomy Placement After Surgical Gastrojejunostomy. AB - PURPOSE: To report a transnasal snare technique for retrograde primary jejunostomy placement after surgical gastrojejunostomy. MATERIALS AND METHODS: Two patients underwent the transnasal snare technique for retrograde primary jejunostomy placement. Patients included two females, age 58 and 62. In both patients, a gooseneck snare was inserted in a transnasal fashion. After insertion of the snare into the jejunum, the location was confirmed with ultrasound. The snare was then targeted using a Chiba needle through which a 0.018-inch wire was advanced and snared through the nose. The wire was exchanged for a 0.035-inch Amplatz wire over which the tract was serially dilated followed by insertion of the jejunostomy catheter through a peel-away sheath. Technical success, complications, and follow-up were recorded. RESULTS: Primary jejunostomy placement was technically successful in both patients. No minor or major complications occurred. Both patients received enteral nutrition the day following placement. Follow-up was at 54 and 38 days for patients 1 and 2, respectively. CONCLUSION: The transnasal snare technique provides a novel alternative for primary jejunostomy insertion allowing for targeting of the jejunum with improved procedural success and no complications. PMID- 28879521 TI - FCRLA-A Resident Endoplasmic Reticulum Protein that Associates with Multiple Immunoglobulin Isotypes in B Lineage Cells. AB - FCRLA is homologous to receptors for the Fc portion of IgG (FcgammaR) and is located in the same region of human chromosome one, but has several unusual and unique features. It is a soluble resident ER protein retained in this organelle by unknown mechanisms involving the N-terminal domain, a disordered domain with three Cys residues in close proximity in the human protein. Unlike the FcgammaRs, FCRLA is not glycosylated and has no transmembrane region. FCRLA is included in this CTMI volume on IgM-binding proteins because it binds IgM in the ER, but quite surprisingly, given the isotype-restricted ligand specificity of the other FcRs, it also binds all other Ig isotypes so far tested, IgG and IgA. In the case of IgM, there is even preferential binding of the secretory and not the transmembrane form. Among B cells, FCRLA is most highly expressed in the germinal center and shows little expression in plasma cells. Based on these observations, we propose that one human FCRLA function is to stop GC B cells from secreting IgM, which would act as a decoy receptor, thus preventing the B cells from capturing antigen, processing it, and presenting the antigen-derived peptides to T follicular helper cells. Without help from these T cells, there would be limited B cell isotype switching, proliferation, and differentiation. On the other hand, FCRLA is downregulated in plasma cells, where IgM secretion is an essential function. FCRLA may also act as a chaperone involved by unknown mechanisms in the proper assembly of Ig molecules of all isotypes. PMID- 28879522 TI - Cell Non-autonomous UPRER Signaling. AB - The UPRER is an important regulator of secretory pathway homeostasis, and plays roles in many physiological processes. Its broad range of targets and ability to modulate secretion and membrane trafficking make it perfectly positioned to influence intercellular communication, enabling the UPRER to coordinate physiological processes between cells and tissues. Recent evidence suggests that the activation of the UPRER can itself be communicated between cells. This cell non-autonomous route to UPRER activation occurs in multiple species, and enables organism-wide responses to stress that involve processes as diverse as immunity, metabolism, aging and reproduction. It may also play roles in disease progression, making the pathways that mediate cell non-autonomous UPRER signaling a potential source of novel future therapeutics. PMID- 28879523 TI - Regulatory T Cells: Molecular and Cellular Basis for Immunoregulation. AB - CD4+ regulatory T cells (Tregs) are a highly immune-suppressive subset of CD4+ T cells, characterized by expression of the master regulatory transcription factor FOXP3. Tregs are proven to play central roles in the maintenance of self tolerance in healthy individuals. Tregs are involved in maintaining immune homeostasis: they protect hosts from developing autoimmune diseases and allergy, whereas in malignancies, they promote tumor progression by suppressing anti-tumor immunity. Elucidating factors influencing Treg homeostasis and function have important implications for understanding disease pathogenesis and identifying therapeutic opportunities. Thus, the manipulating Tregs for up- or down regulation of their suppressive function is a new therapeutic strategy for treating various diseases including autoimmune disorders and cancer. This review will focus on recent advances in how Tregs integrate extracellular and intracellular signals to control their survival and stability. Deeper mechanistic understanding of disease-specific Treg development, maintenance, and function could make disease-specific Treg-targeted therapy more effective, resulting in an increase of efficacy and decrease of side effects related to manipulating Tregs. PMID- 28879524 TI - Uptake of Clostridial Neurotoxins into Cells and Dissemination. AB - Clostridial neurotoxins, botulinum neurotoxins (BoNT) and tetanus neurotoxin (TeNT), are potent toxins, which are responsible for severe neurological diseases in man and animals. BoNTs induce a flaccid paralysis (botulism) by inhibiting acetylcholine release at the neuromuscular junctions, whereas TeNT causes a spastic paralysis (tetanus) by blocking the neurotransmitter release (glycine, GABA) in inhibitory interneurons within the central nervous system. Clostridial neurotoxins recognize specific receptor(s) on the target neuronal cells and enter via a receptor-mediated endocytosis. They transit through an acidic compartment which allows the translocation of the catalytic chain into the cytosol, a prerequisite step for the intracellular activity of the neurotoxins. TeNT migrates to the central nervous system by using a motor neuron as transport cell. TeNT enters a neutral pH compartment and undergoes a retrograde axonal transport to the spinal cord or brain, where the whole undissociated toxin is delivered and interacts with target neurons. Botulism most often results from ingestion of food contaminated with BoNT. Thus, BoNT passes through the intestinal epithelial barrier mainly via a transcytotic mechanism and then diffuses or is transported to the neuromuscular junctions by the lymph or blood circulation. Indeed, clostridial neurotoxins are specific neurotoxins which transit through a transport cell to gain access to the target neuron, and use distinct trafficking pathways in both cell types. PMID- 28879525 TI - Colonic Spirochetes: What Has Genomics Taught Us? AB - The 'colonic' spirochetes assigned to the genus Brachyspira are slow-growing anaerobic bacteria. The genus includes both pathogenic and non-pathogenic species, and these variously colonise the large intestines of different species of birds and animals, including humans. Scientific understanding of the physiology and molecular biology of Brachyspira spp. remains very limited compared with that of other pathogenic spirochetes, and there are few descriptions of successful genetic manipulations undertaken to investigate gene function. An important boost to knowledge occurred in 2009 when, for the first time, the whole genome sequence of a Brachyspira strain (Brachyspira hyodysenteriae strain WA1) was obtained. The genomics analysis provided a significant increase in knowledge: for example, a previously unknown ~36 Kb plasmid was discovered and metabolic pathways were constructed. The study also revealed likely acquisition of genes involved in transport and central metabolic functions from other enteric bacterial species. Four subsequent publications have provided a similarly detailed analysis of other Brachyspira genomes, but of these only two included more than one strain of a species (20 strains of B. hyodysenteriae in one and three strains of B. pilosicoli in the other). Since then, more Brachyspira genomes have been made publicly available, with the sequences of at least one representative of each of the nine officially recognised species deposited at public genome repositories. All species have a single circular chromosome varying in size from ~2.5 to 3.3 Mb, with a C + G content of around 27%. In this chapter, we summarise the current knowledge and present a preliminary comparative genomic analysis conducted on 56 strains covering the official Brachyspira species. Besides providing detailed genetic maps of the bacteria, this analysis has revealed gene island rearrangements, putative phenotypes (including antimicrobial drug resistance) and genetic mutation mechanisms that enable brachyspires to evolve and respond to stress. The application of Next-Generation Sequencing (NGS) to generate genomic data from many more Brachyspira species and strains increasing will improve our understanding of these enigmatic spirochetes. PMID- 28879527 TI - Diabetes and pachymetry changes in pregnancy. AB - BACKGROUND: Purpose of this study is to evaluate changes in the central corneal thickness (CCT) in patients during the third trimester and postpartum phases of normal pregnancy, pregestational diabetes mellitus (DM), and gestational diabetes mellitus (GDM). METHODS: This was a prospective study. Patients that fulfilled the inclusion criteria were recruited from the obstetric clinic. They were grouped into normal pregnancy, pregestational DM, and GDM. Ophthalmic assessment and haematological investigations were done during the third trimester (after 28 weeks of gestation) and in the postpartum phase (6 weeks postpartum). RESULTS: A total of 192 pregnant patients were recruited for this study. Out of the 192 patients, only 143 of them came back for their follow-up 6 weeks postpartum. A total of 70 (36.5%) normal pregnancy patients, 51 (26.6%) DM patients, and 71 (36.9%) GDM patients were included in this prospective study. Our study showed that the CCT decreased postpartum in all three groups. Patients in all three groups did not have significantly different CCT during the third trimester of pregnancy and postpartum phase. However, patients who had thicker CCT irrespective of the grouping during the third trimester also had a thicker CCT post-delivery (p value <0.001). However, these changes did not appear to affect refractive error and visual acuity. CONCLUSIONS: Diabetes mellitus during pregnancy did not appear to influence the CCT. PMID- 28879526 TI - Intracardiac Echocardiography for Structural Heart and Electrophysiological Interventions. AB - PURPOSE OF REVIEW: With an increasing number of interventional procedures performed for structural heart disease and cardiac arrhythmias each year, echocardiographic guidance is necessary for safe and efficient results. The purpose of this review article is to overview the principles of intracardiac echocardiography (ICE) and describes the peri-interventional role of ICE in a variety of structural heart disease and electrophysiological interventions. RECENT FINDINGS: Both transthoracic (TTE) and transesophageal echocardiography have limitations. ICE provides the advantage of imaging from within the heart, providing shorter image distances and higher resolution. ICE may be performed without sedation and avoids esophageal intubation as with transesophageal echocardiography (TEE). Limitations of ICE include the need for additional venous access with possibility of vascular complications, potentially higher costs, and a learning curve for new operators. Data supports the use of ICE in guiding device closure of interatrial shunts, transseptal puncture, and electrophysiologic procedures. This paper reviews the more recent reports that ICE may be used for primary guidance or as a supplement to TEE in patients undergoing left atrial appendage (LAA) closure, interatrial shunt closure, transaortic valve implantation (TAVI), percutaneous mitral valve repair (PMVR), paravalvular leak (PVL) closure, aortic interventions, transcatheter pulmonary valve replacement (tPVR), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) closure. ICE imaging technology will continue to expand and help improve structural heart and electrophysiology interventions. PMID- 28879528 TI - Effects of chronic kidney disease on myocardial washout rate of thallium-201 in patients with normal myocardial perfusion on single photon emission computed tomography. AB - BACKGROUND: Myocardial perfusion single photon emission computed tomography (SPECT) is often performed even in patients with chronic kidney disease (CKD). We assessed the effects of CKD on myocardial washout rate (WR) of thallium (Tl)-201 in patients with normal myocardial perfusion on SPECT. METHODS: Two hundred and fifty-six patients with normal myocardial perfusion were enrolled in this study. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Patients with eGFR >= 60 ml/min/1.73 m2 were assigned to a control group. The mean myocardial WR of Tl-201 was calculated from the stress and the redistribution Bull's eye maps. RESULTS: With progressive CKD stages, systolic blood pressure and incindence of hypertension were increased. All patients in CKD stage 5 group were being treated with hemodialysis. Myocardial WR of Tl-201 was significantly higher in all of the CKD groups than control group. With progressive CKD stages, myocardial WR of Tl-201 was increased (stage 3, 52.2 +/- 9.2%; stage 4, 55.5 +/- 8.1%; and stage 5, 58.9 +/- 5.6%). Multivariate analysis showed that hemoglobin (beta = -0.24, p < 0.001) and eGFR (beta = -0.24, p = 0.002) were the major determinants of myocardial WR of Tl-201, but hemodialysis was not. CONCLUSIONS: Our data suggest that CKD is associated with increased myocardial WR of Tl-201 in patients with normal perfusion on SPECT. PMID- 28879529 TI - Costs and Treatment Pathways for Type 2 Diabetes in the UK: A Mastermind Cohort Study. AB - INTRODUCTION: Medication therapy for type 2 diabetes has become increasingly complex, and there are few reliable data on the current state of clinical practice. We report treatment pathways and associated costs of medication therapy for people with type 2 diabetes in the UK, their variability and changes over time. METHODS: Prescription and biomarker data for 7159 people with type 2 diabetes were extracted from the GoDARTS cohort study, covering the period 1989 2013. Average follow-up was 10 years. Individuals were prescribed on average 2.4 (SD: 1.2) drugs with average annual costs of L241. We calculated summary statistics for first- and second-line therapies. Linear regression models were used to estimate associations between therapy characteristics and baseline patient characteristics. RESULTS: Average time from diagnosis to first prescription was 3 years (SD: 4.0 years). Almost all first-line therapy (98%) was monotherapy, with average annual cost of L83 (SD: L204) for 3.8 (SD: 3.5) years. Second-line therapy was initiated in 73% of all individuals, at an average annual cost of L219 (SD: L305). Therapies involving insulin were markedly more expensive than other common therapies. Baseline HbA1c was unrelated to future therapy costs, but higher average HbA1c levels over time were associated with higher costs. CONCLUSIONS: Medication therapy has undergone substantial changes during the period covered in this study. For example, therapy is initiated earlier and is less expensive than in the past. The data provided in this study will prove useful for future modelling studies, e.g. of stratified treatment approaches. PMID- 28879531 TI - PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing L asparaginase: efficacy and safety. PMID- 28879530 TI - Correlation analyses revealed global microRNA-mRNA expression associations in human peripheral blood mononuclear cells. AB - MicroRNAs (miRNAs) can regulate gene expression through binding to complementary sites in the 3'-untranslated regions of target mRNAs, which will lead to existence of correlation in expression between miRNA and mRNA. However, the miRNA mRNA correlation patterns are complex and remain largely unclear yet. To establish the global correlation patterns in human peripheral blood mononuclear cells (PBMCs), multiple miRNA-mRNA correlation analyses and expression quantitative trait locus (eQTL) analysis were conducted in this study. We predicted and achieved 861 miRNA-mRNA pairs (65 miRNAs, 412 mRNAs) using multiple bioinformatics programs, and found global negative miRNA-mRNA correlations in PBMC from all 46 study subjects. Among the 861 pairs of correlations, 19.5% were significant (P < 0.05) and ~70% were negative. The correlation network was complex and highlighted key miRNAs/genes in PBMC. Some miRNAs, such as hsa-miR 29a, hsa-miR-148a, regulate a cluster of target genes. Some genes, e.g., TNRC6A, are regulated by multiple miRNAs. The identified genes tend to be enriched in molecular functions of DNA and RNA binding, and biological processes such as protein transport, regulation of translation and chromatin modification. The results provided a global view of the miRNA-mRNA expression correlation profile in human PBMCs, which would facilitate in-depth investigation of biological functions of key miRNAs/mRNAs and better understanding of the pathogenesis underlying PBMC-related diseases. PMID- 28879532 TI - Basic leucine zipper domain transcription factors: the vanguards in plant immunity. AB - Regulation of spatio-temporal expression patterns of stress tolerance associated plant genes is an essential component of the stress responses. Eukaryotes assign a large amount of their genome to transcription with multiple transcription factors (TFs). Often, these transcription factors fit into outsized gene groups which, in several cases, exclusively belong to plants. Basic leucine zipper domain (bZIP) transcription factors regulate vital processes in plants and animals. In plants, bZIPs are implicated in numerous fundamental processes like seed development, energy balance, and responses to abiotic or biotic stresses. Systematic analysis of the information obtained over the last two decades disclosed a constitutive role of bZIPs against biotic stress. bZIP TFs are vital players in plant innate immunity due to their ability to regulate genes associated with PAMP-triggered immunity, effector-triggered immunity, and hormonal signaling networks. Expression analysis of studied bZIP genes suggests that exploration and functional characterization of novel bZIP TFs in planta is helpful in improving crop resistance against pathogens and environmental stresses. Our review focuses on major advancements in bZIP TFs and plant responses against different pathogens. The integration of genomics information with the functional studies provides new insights into the regulation of plant defense mechanisms and engineering crops with improved resistance to invading pathogens. Conclusively, succinct functions of bZIPs as positive or negative regulator mediate resistance to the plant pathogens and lay a foundation for understanding associated genes and TFs regulating different pathways. Moreover, bZIP TFs may offer a comprehensive transgenic gizmo for engineering disease resistance in plant breeding programs. PMID- 28879533 TI - Patient-specific activity or scan-time in SPECT myocardial perfusion imaging: A hands-on approach. PMID- 28879534 TI - Children and Careers: How Family Size Affects Parents' Labor Market Outcomes in the Long Run. AB - We estimate the effect of family size on various measures of labor market outcomes over the whole career until retirement, using instrumental variables estimation in data from Norwegian administrative registers. Parents' number of children is instrumented with the sex mix of their first two children. We find that having additional children causes sizable reductions in labor supply for women, which fade as children mature and even turn positive for women without a college degree. Among women with a college degree, there is evidence of persistent and even increasing career penalties of family size. Having additional children reduces these women's probability of being employed by higher-paying firms, their earnings rank within the employing firm, and their probability of being the top earner at the workplace. Some of the career effects persist long after labor supply is restored. We find no effect of family size on any of men's labor market outcomes in either the short or long run. PMID- 28879535 TI - Hypercalcemia: a consultant's approach. AB - Due to their daily involvement in mineral metabolism, nephrologists are often asked to consult on children with hypercalcemia. This might become even more pertinent when the hypercalcemia is associated with acute kidney injury and/or hypercalciuria and renal calcifications. The best way to assess the severity of hypercalcemia is by measurement of plasma ionized calcium, and if not available by adjusting serum total calcium to albumin concentration. The differential diagnosis of the possible etiologies of the disturbance in the mineral homeostasis starts with the assessment of serum parathyroid hormone concentration, followed by that of vitamin D metabolites in search of both genetic and acquired etiologies. Several tools are available to acutely treat hypercalcemia with the current main components being fluids, loop diuretics, and antiresorptive agents. This review will address the pathophysiologic mechanisms, clinical manifestations, and treatment modalities involved in hypercalcemia. PMID- 28879536 TI - Binding affinities of the farnesoid X receptor in the D3R Grand Challenge 2 estimated by free-energy perturbation and docking. AB - We have studied the binding of 102 ligands to the farnesoid X receptor within the D3R Grand Challenge 2016 blind-prediction competition. First, we employed docking with five different docking software and scoring functions. The selected docked poses gave an average root-mean-squared deviation of 4.2 A. Consensus scoring gave decent results with a Kendall's tau of 0.26 +/- 0.06 and a Spearman's rho of 0.41 +/- 0.08. For a subset of 33 ligands, we calculated relative binding free energies with free-energy perturbation. Five transformations between the ligands involved a change of the net charge and we implemented and benchmarked a semi analytic correction (Rocklin et al., J Chem Phys 139:184103, 2013) for artifacts caused by the periodic boundary conditions and Ewald summation. The results gave a mean absolute deviation of 7.5 kJ/mol compared to the experimental estimates and a correlation coefficient of R 2 = 0.1. These results were among the four best in this competition out of 22 submissions. The charge corrections were significant (7-8 kJ/mol) and always improved the results. By employing 23 intermediate states in the free-energy perturbation, there was a proper overlap between all states and the precision was 0.1-0.7 kJ/mol. However, thermodynamic cycles indicate that the sampling was insufficient in some of the perturbations. PMID- 28879538 TI - Persistence length of collagen molecules based on nonlocal viscoelastic model. AB - Persistence length is one of the most interesting properties of a molecular chain, which is used to describe the stiffness of a molecule. The experimentally measured values of the persistence length of the collagen molecule are widely scattered from 14 to 180 nm. Therefore, an alternative approach is highly desirable to predict the persistence length of a molecule and also to explain the experimental results. In this paper, a nonlocal viscoelastic model is developed to obtain the persistence length of the collagen molecules in solvent. A new explicit formula is proposed for the persistence length of the molecule with the consideration of the small-scale effect, viscoelastic properties of the molecule, loading frequency, and viscosity of the solvent. The presented model indicates that there exists a range of molecule lengths in which the persistence length strongly depends on the frequency and spatial mode of applied loads, small-scale effect, and viscoelastic properties of the collagen. PMID- 28879537 TI - Assessing reserve-building pursuits and person characteristics: psychometric validation of the Reserve-Building Measure. AB - AIMS: A growing body of research suggests that regularly engaging in stimulating activities across multiple domains-physical, cultural, intellectual, communal, and spiritual-builds resilience. This project investigated the psychometric characteristics of the DeltaQuest Reserve-Building Measure for use in prospective research. METHODS: The study included Rare Patient Voice panel participants. The web-based survey included the Reserve-Building Measure with one-week re-test, measures of quality of life (QOL) and well-being (PROMIS General Health; NeuroQOL Cognitive Function and Positive Affect & Well-Being short-forms; Ryff Environmental Mastery subscale); and the Big Five Inventory-10 personality measure. Classical test theory and item response theory (IRT) analyses investigated psychometric characteristics of the Reserve-Building Measure. RESULTS: This North American sample (n = 592) included both patients and caregivers [mean age = 44, SD 19)]. Psychometric analyses revealed distinct subscales measuring current reserve-building activities (Active in the World, Games, Outdoors, Creative, Religious/Spiritual, Exercise, Inner Life, Shopping/Cooking, Passive Media Consumption,), past reserve-building activities (Childhood Activities, Achievement), and reserve-related person-factors (Perseverance, Current and Past Social Support, and Work Value). Test-retest stability (n = 101) was moderately high for 11 of 15 subscales (ICC range 0.78 0.99); four were below 0.59 indicating a need for further refinement. IRT analyses supported the item functioning of all subscales. Correlational analyses suggest the measure's subscales tap distinct constructs (range r = 0.11-0.46) which are not redundant with QOL, well-being, or personality (range r = 0.11 0.48). CONCLUSIONS: The Reserve-Building Measure provides a measure of activities and person-factors related to reserve that may potentially be useful in prospective research. PMID- 28879540 TI - Enasidenib: First Global Approval. AB - Enasidenib (Idhifa(r)) is an oral isocitrate dehydrogenase-2 (IDH2) inhibitor developed by Celgene Corporation under a global, exclusive license from Agios Pharmaceuticals. Enasidenib has been approved in the USA for the treatment of adults with relapsed or refractory acute myeloid leukaemia (AML) and an IDH2 mutation as detected by an FDA-approved test. It is at various stages of development in other countries for AML, myelodysplastic syndromes and solid tumours. This article summarizes the milestones in the development of enasidenib leading to this first global approval in the USA for the treatment of adults with relapsed or refractory IDH2-mutated AML. PMID- 28879539 TI - Synergistic effect of two beta globin gene cluster mutations leading to the hereditary persistence of fetal hemoglobin (HPFH) phenotype. AB - Co-inheritance of gamma and beta globin gene mutations in a compound heterozygous state is rare but of clinical interest as it provides an important data on understanding the HbF expression. Hematological analysis was carried out (Sysmex KX-21). F-cells were enumerated using flow cytometry. Beta globin gene was analysed by CRDB technique and by DNA sequencing. Gamma globin promoter region was sequenced and expression studies were carried out using real time Taqman assay. We report a family, where two inherited defects of the beta globin gene cluster segregate. The proband and her sibling were compound heterozygotes for a novel Ggamma promoter mutation and the 619 bp deletion a common Indian beta thalassemia mutation. Molecular characterization revealed that the father (HbA2 5.1%, HbF 5.4%), proband (HbA2 3.6%, HbF 31.7%) and her brother (HbA2 3.9%, HbF 23.6%) were heterozygous for the 619 bp deletion. The mother (HbA2 2.1%, HbF 3.4%) had a normal beta globin gene. As both the children showed high HbF levels, the gamma globin gene work up was carried out. The Ggamma-globin gene promoter analysis revealed that the mother and the two children were heterozygous for a 5 bp deletion -ATAAG (-533 to -529) that resides in the GATA binding site. These findings suggest that the 5 bp deletion in the Ggamma globin promoter has a functional role in silencing the gamma-globin gene expression in adults by disrupting GATA-1 binding and the associated repressor complex and results in the up-regulation of gamma globin gene expression. When co-inherited with beta thalassemia trait it leads to a phenotype of HPFH. PMID- 28879542 TI - Competency-Based Education in Low Resource Settings: Development of a Novel Surgical Training Program. AB - BACKGROUND: The unmet burden of surgical disease represents a major global health concern, and a lack of trained providers is a critical component of the inadequacy of surgical care worldwide. Competency-based training has been advanced in high-income countries, improving technical skills and decreasing training time, but it is poorly understood how this model might be applied to low and middle-income countries. We describe the development of a competency-based program to accelerate specialty training of in-country providers in cleft surgery techniques. METHODS: The program was designed and piloted among eight trainees at five international cleft lip and palate surgical mission sites in Latin America and Africa. A competency-based evaluation form, designed for the program, was utilized to grade general technical and procedure-specific competencies, and pre- and post-training scores were analyzed using a paired t test. RESULTS: Trainees demonstrated improvement in average procedure-specific competency scores for both lip repairs (60.4-71.0%, p < 0.01) and palate (50.6-66.0%, p < 0.01). General technical competency scores also improved (63.6-72.0%, p < 0.01). Among the procedural competencies assessed, surgical markings showed the greatest improvement (19.0 and 22.8% for lip and palate, respectively), followed by nasal floor/mucosal approximation (15.0%) and hard palate dissection (17.1%). CONCLUSION: Surgical delivery models in LMICs are varied, and trade-offs often exist between goals of case throughput, quality and training. Pilot program results show that procedure-specific and general technical competencies can be improved over a relatively short time and demonstrate the feasibility of incorporating such a training program into surgical outreach missions. PMID- 28879541 TI - Postural perturbation does not reset stepping rhythm in humans, but brief intermission does. AB - In the present study, we tested a hypothesis that the rhythm generator in humans keeps the rhythm of periodic motor output during brief inactivation of the pattern generator. This investigation was made through testing whether the step rhythm was reset after an interruptive event. A reset of the step rhythm was defined as an observation that the step re-emerges at random timing after an interruptive event regardless of the step rhythm before the interruption. This observation reflects an intermission of rhythm-keeping activity. Healthy participants stepped on a platform that could translate forward or backward. They continued stepping after the platform translation (non-stop session) or stopped briefly after the translation before resuming step with their own timing (stop session). In the non-stop session, the second step after the platform translation appeared at the integer multiple of the pre-existing step period in most participants, indicating that step rhythm was not reset. This finding indicates that postural perturbation does not interfere the rhythm-keeping activity. In the stop session, the step immediately after the intermission of stepping appeared at random time regardless of the step rhythm before the intermission in most participants. The actual side of the first step after the intermission was consistent with the predicted first step side at a 0.5 probability. Those findings indicate that step rhythm is reset after brief intermission of stepping, and contradict with the hypothesis that the activity of the rhythm generator is maintained, while the pattern generator is temporally inactive during a brief intermission of periodic motor output. This analysis could help to determine whether rhythm-keeping activity is inactivated by an interruptive event during periodic motor activity. PMID- 28879543 TI - Apex predatory mammals as bioindicator species in environmental monitoring of elements in Dinaric Alps (Croatia). AB - Tissue element investigations of apex terrestrial mammals are very scarce in Europe. We quantified 16 essential and nonessential elements in the kidney cortex, liver, and muscle tissue of 467 brown bears (Ursus arctos), 125 gray wolves (Canis lupus), one Eurasian lynx (Lynx lynx), and three golden jackals (Canis aureus) from Croatia by inductively coupled plasma mass spectrometry (ICP MS). Renal cadmium (0.6% of animals) and lead (1%) and hepatic lead (5%) were found in toxicologically relevant levels for mammals only in bears, while the other elements were within normal range. The association of age, sex, season, and region with measured tissue elements in bear and wolf was estimated by multiple regression analyses. Age-related accumulation of cadmium was observed in bears and wolves. Lead tissue content increased with the age of bears but declined in wolves. Female bears and wolves had higher arsenic, iron, and thallium than males in some tissues. Also, cadmium, mercury, copper, zinc, selenium, molybdenum, and uranium were more abundant only in female bears. Male bears had higher potassium, zinc, and magnesium, while male wolves had higher calcium in some tissues compared to female wolves. Seasonal differences were mainly observed for bears' tissues and region-specific differences only in wolves. The bear kidneys had the highest levels of cobalt, copper, molybdenum, cadmium, and lead among the four studied species. The element levels reported for bears and wolves represent baseline values for the Dinaric population. PMID- 28879544 TI - Brain cortical characteristics of lifetime cognitive ageing. AB - Regional cortical brain volume is the product of surface area and thickness. These measures exhibit partially distinct trajectories of change across the brain's cortex in older age, but it is unclear which cortical characteristics at which loci are sensitive to cognitive ageing differences. We examine associations between change in intelligence from age 11 to 73 years and regional cortical volume, surface area, and thickness measured at age 73 years in 568 community dwelling older adults, all born in 1936. A relative positive change in intelligence from 11 to 73 was associated with larger volume and surface area in selective frontal, temporal, parietal, and occipital regions (r < 0.180, FDR corrected q < 0.05). There were no significant associations between cognitive ageing and a thinner cortex for any region. Interestingly, thickness and surface area were phenotypically independent across bilateral lateral temporal loci, whose surface area was significantly related to change in intelligence. These findings suggest that associations between regional cortical volume and cognitive ageing differences are predominantly driven by surface area rather than thickness among healthy older adults. Regional brain surface area has been relatively underexplored, and is a potentially informative biomarker for identifying determinants of cognitive ageing differences. PMID- 28879545 TI - Real-life use of onabotulinumtoxinA for symptom relief in patients with chronic migraine: REPOSE study methodology and baseline data. AB - BACKGROUND: Migraine is a debilitating neurological disorder that affects 14.1% of the US and 14.7% of the European populations. Chronic migraine (CM) is broadly defined as headache occurring on >=15 days per month for >=3 months, and has an estimated worldwide prevalence of 1.4% to 2.2%. OnabotulinumtoxinA is currently approved for the treatment of CM in most European countries, and is the only preventative treatment approved for adults with CM, based on results from the PREEMPT clinical trial programme. The ongoing prospective, observational REal life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilisation, and Patient-reported OutcomeS observed in practice (REPOSE) Study aims to describe real-world healthcare resource utilisation and patient-reported outcomes over a 2-year period in Germany, Italy, Norway, Russia, Spain, Sweden, and the United Kingdom, among patients with CM prescribed onabotulinumtoxinA. METHODS: Herein, methodology and baseline characteristics of patients who participated for >=6 months in REPOSE are reported. No outcomes data are presented, although the methods for collecting these data are detailed. In REPOSE, onabotulinumtoxinA is administered at baseline and each follow-up visit (approximately every 3 months) during the 24-month treatment period, according to the treating physician's best clinical judgment and standard of care, guided by the terms of the marketing authorisation described in the Summary of Product Characteristics. Outcome assessments include Migraine-Specific Quality of Life Questionnaire (MSQ), EuroQol Group Questionnaire (EQ-5D), headache-day frequency, treatment satisfaction, headache-related healthcare resource utilisation (ie, healthcare professional visits, hospital admissions, medication use), onabotulinumtoxinA utilisation (ie, dose, sites), and safety/tolerability. RESULTS: As of the interim assessment date for this analysis, the study has enrolled 644 patients from 78 sites throughout Europe, and baseline data are available for 336 patients from 61 sites who participated in the study for >=6 months. Baseline measures indicate substantial disease burden and healthcare resource utilisation. CONCLUSIONS: Final results from the REPOSE Study will provide the largest real world, long-term analysis of the clinical use of onabotulinumtoxinA for the treatment of CM and will add important information to existing real-world findings. Future analyses will assess the long-term safety and efficacy of onabotulinumtoxinA in this population. PMID- 28879546 TI - The Btk-dependent PIP5K1gamma lipid kinase activation by Fas counteracts FasL induced cell death. AB - The Fas/FasL system plays a critical role in death by apoptosis and immune escape of cancer cells. The Fas receptor being ubiquitously expressed in tissues, its apoptotic-inducing function, initiated upon FasL binding, is tightly regulated by several negative regulatory mechanisms to prevent inappropriate cell death. One of them, involving the non-receptor tyrosine kinase Btk, was reported mainly in B cells and only poorly described. We report here that Btk negatively regulates, through its tyrosine kinase activity, the FasL-mediated cell death in epithelial cell lines from colon cancer origin. More importantly, we show that Btk interacts not only with Fas but also with the phosphatidylinositol-4-phosphate 5-kinase, PIP5K1gamma, which, upon stimulation by Fas ligand, is responsible of a rapid and transient synthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). This production requires both the presence and the tyrosine kinase activity of Btk, and participates in the negative regulation of FasL-mediated cell death since knocking down PIP5K1gamma expression significantly strengthens the apoptotic signal upon FasL engagement. Altogether, our data demonstrate the cooperative role of Btk and PIP5K1gamma in a FasL-induced PI(4,5)P2 production, both proteins participating to the threshold setting of FasL-induced apoptotic commitment in colorectal cell lines. PMID- 28879547 TI - Comparison of ICD-9 Codes for Depression and Alcohol Misuse to Survey Instruments Suggests These Codes Should Be Used with Caution. AB - BACKGROUND: Research suggests depression and alcohol misuse are highly prevalent among chronic hepatitis C (CHC) patients, which is of clinical concern. AIMS: To compare ICD-9 codes for depression and alcohol misuse to validated survey instruments. METHODS: Among CHC patients, we assessed how well electronic ICD-9 codes for depression and alcohol misuse predicted these disorders using validated instruments. RESULTS: Of 4874 patients surveyed, 56% were male and 52% had a history of injection drug use. Based on the PHQ-8, the prevalence of depression was 30% compared to 14% based on ICD-9 codes within 12 months of survey, 37% from ICD-9 codes any time before or within 12 months after survey, and 48% from ICD-9 codes any time before or within 24 months after survey. ICD-9 codes predicting PHQ-8 depression had a sensitivity ranging from 59 to 88% and a specificity ranging from 33 to 65%. Based on the AUDIT-C, the prevalence of alcohol misuse was 21% compared to 3-23% using ICD-9 codes. The sensitivity of ICD-9 codes to predict AUDIT-C score ranged from 9 to 35% and specificity from 80 to 98%. Overall 39% of patients reported ever binge drinking, with a sensitivity of ICD-9 to predict binge drinking ranging from 7 to 33% and a specificity from 84 to 98%. More than half of patients had either an ICD-9 code for depression, a survey score indicating depression, or both (59%); more than one-third had the same patterns for alcohol misuse (36%). CONCLUSIONS: ICD-9 codes were limited in predicting current depression and alcohol misuse, suggesting that caution should be exercised when using ICD-9 codes to assess depression or alcohol misuse among CHC patients. PMID- 28879548 TI - Cepharanthine Inhibits IFN-gamma-Induced CXCL10 by Suppressing the JAK2/STAT1 Signal Pathway in Human Salivary Gland Ductal Cells. AB - Cepharanthine, a biscolaurine alkaloid isolated from the plant Stephania cephalantha Hayata, has been reported to have potent anti-inflammatory properties. Here, we investigated the effects of cepharanthine on the expression of CXCL10 (a CXC chemokine induced by interferon-gamma [IFN-gamma] that has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions) in IFN-gamma-treated human salivary gland cell lines. We observed that IFN-gamma-induced CXCL10 production in NS-SV-DC cells (a human salivary gland ductal cell line), but not in NS-SV-AC cells (a human salivary gland acinar cell line). Cepharanthine inhibited the IFN-gamma-induced CXCL10 production in NS SV-DC cells. A Western blot analysis showed that cepharanthine prevented the phosphorylation of JAK2 and STAT1, but did not interfere with the NF-kappaB pathway. Moreover, cepharanthine inhibited the IFN-gamma-mediated chemotaxis of Jurkat T cells. These results suggest that cepharanthine suppresses IFN-gamma induced CXCL10 production via the inhibition of the JAK2/STAT1 signaling pathway in human salivary gland ductal cells. Our findings also indicate that cepharanthine could inhibit the chemotaxis of Jurkat T cells by reducing CXCL10 production. PMID- 28879549 TI - Decreased platelet count in children with epilepsy treated with valproate and its relationship to the immature platelet fraction. AB - This study examined relationships between valproate (VPA) and platelet count and immature platelet fraction (IPF). We compared the platelet count and IPF among three groups of children: those treated with VPA, those treated with other antiepileptic drugs (AEDs), and a reference group. IPF was measured using flow cytometry, and absolute immature platelet count (A-IPC) was calculated. The platelet count was significantly lower in the VPA group than in other AED and reference groups. In all groups, IPF was negatively correlated with platelet count. IPF was significantly higher in the VPA group than in the reference group, whereas A-IPC was similar among all groups. After stratification of the platelet count, IPF and A-IPC of the three groups did not differ significantly in any strata. No relationship was observed between serum VPA level and platelet count, IPF, or A-IPC. Our study suggests that VPA is associated with a decreased platelet count, although thrombocytopoiesis is not affected, even in children with a reduced platelet count. The suppression of platelet production in the bone marrow is unlikely to be the cause of thrombocytopenia in patients treated with VPA. PMID- 28879550 TI - New Protocol Based on UHPLC-MS/MS for Quantitation of Metabolites in Xylose Fermenting Yeasts. AB - Xylose fermentation is a bottleneck in second-generation ethanol production. As such, a comprehensive understanding of xylose metabolism in naturally xylose fermenting yeasts is essential for prospection and construction of recombinant yeast strains. The objective of the current study was to establish a reliable metabolomics protocol for quantification of key metabolites of xylose catabolism pathways in yeast, and to apply this protocol to Spathaspora arborariae. Ultra high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC MS/MS) was used to quantify metabolites, and afterwards, sample preparation was optimized to examine yeast intracellular metabolites. S. arborariae was cultivated using xylose as a carbon source under aerobic and oxygen-limited conditions. Ion pair chromatography (IPC) and hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) were shown to efficiently quantify 14 and 5 metabolites, respectively, in a more rapid chromatographic protocol than previously described. Thirteen and eleven metabolites were quantified in S. arborariae under aerobic and oxygen-limited conditions, respectively. This targeted metabolomics protocol is shown here to quantify a total of 19 metabolites, including sugars, phosphates, coenzymes, monosaccharides, and alcohols, from xylose catabolism pathways (glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle) in yeast. Furthermore, to our knowledge, this is the first time that intracellular metabolites have been quantified in S. arborariae after xylose consumption. The results indicated that fine control of oxygen levels during fermentation is necessary to optimize ethanol production by S. arborariae. The protocol presented here may be applied to other yeast species and could support yeast genetic engineering to improve second generation ethanol production. Graphical Abstract ?. PMID- 28879551 TI - Clinical grade manufacturing of genetically modified, CAR-expressing NK-92 cells for the treatment of ErbB2-positive malignancies. AB - BACKGROUND: The NK-92/5.28.z cell line (also referred to as HER2.taNK) represents a stable, lentiviral-transduced clone of ErbB2 (HER2)-specific, second-generation CAR-expressing derivative of clinically applicable NK-92 cells. This study addresses manufacturing-related issues and aimed to develop a GMP-compliant protocol for the generation of NK-92/5.28.z therapeutic doses starting from a well-characterized GMP-compliant master cell bank. MATERIALS AND METHODS: Commercially available GMP-grade culture media and supplements (fresh frozen plasma, platelet lysate) were evaluated for their ability to support expansion of NK-92/5.28.z. Irradiation sensitivity and cytokine release were also investigated. RESULTS: NK-92/5.28.z cells can be grown to clinically applicable cell doses of 5 * 108 cells/L in a 5-day batch culture without loss of viability and potency. X-Vivo 10 containing recombinant transferrin supplemented with 5% FFP and 500 IU/mL IL-2 in VueLife 750-C1 bags showed the best results. Platelet lysate was less suited to support NK-92/5.28.z proliferation. Irradiation with 10 Gy completely abrogated NK-92/5.28.z proliferation and preserved viability and potency for at least 24 h. NK-92/5.28.z showed higher baseline cytokine release compared to NK-92, which was significantly increased upon encountering ErbB2(+) targets [GZMB (twofold), IFN-gamma (fourfold), IL-8 (24-fold) and IL-10 (fivefold)]. IL-6 was not released by NK cells, but was observed in some stimulated targets. Irradiation resulted in upregulation of IL-8 and downregulation of sFasL, while other cytokines were not impacted. CONCLUSION: Our concept suggests NK-92/5.28.z maintenance culture from which therapeutic doses up to 5 * 109 cells can be expanded in 10 L within 5 days. This established process is feasible to analyze NK-92/5.28.z in phase I/II trials. PMID- 28879553 TI - Frontal lobe syndrome associated with intracranial hemorrhages. PMID- 28879554 TI - Congenital dyserythropoietic anemia type II mimicking hereditary spherocytosis in Indian patient with SEC23B-Y462C mutations. PMID- 28879552 TI - Considerations for Hartmann's reversal and Hartmann's reversal outcomes-a multicenter study. AB - PURPOSE: Hartmann's procedure is commonly practiced in emergent cases with the restoration of bowel continuity planned at a second stage. This study assessed the rate of restorations following Hartmann's procedure and evaluated factors affecting decision-making. METHODS: Data on patient demographics, comorbidities, causes for Hartmann's procedure, reversal rate, and complications were collected in a multicenter retrospective cohort study of patients who underwent Hartmann's procedure in five medical centers. RESULTS: Six hundred forty patients underwent Hartmann's procedure for diverticular disease (36.1%), obstructing malignancy (31.8%), benign obstruction (5%), and other reasons (23.1%). Overall, 260 (40.6%) patients underwent subsequent restoration of bowel continuity. One hundred twenty one (46.5%) patients had post-reversal complications, with an average Clavien Dindo score of 1.4 and a mortality rate of 0.77%. Decision to avoid reversal was mostly related to comorbidities (49.7%) and metastatic disease (21.6%). Factors associated with the decision to restore bowel continuity included male gender (P = 0.02), patient age (62.3 years in Hartmann's reversal patients vs 73.5 years in non-reversal patients; P < 0.0001), number of comorbidities (1.1 vs 1.58; P < 0.001), average Charlson score (1.93 vs 3.44; P < 0.001), and a neoplastic etiology (P < 0.0001). A sub-analysis excluding all patients who died in the 30 days following Hartmann's procedure showed similar factors associated with ostomy closure. CONCLUSION: Many patients do not have restoration of bowel continuity after undergoing Hartmann's procedure. Hartmann's reversal is associated with a significant postoperative morbidity. Surgeons and patients should be aware of the possibility that the colostomy might become permanent. PMID- 28879555 TI - Effects of photodynamic therapy plus intravitreal aflibercept with subtenon triamcinolone injections for aflibercept-resistant polypoidal choroidal vasculopathy. PMID- 28879556 TI - We are operating too much. AB - With the increase of superspecialisation, there has been a recent trend for a rising number of operations for both trauma and orthopaedic ailments. This flies against the results of properly planned, well performed, adequately powered, with clinically relevant outcome measures and long enough follow-up level I studies which challenge the received wisdom that surgery is actually superior to conservative management or even supervised neglect. This editorial outlines some of these issues, and suggests that orthopaedic and trauma surgeons should actually think twice before operating on anything that comes our way. PMID- 28879557 TI - A Pilot Study of Perceived Mouth Dryness, Perceived Swallowing Effort, and Saliva Substitute Effects in Healthy Adults Across the Age Range. AB - Xerostomia, or perceived mouth dryness, increases with advancing age, but its influence on swallowing effort is unknown. This study: (1) quantified relationships among age, perceived sense of swallowing effort, and ratings of perceived mouth dryness, and (2) examined changes in swallowing effort following application of a gel-based saliva substitute in healthy participants. This was a cross-sectional observational study and data were collected from attendees of a community healthy aging fair. Forty-two healthy participants (mean age = 65 years; 20 female) were enrolled. Each participant rated perceived effort with swallowing and perceived mouth dryness on a 10-cm horizontal, undifferentiated line. After participants applied a gel-based saliva substitute (Biotene(r) Oral Balance) to their tongue and oral mucosa, they rated perceived effort with swallowing again. Age was associated with greater perceived mouth dryness (r = 0.37, p < 0.03) but not with perceived swallowing effort (r = 0.16, p = 0.32). Perceived mouth dryness was associated with greater perceived swallowing effort (r = 0.62, p < 0.001). Perceived swallowing effort declined following application of the salivary substitute (mean difference = 9.39 mm, p < 0.002). Age was found to be a significant predictor of perceived mouth dryness (p < .02); and perceived mouth dryness was found to significantly predict perceived swallow effort (p < .001). Perceived mouth dryness increased with advancing age, but perceived swallowing effort did not. Regardless of age, participants with higher levels of perceived mouth dryness also reported more perceived effort with swallowing suggesting a role for adequate oral lubrication in this perception. Even in healthy participants, use of a gel-based saliva substitute lowered perceived swallowing effort. PMID- 28879558 TI - Second opinion strategies in breast pathology: a decision analysis addressing over-treatment, under-treatment, and care costs. AB - PURPOSE: To estimate the potential near-term population impact of alternative second opinion breast biopsy pathology interpretation strategies. METHODS: Decision analysis examining 12-month outcomes of breast biopsy for nine breast pathology interpretation strategies in the U.S. health system. Diagnoses of 115 practicing pathologists in the Breast Pathology Study were compared to reference standard-consensus diagnoses with and without second opinions. Interpretation strategies were defined by whether a second opinion was sought universally or selectively (e.g., 2nd opinion if invasive). Main outcomes were the expected proportion of concordant breast biopsy diagnoses, the proportion involving over- or under-interpretation, and cost of care in U.S. dollars within one-year of biopsy. RESULTS: Without a second opinion, 92.2% of biopsies received a concordant diagnosis. Concordance rates increased under all second opinion strategies, and the rate was highest (95.1%) and under-treatment lowest (2.6%) when all biopsies had second opinions. However, over-treatment was lowest when second opinions were sought selectively for initial diagnoses of invasive cancer, DCIS, or atypia (1.8 vs. 4.7% with no 2nd opinions). This strategy also had the lowest projected 12-month care costs ($5.907 billion vs. $6.049 billion with no 2nd opinions). CONCLUSIONS: Second opinion strategies could lower overall care costs while reducing both over- and under-treatment. The most accurate cost saving strategy required second opinions for initial diagnoses of invasive cancer, DCIS, or atypia. PMID- 28879559 TI - Yonsei Experience of 5000 Gasless Transaxillary Robotic Thyroidectomies. AB - BACKGROUND: Since the use of robot systems in thyroid surgery was introduced in 2007, we have advanced a novel method of robotic thyroidectomy (RT) using a gasless transaxillary approach (TAA). We report our experience with this technique and detail the surgical outcome of 5000 robotic thyroidectomies. METHODS: From October 2007 to May 2016, we successfully performed 5000 robotic thyroidectomies using a gasless TAA at the Department of Surgery, Yonsei University Health System. The medical records of the patients are reviewed retrospectively, and the details of clinicopathologic characteristics, operation times, perioperative complications, and oncologic outcomes are analyzed. RESULTS: The 5000 patients with thyroid tumor (4804 with cancer and 196 with benign tumor) underwent RT using a gasless TAA. Mean operation time was 134.5 +/- 122.0 min. The most common histologic subtype of thyroid cancer was papillary (98%), and the mean tumor size was 8.0 +/- 6.0 mm. Stage I was found in 85.4% patients regarding tumor nodes metastasis staging. The 196 benign tumors consisted of 104 adenomatous hyperplasias (53.0%), 43 follicular adenomas (21.9%), 30 Graves' diseases (15.3%), and 19 others (9.7%). Postoperative complication occurred in 24.1% without any serious one, and overall morbidity tended to decrease over time. No disease-specific mortality was observed during the follow-up period. Locoregional recurrence was developed in 26 patients (0.5%). CONCLUSION: The authors have tried to improve RT technique using gasless TAA and achieved acceptable surgical outcomes. The rapid evolution of surgical robot technology and our constant effort to advance RT technique using gasless TAA would make it possible to reduce the perioperative morbidity and gain the best possible operative and oncologic outcomes. PMID- 28879561 TI - Backbone 1H, 13C and 15N chemical shift assignment of full-length human uracil DNA glycosylase UNG2. AB - Human uracil N-glycosylase isoform 2-UNG2 consists of an N-terminal intrinsically disordered regulatory domain (UNG2 residues 1-92, 9.3 kDa) and a C-terminal structured catalytic domain (UNG2 residues 93-313, 25.1 kDa). Here, we report the backbone 1H, 13C, and 15N chemical shift assignment as well as secondary structure analysis of the N-and C-terminal domains of UNG2 representing the full length UNG2 protein. PMID- 28879560 TI - Involvement of miR-155/FOXO3a and miR-222/PTEN in acquired radioresistance of colorectal cancer cell line. AB - PURPOSE: Finding a novel biomarker for determining the radiosensitivity of colorectal cancer (CRC) is critical. The aim of this study is to evaluate the role of two main miRNAs including miR-222 and miR-155 in radiation response of CRC. MATERIALS AND METHODS: The radioresistant CRC cell lines were established by exposing the HCT 116 cell line to fractional X-ray radiation. SubG1 fraction analysis, MTT and clonogenic assays were applied to evaluate acquired radioresistant cell line radiosensitivity. miR-222/PTEN and miR-155/FOXO3a expressions were detected by RT PCR. RESULTS: The clonogenic assay and sub G1fraction analysis indicated that the RR2 sub-line was significantly more resistant than the parental cell line. MiR-222 and miR-155 were significantly upregulated in the radioresistant cell lines compared with the parental cell lines. The PTEN and FOXO3a expressions in the radioresistant cell lines were significantly higher than in the parental line. CONCLUSION: These observations indicate that miR-222 and miR-155 could induce radiation resistance in colorectal cancer by targeting PTEN and FOXO3a genes, respectively. Therefore, miR-222 and miR-155 can be suggested as good biomarkers of CRC radiation response. PMID- 28879562 TI - The Knowledge of South African Men Relating to Cervical Cancer and Cervical Cancer Screening. AB - Cervical cancer is the second most common cancer in South African women, but the most common cancer in Black women. Despite having a national cervical cancer screening programme, most women present with advanced disease. Men play a role in cervical cancer as the HPV, the major cause of cervical cancer, is sexually transmitted. The purpose of our study was to describe the knowledge men, living in Muldersdrift, had about cervical cancer, cervical cancer screening and the cervical cancer screening programme and how they preferred to be taught about these health issues. We used a survey design and convenience sampling to select 101 men older than 18 years (n = 101). A pretested self-developed questionnaire was used as the data collection instrument, and the data were analyzed using the SPSS version 22-computer program and quantitative content analyses. The Fischer's exact test measured associations between variables (p = 0.05). The ages of the sample (n = 101) ranged from 18 to 92 years; most were from the Zulu cultural group, unemployed and unmarried. The majority (66.3%, n = 67) had not heard of cervical cancer, the cervical cancer screening programme (60.4%, n = 61) or the Pap smear (67.3%, n = 68). Age and educational level did not influence having ever heard of these health issues. HPV infection was the most well-known risk factor, and the very late symptoms of cervical cancer were the least known. Most men preferred to be educated in a group, which provided a practical, feasible and cost effective way of educating men living in this community about these health issues. PMID- 28879563 TI - Erratum to: The Sesquiterpene Lactone, Budlein A, Inhibits Antigen-Induced Arthritis in Mice: Role of NF-kappaB and Cytokines. PMID- 28879564 TI - The effect of breathing on ductus arteriosus blood flow directly after birth. AB - : Spontaneous breathing at birth influences ductus arteriosus (DA) flow. This study quantifies the effect of breathing on DA shunting directly after birth. In healthy term infants born by elective cesarean section, simultaneous measurements of DA shunting and tidal volumes during spontaneous breathing were performed at 2 5, 5-8, and 10-13 min after birth. Eight infants with a mean (SD) gestational age of 40 (1) weeks and 3216 (616) grams were studied. Inspiratory tidal volume was 5.8 (3.3-7.7), 5.7 (4.0-7.1), and 5.2 (4.3-6.1) mL/kg at 2-5, 5-8, and 10-13 min. The velocity time integral of left-to-right shunting significantly increased during inspiration when compared to expiration (8.4 (5.2) vs. 3.7 (2.3) cm, 8.9 (4.4) vs. 5.6 (3.4) cm, and 14.0 (6.7) vs. 8.4 (6.9) cm; all p < 0.0001) at 2-5, 5-8, and 10-13 min, respectively. In contrast, right-to-left shunting was not different between inspiration and expiration at 2-5 and 10-13 min (11.1 (2.4) vs. 11.1 (2.6) cm and 10.7 (2.3) vs. 10.6 (3.0) cm; p > 0.05), but there was a small increase at 5-8 min (12.1 (2.4) vs. 10.8 (2.9) cm; p = 0.001) during expiration. CONCLUSION: Directly after birth, ductal shunting is influenced by breathing effort, predominantly with an increase in left-to-right shunt due to inspiration. What is Known: * Spontaneous breathing at birth influences ductus arteriosus flow and pulmonary blood flow. * Crying causes a significant increase in left-to-right ductus arteriosus shunting. What is New: * Left-to-right ductus arteriosus shunting increases during inspiration compared to expiration. * Breathing is important for ductal shunting and contributes to pulmonary blood flow. PMID- 28879565 TI - Comparative computational assessment of the pathogenicity of mutations in the Aspartoacylase enzyme. AB - Aspartoacylase (ASPA) is a zinc-dependent abundant enzyme in the brain, which catalyzes the conversion of N-acetyl aspartate (NAA) into acetate and aspartate. Mutations in the ASPA gene are associated with the development of Canavan disease (CD), leading to the deficiency of ASPA activity. Patients with CD were characterized by degeneration of the white matter of the brain. We reported earlier on two patients with severe form of CD that both had two novel missense mutations in the ASPA: c.427 A > G; p. I143V and c.557 T > A; p. V186D (Zaki et al. 2017a), patient 1 harbored both mutations (p.I143V and p.V186D) in a heterozygous form together with four other mutations, and patient 2 had both mutations in homozygous form. Wijayasinghe et al. (2014) crystallized the 3D structures of four different ASPA mutants (p.K213E, p.Y231C, p.E285A, and p.F295S). In this study, we used in silico prediction methods and molecular dynamics simulation (MDS) to understand the structural impact of all these mutations. Moreover, we used molecular docking (MD) to investigate the binding patterns of the NAA substrate to the native and mutant proteins. Among the mutations, p.E285A (crystallized mutant) was predicted to be the most deleterious for the protein function and the least deleteriousness mutant was the p.I143V (novel mutant). Among the novel mutations, p.V186D was observed to be disruptive for both the zinc binding and NAA binding than the p.I143V. This study provides practical insights on the effect of these mutations on the ASPA function and might serve as a platform for drug design for CD treatment. PMID- 28879566 TI - Success Rate and Complications of Sharp Recanalization for Treatment of Central Venous Occlusions. AB - PURPOSE: To evaluate success and safety of needle (sharp) recanalization as a method to re-establish access in patients with chronic central venous occlusions. MATERIALS AND METHODS: Thirty-nine consecutive patients who underwent this procedure were retrospectively reviewed to establish success rate and associated complications. In all cases, a 21- or 22-gauge needle was used to restore connection between two chronically occluded segments after conventional wire and catheter techniques had failed. The needle was guided toward a target placed through a separate access by fluoroscopic guidance. When successful, the procedure was completed by placing a catheter, ballooning the segment, and/or stenting. RESULTS: The procedure was successful in 37 of the 39 patients (95%). The vast majority of the treated lesions were in the SVC and/or right innominate vein. Occlusions ranged in length between 10 and 110 mm, and the average length of occluded venous segment was 40 mm in the treated group. There were four minor (SIR classification B) complications involving pain management after the procedure. There were two major (SIR classification D) complications both of which involved hemorrhage into the pericardium treated with covered stents (5.1%). CONCLUSIONS: Sharp recanalization is a viable procedure for patients who have exhausted standard wire and catheter techniques. The operator performing this procedure should be familiar with potential complications so that they can be addressed urgently if needed. PMID- 28879567 TI - mPGES-1-derived prostaglandin E2 stimulates Stat3 to promote podocyte apoptosis. AB - We previously reported that microsomal prostaglandin E synthase-1 (mPGES-1) contributed to adriamycin (Adr)-induced podocyte apoptosis. However, the molecular mechanism remains unclear. Here we studied the role of mPGES-1/PGE2 cascade in activating Stat3 signaling and the contribution of Stat3 in PGE2- and Adr-induced podocyte apoptosis. In murine podocytes, PGE2 dose- and time dependently increased the phosphorylation of Stat3 in line with the enhanced cell apoptosis and reduced podocyte protein podocin. In agreement with the increased Stat3 phosphorylation, Stat3-derived cytokines including IL-6, IL-17, MCP-1, and ICAM-1 were significantly upregulated following PGE2 treatment. By application of a specific Stat3 inhibitor S3I-201, PGE2-induced podocyte apoptosis was largely abolished in parallel with a blockade of podocin reduction. Next, we observed that Adr treatment also enhanced p-Stat3 and activated mPGES-1/PGE2 cascade. Blockade of Stat3 by S3I-201 significantly ameliorated Adr-induced cell apoptosis and podocin reduction. More interestingly, silencing mPGES-1 in podocytes by mPGES-1 siRNA blocked Adr-induced increments of Stat-3 phosphorylation, PGE2 production, and Stat3-derived inflammatory cytokines. Taken together, this study suggested that mPGES-1-derived PGE2 could activate Stat3 signaling to promote podocyte apoptosis. Targeting mPGES-1/PGE2/Stat3 signaling might be a potential strategy for the treatment of podocytopathy. PMID- 28879568 TI - A Model-Based Approach to Simultaneous Clustering and Dimensional Reduction of Ordinal Data. AB - The literature on clustering for continuous data is rich and wide; differently, that one developed for categorical data is still limited. In some cases, the clustering problem is made more difficult by the presence of noise variables/dimensions that do not contain information about the clustering structure and could mask it. The aim of this paper is to propose a model for simultaneous clustering and dimensionality reduction of ordered categorical data able to detect the discriminative dimensions discarding the noise ones. Following the underlying response variable approach, the observed variables are considered as a discretization of underlying first-order latent continuous variables distributed as a Gaussian mixture. To recognize discriminative and noise dimensions, these variables are considered to be linear combinations of two independent sets of second-order latent variables where only one contains the information about the cluster structure while the other one contains noise dimensions. The model specification involves multidimensional integrals that make the maximum likelihood estimation cumbersome and in some cases infeasible. To overcome this issue, the parameter estimation is carried out through an EM-like algorithm maximizing a composite log-likelihood based on low-dimensional margins. Examples of application of the proposal on real and simulated data are performed to show the effectiveness of the proposal. PMID- 28879569 TI - [Virus-associated arthritis]. AB - Epidemiological studies suggest a viral etiology in approximately 1% of patients presenting with acute arthritis. The arthritogenic effect of viral infections may be related to viral invasion of synovial cells, the cellular and humoral immune response to viral antigens or by induction of autoimmunity. Viral arthritis can mimic rheumatoid arthritis by presenting as a symmetrical polyarticular disease often accompanied by a rash and influenza-like symptoms. Serological testing for pathogen-specific IgM and IgG antibodies is frequently performed for establishing a viral etiology of arthritis. Virus isolation from the joints or detection of viral nucleic acids in the synovium or synovial fluid is only rarely successful and does not always provide proof of a viral origin of arthritis. While viral arthritis in most cases is self-limiting, protracted disease can occur. PMID- 28879571 TI - Risk Factors for Non-Contact Injury in Adolescent Cricket Pace Bowlers: A Systematic Review. AB - BACKGROUND: Adolescent cricket pace bowlers are prone to injury. Recognising the risk factors for non-contact injury in this population will aid future injury prevention strategies. OBJECTIVE: To identify the risk factors for non-contact injury in adolescent cricket pace bowlers. METHODS: We systematically searched PubMed, Cochrane Library, PEDro, SPORTDiscus, Embase, and the South African Journal of Sports Medicine to identify all experimental and observational studies reporting risk factors for non-contact injuries in pace bowlers (aged 12-19 years). The search syntax included terms relevant to cricket bowling, injury, and known risk factors for injury. The Newcastle-Ottawa Quality Assessment Scale and a modified Newcastle-Ottawa Quality Assessment Scale were used to assess the risk of bias in the cohort and cross-sectional studies, respectively. RESULTS: Sixteen studies (five cross-sectional studies, 11 cohort studies) comprising 687 participants (96% male, 75% playing cricket in Australia) met the selection criteria and were included for qualitative synthesis. Three cross-sectional studies were rated as high risk of bias and two as very high risk of bias. For the cohort studies, three were rated as low risk of bias, and eight as high risk of bias. Injury was associated with bowling biomechanics (excessive lateral trunk flexion and pelvis/hip kinematics), reduced trunk endurance, poor lumbo-pelvic hip movement control, and early signs of lumbar bone stress. Conflicting results were found by studies examining the mixed technique, bowling workload and quadratus lumborum asymmetry. CONCLUSIONS: The current systematic review identified a number bowling biomechanics and various neuromuscular deficiencies as risk factors for non-contact injury in adolescent pace bowlers. These factors may provide a useful target for future interventional research aiming to prevent injury in this population. Future studies should utilise prospective cohort designs, and ensure that participants are injury-free at baseline, confounding factors are well controlled and attrition rates are reported. REGISTRATION: This systematic review was registered a priori (PROSPERO, CRD42016043956). PMID- 28879570 TI - Preoperative Pulmonary Function Tests Predict Aspiration Pneumonia After Gastric Endoscopic Submucosal Dissection. AB - BACKGROUND: ESD allows higher rates of en-bloc and R0 resections, but has occasionally complications such as aspiration pneumonia. Factors associated with aspiration pneumonia are not completely understood. AIMS: To analyze the relationship between aspiration pneumonia and preoperative factors including pulmonary function tests. METHODS: A total of 978 patients with gastric tumors who had received pulmonary function tests were treated by ESD between June 2006 and May 2014. Pulmonary function tests were assessed using a spirometer. The patients were categorized into four groups according to the predicted vital capacity (%VC) and forced expiratory volume in 1 s as a percentage of forced vital capacity (FEV1.0%): normal; restrictive pulmonary dysfunction; obstructive; and mixed. The factors associated with aspiration pneumonia were retrospectively analyzed. RESULTS: Among the 268 cases with abnormal pulmonary function, 10 cases (3.7%) developed aspiration pneumonia. On the other hand, 7 cases (1.0%) with normal pulmonary function developed pneumonia. There was a significant correlation between pulmonary function and aspiration pneumonia (p = 0.010). When the pulmonary function cases were stratified into subgroups, 2.5% of cases with obstructive pulmonary dysfunction developed pneumonia, 5.5% with restrictive and 5.3% with mixed. By logistic regression analysis, pulmonary function, the presence of cerebral vascular disease, and procedure time were identified as significant independent risk factors associated with aspiration pneumonia. The odds ratios for pulmonary function, cerebral vascular disease, and procedure time were 3.6, 5.1, and 5.2, respectively. CONCLUSIONS: Preoperative pulmonary function tests may be useful markers to evaluate the risk for aspiration pneumonia after gastric ESD. PMID- 28879572 TI - Diligustilide releases H2S and stabilizes S-nitrosothiols in ethanol-induced lesions on rat gastric mucosa. AB - (Z,Z')-Diligustilide (DLG) or levistolide A is a dimeric phthalide isolated from Ligusticum porteri (Osha), the roots of which are used in the traditional treatment of many diseases including gastric aches. However, its action has not been completely elucidated. We analyzed the contributions of hydrogen sulfide and S-nitrosothiols to the action of DLG. Animals were pretreated with freshly formed in vitro nitrosothiol using Na2S and sodium nitroprusside to elucidate participation in the action of DLG. We also evaluated the production of H2S in vivo and in real time on the stomach via a specific electrode introduced into the stomachs of anaesthetized animals pretreated with DLG. Treatment with 10 mg/kg DLG increases gastric H2S production in vivo from 7.8 +/- 0.81 ppm to 13.1 +/- 3.01 ppm and prevents the decrease in gastric injury caused by absolute ethanol. In addition, it maintains endogenous concentrations of GSH and NO.. Exogenous S nitrosothiols protect the gastric mucosa from damage, suggesting that the action of DLG might be associated with S-nitrosothiol and H2S formation. PMID- 28879573 TI - Metabolism or behavior: explaining the performance of aphids on alkaloid producing fungal endophytes in annual ryegrass (Lolium multiflorum). AB - Plant-herbivore interactions are often mediated by plant microorganisms, and the "defensive mutualism" of epichloid fungal endophytes of grasses is an example. These endophytes synthesize bioactive alkaloids that generally have detrimental effects on the performance of insect herbivores, but the underlying mechanisms are not well understood. Our objective was to determine whether changes in the physiology and/or behavior of aphids explain the changes in performance of insects feeding on endophytic plants. We studied the interaction between the aphid Rhopalosiphum padi and the annual ryegrass Lolium multiflorum symbiotic (E+) or not symbiotic (E-) with the fungus Epichloe occultans that can synthesize loline alkaloids. We hypothesized that aphids feeding on E+ plants have higher energetic demands for detoxification of fungal alkaloids, thereby negatively impacting the individual performance, population growth, and structure. Aphids growing on E+ plants had lower values in morphometric and functional variables of individual performance, displayed lower birth rate, smaller population size, and dramatic structural changes. However, aphids exhibited lower values of standard metabolic rate (SMR) on E+ plants, which suggests no high costs of detoxification. Behavioral variables during the first 8 h of feeding showed that aphids did not change the phloem sap ingestion with the presence of fungal endophytes. We hypothesize that aphids may maintain phloem sap ingestion according to their fungal alkaloid tolerance capacity. In other words, when alkaloid concentrations overcome tolerance threshold, ingestion of phloem should decrease, which may explain the observed lower values of SMR in E+ feeding aphids. PMID- 28879574 TI - Genetic variants impacting metabolic outcomes among people on clozapine: a systematic review and meta-analysis. AB - Clozapine is the gold standard medication for treatment refractory schizophrenia, but unfortunately, its use is also associated with many adverse metabolic side effects. There may be a strong genetic component to the development of these adverse effects. We undertook a systematic review to examine the evidence for genetic variation being associated with secondary metabolic outcomes in patients with schizophrenia on clozapine, under both longitudinal and cross-sectional study designs. We limited studies to those examining patients definitely taking clozapine, unlike prior reviews that have examined metabolic effects of patients taking a range of antipsychotic medications. We found associations with outcomes such as increases in BMI and metabolic syndrome for variants in genes such as LEP and HTR2C. Meta-analysis of rs381328 in HTR2C revealed that the presence of the T allele led to a 0.63 kg/m2 (95% CI - 1.06 to - 0.19; p = 0.005) decrease in BMI compared to the C allele. Study and population heterogeneity and lack of statistical power among reviewed articles mean that evidence is lacking to warrant prophylactic genotyping of patients commencing clozapine to predict those at increased risk of developing adverse metabolic effects. Further efforts to establish collaborative consortia, consensus around study design and replication studies in independent populations should be encouraged. PMID- 28879575 TI - In-Hospital Mortality for Hepatic Portal Venous Gas: Analysis of 1590 Patients Using a Japanese National Inpatient Database. AB - BACKGROUND: Hepatic portal venous gas (HPVG) is rare but potentially serious condition. Main cause of HPVG is bowel ischemia, while detection of HPVG without bowel ischemia may have been increasing possibly due to widespread use of computed tomography. However, little is known about variation in etiologies of HPVG and mortality of HPVG with each etiology. We examined patient backgrounds, underlying diseases, and in-hospital mortality of HPVG patients using a national inpatient database. METHODS: Using the Diagnosis Procedure Combination database in Japan, we identified inpatients diagnosed with HPVG from July 1, 2010 to March 31, 2015. Patients' data included age, sex, comorbidities at admission, complications after admission, body mass index, surgical procedures, medications, and discharge status. In-hospital mortality was compared between the subgroups divided by the patient backgrounds and underlying diseases. RESULTS: A total of 1590 patients were identified during the study period. The mean age was 79.3 years old and the proportion of bowel ischemia was 53%. The overall in-hospital mortality was 27.3%. In-hospital mortality of HPVG with bowel ischemia, gastrointestinal tract (GIT) obstruction or dilation, GIT perforation, GIT infection, or sepsis was 26.8, 31.1, 33.3, 13.6, or 56.4%, respectively. Among patients with bowel ischemia, 32.2% patients received operation and their in hospital mortality was 16.5%. CONCLUSIONS: HPVG patients in the present study were relatively older but less likely to die than those in previous studies. Attention should be paid to the fact that mortality of HPVG without bowel ischemia was not always lower compared to that with bowel ischemia. PMID- 28879576 TI - Effects of acute resistance training modality on corticospinal excitability, intra-cortical and neuromuscular responses. AB - OBJECTIVE: Although neural adaptations from strength training are known to occur, the acute responses associated with heavy-strength (HST) and hypertrophy training (HYT) remain unclear. Therefore, we aimed to compare the acute behaviour of corticospinal responses following a single session of HST vs HYT over a 72-h period. METHODS: Fourteen participants completed a random counterbalanced, crossover study that consisted of a single HST session [5 sets * 3 repetition maximum (RM)], a HYT session (3 sets * 12 RM) of the leg extensors and a control session (CON). Single- and paired-pulse transcranial magnetic stimulation (TMS) was used to measure changes in motor-evoked potential (MEP) amplitude, corticospinal silent period (CSP), intra-cortical facilitation (ICF), short interval intra-cortical inhibition (SICI) and long-interval intra-cortical inhibition (LICI). Additionally, maximal muscle compound wave (M MAX) of the rectus femoris (RF) and maximal voluntary isometric contraction (MVIC) of the leg extensors were taken. All measures were taken at baseline, immediately post and 2, 6, 24, 48 and 72 h post-training. RESULTS: A significant condition x time interaction was observed for MVIC (P = 0.001), M MAX (P = 0.003), MEP amplitude (P < 0.001) and CSP (P = 0.002). No differences were observed between HST and HYT for all neurophysiological measures. No changes in SICI, ICF and LICI were observed compared to baseline. CONCLUSION: Our results suggest that: (1) the acute behaviour of neurophysiological measures is similar between HST and HYT; and (2) the increase in corticospinal excitability may be a compensatory response to attenuate peripheral fatigue. PMID- 28879577 TI - Models and tissue mimics for brain shift simulations. AB - Capturing the deformation of human brain during neurosurgical operations is an extremely important task to improve the accuracy or surgical procedure and minimize permanent damage in patients. This study focuses on the development of an accurate numerical model for the prediction of brain shift during surgical procedures and employs a tissue mimic recently developed to capture the complexity of the human tissue. The phantom, made of a composite hydrogel, was designed to reproduce the dynamic mechanical behaviour of the brain tissue in a range of strain rates suitable for surgical procedures. The use of a well controlled, accessible and MRI compatible alternative to real brain tissue allows us to rule out spurious effects due to patient geometry and tissue properties variability, CSF amount uncertainties, and head orientation. The performance of different constitutive descriptions is evaluated using a brain-skull mimic, which enables 3D deformation measurements by means of MRI scans. Our combined experimental and numerical investigation demonstrates the importance of using accurate constitutive laws when approaching the modelling of this complex organic tissue and supports the proposal of a hybrid poro-hyper-viscoelastic material formulation for the simulation of brain shift. PMID- 28879578 TI - Improved wedge method for the measurement of sub-millimeter slice thicknesses in magnetic resonance imaging. AB - The standard method for measuring the slice thickness of magnetic resonance images uses the inclined surface of a wedge (wedge method); it is sensitive to small increases in noise because of the differentiation of the edge response function (ERF) required. The purpose of this study was to improve the wedge method by fitting a curve to the ERF. The curve-fit function was obtained by convolving an ideal ERF (a ramp function) with a Gaussian function to represent ERF blurring. Measurements of 5- and 3-mm slice thicknesses were performed on a 3T scanner using the conventional wedge method, the improved wedge method, and another standard method using an inclined slab (slab method). Subsequently, 0.5- and 0.25-mm slice thicknesses from multiple slices acquired using a three dimensional sequence were measured using the improved wedge method. When measuring 5-mm slices, the differences in measurements obtained using the improved wedge method and the conventional slab and wedge methods were very small: <0.6% of the 5-mm slice thickness. The difference was <=1.7% for 3-mm slices. For 0.5- and 0.25-mm slices, the mean values obtained using the improved wedge method were 0.543 +/- 0.007 mm and 0.247 +/- 0.015 mm, with a 1.2 and 5.9% coefficient of variation across slices, respectively. The improved wedge method is valid and potentially applicable to the measurement of sub-millimeter slice thicknesses. PMID- 28879579 TI - Novel Selectivity-Based Forensic Toxicological Validation of a Paper Spray Mass Spectrometry Method for the Quantitative Determination of Eight Amphetamines in Whole Blood. AB - Paper spray tandem mass spectrometry is used to identify and quantify eight individual amphetamines in whole blood in 1.3 min. The method has been optimized and fully validated according to forensic toxicology guidelines, for the quantification of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxy-N-methylamphetamine (MDMA), 3,4-methylenedioxy-N ethylamphetamine (MDEA), para-methoxyamphetamine (PMA), para methoxymethamphetamine (PMMA), and 4-fluoroamphetamine (4-FA). Additionally, a new concept of intrinsic and application-based selectivity is discussed, featuring increased confidence in the power to discriminate the amphetamines from other chemically similar compounds when applying an ambient mass spectrometric method without chromatographic separation. Accuracy was within +/-15% and average precision was better than 15%, and better than 20% at the LLOQ. Detection limits between 15 and 50 ng/mL were obtained using only 12 MUL of whole blood. Graphical abstract ?. PMID- 28879582 TI - [Vestibular schwannoma - part 2]. PMID- 28879580 TI - Plant and Animal microRNAs (miRNAs) and Their Potential for Inter-kingdom Communication. AB - microRNAs (miRNAs) comprise a class of ~18-25 nucleotide (nt) single-stranded non coding RNAs (sncRNAs) that are the smallest known carriers of gene-encoded, post transcriptional regulatory information in both plants and animals. There are many fundamental similarities between plant and animal miRNAs-the miRNAs of both kingdoms play essential roles in development, aging and disease, and the shaping of the transcriptome of many cell types. Both plant and animal miRNAs appear to predominantly exert their genetic and transcriptomic influences by regulating gene expression at the level of messenger RNA (mRNA) stability and/or translational inhibition. Certain miRNA species, such as miRNA-155, miRNA-168, and members of the miRNA-854 family may be expressed in both plants and animals, suggesting a common origin and functional selection of specific miRNAs over vast periods of evolution (for example, Arabidopsis thaliana-Homo sapiens divergence ~1.5 billion years). Although there is emerging evidence for cross-kingdom miRNA communication-that plant-enriched miRNAs may enter the diet and play physiological and/or pathophysiological roles in human health and disease-some research reports repudiate this possibility. This research paper highlights some recent, controversial, and remarkable findings in plant- and animal-based miRNA signaling research with emphasis on the intriguing possibility that dietary miRNAs and/or sncRNAs may have potential to contribute to both intra- and inter kingdom signaling, and in doing so modulate molecular-genetic mechanisms associated with human health and disease. PMID- 28879581 TI - Activation of blood coagulation and thrombin generation in acute ischemic stroke treated with rtPA. AB - The impact of thrombolysis with recombinant tissue plasminogen activator (rtPA) on blood coagulation in acute ischemic stroke (AIS) patients is not completely understood. We studied the effect of thrombolysis on the thrombin generation (TG) profile as well as coagulant activity of activated factors IX (FIXa), XI (FXIa) and tissue factor (TF) in AIS patients. In a case-control study, TG parameters as well as FIXa, FXIa and TF levels were assessed in 95 AIS patients, including individuals receiving rtPA treatment within 4.5 h since AIS onset (n = 71, 74.7%) and those ineligible for thrombolysis (n = 24, 25.3%). Blood samples were collected at baseline and after 24 h since admission. The two groups were similar with regard to demographics and clinical factors. In thrombolysed patients, all TG parameters measured after 24 h were markedly decreased, with strongest impact on lag time (LT), when compared with the baseline values (81.3% longer LT, p < 0.0001), as well as when compared to the non-thrombolysed group (86% longer LT, p = 0.002). In non-thrombolysed AIS patients the TG remained unaltered. Logistic regression adjusted for potential confounders showed that high baseline ETP value (the top quartile) was solely predicted by the presence of circulating FIXa, whereas after 24 h FXIa predicted high ETP in the subgroup of thrombolysed and in all AIS patients. Thrombolysis in AIS patients markedly attenuates the TG. Elevated FXIa contributes to thrombin formation capacity after 24 h, highlighting a role of this factor in the regulation of blood coagulation in AIS. PMID- 28879583 TI - ? PMID- 28879585 TI - The IRAD and beyond: what have we unravelled so far? AB - Acute aortic dissection is a life-threatening condition associated with high morbidity and mortality rates and a long history of challenges to both diagnose and manage this condition successfully. The International Registry of Acute Aortic Dissection (IRAD) was established in 1996 as a global database to understand this old disease better and improve care for dissection. IRAD initially targeted various areas including etiological factors of dissection, modes of presentation, clinical features, physical findings, imaging, management, and outcomes, and is currently branching out in more specific fields such as endovascular intervention, genetic profiling, and functional imaging. Although presenting symptoms and physical findings have not changed significantly over two decades, the widespread use of computed tomography is standard and has improved the diagnostic pathway. Moreover, more patients are managed with appropriate procedures, such as surgery in type A, and endovascular therapy in subsets of type B aortic dissection. With these ongoing improvements in swift diagnostic work-up and therapeutic care, fewer patients are not getting appropriate treatment and more patients survive once they reach hospital. PMID- 28879584 TI - Adverse Event Profile of Pyrimethamine-Based Therapy in Toxoplasmosis: A Systematic Review. AB - INTRODUCTION: Approximately a third of the population worldwide is chronically infected with Toxoplasma gondii. Pyrimethamine-based regimens are recommended for the treatment of toxoplasmosis. OBJECTIVE: The aim was to evaluate the safety profile of pyrimethamine-based treatment for the three main Toxoplasma manifestations: toxoplasmic encephalitis (TE), ocular toxoplasmosis, and congenital toxoplasmosis. METHODS: PubMed, Cochrane Library, and Google Scholar databases were searched through August 1, 2016. Randomized, observational, prospective/retrospective, and cohort studies were eligible. Thirty-one studies were included with a total of 2975 patients. Of these, 13 were in congenital toxoplasmosis (n = 929), 11 in ocular toxoplasmosis (n = 1284), and seven in TE (n = 687). Across manifestations, adverse event (AE)-related treatment discontinuation and/or change in therapy involved <=37% of patients and occurred in >55% of studies: 100% for ocular toxoplasmosis, 57.1% for TE, and 61.5% for congenital toxoplasmosis. The most commonly observed AEs were bone marrow suppression, dermatologic, and gastrointestinal (GI). The prevalence of bone marrow suppression-related AEs was <=50% in congenital toxoplasmosis, <=42.7% in TE, and <=9.0% in ocular toxoplasmosis. The frequency of GI and dermatologic AEs were <=100 and <=11.1%, respectively, for ocular toxoplasmosis, <=10.7 and <=17.9% for TE, and <=10.8 and <=2.1% for congenital toxoplasmosis. Steven Johnson syndrome was reported in two patients with ocular toxoplasmosis and one with TE. CONCLUSION: The AE profile associated with pyrimethamine-based treatments differed by each manifestation of toxoplasmosis and within a given manifestation. Hematologic AEs occurred across all manifestations indicating the importance of monitoring the blood of patients administered pyrimethamine-based regimens. PMID- 28879588 TI - Active immunization against poliomyelitis. PMID- 28879591 TI - Marriage as a Search for Healing : by Jerry M. Lewis (New York: Brunner/Mazel Publishers, 1997). PMID- 28879586 TI - Multiple Myeloma Presenting as Massive Amyloid Deposition in a Parathyroid Gland Associated with Amyloid Goiter: A Medullary Thyroid Carcinoma Mimic on Intra operative Frozen Section. AB - Clinical examples of amyloid deposition in parathyroid glands are exceedingly rare and usually present as an incidental finding in a patient with amyloid goiter. Here, we present the first histologically documented case of parathyroid amyloid deposition that presented as a mass. The patient did not have hyperparathyroidism. The parathyroid gland was submitted for intra-operative frozen section and concern for medullary thyroid carcinoma was raised. An important histologic clue arguing against medullary thyroid carcinoma was the evenly dispersed nature of the amyloid. Histologic perinuclear clearing and parathyroid hormone immunohistochemistry confirmed parathyroid origin on permanent sections. The patient was also found to have associated amyloid goiter. Mass spectrometry of the amyloid showed it to be composed of kappa light chains. On further work-up, the patient was diagnosed with multiple myeloma. Awareness of parathyroid amyloid deposition is important as it is a histologic mimic of medullary thyroid carcinoma, especially on frozen section. Amyloid typing with evaluation for multiple myeloma in any patient with kappa or lambda light chain restriction is also important. PMID- 28879592 TI - [Brain tumours]. PMID- 28879594 TI - Body mass index changes after unicompartmental knee arthroplasty do not adversely influence patient outcomes. AB - PURPOSE: The objective of this study is to evaluate the prevalence of patients who lost or gained weight following unicompartmental knee arthroplasty (UKA), the effect of post-operative body mass index (BMI) changes on functional outcomes and quality of life (QoL), and predictive factors associated with BMI changes. METHODS: Prospectively collected data of 1043 patients who underwent UKA between 2000 and 2014 were reviewed. BMI, Knee Society Knee Score and Function Score, Oxford Knee Score (OKS), Short-Form 36 (SF-36) Physical Component Score (PCS) and Mental Component Score and proportion of patients attaining OKS/SF-36 minimal clinically important differences (MCID) were recorded preoperatively and at 2 years post-operatively. The patients were stratified into three groups based on weight changes for further analysis. RESULTS: Following UKA, 138 (13.3%) patients had lost weight, 695 (66.6%) maintained their weight, and 210 (20.1%) gained weight. Patients in all groups demonstrated significant improvements in functional and SF-36 PCS scores at 2 years post-operatively. There were no significant differences in functional outcomes, QoL or revision rate between the groups. Post-operative BMI changes were not correlated with any outcome scores or attainment of MCID (n.s.). CONCLUSIONS: This is the first study that evaluates change in BMI following UKA. It demonstrated a higher proportion of patients who gained weight as compared to those who lost weight. Post-operative BMI changes did not appear to affect outcomes of UKA. These findings will provide important information to surgeons when counselling patients regarding BMI change and its effect on outcomes after UKA. LEVELS OF EVIDENCE: Level III. PMID- 28879595 TI - Preemptive plerixafor injection added to pegfilgrastim after chemotherapy in non Hodgkin lymphoma patients mobilizing poorly. AB - Filgrastim is usually combined with chemotherapy to mobilize hematopoietic progenitor cells in non-Hodgkin lymphoma (NHL) patients. Limited information is available on the efficacy of a preemptive plerixafor (PLER) injection in poor mobilizers after chemotherapy and pegfilgrastim. In this prospective study, 72 patients with NHL received chemotherapy plus pegfilgrastim, and 25 hard-to mobilize patients received also PLER. The usefulness and efficacy of our previously developed algorithm for PLER use in pegfilgrastim-containing mobilization regimen were evaluated as well as the graft cellular composition, hematological recovery, and outcome after autologous stem cell transplantation (auto-SCT) according to the PLER use. A median 3.4-fold increase in blood CD34+ cell counts was achieved after the first PLER dose. The minimum collection target was achieved in the first mobilization attempt in 66/72 patients (92%) and 68 patients (94%) proceeded to auto-SCT. An algorithm for PLER use was fulfilled in 76% of the poor mobilizers. Absolute numbers of T-lymphocytes and NK cells were significantly higher in the PLER group, whereas the number of CD34+ cells collected was significantly lower. Early neutrophil engraftment was slower in the PLER group, otherwise hematological recovery was comparable within 12 months from auto-SCT. No difference was observed in survival according to the PLER use. Chemotherapy plus pegfilgrastim combined with preemptive PLER injection is an effective and convenient approach to minimize collection failures in NHL patients intended for auto-SCT. A significant effect of PLER on the graft cellular composition was observed, but no difference in outcome after auto-SCT was detected. PMID- 28879596 TI - Interaction between attentional systems and episodic memory encoding: the impact of conflict on binding of information. AB - Episodic memory (EM) is defined as a long-term memory system that stores information that can be retrieved along with details of the context of the original events (binding). Several studies have shown that manipulation of attention during encoding can impact subsequent memory performance. An influential model of attention distinguishes between three partially independent attentional networks: the alerting, the orienting and the executive or conflict resolution component. To date, the impact of the engagement of these sub-systems during encoding on item and relational context binding has not been investigated. Here, we developed a new task combining the Attentional Network Test and an incidental episodic memory encoding task to study this issue. We reported that when the alerting network was not solicited, resolving conflict hindered item encoding. Moreover, resolving conflict, independently of the cueing condition, had a negative impact on context binding. These novel findings could have a potential impact in the understanding EM formation, and memory disorders in different populations, including healthy elderly people. PMID- 28879597 TI - Prenatal congenital vertical talus (rocker bottom foot): a marker for multisystem anomalies. AB - BACKGROUND: Congenital vertical talus is a rare foot anomaly characterized by a prominent calcaneus and rigid forefoot dorsiflexion. While congenital vertical talus has been associated with anomalies such as trisomy 18, myelomeningocele and arthrogryposis, postnatal series have reported cases of isolated congenital vertical talus. OBJECTIVE: The purpose of our study was to determine the incidence of isolated congenital vertical talus prenatally and identify the most common anomalies associated with this finding. MATERIALS AND METHODS: A retrospective review was performed of congenital vertical talus cases identified in our fetal center from 2006 to 2015. The prenatal US and MR imaging appearance of congenital vertical talus was evaluated and differentiation from congenital talipes equinovarus was assessed. Studies were evaluated for additional abnormalities affecting the central nervous system, face, limbs, viscera, growth and amniotic fluid. Imaging findings were recorded and correlated with outcomes when available. RESULTS: Twenty-four cases of congenital vertical talus were identified prenatally (gestational age: 19-36 weeks). All 24 had prenatal US and 21 also underwent fetal MRI on the same day. There were no isolated cases of congenital vertical talus in this series; all 24 had additional anomalies identified prenatally. Sixteen cases had bilateral congenital vertical talus (67%). Additional anomalies were identified in the brain (15), spine (11), face (6), abdominal wall (3), heart (8) and other limbs (12). Chromosomal abnormalities were identified in 6 of 20 patients who underwent genetic testing. Overall, US held some advantage in detecting the abnormality: in 10 cases, US depicted congenital vertical talus more clearly than MRI; in 8 cases, US and MRI were equal in detection and in 3 cases, MRI was superior. In 9/15 cases with intracranial abnormalities, MRI was superior to US in demonstrating structural anomalies. Outcomes included termination (11), intrauterine fetal demise (1), stillbirth or immediate neonatal demise (5), lost to follow-up (1), and 6 survivors with postnatal follow-up. CONCLUSION: In our series, there were no cases of isolated congenital vertical talus, with additional anomalies variably affecting multiple systems including the brain, spine, face, viscera and limbs. When congenital vertical talus is identified prenatally, a thorough search for additional anomalies is indicated. Fetal MRI can be a useful adjunct in confirming the diagnosis and further delineating additional anomalies, particularly in the brain and spine. PMID- 28879598 TI - Implications of Intrahepatic Cholangiocarcinoma Etiology on Recurrence and Prognosis after Curative-Intent Resection: a Multi-Institutional Study. AB - BACKGROUND: We sought to investigate the prognosis of patients following curative intent surgery for intrahepatic cholangiocarcinoma (ICC) stratified by hepatitis B (HBV-ICC), hepatolithiasis (Stone-ICC), and no identifiable cause (conventional ICC) etiologic subtype. METHODS: 986 patients with HBV-ICC (n = 201), stone-ICC (n = 103), and conventional ICC (n = 682) who underwent curative-intent resection were identified from a multi-institutional database. Propensity score matching (PSM) was used to mitigate residual bias. RESULTS: HBV-ICC patients more often had cirrhosis, earlier stage tumors, a mass-forming lesion, well-to-moderate tumor differentiation, and an R0 resection versus stone-ICC or conventional ICC patients. Five-year recurrence-free survival among HBV-ICC and conventional ICC patients was 23.9 and 17.8%, respectively, versus a recurrence-free of only 8.3% among patients with stone-ICC. Similarly, 5-year overall survival among patients with stone-ICC was only 18.3% compared with 48.9 and 38.0% for patients with HBV ICC and conventional ICC, respectively. On PSM, patients with stone-ICC group had equivalent long-term outcomes as HBV-ICC patients. In contrast, on PSM, stone-ICC patients had a median overall survival of only 18.0 months versus 44.0 months for patients with conventional ICC. Median overall survival after intrahepatic-only recurrence among patients who had stone-ICC (6.0 months) was worse than OS among HBV-ICC (13.0 months) or conventional ICC (12.0 months) (p = 0.006 and p = 0.082, respectively). CONCLUSIONS: While HBV-ICC had a better prognosis on unadjusted analyses, these differences were mitigated on PSM suggesting no stage-for-stage differences in outcomes compared with stone-ICC or conventional ICC. In contrast, patients with stone-ICC had worse long-term outcomes. These data highlight the relative importance of ICC etiology relative to established clinicopathological factors in the prognosis of patients with ICC. PMID- 28879599 TI - Secular trends in sickness absence among Swedish patients with ankylosing spondylitis and psoriatic arthritis. AB - The aim was to investigate whether secular trends in sickness absence (SA) were present in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) receiving their diagnosis between 2002 and 2011. A repeated cross-sectional study design was used. Patients were identified in the Skane Healthcare Register (SHR). A washout period of 18 months was applied. The general population seeking health care was used as a reference cohort. SA data from 2003 to 2012 were obtained from the Swedish Social Insurance Agency and converted into net days of SA per year. Within diagnosis and sex, the average number of net days of SA during the calendar year following diagnosis was calculated and plotted against calendar year together with the corresponding SA of the age-standardized reference population. Linear regression on aggregated data, within diagnosis and sex, was applied to formally investigate differences in secular trends among patients and referents. There were 3173 patients and 992,502 referents. Among men diagnosed with AS, the average amount of SA declined by 8.1 net days per year in patients as compared with 2.4 in the referents (p = 0.01). Among PsA patients, the average amount of SA declined by 11.7 net days per year in women as compared with 2.7 in the referents (p < 0.001) and by 7.6 net days per year in men as compared with 1.9 in the referents (p < 0.001). Secular trends of declining SA were present among AS and PsA patients. Trends were also present among the referents, although not at all of the same magnitude. PMID- 28879600 TI - Infections and the kidney: a tale from the tropics. AB - Tropical infections are caused by a variety of bacteria, viruses and parasitic organisms across varying geographical regions and are more often reported in adults than in children. Most of the infections are acute, presenting as a febrile illness with involvement of multiple organ systems, including the kidney. The gamut of renal manifestations extends from asymptomatic urinary abnormalities to acute kidney injury and-albeit rarely-chronic kidney disease. Tropical infections can involve the glomerular, tubulointerstitial and vascular compartments of the kidney. Leptospirosis, malaria, dengue, rickettsial fever and schistosomiasis are the most prevalent tropical infections which affect the kidneys of children living in the tropics. In this review we discuss renal involvement in these most prevalent tropical infections. PMID- 28879601 TI - Investigations on the dose-response relationship of combined exposure to low doses of three anti-androgens in Wistar rats. AB - The current investigation examines whether combined exposure to three anti androgens (flutamide, prochloraz, vinclozolin) result in interference with endocrine homeostasis when applied at very low dose levels, and whether the results of combined exposure are more pronounced than to the individual compounds. A pre-post-natal in vivo study design was chosen with more parameters than regulatory testing protocols require (additional endpoints addressing hormone levels, morphology and histopathological examinations). Dose levels were chosen to represent the lowest observed adverse effect level (LOAEL), the no observed adverse effect level (NOAEL), and the acceptable daily intake for each individual substance. Anti-androgenic changes were observable at the effect level (LOAEL) but not at lower exposures. Nipple/areola counts appeared to be a sensitive measure of effect, in addition to male sex organ weights at sexual maturation, and finally gross findings. The results indicate the absence of evidence for effects at low or very low dose levels. No (adverse) effects were seen at the NOAEL dose. A non-monotonic dose-response relationship was not evident. Combined exposure at LOAEL level resulted in enhanced responses for anogenital index, number of areolas/nipples, delayed preputial separation and reduced ventral prostate weight in comparison to the individual compounds. PMID- 28879602 TI - A fluorescent, supramolecular chemosensor to follow steroid depletion in bacterial cultures. AB - Steroids have been identified as endocrine-disrupting agents, which are thought to impact the fertility of aquatic organisms and may even have direct effects on humans. The removal of steroids from wastewater is therefore essential, and this is most efficiently achieved by microbial treatment. We report herein a simple fluorescent method to identify microorganisms that are capable of steroid degradation and to optimize the conditions for steroid removal. The method is based on the supramolecular macrocycle cucurbit[8]uril (CB8), which can bind either the fluorescent dye berberine or a steroid in their inner cavity. In absence of steroid, the cavity is free to bind the dye, leading to a strong increase in fluorescence. In contrast, in the presence of steroid, the dye is displaced into the bulk solution. This principle affords a stable (no thermal or photodegradation was noted), fluorescent chemosensor (excitation ca. 450 nm, maximum emission at 525 nm), which can detect testosterone at concentrations > 0.7 MUM. We show that this displacement principle can be applied to follow the removal of micromolar concentrations of the steroid testosterone from a bacterial culture of Buttiauxella sp. S19-1. The reliability of the chemosensor in screening applications is demonstrated by an excellent Z-factor, which was in the range of 0.52 to 0.74 for all experiments carried out with this assay. Graphical abstract Steroid depletion by bacterial cultures can be followed by fluorescence spectroscopy using a supramolecular chemosensor based on berberine and cucurbit[8]uril. PMID- 28879603 TI - Cohort Contributions to Race- and Gender-Specific Trends in the Incidence of Hepatocellular Carcinoma in the USA. AB - INTRODUCTION: Increasing incidence of lifelong obesity and associated nonalcoholic steatohepatitis in younger birth cohorts may have contributed to growing incidence of hepatocellular carcinoma (HCC) in the USA. Yet, the contribution of cohort effects to trends in HCC incidence is unclear. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) program 1973-2013, race- and gender-specific trends in HCC incidence in the USA were decomposed using age-period-cohort (APC) modeling. RESULTS: Among SEER registry sites included in the analysis, there were 25,532 cases of HCC diagnosed including 15,867 (62%) White males, 3541 (14%) Black males, 5009 (20%) White females, and 1115 (4%) Black females. HCC incidence increases across periods, especially among men. Underlying this increase, APC models found significant cohort effects among White men, White women, and Black men, with rapid growth in HCC risk among cohorts born after 1940. A similar cohort trend among Black women did not reach statistical significance when compared to an age-period model. CONCLUSIONS: Cohort-specific trends have significantly contributed to increasing HCC incidence in recent decades. The rapid increase in HCC risk among younger cohorts suggests that the incidence of HCC will continue increasing in the near future. PMID- 28879604 TI - Experiments for the Development of a Steerable Microcatheter. AB - PURPOSE: Sumitomo Bakelite has developed a steerable microcatheter with a mechanism on the handle for changing the direction of the catheter tip. Experiments were conducted in an animal model to evaluate the practicality of the catheter with the goal of introduction into clinical use. MATERIALS AND METHODS: The steerable microcatheter has the following specifications: external diameter 2.4F/2.9F (distal/proximal portion); internal diameter 0.021 inches; effective length 125 cm; and it is fitted with a dial on the proximal portion for moving the tip. Five interventional radiologists evaluated the microcatheter in animal experiments using piglets. The test catheter was compared with commercial straight microcatheters based on procedure time required to insert the catheter into two prescribed patterns of arterial branching (P-1: hepatic artery, P-2: iliac artery), fluoroscopy time, amount of contrast agent used, and frequency of guidewire use. Furthermore, the renal arteries into which each catheter was inserted were excised and examined for the extent of vascular damage. RESULTS: Compared to the commercial products, the steerable microcatheter used without a guidewire required shorter procedure time (43.0/75.2% reductions in P-1/P-2), fluoroscopy time tended to be shorter (5.1/74.1% reductions), and the amount of contrast agent used tended to be lower (38.2/52.3% reductions). No damage was seen to the luminal surface of the renal arteries traversed by either microcatheter. During the experiment, there were no problems or defects with either microcatheter while intravascular procedure. CONCLUSION: These animal experiments confirmed that the steerable microcatheter had the functionality required for its development as a commercial medical device. PMID- 28879605 TI - In-vitro evaluation of limitations and possibilities for the future use of intracorporeal gas exchangers placed in the upper lobe position. AB - The lack of donor organs has led to the development of alternative "destination therapies", such as a bio-artificial lung (BA) for end-stage lung disease. Ultimately aiming at a fully implantable BA, general capabilities and limitations of different oxygenators were tested based on the model of BA positioning at the right upper lobe. Three different-sized oxygenators (neonatal, paediatric, and adult) were tested in a mock circulation loop regarding oxygenation and decarboxylation capacities for three respiratory pathologies. Blood flows were imitated by a roller pump, and respiration was imitated by a mechanical ventilator with different FiO2 applications. Pressure drops across the oxygenators and the integrity of the gas-exchange hollow fibers were analyzed. The neonatal oxygenator proved to be insufficient regarding oxygenation and decarboxylation. Despite elevated pCO2 levels, the paediatric and adult oxygenators delivered comparable sufficient oxygen levels, but sufficient decarboxylation across the oxygenators was ensured only at flow rates of 0.5 L min. Only the adult oxygenator indicated no significant pressure drops. For all tested conditions, gas-exchange hollow fibers remained intact. This is the first study showing the general feasibility of delivering sufficient levels of gas exchange to an intracorporeal BA via patient's breathing, without damaging gas exchange hollow fiber membranes. PMID- 28879606 TI - History of clubfoot treatment; part III (twentieth century): back to the future. AB - Clubfoot is one of the most common congenital orthopaedic anomalies and was described by Hippocrates in the year 400 BC. From manipulation in antiquity to splint and plaster in the Renaissance the treatment had improved before tenotomy. Many surgical treatments were tested during the nineteenth and twentieth centuries and will be explained in this manuscript; however, the pathology still continues to challenge the paediatric orthopedic surgeon as it has a notorious tendency to relapse, irrespective of whether the foot is treated with conservative or operative means. Part of the reason that the foot relapses is the surgeon's failure to recognize the underlying pathoanatomy. Clubfoot is often automatically assumed to be an equinovarus deformity, however, other permutations and combinations, such as calcaneovalgus, equinovalgus and calcaneovarus, are possible. Out of these combinations, calcaneovalgus occurs most frequently, followed by equinovarus deformity. In more than 90% of the cases, calcaneovalgus responds to conservative treatment, which involves passive manipulation and usually does not require casting or operative intervention as has been demonstrated by Ponseti. PMID- 28879608 TI - Response to the letter to the editor of Lambros et al. PMID- 28879607 TI - Arthroscopic management of suprascapular neuropathy of the shoulder improves pain and functional outcomes with minimal complication rates. AB - PURPOSE: The purpose of this study was to systematically assess the arthroscopic management of suprascapular neuropathy, including the aetiology, surgical decision-making, clinical outcomes, and complications associated with the procedure. METHODS: Three databases [PubMed, Ovid (Medline), and Embase] were searched. Systematic literature screening and data abstraction was performed in duplicate to present a review of studies reporting on arthroscopic management of suprascapular neuropathy. The quality of the included studies was assessed using level of evidence and the MINORS (Methodological Index for Nonrandomized Studies) checklist. RESULTS: In total, 40 studies (17 case reports, 20 case series, 2 retrospective comparative studies, and 1 prospective comparative study) were identified, including 259 patients (261 shoulders) treated arthroscopically for suprascapular neuropathy. The most common aetiology of suprascapular neuropathy was suprascapular nerve compression by a cyst at the spinoglenoid notch (42%), and the decision to pursue arthroscopic surgery was most commonly based on the results of clinical findings and investigations (47%). Overall, 97% of patients reported significant improvement in or complete resolution of their pre-operative symptoms (including pain, strength, and subjective function of the shoulder) over a mean follow-up period of 23.7 months. Further, there was a low overall complication rate (4%) associated with the arthroscopic procedures. CONCLUSION: While most studies evaluating arthroscopic management of suprascapular neuropathy are uncontrolled studies with lower levels of evidence, results indicate that such management provides patients with significant improvements in pain, strength, and subjective function of the shoulder, and has a low incidence of complications. Patients managed arthroscopically for suprascapular neuropathy may expect significant improvements in pain, strength, and subjective function of the shoulder. LEVEL OF EVIDENCE: Level IV, systematic review of level II to IV studies. PMID- 28879609 TI - [Bacterial skin and soft tissue infections]. AB - Bacterial skin and soft tissue infections are frequent and represent one of the most important differential diagnoses in patients presenting with reddened and swollen skin and soft tissue. Among these infections, cellulitis (phlegmon), erysipelas and abscesses are the most frequent. Whereas erysipelas is almost exclusively caused by streptococci and can be successfully treated with penicillin, an effective antibiotic therapy targeted at Staphylococcus aureus should be empirically considered for abscesses and phlegmon; other pathogens, such as gram negative and anaerobic bacteria can be found in patients with the corresponding underlying disease and certain risk factors. Severe necrotizing soft tissue infections are acutely life-threatening and require rapid and broad antibiotic therapy followed by immediate surgery. Depending on the medical history or exposure (including bite wounds), other pathogens may have to be considered in special situations including the increasing prevalence of community acquired methicillin-resistant Staphylococcus aureus (MRSA) outside hospitals. PMID- 28879610 TI - Reply to Lancelot et al.: 'Lack of evidence of a relationship between magnetic resonance signal intensity changes in the globus pallidus and dentate nucleus, and repeated administrations of gadoterate meglumine in children'. PMID- 28879611 TI - Evaluation of 15N-detected H-N correlation experiments on increasingly large RNAs. AB - Recently, 15N-detected multidimensional NMR experiments have been introduced for the investigation of proteins. Utilization of the slow transverse relaxation of nitrogen nuclei in a 15N-TROSY experiment allowed recording of high quality spectra for high molecular weight proteins, even in the absence of deuteration. Here, we demonstrate the applicability of three 15N-detected H-N correlation experiments (TROSY, BEST-TROSY and HSQC) to RNA. With the newly established 15N detected BEST-TROSY experiment, which proves to be the most sensitive 15N detected H-N correlation experiment, spectra for five RNA molecules ranging in size from 5 to 100 kDa were recorded. These spectra yielded high resolution in the 15N-dimension even for larger RNAs since the increase in line width with molecular weight is more pronounced in the 1H- than in the 15N-dimension. Further, we could experimentally validate the difference in relaxation behavior of imino groups in AU and GC base pairs. Additionally, we showed that 15N detected experiments theoretically should benefit from sensitivity and resolution advantages at higher static fields but that the latter is obscured by exchange dynamics within the RNAs. PMID- 28879613 TI - Vaccines for Conservation: Plague, Prairie Dogs & Black-Footed Ferrets as a Case Study. AB - The endangered black-footed ferret (Mustela nigripes) is affected by plague, caused by Yersinia pestis, both directly, as a cause of mortality, and indirectly, because of the impacts of plague on its prairie dog (Cynomys spp.) prey base. Recent developments in vaccines and vaccine delivery have raised the possibility of plague control in prairie dog populations, thereby protecting ferret populations. A large-scale experimental investigation across the western US shows that sylvatic plague vaccine delivered in oral baits can increase prairie dog survival. In northern Colorado, an examination of the efficacy of insecticides to control fleas and plague vaccine shows that timing and method of plague control is important, with different implications for long-term and large scale management of Y. pestis delivery. In both cases, the studies show that ambitious field-work and cross-sectoral collaboration can provide potential solutions to difficult issues of wildlife management, conservation and disease ecology. PMID- 28879612 TI - How long noncoding RNAs enforce their will on mitochondrial activity: regulation of mitochondrial respiration, reactive oxygen species production, apoptosis, and metabolic reprogramming in cancer. AB - The cellular transcriptome contains a wide diversity of untranslated RNAs, of which the class of regulatory long noncoding RNAs (lncRNAs) has only recently been recognized. Evidence swiftly accumulates of lncRNAs influencing mitochondrial activities of eukaryotic cells, and perturbed expression is conspicuously associated with human diseases. In this review, we describe the multifaceted effects of lncRNAs on mitochondrial function, more particularly on the balance between oxidative phosphorylation and glycolysis, on the production of reactive oxygen species, and on apoptosis in human cells. Emphasis is placed on the involvement of lncRNAs in cancer metabolism, as tumor cells rely heavily on modifications of mitochondrial functioning as an essential component for sustained tumorigenesis and cancer progression. From the nonexhaustive list of lncRNAS described in this review, ANRIL, AScmtRNA, H19, HOTAIR, LincRNA-p21, MALAT1, RMRP, SAMMSON, and VL30 have emerged as potent regulators of mitochondrial metabolism. Due to their key role in cancer progression, they represent potential targets of innovative lncRNA-based treatment strategies. PMID- 28879614 TI - Plant sex affects the structure of plant-pollinator networks in a subtropical forest. AB - Although it has long been recognized that the diversified sexual systems of plants could influence community patterns and pollination specialization, plant sex is not usually incorporated to quantify plant-pollinator networks. In this study, we observed 1776 visitations corresponding to 84 pollinator species and 28 plant species (19 sexually monomorphic plants and 9 dioecious plants) in a subtropical forest, China. We constructed three networks by, respectively, combining visitations to dioecious female and male plants at the species level, separating them, and retaining the shared visitations between them. When the shared visitations between male and female plants were considered, the modularity was increased and the nestedness was decreased with a significantly low robustness for the plant community. Only in this network, most dioecious and hermaphroditic plants were associated with different pollinator groups and separated to different modules. The results also showed that dioecious plants were more generalized and more likely to be module hubs in sex-combined network and sex-separated network but not in sex-shared network. Only in the sex separated network, pollinators in dioecious modules were less selective than in hermaphroditic modules. Our study shows incorporating the different visitations between plant sexes could affect the analysis of key network structure properties and the description of pollination niche. To better understand niche partitioning and stability of plant-pollinator communities, it is necessary to compare pollination networks considering plant sexual diversity. PMID- 28879615 TI - Synthesis of novel quinazolin-4(3H)-one derivatives containing the 7-oxo-1,2,4 triazolo[1,5-a]pyrimidine moiety as effective agricultural bactericides against the pathogen Xanthomonas oryzae pv. oryzae. AB - A series of novel quinazolin-4-one derivatives (7a-7n) bearing the 7-oxo-1,2,4 triazolo[1,5-a]pyrimidine moiety were designed, synthesized and evaluated for their inhibition activities against phytopathogenic bacteria and fungi in vitro. All of the target compounds were fully characterized through [Formula: see text] NMR, [Formula: see text] NMR, HRMS and IR spectra. Among these compounds, the structure of compound 7e was unambiguously confirmed via single-crystal X-ray diffraction analysis. The turbidimetric assays indicated that compounds 7b, 7d, 7g, 7k and 7n exhibited much more potent inhibition activities against the pathogen Xanthomonas oryzae pv. oryzae (Xoo), relative to control Bismerthiazol. Moreover, antibacterial activities of compounds 7j, 7k and 7n against the pathogen Xanthomonas axonopodis pv. citri (Xac) were comparable to that of control Bismerthiazol. As for the pathogen Ralstonia solanacearum (Rs), only compounds 7g and 7i demonstrated inhibition activities similar to control Thiadiazole-copper. Moreover, this class of compounds did not display inhibition activity against three fungi tested. The above findings indicated that quinazolin 4-one derivatives containing the 7-oxo-1,2,4-triazolo[1,5-a]pyrimidine moiety have a potential as promising candidates for the development of new and more efficient agricultural bactericides. PMID- 28879616 TI - Isolation and identification of five cold-inducible promoters from Oryza sativa. AB - MAIN CONCLUSION: Five promoters of the cold-inducible rice genes were isolated. The quantitative and qualitative expression analyses in the high generation transgenic rice suggest that the genes are stably induced by low temperature. Cold-inducible promoters are highly desirable for stress-inducible gene expression in crop genetic engineering. In this study, five rice genes, including OsABA8ox1, OsMYB1R35, OsERF104, OsCYP19-4, and OsABCB5, were found to be transcriptionally induced by cold stress. The promoters of these five genes were isolated, and their activities were identified in various tissues of transgenic rice plants at different growth stages both before and after cold stress. Histochemical staining, quantitative fluorescence assays, and GUSplus gene expression assays in corresponding promoter-GUSplus transgenic rice plants confirmed that the five promoters were cold-inducible with different expression patterns and strengths. The OsABA8ox1 and OsERF104 promoters had very low background expression; in contrast, the OsMYB1R35 promoter had higher basal activity in the roots, and OsCYP19-4 promoter activity was preferentially high in leaves and flowers of untreated transgenic lines. The OsABCB5 promoter had the highest basal activity among the five promoters. After cold induction, the activities of the OsABA8ox1, OsMYB1R35, and OsABCB5 promoters were high in both roots and leaves, slightly lower than that of the constitutively expressed OsActin1 promoter but comparable to that of the AtRD29A promoter. During the cold treatment time course, the activities of OsABA8ox1 and OsABCB5 promoters were quickly up-regulated in the early period and peaked at 24 h, after which the induction level gradually decreased until 48 h. The activities of the OsMYB1R35 and OsCYP19-4 promoters increased under stress in a time-dependent manner, while OsERF104 promoter activity began to increase at 4 h and then decreased strongly. Furthermore, activities' analysis in T3, T4, and T5 homozygous progeny of single copy plants revealed that five promoters maintained their activities at comparable levels with no evidence of silencing under cold stress. Overall, the five cold-inducible rice promoters described herein could potentially be used in crop biotechnology. PMID- 28879618 TI - Assessment and review of organochlorine pesticide pollution in Kyrgyzstan. AB - The current study describes the preliminary assessment and securing activities of the largest and most hazardous POPs-contaminated sites in Kyrgyzstan. In 2010, cattle died and population were found with high pesticide levels in blood, human milk, and placenta. In the first phase of the study, a historic assessment of the pesticide dumping at the landfill/dump sites have been conducted. In the second phase, soil analysis for organochlorine pesticides in the areas of the pesticide disposal sites, the former pesticides storehouses, agro-air strips, and the cotton-growing fields were conducted. By this assessment, a first overview of the types and sources of pollution and of the scale of the problem is compiled including information gaps. From major pesticides used, DDT, DDE, and HCH were measured in the highest concentrations. With the limited analytical capacity present, a reasonable risk assessment could be performed. This paper also reports on practical risk reduction measures that have been carried out recently at the two major pesticide disposal sites with support of a Dutch environmental engineering company, an international NGO (Green Cross Switzerland) and local authorities from the Suzak region within an UN project. Local population living near the sites of the former pesticide storehouses and agro-airstrips are advised not to cultivate vegetables and melons or to raise cattle on these areas. Instead, it is recommended to grow technical crops or plant trees. Further recommendations on monitoring and assessment is given including the suggestion to consider the findings in the National Implementation Plan of Kyrgyzstan. PMID- 28879617 TI - High but not moderate-intensity endurance training increases pain tolerance: a randomised trial. AB - PURPOSE: To examine the effect of high-intensity interval training (HIIT) compared to volume-matched moderate-intensity continuous training (CONT) on muscle pain tolerance and high-intensity exercise tolerance. METHODS: Twenty healthy adults were randomly assigned (1:1) to either 6 weeks of HIIT [6-8 * 5 min at halfway between lactate threshold and maximal oxygen uptake (50%Delta)] or volume-matched CONT (~60-80 min at 90% lactate threshold) on a cycle ergometer. A tourniquet test to examine muscle pain tolerance and two time to exhaustion (TTE) trials at 50%Delta to examine exercise tolerance were completed pre- and post training; the post-training TTE trials were completed at the pre-training 50%Delta (same absolute-intensity) and the post-training 50%Delta (same relative intensity). RESULTS: HIIT and CONT resulted in similar improvements in markers of aerobic fitness (all P >= 0.081). HIIT increased TTE at the same absolute- and relative-intensity as pre-training (148 and 43%, respectively) to a greater extent than CONT (38 and -4%, respectively) (both P <= 0.019). HIIT increased pain tolerance (41%, P < 0.001), whereas CONT had no effect (-3%, P = 0.720). Changes in pain tolerance demonstrated positive relationships with changes in TTE at the same absolute- (r = 0.44, P = 0.027) and relative-intensity (r = 0.51, P = 0.011) as pre-training. CONCLUSION: The repeated exposure to a high-intensity training stimulus increases muscle pain tolerance, which is independent of the improvements in aerobic fitness induced by endurance training, and may contribute to the increase in high-intensity exercise tolerance following HIIT. PMID- 28879619 TI - Borrelia miyamotoi, Other Vector-Borne Agents in Cat Blood and Ticks in Eastern Maryland. AB - We collected blood and tick samples in eastern Maryland to quantify vector-borne pathogen exposure and infection in healthy cats and to assess occupational disease risk to veterinary professionals and others who regularly interact with household pets. Thirty-six percent of healthy cats parasitized by ticks at time of examination (9/25) were exposed to, and 14% of bloods (7/49) tested PCR positive for, at least one vector-borne pathogen including several bloods and ticks with Borrelia miyamotoi, a recently recognized tick-borne zoonotic bacterium. There was no indication that high tick burdens were associated with exposure to vector-borne pathogens. Our results underscore the potential importance of cats to human vector-borne disease risk. PMID- 28879620 TI - Historical perspectives on the biology of brain metastasis. PMID- 28879621 TI - Survival Analysis of Advanced HCC Treated with Radioembolization: Comparing Impact of Clinical Performance Status Versus Vascular Invasion/Metastases. AB - PURPOSE: In this study, we aim to compare the effects of prognostic indicators on survival analysis for Barcelona Clinic Liver Cancer (BCLC) C patients undergoing yttrium-90 radioembolization (Y-90). METHODS: A prospectively acquired database (2003-2017) for BCLC C hepatocellular carcinoma (HCC) patients that underwent radioembolization with Y-90 was searched. The criteria for BCLC C status (Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2, metastases, and/or portal vein thrombosis (PVT)) were recorded. Kaplan-Meier survival analyses were performed from the date of the first radioembolization with Y-90, censored to curative treatment, to determine median overall survival (OS). Cox regression hazards model was used for multivariate analyses. Significance was set at P < 0.05. RESULTS: 547 BCLC C patients treated with radioembolization with Y 90 had a median OS of 10.7 months (range: 9.5-12.9). 43% (233 of 547) patients classified as BCLC C solely by their ECOG PS had a median OS of 19.4 months (14.7 23.7); 57% (314 of 547) patients with PVT/metastases had a median OS of 7.7 months (6.7-8.7). On multivariate analysis, ECOG PS was not found to be a statistically significant prognostic indicator of OS in BCLC C whereas metastases and PVT exhibited hazards ratios (95%CI) of 0.51 (0.38-0.69) and 0.49 (0.38 0.63), respectively (P < 0.0001). CONCLUSION: Patients classified as BCLC C due to ECOG PS 1 demonstrated longer survival when compared to those presenting with PVT, metastases and/or ECOG PS 2. Hence, ECOG PS 1, as an isolated variable, may not be a true indicator of advanced disease. PMID- 28879622 TI - Simulation-Based Design of ED Operations with Care Streams to Optimize Care Delivery and Reduce Length of Stay in the Emergency Department. AB - Faced with the opportunity to significantly deviate from classic operations, a new emergency department (ED) and novel strategy for patient care delivery were simultaneously initiated with the aid of model-based simulation. To answer the design and implementation questions, a traditional strategy for construction of discrete-eventmodel simulation was employed to define ED operations for a newly constructed facility in terms of workflow, variables, resources, structure, process logic and associated assumptions. Benefits were achieved before, during and after implementation of an unprecedented operations strategy-i.e., the organization of the ED care delivery around four care streams: Critical, Diagnostic, Therapeutic and Fast Track. Prior to opening, it shed light on the range of context variables where benefits might be anticipated, and it facilitated staff understanding and judgements of performance. Two years after opening, the operations data is compared to the simulation with encouraging results that shed light on where to continue pursuit of improvement. PMID- 28879623 TI - The risk factors associated with postoperative hemorrhage after tooth extraction: a multi-center retrospective study of patients receiving oral antithrombotic therapy. AB - The purpose of this study was to retrospectively investigate the multivariate relationships between specific risk factors and postoperative hemorrhage after tooth extraction in patients who were prescribed oral antithrombotic therapy. Risk factors for postoperative hemorrhage after tooth extraction were evaluated using univariate and multivariate analyses. Patient characteristics such as age and gender; the presence or absence of known comorbidities such as diabetes mellitus, hypertension, cerebral infarction, and alcohol consumption; and perioperative diarrhea were assessed. The drug used for antithrombotic therapy, preoperative blood test results, the presence or absence of preoperative antibiotics or nonsteroidal anti-inflammatory drug (NSAID) administration, the total number of extracted teeth, and the type of surgical procedures were also evaluated. We found that the preoperative administration of antibiotics (odds ratio (OR) = 2.52), an increased prothrombin time international normalized ratio (PT-INR) value (OR = 1.94), and the extraction of multiple teeth (OR = 2.10) were significantly associated with postoperative hemorrhage. There was no significant association between postoperative hemorrhage and any other demographic factors or comorbidities, including concomitant alcohol use. We demonstrated the multivariate relationship between the risk factors and postoperative hemorrhage after tooth extraction in patients receiving oral antithrombotic therapy. Surgeons should be aware of these risks and monitor the PT-INR of anticoagulated patients. PMID- 28879625 TI - Effects of Arsenic Compounds on Microminerals Content and Antioxidant Enzyme Activities in Rat Liver. AB - Interactions of arsenic with essential trace elements may result in disturbances on body homeostasis. In the present study, we aimed to investigate the effects of different arsenic compounds on micromineral content and antioxidant enzyme activities in rat liver. Male Wistar rats were randomly divided into five groups and exposed to sodium arsenite and sodium arsenate at 0.01 and 10 mg/L for 8 weeks in drinking water. The concentration of arsenic increased in the liver of all arsenic-exposed animals. The proportion of zinc and copper increased in animals exposed to 0.01 mg/L sodium arsenite. In addition, these animals presented a reduction in magnesium and sodium content. Superoxide dismutase activity decreased mainly in arsenite-exposed animals, whereas catalase activity decreased in animals exposed to 10 mg/L sodium arsenate. Further, exposure to sodium arsenate at 10 mg/L altered copper and magnesium content in the liver, and reduced total protein levels. Overall, both arsenic compounds altered the liver histology, with reduction in the proportion of cytoplasm and hepatocyte, and increased the percentage of sinusoidal capillaries and macrophages. In conclusion, our findings showed that oral exposure to arsenic compounds disturbs the trace elements balance in the liver, especially at low concentration, altering enzymatic and stereological parameters. We concluded that despite the increase in trace elements content, the antioxidant enzyme activities were downregulated and did not prevent morphological alterations in the liver of animals exposed to both arsenic compounds. PMID- 28879624 TI - The herbicides trifluralin and tebuthiuron have no genotoxic or mutagenic potential as evidenced by genetic tests. AB - Brazil has been the largest world consumer of pesticides since 2008, followed by the USA. The herbicides trifluralin and tebuthiuron have been widely applied in agriculture. These herbicides are selective for some plant species, and their use brings various benefits. However, the genotoxic and mutagenic effects of tebuthiuron on non-target organisms are poorly known, and in addition, the effects of trifluralin must be better investigated. Therefore, this study employed genetic tests including the comet assay and micronucleus test to evaluate the genotoxic effects of trifluralin and tebuthiuron on HepG2 cells. In addition, we have used the Ames test to assess the mutagenic effects of the herbicides on the TA97a, TA98, TA100, and TA1535 strains of Salmonella typhimurium. On the basis of the comet assay and the micronucleus test, trifluralin did not cause genetic damage to HepG2 cells. In addition, trifluralin did not impact the tested S. typhimurium strains. Regarding tebuthiuron, literature has shown that this herbicide damaged DNA in Oreochromis niloticus. Nevertheless, we have found that tebuthiuron was not genotoxic to either HepG2 cells or the S. typhimurium strains. Therefore, neither trifluralin nor tebuthiuron exerted genotoxic or mutagenic potential at the tested conditions. PMID- 28879626 TI - Effects of membrane deformability and bond formation/dissociation rates on adhesion dynamics of a spherical capsule in shear flow. AB - Cellular adhesion plays a critical role in biological systems and biomedical applications. Cell deformation and biophysical properties of adhesion molecules are of significance for the adhesion behavior. In the present work, dynamic adhesion of a deformable capsule to a planar substrate, in a linear shear flow, is numerically simulated to investigate the combined influence of membrane deformability (quantified by the capillary number) and bond formation/dissociation rates on the adhesion behavior. The computational model is based on the immersed boundary-lattice Boltzmann method for the capsule-fluid interaction and a probabilistic adhesion model for the capsule-substrate interaction. Three distinct adhesion states, detachment, rolling adhesion and firm adhesion, are identified and presented in a state diagram as a function of capillary number and bond dissociation rate. The impact of bond formation rate on the state diagram is further investigated. Results show that the critical bond dissociation rate for the transition of rolling or firm adhesion to detachment is strongly related to the capsule deformability. At the rolling-adhesion state, smaller off rates are needed for larger capillary number to increase the rolling velocity and detach the capsule. In contrast, the critical off rate for firm-to detach transition slightly increases with the capillary number. With smaller on rate, the effect of capsule deformability on the critical off rates is more pronounced and capsules with moderate deformability are prone to detach by the shear flow. Further increasing of on rate leads to large expansion of both rolling-adhesion and firm-adhesion regions. Even capsules with relatively large deformability can maintain stable rolling adhesion at certain off rate. PMID- 28879627 TI - The effect of viscosity, friction, and sonication on the morphology and metabolite production from Aspergillus terreus ATCC 20542. AB - This study investigates the effects of viscosity, friction, and sonication on the morphology and the production of lovastatin, (+)-geodin, and sulochrin by Aspergillus terreus ATCC 20542. Sodium alginate and gelatine were used to protect the fungal pellet from mechanical force by increasing the media viscosity. Sodium alginate stimulated the production of lovastatin by up to 329.0% and sulochrin by 128.7%, with inhibitory effect on (+)-geodin production at all concentrations used. However, the use of gelatine to increase viscosity significantly suppressed lovastatin, (+)-geodin, and sulochrin's production (maximum reduction at day 9 of 42.7, 60.8, and 68.3%, respectively), which indicated that the types of chemical play a major role in metabolite production. Higher viscosity increased both pellet biomass and size in all conditions. Friction significantly increased (+) geodin's titre by 1527.5%, lovastatin by 511.1%, and sulochrin by 784.4% while reducing pellet biomass and size. Conversely, sonication produced disperse filamentous morphology with significantly lower metabolites. Sodium alginate induced lovastatin and sulochrin production suggest that these metabolites are not affected by viscosity; rather, their production is affected by the specific action of certain chemicals. In contrast, low viscosity adversely affected (+) geodin's production, while pellet disintegration can cause a significant production of (+)-geodin. PMID- 28879628 TI - In vitro Approaches to Support Bioequivalence and Substitutability of Generic Proton Pump Inhibitors via Nasogastric Tube Administration. AB - Administration of proton pump inhibitors (PPIs) through nasogastric tubes may present risks. If the PPI drug products are not prepared properly, clogging or obstruction of nasogastric tubes can pose a safety concern. In addition, the integrity of the enteric coating of the drug product may be damaged resulting in reduced bioavailability of the active moiety. From the perspective of administration of generic PPIs when compared to the reference drug product, differences in formulation can potentially result in a greater relative risk for the generic drug product. As part of the assessment of bioequivalence, the Office of Generic Drugs (OGD) has developed a suite of in vitro testing to compare the delivery of the generic and reference products via nasogastric tubes. These in vitro tests assess essential attributes associated with the likelihood of clogging and maintenance of the enteric coating. These in vitro tests include studies evaluating sedimentation, granule size distribution, drug recovery, and acid resistance. One of the challenges is that while the administration of PPIs through nasogastric tubes is common in clinical practice, this issue is not uniformly addressed in the FDA approved label of the reference drug products. This paper discusses the design and rationale for in vitro testing of PPI formulations with respect to bioequivalence via nasogastric tube administration and in addition, it summarizes commonly occurring deficiencies in the in vitro nasogastric tube testing of 14 recent Abbreviated New Drug Applications (ANDA) submitted for five generic PPI drug products. PMID- 28879629 TI - Feasibility of Coping Effectiveness Training for Caregivers of Children with Autism Spectrum Disorder: a Genetic Counseling Intervention. AB - Caregivers of children with autism spectrum disorder (ASD) may find it difficult to feel a sense of control and to cope with the overall physical and emotional demands of caring for their child. While caregivers are able to successfully cope with a high level of stress, there are limits to their resources and abilities to cope over time. Genetic counselors working with affected families may be able to help parents more effectively manage stress related to the disorder. Few short term interventions have been reported in genetic counseling yet implementation of evidence-based examples may be achievable. This study aimed to assess the feasibility of a coping effectiveness training (CET) intervention designed to enhance coping self-efficacy (CSE) among caregivers of children with ASD, with the eventual goal of translating this intervention into genetic counseling practice. A randomized treatment-control design was used to investigate the feasibility of an intervention using CET among caregivers of children with ASD. The primary outcome was the feasibility of the intervention; the secondary outcome was improvements in CSE in the intervention group as compared to the control group. Caregivers were recruited and randomized into the treatment (n=15) or control (n=13) groups. Of these, 22 completed the study (retention: 78.6%). The intervention was highly feasible; most caregivers found the CET helpful, practical, useful, and relatively easy to attend. The treatment group demonstrated significantly increased CSE from pre-intervention to post intervention (p=0.02). Between group differences were not significant when comparing the pre-post changes. We provide preliminary evidence that CET may be beneficial to caregivers of children with ASD. The results of this feasibility study support development of a phase II study of this intervention in a larger cohort, aimed to be implemented into a genetic counseling setting. PMID- 28879630 TI - Polymorphism in IKZF1 gene affects clinical outcome in diffuse large B-cell lymphoma. AB - IKZF1 encodes a transcription factor involved in B-cell maturation and differentiation. We genotyped 218 diffuse large B-cell lymphoma (DLBCL) patients and 715 unrelated controls using a TaqMan allelic discrimination assay. No statistical difference was observed in the genotype distribution of the IKZF1 rs4132601 polymorphism between DLBCL patients and controls. However, the 2-year PFS rate of patients with the IKZF1 TT genotype was 54.3% compared to 68.6% in those with the IKZF1 G+ genotypes. Moreover, the IKZF1 rs4132601 polymorphism retained its independent prognostic impact on PFS. A more pronounced effect of the IKZF1 TT genotype on PFS was detected in patients with low/intermediate low IPI-risk group. When analysis was restricted to patients with GCB-type pattern, those with the IKZF1 TT genotype achieved a lower 5-year OS rate than the patients with the IKZF1 G+ genotypes (19.6 vs. 56%). This study provides the first evidence for the association of IKZF1 variants with DLBCL outcome. PMID- 28879631 TI - Biodegradation of phenol and its derivatives by engineered bacteria: current knowledge and perspectives. AB - Biodegradation of phenolic compounds is a promising alternative to physical and chemical methods used to remove these toxic pollutants from the environment. The ability of various microorganisms to metabolize phenol and its derivatives (alkylphenols, nitrophenols and halogenated derivatives) has therefore been intensively studied. Knowledge of the enzymes catalyzing the individual reactions, the genes encoding these enzymes and the regulatory mechanisms involved in the expression of the respective genes in bacteria serves as a basis for the development of more efficient degraders of phenols via genetic engineering methods. Engineered bacteria which efficiently degrade phenolic compounds were constructed in laboratories using various approaches such as cloning the catabolic genes in multicopy plasmids, the introduction of heterologous genes or broadening the substrate range of key enzymes by mutagenesis. Efforts to apply the engineered strains in in situ bioremediation are problematic, since engineered strains often do not compete successfully with indigenous microorganisms. New efficient degraders of phenolic compounds may be obtained by complex approaches at the organism level, such as genome shuffling or adaptive evolution. The application of these engineered bacteria for bioremediation will require even more complex analysis of both the biological characteristics of the degraders and the physico-chemical conditions at the polluted sites. PMID- 28879632 TI - Real-Time Clustered Multiple Signal Classification (RTC-MUSIC). AB - Magnetoencephalography (MEG) and electroencephalography provide a high temporal resolution, which allows estimation of the detailed time courses of neuronal activity. However, in real-time analysis of these data two major challenges must be handled: the low signal-to-noise ratio (SNR) and the limited time available for computations. In this work, we present real-time clustered multiple signal classification (RTC-MUSIC) a real-time source localization algorithm, which can handle low SNRs and can reduce the computational effort. It provides correlation information together with sparse source estimation results, which can, e.g., be used to identify evoked responses with high sensitivity. RTC-MUSIC clusters the forward solution based on an anatomical brain atlas and optimizes the scanning process inherent to MUSIC approaches. We evaluated RTC-MUSIC by analyzing MEG auditory and somatosensory data. The results demonstrate that the proposed method localizes sources reliably. For the auditory experiment the most dominant correlated source pair was located bilaterally in the superior temporal gyri. The highest activation in the somatosensory experiment was found in the contra lateral primary somatosensory cortex. PMID- 28879633 TI - The Initial Evaluation and Management of a Patient with Heart Failure. AB - PURPOSE OF REVIEW: The goal of this review is to summarize and discuss a thorough and effective manner in the evaluation of the patient with heart failure. RECENT FINDINGS: Heart failure is a prevalent disease worldwide and while the diagnosis of heart failure has remained relatively unchanged via a careful history and physical examination, identification of the etiology of the heart failure and treatment has made significant advances. Mechanical circulatory support (MCS), neprilysin inhibitors, and chronic resynchronization therapy (CRT) are just some of the relatively recent therapies afforded to assist heart failure patients. Heart failure is a complicated, multifactorial diagnosis that requires a careful history and physical for diagnosis with the support of laboratory tests. While the prognosis for heart failure patients remains poor in comparison to other cardiovascular disease and even certain cancers, new advancements in therapy have shown survival and quality of life improvement. PMID- 28879634 TI - Does low uranium concentration generates phytotoxic symptoms in Pisum sativum L. in nutrient medium? AB - Due to excessive mining and use of radionuclide especially uranium (U) and its fission products, numerous health hazards as well as environmental contamination worldwide have been created. The present study focused on demonstrating whether low concentration of U treatment in liquid nutient medium may translocate traces of U in plants and in fruits of Pisum sativum after 30 and 60 days of exposure for the safe use as a food supplement for human/animals. Hydroponically grown plants (in amended Hoagland medium) were treated with two different concentrations of uranium ([U] = 100 and 500 nM, respectively). Plants showed a decrease in total chlorophyll after 60 days of treatment. On the other hand, Eh of the nutrient medium was not affected from the initial days till 60 days of treatment, but pH of nutrient medium was increased upon durations, highest at 60 days of treatment. In seeds, micro/macro elements were under limit as well as U concentration was also under detection limit. We did not observe any U in the above ground parts (shoots/seeds) of the plant, i.e., under detection limit. Our observation suggests that P. sativum plants may be useful to grow at low radionuclide [U]-contaminated areas for safe human/animal use, but for other fission products, we have to investigate further for the safe human/animal use. PMID- 28879635 TI - Ectopic Hamartomatous Thymoma: A Review Of The Literature With Report Of New Cases And Proposal Of A New Name: Biphenotypic Branchioma. AB - Ectopic hamartomatous thymoma (EHT) is a rare benign neoplasm of the lower neck suggesting branchial origin. Despite use of the term thymoma in the nomenclature, there is no evidence of thymic origin or differentiation. It affects middle-aged adults with a remarkable male predominance. To date less than 80 cases have been reported in the English literature. We present here two additional cases of EHT. The first is a benign case in a 31-year-old man, showing typical histological features. The second is a malignant case in a 70-year-old woman, showing intraductal carcinoma arising in intimate association with an EHT. These cases are presented in the context of a review of cases reported in the English literature. The exact origin has not been identified, but is considered to be of branchial apparatus, creating a quandary about the best terminology. Recently, the designation "branchial anlage mixed tumor" or "thymic anlage tumor" were proposed, but do not quite reflect the true nature of the neoplasm. To avoid taxonomic confusion, international consensus on terminology is desired. As this entity is a neoplasm that shows dual mesoderm and endoderm derivation/differentiation, we propose a new name "biphenotypic branchioma." PMID- 28879636 TI - [Cr3O(O2CCH2CH3)6(H2O)3]NO3.H2O (Cr3) Toxicity Potential in Bacterial and Mammalian Cells. AB - Chromium(III) has generally been considered to be essential for proper carbohydrate and lipid metabolism, and, despite recent evidence to the contrary, chromium(III)-containing compounds remain one of the most popular commercial dietary supplements. Cr3, or [Cr3O(O2CCH2CH3)6(H2O)3]NO3.H2O, is a trivalent chromium compound that is a promising chromium nutritional supplement. Studies with Cr3 have indicated that it is non-toxic in developmental and short- and long term exposure studies in rodents, but the safety of this compound to chromosomes and cells has not been explored. The current study evaluates the mutagenicity, cytotoxicity, and clastogenicity of Cr3 in bacterial and mammalian cells and compares these results with similar studies using the bestselling Cr(III) nutritional supplement, chromium picolinate (CrPic). The mutagenicity of CrPic and Cr3 was tested in Escherichia coli FX-11 and Salmonella typhimurium (TA 98 and TA 100). Cytotoxicity was measured as a decrease in plating efficiency relative to controls after treatment with Cr3 and CrPic for 24 h in CHO K1 cells. Clastogenicity was measured by counting the number of metaphases damaged and of the total number chromosomal aberrations in CHO K1 cells. Mutagenesis assays in E. coli and S. typhimurium were negative. All treatments of Cr3 produced >= 84% plating efficiency except 80 MUg/cm2, which reduced the plating efficiency to 62%. Cr3 at any treatment level did not produce a significant increase in the number of cells with abnormal metaphases, while treatments using >= 40 MUg/cm2 of CrPic elevated the number significantly. These data suggest that Cr3 is significantly less mutagenic in bacteria cells and less clastogenic in CHO K1 cells, while CrPic is clastogenic in CHO K1 cells. PMID- 28879637 TI - Oligo p-Phenylenevinylene Derivatives as Electron Transfer Matrices for UV-MALDI. AB - Phenylenevinylene oligomers (PVs) have outstanding photophysical characteristics for applications in the growing field of organic electronics. Yet, PVs are also versatile molecules, the optical and physicochemical properties of which can be tuned by manipulation of their structure. We report the synthesis, photophysical, and MS characterization of eight PV derivatives with potential value as electron transfer (ET) matrices for UV-MALDI. UV-vis analysis show the presence of strong characteristic absorption bands in the UV region and molar absorptivities at 355 nm similar or higher than those of traditional proton (CHCA) and ET (DCTB) MALDI matrices. Most of the PVs exhibit non-radiative quantum yields (phi) above 0.5, indicating favorable thermal decay. Ionization potential values (IP) for PVs, calculated by the Electron Propagator Theory (EPT), range from 6.88 to 7.96 eV, making these oligomers good candidates as matrices for ET ionization. LDI analysis of PVs shows only the presence of radical cations (M+.) in positive ion mode and absence of clusters, adducts, or protonated species; in addition, M+. threshold energies for PVs are lower than for DCTB. We also tested the performance of four selected PVs as ET MALDI matrices for analytes ranging from porphyrins and phthalocyanines to polyaromatic compounds. Two of the four PVs show S/N enhancement of 1961% to 304% in comparison to LDI, and laser energy thresholds from 0.17 MUJ to 0.47 MUJ compared to 0.58 MUJ for DCTB. The use of PV matrices also results in lower LODs (low fmol range) whereas LDI LODs range from pmol to nmol. Graphical Abstract ?. PMID- 28879639 TI - Nitisinone-Induced Keratopathy in Alkaptonuria: A Challenging Diagnosis Despite Clinical Suspicion. AB - Alkaptonuria is a rare disorder of amino acid metabolism that causes premature large joint and spine arthropathy and cardiac valvular disease. It is characterised by elevated levels of homogentisic acid. Nitisinone (NTBC) is a benzoylcyclohexane-1,3-dione that reversibly inhibits the activity of the enzymatic step immediately prior to homogentisate dioxygenase, hence reducing the production of homogentisic acid. Thus it is thought that nitisinone might be a treatment for alkaptonuria. A side effect of NTBC therapy is elevation of plasma tyrosine levels in a manner analogous to tyrosinemia type 2, another related condition which causes a painful palmoplantar hyperkeratosis and eye pathology described as conjunctivitis and herpetic-like corneal ulceration. There are only two previous reports of NTBC causing eye symptoms in patients with alkaptonuria. Here we provide further evidence of this side effect of treatment and its resolution with cessation of NTBC. Repeat challenges with NTBC provoked symptoms, but introducing a low protein diet with low dose NTBC was successful in controlling plasma tyrosine levels and the patient remained free of symptoms when levels were below 600 MUmol/L. Our patient was remarkable for the low dose of NTBC that precipitated symptoms (as little as 0.5 mg daily), and for the difficulty in proving its causation despite clinical suspicion. PMID- 28879640 TI - Creative tensions: mutual responsiveness adapted to private sector research and development. AB - The concept of mutual responsiveness is currently based on little empirical data in the literature of Responsible Research and Innovation (RRI). This paper explores RRI's idea of mutual responsiveness in the light of recent RRI case studies on private sector research and development (R&D). In RRI, responsible innovation is understood as a joint endeavour of innovators and societal stakeholders, who become mutually responsive to each other in defining the 'right impacts' of the innovation in society, and in steering the innovation towards realising those impacts. Yet, the case studies identified several reasons for why the idea of mutual responsiveness does not always appear feasible or desirable in actual R&D situations. Inspired by the discrepancies between theory and practice, we suggest three further elaborations for the concept of responsiveness in RRI. Process-responsiveness is suggested for identifying situations that require stakeholder involvement specifically during R&D. Product-responsiveness is suggested for mobilising the potential of innovation products to be adaptable according to diverse stakeholder needs. Presponsiveness is suggested as responsiveness towards stakeholders that are not (yet) reachable at a given time of R&D. Our aim is to contribute to a more tangible understanding of responsiveness in RRI, and suggest directions for further analysis in upcoming RRI case studies. PMID- 28879638 TI - Impact of Etoposide on BRCA1 Expression in Various Breast Cancer Cell Lines. AB - Breast cancer 1 (BRCA1), as a tumor suppressor, exerts an effective influence on protecting DNA integrity to suppress the development of breast cancer (BC). BRCA1 expression is induced in response to DNA-damaging agents such as etoposide. Germline BRCA1 gene mutations are associated with development of hereditary BC. However, besides BRCA-mutated BCs, some sporadic cancers may also exhibit a BRCA like phenotype, displaying so-called 'BRCAness'. This common phenotype may respond to similar therapeutic approaches as BRCA-mutated tumors and may thus have important implications for the clinical management of these cancers. In order to determine whether and how etoposide regulates the protein levels of BRCA1 in BC cells, we exposed a panel of five selected cell lines to etoposide, compared the results to untreated control cells, and then stained the cells with the specific, reliable, and reproducible MS110 antibody directed against phosphorylated Ser1423 BRCA1. By evaluating cytoplasmic BRCA1 protein levels, we were able to distinguish three aggressive BC subtypes with BRCAness characteristics. In addition, determination of early and late apoptosis helped to complete the analysis of BRCA1 functions in the DNA damage pathway of aggressive BC. In conclusion, our study suggested that high cytoplasmic BRCA1 protein levels could be considered as a potential predictive marker for response to chemotherapy in both sporadic and hereditary BC. Tumors with either BRCAness phenotype or germline BRCA1 mutation are both aggressive BCs associated with poor prognosis and could both be subjected to targeted therapies against BRCA1-mutated BC in future clinical management strategies. PMID- 28879641 TI - 3D Atlas of the Brain, Head and Neck in 2953 pieces. PMID- 28879643 TI - Adenoid Cystic Carcinoma of the Oral Cavity: Radiology-Pathology Correlation. AB - Adenoid cystic carcinoma in the oral cavity is an uncommon salivary gland malignancy that has a propensity for perineural spread. A high-grade variant is evidenced by an abundance of pleomorphic cells, loss of the classic biphasic epithelial-myoepithelial growth pattern, and comedonecrosis, as well as elevated Ki-67. CT and MRI can both be useful for demonstrating the extent of invasion in oral cavity-associated adenoid cystic carcinoma, which can attain the inferior alveolar nerve for perineural spread by direct invasion through the mandible. Reflecting the aggressive nature of this high-grade malignancy, 18FDG-PET can demonstrate hypermetabolism and can be useful for staging. These features are exemplified in this sine qua non radiology-pathology correlation article. PMID- 28879642 TI - Determination of Fecal Sterols Following a Diet with and without Plant Sterols. AB - The aim of this study was to develop a method for neutral fecal sterols determination in subjects receiving a normal diet with or without a plant sterols enriched beverage using gas chromatography-mass spectrometry (GC/MS). Sample preparation conditions (homogenization of lyophilized feces with water) were evaluated. Sterol determination required direct hot saponification, unsaponifiable extraction with hexane, and the formation of trimethylsilyl (TMS) ether derivatives. The method allows the quantification of cholesterol, plant sterols and their metabolites (coprostanol, coprostanone, cholestanol, cholestanone, methylcoprostanol, methylcoprostanone, ethylcoprostenol, stigmastenol, ethylcoprostanol and ethylcoprostanone). Good linearity was obtained (r > 0.96) and interference was only observed for coprostanone, where the standard addition method proved necessary for quantification. The limits of detection (LOD) ranged from 0.10 to 3.88 ug/g dry feces and the limits of quantitation (LOQ) from 0.34 to 12.94 ug/g dry feces. Intra- and inter-assay precision (RSD %) were 0.9-9.2 and 2.1-11.3, respectively. Accuracy, expressed as percentage recovery (80-119%) was obtained for all determined sterols. PMID- 28879644 TI - Adenosine reduces reactive oxygen species and interleukin-8 production by Trichomonas vaginalis-stimulated neutrophils. AB - Trichomonas vaginalis is a flagellated protozoan that affects the human urogenital tract causing 276.4 million new infections a year. The parasite elicits a vaginal mucosal infiltration of immune cells, especially neutrophils which are considered to be primarily responsible for cytological change observed at the infection site as well as the major contributor in the inflammatory response against the parasite. Extracellular nucleotides and their nucleosides are signaling compounds involved in several biological processes, including inflammation and immune responses. Once in the extracellular space, the nucleotides and nucleosides can directly activate the purinergic receptors. Herein, we investigated the involvement of purinergic signaling on the production of reactive oxygen species (ROS) and cytokines by T. vaginalis-stimulated neutrophils. Parasites were able to induce an increase in ROS and IL-8 levels while they did not promote IL-6 secretion or neutrophil elastase activity. Adenine and guanine nucleotides or nucleosides were not able to modulate ROS and cytokine production; however, when T. vaginalis-stimulated neutrophils were incubated with adenosine and adenosine deaminase inhibitor, the levels of ROS and IL-8 were significantly reduced. These immunosuppressive effects were probably a response to the higher bioavailability of adenosine found in the supernatant as result of inhibition of enzyme activity. The involvement of P1 receptors was investigated by immunofluorescence and A1 receptor was the most abundant. Our data show that the influence of purinergic signaling, specifically those effects associated with adenosine accumulation, on the modulation of production of proinflammatory mediators by T. vaginalis-stimulated neutrophils contribute to the understanding of immunological aspects of trichomoniasis. PMID- 28879645 TI - Pharmacokinetic Effects of Antidrug Antibodies Occurring in Healthy Subjects After a Single Dose of Intravenous Infliximab. AB - BACKGROUND: Infliximab pharmacokinetic studies have been performed in patients receiving chronic infliximab therapy. In these patients, infliximab antidrug antibodies (ADAs) increase infliximab clearance and decrease serum levels and drug efficacy. OBJECTIVE: This study analyzed the pharmacokinetic effect of infliximab ADAs in healthy subjects receiving a single dose of intravenous infliximab. METHODS: Data were obtained from a single-blind, parallel-group, single-dose study of healthy subjects receiving 5 mg/kg of intravenous SB2 (infliximab biosimilar), EU-sourced Remicade (EU-IFX) or US-sourced Remicade (US IFX). Serum infliximab was measured at 1, 2, 3, 6, 12, 24, 48, and 72 h and at 5, 7, 14, 21, 28, 42, 56, and 70 days after administration. ADAs were measured pre dose and at 29 and 71 days. Data from the first ten subjects randomized to each treatment arm were utilized for this study. A two-compartment model of the serum infliximab vs. time curve was developed using nonlinear regression. RESULTS: At 10 weeks, 11 subjects (37%) developed ADAs. ADAs were detected in four subjects after SB2, one subject after EU-IFX, and six subjects after US-IFX infusion. Of these, neutralizing antibodies occurred in one subject after SB2, in no subjects after EU-IFX, and in three subjects after US-IFX infusion. Infliximab clearance was increased in subjects with ADAs vs. those without ADAs (12.89 +/- 2.69 vs. 9.90 +/- 1.74 ml/h; p < 0.0005). The elimination half-time was shorter in subjects with ADAs (282.4 +/- 56.4 vs. 343.3 +/- 61.9 h; p < 0.01). Serum infliximab measured at 8 weeks correlated closely with infliximab clearance (R 2 = 0.5494; p < 0.0001). CONCLUSION: ADAs are common in healthy subjects after a single intravenous dose of infliximab and result in faster infliximab clearance, shorter elimination time, and lower serum infliximab levels. These data confirm that ADAs are common with biologic therapy and significantly impact the efficacy of these drugs. PMID- 28879646 TI - Acromegaly treatment in Romania. How close are we to disease control? AB - INTRODUCTION: In Romania, no nationwide data for acromegaly treatment and control rate are available. Our objective was to assess the acromegaly control rate in a tertiary referral centre, which covers an important part of Romanian territory and population of patients with acromegaly. MATERIALS AND METHODS: We reviewed the records of all 164 patients (49 males and 115 females; median age 55 [47, 63.5] years) with newly or previously diagnosed acromegaly, who have been assessed at least once in our tertiary referral centre between January 1, 2012 and March 31, 2016. This sample represents 13.6% of the total expected 1200 Romanian patients with acromegaly and covers 82.9% of the counties in Romania. Control of acromegaly was defined as a random serum growth hormone (GH) < 1 ng/mL and an age-normalised serum insulin-like growth factor-I (IGF-I) value. The GH and IGF-I values used for calculation of the control rate were those at the last evaluation. The same assays for GH and IGF-I measurement were used in all patients. RESULTS: There were 147 treated and 17 untreated patients. Of the 147 patients assessed after therapy, 137 (93.2%) had pituitary surgery, 116 (78.9%) were on medical treatment at the last evaluation, and 67 (45.5%) had radiotherapy. Seventy-one (48.3%) had a random GH < 1 ng/mL, 54 (36.7%) had a normalised, age-adjusted IGF-I, and 42 (28.6%) had both normal random serum GH and IGF-I. CONCLUSIONS: In Romania, acromegaly benefits from the whole spectrum of therapeutic interventions. However, the control rate remains disappointing. PMID- 28879647 TI - Evaluation of vitamin D concentration in a population of young, healthy women - the effects of vitamin D supplementation. AB - INTRODUCTION: The goal of the study was an evaluation of serum vitamin D concentrations in healthy young women. MATERIAL AND METHODS: A total of 106 healthy women, aged 20-30 years, were included in the study. Monthly evaluation - for three months - of the effects of calcium (500 mg) and vitamin D (1500 IU) administration in women with baseline values of vitamin D < 20 ng/mL (Group 1) plus the effects of an 800 IU/d dose in women with the baseline value of D > 20 ng/mL (Group 2). Additionally, calcium and PTH concentrations were assessed at the study onset and after a three-month supplementation. Only 67 women adhered to the prescribed therapeutic regime during the three months of observation. RESULTS: The mean vitamin D concentration in the entire study group was 16.56 ng/mL, being 12.6 ng/mL in Group 1 and 25.22 ng/mL in Group 2. In the course of vitamin D administration, its concentration increased statistically significantly, both in the entire group and in the subgroups, at all time points compared with the study onset. Moreover, its concentration in the whole population and in Group 1 was significantly higher in each of the time points not only in relation to the baseline, but also in comparison with the results of the previous measurements (after 1 and 2 months of supplementation). In Group 2, vitamin D levels also increased systematically throughout the whole study period, and after 3 months its concentration was significantly higher than after 1 and 2 months. Although there were no differences in calcium concentration after those three months, a statistically significant drop of PTH (p < 0.05) was recorded in the entire population and in Group 1. CONCLUSIONS: A moderate deficiency of vitamin D was observed in the studied population of young women. A supplementation with calcium plus vitamin D brought about an increase of vitamin D concentration as early as in the first month of administration. The optimal concentration of > 30 ng/mL was achieved in Group 1 after three months of vitamin D administration in 1500 IU/d dose. PMID- 28879648 TI - Is there any difference in acromegaly and other chronic disease in quality of life and psychiatric morbidity? AB - INTRODUCTION: The study aimed to evaluate the psychological profile of patients with acromegaly in comparison to other chronic diseases such as non-functioning pituitary adenomas, Cushing disease, and plaque psoriasis, and to a healthy control group. MATERIAL AND METHODS: A total sample of 153 participants in clinical groups underwent a cross-sectional assessment including the quality of life (AcroQoL, WHOQoL-BREF), psychiatric morbidity (GHQ-28), and the acceptance of illness (AIS), as well as 65 participants in the healthy control group. RESULTS: The whole study sample had a predominance of urban married females (61%) with medium level of education (41%). Patients with acromegaly were diagnosed significantly later than patients from other clinical groups, after the onset of the first symptoms. Acromegaly was related to the presence of more symptoms of anxiety and insomnia, and poorer social relationships compared with the general population but not more than in other chronic diseases. A better quality of life score in all domains of WHOQoL-BREF was associated with a better score on the acceptance of illness scale and lower scores on GHQ-28. CONCLUSIONS: Psychiatric morbidity, mainly anxiety and insomnia, occurs in 50% of patients with acromegaly. However, the psychological wellbeing and mood seem to be related to other factors such as the acceptance of the illness. Thus, concerning the diagnosis, treatment, and monitoring of acromegaly an interdisciplinary approach, taking into account psychological and psychiatric consultation, is needed. PMID- 28879649 TI - Melatonin receptor 1B gene polymorphism rs10830963 and gestational diabetes mellitus among a Chinese population: a meta-analysis of association studies. AB - INTRODUCTION: Studies have been conducted to investigate the association between rs10830963 of MTNR1B and the risk of gestational diabetes mellitus (GDM), but with inconclusive results. We aimed to clarify these controversies, especially with regard to the association in the Chinese population. MATERIAL AND METHODS: A systemic literature reference search inclusive to August 12, 2016 yielded 35 articles, from which 11 studies met the inclusion criteria for the final meta analysis, including 3889 patients with GDM and 6708 controls. RESULTS: We found statistically significant associations between rs10830963 and GDM using odds ratios (ORs) and 95% confidence intervals (CIs) [GG genotype vs. CC genotype: OR = 1.70, 95%CI: 1.38-2.10; G allele vs C allele: OR = 1.27, 95%CI: 1.20-1.36; GG+CG vs. CC (dominant model): OR = 1.31, 95%CI: 1.20-1.44; GG vs CG+CC (recessive model): OR = 1.41, 95%CI: 1.26-1.58]. In subgroup analyses stratified by ethnicity, we also observed rs10830963 to be associated with significantly increased risk of GDM in all genetic models in the Chinese population. CONCLUSIONS: Our meta-analysis indicated that the rs10830963 polymorphism might serve as a risk factor of GDM in the Chinese population. PMID- 28879650 TI - Vascular and cardiac function in young adults with classical congenital adrenal hyperplasia. AB - INTRODUCTION: Patients with classical congenital adrenal hyperplasia (CAH) have increased cardiovascular risk, but the vascular and cardiac function during longitudinal corticoids replacement therapy is not known thoroughly. MATERIAL AND METHODS: Cross-sectional study of 19 Caucasian adults with CAH (age 23.7 +/- 3.8 years; twelve males) compared to 20 healthy volunteers matched for origin, sex, age, and body mass index (BMI). All of the participants were assessed for flow mediated dilatation of the brachial artery (FMD), intima-media thickness of the common carotid artery (cIMT) and common femoral artery (fIMT), standard echocardiography, and global longitudinal left ventricular function using two dimensional speckle-tracking echocardiography (LSTE). RESULTS: The patients with CAH, compared with controls, had decreased FMD (9.4 +/- 3.9 vs. 19.8 +/- 5.2; p < 0.01), and the difference was still significant after correction for potential confounders. cIMT and fIMT were higher in the CAH group at baseline (for cIMT 0.47 +/- 0.4 mm vs. 0.40 +/- 0.03 mm; p < 0.01, for fIMT 0.47 +/- 0.05 mm vs. 0.41 +/- 0.04 mm; p < 0.01) but not after correction for potential confounders. The CAH subjects, compared with controls, had normal or similar left ventricular (LV) ejection fraction and LV mass index. The mean absolute value of LSTE differed in the CAH patients compared with controls (-20.5% +/- 1.2 vs. -22.5% +/ 1.7; p < 0.01), but it was still within the normal range. CONCLUSIONS: Young adults with CAH and glucocorticoid long-lasting treatment had impaired FMD, an insignificant increase of IMT, and subclinical changes in LV diastolic function in echocardiography. PMID- 28879651 TI - Preliminary studies on the differential expression of adrenocorticotropic hormone receptor in adrenal adenomas. AB - INTRODUCTION: The ACTH receptor (ACTHR) is primarily expressed in the adrenal cortex. Previous studies focused on the regulatory function of ACTHR in glucocorticoid secretion, but research on adrenal tumours is rare. The aim of this study was to evaluate ACTHR expression in common adrenal adenomas and investigate its influence on adrenal tumorigenesis using adrenocortical H295R cells. MATERIALS AND METHODS: Real-time polymerase chain reaction and western blot were used to detect the expression of ACTHR in 18 aldosterone-producing adenomas, 16 cortisol-producing adenomas, 9 non-functional adenomas, and 12 normal adrenal samples. Lentiviral vector pLVX-mCMV-ACTHR-ZsGreen was transfected into the H295R cells to increase ACTHR expression. WST-1 and cell count were applied to evaluate cell proliferation at different ACTHR levels. TUNEL staining was used to measure cell apoptosis. RESULTS: Compared with normal adrenal samples, the aldosterone-producing adenoma samples had higher ACTHR mRNA and protein levels. However, the mRNA and protein levels of ACTHR in non-functional adenomas and cortisol-producing adenomas were lower than those in the normal adrenal samples. Proliferative activity in the experimental cells was higher than that in the control cells in the first three days. The proliferative activity peaked in the second day. However, this trend was reversed in the fourth day and became more apparent with time. By contrast, TUNEL staining showed that ACTHR overexpression did not induce a significant difference between the two groups. CONCLUSIONS: Differential ACTHR expression may be determined by different types of adrenocortical tumours. ACTHR is more likely to have induced the proliferation rather than the apoptosis of H295R cells. PMID- 28879652 TI - Primary squamous-cell thyroid carcinoma - a successful treatment with five-year follow-up. AB - Squamous cell carcinoma is an extremely rare neoplasm of the thyroid (SCTC) that represents no more than 1% of all primary thyroid malignancies. We report a case of a 42-year-old woman with rapidly growing mass in the right lower neck, primarily diagnosed in fineneedle aspiration cytology as a low-differentiated carcinoma. After the surgery, exclusion of all the other possible primary tumour locations, and immunohistochemistry tests, the diagnosis of primary squamous cell carcinoma of the thyroid gland was established. Because of close surgical margins and metastatic neck node, the patient was referred to adjuvant postoperative irradiation. With five-year follow-up the patient is free of disease and still in very good condition. PMID- 28879653 TI - Primary neuroendocrine carcinoma of the breast - a report of four cases. AB - Breast neuroendocrine tumours are rare, accounting for up to 5% of all breasts tumours and approximately 1% of all neuroendocrine tumours. In most cases, breast neuroendocrine tumours are histologically and moderately well differentiated. Neuroendocrine breast tumours lack characteristic imaging patterns. The histopathological assessment of these tumours is difficult, and in most cases the correct diagnosis is made after proper examination of the postsurgical specimen. PMID- 28879654 TI - Prognostic effect of parotid area lymph node metastases after preliminary diagnosis of nasopharyngeal carcinoma: a propensity score matching study. AB - Parotid area lymph node (PLN) metastasis in nasopharyngeal carcinoma (NPC) is rare, and its prognosis remains largely unknown. Our study aimed to investigate the prognostic value and staging categories of PLN metastasis in patients with NPC and treated with intensity-modulated radiation therapy (IMRT), to provide a reference for clinical treatment for NPC with PLN metastasis. Records for 1616 untreated NPC patients without distant metastasis was retrospectively reviewed. All patients underwent magnetic resonance imaging (MRI) examination prior to treatment and then received IMRT as their primary treatment. Forty-five NPC patients (2.8%) showed initial PLN metastasis on follow-up MRI. PLN metastasis was significantly associated with the N classification and clinical stage. Univariate analysis showed that PLN metastasis had an unfavorable influence on overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and regional relapse-free survival (RRFS) in NPC patients. Using propensity score matching (PSM) to calibrate selection bias and confounding bias, it was observed that PLN metastasis remained an adverse prognostic factor for OS, PFS, DMFS, and RRFS. Furthermore, the 5-year DMFS and RRFS curves for PLN metastasis were significantly separated from that for N2 disease but crossed that for N3 disease. Therefore, PLN metastasis was found to be an adverse prognostic factor for NPC and to be associated with the same DMFS as N3 disease. Therefore, more aggressive therapeutic strategies consistent with those for N3 disease are recommended for NPC with PLN metastasis to reduce distant metastasis. PMID- 28879655 TI - Pretreatment with fish oil attenuates heart ischaemia consequences in rats. AB - NEW FINDINGS: What is the central question of this study? We investigated whether pretreatment with fish oil could prevent the major consequences of ischaemic injury to the heart. What is the main finding and its importance? Fish oil pretreatment attenuated the consequences of ischaemic injury as indicated by the small infarction area and the preservation of systolic function and coronary blood flow. These findings support the use of fish oil in order to reduce the impact of heart ischaemia. omega-3 Polyunsaturated fatty acid (omega-3 PUFA)-rich fish oil supplementation has protective effects on heart ischaemic injury. Left ventricular (LV) ischaemia was induced in rats by permanent ligation of the left descending coronary artery. Saline, fish oil or soybean oil was administered daily by gavage [3 g (kg body weight)-1 ] for 20 days before inducing ischaemia. Outcomes were assessed 24 h after left descending coronary artery ligation. Pretreatment with fish oil decreased the omega-6/omega-3 fatty acid ratio in the LV. A reduction in infarct size and in the intensity of ventricular systolic dysfunction was found in the fish oil group compared with the saline or soybean oil groups through echocardiographic evaluation. Before infarction, LV glycogen concentrations were decreased in the fish oil group compared with the saline group. Soybean oil pretreatment led to a further increase in the LV levels of CINC-2/alphabeta, IL-1beta and TNF-alpha induced by the heart infarction. In heart-infarcted rats, fish oil pretreatment decreased creatine kinase and caspase 3 activities; prevented the decrease in the coronary blood flow; increased LV contents of ATP and lactate; increased the mRNA levels of iNOS, eNOS, HIF1alpha, GLUT1, VEGF-alpha and p53 in the LV as measured by RT-PCR; and did not change LV pro-inflammatory cytokine concentrations compared with the control group. Fish oil protected the heart from ischaemia, as indicated by the decrease in the heart infarction area and systolic dysfunction associated with increased LV ATP concentrations and maintenance of the coronary blood flow with no change in pro inflammatory cytokine levels. PMID- 28879656 TI - Variability in responses observed in human white adipose tissue models. AB - Obesity is a risk factor for a myriad of diseases including diabetes, cardiovascular dysfunction, cirrhosis, and cancer, and there is a need for new systems to study how excess adipose tissue relates to the onset of disease processes. This study provides proof-of-concept patient-specific tissue models of human white adipose tissue to accommodate the variability in human samples. Our 3D tissue engineering approach established lipolytic responses and changes in insulin-stimulated glucose uptake from small volumes of human lipoaspirate, making this methodology useful for patient specific sample source assessments of treatment strategies, drug responses, disease mechanisms, and other responses that vary between patients. Mature unilocular cells were maintained ex vivo in silk porous scaffolds for up to a month of culture and imaged non-invasively with coherent anti-Stokes Raman scattering. Interestingly, differences in responsiveness between tissues were observed in terms of magnitude of lipolysis, ability to suppress lipolysis, differences in glucose uptake, and lipid droplet size. Body mass index was not a factor in determining tissue responsiveness; rather, it is speculated that other unknown variables in the backgrounds of different patients (ethnicity, athleticism, disease history, lifestyle choices, etc.) likely had a more significant effect on the observed differences. This study reinforces the need to account for the variability in backgrounds and genetics within the human population to determine adipose tissue responsiveness. In the future, this tissue system could be used to inform individualized care strategies-enhancing therapeutic precision, improving patient outcomes, and reducing clinical costs. PMID- 28879657 TI - An exploratory investigation of echocardiographic parameters and the effects of posture on cardiac structure and function in the Livingstone's fruit bat (Pteropus livingstonii). AB - There is growing evidence that dilated cardiomyopathy may be a major cause of death in captive Livingstone's fruit bats (Pteropus livingstonii). Therefore, the primary aim of this prospective, exploratory study was to examine whether a systematic cardiac ultrasound protocol is feasible in this critically endangered species and to report basic measures of cardiac structure and function from a cohort of apparently healthy bats. A secondary aim was to test the effect posture (dorsal recumbency vs. roosting) has upon cardiac function in this species. Transthoracic echocardiograms, including 2D, Doppler, and tissue Doppler measures of cardiac structure and function were completed as part of routine health examinations for bats at a single center (n = 19). Bats were then grouped by age and disease status and the mean and range data reported for each group. In healthy adult bats, with the exception of a reduction in heart rate (P <= 0.05), right atrial systolic area (P <= 0.05), and right ventricular velocity during atrial contraction, there were no significant changes in cardiac structure or function in response to the roosting position. However, in the bats presenting with dilated cardiomyopathy the current data suggest that left ventricular ejection fraction is improved while roosting. Further work is required to confirm our initial findings, generate diagnostic reference intervals, and explore the causes of dilated cardiomyopathy in this species. PMID- 28879658 TI - Long-term outcomes in patients treated with proton therapy for localized prostate cancer. AB - The aim of this retrospective study was to report long-term clinical outcomes in patients treated with proton therapy (PT) for localized prostate cancer. Between 2001 and 2014, 1375 consecutive patients were treated with PT. Patients were classified into prognostic risk groups based on the National Comprehensive Cancer Network criteria. Freedom from biochemical relapse (FFBR), cancer-specific survival (CSS) and incidence of late gastrointestinal (GI)/genitourinary (GU) toxicities were calculated. Multivariate analysis was performed to identify clinical prognostic factors for FFBR and late toxicities. The median follow-up period was 70 months (range, 4-145 months). In total, 99% of patients received 74 Gy (relative biologic effectiveness [RBE]); 56% of patients received neoadjuvant androgen deprivation therapy. For the low-, intermediate-, high-, and very high risk groups, 5-year FFBR was 99% (95% confidence intervals [CI], 96-100%), 91% (95% CI, 88-93%), 86% (95% CI, 82-89%), and 66% (95% CI, 53-76%), respectively, and 5-year CSS was 100% (95% CI, 100-100%), 100% (95% CI, 100-100%) , 99% (95% CI, 97-100%), and 95% (95% CI, 94-98%), respectively. Patient age, T classification, Gleason score, prostate-specific antigen, and percentage of positive cores were significant prognostic factors for FFBR. Grade 2 or higher GI and GU toxicities were 3.9% and 2.0%. Patient age was a prognostic factor for both late GI and GU toxicities. This study represents the largest cohort of patients treated with PT for localized prostate cancer, with the longest follow up to date. Our results demonstrate that the biochemical control of PT is favorable particularly for high- and very high-risk patients with lower late genitourinary toxicity and indicates the necessity of considering patient age in the treatment protocols. PMID- 28879659 TI - Extracellular matrix particle-glycosaminoglycan composite hydrogels for regenerative medicine applications. AB - Tissue extracellular matrix (ECM) is a complex material made up of fibrous proteins and ground substance (glycosaminoglycans, GAGs) that are secreted by cells. ECM contains important biological cues that modulate cell behaviors, and it also serves as a structural scaffold to which cells can adhere. For clinical applications, where immune rejection is a constraint, ECM can be processed using decellularization methods intended to remove cells and donor antigens from tissue or organs, while preserving native biological cues essential for cell growth and differentiation. In this study, a decellularized ECM-based composite hydrogel was formulated by using modified GAGs that covalently bind tissue particles. These GAG-ECM composite hydrogels combine the advantages of solid decellularized ECM scaffolds and pepsin-digested ECM hydrogels by facilitating ECM hydrogel formation without a disruptive enzymatic digestion process. Additionally, engineered hydrogels can contain more than one type of ECM (from bone, fat, liver, lung, spleen, cartilage, or brain), at various concentrations. These hydrogels demonstrated tunable gelation kinetics and mechanical properties, offering the possibility of numerous in vivo and in vitro applications with different property requirements. Retained bioactivity of ECM particles crosslinked into this hydrogel platform was confirmed by the variable response of stem cells to different types of ECM particles with respect to osteogenic differentiation in vitro, and bone regeneration in vivo. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 147-159, 2018. PMID- 28879660 TI - National trends in long-term use of prescription opioids. AB - PURPOSE: This study examined recent trends and correlates of prescription opioid use and long-term use in the United States. METHODS: Data were from 47 356 adult participants of National Health and Nutrition Survey from 1999-2000 to 2013-2014. Participants were asked about prescription medications used in the past 30 days. Long-term use of prescription opioids was defined by use for 90 days or longer. RESULTS: The prevalence of prescription opioid use increased from 4.1% of US adults in 1999-2000 to 6.8% in 2013-2014 (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 1.10-1.75, P = .007). This trend was driven by a sharp increase in long-term use which increased from 1.8% to 5.4% (OR = 2.22, 95% CI = 1.65 3.00, P < .001). Of all opioid users in 2013-2014, 79.4% were long-term users compared with 45.1% in 1999-2000. Long-term use was associated with poorer physical health, concurrent benzodiazepine use, and history of heroin use. CONCLUSIONS: The findings highlight the need for research on potential benefits and harms of long-term use of opioids and efforts to restrict long-term use to patients for whom the benefits outweigh the risks. PMID- 28879662 TI - Setting research priorities in tobacco control: a stakeholder engagement project. AB - BACKGROUND AND AIMS: The Cochrane Tobacco Addiction Group (TAG) conducts systematic reviews of the evidence for tobacco cessation and prevention interventions. In 2016 TAG conducted a priority-setting, stakeholder engagement project to identify where further research is needed in the areas of tobacco control and smoking cessation. DESIGN: The project comprised two surveys and a workshop. A range of stakeholders participated, including members of the public (smokers and ex-smokers), clinicians, researchers, research funders, health-care commissioners and public health organizations. The first survey phase identified unanswered research questions in the field of tobacco control. The second phase asked participants to rank these, with overall rankings calculated by combining scores across participants. The workshop allowed attendees to discuss prioritization of topics and questions in more depth. Workshop discussions were transcribed and analysed thematically, and a final voting activity at the close of the workshop allowed participants to choose topics to prioritize and to de prioritize. FINDINGS: A total of 304 stakeholders (researchers, health professionals, smokers and ex-smokers, guideline developers, research funders and policymakers, representing 28 countries) identified 183 unanswered research questions. These were categorized into 15 research categories. A total of 175 participants prioritized categories and questions in the second survey phase, with 'electronic cigarettes'; 'addressing inequalities'; and 'mental health and other substance abuse' prioritized as the top three categories. Forty-three stakeholders attended the workshop and discussed reasons for and against category prioritization. Prioritized research categories largely mirrored those in the survey stage, although 'treatment delivery' also emerged as a key category. Five cross-cutting themes emerged: efficacy; relative efficacy; cost effectiveness; addressing inequalities; and different types of evidence. CONCLUSIONS: There are many unanswered questions in the field of tobacco control. Stakeholders highlighted electronic cigarettes, addressing inequalities and mental health and other substance abuse as key areas for further research, and efficacy, relative efficacy, cost-effectiveness and use of non-randomized studies as important themes cutting across research areas. Future prioritization work would benefit from targeting non-US and non-UK stakeholders explicitly and from examining where priorities may differ based on stakeholder group. PMID- 28879661 TI - Survival of cutaneous melanoma based on sex, age, and stage in the United States, 1992-2011. AB - Women diagnosed with cutaneous melanoma have a survival advantage compared to men, which has been hypothesized to be due to difference in behavior and/or biology (sex hormones). It remains controversial whether this advantage is dependent on age or stage of disease. We sought to compare melanoma-specific survival between females in pre, peri, and postmenopausal age groups to males in the same age group, adjusting for stage of disease. This is a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed from 1 January 1992 through 31 January 2011 with primary invasive cutaneous melanoma were included in our cohort. Melanoma-specific survival was the main outcome studied. Of the 106,511 subjects that were included, 45% were female. Females in all age groups (18-45, 46-54, and >=55) with localized and regional disease, were less likely to die from melanoma compared to males in the same age group. Among patients with localized and regional disease, the relative risk of death due to melanoma increased with advancing age at diagnosis; this increase was more pronounced among females than males. In contrast, we observed no female survival advantage among patients with distant disease and no effect of age on relative risk of death from melanoma. Females with localized and regional melanoma have a decreased risk of death compared to males within all age groups. Our data show no differences in survival between men and women with metastatic melanoma, indicating that the influence of sex on survival is limited to early stage disease but not confined to pre or perimenopausal age groups. PMID- 28879663 TI - Roadside drug testing: An evaluation of the Alere DDS(r) 2 mobile test system. AB - The number of drivers using drugs has increased over the last few years, and is likely to continue its upward trend. Testing drivers for alcohol use is routine and standardized, but the same is not true for the identification of driving under the influence of drugs (DUID). The Drug Evaluation and Classification Program (DECP) was developed to train police officers to recognize the signs and symptoms of recent drug use and remains an invaluable program; however, there are insufficient numbers of these highly trained drug recognition experts (DREs) available to attend every potential drug involved traffic incident. While blood and urine samples are used to test for drugs in a driver, both have disadvantages, particularly as they pertain to the length of time required after a traffic stop to sample collection. Therefore, the development of oral fluid testing devices which can be operated at the roadside and have the potential to assist officers in the identification of drug use is a major advancement in DUID cases. This project evaluated the performance of one instrumental oral fluid roadside testing device (Alere DDS(r)2) compared to DRE opinion, oral fluid laboratory-based analysis, and routine blood testing. The results showed that there was a good correlation with DRE observations and the device performance was >80% in all drug categories compared to laboratory-based analytical testing, both in oral fluid and blood, with few exceptions. The instrument can be considered a useful tool to assist law enforcement in identifying a drugged driver. Because the device does not test for all potentially impairing drugs, the opinion of the police officer regarding the condition of the driver should still be considered the most important aspect for arrest and further action. PMID- 28879664 TI - Fast simulations of multidimensional NMR spectra of proteins and peptides. AB - To simulate full multidimensional nuclear magnetic resonance spectra of peptides and proteins in a reasonable time frame, a strategy for separating the time consuming full-density matrix calculations from the chemical shift prediction and calculation of coupling patterns is presented. The simulation setup uses SIMulation Program for SOlid-state NMR (SIMPSON) to calculate total correlation spectroscopy transfer amplitudes and average distances as a source for nuclear Overhauser effect spectroscopy transfer amplitudes. Simulated 1 H 1D, 2D total correlation spectroscopy, and 2D nuclear Overhauser effect spectroscopy nuclear magnetic resonance spectra of peptides with sequence Pro?Ala?Gly?Tyr?Asn and Asn?Phe?Gly?Ala?Ile?Leu and of ubiquitin are presented. In all cases, the simulations lasted from a few seconds to tens of seconds on a normal laptop computer. PMID- 28879665 TI - Effects of low-to-moderate alcohol supplementation on urinary estrogen metabolites in postmenopausal women in a controlled feeding study. AB - Heavy alcohol drinking is associated with increased breast cancer risk, but associations with low-to-moderate alcohol consumption are less clear and the biological mechanisms are not well defined. The objective of this study was to evaluate the effects of 8 weeks of low (15 g/d) and moderate (30 g/d) alcohol ingestion on concentrations of 15 urinary estrogen metabolites (EMs) in postmenopausal women (n = 51) in a controlled feeding study with a randomized crossover design. Compared to no alcohol, 15 g/day for 8 weeks had no effect on urinary EMs. However, compared to no alcohol, 30 g/day for 8 weeks decreased urinary 2-hydroestrone (2-OHE1) by 3.3% (P = 0.055) and increased 16-epiestriol (16-EpiE3) by 26.6% (P = 0.037). Trends for reduced urinary 2-OHE1 (P = 0.045), reduced ratio of 2-OH:16OH pathways (P = 0.008), and increased 16-EpiE3 (P = 0.035) were observed as alcohol ingestion increased from 0 g to 15 g to 30 g/d. Moderate alcohol consumption for 8 weeks had modest effects on urinary concentrations of 2-OHE1 and 16-EpiE3 among postmenopausal women in a carefully controlled feeding study. PMID- 28879666 TI - Perforating ocular fishhook trauma: a case report. PMID- 28879667 TI - Clinical biomicroscopy and retinoscopy findings of keratoconus in a Middle Eastern population. AB - BACKGROUND: The present work was conducted to investigate the prevalence of clinical biomicroscopy and retinoscopy findings of corneas with keratoconus (KC) at first presentation and their relationship with disease severity. METHOD: In a prospective cross-sectional study, 371 consecutive KC patients were examined by slitlamp biomicroscopy and retinoscopy at the time of diagnosis. This research evaluates the prevalence of clinical findings such as a corneal protrusion, Vogt's striae, Fleischer's ring, Munson's sign, Rizzuti's sign, corneal scars, as well as any additional KC signs such as prominent nerve fibres, scissoring reflex and Charleaux 'oil droplet' sign on retinoscopy. Keratometry (mean K), central and thinnest corneal thickness (CCT and TCT), anterior and posterior elevation (AE and PE), and astigmatism by means of Pentacam, and visual acuity (VA) were recorded for each patient. The severity of KC was graded on the basis of the Keratoconus Severity Score. RESULTS: Corneal protrusion, scissoring reflex, corneal thinning, Fleischer's ring, and prominent nerve fibres were the most prevalent findings in the keratoconic corneas (71.7 per cent, 64.2 per cent, 56.6 per cent, 55.5 per cent and 54.7 per cent, respectively). Those KC patients with these clinical findings had significantly higher mean K, AE and PE, while having significantly lower CCT, TCT and VA compared to those who did not present these signs (p < 0.05). The presence of clinical findings was associated with more severe disease (p < 0.001, all comparisons). Wearing contact lenses was associated with the increase in the risk of corneal scarring (p = 0.009, odds ratio = 1.761, 95 per cent confidence interval = 1.126 to 2.755). CONCLUSION: This study provided information regarding the presence of the clinical slitlamp biomicroscopic and retinoscopic findings with severity of KC. A positive association was found between the presence of clinical signs and topographic parameters. In addition, wearing contact lenses was associated with the increase in the risk of corneal scarring. PMID- 28879668 TI - N-Acetylcysteine as a chemical scavenger for sulfur mustard: New insights by mass spectrometry. AB - The vesicant sulfur mustard (SM) is a banned chemical warfare agent. Although, SM has been used in combat since WWI, there is no causal therapy currently available. Accordingly, development and investigation of antidotes and scavengers targeting SM are of high clinical relevance. N-acetylcysteine (NAC) was shown to mitigate symptoms of SM intoxications in vitro and in vivo. However, it is still unclear whether the beneficial effects of NAC are only due to physiological processes or also due to chemical scavenging of SM. Therefore, in this study, we examined the scavenging potential of NAC toward SM. Co-incubations of SM and different NAC concentrations in human serum were performed to monitor diverse adducts (covalent reaction products) of human serum albumin (HSA), NAC, and SM. After proteolytic cleavage of HSA with proteinase K the alkylated tripeptide hydroxyethylthioethyl-CysProPhe (HETE-CPF) and the disulfide bridged tripeptide NAC-CPF were detected. Samples were analyzed by microbore liquid chromatography electrospray ionization-high-resolution tandem-mass spectrometry (MULC-ESI MS/HR MS). Furthermore, degradation kinetics of SM in phosphate buffered saline were measured in the presence and absence of NAC. Although NAC-CPF was identified and characterized for the first time by mass spectrometry and reaction products of NAC and SM were detected and identified by MS/HR MS, analyses clearly documented minor reactivity not significantly contributing to reduction of SM concentrations. Therefore, we conclude that chemical scavenging of SM by NAC does not play the key role in NAC therapy of SM poisoning. PMID- 28879669 TI - Optimizing combination of vascular endothelial growth factor and mesenchymal stem cells on ectopic bone formation in SCID mice. AB - INTRODUCTION: Insufficient blood supply may limit bone regeneration in bone defects. Vascular endothelial growth factor (VEGF) promotes angiogenesis by increasing endothelial migration. This outcome, however, could depend on time of application. Sheep mesenchymal stem cells (MSCs) in severe combined immunodeficient (SCID) mice were used in this study to evaluate optimal time points for VEGF stimulation to increase bone formation. METHODS: Twenty-eight SCID (NOD.CB17-Prkdcscid /J) mice had hydroxyapatite granules seeded with 5 * 105 MSCs inserted subcutaneous. Pellets released VEGF on days 1-7, days 1-14, days 1 21, days 1-42, days 7-14, and days 21-42. After 8 weeks, the implant-bone-blocks were harvested, paraffin embedded, sectioned, and stained with both hematoxylin and eosin (HE) and immunohistochemistry for human vimentin (hVim) staining. Blood samples were collected for determination of bone-related biomarkers in serum. RESULTS: The groups with 5 * 105 MSCs and VEGF stimulation on days 1-14 and days 1-21 showed more bone formation when compared to the control group of 5 * 105 MSCs alone (p < 0.01). Serum biomarkers had no significant values. The hVim staining confirmed the ovine origin of the observed ectopic bone formation. CONCLUSION: Optimal bone formation of MSCs was reached when stimulating with VEGF during the first 14 or 21 days after surgery. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3326-3332, 2017. PMID- 28879670 TI - Assessments for bone regeneration using the polycaprolactone SLUP (salt-leaching using powder) scaffold. AB - Salt-leaching using powder (SLUP) scaffolds are novel salt-leaching scaffolds with well-interconnected pores that do not require an organic solvent or high pressure. In this study, in vitro and in vivo cell behaviors were assessed using a PCL (polycaprolactone) SLUP scaffold. Moreover, using PCL, conventional salt leaching and 3D-plotted scaffolds were fabricated as control scaffolds. Morphology, mechanical property, water absorption, and in vitro/in vivo cell response assessments were performed to clarify the characteristics of the SLUP scaffold compared with control scaffolds. Consequently, we verified that the interconnectivity between the pores of the SLUP scaffold was enhanced compared with conventional salt-leaching scaffolds. Moreover, in vitro cell attachment and proliferation of the SLUP scaffold were higher than those of the 3D-plotted scaffold because of their morphological characteristic. Furthermore, we revealed that new bone formation and bone ingrowth of the SLUP scaffold was superior to those of the calvarial defect model and 3D-plotted scaffold because of the high porosity and improved interconnectivity of pores by the SLUP technique without high pressure using powders. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3432-3444, 2017. PMID- 28879671 TI - Manipulation of Biomolecule-Modified Liquid-Metal Blobs. AB - Soft and deformable liquid metals (LMs) are building components in various systems related to uncertain and dynamic task environments. Herein we describe the development of a biomolecule-triggered external-manipulation method involving LM conjugates for the construction of future innovative soft robotics operating in physiological environments. Functional soft hybrids composed of a liquid-metal droplet, a thiolated ligand, and proteins were synthesized for the expression of diverse macroscopic commands, such as attachment to cells, binary fusion, and self-propelled movement through molecular recognition and enzymatic reactions. Our technology could be used to create new state-of-the-art soft robots for chemical and biomedical engineering applications. PMID- 28879672 TI - Three-factor structure and psychometric properties of Witte's Risk Behaviour Diagnosis Scale: A French version adapted to diabetes. AB - The aim of this study was to verify the psychometric properties and the factorial structure of Witte's Risk Behaviour Diagnosis (RBD). This article shows the results of a French version of the RBD adapted to diabetes screening. An exploratory factor analysis was carried out in order to understand the number of underlying factors, a confirmatory factor analysis was performed and the four factor model proposed by the author and alternative models were compared. The concurrent validity was tested by a correlational analysis with the Perceived Fear Emotions Scale. The results confirmed a stable factor structure for the 12 item version, with three factors reflecting total efficacy, severity of and susceptibility to threat. The value of having a psychometrically valid instrument to assess the impact of fear appeal-based campaigns is linked to the current lack of a comprehensive assessment tool and the importance of preventing health risk behaviours. PMID- 28879673 TI - Response of preosteoblasts to titanium with periodic micro/nanometer scale grooves produced by femtosecond laser irradiation. AB - To investigate the cellular response to designed topography in vitro, we studied the adhesion, proliferation, osteogenic differentiation, and calcification of mouse preosteoblasts (MC3T3-E1) cultured on titanium (Ti) surfaces with periodic micrometer scale grooves containing nanometer scale ripples in the vertical direction fabricated by single-shot, femtosecond laser irradiation (fsTi). The surface composition and chemical state of fsTi were almost the same as those of mirror-polished Ti without femtosecond laser irradiation (mTi). Cells cultured on fsTi were highly aligned, whereas the cell proliferation rate on fsTi was less than that on mTi. Higher gene expressions of Spp1 and Bglap1 were detected in cells cultured on fsTi than those on mTi, indicating that the periodic micro/nanometer scale grooves topography promoted osteogenic differentiation and calcification. This initial activation of osteoinduction on fsTi generated calcified deposits that were thicker and larger than those on mTi and hence, osteoconductivity was promoted on fsTi. Our findings indicate that femtosecond laser irradiation is a technique with potential for controlling biomaterial-cell interfaces and, in particular, the promotion of osseointegration of Ti. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3456-3464, 2017. PMID- 28879674 TI - Comparisons between elastographic stiffness scores for benign versus malignant lymph nodes in dogs and cats. AB - Lymph node evaluation is an important component of oncology staging in dogs and cats, however diagnosis of malignancy currently requires cytology or histopathology. Elastography is an ultrasound technique that allows estimation of tissue stiffness. In people, it has been shown to increase the sensitivity of sonography in detection of metastatic lymph nodes. The objective of this prospective, cross-sectional study was to determine if elastographic stiffness differs for malignant versus benign canine and feline lymph nodes that were considered abnormal in gray-scale ultrasound imaging. Animals scheduled for ultrasound-guided fine needle aspirates of a lymph node at a single center were prospectively enrolled. Elastography was performed by a board-certified veterinary radiologist (G.S.) prior to tissue sampling. Softness was scored qualitatively as 1-4 (1 = hard; 4 = soft) on an image depicted by a color scale (blue = hard, red = soft). Quantitative analysis was performed using custom-made software. Fifty-one lymph nodes were included in the evaluation, 21 had benign and 30 had neoplastic cytology. Benign lymph nodes were softer (median score of 2.5, range 1-4) than malignant lymph nodes (median = 2, range 1-3), and differences were significant in qualitative and quantitative analyses (P < 0.01). Of the lymph nodes with a score of 2 or below (hard), 19/25 (76%) were malignant, of the lymph nodes with a score over 2 (soft), 24/36 (67%) were benign. Findings indicated that elastographic stiffness scores differed between benign and malignant lymph node groups; however overlapping scores for the two groups limited the use of this technique for routine clinical diagnosis of malignancy. PMID- 28879676 TI - Understanding MCP-MOD dose finding as a method based on linear regression. AB - MCP-MOD is a testing and model selection approach for clinical dose finding studies. During testing, contrasts of dose group means are derived from candidate dose response models. A multiple-comparison procedure is applied that controls the alpha level for the family of null hypotheses associated with the contrasts. Provided at least one contrast is significant, a corresponding set of "good" candidate models is identified. The model generating the most significant contrast is typically selected. There have been numerous publications on the method. It was endorsed by the European Medicines Agency. The MCP-MOD procedure can be alternatively represented as a method based on simple linear regression, where "simple" refers to the inclusion of an intercept and a single predictor variable, which is a transformation of dose. It is shown that the contrasts are equal to least squares linear regression slope estimates after a rescaling of the predictor variables. The test for each contrast is the usual t statistic for a null slope parameter, except that a variance estimate with fewer degrees of freedom is used in the standard error. Selecting the model corresponding to the most significant contrast P value is equivalent to selecting the predictor variable yielding the smallest residual sum of squares. This criteria orders the models like a common goodness-of-fit test, but it does not assure a good fit. Common inferential methods applied to the selected model are subject to distortions that are often present following data-based model selection. PMID- 28879677 TI - Transcriptomic analysis of gingival mesenchymal stem cells cultured on 3D bioprinted scaffold: A promising strategy for neuroregeneration. AB - The combined approach of mesenchymal stem cells (MSCs) and scaffolds has been proposed as a potential therapeutic tool for the treatment of neurodegenerative diseases. Indeed, even if MSCs can promote neuronal regeneration, replacing lost neurons or secreting neurotrophic factors, many limitations still exist for their application in regenerative medicine, including the low survival and differentiation rate. The scaffolds, by mimicking the endogenous microenvironment, have shown to promote cell survival, proliferation, and differentiation. In this work, gingival mesenchymal stem cells (GMSCs), isolated from healthy donors, were expanded in vitro, by culturing them adherent in plastic dishes (CTR-GMSCs) or on a poly(lactic acid) scaffold (SC-GMSCs). In order to evaluate the survival and the neurogenic differentiation potential, we performed a comparative transcriptomic analysis between CTR-GMSCs and SC-GMSCs by next generation sequencing. We found that SC-GMSCs showed an increased expression of neurogenic and prosurvival genes. In particular, genes involved in neurotrophin signaling and PI3K/Akt pathways were upregulated. On the contrary, proapoptotic and negative regulator of neuronal growth genes were downregulated. Moreover, nestin and GAP-43 protein levels increased in SC-GMSCs, confirming the neurogenic commitment of these cells. In conclusion, the scaffold, providing a trophic support for MSCs, may promote GMSCs differentiation toward a neuronal phenotype and survival. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 126-137, 2018. PMID- 28879675 TI - miR-199a-3p and miR-214-3p improve the overall survival prediction of muscle invasive bladder cancer patients after radical cystectomy. AB - To improve the clinical decision-making regarding further treatment management and follow-up scheduling for patients with muscle-invasive bladder cancer (MIBC) after radical cystectomy (RC), a better prediction accuracy of prognosis for these patients is urgently needed. The objective of this study was to evaluate the validity of differentially expressed microRNAs (miRNAs) based on a previous study as prognostic markers for overall survival (OS) after RC in models combined with clinicopathological data. The expression of six miRNAs (miR-100-5p, miR-130b 3p, miR-141-3p, miR-199a-3p, miR-205-5p, and miR-214-3p) was measured by RT-qPCR in formalin-fixed, paraffin-embedded tissue samples from 156 MIBC patients who received RC in three urological centers. Samples from 2000 to 2013 were used according to their tissue availability, with follow-up until June 2016. The patient cohort was randomly divided into a training (n = 100) and test set (n = 56). Seventy-three samples from adjacent normal tissue were used as controls. Kaplan-Meier, univariate and multivariate Cox regression, and decision curve analyses were carried out to assess the association of clinicopathological variables and miRNAs to OS. Both increased (miR-130b-3p and miR-141-3p) and reduced (miR-100-5p, miR-199a-3p, and miR-214-3p) miRNA expressions were found in MIBC samples in comparison to nonmalignant tissue samples (P < 0.0001). miR-199a 3p and miR-214-3p were independent markers of OS in Cox regression models with the significant clinicopathological variables age, tumor status, and lymph node status. The prediction model with the clinicopathological variables was improved by these two miRNAs in both sets. The predictive benefit was confirmed by decision curve analysis. In conclusion, the inclusion of both miRNAs into models based on clinical data for the outcome prediction of MIBC patients after RC could be a valuable approach to improve prognostic accuracy. PMID- 28879678 TI - A Diversity-Oriented Library of Fluorophore-Modified Receptors Constructed from a Chemical Library of Synthetic Fluorophores. AB - The practical application of biosensors can be determined by evaluating the sensing ability of fluorophore-modified derivatives of a receptor with appropriate recognition characteristics for target molecules. One of the key determinants for successfully obtaining a useful biosensor is wide variation in the fluorophores attached to a given receptor. Thus, using a larger fluorophore modified receptor library provides a higher probability of obtaining a practically useful biosensor. However, no effective method has yet been developed for constructing such a diverse library of fluorophore-modified receptors. Herein, we report a method for constructing fluorophore-modified receptors by using a chemical library of synthetic fluorophores with a thiol-reactive group. This library was converted into a library of fluorophore-modified adenosine binding ribonucleopeptide (RNP) receptors by introducing the fluorophores to the Rev peptide of the RNP complex by alkylation of the thiol group. This method enabled the construction of 263 fluorophore-modified ATP-binding RNP receptors and allowed the selection of suitable receptor-based fluorescent sensors that target ATP. PMID- 28879679 TI - Antioxidant activity of oleuropein and semisynthetic acetyl-derivatives determined by measuring malondialdehyde in rat brain. AB - OBJECTIVES: The purpose of this study was the evaluation of the antioxidant activity of natural and semisynthetic polyphenol derivatives from Olea europea L., by assessing malondialdehyde (MDA), an important marker of oxidative stress. METHODS: Polyphenol as hydroxytyrosol, oleuropein, oleuropein aglycone as mix of four tautomeric forms and their respective acetyl-derivatives were obtained from olive leaves using semisynthetic protocols. These compounds were administered intraperitoneally to Wistar rats treated with paraquat, an herbicide which is able to cause oxidative stress after central administration. Malondialdehyde was derivatized with 2,4-dinitrophenylhydrazine to produce hydrazone that was purified by solid-phase extraction. Using high-performance liquid chromatography coupled with a diode array, free and total MDA was measured on homogenate rat brain as marker of lipid peroxidation. The analytical method was fully validated and showed linearity in the tested concentration range, with detection limit of 5 ng/ml. Recovery ranged from 94.1 to 105.8%. KEY FINDINGS: Both natural and semisynthetic polyphenol derivatives from a natural source as olive leaves were able to reduce MDA detection. The more lipophilic acetyl-derivatives showed an antioxidant activity greater than parent compounds. This potency seems to put in evidence a strict correlation between lipophilicity and bioavailability. PMID- 28879680 TI - Combining growth factor releasing microspheres within aligned nanofibers enhances neurite outgrowth. AB - Current treatments for peripheral nerve injuries include autografts, the gold standard, and commercially available nerve growth conduits (NGCs). Autografts have several drawbacks including donor site morbidity and nerve size mismatch, which lead to incomplete recovery. However, even with these drawbacks, autografts work better then commercially available NGCs that lack sufficient cues to promote complete regeneration. This study evaluated a combination of biomaterial components that can be added to the hollow internal space of a NGC to promote and direct nerve regeneration; specifically, mechanical, chemical, and topographical cues. Methacrylated hyaluronic acid (MeHA, mechanical cue) is electrospun into aligned fibers (topographical cue), with poly-lactic-co-glycolic acid microspheres to deliver nerve growth factor (NGF, chemical cue). The properties of the scaffold were evaluated under physiological conditions using environmental scanning electron microscopy and mechanical testing. The resulting scaffolds have hydrated porosities of 35-55% and Young's modulus in the range of 0.43-2.86 MPa. Enzyme-linked immunosorbent assay showed that NGF is released from the microspheres for up to 4 weeks. Dorsal root ganglia (DRG) neurons showed that the released NGF is bioactive. DRG testing on the scaffolds also showed that the combination of NGF released from the microspheres and the aligned nanofibers significantly enhanced neurite outgrowth. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 17-25, 2018. PMID- 28879681 TI - Aromatic Halogenation by Using Bifunctional Flavin Reductase-Halogenase Fusion Enzymes. AB - The remarkable site selectivity and broad substrate scope of flavin-dependent halogenases (FDHs) has led to much interest in their potential as biocatalysts. Multiple engineering efforts have demonstrated that FDHs can be tuned for non native substrate scope and site selectivity. FDHs have also proven useful as in vivo biocatalysts and have been successfully incorporated into biosynthetic pathways to build new chlorinated aromatic compounds in several heterologous organisms. In both cases, reduced flavin cofactor, usually supplied by a separate flavin reductase (FR), is required. Herein, we report functional synthetic, fused FDH-FR proteins containing various FDHs and FRs joined by different linkers. We show that FDH-FR fusion proteins can increase product titers compared to the individual components for in vivo biocatalysis in Escherichia coli. PMID- 28879682 TI - Criminal thinking shifts among male prisoners participating in a cognitive-based education programme. AB - BACKGROUND: Many prisoners rationalise criminal behaviour, and this type of thinking has been linked to recidivism. Correctional programmes for modifying criminal thinking can reshape how offenders view themselves and their circumstances. AIM: Our aim was to test whether participation in a cognitive based curriculum called Steps to Economic and Personal Success (STEPS) was associated with changes in criminal thinking. METHODS: The STEPS curriculum is delivered in 15 video-based facilitated classes. A pre-intervention/post intervention survey design was applied to 128 adult male prisoners who completed the programme. Criminal thinking was measured by the Texas Christian University Criminal Thinking Scale, a self-report instrument with the six domains: entitlement, justification, power orientation, cold heartedness, criminal rationalisation and personal irresponsibility. RESULTS: Participants had lower scores in most of the criminal thinking domains after the intervention than before, with largest reductions in justification and power orientation. CONCLUSION: Findings provide evidence that attitudes to crime can be changed in a correctional setting, and the programme under study shows promise as an effective intervention for changing these attitudes among prisoners. Future research should build on these findings to examine whether and how such changes are related to desistance from offending behaviours. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28879683 TI - Psychological status in depressive patients correlates with metabolic gene expression. PMID- 28879684 TI - Epigenetic regulation of sirtuin 1-induced skeletal muscle mass: exercise and heart disease. PMID- 28879685 TI - Interface-Driven Structural Distortions and Composition Segregation in Two Dimensional Heterostructures. AB - The discovery of emergent phenomena in 2D materials has sparked substantial research efforts in the materials community. A significant experimental challenge for this field is exerting atomistic control over the structure and composition of the constituent 2D layers and understanding how the interactions between layers drive both structure and properties. While no segregation for single bilayers was observed, segregation of Pb to the surface of three bilayer thick PbSe-SnSe alloy layers was discovered within [(Pbx Sn1-x Se)1+delta ]n (TiSe2 )1 heterostructures using electron microscopy. This segregation is thermodynamically favored to occur when Pbx Sn1-x Se layers are interdigitated with TiSe2 monolayers. DFT calculations indicate that the observed segregation depends on what is adjacent to the Pbx Sn1-x Se layers. The interplay between interface- and volume-free energies controls both the structure and composition of the constituent layers, which can be tuned using layer thickness. PMID- 28879686 TI - Development of a bioactive porous collagen/beta-tricalcium phosphate bone graft assisting rapid vascularization for bone tissue engineering applications. AB - We developed collagen (COL) and collagen/beta tricalcium phosphate (COL/beta-TCP) scaffolds with a beta-TCP/collagen weight ratio of 4 by freeze-drying. Mouse bone marrow-derived mesenchymal stem cells (BMMSCs) were cultured on these scaffolds for 14 days. Samples were characterized by physicochemical analyses and their biological properties such as cell viability and alkaline phosphatase (ALP) activity was, also, examined. Additionally, the vascularization potential of the prepared scaffolds was tested subcutaneously in Wistar rats. We observed a microporous structure with large porosity (~95-98%) and appropriate pore size (120-200 um). The COL/beta-TCP scaffolds had a much higher compressive modulus (970 +/- 1.20 KPa) than pure COL (0.8 +/- 1.82 KPa). In vitro model of apatite formation was established by immersing the composite scaffold in simulated body fluid for 7 days. An ALP assay revealed that porous COL/beta-TCP can effectively activate the differentiation of BMMSCs into osteoblasts. The composite scaffolds also promoted vascularization with good integration with the surrounding tissue. Thus, introduction of beta-TCP powder into the porous collagen matrix effectively improved the mechanical and biological properties of the collagen scaffolds, making them potential bone substitutes for enhanced bone regeneration in orthopedic and dental applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 73-85, 2018. PMID- 28879688 TI - Building a learning culture and prevention of error - to near miss or not. AB - This editorial provides an insight into learning and prevention of error through near miss event reporting. PMID- 28879687 TI - Recombinant Synthesis of Hybrid Lipid-Peptide Polymer Fusions that Self-Assemble and Encapsulate Hydrophobic Drugs. AB - Inspired by biohybrid molecules that are synthesized in Nature through post translational modification (PTM), we have exploited a eukaryotic PTM to recombinantly synthesize lipid-polypeptide hybrid materials. By co-expressing yeast N-myristoyltransferase with an elastin-like polypeptide (ELP) fused to a short recognition sequence in E. coli, we show robust and high-yield modification of the ELP with myristic acid. The ELP's reversible phase behavior is retained upon myristoylation and can be tuned to span a 30-60 degrees C. Myristoylated ELPs provide a versatile platform for genetically pre-programming self-assembly into micelles of varied size and shape. Their lipid cores can be loaded with hydrophobic small molecules by passive diffusion. Encapsulated doxorubicin and paclitaxel exhibit cytotoxic effects on 4T1 and PC3-luc cells, respectively, with potencies similar to chemically conjugated counterparts, and longer plasma circulation than free drug upon intravenous injection in mice. PMID- 28879689 TI - Patient safety is everyone's business. AB - This editorial addresses the importance of incident reporting, checklists and a just culture to patient safety. PMID- 28879690 TI - Design principles for lymphatic drainage of fluid and solutes from collagen scaffolds. AB - In vivo, tissues are drained of excess fluid and macromolecules by the lymphatic vascular system. How to engineer artificial lymphatics that can provide equivalent drainage in biomaterials remains an open question. This study elucidates design principles for engineered lymphatics, by comparing the rates of removal of fluid and solute through type I collagen gels that contain lymphatic vessels or unseeded channels, or through gels without channels. Surprisingly, no difference was found between the fluid drainage rates for gels that contained vessels or bare channels. Moreover, solute drainage rates were greater in collagen gels that contained lymphatic vessels than in those that had bare channels. The enhancement of solute drainage by lymphatic endothelium was more pronounced in longer scaffolds and with smaller solutes. Whole-scaffold imaging revealed that endothelialization aided in solute drainage by impeding solute reflux into the gel without hindering solute entry into the vessel lumen. These results were reproduced by computational models of drainage with a flow-dependent endothelial hydraulic conductivity. This study shows that endothelialization of bare channels does not impede the drainage of fluid from collagen gels and can increase the drainage of macromolecules by preventing solute transport back into the scaffold. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 106-114, 2018. PMID- 28879691 TI - The Correlation between Body Mass Index and Routine Parameters in Men Over Fifty. AB - PURPOSE: This study aimed to investigate the relationships between body mass index (BMI) and prostate-specific antigen (PSA) levels, international prostate symptom score (IPSS), quality of life (QoL), and prostate volume (PV). MATERIALS AND METHODS: Height, weight, PSA levels, PV, and IPSS were analyzed in 15,435 patients who underwent a prostate examination between 2001 and 2014. Patients aged <50 years or with a PSA level >=10 ng/mL were excluded. The relationships between BMI and PSA, IPSS, QoL, and PV were analyzed by a scatter plot, one-way analysis of variance, and the Pearson correlation coefficient. RESULTS: The mean age was 71.95+/-7.63 years, the mean BMI was 23.59+/-3.08 kg/m2, the mean PSA level was 1.45+/-1.45 ng/mL, the mean IPSS was 15.53+/-8.31, the mean QoL score was 3.48+/-1.25, and the mean PV was 29.72+/-14.02 mL. PSA, IPSS, and QoL showed a tendency to decrease with increasing BMI, and there were statistically significant differences for each parameter (p<=0.001). PV showed a significant tendency to increase with BMI (p<0.001). In the correlation analysis, BMI showed a statistically significant correlation (p<0.001) with PSA, IPSS, and QoL, although the correlations were very weak. In contrast, BMI showed a significant correlation with PV (p<0.001), with a meaningful Pearson correlation coefficient of 0.124. CONCLUSIONS: Higher BMI was associated with lower PSA levels and higher IPSS and QoL scores. Meanwhile, PV increased with BMI. Although obese individuals had a greater PV, obesity did not aggravate lower urinary tract symptoms. PMID- 28879692 TI - Safety and Effectiveness of Once-Daily Tadalafil (5 mg) Therapy in Korean Men with Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms in a Real-World Clinical Setting: Results from a Post-Marketing Surveillance Study. AB - PURPOSE: The aim of this study was to investigate the safety and effectiveness of tadalafil 5 mg once daily (quaque die [everyday], QD) among Korean men with benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) in a real world clinical setting. MATERIALS AND METHODS: This was a single-country, prospective, observational cohort study in which patients newly prescribed tadalafil 5 mg QD for the treatment of BPH/LUTS were followed-up for 12+/-2 or 24+/-2 weeks, or to the last treatment, during post-marketing surveillance. Safety was evaluated in terms of the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Effectiveness was assessed by changes in the International Prostate Symptom Score (IPSS) from baseline to each endpoint. RESULTS: All patients receiving >=1 dose of tadalafil 5 mg QD (N=637) were included in the safety population. Two percent of patients (n=13) experienced 15 TEAEs of mild (n=10; 66.7%) or moderate (n=5; 33.3%) severity. No severe TEAEs and no SAEs were reported. Effectiveness evaluations included all patients receiving tadalafil who had both baseline and endpoint observations (12 week, N=265; 24-week, N=44). Compared with baseline, the mean IPSS total score (+/-standard error) significantly improved by 4.7+/-0.3 and 6.4+/-0.7 points at the 12- and 24-week endpoints, respectively (p<0.0001), with significant improvements also observed on the storage, voiding, and quality of life subscores. In total, 69.1% of the patients had a clinically meaningful >=3-point improvement in the IPSS total score. CONCLUSIONS: Tadalafil 5 mg QD was well tolerated and effective in Korean men with BPH/LUTS in a real-world clinical setting. PMID- 28879693 TI - Collagenase Clostridium Histolyticum in the Treatment of Peyronie's Disease: Review of a Minimally Invasive Treatment Option. AB - Peyronie's disease (PD) is an inflammatory disorder characterized by an abnormal collagen deposition in the tunica albuginea of the penis, leading to fibrous and non-compliant plaques that can impede normal erection. Although pharmacological treatments are available, only intralesional injection therapy and surgical reconstruction have demonstrated tangible clinical efficacy in the management of this condition. Intralesional injection of collagenase clostridium histolyticum (CCH) has come to the forefront of minimally invasive treatment of PD. In this review, the authors provide an update on the safety, efficacy, and indications for CCH. The efficacy of CCH will be assessed on the basis of improvement in the severity of penile fibrosis, curvature, and pain. Numerous well-designed clinical trials and post-approval studies involving more than 1,500 patients have consistently demonstrated the efficacy and tolerability of CCH in the treatment of PD. CCH significantly decreases penile curvature and plaque consistency, as well as improves quality of life. Post-approval studies continue to demonstrate the efficacy of CCH despite broader inclusion criteria for treatment, such as the case with acute phase disease and atypical plaque deformities (i.e., ventral plaques, hourglass narrowing). CCH continues to be the gold standard for non surgical management of stable phase PD, in the absence of strong evidence supporting oral therapy agents and ongoing evaluation of extracorporeal shockwave therapy. However, recent studies are beginning to provide precedent for the use of CCH in the management of acute phase and atypical PD. PMID- 28879694 TI - Male Infertility Associated with a Supernumerary Marker Chromosome. AB - A marker chromosome (mar) is a structurally abnormal chromosome in which no part can be identified. The significance of a marker varies, depending on the material contained within the marker. Very few reports have been published of marker chromosomes associated with male infertility. Here, we report the case of an infertile man with a rare variant of a marker chromosome of a mos 47,XY,+mar[25]/46,XY[25] karyotype. PMID- 28879695 TI - Functional Genetic Variants in SPHK1 Affect Susceptibility to Gastric Cancer in a Chinese Population. AB - BACKGROUND: An escalating number of studies have provided identified evidence that sphingosine kinase 1 (SPHK1) plays an essential role in carcinogenesis. This present study was devised to seek the possible correlation of two tag single nucleotide polymorphisms (SNPs) in SPHK1 (rs3744037 T>C, rs346801 C>T) with the susceptibility to gastric cancer (GC). METHODS: This present case-control study was comprised of 710 patients with GC and 710 gender- and age-matched cancer-free individuals. The genotypes of the individuals were acquired by the TaqMan-MGB method. SPHK1 mRNA level was examined in 60 paired cancerous and noncancerous tissues using quantitative reverse transcription-polymerase chain reaction (qRT PCR). RESULTS: Our results suggested that the variant genotype T allele of SPHK1 rs346801 increased the GC risk in the study population [CT vs. CC, odds ratio (OR) = 1.385, 95% confidence interval (CI) = 1.096 - 1.751; TT vs. CC, OR = 2.502, 95% CI = 1.078 - 5.806; CT+TT vs. CC, OR = 1.434, 95% CI = 1.140 - 1.804]. Furthermore, in stratified analyses, rs346801 variant genotypes were associated with a conspicuous risk of GC in younger individuals (< 62 years), females, non smokers, and individuals from rural areas. In addition, the carriers with variant genotype CT, TT, and CT+TT were observed to possess the higher SPHK1 messenger RNA levels than those with CC genotype in GC specimens. CONCLUSIONS: These results strongly demonstrated that the SPHK1 rs346801 C>T polymorphism may contribute to the susceptibility to gastric cancer in Chinese population and affect the expression of SPHK1 and, therefore, may act as a novel biomarker for predicting gastric cancer. PMID- 28879696 TI - Clinical Usefulness of Measuring Red Blood Cell Distribution Width in Patients with Hepatitis B Virus-Related Acute-On-Chronic Liver Failure. AB - BACKGROUND: The red blood cell distribution width (RDW) is increased in chronic liver disease, but its clinical significance in hepatitis B virus-related acute on-chronic liver failure (HBV-ACLF) is still unclear. The aim of the present study was to investigate the clinical significance of RDW in HBV-ACLF patients. METHODS: The medical records of HBV-ACLF patients who were admitted to The Second Affiliated Hospital of Anhui Medical University between April 2012 and December 2015 were retrospectively reviewed. Correlations between RDW, neutrophil lymphocyte ratio (NLR), and the model for end-stage liver disease (MELD) scores were analyzed using the Spearman's approach. Multivariable stepwise logistic regression test was used to evaluate independent clinical parameters predicting 3 month mortality of HBV-ACLF patients. The association between RDW and hospitalization outcome was estimated by receiver operating curve (ROC) analysis. Patient survival was estimated by Kaplan-Meier analysis and subsequently compared by log-rank test. RESULTS: Sixty-two HBV-ACLF patients and sixty CHB patients were enrolled. RDW were increased in HBVACLF patients and positively correlated with the NLR as well as MELD scores. Multivariate analysis demonstrated that RDW value was an independent predictor for mortality. RDW had an area under the ROC of 0.799 in predicting 3-month mortality of HBV-ACLF patients. Patients with HBV ACLF who had RDW > 17% showed significantly poorer survival than those who had RDW <= 17%. CONCLUSIONS: RDW values are significantly increased in patients with HBV-ACLF. Moreover, RDW values are an independent predicting factor for an in hospital mortality in patients with HBV-ACLF. PMID- 28879697 TI - Exogenous Brain-Derived Neurotrophic Factor at a 50 ng/mL Concentration has a Significant Protective Effect on Bilirubin-Induced Cerebral Cortex Neuronal Injury. AB - BACKGROUND: Bilirubin encephalopathy is a common disabling disease in neonates. Brain-derived neurotrophic factor (BDNF) plays an important role in the repair and regeneration of nerves following injury, as well as the maintenance of neuronal growth and differentiation. This study aimed to investigate the effect of exogenous BDNF on the apoptosis and survival of in vitro cultured neurons injured by bilirubin as well as determine the optimal BDNF concentration. METHODS: Rat cerebral cortex neurons cultured for 8 days were randomly divided into the control, bilirubin, and BDNF groups. A bilirubin injury model was established. BDNF was added to the BDNF group at a final concentration of 5, 50, and 100 ng/mL 4 hours prior to the addition of bilirubin. The cell morphology was observed via phase contrast microscopy, and the cell viability and apoptotic rate were detected using the methyl thiazolyl tetrazolium method and flow cytometry. RESULTS: The neuronal viability in the bilirubin group was significantly decreased and the apoptotic rate was significantly increased compared with the control group. BDNF significantly improved the impact of bilirubin on neuronal activity; the apoptotic rate was significantly decreased (p < 0.05); however, within 24 - 48 hours, BDNF had no significant effect on the nerve cell viability (p > 0.05). Moreover, the protective effect of different BDNF concentrations also varied (p < 0.05), with the most substantial protective effect at a final concentration of 50 ng/mL. CONCLUSIONS: Bilirubin may damage rat cerebral cortex neurons and induce their apoptosis, whereas BDNF has a protective effect on bilirubin-induced cerebral cortex neuronal injury. PMID- 28879698 TI - Undetectable Vancomycin Concentrations Utilizing a Particle Enhanced Turbidimetric Inhibition Immunoassay in a Patient with an Elevated IgM Level. AB - BACKGROUND: A case of undetectable vancomycin concentrations with the use of a particle enhanced turbidimetric inhibition immunoassay is reported. METHODS: A 73 year-old woman with B-cell lymphoma, chronic neutropenia with myelodysplastic syndrome and elevated IgM levels displayed repeated undetectable vancomycin concentrations, despite appropriate empiric vancomycin dosing. The vancomycin concentrations were processed utilizing a particle enhanced turbidimetric inhibition immunoassay (PETINIA). Patients with high concentrations of paraproteins in their serum may have interference with the PETINIA. This may include patients with plasma cell dyscrasias and lymphoreticular malignancies associated with abnormal immunoglobulin synthesis. RESULTS: Repeated undetectable vancomycin drug concentrations prompted us to send a serum sample to an outside facility to utilize another standardized assay, enzyme multiplied immunoassay (EMIT), which resulted in a detectable vancomycin serum concentration. The patient's undetectable vancomycin drug concentrations with the PETINIA may have been due to abnormal immunoglobulin synthesis interference with the assay. A limited number of case reports have been published demonstrating undetectable or unexpectedly elevated vancomycin concentrations due to monoclonal immunoglobulin interference in patients with immunological disorders. CONCLUSIONS: A 73-year-old woman with B-cell lymphoma, chronic neutropenia with myelodysplastic syndrome and elevated IgM levels may have had interference with a PETINIA resulting in undetectable vancomycin concentrations. PMID- 28879699 TI - Interleukin 20 Gene Polymorphism (rs1518108) is not Associated with Sustained Virological Response in Iranian Patients with Hepatitis C Virus Infection. AB - METHODS: This case-control study, was performed on 136 blood samples based on 81 patients with chronic HCV genotypes 1 and 3 including 64 SVR positive and 17 negative and 55 healthy individual controls. DNA was isolated from the samples and the frequency of the polymorphism was analyzed using a PCR-RFLP method. Finally, the products were detected on 3.5% agarose gel electrophoresis. RESULTS: The analysis of the data for C/T polymorphism indicated that the CC genotype was found in 19 of 64 patients who achieved SVR, while the TT genotype was detected in 3 patients and SVR was achieved in 2. Finally, heterozygous CT was identified in 53 patients and 10 patients were resistant to treatment. CONCLUSIONS: The results did not support any significant effects of TT or CT genotypes on susceptibility to HCV infection (p = 0.935, OR = 1.031, CI = 0.464 - 2.026). Moreover, there was no significant correlation between SVR to PEG-IFN combined by ribavirin therapy in patients with genotype CC (p = 0.601, OR = 0.736, CI = 0.234 - 2.319). PMID- 28879700 TI - Whole Exome Sequencing Identifies a c.C2566T Mutation in the Androgen Receptor in a Chinese Family. AB - BACKGROUND: Whole exome sequencing (WES) is one of the most valuable tools for the detection of Mendelian diseases in clinical laboratory. We performed WES for a family of 46,XY disorders of gender development and compared the applicability of public databases for the subsequent phenotype studies of WES-identified mutations. METHODS: DNA samples from the two patients were analyzed by WES. The mutated protein was studied using the HomoloGene database, Polyphen2, and SIFT. The phenotype of the mutation was studied using ClinVar, the androgen receptor gene mutations database, AR database at Leiden Open Variation Database, and PubMed. RESULTS: A c.C2566T (p.R856C) mutation in the androgen receptor gene was detected for the patients. The in silico studies indicated that the p.R856C mutation is deleterious to the function of the androgen receptor. Unlike those of other databases, the variations listed in the androgen receptor gene mutations database were classified as complete androgen insensitivity-, partial androgen insensitivity-, or mild androgen insensitivity-relevant according to their clinical phenotype. In addition, the publications of the collected mutations in the androgen receptor gene mutations database are complete and easily accessible, which facilitates in depth studies of clinically identified mutations. CONCLUSIONS: We identified a c.C2566T (p.R856C) mutation of the AR gene in cases of familial complete androgen insensitivity by WES, and provided genetic counseling to related family members. This is the first study reporting this mutation in Chinese patients. We also compared the applicability of several public databases for phenotype studies of clinically identified Androgen Receptor mutations and suggest that the androgen receptor gene mutations database best satisfies clinical demands. PMID- 28879701 TI - miRNAs Expressions and Interaction with Biological Systems in Patients with Alzheimer's Disease. Using miRNAs as a Diagnosis and Prognosis Biomarker. AB - BACKGROUND: A high percentage of patients develop Alzheimer's disease (AD). The main signs are loss of memory and cognitive functions which have a significant impact on lifestyle. Numerous studies have been conducted to identify new biomarkers for early diagnosis of patients with AD. An ideal biomarker is represented by the expression of miRNAs. In this paper, we want to summarize expressions miRNAs in AD. We also want to present the pathophysiological and genetic interactions of miRNAs with protein systems in these patients. METHODS: For the study, we examined available studies in scientific databases, such as PubMed and Scopus. The studies were searched using the keywords "miRNAs expression", "Alzheimer's disease", "genetic polymorphisms", and "genetic biomarkers". RESULTS: For the assessment and monitoring of patients with AD, the expression of miRNAs can be used successfully due to increased specificity and selectivity. Moreover, the expression of miRNAs can provide important answers regarding possible genetic interactions and genetic therapeutic regimens. CONCLUSIONS: For the evaluation and non-invasive monitoring of patients with Alzheimer's disease the expression of miRNAs can be successfully used. PMID- 28879702 TI - Diagnostic Values of sVEGFR-1 and Endostatin in Malignant Pleural Effusions in Patients with Lung Cancer. AB - BACKGROUND: The diagnosis of malignant pleural effusion (MPE) remains a common clinical challenge because of the sensitivity of conventional cytology for the detection is insufficient. Thus, a sensitive clinical marker for diagnosis is required. The aim of this study was to assess the role of two anti-angiogenic cytokines, soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and endostatin, in diagnosing MPE. METHODS: Effusion samples from 44 patients with MPE caused by lung cancer and from 36 patients with benign pleural effusion (BPE) were collected. The concentrations of sVEGFR-1 and endostatin in pleural fluid were determined by an enzyme-linked immunosorbent assay (ELISA). The diagnostic performance was measured by receiver operating characteristic curves (ROCs). RESULTS: The levels of sVEGFR-1 and endostatin in MPE due to lung cancer were significantly higher than those in BPE (p < 0.05). The sensitivity and specificity of endostatin were 52.27% and 86.11%, respectively, while for sVEGFR 1, the sensitivity was 88.64% and the specificity was 58.33%. Interestingly, the combination of sVEGFR1 and endostatin produced better sensitivity and specificity of 72.73% and 83.33%, respectively. In addition, the levels of sVEGFR-1 and endostatin were significantly related to each other (p < 0.05), and the levels of endostatin in bloody effusions were significantly higher than those in non-bloody effusions (p < 0.05). CONCLUSIONS: Our study indicated that the levels of sVEGFR 1 and endostatin were significantly elevated in MPE. The combined detection of sVEGFR-1 and endostatin may be useful in the diagnosis of MPE. PMID- 28879703 TI - A Novel Case of 15q24 Microdeletion Syndrome Detected by MLPA in a Chinese Family. AB - BACKGROUND: Chromosome 15q24 microdeletion syndrome is a rare disease. To date, only 40 cases have been reported. Here, we also confirmed a 15q24 microdeletion syndrome in a chorionic villus of miscarriage. METHODS: The microdeletion was screened by multiplex ligation-dependent probe amplification (MLPA) and then identified by chromosomal microarray analysis (CMA). RESULTS: A 15q24 microdeletion syndrome was screened by MLPA in the chorionic villus of miscarriage in a Chinese family and was confirmed to be a de novo 3.143 Mb 15q24.1q24.2 deletion (chr15:72930195-76073450) by chromosomal microarray analysis (CMA). CONCLUSIONS: We first reported the 15q24 microdeletion syndrome screened by MLPA in Chinese population, and we also considered that the technique of MLPA with a suitable kit and probe could screen such a rare microdeletion quickly, economically, and efficiently. PMID- 28879704 TI - A Case of Cutaneous Involvement in T Lymphoblastic Lymphoma Leukemia. AB - BACKGROUND: Cutaneous involvement is more prevalent in B lymphoblastic lymphoma (B-LBL) than T lymphoblastic lymphoma (T-LBL). The authors describe a rare case of cutaneous involvement in a 25-year-old woman with T lymphoblastic lymphoma leukemia. METHODS: Hematologic investigation, bone marrow aspirate and biopsy, cytogenetic analysis and cutaneous lesion biopsy were performed. RESULTS: The patient achieved complete remission after induction therapy with the regimen of CHOEP + P, then received another CHOEP + P regimen. Unfortunately, the patient refused further treatment and was lost to follow-up. CONCLUSIONS: Skin biopsy, immunohistochemistry of the skin lesions, bone marrow aspirate, and biopsy are important to confirm a diagnosis of T-LBL. Cutaneous involvement in T-LBL as a prognostic factor needs further studies. PMID- 28879705 TI - Guillain-Barre Syndrome Induced by Heat Stroke: a Case Report and Literature Review. AB - BACKGROUND: Heat stroke is a potentially fatal condition that is caused by elevated core temperature. GuillainBarre syndrome (GBS) induced by heat stroke is extremely rare, and its manifestation with damage to multiple cranial nerves has not been described. METHODS: We describe a rare case of GBS induced by heat stroke with damage to multiple cranial and peripheral nerves. The clinical, radiological, and electrophysiological profiles were presented and analyzed. RESULTS: A 41-year-old man presented with aggressive speech difficulty, dysphagia, right blepharoptosis, and quadriplegia following coma. A diagnosis of glossopharyngeal, vagus, oculomotor, and peripheral nerve damage was made. After immunoglobulin administration, the patient's neurological deficiencies were relieved significantly. During a follow-up period of 3 months, the patient experienced complete remission. CONCLUSIONS: To our knowledge, this is the first reported case of GBS induced by heat stroke presenting with damage to multiple cranial and peripheral nerves. The early diagnosis and timely immunological treatment of GBS should be emphasized, as they facilitate a favorable prognosis. PMID- 28879706 TI - National Survey on Internal Quality Control Practice for Lipid Parameters in Laboratories of China from 2014 to 2016. AB - BACKGROUND: To investigate the situation of Internal Quality Control (IQC) practice for total cholesterol, triglycerides, HDL-cholesterol and LDL cholesterol from 2014 to 2016 in laboratories in China and provide improvement measurements. METHODS: A web-based External Quality Assessment (EQA) system was used to collect IQC data of lipid parameters in laboratories which continuously participated in the national EQA programs in China from 2014 to 2016. Pass rate of the coefficients of variation (CVs) of two level quality controls in four lipid parameters were calculated according to six quality specifications for precision to evaluate the current status of precision level of the four lipid parameters and their change over time in China. RESULTS: 533, 512, 504, and 466 laboratories continuously reported the data of level one for total cholesterol, triglyceride, HDL-cholesterol and LDL-cholesterol, and 212, 210, 208 and 198 laboratories reported the level two, respectively. The percentage of laboratories meeting the quality specification varied based on different criteria. Non significant change can be found in the pass rate of CVs over time. The number of laboratories using a closed system increased over time, but still only accounted for a small proportion. There is no significant difference in the pass rate of CVs between closed and open systems. CONCLUSIONS: Triglycerides currently have a fairly good performance in China. While the performance of laboratories on total cholesterol, HDL-cholesterol and LDL-cholesterol has yet to be improved. PMID- 28879707 TI - Analysis of Hepatitis C Virus NS5A Region in Patients with Cirrhosis Using an Ultra-Deep Pyrosequencing Method. AB - BACKGROUND: HCV (Hepatitis C Virus) is genetically more diverse than HBV and HIV (Human Immunodeficiency Virus) and exists as quasispecies within infected individuals. This is due to the lack of efficient proofreading of the viral RNA dependent RNA polymerase. Consequently, quasispecies emerge depending on the mutation rate of the viral polymerase, which may display a high level of genetic variability in a population. In infected individuals, HCV replicates and circulates as quasispecies composed of a complex mixture of different but closely related genomes that undergoes continuous change due to competitive selection and cooperation between arising mutants. The aim of this study is to investigate mutations in the NS5A region as a whole, including ISDR, PKRBD, IRRDR, and V3 of HCV genotype 1b cirrhosis patients being naive and nonresponders, treated with IFN (interferon) + ribavirin (RBN) by using an ultra-deep pyrosequencing method (UDPS). METHODS: During the study, five patients (four females, and one male, mean age 59.8 +/- 11 years) with HCV related cirrhosis were analyzed. Three patients received IFN + RBN for six months, but two patients did not receive any therapy. HCV-RNA concentrations in patients' sera were determined using a COBAS AMPLICOR HCV MONITOR Test, Version 2.0. Genotyping was performed by using a commercial reverse hybridization method, Line Probe Assay. The quasispecies for the NS5A region were investigated using UDPS. RESULTS: All five patients were HCV genotype 1b (Mean Child-Pugh score 7.2 +/- 1.9, 2 pts Child A, 2 pts Child B, and one pt Child C) but only one patient had hepatocellular carcinoma (HCC). A total of 19 different mutations were detected in each of the five patients (ranging from 3 to 6 mutations per patient). In all five patients, several mutations in the ISDR and PKR-BD regions were detected. On the other hand, mutations in the V3 and IRRDR regions were only detected in one patient. CONCLUSIONS: UDPS is a new sequencing technology and a very sensitive method in detection of quasispecies with low frequency NS5A region mutations. These mutations may affect the antiviral response and development of HCC. However, further studies in larger number of patients should be conducted to clarify this hypothesis. PMID- 28879708 TI - Lung Squamous Cell Carcinoma with De Novo c-Met Amplification. AB - The study presented a case of lung squamous cell carcinoma (SCC) with de novo c Met amplification. Four cycles of neoadjuvant chemotherapy were administered and partial response was achieved. Surgery was performed and the surgical margin was positive. Pathological diagnosis was lung SCC with c-ros oncogene 1 (ROS1) (+, 5%) and c-Met (++, 20%). The ROS1 rearrangement and c-Met amplification were detected using fluorescence in situ hybridization, and the result showed c-Met amplification positive and ROS1 negative. Four weeks after surgery, thoracic computed tomography scan showed a relapse of hilar and mediastinal lymph nodes. After three days, the patient died of hemoptysis. PMID- 28879710 TI - Heat Shock Protein 90 Alpha, Lass B Member 1: a Key Regulative Gene of Monitoring Duodenal Tumor for Obesity Induced by High-Fat Diet. AB - BACKGROUND: Effective methods of preventing and treating duodenal carcinoma, especially cancer induced by obesity (resulting from a high-fat diet) remains a longstanding challenge in medicine. METHODS: With regard to the objective, key genes were explored in the evolutional process in a group of normal, obese (high fat diet), and duodenal tumor mice. Here, 23 genes were selected by the bioinformatics method. In order to correct the result, verification experiments were performed twice through online analysis. RESULTS: Finally, heat shock protein 90 alpha class B member 1, enriched in inflammation, tumors and steroid hormones-related pathways, was the statistically different gene in the evolutional process. CONCLUSIONS: This work provided a new perspective to understand the evolutional process in a group of normal, obese (high-fat diet), and duodenal tumor mice and a potential target gene for monitoring duodenal tumors for normal individuals especially for obesity induced by high-fat diet. PMID- 28879709 TI - Reference Intervals for Fecal Calprotectin in Adults Using Two Different Extraction Methods in the Uppsala-SCAPIS Cohort. AB - BACKGROUND: Fecal calprotectin measurement is generally recommended to exclude inflammatory bowel disease (IBD) in patients with suspected IBD. A problem with the fecal calprotectin assays so far has been the rather long test-turnaround times. Recently a particle enhanced turbidimetric immunoassay (PETIA) for fecal calprotectin with assay times of approximately 10 minutes has been introduced on the European market. The aim of this study was to define reference intervals for adults with this new fecal calprotectin PETIA using two different extraction methods. METHODS: Samples were collected from 382 healthy individuals from the Swedish CArdioPulmonary bioImage Study (SCAPIS) Uppsala cohort in the age range 50 - 65 years. 202 samples were processed with CALEX(r) Cap extraction device (BUHLMANN, Schonenbuch, Switzerland) and 180 samples were extracted using weighed samples. The extracted samples were analyzed on a Mindray BS-380 using the fCal Turbo PETIA reagent (BUHLMANN). RESULTS: The calculated reference values for the Calex device were < 199 ug/g for the whole cohort, < 184 ug/g for females, and < 215 ug/g for males, while the corresponding values for weighed samples were < 153 ug/g for the whole cohort, < 141 ug/g for females, and < 215 ug/g for males. There were no significant statistical differences for calprotectin levels in males and females. CONCLUSIONS: The CALEX device yielded slightly higher calprotectin values. As there were no significant gender differences, the study indicates gender independent reference intervals of < 199 ug/g feces for the CALEX device and < 153 ug/g feces for weighed samples in patients in the 50 - 65 year age range. PMID- 28879711 TI - Systematic Comparison of IgM and IgG ABO Antibody Titers by Using Tube and Gel Card Techniques and its Relevance for ABO-Incompatible Kidney Transplantation. AB - BACKGROUND: Although the determination of the ABO antibody titers is necessary for the decision-making in ABOincompatible (ABOi) kidney transplantations, various methods for the determination of the ABO antibody titers are being used. However, the absence of uniform standards makes their comparability far more difficult. Two of the most commonly used methods are the tube method and the gel card method. In this study, we systematically investigate to what extent these two methods affect the result of ABO antibody titers. METHODS: ABO antibodies were determined from plasmas of 90 donors (30 individuals each with blood group A, B, and O). Seven further donors with blood group A, B, and AB provided erythrocytes for the testing. A total of 360 ABO antibody titers were determined; 180 tests for each method, each with 90 determinations of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody titers. In addition, we also made a differentiation by blood groups to find out if and to what extent the blood groups have an impact on the results. RESULTS: Our analysis shows that the choice of method has a highly significant (p < 0.0001) impact on the titer level of the ABO antibodies. The median values of ABO antibody titers determined by using the gel card method are two titer steps lower than the titers, which are determined when using the tube method. Moreover, our data shows that there are major differences in the ABO antibody titer level among the blood groups, regardless of the choice of methods. CONCLUSIONS: We consider changing to the gel card method for determining the ABO antibody titers as a simple and effective way to achieve a standardized and uniform method. Here, too, the clinicians should be provided with sufficient information by the laboratories, in order to draw the right consequence from this change, while considering all the relevant data. As a consequence of this study, the transplant center of the University of Hamburg Eppendorf paired a change from tube to gel card regarding the ABO antibody titer determination of ABOi kidney transplantations with an intensification of the preoperative target titer from <= 1:8 to <= 1:4. PMID- 28879712 TI - Prevalence of ST131 and ST1193 Among Bloodstream Isolates of Escherichia coli not Susceptible to Ciprofloxacin in a Tertiary Care University Hospital in Korea, 2013 - 2014. AB - We investigated the ST distribution of bloodstream isolates of E. coli that were not susceptible to ciprofloxacin (CIP-NS isolates), collected from 2013 to 2014 in a tertiary care hospital. Fifty-nine CIP-NS isolates were collected. ST131 was the most frequent ST (37.3%) isolate, followed by ST1193 (23.7%). ST131 and ST1193 showed significant differences in ESBL production and lactose fermentation. Further study should be continued on the monitoring of resistant strains. PMID- 28879713 TI - Impact of Moderate Altitude on Pro-Inflammatory Cytokines in Healthy Volunteers. AB - BACKGROUND: The induction of microvascular inflammation and the effects on cytokine production in blood due to hypoxia has been shown in the past. We have previously reported a statistically significant increase of the pro-inflammatory cytokine interleukin-8 (IL-8) in normobaric hypoxia in the setting of a hypoxia chamber. In the present study, we sought to analyze plasma levels of inflammatory cytokines in a real-life stetting in order to foster our knowledge on hypoxia induced microvascular inflammation at moderate altitude. METHODS: Pro inflammatory cytokines (IL-8, IL-6, TNF-alpha) were measured in an experimental field study, exposing 18 healthy volunteers to moderate hypoxia while staying at a mountain lodge in Diavolezza, Switzerland (2978 meters above sea level). Plasma cytokine levels were measured by ELISA. RESULTS: In contradiction to our results in a normobaric hypoxia-chamber, exposure to moderate hypoxia led to a significant decrease of plasma IL-8 levels in a real-life setting (from 2.902 (1.046 - 4.984) pg/mL to 1.395 (0.698 - 3.712) pg/mL, p = 0.034). Concentrations of IL-6 and TNF-alpha did not show statistically significant changes in comparison to baseline measurements. CONCLUSIONS: The results of this study show a decrease of proinflammatory cytokine IL-8 in a real life setting of moderate altitude in healthy individuals. Initiation of angiogenesis or subliminal stimulus for an altitude-induced inflammatory reaction may be explanations for this unexpected finding. PMID- 28879714 TI - Serum IgG4 Concentration in IgG4-Related Disease. AB - BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated and chronic fibroinflammatory condition that affects almost any organ and often involves multiple organs in the same patient. In this review article, we address the clinical utility of measuring serum immunoglobulin G subclass 4 concentration ([IgG4]) in IgG4-RD diagnosis and in disease monitoring. METHODS: We discuss the latest literature on the relevance of [IgG4] to the investigation and management of IgG4RDs. In addition, we discuss the potential role of serum [IgG4] measurements in other inflammatory conditions and cancers. RESULTS: Increasing awareness of IgG4-RD among clinicians has led to a growing list of organ systems that can be affected by this chronic condition and the development of new organ specific diagnostic guidelines. Diagnosis of IgG4-RD depends on multiple clinical and laboratory tests, including serology. Quantification of serum [IgG4] is included in all IgG4-RD diagnostic guidelines available to-date. The scientific literature supports the idea that elevated serum [IgG4], typically > 135 mg/dL, identifies patients with a more active form of the disease, which correlates with increased concentrations of inflammatory serum biomarkers and hypocomplementemia, increased number of organs affected by the disease, and more extensive organ involvement. These patients seem more resistant to treatment and experience a shorter time to disease relapse compared to IgG4-RD patients with normal serum [IgG4] at the time of diagnosis. CONCLUSIONS: Despite better understanding of how to diagnose IgG4-RD, monitoring for accurate prediction of disease relapse, which may involve organs not affected at the time of presentation, is poorly understood. Timely diagnosis and early detection of disease relapse is important to avoid delayed treatment and potential organ damage. PMID- 28879715 TI - Bacteremia Caused by Campylobacter Fetus in a Patient With Hepatitis B Virus Infection Complicated with Alcoholic Liver Cirrhosis. AB - Campylobacter fetus (C. fetus) bacteremia is rarely reported. In this article, a 51-year-old Chinese woman with severe hepatitis B virus infection complicated with alcoholic liver cirrhosis was admitted with a 3-month history of fatigue, jaundice, and edema of lower extremity, as well as presenting a high fever. Blood cultures were positive for Campylobacter fetus. The patient was started on treatment with cefuroxime, which was switched after 3 days to meropenem for an additional 2 weeks. The patient was successfully treated with the 3-week course of intravenous antibiotic therapy. PMID- 28879716 TI - Concomitant Occurrence of Blastic Plasmacytoid Dendritic Cell Neoplasm and Acute Myeloid Leukaemia after Lenalidomide Treatment for. AB - BACKGROUND: Myelodysplastic syndromes with chromosome 5 long arm deletion (5q mds) may benefit from lenalidomide treatment. However, unresponsive patients have a high risk for clonal evolution and progression to acute myeloid leukemia. Case: We describe a 5q-patient treated with lenalidomide, who concomitantly developed acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm, a rare and highly aggressive lymphoma. CONCLUSIONS: Evolution of 5q- syndrome to acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm may have occurred through various mechanisms, including persistence of neoplastic lenalidomide-resistant stem cells and selection of a more aggressive clone via lenalidomide augmentation of the ARPC1B gene, or because of lenalidomide stimulation on dendritic cells. Further studies are needed to clarify lenalidomide oncogenic potential. PMID- 28879717 TI - Increased Expression of Long Noncoding RNA RP11-62F24.2 in Gastric Cancer and Its Clinical Significance. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides and have no proteincoding capacity. In recent years, they have been believed to be major players in biological processes. However, there is limited understanding of the many lncRNAs' expressions and their clinical significances in gastric cancer. METHODS: Quantitative RT-PCR was performed to investigate the lncRNA expression in gastric cancer. Then, we further explored the potential association between RP11-62F24.2 level and the clinicopathological features in gastric cancer tissue samples. RESULTS: The results showed that RP11-62F24.2 was significantly upregulated in gastric cancer tissues compared with matched normal tissues (p < 0.05). Its expression level was significantly correlated with invasion and tumor size. CONCLUSIONS: These results indicated that lncRNA RP11 62F24.2 may be a potential biomarker in the diagnosis of gastric cancer. PMID- 28879718 TI - Interleukin 6 Receptor (IL6-R) Gene Polymorphisms Underlie Susceptibility to Rheumatoid Arthritis. AB - BACKGROUND: Increased production of interleukin 6 (IL-6) is associated with rheumatoid arthritis that acts through its receptor, IL-6R (interleukin 6 receptor). Various single nucleotide polymorphisms in the IL6R gene conferring susceptibility to rheumatoid arthritis have been identified in various populations yet these associations have not been fully established. The present study was pursued with the aim to evaluate a possible association between three single nucleotide polymorphisms (rs2228145, rs4537545, rs4845617) of the IL6R gene and rheumatoid arthritis in Pakistani patients. METHODS: For this purpose, we recruited 60 patients diagnosed with rheumatoid arthritis and 60 healthy age and gender matched controls. Blood samples were collected and DNA was extracted. Sanger DNA sequencing was performed to evaluate the SNPs in IL6R and the data were statistically evaluated using chi-square test. RESULTS: Results of our study indicated that rs2228145 and rs4845617 were significantly associated with rheumatoid arthritis in Pakistani population. However, no association could be established between IL6R (rs4537545) and rheumatoid arthritis in Pakistani population. CONCLUSIONS: This study reports a possible genetic association of IL6R (rs2228145 and rs4845617) to the genetic susceptibility of rheumatoid arthritis. PMID- 28879719 TI - Interleukin-24 Concentrations Not Related with Age, but Affect Pro- and Anti Inflammatory Cytokines Differently in Healthy Donors. AB - BACKGROUND: Interleukin 24 (IL-24) is expressed at different levels in a variety of tumor tissues and matched normal tissues and is regarded as a potential tumor biomarker as its expression levels in tumor tissues are associated with tumor patient prognosis. At present, the expression level of IL-24 in healthy human peripheral blood is unknown. METHODS: In this study, 1940 blood samples were collected using different processing methods from healthy donors. ELISA was used to detect IL-24 concentrations. RESULTS: The results showed that processing methods had the greatest influence on test results, with the highest IL24 concentration in EDTA plasma and the lowest in sodium citrate plasma. Lengths of storage time at 4 degrees C had no obvious effect on IL-24 test results, and IL 24 in peripheral blood was stable for 15 days. IL-24 concentration in the sera of healthy donors showed no associations with age, blood glucose, hemoglobin, total cholesterol, carcinoembryonic antigen, absolute lymphocyte counts, alpha fetoprotein, white blood cells, thyroid stimulating hormone, or cereal third transaminase. We also confirmed that IL-24 expression level in the blood of healthy subjects was positively correlated with pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6), but negatively correlated with anti-inflammatory cytokine, IL-10. CONCLUSIONS: We observed that sample processing methods influence the detection of IL-24 levels as EDTA plasma had the highest IL-24 concentration, and citric acid sodium, the lowest. Age, gender, and physical and chemical indicators were not related to IL-24 concentrations. We confirmed the IL-24 concentration was positively related to IL 6 and TNF-alpha and negatively to IL-10. PMID- 28879720 TI - Long Non-Coding RNA Expression Signature Hallmarks Promising Efficacy in Identification of Human Non-Small Cell Lung Cancer: a Meta-Analysis Study. AB - BACKGROUND: The long non-coding RNAs (lncRNAs) are significantly altered in an expanding list of malignant neoplasms, suggesting that they might be popularized as potential biomarkers for cancer detection. This study sought to validate the diagnostic efficacy of lncRNA expression signature(s) as potential biomarker(s) for non-small cell lung cancer (NSCLC) diagnosis. METHODS: We conducted the online databases search for all eligible studies. A quantitative meta-analysis was performed using Stata 12.0 and Meta-Disc 1.4 statistical programs. Sensitivity analysis and a meta-regression test were applied to deeply trace the underlying heterogeneity sources. RESULTS: Eight cohorts comprised 775 NSCLC patients and 630 matched controls were included. Our data manifested that lncRNA expression profiling harbored a pooled sensitivity of 0.77 (95% CI: 0.71 - 0.82) and specificity of 0.86 (95% CI: 0.80 - 0.90) in discriminating NSCLC cases from cancer-free individuals, along with an AUC (area under the curve) value of 0.88. Further subgroup analysis revealed that paralleled testing of lncRNAs (sensitivity, specificity, and AUC of 0.90, 0.80 and 0.96, respectively) substantially strengthened the diagnostic efficacy as compared with the single testing pattern (sensitivity, specificity, and AUC of 0.71, 0.77 and 0.82, respectively). Other stratified analysis of ethnicity, histology type, and test matrix also presented robust results. CONCLUSIONS: Altogether, our results indicate that lncRNA expression signature(s) might be applicable as complementary biomarker(s) for the identification of NSCLC. PMID- 28879721 TI - Value of Red Cell Distribution Width in Assessing the Severity of Hepatitis B Virus-Related Decompensated Cirrhosis. AB - BACKGROUND: Hepatitis B virus infection is the main reason for liver cirrhosis in China. Thus, evaluating the disease severity of hepatitis B-related decompensated cirrhosis (HBV-DeCi) is very important. The red cell distribution width (RDW) is thought to be correlated with the severity of various diseases. The purpose of this investigation is to verify whether RDW can estimate the disease severity of HBV-DeCi. METHODS: This retrospective study included 172 subjects who had been diagnosed with HBV-DeCi. They were categorized into three groups on the basis of their RDW values. Receiver operating curve (ROC) was used to estimate the severity predictive performances and binary logistic regression was used to assess the independent variable predicting the severity of liver disease. RESULTS: The RDW values were evidently increased in the HBV-DeCi patients in comparison with the healthy controls (18.00% +/- 0.04 vs. 13.19% +/- 0.74, p < 0.001). There was also a significant difference in the model for endstage liver disease score of the three different RDW groups of A, B and C (13.2 +/- 4.6, 16.0 +/- 9.0, and 18.8 +/- 6.5, p = 0.002). The RDW was an independent risk factor of the severity of HBV-DeCi. The cutoff level for RDW was > 14.0%, where the sensitivity and specificity were 90.7%, 100.0%, respectively, and the area under the curve (AUC) of ROC was 0.969. For a combination of RDW and MELD score, the AUC was 0.997, and the sensitivity and specificity were 98.3% and 99.1%, respectively. CONCLUSIONS: The RDW is a simple biomarker that may play an important role in predicting the severity of HBVDeCi. PMID- 28879722 TI - Novel and Simple Approach to Estimating the Actual Incidence of Blood and Body Fluid Exposure. AB - BACKGROUND: There is no current way to determine the actual blood and body fluid exposure (BBFE) incidence in hospitals. We propose a simple, reliable, and widely available method for the accurate estimation of BBFE. METHODS: Data for BBFE for healthcare workers between 2006 and 2015 at Osaka University Hospital were retrospectively extracted from the electronic records. Annual positivity of hepatitis C virus (HCV) antibody in the source individuals and overall patient population were calculated over time. We created an estimation formula focusing on the difference in HCV positivity between the source individuals and overall patient population for the actual number of BBFEs. A linear regression model was used to evaluate the temporal change in the reported and estimated BBFEs. RESULTS: During the study period, 937 BBFEs were reported. HCV positivity between the post-BBFE cohort and overall patient population greatly differed; the incidence ratio ranged from 2.1 to 5.7. The linear regression model revealed that the reported BBFEs did not significantly change during the study period (the slope, 1.315 [95% confidence interval (C.I.): -0.849 to 3.480, p = 0.199]). The annual incidence ratio of the estimated and reported BBFEs significantly reduced over time (the slope, -0.287 [95% C.I.: -0.488 to -0.086, p = 0.011]), indicating that, although the reported number of BBFEs seemed unchanged, the estimated incidence decreased. CONCLUSIONS: We propose a novel and simple approach to estimating the actual incidence of BBFEs in hospitals using the difference in HCV positivity between the post-BBFE cohort and overall patient population. PMID- 28879723 TI - Mean Platelet Volume and Platelet Count are Elevated in Patients with Subacute Thyroiditis. AB - BACKGROUND: Platelet parameters have been studied in many diseases. This study explored the changes of mean platelet volume (MPV) and platelet count (PLT) in subacute thyroiditis (SAT). METHODS: We retrospectively studied 44 patients with SAT and 45 healthy individuals. Diagnosis was confirmed by pathologic examination of surgical specimens. RESULTS: There were no significant differences in age and gender between the SAT group and the control group. We compared the above indexes between the two groups. WBC and PLT were significantly higher and MPV was obviously lower in the SAT group. PLT had high sensitivity for diagnosis of SAT. CONCLUSIONS: PLT was elevated and MPV was decreased in SAT patients. A negative correlation between PLT and MPV was found. PMID- 28879724 TI - UGT1A1 Gene Polymorphism Predicts Irinotecan-Induced Severe Neutropenia and Diarrhea in Chinese Cancer Patients. AB - BACKGROUND: Irinotecan was widely used in colon cancer and lung cancer, etc., and adverse reactions occur some times. The primary aim of this research is to investigate the association between UGT1A1 gene polymorphisms and irinotecan related adverse effect in Chinese Han population with a novel kind of gene chip technology. METHODS: UGT1A1*6/*28 gene polymorphisms were detected by PCR and gene chip as well as sequencing. The correlation between UGT1A1 gene polymorphisms and severe delayed diarrhea or neutropenia and effect on response rate and progression-free survival were analyzed. RESULTS: A total of 106 patients receiving irinotecan-based regimens and with detected UGT1A1 gene polymorphisms were enrolled in this research. According to our results, no significant differences of severe diarrhea were found in patients with UGT1A1*6 genotypes (p = 0.608). However, the incidence of severe diarrhea in patients with TA7/7 genotype (66.7%, 4/6) was significantly higher than that in patients with TA6/7 (31.5%, 6/19) or TA6/6 (1.28%, 1/78) genotypes (p < 0.001). The incidence of severe hematologic toxicity in patients with AA (100%, 2/2) was significantly higher than that in patients with GA (33.3%, 7/21) or GG genotype (7.23%, 6/83) (p = 0.011). CONCLUSIONS: In terms of irinotecan-based regimens in cancers, UGT1A1*6 plays a more vital role in hematologic toxicity (p = 0.011) whereas UGT1A1*28 get more involved in diarrhea (p < 0.001). PMID- 28879725 TI - Quantification of Renal Function and Cardiovascular Mortality in Patients Admitted to the Emergency Department with Suspected Acute Coronary Syndromes. AB - BACKGROUND: Increases in the novel serum marker cystatin C are detectable much earlier in the course of chronic kidney disease (CKD) even when levels of serum creatinine are still in the normal range. A major factor causing a decrease in serum creatinine is increasing age. Patients with CKD are more likely to develop cardiovascular disease (CVD) than a healthy population and to suffer premature deaths from CVD related to CKD. The aim of this study was to investigate whether cystatin C, serum creatinine, and estimated glomerular filtration rate (eGFR) predict cardiovascular mortality in patients admitted to the emergency department (ED) with suspected acute coronary syndromes (ACS). METHODS: In 1,282 patients (mean age 62 +/- 15 years, 477 women, 805 men) with suspected ACS, baseline cystatin C concentrations, serum creatinine, and estimated glomerular filtration rate (eGFR) were measured at the ED. Clinical assessment and serial high sensitivity cardiac troponin T (hs-cTnT) measurements were used for the diagnosis of ACS. Seventeen cardiovascular deaths were registered during a median follow-up of 365 days. RESULTS: HRs from univariate Cox regression models for each of the potential biomarkers were 12.02 (95% CI 5.10 - 28.34) for cystatin C, 4.53 (1.75 11.70) for serum creatinine, and 0.97 (0.96 - 0.99) for eGFR. All three biomarkers showed a significant association with cardiovascular mortality in univariate analyses. The HRs from a model with all three potential biomarkers were 59.21 (95% CI 9.69 - 361.76) for cystatin C, 0.08 (0.01 - 0.58) for serum creatinine, and 0.98 (0.96 - 1.01) for eGFR. The risk association was significant for ln (cystatin C) and ln (serum creatinine). CONCLUSIONS: Results of this prospective study show that the quantification of renal function using cystatin C is useful for predicting cardiovascular mortality in patients with suspected ACS at the ED. PMID- 28879726 TI - [Analysis of several key problems of good agricultural practice (GAP) of Chinese materia medica]. AB - This paper reviewed the historical background of the GAP, analyzed the development experience of five Ps (GMP, GLP, GSP, GCP, GAP), analyzed the GAP based on economic theories, and pointed out that the core problem of GAP is ignoring economic laws. Once the GAP, is a process of certification, but neither the GAP announcement could be transformed into signal transmission quality in the product market, nor consumers could recognize the difference between GAP and non GAP herbs in the terminal market, so manufacturers lack motivation for GAP certification. In this paper, we pointed out, that the GAP certification system should be redesigned under the guidance of economics, third party certification body, supervised by drug administration organization, to certificate GAP as high quality standards, to improve signal transduction mechanism of GAP certification, and to integrate GAP with the market. PMID- 28879727 TI - [Absorption and metabolism of Chuanxiong Rhizoma decoction with multi-component sequential metabolism method]. AB - The multiple components in Chinese herbal medicines (CHMS) will experience complex absorption and metabolism before entering the blood system. Previous studies often lay emphasis on the components in blood. However, the dynamic and sequential absorption and metabolism process following multi-component oral administration has not been studied. In this study, the in situ closed-loop method combined with LC-MS techniques were employed to study the sequential process of Chuanxiong Rhizoma decoction (RCD). A total of 14 major components were identified in RCD. Among them, ferulic acid, senkyunolide J, senkyunolide I, senkyunolide F, senkyunolide G, and butylidenephthalide were detected in all of the samples, indicating that the six components could be absorbed into blood in prototype. Butylphthalide, E-ligustilide, Z-ligustilide, cnidilide, senkyunolide A and senkyunolide Q were not detected in all the samples, suggesting that the six components may not be absorbed or metabolized before entering the hepatic portal vein. Senkyunolide H could be metabolized by the liver, while senkyunolide M could be metabolized by both liver and intestinal flora. This study clearly demonstrated the changes in the absorption and metabolism process following multi component oral administration of RCD, so as to convert the static multi-component absorption process into a comprehensive dynamic and continuous absorption and metabolism process. PMID- 28879728 TI - [Overall intestinal permeability of multiple components in lotus leaves]. AB - In the study of biopharmaceutics classification system of Chinese materia medica (CMMBCS), the interactions of multiple components in the absorption should be taken into consideration in simultaneous multi-component determination. To investigate the absorption of multiple components, the in vitro everted gut sac model was used in this study, wtih lotus leaves as the research object. Aquantitative analysis was also carried out for the known components in this study. Totally 19 components in lotus extracts were absorbed by the intestinal tract, the Papp levels of the known components were nuciferine (1*10-5-1*10-6 cm*s-1), rutin (1*10-6-1*10-7 cm*s-1), hyperoside (1*10-6 cm*s-1), isoquercitrin (1*10-6-1*10-7 cm*s-1) and astragalin (1*10-6-1*10-7 cm*s-1), respectively. These components showed a low permeability under a multi-component environment. This study was carried out to lay a foundation for further relevant target studies for different categories of components. PMID- 28879729 TI - [Evaluation for impacts of gut wall metabolism of multiple components in Chuanxiong Rhizoma during intestinal absorption with S9 incubation]. AB - The information of drug deposition in the intestine is required in the study for the drug absorption in biopharmaceutics classification system (BCS). To illustrate the impacts of gut wall metabolism on the absorption, metabolism of multiple components in Chuanxiong Rhizoma in gut wall was tested by rat S9 incubation in vitro. The chemical fingerprint technology was used in this study to simultaneously detect multiple components in Chuanxiong, and peak areas before and after S9 incubation were compared. The results showed that senkyunolide I and several constituents were metabolized by gut wall, and one new metabolite was founded. However, ferulic acid and other compounds remained unchanged after incubation. Therefore, the subsequent intestinal permeability of multiple components in Chuanxiong that were not metabolized in the intestine was suggested to be detected directly by in situ single-pass intestinal perfusion (SPIP).Nonetheless, the intestinal permeability of the constituents that were metabolized in the intestine shall be explored by appropriate approaches. PMID- 28879730 TI - [Study on property of biopharmaceutics classification system of berberine in Huanglian decoction]. AB - The study of single component in the multicomponent environment is one of the basic researches for biopharmaceutics classification system of Chinese materia medica (CMMBCS). That is to say, the classification research shall be based on the respective lift of solubility and permeability in the multicomponent environment, besides solubility and intestinal permeability of the single component. We chose berberine as the main research object to investigate the changes of its solubility and intestinal permeability in Huanglian decoction. Shake-flask and HPLC were used to detect the solubility of berberine in different pH buffer solutions and different concentrations of Huanglian decoction. In situ single-pass intestinal perfusion (SPIP) and intestinal perfusion with venous sampling (IPVS) were carried out to study berberine's intestinal absorption and absorption into blood, respectively. PMID- 28879731 TI - [Biopharmaceutics classification and absorption mechanisms primary study on four kinds of flavonoids]. AB - The solubility and permeability on four kinds of flavonoids (kaempferol, hesperidin, apigenin, genistein) were test according to the theory of biopharmaceutics classification system (BCS), and their absorption mechanism. The solubility was investigated by the method in determination of solubility of "Chinese Pharmacopoeia 2010". To detect appearance permeability of compounds mentioned above, the appropriate concentrations were selected by the MTT method in cell transfer experiments in Caco-2 cell model, which established by in vitro cell culture method. Therefore, these compounds were classified with BCS according to solubility and permeability. In addition, to explore absorption mechanisms, the experiments in three different concentrations of compounds in high, medium and low in bidirectional transformation methods in Caco-2 cell model contacted. The study indicated that all of kaempferol, hesperidin, apigenin, genistein have the characteristics in low solubility and high permeability, which belong to BCSII, and the absorption mechanism of kaempferol was active transportation. Whereas, hesperidin, apigenin, genistein were passive transportation. In this study, it carried out initial explorations on establishment of determination for solubility and permeability in flavonoids, and provided theoretical reference for further research on BCS in traditional Chinese medicine. PMID- 28879732 TI - [Research progress on chemical constituents and their differences between Lonicerae Japonicae Flos and Lonicerae Flos]. AB - The dried flower buds or initial flowers of Lonicerae Japonicae Flos and Lonicerae Flos, which belong to different species of Lonicera or Caprifoliaceae, are usually taken to clear away heat and toxic material and treat the exopathogenic wind-heat. They are two different herbs, and due to various reasons, there are far more controversies. This paper reviews the research on the chemical constituents and their differences between Lonicerae Japonicae Flos and Lonicerae Flos. Both of them contain the similar chemical constituents, such as organic acids, flavonoids, triterpenoidal saponins, iridoids, volatile oils and trace elements. But there are also differences between them. The main differences:Lonicerae Japonicae Flos contains a wealth of iridoids and flavonoids, while Lonicerae Flos contains more kinds of triterpenoidal saponins; the content of chlorogenic acid in Lonicerae Flos is significantly higher than that of Lonicerae Japonicae Flos; the content of rutin, luteoloside,luteolin-7-O beta-D-galactoside and lonicerin in Lonicerae Japonicae Flos is much higher than that of Lonicerae Flos; the content of Fe and Ni in Lonicerae Japonicae Flos is higher, while the content of Mn is higher in Lonicerae Flos. Finally, main problems and suggestions on chemical composition between Lonicerae Japonicae Flos and Lonicerae Flos were also discussed. PMID- 28879733 TI - [Correlation analysis between effectiveness of element in rhizonsphere soil and quality of Danshen (Salvia miltiorrhiza)]. AB - In order to investigate the content and distribution of available element in the rhizonsphere soil of the growing areas of Salvia miltiorrhiza Bunge, the contents of available element (N,P,K,B,Cu,Zn,Fe,Mn) in 26 soil samples were tested and evaluated. The results showed that the contents of available P and Fe were very plentiful, available K, Cu and Zn were rich, available N and Mn were deficient, available B was extremely deficient in all growing areas of S. miltiorrhiza of eight provinces in China. The correlation analysis showed that the contents of eight kinds of available elements were varying degree correlation. The stepwise regression analysis between the contents of available elements of rhizonsphere soil and ten kinds of active ingredients of Danshen (Salviae Miltiorrhizae Radix et Rhizoma) were researched. The results showed that the rates of contribution of available N,B,Mn and Fe to quality of Danshen were relatively large and they were the significant factors, and the other factors did not show statistical significance. The recommended fertilizing strategies is that the usage of N,B and Mn fertilizers should be controlled according to different stages of growth of S. miltiorrhiza, and P fertilizer should be reduced in all growing areas of S. miltiorrhiza. PMID- 28879734 TI - [HPLC-ELSD for determining contents of three triterpenoidal saponins in fruits of Buddleja lindleyana from different habitats]. AB - To establish an HPLC-ELSD method for the quantification of triterpenoids in the fruits of Buddleja lindleyana. The RP-HPLC-ELSD method was used for the determination of triterpenoids in B. lindleyana fruits, which were collected from different habitats. The column used was a packed with 5 MUm stationary phase Waters SunFireTM C18 (4.6 mm*150 mm, 5 MUm). The mobile phase consisted of Methanol-water(82?18) at a flow rate of 1 mL*min-1. Column temperature: 30 C. ELSD conditions: drift tube temperature: 106 C; carrier gas (nitrogen) flow rate: 1.5 L*min-1; amplification factor: 1. The calibration curves showed good linear relationship on a range from 0.702 to 28.08 MUg(r=0.999 2) for Clinoposaponin III, 0.390 to 15.60 MUg(r=0.998 9) for Desrhamnoverbascosaponin and 0.192 to 7.68MUg(r=0.999 0) for Mimengoside I. The average recovery rate(n=6) were 99.41%, 99.08% and 98.67% and it's RSD were 0.86%, 1.56% and 1.80%. This method can be used to determine the contents of triterpenoids in the fruits of Buddleja lindleyana for its simplicity, accurateness and reliability. PMID- 28879735 TI - [Effect of moisture content on vigor of Cyathula officinalis seeds and its anti aging mechanism analysis]. AB - Effects of nine different moisture contents on vigor of Cyathula officinalis seeds and its anti-aging mechanism were studied by artificial accelerated aging through high temperature and wet. The research results showedthat seed vigor were generally decreased after artificial aging; in general, seed vigor and its anti aging ability are relatively stronger within the scope of 6.55%-4.78% moisture content, the increase range of seed conductivity, peroxidase activity, malondialdehyde content,and reduce amplitude of activityof dehydrogenase , superoxide dismutaseare alllower as well. And when the moisture content reduced to 5.77%, all of the germination tests index of the non-aged seeds are the highest, and the activity of peroxidase the lowest,conductivity of leaching solution relatively low, activity of dehydrogenase and superoxide dismutase the highest,and catalase activityrelatively high.Therefore, in the low temperature germplasm preservation of C. officinalis seeds, the seed moisture content should be controlled close to the range of (5.70+/-1)% to keep higher vigor and anti aging ability. PMID- 28879736 TI - [Community composition and diversity of endophytic fungi from roots of Sinopodophyllum hexandrum in forest of Upper-north mountain of Qinghai province]. AB - High throughput sequencing technology is also called Next Generation Sequencing (NGS), which can sequence hundreds and thousands sequences in different samples at the same time. In the present study, the culture-independent high throughput sequencing technology was applied to sequence the fungi metagenomic DNA of the fungal internal transcribed spacer 1(ITS 1) in the root of Sinopodophyllum hexandrum. Sequencing data suggested that after the quality control, 22 565 reads were remained. Cluster similarity analysis was done based on 97% sequence similarity, which obtained 517 OTUs for the three samples (LD1, LD2 and LD3). All the fungi which identified from all the reads of OTUs based on 0.8 classification thresholds using the software of RDP classifier were classified as 13 classes, 35 orders, 44 family, 55 genera. Among these genera, the genus of Tetracladium was the dominant genera in all samples(35.49%, 68.55% and 12.96%).The Shannon's diversity indices and the Simpson indices of the endophytic fungi in the samples ranged from 1.75-2.92, 0.11-0.32, respectively.This is the first time for applying high through put sequencing technol-ogyto analyze the community composition and diversity of endophytic fungi in the medicinal plant, and the results showed that there were hyper diver sity and high community composition complexity of endophytic fungi in the root of S. hexandrum. It is also proved that the high through put sequencing technology has great advantage for analyzing ecommunity composition and diversity of endophtye in the plant. PMID- 28879737 TI - [Preparation and characterization of ginsenoside-Rh2 lipid nanoparticles and synergistic effect with borneol in resisting tumor activity]. AB - To prepare ginsenoside-Rh2 lipid nanoparticles, and investigate the synergistic effect with borneol in resisting tumor activity in vitro. Ginsenoside-Rh2 lipid nanoparticles were prepared by ultrasonic-assisted solvent evaporation method, and orthogonal design was adopted to optimize formulation process. Its encapsulation efficiency, drug loading ratio, particle size distribution, Zeta potential, morphology and in vitro drug release behavior were characterized, and synergistic effect with borneol in resisting tumor activity were preliminarily studied by MTT. These nanoemulsion particles prepared by the optimized process method were rounding and even in a good shape. Encapsulation efficiency and drug loading ratio of three batches of nanoemulsion particles were (77.3+/-2.5)% and (7.2+/-0.2)%, respectively. Nanoemulsion particles showed an obvious sustained release characteristics, with 52.42% cumulative release within 96 h. The killing effect of nanoemulsion particles on glioma cells was dose-dependent, with IC50 of 22.33 MUmol*L-1 and 11.46 MUmol*L-1 after 24 h and 48 h, respectively. After the combination with borneol, the killing effect of nanoemulsion particles on glioma cells was dose-dependent, with IC50 of 16.36 MUmol*L-1 and 8.04 MUmol*L-1 after 24 h and 48 h, respectively. PMID- 28879738 TI - [Screening and identification of DPP-4 inhibitors from Xiaokean formula by a fluorescent probe]. AB - Fluorescent bio-probes have attracted increasing attentions in studies for screening bioactive compounds from traditional Chinese medicines. In this study, a new-type fluorescent probe with the function of aggregation-induced emission (AIE) was used to screen dipeptidyl peptidase-4 (DPP-4) inhibitor from Xiaokean formula, which has been clinically used for the treatment of type 2 diabetes mellitus. Potential DPP-4 inhibitors were screened by the fluorescent probe, with diprotin A as the positive control; totally 43 components were isolated from Xiaokean formula by systematic separation. The results showed that 13 components can exert inhibitory effects on DPP-4 activity; 16 compounds were further identified by liquid chromatography-mass spectrometry (LC-MS) from those active components. The inhibitory effects of 14 compounds were further verified, while five of them showed significant inhibition against DPP-4. Salvianolicacid C, ginsenoside Rg5 and timosaponin AI inhibited DPP-4 activity at the concentration of 5-50 MUmol*L-1 in a dose-dependent manner. Thus, our study provided a successful example for screening bioactive compounds from traditional Chinese medicines by using a novelfluorescent probe. PMID- 28879739 TI - [Iridoids from stem bark of Syringa pinnatifolia]. AB - One new iridoid, named alashanidoid A, and five known analogues, were isolated from the stem bark of Syringa pinnatifolia by various chromatographic methods. Their structures were determined on the basis of MS and NMR spectroscopic data analyses, and comparison with those in literature. Among them, compounds 3-5 were isolated from this genus for the first time, and 2 and 6 were isolated from the species for the first time.These isolates were tested for their in vitro anti inflammatory activities against NO production in lipopolysaccharide(LPS)-induced RAW264.7 macrophages in mice and cytotoxicity of HepG2 cell line, however, no obvious activity was observed at the concentration of 40 MUmol*L-1. PMID- 28879740 TI - [Triterpenoid saponins from Bupleurum marginatum var. stenophyllum]. AB - Twelve compounds were obtained by phytochemical investigation of 70% EtOH ( containing 0.5%NH3*H2O )extract of the roots of Bupleurum marginatum var. stenophyllum. Based on comparison of their spectral data, including HR-ESI-MS, 1H NMR, 13C-NMR data, with those of the literature, their structures were elucidated as saikosaponin b2 (1), saikosaponin a(2), saikosaponin b1(3), saikosaponin d (4), hydroxysaikosaponin a (5), saikosaponin b3 (6), saikosaponin c(7),saikosaponin i (8), saikosaponin f (9), chikusaikosides II(10), saikosaponin s (11), and saikosaponin I(12). All compounds belong to olean-type triterpenoid saponin and compounds 1, 3, 5, 8-9,11, and 12 were isolated from this plant for the first time. At a concentration of 20 MUmol*L-1, compounds 2, 4, 6, 8, 11 and 12 showed strong inhibition activity against influenza virus WSN33 with the inhibition rate of 91.3%,88.6%,53.4%,61.3%,77.3% and 57.4%,respectively. PMID- 28879741 TI - [Identification of chemical constituents in Scrophulariae Radix by HPLC-IT-TOF MS]. AB - This experiment was performed to establish a qualitative analysis on chemical constituents of Scrophulariae Radix by HPLC-ESI-IT-TOF-MS.The analysis was conducted on a C18 column (Kromasil 100-5, 4.6 mm*250 mm, 5 MUm) with 0.1% formic acid-acetonitrile as the mobile phase for gradient elution; ESI ion source was used for mass spectra, and data were collected innegative and positive modes. The results showed that 64 compounds from Scrophulariae Radix had been identified by analyzing negative ion mass data including element composition and by comparing with data from literature. Two new compounds (4-hydroxy-6-O-methylcatalpol and acetylangoroside C) and seventeen known compounds were detected from Scrophulariae Radix for the first time. Seventeen known compounds included twelve iridoid glycosides, three phenylpropanoid glycosides and two other kind compounds. This study will provide chemical basis for elucidation of the effective substance in the Scrophulariae Radix. PMID- 28879743 TI - [Thymopolypeptides combined with matrine type alkaloids suppress HBV replication]. AB - To investigate the antiviral effect of thymopolypeptides combined with 4 kinds of matrine type alkaloids on HepG2.2.15 cells, oxymatrine, sophocarpidine, sophocarpine, and sophoridine (at concentration of 0.2 mmol*L-1 respectively) were respectively combined with thymopolypeptides (0.025, 0.1 g*L-1), and after 48 h and 72 h treatment on HepG2.2.15 cells, the cells and supernatants were collected. The cells activity in various groups was determined by CCK-8 method to evaluate the toxic effects of the drugs on HepG2.2.15 cells. Enzyme linked immunosorbent assay (ELISA) was used to determine HBeAg and HBsAg levels in cellular supernatants. HBV DNA levels in cellular supernatants andcells were quantified with fluorogenic quantitative PCR method; and the expression level of IFN-alpha in supernatants was detected with CBA method. The results indicated that single thymopolypeptides at 0.025-0.4 g*L-1 had no toxicity to cells. Thymopolypeptides in this concentration range combined with 0.2 mmol*L-1 matrine type alkaloids also had no toxicity to cells. Anti-HBV activity of drug combination was better than that of alkali or thymopolypeptides alone. Thymopolypeptides at 0.025 g*L-1 had better inhibitory effect than thymopolypeptides at 0.1 g*L-1 on intracellular HBV DNA expression, but the inhibitory effect on supernatant HBeAg level was on the contrary. Anti-HBV activity was similar between alkaloids combined with 0.1 g*L-1 and alkaloids combined with 0.025 g*L-1. There was no statistical difference in anti-HBV effect between various combined groups (P<0.05). In general, 72 h anti-HBV effect was better than 48 h anti-HBV effect (P<0.05). The expression of IFN-alpha was increased after drug combination, with positive correlation to the changes of other four indicators (P<0.05). In conclusion, oxymatrine, sophocarpidine, sophocarpine and sophoridine combined with thymopolypeptides could inhibit HBsAg and HBeAg secretion in HepG2.2.15 cells and HBV DNA replication, and further promote the antiviral effect by promoting the expression of IFN-alpha. PMID- 28879742 TI - [Effect of six class of Kaixin San formulas on pharmacological and preliminary mechanism of Alzheimer's disease mice]. AB - The efficacy of Chinese herbal formulas in treating Alzheimer has been proved in many studies. In this study, six different Kaixin San formulas were compared to investigate their effects on learning and memory decline, brain-derived neurotrophic factor (BDNF) in the hippocampus, tau protein, acetylcholinesterase (AChE) and N-terminal pro-brain natriuretic peptide (NT-proBNP). Kunming mice were selected and established a mouse model of Alzheimer's by intraperitoneal injection of D-galactose and sodium nitrite, continued intragastric 4 weeks, using the ability of learning and memory in Morris water maze test to evaluate the animals in each group; the content of BDNF in the hippocampus of mice with Western blotting detected; ELISA method for the detection of each group of mice hippocampal tau protein,p-Tau protein, Abeta,Ach,AchE and serum NT-proBNP levels. The results showed that, Kaixin San of Qianjin Yaofang three dose recorded significantly improved learning and memory ability of mice; increased the content of BDNF and Ach in the hippocampus; decreased the content of Abeta, Tau protein, p-Tau protein in the hippocampus; high, middle dose significantly decreased the serum NT-proBNP and AchE in hippocampus, the effect is most significant. Part dose of Kaixin San of Yixin Fang, Kaixin Wan of Yimen Fang, Dingzhi Xiaowan of Beji Qianjin Yaofang and Dingzhi Wan of Guji Luyan could improve the learning and memory ability evaluation indicators, significantly increased BDNF and Ach in the hippocampus of AD model mice, reduced the Abeta, Tau protein, p-Tau protein in hippocampus of AD model mice, decreased the NT-proBNP and AchE in serum of AD mice, the effect is more significant. Three does of Buxin Tang of Qianjin Yi had no effects of treatment in Alzheimer's disease. The results showed the treatment in AD of Kaixin San of Qianjin Yaofang is the most significant. PMID- 28879744 TI - [Protective effect of beta-asarone on PC12 cells injury induced by Abeta1-42 astrocytic activation]. AB - This study was aimed to investigate the protective effect and mechanism of beta asarone on PC12 cells injury induced byAbeta1-42 activated astrocytes, and provide experimental basis for beta-asarone application in the prevention and control of Alzheimer's disease (AD). Firstly, RA-h and PC12 cells were co cultured in the special transwell chamber, and the Real time cell analysis (RTCA) system was used to real-time observe its effect on PC12 cells survival rate in the co-culture system after astrocytes injury induced by Abeta1-42. The best intervention time of beta-asarone was selected according to the survival curve and parameters generated automatically. beta-asarone with different concentrations was used for intervention on astrocytes, then the changes of PC12 cells survival rate in the co-culture system were observed. Secondly, MTT assay was used to detect the effect of Abeta1-42 on PC12 cells survival rate as well as the intervention effect of beta-asarone, and verify the testing results of RTCA. The levels of IL-1beta, TNF-alpha and BDNF in culture media of the lower chamber were detected by ELISA. The NF-kappaB activity and phosphorylation levels of ERK, p38 and JNK were detected by Western blot. Results showed that beta-asarone (55.5 mg*L-1) could significantly slowdown the decline of PC12 cells survival rate caused by Abeta1-42-induced RA-h activation (P<0.01), significantly reduce the levels of IL-1beta, TNF-alpha and the phosphorylation levels of ERK, p38 and JNK in culture media of the lower chamber (P<0.01). beta-asarone(166.7 mg*L-1) could promote the release of BDNF in culture media of the lower chamber(P<0.05). These results indicated that Abeta1-42 could induce RA-h activation and its release of IL-1beta, TNF-alpha and other inflammatory factors to aggravate the PC12 cells injury; beta-asarone could reduce the levels of IL-1beta, TNF-alpha, promote the release of BDNF, and inhibit the NF-kappaB activity as well as phosphorylation levels of ERK, p38 and JNK protein in PC12 cells. PMID- 28879745 TI - [Exploration research on hepatotoxic constituents from Polygonum multiflorum root]. AB - By observing the cytotoxic effects of anthraquinones on HepG2 cell and using the precision-cut liver slices technique to authenticate the cytotoxic constituents, the paper aims to explore the material basis of Polygonum multiflorum root to cause liver toxicity. Firstly, MTT method was used to detect the effect of 11 anthraquinone derivatives on HepG2 cell. Then, the clear cytotoxic ingredients were co-cultured with rat liver slices for 6h respectively, and the liver tissue homogenate was prepared. BCA method was used to determine the content of protein in the homogenate and continuous monitoring method was used to monitor the leakage of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamine amino transpeptidase (GGT) and lactate dehydrogenase (LDH). The toxic effect of these ingredients on liver tissue was tested by calculating the leakage rate of the monitored enzymes. As a result, rhein, emodin, physcion-8-O beta-D-glucopyranoside and physcion-8-O-(6'-O-acetyl)-beta-D-glucopyranoside showed cytotoxic effects on HepG2 cell and their IC50 values were 71.07, 125.62, 242.27, 402.32 MUmol*L-1 respectively, but the other 7 compounds are less toxic and their IC50 values can not be calculated. The precision-cut liver slices tests showed that rhein group of 400 MUmol*L-1 concentration significantly increased the leakage rate of ALT, AST and LDH (P<0.01), and the rhein group of 100 MUmol*L 1 concentration only increased the leakage rate of LDH (P<0.05). With the increase of rhein concentration, the protein content in liver slices decreased significantly (P<0.05) with a certain range of does. Emodin group of 400 MUmol*L 1 concentration significantly increased the leakage rate of ALT, GGT and LDH (P<0.01). Physcion-8-O-beta-D-glucopyranoside group of 800 MUmol*L-1 concentration also significantly increased the leakage rate of ALT, AST and LDH (P<0.01 or P<0.05), but the group of 200 MUmol*L-1 concentration only significantly increased the LDH leakage (P<0.05). Along with the increase of the concentration of physcion-8-O-beta-D-glucopyranoside, the leakage rate of ALT, AST and LDH showed a trend of increase, but the protein content in liver slices was in decline. Furthermore, MTT reduction ability of liver slices significantly decreased (P<0.01) in the physcion-8-O-beta-D-glucopyranoside group of 800 MUmol*L-1 concentration. The results suggested that rhein, emodin and physcion-8 O-beta-D-glucopyranoside at high concentrations (>=400 MUmol*L-1) can produce some damage to the liver tissue. However, the exposure levels of these constituents are very low, so to reach the toxic concentration (400 MUmol*L-1 or 800 MUmol*L-1) an adult of 65 kg body weight will need at least a single oral 4 898 g, 339 g and 5 581 g of P.multiflorum root respectively, which is far from the statutory dose of crude P. multiflorum root (3-6 g) or its processed product (6-12 g). Therefore, the conclusion that anthraquinones are the prime constituents of the hepatotoxicity of P. multiflorum root are still not be proved. PMID- 28879746 TI - [Effect and mechanism of danshensu on hepatitis B virus reverse transcriptase and antigen expression]. AB - MTT assay was used in this study to investigate the inhibitory effect of danshensu on the activity of 2.2.15 cells among human hepatoma cell line (HepG2); indirect fluorescence labeling method was used to measure the changes of reactive oxygen levels in the cells; ELISA method was used to determine hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) levels in cellular supernatants; HBV DNA level was measured with fluorogenic quantitative PCR method. The inhibitory effect of danshensu on HBV RT(hepatitis B virus reverse transcriptase) was studied by using enzyme inhibition dynamics, and the effect of danshensu on secondary structure of HBV reverse transcriptase was monitored by using circular dichroism. The results showed that danshensu had a good inhibitory effect on the growth of HepG2.2.15 cells, with a half inhibitory concentration (IC50) of (15.35+/-2.43) MUmol*L-1; danshensu could significantly inhibit HBsAg and HBeAg expressions, and showed an inhibitory effect on HBV DNA replication. In addition, danshensu was an effective inhibitor for HBV reverse transcriptase [IC50 (21.32+/-2.43) MUmol*L-1]. The fluorescence labeling results showed that the reactive oxygen levels in the cells were increased with the increase of danshensu concentration. Circular dichroism analysis showed that danshensu could induce partial change of conformation of HBV reverse transcriptase and gradually increased alpha-helical content. These results indicated that danshensu could make the structure of the enzyme become closer by binding to HBV reverse transcriptase, which was not conducive to the formation of the active center, so it could finally decrease the activity of HBV reverse transcriptase. Such decrease in enzyme activity would directly affect the HBV DNA replication, and combined with the decrease of the antigen levels, the effect of danshensu on HBV was increased. PMID- 28879747 TI - [Protective effects of oxymatrine against H2O2-induced damage in L02 cells]. AB - To investigate the protective effects of oxymatrine (OMT) against H2O2-induced damage in L02 cells and research the mechanism,L02 cells were used as the research object. The oxidative stress model of L02 was established by hydrogen peroxide (H2O2). CCK-8 was used to detect the cell activation of L02 cells treated by different OMT. FCM (flow cytometry) assay was used to evaluate the cell proliferation of L02 cells treated by OMT. The apoptosis of L02 cells was detected using Annexin-V/7-AAD apoptosis detection kit. The level of ROS was detected by DCFH-DA fluorescence probe. The GSH-PX and SOD were detected by micro plate and colorimetric method. Results showed that when the concentration of OMT is between 6.25 and 100 mg*L-1, it could promote the production of NADPH and strengthen the activity of GSH-PX and SOD to get rid of the ROS to protect the L02 cell from the apoptosis of L02 cell induced by H2O2. PMID- 28879748 TI - [Target protein candidates of hypothalamus in aging rats with intervention by Qiongyugao]. AB - To explore the associated proteins of the hypothalamus in aging rat models with intervention by Qiongyugao(QYG) based on iTRAQ technology, find out the target protein candidates and investigate the mechanism of delaying aging for Qiongyugao. The results showed that Qiongyugao increased GSH-Px activity in serum and SOD activity in liver; the total protein count identified by iTRAQ was 3 522, FDR<1%. There were 20 kinds of differential proteins between the blank group and model group; there were 295 kinds of differential proteins between model group and QYG group, and 40 kinds of them had a difference multiple >=1.30 (the maximum value was 1.47). Compared with blank group, there were 14 kinds of proteins that were down-regulated in model group and up-regulated in QYG group. Combined with literature search and gene function search, 12 kinds of target protein candidates were screened out : ST18, Ptprc, PSMB8, INPP4B, Shc3, Pik3r1, PIP5K1C, Nampt, Rasgrp2, Asah2, Pdpk1, and Map2k7. The expression of nuclear factor-kappa B (NF kappaB) in the hypothalamic inflammatory pathway was detected by Western blot and the results showed that its expression level in model group(0.96) was higher than that in control group(0.85), while its expression level in QYG group(0.89) was lower than that in model group. Q-PCR results showed that the relative mRNA expression levels of PIP5K1C and Ptprc in model group were significantly lower than those in blank group(P<0.01); while compared with the model group, the mRNA expression levels of PIP5K1C and Ptprc in QYG group were significantly increased(P<0.01) . This result was consistent with proteomics data. QYG may delay aging by regulating hypothalamic inflammatory reaction. PMID- 28879749 TI - [3D evaluation model for drug hepatotoxicity testing on HepG2 cells and its application in drug safety evaluation]. AB - 3D in vitro toxicity testing model was developed by magnetic levitation method for culture of the human hepatoma cell line HepG2 and applied to evaluate the drug hepatotoxicity. After formation of stable 3D structure for HepG2 cells, their glycogen storage capacity under 2D and 3D culture conditions were detected by immunohistochemistry technology, and the mRNA expression levels of phase I and II drug metabolism enzymes, drug transporters, nuclear receptors and liver specific marker albumin(ALB) were compared between 2D and 3D culture conditions by using RT-PCR method. Immunohistochemistry results showed that HepG2 cells had abundant glycogen storage capacity under 3D culture conditions, which was similar to human liver tissues. The mRNA expression levels of major drug metabolism enzymes, drug transporters, nuclear receptors and ALB in HepG2 cells under 3D culture conditions were up-regulated as compared with 2D culture conditions. For drug hepatotoxicity evaluation, the typical hepatotoxic drug acetaminophen(APAP), and most reported drugs Polygonum multiflorum Thunb.(Chinese name He-shou-wu) and Psoraleae corylifolia L.(Chinese name Bu-gu-zhi) were selected for single dose and repeated dose(7 d) exposure. In the repeated dose exposure test, 3D HepG2 cells showed higher sensitivity. This established 3D HepG2 cells model with magnetic levitation 3D culture techniques was more close to the human liver tissues both in morphology and functions, so it was a better 3D hepatotoxicity evaluation model. PMID- 28879750 TI - [Effect of vinegar-processed Curcumae Rhizoma on bile metabolism in rats]. AB - To explore the effect of vinegar-processed Curcumae Rhizoma on endogenous metabolites in bile by investigating the endogenous metabolites difference in bile before and after Curcumae Rhizoma was processed with vinegar. Alcohol extracts of crude and vinegar-processed Curcumae Rhizoma, as well as normal saline were prepared respectively, which were then given to the rats by intragastric administration for 0.5 h. Then common bile duct intubation drainage was conducted to collect 12 h bile of the rats. UPLC-TOF-MS analysis of bile samples was applied after 1?3 acetonitrile protein precipitation; unidimensional statistics were combined with multivariate statistics and PeakView software was compared with network database to identify the potential biomarkers. Vinegar processed Curcumae Rhizoma extracts had significant effects on metabolites spectrum in bile of the rats. With the boundaries of P<0.05, 13 metabolites with significant differences were found in bile of crude and vinegar-processed Curcumae Rhizoma groups, and 8 of them were identified when considering the network database. T-test unidimensional statistical analysis was applied between administration groups and blank group to obtain 7 metabolites with significant differences and identify them as potential biomarkers. 6 of the potential biomarkers were up-regulated in vinegar-processed group, which were related to the metabolism regulation of phospholipid metabolism, fat metabolism, bile acid metabolism, and N-acylethanolamine hydrolysis reaction balance, indicating the mechanism of vinegar-processed Curcumae Rhizoma on endogenous metabolites in bile of the rats. PMID- 28879751 TI - [Traditional Chinese medicine syndrome distribution and neuroendocrine mechanisms of irritable bowel syndrome: cross-sectional study]. AB - In order to clarify the traditional Chinese medicine(TCM) syndrome distribution and pathogenesis of irritable bowel syndrome(IBS), the patients in the first affiliated hospital of Guangzhou university of Chinese medicine were enrolled for the cross-sectional study. The data of 12 sociological variables, 13 risk factors, 84 symptoms and signs variables(in 9 aspects), and 19 neuroendocrine indices were extracted for group-between analysis with one-way ANOVA, chi-square test and nonparametric test, and the relationship analysis between clinical symptoms and diseases sub-types was done with binary Logistic regression. In addition, the patterns of TCM syndromes were divided by several syndrome factors to analyze the difference in neuroendocrine indices between various patterns and syndrome factors. A total of 383 IBS patients were enrolled, including 353(92.2%) cases of diarrhea, 14(3.7%) cases of constipation and 16(4.1%) cases of mixed types. In IBS-diarrhea patients, there were 291(76.0%), 18(4.7%), 48(12.5%) and 26(6.8%)cases of syndrome of liver depression and spleen deficiency (sLDSD), syndrome of liver depression and qi stagnation (sLDQS), syndrome of dampness-heat in the spleen and stomach (sDHSS), and syndrome of spleen deficiency with dampness encumbrance (sSDDE) respectively. There was significant differences in blood groups between IBS-diarrhea patients, IBS-constipation patients and IBS mixed types patients; their disease classification was significantly correlated with the allergies, drinking, irregular meals habits, no or less vacations, and other causes of morbidity (P<0.05, f<0.3). A total of 15 symptoms and signs variables (e.g., chills, facial abnormalities, epigastric fullness, etc.) had significant differences between different groups (P<0.05), and 5, 8, 5 variables were respective independent factors for IBS-diarrhea, constipation and mixed type. There was no significant difference in neuroendocrine indices between various groups. The sLDSD, sLDQS, sDHSS, sSDDE patients had significant differences in genders, living conditions and occupations, and the TCM syndrome type was significantly correlated with the drinking, smoking, no or less breakfast, less than 8 sleeping hours(P<0.05, f<0.3). Meanwhile, a total of 14 symptoms and signs variables (e.g., dysphoria heat, fatigue, stretching, etc.) had significant differences between various groups(P<0.05) and 3, 4, 6, 3 variables were respective independent factors for sLDSD, sLDQS, sDHSS, and sSDDE. There were significant differences in acetylcholine(Ach) and angiotensin II(AT II) between the sLDSD group and sSDDE group. There were significant difference in Ach, AT-II, adrenotrophin(ACTH) and estradiol (E2) in comparison between several pattern factors. This study preliminary identified the sociological characters, risk factors, syndromes distribution, diseases and subgroup mechanisms of this disease. More samples and multi-centers are required for future study to improve the scientificity and representativeness. PMID- 28879752 TI - [Clinical application characteristics of Danggui-Chuanxiong herb pair in Chinese medicines on basis of real-world]. AB - To analyze the clinical application characteristics of Danggui-Chuanxiong(DG-CX) herb pair in Chinese medicines on basis of real-world, and provide reference for explaining the inherent compatibility regularity and the relationship between clinical applications and disease species. From April 1, 2014 to June 30, 2014, a total of 8 792 prescriptions with both "DG"and "CX" in a large third-grade class A traditional Chinese medicine(TCM) hospital were selected to establish the database for analyzing the ratio, dosage, and corresponding disease species of DG CX herb pair. The results showed that, "DG-CX" with ratio "1?1" had the highest frequency in clinical application(42.4%); the dosage was mainly of 15 g for both DG and CX; the disease species were mainly of encephalopathy and pulmonary diseases. "DG-CX" herb pairs with a ratio greater than "1?1" accounted for 33.3% of all the prescriptions, and the ratio "3?2" appeared to be most frequent among them; the dosage was mainly of 15 g for DG and and 10 g for CX; the disease species were mainly of encephalopathy diseases. "DG-CX" herb pairs with a ratio less than "1?1" accounted for 24.3% of all the prescriptions, and the ratio "2?3" appeared to be most frequent among them; the dosage was mainly of 10 g for DG and 15 g for CX; the disease species were mainly of encephalopathy diseases. Statistical method was applied to study the compatibility and application characteristics of Chinese herb pairs in clinical prescriptions, effectively discover the medication regularity, provide theoretical basis for clinical herbal prescriptions and provide scientific guidance and reliable data for modern research of Chinese herb pairs. PMID- 28879753 TI - [Analysis on composition principles of formulae containing Gardeniae Fructus in dictionary of traditional Chinese medicine prescriptions]. AB - Gardeniae Fructus, which is widely used in health foods and clinical medicines, is a type of edible food and medicine. Dictionary of traditional Chinese medicine prescriptions provides good materials for prescription analysis and the R&D of traditional Chinese medicines. The composition regularity of formulae containing Gardeniae Fructus in dictionary of traditional Chinese medicine prescriptions was analyzed on the basis of the traditional Chinese medicine inheritance support system(TCMISS), in order to provide reference for clinical application and the R&D of new drugs. TCMISS was applied to establish a database of prescriptions containing Gardeniae Fructus. The software's frequency statistics and association rules and other date mining technologies were adopted to analyze commonly used drugs, combination rules and core combined formulae containing Gardeniae Fructus. Totally 3 523 prescriptions were included in this study and involved 1 725 Chinese herbs. With a support degree of 352(10%) and confidence coefficient of 90%, 57 most commonly used drug combinations were screened. Drugs adopted in core combinations were relatively concentrated and selected according to definite composition methods. They were used to mainly treat 18 diseases. Gardeniae Fructus have often been combined with herbs for heat-clearing and detoxification, expelling pathogenic wind, relieving exterior syndrome, invigorating the circulation of blood and gas and promoting blood circulation for removing blood stasis to mainly treat jaundice, typhoid, headache and other syndromes. PMID- 28879754 TI - [Research on evolution and transition of quality evaluation of Shihu]. AB - Shihu is one of the most valuable Chinese medicines in China. The sources of Shihu are complex and the quality evaluation of it mainly depends on morphologic characteristics distinction. In order to understand the Shihu's quality evaluation concept of Chinese herbalists in the past dynasties. This paper summarizes the methods of quality evaluation in ancient bencao systematically. The ancient bencao records that the quality of Shihu is closely related to its germplasm, habitat, processing and character. The concept of germplasm about shihu includes generalized and narrow sense, besides, the clinical applications of Dendrobium huoshanenese, D. officinale and D. nobile are focused on different diseases. D. huoshanenese has been regarded as Dao-di herbs since Qing Dynasty. The main products of Shihu contain fresh goods and dry goods, their clinical applications are also treated differently. Fengdou is one of the commodity specifications in Shihu. Its processing method probably dated from the Qing Dynasty, but now, it has become the mainstream commodityform. There was a common sense that different kinds of Shihu owed different characters and curative effects in ancient bencao, and the quality would enhance with the increasing viscidity. Therefore, the "Germplasm", "Geoherbs", "processing", "characters" were integrated into traditional quality evaluation methods of Shihu. Meanwhile, we should pay attention to the clinical efficacy of shihu with different species and processing methods. PMID- 28879755 TI - [New study on species of Chinese medicine dragon's blood]. AB - Through comprehensive study on the descriptions of dragon's blood in traditional medical books, we pointed out that before Tang Dynasty, Butea monosperma was used as dragon's blood; during Tang and Song Dynasty, Liquidambar formosana. was used as dragon's blood; in Commentaries on the illustrations of Song Dynasty, the author made a mistake by combined the descriptions of Butea monosperma with the descriptions of the prepared medicine of Dracaena cochinchinensis in dragon's blood, and thus the oversea species D. cochinchinensis became the mainstream of dragon's blood source in homeland. Until the foundation of the Republic of China, Daemonorops draco replaced D. cochinchinensis to the main source of dragon's blood. PMID- 28879756 TI - [New records of distribution of medical plants in Anhui province]. AB - During the fourth national survey of Chinese material medica resources inventory, 9 species of medical plants in Huangshan area of Anhui Province were newly recorded, including Microlepia calvescens, Dryopteris hangchowensis, Fatoua pilosa, Girardinia chingiana, Lecanthus peduncularis, Galium kamtschaticum, Carpesium minus,Cirsium racemiforme, Globba racemosa, which belong to seven families and nine genera. Among these, 3 genera (Girardinia, Lecanthus, Globba) are new geographical distribution in Anhui Province. All of voucher specimens are preserved in ACM. These discoveries enrich the content of flora in Anhui and provide fundamental materials for studying the plants of Anhui. PMID- 28879757 TI - [Indiscriminate use of Latin name for natural Cordyceps sinensis insect-fungi complex and multiple Ophiocordyceps sinensis fungi]. AB - Natural Cordyceps sinensis(Dongchongxiacao) is an insect-fungi complex containing multiple Ophiocordyceps sinensis(=Cordyceps sinensis) fungi and dead body of larva of the family of Hepialidae. But natural C. sinensis and O. sinensis fungi use the same Latin name, resulting in uncertainty of the specific meaning, even disturbing the formulation and implementation of governmental policies and regulations, and influencing consumer psychology onthe market. This paper reviews the history and current status of the indiscriminate use of the Latin name O. sinensis for both the natural insect-fungi complex C. sinensis and O. sinensis fungi and lists the rename suggetions. Some scholars suggested using the term O. sinensis for the fungi and renaming the natural C. sinensis "Chinese cordyceps". Others suggested renaming the natural C. sinensis "Ophiocordyceps & Hepialidae". Both suggestions have not reached general consensus due to various academic concerns. This paper also reviews the exacerbation of the academic uncertainties when forcing implementing the 2011 Amsterdam Declaration "One Fungus=One Name" under the academic debate. Joint efforts of mycological, zoological and botany TCM taxonomists and properly initiating the dispute systems offered by International Mycology Association may solve the debate on the indiscriminate use of the Latin name O.sinensis for the natural insect-fungi complex,the teleomorph and anamorph(s) of O. sinensis fungi. PMID- 28879758 TI - Light-Controlled BMSC Sheet-Implant Complexes with Improved Osteogenesis via an LRP5/beta-Catenin/Runx2 Regulatory Loop. AB - The combination of bone marrow mesenchymal stem cell (BMSC) sheets and titanium implants (BMSC sheet-implant complexes) can accelerate osseointegration. However, methods of fabricating BMSC sheet-implant complexes are quite limited, and the survival of BMSC sheet-implant complexes is one of the key barriers. Here, we show that a light-controlled fabricating system can generate less injured BMSC sheet-implant complexes with improved viability and osteogenesis and that noninvasive monitoring of the viability of BMSC sheet-implant complexes using a lentiviral delivery system is feasible. Enhanced green fluorescent protein- and luciferase-expressing BMSC sheets were used to track the viability of BMSC sheet implant complexes in vivo. The experiments of micro-computed tomography analysis and hard tissue slices were performed to evaluate the osteogenic ability of BMSC sheet-implant complexes in vivo. The results showed that BMSC sheet-implant complexes survived for almost 1 month after implantation. Notably, BMSC sheet implant complexes fabricated by the light-controlled fabricating system had upregulating expression levels of low-density lipoprotein-receptor-related protein 5 (LRP5), beta-catenin, and runt-related transcription factor 2 (Runx2) compared to the complexes fabricated by mechanical scraping. Furthermore, we found that Runx2 directly bound to the rat LRP5 promoter and the LRP5/beta catenin/Runx2 regulatory loop contributed to the enhancement of the osseointegrating potentials. In this study, we successfully fabricated BMSC sheet implant complexes with improved viability and osteogenesis and established a feasible, noninvasive, and continuous method for tracking BMSC sheet-implant complexes in vivo. Our findings lay the foundation for the application of BMSC sheet-implant complexes in vivo and open new avenues for engineered BMSC sheet implant complexes. PMID- 28879759 TI - Improving Efficiency and Reproducibility of Perovskite Solar Cells through Aggregation Control in Polyelectrolytes Hole Transport Layer. AB - Here, we report that the performance of perovskite solar cells (PSCs) can be improved by aggregation control in polyelectrolytes interlayer. Through counterions tailoring and solvent optimization, the strong aggregation of polyelectrolytes P3CT-Na can be broken up by P3CT-CH3NH2. When using P3CT-CH3NH2 to replace P3CT-Na as hole transport layer, the average efficiency is greatly improved from 16.9 to 18.9% (highest 19.6%). Importantly, efficiency over 15% is obtained in 1 cm2 devices with P3CT-CH3NH2, ~50% higher than that with P3CT-Na (10.3%). Our work demonstrates the important role of aggregation control in polyelectrolytes interlayer, providing new opportunities to promote its application in PSCs. PMID- 28879760 TI - Reprogrammable, Reprocessible, and Self-Healable Liquid Crystal Elastomer with Exchangeable Disulfide Bonds. AB - A liquid crystal elastomer (LCE) can be regarded as an integration of mesogenic molecules into a polymer network. The LCE can generate large mechanical actuation when subjected to various external stimuli. Recently, it has been extensively explored to make artificial muscle and multifunctional devices. However, in the commonly adopted two-step crosslinking method for synthesizing monodomain LCEs, the LCE needs to be well-cross-linked in the first step before stretching, which increases the disorder of mesogenic molecules in the final state of the LCE and makes it very challenging to fabricate the LCE of complex shapes. In this article, we developed a new LCE with disulfide bonds, which can be reprogrammed from the polydomain state to the monodomain state either through heating or UV illumination, owing to the rearrangement of the polymer network induced by the metathesis reaction of disulfide bonds. In addition, the newly developed LCE can be easily reprocessed and self-healed by heating. Because of the excellent reprogrammability as well as reprocessability of the LCE, we further fabricated LCE-based active micropillar arrays through robust imprint lithography, which can be hardly achieved using the LCE prepared previously. Finally, we showed an excellent long-term durability of the newly developed LCE. PMID- 28879761 TI - New and Efficient Electrocatalyst for Hydrogen Production from Water Splitting: Inexpensive, Robust Metallic Glassy Ribbons Based on Iron and Cobalt. AB - Efficient, stable electrocatalysts are required to promote the hydrogen evolution reaction (HER) to obtain hydrogen as a clean, sustainable fuel via water splitting. In the present work, ribbons of the metallic glass Fe40Co40P13C7 were produced using a conventional melt-spinning technique and assessed as electrocatalysts for HER. In 0.5 M H2SO4, these ribbons generated an overpotential of 118 mV at a current density of 10 mA cm-2. This overpotential remained essentially constant over 20 h under these conditions. On the basis of the excellent properties, these glassy ribbons represent a new type of highly active, robust HER catalyst suitable for practical applications. PMID- 28879762 TI - Catalytic Enantioselective Vinylogous Allylic Alkylation of Coumarins. AB - An unprecedented, organocatalytic enantioselective vinylogous gamma-allylic alkylation of 4-methylcoumarins has been developed. Using allylic carbonates as the allyl source, this reaction is catalyzed by Lewis basic dimeric Cinchona alkaloid (QD)2PHAL and proceeds exclusively in a gamma- and branched-selective manner to produce densely functionalized coumarin derivatives generally in good yields with good to high enantioselectivities (up to 97:3 er). PMID- 28879763 TI - Hydrogelation of a Naphthalene Diimide Appended Peptide Amphiphile and Its Application in Cell Imaging and Intracellular pH Sensing. AB - This study reports the self-assembly and application of a naphthalene diimide (NDI)-appended peptide amphiphile (PA). H-bonding among the peptide moiety in conjunction with pi-stacking between NDI and hydrophobic interactions within the alkyl chain are the major driving forces behind the stepwise aggregation of the PA to form hydrogels. The PA produced efficient self-assemblies in water, forming a nanofibrous network that further formed a self-supportive hydrogel. The molecule followed a three-step self-assembly mechanism. At a lower concentration (50 MUM), it forms extremely small aggregates with a very low population of the molecules. With an increase in concentration, spherical aggregates are formed above 450 MUM concentration. Importantly, this water-soluble conjugate was found to be nontoxic, cell permeable, and usable for cell imaging. Moreover, the aggregation process and consequently the emission behavior are highly responsive to the pH of the medium. Thus, the pH responsive aggregation and emission behavior has an extended biological application for assessing intracellular pH. The biocompatibility and intracellular pH determining capability suggest it is a promising candidate for use as a supramolecular material in biomedical applications. PMID- 28879764 TI - Palladium-Catalyzed Aerobic Oxygenation of Allylarenes. AB - An efficient and practical protocol for the synthesis of (E)-allylethers from readily available olefins with alcohols or phenols was developed. This aerobic oxidative allylic C-H oxygenation protocol features mild conditions, broad substrate scope, and high atom and step economy, making it a valuable and convenient synthetic method. Notably, molecular oxygen is the sole oxidant in this novel transformation. PMID- 28879765 TI - Transfer of Materials from Water to Solid Surfaces Using Liquid Marbles. AB - Remotely controlling the movement of small objects is desirable, especially for the transportation and selection of materials. Transfer of objects between liquid and solid surfaces and triggering their release would allow for development of novel material transportation technology. Here, we describe the remote transport of a material from a water film surface to a solid surface using quasispherical liquid marbles (LMs). A light-induced Marangoni flow or an air stream is used to propel the LMs on water. As the LMs approach the rim of the water film, gravity forces them to slide down the water rim and roll onto the solid surface. Through this method, LMs can be efficiently moved on water and placed on a solid surface. The materials encapsulated within LMs can be released at a specific time by an external stimulus. We analyzed the velocity, acceleration, and force of the LMs on the liquid and solid surfaces. On water, the sliding friction due to the drag force resists the movement of the LMs. On a solid surface, the rolling distance is affected by the surface roughness of the LMs. PMID- 28879766 TI - Label-Free Transient Absorption Microscopy for Red Blood Cell Flow Velocity Measurement in Vivo. AB - Red blood cells have intrinsic transient absorption property at the near-infrared region, allowing for label-free detection and imaging. We present a new approach to measure the blood flow velocity in vivo with a transient absorption microscope and correlation analyses of signal sequences. With specific scan modes, we have quantitatively obtained the flow velocity in capillaries, arteries, and veins in a live zebrafish with accuracy of about 30 MUm/s. In addition, a high-resolution three-dimensional vessel network can be reconstructed through this approach with spatial resolution of 1 MUm. PMID- 28879768 TI - Supramolecular Copolymerization of Short Peptides and Polyoxometalates: toward the Fabrication of Underwater Adhesives. AB - Peptide assembly has reached exquisite levels of efficiency in the creation of bioactive materials. However, we have not yet been able to take what we have learned from peptide assembly to develop a general strategy for the fabrication of biomimetic underwater adhesives, which retain significant advantages as medical glue for clinical treatment. Herein we report a simple approach to prepare peptide-based adhesives through the supramolecular polymerization of cationic peptides drove by polyoxometalates (PMs). Mass spectra, Fourier transform infrared spectra and 183W NMR spectra confirmed the structural integrity of peptides and PMs during the coassembly process. Scanning electron microscopy demonstrated that the multivalent interactions between peptides and polyoxometaltes led to the formation of robust 3D network structures. The rheological study revealed that the peptide/PM assemblies exhibited mechanically rigid gel-like behavior and self-healing property. Interestingly, the assemblies showed the capacity to adhere various wet solid materials under waterline. The shear strength of the peptide-based adhesives are stronger than that of the commercially available fibrin glue. This finding is exciting and serves to expand our capability of the fabrication of peptide-based materials. PMID- 28879767 TI - Transmembrane Pore Structures of beta-Hairpin Antimicrobial Peptides by All-Atom Simulations. AB - Protegrin-1 is an 18-residue beta-hairpin antimicrobial peptide (AMP) that has been suggested to form transmembrane beta-barrels in biological membranes. However, alternative structures have also been proposed. Here, we performed multimicrosecond, all-atom molecular dynamics simulations of various protegrin-1 oligomers on the membrane surface and in transmembrane topologies. The membrane surface simulations indicated that protegrin dimers are stable, whereas trimers and tetramers break down. Tetrameric arcs remained stably inserted in lipid membranes, but the pore water was displaced by lipid molecules. Unsheared protegrin beta-barrels opened into beta-sheets that surrounded stable aqueous pores, whereas tilted barrels with sheared hydrogen bonding patterns were stable in most topologies. A third type of observed pore consisted of multiple small oligomers surrounding a small, partially lipidic pore. We also considered the beta-hairpin AMP tachyplesin, which showed less tendency to oligomerize than protegrin: the octameric bundle resulted in small pores surrounded by six peptides as monomers and dimers, with some peptides returning to the membrane surface. The results imply that multiple configurations of protegrin oligomers may produce aqueous pores and illustrate the relationship between topology and putative steps in protegrin-1's pore formation. However, the long-term stability of these structures needs to be assessed further. PMID- 28879769 TI - Asymmetric Hydrogenation of Isoquinolines and Pyridines Using Hydrogen Halide Generated in Situ as Activator. AB - By employing halogenide trichloroisocyanuric acid as a traceless activation reagent, a general iridium-catalyzed asymmetric hydrogenation of isoquinolines and pyridines is developed with up to 99% ee. This method avoids tedious steps of installation and removal of the activating groups. The mechanism studies indicated that hydrogen halide generated in situ acted as an activator of isoquinolines and pyridines. PMID- 28879770 TI - In Situ Synthesis of Monomer Casting Nylon-6/Graphene-Polysiloxane Nanocomposites: Intercalation Structure, Synergistic Reinforcing, and Friction Reducing Effect. AB - On the basis of the industrialized graphene nanosheets (GNs) product, we synthesized monomer casting nylon-6 (MC PA6)/GN-3-aminopropyl-terminated poly(dimethylsiloxane) (APDMS) nanocomposite in situ through the anchoring effect of APDMS onto the GN surface. APDMS/PA6 molecules were confirmed to intercalate into the GN layers by the formation of strong interfacial interactions. The intercalation ratio and the average layer thickness of the grafted GN sample decreased in the presence of APDMS. Moreover, for MC PA6/GN-APDMS nanocomposite, GN-APDMS was uniformly distributed in the matrix and no phase separation was observed. The size of spherical APDMS particles was obviously reduced compared with that of MC PA6/APDMS composite, revealing a strong interaction between APDMS and GN and the enhancement of compatibility in the composite system. Compared with neat MC PA6, the addition of GN-APDMS resulted in 12% increase in the tensile strength and 37% increase in the impact strength; meanwhile, increase in both the storage modulus (E') and the glass transition temperature (Tg) indicated synergistic reinforcing and toughening effect of GN-APDMS on MC PA6. Furthermore, over 81 and 48% reduction in the friction coefficient and the specific wear rate, respectively, was achieved for the nanocomposite, and the worn surface displayed flat and smooth features with a uniform depth distribution, a low annealing effect, and a reduced friction heat, further confirming the synergistic friction reducing effect of GN-APDMS on MC PA6. PMID- 28879771 TI - Nanopore-Based Electrochemiluminescence for Detection of MicroRNAs via Duplex Specific Nuclease-Assisted Target Recycling. AB - In this study, we proposed a nanopore-based electrochemiluminescence (ECL) sensor combined with duplex-specific nuclease (DSN)-assisted target recycling amplification to detect microRNAs. Because of the synergetic effect of electrostatic repulsion and volume exclusion of gold nanoparticle-labeled DNA capture (DNA-Au NPs) to the negatively charged luminol anion probe, the DNA-Au NP modified anodized aluminum oxide (AAO) nanopore electrode exhibited high ECL decline in comparison with the bare AAO electrode. Upon the introduction of DSN and target microRNA, the specific DNA-RNA binding and enzyme cleaving could trigger the detachment of capture DNA from the membrane surface, resulting in uncapping of AAO and an increased ECL signal. For comparison, positively charged Ru(bpy)32+ was used as the ECL probe instead of luminol. Because the electrostatic attraction effect between DNA and Ru(bpy)32+ is partially offset by the volume exclusion effect of Au NPs, the AAO electrode modified with only DNA capture is more suitable for the Ru(bpy)32+ case. In our experiment, the case of negatively charged luminol combined with the synergetic effect of electrostatic repulsion and volume exclusion of DNA-Au NPs provides a quantitative readout proportional to the target microRNA concentration in the range of 1.0 fM to 1.0 nM, with a lower detection limit of 1 fM. PMID- 28879772 TI - Brain Membrane Proteome and Phosphoproteome Reveal Molecular Basis Associating with Nursing and Foraging Behaviors of Honeybee Workers. AB - The brain is a vital organ in regulating complex social behaviors of honeybees including learning and memory. Knowledge of how brain membrane proteins and their phosphorylation underlie the age-related behavioral polyethism is still lacking. A hitherto age-resolved brain membrane proteome and phosphoproteome were reported in adult worker bees from two strains of honeybee (Apis mellifera ligustica): Italian bee (ITB) and Royal Jelly bee (RJB), a line selected from ITB for increased RJ outputs over four decades. There were 1079 membrane protein groups identified, and 417 unique phosphosites were located in 179 membrane protein groups mainly phosphorylated by kinase families of MAPKs, CDKs, and CK2. Age resolved dynamics of brain membrane proteome and phosphoproteome are indicative of their correlation with the neurobiological requirements during the adult life of honeybee workers. To stimulate immature brain cell development in newly emerged bees (NEBs), the enriched functional classes associated with metabolism of carbohydrates, nucleosides, and lipids by the up-regulated proteins suggest their enhanced role in driving cell maturity of the brain. In nurse bees (NBs) and forager bees (FBs), a higher number of membrane proteins and phosphoproteins were expressed as compared with in the young stages, and the enriched signal transduction-related pathways by the up-regulated proteins suggest their significances in sustaining the intensive information processing during nursing and foraging activities. Notably, RJB has shaped unique membrane proteome and phosphoproteome settings to consolidate nursing and foraging behaviors in response to decades of selection underpinning the elevated RJ yields. In RJB NBs, the enriched pathways of phosphatidylinositol signaling and arachidonic acid metabolism indicate a stronger olfaction sensation in response to larval pheromone stimulation. In RJB FBs, the enriched pathways related to signal processing such as SNARE interactions in vesicular transport, wnt signaling, TGF beta signaling, and taurine and hypotaurine metabolism suggest an enhanced nerve sensitivity to prime the stronger tendency to pollen collection. Our data gain a novel insight into membrane proteome and phosphoproteome-driven cerebral regulation of honeybee behaviors, which is potentially useful for further neurobiological investigation in both honeybees and other social insects. PMID- 28879773 TI - Association of admission and discharge anemia status with outcomes in patients hospitalized for acute decompensated heart failure: Differences between patients with preserved and reduced ejection fraction. AB - BACKGROUND: In acute decompensated heart failure patients with a preserved or reduced ejection fraction, the association of admission and discharge anemia status with outcomes remains unclear. METHODS AND RESULTS: Of the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4433 patients (2017 with a preserved and 2416 with a reduced ejection fraction) were examined to investigate associations among the anemia status at admission and discharge (no anemia, developed anemia, resolved anemia, or persistent anemia), a preserved or reduced ejection fraction and the primary endpoint (all cause death and readmission for heart failure). In the preserved ejection fraction group, adjusted analysis showed that either developed or persistent anemia was associated with a significantly higher risk of the primary endpoint relative to no anemia (hazard ratio: 1.53; 95% confidence interval (CI): 1.11 2.11; p=0.009 and hazard ratio: 1.60; 95% CI: 1.26-2.04; p<0.001, respectively), but there was no association between resolved anemia and the primary endpoint (hazard ratio: 0.98; 95% CI: 0.67-1.45; p=0.937). In the reduced ejection fraction group, either developed or resolved anemia was associated with a tendency toward higher risk of the primary endpoint relative to no anemia (hazard ratio: 1.29; 95% CI: 0.95-1.62; p=0.089, and hazard ratio: 1.31; 95% CI: 0.96 1.77; p=0.085, respectively), while persistent anemia was associated with a significantly higher risk of the primary endpoint relative to no anemia (hazard ratio: 1.36; 95% CI: 1.12-1.65; p=0.002). CONCLUSIONS: In acute decompensated heart failure patients, the association of admission and discharge anemia status with outcomes differs markedly between patients with a preserved or reduced ejection fraction. PMID- 28879775 TI - Direct, indirect and total bilirubin and risk of incident coronary heart disease in the Dongfeng-Tongji cohort. AB - BACKGROUND: Total bilirubin (TBIL) is known to be inversely associated with coronary heart disease (CHD) risk, however, whether this association is dose response remains inconsistent and it is unclear which subtype of bilirubin is responsible for the potential protective effect. METHODS: We included 12,097 participants who were free of CHD, stroke, cancer and potential liver, biliary and renal diseases at baseline from September 2008 to June 2010 and were followed up until October 2013. Cox proportional hazards models were used to assess the hazard ratios (HR) and 95% confidence interval (95% CI) of bilirubin with incident CHD risk. RESULTS: The adjusted HRs for incident CHD increased with increasing direct bilirubin (DBIL) (p for trend = .013). Participants within the highest quintile of DBIL had 30% higher risk of incident CHD compared to those in the lowest quintile (95% CI: 1.07, 1.58). In contrast, compared with subjects in the lowest quintile of TBIL, those in the third quintile had the lowest of 24% risk for CHD incidence (95% CI: 0.63, 0.92), which showed a U-shaped association (p for quadratic trend = .040). CONCLUSIONS: DBIL was associated with a dose response increased risk for CHD incidence. However, a U-shaped association existed between TBIL, indirect bilirubin and incident CHD risk. Key messages Direct bilirubin is independently associated with incident coronary heart disease (CHD) in a dose-response manner. A similarly consistent U-shaped association was found between total bilirubin, indirect bilirubin and incident CHD. The potential protective effect of total bilirubin within the normal range on incident CHD should be mainly attributed to mild-to moderate elevated levels of indirect bilirubin. PMID- 28879776 TI - Themes Associated With Top-Grossing Films Released From 2005 to 2015. AB - Films continue to be a popular form of entertainment among children. The objective of this study was to determine the most common themes found in the top grossing films released from 2005 to 2015. Forty-five films were independently viewed and analyzed by 5 reviewers. The most common positive themes were "importance of helping others," "working as a team," and "standing up for what you believe in" (5.71, 4.08, and 3.78 mean events per hour, respectively). The most common negative themes were "use of guns/knives/lethal weapons," "acts of violence/fighting," and "demonstrating excessive anger" (5.78, 5.64, and 3.09 mean events per hour, respectively). In conclusion, the most common positive themes in our sample were associated with service, collaboration, and courage, and the most common negative themes were associated with violence. We encourage co-viewing and active mediation, focusing on the positive and negative themes found in film, as a method to guide children through their development process. PMID- 28879777 TI - Morphological transition of Helicobacter pylori adapted to water. AB - AIM: This study aims to investigate the morphological transition of Helicobacter pylori during adaptation to water. MATERIALS & METHODS: Different strains were adapted to water. Changes regarding cultivability and cellular morphology were recorded. Expression of 11 genes involved in H. pylori morphological changes was evaluated by real-time PCR. RESULTS: H. pylori presented increased cultivability in water after adaptation. The permanent loss of the spiral shape was observed, but no transition into coccoid form has occurred. Expression levels of genes involved in peptidoglycan assembly of H. pylori 26695 have shown significant changes between adapted and nonadapted strains. CONCLUSION: Adaption to water favors the culturable phenotype and the morphological transition to the rod shape, into a process that implicates the peptidoglycan turnover. PMID- 28879778 TI - Percutaneous extracorporeal membrane oxygenation in electrical storm: five case reports addressing efficacy, transferring allowance or radiofrequency ablation support. AB - Extracorporeal membrane oxygenation systems have undergone rapid technological improvements and are now feasible options for medium-term support of severe cardiac or pulmonary failure. We report five cases of electrical storm that was rescued by the insertion of peripheral veno-arterial extracorporeal membrane oxygenation systems. This device could help to restore systemic circulation as well as permitting organ perfusion in patients with cardiogenic shock in relation to electrical storm thus achieving greater electrical stability. Also, in some cases extracorporeal membrane oxygenation support could facilitate electrophysiology study. PMID- 28879779 TI - Supervising trainees in research: what does it take to be a scholarly project supervisor? AB - OBJECTIVES: Scholarly projects (SPs) are a compulsory component of psychiatry training in Australasia. This article outlines the role of a research supervisor in supporting a trainee to complete an SP. METHODS: A total of 10 old age and forensic psychiatry SPs were reviewed with regard to aims, methodology, supervisor input, trainee tasks and additional resources. RESULTS: The main supervisor tasks are described and discussed. They include practical advice on study design, ethics applications, critical appraisal, data analysis, academic writing and publication. CONCLUSIONS: Supervising SPs can bring significant rewards in awakening a trainee's interest in research. Key competencies for research supervision are discussed and further recommendations for supervisor support and training are provided. PMID- 28879780 TI - Management of patients with inflammatory bowel disease and spondyloarthritis. AB - INTRODUCTION: More than half of the patients with inflammatory bowel disease (IBD) experience at least one extra-intestinal manifestation (EIM). The most common EIM in patients with IBD is spondyloarthritis (SpA). Microscopic intestinal inflammation is documented in almost 50% of the patients with SpA. Areas covered: We give an overview of the classification, the epidemiology and the diagnosis of IBD and SpA. The treatment goals, the pharmacologic management options and the available treatment guidelines in IBD patients with SpA are discussed. Expert commentary: The coexistence of IBD and SpA generates challenges and opportunities for both the gastroenterologist and the rheumatologist. The potential of drugs with a gut-specific mode of action in the treatment of IBD related arthritis warrants further exploration. PMID- 28879781 TI - An investigation of the use of the Kinect system as a measure of dynamic balance and forward reach in the elderly. AB - OBJECTIVE: To investigate the reliability and correlations of Kinect-derived valuables of forward reach distance and velocity with the traditional functional reach distance, scores on posturography, and other measures of physical fitness. DESIGN: Observational study. SETTING: Community hospital. SUBJECTS: Individuals >65 years who attended a geriatric health examination were enrolled. MAIN MEASURES: The Kinect system was used to record the reach distance and velocity of the forward reach test. Center of pressure displacement was measured by posturography. Physical fitness performance was assessed using the 2-Minute Step Test, the 30-Second Chair Stand Test, the Sit-and-Reach Test, grip strength, and walking speed. RESULTS: A total of 442 individuals were enrolled (mean age: 73.3 +/- 5.2 years). Forward reach tracking using the Kinect system showed good repeatability and correlated with traditional functional reach ( r = 0.719, P < 0.001); the reaching velocity correlated with scores on posturography ( r = 0.257, P = 0.047). Reach distances were significantly decreased in the older group (>=75 years) than in the younger group (<75 years) ( P < 0.001). CONCLUSION: The Kinect system provides a simple, reliable, and age-sensitive assessment of balance in older adults. The valuables correlate with the traditional functional reach, scores on posturography, and physical fitness performance. It provides alternative representation of both static and dynamic balance function. PMID- 28879783 TI - A 5-Step Approach Protocol Using CareLink Therapy Software in Type 1 Diabetes Patients. PMID- 28879782 TI - Characteristics and trends of clinical trials funded by the National Institutes of Health between 2005 and 2015. AB - Background The National Institutes of Health is one of the largest biomedical research agencies in the world. Clinical trials are an important component of National Institutes of Health research efforts. Given the recent updates in National Institutes of Health trial reporting requirements, more information regarding the current state of National Institutes of Health-funded clinical trials is warranted. The objective of this analysis was to describe characteristics and trends of clinical trials funded by the National Institutes of Health over time and by Institutes and Centers of the National Institutes of Health. Methods Interventional studies funded by the National Institutes of Health and registered in ClinicalTrials.gov between 2005 and 2015 were included in the analysis. Trials were identified from the 27 March 2016 Clinical Trials Transformation Initiative Aggregate Analysis of ClinicalTrials.gov database. A descriptive analysis of trials by year and National Institutes of Health Institute/Center was performed. Results There were 12,987 National Institutes of Health-funded clinical trials registered between 2005 and 2015. There were 1,580, 1,116, and 930 trials registered in 2005, 2010, and 2015, respectively. The majority were early-development trials (phases 0, 1, or 2; 53%), randomized (61%), and single-center (63%). Trial demographics have remained unchanged over time. Median trial sample size was 64 (interquartile range 29-192) with 10% of trials enrolling >=500 participants. Most trials were completed within 5 years of enrollment start (69%). Trial characteristics varied considerably across National Institutes of Health Institutes and Centers. Results were reported under the assumptions that most National Institutes of Health-funded trials are registered in ClinicalTrials.gov and that trials are being registered completely and accurately. Conclusion In conclusion, there has been a decline in the number of trials being funded over time, explained in part by a relatively constant budget, increases in trial costs, or other factors that cannot be quantified. National Institutes of Health-funded trials are relatively small and tend to be single centered. There are substantial differences in the number and types of trials done by Institutes and Centers within the National Institutes of Health. PMID- 28879784 TI - Non-chemotherapy drug-induced neutropenia - an update. AB - INTRODUCTION: To date, non-chemotherapy drug-induced severe neutropenia (neutrophil count of <=0.5 x 109/L) also called idiosyncratic drug-induced agranulocytosis is little discussed in the literature. In the present paper, we report and discuss the clinical data and management of this rare disorder. Areas covered: To do this, we carried out a review of the literature using PubMed database of the US National Library of Medicine. We also used data from the American Society of Hematology educational books, textbooks of Hematology and Internal medicine, and information gleaned from international meetings. Expert opinion: Idiosyncratic agranulocytosis remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients. In this context, several prognostic factors have been identified that may be helpful when identifying 'susceptible' patients. Old age (>65 years), septicemia or shock, renal failure, and a neutrophil count <=0.1 * 109/L have been consensually accepted as poor prognostic factors. In our experience, modern management with pre-established procedures, intravenous broad spectrum antibiotics and hematopoietic growth factors (particularly G-CSF) is likely to improve the prognosis. Thus with appropriate management, the mortality rate is currently between 5 to 10%. PMID- 28879785 TI - Contribution of VMA5 to vacuolar function, stress response, ion homeostasis and autophagy in Candida albicans. AB - AIM: V-ATPase is a conservative multi-subunit enzyme in eukaryotes and modulates several cellular responses. This study aimed to illustrate the roles of Vma5 in vacuolar function, oxidative stress response, calcium homeostasis, autophagy and virulence. MATERIALS & METHODS: The vma5Delta/Delta mutant was obtained using PCR mediated homologous recombination. The functions of Vma5 were investigated by a series of biochemical and systemic infection methods. RESULTS: Disruption of VMA5 led to growth inhibition, vacuolar dysfunction, disturbance of calcium homeostasis and inhibition of calcium-related oxidative stress response. Furthermore, its deletion caused defects in autophagy completion and hyphal development, and resulted in attenuated Candida albicans virulence. CONCLUSION: Our findings provide new insights into V-ATPase functions in C. albicans, and reveal a potential candidate for development of antifungal drugs. PMID- 28879786 TI - Pharmacological management of type 2 diabetes: what's new in 2017? AB - INTRODUCTION: Novelties in the management of type 2 diabetes are dominated by the commercialisation of new glucose-lowering agents, which offer alternatives to older antidiabetic medications, and by the publication of several prospective placebo-controlled outcome trials, which demonstrated not only cardiovascular safety but also cardiovascular and renal protection with some new medications. Areas covered: Updates regarding the use of glucose-lowering agents are discussed from a clinical point of view. Some new viewpoints concern older antidiabetic agents such as metformin, sulfonylureas and glitazones whose benefit-risk balance has been revisited, especially in high risk patients. The recent data regarding DPP-4 inhibitors (gliptins) focused on the safety profile of this pharmacological class, including in patients with impaired renal function. The highlight concerns the cardiovascular (and renal) protection by some GLP-1 receptor agonists (liraglutide, semaglutide) and SGLT2 inhibitors (empagliflozin, canagliflozin) in patients with high cardiovascular risk. Finally, efficacy and safety of new combinations and advances in insulin therapy will be briefly discussed. Expert commentary: The recent data from randomized controlled trials, meta-analyses and observational real-life studies should trigger a revision of the algorithm for the treatment of hyperglycemia in type 2 diabetes, especially in patients with high cardiovascular and/or renal risk. PMID- 28879787 TI - Moving forward with treatment options for HIV-infected children. AB - INTRODUCTION: Current international guidelines recommend to treat all HIV-1 infected patients regardless of CD4 cell count. Despite the remarkable worldwide progress for universal access to antiretroviral during the last decade, the pediatric population remains fragile due to lack of randomized studies, inappropriate antiretroviral formulations, adherence difficulties, drug toxicity and development of resistance. Areas covered: This review summarizes the latest recommendations and advances for the treatment of HIV-infected children and highlights the potential complications of a lifelong antiretroviral treatment initiated early in life. Expert opinion: International guidelines recommend to start combination antiretroviral therapy (cART) as fast as possible in all children diagnosed with HIV-1. The principal goal is to improve survival and reduce mortality as well as rapidly decrease HIV reservoirs. This remains a challenge in resource-limited settings were diagnostic tools and treatment access may be limited. Different new strategies are in the pipeline such as immunotherapy in combination with very early cART initiation to seek remission or functional cure. For the time being and awaiting for long term remission or cure, there is a need for further pharmacokinetics studies, more pediatric formulations with improved palatability and implementation of randomized trials for the newer antiretroviral drugs. PMID- 28879788 TI - Development of an epitope-based HIV-1 vaccine strategy from HIV-1 lipopeptide to dendritic-based vaccines. AB - INTRODUCTION: Development of a safe, effective and globally affordable Human Immunodeficiency Virus strain 1 (HIV-1) vaccine offers the best hope for future control of the HIV-1 pandemic. However, with the exception of the recent RV144 trial, which elicited a modest level of protection against infection, no vaccine candidate has shown efficacy in preventing HIV-1 infection or in controlling virus replication in humans. There is also a great need for a successful immunotherapeutic vaccine since combination antiretroviral therapy (cART) does not eliminate the reservoir of HIV-infected cells. But to date, no vaccine candidate has proven to significantly alter the natural history of an individual with HIV-1 infection. Areas covered: For over 25 years, the ANRS (France Recherche Nord&Sud Sida-HIV hepatites) has been committed to an original program combining basic science and clinical research developing an epitope-based vaccine strategy to induce a multiepitopic cellular response against HIV-1. This review describes the evolution of concepts, based on strategies using HIV-1 lipopeptides towards the use of dendritic cell (DC) manipulation. Expert commentary: Understanding the crucial role of DCs in immune responses allowed moving from the non-specific administration of HIV-1 sequences with lipopeptides to DC-based vaccines. These DC-targeting strategies should improve HIV-1 vaccine efficacy. PMID- 28879789 TI - A review article on brodalumab in the treatment of moderate-to-severe plaque psoriasis. AB - Psoriasis is a chronic immune-mediated skin disorder affecting approximately 2-3% of the worldwide population. Recent advances in our understanding of the immunopathogenesis of psoriasis have resulted in novel therapeutic agents. IL-17, a pro-inflammatory cytokine, plays a pivotal role in psoriasis. Therapeutic agents targeting this cytokine have shown clinical effectiveness in the treatment of moderate-to-severe plaque psoriasis. Brodalumab, a human antibody against IL 17 receptor A, has been approved by the US FDA in February 2017, by the Japanese Pharmaceuticals and Medical Devices Agency in July 2016 and by the EMA in July 2017 for the treatment of moderate-to-severe psoriasis. This article reviews the published data relating to brodalumab for the treatment of moderate-to-severe plaque psoriasis. PMID- 28879790 TI - Validity of test stimuli for nasalance measurement in speakers of Jordanian Arabic. AB - OBJECTIVE: The objective of the study was to establish the validity of passages for measuring nasalance of Jordanian speakers of Arabic. DESIGN: Two Arabic text passages were constructed; the Spring Passage is devoid of nasal consonants and the Home Passage contains both oral and nasal consonants. Nasalance was measured for participants while reciting each passage three times. Perceptual ratings of hypernasality were also obtained for each participant on each passage using a 5 point equal-appearing rating scale. PARTICIPANTS: Forty-seven children and adults ranging in age between 9 and 26 years participated in the study. Twenty-three participants had no history of communication disorders, and 24 had repaired cleft palate. RESULTS: Correlation coefficient between ratings of hypernasality and the nasalance scores was significant for the Spring Passage (r = 0.88, p > 0.001) and for the Home Passage (r = 0.78, p > .001). Using cutoff scores of 17% and 36% of nasalance for the Spring and the Home Passages, respectively, and a threshold score of 1.5 for hypernasality, sensitivity for the Spring Passage was 88% and the Home Passage was 78%. CONCLUSIONS: Results showed the validity of the Spring Passage and the Home Passage in measuring nasalance scores as proved by their high sensitivity and strong correlation with perceptual rating of hypernasality. PMID- 28879791 TI - Incorporation of PCSK9 inhibitors into prevention of atherosclerotic cardiovascular disease. AB - Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) has become recently more complex than ever, leaving the clinicians perplexed with outdated guidelines and emerging evidence about new LDL-C lowering therapies. 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines have focused on high intensity statin therapy for specific groups of patients, while abandoning long established LDL-C goals, a strategy which no longer seems valid. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors have emerged as the add-on therapy on top of statins and/or ezetimibe for the treatment of hypercholesterolemia and ASCVD prevention. In several clinical trials, PCSK9 inhibitors have demonstrated their safety and robust LDL-C-lowering power. One completed cardiovascular (CV) outcomes trial (FOURIER; Further Cardiovascular Outcomes Research with PCSK9 Inhibitions in Subjects with Elevated Risk) has demonstrated that PCSK9 inhibition reduces rates of CV death as well as non-fatal stroke and MI, while another major CV outcome trial is under way (ODYSSEY-OUTCOMES). Several trials studying CV benefits of novel LDL-C-lowering therapies are also being conducted. Prompt revision of ACC/AHA guidelines is necessary. In the meantime, physicians need to use clinical judgment integrating the most recent evidence into their practice. PMID- 28879795 TI - The Literature of EOH II. The Scientific Research Paper. PMID- 28879792 TI - Analysis of acute naproxen administration on memory in young adults: A randomized, double-blind, placebo-controlled study. AB - Nonsteroidal anti-inflammatory drugs work by non-selectively inhibiting cyclooxygenase enzymes. Evidence indicates that metabolites of the cyclooxygenase pathway play a critical role in the process of learning and memory. We evaluated whether acute naproxen treatment impairs short-term working memory, episodic memory, or semantic memory in a young, healthy adult population. Participants received a single dose of placebo or naproxen (750 mg) in random order separated by 7-10 days. Two hours following administration, participants completed five memory tasks. The administration of acute high-dose naproxen had no effect on memory in healthy young adults. PMID- 28879796 TI - Assessment of the pulmonary CYP1A1 metabolism of mavoglurant (AFQ056) in rat. AB - 1. AFQ056 phenotyping results indicate that CYP1A1 is responsible for the formation of the oxidative metabolite, M3. In line with the predominant assumption that CYP1A1 is mainly expressed in extrahepatic tissues, only traces of M3 were detected in hepatic systems. The aim of this study was to investigate the pulmonary CYP1A1 mediated metabolism of AFQ056 in rat. 2. Western blot analysis confirmed that CYP1A1 is expressed in rat lung albeit at low levels. M3 formation was clearly observed in recombinant rat CYP1A1, lung microsomes and lung tissue slices and was strongly inhibited by ketoconazole in the incubations. As CYP3A4 and CYP2C9 metabolites were only observed at trace levels, we concluded that the reduced M3 formation was due to CYP1A1 inhibition. 3. AFQ056 lung clearance (CLlung) as estimated from in vitro data was predicted to be negligible (<1% pulmonary blood flow). This was confirmed by in vivo experiments where intravenous and intra-arterial dosing to rats failed to show significant pulmonary extraction. 4. While rat lung may make a contribution to the formation of M3, it is unlikely to be the only organ involved in this process and further experiments are required to investigate the potential metabolic elimination routes for AFQ056. PMID- 28879797 TI - Amorfrutin A inhibits TNF-alpha induced JAK/STAT signaling, cell survival and proliferation of human cancer cells. AB - CONTEXT: Amorfrutin A is a natural product isolated from the fruits of Amorpha fruticosa L. and has been shown to exhibit multiple bioeffector functions. In the present study, we investigated whether amorfrutin A exerts anticancer effects by inhibiting STAT3 activation in cervical cancer cells. OBJECTIVE: To investigate the effectiveness of amorfrutin A as a treatment of cancer, and determine the underlying pharmacological mechanism of action. MATERIALS AND METHODS: HeLa, SK Hep1, MDA-MB-231 and HCT116 cells were used in this study. Major assays were luciferase reporter assay, MTT, Western blot analysis, immunofluorescence assay, reverse transcription-PCR (RT-PCR), flow cytometric analysis, EdU labeling and immunofluorescence, xenografted assay. RESULTS: Amorfrutin A significantly inhibited tumor necrosis factor-alpha (TNF-alpha)-induced phosphorylation and nuclear translocation of STAT3 in human cervical carcinoma cells. Amorfrutin A also inhibited activation of the upstream kinases Janus-activated kinase 1 (JAK1), JAK2 and Src signaling pathways. Furthermore, amorfrutin A increased the expression of p53, p21, p27, induced cell cycle arrest in the G1 phase as well as decreased levels of various oncogene protein products. In vivo studies further confirmed the inhibitory effect of amorfrutin A on the expression of STAT3 proteins, leading to a decrease growth of HeLa cells in a xenograft tumor model. DISCUSSION AND CONCLUSIONS: The results indicated that amorfrutin A is a potent inhibitor of STAT3 and provide new perspectives into the mechanism of its anticancer activity. PMID- 28879799 TI - Review of Before Their Time: The World of Child Labor. PMID- 28879798 TI - Inhalation exposure of nano diamond induced oxidative stress in lung, heart and brain. AB - 1. Today, diamond nanoparticles have several industrial applications. Nano diamond (ND) as a carbon allotrope diffuses in the air easily during producing and processing procedures. 2. In this study, we investigated sub-acute exposed to ND at the exposure chamber in mice. The animals were divided into two groups (control and exposed group to ND at the concentration of 3 ug/m3 for 3 h/day, 5 days/week for 30 days) in a whole-body inhalation chamber. 3. Our results showed that exposure to ND induced the hematological and biochemical changes. The target organs for ND were the lungs, brain and heart in the mice, respectively. Also, ND increased reactive oxygen species (ROS) generation, lipid peroxidation (LPO), the collapse of mitochondrial membrane potential (MMP), decreased a level of reduced glutathione (GSH) and finally increased a level of glutathione disulfide (GSSG) in lung, brain and heart tissues. Our results suggest that exposure to ND can induce oxidative stress in the tissue mentioned. 4. These results suggest that exposure of researchers and workers with diamond nanoparticles probably increase a risk of respiratory, cardiovascular and cerebral disorders through oxidative stress. However, good ventilation, appropriate personal protective equipment and using of anti-oxidant compounds in daily diet of worker are suggested. PMID- 28879800 TI - Acute caffeine ingestion affects surround suppression of perceived contrast. AB - Caffeine is a widely used psychostimulant that is associated with increased acetylcholine levels in mammalian brain and acetycholinesterase antagonism. Acetylcholine, a neuromodulator, plays an important role in the processing of visual information. One key example in human vision, thought to at least partly involve cholinergic neuromodulation, is perceptual surround suppression of contrast, whereby the perceived contrast of a pattern is altered by the presence of a neighbouring pattern. Perceptual surround suppression is weaker with pharmacological administration of donepezil (a centrally-acting acetylcholine enzyme inhibitor) in healthy human observers. Here, we test whether temporarily manipulating caffeine levels (from complete washout to a controlled dose of caffeine) has a similar effect on perceptual surround suppression in 21 healthy young adults (aged 20-24 years, 11 females). Neither ingestion of a caffeine pill nor placebo altered contrast judgments when the target pattern was presented on a uniform grey background ( p=0.54). With caffeine ingestion, perceptual surround suppression strength was reduced relative to baseline (prior to pill ingestion, p=0.003) and placebo ( p=0.029), irrespective of whether the surround was oriented parallel or orthogonal to the central target. While daily habitual caffeine consumption of low-to-moderate doses (<400 mg/day, estimated from a written questionnaire) is not predictive of performance, our study indicates that acute consumption of caffeine on the day of testing influences perceptual surround suppression strength. Perceptual surround suppression is predominantly attributed to inhibitory processes involving the major cortical inhibitory neurotransmitter, gamma-aminobutyric acid. Our results point to the involvement of other neuromodulators, possibly cholinergic, in perceptual surround suppression. PMID- 28879801 TI - Systematic Review and Meta-analysis of Seizure Recurrence After a First Unprovoked Seizure in 815 Neurologically and Developmentally Normal Children. AB - Limited data exist for health care providers regarding seizure recurrence after a first unprovoked seizure in previously neurologically and developmentally normal children. A systematic review and meta-analysis was conducted to assess seizure recurrence after a first unprovoked seizure by performing an electronic search in PubMed, Embase, and Scopus. Six studies from 2817 met the inclusion criteria. The sample size consisted of 815 neurologically and developmentally normal children (1 month-17.5 years) on no antiepileptic drugs. This systematic review and meta analysis estimated a recurrence rate within 3 years of 45% (95% CI: 37%, 60%). This estimate provides a touchstone for health care providers who are managing this particular population of children. PMID- 28879803 TI - Practice patterns of retrievable inferior vena cava filters and predictors of filter retrieval in patients with pulmonary embolism. AB - Retrievable inferior vena cava (IVC) filters are increasingly used in patients with venous thromboembolism (VTE) who have contraindications to anticoagulant therapy. However, previous studies have shown that many retrievable filters are left permanently in patients. This study aimed to identify the common indications for IVC filter insertion, the filter retrieval rate, and the predictive factors for filter retrieval attempts. To this end, a retrospective cohort study was performed at a tertiary care center in South Korea between January 2010 and May 2016. Electronic medical charts were reviewed for patients with pulmonary embolism (PE) who underwent IVC filter insertion. A total of 439 cases were reviewed. The most common indication for filter insertion was a preoperative/procedural aim, followed by extensive iliofemoral deep vein thrombosis (DVT). Retrieval of the IVC filter was attempted in 44.9% of patients. The retrieval success rate was 93.9%. History of cerebral hemorrhage, malignancy, and admission to a nonsurgical department were the significant predictive factors of a lower retrieval attempt rate in multivariate analysis. With the increased use of IVC filters, more issues should be addressed before placing a filter and physicians should attempt to improve the filter retrieval rate. PMID- 28879802 TI - Anti-nociceptive interactions between opioids and a cannabinoid receptor 2 agonist in inflammatory pain. AB - The cannabinoid 1 receptor and cannabinoid 2 receptor can both be targeted in the treatment of pain; yet, they have some important differences. Cannabinoid 1 receptor is expressed at high levels in the central nervous system, whereas cannabinoid 2 receptor is found predominantly, although not exclusively, outside the central nervous system. The objective of this study was to investigate potential interactions between cannabinoid 2 receptor and the mu-opioid receptor in pathological pain. The low level of adverse side effects and lack of tolerance for cannabinoid 2 receptor agonists are attractive pharmacotherapeutic traits. This study assessed the anti-nociceptive effects of a selective cannabinoid 2 receptor agonist (JWH-133) in pathological pain using mice subjected to inflammatory pain using the formalin test. Furthermore, we examined several ways in which JWH-133 may interact with morphine. JWH-133 produces dose-dependent anti nociception during both the acute and inflammatory phases of the formalin test. This was observed in both male and female mice. However, a maximally efficacious dose of JWH-133 (1 mg/kg) was not associated with somatic withdrawal symptoms, motor impairment, or hypothermia. After eleven once-daily injections of 1 mg/JWH 133, no tolerance was observed in the formalin test. Cross-tolerance for the anti nociceptive effects of JWH-133 and morphine were assessed to gain insight into physiologically relevant cannabinoid 2 receptor and mu-opioid receptor interaction. Mice made tolerant to the effects of morphine exhibited a lower JWH 133 response in both phases of the formalin test compared to vehicle-treated morphine-naive animals. However, repeated daily JWH-133 administration did not cause cross-tolerance for morphine, suggesting opioid and cannabinoid 2 receptor cross-tolerance is unidirectional. However, preliminary data suggest co administration of JWH-133 with morphine modestly attenuates morphine tolerance. Isobolographic analysis revealed that co-administration of JWH-133 and morphine has an additive effect on anti-nociception in the formalin test. Overall these findings show that cannabinoid 2 receptor may functionally interact with mu opioid receptor to modulate anti-nociception in the formalin test. PMID- 28879804 TI - Evaluation of the endocrine-disrupting effects of homosalate (HMS) and 2 ethylhexyl 4-dimethylaminobenzoate (OD-PABA) in rat pups during the prenatal, lactation, and early postnatal periods. AB - Homosalate (HMS) and 2-ethylhexyl 4-dimethylaminobenzoate (OD-PABA) are ultraviolet filters. We aimed to investigate the effects of dermal exposure to HMS and OD-PABA during the prenatal, lactation, and early infancy periods on pubertal development and thyroid function in male and female rats. The thyroid glands, uteri, testes, prostate glands, and seminal vesicles were excised and weighed, the reproductive organs were analyzed histologically, and the serum hormone levels were measured. In the prenatal period, the thyroxine (T4) levels increased in the female rats in the exposed groups ( p < 0.05); the thyroid weights, reproductive organ weights, and gonadal hormone levels were not altered. In males, the testosterone levels decreased ( p < 0.05), but the thyroid weights, T4 levels, prostate, and testis weights were not changed. In the lactation period, the weights of the thyroid glands increased in the exposed female groups ( p < 0.05), but the T4, gonadal hormone levels, and reproductive organ weights were not changed. In the males, the thyroid gland weights, T4 levels, reproductive organ weights, and gonadal hormone levels were not changed. During infancy, the thyroid gland weights increased in the female rats in the exposed groups ( p < 0.05), but the T4 levels, gonadal hormone levels, and reproductive organ weights were not affected. In the male rats in the exposed groups, the T4 levels were increased ( p < 0.05), but the thyroid and reproductive organ weights, gonadal hormone levels were not affected. Organ histopathology was not affected in all groups. HMS and OD-PABA do not have endocrine disruptor effects on thyroid function and the pubertal development of female and male rats. PMID- 28879805 TI - Venom peptides as therapeutics: advances, challenges and the future of venom peptide discovery. AB - INTRODUCTION: Animal venoms are complex chemical arsenals. Most venoms are rich in bioactive peptides with proven potential as research tools, drug leads and drugs. Areas covered: We review recent advances in venom-peptide discovery, particularly the adoption of combined transcriptomic/proteomic approaches for the exploration of venom composition. Expert commentary: Advances in transcriptomics and proteomics have dramatically altered the manner and rate of venom-peptide discovery. The increasing trend towards a toxin-driven approach, as opposed to traditional target-based screening of venoms, is likely to expedite the discovery of venom-peptides with novel structures and new and unanticipated mechanisms of action. At the same time, these advances will drive the development of higher throughput approaches for target identification. Taken together, these approaches should enhance our understanding of the natural ecological function of venom peptides and increase the rate of identification of novel venom-derived pharmacological tools, drug leads and drugs. PMID- 28879807 TI - The Literature of EOH. III. The Review Paper. PMID- 28879806 TI - Distinct sensitivity to caffeine-induced insomnia related to age. AB - Caffeine acts by antagonizing the effect of the endogenous homeostatic sleep factor adenosine. In the current study we aimed to evaluate the pattern of caffeine-induced insomnia and its relation to age and sex in a general population sample derived from a web survey. The sample included 75,534 participants (28.1% men) from 18 to 75 years who answered self-report questionnaires by accessing a website in Brazilian Portuguese (BRAINSTEP project). In our sample, 3620 (17.0%) men and 9920 (18.3%) women reported insomnia due to caffeine intake. Caffeine induced insomnia increased with aging in both men and women. This difference remained after adjusting for sociodemographic, psychiatric and sleep related variables as well as caffeine intake. Women showed higher proportion of caffeine induced insomnia than men, but this difference did not remain after controlling for covariates. Also, individuals with caffeine-induced insomnia reported poorer sleep quality, higher latency to fall asleep and a higher proportion of psychiatric diagnoses and daily use of hypnotic drugs. In conclusion, our results show an age-associated increase in caffeine-induced insomnia and poorer mental health indicators among people with caffeine-induced insomnia complaints. PMID- 28879809 TI - The Funny-Looking B. PMID- 28879811 TI - Introduction. PMID- 28879812 TI - Evidence-Based Practice and Social Work. AB - The essential features of contemporary evidence-based practice (EBP) are outlined, with specific reference to the applications of this model to various areas of social work, micro through macro. EBP is seen as a welcome addition to our field, representing a fuller and more comprehensive development of earlier and related positions such as empirical clinical practice within social work, and the delineation of empirically-supported therapies within psychology. Social work should proactively adopt EBP as its preferred conceptual model, reorient BSW and MSW training programs along the lines advocated by EBP, and inculcate these principles into the delivery of social work services. This is seen as both a professional and ethical imperative necessary for the survival of the field. PMID- 28879813 TI - Child and Adolescent Alcohol Use and Abuse. AB - Alcohol abuse adversely affects the social, psychological, and physical health of children and adolescents. Therefore, it is imperative that youth receive the most reliable and valid assessment and methodologically proven interventions understood by research to date. Empirically supported child and adolescent assessment and interventions are described. PMID- 28879814 TI - Adolescent Preventive Health and Teams-Games-Tournaments. AB - The problematic behaviors of teenagers and the subsequent negative consequences are extensive and well documented: unwanted pregnancy, substance abuse, violent behavior, depression, and social and psychological consequences of unemployment. In this article the authors review an approach that uses a cooperative learning, empirically-based intervention that employs peers as teachers. This intervention of choice is Teams-Games-Tournaments (TGT), a paradigm backed by four decades of empirical support. The application of TGT in preventive health programs incorporates elements in common with other prevention programs that are based on a public health orientation and comprise the essential components of health education, that is skills training and practice in applying skills. The Teams Games-Tournaments intervention supports the idea that children and adolescents from various socioeconomic classes, between the ages of 8 to 18, in classrooms or groups ranging in size from 4 to 17 members, can work together effectively in cooperative instructional situations where group members serve as teachers for one another. Teams-Games-Tournaments has been applied successfully in such diverse areas as adolescent development, sexuality education, psychoactive substance use, anger control, coping with depression and suicide, nutrition, comprehensive employment preparation, and family intervention. This article reviews the extensive research on TGT using examples of successful projects in substance abuse and nutrition. Issues are raised that relate to the implementation of preventive health strategies for adolescents, including cognitive aspects, social and family networks, and intervention components. PMID- 28879815 TI - Treating Anorexia Nervosa and Bulimia Nervosa. AB - Research on the treatment of eating disorders is a relatively new field, dating back approximately 20 years (Peterson & Mitchell, 1999). The purpose of this article is to describe the most widely used treatments for anorexia nervosa (AN) and bulimia nervosa (BN) and review the existing literature on the effectiveness of the identified treatments. Specifically, this article examines the effectiveness of cognitive-behavioral therapy, family therapy, interpersonal therapy, and pharmacotherapy in the treatment of AN and BN. Each of the reviewed treatment modalities has some level of effectiveness, either alone or in conjunction with another treatment approach, in treating either AN or BN. PMID- 28879816 TI - Revisiting Recent Research on Social Learning Theory as an Etiological Proposition for Sexually Abusive Male Adolescents. AB - This article examines social learning theory as a construct that is applicable to adolescent sexual abusers based upon recent published research. Bandura's (1986) work is used to outline the theory and then research on victimization, aggression, criminality, pornography and personality is reviewed to assess the theory as a reasonable fit for adolescent sexually abusive behavior. Research implications are offered that argue for rigorous research methods in the field to allow for further test of this theory. PMID- 28879818 TI - HIGH PREVALENCE OF VOLUNTARY STERILIZATION AMONG AMERICAN WOMEN EXPLAINED BY TRADE-OFFS RESULTING FROM MALE PARENTAL COMMITMENT. AB - SummaryTubal ligation is the modal form of family planning among American women aged 30 and older. As the preference for tubal ligation over cheaper, lower risk and more reliable methods, such as vasectomy, has puzzled experts, a theoretical approach that explains this preference would be useful. The present study investigates the high prevalence of voluntary sterilization among American women from the perspective of life history theory, arguing that the trade-offs between investing in current and future offspring will favour tubal ligation when women cannot obtain reliable male commitment to future parental investment. Data came from the National Survey of Fertility Barriers (NSFB), a nationally representative survey of 4712 American women aged 25-45 conducted between 2004 and 2007. Four novel predictions of the prevalence of tubal ligation, drawn from life history theory, were developed and tested: 1) it is most common among unpartnered women with children, and least common among married women with children; 2) it is negatively correlated with age at first birth; 3) it is least common among highly educated women without children, and most common among less educated women with children; and 4) among women with two or more children, it is positively correlated with lifetime number of long-term partners. These predictions were tested using multivariate regression analysis. The first prediction was not supported: women with children were more likely to be sterilized, regardless of their marital status. The other three predictions were all supported by the data. The results suggest that trade-offs influence women's decisions to undergo voluntary sterilization. Women are most likely to opt for tubal ligation when the costs of an additional child will impinge on their ability to invest in existing offspring, especially in the context of reduced male commitment. PMID- 28879817 TI - Editorial: Proteomic alterations by mutations involved in Parkinson's disease and related disorders. PMID- 28879819 TI - Clinical utility of MRI and SPECT in the diagnosis of cognitive impairment referred to memory clinic. AB - : ABSTRACTBackground:Despite of their limited availability and potential for significant variation between and within each modality, this is the first study to prospectively measure the clinical utility of MRI and/or SPECT brain scanning in addition to the routine diagnostic workup of patients presenting to memory clinic. METHODS: A single center study was conducted over a convenience of 12 month sampling period. For each patient referred for MRI and/or SPECT scanning, the primary geriatrician or psychogeriatrician was asked to assign an initial diagnosis. The initial diagnosis was then compared with the final consensus diagnosis after any scans or neuropsychology testing had been completed. RESULTS: During the 12-month study period, 66 patients (26%) were referred for scans out of a total of 253 patients included in the study. There were 16/44 (36%) positive MRI outcomes and 13/35 (37%) positive SPECT outcomes. The diagnosis changed consistent with the MRI scan findings in 11/44 (25%) and changed consistent with the SPECT scan findings in 9/35 (26%). Potentially reversible pathology was identified in a single patient, 1/50 (2%), via an MRI scan that suggested normal pressure hydrocephalus. The number needed to test for one positive outcome was 3.8 (95% CI 2.0-23.3), 6.0 (95% CI NA), and 1.7 (95% CI 1.3-2.5) for MRI only, SPECT only, and MRI and SPECT together, respectively. CONCLUSIONS: The clinical utility of MRI and/or SPECT scanning in this study may be broadly superior to the available international evidence, and further research is needed to identify predictors of positive scan outcomes. PMID- 28879820 TI - Effects of the Healthy Start randomized intervention on dietary intake among obesity-prone normal-weight children. AB - OBJECTIVE: The study aimed to evaluate the impact of a 15-month intervention on dietary intake conducted among obesity-prone normal-weight pre-school children. DESIGN: Information on dietary intake was obtained using a 4 d diet record. A diet quality index was adapted to assess how well children's diet complied with the Danish national guidelines. Linear regression per protocol and intention-to treat analyses of differences in intakes of energy, macronutrients, fruit, vegetables, fish, sugar-sweetened beverages and diet quality index between the two groups were conducted. SETTING: The Healthy Start study was conducted during 2009-2011, focusing on changing diet, physical activity, sleep and stress management to prevent excessive weight gain among Danish children. SUBJECTS: From a population of 635 Danish pre-school children, who had a high birth weight (>=4000 g), high maternal pre-pregnancy BMI (>=28.0 kg/m2) or low maternal educational level (<10 years of schooling), 285 children completed the intervention and had complete information on dietary intake. RESULTS: Children in the intervention group had a lower energy intake after the 15-month intervention (group means: 5.29 v. 5.59 MJ, P=0.02) compared with the control group. We observed lower intakes of carbohydrates and added sugar in the intervention group compared with the control group after the intervention (P=0.002, P=0.01). CONCLUSIONS: The intervention resulted in a lower energy intake, particularly from carbohydrates and added sugar after 15 months of intervention, suggesting that dietary intake can be changed in a healthier direction in children predisposed to obesity. PMID- 28879821 TI - Associations between perceived friends' support of healthy eating and meal skipping in adolescence. AB - OBJECTIVE: Meal skipping is a relatively common behaviour during adolescence. As peer influence increases during adolescence, friendship groups may play a role in determining eating patterns such as meal skipping. The current study examined cross-sectional and longitudinal associations between perceived friends' support of healthy eating and breakfast and lunch skipping among adolescents. DESIGN: Survey of intrapersonal, social and environmental factors that may influence eating patterns at baseline (2004/05) and follow-up (2006/07). SETTING: Thirty seven secondary schools in Victoria, Australia. SUBJECTS: Sample of 1785 students aged 12-15 years at baseline. RESULTS: Adolescents who reported that their friends sometimes or often ate healthy foods with them were less likely (adjusted OR; 95 % CI) to skip breakfast (sometimes: 0.71; 0.57, 0.90; often: 0.54; 0.38, 0.76) or lunch (sometimes: 0.61; 0.41, 0.89; often: 0.59; 0.37, 0.94) at baseline than those who reported their friends never or rarely displayed this behaviour. Although this variable was associated with lunch skipping at follow-up, there was no evidence of an association with breakfast skipping at follow-up. There was no evidence of an association between perceived encouragement of healthy eating, and an inconsistent relationship between perceived discouragement of junk food consumption, and meal skipping. CONCLUSIONS: Friends eating healthy foods together may serve to reduce meal skipping during early adolescence, possibly due to the influence of directly observable behaviour and shared beliefs held by those in the same friendship group. Verbal encouragement or discouragement from friends may be less impactful an influence on meal skipping (than directly observable behaviours) in adolescents. PMID- 28879822 TI - The impact of pathogen burden on leukocyte telomere length in the Multi-Ethnic Study of Atherosclerosis. AB - Several infections have been linked to telomere shortening and in some cases these associations have varied by sex. We assessed the association between seropositivity to four persistent pathogens (cytomegalovirus (CMV), herpes simplex virus-1, Helicobacter pylori, Chlamydia pneumoniae), and total pathogen burden on leukocyte telomere length in a diverse US sample. Data came from the Multi-Ethnic Study of Atherosclerosis, a population-based cohort study. We utilized cross-sectional survey data, and biological samples from participants tested for pathogens and telomere length (N = 163). Linear regression was used to examine the association between seropositivity for individual pathogens as well as total pathogen burden and telomere length, adjusting for various confounders. CMV seropositivity and increased total pathogen burden level were significantly associated with shorter telomere length among females (beta = -0.1204 (standard error (s.e.) 0.06), P = 0.044) and (beta = -0.1057 (s.e. = 0.05), P = 0.033), respectively. There was no statistically significant association among males. Our findings suggest that prevention or treatment of persistent pathogens, in particular CMV, may play an important role in reducing telomere shortening over the life course among women. Future research is needed to confirm these novel findings in larger longitudinal samples. PMID- 28879823 TI - First-time mothers' breast-feeding maintenance: role of experiences and changes in maternal perceptions. AB - OBJECTIVE: Breast-feeding initiation rates have increased in the USA; however, maintenance of breast-feeding for recommended durations is low. The objective of the present study was to identify factors that may facilitate breast-feeding for longer durations among first-time mothers, including physiological and social experiences and changes in maternal perceptions. DESIGN: Survival analysis and linear regression methods were used to explore the relationship between experiences and breast-feeding duration, and the possible mediating effect of changes in maternal perceptions. SETTING: Secondary data from the Infant Feeding Practices Study II, conducted in the USA between 2005 and 2007. SUBJECTS: Data from 762 first-time mothers who ever breast-fed were analysed. RESULTS: Experiencing trouble with baby's latch, problems with milk flow/supply and painful breast-feeding were significantly associated with breast-feeding duration (64, 26 and 36 % shorter duration, respectively). Meanwhile, positive changes in perception with respect to breast-feeding self-efficacy, opinion about infant feeding and belief about breast milk were associated with 16-27 % longer duration. Furthermore, changes in perception were observed to partially mediate the impact of physiological experiences on breast-feeding duration. CONCLUSIONS: Perceptions of breast-feeding self-efficacy, beliefs and opinions can change over time and are influenced by breast-feeding experiences. The combined effect of experience and perception plays a key role in influencing breast-feeding duration. Future research should explore interventions to maintain or improve these perceptions while accounting for physiological experiences to support breast-feeding for recommended durations among first-time mothers. PMID- 28879824 TI - Under-reporting giardiasis: time to consider the public health implications. AB - Giardiasis is a treatable disease, caused by the flagellated protozoan parasite, Giardia duodenalis (G. duodenalis). It is one of the most common enteric parasites found globally to cause gastrointestinal disturbances, and infections may result in long-term irritable bowel syndrome-like symptoms. It is a common misconception that giardiasis is associated with foreign travel, which results in locally acquired cases in the UK being underdiagnosed. This report highlights the findings from one large Scottish Health Board, arising from a change in testing methodology, which resulted in the screening of all stools submitted for enteric investigations for G. duodenalis. Previous selection criteria were restricted to patients with a travel history to specific regions of the world, or on the basis of certain clinical details. In this report, clinical details were recorded from samples shown to be positive using two methods: an ELISA-based antigen detection assay and microscopy. Clinical details were assessed for a total of 28 laboratory confirmed positive cases against the original selection criteria. Twenty-six cases (93%) would have been excluded from Giardia testing if the previous selection criteria had been applied. Although nine cases stated foreign travel, only two had been to regions deemed to be 'high risk'. Therefore, those seven cases that travelled to perceived 'low-risk' regions would have been excluded from testing for this reason. This summary highlights the need for significant improvements to the selection criteria for Giardia testing. Laboratories should be encouraged towards the testing of all routinely submitted stools for this neglected pathogen to ensure cases that are acquired locally are properly identified and treated effectively. PMID- 28879825 TI - Changes in consumption of food away from home and intakes of energy and other nutrients among US working-age adults, 2005-2014. AB - OBJECTIVE: To document changes in consumption of food away from home (FAFH) and intakes of selected nutrients by working-age adults between 2005-06 and 2013-14, covering the most recent recessionary period and recovery. DESIGN: Means were compared across survey rounds relative to 2005-06. Multivariate regression was used to account for changes in demographic characteristics over time. SETTING: National Health and Nutrition Examination Survey (NHANES), 2005-2014. SUBJECTS: Working-age adults born in 1951-80 (n 12 129) and adolescents and young adults born in 1981-90 (n 5197) who reported day 1 dietary intake data. RESULTS: Approximately 34 % of energy consumed by working-age adults came from FAFH (14 % from fast foods) in 2005-06. Levels of FAFH consumption were lowest in 2009-10, at 28 and 11 % of energy from FAFH and fast foods, respectively. Percentage of energy from fast foods was 1.9 percentage points higher in 2013-14. Percentage of energy from saturated fat and total mg of cholesterol consumed were lower in 2009 14, while intake of fibre was higher in 2011-14. At-home foods had less saturated fat and more fibre in 2009-14. The greater the percentage of energy from FAFH in the day, the greater the intakes of fat and cholesterol. Percentage of energy from FAFH was highest among those born in 1981-90 and lowest among those born in 1951-60. CONCLUSIONS: FAFH is a significant source of energy, fat and cholesterol among working-age adults. Menu labelling may lower FAFH's energy content and make it easier for consumers to choose more healthful items. PMID- 28879826 TI - Management of paediatric acute mastoiditis: systematic review. AB - BACKGROUND: Acute mastoiditis remains the commonest intratemporal complication of otitis media in the paediatric population. There has been a lack of consensus regarding the diagnosis and management of acute mastoiditis, resulting in considerable disparity in conservative and surgical management. OBJECTIVES: To review the current literature, proposing recommendations for the management of paediatric acute mastoiditis and appraising the treatment outcomes. METHOD: A systematic review was conducted using PubMed, Web of Science and Cochrane Library databases. RESULTS: Twenty-one studies were included, with a total of 564 patients. Cure rates of medical treatment, conservative surgery and mastoidectomy were 95.9 per cent, 96.3 per cent and 89.1 per cent, respectively. CONCLUSION: Mastoidectomy may be the most definitive treatment available; however, reviewed data suggest that conservative treatment alone has high efficacy as first-line treatment in uncomplicated cases of acute mastoiditis, and conservative therapy may be an appropriate first-line management when treating acute mastoiditis. PMID- 28879827 TI - The prevalence and factors associated with stunting among infants aged 6 months in a peri-urban South African community. AB - OBJECTIVE: To determine the prevalence and factors associated with stunting in 6 month-old South African infants. DESIGN: This cross-sectional study was part of the baseline of a randomized controlled trial. Weight-for-length, length-for-age and weight-for-age Z-scores were based on the WHO classification. Blood samples were analysed for Hb, plasma ferritin and soluble transferrin receptor (sTfR). Socio-economic, breast-feeding and complementary feeding practices were assessed by questionnaire. Setting/Subjects Infants aged 6 months (n 750) from a peri urban area of Matlosana Municipality, North West Province of South Africa. RESULTS: Stunting, underweight, wasting and overweight affected 28.5, 11.1, 1.7 and 10.1 % of infants, respectively. Exclusive breast-feeding to 6 months of age was reported in 5.9 % of the infants. Multivariable binary logistic regression showed that birth weight (OR=0.12; 95 % CI 0.07, 0.21, P8.3 mg/l) concentrations. CONCLUSIONS: The association between stunting and lower birth weight, shorter maternal height and male sex reflects possibly the intergenerational origins of stunting. Therefore, interventions that focus on improving preconceptual and maternal nutritional status, combined with strategies to promote appropriate infant feeding practices, may be an important strategy to prevent stunting in vulnerable settings. PMID- 28879828 TI - Potential of telepresence robots to enhance social connectedness in older adults with dementia: an integrative review of feasibility. AB - BACKGROUND: Socially assistive robots are increasingly used as a therapeutic tool for people with dementia, as a means to improve quality of life through social connection. This paper presents a mixed-method integrative review of telepresence robots used to improve social connection of people with dementia by enabling real time communication with their carers. METHODS: A systematic search of Medline, ProQuest, PubMed, Scopus, Web of Science, CINAHL, EMBASE, and the Cochrane library was conducted to gather available evidence on the use of telepresence robots, specifically videoconferencing, to improve social connectedness, in people with dementia. A narrative synthesis was used to analyze the included studies. RESULTS: A review of 1,035 records, identified four eligible peer reviewed publications, reporting findings about three different mobile telepresence robots. The study designs included qualitative and mixed-methods approaches, focusing primarily on examining the feasibility and acceptability of the telepresence robots within the context of dementia care. These studies reported both positive outcomes of using telepresence robots to connect people with dementia to others, as well as barriers, such as a lack of experience in using a robot and technological issues. CONCLUSION: Although limited, the current literature suggests that telepresence robots have potential utility for improving social connectedness of people with dementia and their carers. However, more systematic feasibility studies are needed to inform the development of telepresence robots followed by clinical trials to establish efficacy within dementia care. PMID- 28879829 TI - Five-year surveillance of human tuberculosis caused by Mycobacterium bovis in Bologna, Italy: an underestimated problem. AB - Human tuberculosis (TB) caused by Mycobacterium bovis surveillance is affected by a lack of data. The aims of the present study were: (i) to estimate the proportion of human TB caused by M. bovis over a period of 5 years in Bologna, Northern Italy, which, like most Western European countries, has been declared bovine TB-free; (ii) to compare the genetic profiles of M. bovis strains identified in humans with those circulating in cattle in the last 15 years in Italy. Among 511 TB patients, the proportion of human TB caused by M. bovis was 1.76%, significantly associated to extra-pulmonary localization (P = 0.004) and to being elderly (P < 0.001) and Italy-born (P = 0.036). The molecular epidemiology analysis by spoligotyping and Multilocus Variable Tandem Repeat Analysis confirmed that most M. bovis strains from Italy-born patients matched those circulating in cattle herds in Italy between 2001 and 2016. Two cases of Mycobacterium bovis BCG infection were also characterized. In conclusion, the rate of human TB caused by M. bovis was not negligible, highlighting the relevance of molecular typing in evaluating the effectiveness of programmes designed to eradicate TB in cattle in Italy. PMID- 28879830 TI - The legislative framework for salt iodization in Asia and the Pacific and its impact on programme implementation. AB - OBJECTIVE: Fortification of food-grade (edible) salt with iodine is recommended as a safe, cost-effective and sustainable strategy for the prevention of iodine deficiency disorders. The present paper examines the legislative framework for salt iodization in Asian countries. DESIGN: We reviewed salt iodization legislation in thirty-six countries in Asia and the Pacific. We obtained copies of existing and draft legislation for salt iodization from UNICEF country offices and the WHO's Global Database of Implementation of Nutrition Actions. We compiled legislation details by country and report on commonalities and gaps using a standardized form. The association between type of legislation and availability of iodized salt in households was assessed. RESULTS: We identified twenty-one countries with existing salt iodization legislation, of which eighteen were mandatory. A further nine countries have draft legislation. The majority of countries with draft and existing legislation used a mandatory standard or technical regulation for iodized salt under their Food Act/Law. The remainder have developed a 'stand-alone' Law/Act. Available national surveys indicate that the proportion of households consuming adequately iodized salt was lowest in countries with no, draft or voluntary legislation, and highest in those where the legislation was based on mandatory regulations under Food Acts/Laws. CONCLUSIONS: Legislation for salt iodization, particularly mandatory legislation under the national food law, facilitates universal salt iodization. However, additional important factors for implementation of salt iodization and maintenance of achievements include the salt industry's structure and capacity to adequately fortify, and official commitment and capacity to enforce national legislation. PMID- 28879831 TI - Adherence to dietary recommendations for Swedish adults across categories of greenhouse gas emissions from food. AB - OBJECTIVE: To explore associations between diet-related greenhouse gas emissions (GHGE), nutrient intakes and adherence to the Nordic Nutrition Recommendations among Swedish adults. DESIGN: Diet was assessed by 4d food records in the Swedish National Dietary Survey. GHGE was estimated by linking all foods to carbon dioxide equivalents, using data from life cycle assessment studies. Participants were categorized into quartiles of energy-adjusted GHGE and differences between GHGE groups regarding nutrient intakes and adherence to nutrient recommendations were explored. SETTING: Sweden. SUBJECTS: Women (n 840) and men (n 627) aged 18 80 years. RESULTS: Differences in nutrient intakes and adherence to nutrient recommendations between GHGE groups were generally small. The dietary intake of participants with the lowest emissions was more in line with recommendations regarding protein, carbohydrates, dietary fibre and vitamin D, but further from recommendations regarding added sugar, compared with the highest GHGE group. The overall adherence to recommendations was found to be better among participants with lower emissions compared with higher emissions. Among women, 27 % in the lowest GHGE group adhered to at least twenty-three recommendations compared with only 12 % in the highest emission group. For men, the corresponding figures were 17 and 10 %, respectively. CONCLUSIONS: The study compared nutrient intakes as well as adherence to dietary recommendations for diets with different levels of GHGE from a national dietary survey. We found that participants with low-emission diets, despite higher intake of added sugar, adhered to a larger number of dietary recommendations than those with high emissions. PMID- 28879832 TI - Supermarket access, transport mode and BMI: the potential for urban design and planning policy across socio-economic areas. AB - OBJECTIVE: To investigate dietary intake, BMI and supermarket access at varying geographic scales and transport modes across areas of socio-economic disadvantage, and to evaluate the implementation of an urban planning policy that provides guidance on spatial access to supermarkets. DESIGN: Cross-sectional study used generalised estimating equations to investigate associations between supermarket density and proximity, vegetable and fruit intake and BMI at five geographic scales representing distances people travel to purchase food by varying transport modes. A stratified analysis by area-level disadvantage was conducted to detect optimal distances to supermarkets across socio-economic areas. Spatial distribution of supermarket and transport access was analysed using a geographic information system. SETTING: Melbourne, Australia. SUBJECTS: Adults (n 3128) from twelve local government areas (LGA) across Melbourne. RESULTS: Supermarket access was protective of BMI for participants in high disadvantaged areas within 800 m (P=0.040) and 1000 m (P=0.032) road network buffers around the household but not for participants in less disadvantaged areas. In urban growth area LGA, only 26 % of dwellings were within 1 km of a supermarket, far less than 80-90 % of dwellings suggested in the local urban planning policy. Low public transport access compounded disadvantage. CONCLUSIONS: Rapid urbanisation is a global health challenge linked to increases in dietary risk factors and BMI. Our findings highlight the importance of identifying the most appropriate geographic scale to inform urban planning policy for optimal health outcomes across socio-economic strata. Urban planning policy implementation in disadvantaged areas within cities has potential for reducing health inequities. PMID- 28879833 TI - Prevalence of mild behavioral impairment in mild cognitive impairment and subjective cognitive decline, and its association with caregiver burden. AB - BACKGROUND: Mild behavioral impairment (MBI) describes later life acquired, sustained neuropsychiatric symptoms (NPS) in cognitively normal individuals or those with mild cognitive impairment (MCI), as an at-risk state for incident cognitive decline and dementia. We developed an operational definition of MBI and tested whether the presence of MBI was related to caregiver burden in patients with subjective cognitive decline (SCD) or MCI assessed at a memory clinic. METHODS: MBI was assessed in 282 consecutive memory clinic patients with SCD (n = 119) or MCI (n = 163) in accordance with the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria. We operationalized a definition of MBI using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Caregiver burden was assessed using the Zarit caregiver burden scale. Generalized linear regression was used to model the effect of MBI domains on caregiver burden. RESULTS: While MBI was more prevalent in MCI (85.3%) than in SCD (76.5%), this difference was not statistically significant (p = 0.06). Prevalence estimates across MBI domains were affective dysregulation (77.8%); impulse control (64.4%); decreased motivation (51.7%); social inappropriateness (27.8%); and abnormal perception or thought content (8.7%). Affective dysregulation (p = 0.03) and decreased motivation (p=0.01) were more prevalent in MCI than SCD patients. Caregiver burden was 3.35 times higher when MBI was present after controlling for age, education, sex, and MCI (p < 0.0001). CONCLUSIONS: MBI was common in memory clinic patients without dementia and was associated with greater caregiver burden. These data show that MBI is a common and clinically relevant syndrome. PMID- 28879834 TI - Prospective associations between dietary patterns and body composition changes in European children: the IDEFICS study. AB - OBJECTIVE: To describe dietary patterns by applying cluster analysis and to describe the cluster memberships of European children over time and their association with body composition changes. DESIGN: The analyses included k-means clustering based on the similarities between the relative frequencies of consumption of forty-three food items and regression models were fitted to assess the association between dietary patterns and body composition changes. SETTING: Primary schools and pre-schools of selected regions in Italy, Estonia, Cyprus, Belgium, Sweden, Hungary, Germany and Spain. SUBJECTS: Participants (n 8341) in the baseline (2-9 years old) and follow-up (4-11 years old) surveys of the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS) study. RESULTS: Three persistent clusters were obtained at baseline and follow-up. Children consistently allocated to the 'processed' cluster presented increased BMI (beta=0.050; 95 % CI 0.006, 0.093), increased waist circumference (beta=0.071; 95 % CI 0.001, 0.141) and increased fat mass gain (beta=0.052; 95 % CI 0.014, 0.090) over time v. children allocated to the 'healthy' cluster. Being in the 'processed'-'sweet' cluster combination was also linked to increased BMI (beta=0.079; 95 % CI 0.015, 0.143), increased waist circumference (beta=0.172; 95 % CI 0.069, 0.275) and increased fat mass gain (beta=0.076; 95 % CI 0.019, 0.133) over time v. the 'healthy' cluster. CONCLUSIONS: Children consistently showing a processed dietary pattern or changing from a processed pattern to a sweet pattern presented the most unfavourable changes in fat mass and abdominal fat. These findings support the need to promote overall healthy dietary habits in obesity prevention and health promotion programmes targeting children. PMID- 28879835 TI - The nutritional quality of New Zealand breakfast cereals: an update. AB - OBJECTIVE: To compare the nutritional quality of New Zealand breakfast cereals in 2013 and 2017. DESIGN: Nutrition Information Panel data were collected from all cereals available from two large supermarket chains in 2017 and compared with earlier published data collected in 2013. SETTING: Urban New Zealand supermarkets. SUBJECTS: The nutritional content of breakfast cereals ('biscuits and bites', 'brans', 'bubbles, flakes and puffs', 'children's cereals', 'muesli' and 'oats') was analysed for total energy, protein, fat (total and saturated), carbohydrate, sugar, fibre and Na. The Nutrient Profile Scoring Criterion (NPSC) for each cereal was calculated to determine the proportion of 'less healthy' cereals (NPSC>=4) in each product category. RESULTS: The energy and fat content of bubbles, flakes and puffs, muesli and oats were significantly higher in 2017 compared with 2013 (all P<=0.01). However, there was a small reduction in Na overall in 2017 (P<0.05). There was no change between 2013 and 2017 in the proportion of 'healthy' or 'less healthy' breakfast cereals available. CONCLUSIONS: The nutrient profile of breakfast cereals has not improved since 2013, suggesting that industry self-regulation of the nutritional composition of cereals in New Zealand is not working and needs urgent reconsideration. PMID- 28879836 TI - Care staff and the creative arts: exploring the context of involving care personnel in arts interventions. AB - BACKGROUND: Arts-based interventions play an important role in the care of people with dementia. Yet, creative arts are seldom implemented as a tool to enhance the care and wellbeing of people with dementia. METHODS: We examined the involvement of care staff in creative arts activities in residential care. Aspects of involvement that appear to influence outcomes in people with dementia were identified and analyzed. A broad systematic literature search of MedLine, EMBASE, PsychInfo, CINAHL, ASSIA, SCOPUS, and Web of Science led to the identification of 14 papers. The studies identified through the search process were examined in terms of intervention, context, mechanism and outcome, and the relationships between these aspects. RESULTS: Training sessions were identified as an opportunity to educate care personnel on useful techniques that are relevant to daily care practice. Evidence from the literature suggests that creative arts programs play a significant role in the way staff and residents interact and as a result influence the care practice of staff. Under certain conditions creative arts programs, that involve and engage staff, facilitate enhanced interactions and improve care strategies, which leads to the recognition and validation of personhood in residents with dementia. CONCLUSIONS: These findings provide a basis for illustrating which elements of care staff involvement in creative arts programs could be implemented in residential care contexts in order to have the upmost benefit. PMID- 28879837 TI - Bacillus endozanthoxylicus sp. nov., an endophytic bacterium isolated from Zanthoxylum bungeanum Maxim leaves. AB - A Gram-stain-positive, rod-shaped, motile bacterium, designated as 1404T, was isolated from leaves of Chinese red pepper (Huajiao) (Zanthoxylum bungeanum Maxim) collected from Gansu, north-west China. Spores were not observed under a range of conditions. Strain 1404T was observed to grow at 15-45 degrees C and pH 6.0-10.0 and in presence of 0-5 % (w/v) NaCl concentration. The cell wall of strain 1404T was found to contain meso-diaminopimelic acid, and the predominant respiratory quinone was identified as MK-7. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unidentified phospholipid as well as three unidentified polar lipids. The major fatty acids profile of strain 1404T consisted of iso-C15 : 0 (25.6 %), anteiso C15 : 0 (18.4 %) and iso-C14 : 0 (12.1 %). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain 1404T was affiliated to the genus Bacillus and was closely related to Bacillusoryzisoli 1DS3-10T, Bacillusbenzoevorans DSM 5391T and Bacilluscirculans DSM 11T with sequence similarity of 98.3, 98.2 and 96.9 %, respectively. The G+C content of the genomic DNA was determined to be 39.4 mol%. DNA-DNA hybridization values indicated that relatedness between strain 1404T and the type strains of closely related species of the genus Bacillus was below 41 %. Therefore, on the basis of the data from the polyphasic taxonomic study presented, strain 1404T represents a novel species of the genus Bacillus, for which the name proposed is Bacillus endozanthoxylicus sp. nov. The type strain is 1404T (=CCTCC AB 2017021T=KCTC 33827T). PMID- 28879838 TI - Agarilytica rhodophyticola gen. nov., sp. nov., isolated from Gracilaria blodgettii. AB - A novel Gram-stain-negative, rod-shaped, non-spore-forming, aerobic, agarolytic bacterium, designated 017T, was isolated from Gracilaria blodgettii collected at the coast of Lingshui county, Hainan province, China. Optimal growth occurred at 28-33 degrees C (range 15-40 degrees C), with 3 % (w/v) NaCl (range 2-4 %) and at pH 8.0 (range pH 6.5-8.5). Cells of strain 017T were motile and formed yellow colonies on marine agar 2216. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 017T shared the highest similarity with Teredinibacter turnerae T7902T (94.4 %). The predominant polar lipids of the novel isolate consisted of phosphatidylglycerol, phosphatidylethanolamine, aminophospholipid and some other unknown lipids. Major cellular fatty acids (>10 %) were C16 : 0, C18 : 1omega7c and summed feature 3 (C16 : 1omega7c/iso-C15 : 0 2-OH), and the sole respiratory lipoquinone was Q-8. The DNA G+C content of strain 017T was 40.2 mol%. Comparative analysis of 16S rRNA gene sequences and phenotypic characterization indicated that strain 017T represents a novel species in a new genus of the family Cellvibrionaceae, order Cellvibrionales, for which the name Agarilytica rhodophyticola gen. nov., sp. nov. is proposed. The type strain of Agarilytica rhodophyticola is 017T (=KCTC 42584T=MCCC 1H00123T). PMID- 28879839 TI - Ramlibacter rhizophilus sp. nov., isolated from rhizosphere soil of national flower Mugunghwa from South Korea. AB - A Gram-negative, aerobic, non-motile, long rods or coccoid without flagellum strain, designated THG-YS3.2.7T, was isolated from therhizosphere soil of a Mugunghwa flower collected from Kyung Hee University, Yongin, South Korea. Growth occurred at 10-40 degrees C (optimum 28-37 degrees C), at pH 6-8 (optimum 7) and at 0-5 % NaCl (optimum 1 %). The predominant ubiquinone was ubiquinone 8 (Q 8). The major cellular fatty acids were C10 : 0, C10 : 0 3OH, C16 : 0, C17 : 0, C17 : 0 cyclo, C18 : 0, C18 : 3omega6c (6,9,12), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and summed feature 8 (C18 : 1 omega7c and/or C18 : 1omega6c). The major polar lipids were diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylcholine (PC). The DNA G+C content of strain THG-YS3.2.7T was 69.4 mol%. Based on 16S rRNA gene sequence analysis, the nearest phylogenetic neighbours of strain THG YS3.2.7T were identified as Ramlibacter henchirensis DSM 14656T (97.92 %), Ramlibacter tataouinensis DSM 14655T (97.90 %), Ramlibacter solisilvae KACC 17567T (97.04 %). DNA-DNA hybridization values between strain THG-YS3.2.7T and R. henchirensis DSM 14656T, R. tataouinensis DSM 14655T, R. solisilvae KACC 17567T were 32.5+/-1.5, 43.1+/-1.1, 42.8+/-1.1 %, respectively. On the basis of the phylogenetic analysis, chemotaxonomic data, physiological characteristics and DNA DNA hybridization data, strain THG-YS3.2.7T represent a novel species of the genus Ramlibacter, for which the name Ramlibacter rhizophilus sp. nov. is proposed. The type strain is THG-YS3.2.7T (=KCTC 52083T=CCTCC AB 2015357T). PMID- 28879840 TI - Larkinella ripae sp. nov., isolated from seashore soil. AB - Strain 15J11-11T was isolated from soil collected at the seashore and was Gram staining-negative, short-rod-shaped, gliding and pale-pink pigmented. Flexirubin type pigments were absent. The isolate grew at a temperature range of 15 to 30 degrees C and a pH range of 7 to 8. Comparative 16S rRNA gene sequence studies showed that strain 15J11-11T belonged to the genus Larkinella within the phylum Bacteroidetes and was most closely related to Larkinella arboricola Z0532T (95.6 %), Larkinella bovis M2TB15T (95.4 %), and Larkinella insperata LMG 22510T (95.2 %). The genomic DNA G+C content of strain 15J11-11T was 53.2 mol%. The strain contained phosphatidylethanolamine, phosphatidylserine, an unidentified aminophospholipid and two unidentified polar lipids as the major polar lipids; menaquinone-7 as the predominant quinone and C16 : 1omega5c, iso-C15 : 0 and iso C17 : 0 3-OH as the major fatty acids which supported the affiliation of strain 15J11-11T to the genus Larkinella. Based on its phenotypic properties and phylogenetic distinctiveness, strain 15J11-11T represents a novel species of the genus Larkinella, for which the name Larkinella ripae sp. nov. is proposed. The type strain is 15J11-11T (=KCTC 42996T=JCM 31657T). PMID- 28879841 TI - Pontibacterium granulatum gen. nov., sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, strictly aerobic, moderately halophilic bacterium, designated A-1T, was isolated from a tidal flat of the Taean coast in South Korea. Cells were motile rods with a single flagellum showing oxidase-negative and catalase-positive activities and contained poly-beta-hydroxyalkanoic acid granules. Growth of strain A-1T was observed at 20-40 degrees C (optimum, 30 degrees C), pH 6.0-10.5 (optimum, pH 7.0) and in the presence of 1.0-6.0 % (w/v) NaCl (optimum, 2.0 %). Strain A-1T contained C16 : 0, summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c) and summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c) as the major fatty acids. The major polar lipids of strain A-1T were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The isoprenoid quinones detected were ubiquinone-7 and ubiquinone-8. The G+C content of the genomic DNA was 51.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain A 1T formed a distinct phylogenetic lineage from other genera within the family Oceanospirillaceae. Strain A-1T shared low 16S rRNA gene sequence similarities with other taxa (<=94.9 %). On the basis of phenotypic, chemotaxonomic and molecular properties, it is clear that strain A-1T represents a novel genus and species of the family Oceanospirillaceae, for which the name Pontibacterium granulatum gen. nov., sp. nov. is proposed. The type strain is A-1T (=KACC 18119T=JCM 30136T). PMID- 28879842 TI - Maribacter pelagius sp. nov., isolated from seawater. AB - A Gram-stain-negative, gliding, non-endospore-forming and slightly halophilic bacterial strain, CBA3204T, was isolated from seawater and characterized by polyphasic taxonomic analysis. Phylogenetic analysis based on 16S rRNA sequences revealed that strain CBA3204T formed a distinct lineage within the family Flavobacteriaceae. The 16S rRNA sequences of strain CBA3204T had a sequence similarity level of 96.96 % to Maribacter arcticus KOPRI 20941T as the nearest phylogenetic neighbour. The strain grew optimally at 25-30 degrees C and in the presence of 2-4 % (w/v) NaCl. The dominant menaquinone was MK-6 and the major fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 1 G. The DNA G+C content was 35.1 mol%. There were some differences in phenotypic properties among strain CBA3204T and other Maribacter species. On the basis of polyphasic analysis containing phenotypic, phylogenetic and chemotaxonomic data, strain CBA3204T (=KACC 17671T=JCM 19533T) is proposed as a novel species Maribacter pelagius sp. nov. PMID- 28879843 TI - Transfer of 13 species of the genus Burkholderia to the genus Caballeronia and reclassification of Burkholderia jirisanensis as Paraburkholderia jirisanensis comb. nov. AB - A recent study of a group of Burkholderia glathei-like bacteria resulted in the description of 13 novel species of the genus Burkholderia. However, our analysis of phylogenetic positions of these species and their molecular signatures (conserved protein sequence indels) showed that they belong to the genus Caballeronia, and we propose to transfer them to this genus. The reclassified species names are proposed as Caballeroniaarationis comb. nov., Caballeroniaarvi comb. nov., Caballeroniacalidae comb. nov., Caballeroniacatudaia comb. nov., Caballeroniaconcitans comb. nov., Caballeroniafortuita comb. nov., Caballeroniaglebae comb. nov., Caballeroniahypogeia comb. nov., Caballeroniapedi comb. nov., Caballeroniaperedens comb. nov., Caballeroniaptereochthonis comb. nov., Caballeroniatemeraria comb. nov. and Caballeronia turbans comb. nov. It is also proposed to reclassify Burkholderia jirisanensis as Paraburkholderiajirisanensis comb. nov. Based on the results of the polyphasic study, B. jirisanensis had been described as a member of the A-group of the genus Burkholderiaand the most closely related to Burkholderia rhizosphaerae, Burkholderia humisilvae and Burkholderia solisilvae currently classified as belonging to the genus Paraburkholderia. PMID- 28879844 TI - Lactobacillus silagincola sp. nov. and Lactobacillus pentosiphilus sp. nov., isolated from silage. AB - Three Gram-stain positive, non-motile, non-spore-forming, catalase-negative and rod-shaped bacterial strains (IWT5T, IWT25T and IWT140), isolated from silage, were investigated by using a polyphasic taxonomic approach. Strains IWT5T and IWT25T grew at 10-37 degrees C and 30-37 degrees C, and at pH 4.0-7.5 and 4.0 7.0, respectively. The G+C contents of genomic DNA of strains IWT5T and IWT25T were 43.2 and 44.4 mol%, respectively. Strains IWT5T and IWT25T contained C16 : 0, C18 : 1 omega9c and summed feature 7 (unknown 18.846/C19 : 1 omega6c/C19 : 0cyclo omega10c) as the major fatty acids. Strain IWT5T was most closely related to the type strains of Lactobacillus mixtipabuli (99.9 % 16S rRNA gene sequence similarity) and Lactobacillus silagei (99.5 %). For IWT25T, the 16S rRNA gene sequence similarities with the closely related neighbour type strains L. mixtipabuli and L. silagei were 99.5 and 99.5 %, respectively. The 16S rRNA gene sequence similarities among the three novel isolates were 99.5-99.9 %. The average nucleotide identities of strains IWT5T and IWT25T to other neighbours of the genus Lactobacillus were less than 82 % and the genomes of IWT25T and IWT140 shared 97.3 % average nucleotide identity, demonstrating that the three strains were allocated to two different novel species of the genus Lactobacillus. Together with multilocus sequence analysis, phenotypic and chemotaxonomic characteristics, strains IWT5T (=JCM 31144T=DSM 102973T) and IWT25T (=JCM 31145T=DSM 102974T) are proposed as the type strains of novel species of the genus Lactobacillus, with the names Lactobacillus silagincola sp. nov. and Lactobacillus pentosiphilus sp. nov., respectively. PMID- 28879845 TI - Pseudokineococcus basanitobsidens sp. nov., isolated from volcanic rock. AB - A novel Gram-strain-positive, non-spore-forming bacterial strain, designated SKC1 2T, was isolated from volcanic rock of the scoria cone of Seobjikoji, Jeju, Republic of Korea. Cells were aerobic, catalase-positive, oxidase-negative, motile and cocci. Colonies of cells were dark orange-coloured, circular, smooth and convex. Phylogenetic analyses based on 16S rRNA gene sequences indicated that the isolate was related to members of the genus Pseudokineococcus. Phylogenetic neighbours were P. marinus KCCM 42250T (98.2 %, 16S rRNA gene sequence similarity) and P. lusitanus DSM 23768T (98.0 %). The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. The predominant respiratory quinone was MK-9(H2). The predominant respiratory quinone was MK 9(H2) and the major fatty acid was anteiso-C15 : 0. The polar lipid profile included major amounts of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, two unidentified phospholipids and two unidentified phosphoglycolipids. The DNA G+C content was 74.9 mol%. DNA-DNA relatedness values between strain SKC1-2T and P. lusitanus DSM 23768T or P. marinus KCCM 42250T were 37.5-38.1 % or 45.4-46.4 %, respectively. On the basis of the phenotypic differences and DNA-DNA relatedness data, the isolate represents a new species of the genus Pseudokineococcus, for which the name Pseudokineococcus basanitobsidens sp. nov. is proposed. The type strain is SKC1-2T (=DSM 103726T=KCCM 43221T). PMID- 28879846 TI - Promicromonospora soli sp. nov., a novel actinomycete isolated from soil. AB - A novel actinobacterium, designated strain NEAU-GS50T, was isolated from soil collected from Mount Song and characterized by using a polyphasic approach. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that the organism should be assigned to the genus Promicromonospora and that it forms a monophyletic clade with its closest relatives Promicromonospora umidemergens JCM 17975T (98.94 % 16S rRNA gene sequence similarity), Promicromonospora alba 1C HV12T (98.82 %) and Promicromonospora kermanensis DSM45485T (98.68 %). Similarly, chemotaxonomic data including major menaquinones, fatty acid compositions and polar lipid profiles, also supported the placement of strain NEAU-GS50T in the genus Promicromonospora. However, DNA-DNA relatedness, physiological and biochemical data showed that strain NEAU-GS50T could be distinguished from its closest relatives. Therefore, strain NEAU-GS50T represents a novel species of the genus Promicromonospora, for which the name Promicromonospora soli sp. nov. is proposed, with strain NEAU-GS50T (CGMCC4.7398T=DSM 104515T) as the type strain. PMID- 28879847 TI - Endozoicomonas acroporae sp. nov., isolated from Acropora coral. AB - Strain Acr-14T, isolated from Acropora coral, was characterized by using a polyphasic taxonomy approach. Cells of strain Acr-14T were Gram-stain-negative, aerobic, non-motile, poly-beta-hydroxybutyrate-accumulating, rod-shaped and formed creamy white colonies. Optimal growth occurred at 30 degrees C, pH 7 and in the presence of 2 % NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Acr-14T belonged to the genus Endozoicomonas and was most closely related to Endozoicomonas atrinae WP70T with sequence similarity of 96.7 %. Strain Acr-14T contained summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C16 : 0 as the predominant fatty acids. The predominant isoprenoid quinone was Q-9. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The genomic DNA G+C content of strain Acr-14T was 49.1 mol%. Differential phenotypic properties, together with the phylogenetic inference, demonstrated that strain Acr-14T should be classified as a novel species of the genus Endozoicomonas, for which the name Endozoicomonas acroporae sp. nov. is presented. The type strain is Acr-14T (=BCRC 80922T=LMG 29482T=KCTC 42901T). PMID- 28879848 TI - Altererythrobacter deserti sp. nov., isolated from desert soil. AB - A Gram-stain-negative, aerobic, short rod-shaped, non-motile bacterium (THG-S3T), was isolated from desert soil. Growth occurred at 15-35 degrees C (optimum 28 degrees C), at pH 5-10 (optimum 7) and at 0-4 % NaCl (optimum 1 %). Based on 16S rRNA gene sequence analysis, the nearest phylogenetic neighbours of strain THG S3T were identified as Altererythrobacter rigui KCTC 42620T (99.0 %), Altererythrobacter dongtanensis KCTC 22672T (97.1 %), Altererythrobacter xinjiangensis CCTCC AB 207166T (96.9 %), Altererythrobacter troitsensis KCTC 12303T (96.9 %). Levels of relatedness among strain THG-S3T and other Altererythrobacter species were lower than 96.0 %. DNA-DNA hybridization values between strain THG-S3T and A. rigui KCTC 42620T, A. dongtanensis KCTC 22672T, A. xinjiangensis CCTCC AB 207166T and A. troitsensis KCTC 12303T were 59.7 % (42.8 %, reciprocal analysis), 45.1 % (36.3 %), 34.7 % (25.1 %) and 15.1 % (12.3 %), respectively. The DNA G+C content of strain THG-S3T was 69 mol%. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and three unidentified lipids The quinone was ubiquinone-10. The major fatty acids were C16 : 0, C17 : 1 omega6c, C18 : 1 omega7c and summed feature 3 (C16 : 1 omega7c and/or C16 : 1 omega6c). On the basis of the phylogenetic analysis, chemotaxonomic data, physiological characteristics and DNA-DNA hybridization data, strain THG-S3T represents a novel species of the genus Altererythrobacter, for which the name Altererythrobacter deserti sp. nov. is proposed. The type strain is THG-S3T (=KACC 19190T=CGMCC 1.15959T). PMID- 28879849 TI - Altererythrobacter xixiisoli sp. nov., isolated from wetland soil. AB - A Gram-stain-negative, coccoid, yellow, non-motile, aerobic bacterium, designated strain S36T, was isolated from soil of the Xixi wetland in Zhejiang province, PR China. Phylogenetic analysis, based on 16S rRNA gene sequences, revealed that strain S36T could represent a novel species of genus Altererythrobacter showing highest similarity to Altererythrobacter atlanticus 26DY36T (96.31 % 16S rRNA gene sequence similarity). The temperature, pH and NaCl concentration ranges for growth were 10-37 degrees C (optimum 32 degrees C), pH 5.0-10.0 (optimum pH 7.0) and 0.5-3 % (optimum 1 %, w/v), respectively. The predominant respiratory quinone of strain S36T was Q-10. The major fatty acids were C16 : 0, C17 : 1omega6c, C18 : 1omega7c and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH). The G+C content of the genomic DNA was 62.7 mol%. These data all support the affiliation of strain S36T to the genus Altererythrobacter. The polar lipids profile of strain S36T comprised diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two unidentified phospholipids and two unidentified glycolipids. The results of physiological and biochemical tests allowed differentiation of strain S36T from other members of the genus Altererythrobacter. Therefore, strain S36T represents a novel species of the genus Altererythrobacter, for which the name Altererythrobacter xixiisoli sp. nov. is proposed; the type strain is S36T (=CGMCC 1.12804T=NBRC 110413T). PMID- 28879850 TI - Limibaculum halophilum gen. nov., sp. nov., a new member of the family Rhodobacteraceae. AB - A Gram-stain-negative, cream-pigmented, aerobic, non-motile, non-spore-forming and short-rod-shaped bacterial strain, designated CAU 1123T, was isolated from mud from reclaimed land. The strain's taxonomic position was investigated by using a polyphasic approach. Strain CAU 1123T grew optimally at 37 degrees C and at pH 7.5 in the presence of 2 % (w/v) NaCl. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain CAU 1123T formed a monophyletic lineage within the family Rhodobacteraceae with 93.8 % or lower sequence similarity to representatives of the genera Rubrimonas, Oceanicella, Pleomorphobacterium, Rhodovulum and Albimonas. The major fatty acids were C18 : 1 omega7c and 11-methyl C18 : 1 omega7c and the predominant respiratory quinone was Q-10. The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, two unidentified phospholipids, one unidentified aminolipid and one unidentified lipid. The DNA G+C content was 71.1 mol%. Based on the data from phenotypic, chemotaxonomic and phylogenetic studies, it is proposed that strain CAU 1123T represents a novel genus and novel species of the family Rhodobacteraceae, for which the name Limibaculumhalophilum gen. nov., sp. nov. The type strain is CAU 1123T (=KCTC 52187T, =NBRC 112522T). PMID- 28879852 TI - Type III CRISPR-Cas System: Introduction And Its Application for Genetic Manipulations. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated (Cas) genes provide adaptive immunity against invasion of foreign nucleic acids in archaea and bacteria. The system functions in three distinct stages: adaptation, biogenesis, and interference. CRISPR-Cas systems are currently classified into at least five different types, each with a signature protein among which Type III systems exhibit a dual DNA/RNA interference activity. Structures of a few Type III surveillance complexes have been determined: they are composed of several different subunits and exhibit striking architectural similarities to Type I surveillance complexes. Here, we review the genetic, biochemical, and structural studies concerning CRISPR-Cas Type III systems and discuss their application for genetic manipulations, including genome engineering and gene silencing. PMID- 28879853 TI - dCas9: A Versatile Tool for Epigenome Editing. AB - The epigenome is a heritable layer of information not encoded in the DNA sequence of the genome, but in chemical modifications of DNA or histones. These chemical modifications, together with transcription factors, operate as spatiotemporal regulators of genome activity. Dissecting epigenome function requires controlled site-specific alteration of epigenetic information. Such control can be obtained using designed DNA-binding platforms associated with effector domains to function as targeted transcription factors or epigenetic modifiers. Here, we review the use of dCas9 as a novel and versatile tool for fundamental studies on epigenetic landscapes, chromatin structure and transcription regulation, and the potential of this approach in basic research in these fields. PMID- 28879851 TI - Fundamental bound on the persistence and capacity of short-term memory stored as graded persistent activity. AB - It is widely believed that persistent neural activity underlies short-term memory. Yet, as we show, the degradation of information stored directly in such networks behaves differently from human short-term memory performance. We build a more general framework where memory is viewed as a problem of passing information through noisy channels whose degradation characteristics resemble those of persistent activity networks. If the brain first encoded the information appropriately before passing the information into such networks, the information can be stored substantially more faithfully. Within this framework, we derive a fundamental lower-bound on recall precision, which declines with storage duration and number of stored items. We show that human performance, though inconsistent with models involving direct (uncoded) storage in persistent activity networks, can be well-fit by the theoretical bound. This finding is consistent with the view that if the brain stores information in patterns of persistent activity, it might use codes that minimize the effects of noise, motivating the search for such codes in the brain. PMID- 28879854 TI - Treating Genetic Disorders Using State-Of-The-Art Technology. AB - CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated Protein 9), basically a bacterial immune system is now widely applicable to engineer genomes of a number of cells and organisms because of its simplicity and robustness. In research avenue the system has been optimized to regulate gene expression, modify epigenome and edit target locus. These applications make CRISPR/Cas9, a technology of choice to edit disease causing mutations as well as the epigenome more efficiently than ever before. Meanwhile its application in in vivo and ex vivo cells is encouraging the scientific community for more vigorous gene therapy and in clinical setups for therapeutic genome editing. Here we review the recent advances that CRISPR-Cas9 mediated genome editing has achieved and is reported in previous studies and address the challenges associated with it. PMID- 28879855 TI - An Era of CRISPR/ Cas9 Mediated Plant Genome Editing. AB - Recently the engineered nucleases have revolutionized genome editing to perturb gene expression at specific sites in complex eukaryotic genomes. Three important classes of these genome editing tools are Moreover, the more recent type II Clustered Regularly Inter-spaced Short Palindromic Repeats/Crispr associated protein (CRISPR/Cas9) system has become the most favorite plant genome editing tool for its precision and RNA based specificity unlike its counterparts which rely on protein based specificity. Plasmid-mediated co-delivery of multiple sgRNAs and Cas9 to the Plant cell can simultaneously alter more than one target loci which enable multiplex genome editing. In this review, we discuss recent advancements in the CRISPR/ Cas9 technology mechanism, theory and its applications in plants and agriculture. We also suggest that the CRISPR/ Cas9 as an effective genome editing tool, has vast potential for crop improvement and studying gene regulation mechanism and chromatin remodeling. PMID- 28879856 TI - CRISPR/Cas9-Mediated Immunity in Plants Against Pathogens. AB - Global crop production is highly threatened due to pathogen invasion. The huge quantity of pesticides application, although harmful to the environment and human health, is carried out to prevent the crop losses worldwide, every year. Therefore, understanding the molecular mechanisms of pathogenicity and plant resistance against pathogen is important. The resistance against pathogens is regulated by three important phytohormones viz. salicylic acid (SA), jasmonic acid (JA) and ethylene (ET). Here we review possible role of CRISPR technology to understand the plant pathogenicity by mutating genes responsible for pathogen invasion or up-regulating the phytohormones genes or resistant genes. Thus hormone biosynthesis genes, receptor and feeding genes of pathogens could be important targets for modifications using CRISPR/Cas9 following multiplexing tool box strategy in order to edit multiple genes simultaneously to produce super plants. Here we put forward our idea thatthe genes would be either mutated in case of plant receptor protein targets of pathogens or up-regulation of resistant genes or hormone biosynthesis genes will be better choice for resistance against pathogens. PMID- 28879857 TI - Improving CRISPR-Cas9 On-Target Specificity. AB - The CRISPR-Cas9 has revolutionized the field of molecular biology, medical genetics and medicine. The technology is robust, facile and simple to achieve genome targeting in cells and organisms. However, to propagate these nucleases for therapeutic application, the on-target specificity is of paramount importance. Although the binding and cleavage of off-target sites by Cas9 is issue of concern, however the specificity of CRISPR technology is greatly improved in current research employing the use of engineer nucleases, improved gRNA selection, novel Cas9 orhtologs and the advancement in methods to detect and screen off-target sites and its effects. Here we summarize the advances in this state-of-the-art technology that will equip the genome editing tools to be applied in clinical research. The researcher should optimize these methods with emphasize to achieve perfection in the specificity. PMID- 28879858 TI - CRISPR Mediated Genome Engineering and its Application in Industry. AB - The CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR-associated nuclease 9) method has been dramatically changing the field of genome engineering. It is a rapid, highly efficient and versatile tool for precise modification of genome that uses a guide RNA (gRNA) to target Cas9 to a specific sequence. This novel RNA-guided genome-editing technique has become a revolutionary tool in biomedical science and has many innovative applications in different fields. In this review, we briefly introduce the Cas9-mediated genome editing tool, summarize the recent advances in CRISPR/Cas9 technology to engineer the genomes of a wide variety of organisms, and discuss their applications to treatment of fungal and viral disease. We also discuss advantageous of CRISPR/Cas9 technology to drug design, creation of animal model, and to food, agricultural and energy sciences. Adoption of the CRISPR/Cas9 technology in biomedical and biotechnological researches would create innovative applications of it not only for breeding of strains exhibiting desired traits for specific industrial and medical applications, but also for investigation of genome function. PMID- 28879859 TI - Applications of CRISPR/Cas9 in Reproductive Biology. AB - Genome editing is unraveling its benefits in wide areas of scientific development and understanding. The advances of genome editing from ZFNs and TALLENs to CRISPRs defines it wide applicability. Reproduction is the fundamental process by which all organisms maintain their generations. CRISPR/Cas9, a new versatile genome editing tool is recently tamed to correct several disease causing genetic mutations spreading its arms to improve reproductive health. It not only edit harmful genetic mutations but is also applied to control the spread of parasitic diseases like malaria by introducing selfish genetic elements, propagated through generations and population via reproduction. These applications made us to review the recent developments of CRISPRs use in reproductive biology. PMID- 28879860 TI - Ethical Issues Regarding CRISPR Mediated Genome Editing. AB - CRISPR-Cas9 has emerged as a simple, precise and most rapid genome editing technology. With a number of promising applications ranging from agriculture and environment to clinical therapeutics, it is greatly transforming the field of molecular biology. However, there are certain ethical, moral and safety concerns related to the attractive applications of this technique. The most contentious issues concerning human germline modifications are the challenges to human safety and morality such as risk of unforeseen, undesirable effects in clinical applications particularly to correct or prevent genetic diseases, matter of informed consent and the risk of exploitation for eugenics. Stringent regulations and guidelines as well as worldwide debate and awareness are required to ensure responsible and wise use of CRISPR mediated genome editing technology. There is a need for an extensive dialogue among scientists, ethicists, industrialists and policy makers on its societal implications. The opinion of different elements of the society including the general public as well as religious scholars is also critical. In countries with existing legislative framework, it might be appropriate to allow CRISPR based research to proceed with proper justification. However, much anticipated future clinical applications must be strictly regulated with newly established regulations. PMID- 28879862 TI - Improved charge separation efficiency of hematite photoanodes by coating an ultrathin p-type LaFeO3 overlayer. AB - Many metal-oxide candidates for photoelectrochemical water splitting exhibit localized small polaron carrier conduction. Especially hematite (alpha-Fe2O3) photoanodes often suffer from low carrier mobility, which causes the serious bulk electron-hole recombination and greatly limits their PEC performances. In this study, the charge separation efficiency of hematite was enhanced greatly by coating an ultrathin p-type LaFeO3 overlayer. Compared to the hematite photoanodes, the solar water splitting photocurrent of the Fe2O3/LaFeO3 n-p junction exhibits a 90% increase at 1.23 V versus the reversible hydrogen electrode, due to enlarging the band bending and expanding the depletion layer. PMID- 28879861 TI - Integrating exhaled breath diagnostics by disease-sniffing dogs with instrumental laboratory analysis. AB - Dogs have been studied for many years as a medical diagnostic tool to detect a pre-clinical disease state by sniffing emissions directly from a human or an in vitro biological sample. Some of the studies report high sensitivity and specificity in blinded case-control studies. However, in these studies it is completely unknown as to which suites of chemicals the dogs detect and how they ultimately interpret this information amidst confounding background odors. Herein, we consider the advantages and challenges of canine olfaction for early (meaningful) detection of cancer, and propose an experimental concept to narrow the molecular signals used by the dog for sample classification to laboratory based instrumental analysis. This serves two purposes; first, in contrast to dogs, analytical methods could be quickly up-scaled for high throughput sampling. Second, the knowledge gained from identifying probative chemicals could be helpful in learning more about biochemical pathways and disease progression. We focus on exhaled breath aerosol, arguing that the semi-volatile fraction should be given more attention. Ultimately, we conclude that the interaction between dog based and instrument-based research will be mutually beneficial and accelerate progress towards early detection of cancer by breath analysis. PMID- 28879863 TI - A novel, stepwise approach combining conventional and endobronchial ultrasound needle aspiration for mediastinal lymph node sampling. AB - BACKGROUND AND OBJECTIVES: Since the introduction of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA), most pulmonary centers use this technique exclusively for mediastinal lymph node (LN) sampling. Conventional "blind" TBNA (cTBNA), however, is cheaper, more accessible, provides more tissue, and requires less training. We evaluated whether sampling of mediastinal LN using EBUS-TBNA or cTBNA according to a predefined set of criteria provides acceptable diagnostic yield. MATERIALS AND METHODS: Sampling method was determined prospectively according to a predefined set of criteria based on LN station, LN size, and presumed diagnosis. Sensitivity, specificity, positive, and negative predictive value were evaluated for each modality. RESULTS: One hundred and eighty-six biopsies were carried out over a 3-year period (86 cTBNA, 100 EBUS TBNA). Seventy-seven percent of LN biopsied by EBUS-TBNA were <20 mm, while 83% of cTBNA biopsies were >=20 mm. Most common sites of cTBNA sampling were station 7, 4R, and 11R as opposed to 7, 11R, 4R, and 4 L in the case of EBUS-TBNA. Most common EBUS-TBNA diagnosis was malignancy versus sarcoidosis in cTBNA. EBUS-TBNA and cTBNA both had a true positive yield of 65%, but EBUS-TBNA had a higher true negative rate (21% vs. 2% for cTBNA) and a lower false negative rate (7% vs. 28%). Sensitivity, specificity, positive predictive value, and negative predictive value for EBUS-TBNA were 90%, 100%, 100%, and 75%, respectively, and for cTBNA were 68%, 100%, 100%, and 7%, respectively. CONCLUSION: A stepwise approach based on LN size, station, and presumed diagnosis may be a reasonable, cost-effective approach in choosing between cTBNA and EBUS-TBNA. PMID- 28879864 TI - Linked Color Imaging Technology for Diagnosis of Gastric Mucosa-associated Lymphoid Tissue Lymphoma. PMID- 28879865 TI - Proton-pump inhibitor use does not affect semen quality in subfertile men. AB - Proton-pump inhibitors (PPIs) are among the most widely used drugs worldwide. PPI use has recently been linked to adverse changes in semen quality in healthy men; however, the effects of PPI use on semen parameters remain largely unknown specifically in cases with male factor infertility. We examined whether PPI use was associated with detrimental effects on semen parameters in a large population of subfertile men. We retrospectively reviewed data from 12 257 subfertile men who had visited our fertility clinic from 2003 to 2013. Patients who reported using any PPIs for >3 months before semen sample collection were included; 7698 subfertile men taking no medication served as controls. Data were gathered on patient age, medication use, and conventional semen parameters; patients taking any known spermatotoxic medication were excluded. Linear mixed-effect regression models were used to test the effect of PPI use on semen parameters adjusting for age. A total of 248 patients (258 samples) used PPIs for at least 3 months before semen collection. In regression models, PPI use (either as the only medication or when used in combination with other nonspermatotoxic medications) was not associated with statistically significant changes in semen parameters. To our knowledge, this is the largest study to compare PPI use with semen parameters in subfertile men. Using PPIs was not associated with detrimental effects on semen quality in this retrospective study. PMID- 28879866 TI - Management and outcomes of penile fracture: a retrospective analysis of 62 cases with long-term assessment. PMID- 28879867 TI - PSA screening - for whom and when? PMID- 28879868 TI - Mycobacterium chelonae infection complicating traumatic and surgical wounds: A case series. AB - Mycobacterium chelonae is a rapidly growing non-tuberculous mycobacterium. The skin and soft tissue infections due to this organism are steadily on the rise and need to be delineated specifically as most of these are not responsive to routine antituberculosis treatment. Here, we report 3 different presentations caused by Mycobacterium chelonae in traumatic and surgical wounds. Mycobacterium chelonae can complicate surgical or traumatic wounds.This infection may also present as injection site abscesses. Diabetics on insulin injections are especially at risk. A high index of suspicion is necessary in long standing culture negative lesions for clinching the diagnosis. PCR can be helpful in confirming the diagnosis. PMID- 28879869 TI - Pemphigus vegetans arising in umbilicus: Successful clearance with intralesional steroid. PMID- 28879870 TI - A study of the histopathology of palmo-plantar psoriasis and hyperkeratotic palmo plantar dermatitis. AB - BACKGROUND AND OBJECTIVES: Palmo-plantar psoriasis and dermatitis show several overlapping clinical features. We undertook this retrospective study to elucidate and compare the histological findings in these two dermatoses. MATERIALS AND METHODS: Biopsies of 31 clinically diagnosed cases of palmo-plantar psoriasis and 24 cases of hyperkeratotic palmo-plantar dermatitis, with concomitant presence of representative lesions at other body sites, were retrieved and analysed. RESULTS: Histologically, confluent parakeratosis, suprapapillary thinning and dermal edema were observed in significantly greater number of palmo-plantar psoriasis biopsies while an inflammatory infiltrate confined to the papillary dermis only, was a significant feature in palmo-plantar dermatitis. The two conditions could not be differentiated on the basis of features like focal parakeratosis, presence of neutrophils and fibrin globules in the stratum corneum, hypogranulosis, acanthosis, spongiosis, rete ridge pattern, or vascularity. CONCLUSION: Histopathology of palmo-plantar psoriasis and dermatitis can have several overlapping features. In our study, we found only few features as strong pointers towards psoriasis. PMID- 28879871 TI - The cover page. PMID- 28879872 TI - Memorable clinical experiences, all in one year at Queen Square, London, United Kingdom (1968-1969): A tribute to Neurology legends. PMID- 28879873 TI - Dr. Harry M. Zimmerman (1901 - 1995): Neuropathologist who autopsied Dr. Harvey Cushing, and his interactions with Indian colleagues. PMID- 28879874 TI - Diffusion tensor imaging in spinal pathology: A robust investigative tool in clinical practice. PMID- 28879875 TI - Spinal cord diffusion tensor imaging: Developing a research tool for clinical use. PMID- 28879876 TI - Muscular dystrophy: The long road ahead. PMID- 28879878 TI - Guillian-Barre syndrome and variants: Antiganglioside antibodies. PMID- 28879877 TI - Muscular dystrophies: An Indian scenario. PMID- 28879879 TI - Enigmas in immunobiology of Guillain-Barre syndrome: Ganglioside antibodies and beyond! PMID- 28879880 TI - Antiganglioside antibody: A hope or hype? PMID- 28879881 TI - Can arterial spin labelling really replace dynamic susceptibility contrast perfusion techniques for assessing brain tumours in clinical practice? PMID- 28879882 TI - Arterial spin labelling: A novel promising perfusion technique - Can it be a replacement to dynamic susceptibility contrast MRI ? PMID- 28879883 TI - The role of diffusion tensor imaging in spinal pathology: A review. AB - Diffusion tensor imaging (DTI) allows for noninvasive, in vivo visualization of white matter fiber tracts in the central nervous system by measuring the diffusion of water molecules. It provides both quantitative and qualitative (i.e., tractography) means to describe a region-of-interest. While protocols for the use of DTI are better established in the brain, the efficacy and potential applications of DTI in spinal cord pathology are less understood. In this review, we examine the current literature regarding the use of DTI in the spinal cord pathology, and in particular its diagnostic and prognostic value in traumatic injury, spinal tumors, cervical myelopathies, amyotrophic lateral sclerosis, and multiple sclerosis. Although structural magnetic resonance imaging (MRI) has long been the gold standard for noninvasive imaging of soft tissues, DTI provides additional tissue characteristics not found in the conventional MRI. We place emphasis on the unique characteristics of DTI, its potential value as an adjunct imaging modality, and its impact on clinical practice. PMID- 28879884 TI - Global muscular dystrophy research: A 25-year bibliometric perspective. AB - Muscular dystrophy is a genetic disorder leading to progressive weakness of muscles caused due to dysfunction in or lack of protein in muscle cells. The prevalence of muscular dystrophy has been observed globally and is becoming a critical area of study for better health services. The purpose of the study is to analyze the research strength of muscular dystrophy using bibliographic literature. A quantitative literature analysis was carried out on muscular dystrophy from 1991 to 2015 for assessing the global research trends. This literature-based study was conducted using the documents retrieved from the Science Citation Index using the keywords: Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), Congenital Muscular Dystrophy (CMD), Myotonic Dystrophy, Emery-Dreifuss Muscular Dystrophy, Facioscapulohumeral Muscular Dystrophy, Oculopharyngeal Muscular Dystrophy, and Limb-Girdle Muscular Dystrophy. Analysis was done for annual productivity of publication, authorship, collaboration, country performance, citation frequency, characteristics of most cited document, journal productivity, etc. PMID- 28879885 TI - Anti-ganglioside antibodies profile in Guillain-Barre syndrome: Correlation with clinical features, electrophysiological pattern, and outcome. AB - BACKGROUND: Guillain-Barre syndrome (GBS) and its subtypes are associated with distinct anti-ganglioside antibodies. Hence, we aimed to determine the frequency of anti-ganglioside antibodies and its correlation with clinical features, electrophysiological patterns, and outcome in patients with GBS. MATERIAL AND METHODS: The data regarding clinical features, electrophysiological patterns, and outcome at 6 months were collected and analyzed from the case records of patients diagnosed with GBS during 2008-2013 at a tertiary care hospital in south India. RESULTS: A total of 204 patients with GBS were studied, and 73 patients (mean age: 37.6 +/- 17.5 years) who underwent anti-ganglioside antibody testing were analyzed. Male-to-female ratio was 2.5:1. IgG anti-ganglioside antibodies were positive in 41/73 patients. The most common IgG anti-ganglioside antibody observed in the acute demyelinating variant was anti-GT1b (n = 13; 17.8%), and, those in the acute axonal variant were anti-GM1, anti-GM2, anti-GD1b, and anti GT1b antibodies (n = 9;12.3% each). Three patients died and 5 patients were unable to walk independently at the end of 6 months. CONCLUSIONS: The frequency of anti-ganglioside antibodies in our cohort with GBS was 56%, with IgG anti-GT1b antibody being the most common. The anti-ganglioside antibodies were significantly positive in acute motor axonal neuropathy (AMAN) subtype of GBS. The presence of anti-ganglioside antibodies was not found to be of significant use in predicting the outcome. Although it was observed that the absence, and not the presence, of anti-ganglioside antibodies was associated with antecedent infection, dysautonomia, and requirement of ventilator support, the overall disease severity was not antibody dependant. PMID- 28879886 TI - A study on the clinical outcomes and management of meningitis at a tertiary care centre. AB - BACKGROUND: Meningitis is a life threatening central nervous system infection that is prevalent worldwide. Many studies have been conducted on bacterial meningitis, but the information is inadequate on the other types of meningitis, especially prevalent in India. Regional information regarding trends, in terms of etiology and microbiological susceptibility, are essential for timely and adequate management of meningitis. AIMS: The present study was undertaken to evaluate the changing epidemiology of meningitis by reviewing the causative agents, the available laboratory methods for making the etiological diagnosis, the risk factors and the clinical outcomes, and the management of meningitis in our patient population. MATERIALS AND METHODS: It is an observational study conducted at a tertiary care centre. A structured data form was designed to collect the information from the medical records and charts of medical investigations of the patients. Details regarding etiological agents, prevalence of clinical features and management were recorded and interpreted. RESULTS: A total of 147 patients suspected to be having meningitis were included. The common types of meningitis in our study were aseptic (39%), tuberculous (28%), pyogenic (28%), fungal (3%) and others (2%). The classical triad of headache with fever, neck stiffness, and altered mental sensorium was seen in 26% patients, and 83% had at least 2 out of these 4 symptoms. The incidence of seizures was found to be 63% in the presence of aseptic meningitis. Significant clinical improvement was seen in 89% of the patients suffering from aseptic meningitis. CONCLUSIONS: Aseptic meningitis was found to be the predominant type among all different varieties of meningitis. An increased incidence of meningitis was seen in patients with diabetes mellitus. The incidence of seizures was high in viral/aseptic meningitis. The empirical treatment given in most of the cases was ceftriaxone. Isolation of the culpable organisms was possible in a very few cases due to the usage of empirical antibiotics prior to the performance of the lumbar puncture for the diagnostic analysis of the cerebrospinal fluid. PMID- 28879887 TI - Characteristics of nerve conduction studies in carpal tunnel syndrome. AB - BACKGROUND: Numerous nerve conduction tests are used for the electrodiagnosis of carpal tunnel syndrome (CTS), with a wide range of sensitivity and specificity reported for each test in clinical studies. AIMS: The purpose of this study was to compare the diagnostic accuracy of various nerve conduction tests and determine the properties of the most accurate test. SETTINGS AND DESIGN: A prospective observational case control study. PATIENTS AND METHODS: Eighty patients with clinically confirmed CTS and 80 asymptomatic healthy controls were included in the study. All patients underwent the routine hematological investigations as per the protocol. All cases and controls were subjected to various nerve conduction study protocols for CTS. Results were analyzed statistically. STATISTICAL ANALYSIS USED: The two-tailed Student's t-test was used for the comparative statistical analysis. The sensitivity of each test was calculated as (the number of hands with an abnormal study result/the number of CTS hands) * 100. Comparison between percentages was performed by the McNemar test. RESULTS: The mean age was 38.19 +/- 10.13 years and the female:male ratio was 1.5:1. The mean duration of disease was 0.89 +/- 0.61 years. Hypothyroidism was present in 21 (26.25%) patients, whereas 13 (16.25%) and 4 (5%) patients had diabetes mellitus and rheumatoid arthritis, respectively. The median nerve motor latency was 4.73 +/- 0.83 ms while the sensory latency was 3.44 +/- 0.56 ms. The median nerve orthodomic sensory latency was found to be 2.57 +/- 0.31 ms. The conduction velocity across the palm and wrist was 41.37 +/- 0.67 ms. The sensitivity was the highest in the inching method (86.25%) and lowest for the conventional median motor and sensory latencies (56.25% and 45%, respectively). CONCLUSIONS: Addition of a single test of median and ulnar sensory latency, the median and radial sensory latency or the inching method, in routine protocol will improve the sensitivity for the diagnosis of CTS in all patients. PMID- 28879888 TI - Carpal tunnel syndrome with equivocal electrophysiological findings: Additional testing may improve diagnostic sensitivity. PMID- 28879889 TI - Predictors of quality of life among adolescents with epilepsy in the state of Andhra Pradesh. AB - OBJECTIVES: Assessment of quality of life (QOL) reveals the impact of diseases and factors responsible for the impairment of quality of life. The purpose of this study was to evaluate the QOL among adolescents with epilepsy (AWE) in the state of Andhra Pradesh. MATERIALS AND METHODS: One hundred and fifty AWE aged 13 19 years were evaluated for QOL using the Telugu version of the Quality of Life in Epilepsy Inventory for Adolescents (QOLIE) AD-48 and the data were analyzed to predict the factors responsible for determining the QOL. RESULTS: The mean age of AWE was 15.86 +/- 2.14 years. The age at onset of seizures among AWE was 9.28 +/- 4.90 years. Generalized (45%) and partial seizures (34%) were the predominant types of seizures. The majority of AWE (77%) were taking anti epileptic medication for 1-8 years, were on monotherapy (55%), and were seizure free for the last 1 year (56%). The mean total QOL score in AWE was 72 +/- 15. The high school-educated, seizure-free, and monotherapy-taking AWEs showed a significantly higher mean total QOL when compared to the primary school- educated, seizure frequent, and polytherapy-taking AWEs (P < 0.01). Education (standardized beta [Sbeta] = 0.163 P < 0.05), seizure frequency (Sbeta-0.603; P < 0.01), and poly therapy (Sbeta-0.08; P < 0.01) were significant predictors of QOL in AWE. CONCLUSIONS: The results of the study suggest that in addition to seizure control, encouraging monotherapy and enhancing the education level may improve the QOL in AWE. PMID- 28879890 TI - Evaluation of hand function in healthy individuals and patients undergoing uninstrumented central corpectomy for cervical spondylotic myelopathy using nine hole peg test. AB - OBJECTIVES: To evaluate the hand function in healthy individuals and in patients with cervical spondylotic myelopathy (CSM) undergoing central corpectomy using the nine-hole peg test (NHPT). MATERIALS AND METHODS: The NHPT was performed in healthy adults and in patients with CSM; overall, five trials were performed in the right and left hand separately. The preoperative and follow up NHPT score was compared to the normal and correlated with Nurick and modified Japanese Orthopedic Association (mJOA) scales. RESULTS: The NHPT score was significantly less in adult healthy female compared to adult healthy male subjects (difference, 0.71 s, P < 0.002). The distribution of the NHPT scores in normal adults followed the normal binomial distribution. The time taken to perform the NHPT with the right hand was significantly lower than the time taken to perform the NHPT with the left hand in both the sexes (P < 0.001). Thirty-six of the 47 patients with CSM (76.6%) had a prolonged preoperative NHPT score. There was a strong negative correlation between the preoperative NHPT score and the preoperative upper limb component of the modified-Japanese Orthopedic Association (UlmJOA) score. No significant change was detected in the NHPT score at one week postoperatively. On follow-up at six months or more (n = 21), the NHPT score normalized in five (35.7%) of the 14 patients in whom it was prolonged preoperatively. The NHPT score remained the same as the preoperative status in the other 16 patients, 7 of whom had a normal score preoperatively. The change in the NHPT score at follow-up did not correlate with the change in the UlmJOA score. CONCLUSIONS: Normative data among the Indian population suggest that female subjects have significantly lower scores than the male ones, and that there is a difference between the two sides that needs to be considered while reporting the NHPT scores in disease. The NHPT scores were prolonged preoperatively in CSM and showed a correlation with the UlmJOA score, and there was no significant change noted at one week follow up. While the NHPT score is a good quantitative test to evaluate hand function in patients with CSM and could detect subtle hand dysfunction preoperatively, it has a limited role, when used alone, to detect changes in hand function postoperatively. PMID- 28879891 TI - Restoration of hand function: A critical parameter during neurorehabilitation, and the confounding factors influencing its evaluation. PMID- 28879892 TI - Nine-hole peg test for evaluation of hand function: The advantages and shortcomings. PMID- 28879893 TI - A novel swine model of subarachnoid hemorrhage-induced cerebral vasospasm. AB - OBJECTIVE: One of the most serious complications following subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI) secondary to symptomatic vasospasm. An animal model mimicking post SAH vasospasm is essential for enabling the translation of newer technologies from the conceptual phase to animal studies, and eventually to clinical trials. Various animal models of DCI following SAH have been reported, with canine models being the most common. Due to the similarity of the swine cardiovascular system and its dimensions to the human's system, the main objective of this study was to establish a consistent and quantitatively representative model of SAH-induced vasospasm in swine. MATERIALS AND METHODS: Twelve female swines (57 +/- 3 kg) were injected twice (with a 2-day interval between injections) with autologous blood into the subarachnoid space at the level of C2-3 vertebrae. Different volumes were injected to identify clinical and radiological changes. The effect of volume variations on hematoma size and vasospasm intensity in the circle of Willis arteries were studied 7-14 days after the first injection using ascending pharyngeal angiographic measurements of vessel diameter. Neurological outcome using a modified scoring table based on clinical parameters (e.g., appetite, behavior, walking, posture, and eye movement) was recorded. RESULTS: Our results demonstrate that between volume combinations, intrathecal injection of 12 ml followed by 15 ml, with a 2-day interval in between, resulted in the most extensive angiographically-assessed vasospasm 12 +/- 2 days following the first injection. The degree of vasospasm in the intracranial internal carotid artery was 22% and 16% for the left and right sides, respectively. Vasoconstriction of the anterior cerebral artery was 34% and 27% for the left and right sides, respectively. The vasoconstriction was not associated with either overt clinical signs or clinical outcome, which is indicative of an ischemic event. CONCLUSIONS: The relative scarcity of swine models for SAH-induced vasospasm motivated us to develop and quantify a straightforward protocol for producing consistent mild-to moderate vasospasm following SAH. As swine is commonly used in translational cardiovascular research, we believe that this study constitutes an important phase in the study of SAH and in developing pharmacological agents and medical devices for interventions. PMID- 28879894 TI - Animal models for cerebral vasospasm: Where do we stand? PMID- 28879895 TI - Perfusion MR imaging of enhancing brain tumors: Comparison of arterial spin labeling technique with dynamic susceptibility contrast technique. AB - OBJECTIVE: Arterial spin labeling (ASL) magnetic resonance (MR) perfusion is a noninvasive and repeatable method for quantitatively measuring cerebral blood flow (CBF). This study aims to compare measurements of ASL-derived CBF with dynamic susceptibility contrast (DSC) MRI in the assessment of enhancing brain tumors (primary and metastatic), with an aim to use ASL as an alternative to DSC. MATERIALS AND METHODS: Thirty patients with newly diagnosed brain tumors (16 meningiomas, 6 gliomas, 3 metastases, 2 cerebellopontine angle schwannoma, 1 central neurocytoma, and 2 low-grade gliomas) were examined using a 3T MR scanner. Values of CBF, regional cerebral blood flow (rCBF), and regional cerebral blood volume (rCBV) were determined in the tumor (T) as well as in the contralateral normal gray matter (GM) and white matter (WM). Tumor-to-GM or WM CBF, rCBF, and rCBV ratios were calculated to estimate normalized perfusion values (i.e., ASL normalized tumor blood flow [nTBF], DSC nTBF, and DSC normalized tumor blood volume [nTBV]) from the ASL and DSC techniques. ASL and DSC MRI derived perfusion parameters were compared using paired t-test and correlated using Pearson correlation coefficient. RESULTS: Mean values for ASL nTBF and DSC nTBF using contralateral GM as the reference point were 2.98 +/- 1.67and 2.91 +/- 1.43, respectively. A very strong correlation coefficient was found between ASL nTBF and DSC nTBF with contralateral GM as the reference region (r = 0.903; R2= 0.813). Mean DSC nTBF and DSC nTBV also showed strong correlation (r = 0.83; R2= 0.701). CONCLUSION: Our study results suggested that measurement of CBF from ASL possesses the potential for a noninvasive assessment of blood flow in intracranial tumors as an alternate to DSC MRI, in those patients requiring multiple follow-up imaging and in patients with impaired renal functions. PMID- 28879896 TI - A comparison of the recovery profiles of desflurane and isoflurane anesthesia in patients undergoing elective supratentorial craniotomy: A randomized controlled trial. AB - CONTEXT: Few studies have compared recovery profiles of desflurane and isoflurane for patients undergoing elective supratentorial craniotomy. It is not known if the choice of inhalational agent can affect the duration of transient postoperative neurological deficits in these patients. AIMS: To compare the effect of desflurane and isoflurane on time-to-emergence and time-to-recovery of transient postoperative neurological deficits in patients undergoing supratentorial craniotomy. SETTINGS AND DESIGN: Prospective, double-blinded, randomized controlled trial at a tertiary care hospital. METHODS AND MATERIALS: We randomly assigned 60 patients to receive either desflurane or isoflurane during elective supratentorial craniotomy for intra-axial mass lesions. Time-to emergence and time-to-recovery of transient postoperative neurological deficits were recorded and compared. STATISTICAL ANALYSIS USED: Parametric variables were compared by the Student's t test. Baseline data was compared using Pearson's chi square test, Fisher's exact test and two proportion Z test. RESULTS: There was a 35.7%, 31.4% and 34.5% reduction in median times to eye opening, obeying commands and orientation in the desflurane group (n=27) as compared to the isoflurane group (n=28). Five patients were enrolled but not included for analysis-Twelve patients sustained transient neurological deficits after surgery (desflurane, n=3; isoflurane, n=9). No significant difference in the time-to-recovery of transient postoperative neurological deficits was observed. CONCLUSIONS: Desflurane significantly reduced emergence times, and was able to facilitate an early neurological examination for patients. Additional studies are required to establish the impact of inhalational agents on transient postoperative neurological deficits. PMID- 28879897 TI - The art of waking up a neurosurgical patient: It is time to hone our skills. PMID- 28879898 TI - Progressive multifocal leukoencephalopathy in a 44-year old male with idiopathic CD4+ T-lymphocytopenia treated with mirtazapine and mefloquine. AB - Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the central nervous system caused by the reactivation of John Cunningham virus (JCV) in immunocompromised patients, most commonly in human immunodeficiency virus (HIV) infection, and less commonly in those receiving various immunosuppressive regimens. Prognosis of untreated PML is grave and the mainstay of treatment is the reversal of immunosuppression, usually by institution of antiretroviral drugs in HIV patients and cessation of immunosuppressive therapies in others. PML is increasingly being reported in those with minimal or occult immunosuppression. A small fraction of these patients meet the criteria for idiopathic CD4+ T-lymphocytopenia (ICL) after exclusion of all secondary causes of lymphocytopenia, including HIV. A 44-year old previously healthy male presented with clinical and radiological features suggestive of PML. Cerebrospinal fluid samples were repeatedly negative for JCV. Immunohistochemistry on brain biopsy eventually confirmed PML. Despite extensive work-up, the only abnormality detected was an unexplained and persistently low absolute CD4+ T-lymphocyte count. Based on the limited available literature on the treatment of non-HIV PML, he was treated with a combination of mirtazapine and mefloquine with clinical improvement. Non-HIV PML remains relatively uncommon, and PML as a presenting feature of ICL is rare. It is important to document and follow these patients to be able to assess the relative risks associated with various causes and formulate effective therapeutic strategies. PMID- 28879899 TI - Hyperekplexia: A forgotten diagnosis clinched by next-generation sequencing. AB - Hyperekplexia is a rare early neonatal onset, potentially treatable, neurological disorder, characterized by a triad of immediate neonatal-onset stiffness, an exaggerated startle reflex in response to tactile or auditory stimuli followed by short periodical generalized stiffness. It is a monogenic genetically heterogeneous condition which can be potentially life threatening due to apneic episodes and is usually misdiagnosed as seizures. Here, we report two female siblings with hyperekplexia who were being treated by multiple antiepileptic medications for seizure-like episodes. Hyperekplexia was diagnosed by next generation sequencing, which has emerged as a powerful diagnostic tool over the last few years. PMID- 28879900 TI - Simultaneous odontoid excision with bilateral posterior C1-2 distraction and stabilization utilizing bilateral posterolateral corridors and a single posterior midline incision. AB - A simultaneous odontoid decompression and bilateral posterior atlanto-axial facetal distraction, C1-2 joint spacer/bone graft placement and stabilization may be performed utilizing the 'posterior-only' approach. This procedure may be performed utilizing a single posterior midline incision, a bilateral posterior approach to the C1-2 facet joints and a bilateral posterolateral approach to the odontoid process and C2 body. It may be carried out in situations where a C1-2 non-reduction/partial reduction using a 'posterior alone' procedure is anticipated due to the complex bony/soft tissue configuration anterior at the thecal sac existing at the cervicomedullary junction. In the four cases described in this report, the procedure led to a successful circumferential decompression at the level of foramen magnum along with posterior C1-2 facetal distraction and stabilization in various complex craniovertebral junction anomalies (atlantoaxial dislocation [AAD] and/or a high basilar invagination [BI] associated with a significantly retroverted dens, along with a rotatory component, due to grossly asymmetrical facet joints). This technique may also be utilized in those diseases that result in an anterior osteoligamentous mass at the CVJ associated with C1-2 instability. PMID- 28879901 TI - BRAF gene alterations and enhanced mammalian target of rapamycin signaling in gangliogliomas. AB - BACKGROUND: Gangliogliomas (GGs) are slow-growing glioneuronal tumors seen in children and young adults. They are associated with intractable epilepsy, and have recently been found to harbor BRAF (B- rapidly accelerated fibrosarcoma) gene mutations. However, the mammalian target of rapamycin (mTOR) signaling pathway, downstream of BRAF, has not been evaluated extensively in GGs. MATERIALS AND METHODS: GG cases were retrieved, clinical data obtained, and histopathological features reviewed. Sequencing for BRAF V600E mutation, analysis of BRAF copy number by quantitative real-time polymerase chain reaction, and immunohistochemistry for mTOR pathway markers p-S6 and p-4EBP1 were performed. RESULTS: Sixty-four cases of GG were identified (0.9% of central nervous system tumors). Of these, 28 had sufficient tumor tissue for further evaluation. Mixed glial and neuronal morphology was the commonest (64%) type. Focal cortical dysplasia was identified in the adjacent cortex (6 cases). BRAF V600E mutation was identified in 30% of GGs; BRAF copy number gain was observed in 50% of them. p-S6 and p-4EBP1 immunopositivity was seen in 57% cases each. Thus, mTOR pathway activation was seen in 81% cases, and was independent of BRAF alterations. 87% patients had Engel grade I outcome, while 13% had Engel grade II outcome. Both the Engel grade II cases analyzed showed BRAF V600E mutation. CONCLUSION: BRAF V600E mutation is frequent in GGs, as is BRAF gain; the former may serve as a target for personalized therapy in patients with residual tumors, necessitating its assessment in routine pathology reporting of these tumors. Evidence of mTOR pathway activation highlights similarities in the pathogenetic mechanisms underlying GG and focal cortical dysplasia, and suggests that mTOR inhibitors may be of utility in GG patients with persistent seizures after surgery. PMID- 28879902 TI - Review of tremor in Parkinson's disease and atypical parkinsonian disorders. AB - Rest tremor (RT), a cardinal feature of Parkinson's disease (PD) is often accompanied by other types of tremor such as action tremor, which includes postural tremor, kinetic tremor, re-emergent tremor (ReT), and orthostatic tremor (OT). Literature on other tremors of PD, especially ReT and OT, is scarce. Tremor can be present in any of the atypical parkinsonian disorders such as progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and dementia with Lewy bodies. RT can even be the presenting symptom of these disorders. The objective of this review is to provide a comprehensive review of lesser known tremors in PD and to critically look at the prevalence of tremor in atypical Parkinsonian disorders. PMID- 28879903 TI - Management strategies in tremors: A bird's eye view. PMID- 28879904 TI - A neurosurgical perspective to approaches to the orbit: A cadaveric study. AB - Neurosurgeons are getting increasingly involved in surgery for orbital tumours. The various approaches to the orbit can be challenging. The authors have demonstrated on cadavers the various approaches to the orbit which are required to be mastered by the neurosurgeon. The superior approaches which include the transcranial, supraorbital and the hybrid approaches are the most commonly utilized surgical approaches by the neurosurgeon for excision of orbital pathologies. The lateral orbitotomy is an elegant approach for excision of the tumours lateral to the optic Nerve and lacrimal gland tumours. The authors also demonstrate the medial approach through a medial orbitotomy which is a relatively unfamiliar approach to neurosurgeons. The importance of the various landmarks in each approach is emphasised along with the methods to minimize complications. It is imperative that neurosurgeons are intimately familiar with the microsurgical anatomy of the orbit and the various approaches to it. PMID- 28879905 TI - Endonasal endoscopic approach to orbit. PMID- 28879906 TI - Neurosurgery at Kasturba Medical College: Past, present and future. AB - Kasturba Medical College (KMC), Manipal, is the oldest and one of the most reputed medical institutes in coastal Karnataka, catering to a population of over 4 million, spanning a stretch of over 350 kms along the southwest coast of India from Mangalore to Goa. The Department of Neurosurgery at KMC, established in 1968, continues to be the leading and most preferred referral center providing high quality neurosurgical services in this region. The article provides an insight into the origin of the department, its infancy and teething troubles, its continuous growth and landmark achievements over the years. This brief review also highlights the current area of focus and describes the plans for its future development. PMID- 28879907 TI - A summary of some of the recently published, seminal papers in neuroscience. PMID- 28879909 TI - Acute spinal cord infarction after aortobifemoral bypass. PMID- 28879908 TI - Multiple paraneoplastic antibodies (anti-SOX1, anti-Hu, and anti-Amphiphysin) detected in a patient with limbic encephalitis and small cell lung cancer. PMID- 28879910 TI - MRI findings in a fetus with a tight cord around the neck. PMID- 28879911 TI - Neurosarcoidosis-induced longitudinal extensive transverse myelitis. PMID- 28879912 TI - A case of clear cell ependymoma with bizarre aggressiveness: Are we underestimating its ferocity? PMID- 28879913 TI - Acute hemicerebellitis in children: A report and literature review. PMID- 28879914 TI - Palatal tremor secondary to a dolichoectatic basilar artery. PMID- 28879915 TI - Novel c.775_781dup,p(Thr261fs) mutation in SPG 7 gene in a patient with hereditary spastic paraparesis. PMID- 28879916 TI - Meningitis, polyradiculopathy, and optic nerve involvement in neurobrucellosis: A rare clinical presentation. PMID- 28879917 TI - Anarthria in a patient with bilateral striopallidodentate calcinosis. PMID- 28879918 TI - Magnetic resonance imaging findings in heat stroke-related encephalopathy. PMID- 28879919 TI - Faciobrachial dystonic spells: Presenting feature of autoimmune encephalopathy. PMID- 28879920 TI - Stiff-person syndrome after thymectomy in myasthenia gravis mimicking a post thymectomy myasthenic crisis. PMID- 28879921 TI - Spinocerebellar ataxia type 2 associated with amyotrophic lateral sclerosis. PMID- 28879922 TI - Commentary: Amyotrophic lateral sclerosis: Ongoing search for prognostic biomarkers of longevity. PMID- 28879923 TI - Unusual presentation and temporal events in a patient with cavernous carotid aneurysm. PMID- 28879924 TI - "Round the Houses" sign and apraxia of eyelid opening in a 62-year old man. PMID- 28879925 TI - Granular cell tumor at an unusual site masquerading as a neurofibroma. PMID- 28879926 TI - Thyrotropic pituitary adenoma with plurihormonal immunoreactivity. PMID- 28879927 TI - Hemorrhagic colloid cyst. PMID- 28879928 TI - Primary pituitary abscess in preadolescence mimicking a sellar mass. PMID- 28879929 TI - Intracranial inflammatory pseudotumor presenting as an en plaque mass. PMID- 28879930 TI - Management of a case of neglected atlantoaxial rotatory dislocation. PMID- 28879931 TI - Dural-based giant cavernous hemangioma mimicking a meningioma: Lessons learnt. PMID- 28879932 TI - Rosette-forming glioneuronal tumor of the fourth ventricle. PMID- 28879933 TI - Subgaleoatrial shunt: Further progress in the management of iatrogenic cranial pseudomeningoceles. PMID- 28879934 TI - Primary epithelioid hemangioendothelioma of the dorsal spine: A review. PMID- 28879935 TI - Spontaneous resolution of syringomyelia in Chiari I malformation: A review of literature. PMID- 28879936 TI - Gestational Wernicke's encephalopathy. PMID- 28879937 TI - Canavan disease with typical brain MRI and MRS findings. PMID- 28879938 TI - Isoniazid toxicity presenting as bilateral dentate hyperintensities. PMID- 28879939 TI - A report of third case of Susac syndrome from India. PMID- 28879940 TI - Isolated globus pallidi hypointensities in type 2 GM1 gangliosidoses. PMID- 28879941 TI - A rare cause of neck pain: Holocord intramedullary lipoma. PMID- 28879942 TI - Incidental finding of an accessory middle cerebral artery in a patient with multiple aneurysms. PMID- 28879943 TI - Synthesis and Characterization of Self-Assembled Nanogels Made of Pullulan. AB - Self-assembled nanogels made of hydrophobized pullulan were obtained using a versatile, simple, reproducible and low-cost method. In a first reaction pullulan was modified with hydroxyethyl methacrylate or vinyl methacrylate, further modified in the second step with hydrophobic 1-hexadecanethiol, resulting as an amphiphilic material, which self-assembles in water via the hydrophobic interaction among alkyl chains. Structural features, size, shape, surface charge and stability of the nanogels were studied using hydrogen nuclear magnetic resonance, fluorescence spectroscopy, cryo-field emission scanning electron microscopy and dynamic light scattering. Above the critical aggregation concentration spherical polydisperse macromolecular micelles revealed long-term colloidal stability in aqueous medium, with a nearly neutral negative surface charge and mean hydrodynamic diameter in the range 100-400 nm, depending on the polymer degree of substitution. Good size stability was observed when nanogels were exposed to potential destabilizing pH conditions. While the size stability of the nanogel made of pullulan with vinyl methacrylate and more hydrophobic chains grafted was affected by the ionic strength and urea, nanogel made of pullulan with hydroxyethyl methacrylate and fewer hydrophobic chains grafted remained stable. PMID- 28879944 TI - Enhancing Crystallinity and Orientation by Hot-Stretching to Improve the Mechanical Properties of Electrospun Partially Aligned Polyacrylonitrile (PAN) Nanocomposites. AB - Partially aligned polyacrylonitrile (PAN)-based nanofibers were electrospun from PAN and PAN/single-walled carbon nanotubes (SWNTs) in a solution of dimethylformamide (DMF) to make the nanofiber composites. The as-spun nanofibers were then hot-stretched in the oven to enhance its orientation and crystallinity. With the introduction of SWNTs and by the hot-stretched process, the mechanical properties will be enhanced correspondingly. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray scattering (XRD), differential scanning calorimetry (DSC), and the tensile test were used to characterize the microstructure and performances of the nanofibers. The orientation and crystallinity of the as-spun and hot-stretched nanofibers confirmed by X-ray have increased. Differential scanning calorimetry showed that the glass transition temperature of PAN increased about 3 degrees C by an addition of 0.75 wt% SWNTs indicating a strong interfacial interaction between PAN and SWNTs. The tensile strength and the modulus of the nanofibers increased revealing significant load transfer across the nanotube-matrix interface. For PAN nanofibers, the improved fiber alignment, orientation and crystallinity resulted in enhanced mechanical properties, such as the tensile strength and modulus of the nanofibers. It was concluded that the hot-stretched nanofiber and the PAN/SWNTs nanofibers can be used as a potential precursor to produce high-performance nanocomposites. PMID- 28879945 TI - Prior Surface Integrity Assessment of Coated and Uncoated Carbide Inserts Using Atomic Force Microscopy. AB - Coated carbide inserts are considered vital components in machining processes and advanced functional surface integrity of inserts and their coating are decisive factors for tool life. Atomic Force Microscopy (AFM) implementation has gained acceptance over a wide spectrum of research and science applications. When used in a proper systematic manner, the AFM features can be a valuable tool for assessment of tool surface integrity. The aim of this paper is to assess the integrity of coated and uncoated carbide inserts using AFM analytical parameters. Surface morphology of as-received coated and uncoated carbide inserts is examined, analyzed, and characterized through the determination of the appropriate scanning setting, the suitable data type imaging techniques and the most representative data analysis parameters using the MultiMode AFM microscope in contact mode. The results indicate that it is preferable to start with a wider scan size in order to get more accurate interpretation of surface topography. Results are found credible to support the idea that AFM can be used efficiently in detecting flaws and defects of coated and uncoated carbide inserts using specific features such as "Roughness" and "Section" parameters. A recommended strategy is provided for surface examination procedures of cutting inserts using various AFM controlling parameters. PMID- 28879946 TI - Magnetoelectric Interactions in Lead-Based and Lead-Free Composites. AB - Magnetoelectric (ME) composites that simultaneously exhibit ferroelectricity and ferromagnetism have recently gained significant attention as evident by the increasing number of publications. These research activities are direct results of the fact that multiferroic magnetoelectrics offer significant technological promise for multiple devices. Appropriate choice of phases with co-firing capability, magnetostriction and piezoelectric coefficient, such as Ni-PZT and NZFO-PZT, has resulted in fabrication of prototype components that promise transition. In this manuscript, we report the properties of Ni-PZT and NZFO-PZT composites in terms of ME voltage coefficients as a function of frequency and magnetic DC bias. In order to overcome the problem of toxicity of lead, we have conducted experiments with Pb-free piezoelectric compositions. Results are presented on the magnetoelectric performance of Ni-NKN, Ni-NBTBT and NZFO-NKN, NZFO-NBTBT systems illustrating their importance as an environmentally friendly alternative. PMID- 28879947 TI - Efficacy and Durability in Direct Labeling of Mesenchymal Stem Cells Using Ultrasmall Superparamagnetic Iron Oxide Nanoparticles with Organosilica, Dextran, and PEG Coatings. AB - We herein report a comparative study of mesenchymal stem cell (MSC) labeling using spherical superparamagnetic iron oxide (SPIO) nanoparticles containing different coatings, namely, organosilica, dextran, and poly(ethylene glycol) (PEG). These nanomaterials possess a similar SPIO core size of 6-7 nm. Together with their coatings, the overall sizes are 10-15 nm for all SPIO@SiO2, SPIO@dextran, and SPIO@PEG nanoparticles. These nanoparticles were investigated for their efficacies to be uptaken by rabbit bone marrow-derived MSCs without any transfecting agent. Experimentally, both SPIO@SiO2 and SPIO@PEG nanoparticles could be successfully uptaken by MSCs while the SPIO@dextran nanoparticles demonstrated limited labeling efficiency. The labeling durability of SPIO@SiO2 and SPIO@PEG nanoparticles in MSCs after three weeks of culture were compared by Prussian blue staining tests. SPIO@SiO2 nanoparticles demonstrated more blue staining than SPIO@PEG nanoparticles, rendering them better materials for MSCs labeling by direct uptake when durable intracellullar retention of SPIO is desired. PMID- 28879948 TI - New Approaches to the Computer Simulation of Amorphous Alloys: A Review. AB - In this work we review our new methods to computer generate amorphous atomic topologies of several binary alloys: SiH, SiN, CN; binary systems based on group IV elements like SiC; the GeSe2 chalcogenide; aluminum-based systems: AlN and AlSi, and the CuZr amorphous alloy. We use an ab initio approach based on density functionals and computationally thermally-randomized periodically-continued cells with at least 108 atoms. The computational thermal process to generate the amorphous alloys is the undermelt-quench approach, or one of its variants, that consists in linearly heating the samples to just below their melting (or liquidus) temperatures, and then linearly cooling them afterwards. These processes are carried out from initial crystalline conditions using short and long time steps. We find that a step four-times the default time step is adequate for most of the simulations. Radial distribution functions (partial and total) are calculated and compared whenever possible with experimental results, and the agreement is very good. For some materials we report studies of the effect of the topological disorder on their electronic and vibrational densities of states and on their optical properties. PMID- 28879949 TI - Open-Cellular Co-Base and Ni-Base Superalloys Fabricated by Electron Beam Melting. AB - Reticulated mesh samples of Co-29Cr-6Mo alloy and Ni-21Cr-9Mo-4Nb alloy (625) and stochastic foam samples of Co-29Cr-6Mo alloy fabricated by electron beam melting were characterized by optical metallography, and the dynamic stiffness (Young's modulus) was measured by resonant frequency analysis. The relative stiffness (E/Es) versus relative density (rho/rhos) plotted on a log-log basis resulted in a fitted straight line with a slope n ? 2, consistent with that for ideal open cellular materials. PMID- 28879950 TI - Gold Nanostructures for Surface-Enhanced Raman Spectroscopy, Prepared by Electrodeposition in Porous Silicon. AB - Electrodeposition of gold into porous silicon was investigated. In the present study, porous silicon with ~100 nm in pore diameter, so-called medium-sized pores, was used as template electrode for gold electrodeposition. The growth behavior of gold deposits was studied by scanning electron microscope observation of the gold deposited porous silicon. Gold nanorod arrays with different rod lengths were prepared, and their surface-enhanced Raman scattering properties were investigated. We found that the absorption peak due to the surface plasmon resonance can be tuned by changing the length of the nanorods. The optimum length of the gold nanorods was ~600 nm for surface-enhanced Raman spectroscopy using a He-Ne laser. The reason why the optimum length of the gold nanorods was 600 nm was discussed by considering the relationship between the absorption peak of surface plasmon resonance and the wavelength of the incident laser for Raman scattering. PMID- 28879951 TI - Structural Consideration in Designing Organotin Polyethers to Arrest the Growth of Breast Cancer Cells In Vitro. AB - The ability to inhibit cancer is inherent in organotin materials yet the structural relationships that regulate/direct this activity remains unknown. We measured antitumor activity using a matched pair of cell lines MDA-MB-231 cells that are estrogen-independent, estrogen receptor negative and MCF-7 cells, a cell line that is estrogen receptor (ER) positive. Those polyethers that contained a O phenyl unit were able to significantly inhibit the non-estrogen sensitive cell line but were much less effective against the estrogen sensitive cell line; that is, the human breast cancer cell line MDA-MB-231 showed better test results for polymers derived from diols containing the O-phenyl moiety than the breast cancer cell line MCF-7, a well-characterized estrogen receptor positive control cell line. Those polyethers that did not contain the O-phenyl unit inhibited both cell lines approximately the same. The differential activity of the O-phenyl containing polyethers is likely due to the estrogen-sensitive cells combining with some of the organotin polyethers minimizing their ability to inhibit cell growth. PMID- 28879952 TI - Progress of Application Researches of Porous Fiber Metals. AB - Metal fiber porous materials with intrinsic properties of metal and functional properties of porous materials have received a great deal of attention in the fundamental research and industry applications. With developments of the preparation technologies and industrial requirements, porous fiber metals with excellent properties are developed and applied in many industry areas, e.g., sound absorption, heat transfer, energy absorption and lightweight structures. The applied research progress of the metal fiber porous materials in such application areas based on the recent work in our group was reviewed in this paper. PMID- 28879953 TI - Electrochemically Formed Porous Silica. AB - Controlled electrochemical formation of porous silica can be realized in dilute aqueous, neutral-pH, fluoride medium. Formation of a porous film is initiated by sweeping the potential applied to silicon to values higher than 20 V. Film formation, reaching a steady state, may be pursued in a wide range of potentials, including lower potentials. The origin of a threshold potential for porous film initiation has been explained quantitatively. All of the films appear mesoporous. Films grown at high potentials exhibit a variety of macrostructures superimposed on the mesoporosity. These macrostructures result from selective dissolution of silica induced by local pH lowering due to oxygen evolution. Films grown at potentials lower than 15 V appear uniform on the micrometer scale. However, all of the films also exhibit a stratified structure on the scale of a few tens of nanometres. This periodic structure can be traced back to the oscillatory behavior observed during the electrochemical dissolution of silicon in fluoride medium. It suggests that periodic breaking of the growing film may be responsible for this morphology. PMID- 28879954 TI - Preparation, Characterization and Performance of Templated Silica Membranes in Non-Osmotic Desalination. AB - In this work we investigate the potential of a polyethylene glycol-polypropylene glycol-polyethylene glycol, tri-block copolymer as a template for a hybrid carbon/silica membrane for use in the non-osmotic desalination of seawater. Silica samples were loaded with varying amounts of tri-block copolymer and calcined in a vacuum to carbonize the template and trap it within the silica matrix. The resultant xerogels were analyzed with FTIR, Thermogravimetric analysis (TGA) and N2 sorption techniques, wherein it was determined that template loadings of 10 and 20% produced silica networks with enhanced pore volumes and appropriately sized pores for desalination. Membranes were created via two different routes and tested with feed concentrations of 3, 10 and 35 ppk of NaCl at room temperature employing a transmembrane pressure drop of 85% (in most cases >95%) and fluxes higher than 1.6 kg m-2 h-1. Furthermore, the carbonized templated membranes displayed equal or improved performance compared to similarly prepared non-templated silica membranes, with the best results of a flux of 3.7 kg m-2 h-1 with 98.5% salt rejection capacity, exceeding previous literature reports. In addition, the templated silica membranes exhibited superior hydrostability demonstrating their potential for long-term operation. PMID- 28879955 TI - Thermodynamic Origin of the Vitreous Transition. AB - The vitreous transition is characterized by a freezing of atomic degrees of freedom at a temperature Tg depending on the heating and cooling rates. A kinetic origin is generally attributed to this phenomenon instead of a thermodynamic one which we develop here. Completed homogeneous nucleation laws reflecting the energy saving due to Fermi energy equalization of nascent crystals and their melt are used. They are applied to bulk metallic glasses and extended to inorganic glasses and polymers. A transition T*g among various Tg corresponds to a crystal homogeneous nucleation temperature, leading to a preliminary formation of a cluster distribution during the relaxation time preceding the long steady-state nucleation time of crystals in small samples. The thermally-activated energy barrier DeltaG*2ls/kBT at T*g for homogeneous nucleation is nearly the same in all glass-forming melts and determined by similar values of viscosity and a thermally-activated diffusion barrier from melt to cluster. The glass transition T*g is a material constant and a linear function of the energy saving associated with charge transfers from nascent clusters to the melt. The vitreous transition and the melting temperatures alone are used to predict the free-volume disappearance temperature equal to the Vogel-Fulcher-Tammann temperature of fragile glass-forming melts, in agreement with many viscosity measurements. The reversible thermodynamic vitreous transition is determined by the disappearance temperature T*g of the fully-relaxed enthalpy Hr that is not time dependent; the observed specific heat jump at T*g is equal to the proportionality coefficient of Hr with (T*g - Ta) for T <= T*g as expected from the enthalpy excess stored by a quenched undercooled melt at the annealing temperature Ta and relaxed towards an equilibrium vitreous state. However, the heat flux measurements found in literature over the last 50 years only gave an out-of-equilibrium Tg since the enthalpy is continuous at T*g without visible heat jump. PMID- 28879956 TI - Role of Titanium Surface Topography and Surface Wettability on Focal Adhesion Kinase Mediated Signaling in Fibroblasts. AB - Changes of titanium surface roughness and surface free energy may influence protein absorption that increases cell differentiation through activation of focal adhesion kinase related pathways. However, the influence of titanium surface roughness and hydrophilicity on fibroblast behavior is not well understood. The aim of this study was to investigate the influence of topography and hydrophilicity on fibroblast attachment, spreading, morphology, intracellular signaling, proliferation, and collagen I mRNA levels. Using a cellular FAK knockout (FAK-/-) model and wild-type (WT) controls, we also investigated the contribution of adhesion in fibroblasts cultured on smooth (PT), sand-blasted, large grit, acid-etched (SLA) and hydrophilic SLA topographies. Loss of FAK did not significantly affect fibroblast attachment to any surface, but SLA and hydrophilic SLA surface attenuated spreading of WT cells significantly more than FAK-/- fibroblasts. Both FAK-/- and WT cells formed numerous focal adhesions on PT surfaces, but significantly less on SLA and hydrophilic SLA surfaces. In WT cells, phosphorylation levels of FAK were lower on SLA and hydrophilic SLA in comparison with PT 24 h post seeding. Labeling of cells with antibodies to cortactin showed that FAK-/-cells contained significantly more cortactin-rich focal adhesion in comparison with WT cells on PT surfaces, but not on SLA or hydrophilic SLA. ERK 1/2 phosphorylation was highest in WT cells on all surfaces which correlated with collagen I expression levels. We conclude that fibroblasts are sensitive to changes in surface roughness and hydrophilicity, with adhesive interactions mediated through FAK, an important modulator of fibroblast response. PMID- 28879957 TI - Magnetic Nanoparticles Embedded in a Silicon Matrix. AB - This paper represents a short overview of nanocomposites consisting of magnetic nanoparticles incorporated into the pores of a porous silicon matrix by two different methods. On the one hand, nickel is electrochemically deposited whereas the nanoparticles are precipitated on the pore walls. The size of these particles is between 2 and 6 nm. These particles cover the pore walls and form a tube-like arrangement. On the other hand, rather well monodispersed iron oxide nanoparticles, of 5 and 8 nm respectively, are infiltrated into the pores. From their size the particles would be superparamagnetic if isolated but due to magnetic interactions between them, ordering of magnetic moments occurs below a blocking temperature and thus the composite system displays a ferromagnetic behavior. This transition temperature of the nanocomposite can be varied by changing the filling factor of the particles within the pores. Thus samples with magnetic properties which are variable in a broad range can be achieved, which renders this composite system interesting not only for basic research but also for applications, especially because of the silicon base material which makes it possible for today's process technology. PMID- 28879958 TI - Nanohardness and Residual Stress in TiN Coatings. AB - TiN films were prepared by the Cathodic arc evaporation deposition method under different negative substrate bias. AFM image analyses show that the growth mode of biased coatings changes from 3D island to lateral when the negative bias potential is increased. Nanohardness of the thin films was measured by nanoindentation, and residual stress was determined using Grazing incidence X ray diffraction. The maximum value of residual stress is reached at -100 V substrate bias coinciding with the biggest values of adhesion and nanohardness. Nanoindentation measurement proves that the force-depth curve shifts due to residual stress. The experimental results demonstrate that nanohardness is seriously affected by the residual stress. PMID- 28879959 TI - Layer Transfer from Chemically Etched 150 mm Porous Si Substrates. AB - We demonstrate for the first time the successful layer transfer of an epitaxially grown monocrystalline Si film from a purely chemically etched porous Si substrate of 150 mm diameter to a glass carrier. The surface conditioning for all Si layer transfer processes based on porous Si has been, up to now without exception, carried out by electrochemical etching. In contrast, our chemical stain etching process uses an aqueous HF-rich HF/HNO3 solution. The porosity increases with increasing doping concentration of the Si substrate wafer and with increasing porous layer thickness. In contrast to the electrochemically etched double layers, the porosity profile of the stain etched substrates is highest at the original wafer surface and lowest at the interface between the porous layer and the Si bulk. The epitaxy process is adapted to the high porosity at the surface with regard to the reorganization of the porous layer. PMID- 28879960 TI - Study of Ni Metallization in Macroporous Si Using Wet Chemistry for Radio Frequency Cross-Talk Isolation in Mixed Signal Integrated Circuits. AB - A highly conductive moat or Faraday cage of through-the-wafer thickness in Si substrate was proposed to be effective in shielding electromagnetic interference thereby reducing radio frequency (RF) cross-talk in high performance mixed signal integrated circuits. Such a structure was realized by metallization of selected ultra-high-aspect-ratio macroporous regions that were electrochemically etched in p- Si substrates. The metallization process was conducted by means of wet chemistry in an alkaline aqueous solution containing Ni2+ without reducing agent. It is found that at elevated temperature during immersion, Ni2+ was rapidly reduced and deposited into macroporous Si and a conformal metallization of the macropore sidewalls was obtained in a way that the entire porous Si framework was converted to Ni. A conductive moat was as a result incorporated into p- Si substrate. The experimentally measured reduction of crosstalk in this structure is 5~18 dB at frequencies up to 35 GHz. PMID- 28879961 TI - Microstructural and Process Characterization of Conductive Traces Printed from Ag Particulate Inks. AB - Conductive inks are key enablers for the use of printing techniques in the fabrication of electronic systems. Focus on the understanding of aspects controlling the electrical performance of conductive ink is paramount. A comparison was made between microparticle Ag inks and an Ag nanoparticle ink. The microstructures resulting from thermal cure processes were characterized morphologically and also in terms of their effect on the resistivity of printed traces. For microparticle inks, the variability of resistivity measurements between samples as defined by coefficient of variation (CV) was greater than 0.1 when the resistivity was 10 to 50 times that of bulk Ag. When the resistivity was lower (~1.4 times that of bulk Ag) the CV of sample sets was less than 0.1. In the case of the nanoparticle ink, resistivity was found to decrease by a factor ranging from 1.2 to 1.5 after doubling the amount of layers printed prior to curing though it was expected to remain the same. Increasing the amount of layers printed also enhanced the sintering process. PMID- 28879962 TI - Luminescent Afterglow Behavior in the M2Si5N8: Eu Family (M = Ca, Sr, Ba). AB - Persistent luminescent materials are able to emit light for hours after being excited. The majority of persistent phosphors emit in the blue or green region of the visible spectrum. Orange- or red-emitting phosphors, strongly desired for emergency signage and medical imaging, are scarce. We prepared the nitrido silicates Ca2Si5N8:Eu (orange), Sr2Si5N8:Eu (reddish), Ba2Si5N8:Eu (yellowish orange), and their rare-earth codoped variants (R = Nd, Dy, Sm, Tm) through a solid state reaction, and investigated their luminescence and afterglow properties. In this paper, we describe how the persistent luminescence is affected by the type of codopant and the choice and ratio of the starting products. All the materials exhibit some form of persistent luminescence, but for Sr2Si5N8:Eu,R this is very weak. In Ba2Si5N8:Eu the afterglow remains visible for about 400 s, and Ca2Si5N8:Eu,Tm shows the brightest and longest afterglow, lasting about 2,500 s. For optimal persistent luminescence, the dopant and codopant should be added in their fluoride form, in concentrations below 1 mol%. A Ca3N2 deficiency of about 5% triples the afterglow intensity. Our results show that Ba2Si5N8:Eu(,R) and Ca2Si5N8:Eu(,R) are promising persistent phosphors for applications requiring orange or red light. PMID- 28879964 TI - Synthesis and Properties of a Chiroptically Active Oligomer from 3,4 Ethylenedioxythiophene and (-)-Myrtenal. AB - Oxidative polycondensation of 3,4-ethylenedioxythiophene and (-)-myrtenal was carried out with POCl3. A p-conjugated system thus constructed consists of aromatic and quinoidal alternating structure linked via methine groups. We examined iodine doping effect for the resultant material with electron spin resonance spectroscopy. Circular dichroism spectra in chloroform solution showed blue-shift with increase of iodine concentration. This result indicates that the doping process can tune chiroptical activity of the chiral pi-conjugated system. PMID- 28879965 TI - A Mechanochemical Approach to Porous Silicon Nanoparticles Fabrication. AB - Porous silicon samples have been reduced in nanometric particles by a well known industrial mechanical process, the ball grinding in a planetary mill; the process has been extended to crystalline silicon for comparison purposes. The silicon nanoparticles have been studied by X-ray diffraction, infrared spectroscopy, gas porosimetry and transmission electron microscopy. We have estimated crystallites size from about 50 nm for silicon to 12 nm for porous silicon. The specific surface area of the powders analyzed ranges between 100 m2/g to 29 m2/g depending on the milling time, ranging from 1 to 20 h. Electron microscopy confirms the nanometric size of the particles and reveals a porous structure in the powders obtained by porous silicon samples which has been preserved by the fabrication conditions. Chemical functionalization during the milling process by a siloxane compound has also been demonstrated. PMID- 28879966 TI - Storage Phosphors for Medical Imaging. AB - Computed radiography (CR) uses storage phosphor imaging plates for digital imaging. Absorbed X-ray energy is stored in crystal defects. In read-out the energy is set free as blue photons upon optical stimulation. In the 35 years of CR history, several storage phosphor families were investigated and developed. An explanation is given as to why some materials made it to the commercial stage, while others did not. The photo stimulated luminescence mechanism of the current commercial storage phosphors, BaFBr:Eu2+ and CsBr:Eu2+ is discussed. The relation between storage phosphor plate physical characteristics and image quality is explained. It is demonstrated that the morphology of the phosphor crystals in the CR imaging plate has a very significant impact on its performance. PMID- 28879963 TI - Antiviral Activity of Metal-Containing Polymers-Organotin and Cisplatin-Like Polymers. AB - Polymers containing platinum and to a lesser extent tin, have repeatedly demonstrated antitumor activity in vitro and in vivo against a variety of cell and tumor types. The mechanisms responsible for the antitumor activity include inducing a delay in cell proliferation and sister chromatid exchanges blocking tumor growth. As most DNA and some RNA viruses require, and even induce, infected cells to initiate DNA replication and subsequent cell division, compounds with antitumor activity will very likely also possess antiviral activity. This article examines the use of metal-containing polymers as a novel class of antivirals. PMID- 28879967 TI - Fabrication of Multiferroic Co-Substituted BiFeO3 Epitaxial Films on SrTiO3 (100) Substrates by Radio Frequency Magnetron Sputtering. AB - The 10 at.% Co-substituted BiFeO3 films (of thickness 50 nm) were successfully prepared by radio frequency (r.f.) magnetron sputtering on SrTiO3 (100) substrates with epitaxial relationships of [001](001)Co-BiFeO3//[001](001)SrTiO3. In this study, a single phase Co-substituted BiFeO3 epitaxial film was fabricated by r.f. magnetron sputtering. Sputtering conditions such as Ar, O2 gas pressure, annealing temperature, annealing atmosphere, and sputtering power were systematically changed. It was observed that a low Ar gas pressure and low sputtering power is necessary to suppress the formation of the secondary phases of BiOx. The Co-substituted BiFeO3 films were crystalized with post-annealing at 600 degrees C in air. The process window for single phase films is narrower than that for pure BiFeO3 epitaxial films. By substituting Fe with Co in BiFeO3, the magnetization at room temperature increased to 20 emu/cm3. This result suggests that Co-substituted BiFeO3 films can be used in spin-filter devices. PMID- 28879968 TI - Correlation of Nitrogen Sorption and Confocal Laser Scanning Microscopy for the Analysis of Amino Group Distributions on Mesoporous Silica. AB - Aminopropylalkoxysilanes are frequently used for the functionalization of mesoporous silica. The analysis of amino group distributions on arrays of silica nanochannels by a combination of nitrogen sorption and confocal laser scanning microscopy provides valuable insight into the mechanisms underlying the interaction of these silanes with mesoporous silica surfaces. Tendencies towards external surface functionalization, non-uniform distribution in the pores, and hydrolysis of the silica framework are shown to depend to a large extent on the mobility of the aminopropylalkoxysilane molecules, which can be adjusted by the number and type of alkoxy groups. PMID- 28879969 TI - The Role Played by Computation in Understanding Hard Materials. AB - In the last decade, computation has played a valuable role in the understanding of materials. Hard materials, in particular, are only part of the application. Although materials involving B, C, N or O remain the most valued atomic component of hard materials, with diamond retaining its distinct superiority as the hardest, other materials involving a wide variety of metals are proving important. In the present work the importance of both ab-initio approaches and molecular dynamics aspects will be discussed with application to quite different systems. On one hand, ab-initio methods are applied to lightweight systems and advanced nitrides. Following, the use of molecular dynamics will be considered with application to strong metals that are used for high temperature applications. PMID- 28879970 TI - Teriparatide Therapy as an Adjuvant for Tissue Engineering and Integration of Biomaterials. AB - Critically sized large bone defects commonly result from trauma, radical tumor resections or infections. Currently, massive allografting remain as the clinical standard to treat these critical defects. Unfortunately, allograft healing is limited by the lack of osteogenesis and bio-integration of the graft to the host bone. Based on its widely studied anabolic effects on the bone, we have proposed that teriparatide [recombinant parathyroid hormone (PTH1-34)] could be an effective adjuvant for massive allograft healing. In support of this theory, here we review studies that have demonstrated that intermittent PTH1-34 treatment enhances and accelerates the skeletal repair process via a number of mechanisms including: effects on mesenchymal stem cells (MSC), angiogenesis, chondrogenesis, bone formation and remodeling. We also review the current literature on the effects of PTH1-34 therapy on bone healing, and discuss this drug's long term potential as an adjuvant for endogenous tissue engineering. PMID- 28879971 TI - Optical Properties of ZnO Nanoparticles Capped with Polymers. AB - Optical properties of ZnO nanoparticles capped with polymers were investigated. Polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) were used as capping reagents. ZnO nanoparticles were synthesized by the sol-gel method. Fluorescence and absorption spectra were measured. When we varied the timing of the addition of the polymer to the ZnO nanoparticle solution, the optical properties were drastically changed. When PEG was added to the solution before the synthesis of ZnO nanoparticles, the fluorescence intensity increased. At the same time, the total particle size increased, which indicated that PEG molecules had capped the ZnO nanoparticles. The capping led to surface passivation, which increased fluorescence intensity. However, when PEG was added to the solution after the synthesis of ZnO nanoparticles, the fluorescence and particle size did not change. When PVP was added to the solution before the synthesis of ZnO nanoparticles, aggregation of nanoparticles occurred. When PVP was added to the solution after the synthesis of ZnO nanoparticles, fluorescence and particle size increased. This improvement of optical properties is advantageous to the practical usage of ZnO nanoparticles, such as bioimaging. PMID- 28879972 TI - In Vivo Corrosion of Two Novel Magnesium Alloys ZEK100 and AX30 and Their Mechanical Suitability as Biodegradable Implants. AB - In magnesium alloys, the components used modify the alloy properties. For magnesium implants in contact with bone, rare earths alloys are commonly examined. These were shown to have a higher corrosion resistance than other alloys and a high mechanical strength, but their exact composition is hard to predict. Therefore a reduction of their content could be favorable. The alloys ZEK100 and AX30 have a reduced content or contain no rare earths at all. The aim of the study was to investigate their in vivo degradation and to assess the suitability of the in vivo uCT for the examination of their corrosion. Implants were inserted in rabbit tibiae. Clinical examinations, X-rays and in vivo uCT scans were done regularly. Afterwards implants were analyzed with REM, electron dispersive X-ray (EDX), weighing and mechanical testing. The in vivo uCT is of great advantage, because it allows a quantification of the corrosion rate and qualitative 3D assessment of the corrosion morphology. The location of the implant has a remarkable effect on the corrosion rate. Due to its mechanical characteristics and its corrosion behavior, ZEK100 was judged to be suitable, while AX30, which displays favorable degradation behavior, has too little mechanical strength for applications in weight bearing bones. PMID- 28879973 TI - Delocalization of Electrons in Strong Insulators at High Dynamic Pressures. AB - Systematics of material responses to shock flows at high dynamic pressures are discussed. Dissipation in shock flows drives structural and electronic transitions or crossovers, such as used to synthesize metallic liquid hydrogen and most probably Al2O3 metallic glass. The term "metal" here means electrical conduction in a degenerate system, which occurs by band overlap in degenerate condensed matter, rather than by thermal ionization in a non-degenerate plasma. Since H2 and probably disordered Al2O3 become poor metals with minimum metallic conductivity (MMC) virtually all insulators with intermediate strengths do so as well under dynamic compression. That is, the magnitude of strength determines the split between thermal energy and disorder, which determines material response. These crossovers occur via a transition from insulators with electrons localized in chemical bonds to poor metals with electron energy bands. For example, radial extents of outermost electrons of Al and O atoms are 7 a0 and 4 a0, respectively, much greater than 1.7 a0 needed for onset of hybridization at 300 GPa. All such insulators are Mott insulators, provided the term "correlated electrons" includes chemical bonds. PMID- 28879975 TI - Magnetization Dynamics of Amorphous Ribbons and Wires Studied by Inductance Spectroscopy. AB - Inductance spectroscopy is a particular formulation variant of the well known complex impedance formalism typically used for the electric characterization of dielectric, ferroelectric, and piezoelectric materials. It has been successfully exploited as a versatile tool for characterization of the magnetization dynamics in amorphous ribbons and wires by means of simple experiments involving coils for sample holding and impedance analyzer equipment. This technique affords the resolution of the magnetization processes in soft magnetic materials, in terms of reversible deformation of pinned domain walls, domain wall displacements and spin rotation, for which characteristic parameters such as the alloy initial permeability and the relaxation frequencies, indicating the dispersion of each process, can be defined. Additionally, these parameters can be correlated with chemical composition variation, size effects and induced anisotropies, leading to a more physical insight for the understanding of the frequency dependent magnetic response of amorphous alloys, which is of prime interest for the development of novel applications in the field of telecommunication and sensing technologies. In this work, a brief overview, together with recent progress on the magnetization dynamics of amorphous ribbons, wires, microwires and biphase wires, is presented and discussed for the intermediate frequency interval between 10 Hz and 13 MHz. PMID- 28879974 TI - Negative Refractive Index Metasurfaces for Enhanced Biosensing. AB - In this paper we review some metasurfaces with negative values of effective refractive index, as scaffolds for a new generation of surface plasmon polariton based biological or chemical sensors. The electromagnetic properties of a metasurface may be tuned by its full immersion into analyte, or by the adsorption of a thin layer on it, both of which change its properties as a plasmonic guide. We consider various simple forms of plasmonic crystals suitable for this purpose. We start with the basic case of a freestanding, electromagnetically symmetrical plasmonic slab and analyze different ultrathin, multilayer structures, to finally consider some two-dimensional "wallpaper" geometries like split ring resonator arrays and fishnet structures. A part of the text is dedicated to the possibility of multifunctionalization where a metasurface structure is simultaneously utilized both for sensing and for selectivity enhancement. Finally we give an overview of surface-bound intrinsic electromagnetic noise phenomena that limits the ultimate performance of a metasurfaces sensor. PMID- 28879976 TI - Surfactant Effects on Microemulsion-Based Nanoparticle Synthesis. AB - The effect of the surfactant on the size, polydispersity, type of size distribution and structure of nanoparticles synthesized in microemulsions has been studied by computer simulation. The model simulates the surfactant by means of two parameters: the intermicellar exchange parameter, kex, related to dimer life time, and film flexibility parameter, f, related to interdroplet channel size. One can conclude that an increase in surfactant flexibility leads to bigger and polydisperse nanoparticle sizes. In addition, at high concentrations, the same reaction gives rise to a unimodal distribution using a flexible surfactant, and a bimodal distribution using a rigid one. In relation to bimetallic nanoparticles, if the nanoparticle is composed of two metals with a moderate difference in reduction potentials, increasing the surfactant flexibility modifies the nanoparticle structure, giving rise to a transition from a nanoalloy (using a rigid film) to a core-shell structure (using a flexible one). PMID- 28879977 TI - Active Microwave Metamaterials Incorporating Ideal Gain Devices. AB - Incorporation of active devices/media such as transistors for microwave and gain media for optics may be very attractive for enabling desired low loss and broadband metamaterials. Such metamaterials can even have gain which may very well lead to new and exciting physical phenomena. We investigate microwave composite right/left-handed transmission lines (CRLH-TL) incorporating ideal gain devices such as constant negative resistance. With realistic lumped element values, we have shown that the negative phase constant of this kind of transmission lines is maintained (i.e., left-handedness kept) while gain can be obtained (negative attenuation constant of transmission line) simultaneously. Possible implementation and challenging issues of the proposed active CRLH-TL are also discussed. PMID- 28879979 TI - Plasmonic Coaxial Waveguides with Complex Shapes of Cross-Sections. AB - In this paper, we describe waveguide properties of new optical waveguides made of noble metals and filled with glass and air. Such waveguides are coaxial cables and differ from a conventional coaxial in the shape of their central rods. Coaxial waveguide with annular and elliptic central rods are considered. Numerical simulations demonstrate that these waveguides, having nanosize cross section, support propagation of few comparatively low-loss modes, having phase velocity close to the speed of light and the fields localized in a small area outside a metal. We illustrate excitation of these coaxial modes by dipole-like sources. PMID- 28879978 TI - Optical and Electric Multifunctional CMOS Image Sensors for On-Chip Biosensing Applications. AB - In this review, the concept, design, performance, and a functional demonstration of multifunctional complementary metal-oxide-semiconductor (CMOS) image sensors dedicated to on-chip biosensing applications are described. We developed a sensor architecture that allows flexible configuration of a sensing pixel array consisting of optical and electric sensing pixels, and designed multifunctional CMOS image sensors that can sense light intensity and electric potential or apply a voltage to an on-chip measurement target. We describe the sensors' architecture on the basis of the type of electric measurement or imaging functionalities. PMID- 28879980 TI - Sub-Wavelength Resonances in Metamaterial-Based Multi-Cylinder Configurations. AB - Sub-wavelength resonances known to exist in isolated metamaterial-based structures of circular cylindrical shape are investigated with the purpose of determining whether the individual resonances are retained when several of such resonant structures are grouped to form a new structure. To this end, structures consisting of 1, 2 and 4 sets of metamaterial-based concentric cylinders excited by an electric line current are analyzed numerically. It is demonstrated that these structures recover the resonances of the individual structures even when the cylinders are closely spaced and the new structure is thus electrically small. The investigation is conducted through a detailed analysis of the electric near-field distribution as well as the radiation resistance in those cases where the individual structures are made of simple dielectric materials in conjunction with simple, but lossy and dispersive, metamaterials. PMID- 28879981 TI - 1H Nuclear Magnetic Resonance of Lodgepole Pine Wood Chips Affected by the Mountain Pine Beetle. AB - In this study, wood-water interactions of mountain pine beetle affected lodgepole pine were found to vary with time since death. Based on an analysis of magnetization components and spin-spin relaxation times from 1H NMR, it was determined that the mountain pine beetle attack does not affect the crystalline structure of the wood. Both the amorphous structure and the water components vary with time since death, which could be due to the fungi present after a mountain pine beetle attack, as well as the fact that wood from the grey-stage of attack cycles seasonally through adsorption and desorption in the stand. PMID- 28879982 TI - Emission Enhancement in a Plasmonic Waveguide at Cut-Off. AB - Enhancement of molecular emission is usually obtained by coupling small optical emitters with external resonant structures and systems, as first established by Purcell several decades ago, and verified in several recent investigations using molecules or quantum dots coupled with plasmonic nanoantennas. Here we theoretically investigate in detail a different mechanism for emission enhancement, based on our recent idea of a plasmonic nanolauncher [Phys. Rev. Lett. 2009, 103, 043902], i.e., a metamaterial-inspired ultranarrow waveguide channel operating near its cut-off frequency. Such system is not necessarily at resonance, but its peculiar operation may provide enhanced emission over a relatively broad physical area, which may allow enhancement of emission independent of the position of an individual or of a group of molecules along such plasmonic channel, and the possibility to bend and route the emitted energy with large flexibility. We present here extensive theoretical and numerical results that confirm this intuition and may envision a novel method for molecular emission enhancement at the nanoscale, with more flexibility than the conventional Purcell resonance techniques. PMID- 28879983 TI - Multiferroic Compounds with Double-Perovskite Structures. AB - New multiferroic compounds with double-perovskite structures were synthesized. Bi2NiMnO6 was synthesized in bulk form by high-pressure synthesis and also in a thin-film form by epitaxial growth. The material showed both ferromagnetic and ferroelectric properties, i.e., the multiferroic property at low temperature. Bi2FeCrO6 was also fabricated in a (1 1 1) oriented BiFeO3/BiCrO3 artificial superlattice, with a 1/1 stacking period. The superlattice film showed ferromagnetic behavior and polarization switching at room temperature. In the compounds, Bi3+ ion, located at the A site in the perovskite structure, caused ferroelectric structural distortion, and the B-site ordering of the Ni2+ and Mn4+ ions (Fe3+ and Cr3+ ions) in a rock-salt configuration led to ferromagnetism according to the Kanamori-Goodenough rule. PMID- 28879984 TI - Roll-to-Roll Processing of Inverted Polymer Solar Cells using Hydrated Vanadium(V)Oxide as a PEDOT:PSS Replacement. AB - The use of hydrated vanadium(V)oxide as a replacement of the commonly employed hole transporting material PEDOT:PSS was explored in this work. Polymer solar cells were prepared by spin coating on glass. Polymer solar cells and modules comprising 16 serially connected cells were prepared using full roll-to-roll (R2R) processing of all layers. The devices were prepared on flexible polyethyleneterphthalate (PET) and had the structure PET/ITO/ZnO/P3HT:PCBM/V2O5.(H2O)n/Ag. The ITO and silver electrodes were processed and patterned by use of screen printing. The zinc oxide, P3HT:PCBM and vanadium(V)oxide layers were processed by slot-die coating. The hydrated vanadium(V)oxide layer was slot-die coated using an isopropanol solution of vanadyl-triisopropoxide (VTIP). Coating experiments were carried out to establish the critical thickness of the hydrated vanadium(V)oxide layer by varying the concentration of the VTIP precursor over two orders of magnitude. Hydrated vanadium(V)oxide layers were characterized by profilometry, scanning electron microscopy, energy dispersive X-ray spectroscopy, and grazing incidence wide angle X-ray scattering. The power conversion efficiency (PCE) for completed modules was up to 0.18%, in contrast to single cells where efficiencies of 0.4% were achieved. Stability tests under indoor and outdoor conditions were accomplished over three weeks on a solar tracker. PMID- 28879985 TI - Organic Zeolite Analogues Based on Multi-Component Liquid Crystals: Recognition and Transformation of Molecules within Constrained Environments. AB - In liquid crystals (LCs), molecules are confined in peculiar environments, where ordered alignment and certain mobility are realized at the same time. Considering these characteristics, the idea of "controlling molecular events within LC media" seems reasonable. As a suitable system for investigating this challenge, we have recently developed a new class of ionic LCs; the salts of amphiphilic carboxylic acids with 2-amino alcohols, or those of carboxylic acids with amphiphilic 2 amino alcohols, have a strong tendency to exhibit thermotropic LC phases. Because of the noncovalent nature of the interaction between molecules, one of the two components can easily be exchanged with, or transformed into, another molecule, without distorting the original LC architecture. In addition, both components are common organic molecules, and a variety of compounds are easily available. Taking advantage of these characteristics, we have succeeded in applying two-component LCs as chiral media for molecular recognition and reactions. This review presents an overview of our recent studies, together with notable reports related to this field. PMID- 28879987 TI - Electronic and Structural Properties of ABO3: Role of the B-O Coulomb Repulsions for Ferroelectricity. AB - We have investigated the role of the Ti-O Coulomb repulsions in the appearance of the ferroelectric state in BaTiO3 as well as the role of the Zn-O Coulomb repulsions in BiZn0.5Ti0.5O3, using a first-principles calculation with optimized structures. In tetragonal BaTiO3, it is found that the Coulomb repulsions between Ti 3s and 3p states and O 2s and 2p states have an important role for the appearance of Ti ion displacement. In BiZn0.5Ti0.5O3, on the other hand, the stronger Zn-O Coulomb repulsions, which are due to the 3s, 3p, and 3d (d10) states of the Zn ion, have more important role than the Ti-O Coulomb repulsions for the appearance of the tetragonal structure. Our suggestion is consistent with the other ferroelectric perovskite oxides ABO3 in the appearance of tetragonal structures as well as rhombohedral structures. PMID- 28879986 TI - Thermotropic Ionic Liquid Crystals. AB - The last five years' achievements in the synthesis and investigation of thermotropic ionic liquid crystals are reviewed. The present review describes the mesomorphic properties displayed by organic, as well as metal-containing ionic mesogens. In addition, a short overview on the ionic polymer and self-assembled liquid crystals is given. Potential and actual applications of ionic mesogens are also discussed. PMID- 28879988 TI - Enhanced Hydrogen Storage Kinetics of Nanocrystalline and Amorphous Mg2Ni-type Alloy by Melt Spinning. AB - Mg2Ni-type Mg2Ni1-xCox (x = 0, 0.1, 0.2, 0.3, 0.4) alloys were fabricated by melt spinning technique. The structures of the as-spun alloys were characterized by X ray diffraction (XRD) and transmission electron microscopy (TEM). The hydrogen absorption and desorption kinetics of the alloys were measured by an automatically controlled Sieverts apparatus. The electrochemical hydrogen storage kinetics of the as-spun alloys was tested by an automatic galvanostatic system. The results show that the as-spun (x = 0.1) alloy exhibits a typical nanocrystalline structure, while the as-spun (x = 0.4) alloy displays a nanocrystalline and amorphous structure, confirming that the substitution of Co for Ni notably intensifies the glass forming ability of the Mg2Ni-type alloy. The melt spinning treatment notably improves the hydriding and dehydriding kinetics as well as the high rate discharge ability (HRD) of the alloys. With an increase in the spinning rate from 0 (as-cast is defined as spinning rate of 0 m/s) to 30 m/s, the hydrogen absorption saturation ratio () of the (x = 0.4) alloy increases from 77.1 to 93.5%, the hydrogen desorption ratio () from 54.5 to 70.2%, the hydrogen diffusion coefficient (D) from 0.75 * 10-11 to 3.88 * 10-11 cm2/s and the limiting current density IL from 150.9 to 887.4 mA/g. PMID- 28879989 TI - Laser Fabrication of 3D Gelatin Scaffolds for the Generation of Bioartificial Tissues. AB - In the present work, the two-photon polymerization (2PP) technique was applied to develop precisely defined biodegradable 3D tissue engineering scaffolds. The scaffolds were fabricated via photopolymerization of gelatin modified with methacrylamide moieties. The results indicate that the gelatin derivative (GelMod) preserves its enzymatic degradation capability after photopolymerization. In addition, the developed scaffolds using 2PP support primary adipose-derived stem cell (ASC) adhesion, proliferation and differentiation into the anticipated lineage. PMID- 28879990 TI - {Fe6O2}-Based Assembly of a Tetradecanuclear Iron Nanocluster. AB - The tetradecanuclear FeIII pivalate nanocluster [Fe14O10(OH)4(Piv)18], comprising a new type of metal oxide framework, has been solvothermally synthesized from a hexanuclear iron pivalate precursor in dichlormethane/acetonitrile solution. Magnetic measurements indicate the presence of very strong antiferromagnetic interactions in the cluster core. PMID- 28879991 TI - Masonry Columns Confined by Steel Fiber Composite Wraps. AB - The application of steel fiber reinforced polymer (SRP) as a means of increasing the capacity of masonry columns is investigated in this study. The behavior of 23 solid-brick specimens that are externally wrapped by SRP sheets in low volumetric ratios is presented. The specimens are subjected to axial monotonic load until failure occurs. Two widely used types of masonry columns of differing square cross-sections were tested in compression (square and octagonal cross-sections). It is concluded that SRP-confined masonry behaves very much like fiber reinforced polymers (FRP)-confined masonry. Confinement increases both the load-carrying capacity and the deformability of masonry almost linearly with average confining stress. A comparative analysis between experimental and theoretical values computed in compliance with the Italian Council of Research (CNR) was also developed. PMID- 28879992 TI - Cell-Based Fabrication of Organic/Inorganic Composite Gel Material. AB - Biomaterials containing components similar to the native biological tissue would have benefits as an implantable scaffold material. To obtain such biomimetic materials, cells may be great contributors because of their crucial roles in synthetic organics. In addition, the synthesized organics-especially those derived from osteogenic differentiated cells-become a place where mineral crystals nucleate and grow even in vitro. Therefore to fabricate an organic/inorganic composite material, which is similar to the biological osteoid tissue, bone marrow derived mesenchymal stem cells (BMSCs) were cultured in a 3D fibrin gel in this study. BMSCs secreted bone-related proteins that enhanced the biomineralization within the gel when the cells were cultured with an osteogenic differentiation medium. The compositions of both synthesized matrices and precipitated minerals in the obtained materials altered depending on the cell culture period. The mineral obtained in the 3D gel showed low crystalline hydroxyapatite. The composite materials also showed excellent osteoconductivity with new bone formation when implanted in mice tibiae. Thus, we demonstrated the contributions of cells for fabricating implantable organic/inorganic composite gel materials and a method for controlling the material composition in the gel. This cell-based material fabrication method would be a novel method to fabricate organic/inorganic composite biomimetic materials for bone tissue engineering. PMID- 28879994 TI - In vitro Biocompatibility of New Silver(I) Coordination Compound Coated-Surfaces for Dental Implant Applications. AB - Biofilm formation on implant materials causes a common problem: resistance to aggressive pharmacological agents as well as host defenses. Therefore, to reduce bacterial adhesion to implant surfaces we propose to use silver(I) coordination networks as it is known that silver is the most powerful antimicrobial inorganic agent. As a model surface, self-assembled monolayers (SAMs) on gold Au(111) was used to permit permanent attachment of our silver(I) coordination networks. The surface coatings showed typical nano-structured surfaces with a good biocompatibility for soft-tissue integration with fibroblast cells. PMID- 28879993 TI - A New Highly Bioactive Composite for Scaffold Applications: A Feasibility Study. AB - Hydroxyapatite (HA) has been widely investigated as scaffolding material for bone tissue engineering, mainly for its excellent biocompatibility. Presently, there is an increasing interest in the composites of hydroxyapatite with bioactive glasses, with the aim to obtain systems with improved bioactivity or mechanical properties. Moreover, modifying the ratio between bioactive glass and hydroxyapatite results in the possibility of controlling the reaction rate of the composite scaffold in the human body. However, high temperature treatments are usually required in order to sinter HA-based composites, causing the bioactive glass to crystallize into a glass-ceramic, with possible negative effects on its bioactivity. In the present research work, a glass composition belonging to the Na2O-CaO-P2O5-SiO2 system, with a reduced tendency to crystallize, is applied to realize HA-based composites. The novel samples can be sintered at a relative low temperature (750 degrees C) compared to the widely studied HA/45S5 Bioglass(r) composites. This fact greatly helps to preserve the amorphous nature of the glass, with excellent effects in terms of bioactivity, according to in vitro tests. As a first application, the obtained composites are also tested to realize highly porous scaffolds by means of the standard burning out method. PMID- 28879995 TI - Coalescence and Collisions of Gold Nanoparticles. AB - We study the assembling of small gold clusters subject to collisions and close contact coalescence by using molecular dynamics simulations to simulate events that occur typically in the sputtering process of synthesis. Our results support the notion that the kinetics of coalescence processes strongly determine the geometry and structure of the final particle. While impact velocities, relative orientations, and the initial shape of the interacting particles are unlikely to strictly determine the structural details of the newly formed particle, we found that high initial temperatures and/or impact velocities increase the probability of appearance of icosahedral-like structures, Wulff polyhedra are likely to be formed as a product of the interactions between nanospheres, while the appearance of fcc particles of approximately cuboctahedral shape is mainly due to the interaction between icosahedra. PMID- 28879996 TI - Different Molecular Weight Chitosan-Based Membranes for Tissue Regeneration. AB - Natural polymers, such as chitosan, obtained from chitin, are been widely studied for use in the tissue regeneration field. This study established a protocol to attain membranes made from this biopolymer, consisting of high or low molecular weight chitosan. The biocompatibility of these membranes was histologically evaluated, comparing them to collagen membrane surgically implanted in rat subcutaneous tissue. Fifteen Holtzmann rats were divided in three experimental groups: High and Low Molecular Weight Chitosan membranes (HMWC and LMWC) and Collagen membranes (C-control group); each of them with three experimental periods: 7, 15 and 30 days. As a result, after the seven days evaluation, the membranes were present and associated with a variable degree of inflammation, and after the 15 and 30 days evaluations, the membranes were absent in all groups. It is concluded that the chitosan-based membranes were successfully attained and presented comparable resorption times to collagen membranes. PMID- 28879998 TI - A Review of Domain Modelling and Domain Imaging Techniques in Ferroelectric Crystals. AB - The present paper reviews models of domain structure in ferroelectric crystals, thin films and bulk materials. Common crystal structures in ferroelectric materials are described and the theory of compatible domain patterns is introduced. Applications to multi-rank laminates are presented. Alternative models employing phase-field and related techniques are reviewed. The paper then presents methods of observing ferroelectric domain structure, including optical, polarized light, scanning electron microscopy, X-ray and neutron diffraction, atomic force microscopy and piezo-force microscopy. Use of more than one technique for unambiguous identification of the domain structure is also described. PMID- 28879997 TI - Electro-Optic Effects in Colloidal Dispersion of Metal Nano-Rods in Dielectric Fluid. AB - In modern transformation optics, one explores metamaterials with properties that vary from point to point in space and time, suitable for application in devices such as an "optical invisibility cloak" and an "optical black hole". We propose an approach to construct spatially varying and switchable metamaterials that are based on colloidal dispersions of metal nano-rods (NRs) in dielectric fluids, in which dielectrophoretic forces, originating in the electric field gradients, create spatially varying configurations of aligned NRs. The electric field controls orientation and concentration of NRs and thus modulates the optical properties of the medium. Using gold (Au) NRs dispersed in toluene, we demonstrate electrically induced change in refractive index on the order of 0.1. PMID- 28879999 TI - Iron Oxide Silica Derived from Sol-Gel Synthesis. AB - In this work we investigate the effect of iron oxide embedded in silica matrices as a function of Fe/Si molar ratio and sol pH. To achieve homogeneous dispersion of iron oxide particles, iron nitrate nonahydrate was dissolved in hydrogen peroxide and was mixed with tetraethyl orthosilicate and ethanol in a sol-gel synthesis method. Increasing the calcination temperature led to a reduction in surface area, although the average pore radius remained almost constant at about 10 A, independent of the Fe/Si molar ratio or sol pH. Hence, the densification of the matrix was accompanied by similar reduction in pore volume. However, calcination at 700 degrees C resulted in samples with similar surface area though the iron oxide content increased from 5% to 50% Fe/Si molar ratio. As metal oxide particles have lower surface area than polymeric silica structures, these results strongly suggest that the iron oxides opposed the silica structure collapse. The effect of sol pH was found to be less significant than the Fe/Si molar ratio in the formation of molecular sieve structures derived from iron oxide silica. PMID- 28880000 TI - Durability of Starch Based Biodegradable Plastics Reinforced with Manila Hemp Fibers. AB - The biodegradability of Manila hemp fiber reinforced biodegradable plastics was studied for 240 days in a natural soil and 30 days in a compost soil. After biodegradability tests, weights were measured and both tensile strength tests and microscopic observation were performed to evaluate the biodegradation behavior of the composites. The results indicate that the tensile strength of the composites displays a sharp decrease for up to five days, followed by a gradual decrease. The weight loss and the reduction in tensile strength of biodegradable composite materials in the compost soil are both significantly greater than those buried in natural soil. The biodegradability of these composites is enhanced along the lower portion because this area is more easily attacked by microorganisms. PMID- 28880001 TI - Sol-Gel Entrapped Levonorgestrel Antibodies: Activity and Structural Changes as a Function of Different Polymer Formats. AB - The paper describes development of a sol-gel based immunoaffinity method for the steroid hormone levonorgestrel (LNG) and the effects of changes in the sol-gel matrix format on the activity of the entrapped antibodies (Abs) and on matrix structure. The best sol-gel format for Ab entrapment was found to be a tetramethoxysilane (TMOS) based matrix at a TMOS:water ratio of 1:8, containing 10% polyethylene glycol (PEG) of MW 0.4 kDa. Addition of higher percentages of PEG or a higher MW PEG did not improve activity. No activity was obtained with a TMOS:water ratio of 1:12, most likely because of the very dense polymer that resulted from these polymerization conditions. Only minor differences in the non specific binding were obtained with the various formats. TMOS was found to be more effective than tetrakis (2-hydroxyethyl)orthosilicate (THEOS) for entrapment of anti-levonorgestrel (LNG) Abs. However, aging the THEOS-based sol-gel for a few weeks at 4 degrees C stabilized the entrapped Abs and increased its binding capacity. Confocal fluorescent microscopy with fluorescein isothiocyanate (FITC) labeled immunoglobulines (IgGs) entrapped in the sol-gel matrix showed that the entrapped Abs were distributed homogenously within the gel. Scanning electron microscopy (SEM) images have shown the diverse structures of the various sol-gel formats and precursors. PMID- 28880002 TI - Progress in Nano-Engineered Anodic Aluminum Oxide Membrane Development. AB - The anodization of aluminum is an electro-chemical process that changes the surface chemistry of the metal, via oxidation, to produce an anodic oxide layer. During this process a self organized, highly ordered array of cylindrical shaped pores can be produced with controllable pore diameters, periodicity and density distribution. This enables anodic aluminum oxide (AAO) membranes to be used as templates in a variety of nanotechnology applications without the need for expensive lithographical techniques. This review article is an overview of the current state of research on AAO membranes and the various applications of nanotechnology that use them in the manufacture of nano-materials and devices or incorporate them into specific applications such as biological/chemical sensors, nano-electronic devices, filter membranes and medical scaffolds for tissue engineering. PMID- 28880003 TI - Dual-Scale Polymeric Constructs as Scaffolds for Tissue Engineering. AB - This research activity was aimed at the development of dual-scale scaffolds consisting of three-dimensional constructs of aligned poly(epsilon-caprolactone) (PCL) microfilaments and electrospun poly(lactic-co-glycolic acid) (PLGA) fibers. PCL constructs composed by layers of parallel microsized filaments (0/90 degrees lay-down pattern), with a diameter of around 365 MUm and interfilament distance of around 191 MUm, were produced using a melt extrusion-based additive manufacturing technique. PLGA electrospun fibers with a diameter of around 1 MUm were collected on top of the PCL constructs with different thicknesses, showing a certain degree of alignment. Cell culture experiments employing the MC3T3 murine preosteoblast cell line showed good cell viability and adhesion on the dual-scale scaffolds. In particular, the influence of electrospun fibers on cell morphology and behavior was evident, as well as in creating a structural bridging for cell colonization in the interfilament gap. PMID- 28880004 TI - Crosslinked Graft Copolymer of Methacrylic Acid and Gelatin as a Novel Hydrogel with pH-Responsiveness Properties. AB - In this paper, a novel gelatin-based hydrogel was synthesized through crosslinking graft copolymerization of methacrylic acid (MAA) onto gelatin, using ammonium persulfate (APS) as a free radical initiator in the presence of methylenebisacrylamide (MBA) as a crosslinker. A proposed mechanism for hydrogel formation was suggested and the structure of the product was established using FTIR spectroscopy and gravimetric analysis of the products. Moreover, morphology of the samples was examined by scanning electron microscopy (SEM) and thermogravimetric analysis (TGA/DTG). The effect of reaction variables such as concentration of APS and MBA were systematically optimized to achieve a hydrogel with swelling capacity as high as possible. The gelatin-g-PMAA hydrogel exhibited a pH-responsiveness character so that a swelling-deswelling pulsatile behavior was recorded at pHs 2 and 8. This on-off switching behavior makes the hydrogel as a good candidate for controlled delivery of bioactive agents. PMID- 28880006 TI - Synthesis, Characterization and Photophysical Properties of Pyridine-Carbazole Acrylonitrile Derivatives. AB - We synthesized three novel highly fluorescent compounds, 2-(2'-pyridyl)-3-(N ethyl-(3'-carbazolyl))acrylonitrile, 2-(3"-pyridyl)-3-(N-ethyl-(3' carbazolyl))acrylonitrile, and 2-(4-pyridyl)-3-(N-ethyl-(3' carbazolyl))acrylonitrile by Knoevenagel condensation. The first two were synthesized without solvent in the presence of piperidine as a catalyst; the third was synthesized without a catalyst and with N,N-dimethylformamide as a solvent. In solution, the molar absorption coefficients showed absorptions at 380, 378, and 396 nm, respectively; in solid state, absorptions were at 398, 390, and 442 nm, respectively. The fluorescence emission was at 540, 540 and 604 nm, respectively, the 2-(4-pyridyl)-3-(N-ethyl-(3'-carbazolyl))acrylonitrile showed a red shift in the emission of 64 nm compared to the other two compounds. The fluorescence quantum yield for the compounds in powder form showed values of 0.05, 0.14, and 0.006, respectively; compared with the value measured for the Alq3 reference, 2-(3"-pyridyl)-3-(N-ethyl-(3'-carbazolyl))acrylonitrile had a lightly higher value. The third harmonic generation measurement for 2-(2' pyridyl)-3-(N-ethyl-(3'-carbazolyl))acrylonitrile yielded a chi(3) value of 5.5 * 10-12 esu, similar to that reported for commercial polymers. PMID- 28880005 TI - A Preliminary Study on the Effect of Macro Cavities Formation on Properties of Carbon Nanotube Bucky-Paper Composites. AB - In this study, we focus on processing and characterizing composite material structures made of carbon nanotubes (CNTs) and reproducibly engineering macro pores inside their structure. Highly porous bucky-papers were fabricated from pure carbon nanotubes by dispersing and stabilizing large 1 MUm polystyrene beads within a carbon nanotube suspension. The polystyrene beads, homogeneously dispersed across the thickness of the bucky-papers, were then either dissolved or carbonized to generate macro cavities of different shape and properties. The impact of adding these macro cavities on the porosity, specific surface area and Young's modulus was investigated and some benefits of the macro cavities will be demonstrated. PMID- 28880007 TI - Using Converter Dust to Produce Low Cost Cementitious Composites by in situ Carbon Nanotube and Nanofiber Synthesis. AB - Carbon nanotubes (CNTs) and nanofibers (CNFs) were synthesized on clinker and silica fume particles in order to create a low cost cementitious nanostructured material. The synthesis was carried out by an in situ chemical vapor deposition (CVD) process using converter dust, an industrial byproduct, as iron precursor. The use of these materials reduces the cost, with the objective of application in large-scale nanostructured cement production. The resulting products were analyzed by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and thermogravimetric analysis (TGA) and were found to be polydisperse in size and to have defective microstructure. Some enhancement in the mechanical behavior of cement mortars was observed due to the addition of these nano-size materials. The contribution of these CNTs/CNFs to the mechanical strength of mortar specimens is similar to that of high quality CNTs incorporated in mortars by physical mixture. PMID- 28880008 TI - Bond Behavior of Historical Clay Bricks Strengthened with Steel Reinforced Polymers (SRP). AB - In the strengthening interventions of past and historical masonry constructions, the non-standardized manufacture processes, the ageing and the damage of masonry units, could significantly affect the properties of the surfaces where strengthening materials are applied. This aspect requires particular care in evaluating the performance of externally bonded strengthening layers, especially with reference to the detachment mechanism. The bond response of old masonries could be very different from that occurring in new masonry units which are the ones generally considered in most of the bond tests available in technical literature. The aim of the present paper is the study of the bond behavior of historical clay bricks strengthened with steel reinforced polymers (SRP) materials. In particular, the results of an experimental study concerning new manufactured clay bricks and old bricks extracted from different historical masonry buildings are presented. The obtained results, particularly in terms of bond resistance, detachment mechanism and strain distributions, are discussed for the purpose of analyzing the peculiarities of the historical bricks in comparison with new manufactured ones. Some considerations on the efficacy of the theoretical formulations of the recent Italian code are also carried out. PMID- 28880010 TI - Chronic pancreatitis. AB - Chronic pancreatitis is defined as a pathological fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathological responses to parenchymal injury or stress. Potential causes can include toxic factors (such as alcohol or smoking), metabolic abnormalities, idiopathic mechanisms, genetics, autoimmune responses and obstructive mechanisms. The pathophysiology of chronic pancreatitis is fairly complex and includes acinar cell injury, acinar stress responses, duct dysfunction, persistent or altered inflammation, and/or neuro-immune crosstalk, but these mechanisms are not completely understood. Chronic pancreatitis is characterized by ongoing inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Functional consequences include recurrent or constant abdominal pain, diabetes mellitus (endocrine insufficiency) and maldigestion (exocrine insufficiency). Diagnosing early-stage chronic pancreatitis is challenging as changes are subtle, ill-defined and overlap those of other disorders. Later stages are characterized by variable fibrosis and calcification of the pancreatic parenchyma; dilatation, distortion and stricturing of the pancreatic ducts; pseudocysts; intrapancreatic bile duct stricturing; narrowing of the duodenum; and superior mesenteric, portal and/or splenic vein thrombosis. Treatment options comprise medical, radiological, endoscopic and surgical interventions, but evidence-based approaches are limited. This Primer highlights the major progress that has been made in understanding the pathophysiology, presentation, prevalence and management of chronic pancreatitis and its complications. PMID- 28880011 TI - Corrigendum: Guilty repair sustains cooperation, angry retaliation destroys it. AB - This corrects the article DOI: 10.1038/srep46709. PMID- 28880012 TI - GOLPH2-regulated oncolytic adenovirus, GD55, exerts strong killing effect on human prostate cancer stem-like cells in vitro and in vivo. AB - GOLPH2 (also called GP73) is a Golgi glycoprotein, which has been identified as a novel tumor marker upregulated in various cancers, including prostate cancer (PCa). GD55 is a novel GOLPH2-regulated oncolytic adenovirus that exhibits a strong killing effect on hepatoma cells. Here, we investigate the antitumor effect of GD55 on prostate cancer stem cell (CSC)-like cells in vitro and in vivo. Prostate CSC-like sphere cells were acquired and enriched by culturing DU145, LNCap or P3 prostate cancer cells in suspension. The prostate CSC-like sphere cells were capable of self-renewal, differentiation and quiescence, displaying tumorigenic feature and chemo-resistance to 5-FU, doxorubicin and DDP. Treatment with GD55 (1, 5, 10 MOI) dose-dependently suppressed the viability of DU145 sphere cells, which was a more pronounced compared to its cytotoxic action on the parental DU145 cells. In a mouse xenograft prostate CSC-like model, intratumoral injection of GD55 markedly suppressed the growth rate of xenograft tumors and induced higher levels of cell death and necrosis within the tumor tissues. Our results demonstrate that GD55 infection exerts strong anticancer effects on prostate CSC-like cells in vitro and in vivo, and has a potential to be used in the clinical therapy of PCa. PMID- 28880013 TI - Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non small cell lung cancer cells. AB - Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In NSCLC patients, an EGFR mutation is likely to be correlated with high levels of expression of programmed death ligand-1 (PD-L1). Here, we showed that osimertinib decreased PD-L1 expression in human EGFR mutant NSCLC cells in vitro. Osimertinib (125 nmol/L) markedly suppressed PD-L1 mRNA expression in both NCI-H1975 and HCC827 cells. Pretreatment with the N-linked glycosylation inhibitor tunicamycin, osimertinib clearly decreased the production of new PD-L1 protein probably due to a reduction in mRNA. After blocking transcription and translation processes with actinomycin D and cycloheximide, respectively, osimertinib continued to reduce the expression of PD-L1, demonstrating that osimertinib might degrade PD-L1 at the post translational level, which was confirmed by a cycloheximide chase assay, revealing that osimertinib (125 nmol/L) decreased the half-life of PD-L1 from approximately 17.8 h and 13.8 h to 8.6 h and 4.6 h, respectively, in NCI-H1975 and HCC827 cells. Pretreatment with the proteasome inhibitors (MG-132 or bortezomib) blocked the osimertinib-induced degradation of PD-L1, but an inhibitor of autophagy (chloroquine) did not. In addition, inhibition of GSK3beta by LiCl prevented osimertinib-induced PD-L1 degradation. The results demonstrate that osimertinib reduces PD-L1 mRNA expression and induces its protein degradation, suggesting that osimertinib may reactivate the immune activity of T cells in the tumor microenvironment in EGFR-mutated NSCLC patients. PMID- 28880014 TI - Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy. AB - Natural killer (NK) cells are potential effector cells in cell-based cancer immunotherapy, particularly in the control of hematological malignancies. The chimeric antigen receptor (CAR) is an artificially modified fusion protein that consists of an extracellular antigen recognition domain fused to an intracellular signaling domain. T cells genetically modified with a CAR have demonstrated remarkable success in the treatment of hematological cancers. Compared to T cells, CAR-transduced NK cells (CAR-NK) exhibit several advantages, such as safety in clinical use, the mechanisms by which they recognize cancer cells, and their abundance in clinical samples. Human primary NK cells and the NK-92 cell line have been successfully transduced to express CARs against both hematological cancers and solid tumors in pre-clinical and clinical trials. However, many challenges and obstacles remain, such as the ex vivo expansion of CAR-modified primary NK cells and the low transduction efficiency of NK cells. Many strategies and technologies have been developed to improve the safety and therapeutic efficacy in CAR-based immunotherapy. Moreover, NK cells express a variety of activating receptors (NKRs), such as CD16, NKG2D, CD226 and NKp30, which might specifically recognize the ligands expressed on tumor cells. Based on the principle of NKR recognition, a strategy that targets NKRs is rapidly emerging. Given the promising clinical progress described in this review, CAR- and NKR-NK cell-based immunotherapy are likely promising new strategies for cancer therapy. PMID- 28880015 TI - Integrated pharmacokinetic/viral dynamic model for daclatasvir/asunaprevir in treatment of patients with genotype 1 chronic hepatitis C. AB - In order to develop an integrated pharmacokinetic/viral dynamic (PK/VD) model to predict long-term virological response rates to daclatasvir (DCV) and asunaprevir (ASV) combination therapy in patients infected with genotype 1 (GT1) chronic hepatitis C virus (HCV), a systematic publication search was conducted for DCV and ASV administered alone and/or in combination in healthy subjects or patients with GT1 HCV infection. On the basis of a constructed meta-database, an integrated PK/VD model was developed, which adequately described both DCV and ASV PK profiles and viral load time curves. The IC50 values of DCV and ASV were estimated to be 0.041 and 2.45 MUg/L, respectively, in GT1A patients. A sigmoid Emax function was applied to describe the antiviral effects of DCV and ASV, depending on the drug concentrations in the effect compartment. An empirical exponential function revealed that IC50 changing over time described drug resistance in HCV GT1A patients during DCV or ASV monotherapy. Finally, the PK/VD model was evaluated externally by comparing the expected and observed virological response rates during and post-treatment with DCV and ASV combination therapy in HCV GT1B patients. Both the rates were in general agreement. Our PK/VD model provides a useful platform for the characterization of pharmacokinetic/pharmacodynamic relationships and the prediction of long-term virological response rates to aid future development of direct acting antiviral drugs. PMID- 28880017 TI - Will rising prices and budget constraints prevent patients from accessing novel gene therapies? PMID- 28880018 TI - Spinraza-the patient perspective. PMID- 28880016 TI - (5R)-5-hydroxytriptolide ameliorates anti-glomerular basement membrane glomerulonephritis in NZW mice by regulating Fcgamma receptor signaling. AB - (5R)-5-hydroxytriptolide (LLDT-8) is a novel triptolide analog that has been identified as a promising candidate for treating autoimmune diseases and has been shown to be effective in treating murine collagen-induced arthritis and lupus nephritis. In the present study, we investigated the therapeutic effect and possible mechanism of action of LLDT-8 in a murine anti-glomerular basement membrane (GBM) glomerulonephritis model. NZW mice were injected with rabbit anti GBM serum (500 MUL, ip). The mice were orally treated with LLDT-8 (0.125 mg/kg, every other day) or a positive control prednisolone (2 mg/kg every day) for 14 d. Blood and urine samples as well as spleen and kidney tissues were collected for analyses. LLDT-8 treatment did not affect the generation of mouse anti-rabbit antibodies. LLDT-8 significantly reversed established proteinuria, improved renal histopathology and attenuated renal dysfunction in glomerulonephritis mice. Furthermore, LLDT-8 inhibited inflammation in the kidney evidenced by significantly decreasing C3 and IgG deposition, reducing the levels of the pathogenic cytokines TNF-alpha, IL-6, IL-17, and IFN-gamma, and reducing related chemokine expression and leukocyte infiltration in kidneys. Moreover, LLDT-8 treatment significantly increased the expression of FcgammaRIIB in the kidney and spleen. In addition, the treatment restored the reduced expression of FcgammaRIIB on the surface of kidney effector cells, CD11b+ cells, and interfered with FcgammaR-dependent signaling, especially FcgammaRIIB-mediated downstream kinases, such as BTK. These results demonstrate that LLDT-8 ameliorates anti-GBM glomerulonephritis by regulating the Fcgamma receptor signaling. PMID- 28880019 TI - Market access of Spinraza (Nusinersen) for spinal muscular atrophy: intellectual property rights, pricing, value and coverage considerations. PMID- 28880020 TI - Novel GP64 envelope variants for improved delivery to human airway epithelial cells. AB - Lentiviral vectors pseudotyped with the baculovirus envelope protein GP64 transduce primary cultures of human airway epithelia (HAE) at their apical surface. Our goal in this study was to harness a directed evolution approach to develop a novel envelope glycoprotein with increased transduction properties for HAE. Using error-prone PCR, a library of GP64 mutants was generated and used to prepare a diverse pool of lentiviral virions pseudotyped with GP64 variants. The library was serially passaged on HAE and three GP64 mutations were recovered. Single-, double- and the triple-combination mutant envelope glycoproteins were compared with wild-type GP64 for their ability to transduce HAE. Our results suggest that lentiviral vectors pseudotyped with evolved GP64 transduced HAE with greater efficiency than wild-type GP64. This effect was not observed in primary cultures of porcine airway epithelial cells, suggesting that the directed evolution protocol was species specific. In summary, our studies indicate that serial passage of a GP64 mutant library yielded specific variants with improved HAE cell tropism, yielding tools with the potential to improve the success of gene therapy for airway diseases. PMID- 28880022 TI - Basic research: Standardizing animal atherosclerosis studies to improve reproducibility. PMID- 28880021 TI - Long-term expression of melanopsin and channelrhodopsin causes no gross alterations in the dystrophic dog retina. AB - Several preclinical studies have investigated the potential of algal channelrhodopsin and human melanopsin as optogenetic tools for vision restoration. In the present study, we assessed the potentially deleterious effects of long-term expression of these optogenes on the diseased retina in a large animal model of retinal degeneration, the RPE65-deficient Briard dog model of Leber congenital amaurosis. Intravitreal injection of adeno-associated virus vectors expressing channelrhodopsin and melanopsin had no effect on retinal thickness over a 16-month period post injection. Our data support the safety of the optogenetic approach for the treatment of blindness. PMID- 28880024 TI - Dyslipidaemia: Monoclonal antibody targeting lipoprotein-bound human apoC-III. PMID- 28880023 TI - Sudden infant death syndrome and inherited cardiac conditions. AB - Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality in developed countries, characterized by the death of infants for no obvious reason and without prior warning. The complex interaction of multiple factors in the pathogenesis of SIDS is illustrated by the 'triple risk hypothesis', which proposed that SIDS results from a convergence of three overlapping risk factors: a critical developmental period, an exogenous stressor, and underlying genetic and/or nongenetic vulnerability in the infant. Rare variants in genes associated with inherited arrhythmia syndromes and cardiomyopathies have been proposed as the substrate for an infant's critical vulnerability in a small subset of SIDS cases. Given the potential risk of inherited cardiac disease, current guidelines recommend post-mortem genetic testing (molecular autopsy) and cardiological investigation of the surviving family, complemented by targeted genetic testing if appropriate. In this Review, we highlight the latest developments in understanding the spectrum and prevalence of cardiac-mediated SIDS, and discuss the clinical implications of SIDS in the surviving family and the general population. PMID- 28880025 TI - Expert consensus document: A 'diamond' approach to personalized treatment of angina. AB - In clinical guidelines, drugs for symptomatic angina are classified as being first choice (beta-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for traditional first-choice drugs. Considering some drugs, but not others, to be first choice is, therefore, difficult. Moreover, double or triple therapy is often needed to control angina. Patients with angina can have several comorbidities, and symptoms can result from various underlying pathophysiologies. Some agents, in addition to having antianginal effects, have properties that could be useful depending on the comorbidities present and the mechanisms of angina, but the guidelines do not provide recommendations on the optimal combinations of drugs. In this Consensus Statement, we propose an individualized approach to angina treatment, which takes into consideration the patient, their comorbidities, and the underlying mechanism of disease. PMID- 28880026 TI - Corrigendum: Towards automatic pulmonary nodule management in lung cancer screening with deep learning. AB - This corrects the article DOI: 10.1038/srep46479. PMID- 28880027 TI - Tandem Wittig/Diels-Alder diversification of genetically encoded peptide libraries. AB - In this paper, we developed a tandem of two carbon-carbon bond-forming reactions to chemically diversify the libraries of peptides displayed on a bacteriophage. The Wittig reaction of a biotin-ester from a stabilized phosphorane ylide with model peptides containing N-terminal glyoxal exhibits reaction rates of 0.07 to 5 M-1 s-1 in water at pH 6.5-8. The log(k) scaled linearly with pH from pH 6 to 8; above pH 9 the reaction is accompanied by the hydrolysis of the ester functionality. Capture of the phage displaying the biotinylated product by streptavidin beads confirmed the rate of this reaction in a library of 108 peptides (k = 0.23 M-1 s-1 at pH = 6.5) and also confirmed the regioselectivity of this modification. Olefins introduced into the Wittig reaction can act as Michael acceptors: addition of glutathione, cysteamine, and DYKDDDDKC ("FLAG Cys") peptide occurs with k = 0.12-4.1 M-1 s-1 at pH 7.8. Analogous reactions with the DYKDDDDKC peptide take place on phage-displayed peptides modified via the Wittig reaction. This reaction is manifested as a progressive emergence of a FLAG-epitope on the phage and detected by the capture of this phage using an anti FLAG antibody. Olefins introduced into the Wittig reaction also act as dienophiles in the Diels-Alder reaction with cyclopentadiene. The conversion of the dienophile to norbornene-like adducts on the phage was observed by monitoring the disappearance of the thiol-reactive olefin on the phage. This report broadens the reaction scope of genetically-encoded peptide libraries displayed on the phage, expanding the structural diversity of these platforms and increasing their potential to be used in screening against important protein targets. The possibility of monitoring tandem reactions by the use of different labels illustrates the feasibility of obtaining highly functionalized peptides with chemical motifs impossible to achieve using conventional translational machinery. PMID- 28880028 TI - Why do zeolites induce an unprecedented electronic state on exchanged metal ions? AB - Understanding the exact position and the detailed role of the Al array in zeolites is essential for elucidating the origin of unique properties that can be derived from the metal-ion exchanged in zeolite samples and for designing zeolite materials with high efficiency in catalytic and adsorption processes. In this work, we investigate, for the first time, the important role of the Al array in the reactivity observed on the metal-ion exchanged in zeolites on the basis of the calculation method by utilizing the spontaneous heterolytic cleavage of H2 observed experimentally on the Zn2+-ion exchanged in MFI-type zeolites (Zn2+-MFI) as the model reaction. In the case of calculation, two main types of models for considering the Al positions in MFI-type zeolites were adopted: in the first type, the Al atoms with appropriate distances are aligned in the circumferential direction of the straight channel (abbreviated as a circumferentially arrayed Al Al site); in the second type, the nearest neighbouring Al atoms with appropriate distances are directed toward the straight channel axis (abbreviated as a channel directionally arrayed Al-Al site). Results indicated that the Al-array direction governs the reactivity of Zn2+-MFI. The former type of array well explains the experimental fact that spontaneous and irreversible heterolysis of H2 takes place on Zn2+-MFI, even at room temperature, whereas the latter type of array is less reactive; high activation energy is required for the heterolytic cleavage of H2 (ca. >70 kJ mol-1). A detailed analysis of the geometric and electronic structures of a series of Zn2+-MFI models with various Al-array directions clarified the following facts: the circumferentially arrayed Al-Al site induces an inevitable environment around the Zn2+ site, with the simultaneous existence of both a Lewis acid point (coordinatively unsaturated and distorted Zn2+) and a Lewis base point (the lattice oxygen atom juxtaposed with exchanged Zn2+, which participates in the activation of H2: OjL). It is the circumferentially arrayed Al-Al atoms that confer acidic and basic nature on the metal ion and the lattice oxygen atom (OjL), and ultimately trigger the heterolytic dissociation of H2, even at 300 K. PMID- 28880029 TI - Fluorescence labelling of extracellular vesicles using a novel thiol-based strategy for quantitative analysis of cellular delivery and intracellular traffic. AB - Extracellular vesicles, including exosomes, are naturally derived nanovesicles generated in and released by numerous cell types. As extracellular entities they have the capacity to interact with neighbouring cells and distant tissues and affect physiological processes as well as being implicated in numerous diseases including tumorigenesis and neurodegeneration. They are also under intense investigation as delivery vectors for biotherapeutics. The ways in which EVs interact with recipient cells to influence cell physiology and deliver a macromolecular payload are at the early stages of exploration. A significant challenge within these studies is the ability to label EVs directly or indirectly with fluorescent probes to allow visualization without compromising functionality. Here, we present a thiol-based fluorescence labelling method allowing comprehensive analysis of the cellular uptake of prostate cancer derived EVs in live cells using confocal microscopy. Labelling of the EVs in this way did not influence their size and had no effect on their ability to induce differentiation of lung fibroblasts to myofibroblasts. For endocytosis analyses, depletion of key endocytic proteins and the use of chemical inhibitors (Dynasore, EIPA, Rottlerin and IPA-3) indicated that fluid-phase endocytosis and/or macropinocytosis was involved in EV internalisation. Over a period of six hours EVs were observed to increasingly co-localise with lysosomes, indicating a possible termination point following internalisation. Overall this method provides new opportunities for analysing the cellular dynamics of EVs as biological entities affecting cell and whole body physiology as well as investigating their potential as drug delivery vectors. PMID- 28880030 TI - Quantitative detection of isotopically enriched E. coli cells by SERS. AB - It is clear that investigating how bacterial cells work by analysing their functional roles in microbial communities is very important in environmental, clinical and industrial microbiology. The benefits of linking genes to their respective functions include the reliable identification of the causative agents of various diseases, which would permit appropriate and timely treatment in healthcare systems. In industrial and municipal wastewater treatment and management, such knowledge may allow for the manipulation of microbial communities, such as through bioaugmentation, in order to improve the efficiency and effectiveness of bioremediation processes. Stable isotope probing coupled with identification techniques has emerged to be a potentially reliable tool for the discrimination, identification and characterization of bacteria at community and single cell levels, knowledge which can be utilized to link microbially mediated bioprocesses to phylogeny. Development of the surface-enhanced Raman scattering (SERS) technique offers an exciting alternative to the Raman and Fourier-transform infrared spectroscopic techniques in understanding the metabolic processes of microorganisms in situ. SERS employing Ag and Au nanoparticles can significantly enhance the Raman signal, making it an exciting candidate for the analysis of the cellular components of microorganisms. In this study, Escherichia coli cells were cultivated in minimal medium containing different ratios of 12C/13C glucose and/or 14N/15N ammonium chloride as the only carbon and nitrogen sources respectively, with the overall final concentrations of these substrates being constant. After growth, the E. coli cells were analyzed with SERS employing an in situ synthesis of Ag nanoparticles. This novel investigation of the SERS spectral data with multivariate chemometrics demonstrated clear clusters which could be correlated to the SERS spectral shifts of biomolecules from cells grown and hence labelled with 13C and 15N atoms. These shifts reflect the isotopic content of the bacteria and quantification of the isotope levels could be established using chemometrics based on partial least squares regression. PMID- 28880031 TI - Recent advances in the synthesis of analogues of phytohormones strigolactones with ring-closing metathesis as a key step. AB - In this paper, we synthesized and evaluated the biological activity of structural analogues of natural strigolactones in which the butenolide D-ring has been replaced with a gamma-lactam. The key step to obtain the alpha,beta-unsaturated gamma-lactam was an RCM on suitably substituted amides. Strigolactones (SLs) are plant hormones with various developmental functions. As soil signaling chemicals, they are required for establishing beneficial mycorrhizal plant/fungus symbiosis. Beside these auxinic roles, recently SLs have been successfully investigated as antitumoral agents. Peculiar to the SL perception system is the enzymatic activity of the hormone receptor. SARs data have shown that the presence of the butenolide D-ring is crucial to retain the biological activity. The substitution of the butenolide with a lactam might shed light on the mechanism of perception. In the following, a dedicated in silico study suggested the binding modes of the synthesized compounds to the receptor of SLs in plants. PMID- 28880032 TI - In vitro and in vivo inhibitory effects of a Pleurotus eryngii protein on colon cancer cells. AB - Edible mushrooms have been considered as a good source of bioactive components with various health benefits. Our previous study demonstrated the identity of a novel protein from Pleurotus eryngii, namely PEP, and its anti-inflammatory activities. Herein, we further determined the inhibitory effects of PEP against colon cancer cells. PEP suppressed the proliferation of human and murine colon cancer HCT116 and MC38 cells in a dose and time-dependent fashion, while it showed no inhibitory effect on normal human colonic myofibroblasts CCD-18Co at the same concentrations tested. Moreover, PEP induced cell cycle arrest and led to extensive cellular apoptosis in colon cancer cells, which was associated with the downregulation of cell cycle-related signaling proteins, e.g. cyclin B, cyclin E and cdc-2, and the upregulation of apoptosis-related signaling proteins, e.g. p53 and c-PARP. The results from an in vivo study showed that PEP treatment significantly suppressed tumor development of allograft colon cancer cells in mice, and this inhibition was associated with the upregulation of p21, p53, caspase-3 and cleaved caspase-3. Overall, our results provided a basis for PEP as a promising preventive agent against colon cancer. PMID- 28880033 TI - Cooperative hydrogen bonds form a pseudocycle stabilizing an isolated complex of isocyanic acid with urea. AB - The shapes of macromolecules and their complexes with small molecules are often determined by extended networks of hydrogen bonds. Here, for the first time, we provide a detailed description of a cooperative pair of hydrogen bonds to an individual molecule of urea. The structure and properties of a gas phase complex formed between urea and isocyanic acid are characterised through microwave spectroscopy and ab initio calculations at the CCSD(T)(F12*)/aug-cc-pVTZ level. PMID- 28880034 TI - Quantum dots: from fluorescence to chemiluminescence, bioluminescence, electrochemiluminescence, and electrochemistry. AB - During the past decade, nanotechnology has become one of the major forces driving basic and applied research. As a novel class of inorganic fluorochromes, research into quantum dots (QDs) has become one of the fastest growing fields of nanotechnology today. QDs are made of a semiconductor material with tunable physical dimensions as well as unique optoelectronic properties, and have attracted multidisciplinary research efforts to further their potential bioanalytical applications. Recently, numerous optical properties of QDs, such as narrow emission band peaks, broad absorption spectra, intense signals, and remarkable resistance to photobleaching, have made them biocompatible and sensitive for biological assays. In this review, we give an overview of these exciting materials and describe their potential, especially in biomolecules analysis, including fluorescence detection, chemiluminescence detection, bioluminescence detection, electrochemiluminescence detection, and electrochemical detection. Finally, conclusions are made, including highlighting some critical challenges remaining and a perspective of how this field can be expected to develop in the future. PMID- 28880035 TI - Catching the electron in action in real space inside a Ge-Si core-shell nanowire transistor. AB - Catching the electron in action in real space inside a semiconductor Ge-Si core shell nanowire field effect transistor (FET), which has been demonstrated (J. Xiang, W. Lu, Y. Hu, Y. Wu, H. Yan and C. M. Lieber, Nature, 2006, 441, 489) to outperform the state-of-the-art metal oxide semiconductor FET, is central to gaining unfathomable access into the origin of its functionality. Here, using a quantum transport approach that does not make any assumptions on electronic structure, charge, and potential profile of the device, we unravel the most probable tunneling pathway for electrons in a Ge-Si core-shell nanowire FET with orbital level spatial resolution, which demonstrates gate bias induced decoupling of electron transport between the core and the shell region. Our calculation yields excellent transistor characteristics as noticed in the experiment. Upon increasing the gate bias beyond a threshold value, we observe a rapid drop in drain current resulting in a gate bias driven negative differential resistance behavior and switching in the sign of trans-conductance. We attribute this anomalous behavior in drain current to the gate bias induced modification of the carrier transport pathway from the Ge core to the Si shell region of the nanowire channel. A new experiment involving a four probe junction is proposed to confirm our prediction on gate bias induced decoupling. PMID- 28880036 TI - Reactivity of the geminal phosphinoborane tBu2PCH2BPh2 towards alkynes, nitriles, and nitrilium triflates. AB - The reactivity of the geminal phosphinoborane tBu2PCH2BPh2 towards terminal alkynes, nitriles and nitrilium salts is investigated. Terminal alkynes react via C-H bond splitting (deprotonation) resulting in the formation of phosphonium borates. In contrast, both nitriles and nitrilium salts undergo addition reactions resulting in the formation of five-membered heterocycles. All compounds were characterized by multinuclear NMR spectroscopy, and single-crystal X-ray structure determinations. Insight into the reaction mechanisms was gained by DFT calculations. PMID- 28880037 TI - The role of spin states in the catalytic mechanism of the intra- and extradiol cleavage of catechols by O2. AB - Iron-dependent enzymes and biomimetic iron complexes can catalyze the ring cleavage of very inert, aromatic compounds. The mechanisms of these transformations and the factors that lead either to extradiol cleavage or intradiol cleavage have not been fully understood. By using density functional theory we have elucidated the mechanism of the catalytic cycle for two biomimetic complexes, and explained the difference in the experimentally obtained products. PMID- 28880038 TI - Palladium-catalyzed, unsymmetrical homocoupling of thiophenes via carbon-sulfur bond activation: a new avenue to homocoupling reactions. AB - The Pd-catalyzed, CN-directed unsymmetrical synthesis of 2,4'-bithiophenes via an unprecedented homocoupling reaction is described. The NH2/CN/SMe arrangement breaks the routine. The cooperative performance of the functional groups in thiophenes would open up a new vision in the field of metal catalysis homocoupling reactions by joining the electrophilic and nucleophilic motifs of the substrate. Furthermore, it is found that the alpha-chelating effect of the carbonyl group in amino thiophene offers a new class of synthetic protocols for C N cross-coupling with arylboronic acids. The bidentate N,O-chelation provides a series of advantages such as copper-catalyzed, ligand- and base-free under open flask conditions. Interestingly, the combination of the C-N cross coupling/homocoupling reactions in a domino fashion led to the bithiophene adducts featuring the C(Ar)-N bond cleavage in the nitrogen that bridged between the two thiophene units. PMID- 28880039 TI - Why can a gold salt react as a base? AB - This study shows that gold salts [(L)AuX] (L = PMe3, PPh3, JohnPhos, IPr; X = SbF6, PF6, BF4, TfO, Tf2N) act as bases in aqueous solutions and can transform acetone to digold acetonyl complexes [(L)2Au2(CH2COCH3)]+ without any additional base present in solution. The key step is the formation of digold hydroxide complexes [(L)2Au2(OH)]+. The kinetics of the formation of the digold complexes and their mutual transformation is studied by electrospray ionization mass spectrometry and the delayed reactant labelling method. We show that the formation of digold hydroxide is the essential first step towards the formation of the digold acetonyl complex, the reaction is favoured by more polar solvents, and the effect of counter ions is negligible. DFT calculations suggest that digold hydroxide and digold acetonyl complexes can exist in solution only due to the stabilization by the interaction with two gold atoms. The reaction between the digold hydroxide and acetone proceeds towards the dimer {[(L)Au(OH)].[(L)Au(CH3COCH3)]+}. The monomeric units interact at the gold atoms in the perpendicular arrangement typical of the gold clusters bound by the aurophilic interaction. The hydrogen is transferred within the dimer and the reaction continues towards the digold acetonyl complex and water. PMID- 28880041 TI - Less stable tautomers form stronger hydrogen bonds: the case of water complexes. AB - Hydrogen bonding in cyclic complexes of water with tautomeric pairs of molecules M0 and M1 is calculated to be stronger by more than 25% for the less stable tautomer M1 in all cases where the energy gap between the two tautomers is large (DeltaE(M0 - M1) > 10 kcal mol-1). This is accompanied by a large red-shift (>200 cm-1) of the N-H/O-H stretch frequency in the complexes involving M1. Large barriers for double proton transfer in both directions should permit an experimental verification. Exceptions to this rule were found in heterocycles with an N-C[double bond, length as m-dash]O fragment incorporated into a conjugated cycle resulting in two nearly degenerate tautomers - keto and enol forms. The wavefunction of the keto form has a large contribution from a zwitterionic VB structure which is also aromatic. This increases the polarity of the keto group, making the oxygen atom a strong H-bond acceptor. It can also stabilize the keto form below the aromatic enol form. In this case the extra-HB stabilization is observed for the most stable tautomer (i.e. for the keto form). H-bonding enhances the aromatic character of less aromatic molecules, but the more aromatic tautomers partially loose aromaticity. PMID- 28880040 TI - Analysis of the vibronic structure of the trans-stilbene fluorescence and excitation spectra: the S0 and S1 PES along the Ce[double bond, length as m dash]Ce and Ce-Cph torsions. AB - We analyze the highly resolved vibronic structure of the low energy (<=200 cm-1) region of the fluorescence and fluorescence excitation spectra of trans-stilbene in supersonic beams. In this spectral region the vibronic structure is associated mainly with vibrational levels of the Ce-Ce torsion (tau) and the au combination of the two Ce-Cph bond twisting (phi). We base this analysis on the well established S0(tau, phi) two-dimensional potential energy surface (PES) and on a newly refined S1(tau, phi) PES. We obtain vibrational eigenvalues and eigenvectors of the anharmonic S0(tau, phi) and S1(tau, phi) PES using a numerical procedure based on the Meyer's flexible model [R. Meyer, J. Mol. Spectrosc., 1979, 76, 266]. Then we derive Franck-Condon factors and therefore intensities of the relevant vibronic bands for the S0 -> S1 excitation and S1 -> S0 fluorescence spectra. Furthermore, we assess the role of the bg combination of the two Ce-Cph bond twisting (nu48) in the structure of the S1 -> S0 fluorescence spectra. By the use of these results we are able to assign most of the low energy vibrational levels of the S0 -> S1 excitation spectra and of the fluorescence spectra of the emission from several low energy S1 vibronic levels. The good agreement between the observed and the computed vibrational structure of the S0 > S1 and S1 -> S0 spectra suggests that the proposed picture of the E1(tau, phi) and E0(tau, phi) PES, in particular along the coordinate tau governing trans-cis photo-isomerization in S1, is accurate. In S0, the barriers for the Ce[double bond, length as m-dash]Ce torsion and for the au type Ce-Cph bond twisting are 16 080 cm-1 and 3125 cm-1, respectively, while in S1, where the bond orders of the Ce[double bond, length as m-dash]Ce and Ce-Cph bonds are reversed, the two barriers become 1350 cm-1 and 8780 cm-1, respectively. PMID- 28880042 TI - The fluorescently responsive 3-(naphthalen-1-ylethynyl)-3-deaza-2'-deoxyguanosine discriminates cytidine via the DNA minor groove. AB - A new environmentally responsive fluorescent nucleoside, 3-(naphthalen-1 ylethynyl)-3-deaza-2'-deoxyguanosine (3nzG), has been synthesized. The nucleoside, 3nzG, exhibited solvatochromic properties and when introduced into ODN probes it was able to recognize 2'-deoxycytidine in target strands by a distinct change in its emission wavelength through probing microenvironmental changes in the DNA minor groove. Thus, 3nzG has the potential for use as a fluorescent probe molecule for micro-structural studies of nucleic acids including the detection of single-base alterations in target DNA sequences. PMID- 28880043 TI - [Interstitial nephritis in pigs]. AB - OBJECTIVE: Interstitial nephritis as a form of renal diseases can be found frequently among pigs. Nevertheless, prevalence and aetiology need to be investigated in more detail as reports about detailed analysis are lacking. MATERIAL AND METHODS: In the present study, a total of 169 kidneys of conventionally and organically raised pigs were randomly chosen at slaughter and classified according to the degree of inflammation and the participating inflammatory cells. Moreover, PCV2 as an infectious agent was analysed by immunohistochemistry and in-situ hybridisation. RESULTS: All of the investigated kidneys displayed mild interstitial lesions. Inflammatory cells included lymphocytes, macrophages, plasma cells, eosinophilic and neutrophilic granulocytes. Significant (p <= 0.0001) differences concerning the grade of inflammation and inflammatory cell occurrence could be observed between kidneys of conventionally and organically raised pigs. In comparison to conventionally raised pigs organically raised pigs showed significant (p <= 0.0001) more frequently a mild form of nephritis as well as a significant (p <= 0.0001) more frequent occurrence of lymphocytes and macrophages. In contrast to that, conventionally raised pigs had a significant (p <= 0.0001) higher occurrence rate of a mild to moderate form of nephritis as well as a significant (p <= 0.0001) higher level in occurrence of lymphocytes, macrophages, plasma cells, and neutrophilic granulocytes when compared to organically raised pigs. PCV2 DNA was detected in the kidney of only one animal. CONCLUSION: Interstitial nephritis was found in conventionally and organically raised pigs and PCV2 was ruled out as a major pathogen for interstitial nephritis in slaughter pigs. CLINICAL RELEVANCE: Because of the high prevalence and unknown cause further investigations are necessary to delineate the clinic relevance of this alteration and its pathogenesis. PMID- 28880044 TI - [Management of the dry and transition periods of dairy cattle in free stall housing systems in Lower Saxony. Part 1: Farm management. Teil 1: Betriebsmanagement]. AB - OBJECTIVE: Describing husbandry and management of dairy cows during the dry and transition periods on farms of different sizes in Lower Saxony, Germany. MATERIAL AND METHODS: A total of 51 dairy farms were visited and asked via questionnaire about the husbandry and management in the following categories: general operating data, stable and husbandry of milking cows, dry cows, transition cows and the youngstock, pasture management, feeding, health data and prophylactic treatments. In addition, during a farm inspection, data on cow comfort were collected. RESULTS: German Holstein was the predominant breed on the dairy farms. Most cattle were kept in three-rowed free-stall housing systems (74%) with straw bedding (47%) without division in productivity groups (59%). The dry cows were most frequently separated in two groups (68%) in free-stall housing systems (68%). The heifers were similarly mainly kept in free-stall housing systems (67%) and were mostly separated according to their reproductive status (74%). On 29% of the farms, pasture grazing was not practiced at any time. On 80% of the farms, cows were fed a mixed ration with computerized concentrate supplementation and on 68% of the farms biphasic dry cow diets were used. The most frequently stated health problems were of the limb and claw (61%). Prophylaxis of ketosis was practiced on 21% of the farms and milk-fever prophylaxis on 12% of the farms, both for each individual cow around calving. CONCLUSION AND CLINICAL RELEVANCE: Husbandry and management on farms differ widely and are still in need of optimization with respect to barn concepts, implementation of production groups and feeding, as well as veterinary consultation with respect to health problems and prophylactic measures. PMID- 28880045 TI - [Factors influencing first-colostrum calcium concentration in Holstein-Friesian cows and the relationship to postpartum calcium concentration]. AB - OBJECTIVE: To investigate the factors that affect the calcium content of the first colostrum (milk exclusively of the first withdrawal) and the relationship to the blood calcium concentration. We tested the hypotheses that the lactation number is the main influence factor and that there is a relationship to the postpartum serum calcium concentration. MATERIAL AND METHODS: An observational study was conducted from April 2012 to March 2013 at a commercial dairy farm (2278 Holstein-Friesian cows). The analysis comprised the following variables: blood serum concentrations of calcium, phosphate, non-esterified fatty acids, and beta-hydroxybutyrate; back-fat thickness; daily milk production; calving data; lactation number; male parent of the cow; length of gestation; age at first calving; dry-period duration; fertility parameters of prelactation; diseases during the dry period and up to 3 days postpartum. A stepwise analysis of the data for correlations and influencing factors was conducted by means of variance, correlation, and multiple linear regression analyses. RESULTS: The mean calcium concentration of the colostrum was 2386 mg/l (standard deviation 550 mg/l), with heifers having a higher value by 148.5 mg/l than pluriparous cows. Factors influencing the colostrum calcium content were the mean milk production during the first week of lactation and the back-fat thickness at drying off. The correlation to the milk production was negative, which may be a dilution effect. An increase in back-fat thickness caused an increase in the colostrum calcium concentration. Together, these two factors explained 25% of the colostrum calcium variation. The lactation number and the blood calcium concentration were not significant influence factors on the colostrum calcium content. CONCLUSION AND CLINICAL RELEVANCE: The hypotheses could not be confirmed in that there was neither a relationship of to the blood calcium concentration nor of the lactation number with the colostrum calcium content. The colostrum calcium content displayed a wide individual variation. However, there was a possible influence through milk production and back-fat thickness, but this would not be beneficial with regard to prophylaxis of parturient paresis. PMID- 28880046 TI - Clinical decisions support malfunctions in a commercial electronic health record. AB - OBJECTIVES: Determine if clinical decision support (CDS) malfunctions occur in a commercial electronic health record (EHR) system, characterize their pathways and describe methods of detection. METHODS: We retrospectively examined the firing rate for 226 alert type CDS rules for detection of anomalies using both expert visualization and statistical process control (SPC) methods over a five year period. Candidate anomalies were investigated and validated. RESULTS: Twenty-one candidate CDS anomalies were identified from 8,300 alert-months. Of these candidate anomalies, four were confirmed as CDS malfunctions, eight as false positives, and nine could not be classified. The four CDS malfunctions were a result of errors in knowledge management: 1) inadvertent addition and removal of a medication code to the electronic formulary list; 2) a seasonal alert which was not activated; 3) a change in the base data structures; and 4) direct editing of an alert related to its medications. 154 CDS rules (68%) were amenable to SPC methods and the test characteristics were calculated as a sensitivity of 95%, positive predictive value of 29% and F-measure 0.44. DISCUSSION: CDS malfunctions were found to occur in our EHR. All of the pathways for these malfunctions can be described as knowledge management errors. Expert visualization is a robust method of detection, but is resource intensive. SPC-based methods, when applicable, perform reasonably well retrospectively. CONCLUSION: CDS anomalies were found to occur in a commercial EHR and visual detection along with SPC analysis represents promising methods of malfunction detection. PMID- 28880047 TI - Comparison of secure messaging application (WhatsApp) and standard telephone usage for consultations on Length of Stay in the ED. A prospective randomized controlled study. AB - OBJECTIVE: Consultation, the process of an Emergency Physician seeking an opinion from other specialties, occurs frequently in the Emergency Department (ED). The aim of this study was to determine the effect of secure messaging application (WhatsApp) usage for medical consultations on Emergency Department Length of Stay (ED LOS) and consult time. METHODS: We conducted a prospective, randomized controlled trial in the ED using allocation concealment over three months. Consultations requested in the ED were allocated into two groups: consultations requested via the secure messaging application and consultations requested by telephone as verbal. RESULTS: A total of 439 consultations requested in the ED were assessed for eligibility and 345 were included in the final analysis: 173 consultations were conducted using secure messaging application and 172 consultations were conducted using standard telephone communications. The median ED LOS was 240 minutes (IQR:230-270, 95% CI:240 to 255.2) for patients in the secure messaging application group and 277 minutes (IQR:270-287.8, 95% CI:277 to 279) for patients in the telephone group. The median total ED LOS was significantly lower among consults conducted using Secure messaging application relative to consults conducted by telephone (median dif: -30, 95%CI:-37to-25, p<0.0001). The median consult time was 158 minutes (IQR:133 to 177.25, 95% CI:150 to 169) for patients in the Secure messaging application group and 170 minutes (IQR:165 to 188.5, 95% CI:170-171) for patients in the Telephone group (median dif: -12, 95%CI:-19 to-7,p<0.0001). Consultations completed without ED arrival was 61.8% in the secure messaging group and 33.1% in the Telephone group (dif: 28.7, 95% CI:48.3 to 66, p<0.001). CONCLUSIONS: Use of secure messaging application for consultations in the ED reduces the total ED LOS and consultation time. Consultation with secure messaging application eliminated more than half of in-person ED consultation visits. PMID- 28880048 TI - Histopathological changes associated to an absorbable fibrin patch (Tachosil(r)) covering in an experimental model of high-risk colonic anastomoses. AB - BACKGROUND: TachoSil(r) is a fibrin sponge that contains fibrinogen and thrombin and is a useful adjuvant to enhance control of air leaks in thoracic surgery and to control bleeding in vascular and general surgery. Its use in intestinal surgery to prevent suture dehiscence is currently under investigation. MATERIAL AND METHODS: We report the results of a prospective randomized experimental study on 33 large white pigs in which a high-risk suture was created by induction of ischemia. We randomly employed TachoSil(r) to cover the anastomosis in half of the animals compared to a control group of uncovered anastomosis. After euthanasia, postmortem analysis was performed describing the findings related to anastomotic leakage, peritonitis and grade of adhesions. The entire anastomosis was resected in bloc and sent for histopathological analysis. A single blinded pathologist evaluated the histopathological features of the specimens. RESULTS: We found statistically significant differences favouring the patch in decreasing leakage in the covered group. The healing process did not show significant differences between groups, although a higher rate of microscopic abscess was observed in the covered group. CONCLUSION: The use of fibrin sealants covering high-risk intestinal sutures has a positive effect in avoiding macroscopic anastomotic leakage. The patch did not have any influence in the anastomotic healing process, however, as a result of the effect in containing the inflammatory response, it may increase the rate of abscess. PMID- 28880050 TI - Effects of nanotechnology-based devices on postural control in healthy subjects. AB - BACKGROUND: The aim of the present preliminary randomized controlled study was to ascertain whether the use of newly developed nanotechnologies-based patches can influence posture control of healthy subjects. METHODS: Thirty healthy female subjects (age 39.4 years, BMI 22.74 kg/m2) were randomly assigned to two groups: one with active patches and a control group with sham patches. Two patches were applied with a tape: one on the subject's sternum and the other on the C7 apophysis. Body sway during quiet upright stance was recorded with a dynamometric platform. Each subject was tested under two visual conditions, eyes open and closed. We used a blocked stratified randomization procedure conducted by a third party. RESULTS: Subjects wearing the sham patches showed a significant increase of the center of pressure sway area after 4 hours when they performed the habitual moderate-intensity work activities. In the active patch group, a decrease of the sway path was evident, providing evidence of an enhanced balance control. CONCLUSIONS: Our preliminary findings on healthy subjects indicate that nanotechnological devices generating ultra-low electromagnetic fields can improve posture control. PMID- 28880049 TI - Sleep and glycemic control in adolescents with type 1 diabetes. AB - BACKGROUND: Increasing evidence link sleep curtailment and circadian misalignment with adverse metabolic outcome. Adolescents might be most affected, given their late sleep timing and early school and work start times. OBJECTIVE: Our aim was to examine the impact of poor sleeping habits on glycemic control in adolescents with type 1 diabetes. SUBJECTS AND METHODS: This was a non-interventional multicenter study across Germany recruiting pubertally mature adolescents with type 1 diabetes. Medical records were used to collect information on diabetes duration, treatment, and complications. Participants self-reported sleep quality, timing, chronotype, and social jetlag-a measure of circadian misalignment. Hemoglobin A1c (HbA1c) was determined at the time of questionnaire response. We used multivariable linear regression models to examine associations between sleep and glycemic control. RESULTS: A total of 191 patients aged 16.5 years (mean HbA1c 8.0% [64 mmol/mol]) were included in this study. In multivariable adjusted analyses, sleep quality was significantly associated with HbA1c (mean difference; beta = -0.07, P = .05). Stratified analysis indicated that this association might be stronger in boys and also in children with migration background. In contrast, neither sleep duration, sleep debt, chronotype, nor social jetlag was associated with HbA1c . Secondary analyses showed that social jetlag was significantly associated with levels of insulin requirements (mean difference; beta = 0.035, P = .03). CONCLUSIONS: Our study suggests that poor sleep quality is associated with increased HbA1c in adolescents with type 1 diabetes and that higher levels of circadian misalignment are associated with increased insulin requirements. If replicated, our results indicate a clinical relevance of sleep habits in adolescents with type 1 diabetes. PMID- 28880051 TI - Depression mediates the association between physical inactivity and cognitive impairment in Korean older adults. AB - BACKGROUND: This study investigated the association between physical activity and cognitive impairment in older adults. METHODS: Data from 10245 Korean adults (4428 men and 5817 women) who participated in the 2008 baseline survey of the living profiles of older people survey were used for this analysis. Compared with low PA men, moderate PA men only had significantly lower odds-ratio (OR) and 95% confidence interval (95% CI) (OR=0.795, 95% CI: 0.654~0.965, P=0.021) for having cognitive impairment even after adjusting for measured covariates, which was no longer significant when additionally adjusted for depressive symptoms (OR=0.862, 95% CI: 0.707~1.051, P=0.143). RESULTS: Compared with low PA women, moderate- and high PA women had significantly lower risks of cognitive impairment (OR=0.830, 95% CI: 0.712~0.969, P=0.018 and OR=0.784, 95% CI: 0.651~0.943, P=0.010, respectively) even after adjusted for the measured covariates, which was no longer significant when additionally adjusted for depressive symptoms (OR=0.897, 95% CI: 0.776~1.049, P=0.173 and OR=0.919, 95% CI: 0.761~1.111, P=0.385, respectively). CONCLUSIONS: These findings suggest that depression mediates the inverse relationship between physical activity and cognitive decline among older adults. PMID- 28880052 TI - Effects of volleyball plyometric intervention program on vertical jumping ability in male volleyball players. AB - BACKGROUND: This study aimed to investigate the effect of a 6-week plyometric exercise training program on the development of lower limb explosive power in terms of vertical jumping ability in university level volleyball players. The study involved 9 male volleyball players from the AWF Wroclaw University Sports Club, with a minimum of 5 years of training and competition experience. The program consisted of various bounds, hops, and jumps in vertical, horizontal, and mixed directions. During the program, a progressive overload of plyometric intervention was applied. Lower limb explosive power in the form of vertical jumping ability was developed and tested. METHODS: The jumping ability was evaluated via 5 types of maximum-effort vertical jumps, using the Opto Jump system. In addition, once each week, the heart rate was recorded using a heart rate monitor (Polar RS300X GPS). RESULTS: The only significant correlation was found between squat jump and number of jumps and between counter movement jump and heart rate. CONCLUSIONS: From a practical standpoint, the improvement, which was noticed after 3 and 6 weeks, seems to optimal period for volleyball players adaptation to significant increased training load. PMID- 28880054 TI - Effects of family-centered care based on timing it right on the care ability and the quality of life of family members of patients with acute myocardial infarction. PMID- 28880053 TI - Liver fibrosis: the 2017 state of art. AB - Liver fibrosis is a wound-healing response to a wide spectrum of chronic liver injuries. It is characterized by loss of hepatocytes and alteration in hepatic architecture following an imbalance between extracellular matrix synthesis and degradation. Irrespectively of underlying etiology, fibrosis may progress to cirrhosis and specific pathogenetic mechanisms as well as different disease patterns may be identified according to etiology. Liver biopsy is still considered the gold standard for fibrosis assessment, despite the fact that it is invasive, has poor patient compliance and is not exempt of complications. Several reliable and non-invasive tools are currently used in clinical practice, including imaging methods and surrogate serum biomarkers, commonly combined into composite scores. The main limitation of non-invasive methods is the low performance in the discrimination of intermediate stages of fibrosis. However, with the recent availability of novel treatment options, particularly for chronic hepatitis C, a precise staging of liver fibrosis is becoming clinically less relevant. Conversely, since patients with cirrhosis need to be monitored for the risk of hepatocellular carcinoma development, the accurate detection of this condition is a primary endpoint. Finally, several promising antifibrotic agents are under investigation in phase I and II trials. Nevertheless, further efforts are needed for the identification of novel potential targets for the development of antifibrotic drugs able to arrest, and possibly revert liver fibrogenesis. PMID- 28880055 TI - Resistant hypertension: an overview. AB - Despite the availability of anti-hypertensive medications with proven efficacy and good tolerability, many hypertensive patients have blood pressure (BP) levels not at the goals set by international societies. Some of these patients are either non-adherent to the prescribed drugs or not optimally treated. However, a proportion has resistant hypertension (RH) defined as office BP above goal despite the use of >=3 antihypertensive medications at maximally tolerated doses (one ideally being a diuretic). Diagnosis of RH based upon office measurements, however, needs confirmation through 24-h BP monitoring to exclude "white coat" RH since cardiovascular events and mortality rates follow mean ambulatory BPs. Standardized combination therapy based upon angiotensin converting enzyme inhibitors or angiotensin receptor blockers, amlodipine or other dihydropiridine calcium channel blockers and thiazide or thiazide-like diuretics has been advocated to treat RH with spironolactone as preferred fourth add-on drug. Interventional procedures such as renal denervation have been devised to treat RH and tested with insofar not positive results in series of patients not responding to medical treatment. It is unclear whether RH constitutes a specific phenotype of EH or should rather be considered a more serious form of uncontrolled hypertension. Whatever the case, its presence associates with an increased cardio and cerebrovascular risk and deserves, therefore, particular care. PMID- 28880056 TI - Ultrasound and ultrasound-related techniques in endocrine diseases. AB - Ultrasound examination has become essential to evaluate morphology and size of several endocrine glands and detect the presence of lesions within these organs. Nevertheless, with the recent advances of ultrasound technology, we have opportunity to correlate the echostructure of thyroid, ovary, testis, parathyroids, etc. to their function. Thus, the ultrasound systems are in-office essential instruments for many clinical specialists. Herein we presented the most updated information about the use of ultrasound in specific endocrine-related issues, such as thyroid, parathyroid, adrenal gland, and testicle. PMID- 28880057 TI - Comparative study of thyroid hormone and antithyroid antibody levels in patients with gestational diabetes mellitus and pregnant patients with diabetes. AB - BACKGROUND: The aim of this study was to investigate the levels of thyroid hormone and antithyroid antibodies and their relationship with pregnancy outcome in patients with gestational diabetes mellitus (GDM) and diabetic patients. METHODS: Fifty patients with GDM and 50 pregnant patients with diabetes were selected. Their levels of fasting blood glucose (FBG), glycosylated hemoglobin, FT3, FT4, TGab, TSH, TPOab were measured until parturition. RESULTS: There were no statistically significant differences in the age, gestational age, weight, FBG and glycosylated hemoglobin between the two groups (P>0.05). The levels of FT3 and FT4 in patients with GDM were significantly lower than those in diabetic pregnant patients, while the levels of TSH, TGab, TPOab of GDM patients were significantly higher than in diabetic pregnant patients (P<0.05). The total incidence rates of premature delivery, post-term birth and cesarean section in patients with GDM were significantly higher than those in diabetic pregnant patients. At six-month follow-up, the intellectual levels of infants delivered by patients with GDM were significantly lower than those of diabetic pregnant patients (P<0.05). CONCLUSIONS: The levels of thyroid hormones and related antibodies in patients with GDM were abnormal, which may have affected outcome of pregnancy and the intellectual level of their infants. PMID- 28880058 TI - Acromegaly and bone. AB - Growth hormone (GH) and insulin-like growth factor-I (IGF-I) have pleiotropic effects on the skeleton throughout the lifespan by influencing bone formation and resorption. Despite these positive effects on skeletal metabolism, in presence of GH and IGF-I excess, bone turnover increases excessively leading to deterioration of bone microarchitecture and high risk of fragility fractures, thereby impairing quality of life. Coexistent hypogonadism, diabetes mellitus, hypovitaminosis D, hyperparathyroidism, and over-replacement with glucocorticoids impair bone framework, however, the effects of acromegaly on bone mineral density (BMD) are still controversial and despite normalization of bone turnover after treatment, the risk for fractures remains increased. As a matter of fact, a major clinical aspect emerging from the studies published so far is the lack of clinical diagnostic tools able to reliably predict the appearance of fractures in patients with acromegaly occurring even in the presence of normal or low-normal BMD. New radiological software and clinical devices have been employed in acromegaly patients highlighting a significant impairment of both cortical and cancellous bone. In this article, we summarize the pathophysiology, clinical aspects and the new diagnostic tools to better understand bone impairment in acromegaly. PMID- 28880059 TI - Evaluation of somatic genomic imbalances in thyroid carcinomas of follicular origin by CGH-based approaches. AB - Application of distinct technologies of cancer genome analysis has provided important information for the molecular characterization of several human neoplasia, including follicular cell-derived thyroid carcinoma. Among them, comparative genomic hybridization (CGH)-based procedures have been extensively applied to evaluate genomic imbalances present in these tumours, obtaining data leading to an increase in the understanding of their complexity and diversity. In this review, after a brief overview of the most commonly used CGH-based technichs, we will describe the major results deriving from the most influential studies in the literature which used this approach to investigate the genomic aberrations of thyroid cancer cells. In most studies a small number of patients have been analyzed. Deletions and duplications at different chromosomal regions were detected in all investigated cohorts. A higher number of genomic imbalances has been detected in anaplastic or poorly differentiated thyroid carcinomas compared to well differentiated ones. Limitations in the interpretation of the results, as well the potential impact in the clinical practice are discussed. Though a quite heterogeneous picture arises from results so far available, CGH array, combined with other methodologies as well as an accurate clinical management, may offer novel opportunities for a better stratification of thyroid cancer patients. PMID- 28880060 TI - Comparison of orthopantomography and CT accuracy in predicting inferior alveolar nerve injury following lower third molar surgical extraction. AB - BACKGROUND: The aim of this study was to compare orthopantomography (OPG) and computed tomography (CT) accuracy in predicting inferior alveolar nerve (IAN) injury after lower wisdom teeth extraction. METHODS: Twenty-three patients with completely impacted lower third molars were enrolled in this study and OPG and CT exams were obtained before surgical intervention. Finally, a total of 26 lower third molars were extracted and cases of paresthesia following a IAN lesion have been registered. Then, OPG and CT images of the same patients have been randomly submitted to four experienced oral surgeons (with a seniority of at least 5 years) who were required to predict the possibility of a IAN injury by only evaluating the radiological exams. The images were anonymous and have been submitted to the surgeons without an order avoiding to influencing the answers. The agreement between the predicted and the real outcomes was statistically evaluated using the positive predictive value (PPV), the negative predictive value (NPV), Sensitivity, Specificity and the Spearman's rank correlation coefficient. RESULTS: A perfect agreement between OPG-based prevision and the real development of paresthesia due to IAN injury has been observed. This agreement was only moderate when considering CT images. CONCLUSIONS: OPG is a first-level diagnostic exam that provides enough information for predicting IAN lesions after impacted lower third molars surgery. CT is a second-level radiological exam that provides more information on roots morphology and on the amount of the contiguity between roots and mandibular canal resulting useful in performing a minimally invasive surgery. PMID- 28880061 TI - Clinical course of asthma patients with H1N1 influenza infection and oseltamivir. AB - BACKGROUND: H1N1 influenza virus prevailed throughout the world in 2009. However, there are few reports on the clinical features of H1N1 influenza infection in adult asthma patients. We evaluated the clinical features in asthma patients with H1N1 influenza infection who took oseltamivir and compared them to those with other upper respiratory infections. METHODS: We reviewed asthma patients over 15 years of age who had visited Seoul National University Hospital and Seoul National University Bundang Hospital for suspected H1N1 influenza infection from August 2009 to March 2010. Various clinical features such as hospital admission days, respiratory symptoms, basal lung function, and past history was compared between H1N1 influenza PCR positive and negative groups. RESULTS: A total of 111 asthmatics were enrolled. All patients took oseltamivir. H1N1 RT-PCR was positive in 62 patients (55.9%), negative in 49 patients (44.1%). Wheezing developed more frequently in the H1N1 positive group. (43.5 vs. 16.7%, P=0.044). The rate of acute asthma exacerbations and pneumonia development were higher in the H1N1 positive group (59.7 vs. 51%, P=0.015, 25.0% vs. 0%, P<0.001). The rates for emergency room visit, hospital admissions, intensive care unit admissions, hospital days were not different between the groups. Underlying medical conditions were accompanied more frequently in the H1N1 negative patients (21.6% vs. 30.6%, P=0.002), especially cardiac disease (7.2% vs. 15.3%, P=0.011). CONCLUSIONS: H1N1 influenza infection may affect the clinical course of asthma combined with more severe manifestations; however, Oseltamivir could have affected the clinical course of H1N1 infected patients and made it milder than expected. PMID- 28880063 TI - Correction to "Silver Nanowire/MnO2 Nanowire Hybrid Polymer Nanocomposites: Materials with High Dielectric Permittivity and Low Dielectric Loss". PMID- 28880062 TI - Following the ACA Repeal-and-Replace Effort, Where Does the U.S. Stand on Insurance Coverage? Findings from the Commonwealth Fund Affordable Care Act Tracking Survey, March--June 2017. AB - Issue: After Congress's failure to repeal and replace the Affordable Care Act, some policy leaders are calling for bipartisan approaches to address weaknesses in the law's coverage expansions. To do this, policymakers will need data about trends in insurance coverage, reasons why people remain uninsured, and consumer perceptions of affordability. Goal: To examine U.S. trends in insurance coverage and the demographics of the remaining uninsured population, as well as affordability and satisfaction among adults with marketplace and Medicaid coverage. Methods: Analysis of the Commonwealth Fund Affordable Care Act Tracking Survey, March-June 2017 Findings and Conclusions: The uninsured rate among 19-to 64-year-old adults was 14 percent in 2017, or an estimated 27 million people, statistically unchanged from one year earlier. Uninsured rates ticked up significantly in three subgroups: 35-to-49-year-olds, adults with incomes of 400 percent of poverty or more (about $48,000 for an individual), and adults living in states that had not expanded Medicaid. Half of uninsured adults, or an estimated 13 million, are likely eligible for marketplace subsidies or the Medicaid expansion in their state. Four of 10 uninsured adults are unaware of the marketplaces. Adults in marketplace plans with incomes below 250 percent of poverty are much more likely to view their premiums as easy to afford compared with people with higher incomes. Policies to improve coverage include a federal commitment to supporting the marketplaces and the 2018 open enrollment period, expansion of Medicaid in 19 remaining states, and enhanced subsidies for people with incomes of 250 percent of poverty or more. PMID- 28880064 TI - Fullerene-Free Organic Solar Cells with an Efficiency of 10.2% and an Energy Loss of 0.59 eV Based on a Thieno[3,4-c]Pyrrole-4,6-dione-Containing Wide Band Gap Polymer Donor. AB - Although the combination of wide band gap polymer donors and narrow band gap small-molecule acceptors achieved state-of-the-art performance as bulk heterojunction (BHJ) active layers for organic solar cells, there have been only several of the wide band gap polymers that actually realized high-efficiency devices over >10%. Herein, we developed high-efficiency, low-energy-loss fullerene-free organic solar cells using a weakly crystalline wide band gap polymer donor, PBDTTPD-HT, and a nonfullerene small-molecule acceptor, ITIC. The excessive intermolecular stacking of ITIC is efficiently suppressed by the miscibility with PBDTTPD-HT, which led to a well-balanced nanomorphology in the PBDTTPD-HT/ITIC BHJ active films. The favorable optical, electronic, and energetic properties of PBDTTPD-HT with respect to ITIC achieved panchromatic photon-to-current conversion with a remarkably low energy loss (0.59 eV). PMID- 28880065 TI - A Low-Cost and High-Performance Sulfonated Polyimide Proton-Conductive Membrane for Vanadium Redox Flow/Static Batteries. AB - A novel side-chain-type fluorinated sulfonated polyimide (s-FSPI) membrane is synthesized for vanadium redox batteries (VRBs) by high-temperature polycondensation and grafting reactions. The s-FSPI membrane has a vanadium ion permeability that is over an order of magnitude lower and has a proton selectivity that is 6.8 times higher compared to those of the Nafion 115 membrane. The s-FSPI membrane possesses superior chemical stability compared to most of the linear sulfonated aromatic polymer membranes reported for VRBs. Also, the vanadium redox flow/static batteries (VRFB/VRSB) assembled with the s-FSPI membranes exhibit stable battery performance over 100- and 300-time charge discharge cycling tests, respectively, with significantly higher battery efficiencies and lower self-discharge rates than those with the Nafion 115 membranes. The excellent physicochemical properties and VRB performance of the s FSPI membrane could be attributed to the specifically designed molecular structure with the hydrophobic trifluoromethyl groups and flexible sulfoalkyl pendants being introduced on the main chains of the membrane. Moreover, the cost of the s-FSPI membrane is only one-fourth that of the commercial Nafion 115 membrane. This work opens up new possibilities for fabricating high-performance proton-conductive membranes at low costs for VRBs. PMID- 28880066 TI - Environmentally Safe Mercury(II) Ions Aided Zero-Background and Ultrasensitive SERS Detection of Dipicolinic Acid. AB - Field, reliable, and ultrasensitive detection of dipicolinic acid (DPA), a general biomarker of bacterial spores and especially Bacillus anthracis, is highly desirable but still challenging in current biometric security emergency response system. Herein we report an environmentally safe mercury(II) ions mediated and competitive coordination interaction based approach for rationally designed surface-enhanced Raman scattering (SERS)-active gold nanoparticles (AuNPs), enabling rapid, ultrasensitive and zero-background detection of DPA without the pretreatment of samples. By means of competitiveness, these papain capped gold nanoparticles (P-AuNPs) are induced to undergo controllable aggregation upon the addition of Hg2+ ions and DPA with a concentration range (1 nM~8 MUM), which correspondingly cause quantitative changes of SERS intensity of cresyl violet acetate (CVa) conjugated AuNPs. The decreased Raman intensity obtained by subtracting two cases of additives that contain only Hg2+ and the mixture of Hg2+ and DPA is proportional to the concentration of DPA over a range of 1 nM~8 MUM (R2 = 0.9824), with by far the lowest limit of detection (LOD) of 67.25 pM (0.01 ppb, S/N = 3:1). Of particular significance, mercury(II) ions actually play two roles in the process of measurements: a mediator for two designed competitive ligands (DPA and papain), and also a scavenger for the possibly blended ligands due to the different interaction time between DPA and the interferent with Hg2+ ions, which guarantees the interference-free detection of DPA even under real conditions. PMID- 28880067 TI - Selective Electrochemical Reduction of CO2 to Ethylene on Nanopores-Modified Copper Electrodes in Aqueous Solution. AB - Electrochemical reduction of carbon dioxide was carried out on copper foil electrodes modified with nanopores on the surface. Such nanopores modified structure was obtained through an alloying-dealloying process. Scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy confirmed the formation of alloy layer and the final nanoporous morphology of such copper electrodes. When used in electrolysis process, the as-prepared nanopores-modified electrodes can suppress the Faradaic efficiency toward methane to less than 1%, while keeping that of ethylene in a high level of 35% in aqueous 0.1 M KHCO3 solution under -1.3 V (vs reversible hydrogen electrode), thus revealing a remarkable selectivity toward ethylene production. The high yield of ethylene can be ascribed to the exposed specific crystalline orientations. PMID- 28880068 TI - Direct Electrophoretic Deposition of Binder-Free Co3O4/Graphene Sandwich-Like Hybrid Electrode as Remarkable Lithium Ion Battery Anode. AB - Co3O4 is emerging as a promising anode candidate for lithium ion batteries (LIBs) with high theoretical capacity (890 mAh g-1) but suffers from poor electrochemical cycling stability resulting from the inferior intrinsic electronic conductivity and large volume changes during electrochemical cycling. Here, a new electrophoretic deposition Co3O4/graphene (EPD Co3O4/G) hybrid electrode is developed to improve the electrochemical performance. Through EPD, Co3O4 nanocubes can be homogeneously embedded between graphene sheets to form a sandwich-like structure. Owing to the excellent flexibility of graphene and a large number of voids in this sandwich-like structure, the structural integrity and unobstructed conductive network can be maintained during cycling. Moreover, the electrode kinetics has proved to be a fast surface-controlled lithium storage process. As a result, the Co3O4/G hybrid electrode exhibits high specific capacity and excellent electrochemical cycling performance. The Co3O4/G hybrid electrode was also further studied by in situ electrochemical XRD to understand the relationship of its structure and performance: (1) The observed LixCo3O4 indicates an intermediate of possible small volume change in the first discharging. (2) The theoretical capacity achievement of the Co3O4 in hybrid electrode was evidenced. (3) The correlation between the electrochemical performance and the structural evolution of the Co3O4/G hybrid electrode was discussed detailedly. PMID- 28880069 TI - Flexible Poly(vinyl chloride) Nanocomposites Reinforced with Hyperbranched Polyglycerol-Functionalized Graphene Oxide for Enhanced Gas Barrier Performance. AB - Herein, we describe the preparation of flexible poly(vinyl chloride) (PVC) containing hyperbranched polyglycerol (HPG)-functionalized graphene oxide (HGO) as a reinforcing filler and reveal that the obtained composites exhibit greatly improved gas barrier properties. Moreover, we show that HGO, synthesized by surface-initiated ring-opening polymerization of glycidol followed by esterification with butyric anhydride, exists as individual exfoliated nanosheets possessing abundant functional groups capable of interacting with PVC. A comparative study of butyl-terminated graphene oxide (BGO) reveals that functionalization with HPG is of key importance for achieving a uniform dispersion of HGO in the PVC matrix and results in strong interfacial interactions between HGO and PVC. As a result, flexible PVC/HGO nanocomposite films exhibit significantly enhanced tensile strength and toughness compared to those of neat plasticized PVC while maintaining its inherent stretchability. Furthermore, the two-dimensional planar structure and homogeneous distribution of HGO in PVC/HGO nanocomposites make gas molecules follow a highly tortuous path, resulting in remarkably reduced oxygen permeability, which is more than 60% lower than that of neat plasticized PVC. Consequently, HGO is demonstrated to be promising component of flexible and gas-impermeable PVC films for a wide range of applications. PMID- 28880070 TI - Tris(trimethylsilyl) Phosphite as an Efficient Electrolyte Additive To Improve the Surface Stability of Graphite Anodes. AB - Tris(trimethylsilyl) phosphite (TMSP) has received considerable attention as a functional additive for various cathode materials in lithium-ion batteries, but the effect of TMSP on the surface stability of a graphite anode has not been studied. Herein, we demonstrate that TMSP serves as an effective solid electrolyte interphase (SEI)-forming additive for graphite anodes in lithium-ion batteries (LIBs). TMSP forms SEI layers by chemical reactions between TMSP and a reductively decomposed ethylene carbonate (EC) anion, which is strikingly different from the widely known mechanism of the SEI-forming additives. TMSP is stable under cathodic polarization, but it reacts chemically with radical anion intermediates derived from the electrochemical reduction of the carbonate solvents to generate a stable SEI layer. These TMSP-derived SEI layers improve the interfacial stability of the graphite anode, resulting in a retention of 96.8% and a high Coulombic efficiency of 95.2%. We suggest the use of TMSP as a functional additive that effectively stabilizes solid electrolyte interfaces of both the anode and cathode in lithium-ion batteries. PMID- 28880071 TI - Phase-Field Based Multiscale Modeling of Heterogeneous Solid Electrolytes: Applications to Nanoporous Li3PS4. AB - Modeling the effective ion conductivities of heterogeneous solid electrolytes typically involves the use of a computer-generated microstructure consisting of randomly or uniformly oriented fillers in a matrix. However, the structural features of the filler/matrix interface, which critically determine the interface ion conductivity and the microstructure morphology, have not been considered during the microstructure generation. Using nanoporous beta-Li3PS4 electrolyte as an example, we develop a phase-field model that enables generating nanoporous microstructures of different porosities and connectivity patterns based on the depth and the energy of the surface (pore/electrolyte interface), both of which are predicted through density functional theory (DFT) calculations. Room temperature effective ion conductivities of the generated microstructures are then calculated numerically, using DFT-estimated surface Li-ion conductivity (3.14 * 10-3 S/cm) and experimentally measured bulk Li-ion conductivity (8.93 * 10-7 S/cm) of beta-Li3PS4 as the inputs. We also use the generated microstructures to inform effective medium theories to rapidly predict the effective ion conductivity via analytical calculations. When porosity approaches the percolation threshold, both the numerical and analytical methods predict a significantly enhanced Li-ion conductivity (1.74 * 10-4 S/cm) that is in good agreement with experimental data (1.64 * 10-4 S/cm). The present phase-field based multiscale model is generally applicable to predict both the microstructure patterns and the effective properties of heterogeneous solid electrolytes. PMID- 28880072 TI - Novel Smart Microreactors Equipped with Responsive Catalytic Nanoparticles on Microchannels. AB - Nowadays efficient and reliable control of highly exothermic reactions to effectively prevent overheating or even explosions still remains a challenging task, although newly developed microreactor technology has shown promise. Here, we report a novel smart microreactor system equipped with responsive catalytic nanoparticles on microchannels for self-regulated control over highly exothermic reactions by responding to the reaction-generated heat. On the basis of shrinking/swelling behaviors of polymeric networks in the responsive catalytic nanoparticles, the smart microreactor could respond to the change of reaction temperature to tune the catalysis activity of catalytic particles in a thermo feedback process. As a breakthrough result, highly exothermic reactions carried out in such a microreactor can be well-controlled in a self-regulation process without any manual assistance, efficiently ensuring the safety of the reaction. Such smart responsive catalytic systems have high potential and are attractive as a new generation of efficient tools that feature a self-regulation property for highly exothermic catalytic reactions. PMID- 28880073 TI - Elucidating the Intercalation Pseudocapacitance Mechanism of MoS2-Carbon Monolayer Interoverlapped Superstructure: Toward High-Performance Sodium-Ion Based Hybrid Supercapacitor. AB - Two-dimensional (2D) layered materials have shown great promise for electrochemical energy storage applications. However, they are usually limited by the sluggish kinetics and poor cycling stability. Interface modification on 2D layered materials provides an effective way for increasing the active sites, improving the electronic conductivity, and enhancing the structure stability so that it can potentially solve the major issues on fabricating energy storage devices with high performance. Herein, we synthesize a novel MoS2-carbon (MoS2-C) monolayer interoverlapped superstructure via a facile interface-modification route. This interlayer overlapped structure is demonstrated to have a wide sodium ion intercalation/deintercalation voltage range of 0.4-3.0 V and the typical pseudocapacitive characteristics in fast kinetics, high reversibility, and robust structural stability, thus displaying a large reversible capacity, a high rate capability, and an improved cyclability. A full cell of sodium-ion hybrid supercapacitor based on this MoS2-C hybrid architecture can operate up to 3.8 V and deliver a high energy density of 111.4 Wh kg-1 and a high power density exceeding 12 000 W kg-1. Furthermore, a long cycle life of 10 000 cycles with over 77.3% of capacitance retention can be achieved. PMID- 28880074 TI - Multibond Model of Single-Asperity Tribochemical Wear at the Nanoscale. AB - Single-asperity wear experiments and simulations have identified different regimes of wear including Eyring- and Archard-like behaviors. A multibond dynamics model has been developed based on the friction model of Filippov et al. [Phys. Rev. Lett. 92, 135503 (2004)]. This new model captures both qualitatively distinct regimes of single-asperity wear under a unified theoretical framework. In this model, the interfacial bond formation, wearless rupture, and transfer of atoms are governed by three competing thermally activated processes. The Eyring regime holds under the conditions of low load and low adhesive forces; few bonds form between the asperity and the surface, and wear is a rare and rate-dependent event. As the normal stress increases, the Eyring behavior of wear rate breaks down. A nearly rate-independent regime arises under high load or high adhesive forces, in which wear becomes very nearly, but not precisely, proportional to sliding distance. In this restricted regime, the dependence of wear rate per unit contact area is nearly independent of the normal stress at the point of contact. In true contact between rough elastic surfaces, where contact area is expected to grow linearly with normal load, this would lead to behavior very similar to that described by the Archard equation. Detailed comparisons to experimental and molecular dynamics simulation investigations illustrate both Eyring and Archard regimes, and an intermediate crossover regime between the two. PMID- 28880075 TI - Integrated Energy Aerogel of N,S-rGO/WSe2/NiFe-LDH for Both Energy Conversion and Storage. AB - High-performance active materials for energy-storage and energy-conversion applications require a novel class of electrodes: ones with a structure conducive to conductivity, large specific surface area, high porosity, and mechanical robustness. Herein, we report the design and fabrication of a new ternary hybrid aerogel. The process entails an in situ assembly of 2D WSe2 nanosheets and NiFe LDH nanosheets on a 3D N,S-codoped graphene framework, accomplished by a facile hydrothermal method and electrostatic self-assembly technology. The obtained nanocomposite architecture maximizes synergistic effects among its three 2D-layer components. To assess the performance of this hybrid material, we deployed it as an advanced electrode in overall water splitting and in a supercapacitor. Results in both scenarios attest to its excellent electrochemical properties. Specifically, serving as a catalyst in an oxygen evolution reaction, our nanocomposite requires overpotentials of 1.48 and 1.59 V to obtain current densities of 10 and 100 mA cm-2, respectively. The hybrid material also efficiently electrocatalyzes hydrogen evolution reactions in base solution, necessitating overpotentials of -50 and -237 mV for current densities of 1.0 and 100 mA cm-2, respectively. The 3D hybrid, when applied to a symmetric supercapacitor device, achieves 125.6 F g-1 capacitance at 1 A g-1 current density. In summary, our study elucidates a new strategy to maximize efficiency via synergetic effects that is likely applicable to other 2D materials. PMID- 28880076 TI - Exploiting Overlapping Advantages of In Vitro and In Cellulo Selection Systems to Isolate a Novel High-Affinity cJun Antagonist. AB - We have combined two peptide library-screening systems, exploiting the benefits offered by both to select novel antagonistic agents of cJun. CIS display is an in vitro cell-free system that allows very large libraries (<=1014) to be interrogated. However, affinity-based screening conditions can poorly reflect those relevant to therapeutic application, particularly for difficult intracellular targets, and can lead to false positives. In contrast, an in cellulo screening system such as the Protein-fragment Complementation Assay (PCA) selects peptides with high target affinity while additionally profiling for target specificity, protease resistance, solubility, and lack of toxicity in a more relevant context. A disadvantage is the necessity to transform cells, limiting library sizes that can be screened to <=106. However, by combining both cell-free and cell-based systems, we isolated a peptide (CPW) from a ~1010 member library, which forms a highly stable interaction with cJun (Tm = 63 degrees C, Kd = 750 nM, DeltaG = -8.2 kcal/mol) using the oncogenic transcriptional regulator Activator Protein-1 (AP-1) as our exemplar target. In contrast, CIS display alone selected a peptide with low affinity for cJun (Tm = 34 degrees C, Kd = 25 MUM, DeltaG = -6.2 kcal/mol), highlighting the benefit of CIS -> PCA. Furthermore, increased library size with CIS -> PCA vs PCA alone allows the freedom to introduce noncanonical options, such as interfacial aromatics, and solvent exposed options that may allow the molecule to explore alternative structures and interact with greater affinity and efficacy with the target. CIS > PCA therefore offers significant potential as a peptide-library screening platform by synergistically combining the relative attributes of both assays to generate therapeutically interesting compounds that may otherwise not be identified. PMID- 28880077 TI - Loss of Fourth Electron-Transferring Tryptophan in Animal (6-4) Photolyase Impairs DNA Repair Activity in Bacterial Cells. AB - (6-4) photolyases [(6-4)PLs] are flavoproteins that use blue light to repair the ultraviolet-induced pyrimidine(6-4)pyrimidone photoproduct in DNA. Their flavin adenine dinucleotide (FAD) cofactor can be reduced to its repair-active FADH- form by a photoinduced electron transfer reaction. In animal (6-4)PLs, a chain of four Trp residues was suggested to be involved in a stepwise transfer of an oxidation hole from the flavin to the surface of the protein. Here, we investigated the effect of mutation of the fourth Trp on the DNA photorepair activity of Xenopus laevis (6-4)PL (Xl64) in bacterial cells. The photoreduction and photorepair properties of this mutant protein were independently characterized in vitro. Our results demonstrate that the mutation of the fourth Trp in Xl64 drastically impairs the DNA repair activity in cells and that this effect is due to the inhibition of the photoreduction process. We thereby show that the photoreductive formation of FADH- through the Trp tetrad is essential for the biological function of the animal (6-4)PL. The role of the Trp cascade, and of the fourth Trp in particular, is discussed. PMID- 28880078 TI - The Role of Disulfide Bond Replacements in Analogues of the Tarantula Toxin ProTx II and Their Effects on Inhibition of the Voltage-Gated Sodium Ion Channel Nav1.7. AB - Spider venom toxins, such as Protoxin-II (ProTx-II), have recently received much attention as selective Nav1.7 channel blockers, with potential to be developed as leads for the treatment of chronic nocioceptive pain. ProTx-II is a 30-amino acid peptide with three disulfide bonds that has been reported to adopt a well-defined inhibitory cystine knot (ICK) scaffold structure. Potential drawbacks with such peptides include poor pharmacodynamics and potential scrambling of the disulfide bonds in vivo. In order to address these issues, in the present study we report the solid-phase synthesis of lanthionine-bridged analogues of ProTx-II, in which one of the three disulfide bridges is replaced with a thioether linkage, and evaluate the biological properties of these analogues. We have also investigated the folding and disulfide bridging patterns arising from different methods of oxidation of the linear peptide precursor. Finally, we report the X-ray crystal structure of ProTx-II to atomic resolution; to our knowledge this is the first crystal structure of an ICK spider venom peptide not bound to a substrate. PMID- 28880080 TI - Comparison Study of Polar and Nonpolar Contributions to Solvation Free Energy. AB - In this study, we compared the contributions of polar and nonpolar interactions to the solvation free energy of a solute in solvent, which is decomposed into four different terms based on the nature of interactions: (i) electrostatic solvation free energy term counting for the work done to move solute charges from fixed points in some reference environment to their configuration positions in solvent; (ii) solute-solvent van der Waals dispersion interactions; (iii) change on solvent-solvent interactions and solvent entropy due to reorganization of solvent around solute cavity in solvent; and (iv) compensation of electrostatic forces acting on the dielectric surface boundary between solvent and solute. We compared these contributions to each other for a data set of 573 proteins, which were prepared using CHARMM22 and AMBER force fields. In addition, we compared the calculated with experimental hydration free energies for a data set of 642 small molecules, which were prepared using the general AMBER force field. Our results indicated the significance of each term to the total solvation free energy. PMID- 28880081 TI - Formation of Reactive Intermediates, Color, and Antioxidant Activity in the Maillard Reaction of Maltose in Comparison to d-Glucose. AB - In this study, the Maillard reaction of maltose and d-glucose in the presence of l-alanine was investigated in aqueous solution at 130 degrees C and pH 5. The reactivity of both carbohydrates was compared in regards of their degradation, browning, and antioxidant activity. In order to identify relevant differences in the reaction pathways, the concentrations of selected intermediates such as 1,2 dicarbonyl compounds, furans, furanones, and pyranones were determined. It was found, that the degradation of maltose predominantly yields 1,2-dicarbonyls that still carry a glucosyl moiety and thus subsequent reactions to HMF, furfural, and 2-acetylfuran are favored due to the elimination of d-glucose, which is an excellent leaving group in aqueous solution. Consequently, higher amounts of these heterocycles are formed from maltose. 3-deoxyglucosone and 3 deoxygalactosone represent the only relevant C6-1,2-dicarbonyls in maltose incubations and are produced in nearly equimolar amounts during the first 60 min of heating as byproducts of the HMF formation. PMID- 28880079 TI - Quantitative Multiple-Reaction Monitoring Proteomic Analysis of Gbeta and Ggamma Subunits in C57Bl6/J Brain Synaptosomes. AB - Gbetagamma dimers are one of the essential signaling units of activated G protein coupled receptors (GPCRs). There are five Gbeta and 12 Ggamma subunits in humans; numerous studies have demonstrated that different Gbeta and Ggamma subunits selectively interact to form unique Gbetagamma dimers, which in turn may target specific receptors and effectors. Perturbation of Gbetagamma signaling can lead to impaired physiological responses. Moreover, previous targeted multiple reaction monitoring (MRM) studies of Gbeta and Ggamma subunits have shown distinct regional and subcellular localization patterns in four brain regions. Nevertheless, no studies have quantified or compared their individual protein levels. In this study, we have developed a quantitative MRM method not only to quantify but also to compare the protein abundance of neuronal Gbeta and Ggamma subunits. In whole and fractionated crude synaptosomes, we were able to identify the most abundant neuronal Gbeta and Ggamma subunits and their subcellular localizations. For example, Gbeta1 was mostly localized at the membrane while Gbeta2 was evenly distributed throughout synaptosomal fractions. The protein expression levels and subcellular localizations of Gbeta and Ggamma subunits may affect the Gbetagamma dimerization and Gbetagamma-effector interactions. This study offers not only a new tool for quantifying and comparing Gbeta and Ggamma subunits but also new insights into the in vivo distribution of Gbeta and Ggamma subunits, and Gbetagamma dimer assembly in normal brain function. PMID- 28880082 TI - Perovskite-Type InCoO3 with Low-Spin Co3+: Effect of In-O Covalency on Structural Stabilization in Comparison with Rare-Earth Series. AB - Perovskite rare-earth cobaltites ACoO3 (A = Sc, Y, La-Lu) have been of enduring interest for decades due to their unusual structural and physical properties associated with the spin-state transitions of low-spin Co3+ ions. Herein, we have synthesized a non-rare-earth perovskite cobaltite, InCoO3, at 15 GPa and 1400 degrees C and investigated its crystal structure and magnetic ground state. Under the same high-pressure and high-temperature conditions, we also prepared a perovskite-type ScCoO3 with an improved cation stoichiometry in comparison to that in a previous study, where synthesis at 6 GPa and 1297 degrees C yielded a perovskite cobaltite with cation mixing on the A-site, (Sc0.95Co0.05)CoO3. The two perovskite phases have nearly stoichiometric cation compositions, crystallizing in the orthorhombic Pnma space group. In the present investigation, comprehensive studies on newly developed and well-known Pnma ACoO3 perovskites (A = In, Sc, Y, Pr-Lu) show that InCoO3 does not fulfill the general evolution of crystal metrics with A-site cation size, indicating that InCoO3 and rare-earth counterparts have different chemistry for stabilizing the Pnma structures. Detailed structural analyses combined with first-principles calculations reveal that the origin of the anomaly for InCoO3 is ascribed to the A-site cation displacements that accompany octahedral tilts; despite the highly tilted CoO6 network, the In-O covalency makes In3+ ions reluctant to move from their ideal cubic-symmetry position, leading to less orthorhombic distortion than would be expected from electrostatic/ionic size mismatch effects. Magnetic studies demonstrate that InCoO3 and ScCoO3 are diamagnetic with a low-spin state of Co3+ below 300 K, in contrast to the case of (Sc0.95Co0.05)CoO3, where the high-spin Co3+ ions on the A-site generate a large paramagnetic moment. The present work extends the accessible composition range of the low-spin orthocobaltite series and thus should help to establish a more comprehensive understanding of the structure-property relation. PMID- 28880083 TI - Solvent-Free Biodiesel Production Catalyzed by Crude Lipase Powder from Seeds: Effects of Alcohol Polarity, Glycerol, and Thermodynamic Water Activity. AB - The aim of this work was to evaluate the potential of crude lipase powders made from Adansonia grandidieri and Jatropha mahafalensis seeds for the synthesis of fatty acid alkyl esters in a solvent-free system. The influence of the nature of the alcohol, the amount of glycerol, and hydration of the powder was investigated. Results showed that the activity of these crude lipase powders was inversely proportional to the alcohol polarity and the amount of the glycerol in the reaction medium. To ensure optimum activity, A. grandidieri and J. mahafalensis powders must be conditioned to a water activity of 0.33 and 0.66. To obtain a fatty acid ethyl ester yield greater than 95% with A. grandidieri, ethanol should be introduced at an amount corresponding to a triacylglycerol to ethanol molar ratio of 2:1 every 15 h for 96 h and use 25% of preconditioned crude lipase powders (2 additions of 12.5%). PMID- 28880084 TI - Chemical Composition and Water Permeability of Fruit and Leaf Cuticles of Olea europaea L. AB - The plant cuticle, protecting against uncontrolled water loss, covers olive (Olea europaea) fruits and leaves. The present study describes the organ-specific chemical composition of the cuticular waxes and the cutin and compares three developmental stages of fruits (green, turning, and black) with the leaf surface. Numerous organ-specific differences, such as the total coverage of cutin monomeric components (1034.4 MUg cm-2 and 630.5 MUg cm-2) and the cuticular waxes (201.6 MUg cm-2 and 320.4 MUg cm-2) among all three fruit stages and leaves, respectively, were detected. Water permeability as the main cuticular function was 5-fold lower in adaxial leaf cuticles (2.1 * 10-5 m s-1) in comparison to all three fruit stages (9.5 * 10-5 m s-1). The three fruit developmental stages have the same cuticular water permeability. It is hypothesized that a higher weighted average chain length of the acyclic cuticular components leads to a considerably lower permeability of the leaf as compared to the fruit cuticle. PMID- 28880085 TI - Isotropic Zero Thermal Expansion and Local Vibrational Dynamics in (Sc,Fe)F3. AB - Scandium fluoride (ScF3) exhibits a pronounced negative thermal expansion (NTE), which can be suppressed and ultimately transformed into an isotropic zero thermal expansion (ZTE) by partially substituting Sc with Fe in (Sc0.8Fe0.2)F3 (Fe20). The latter displays a rather small coefficient of thermal expansion of -0.17 * 10 6/K from 300 to 700 K. Synchrotron X-ray and neutron pair distribution functions confirm that the Sc/Fe-F bond has positive thermal expansion (PTE). Local vibrational dynamics based on extended X-ray absorption fine structure indicates a decreased anisotropy of relative vibration in the Sc/Fe-F bond. Combined analysis proposes a delicate balance between the counteracting effects of the chemical bond PTE and NTE from transverse vibration. The present study extends the scope of isotropic ZTE compounds and, more significantly, provides a complete local vibrational dynamics to shed light on the ZTE mechanism in chemically tailored NTE compounds. PMID- 28880086 TI - Adsorption and Photodesorption of CO from Charged Point Defects on TiO2(110). AB - The adsorption and photochemistry of CO on rutile TiO2(110) are studied with scanning tunneling microscopy (STM), temperature-programmed desorption, and angle resolved photon-stimulated desorption (PSD) at low temperatures. Site occupancies, when weighted by the concentration of each kind of adsorption site on the reduced surface, show that the adsorption probability is the highest for the bridging oxygen vacancies (VO). The probability distribution for the different adsorption sites corresponds to very small differences in CO adsorption energies (<0.02 eV). UV irradiation stimulates diffusion and desorption of CO at low temperature. CO photodesorbs primarily from the vacancies with a bimodal angular distribution, indicating some scattering from the surface, which also leads to photostimulated diffusion. Hydroxylation of VO's does not significantly change the CO PSD yield or the angular distribution, which suggests that photodesorption can be initiated by recombination of photogenerated holes with excess electrons localized near the charged point defect (either VO or bridging hydroxyl). PMID- 28880087 TI - Predicting Accurate Solvation Free Energy in n-Octanol Using 3D-RISM-KH Molecular Theory of Solvation: Making Right Choices. AB - Molecular theory of solvation, a.k.a., three-dimensional reference interaction site model theory of solvation with Kovalenko-Hirata closure relation (3D-RISM KH), is an accurate and fast theory predicting solvation free energy and structure. Here we report a benchmark study of n-octanol solvation free energy calculations using this theory. The choice of correct force field parameters is quintessential for the success of 3D-RISM theory, and we present a guideline to obtain them for n-octanol solvent. Our best prediction of the solvation free energy on a set of 205 small organic molecules supplemented with the so-called "universal correction" scheme yields relative mean unsigned error of 0.94 kcal/mol against the reported database. The best agreement is obtained with the united atom (UA) type force field parametrization of n-octanol with the van der Waals parameters of hydroxyl hydrogen reported by Kobryn et al. [ Kobryn , A. E. ; Kovalenko , A. J. Chem. Phys. 2008 , 129 , 134701 ]. PMID- 28880088 TI - Brain Accumulation of Ponatinib and Its Active Metabolite, N-Desmethyl Ponatinib, Is Limited by P-Glycoprotein (P-GP/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2). AB - Ponatinib is an oral BCR-ABL1 inhibitor for treatment of advanced leukemic diseases that carry the Philadelphia chromosome, specifically containing the T315I mutation yielding resistance to previously approved BCR-ABL1 inhibitors. Using in vitro transport assays and knockout mouse models, we investigated whether the multidrug efflux transporters ABCB1 and ABCG2 transport ponatinib and whether they, or the drug-metabolizing enzyme CYP3A, affect the oral availability and brain accumulation of ponatinib and its active N-desmethyl metabolite (DMP). In vitro, mouse Abcg2 and human ABCB1 modestly transported ponatinib. In mice, both Abcb1 and Abcg2 markedly restricted brain accumulation of ponatinib and DMP, but not ponatinib oral availability. Abcg2 deficiency increased DMP plasma levels ~3-fold. Cyp3a deficiency increased the ponatinib plasma AUC 1.4-fold. Our results suggest that pharmacological inhibition of ABCG2 and ABCB1 during ponatinib therapy might benefit patients with brain (micro)metastases positioned behind an intact blood-brain barrier, or with substantial expression of these transporters in the malignant cells. CYP3A inhibitors might increase ponatinib oral availability, enhancing efficacy but possibly also toxicity of this drug. PMID- 28880089 TI - Pickering Membranes Stabilized by Saturn Particles. AB - We report on a novel method to synthesize particles-called by us Saturn particles having two hydrophobic caps that oppose each other and are separated from each other by a hydrophilic belt that encircles the particle. Mixtures of these particles with water and air, without the usage of low molar mass surfactants, easily form Pickering foams and Pickering membranes that are stable for days. These Pickering membranes are composed of a thin film of water into which the particles are embedded in such a way that the belt is surrounded by the water and the caps protrude out of the water into the air at the top and bottom side of the water film. As expected for a liquid membrane, these Pickering membranes are permeable for gases, with the permeance being proportional to the solubility and diffusion coefficient of the gas considered. Experimentally obtained permeance values agree reasonably well with theoretical calculations. PMID- 28880090 TI - Thermoresponsive Stability of Colloids in Butyl Acetate/Ethanol Binary Solvent Realized by Grafting Linear Acrylate Copolymers. AB - We have developed a new class of thermoresponsive colloids that can exhibit a sharp reversible transition between dispersion and aggregation in binary BuAc/EtOH solvents based on the UCST (upper critical solution temperature)-type phase separation. This is realized by grafting linear PMMA-BA (random) copolymer onto the colloidal particles. We have selected TiO2/PS hybrid spheres (HSs) as a model system to demonstrate our general design concept. By grafting the linear PMMA-BA copolymer onto the HS surface, with the molecular weight from 30 to 40 kDa, we found that the thermoresponsive transition between dispersion and aggregation is fast, sharp, and reversible. At high mass fractions of the HSs, we have even observed a sharp transition between dispersion and gelation (or phase separation). The transition temperature can be tuned by varying the binary solvent composition, BuAc/EtOH, and the molecular weight of the grafted linear copolymer in the range from 5 to 55 degrees C. One of the most important features of this work is that the thermoresponsive materials used in organic solvents are initially synthesized in water with widely applied conventional (instead of research-based) techniques, thus being well suited for industrial production. In addition, the proposed approach is rather general and applicable to realizing the thermoresponsive transition for various types of colloids and nanoparticles. PMID- 28880091 TI - Mycolic Acid Containing Bacterium Stimulates Tandem Cyclization of Polyene Macrolactam in a Lake Sediment Derived Rare Actinomycete. AB - Two novel macrolactams, dracolactams A and B, were identified from a combined culture of Micromonospora species and a mycolic-acid containing bacterium (MACB). Their structures and stereochemistries were completely assigned, based on spectroscopic analyses and chemical derivatization. Both dracolactams were probably generated from a common macrolactam precursor produced by the Micromonospora species. In this combined-culture system, MACB is likely to activate cryptic oxidase genes in the Micromonospora species and induce the downstream polyene macrolactam cyclization. PMID- 28880092 TI - Using Peptide Aptamer Targeted Polymers as a Model Nanomedicine for Investigating Drug Distribution in Cancer Nanotheranostics. AB - Theranostics is a strategy that combines multiple functions such as targeting, stimulus-responsive drug release, and diagnostic imaging into a single platform, often with the aim of developing personalized medicine.1,2 Based on this concept, several well-established hyperbranched polymeric theranostic nanoparticles were synthesized and characterized as model nanomedicines to investigate how their properties affect the distribution of loaded drugs at both the cell and whole animal levels. An 8-mer peptide aptamer was covalently bound to the periphery of the nanoparticles to achieve both targeting and potential chemosensitization functionality against heat shock protein 70 (Hsp70). Doxorubicin was also bound to the polymeric carrier as a model chemotherapeutic drug through a degradable hydrazone bond, enabling pH-controlled release under the mildly acid conditions that are found in the intracellular compartments of tumor cells. In order to track the nanoparticles, cyanine-5 (Cy5) was incorporated into the polymer as an optical imaging agent. In vitro cellular uptake was assessed for the hyperbranched polymer containing both doxorubicin (DOX) and Hsp70 targeted peptide aptamer in live MDA-MB-468 cells, and was found to be greater than that of either the untargeted, DOX-loaded polymer or polymer alone due to the specific affinity of the peptide aptamer for the breast cancer cells. This was also validated in vivo with the targeted polymers showing much higher accumulation within the tumor 48 h postinjection than the untargeted analogue. More detailed assessment of the nanomedicine distribution was achieved by directly following the polymeric carrier and the doxorubicin at both the in vitro cellular level via compartmental analysis of confocal images of live cells and in whole tumors ex vivo using confocal imaging to visualize the distribution of the drug in tumor tissue as a function of distance from blood vessels. Our results indicate that this polymeric carrier shows promise as a cancer theranostic, demonstrating active targeting to tumor cells with the capability for simultaneous drug release. PMID- 28880093 TI - Quantification of Transporter and Receptor Proteins in Dog Brain Capillaries and Choroid Plexus: Relevance for the Distribution in Brain and CSF of Selected BCRP and P-gp Substrates. AB - Transporters at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a pivotal role as gatekeepers for efflux or uptake of endogenous and exogenous molecules. The protein expression of a number of them has already been determined in the brains of rodents, nonhuman primates, and humans using quantitative targeted absolute proteomics (QTAP). The dog is an important animal model for drug discovery and development, especially for safety evaluations. The purpose of the present study was to clarify the relevance of the transporter protein expression for drug distribution in the dog brain and CSF. We used QTAP to examine the protein expression of 17 selected transporters and receptors at the dog BBB and BCSFB. For the first time, we directly linked the expression of two efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), to regional brain and CSF distribution using specific substrates. Two cocktails, each containing one P-gp substrate (quinidine or apafant) and one BCRP substrate (dantrolene or daidzein) were infused intravenously prior to collection of the brain. Transporter expression varied only slightly between the capillaries of different brain regions and did not result in region-specific distribution of the investigated substrates. There were, however, distinct differences between brain capillaries and choroid plexus. Largest differences were observed for BCRP and P-gp: both were highly expressed in brain capillaries, but no BCRP and only low amounts of P-gp were detected in the choroid plexus. Kp,uu,brain and Kp,uu,CSF of both P-gp substrates were indicative of drug efflux. Also, Kp,uu,brain for the BCRP substrates was low. In contrast, Kp,uu,CSF for both BCRP substrates was close to unity, resulting in Kp,uu,CSF/Kp,uu,brain ratios of 7 and 8, respectively. We conclude that the drug transporter expression profiles differ between the BBB and BCSFB in dogs, that there are species differences in the expression profiles, and that CSF is not a suitable surrogate for unbound brain concentrations of BCRP substrates in dogs. PMID- 28880094 TI - Enantiospecific Synthesis of beta-Substituted Tryptamines. AB - Functionalized tryptamines are targets of interest for development as small molecule therapeutics. The ring opening of aziridines with indoles is a powerful method for tryptamine synthesis where isomer formation can be controlled. 3,5 Dinitrobenzoyl (DNB)-protected aziridines undergo regioselective, enantiospecific ring opening to produce beta-substituted tryptamines for a series of indoles. Attack at the more substituted aziridine carbon occurs in an SN2-like fashion to generate DNB-tryptamine products as synthetic precursors. PMID- 28880096 TI - Synthesis of Octahydro- and Decahydroquinolines by a One-Pot Cascade Reaction of Tetrasubstituted Enecarbamate. AB - A transition-metal-catalyzed cyclopropanation followed by ring opening was investigated for the synthesis of octahydroquinolines 4 and decahydroquinolines 5 having a quaternary carbon center at the angular position, which are core structures of the fawcettimine-type alkaloids. A tandem reaction was also established for the synthesis of decahydroquinolines 5 and the tricyclic compound 6 through an iminium ion intermediate, readily produced by acidic treatment of cyclopropane 2. PMID- 28880095 TI - Transition-Metal-Free Quinoline Synthesis from Acetophenones and Anthranils via Sequential One-Carbon Homologation/Conjugate Addition/Annulation Cascade. AB - A transition-metal-free method for the construction of functionalized quinolines from readily available acetophenones and anthranils is reported. This one-pot reaction cascade involves in situ generation of alpha,beta-unsaturated ketones from the acetophenone via one-carbon homologation by DMSO followed by the aza Michael addition of anthranils and subsequent annulation. DMSO acted in this reaction not only as solvent but also as one carbon source, thus providing a highly atom-economical and environmentally benign approach for the synthesis of 3 substituted quinolines. PMID- 28880097 TI - Constructing emotion categorization: Insights from developmental psychology applied to a young adult sample. AB - Previous research has found that the categorization of emotional facial expressions is influenced by a variety of factors, such as processing time, facial mimicry, emotion labels, and perceptual cues. However, past research has frequently confounded these factors, making it impossible to ascertain how adults use this varied information to categorize emotions. The current study is the first to explore the magnitude of impact for each of these factors on emotion categorization in the same paradigm. Participants (N = 102) categorized anger and disgust emotional facial expressions in a novel computerized task, modeled on similar tasks in the developmental literature with preverbal infants. Experimental conditions manipulated (a) whether the task was time-restricted, and (b) whether the labels "anger" and "disgust" were used in the instructions. Participants were significantly more accurate when provided with unlimited response time and emotion labels. Participants who were given restricted sorting time (2s) and no emotion labels tended to focus on perceptual features of the faces when categorizing the emotions, which led to low sorting accuracy. In addition, facial mimicry related to greater sorting accuracy. These results suggest that when high-level (labeling) categorization strategies are unavailable, adults use low-level (perceptual) strategies to categorize facial expressions. Methodological implications for the study of emotion are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28880098 TI - Moving research on health and close relationships forward-a challenge and an obligation: Introduction to the special issue. AB - Close relationships are integral to the health and adaptation of our species. The evidence is incontestable, and it is the building block upon which future theory, research, and practice rests. This foreword notes the distinct domains and independent histories of relationship science and health psychology and calls for further thorough integration within the broader context of team science. The articles in this special issue focus on interpersonal mechanisms, cultural specificity, personality and emotion regulation, couples dynamics in chronic disease, and the increasingly complex biological mechanisms involved in linking relationships to health outcomes. They point to the importance of life stage, especially childhood and late adulthood, for understanding unique relationship and health issues. The challenge remains to translate existing and future knowledge into interventions to improve social relationships for the benefit of physical and mental health. (PsycINFO Database Record PMID- 28880099 TI - Advancing social connection as a public health priority in the United States. AB - A robust body of scientific evidence has indicated that being embedded in high quality close relationships and feeling socially connected to the people in one's life is associated with decreased risk for all-cause mortality as well as a range of disease morbidities. Despite mounting evidence that the magnitude of these associations is comparable to that of many leading health determinants (that receive significant public health resources), government agencies, health care providers and associations, and public or private health care funders have been slow to recognize human social relationships as either a health determinant or health risk marker in a manner that is comparable to that of other public health priorities. This article evaluates current evidence (on social relationships and health) according to criteria commonly used in determining public health priorities. The article discusses challenges for reducing risk in this area and outlines an agenda for integrating social relationships into current public health priorities. (PsycINFO Database Record PMID- 28880101 TI - Incorporating the cultural diversity of family and close relationships into the study of health. AB - Relationships are at the center of the human social environment, and their quality and longevity are now recognized to have particular relevance for health. The goal of this article is to bring attention to the role of culture in how relationships, particularly close relationships and family relationships, influence health. To this end, 2 contexts that are characterized by 2 distinct forms of cultural collectivism (East Asian and Latino) are spotlighted to highlight the unique patterns that underlie broader cultural categories (e.g., collectivism). In addition, related research on other understudied cultures and nonethnic or nonnational forms of culture (e.g., social class, religion) is also discussed. The review centers on social support, a key pathway through which relationships shape psychological and physical health, as the psychological process that has received the most empirical attention in this area. Overall, it is clear that new and more systematic approaches are needed to generate a more comprehensive, novel, and inclusive understanding of the role of culture in relationship processes that shape health. Three recommendations are offered for researchers and professionals to generate and incorporate knowledge of culture specific relationship processes into their understanding of health. (PsycINFO Database Record PMID- 28880100 TI - Interpersonal mechanisms linking close relationships to health. AB - Close relationships play a vital role in human health, but much remains to be learned about specific mechanisms of action and potential avenues for intervention. This article provides an evaluation of research on close relationships processes relevant to health, drawing on themes from major relationship science theories to present a broad conceptual framework for understanding the interpersonal processes and intrapersonal pathways linking relationships to health and disease outcomes. The analysis reveals that both social connection and social disconnection broadly shape biological responses and behaviors that are consequential for health. Furthermore, emerging work offers insights into the types of social dynamics that are most consequential for health, and the potential pathways through which they operate. Following from this analysis, the authors suggest several research priorities to facilitate the translation of discoveries from relationship science into relationship-based interventions and public health initiatives. These priorities include developing finer grained theoretical models to guide research, the systematic investigation of potential mediating pathways such as dyadic influences on health behavior and physiological coregulation, and taking into account individual differences and contextual factors such as attachment style, gender, socioeconomic status, and culture. In addition, a pressing need exists for laboratory and field research to determine which types of interventions are both practical and effective. (PsycINFO Database Record PMID- 28880102 TI - Childhood close family relationships and health. AB - Emerging data suggest that during childhood, close family relationships can ameliorate the impact that adversity has on life span physical health. To explain this phenomenon, a developmental stress buffering model is proposed in which characteristics of family relationships including support, conflict, obligation, and parenting behaviors evolve and change from childhood to adolescence. Together, these characteristics govern whether childhood family relationships are on balance positive enough to fill a moderating role in which they mitigate the effects that childhood adversities have on physical health. The benefits of some family relationship characteristics are hypothesized to stay the same across childhood and adolescence (e.g., the importance of comfort and warmth from family relationships) whereas the benefits of other characteristics are hypothesized to change from childhood to adolescence (e.g., from a need for physical proximity to parents in early childhood to a need for parental availability in adolescence). In turn, close, positive family relationships in childhood operate via a variety of pathways, such as by reducing the impact that childhood stressors have on biological processes (e.g., inflammation) and on health behaviors that in turn can shape physical health over a lifetime. (PsycINFO Database Record PMID- 28880104 TI - Intimate relationships, individual adjustment, and coronary heart disease: Implications of overlapping associations in psychosocial risk. AB - Being married or involved in a similar intimate relationship is associated with reduced risk of coronary heart disease (CHD). However, the quality of these relationships matters, as strain and disruption are associated with increased risk. These effects are typically studied separately from well-established psychosocial factors for CHD that are aspects of personality and emotional adjustment, even though discord and disruption in intimate relationships are related to these same individual characteristics. Thus, research to date tends to parse correlated risks, often taking a piecemeal approach by focusing on intimate relationships without considering aspects of personality and emotional adjustment that contribute to risk and protection, or focusing on individual-level risks while largely ignoring closely related health-relevant relationships. As an alternative, this article describes an integrative approach, first reviewing associations of the quality of intimate relationships with personality characteristics and aspects of emotional adjustment that confer CHD risk, and then discussing conceptual models of these associations and the biobehavioral mechanisms linking them with CHD. Current approaches to couple interventions are then discussed, including those that have a combined focus on intimate relationship difficulties and emotional adjustment. An integrative agenda for future research emphasizes aggregated risks, combining concepts and methods in current relationship science with those in biobehavioral research on CHD, and including parallel disparities in relationship functioning, emotional adjustment, and CHD risk. Such efforts could ultimately inform empirically based assessments and interventions for interrelated aspects of individuals and their intimate relationships that influence the development and course of CHD. (PsycINFO Database Record PMID- 28880105 TI - Integrative pathways linking close family ties to health: A neurochemical perspective. AB - The quality of one's familial life, for better or worse, has been linked to physical health. Such associations are evident across a number of acute and chronic conditions and highlight the widespread impact that close relationships have on physical health. However, the field currently lacks a complete understanding of the integrative biological pathways underlying the association between close relationships and disease risk. This article reviews the main peripheral biological and central nervous system pathways linking positive and negative familial relationship processes to physical health outcomes. It emphasizes the role of neurochemical pathways in mediating the influence of social relationships on health-relevant peripheral physiological systems using the oxytocin system as a model. Such neurochemical approaches are an important step toward a more integrative understanding of complex biological pathways and has novel theoretical and intervention implications. (PsycINFO Database Record PMID- 28880103 TI - Close social ties and health in later life: Strengths and vulnerabilities. AB - The world is aging at an unprecedented rate, with older adults representing the fastest-growing segment of the population in most economically developed and developing countries. This demographic shift leaves much uncharted territory for researchers who study social relationships and health. Social relationships exert powerful influences on physical health in later adulthood, a critical consideration given age-related increases in the prevalence of chronic health conditions and physical disability. A large body of research indicates that older adults report greater satisfaction with their social networks than do younger adults, and that they often take measures to minimize their exposure to negative social encounters. These emotionally satisfying and generally positive social ties afford some health protection against a backdrop of mounting physical limitations and play an important role when juxtaposed with the potentially health-damaging frictions that sometimes emerge in older adults' social relationships. Although most older adults report that they are satisfied with their social ties, some older adults experience frequent conflicts or ambivalent exchanges with members of their social networks, and these experiences detract from their health. In addition, many older adults will experience the loss of one or more close relationships during the course of their lives, with ramifications for their health and, often, for the reorganization of their social lives over time. Understanding how both the strengths and vulnerabilities of close social relationships affect health and well-being in later life is an important goal, particularly in view of the accelerating rate of population aging worldwide. (PsycINFO Database Record PMID- 28880106 TI - Close relationships and the management of chronic illness: Associations and interventions. AB - Self-management of a chronic illness involves not only monitoring symptoms, adhering to medication regimens, and keeping medical appointments but also making and maintaining difficult lifestyle changes. This article highlights correlational and intervention research suggesting family members are influential in children's and adults' illness management. The argument is made that a dyadic approach to chronic illness management that targets the influence of close relationships may yield more sustainable effects on patient behavior than has been achieved in the past. In particular, dyadic approaches aimed at helping patients and family members to find ways to collaborate in goal setting for these behaviors is recommended. Such dyadic interventions may also benefit family members who are ill or are at risk because of poor health behaviors. (PsycINFO Database Record PMID- 28880107 TI - Association of GOLPH2 expression with survival in non-small-cell lung cancer: clinical implications and biological validation. AB - AIM: We investigated the role of GOLPH2 in non-small-cell lung cancer (NSCLC). METHODS: We analyzed the relationship between the expression of GOLPH2 and the clinical pathological characteristics of patients with NSCLC. The function of GOLPH2 in NSCLC cell lines was also explored through overexpression and knockdown studies. RESULTS: The positive expression rate of GOLPH2 protein in NSCLC tissue was higher than that of normal lung tissue. We found that positive GOLPH2 expression was closely associated with unfavorable features of patients with NSCLC. The GOLPH2 expression was an independent predictor of the prognosis of patients with NSCLC. That GOLPH2 can promote the proliferation and invasion of NSCLC cells. CONCLUSION: The GOLPH2 is a novel marker for NSCLC. PMID- 28880109 TI - How adolescents perceive that community-based exercise improves their well-being. AB - OBJECTIVES: To determine if adolescents perceive community-based exercise as beneficial to their well-being and in what ways. METHODS: A New South Wales Police Citizens Youth Club ran a four-week fitness course. The classes involved: 1) sports including basketball and soccer, 2) non-contact boxing drills, and 3) games, both team games such as dodgeball and non-team games such as line tag. Parental consent to offer a survey at the completion of the course was requested during registration. The survey was the Warwick Edinburgh Mental Well-being Scale; it was minimally modified to measure perceived benefit to mental well being instead of actual benefit. RESULTS: Thirty-one high school adolescents, ages 13-18, completed the survey. As a group, participants reported that they believed their well-being had improved after the course. The mean score for each survey item showed an improvement in every area of mental well-being for this sample of adolescents. Thirty-two per cent of adolescents reported having less energy. Survey scores indicated a statistically significant improvement in perceived well-being ( p<0.0001). CONCLUSIONS: The results of this study suggest that four weeks of community-based exercise improves perceived mental well-being in adolescent participants. PMID- 28880110 TI - Protein tyrosine phosphatase 1B inhibitory activity of cone oils from Juniperus chinensis cv. Kaizuca and in silico theoretical explanation. AB - Juniperus chinensis cv. Kaizuca has extensive pharmacological activities. The cone oils exhibited protein tyrosine phosphatase 1B inhibitory activity in vitro. The IC50 value was 4.49 +/- 0.04 MUg/mL. A total of 17 compounds were characterised from the cone oils by GC-MS. In order to explain the activity against protein tyrosine phosphatase 1B, the identified compounds from cone oils were individually docked with the protein tyrosine phosphatase 1B protein by virtual molecular docking. As a result, thunbergene was completely wrapped by the active site of protein tyrosine phosphatase 1B, and its binding energy was -6.41 kcal/mol. The result indicated that thunbergene possessed the potential protein tyrosine phosphatase 1B inhibitory activity, which may be responsible for the activity of cone oils. PMID- 28880108 TI - Reduced length of uninterrupted institutional stay after implementing a fast track protocol for primary total hip replacement. AB - Background and purpose - Fast-track protocols have been successfully implemented in many hospitals as they have been shown to result in shorter length of stay (LOS) without compromising results. We evaluated the effect of fast-track implementation on the use of institutional care and results after total hip replacement (THR). Patients and methods - 3,193 THRs performed in 4 hospitals between 2009-2010 and 2012-2013 were identified from the Finnish Hospital Discharge Register and the Finnish Arthroplasty Register. Hospitals were classified as fast-track (Hospital A) and non-fast-track (Hospitals B, C, and D). We analyzed LOS, length of uninterrupted institutional care (LUIC, including LOS), discharge destination, readmission, revision rate, and mortality in each hospital. We compared these outcomes for THRs performed in Hospital A before and after fast-track implementation and we also compared outcomes, excluding readmission rates, with the corresponding outcomes for the other hospitals. Results - After fast-track implementation, median LOS in Hospital A diminished from 5 to 2 days (p < 0.001) and (median) LUIC from 6 to 3 (p = 0.001) days. No statistically significant changes occurred in discharge destination. However, the reduction in LOS was combined with an increase in the 42-day readmission rate (3.1% to 8.3%) (p < 0.001). A higher proportion of patients were at home 1 week after THR (p < 0.001) in Hospital A after fast-tracking than before. Interpretation - The fast-track protocol reduces LUIC but needs careful implementation to maintain good quality of care throughout the treatment process. PMID- 28880111 TI - Anti-NDV activity of 9-oxo10,11-dehydroageraphorone extracted from Eupatorium adenophorum Spreng in vitro. AB - The purpose of this study was to investigate the anti-Newcastle disease virus (NDV) activities of 9-oxo-10,11-dehydroageraphorone (euptox A) from Eupatorium adenophorum Spreng (E. adenophorum) in vitro. NDV infection of chicken embryo fibroblasts (CEFs) was performed. Cytotoxicities and antiviral activities of euptox A was assessed by the MTT method. The interaction of NDV with cell membrane protein was detected by virus overlay protein binding assay (VOPBA). The expression levels of NDV genes in CEFs was tested by RTFQ PCR. The results showed that the maximal safe concentrations of euptox A to CEFs was 10 MUg/mL. Euptox A could directly neutralise NDV, inhibit the infectivity of NDV to CEFs and block intracellular NDV treat NDV infection. And euptox A brings competitiveness inhibition for NDV binding to its receptors and then prevent NDV infection. These results indicated that euptox A possessed anti-NDV activity has potential use as components of a natural antiviral drug. PMID- 28880112 TI - Coumarins and alkaloids from the roots of Toddalia asiatica. AB - The EtOAc and MeOH extracts of the roots of Toddalia asiatica Lam. were investigated for the roots' chemical constituents. Two new compounds including 2'R-acetoxytoddanol (1) and 8S-10-O-demethylbocconoline (3) as well as 15 known compounds were isolated. Compound 10 showed strong cytotoxicity against KB cells with an IC50 value of 2.60 MUg/mL, which is nearly equal to the ellipticine standard, but showed no activity against Vero cells. Alkaloid 3 displayed weak cytotoxicity against the KB cell line with an IC50 value of 21.69 MUg/mL. PMID- 28880114 TI - A new pair of enantiomeric lignans from the fruits of Morinda citrifolia and their absolute configuration. AB - A new pair of sesamin-type lignan enantiomers (+/-)-morifolia A (1a/1b) together with eight known analogues (2-9) were isolated from the fruits of Morinda citrifolia. Their structures were established by spectroscopic data and the absolute configurations of 1a/1b were determined by ECD calculation. All compounds were examined for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW 264.7 macrophages, and compounds 1a, 1b, 2-4 and 7-9 exhibited pronounced inhibition with IC50 values in the range of 1.97-8.01 (MUM, being more active than the positive control, quercetin (IC50 = 15.32 (M). PMID- 28880113 TI - Increasing age and tear size reduce rotator cuff repair healing rate at 1 year. AB - Background and purpose - There is a need to understand the reasons why a high proportion of rotator cuff repairs fail to heal. Using data from a large randomized clinical trial, we evaluated age and tear size as risk factors for failure of rotator cuff repair. Patients and methods - Between 2007 and 2014, 65 surgeons from 47 hospitals in the National Health Service (NHS) recruited 447 patients with atraumatic rotator cuff tendon tears to the United Kingdom Rotator Cuff Trial (UKUFF) and 256 underwent rotator cuff repair. Cuff integrity was assessed by imaging in 217 patients, at 12 months post-operation. Logistic regression analysis was used to determine the influence of age and intra operative tear size on healing. Hand dominance, sex, and previous steroid injections were controlled for. Results - The overall healing rate was 122/217 (56%) at 12 months. Healing rate decreased with increasing tear size (small tears 66%, medium tears 68%, large tears 47%, and massive tears 27% healed). The mean age of patients with a healed repair was 61 years compared with 64 years for those with a non-healed repair. Mean age increased with larger tear sizes (small tears 59 years, medium tears 62 years, large tears 64 years, and massive tears 66 years). Increasing age was an independent factor that negatively influenced healing, even after controlling for tear size. Only massive tears were an independent predictor of non-healing, after controlling for age. Interpretation - Although increasing age and larger tear size are both risks for failure of rotator cuff repair healing, age is the dominant risk factor. PMID- 28880115 TI - Physiologic and metabolic effects of exogenous kojic acid and tyrosol, chemicals produced by endophytic fungus, on wheat seeds germination. AB - Antioxidant compounds have the ability to scavenge the reactive oxygen species in an attempt to minimise damage in seeds during the germination. This study aimed to evaluate the physiological and metabolic process of two well-established antioxidant compounds: kojic acid and hydroxyphenyl ethanol (tyrosol), at increasing concentrations, on wheat seeds. The use of different concentrations of tyrosol or kojic acid not showed any interference on seed germination rate. However, we observed isolated effect of antioxidants and their concentrations to: germination speed index, shoot length and electrolyte leakage; and significant interaction between the factors to: seedling total length, seedling fresh matter and alpha-amylase activity. Our results suggest that the use of antioxidant molecules can be applied on seed treatments for protection against damage oxidative stress and improve seed metabolism. PMID- 28880116 TI - Photoacoustic Imaging for Noninvasive Periodontal Probing Depth Measurements. AB - The periodontal probe is the gold standard tool for periodontal examinations, including probing depth measurements, but is limited by systematic and random errors. Here, we used photoacoustic ultrasound for high-spatial resolution imaging of probing depths. Specific contrast from dental pockets was achieved with food-grade cuttlefish ink as a contrast medium. Here, 39 porcine teeth (12 teeth with artificially deeper pockets) were treated with the contrast agent, and the probing depths were measured with novel photoacoustic imaging and a Williams periodontal probe. There were statistically significant differences between the 2 measurement approaches for distal, lingual, and buccal sites but not mesial. Bland-Altman analysis revealed that all bias values were < +/-0.25 mm, and the coefficients of variation for 5 replicates were <11%. The photoacoustic imaging approach also offered 0.01-mm precision and could cover the entire pocket, as opposed to the probe-based approach, which is limited to only a few sites. This report is the first to use photoacoustic imaging for probing depth measurements with potential implications to the dental field, including tools for automated dental examinations or noninvasive examinations. PMID- 28880117 TI - International variation in shoulder arthroplasty. AB - Background and purpose - The number of shoulder registries increases. We assessed international trends in use of shoulder arthroplasty, and described the current state of procedure selection and outcome presentation as documented in national and regional joint registries. Methods - Published reports from 9 population based shoulder arthroplasty registries (country/region: Norway, Sweden, New Zealand, Denmark, California, Australia, Emilia-Romagna, Germany, and United Kingdom) were analyzed. Data were extracted on age, sex, disease indication, type of surgical procedure, surgical volume, and outcomes. Results - Shoulder arthroplasty incidence rate in 2012 was 20 procedures/105 population with a 6 fold variation between the highest (Germany) and lowest (United Kingdom) country. The annual incidence rate increased 2.8-fold in the past decade. Within the indications osteoarthritis, fracture, and cuff-tear arthropathy variations in procedure choice between registries were large. Outcomes evaluation focused on revision in all registries, but different measures and strata were used. Only Australia provided revision rates for prosthesis brands stratified by both indication and procedure. Finally, in 2 registries with available data surgeons performed on average 10-11 procedures yearly. Interpretation - Annual incidence rates of shoulder arthroplasty have almost tripled over the past decade. There is wide variation in procedure selection for the major indications, a low average surgeon volume, a substantial number of brands with small annual volume, and large variation in outcome presentation. The internationally increasing registry activity is an excellent basis for improving the so far weak evidence in shoulder arthroplasty. PMID- 28880118 TI - Effects of flour or flaxseed oil upon testis mass in rats subjected to early weaning. AB - Study evaluates testis mass in rats subjected to early weaning and subsequently nourished with diet containing flour or flaxseed oil. Pups were weaned for separation from mothers at 14 days (early weaning, EW) and 21 days (control, C). After 21 days, the control group (C60) was nourished with control diet. EW was divided as: control (EWC60), flaxseed flour (EWFF60) and flaxseed oil (EWFO60) group diets for the next 60 days. At 21st and 60th day, body mass, serum cholesterol and triglycerides and testis mass were evaluated. At 21 day, EW group showed lower (p < 0.05) body mass, serum cholesterol and testis mass. At 60 days, EWC60 and EWFO60 groups showed lower (p < 0.05) body mass (vs. C60 and EWFF60). EWFF60 group showed lower (p < 0.05) serum cholesterol (vs. EWC60 and EWFO60) and higher (p < 0.05) testis mass (vs. C60, EWC60 and EWFO60). Flaxseed flour (vs. oil) was associated with higher testis mass following early weaning. PMID- 28880119 TI - Aldose reductase inhibitory activity studies of THERACURMIN. AB - THERACURMIN a commercially available nano-dispersion of curcumin used to treat after effects of alcohol has been evaluated for in vitro ARI activity on Aldose reductase isolated from the bovine lens. As envisaged, the product displays better ARI activity with IC50 value of 3 MUM. The observed ARI activity of THERACURMIN is of therapeutic significance as the limited bioavailability of curcumin limits its clinical use. PMID- 28880120 TI - Reward-related limbic memory and stimulation of the cannabinoid system: An upgrade in value attribution? AB - While a lot is known about the mechanisms promoting aversive learning, the impact of rewarding factors on memory has received comparatively less attention. This research investigates reward-related explicit memory in male rats, by taking advantage of the emotional-object recognition test. This is based on the prior association, during conditioned learning, between a rewarding experience (the encounter with a receptive female rat) and an object; afterwards rat discrimination and recognition of the 'emotional object' is recorded in the presence of a novel object, as a measure of positive limbic memory formation. Since endocannabinoids are critical for processing reward and motivation, the consequences of the stimulation of cannabinoid signalling are also assessed by the administration of WIN 55,212-2 at pre- and post-conditioning time. Our results show that rats encode the association between object and rewarding experience, form positive limbic memory of the emotional object, and retrieve this information in the face of novelty. Stimulation of the cannabinoid system at pre-conditioning time is able to strengthen reward-related explicit memory in the presence of novelty, whereas post-conditioning activation increases approach behaviour to novel stimuli. The assessment of limbic memory by the emotional object recognition test can help unveiling the addictive and confounding properties of psychotropic drugs. PMID- 28880121 TI - Improvement of anti-biofouling properties of hollow fiber membranes with bismuth BAL chelates (BisBAL). AB - In this study, hollow fiber membranes with and without bismuth dimercaptopropanol (Bis-BAL) additive were fabricated. Membranes were characterized in terms of permeability, surface properties, anti-biofouling and antibacterial properties. Membranes were operated in a lab-scale submerged membrane bioreactor (MBR). During the MBR operation, flux, chemical oxygen demand, volatile suspended solids and suspended solids were calculated for 30 days. Results showed that extracellular polymeric substance and soluble microbial product amounts were decreased in BisBAL-containing membranes. BisBAL-added membranes had the ability to inhibit the growth of Escherichia coli. BisBAL as an additive for membranes was found to be an effective, cheap alternative for enhancing anti-biofouling properties of the membranes. PMID- 28880122 TI - Expression of AMPK, SIRT1, and ACC Differs between Winter- and Summer Acclimatized Djungarian Hamsters. AB - The wintering strategy of the Djungarian hamster (Phodopus sungorus) includes a naturally occurring decrease in food intake and body mass. Our aim was to investigate the conceivable role of the metabolic regulators, AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), in the seasonal adaptation of the Djungarian hamster. In addition, a rate-limiting enzyme in fatty acid synthesis and oxidation, acetyl CoA carboxylase (ACC), was studied. Relative protein expressions and phosphorylated forms (pAMPK and pACC) were determined by Western blot from subcutaneous white adipose tissues (sWAT), abdominal white adipose tissues (aWAT), interscapular brown adipose tissues (iBAT), skeletal muscle, and hypothalamus of winter- and summer-acclimatized hamsters. The winter group had higher AMPK expression in sWAT, aWAT, and iBAT, but the relative amount of phosphorylated protein (pAMPK/AMPK ratio) was lower in these tissues. Furthermore, ACC expression was higher in sWAT and iBAT of the winter animals. pACC (inactive form) levels were higher in all adipose tissues, yet a lower pACC/ACC ratio was detected in iBAT of the winter hamsters. Muscle AMPK expression was lower but pAMPK/AMPK ratio higher in the winter group. SIRT1 expression was higher in muscle and all adipose tissues of the winter hamsters. Hypothalamic protein expressions did not differ between the groups. Higher expressions of AMPK, ACC, and SIRT1 in WAT and iBAT of the winter hamsters suggest a role in the regulation of lipid reserves and increased thermogenic capacity characteristic to the winter-adapted Djungarian hamsters. PMID- 28880123 TI - Commentary: "Validation of a Theory of Planned Behavior-Based Questionnaire to Examine Factors Associated With Milk Expression" by Y. K. Bai & L. M. Dinour. PMID- 28880124 TI - Efficacy and safety of posaconazole in hematopoietic stem cell transplantation patients with invasive fungal disease. AB - AIM: Invasive fungal disease (IFD) is a significant cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT) patients. This study reports real-world efficacy and safety of posaconazole (POS) in HSCT recipients with IFD. PATIENTS & METHODS: We performed a retrospective study to investigate the efficacy and safety of POS oral suspension in 45 HSCT patients with IFD from December 2013 to December 2016. RESULTS: The success rate at 12 weeks after POS treatment was 57.8%. Multivariate logistic regression analysis showed that persistent neutropenia, severe graft-versus-host disease, high-dose steroid and cytomegalovirus infection were independently associated with inferior responses to POS. POS caused some adverse effects of mild or moderate severity that were of short duration. CONCLUSION: This study provides encouraging data regarding the efficacy and safety of POS in HSCT recipients. Neutropenia, graft-versus-host disease, steroid use and cytomegalovirus infection are possibly associated with inferior responses to POS therapy. PMID- 28880125 TI - Consensus statement of the international summit on intellectual disability and Dementia related to post-diagnostic support. AB - OBJECTIVES: Post diagnostic support (PDS) has varied definitions within mainstream dementia services and different health and social care organizations, encompassing a range of supports that are offered to adults once diagnosed with dementia until death. METHOD: An international summit on intellectual disability and dementia held in Glasgow, Scotland in 2016 identified how PDS applies to adults with an intellectual disability and dementia. The Summit proposed a model that encompassed seven focal areas: post-diagnostic counseling; psychological and medical surveillance; periodic reviews and adjustments to the dementia care plan; early identification of behaviour and psychological symptoms; reviews of care practices and supports for advanced dementia and end of life; supports to carers/ support staff; and evaluation of quality of life. It also explored current practices in providing PDS in intellectual disability services. RESULTS: The Summit concluded that although there is limited research evidence for pharmacological or non-pharmacological interventions for people with intellectual disability and dementia, viable resources and guidelines describe practical approaches drawn from clinical practice. Post diagnostic support is essential, and the model components in place for the general population, and proposed here for use within the intellectual disability field, need to be individualized and adapted to the person's needs as dementia progresses. CONCLUSIONS: Recommendations for future research include examining the prevalence and nature of behavioral and psychological symptoms (BPSD) in adults with an intellectual disability who develop dementia, the effectiveness of different non pharmacological interventions, the interaction between pharmacological and non pharmacological interventions, and the utility of different models of support. PMID- 28880126 TI - Detecting allocentric and egocentric navigation deficits in patients with schizophrenia and bipolar disorder using virtual reality. AB - Present evidence suggests that the use of virtual reality has great advantages in evaluating visuospatial navigation and memory for the diagnosis of psychiatric or other neurological disorders. There are a few virtual reality studies on allocentric and egocentric memories in schizophrenia, but studies on both memories in bipolar disorder are lacking. The objective of this study was to compare the performance of allocentric and egocentric memories in patients with schizophrenia and bipolar disorder. For this resolve, an advanced virtual reality navigation task (VRNT) was presented to distinguish the navigational performances of these patients. Twenty subjects with schizophrenia and 20 bipolar disorder patients were compared with 20 healthy-matched controls on the newly developed VRNT consisting of a virtual neighbourhood (allocentric memory) and a virtual maze (egocentric memory). The results demonstrated that schizophrenia patients were significantly impaired on all allocentric, egocentric, visual, and verbal memory tasks compared with patients with bipolar disorder and normal subjects. Dissimilarly, the performance of patients with bipolar disorder was slightly lower than that of control subjects in all these abilities, but no significant differences were observed. It was concluded that allocentric and egocentric navigation deficits are detectable in patients with schizophrenia and bipolar disorder using VRNT, and this task along with RAVLT and ROCFT can be used as a valid clinical tool for distinguishing these patients from normal subjects. PMID- 28880127 TI - Evaluation of Regional-Scale Receptor Modeling. AB - The ability of receptor models to estimate regional contributions to fine particulate matter (PM2.5) was assessed with synthetic, speciated datasets at Brigantine National Wildlife Refuge (BRIG) in New Jersey and Great Smoky Mountains National Park (GRSM) in Tennessee. Synthetic PM2.5 chemical concentrations were generated for the summer of 2002 using the Community Multiscale Air Quality (CMAQ) model and chemically speciated PM2.5 source profiles from the U.S. Environmental Protection Agency (EPA)'s SPECIATE and Desert Research Institute's source profile databases. CMAQ estimated the "true" contributions of seven regions in the eastern United States to chemical species concentrations and individual source contributions to primary PM2.5 at both sites. A seven-factor solution by the positive matrix factorization (PMF) receptor model explained approximately 99% of the variability in the data at both sites. At BRIG, PMF captured the first four major contributing sources (including a secondary sul-fate factor), although diesel and gasoline vehicle contributions were not separated. However, at GRSM, the resolved factors did not correspond well to major PM2.5 sources. There were no correlations between PMF factors and regional contributions to sulfate at either site. Unmix produced five- and seven factor solutions, including a secondary sulfate factor, at both sites. Some PMF factors were combined or missing in the Unmix factors. The trajectory mass balance regression (TMBR) model apportioned sulfate concentrations to the seven source regions using Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) trajectories based on Meteorological Model Version 5 (MM5) and Eta Data Simulation System (EDAS) meteorological input. The largest estimated sulfate contributions at both sites were from the local regions; this agreed qualitatively with the true regional apportionments. Estimated regional contributions depended on the starting elevation of the trajectories and on the meteorological input data. PMID- 28880128 TI - Thank You for Your Continued Support. PMID- 28880129 TI - Toward Effective Source Apportionment Using Positive Matrix Factorization: Experiments with Simulated PM2.5 Data. AB - To elucidate the relationship between factors resolved by the positive matrix factorization (PMF) receptor model and actual emission sources and to refine the PMF modeling strategy, speciated PM2.5 (particulate matter with aerodynamic diameter <2.5 MUm) data generated from a state-of-the-art chemical transport model for two rural sites in the eastern United States are subjected to PMF analysis. In addition to chi-2 and R 2 used to infer the quality of fitting, the interpretability of PMF factors with respect to known primary and secondary sources is evaluated using a root mean square difference analysis. For the most part, factors are found to represent imperfect combinations of sources, and the optimal number of factors should be just adequate to explain the input data (e.g., R 2 > 0.95). Retaining more factors in the model does not help resolve minor sources, unless temporal resolution of the data is increased, thus allowing more information to be used by the model. If guided with a priori knowledge of source markers and/or special events, rotation of factors leads to more interpretable PMF factors. The choice of uncertainty weighting coefficients greatly influences the PMF modeling results, but it cannot usually be determined for simulated or real-world data. A simple test is recommended to check whether the weighting coefficients are suitable. However, uncertainties in the data divert PMF solutions even when the optimal weighting coefficients and number of factors are in place. PMID- 28880130 TI - The effects of semi-immersive virtual reality therapy on standing balance and upright mobility function in individuals with chronic incomplete spinal cord injury: A preliminary study. AB - BACKGROUND: Individuals with chronic incomplete spinal cord injury (iSCI) commonly face persistent balance or mobility impairments. Virtual reality (VR) therapy is a useful rehabilitation approach; however, little is known about its effects in individuals with chronic iSCI. OBJECTIVE: To investigate the effects of semi-immersive VR therapy on standing balance and upright mobility function in individuals with chronic iSCI. METHODS: Ten subjects with chronic iSCI underwent VR therapy 30 minutes a day, 3 days a week, for 6 weeks. Limit of stability (LOS) and the Berg Balance Scale (BBS) were used to evaluate standing balance function. The Timed Up & Go (TUG) test, Activities-specific Balance Confidence (ABS) Scale, and Walking Index for Spinal Cord Injury-II (WISCI-II) were used to measure the subject's upright mobility function. Outcomes were assessed and recorded pre- and post-intervention. RESULTS: After semi-immersive VR therapy, LOS and BBS scores were significantly increased. In addition, the TUG test results increased significantly over time, while ABC scale scores and WSCI-II levels improved significantly. CONCLUSION: This study is the first to assess the effects of semi immersive VR therapy for patients with chronic iSCI and limited functional abilities. These results indicated that semi-immersive VR therapy has a positive effect and is a useful intervention for standing balance and upright mobility function in patients with chronic iSCI. PMID- 28880131 TI - Prediction of specific hand movements using electroencephalographic signals. AB - OBJECTIVE: To identify specific hand movements from electroencephalographic activity. DESIGN: Proof of concept study. SETTING: Rehabilitation hospital in Toronto, Canada. PARTICIPANTS: Fifteen healthy individuals with no neurological conditions. INTERVENTION: Each individual performed six different hand movements, including four grasps commonly targeted during rehabilitation. All of them used their dominant hand and four of them repeated the experiment with their non dominant hand. EEG was acquired from 8 different locations (C1, C2, C3, C4, CZ, F3, F4 and Fz). Time-frequency distributions (spectrogram) of the pre-movement EEG activity for each electrode were generated and each of the time-resolved spectral components (1 Hz to 50 Hz) was correlated with a hyperbolic tangent function to detect power decreases. The spectral components and time ranges with the largest correlation values were identified using a threshold. The resulting features were then used to implement a distance-based classifier. OUTCOME MEASURES: Accuracy of classification. RESULTS: A minimum of three different dominant hand movements were classified correctly with average accuracies between 65-75% across all 15 participants. Average accuracies between 67-85% for the same three movements were achieved across four of the 15 participants who were tested with their non-dominant hand. CONCLUSION: The results suggest that it may be possible to predict specific hand movements from a small number of electroencephalographic electrodes. Further studies including members of the spinal cord injury community are necessary to verify the suitability of the proposed process. PMID- 28880132 TI - Linking spinal cord injury rehabilitation between the World Wars: The R. Tait McKenzie legacy. AB - Spinal cord injury (SCI) medicine emerged after World War II due to mass casualties, which required specialized treatment centers. This approach to categorical care, however, was first developed during World War I, led by pioneers R. Tait McKenzie and George Deaver, who demonstrated that soldiers disabled by paralysis could return to society through fitness/mobility, recreational and vocational training. McKenzie, a Canadian and the first professor of physical therapy in the US, influenced Deaver and military physicians in Britain, Canada, and the U.S. with his achievements and publications. Although early mortality from SCI was high, advances in the treatment of skin and bladder complications coupled with rehabilitation developed through lessons learned in World War I, resulted in major changes in survival and quality of life for veterans of World War II in England, US, and Canada. Harry Botterell and Al Jousse, founders of Lyndhurst Lodge, the first SCI center in Canada, adopted Deaver's principles and techniques of rehabilitation and Donald Munro's approach to medical complications. The consequences of failing to organize continuity of care in World War I were recognized both by consumers and physicians. Together with John Counsell, a World War II veteran, they formed the Canadian Paraplegic Association, which "revolutionized" the care of veterans with SCI, as well as civilians, women, and children. PMID- 28880135 TI - LETTERS TO THE EDITOR. PMID- 28880133 TI - Epidemiological study of Spinal Cord Injury individuals from halfway houses in Shanghai, China. AB - OBJECTIVE: To describe the characteristics of spinal cord injury (SCI) individuals in Shanghai and examine their treatment and rehabilitation for traumatic and complete SCI individuals. DESIGN: Community-based secondary data analyses. SETTING: Shanghai, China. METHODS: We analyzed gender, age at injury, complications, disturbances of function, treatment, etiology, and severity of injury of SCI individuals that enrolled in "halfway houses", government-supported community co-op centers. Bivariate statistical analyses were conducted to examine the factors associated with complete and traumatic SCI. RESULTS: We analyzed 808 SCI individuals who participated in halfway houses in Shanghai during 2009-2015. The male-to-female ratio was 2.1:1. The proportion of middle or elder age groups at injury (age 46 to 60 and age 61 or over) showed a rising trend from 1970 to 2015. The leading causes of SCIs in Shanghai were traumatic injuries (58%), followed by disease (29.5%). The proportion of traumatic injuries decreased over time, while the proportion of non-traumatic injuries rose significantly. A majority of traumatic injury individuals were aged between 16-45. CONCLUSION: The middle or elder age groups at injury among SCI individuals increased continuously from 1970 to 2015. The principal causes of injury in Shanghai were traumatic injuries and disease-related injuries. Men had a higher prevalence of traumatic SCI in Shanghai. Preventive measures should focus on male and middle-aged adults. As a fast-aging society in Shanghai, more effective prevention, medical care, and rehabilitation schemes should be implemented for aging SCI individuals. PMID- 28880138 TI - Windsor, Ontario Exposure Assessment Study: Design and Methods Validation of Personal, Indoor, and Outdoor Air Pollution Monitoring. AB - The Windsor, Ontario Exposure Assessment Study evaluated the contribution of ambient air pollutants to personal and indoor exposures of adults and asthmatic children living in Windsor, Ontario, Canada. In addition, the role of personal, indoor, and outdoor air pollution exposures upon asthmatic children's respiratory health was assessed. Several active and passive sampling methods were applied, or adapted, for personal, indoor, and outdoor residential monitoring of nitrogen dioxide, volatile organic compounds, particulate matter (PM; PM <= 2.5 MUm [PM2.5] and <= 10 MUm [PM10] in aerodynamic diameter),elemental carbon, ultrafine particles, ozone, air exchange rates, allergens in settled dust, and particulate associated metals. Participants completed five consecutive days of monitoring during the winter and summer of 2005 and 2006. During 2006, in addition to undertaking the air pollution measurements, asthmatic children completed respiratory health measurements (including peak flow meter tests and exhaled breath condensate) and tracked respiratory symptoms in a diary. Extensive quality assurance and quality control steps were implemented, including the collocation of instruments at the National Air Pollution Surveillance site operated by Environment Canada and at the Michigan Department of Environmental Quality site in Allen Park, Detroit, MI. During field sampling, duplicate and blank samples were also completed and these data are reported. In total, 50 adults and 51 asthmatic children were recruited to participate, resulting in 922 participant days of data. When comparing the methods used in the study with standard reference methods, field blanks were low and bias was acceptable, with most methods being within 20% of reference methods. Duplicates were typically within less than 10% of each other, indicating that study results can be used with confidence. This paper covers study design, recruitment, methodology, time activity diary, surveys, and quality assurance and control results for the different methods used. [Box: see text]. PMID- 28880139 TI - Dysphagia screening after intracerebral hemorrhage. AB - Background Dysphagia screening is recommended after acute stroke to identify patients at risk of aspiration and implement appropriate care. However, little is known about the frequency and outcomes of patients undergoing dysphagia screening after intracerebral hemorrhage (ICH). Methods We used the Ontario Stroke Registry from 1 April 2010 to 31 March 2013 to identify patients hospitalized with acute stroke and to compare dysphagia screening rates in those with ICH and ischemic stroke. In patients with ICH we assessed predictors of receiving dysphagia screening, predictors of failing screening, and outcomes after failing screening. Results Among 1091 eligible patients with ICH, 354 (32.4%) patients did not have documented dysphagia screening. Patients with mild ICH were less likely to receive screening (40.4% of patients were omitted, adjusted odds ratio (aOR) 0.40, 95% confidence interval (CI) 0.26-0.63). Older age, greater stroke severity, speech deficits, lower initial level of consciousness, and admission to intensive care unit were predictive of failing the screening test. Failing screening was associated with poor outcomes, including pneumonia (aOR 5.3, 95% CI 2.36-11.88), severe disability (aOR 4.78, 95% CI 3.08-7.41), and 1-year mortality (adjusted hazard ratio 2.1, 95% CI 1.38-3.17). When compared to patients with ischemic stroke, patients with ICH were less likely to receive dysphagia screening (aOR 0.64, 95% CI 0.54-0.76) and more likely to fail screening (aOR 1.98, 95% 1.62-2.42). Conclusion One-third of patients with ICH did not have documented dysphagia screening, increasing to 40% in patients with mild clinical severity. Failing screening was associated with poor outcomes. Patients with ICH were less like to receive screening and twice as likely to fail compared to patients with ischemic stroke, and thus efforts should be made to include ICH patients in dysphagia screening protocols whenever possible. PMID- 28880140 TI - [Diving accident-induced arterial gas embolism]. AB - BACKGROUND: During scuba diving, nitrogen dissolves into the body tissues due to elevated pressure under water. During a sudden drop in pressure due to a rapid return to the water surface, arterial gas embolism can arise from pulmonary barotrauma. In a later phase, nitrogen bubbles can also arise in the venous circulation (decompression sickness). Arterial bubbles can incur vascular damage, obstruction, hypoxia and infarction. CASE DESCRIPTION: A 53-year-old healthy sport diver presented at the emergency department in a hypovolemic shock with progressive paresis of all the extremities. He had made an emergency ascent from a depth of 47 meter. During recompression therapy his condition deteriorated. It transpired that he had an patent foramen ovale. As a consequence of this, nitrogen bubbles due to decompression sickness entered the arterial circulation. Despite maximum therapeutic intervention the patient remained paretic. CONCLUSION: After an ill-fated dive, this patient with patent foramen ovale contracted arterial gas embolism due to pulmonary barotrauma and, at a later stage, decompression sickness. There was increasing damage to the spinal cord resulting in severe physiological disruption. PMID- 28880141 TI - [Clioquinol use for Dientamoeba fragilis infections is questionable]. AB - Clioquinol is used for treatment of amoebiasis and infection with Dientamoeba fragilis. In a guideline of the Dutch Working Party on Antibiotic Policy, clioquinol is recommended as a first-choice treatment for Dientamoeba fragilis. This drug, however, is associated with subacute myelo-optico-neuropathy (SMON). It was withdrawn from the market worldwide in 1985 by manufacturer Ciba-Geigy. Although the Dutch Medicines Evaluation Board has registered no products for systemic use of clioquinol since then, the drug is available as a pharmacy compounded drug and the last few years the use of clioquinol in the Netherlands has risen again. The Netherlands Pharmacovigilance Centre Lareb has received a growing number of reports of adverse drug reactions (ADRs) associated with the use of clioquinol, including nervous system disorder ADRs occurring at recommended dosages. Therefore, we debate the use of clioquinol as a first-choice treatment option for Dientamoeba fragilis. PMID- 28880142 TI - [An elderly couple dies of natural causes on the same day]. AB - BACKGROUND: A 77-year-old woman died of metastatic colorectal cancer. On that same day, her 82-year-old husband, who had stayed in bed next to her during the last days of her life, also died. CASE DESCRIPTION: We describe their two separate trajectories to death: anticipated dying and unexpected death with diagnostic uncertainty. We analysed the general practitioner's role in this scenario. Existential suffering was partly the reason for commencing palliative sedation for the husband after his wife had died. CONCLUSION: General practitioners might find it difficult to change their course in care management for terminal patients from "life preserving" to "letting go". An effective handover between physicians is essential in the palliative phase. No evidence was found in literature for the hypothesis that dying people can influence their own time of death. PMID- 28880143 TI - [An infant with a nevus on the upper leg]. AB - We present a 4-month-old infant with an eczematous halo around a congenital melanocytic nevus. After diagnostic excision, histopathologic examination revealed a Meyerson's nevus. This is a benign skin tumour that may show clinical signs of melanoma. It is therefore important to include Meyerson's nevus in the differential diagnosis of melanoma. PMID- 28880144 TI - [Periodical medication review: bigger and better?] AB - The Netherlands' practice guideline 'Polypharmacy in older people' (2012) proposed selecting patients who would benefit from a periodical medication review. The guideline committee made it clear that firm evidence supporting selection was lacking, and recent studies evaluating the effects of medication review on relevant patient-related outcomes have failed to show a positive effect on almost any of these outcomes. Regulatory authorities have advised expanding the target population for medication review. We have to conclude, however, that rather than implementing medication reviews across a broad population of older people, many with a low risk of adverse events, it may be more cost-effective to limit this potentially useful but time-consuming intervention to a more select population who would benefit the most from it. PMID- 28880145 TI - [Dementia care in Germany]. AB - In Germany there are approximately 1.6 million people with dementia. A quarter of them live in a care home, often alongside residents who have a physical condition. The quality of nursing for physical conditions is good; although specialised dementia care is less developed, this lag is slowly being addressed. Medical care in German care homes is delivered by GPs. Preservation of life is the norm. Due to the lack of both advance care planning and a non-resuscitation policy, many care home residents with dementia undergo life-extending measures. Through the use of an advance health care directive, people can protect themselves from such a situation occurring. PMID- 28880147 TI - Correction: Re-visiting the trans insertion model for complexin clamping. PMID- 28880146 TI - The physical dimensions of amyloid aggregates control their infective potential as prion particles. AB - Transmissible amyloid particles called prions are associated with infectious prion diseases in mammals and inherited phenotypes in yeast. All amyloid aggregates can give rise to potentially infectious seeds that accelerate their growth. Why some amyloid seeds are highly infectious prion particles while others are less infectious or even inert, is currently not understood. To address this question, we analyzed the suprastructure and dimensions of synthetic amyloid fibrils assembled from the yeast (Saccharomyces cerevisiae) prion protein Sup35NM. We then quantified the ability of these particles to induce the [PSI+] prion phenotype in cells. Our results show a striking relationship between the length distribution of the amyloid fibrils and their ability to induce the heritable [PSI+] prion phenotype. Using a simple particle size threshold model to describe transfection activity, we explain how dimensions of amyloid fibrils are able to modulate their infectious potential as prions. PMID- 28880148 TI - Reconciling isothermal titration calorimetry analyses of interactions between complexin and truncated SNARE complexes. AB - Neurotransmitter release depends on the SNARE complex formed by syntaxin-1, synaptobrevin and SNAP-25, as well as on complexins, which bind to the SNARE complex and play active and inhibitory roles. A crystal structure of a Complexin I fragment bearing a so-called 'superclamp' mutation bound to a truncated SNARE complex lacking the C-terminus of the synaptobrevin SNARE motif (SNAREDelta60) suggested that an 'accessory' alpha-helix of Complexin-I inhibits release by inserting into the C-terminus of the SNARE complex. Previously, isothermal titration calorimetry (ITC) experiments performed in different laboratories yielded apparently discrepant results in support or against the existence of such binding mode in solution (Trimbuch et al., 2014; Krishnakumar et al., 2015). Here, ITC experiments performed to solve these discrepancies now show that the region containing the Complexin-I accessory helix and preceding N-terminal sequences does interact with SNAREDelta60, but the interaction requires the polybasic juxtamembrane region of syntaxin-1 and is not affected by the superclamp mutation within the experimental error of these experiments. PMID- 28880151 TI - Salivary Markers for Quantitative Dehydration Estimation During Physical Exercise. AB - Salivary markers have been proposed as noninvasive and easy-to-collect indicators of dehydrations during physical exercise. It has been demonstrated that threshold based classifications can distinguish dehydrated from euhydrated subjects. However, considerable challenges were reported simultaneously, for example, high intersubject variabilities in these markers. Therefore, we propose a machine learning approach to handle the intersubject variabilities and to advance from binary classifications to quantitative estimations of total body water (TBW) loss. For this purpose, salivary samples and reference values of TBW loss were collected from ten subjects during a 2-h running workout without fluid intake. The salivary samples were analyzed for previously investigated markers (osmolality, proteins) as well as additional unexplored markers (amylase, chloride, cortisol, cortisone, and potassium). Processing all these markers with a Gaussian process approach showed that quantitative TBW loss estimations are possible within an error of 0.34 l, roughly speaking, a glass of water. Furthermore, a data analysis illustrated that the salivary markers grow nonlinearly during progressive dehydration, which is in contrast to previously reported linear observations. This insight could help to develop more accurate physiological models for salivary markers and TBW loss. Such models, in turn, could facilitate even more precise TBW loss estimations in the future. PMID- 28880149 TI - Dual function of the PI3K-Akt-mTORC1 axis in myelination of the peripheral nervous system. AB - Myelination is a biosynthetically demanding process in which mTORC1, the gatekeeper of anabolism, occupies a privileged regulatory position. We have shown previously that loss of mTORC1 function in Schwann cells (SCs) hampers myelination. Here, we genetically disrupted key inhibitory components upstream of mTORC1, TSC1 or PTEN, in mouse SC development, adult homeostasis, and nerve injury. Surprisingly, the resulting mTORC1 hyperactivity led to markedly delayed onset of both developmental myelination and remyelination after injury. However, if mTORC1 was hyperactivated after myelination onset, radial hypermyelination was observed. At early developmental stages, physiologically high PI3K-Akt-mTORC1 signaling suppresses expression of Krox20 (Egr2), the master regulator of PNS myelination. This effect is mediated by S6K and contributes to control mechanisms that keep SCs in a not-fully differentiated state to ensure proper timing of myelination initiation. An ensuing decline in mTORC1 activity is crucial to allow myelination to start, while remaining mTORC1 activity drives myelin growth. PMID- 28880150 TI - Post-translational thioamidation of methyl-coenzyme M reductase, a key enzyme in methanogenic and methanotrophic Archaea. AB - Methyl-coenzyme M reductase (MCR), found in strictly anaerobic methanogenic and methanotrophic archaea, catalyzes the reversible production and consumption of the potent greenhouse gas methane. The alpha subunit of MCR (McrA) contains several unusual post-translational modifications, including a rare thioamidation of glycine. Based on the presumed function of homologous genes involved in the biosynthesis of thioviridamide, a thioamide-containing natural product, we hypothesized that the archaeal tfuA and ycaO genes would be responsible for post translational installation of thioglycine into McrA. Mass spectrometric characterization of McrA from the methanogenic archaeon Methanosarcina acetivorans lacking tfuA and/or ycaO revealed the presence of glycine, rather than thioglycine, supporting this hypothesis. Phenotypic characterization of the ?ycaO-tfuA mutant revealed a severe growth rate defect on substrates with low free energy yields and at elevated temperatures (39 degrees C - 45 degrees C). Our analyses support a role for thioglycine in stabilizing the protein secondary structure near the active site. PMID- 28880153 TI - Erratum to "Visually Meaningful Histopathological Features for Automatic Grading of Prostate Cancer". PMID- 28880154 TI - Micromagnetic Stimulation of the Mouse Auditory Cortex In Vivo Using an Implantable Solenoid System. AB - OBJECTIVE: Recent studies have reported that micromagnetic stimulation ( MS), which can activate neurons and neural networks via submillimeter inductors, may address several limitations of conventional magnetic stimulation methods. Previous studies have examined the effects of MS on single neurons, yet little is known about how MS can affect brain tissue including local neural networks. Here, we propose a new, readily available implantable MS system and computationally and experimentally evaluate its validity. METHODS: We conducted numerical calculations and experiments to evaluate the physical characteristics, including magnetic flux density, temperature, coil impedance, and structural integrity of the flexible board supporting the MS coils. We then compared sound- and MS-driven neural responses in the mouse auditory cortex using flavoprotein autofluorescence imaging. RESULTS: Our system successfully activated neural tissue, and we observed activity propagation in local neural networks on the brain surface beyond restricted activation of single neurons. Examining the relationships between stimulation parameters and response characteristics, we found that stimulation amplitude and pulse width were the two most important parameters to effectively induce neural activity. CONCLUSION: Our MS device has sufficient potential to drive the brain as an implantable magnetic stimulator for basic neuroscience and clinical applications, although further investigation is required. SIGNIFICANCE: MS can selectively drive and modulate activity in local neural network even at an in vivo tissue level. PMID- 28880155 TI - Identification of Ion Currents Components Generating Field Potential Recorded in MEA From hiPSC-CM. AB - OBJECTIVE: Multi electrodes arrays (MEAs) combined with cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) can enable high- or medium throughput drug screening in safety pharmacology. This technology has recently attracted a lot of attention, in particular from an international initiative named CiPA. But it is currently limited by the difficulty to analyze the measured signals. We propose a strategy to analyze the signals acquired by the MEA and to automatically deduce the channels affected by the drug. METHODS: Our method is based on the bidomain equations, a model for the MEA electrodes, and an inverse problem strategy. RESULTS: in silico MEA signals are obtained for two commercial devices and an example of early after depolarization is presented. Then, by processing real signals obtained for four different compounds, our algorithm was able to provide dose-response curves for potassium, sodium, and calcium channels. For ivabradine and moxifloxacin, the IC50 and dose-response curves are in very good agreement with known values. SIGNIFICANCE: The proposed strategy offers a possible answer to a major question raised by the community of safety pharmacology. By allowing a more automated analysis of the signals, our approach could contribute to promote the technology based on MEA and hiPSC-CMs and, therefore, improve reliability and efficiency of drug screening. PMID- 28880152 TI - An Open Benchmark Challenge for Motion Correction of Myocardial Perfusion MRI. AB - Cardiac magnetic resonance perfusion examinations enable noninvasive quantification of myocardial blood flow. However, motion between frames due to breathing must be corrected for quantitative analysis. Although several methods have been proposed, there is a lack of widely available benchmarks to compare different algorithms. We sought to compare many algorithms from several groups in an open benchmark challenge. Nine clinical studies from two different centers comprising normal and diseased myocardium at both rest and stress were made available for this study. The primary validation measure was regional myocardial blood flow based on the transfer coefficient (Ktrans), which was computed using a compartment model and the myocardial perfusion reserve (MPR) index. The ground truth was calculated using contours drawn manually on all frames by a single observer, and visually inspected by a second observer. Six groups participated and 19 different motion correction algorithms were compared. Each method used one of three different motion models: rigid, global affine, or local deformation. The similarity metric also varied with methods employing either sum-of-squared differences, mutual information, or cross correlation. There were no significant differences in Ktrans or MPR compared across different motion models or similarity metrics. Compared with the ground truth, only Ktrans for the sum-of squared differences metric, and for local deformation motion models, had significant bias. In conclusion, the open benchmark enabled evaluation of clinical perfusion indices over a wide range of methods. In particular, there was no benefit of nonrigid registration techniques over the other methods evaluated in this study. The benchmark data and results are available from the Cardiac Atlas Project ( www.cardiacatlas.org). PMID- 28880156 TI - A High-Resolution Minimicroscope System for Wireless Real-Time Monitoring. AB - OBJECTIVE: Compact, cost-effective, and high-performance microscope that enables the real-time imaging of cells and lab-on-a-chip devices is highly demanded for cell biology and biomedical engineering. This paper aims to present the design and application of an inexpensive wireless minimicroscope with resolution up to 2592 * 1944 pixels and speed up to 90 f/s. METHODS: The minimicroscope system was built on a commercial embedded system (Raspberry Pi). We modified a camera module and adopted an inverse dual lens system to obtain the clear field of view and appropriate magnification for tens of micrometer objects. RESULTS: The system was capable of capturing time-lapse images and transferring image data wirelessly. The entire system can be operated wirelessly and cordlessly in a conventional cell culturing incubator. The developed minimicroscope was used to monitor the attachment and proliferation of NIH-3T3 and HEK 293 cells inside an incubator for 50 h. In addition, the minimicroscope was used to monitor a droplet generation process in a microfluidic device. The high-quality images captured by the minimicroscope enabled us an automated analysis of experimental parameters. CONCLUSION: The successful applications prove the great potential of the developed minimicroscope for monitoring various biological samples and microfluidic devices. SIGNIFICANCE: This paper presents the design of a high resolution minimicroscope system that enables the wireless real-time imaging of cells inside the incubator. This system has been verified to be a useful tool to obtain high-quality images and videos for the automated quantitative analysis of biological samples and lab-on-a-chip devices in the long term. PMID- 28880157 TI - Hierarchical Sparse Representation for Robust Image Registration. AB - Similarity measure is an essential component in image registration. In this article, we propose a novel similarity measure for registration of two or more images. The proposed method is motivated by the fact that optimally registered images can be sparsified hierarchically in the gradient domain and frequency domain with the separation of sparse errors. One of the key advantages of the proposed similarity measure is its robustness in dealing with severe intensity distortions, which widely exist on medical images, remotely sensed images and natural photos due to differences of acquisition modalities or illumination conditions. Two efficient algorithms are proposed to solve the batch image registration and pair registration problems in a unified framework. We have validated our method on extensive and challenging data sets. The experimental results demonstrate the robustness, accuracy and efficiency of our method over nine traditional and state-of-the-art algorithms on synthetic images and a wide range of real-world applications. PMID- 28880158 TI - Highly Articulated Kinematic Structure Estimation Combining Motion and Skeleton Information. AB - In this paper, we present a novel framework for unsupervised kinematic structure learning of complex articulated objects from a single-view 2D image sequence. In contrast to prior motion-based methods, which estimate relatively simple articulations, our method can generate arbitrarily complex kinematic structures with skeletal topology via a successive iterative merging strategy. The iterative merge process is guided by a density weighted skeleton map which is generated from a novel object boundary generation method from sparse 2D feature points. Our main contributions can be summarised as follows: (i) An unsupervised complex articulated kinematic structure estimation method that combines motion segments with skeleton information. (ii) An iterative fine-to-coarse merging strategy for adaptive motion segmentation and structural topology embedding. (iii) A skeleton estimation method based on a novel silhouette boundary generation from sparse feature points using an adaptive model selection method. (iv) A new highly articulated object dataset with ground truth annotation. We have verified the effectiveness of our proposed method in terms of computational time and estimation accuracy through rigorous experiments with multiple datasets. Our experiments show that the proposed method outperforms state-of-the-art methods both quantitatively and qualitatively. PMID- 28880159 TI - Bilinear Factor Matrix Norm Minimization for Robust PCA: Algorithms and Applications. AB - The heavy-tailed distributions of corrupted outliers and singular values of all channels in low-level vision have proven effective priors for many applications such as background modeling, photometric stereo and image alignment. And they can be well modeled by a hyper-Laplacian. However, the use of such distributions generally leads to challenging non-convex, non-smooth and non-Lipschitz problems, and makes existing algorithms very slow for large-scale applications. Together with the analytic solutions to $?ell _{p}$ -norm minimization with two specific values of $p$ , i.e., $p=1/2$ and $p=2/3$ , we propose two novel bilinear factor matrix norm minimization models for robust principal component analysis. We first define the double nuclear norm and Frobenius/nuclear hybrid norm penalties, and then prove that they are in essence the Schatten- $1/2$ and $2/3$ quasi-norms, respectively, which lead to much more tractable and scalable Lipschitz optimization problems. Our experimental analysis shows that both our methods yield more accurate solutions than original Schatten quasi-norm minimization, even when the number of observations is very limited. Finally, we apply our penalties to various low-level vision problems, e.g., text removal, moving object detection, image alignment and inpainting, and show that our methods usually outperform the state-of-the-art methods. PMID- 28880161 TI - Unsupervised Segmentation of 5D Hyperpolarized Carbon-13 MRI Data Using a Fuzzy Markov Random Field Model. AB - Hyperpolarized MRI with 13C-labelled compounds is an emerging clinical technique allowing in vivo metabolic processes to be characterized non-invasively. Accurate quantification of 13C data, both for clinical and research purposes, typically relies on the use of region-of-interest analysis to detect and compare regions of altered metabolism. However, it is not clear how this should be determined from the five-dimensional data produced and most standard methodologies are unable to exploit the multidimensional nature of the data. Here we propose a solution to the novel problem of 13C image segmentation using a hybrid Markov random field model with continuous fuzzy logic. The algorithm fully utilizes the multi dimensional data format in order to classify each voxel into one of six distinct classes based on its metabolic characteristics. Bayesian priors fully incorporate spatial, temporal and ratiometric contextual information whilst image contrast from multiple spectral dimensions are considered concurrently by using an analogy from color image segmentation. Performance of the algorithm is demonstrated on in silico data, where the superiority of the approach over a reference thresholding method is consistently observed. Application to in vivo animal data from a pre clinical subcutaneous tumor model illustrates the ability of the MRF algorithm to successfully detect tumor location whilst avoiding image artifacts. This work has the potential to assist the analysis of human hyperpolarized 13C data in the future. PMID- 28880160 TI - PVR: Patch-to-Volume Reconstruction for Large Area Motion Correction of Fetal MRI. AB - In this paper, we present a novel method for the correction of motion artifacts that are present in fetal magnetic resonance imaging (MRI) scans of the whole uterus. Contrary to current slice-to-volume registration (SVR) methods, requiring an inflexible anatomical enclosure of a single investigated organ, the proposed patch-to-volume reconstruction (PVR) approach is able to reconstruct a large field of view of non-rigidly deforming structures. It relaxes rigid motion assumptions by introducing a specific amount of redundant information that is exploited with parallelized patchwise optimization, super-resolution, and automatic outlier rejection. We further describe and provide an efficient parallel implementation of PVR allowing its execution within reasonable time on commercially available graphics processing units, enabling its use in the clinical practice. We evaluate PVR's computational overhead compared with standard methods and observe improved reconstruction accuracy in the presence of affine motion artifacts compared with conventional SVR in synthetic experiments. Furthermore, we have evaluated our method qualitatively and quantitatively on real fetal MRI data subject to maternal breathing and sudden fetal movements. We evaluate peak-signal-to-noise ratio, structural similarity index, and cross correlation with respect to the originally acquired data and provide a method for visual inspection of reconstruction uncertainty. We further evaluate the distance error for selected anatomical landmarks in the fetal head, as well as calculating the mean and maximum displacements resulting from automatic non-rigid registration to a motion-free ground truth image. These experiments demonstrate a successful application of PVR motion compensation to the whole fetal body, uterus, and placenta. PMID- 28880162 TI - Radon Space Dose Optimization in Repeat CT Scanning. AB - We present a new method for on-line radiation dose optimization in repeat computer tomography (CT) scanning. Our method uses the information of the baseline scan during the repeat scanning to significantly reduce the radiation dose without compromising the repeat scan quality. It automatically registers the patient to the baseline scan using fractional scanning and detects in sinogram space the patient regions where changes have occurred without having to reconstruct the repeat scan image. It scans only these regions in the patient, thereby considerably reducing the necessary radiation dose. It then completes the missing values of the sparsely sampled repeat scan sinogram with those of the fully sampled baseline sinogram in regions where no changes were detected and computes the repeat scan image by standard filtered backprojection reconstruction. Experiments on a patient scan with simulated changes yield a mean recall of 98% using <19% of a full dose. Experiments on real CT scans of an abdomen phantom produce similar results, with a mean recall of 94.5% and only 14.4% of a full dose more than the theoretical optimum. As hardly any changed rays are missed, the reconstructed images are practically indistinguishable from a full dose scan. Our method successfully detects small, low contrast changes and produces an accurate repeat scan reconstruction using three times less radiation than an image space baseline method. PMID- 28880163 TI - Structured Sparse Principal Components Analysis With the TV-Elastic Net Penalty. AB - Principal component analysis (PCA) is an exploratory tool widely used in data analysis to uncover the dominant patterns of variability within a population. Despite its ability to represent a data set in a low-dimensional space, PCA's interpretability remains limited. Indeed, the components produced by PCA are often noisy or exhibit no visually meaningful patterns. Furthermore, the fact that the components are usually non-sparse may also impede interpretation, unless arbitrary thresholding is applied. However, in neuroimaging, it is essential to uncover clinically interpretable phenotypic markers that would account for the main variability in the brain images of a population. Recently, some alternatives to the standard PCA approach, such as sparse PCA (SPCA), have been proposed, their aim being to limit the density of the components. Nonetheless, sparsity alone does not entirely solve the interpretability problem in neuroimaging, since it may yield scattered and unstable components. We hypothesized that the incorporation of prior information regarding the structure of the data may lead to improved relevance and interpretability of brain patterns. We therefore present a simple extension of the popular PCA framework that adds structured sparsity penalties on the loading vectors in order to identify the few stable regions in the brain images that capture most of the variability. Such structured sparsity can be obtained by combining, e.g., and total variation (TV) penalties, where the TV regularization encodes information on the underlying structure of the data. This paper presents the structured SPCA (denoted SPCA-TV) optimization framework and its resolution. We demonstrate SPCA-TV's effectiveness and versatility on three different data sets. It can be applied to any kind of structured data, such as, e.g., -dimensional array images or meshes of cortical surfaces. The gains of SPCA-TV over unstructured approaches (such as SPCA and ElasticNet PCA) or structured approach (such as GraphNet PCA) are significant, since SPCA-TV reveals the variability within a data set in the form of intelligible brain patterns that are easier to interpret and more stable across different samples. PMID- 28880164 TI - Low-Dose Dynamic Cerebral Perfusion Computed Tomography Reconstruction via Kronecker-Basis-Representation Tensor Sparsity Regularization. AB - Dynamic cerebral perfusion computed tomography (DCPCT) has the ability to evaluate the hemodynamic information throughout the brain. However, due to multiple 3-D image volume acquisitions protocol, DCPCT scanning imposes high radiation dose on the patients with growing concerns. To address this issue, in this paper, based on the robust principal component analysis (RPCA, or equivalently the low-rank and sparsity decomposition) model and the DCPCT imaging procedure, we propose a new DCPCT image reconstruction algorithm to improve low dose DCPCT and perfusion maps quality via using a powerful measure, called Kronecker-basis-representation tensor sparsity regularization, for measuring low rankness extent of a tensor. For simplicity, the first proposed model is termed tensor-based RPCA (T-RPCA). Specifically, the T-RPCA model views the DCPCT sequential images as a mixture of low-rank, sparse, and noise components to describe the maximum temporal coherence of spatial structure among phases in a tensor framework intrinsically. Moreover, the low-rank component corresponds to the "background" part with spatial-temporal correlations, e.g., static anatomical contribution, which is stationary over time about structure, and the sparse component represents the time-varying component with spatial-temporal continuity, e.g., dynamic perfusion enhanced information, which is approximately sparse over time. Furthermore, an improved nonlocal patch-based T-RPCA (NL-T-RPCA) model which describes the 3-D block groups of the "background" in a tensor is also proposed. The NL-T-RPCA model utilizes the intrinsic characteristics underlying the DCPCT images, i.e., nonlocal self-similarity and global correlation. Two efficient algorithms using alternating direction method of multipliers are developed to solve the proposed T-RPCA and NL-T-RPCA models, respectively. Extensive experiments with a digital brain perfusion phantom, preclinical monkey data, and clinical patient data clearly demonstrate that the two proposed models can achieve more gains than the existing popular algorithms in terms of both quantitative and visual quality evaluations from low-dose acquisitions, especially as low as 20 mAs. PMID- 28880165 TI - Power Spectrum Computation for an Arbitrary Phase Noise Using Middleton's Convolution Series: Implementation Guideline and Experimental Illustration. AB - In this paper, we revisit the convolution series initially introduced by Middleton several decades ago to determine the power spectrum (or spectral line shape) of a periodic signal from its phase noise power spectral density. This topic is of wide interest, as it has an important impact on many scientific areas that involve lasers and oscillators. We introduce a simple guideline that enables a fairly straightforward computation of the power spectrum corresponding to an arbitrary phase noise. We show the benefit of this approach on a computational point of view, and apply it to various types of experimental signals with different phase noise levels, showing a very good agreement with the experimental spectra. This approach also provides a qualitative and intuitive understanding of the power spectrum corresponding to different regimes of phase noise. PMID- 28880167 TI - Lead-Free Piezoelectric Ceramic Coatings Fabricated by Thermal Spray Process. AB - This paper starts from a review on the progress in fabrication of piezoelectric ceramic coatings by thermal spray method. For our experimental work, two types of lead-free piezoelectric ceramic coatings, including potassium-sodium niobate based and bismuth sodium titanate-based, are fabricated by thermal spray process, and their structure, morphology, and piezoelectric properties are characterized. Our obtained lead-free ceramic coatings exhibit single phase of perovskite structure, relatively dense morphology, and competitive piezoelectric coefficients. The mechanism of forming the piezoelectric perovskite crystalline phase by thermal spray involving melting-recrystallization process is analyzed in comparison to that of ceramic synthesis through solid-state reaction. Suppression of volatile loss and decomposition at high temperature due to the extremely high melting and cooling rate in the thermal spray process, and the impact on the resulting structure are discussed. Significant advantages of the thermal spray method over alternative processing methods for forming piezoelectric ceramic coatings are summarized. The combination of environmentally friendly lead-free compositions and the scalable thermal spray processing method will promote more applications of piezoelectric ceramic coatings for producing distributive sensors and transducers, and forming advanced smart structures and systems. PMID- 28880168 TI - A New Dynamic Complex Baseband Pulse Compression Method for Chirp-Coded Excitation in Medical Ultrasound Imaging. AB - Chirp-coded excitation can increase the signal-to-noise ratio (SNR) without degrading the axial resolution. Effective pulse compression (PC) is important to maintain the axial resolution and can be achieved with radio frequency (RF) and complex baseband (CBB) data (i.e., and , respectively). can further reduce the computational complexity compared to ; however, suffers from a degraded SNR due to tissue attenuation. In this paper, we propose a new dynamic CBB PC method ( that can improve the SNR while compensating for tissue attenuation. The compression filter coefficients in the method are generated by dynamically changing the demodulation frequencies along with the depth. For PC, the obtained coefficients are independently applied to the in-phase and quadrature components of the CBB data. To evaluate the performance of the proposed method, simulation, phantom, and in vivo studies were conducted, and all three studies showed improved SNR, i.e., maximally 3.87, 7.41, and 5.75 dB, respectively. In addition, the measured peak range sidelobe level of the proposed method yielded lower values than the and , and it also derived a suitable target location, i.e., a <0.07-mm target location error, while maintaining the axial resolution. In an in vivo abdominal experiment, the method depicted brighter and clearer features in the hyperechoic region because highly correlated signals were produced by compensating for tissue attenuation. These results demonstrated that the proposed method can improve the SNR of chirp-coded excitation while preserving the axial resolution and the target location and reducing the computational complexity. PMID- 28880166 TI - Catheter Hydrophone Aberration Correction for Transcranial Histotripsy Treatment of Intracerebral Hemorrhage: Proof-of-Concept. AB - Histotripsy is a minimally invasive ultrasound therapy that has shown rapid liquefaction of blood clots through human skullcaps in an in vitro intracerebral hemorrhage model. However, the efficiency of these treatments can be compromised if the skull-induced aberrations are uncorrected. We have developed a catheter hydrophone which can perform aberration correction (AC) and drain the liquefied clot following histotripsy treatment. Histotripsy pulses were delivered through an excised human skullcap using a 256-element, 500-kHz hemisphere array transducer with a 15-cm focal distance. A custom hydrophone was fabricated using a mm PZT-5h crystal interfaced to a coaxial cable and integrated into a drainage catheter. An AC algorithm was developed to correct the aberrations introduced between histotripsy pulses from each array element. An increase in focal pressure of up to 60% was achieved at the geometric focus and 27%-62% across a range of electronic steering locations. The sagittal and axial -6-dB beam widths decreased from 4.6 to 2.2 mm in the sagittal direction and 8 to 4.4 mm in the axial direction, compared to 1.5 and 3 mm in the absence of aberration. After performing AC, lesions with diameters ranging from 0.24 to 1.35 mm were generated using electronic steering over a mm grid in a tissue-mimicking phantom. An average volume of 4.07 +/- 0.91 mL was liquefied and drained after using electronic steering to treat a 4.2-mL spherical volume in in vitro bovine clots through the skullcap. PMID- 28880169 TI - Noise Equalization for Ultrafast Plane Wave Microvessel Imaging. AB - Ultrafast plane wave microvessel imaging significantly improves ultrasound Doppler sensitivity by increasing the number of Doppler ensembles that can be collected within a short period of time. The rich spatiotemporal plane wave data also enable more robust clutter filtering based on singular value decomposition. However, due to the lack of transmit focusing, plane wave microvessel imaging is very susceptible to noise. This paper was designed to: 1) study the relationship between ultrasound system noise (primarily time gain compensation induced) and microvessel blood flow signal and 2) propose an adaptive and computationally cost effective noise equalization method that is independent of hardware or software imaging settings to improve microvessel image quality. PMID- 28880170 TI - Rapid Spatial Mapping of Focused Ultrasound Fields Using a Planar Fabry-Perot Sensor. AB - Measurement of high acoustic pressures is necessary in order to fully characterize clinical high-intensity focused ultrasound (HIFU) fields, and for accurate validation of computational models of ultrasound propagation. However, many existing measurement devices are unable to withstand the extreme pressures generated in these fields, and those that can often exhibit low sensitivity. Here, a planar Fabry-Perot interferometer with hard dielectric mirrors and spacer was designed, fabricated, and characterized, and its suitability for measurement of nonlinear focused ultrasound fields was investigated. The noise equivalent pressure (NEP) of the scanning system scaled with the adjustable pressure detection range between 49 kPa for pressures up to 8 MPa and 152 kPa for measurements up to 25 MPa, over a 125 MHz measurement bandwidth. Measurements of the frequency response of the sensor showed that it varied by less than 3 dB in the range 1-62 MHz. The effective element size of the sensor was 65 and waveforms were acquired at a rate of 200 Hz. The device was used to measure the acoustic pressure in the field of a 1.1 MHz single-element spherically focused bowl transducer. Measurements of the acoustic field at low pressures compared well with measurements made using a Polyvinylidene difluoride needle hydrophone. At high pressures, the measured peak focal pressures agreed well with the focal pressure modeled using the Khokhlov-Zabolotskaya-Kuznetsov equation. Maximum peak positive pressures of 25 MPa and peak negative pressures of 12 MPa were measured, and planar field scans were acquired in scan times on the order of 1 min. The properties of the sensor and scanning system are well suited to measurement of nonlinear focused ultrasound fields, in both the focal region and the low pressure peripheral regions. The fast acquisition speed of the system and its low NEP are advantageous, and with further development of the sensor, it has potential in application to HIFU metrology. PMID- 28880171 TI - Q-Factor Spectrum of a Piezoceramic Resonator and Method for Piezoelectric Loss Factor Determination. AB - The quality factor (Q) spectrum of a piezoceramic resonator, as a Q-factor frequency dependence for the specific resonator and its vibrational modes, was determined under baseline low-excitation level with a new approach proposed. The theoretical prediction was experimentally confirmed that the resonator Q-factor increases with frequency nearly linearly from the resonance reaching its maximum near the antiresonance. For the industrial PZT-5A piezoceramic the antiresonance to-resonance quality factor ratio is 1.8 to 2.4 as much, depending on the type of vibration. As the theory states, this effect is directly related to the piezoelectric "losses" in piezoceramics, usually represented by the imaginary part of complex piezocoefficients, which have a unique property of lowering the total cumulative energy dissipation in a resonator in certain frequency intervals. Based on the electromechanical Q-factor (EMQ) concept, a new relatively simple method was proposed for the piezoelectric loss factor determination at just a single resonance frequency-it requires measurements of the resonance Q-factor and its frequency derivative at the resonance, or the first and second frequency derivatives of the immittance phase at the resonance. Experimentally determined is close to near 0.8 of its upper (positive) phenomenological limit in the conventional PZT-5A piezoceramic at the basic vibrational modes. The piezoelectric loss factor, theoretically reaching the upper limit, can provide extremely high value of the Q-factor (near the fundamental antiresonance) with possible an order of magnitude EMQ increase. That paradoxical fact for the piezoelectric "losses" is a novel possible way of improving the piezoceramic performance and operation. PMID- 28880172 TI - Spectrum Compensation for Time-Reversal Method on Ultrasonic Target Detection Using Pulse Compression. AB - This paper discusses a method of time reversal (TR) for target detection using a signal with a higher signal-to-noise ratio (SNR) and higher resolution. To acquire a signal with a higher SNR and broader spectrum, we have proposed a sensitivity-compensated (SC) signal. In this paper, we propose three types of SC for-TR signals. An SC-amplitude-modulated (AM)-for-TR signal and an SC-frequency modulated (FM)-for-TR signal are calculated using squared spectrum compensation. Moreover, to enhance the transmitting energy of a time-reversed wave for a higher SNR, we propose an SC-amplitude-and-frequency-modulated-for-TR (SCAFM-for-TR) signal. The SCAFM-for-TR signal is calculated by AM and FM for deriving a TR wave with a constant envelope waveform and compensated spectrum. In this paper, the efficiency of the SC-for-TR signals is investigated on target ranging in water using pulse compression. Accordingly, the SC-for-TR signals derive a pulse compressed signal with a higher resolution. In addition, the precision of target ranging using the SCAFM-for-TR signal is greater than that using the other SC-for TR signals at an arrangement when a target was fixed at a position where a signal with a lower SNR is received. These results show that the measurements using the SC-for-TR signals improve time resolution and the SNR. PMID- 28880173 TI - Reflection Removal Under Fast Forward Camera Motion. AB - The image quality of an in-vehicle black box camera is often degraded by the reflections of internal objects, dirt, and dust on the windshield. In this paper, we propose a novel algorithm that simultaneously removes the reflections and small dirt artifacts from in-vehicle black box videos under fast forward camera motion. The algorithm exploits the spatiotemporal coherence of the reflection and dirt, which remain stationary relative to the fast-moving background. Unlike previous algorithms, the algorithm first separates stationary reflection and then restores the background scene. To this end, we propose an average image prior, thereby imposing spatiotemporal coherence. The separation model is a two-layer model composed of stationary and background layers, where different gradient sparsity distributions are utilized in a region-based manner. Motion compensation in postprocessing is proposed to alleviate layer jitter due to vehicle vibrations. In evaluation experiments, the proposed algorithm successfully extracts the stationary layer from several real and synthetic black box videos. PMID- 28880174 TI - Learning the Distribution Preserving Semantic Subspace for Clustering. AB - This paper proposes a new clustering method for images called distribution preserving indexing (DPI). It aims to find a lower dimensional semantic space approximating the original image space in the sense of preserving the distribution of the data. In the theory, the intrinsic structure of the data clusters can be described by the distribution of the data effectively. Therefore, the cluster structure of the data in a lower dimensional semantic space derived by the DPI becomes clear. Unlike these distance-based clustering methods, which reveal the intrinsic Euclidean structure of data, our method attempts to discover the intrinsic cluster structure of the data space that actually is the union of some sub-manifolds. Moreover, we propose a revised kernel density estimator for the case of high-dimensional data, which is a crucial step in DPI. In addition, we provide a theoretical analysis of the bound of our method. Finally, the extensive experiments compared with other algorithms, on COIL20, CBCL, and MNIST demonstrate the effectiveness of our proposed approach. PMID- 28880175 TI - Hyper-Lapse From Multiple Spatially-Overlapping Videos. AB - Hyper-lapse video with high speed-up rate is an efficient way to overview long videos, such as a human activity in first-person view. Existing hyper-lapse video creation methods produce a fast-forward video effect using only one video source. In this paper, we present a novel hyper-lapse video creation approach based on multiple spatially-overlapping videos. We assume the videos share a common view or location, and find transition points where jumps from one video to another may occur. We represent the collection of videos using a hyper-lapse transition graph; the edges between nodes represent possible hyper-lapse frame transitions. To create a hyper-lapse video, a shortest path search is performed on this digraph to optimize frame sampling and assembly simultaneously. Finally, we render the hyper-lapse results using video stabilization and appearance smoothing techniques on the selected frames. Our technique can synthesize novel virtual hyper-lapse routes, which may not exist originally. We show various application results on both indoor and outdoor video collections with static scenes, moving objects, and crowds. PMID- 28880176 TI - Spectral-Spatial Scale Invariant Feature Transform for Hyperspectral Images. AB - Spectral-spatial feature extraction is an important task in hyperspectral image processing. In this paper we propose a novel method to extract distinctive invariant features from hyperspectral images for registration of hyperspectral images with different spectral conditions. Spectral condition means images are captured with different incident lights, viewing angles, or using different hyperspectral cameras. In addition, spectral condition includes images of objects with the same shape but different materials. This method, which is named spectral spatial scale invariant feature transform (SS-SIFT), explores both spectral and spatial dimensions simultaneously to extract spectral and geometric transformation invariant features. Similar to the classic SIFT algorithm, SS-SIFT consists of keypoint detection and descriptor construction steps. Keypoints are extracted from spectral-spatial scale space and are detected from extrema after 3D difference of Gaussian is applied to the data cube. Two descriptors are proposed for each keypoint by exploring the distribution of spectral-spatial gradient magnitude in its local 3D neighborhood. The effectiveness of the SS-SIFT approach is validated on images collected in different light conditions, different geometric projections, and using two hyperspectral cameras with different spectral wavelength ranges and resolutions. The experimental results show that our method generates robust invariant features for spectral-spatial image matching. PMID- 28880178 TI - Adaptive Chroma Subsampling-Binding and Luma-Guided Chroma Reconstruction Method for Screen Content Images. AB - In this paper, we propose a novel adaptive chroma subsampling-binding and luma guided (ASBLG) chroma reconstruction method for screen content images (SCIs). After receiving the decoded luma and subsampled chroma image from the decoder, a fast winner-first voting strategy is proposed to identify the used chroma subsampling scheme prior to compression. Then, the decoded luma image is subsampled as the identified subsampling scheme was performed on the chroma image such that we are able to conclude an accurate correlation between the subsampled decoded luma image and the decoded subsampled chroma image. Accordingly, an adaptive sliding window-based and luma-guided chroma reconstruction method is proposed. The related computational complexity analysis is also provided. We take two quality metrics, the color peak signal-to-noise ratio (CPSNR) of the reconstructed chroma images and SCIs and the gradient-based structure similarity index (CGSS) of the reconstructed SCIs to evaluate the quality performance. Let the proposed chroma reconstruction method be denoted as 'ASBLG'. Based on 26 typical test SCIs and 6 JCT-VC test screen content video sequences (SCVs), several experiments show that on average, the CPSNR gains of all the reconstructed UV images by 4:2:0(A)-ASBLG, SCIs by 4:2:0(MPEG-B)-ASBLG, and SCVs by 4:2:0(A)-ASBLG are 2.1, 1.87, and 1.87 dB, respectively, when compared with that of the other combinations. Specifically, in terms of CPSNR and CGSS, CSBILINEAR-ASBLG for the test SCIs and CSBICUBIC-ASBLG for the test SCVs outperform the existing state-of-the-art comparative combinations, where CSBILINEAR and CSBICUBIC denote the luma-aware based chroma subsampling schemes by Wang et al. PMID- 28880177 TI - Hashing with Angular Reconstructive Embeddings. AB - Large-scale search methods are increasingly critical for many content-based visual analysis applications, among which hashing-based approximate nearest neighbor search techniques have attracted broad interests due to their high efficiency in storage and retrieval. However, existing hashing works are commonly designed for measuring data similarity by the Euclidean distances. In this paper, we focus on the problem of learning compact binary codes using the cosine similarity. Specifically, we proposed novel angular reconstructive embeddings (ARE) method, which aims at learning binary codes by minimizing the reconstruction error between the cosine similarities computed by original features and the resulting binary embeddings. Furthermore, we devise two efficient algorithms for optimizing our ARE in continuous and discrete manners, respectively. We extensively evaluate the proposed ARE on several large-scale image benchmarks. The results demonstrate that ARE outperforms several state-of the-art methods. PMID- 28880179 TI - Bridging from Goals to Tasks with Design Study Analysis Reports. AB - Visualization researchers and practitioners engaged in generating or evaluating designs are faced with the difficult problem of transforming the questions asked and actions taken by target users from domain-specific language and context into more abstract forms. Existing abstract task classifications aim to provide support for this endeavour by providing a carefully delineated suite of actions. Our experience is that this bottom-up approach is part of the challenge: low level actions are difficult to interpret without a higher-level context of analysis goals and the analysis process. To bridge this gap, we propose a framework based on analysis reports derived from open-coding 20 design study papers published at IEEE InfoVis 2009-2015, to build on the previous work of abstractions that collectively encompass a broad variety of domains. The framework is organized in two axes illustrated by nine analysis goals. It helps situate the analysis goals by placing each goal under axes of specificity (Explore, Describe, Explain, Confirm) and number of data populations (Single, Multiple). The single-population types are Discover Observation, Describe Observation, Identify Main Cause, and Collect Evidence. The multiple-population types are Compare Entities, Explain Differences, and Evaluate Hypothesis. Each analysis goal is scoped by an input and an output and is characterized by analysis steps reported in the design study papers. We provide examples of how we and others have used the framework in a top-down approach to abstracting domain problems: visualization designers or researchers first identify the analysis goals of each unit of analysis in an analysis stream, and then encode the individual steps using existing task classifications with the context of the goal, the level of specificity, and the number of populations involved in the analysis. PMID- 28880180 TI - ConceptVector: Text Visual Analytics via Interactive Lexicon Building Using Word Embedding. AB - Central to many text analysis methods is the notion of a concept: a set of semantically related keywords characterizing a specific object, phenomenon, or theme. Advances in word embedding allow building a concept from a small set of seed terms. However, naive application of such techniques may result in false positive errors because of the polysemy of natural language. To mitigate this problem, we present a visual analytics system called ConceptVector that guides a user in building such concepts and then using them to analyze documents. Document analysis case studies with real-world datasets demonstrate the fine-grained analysis provided by ConceptVector. To support the elaborate modeling of concepts, we introduce a bipolar concept model and support for specifying irrelevant words. We validate the interactive lexicon building interface by a user study and expert reviews. Quantitative evaluation shows that the bipolar lexicon generated with our methods is comparable to human-generated ones. PMID- 28880181 TI - EVA: Visual Analytics to Identify Fraudulent Events. AB - Financial institutions are interested in ensuring security and quality for their customers. Banks, for instance, need to identify and stop harmful transactions in a timely manner. In order to detect fraudulent operations, data mining techniques and customer profile analysis are commonly used. However, these approaches are not supported by Visual Analytics techniques yet. Visual Analytics techniques have potential to considerably enhance the knowledge discovery process and increase the detection and prediction accuracy of financial fraud detection systems. Thus, we propose EVA, a Visual Analytics approach for supporting fraud investigation, fine-tuning fraud detection algorithms, and thus, reducing false positive alarms. PMID- 28880182 TI - Pondering the Concept of Abstraction in (Illustrative) Visualization. AB - We explore the concept of abstraction as it is used in visualization, with the ultimate goal of understanding and formally defining it. Researchers so far have used the concept of abstraction largely by intuition without a precise meaning. This lack of specificity left questions on the characteristics of abstraction, its variants, its control, or its ultimate potential for visualization and, in particular, illustrative visualization mostly unanswered. In this paper we thus provide a first formalization of the abstraction concept and discuss how this formalization affects the application of abstraction in a variety of visualization scenarios. Based on this discussion, we derive a number of open questions still waiting to be answered, thus formulating a research agenda for the use of abstraction for the visual representation and exploration of data. This paper, therefore, is intended to provide a contribution to the discussion of the theoretical foundations of our field, rather than attempting to provide a completed and final theory. PMID- 28880183 TI - Gaussian Process Autoregression for Simultaneous Proportional Multi-Modal Prosthetic Control With Natural Hand Kinematics. AB - Matching the dexterity, versatility, and robustness of the human hand is still an unachieved goal in bionics, robotics, and neural engineering. A major limitation for hand prosthetics lies in the challenges of reliably decoding user intention from muscle signals when controlling complex robotic hands. Most of the commercially available prosthetic hands use muscle-related signals to decode a finite number of predefined motions and some offer proportional control of open/close movements of the whole hand. Here, in contrast, we aim to offer users flexible control of individual joints of their artificial hand. We propose a novel framework for decoding neural information that enables a user to independently control 11 joints of the hand in a continuous manner-much like we control our natural hands. Toward this end, we instructed six able-bodied subjects to perform everyday object manipulation tasks combining both dynamic, free movements (e.g., grasping) and isometric force tasks (e.g., squeezing). We recorded the electromyographic and mechanomyographic activities of five extrinsic muscles of the hand in the forearm, while simultaneously monitoring 11 joints of hand and fingers using a sensorized data glove that tracked the joints of the hand. Instead of learning just a direct mapping from current muscle activity to intended hand movement, we formulated a novel autoregressive approach that combines the context of previous hand movements with instantaneous muscle activity to predict future hand movements. Specifically, we evaluated a linear vector autoregressive moving average model with exogenous inputs and a novel Gaussian process ( ) autoregressive framework to learn the continuous mapping from hand joint dynamics and muscle activity to decode intended hand movement. Our approach achieves high levels of performance (RMSE of 8 degrees /s and ). Crucially, we use a small set of sensors that allows us to control a larger set of independently actuated degrees of freedom of a hand. This novel undersensored control is enabled through the combination of nonlinear autoregressive continuous mapping between muscle activity and joint angles. The system evaluates the muscle signals in the context of previous natural hand movements. This enables us to resolve ambiguities in situations, where muscle signals alone cannot determine the correct action as we evaluate the muscle signals in their context of natural hand movements. autoregression is a particularly powerful approach which makes not only a prediction based on the context but also represents the associated uncertainty of its predictions, thus enabling the novel notion of risk-based control in neuroprosthetics. Our results suggest that autoregressive approaches with exogenous inputs lend themselves for natural, intuitive, and continuous control in neurotechnology, with the particular focus on prosthetic restoration of natural limb function, where high dexterity is required for complex movements. PMID- 28880184 TI - Seizure Classification From EEG Signals Using Transfer Learning, Semi-Supervised Learning and TSK Fuzzy System. AB - Recognition of epileptic seizures from offline EEG signals is very important in clinical diagnosis of epilepsy. Compared with manual labeling of EEG signals by doctors, machine learning approaches can be faster and more consistent. However, the classification accuracy is usually not satisfactory for two main reasons: the distributions of the data used for training and testing may be different, and the amount of training data may not be enough. In addition, most machine learning approaches generate black-box models that are difficult to interpret. In this paper, we integrate transductive transfer learning, semi-supervised learning and TSK fuzzy system to tackle these three problems. More specifically, we use transfer learning to reduce the discrepancy in data distribution between the training and testing data, employ semi-supervised learning to use the unlabeled testing data to remedy the shortage of training data, and adopt TSK fuzzy system to increase model interpretability. Two learning algorithms are proposed to train the system. Our experimental results show that the proposed approaches can achieve better performance than many state-of-the-art seizure classification algorithms. PMID- 28880185 TI - 3-D Object Recognition of a Robotic Navigation Aid for the Visually Impaired. AB - This paper presents a 3-D object recognition method and its implementation on a robotic navigation aid to allow real-time detection of indoor structural objects for the navigation of a blind person. The method segments a point cloud into numerous planar patches and extracts their inter-plane relationships (IPRs).Based on the existing IPRs of the object models, the method defines six high level features (HLFs) and determines the HLFs for each patch. A Gaussian-mixture-model based plane classifier is then devised to classify each planar patch into one belonging to a particular object model. Finally, a recursive plane clustering procedure is used to cluster the classified planes into the model objects. As the proposed method uses geometric context to detect an object, it is robust to the object's visual appearance change. As a result, it is ideal for detecting structural objects (e.g., stairways, doorways, and so on). In addition, it has high scalability and parallelism. The method is also capable of detecting some indoor non-structural objects. Experimental results demonstrate that the proposed method has a high success rate in object recognition. PMID- 28880186 TI - Cooperative Raman Spectroscopy for Real-Time In Vivo Nano-Biosensing. AB - In the last few decades, the development of miniature biological sensors that can detect and measure different phenomena at the nanoscale has led to transformative disease diagnosis and treatment techniques. Among others, biofunctional Raman nanoparticles have been utilized in vitro and in vivo for multiplexed diagnosis and detection of different biological agents. However, existing solutions require the use of bulky lasers to excite the nanoparticles and similarly bulky and expensive spectrometers to measure the scattered Raman signals, which limit the practicality and applications of this nano-biosensing technique. In addition, due to the high path loss of the intra-body environment, the received signals are usually very weak, which hampers the accuracy of the measurements. In this paper, the concept of cooperative Raman spectrum reconstruction for real-time in vivo nano-biosensing is presented for the first time. The fundamental idea is to replace the single excitation and measurement points (i.e., the laser and the spectrometer, respectively) by a network of interconnected nano-devices that can simultaneously excite and measure nano-biosensing particles. More specifically, in the proposed system, a large number of nanosensors jointly and distributively collect the Raman response of nano-biofunctional nanoparticles (NBPs) travelling through the blood vessels. This paper presents a detailed description of the sensing system and, more importantly, proves its feasibility, by utilizing the accurate models of optical signal propagation in intra-body environment and low complexity estimation algorithms. The numerical results show that with a certain density of NBPs, the reconstructed Raman spectrum can be recovered and utilized to accurately extract the targeting intra-body information. PMID- 28880188 TI - A Review of Safety and Hazards Associated With the Artificial Pancreas. AB - The artificial pancreas (AP) is a closed-loop device with the potential to reduce the complications associated with type 1 diabetes mellitus by maintaining euglycemia in patients. The AP encompasses an algorithm that determines the amount of insulin (and other hormones) to be administered to the patient via a continuous subcutaneous insulin infusion pump using information provided by a continuous glucose monitor and other sensors. As the AP approaches commercialization, special attention must be given to safety within all the individual components, including physiological changes in the patient, as well as safety issues that can arise when these components are combined into a single system. Therefore, we analyzed the specific hazards applicable to the AP with the aim of exposing areas of safety that are yet to be addressed. PMID- 28880187 TI - Integrating Imaging Genomic Data in the Quest for Biomarkers of Schizophrenia Disease. AB - It's increasingly important but difficult to determine potential biomarkers of schizophrenia (SCZ) disease, owing to the complex pathophysiology of this disease. In this study, a network-fusion based framework was proposed to identify genetic biomarkers of the SCZ disease. A three-step feature selection was applied to single nucleotide polymorphisms (SNPs), DNA methylation, and functional magnetic resonance imaging (fMRI) data to select important features, which were then used to construct two gene networks in different states for the SNPs and DNA methylation data, respectively. Two health networks (one is for SNP data and the other is for DNA methylation data) were combined into one health network from which health minimum spanning trees (MSTs) were extracted. Two disease networks also followed the same procedures. Those genes with significant changes were determined as SCZ biomarkers by comparing MSTs in two different states and they were finally validated from five aspects. The effectiveness of the proposed discovery framework was also demonstrated by comparing with other network-based discovery methods. In summary, our approach provides a general framework for discovering gene biomarkers of the complex diseases by integrating imaging genomic data, which can be applied to the diagnosis of the complex diseases in the future. PMID- 28880190 TI - Learning Semantic-Aligned Action Representation. AB - A fundamental bottleneck for achieving highly discriminative action representation is that local motion/appearance features are usually not semantic aligned. Namely, a local feature, such as a motion vector or motion trajectory, does not possess any attribute that indicates which moving body part or operated object it is associated with. This mostly leads to global feature pooling/representation learning methods that are often too coarse. Inspired by the recent success of end-to-end (pixel-to-pixel) deep convolutional neural networks (DCNNs), in this paper, we first propose a DCNN architecture, which maps a human centric image region onto human body part response maps. Based on these response maps, we propose a second DCNN, which achieves semantic-aligned feature representation learning. Prior knowledge that only a few parts are responsible for a certain action is also utilized by introducing a group (part) sparseness prior during feature learning. The learned semantic-aligned feature not only boosts the discriminative capability of action representation, but also possesses the good nature of robustness to pose variations and occlusions. Finally, an iterative mining method is employed for learning discriminative action primitive detectors. Extensive experiments on action recognition benchmarks demonstrate a superior recognition performance of the proposed framework. PMID- 28880189 TI - Event-Triggered State Estimation for Delayed Stochastic Memristive Neural Networks With Missing Measurements: The Discrete Time Case. AB - In this paper, the event-triggered state estimation problem is investigated for a class of discrete-time stochastic memristive neural networks (DSMNNs) with time varying delays and missing measurements. The DSMNN is subject to both the additive deterministic disturbances and the multiplicative stochastic noises. The missing measurements are governed by a sequence of random variables obeying the Bernoulli distribution. For the purpose of energy saving, an event-triggered communication scheme is used for DSMNNs to determine whether the measurement output is transmitted to the estimator or not. The problem addressed is to design an event-triggered estimator such that the dynamics of the estimation error is exponentially mean-square stable and the prespecified disturbance rejection attenuation level is also guaranteed. By utilizing a Lyapunov-Krasovskii functional and stochastic analysis techniques, sufficient conditions are derived to guarantee the existence of the desired estimator, and then, the estimator gains are characterized in terms of the solution to certain matrix inequalities. Finally, a numerical example is used to demonstrate the usefulness of the proposed event-triggered state estimation scheme. PMID- 28880191 TI - Exploiting Spatio-Temporal Structure With Recurrent Winner-Take-All Networks. AB - We propose a convolutional recurrent neural network (ConvRNNs), with winner-take all (WTA) dropout for high-dimensional unsupervised feature learning in multidimensional time series. We apply the proposed method for object recognition using temporal context in videos and obtain better results than comparable methods in the literature, including the deep predictive coding networks (DPCNs) previously proposed by Chalasani and Principe. Our contributions can be summarized as a scalable reinterpretation of the DPCNs trained end-to-end with backpropagation through time, an extension of the previously proposed WTA autoencoders to sequences in time, and a new technique for initializing and regularizing ConvRNNs. PMID- 28880192 TI - Global Exponential Stability of Impulsive Fuzzy High-Order BAM Neural Networks With Continuously Distributed Delays. AB - This paper investigates the stability of equilibrium point and periodic solution for impulsive fuzzy high-order bidirectional associative memory neural networks with continuously distributed delays. By applying the inequality analysis technique, -matrix, and Banach contraction mapping principle and constructing some suitable Lyapunov functionals, some sufficient conditions for the uniqueness and global exponential stability of equilibrium point and global exponential stability of periodic solutions are established. In addition, three examples with numerical simulations are presented to demonstrate the feasibility and effectiveness of the theoretical results. PMID- 28880193 TI - Beyond Pairwise Matching: Person Reidentification via High-Order Relevance Learning. AB - Person reidentification has attracted extensive research efforts in recent years. It is challenging due to the varied visual appearance from illumination, view angle, background, and possible occlusions, leading to the difficulties when measuring the relevance, i.e., similarities, between probe and gallery images. Existing methods mainly focus on pairwise distance metric learning for person reidentification. In practice, pairwise image matching may limit the data for comparison (just the probe and one gallery subject) and yet lead to suboptimal results. The correlation among gallery data can be also helpful for the person reidentification task. In this paper, we propose to investigate the high-order correlation among the probe and gallery data, not the pairwise matching, to jointly learn the relevance of gallery data to the probe. Recalling recent progresses on feature representation in person reidentification, it is difficult to select the best feature and each type of feature can benefit person description from different aspects. Under such circumstances, we propose a multihypergraph joint learning algorithm to learn the relevance in corporation with multiple features of the imaging data. More specifically, one hypergraph is constructed using one type of feature and multiple hypergraphs can be generated accordingly. Then, the learning process is conducted on the multihypergraph structure, and the identity of a probe is determined by its relevance to each gallery data. The merit of the proposed scheme is twofold. First, different from pairwise image matching, the proposed method jointly explores the relationships among different images. Second, multimodal data, i.e., different features, can be formulated in the multihypergraph structure, which can convey more information in the learning process and can be easily extended. We note that the proposed method is a general framework to incorporate with any combination of features, and thus is flexible in practice. Experimental results and comparisons with the state-of the-art methods on three public benchmarking data sets demonstrate the superiority of the proposed method. PMID- 28880194 TI - Stability and Guaranteed Cost Analysis of Time-Triggered Boolean Networks. AB - This paper investigates stability and guaranteed cost of time-triggered Boolean networks (BNs) based on the semitensor product of matrices. The time triggering is generated by mode-dependent average dwell-time switching signals in the BNs. With the help of the copositive Lyapunov function, a sufficient condition is derived to ensure that the considered network is globally stable under a designed average dwell-time switching signal. Subsequently, an infinite time cost function is further discussed and its bound is presented according to the obtained stability result. Numerical examples are finally given to show the feasibility of the theoretical results. PMID- 28880195 TI - LANN-SVD: A Non-Iterative SVD-Based Learning Algorithm for One-Layer Neural Networks. AB - In the scope of data analytics, the volume of a data set can be defined as a product of instance size and dimensionality of the data. In many real problems, data sets are mainly large only on one of these aspects. Machine learning methods proposed in the literature are able to efficiently learn in only one of these two situations, when the number of variables is much greater than instances or vice versa. However, there is no proposal allowing to efficiently handle either circumstances in a large-scale scenario. In this brief, we present an approach to integrally address both situations, large dimensionality or large instance size, by using a singular value decomposition (SVD) within a learning algorithm for one layer feedforward neural network. As a result, a noniterative solution is obtained, where the weights can be calculated in a closed-form manner, thereby avoiding low convergence rate and also hyperparameter tuning. The proposed learning method, LANN-SVD in short, presents a good computational efficiency for large-scale data analytic. Comprehensive comparisons were conducted to assess LANN-SVD against other state-of-the-art algorithms. The results of this brief exhibited the superior efficiency of the proposed method in any circumstance. PMID- 28880196 TI - Estimation of Pulse Transit Time From Radial Pressure Waveform Alone by Artificial Neural Network. AB - OBJECTIVE: To validate the feasibility of the estimation of pulse transit time (PTT) by artificial neural network (ANN) from radial pressure waveform alone. METHODS: A cascade ANN with ten-fold cross validation was applied to invasively and simultaneously recorded aortic and radial pressure waveforms during rest and nitroglycerin infusion () for the estimation of mean and beat-to-beat PTT. The results of the ANN models were compared to a multiple linear regression (LR) model when the features of radial arterial pressure waveform in time and frequency domains were used as the predictors of the models. RESULTS: For the estimation of mean PTT and beat-to-beat PTT by ANN ( ), the correlation coefficient between the and the measured PTT () (mean: ; beat-to-beat: ) is higher than that between the PTT estimated by LR ( ) and (mean: ; beat-to-beat: ). The standard deviation (SD) of the difference between the and ( ; beat-to beat: ) is significantly less than that between the and (; beat-to-beat: 10 ms), but no significant difference exists between their mean ( ). The lack of frequency features of radial pressure waveform caused obvious reduction in the correlation coefficient and SD of the difference between the and . The performance of the ANN was improved by increasing the sample number but not by increasing the neuron number. CONCLUSION: ANN is a potential method of PTT estimation from a single pressure measurement at radial artery. PMID- 28880197 TI - Short Course of Postoperative Hepatitis B Immunoglobulin Plus Antivirals Prevents Reinfection of Liver Transplant Recipients. AB - BACKGROUND: Hepatitis B immune globulin (HBIG) has been an integral component of prophylaxis against hepatitis B virus (HBV) recurrence in liver transplantation (LT) recipients, but HBIG is costly and inconvenient to administer, prompting consideration of alternative regimens. METHODS: In this retrospective cohort, we report on the success of antiviral therapy combined with a short course (in hospital only) HBIG in liver transplant recipients with HBV DNA less than 100 IU/mL pre-LT. RESULTS: A total of 42 hepatitis B surface antigen (HBsAg) positive, human immunodeficiency virus and hepatitis D virus-negative patients with pretransplant HBV DNA undetectable to 100 IU/mL who received HBIG 5000 IU in anhepatic phase and daily for 5 days together with nucleos(t)ide analogues indefinitely yielded 1- and 3-year cumulative incidences of recurrence, defined by positive serum HBsAg, of 2.9% (upper 95% confidence interval, 19%). One patient had HBV viremia 16 months post-LT without detectable HBsAg. Both patients with either HBsAg positivity or viremia had recurrent hepatocellular carcinoma diagnosed within a month of detection. Post-LT survival was 98% and 94% at 1 and 5 years, respectively. CONCLUSIONS: We conclude that a very short course of HBIG combined with long-term antiviral therapy is highly effective in preventing HBV recurrence and should be the preferred strategy for LT recipients with undetectable or low-level viremia at time of LT. PMID- 28880198 TI - Aptamer-Based Single-Step Assay by the Fluorescence Enhancement on Electroless Plated Nano Au Substrate. AB - A new single-step aptamer-based surface-enhanced fluorescent optical sensor is built, by combining an aptamer-target interaction for target recognition and a fluorophore interaction for signal enhancement. The developed aptasensor is simple, sensitive, specific and stable for the detection of thrombin. A new nanometallic Au structure in the range of 100 nm was constructed through effective electroless plating method on a Cu thin film. Cu+ ions act as sacrificial seeds for the reduction of Au2+/3+ ions to form Au nanolawns. In order to utilize the structure for a fluorescence-based sensor, aptamer conjugated with Cy3 was immobilized on the nanogold substrate through electrostatic attraction. The Au substrate was coated with chitosan (molecular weight 1000 Da). Thrombin binding aptamer (TBA) was applied as a model system demonstrating the aptamer-based fluorescence assay on nanogold substrates. Thrice enhanced fluorescence emission was achieved with Cy3-conjugated TBA stably immobilized on the chitosan-coated Au substrate. The intensity change was proportional to the concentration of thrombin from 10 MUM to 10 pM, whereas the intensity change was ignorable for other proteins such as human serum albumin (HSA). Aptamer-based assay benefited from simple immobilization of receptors and Au nanostructure contributed in building an effective surface enhancing/positively charged substrate was proved. Such an aptasensor holding high utilities for point-of-care devices by incorporating simplicity, sensitivity and selectivity in detection, low-cost for test, small sample volumes has been developed. PMID- 28880199 TI - The Role of Focal Adhesion Kinase in Keratinocyte Fibrogenic Gene Expression. AB - Abnormal skin scarring causes functional impairment, psychological stress, and high socioeconomic cost. Evidence shows that altered mechanotransduction pathways have been linked to both inflammation and fibrosis, and that focal adhesion kinase (FAK) is a key mediator of these processes. We investigated the importance of keratinocyte FAK at the single cell level in key fibrogenic pathways critical for scar formation. Keratinocytes were isolated from wildtype and keratinocyte specific FAK-deleted mice, cultured, and sorted into single cells. Keratinocytes were evaluated using a microfluidic-based platform for high-resolution transcriptional analysis. Partitive clustering, gene enrichment analysis, and network modeling were applied to characterize the significance of FAK on regulating keratinocyte subpopulations and fibrogenic pathways important for scar formation. Considerable transcriptional heterogeneity was observed within the keratinocyte populations. FAK-deleted keratinocytes demonstrated increased expression of genes integral to mechanotransduction and extracellular matrix production, including Igtbl, Mmpla, and Col4a1. Transcriptional activities upon FAK deletion were not identical across all single keratinocytes, resulting in higher frequency of a minor subpopulation characterized by a matrix-remodeling profile compared to wildtype keratinocyte population. The importance of keratinocyte FAK signaling gene expression was revealed. A minor subpopulation of keratinocytes characterized by a matrix-modulating profile may be a keratinocyte subset important for mechanotransduction and scar formation. PMID- 28880201 TI - Decrease in Healthcare Utilization and Costs for Opioid Users Following Residential Integrated Treatment for Co-Occurring Disorders. AB - BACKGROUND: Opioid use results in higher healthcare utilization and costs, particularly among those with co-occurring mental health disorders. Presumably, effective treatment would result in a reduction in healthcare utilization and costs. To date, research has not examined this question. As such, the purpose of this study was to estimate and compare pre- and post-treatment healthcare utilization and costs for individuals receiving residential integrated treatment for co-occurring mental health and opioid use disorders. METHODS: A single-group, repeated measures design was used to examine changes in pre- and post-treatment healthcare utilization and costs among a sample of individuals with co-occurring mental health and opioid use disorders who received residential, integrated treatment. RESULTS: Significant reductions in emergency rooms visits, inpatient admissions, and resulting costs were observed in the six months following treatment. CONCLUSIONS: Residential, integrated treatment of co-occurring mental health and opioid use disorders can significantly decrease both utilization and cost of healthcare among opioid users with co-occurring mental health disorders. PMID- 28880200 TI - The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models. AB - Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. Although it is among the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact to the society, no effective treatment for ASD is yet available, possibly because its neurobiological basis is not clearly understood hence specific drugs have not yet been developed. The endocannabinoid (EC) system represents a major neuromodulatory system involved in the regulation of emotional responses, behavioral reactivity to context, and social interaction. Furthermore, the EC system is also affected in conditions often present in subsets of patients diagnosed with ASD, such as seizures, anxiety, intellectual disabilities, and sleep pattern disturbances. Despite the indirect evidence suggestive of an involvement of the EC system in ASD, only a few studies have specifically addressed the role of the EC system in the context of ASD. This review describes the available data on the investigation of the presence of alterations of the EC system as well as the effects of its pharmacological manipulations in animal models of ASD-like behaviors. PMID- 28880202 TI - Research on the Optimum Water Content of Detecting Soil Nitrogen Using Near Infrared Sensor. AB - Nitrogen is one of the important indexes to evaluate the physiological and biochemical properties of soil. The level of soil nitrogen content influences the nutrient levels of crops directly. The near infrared sensor can be used to detect the soil nitrogen content rapidly, nondestructively, and conveniently. In order to investigate the effect of the different soil water content on soil nitrogen detection by near infrared sensor, the soil samples were dealt with different drying times and the corresponding water content was measured. The drying time was set from 1 h to 8 h, and every 1 h 90 samples (each nitrogen concentration of 10 samples) were detected. The spectral information of samples was obtained by near infrared sensor, meanwhile, the soil water content was calculated every 1 h. The prediction model of soil nitrogen content was established by two linear modeling methods, including partial least squares (PLS) and uninformative variable elimination (UVE). The experiment shows that the soil has the highest detection accuracy when the drying time is 3 h and the corresponding soil water content is 1.03%. The correlation coefficients of the calibration set are 0.9721 and 0.9656, and the correlation coefficients of the prediction set are 0.9712 and 0.9682, respectively. The prediction accuracy of both models is high, while the prediction effect of PLS model is better and more stable. The results indicate that the soil water content at 1.03% has the minimum influence on the detection of soil nitrogen content using a near infrared sensor while the detection accuracy is the highest and the time cost is the lowest, which is of great significance to develop a portable apparatus detecting nitrogen in the field accurately and rapidly. PMID- 28880203 TI - Temperature Dependence of Faraday Effect-Induced Bias Error in a Fiber Optic Gyroscope. AB - Improving the performance of interferometric fiber optic gyroscope (IFOG) in harsh environments, such as magnetic field and temperature field variation, is necessary for its practical applications. This paper presents an investigation of Faraday effect-induced bias error of IFOG under varying temperature. Jones matrix method is utilized to formulize the temperature dependence of Faraday effect induced bias error. Theoretical results show that the Faraday effect-induced bias error changes with the temperature in the non-skeleton polarization maintaining (PM) fiber coil. This phenomenon is caused by the temperature dependence of linear birefringence and Verdet constant of PM fiber. Particularly, Faraday effect-induced bias errors of two polarizations always have opposite signs that can be compensated optically regardless of the changes of the temperature. Two experiments with a 1000 m non-skeleton PM fiber coil are performed, and the experimental results support these theoretical predictions. This study is promising for improving the bias stability of IFOG. PMID- 28880204 TI - Is the Effect of Body Mass Index on Hypertension Modified by the Elevation? A Cross-Sectional Study of Rural Areas in Japan. AB - Obesity is an established independent risk factor for developing hypertension. A recent study showed that the effect of obesity on hypertension varies by the elevation of the residence area. Thus, we hypothesized that the interaction effect of body mass index (BMI) and elevation has a significant association with hypertension. The first aim of this cross-sectional study was to examine whether BMI was associated with hypertension, after adjustment for covariates. The second aim was to examine whether the interaction term between BMI and elevation was associated with hypertension, after adjustment for covariates. Data were collected from a cross-sectional study conducted in a rural area of Japan in 2016. After excluding participants with missing data (n = 2), data from 729 participants were analyzed. We found that BMI was significantly associated with hypertension. In addition, the interaction term between BMI and elevation had a significant association with hypertension. The findings of the present study support the recent evidence that high BMI is an independent risk factor for hypertension, but its effect varies by elevation. Thus, context-specific interventions could be an effective approach to prevent hypertension in this area. PMID- 28880205 TI - Poor Hand Hygiene Procedure Compliance among Polish Medical Students and Physicians-The Result of an Ineffective Education Basis or the Impact of Organizational Culture? AB - Objective: The objective of the study was to examine the knowledge of Polish physicians and medical students about the role of hand hygiene (HH) in healthcare associated infection (HAI) prevention. Study design: A survey was conducted using an author-prepared questionnaire, which was filled out on the first day of hospital work (or internship) by newly admitted physicians who had worked in other hospitals and students of different medical schools in Poland. Methods: 100 respondents participated in the study: 28 students, 18 medical interns and 54 physicians. Results: As many as 3/4 of physicians and students did not use the HH techniques correctly. The respondents declared that they perform HH in the following situations: 74.4% of respondents before an aseptic task; 60.8% before patient contact; 57.0% after patient contact; 11.5% after body fluid exposure risk, and only two respondents (1.1%) after contact with patient surroundings. 64% of respondents declared that their supervisor checked their knowledge of the HH technique when they were touching patients, but their supervisors checked the five instances for HH only in the case of 27 respondents (27%). Students experienced any control of HH in the workplace less often. Interns and physicians mentioned that the most important preventive action in HAI is HH, but for students it is the use of gloves. Conclusions: The level of knowledge and skills of physicians and students in the field of HH is insufficient. Deficiencies in skills and knowledge of HH were identified as early as at the level of the first internship. PMID- 28880207 TI - Rapid Evaporation of Water on Graphene/Graphene-Oxide: A Molecular Dynamics Study. AB - To reveal the mechanism of energy storage in the water/graphene system and water/grapheme-oxide system, the processes of rapid evaporation of water molecules on the sheets of graphene and graphene-oxide are investigated by molecular dynamics simulations. The results show that both the water/graphene and water/grapheme-oxide systems can store more energy than the pure water system during evaporation. The hydroxyl groups on the surface of graphene-oxide are able to reduce the attractive interactions between water molecules and the sheet of graphene-oxide. Also, the radial distribution function of the oxygen atom indicates that the hydroxyl groups affect the arrangement of water molecules at the water/graphene-oxide interface. Therefore, the capacity of thermal energy storage of the water/graphene-oxide system is lower than that of the water/graphene system, because of less desorption energy at the water/graphene oxide interface. Also, the evaporation rate of water molecules on the graphene oxide sheet is slower than that on the graphene sheet. The Leidenfrost phenomenon can be observed during the evaporation process in the water/grapheme-oxide system. PMID- 28880208 TI - Dual Role of MiR-21-Mediated Signaling in HUVECs and Rat Surgical Flap under Normoxia and Hypoxia Condition. AB - Restoring sufficient vascularity of the ischemia/hypoxia flap is always the critical issue in flap surgeries. In a previous studies microRNA-21 (miR-21) expression was upregulated after rat skin flap surgery. MiR-21 has been reported to be induced by hypoxia and the function of miR-21 involves in the process of angiogenesis. However, the precise regulatory mechanisms in miR-21-mediated pathways are still unclear. These issues were investigated via in vitro and in vivo experiments in this study. In human umbilical vein endothelial cells (HUVEC), the expression of hsa-miR-21-5p was induced after hypoxic culture and the induction of hsa-miR-21-5p was suppressed after sequential normoxic culture. Moreover, transfection of hsa-miR-21-5p mimic enhanced tube formation capacity in normoxia, but attenuated it in hypoxia. Furthermore, bioinformatic analysis suggested that SMAD7 was a predicted target of hsa-miR-21-5p. Our results demonstrated the effect of hsa-miR-21-5p was different on SMAD7 expression in normoxia and hypoxia. In rat skin flaps, blockage of miR-21-5p significantly increased angiogenesis via analysis of color laser Doppler imaging and repressed SMAD7 expression in ischemic skin tissue. Our study showed the opposite effect of miR-21-5p mediating angiogenesis in normoxia and hypoxia, providing important implications regarding the design of novel miRNA-based therapeutic strategies in flap surgeries. PMID- 28880209 TI - Variations in Obesity Rates between US Counties: Impacts of Activity Access, Food Environments, and Settlement Patterns. AB - There is much ongoing research about the effect of the urban environment as compared with individual behaviour on growing obesity levels, including food environment, settlement patterns (e.g., sprawl, walkability, commuting patterns), and activity access. This paper considers obesity variations between US counties, and delineates the main dimensions of geographic variation in obesity between counties: by urban-rural status, by region, by area poverty status, and by majority ethnic group. Available measures of activity access, food environment, and settlement patterns are then assessed in terms of how far they can account for geographic variation. A county level regression analysis uses a Bayesian methodology that controls for spatial correlation in unmeasured area risk factors. It is found that environmental measures do play a significant role in explaining geographic contrasts in obesity. PMID- 28880210 TI - Comparative Pharmacokinetic Study for Linezolid and Two Novel Antibacterial Oxazolidinone Derivatives in Rabbits: Can Differences in the Pharmacokinetic Properties Explain the Discrepancies between Their In Vivo and In Vitro Antibacterial Activities? AB - This is a comparative pharmacokinetics study of linezolid (Lzd), and two novel oxazolidinone antibacterial agents-PH027 and PH051-in rabbits to determine if the discrepancy between the in vitro and in vivo activities of the novel compounds is due to pharmacokinetic factors. The pharmacokinetics after IV and oral administration, plasma protein binding and tissue distribution for the three compounds were compared. The elimination half-lives were 52.4 +/- 6.3, 68.7 +/- 12.1 and 175 +/- 46.1 min for Lzd, PH027 and PH051, respectively. The oral bioavailability for Lzd, PH027 and PH051 administered as suspension were 38.7%, 22.1% and 4.73%, which increased significantly when administered as microemulsion to 51.7%, 72.9% and 13.9%. The plasma protein binding were 32-34%, 37-38% and 90 91% for Lzd, PH027 and PH051. The tissue distribution for PH027 and PH051 in all investigated tissues were higher than that for Lzd. It can be concluded that the lower bioavailability of PH027 and PH051 compared to Lzd when administered as suspension is the main cause of their lower in vivo activity, despite their comparable in vitro activity. Differences in the other pharmacokinetic characteristics cannot explain the lower in vivo activity. The in vivo activity of the novel compounds should be re-evaluated using formulations with good oral bioavailability. PMID- 28880212 TI - Topological Characterization of Carbon Graphite and Crystal Cubic Carbon Structures. AB - Graph theory is used for modeling, designing, analysis and understanding chemical structures or chemical networks and their properties. The molecular graph is a graph consisting of atoms called vertices and the chemical bond between atoms called edges. In this article, we study the chemical graphs of carbon graphite and crystal structure of cubic carbon. Moreover, we compute and give closed formulas of degree based additive topological indices, namely hyper-Zagreb index, first multiple and second multiple Zagreb indices, and first and second Zagreb polynomials. PMID- 28880206 TI - Comparative Response of Brain to Chronic Hypoxia and Hyperoxia. AB - Two antithetic terms, hypoxia and hyperoxia, i.e., insufficient and excess oxygen availability with respect to needs, are thought to trigger opposite responses in cells and tissues. This review aims at summarizing the molecular and cellular mechanisms underlying hypoxia and hyperoxia in brain and cerebral tissue, a context that may prove to be useful for characterizing not only several clinically relevant aspects, but also aspects related to the evolution of oxygen transport and use by the tissues. While the response to acute hypoxia/hyperoxia presumably recruits only a minor portion of the potentially involved cell machinery, focusing into chronic conditions, instead, enables to take into consideration a wider range of potential responses to oxygen-linked stress, spanning from metabolic to genic. We will examine how various brain subsystems, including energetic metabolism, oxygen sensing, recruitment of pro-survival pathways as protein kinase B (Akt), mitogen-activated protein kinases (MAPK), neurotrophins (BDNF), erythropoietin (Epo) and its receptors (EpoR), neuroglobin (Ngb), nitric oxide (NO), carbon monoxide (CO), deal with chronic hypoxia and hyperoxia to end-up with the final outcomes, oxidative stress and brain damage. A more complex than expected pattern results, which emphasizes the delicate balance between the severity of the stress imposed by hypoxia and hyperoxia and the recruitment of molecular and cellular defense patterns. While for certain functions the expectation that hypoxia and hyperoxia should cause opposite responses is actually met, for others it is not, and both emerge as dangerous treatments. PMID- 28880211 TI - Dual-Mode Electro-Optical Techniques for Biosensing Applications: A Review. AB - The monitoring of biomolecular interactions is a key requirement for the study of complex biological processes and the diagnosis of disease. Technologies that are capable of providing label-free, real-time insight into these interactions are of great value for the scientific and clinical communities. Greater understanding of biomolecular interactions alongside increased detection accuracy can be achieved using technology that can provide parallel information about multiple parameters of a single biomolecular process. For example, electro-optical techniques combine optical and electrochemical information to provide more accurate and detailed measurements that provide unique insights into molecular structure and function. Here, we present a comparison of the main methods for electro-optical biosensing, namely, electrochemical surface plasmon resonance (EC-SPR), electrochemical optical waveguide lightmode spectroscopy (EC-OWLS), and the recently reported silicon-based electrophotonic approach. The comparison considers different application spaces, such as the detection of low concentrations of biomolecules, integration, the tailoring of light-matter interaction for the understanding of biomolecular processes, and 2D imaging of biointeractions on a surface. PMID- 28880213 TI - Comparative Gene Mapping as a Tool to Understand the Evolution of Pest Crop Insect Chromosomes. AB - The extent of the conservation of synteny and gene order in aphids has been previously investigated only by comparing a small subset of linkage groups between the pea aphid Acyrthosiphon pisum and a few other aphid species. Here we compared the localization of eight A. pisum scaffolds (covering more than 5 Mb and 83 genes) in respect to the Drosophila melanogaster Muller elements identifying orthologous loci spanning all the four A. pisum chromosomes. Comparison of the genetic maps revealed a conserved synteny across different loci suggesting that the study of the fruit fly Muller elements could favour the identification of chromosomal markers useful for the study of chromosomal rearrangements in aphids. A. pisum is the first aphid species to have its genome sequenced and the finding that there are several chromosomal regions in synteny between Diptera and Hemiptera indicates that the genomic tools developed in A. pisum will be broadly useful not only for the study of other aphids but also for other insect species. PMID- 28880215 TI - The Effect of Flexible Pavement Mechanics on the Accuracy of Axle Load Sensors in Vehicle Weigh-in-Motion Systems. AB - Weigh-in-Motion systems are tools to prevent road pavements from the adverse phenomena of vehicle overloading. However, the effectiveness of these systems can be significantly increased by improving weighing accuracy, which is now insufficient for direct enforcement of overloaded vehicles. Field tests show that the accuracy of Weigh-in-Motion axle load sensors installed in the flexible (asphalt) pavements depends on pavement temperature and vehicle speeds. Although this is a known phenomenon, it has not been explained yet. The aim of our study is to fill this gap in the knowledge. The explanation of this phenomena which is presented in the paper is based on pavement/sensors mechanics and the application of the multilayer elastic half-space theory. We show that differences in the distribution of vertical and horizontal stresses in the pavement structure are the cause of vehicle weight measurement errors. These studies are important in terms of Weigh-in-Motion systems for direct enforcement and will help to improve the weighing results accuracy. PMID- 28880214 TI - Monitoring Autophagy Immunohistochemically and Ultrastructurally during Human Head and Neck Carcinogenesis. Relationship with the DNA Damage Response Pathway. AB - Autophagy is a catabolic process that preserves cellular homeostasis. Its exact role during carcinogenesis is not completely defined. Specifically in head and neck cancer, such information from clinical settings that comprise the whole spectrum of human carcinogenesis is very limited. Towards this direction, we examined the in situ status of the autophagy-related factors, Beclin-1, microtubule-associated protein 1 light chain 3, member B (LC3B) and sequestosome 1/p62 (p62) in clinical material covering all histopathological stages of human head and neck carcinogenesis. This material is unique as each panel of lesions is derived from the same patient and moreover we have previously assessed it for the DNA damage response (DDR) activation status. Since Beclin-1, LC3B and p62 reflect the nucleation, elongation and degradation stages of autophagy, respectively, their combined immunohistochemical (IHC) expression profiles could grossly mirror the autophagic flux. This experimental approach was further corroborated by ultrastructural analysis, applying transmission electron microscopy (TEM). The observed Beclin-1/LC3B/p62 IHC patterns, obtained from serial sections analysis, along with TEM findings are suggestive of a declined authophagic activity in preneoplastic lesions that was restored in full blown cancers. Correlating these findings with DDR status in the same pathological stages are indicative of: (i) an antitumor function of autophagy in support to that of DDR, possibly through energy deprivation in preneoplastic stages, thus preventing incipient cancer cells from evolving; and (ii) a tumor-supporting role in the cancerous stage. PMID- 28880216 TI - Inhibition of NAT10 Suppresses Melanogenesis and Melanoma Growth by Attenuating Microphthalmia-Associated Transcription Factor (MITF) Expression. AB - N-acetyltransferase 10 (NAT10) has been considered a target for the treatment of human diseases such as cancer and laminopathies; however, its functional role in the biology of melanocytes is questionable. Using a small molecule or small interfering RNA targeting NAT10, we examined the effect of NAT10 inhibition on melanogenesis and melanoma growth in human and mouse melanoma cells. Genetic silencing or chemical inhibition of NAT10 resulted in diminished melanin synthesis through the suppression of melanogenesis-stimulating genes such as those encoding dopachrome tautomerase (DCT) and tyrosinase in B16F10 melanoma cells. In addition, NAT10 inhibition significantly increased cell cycle arrest in S-phase, thereby suppressing the growth and proliferation of malignant melanoma cells in vitro and in vivo. These results demonstrate the potential role of NAT10 in melanogenesis and melanoma growth through the regulation of microphthalmia associated transcription factor (MITF) expression and provide a promising strategy for the treatment of various skin diseases (melanoma) and pigmentation disorders (chloasma and freckles). PMID- 28880217 TI - The Ameliorative Effects of a Tocotrienol-Rich Fraction on the AGE-RAGE Axis and Hypertension in High-Fat-Diet-Fed Rats with Metabolic Syndrome. AB - The clinical value of tocotrienols is increasingly appreciated because of the unique therapeutic effects that are not shared by tocopherols. However, their effect on metabolic syndrome is not well-established. This study aimed to investigate the effects of a tocotrienol-rich fraction (TRF) from palm oil in high-fat-diet-treated rats. Male, post-weaning Sprague Dawley rats were provided high-fat (60% kcal) diet for eight weeks followed by a TRF (60 mg/kg) treatment for another four weeks. Physical, metabolic, and histological changes were compared to those on control and high-fat diets respectively. High-fat feeding for eight weeks induced all hallmarks of metabolic syndrome. The TRF reversed systolic and diastolic hypertension, hypercholesterolemia, hepatic steatosis, impaired antioxidant defense, and myeloperoxidase hyperactivity triggered by the high-fat diet. It also conferred an inhibitory effect on protein glycation to reduce glycated hemoglobin A1c and advanced glycation end products (AGE). This was accompanied by the suppression of the receptor for advanced glycation end product (RAGE) expression in the liver. The treatment effects on visceral adiposity, glycemic control, triglyceride level, as well as peroxisome proliferator-activated receptor alpha and gamma expression were negligible. To conclude, treatment with a TRF exhibited protective effects on the cardiovascular and liver health in addition to the amelioration of plasma redox imbalance and AGE-RAGE activation. Further investigation as a therapy for metabolic syndrome is therefore worthwhile. PMID- 28880218 TI - Development of Multiplexed Infectious Disease Lateral Flow Assays: Challenges and Opportunities. AB - Lateral flow assays (LFAs) are the mainstay of rapid point-of-care diagnostics, with the potential to enable early case management and transform the epidemiology of infectious disease. However, most LFAs only detect single biomarkers. Recognizing the complex nature of human disease, overlapping symptoms and states of co-infections, there is increasing demand for multiplexed systems that can detect multiple biomarkers simultaneously. Due to innate limitations in the design of traditional membrane-based LFAs, multiplexing is arguably limited to a small number of biomarkers. Here, we summarize the need for multiplexed LFA, key technical and operational challenges for multiplexing, inherent in the design and production of multiplexed LFAs, as well as emerging enabling technologies that may be able to address these challenges. We further identify important areas for research in efforts towards developing multiplexed LFAs for more impactful diagnosis of infectious diseases. PMID- 28880219 TI - Influence of Skeletal Muscle Carnosine Content on Fatigue during Repeated Resistance Exercise in Recreationally Active Women. AB - Carnosine is a naturally occurring intramuscular dipeptide that is thought to attenuate fatigue during high-intensity exercise. Carnosine content is influenced by various factors, including gender and diet. Despite research reporting that carnosine content is lower in women compared to men and lower in vegetarians compared to omnivores, no investigations have examined carnosine content in women based on dietary protein intake and its effect on muscle fatigue. Twenty recreationally active women were assigned to either a high (HI; n = 5), moderate (MOD; n = 10), or low (LO; n = 5) group based upon intramuscular carnosine content of the vastus lateralis. Each participant underwent two unilateral maximal voluntary isometric contractions (MVIC) of the knee extensors separated by an isokinetic exercise protocol consisting of five sets of 50 repeated maximal unilateral contractions. Magnitude-based inferences were used to analyze group differences. Percent decline in rate of force development and peak torque (PT) during the MVICs and changes in PT and mean torque during the muscle-fatiguing protocol were lower in HI compared to both MOD and LO. Additionally, absolute and relative dietary protein intake were greater in HI compared to MOD or LO. Results indicated that greater intramuscular carnosine content was reflective of greater dietary protein intake and that individuals with higher carnosine content displayed a greater attenuation of fatigue compared to those with lower carnosine. PMID- 28880220 TI - Real-Time Two-Dimensional Magnetic Particle Imaging for Electromagnetic Navigation in Targeted Drug Delivery. AB - Magnetic nanoparticles (MNPs) are effective drug carriers. By using electromagnetic actuated systems, MNPs can be controlled noninvasively in a vascular network for targeted drug delivery (TDD). Although drugs can reach their target location through capturing schemes of MNPs by permanent magnets, drugs delivered to non-target regions can affect healthy tissues and cause undesirable side effects. Real-time monitoring of MNPs can improve the targeting efficiency of TDD systems. In this paper, a two-dimensional (2D) real-time monitoring scheme has been developed for an MNP guidance system. Resovist particles 45 to 65 nm in diameter (5 nm core) can be monitored in real-time (update rate = 2 Hz) in 2D. The proposed 2D monitoring system allows dynamic tracking of MNPs during TDD and renders magnetic particle imaging-based navigation more feasible. PMID- 28880221 TI - The Macular Carotenoids Lutein and Zeaxanthin Are Related to Increased Bone Density in Young Healthy Adults. AB - Lutein (L) and zeaxanthin (Z) status can be quantified by measuring their concentrations both in serum and, non-invasively, in retinal tissue. This has resulted in a unique ability to assess their role in a number of tissues ranging from cardiovascular to central nervous system tissue. Recent reports using animal models have suggested yet another role, a developmental increase in bone mass. To test this, we assessed L and Z status in 63 young healthy adults. LZ status was determined by measuring LZ in serum (using HPLC) and retina tissue (measuring macular pigment optical density, MPOD, using customized heterochromatic flicker photometry). Bone density was measured using dual-energy X-ray absorptiometry (DXA). Although serum LZ was generally not related to bone mass, MPOD was significantly related to bone density in the proximal femur and lumbar spine. In general, our results are consistent with carotenoids, specifically LZ, playing a role in optimal bone health. PMID- 28880223 TI - How Social Care Beneficiaries in Poland Rate Relative Harmfulness of Various Tobacco and Nicotine-Containing Products. AB - The aim of the study was to examine how social care beneficiaries rate the relative harmfulness of tobacco/nicotine-containing products compared to traditional cigarettes. This information is crucial for the development of effective tobacco control strategies targeting disadvantaged populations. The cross-sectional study covered 1817 respondents who were taking advantage of social aid services offered by the local social care institutions in the Piotrkowski district, via face-to-face interviews. The linear regression analysis indicated that relative to women, men consider slim cigarettes, smokeless tobacco and e-cigarettes to be more harmful than traditional cigarettes (p < 0.05). The smokers of traditional cigarettes reported menthol cigarettes to be less harmful than traditional cigarettes, relative to the non-smokers (p = 0.05). The current results demonstrate that social care beneficiaries are not aware of the fact that some products are less harmful than others. Education concerning tobacco/nicotine products should include advice on how to reduce the adverse health effects of smoking (e.g., avoiding inhalation of combusted products), while driving the awareness that no nicotine-containing products are safe. PMID- 28880222 TI - Western Dietary Pattern Is Associated with Irritable Bowel Syndrome in the French NutriNet Cohort. AB - Background: Diet appears to play a key role in the pathogenesis of the irritable bowel syndrome (IBS). Some dietary patterns (DP) could increase the risk of triggering or worsening IBS symptoms. This cross-sectional study aimed to assess the association between a posteriori derived DP and IBS in a large French population, the web-based NutriNet-Sante cohort. Methods: Study population included participants of the NutriNet-Sante study who completed a questionnaire based on Rome III criteria assessing IBS. A principal component analysis (PCA) was performed to identify major DPs based on 29 food groups' consumption. Associations between DP quintiles and IBS were investigated with multivariable logistic regressions. Results: 44,350 participants were included, with 2423 (5.5%) presenting IBS. Three major DP were extracted using PCA, "healthy," "western," and "traditional." After adjustments on confounders, the "western" DP was positively associated with IBS (OR Q5 vs. Q1 = 1.38, 95% CI 1.19-1.61, p trend < 0.0001) and the "traditional" DP was positively associated with IBS in women (OR Q5 vs. Q1 = 1.29 95% CI 1.08-1.54, p trend = 0.001). Conclusions: In this study, a "western" DP-highly correlated with the consumption of fatty and sugary products and snacks-was associated with a moderate increased risk of IBS. PMID- 28880224 TI - Parenteral Nutrition-Associated Liver Disease: The Role of the Gut Microbiota. AB - Parenteral nutrition (PN) provides life-saving nutritional support in situations where caloric supply via the enteral route cannot cover the necessary needs of the organism. However, it does have serious adverse effects, including parenteral nutrition-associated liver disease (PNALD). The development of liver injury associated with PN is multifactorial, including non-specific intestine inflammation, compromised intestinal permeability, and barrier function associated with increased bacterial translocation, primary and secondary cholangitis, cholelithiasis, short bowel syndrome, disturbance of hepatobiliary circulation, lack of enteral nutrition, shortage of some nutrients (proteins, essential fatty acids, choline, glycine, taurine, carnitine, etc.), and toxicity of components within the nutrition mixture itself (glucose, phytosterols, manganese, aluminium, etc.). Recently, an increasing number of studies have provided evidence that some of these factors are directly or indirectly associated with microbial dysbiosis in the intestine. In this review, we focus on PN-induced changes in the taxonomic and functional composition of the microbiome. We also discuss immune cell and microbial crosstalk during parenteral nutrition, and the implications for the onset and progression of PNALD. Finally, we provide an overview of recent advances in the therapeutic utilisation of pro- and prebiotics for the mitigation of PN-associated liver complications. PMID- 28880225 TI - Silver Oxide Coatings with High Silver-Ion Elution Rates and Characterization of Bactericidal Activity. AB - This paper reports the synthesis and characterization of silver oxide films for use as bactericidal coatings. Synthesis parameters, dissolution/elution rate, and bactericidal efficacy are reported. Synthesis conditions were developed to create AgO, Ag2O, or mixtures of AgO and Ag2O on surfaces by reactive magnetron sputtering. The coatings demonstrate strong adhesion to many substrate materials and impede the growth of all bacterial strains tested. The coatings are effective in killing Escherichia coli and Staphylococcus aureus, demonstrating a clear zone of-inhibition against bacteria growing on solid media and the ability to rapidly inhibit bacterial growth in planktonic culture. Additionally, the coatings exhibit very high elution of silver ions under conditions that mimic dynamic fluid flow ranging between 0.003 and 0.07 ppm/min depending on the media conditions. The elution of silver ions from the AgO/Ag2O surfaces was directly impacted by the complexity of the elution media, with a reduction in elution rate when examined in complex cell culture media. Both E. coli and S. aureus were shown to bind ~1 ppm Ag+/mL culture. The elution of Ag+ resulted in no increases in mammalian cell apoptosis after 24 h exposure compared to control, but apoptotic cells increased to ~35% by 48 and 72 h of exposure. Taken together, the AgO/Ag2O coatings described are effective in eliciting antibacterial activity and have potential for application on a wide variety of surfaces and devices. PMID- 28880226 TI - Quantitative Analysis, Extraction Optimization, and Biological Evaluation of Cudrania tricuspidata Leaf and Fruit Extracts. AB - Cudrania tricuspidata Bureau (Moraceae) shows numerous pharmacological effects and has been used in traditional herbal remedies for inflammation, gastritis, tumors, and liver diseases. However, no validated analytical method for the standardization and optimization of the biological properties of C. tricuspidata preparations has been reported. We developed and validated a reverse-phase high performance liquid chromatography (HPLC) method for the separation and quantification of active markers. Ethanolic extracts of C. tricuspidata leaves were prepared and evaluated for chemical profiles and biological activities. The 80% ethanolic extract demonstrated the greatest antioxidant activity and phenolic content, while the 100% ethanolic extract had the greatest total flavonoid content and xanthine oxidase (XO) inhibitory activity. The validated HPLC method confirmed that chlorogenic acid, rutin, and kaempferol were present in C. tricuspidata leaf extracts. We postulated that the antioxidant and anti hyperuricemic/gout effects of C. tricuspidata extract could be attributed to these marker compounds. Our results suggested that the flavonoid-rich fraction of the leaf extract may be utilized for the treatment and prevention of hyperuricemia-related diseases, and the validated method and marker compounds could be applied for the quality control of C. tricuspidata preparations. PMID- 28880228 TI - A Multi-Sensor Data Fusion Approach for Atrial Hypertrophy Disease Diagnosis Based on Characterized Support Vector Hyperspheres. AB - Disease diagnosis can be performed based on fusing the data acquired by multiple medical sensors from patients, and it is a crucial task in sensor-based e healthcare systems. However, it is a challenging problem that there are few effective diagnosis methods based on sensor data fusion for atrial hypertrophy disease. In this article, we propose a novel multi-sensor data fusion method for atrial hypertrophy diagnosis, namely, characterized support vector hyperspheres (CSVH). Instead of constructing a hyperplane, as a traditional support vector machine does, the proposed method generates "hyperspheres" to collect the discriminative medical information, since a hypersphere is more powerful for data description than a hyperplane. In detail, CSVH constructs two characterized hyperspheres for the classes of patient and healthy subject, respectively. The hypersphere for the patient class is developed in a weighted version so as to take the diversity of patient instances into consideration. The hypersphere for the class of healthy people keeps furthest away from the patient class in order to achieve maximum separation from the patient class. A query is labelled by membership functions defined based on the two hyperspheres. If the query is rejected by the two classes, the angle information of the query to outliers and overlapping-region data is investigated to provide the final decision. The experimental results illustrate that the proposed method achieves the highest diagnosis accuracy among the state-of-the-art methods. PMID- 28880227 TI - Providing Personalized Energy Management and Awareness Services for Energy Efficiency in Smart Buildings. AB - Considering that the largest part of end-use energy consumption worldwide is associated with the buildings sector, there is an inherent need for the conceptualization, specification, implementation, and instantiation of novel solutions in smart buildings, able to achieve significant reductions in energy consumption through the adoption of energy efficient techniques and the active engagement of the occupants. Towards the design of such solutions, the identification of the main energy consuming factors, trends, and patterns, along with the appropriate modeling and understanding of the occupants' behavior and the potential for the adoption of environmentally-friendly lifestyle changes have to be realized. In the current article, an innovative energy-aware information technology (IT) ecosystem is presented, aiming to support the design and development of novel personalized energy management and awareness services that can lead to occupants' behavioral change towards actions that can have a positive impact on energy efficiency. Novel information and communication technologies (ICT) are exploited towards this direction, related mainly to the evolution of the Internet of Things (IoT), data modeling, management and fusion, big data analytics, and personalized recommendation mechanisms. The combination of such technologies has resulted in an open and extensible architectural approach able to exploit in a homogeneous, efficient and scalable way the vast amount of energy, environmental, and behavioral data collected in energy efficiency campaigns and lead to the design of energy management and awareness services targeted to the occupants' lifestyles. The overall layered architectural approach is detailed, including design and instantiation aspects based on the selection of set of available technologies and tools. Initial results from the usage of the proposed energy aware IT ecosystem in a pilot site at the University of Murcia are presented along with a set of identified open issues for future research. PMID- 28880229 TI - Study on Topology Optimization Design, Manufacturability, and Performance Evaluation of Ti-6Al-4V Porous Structures Fabricated by Selective Laser Melting (SLM). AB - The combination of topology optimization (TOP) and selective laser melting (SLM) provides the possibility of fabricating the complex, lightweight and high performance geometries overcoming the traditional manufacturing "bottleneck". This paper evaluates the biomechanical properties of porous structures with porosity from 40% to 80% and unit cell size from 2 to 8 mm, which are designed by TOP and manufactured by SLM. During manufacturability exploration, three typical structures including spiral structure, arched bridge structure and structures with thin walls and small holes are abstracted and investigated, analyzing their manufacturing limits and forming reason. The property tests show that dynamic elastic modulus and compressive strength of porous structures decreases with increases of porosity (constant unit cell size) or unit cell size (constant porosity). Based on the Gibson-Ashby model, three failure models are proposed to describe their compressive behavior, and the structural parameter lambda is used to evaluate the stability of the porous structure. Finally, a numerical model for the correlation between porous structural parameters (unit cell size and porosity) and elastic modulus is established, which provides a theoretical reference for matching the elastic modulus of human bones from different age, gender and skeletal sites during innovative medical implant design and manufacturing. PMID- 28880230 TI - Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3 (Phenylcarbamoyl)-pyrazine-2-carboxylic Acids. AB - Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine 2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity. Antimycobacterial, antibacterial and antifungal growth inhibiting activity was investigated in all prepared compounds. 3-[(4 Nitrophenyl)carbamoyl]pyrazine-2-carboxylic acid (16) exerted high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 1.56 MUg.mL-1 (5 MUM). Propyl 3-{[4-(trifluoromethyl)phenyl]carbamoyl}pyrazine-2 carboxylate (18a) showed also high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 3.13 MUg.mL-1. In vitro cytotoxicity of the active compounds was investigated and no significant cytotoxic effect was observed. Based to structural similarity to known inhibitors of decaprenylphosphoryl-beta-d-ribose oxidase, DprE1, we performed molecular docking of the prepared acids to DprE1. These in silico experiments indicate that modification of the linker connecting aromatic parts of molecule does not have any negative influence on the binding. PMID- 28880231 TI - The Impact of Sex and 25(OH)D Deficiency on Metabolic Function in Mice. AB - Both dietary fat and vitamin D deficiency have been linked with increased incidence of non-alcoholic fatty liver disease and insulin resistance. While sex differences in disease prevalence and severity are well known, the impact on disease pathogenesis remains unclear. To further explore the effect of these exposures on metabolic function, C57BL/6 male and female mice were weaned onto one of four diets; low fat vitamin D replete, low fat vitamin D deficient, or two high fat diets, one vitamin D replete and one deficient. Visceral fat, hepatic adiposity, and insulin resistance were measured after five and a half weeks. Vitamin D deficiency, independent of dietary fat, increased hepatic fat accumulation in both sexes (p = 0.003), although did not increase hepatic expression of interleukin-6 (p = 0.92) or tumor necrosis factor-alpha (p = 0.78). Males were observed to have greater insulin resistance (glucose area under the curve: p < 0.001, homeostatic model assessment for insulin resistance: p = 0.046), and have greater visceral adiposity (p < 0.001), while female mice had greater hepatic fat accumulation (p < 0.001). This study is the first to demonstrate vitamin D deficiency alone can cause hepatic accumulation while also being the first to observe higher liver fat percentages in female mice. PMID- 28880232 TI - Railway Tunnel Clearance Inspection Method Based on 3D Point Cloud from Mobile Laser Scanning. AB - Railway tunnel clearance is directly related to the safe operation of trains and upgrading of freight capacity. As more and more railway are put into operation and the operation is continuously becoming faster, the railway tunnel clearance inspection should be more precise and efficient. In view of the problems existing in traditional tunnel clearance inspection methods, such as low density, slow speed and a lot of manual operations, this paper proposes a tunnel clearance inspection approach based on 3D point clouds obtained by a mobile laser scanning system (MLS). First, a dynamic coordinate system for railway tunnel clearance inspection has been proposed. A rail line extraction algorithm based on 3D linear fitting is implemented from the segmented point cloud to establish a dynamic clearance coordinate system. Second, a method to seamlessly connect all rail segments based on the railway clearance restrictions, and a seamless rail alignment is formed sequentially from the middle tunnel section to both ends. Finally, based on the rail alignment and the track clearance coordinate system, different types of clearance frames are introduced for intrusion operation with the tunnel section to realize the tunnel clearance inspection. By taking the Shuanghekou Tunnel of the Chengdu-Kunming Railway as an example, when the clearance inspection is carried out by the method mentioned herein, its precision can reach 0.03 m, and difference types of clearances can be effectively calculated. This method has a wide application prospects. PMID- 28880233 TI - Magnetoelectric Force Microscopy on Antiferromagnetic 180? Domains in Cr2O3. AB - Magnetoelectric force microscopy (MeFM) is characterized as methodical tool for the investigation of antiferromagnetic domain states, in particular of the 180 ? variety. As reference compound for this investigation we use Cr 2 O 3 . Access to the antiferromagnetic order is provided by the linear magnetoelectric effect. We resolve the opposite antiferromagnetic 180 ? domain states of Cr 2 O 3 and estimate the sensitivity of the MeFM approach, its inherent advantages in comparison to alternative techniques and its general feasibility for probing antiferromagnetic order. PMID- 28880234 TI - Typhonium giganteum Lectin Exerts A Pro-Inflammatory Effect on RAW 264.7 via ROS and The NF-kappaB Signaling Pathway. AB - Typhonii rhizoma, a widely used herb in traditional Chinese medicine, has acute irritating toxicity related to Typhonium giganteum lectin (TGL). TGL exhibits acute inflammatory effects, but the underlying molecular mechanisms are largely unknown. This paper is designed to assess the pro-inflammatory response of TGL on RAW 264.7 cells. RAW 264.7 treated with 6.25, 12.5, 25, and 50 ug/mL TGL showed elevated levels of inflammatory factors (TNF-alpha, IL-1beta) and of p-IkappaB and p-p65, all dose-dependent, indicating that TGL had a substantial inflammatory effect and mobilized the nuclear factor-kappaB (NF-kappaB) pathway. All four TGL treatments also induced the up-regulation of reactive oxygen species (ROS) and cytosolic free Ca2+ and down-regulation of mitochondrial membrane potential (MMP). The production of cytokines and p-IkappaB, p-p65 were reduced by N acetylcysteine (NAC), an ROS scavenger, which somewhat abrogated ROS production. The results showed the TGL-activated inflammatory signaling pathway NF-kappaB to be associated with the overproduction of ROS. Moreover, 50 MUg/mL treatment with TGL led to cell apoptosis after 1 h and increased necrosis over time. These results provided potential molecular mechanisms for the observed inflammatory response to TGL including up-regulation of ROS and cytosolic free Ca2+, down regulation of MMP, the mobilization of the NF-kappaB pathway, and the subsequent overproduction of pro-inflammatory factors resulting in apoptosis. Long-term stimulation with TGL resulted in strong toxic effects related to inflammation that induced necrosis in macrophages. PMID- 28880235 TI - Risk Assessment of Metals in Urban Soils from a Typical Industrial City, Suzhou, Eastern China. AB - Risk of metals in urban soils is less studied, compared to that in other types of soils, hindering accurate assessment of human exposure to metals. In this study, the concentrations of five metals (As, Cd, Cr, Pb, and Hg) were analyzed in 167 surface soil samples collected from Suzhou city and their potential ecological and human health risks were assessed. The mean concentrations of As, Cd, Pb, and Hg except Cr, were higher than the background values in Jiangsu Province. Metal concentrations varied among districts, where sites of high contamination showed a punctate distribution. Principal components and correlation analyses revealed that As, Pb, and Cd could originate from the same sources. The geo-accumulation (Igeo) and potential ecological risk indices (RI) were calculated and the relatively low values of Igeo (<0) and RI (<150) suggested generally low ecological risk. The noncarcinogenic risks of the metals were relatively low for Suzhou residents (i.e., average hazard index or HI: 0.1199 for adults and 0.5935 for children, <1), while the total carcinogenic risks (TCR) of Cr and As were acceptable (TCR in the range of 1.0 * 10-6 to 1.0 * 10-4). Children faced a higher threat than adults. Results of Monte-Carlo simulations were lower than those obtained from models using deterministic parameters. Of all the uncertain parameters, the ingestion rate and body weight were the most sensitive for adults and children, respectively, while As was an important factor for both. The results as well as the factors controlling risks of metals could help better understand the risks of metals in urban soils of industrial cities in China. PMID- 28880236 TI - Sedentary and Physical Activity Patterns in Adults with Intellectual Disability. AB - Little is known about the patterns of sedentary time (ST) and physical activity (PA) levels throughout the week among adults and older adults with Intellectual Disability (ID). We analyzed ST and PA patterns of adults and older adults with ID. Forty-two adults and 42 older adults with mild to severe ID participated in this study. Height and weight were obtained to calculate Body Mass Index (BMI). Body fat and fat-free mass percentages were also obtained. Patterns of PA levels and ST were assessed with GT3X Actigraph accelerometers. Adults performed higher amounts of total PA and moderate to vigorous PA than older adults during the week, on weekdays and in center time (all p > 0.05). No differences between males and females were found for either PA levels or ST. Only 10.7% of the participants met the global recommendations on PA for health. The participants of the current study showed low PA levels and a high prevalence of ST. Interestingly, when comparing age and/or sex groups, no differences were observed for ST. Our findings provide novel and valuable information to be considered in future interventions aiming to increase PA levels and reduce ST. PMID- 28880237 TI - Analysis of Baseline Computerized Neurocognitive Testing Results among 5-11-Year Old Male and Female Children Playing Sports in Recreational Leagues in Florida. AB - There is a paucity of data related to sports injuries, concussions, and computerized neurocognitive testing (CNT) among very young athletes playing sports in recreational settings. The purpose of this study was to report baseline CNT results among male and female children, ages 5-11, playing sports in Hillsborough County, Florida using ImPACT Pediatric, which is specifically designed for this population. Data were collected from 2016 to 2017. The results show that 657 baseline tests were conducted and t-tests and linear regression were used to assess mean significant differences in composite scores with sex and age. Results showed that females scored better on visual memory and in general as age increased, baseline scores improved. The results can be used to build further studies on the use of CNT in recreational settings and their role in concussion treatment, management, and interventions. PMID- 28880239 TI - Strait Gate: Special Issue on Advances in Silicon Chemistry. AB - Manufacturing high-purity element silicon and organic polysilicones are two major silicon industries, supporting the basis of the modern electronic industry and our daily lives [...]. PMID- 28880238 TI - Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal Cancer Patients: A Review. AB - BACKGROUND: One of the main chemotherapeutic drugs used on a routine basis in patients with metastatic colorectal cancer ((m)CRC) is the topoisomerase-1 inhibitor, irinotecan. However, its usefulness is limited by the pre-existing or inevitable development of resistance. The ATP-binding cassette (ABC) transporter ABCG2/breast cancer resistance protein (BRCP) through its function in xenobiotic clearance might play an important role in irinotecan resistance. With a goal to evaluate the clinical significance of ABCG2 measurements, we here review the current literature on ABCG2 in relation to irinotecan treatment in CRC patients. RESULTS: Few studies have evaluated the association between ABCG2 gene or protein expression and prognosis in CRC patients. Discordant results were reported. The discrepancies might be explained by the use of different criteria for interpretation of results in the immunohistochemistry studies. Only one large study evaluated the ABCG2 protein expression and efficacy of irinotecan in mCRC (CAIRO study, n = 566). This study failed to demonstrate any correlation between ABCG2 protein expression in the primary tumor and response to irinotecan-based treatment. We recently raised questions on how to evaluate ABCG2 immunoreactivity patterns, and the results in the CAIRO study might be influenced by using a different scoring protocol than the one proposed by us. In contrast, our recent exploratory study of ABCG2 mRNA expression in 580 patients with stage III primary CRC (subgroup from the randomized PETACC-3 study) indicated that high ABCG2 tumor tissue mRNA expression might be predictive for lack of efficacy of irinotecan. CONCLUSION: The biological role of ABCG2 in predicting clinical irinotecan sensitivity/resistance in CRC is uncertain. In particular, the significance of ABCG2 cellular localization needs to be established. Data concerning ABCG2 mRNA expression and prediction of adjuvant irinotecan efficacy are still sparse and need to be confirmed. PMID- 28880240 TI - Effect of Sipjeondaebo-Tang on the Pharmacokinetics of S-1, an Anticancer Agent, in Rats Evaluated by Population Pharmacokinetic Modeling. AB - S-1 (TS-1(r)) is an oral fluoropyrimidine anticancer agent containing tegafur, oteracil, and gimeracil. Sipjeondaebo-tang (SDT) is a traditional oriental herbal medicine that has potential to alleviate chemotherapy-related adverse effects. The aim of the present study was to evaluate the effect of SDT on the pharmacokinetics of S-1. Sprague-Dawley rats were pretreated with a single dose or repeated doses of SDT for seven consecutive days (1200 mg/kg/day). After the completion of pretreatment with SDT, S-1 was orally administered and plasma concentrations of tegafur, its active metabolite 5-FU, and gimeracil were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). A population pharmacokinetic model was developed to evaluate the effect of SDT on pharmacokinetics of tegafur and 5-FU. Although a single dose of SDT did not have any significant effect, the absorption rate of tegafur decreased, and the plasma levels of 5-FU reduced significantly in rats pretreated with SDT for seven days in parallel to the decreased gimeracil concentrations. Population pharmacokinetic modeling also showed the enhanced elimination of 5-FU in the SDT-pretreated group. Repeated doses of SDT may inhibit the absorption of gimeracil, an inhibitor of 5-FU metabolism, resulting in enhanced elimination of 5-FU and decrease its plasma level. PMID- 28880241 TI - Cyclodextrin-Catalyzed Organic Synthesis: Reactions, Mechanisms, and Applications. AB - Cyclodextrins are well-known macrocyclic oligosaccharides that consist of alpha (1,4) linked glucose units and have been widely used as artificial enzymes, chiral separators, chemical sensors, and drug excipients, owing to their hydrophobic and chiral interiors. Due to their remarkable inclusion capabilities with small organic molecules, more recent interests focus on organic reactions catalyzed by cyclodextrins. This contribution outlines the current progress in cyclodextrin-catalyzed organic reactions. Particular emphases are given to the organic reaction mechanisms and their applications. In the end, the future directions of research in this field are proposed. PMID- 28880242 TI - Synthesis and Antidepressant Activity Profile of Some Novel Benzothiazole Derivatives. AB - Within the scope of our new antidepressant drug development efforts, in this study, we synthesized eight novel benzothiazole derivatives 3a-3h. The chemical structures of the synthesized compounds were elucidated by spectroscopic methods. Test compounds were administered orally at a dose of 40 mg/kg to mice 24, 5 and 1 h before performing tail suspension, modified forced swimming, and activity cage tests. The obtained results showed that compounds 3c, 3d, 3f-3h reduced the immobility time of mice as assessed in the tail suspension test. Moreover, in the modified forced swimming tests, the same compounds significantly decreased the immobility, but increased the swimming frequencies of mice, without any alteration in the climbing frequencies. These results, similar to the results induced by the reference drug fluoxetine (20 mg/kg, po), indicated the antidepressant-like activities of the compounds 3c, 3d, 3f-3h. Owing to the fact that test compounds did not induce any significant alteration in the total number of spontaneous locomotor activities, the antidepressant-like effects of these derivatives seemed to be specific. In order to predict ADME parameters of the synthesized compounds 3a-3h, some physicochemical parameters were calculated. The ADME prediction study revealed that all synthesized compounds may possess good pharmacokinetic profiles. PMID- 28880244 TI - Forbidden Coherence Transfer of 19F Nuclei to Quantitatively Measure the Dynamics of a CF3-Containing Ligand in Receptor-Bound States. AB - The dynamic property of a ligand in the receptor-bound state is an important metric to characterize the interactions in the ligand-receptor interface, and the development of an experimental strategy to quantify the amplitude of motions in the bound state is of importance to introduce the dynamic aspect into structure guided drug development (SGDD). Fluorine modifications are frequently introduced at the hit-to-lead optimization stage to enhance the binding potency and other characteristics of a ligand. However, the effects of fluorine modifications are generally difficult to predict, owing to the pleiotropic nature of the interactions. In this study, we report an NMR-based approach to experimentally evaluate the local dynamics of trifluoromethyl (CF3)-containing ligands in the receptor-bound states. For this purpose, the forbidden coherence transfer (FCT) analysis, which has been used to study the dynamics of methyl moieties in proteins, was extended to the 19F nuclei of CF3-containing ligands. By applying this CF3-FCT analysis to a model interaction system consisting of a ligand, AST 487, and a receptor, p38alpha, we successfully quantified the amplitude of the CF3 dynamics in the p38alpha-bound state. The strategy would bring the CF3 containing ligands within the scope of dynamic SGDD to improve the affinity and specificity for the drug-target receptors. PMID- 28880243 TI - Simultaneous Determination of Seven Phenolic Acids in Rat Plasma Using UHPLC-ESI MS/MS after Oral Administration of Echinacea purpurea Extract. AB - A rapid and sensitive Ultra High Performance Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry (UHPLC-ESI-MS/MS) method was developed and validated to simultaneously determine the concentration of seven phenolic acids (syringic acid, ferulic acid, caffeic acid, vanillic acid, p-coumaric acid, 3,4 dihydroxybenzoic acid and 4-hydroxybenzoic acid) in rat plasma after oral administration of Echinacea purpurea extract. After mixing with the internal standard (IS), butylparaben, plasma samples were prepared by liquid-liquid extraction with ethyl acetate. The separation was performed using the Agilent Eclipse Plus C18 column (1.8 MUm, 2.1 mm * 50 mm) with a gradient system consisting of solution A (0.1% acetic acid in water) and solution B (methanol) at a flow rate of 0.3 mL/min. The detection was accomplished by a multiple reaction monitoring (MRM) mode with electrospray ionization (ESI). The method was validated in terms of linearity, precision, accuracy, extraction recovery, matrix effect and stability. This method was successfully applied to study the pharmacokinetic properties of the seven compounds after oral administration of Echinacea purpurea extract in rats. PMID- 28880245 TI - Evaluation of the Healing Potential of Demineralized Dentin Matrix Fixed with Recombinant Human Bone Morphogenetic Protein-2 in Bone Grafts. AB - We aimed to evaluate the efficacy of demineralized dentin matrix (DDM) fixed with recombinant human bone morphogenetic protein-2 (rhBMP-2) through an experimental and a clinical study. Unilateral upper second and third premolars of eight beagles were extracted. A mucoperiosteal flap was elevated around the extraction socket, and a bone defect was made using a surgical drill. Each DDM was fixed with rhBMP-2, and autogenous bone was grafted at the bone defect area with a collagenous membrane. The beagles were euthanized at two, four, eight, and 12 weeks after receiving the bone graft. Block specimens involving grafted bone and surrounding natural bone were extracted. A total of 23 patients who received bone grafts using human DDM fixed with rhBMP-2 (AutoBT BMP) with implant placements (36 implants; maxilla: 14, mandible: 22) were selected. The implant stability, marginal bone loss, and clinical outcome were evaluated. Three trephine cores were harvested fourmonths after bone grafting, and histologic examination was performed. In the histological evaluation performed four weeks after the bone graft, autogenous bone showed 52% new bone formation and DDM fixed with rhBMP-2 showed 33% new bone formation. Twelve weeks after the bone graft, autogenous bone showed 75% new bone formation and DDM fixed with rhBMP-2 showed 48% new bone formation. In the clinical study, favorable osseointegration was obtained in 35 out of 36 implant sites (one case of osseointegration failure). In all cases, severe complications were not observed. Histomorphometrically, new bone formation was observed in 14.98% of the cases. The residual DDM particles were 6.22%. AutoBT BMP provides good osteoinductive and osteoconductive potential and clinical efficacy. PMID- 28880246 TI - Dental Composite Formulation Design with Bioactivity on Protein Adsorption Combined with Crack-Healing Capability. AB - Fracture and secondary caries are the primary reasons for the failure of dental restorations. To face this omnipresent problem, we report the formulation design and synthesis of a protein-resistant dental composite composed of 2 methacryloyloxyethyl phosphorylcholine (MPC) that also can self-repair damage and recover the load-bearing capability via microencapsulated triethylene glycol dimethacrylate (TEGDMA) and N,N-dihydroxy ethyl-p-toluidine (DHEPT). The bioactivity of the resulting MPC-microencapsulated TEGDMA-DHEPT was evaluated on protein adsorption through early bacterial attachment. Its mechanical properties were also investigated, including self-healing assessment. Microcapsules of poly (urea-formaldehyde) (PUF) were synthesized by incorporating a TEGDMA-DHEPT healing liquid. A set of composites that contained 7.5% of MPC, 10% of microcapsules, and without MPC/microcapsules were also prepared as controls. The two distinct characteristics of strong protein repellency and load-bearing recovery were achieved by the combined strategies. The novel dual composite with a combination of protein-repellent MPC and PUF microcapsules for restoring microcracks is a promising strategy for dental restorations to address the two main challenges of fracture and secondary caries. The new dual composite formulation design has the potential to improve the longevity of dental restorations significantly. PMID- 28880247 TI - The Actin Cytoskeleton Is Involved in Glial Cell Line-Derived Neurotrophic Factor (GDNF)-Induced Ret Translocation into Lipid Rafts in Dopaminergic Neuronal Cells. AB - Glial cell line-derived neurotrophic factor (GDNF), a potential therapeutic factor for Parkinson's disease (PD), exerts its biological effects through the Ret receptor tyrosine kinase. The redistribution of Ret into lipid rafts substantially influences Ret signaling, but the mechanisms underlying Ret translocation remain unclear. The purpose of our study was to further explore the signaling mechanisms of GDNF and to determine whether the actin cytoskeleton is involved in the GDNF-induced Ret translocation into lipid rafts. In MN9D dopaminergic neuronal cells, we used density gradient centrifugation and immunofluorescence confocal microscopy to separate and visualize lipid rafts, co immunoprecipitation to analyze protein-protein interactions, and latrunculin B (Lat B) and jasplakinolide (Jas) to disrupt and enhance the polymerization of the actin cytoskeleton, respectively. The results showed that Ret translocated into lipid rafts and coimmunoprecipitated with actin in response to GDNF treatment. After Lat B or Jas treatment, the Ret-F-actin association induced by GDNF was impaired or enhanced respectively and then the levels of Ret translocated into lipid rafts were correspondingly inhibited or promoted. These data indicate that actin polymerization and cytoskeletal remodeling are integral to GDNF-induced cell signaling in dopaminergic cells and define a new role of the actin cytoskeleton in promoting Ret redistribution into lipid rafts. PMID- 28880248 TI - X-ray Free Electron Laser Determination of Crystal Structures of Dark and Light States of a Reversibly Photoswitching Fluorescent Protein at Room Temperature. AB - The photochromic fluorescent protein Skylan-NS (Nonlinear Structured illumination variant mEos3.1H62L) is a reversibly photoswitchable fluorescent protein which has an unilluminated/ground state with an anionic and cis chromophore conformation and high fluorescence quantum yield. Photo-conversion with illumination at 515 nm generates a meta-stable intermediate with neutral trans chromophore structure that has a 4 h lifetime. We present X-ray crystal structures of the cis (on) state at 1.9 Angstrom resolution and the trans (off) state at a limiting resolution of 1.55 Angstrom from serial femtosecond crystallography experiments conducted at SPring-8 Angstrom Compact Free Electron Laser (SACLA) at 7.0 keV and 10.5 keV, and at Linac Coherent Light Source (LCLS) at 9.5 keV. We present a comparison of the data reduction and structure determination statistics for the two facilities which differ in flux, beam characteristics and detector technologies. Furthermore, a comparison of droplet on demand, grease injection and Gas Dynamic Virtual Nozzle (GDVN) injection shows no significant differences in limiting resolution. The photoconversion of the on- to the off-state includes both internal and surface exposed protein structural changes, occurring in regions that lack crystal contacts in the orthorhombic crystal form. PMID- 28880249 TI - Event-Associated Oxygen Consumption Rate Increases ca. Five-Fold When Interictal Activity Transforms into Seizure-Like Events In Vitro. AB - Neuronal injury due to seizures may result from a mismatch of energy demand and adenosine triphosphate (ATP) synthesis. However, ATP demand and oxygen consumption rates have not been accurately determined, yet, for different patterns of epileptic activity, such as interictal and ictal events. We studied interictal-like and seizure-like epileptiform activity induced by the GABAA antagonist bicuculline alone, and with co-application of the M-current blocker XE 991, in rat hippocampal slices. Metabolic changes were investigated based on recording partial oxygen pressure, extracellular potassium concentration, and intracellular flavine adenine dinucleotide (FAD) redox potential. Recorded data were used to calculate oxygen consumption and relative ATP consumption rates, cellular ATP depletion, and changes in FAD/FADH2 ratio by applying a reactive diffusion and a two compartment metabolic model. Oxygen-consumption rates were ca. five times higher during seizure activity than interictal activity. Additionally, ATP consumption was higher during seizure activity (~94% above control) than interictal activity (~15% above control). Modeling of FAD transients based on partial pressure of oxygen recordings confirmed increased energy demand during both seizure and interictal activity and predicted actual FAD autofluorescence recordings, thereby validating the model. Quantifying metabolic alterations during epileptiform activity has translational relevance as it may help to understand the contribution of energy supply and demand mismatches to seizure-induced injury. PMID- 28880250 TI - Glycans as Regulatory Elements of the Insulin/IGF System: Impact in Cancer Progression. AB - The insulin/insulin-like growth factor (IGF) system in mammals comprises a dynamic network of proteins that modulate several biological processes such as development, cell growth, metabolism, and aging. Dysregulation of the insulin/IGF system has major implications for several pathological conditions such as diabetes and cancer. Metabolic changes also culminate in aberrant glycosylation, which has been highlighted as a hallmark of cancer. Changes in glycosylation regulate every pathophysiological step of cancer progression including tumour cell-cell dissociation, cell migration, cell signaling and metastasis. This review discusses how the insulin/IGF system integrates with glycosylation alterations and impacts on cell behaviour, metabolism and drug resistance in cancer. PMID- 28880252 TI - BMRC: A Bitmap-Based Maximum Range Counting Approach for Temporal Data in Sensor Monitoring Networks. AB - Due to the rapid development of the Internet of Things (IoT), many feasible deployments of sensor monitoring networks have been made to capture the events in physical world, such as human diseases, weather disasters and traffic accidents, which generate large-scale temporal data. Generally, the certain time interval that results in the highest incidence of a severe event has significance for society. For example, there exists an interval that covers the maximum number of people who have the same unusual symptoms, and knowing this interval can help doctors to locate the reason behind this phenomenon. As far as we know, there is no approach available for solving this problem efficiently. In this paper, we propose the Bitmap-based Maximum Range Counting (BMRC) approach for temporal data generated in sensor monitoring networks. Since sensor nodes can update their temporal data at high frequency, we present a scalable strategy to support the real-time insert and delete operations. The experimental results show that the BMRC outperforms the baseline algorithm in terms of efficiency. PMID- 28880251 TI - Studying Electrotaxis in Microfluidic Devices. AB - Collective cell migration is important in various physiological processes such as morphogenesis, cancer metastasis and cell regeneration. Such migration can be induced and guided by different chemical and physical cues. Electrotaxis, referring to the directional migration of adherent cells under stimulus of electric fields, is believed to be highly involved in the wound-healing process. Electrotactic experiments are conventionally conducted in Petri dishes or cover glasses wherein cells are cultured and electric fields are applied. However, these devices suffer from evaporation of the culture medium, non-uniformity of electric fields and low throughput. To overcome these drawbacks, micro-fabricated devices composed of micro-channels and fluidic components have lately been applied to electrotactic studies. Microfluidic devices are capable of providing cells with a precise micro-environment including pH, nutrition, temperature and various stimuli. Therefore, with the advantages of reduced cell/reagent consumption, reduced Joule heating and uniform and precise electric fields, microfluidic chips are perfect platforms for observing cell migration under applied electric fields. In this paper, I review recent developments in designing and fabricating microfluidic devices for studying electrotaxis, aiming to provide critical updates in this rapidly-growing, interdisciplinary field. PMID- 28880253 TI - Modeling Burns for Pre-Cooled Skin Flame Exposure. AB - On a television show, a pre-cooled bare-skinned person (TV host) passed through engulfing kerosene flames. The assumption was that a water film should protect him during 0.74 s flame exposure in an environment of 86 kW/m2 heat flux. The TV host got light burn inflammation on the back, arms and legs. The present work studies skin temperatures and burn damage integral of such dangerous flame exposure. The skin temperature distribution during water spray pre-cooling, transport to the flames, flame exposure, transport to the water pool, and final water pool cooling is modelled numerically. Details of the temperature development of the skin layers are presented, as well as the associated damage integral. It is shown that 5 degrees C water spray applied for a 30 s period pre cooled the skin sufficiently to prevent severe skin injury. Soot marks indicate that the water layer evaporated completely in some areas resulting in skin flame contact. This exposed dry skin directly to the flames contributing significantly to the damage integral. It is further analyzed how higher water temperature, shorter pre-cooling period or longer flame exposure influence the damage integral. It is evident that minor changes in conditions could lead to severe burns and that high heat flux levels at the end of the exposure period are especially dangerous. This flame stunt should never be repeated. PMID- 28880254 TI - Concrete Crack Identification Using a UAV Incorporating Hybrid Image Processing. AB - Crack assessment is an essential process in the maintenance of concrete structures. In general, concrete cracks are inspected by manual visual observation of the surface, which is intrinsically subjective as it depends on the experience of inspectors. Further, it is time-consuming, expensive, and often unsafe when inaccessible structural members are to be assessed. Unmanned aerial vehicle (UAV) technologies combined with digital image processing have recently been applied to crack assessment to overcome the drawbacks of manual visual inspection. However, identification of crack information in terms of width and length has not been fully explored in the UAV-based applications, because of the absence of distance measurement and tailored image processing. This paper presents a crack identification strategy that combines hybrid image processing with UAV technology. Equipped with a camera, an ultrasonic displacement sensor, and a WiFi module, the system provides the image of cracks and the associated working distance from a target structure on demand. The obtained information is subsequently processed by hybrid image binarization to estimate the crack width accurately while minimizing the loss of the crack length information. The proposed system has shown to successfully measure cracks thicker than 0.1 mm with the maximum length estimation error of 7.3%. PMID- 28880256 TI - Improvement of Early Strength of Cement Mortar Containing Granulated Blast Furnace Slag Using Industrial Byproducts. AB - In the field of construction, securing the early strength of concrete (on the first and third days of aging) has been an important problem in deciding the mold release time (i.e., shortening the construction time period). Therefore, the problem of reduced compressive strength in the early aging stage caused by mixing granulated blast furnace slag (GBFS) with concrete must certainly be resolved. In this study, we conduct experiments to explore methods for generating a concrete that develops an early strength equivalent to that of 100% OPC. The objective of this study is the development of an early-strength accelerator (ESA) made from an industrial by-product, for a GBFS-mixed cement mortar. This study also analyzes the mechanism of the early-strength generation in the concrete to evaluate the influence of the burning temperature of ESA on the optimal compressive strength of the concrete. According to the results of the experiment, GBFS, whose ESA is burnt at 800 degrees C, shows an activation factor of 102.6-104.7% in comparison with 100% OPC on the first and third days during early aging, thereby meeting the target compressive strength. The results of the micro-analytic experiment are as follows: ESA showed a pH of strongly alkaline. In addition, it was found that the content of SO3 was high in the chemical components, thus activating the hydration reaction of GBFS in the early age. This initial hydration reaction was thought to be due to the increase in the filling effect of the hydrate and the generation of C-S-H of the early age by the mass production of Ettringite. PMID- 28880255 TI - Evaluation of Different Dose-Response Models for High Hydrostatic Pressure Inactivation of Microorganisms. AB - Modeling of microbial inactivation by high hydrostatic pressure (HHP) requires a plot of the log microbial count or survival ratio versus time data under a constant pressure and temperature. However, at low pressure and temperature values, very long holding times are needed to obtain measurable inactivation. Since the time has a significant effect on the cost of HHP processing it may be reasonable to fix the time at an appropriate value and quantify the inactivation with respect to pressure. Such a plot is called dose-response curve and it may be more beneficial than the traditional inactivation modeling since short holding times with different pressure values can be selected and used for the modeling of HHP inactivation. For this purpose, 49 dose-response curves (with at least 4 log10 reduction and >=5 data points including the atmospheric pressure value (P = 0.1 MPa), and with holding time <=10 min) for HHP inactivation of microorganisms obtained from published studies were fitted with four different models, namely the Discrete model, Shoulder model, Fermi equation, and Weibull model, and the pressure value needed for 5 log10 (P5) inactivation was calculated for all the models above. The Shoulder model and Fermi equation produced exactly the same parameter and P5 values, while the Discrete model produced similar or sometimes the exact same parameter values as the Fermi equation. The Weibull model produced the worst fit (had the lowest adjusted determination coefficient (R2adj) and highest mean square error (MSE) values), while the Fermi equation had the best fit (the highest R2adj and lowest MSE values). Parameters of the models and also P5 values of each model can be useful for the further experimental design of HHP processing and also for the comparison of the pressure resistance of different microorganisms. Further experiments can be done to verify the P5 values at given conditions. The procedure given in this study can also be extended for enzyme inactivation by HHP. PMID- 28880257 TI - Inverse association between cigarette and water pipe smoking and hypertension in an elderly population in Iran: Bushehr elderly health programme. AB - The collected data in Bushehr Elderly Health (BEH) Program which had detailed the data on participants' smoking status and habits, was analysed to investigate the association between smoking of both water pipes and cigarettes and hypertension in an elderly population. Three thousand elderly men and women who participated in the baseline assessment of the BEH Program-a prospective population-based study being conducted in Bushehr, Iran-were selected randomly through a multistage, stratified cluster sampling method. Systolic and diastolic blood pressures were measured twice using a mercury sphygmomanometer, and researchers asked participants about medical history of hypertension as well as history of cigarette and water pipe smoking. Researchers used binary logistic regression models to assess the association of hypertension and smoking, and found an inverse, statistically significant association between current smoking and hypertension (odds ratio (OR)=0.50 (95% confidence interval (CI)=0.41, 0.60)). The association remained statistically significant after controlling for age, education and body mass index (OR=0.54 (95% CI=0.45, 0.66)). Findings were consistent for cigarette and water pipe smoking by sex (all ORs were inverse and statistically significant). Both cigarette and water pipe smoking were associated with reduced hypertension among older people, but the strength of association was different between men and women and also between cigarette and water pipe smoking. The reasons behind the association as well as the differences observed need to be investigated through more comprehensive, longitudinal studies. PMID- 28880258 TI - Do trials reduce uncertainty? Assessing impact through cumulative meta-analysis of neonatal RCTs. AB - OBJECTIVE: To assess the impact of the latest randomized controlled trial (RCT) to each systematic review (SR) in Cochrane Neonatal Reviews. STUDY DESIGN: We selected meta-analyses reporting the typical point estimate of the risk ratio for the primary outcome of the latest study (n=130), mortality (n=128) and the mean difference for the primary outcome (n=44). We employed cumulative meta-analysis to determine the typical estimate after each trial was added, and then performed multivariable logistic regression to determine factors predictive of study impact. RESULTS: For the stated primary outcome, 18% of latest RCTs failed to narrow the confidence interval (CI), and 55% failed to decrease the CI by ?20%. Only 8% changed the typical estimate directionality, and 11% caused a change to or from significance. Latest RCTs did not change the typical estimate in 18% of cases, and only 41% changed the typical estimate by at least 10%. The ability to narrow the CI by >20% was negatively associated with the number of previously published RCTs (odds ratio 0.707). Similar results were found in analysis of typical estimates for the outcomes of mortality and mean difference. CONCLUSION: Across a broad range of clinical questions, the latest RCT failed to substantially narrow the CI of the typical estimate, to move the effect estimate or to change its statistical significance in a majority of cases. Investigators and grant peer review committees should consider prioritizing less-studied topics or requiring formal consideration of optimal information size based on extant evidence in power calculations. PMID- 28880259 TI - Management of asymptomatic neonates born in the setting of chorioamnionitis: a safety comparison of the well-baby and intensive care setting. AB - BACKGROUND: Evaluate the safety of a change in care setting for asymptomatic neonates born to mothers with chorioamnionitis from the neonatal intensive care unit to the well baby nursery.Local problem:The neonatal intensive care unit evaluation and management of babies born to mothers with chorioamionitis often involves separation of the mother-baby dyad and more invasive interventions. METHODS: A single-center pre/post-intervention study of neonates born from January 2011 to November 2016, comparing safety outcomes in the neonatal intensive care unit (pre-intervention) and well baby nursery (post-intervention), following initiation of a triage protocol. INTERVENTIONS: A protocolized, systematic change was done in the practice location. RESULTS: Groups were similar for time to first antibiotic administration, sepsis symptom development and positive blood cultures. Length of stay (median 73.5 vs 64.4 h, P=0.0192) and % of neonates with intravenous fluid exposure (50.4% vs 7.6%, P<0.0001) were lower in the post-intervention group. Exclusive breastfeeding rates improved (pre-7.3% vs post-46.1%, P<0.0001). CONCLUSIONS: Asymptomatic neonates born to mothers with chorioamnionitis were safely treated in a well baby nursery under the guidance of a protocol for triage, thereby reducing NICU exposure for these neonates. PMID- 28880261 TI - Bronchopulmonary dysplasia-associated pulmonary hypertension: clues from placental pathology. AB - OBJECTIVES: Bronchopulmonary dysplasia (BPD) and the associated complication of pulmonary hypertension (PH) leads to increased mortality and a longer length of stay among survivors. Placental histopathology may give early clues of subsequent events. The objective was to evaluate the relationship of maternal vascular underperfusion (MVU) changes on placental histopathology with subsequent development of BPD-associated PH in a cohort of extremely premature infants. STUDY DESIGN: In a cohort of preterm infants '?28 weeks' gestational age (GA) and with 'severe' BPD, this retrospective study evaluated specific placental histopathological changes and assessed the relationship with subsequent development of PH. 'Severe' BPD was defined as the need for ?30% oxygen and/or positive pressure ventilation at 36 weeks postmenstrual age. Placental and echocardiographic assessments were done by investigators masked to the grouping and clinical outcomes. RESULTS: Fifty six infants with severe BPD formed the cohort; PH was noted in 22 (39.3%) infants. The GA of the infants with and without PH was comparable (25.8+/-1.6 vs 25.8+/-1.3 weeks, P=0.9). On placental histopathological examination, 13 (23%) had features of MVU. On univariate logistic regression, the presence of changes consistent with MVU increased the relative risk of subsequent BPD-associated PH by 2.75 (95% confidence interval 1.56 to 4.85, P=0.004). The significance persisted after adjustment for GA. Stratification by the presence or absence of fetal growth restriction, yielded nonsignificant associations (P=0.17). CONCLUSION: Based on the results of the present study, specific placental histopathological changes may give early clues to the subsequent development of BPD-associated PH. PMID- 28880260 TI - Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants. AB - OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns. STUDY DESIGN: The original study was a multicenter RCT. Eligibility: ?34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives. PMID- 28880262 TI - Acceleration of pancreatic tumorigenesis under immunosuppressive microenvironment induced by Reg3g overexpression. AB - Reg3g is a potential risk for pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that Reg3g promoted pancreatic carcinogenesis via a STAT3 signaling pathway in a murine model of chronic pancreatitis. Whether the immune response is involved in tumorigenesis induced by Reg3g remains unknown. In this study, Reg3g-regulated tumor immunity was evaluated in tumor-implanted murine models, immune cells, and tumor microenvironment. In mice that had been orthotopically or ectopically implanted with Panc02 cells, Reg3g overexpression increased EGFR and Ki67, diminished MHC-I and caspase-3 expression, and accelerated growth of tumors. By interacting with PD-1/PD-L1, Reg3g also promoted differentiation of Tregs and recruitment of MDSC, retarded maturation of DCs and inactivation of CD8+ T cells, and suppressed cross-priming of CD8+ T-cell responses by DCs in tumor-bearing mice. Knockdown of Reg3g delayed tumor development in normal mice, but not in CD8+ T-cell-deficient mice. In vitro, Reg3g upregulated EGFR in DCs, activated heme oxygenase-1 (Hmox1) involved JAK2/STAT3 signaling, raised levels of Th2 cytokines in and suppressed maturation of DCs, and enhanced tumor cell proliferation. These results reveal a novel role of Reg3g as an immunosuppressive promoter that weakens tumor-specific antigenicity and suppresses antitumor effects of CD8+ T cells in a murine model of pancreatic cancer. Reg3g produces these effects by activating the JAK2/STAT3 signaling pathway in DCs, triggering the generation of an immunosuppressive tumor microenvironment. PMID- 28880263 TI - LRP6 is identified as a potential prognostic marker for oral squamous cell carcinoma via MALDI-IMS. AB - Oral squamous cell carcinoma (OSCC) is a leading cause of cancer-related deaths worldwide, with 500 000 new cases each year. However, the mechanisms underlying OSCC development are relatively unknown. In this study, matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS)-based proteomic strategy was used to profile the differentially expressed peptides/proteins between OSCC tissues and their adjacent noncancerous tissues. Sixty-seven unique peptide peaks and five distinct proteins were identified with changed expression levels. Among them, LRP6 expression was found to be upregulated in OSCC tissues, and correlated with a cluster of clinicopathologic parameters, including smoking, drinking, tumor differentiation status, lymph node metastasis and survival time. Notably, knockdown of LRP6 inhibited the proliferation ability of OSCC cells. Furthermore, we demonstrated that the expression of LRP6 in OSCC cells is positively correlated with its downstream oncogene, FGF8. The present study suggests that LRP6 could be a potential biomarker for OSCC patients, and might further assist in the therapeutic decisions in OSCC treatment. PMID- 28880264 TI - Knockdown of SIRT7 enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells partly via activation of the Wnt/beta-catenin signaling pathway. AB - Sirtuin 7 (SIRT7) is a NAD+-dependent deacetylase in the sirtuin family. In a previous study, human bone marrow mesenchymal stem cells (hBMSCs) with reduced SIRT7 activity were developed to evaluate the effect of SIRT7 on osteogenesis. SIRT7 knockdown significantly enhanced osteoblast-specific gene expression, alkaline phosphatase activity, and mineral deposition in vitro. Additionally, SIRT7 knockdown upregulated beta-catenin. The enhanced osteogenesis due to SIRT7 knockdown was partially rescued by a Wnt/beta-catenin inhibitor. Furthermore, SIRT7 knockdown hBMSCs combined with a chitosan scaffold significantly promoted bone formation in a rat tibial defect model, as determined by imaging and histological examinations. These findings suggest that SIRT7 has an essential role in osteogenic differentiation of hBMSCs, partly by activation of the Wnt/beta-catenin signaling pathway. PMID- 28880265 TI - CDP138 silencing inhibits TGF-beta/Smad signaling to impair radioresistance and metastasis via GDF15 in lung cancer. AB - CDP138, a CDK5 binding partner, regulates cell proliferation and migration. However, the mechanisms by which CDP138 functions in these processes remain unclear. In this study, we show that CDP138 is frequently overexpressed and that high levels of CDP138 are correlated with lymph node metastasis in lung cancer. Furthermore, we provide evidence that CDP138-depleted lung cancer cells exhibit enhanced radiosensitivity as well as reduced migration and invasion. Mechanistically, we identify GDF15, a member of the TGF-beta superfamily, as a key downstream effector of CDP138. CDP138 silencing attenuates TGF-beta/Smad signaling activation at least in part through the downregulation of GDF15. More importantly, the observed phenotypes caused by CDP138 knockdown are partially dependent on GDF15 inhibition. Together, our findings demonstrate that CDP138 positively modulates the TGF-beta/Smad signaling pathway via GDF15 to promote radioresistance and metastasis, suggesting CDP138 as a potential oncogenic biomarker and a promising therapeutic target in the treatment of lung cancer. PMID- 28880266 TI - The intracellular angiotensin system buffers deleterious effects of the extracellular paracrine system. AB - The 'classical' renin-angiotensin system (RAS) is a circulating system that controls blood pressure. Local/paracrine RAS, identified in a variety of tissues, including the brain, is involved in different functions and diseases, and RAS blockers are commonly used in clinical practice. A third type of RAS (intracellular/intracrine RAS) has been observed in some types of cells, including neurons. However, its role is still unknown. The present results indicate that in brain cells the intracellular RAS counteracts the intracellular superoxide/H2O2 and oxidative stress induced by the extracellular/paracrine angiotensin II acting on plasma membrane receptors. Activation of nuclear receptors by intracellular or internalized angiotensin triggers a number of mechanisms that protect the cell, such as an increase in the levels of protective angiotensin type 2 receptors, intracellular angiotensin, PGC-1alpha and IGF 1/SIRT1. Interestingly, this protective mechanism is altered in isolated nuclei from brains of aged animals. The present results indicate that at least in the brain, AT1 receptor blockers acting only on the extracellular or paracrine RAS may offer better protection of cells. PMID- 28880267 TI - p73 is required for appropriate BMP-induced mesenchymal-to-epithelial transition during somatic cell reprogramming. AB - The generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming holds great potential for modeling human diseases. However, the reprogramming process remains very inefficient and a better understanding of its basic biology is required. The mesenchymal-to-epithelial transition (MET) has been recognized as a crucial step for the successful reprogramming of fibroblasts into iPSCs. It has been reported that the p53 tumor suppressor gene acts as a barrier of this process, while its homolog p63 acts as an enabling factor. In this regard, the information concerning the role of the third homolog, p73, during cell reprogramming is limited. Here, we derive total Trp73 knockout mouse embryonic fibroblasts, with or without Trp53, and examine their reprogramming capacity. We show that p73 is required for effective reprogramming by the Yamanaka factors, even in the absence of p53. Lack of p73 affects the early stages of reprogramming, impairing the MET and resulting in altered maturation and stabilization phases. Accordingly, the obtained p73-deficient iPSCs have a defective epithelial phenotype and alterations in the expression of pluripotency markers. We demonstrate that p73 deficiency impairs the MET, at least in part, by hindering BMP pathway activation. We report that p73 is a positive modulator of the BMP circuit, enhancing its activation by DNp73 repression of the Smad6 promoter. Collectively, these findings provide mechanistic insight into the MET process, proposing p73 as an enhancer of MET during cellular reprogramming. PMID- 28880268 TI - Cezanne predicts progression and adjuvant TACE response in hepatocellular carcinoma. AB - We have previously reported that Cezanne could be a prognostic biomarker for survival in hepatocellular carcinoma (HCC) patients. However, the role of Cezanne genes in HCC cells and its response to postoperative adjuvant transcatheter arterial chemoembolization (TACE) in HCC patients remains unknown. In this study, Cezanne expression was detected in human HCC using real-time PCR, western blot and immunohistochemistry. The function of Cezanne in HCC cells was determined by Transwell invasion assays and nude mice metastasis assay. The response of Cezanne in patients who received adjuvant TACE after hepatectomy was evaluated. Functional study demonstrated that interference of Cezanne expression promoted the migration and invasion of HCC cells in vitro and boosted metastasized HCC formation in mice. Upregulation of Cezanne diminished the adhesion and migration of hepatoma cells. Further study indicated that Cezanne might inhibit invasion of HCC cells by inducing epithelial-mesenchymal transition (EMT). In addition, patients with low Cezanne expression had significant improvement in prognosis after receiving adjuvant TACE. In contrast, patients with high Cezanne expression had a poorer response to adjuvant TACE. Moreover, Cezanne status was associated with response to adjuvant TACE in patients subgroup stratified by vascular invasion, tumor size and tumor number. In conclusion, Cezanne may be a novel antioncogene that has a pivotal role in the invasion of HCC and contribute to the selection of patients who may benefit from adjuvant TACE to prevent recurrence. PMID- 28880269 TI - A stress-induced cellular aging model with postnatal neural stem cells. AB - This corrects the article DOI: 10.1038/cddis.2014.82. PMID- 28880270 TI - Circulating microRNAs in breast cancer: novel diagnostic and prognostic biomarkers. AB - Effective management of breast cancer depends on early diagnosis and proper monitoring of patients' response to therapy. However, these goals are difficult to achieve because of the lack of sensitive and specific biomarkers for early detection and for disease monitoring. Accumulating evidence in the past several years has highlighted the potential use of peripheral blood circulating nucleic acids such as DNA, mRNA and micro (mi)RNA in breast cancer diagnosis, prognosis and for monitoring response to anticancer therapy. Among these, circulating miRNA is increasingly recognized as a promising biomarker, given the ease with which miRNAs can be isolated and their structural stability under different conditions of sample processing and isolation. In this review, we provide current state-of the-art of miRNA biogenesis, function and discuss the advantages, limitations, as well as pitfalls of using circulating miRNAs as diagnostic, prognostic or predictive biomarkers in breast cancer management. PMID- 28880271 TI - Matrine derivate MASM uncovers a novel function for ribosomal protein S5 in osteoclastogenesis and postmenopausal osteoporosis. AB - Postmenopausal osteoporosis (POMP) is a public health problem characterized by decreased bone density and increased fracture risk. Over-activated osteoclastogenesis plays a vital role in POMP. Here we developed a novel bioactive compound MASM (M19) based on sophocarpine. Although it showed no significant effects on osteogenesis and adipogenesis for bone marrow-derived mesenchymal stem cells (BMSCs) in vitro, it could significantly inhibit RANKL/M CSF induced osteoclastogenesis through suppressing NF-kappaB, MAPKs and PI3K/Akt pathways in vitro and ameliorate bone loss in ovariectomized mice in vivo. Ribosomal protein s5 (RPS5) has been identified as a target of M19 and regulates PI3K/Akt, NF-kappaB and MAPKs pathways in osteoclastogenesis. Overexpressions of RPS5 synergistically inhibited osteoclastogenesis with M19 while silencing RPS5 compromised M19 inhibitory effects on osteoclastogenesis in vitro. Among the three pathways, Akt plays a major role in M19 effects. The Akt activator SC79 partially reversed the inhibitory effects on osteoclastogenesis by M19 and RPS5 knocking-down. It indicates that RPS5 serves as a potential candidate target for inhibiting osteoclastogenesis and osteoporosis therapy and M19 is a promising agent for POMP treatment. PMID- 28880272 TI - Abcb1a and Abcb1b genes function differentially in blood-testis barrier dynamics in the rat. AB - During spermatogenesis, immature spermatocytes traverse the blood-testis barrier (BTB) and enter the apical apartment of seminiferous epithelium for further development. This course involves extensive junction disassembly and reassembly at the BTB. P-glycoprotein is known to be coded by two genes in rodents, namely Abcb1a and Abcb1b. Our previous studies showed that simultaneously silencing Abcb1a and Abcb1b genes in Sertoli cells impeded BTB integrity. However, the individual role of Abcb1a and Abcb1b in regulating BTB dynamics remains uninvestigated. Here, single knockdown of Abcb1a by RNAi impeded the in vitro Sertoli cell permeability barrier via redistributing TJ proteins, accelerating endocytosis, and affecting endocytic vesicle-mediated protein transportation that undermined Sertoli cell barrier. F5-peptide model was used to induce cell junction disruption and subsequent restructuring in primary Sertoli cells. F5 peptide perturbed this barrier, but its removal allowed barrier 'resealing'. Abcb1b knockdown was found to inhibit barrier resealing following F5-peptide removal by suppressing the restore of the expression and distribution of junction proteins at BTB, and reducing the migration of internalized junction proteins back to Sertoli cell interface. In summary, Abcb1a is critical in maintaining BTB integrity, while Abcb1b is crucial for junction reassembly at the BTB. PMID- 28880273 TI - Tailored therapy guided by multichannel intraluminal impedance pH monitoring for refractory non-erosive reflux disease. AB - A relevant percentage of non-erosive reflux disease (NERD) is refractory to proton pump inhibitors (PPIs) treatment. Multichannel intraluminal impedance pH (MII-pH) monitoring should give useful pathophysiological information about refractoriness. Therefore, our aim was to assess whether this technique could be useful to guide a 'tailored' therapy in refractory NERD. We retrospectively recruited NERD patients undergoing MII-pH monitoring for unsuccessful treatment. All patients had undergone upper endoscopy, and those with erosive esophagitis were excluded. No patient received PPI during MII-pH monitoring. Subjects were subgrouped into three categories: acid reflux, non-acid reflux and functional heartburn. MII-pH-guided therapy was performed for 4 weeks as follows: patients with acid reflux received PPI at double dose, patients with non-acid reflux PPI at full dose plus alginate four times a day and patients with functional heartburn levosulpiride 75 mg per day. A visual analog scale (VAS) ranging from 0 to 100 mm was administered before and after such tailored therapy to evaluate overall symptoms. Responders were defined by VAS improvement of at least 40%. Sixty-nine patients with refractory NERD were selected (female-male ratio 43 : 26, mean age 47.6+/-15.2 years). Overall effectiveness of tailored therapy was 84% without statistical difference among subgroups (88.5% acid reflux, 92% non acid reflux, 66.6% functional heartburn; P=0.06). Univariate analysis showed that therapy failure directly correlated with functional heartburn diagnosis (OR=4.60) and suggested a trend toward a negative correlation with smoking and a positive one with nausea. However, at multivariate analysis, these parameters were not significant. Functional heartburn experienced a lower median percent VAS reduction than acid reflux (52.5% versus 66.6%, P<0.01) even if equal to non-acid reflux (66.6%). In conclusion, a tailored approach to refractory NERD, guided by MII-pH monitoring, demonstrated to be effective and should be promising to cure symptom persistence after conventional therapy failure. Nevertheless, standardized guidelines are advisable. PMID- 28880274 TI - The functional relationship between transglutaminase 2 and transforming growth factor beta1 in the regulation of angiogenesis and endothelial-mesenchymal transition. AB - The importance of transglutaminase 2 (TG2) in angiogenesis has been highlighted in recent studies, but other roles of this multi-functional enzyme in endothelial cell (EC) function still remains to be fully elucidated. We previously showed that the extracellular TG2 is involved in maintaining tubule formation in ECs by a mechanism involving matrix-bound vascular endothelial growth factor (VEGF) signalling. Here, by using the ECs and fibroblast co-culture and ECs 3D culture models, we demonstrate a further role for TG2 in both endothelial tubule formation and in tubule loss, which involves its role in the regulation of transforming growth factor beta1 (TGFbeta1) and Smad signalling. We demonstrate that inhibition of tubule formation by TG2 inhibitors can be restored by add-back of exogenous TGFbeta1 at pg/ml levels and show that TG2 -/- mouse ECs are unable to form tubules in 3D culture and display negligible Smad signalling compared to wild-type cells. Loss of tubule formation in the TG2 -/- ECs can be reconstituted by transduction with TG2. We demonstrate that extracellular TG2 also has an important role in TGFbeta1-induced transition of ECs into myofibroblast-like cells (endothelial-mesenchymal transition), resulting in loss of EC tubules and tubule formation. Our data also indicate that TG2 may have a role in regulating TGFbeta signalling through entrapment of active TGFbeta1 into the extracellular matrix. In conclusion, our work demonstrates that TG2 has multi-functional roles in ECs where its ability to fine-tune of TGFbeta1 signalling means it can be involved in both endothelial tubule formation and tubule rarefaction. PMID- 28880275 TI - LGR5 promotes cancer stem cell traits and chemoresistance in cervical cancer. AB - Cancer stem cells (CSCs), also known as tumor-initiating cells, contribute to tumorigenesis, resistance to chemoradiotherapy and recurrence in human cancers, suggesting targeting CSCs may represent a potential therapeutic strategy. Leucine rich repeat-containing G-protein-coupled receptor 5 (LGR5) has recently been found to be a bona fide marker of colorectal CSCs. Our previous study showed that LGR5 functions as a tumor promoter in cervical cancer by activating the Wnt/beta catenin pathway. However, very little is known about the function or contribution of LGR5 to cervical CSCs. Here, we have modulated the expression of LGR5 using an overexpression vector or short hairpin RNA in cervical cancer cell lines. We demonstrated that elevated LGR5 expression in cervical cancer cells increased tumorsphere-forming efficiency; conferred chemoresistance to cisplatin treatment; augmented cell migration, invasion and clonogenicity; and elevated the levels of stem cell-related transcription factors in vitro. Furthermore, modulated LGR5+ cells, unlike LGR5- cells, were highly tumorigenic in vivo. In addition, the modulated LGR5+ cells could give rise to both LGR5+ and LGR5- cells in vitro and in vivo, thereby establishing a cellular hierarchy. Finally, we found that the increased tumorsphere-forming efficiency induced by LGR5 could be regulated through the inhibition or activation of the Wnt/beta-catenin pathway in cervical cancer cells. Taken together, these results indicate that LGR5 has a vital oncogenic role by promoting cervical CSC traits and may represent a potential clinical target. PMID- 28880277 TI - Use of a neonatal rat system as a bioincubator to generate adult-like mature cardiomyocytes from human and mouse pluripotent stem cells. AB - Pluripotent stem cells (PSCs), including induced PSCs, hold great potential for personalized disease modeling, drug testing and cell-based therapeutics. However, cells differentiated from PSCs remain immature in a dish, and thus there are serious caveats to their use in modeling adult-onset diseases such as cardiomyopathies and Alzheimer's disease. By taking advantage of knowledge gained about mammalian development and from bioinformatics analyses, we recently developed a neonatal rat system that enables maturation of PSC-derived cardiomyocytes into cardiomyocytes analogous to those seen in adult animals. Here we describe a detailed protocol that describes how to initiate the in vitro differentiation of mouse and human PSCs into cardiac progenitor cells, followed by intramyocardial delivery of the progenitor cells into neonatal rat hearts, in vivo incubation and analysis. The entire process takes ~6 weeks, and the resulting cardiomyocytes can be analyzed for morphology, function and gene expression. The neonatal system provides a valuable tool for understanding the maturation and pathogenesis of adult human heart muscle cells, and this concept may be expanded to maturing other PSC-derived cell types, including those containing mutations that lead to the development of diseases in the adult. PMID- 28880278 TI - Preparation of biogenic gas vesicle nanostructures for use as contrast agents for ultrasound and MRI. AB - Gas vesicles (GVs) are a unique class of gas-filled protein nanostructures that are detectable at subnanomolar concentrations and whose physical properties allow them to serve as highly sensitive imaging agents for ultrasound and MRI. Here we provide a protocol for isolating GVs from native and heterologous host organisms, functionalizing these nanostructures with moieties for targeting and fluorescence, characterizing their biophysical properties and imaging them using ultrasound and MRI. GVs can be isolated from natural cyanobacterial and haloarchaeal host organisms or from Escherichia coli expressing a heterologous GV gene cluster and purified using buoyancy-assisted techniques. They can then be modified by replacing surface-bound proteins with engineered, heterologously expressed variants or through chemical conjugation, resulting in altered mechanical, surface and targeting properties. Pressurized absorbance spectroscopy is used to characterize their mechanical properties, whereas dynamic light scattering (DLS)and transmission electron microscopy (TEM) are used to determine nanoparticle size and morphology, respectively. GVs can then be imaged with ultrasound in vitro and in vivo using pulse sequences optimized for their detection versus background. They can also be imaged with hyperpolarized xenon MRI using chemical exchange saturation transfer between GV-bound and dissolved xenon-a technique currently implemented in vitro. Taking 3-8 d to prepare, these genetically encodable nanostructures enable multimodal, noninvasive biological imaging with high sensitivity and potential for molecular targeting. PMID- 28880276 TI - LncRNA ZNF503-AS1 promotes RPE differentiation by downregulating ZNF503 expression. AB - Long noncoding RNAs (lncRNAs) have important roles in various biological processes. Our previous work has revealed that dedifferentiation of retinal pigment epithelium (RPE) cells contributes to the pathology of age-related macular degeneration (AMD). Herein, we show roles of lncRNAs in RPE differentiation. We used microarray to identify lncRNA expression profiles in human induced pluripotent stem cells (hiPSCs) and hiPSC-derived RPE cells. A total of 217 differentially expressed lncRNAs along with the differentiation were initially identified, among which 13 lncRNAs showed a consistent fold change of over 2. LncRNA ZNF503-AS1, located in the cytoplasm of RPE cells, was found consistently upregulated along with RPE differentiation, and downregulated in the RPE-choroid of AMD patients. In vitro study further suggested that ZNF503-AS1 insufficiency could inhibit RPE differentiation, and promote its proliferation and migration. As ZNF503-AS1 is transcribed from the antisense strand of the ZNF503 gene locus, we further revealed its regulatory role in ZNF503 expression. ZNF503-AS1 was reversely correlated with ZNF503 expression. Our results also suggested that ZNF503 could inhibit RPE differentiation, and promote its proliferation and migration. Thus, ZNF503-AS1 potentially promotes RPE differentiation through downregulation of ZNF503 expression. In addition, nuclear factor-kappaB was recognized as a potential upstream transcript factor for ZNF503 AS1, which might participate in promoting RPE differentiation by regulating the expression of ZNF503-AS1. Taken together, our study identifies a group of RPE differentiation relevant lncRNAs, and the potential role of ZNF503-AS1 in the pathology of atrophic AMD, which might help with the intervention of AMD patients. PMID- 28880279 TI - Live-cell confocal microscopy and quantitative 4D image analysis of anchor-cell invasion through the basement membrane in Caenorhabditis elegans. AB - Cell invasion through basement membrane (BM) barriers is crucial in development, leukocyte trafficking and the spread of cancer. The mechanisms that direct invasion, despite their importance in normal and disease states, are poorly understood, largely because of the inability to visualize dynamic cell-BM interactions in vivo. This protocol describes multichannel time-lapse confocal imaging of anchor-cell invasion in live Caenorhabditis elegans. Methods presented include outline-slide preparation and worm growth synchronization (15 min), mounting (20 min), image acquisition (20-180 min), image processing (20 min) and quantitative analysis (variable timing). The acquired images enable direct measurement of invasive dynamics including formation of invadopodia and cell membrane protrusions, and removal of BM. This protocol can be combined with genetic analysis, molecular-activity probes and optogenetic approaches to uncover the molecular mechanisms underlying cell invasion. These methods can also be readily adapted by any worm laboratory for real-time analysis of cell migration, BM turnover and cell-membrane dynamics. PMID- 28880280 TI - Multiparametric characterization of rare HIV-infected cells using an RNA-flow FISH technique. AB - Efforts to cure HIV are hampered by limited characterization of the cells supporting HIV replication in vivo and inadequate methods for quantifying the latent viral reservoir in individuals receiving antiretroviral therapy (ART). We describe a protocol for flow cytometric identification of viral reservoirs, based on concurrent detection of cellular HIV Gagpol mRNA by in situ RNA hybridization combined with antibody staining for the HIV Gag protein. By simultaneously detecting both HIV RNA and protein, the CD4 T cells harboring translation competent virus can be identified. The HIVRNA/Gag method is 1,000-fold more sensitive than Gag protein staining alone, with a detection limit of 0.5-1 Gagpol mRNA+/Gag protein+ cells per million CD4 T cells. Uniquely, the HIVRNA/Gag assay also allows parallel phenotyping of viral reservoirs, including reactivated latent reservoirs in clinical samples. The assay takes 2 d, and requires antibody labeling for surface and intracellular markers, followed by mRNA labeling and multiple signal amplification steps. PMID- 28880282 TI - Quantum gravity: Quantum effects in the gravitational field. PMID- 28880281 TI - A right-handed signalling pathway drives heart looping in vertebrates. AB - Most animals show external bilateral symmetry, which hinders the observation of multiple internal left-right (L/R) asymmetries that are fundamental to organ packaging and function. In vertebrates, left identity is mediated by the left specific Nodal-Pitx2 axis that is repressed on the right-hand side by the epithelial-mesenchymal transition (EMT) inducer Snail1 (refs 3, 4). Despite some existing evidence, it remains unclear whether an equivalent instructive pathway provides right-hand-specific information to the embryo. Here we show that, in zebrafish, BMP mediates the L/R asymmetric activation of another EMT inducer, Prrx1a, in the lateral plate mesoderm with higher levels on the right. Prrx1a drives L/R differential cell movements towards the midline, leading to a leftward displacement of the cardiac posterior pole through an actomyosin-dependent mechanism. Downregulation of Prrx1a prevents heart looping and leads to mesocardia. Two parallel and mutually repressed pathways, respectively driven by Nodal and BMP on the left and right lateral plate mesoderm, converge on the asymmetric activation of the transcription factors Pitx2 and Prrx1, which integrate left and right information to govern heart morphogenesis. This mechanism is conserved in the chicken embryo, and in the mouse SNAIL1 acts in a similar manner to Prrx1a in zebrafish and PRRX1 in the chick. Thus, a differential L/R EMT produces asymmetric cell movements and forces, more prominent from the right, that drive heart laterality in vertebrates. PMID- 28880285 TI - Maryam Mirzakhani (1977-2017). PMID- 28880284 TI - Direct instrumental identification of catalytically active surface sites. AB - The activity of heterogeneous catalysts-which are involved in some 80 per cent of processes in the chemical and energy industries-is determined by the electronic structure of specific surface sites that offer optimal binding of reaction intermediates. Directly identifying and monitoring these sites during a reaction should therefore provide insight that might aid the targeted development of heterogeneous catalysts and electrocatalysts (those that participate in electrochemical reactions) for practical applications. The invention of the scanning tunnelling microscope (STM) and the electrochemical STM promised to deliver such imaging capabilities, and both have indeed contributed greatly to our atomistic understanding of heterogeneous catalysis. But although the STM has been used to probe and initiate surface reactions, and has even enabled local measurements of reactivity in some systems, it is not generally thought to be suited to the direct identification of catalytically active surface sites under reaction conditions. Here we demonstrate, however, that common STMs can readily map the catalytic activity of surfaces with high spatial resolution: we show that by monitoring relative changes in the tunnelling current noise, active sites can be distinguished in an almost quantitative fashion according to their ability to catalyse the hydrogen-evolution reaction or the oxygen-reduction reaction. These data allow us to evaluate directly the importance and relative contribution to overall catalyst activity of different defects and sites at the boundaries between two materials. With its ability to deliver such information and its ready applicability to different systems, we anticipate that our method will aid the rational design of heterogeneous catalysts. PMID- 28880287 TI - Molecular biology: Rhino gives voice to silent chromatin. PMID- 28880288 TI - Applied physics: Quantum signals could soon span the globe. PMID- 28880289 TI - Herbarium collections: Venezuela's botanic heritage in jeopardy. PMID- 28880292 TI - Biomedical literature: Testers wanted for article search tool. PMID- 28880290 TI - Tribute to Daedalus: Fertile mind that led to unexpected places. PMID- 28880294 TI - Discrete and broadband electron acceleration in Jupiter's powerful aurora. AB - The most intense auroral emissions from Earth's polar regions, called discrete for their sharply defined spatial configurations, are generated by a process involving coherent acceleration of electrons by slowly evolving, powerful electric fields directed along the magnetic field lines that connect Earth's space environment to its polar regions. In contrast, Earth's less intense auroras are generally caused by wave scattering of magnetically trapped populations of hot electrons (in the case of diffuse aurora) or by the turbulent or stochastic downward acceleration of electrons along magnetic field lines by waves during transitory periods (in the case of broadband or Alfvenic aurora). Jupiter's relatively steady main aurora has a power density that is so much larger than Earth's that it has been taken for granted that it must be generated primarily by the discrete auroral process. However, preliminary in situ measurements of Jupiter's auroral regions yielded no evidence of such a process. Here we report observations of distinct, high-energy, downward, discrete electron acceleration in Jupiter's auroral polar regions. We also infer upward magnetic-field-aligned electric potentials of up to 400 kiloelectronvolts, an order of magnitude larger than the largest potentials observed at Earth. Despite the magnitude of these upward electric potentials and the expectations from observations at Earth, the downward energy flux from discrete acceleration is less at Jupiter than that caused by broadband or stochastic processes, with broadband and stochastic characteristics that are substantially different from those at Earth. PMID- 28880295 TI - Surface science: Catalytic hotspots get noisy. PMID- 28880296 TI - Materials science: Pulley protection in batteries. PMID- 28880298 TI - North Korea's nuclear test, cash for Italy's scientists and Zika-vaccine pause. PMID- 28880297 TI - How labs are coping with Hurricane Harvey's devastating floods. PMID- 28880299 TI - Germany must go back to its low-carbon future. PMID- 28880301 TI - Budget battle looms for US science programmes. PMID- 28880300 TI - Stop this waste of people, animals and money. PMID- 28880302 TI - Skeleton plundered from Mexican cave was one of the Americas' oldest. PMID- 28880303 TI - Massive Ebola data site planned to combat outbreaks. PMID- 28880304 TI - Plot a course through the genome. PMID- 28880305 TI - Artificial warming trial reveals striking sea-floor changes. PMID- 28880306 TI - Cuckoo call adds another layer of deception. PMID- 28880307 TI - Merkel deserves another term as German chancellor. PMID- 28880308 TI - Illegitimate journals scam even senior scientists. PMID- 28880309 TI - Science must acknowledge its past mistakes and crimes. PMID- 28880310 TI - The secret to Germany's scientific excellence. PMID- 28880311 TI - Scavenger templates: a systems chemistry approach to the synthesis of porphyrin based molecular wires. AB - A hexa-pyridyl template can be used as a scavenger to facilitate the synthesis of a linear porphyrin dodecamer from a mixture of linear hexamers with one or two terminal reactive groups. The template suppresses polymer formation by rapidly cyclizing the fully deprotected hexamer, thus up-regulating formation of the linear dodecamer. PMID- 28880312 TI - Faradaic processes beyond Nernst's law: density functional theory assisted modelling of partial electron delocalisation and pseudocapacitance in graphene oxides. AB - The study of electron delocalisation in oxygen atom segregated zones in graphene, aided by the first-principles density functional theory, has revealed extra energy bands of >=2 eV wide around the Fermi level, predicting Faradaic charge storage occurring in a wide range of potentials, which disagrees with Nernst's law but accounts well for the so called pseudocapacitance of heteroatom-modified graphene based electrode materials in supercapacitors. PMID- 28880313 TI - 3D printed poly(epsilon-caprolactone) scaffolds modified with hydroxyapatite and poly(propylene fumarate) and their effects on the healing of rabbit femur defects. AB - A large variety of approaches have been used to treat large and irregular shaped bone defects with less than optimal success due to material or design issues. In recent years patient specific constructs prepared by additive manufacturing provided a solution to the need for shaping implants to fit irregular defects in the surgery theater. In this study, cylindrical disks of poly(epsilon caprolactone) (PCL) were printed by fused deposition modeling and modified with nanohydroxyapatite (HAp) and poly(propylene fumarate) (PPF) to create a mechanically strong implant with well-defined pore size and porosity, controllable surface hydrophilicity (with PPF) and osteoconductivity (with HAp). Cytotoxicity, irritation and inflammation tests demonstrated that the scaffolds were biocompatible. PCL/HAp and PCL/HAp/PPF scaffolds were implanted in the femurs of rabbits with and without seeding with rabbit Bone Marrow Stem Cells (BMSC) and examined after 4 and 8 weeks with micro-CT, mechanically and histologically. BMSC seeded PCL/HAp/PPF scaffolds showed improved tissue regeneration as determined by bone mineral density and micro-CT. Compressive and tension stiffness values (394 and 463 N mm-1) were significantly higher than those of the healthy rabbit femur (316 and 392 N mm-1, respectively) after 8 weeks of implantation. These 3D implants have great potential for patient specific bone defect treatments. PMID- 28880315 TI - A methyl pivalate based electrolyte for non-aqueous lithium-oxygen batteries. AB - A methyl pivalate (MP) based electrolyte was for the first time reported for non aqueous lithium-oxygen (Li-O2) batteries. This new electrolyte in both superoxide radical solution and a real Li-O2 battery environment showed good chemical stability against superoxide radicals, which was confirmed by 1H NMR and 13C NMR measurements. PMID- 28880314 TI - High yielding and extremely site-selective covalent functionalization of graphene. AB - We describe a method to functionalize graphene covalently with 92% yield and 98% site-selectivity and strict spatial periodicity on the nanometer scale. This method could be extended to other functional molecules. PMID- 28880317 TI - Two fluorescein-based chemosensors for the fast detection of 2,4,6-trinitrophenol (TNP) in water. AB - Two fluorescein-based chemosensors have been developed. They exhibited rapid and selective detection of 2,4,6-trinitrophenol (TNP) via fluorescence quenching both in ethanol and water solution when excited by visible light. PMID- 28880316 TI - A modular design for minor groove binding and recognition of mixed base pair sequences of DNA. AB - The design and synthesis of compounds that target mixed, AT/GC, DNA sequences is described. The design concept connects two N-methyl-benzimidazole-thiophene single GC recognition units with a flexible linker that lets the compound fit the shape and twist of the DNA minor groove while covering a full turn of the double helix. PMID- 28880318 TI - Palladium-catalyzed oxidative amination of homoallylic alcohols: sequentially installing carbonyl and amino groups along an alkyl chain. AB - A novel Pd-catalyzed intermolecular cascade oxidative amination of homoallylic alcohols to yield beta-amino ketones has been developed by using TBHP as the terminal oxidant. The synthetic utility of the reaction can be performed by installing the carbonyl and amino groups along an alkyl chain in one step, offering several advantages such as simple starting materials and easy operation. The resultant beta-amino ketones should have potential applications in the fields of biopharmaceutical and functional materials. PMID- 28880319 TI - Rational design of a fast and selective near-infrared fluorescent probe for targeted monitoring of endogenous nitric oxide. AB - The real-time monitoring of nitric oxide (NO) at the subcellular level is still a great challenge. To attain this goal, we developed a fast and selective near infrared (NIR) fluorescent probe for the targeted tracing of endogenous NO. This probe possesses vital features for the real-time detection of intracellular NO including a significant turn-on NIR response, high specificity, and a fast response by a controlled photoinduced electron transfer (PET) process, which is applicable to the real-time monitoring of endogenous NO in mitochondria. PMID- 28880320 TI - Using a non-spin flip model to rationalize the irregular patterns observed in the activation of the C-H and Si-H bonds of small molecules by CpMCO (M = Co, Rh) complexes. AB - The activation of the C-H and Si-H bonds of CH(CH3)3 and SiH(CH3)3 molecules by organometallic compounds CpMCO (M = Co, Rh) has been investigated through DFT and CASSCF-MRMP2 calculations. In particular, we have analyzed the pathways joining the lowest-lying triplet and singlet states of the reactants with the products arising from the insertion of the metal atom into the C-H or Si-H bonds of the organic molecules. Channels connecting the reactants with the inserted structure Cp(CO)H-M-C(CH3)3 through the oxidative addition of the C-H bond of the organic molecule to the metal fragment were found only for the reaction CpRhCO + CH(CH3)3. However, inserted structures could also be obtained for the interactions of SiH(CH3)3 with CpCoCO and CpRhCO by two sequential reactions involving the formation and rebounding of the radical fragments Cp(CO)H-M + Si(CH3)3. According to this two-step reaction scheme, the complex CpCoCO is unable to activate the C-H bond of the CH(CH3)3 molecule due to the high energy at which the radical fragments Cp(CO)H-M + C(CH3)3 are located. The picture attained for these interactions is consistent with the available experimental data for this kind of reaction and allows rationalization of the differences in the reactivity patterns determined for them without using spin-flip models, as has been proposed in previous studies. PMID- 28880321 TI - Real-time dynamic SERS detection of galectin using glycan-decorated gold nanoparticles. AB - We present the application of surface-enhanced Raman scattering (SERS) spectroscopy for the fast, sensitive and highly specific detection of the galectin-9 (Gal-9) protein in binding buffer (mimicking natural conditions). The method involves the use of specifically designed nanotags comprising glycan decorated gold nanoparticles encoded with 4-mercaptobenzoic acid. At fast time scales Gal-9 can be detected down to a concentration of 1.2 nM by monitoring the SERS signal of the reporter, driven by aggregation of the functionalized Au NPs tags, induced by Gal-9 recognition. We additionally demonstrate that the sensitivity and concentration working range of the sensor can be tuned via control of aggregation dynamics and cluster size distribution. PMID- 28880322 TI - Peptides, polypeptides and peptide-polymer hybrids as nucleic acid carriers. AB - Cell penetrating peptides (CPPs), and protein transduction domains (PTDs) of viruses and other natural proteins serve as a template for the development of efficient peptide based gene delivery vectors. PTDs are sequences of acidic or basic amphipathic amino acids, with superior membrane trespassing efficacies. Gene delivery vectors derived from these natural, cationic and cationic amphipathic peptides, however, offer little flexibility in tailoring the physicochemical properties of single chain peptide based systems. Owing to significant advances in the field of peptide chemistry, synthetic mimics of natural peptides are often prepared and have been evaluated for their gene expression, as a function of amino acid functionalities, architecture and net cationic content of peptide chains. Moreover, chimeric single polypeptide chains are prepared by a combination of multiple small natural or synthetic peptides, which imparts distinct physiological properties to peptide based gene delivery therapeutics. In order to obtain multivalency and improve the gene delivery efficacies of low molecular weight cationic peptides, bioactive peptides are often incorporated into a polymeric architecture to obtain novel 'polymer-peptide hybrids' with improved gene delivery efficacies. Peptide modified polymers prepared by physical or chemical modifications exhibit enhanced endosomal escape, stimuli responsive degradation and targeting efficacies, as a function of physicochemical and biological activities of peptides attached onto a polymeric scaffold. The focus of this review is to provide comprehensive and step-wise progress in major natural and synthetic peptides, chimeric polypeptides, and peptide-polymer hybrids for nucleic acid delivery applications. PMID- 28880323 TI - Wormlike micelles versus water-soluble polymers as rheology-modifiers: similarities and differences. AB - Wormlike micelles (WLMs) formed from surfactants have attracted much attention for their ability to thicken water in a manner similar to water-soluble polymers. It is known that WLMs are cylindrical filaments that can attain very long contour lengths (~few MUm), akin to chains of polymers with ultra-high molecular weights (UHMWs). In this study, we aim to make a direct comparison between the thickening capabilities of WLMs and UHMW polymers. The chosen surfactant is erucyl dimethyl amidopropyl betaine (EDAB), a C22-tailed zwitterionic surfactant known to form particularly long WLMs independent of salt. The chosen polymer is nonionic polyacrylamide (PAM) having an UHMW of 12 MDa. Both EDAB WLMs and the PAM show strong thickening capability in saline water at 25 degrees C, but the WLMs are more efficient. For example, a 1.0 wt% EDAB WLM sample has a similar zero-shear viscosity eta0 (~40 000 mPa s) to a 2.5 wt% PAM solution. When temperature is increased, both samples show an exponential reduction in viscosity, but the WLMs are more sensitive to temperature. Microstructural differences between the two systems are confirmed by data from small-angle neutron scattering (SANS) and cryo transmission electron microscopy (cryo-TEM). As expected, the key differences are that the WLM chains have a larger core radius (Rcore) and in turn, a longer persistence length (lp) than the PAM chains. PMID- 28880324 TI - Electrografted monolayer based on a naphthalene diimide-ruthenium terpyridine complex dyad: efficient creation of large-area molecular junctions with high current densities. AB - An electron donor-acceptor dyad has been designed for the creation of large-area molecular junctions (MJ). Diazonium cation electrografting was used to form well controlled monolayers. The robustness of the monolayer enabled the creation of MJs using direct top-coat evaporation with a high yield of operating devices. PMID- 28880326 TI - Fast flip-flop of halogenated cobalt bis(dicarbollide) anion in a lipid bilayer membrane. AB - Transmembrane translocation (flip-flop) of cobalt bis(dicarbollide) (COSAN) anions, elicited by application of a voltage-jump across the lipid bilayer membrane, manifested itself in monoexponential electrical current transients in the microsecond time scale. Halogenation of COSAN led to multi-fold acceleration of the flip-flop, the effect increasing with the molecular weight of the halogens. The exception was a fluorinated analog which exhibited slowing of the translocation kinetics. Measurements of the fluorescence ratio of the dye di-4 ANEPPS in lipid vesicles showed significant differences in the adsorption of studied hydrophobic anions. Based on these data, it can be concluded that COSAN and COSAN-F2 were located on the surface of the lipid membrane in the cisoid conformation increasing the dipole potential of the lipid membrane, while other halogenated COSAN analogs were adsorbed in the transoid conformation. Differences in the flip-flop kinetics of COSAN analogs were attributed to variation in the molecular volume of the anions and their orientation on the membrane surface. PMID- 28880325 TI - Computational study on the origin of the cancer immunotherapeutic potential of B and T cell epitope peptides. AB - Immune therapy is generally seen as the future of cancer treatment. The discovery of tumor-associated antigens and cytotoxic T lymphocyte epitope peptides spurned intensive research into effective peptide-based cancer vaccines. One of the major obstacles hindering the development of peptide-based cancer vaccines is the lack of humoral response induction. As of now, very limited work has been performed to identify epitope peptides capable of inducing both cellular and humoral anticancer responses. In addition, no research has been carried out to analyze the structure and properties of peptides responsible for such immunological activities. This study utilizes a machine learning method together with interpretable descriptors in an attempt to identify parameters determining the immunotherapeutic activity of cancer epitope peptides. PMID- 28880327 TI - Liposome-encoded magnetic beads initiated by padlock exponential rolling circle amplification for portable and accurate quantification of microRNAs. AB - Development of reliable and affordable quantitative methods for miRNAs with high specificity and sensitivity is a central challenge to make miRNA testing a routine part of medical care with respect to cancer. Herein, we propose a strategy for glucoamylase-encapsulated liposome-encoded magnetic beads initiated by padlock exponential rolling circle amplification (P-ERCA) for portable and accurate quantification of miRNA by using a glucometer readout. PMID- 28880328 TI - Visible-light/temperature dual-responsive hydrogel constructed by alpha cyclodextrin and an azobenzene linked surfactant. AB - A novel photo-responsive anionic surfactant with a dimethylamino-substituted azobenzene located at the end of the hydrophobic chain, 6-(4 dimethylaminoazobenzene-4'-oxy)hexanoate sodium (DAH), has been designed. Through the host-guest interaction in aqueous solution, the trans-DAH could be spontaneously included by using two native alpha-cyclodextrin (alpha-CD) molecules. The formed hydrophilic inclusion complex (DAH@2alpha-CD), however, could act as a gelator to induce the formation of a supramolecular hydrogel, which is driven mainly by hydrogen bonds between neighboring alpha-CDs and also between the carboxylate in DAH and water. Compared with common hydrogels that consist of networks with fibres or discrete polymer chains, the hydrogel formed by DAH@2alpha-CD was composed of periodic lamellar structures possessing good shear-thinning behavior and much swollen water layers. The more interesting point for such a hydrogel was its visible-light responsibility for gel-sol reversible phase transition. This originated from the introduction of an electron-donating group (dimethylamino) to azobenzene, which noticeably red-shifted the responsive wavelength for its trans-to-cis isomerization. It was also worth noting that the host-guest interaction between azobenzene in DAH and alpha-CD significantly improved the photo-transition efficiency from trans to cis forms of azobenzene, which played a critical role in the visible-light responsibility of the hydrogel. This unique visible-light-responsive behavior combined with the inherent thermo responsive property from alpha-CD should make the prepared hydrogel find more potential applications in biomedical systems. PMID- 28880329 TI - Exploiting Le Chatelier's principle for a one-pot synthesis of nontoxic HHogGNPs with the sharpest nanoscopic features suitable for tunable plasmon spectroscopy and high throughput SERS sensing. AB - Applying Le Chatelier's principle, a one-pot synthesis method is reported that generates highly anisotropic hedgehog gold nanoparticles (HHogGNPs), undemanding of a preformed seed or surfactant. These non-toxic HHogGNPs are potent candidates for nanomedicinal applications owing to their broad-band plasmon tunability, gigantic Raman enhancement and remarkable retention in a highly salted physiological environment. PMID- 28880330 TI - Effect of mode of addition of flaxseed oil on the quality characteristics of chicken sausage containing vitamin E and omega 3 fatty acids at levels to support a health claim. AB - Vitamin E and omega-3 fatty acids can be incorporated into meat products at levels supporting health claims of "protecting against oxidative stress" and "maintaining normal blood cholesterol levels", respectively. Chicken sausages were formulated to contain vitamin E (12 mg per 100 g) and flaxseed oil (2 g per 100 g) using different oil incorporation methods. The formulations were: (1) control (no oil); (2) oil; (3) emulsified oil; (4) freeze-dried encapsulated oil; (5) freeze-dried encapsulated oil with cross-linker genipin; (6) spray-dried encapsulated oil. alpha-Linolenic acid and alpha-tocopherol were retained in all fortified formulations at levels to meet nutrient and health claims but emulsification or encapsulation had no additional benefit in retention following cooking or on product quality as measured by proximate composition, lipid oxidation, colour, microbial analysis, cook loss and texture profile analysis. While the addition of flaxseed oil had a negative effect on consumer acceptance of flavour (although not when emulsified), overall acceptance of the chicken sausages was only reduced significantly (p <= 0.05) when oil was encapsulated. PMID- 28880331 TI - Ciliary Muscle Electrostimulation to Restore Accommodation in Patients With Early Presbyopia: Preliminary Results. AB - PURPOSE: To report short-term results of pulsed ciliary muscle electrostimulation to improve near vision, likely through restoring accommodation in patients with emmetropic presbyopia. METHODS: In a prospective non-randomized trial, 27 patients from 40 to 51 years old were treated and 13 age- and refraction-matched individuals served as untreated controls. All patients had emmetropia and needed near sphere add between +0.75 and +1.50 diopters. The protocol included four sessions (one every 2 weeks within a 2-month period) of bilateral pulsed (2 sec on; 6 sec off) micro-electrostimulation with 26 mA for 8 minutes, using a commercially available medical device. The uncorrected distance visual acuity (UDVA) (logMAR) for each eye, uncorrected near (40 cm) visual acuity in each eye (UNVA) and with both eyes (UNVA OU) (logMAR), and reading speed (number of words read per minute at 40 cm) were measured preoperatively and 2 weeks after each session. Overall satisfaction (0 to 4 scale) was assessed 2 weeks after the last session. RESULTS: UDVA did not change and no adverse events were noted in either group. Bilateral and monocular UNVA and reading speed were stable in the control group, whereas they continuously improved in the treated group (Friedman, P < .00001). Post-hoc significant differences were found for monocular and binocular UNVA after the second treatment and after the first treatment considering words read per minute (P < .001). One patient (3.7%) was not satisfied and 18 patients (66.7%) were very satisfied (score of 4). Average satisfaction score was 3 (satisfied). CONCLUSIONS: Ciliary muscle contraction to restore accommodation was safe and improved the short-term accommodative ability of patients with early emmetropic presbyopia. [J Refract Surg. 2017;33(9):578-583.]. PMID- 28880332 TI - A Technique to Reduce Incidence of Opaque Bubble Layer Formation During LASIK Flap Creation Using the VisuMax Femtosecond Laser. AB - PURPOSE: To identify risk factors for opaque bubble layer (OBL) formation and compare the incidence of OBL using a cone modification technique versus the original technique for LASIK flap creation using the VisuMax laser (Carl Zeiss Meditec, Jena, Germany). METHODS: This retrospective study examined videos of flap creation using the VisuMax laser to identify OBL occurrence. Eyes were divided into three groups: eyes where OBL occurred using the original technique (OBL group), eyes where OBL did not occur using the original technique (no OBL group), and eyes in which the cone modification technique was used for LASIK flap creation (larger flap diameter) (cone modification technique group). Preoperative measurements including simulated keratometry (flat and steep) values, white-to white distance (WTW), pachymetry, patient age and gender, amount of correction, flap parameters, energy setting, corneal hysteresis, and corneal resistance factor were analyzed to identify parameters with statistical difference between the OBL and no OBL groups. Incidence of OBL was compared between the original and cone modification techniques. RESULTS: OBL incidence was significantly lower with the cone modification technique (7.6%; 7 of 92 eyes) than with the original technique (28.8%; 34 of 118 eyes) (Fisher's exact test, P = .0009). Factors identified with a significant difference between eyes with and without OBL using the original technique were: corneal thickness (OBL: 561.2 MUm, no OBL: 549.6 MUm, P = .0132), WTW diameter (OBL: 11.6 mm, no OBL: 11.9 mm, P = .0048), corneal resistance factor (OBL: 10.4 mm Hg, no OBL: 9.6 mm Hg, P = 0.0329), and corneal astigmatism (OBL: 0.80 diopter, no OBL: 1.00 diopter, P = .0472) CONCLUSIONS: Less astigmatic, thicker, denser, and smaller corneas increased the risk of OBL using the original technique for flap creation. The cone modification technique was associated with lower risk of OBL formation, even in eyes with significant risk factors for OBL using the original technique. [J Refract Surg. 2017;33(9):584-590.]. PMID- 28880333 TI - Predicting Refractive Surgery Outcome: Machine Learning Approach With Big Data. AB - PURPOSE: To develop a decision forest for prediction of laser refractive surgery outcome. METHODS: Data from consecutive cases of patients who underwent LASIK or photorefractive surgeries during a 12-year period in a single center were assembled into a single dataset. Training of machine-learning classifiers and testing were performed with a statistical classifier algorithm. The decision forest was created by feature vectors extracted from 17,592 cases and 38 clinical parameters for each patient. A 10-fold cross-validation procedure was applied to estimate the predictive value of the decision forest when applied to new patients. RESULTS: Analysis included patients younger than 40 years who were not treated for monovision. Efficacy of 0.7 or greater and 0.8 or greater was achieved in 16,198 (92.0%) and 14,945 (84.9%) eyes, respectively. Efficacy of less than 0.4 and less than 0.5 was achieved in 322 (1.8%) and 506 (2.9%) eyes, respectively. Patients in the low efficacy group (< 0.4) had statistically significant differences compared with the high efficacy group (>= 0.8), yet were clinically similar (mean differences between groups of 0.7 years, of 0.43 mm in pupil size, of 0.11 D in cylinder, of 0.22 logMAR in preoperative CDVA, of 0.11 mm in optical zone size, of 1.03 D in actual sphere treatment, and of 0.64 D in actual cylinder treatment). The preoperative subjective CDVA had the highest gain (most important to the model). Correlations analysis revealed significantly decreased efficacy with increased age (r = -0.67, P < .001), central corneal thickness (r = -0.40, P < .001), mean keratometry (r = -0.33, P < .001), and preoperative CDVA (r = -0.47, P < .001). Efficacy increased with pupil size (r = 0.20, P < .001). CONCLUSIONS: This model could support clinical decision making and may lead to better individual risk assessment. Expanding the role of machine learning in analyzing big data from refractive surgeries may be of interest. [J Refract Surg. 2017;33(9):592-597.]. PMID- 28880334 TI - A Multicenter Retrospective Survey of Refractive Surgery in 78,248 Eyes. AB - PURPOSE: To retrospectively evaluate the current practice, trends, and outcomes of refractive surgery in Japan. METHODS: This multicenter survey comprised 78,248 eyes of 39,727 consecutive patients who underwent refractive surgery at 45 major institutions in Japan. The corresponding ophthalmologists responded to a selfadministered questionnaire. The authors especially evaluated the safety, efficacy, predictability, stability, and adverse events of LASIK and phakic intraocular lens (IOL) implantation 3 months postoperatively. RESULTS: The most common refractive surgery was LASIK (90.9%), followed by corneal inlay (5.0%), posterior chamber phakic IOL implantation (1.3%), laser-assisted subepithelial keratomileusis (1.0%), refractive lens exchange (0.9%), photorefractive keratectomy (0.3%), and refractive lenticule extraction (0.2%). For subgroup analysis, 69,987 eyes (99.5%) and 67,512 eyes (95.9%) achieved corrected and uncorrected distance visual acuity of 20/20 or better, respectively, after LASIK, and 935 eyes (98.8%) and 890 eyes (94.1%), respectively, after phakic IOL implantation. There were 69,176 eyes (98.3%) and 908 eyes (96.0%) within +/-1.00 diopter (D) of the attempted correction after LASIK and phakic IOL implantation, respectively. There were 1,926 eyes (2.7%) and 1 eye (0.1%) with changes in refraction of 1.00 D or less from 1 week to 3 months after LASIK and phakic IOL implantation, respectively. No vision-threatening complications occurred in any case. CONCLUSIONS: According to this survey, LASIK remains the most prevalent surgical technique in Japan. Both LASIK and phakic IOL implantation offered good safety and efficacy outcomes, yielding predictable and stable results. [J Refract Surg. 2017;33(9):598-602.]. PMID- 28880335 TI - Refractive Outcomes of 20 Eyes Undergoing ICL Implantation for Correction of Hyperopic Astigmatism. AB - PURPOSE: To analyze 1-week, 1-month, and 12-month postoperative refractive outcomes of eyes that under-went ICL implantation to correct hyperopic astigmatism. METHODS: The study enrolled 20 eyes of patients with an average age of 32 years (range: 21 to 40 years). The outcomes of spherical and cylindrical refraction, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), vault, and angle parameters were evaluated 1 week, 1 month, and 12 months postoperatively. RESULTS: The preoperative mean UDVA was 0.15 +/- 0.11 (decimal) (20/133 Snellen) and increased to 0.74 +/- 0.25 (20/27 Snellen) postoperatively, with a change of 0.59 (decimal) (20/33.9 Snellen) (P < .0001), which was statistically significant. The preoperative mean CDVA was 0.74 +/- 0.25 (decimal) (20/27 Snellen) and increased to 0.78 +/- 0.21 (20/25 Snellen), with a change of 0.03 (decimal) (20/666 Snellen) (P < .052), which was not statistically significant. The mean preoperative sphere was 6.86 +/- 1.77 diopters (D) and the mean preoperative cylinder was -1.44 +/- 0.88 D. The mean 12-month postoperative sphere decreased to 0.46 +/- 0.89 D (P < .001) and cylinder decreased to -0.61 +/ 0.46 D (P < .001), with a change of 6.40 D, both of which were statistically significant. The mean 1-month postoperative vault was 0.65 +/- 0.13 mm and decreased to 0.613 +/- 0.10 mm at 1 year postoperatively, with a change of 0.44 mm (P < .003). The preoperative/12-month and 1-month/12-month trabecular-iris angle (TIA), trabecular-iris space area 500 mm from the scleral spur (TISA500), and angle opening distance 500 mm from the scleral spur (AOD500) values were analyzed nasally, temporally, and inferiorly. All differences were statistically significant between preoperative/12-month analysis. The only differences between 1- and 12-month analysis were on TISA500 inferior (P < .002) and AOD500 nasal (0.031) values. CONCLUSIONS: ICL hyperopic toric implantation is a safe method and provides stable refractive outcomes in patients with high hyperopia (up to 10.00 D) and astigmatism (up to 6.00 D). [J Refract Surg. 2017;33(9):604-609.]. PMID- 28880336 TI - Toric ICL Implantation After Sequential Intracorneal Ring Segments Implantation and Corneal Cross-linking in Keratoconus: 2-Year Follow-up. AB - PURPOSE: To evaluate 6-month and 2-year safety and clinical outcomes of Visian toric Implantable Collamer Lens (toric ICL) (STAAR Surgical, Monrovia, CA) implantation for the treatment of residual refractive errors after sequential intracorneal ring segments (ICRS) insertion and cross-linking (CXL) in keratoconus. METHODS: This consecutive case series included the results of a three-step ICRS-CXL-toric ICL procedure in 16 eyes of 13 patients with moderate to severe keratoconus (stages II and III of Amsler-Krumeich classification). The ICRS and CXL procedures were performed sequentially with an interval of 4 weeks and the toric ICL implantation was performed at least 6 months after CXL. Data were collected preoperatively, at 6 months after sequential ICRS-CXL, and at 6 and 24 months following toric ICL implantation. All 16 eyes were evaluated at the 2-year follow-up. RESULTS: There was a significant decrease in keratometry (steep, flat, and maximum) and refraction (sphere and spherical equivalence, but not cylinder) and a significant increase in both uncorrected (UDVA) (from 1.06 to 0.76 logMAR, P = .004) and corrected (CDVA) (from 0.42 to 0.26 logMAR; P = .002) distance visual acuity 6 months following sequential ICRS-CXL, whereas UDVA and refraction significantly improved 6 months after ICL insertion (UDVA reached 0.33 logMAR, P = .001). At the 24-month follow-up, UDVA and keratometric readings were stable, whereas CDVA, sphere, and cylinder showed a significant improvement. CONCLUSIONS: Implantation of Visian toric ICL following sequential ICRS insertion and CXL is an effective and safe option for correcting high residual refractive error and improving visual acuity in patients with moderate to severe keratoconus in the long term. [J Refract Surg. 2017;33(9):610-616.]. PMID- 28880337 TI - Effect of Lowering Laser Energy on the Surface Roughness of Human Corneal Lenticules in SMILE. AB - PURPOSE: To determine the effect of lowering femtosecond laser energy on the surface quality of the intrastromal interface during small incision lenticule extraction (SMILE). METHODS: Forty age- and diopter-matched female patients (40 eyes) with moderate myopia received SMILE with different energy levels (100 to 150 nJ) and fixed spot separation (4.5 MUm). Five human corneal lenticules from each energy group were evaluated by atomic force microscopy and scanning electron microscopy (SEM). Both anterior and posterior surface characteristics of the lenticules were assessed. RESULTS: All measurements of surface roughness were approximately three times higher and in the anterior and posterior surface of the lenticules with the energy level of 150 nJ than with 100 nJ (P < .001). Furthermore, atomic force microscopy analysis found that energy differences of 15 nJ or more made a significant difference in surface roughness at energy levels of 115 nJ or higher. Interestingly, there was no significant difference in all roughness values of both surfaces among the 100, 105, and 110 nJ groups. In addition, all values of surface roughness were significantly positively correlated with laser energy for both anterior and posterior surfaces of the lenticule (P < .001). Consistent with atomic force microscopy results, SEM also showed that the SMILE lenticules in the higher laser energy group had more irregular surfaces. CONCLUSIONS: Lowering laser energy levels can improve surface quality of the lenticule of SMILE. To achieve better visual outcomes with faster recovery after the procedure, it is recommended to reduce the laser energy to less than 115 nJ at a spot separation of 4.5 MUm. [J Refract Surg. 2017;33(9):617 624.]. PMID- 28880338 TI - Comparison of Corneal Deformation Parameters in Keratoconic and Normal Eyes Using a Non-contact Tonometer With a Dynamic Ultra-High-Speed Scheimpflug Camera. AB - PURPOSE: To evaluate and compare biomechanical properties in normal and keratoconic eyes using a dynamic ultra-high-speed Scheimpflug camera equipped with a non-contact tonometer (Corvis ST; Oculus Optikgerate GmbH, Wetzlar, Germany). METHODS: This retrospective study evaluated 89 eyes (47 normal, 42 keratoconic) and a validation arm of 72 eyes (33 normal, 39 keratoconic) using the Corvis ST. A diagnosis of keratoconus was established by clinical findings confirmed by topography and tomography. Dynamic corneal response parameters collected by the Corvis ST (A1 velocity, deformation amplitude [DA], DA Ratio Max 1mm, and Max Inverse Radius) and a stiffness parameter at first applanation (SP A1) were incorporated into a novel logistic regression equation (DCR index). Area under the receiver operating curve (AUC) was used to assess the sensitivity and specificity of the DCR index. RESULTS: DA, DA Ratio Max 1mm, Max Inverse Radius, and SP-A1 were each found to be statistically significantly different between normal and keratoconic eyes (Mann-Whitney test [independent samples]; P = .0077, < .0001, < .0001, and < .0001, respectively; significance level: P < .05). DCR index demonstrated high sensitivity, specificity, and overall correct detection rate (92.9%, 95.7%, and 94.4%, respectively; AUC = 98.5). The sensitivity and overall correct detection rate improved when eyes with Topographical Keratoconus Classification grades (TKC) greater than 0 were reevaluated (from 92.9% to 96.6% and from 94.4% to 96.1%, respectively). CONCLUSIONS: Combining multiple biomechanical parameters (A1 velocity, DA, DA Ratio Max 1mm, Max Inverse Radius, and SP-A1) into a logistic regression equation allows for high sensitivity and specificity for distinguishing keratoconic from normal eyes. [J Refract Surg. 2017;33(9):625-631.]. PMID- 28880339 TI - Comparison of Corneal Dynamic and Tomographic Analysis in Normal, Forme Fruste Keratoconic, and Keratoconic Eyes. AB - PURPOSE: To investigate and compare the diagnostic ability of corneal tomography and dynamic corneal response to differentiate between normal eyes and those with forme fruste keratoconus and keratoconus. METHODS: Corneal tomography was performed using Pentacam (Pentacam HR; Oculus Optikgerate, Wetzlar, Germany). Corneal deformation response was captured via Corvis ST (Optikgerate) using a beta version of Corvis software. Classification analysis between normal eyes and eyes with forme fruste keratoconus and between normal and keratoconic eyes was evaluated using receiver operating characteristic curves. The area under the ROC curve (AUC) and partial AUC (pAUC) for each classifying parameter were compared. RESULTS: Twenty-one patients with forme fruste keratoconus in one eye and clinically evident keratoconus in the fellow eye and 38 normal individuals were recruited. Overall, 21 eyes with forme fruste keratoconus and 18 eyes with keratoconus were compared with 73 normal eyes. The mean age of the participants was comparable between groups. Comparative analysis between Pentacam and Corvis ST parameters showed significantly lower AUC and pAUC for Corvis ST parameters in differentiating keratoconic from normal eyes (P >= .049). However, comparable AUC and pAUC was observed between the Corvis Biomechanical Index (AUC = 0.785; pAUC = 0.079) and D value of the Belin/Ambrosio Enhanced Ectasia Display (AUC = 0.757; pAUC = 0.068) (P >= .477) for detection of forme fruste keratoconus with sensitivities of 63.2% and 52.6%, given a common specificity of 80.3%. CONCLUSIONS: The current study showed the feasibility of use of non-tomographical parameters obtained from the Corvis ST for differentiating normal eyes and those with forme fruste keratoconus and keratoconus. The diagnostic ability of the Corvis ST was comparable to that of the Pentacam for differentiating normal eyes and eyes with forme fruste keratoconus. [J Refract Surg. 2017;33(9):632-638.]. PMID- 28880340 TI - Topography-Guided Photorefractive Keratectomy in the Treatment of Corneal Scarring. AB - PURPOSE: To report the outcome of topography-guided photorefractive keratectomy (TG-PRK) in the treatment of patients with corneal scarring. METHODS: A retrospective, interventional case series including 6 eyes of 6 patients with corneal scarring and irregular astigmatism who underwent TG-PRK. The etiologies for scarring were: infectious corneal ulcers, foreign body trauma, LASIK flap buttonhole, and lamellar keratoplasties performed to correct corneal perforation secondary to corneal melting. Main outcome measures were corrected distance visual acuity, uncorrected distance visual acuity, manifest refraction, and corneal regularity on topography maps. RESULTS: Average age was 56.5 +/- 19.6 years and average follow-up time was 14.8 +/- 6.1 months. Three patients had corneal scarring with cataract and underwent TG-PRK to achieve sufficient regularization of corneal astigmatism to enable the implantation of a toric intraocular lens (IOL). The three remaining patients had TG-PRK performed to improve visual acuity, and all had improvement in uncorrected (improvement between one and three Snellen lines) and corrected (improvement between two and three Snellen lines) distance visual acuity. There were no intraoperative or postoperative complications and no loss of visual acuity. CONCLUSIONS: The use of TG-PRK for corneal scarring may improve visual acuity in selected cases, obviate the need for keratoplasty in some cases, and facilitate toric IOL implantation in some cases. [J Refract Surg. 2017;33(9):639-644.]. PMID- 28880341 TI - Femtosecond Laser-Assisted Intraocular Lens Fragmentation: Low Energy Transection. AB - PURPOSE: To describe a case of femtosecond laser-assisted hydrophobic intraocular lens transection. METHODS: Case report. RESULTS: Femtosecond laser-assisted transection of a one-piece acrylic hydrophobic intraocular lens for explantation via a small surgical incision was successfully performed with low energy parameters. CONCLUSIONS: This case illustrates a novel and effective clinical application of the femtosecond laser. [J Refract Surg. 2017;33(9):646-648.]. PMID- 28880342 TI - Differential Diagnosis of Erythema Multiforme in Childhood: A Comment to Siedner Weintraub et al. PMID- 28880343 TI - Granuloma Faciale Treatment: A Systematic Review. AB - Granuloma faciale is an uncommon benign chronic dermatosis characterized by reddish-brown to violaceous asymptomatic plaques appearing predominantly on the face. The pathogenesis of granuloma faciale remains unclear, and it is frequently unresponsive to therapy. This systematic review aims to summarize all recent publications on the management of granuloma faciale. The publications are mainly individual case reports, small case series and a few retrospective studies. Treatment options included topical, intralesional and systemic corticosteroids, topical pimecrolimus and tacrolimus, topical and systemic dapsone, systemic hydroxychloroquine, clofazimine, and tumour necrosis factor-alpha inhibitors. More invasive therapies using lasers as well as cryosurgery and surgery were also reported. Topical glucocorticosteroids and tacrolimus remain treatments of first choice, possibly supplemented by topical dapsone. PMID- 28880345 TI - [Neuro-science fiction?] PMID- 28880344 TI - Need for Improved Definition of "Chronic Wounds" in Clinical Studies. PMID- 28880346 TI - [ROM for the elderly: a prospective cohort study of the outcomes on the HoNOS 65+ in various diagnostic groups]. AB - BACKGROUND: Routine outcome monitoring (rom) provides us with opportunities to study treatment outcome in daily clinical practice and to learn from the results.
AIM: To assess the changes that occur in the psychological and social functioning of patients in geriatric psychiatry who are suffering from substance dependence, mood disorder, anxiety disorder, psychotic disorder, or personality disorder.
METHOD: We analysed data relating to 1,810 patients (aged 60-101) from nine mental health care organisations that together form SynQuest cv. The total scores and item scores on the Health of the Nation Outcome Scales for older people (Honos 65+) at the beginning and end of treatment were also analysed and were linked to the diagnosis.
RESULTS: Patients improved significantly (es=0.8). The degree of improvement depended on the patient's principal diagnosis; patients with a mood or anxiety disorder improved the most (es=1.0 and 0.8). The degree of improvement varied per Honos 65+ item. In particular, patients with 'depressive problems' and 'other mental and behavioral problems' showed considerable improvement.
CONCLUSION: Many older patients benefited from the treatment they received in gerontopsychiatry departments. This helps to give elderly patients with psychiatric disorders hope for the future. The scores on the individual items of the Honos 65+ can help clinicians to tailor treatment to the patient's specific problems and to monitor and evaluate treatment outcome in conjunction with the patient. PMID- 28880347 TI - [Using resource groups in assertive community treatment; literature review and recommendation]. AB - BACKGROUND: In psychiatry there is an increasing interest in giving patients and their relatives control over the goals of treatment and the way in which treatment is carried out. A structural method of organising this within assertive community treatment (ACT) is to let patients and their relatives participate in what is known as a resource group (RG).
AIM: To provide a systematic view of the advantages of giving patients control over their treatment and the way in which it is carried out via ACT, particularly if this control is organised in the form of an RG.
METHOD: We reviewed the relevant literature on the basis of search instructions in the databases of PubMed and Cochrane Library. We found nine trials that had a randomised controlled design (RCT). Only one of these RCTs involved the use of an RG in ACT.
RESULTS: The approaches used in ACT, whereby patients with schizophrenia had control over their treatment, led to significant improvements that were considerably greater than those achieved in standard care. Improvements were found in symptomatology, social functioning and in the quality of life. There are indications that treatment satisfaction and social functioning improve still further if patients' control over their treatment is organised in an RG.
CONCLUSION: Research demonstrates that positive results are achieved with ACT whereby patients have control over their treatment and the way in which it is carried out. However, further research is needed to determine whether this addition to ACT in the form of an RG is superior to other approaches used previously in ACT, particularly if it concerns the inclusion of an RG. PMID- 28880348 TI - [Psychodynamic consequences of a family history with psychiatric disorders]. AB - BACKGROUND: A positive family history for psychiatric disorders is the most important risk indicator for developing psychopathology. Often, the psychological consequences of a positive family history are insufficiently acknowledged.
AIM: To provide insight into the psychodynamics of children who grow up in a family with psychopathology, such as psychosis, to demonstrate how these effects can last a lifetime, and to suggest ways in which such effects might be prevented.
METHOD: We review the relevant literature, discuss theoretical concepts, and make clinical recommendations.
RESULTS: Parental psychopathology, including psychosis, can have a strong and lasting influence on the child's identity and sense of self.
CONCLUSION: A positive family history for psychiatric disorders has the potential to seriously disrupt the normal development of identity and sense of self. Various types of psychosocial interventions might be able to reduce these harmful effects. PMID- 28880349 TI - [Parental alienation and the controversy surrounding psychiatric diagnostics]. AB - BACKGROUND: The phenomenon of parental alienation can arise when a child allies with one parent and refuses to have contact with the other parent. The concept has attracted a great deal of attention over the last few years. There has been controversy about whether parental alienation should be recognised as a psychiatric syndrome of the alienated child caught up in a conflict between supporters and opponents.
AIM: To try to determine whether parental alienation belongs to psychiatric diagnostics.
METHOD: We made a careful study of various databases in order to find literature relating to parental alienation.
RESULTS: Parental alienation is situated on the border between psychiatry, sociology and justice. One of the main tasks of psychiatry in this border area is to safeguard the domain of diagnostics.
CONCLUSION: Because so much attention is being given to the question of whether parental alienation syndrome should be recognised as a diagnosis, there is often a tendency to ignore the possible impact of parental alienation and to pay very little attention to ways of coping with the problem. PMID- 28880350 TI - [ROM as a GPS navigation system: how can ROM be used routinely in treatment procedures?] AB - BACKGROUND: Routine outcome monitoring (rom) is becoming an integral part of many treatment procedures. In order to promote the use of rom in such procedures attention needs to focus more on the functions of rom than on implementation strategies.
AIM: To clarify what functions rom must be able to perform for the clinician and client if it is to be used routinely.
METHOD: We discuss the functions of rom as described in the literature.
RESULTS: The fundamental role of rom is to signal that the client is not responding satisfactorily to treatment. Therefore, rom has to perform three main functions: 1. predict, at any moment, whether the goal will be reached via the current route; 2. provide, at crucial moments, correct and meaningful information about what options are available that will make it easier to achieve the desired goals; 3. integration - in such a way that the system can be used routinely and will switch on automatically when treatments starts.
CONCLUSION: rom seems to be able to provide a range of functions that are urgently required by clinicians and their clients. PMID- 28880351 TI - [Refeeding syndrome during alcohol detoxification]. AB - Refeeding syndrome (RS) can occur when malnourished patients are reintroduced to carbohydrates. The symptoms are caused by a combination of electrolyte shifts and fluid retention. Symptoms are wide-ranging; some patients may suffer from harmless muscle cramps, others from more severe neurological and cardiological symptoms that can even lead to death. Although alcohol dependence is a risk factor for the development of RS, little attention is being given to this problem in addiction treatment. In this article we report a case of RS that occurred during alcohol detoxification. We also present the results of a pilot study on the incidence of RS during the alcohol detoxification of 12 patients. PMID- 28880352 TI - [Transformation of mental health care in Belgium: good vision, difficult implementation?] PMID- 28880353 TI - [Sleep-wake patterns in adults with autism spectrum disorders in a clinical setting: a pilot study]. AB - BACKGROUND: The negative consequences of sleep-wake disorders in the general population and in children with an autism spectrum disorder (ASD) are well established. However, little is known about sleep-wake disorders in adults with ASD.
AIM: To study and measure sleep-wake disorders and sleep-wake patterns in adults in a clinical facility who have been diagnosed primarily as having ASD without any comorbid intellectual disability.
METHOD: We assessed the sleep patterns of 19 patients in a residential facility. We asked patients to provide their sleep history, answer questionnaires and keep a sleep diary (subjective measurement). We also asked patients to collect actigraphy data (objective measurement) for seven days and to provide information about comorbid symptoms of anxiety and depression and use of medication.
RESULTS: Nine patients (47%) had undiagnosed comorbid sleep-wake disorders. Patients in our study overrated their sleep efficiency (diary) compared to objective data (actigraphy). However, patients' subjective sleep quality did match patients' sleep efficiency. Only two out of 14 patients with symptoms of anxiety and/or depression were diagnosed with a comorbid depressive disorder, 15 patients were treated with medication.
CONCLUSION: Sleep-wake disorders and comorbid symptoms of anxiety and depression might be more prevalent in adults with ASD in a residential facility than reported so far. This possibility needs to be considered more carefully during the diagnostic process and during treatment. PMID- 28880354 TI - [Pimavanserin: a new treatment for the Parkinson's disease psychosis]. AB - BACKGROUND: Clozapine is an effective drug for treating psychosis in Parkinson's disease (PDP) and is registered as such in the Netherlands. However, clozapine can have adverse effects, including agranulocytosis. The new drug pimavanserin was recently registered in the United States for the treatment of PDP.
AIM: To review the literature on pimavanserin and discuss the position it currently occupies in the Netherlands as a potential treatment for PDP.
METHOD: Systematic search of the literature.
RESULTS: We found reports on four randomised controlled trials (RCTs), one review and six articles about the pharmacokinetics and pharmacodynamics of pimavanserin. Pimavanserin is an effective treatment for PDP, and, like clozapine, it has very few negative effects on motor skills. However, all of the RCTs were funded by the manufacturer of pimavanserin and the trials were conducted in a very selective patient population. This means that results cannot be generalised. Long-term results are not yet available. In earlier trials clozapine was shown to have a greater and faster antipsychotic effect. Many clinicians and psychiatrists have a great deal of experience with this drug. Another important point is that no-one has yet conducted a trial comparing clozapine and pimavanserin.
CONCLUSION: Given that the current second drug of choice, namely quetiapine, has not been found to be effective for PDP, we are of the opinion that - if pimavanserin is registered in the Netherlands - pimavanserin could be used when the current drug of choice, clozapine, is not completely effective or is poorly tolerated. For patients who have cognitive impairments in addition to psychosis, we advise testing the patient's reaction to a cholinesterase inhibitor before starting the patient on a course of antipsychotics. PMID- 28880355 TI - [Mental health as a front-line service for bewildered persons]. AB - BACKGROUND: 'Bewildered persons' have often been in the news over the last few years. There has been much discussion about the meaning of the term 'bewildered persons', the number of people involved, the way the problem should be tackled and the role of the mental health services.
AIM: To look critically at the term 'bewildered persons' and to discuss the suspected increase in numbers and the role of mental health services.
METHOD: Review and discussion of the relevant literature relating to 'bewildered persons' which has been published in the last 25 years.
RESULTS: The term 'bewildered persons' is a general label given by the Dutch police to several groups of people. Suicide rates are rising and more and more people are being compulsorily admitted to psychiatric clinics and hospitals. These factors indicate that increasing numbers of people may now be a danger to themselves and to their fellow-citizens. It is not clear whether the increase in numbers is real or simply reflects the extra attention given by the police. These people may in fact be a new group consisting of persons already known to the mental health services. A national team that aims to improve the care of 'bewildered persons' has made several recommendations to stop the increase: prevention and better cooperation between municipalities and mental health facilities. In our view the mental health services should operate at the front-line of the public mental health service, providing low-threshold diagnostics, assertive outreach and treatment for patients who have mental disorders but are unwilling to accept care or treatment. Such a service requires adequate finance, good cooperative agreements and removal of the bureaucratic and financial barriers that prevent patients from seeking care.
CONCLUSION: 'Bewildered persons' is an umbrella term used to denote people who urgently require care and are a public nuisance and who display disturbing behavior. 'Bewildered persons', who now form a part of the group of people targeted by the public health services, have been around for a long time but have been referred to by different names. They require the structured assistance of integrated care, access to social and medical services and timely diagnosis and treatment. People who have somehow slipped through the net of care facilities should not be left to fend for themselves. PMID- 28880356 TI - [Diagnostics of attachment in child and adolescent psychiatry]. AB - BACKGROUND: Growing concern about how the neglect and abuse of children can be tackled and prevented has led to increased interest in the parent-child relationship and the concept of attachment. It is vitally important that the diagnostics relating to attachment are accurate. One of the main problems is that up till now the parent-child relationship has not been assessed and analysed in accordance with reliable, unambiguous standards.
AIM: To search the literature in order to identify the prerequisites for reliable diagnostics of attachment.
METHOD: PubMed articles concerning instruments for measuring attachment were reviewed. The found articles were based on more extensive search strategies used in English-language meta-analysis, and included reflections on possible implications of mental health care.
RESULTS: Accurate detailed analysis of attachment is particularly important in cases that involve cumulative risk factors. The task must be performed by trained professionals who used thoroughly tested, reliable measuring instruments.
CONCLUSION: The application of the concept of attachment in child and adolescent psychiatry is in its infancy. Those applying the concept need to have breadth of vision and evidence-based skills in applying relevant diagnostics. PMID- 28880357 TI - [The use of dexmedetomidine in extreme agitation]. AB - BACKGROUND: In clinical practice antipsychotics, benzodiazepines and/or antihistamines are used to calm agitated patients. If agitation persists and patients have contraindications for these substances, then anesthetics, such as propofol, can also be used as well, to serve as a sedative. Our attention was drawn to a particular case in which dexmedetomidine was used as a sedative.
AIM: To study the literature on the use of alpha2-agonists, such as dexmedetomidine, in the treatment of extreme agitation.
METHOD: We reviewed the relevant scientific literature.
RESULTS: alpha2-agonists, such as dexmedetomidine, are new anesthetic agents that have analgetic and sympatholytic effects without suppressing respiration. These agents are used frequently in intensive care because their sedative effect are short-lived and do not cause amnesia, sleep deprivation or cognitive disturbance. Excited delirium syndrome (eds) is a type of extreme agitation for which dexmedetomidine can be used.
CONCLUSION: There may well be a place for dexmedetomidine in the treatment of extreme agitation when standard treatments have failed. Further research is needed in order to ascertain whether dexmedetomidine should play a role in such treatment. PMID- 28880359 TI - [A young boy with periodic strange behavior and hypersomnia: Kleine-Levin syndrome]. AB - Kleine-Levin syndrome is a rare neuro-psychiatric disease. Most of the young patients are males who present with hypersomnia, cognitive dysfunction, altered perception, eating disorder (e.g. hyperphagia) or disinhibited behaviour (e.g. hypersexuality). Psychiatric symptoms such as apathy, delusions and hallucinations, depressed mood and compulsive behaviours also appear often and result frequently in a psychiatric referral. These symptoms, however, should be distinguished from those of psychiatric diseases as early as possible in order to ensure that patients do not receive the wrong treatment. We present the case of an 11-year-old boy in whom the psychiatric symptoms were initially the most prominent ones. PMID- 28880358 TI - [Lithium and its protective effect in Alzheimer's disease]. AB - BACKGROUND: Lithium is associated with adverse effects on cognitive functioning. However, there are published trials that have investigated the protective effects of lithium in cognitive decline.
AIM: To review studies that investigate the potentially protective effects of lithium on cognitive disorders.
METHOD: We studied English-language and Dutch reports on controlled, clinical trials published up to October 2016.
RESULTS: We found four relevant articles. Two studies indicated that cognitive functioning remained more stable when patients were given lithium than when they were given a placebo. One study, however, could not detect any difference between the effects of lithium and the effects of placebos. The fourth study, which examined patients' ability to tolerate lithium, could not find any difference in the cognitive functioning of patients.
CONCLUSION: The reported results indicate that the cognitive functioning of patients with pre-stage Alzheimer's disease remains more stable after patients have taken lithium than after they have taken a placebo. PMID- 28880360 TI - The effect of whole body vibration on fracture healing - a systematic review. AB - This systematic review examines the efficacy and safety of whole body vibration (WBV) on fracture healing. A systematic literature search was conducted with relevant keywords in PubMed and Embase, independently, by two reviewers. Original animal and clinical studies about WBV effects on fracture healing with available full-text and written in English were included. Information was extracted from the included studies for review. In total, 19 articles about pre-clinical studies were selected. Various vibration regimes are reported; of those, the frequencies of 35 Hz and 50 Hz show better results than others. Most of the studies show positive effects on fracture healing after vibration treatment and the responses to vibration are better in ovariectomised (OVX) animals than non-OVX ones. However, several studies provide insufficient evidence to support an improvement of fracture healing after vibration and one study even reports disruption of fracture healing after vibration. In three studies, vibration results in positive effects on angiogenesis at the fracture site and surrounding muscles during fracture healing. No serious complications or side effects of vibration are found in these studies. WBV is suggested to be beneficial in improving fracture healing in animals without safety problem reported. In order to apply vibration on fractured patients, more well-designed randomised controlled clinical trials are needed to examine its efficacy, regimes and safety. PMID- 28880361 TI - A randomized multicenter study: safety and efficacy of mini-pool intravenous immunoglobulin versus standard immunoglobulin in children aged 1-18 years with immune thrombocytopenia. AB - BACKGROUND: Because there is a global shortage of intravenous immunoglobulin, there is a need for new products to fill the gap. STUDY DESIGN AND METHODS: This was a multicenter, open-label study investigating the safety and efficacy of a newly developed mini-pool intravenous immunoglobulin G for children with immune thrombocytopenia. Seventy-two patients ages 1 to 18 years with newly diagnosed (<1 month) immune thrombocytopenia who had platelet counts from 5 to 20 * 109 /L with no serious bleeding were recruited from four centers in Egypt. Eligible patients were randomized into three groups 1:1:1. Group A (n = 24) received blood group-specific mini-pool intravenous immunoglobulin in a dose equivalent to immunoglobulin 1 g/kg over 6 to 8 hours, Group B (n = 24) received standard intravenous immunoglobulin (approximately 1g/kg) as a single dose, and Group C (n = 24) did not receive any platelet-enhancing therapy. Parents signed informed consent. RESULTS: Of the patients who received mini-pool intravenous immunoglobulin, 14 achieved a complete response (CR) (58.8%), and four had a response (16.6%). Of the patients who received intravenous immunoglobulin G, 16 achieved a complete response (66.6%), and four had a response (16.6%). In Group C, eight patients achieved a complete response (33.3%), and four had a response (16.6%). The median time to response was 8, 9, and 21 days in Group A, B, and C, respectively, which was significantly higher in Group C than Groups A and B (p < 0.001). Patients in Groups A and B reported 16 adverse drug reactions. CONCLUSION: Mini-pool intravenous immunoglobulin G was well tolerated, presented no safety issues, and was effective in the treatment of immune thrombocytopenia, with efficacy comparable to that of the standard intravenous immunoglobulin G group, and it was significantly more effective than no treatment. PMID- 28880362 TI - Cold platelets for trauma-associated bleeding: regulatory approval, accreditation approval, and practice implementation-just the "tip of the iceberg". AB - BACKGROUND: Laboratory and clinical evidence suggest that cold-stored platelets (CS-PLTs) might be preferable to room temperature platelets (RT-PLTs) for active bleeding. Ease of prehospital use plus potential hemostatic superiority led our facility to pursue approval of CS-PLTs for actively bleeding trauma patients. STUDY DESIGN AND METHODS: From November 18, 2013, through October 8, 2015, correspondence was exchanged between our facility, the AABB, and the US Food and Drug Administration (FDA). An initial AABB variance request was for 5-day CS-PLTs without agitation. The AABB deferred its decision pending FDA approval to use our platelet (PLT) bags for CS-PLTs. On March 27, 2015, the FDA approved 3-day CS PLTs without agitation. On October 8, 2015, the AABB approved 3-day CS-PLTs without agitation and without bacterial testing for actively bleeding trauma patients. Our facility's goal is to carry CS-PLTs on air ambulances. RESULTS: CS PLTs have been used for trauma patients at our facility since October 2015. As of August 2016, a total of 21 (19.1%) of 119 CS-PLTs have been transfused. The short 3-day storage period combined with the formation of clots in plasma-rich CS-PLTs during storage have been the major causes of a high (80.9%) discard rate. CONCLUSION: In the future, pathogen-reduced (PR), PLT additive solution (PAS) CS PLTs seem more practical due to low risks of bacterial contamination and storage related clotting. This should make longer storage of CS-PLTs feasible (e.g., 10 days or more). With a longer shelf life, PR PAS CS-PLTs could potentially be used in a wider range of patient populations. PMID- 28880363 TI - Apheresis technology correlates with bacterial contamination of platelets and reported septic transfusion reactions. AB - BACKGROUND: Apheresis technology to collect platelet (PLT) components differs among devices. We evaluated the relationship of the plateletpheresis device with bacterial contamination and reported septic transfusion reactions. STUDY DESIGN AND METHODS: Plateletpheresis was performed using Amicus (Fenwal, a Fresenius Kabi Company) or Trima (Trima Accel, TerumoBCT) from 2010 to 2014. All donations used inlet-line sample diversion and were tested by quality control (QC; Day 1) aerobic culture. Rates of bacterial contamination and septic reactions to PLTs were calculated for both devices. RESULTS: During the 5-year study period, plateletpheresis collections using Amicus and Trima devices totaled 1,486,888 and 671,955 donations, respectively. The rate of confirmed-positive bacterial cultures of apheresis PLT donations was significantly higher with Amicus than with Trima (252 vs. 112 per 106 donations [odds ratio {OR}, 2.3; 95% confidence interval {CI}, 1.8-2.9]). Septic transfusion reactions were caused by 30 apheresis PLT units from 25 contaminated Amicus procedures and three apheresis PLT units from three contaminated Trima procedures. The overall rate of septic reactions was significantly higher with apheresis PLT components collected with Amicus than with Trima (16.8 vs. 4.5 per 106 donations [OR, 3.8; 95% CI, 1.1 12.5]). All apheresis PLT components implicated in septic transfusion reactions had negative QC culture results incubated through Day 5 (i.e., false negatives). CONCLUSION: Apheresis technology affects bacterial contamination of plateletpheresis collections. The device-specific, higher rate of confirmed positive bacterial culture results also correlated with a significantly higher rate of reported septic transfusion reactions to apheresis PLTs. PMID- 28880364 TI - Reply to letter 'Early identification of renal tubular injury: more questions than solutions'. PMID- 28880365 TI - Use of urine N-acetyl-beta-D-glucosaminidase for early identification of renal tubular injury: more questions than solutions. PMID- 28880366 TI - Determining the inventory impact of extended-shelf-life platelets with a network simulation model. AB - BACKGROUND: The regulatory shelf life for platelets (PLTs) in many jurisdictions is 5 days. PLT shelf life can be extended to 7 days with an enhanced bacterial detection algorithm. Enhanced testing, however, comes at a cost, which may be offset by reductions in wastage due to longer shelf life. This article describes a method for estimating systemwide reductions in PLT outdates after PLT shelf life is extended. STUDY DESIGN AND METHODS: A simulation was used to evaluate the impact of an extended PLT shelf life within a national blood network. A network model of the Canadian Blood Services PLT supply chain was built and validated. PLT shelf life was extended from 5 days to 6, 7, and 8 days and runs were completed to determine the impact on outdates. RESULTS: Results suggest that, in general, a 16.3% reduction in PLT wastage can be expected with each additional day that PLT shelf life is extended. Both suppliers and hospitals will experience fewer outdating units, but wastage will decrease at a faster rate at hospitals. No effect was seen by blood group, but there was some evidence that supplier site characteristics influences both the number of units wasted and the site's ability to benefit from extended-shelf-life PLTs. CONCLUSION: Extended-shelf-life PLTs will reduce wastage within a blood supply chain. At 7 days, an improvement of 38% reduction in wastage can be expected with outdates being equally distributed between suppliers and hospital customers. PMID- 28880367 TI - Cytokeratin-positive primary effusion lymphoma: a diagnostic challenge. PMID- 28880368 TI - Optimization of Monte Carlo particle transport parameters and validation of a novel high throughput experimental setup to measure the biological effects of particle beams. AB - PURPOSE: Accurate modeling of the relative biological effectiveness (RBE) of particle beams requires increased systematic in vitro studies with human cell lines with care towards minimizing uncertainties in biologic assays as well as physical parameters. In this study, we describe a novel high-throughput experimental setup and an optimized parameterization of the Monte Carlo (MC) simulation technique that is universally applicable for accurate determination of RBE of clinical ion beams. Clonogenic cell-survival measurements on a human lung cancer cell line (H460) are presented using proton irradiation. METHODS: Experiments were performed at the Heidelberg Ion Therapy Center (HIT) with support from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg, Germany using a mono-energetic horizontal proton beam. A custom-made variable range selector was designed for the horizontal beam line using the Geant4 MC toolkit. This unique setup enabled a high-throughput clonogenic assay investigation of multiple, well defined dose and linear energy transfer (LETs) per irradiation for human lung cancer cells (H460) cultured in a 96-well plate. Sensitivity studies based on application of different physics lists in conjunction with different electromagnetic constructors and production threshold values to the MC simulations were undertaken for accurate assessment of the calculated dose and the dose-averaged LET (LETd ). These studies were extended to helium and carbon ion beams. RESULTS: Sensitivity analysis of the MC parameterization revealed substantial dependence of the dose and LETd values on both the choice of physics list and the production threshold values. While the dose and LETd calculations using FTFP_BERT_LIV, FTFP_BERT_EMZ, FTFP_BERT_PEN and QGSP_BIC_EMY physics lists agree well with each other for all three ions, they show large differences when compared to the FTFP_BERT physics list with the default electromagnetic constructor. For carbon ions, the dose corresponding to the largest LETd value is observed to differ by as much as 78% between FTFP_BERT and FTFP_BERT_LIV. Furthermore, between the production threshold of 700 MUm and 5 MUm, proton dose varies by as much as 19% corresponding to the largest LETd value sampled in the current investigation. Based on the sensitivity studies, the FTFP_BERT physics list with the low energy Livermore electromagnetic constructor and a production threshold of 5 MUm was employed for determining accurate dose and LETd . The optimized MC parameterization results in a different LETd dependence of the RBE curve for 10% SF of the H460 cell line irradiated with proton beam when compared with the results from a previous study using the same cell line. When the MC parameters are kept consistent between the studies, the proton RBE results agree well with each other within the experimental uncertainties. CONCLUSIONS: A custom high-throughput, high-accuracy experimental design for accurate in vitro cell survival measurements was employed at a horizontal beam line. High sensitivity of the physics-based optimization establishes the importance of accurate MC parameterization and hence the conditioning of the MC system on a case-by-case basis. The proton RBE results from current investigations are observed to agree with a previous measurement made under different experimental conditions. This establishes the consistency of our experimental findings across different experiments and institutions. PMID- 28880369 TI - Optimization of beam arrangements in proton minibeam radiotherapy by cell survival simulations. AB - PURPOSE: Proton minibeam radiotherapy using submillimeter beam dimensions allows to enhance tissue sparing in the entrance channel by spatial fractionation additionally to advantageous proton depth dose distribution. In the entrance channel, spatial fractionation leads to reduced side effects compared to conventional proton therapy. The submillimeter sized beams widen with depth due to small angle scattering and enable therefore, in contrary to x-ray microbeam radiation therapy (MRT), the homogeneous irradiation of a tumor. Proton minibeams can either be applied as planar minibeams or pencil shaped with an additional possibility to vary between a quadratic and a hexagonal arrangement for pencil minibeams. The purpose of this work is to deduce interbeam distances to achieve a homogeneous dose distribution for different tumor depths and tumor thicknesses. Furthermore, we aim for a better understanding of the sparing effect on the basis of surviving cells calculated by the linear-quadratic model. METHODS: Two dimensional dose distributions are calculated for proton minibeams of different shapes and arrangements. For a tumor in 10-15 cm depth, treatment plans are calculated with initial beam size of sigma0 = 0.2 mm in a water phantom. Proton minibeam depth dose distributions are finally converted into cell survival using a linear-quadratic model. RESULTS: Inter proton beam distances are maximized under the constraint of dose homogeneity in the tumor for tumor depths ranging from 4 to 15 cm and thickness ranging from 0.5 to 10 cm. Cell survival calculations for a 5 cm thick tumor covered by 10 cm healthy tissue show less cell death by up to 85%, especially in the superficial layers, while keeping the cell death in the tumor as in conventional therapy. In the entrance channel, the pencil minibeams result in higher cell survival in comparison to the planar minibeams while all proton minibeam irradiations show higher cell survival than conventional broadbeam irradiation. CONCLUSION: The deduced constraints for interbeam distances simplify treatment planning for proton minibeam radiotherapy applications in future studies. The cell survival results indicate that proton minibeam radiotherapy reduces side effects but keeps tumor control as in conventional proton therapy. It makes proton minibeam, especially pencil minibeam radiotherapy a potentially attractive new approach for radiation therapy. PMID- 28880370 TI - Langerhans cell histiocytosis in an adult female presenting with widespread confluent crusted papules and review of adult cases confined to skin. PMID- 28880371 TI - Cultures of choice: towards a sociology of choice as a cultural phenomenon. AB - The article explores different ways to conceptualize the relationship between choice and culture. These two notions are often constructed as opposites: while sociologies of modernization (such as Giddens') portray a shift from cultural traditions to culturally disembedded choice, dispositional sociologies (such as Bourdieu's) uncover cultural determination as the hidden truth behind apparent choice. However, choice may be real and cultural simultaneously. Culture moulds choice not only by inculcating dispositions or shaping repertoires of alternatives, but also by offering culturally specific choice practices, ways of choosing embedded in meaning, normativity, and materiality; and by shaping attributions of choice in everyday life. By bringing together insights from rival schools, I portray an outline for a comparative cultural sociology of choice, and demonstrate its purchase while discussing the digitalization of choice; and cultural logics that shape choice attribution in ways opposing neoliberal trends. PMID- 28880372 TI - The making of a moral economy: women's views of monetary transactions in an 'egg sharing for research' scheme. AB - There are growing debates about the appropriateness of offering money in exchange for the provision of bodily materials for clinical treatment and research. The bioethics literature and many practice guidelines have generally been opposed to such entanglement, depicting the use of money as contaminating, creating undue inducement, exploitation and commodification of the human body. However, two elements have been missing from these debates: (i) the perspectives of those people providing bodily materials when money is offered; and (ii) systematic empirical engagement with the notion of 'money' itself. This article seeks to fill those gaps in knowledge by providing detailed insights from a project investigating the views and experiences of women who volunteered to provide eggs for research in exchange for reduced fees for fertility treatment. Analysis of 29 semi-structured interviews reveals multiple ways in which volunteers reason through the involvement of 'money' in this domain and shows how their accounts diverge from pessimistic understandings of the role of monies in everyday life. When volunteers speak in detail about the monetary aspects of their participation they draw major, recurring, distinctions in five overlapping areas: their depiction of the monetized world of fertility treatment; their views of the different forms that money can take; a distancing of their actions from their understandings of how markets and commodities work; their location of the transactions within a particular clinic, and the ongoing importance of their eggs, post-transaction. This article: (i) responds to calls for concrete case studies to assist understandings of the inter-relationships of money and specific aspects of social life; (ii) adds to the sociology of money literature by providing empirical insights into how notions of money are deployed; (iii) presents much-needed perspectives from providers of bodily materials; and (iv) contributes to ongoing conversations between bioethics and sociology. PMID- 28880373 TI - Supernatants and lipids from stored red blood cells activate pulmonary microvascular endothelium through the BLT2 receptor and protein kinase C activation. AB - BACKGROUND: Although transfusion is a lifesaving intervention, it may be associated with significant morbidity in injured patients. We hypothesize that stored red blood cells (RBCs) induce proinflammatory activation of human pulmonary microvascular endothelial cells (HMVECs) resulting in neutrophil (PMN) adhesion and predisposition to acute lung injury (ALI). STUDY DESIGN AND METHODS: Ten units of RBCs were collected; 50% (by weight) were leukoreduced (LR-RBCs) and the remainder was unmodified and stored in additive solution-5 (AS-5). An additional 10 units of RBCs were collected, leukoreduced, and stored in AS-3. HMVECs were incubated with [10%-40%]FINAL of the supernatants on Day (D)1 to D42 of storage, lipid extracts, and purified lipids. Endothelial surface expression of intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-8 release, and PMN adhesion to HMVECs were measured. HMVEC signaling via the BLT2 receptor was evaluated. Supernatants and lipids were also employed as the first event in a two event model of ALI. RESULTS: The supernatants [10%-40%]FINAL from D21 LR-RBCs and D42 RBCs and LR-RBCs and the lipids from D42 stored in AS-5 induced increased ICAM-1 surface expression on endothelium, IL-8 release, and PMN adhesion. In addition, the supernatants [20%-40%]FINAL from D21 and D42 RBCs in AS-5 also increased endothelial surface expression of ICAM-1. D42 supernatants and lipids also caused coprecipitation of beta-arrestin-1 with BLT2, protein kinase C (PKC)betaI , and PKCdelta and served as the first event in a two-event rodent model of ALI. CONCLUSION: Lipids that accumulate during RBC storage activate endothelium and predispose to ALI, which may explain some of the adverse events associated with the transfusion of critically injured patients. PMID- 28880374 TI - Skeletal and myocardial microvascular blood flow in hydroxycarbamide-treated patients with sickle cell disease. AB - In sickle cell disease (SCD), abnormal microvascular function combined with chronic anaemia predisposes patients to perfusion-demand mismatch. We hypothesized that skeletal muscle and myocardial perfusion, normalized to the degree of anaemia, is reduced at basal-state compared to controls, and that this defect is ameliorated by hydroxycarbamide (HC; also termed hydroxyurea) therapy. Twenty-one SCD patients, of whom 15 were treated with HC, and 27 controls underwent contrast-enhanced ultrasound (CEU) perfusion imaging of the forearm as well as the myocardium. HC treatment was associated with lower white cell and reticulocyte counts, and higher fetal haemoglobin and total haemoglobin levels. When corrected for the degree of anaemia in SCD patients, skeletal flow in HC treated patients was significantly higher than in untreated SCD patients (217.7 +/- 125.4 vs. 85.9 +/- 40.2, P = 0.018). Similarly, when normalized for both anaemia and increased myocardial work, resting myocardial perfusion was also significantly higher in HC-treated patients compared with untreated SCD patients (0.53 +/- 0.47 vs. 0.13 +/- 0.07, P = 0.028). Haemoglobin F (HbF) levels correlated with skeletal muscle microvascular flow (r = 0.55, P = 0.01). In conclusion, patients with SCD not on HC therapy have resting flow deficits in both skeletal muscle and myocardial flow. HC therapy normalizes flow and there is a direct correlation with HbF levels. Clinical trial registration ClinicalTrials.gov Identifier: NCT01602809; https://clinicaltrials.gov/ct2/show/NCT01602809?term=sACHDEV&rank=9. PMID- 28880376 TI - 'Luck, chance, and happenstance? Perceptions of success and failure amongst fixed term academic staff in UK higher education'. AB - What does it mean to attribute success to 'luck', but failure to personal deficiency? In 2015/16, more than 34 per cent of academic employees in UK higher education institutions were employed on temporary contracts, and the sector itself has undergone a substantial transformation in recent years in terms of expansion, measurement, and marketization. Based on two waves of interviews conducted with fixed-term academic employees at different career stages, the article explores the narrativization of success and failure amongst staff working at the 'sharp end' of the so-called neoliberal academy. Arguing that precarious employment situations precipitate the feeling of being 'out of control', the majority of the participants' narratives were characterized by a distinct lack of agency. The paper explores the recourse to notions of chance and the consolidation of 'luck' as an explanatory factor in accounting for why good things happen; however, in tandem with this inclination is the tendency to individualize failure when expectations have been thwarted. While accounts of fixed-term work are suffused with notions of chance and fortune, 'luck' remains an under-researched concept within sociology. The article thus concludes by considering what the analysis of 'luck' might offer for a fuller, politicized understanding of processes at work in the contemporary academy. PMID- 28880377 TI - Detection of clinically relevant early genomic lesions in B-cell malignancies from circulating tumour DNA using a single hybridisation-based next generation sequencing assay. PMID- 28880375 TI - Melatonin: does it have utility in the treatment of haematological neoplasms? AB - Melatonin, discovered in 1958 in the bovine pineal tissue, is an indoleamine that modulates circadian rhythms and has a wide variety of other functions. Haematological neoplasms are the leading cause of death in children and adolescents throughout the world. Research has demonstrated that melatonin is a low-toxicity protective molecule against experimental haematological neoplasms, but the mechanisms remain poorly defined. Here, we provide an introduction to haematological neoplasms and melatonin, especially as they relate to the actions of melatonin on haematological carcinogenesis. Secondly, we summarize what is known about the mechanisms of action of melatonin in the haematological system, including its pro-apoptotic, pro-oxidative, anti-proliferative and immunomodulatory actions. Thirdly, we discuss the advantages of melatonin in combination with other drugs against haematological malignancy, as well as its other benefits on the haematological system. Finally, we summarize the findings that are contrary to the suppressive effects of melatonin on cancers of haematological origin. We hope that this information will be helpful in the design of studies related to the therapeutic efficacy of melatonin in haematological neoplasms. PMID- 28880378 TI - Leukocyte and plasma activation profiles in chronically transfused patients with a history of allergic reactions. AB - BACKGROUND: Allergic transfusion reactions are drawbacks to the benefits of transfusion. Classically, allergic transfusion reactions depend on histamine release from mast cells or basophils, but other leukocyte subsets may also be important. Thus, we propose to better define the exact leukocyte subsets involved in allergic transfusion reactions. STUDY DESIGN AND METHODS: The overall objective of the current study was to compare the activation of specific peripheral blood leukocyte subsets (monocytes, neutrophils, eosinophils, and basophils) in a cohort of 13 patients who received chronic transfusions and had a history of allergic transfusion reactions compared with a control group of patients who received chronic transfusions and had no history of allergic transfusion reactions. Leukocyte subsets were analyzed by flow cytometry at baseline and after red blood cell transfusion, and cytokine levels in platelet free plasma collected at the same time points were measured by Luminex assay. RESULTS: Flow cytometry and cytokine profiles before and after transfusion did not differ significantly between patients who did and did not have a history of allergic transfusion reactions (p > 0.05). However, post-transfusion samples from both groups showed a decrease in CD63 expression in basophils, monocytes, and eosinophils and a decrease in CD45 expression in all leukocyte subsets compared with pretransfusion samples. Interleukin 10 levels increased after transfusion in the group with a history of allergic transfusion reactions (p = 0.0469), and RANTES (regulated upon activation, normal T-cell expressed and secreted) was significantly decreased post-transfusion in all patients (p = 0.0122). CONCLUSION: None of the leukocyte subsets from patients who had a history of allergic transfusion reactions significantly increased in activation either before or after transfusion. All leukocyte subsets from patients who did and did not have a history of allergic transfusion reactions decreased in their activation profile upon transfusion challenge. PMID- 28880379 TI - Red blood cell alloimmunization in neonates and children up to 3 years of age. AB - BACKGROUND: An alloimmune response to red blood cell (RBC) transfusion in neonates is a rare event. Several guidelines recommend limited pretransfusion testing in neonates. The evidence for these recommendations is based on small studies with sample sizes of between 30 and 90 infants. STUDY DESIGN AND METHODS: We conducted a retrospective cohort study among consecutive patients who received transfusions at a single university medical center. All non-alloimmunized patients who had received their first RBC transfusion between 1994 and 2013 and who underwent at least one antibody screening follow-up visit between 7 and 365 days after transfusion were included. RESULTS: The incidence of alloimmunization in the control group of 17,084 adult patients age 45 years or older who had received a median of 5 RBC units (interquartile range, 2-12 RBC units) was 3.55% (n = 607 alloimmunized patients). After transfusion of 40 RBC units, the cumulative incidence of alloimmunization in adult controls was 10.24% (95% confidence interval, 7.71%-13.17%). In total, 1641 neonates and children up to age 3 years received a median of 4 RBC units (interquartile range, 2-7 RBC units) in a median of two RBC transfusion episodes (interquartile range, one to five RBC transfusion episodes). Two children developed anti-M and anti-E antibodies post transfusion at the ages of 181 and 611 days, respectively. CONCLUSION: To our knowledge, this study presents the largest longitudinal cohort study of RBC alloimmunization in neonates. Antibodies against RBC antigens were not detected within the first 6 months of life. Repeat antibody screening and cross-matching during the first months of life can be safely omitted. PMID- 28880380 TI - Faster Improvement in Migraine Pain Intensity and Migraine-Related Disability at Early Time Points with AVP-825 (Sumatriptan Nasal Powder Delivery System) versus Oral Sumatriptan: A Comparative Randomized Clinical Trial Across Multiple Attacks from the COMPASS Study. AB - BACKGROUND: Fast relief of migraine pain, associated symptoms, and migraine related disability are priorities in the acute treatment of migraine. Efforts to improve the pharmacokinetic profiles of acute migraine treatments with the aim of providing faster relief include the development of non-oral routes of administration. AVP-825 (ONZETRA(r) Xsail(r) ) is a delivery system containing 22 mg sumatriptan powder that uses a patient's own breath to deliver medication intranasally, targeting the upper posterior nasal cavity beyond the narrow nasal valve, an area lined with vascular mucosa conducive to rapid drug absorption into the systemic circulation. While most studies comparing treatments measure differences in proportions of patients achieving a dichotomous endpoint at fixed time intervals, in this study we compare trajectories of migraine pain and disability over time for AVP-825 versus 100 mg oral sumatriptan tablets. METHODS: We used data from the COMPASS study (NCT01667679, clinicaltrials.gov), a double blind, double-dummy, active-comparator, cross-over study of people with a diagnosis of migraine. Participants treated up to five qualifying migraine attacks within 1 hour of onset with either AVP-825 plus placebo tablets or 100 mg oral sumatriptan tablets plus placebo delivery system during the first of two 12 week treatment periods, and then switched treatment sequences to treat up to five more attacks in the second treatment period. Patients recorded ordinal migraine pain intensity and migraine-related disability before dosing (predose), and at 10, 15, 30, 45, 60, 90 and 120 minutes. Three-level ordinal multilevel models accounted for unique data structure (repeated measures nested within attacks for each patient) and tested for treatment differences in migraine pain and migraine related disability through the first 2 hours of attacks post dose. RESULTS: Among 259 study participants (mean age 40.0 years, 84.6% female, 78.4% white), there was significant between and within person variability in migraine pain intensity and migraine-related disability. A typical individual showed significantly faster reductions in migraine pain over the first 30 minutes and migraine-related disability over the first 45 minutes when treating with AVP-825 compared with oral sumatriptan. Overall levels of pain and disability also favored AVP-825 over 2 h following treatment. Model-based odds ratios (OR) comparing AVP-825 to oral sumatriptan ranged from 0.38 to 0.76 for pain and 0.37 to 0.65 for disability, with OR <1 indicating reduced pain/disability in the AVP-825 condition. CONCLUSIONS: Compared with 100 mg oral sumatriptan, treatment with AVP-825 was associated with faster reductions in migraine pain intensity and migraine-related disability starting at 10 minutes postdose and continuing through the first 30 minutes for migraine pain intensity and the first 45 minutes for migraine-related disability, resulting in lower overall pain intensity and disability that lasted through the first 2 h following treatment. Both migraine pain intensity and disability varied substantially both across subjects and within subjects across attacks. PMID- 28880381 TI - Evaluation of feasibility of 1.5 Tesla prostate MRI using body coil RF transmit in a patient with an implanted vagus nerve stimulator. AB - PURPOSE: To assess risks of RF-heating of a vagus nerve stimulator (VNS) during 1.5 T prostate MRI using body coil transmit and to compare these risks with those associated with MRI head exams using a transmit/receive head coil. METHODS: Spatial distributions of radio-frequency (RF) B1 fields generated by transmit/receive (T/R) body and head coils were empirically assessed along the long axis of a 1.5 T MRI scanner bore. Measurements were obtained along the center axis of the scanner and laterally offset by 15 cm (body coil) and 7 cm (head coil). RF-field measurements were supplemented with direct measurements of RF-heating of 15 cm long copper wires affixed to and submerged in the "neck" region of the gelled saline-filled (sodium chloride and polyacrylic acid) "head and-torso" phantom. Temperature elevations at the lead tips were measured using fiber-optic thermometers with the phantom positioned at systematically increased distances from the scanner isocenter. RESULTS: B1 field measurements demonstrated greater than 10 dB reduction in RF power at distances beyond 28 cm and 24 cm from isocenter for body and head coil, respectively. Moreover, RF power from body coil transmit at distances greater than 32 cm from isocenter was found to be lower than from the RF power from head coil transmit measured at locations adjacent to the coil array at its opening. Correspondingly, maximum temperature elevations at the tips of the copper wires decreased with increasing distance from isocenter - from 7.4 degrees C at 0 cm to no appreciable heating at locations beyond 40 cm. CONCLUSIONS: For the particular scanner model evaluated in this study, positioning an implanted VNS farther than 32 cm from isocenter (configuration achievable for prostate exams) can reduce risks of RF-heating resulting from the body coil transmit to those associated with using a T/R head coil. PMID- 28880383 TI - Diagnosis of broncho-pleural fistula: Is there a role for sonography? PMID- 28880382 TI - Reproducibility of point-of-care ultrasonography for central vein diameter measurement: Separating image acquisition from interpretation. AB - PURPOSE: Central vein point-of-care ultrasonography must be reproducible to detect intravascular volume changes. We sought to determine which measurement step, image acquisition or interpretation, could be more compromising for reproducibility. METHODS: Three investigators each acquired inferior vena cava (IVC) and internal jugular (IJV) vein ultrasonographic sequences (US) from a convenience sample of 21 hospitalized general medicine participants and then interpreted each US three separate times. We partitioned the random errors of acquisition and interpretation, attributing wider dispersions of each to larger reductions in reproducibility. RESULTS: We analyzed 351 interpretations of 39 IVC and 432 interpretations of 48 IJV US. Reproducibility of the maximum (standard error of measurement 3.3 mm [95% confidence interval, CI 2.7-4.2 mm]) and minimum (4.8 mm [3.9-6.3 mm]) IVC diameter measurements were worse than that of the mediolateral (2.5 mm [2.0-3.2 mm]) and anteroposterior (2.5 mm [2.0-3.1 mm]) IJV diameters. The dispersions of random measurement errors were wider among acquisitions than interpretations. CONCLUSIONS: Among our investigators, central vein diameter measurements obtained by point-of-care ultrasonography are not sufficiently reproducible to distinguish clinically meaningful intravascular volume changes from measurement errors. Reproducibility could be most effectively improved by reducing the random measurement errors of acquisition. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:488-496, 2017. PMID- 28880384 TI - Transabdominal sonography to measure the total vaginal and mucosal thicknesses. AB - Transabdominal and transvaginal sonography are used to measure bladder wall and detrusor thickness. Only transvaginal sonography has been used to measure the vaginal wall thickness. We describe the use of transabdominal sonography to measure the total vaginal wall thickness and total vaginal mucosal thickness at the bladder trigone. The mean bladder wall thickness and SD from published data were within the 95% confidence interval of our data. Total vaginal and mucosal thicknesses are reliable measurements, which require specific evaluation in a postmenopausal population. They could be used to quantify vaginal atrophy and could correlate to symptoms of atrophy and response to treatment. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:461-464, 2017. PMID- 28880388 TI - Wearable medical device improves survival for glioblastoma patients. PMID- 28880385 TI - Echocardiographic features of right ventricular diverticulum: A case report. AB - Right ventricular diverticulum is a rare form of cardiac deformity, with a very few cases caused by pericarditis. A 60-year-old man sought medication because of chest congestion and shortness of breath. CT showed a soft tissue mass at the heart apex and pericardial calcification. Doppler echocardiography demonstrated a mixed cystic solid mass at the right ventricular apex. Surgical cure confirmed the diagnosis of right ventricular apex diverticulum with pericarditis. Echocardiography is contributive to the diagnosis of ventricular diverticula in measuring their size and showing the local thinning of the ventricular wall with localized bulging and abnormal motion. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:531-534, 2017. PMID- 28880389 TI - More breast cancer patients could benefit from PARP inhibitors. PMID- 28880390 TI - Researchers delve into thyroid cancer disparities in race and age: Incidence of the disease continues to grow, but at a slower rate in some groups. PMID- 28880391 TI - Meta-analysis of the association between alcohol consumption and abdominal aortic aneurysm. AB - BACKGROUND: Alcohol is a possible risk factor for abdominal aortic aneurysm (AAA), but evidence from individual studies is weak and inconsistent. Existing narrative reviews suggest the possibility of non-linear associations. The aim here was to quantify any association using a systematic literature review, followed by dose-response meta-analysis of prospective studies. METHODS: MEDLINE, Embase and Web of Science were searched systematically to January 2017 for relevant prospective studies of alcohol consumption and AAA risk. Summary estimates of highest versus lowest levels of consumption, and linear and non linear dose-response curves were quantified using random-effects models. RESULTS: Eleven relevant cohorts were identified describing results from 3580 individuals with among 473 092 participants. Data were extracted from ten cohorts for meta analyses of high versus low levels of alcohol consumption (risk ratio for AAA 0.93, 95 per cent c.i. 0.78 to 1.11; P = 0.4, I2 = 47 per cent). The linear dose response risk ratio for AAA, derived from 11 cohorts, was 1.00 (0.97 to 1.04) per 8 g alcohol per day (P = 0.9, I2 = 73 per cent). Non-linear dose-response results showed a tick-shaped curve with lower risk up to 2 units/day, but increasing risk beyond that (P = 0.05). The increase in risk beyond 2 units/day was stronger in men than in women. CONCLUSION: Although the linear dose-response analysis revealed little evidence of an association between alcohol consumption and AAA risk, a tick-shaped trend in the association was observed. This non linear dose-response analysis revealed reduced risks for alcohol consumption below 2 units/day, masking increased risks for 2 or more units/day. PMID- 28880392 TI - Pedal peptide/orcokinin-type neuropeptide signaling in a deuterostome: The anatomy and pharmacology of starfish myorelaxant peptide in Asterias rubens. AB - Pedal peptide (PP) and orcokinin (OK) are related neuropeptides that were discovered in protostomian invertebrates (mollusks, arthropods). However, analysis of genome/transcriptome sequence data has revealed that PP/OK-type neuropeptides also occur in a deuterostomian phylum-the echinoderms. Furthermore, a PP/OK-type neuropeptide (starfish myorelaxant peptide, SMP) was recently identified as a muscle relaxant in the starfish Patiria pectinifera. Here mass spectrometry was used to identify five neuropeptides (ArPPLN1a-e) derived from the SMP precursor (PP-like neuropeptide precursor 1; ArPPLNP1) in the starfish Asterias rubens. Analysis of the expression of ArPPLNP1 and neuropeptides derived from this precursor in A. rubens using mRNA in situ hybridization and immunohistochemistry revealed a widespread pattern of expression, with labeled cells and/or processes present in the radial nerve cords, circumoral nerve ring, digestive system (e.g., cardiac stomach) and body wall-associated muscles (e.g., apical muscle) and appendages (e.g., tube feet and papulae). Furthermore, our data provide the first evidence that neuropeptides are present in the lateral motor nerves and in nerve processes innervating interossicular muscles. In vitro pharmacological tests with SMP (ArPPLN1b) revealed that it causes dose-dependent relaxation of apical muscle, tube foot and cardiac stomach preparations from A. rubens. Collectively, these anatomical and pharmacological data indicate that neuropeptides derived from ArPPLNP1 act as inhibitory neuromuscular transmitters in starfish, which contrasts with the myoexcitatory actions of PP/OK-type neuropeptides in protostomian invertebrates. Thus, the divergence of deuterostomes and protostomes may have been accompanied by an inhibitory excitatory transition in the roles of PP/OK-type neuropeptides as regulators of muscle activity. PMID- 28880393 TI - The feasibility and acceptability of nurse-led chronic disease management interventions in primary care: An integrative review. AB - AIMS: To explore the feasibility and acceptability of nurse-led chronic disease management and lifestyle risk factor reduction interventions in primary care (general practice/family practice). BACKGROUND: Growing international evidence suggests that interventions delivered by primary care nurses can assist in modifying lifestyle risk factors and managing chronic disease. To date, there has been limited exploration of the feasibility and acceptability of such interventions. DESIGN: Integrative review guided by the work of Whittemore and Knafl (). DATA SOURCES: Database search of CINAHL, Medline and Web of Science was conducted to identify relevant literature published between 2000-2015. REVIEW METHODS: Papers were assessed for methodological quality and data abstracted before thematic analysis was undertaken. RESULTS: Eleven papers met the inclusion criteria. Analysis uncovered four themes: (1) facilitators of interventions; (2) barriers to interventions; (3) consumer satisfaction; and (4) primary care nurse role. CONCLUSION: Literature supports the feasibility and acceptability of nurse led interventions in primary care for lifestyle risk factor modification. The ongoing sustainability of these interventions rests largely on organizational factors such as funding, educational pathways and professional support of the primary care nursing role. Further robust research around primary care nurse interventions is required to strengthen the evidence base. PMID- 28880395 TI - Predictors of depressive symptoms among psychiatric nurses who suffered from workplace violence. AB - AIMS: We examined the possible factors that contributed to or prevented developing depressive symptoms among psychiatric nurses who suffered from workplace violence under Hill's ABC-X Model. BACKGROUND: Workplace violence related depressive symptoms are some of the major causes leading to impaired quality of life of victims and a heavy burden on society. DESIGN: This is a cross sectional and correlational study. METHOD: All participants were recruited from psychiatric wards of six hospitals in Taiwan. The data were collected through structured questionnaires from October 2013-March 2014 and a total of 278 psychiatric wards nurses participated in this study and completed all questionnaires. Logistic regression was used to examine the relationships among types and severity of violence, social support and depressive symptoms. RESULTS: Of assaulted psychiatric ward nurses, 75.9% had depressive symptoms and those with higher family support had significantly lower depressive symptoms. CONCLUSIONS: Family support plays the most important role among assaulted psychiatric ward nurses as a protective factor against developing depressive symptoms in this study. PMID- 28880394 TI - An assessment of pregnant women's knowledge and use of the Internet for medication safety information and purchase. AB - AIM: The aim of this study was to assess pregnant women's Internet searching activity about medication safety, knowledge and perceptions of medication risk and willingness to take prescribed and non-prescribed medication or make online medication purchases. BACKGROUND: Online medication advice for pregnant women is complex. The quality and veracity of this data is increasingly important as more midwives report women are bringing retrieved online information to clinical appointments. Pregnant women's use of the Internet for seeking medication advice and purchasing medications has not yet been fully investigated. DESIGN: Online survey conducted from January - March 2013. FINDINGS: Of the 284 respondents, 39% were taking a medication when they became pregnant and 76% had searched the Internet for medication safety information. Analgesics were the most commonly searched category (41%). Health service sites were the most common online source and regarded as the most helpful and trusted. Regardless of age and education level, 90% of women agreed that if trying to become pregnant they would reconsider taking any medications because of the potential risk to their unborn baby. Forty-six percent of women with higher levels of education consider buying medication online as safe, a greater proportion than those of lower education. Five percent of women reported buying medication online. CONCLUSION: The lack of specific recommendations for medication use during pregnancy is challenging for healthcare staff and pregnant women who need robust evidence to make informed treatment decisions. The Internet is a recognized, commonly accessed, source of medication information for pregnant women. PMID- 28880396 TI - Drug repurposing to treat asthma and allergic disorders: Progress and prospects. AB - Allergy and atopic asthma have continued to become more prevalent in modern society despite the advent of new treatments, representing a major global health problem. Common medications such as antihistamines and steroids can have undesirable long-term side-effects and lack efficacy in some resistant patients. Biologic medications are increasingly given to treatment-resistant patients, but they can represent high costs, complex dosing and management, and are not widely available around the world. The field needs new, cheap, and convenient treatment options in order to bring better symptom relief to patients. Beyond continued research and development of new drugs, a focus on drug repurposing could alleviate this problem by repositioning effective and safe small-molecule drugs from other fields of medicine and applying them toward the treatment for asthma and allergy. Herein, preclinical models, case reports, and clinical trials of drug repurposing efficacy in allergic disease are reviewed. Novel drugs are also proposed for repositioning based on their mechanism of action to treat asthma and allergy. Overall, drug repurposing could become increasingly important as a way of advancing allergy and atopic asthma therapy, filling a need in treatment of patients today. PMID- 28880397 TI - Transcranial Doppler: a stethoscope for the brain-neurocritical care use. AB - Transcranial Doppler (TCD) ultrasonography is a noninvasive bedside monitoring technique that can evaluate cerebral blood flow hemodynamics in the intracranial arterial vasculature. TCD allows assessment of linear cerebral blood flow velocity, with a high temporal resolution and is inexpensive, reproducible, and portable. The aim of this review is to provide an overview of the most commonly used TCD derived signals and measurements used commonly in neurocritical care. We describe both basic (flow velocity, pulsatility index) and advanced concepts, including critical closing pressure, wall tension, autoregulation, noninvasive intracranial pressure, brain compliance, and cerebrovascular time constant; we also describe the clinical applications of TCD to highlight their utility in the diagnosis and monitoring of cerebrovascular diseases as the "stethoscope for the brain." PMID- 28880399 TI - Failing to meet relative humidity targets for incubated neonates causes higher heat loss and metabolic costs in the first week of life. AB - AIM: Frequent nursing procedures can modify a newborn infant's thermal environment when their incubator is opened. This study evaluated the impact of relative humidity (RH) on preterm infants in closed incubators and calculated their heat loss and additional metabolic cost. METHODS: We studied 45 preterm infants born before 32 + 0 weeks, nursed at the neonatal intensive care unit at Amiens University Hospital, France from January 2009 to November 2011. Their body, skin and air temperatures and the incubator's RH were continuously recorded from day 1 to 8 of life, and the differences between the measured and target RH were calculated. Body heat loss (BHL) was also calculated. RESULTS: On day one, the measured RH (68.7 +/- 1.0%) was significantly lower than the target RH (75%, p < 0.05), but this difference, together with BHL (p < 0.001) and evaporative heat loss (p < 0.001), fell significantly over time (p < 0.05). The additional metabolic cost correlated with the difference between measured and target RH (p < 0.001). CONCLUSION: RH from day 1 to 8 was below the recommended target value for preterm infants and resulted in high evaporative and greater total BHL and additional metabolic cost. The findings pose numerous challenges, including nursing care and incubator design. PMID- 28880398 TI - Association of Incident, Clinically Undiagnosed Radiographic Vertebral Fractures With Follow-Up Back Pain Symptoms in Older Men: the Osteoporotic Fractures in Men (MrOS) Study. AB - Prior data in women suggest that incident clinically undiagnosed radiographic vertebral fractures (VFs) often are symptomatic, but misclassification of incident clinical VF may have biased these estimates. There are no comparable data in men. To evaluate the association of incident clinically undiagnosed radiographic VF with back pain symptoms and associated activity limitations, we used data from the Osteoporotic Fractures in Men (MrOS) Study, a prospective cohort study of community-dwelling men aged >=65 years. A total of 4396 men completed spine X-rays and symptom questionnaires at baseline and visit 2, about 4.6 years later. Incident clinical VFs during this interval were defined by self reported clinical diagnosis plus community imaging showing a centrally adjudicated >=1 increase in semiquantitative (SQ) grade in any thoracic or lumbar vertebra versus baseline study X-rays. Incident radiographic VFs (>=1 increase in SQ grade between baseline and visit 2 study X-rays) were categorized as radiographic-only (not clinically diagnosed) or radiographic plus clinical (also clinically diagnosed). Multivariable-adjusted log binomial regression was used to calculate prevalence ratios (PRs) and 95% confidence intervals (CIs). Men with incident radiographic plus clinical VF were most likely to have back pain symptoms and associated activity limitation at follow-up. However, versus men without incident VF, those with incident radiographic-only VF also were significantly more likely at follow-up to report any back pain (70% versus 59%; PR, 1.2 [95% CI, 1.1 to 1.3]), severe back pain (8% versus 4%; PR, 1.9 [95% CI, 1.1 to 3.3]), bother from back pain most/all the time (22% versus 13%; PR, 1.7 [95% CI, 1.3 to 2.2]), and limited usual activity from back pain (34% versus 18%; PR, 1.9 [95% CI, 1.5 to 2.4]). Clinically undiagnosed, incident radiographic VFs were associated with an increased likelihood of back pain symptoms and associated activity limitation. Results suggest incident radiographic-only VFs often were symptomatic, and were associated with both new and worsening back pain. Preventing these fractures may reduce back pain and related disability in older men. (c) 2017 American Society for Bone and Mineral Research. PMID- 28880400 TI - Effects of ivermectin and its combination with alpha lipoic acid on expression of IGFBP-3 and HSPA1 genes and male rat fertility. AB - This study was conducted to evaluate the effects of ivermectin (IVM) with therapeutic dose (injected with 0.56 mg/kg b.wt.) either alone or combined with alpha lipoic acid (ALA) (50 mg/kg b.wt daily) on expression of testicular insulin like growth factor binding protein-3 (IGFBP-3) and heat-shock protein A1 (HSPA1)) genes in the testes, as well as on male rat fertility parameters. Results revealed that expression levels of IGFBP-3 and HSPA1 were significantly increased in testis of the IVM-treated group relative to the control group. Furthermore, injection of ivermectin showed a significant decrease in serum testosterone level, sperm count, motility %, live sperm% and index weight of reproductive organs, and a significant increase in sperm abnormalities. Moreover, IVM induced oxidative stress and pathological alterations in the testes. Meanwhile, the administration of ALA with IVM prevented testicular damage and improved all previous parameters. We concluded that ivermectin has undesirable effects on male fertility and altered expression of IGFBP-3 and HSPA1 genes in the testes, while the administration of alpha lipoic acid can ameliorate the adverse effects of ivermectin. PMID- 28880402 TI - Sonographic Characteristics of Apocrine Nodular Hidradenoma of the Skin. AB - Nodular hidradenomas are benign sweat gland-derived tumors that can produce clinical and dermatoscopic misdiagnoses. Histologically, these tumors can be classified into eccrine and apocrine subtypes. We present the sonographic characteristics of 6 cases of apocrine nodular hidradenomas, which, to our knowledge, is so far the largest series reported. A detailed sonographic analysis included layers, body location, shape, diameters, echostructure patterns, and vascularity. Two sonographic signs not previously reported in these or other common dermatologic lesions were detected: "snow falling" and "fluid-fluid level." The sonographic characteristics of apocrine nodular hidradenomas can support their earlier and more precise diagnosis. PMID- 28880401 TI - Reduced number of CD169+ macrophages in pre-metastatic regional lymph nodes is associated with subsequent metastatic disease in an animal model and with poor outcome in prostate cancer patients. AB - BACKGROUND: Tumor-derived antigens are captured by CD169+ (SIGLEC1+ ) sinus macrophages in regional lymph nodes (LNs), and are presented to effector cells inducing an anti-tumor immune response. Reduced CD169 expression in pre metastatic regional LNs is associated with subsequent metastatic disease and a poor outcome in several tumor types, but if this is the case in prostate cancer has not been explored. METHODS: CD169 expression was measured with immunohistochemistry in metastasis-free regional LNs from 109 prostate cancer patients treated with prostatectomy (January 1996 to April 2002). Possible associations of CD169 expression with PSA-relapse, prostate cancer death, Gleason score, and other clinical data were assessed using Kaplan-Meier survival- and Cox regression analysis. In addition, the Dunning rat prostate tumor model was used to examine CD169 expression in pre-metastatic LNs draining either highly metastatic MatLyLu- or poorly metastatic AT1-tumors. RESULTS: In patients with low CD169 immunostaining in metastasis-free regional LNs, 8 of the 27 patients died from prostate cancer compared with only three of the 82 patients with high immunostaining (P < 0.001). CD169 expression in regional LNs was not associated with PSA-relapse. Rats with highly metastatic tumors had decreased CD169 immunoreactivity in pre-metastatic regional LNs compared with rats with poorly metastatic tumors. CONCLUSION: Low expression of CD169 in metastasis-free regional LNs indicates a reduced anti-tumor immune response. If verified in other studies, CD169 expression in regional LNs could, in combination with other factors, potentially be used as a marker of prostate cancer aggressiveness. PMID- 28880404 TI - Cultivation and quantitative single-cell analysis of Saccharomyces cerevisiae on a multifunctional microfluidic device. AB - Here, we present a multifunctional microfluidic device whose integrative design enables to combine cell culture studies and quantitative single cell biomolecule analysis. The platform consists of 32 analysis units providing two key features; first, a micrometer-sized trap for hydrodynamic capture of a single Saccharomyces cerevisiae (S. cerevisiae) yeast cell; second, a convenient double-valve configuration surrounding the trap. Actuating of the outer valve with integrated opening results in a partial isolation in a volume of 11.8 nL, i.e. the cell surrounding fluid can be exchanged diffusion-based without causing shear stress or cell loss. Actuation of the inner ring-shaped valve isolates the trapped cell completely in a small analysis volume of 230 pL. The device was used to determine the growth rate of yeast cells (S. cerevisiae) under under optimum and oxidative stress conditions. In addition, we successfully quantified the cofactor beta nicotinamide adenine dinucleotide phosphate (NAD(P)H) in single and few cells exposed to the different microenvironments. In conclusion, the microdevice enables to analyze the influence of an external stress factor on the cellular fitness in a fast and more comprehensive way as cell growth and intracellular biomolecule levels can be investigated. PMID- 28880403 TI - Natural immunoglobulin M initiates an inflammatory response important for both hepatic ischemia reperfusion injury and regeneration in mice. AB - : Complement plays a role in both hepatic ischemia reperfusion (IR) injury (IRI) and liver regeneration, but it is not clear how complement is activated in either process. We investigated the role of self-reactive immunoglobulin M (IgM) antibodies in activating complement after hepatic IR and liver resection. Natural IgM antibodies that recognize danger-associated molecular patterns (neoepitopes) activate complement following both hepatic IR and liver resection. Antibody deficient Rag1-/- mice were protected from hepatic IRI, but had increased hepatic injury and an impaired regenerative response after 70% partial hepatectomy (PHx). We identified two IgM monoclonal antibodies (mAbs) that specifically reversed the effect of Rag1 deficiency in both models; B4 (recognizes Annexin IV) and C2 (recognizes subset of phospholipids). Focusing on the B4-specific response, we demonstrated sinusoidal colocalization of IgM and C3d in Rag1-/- mice that were reconstituted with B4 mAb, and furthermore that the Annexin IV neoepitope is specifically and similarly expressed after both hepatic IR and PHx in wild-type (WT) mice. A single-chain antibody construct (scFv) derived from B4 mAb blocked IgM binding and reduced injury post-IR in WT mice, although, interestingly, B4scFv did not alter regeneration post-PHx, indicating that anti-Annexin IV antibodies are sufficient, but not necessary, for the regenerative response in the context of an entire natural antibody repertoire. We also demonstrated expression of the B4 neoepitope in postischemic human liver samples obtained posttransplantation and a corollary depletion in IgM recognizing the B4 and C2 neoepitopes in patient sera following liver transplantation. CONCLUSION: These data indicate an important role for IgM in hepatic IRI and regeneration, with a similar cross-species injury-specific recognition system that has implications for the design of neoepitope targeted therapeutics. (Hepatology 2017). PMID- 28880405 TI - Differentiation of the Follicular Variant of Papillary Thyroid Carcinoma From Classic Papillary Thyroid Carcinoma: An Ultrasound Analysis and Complement to Fine-Needle Aspiration Cytology. AB - OBJECTIVES: It is difficult to establish a diagnosis of the follicular variant of papillary thyroid carcinoma (PTC) using fine-needle aspiration cytology (FNAC). Preoperative features on ultrasound (US) imaging are different between follicular PTC and classic PTC. This study developed a risk score system to differentiate follicular PTC from classic PTC and to correlate the risk score of follicular PTC with its FNAC categories and pathologic features. METHODS: The US features, FNAC results, and pathologic reports of 156 follicular PTC nodules and 152 classic PTC nodules from 296 patients with PTC along with their clinical characteristics were reviewed retrospectively. A risk score system based on US features was developed by multivariate logistic regression to differentiate classic PTC from follicular PTC nodules. The risk scores were then correlated with the FNAC category and pathologic features of the nodules. RESULTS: The US risk score (5 * echogenicity + 3 * calcifications + 3 * marginal regularity) had an area under the receiver operating characteristic curve of 0.85 and a cutoff value of 8.0, with specificity of 87% and sensitivity of 69% for predicting a classic PTC nodule. The follicular PTC nodules with low Bethesda categorization (I-III) had a median US risk score of 6 (range, 0-11), which was higher than that of nodules with high categorization (IV-VI; median, 3; range, 0-11). CONCLUSIONS: The US risk score may be useful in differentiating classic PTC from follicular PTC and complementary to FNAC in identifying follicular PTC. PMID- 28880406 TI - Incidental neuronal intermediate filament inclusion pathology: unexpected biopsy findings in a 37-year-old woman with epilepsy. PMID- 28880407 TI - Biomarkers in solid organ transplantation. AB - Recipients of solid organs such as the kidney and heart are treated with standard immunosuppressive regimens, and personalized medicine has not yet reached the clinic for this patient population. Biomarkers potentially will allow treatment regimens to be adjusted, according to the needs of the individual patient. Biomarkers may reflect the degree of immunosuppression of the immune system, or they may reflect early damage to the transplanted organ. PMID- 28880408 TI - Quality evaluation of Guan-Xin-Ning injection based on fingerprint analysis and simultaneous separation and determination of seven bioactive constituents by capillary electrophoresis. AB - The purpose of this study was to develop a comprehensive, rapid and practical capillary electrophoresis (CE) method for quality control (QC) of Guan-Xin-Ning (GXN) injection based on fingerprint analysis and simultaneous separation and determination of seven constituents. In fingerprint analysis, a capillary zone electrophoresis (CZE) method with a running buffer of 30 mM borate solution (pH 9.3) was established. Meanwhile, ten batches of samples were used to establish the fingerprint electropherogram and 34 common peaks were obtained within 20 min. The RSD of relative migration times (RMT) and relative peak areas (RPA) were less than 5%. In order to further evaluate the quality of GXN injection, a micellar electrokinetic chromatography (MEKC) method was developed for simultaneous separation and determination of bioactive constituents. Seven components reached baseline separation with a running buffer containing 35 mM SDS and 45 mM borate solution (pH 9.3). A good linearity was obtained with correlation coefficients from 0.9906 to 0.9997. The LOD and LOQ ranged from 0.12 to 1.50 MUg/mL and from 0.40 to 4.90 MUg/mL, respectively. The recoveries ranged between 99.0 and 104.4%. Therefore, it was concluded that the proposed method can be used for full-scale quality analysis of GXN injection. PMID- 28880410 TI - Staff awareness of food and fluid care needs for older people with dementia in residential care: A qualitative study. AB - AIMS AND OBJECTIVES: To examine awareness of aged care home staff regarding daily food and fluid care needs of older people with dementia. BACKGROUND: Older people in residential care frequently are malnourished, and many have dementia. Staff knowledge of the food and fluid needs of people with dementia is limited. Qualitative research on this topic is scarce but can provide insight into how nutrition and hydration care may be improved. DESIGN: Qualitative, interview based study. METHODS: Eleven staff in a range of positions at one care home were interviewed regarding their perceptions of current and potential food/fluid care practices. Transcripts were coded and analysed thematically. RESULTS: Key food and fluid issues reported by these staff members were weight loss and malnutrition, chewing and swallowing difficulties (dysphagia), and inadequate hydration. Staff identified a number of current care practices that they felt to be effective in facilitating older people's food and fluid intake, including responsiveness to their needs. Staff suggestions to facilitate food and fluid intake centred on improved composition and timing of meals, enhanced physical and social eating environment, and increased hydration opportunities. Staff commented on factors that may prevent changes to care practices, particularly the part-time workforce, and proposed changes to overcome such barriers. CONCLUSIONS: Staff were aware of key food and fluid issues experienced by the older people in their care and of a range of beneficial care practices, but lacked knowledge of many promising care practices and/or how to implement such practices. RELEVANCE TO CLINICAL PRACTICE: Staff need to be supported to build on their existing knowledge around effective food and fluid care practices. The numerous ideas staff expressed for changing care practices can be leveraged by facilitating staff networking to work and learn together to implement evidence-based change. PMID- 28880409 TI - The Rate of Cervical Length Shortening in the Management of Vasa Previa. AB - OBJECTIVES: There is no consensus about the optimal surveillance strategy in women with a diagnosis of vasa previa. The aim of this study was to evaluate the role of the rate of change in cervical length measurements in the management of singleton pregnancies with a diagnosis of vasa previa. METHODS: We performed a retrospective case-control study of our databases for pregnancies with a prenatal diagnosis of vasa previa that were followed with transvaginal sonography for cervical length and evaluated the impact of the changes in cervical length on the need for emergency cesarean delivery. RESULTS: The cohort included 29 singleton pregnancies with a prenatal diagnosis of vasa previa in the second trimester. There were 14 and 15 pregnancies that underwent elective and emergency cesarean delivery, respectively. The rate of cervical length shortening was significantly slower for women with elective compared to emergency cesarean delivery (median [range], 0.7 [0.1-2.0] versus 1.5 [0.25-3.0] mm/wk; P = .011). For each additional millimeter-per-week decrease in cervical length, the odds of emergency cesarean delivery increased by 6.50 (95% confidence interval, 1.02-41.20). The receiver operating characteristic curve for the rate of cervical length shortening in the prediction of emergency cesarean delivery yielded an area under the curve of 0.85 (95% confidence interval, 0.69-0.99). CONCLUSIONS: Our findings indicate an association between the rate of cervical length shortening and the risk of emergency cesarean delivery in pregnancies with a diagnosis of vasa previa in the second trimester. Further multicentric studies are required to validate our data prospectively and, in particular, the role of serial cervical length measurements in determining the optimal delivery time for individual cases. PMID- 28880411 TI - Preschool children living in joint physical custody arrangements show less psychological symptoms than those living mostly or only with one parent. AB - AIM: Joint physical custody (JPC), where children spend about equal time in both parent's homes after parental separation, is increasing. The suitability of this practice for preschool children, with a need for predictability and continuity, has been questioned. METHODS: In this cross-sectional study, we used data on 3656 Swedish children aged three to five years living in intact families, JPC, mostly with one parent or single care. Linear regression analyses were conducted with the Strengths and Difficulties Questionnaire, completed by parents and preschool teachers, as the outcome measure. RESULTS: Children in JPC showed less psychological problems than those living mostly (adjusted B 1.81; 95% CI [0.66 to 2.95]) or only with one parent (adjusted B 1.94; 95% CI [0.75 to 3.13]), in parental reports. In preschool teacher reports, the adjusted Betas were 1.27, 95% CI [0.14 to 2.40] and 1.41, 95% CI [0.24 to 2.58], respectively. In parental reports, children in JPC and those in intact families had similar outcomes, while teachers reported lower unadjusted symptom scores for children in intact families. CONCLUSION: Joint physical custody arrangements were not associated with more psychological symptoms in children aged 3-5, but longitudinal studies are needed to account for potential preseparation differences. PMID- 28880412 TI - Diagnostic Efficiency of Quantitative Contrast-Enhanced Ultrasound Indicators for Discriminating Benign From Malignant Solid Thyroid Nodules. AB - OBJECTIVES: We aimed to determine the most efficient quantitative parameters to establish a contrast-enhanced ultrasound (US) assessment system for distinguishing between benign and malignant thyroid nodules. METHODS: A total of 167 patients with thyroid solitary nodules had the diagnosis confirmed by surgery or fine-needle aspiration. Quantitative contrast-enhanced US indicators (time to peak, time from peak to one-half, ascend slope, descend slope, peak intensity, and area under the curve [AUC]) were gathered in nodule and perinodule areas. Univariate and multivariate logistic regression analyses were performed. Receiver operating characteristic curves were generated. Sensitivities, specificities, and positive and negative predictive values were calculated to identify the best cutoff value. RESULTS: The univariate logistic regression model showed that the peak intensity, ascend slope, descend slope, and AUC were significant indicators for discriminating benign from malignant nodules under contrast-enhanced US (P < .0001). For thyroid nodules, low peak intensity, ascend slope, and AUC and high descend slope values were significant indicators of malignancy. However, in perinodule areas, high peak intensity, ascend slope, and AUC and low descend slope values were significantly associated with malignancies. The cutoff values for the nodule peak intensity, ascend slope, descend slope, and AUC were 20.75, 0.91, -0.2, and 1818.23, respectively. The cutoff values for the ratios of the nodule versus perinodule peak intensity, ascend slope, descend slope, and AUC were 0.90, 0.95, 0.96, and 0.96. The nodule-to-perinodule peak intensity ratio showed the best diagnostic efficiency, with 80.41% sensitivity and 80.00% specificity. CONCLUSIONS: Quantitative contrast-enhanced US indicators help discriminate benign from malignant thyroid nodules. The nodule-to-perinodule peak intensity ratio showed the best diagnostic efficiency. PMID- 28880413 TI - Curcuminoids Lower Plasma Leptin Concentrations: A Meta-analysis. AB - Curcumin is a naturally occurring polyphenol that has been suggested to improve several metabolic diseases. Leptin is an adipokine involved in metabolic status and appetite, with marked crosstalk with other systems. Available data suggest that curcumin may affect leptin levels; therefore, this meta-analysis was performed to evaluate this. A systematic review and meta-analysis were undertaken on all randomized controlled trials of curcumin studies that included the measurement of leptin. The search included PubMed-Medline, Scopus, ISI Web of Knowledge, and Google Scholar databases. Quantitative data synthesis was performed by using a random-effects model, with standardized mean difference and 95% confidence interval as summary statistics. A funnel plot, Begg's rank correlation, and Egger's weighted regression tests assessed the presence of publication bias. Four eligible articles comprising five treatment arms were selected for the meta-analysis. Meta-analysis showed a significant decrease in plasma leptin concentrations following curcumin treatment (standardized mean difference: -0.69, 95% confidence interval: -1.16, -0.23, p = 0.003; I2 = 76.53%). There was no evidence of publication bias. This meta-analysis showed that curcumin supplementation is associated with a decrease in leptin levels that may be regarded as a potential mechanism for the metabolic effects of curcumin. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28880414 TI - Levodopa treatment and dendritic spine pathology. AB - Parkinson's disease (PD) is a neurodegenerative disorder associated with the progressive loss of nigrostriatal dopaminergic neurons. Levodopa is the most effective treatment for the motor symptoms of PD. However, chronic oral levodopa treatment can lead to various motor and nonmotor complications because of nonphysiological pulsatile dopaminergic stimulation in the brain. Examinations of autopsy cases with PD have revealed a decreased number of dendritic spines of striatal neurons. Animal models of PD have revealed altered density and morphology of dendritic spines of neurons in various brain regions after dopaminergic denervation or dopaminergic denervation plus levodopa treatment, indicating altered synaptic transmission. Recent studies using rodent models have reported dendritic spine head enlargement in the caudate-putamen, nucleus accumbens, primary motor cortex, and prefrontal cortex in cases where chronic levodopa treatment following dopaminergic denervation induced dyskinesia-like abnormal involuntary movement. Hypertrophy of spines results from insertion of alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid receptors into the postsynaptic membrane. Such spine enlargement indicates hypersensitivity of the synapse to excitatory inputs and is compatible with a lack of depotentiation, which is an electrophysiological hallmark of levodopa-induced dyskinesia found in the corticostriatal synapses of dyskinetic animals and the motor cortex of dyskinetic PD patients. This synaptic plasticity may be one of the mechanisms underlying the priming of levodopa-induced complications such as levodopa-induced dyskinesia and dopamine dysregulation syndrome. Drugs that could potentially prevent spine enlargement, such as calcium channel blockers, N-methyl-D-aspartate receptor antagonists, alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid receptor antagonists, and metabotropic glutamate receptor antagonists, are candidates for treatment of levodopa-induced complications in PD. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28880415 TI - Pregnant substance abusers in voluntary and coercive treatment in Norway: Therapists' reflections on change processes and attachment experiences. AB - AIMS AND OBJECTIVES: To explore therapists' discourses on treatment processes, when working with pregnant substance abusers in voluntary and coercive treatment, and looking for the clinical implications of these discourses. BACKGROUND: Treatment of substance use disorder faces many challenges. One is pregnancy and motherhood, which are vulnerable and complex processes. The literature emphasises lack of optimal and knowledge-based treatment for this group. DESIGN: The study follows a Foucauldian inspired discourse analysis. METHOD: Forty therapists from four different residential units in Norway, offering both voluntary and coercive treatment of pregnant women with substance use disorders, were interviewed in focus groups. The semi-structured interview schedule focused on exploring how therapists' discourses on change processes and relationship experiences informed their clinical practice. RESULTS: How to start "healthy" attachment processes between the pregnant woman and the unborn child was the dominant discourse among the therapists. Another important theme was coercion, and whether that as a contextual frame was negative or positive in creating attachment between mother and child. Other discourses were varieties of understanding attachment when the mothers had difficulties with substance abuse, the mothers' own attachment histories, and social and cultural challenges. CONCLUSION: Systematic work with attachment issues between the pregnant woman and her unborn child was the dominant perspective of nearly all the therapists. The contextual factors in the lives of the women were less prioritised, even though they are of decisive importance for the relationship between mother and child. RELEVANCE TO CLINICAL PRACTICE: Treatment professionals need to focus more on the discursive dilemmas encountered in the relation between substance use disorders and the unborn child. PMID- 28880416 TI - The effect of self-administered superficial local hot and cold application methods on pain, functional status and quality of life in primary knee osteoarthritis patients. AB - AIMS AND OBJECTIVES: To investigate the effect of the self-administered superficial local hot and cold applications on pain, and the functional status and the quality of life in primary knee osteoarthritis patients. BACKGROUND: Superficial local hot and cold application is used as a nonpharmacological method for the treatment of knee osteoarthritis. However, various guidelines for the management of knee osteoarthritis have conflicting recommendation for hot and cold therapy. DESIGN: A randomised clinical trial design. METHODS: The sample consisted of patients (n = 96) who were diagnosed with primary knee osteoarthritis. During the application stage, patients were designated to the hot and cold application groups and administered hot and cold application twice a day for 3 weeks together with standard osteoarthritis treatment. The control group only used standard osteoarthritis treatment. The data were collected with a Descriptive Information Form, a Pain Scale, the WOMAC Osteoarthritis Index, the Nottingham Health Profile (NHP) and a Patient Satisfaction Evaluation Form. Outcome measures included pain intensity, functional status and quality of life. RESULTS: We found decreased primary measurement pain scores and improved functional status scores and quality of life scores after the application programme compared to the pre-application stage in both the hot and cold application groups. Once the application was completed, the pain scores, functional status scores and quality-of-life scores on the second measurements were found to be still statistically lower than the pre-application scores but higher than the first measurement ([p < .001, chi2 = 48.000; p < .001, chi2 = 34.000], [p < .001, chi2 = 22.000; p = .001 chi2 =14.000] and [p = .005, chi2 = 16.000; p = .001, chi2 = 12.500]). There was no difference in the perceived pain, functional status and quality of life between the pre-application, postapplication and 2 weeks postapplication periods of the individuals in three groups (p > .05). CONCLUSION: It was found that both hot and cold application resulted in a mild improvement in pain, functional status and quality of life, but this improvement was not sufficient to create a significant difference between the groups. RELEVANCE TO CLINICAL PRACTICE: This study contributes to the literature on hot and cold application methods as self-management strategies for patients with knee osteoarthritis. PMID- 28880417 TI - Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease. AB - Our understanding of the underlying biology of Alzheimer's disease (AD) has been steadily progressing; however, this is yet to translate into a successful treatment in humans. The use of transgenic mouse models has helped to develop our understanding of AD, not only in terms of disease pathology, but also with the associated cognitive impairments typical of AD. Plaques and neurofibrillary tangles are often among the last pathological changes in AD mouse models, after neuronal loss and gliosis. There is a general consensus that successful treatments need to be applied before the onset of these pathologies and associated cognitive symptoms. This review discusses the different types of AD mouse models in terms of the temporal progression of the disease, how well they replicate the pathological changes seen in human AD and their cognitive defects. We provide a critical assessment of the behavioural tests used with AD mice to assess cognitive changes and decline, and discuss how successfully they correlate with cognitive impairments in humans with AD. This information is an important tool for AD researchers when deciding on appropriate mouse models, and when selecting measures to assess behavioural and cognitive change. PMID- 28880418 TI - Diagnostic utility of cerebrospinal fluid alpha-synuclein in Parkinson's disease: A systematic review and meta-analysis. AB - BACKGROUND: The accumulation of misfolded alpha-synuclein aggregates is associated with PD. However, the diagnostic value of the alpha-synuclein levels in CSF is still under investigation. METHODS: A comprehensive search of the literature was performed, yielding 34 studies eligible for meta-analysis. We included studies that reported data on CSF total, oligomeric and phosphorylated alpha-synuclein in patients with PD and healthy participants, neurological controls, or other parkinsonisms. Standardized mean differences were pooled using random-effects models, and heterogeneity was reported as I2 . Bivariate random effects meta-analysis was also performed on diagnostic data. Methodological quality of the selected studies was assessed using the QUADAS-2 tool. RESULTS: Concentrations of alpha-synuclein species in PD did not show significant differences with respect to the levels found in other parkinsonisms. Total alpha synuclein was significantly reduced in PD when compared with controls (standardized mean differences -0.48; P < .001, I2 = 60%). Oligomeric (standardized mean differences 0.57; P < .001, I2 = 44%) and phosphorylated alpha synuclein (standardized mean differences 0.86; P < .001) were significantly increased in PD when compared with controls. Sensitivity and specificity for distinguishing PD and controls were 0.72 and 0.65, respectively, for total alpha synuclein, and 0.71 and 0.64, respectively, for oligomeric alpha-syn. CONCLUSION: Most of the studies were at high risk of bias and have concerns regarding applicability. Diagnostic performance of CSF alpha-synuclein species is still below what would be considered acceptable for their introduction in clinical practice. Future research should focus on combining alpha-synuclein species with other biochemical markers as well on improving the standardization of current assays. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28880419 TI - Effects of a nurse-led transitional care programme on readmission, self-efficacy to implement health-promoting behaviours, functional status and life quality among Chinese patients with coronary artery disease: A randomised controlled trial. AB - AIMS AND OBJECTIVES: To examine the effectiveness of a nurse-led transitional care programme on readmission, self-efficacy to implement health-promoting behaviours, functional status and life quality among Chinese patients with coronary artery disease. BACKGROUND: Coronary artery disease is a major cause of mortality in China. Transitional care could help to ensure improved patient outcomes. Nevertheless, our knowledge of how to perform transitional care for patients with coronary artery disease is insufficient in mainland China. DESIGN: Randomised controlled trial. METHODS: The nurse-led transitional care intervention in the experimental group adopted the Omaha system and Pender's health-promoting model as its frameworks. The control group received a comparable length routine care and follow-up contacts. Evaluations were conducted at baseline before discharge and after 7 months after discharge using hospital readmission rate, self-rated abilities for health practices scale and Seattle Angina Questionnaire for functional status and life quality. Data were collected between March 2014-October 2014. RESULTS: Compared with the control group, participants in the experimental group showed greater self-efficacy to implement health-promoting behaviours, more angina stability, less angina frequency, more satisfaction with treatment and better quality of life. The difference in readmission rate and physical limitations was not significant between the two groups. CONCLUSION: This study provides evidence for the effectiveness of a nurse led transitional care programme in improving the ability to implement health promoting behaviours, the functional status and life quality among Chinese patients with coronary artery disease. RELEVANCE TO CLINICAL PRACTICE: The nurse led transitional care programme is helpful for coronary artery disease patients to promote their effective transfer from hospital to community and provide an evidence for nursing managers to train their nurses for transitional care knowledge and skills. PMID- 28880420 TI - Latent Risk Subtypes Based on Injection and Sexual Behavior Among People Who Inject Drugs in Rural Puerto Rico. AB - BACKGROUND: People who inject drugs (PWID) in Puerto Rico engage in high levels of injection and sexual risk behavior, and they are at high risk for HIV and hepatitis C (HCV) infection, relative to their US counterparts. Less is known, however, about the clustering of risk behavior conducive to HIV and HCV infection among rural Puerto Rican communities. OBJECTIVES: The purpose of this study was to examine concurrent injection and sexual risk subtypes among a rural sample of PWID in Puerto Rico. METHODS: Data were drawn from a respondent-driven sample collected in 2015 of 315 PWID in 4 rural communities approximately 30-40 miles from San Juan. Latent class analysis (LCA) was used to examine risk subtypes using 3 injection and 3 sexual risk indicators. In addition, demographic and other PWID characteristics were examined as possible predictors of latent class membership. RESULTS: Four LCA subtypes were identified: low risk (36%), high injection/low sexual risk (22%), low injection/high sexual risk (20%), and high risk (22%). Younger age and past year homelessness predicted high risk latent class membership, relative to the other classes. In addition, daily speedball use predicted membership in the high injection/low sexual risk class, relative to the low risk and low injection/high sexual risk classes. CONCLUSION/IMPORTANCE: The findings suggest ways in which PWID risk clusters can be identified for targeted interventions. PMID- 28880421 TI - Diffuse midline gliomas with histone H3-K27M mutation: A rare case with PNET-like appearance and neuropil-like islands. AB - Diffuse midline glioma with histone H3-K27M mutation is a new tumor entity defined by the 2016 WHO Classification of Tumors of the Central Nervous System. A 51-year-old Chinese woman presented with neck pain for a month. Subsequent MRI revealed an intramedullary neoplasm extending from C5 to C7. Histologically, the cellular area of the tumor was composed of primitive, poorly differentiated, small cells with scant cytoplasm, nuclear molding, and brisk mitotic activity, exhibiting PNET-like appearance, while in the hypocellular area, oligodendroglioma-like cells were observed. More importantly, neuropil-like islands were observed in the cellular area. Microvascular proliferation was noted, with no necrosis. Besides histone H3K27M mutation, immunohistochemical staining also showed that the tumor cells were positive for oligodendrocyte lineage transcription factor 2 and ATRX. The neuropil-like areas were positive for synaptophysin, intermingled with scattered neuronal nuclear antigen positive cells. The Ki-67 proliferation index was about 30%, and tumor cells were highly immunopositive for p53. Sequencing for IDH1 codon 132 and IDH2 codon 172 gene mutations showed negative results. Furthermore, fluorescent analysis revealed 1p deletion in the lesion but no 19q deletion. Based on these findings, the tumor was diagnosed as diffuse midline gliomas with histone H3-K27M mutation in the spinal cord, corresponding to WHO grade IV. After 4 months of remission, the tumor recurred; 2 months later, the patient died. Herein, we report an extremely rare case of diffuse midline glioma with histone H3K27M mutation, which was morphologically characterized simultaneously by primitive neuroectodermal tumor like appearance and neuropil-like islands. PMID- 28880422 TI - Deep brain stimulation modulates the shape of cortical beta oscillations in Parkinson's disease. PMID- 28880424 TI - XXXV Annual Scientific Meeting of the British Blood Transfusion Society, SEC Centre, Glasgow, UK, 13-15 September 2017. PMID- 28880423 TI - Variation in job titles within the nursing workforce. AB - AIMS AND OBJECTIVES/BACKGROUND: The work of specialist nursing has been under scrutiny for many years in the UK due to a perception that it is not cost effective. A common issue is the lack of consistency of job titles, which causes confusion to the public, employing organisations, colleagues and commissioners of services. Lack of consistency has implications for the wider perception of advanced specialist practice in the worldwide community and the workforce more generally. This study aims to understand the variation in job titles in the UK population. METHODS: A pre-existing data set of accrued studies into the work of nurses working in specialisms was mined for insight (N = 17,960). This study used knowledge discovery through data and descriptive statistics to perform secondary analysis. RESULTS: Mining these data revealed 595 job titles in use in 17,960 specialist posts once the specialism had been removed. The most commonly used titles were Clinical Nurse Specialist, Nurse Specialist/Specialist Nurse, Advanced Nurse Practitioner and Nurse Practitioner. There were three other primary groupings. These were variants with a specialist or technical prefix of suffix, for example Nurse Endoscopist, variants of seniority such as trainee, senior nurse for [specialism] or variants of function such as Nurse Prescriber. The clustering was driven primarily by pay band. A total of 323 posts were recorded as holding titles such as Advanced Nurse Practitioner or Specialist Nurse who were not registered with the Nursing & Midwifery Council. RELEVANCE TO CLINICAL PRACTICE: In this data set, there is a large array of titles, which appear to have little relationship with other factors like education. This is confusing to the public, employers and those commissioning services. It also demonstrates that the previous assumptions by Council for Healthcare Regulatory Excellence that advanced practice labels are associated with career progression are unsound and should be addressed by the regulator. PMID- 28880426 TI - Dual Visible Light-Triggered Photoswitch of a Diarylethene Supramolecular Assembly with Cucurbit[8]uril. AB - Research on photochromic molecules switched by visible light is of particular interest for their application in bioimaging and stimuli-responsive materials. Here, a photoswitchable supramolecular assembly comprised of monocharged bispyridinium-modified diarylethenes (DAEs) and cucurbit[8]uril (CB[8]) has been constructed, which exhibits reversible photochromic behaviour with visible light in both directions. The transformation of CB[8] not only prompts the DAEs to form charge-transfer complexes, but also restricts its intramolecular rotation to enhance fluorescence emission. In this CB[8]-containing supramolecular system, the pi-conjugation is extended and its absorption is bathochromically shifted for visible light-driven cyclization of DAEs. Meanwhile, the fluorescence of the supramolecular assembly can also be reversibly modulated by visible light. These findings may furnish a new strategy for the development of visible light-driven fluorescent biomaterials and molecular machines. PMID- 28880425 TI - Chronic sleep reduction is associated with academic achievement and study concentration in higher education students. AB - Inadequate sleep impairs cognitive function and has been associated with worse academic achievement in higher education students; however, studies that control for relevant background factors and include knowledge on sleep hygiene are scarce. This study examined the association of chronic sleep reduction (i.e. symptoms of chronic sleep reduction such as shortness of sleep, sleepiness and irritation), subjective sleep quality and sleep hygiene knowledge with academic achievement (grades and study credits) and study concentration among 1378 higher education students (71% female, mean age 21.73 years, SD = 3.22) in the Netherlands. Demographic, health, lifestyle and study behaviour characteristics were included as covariates in hierarchical regression analyses. After controlling for significant covariates, only chronic sleep reduction remained a significant predictor of lower grades (last exam, average in current academic year). Better sleep quality and sleep hygiene knowledge were associated with better academic achievement, but significance was lost after controlling for covariates, except for a remaining positive association between sleep hygiene beliefs and grades in the current academic year. Moreover, better sleep quality and lower scores on chronic sleep reduction were associated with better study concentration after controlling for significant covariates. To conclude, chronic sleep reduction is associated with academic achievement and study concentration in higher education students. Inadequate sleep hygiene knowledge is moderately associated with worse academic achievement. Future research should investigate whether sleep hygiene interventions improve academic achievement in students of higher education. PMID- 28880428 TI - Induction of autophagy by an oleanolic acid derivative, SZC017, promotes ROS dependent apoptosis through Akt and JAK2/STAT3 signaling pathway in human lung cancer cells. AB - The signal transducers and activators of transcription 3 (STAT3) signaling pathway is a common feature in many solid tumors including non-small cell lung cancer, whereas current therapies usually fail to treat this disease in majority of cases. In the present study, we aimed to investigate the cytotoxic effect and the underlying mechanisms of SZC017, an oleanolic acid derivative, on human lung cancer cells. Cell viability was significantly decreased in SZC017-treated lung cancer cells. Mechanistically, SZC017 reduced A549 cell viability by activating both apoptosis and autophagy pathways. SZC017 was able to inhibit the phosphorylation of Akt, JAK2, and STAT3 in A549 cells, resulting in the inactivation of Akt and JAK2/STAT3 signaling pathways. In addition, SZC017 could induce ROS generation and Ca2+ release. Pretreatment with N-Acetyl L-Cysteine, a ROS scavenger, could fully reverse SZC017-induced ROS and increase the expression of Akt, p-STAT3, and procaspase-3, while decrease the ratio of LC3-II/I and the expression of Beclin-1. In summary, our study provides pharmacological evidence that SZC017 exhibits potential use in the treatment of lung cancer. PMID- 28880427 TI - Stigmatic exudate in the Annonaceae: Pollinator reward, pollen germination medium or extragynoecial compitum? AB - Although "dry-type" stigmas are widely regarded as ancestral in angiosperms, the early-divergent family Annonaceae has copious stigmatic exudate. We evaluate three putative functions for this exudate: as a nutritive reward for pollinators; as a pollen germination medium; and as an extragynoecial compitum that enables pollen tube growth between carpels. Stigmatic exudate is fructose dominated (72.2%), but with high levels of glucose and sucrose; the dominance of hexose sugars and the diversity of amino acids observed, including many that are essential for insects, support a nutritive role for pollinators. Sugar concentration in pre-receptive flowers is high (28.2%), falling during the peak period of stigmatic receptivity (17.4%), and then rising again toward the end of the pistillate phase (32.9%). Pollen germination was highest in sugar concentrations <20%. Sugar concentrations during the peak pistillate phase therefore provide optimal osmolarity for pollen hydration and germination; subsequent changes in sugar concentration during anthesis reinforce protogyny (in which carpels mature before stamens), enabling the retention of concentrated exudate into the staminate phase as a pollinator food reward without the possibility of pollen germination. Intercarpellary growth of pollen tubes was confirmed: the exudate therefore also functions as a suprastylar extragynoecial compitum, overcoming the limitations of apocarpy. PMID- 28880429 TI - List randomization for soliciting experience of intimate partner violence: Application to the evaluation of Zambia's unconditional child grant program. AB - Social scientists have increasingly invested in understanding how to improve data quality and measurement of sensitive topics in household surveys. We utilize the technique of list randomization to collect measures of physical intimate partner violence in an experimental impact evaluation of the Government of Zambia's Child Grant Program. The Child Grant Program is an unconditional cash transfer, which targeted female caregivers of children under the age of 5 in rural areas to receive the equivalent of US $24 as a bimonthly stipend. The implementation results show that the list randomization methodology functioned as planned, with approximately 15% of the sample identifying 12-month prevalence of physical intimate partner violence. According to this measure, after 4 years, the program had no measurable effect on partner violence. List randomization is a promising approach to incorporate sensitive measures into multitopic evaluations; however, more research is needed to improve upon methodology for application to measurement of violence. PMID- 28880430 TI - Human Leukocyte Antigen Sensitization in Solid Organ Transplantation: A Primer on Terminology, Testing, and Clinical Significance for the Apheresis Practitioner. AB - The human leukocyte antigen (HLA) system is an important immunologic barrier that must be considered for successful solid organ transplantation. Formation of donor specific HLA antibodies in solid organ transplantation is an important cause of allograft injury and may contribute to recipient morbidity and mortality. Therapeutic plasma exchange is often requested to lower HLA antibody levels prior to or after transplantation and for management of HLA antibodies in the context of organ rejection. In this review, we summarize the current terminology, laboratory testing, and clinical significance of HLA sensitization in the solid organ transplant population. Furthermore, to illustrate applications of HLA testing in clinical practice, we summarize our own lung and kidney institutional protocols for managing HLA antibodies in the peri-transplant setting. PMID- 28880431 TI - The role of herbivore- and plant-related experiences in intraspecific host preference of a relatively specialized parasitoid. AB - Parasitoids use odor cues from infested plants and herbivore hosts to locate their hosts. Specialist parasitoids of generalist herbivores are predicted to rely more on herbivore-derived cues than plant-derived cues. Microplitis croceipes (Cresson) (Hymenoptera: Braconidae) is a relatively specialized larval endoparasitoid of Heliothis virescens (F.) (Lepidoptera: Noctuidae), which is a generalist herbivore on several crops including cotton and soybean. Using M. croceipes/H. virescens as a model system, we tested the following predictions about specialist parasitoids of generalist herbivores: (i) naive parasitoids will show innate responses to herbivore-emitted kairomones, regardless of host plant identity and (ii) herbivore-related experience will have a greater influence on intraspecific oviposition preference than plant-related experience. Inexperienced (naive) female M. croceipes did not discriminate between cotton-fed and soybean fed H. virescens in oviposition choice tests, supporting our first prediction. Oviposition experience alone with either host group influenced subsequent oviposition preference while experience with infested plants alone did not elicit preference in M. croceipes, supporting our second prediction. Furthermore, associative learning of oviposition with host-damaged plants facilitated host location. Interestingly, naive parasitoids attacked more soybean-fed than cotton fed host larvae in two-choice tests when a background of host-infested cotton odor was supplied, and vice versa. This suggests that plant volatiles may have created an olfactory contrast effect. We discussed ecological significance of the results and concluded that both plant- and herbivore-related experiences play important role in parasitoid host foraging. PMID- 28880432 TI - Tyrosine-Kinase Inhibitors for Treatment in Hemodialysis Patients on Kidney Transplant Waiting List. Comment on: Nakai et al. PMID- 28880433 TI - The effect of hydroxyapatite nanoparticles on mechanical behavior and biological performance of porous shape memory polyurethane scaffolds. AB - The scaffold which provides space for cell growth, proliferation, and differentiation, is a key factor in bone tissue engineering. However, improvements in scaffold design are needed to precisely match the irregular boundaries of bone defects as well as facilitate clinical application. In this study, controllable three-dimensional (3D) porous shape memory polyurethane/nano hydroxyapatite (SMPU/nHAP) composite scaffold was successfully fabricated for bone defect reparation. Detailed studies were performed to evaluate its structure, apparent density, porosity, and mechanical properties, emphasizing the contribution of nHAP particles on shape recovery behaviors and biological performance in vitro. The effect of nHAP particles in porous SMPU/nHAP composite scaffold was found to enhance the compression resistance by 37%, shorten the compression recovery time by 41%, reduce the tensile resistance by 78%, reach the shape recovery ratio of 99%, and promote the cell proliferation by 13% after 7 days of culture. These results revealed that the 3D structure and aperture of as prepared scaffold were controllable. And in minimally invasive surgery and bone repair surgery, this porous composite scaffold could significantly reduce the operative time and promote the bone cell growth. Therefore, this porous SMPU/nHAP composite scaffold design has potential applications for the bone tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 244-254, 2018. PMID- 28880434 TI - A Bayesian CUSUM plot: Diagnosing quality of treatment. AB - OBJECTIVES: To present a CUSUM plot based on Bayesian diagnostic reasoning displaying evidence in favour of "healthy" rather than "sick" quality of treatment (QOT), and to demonstrate a technique using Kaplan-Meier survival curves permitting application to case series with ongoing follow-up. METHODS: For a case series with known final outcomes: Consider each case a diagnostic test of good versus poor QOT (expected vs. increased failure rates), determine the likelihood ratio (LR) of the observed outcome, convert LR to weight taking log to base 2, and add up weights sequentially in a plot showing how many times odds in favour of good QOT have been doubled. For a series with observed survival times and an expected survival curve: Divide the curve into time intervals, determine "healthy" and specify "sick" risks of failure in each interval, construct a "sick" survival curve, determine the LR of survival or failure at the given observation times, convert to weights, and add up. RESULTS: The Bayesian plot was applied retrospectively to 39 children with acute lymphoblastic leukaemia with completed follow-up, using Nordic collaborative results as reference, showing equal odds between good and poor QOT. In the ongoing treatment trial, with 22 of 37 children still at risk for event, QOT has been monitored with average survival curves as reference, odds so far favoring good QOT 2:1. CONCLUSION: QOT in small patient series can be assessed with a Bayesian CUSUM plot, retrospectively when all treatment outcomes are known, but also in ongoing series with unfinished follow-up. PMID- 28880435 TI - Thrombocytopenia and CD34 expression is decoupled from alpha-granule deficiency with mutation of the first growth factor-independent 1B zinc finger. AB - : Essentials The phenotypes of different growth factor-independent 1B (GFI1B) variants are not established. GFI1B variants produce heterogeneous clinical phenotypes dependent on the site of mutation. Mutation of the first non-DNA binding zinc-finger causes a mild platelet and clinical phenotype. GFI1B regulates the CD34 promoter; platelet CD34 expression is an indicator of GFI1B mutation. SUMMARY: Background Mutation of the growth factor-independent 1B (GFI1B) fifth DNA-binding zinc-finger domain causes macrothrombocytopenia and alpha-granule deficiency leading to clinical bleeding. The phenotypes associated with GFI1B variants disrupting non-DNA-binding zinc-fingers remain uncharacterized. Objectives To determine the functional and phenotypic consequences of GFI1B variants disrupting non-DNA-binding zinc-finger domains. Methods The GFI1B C168F variant and a novel GFI1B c.2520 + 1_2520 + 8delGTGGGCAC splice variant were identified in four unrelated families. Phenotypic features, DNA-binding properties and transcriptional effects were determined and compared with those in individuals with a GFI1B H294 fs mutation of the fifth DNA-binding zinc-finger. Patient-specific induced pluripotent stem cell (iPSC)-derived megakaryocytes were generated to facilitate disease modeling. Results The DNA binding GFI1B variant C168F, which is predicted to disrupt the first non-DNA binding zinc-finger domain, is associated with macrothrombocytopenia without alpha-granule deficiency or bleeding symptoms. A GFI1B splice variant, c.2520 + 1_2520 + 8delGTGGGCAC, which generates a short GFI1B isoform that lacks non-DNA binding zinc-fingers 1 and 2, is associated with increased platelet CD34 expression only, without quantitative or morphologic platelet abnormalities. GFI1B represses the CD34 promoter, and this repression is attenuated by different GFI1B zinc-finger mutations, suggesting that deregulation of CD34 expression occurs at a direct transcriptional level. Patient-specific iPSC-derived megakaryocytes phenocopy these observations. Conclusions Disruption of GFI1B non DNA-binding zinc-finger 1 is associated with mild to moderate thrombocytopenia without alpha-granule deficiency or bleeding symptomatology, indicating that the site of GFI1B mutation has important phenotypic implications. Platelet CD34 expression appears to be a common feature of perturbed GFI1B function, and may have diagnostic utility. PMID- 28880436 TI - Redox luminescence switch based on Mn2+ -doped NaYF4 :Yb,Er upconversion nanorods. AB - An redox luminescence switch was developed for the sensing of glutathione (GSH), l-cysteine (Cys) or l-ascorbic acid (AA) based on redox reaction. The Mn2+ -doped NaYF4 :Yb,Er upconversion nanorods (UCNRs) with an emission peak located in the red region were synthesized. The luminescence intensity of the UCNRs could be quenched due to the Mn2+ could be oxidized to MnO2 by KMnO4 . Subsequently, when the AA, GSH or Cys was added into the MnO2 modified upconversion nanosystem, which could reduced MnO2 to Mn2+ and the luminescence intensity was recovered. The concentration ranges of the nanosystem are 0.500-3.375 mM (R2 = 0.99) for AA, 0.6250-11.88 mM (R2 = 0.99) for GSH and 0.6250-9.375 mM (R2 = 0.99) for Cys, respectively. PMID- 28880438 TI - Prevalence and factors associated with mild cognitive impairment among Chinese older adults with depression. AB - AIM: Depression and mild cognitive impairment (MCI) are common among older adults. Most of the existing studies were carried out in developed countries, and evidence from developing countries are lacking. In the present study, using a national sample, we aimed to describe the prevalence of MCI and its associated factors among Chinese older adults with depression. METHOD: The present study uses data from a national survey of the 2011 Comprehensive Assessment of Elderly Health, which involved 8113 older adults from eight provinces or municipalities directly under the Central Government of six regions in China. The Geriatric Depression Scale was used to assess depression, and the Mini-Mental State Examination was used as the measurement of cognitive function. RESULTS: The results showed that the prevalence of geriatric depression was 15.9%, and 36.4% of those with depression had MCI. Geriatric depression was found to be significantly associated with MCI after controlling for demographics. Among participants with geriatric depression, female sex, older age, rural or suburban residence, poor physical health status, education level of illiterate or elementary school, having no daily physical activity, and living in Central China or West China were associated with an increased risk of MCI. CONCLUSIONS: The present study showed a high prevalence rate of MCI among Chinese older adults with depression. Early screening and treatment for MCI are necessary among people with geriatric depression. Further research and health services innovations are required to address the high prevalence of MCI in this population. Geriatr Gerontol Int 2018; 18: 263-268. PMID- 28880437 TI - Prevalence of Earlobe Creases and Their Association With History of Cardiovascular Disease in Patients Undergoing Hemodialysis: A Cross-Sectional Study. AB - Earlobe creases are surrogate markers for high risk of cardiovascular disease. There is no data concerning earlobe creases among hemodialysis patients, who have an increased risk of cardiovascular disease. A cross-sectional study was conducted to determine the prevalence of earlobe creases and their association with prevalent cardiovascular disease among hemodialysis patients. Patients undergoing hemodialysis were recruited from five outpatient hemodialysis centers. Both earlobes were photographed during a dialysis session with the patient in a supine position and the photos evaluated independently by two experienced nephrologists blinded to the participants' clinical characteristics. Prevalent cardiovascular diseases were defined as a history of myocardial infarction, cerebrovascular accident, or peripheral vascular disease. Sensitivity, specificity, and positive and negative predictive values for detection of prevalent cardiovascular disease were calculated. Logistic analysis was used to examine the association between earlobe creases and prevalent cardiovascular disease. Earlobe creases were identified in 24.5% of 330 hemodialysis patients (200 men; mean age, 67.8 years). The prevalence of earlobe creases increased with age for men (P for trend <0.0001), but not for women (P for trend = 0.07). Sensitivity, specificity, and positive and negative predictive values were 30.9% (95% confidence interval, 21.9-41.6), 77.5% (71.9-82.3), 30.9% (21.9-41.6), and 77.5% (71.9-82.3), respectively. Multivariate logistic analyses indicated the prevalence of earlobe crease was not associated with prevalent cardiovascular diseases. The prevalence is similar to that previously reported for Japanese individuals not undergoing dialysis. No association between earlobe creases and prevalent cardiovascular diseases was identified. PMID- 28880439 TI - Complete response in a patient with stage IV adrenocortical carcinoma treated with adjuvant trans-catheter arterial chemo-embolization (TACE). AB - Adrenocortical carcinoma is a rare cancer, with estimate population incidence of 0.7-2.0 cases per 1 million each year. It also carries poor prognosis with estimated 5-year survival of less than 15% of those with metastatic disease and has a poor response to cytotoxic treatment. A randomized controlled trial published in 2012 by Fassnacht et al. demonstrated improved progression-free survival with first-line etoposide-doxirubicin-cisplatin-mitotane (EDP-M) compared to first-line streptozocin-mitotane in patients with stage III-IV disease. We report a case of a 25-year-old female diagnosed with adrenocortical carcinoma with liver and lung metastases treated with adjuvant EDP-M chemotherapy. During her treatment, the patient experienced ongoing significant liver-associated burden of disease, which prompted a trial of trans-hepatic arterial chemoembolization with doxorubicin and mitomycin. The patient subsequently experienced complete remission of disease at 18 months with no fludeoxyglucose (FDG) avid lesions on PET/CT. PMID- 28880440 TI - Editorial: subgroups in irritable bowel syndrome-more than just diarrhoea and constipation? Authors' reply. PMID- 28880441 TI - Letter: CYP2C19 polymorphisms and exacerbation of rabeprazole's effects on celecoxib-induced small bowel injury-authors' reply. PMID- 28880442 TI - Editorial: challenges in the development of a magnetic resonance imaging index for fistulising Crohn's disease. PMID- 28880443 TI - Editorial: diagnosing bile acid diarrhoea with blood tests. PMID- 28880444 TI - Letter: the potential risk of HBV reactivation in patients with resolved HBV infection during direct-acting antiviral therapy. PMID- 28880445 TI - Editorial: subgroups in irritable bowel syndrome-more than just diarrhoea and constipation? PMID- 28880446 TI - Letter: CYP2C19 polymorphisms and exacerbation of rabeprazole's effects on celecoxib-induced small bowel injury. PMID- 28880447 TI - Letter: bleeding in cirrhotics receiving coronary stenting and antiplatelet therapy. PMID- 28880448 TI - Letter: the potential risk of HBV reactivation in patients with resolved HBV infection during direct-acting antiviral therapy - authors' reply. PMID- 28880449 TI - Reduced risk of decompensation and death associated with use of statins in patients with alcoholic cirrhosis. A nationwide case-cohort study. AB - BACKGROUND: Reports have indicated that the use of statins may ameliorate the course of cirrhosis. AIM: To determine the relationship between use of statins and mortality rate in patients with cirrhosis. METHODS: We did a retrospective case-cohort analysis based on data from the Danish registers from the period 1995 through 2014. Index date was time of diagnosis of cirrhosis (ICD-10: K703) and cohort entry depended on whether the patient was statin user or not. We used propensity score matching with a statin:non-statin ratio of 1:2. We included the exposure to statins (ATC classification C10AA) from the index date until death or end of follow-up based on prescription claims. Use of statins based on at least two statin claims as well as the longitudinal pattern over time of statin claims was tested against mortality. The main outcome was mortality rate. RESULTS: A total of 24 748 patients with alcoholic cirrhosis were identified and 5417 were eligible for matching. The mean age was 56 (SD 10) years and 36% were females. The prevalence of use of statins was 15%. We included 744 in the matched cohort. Mortality rates were 88 (95% CI 73-105) per 1000 years for patients using statin and 127 (95% CI 114-141) for non-statin patients with a HR of 0.57 (95% CI 0.45 0.71). A more regular pattern of statin claims was related to a lower risk of death. CONCLUSIONS: Our results showed an association between regular use of statins and reduced mortality in patients with alcoholic cirrhosis. PMID- 28880450 TI - Letter: the importance of dosing and baseline haemoglobin when establishing the relative efficacy of intravenous iron therapies. PMID- 28880451 TI - Editorial: treatments for non-alcoholic steatohepatitis - still a long way to go. PMID- 28880452 TI - Letter: bleeding in cirrhotics receiving coronary stenting and antiplatelet therapy - author's reply. PMID- 28880453 TI - Letter: the importance of dosing and baseline haemoglobin when establishing the relative efficacy of intravenous iron therapies-authors' reply. PMID- 28880454 TI - Erratum. PMID- 28880455 TI - Automated cell counts on CSF samples: A multicenter performance evaluation of the GloCyte system. AB - OBJECTIVES: Automated cell counters have replaced manual enumeration of cells in blood and most body fluids. However, due to the unreliability of automated methods at very low cell counts, most laboratories continue to perform labor intensive manual counts on many or all cerebrospinal fluid (CSF) samples. This multicenter clinical trial investigated if the GloCyte System (Advanced Instruments, Norwood, MA), a recently FDA-approved automated cell counter, which concentrates and enumerates red blood cells (RBCs) and total nucleated cells (TNCs), is sufficiently accurate and precise at very low cell counts to replace all manual CSF counts. METHODS: The GloCyte System concentrates CSF and stains RBCs with fluorochrome-labeled antibodies and TNCs with nucleic acid dyes. RBCs and TNCs are then counted by digital image analysis. Residual adult and pediatric CSF samples obtained for clinical analysis at five different medical centers were used for the study. Cell counts were performed by the manual hemocytometer method and with the GloCyte System following the same protocol at all sites. The limits of the blank, detection, and quantitation, as well as precision and accuracy of the GloCyte, were determined. RESULTS: The GloCyte detected as few as 1 TNC/MUL and 1 RBC/MUL, and reliably counted as low as 3 TNCs/MUL and 2 RBCs/MUL. The total coefficient of variation was less than 20%. Comparison with cell counts obtained with a hemocytometer showed good correlation (>97%) between the GloCyte and the hemocytometer, including at very low cell counts. CONCLUSIONS: The GloCyte instrument is a precise, accurate, and stable system to obtain red cell and nucleated cell counts in CSF samples. It allows for the automated enumeration of even very low cell numbers, which is crucial for CSF analysis. These results suggest that GloCyte is an acceptable alternative to the manual method for all CSF samples, including those with normal cell counts. PMID- 28880457 TI - Development of quality metrics for ambulatory care in pediatric patients with tetralogy of Fallot. AB - OBJECTIVE: The objective of this study was to develop quality metrics (QMs) relating to the ambulatory care of children after complete repair of tetralogy of Fallot (TOF). DESIGN: A workgroup team (WT) of pediatric cardiologists with expertise in all aspects of ambulatory cardiac management was formed at the request of the American College of Cardiology (ACC) and the Adult Congenital and Pediatric Cardiology Council (ACPC), to review published guidelines and consensus data relating to the ambulatory care of repaired TOF patients under the age of 18 years. A set of quality metrics (QMs) was proposed by the WT. The metrics went through a two-step evaluation process. In the first step, the RAND-UCLA modified Delphi methodology was employed and the metrics were voted on feasibility and validity by an expert panel. In the second step, QMs were put through an "open comments" process where feedback was provided by the ACPC members. The final QMs were approved by the ACPC council. RESULTS: The TOF WT formulated 9 QMs of which only 6 were submitted to the expert panel; 3 QMs passed the modified RAND-UCLA and went through the "open comments" process. Based on the feedback through the open comment process, only 1 metric was finally approved by the ACPC council. CONCLUSIONS: The ACPC Council was able to develop QM for ambulatory care of children with repaired TOF. These patients should have documented genetic testing for 22q11.2 deletion. However, lack of evidence in the literature made it a challenge to formulate other evidence-based QMs. PMID- 28880456 TI - Urinary miR-155-5p and CXCL10 as prognostic and predictive biomarkers of rejection, graft outcome and treatment response in kidney transplantation. AB - AIMS: MicroRNAs (miRNAs) may be useful biomarkers of rejection and allograft outcome in kidney transplantation. Elevated urinary CXCL10 levels have been associated with acute rejection (AR) and may predict allograft failure. We examined the correlation of miRNA, CXCL10 levels and immunosuppressive drug exposure with AR and graft function in kidney transplant recipients. METHODS: Eighty de novo kidney transplant recipients were recruited from four European centres. All patients received tacrolimus, mycophenolate mofetil, and methylprednisolone. Urinary pellet expression of miR-142-3p, miR-210-3p and miR 155-5p was assessed by quantitative real-time polymerase chain reaction and urinary CXCL10 levels by enzyme-linked immunosorbent assay at the 1st week and the 1st , 2nd , 3rd and 6th months post-transplantation. RESULTS: Eight patients experienced AR. Before and during AR, patients showed a significant increase of urinary miR-142-3p, miR-155-5p and CXCL10 levels and a decrease of miR-210-3p levels. Receiver operating characteristic curve analysis showed that miR-155-5p (area under the curve = 0.875; P = 0.046) and CXCL10 (area under the curve = 0.865; P = 0.029) had excellent capacity to discriminate between rejectors and nonrejectors. The optimal cut-off values for the prognosis of AR were 0.51, with 85% sensitivity and 86% specificity for miR-155-5p and 84.73 pg ml-1 , with 84% sensitivity and 80% specificity for CXCL10. miR-155-5p and CXCL10 levels correlated with glomerular filtration rate. Levels of both biomarkers normalized after recovery of graft function. CONCLUSIONS: The regular early post transplantation monitoring of urinary miR-155-5p and CXCL10 can help in the prognosis of AR and graft dysfunction. Large prospective randomized multicentre trials are warranted to refine our cut-off values and validate the clinical usefulness of these biomarkers. PMID- 28880459 TI - Current Advances in Quantum-Dots-Based Photoelectrochemical Immunoassays. AB - As a newly developed technique, photoelectrochemical (PEC) immunoassays have attracted great attention in recent years because of their low cost and desirable sensitivity. Because the detection signal originates from the photoelectric conversion of photoelectric materials, the appearance and application of quantum dots (QDs), which possess unique photophysical properties and regulated optoelectronic characteristics, has taken the development of PEC immunoassays to new heights. This review concisely introduces the general mechanism of QDs-based photoelectric conversion for immunoassays and summarizes the current advances in QD applications in immunoassays. Given that signal strategies and photoactive materials are the key elements in PEC biosensor systems, we comprehensively highlight the state-of-the-art signaling strategies and various applications of QDs in PEC immunoassays to introduce advances in QDs-based PEC immunoassays. Finally, challenges and future developmental trends are briefly discussed. PMID- 28880458 TI - Determinants of platelet count in pediatric patients with congenital cyanotic heart disease: Role of immature platelet fraction. AB - OBJECTIVES: Congenital heart defects are common noninfectious causes of mortality in children. Bleeding and thrombosis are both limiting factors in the management of such patients. We assessed the frequency of thrombocytopenia in pediatric patients with congenital cyanotic heart disease (CCHD) and evaluated determinants of platelet count including immature platelet fraction (IPF) and their role in the pathogenesis of thrombocytopenia. METHODS: Forty-six children and adolescents with CCHD during pre-catheter visits were studied; median age was 20.5 months. Complete blood count including IPF as a marker of platelet production and reticulated hemoglobin content (RET-He) as a marker of red cell production and iron status were done on Sysmex XE 2100 (Sysmex, Japan). C-reactive protein, prothrombin time (PT), Activated partial thromboplastin time (APTT) were also assessed. RESULTS: Thrombocytopenia was found in 6 patients (13%). PT was prolonged (P = .016) and IPF was significantly higher in patients with thrombocytopenia compared with patients with normal platelet count (14.15 +/- 5.2% vs 6.68 +/- 3.39%; P = .003). Platelet count was negatively correlated with IPF while significant positive correlations were found between IPF and hemoglobin, red blood cells (RBCs) count, hematocrit (Hct), PT, reticulocytes count, and immature reticulocyte fraction. CONCLUSIONS: We suggest that elevated IPF in CCHD patients with thrombocytopenia may denote peripheral platelets destruction as an underlying mechanism. Hemoglobin level, RBCs count, Hct, and RET-He were not significant determinants for platelet count in CCHD. PMID- 28880460 TI - Cryopreserved Off-the-Shelf Allogeneic Adipose-Derived Stromal Cells for Therapy in Patients with Ischemic Heart Disease and Heart Failure-A Safety Study. AB - The present first-in-human clinical trial evaluated the safety and feasibility of a newly developed and cryopreserved Cardiology Stem Cell Centre adipose-derived stromal cell (CSCC_ASC) product from healthy donors for intramyocardial injection in ten patients with ischemic heart disease and ischemic heart failure (IHF). Batches of CSCC_ASC were isolated from three healthy donors by liposuction from abdominal adipose tissue. Adipose mesenchymal stromal cells were culture expanded in bioreactors without the use of animal constituents, cryopreserved, and stored in vials in nitrogen dry-storage containers until use. Direct injection of CSCC_ASC into the myocardium did not cause any complications or serious adverse events related to either treatment or cell administration in a 6-month follow-up period. Four out of ten heart failure patients developed donor-specific de novo human leukocyte antigen (HLA) class I antibodies, and two out of ten patients had donor-specific HLA antibodies already at baseline. There were no clinical symptoms or changes in inflammatory parameters in the follow-up period that indicated an ongoing immune response. There was a tendency toward improvement in cardiac function after CSCC_ASC treatment at 6-month follow-up: left ventricular end systolic volume decreased and left ventricular ejection fraction increased. In addition, exercise capacity increased. These changes were independent of the presence or absence of HLA antibodies. It is concluded that the newly developed cryopreserved product CSCC_ASC from healthy donors was a safe and feasible treatment. We observed a tendency toward efficacy in patients with IHF. These findings have to be confirmed in larger placebo controlled clinical trials. Stem Cells Translational Medicine 2017;6:1963-1971. PMID- 28880461 TI - Grief reactions of couples to perinatal loss: A one-year prospective follow-up. AB - AIMS AND OBJECTIVES: To explore couples' perceptions of the effects of perinatal loss on their marital relationship, social support and grief 1 year postloss, and analyse what factors changed the severity of their grief. BACKGROUND: Perinatal losses are traumatic events in the lives of families and can have serious long term consequences for the psychological health of parents and any subsequent children. DESIGN: A prospective follow-up study. METHODS: We recruited, at a teaching hospital in southern Taiwan, a convenience sample of 30 couples whose babies either miscarried or were stillborn. At 1 month (T1), 3 months (T2), 6 months (T3) and 1 year (T4) after the pregnancy loss, all participants completed four questionnaires. To analyse the changing status of their grief and its related factors, we used a generalised estimating equation (GEE) to account for correlations between repeated observations. RESULTS: Postbereavement grief levels fell over the four time-points. Mothers reported feeling more grief than did the fathers. Couples with a history of infertility, no religious beliefs or no living children before the loss felt more grief from a perinatal miscarriage or stillbirth. Furthermore, couples reported more grief if their marital satisfaction level was low, if their socioemotional support from husband's parents was low or if they had never participated in a ritual for their deceased baby. CONCLUSIONS: Six months postloss is the crucial period for bereaved parents after a perinatal loss. Being a mother, having no previous living children and low-level socioemotional support from the husband's parents are significant high risk factors for a high level of grief 1 year after perinatal death. RELEVANCE TO CLINICAL PRACTICE: We recommend that health professionals increase their ability to identify the factors that psychologically affect postloss grief. Active postloss follow-up programmes should focus on these factors to offer specific support and counselling. PMID- 28880462 TI - Indeterminate dendritic cell neoplasm of the skin: A 2-case report and review of the literature. AB - Indeterminate dendritic cell neoplasm (IDCN) is an exceedingly rare and mostly cutaneous histiocytosis, frequently associated with other hematopoietic malignancies. We report 2 cases of multilesional cutaneous IDCN. A 55-year-old male with no associated malignancy and complete response to ultraviolet phototherapy; and a 72-year-old male with chronic myelomonocytic leukemia (CMML). Both cases showed histiocytoid cytology, positivity for CD1a and no expression of langerin or BRAFV600E . With our patients, the literature describes 79 cases of IDCNs, including 65 (82%) with only skin involvement, 7 cases (9%) with involvement of skin and a second site, 5 cases (6%) involving lymph nodes only, 1 splenic lesion and 1 systemic disease. Seventeen cases (22%) were associated with other hematopoietic malignancies, most commonly CMML (6 cases), follicular lymphoma (4 cases) and acute myeloid leukemia (3 cases). All IDCNs associated with myeloid malignancies were limited to the skin, while most cases associated with lymphoma were limited to lymph nodes. Reported responses of cutaneous lesions to ultraviolet phototherapy are encouraging, while systemic chemotherapy is appropriate for clinically aggressive cases and treatment of associated malignancies. Recognition of the clinico-morphologic spectrum of IDCNs should prevent misdiagnoses and prompt investigation of possible associated neoplasms. PMID- 28880463 TI - Exploratory and descriptive study on nutritional characteristics and quality of eggs from Chilean partridge (Nothoprocta perdicaria). AB - This work aims to contribute more information on tinamou eggs by performing an exploratory and descriptive study of some of their nutritional and quality characteristics. The chemical composition of tinamou egg showed a high protein content in white (85% dry basis) and high lipid concentration in yolk (52% db). The iron (Fe) content in white was higher than hen egg (0.47 mg/100 g) and this could be associated with the observed pinkish color of the white. As in the hen egg, the major fatty acids in tinamou yolk were: oleic (39%), linoleic (23%) and palmitic (20%). The cholesterol content of tinamou was 21.2 mg/g of yolk, and 100 g of whole egg provides 589 mg of cholesterol. As in the hen egg, tinamou egg white showed high levels of lysine, sulfur-containing amino acids, threonine and valine with respect to the recommended allowance for an adult man. All essential amino acids with the exception of histidine cover the adult requirements. The shell inorganic composition of these eggs is calcium carbonate and the morphology was similar to other avian eggs. Tinamou egg is small and elongated, with a dark brown color. The eggshell is thinner and experiences more deformation but less breaking strength than hen eggshell. PMID- 28880464 TI - Dual growth factor-immobilized asymmetrically porous membrane for bone-to-tendon interface regeneration on rat patellar tendon avulsion model. AB - Insufficient repair of the bone-to-tendon interface (BTI) with structural/compositional gradients has been a significant challenge in orthopedics. In this study, dual growth factor (platelet-derived growth factor-BB [PDGF-BB] and bone morphogenetic protein-2 [BMP-2])-immobilized polycaprolactone (PCL)/Pluronic F127 asymmetrically porous membrane was fabricated to estimate its feasibility as a potential strategy for effective regeneration of BTI injury. The growth factors immobilized (via heparin-intermediated interactions) on the membrane were continuously released for up to ~80% of the initial loading amount after 5 weeks without a significant initial burst. From the in vivo animal study using a rat patellar tendon avulsion model, it was observed that the PDGF-BB/BMP 2-immobilized membrane accelerates the regeneration of the BTI injury, probably because of the continuous release of both growth factors (biological stimuli) and their complementary effect to create a multiphasic structure (bone, fibrocartilage, and tendon) like a native structure, as well as the role of the asymmetrically porous membrane as a physical barrier (nanopore side; prevention of fibrous tissue invasion into the defect site) and scaffold (micropore side; guidance for tissue regeneration). (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 115-125, 2018. PMID- 28880466 TI - Enhanced hemostasis with a sealant consisting of Hydrofit and Surgicel. AB - Bleeding is a serious concern during surgery for acute aortic dissections. We have used Hydrofit and Surgicel together to achieve hemostasis at the graft anastomotic sites during replacement of the ascending aorta and aortic arch. Complete hemostasis was achieved without further need for any additional sutures. PMID- 28880465 TI - Profiling novel metabolic biomarkers for Parkinson's disease using in-depth metabolomic analysis. AB - OBJECTIVE: To profile the amine/phenol submetabolome to determine potential metabolite biomarkers associated with Parkinson's disease (PD) and PD with incipient dementia. METHODS: At baseline of a 3-wave (18-month intervals) longitudinal study, serum samples were collected from 42 healthy controls and 43 PD patients. By wave 3 (year 3), 16 PD patients were diagnosed with dementia and were classified as PD with incipient dementia at baseline. Metabolomic profiling using dansylation isotope labeling liquid chromatography mass spectrometry was conducted to compare controls with the full PD, PD with no dementia, and PD with incipient dementia groups. RESULTS: Metabolomic analyses detected 719 common metabolites in 80% of the samples. Some were significantly altered in pairwise comparison of different groups (fold change of >1.2 or <0.83 with q < 0.05). We discriminated PD and controls by using a 5-metabolite panel, vanillic acid, 3 hydroxykynurenine, isoleucyl-alanine, 5-acetylamino-6-amino-3-methyluracil, and theophylline. The receiver operating characteristic curve produced an area-under the-curve value of 0.955 with 87.5% sensitivity and 93.0% specificity. In comparing PD with no dementia with PD with incipient dementia, we used an 8 metabolite panel, His-Asn-Asp-Ser, 3,4-dihydroxyphenylacetone, desaminotyrosine, hydroxy-isoleucine, alanyl-alanine, putrescine [-2H], purine [+O] and its riboside. This produced an area-under-the-curve value of 0.862 with 80.0% sensitivity and 77.0% specificity. CONCLUSIONS: The significantly altered metabolites can be used to differentiate (1) PD patients from healthy controls with high accuracy and (2) the stable PD with no dementia group from those with incipient dementia. Following further validation in larger cohorts, these metabolites could be used for both discrimination and establishing prognosis in PD. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28880467 TI - Patient prosthetic mismatch following aortic valve replacement-It may not all be due to the prosthesis. PMID- 28880468 TI - Lugones' technique for correction of Scimitar syndrome. AB - Several surgical techniques have been described to channel the right pulmonary venous return to the left atrium in the Scimitar syndrome which includes direct reimplantation, graft interposition, or repair. Because these techniques can result in pathway obstruction, Lugones has devised a technique which uses in situ pericardium to construct a wide tunnel connecting the pulmonary venous return to the left atrium. We report the use of Lugones technique in an adult with Scimitar syndrome. PMID- 28880469 TI - Quadricuspid aortic valve replacement. PMID- 28880470 TI - A new device to maintain the sternum open. PMID- 28880472 TI - Role of the glucose-sensing receptor in insulin secretion. AB - Glucose is a primary stimulator of insulin secretion. It has been thought that glucose exerts its effect by a mechanism solely dependent on glucose metabolism. We show here that glucose induces rapid Ca2+ and cyclic AMP signals in beta cells. These rapid signals are independent of glucose-metabolism and are reproduced by non-metabolizable glucose analogues. These results led us to postulate that glucose activates a cell-surface receptor, namely the glucose sensing receptor. Rapid signals induced by glucose are blocked by inhibition of a sweet taste receptor subunit T1R3 and a calcium-sensing receptor subunit CaSR. In accordance with these observations, T1R3 and CaSR form a heterodimer. In addition, a heterodimer of T1R3 and CaSR is activated by glucose. These results suggest that a heterodimer of T1R3 and CaSR is a major component of the glucose sensing receptor. When the glucose-sensing receptor is blocked, glucose-induced insulin secretion is inhibited. Also, ATP production is significantly attenuated by the inhibition of the receptor. Conversely, stimulation of the glucose-sensing receptor by either artificial sweeteners or non-metabolizable glucose analogue increases ATP. Hence, the glucose-sensing receptor signals promote glucose metabolism. Collectively, glucose activates the cell-surface glucose-sensing receptor and promotes its own metabolism. Glucose then enters the cells and is metabolized through already activated metabolic pathways. The glucose-sensing receptor is a key molecule regulating the action of glucose in beta-cells. PMID- 28880473 TI - NMDAR antagonists for the treatment of diabetes mellitus-Current status and future directions. AB - Diabetes mellitus is characterized by chronically elevated blood glucose levels accelerated by a progressive decline of insulin-producing beta-cells in the pancreatic islets. Although medications are available to transiently adjust blood glucose to normal levels, the effects of current drugs are limited when it comes to preservation of a critical mass of functional beta-cells to sustainably maintain normoglycemia. In this review, we recapitulate recent evidence on the role of pancreatic N-methyl-D-aspartate receptors (NMDARs) in beta-cell physiology, and summarize effects of morphinan-based NMDAR antagonists that are beneficial for insulin secretion, glucose tolerance and islet cell survival. We further discuss NMDAR-mediated molecular pathways relevant for neuronal cell survival, which may also be important for the preservation of beta-cell function and mass. Finally, we summarize the literature for evidence on the role of NMDARs in the development of diabetic long-term complications, and highlight beneficial pharmacologic aspects of NMDAR antagonists in diabetic nephropathy, retinopathy as well as neuropathy. PMID- 28880471 TI - Signals in the pancreatic islet microenvironment influence beta-cell proliferation. AB - The progressive loss of pancreatic beta-cell mass that occurs in both type 1 and type 2 diabetes is a primary factor driving efforts to identify strategies for effectively increasing, enhancing or restoring beta-cell mass. While factors that seem to influence beta-cell proliferation in specific contexts have been described, reliable stimulation of human beta-cell proliferation has remained a challenge. Importantly, beta-cells exist in the context of a complex, integrated pancreatic islet microenvironment where they interact with other endocrine cells, vascular endothelial cells, extracellular matrix, neuronal projections and islet macrophages. This review highlights different components of the pancreatic microenvironment, and reviews what is known about how signaling that occurs between beta-cells and these other components influences beta-cell proliferation. Future efforts to further define the role of the pancreatic islet microenvironment on beta-cell proliferation may lead to the development of successful approaches to increase or restore beta-cell mass in diabetes. PMID- 28880474 TI - beta-Cell signalling and insulin secretagogues: A path for improved diabetes therapy. AB - Insulin secretagogues including sulfonylureas, glinides and incretin-related drugs such as dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists are widely used for treatment of type 2 diabetes. In addition, glucokinase activators and G-protein-coupled receptor 40 (GPR40) agonists also have been developed, although the drugs are not clinically usable. These different drugs exert their effects on insulin secretion by different mechanisms. Recent advances in beta-cell signalling studies have not only deepened our understanding of insulin secretion but also revealed novel mechanisms of insulin secretagogues. Clarification of the signalling mechanisms of the insulin secretagogues will contribute to improved drug therapy for diabetes. PMID- 28880475 TI - Recent new insights into the role of SNARE and associated proteins in insulin granule exocytosis. AB - Initial work on the exocytotic machinery of predocked insulin secretory granules (SGs) in pancreatic beta-cells mimicked the SNARE hypothesis work in neurons, which includes SM/SNARE complex and associated priming proteins, fusion clamps and Ca2+ sensors. However, beta-cell SGs, unlike neuronal synaptic vesicles, exhibit a biphasic secretory response that requires additional distinct features in exocytosis including newcomer SGs that undergo minimal docking time at the plasma membrane (PM) before fusion and multi-SG (compound) fusion. These exocytotic events are mediated by Munc18/SNARE complexes distinct from that which mediates predocked SG fusion. We review some recent insights in SNARE complex assembly and the promiscuity in SM/SNARE complex formation, whereby both contribute to conferring different insulin SG fusion kinetics. Some SNARE and associated proteins play non-fusion roles, including tethering SGs to Ca2+ channels, SG recruitment from cell interior to PM, and inhibitory SNAREs that block the action of profusion SNAREs. We discuss new insights into how sub-PM cytoskeletal mesh gates SG access to the PM and the targeting of SG exocytosis to PM domains in functionally polarized beta-cells within intact islets. These recent developments have major implications on devising clever SNARE replacement therapies that could restore the deficient insulin secretion in diabetic islet beta-cells. PMID- 28880476 TI - Allosteric modulation as a unifying mechanism for receptor function and regulation. AB - Four major receptor families enable cells to respond to chemical and physical signals from their proximal environment. The ligand- and voltage-gated ion channels, G-protein-coupled receptors, nuclear hormone receptors and receptor tyrosine kinases are all allosteric proteins that carry multiple, spatially distinct, yet conformationally linked ligand-binding sites. Recent studies point to common mechanisms governing the allosteric transitions of these receptors, including the impact of oligomerization, pre-existing and functionally distinct conformational ensembles, intrinsically disordered regions, and the occurrence of allosteric modulatory sites. Importantly, synthetic allosteric modulators are being discovered for these receptors, providing an enriched, yet challenging, landscape for novel therapeutics. PMID- 28880477 TI - Exosomes as new players in metabolic organ cross-talk. AB - Blood glucose homeostasis requires a constant communication between insulin secreting and insulin-sensitive cells. A wide variety of circulating factors, including hormones, cytokines and chemokines work together to orchestrate the systemic response of metabolic organs to changes in the nutritional state. Failure in the coordination between these organs can lead to a rise in blood glucose levels and to the appearance of metabolic disorders such as diabetes mellitus. Exosomes are small extracellular vesicles (EVs) that are produced via the endosomal pathway and are released from the cells upon fusion of multivesicular bodies with the plasma membrane. There is emerging evidence indicating that these EVs play a central role in cell-to-cell communication. The interest in exosomes exploded when they were found to transport bioactive proteins, messenger RNA (mRNAs) and microRNA (miRNAs) that can be transferred in active form to adjacent cells or to distant organs. In this review, we will first outline the mechanisms governing the biogenesis, the cargo upload and the release of exosomes by donor cells as well as the uptake by recipient cells. We will then summarize the studies that support the novel concept that miRNAs and other exosomal cargo components are new important vehicles for metabolic organ cross talk. PMID- 28880479 TI - A 4D view on insulin secretory granule turnover in the beta-cell. AB - Insulin secretory granule (SG) turnover consists of several highly regulated processes allowing for proper beta-cell function and insulin secretion. Besides the spatial distribution of insulin SGs, their age has great impact on the likelihood of their secretion and their behaviour within the beta-cell. While quantitative measurements performed decades ago demonstrated the preferential secretion of young insulin, new experimental approaches aim to investigate insulin ageing at the granular level. Live-cell imaging, automated image analysis and correlative light and electron microscopy have fostered knowledge of age defined insulin SG dynamics, their interaction with the cytoskeleton and ultrastructural features. Here, we review our recent work in regards to the connection between insulin SG age, SG dynamics, intracellular location and interaction with other proteins. PMID- 28880478 TI - Role of G-proteins in islet function in health and diabetes. AB - Glucose-stimulated insulin secretion (GSIS) involves interplay between metabolic and cationic events. Seminal contributions from multiple laboratories affirm essential roles for small G-proteins (Rac1, Cdc42, Arf6, Rab27A) in GSIS. Activation of these signalling proteins promotes cytoskeletal remodeling, transport and docking of insulin granules on the plasma membrane for exocytotic secretion of insulin. Evidence in rodent and human islets suggests key roles for lipidation (farnesylation and geranylgeranylation) of these G-proteins for their targeting to appropriate cellular compartments for optimal regulation of effectors leading to GSIS. Interestingly, however, inhibition of prenylation appears to cause mislocalization of non-prenylated, but (paradoxically) activated G-proteins, in "inappropriate" compartments leading to activation of stress kinases and onset of mitochondrial defects, loss in GSIS and apoptosis of the islet beta-cell. This review highlights our current understanding of roles of G proteins and their post-translational lipidation (prenylation) signalling networks in islet function in normal health, metabolic stress (glucolipotoxicity and ER stress) and diabetes. Critical knowledge gaps that need to be addressed for the development of therapeutics to halt defects in these signalling steps in beta-cells in models of impaired insulin secretion and diabetes are also highlighted and discussed. PMID- 28880480 TI - Monoacylglycerol signalling and ABHD6 in health and disease. AB - Lipid metabolism dysregulation underlies chronic pathologies such as obesity, diabetes and cancer. Besides their role in structure and energy storage, lipids are also important signalling molecules regulating multiple biological functions. Thus, understanding the precise lipid metabolism enzymatic steps that are altered in some pathological conditions is helpful for designing better treatment strategies. Several monoacylglycerol (MAG) species are only recently being recognized as signalling lipid molecules in different tissues. Recent studies indicated the importance of the ubiquitously expressed serine hydrolase alpha/beta-hydrolase domain 6 (ABHD6), which is a MAG hydrolase, in regulating signalling competent MAG in both central and peripheral tissues. The central and peripheral function of the endocannabinoid 2-arachidonoylglycerol, which is a 2 MAG, and its breakdown by both ABHD6 and classical MAG lipase has been well documented. ABHD6 and its substrate MAG appear to be involved in the regulation of various physiological and pathological processes including insulin secretion, adipose browning, food intake, neurotransmission, autoimmune disorders, neurological and metabolic diseases as well as cancer. Diverse cellular targets such as mammalian unc13-1 (Munc13-1), PPARs, GPR119 and CB1/2 receptors, for MAG mediated signalling processes have been proposed in different cell types. The purpose of this review is to provide a comprehensive summary of the current state of knowledge regarding ABHD6/MAG signalling and its possible therapeutic implications. PMID- 28880481 TI - beta-Cells are not uniform after all-Novel insights into molecular heterogeneity of insulin-secreting cells. AB - While the beta-cells of the endocrine pancreas are defined as cells with high levels of insulin production and tight stimulus-secretion coupling, the existence of functional heterogeneity among them has been known for decades. Recent advances in molecular technologies, in particular single-cell profiling on both the protein and messenger RNA level, have uncovered that beta-cells exist in several antigenically and molecularly definable states. Using antibodies to cell surface markers or multidimensional clustering of beta-cells using more than 20 protein markers by mass cytometry, 4 distinct groups of beta-cells could be differentiated. However, whether these states represent permanent cell lineages or are readily interconvertible from one group to another remains to be determined. Nevertheless, future analysis of the pathogenesis of type 1 and type 2 diabetes will certainly benefit from a growing appreciation of beta-cell heterogeneity. Here, we aim to summarize concisely the recent advances in the field and their possible impact on our understanding of beta-cell physiology and pathophysiology. PMID- 28880483 TI - Alain Ktorza, PhD. PMID- 28880482 TI - Metabolomics applied to islet nutrient sensing mechanisms. AB - After multiple decades of investigation, the precise mechanisms involved in fuel stimulated insulin secretion are still being revealed. One avenue for gaining deeper knowledge is to apply emergent tools of "metabolomics," involving mass spectrometry and nuclear magnetic resonance-based profiling of islet cells in their fuel-stimulated compared with basal states. The current article summarizes recent insights gained from application of metabolomics tools to the specific process of glucose-stimulated insulin secretion, revealing 2 new mechanisms that may provide targets for improving insulin secretion in diabetes. PMID- 28880484 TI - Health checkup behavior and individual health beliefs in older adults. AB - AIM: Despite Japan being a developed nation, half of its older population does not attend regular health checkups. The aim of the present study was to examine the individual health beliefs and personal recommendations that strongly influence health checkup attendance among community-dwelling older adults. METHODS: In 2013, questionnaires were sent to 5401 community-dwelling older adults who were not receiving long-term institutionalized care. The response rate was 94.3%. We analyzed response data from 4984 older adults using multiple imputation to manage missing data. Participation in health checkups was defined as having undergone at least one checkup in the past 3 years, and non participation as having attended no checkups in this period. RESULTS: The participants' mean age was 75.8 years, and 57.9% were women. The adjusted odds ratio of health checkup participation ranged from 1.35 (95% confidence interval [CI] 1.13-1.61) to 1.62 (95% CI 1.34-1.95) for positive individual health beliefs about health checkups, and was 2.21 (95% CI: 1.51-3.24) and 1.28 (95% CI: 1.17 2.08) for recommendations to participate from family and neighbors, respectively. All odds ratios were adjusted for age, sex, driving by oneself to daily shopping or clinic, paid work, method of response, internal medical therapy, polypharmacy, serious disease, periodic blood test, frailty and neighborly relationships. CONCLUSIONS: The present findings suggest that both individual and community approaches might be effective in promoting participation in health checkups among community-dwelling older adults. Geriatr Gerontol Int 2018; 18: 338-351. PMID- 28880485 TI - Pediatric diabetes training for healthcare professionals in Europe: Time for change. AB - BACKGROUND: Training for healthcare professionals (HCPs) in Europe who care for children and young people (CYP) with type 1 diabetes and their families is variable depending on the country. Building on the work of SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) and using the German Certified Diabetes Educators (CDEs) curriculum, a European collaboration of pediatric diabetes experts aimed to (1) establish current core elements that should be included in a pediatric diabetes education training course and (2) create a template for a European CDE's training curriculum. METHODS: A qualitative methodology incorporating a survey questionnaire, focus group discussions, individual semi-structured interviews and workshops was employed to explore participants' experiences and opinions. HCPs-pediatric consultants, diabetes nurses, dietitians and psychologists, national and local diabetes leads, academic and education leads and children, and young people with diabetes and families took part in the study. The total number of participants equaled 186. RESULTS: A template for a European Certified Diabetes Educator Curriculum (EU-CDEC) was developed based on the themes that emerged from the participants' expertise and experiences. This provides a model for HCPs' pediatric diabetes training provision. CONCLUSIONS: There is a severe shortage of high quality, standardized training for HCPs across the majority of European countries. Lack of trained HCPs for CYP with diabetes will result in the delivery of suboptimal care and impact on health, wellbeing and clinical and psychological outcomes. The EU-CDEC template can be used to increase access to high quality training provision for all HCPs across Europe and worldwide. PMID- 28880486 TI - Out of focus: tailoring the cascade of care to the needs of women living with HIV. AB - Around half of the global adult HIV-positive population are women, yet historically women have been under-represented in clinical studies of antiretroviral therapy (ART) and there has been minimal exploration of gender specific factors related to the response to and appropriateness of treatment choices in women living with HIV (WLWH). There are several key issues pertaining to the cascade of HIV care that make it important to differentiate WLWH from men living with HIV. Factors that are gender specific may impact on the status of WLWH, affecting access to diagnosis and treatment, optimal clinical management, ART outcomes, retention in care, and the overall long-term wellbeing of WLWH. In this review, we discuss the results of recently reported women-only clinical trials and highlight the key unmet needs of WLWH as they pertain to the cascade of HIV care across World Health Organization European Region countries. As significant knowledge gaps remain, the review identifies key areas where further research is required, in order to support improved management of WLWH and guide informed clinical decision-making, including addressing psychosocial factors as part of comprehensive care. PMID- 28880487 TI - Oxidized low-density lipoprotein (ox-LDL) promotes cardiac differentiation of bone marrow mesenchymal stem cells via activating ERK1/2 signaling. AB - BACKGROUND/AIMS: The differentiation efficiency of bone marrow mesenchymal stem cells (BM-MSCs) is low in vivo after transplantation. Therefore, it is necessary to look for effective reagents for enhancing cardiac differentiation of BM-MSCs. It has been reported that cardiac differentiation of stem cells depends on the activation of extracellular signal-regulated protein 1/2 (ERK1/2) signaling. Oxidized low-density lipoprotein (ox-LDL) is a potent reagent for ERK1/2 activation. This indicates that ox-LDL may be a potential reagent to stimulate cardiac differentiation of stem cells. In this study, we investigated the effect of ox-LDL on cardiac differentiation of BM-MSCs and its relationship with ERK1/2 signaling. METHODS: BM-MSCs were isolated from mouse bone marrow, cultured in DMEM supplemented with 15% FBS, and passaged up to the 3rd passage. Following culture with 5 MUg/mL ox-LDL for 3 weeks, the cardiac differentiation of the 3rd passage BM-MSCs was identified by immunostaining, Western blotting, and RT-PCR assays for measuring the expression of cardiac-specific markers. To further explore the role of ERK1/2 signaling in cardiac differentiation of BM-MSCs, we simultaneously exposed BM-MSCs to ERK1/2 inhibitor (U0126) and ox-LDL, and identified the cardiac differentiation again. RESULTS: The expressions of cardiac specific markers including alpha-cardiac actin, alpha-MHC, beta-MHC, ANP, and BNP were markedly increased in BM-MSCs following treatment with ox-LDL (P < .05), which indicates a directional differentiation of BM-MSCs to cardiac cells. Further, ox-LDL could also activate ERK1/2 in BM-MSCs, and application of U0126 markedly inhibited ox-LDL-induced cardiac transformation of BM-MSCs. CONCLUSIONS: Ox-LDL induces cardiac differentiation of BM-MSCs via activation of ERK1/2 signaling. PMID- 28880488 TI - Characteristics and Prognosis of Hepatocellular Carcinoma in Japanese Patients Undergoing Dialysis. AB - Patients with end-stage renal disease who are undergoing dialysis may be at high risk of developing hepatocellular carcinoma (HCC). We investigated the characteristics and prognosis of HCC in patients undergoing dialysis in Japan. Patients characteristics, progression of HCC at diagnosis, and survival rates after diagnosis were compared between 108 HCC patients undergoing dialysis and 526 non-dialysis patients followed up at liver center. The comparisons were also performed after adjusting for patient age, gender, platelet count, and etiology using propensity-score matching. HCC was more advanced in patients undergoing dialysis than in non-dialysis controls. The 3- and 5-year survival rates of patients undergoing dialysis were 56.3% and 38.3%, respectively, which were lower than those of non-dialysis controls (66.5% and 52.7%, respectively, P = 0.0026). The results were the same after propensity score matching (P = 0.0014). In Japan, HCC was more advanced at diagnosis in patients undergoing dialysis in comparison to HCC in patients at liver centers, resulting in a lower survival rate after diagnosis. PMID- 28880489 TI - miRNA-4317 suppresses human gastric cancer cell proliferation by targeting ZNF322. AB - Studies have shown that miR-4317 is dysregulated in tumor, but the biologic role of miR-4317 in tumor development and progression remains unknown. The present study aimed to investigate the role of miR-4317 in human gastric cancer. Quantitative real-time PCR was used to quantify miR-4317 expression levels in clinical gastric cancer specimens and cell lines. MTT, colony formation and cell cycle assays were performed to identify the contributions of miR-4317 to cell proliferation in gastric cancer cell lines. The results showed that miR-4317 was significantly decreased in 17 clinical gastric cancer specimens compared with adjacent non-tumor stomach tissues. Forced expression of miR-4317 suppressed gastric cancer cell proliferation and blocked S-G2/M transition. Bioinformatics and dual-luciferase reporter assays confirmed that ZNF322 is a direct target of miR-4317. Silencing ZNF322 recapitulated the cellular and molecular effects seen upon miR-4317 overexpression. These findings indicate that miR-4317 represses the proliferation of gastric cancer cell, at least in part, by targeting and suppressing ZNF322 and that it may serve as a therapeutic target for gastric cancer treatment. PMID- 28880490 TI - Not all phonological awareness deficits are created equal: evidence from a comparison between children with Otitis Media and poor readers. AB - Children with reading difficulties and children with a history of repeated ear infections (Otitis Media, OM) are both thought to have phonological impairments, but for quite different reasons. This paper examines the profile of phonological and morphological awareness in poor readers and children with OM. Thirty-three poor readers were compared to individually matched chronological age and reading age controls. Their phonological awareness and morphological awareness skills were consistently at the level of reading age matched controls. Unexpectedly, a significant minority (25%) of the poor readers had some degree of undiagnosed mild or very mild hearing loss. Twenty-nine children with a history of OM and their matched controls completed the same battery of tasks. They showed relatively small delays in their literacy and showed no impairment in morphological awareness but had phonological awareness scores below the level of reading age matched controls. Further analysis suggested that this weakness in phonological awareness was carried by a specific weakness in segmenting and blending phonemes, with relatively good performance on phoneme manipulation tasks. Results suggest that children with OM show a circumscribed deficit in phoneme segmentation and blending, while poor readers show a broader metalinguistic impairment which is more closely associated with reading difficulties. PMID- 28880491 TI - Reflecting on clinical practice: hectoring talk or reality? AB - Reflection can be seen as a useful tool to enable the practitioner to explore the everyday world of clinical practice. This paper reviews the background to reflection and its relevance to nursing in reducing the theory - practice gap and its role in generating theory from practice. Exemplars from clinical practice are reflected upon and Carper's (1978) 'Patterns of Knowing' are used as a framework to identify nursing knowledge embedded in practice. The process of reflection is critically discussed in the light of the author's experience. PMID- 28880492 TI - Editorial. PMID- 28880493 TI - Research in Brief: Health education needs of people with schizophrenia taking clozapine. PMID- 28880494 TI - Clinical psychopathology in youth at familial high risk for psychosis. AB - AIM: While the course of psychopathology has been explored from an index mental health diagnosis onwards, there are few detailed, prospective studies of the occurrence of clinical psychopathology in youth with familial risk for severe mental illnesses such as psychosis. We sought to describe the appearance of Axis I psychopathology in a unique sample of adolescents with a family history of schizophrenia (FHR). METHODS: One hundred and sixty two first- and second-degree relatives (mean age 15.7 +/- 3.6; range 8-25) of probands with schizophrenia or schizoaffective disorder were assessed at baseline and annual intervals for up to 3 years, focusing on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) Axis I psychopathology. RESULTS: Fourteen individuals (8.6%) developed a psychotic disorder. One hundred and five subjects (65%) met criteria for an Axis I disorder over the course of the study, the most common of which was a depressive episode (40 subjects; 25%). Of the 148 individuals who did not develop psychosis, 91 (61%) had one or more Axis I disorders compared with 10/14 converters who had a comorbid Axis I disorder (71%). Ordered by increasing age of onset, diagnoses included cognitive and externalizing disorders, anxiety disorders, affective disorders, substance use disorders and psychotic disorders. CONCLUSIONS: In addition to an elevated risk of psychosis, young FHR relatives manifest a broad range of non-psychotic Axis I psychopathology in childhood and adolescence. This breadth of diagnoses has implications for the structure and function of mental health services for young people. PMID- 28880495 TI - Case report of perineal hernia after laparoscopic abdominoperineal resection. AB - Perineal hernia (PH) is a rare complication following laparoscopic abdominoperineal resection (APR) for rectal cancer. We present a case report of perineal hernia after laparoscopic APR and discuss its management. The patient was a 77-year-old man who was diagnosed with lower rectal cancer. He underwent laparoscopic APR and bilateral lateral lymph node dissection. Two months after the surgery, pain and bulging in the perineal region developed, and PH was diagnosed by CT. Repair with a polypropylene mesh was performed using a combination of laparoscopic abdominal and transperineal approaches. Reportedly, the incidence of secondary PH after APR has increased along with the rate of laparoscopic surgery. Treatment of secondary PH with transperineal repair alone may cause injuries to other organs because of adhesion of the pelvic viscera. In the present case, we safely repaired the hernia repair using a laparoscopy assisted perineal approach. PMID- 28880496 TI - Sensitivity to auditory-tactile colocation in early infancy. AB - An ability to detect the common location of multisensory stimulation is essential for us to perceive a coherent environment, to represent the interface between the body and the external world, and to act on sensory information. Regarding the tactile environment "at hand", we need to represent somatosensory stimuli impinging on the skin surface in the same spatial reference frame as distal stimuli, such as those transduced by vision and audition. Across two experiments we investigated whether 6- (n = 14; Experiment 1) and 4-month-old (n = 14; Experiment 2) infants were sensitive to the colocation of tactile and auditory signals delivered to the hands. We recorded infants' visual preferences for spatially congruent and incongruent auditory-tactile events delivered to their hands. At 6 months, infants looked longer toward incongruent stimuli, whilst at 4 months infants looked longer toward congruent stimuli. Thus, even from 4 months of age, infants are sensitive to the colocation of simultaneously presented auditory and tactile stimuli. We conclude that 4- and 6-month-old infants can represent auditory and tactile stimuli in a common spatial frame of reference. We explain the age-wise shift in infants' preferences from congruent to incongruent in terms of an increased preference for novel crossmodal spatial relations based on the accumulation of experience. A comparison of looking preferences across the congruent and incongruent conditions with a unisensory control condition indicates that the ability to perceive auditory-tactile colocation is based on a crossmodal rather than a supramodal spatial code by 6 months of age at least. PMID- 28880497 TI - Metal-Organic Frameworks (MOFs) as Functional Supramolecular Architectures for Anion Recognition and Sensing. AB - Metal-organic frameworks (MOFs) have experienced a tremendous growth during last few decades as porous crystalline molecular materials. The comprehensive effect of structural diversity, tunability and high surface area makes MOFs suitable for multifarious applications. MOFs can act as potential receptors toward different target components along with ionic species, small molecules, solvents, explosives etc. Anion recognition remains an important phenomena due to its involvement in many chemical and biological processes. Ligand designing, incorporation of appropriate functional groups and post-synthetic modifications are key strategies in MOFs for selective recognition and scavenging of environmentally toxic and detrimental anions (i. e. cyanide, oxo-anions etc.). The main focus of this personal account is on our research towards development and potential applications of MOFs with special emphasis on selective and sensitive anion sensing. PMID- 28880499 TI - Transurethral microwave thermotherapy. PMID- 28880500 TI - Hip resurfacing. PMID- 28880501 TI - Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis PMID- 28880502 TI - Buprenorphine for the Neonatal Abstinence Syndrome. PMID- 28880503 TI - Buprenorphine for the Neonatal Abstinence Syndrome. PMID- 28880519 TI - High-Performance Doping-Free Hybrid White OLEDs Based on Blue Aggregation-Induced Emission Luminogens. AB - Doping-free white organic light-emitting diodes (DF-WOLEDs) have aroused research interest because of their simple properties. However, to achieve doping-free hybrid WOLEDs (DFH-WOLEDs), avoiding aggregation-caused quenching is challenging. Herein, blue luminogens with aggregation-induced emission (AIE) characteristics, for the first time, have been demonstrated to develop DFH-WOLEDs. Unlike previous DFH-WOLEDs, both thin (<1 nm) and thick (>10 nm) AIE luminogen (AIEgen) can be used for devices, enhancing the flexibility. Two-color devices show (i) pure white emission, (ii) high CRI (85), and (iii) high efficiency. Particularly, 19.0 lm W1- is the highest for pure-white DF-WOLEDs, while 35.0 lm W1- is the best for two-color hybrid WOLEDs with CRI >= 80. A three-color DFH-WOLED shows broad color correlated temperature span (2301-11628 K), (i) the first sunlight-like OLED (2500-8000 K) operating at low voltages, (ii) the broadest span among sunlight like OLED, and (iii) possesses comparable efficiency with the best doping counterpart. Another three-color DFH-WOLED exhibits CRI > 90 at >=3000 cd m-2, (i) the first DF-WOLED with CRI >= 90 at high luminances, and (ii) the CRI (92.8) is not only the highest among AIE-based WOLEDs but also the highest among DF WOLEDs. Such findings may unlock an alternative concept to develop DFH-WOLEDs. PMID- 28880520 TI - Conductive Polymer Waving in Liquid Nitrogen. AB - The poor mechanical properties and processability of pristine heterocyclic conductive polymers represent the most notable scientific and technological challenges that have greatly limited the application of these polymers. We report a soft and mechanically processable free-standing pristine polypyrrole (PPy) membrane (PPy-N) that is as soft in liquid nitrogen (-196 degrees C) as it is at room temperature, despite a glass transition temperature (Tg) above 100 degrees C. This PPy membrane also displays a highly attractive combination of properties, including mechanical processability, lightweight (9 g m-2), large surface area (14.5 m2 g-1), stable electrothermal behavior, amphiphilicity, excellent cytocompatibility, and easy synthesis, at virtually any size. This discovery demonstrates an approach to changing the mechanical property of heterocyclic conductive polymer with no chemical alterations or compounding and may enhance the development of inherently conducting polymers for applications in energy storage and biomedicine and as lightweight conducting and heating materials. PMID- 28880521 TI - Peptide Dendrons as Thermal-Stability Amplifiers for Immunoglobulin G1 Monoclonal Antibody Biotherapeutics. AB - Biotherapeutics such as monoclonal antibodies (mAbs) have a major share of the pharmaceutical industry for treatment of life-threatening chronic diseases such as cancer, skin ailments, and immune disorders. Instabilities such as aggregation, fragmentation, oxidation, and reduction have resulted in the practice of storing these products at low temperatures (-80 to -20 degrees C). However, reliable storage at these temperatures can be a challenge, particularly in developing and underdeveloped countries; hence, lately, there has been a renewed interest in creating formulations that would offer stability at higher temperatures (25 to 55 degrees C). Most therapeutic formulations contain excipients such as salts, sugars, amino acids, surfactants, and polymers to provide stability to the biotherapeutic, but their efficacy at high temperatures is limited. The current work proposes the use of peptide dendrons of different generations to create formulations that would be stable at high temperature. Among these dendrons, third-generation lysine dendron L6 has been identified to provide the highest stability to mAbs, as demonstrated by a host of analytical techniques such as size-exclusion chromatography (SEC), dynamic light scattering (DLS), Nanoparticle tracking Analysis (NTA), and circular dichroism (CD). The biocompatibility of these dendrons was confirmed by hemolytic activity tests. Non interference of the dendrons with the activity of the mAb was confirmed using a surface plasmon resonance (SPR) based activity assay. We hope that this study will stimulate utilization of such higher-generation dendrons for enhancing the thermal stability of mAbs. PMID- 28880522 TI - Correction to "Vitamin-Derived Nanolipoidal Carriers for Brain Delivery of Dimethyl Fumarate: A Novel Approach with Preclinical Evidence". PMID- 28880523 TI - Efficient Removal of Heavy Metals from Polluted Water with High Selectivity for Mercury(II) by 2-Imino-4-thiobiuret-Partially Reduced Graphene Oxide (IT-PRGO). AB - A novel chelating adsorbent, based on the chemical modification of graphene oxide by functionalization amidinothiourea to form 2-imino-4-thiobiuret-partially reduced graphene oxide (IT-PRGO), is used for the effective extraction of the toxic metal ions Hg(II), Cu(II), Pb(II), Cr(VI), and As(V) from wastewater. FTIR and Raman spectroscopy, XRD, and XPS confirm the successful incorporation of the amidinothiourea groups within the partially reduced GO nanosheets through nucleophilic substitution reactions with the acyl chloride groups in the chemically modified GO. The IT-PRGO adsorbent shows exceptional selectivity for the extraction of Hg(II) with a capacity of 624 mg/g, placing it among the top of carbon-based materials known for the high capacity of Hg(II) removal from aqueous solutions. The maximum sorption capacities for As(V), Cu(II), Cr(VI), and Pb(II) are 19.0, 37.0, 63.0, and 101.5 mg/g, respectively. The IT-PRGO displays a 100% removal of Hg(II) at concentrations up to 100 ppm with 90%, 95%, and 100% removal within 15, 30, and 90 min, respectively, at 50 ppm concentration. In a mixture of six heavy metal ions containing 10 ppm of each ion, the IT-PRGO shows a removal of 3% Zn(II), 4% Ni(II), 9% Cd(II), 21% Cu(II), 63% Pb(II), and 100% Hg(II). A monolayer adsorption behavior is suggested based on the excellent agreement of the experimental sorption isotherms with the Langmuir model. The sorption kinetics can be fitted well to a pseudo-second-order kinetic model which suggests a chemisorption mechanism via the amidinothiourea groups grafted on the reduced graphene oxide nanosheets. Desorption studies demonstrate that the IT-PRGO is easily regenerated with the desorption of the metal ions Hg(II), Cu(II), Pb(II), Cr(VI), and As(V) reaching 96%, 100%, 100%, 96%, and 100%, respectively, from their maximum sorption capacities using different eluents. The IT-PRGO is proposed as a top performing remediation adsorbent for the extraction of heavy metals from waste and polluted water. PMID- 28880524 TI - Nonconjugated Polymer Poly(vinylpyrrolidone) as an Efficient Interlayer Promoting Electron Transport for Perovskite Solar Cells. AB - The interfaces between perovskite layer and electrodes play a crucial role on efficient charge transport and extraction in perovskite solar cells (PSCs). Herein, for the first time we applied a low-cost nonconjugated polymer poly(vinylpyrrolidone) (PVP) as a new interlayer between PCBM electron transport layer (ETL) and Ag cathode for high-performance inverted planar heterojunction perovskite solar cells (iPSCs), leading to a dramatic efficiency enhancement. The CH3NH3PbI3-xClx-based iPSC device incorporating the PVP interlayer exhibited a power conversion efficiency (PCE) of 12.55%, which is enhanced by ~15.9% relative to that of the control device without PVP interlayer (10.83%). The mechanistic investigations based on morphological, optical, and impedance spectroscopic characterizations reveal that incorporation of PVP interlayer promotes electron transport across the CH3NH3PbI3-xClx perovskite/Ag interface via PCBM ETL. Besides, PVP incorporation induces the formation of a dipole layer, which may enhance the built-in potential across the device, conjunctly promoting electron transport from PCBM to Ag cathode and consequently leading to significantly improved fill factor (FF) from 58.98 to 66.13%. PMID- 28880526 TI - High-Performance Charge Transport in Semiconducting Armchair Graphene Nanoribbons Grown Directly on Germanium. AB - The growth of graphene on Ge(001) via chemical vapor deposition can be highly anisotropic, affording the facile synthesis of crystallographically controlled, narrow, long, oriented nanoribbons of graphene that are semiconducting, whereas unpatterned continuous graphene is semimetallic. This bottom-up growth overcomes long-standing challenges that have limited top-down ribbon fabrication (e.g., inadequate resolution and disordered edges) and yields ribbons with long segments of smooth armchair edges. The charge transport characteristics of sub-10 nm ribbons synthesized by this technique (which are expected to have band gaps sufficiently large for semiconductor electronics applications) have not yet been characterized. Here, we show that sub-10 nm nanoribbons grown on Ge(001) can simultaneously achieve a high on/off conductance ratio of 2 * 104 and a high on state conductance of 5 MUS in field-effect transistors, favorably comparing to or exceeding the performance of nanoribbons fabricated by other methods. These promising results demonstrate that the direct synthesis of nanoribbons on Ge(001) could provide a scalable pathway toward the practical realization of high performance semiconducting graphene electronics, provided that the width uniformity and positioning of the nanoribbons are improved. PMID- 28880525 TI - MitoNEET (CISD1) Knockout Mice Show Signs of Striatal Mitochondrial Dysfunction and a Parkinson's Disease Phenotype. AB - Mitochondrial dysfunction is thought to play a significant role in neurodegeneration observed in Parkinson's disease (PD), yet the mechanisms underlying this pathology remain unclear. Here, we demonstrate that loss of mitoNEET (CISD1), an iron-sulfur containing protein that regulates mitochondrial bioenergetics, results in mitochondrial dysfunction and loss of striatal dopamine and tyrosine hydroxylase. Mitochondria isolated from mice lacking mitoNEET were dysfunctional as revealed by elevated reactive oxygen species (ROS) and reduced capacity to produce ATP. Gait analysis revealed a shortened stride length and decreased rotarod performance in knockout mice, consistent with the loss of striatal dopamine. Together, these data suggest that mitoNEET KO mice exhibit many of the characteristics of early neurodegeneration in PD and may provide a novel drug discovery platform to evaluate compounds for enhancing mitochondrial function in neurodegenerative disorders. PMID- 28880527 TI - Two Analogous Polyhedron-Based MOFs with High Density of Lewis Basic Sites and Open Metal Sites: Significant CO2 Capture and Gas Selectivity Performance. AB - By means of modulating the axial ligand and adopting supermolecular building blocks (SBBs) strategy, two polyhedron-based metal-organic frameworks (PMOFs) have been successfully synthesized [Cu6(C17O9N2H8)3(C6H12N2)(H2O)2(DMF)2].3DMF.8H2O (JLU-Liu46) and [Cu6(C17O9N2H8)3(C4H4N2)(H2O)2(DMF)2].3DMF.8H2O (JLU-Liu47), which possess a high density of Lewis basic sites (LBSs) and open metal sites (OMSs). Since the size of axial ligand in JLU-Liu47 is smaller than that in JLU-Liu46, JLU-Liu47 shows larger pore volume and higher BET surface area. Then, the adsorption ability of JLU-Liu47 for some small gases is better than JLU-Liu46. It is worthwhile to mention that both of the two compounds exhibit outstanding adsorption capability for CO2 ascribed to the introducing of urea groups. In addition, the theoretical ideal adsorbed solution theory (IAST) calculation and transient breakthrough simulation indicate that JLU-Liu46 and JLU-Liu47 should be potential materials for gas storage and separation, particularly for CO2/N2, CO2/CH4, and C3H8/CH4 separation. PMID- 28880528 TI - Silver-Coated Colloidosomes as Carriers for an Anticancer Drug. AB - Small drug molecules are widely developed and used in the pharmaceutical industry. In the past few years, loading and delivering such molecules using polymer-shell colloidosomes has attracted interest. Traditional polymer capsules fail to encapsulate low-molecular-weight materials for long times, since they are inherently porous and permeable for small molecules. In this paper, we report a method for encapsulating an anticancer drug with small molecule weight, for cell viability tests. The silver-coated colloidosomes are prepared by making an aqueous core capsule with a polymer shell and then adding AgNO3, surfactant, and l-ascorbic acid to form a second shell. The capsules are impermeable and can be triggered using ultrasound. We propose to use the capsules as drug carriers. The silver demonstrates a low cytotoxicity for up to 10 capsules per cell. After the silver shells are triggered by ultrasound, the released doxorubicin, the broken silver fragments, and the doxorubicin loading on the capsule surface all kill cells. The results demonstrate a nonpermeable silver-shell microcapsule with ultrasound sensitivity for potential medical applications. PMID- 28880529 TI - High-Velocity Saturation in Graphene Encapsulated by Hexagonal Boron Nitride. AB - We measure drift velocity in monolayer graphene encapsulated by hexagonal boron nitride (hBN), probing its dependence on carrier density and temperature. Due to the high mobility (>5 * 104 cm2/V/s) of our samples, the drift velocity begins to saturate at low electric fields (~0.1 V/MUm) at room temperature. Comparing results to a canonical drift velocity model, we extract room-temperature electron saturation velocities ranging from 6 * 107 cm/s at a low carrier density of 8 * 1011 cm-2 to 2.7 * 107 cm/s at a higher density of 4.4 * 1012 cm-2. Such drift velocities are much higher than those in silicon (~107 cm/s) and in graphene on SiO2, likely due to reduced carrier scattering with surface optical phonons whose energy in hBN (>100 meV) is higher than that in other substrates. PMID- 28880530 TI - Novel in Situ Techniques for Studies of Model Catalysts. AB - Motivated mainly by catalysis, gas-surface interaction between single crystal surfaces and molecules has been studied for decades. Most of these studies have been performed in well-controlled environments and have been instrumental for the present day understanding of catalysis, providing information on surface structures, adsorption sites, and adsorption and desorption energies relevant for catalysis. However, the approach has been criticized for being too far from a catalyst operating under industrial conditions at high temperatures and pressures. To this end, a significant amount of effort over the years has been used to develop methods to investigate catalysts at more realistic conditions under operating conditions. One result from this effort is a vivid and sometimes heated discussion concerning the active phase for the seemingly simple CO oxidation reaction over the Pt-group metals in the literature. In recent years, we have explored the possibilities to perform experiments at conditions closer to those of a technical catalyst, in particular at increased pressures and temperatures. In this contribution, results from catalytic CO oxidation over a Pd(100) single crystal surface using Near Ambient Pressure X-ray Photo emission Spectroscopy (NAPXPS), Planar Laser-Induced Fluorescence (PLIF), and High Energy Surface X-ray Diffraction (HESXRD) are presented, and the strengths and weaknesses of the experimental techniques are discussed. Armed with structural knowledge from ultrahigh vacuum experiments, the presence of adsorbed molecules and gas-phase induced surface structures can be identified and related to changes in the reactivity or to reaction induced gas-flow limitations. In particular, the application of PLIF to catalysis allows one to visualize how the catalyst itself changes the gas composition close to the model catalyst surface upon ignition, and relate this to the observed surface structures. The effect obscures a straightforward relation between the active phase and the activity, since in the case of CO oxidation, the gas-phase close to the model catalyst surface is shown to be significantly more oxidizing than far away from the catalyst. We show that surface structural knowledge from UHV experiments and the composition of the gas phase close to the catalyst surface are crucial to understand structure-function relationships at semirealistic conditions. In the particular case of Pd, we argue that the surface structure of the PdO(101) has a significant influence on the activity, due to the presence of Coordinatively Unsaturated Sites (CUS) Pd atoms, similar to undercoordinated Ru and Ir atoms found for RuO2(110) and IrO2(110), respectively. PMID- 28880531 TI - Janus Nanocomposite Hydrogels for Chirality-Dependent Cell Adhesion and Migration. AB - Recently, there has been much interest in the chirality-dependent cell affinity to enantiomorphous nanomaterials (NMs), since, at the nanoscale level, enantiomers of (bio)molecules have different effects on cell behaviors. In this respect, this study used enantiomorphous NMs with which to generate the Janus nanocomposite (NC) hydrogels as multifunctional biomaterials for studying chirality-dependent cell adhesion and cell migration. These Janus NC hydrogels possess two enantiomorphous NC hydrogels, in which the different halves of the hydrogel contain the opposite enantiomers of a biopolymer functionalized nanomaterials. Thus, the enantiomers contact each other only at the midline of the hydrogel but are otherwise separated, yet they are present in the same system. This advanced system allows us to simultaneously study the impact that each enantiomer of a biopolymer has on cell behavior under the same reaction conditions, at the same time, and using only a single biomaterial. Our results show that cells have higher affinity for and migrate toward the part of the Janus NC hydrogel containing the biopolymer enantiomer that the cells prefer. PMID- 28880532 TI - High Quantum Yield Blue Emission from Lead-Free Inorganic Antimony Halide Perovskite Colloidal Quantum Dots. AB - Colloidal quantum dots (QDs) of lead halide perovskite have recently received great attention owing to their remarkable performances in optoelectronic applications. However, their wide applications are hindered from toxic lead element, which is not environment- and consumer-friendly. Herein, we utilized heterovalent substitution of divalent lead (Pb2+) with trivalent antimony (Sb3+) to synthesize stable and brightly luminescent Cs3Sb2Br9 QDs. The lead-free, full inorganic QDs were fabricated by a modified ligand-assisted reprecipitation strategy. A photoluminescence quantum yield (PLQY) was determined to be 46% at 410 nm, which was superior to that of other reported halide perovskite QDs. The PL enhancement mechanism was unraveled by surface composition derived quantum well band structure and their large exciton binding energy. The Br-rich surface and the observed 530 meV exciton binding energy were proposed to guarantee the efficient radiative recombination. In addition, we can also tune the inorganic perovskite QD (Cs3Sb2X9) emission wavelength from 370 to 560 nm via anion exchange reactions. The developed full-inorganic lead-free Sb-perovskite QDs with high PLQY and stable emission promise great potential for efficient emission candidates. PMID- 28880533 TI - Damage-Free Smooth-Sidewall InGaAs Nanopillar Array by Metal-Assisted Chemical Etching. AB - Producing densely packed high aspect ratio In0.53Ga0.47As nanostructures without surface damage is critical for beyond Si-CMOS nanoelectronic and optoelectronic devices. However, conventional dry etching methods are known to produce irreversible damage to III-V compound semiconductors because of the inherent high energy ion-driven process. In this work, we demonstrate the realization of ordered, uniform, array-based In0.53Ga0.47As pillars with diameters as small as 200 nm using the damage-free metal-assisted chemical etching (MacEtch) technology combined with the post-MacEtch digital etching smoothing. The etching mechanism of InxGa1-xAs is explored through the characterization of pillar morphology and porosity as a function of etching condition and indium composition. The etching behavior of In0.53Ga0.47As, in contrast to higher bandgap semiconductors (e.g., Si or GaAs), can be interpreted by a Schottky barrier height model that dictates the etching mechanism constantly in the mass transport limited regime because of the low barrier height. A broader impact of this work relates to the complete elimination of surface roughness or porosity related defects, which can be prevalent byproducts of MacEtch, by post-MacEtch digital etching. Side-by-side comparison of the midgap interface state density and flat-band capacitance hysteresis of both the unprocessed planar and MacEtched pillar In0.53Ga0.47As metal-oxide-semiconductor capacitors further confirms that the surface of the resultant pillars is as smooth and defect-free as before etching. MacEtch combined with digital etching offers a simple, room-temperature, and low-cost method for the formation of high-quality In0.53Ga0.47As nanostructures that will potentially enable large-volume production of In0.53Ga0.47As-based devices including three-dimensional transistors and high-efficiency infrared photodetectors. PMID- 28880534 TI - Synthesis and Characterization of Alkylamine-Functionalized Si(111) for Perovskite Adhesion With Minimal Interfacial Oxidation or Electronic Defects. AB - We investigated synthetic strategies for the functionalization of Si(111) surfaces with organic species containing amine moieties. We employed the functionalized surfaces to chemically "glue" perovskites to silicon with efficient electron transfer and minimal oxidation leading to deleterious recombination at the silicon substrate. A two-step halogenation-alkylation reaction produced a mixed allyl-methyl monolayer on Si(111). Subsequent reactions utilized multiple methods of brominating the allyl double bond including reaction with HBr in acetic acid, HBr in THF, and molecular bromine in dichloromethane. Reaction with ammonia in methanol effected conversion of the bromide to the amine. X-ray photoelectron spectroscopy (XPS) quantified chemical states and coverages, transient-microwave photoconductivity ascertained photogenerated carrier lifetimes, atomic force microscopy (AFM) quantified perovskite-silicon adhesion, and nonaqueous photoelectrochemistry explored solar-energy-conversion performance. The HBr bromination followed by the amination yielded a surface with ~10% amine sites on the Si(111) with minimal oxide and surface recombination velocity values below 120 cm s-1, following extended exposures to air. Importantly, conversion of amine sites to ammonium and deposition of methylammonium lead halide via spin coating and annealing did not degrade carrier lifetimes. AFM experiments quantified adhesion between perovskite films and alkylammonium-functionalized or native-oxide silicon surfaces. Adhesion forces/interactions between the perovskite and the alkylammonium-functionalized films were comparable to the interaction between the perovskite and native-oxide silicon surface. Photoelectrochemistry of perovskite thin films on alkylammonium functionalized n+-Si showed significantly higher Voc than n+-Si with a native oxide when in contact with a nonaqueous ferrocene+/0 redox couple. We discuss the present results in the context of utilizing molecular organic recognition to attach perovskites to silicon utilizing organic linkers so as to inexpensively modify silicon for future tandem-junction photovoltaics. PMID- 28880535 TI - Single-Ion Li+, Na+, and Mg2+ Solid Electrolytes Supported by a Mesoporous Anionic Cu-Azolate Metal-Organic Framework. AB - A novel Cu(II)-azolate metal-organic framework (MOF) with tubular pores undergoes a reversible single crystal to single crystal transition between neutral and anionic phases upon reaction with stoichiometric amounts of halide or pseudohalide salts. The stoichiometric transformation between the two phases allows loading of record amounts of charge-balancing Li+, Na+, and Mg2+ ions for MOFs. Whereas the halide/pseudohalide anions are bound to the metal centers and thus stationary, the cations move freely within the one-dimensional pores, giving rise to single-ion solid electrolytes. The respective Li+-, Na+-, and Mg2+-loaded materials exhibit high ionic conductivity values of 4.4 * 10-5, 1.8 * 10-5, and 8.8 * 10-7 S/cm. With addition of LiBF4, the Li+ conductivity improves to 4.8 * 10-4 S/cm. These are the highest values yet observed for MOF solid electrolytes. PMID- 28880536 TI - Lewis Acid-Catalyzed Selective [2 + 2]-Cycloaddition and Dearomatizing Cascade Reaction of Aryl Alkynes with Acrylates. AB - Combined Lewis acid, consisting of two or more Lewis acids, sometimes shows unique catalytic ability, and it may promote reactions which could not be catalyzed by any of the Lewis acids solely. On the other hand, the development of efficient methods for the facile synthesis of cyclobutenes and densely functionalized decalins is an attractive target for synthetic chemists due to their versatile synthetic utilities and widespread occurrence in natural products. Herein, we wish to report an efficient method for the assembly of cyclobutenes and densely functionalized decalin skeletons through In(tfacac)3 TMSBr catalyzed selective [2 + 2]-cycloaddition and dearomatizing cascade reaction of aryl alkynes with acrylates with high chemo- and stereoselectivity. The obtained cyclobutene could be easily converted into cyclobutane as well as synthetically useful 1,4- and 1,5-diketones with high chemo- and stereoselectivity. On the basis of mechanistic studies, plausible reaction mechanisms were proposed for both the [2 + 2]-cycloaddition and the dearomatizing cascade reaction. Finally, the computational studies of reaction mechanisms were conducted, and the results suggest that the combined Lewis acid could efficiently promote both reactions. PMID- 28880537 TI - Hydrophobic Collapse of the Intrinsically Disordered Transcription Factor Myc Associated Factor X. AB - The conformational space of the proto-oncogenic transcription factor Myc associated factor X (MAX) comprises a dynamic equilibrium between a stably folded coiled-coil homodimer and an intrinsically disordered ensemble of states. We show by means of nuclear magnetic resonance spectroscopy that the intrinsically disordered ensemble samples structures that are even as compact as the folded dimer. These extremely dense, hydrophobically collapsed globules might be of importance for interconversion between different conformations of intrinsically disordered proteins. PMID- 28880539 TI - Quick Way to Port Existing C/C++ Chemoinformatics Toolkits to the Web Using Emscripten. AB - Emscripten is a special open source compiler that compiles C and C++ code into JavaScript. By utilizing this compiler, some typical C/C++ chemoinformatics toolkits and libraries are quickly ported to to web. The compiled JavaScript files have sizes similar to native programs, and from a series of constructed benchmarks, the performance of the compiled JavaScript codes is also close to that of the native codes and is better than the handwritten JavaScript codes. Therefore, we believe that Emscripten is a feasible and practical tool for reusing existing C/C++ codes on the web, and many other chemoinformatics or molecular calculation software tools can also be easily ported by Emscripten. PMID- 28880538 TI - Characterization of the Functional Variance in MbtH-like Protein Interactions with a Nonribosomal Peptide Synthetase. AB - Many nonribosomal peptide synthetases (NRPSs) require MbtH-like proteins (MLPs) for solubility or for activation of amino acid substrate by the adenylation domain. MLPs are capable of functional crosstalk with noncognate NRPSs at varying levels. Using enterobactin biosynthesis in Escherichia coli as a model MLP dependent NRPS system, we use in vivo and in vitro techniques to characterize how seven noncognate MLPs influence the function of the enterobactin NRPS EntF when the cognate MLP, YbdZ, is absent. Using a series of in vitro assays to analyze EntF solubility, adenylation, aminoacylation, and in vitro enterobactin production, we show that interactions between MLPs and NRPSs are multifaceted and more complex than previously appreciated. We separate MLP influence on solubility and function in a manner that shows altered solubility is not indicative of a functional MLP/NRPS pair. Although much of the functional variation among these noncognates can be explained by differences in EntF affinity for an MLP or the extent an MLP alters EntF l-Ser affinity, we demonstrate that MLPs can have a broader impact beyond solubility and adenylation. First, we show that a noncognate MLP can affect formation of l-Ser-S-EntF. Second, under in vitro conditions saturating for substrate and MLP, enterobactin production remains compromised in the absence of an appropriate MLP partner. These data suggest that we expand our investigations into how the MLPs influence NRPS enzymology. A more detailed understanding of these influences will be essential for downstream engineering of hybrid NRPS systems. PMID- 28880540 TI - Hydrocarbon and Carbon Dioxide Fluxes from Natural Gas Well Pad Soils and Surrounding Soils in Eastern Utah. AB - We measured fluxes of methane, nonmethane hydrocarbons, and carbon dioxide from natural gas well pad soils and from nearby undisturbed soils in eastern Utah. Methane fluxes varied from less than zero to more than 38 g m-2 h-1. Fluxes from well pad soils were almost always greater than from undisturbed soils. Fluxes were greater from locations with higher concentrations of total combustible gas in soil and were inversely correlated with distance from well heads. Several lines of evidence show that the majority of emission fluxes (about 70%) were primarily due to subsurface sources of raw gas that migrated to the atmosphere, with the remainder likely caused primarily by re-emission of spilled liquid hydrocarbons. Total hydrocarbon fluxes during summer were only 39 (16, 97)% as high as during winter, likely because soil bacteria consumed the majority of hydrocarbons during summer months. We estimate that natural gas well pad soils account for 4.6 * 10-4 (1.6 * 10-4, 1.6 * 10-3)% of total emissions of hydrocarbons from the oil and gas industry in Utah's Uinta Basin. Our undisturbed soil flux measurements were not adequate to quantify rates of natural hydrocarbon seepage in the Uinta Basin. PMID- 28880541 TI - Selenomethionine as a Safer Substitute for Barium Selenate in Long-Acting Injectable Se Supplements for Food-Producing Animals. AB - Nutritional supplementation with selenium (Se) can prevent Se deficiency in food producing animals. Injection with slow-release formulations is a preferred method for free-range grazing sheep and cattle, and barium selenate (BaSeO4) provides optimal efficacy. This chemical can become a health risk to humans if the concentrated depot of an injection site is consumed, and consequently such use is recently banned in the EU. A possible replacement is selenomethionine (SeMet), a naturally occurring form of Se supplementation hitherto only administered orally. In four animal studies we found that injection with SeMet maintained nutritionally adequate concentrations of Se in blood and tissues of lambs for at least 191 days and in blood and milk of dairy cows for at least 95 days. Stereoisomer forms L- and DL-SeMet were functionally equivalent. This is the first demonstration that injectable SeMet can deliver efficacy similar to BaSeO4 but with less risk of undesirable residues in edible tissues. PMID- 28880542 TI - Influence of Size and Shape on the Biodistribution of Nanoparticles Prepared by Polymerization-Induced Self-Assembly. AB - Polymerization-induced self-assembly (PISA) is a facile one-pot synthetic technique for preparing polymeric nanoparticles with different sizes and shapes for application in a variety of fields including nanomedicine. However, the in vivo biodistribution of nanoparticles obtained by PISA still remains unclear. To address this knowledge gap, we report the synthesis, cytotoxicity, and biodistribution in an in vivo tumor-bearing mouse model of polystyrene micelles with various sizes and polystyrene filomicelles with different lengths prepared by PISA. First, a library of nanoparticles was prepared comprised of poly(glycidyl methacrylate)-b-poly(oligo(ethylene glycol) methyl ether methacrylate)-b-polystyrene polymers, and their size and morphology were tuned by varying the polystyrene block length without affecting the surface chemistry. The 3H) ethanolamine, and a biodistribution study was carried out in nude mice bearing HT1080 tumor xenografts 48 h after intravenous delivery. In this model, we found that small spherical polystyrene core nanoparticles with a PEG corona (diameter 21 nm) have the highest tumor accumulation when compared to the larger spherical nanoparticles (diameter 33 nm) or rodlike (diameter 37 nm, contour length 350-500 nm) or wormlike counterparts (diameter 45 nm, contour length 1-2 MUm). This finding has provided critical information on the biodistribution of polystyrene core nanoparticles with a PEG corona of different sizes and shapes prepared by the PISA technique and will inform their use in medical applications. PMID- 28880544 TI - Remote Migratory Cross-Electrophile Coupling and Olefin Hydroarylation Reactions Enabled by in Situ Generation of NiH. AB - A highly efficient strategy for remote reductive cross-electrophile coupling has been developed through the ligand-controlled nickel migration/arylation. This general protocol allows the use of abundant and bench-stable alkyl bromides and aryl bromides for the synthesis of a wide range of structurally diverse 1,1 diarylalkanes in excellent yields and high regioselectivities under mild conditions. We also demonstrated that alkyl bromide could be replaced by the proposed olefin intermediate while using n-propyl bromide/Mn0 as a potential hydride source. PMID- 28880543 TI - The Transition-State Structure for Human MAT2A from Isotope Effects. AB - Human methionine S-adenosyltransferase (MAT2A) catalyzes the formation of S adenosylmethionine (SAM) from ATP and methionine. Synthetic lethal genetic analysis has identified MAT2A as an anticancer target in tumor cells lacking expression of 5'-methylthioadenosine phosphorylase (MTAP). Approximately 15% of human cancers are MTAP-/-. The remainder can be rendered MTAP- through MTAP inhibitors. We used kinetic isotope effect (KIE), commitment factor (Cf), and binding isotope effect (BIE) measurements combined with quantum mechanical (QM) calculations to solve the transition state structure of human MAT2A. The reaction is characterized by an advanced SN2 transition state. The bond forming from the nucleophilic methionine sulfur to the 5'-C of ATP is 2.03 A at the transition state (bond order of 0.67). Departure of the leaving group triphosphate of ATP is well advanced and forms a 2.32 A bond between the 5'-C of ATP and the oxygen of the triphosphate (bond order of 0.23). Interaction of MAT2A with its MAT2B regulatory subunit causes no change in the intrinsic KIEs, indicating the same transition state structure. The transition state for MAT2A is more advanced along the reaction coordinate (more product-like) than that from the near-symmetrical transition state of methionine adenosyltransferase from E. coli. PMID- 28880545 TI - Substantial Expansion of Detectable Size Range in Ionic Current Sensing through Pores by Using a Microfluidic Bridge Circuit. AB - Measuring ionic currents passing through nano- or micropores has shown great promise for the electrical discrimination of various biomolecules, cells, bacteria, and viruses. However, conventional measurements have shown there is an inherent limitation to the detectable particle volume (1% of the pore volume), which critically hinders applications to real mixtures of biomolecule samples with a wide size range of suspended particles. Here we propose a rational methodology that can detect samples with the detectable particle volume of 0.01% of the pore volume by measuring a transient current generated from the potential differences in a microfluidic bridge circuit. Our method substantially suppresses the background ionic current from the MUA level to the pA level, which essentially lowers the detectable particle volume limit even for relatively large pore structures. Indeed, utilizing a microscale long pore structure (volume of 5.6 * 104 aL; height and width of 2.0 * 2.0 MUm; length of 14 MUm), we successfully detected various samples including polystyrene nanoparticles (volume: 4 aL), bacteria, cancer cells, and DNA molecules. Our method will expand the applicability of ionic current sensing systems for various mixed biomolecule samples with a wide size range, which have been difficult to measure by previously existing pore technologies. PMID- 28880546 TI - Transcriptomic and Functional Analyses on the Effects of Dioxin on Insulin Secretion of Pancreatic Islets and beta-Cells. AB - In this study, transcriptomic and Ingenuity Pathway Analysis (IPA) underlined that an ex-vivo TCDD treatment (0.1 nM) stimulated insulin-release in mouse pancreatic islets via the effect on the Akt-mTOR-p70S6K, AMPK and ERK1/2 pathways. Functional studies using both ex-vivo islets and the mouse beta-cell line (Min-6) validated the stimulatory effects of TCDD (0.1 and 1 nM) on basal insulin secretion. At 0.1 nM TCDD treatment on Min-6, Western blot analysis showed activation of ERK1/2 and decreased expression of pyruvate dehydrogenase kinase (PDK). A reduction of PDK expression is associated with an increase of pyruvate dehydrogenase flux. This observation was supported by the detection of significantly higher cellular ATP levels, an increase of glucose-stimulated insulin-secretion (GSIS), and an inhibition of the AMPK pathway. At 1 nM TCDD treatment on Min-6, significant inhibitions of the Akt-mTOR pathway, cellular ATP production, and GSIS were evident. The experimental studies in Min-6 supported the IPA of transcriptomic data in pancreatic islets. Collectively, TCDD treatment caused an elevated basal-insulin release in both islets and beta-cell cultures. Moreover, our data revealed that the modulation of the Akt-mTOR-p70S6K, AMPK and ERK1/2 pathways might be an important component of the mechanism for the TCDD perturbing effects on ATP production in beta-cells in affecting insulin secretion. PMID- 28880547 TI - Probing Distance Dependent Charge-Transfer Character in Excimers of Extended Viologen Cyclophanes Using Femtosecond Vibrational Spectroscopy. AB - Facile exciton transport within ordered assemblies of pi-stacked chromophores is essential for developing molecular photonic and electronic materials. Excimer states having variable charge transfer (CT) character are frequently implicated as promoting or inhibiting exciton mobility in such systems. However, determining the degree of CT character in excimers as a function of their structure has proven challenging. Herein, we report on a series of cyclophanes in which the interplanar distance between two phenyl-extended viologen (ExV2+) chromophores is varied systematically using a pair of o-, m-, or p-xylylene (o-, m-, or p-Xy) covalent linkers to produce o-ExBox4+ (3.5 A), m-ExBox4+ (5.6 A), and p-ExBox4+ (7.0 A), respectively. The cyclophane structures are characterized using NMR spectroscopy in solution and single-crystal X-ray diffraction in the solid state. Femtosecond transient mid-IR and stimulated Raman spectroscopies show that the CT contribution to the excimer states formed in o-ExBox4+ and m-ExBox4+ depends on the distance between the chromophores within the cyclophanes, while in the weak interaction limit, as represented by p-ExBox4+ (7.0 A), the lowest excited singlet state of ExV2+ exclusively photo-oxidizes the p-Xy spacer to give the p Xy+*-ExV+* ion pair. Moreover, the vibrational spectra of the excimer state show that it assumes a geometry that is intermediate between that of the locally excited and CT states, approximately reflecting the degree of CT character. PMID- 28880548 TI - Transketolase A from E. coli Significantly Suppresses Protein Glycation by Glycolaldehyde and Glyoxal in Vitro. AB - Short-chained carbonyl species such as glycolaldehyde and its oxidized pendant glyoxal are highly reactive Maillard agents, leading to the formation of protein modifications. These advanced glycation endproducts have gained considerable interest as they have been linked to various pathologies in vivo. The ability of transketolase to use glycolaldehyde as a substrate suggested the possibility to modulate carbonyl-driven Maillard reactions. Model incubations with recombinant transketolase A from Escherichia coli in the presence of bovine serum albumin and glycolaldehyde indeed led to a decrease in glycolaldehyde concentrations paralleled by the enzymatic conversion to erythrulose. As a result, reversibly protein-bound glycolaldehyde and the major final endproduct N6-carboxymethyl lysine were significantly reduced by approximately 50%, respectively. Glycolaldehyde is easily oxidized to glyoxal in the presence of amines and oxygen. In the presence of transketolase, the lower amounts of glycolaldehyde therefore also strongly suppressed the formation of glyoxal specific arginine modifications, measured as 5-(2-imino-5-oxo-1-imidazolidinyl)norvaline after acid hydrolysis. PMID- 28880549 TI - Binding and Release between Polymeric Carrier and Protein Drug: pH-Mediated Interplay of Coulomb Forces, Hydrogen Bonding, van der Waals Interactions, and Entropy. AB - The accelerating search for new types of drugs and delivery strategies poses challenge to understanding the mechanism of delivery. To this end, a detailed atomistic picture of binding between the drug and carrier is quintessential. Although many studies focus on the electrostatics of drug-vector interactions, it has also been pointed out that entropic factors relating to water and counterions can play an important role. By carrying out extensive molecular dynamics simulations and subsequently validating with experiments, we shed light herein on the binding in aqueous solution between a protein drug and polymeric carrier. We examined the complexation between the polymer poly(ethylene glycol) methyl ether acrylate-b-poly(carboxyethyl acrylate (PEGMEA-b-PCEA) and the protein egg white lysozyme, a system that acts as a model for polymer-vector/protein-drug delivery systems. The complexation has been visualized and characterized using contact maps and hydrogen bonding analyses for five independent simulations of the complex, each running over 100 ns. Binding at physiological pH is, as expected, mediated by Coulombic attraction between the positively charged protein and negatively charged carboxylate groups on the polymer. However, we find that consideration of electrostatics alone is insufficient to explain the complexation behavior at low pH. Intracomplex hydrogen bonds, van der Waals interactions, as well as water-water interactions dictate that the polymer does not release the protein at pH 4.8 or indeed at pH 3.2 even though the Coulombic attractions are largely removed as carboxylate groups on the polymer become titrated. Experiments in aqueous solution carried out at pH 7.0, 4.5, and 3.0 confirm the veracity of the computed binding behavior. Overall, these combined simulation and experimental results illustrate that coulomb interactions need to be complemented with consideration of other entropic forces, mediated by van der Waals interactions and hydrogen bonding, to search for adequate descriptors to predict binding and release properties of polymer-protein complexes. Advances in computational power over the past decade make atomistic molecular dynamics simulations such as implemented here one of the few avenues currently available to elucidate the complexity of these interactions and provide insights toward finding adequate descriptors. Thus, there remains much room for improvement of design principles for efficient capture and release delivery systems. PMID- 28880550 TI - A Polymer Therapeutic Having Universal Heparin Reversal Activity: Molecular Design and Functional Mechanism. AB - Heparins are widely used to prevent blood clotting during surgeries and for the treatment of thrombosis. However, bleeding associated with heparin therapy is a concern. Protamine, the only approved antidote for unfractionated heparin (UFH) could cause adverse cardiovascular events. Here, we describe a unique molecular design used in the development of a synthetic dendritic polycation named as universal heparin reversal agent (UHRA), an antidote for all clinically used heparin anticoagulants. We elucidate the mechanistic basis for the selectivity of UHRA to heparins and its nontoxic nature. Isothermal titration calorimetry based binding studies of UHRAs having different methoxypolyethylene glycol (mPEG) brush structures with UFH as a function of solution conditions, including ionic strength, revealed that mPEG chains impose entropic penalty to the electrostatic binding. Binding studies confirm that, unlike protamine or N-UHRA (a truncated analogue of UHRA with no mPEG chains), the mPEG chains in UHRA avert nonspecific interactions with blood proteins and provide selectivity toward heparins through a combined steric repulsion and Donnan shielding effect (a balance of Fel and Fsteric). Clotting assays reveal that UHRA with mPEG chains did not adversely affect clotting, and neutralized UFH over a wide range of concentrations. Conversely, N-UHRA and protamine display intrinsic anticoagulant activity and showed a narrow concentration window for UFH neutralization. In addition, we found that mPEG chains regulate the size of antidote-UFH complexes, as revealed by atomic force microscopy and dynamic light scattering studies. UHRA molecules with mPEG chains formed smaller complexes with UFH, compared to N-UHRA and protamine. Finally, fluorescence and ELISA experiments show that UHRA disrupts antithrombin-UFH complexes to neutralize heparin's activity. PMID- 28880551 TI - Cationic Poly(benzyl ether)s as Self-Immolative Antimicrobial Polymers. AB - Self-immolative polymers (SIMPs) are macromolecules that spontaneously undergo depolymerization into small molecules when triggered by specific external stimuli. We report here the first examples of antimicrobial SIMPs with potent, rapid, and broad-spectrum bactericidal activity. Their antibacterial and hemolytic activities were examined as a function of cationic functionality. Polymers bearing primary ammonium cationic groups showed more potent bactericidal activity against Escherichia coli, relative to tertiary and quaternary ammonium counterparts, whereas the quaternary ammonium polymers showed the lowest hemolytic toxicity. These antibacterial polycations undergo end-to-end depolymerization when triggered by an externally applied stimulus. Specifically, poly(benzyl ether)s end-capped with a silyl ether group and bearing pendant allyl side chains were converted to polycations by photoinitiated thiol-ene radical addition using cysteamine HCl. The intact polycations are stable in solution, but they spontaneously unzip into their component monomers upon exposure to fluoride ions, with excellent sensitivity and selectivity. Upon triggered depolymerization, the antibacterial potency was largely retained but the hemolytic toxicity was substantially reduced. Thus, we reveal the first example of a self-immolative antibacterial polymer platform that will enable antibacterial materials to spontaneously unzip into biologically active small molecules upon the introduction of a specifically designed stimulus. PMID- 28880553 TI - Investigation of Water Dissociation and Surface Hydroxyl Stability on Pure and Ni Modified CoOOH by Ambient Pressure Photoelectron Spectroscopy. AB - Water adsorption and reaction on pure and Ni-modified CoOOH nanowires were investigated using ambient pressure photoemission spectroscopy (APPES). The unique capabilities of APPES enable us to observe water dissociation and monitor formation of surface species on pure and Ni-modified CoOOH under elevated pressures and temperatures for the first time. Over a large range of pressures (UHV to 1 Torr), water dissociates readily on the pure and Ni-modified CoOOH surfaces at 27 degrees C. With an increase in H2O pressure, a greater degree of surface hydroxylation was observed for all samples. At 1 Torr H2O, ratios of different oxygen species indicate a transformation of CoOOH to CoOxHy in pure and Ni-modified CoOOH. In temperature dependent studies, desorption of weakly bound water and surface dehydroxylation were observed with increasing temperature. Larger percentages of surface hydroxyl groups at higher temperatures were observed on Ni-modified CoOOH compared to pure CoOOH, which indicates an increased stability of surface hydroxyl groups on these Ni-modified surfaces. PMID- 28880552 TI - Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin Intermediate Staphylococcus aureus Infections in Vivo. AB - Our previous work ( Wang et al. J. Med. Chem. 2016 , 59 , 4831 - 4848 ) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors. PMID- 28880555 TI - Modulating the Proton Affinity of Silanol and Siloxane Derivatives by Tetrel Bonds. AB - The proton affinity (PA) on the oxygen atom in silanol and siloxane derivatives is enhanced by the formation of tetrel bonds with small Lewis bases [B...R3SiOH, B...R3SiOSiR3, B...R3SiOSiR3...B; B = H2O, CO, NH3, HCN, H2S; R = H, Me], as shown by MP2/jul-cc-pVTZ calculations. The complexed systems become more basic than ether and other carbon-related compounds, and even more basic than pyridine in some specific cases, reaching values up to 959.4 kJ/mol (H3N...H3SiOSiH3...NH3 complex). Changes on PAs are directly related to very large binding energies for the protonated species. Topological methods and the natural bond orbital scheme are used to rationalize the observed trends. The PA enhancement should be taken into account when dealing with silanols and siloxanes in different environments. PMID- 28880554 TI - Visible Light Promoted Metal- and Photocatalyst-Free Synthesis of Allylarenes. AB - The metal- and photocatalyst-free synthesis of substituted allylarenes has been carried out under visible light driven conditions. The process was based on the photogeneration of aryl radicals from arylazo sulfones and their ensuing reaction with allyl sulfones. The developed procedure was very efficient when using substrates bearing electron-withdrawing groups, and allowed for the preparation of alpha-benzyl styrenes and 2-benzyl acrylates in good yields. PMID- 28880556 TI - Initial Stages in the Formation of Nickel Phosphides. AB - Metal phosphides have emerged as a new powerful class of materials that can be employed as heterogeneous catalysts in transformations mainly to generate new energy vectors and the valorization of renewables. Synthetic protocols based on wet techniques are available and are based on the decomposition of the organic layer decorating the nanoparticles. For nickel, the phosphine of choice is trioctylphosphine, and this leads to the formation of NiPx materials. However, the temperature at which the decomposition starts has been found to depend on the quality of the nickel surface. Density functional theory, DFT, holds the key to analyze the initial steps of the formation of these phosphide materials. We have found how clean nickel surfaces, either (111) or (100), readily breaks the ligand P-C bonds. This triggers the process that leads to the replacement of a surface nickel atom by P and concomintantly forms a Ni adatom on the surface surrounded by two methyl groups, thus starting the formation of the NiPx phase. The whole process requires low energies, in agreement with the low temperature found in the experiments, 150 degrees C. In contrast, if the surface is oxidized, the reaction does not proceed at low temperatures and oxygen vacancies need to be created first to start the P-C bond breaking on the Ni-clean patches. Our results show that the cleaner the surface is, the milder the reactions are required for the NiPx formation, and thus they pave the way for gentler synthetic protocols that can improve the control of these materials. PMID- 28880557 TI - Ag2S Quantum Dot-Sensitized Solar Cells by First Principles: The Effect of Capping Ligands and Linkers. AB - Quantum dots solar cells, QDSCs, are one of the candidates for being a reliable alternative to fossil fuels. However, the well-studied CdSe and CdTe-based QDSCs present a variety of issues for their use in consumer-goods applications. Silver sulfide, Ag2S, is a promising material, but poor efficiency has been reported for QDSCs based on this compound. The potential influence of each component of QDSCs is critical and key for the development of more efficient devices based on Ag2S. In this work, density functional theory calculations were performed to study the nature of the optoelectronic properties for an anatase-TiO2(101) surface sensitized with different silver sulfide nanoclusters. We demonstrated how it is possible to deeply tune of its electronic properties by modifying the capping ligands and linkers to the surface. Finally, an analysis of the electron injection mechanism for this system is presented. PMID- 28880558 TI - Correction to Constituents of Polygala flavescens ssp. flavescens and Their Activity as Inhibitors of Human Lactate Dehydrogenase. PMID- 28880559 TI - Cobalt Intercalated Layered NiFe Double Hydroxides for the Oxygen Evolution Reaction. AB - We present a combined experimental and theoretical study to demonstrate that the electrocatalytic activity of NiFe layered double hydroxides (NiFe LDHs) for the oxygen evolution reaction (OER) can be significantly enhanced by systematic cobalt incorporation using coprecipitation and/or intercalation. Electrochemical measurements show that cobalt modified NiFe LDH possesses an enhanced activity for the OER relative to pristine NiFe LDH. The Co-modified NiFe LDH exhibits overpotentials in the range of 290-322 mV (at 10 mA cm-2), depending on the degree of cobalt content. The best catalyst, cobalt intercalated NiFe LDH achieved a current density of 10 mA cm-2 at an overpotential of ~265 mV (compared to 310 mV for NiFe LDH), with a near unity (99%) faradaic efficiency and long term stability. Density functional theory calculations revealed that enhanced activity of Co-modified NiFe LDH could be attributed to the ability of Co to tune the electronic structure of the NiFe LDH so that optimal binding of OER reaction intermediates could be achieved. PMID- 28880560 TI - From Linear to Foldamer and Assembly: Hierarchical Transformation of a Coplanar Conjugated Polymer into a Microsphere. AB - Despite the coplanar structure, a conjugated alternating copolymer forms amorphous, well-defined microspheres without pi-stacked crystalline domains. Here, we gain insights into the mechanism of how the coplanar conjugated polymer forms amorphous microspheres by means of spectroscopic studies on the assembly/disassembly processes. The difference of the spectral profiles of photoabsorption and photoluminescence with varying solvent/nonsolvent composition clarifies that stepwise assembly takes place through the microsphere formation; [1] intrapolymer linear-to-folding transformation upon diffusion of polar nonsolvent and [2] interpolymer assembly of the foldamers upon further addition of the nonsolvent to form microspheres. As shown in various biopolymers such as proteins and DNA, such stepwise folding and assembly behaviors of conjugated polymers from primary to secondary and tertiary structure open a new way to create transformable functional materials. PMID- 28880561 TI - Therapeutic Mechanistic Studies of ShuFengJieDu Capsule in an Acute Lung Injury Animal Model Using Quantitative Proteomics Technology. AB - ShuFengJieDu capsule (SFJDC), a traditional Chinese medicine (TCM) that contains eight medicinal herbs, has been extensively utilized for the treatment of acute lung injury (ALI) and respiratory infections for more than 30 years in China. SFJDC has also been listed in the official guidelines of the China Food and Drug Administration (CFDA) due to its stable clinical manifestations. However, the underlying mechanism of SFJDC during ALI repair remains unclear. In the present study, we explored the protective and therapeutic mechanisms of SFJDC in a rat model by performing qualitative and label-free quantitative proteomics studies. After establishing lipopolysaccharide (LPS)-induced ALI rat models, we profiled macrophage cells isolated from freshly resected rat lung tissues derived from ALI models and ALI rat lung tissue sections using a high performance liquid chromatography-mass spectrometry (HPLC-MS/MS) shotgun proteomics approach to identify changes in the expression levels of proteins of interest. On the basis of our proteomics results and the results of a protein dysregulation analysis of ALI rat lung tissues and rat lung macrophages, AKT1 was selected as a putative key factor that may play an important role in mediating the effects of SFJDC treatment during ALI progression. Follow-up validation studies demonstrated that AKT1 expression effectively regulates various ALI-related molecules, and Gene Ontology analysis indicated that SFJDC-treated ALI rat macrophages were influenced by AKT1-based networks. Gain- and loss-of-function analyses following lentivirus-AKT1 or lentivirus-si-AKT1 infection in macrophages also indicated that AKT1 was essential for the development of ALI due to its ability to regulate oxidative stress, apoptosis, or inflammatory responses. In summary, SFJDC effectively modulated anti-inflammatory and immunomodulation activity during ALI, potentially due to AKT1 regulation during ALI progression. New insights into SFJDC mechanisms may facilitate the development of novel pharmaceutical strategies to control the expression of inflammatory factors. PMID- 28880562 TI - Nicotabin A, a Sesquiterpenoid Derivative from Nicotiana tabacum. AB - Nicotabin A (1), a sesquiterpenoid derivative possessing a fused 5/6/5/5/5 ring system, was isolated from leaves of Nicotiana tabacum. The structure was elucidated by extensive spectroscopic methods and confirmed by single crystal X ray diffraction. The plausible biosynthetic pathway for 1 was proposed. Compound 1 inhibited nitric oxide production in LPS-activated RAW264.7 macrophages with an IC50 of 22.1 MUM. PMID- 28880563 TI - Softened Mechanical Properties of Graphene Induced by Electric Field. AB - The understanding on the mechanical properties of graphene under the applications of physical fields is highly relevant to the reliability and lifetime of graphene based nanodevices. In this work, we demonstrate that the application of electric field could soften the mechanical properties of graphene dramatically on the basis of the conductive AFM nanoindentation method. It has been found that the Young's modulus and fracture strength of graphene nanosheets suspended on the holes almost stay the same initially and then exhibit a sharp drop when the normalized electric field strength increases to be 0.18 +/- 0.03 V/nm. The threshold voltage of graphene nanosheets before the onset of fracture under the fixed applied load increases with the thickness. Supported graphene nanosheets can sustain larger electric field under the same applied load than the suspended ones. The excessively regional Joule heating caused by the high electric current under the applied load is responsible for the electromechanical failure of graphene. These findings can provide a beneficial guideline for the electromechanical applications of graphene-based nanodevices. PMID- 28880564 TI - Optical Measurement of Radiocarbon below Unity Fraction Modern by Linear Absorption Spectroscopy. AB - High-precision measurements of radiocarbon (14C) near or below a fraction modern 14C of 1 (F14C <= 1) are challenging and costly. An accurate, ultrasensitive linear absorption approach to detecting 14C would provide a simple and robust benchtop alternative to off-site accelerator mass spectrometry facilities. Here we report the quantitative measurement of 14C in gas-phase samples of CO2 with F14C < 1 using cavity ring-down spectroscopy in the linear absorption regime. Repeated analysis of CO2 derived from the combustion of either biogenic or petrogenic sources revealed a robust ability to differentiate samples with F14C < 1. With a combined uncertainty of 14C/12C = 130 fmol/mol (F14C = 0.11), initial performance of the calibration-free instrument is sufficient to investigate a variety of applications in radiocarbon measurement science including the study of biofuels and bioplastics, illicitly traded specimens, bomb dating, and atmospheric transport. PMID- 28880565 TI - Electroabsorption Spectroscopy Studies of (C4H9NH3)2PbI4 Organic-Inorganic Hybrid Perovskite Multiple Quantum Wells. AB - Two-dimensional (2D) organic-inorganic hybrid perovskite multiple quantum wells that consist of multilayers of alternate organic and inorganic layers exhibit large exciton binding energies of order of 0.3 eV due to the dielectric confinement between the inorganic and organic layers. We have investigated the exciton characteristics of 2D butylammonium lead iodide, (C4H9NH3)2PbI4 using photoluminescence and UV-vis absorption in the temperature range of 10 K to 300 K, and electroabsorption spectroscopy. The evolution of an additional absorption/emission at low temperature indicates that this compound undergoes a phase transition at ~250 K. We found that the electroabsorption spectrum of each structural phase contains contributions from both quantum confined exciton Stark effect and Franz-Keldysh oscillation of the continuum band, from which we could determine more accurately the 1s exciton, continuum band edge, and the exciton binding energy. PMID- 28880566 TI - Divinylsulfonamides as Specific Linkers for Stapling Disulfide Bonds in Peptides. AB - A new class of N-phenyl-divinylsulfonamides which can be easily prepared have been successfully developed and utilized as efficient linkers in the field of disulfide bond modification. Functional divinylsulfonamides provide opportunities for the specific introduction of various functionalities, including affinity probes, fluorescent tags, and drugs, into peptides. PMID- 28880567 TI - Direct Synthesis of 4-Quinolones via Copper-Catalyzed Intermolecular Cyclization of Anilines and Alkynes. AB - A unique and direct approach for constructing 4-quinolones from simple and readily available anilines and alkynes is described. Under the optimal conditions, both N-alkyl- and N-aryl-substituted anilines can be successfully transformed into the corresponding 4-quinolones. This reaction is characterized by mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis. PMID- 28880568 TI - Macro- and Micronutrients of Human Milk Composition: Are They Related to Maternal Diet? A Comprehensive Systematic Review. AB - BACKGROUND: This study aims at systematically reviewing the observational and interventional studies on the association of maternal macro- and micronutrient intake with breast milk content. METHODS: We systematically searched the Medline via PubMed, Scopus, and ISI Web of Knowledge till October 2016 with the following search strategy: ("human milk" OR "breast milk" OR "breast milk composition" OR "human breast milk composition" OR "composition breast milk" OR "mother milk" OR "human breast milk") AND ("maternal diet" OR "maternal nutrition"). We also searched Google scholar for increasing the sensitivity of our search. The search was not limited to title and abstract due to the possibility that the desired outcome might have been considered a secondary aim. We excluded conference papers, editorials, letters, commentary, short survey, and notes. The search was refined to English language, and we did not consider any time limitation. To increase the sensitivity and to select more studies, the reference list of the published studies was checked as well. RESULTS: This review included 59 observational and 43 interventional studies on maternal diet related to breast milk composition. Different studies determined the associations and effects of some maternal dietary intake of micro and macronutrients and its reflection in human milk. CONCLUSION: Maternal dietary intake, particularly fatty acids, and some micronutrients, including fat soluble vitamins, vitamin B1, and vitamin C, was related to their content in breast milk composition. PMID- 28880570 TI - Differentially Culturable Tubercule Bacilli Are Generated during Nonpulmonary Tuberculosis Infection. PMID- 28880569 TI - Importing Well-Researched Practices from Other Traditions: Thoughts from a Conservative Society. PMID- 28880571 TI - Minding the Mind-Body Literature: Focusing on Women's Health and Pregnancy. PMID- 28880573 TI - Bacteriocins as food preservatives: Challenges and emerging horizons. AB - The increasing demand for fresh-like food products and the potential health hazards of chemically preserved and processed food products have led to the advent of alternative technologies for the preservation and maintenance of the freshness of the food products. One such preservation strategy is the usage of bacteriocins or bacteriocins producing starter cultures for the preservation of the intended food matrixes. Bacteriocins are ribosomally synthesized smaller polypeptide molecules that exert antagonistic activity against closely related and unrelated group of bacteria. This review is aimed at bringing to lime light the various class of bacteriocins mainly from gram positive bacteria. The desirable characteristics of the bacteriocins which earn them a place in food preservation technology, the success story of the same in various food systems, the various challenges and the strategies employed to put them to work efficiently in various food systems has been discussed in this review. From the industrial point of view various aspects like the improvement of the producer strains, downstream processing and purification of the bacteriocins and recent trends in engineered bacteriocins has also been briefly discussed in this review. PMID- 28880574 TI - Selection of Suitable Internal Control Genes for Accurate Normalization of Real Time Quantitative PCR Data of Buffalo (Bubalus bubalis) Blastocysts Produced by SCNT and IVF. AB - We evaluated the suitability of 10 candidate internal control genes (ICGs), belonging to different functional classes, namely ACTB, EEF1A1, GAPDH, HPRT1, HMBS, RPS15, RPS18, RPS23, SDHA, and UBC for normalizing the real-time quantitative polymerase chain reaction (qPCR) data of blastocyst-stage buffalo embryos produced by hand-made cloning and in vitro fertilization (IVF). Total RNA was isolated from three pools, each of cloned and IVF blastocysts (n = 50/pool) for cDNA synthesis. Two different statistical algorithms geNorm and NormFinder were used for evaluating the stability of these genes. Based on gene stability measure (M value) and pairwise variation (V value), calculated by geNorm analysis, the most stable ICGs were RPS15, HPRT1, and ACTB for cloned blastocysts, HMBS, UBC, and HPRT1 for IVF blastocysts and RPS15, GAPDH, and HPRT1 for both the embryo types analyzed together. RPS18 was the least stable gene for both cloned and IVF blastocysts. Following NormFinder analysis, the order of stability was RPS15 = HPRT1>GAPDH for cloned blastocysts, HMBS = UBC>RPS23 for IVF blastocysts, and HPRT1>GAPDH>RPS15 for cloned and IVF blastocysts together. These results suggest that despite overlapping of the three most stable ICGs between cloned and IVF blastocysts, the panel of ICGs selected for normalization of qPCR data of cloned and IVF blastocyst-stage embryos should be different. PMID- 28880572 TI - Examining Play Counts and Measurements of Injury Incidence in Youth Football. AB - CONTEXT: Whereas researchers have provided estimates for the number of head impacts sustained within a youth football season, less is known about the number of plays across which such impact exposure occurs. OBJECTIVE: To estimate the number of plays in which youth football players participated during the 2013 season and to estimate injury incidence through play-based injury rates. DESIGN: Descriptive epidemiology study. SETTING: Youth football. PATIENTS OR OTHER PARTICIPANTS: Youth football players (N = 2098; age range, 5-15 years) from 105 teams in 12 recreational leagues across 6 states. MAIN OUTCOME MEASURE(S): We calculated the average number of athlete-plays per season and per game using independent-samples t tests to compare age groups (5-10 years old versus 11-15 years old) and squad sizes (<20 versus >=20 players); game injury rates per 1000 athlete-exposures (AEs) and per 10 000 athlete-plays; and injury rate ratios (IRRs) with 95% confidence intervals (CIs) to compare age groups. RESULTS: On average, youth football players participated in 333.9 +/- 178.5 plays per season and 43.9 +/- 24.0 plays per game. Age groups (5- to 10-year-olds versus 11- to 15 year-olds) did not differ in the average number of plays per season (335.8 versus 332.3, respectively; t2086.4 = 0.45, P = .65) or per game (44.1 versus 43.7, respectively; t2092.3 = 0.38, P = .71). However, players from smaller teams participated in more plays per season (373.7 versus 308.0; t1611.4 = 8.15, P < .001) and per game (47.7 versus 41.4; t1523.5 = 5.67, P < .001). Older players had a greater game injury rate than younger players when injury rates were calculated per 1000 AEs (23.03 versus 17.86/1000 AEs; IRR = 1.29; 95% CI = 1.04, 1.60) or per 10 000 athlete-plays (5.30 versus 4.18/10 000 athlete-plays; IRR = 1.27; 95% CI = 1.02, 1.57). CONCLUSIONS: A larger squad size was associated with a lower average number of plays per season and per game. Increasing youth football squad sizes may help reduce head-impact exposure for individual players. The AE-based injury rates yielded effect estimates similar to those of play-based injury rates. PMID- 28880575 TI - From Stem Cell Research to Three-Dimensional Organoids and Their Applications in Cancer Research: Meeting Report on the 9th International Meeting of the Stem Cell Network North Rhine Westphalia. PMID- 28880576 TI - Increasing physical activity through an Internet-based motivational intervention supported by pedometers in a sample of sedentary students: A randomised controlled trial. AB - OBJECTIVE: The aim of this study was to analyse the effect of an Internet-based motivational intervention (IMI) supported by pedometers (in comparison with IMI alone and non-intervention) on increasing daily steps and changing constructs related to physical activity (PA) in a sample of sedentary students. DESIGN: A randomised-controlled trial was conducted with 76 sedentary or low-active college students. The purpose of the IMI was to deliver information to increase motivation and set individualised PA goals. It involved a 3-week intervention and a 3-months follow-up. OUTCOME MEASURES: Objective measures were used to measure daily steps, and self-report questionnaires to assess different constructs related to PA. RESULTS: Results revealed that IMI supported by pedometers condition increased significantly more the daily steps (post-intervention: M = 2069; SD = 1827; follow-up: M = 2227; SD = 2477) and enjoyment than non intervention condition at both points in time. Moreover, results showed that IMI alone condition increased more the scores in variables involved in PA behaviour than non-intervention condition. CONCLUSIONS: This study shows the effectiveness of a self-administered IMI using pedometers in increasing PA and enjoyment, and the effectiveness of the IMI alone in changing different theoretical constructs related to the PA behaviour. PMID- 28880577 TI - Diverse bodies: the challenge of new theoretical approaches to medical anthropology. PMID- 28880578 TI - Correction to: Counting bodies? On future engagements with science studies in medical anthropology. PMID- 28880580 TI - IHC Posters - Saturday and Sunday. PMID- 28880579 TI - Cognitive Emotion Regulation Strategies in Chinese Adolescents with Overweight and Obesity. AB - BACKGROUND: The relationship between psychological factors and obesity has become a hot topic in psychosomatic research. The aim of this study was to examine the characteristics of cognitive emotion regulation (CER) strategies in Chinese adolescents with different weight status. METHODS: Using stratified random cluster sampling, 700 and 321 adolescents were defined as adolescents with overweight status and obese status, respectively. One thousand and twenty-one adolescents with normal-weight status were also selected. All participants completed a general questionnaire and Chinese version of the Cognitive Emotion Regulation Questionnaire. RESULTS: Adolescents in the obesity group obtained the highest scores on self-blame and rumination in three groups, and those from the obesity group obtained lower scores on acceptance, positive refocusing, and positive reappraisal than those from normal group (ps < 0.05). Cognitive emotion regulation strategies had a significant impact on BMI, accounting for 32.0% variance (p < 0.001). Higher scores on self-blame and rumination were associated with higher BMI, but greater acceptance and positive refocusing were associated with lower BMI (ps < 0.05). CONCLUSION: Self-blame, rumination, acceptance, and positive refocusing have considerable effects on BMI in Chinese adolescents. The causal relationship of CER strategies and BMI should be explained more accurately and thoroughly to prevent and intervene in cases of adolescent obesity. PMID- 28880581 TI - IHC Posters - Thursday and Friday. PMID- 28880582 TI - IHC Electronic Posters - Saturday and Sunday. PMID- 28880583 TI - IHC Oral Abstracts. PMID- 28880584 TI - Headache Pathophysiology - Imaging and Neurophysiology. PMID- 28880586 TI - Have Fun and Enjoy it Together at the Joint JSOPMB/CTS Conference. PMID- 28880587 TI - Seventy-Two-Hour Preservation, Resuscitation, and Transplantation of an Isolated Rat Heart with High Partial Pressure Carbon Monoxide Gas (PCO = 400 hPa) and High Partial Pressure Carbon Dioxide (PCO2 = 100 hPa). AB - The cardiac cavity of an isolated rat heart was filled with a Krebs-Henseleit (KH) solution, and the heart was hung in a high-pressure chamber. After the high pressure chamber had been filled with a mixed gas (PCO = 400 hPa, PCO2 = 100 hPa, PO2 = 900 hPa, PHe = 5600 hPa) and preserved for 72 h, we performed a cervical ectopic heart transplantation on a recipient rat and resuscitated the preserved heart. This is the first incidence in the world of a mammalian organ having been successfully preserved and resuscitated after 72 h via a desiccation method. PMID- 28880590 TI - Foot Pain in Relation to Ipsilateral and Contralateral Lower-Extremity Pain in a Population-Based Study. AB - BACKGROUND: Clinical observations note that foot pain can be linked to contralateral pain at the knee or hip, yet we are unaware of any community-based studies that have investigated the sidedness of pain. Because clinic-based patient samples are often different from the general population, the purpose of this study was to determine whether knee or hip pain is more prevalent with contralateral foot pain than with ipsilateral foot pain in a population-based cohort. METHODS: Framingham Foot Study participants (2002-2008) with information on foot, knee, and hip pain were included in this cross-sectional analysis. Foot pain was queried as pain, aching, or stiffness on most days. Using a manikin diagram, participants indicated whether they had experienced pain, aching, or stiffness at the hip or knee and specified the side of any reported pain. Sex specific multinomial logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals for the association of foot pain with knee and hip pain, adjusting for age and body mass index. RESULTS: In the 2,181 participants, the mean +/- SD age was 64 +/- 9 years; 56% were women, and the mean body mass index was 28.6. For men and women, bilateral foot pain was associated with increased odds of knee pain on any side (ORs = 2-3; P < .02). Men with foot pain were more likely to have ipsilateral hip pain (ORs = 2-4; P<.03), whereas women with bilateral foot pain were more likely to have hip pain on any side (OR = 2-3; P < .02). CONCLUSIONS: Bilateral foot pain was associated with increased odds of knee and hip pain in men and women. For ipsilateral foot and hip pain, men had a stronger effect compared with women. PMID- 28880588 TI - How Sensitive Is Genetic Data? AB - The rising demand to use genetic data for research goes hand in hand with an increased awareness of privacy issues related to its use. Using human genetic data in a legally compliant way requires an examination of the legal basis as well as an assessment of potential disclosure risks. Focusing on the relevant legal framework in the European Union, we discuss open questions and uncertainties around the handling of genetic data in research, which can result in the introduction of unnecessary hurdles for data sharing. First, we discuss defining features and relative disclosure risks of some DNA-related biomarkers, distinguishing between the risk for disclosure of (1) the identity of an individual, (2) information about an individual's health and behavior, including previously unknown phenotypes, and (3) information about an individual's blood relatives. Second, we discuss the European legal framework applicable to the use of DNA-related biomarkers in research, the implications of including both inherited and acquired traits in the legal definition, as well as the issue of "genetic exceptionalism"-the notion that genetic information has inherent characteristics that require different considerations than other health and medical information. Finally, by mapping the legal to specific technical definitions, we draw some initial conclusions concerning how sensitive different types of "genetic data" may actually be. We argue that whole genome sequences may justifiably be considered "exceptional" and require special protection, whereas other genetic data that do not fulfill the same criteria should be treated in a similar manner to other clinical data. This kind of differentiation should be reflected by the law and/or other governance frameworks as well as agreed Codes of Conduct when using the term "genetic data." PMID- 28880591 TI - Remote Ischemic ConditioningPromising Potential in Wound Repair in Diabetes? AB - Remote ischemic conditioning involves the use of a blood pressure cuff or similar device to induce brief (3-5 min) episodes of limb ischemia. This, in turn, seems to activate a group of distress signals that has shown the potential ability to improve healing of the heart muscle and other organ systems. Until recently, this has not been tested in people with diabetic foot ulcers. The purpose of this review was to provide background on remote ischemic conditioning and recent data to potentially support its use as an adjunct to healing diabetic foot ulcers and other types of tissue loss. We believe that this inexpensive therapy has the potential to be deployed and incorporated into a variety of other therapies to prime patients for healing and to reduce morbidity in patients with this common, complex, and costly complication. PMID- 28880592 TI - Synovial Lipoma of the Subtalar Joint. AB - Lipomas are benign adipose masses that are rarely associated with synovial membranes. In addition, there are only a few reports describing synovial lipomas in the foot. No reported occurrence of this lesion in the subtalar joint currently exists. This case report documents the presentation, clinical evaluation, advanced imaging, and surgical management of a 45-year-old man with a large synovial lipoma of the subtalar joint. PMID- 28880594 TI - Pregnancy and Pelvic Girdle PainAnalysis of Center of Pressure During Gait. AB - BACKGROUND: A woman's body undergoes many changes during pregnancy, and it adapts by developing compensatory strategies, which can be sources of pain. We sought to analyze the effects of pregnancy and pelvic girdle pain (PGP) on center of pressure (COP) parameters during gait at different speeds. METHODS: Sixty-one healthy pregnant women, 66 women with PGP between 18 and 27 weeks of pregnancy, and 22 healthy nonpregnant women walked at different velocities (slow, preferential, and fast) on a walkway with built-in pressure sensors. An analysis of variance was performed to determine the effects of gait speed and group on COP parameters. RESULTS: In healthy pregnant women and women with PGP, COP parameters were significantly modified compared with those in nonpregnant women (P < .01). Support time was increased regardless of gait speed, and anteroposterior COP displacement was significantly decreased for women with PGP compared with healthy pregnant women. In addition, mediolateral COP displacement was significantly decreased in pregnant women compared with nongravid women. CONCLUSIONS: Gait speed influenced COP displacement and velocity parameters, and gait velocity potentiated the effect of pregnancy on the different parameters. Pelvic girdle pain had an influence on COP anteroposterior length only. With COP parameters being only slightly modified by PGP, the gait of pregnant women with PGP was similar to that of healthy pregnant women but differed from that of nonpregnant women. PMID- 28880595 TI - Lower-Leg and Foot Contributions to Turnout in University-Level Female Ballet DancersA Preliminary Investigation. AB - BACKGROUND: Turnout in ballet is produced through summation of the joint structure characteristics and ranges of motion at the hip, knee, ankle, and foot. Contributions of the hip joint to functional turnout in dancers have received extensive examination, whereas little is known about contributions from the knee, ankle, and foot. The aim of this study was to explore the nonhip components of turnout to dancers' functional turnout in first position by assessing passive external tibiofemoral rotation and active measures of foot pronation, ie, navicular drop and Foot Posture Index. METHODS: Nineteen female university-level dance students aged 16 to 19 years participated in this descriptive correlational study. External tibiofemoral rotation, navicular drop, Foot Posture Index, and functional turnout were measured for the participants' right and left legs. RESULTS: Regression analyses revealed a weak relationship between passive external tibiofemoral rotation and functional turnout. Correlation analysis revealed a moderate negative relationship between passive tibiofemoral external rotation and the Foot Posture Index in functional turnout. CONCLUSIONS: These findings suggest that the lower leg does contribute to dancers' overall position of functional turnout. However, current methods are not useful in predicting a dancer's lower-leg contribution and alignment in functional turnout in first position. PMID- 28880596 TI - Does Baseline Hemoglobin A1c Level Predict Diabetic Foot Ulcer Outcome or Wound Healing Time? AB - BACKGROUND: We sought to evaluate the relationship between baseline hemoglobin A1c (HbA1c) level and clinical outcomes, including foot ulcer outcome (resolved versus unresolved) and wound-healing time, in individuals with type 2 diabetes. METHODS: A prospective observational study was conducted on 99 patients presenting with a diabetic foot ulceration. Patient and ulcer characteristics were recorded. Patients were followed up for a maximum of 1 year. RESULTS: After 1 year of follow-up, 77% of ulcers healed and 23% did not heal. Although this study demonstrated that the baseline HbA1c reading was not a significant predictor of foot ulcer outcome (P = .603, resolved versus amputated), on further statistical analyses, when HbA1c was compared with the time taken for complete ulcer healing in the resolved group (n = 77), it proved to be significant (P = .009). CONCLUSIONS: These findings have important implications for clinical practice, especially in an outpatient setting. Improving glycemic control may improve ulcer outcomes. Prediction of outcome may be helpful for health-care professionals in individualizing and optimizing clinical assessment and management of patients. Identification of determinants of outcome could result in improved health outcomes, improved quality of life, and fewer diabetes-related foot complications. PMID- 28880597 TI - Evaluating Quality of Life in Patients with Hallux Abducto Valgus Deformity After a Taping Technique. AB - BACKGROUND: The aim of this study was to determine the quality of life in patients living with hallux abducto valgus deformity before and after a taping technique. METHODS: This study used a time series, quasi-experimental, same subject design. Thirty-five patients with hallux abducto valgus were recruited in this study. Nonelastic zinc oxide tape was applied for 4 weeks. The Foot Health Status Questionnaire was used to assess the quality of life of participants before and after the intervention. The paired samples t test was used to test for statistical significance at the 95% confidence level. RESULTS: In this study, a statistical reduction was seen in foot pain, foot function, and general foot health (P < .0001) after applying the nonelastic zinc oxide tape for 10 hours daily for 4 weeks. No statistically significant difference was found in the remaining domains of the Foot Health Status Questionnaire, although a difference in mean scores was observed. CONCLUSIONS: Treatment with nonelastic zinc oxide tape led to improved management of hallux abducto valgus and better quality of life; it is a safe, easy-to-use method with minimal adverse effects. Future studies should evaluate this method using larger sample groups and longer treatment periods while comparing this method with alternative treatment approaches, such as exercise or orthotic devices. PMID- 28880599 TI - Giant Plantar Epidermoid Cyst with Invasion of the Interosseous Muscles. AB - Epidermoid cysts of the sole of the foot are rare lesions that must be differentiated from other, more common subcutaneous pathologic abnormalities located on the sole. Cases of epidermoid cysts that extend to the interosseous musculature are rarer still. We report the case of a giant epidermal cyst in a 64 year-old individual that extended to the intrinsic musculature of the third space of the right foot and that was diagnosed after fine-needle aspiration biopsy and subsequent cytologic study. Differential diagnosis of these lesions should be made with the support of additional imaging tests, and diagnostic confirmation should always be obtained after surgical removal and subsequent histopathologic study. PMID- 28880600 TI - Rare Giant Cell Tumor of the Distal Flexor Digitorum Longus Tendon Sheath and Early Diagnosis with Use of Magnetic Resonance Imaging. AB - Giant-cell tumor of the tendon sheath (GCT-TS) is an uncommon occurrence for a foot and ankle surgeon. However, there is a need to recognize the symptoms of typical and atypical presentations of this pathology. These benign neoplasms are recognized clinically as a soft-tissue mass that is usually painless and palpable. The foot and ankle account for only 3% to 5% of all GCT-TS in the body, with most being located in the hand. Giant cell tumor in the tendon sheath occurring in the foot and ankle is usually encountered on the lateral ankle and dorsum of the foot, occupying the extensor tendons. Additionally, it is commonly misdiagnosed clinically. This case study illustrates how early use of magnetic resonance imaging decreased patient morbidity with early recognition and excision of GCT-TS. PMID- 28880601 TI - Onychomycosis InfectionsDo Polymerase Chain Reaction and Culture Reports Agree? AB - BACKGROUND: Mycological culture is the traditional method for identifying infecting agents of onychomycosis despite high false-negative results, slower processing, and complications surrounding nondermatophyte mold (NDM) infections. Molecular polymerase chain reaction (PCR) methods are faster and suited for ascertaining NDM infections. METHODS: To measure agreement between culture and PCR methods for identification of infecting species of suspected onychomycosis, single toenail samples from 167 patients and repeated serial samples from 43 patients with suspected onychomycosis were processed by culture and PCR for identification of 16 dermatophytes and five NDMs. Agreement between methods was quantified using the kappa statistic (kappa). RESULTS: The methods exhibited fair agreement for the identification of all infecting organisms (single samples: kappa = 0.32; repeated samples: kappa = 0.38). For dermatophytes, agreement was moderate (single samples: kappa = 0.44; repeated samples: kappa = 0.42). For NDMs, agreement was poor with single samples (kappa = 0.16) but fair with repeated samples (kappa = 0.25). Excluding false-negative reports from analyses improved agreement between methods in all cases except the identification of NDMs from single samples. CONCLUSIONS: Culture was three or four times more likely to report a false-negative result compared with PCR. The increased agreement between methods observed by excluding false-negative reports statistically clarifies and highlights the major discord caused by false-negative cultures. The increased agreement of NDM identification from poor to fair with repeated sampling along with their poor agreement in the single samples, with and without false negatives, affirms the complications of NDM identification and supports the recommendation that serial samples help confirm the diagnosis of NDM infections. PMID- 28880602 TI - Osteoid Osteoma at the Proximal Diaphysis of the Fifth Metatarsal. AB - The foot is rarely the focus of osteoid osteoma, and only a few of those cases are related to the fifth metatarsal. The present case demonstrates that atypical symptoms with suspicious findings on plain radiographs that are not associated with trauma must be analyzed carefully to determine the nature of the lesion and perform the precise treatment to obtain and sustain the cure. A 29-year-old man presented to the outpatient clinic with a 2-year history of chronic pain in the lateral aspect of his left forefoot. The onset was not related to trauma, surgery, local infection, osteomyelitis, or another entity regarding the proximal fifth metatarsal. The patient noted that the pain was aggravated at night and typically subsided with the use of salicylates or other nonsteroidal anti inflammatory drugs. Initial plain radiographs demonstrated cortical thickening and a lytic lesion at the proximal diaphysis of the fifth metatarsal. Because the pain relief was transient, we suspected an osteoid osteoma lesion, and subsequent magnetic resonance imaging manifested pathognomonic signs of subperiosteal osteoid osteoma. Diagnosis was followed by planning of the surgery that ended the patient's symptoms. PMID- 28880603 TI - Pedal Cutaneous Manifestations of Tuberous Sclerosis. AB - This case report concerns a patient with a painful soft-tissue mass on his fourth toe. He was evaluated for this soft-tissue mass and was diagnosed as having tuberous sclerosis. The podiatric physician should be able to evaluate a patient with a lower-extremity complaint and relate whether this complaint may correlate with a systemic disorder. This case report will make the podiatric physician more aware of tuberous sclerosis and the manifestations of the disorder. PMID- 28880604 TI - A Novel Technique to Determine Foot Contribution to Limb-Length Discrepancy. AB - Evaluation for limb-length discrepancy is an important part of the biomechanical work-up in the podiatric musculoskeletal exam. By understanding the foot's contribution to such a discrepancy, the podiatric clinician will have better insight regarding treatment strategy. This technique will provide the clinician with a simple method to gain such insight. PMID- 28880605 TI - Podiatric Physicians and Genomic Medicine. AB - It has been more than 14 years since identification of the human genome. This phenomenon is creating a revolution in all components of the health-care world. To date, little has been included in the podiatric medical literature despite the fact that so many of the conditions affecting the pedal extremity have genomic implications. Genomics will have a major effect on prevention, diagnosis, and patient management and needs to be included in podiatric medical practice as well as in the curriculum of podiatric medical schools. PMID- 28880607 TI - Mind-Body Therapy for Military Veterans with Post-Traumatic Stress Disorder: A Systematic Review. AB - OBJECTIVE: About one-third of service members returning from post-9/11 deployment in Afghanistan and Iraq report combat-related mental health conditions, but many do not seek conventional treatment. Mind-body therapies have been offered as alternative approaches to decreasing post-traumatic stress disorder (PTSD), but no review of studies with veterans of post-9/11 operations was found. The objective of this study was to fill that gap. DESIGN: A systematic literature review was conducted following the preferred items for systematic reviews and meta-analyses (PRISMA) guidelines. PubMed MeSH terms were used to capture articles reporting on the military population (veteran and veterans) with PTSD who received a portable mind-body intervention (e.g., mindfulness, mind-body therapy, and yoga). PubMed/MEDLINE and PsycINFO were searched. Studies were included if participants were a mixed group of war veterans, as long as some post 9/11 veterans were included. In addition, participants must have had a diagnosis of PTSD or subthreshold PTSD, and the PTSD must have been attributable to combat, rather than another event, such as sexual trauma or natural disaster. RESULTS: Of 175 records identified, 15 met inclusion criteria. Studies reported on seated or gentle yoga that included breath work, meditation, mantra repetition, or breathing exercises. For 14 of the 15 studies, study retention was 70% or higher. Overall, studies reported significant improvements in PTSD symptoms in participants in these interventions. Although each study included post-9/11 veterans, about 85% of participants were from other conflicts, predominantly Vietnam. CONCLUSION: Although findings were positive, future studies are needed to evaluate the short- and long-term impact of mind-body therapies on larger samples of post-9/11 veterans and to address research questions related to broadening service member and veteran participation in these therapies. PMID- 28880606 TI - Fibular-Lengthening Osteotomy to Correct a Malunited Ankle Fracture Using Fresh Frozen Femoral Head Allograft. AB - Malreduction of a distal fibular fracture can lead to degenerative changes in the ankle joint. Previous studies have shown that the selective use of various fibular reconstructive osteotomies may halt the progression of degenerative arthritis by restoring the normal tibiotalar contact area and decreasing the stresses on the articular cartilage. In this case report, we achieved alignment with restoration of the talocrural angle and Shenton's line of the ankle using a transfibular osteotomy and an allogeneic fresh-frozen femoral head graft to fill the resultant defect. The advantage of this procedure is twofold. First, fibular lengthening procedures may potentially decrease the eventual need for joint sacrificing procedures such as an arthrodesis or arthroplasty. Second, an allograft allows for larger deficit correction without concern for donor-site morbidity. To our knowledge, this is the first case report using a fresh-frozen femoral head allograft for a fibular-lengthening osteotomy in the podiatric medical literature. Further research with larger patient populations is needed to establish whether fresh-frozen femoral head allograft is a reliable graft option for fibular-lengthening procedures. PMID- 28880608 TI - Application of a Predictive Growth Model of Pseudomonas spp. for Estimating Shelf Life of Fresh Agaricus bisporus. AB - For prediction of the shelf life of the mushroom Agaricus bisporus, the growth curve of the main spoilage microorganisms was studied under isothermal conditions at 2 to 22 degrees C with a modified Gompertz model. The effect of temperature on the growth parameters for the main spoilage microorganisms was quantified and modeled using the square root model. Pseudomonas spp. were the main microorganisms causing A. bisporus decay, and the modified Gompertz model was useful for modelling the growth curve of Pseudomonas spp. All the bias factors values of the model were close to 1. By combining the modified Gompertz model with the square root model, a prediction model to estimate the shelf life of A. bisporus as a function of storage temperature was developed. The model was validated for A. bisporus stored at 6, 12, and 18 degrees C, and adequate agreement was found between the experimental and predicted data. PMID- 28880609 TI - Improved Metabolic and Psychiatric Outcomes with Discontinuation of Atypical Antipsychotics in Youth Hospitalized in a State Psychiatric Facility. AB - OBJECTIVES: To assess the impact of antipsychotic tapering and discontinuation on measures of metabolic functioning and psychiatric symptom severity in severely impaired youth hospitalized in a psychiatric state hospital. METHODS: The study examined psychiatric and metabolic measures in 67 hospitalized children and adolescents (mean age 11.9; 56 with discontinued use of antipsychotics, 10 with continued use of antipsychotics, and 1 started on an antipsychotic) from admission to discharge. RESULTS: Upon admission, 56 youth were tapered off of antipsychotic medications, started on other forms of pharmacotherapy (92.9% were started on medications used to treat attention-deficit/hyperactivity disorder), and received evidence-based behavioral programming and were ultimately discharged from the hospital. The mean duration of treatment was 228 days for the discontinuation group and 204 days for the continuation group. Significant decreases in body mass index [BMI; t(53) = 7.12, p = 0.0001] and BMI percentile [t(53) = 6.73, p = 0.0001] were found from admission to discharge in the antipsychotic discontinuation group. Changes in BMI, BMI percentile, or systolic blood pressure were not found in the group (n = 10) who were maintained on antipsychotics. Both groups experienced a significant increase in their Global Assessment of Functioning score [t(52) = 19.98, p = 0.0001 for discontinued; t(8) = 5.092, p = 0.001 for maintained]. Psychiatric symptom severity scores significantly improved in many subscales relevant to disruptive behaviors and mood disorders for those who were removed from the medications. For those maintained on the antipsychotics, there were fewer changes in psychiatric symptom scores. CONCLUSION: Discontinuation of atypical antipsychotic medications in conjunction with tailoring treatment to presenting diagnoses resulted in metabolic and psychiatric symptom improvement among severely impaired state hospital inpatient youth. These results serve as a feasibility demonstration that discontinuation of antipsychotics does not provoke psychiatric destabilization, particularly among disruptive behavior disordered youth. PMID- 28880611 TI - The buzz is coming: are you ready to 'bee' a flu fighter? PMID- 28880610 TI - Perceptions and development needs of assistant practitioners supporting individuals with dementia. AB - In the UK there are an estimated 850 000 people living with dementia. The condition costs the NHS L26 billion each year and it is estimated that this amount will treble over the next 30 years. Thus, there is a need for health and social care staff to be increasingly competent in the delivery of care to those living with dementia. The education of staff will improve knowledge and build capability to support and care for individuals with dementia. This research involved 44 assistant practitioners who shared opinions about their preparation for practice in dementia care. Focus groups and questionnaires were used to collect data that were then thematically analysed. The research also considered the assistant practitioner role in relation to workforce development. Key themes were 'training, awareness and knowledge associated with dementia care' and 'the perceptions of the assistant practitioner regarding confidence to support individuals with dementia'. There was role and responsibility protection from staff, for example, doctors and nurses were reluctant to delegate duties to the assistant practitioner. Participants' commentary indicated, however, that they were competent to support service users with dementia, although there were gaps in their experiences. The case study demonstrated the positive achievement of partnership working between a higher education institution and the workplace, which supported the assistant practitioners' learning and development. PMID- 28880612 TI - Resilience in the workplace: personal and organisational factors. AB - Janet Scammell, Associate Professor (Nursing), Bournemouth University, explains that although resilience is seen as a personal attribute, the role of organisational policies in fostering it must not be overlooked. PMID- 28880613 TI - Getting the basics right: why we should focus on infection prevention. PMID- 28880614 TI - Professional and political reflections on the 'grand round': a critical case study. AB - This case study presents a critical reflective account of a change to working practices in one NHS Trust. To promote quality care and effective clinical decision making, a 'grand round' was introduced in the orthopaedic department. Implementation presented frustrations and challenges for members of the multidisciplinary team. These are explored using transformative learning and critical reflection, enabling connections to be made between micro-level interactions of clinical care and macro-level structures that frame healthcare services. It is important that nurses recognise the escalating impact of a neoliberal agenda, and new public management, that drive UK health policy and politics. The value base of nursing is threatened by a corporate culture that measures performance in terms of institutional targets rather than individual care. PMID- 28880615 TI - Defence nursing reflection: getting the most out of revalidation. PMID- 28880616 TI - A nurse by another name? PMID- 28880617 TI - A workforce fit to support. PMID- 28880618 TI - Safe disposal of cytotoxic waste: an evaluation of an air-tight system. AB - A 3-month evaluation was undertaken at the Kent Oncology Centre's chemotherapy day unit (CDU) to trial an air-tight sealing disposal system for cytotoxic waste management. Research has identified the potential risk to staff who handle waste products that are hazardous to health. Staff safety was a driving force behind a trial of a new way of working. This article provides an overview of the evaluation of the Pactosafe system in one clinical area, examining reviews by oncology healthcare workers, the practicalities in the clinical setting, training, cost effectiveness and the environmental benefits. PMID- 28880620 TI - Time to act to improve mental health care services. AB - John Tingle, Reader in Health Law at Nottingham Trent University, discusses the Care Quality Commission report on specialist mental health services. PMID- 28880619 TI - Reflective practice applied in a clinical oncology research setting. AB - : Regular reflective practice group sessions, focusing on enhancing mindfulness, were piloted as part of a support programme for researchers in a clinical oncology setting. METHODS: As a previous systematic review highlighted a wide variety of approaches and a lack of published evidence on the use of specific models for reflective practice in health care, a scoping review of existing literature describing reflective practice models preceded piloting the programme with the research team. The Mindful Attention Awareness Scale (MAAS) was used to assess the benefit for participants. Scores from the first and last session were analysed using a paired-sample t-test. Feedback from questionnaires was analysed using descriptive statistics (for Likert scales) and direct quotes from free text exemplified the experience. RESULTS: Seven people participated. Six were female, all were research nurses except for one research allied health professional. The median age was 37 (range: 23-40 years). The average time since graduation was 10 years (range: 1.5-18 years). All researchers worked in a tertiary oncology setting. Although a total of 21 reflective practice sessions were facilitated, the median number of sessions attended was 9 (range: 2-21). The mean MAAS score improved from 57.83 to 62.83 (p=0.0146). The participants rated the experience and impact as positive. CONCLUSION: The results of the MAAS score indicate that mindfulness was enhanced by the sessions. The feedback from the participants highlighted the impact on their professional development. This is encouraging to support developing similar facilitated reflective practice programmes in different settings. PMID- 28880621 TI - Research into experiential learning in nurse education. AB - This research is founded on an innovative pedagogical project as part of a higher education lecturer teaching qualification. This project involved redesigning the module 'advanced history taking and physical examination with clinical reasoning', a continuing professional development at a higher education institution. The author undertook an exploration of the literature, considering evidence on teaching styles and the way in which students learn and gain knowledge. The module was redesigned, impelemented and then evaluated by the student participants. Key themes in the evaluation centred on the experiential learning style and experiential teaching style. There are numerous internal and external factors that affect teaching, and student learning. Experiential learning has provided a successful teaching pedagogy when applied to clinical skill acquisition, and has positively benefited the module delivery and pass rate, suggesting it has embedded 'deep learning'. Student feedback was positive, and the redesigned module has had a positive impact on student engagement and the teacher-student interaction. PMID- 28880622 TI - Perceived adverse effects from handling systemic anti-cancer therapy agents. AB - This article explores the immediate adverse effects experienced by nurses during the administration of systemic anti-cancer therapy (SACT), specifically cytotoxic chemotherapy, and whether closed systems are being used to minimise exposure risk. Many SACT agents are known to be carcinogenic, teratogenic and mutagenic and this has led to concerns relating to the increased number of healthcare workers potentially exposed to these agents. An anonymous online survey was designed, made up of four questions, to elicit whether adverse effects were experienced by nurses during preparation, administration or following administration of chemotherapy. A total of 46% of respondents stated that they experienced some form of adverse effect either during preparation, administration or following administration of SACT. More formal research is required in this area to explore the relationship between exposure to SACT and perceived adverse effects in healthcare workers administering SACT. PMID- 28880623 TI - Cuts to sexual health services. PMID- 28880624 TI - Promoting mental health first aid literacy in secondary schools. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses a new initiative designed to help teachers in secondary schools better understand and identify mental health issues in children. PMID- 28880625 TI - Biosimilar monoclonal antibodies (mAbs) in oncology. AB - Biological medicines are derived from living cells and organisms. Monoclonal antibodies (mAbs) are biological agents that are widely used to treat malignancies including non-Hodgkin's lymphomas and chronic lymphocytic leukaemia. They are effective but expensive. The patents for many mAbs are expiring, so biosimilar medicines, which contain a version of the active ingredient of the original drug, are being developed. Biological medicines cannot be assessed in the same way as standard generic medications because they are difficult to copy and can change over time. A pathway regulates how biosimilars are assessed and compared with the original drug to ensure they are highly similar and have no clinically meaningful differences in terms of structure, function, pharmacodynamics and mechanism of action, pharmacokinetic properties, clinical efficacy and safety. Truxima(r) ?(rituximab), the first biosimilar monoclonal antibody to be approved for use in the UK in an oncology setting, is biosimilar to intravenous (IV) rituximab; rituximab improves the effectiveness of standard chemotherapy for lymphoma. The two drugs are comparable in efficacy and safety and have the same indications, dosing regimen and storage procedures. PMID- 28880627 TI - Limits to consent to care and treatment. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, considers the requirements for a valid consent and the limits to that consent in light of a case of a surgeon jailed for performing unnecessary operations. PMID- 28880626 TI - Implementing safety huddles. AB - Sam Foster, at time of writing Chief Nurse at Heart of England NHS Foundation Trust, considers the implications for patient outcomes of implementing safety huddles. PMID- 28880654 TI - Comparison of Tolerated and Rejected Islet Grafts: A Gene Expression Study. AB - Recently we showed that donor-specific tolerance to MHC-matched islet allografts in diabetic NOD mice could be induced by simultaneous islet and bone marrow transplantation. Mononuclear cell infiltration surrounding the islets was also found in tolerated grafts. In this study, we compared gene expression in the tolerated and rejected islet grafts by using Affymetrix Murine U74A oligonucleotide arrays. To confirm the results of microarray analysis, we performed real-time PCR and RNase protection assay on selected genes. Of over 12,000 genes studied, 57 genes were expressed at consistently higher levels in tolerated islet grafts, and 524 genes in rejected islet grafts. Genes from a variety of functional clusters were found to be different between rejected and tolerated grafts. In the rejected islet grafts, a number of T-cell surface markers and of cytotoxicity-related genes were highly expressed. Also in the rejected grafts, a number of cytokines and chemokines and their receptors were highly expressed. The differential expression of selected genes found by microarray analysis was also confirmed by real-time PCR and RNase protection assay. Our results indicated that gene microarray analysis can help us to detect gene expression differences representative of the biologic mechanisms of tolerance and rejection. PMID- 28880655 TI - Methods of Human Islet Culture for Transplantation. AB - The ability to maintain isolated human islet preparations in tissue culture has recently been adopted by most islet transplant centers, and improves the safety as well as the practicality of islet transplantation. Maintaining islet viability and recovery, however, remains challenging in a clinical setting, due to stringent conditions required for culture. Islet culture is further complicated by the fact that islets do not form a monolayer. This review aims to clarify media, supplementation, and conditions that have been shown to be relevant to human islets, as well as to offer avenues of future research. Factors examined that may influence islet survival include base medium, glucose concentration, vitamin, inorganic ion, lipid, hormone, growth factor, amino acid, and binding protein composition and concentration, as well as culture temperature and seeding density. In addition, this article reviews novel techniques, such as coculture and matrices, that have been employed in an attempt to improve islet survival and functional viability. PMID- 28880656 TI - Viability of Allogeneic Bone Marrow Stromal Cells following Local Delivery into Patella Tendon in Rabbit Model. AB - Bone marrow stromal cells are potentially useful for tendon repair and regeneration. To provide lasting benefits, the seeded cells must survive implantation at local tendon sites. Our objective was to determine the in vivo fate of allogeneic bone marrow stromal cells (bMSCs) at different time points after implantation into patella tendon defects (i.e., at 2, 3, 5, and 8 weeks). The protocol involved the labeling of bMSCs with green fluorescent protein (GFP) or carboxyfluorescein diacetate (CFDA) before implantation. A window defect (5 * 5 mm) was created at the central portion of rabbit patella tendon and subsequently treated with GFP- or CFDA-marked bMSCs. The marked bMSCs were loaded into the window defect with fibrin glue. Upon sacrifice of the rabbits at the different time points, the implant site of the patellar tendon was immediately retrieved and the viability of the labeled cells was assessed under confocal microscopy. The results showed that the seeded bMSCs remained viable within the tendon wound site for at least 8 weeks after implantation. The cell morphology was changed from a round shape at 2 weeks to a spindle shape at 5 weeks after implantation. This study demonstrated that the bMSCs remained viable for prolonged periods after implantation and therefore have the potential to influence the formation and remodeling of neotendon tissue after tendon repair. PMID- 28880657 TI - Analysis of Multivariables during Porcine Liver Digestion to Improve Hepatocyte Yield and Viability for Use in Bioartificial Liver Support Systems. AB - In order to achieve optimal BALSS function, preparation of porcine hepatocytes with high yield, viability, and P450 activity is known to be important. To date hepatocyte yields have varied from 0.58 * 1010 to 3.45 * 10 and viabilities from 75% to 95% within and between laboratories, even when using the same digestion methods and procedures, indicating that hepatocyte isolation during porcine liver digestion is not fully optimized. The aim of this work was to identify the critical parameters affecting cell recovery during porcine liver harvesting by investigating 21 variables involved in the process, including pig body and liver weight, different digestion times of perfusates, pH, a range of concentrations of sodium and chloride in EDTA, and collagenase perfusates. Univariate and multivariate analysis of a retrospective study (n = 23) revealed that low perfusate pH during the process of digestion had a positive effect on hepatocyte yield (p < 0.05), while high (relative) concentrations of sodium and chloride in the perfusates had significant negative effects on hepatocyte viability (both p < 0.05). Sodium and chloride had narrow optimal ranges for achieving a >90% viability. These findings were then tested in a prospective study (n = 10) and further verified. High hepatocyte viabilities (91.8 +/- 1.6%, p = 0.036) and yields (2.56 +/- 0.48 * 1010) were achieved consistently, and P450IA1 activity was increased after sodium and chloride concentrations and pH in the perfusates were controlled. The physiological mechanism by which sodium and chloride affects hepatocyte viability during porcine liver digestion is discussed. PMID- 28880658 TI - In Vivo Persistence of Donor Cells following Adoptive Transfer of Allogeneic Dendritic Cells in HIV-Infected Patients. AB - Peripheral blood samples from HIV-seropositive individuals enrolled in a pilot clinical trial investigating the use of allogeneic dendritic cell therapy were evaluated for mixed chimerism. In this study, dendritic cells from HLA-identical, HIV-seronegative siblings were used. Patients received an infusion of dendritic cells pulsed with HIV MN gp160 protein or with peptides from HLA-A2 restricted epitopes of env, gag, and pol proteins every month for 6-9 months. Of the five allogeneic dendritic cell recipients, two showed increases in HIV antigen specific immune responses. Allele-specific polymorphisms were identified in three sib-pairs that allowed infused donor cells to be detected using sensitive PCR based molecular methods. Analysis of blood samples from patients showed similar patterns of donor cell persistence after the first infusion, in that cells were detectable for at least 1 week. Also, differences were observed in the kinetics of cell survival between the first and subsequent infusion cycles in all three patients. This suggests variation in HIV-specific immune responses detected among these three patients was not due to differences in persistence of infused donor cells. PMID- 28880659 TI - Islet Cell Transplantation: In Vivo and in Vitro Functional Assessment of Nonhuman Primate Pancreatic Islets. AB - Transplantation of pancreatic islets of Langerhans as a therapeutic approach for treatment of type I diabetes offers an alternative to subcutaneous insulin injections. Normalization of blood glucose levels by transplanted islets may prevent the development of diabetes-related complications. Problems related to rejection, recurrence of autoimmunity, and local inflammation upon transplantation of islets into the liver need to be solved before the implementation of islet cell transplantation can be viewed as a justifiable procedure in a large cohort of patients. Islet cell isolation has been quite successful in small animals, but the translation of this approach to nonhuman primates has been less rewarding. One of the main problems encountered in nonhuman primate models is the difficulty of isolating an adequate number of functional islets for transplantation. The aim of the present study was to develop a method for isolating a sufficient number of viable islets from nonhuman primates to allow for reversal of diabetes. By implementing minor modifications in the automated method for human islet isolation we were able to obtain viable, functional islets that responded normally to glucose stimulation in vitro. These islets were also able to reverse diabetes in immunocompromised nude mice, rendered diabetic by streptozotocin. This method of islet cell isolation has enabled us to proceed with protocols of allogeneic islet cell transplantation in preclinical, nonhuman primate models. PMID- 28880662 TI - Cell Therapy '99: Introduction. PMID- 28880660 TI - Proceedings of the Meeting of the American Society for Neural Transplantation and Repair (ASNTR), 1999. PMID- 28880669 TI - Tribute to Dr. Thomas J. Walsh. PMID- 28880670 TI - Expansion of Hepatic and Hematopoietic Stem Cells Utilizing Mouse Embryonic Liver Explants. AB - Ex vivo embryonic liver explant culture is a novel and attractive approach to obtain abundant hepatic and hematopoietic stem cells. Gene therapy of autologous hepatic and hematopoietic stem cells represents an alternative therapeutic approach to liver transplantation for genetic and metabolic disorders. In this study we characterize the growth and differentiation of hepatic stem cells utilizing embryonic liver cultures. Day 9.5 liver buds are microdissected and cultured under specific conditions. Modulation of growth conditions by addition of hepatocyte growth factor, Flt-3 ligand, and stem cell factor leads to enrichment of hepatic progenitor cells in embryonic liver explants. Under these conditions, we also demonstrate the role of a novel marker PRAJA-1 to identify hepatic stem cells and transitional hepatocytes. Utilization of dexamethasone enhanced pseudolobule formation with increased hepatocytic and biliary differentiation. Transforming growth factor-beta leads to enrichment of biliary cells in the culture. Gut formation is enhanced in the presence of interleukin-3 and blood formation by increasing the mesodermal tissue in these cultures. We also show increased retroviral-mediated expression of the green fluorescent protein expression in the expanded hepatic and hematopoietic stem cells under different culture conditions. Thus, the embryonic liver explant culture is an attractive source for hepatic progenitors and is a possible step towards generating nontumorigenic immortalized hepatocytes with possible transplantation applications. PMID- 28880671 TI - A Coculture Model of Intrahepatic Islet Transplantation: Activation of Kupffer Cells by Islets and Acinar Tissue. AB - Clinical and experimental studies of intrahepatic islet transplantation have allowed histological and systemic observations to be made, but the location of the transplanted islets makes it difficult to assess direct effects on the cells of the liver. An in vitro coculture model of Kupffer cells with islets or pancreatic acinar tissue is described, using porcine tissue and measuring the secretion of thromboxane B2, prostaglandin E2, 6-keto-prostaglandin F1alpha, and prostaglandin F2alpha as an indicator of Kupffer cell stimulation. The results have demonstrated activation of Kupffer cells in the presence of acinar or islet tissue, both when the cells were in direct contact and when separated by a membrane. This indicated that the stimulation was due to a soluble factor or factors, and was confirmed by the culture of Kupffer cells with acinar conditioned medium. The degree of stimulation was much greater with acinar tissue than with islets. In subsequent experiments, aprotinin, an enzyme activation inhibitor, was added to the cocultures in an attempt to reduce Kupffer cell activation. This had no effect, possibly due to the fact that the endogenous pancreatic enzymes may already be activated during digestion of the pancreas. Aprotinin alone caused an increase in secretion of eicosanoids from Kupffer cells. The high response to acinar tissue is of particular relevance to islet autotransplantation in which unpurified pancreatic digest is often transplanted. The clinical effectiveness of aprotinin in the light of these results is discussed. In conclusion, although unable to mimic the complex situation following intrahepatic islet transplantation, the coculture model described here allows the opportunity to assess the events relating to specific cell types, and will provide the scope to undertake more detailed studies on the mechanisms involved. The same model could be applied to the coculture of pancreatic tissue with hepatocytes to determine any effects on the normal function of hepatocytes. PMID- 28880675 TI - Detection of Microbial Contamination during Human Islet Isolation. AB - Current good manufacturing practice (cGMP) islet processing facilities provide an ultraclean environment for the safe production of clinical grade islets for transplantation into immunosuppressed diabetic recipients. The objective of this study was to monitor the rate of microbial contamination in islet products after implementation of good manufacturing practice conditions. Fluid samples for microbial contamination were collected at the following steps: from the pancreas transport solution upon arrival of the organ (n = 157), after surface decontamination of the pancreas with antiseptic agents (n = 89), from islet supernatant at the end of the isolation (n = 104), and from islet supernatant as a final transplantable product after culture (n = 53). Bacterial, fungal, and mycoplasma cultures were conducted for 2, 2, and 3 weeks, respectively. Microbial contamination was detected in 31% of transport solution. The contamination was not associated with the presence of the duodenum during the preservation, cold ischemia time, or procurement team (local vs. distant). Surface decontamination of the pancreas resulted in clearance of 92% of the microbial contamination. Six preparations at the end of the isolation revealed microbial growth. All were de novo contamination during the processing. Fifty-three preparations that met our release criteria in terms of product sterility were transplanted into type 1 diabetic patients. In two instances, positive culture of the islet preparation was reported after transplantation had occurred. No patient showed any clinical findings suggestive of infection or any radiological abnormalities suggestive of abscess; a single dose of antibiotic coverage was given routinely to recipients prior to islet infusion. Although transport solution carries a high risk of microbial contamination, most contaminants become undetectable during islet processing. Microbial contamination in final products is rare, but de novo contamination still occurs during processing even under cGMP conditions. PMID- 28880672 TI - Apoptosis Occurs in Isolated and Banked Primary Mouse Hepatocytes. AB - Isolation and cryopreservation of freshly isolated hepatocytes is considered a standard procedure for the long-term storage of liver cells. However, most existing methods for banking hepatocytes do not allow sufficient recovery of viable cells to meet the needs of basic research or clinical trials of hepatocyte transplantation. The mechanisms underlying this poor rate of hepatocyte recovery are unknown. Although much of the cellular damage in freezing is caused by formation of ice crystals within the cells, this is largely prevented by the use of dimethyl sulfoxide (DMSO) and controlled rate freezing. As we demonstrated recently, necrosis does occur in primary hepatocytes following isolation and cryopreservation. In the present study, we explored the contribution of apoptosis, another form of cell death, in primary hepatocytes banked for transplantation. We evaluated apoptosis of C57BL/6J mouse primary hepatocytes using several different methods. Annexin binding and the TUNEL assay, in conjunction with flow cytometry and confocal laser scanning microscopy, revealed that the percentage of apoptotic cells was dramatically elevated in cryopreserved cells compared with that in the control group of unfrozen cells. DNA laddering detected by DNA electrophoresis in agarose gel also supported the presence of apoptosis in isolated and banked liver cells. Moreover, we found that the addition of glucose (from 10 to 20 mM) into the freezing solution (University of Wisconsin Solution) decreased the rate of apoptosis by 84% and improved the cell attachment at least fourfold in cryopreserved cells. These results suggest that apoptosis might contribute to cell death in isolated and banked primary hepatocytes. PMID- 28880676 TI - Factors Influencing the Loss of beta-Cell Mass in Islet Transplantation. AB - Recent advances in clinical islet transplantation have clearly demonstrated that this procedure can provide excellent glycemic control and often insulin independence in a population of patients with type 1 diabetes. A key limitation in the widespread application of clinical islet transplantation is the requirement of 10,000 islet equivalents/kg in most recipients, generally derived from two or more cadaveric donors. It has been determined that a majority of the transplanted islets fail to engraft and become fully functional. In this review article, the factors that contribute to this early loss of islets following transplantation are discussed in depth. PMID- 28880677 TI - Functional and Phenotypic Alteration of Intrasplenic Lymphocytes Affected by Mesenchymal Stem Cells in a Murine Allosplenocyte Transfusion Model. AB - Previous data have demonstrated that mesenchymal stem cells (MSCs) can exert immunomodulatory activity in vitro, in which of the process nearly all kinds of immune cell subsets are involved. However, there is still a paucity of information about whether and why MSCs inhibit the ongoing immune responses in vivo. Working in a murine splenocyte transfusion model across the major histocompatibility barrier (C57BL/6 -> BALB/c, H2b -> H2d), we have found that MSC coinfusion prolongs the mean survival time (MST) of the recipient mice in a dose-dependent manner and reduces graft-versus-host-associated histopathology in comparison to the allosplenocyte transfusion controls. In vivo eGFP tracing with polymerase chain reaction analysis revealed that grafted MSCs could migrate and settle into the lungs, spleen, liver, intestine, and skin shortly after administration. Further investigations into the functional characteristics of intrasplenic lymphocytes showed that their proliferation and cytotoxic activity against P815 cells (H2d) were significantly restrained by MSC cotransfer. FACS analysis demonstrated that MSC infusion not only increased the proportion of CD4+ subset but also decreased that of CD8+ cells at the belated observation points, resulting in the increase of the ratio of CD4+/CD8+ cells. Also, in contrast to the slight increase of the proportion of CD4+CD25+ T regulatory cells (Tregs) in MSC cotransfer mice, the ratio of Tregs/CD8+ cells was dramatically elevated. Furthermore, RT-PCR analysis on the cytokine array of IL-2, IL-4, IL-12, TNF alpha, and TGF-beta in recipient splenocytes implied the Th1 to Th2 polarization. Therefore, it is deducible that alteration in the proportions of different T lymphocyte subsets may be one of the main mechanisms by which grafted MSCs suppress the ongoing immune responses in vivo. The study here might provide some new clues for the design of therapeutic approaches for MSC transplantation. PMID- 28880678 TI - Assault-related mild traumatic brain injury, expectations of injury outcome, and the effect of different perpetrators: A vignette study. AB - Few studies have examined the effect of varying the assault perpetrator on expectations of outcome from mild TBI. Using a cross sectional between groups design, individuals with no history of mild TBI were randomly allocated to one of two vignette conditions. The vignette depicted a mild TBI with fixed injury parameters and a different assault perpetrator (partner, n = 27; or stranger, n = 27). The participants were instructed to imagine that they had been injured as per the depiction, and then to anticipate the injury consequences 6-months later. An online questionnaire was used including: the Neurobehavioral Symptom Inventory, the Posttraumatic Stress Disorder Checklist-Civilian Version, the Impact of Events Scale-Revised, and the Perceived Ability to Cope with Trauma. The depicted injury was rated for the extent to which it was perceived as life threatening, the subsequent diagnosis, and the global recovery prospects. The anticipated consequences of the injury (symptoms and trauma variables) did not differ across the conditions, all p's > 0.05. The expected outcomes for an assault-related mild TBI were not affected by perpetrator type. However, the study had several limitations and further consideration of this factor may still be warranted. PMID- 28880679 TI - Application of nanocarrier-based drug delivery system in treatment of oral cancer. AB - Oral cancer includes cancer of lips, oral cavity and oropharynx. Oral cancer is the sixth most life-threatening disease affecting 65% of population. The delivery of cytotoxic chemotherapeutic anticancer drugs is a challenging task due to unfavorable properties. Both synthetic chemotherapeutic agents and herbal constituents are used in treatment of oral cancer. The purpose of present article is to overcome the limitations through concept of nanotechnology and conjugation approach. Also, it will provide better therapeutic effect and sustain long life of healthy and recovered cells. Moreover, development in this area will raise opportunities for the oncologist, researchers and pharmaceutical scientists. This review summarizes the clinical findings and patents on various oral anticancer drugs for effective pharmacotherapeutics. PMID- 28880680 TI - The effect and possible clinical efficacy of in vivo inhibition of neutrophil extracellular traps by blockade of PI3K-gamma on the pathogenesis of microscopic polyangiitis. AB - OBJECTIVE: Neutrophil extracellular traps (NETs) are peculiar structures composed of the externalized chromatin with intracellular proteins and formed by activated neutrophils in a reactive oxygen species (ROS)-dependent manner. Aberrant NETs are considered to be autoantigens for anti-neutrophil cytoplasmic antibodies (ANCAs) underling the development of microscopic polyangiitis (MPA). However, little is known regarding the therapeutic efficacy of in vivo inhibition of NET formation (NETosis) on MPA pathogenesis. This study determines whether reducing NETosis prevents ANCA production and improves characteristic involvement. METHODS: A mouse model of MPA induced by administering a novel extract from Candida albicans was devised. By applying this method to mice lacking phosphoinositide 3-kinase gamma (PI3K-gamma), which is indispensable for ROS production in neutrophils, we investigated the levels of in vivo NETs, ANCA titers and histological damage. RESULTS: Our model exhibited accumulation of NETs in vivo, elevation of ANCA titers and characteristic pathologies mimicking human MPA, including small-vessel vasculitis and crescentic glomerulonephritis. Strikingly, these abnormalities were reduced by genetically and/or pharmacologically blocking PI3K-gamma. Moreover, a pharmacological PI3K-gamma blockade decreased the levels of human NETs. CONCLUSION: Our results suggest that in vivo inhibition of NETosis by blocking PI3K-gamma could be a promising therapeutic strategy for the pathogenesis of MPA. PMID- 28880681 TI - Synthesis and antioxidant properties of Lycium barbarum polysaccharides capped selenium nanoparticles using tea extract. AB - Selenium nanoparticles (SeNPs) have attracted increasing interest over the last decades because of their activities on redox balance in human body. However, the SeNPs tend to aggregate into large clusters, resulting in lower bioactivity, bioavailability and biocompatibility. Surface-capping agents on SeNPs play crucial roles in its stabilization and biological activity. Here, a green synthesis method for the preparation of Lycium barbarum polysaccharides capped SeNPs using green tea extracts as reductants under mild conditions, at room temperature, is reported. The structure, size, morphology and thermal behaviour were analyzed by various characterization techniques. The functionalized nanoparticles demonstrated high antioxidant activity, including DPPH and ABTS free radical scavenging. Moreover, the SeNPs significantly protected the H2O2 induced PC-12 cell death. Taken together, these results evidence the possible application of these SeNPs as antioxidants food supplement or ingredient and neuroprotective agent. PMID- 28880682 TI - Investigating patterns of memory impairment in ischemic stroke in an iranian population. AB - Up until the date of this research, studies have examined poststroke cognitive impairments in attention, memory, and executive functions. In this study, we investigated the occurrence of memory problems in various patterns of memory in ischemic stroke patients in an attempt to determine specific memory profiles of the patients. The goal was to determine the severity and patterns of memory impairments in ischemic stroke patients and to identify specific profiles of memory impairments in stroke patients, in order to help therapists to develop more appropriate memory rehabilitation programs for the patients. The sample consisted of 35 patients with ischemic stroke. Thirty-five individuals who were matched with the patients were selected as the control group. Demographic questionnaires, subscales of the Wechsler Memory Scale-III (WMS-III), including logical memory I and II and visual reproduction I and II, digit span from the Wechsler Adult Intelligence Scale-R (WAIS-R), and the Corsi span test were administered to both of the patients and control groups. Multivariate analysis of covariance (MANCOVA) was carried out to unveil possible differences in memory between the two groups. The mean scores of different memory patterns were significantly higher in the control group comparing to the patient group (p < 0.05). Among different aspects of memory, visual long-term memory and visual short-term memory had the largest effect sizes. Substantial impairments were also found in visual short-term memory, visuospatial short-term memory, and visual long-term memory. The findings suggest that the stroke patients have identifiable patterns of memory impairment. PMID- 28880683 TI - RANKL: A therapeutic target for bone destruction in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Recent studies have indicated the critical involvement of osteoclasts in bone destruction in RA. The osteoclast differentiation factor receptor activator of NF-kappaB ligand (RANKL), which belongs to the tumor necrosis factor superfamily, plays a critical role in osteoclast differentiation and bone destruction in RA. Denosumab, an antibody against human RANKL, efficiently suppressed the progression of bone erosion in RA patients in randomized controlled studies, and is considered as a putative therapeutic option for preventing bone destruction in RA. PMID- 28880684 TI - Reduction of methotrexate and glucocorticoids use after the introduction of biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis in daily practice based on the IORRA cohort. AB - OBJECTIVES: To evaluate usage patterns for methotrexate (MTX) and/or glucocorticoids in rheumatoid arthritis (RA) patients receiving biological disease-modifying antirheumatic drugs (bDMARDs) in daily practice. METHODS: Data from RA patients who commenced treatment with bDMARDs (infliximab [IFX], etanercept [ETN], tocilizumab [TCZ], or adalimumab [ADA]) from 2008 to 2010 were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. The proportions of patients taking concomitant MTX and glucocorticoids and doses of these medications were evaluated before and 2 years after initiation of each bDMARD. RESULTS: A total of 470 RA patients who had initiated a bDMARD (IFX: n = 98, ETN: n = 181, TCZ: n = 90, and ADA: n = 101) were evaluated. The proportion of patients taking MTX decreased over time among ETN and TCZ users, while it increased among ADA users. The MTX dose decreased over time among IFX, ETN, and TCZ users, but not among ADA users. Although the rate of glucocorticoid use and dose decreased after bDMARD initiation in all four bDMARD groups, approximately 50% of patients continued to receive glucocorticoids 2 years after bDMARD initiation. CONCLUSION: MTX and glucocorticoid use and doses in daily practice were commonly reduced after the initiation of bDMARDs, with the dose adjustment varied depending on the bDMARD. PMID- 28880685 TI - Tydeman tube for impacted foetal head at caesarean section: Some concerns and suggestions. PMID- 28880686 TI - Preliminary evidence of attenuated blood pressure reactivity to acute stress in adults following a recent marital separation. AB - OBJECTIVE: This study explores cardiovascular reactivity during an acute-stress task in a sample of recently separated adults. DESIGN: In a cross-sectional design, we examined the association between adults' subjective separation-related distress and changes in heart rate and blood pressure across the acute-stress laboratory paradigm in a sample of 133 (n = 49 men) recently separated adults. MAIN OUTCOME MEASURES: Heart rate (HR) and Blood pressure (BP) were recorded across a resting baseline period, a math stressor task, and a recovery period. RESULTS: Multilevel analyses revealed that adults who reported greater separation related distress exhibited higher initial BP and a slower linear increase in BP across the study period. In addition, adults reporting greater separation-related distress evidenced significantly slower declines in diastolic blood pressure (DBP) following the acute-stress task. HR reactivity was not moderated by separation-related distress. CONCLUSIONS: In recently separated adults, preliminary evidence suggests that the context of the stressors may reveal differential patterns of problematic reactivity (exaggerated or blunted responding). Greater emotional intrusion and hyperactivity symptoms may index increased risk for blunted cardiovascular reactivity to general stressors. This pattern of reactivity is consistent with models of allostatic load that emphasise the deleterious effect of hyporesponsivity to environmental demands. PMID- 28880687 TI - TNF-alpha potentiates uric acid-induced interleukin-1beta (IL-1beta) secretion in human neutrophils. AB - OBJECTIVE: Monosodium urate (MSU) has been shown to promote interleukin-1beta (IL 1beta) secretion in human monocytes, but the priming signals for NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway remains elusive. In this study, we investigated the role of Tumor necrosis factor-alpha (TNF-alpha) on MSU-mediated IL-1beta induction in human neutrophils. METHODS: Human neutrophils were stimulated with MSU, in the presence or absence of TNF alpha priming. The cellular supernatants were analyzed for IL-1beta, IL-18, and caspase-1 by enzyme-linked immunosorbent assay (ELISA) methods. Pro-IL-1beta mRNA expressions in human neutrophils were analyzed by real-time PCR method. RESULTS: TNF-alpha stimulation induced pro-IL-1beta mRNA expression; however, MSU stimulation did not induce pro-IL-1beta mRNA expression in human neutrophils. TNF alpha alone or MSU stimulation did not result in efficient IL-1beta secretion in human neutrophils, whereas in TNF-alpha-primed neutrophils, MSU stimulation resulted in a marked IL-1beta and IL-18 secretion. TNF-alpha-primed neutrophils secreted cleaved caspase-1 (p20), in response to MSU stimulation. CONCLUSION: Our data demonstrate that priming of human neutrophils with TNF-alpha promotes uric acid-mediated IL-1beta secretion in the absence of microbial stimulation. These findings provide insights into the neutrophils-mediated inflammatory processes in gouty arthritis. PMID- 28880688 TI - Neonatal rat age, sex and strain modify acute antioxidant response to ozone. AB - Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US and its impact continues to increase in women. Oxidant insults during critical periods of early life appear to increase risk of COPD through-out the life course. To better understand susceptibility to early life exposure to oxidant air pollutants we used Fisher (F344), Sprague-Dawley (SD) and Wistar (WIS) male and female neonatal rat pups to assess: (A) if strain (i.e. genetics), sex, or stage of early life development affected baseline lung antioxidant or redox enzyme levels and (B) if these same factors modulated antioxidant responsiveness to acute ozone exposure (1 ppm * 2 h) on post-natal day (PND) 14, 21, or 28. In air-exposed pups from PND14-28, some parameters were unchanged (e.g. uric acid), some decreased (e.g. superoxide dismutase), while others increased (e.g. glutathione recycling enzymes) especially post-weaning. Lung total glutathione levels decreased in F344 and SD pups, but were relatively unchanged in WIS pups. Post-ozone exposure, data suggest that: (1) the youngest (PND14) pups were the most adversely affected; (2) neonatal SD and WIS pups, especially females, were more prone to ozone effects than males of the same age and (3) F344 neonates (females and males) were less susceptible to oxidative lung insult, not unlike F344 adults. Differences in antioxidant levels and responsiveness between sexes and strains and at different periods of development may provide a basis for assessing later life health outcomes - with implications for humans with analogous genetic or dietary-based lung antioxidant deficits. PMID- 28880689 TI - Prodromal signs and symptoms of serious infections with tocilizumab treatment for rheumatoid arthritis: Text mining of the Japanese postmarketing adverse event reporting database. AB - OBJECTIVE: To search for signs and symptoms before serious infection (SI) occurs in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients. METHODS: Individual case safety reports, including structured (age, sex, adverse event [AE]) and unstructured (clinical narratives) data, were analyzed by automated text mining from a Japanese post-marketing AE-reporting database (16 April 2008 10 April 2015) assuming the following: treated in Japan; TCZ RA treatment; >=1 SI; unable to exclude causality between TCZ and SIs. RESULTS: The database included 7653 RA patients; 1221 reports met four criteria, encompassing 1591 SIs. Frequent SIs were pneumonia (15.9%), cellulitis (9.9%), and sepsis (5.0%). Reports for 782 patients included SI onset date; 60.7% of patients had signs/symptoms <=28 days before SI diagnosis, 32.7% had signs/symptoms with date unidentified, 1.7% were asymptomatic, and 4.9% had unknown signs/symptoms. The most frequent signs/symptoms were for skin (swelling and pain) and respiratory (cough and pyrexia) infections. Among 68 patients who had normal laboratory results for C-reactive protein, body temperature, and white blood cell count, 94.1% had signs or symptoms of infection. CONCLUSION: This study identified prodromal signs and symptoms of SIs in RA patients receiving TCZ. Data mining clinical narratives from post-marketing AE databases may be beneficial in characterizing SIs. PMID- 28880690 TI - Cognitive intervention for early stage dementia: Research and techniques. AB - : Dementia is a growing world-wide phenomenon, impacting more than six million people in the United States. Despite its high projected prevalence, it is a significantly under-estimated phenomena, with estimates ranging from 15 to 25% of the current U.S. POPULATION: The effect of the aging of the population and significant increase in life expectancy has combined to catapult dementia into the range of one of world's most alarming healthcare problems. Diverse and emerging literature in the area of cognitive prevention/intervention for mild cognitive impairment (MCI)/early stage dementia will be reviewed. Additionally, future research and clinical directions will be explored. PMID- 28880691 TI - Changes in serum interleukin-6 levels as possible predictor of efficacy of tocilizumab treatment in rheumatoid arthritis. AB - OBJECTIVES: We aimed to evaluate the association between the change in serum IL-6 during the clinical course of tocilizumab (TCZ) therapy and rheumatoid arthritis (RA) disease activity or occurrence of adverse events. METHODS: General laboratory data including serum IL-6 levels and physical findings were obtained every 4 weeks, and, in addition, at the time when any adverse events occurred. RESULTS: The proportion achieving Clinical Disease Activity Index (CDAI) remission at 52 weeks was significantly lower in 20 patients with serum IL-6 >= 30 pg/ml at 12 weeks than 24 patients with serum IL-6 < 30 pg/ml. In 17 patients with serum IL-6 >= 30 pg/ml at 24 weeks, the proportion achieving CDAI remission was also significantly lower than 27 patients with serum IL-6 < 30 pg/ml then. In these 17 patients, Disease Activity Score (DAS) 28-ESR and CDAI at 52 weeks were significantly higher than those with serum IL-6 < 30 pg/ml. Age- and sex-adjusted logistic regression analysis showed logIL-6 at 12 weeks to be a predictive factor for DAS28-ESR remission at 52 weeks. CONCLUSION: Serum IL-6 levels from 12 to 24 weeks after TCZ initiation better reflect the efficacy of TCZ at 52 weeks. PMID- 28880692 TI - Clinical outcome of pregnancies with the prenatal double bubble sign - a five year experience from one single centre in mainland China. AB - The aim of this study was to describe the risk of aneuploidy, associated structural anomalies and clinical outcome in pregnancies with the prenatal double bubble sign. A retrospective study on ultrasound reports and pregnancy outcomes was performed in 71 foetuses with double bubble sign, who were examined at the Guangzhou Women and Children Medical Center during a five-year period. Forty-nine patients had the regular prenatal care since first trimester; of these, 20 had the sonographic sign before 24 weeks and the remaining 29 had the sonographic diagnosis after 24 weeks. Twenty-two patients presented beyond 24 weeks and the sonographic diagnosis was late. Fetal trisomy 21 was found in one of the 49 patients who had early and regular prenatal visits, but was confirmed in six out of the 22 patients who had late prenatal care. Only one out of the 49 cases had additional malformation. In the 22 subset cases, seven had additional malformations. Two pregnancies ended in intrauterine foetal demise and five patients opted for termination of pregnancy because of additional anomalies or abnormal karyotype. There were 63 live births. Postnatal verification revealed duodenal obstruction secondary to intrinsic or extrinsic cause in 60 cases; three cases excluded duodenal obstruction. The implementation of first trimester screening programme has significantly reduced the number of duodenal obstruction cases with trisomy 21 and associated malformations. Impact statement What is already known on this subject: The double bubble sign is strongly indicative of duodenal atresia. More than one-half of foetuses with duodenal atresia have associated anomalies, especially trisomy 21. What the results of this study add: The clinical outcome of foetuses with double bubble sign was first reported in mainland China. The implementation of first trimester screening programme has significantly reduced the number of duodenal atresia cases with trisomy 21 and associated malformations. What the implications are of these findings for clinical practice and/or further research: The early diagnosis of duodenal obstruction, as well as of other associated anomalies, will allow complementary investigation, immediate and proper care at birth and family counselling. PMID- 28880693 TI - Clinical features and radiological findings of 67 patients with SAPHO syndrome. AB - OBJECTIVES: The purpose of this study was to facilitate the understanding of the SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis) syndrome by analyzing the clinical and radiological features of 67 Japanese patients with SAPHO syndrome. METHODS: Sixty-seven Japanese patients (female/male: 44/23, mean age at onset: 48.5 years) were diagnosed with SAPHO syndrome from 2002 to 2013 at our hospital. Medical records and radiological imaging of these patients were retrospectively reviewed. RESULTS: Among the 67 patients, 41 had dermatological manifestations, such as palmoplantar pustulosis, acne, and psoriasis. Initial symptom was local pain in all patients, and the most common initial site of the symptom was the anterior chest. Bacterial and fungal cultures from 20 bone biopsies were all negative. Histopathological diagnosis of the specimens was non specific inflammation in all cases. Bone lesions were observed in 65 patients (97.0%). On the other hand, articular lesions including enthesitis were found in 31 patients (46.2%). CONCLUSION: SAPHO syndrome had different clinical and radiological aspects. The clinical features were not remarkable, except the dermatological manifestations and the involvement of the anterior chest. Bone lesions including hyperostosis and osteitis were found radiographically in the majority of patients with SAPHO syndrome. These are the characteristics of the SAPHO syndrome, with the exclusion of other bone diseases. PMID- 28880695 TI - Influences on students' assistive technology use at school: the views of classroom teachers, allied health professionals, students with cerebral palsy and their parents. AB - PURPOSE: This study explored how classroom teachers, allied health professionals, students with cerebral palsy, and their parents view high-tech assistive technology service delivery in the classroom. METHODS: Semi-structured interviews with six classroom teachers and six parents and their children were conducted. Additionally, two focus groups comprising 10 occupational therapists and six speech pathologists were carried out. Ethical and confidentiality considerations meant that the groups were not matched. RESULTS: Results revealed that it is often untrained staff member who determine students' educational needs. The participants' experiences suggested that, particularly in mainstream settings, there is a need for support and guidance from a professional with knowledge of assistive technology who can also take a lead and guide classroom teachers in how to meet students' needs. Students' motivation to use the technology was also found to be critical for its successful uptake. CONCLUSIONS: The study points to the need for classroom teachers to be given sufficient time and skill development opportunities to enable them to work effectively with assistive technology in the classroom. The participants' experiences suggest that such opportunities are not generally forthcoming. Only in this way can it be ensured that students with disabilities receive the education that is their right. Implications for Rehabilitation Classroom teachers, allied health professionals, students, parents need ongoing support and opportunities to practise operational, strategic and linguistic skills with the assistive technology equipment. System barriers to the uptake of assistive technology need to be addressed. To address the lack of time available for training, programing and other support activities around assistive technology, dedicated administrative support is crucial. Professional development around the use of the quality low cost ICF-CY checklist is recommended for both school and allied health staff. PMID- 28880694 TI - Pronounced decline of serum HBsAg in chronic hepatitis B patients with long-term effective nucleos(t)ide analogs therapy. AB - AIMS: This study aims to investigate the kinetics of serum HBsAg levels in chronic hepatitis B patients with long-term nucleos(t)ide analogs (NAs) therapy. METHODS: This was a retrospective clinical study. Serum HBsAg in serial samples of 94 patients, who received at least 8 years of NAs therapy, were measured using Elecsys(r) HBsAg II Quant Assay. RESULTS: In this cohort, serum HBsAg levels reduced from 3.80 log10 IU/mL at baseline to 2.72 log10 IU/mL at year 8 (p < .001), and the percentage of patients with HBsAg <1000 IU/mL increased from 14.9% at baseline to 55.3% at year 8 (p < .001). The reduction of serum HBsAg did not differ significantly between patients stratified by baseline virological parameters and type of antiviral agents. But as compared to patients without HBeAg seroconversion, HBsAg levels were significant lower in patients with HBeAg seroconversion (3.19 vs. 2.47 log10 IU/mL at year 8, p = .001). As compared to patients with slow (0-1 log10 IU/mL) or steady HBsAg(<=0 log10 IU/mL) decline at year 1, patients with a rapid HBsAg (>=1 log10 IU/mL) decline had a significantly lower HBsAg levels from year 2 to 8. However, Cox regression analysis showed that only absolute HBsAg levels at year 1 was an independent predictor of subsequent HBsAg <1000 IU/mL at year 8 of antiviral therapy(HR 0.242, p = .004). CONCLUSION: Pronounced HBsAg declines could be achieved in patients after long-term effective therapy with NAs, and on-treatment low serum HBsAg level at year 1 might be a predictor of serum HBsAg <1000 IU/mL at year 8. PMID- 28880696 TI - Sex-discordant monochorionic dizygotic twins: a case report. PMID- 28880697 TI - Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan. AB - OBJECTIVES: To determine the tentative diagnostic criteria and disease severity classification for Castleman disease (CD) and describe the clinical and pathologic features among human herpesvirus 8 (HHV-8) negative idiopathic multicentric CD (iMCD) in the Japanese population. METHODS: We established the working groups for the research of CD in Japan and had meetings to discuss and define the tentative diagnostic criteria and disease severity classification for CD. We subsequently analyzed 142 patients classified into iMCD by using the nationwide Japanese patient registry. RESULTS: We proposed the preliminary diagnostic criteria and disease severity classification for CD based on our discussion. In addition, we made a proposal for the disease activity score. We identified clinical and pathological features of patients with iMCD diagnosed by these diagnostic criteria. In the disease severity classification, 37, 33 and 30% patients were categorized into mild, moderate and severe diseases, respectively. CONCLUSION: This is the first proposal for diagnosis and classification of CD by the Japanese group. Further studies are required to validate whether they can distinguish CD from other inflammatory diseases and to determine their sensitivity and specificity. PMID- 28880699 TI - Mobile ECMO - A divine technology or bridge to nowhere? AB - INTRODUCTION: Extracorporeal life support emerged as a salvage option in patients with therapy-refractory severe hemodynamic or respiratory failure. However, this promising therapy option has been limited by the use of experienced teams in highly specialized tertiary-care centers. Thus, in order to provide this standard of care in local hospitals and due to increasing evidence on improved outcomes using ECMO devices and setting for patients with heart and lung failure, an increasing number of experienced ECMO centers have launched mobile ECMO retrieval services in recent years. Areas covered: This review provides a summary on the current scientific status concerning use, indications and complications of mobile ECMO devices and services. A scientific literature research was conducted in MEDLINE, Embase, Cochrane and Web of Science databases using keywords denoted. Expert commentary: Mobile ECMO devices and setting offer severely ill patients refractory to maximal conventional treatment an option of hemodynamic and/or respiratory stabilization and subsequent transportation to specialized care centers for further treatment. Compared to in-hospital ECMO support, out-of hospital mobile ECMO implantation, transport and retrieval of patients require additional organizational, logistical and clinical efforts. This review provides a summary on the current scientific status concerning use, indications and complications of mobile ECMO services. PMID- 28880698 TI - Cost-effectiveness of a chronic pain intervention for people living with HIV (PLWH). AB - BACKGROUND: Chronic pain is a common, disabling, and costly comorbidity, particularly in people living with HIV (PLWH). This study developed and pilot tested a pain self-management intervention for chronic pain tailored to PLWH called Skills TO Manage Pain (STOMP). OBJECTIVES: Given the additional resources needed to deliver STOMP in HIV clinical settings, an important objective of the pilot study was to assess not only STOMP's preliminary efficacy, but also its cost-effectiveness. RESEARCH DESIGN AND SUBJECTS: The present study draws from a 44-participant, 2-arm randomized pilot trial of the STOMP intervention vs usual care among PLWH and at least moderate chronic pain (Clinicaltrials.gov: NCT02824562). Cost-effectiveness is presented as the incremental cost effectiveness ratio (ICER). Costs were considered from the clinic perspective over a 1-year time horizon using real costs from the pilot trial. It was conservatively assumed there would be no costs savings. The Standard Gamble (SG) method was used to directly measure utilities. RESULTS: Thirty-six participants met inclusion criteria for the present analyses. Mean age was 52 years; 61% were female and 86% were black. The total cost of STOMP was $483.83 per person. Using the SG method, the change in QALYs was 0.15, corresponding to an ICER of $3,225. CONCLUSIONS: STOMP's cost/QALY is substantially lower than the $50,000 to $100,000/QALY benchmark often used to indicate cost-effectiveness. Although based on a pilot trial and, therefore, preliminary, these findings are promising, and suggest the importance of cost analyses in future STOMP trials. PMID- 28880701 TI - ? PMID- 28880700 TI - Anti-Ro52 antibody level is an important marker of fetal congenital heart block risk in anti-Ro/SSA antibody positive pregnancy. AB - OBJECTIVE: The aims of this study are to determine the incidence of congenital heart block (CHB) in the Japanese population and identify maternal factors predicting fetal CHB in anti-Ro/SSA antibody positive pregnancy. METHODS: A retrospective study was performed using 52,147 clinical records of pregnancies followed in a single center. For 183 anti-Ro/SSA antibody-positive women, anti Ro52 and Ro60 antibodies were measured, and the odds of CHB in relation to maternal clinical features were calculated by multivariate analysis. The receiver operating characteristic (ROC) curves for predicting CHB were constructed for the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies. RESULTS: Fetal CHB occurred in two pregnancies among those without known risks such as positive anti Ro/SSA antibody or previous CHB-affected pregnancy, suggesting an incidence similar to that in Caucasian populations. As for the anti-Ro/SSA antibody positive pregnancies, the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies were independent risk factors for fetal CHB and the use of corticosteroids before 18 gestational weeks was an independent protective factor. The area under the ROC was 0.84, 0.73 and 0.74 for anti-Ro52, anti-Ro60 and anti Ro/SSA antibodies, respectively. CONCLUSION: CHB occurred in two among approximately 50,000 pregnancies without known risks such as positive anti-Ro/SSA antibody or previous delivery of CHB-affected babies. Measurement of anti-Ro52 antibody levels may be helpful in extracting a risk group of delivering CHB infants in the anti-Ro/SSA antibody positive pregnancy. PMID- 28880702 TI - The Feasibility and Validity of Body-Worn Sensors to Supplement Timed Walking Tests for Children with Neurological Conditions. AB - AIMS: The 10-meter walk test (10 mWT) and Timed Up and Go (TUG) are assessments of speed/time with a ceiling effect in pediatric populations. This study aimed to (1) determine whether collecting spatiotemporal data with inertial sensors (Mobility Lab, APDM Inc.) during these tests improves their discriminative validity, and (2) evaluate the clinical feasibility of Mobility Lab. METHODS: Fifteen children with spina bifida (SB) or cerebral palsy (CP) (7.9 +/- 3.1 years old) and fifteen age- and sex-matched typically-developing (TD) children completed the 10 mWT and TUG wearing Mobility Lab. Spatiotemporal data were compared between groups. Mobility Lab's potential to distinguish children with SB/CP from TD children was examined using conditional logistic regression. Feasibility was evaluated through participant adherence and a clinical utility scale. RESULTS: For the 10 mWT, group differences (p < 0.01) were found in horizontal and frontal trunk range of motion, horizontal trunk velocity, and swing asymmetry. Children with SB/CP took significantly longer to turn during the TUG. These five variables together distinguished the two groups (p = 0.006). 78% of participants with SB/CP completed the testing protocol. Mobility Lab scored 4/10 on the clinical utility scale. CONCLUSIONS: Instrumenting the 10 mWT and TUG improves the tests' ability to discriminate between children with SB/CP and TD children. PMID- 28880703 TI - The association between surgical complications and the POSSUM score in head and neck reconstruction: a retrospective single-center study. AB - The Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM) is widely used to predict surgical complications affecting various organs. However, there are few reports about objective evaluation methods for head and neck surgery. In this study, we retrospectively examined the association between POSSUM score and actual surgical complications of head and neck reconstruction surgery. In total, 711 patients who underwent head and neck reconstruction after cancer extirpation between January 2007 and January 2015 were studied. The predicted risk of complications was calculated using the POSSUM score and compared with the actual rate of perioperative complications. Perioperative complications occurred in 178 (25%) patients, comprising systemic complications in 52 (7%) patients, surgical site infection of the head and neck area in 78 (11%) patients and failure of the free flap in 55 (8.8%) patients. When patients were divided into a perioperative complication group and a no complication group, a significant difference between the two groups was observed in the predicted postoperative rate calculated from the POSSUM score (p < .0001, odds ratio 1.03, 95% confidence interval = 1.02-1.04). Furthermore, the cutoff value of the POSSUM score calculated from the receiver operating characteristic curve using Youden's index was 43.0%. POSSUM is a useful risk indicator for head and neck reconstruction surgery. It is possible to objectively calculate the prediction level using a standard assessment method without adding burden to any medical facility. Therefore, patients may be considered at high risk for perioperative complications when the POSSUM score is 43.0% or higher. PMID- 28880704 TI - Sample Size Estimation for the U.S. Food and Drug Administration's In Vitro Population Bioequivalence Test of DPIs, MDIs, Nasal Sprays, and Nebules. PMID- 28880706 TI - Identification of cellular responses to low-dose radiation by the profiling of phosphorylated proteins in human B-lymphoblast IM-9 cells. AB - PURPOSE: The aim of this study was to explore the potential for radiation specific signaling of various LDIR-induced effects in human B-lymphoblast IM-9 cells. MATERIALS AND METHODS: Human lymphoblast IM-9 cells were exposed to ionizing radiation at 0.1 and 2 Gy using a 137Cs gamma-irradiator at a dose rate of 0.8 Gy/min. Cell viability and DNA fragmentation were determined using MTT assay and TUNEL assay at 24 h after irradiation. Profiling of protein phosphorylation by radiation was identified using a phospho-antibody array at 4 h after irradiation and Dataset of the profiling was analyzed by IPA. RESULTS: Cell survival and apoptotic signaling were not affected by 0.1 Gy of radiation, whereas 2 Gy induced cellular damage. The analysis of low-dose ionizing radiation (LDIR) or high-dose ionizing radiation (HDIR)-specific responses by IPA generated different results. Various cell maintenance functions were only apparent following the analysis of increased protein phosphorylation by LDIR, whereas several cancer formation- and development-related functions were only detected following the analysis of increased protein phosphorylation by HDIR. CONCLUSIONS: The LDIR-induced protein phosphorylation patterns might be involved in various cell survival responses or cellular maintenance functions, which provide important insight into our understanding of the different effects of LDIR and HDIR. PMID- 28880705 TI - Healthcare Access and Cancer Screening Among Victims of Intimate Partner Violence. AB - BACKGROUND: Intimate partner violence (IPV) victims often experience substantial and persistent mental and physical health problems, including increased risk for chronic disease and barriers to healthcare access. This study investigated the association between IPV and cancer screening. MATERIALS AND METHODS: Behavioral Risk Factor Surveillance System data from the eight states and one U.S. territory that administered the optional IPV module in 2006 were analyzed to examine demographic characteristics, health behaviors, health status, healthcare coverage, use of health services, and cancer screening among men and women who reported IPV victimization compared with those among men and women who did not. IPV victimization included physical violence, threats, and sexual violence. RESULTS: In the nine jurisdictions that administered the IPV module, 23.6% of women and 11.3% of men experienced IPV. Fewer women and men reporting IPV victimization had health insurance, a personal doctor or healthcare provider, or regular checkups within the past 2 years than nonvictims. More male and female IPV victims were current tobacco users and engaged in binge drinking in the past month. IPV victims of both sexes also had poorer health status, lower life satisfaction, less social and emotional support, and more days with poor physical and mental health in the past month than nonvictims. IPV victimization was associated with lower rates of mammography and colorectal cancer screening but not cervical cancer screening in women and was not associated with colorectal cancer screening in men. In multivariable logistic regression results presented as adjusted proportions controlling for demographics, health status, and healthcare access, only the association with mammography screening remained significant, and the magnitude of this association was modest. CONCLUSIONS: There were consistent differences between IPV victims and nonvictims in nearly every measure of healthcare access, health status, and preventive service use. Much of this association seems explained by population characteristics associated with both IPV and lower use of preventive service use, including differences in demographic characteristics, health status, and healthcare access. Healthcare providers could take steps to identify populations at high risk for lack of access or use of preventive services and IPV victimization. PMID- 28880707 TI - Relationship between achievement of physical activity goal and characteristics of patients with rheumatoid arthritis. AB - OBJECTIVES: We aimed to identify the relationship between achievement of a physical activity goal and the characteristics of patients with rheumatoid arthritis (RA). METHODS: Overall, 137 patients with RA who performed physical activity were enrolled. Statistical analysis was performed to examine relationship between patient characteristics and achievement of physical activity goal by univariate analysis, multivariate logistic regression analysis and the receiver operating characteristic method. RESULTS: The significant factors considered for univariate analysis performed to compare RA patients with and without achievement in physical activity goal were age, disease duration, BMI, global VAS, pain VAS, CRP, DAS28-CRP, and HAQ-DI. The significant related factors by multivariate logistic regression analysis were age (OR: 0.926), BMI (OR: 1.180), pain VAS (OR: 0.969), and HAQ-DI (OR: 0.229). The cutoff values were 62.0 years for age (sensitivity 72.5%, specificity 59.6%), 19.7 for BMI (sensitivity 91.2%, specificity 36.2%), 20.0 for pain VAS (sensitivity 63.7%, specificity 71.9%), and 0.30 for HAQ-DI (sensitivity 48.8%, specificity 89.5%). CONCLUSION: We aim to preserve activities of daily living in patients with RA. To achieve physical activity goal, we should control pain VAS, and HAQ-DI. Further, the patients the value of HAQ-DI should be kept very low. PMID- 28880709 TI - Pyrexia in cats: Retrospective analysis of signalment, clinical investigations, diagnosis and influence of prior treatment in 106 referred cases. AB - OBJECTIVES: The main aim of the study was to describe the features and diagnoses of a population of cats referred with pyrexia. Other aims were to report and evaluate the utility of clinical investigations performed, and describe any effect of treatment before referral on temperature at presentation and ability to make a diagnosis. METHODS: Clinical records of cats with pyrexia (?39.2 degrees C) documented at least twice were retrospectively reviewed. Cases were assigned to disease categories (infectious, inflammatory, immune-mediated, neoplastic, miscellaneous and no diagnosis [pyrexia of unknown origin, PUO]) based on diagnosis. The overall value of clinical investigations was assessed by classifying them as 'enabling', 'assisting' or 'no assistance' in achieving each diagnosis. The effect of treatment before referral was assessed for any association with temperature at presentation and ability to make a diagnosis (PUO vs other disease categories). RESULTS: One hundred and six cases were identified. The most common cause of pyrexia was feline infectious peritonitis (22 cats, 20.8%) and the largest disease category was infectious (41/106, 38.7%). Inflammatory conditions were found in 19 (17.9%) cats, neoplasia in 13 (12.3%), miscellaneous causes in 11 (10.4%) and immune-mediated disease in six (5.7%). No diagnosis was reached in 16 (15.0%) cats, often despite extensive diagnostic investigations. Cytology and histopathology most often 'enabled' or 'assisted' in obtaining a diagnosis. Most cats (91, 85.8%) received treatment before referral, with antimicrobial treatment given to 87 (82.1%). Prior treatment before referral was not associated with temperature at presentation nor with success in establishing a diagnosis. CONCLUSIONS AND RELEVANCE: This is the first study investigating causes of pyrexia in cats. Infectious diseases were most common and immune-mediated diseases were comparatively rare. PMID- 28880708 TI - Inhibition of E2F1 activity and cell cycle progression by arsenic via retinoblastoma protein. AB - The regulation of cell cycle progression by steroid hormones and growth factors is important for maintaining normal cellular processes including development and cell proliferation. Deregulated progression through the G1/S and G2/M cell cycle transitions can lead to uncontrolled cell proliferation and cancer. The transcription factor E2F1, a key cell cycle regulator, targets genes encoding proteins that regulate cell cycle progression through the G1/S transition as well as proteins important in DNA repair and apoptosis. E2F1 expression and activity is inhibited by inorganic arsenic (iAs) that has a dual role as a cancer therapeutic and as a toxin that leads to diseases including cancer. An understanding of what underlies this dichotomy will contribute to understanding how to use iAs as a more effective therapeutic and also how to treat cancers that iAs promotes. Here, we show that quiescent breast adenocarcinoma MCF-7 cells treated with 17-beta estradiol (E2) progress through the cell cycle, but few cells treated with E2 + iAs progress from G1 into S-phase due to a block in cell cycle progression. Our data support a model in which iAs inhibits the dissociation of E2F1 from the tumor suppressor, retinoblastoma protein (pRB) due to changes in pRB phosphorylation which leads to decreased E2F1 transcriptional activity. These findings present an explanation for how iAs can disrupt cell cycle progression through E2F1-pRB and has implications for how iAs acts as a cancer therapeutic as well as how it may promote tumorigenesis through decreased DNA repair. PMID- 28880711 TI - Curcumin Alleviates the Functional Gastrointestinal Disorders of Mice In Vivo. AB - Curcumin is a natural polyphenol extracted from the turmeric rhizome, which has a wide range of biological activities, but until now the effects of curcumin on the gastrointestinal peristalsis have not been fully understood. In vivo study, we observed the effects of curcumin on gastric emptying and intestinal propulsion rates of mice in normal state and in delayed state by atropine (ATR) or nitric oxide precursor L-arginine (L-Arg). An in vitro study explored the direct effects of curcumin on the intestinal contractility, but were studied through measuring spontaneous contraction of isolated jejunum of mice. Our results showed that intragastric administration of curcumin (200 mg/kg/day) for 10-20 days significantly improved gastric emptying and intestinal propulsion rates of mice delayed by ATR. Moreover, intragastric administration of curcumin (200 mg/kg/day) for 15 days also significantly improved mice gastric emptying and intestinal propulsion rates delayed by L-Arg. There was no significant effect on normal gastrointestinal propulsion of mice after intragastric administration of curcumin (200 mg/kg/day) for 1-20 days. When normal isolated jejunum of mice were incubated with curcumin in vitro, the amplitude of the spontaneous contractile waves of jejunum was reduced in a concentration-dependent manner. Moreover, curcumin reduced the amplitude of the contractile waves of jejunum in both contracted and relaxed state induced by acetylcholine or ATR individually. Taken together, our results suggest that curcumin has quite different effects on gastrointestinal peristalsis in vivo and in vitro. Moderate dose of curcumin by intragastric administration for more than 10 days can alleviate the functional gastrointestinal disorders of mice, but cannot affect normal gastrointestinal propulsion. PMID- 28880710 TI - Serum Immune Proteins in Limb Lymphedema Reflecting Tissue Processes Caused by Lymph Stasis and Chronic Dermato-lymphangio-adenitis (Cellulitis). AB - BACKGROUND: Lymphedema of limbs affects a large mass of tissues. Pathological changes develop in skin and subcutaneous tissue. Bacterial retention in edema fluid is followed by chronic inflammatory reaction. The question arises whether the chronic processes affecting a large mass of limb tissues are reflected in the serum by appearance of specific proteins accumulating and subsequently absorbed from the lymphedematous tissues Aim: To measure the concentration of serum proteins (1) participating in cellular disintegration such as caspase 1, sFas, high-mobility group box 1 (HMGB1), and serpin, (2) cell growth regulating factors such as cortisol, human growth hormone, keratinocyte growth factor, and insulin like growth factor (IGF), and (3) angiogenic and growth factors such as angiopoetins 1 and 2, adiponectin, leptin, and transforming growth factor beta. RESULTS: We found (1) increased concentration of serum caspase 1, sFas, serpin, and HMGB1 accounting for cellular destruction, (2) raised levels of cortisol and IGF, confirming active cellular processes, and (3) elevated concentrations of angiopoetin 1, adiponectin, and leptin, indicating proliferation of adipose tissue. CONCLUSIONS: Proteins appearing in serum in high concentrations in patients with lymphedema without systemic clinical and biochemical signs of inflammation indicate that multiple processes of destruction and rebuilding proceed in the lymphedematous tissues. Measuring concentration of caspase 1, sFas, serpin, HMGB1 protein, adiponectin, and leptin give insight into these processes. Lymphedema should be considered as tissue process characterized not only by increase in mobile tissue fluid volume but also tissue restructuring. Compression and drainage therapy should be complemented by anti-inflammatory medication. PMID- 28880712 TI - The efficacy of the Eustachian Tube Dysfunction Questionnaire (ETDQ-7) for patulous Eustachian tube patient. AB - OBJECTIVE: To assess the efficacy of the Eustachian Tube Dysfunction Questionnaire (ETDQ-7) for patulous Eustachian tube (PET) patients. METHODS: A prospective survey of medical records identified 36 patients and 47 ears with PET, and 15 patients and 15 ears as control. The ETDQ-7, patulous Eustachian tube handicap inventory-10 (PHI-10) and Likert scale were evaluated. PET patients were divided into two groups based on severity of symptoms using the PHI score. RESULTS: The Cronbach alpha value of the PET group was 0.765. The average total score of the ETDQ-7 in the control group was 7.6 +/- 1.1 and 22.5 +/- 10.0 in the PET group (p < .01). No correlation was found between ETDQ-7 and Likert scale (r = 0.248, p = .09). The average total score of the ETDQ-7 in the mild or moderate PET group was 19.9 +/- 9.0 and 25.3 +/- 11.1 in the severe PET group and this was not statistically different (p = .08). CONCLUSION: The highest ETDQ-7 score was also observed in PET patients and in ET dysfunction patients. These findings necessitate careful discrimination between ET dysfunction and PET in balloon dilation Eustachian tuboplasty (BET) based on ETDQ-7. PMID- 28880713 TI - Sexual Violence as a Key Contributor to Poor Mental Health Among Japanese Women Subjected to Intimate Partner Violence. AB - OBJECTIVES: The aim of this study was to examine the impact of sexual intimate partner violence (IPV) on mental health among Japanese women and to explore to what extent sexual IPV is an important contributor to the severity of mental health problems in comparison with physical and psychological IPV. MATERIALS AND METHODS: A cross-sectional analysis was conducted of the medical records of participants during psychiatric consultation at the Institute of Women's Health, Tokyo Women's Medical University, including 62 women who experienced IPV without sexual violence and 83 women who experienced IPV with sexual violence. Mental health problems were compared, including anxiety, depression, suicidality, post traumatic stress disorder (PTSD), and dissociative experiences. RESULTS: The results demonstrated a higher incidence and severity of somatic symptoms, insomnia, social dysfunction, severe depression and suicidality, PTSD, and dissociative experiences among women in the sexual IPV group than in the women who experienced IPV without sexual violence. In analyzing the relative contribution of sexual, physical, and psychological violence to the severity of mental health problems of the survivors, results indicated that sexual violence was an independent predictor of both PTSD and dissociative experiences. CONCLUSIONS: The present research showed that significant adverse effects on mental health were observed among women who experienced IPV with sexual violence compared with the ones without. These findings provide important implications for considering the specific approaches to meet the needs of those women experiencing sexual IPV and the need for timely and effective interventions, including healthcare, social services, and primary prevention. PMID- 28880714 TI - Long-Term Economic and Employment Outcomes Among Partners of Women With Early Stage Breast Cancer. AB - PURPOSE: Work loss is one of many personal costs for patients with cancer and their families. Many women with breast cancer face long-term job loss that stems from their diagnoses. However, little is known about the economic and employment outcomes of partners of women with breast cancer. METHODS: Women with nonmetastatic breast cancer identified by the Detroit and Los Angeles SEER registries between June 2005 and February 2007 were surveyed at both 9 months and 4 years after diagnosis. Partners were surveyed 4 years after patients' diagnoses. Nonretired partners were asked about employment and financial consequences that stemmed from the patients' breast cancer diagnoses and treatments. RESULTS: A total of 517 (67%) of 774 eligible partners completed the survey; 32% reported worsened financial status attributed to patients' breast cancers. Two hundred forty nonretired partners worked during the year after the patients' diagnoses; 90% were still working 4 years postdiagnosis. A total of 32% of partners decreased their work hours as a result of patients' breast cancer diagnoses and treatments; 64% of partners reported that, as a result of patients' breast cancer diagnoses and treatments, it was very/extremely important to keep working to keep health insurance. Overall, 51% of partners reported that it was very/extremely important to avoid changing jobs, because they were worried about loss of health insurance. CONCLUSION: Nearly one third of partners reported that their financial status was worse because of the patient's breast cancer, although most remained working 4 years after a diagnosis. Partners may continue to work longer than desired to compensate for a loss of financial resources in the family. PMID- 28880715 TI - Defective Mineralization in X-Linked Hypophosphatemia Dental Pulp Cell Cultures. AB - X-linked hypophosphatemia (XLH) is a skeletal disease caused by inactivating mutations in the PHEX gene. Mutated or absent PHEX protein/enzyme leads to a decreased serum phosphate level, which cause mineralization defects in the skeleton and teeth (osteomalacia/odontomalacia). It is not yet altogether clear whether these manifestations are caused solely by insufficient circulating phosphate availability for mineralization or also by a direct, local intrinsic effect caused by impaired PHEX activity. Here, we evaluated the local role of PHEX in a 3-dimensional model of extracellular matrix (ECM) mineralization. Dense collagen hydrogels were seeded either with human dental pulp cells from patients with characterized PHEX mutations or with sex- and age-matched healthy controls and cultured up to 24 d using osteogenic medium with standard phosphate concentration. Calcium quantification, micro-computed tomography, and histology with von Kossa staining for mineral showed significantly lower mineralization in XLH cell-seeded scaffolds, using nonparametric statistical tests. While apatitic mineralization was observed along collagen fibrils by electron microscopy in both groups, Raman microspectrometry indicated that XLH cells harboring the PHEX mutation produced less mineralized scaffolds having impaired mineral quality with less carbonate substitution and lower crystallinity. In the XLH cultures, immunoblotting revealed more abundant osteopontin (OPN), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) than controls, as well as the presence of fragments of these proteins not found in controls, suggesting a role for PHEX in SIBLING protein degradation. Immunohistochemistry revealed altered OPN and DMP1 associated with an increased alkaline phosphatase staining in the XLH cultures. These results are consistent with impaired PHEX activity having local ECM effects in XLH. Future treatments for XLH should target both systemic and local manifestations. PMID- 28880716 TI - Safety and quality in maternal and neonatal care: the introduction of the modified WHO Safe Childbirth Checklist. AB - Maternal and neonatal mortality and morbidity associated with childbirth is a problem of the highest priority. This research has been aimed at testing a modified version of the WHO Safe Childbirth Checklist in one Italian hospital and to evaluate the tool in terms of its impact on clinical practice and safety. Results show that the presence of correctly compiled partogram tool is strongly and significantly associated with the checklist implementation (OR = 14.9, 95% confidence interval [CI] = 3.5, 63.9). Compliance to the checklist was high for mid-wives (96%) and very low for obstetricians (3%). The discrepancy is the result of a misinterpretation by obstetricians: they signed only in case they prescribed therapy or when they identified risk factors, but not to underline that they checked for those factors independently by their existence. While the checklist promotes the interdisciplinary work, field studies generally show strong hierarchical rather than partnership interaction. Practitioner Summary: The study is aimed at evaluating: the checklist impact on clinical practice through a prospective pre- and post-intervention study based on clinical records review, the usability of the tool and the user's compliance. The research gives evidences on the importance of the tool for reducing risks related to delivery. PMID- 28880717 TI - Bivalent Histone Codes on WNT5A during Odontogenic Differentiation. AB - Lineage-committed differentiation is an essential biological program during odontogenesis, which is tightly regulated by lineage-specific genes. Some of these genes are modified by colocalization of H3K4me3 and H3K27me3 marks at promoter regions in progenitors. These modifications, named "bivalent domains," maintain genes in a poised state and then resolve for later activation or repression during differentiation. Wnt5a has been reported to promote odontogenic differentiation in dental mesenchyme. However, relatively little is known about the epigenetic modulations on Wnt5a activation during tooth development. Here, we investigated the spatiotemporal patterns of H3K4me3 and H3K27me3 marks in developing mouse molars. Associated H3K4me3 methylases (mixed-lineage leukemia [MLL] complex) and H3K27me3 demethylases (JMJD3 and UTX) were dynamically expressed between early and late bell stage of human tooth germs and in cultured human dental papilla cells (hDPCs) during odontogenic induction. Poised WNT5A gene was marked by bivalent domains containing repressive marks (H3K27me3) and active marks (H3K4me3) on promoters. The bivalent domains tended to resolve during inducted differentiation, with removal of the H3K27me3 mark in a JMJD3 dependent manner. When JMJD3 was knocked down in cultured hDPCs, odontogenic differentiation was suppressed. The depletion of JMJD3 epigenetically repressed WNT5A activation by increased H3K27me3 marks. In addition, JMJD3 could physically interact with ASH2L, a component of the MLL complex, to form a coactivator complex, cooperatively modulating H3K4me3 marks on WNT5A promoters. Overall, our study reveals that transcription activities of WNT5A were epigenetically regulated by the negotiated balance between H3K27me3 and H3K4me3 marks and tightly mediated by JMJD3 and MLL coactivator complex, ultimately modulating odontogenic commitment during dental mesenchymal cell differentiation. PMID- 28880719 TI - Talking About Death. PMID- 28880718 TI - Codon adaptation to tRNAs with Inosine modification at position 34 is widespread among Eukaryotes and present in two Bacterial phyla. AB - The modification of adenosine to inosine at position 34 of tRNA anticodons has a profound impact upon codon-anticodon recognition. In bacteria, I34 is thought to exist only in tRNAArg, while in eukaryotes the modification is present in eight different tRNAs. In eukaryotes, the widespread use of I34 strongly influenced the evolution of genomes in terms of tRNA gene abundance and codon usage. In humans, codon usage indicates that I34 modified tRNAs are preferred for the translation of highly repetitive coding sequences, suggesting that I34 is an important modification for the synthesis of proteins of highly skewed amino acid composition. Here we extend the analysis of distribution of codons that are recognized by I34 containing tRNAs to all phyla known to use this modification. We find that the preference for codons recognized by such tRNAs in genes with highly biased codon compositions is universal among eukaryotes, and we report that, unexpectedly, some bacterial phyla show a similar preference. We demonstrate that the genomes of these bacterial species contain previously undescribed tRNA genes that are potential substrates for deamination at position 34. PMID- 28880720 TI - Surgical Treatment of Primary Lymphedema. AB - Primary lymphedema is due to abnormal congenital development or dysfunction in the lymphatic system. Limited data exist on the prevalence of primary lymphedema and there are only few studies focusing on primary lymphedema. The purpose of this article is to review the current options for surgical treatment of primary lymphedema. PMID- 28880722 TI - Attitudes of Older Chinese Patients Toward Death and Dying. AB - BACKGROUND: Due to the aging population of China, the need for palliative care will increase. However, one of the barriers to utilization of palliative care is the traditional belief that talking about death and dying is taboo. OBJECTIVE: The aim of this study was to examine to what extent older Chinese patients were willing to answer questions about death and dying by asking them about "fear of death" and their desire to "use advanced life support when dying." DESIGN: Survey questionnaire. SETTING/SUBJECTS: Convenience sample (N = 993 hospitalized patients). RESULTS: Only 215 (21.7%; 95% confidence interval [CI] 16.2%-27.1%) and 99 (9.9%; 95% CI 4.1%-15.8%) patients did not answer the questions related to "fear of death" and "use of advanced life support when dying," respectively, while 439 (44.2%; 95% CI 38.7%-49.7%) answered "yes" and 339 (34.1%; 95% CI 28.7% 39.6%) answered "no" for "fear of death" and 382 (38.5%; 95% CI 32.6%-44.3%) answered "yes" and 512 (51.6%; 95% CI 45.7%-57.4%) answered "no" for "use of advanced life support when dying." In multinomial logistic regression analysis, fear of death was associated with younger age, lowest level of function, and desire to use advanced life support. CONCLUSIONS: The majority of older patients were willing to answer the two questions about death and dying. About one-third of patients were not afraid of death, and older patients were less likely to be afraid of death. More than 50% of patients answered that they would not choose advanced life support when dying. More research in this area is needed to help advance palliative care in China. PMID- 28880723 TI - The effects of emotion regulation strategies on positive and negative affect in early adolescents. AB - Recent research suggests that impaired emotion regulation (ER) may play an important role in the development of youth psychopathology. However, little research has explored the effects of ER strategies on affect in early adolescents. In Study 1 (n = 76), we examined if early adolescents are able to use distraction and whether the effects of this strategy are similar to talking to one's mother. In Study 2 (n = 184), we compared the effects of distraction, cognitive reappraisal, acceptance, and rumination. In both studies, participants received instructions on how to regulate their emotions after a standardised negative mood induction. In general, the results indicated that distraction, but also cognitive reappraisal and acceptance, had promising short-term effects on positive and negative affect in early adolescents. These findings suggest that targeting adaptive ER skills, such as distraction, acceptance, and cognitive reappraisal, may be an important strategy to prevent or treat psychological problems in early adolescents. PMID- 28880721 TI - Role of NADPH oxidase in radiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain. AB - PURPOSE: The present study was designed to investigate our hypothesis that NADPH oxidase plays a role in radiation-induced pro-oxidative and pro-inflammatory environments in the brain. MATERIALS AND METHODS: C57BL/6 mice received either fractionated whole brain irradiation or sham-irradiation. The mRNA expression levels of pro-inflammatory mediators, such as TNF-alpha and MCP-1, were determined by quantitative real-time RT-PCR. The protein expression levels of TNF alpha, MCP-1, NOX-2 and Iba1 were detected by immunofluorescence staining. The levels of ROS were visualized by in situ DHE fluorescence staining. RESULTS: A significant up-regulation of mRNA and protein expression levels of TNF-alpha and MCP-1 was observed in irradiated mouse brains. Additionally, immunofluorescence staining of Iba1 showed a marked increase of microglial activation in mouse brain after irradiation. Moreover, in situ DHE fluorescence staining revealed that fractionated whole brain irradiation significantly increased production of ROS. Furthermore, a significant increase in immunoreactivity of NOX-2 was detected in mouse brain after irradiation. On the contrary, an enhanced ROS generation in mouse brain after irradiation was markedly attenuated in the presence of NOX inhibitors or NOX-2 neutralizing antibody. CONCLUSIONS: These results suggest that NOX-2 may play a role in fractionated whole brain irradiation-induced pro oxidative and pro-inflammatory pathways in mouse brain. PMID- 28880724 TI - Prevalence of Recent Antimicrobial Exposure among Elective Surgical Patients. AB - BACKGROUND: The annual prevalence of antimicrobial exposure is high in the outpatient setting and should be a common exposure for surgical patients. Antimicrobials have negative side effects and may be associated with poor outcomes. Logically, one would expect surgical patients to be particularly susceptible to any negative effects of recent antimicrobial exposure. Despite these observations, however, the prevalence of recent antimicrobial exposure among surgical patients remains undefined. The purpose of this study is to define the prevalence of antimicrobial exposure in patients undergoing elective surgical procedures. METHODS: Patients presenting for elective operations between August 4, 2015 and August 3, 2016 at our institution were asked prospectively about any antimicrobial exposure in the previous three months. Answers were recorded as either Yes, No, or Unsure. Patients were grouped according to age, American Society of Anesthesiologists (ASA) score, primary operative service, and post operative destination. Descriptive statistics were employed using simple percentages and chi-square analysis when appropriate. Cochrane-Armitage test was used to evaluate temporal trends. RESULTS: There were 21,473 elective surgical procedures performed during the study period across 13 operative services. Answers were recorded for 91.2% cases. The overall prevalence of exposure during this period was 28.6%. Exposure varied with age, ASA score, and surgical specialty. Vascular and transplant operations had the highest prevalence of exposure while ophthalmology and pediatric orthopedic procedures had the lowest. Patients with recent antimicrobial exposure were less likely to be discharged home on the same day and more likely to be admitted to an intensive care or intermediate care unit than those who denied recent exposure. CONCLUSION: In this descriptive analysis, the prevalence of recent antimicrobial exposure is overall approximately 28.6% and is higher than anticipated. Further work is needed to determine to what extent, if any, recent antimicrobial exposure impacts post operative outcomes. PMID- 28880725 TI - Synergistic relationship between auxin and cytokinin in the ovary and the participation of the transcription factor SPATULA. AB - The phytohormones auxin and cytokinin are key regulators of plant development, and both regulate almost all aspects of plant growth and development. Communication between auxin-cytokinin signaling pathways has been the subject of intense research. However, few studies have focused specifically on the development of the early gynoecium. We have recently discovered that cytokinin signaling plays a role in the regulation of auxin biosynthesis and transport in the ovary region of the gynoecium, and that the transcription factor SPATULA (SPT) is necessary. Here, we provide evidence that indicates that cytokinin and auxin have a synergistic relationship at the medial domain during gynoecium development, and that SPT is important for this interaction. PMID- 28880726 TI - Parents' Spatial Language Mediates a Sex Difference in Preschoolers' Spatial Language Use. AB - Do boys produce more terms than girls to describe the spatial world-that is, dimensional adjectives (e.g., big, little, tall, short), shape terms (e.g., circle, square), and words describing spatial features and properties (e.g., bent, curvy, edge)? If a sex difference in children's spatial-language use exists, is it related to the spatial language that parents use when interacting with children? We longitudinally tracked the development of spatial-language production in children between the ages of 14 and 46 months in a diverse sample of 58 parent-child dyads interacting in their homes. Boys produced and heard more of these three categories of spatial words, which we call "what" spatial types (i.e., unique "what" spatial words), but not more of all other word types, than girls. Mediation analysis revealed that sex differences in children's spatial talk at 34 to 46 months of age were fully mediated by parents' earlier spatial language use, when children were 14 to 26 months old, time points at which there was no sex difference in children's spatial-language use. PMID- 28880728 TI - Reply to: Precautionary Behaviors and Breast Cancer-Related Lymphedema. PMID- 28880727 TI - Prevalence of Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease in a cohort of patients treated with TNF-alpha inhibitors. AB - BACKGROUND: Treat to target (T2T), aiming at inactive disease (ID), has become the recommended strategy for axial-SpA (ax-SpA). Using the Ankylosing Spondylitis Disease Activity Score (ASDAS), we assessed the prevalence of ID in ax-SpA patients treated with TNFalpha inhibitors (TNFi). METHODS: A multicentric, cross sectional study was performed assessing disease activity status (BASDAI and ASDAS) of consecutive patients with ax-SpA on stable treatment with TNFi for at least six months. We analyzed differences with nonradiographic axSpA (nr-ax-SpA) and the influence of population characteristics and comorbidities in reaching ID. ID was defined as ASDAS-CRP <1.3. RESULTS: A total of 218 patients were enrolled, 165 with AS and 53 with nr-ax-SpA. ASDAS-CRP ID was reached by 89 (40.8%) patients, while 163 (74.8%) of patients achieved good disease control with BASDAI. There were no significant differences between the two diagnostic groups. Multivariate logistic regression demonstrated a negative correlation of concomitant fibromyalgia, higher BASMI and current NSAIDs with the chances of reaching ASDAS-CRP ID or BASDAI <4. CONCLUSION: T2T represents a new challenge in the management of ax-SpA, with recently introduced disease activity measures being significantly more stringent. The prevalence of ID was affected by concomitant fibromyalgia, decreased spine mobility and concomitant NSAIDs. PMID- 28880729 TI - Outcomes following laparoscopic versus open major hepatectomy: a meta-analysis. AB - OBJECTIVE: The role of laparoscopic major hepatectomy (LMH) remains uncertain in current liver surgery. This meta-analysis aimed to compare surgical and oncological outcomes of LMH versus open major hepatectomy (OMH). METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library database to identify all relevant publications. The statistical analysis was performed using Review Manager version 5.3. Continuous variables were calculated by standardized mean differences (SMD) with 95% confidence interval (CI), whereas dichotomous variables were calculated by odds ratio (OR) with 95%CI. RESULTS: A total of 10 eligible studies with 1130 patients were identified, of which 455 (40.3%) patients in the LMH group and 675 (59.7%) patients in the OMH group. LMH was associated with less blood loss (SMD = -0.30, 95%CI: -0.43 to -0.18, p < .00001), less transfusion requirement (OR = 0.49, 95%CI: 0.29-0.82, p = .007), decreased postoperative morbidity (OR = 0.56, 95%CI: 0.42-0.76, p = .0001), and shorter hospital stay (SMD = -0.46, 95%CI: -0.69 to -0.24, p < .0001) when compared with the OMH group. But the operative time was significantly longer in LMH group (SMD = 0.61, 95%CI: 0.79-1.86, p = .01). Both the two groups achieved similar surgical margin and R0 resection rate for malignant lesions. CONCLUSIONS: This meta-analysis demonstrated that LMH appeared to be feasible and safe in current liver surgery. LMH is associated with less blood loss, decreased postoperative morbidity, shorter hospital stay, and comparable oncological outcomes compared with OMH. PMID- 28880730 TI - Tyrosine-derived novel antimicrobial hydantoin polymers: synthesis and evaluation of anti-bacterial activities. AB - A new approach for the design and synthesis of cyclic N-halamine polymers having anti-bacterial activity based on a vinyl derivative of tyrosine-derived hydantoin is reported. The synthesis of N-halamine polymers generally involves the chemical modification of 5,5'-disubstituted hydantoin to introduce polymerizable vinyl moieties thereby restricting the halogen capture only on the amide nitrogen. Here we show the possibility of synthesizing vinyl monomers of N-halamine from alpha amino acids wherein both the amide and imide nitrogens are available for halogen capture. Thus, a hydantoin monomer was synthesized from L-tyrosine and copolymerized with methyl methacrylate and 2-(hydroxyethyl)methacrylate, to obtain random co-polymers. The monomer and its co-polymers were characterized using NMR, IR, HRMS, GPC, DSC, EDAX and TGA analysis. Films of the co-polymers cast from 10% acetone solutions were exposed to sodium hypochlorite solution to activate the hydantoin moieties. The oxidative chlorine content of the films ranged from 0.6 to 0.9%. The activated films were exposed to both Gram positive (S. aureus) and Gram negative (E. coli) bacteria using standard protocols. Polymers having chlorine content as little as 0.6% exhibited 6 log reduction in the bacterial growth within 30 min of exposure. The method allows the halogenation of both amide and imide nitrogens and could be applied to the preparation of a number of vinyl hydantoins from many amino acids. PMID- 28880731 TI - Reference Ranges Using Bioimpedance for Detection of Lymphedema in Chinese Women. AB - BACKGROUND: Bioimpedance is a commonly used technique for detection of early lymphedema. The thresholds used for detection are based on impedance measurements obtained in Western populations. It is unknown whether these thresholds are applicable to a Chinese population. METHODS AND RESULTS: Impedance measurements were obtained for both arms in 391 women, ranging in age from 20 to 84 years, using a standardized protocol. Frequency distributions of interlimb impedance arm ratios for both dominant:non-dominant and non-dominant:dominant were used to determine thresholds at two and three standard deviations (SDs) above the mean. Absolute impedance was significantly higher in the youngest group (20-39 years) compared to other age groups. However, there was no significant effect of age on impedance ratios. Similarly, there was no significant difference between impedance ratios determined in this study and those from recent studies in the Australia and the United States, which used similar protocols. New two and three SDs above the mean thresholds, using a weighted average from the pooled data of these studies are 1.108 and 1.153 for use when the dominant limb is at-risk and 1.072 and 1.116 when the non-dominant limb is at-risk. CONCLUSION: There was no effect of ethnicity on impedance ratios. Consequently, the proposed pooled thresholds can be used, irrespective of ethnicity. PMID- 28880732 TI - Numerical Activities of Daily Living - Financial (NADL-F): A tool for the assessment of financial capacities. AB - Financial capacity is the ability to manage one's own finances according to self interests. Failure in financial decisions and lack of independence when dealing with money can affect people's quality of life and are associated with neuropsychological deficits or clinical conditions such as mild cognitive impairment or Alzheimer's disease. Despite the importance of evaluating financial capacity in the assessment of patients with neuropsychological and psychiatric disorders, only a few tools have been developed. In the present article, the authors introduce the Numerical Activities of Daily Living - Financial (NADL-F) test, a new test to assess financial capacity in clinical populations. The NADL-F is relatively short, yet it encompasses the most common activities involving financial capacities. The NADL-F proved to have satisfactory psychometric properties and overall good validity for measuring financial abilities. Associations with performance on basic neuropsychological tests were investigated, in particular focusing on mathematical abilities as cognitive correlates of financial capacity. Results indicate that the NADL-F could be a useful tool to guide treatments for the enhancement of financial capacities. By sharing all materials and procedures, the authors hope to promote the development of further versions of the NADL-F in different languages, taking into account the necessary adjustments related to different socio-cultural contexts. PMID- 28880734 TI - Precautionary Behaviors and Breast Cancer-Related Lymphedema. PMID- 28880733 TI - Healthcare resource utilization and costs by age and joint location among osteoarthritis patients in a privately insured population. AB - AIMS: To compare healthcare resource utilization and costs between patients aged 18-64 years with osteoarthritis (OA) and matched controls without OA in a privately insured population. METHODS: Patients with OA were selected from de identified US-based employer claims (Q1:1999-Q3:2011). The index date was defined as the first OA diagnosis indicated by ICD-9-CM codes. One year before and after the index date were defined as the baseline and study periods, respectively. A second OA diagnosis during the study period was also required. Patients with OA were matched one-to-one on age, gender, index date, and minimum length of follow up to controls without OA. Baseline characteristics and study period resource utilization and costs (2016 USD) were compared between cohorts. RESULTS: This study identified 199,539 patients with OA (knee: 87,271, hip: 19,953, hand: 15,670, spine: 12,496). The average age was 54 years, and 58% were female. OA patients had higher healthcare resource utilization than matched controls in inpatient, emergency room, and outpatient settings (p < .001 for all). Further, patients with OA had 4-times the excess total medical costs of their matched controls ($14,521 vs $3,629; p < .001). Patients with hip OA had the highest medical costs among all joint locations. Outpatient and pharmacy costs were similar among patients with knee, hip, and hand OA, but higher in patients with spine OA. In sub-group analyses, older patients (45-64 years old) had higher costs. LIMITATIONS: This sample, obtained using claims data, only includes patients who were actively seeking care for OA and were likely symptomatic. Asymptomatic patients would likely not be captured in this analysis. CONCLUSIONS: Patients with OA incur greater healthcare resource utilization and costs than patients without OA, with substantial variation by joint location. PMID- 28880735 TI - 2017 Midwest Zebrafish Meeting Report. AB - The 2017 Midwest Zebrafish meeting was held from June 16 to 18 at the University of Cincinnati, sponsored by the Cincinnati Children's Hospital Divisions of Developmental Biology, Molecular Cardiovascular Biology, and Gastroenterology, Hepatology, and Nutrition. The meeting, organized by Saulius Sumanas, Joshua Waxman, and Chunyue Yin, hosted >130 attendees from 16 different states. Scientific sessions were focused on morphogenesis, neural development, novel technologies, and disease models, with Steve Ekker, Stephen Potter, and Lila Solnica-Krezel presenting keynote talks. In this article, we highlight the results and emerging themes from the meeting. PMID- 28880736 TI - Maternal determinist of term intrauterine growth restriction (IUGR) in the Kingdom of Saudi Arabia. AB - Intrauterine growth restriction was defined as occurring if birth weight of the newborn is below 10th percentile for gestational age. We investigated its maternal determinants in Riyadh, Saudi Arabia by comparing 76 cases to 76 controls to aid in early detection, diagnosis and proper prevention. A history of stillbirth, less than three years interpregnancy intervals, experiencing preeclampsia during pregnancy besides gaining less than nine kilograms during term pregnancy would signal a risk of having intrauterine growth restriction babies. Mothers living in rural areas as well as smokers along with those above 34 years old were associated with the same risk. PMID- 28880737 TI - Cost-effectiveness of osimertinib in the UK for advanced EGFR-T790M non-small cell lung cancer. AB - AIM: This study presents the cost-utility analysis that was developed to inform the NICE health technology assessment of osimertinib vs platinum-based doublet chemotherapy (PDC) in patients with EGFR-T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. METHODS AND MATERIALS: A partitioned survival model with three health states (progression-free, progressed disease, and death) from a UK payer perspective and over lifetime (15 years) was developed. Direct costs included disease management, treatment-related (acquisition, administration, monitoring, adverse events), and T790M testing costs. Efficacy and safety data were taken from clinical trials AURA extension and AURA2 for osimertinib and IMPRESS for PDC. An adjusted indirect treatment comparison was applied to reduce the potential bias in the non-randomized comparison. Parametric functions were utilized to extrapolate survival beyond the observed period. Health state utility values were calculated from EQ-5D data collected in the trials and valued using UK tariffs. Resource use and costs were based on published sources. RESULTS: Osimertinib was associated with a gain of 1.541 quality-adjusted life-years (QALYs) at an incremental cost of L64,283 vs PDC (incremental cost-effectiveness ratio [ICER]: L41,705/QALY gained). Scenario analyses showed that none of the plausible scenarios produced an ICER above L44,000 per QALY gained, and probabilistic sensitivity analyses demonstrated a 63.4% probability that osimertinib will be cost-effective at a willingness-to-pay threshold of L50,000. LIMITATIONS: The analysis is subject to some level of uncertainty inherent to phase 2 single-arm data and the immaturity of the currently available survival data for osimertinib. CONCLUSIONS: Osimertinib may be considered a cost-effective treatment option compared with PDC in the second line setting in patients with EGFR-T790M mutation-positive NSCLC from a UK payer perspective. Further data from the ongoing AURA clinical trial program will reduce the inherent uncertainty in the analysis. PMID- 28880738 TI - Military Sexual Trauma and Obesity Among Women Veterans. AB - BACKGROUND/OBJECTIVE: Posttraumatic stress disorder (PTSD), the experience of military sexual trauma (MST) that may contribute to PTSD, and obesity are three issues that complicate care for our population of new veterans. Our aim was to analyze the association of MST and diagnosed PTSD with obesity among female veterans. MATERIALS AND METHODS: Women 20-103 years old using the Veterans Health Administration (VA) in fiscal year 2014 (October 2013-September 2014) with diagnosis and body-mass data were identified in administrative databases (213,985 of 404,183 women). MST was defined by use of an MST clinic or positive MST screen, PTSD by International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code (309.81), and weight categories from body-mass index. RESULTS: The unadjusted chi-square of MST by obesity showed a modest association: 52% MST affected versus 46% non-MST women were obese. MST status was associated with PTSD (50% MST vs. 15% non-MST women). A multivariable model of obesity adjusting for clinical and demographic covariates estimated a 9% increased risk of obesity from MST (adjusted risk ratio [RR] = 1.09). Younger age, African American race, and chronic disease such as hypertension and dyslipidemia correlated with obesity. Adding PTSD to the model did not affect the association with MST: RR (MST) = 1.09, RR (PTSD) = 1.00 (not significant). CONCLUSIONS: This study showed association of MST with obesity in female veterans, independent of PTSD. Weight gain in patients with trauma may add psychological or medical risk to the burden of disease shouldered by female veterans with MST. Primary care clinicians may need to consider integrating mental health into care of patients with suspected history of trauma especially sexual trauma. PMID- 28880740 TI - Cytogenetic monitoring of hospital staff exposed to ionizing radiation: optimize protocol considering DNA repair genes variability. AB - PURPOSE: Chronic occupational exposure to ionizing radiation (IR) induces a wide spectrum of DNA damages. The aim of this study was to assess the frequencies of micronucleus (MN), sister chromatid exchanges (SCE) and to evaluate their association with XRCC1 399 Arg/Gln and XRCC3 241 Thr/Met polymorphisms in Hospital staff occupationally exposed to IR. MATERIALS AND METHODS: A questionnaire followed by a cytogenetic analysis was concluded for each subject in our study. The exposed subjects were classified into two groups based on duration of employment (Group I < 15 years; Group II >=15years). The genotypes of all individuals (subjects and controls) were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: DNA damage frequencies were significantly greater in IR workers compared with controls (p < .05). However, no association arised between XRCC1 399 Arg/Gln and XRCC3 241 Thr/Met polymorphisms, on one hand, and the severity of DNA damages in the studied cohort of Tunisian population, on the other hand. CONCLUSION: Our data provide evidence for an obvious genotoxic effect associated with IR exposure and reinforce the high sensitivity of cytogenetic assays for biomonitoring of occupationally exposed populations. These results indicate that workers exposed to IR should have periodic monitoring, along their exposure. The variants, rs25487 and rs861539, of XRCC1 and XRCC3 genes have obvious functional effects. Paradoxically, these variants are not associated with the severity of damages, according to used assays, in the studied cohort of Tunisian population, unlike other studies. PMID- 28880739 TI - Methionine-supplemented diet affects the expression of cardiovascular disease related genes and increases inflammatory cytokines in mice heart and liver. AB - Some important environmental factors that influence the development of cardiovascular diseases (CVD) include tobacco, excess alcohol, and unhealthy diet. Methionine obtained from the diet participates in the synthesis of DNA, proteins, lipids and affects homocysteine levels, which is associated with the elevated risk for CVD development. Therefore, the aim of this study was to investigate the manner in which dietary methionine might affect cellular mechanisms underlying CVD occurrence. Swiss albino mice were fed either control (0.3% DL-methionine), methionine-supplemented (2% DL-methionine), or a methionine deprived diet (0% DL-methionine) over a 10-week period. The parameters measured included plasma homocysteine concentrations, oxidative stress by reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, levels of inflammatory cytokines IL-1beta, TNF-alpha, and IL-6, as well as expression of genes associated with CVD. The levels of apolipoprotein A5 (APOA5), a regulator of plasma triglycerides, were measured. The methionine-supplemented diet increased oxidative stress by lowering the GSH/GSSG ratio in heart tissues and decreased expression of the genes Apob, Ctgf, Serpinb2, Spp1, Il1b, and Sell, but elevated expression of Thbs4, Tgfb2, Ccr1, and Vegfa. Methionine-deprived diet reduced expression of Col3a1, Cdh5, Fabp3, Bax, and Hbegf and increased expression of Sell, Ccl5, Itga2, Birc3, Msr1, Bcl2a1a, Il1r2, and Selp. Methionine-deprived diet exerted pro-inflammatory consequences as evidenced by elevated levels of cytokines IL-1beta, TNF-alpha, and IL-6 noted in liver. Methionine-supplemented diet increased hepatic IL-6 and cardiac TNF-alpha. Both methionine supplementation and deprivation lowered hepatic levels of APOA5. In conclusion, data demonstrated that a methionine-supplemented diet modulated important biological processes associated with high risk of CVD development. PMID- 28880741 TI - The impact of repeated organophosphorus pesticide exposure on biomarkers and neurobehavioral outcomes among adolescent pesticide applicators. AB - Egyptian adolescents are hired as seasonal workers to apply pesticides to the cotton crop and may perform this occupation for several years. However, few studies examined the effects of repeated pesticide exposure on health outcomes The goal of this study was to determine the impact of repeated pesticide exposure on neurobehavioral (NB) performance and biomarkers of exposure (urinary metabolite) and effect (cholinesterase activity). Eighty-four adolescents from two field stations in Menoufia, Egypt, were examined four times: before and during pesticide application season in 2010 and again before and during application season in 2011. At each of the four time points, participants completed a questionnaire, performed an NB test battery, and were assessed for urinary levels of the chlorpyrifos metabolite TCPy (3,5,6-trichloro-2-pyridinol) and blood cholinesterase activity. Following the study cohort over two consecutive pesticide application seasons revealed that TCPy levels significantly increased following exposure, and returned to baseline levels following the end of the application season. Blood butyryl cholinesterase activity exhibited a similar pattern. Although NB outcomes displayed learning and practice effects over time, deficits in performance were significantly associated with increased TCPy levels with reduction in the number of NB measures showing improvement over time. Biomarkers of exposure and effect demonstrated changes associated with pesticide application and recovery after application ended. Deficits in NB performance were correlated with elevated pesticide exposure. Data demonstrated that repeated pesticide exposure may exert a long-term adverse impact on human health. PMID- 28880743 TI - Researching Lift-Assists: Nebulous Complexity. PMID- 28880742 TI - Decreased levels of Th17 cells are associated with invasion fungal infections after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Delayed immune reconstitution is an important risk factor for increased susceptibility to fungal pathogens. However, little is known about the association between the recovery of CD4+T cell subsets and invasion fungal infections (IFIs) in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The aim of the study was to analyze the immune reconstitution characteristics of CD4+T cell subsets and their association with the incidence of IFIs over the first 3 months after allo-HSCT. METHODS: Fifty three patients were included, 13 with IFIs. We assessed CD4+T cell subsets and the mRNA expression of specific transcription factors T-bet, GATA3, RORgammat, and Foxp3 in peripheral blood mononuclear cells over three time points. The serum levels of IFN-gamma, IL-6, IL-10, and TGF-beta were detected using the enzyme linked immunosorbent assay. RESULTS: CD4+T cell subsets increased progressively in non-IFI patients after allo-HSCT. In IFI patients, Th17 cell counts were significantly decreased compared to non-IFI patients at 3 months after allo-HSCT. IFI patients showed the lower ratios of RORgammat/GATA3 and RORgammat/Foxp3 compared with non-IFI patients. In addition, we observed increased levels of IFN gamma and IL-10 in IFI patients after allo-HSCT. In the multivariate analysis, the occurrence of IFIs was independently associated with the incidence of IFIs. Finally, we observed a lower CD4:CD8 ratio in IFI patients and its association with Th17 cells. CONCLUSIONS: These findings supported that Th17 cells may be involved in the immune pathology of IFIs after allo-HSCT. PMID- 28880744 TI - The effects of phenylethanoid glycosides, derived from Herba cistanche, on cognitive deficits and antioxidant activities in male SAMP8 mice. AB - Cognitive deficits are closely associated with hippocampal synaptic changes. Phenylethanoid glycosides (PhG), derived from Herba cistanche, are known to exert protective effects on cognitive deficits in Alzheimer's disease (AD); however, the underlying mechanisms of this herbal extract on cognitive performance remain unclear. The aim of this study was thus to examine the protective mechanism attributed to PhG on cognitive deficits in an AD senescence accelerated mouse prone 8 (SAMP8) model. Cognitive deficit parameters examined included (1) Morris water maze (MWM) assessing cognitive performance and (2) quantification of dendritic spine density in hippocampal CA1 region by Golgi staining, a molecular biomarker of synaptic function. In addition, levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD) and gluthathione peroxidase (GSH-Px) were determined to examine the potential role of oxidant processes in cognitive dysfunction. Data showed that PhG significantly decreased escape latency and path length, associated with a rise in the percentage of time spent in the target quadrant and number of platform crossings. In addition, PhG significantly increased dendritic spine density in the hippocampal CA1 region accompanied by elevated expression levels of synaptophysin (SYN) and post synaptic density 95 (PSD-95), reduced MDA content, and elevated the activities of SOD and GSH-Px. Data suggest that the ability of PhG to ameliorate cognitive deficits in SAMP8 mice may be related to promotion in synaptic plasticity involving antioxidant processes. PMID- 28880745 TI - Reply to F. Tomao et al. PMID- 28880747 TI - Pembrolizumab in Programmed Death Ligand 1-Positive Endometrial Cancer. PMID- 28880746 TI - Metastatic Lymph Node Burden and Survival in Oral Cavity Cancer. AB - Purpose Current staging systems for oral cavity cancers incorporate lymph node (LN) size and laterality, but place less weight on the total number of positive metastatic nodes. We investigated the independent impact of numerical metastatic LN burden on survival. Methods Adult patients with oral cavity squamous cell carcinoma undergoing upfront surgical resection for curative intent were identified in the National Cancer Data Base between 2004 and 2013. A neck dissection of a minimum of 10 LNs was required. Multivariable models were constructed to assess the association between the number of metastatic LNs and survival, adjusting for factors such as nodal size, laterality, extranodal extension, margin status, and adjuvant treatment. Results Overall, 14,554 patients met inclusion criteria (7,906 N0 patients; 6,648 node-positive patients). Mortality risk escalated continuously with increasing number of metastatic nodes without plateau, with the effect most pronounced with up to four LNs (HR, 1.34; 95% CI, 1.29 to 1.39; P < .001). Extranodal extension (HR, 1.41; 95% CI, 1.20 to 1.65; P < .001) and lower neck involvement (HR, 1.16; 95% CI, 1.06 to 1.27; P < .001) also predicted increased mortality. Increasing number of nodes examined was associated with improved survival, plateauing at 35 LNs (HR, 0.98; 95% CI, 0.98 to 0.99; P < .001). In multivariable models accounting for the number of metastatic nodes, contralateral LN involvement (N2c status) and LN size were not associated with mortality. A novel nodal staging system derived by recursive partitioning analysis exhibited greater concordance than the American Joint Committee on Cancer (8th edition) system. Conclusion The number of metastatic nodes is a critical predictor of oral cavity cancer mortality, eclipsing other features such as LN size and contralaterality in prognostic value. More robust incorporation of numerical metastatic LN burden may augment staging and better inform adjuvant treatment decisions. PMID- 28880748 TI - Influence of B-Complex Vitamins on the Pharmacokinetics of Ginsenosides Rg1, Rb1, and Ro After Oral Administration. AB - After cultivation of ginseng, ginsenosides, which are the major active ingredients of gingeng, were approved for use by the food industry, and began to be used as added functional ingredients to try to improve the quality and price of functional foods. However, the interaction between different types of ginsenosides and nutrients needs further study. We investigated the effect of B complex vitamins (which are essential nutrients) on the pharmacokinetics of the ginsenosides protopanaxatriol-type saponin Rg1, protopanaxadiol-type saponin Rb1, and oleanolic acid-type saponin Ro after oral administration. Ginsenosides Rg1, Rb1, and Ro, with or without B-complex vitamins, respectively, were administered orally to rats to evaluate their pharmacokinetics. The concentration of ginsenosides in plasma was determined by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters were fitted using WinNonlin v6.2. After oral coadministration with B-complex vitamins, the area under the concentration time curve from zero to infinity (AUC0-infinity) of ginsenoside Rg1 was reduced by 70%, that of ginsenoside Rb1 was reduced by 43%, and that of ginsenoside Ro was reduced by 34%. The AUC0-infinity of ginsenosides Rg1 and Rb1 showed significant differences between different treatments, but the AUC0-infinity of ginsenoside Ro did not. These results suggest significant ginsenoside-nutrient interactions between ginsenosides Rg1, Rb1, and B-complex vitamins. PMID- 28880749 TI - Exposure to decabromodiphenyl ether (BDE-209) produces mitochondrial dysfunction in rat liver and cell death. AB - Polybrominated diphenyl ethers (PBDE) are ubiquitous environmental pollutants. Exposure to these chemicals has been associated with developmental neurotoxicity, endocrine dysfunctions, reproductive disorders, and hepatotoxicity. The widespread use of PBDE as flame retardants has culminated in daily exposure of humans and wildlife to these contaminants and resulted in their banned use. Thus assessment of the potential effects of each PBDE congener on living organisms has become cause for concern. The aim of this study was to (1) examine the effects of decabromodiphenyl ether (BDE)-209 on different functions of HepG2 cells and (2) investigate whether this congener is involved in mitochondrial toxicity. The use of multiple methods was employed to (i) study the influence of BDE-209 on mitochondrial permeability transition (MPT) process in mitochondria isolated from rat liver and (ii) determine the consequential cellular damage. Our results showed that BDE-209 induced matrix swelling related to MPT with 10 uM and ATP depletion with 0.1 uM. In addition, 0.5 MUM BDE-209 reduced HepG2 cell viability, produced collapse of membrane potential, but increased levels of reactive oxygen species (ROS) after 48 h incubation. After 24 h with 5 MUM treatment elevated levels of ROS, DNA fragmentation and cytochrome c release, accompanied by caspase 9 and caspase 3 activation was noted. Taken together, these results suggest that short-duration exposure (24 or 48 h) to 0.5 MUM or 5 MUM BDE-209 concentrations diminished HepG2 cell viability due to apoptosis associated with mitochondrial dysfunction. PMID- 28880750 TI - Effects of Aqua-Lymphatic Therapy on Lower Extremity Lymphedema: A Randomized Controlled Study. AB - BACKGROUND: The purpose of this study is to investigate the effects of the aqua lymphatic therapy (ALT) on unilateral lower extremity lymphedema in the maintenance phase. MATERIALS AND METHODS: This is a randomized controlled trial with a blinded assessor. The study was completed with 30 ALT and 27 control group participants. Foot volume was assessed by a water displacement device, limb volume by circumference measurements, functional capacity by a 6-minute walk test, quality of life by Short Form-36, and social appearance by Social Appearance Anxiety Scale and hopeless by Beck Hopeless Scale. The ALT and the control group had group sessions twice in a week for 6 weeks directed by a physiotherapist. RESULTS: The mean age of ALT patients was 44.50 +/- 13.69 years, whereas that of the control patients was 47.66 +/- 16.82 years. After the intervention, both groups' measurement of edema, functional level, quality of life, as well as social and future concerns improved significantly but this improvement was higher in the ALT group (p < 0.05, p <= 0.001). CONCLUSIONS: ALT was found to be a safe effective method for unilateral lower extremity lymphedema patients during the maintenance phase of Complex Decongestive Physiotherapy. PMID- 28880751 TI - Biomarkers-an unmet need in wound care. PMID- 28880752 TI - Evaluation of osteopontin expression in chronic wounds: a potential prognostic and therapeutic biomarker. AB - OBJECTIVE: Osteopontin (OPN) is abundantly expressed during tissue repair, acting as a powerful chemokine that recruits inflammatory cells such as neutrophils, macrophages, and Langerhans cells. The role of OPN in chronic wounds has not been explored. In this study, we assess the expression levels of OPN in chronic wounds to assess its potential contribution to the exacerbated inflammation seen in chronic ulcers, which is thought to contribute to poor healing. METHODS: This retrospective study included archived biopsies of chronic wounds from several aetiologies. Immunohistochemical staining and blind analysis of OPN expression were carried out. RESULTS: We assessed biopsies from venous leg ulcers (n=5), diabetic foot ulcers (n=5), pyoderma gangrenosum (n=5), squamous cell carcinoma ulcers (n=4), and calciphylaxis ulcers (n=3). The data revealed that all these sets of chronic ulcers expressed high levels of OPN. CONCLUSION: This study provides strong histopathologic evidence that OPN expression is significantly increased in chronic wounds, suggesting that its upregulation could contribute to the exacerbated inflammation. Furthermore, further characterisation of the role of OPN in wound healing could aid the development of specific and efficient anti OPN therapies for the treatment of chronic wounds. PMID- 28880753 TI - Patient-centred care and advocacy: a call to action. PMID- 28880754 TI - The prevalence and incidence of diabetic foot ulcers among five countries in the Arab world: a systematic review. AB - OBJECTIVE: There is a rising incidence of diabetes worldwide; however there seems to be a higher incidence and prevalence rates in the Arab world when compared with the global average. 1 Out of the top 10 countries with the highest prevalence rates, six are Arab countries and almost 20.5 million people in that part of the world live with diabetes. Despite this, published scientific research from the 22 Arab countries is limited and seems to be of lower quality when compared with the rest of the developed world. 2 Therefore, our aim was to explore the contribution of the different Arab countries in the world literature, to identify the diabetic foot ulcer (DFU) prevalence and incidence rates and to quality appraise these studies. METHOD: A systematic review, following PRISMA guidelines, was undertaken to identify the incidence and prevalence of DFUs in the Arab world. The following databases were searched: PubMed, Embase CINAHL, Web of Science (Scopus), Global Health and EBSCO Results: A total of nine papers were identified. The mean prevalence of DFU in Saudi Arabia was 11.85% (4.7-19%), in Egypt was 4.2% (1-7.4%), in Jordan was 4.65% (4-5.3%), in Bahrain was 5.9% and in Iraq was 2.7%. A single study identified DFU incidence in Saudi Arabia as 1.8% between 2009-2010. CONCLUSION: The mean prevalence rates of DFU were highest in Saudi Arabia and Bahrain and lowest in Iraq. Saudi Arabia had the only reported incidence study, thus findings could not be compared to other countries of the Arab world. There were no studies identified during our search reporting prevalence rates of DFU in 17 of the 22 Arab countries. It is clear that further research is required to determine the incidence and prevalance of DFUs in the Arab world and that progress is needed in order to improve the quality of research conducted in those countries. PMID- 28880755 TI - Potential correlation of wound bed score and biomarkers in chronic lower leg wounds: an exploratory study. AB - OBJECTIVE: The wound bed score is a validated tool to monitor wound healing in chronic wounds, and depends on visual examination by trained personnel. This study describes the feasibility of adding some biochemical and immunohistochemical parameters to increase the objectivity and specificity of the wound bed score Method: Patients with chronic wounds on the lower leg with different durations were enrolled to assess the correlation between the wound bed score and specific wound-related biomarkers, namely MMP-9, MMP-2, NGAL, albumin, integrin alpha2/beta1, and other histochemical (CD68, PK1, CD32, fractalkine, periostin) and immunocytochemical markers from biopsies and smears taken from wound edges and bed. RESULTS: The study examined samples from 10 patients. Patients with an unfavourable wound bed score had a low expression of periostin and fractalkine in the wound bed tissue. CD68 PK1 showed a low or negative expression in the majority of the samples. Patients negative for CD68 PK1 were also negative for CD32. Principal component analysis revealed that the albumin level and the amount of proteins were associated with a high wound bed score. Two different subsets of patients could be discriminated either by integrin alpha2/beta1 and albumin percentages or the MMP-9 and MMP-2 activities Conclusion: These preliminary results pave the way towards an improved wound status diagnosis and an advanced quality of wound care and management. These findings need confirming with a large number of patients and at different time points. PMID- 28880756 TI - How Greek nurses perceive and overcome the barriers in implementing treatment for pressure ulcers: 'against the odds'. AB - OBJECTIVE: Although the occurrence of pressure ulcers (PUs) is now considered as an indicator of poor quality nursing care, questions and concerns remain regarding situations where PUs were unavoidable, irrespective of the care provided. The aim of this study was to explore Greek nurses' perceptions about the barriers involved and to identify the factors that influence care planning in PU treatment. METHOD: A grounded theory approach was used and semi-structured interviews were conducted with nurses who provided pressure care to clients in a rehabilitation centre in Greece. Data were analysed using the constant comparative method. RESULTS: We interviewed seven nurses. Findings revealed one main category entitled 'anarchy' in delivery of care consisted of the following three subcategories: interdisciplinary conflicts; total trust in traditional knowledge; and devaluation of other's work/role and a core category 'Against the odds': the perceived value of prevention and treatment can overcome the barriers in treating PUs. CONCLUSION: This study gives an overview of the views and beliefs of nurses about the problems and barriers involved in PU prevention and treatment. The study reveals that although some barriers to good practice may exist, nurses can hold a positive attitude toward PU prevention and treatment, and their perceived value of prevention and treatment may help nurses to overcome the barriers in managing PUs. PMID- 28880757 TI - Prospective observational study of single- or multi-compartment pressure ulcer prevention cushions: PRESCAROH project. AB - OBJECTIVE: In patients with reduced mobility, specialised pressure-relieving supports (mattresses, beds and cushions) are widely used to reduce or relieve the interface pressure between the skin and support surfaces to prevent incidence of pressure ulcers (PUs). The primary objective of these two observational studies was to assess the incidence of PUs in patients at high risk of PUs, seated in a wheelchair using a single- or multi-compartment air cushion. The level of patient satisfaction with the comfort and the views of the care team that used the air cushions were considered as secondary objectives. METHOD: The PRESCAROH project was two prospective observational studies conducted in patients free of PUs at baseline and at high risk of PUs (Braden score <=13 or <=16 for people with spinal cord injury). Patients had to spend more than eight hours a day in a wheelchair and use either a single-compartment air cushion (patient without asymmetry of support) for the first study or a multi-compartment air cushion (patient with asymmetry of support) for the second study. The primary end point was the percentage of patients in whom a PU (sacrum and/or ischium) developed over a 35-day period. The analysis was performed on the full-analysis set (FAS) of patients included with at least a second assessment. RESULTS: We recruited 152 patients, 78 seated on a single-compartment air cushion (SiCAC group) and 74 on a multi-compartment air cushion (MuCAC group), in the two independent studies. All patients were included in the FAS (n=152). Most patients had spinal cord injuries. The average time spent sitting was 10.2 (standard deviation (SD): 2.3) hours a day in the SiCAC group and 9.1 (SD: 1.9) hours a day in the MuCAC group. In the SiCAC group, 6.4% (5/78) of patients dropped out of the study (one patient because of pulmonary infection and four patients for cushion installation problems). In the MuCAC group, 8.1% (6/74) of patients dropped out of the study (three patients because of adverse events not related to cushions, two for onset of PU, one for cushion-related problem). Over the study period of 35 days, 2.6% (2/78) [95% confidence interval (CI): 0.3-9.0%] of patients in the SiCAC group and 4.0% (3/74) [95%CI: 0.8-11.4%] in the MuCAC group developed a PU. CONCLUSION: These two observational studies showed that in patients at high risk of PUs and seated for more than eight hours a day in a wheelchair, the use of a single compartment or multi-compartment air cushion with telescopic cells was associated with a low incidence of PUs. PMID- 28880758 TI - The clinical effectiveness of haemoglobin spray as adjunctive therapy in the treatment of chronic wounds. AB - OBJECTIVE: To investigate wound healing after application of adjunctive topical haemoglobin spray in patients with chronic wounds. METHOD: Consecutive patients with a diversity of chronic wounds (defined as <40% reduction in wound size within 4 weeks) were treated with standard wound care plus haemoglobin spray and evaluated over a 26-week period. Results were compared with a retrospective cohort of 50 consecutive patients treated with standard wound care alone. RESULTS: We evaluated 50 patients for a 26-week evaluation period, during which 45/50 patients (90%) treated with haemoglobin spray were completely healed compared with 19/50 retrospective control patients (38%) (p<0.001). Mean time to complete wound healing was 6.6 weeks (range: 3-22) in the haemoglobin spray group compared with 11.4 weeks (range: 3-25) in the control group (p=0.01). Cox proportional hazards analysis model adjusting for baseline wound size and months wound present also yielded significant treatment effects. Exudate, slough and pain levels were all reduced to a greater extent versus control group. CONCLUSION: Haemoglobin spray resulted in a higher number of healed wounds and a faster rate of healing, as well as a positive impact on other wound parameters. These results are in accordance with other published data and supports the adjunctive use of haemoglobin spray in patients with a wide variety of chronic wounds of all sizes and origins. PMID- 28880759 TI - Evidence generation for wound care dressing selection: reviewing the issues. AB - In the UK, dressings are categorised as medical devices and manufacturers only have to provide limited evidence of effectiveness before dressings are used in clinical practice. Therefore, evidence based on clinical trial methods is scant. As a direct result, governing bodies in the UK are now recommending that decisions to select one dressing over another could mainly be made on price. Placed within the movement critiquing evidence-based practice (EBP), this paper summarises the main issues surrounding the generation of evidence in selecting dressings for wound care, which is immersed in a context that lacks resources, legislative clarity and freedom to choose methodological alternatives. Dressings are therapeutic medical devices rather than consumables and any rationalisation based on costs may have far-reaching implications for wound care clinicians through purchasing decisions and thus may limit their ability to manage wounds effectively. PMID- 28880760 TI - Diabetes and pressure ulcer risk in hip fracture patients: a meta-analysis. AB - OBJECTIVE: The aim of this study was to assess the relationship between diabetes and pressure ulcer (PU) risk in patients with hip fractures. METHOD: Searches of MEDLINE (1966-), ISI Databases (1965-) and Scopus (1996-) were performed for English language studies. The search data was 29 July 2016. Odds ratio (OR) for PUs were calculated for hip fracture patients with or without diabetes and a meta analysis was carried out following meta-analysis of observational studies in epidemiology (MOOSE) guidelines. RESULTS: A total of 8 studies with 22,180 patients were included in this study. The mean PU incidence was 15.1% in group with diabetes compared with 7.5% in the group without diabetes. When comparing with and without diabetes meta-analysis showed the summary OR was 1.825 [95% confidence interval (CI): 1.373-2.425; z=4.15, p<0.00001]. No significant publication bias was found. Sensitivity analysis included prospective studies [OR: 1.383, 95%CI: 1.035-1.847] and pooled the adjusted OR [OR: 1.282, 95%CI: 1.054-1.560] showed the result was robust. Subgroup analysis by PU stage showed the summary OR was 1.474 [95% CI 0.984-2.207] for >= category II PU, and 2.814 [95%CI: 2.115-3.742] for >=category I PU. The meta-regression showed PU incidence explained 27.77% proportion of between-study variance, but statistical test showed no significance (t=-1.96, p=0.097). CONCLUSION: Our meta-analysis indicates that diabetes increases the PU risk in hip fracture patients. Therefore, specific recommendations should apply for the management of diabetic patients with hip fractures at risk of PU. PMID- 28880761 TI - Predictive validity of the Braden scale for assessing risk of developing pressure ulcers and dependence-related lesions. AB - OBJECTIVE: In 2014, a new theoretical model explained the mechanism of the development of pressure ulcers (PUs) and that of seven types of lesions known as dependence-related lesions (DRL). The aim of this study was to calculate the incidence of DRL that have been classified as PUs and to check the predictive validity of the Braden scale for assessing DRL in accordance with the new theoretical model in an intensive care unit (ICU). Method This longitudinal, prospective study was conducted in a Spanish ICU. The patients were monitored for 14 days in the ICU until they developed DRL, died, or were discharged. The patients' risk of developing DRL was assessed each day using the Braden scale. The following parameters were taken as reference for validating the scale: sensitivity (Se), specificity (Sp), positive and negative predictive values (PPV and NPV, respectively), relative risk (RR) and the area under the receiver operating characteristic (ROC) curve. RESULTS: Of the 295 patients included in the study, 27.5% developed DRL, which 50.6% were categorised as PUs, 17.3% caused by moisture, and 13.6% caused by friction. The rest were categorised as caused by a combination of factors. Risk according to the Braden scale was greater in the group of patients with DRL than in the group of patients without. The highest risk score provided the best predictive validity parameters for the DRL (Se 0.90, Sp 0.26, PPV 0.31, NPV 0.78 and RR 3.15 [confidence interval (CI) 95%: 1.42 6.96]). These vaules show the individuals at risk are well detected, although it is at the expense of generating a number of false positive cases. CONCLUSIONS: The Braden scale has demonstrated a moderate capacity for predicting PUs and DRL caused by moisture, but no capacity for predicting DRL caused by friction. PMID- 28880762 TI - Low-quality evidence from RCTs is not giving us answers. PMID- 28880763 TI - Letters: Response to 'Food for thought: innovation and debate' Journal of Wound Care July 2017; 26: 7. PMID- 28880764 TI - Comparing the effectiveness and wash-off resistance of skin barrier creams: a healthy volunteer study. AB - OBJECTIVE: Preventing moisture damage and breakdown of the skin can be a particular challenge for patients with incontinence. The level of protection offered by various skin protectant products can vary according to the chemical nature of the formulation and can decrease following wash procedures. The aim of this study was to compare five silicone-containing skin barrier creams indicated for use on incontinence-associated dermatitis (IAD) in terms of their resistance to a standardised wash cycle in healthy volunteer subjects. METHOD: A skin surface hygrometer (Skicon 200EX) evaluated skin surface conduction non invasively on 36 non-patient subjects using a high-frequency (3.5MHz) electric current. This provided an index of the degree of protection given by barrier products after a single application and also any reduction in barrier properties after a repeated wash procedure. RESULTS: Medi Derma-S barrier cream (MDS), Cavilon barrier cream (CBC) and LBF barrier cream (LBF) all demonstrated statistically significant differences (p<0.001) in the Skicon values following the first moisture challenge compared with Medihoney (MH), Remedy barrier cream (RBC) and the untreated control. All other comparisons were not significant (p>0.05). Statistical analysis following four moisture challenges reflected the results following the first, whereby Skicon values following treatment with MDS, CBC and LBF was significantly different compared with MH, RBC and the untreated control. Again, all other comparisons were not significant (p>0.05). When expressed as percentage barrier effectiveness, the results show a similar pattern to the absolute Skicon values. CONCLUSION: The results of this study show that there were differences between the barrier creams in terms of the initial moisture challenge and the resistance to wash-off following a repeated standardised wash procedure. It was concluded that MDS, CBC and LBF barrier cream all showed significant and equally effective moisture barrier protection and wash off resistance. PMID- 28880765 TI - The Development and Validation of an In Vitro Airway Model to Assess Realistic Airway Deposition and Drug Permeation Behavior of Orally Inhaled Products Across Synthetic Membranes. AB - BACKGROUND: Current in vitro approaches to assess lung deposition, dissolution, and cellular transport behavior of orally inhaled products (OIPs) have relied on compendial impactors to collect drug particles that are likely to deposit in the airway; however, the main drawback with this approach is that these impactors do not reflect the airway and may not necessarily represent drug deposition behavior in vivo. The aim of this article is to describe the development and method validation of a novel hybrid in vitro approach to assess drug deposition and permeation behavior in a more representative airway model. METHODS: The medium sized Virginia Commonwealth University (VCU) mouth-throat (MT) and tracheal bronchial (TB) realistic upper airway models were used in this study as representative models of the upper airway. The TB model was modified to accommodate two Snapwell(r) inserts above the first TB airway bifurcation region to collect deposited nebulized ciprofloxacin-hydrochloride (CIP-HCL) droplets as a model drug aerosol system. Permeation characteristics of deposited nebulized CIP-HCL droplets were assessed across different synthetic membranes using the Snapwell test system. RESULTS: The Snapwell test system demonstrated reproducible and discriminatory drug permeation profiles for already dissolved and nebulized CIP-HCL droplets through a range of synthetic permeable membranes under different test conditions. The rate and extent of drug permeation depended on the permeable membrane material used, presence of a stirrer in the receptor compartment, and, most importantly, the drug collection method. CONCLUSIONS: This novel hybrid in vitro approach, which incorporates a modified version of a realistic upper airway model, coupled with the Snapwell test system holds great potential to evaluate postairway deposition characteristics, such as drug permeation and particle dissolution behavior of OIPs. Future studies will expand this approach using a cell culture-based setup instead of synthetic membranes, within a humidified chamber, to assess airway epithelia transport behavior in a more representative manner. PMID- 28880766 TI - Establishing a Right Frontal Beta Signature for Stopping Action in Scalp EEG: Implications for Testing Inhibitory Control in Other Task Contexts. AB - Many studies have examined the rapid stopping of action as a proxy of human self control. Several methods have shown that a critical focus for stopping is the right inferior frontal cortex. Moreover, electrocorticography studies have shown beta band power increases in the right inferior frontal cortex and in the BG for successful versus failed stop trials, before the time of stopping elapses, perhaps underpinning a prefrontal-BG network for inhibitory control. Here, we tested whether the same signature might be visible in scalp electroencephalography (EEG)-which would open important avenues for using this signature in studies of the recruitment and timing of prefrontal inhibitory control. We used independent component analysis and time-frequency approaches to analyze EEG from three different cohorts of healthy young volunteers (48 participants in total) performing versions of the standard stop signal task. We identified a spectral power increase in the band 13-20 Hz that occurs after the stop signal, but before the time of stopping elapses, with a right frontal topography in the EEG. This right frontal beta band increase was significantly larger for successful compared with failed stops in two of the three studies. We also tested the hypothesis that unexpected events recruit the same frontal system for stopping. Indeed, we show that the stopping-related right-lateralized frontal beta signature was also active after unexpected events (and we accordingly provide data and scripts for the method). These results validate a right frontal beta signature in the EEG as a temporally precise and functionally significant neural marker of the response inhibition process. PMID- 28880767 TI - Cross-language Neighborhood Effects in Learners Indicative of an Integrated Lexicon. AB - This study examined how acquisition of novel words from an unknown language (L2) is influenced by their orthographic similarity with existing native language (L1) words in beginning adult learners. Participants were tested in a two-alternative forced-choice recognition task and a typing production task as they learned to associate 80 L2 (pseudo)words with pictures depicting their meanings. There was no effect of L1 orthographic neighborhood density on accuracy in the two alternative forced-choice task, but typing accuracy was higher for L2 words with many L1 neighbors in the earliest stages of learning. ERPs recorded during a language decision task before and after learning also showed differences as a function of L1 neighborhood density. Across sessions, L2 words with many L1 neighbors elicited slower responses and larger N400s than words with fewer L1 neighbors, suggesting that L1 neighbors continued to influence processing of the L2 words after learning (though to a lesser extent). Finally, ERPs recorded during a typing task after learning also revealed an effect of L1 neighborhood that began about 700 msec after picture onset, suggesting that the cross-language neighborhood effects cannot solely be attributed to bottom-up activation of L1 neighbors. Together, these results demonstrate that strategic associations between novel L2 words and existing L1 neighbors scaffold learning and result in interactions among cross-language neighbors, suggestive of an integrated L1-L2 lexicon. PMID- 28880768 TI - Windsor, Ontario Exposure Assessment Study: Design and Methods Validation of Personal, Indoor, and Outdoor Air Pollution Monitoring. AB - The Windsor, Ontario Exposure Assessment Study evaluated the contribution of ambient air pollutants to personal and indoor exposures of adults and asthmatic children living in Windsor, Ontario, Canada. In addition, the role of personal, indoor, and outdoor air pollution exposures upon asthmatic children's respiratory health was assessed. Several active and passive sampling methods were applied, or adapted, for personal, indoor, and outdoor residential monitoring of nitrogen dioxide, volatile organic compounds, particulate matter (PM; PM <=2.5 MUm [PM2.5] and <= 10 MUm [PM10] in aerodynamic diameter), elemental carbon, ultrafine particles, ozone, air exchange rates, allergens in settled dust, and particulate associated metals. Participants completed five consecutive days of monitoring during the winter and summer of 2005 and 2006. During 2006, in addition to undertaking the air pollution measurements, asthmatic children completed respiratory health measurements (including peak flow meter tests and exhaled breath condensate) and tracked respiratory symptoms in a diary. Extensive quality assurance and quality control steps were implemented, including the collocation of instruments at the National Air Pollution Surveillance site operated by Environment Canada and at the Michigan Department of Environmental Quality site in Allen Park, Detroit, MI. During field sampling, duplicate and blank samples were also completed and these data are reported. In total, 50 adults and 51 asthmatic children were recruited to participate, resulting in 922 participant days of data. When comparing the methods used in the study with standard reference methods, field blanks were low and bias was acceptable, with most methods being within 20% of reference methods. Duplicates were typically within less than 10% of each other, indicating that study results can be used with confidence. This paper covers study design, recruitment, methodology, time activity diary, surveys, and quality assurance and control results for the different methods used. [Box: see text]. PMID- 28880771 TI - The Native Hawaiian and Pacific Islander National Health Interview Survey: Data Collection in Small Populations. PMID- 28880772 TI - Withering Syndrome in Farmed Red Abalone Haliotis rufescens: Thermal Induction and Association with a Gastrointestinal Rickettsiales-like Prokaryote. AB - Withering syndrome (WS) is a chronic wasting disease responsible for mass mortality in wild populations of black abalone Haliotis cracherodii. The etiology of WS is uncertain with limited evidence for the role of a gastrointestinal Rickettsiales-like prokaryote (RLP). We documented for the first time the occurrence of animals with clinical signs of WS and associated morphological changes in another haliotid species, the red abalone H. rufescens. In this study, 60 juvenile red abalone (8 cm) were randomly selected from a farmed population raised at 14 degrees C that was known to have low-intensity RLP infections but lacked clinical signs of WS. The abalone were held in triplicate containers receiving water of approximately 14.7 degrees C (Control, Co) or 18.5 degrees C (elevated temperature, ET) and were fed equally for 220 d. Survival was 100% (30/30) for the Co group and 67% (20/30) for the ET group. The ET group animals had higher RLP infection intensities and showed more clinical signs (mantle retraction, lower weight gain, lower condition index) and morphological changes (digestive gland degeneration) associated with WS. In trials conducted immediately before termination of the experiment, ET group animals fed at half the rate of Co group animals. Among ET group animals, the intensity of RLP infections in the posterior portion of the esophagus was positively correlated with WS clinical signs and morphological changes, whereas no correlations were present among Co group animals. During 1997-1998 and in conjunction with elevated seawater temperatures associated with El Nino, several abalone farms in California experienced a dramatic increase in the proportion of red abalone showing signs of WS. Examination of 66 red abalone from five commercial farms revealed that animals with more advanced RLP infections had more severe WS clinical signs and associated morphological changes. Collectively, these data demonstrate that RLP infection plays a key role in the etiology of WS in red abalone and that warm water enhances the severity of the pathogenic effects of RLP infection. PMID- 28880773 TI - Pfiesteria piscicida and Ulcerative Mycosis of Atlantic Menhaden-Current Status of Understanding. AB - Ulcerative lesions in estuarine finfish are associated with a variety of parasitic, bacterial, and fungal infectious agents as well as water quality and other abiotic stress factors. Atlantic menhaden Brevoortia tyrannus are a severely affected species typically exhibiting solitary, perianal, focal, deep, granulomatous lesions containing oomycete hyphae. Intense recent emphasis in the scientific literature and in the popular press has been placed on Pfiesteria-like dinoflagellates and their toxins as the causative agents for ulcerative finfish lesions in east coast estuaries of the United States. Dramatic descriptive terms for Pfiesteria, including "phantom," "ambush-predator" and "the cell from hell," capable of affecting humans, have appeared in scientific journals and the news media. However, there is no scientific evidence to date that supports a single, causal relationship between the presence of toxic Pfiesteria-like dinoflagellates and fish kills or the associated ulcerative lesions. This is due, at least in part, to the difficulty of maintaining toxic Pfiesteria-like dinoflagellates in clonal culture and, in part, to the presence of other microorganisms in laboratory culture systems. Further, there is at present no toxin-specific probe to identify Pfiesteria toxins in estuarine environments during fish kills, nor has Pfiesteria been isolated from fish lesions. Yet, based on the limited published scientific evidence and the popular press coverage, there have been river closures, notable economic losses, and public alarm due to Pfiesteria. Future research into agents infectious to menhaden, such as Aphanomyces (Oomycetes) and toxin-producing estuarine inhabitants like Pfiesteria, is needed. These organisms and the disease processes in which they are implicated may also serve as markers for overall estuarine condition. Control of microorganisms, including Pfiesteria, to improve finfish health in estuaries is unlikely. However, using the presence of these microorganisms and their Atlantic menhaden hosts as sentinels to help monitor water quality may be a viable approach to assist future estuarine management. PMID- 28880774 TI - Susceptibility of Arctic Char to Experimental Challenge with Infectious Hematopoietic Necrosis Virus (IHNV) and Infectious Pancreatic Necrosis Virus (IPNV). AB - Arctic char Salvelinus alpinus were exposed to the fish pathogens infectious hematopoietic necrosis virus (IHNV) and infectious pancreatic necrosis virus (IPNV) to estimate susceptibility of the species to infection. Fish were immersion challenged at 46, 74, and 95 d posthatch for 5 h in viral concentration of 103 or 105 PFU(plaque-forming units)/mL and were monitored for 21 d postchallenge. Fish that died were assayed individually for virus-associated mortality, and survivors were assayed individually to estimate prevalence of virus carrier status. Arctic char succumbed to IHNV infection with population losses as high as 41%, and prevalence of IHNV carriers in surviving fish was 24% or less with virus titers in carrier fish ranging from 2.5 * 102 PFU/g to greater than 1.3 * 106 PFU/g. Infections with IPNV resulted in losses of 20% or less, and prevalence of IPNV carriers in surviving fish was as high as 82% with virus titers in carrier fish ranging from 2.5 * 102 PFU/g to greater than 5.0 * 106 PFU/g. Logistic regression models were developed for the mortality and infection data for each virus. For IHNV, the odds of dying or becoming infected were significantly greater for the fish from the 74-d age-group than for the fish from the 46-d or 95-d age-groups. Fish exposed to 105 PFU of IHNV/mL had significantly greater odds of dying or becoming infected than fish exposed to 103 PFU/mL. For IPNV, the odds of dying were significantly greater for the 74-d age-group compared with the other two age-groups. The 74-d fish were also significantly more likely to become infected than the 95-d-old fish. Fish exposed to 105 PFU of IPNV/mL had significantly greater odds of dying or becoming infected than fish exposed to 103 PFU of IPNV /mL. PMID- 28880775 TI - A Herpesvirus Associated with Mass Mortality of Juvenile and Adult Koi, a Strain of Common Carp. AB - A herpesvirus was isolated from adult koi, a strain of common carp Cyprinus carpio, suffering mass mortality in two outbreaks-one in the mid-Atlantic region of the United States and the second in Israel. The principal external signs of dying fish were pale and irregularly colored gills. There were few consistent internal signs in either outbreak. The most prominent microscopic lesions were in the gills, where hyperplasia and necrosis of the epithelium were severe. Other lesions included interstitial nephritis, splenitis, and enteritis. Affected cells often contained nuclei with marginated chromatin and faint intranuclear inclusions. Typical herpesvirus particles were present in branchial epithelial cells, hepatocytes, and among circulating leukocytes. Inoculations of the koi fin (KF-1) cell line with tissue extracts from the gill and kidney-spleen resulted in cytopathic effects characterized by severe vacuolation first detected after 7 d incubation at 20 degrees C. Exposures of adult koi to the herpesvirus as propagated in KF-1 cells by bath or intraperitoneal injections resulted in 80 100% mortality during a 26-d period, and the virus was reisolated from the gill, kidney, liver, spleen, intestine, and brain of dead fish. The viral agents from koi in Israel and the United States appear to be similar if not identical; both could be distinguished from Herpesvirus cyprini by indirect fluorescent antibody tests with rabbit anti-H. cyprini serum. Other factors should be examined but we strongly suspect that this newly recognized koi herpesvirus (KHV) has the potential to be a significant cause of mortality among koi and presumably common carp. PMID- 28880776 TI - Brain Monoamine Concentrations as Predictors of Growth Inhibition in Channel Catfish Exposed to Ammonia. AB - Fingerlings of channel catfish Ictalurus punctatus exhibited a significant exposure-dependent decrease in growth (measured by weight gain and increase in total length) and condition factor after 9 weeks of exposure to environmental ammonia. Concentrations of 5-hydroxytryptamine (5-HT) and dopamine in the brain decreased significantly whereas the ratio of 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT increased significantly in exposure-dependent manners. The brain dopamine concentrations and the 5-HIAA : 5-HT ratio collectively explained 88% of the variation in growth due to ammonia exposure. This study demonstrates the potential to predict ammonia-induced inhibition of growth in channel catfish with physiological changes. PMID- 28880777 TI - Hermaphroditism in Laboratory-Cultured Albino Western Mosquitofish. AB - During routine inspection of a colony of albino western mosquitofish Gambusia affinis, approximately 10 females were discovered to have distended abdominal cavities. Cause for the distention was investigated by examination of tissue sections from four sacrificed individuals, all of which suffered severe ascites. Hermaphroditic gonads were seen in two of the fish. PMID- 28880778 TI - Correlation of Transforming Growth Factor-beta Messenger RNA (TGF-beta mRNA) Expression with Cellular Immunoassays in Triamcinolone-Treated Captive Hybrid Striped Bass. AB - Assessing fish immune status with molecular markers has been hampered by a lack of specific reagents. A quantitative polymerase chain reaction (PCR) method (reverse transcription quantitative-competitive PCR, RT-qcPCR) for measuring transforming growth factor-beta (TGF-beta) transcription from a broad range of teleost fish has recently been developed. The quantitative PCR now permits monitoring production of this important immunosuppressive cytokine in response to immunomodulating agents and conditions. We examined anterior kidney and spleen mononuclear cells from hybrid striped bass (female striped bass Morone saxatilis * male white bass M. chrysops) for production of TGF-beta messenger RNA (mRNA) in response to administration of the synthetic glucocorticoid triamcinolone. We also compared TGF-beta transcription with anterior kidney macrophage bactericidal activity and splenic lymphocyte blastogenesis. Anterior kidney mononuclear cell TGF-beta mRNA levels decreased, whereas bactericidal activity increased. Spleen TGF-beta mRNA levels did not change significantly, and splenic lymphocyte pokeweed mitogen stimulation index increased in triamcinolone-treated fish. Since triamcinolone is used therapeutically as a suppressive immunomodulator, the enhanced immune functions indicated by the cellular immunoassays were unexpected; however, the inverse response of TGF-beta production and macrophage bactericidal activity was consistent with the known relationship between TGF-beta and macrophage activation in mammals. Induced immunomodulation in hybrid striped bass was detectable by both traditional cellular immunoassays and the new RT-qcPCR for TGF-beta. PMID- 28880779 TI - Infections of Edwardsiella tarda among Brook Trout in Quebec. AB - Acute bacterial septicemia is commonly diagnosed in brook trout Salvelinus fontinalis of Quebec, Canada. The agents most commonly isolated include Aeromonas salmonicida (furunculosis), Aeromonas hydrophila (motile aeromonad septicemia), and Pseudomonas species. Septicemia in brook trout caused by the gram-negative bacterium Edwardsiella tarda was diagnosed for the first time in the province of Quebec from two different fish farms producing stock for fee fishing establishments. Affected fish displayed nonspecific lesions associated with bacterial septicemia including hemorrhages on the gills and viscera and exophthalmia. Stress-associated immunosuppression due to an increase in summer water temperatures and lack of precipitation were considered as primary causes of these disease outbreaks. PMID- 28880780 TI - Adsorption and Infectivity of Infectious Hematopoietic Necrosis Virus (IHNV) with Various Solids. AB - Adsorption of infectious hematopoietic necrosis virus (IHNV) to sea sand, Japanese acid clay, diatomaceous earth, kaolin, bentonite, quartz sand, chitin, cellulose powder, ion exchange hydrophobic Toyopeal and Cellulofine, alundum, active carbon, silica gel, glass, plastic, and bacterial cells was studied. The IHNV adsorbed to several clays (kaolin, bentonite, Japanese acid clay) and diatomaceous earth in sterilized water with a wide range of pH (5-11) at concentrations of 1, 10, and 100 mg/mL. Except for bentonite, infectivity of clay adsorbed IHNV persisted for as long as 9 weeks. The clay-adsorbed IHNV also persisted in infectivity to rainbow trout Oncorhynchus mykiss, causing cumulative mortality rates of more than 73%. The results suggest that IHNV adsorbed to naturally occurring substances in various aquatic environments may provide a source of infection for susceptible fish inhabiting these environments. PMID- 28880781 TI - Detection of Green Turtle Herpesviral Sequence in Saddleback Wrasse Thalassoma duperrey: A Possible Mode of Transmission of Green Turtle Fibropapilloma. AB - Samples of DNA were prepared from various tissues and organs (including snout, gill, eye, brain, heart, liver, gut content, intestine, swim bladder, spleen, gallbladder, spinal cord, gonad, and muscle) of six healthy appearing reef cleaner fish, saddleback wrasses Thalassoma duperrey, captured from a cleaning station in North Kaneohe Bay, Oahu, Hawaii. The DNA samples were tested for evidence of green turtle herpesvirus infection by nested polymerase chain reaction (PCR). Green turtle herpesviral sequences were detected in snout (3/6), gill (2/6), and liver (1/6). All other tissues were negative. Except for a single nucleotide substitution (from A to G at position 48, resulting in a single amino acid change from isoleucine to methionine at position 16), the DNA sequences detected in the fish were identical to that of a newly reported green turtle herpesvirus. Although preliminary, these data represent the first evidence for an association of a herpesvirus with saddleback wrasse, suggesting that cleaner fish may serve as vectors or carriers for the transmission of the agent causing green turtle fibropapilloma. PMID- 28880782 TI - Increased Virulence in an Introduced Pathogen: Haplosporidium nelsoni (MSX) in the Eastern Oyster Crassostrea virginica. AB - The protistan parasite Haplosporidium nelsoni has caused extensive mortality in the eastern oyster Crassostrea virginica along the mid-Atlantic coast of the United States since 1957. The origin of H. nelsoni has remained unresolved. Molecular diagnostic tools were used to examine the hypothesis that a haplosporidian parasite in the Pacific oyster C. gigas is H. nelsoni. A DNA probe specific for H. nelsoni reacted positively in in situ hybridizations with haplosporidian plasmodia from C. gigas collected in Korea, Japan, and California. Primers that specifically amplify H. nelsoni DNA in the polymerase chain reaction amplified product from Californian C. gigas infected with the haplosporidian parasite. The DNA sequence of the 565-base pair amplified product was identical to the H. nelsoni sequence except for a single nucleotide transition, a similarity of 99.8%. These results are conclusive evidence that the parasite in C. gigas is H. nelsoni and strongly support previous speculation that the parasite was introduced into Californian populations of C. gigas from Japan. Results also support previous speculation that H. nelsoni was introduced from the Pacific Ocean to C. virginica on the East Coast of the United States, likely with known importations of C. gigas. These results document greatly increased virulence in a naive host-parasite association and reinforce potential dangers of intentional, but improper, introductions of exotic marine organisms for aquaculture or resource restoration. PMID- 28880783 TI - Competitive balance trends in elite table tennis: the Olympic Games and World Championships 1988-2016. AB - Competitive balance is important because it enhances outcome uncertainty and therefore it promotes spectator interest, and encourages government investment in a sport. This article analyses the distribution of gold medals, medals, medal points and top eight points amongst nations in table tennis from 1988 to 2016 at the Olympic Games and the World Championships respectively. A normalised version of the Herfindahl-Hirschman Index and a coefficient of variation are calculated for each nation's share of these performance indicators. The key findings are that China dominates both events, with successful female players being more dominant than their male counterparts. The competitive balance for gold medals has declined, whilst there is a trend towards improved competitive balance for top eight points for women, suggesting that more teams are featuring in the top eight (but not necessarily the top three) placings. This research has implications for the development of table tennis competitions. Compared to other racket sports, the issue of competitive imbalance in table tennis is particularly thorny, which threatens the long-term development of this sport. Accordingly, some measures are recommended for the International Olympic Committee and the International Table Tennis Federation to propel a more balanced development of international table tennis. PMID- 28880786 TI - Low-Molecular-Weight Iron Chelates May Be an Alternative to Gadolinium-based Contrast Agents for T1-weighted Contrast-enhanced MR Imaging. AB - Purpose To synthesize two low-molecular-weight iron chelates and compare their T1 contrast effects with those of a commercial gadolinium-based contrast agent for their applicability in dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging. Materials and Methods The animal experiments were approved by the local ethics committee. Two previously described iron (Fe) chelates of pentetic acid (Fe-DTPA) and of trans-cyclohexane diamine tetraacetic acid (Fe-tCDTA) were synthesized with stability constants several orders of magnitude higher than those of gadolinium-based contrast agents. The T1 contrast effects of the two chelates were compared with those of gadopentetate dimeglumine in blood serum phantoms at 1.5 T, 3 T, and 7 T. For in vivo studies, a human breast cancer cell line (MDA-231) was implanted in five mice per group. The dynamic contrast effects of the chelates were compared by performing DCE MR imaging with intravenous application of Fe-DTPA or Fe-tCDTA on day 1 and DCE MR imaging in the same tumors with gadopentetate dimeglumine on day 2. Quantitative DCE maps were generated with software and were compared by means of a one-tailed Pearson correlation test. Results Relaxivities in serum (0.94 T at room temperature) of Fe-tCDTA (r1 = 2.2 mmol-1 . sec-1, r2 = 2.5 mmol-1 . sec-1) and Fe-DTPA (r1 = 0.9 mmol-1 . sec-1, r2 = 0.9 mmol-1 . sec-1) were approximately twofold and fivefold lower, respectively, compared with those of gadopentetate dimeglumine (r1 = 4.1 mmol-1 . sec-1, r2 = 4.8 mmol-1 . sec-1). Used at moderately higher concentrations, however, iron chelates generated similar contrast effects at T1-weighted MR imaging in vitro in serum, in vivo in blood, and for DCE MR imaging of breast cancer xenografts. The volume transfer constant values for Fe-DTPA and Fe-tCDTA in the same tumors correlated well with those observed for gadopentetate dimeglumine (Fe-tCDTA Pearson R, 0.99; P = .0003; Fe DTPA Pearson R, 0.97; P = .003). Conclusion Iron-based contrast agents are promising as alternatives for contrast enhancement at T1-weighted MR imaging and have the potential to contribute to the safety of MR imaging. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28880789 TI - Pathology of Oropharyngeal Fibropapillomatosis in Green Turtles Chelonia mydas. AB - Complete gross and histopathologic examinations of the oral cavity, tongue, pharynx, larynx, and glottis were performed in five Hawaiian green turtles Chelonia mydas with fibropapillomatosis. These examinations demonstrated that the oropharyngeal fibropapillomas were similar to characteristic external fibropapillomas previously described for green turtles. The size, appearance, and anatomic site of the tumors confirmed that these turtles presented total or partial occlusion of the nasopharynx, glottis, larynx, and adjacent tissues. The fibropapillomas of the oropharynx were considered locally invasive and severely modified the morphophysiology of respiration and feeding in these turtles. To the best of our knowledge, this is the first report of oropharyngeal fibropapillomatosis in sea turtles. PMID- 28880787 TI - Targeting STAT3 to Suppress Systemic Pro-Oncogenic Effects from Hepatic Radiofrequency Ablation. AB - Purpose To (a) identify key expressed genes in the periablational rim after radiofrequency ablation (RFA) and their role in driving the stimulation of distant tumor growth and (b) use adjuvant drug therapies to block key identified mediator(s) to suppress off-target tumorigenic effects of hepatic RFA. Materials and Methods This institutional animal care and use committee-approved study was performed in C57BL6 mice (n = 20) and F344 rats (n = 124). First, gene expression analysis was performed in mice after hepatic RFA or sham procedure; mice were sacrificed 24 hours to 7 days after treatment. Data were analyzed for differentially expressed genes (greater than twofold change) and their functional annotations. Next, animals were allocated to hepatic RFA or sham treatment with or without STAT3 (signal transducer and activator of transcription 3) inhibitor S3I-201 for periablational phosphorylated STAT3 immunohistochemistry analysis at 24 hours. Finally, animals with subcutaneous R3230 adenocarcinoma tumors were allocated to RFA or sham treatment with or without a STAT3 inhibitor (S3I-201 or micellar curcumin, eight arms). Outcomes included distant tumor growth, proliferation (Ki-67 percentage), and microvascular density. Results At 24 hours, 217 genes had altered expression (107 upregulated and 110 downregulated), decreasing to 55 genes (27 upregulated and 28 downregulated) and 18 genes (four upregulated, 14 downregulated) at 72 hours and 7 days, respectively. At 24 hours, STAT3 occurred in four of seven activated pathways associated with pro-oncogenic genes at network analysis. Immunohistochemistry analysis confirmed elevated periablational phosphorylated STAT3 24 hours after RFA, which was suppressed with S3I-201 (percentage of positive cells per field: 31.7% +/- 3.4 vs 3.8% +/- 1.7; P < .001). Combined RFA plus S3I-201 reduced systemic distant tumor growth at 7 days (end diameter: 11.8 mm +/- 0.5 with RFA plus S3I-201, 19.8 mm +/- 0.7 with RFA alone, and 15 mm +/- 0.7 with sham procedure; P < .001). STAT3 inhibition with micellar curcumin also suppressed postablation stimulation of distant tumor growth, proliferation, and microvascular density (P < .01). Conclusion Gene expression analysis identified multiple pathways upregulated in the periablational rim after hepatic RFA, of which STAT3 was active in four of seven. Postablation STAT3 activation is linked to increased distant tumor stimulation and can be suppressed with adjuvant STAT3 inhibitors. (c) RSNA, 2017. PMID- 28880788 TI - Use of Nicotine in Electronic Nicotine and Non-Nicotine Delivery Systems by US Adults, 2015. AB - Nicotine in electronic nicotine and non-nicotine delivery systems (ENDS/ENNDS) may present a risk of harm to those with cardiovascular disease and the fetuses of pregnant women. We assessed the extent to which adult users of ENDS/ENNDS used these products with nicotine. We obtained data for this study from a national probability survey of 6051 US adults that was conducted in August and September 2015. Of 399 adult ENDS/ENNDS users who were current smokers, 337 (80.7%) used ENDS/ENNDS containing nicotine, whereas only 29 of 71 (36.9%) ENDS/ENNDS users who were never smokers used ENDS/ENNDS containing nicotine. Assessments of the population health impact of ENDS/ENNDS use among never smokers should take into account the extent to which use involves nicotine. PMID- 28880790 TI - Isolation, Purification, and Molecular Weight Determination of Serum Immunoglobulin from Gulf Menhaden: Development of an Enzyme-Linked Immunosorbent Assay to Assess Serum Immunoglobulin Concentrations from Atlantic Menhaden. AB - An immunoglobulin M (IgM)-like immunoglobulin was isolated by polyethylene glycol precipitation from pooled serum collected from healthy gulf menhaden Brevoortia patronus. The immunoglobulin (Ig) was purified by Sephacryl-400 gel filtration chromatography. The molecular weight of unreduced, purified Ig was determined to be 850 kilodaltons (kD) by high-performance liquid chromatography. A goat antiserum against the purified Ig was produced and determined to react with the serum Ig of both gulf and Atlantic menhaden B. tyrannus by double gel diffusion. When reacted with sera from taxonomically unrelated species of fish, sheepshead minnow Cyprinodon variegatus, striped mullet Mugil cephalus, gulf flounder Paralichthys albigutta, and hybrid striped bass (white bass Morone chrysops * striped bass M. saxatilis), no precipitation bands developed. Furthermore, the specificity of the goat antiserum was shown by Western blot analysis to be for the 77,000-molecular-weight heavy chain of reduced and alkylated gulf and Atlantic menhaden Ig. An indirect enzyme-linked immunosorbent assay (ELISA) was developed for the assessment of Ig concentrations in Atlantic menhaden serum. To illustrate the applicability of the ELISA, we assessed the Ig concentration in the serum of 542 healthy Atlantic menhaden collected from inland bays of Delaware and Maryland in 2000 and 2001. The amount of Ig was estimated to be in the range 0.26-23.50 mg/mL, with a mean of 7.37 and a standard deviation of 5.12 mg/mL. The ELISA was reproducible, as determined by the inter- and intra-assay coefficients of variation (100.SD/mean) of 11.2% and 6.8%, respectively, and used very small amounts (1-2 MUL) of serum to assess the Ig concentrations from menhaden. PMID- 28880791 TI - Case Report: Viral Infectious Pancreatic Necrosis in Farmed Rainbow Trout from Mexico. AB - This case report provides pathologic and confirmatory diagnostic documentation of the first reported clinical epizootic of infectious pancreatic necrosis (IPN) in farmed rainbow trout Oncorhynchus mykiss from central Mexico. Both the gross and microscopic pathology were consistent with IPN. A virus was isolated in cell culture with the cytopathic effect typical of the IPN virus (IPNV). Positive identification as IPNV was achieved by means of an IPNV-specific indirect fluorescent antibody test and reverse transcription-polymerase chain reaction. Further genotyping identified this isolate as the Buhl strain of IPNV, which is a member of the West Buxton (A1) serotype of aquatic birnavirus serogroup A. PMID- 28880792 TI - The Effects of Two Rearing Salinities on Survival and Stress of Winter Flounder Broodstock. AB - The goal of this study was to determine rearing conditions that would improve the survival of broodstock of winter flounder Pleuronectes americanus. We hypothesized that keeping wild winter flounder in iso-osmotic water would reduce the energy costs related to osmoregulation; the resulting energy gain could then be used for growth or immune responses. Eighty fish were randomly separated into four tanks, two containing seawater (SW; 28.7 +/- 0.90/00 (mean +/- SD)) and two containing brackish water (BW; 14.7 +/- 1.70/00). Fish were sampled after 2 and 5 months of captivity for evaluation of their condition and stress status. Between the second and fifth months, the condition index increased significantly in both salinity groups, whereas body water content decreased. No salinity effect in terms of growth, condition, or energy reserves was found. However, the fish in BW showed much lower mortality. We found that the fish in SW had higher levels of the physiological indicators of stress than those in BW, which could have increased the risk of opportunistic infections in the former. Also, thrombocytes were absent in the SW fish after 2 months of captivity, which may have contributed to some mortalities. The lower resistance of certain opportunistic pathogens to BW is another possible explanation as to why fish in BW had lower occurrences of infectious diseases. PMID- 28880793 TI - Errata. PMID- 28880794 TI - Histopathological Evidence of Regeneration following Hepatotoxic Effects of the Cyanotoxin Microcystin-LR in the Hardhead Catfish and Gulf Killifish. AB - The cyanobacterial toxin microcystin-LR (MC-LR) causes liver damage in several freshwater fish species. In the present study, two estuarine species, hardhead catfish Arius felis and gulf killifish Fundulus grandis, were injected intraperitoneally with MC-LR at 45-300 MUg/kg and their livers examined histopathologically for up to 23 d postinjection (PI) in the catfish and 5 d PI in the killifish. The livers from both species exhibited extensive, diffuse hepatocellular necrosis by 6 h PI. The necrosis persisted, and by day 2 large numbers of basophilic cells had emerged throughout the liver parenchyma. These cells occurred individually or in small clusters. By 72 h, the basophilic cells appeared to be highly proliferative with numerous mitotic figures and were arranged in cords and tubules similar to mature hepatic parenchyma. Regeneration of the liver parenchyma was noted in gulf killifish at 5 d PI, as tracts of basophilic cells were still evident. In hardhead catfish, there were no signs of necrosis or proliferating basophilic cells by 9 d PI, and the hepatic parenchyma appeared normal except for the vacuolation of many hepatocytes and some areas of hepatic megalocytosis. The degenerative changes in the two species studied were similar to but more pronounced than those observed in freshwater fish species exposed to MC-LR. Evidence of regeneration from the hepatotoxic effects of MC-LR suggests that the toxin can be used to study regenerative processes in fish livers. PMID- 28880795 TI - The Epidemiology of Bacterial Diseases in Food-Size Channel Catfish. AB - Enteric septicemia of catfish (ESC) and columnaris are the most economically important bacterial diseases affecting the channel catfish Ictalurus punctatus industry in the United States. Although these two diseases have been extensively researched, little is known about their prevalence and epidemiology in production systems. In 1997, a two-part survey of catfish producers in Alabama, Arkansas, Louisiana, and Mississippi was conducted to estimate the proportion of ponds and catfish operations that have these diseases and to develop information on the risk factors associated with reporting an occurrence. The response rates to the two phases of the survey were 65.6% and 75.3%, respectively. Overall, 78.1% of all operations and 42.1% of all ponds experienced problems with ESC/columnaris. Higher percentages of large operations and ponds on large operations experienced these problems. The most frequently reported average loss per outbreak of the two diseases was 200-2,000 lb (1 lb = 0.454 kg) per outbreak. Univariate analysis and multivariable regression modeling of the survey data identified three possible risk factors associated with ESC/columnaris, namely, operation size, stocking density, and feeding rate. Conversely, operations that produced their own fingerlings and those that drained ponds at intervals of 3 years or less were less likely to report losses. The associations identified in this study do not establish firm causal relationships, but they do generate hypotheses about managerial and environmental interactions that represent substantial risks to production. PMID- 28880796 TI - Vaccination against Furunculosis in Arctic Char: Efficacy of a Commercial Vaccine. AB - Arctic char Salvelinus alpinus are susceptible to furunculosis, a serious bacterial disease that affects the productivity of salmonid farms around the world. The objective of this laboratory study was to evaluate the efficacy of a commercially available vaccine against furunculosis in two strains of Arctic char. Labrador and Nauyuk char were injected with Aqua Health Furogen 2 or 0.9% NaCl. At 87 and 108 d postvaccination, fish were challenged with Aeromonas salmonicida by immersion. In both challenges, the Aqua Health vaccine provided significant protection against furunculosis; percent cumulative mortality was significantly (P = 0.005) greater for the fish vaccinated with 0.9% NaCl than for those vaccinated with Furogen 2. Strain (P = 0.30), days since vaccination (P = 0.38), and the interaction between vaccine and strain (P = 0.40) were not significant. The point estimate for the preventive fraction (PF) was greater than 0.90 for the Labrador fish vaccinated with Furogen 2; for the Nauyuk fish, the PF was 0.89 and 0.38 at 87 and 108 d, respectively. Relative proportion survival values were also estimated and were usually similar to, but always lower than, the PF estimates. PMID- 28880797 TI - Naturally Occurring Invasive Walleye Dermal Sarcoma and Attempted Experimental Transmission of the Tumor. AB - During the spring 2000 spawning season in Oneida Lake, New York, three walleyes Stizostedion vitreum with invasive walleye dermal sarcoma (WDS) were found. This was the first observation of invasive WDS in wild adult walleyes. A transmission trial was attempted to determine whether the virus associated with these invasive lesions would support the development of invasive WDS in an experimental transmission model. Transmission using inocula prepared from the invasive lesions was very poor compared with that resulting from our typical pooled-tumor inoculum. In addition, no invasive WDS developed. We believe that these results are due, in part, to a relatively low amount of virus in the invasive tumors, which appeared to be in a necrotic state. PMID- 28880798 TI - In Memoriam. PMID- 28880799 TI - Dose Titration of Walleye Dermal Sarcoma (WDS) Tumor Filtrate. AB - Walleyes Stizostedion vitreum were challenged with a topical application of a dilution series of cell-free dermal sarcoma tumor filtrates to determine the minimum dose of virus needed to induce these walleye tumors. A series of six 10 fold dilutions of the filtrate were applied to the side of the fish, which were allowed to develop grossly visible tumors at 15 degrees C for 20 weeks. Quantification of the virus in the filtrates was accomplished by quantitative (real-time) reverse transcriptase-polymerase chain reaction. We determined that there are approximately 1010 viral RNA copies in 100 MUL of walleye dermal sarcoma inoculum. The minimum dose of walleye dermal sarcoma virus that could induce tumors by the topical challenge method was the 1,000-fold dilution of this 1010 inoculum, or approximately 107 viral RNA copies. PMID- 28880800 TI - Morphologic, Pathologic, and Genetic Investigations of Bolbophorus Species Affecting Cultured Channel Catfish in the Mississippi Delta. AB - Trematodes belonging to the genus Bolbophorus have recently been reported as the cause of substantial morbidity and mortality in cultured channel catfish Ictalurus punctatus in Mississippi and Louisiana. Previous investigators identified only a single species, B. confusus. In this investigation, genetic techniques were used to identify all stages of the parasite in all of its hosts. The 18s rRNA genes from specimens collected in Mississippi were sequenced and compared; this analysis revealed that there are two distinct species, B. damnificus (previously identified as B. confusus) and another, undescribed species. (Phylogenetic analysis indicated that a third species, B. levantinus, is also closely related to the Mississippi species.) Species-specific polymerase chain reaction assays capable of identifying and differentiating between these two parasites were developed. Both species were found to infect the first intermediate host (the ram's horn snail Planorbella trivolvis) in commercial channel catfish ponds, but only B. damnificus was recovered from the fish themselves. The new, unidentified Bolbophorus species was determined to be highly pathogenic to a number of fish species. The contribution of B. damnificus to disease in cultured channel catfish remains undetermined. Future investigations of these parasites must now take into account the presence of two distinct species. PMID- 28880801 TI - EFFECT OF CATALYST PREPARATION CONDITIONS ON THE HYDRODESULFURIZATION OF THIOPHENE OVER Co-Mo/gamma-Al2O3. AB - The purpose of this research was to study the effects of preparation conditions on the catalytic properties of the Co-Mo/gamma-Al2O3 catalyst. The work included catalyst preparations and reactions. In the preparations, cobalt-impregnated Mo/gamma-Al2O3 (designated as IcIM) was found to have a promoting effect on the hydrodesulfurization (HDS) of thiophene. Activity and stability of IcIM was higher than that of Mo/gamma-Al2O3. Conversely, when cobalt was added onto Mo/gamma-Al2O3 by the mechanical mixing method, no promoting effect was observed. Mo/gamma-Al2O3 was also prepared using the two different methods (incipient impregnation or mechanical mixing). The differently prepared Mo/gamma-Al2O3 resulted in no obvious difference in activity of IcIM. It was further found that Co-Mo/gamma-Al2O3 activity initially increased appreciably with Mo content and leveled off at Mo contents above 9 wt.%. The catalyst exhibited a maximum activity at Co/Mo ratio 0.3. The order in which metal species were added had a great influence on the activity of the Co-Mo/gamma-Al2O3 catalyst. Higher activity was obtained when Co was added into Mo/gamma-Al2O3 as opposed to Mo added into Co/gamma-Al2O3. PMID- 28880802 TI - ESTIMATION OF ATMOSPHERIC MIXING HEIGHTS OVER LARGE AREAS USING DATA FROM AIRPORT METEOROLOGICAL STATIONS. AB - For this study, ground and sounding meteorological data at 16 airports were used for estimating the atmospheric mixing heights in Hebei Province of China, including Beijing and Tanjing areas. Three methods were compared for this purpose, which are the dry adiabatic method, the conventional Nozaki model, and a modified Nozaki model. The feasibility of using airport meteorological data to determine mixing heights in large area was verified through the use of measured mixing heights and observed SO2 vertical profiles. The study not only estimated the mixing heights over large areas but also compared different early morning sounding temperature profiles to identify feasibility of using 2:00 a.m. sounding profiles to estimate mixing height by the dry adiabatic method. The paper also described the mixing heights over different areas such as mountain, sea boundary and plain areas. The results have considerable significance for air quality prediction and environmental management. A novel approach to estimation of atmospheric mixing heights over large area is introduced, requiring only the input of readily available airport meteorological data. PMID- 28880803 TI - THE BENEFITS AND RISKS OF USING RIVER SEDIMENT FOR VIETNAMESE AGRICULTURE: A CASE STUDY OF THE NHIEU LOC CANAL IN HO CHI MINH CITY. AB - This study was conducted to assess the potential of river sediment for amendment of agricultural land with respect to heavy metal mobilization. The mobility and concentration of bioavailable heavy metal containing in the sediment were evaluated with the use of DTPA (diethylenetriamine pentaacetic acid) extraction techniques. Sum of metals in exchangeable and carbonate fractions obtained from sequential extraction scheme was used to evaluate the potential plant available. Four land blocks of size (1 m * 5.8 m) were prepared for cabbage field experiment and applied with different loading rates of sediment (~28 and 42 ton/ha or equivalent to 100 kgN/ha and 150 kgN/ha). In parallel test, land blocks treated with fertilizer at similar nitrogen loading rates were also conducted for comparisons. Pure soil plot was used as a control system. Results show that both plant available and total heavy metal concentration were found higher in those plots treated with higher loading rates of sediment (42 ton/ha). The concentrations of heavy metals (Cu,Zn,Pb) in soil were decreased with time after crop harvesting and the residues remain in the soil were well below those of the UK, USA and Germany standards. Simple linear regression was used to show the correlation between the DTPA extractable metals and the plant metals fractions (root and shoot) resulting from fertilizer and sediment applications in the amended soils. In most cases, plant available metal concentrations showed positively correlated with plant metal uptake concentrations (R 2 = 0.01-0.95, n = 3). Concentration of metals in the cabbage tissue detected: Zn at 131.53 +/- 10.43 mg kg-1 DM, Cu at 20.84 +/- 1.62 mg kg-1 DM, Pb at 0.09 +/- 0.01 mg kg-1 DM, Cd at 0.21 +/- 0.09 mg kg-1 DM and Ni at 0.44 +/- 0.05 mg kg-1 DM. None of these metals concentration exceeded the tolerable limits of plant. One-way analysis of variance (ANOVA) was applied to find out the effect of different soil amendments on cabbage yield in term of fresh and dry weights. The sequence of crop yields in this field studies for amended soils is chemical fertilizer>sediment>control soil. PMID- 28880804 TI - AN EVALUATION OF RESIDUES AT AN OIL REFINERY SITE FOLLOWING FIRES. AB - Soil pollution at the oil refinery at Novi Sad following destruction of crude oil and its products in storage tanks during the Kosovo conflict was investigated. More than 100, 000 t of crude oil and its products were destroyed, and about 90% of these were burnt off, 10% leached and 130 t recovered. The acute injection of polycyclic aromatic hydrocarbons (PAHs) to the air of the town was widespread depending on the weather conditions and ranged from 1-431, 000 ng/m3. The presence of PAHs, polychlorinated biphenyls (PCBs), and elements in the surface zone and soil core samples taken from various sites were determined up to a depth of 100 cm. Concentrations of PAHs were in the range between 0.75 and 86.19 ug/g dry soil. The contaminated soil can be expected to act as a permanent pollution source, while the mobile constituents are likely to cause groundwater pollution. PMID- 28880805 TI - A Prospective One-Year Microbiologic Survey of Combined Pneumonia and Respiratory Failure. AB - BACKGROUND: Pneumonia and respiratory failure are common problems in the intensive care unit (ICU) setting, often occurring together. The relative prevalence of pneumonia types (community acquired, hospital acquired, ventilator associated) and causative pathogens is not well described in patients with respiratory failure. METHODS: This was a prospective observational cohort study conducted in the medical ICU (34 beds) of Barnes-Jewish Hospital, an academic referral center of 1,300 beds from January 2016-December 2016. All patients who were prospectively adjudicated to have respiratory failure and pneumonia (RFP) regardless of pneumonia type were classified into one of four microbiologic categories: pathogen negative, antibiotic-susceptible pathogen (according to ceftriaxone susceptibility), antibiotic-resistant pathogen, and viruses. The primary outcomes assessed were the hospital mortality rate and inappropriate initial antibiotic therapy (IIAT) for non-viral pathogens. RESULTS: Among 364 consecutive patients with RFP, 63 (17.3%) had organisms that were antibiotic susceptible, 104 (28.6%) had antibiotic-resistant organisms, 118 (32.4%) were pathogen negative, and 79 (21.7%) had viral infections. For these categories, IIAT occurred in 3.2%, 21.2%, 0.8%, and 0, respectively (p < 0.001). Vasopressor requiring shock was present in 61.9%, 72.1%, 68.6%, and 67.1%, respectively (p = 0.585), and the hospital mortality rates were 27.0%, 48.1%, 31.4%, and 36.7%, respectively (p = 0.020). Multivariable logistic regression analysis identified IIAT as an independent predictor of in-hospital death (adjusted odds ratio 5.28; 95% confidence interval 2.72-10.22; p = 0.012). Male gender, increasing Acute Physiology and Chronic Health Evaluation (APACHE) II scores, greater age, and the presence of shock also predicted death. CONCLUSIONS: Microbiologic categorization of patients with RFP suggests that antibiotic-resistant pathogens and viruses are associated with the highest mortality rates. Vasopressor-requiring shock was common regardless of the microbiologic categorization of RFP. Future development and use of rapid diagnostics and novel therapeutics targeting specific RFP pathogens may allow more timely administration of appropriate antimicrobial therapy and enhance antibiotic stewardship practices. PMID- 28880806 TI - Profound barriers to basic cancer care most notably experienced by uninsured women: Historical note on the present policy considerations. AB - America is considering the replacement of Obamacare with Trumpcare. This historical cohort revisited pre-Obamacare colon cancer care among people living in poverty in California (N = 5,776). It affirmed a gender by health insurance hypothesis on nonreceipt of surgery such that uninsured women were at greater risk than uninsured men. Uninsured women were three times as likely as insured women to be denied access to such basic care. Similar men were two times as likely. America is bound to repeat such profound health care inequities if Obamacare is repealed. Instead, Obamacare ought to be retained and strengthened in all states, red and blue. PMID- 28880807 TI - "My heart is in his hands": The lived spiritual experiences of Congolese refugee women survivors of sexual violence. AB - The Democratic Republic of Congo (DRC) has experienced widespread violence, including sexual violence. Sexual violence toward women includes rape, genital mutilation, and sexual slavery. Many Congolese have sought to escape such conditions as refugees in the USA. In the present study, we examined lived spiritual experiences of nine Congolese refugee women survivors of sexual violence. Overall, this study provides new insights into participants' experiences of spirituality in the aftermath of sexual trauma and in living as a refugees. Consensual qualitative research (CQR) methods were used to analyze participants' responses to a semistructured interview protocol. Participants endorsed faith that God was in control, reliance on prayer, gratitude toward God, and difficulty practicing their faith in the USA relative to Africa. Results indicated that religion/spirituality is an integral part of the women's lives and that it appears to facilitate coping. Clinical and community mental health implications are discussed. PMID- 28880808 TI - Trauma and spirituality: Empirical advances in an understudied area of community experience. AB - Trauma and spirituality represent an understudied area of community experience. As in introductory article for this themed issue for the Journal of Prevention & Intervention in the Community, this article describes the importance of considering these topics together for individuals and communities across the world. PMID- 28880809 TI - Urban ministry workers' positive experiences of interpersonal and religious support during crisis. AB - Research on faith-based urban workers is limited despite the chronic and traumatic exposure inherent in their work. This study details the perception of positive interpersonal relationships during a time of trauma or crisis as described in semistructured 2- to 3-hour interviews with 13 faith-based urban workers in Los Angeles, California. Using strategies consistent with Consensual Qualitative Research, categories and subcategories defining positive interpersonal relationships were identified. Resulting categories suggested that there are specific characteristics, products, and types of relationships that urban workers experience as important during the time of trauma or crisis. Positive experiences were often religious in nature and included feeling supported, feeling connected, relationship growth, sharing and listening, authenticity, and feeling as through relationships facilitated personal growth or coping. The findings highlight participants' need for both practical support and relational support which reflects and enhances their spiritual commitment. PMID- 28880811 TI - The role of religion in youth exposed to disasters in Sri Lanka. AB - Little research is available on the role of religious coping among youth exposed to disasters. This study examined the role of general and religious coping in a sample of 669 Sri Lankan Buddhist, Hindu, Muslim, and Christian youth (mean age = 14). Youth completed a survey with measures of exposure to disaster-related stressors, psychological and psychosocial functioning, and general and religious coping. Exposure to stressors was the most consistent predictor of negative outcomes, while approach-related coping predicted better outcomes for Buddhist and Hindu youth. Religious coping was the highest reported type of coping for all four religious groups, but was not significantly associated with any of the measured outcomes. The results suggest that Sri Lankan youth of different religious backgrounds are probably more similar than different in the ways they cope with adversity. PMID- 28880810 TI - Theodicies and professional quality of life in a nationally representative sample of chaplains in the veterans' health administration. AB - This study examined the role of theodicies or theological/philosophic attempts to resolve existential dilemmas related to evil and human suffering in chaplains' professional quality of life (ProQOL). A nationally representative sample of 298 VHA chaplains completed the recently developed Views of Suffering Scale (Hale Smith, Park, & Edmondson, 2012 ) and ProQOL-5 (Stamm, 2010 ). Descriptive results revealed that 20-50% endorsed strong theistic beliefs in a compassionate deity who reciprocally suffers with hurting people, God ultimately being responsible for suffering, and that suffering can provide opportunities for intimate encounters with God and personal growth. Other results indicated that chaplains' beliefs about human suffering were differentially linked with their sense of enjoyment/purpose in working with veterans. These results suggest that theodicies might serve as a pathway to resilience for individuals in spiritual communities and traditions in USA, particularly for clinicians and ministry professionals who are committed to serving the needs of traumatized persons. PMID- 28880812 TI - Spiritual well-being after trauma: Correlates with appraisals, coping, and psychological adjustment. AB - Spiritual issues are often implicated in trauma, yet little research has examined the specific pathways through which trauma may affect spiritual well-being or relations between spiritual well-being and other aspects of adjustment following trauma. Such information would be helpful in developing psychological interventions for trauma recovery. In a sample of 436 college students who had survived a traumatic experience, a transactional stress and coping perspective were used to examine both predictors of three components of spiritual well-being (faith, meaning, and peace) and relations between spiritual well-being and other aspects of psychological adjustment. Results suggest that different patterns of appraisals and coping predict each component of spiritual well-being and that all three components-particularly those of meaning and peace-are related to psychological adjustment. These results suggest that spiritual well-being is an important posttraumatic outcome warranting future research and clinical attention. PMID- 28880813 TI - Associations between trauma exposure, religious coping, and psychiatric distress in a community sample in Nairobi, Kenya. AB - Adults (N = 703) in Nairobi, Kenya completed a screening survey in the aftermath of the postelection violence (PEV) of 2008. This study examined associations between exposure to PEV, prior trauma exposure, religious coping, and psychiatric distress. Results indicated a dose-response effect of the amount of PEV and prior trauma exposure on the severity of concurrent symptoms of psychiatric distress. Over 90% of the sample reported a religious affiliation, and the majority of participants also reported frequent use of religious coping strategies. However, there was no significant effect for the use of turning to religion as a form of coping on psychiatric distress. Study results aligned with existing research on the dose-response, cumulative effect of frequent exposure to trauma. Further research can investigate the nuanced ways that community members use their religion to cope. PMID- 28880815 TI - Effects of a national smoking ban on hospital admissions for cardiovascular diseases: a time-series analysis in Taiwan. AB - On January 11, 2009, a comprehensive smoking ban was implemented in Taiwan. The aim of this study was to evaluate the effect of this ban on hospital admissions for ischemic heart disease (IHD). Trends in the country-level monthly hospital admission rates for IHD were determined and frequency compared to other conditions such as control conditions cholecystitis, bowel obstruction, and appendicitis from January 1997 (1 year before the first phase of smoke-free laws was implemented) to December 2012 (3 years after the second phase of the ban). Poisson regression with a monthly time-series model was used to determine alterations in the trend of admission rates for IHD with comparison to rates of other disorders after the ban. Hospital admissions for IHD decreased by 0.8% (incidence rate ratio [RR]: 0.992; 95% confidence interval [CI] = 0.991-0.994) and 1.1% (incidence RR: 0.989; 95% CI = 0.988-0.991) following the first (September 19, 1997 to January 10, 2009) and second (January 11, 2009 to December 31, 2012) phases of the ban, respectively, compared with those prior to the pre ban period, the corresponding values for the control conditions were 0.6% (95% CI = 0.5%-0.7%) and 0.7% (95% CI = 0.6%-0.9%). The admission rates significantly fell for both men and women and for all examined age categories after both first and second phases of the ban. The present findings provide evidence of a significant reduction in hospital admissions for IHD in Taiwan following smoking bans. PMID- 28880814 TI - Investigation of full-scale ozonation at a municipal wastewater treatment plant using a toxicity-based evaluation concept. AB - Effluents from municipal wastewater treatment plants (WWTPs) are known to be point sources of micropollutants for surface waters. The aim of this study was to examine a reconstructed full-scale ozonation equipped with a pump-injector system for ozone (O3) dosage and a fluidized moving-bed reactor as biological posttreatment at a municipal WWTP utilizing an effect-directed approach. This approach consists of chemical analysis in combination with toxicological tests for the assessment of treatment efficiency of the plant. Chemical analysis showed elimination rates > 80% for pharmaceuticals and industrial chemicals. Analysis of endocrine disruptors was limited due to substance concentrations below the limit of detection (LOD). Estrogenic activity was detected by the Arxula Adeninivorans yeast estrogen screen (A-YES) at low concentrations (pg to ng EEQ/l range). Estrogenic activity was reduced by more than 90% after ozonation. In contrast, androgenic activity (measured in the Adeninivorans yeast androgen screen, A-YAS) was still found after O3 treatment and after biological posttreatment, which is consistent with the data obtained by chemical analysis. Furthermore, no marked genotoxic or cytotoxic effects were observed after ozonation using the alkaline comet and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid (MTT) assays, respectively. Results suggest that the applied specific O3 dose of 0.4 mgO3/mgDOC is a safe operation setup in terms of toxicologically relevant transformation products. In addition, no adverse effects on primary producers, as evidenced by algae growth inhibition tests, were detected. The monitored biofilm growth in the biological posttreatment exhibited a steady state after one month. Based on computational fluid dynamics (CFD) simulations and biomass, one might conclude that O3 did not apparently enter biological posttreatment to a great extent and that hydraulic retention time in the O3 reactor was sufficient. Our data demonstrate the effectiveness of a full-scale O3 treatment in combination with a fluidized moving-bed reactor as biological posttreatment for the reduction of a majority of micropollutants without the release of relevant toxic transformation products as assessed by a chemical and toxicity-based approach. PMID- 28880818 TI - Letters to the Editor. PMID- 28880816 TI - 5-Aza-2'-deoxycytidine, a DNA methylation inhibitor, induces cytotoxicity, cell cycle dynamics and alters expression of DNA methyltransferase 1 and 3A in mouse hippocampus-derived neuronal HT22 cells. AB - Epigenetic processes such as DNA methylation are essential for processes of gene expression in normal mammalian development. DNA methyltransferases (DNMT) are responsible for initiating and maintaining DNA methylation. It is known that 5 Aza-CdR, an inhibitor of DNMT induces cytotoxicity by reducing DNMT activity in various tumor cell lines. However, disturbances in neuronal DNA methylation may also play a role in altered brain functions. Thus, it was of interest to determine whether alterations in DNA methylation might be associated with neuronal functions by using 5-Aza-CdR, on mouse hippocampus-derived neuronal HT22 cell line. In particular, the aim of this study was to investigate the effects of 5-Aza-CdR on cell growth inhibition, cell cycle arrest, apoptosis as well as the expression levels of DNMT in HT22 cells. HT22 cells were incubated with 5 or 20 MUmol/L 5-Aza-CdR for 24 h. Data showed that 5-Aza-CdR at both concentrations significantly inhibited proliferation of HT22 cells and exacerbated cytoplasmic vacuolization. Flow cytometry analysis demonstrated that 5-Aza-CdR treatment at both concentrations decreased early apoptosis but enhanced late apoptosis. Cell cycle analysis illustrated that 5-Aza-CdR treatment induced S phase arrest. Further, incubation with 5-Aza-CdR produced a down-regulation in expression of mRNA and protein DNMT1 and 3A but no marked changes were noted in DNMT 3B and p21 expression. In addition, DNMT1 activity was significantly decreased at both 5-Aza CdR concentrations. Evidence indicates that 5-Aza-CdR induced cytotoxicity was associated with altered mRNA and protein expression of DNMT 1 and 3A associated with reduced DNMT1 activity in HT22 cells which might affect brain functions. PMID- 28880821 TI - Gu Xueqi (1911-2007). PMID- 28880822 TI - Tips for the New Teacher. PMID- 28880825 TI - Transient Elevated Serum Prolactin in Trans Women Is Caused by Cyproterone Acetate Treatment. AB - PURPOSE: Hormone treatment in trans women in Europe usually consists of the administration of estrogens and antiandrogens, for example, cyproterone acetate (CPA). Mild serum prolactin elevations during follow-up are attributed to estrogen therapy. This analysis evaluates whether CPA contributes to the elevation of prolactin in trans women receiving gender affirming hormones. METHODS: This study is part of the endocrine part of the European Network for the Investigation of Gender Incongruence (ENIGI). Belgian data were selected for this substudy. Trans women who initiated gender affirming hormone treatment and underwent orchiectomy were prospectively evaluated. Trans women were treated with oral CPA 50 mg in combination with estrogen substitution. Postsurgery, estrogen was reinitiated in an unchanged dose. Sex steroids, gonadotropins, and prolactin were compared at baseline, pre- and postsurgery in patients receiving orchiectomy, and at baseline, 12, and 18 months in patients who did not undergo orchiectomy. RESULTS: One hundred and seven trans women participated in this analysis, with a mean age of 31.5 years. An increase in serum prolactin levels was seen in the group undergoing orchiectomy (23.72 MUg/L) and not undergoing orchiectomy (23.05 MUg/L) at the preoperative and 12-month visit, compared with baseline (9.42 MUg/L, P = 0.002 and 9.94 MUg/L, P < 0.001, respectively). After orchiectomy, a decline in prolactin levels (10.17 MUg/L, P < 0.001) occurred. CONCLUSIONS: CPA is likely to cause a temporary increase in serum prolactin, with prolactin levels returning to normal after orchiectomy and CPA discontinuation. PMID- 28880829 TI - Letters to the Editor. PMID- 28880830 TI - Developing a High-Resolution Vehicular Emission Inventory by Integrating an Emission Model and a Traffic Model: Part 2-A Case Study in Beijing. AB - A grid-based, bottom-up method has been proposed by combining a vehicle emission model and a travel demand model to develop a high-resolution vehicular emission inventory for Chinese cities. Beijing is used as a case study in which the focus is on fuel consumption and emissions from hot-stabilized activities of light-duty gasoline vehicles (LGVs) in 2005. The total quantity of emissions, emission intensity, and spatial distribution of emissions at 1- by 1-km resolution are presented and compared with results from other inventory methods commonly used in China. The results show that the total daily fuel consumption and vehicular emissions of carbon dioxide, carbon monoxide, hydrocarbons, and oxides of nitrogen from LGVs in the Beijing urban area in 2005 were 1.95 * 107 L, 4.28 * 104 t, 1.97 * 103 t, 0.28 * 103 t, and 0.14 * 103 t, respectively. Vehicular fuel consumption and emissions show spatial variations that are consistent with the traffic characteristics. The grid-based inventory developed in this study reflects the influence of traffic conditions on vehicle emissions at the microscale and may be applied to evaluate the effectiveness of traffic-related measures on emission control in China. PMID- 28880831 TI - Developing a High-Resolution Vehicular Emission Inventory by Integrating an Emission Model and a Traffic Model: Part 1-Modeling Fuel Consumption and Emissions Based on Speed and Vehicle-Specific Power. AB - To improve the accuracy and applicability of vehicular emission models, this study proposes a speed and vehicle-specific power (VSP) modeling method to estimate vehicular emissions and fuel consumption using data gathered by a portable emissions monitoring system (PEMS). The PEMS data were categorized into discrete speed-VSP bins on the basis of the characteristics of vehicle driving conditions and emissions in Chinese cities. Speed-VSP modal average rates of emissions (or fuel consumption) and the time spent in the corresponding speed-VSP bins were then used to calculate the total trip emissions (or fuel consumption) and emission factors (or fuel economy) under specific average link speeds. The model approach was validated by comparing it against measured data with prediction errors within 20% for trip emissions and link-speed-based emission factors. This analysis is based on the data of light-duty gasoline vehicles in China; however, this research approach could be generalized to other vehicle fleets in other countries. This modeling method could also be coupled with traffic demand models to establish high-resolution emissions inventories and evaluate the impacts of traffic-related emission control measures. PMID- 28880833 TI - Emission Characteristics of Granulated Fuel Produced from Sewage Sludge and Coal Slime. AB - The neutralization of wastewater treatment residues is an issue for many countries. The European Union (EU) legal regulations have limited the use of the residues in agriculture and implemented a ban for their disposal. Therefore, urgent action should be taken to find solutions for the safe disposal of sewage sludge. The problem refers in particular to the new EU member countries, including Poland, where one can now observe an intensive development of sewage system networks and new sewage treatment plants. At the same time, these countries have few installations for thermal sewage sludge utilization (e.g., there is only one installation of that type in Poland). Simultaneously, there are many coal-fired mechanical stoker-fired boilers in some of these countries. This paper presents suggestions for the production of granulated fuel from sewage sludge and coal slime. Additionally, among others, lime was added to the fuel to decrease the sulfur compounds emission. Results are presented of research on fuel with two average grain diameters (~15 and 35 mm). The fuel with such diameters is adapted to the requirements of the combustion process taking place in a stokerfired boiler. The research was aimed at identifying the behavior of the burning fuel, with special attention paid to its emission properties (e.g., to the emissions of oxides of nitrogen [NOx], sulfur dioxide [SO2], and carbon mon oxide [CO], among others). The concentration and emission values were compared with similar results obtained while burning hard coal. The combustion process was carried out in a laboratory stand where realization of the large-scale tests is possible. The laboratory stand used made simulation possible for a wide range of burning processes in mechanical stoker-fired boilers. PMID- 28880836 TI - Highly Pathogenic Avian Influenza A(H7N9) Virus, Tennessee, USA, March 2017. AB - In March 2017, highly pathogenic avian influenza A(H7N9) was detected at 2 poultry farms in Tennessee, USA. Surveillance data and genetic analyses indicated multiple introductions of low pathogenicity avian influenza virus before mutation to high pathogenicity and interfarm transmission. Poultry surveillance should continue because low pathogenicity viruses circulate and spill over into commercial poultry. PMID- 28880837 TI - Public Health 3.0: A Call to Action for Public Health to Meet the Challenges of the 21st Century. AB - Public health is what we do together as a society to ensure the conditions in which everyone can be healthy. Although many sectors play key roles, governmental public health is an essential component. Recent stressors on public health are driving many local governments to pioneer a new Public Health 3.0 model in which leaders serve as Chief Health Strategists, partnering across multiple sectors and leveraging data and resources to address social, environmental, and economic conditions that affect health and health equity. In 2016, the US Department of Health and Human Services launched the Public Health 3.0 initiative and hosted listening sessions across the country. Local leaders and community members shared successes and provided insight on actions that would ensure a more supportive policy and resource environment to spread and scale this model. This article summarizes the key findings from those listening sessions and recommendations to achieve Public Health 3.0. PMID- 28880838 TI - Aspirin for Prevention of Cardiovascular Disease. AB - We used data from the 2013 Mississippi Behavioral Risk Factor Surveillance System to examine aspirin use for the prevention of primary and secondary cardiovascular disease (CVD), based on the 2009 US Preventive Services Task Force (USPSTF) guidelines, among Mississippi men (aged 45-79 y) and women (aged 55-79 y) and to explore differences in aspirin use by sociodemographic characteristics. Among those without CVD, 39.1% of men and 45.9% of women reported taking aspirin, and among those with CVD, 85.9% of men and 85.1% of women reported taking aspirin. Data on preventive use of aspirin by sociodemographic characteristics yielded mixed results. PMID- 28880839 TI - Differences Between Younger and Older US Adults With Multiple Chronic Conditions. AB - INTRODUCTION: Adults with multiple (>=2) chronic conditions (MCCs) account for a large portion of US health care costs. Despite the increase in MCC rates with age, most people with MCCs are working age. The study objective was to compare adults with MCCs who were younger than 65 years with those aged 65 years or older on selected measures to better understand the differences between groups and inform interventions that could lower health care costs. METHODS: Data from respondents to the 2015 Behavioral Risk Factor Surveillance System data (N = 201,711) were used to compare adults aged 65 or older with MCCs with those younger than 65 with MCCs in unadjusted and adjusted analyses on chronic conditions, quality of life measures, disability status, access to health care, and modifiable risk factors. MCCs were based on up to 12 chronic conditions (heart disease, stroke, asthma, arthritis, chronic obstructive pulmonary disease, high cholesterol, cognitive impairment, diabetes, depression, chronic kidney disease, cancer other than skin, and hypertension). RESULTS: Consistent with 80% of all adults being younger than 65, more than 60% of adults with MCCs were younger than 65 years. Compared with adults aged 65 or older with MCCs, those younger than 65 were more likely to report asthma, cognitive impairment, depression, smoking, obesity, poorer access to health care, disability, and worse quality of life in both unadjusted and adjusted analysis. CONCLUSION: To decrease the burden of chronic diseases, adults younger than 65 with MCCs should get the treatment they need to reduce the chance of developing more chronic conditions as they age. The ultimate goal is to improve health status and reduce health care costs for everyone with MCCs. PMID- 28880840 TI - Implementation of Best Practices in Obesity Prevention in Child Care Facilities: The Arizona Empower Program, 2013-2015. AB - INTRODUCTION: Obesity is a major health concern in every US age group. Approximately one in 4 children in Arizona's Special Supplemental Nutrition Program for Women, Infants, and Children is overweight or obese. The Arizona Department of Health Services developed the Empower program to promote healthy environments in licensed child care facilities. The program consists of 10 standards, including one standard for each of these 5 areas: physical activity and screen time, breastfeeding, fruit juice and water, family-style meals, and staff training. The objective of this evaluation was to determine the level of implementation of these 5 Empower standards. METHODS: A self-assessment survey was completed from July 2013 through June 2015 by 1,850 facilities to evaluate the level of implementation of 5 Empower standards. We calculated the percentage of facilities that reported the degree to which they implemented each standard and identified common themes in comments recorded in the survey. RESULTS: All facilities reported either full or partial implementation of the 5 standards. Of 1,678 facilities, 21.7% (n = 364) reported full implementation of all standards, and 78.3% (n = 1,314) reported at least partial implementation. Staff training, which has only one component, had the highest level of implementation: 77.4% (n = 1,299) reported full implementation. Only 44.0% (n = 738) reported full implementation of the standard on a breastfeeding-friendly environment. CONCLUSION: Arizona child care facilities have begun to implement the Empower program, but facilities will need more education, technical assistance, and support in some areas to fully implement the program. PMID- 28880841 TI - Iron replacement therapy: entering the new era without misconceptions, but more research is needed. PMID- 28880843 TI - A novel dual gating approach using joint inertial sensors: implications for cardiac PET imaging. AB - Positron emission tomography (PET) is a non-invasive imaging technique which may be considered as the state of art for the examination of cardiac inflammation due to atherosclerosis. A fundamental limitation of PET is that cardiac and respiratory motions reduce the quality of the achieved images. Current approaches for motion compensation involve gating the PET data based on the timing of quiescent periods of cardiac and respiratory cycles. In this study, we present a novel gating method called microelectromechanical (MEMS) dual gating which relies on joint non-electrical sensors, i.e. tri-axial accelerometer and gyroscope. This approach can be used for optimized selection of quiescent phases of cardiac and respiratory cycles. Cardiomechanical activity according to echocardiography observations was investigated to confirm whether this dual sensor solution can provide accurate trigger timings for cardiac gating. Additionally, longitudinal chest motions originating from breathing were measured by accelerometric- and gyroscopic-derived respiratory (ADR and GDR) tracking. The ADR and GDR signals were evaluated against Varian real-time position management (RPM) signals in terms of amplitude and phase. Accordingly, high linear correlation and agreement were achieved between the reference electrocardiography, RPM, and measured MEMS signals. We also performed a Ge-68 phantom study to evaluate possible metal artifacts caused by the integrated read-out electronics including mechanical sensors and semiconductors. The reconstructed phantom images did not reveal any image artifacts. Thus, it was concluded that MEMS-driven dual gating can be used in PET studies without an effect on the quantitative or visual accuracy of the PET images. Finally, the applicability of MEMS dual gating for cardiac PET imaging was investigated with two atherosclerosis patients. Dual gated PET images were successfully reconstructed using only MEMS signals and both qualitative and quantitative assessments revealed encouraging results that warrant further investigation of this method. PMID- 28880845 TI - Insulin degludec/liraglutide (Xultophy 100/3.6) for type 2 diabetes. PMID- 28880846 TI - Prasterone (Intrarosa) for dyspareunia. PMID- 28880847 TI - Safinamide (Xadago) for Parkinson's disease. PMID- 28880842 TI - Current misconceptions in diagnosis and management of iron deficiency. AB - The prevention and treatment of iron deficiency is a major public health goal. Challenges in the treatment of iron deficiency include finding and addressing the underlying cause and the selection of an iron replacement product which meets the needs of the patient. However, there are a number of non-evidence-based misconceptions regarding the diagnosis and management of iron deficiency, with or without anaemia, as well as inconsistency of terminology and lack of clear guidance on clinical pathways. In particular, the pathogenesis of iron deficiency is still frequently not addressed and iron not replaced, with indiscriminate red cell transfusion used as a default therapy. In our experience, this imprudent practice continues to be endorsed by non-evidence-based misconceptions. The intent of the authors is to provide a consensus that effectively challenges these misconceptions, and to highlight evidence-based alternatives for appropriate management (referred to as key points). We believe that this approach to the management of iron deficiency may be beneficial for both patients and healthcare systems. We stress that this paper solely presents the Authors' independent opinions. No pharmaceutical company funded or influenced the conception, development or writing of the manuscript. PMID- 28880848 TI - Deflazacort (Emflaza) for Duchenne muscular dystrophy. PMID- 28880849 TI - Drugs for asthma. PMID- 28880850 TI - Comparison table: some inhaled drugs for treatment of asthma. PMID- 28880851 TI - Comparison table: correct use of inhalers. PMID- 28880852 TI - RNA Sequencing Uncovers Molecular Mechanisms Underlying Pathological Complete Response to Chemotherapy in Patients with Operable Breast Cancer. AB - BACKGROUND This study aimed to identify key genes contributing to pathological complete response (pCR) to chemotherapy by mRNA sequencing (RNA-seq). MATERIAL AND METHODS RNA was extracted from the frozen biopsy tissue of patients with pathological complete response and patients with non-pathological complete response. Sequencing was performed on the HiSeq2000 platform. Differentially expressed genes (DEGs) were identified between the pCR group and non-pCR (NpCR) group. Pathway enrichment analysis of DEGs was performed. A protein-protein interaction network was constructed, then module analysis was performed to identify a subnetwork. Finally, transcription factors were predicted. RESULTS A total of 673 DEGs were identified, including 419 upregulated ones and 254 downregulated ones. The PPI network constructed consisted of 276 proteins forming 471 PPI pairs, and a subnetwork containing 18 protein nodes was obtained. Pathway enrichment analysis revealed that PLCB4 and ADCY6 were enriched in pathways renin secretion, gastric acid secretion, gap junction, inflammatory mediator regulation of TRP channels, retrograde endocannabinoid signaling, melanogenesis, cGMP-PKG signaling pathway, calcium signaling pathway, chemokine signaling pathway, cAMP signaling pathway, and rap1 signaling pathway. CNR1 was enriched in the neuroactive ligand-receptor interaction pathway, retrograde endocannabinoid signaling pathway, and rap1 signaling pathway. The transcription factor-gene network consists of 15 transcription factors and 16 targeted genes, of which 5 were downregulated and 10 were upregulated. CONCLUSIONS We found key genes that may contribute to pCR to chemotherapy, such as PLCB4, ADCY6, and CNR1, as well as some transcription factors. PMID- 28880854 TI - Announcement: Community Preventive Services Task Force Recommendation for Intensive Lifestyle Interventions for Patients with Type 2 Diabetes. PMID- 28880853 TI - Health-Related Behaviors and Academic Achievement Among High School Students - United States, 2015. AB - Studies have shown links between educational outcomes such as letter grades, test scores, or other measures of academic achievement, and health-related behaviors (1-4). However, as reported in a 2013 systematic review, many of these studies have used samples that are not nationally representative, and quite a few studies are now at least 2 decades old (1). To update the relevant data, CDC analyzed results from the 2015 national Youth Risk Behavior Survey (YRBS), a biennial, cross-sectional, school-based survey measuring health-related behaviors among U.S. students in grades 9-12. Analyses assessed relationships between academic achievement (i.e., self-reported letter grades in school) and 30 health-related behaviors (categorized as dietary behaviors, physical activity, sedentary behaviors, substance use, sexual risk behaviors, violence-related behaviors, and suicide-related behaviors) that contribute to leading causes of morbidity and mortality among adolescents in the United States (5). Logistic regression models controlling for sex, race/ethnicity, and grade in school found that students who earned mostly A's, mostly B's, or mostly C's had statistically significantly higher prevalence estimates for most protective health-related behaviors and significantly lower prevalence estimates for most health-related risk behaviors than did students with mostly D's/F's. These findings highlight the link between health-related behaviors and education outcomes, suggesting that education and public health professionals can find their respective education and health improvement goals to be mutually beneficial. Education and public health professionals might benefit from collaborating to achieve both improved education and health outcomes for youths. PMID- 28880855 TI - Notes from the Field: Clostridium perfringens Outbreak at a Catered Lunch - Connecticut, September 2016. PMID- 28880856 TI - Update: Increase in Human Infections with Novel Asian Lineage Avian Influenza A(H7N9) Viruses During the Fifth Epidemic - China, October 1, 2016-August 7, 2017. AB - Among all influenza viruses assessed using CDC's Influenza Risk Assessment Tool (IRAT), the Asian lineage avian influenza A(H7N9) virus (Asian H7N9), first reported in China in March 2013,* is ranked as the influenza virus with the highest potential pandemic risk (1). During October 1, 2016-August 7, 2017, the National Health and Family Planning Commission of China; CDC, Taiwan; the Hong Kong Centre for Health Protection; and the Macao CDC reported 759 human infections with Asian H7N9 viruses, including 281 deaths, to the World Health Organization (WHO), making this the largest of the five epidemics of Asian H7N9 infections that have occurred since 2013 (Figure 1). This report summarizes new viral and epidemiologic features identified during the fifth epidemic of Asian H7N9 in China and summarizes ongoing measures to enhance pandemic preparedness. Infections in humans and poultry were reported from most areas of China, including provinces bordering other countries, indicating extensive, ongoing geographic spread. The risk to the general public is very low and most human infections were, and continue to be, associated with poultry exposure, especially at live bird markets in mainland China. Throughout the first four epidemics of Asian H7N9 infections, only low pathogenic avian influenza (LPAI) viruses were detected among human, poultry, and environmental specimens and samples. During the fifth epidemic, mutations were detected among some Asian H7N9 viruses, identifying the emergence of high pathogenic avian influenza (HPAI) viruses as well as viruses with reduced susceptibility to influenza antiviral medications recommended for treatment. Furthermore, the fifth-epidemic viruses diverged genetically into two separate lineages (Pearl River Delta lineage and Yangtze River Delta lineage), with Yangtze River Delta lineage viruses emerging as antigenically different compared with those from earlier epidemics. Because of its pandemic potential, candidate vaccine viruses (CVV) were produced in 2013 that have been used to make vaccines against Asian H7N9 viruses circulating at that time. CDC is working with partners to enhance surveillance for Asian H7N9 viruses in humans and poultry, to improve laboratory capability to detect and characterize H7N9 viruses, and to develop, test and distribute new CVV that could be used for vaccine production if a vaccine is needed. PMID- 28880857 TI - BRCA Genetic Testing and Receipt of Preventive Interventions Among Women Aged 18 64 Years with Employer-Sponsored Health Insurance in Nonmetropolitan and Metropolitan Areas - United States, 2009-2014. AB - PROBLEM/CONDITION: Genetic testing for breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations can identify women at increased risk for breast and ovarian cancer. These testing results can be used to select preventive interventions and guide treatment. Differences between nonmetropolitan and metropolitan populations in rates of BRCA testing and receipt of preventive interventions after testing have not previously been examined. PERIOD COVERED: 2009-2014. DESCRIPTION OF SYSTEM: Medical claims data from Truven Health Analytics MarketScan Commercial Claims and Encounters databases were used to estimate rates of BRCA testing and receipt of preventive interventions after BRCA testing among women aged 18-64 years with employer-sponsored health insurance in metropolitan and nonmetropolitan areas of the United States, both nationally and regionally. RESULTS: From 2009 to 2014, BRCA testing rates per 100,000 women aged 18-64 years with employer-sponsored health insurance increased 2.3 times (102.7 to 237.8) in metropolitan areas and 3.0 times (64.8 to 191.3) in nonmetropolitan areas. The relative difference in BRCA testing rates between metropolitan and nonmetropolitan areas decreased from 37% in 2009 (102.7 versus 64.8) to 20% in 2014 (237.8 versus 191.3). The relative difference in BRCA testing rates between metropolitan and nonmetropolitan areas decreased more over time in younger women than in older women and decreased in all regions except the West. Receipt of preventive services 90 days after BRCA testing in metropolitan versus nonmetropolitan areas throughout the period varied by service: the percentage of women who received a mastectomy was similar, the percentage of women who received magnetic resonance imaging of the breast was lower in nonmetropolitan areas (as low as 5.8% in 2014 to as high as 8.2% in 2011) than metropolitan areas (as low as 7.3% in 2014 to as high as 10.3% in 2011), and the percentage of women who received mammography was lower in nonmetropolitan areas in earlier years but was similar in later years. INTERPRETATION: Possible explanations for the 47% decrease in the relative difference in BRCA testing rates over the study period include increased access to genetic services in nonmetropolitan areas and increased demand nationally as a result of publicity. The relative differences in metropolitan and nonmetropolitan BRCA testing rates were smaller among women at younger ages compared with older ages. PUBLIC HEALTH ACTION: Improved data sources and surveillance tools are needed to gather comprehensive data on BRCA testing in the United States, monitor adherence to evidence-based guidelines for BRCA testing, and assess receipt of preventive interventions for women with BRCA mutations. Programs can build on the recent decrease in geographic disparities in receipt of BRCA testing while simultaneously educating the public and health care providers about U.S. Preventive Services Task Force recommendations and other clinical guidelines for BRCA testing and counseling. PMID- 28880859 TI - QuickStats: Age-Adjusted Death Rates* from Unintentional Falls Among Adults Aged >=65 Years,? by Sex - National Vital Statistics System, United States, 2000-2015. PMID- 28880858 TI - Vital Signs: Recent Trends in Stroke Death Rates - United States, 2000-2015. AB - INTRODUCTION: The prominent decline in U.S. stroke death rates observed for more than 4 decades has slowed in recent years. CDC examined trends and patterns in recent stroke death rates among U.S. adults aged >=35 years by age, sex, race/ethnicity, state, and census region. METHODS: Trends in the rates of stroke as the underlying cause of death during 2000-2015 were analyzed using data from the National Vital Statistics System. Joinpoint software was used to identify trends in stroke death rates, and the excess number of stroke deaths resulting from unfavorable changes in trends was estimated. RESULTS: Among adults aged >=35 years, age-standardized stroke death rates declined 38%, from 118.4 per 100,000 persons in 2000 to 73.3 per 100,000 persons in 2015. The annual percent change (APC) in stroke death rates changed from 2000 to 2015, from a 3.4% decrease per year during 2000-2003, to a 6.6% decrease per year during 2003-2006, a 3.1% decrease per year during 2006-2013, and a 2.5% (nonsignificant) increase per year during 2013-2015. The last trend segment indicated a reversal from a decrease to a statistically significant increase among Hispanics (APC = 5.8%) and among persons in the South Census Region (APC = 4.2%). Declines in stroke death rates failed to continue in 38 states, and during 2013-2015, an estimated 32,593 excess stroke deaths might not have occurred if the previous rate of decline could have been sustained. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Prior declines in stroke death rates have not continued in recent years, and substantial variations exist in timing and magnitude of change by demographic and geographic characteristics. These findings suggest the importance of strategically identifying opportunities for prevention and intervening in vulnerable populations, especially because effective and underused interventions to prevent stroke incidence and death are known to exist. PMID- 28880860 TI - Response to "Acute kidney injury occurs only rarely in patients with Kawasaki disease". PMID- 28880861 TI - Oocyte-derived histone H3 lysine 27 methylation controls gene expression in the early embryo. PMID- 28880862 TI - Aging: rewiring the circadian clock. PMID- 28880864 TI - Identification of an allosteric network that influences assembly and function of group II chaperonins. PMID- 28880863 TI - Eukaryotic ribosome assembly, transport and quality control. AB - Eukaryotic ribosome synthesis is a complex, energy-consuming process that takes place across the nucleolus, nucleoplasm and cytoplasm and requires more than 200 conserved assembly factors. Here, we discuss mechanisms by which the ribosome assembly and nucleocytoplasmic transport machineries collaborate to produce functional ribosomes. We also highlight recent cryo-EM studies that provided unprecedented snapshots of ribosomes during assembly and quality control. PMID- 28880865 TI - A tripartite interface that regulates vesicle fusion. PMID- 28880866 TI - Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation. AB - Ribosomal RNAs (rRNAs) are transcribed from two multicopy DNA arrays: the 5S ribosomal DNA (rDNA) array residing in a single human autosome and the 45S rDNA array residing in five human autosomes. The arrays are among the most variable segments of the genome, exhibit concerted copy number variation (cCNV), encode essential components of the ribosome, and modulate global gene expression. Here we combined whole genome data from >700 tumors and paired normal tissues to provide a portrait of rDNA variation in human tissues and cancers of diverse mutational signatures, including stomach and lung adenocarcinomas, ovarian cancers, and others of the TCGA panel. We show that cancers undergo coupled 5S rDNA array expansion and 45S rDNA loss that is accompanied by increased estimates of proliferation rate and nucleolar activity. These somatic changes in rDNA CN occur in a background of over 10-fold naturally occurring rDNA CN variation across individuals and cCNV of 5S-45S arrays in some but not all tissues. Analysis of genetic context revealed associations between cancer rDNA CN amplification or loss and the presence of specific somatic alterations, including somatic SNPs and copy number gain/losses in protein coding genes across the cancer genome. For instance, somatic inactivation of the tumor suppressor gene TP53 emerged with a strong association with coupled 5S expansion / 45S loss in several cancers. Our results uncover frequent and contrasting changes in the 5S and 45S rDNA along rapidly proliferating cell lineages with high nucleolar activity. We suggest that 5S rDNA amplification facilitates increased proliferation, nucleolar activity, and ribosomal synthesis in cancer, whereas 45S rDNA loss emerges as a byproduct of transcription-replication conflict in rapidly replicating tumor cells. The observations raise the prospects of using the rDNA arrays as re-emerging targets for the design of novel strategies in cancer therapy. PMID- 28880868 TI - Towards assessing cortical bone porosity using low-frequency quantitative acoustics: A phantom-based study. AB - PURPOSE: Cortical porosity is a key characteristic governing the structural properties and mechanical behaviour of bone, and its quantification is therefore critical for understanding and monitoring the development of various bone pathologies such as osteoporosis. Axial transmission quantitative acoustics has shown to be a promising technique for assessing bone health in a fast, non invasive, and radiation-free manner. One major hurdle in bringing this approach to clinical application is the entanglement of the effects of individual characteristics (e.g. geometry, porosity, anisotropy etc.) on the measured wave propagation. In order to address this entanglement problem, we therefore propose a systematic bottom-up approach, in which only one bone property is varied, before addressing interaction effects. This work therefore investigated the sensitivity of low-frequency quantitative acoustics to changes in porosity as well as individual pore characteristics using specifically designed cortical bone phantoms. MATERIALS AND METHODS: 14 bone phantoms were designed with varying pore size, axial-, and radial pore number, resulting in porosities (bone volume fraction) between 0% and 15%, similar to porosity values found in human cortical bone. All phantoms were manufactured using laser sintering, measured using axial transmission acoustics and analysed using a full-wave approach. Experimental results were compared to theoretical predictions based on a modified Timoshenko theory. RESULTS: A clear dependence of phase velocity on frequency and porosity produced by increasing pore size or radial pore number was demonstrated, with the velocity decreasing by between 2-5 m/s per percent of additional porosity, which corresponds to -0.5% to -1.0% of wave speed. While the change in phase velocity due to axial pore number was consistent with the results due to pore size and radial pore number, the relative uncertainties for the estimates were too high to draw any conclusions for this parameter. CONCLUSIONS: This work has shown the capability of low-frequency quantitative acoustics to reflect changes in porosity and individual pore characteristics and demonstrated that additive manufacturing is an appropriate method that allows the influence of individual bone properties on the wave propagation to be systematically assessed. The results of this work opens perspectives for the efficient development of a multi-frequency, multi-mode approach to screen, diagnose, and monitor bone pathologies in individuals. PMID- 28880867 TI - Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study. AB - BACKGROUND: Sickle cell disease (SCD), a congenital hemolytic anemia that exacts terrible global morbidity and mortality, is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells (RBCs). Fetal hemoglobin (HbF) interferes with this polymerization, but HbF is epigenetically silenced from infancy onward by DNA methyltransferase 1 (DNMT1). METHODS AND FINDINGS: To pharmacologically re-induce HbF by DNMT1 inhibition, this first-in-human clinical trial (NCT01685515) combined 2 small molecules-decitabine to deplete DNMT1 and tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA), the enzyme that otherwise rapidly deaminates/inactivates decitabine, severely limiting its half life, tissue distribution, and oral bioavailability. Oral decitabine doses, administered after oral THU 10 mg/kg, were escalated from a very low starting level (0.01, 0.02, 0.04, 0.08, or 0.16 mg/kg) to identify minimal doses active in depleting DNMT1 without cytotoxicity. Patients were SCD adults at risk of early death despite standard-of-care, randomized 3:2 to THU-decitabine versus placebo in 5 cohorts of 5 patients treated 2X/week for 8 weeks, with 4 weeks of follow up. The primary endpoint was >= grade 3 non-hematologic toxicity. This endpoint was not triggered, and adverse events (AEs) were not significantly different in THU-decitabine-versus placebo-treated patients. At the decitabine 0.16 mg/kg dose, plasma concentrations peaked at approximately 50 nM (Cmax) and remained elevated for several hours. This dose decreased DNMT1 protein in peripheral blood mononuclear cells by >75% and repetitive element CpG methylation by approximately 10%, and increased HbF by 4%-9% (P < 0.001), doubling fetal hemoglobin-enriched red blood cells (F-cells) up to approximately 80% of total RBCs. Total hemoglobin increased by 1.2-1.9 g/dL (P = 0.01) as reticulocytes simultaneously decreased; that is, better quality and efficiency of HbF-enriched erythropoiesis elevated hemoglobin using fewer reticulocytes. Also indicating better RBC quality, biomarkers of hemolysis, thrombophilia, and inflammation (LDH, bilirubin, D dimer, C-reactive protein [CRP]) improved. As expected with non-cytotoxic DNMT1 depletion, platelets increased and neutrophils concurrently decreased, but not to an extent requiring treatment holds. As an early phase study, limitations include small patient numbers at each dose level and narrow capacity to evaluate clinical benefits. CONCLUSION: Administration of oral THU-decitabine to patients with SCD was safe in this study and, by targeting DNMT1, upregulated HbF in RBCs. Further studies should investigate clinical benefits and potential harms not identified to date. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01685515. PMID- 28880869 TI - Differences in chemical constituents of Artemisia annua L from different geographical regions in China. AB - BACKGROUND: Daodi-herb is a part of Chinese culture, which has been naturally selected by traditional Chinese medicine clinical practice for many years. Sweet wormwood herb is a kind of Daodi-herb, and comes from Artemisia annua L. Artemisinin is a kind of effective antimalarial drug being extracted from A. annua. Because of artemisinin, Sweet wormwood herb earns a reputation. Based on the Pharmacopoeia of the People's Republic of China (PPRC), Sweet wormwood herb can be used to resolve summerheat-heat, and prevent malaria. Besides, it also has other medical efficacies. A. annua, a medicinal plant that is widely distributed in the world contains many kinds of chemical composition. Research has shown that compatibility of artemisinin, scopoletin, arteannuin B and arteannuic acid has antimalarial effect. Compatibility of scopoletin, arteannuin B and arteannuic acid is conducive to resolving summerheat-heat. Chemical constituents in A. annua vary significantly according to geographical locations. So, distribution of A. annua may play a key role in the characteristics of efficacy and chemical constituents of Sweet wormwood herb. It is of great significance to study this relationship. OBJECTIVES: We mainly analyzed the relationship between the chemical constituents (arteannuin B, artemisinin, artemisinic acid, and scopoletin) with special efficacy in A. annua that come from different provinces in china, and analyzed the relationship between chemical constituents and spatial distribution, in order to find out the relationship between efficacy, chemical constituents and distribution. METHODS: A field survey was carried out to collect A. annua plant samples. A global positioning system (GPS) was used for obtaining geographical coordinates of sampling sites. Chemical constituents in A. annua were determined by liquid chromatography tandem an atmospheric pressure ionization-electrospray mass spectrometry. Relationship between chemical constituents including proportions, correlation analysis (CoA), principal component analysis (PCA) and cluster analysis (ClA) was displayed through Excel and R software version2.3.2(R), while the one between efficacy, chemical constituents and spatial distribution was presented through ArcGIS10.0, Excel and R software. RESULTS: According to the results of CoA, arteannuin B content presented a strong positive correlation with artemisinic acid content (p = 0), and a strong negative correlation with artemisinin content (p = 0). Scopoletin content presented a strong positive correlation with artemisinin content (p = 0), and a strong negative correlation with artemisinic acid content (p = 0). According to the results of PCA, the first two principal components accounted for 81.57% of the total accumulation contribution rate. The contribution of the first principal component is about 45.12%, manly including arteannuin B and artemisinic acid. The contribution of the second principal component is 36.45% of the total, manly including artemisinin and scopoletin. According to the ClA by using the principal component scores, 19 provinces could be divided into two groups. In terms of provinces in group one, the proportions of artemisinin are all higher than 80%. Based on the results of PCA, ClA, percentages and scatter plot analysis, chemical types are defined as "QHYS type", "INT type" and "QHS type." CONCLUSION: As a conclusion, this paper shows the relationship between efficacy, chemical constituents and distribution. Sweet wormwood herb with high arteannuin B and artemisinic acid content, mainly distributes in northern China. Sweet wormwood herb with high artemisinin and scopoletin content has the medical function of preventing malaria, which mainly distributes in southern China. In this paper, it is proved that Sweet wormwood Daodi herb growing in particular geographic regions, has more significant therapeutical effect and higher chemical constituents compared with other same kind of CMM. And also, it has proved the old saying in China that Sweet wormwood Daodi herb which has been used to resolve summerheat-heat and prevent malaria, which distributed in central China. But in modern time, Daodi Sweet wormwood herb mainly has been used to extract artemisinin and prevent malaria, so the Daod-region has transferred to the southern China. PMID- 28880870 TI - C1-inactivator is upregulated in glioblastoma. AB - BACKGROUND: Glioblastoma is the most common and aggressive type of primary brain tumor in adults. A key problem is the capacity of glioma cells to inactivate the body's immune response. The complement system acts as a functional bridge between the innate and adaptive immune response. Still, the role of the complement system has almost been forgotten in glioma research. In our present study, we hypothesize that C1 inactivator (C1-IA) is upregulated in astrocytoma grade IV, and that its inhibition of the complement system has beneficial effects upon survival. METHODS AND RESULTS: We have explored this hypothesis both on gene and protein levels and found an upregulation of C1-IA in human glioblastoma cells using data from a publicly available database and our own mRNA material from glioblastoma patients. Furthermore, we demonstrated the presence of C1-IA by using immunohistochemistry on glioma cells from both humans and rats in vitro. Finally, we could demonstrate a significantly increased survival in vivo in animals inoculated intracerebrally with glioma cells pre-coated with C1-IA antibodies as compared to control animals. CONCLUSIONS: Our findings indicate that overexpression of C1-IA is present in glioblastomas. This could be demonstrated both at the gene level from patients with glioblastoma, on mRNA level and with immunohistochemistry. Treatment with antibodies against C1-IA had beneficial effects on survival when tested in vivo. PMID- 28880871 TI - Are vent crab behavioral preferences adaptations for habitat choice? AB - Hydrothermal vent organisms are adapted to their extreme and patchily distributed habitats. They are expected to have evolved mechanisms that keep them in their specific habitation. Since little is known about the recruitment or habitat selection of HV organisms such as brachyurans, we examined the properties of several hydrothermal vent-associated cues on the behavior of the hydrothermal vent (HV) crab Xenograpsus testudinatus in the laboratory that were contrasted by the offering of non-vent cues. This crab species is endemic and dominates the vent fauna of Turtle Island off the NE coast of Taiwan. HV crabs were separately and in combination offered the following vent-specific cues: (1) sulfuric sediment, (3) air-bubbling, (4) elevated temperature, (5) dead settled zooplankton, (7) other crabs, and (8) shade. The non-vent-specific cues were: (2) quarz sediment, (6) dead fish, (8) light. These cues were provided on either side of a two-choice chamber. The movement of individual crabs was monitored: as initial and final choices, and as the proportion of time the crabs spent in each compartment (resident time). Cues were offered alone and no such cue as a control in the same set-up. Sulfuric sediments and dead fish were significantly more attractive to females, and other crabs irrespective of gender were significantly more attractive to males. When compared to expected distributions, crabs, irrespective of gender, significantly avoided light and tended to select other crabs, air-bubbling, sulfuric sediment, elevated temperature, dead fish, dead zooplankton, and quarz sediments in the order of decreasing importance. Data do not support the hypothesis that dead settled zooplankton was particularly attractive nor that the other gender was selected. A combination of several vent associated cues (sulfuric sediment, elevated temperature, air-bubbling) facilitated the strongest attraction to the crabs as reflected by all response variables. The 'first choice' responses were always consistent with the side of the choice compartment in which they spent the longest amount of time (resident time), but not with the 'final choice' of crabs, suggesting that the 'resident time' in addition to their 'first choice' is more reliable than just the 'final choice'. The present results provide the first indication that several vent associated habitat cues function as attractors for HV crabs. Habitat choice is also reflected by crab larval distribution in the field which tend to stay near the bottom not to be carried away from their specific habitat. PMID- 28880873 TI - "T-bet"-ing on autoimmunity variants. PMID- 28880872 TI - Microtubule-actin crosslinking factor 1 (Macf1) domain function in Balbiani body dissociation and nuclear positioning. AB - Animal-vegetal (AV) polarity of most vertebrate eggs is established during early oogenesis through the formation and disassembly of the Balbiani Body (Bb). The Bb is a structure conserved from insects to humans that appears as a large granule, similar to a mRNP granule composed of mRNA and proteins, that in addition contains mitochondria, ER and Golgi. The components of the Bb, which have amyloid like properties, include germ cell and axis determinants of the embryo that are anchored to the vegetal cortex upon Bb disassembly. Our lab discovered in zebrafish the only gene known to function in Bb disassembly, microtubule-actin crosslinking factor 1a (macf1a). Macf1 is a conserved, giant multi-domain cytoskeletal linker protein that can interact with microtubules (MTs), actin filaments (AF), and intermediate filaments (IF). In macf1a mutant oocytes the Bb fails to dissociate, the nucleus is acentric, and AV polarity of the oocyte and egg fails to form. The cytoskeleton-dependent mechanism by which Macf1a regulates Bb mRNP granule dissociation was unknown. We found that disruption of AFs phenocopies the macf1a mutant phenotype, while MT disruption does not. We determined that cytokeratins (CK), a type of IF, are enriched in the Bb. We found that Macf1a localizes to the Bb, indicating a direct function in regulating its dissociation. We thus tested if Macf1a functions via its actin binding domain (ABD) and plectin repeat domain (PRD) to integrate cortical actin and Bb CK, respectively, to mediate Bb dissociation at the oocyte cortex. We developed a CRISPR/Cas9 approach to delete the exons encoding these domains from the macf1a endogenous locus, while maintaining the open reading frame. Our analysis shows that Macf1a functions via its ABD to mediate Bb granule dissociation and nuclear positioning, while the PRD is dispensable. We propose that Macf1a does not function via its canonical mechanism of linking two cytoskeletal systems together in dissociating the Bb. Instead our results suggest that Macf1a functions by linking one cytoskeletal system, cortical actin, to another structure, the Bb, where Macf1a is localized. Through this novel linking process, it dissociates the Bb at the oocyte cortex, thus specifying the AV axis of the oocyte and future egg. To our knowledge, this is also the first study to use genome editing to unravel the module-dependent function of a cytoskeletal linker. PMID- 28880874 TI - Discovery and mode of action of a novel analgesic beta-toxin from the African spider Ceratogyrus darlingi. AB - Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 MUM) but not Cav1.3 or Cav3.1 (IC50 > 30 MUM) in fluorimetric assays. In patch-clamp electrophysiological assays Cd1a inhibited rat Cav2.2 with similar potency (IC50 3 MUM) without influencing the voltage dependence of Cav2.2 activation gating, suggesting that Cd1a doesn't act on Cav2.2 as a classical gating modifier toxin. The Cd1a binding site on Cav2.2 did not overlap with that of the pore blocker omega-conotoxin GVIA, but its activity at Cav2.2-mutant indicated that Cd1a shares some molecular determinants with GVIA and MVIIA, localized near the pore region. Cd1a also inhibited human Nav1.1-1.2 and Nav1.7-1.8 (IC50 0.1-6.9 MUM) but not Nav1.3-1.6 (IC50 > 30 MUM) in fluorimetric assays. In patch-clamp assays, Cd1a strongly inhibited human Nav1.7 (IC50 16 nM) and produced a 29 mV depolarising shift in Nav1.7 voltage dependence of activation. Cd1a (400 pmol) fully reversed Nav1.7-evoked pain behaviours in mice without producing side effects. In conclusion, Cd1a inhibited two anti-nociceptive targets, appearing to interfere with Cav2.2 inactivation gating, associated with the Cav2.2 alpha subunit pore, while altering the activation gating of Nav1.7. Cd1a was inactive at some of the Nav and Cav channels expressed in skeletal and cardiac muscles and nodes of Ranvier, apparently contributing to the lack of side effects at efficacious doses, and suggesting potential as a lead for development of peripheral pain treatments. PMID- 28880875 TI - Scaling-up the Xpert MTB/RIF assay for the detection of tuberculosis and rifampicin resistance in India: An economic analysis. AB - BACKGROUND: India is considering the scale-up of the Xpert MTB/RIF assay for detection of tuberculosis (TB) and rifampicin resistance. We conducted an economic analysis to estimate the costs of different strategies of Xpert implementation in India. METHODS: Using a decision analytical model, we compared four diagnostic strategies for TB patients: (i) sputum smear microscopy (SSM) only; (ii) Xpert as a replacement for the rapid diagnostic test currently used for SSM-positive patients at risk of drug resistance (i.e. line probe assay (LPA)); (iii) Upfront Xpert testing for patients at risk of drug resistance; and (iv) Xpert as a replacement for SSM for all patients. RESULTS: The total costs associated with diagnosis for 100,000 presumptive TB cases were: (i) US$ 619,042 for SSM-only; (ii) US$ 575,377 in the LPA replacement scenario; (iii) US$ 720,523 in the SSM replacement scenario; and (iv) US$ 1,639,643 in the Xpert-for-all scenario. Total cohort costs, including treatment costs, increased by 46% from the SSM-only to the Xpert-for-all strategy, largely due to the costs associated with second-line treatment of a higher number of rifampicin-resistant patients due to increased drug-resistant TB (DR-TB) case detection. The diagnostic costs for an estimated 7.64 million presumptive TB patients would comprise (i) 19%, (ii) 17%, (iii) 22% and (iv) 50% of the annual TB control budget. Mean total costs, expressed per DR-TB case initiated on treatment, were lowest in the Xpert for-all scenario (US$ 11,099). CONCLUSIONS: The Xpert-for-all strategy would result in the greatest increase of TB and DR-TB case detection, but would also have the highest associated costs. The strategy of using Xpert only for patients at risk for DR-TB would be more affordable, but would miss DR-TB cases and the cost per true DR-TB case detected would be higher compared to the Xpert-for-all strategy. As such expanded Xpert strategy would require significant increased TB control budget to ensure that increased case detection is followed by appropriate care. PMID- 28880876 TI - Induced mitochondrial membrane potential for modeling solitonic conduction of electrotonic signals. AB - A cable model that includes polarization-induced capacitive current is derived for modeling the solitonic conduction of electrotonic potentials in neuronal branchlets with microstructure containing endoplasmic membranes. A solution of the nonlinear cable equation modified for fissured intracellular medium with a source term representing charge 'soakage' is used to show how intracellular capacitive effects of bound electrical charges within mitochondrial membranes can influence electrotonic signals expressed as solitary waves. The elastic collision resulting from a head-on collision of two solitary waves results in localized and non-dispersing electrical solitons created by the nonlinearity of the source term. It has been shown that solitons in neurons with mitochondrial membrane and quasi-electrostatic interactions of charges held by the microstructure (i.e., charge 'soakage') have a slower velocity of propagation compared with solitons in neurons with microstructure, but without endoplasmic membranes. When the equilibrium potential is a small deviation from rest, the nonohmic conductance acts as a leaky channel and the solitons are small compared when the equilibrium potential is large and the outer mitochondrial membrane acts as an amplifier, boosting the amplitude of the endogenously generated solitons. These findings demonstrate a functional role of quasi-electrostatic interactions of bound electrical charges held by microstructure for sustaining solitons with robust self-regulation in their amplitude through changes in the mitochondrial membrane equilibrium potential. The implication of our results indicate that a phenomenological description of ionic current can be successfully modeled with displacement current in Maxwell's equations as a conduction process involving quasi-electrostatic interactions without the inclusion of diffusive current. This is the first study in which solitonic conduction of electrotonic potentials are generated by polarization-induced capacitive current in microstructure and nonohmic mitochondrial membrane current. PMID- 28880877 TI - Incidence trends of type 1 diabetes before and after the reunification in children up to 14 years of age in Saxony, Eastern Germany. AB - AIMS: The aim of this study was to analyze the incidence rates of type 1 diabetes in Saxony before and after the German reunification. METHODS: The study examined two registries: one until 1990 and one since 1999. Only patients under 15 years of age with type 1 diabetes and living in Saxony were included in the study. Standardized incidence rates were described based on direct age standardization procedures using the Standard European Population for each calendar year between the observation periods 1982-1989 and 1999-2014. Age was grouped into three classes: 0-4, 5-9 and 10-14 years of age. Incidence data were presented as age standardized incidence rates per 100,000 person-years (PY) with 95% confidence intervals [CI]. Joinpoint regression was used for trend analyses and Poisson regression was used to adjust for the effects of age and sex on the incidence. RESULTS: A total number of 2,092 incident cases of type 1 diabetes (1,109 males; 983 females) were included. The age-standardized incidence rates of type 1 diabetes per 100,000 PY was 7.9 [95%CI 6.8; 8.9] in the period from 1982-1989 and 20.1 [95%CI 14.0; 26.1] in the period from 1999-2014. The yearly increase in incidence over the entire time period (1982-2014) was 4.3% according to the average annual percent change (AAPC) method, and estimated to be 4.4% [95% CI 4.0; 4.8%] using a Poisson regression model adjusting for sex and age group. CONCLUSION: In this study, a significantly increasing incidence of type 1 diabetes was observed after reunification. In future studies it would be interesting to follow up on the question of which environmental and lifestyle factors could be causing the increasing type 1 diabetes incidence. PMID- 28880878 TI - Rapid and accurate interpretation of dengue diagnostics in the context of dengue vaccination implementation: Viewpoints and guidelines issued from an experts group consultation. PMID- 28880879 TI - LOTUS overexpression accelerates neuronal plasticity after focal brain ischemia in mice. AB - Nogo receptor-1 (NgR1) and its ligands inhibit neuronal plasticity and limit functional recovery after brain damage such as ischemic stroke. We have previously shown that lateral olfactory tract usher substance (LOTUS) antagonizes NgR1-mediated signaling. Here, we investigated whether LOTUS enhances neuronal plasticity and functional recovery after brain focal ischemia in adult mice. Focal ischemic infarcts were induced in wild-type and LOTUS-overexpressing transgenic mice via middle cerebral artery occlusion. Endogenous LOTUS expression was increased in brain and cervical spinal cord of the contralateral side of ischemia in the chronic phase after brain ischemia. LOTUS overexpression accelerated midline-crossing axonal sprouting from the contralateral side to the ipsilateral side of ischemia in the medullar reticular formation and gray matter of denervated cervical spinal cord. Importantly, LOTUS overexpression improved neurological score highly correlated with laterality ratio of corticoreticular fibers of the medulla oblongata, indicating that LOTUS overexpression may overcome the inhibitory environment induced by NgR1 signaling for damaged motor pathway reconstruction after ischemic stroke. Thus, our data suggest that LOTUS overexpression accelerates neuronal plasticity in the brainstem and cervical spinal cord after stroke and LOTUS administration is useful for future therapeutic strategies. PMID- 28880880 TI - Volunteer motivators for participating in HIV vaccine clinical trials in Nairobi, Kenya. AB - BACKGROUND: 1.5 million Kenyans are living with HIV/AIDS as per 2015 estimates. Though there is a notable decline in new HIV infections, continued effort is still needed to develop an efficacious, accessible and affordable HIV vaccine. HIV vaccine clinical trials bear risks, hence a need to understand volunteer motivators for enrolment, retention and follow-up. Understanding the factors that motivate volunteers to participate in a clinical trial can help to strategize, refine targeting and thus increase enrolment of volunteers in future HIV vaccine clinical trials. The health belief model classifies motivators into social benefits such as 'advancing research' and collaboration with science, and personal benefits such as health benefits and financial interests. METHOD: A thematic analysis was carried out on data obtained from four HIV clinical trials conducted at KAVI-Institute of Clinical Research in Nairobi Kenya from 2009 to 2015. Responses were obtained from a Questionnaire administered to the volunteers during their screening visit at the research site. RESULTS: Of the 281 healthy, HIV-uninfected volunteers participating in this study; 38% were motivated by personal benefits including, 31% motivated by health benefits and 7% motivated by possible financial gains. In addition, 62% of the volunteers were motivated by social benefits with 20% of who were seeking to help their family/society/world while 42% were interested in advancing research. CONCLUSION: The majority of volunteers in the HIV vaccine trials at our site were motivated by social benefits, suggesting that altruism can be a major contributor to participation in HIV vaccine studies. Personal benefits were a secondary motivator for the volunteers. The motivators to volunteer in HIV clinical trials were similar across ages, education level and gender. Education on what is needed (including volunteer participation) to develop an efficacious vaccine could be the key to greater volunteer motivation to participate in HIV vaccine clinical trials. PMID- 28880881 TI - Comprehensive analysis of the codon usage patterns in the envelope glycoprotein E2 gene of the classical swine fever virus. AB - The classical swine fever virus (CSFV), circulating worldwide, is a highly contagious virus. Since the emergence of CSFV, it has caused great economic loss in swine industry. The envelope glycoprotein E2 gene of the CSFV is an immunoprotective antigen that induces the immune system to produce neutralizing antibodies. Therefore, it is essential to study the codon usage of the E2 gene of the CSFV. In this study, 140 coding sequences of the E2 gene were analyzed. The value of effective number of codons (ENC) showed low codon usage bias in the E2 gene. Our study showed that codon usage could be described mainly by mutation pressure ENC plot analysis combined with principal component analysis (PCA) and translational selection-correlation analysis between the general average hydropathicity (Gravy) and aromaticity (Aroma), and nucleotides at the third position of codons (A3s, T3s, G3s, C3s and GC3s). Furthermore, the neutrality analysis, which explained the relationship between GC12s and GC3s, revealed that natural selection had a key role compared with mutational bias during the evolution of the E2 gene. These results lay a foundation for further research on the molecular evolution of CSFV. PMID- 28880882 TI - Putting the methodological brakes on claims to measure national happiness through Twitter: Methodological limitations in social media analytics. AB - With the rapid global proliferation of social media, there has been growing interest in using this existing source of easily accessible 'big data' to develop social science knowledge. However, amidst the big data gold rush, it is important that long-established principles of good social research are not ignored. This article critically evaluates Mitchell et al.'s (2013) study, 'The Geography of Happiness: Connecting Twitter Sentiment and Expression, Demographics, and Objective Characteristics of Place', demonstrating the importance of attending to key methodological issues associated with secondary data analysis. PMID- 28880883 TI - Multi-scale modelling to evaluate building energy consumption at the neighbourhood scale. AB - A new methodology is proposed to couple a meteorological model with a building energy use model. The aim of such a coupling is to improve the boundary conditions of both models with no significant increase in computational time. In the present case, the Canopy Interface Model (CIM) is coupled with CitySim. CitySim provides the geometrical characteristics to CIM, which then calculates a high resolution profile of the meteorological variables. These are in turn used by CitySim to calculate the energy flows in an urban district. We have conducted a series of experiments on the EPFL campus in Lausanne, Switzerland, to show the effectiveness of the coupling strategy. First, measured data from the campus for the year 2015 are used to force CIM and to evaluate its aptitude to reproduce high resolution vertical profiles. Second, we compare the use of local climatic data and data from a meteorological station located outside the urban area, in an evaluation of energy use. In both experiments, we demonstrate the importance of using in building energy software, meteorological variables that account for the urban microclimate. Furthermore, we also show that some building and urban forms are more sensitive to the local environment. PMID- 28880884 TI - Two passive mechanical conditions modulate power generation by the outer hair cells. AB - In the mammalian cochlea, small vibrations of the sensory epithelium are amplified due to active electro-mechanical feedback of the outer hair cells. The level of amplification is greater in the base than in the apex of the cochlea. Theoretical studies have used longitudinally varying active feedback properties to reproduce the location-dependent amplification. The active feedback force has been considered to be proportional to the basilar membrane displacement or velocity. An underlying assumption was that organ of Corti mechanics are governed by rigid body kinematics. However, recent progress in vibration measurement techniques reveals that organ of Corti mechanics are too complicated to be fully represented with rigid body kinematics. In this study, two components of the active feedback are considered explicitly-organ of Corti mechanics, and outer hair cell electro-mechanics. Physiological properties for the outer hair cells were incorporated, such as the active force gain, mechano-transduction properties, and membrane RC time constant. Instead of a kinematical model, a fully deformable 3D finite element model was used. We show that the organ of Corti mechanics dictate the longitudinal trend of cochlear amplification. Specifically, our results suggest that two mechanical conditions are responsible for location-dependent cochlear amplification. First, the phase of the outer hair cell's somatic force with respect to its elongation rate varies along the cochlear length. Second, the local stiffness of the organ of Corti complex felt by individual outer hair cells varies along the cochlear length. We describe how these two mechanical conditions result in greater amplification toward the base of the cochlea. PMID- 28880885 TI - Markers of intestinal permeability are already altered in early stages of non alcoholic fatty liver disease: Studies in children. AB - BACKGROUND & AIMS: Recent studies have shown that patients with manifest non alcoholic fatty liver disease (NAFLD), e.g. steatosis grade 3 or steatohepatitis with or without beginning fibrosis frequently show altered fecal microbiota composition and elevated bacterial endotoxin levels. However, if these alterations are signs of a progressing disease or are already found in initial disease stages has not yet been clarified. METHODS: Twenty children with simple steatosis (grade 1) diagnosed by ultrasound and 29 normal weight healthy control children (age <10 years) were included in the study (mean age 7.6 +/- 1.1 years). Metabolic parameters, markers of intestinal barrier function and inflammation were determined. RESULTS: Activity of alanine aminotransferase, concentrations of some markers of inflammation and insulin resistance were significantly higher in plasma of NAFLD children than in controls. When compared to controls, plasma bacterial endotoxin and lipopolysaccharide-binding protein (LBP) levels were significantly higher in NAFLD children (+50% and +24%, respectively), while soluble CD14 serum and D-lactate plasma levels as well as the prevalence of small intestinal bacterial overgrowth did not differ between groups. Plasma endotoxin and LBP levels were positive associated with proinflammatory markers like plasminogen activator inhibitor-1, c-reactive protein, interleukin-6 and leptin while no associations with markers of insulin resistance were found. CONCLUSIONS: Taken together, our results indicate that even in juvenile patients with early stages of NAFLD e.g. simple steatosis grade 1, plasma endotoxin concentrations are already elevated further suggesting that intestinal barrier dysfunction might be present already in the initial phases of the disease. PMID- 28880887 TI - The effect of health status and living arrangements on long term care models among older Chinese: A cross-sectional study. AB - BACKGROUND: Currently, there are many studies focusing on the influencing factors of the elderly people's living arrangements or health status, but little is known about the relationship between living arrangements or health status and long-term care models for the old-age, especially the joint effects. OBJECTIVE: We aimed to assess the effects of health status and living arrangements on long-term care models (LTCM) among the elderly of Xiamen, China, especially their cumulative joint effects. METHODS: A total of 14,373 participants aged >= 60 years by multistage sampling in Xiamen of China were enrolled. Multinomial logistic regression was used to estimate the Odds ratios (ORs) regressing LTCM on health status and living arrangements using the Anderson model as theoretical framework. RESULTS: Totally, 14,292 valid questionnaires were obtained, of which 86.37% selected home care. With the increase of disability degree, older people are more likely to choose institutional care, compared to living alone (ORs = 1.75, 2.06, 4.00, 4.01 for the "relatively independent', "mild disability', "moderate disability', and "total disability', respectively, in comparison with "completely independent'). The elderly living with children and other family members preferred to choose home care. (ORs = 0.50, 0.39, 0.40, and 0.43 for the "living with children', "living with spouse', "living with children and spouse', and "living with others', respectively, in comparison with "alone'). Additionally, residence, number of children, education level, and feelings of loneliness were the determinants of the choice of social pension. CONCLUSION: A multitude of older people are trended to choose home care in Xiamen of China. There was an interaction and joint effect between the degree of disability and the living arrangements on LTCM. Therefore, policymakers should pay close attention to care for those living alone, childless, and disabled elders to meet their care needs, especially in home care. In addition, the social construction of facilities for elders in rural areas should be strengthened. PMID- 28880886 TI - The osteogenic cell surface marker BRIL/IFITM5 is dispensable for bone development and homeostasis in mice. AB - BRIL (bone-restricted IFITM-like), is a short transmembrane protein expressed almost exclusively in osteoblasts. Although much is known about its bone restricted gene expression pattern and protein biochemical and topological features, little information is available for BRIL physiological function. Two autosomal dominant forms of osteogenesis imperfecta (OI) are caused by distinct, but recurrent mutations in the BRIL gene. Yet, the underlying mechanisms by which those mutations lead to OI are still poorly understood. A previous report indicated that BRIL knockout (KO) mice had bone deformities, shortened long bones, and reproductive problems. Here we generated and systematically analyzed the skeletal phenotype of a new global Bril KO/LacZ knockin mouse model. KO mice reproduced and thrived normally up to 12 month of age. The skeletal phenotype of KO and WT littermates was assessed at embryonic (E13.5 to E18.5) and postnatal (2 days, 3 weeks, 3 months and 8 months) time-points. Embryos from E13.5 through to E18.5 showed significant X-Gal staining in all skeletal elements without any apparent patterning anomalies. Although bone deformities were never observed at any postnatal ages, minor and transient differences were noted in terms of bone length and static uCT parameters, but not systematically across all ages and genders. These changes, however, were not accompanied by significant alteration in bone material properties as assessed by a 3-point bending test. In addition, no changes were detected in circulating serum markers of bone turnover (P1NP, CTX I, and osteocalcin). Gene expression monitoring also revealed no major impact of the loss of BRIL. Further, when mice were challenged with a surgically-induced fracture in tibia, bones repaired equally well in the KO mice as compared to WT. Finally, we showed that BRIL C-terminus is not a bona fide binding site for calcium. In conclusion, our in depth analysis suggest that skeletal patterning, bone mass accrual and remodeling in mice proceeded independent of BRIL. PMID- 28880888 TI - Temporal interpolation alters motion in fMRI scans: Magnitudes and consequences for artifact detection. AB - Head motion can be estimated at any point of fMRI image processing. Processing steps involving temporal interpolation (e.g., slice time correction or outlier replacement) often precede motion estimation in the literature. From first principles it can be anticipated that temporal interpolation will alter head motion in a scan. Here we demonstrate this effect and its consequences in five large fMRI datasets. Estimated head motion was reduced by 10-50% or more following temporal interpolation, and reductions were often visible to the naked eye. Such reductions make the data seem to be of improved quality. Such reductions also degrade the sensitivity of analyses aimed at detecting motion related artifact and can cause a dataset with artifact to falsely appear artifact free. These reduced motion estimates will be particularly problematic for studies needing estimates of motion in time, such as studies of dynamics. Based on these findings, it is sensible to obtain motion estimates prior to any image processing (regardless of subsequent processing steps and the actual timing of motion correction procedures, which need not be changed). We also find that outlier replacement procedures change signals almost entirely during times of motion and therefore have notable similarities to motion-targeting censoring strategies (which withhold or replace signals entirely during times of motion). PMID- 28880889 TI - Loss of Kaiso expression in breast cancer cells prevents intra-vascular invasion in the lung and secondary metastasis. AB - The metastatic activity of breast carcinomas results from complex genetic changes in epithelial tumor cells and accounts for 90% of deaths in affected patients. Although the invasion of the local lymphatic vessels and veins by malignant breast tumor cells and their subsequent metastasis to the lung, has been recognized, the mechanisms behind the metastatic activity of breast tumor cells to other distal organs and the pathogenesis of metastatic cancer are not well understood. In this study, we utilized derivatives of the well-established and highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231 (MDA 231) to study breast tumor metastasis in a mouse model. These MDA-231 derivatives had depleted expression of Kaiso, a POZ-ZF transcription factor that is highly expressed in malignant, triple negative breast cancers. We previously reported that Kaiso depletion attenuates the metastasis of xenografted MDA-231 cells. Herein, we describe the pathological features of the metastatic activity of parental (Kaisopositive) versus Kaisodepleted MDA-231 cells. Both Kaisopositive and Kaisodepleted MDA-231 cells metastasized from the original tumor in the mammary fat pad to the lung. However, while Kaisopositive cells formed large masses in the lung parenchyma, invaded large pulmonary blood vessels and formed secondary metastases and large tumors in the distal organs, Kaisodepleted cells metastasized only to the lung where they formed small metastatic lesions. Importantly, intravascular invasion and secondary metastases in distal organs were not observed in mice xenografted with Kaisodepleted cells. It thus appears that the lung may constitute a barrier for less invasive breast tumors such as the Kaisodepleted TNBC cells; this barrier may limit tumor growth and prevents Kaisodepleted TNBC cells from invading the pulmonary blood vessels and forming secondary metastases in distal organs. PMID- 28880890 TI - Dissection of mammalian orthoreovirus u2 reveals a self-associative domain required for binding to microtubules but not to factory matrix protein uNS. AB - Mammalian orthoreovirus protein MU2 is a component of the viral core particle. Its activities include RNA binding and hydrolysis of the gamma-phosphate from NTPs and RNA 5'-termini, suggesting roles as a cofactor for the viral RNA dependent RNA polymerase, lambda3, first enzyme in 5'-capping of viral plus strand RNAs, and/or prohibitory of RNA-5'-triphosphate-activated antiviral signaling. Within infected cells, MU2 also contributes to viral factories, cytoplasmic structures in which genome replication and particle assembly occur. By associating with both microtubules (MTs) and viral factory matrix protein MUNS, MU2 can anchor the factories to MTs, the full effects of which remain unknown. In this study, a protease-hypersensitive region allowed MU2 to be dissected into two large fragments corresponding to residues 1-282 and 283-736. Fusions with enhanced green fluorescent protein revealed that these amino- and carboxyl-terminal regions of MU2 associate in cells with either MTs or MUNS, respectively. More exhaustive deletion analysis defined MU2 residues 1-325 as the minimal contiguous region that associates with MTs in the absence of the self associating tag. A region involved in MU2 self-association was mapped to residues 283-325, and self-association involving this region was essential for MT association as well. Likewise, we mapped that MUNS-binding site in MU2 relates to residues 290-453 which is independent of MU2 self-association. These findings suggest that MU2 monomers or oligomers can bind to MTs and MUNS, but that self association involving MU2 residues 283-325 is specifically relevant for MT association during viral factories formation. PMID- 28880891 TI - Altered right anterior insular connectivity and loss of associated functions in adolescent chronic fatigue syndrome. AB - Impairments in cognition, pain intolerance, and physical inactivity characterize adolescent chronic fatigue syndrome (CFS), yet little is known about its neurobiology. The right dorsal anterior insular (dAI) connectivity of the salience network provides a motivational context to stimuli. In this study, we examined regional functional connectivity (FC) patterns of the right dAI in adolescent CFS patients and healthy participants. Eighteen adolescent patients with CFS and 18 aged-matched healthy adolescent control participants underwent resting-state functional magnetic resonance imaging. The right dAI region of interest was examined in a seed-to-voxel resting-state FC analysis using SPM and CONN toolbox. Relative to healthy adolescents, CFS patients demonstrated reduced FC of the right dAI to the right posterior parietal cortex (PPC) node of the central executive network. The decreased FC of the right dAI-PPC might indicate impaired cognitive control development in adolescent CFS. Immature FC of the right dAI-PPC in patients also lacked associations with three known functional domains: cognition, pain and physical activity, which were observed in the healthy group. These results suggest a distinct biological signature of adolescent CFS and might represent a fundamental role of the dAI in motivated behavior. PMID- 28880893 TI - Trends in summer bottom-water temperatures on the northern Gulf of Mexico continental shelf from 1985 to 2015. AB - We quantified trends in the 1985 to 2015 summer bottom-water temperature on the northern Gulf of Mexico (nGOM) continental shelf for data collected at 88 stations with depths ranging from 3 to 63 m. The analysis was supplemented with monthly data collected from 1963 to 1965 in the same area. The seasonal summer peak in average bottom-water temperature varied concurrently with air temperature, but with a 2- to 5-month lag. The summer bottom-water temperature declined gradually with depth from 30 oC at stations closest to the shore, to 20 oC at the offshore edge of the study area, and increased an average 0.051 oC y-1 between1963 and 2015. The bottom-water warming in summer for all stations was 1.9 times faster compared to the rise in local summer air temperatures, and 6.4 times faster than the concurrent increase in annual global ocean sea surface temperatures. The annual rise in average summer bottom-water temperatures on the subtropical nGOM continental shelf is comparable to the few published temperature trend estimates from colder environments. These recent changes in the heat storage on the nGOM continental shelf will affect oxygen and carbon cycling, spatial distribution of fish and shrimp, and overall species diversity. PMID- 28880892 TI - Beyond HIV-serodiscordance: Partnership communication dynamics that affect engagement in safer conception care. AB - INTRODUCTION: We explored acceptability and feasibility of safer conception methods among HIV-affected couples in Uganda. METHODS: We recruited HIV-positive men and women on antiretroviral therapy (ART) ('index') from the Uganda Antiretroviral Rural Treatment Outcomes cohort who reported an HIV-negative or unknown-serostatus partner ('partner'), HIV-serostatus disclosure to partner, and personal or partner desire for a child within two years. We conducted in-depth interviews with 40 individuals from 20 couples, using a narrative approach with tailored images to assess acceptability of five safer conception strategies: ART for the infected partner, pre-exposure prophylaxis (PrEP) for the uninfected partner, condomless sex timed to peak fertility, manual insemination, and male circumcision. Translated and transcribed data were analyzed using thematic analysis. RESULTS: 11/20 index participants were women, median age of 32.5 years, median of 2 living children, and 80% had HIV-RNA <400 copies/mL. Awareness of HIV prevention strategies beyond condoms and abstinence was limited and precluded opportunity to explore or validly assess acceptability or feasibility of safer conception methods. Four key partnership communication challenges emerged as primary barriers to engagement in safer conception care, including: (1) HIV serostatus disclosure: Although disclosure was an inclusion criterion, partners commonly reported not knowing the index partner's HIV status. Similarly, the partner's HIV-serostatus, as reported by the index, was frequently inaccurate. (2) Childbearing intention: Many couples had divergent childbearing intentions and made incorrect assumptions about their partner's desires. (3) HIV risk perception: Participants had disparate understandings of HIV transmission and disagreed on the acceptable level of HIV risk to meet reproductive goals. (4) Partnership commitment: Participants revealed significant discord in perceptions of partnership commitment. All four types of partnership miscommunication introduced constraints to autonomous reproductive decision-making, particularly for women. Such miscommunication was common, as only 2 of 20 partnerships in our sample were mutually-disclosed with agreement across all four communication themes. CONCLUSIONS: Enthusiasm for safer conception programming is growing. Our findings highlight the importance of addressing gendered partnership communication regarding HIV disclosure, reproductive goals, acceptable HIV risk, and commitment, alongside technical safer conception advice. Failing to consider partnership dynamics across these domains risks limiting reach, uptake, adherence to, and retention in safer conception programming. PMID- 28880894 TI - In Ovo and dietary administration of oligosaccharides extracted from palm kernel cake influence general health of pre- and neonatal broiler chicks. AB - Palm kernel cake (PKC) is the main byproduct from the palm oil industry in several tropical countries that contains considerable amounts of oligosaccharide. We earlier demonstrated beneficial prebiotic effects of oligosaccharides extract of PKC (OligoPKC) in starter and finisher broiler birds. This study was envisaged to elucidate the effects of in ovo and/or oral administration of the OligoPKC on prenatal and post-hatched broiler chicks. A total of 140 broiler (Cobb500) eggs were randomly divided into two groups (n = 70 each), and on day 12 of incubation, eggs in one group received in ovo injection of 0.1 mL (containing 20 mg) of OligoPKC, while those in the other group received 0.1 mL of saline (placebo) solution. Of these in ovo placebo or OligoPKC injected eggs, after hatching, six chicks from each group were sampled for day-one analysis, while 48 chicks from each group were randomly allocated to two dietary regimes involving either no feeding or feeding of OligoPKC through basal diet for a 14 days experiment forming the experimental groups as: (i) saline-injected (Control, C), (ii) OligoPKC-injected (PREBovo), (iii) saline-injected, but fed 1% OligoPKC (PREBd), and (iv) OligoPKC-injected and also 1% OligoPKC (PREBovo+d). In ovo injection of prebiotic OligoPKC had no effect on body weight and serum immunoglobulins concentrations of day old chicks, except for IgG, which was increased significantly (P<0.05). Body weight and feed conversion ratio of 14 days old chicks were neither affected by in ovo injection nor feeding of OligoPKC. However, populations of cecal total bacteria and major beneficial bacteria of the chicks were markedly enhanced by feeding of OligoPKC (PREBd and PREBovo+d > C and PREBovo), but lesser influenced by in ovo OligoPKC injection. Irrespective of its prior in ovo exposure, chicks fed OligoPKC diets had lower population of pathogenic bacteria. Overall serum immunoglobulin status of birds was improved by feeding of OligoPKC but in ovo OligoPKC injection had minor effect on that. In most cases, in ovo OligoPKC injection and feeding of OligoPKC reduced the expression of nutrient transporters in the intestine and improved antioxidant capacity of liver and serum. It is concluded that in ovo injection of OligoPKC increased IgG production and antioxidant capacity in serum and liver of prenatal chicks and had limited carrying-over effects on the post-hatched chicks comparing to the supplementary feeding of OligoPKC. PMID- 28880895 TI - LAG-3 potentiates the survival of Mycobacterium tuberculosis in host phagocytes by modulating mitochondrial signaling in an in-vitro granuloma model. AB - CD4+ T-cell mediated Th1 immune responses are critical for immunity to TB. The immunomodulatory protein, lymphocyte activation gene-3 (LAG-3) decreases Th1-type immune responses in T-cells. LAG-3 expression is significantly induced in the lungs of macaques with active TB and correlates with increased bacterial burden. Overproduction of LAG-3 can greatly diminish responses and could lead to uncontrolled Mtb replication. To assess the effect of LAG-3 on the progression of Mtb infection, we developed a co-culture system wherein blood-derived macrophages are infected with Mtb and supplemented with macaque blood or lung derived CD4+ T cells. Silencing LAG-3 signaling in macaque lung CD4+ T-cells enhanced killing of Mtb in co-cultures, accompanied by reduced mitochondrial electron transport and increased IFN-gamma expression. Thus, LAG-3 may modulate adaptive immunity to Mtb infection by interfering with the mitochondrial apoptosis pathway. Better understanding this pathway could allow us to circumvent immune features that promote disease. PMID- 28880896 TI - Extract of Spatholobus suberctus Dunn ameliorates ischemia-induced injury by targeting miR-494. AB - Cerebral stroke is a leading cause of death and permanent disability. The current therapeutic outcome of ischemic stroke (>85% of all strokes) is very poor, thus novel therapeutic drug is urgently needed. In vitro cell model of ischemia was established by oxygen-glucose deprivation (OGD) and in vivo animal model of ischemia was established by middle cerebral artery occlusion (MCAO). The effects of Spatholobus suberctus Dunn extract (SSCE) on OGD-induced cell injury, MCAO induced neural injury and miR-494 level were all evaluated. The possible target genes were virtually screened utilizing bioinformatics and verified by luciferase assay. Subsequently, the effects of abnormally expressed miR-494 on OGD-induced cell injury and target gene expression were determined. Additionally, whether SSCE affected target gene expression through modulation of miR-494 was studied. Finally, the effects of aberrantly expressed Sox8 on OGD-induced injury and signaling pathways were estimated. SSCE reduced OGD-induced cell injury and ameliorated MCAO-induced neuronal injury, along with down-regulation of miR-494. Then, OGD-induced cell injury was increased by miR-494 overexpression but decreased by miR-494 silence. Sox8 was a target gene of miR-494, and SSCE could up-regulate Sox8 expression via down-regulating miR-494. Afterwards, OGD-induced cell injury was proved to be increased by Sox8 inhibition but reduced by Sox8 overexpression. Finally, OGD-induced inhibition of PI3K/AKT/mTOR and MAPK pathways was further inhibited by Sox8 silence but activated by Sox8 overexpression. SSCE ameliorates ischemia-induced injury both in vitro and in vivo by miR-494-mediated modulation of Sox8, involving activations of PI3K/AKT/mTOR and MAPK pathways. PMID- 28880897 TI - Changes in soil microbial communities after 10 years of winter wheat cultivation versus fallow in an organic-poor soil in the Loess Plateau of China. AB - Agricultural management methods, such as cultivation or fallowing, have led to significant changes in soil fertility and hence, crop yield. Such changes may have stemmed from changes in soil microbial communities and associated biogeochemical processes. This phenomenon is particularly true in organic-poor soil in the Loess Plateau of China. In this study, we examined three existing soil management regimes as part of a 10-year field experiment and evaluated their effects on fungal and bacterial community structures by performing high throughput 454 pyrosequencing. These management regimes were (i) fertilized winter wheat (Triticum aestivum L.) (FW), (ii) continuous natural fallow with weeds but without crop grown (NF), and (iii) continuous bare fallow without weeds or crop grown (BF). After 10 years, soil organic carbon (SOC), microbial biomass carbon (MBC), and available potassium (K) concentrations were highest in NF. Soil N behaved differently, with BF obtaining the highest nitrate nitrogen (N). Meanwhile, slight differences in total N (TN) were observed among FW, NF, and BF. Available phosphorus (P) was highest and available K was lowest in FW. Microbial communities were dominated by Ascomycota (59.1% of fungal sequences), and Acidobacteria, Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria (75.7% of bacterial sequences) in FW, NF and BF at the phylum level. Soil management regimes did not affect the fungal and bacterial richness and diversity but significantly modified their community compositions. Compared with FW, the abundances of Ascomycota (fungi phylum) and Alternaria, Gibberella, and Emericella (fungi genus) were increased by NF, whereas the values of Chaetomium, Humicola, and Cryptococcus (fungi genus) were decreased by BF. The abundances of Verrucomicrobia (bacteria phylum), and Steroidobacter (bacteria genus) were increased by NF, and Bacteroides (bacteria genus) was increased by BF. Canonical correspondence analysis showed that SOC, available P, and TN might be the key factors in community formation. Therefore, the decadal absence of plants (BF) affected soil fertility by increased available K and nitrate N, whileas natural fallow (NF) affected soil fertility by increased SOC, available K, and MBC, and they all changed fungal and bacterial community compositions. PMID- 28880898 TI - QTL mapping of selenium content using a RIL population in wheat. AB - Selenium (Se) is an essential trace element that plays various roles in human health. Understanding the genetic control of Se content and quantitative trait loci (QTL) mapping provide a basis for Se biofortification of wheat to enhance grain Se content. In the present study, a set of recombinant inbred lines (RILs) derived from two Chinese winter wheat varieties (Tainong18 and Linmai6) was used to detect QTLs for Se content in hydroponic and field trials. In total, 16 QTLs for six Se content-related traits were detected on eight chromosomes, 1B, 2B, 4B, 5A, 5B, 5D, 6A, and 7D. Of these, seven QTLs were detected at the seedling stage and nine at the adult stage. The contribution of each QTL to Se content ranged from 7.37% to 20.22%. QSsece-7D.2, located between marker loci D-3033829 and D 1668160, had the highest contribution (20.22%). This study helps in understanding the genetic basis for Se contents and will provide a basis for gene mapping of Se content in wheat. PMID- 28880899 TI - Effects of sedation on subjective perception of pain intensity and autonomic nervous responses to pain: A preliminary study. AB - Rather than relying solely on subjective pain evaluation using means such as the visual analogue scale (VAS), in clinical situations it is possible to observe evoked responses of the autonomic nervous system (ANS) as objective indicators. Few studies, however, have reported these relationships under finely controlled sedation. 16 healthy male participants were administrated in intravenous sedation with either propofol or midazolam randomly. We initially determined, using pharmacokinetic simulation, the effect-site concentration (Ce) of anaesthetic at loss of response to verbal command and eyelash reflex (Ce-LOR). Then subsequently adjusted Ce to 75%, 50%, and 25% of Ce-LOR to achieve deep, moderate, and light sedation. At awake control state and each sedation level, a noxious electrical stimulation was applied three times at the right forearm, an average pain intensity of the three stimuli was rated on a VAS (0-10). Changes in the peripheral perfusion index measured by oximetry were used as an indicator of ANS response. We analyzed the influence of sedation level on VAS and ANS responses compared to the awake control state. While ANS responses were similar in all conditions, VAS was statistically significantly lower in moderate (5.6+/-0.6, p <0.005) or deep (5.3+/-0.6, p <0.001) sedation than in the awake state (7.2+/ 0.4). This study revealed that even when the ANS responds similarly to the same stimulation, subjective pain perception is attenuated by sedation. A cerebral mechanism other than that of the brainstem might determine subjective pain intensity. PMID- 28880900 TI - Phase separation of the plasma membrane in human red blood cells as a potential tool for diagnosis and progression monitoring of type 1 diabetes mellitus. AB - Glycosylation, oxidation and other post-translational modifications of membrane and transmembrane proteins can alter lipid density, packing and interactions, and are considered an important factor that affects fluidity variation in membranes. Red blood cells (RBC) membrane physical state, showing pronounced alterations in Type 1 diabetes mellitus (T1DM), could be the ideal candidate for monitoring the disease progression and the effects of therapies. On these grounds, the measurement of RBC membrane fluidity alterations can furnish a more sensitive index in T1DM diagnosis and disease progression than Glycosylated hemoglobin (HbA1c), which reflects only the information related to glycosylation processes. Here, through a functional two-photon microscopy approach we retrieved fluidity maps at submicrometric scale in RBC of T1DM patients with and without complications, detecting an altered membrane equilibrium. We found that a phase separation between fluid and rigid domains occurs, triggered by systemic effects on membranes fluidity of glycation and oxidation. The phase separation patterns are different among healthy, T1DM and T1DM with complications patients. Blood cholesterol and LDL content are positively correlated with the extent of the phase separation patterns. To quantify this extent a machine learning approach is employed to develop a Decision-Support-System (DSS) able to recognize different fluidity patterns in RBC. Preliminary analysis shows significant differences(p<0.001) among healthy, T1DM and T1DM with complications patients. The development of an assay based on Phase separation of the plasma membrane of the Red Blood cells is a potential tool for diagnosis and progression monitoring of type 1 diabetes mellitus, and could allow customization and the selection of medical treatments in T1DM in clinical settings, and enable the early detection of complications. PMID- 28880901 TI - ABO blood type and the risk of cancer - Findings from the Shanghai Cohort Study. AB - ABO blood type is an inherited characteristic. The associations between ABO blood type and risk of all cancer and specific cancers were examined in a prospective cohort study of 18,244 Chinese men enrolled in 1986. During the 25 years of follow-up, 3,973 men developed cancer including 964 lung cancers, 624 colorectal cancers, 560 gastric cancers, 353 liver cancers, and 172 urinary bladder cancers. Hazard ratios (HR) for all cancer and specific cancers by ABO blood type were calculated using Cox proportional hazards models. Compared with blood type A, blood type B was associated with statistically significant reduced risk of all cancers (HR, 0.91, 95% CI:0.84, 0.99). Both blood types B and AB were associated with significantly lower risk of gastrointestinal cancer and colorectal cancer, respectively. Blood type B was also associated with significantly lower risk of stomach cancer and bladder cancer, while blood type AB was associated with significantly increased risk of liver cancer. By histological type, blood types B and AB were associated with lower risk of epidermoid carcinoma and adenocarcinoma, but were not associated with risk of sarcoma, lymphoma, leukemia or other cell types of cancer. The findings of this study support a role of genetic traits related to ABO blood type in the development of cancers in the gastrointestinal and urinary tracts. PMID- 28880902 TI - Clonidine used as a perineural adjuvant to ropivacaine, does not prolong the duration of sensory block when controlling for systemic effects: A paired, blinded, randomized trial in healthy volunteers. AB - BACKGROUND: Clonidine used as an adjuvant to ropivacaine have been shown to prolong the duration of peripheral nerve blocks. The mechanism of action remains unclear. We hypothesized, that clonidine used as an adjuvant to ropivacaine extends the duration of an adductor canal block (ACB) by a peripheral mechanism, compared to ropivacaine alone when controlling for systemic effects. METHODS: We conducted a paired, blinded, randomized trial in healthy volunteers. Participants received bilateral ACBs containing 20 ml ropivacaine 0.5% + 1 ml clonidine 150MUg/ml in one leg and 20 ml ropivacaine 0.5% + 1 ml saline in the other leg. The primary outcome measure was duration of sensory block assessed by temperature sensation (alcohol swab). Secondary outcome measures were duration of sensory block assessed by: pinprick, maximum pain during tonic heat stimulation, warmth detection threshold and heat pain detection threshold. RESULTS: We enrolled 21 volunteers and all completed the trial. There was no difference in duration of sensory block assessed with an alcohol swab: Mean duration in the leg receiving ropivacaine + clonidine was 19.4h (SD 2.7) compared to 19.3h (SD 2.4) in the leg receiving ropivacaine + placebo with a mean difference of 0.1h (95% CI: -1.0 to 1.3), P = 0.83. No differences in block duration were detected when assessed by: Pinprick, mean difference 0.0 h (95% CI: -1.3 to 1.3), maximum pain during tonic heat stimulation, mean difference -0.7 h (95% CI: -2.1 to 0.8), warmth detection threshold, mean difference -0.1 h (95% CI: -1.8 to 1.6) or heat pain detection threshold, mean difference -0.2 h (95% CI: -1.7 to 1.4). CONCLUSIONS: Administering clonidine perineurally as an adjuvant to ropivacaine in an ACB did not prolong the duration of sensory block in a setup controlling for systemic effects of clonidine. PMID- 28880903 TI - Functional differences between PD-1+ and PD-1- CD4+ effector T cells in healthy donors and patients with glioblastoma multiforme. AB - Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3 effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1+CD4+ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNgamma. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1+ CD4 effectors. In the context of GBM, tumors were enriched in PD-1+ CD4+ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1+TIM-3+ CD4+ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4+ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1-CD4+ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1-CD4+ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. PMID- 28880904 TI - Prospective comparison of two models of integrating early infant male circumcision with maternal child health services in Kenya: The Mtoto Msafi Mbili Study. AB - As countries scale up adult voluntary medical male circumcision (VMMC) for HIV prevention, they are looking ahead to long term sustainable strategies, including introduction of early infant male circumcision (EIMC). To address the lack of evidence regarding introduction of EIMC services in sub-Saharan African settings, we conducted a simultaneous, prospective comparison of two models of EIMC service delivery in Homa Bay County, Kenya. In one division a standard delivery package (SDP) was introduced and included health facility-based provision of EIMC services with community engagement for client referral versus in a different division a standard package plus (SDPplus) that included community-delivered EIMC services. Babies 1-60 days old were eligible for EIMC. A representative sample of mothers and fathers of baby boys at 16 health facilities was surveyed. We examined differences between mothers and fathers in the SDP and SDPplus divisions and identified factors associated with EIMC uptake. We report adjusted prevalence ratios (aPR). Of 1660 mothers interviewed, 1501 (89%) gave approval to contact the father, and 1259 fathers (84%) were interviewed. The proportion of babies circumcised was slightly greater in the SDPplus division than the SDP division (27.3% vs 23.7%), but the difference was not significant (p = 0.08). In adjusted analyses, however, the prevalence of babies being circumcised was greater in the SDPplus division (aPR = 1.23, 95% CI:1.04-1.45) and the factors associated with a baby being circumcised were the mother having received information about EIMC (during pregnancy, aPR = 4.81, 95% CI: 2.21-3.42), having discussed circumcision with the father if married or cohabiting (aPR = 5.39, 95% CI: 3.31-8.80) or being single (aPR = 5.67, 95% CI: 3.31-9.69), perceiving herself to be living with HIV (aPR = 1.39, 95% CI: 1.15-1.67), or having a post-secondary education (aPR = 1.33, 95% CI: 1.04-1.69), and the father being Muslim (aPR = 1.85, 95% CI: 1.29 2.65) or circumcised (aPR = 1.34, 95% CI: 1.13-1.59). The median age of 2117 babies circumcised was 8 days (IQR: 1-36), and the median weight was 3.6 kg (IQR: 3.2-4.4). There were 6 moderate adverse events (AEs) (0.28%); 5 severe AEs (0.24%), all involving an injury to the glans penis, requiring hospitalization and corrective surgery; and one death probably related to the procedure. There were no AEs among the 365 procedures performed outside health facilities. Information and education campaigns must reach members of the general population, especially men and fathers, who are influential to the EIMC decision. Serious AEs using the Mogen clamp are rare, but do occur and require efficient, reliable emergency back-up. Our results can assist countries considering scale-up of EIMC services for HIV prevention as their adult VMMC programs mature. PMID- 28880906 TI - Consequences of insecticide resistance on malaria transmission. PMID- 28880905 TI - Population genetics of Southern Hemisphere tope shark (Galeorhinus galeus): Intercontinental divergence and constrained gene flow at different geographical scales. AB - The tope shark (Galeorhinus galeus Linnaeus, 1758) is a temperate, coastal hound shark found in the Atlantic and Indo-Pacific oceans. In this study, the population structure of Galeorhinus galeus was determined across the entire Southern Hemisphere, where the species is heavily targeted by commercial fisheries, as well as locally, along the South African coastline. Analysis was conducted on a total of 185 samples using 19 microsatellite markers and a 671 bp fragment of the NADH dehydrogenase subunit 2 (ND2) gene. Across the Southern Hemisphere, three geographically distinct clades were recovered, including one from South America (Argentina, Chile), one from Africa (all the South African collections) and an Australia-New Zealand clade. Nuclear data revealed significant population subdivisions (FST = 0.192 to 0.376, p<0.05) indicating limited gene flow for tope sharks across ocean basins. Marked population connectivity was however evident across the Indian Ocean based on Bayesian clustering analysis. More locally in South Africa, F-statistics and multivariate analysis supported moderate to high gene flow across the Atlantic/Indian Ocean boundary (FST = 0.035 to 0.044, p<0.05), with exception of samples from Struisbaai and Port Elizabeth which differed significantly from the rest. Discriminant and Bayesian clustering analysis indicated admixture in all sampling populations, decreasing from west to east, corroborating possible restriction to gene flow across regional oceanographic barriers. Mitochondrial sequence data recovered seven haplotypes (h = 0.216, pi = 0.001) for South Africa, with one major haplotype shared by 87% of the individuals and at least one private haplotype for each sampling location except Port Elizabeth. As with many other coastal shark species with cosmopolitan distribution, this study confirms the lack of both historical dispersal and inter-oceanic gene flow while also implicating contemporary factors such as oceanic currents and thermal fronts to drive local genetic structure of G. galeus on a smaller spatial scale. PMID- 28880907 TI - Comparison of electrochemical skin conductance and vibration perception threshold measurement in the detection of early diabetic neuropathy. AB - The early diagnosis of diabetic peripheral neuropathy (DPN) is challenging. Sudomotor dysfunction is one of the earliest detectable abnormalities in DPN. The present study aimed to determine the diagnostic performance of the electrochemical skin conductance (ESC) test in detecting early DPN, compared with the vibration perception threshold (VPT) test and diabetic neuropathy symptom (DNS) score, using the modified neuropathy disability score (NDS) as the reference standard. Five hundred and twenty-three patients with type 2 diabetes underwent an NDS-based clinical assessment for neuropathy. Participants were classified into the DPN and non-DPN groups based on the NDS (>= 6). Both groups were evaluated further using the DNS, and VPT and ESC testing. A receiver operator characteristic (ROC) curve analysis was performed to compare the efficacy of ESC measurements with those of DNS and VPT testing in detecting DPN. The DPN group (n = 110, 21%) had significantly higher HbA1c levels and longer diabetes durations compared with the non-DPN group (n = 413). The sensitivity of feet ESC < 60 MUS, VPT testing, and DNS in detecting DPN were 85%, 72%, and 52%, respectively. The specificity of feet ESC, VPT, and DNS in detecting DPN were 85%, 90% and 60% respectively. The areas under the curves of the ROC plots for feet ESC, VPT testing, and DNS were 0.88, 0.84, and 0.6, respectively. A significant inverse linear relationship was noted between VPT and feet ESC (r = 0.45, p = <0.0001). The odds ratios for having DPN, based on the mean feet ESC testing < 60 MUS, VPT testing > 15 V, and DNS >= 1, were 16.4, 10.9 and 1.8, respectively. ESC measurement is an objective and sensitive technique for the early detection of DPN. Feet ESC measurement was superior to VPT testing for identifying patients with early DPN. PMID- 28880908 TI - Prostacyclin, thromboxane and glomerular filtration rate are abnormal in sickle cell pregnancy. AB - BACKGROUND: Pregnancy increases the risk of morbidity and mortality in sickle cell disease. We previously showed pregnant women with sickle cell disease to have a relatively low plasma renin concentration in late pregnancy, associated with a lack of the expected plasma volume expansion. We hypothesized this to be due to increased systemic vascular resistance through an imbalance between the vasodilator prostacyclin and vasoconstrictor thromboxane, associated with decreased glomerular filtration rate (GFR). OBJECTIVE: To compare estimated prostacyclin, thromboxane and GFR in non-pregnant and pregnant women with hemoglobin SS (HbSS) and AA (HbAA). STUDY DESIGN: Four groups of 20 normotensive, nulliparous women were studied in Lagos, Nigeria: pregnant HbSS or HbAA women at 36-40 weeks gestation; non-pregnant HbSS and HbAA controls. We measured stable metabolites of prostacyclin and thromboxane A2 by enzyme-linked immunosorbent assay; GFR using the Cockcroft-Gault equation. Data analysis was by independent (Student's) t-test or Mann-Whitney U test for comparisons between any two groups of continuous variables, univariate ANOVA for multiple groups and Pearson's correlation coefficient for degree of association between variables. RESULTS: HbSS women had lower serum 6-keto-PGF1alpha concentrations than HbAA, whether pregnant or non-pregnant (P<0.001; P<0.004 respectively). Conversely, pregnant HbSS women had higher serum TxB2 (P<0.001); non-pregnant HbSS women had non significantly higher TxB2 concentrations. The 6-keto-PGF1alpha:TxB2 ratio was markedly increased (pro-vasodilatory) in HbAA pregnancy (P<0.001) but reduced in HbSS pregnancy (P = 0.037). GFRs (mL/min) were higher in non-pregnant HbSS than HbAA (P<0.008) but only marginally raised in HbSS women in late pregnancy (P = 0.019) while markedly raised in HbAA pregnancy (P<0.001). CONCLUSION: The lower ratio of prostacyclin-thromboxane metabolites in HbSS pregnancy may indicate endothelial damage and an increased tendency to vasoconstriction and clotting. If confirmed by subsequent longitudinal studies, interventions to increase prostacyclin and reduce thromboxane, such as low dose aspirin, may be potentially useful in their management. PMID- 28880909 TI - In-vivo biological activity and glycosylation analysis of a biosimilar recombinant human follicle-stimulating hormone product (Bemfola) compared with its reference medicinal product (GONAL-f). AB - Recombinant human follicle-stimulating hormone (r-hFSH) is widely used in fertility treatment. Although biosimilar versions of r-hFSH (follitropin alfa) are currently on the market, given their structural complexity and manufacturing process, it is important to thoroughly evaluate them in comparison with the reference product. This evaluation should focus on how they differ (e.g., active component molecular characteristics, impurities and potency), as this could be associated with clinical outcome. This study compared the site-specific glycosylation profile and batch-to-batch variability of the in-vivo bioactivity of Bemfola, a biosimilar follitropin alfa, with its reference medicinal product GONAL-f. The focus of this analysis was the site-specific glycosylation at asparagine (Asn) 52 of the alpha-subunit of FSH, owing to the pivotal role of Asn52 glycosylation in FSH receptor (FSHR) activation/signalling. Overall, Bemfola had bulkier glycan structures and greater sialylation than GONAL-f. The nominal specific activity for both Bemfola and GONAL-f is 13,636 IU/mg. Taking into account both the determined potency and the nominal amount the average specific activity of Bemfola was 14,522 IU/mg (105.6% of the nominal value), which was greater than the average specific activity observed for GONAL-f (13,159 IU/mg; 97.3% of the nominal value; p = 0.0048), although this was within the range stated in the product label. A higher batch-to-batch variability was also observed for Bemfola versus GONAL-f (coefficient of variation: 8.3% vs 5.8%). A different glycan profile was observed at Asn52 in Bemfola compared with GONAL-f (a lower proportion of bi-antennary structures [~53% vs ~77%], and a higher proportion of tri-antennary [~41% vs ~23%] and tetra-antennary structures [~5% vs <1%]). These differences in the Asn52 glycan profile might potentially lead to differences in FSHR activation. This, together with the greater bioactivity and higher batch-to-batch variability of Bemfola, could partly explain the reported differences in clinical outcomes. The clinical relevance of the differences observed between GONAL-f and Bemfola should be further investigated. PMID- 28880910 TI - No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study. AB - Serotonin (5-HT) brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo serotonin 4 receptor (5-HT4R) brain availability, which has recently become possible to image with Positron Emission Tomography (PET). This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone in the healthy brain. In 69 healthy participants (18 females), the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R) and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC) were investigated using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits and regional 5-HT4R binding (all p-values > .17) or the latent construct of global 5-HT4R levels (all p-values > .37). Our findings indicate that NEO personality traits and 5-HT4R are not related in healthy participants. Under the assumption that global 5-HT4R levels index 5-HT tone, our data also suggest that 5-HT tone per se is not directly implicated in normal personality traits. PMID- 28880911 TI - Novel cutting-edge metabolite-based diagnostic tools for aspergillosis. PMID- 28880912 TI - Correction: Association of miR-196a-2 and miR-499 variants with ulcerative colitis and their correlation with expression of respective miRNAs. AB - [This corrects the article DOI: 10.1371/journal.pone.0173447.]. PMID- 28880914 TI - Advocacy for identifying certain animal diseases as "neglected". PMID- 28880913 TI - Staphylococcal enterotoxin-like X (SElX) is a unique superantigen with functional features of two major families of staphylococcal virulence factors. AB - Staphylococcus aureus is an opportunistic pathogen that produces many virulence factors. Two major families of which are the staphylococcal superantigens (SAgs) and the Staphylococcal Superantigen-Like (SSL) exoproteins. The former are immunomodulatory toxins that induce a Vbeta-specific activation of T cells, while the latter are immune evasion molecules that interfere with a wide range of innate immune defences. The superantigenic properties of Staphylococcal enterotoxin-like X (SElX) have recently been established. We now reveal that SElX also possesses functional characteristics of the SSLs. A region of SElX displays high homology to the sialyl-lactosamine (sLacNac)-specific binding site present in a sub-family of SSLs. By analysing the interaction of SElX with sLacNac containing glycans we show that SElX has an equivalent specificity and host cell binding range to the SSLs. Mutation of key amino acids in this conserved region affects the ability of SElX to bind to cells of myeloid origin and significantly reduces its ability to protect S. aureus from destruction in a whole blood killing (WBK) assay. Like the SSLs, SElX is up-regulated early during infection and is under the control of the S. aureus exotoxin expression (Sae) two component gene regulatory system. Additionally, the structure of SElX in complex with the sLacNac-containing tetrasaccharide sialyl Lewis X (sLeX) reveals that SElX is a unique single-domain SAg. In summary, SElX is an 'SSL-like' SAg. PMID- 28880915 TI - An optimized method for counting dopaminergic neurons in zebrafish. AB - In recent years, considerable effort has been devoted to the development of a fish model for Parkinson's disease (PD) to examine the pathological mechanisms of neurodegeneration. To effectively evaluate PD pathology, the ability to accurately and reliably count dopaminergic neurons is important. However, there is currently no such standardized method. Due to the relatively small number of dopaminergic neurons in fish, stereological estimation would not be suitable. In addition, serial sectioning requires proficiency to not lose any sections, and it permits double counting due to the large size of some of the dopaminergic neurons. In this study, we report an optimized protocol for staining dopaminergic neurons in zebrafish and provide a reliable counting method. Finally, using our optimized protocol, we confirmed that administration of 6-hydroxydopamine (a neurotoxin) or the deletion of the PINK1 gene (one of the causative genes of familiar PD) in zebrafish caused significant reduction in the number of dopaminergic and noradrenergic neurons. In summary, this method will serve as an important tool for the appropriate evaluation and establishment of fish PD models. PMID- 28880916 TI - A segmentation method for lung nodule image sequences based on superpixels and density-based spatial clustering of applications with noise. AB - The fast and accurate segmentation of lung nodule image sequences is the basis of subsequent processing and diagnostic analyses. However, previous research investigating nodule segmentation algorithms cannot entirely segment cavitary nodules, and the segmentation of juxta-vascular nodules is inaccurate and inefficient. To solve these problems, we propose a new method for the segmentation of lung nodule image sequences based on superpixels and density based spatial clustering of applications with noise (DBSCAN). First, our method uses three-dimensional computed tomography image features of the average intensity projection combined with multi-scale dot enhancement for preprocessing. Hexagonal clustering and morphological optimized sequential linear iterative clustering (HMSLIC) for sequence image oversegmentation is then proposed to obtain superpixel blocks. The adaptive weight coefficient is then constructed to calculate the distance required between superpixels to achieve precise lung nodules positioning and to obtain the subsequent clustering starting block. Moreover, by fitting the distance and detecting the change in slope, an accurate clustering threshold is obtained. Thereafter, a fast DBSCAN superpixel sequence clustering algorithm, which is optimized by the strategy of only clustering the lung nodules and adaptive threshold, is then used to obtain lung nodule mask sequences. Finally, the lung nodule image sequences are obtained. The experimental results show that our method rapidly, completely and accurately segments various types of lung nodule image sequences. PMID- 28880917 TI - Analysis of HIV prevalence among pregnant women in Liangshan Prefecture, China, from 2009 to 2015. AB - BACKGROUND: Yi people make up about 50% of the population in Liangshan Prefecture, Sichuan Province, China, but accounted for 88.07% of new HIV cases in the prefecture from 2011 to 2013. This study evaluated HIV prevalence in pregnant women of Liangshan Prefecture using HIV sentinel surveillance (HSS) data over the period of 2009 to 2015. METHODS: Xichang, Zhaojue County, and Butuo County were selected as HSS sites. We investigated the temporal trends in HIV prevalence in these areas, and the association between demographic and behavioral characteristics and risk of HIV infection. RESULTS: Data on a total of 2797 pregnant women in Xichang and 3983 pregnant women in Zhaojue and Butuo was collected for the period 2009 to 2015. There was a fluctuating HIV prevalence among pregnant women of Xichang, with a rate of 0.75% in 2015 (chi2trend = 2.27, P = 0.13). HIV prevalence among pregnant women of Zhaojue and Butuo was consistently high, varying between 3.4% (9/267, 2011) and 10.3% (82/796, 2012) over the period of 2010 to 2015 (chi2trend = 0.12, P = 0.73). In Xichang, we found that Yi ethnicity (OR = 11.37, 95% CI = 2.92-44.25) and a husband who used drugs (OR = 32.13, 95% CI = 5.33-193.67) were significantly associated with HIV risk in pregnant women. For Zhaojue and Butuo, we observed that pregnant women had a higher risk of HIV infection when they were over 30 years old (OR = 1.72, 95% CI = 1.17-2.52), when they had a higher number of previous births, when their husbands had a history of migrating for work (OR = 1.56, 95% CI = 1.16-2.08), and when they had a history of other sexually transmitted infections (OR = 2.19, 95% CI = 1.16-2.08). Compared to those with a primary school education or below, pregnant women with a secondary or high school education level had a lower risk of HIV infection (OR = 0.28, 95% CI = 0.09-0.89). CONCLUSION: Our results indicate that there is a serious HIV epidemic among pregnant Yi women, especially for those with less education, more past births, or a husband with a history of out-migrating for work or STD infection. PMID- 28880918 TI - Cerebrovascular gene expression in spontaneously hypertensive rats. AB - Hypertension is a hemodynamic disorder and one of the most important and well established risk factors for vascular diseases such as stroke. Blood vessels exposed to chronic shear stress develop structural changes and remodeling of the vascular wall through many complex mechanisms. However, the molecular mechanisms involved are not fully understood. Hypertension-susceptible genes may provide a novel insight into potential molecular mechanisms of hypertension and secondary complications associated with hypertension. The aim of this exploratory study was to identify gene expression differences in the middle cerebral arteries between 12-week-old male spontaneously hypertensive rats and their normotensive Wistar Kyoto rats using an Affymetrix whole-transcriptome expression profiling. Quantitative PCR and western blotting were used to verify genes of interest. 169 genes were differentially expressed in the middle cerebral arteries from hypertensive compared to normotensive rats. The gene expression of 72 genes was decreased and the gene expression of 97 genes was increased. The following genes with a fold difference >=1.40 were verified by quantitative PCR; Postn, Olr1, Fas, Vldlr, Mmp2, Timp1, Serpine1, Mmp11, Cd34, Ptgs1 and Ptgs2. The gene expression of Postn, Olr1, Fas, Vldlr, Mmp2, Timp1 and Serpine1 and the protein expression of LOX1 (also known as OLR1) were significantly increased in the middle cerebral arteries from spontaneously hypertensive rats compared to Wistar Kyoto rats. In conclusion, the identified genes in the middle cerebral arteries from spontaneously hypertensive rats could be possible mediators of the vascular changes and secondary complications associated with hypertension. This study supports the selection of key genes to investigate in the future research of hypertension-induced end-organ damage. PMID- 28880919 TI - Factors governing the prevalence and richness of avian haemosporidian communities within and between temperate mountains. AB - Mountains are well-suited systems to disentangle the factors driving distribution of parasites due to their heterogeneity of climatic and habitat conditions. However, the information about the relative importance of environmental factors governing the distribution of avian haemosporidians on temperate mountains is very limited. The main goal of the present study is to identify the factors determining prevalence and richness in avian haemosporidians (Plasmodium, Haemoproteus and Leucocytozoon) at the community level along elevational gradients on two mountain ranges located around the northern and southern limits of the Iberian Peninsula (Spain). We used samples from 68 avian species and 1,460 breeding individuals caught over widespread woodland and open habitats. Our findings confirmed the importance of climatic variables explaining prevalence and richness on Iberian mountains. However, landscape variables and other factors named host richness and migration behaviour explained more variation than climatic ones. Plasmodium genus preferred open and warm habitats. Water sources were also important for the southern but not for the northern mountain. Haemoproteus and Leucocytozoon showed affinities for woodland areas. Climatic conditions for Haemoproteus and Leucocytozoon were dependent on the mountain range suggesting some adaptation of avian haemosporidian and their invertebrate vectors to the climatic particularities of both mountain massifs. In contrast to Plasmodium and Haemoproteus genera, Leucocytozoon prevalence and richness values were significantly higher in the southern mountain range. Overall, our findings at the community level has enriched the relative weight and effect direction of environmental factors governing the distribution and prevalence of the avian haemosporidian community. Also, our results provide a caution message about the precision of predictive models on parasite distributions based on climatic variables, since such predictions could overestimate the effect of climate change scenarios on the transmission of the haemosporidians. PMID- 28880920 TI - The Staphylococcus aureus superantigen SElX is a bifunctional toxin that inhibits neutrophil function. AB - Bacterial superantigens (SAgs) cause Vbeta-dependent T-cell proliferation leading to immune dysregulation associated with the pathogenesis of life-threatening infections such as toxic shock syndrome, and necrotizing pneumonia. Previously, we demonstrated that staphylococcal enterotoxin-like toxin X (SElX) from Staphylococcus aureus is a classical superantigen that exhibits T-cell activation in a Vbeta-specific manner, and contributes to the pathogenesis of necrotizing pneumonia. Here, we discovered that SElX can also bind to neutrophils from human and other mammalian species and disrupt IgG-mediated phagocytosis. Site-directed mutagenesis of the conserved sialic acid-binding motif of SElX abolished neutrophil binding and phagocytic killing, and revealed multiple glycosylated neutrophil receptors for SElX binding. Furthermore, the neutrophil binding deficient mutant of SElX retained its capacity for T-cell activation demonstrating that SElX exhibits mechanistically independent activities on distinct cell populations associated with acquired and innate immunity, respectively. Finally, we demonstrated that the neutrophil-binding activity rather than superantigenicity is responsible for the SElX-dependent virulence observed in a necrotizing pneumonia rabbit model of infection. Taken together, we report the first example of a SAg, that can manipulate both the innate and adaptive arms of the human immune system during S. aureus pathogenesis. PMID- 28880921 TI - Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET) Rationale and database description. AB - OBJECTIVES: Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET; NCT03152422) aims: (i) to construct new multidimensional urinary proteomic (UP) classifiers that after heart transplantation (HTx) help in detecting graft vasculopathy, monitoring immune system activity and graft performance, and in adjusting immunosuppression; (ii) to sequence UP peptide fragments and to identify key proteins mediating HTx-related complications; (iii) to validate UP classifiers by demonstrating analogy between UP profiles and tissue proteomic signatures (TP) in diseased explanted hearts, to be compared with normal donor hearts; (iv) and to identify new drug targets. This article describes the uPROPHET database construction, follow-up strategies and baseline characteristics of the HTx patients. METHODS: HTx patients enrolled at the University Hospital Gasthuisberg (Leuven) collected mid-morning urine samples. Cardiac biopsies were obtained at HTx. UP and TP methods and the statistical work flow in pursuit of the research objectives are described in detail in the Data supplement. RESULTS: Of 352 participants in the UP study (24.4% women), 38.9%, 40.3%, 5.7% and 15.1% had ischemic, dilated, hypertrophic or other cardiomyopathy. The median interval between HTx and first UP assessment (baseline) was 7.8 years. At baseline, mean values were 56.5 years for age, 25.2 kg/m2 for body mass index, 142.3/84.8 mm Hg and 124.2/79.8 mm Hg for office and 24-h ambulatory systolic/diastolic pressure, and 58.6 mL/min/1.73 m2 for the estimated glomerular filtration rate. Of all patients, 37.2% and 6.5% had a history of mild (grade = 1B) or severe (grade >= 2) cellular rejection. Anti-body mediated rejection had occurred in 6.2% patients. The number of follow-up urine samples available for future analyses totals over 950. The TP study currently includes biopsies from 7 healthy donors and 15, 14, and 3 patients with ischemic, dilated, and hypertrophic cardiomyopathy. CONCLUSIONS: uPROPHET constitutes a solid resources for UP and TP research in the field of HTx and has the ambition to lay the foundation for the clinical application of UP in risk stratification in HTx patients. PMID- 28880922 TI - Aphid secondary symbionts do not affect prey attractiveness to two species of predatory lady beetles. AB - Heritable symbionts have been found to mediate interactions between host species and their natural enemies in a variety of organisms. Aphids, their facultative symbionts, and their potential fitness effects have been particularly well studied. For example, the aphid facultative symbiont Regiella can protect its host from infection from a fungal pathogen, and aphids with Hamiltonella are less likely to be parasitized by parasitic wasps. Recent work has also found there to be negative fitness effects for the larvae of two species of aphidophagous lady beetles that consumed aphids with facultative symbionts. In both species, larvae that consumed aphids with secondary symbionts were significantly less likely to survive to adulthood. In this study we tested whether adult Harmonia axyridis and Hippodamia convergens lady beetles avoided aphids with symbionts in a series of choice experiments. Adults of both lady beetle species were as likely to choose aphids with symbionts as those without, despite the potential negative fitness effects associated with consuming aphids with facultative symbionts. This may suggest that under natural conditions aphid secondary symbionts are not a significant source of selection for predatory lady beetles. PMID- 28880923 TI - Automatic machine-learning based identification of jogging periods from accelerometer measurements of adolescents under field conditions. AB - BACKGROUND: Assessment of health benefits associated with physical activity depend on the activity duration, intensity and frequency, therefore their correct identification is very valuable and important in epidemiological and clinical studies. The aims of this study are: to develop an algorithm for automatic identification of intended jogging periods; and to assess whether the identification performance is improved when using two accelerometers at the hip and ankle, compared to when using only one at either position. METHODS: The study used diarized jogging periods and the corresponding accelerometer data from thirty-nine, 15-year-old adolescents, collected under field conditions, as part of the GINIplus study. The data was obtained from two accelerometers placed at the hip and ankle. Automated feature engineering technique was performed to extract features from the raw accelerometer readings and to select a subset of the most significant features. Four machine learning algorithms were used for classification: Logistic regression, Support Vector Machines, Random Forest and Extremely Randomized Trees. Classification was performed using only data from the hip accelerometer, using only data from ankle accelerometer and using data from both accelerometers. RESULTS: The reported jogging periods were verified by visual inspection and used as golden standard. After the feature selection and tuning of the classification algorithms, all options provided a classification accuracy of at least 0.99, independent of the applied segmentation strategy with sliding windows of either 60s or 180s. The best matching ratio, i.e. the length of correctly identified jogging periods related to the total time including the missed ones, was up to 0.875. It could be additionally improved up to 0.967 by application of post-classification rules, which considered the duration of breaks and jogging periods. There was no obvious benefit of using two accelerometers, rather almost the same performance could be achieved from either accelerometer position. CONCLUSIONS: Machine learning techniques can be used for automatic activity recognition, as they provide very accurate activity recognition, significantly more accurate than when keeping a diary. Identification of jogging periods in adolescents can be performed using only one accelerometer. Performance wise there is no significant benefit from using accelerometers on both locations. PMID- 28880924 TI - Localization of (photo)respiration and CO2 re-assimilation in tomato leaves investigated with a reaction-diffusion model. AB - The rate of photosynthesis depends on the CO2 partial pressure near Rubisco, Cc, which is commonly calculated by models using the overall mesophyll resistance. Such models do not explain the difference between the CO2 level in the intercellular air space and Cc mechanistically. This problem can be overcome by reaction-diffusion models for CO2 transport, production and fixation in leaves. However, most reaction-diffusion models are complex and unattractive for procedures that require a large number of runs, like parameter optimisation. This study provides a simpler reaction-diffusion model. It is parameterized by both leaf physiological and leaf anatomical data. The anatomical data consisted of the thickness of the cell wall, cytosol and stroma, and the area ratios of mesophyll exposed to the intercellular air space to leaf surfaces and exposed chloroplast to exposed mesophyll surfaces. The model was used directly to estimate photosynthetic parameters from a subset of the measured light and CO2 response curves; the remaining data were used for validation. The model predicted light and CO2 response curves reasonably well for 15 days old tomato (cv. Admiro) leaves, if (photo)respiratory CO2 release was assumed to take place in the inner cytosol or in the gaps between the chloroplasts. The model was also used to calculate the fraction of CO2 produced by (photo)respiration that is re assimilated in the stroma, and this fraction ranged from 56 to 76%. In future research, the model should be further validated to better understand how the re assimilation of (photo)respired CO2 is affected by environmental conditions and physiological parameters. PMID- 28880925 TI - Similar levels of gene content variation observed for Pseudomonas syringae populations extracted from single and multiple host species. AB - Bacterial strains of the same species collected from different hosts frequently exhibit differences in gene content. In the ubiquitous plant pathogen Pseudomonas syringae, more than 30% of genes encoded by each strain are not conserved among strains colonizing other host species. Although they are often implicated in host specificity, the role of this large fraction of the genome in host-specific adaptation is largely unexplored. Here, we sought to relate variation in gene content between strains infecting different species to variation that persists between strains on the same host. We fully sequenced a collection of P. syringae strains collected from wild Arabidopsis thaliana populations in the Midwestern United States. We then compared patterns of variation observed in gene content within these A. thaliana-isolated strains to previously published P. syringae sequence from strains collected on a diversity of crop species. We find that strains collected from the same host, A. thaliana, differ in gene content by 21%, 2/3 the level of gene content variation observed across strains collected from different hosts. Furthermore, the frequency with which specific genes are present among strains collected within the same host and among strains collected from different hosts is highly correlated. This implies that most gene content variation is maintained irrespective of host association. At the same time, we identify specific genes whose presence is important for P. syringae's ability to flourish within A. thaliana. Specifically, the A. thaliana strains uniquely share a genomic island encoding toxins active against plants and surrounding microbes, suggesting a role for microbe-microbe interactions in dictating the abundance within this host. Overall, our results demonstrate that while variation in the presence of specific genes can affect the success of a pathogen within its host, the majority of gene content variation is not strongly associated with patterns of host use. PMID- 28880926 TI - Determination of medical abortion eligibility by women and community health volunteers in Nepal: A toolkit evaluation. AB - OBJECTIVE: To determine if pregnant, literate women and female community health volunteers (FCHVs) in Nepal can accurately determine a woman's eligibility for medical abortion (MA) using a toolkit, compared to comprehensive abortion care (CAC) trained providers. STUDY DESIGN: We conducted a prospective diagnostic accuracy study in which women presenting for first trimester abortion, and FCHVs, independently assessed each woman's eligibility for MA using a modified gestational dating wheel to determine gestational age and a nine-point checklist of MA contraindications or cautions. Ability to determine MA eligibility was compared to experienced CAC-providers using Nepali standard of care. RESULTS: Both women (n = 3131) and FCHVs (n = 165) accurately interpreted the wheel 96% of the time, and the eligibility checklist 72% and 95% of the time, respectively. Of the 649 women who reported potential contraindications or cautions on the checklist, 88% misidentified as eligible. Positive predictive value (PPV) of women's assessment of eligibility based on gestational age was 93% (95% CI 92, 94) compared to CAC-providers' (n = 47); PPV of the medical contraindications checklist and overall (90% [95% CI 88, 91] and 93% [95% CI 92, 94] respectively) must be interpreted with caution given women's difficulty using the checklist. PPV of FCHVs' determinations were 93% (95% CI 92, 94), 90% (95% CI 89,91), and 93% (95% CI 91, 94) respectively. CONCLUSION: Although a promising strategy to assist women and FCHVs to assess MA eligibility, further refinement of the eligibility tools, particularly the checklist, is needed before their widespread use. PMID- 28880929 TI - Correction: Floristic characteristics and affinities in Lao PDR, with a reference to the biogeography of the Indochina peninsula. AB - [This corrects the article DOI: 10.1371/journal.pone.0179966.]. PMID- 28880928 TI - Pseudempleurosoma haywardi sp. nov. (Monogenea: Ancyrocephalidae (sensu lato) Bychowsky & Nagibina, 1968): An endoparasite of croakers (Teleostei: Sciaenidae) from Indonesia. AB - An endoparasitic monogenean was identified for the first time from Indonesia. The oesophagus and anterior stomach of the croakers Nibea soldado (Lacepede) and Otolithes ruber (Bloch & Schneider) (n = 35 each) sampled from the South Java coast in May 2011 and Johnius amblycephalus (Bleeker) (n = 2) (all Sciaenidae) from Kedonganan fish market, South Bali coast, in November 2016, were infected with Pseudempleurosoma haywardi sp. nov. Prevalences in the first two croakers were 63% and 46%, respectively, and the two J. amblycephalus harboured three and five individuals. All three croakers represent new hosts for this monogenean genus. We provide infection rates, light microscopical observations, 3D confocal microscopical illustrations, and a morphometric comparison with all congeners. The new species differs in body size, the position and shape of the ovary and testes, and especially in the composition of the dorsal anchor complex, with the dorsal bar being anteriorly concave rather than planar or convex as in its congeners. The dorsal and ventral anchors of this new species are the longest in the genus, whereas the male copulatory organ is the smallest. The first DNA sequences for a member of this genus demonstrate the greatest similarity with endoparasitic freshwater monogeneans from African cichlid fishes. This suggests a freshwater origin for these marine endoparasitic monogeneans. PMID- 28880927 TI - SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially precise nitric oxide to modulate SCF- and or KIT-expressing cell functions. AB - We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation. PMID- 28880930 TI - Liver stiffness measurement predicts liver-related events in patients with chronic hepatitis C: A retrospective study. AB - The management of patients with chronic hepatitis C (CHC) depends on their clinical stage. Thus, noninvasive early recognition of patients with CHC at high risk for developing liver-related events (LREs) is important because it ensures optimal preventative management strategies may be employed that can affect the course of CHC disease. Our aim was to determine whether liver stiffness measurement (LSM) in hepatitis C virus (HCV)-infected patients is associated with a risk of LREs, particularly in cirrhotic patients. We carried out a retrospective study on 343 HCV-infected patients stratified according to cirrhosis (LSM<12.5 kPa vs. LSM>=12.5 kPa), and the cirrhotic patient group (LSM>=12.5 kPa) was divided according to risk of esophageal varices (LSM <25 kPa vs. LSM>=25 kPa). For all patients, each incremental unit in the natural logarithm (Ln) of LSM was associated with 14.76 times higher risk of developing LREs (p<0.001). Patients with cirrhosis (LSM>=12.5 kPa) had a higher risk of LREs than patients without cirrhosis (LSM<12.5 kPa) [adjusted hazard ratio (aHR) = 30.97; p<0.001]. When only cirrhotic patients were analyzed (n = 60), each incremental unit in the Ln of LSM was associated with 10.56 times higher risk of developing LREs (p = 0.010). Patients with LSM>=25 kPa had a greater risk for LRE development compared to those with LSM<25 kPa (aHR = 3.65; p = 0.045). The AUROC for predicting the onset of LREs was 0.876 in all patients and 0.729 in cirrhotic patients. In conclusion, LSM was associated with an increased risk of developing LREs in HCV-infected patients, even within the group of cirrhotic patients. PMID- 28880931 TI - Restrictive intraoperative fluid optimisation algorithm improves outcomes in patients undergoing pancreaticoduodenectomy: A prospective multicentre randomized controlled trial. AB - We aimed to evaluate perioperative outcomes in patients undergoing pancreaticoduodenectomy with or without a cardiac output goal directed therapy (GDT) algorithm. We conducted a multicentre randomised controlled trial in four high volume hepatobiliary-pancreatic surgery centres. We evaluated whether the additional impact of a intraoperative fluid optimisation algorithm would influence the amount of fluid delivered, reduce fluid related complications, and improve length of hospital stay. Fifty-two consecutive adult patients were recruited. The median (IQR) duration of surgery was 8.6 hours (7.1:9.6) in the GDT group vs. 7.8 hours (6.8:9.0) in the usual care group (p = 0.2). Intraoperative fluid balance was 1005mL (475:1873) in the GDT group vs. 3300mL (2474:3874) in the usual care group (p<0.0001). Total volume of fluid administered intraoperatively was also lower in the GDT group: 2050mL (1313:2700) vs. 4088mL (3400:4525), p<0.0001 and vasoactive medications were used more frequently. There were no significant differences in proportions of patients experiencing overall complications (p = 0.179); however, fewer complications occurred in the GDT group: 44 vs. 92 (Incidence Rate Ratio: 0.41; 95%CI 0.24 to 0.69, p = 0.001). Median (IQR) length of hospital stay was 9.5 days (IQR: 7.0, 14.3) in the GDT vs. 12.5 days in the usual care group (IQR: 9.0, 22.3) for an Incidence Rate Ratio 0.64 (95% CI 0.48 to 0.85, p = 0.002). In conclusion, using a surgery-specific, patient-specific goal directed restrictive fluid therapy algorithm in this cohort of patients, can justify using enough fluid without causing oedema, yet as little fluid as possible without causing hypovolaemia i.e. "precision" fluid therapy. Our findings support the use of a perioperative haemodynamic optimization plan that prioritizes preservation of cardiac output and organ perfusion pressure by judicious use of fluid therapy, rational use of vasoactive drugs and timely application of inotropic drugs. They also suggest the need for further larger studies to confirm its findings. PMID- 28880932 TI - Reversible unfolding of infectious prion assemblies reveals the existence of an oligomeric elementary brick. AB - Mammalian prions, the pathogens that cause transmissible spongiform encephalopathies, propagate by self-perpetuating the structural information stored in the abnormally folded, aggregated conformer (PrPSc) of the host-encoded prion protein (PrPC). To date, no structural model related to prion assembly organization satisfactorily describes how strain-specified structural information is encoded and by which mechanism this information is transferred to PrPC. To achieve progress on this issue, we correlated the PrPSc quaternary structural transition from three distinct prion strains during unfolding and refolding with their templating activity. We reveal the existence of a mesoscopic organization in PrPSc through the packing of a highly stable oligomeric elementary subunit (suPrP), in which the strain structural determinant (SSD) is encoded. Once kinetically trapped, this elementary subunit reversibly loses all replicative information. We demonstrate that acquisition of the templating interface and infectivity requires structural rearrangement of suPrP, in concert with its condensation. The existence of such an elementary brick scales down the SSD support to a small oligomer and provide a basis of reflexion for prion templating process and propagation. PMID- 28880933 TI - Range of glucose as a glycemic variability and 3-month outcome in diabetic patients with acute ischemic stroke. AB - Glycemic variability (GV) is reportedly a predictor for poor outcome in various clinical conditions. We aimed to assess whether GV during hospital admission is associated with poor outcomes in patients with acute ischemic stroke (AIS) and diabetes. We prospectively enrolled consecutive patients with AIS from the registry of 6 tertiary hospitals between January 2013 and December 2014. For the GV index, we used a glucose level range that was divided into 4 quartiles. Multivariable binary and ordinal logistic regression analyses were performed to determine the association between GV and the modified Rankin Scale score (3-6) at 3 months. We enrolled 1,504 patients with AIS and diabetes (mean age, 68.1 years; male, 57.2%), of which 35.1% had poor outcomes at 3 months. An increasing glucose range quartile was positively associated with initial neurologic severity and development of hypoglycemia during hospital admission. Multivariable analysis showed that the glucose level range quartile was associated with poor outcomes, even after adjusting for the number of glucose measurement and hypoglycemia (odds ratio [OR] Q2 vs. Q1: 1.50, 95% confidence interval [CI]: 1.02-2.18; OR Q3 vs. Q1: 2.01, 95% CI: 1.34-3.01; OR Q4 vs. Q1: 1.98, 95% CI: 1.22-3.23). These associations remained significant after dichotomization according to glycated hemoglobin levels at admission. An increasing glucose level range as a GV index during hospital admission was associated with poor functional outcomes at 3 months in patients with AIS and diabetes. PMID- 28880934 TI - DNA methylation patterns and gene expression associated with litter size in Berkshire pig placenta. AB - Increasing litter size is of great interest to the pig industry. DNA methylation is an important epigenetic modification that regulates gene expression, resulting in livestock phenotypes such as disease resistance, milk production, and reproduction. We classified Berkshire pigs into two groups according to litter size and estimated breeding value: smaller (SLG) and larger (LLG) litter size groups. Genome-wide DNA methylation and gene expression were analyzed using placenta genomic DNA and RNA to identify differentially methylated regions (DMRs) and differentially expressed genes (DEGs) associated with litter size. The methylation levels of CpG dinucleotides in different genomic regions were noticeably different between the groups, while global methylation pattern was similar, and excluding intergenic regions they were found the most frequently in gene body regions. Next, we analyzed RNA-Seq data to identify DEGs between the SLG and LLG groups. A total of 1591 DEGs were identified: 567 were downregulated and 1024 were upregulated in LLG compared to SLG. To identify genes that simultaneously exhibited changes in DNA methylation and mRNA expression, we integrated and analyzed the data from bisulfite-Seq and RNA-Seq. Nine DEGs positioned in DMRs were found. The expression of only three of these genes (PRKG2, CLCA4, and PCK1) was verified by RT-qPCR. Furthermore, we observed the same methylation patterns in blood samples as in the placental tissues by PCR based methylation analysis. Together, these results provide useful data regarding potential epigenetic markers for selecting hyperprolific sows. PMID- 28880935 TI - Post-fatigue recovery of power, postural control and physical function in older women. AB - Low muscle power, particularly at high velocities, has been linked to poor physical function in older adults. Any loss in muscle power following fatiguing exercise or daily activities could impact physical function and postural control until power has fully recovered. To test the overall hypothesis that a common task such as walking can result in prolonged power loss and decreased physical function and balance, 17 healthy older (66-81 years) women completed a 32-min walking test (32MWT) designed to induce neuromuscular fatigue, followed by 60min of recovery (60R). Fatigue and recovery of knee extensor muscle power (3 velocities) were quantified by dynamometry. Function was quantified by chair rise time and postural control by measures of center of pressure (COP) range (mm) and velocity (mm.s-1) during quiet stance. Power declined at all velocities by 8-13% 2min following the 32MWT (p<=0.02) and remained depressed by 8-26% at 60R (p<=0.04). Postural control decreased following the 32MWT, indicated by increased COP range in the anterior-posterior (AP, p<0.01) direction and a trend in the medial-lateral (ML) direction (p = 0.09), and returned to baseline by 60R (p>=0.10). COP velocity was unchanged immediately following the 32MWT, but at 60R was lower in ML (p = 0.03) and tended to be reduced in AP (p = 0.07). Changes in high-velocity power (270 degrees .s-1) were associated with altered postural control (p = 0.02) and chair rise performance (p<=0.03). These results provide evidence of long-duration neuromuscular changes following fatigue in healthy older women that may place them at increased risk for functional deficits during everyday mobility tasks. PMID- 28880936 TI - Reduced microRNA-503 expression augments lung fibroblast VEGF production in chronic obstructive pulmonary disease. AB - Alterations in microRNA (miRNA) expression may contribute to COPD pathogenesis. In COPD, lung fibroblast repair functions are altered in multiple ways, including extracellular mediator release. Our prior study revealed miR-503 expression is decreased in COPD lung fibroblasts, although the exact role played by miR-503 is undetermined. The current study examined a role of miR-503 in cytokine, growth factor and fibronectin production by lung fibroblasts from patients with and without COPD. Primary adult lung fibroblasts were isolated from patients with or without COPD. MiR-503 expression and interleukin (IL)-6, -8, PGE2, HGF, KGF, VEGF and fibronectin release were examined with or without inflammatory cytokines, IL 1beta and tumor necrosis factor (TNF)-alpha. MiR-503 expression was decreased in COPD lung fibroblasts. The expression of miR-503 was positively correlated with %FVC, %FEV1, and %DLco as well as IL-6, -8, PGE2, HGF, KGF, and VEGF in the absence or presence of IL-1beta/TNF-alpha. In addition, IL-8 and VEGF release from COPD lung fibroblasts were increased compared to those from control. Exogenous miR-503 inhibited VEGF release from primary adult and fetal lung fibroblasts but not IL-8 release. As expected, COPD fibroblasts proliferated more slowly than control fibroblasts. MiR-503 did not affect proliferation of either control or COPD lung fibroblasts. MiR-503 inhibition of VEGF protein production and mRNA was mediated by direct binding to the 3' untranslated region of VEGF mRNA. Endogenous miR-503 was differently regulated by exogenous stimulants associated with COPD pathogenesis, including IL-1beta/TNF-alpha, TGF-beta1 and PGE2. Endogenous miR-503 inhibition augmented VEGF release by IL-1beta/TNF-alpha and TGF-beta1 but not by PGE2, demonstrating selectivity of miR-503 regulation of VEGF. In conclusions, reduced miR-503 augments VEGF release from lung fibroblasts from patients with COPD. Since VEGF contributes to disturbed vasculature in COPD, altered miR-503 production might play a role in modulating fibroblast-mediated vascular homeostasis in COPD. PMID- 28880937 TI - Differential expression of tetraspanin superfamily members in dendritic cell subsets. AB - Dendritic cells (DCs), which are essential for initiating immune responses, are comprised of different subsets. Tetraspanins organize dendritic cell membranes by facilitating protein-protein interactions within the so called tetraspanin web. In this study we analyzed expression of the complete tetraspanin superfamily in primary murine (CD4+, CD8+, pDC) and human DC subsets (CD1c+, CD141+, pDC) at the transcriptome and proteome level. Different RNA and protein expression profiles for the tetraspanin genes across human and murine DC subsets were identified. Although RNA expression levels of CD37 and CD82 were not significantly different between human DC subsets, CD9 RNA was highly expressed in pDCs, while CD9 protein expression was lower. This indicates that relative RNA and protein expression levels are not always in agreement. Both murine CD8alpha+ DCs and its regarded human counterpart, CD141+ DCs, displayed relatively high protein levels of CD81. CD53 protein was highly expressed on human pDCs in contrast to the relatively low protein expression of most other tetraspanins. This study demonstrates that tetraspanins are differentially expressed by human and murine DC subsets which provides a valuable resource that will aid the understanding of tetraspanin function in DC biology. PMID- 28880939 TI - ARF6 mediates nephrin tyrosine phosphorylation-induced podocyte cellular dynamics. AB - ADP-ribosylation factor 6 (ARF6) is a small GTPase necessary for regulating cellular structure, motility, and vesicle trafficking. In several cellular systems, ARF6 was shown to regulate actin dynamics in coordination with Rac1, a Rho small GTPase. We examined the function of ARF6 in the kidney podocyte because Rac1 was implicated in kidney diseases involving this cell. We found that ARF6 expression was enriched in human podocytes and that it modulated podocyte cytoskeletal dynamics through a functional interaction with nephrin, an intercellular junction protein necessary for podocyte injury-induced signaling requiring activation by tyrosine phosphorylation of its cytoplasmic domain. ARF6 was necessary for nephrin activation-induced ruffling and focal adhesion turnover, possibly by altering Rac1 activity. In podocyte-specific Arf6 (ARF6_PodKO) knockout mice, ARF6 deficiency did not result in a spontaneous kidney developmental phenotype or proteinuria after aging. However, ARF6_PodKO mice exhibited distinct phenotypes in two in vivo glomerular injury models. In the protamine sulfate perfusion model, which induced acute podocyte effacement, ARF6_PodKO mice were protected from podocyte effacement. In the nephrotoxic serum nephritis model, which induced immune-complex mediated injury, ARF6_PodKO mice exhibited aggravated proteinuria. Together, these observations suggest that while ARF6 is necessary for nephrin tyrosine phosphorylation-induced cytoskeletal dynamics in cultured podocytes, ARF6 has pleotropic podocyte roles in vivo, where glomerular injury-specific mechanisms might activate distinct signaling pathways that dictate whether ARF6 activity is beneficial or deleterious for maintaining the integrity of the glomerular filtration barrier. PMID- 28880938 TI - PrPC expression and prion seeding activity in the alimentary tract and lymphoid tissue of deer. AB - The agent responsible for prion diseases is a misfolded form of a normal protein (PrPC). The prion hypothesis stipulates that PrPC must be present for the disease to manifest. Cervid populations across the world are infected with chronic wasting disease, a horizontally-transmissible prion disease that is likely spread via oral exposure to infectious prions (PrPCWD). Though PrPCWD has been identified in many tissues, there has been little effort to characterize the overall PrPC expression in cervids and its relationship to PrPCWD accumulation. We used immunohistochemistry (IHC), western blot and enzyme-linked immunosorbent assay to describe PrPC expression in naive white-tailed deer. We used real-time, quaking-induced conversion (RT-QuIC) to detect prion seeding activity in CWD infected deer. We assessed tissues comprising the alimentary tract, alimentary associated lymphoid tissue and systemic lymphoid tissue from 5 naive deer. PrPC was expressed in all tissues, though expression was often very low compared to the level in the CNS. IHC identified specific cell types wherein PrPC expression is very high. To compare the distribution of PrPC to PrPCWD, we examined 5 deer with advanced CWD infection. Using RT-QuIC, we detected prion seeding activity in all 21 tissues. In 3 subclinical deer sacrificed 4 months post-inoculation, we detected PrPCWD consistently in alimentary-associated lymphoid tissue, irregularly in alimentary tract tissues, and not at all in the brain. Contrary to our hypothesis that PrPC levels dictate prion accumulation, PrPC expression was higher in the lower gastrointestinal tissues than in the alimentary-associated lymphoid system and was higher in salivary glands than in the oropharyngeal lymphoid tissue. These data suggest that PrPC expression is not the sole driver of prion accumulation and that alimentary tract tissues accumulate prions before centrifugal spread from the brain occurs. PMID- 28880940 TI - Development of body, head and brain features in the Australian fat-tailed dunnart (Sminthopsis crassicaudata; Marsupialia: Dasyuridae); A postnatal model of forebrain formation. AB - Most of our understanding of forebrain development comes from research of eutherian mammals, such as rodents, primates, and carnivores. However, as the cerebral cortex forms largely prenatally, observation and manipulation of its development has required invasive and/or ex vivo procedures. Marsupials, on the other hand, are born at comparatively earlier stages of development and most events of forebrain formation occur once attached to the teat, thereby permitting continuous and non-invasive experimental access. Here, we take advantage of this aspect of marsupial biology to establish and characterise a resourceful laboratory model of forebrain development: the fat-tailed dunnart (Sminthopsis crassicaudata), a mouse-sized carnivorous Australian marsupial. We present an anatomical description of the postnatal development of the body, head and brain in dunnarts, and provide a staging system compatible with human and mouse developmental stages. As compared to eutherians, the orofacial region develops earlier in dunnarts, while forebrain development is largely protracted, extending for more than 40 days versus ca. 15 days in mice. We discuss the benefits of fat tailed dunnarts as laboratory animals in studies of developmental biology, with an emphasis on how their accessibility in the pouch can help address new experimental questions, especially regarding mechanisms of brain development and evolution. PMID- 28880941 TI - A structured training program for health workers in intravenous treatment with fluids and antibiotics in nursing homes: A modified stepped-wedge cluster randomised trial to reduce hospital admissions. AB - OBJECTIVES: Hospitalization is potentially detrimental to nursing home patients and resource demanding for the specialist health care. This study assessed if a brief training program in administrating intravenous fluids and antibiotics in nursing homes could reduce hospital transfers and ensure high quality care locally. DESIGN: A pragmatic and modified cluster randomized stepped-wedge trial with randomization on nursing home level. PARTICIPANTS: 330 cases in 296 nursing home residents from 30 nursing homes were included. Cases were patients provided intravenous antibiotics or intravenous fluids, in nursing home or hospital. Primary outcome was localization of treatment, secondary outcomes were number of days treated, days of hospitalization among admitted patients, type of antibiotics used and 30-day mortality. INTERVENTION: The nursing homes sequentially received a one-day educational program for the health workers including theory and practical training in intravenous treatment of dehydration and infection, run by two skilled nurses. After completing the training program, the nursing homes had competence to provide intravenous treatment locally. RESULTS: The intervention had a highly significant effect on treatment in nursing homes (OR 8.35, 2.08 to 33.6; P<0.01, or RR 2.23, 1.48 to 2.56). The number treated in nursing homes was stable over time; the number treated in hospital gradually decreased (chi square for trend P< 0.001). Among patients receiving intravenous antibiotics in the nursing homes, 50 (46%) died within 30 days, compared to 30 (36%) treated in the hospital (P = 0.19). Among patients receiving intravenous fluids locally, 21 (19%) died within 30 days, compared to 2 (8%) in the hospital group (P = 0.34). Mortality was associated with reduced consciousness and elevated c-reactive protein. CONCLUSIONS: A brief educational program delivered to nursing home personnel was feasible and effective in reducing acute hospital admissions from nursing homes for treatment of dehydration and infections. PMID- 28880942 TI - Live-cell imaging to measure BAX recruitment kinetics to mitochondria during apoptosis. AB - The pro-apoptotic BCL2 gene family member, BAX, plays a pivotal role in the intrinsic apoptotic pathway. Under cellular stress, BAX recruitment to the mitochondria occurs when activated BAX forms dimers, then oligomers, to initiate mitochondria outer membrane permeabilization (MOMP), a process critical for apoptotic progression. The activation and recruitment of BAX to form oligomers has been studied for two decades using fusion proteins with a fluorescent reporter attached in-frame to the BAX N-terminus. We applied high-speed live cell imaging to monitor the recruitment of BAX fusion proteins in dying cells. Data from time-lapse imaging was validated against the activity of endogenous BAX in cells, and analyzed using sigmoid mathematical functions to obtain detail of the kinetic parameters of the recruitment process at individual mitochondrial foci. BAX fusion proteins behave like endogenous BAX during apoptosis. Kinetic studies show that fusion protein recruitment is also minimally affected in cells lacking endogenous BAK or BAX genes, but that the kinetics are moderately, but significantly, different with different fluorescent tags in the fusion constructs. In experiments testing BAX recruitment in 3 different cell lines, our results show that regardless of cell type, once activated, BAX recruitment initiates simultaneously within a cell, but exhibits varying rates of recruitment at individual mitochondrial foci. Very early during BAX recruitment, pro apoptotic molecules are released in the process of MOMP, but different molecules are released at different times and rates relative to the time of BAX recruitment initiation. These results provide a method for BAX kinetic analysis in living cells and yield greater detail of multiple characteristics of BAX-induced MOMP in living cells that were initially observed in cell free studies. PMID- 28880943 TI - Non-pulmonary vein mediated atrial fibrillation: A novel sub-phenotype. AB - BACKGROUND: Atrial fibrillation (AF) is a mechanistically heterogeneous disorder, and the ability to identify sub-phenotypes ("endophenotypes") of AF would assist in the delivery of personalized medicine. We used the clinical response to pulmonary vein isolation (PVI) to identify a sub-group of patients with non-PV mediated AF and sought to define the clinical associations. METHODS: Subjects enrolled in the Vanderbilt AF Ablation Registry who underwent a repeat AF ablation due to arrhythmia recurrence were analyzed on the basis of PV reconnection. Subjects who had no PV reconnection were defined as "non-PV mediated AF". A comparison group of subjects were identified who had AF that was treated with PVI-only and experienced no arrhythmia recurrence >12 months. They were considered a group enriched for "PV-mediated AF". Univariate and multivariable binary logistic regression analysis was performed to investigate clinical associations between the PV and non-PV mediated AF groups. RESULTS: Two hundred and twenty nine subjects underwent repeat AF ablation and thirty three (14%) had no PV reconnection. They were compared with 91 subjects identified as having PV-mediated AF. Subjects with non-PV mediated AF were older (64 years [IQR 60,71] vs. 60 [52,67], P = 0.01), more likely to have non-paroxysmal AF (82% [N = 27] vs. 35% [N = 32], P<0.001), and had a larger left atrium (LA) (4.2cm [3.6,4.8] vs. 4.0 [3.3,4.4], P = 0.04). In univariate analysis, age (per decade: OR 1.56 [95% CI: 1.04 to 2.33], P = 0.03), LA size (per cm: OR 1.8 [1.06 to 3.21], P = 0.03) and non-paroxysmal AF (OR 8.3 [3.10 to 22.19], P<0.001) were all significantly associated with non-PV mediated AF. However, in multivariable analysis only non-paroxysmal AF was independently associated with non-PV mediated AF (OR 7.47 [95% CI 2.62 to 21.29], P<0.001), when adjusted for age (per decade: OR 1.25 [0.81 to 1.94], P = 0.31), male gender (OR 0.48 [0.18 to 1.28], P = 0.14), and LA size (per 1cm: 1.24 [0.65 to 2.33], P = 0.52). CONCLUSIONS: Non paroxysmal AF was the only clinical variable found to be independently associated with non-PV mediated AF. We demonstrated that analysis of AF ablation outcomes data can serve as a tool to successfully identify a sub-phenotype of subjects who have non-PV mediated AF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID # NCT02404415. PMID- 28880945 TI - Causal knowledge promotes behavioral self-regulation: An example using climate change dynamics. AB - Adopting successful climate change mitigation policies requires the public to choose how to balance the sometimes competing goals of managing CO2 emissions and achieving economic growth. It follows that collective action on climate change depends on members of the public to be knowledgeable of the causes and economic ramifications of climate change. The existing literature, however, shows that people often struggle to correctly reason about the fundamental accumulation dynamics that drive climate change. Previous research has focused on using analogy to improve people's reasoning about accumulation, which has been met with some success. However, these existing studies have neglected the role economic factors might play in shaping people's decisions in relation to climate change. Here, we introduce a novel iterated decision task in which people attempt to achieve a specific economic goal by interacting with a causal dynamic system in which human economic activities, CO2 emissions, and warming are all causally interrelated. We show that when the causal links between these factors are highlighted, people's ability to achieve the economic goal of the task is enhanced in a way that approaches optimal responding, and avoids dangerous levels of warming. PMID- 28880944 TI - Spatiotemporal and molecular epidemiology of cutaneous leishmaniasis in Libya. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is a major public health problem in Libya. In this paper, we describe the eco-epidemiological parameters of CL during the armed conflict period from January 2011 till December 2012. Current spatiotemporal distributions of CL cases were explored and projected to the future using a correlative modelling approach. In addition the present results were compared with our previous data obtained for the time period 1995-2008. METHODOLOGY/PRINCIPAL FINDINGS: We investigated 312 CL patients who presented to the Dermatology Department at the Tripoli Central Hospital and came from 81 endemic areas distributed in 10 districts. The patients presented with typical localized lesions which appeared commonly on the face, arms and legs. Molecular identification of parasites by a PCR-RFLP approach targeting the ITS1 region of the rDNA was successful for 81 patients with two causative species identified: L. major and L. tropica comprised 59 (72.8%) and 22 (27.2%) cases, respectively. Around 77.3% of L. tropica CL and 57.7% of L. major CL caused single lesions. Five CL patients among our data set were seropositive for HIV. L. tropica was found mainly in three districts, Murqub (27.3%), Jabal al Gharbi (27.3%) and Misrata (13.7%) while L. major was found in two districts, in Jabal al Gharbi (61%) and Jafara (20.3%). Seasonal occurrence of CL cases showed that most cases (74.2%) admitted to the hospital between November and March, L. major cases from November till January (69.4%), and L. tropica cases mainly in January and February (41%). Two risk factors were identified for the two species; the presence of previously infected household members, and the presence of rodents and sandflies in patient's neighborhoods. Spatiotemporal projections using correlative distribution models based on current case data and climatic conditions showed that coastal regions have a higher level of risk due to more favourable conditions for the transmitting vectors. CONCLUSION: Future projection of CL until 2060 showed a trend of increasing incidence of CL in the north western part of Libya, a spread along the coastal region and a possible emergence of new endemics in the north-eastern districts of Libya. These results should be considered for control programs to prevent the emergence of new endemic areas taking also into consideration changes in socio-economical factors such as migration, conflicts, urbanization, land use and access to health care. PMID- 28880946 TI - Beyond group engagement: Multiple pathways from encounters with the police to cooperation and compliance in Northern Ireland. AB - In a sample of young people in Northern Ireland (N = 819), we examine the relationships between the quality of experience with police officers and police legitimacy. We examine potential pathways through which experiences may either support or undermine the legitimacy of the police, and thus cooperation and compliance with them. We find evidence that perceptions of the police as having goals that align with those of wider society, and as being fair in general, mediate relations between the quality of encounters and legitimacy, which in turn mediates the relation with cooperation and compliance. Identification with wider society was not a reliable mediator, contrary to our predictions based on the Group Engagement Model. Moreover, our analysis of the structure of police fairness perceptions finds no support for the distinction between procedural and distributive police fairness as usually conceived. Implications for the social psychological understanding of legitimate authority are discussed. PMID- 28880947 TI - Comparing hair-morphology and molecular methods to identify fecal samples from Neotropical felids. AB - To avoid certain problems encountered with more-traditional and invasive methods in behavioral-ecology studies of mammalian predators, such as felids, molecular approaches have been employed to identify feces found in the field. However, this method requires a complete molecular biology laboratory, and usually also requires very fresh fecal samples to avoid DNA degradation. Both conditions are normally absent in the field. To address these difficulties, identification based on morphological characters (length, color, banding, scales and medullar patterns) of hairs found in feces could be employed as an alternative. In this study we constructed a morphological identification key for guard hairs of eight Neotropical felids (jaguar, oncilla, Geoffroy's cat, margay, ocelot, Pampas cat, puma and jaguarundi) and compared its efficiency to that of a molecular identification method, using the ATP6 region as a marker. For this molecular approach, we simulated some field conditions by postponing sample-conservation procedures. A blind test of the identification key obtained a nearly 70% overall success rate, which we considered equivalent to or better than the results of some molecular methods (probably due to DNA degradation) found in other studies. The jaguar, puma and jaguarundi could be unequivocally discriminated from any other Neotropical felid. On a scale ranging from inadequate to excellent, the key proved poor only for the margay, with only 30% of its hairs successfully identified using this key; and have intermediate success rates for the remaining species, the oncilla, Geoffroy's cat, ocelot and Pampas cat, were intermediate. Complementary information about the known distributions of felid populations may be necessary to substantially improve the results obtained with the key. Our own molecular results were even better, since all blind-tested samples were correctly identified. Part of these identifications were made from samples kept in suboptimal conditions, with some samples remaining outdoors for up to seven days, simulating conditions in the field. It appears that both methods can be used, depending on the available laboratory facilities and on the expected results. PMID- 28880948 TI - Prevention of vaginal and rectal HIV transmission by antiretroviral combinations in humanized mice. AB - With more than 7,000 new HIV infections daily worldwide, there is an urgent need for non-vaccine biomedical prevention (nBP) strategies that are safe, effective, and acceptable. Clinical trials have demonstrated that pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) can be effective at preventing HIV infection. In contrast, other trials using the same ARVs failed to show consistent efficacy. Topical (vaginal and rectal) dosing is a promising regimen for HIV PrEP as it leads to low systematic drug exposure. A series of titration studies were carried out in bone marrow/liver/thymus (BLT) mice aimed at determining the adequate drug concentrations applied vaginally or rectally that offer protection against rectal or vaginal HIV challenge. The dose-response relationship of these agents was measured and showed that topical tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) can offer 100% protection against rectal or vaginal HIV challenges. From the challenge data, EC50 values of 4.6 MUM for TDF and 0.6 MUM for FTC for HIV vaginal administration and 6.1 MUM TDF and 0.18 MUM for FTC for rectal administration were obtained. These findings suggest that the BLT mouse model is highly suitable for studying the dose-response relationship in single and combination ARV studies of vaginal or rectal HIV exposure. Application of this sensitive HIV infection model to more complex binary and ternary ARV combinations, particularly where agents have different mechanisms of action, should allow selection of optimal ARV combinations to be advanced into pre clinical and clinical development as nBP products. PMID- 28880949 TI - Maternal hypothalamic-pituitary-adrenal axis response to foraging uncertainty: A model of individual vs. social allostasis and the "Superorganism Hypothesis". AB - INTRODUCTION: Food insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term "social allostasis." We postulate that maternal food insecurity induces a "superorganism" state through coordination of individual HPA axis response. METHODS: Twenty-four socially housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments. RESULTS: Despite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our "dyadic vulnerability" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively "advantaged" dyads exhibited maternal cortisol increases in response to VFD exposure. COMMENT: In response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a "superorganism" version of HPA axis homeostasis, provisionally termed "social allostasis." PMID- 28880950 TI - Correction: Pollination Mode and Mating System Explain Patterns in Genetic Differentiation in Neotropical Plants. AB - [This corrects the article DOI: 10.1371/journal.pone.0158660.]. PMID- 28880952 TI - Large scale expression and purification of secreted mouse hephaestin. AB - Hephaestin is a large membrane-anchored multicopper ferroxidase involved in mammalian iron metabolism. Newly absorbed dietary iron is exported across the enterocyte basolateral membrane by the ferrous iron transporter ferroportin, but hephaestin increases the efficiency of this process by oxidizing the transported iron to its ferric form and promoting its release from ferroportin. Deletion or mutation of the hephaestin gene leads to systemic anemia with iron accumulation in the intestinal epithelium. The crystal structure of human ceruloplasmin, another multicopper ferroxidase with 50% sequence identity to hephaestin, has provided a framework for comparative analysis and modelling. However, detailed structural information for hephaestin is still absent, leaving questions relating to metal coordination and binding sites unanswered. To obtain structural information for hephaestin, a reliable protocol for large-scale purification is required. Here, we present an expression and purification protocol of soluble mouse hephaestin, yielding milligram amounts of enzymatically active, purified protein using the baculovirus/insect cell system. PMID- 28880951 TI - Contrasting seasonal drivers of virus abundance and production in the North Pacific Ocean. AB - The North Pacific Ocean (between approximately 0 degrees N and 50 degrees N) contains the largest continuous ecosystem on Earth. This region plays a vital role in the cycling of globally important nutrients as well as carbon. Although the microbial communities in this region have been assessed, the dynamics of viruses (abundances and production rates) remains understudied. To address this gap, scientific cruises during the winter and summer seasons (2013) covered the North Pacific basin to determine factors that may drive virus abundances and production rates. Along with information on virus particle abundance and production, we collected a spectrum of oceanographic metrics as well as information on microbial diversity. The data suggest that both biotic and abiotic factors affect the distribution of virus particles. Factors influencing virus dynamics did not vary greatly between seasons, although the abundance of viruses was almost an order of magnitude greater in the summer. When considered in the context of microbial community structure, our observations suggest that members of the bacterial phyla Proteobacteria, Planctomycetes, and Bacteroidetes were correlated to both virus abundances and virus production rates: these phyla have been shown to be enriched in particle associated communities. The findings suggest that environmental factors influence virus community functions (e.g., virion particle degradation) and that particle-associated communities may be important drivers of virus activity. PMID- 28880953 TI - Direct and indirect impact of 10-valent pneumococcal conjugate vaccine introduction on pneumonia hospitalizations and economic burden in all age-groups in Brazil: A time-series analysis. AB - Background: Ten-valent pneumococcal conjugate vaccine (PCV10) was introduced in the National Immunization Program of Brazil in March/2010. Although there are recent reports of PCV10 impact on pneumonia hospitalizations, there is still uncertainty regarding the indirect impact in individuals non-targeted by vaccination. We assessed both direct and indirect effect of PCV10 on pneumonia hospitalizations and the impact on the economic burden of pneumonia hospitalizations. Methods: An interrupted time-series analysis was conducted considering monthly rates of pneumonia hospitalizations and comparison groups, in all age-groups, from January/2005-December/2015. We used records of the National Hospitalizations Information System. Observed pneumonia rates in the post vaccination period (2011-2015) were compared to predicted rates, should PCV10 had not been introduced. Relative percent difference in rates and its 95% confidence interval were estimated. The number of pneumonia hospitalizations averted by vaccination was calculated as the difference between the predicted and observed cumulative number of pneumonia hospitalizations in the post-vaccination period. The impact of PCV10 on economic burden was presented as averted costs of pneumonia hospitalization. Results: Significant decrease in rates of pneumonia hospitalization was observed in both children targeted by vaccination (17.4% 26.5%; p<0.01), and in age-groups not targeted by vaccination (11.1%-27.1%, in individuals 10-49 years; p<0.01). In contrast, PCV10 introduction did not alter the increasing trends in pneumonia hospitalization among elderly >=65 years. A total of 457,564 pneumonia hospitalizations was averted in Brazil for individuals aged <50 years, with a total averted costs of BRL 383.2 million (Int$ 225.2 million, and USD 147 million) for the 5 year period after PCV introduction. Conclusion: Vaccination with PCV10 5 years after its introduction in Brazil was associated with a relevant reduction in pneumonia hospitalization in the target age-groups, with an indirect effect in individuals aged 10-49 years, and significant reduction in associated economic burden. The increasing trends in pneumonia hospitalization rates in the elderly is a matter of concern for public health and should be further investigated. PMID- 28880954 TI - First interspecific genetic linkage map for Castanea sativa x Castanea crenata revealed QTLs for resistance to Phytophthora cinnamomi. AB - The Japanese chestnut (Castanea crenata) carries resistance to Phytophthora cinnamomi, the destructive and widespread oomycete causing ink disease. The European chestnut (Castanea sativa), carrying little to no disease resistance, is currently threatened by the presence of the oomycete pathogen in forests, orchards and nurseries. Determining the genetic basis of P. cinnamomi resistance, for further selection of molecular markers and candidate genes, is a prominent issue for implementation of marker assisted selection in the breeding programs for resistance. In this study, the first interspecific genetic linkage map of C. sativa x C. crenata allowed the detection of QTLs for P. cinnamomi resistance. The genetic map was constructed using two independent, control-cross mapping populations. Chestnut populations were genotyped using 452 microsatellite and single nucleotide polymorphism molecular markers derived from the available chestnut transcriptomes. The consensus genetic map spans 498,9 cM and contains 217 markers mapped with an average interval of 2.3 cM. For QTL analyses, the progression rate of P. cinnamomi lesions in excised shoots inoculated was used as the phenotypic metric. Using non-parametric and composite interval mapping approaches, two QTLs were identified for ink disease resistance, distributed in two linkage groups: E and K. The presence of QTLs located in linkage group E regarding P. cinnamomi resistance is consistent with a previous preliminary study developed in American x Chinese chestnut populations, suggesting the presence of common P. cinnamomi defense mechanisms across species. Results presented here extend the genomic resources of Castanea genus providing potential tools to assist the ongoing and future chestnut breeding programs. PMID- 28880955 TI - Zika genomics urgently need standardized and curated reference sequences. PMID- 28880956 TI - Effect of a new motorway on social-spatial patterning of road traffic accidents: A retrospective longitudinal natural experimental study. AB - BACKGROUND: The World Health Organisation reports that road traffic accidents (accidents) could become the seventh leading cause of death globally by 2030. Accidents often occur in spatial clusters and, generally, there are more accidents in less advantaged areas. Infrastructure changes, such as new roads, can affect the locations and magnitude of accident clusters but evidence of impact is lacking. A new 5-mile motorway extension was opened in 2011 in Glasgow, Scotland. Previous research found no impact on the number of accidents but did not consider their spatial location or socio-economic setting. We evaluated impacts on these, both locally and city-wide. METHODS: We used STATS19 data covering the period 2008 to 2014 and describing the location and details of all reported accidents involving a personal injury. Poisson-based continuous scan statistics were used to detect spatial clusters of accidents and any change in these over time. Change in the socio-economic distribution of accident cluster locations during the study period was also assessed. RESULTS: In each year accidents were strongly clustered, with statistically significant clusters more likely to occur in socio-economically deprived areas. There was no significant shift in the magnitude or location of accident clusters during motorway construction or following opening, either locally or city-wide. There was also no impact on the socio-economic patterning of accident cluster locations. CONCLUSIONS: Although urban infrastructure changes occur constantly, all around the world, this is the first study to evaluate the impact of such changes on road accident clusters. Despite expectations to the contrary from both proponents and opponents of the M74 extension, we found no beneficial or adverse change in the socio-spatial distribution of accidents associated with its construction, opening or operation. Our approach and findings can help inform urban planning internationally. PMID- 28880957 TI - Mapping the STK4/Hippo signaling network in prostate cancer cell. AB - Dysregulation of MST1/STK4, a key kinase component of the Hippo-YAP pathway, is linked to the etiology of many cancers with poor prognosis. However, how STK4 restricts the emergence of aggressive cancer remains elusive. Here, we investigated the effects of STK4, primarily localized in the cytoplasm, lipid raft, and nucleus, on cell growth and gene expression in aggressive prostate cancer. We demonstrated that lipid raft and nuclear STK4 had superior suppressive effects on cell growth in vitro and in vivo compared with cytoplasmic STK4. Using RNA sequencing and bioinformatics analysis, we identified several differentially expressed (DE) genes that responded to ectopic STK4 in all three subcellular compartments. We noted that the number of DE genes observed in lipid raft and nuclear STK4 cells were much greater than cytoplasmic STK4. Our functional annotation clustering showed that these DE genes were commonly associated with oncogenic pathways such as AR, PI3K/AKT, BMP/SMAD, GPCR, WNT, and RAS as well as unique pathways such as JAK/STAT, which emerged only in nuclear STK4 cells. These findings indicate that MST1/STK4/Hippo signaling restricts aggressive tumor cell growth by intersecting with multiple molecular pathways, suggesting that targeting of the STK4/Hippo pathway may have important therapeutic implications for cancer. PMID- 28880959 TI - Correction: A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma. AB - [This corrects the article DOI: 10.1371/journal.pone.0175638.]. PMID- 28880958 TI - Think globally, act locally: Phylodynamic reconstruction of infectious bronchitis virus (IBV) QX genotype (GI-19 lineage) reveals different population dynamics and spreading patterns when evaluated on different epidemiological scales. AB - Infectious bronchitis virus (IBV) represents one of the poultry industry major threats, particularly in high density producing countries. The emergence and spread of new IBV genotypes have frustrated the various disease control efforts implemented over time. Despite that, few comprehensive and large scale studies have been performed to understand the international and local spreading dynamics of this virus. In the present work, these phenomena were evaluated by implementing a Bayesian phylodynamic approach to reconstruct the epidemiological patterns and population history of the QX genotype (currently renamed GI-19 lineage), the most relevant IBV lineage of the Old-World. Our analysis, based on 807 partial S1 sequences of strains collected from 18 countries between 1993 and 2015, demonstrates that this genotype originated in China well before its first identification. After a prolonged local circulation, it started spreading to other European, Asian and Middle East countries in successive waves, which were mirrored by concomitant fluctuations in viral population size. Interestingly, the within-Europe spread was characterized by a higher estimated migration rate compared with the inter-continental one, potentially reflecting the closer geographic and economic relationships among these countries. Nevertheless, the colonization of new states by the GI-19 lineage appeared to occur mostly by single introduction events in both intra and inter-continental spread, likely because of epidemiological factor and health policy combination which seems to prevent the frequent introduction and mixing of different strains. On the other hand, the within Italy QX circulation reconstruction showed a much more intricate connection network among different locations, evidencing the difficulty in controlling IBV spread especially in highly densely poultry populated areas. The presence of several well supported epidemiological links among distantly related Italian regions testifies that animal transportation and indirect transmission routes rather than local airborne diffusion contribute to the QX success and persistence at local scale. Globally, the spreading dynamics and evolution of the QX genotype were reconstructed from its very origin to nowadays, demonstrating the need of more effective direct control measures, particularly within each country. Unfortunately, the incompleteness of available molecular epidemiology data represents an insurmountable limit which leaves many questions currently unsolved, thus highlighting the compulsoriness of a structured monitoring and data sharing system implementation. PMID- 28880960 TI - Correction: Correction: A Novel Rhabdovirus Associated with Acute Hemorrhagic Fever in Central Africa. AB - [This corrects the article DOI: 10.1371/journal.ppat.1002924.]. PMID- 28880961 TI - Experimental verification of subthreshold laser therapy using conventional pattern scan laser. AB - PURPOSE: Leading-edge therapeutic laser technologies are not available at every medical facility; therefore, alternative approaches incorporating novel advances in digital and laser technology into more readily available conventional methods have generated significant research interest. Using a rabbit model, this study investigated whether the algorithm used in the Endpoint Management (EM) software system of the latest devices could enable subthreshold laser treatment in conventional retinal tissue laser therapy systems. MATERIALS AND METHODS: Two types of devices were used, the PASCAL Streamline 577 and the MC 500-VixiTM, and the laser method was classified into three categories: EM; single-shot using PASCAL with arbitrary energy settings (PSS-SDM); and MC500-VixiTM (VX-SDM), which were performed in eight eyes from four Dutch-Belted rabbits. In EM, 100 mW (100%) was set as a landmark, and the laser energy parameters were gradually decreased to 80%, 60%, 50%, 40%, 30%, 20%, and 10%, using a 2 * 3 square pattern. In PSS SDM and VX-SDM, as control, the laser energy was gradually decreased to 100, 80, 60, 50, 40, 30, 20, and 10 mW. The laser settings were fixed at 200 MUm, 20 ms, and a wavelength of 577 MUm. To identify and compare the extent of tissue damage at each spot size, optical coherence tomography (OCT) and histological findings were used to construct a three-dimensional histopathology image using a confocal laser scanning fluorescence microscope. RESULTS: The spot size at 50% setting on EM was 7183 MUm2; PSS-SDM required 50 mW (5503 MUm2) to 60 mW (10279 MUm2) and VX SDM required 50 mW (7423 MUm2) to create the approximate spot size. Furthermore, at 50 mW of PSS-SDM and VX-SDM, the extent of tissue damage in all three methods was generally in accord with the outer nuclear layer by OCT and inner nuclear layer by histopathological imaging. CONCLUSION: These findings suggest that it may be possible to perform subthreshold laser therapy using approximations from the EM algorithm. PMID- 28880963 TI - Correction: Intestinal calcium and bile salts facilitate germination of Clostridium difficile spores. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006443.]. PMID- 28880962 TI - Spatially explicit multi-threat assessment of food tree species in Burkina Faso: A fine-scale approach. AB - Over the last decades agroforestry parklands in Burkina Faso have come under increasing demographic as well as climatic pressures, which are threatening indigenous tree species that contribute substantially to income generation and nutrition in rural households. Analyzing the threats as well as the species vulnerability to them is fundamental for priority setting in conservation planning. Guided by literature and local experts we selected 16 important food tree species (Acacia macrostachya, Acacia senegal, Adansonia digitata, Annona senegalensis, Balanites aegyptiaca, Bombax costatum, Boscia senegalensis, Detarium microcarpum, Lannea microcarpa, Parkia biglobosa, Sclerocarya birrea, Strychnos spinosa, Tamarindus indica, Vitellaria paradoxa, Ximenia americana, Ziziphus mauritiana) and six key threats to them (overexploitation, overgrazing, fire, cotton production, mining and climate change). We developed a species specific and spatially explicit approach combining freely accessible datasets, species distribution models (SDMs), climate models and expert survey results to predict, at fine scale, where these threats are likely to have the greatest impact. We find that all species face serious threats throughout much of their distribution in Burkina Faso and that climate change is predicted to be the most prevalent threat in the long term, whereas overexploitation and cotton production are the most important short-term threats. Tree populations growing in areas designated as 'highly threatened' due to climate change should be used as seed sources for ex situ conservation and planting in areas where future climate is predicting suitable habitats. Assisted regeneration is suggested for populations in areas where suitable habitat under future climate conditions coincides with high threat levels due to short-term threats. In the case of Vitellaria paradoxa, we suggest collecting seed along the northern margins of its distribution and considering assisted regeneration in the central part where the current threat level is high due to overexploitation. In the same way, population-specific recommendations can be derived from the individual and combined threat maps of the other 15 food tree species. The approach can be easily transferred to other countries and can be used to analyze general and species specific threats at finer and more local as well as at broader (continental) scales in order to plan more selective and efficient conservation actions in time. The concept can be applied anywhere as long as appropriate spatial data are available as well as knowledgeable experts. PMID- 28880964 TI - Correction: HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006348.]. PMID- 28880965 TI - Multiple evolutionary origins of Trypanosoma evansi in Kenya. AB - Trypanosoma evansi is the parasite causing surra, a form of trypanosomiasis in camels and other livestock, and a serious economic burden in Kenya and many other parts of the world. Trypanosoma evansi transmission can be sustained mechanically by tabanid and Stomoxys biting flies, whereas the closely related African trypanosomes T. brucei brucei and T. b. rhodesiense require cyclical development in tsetse flies (genus Glossina) for transmission. In this study, we investigated the evolutionary origins of T. evansi. We used 15 polymorphic microsatellites to quantify levels and patterns of genetic diversity among 41 T. evansi isolates and 66 isolates of T. b. brucei (n = 51) and T. b. rhodesiense (n = 15), including many from Kenya, a region where T. evansi may have evolved from T. brucei. We found that T. evansi strains belong to at least two distinct T. brucei genetic units and contain genetic diversity that is similar to that in T. brucei strains. Results indicated that the 41 T. evansi isolates originated from multiple T. brucei strains from different genetic backgrounds, implying independent origins of T. evansi from T. brucei strains. This surprising finding further suggested that the acquisition of the ability of T. evansi to be transmitted mechanically, and thus the ability to escape the obligate link with the African tsetse fly vector, has occurred repeatedly. These findings, if confirmed, have epidemiological implications, as T. brucei strains from different genetic backgrounds can become either causative agents of a dangerous, cosmopolitan livestock disease or of a lethal human disease, like for T. b. rhodesiense. PMID- 28880967 TI - A novel approach for predicting microbe-disease associations by bi-random walk on the heterogeneous network. AB - Since the microbiome has a significant impact on human health and disease, microbe-disease associations can be utilized as a valuable resource for understanding disease pathogenesis and promoting disease diagnosis and prognosis. Accordingly, it is necessary for researchers to achieve a comprehensive and deep understanding of the associations between microbes and diseases. Nevertheless, to date, little work has been achieved in implementing novel human microbe-disease association prediction models. In this paper, we develop a novel computational model to predict potential microbe-disease associations by bi-random walk on the heterogeneous network (BiRWHMDA). The heterogeneous network was constructed by connecting the microbe similarity network and the disease similarity network via known microbe-disease associations. Microbe similarity and disease similarity were calculated by the Gaussian interaction profile kernel similarity measure; moreover, a logistic function was applied to regulate disease similarity. Additionally, leave-one-out cross validation and 5-fold cross validation were implemented to evaluate the predictive performance of our method; both cross validation methods performed well. The leave-one-out cross validation experiment results illustrate that our method outperforms other previously proposed methods. Furthermore, case studies on asthma and inflammatory bowel disease prove the favorable performance of our method. In conclusion, our method can be considered as an effective computational model for predicting novel microbe-disease associations. PMID- 28880966 TI - The prolyl 4-hydroxylase inhibitor GSK360A decreases post-stroke brain injury and sensory, motor, and cognitive behavioral deficits. AB - There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4 hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes. Vehicle or an established protective dose (30 mg/kg, p.o.) of GSK360A was administered to male Sprague Dawley rats. Initially, GSK360A pharmacokinetics and organ distribution were determined, and then PHD-HIF pharmacodynamic markers were measured (i.e., to validate the pharmacological effects of the GSK360A administration regimen). Results obtained using this validated PHD dose-regimen indicated significant improvement by GSK360A (30mg/kg); administered at 18 and 5 hours prior to transient middle cerebral artery occlusion (stroke). GSK360A exposure and plasma, kidney and brain HIF-PHD pharmacodynamics endpoints (e.g., erythropoietin; EPO and Vascular Endothelial Growth Factor; VEGF) were measured. GSK360A provided rapid exposure in plasma (7734 ng/ml), kidney (45-52% of plasma level) and brain (1-4% of plasma level), and increased kidney EPO mRNA (80-fold) and brain VEGF mRNA (2-fold). We also observed that GSK360A increased plasma EPO (300-fold) and VEGF (2-fold). Further assessments indicated that GSK360A reduced post-stroke surgery neurological deficits (47-64%), cognitive dysfunction (60-75%) and brain infarction (30%) 4 weeks later. Thus, PHD inhibition using GSK360A pretreatment produced long-term post-stroke brain protection and improved behavioral functioning. These data support PHD inhibition, specifically by GSK360A, as a potential strategy for pre-surgical use to reduce brain injury and functional decline due to surgery-related cerebral injury. PMID- 28880968 TI - Purification and characterization of a novel metalloprotease from fruiting bodies of Oudemansiella radicata. AB - In this study, a 39-kDa metalloprotease was purified from a rare edible mushroom with health-promoting activities, Oudemansiella radicata, using a purification protocol which entailed anion exchange chromatography on DEAE-cellulose and Q Sepharose columns and gel filtration by fast protein liquid chromatography on a Superdex 75 column. Some peptide sequences were obtained by LC-MS/MS analysis and one of the sequences, DAWIQADVNR, manifested 90% identity to Coprinopsis cinerea metalloprotease. The optimal reaction pH and temperature for Oudemansiella radicata protease were pH 7.0 and 50 degrees C, respectively. The protease was purified 79-fold and demonstrated a specific protease activity of 2.42 U/mg. The Km of the purified protease for the casein substrate was 0.65 mg/mL at pH 7.0 and 50 degrees C. The activity of the protease was inhibited by Cd2+, Hg2+, Cu2+, Pb2+ and Fe3+ ions, but was enhanced by K+, Mn2+ and Fe2+ ions. The marked suppression of the protease activity by EDTA indicates that the protease is a metalloprotease. PMID- 28880969 TI - Anti-inflammatory activities of garlic sprouts, a source of alpha-linolenic acid and 5-hydroxy-l-tryptophan, in RAW 264.7 cells. AB - The purpose of this study was to analyze the indolic, phenolic, and fatty acid content and antioxidant activity of garlic sprouts growing in the dark and in the daylight. The pro- or anti-inflammatory properties of the garlic sprout extract were investigated by evaluating the cyclooxygenase-2 (COX-2), prostaglandin E synthase (cPGES), glutathione S transferase (GSTM1), nuclear factor NF-kappaB, peroxisome proliferator-activated receptors (PPARs), and aryl hydrocarbon receptor (AhR) protein levels in the RAW 264.7 cells activated with lipopolysaccharide (LPS). The highest amount of total indolic (73.56 mg/100 g f.w.) and phenolic compounds (36.23 mg/100 g f.w.) was detected in garlic sprouts grown in the daylight. Studies on antioxidant activity (the FRAP and DPPH method) of garlic sprouts showed that this activity is significantly higher for sprouts grown in full access to light when compared to those grown in the dark. In garlic sprout extracts, alpha-linolenic acid (ALA) was found to be in greater amount. COX-2 and cPGES level was lower when compared to LPS alone activated cells. After garlic extract treatment, higher level of GSTM1, PPARUpsilon, cytosolic p50 and p65 protein, as well as a lower NF-KB p50/p65 activity was noted in the RAW 264.7 cells which suggested PPARs and AhR transrepression mechanism of NF-KB signalling. The obtained results indicate Allium sativum sprouts are a rich source of n-3 fatty acids, indolic and phenolic compounds characterized by anti inflammatory and antioxidative activity, which may support their high therapeutic and dietary potential. PMID- 28880970 TI - Optimization of Western blotting analysis for the isolation and detection of membrane xenobiotic transporter ABCG2. AB - All organisms are exposed to numerous stress factors, which include harmful xenobiotics. The diversity of these compounds is enormous, thus in the course of evolution diverse biological defense mechanisms at various levels of organization have developed. One of them engages an evolutionarily conserved family of transporters from the ABC superfamily, found in most species - from bacteria to humans. An important example of such a transporter is the breast cancer resistance protein (BCRP/ABCG2), a typical integral membrane protein. It plays a key role in the absorption, distribution and elimination of a wide variety of xenobiotics, including drugs used in chemotherapy, and is involved in multidrug resistance. It also protects against phototoxic chlorophyll derivatives of dietary origin. BCRP is a hemitransporter which consists of one transmembrane domain, made of six alpha-helices forming a characteristic pore structure, and one ATP-binding domain, which provides the energy from ATP hydrolysis, required for active transport of the substrates. The isolation of BCRP is still not an easy task, because its insolubility in water and the presence of membrane rafts pose serious methodological and technical challenges during the purification. The aim of this study was to optimize the methods for detection and isolation of BCRP enriched fractions obtained from animal tissue samples. In this report we describe an optimization of isolation of a BCRP-enriched membrane fraction, which is suitable for further protein quantitative and qualitative analysis using the molecular biology tools. PMID- 28880973 TI - A New Monoclonal Protein Detected in a Patient With Myeloma Undergoing Elotuzumab Therapy. PMID- 28880974 TI - Pathogenesis of Ocular Findings in Congenital Zika Syndrome. PMID- 28880971 TI - Development and Validation of a Novel Acute Myeloid Leukemia-Composite Model to Estimate Risks of Mortality. AB - Importance: To our knowledge, this multicenter analysis is the first to test and validate (1) the prognostic impact of comorbidities on 1-year mortality after initial therapy of acute myeloid leukemia (AML) and (2) a novel, risk-stratifying composite model incorporating comorbidities, age, and cytogenetic and molecular risks. Objective: To accurately estimate risks of mortality by developing and validating a composite model that combines the most significant patient-specific and AML-specific features. Design, Setting, and Participants: This is a retrospective cohort study. A series of comorbidities, including those already incorporated into the hematopoietic cell transplantation-comorbidity index (HCT CI), were evaluated. Patients were randomly divided into a training set (n = 733) and a validation set (n = 367). In the training set, covariates associated with 1 year overall mortality at a significance level of P < .10 constructed a multivariate Cox proportional hazards model in which the impact of each covariate was adjusted for that of all others. Then, the adjusted hazard ratios were used as weights. Performances of models were compared using C statistics for continuous outcomes and area under the curve (AUC) for binary outcomes. Exposures: Initial therapy for AML. Main Outcomes and Measures: Death within 1 year after initial therapy for AML. Results: A total of 1100 patients, ages 20 to 89 years, were treated for AML between January 1, 2008, and December 31, 2012, at 5 academic institutions specialized in treating AML; 605 (55%) were male, and 495 (45%) were female. In the validation set, the original HCT-CI had better C statistic and AUC estimates compared with the AML comorbidity index for prediction of 1-year mortality. Augmenting the original HCT-CI with 3 independently significant comorbidities, hypoalbuminemia, thrombocytopenia, and high lactate dehydrogenase level, yielded a better C statistic of 0.66 and AUC of 0.69 for 1-year mortality. A composite model comprising augmented HCT-CI, age, and cytogenetic/molecular risks had even better predictive estimates of 0.72 and 0.76, respectively. Conclusions and Relevance: In this cohort study, comorbidities influenced 1-year survival of patients with AML, and comorbidities are best captured by an augmented HCT-CI. The augmented HCT-CI, age, and cytogenetic/molecular risks could be combined into an AML composite model that could guide treatment decision-making and trial design in AML. Studying physical, cognitive, and social health might further clarify the prognostic role of aging. Targeting comorbidities with interventions alongside specific AML therapy might improve survival. PMID- 28880972 TI - Effect of Modified Vaccinia Ankara-5T4 and Low-Dose Cyclophosphamide on Antitumor Immunity in Metastatic Colorectal Cancer: A Randomized Clinical Trial. AB - Importance: The success of immunotherapy with checkpoint inhibitors is not replicated in most cases of colorectal cancer; therefore, different strategies are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of cases of metastatic colorectal cancer (mCRC). Preliminary data using modified vaccinia Ankara-5T4 (MVA-5T4) in mCRC demonstrated that it safely induced serologic and T-cell responses. Objective: To determine whether antitumor immunity in mCRC could be increased using MVA-5T4, metronomic low-dose cyclophosphamide, or a combination of both treatments. Design, Setting, and Participants: In this randomized clinical trial, 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy were enrolled at a single center and randomized to watch and wait (n = 9), cyclophosphamide treatment only (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide (n = 18). Patients were enrolled and treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed based on intention to treat. Interventions: Patients randomized to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1 * 109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106. Main Outcomes and Measures: The predefined primary end point was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7. Secondary end points included analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS). Results: Fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody immune responses were significantly increased in the MVA-5T4 (83.41 [36.09] relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P = .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients, resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P = .008). No grade 3 or 4 adverse events were observed. Conclusions and Relevance: This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects. Larger clinical trials are planned to further validate these data. Trial Registration: isrctn.org Identifier: ISRCTN54669986. PMID- 28880975 TI - Nutrition Counseling in Clinical Practice: How Clinicians Can Do Better. PMID- 28880976 TI - The Waiting Room. PMID- 28880977 TI - Speech Situation Checklist-Revised: Investigation With Adults Who Do Not Stutter and Treatment-Seeking Adults Who Stutter. AB - Purpose: The aim of this study was to evaluate the usefulness of the Speech Situation Checklist for adults who stutter (SSC) in differentiating people who stutter (PWS) from speakers with no stutter based on self-reports of anxiety and speech disruption in communicative settings. The SSC's psychometric properties were examined, norms were established, and suggestions for treatment were formulated. Method: The SSC was administered to 88 PWS seeking treatment and 209 speakers with no stutter between the ages of 18 and 62. The SSC consists of 2 sections investigating negative emotional reaction and speech disruption in 38 speech situations that are identical in both sections. Results: The SSC-Emotional Reaction and SSC-Speech Disruption data show that these self-report tests differentiate PWS from speakers with no stutter to a statistically significant extent and have great discriminative value. The tests have good internal reliability, content, and construct validity. Age and gender do not affect the scores of the PWS. Conclusions: The SSC-Emotional Reaction and SSC-Speech Disruption seem to be powerful measures to investigate negative emotion and speech breakdown in an array of speech situations. The item scores give direction to treatment by suggesting speech situations that need a clinician's attention in terms of generalization and carry-over of within-clinic therapeutic gains into in vivo settings. PMID- 28880979 TI - Conjunctival and Limbal Transplantation From the Same Living-Related Bone Marrow Donor to Patients With Severe Ocular Graft-vs-Host Disease. PMID- 28880978 TI - Quantitative Assessment of Microstructural Changes of the Retina in Infants With Congenital Zika Syndrome. AB - Importance: A better pathophysiologic understanding of the neurodevelopmental abnormalities observed in neonates exposed in utero to Zika virus (ZIKV) is needed to develop treatments. The retina as an extension of the diencephalon accessible to in vivo microcopy with spectral-domain optical coherence tomography (SD-OCT) can provide an insight into the pathophysiology of congenital Zika syndrome (CZS). Objective: To quantify the microstructural changes of the retina in CZS and compare these changes with those of cobalamin C (cblC) deficiency, a disease with potential retinal maldevelopment. Design, Setting, and Participants: This case series included 8 infants with CZS and 8 individuals with cblC deficiency. All patients underwent ophthalmologic evaluation at 2 university teaching hospitals and SD-OCT imaging in at least 1 eye. Patients with cblC deficiency were homozygous or compound heterozygotes for mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Data were collected from January 1 to March 17, 2016, for patients with CZS and from May 4, 2015, to April 23, 2016, for patients with cblC deficiency. Main Outcomes and Measures: The SD-OCT cross-sections were segmented using automatic segmentation algorithms embedded in the SD-OCT systems. Each retinal layer thickness was measured at critical eccentricities using the position of the signal peaks and troughs on longitudinal reflectivity profiles. Results: Eight infants with CZS (5 girls and 3 boys; age range, 3-5 months) and 8 patients with cblC deficiency (3 girls and 5 boys; age range, 4 months to 15 years) were included in the analysis. All 8 patients with CZS had foveal abnormalities in the analyzed eyes (8 eyes), including discontinuities of the ellipsoid zone, thinning of the central retina with increased backscatter, and severe structural disorganization, with 3 eyes showing macular pseudocolobomas. Pericentral retina with normal lamination showed a thinned (<30% of normal thickness) ganglion cell layer (GCL) that colocalized in 7 of 8 eyes with a normal photoreceptor layer. The inner nuclear layer was normal or had borderline thinning. The central retinal degeneration was similar to that of cblC deficiency. Conclusions and Relevance: Congenital Zika syndrome showed a central retinal degeneration with severe GCL loss, borderline inner nuclear layer thinning, and less prominent photoreceptor loss. The findings provide the first, to date, in vivo evidence in humans for possible retinal maldevelopment with a predilection for retinal GCL loss in CZS, consistent with a murine model of the disease and suggestive of in utero depletion of this neuronal population as a consequence of Zika virus infection. PMID- 28880981 TI - Timing of Pregnancy and Survival in Women With Breast Cancer. PMID- 28880980 TI - Progressive Tinnitus Management Level 3 Skills Education: A 5-Year Clinical Retrospective. AB - Purpose: The primary purpose of this study was to determine whether progressive tinnitus management Level 3 skills education workshops conducted at the Bay Pines and Boston Veterans Affairs hospitals result in consistent use of the presented tinnitus management strategies by patients 1-5 years after completing the workshops. Method: In fiscal year (FY) 2015, the tinnitus workshop follow-up form was mailed to all veterans who completed the Level 3 workshops between FY 2010 and FY 2014. Data were compiled to determine which, if any, of the skills taught in the workshops were being used 1-5 years after completion of the workshops and the impact on quality-of-life indicators. Results: All self-management skills were being utilized up to 5 years postcompletion; therapeutic sound was utilized the most. The majority of patients reported an improved ability to manage reactions to tinnitus and improved quality-of-life indicators. Over 90% of patients from both sites recommended the program to others with tinnitus. Conclusion: The self-management skills taught in the progressive tinnitus management Level 3 workshops are sustained over time even when limited resources prevent the full complement of workshops or the involvement of mental health services. The workshops can also be successfully implemented through remote delivery via videoconferencing (telehealth). Supplemental Materials: https://doi.org/10.23641/asha.5370883. PMID- 28880983 TI - Chimeric Antigen Receptor (CAR) T-Cell Therapy. PMID- 28880982 TI - Association Between Eyelid Laxity and Obstructive Sleep Apnea. AB - Importance: While much has been reported on the relationship between floppy eyelid syndrome and obstructive sleep apnea (OSA), the diagnostic criteria of floppy eyelid syndrome are often subjective and vague. Objective: To evaluate the association between OSA and quantitative markers of eyelid laxity or secondary ocular surface disease in a sleep clinic population. Design, Setting, and Participants: This investigation was a cross-sectional observational study at the Center for Sleep Medicine at Icahn School of Medicine at Mount Sinai. Participants were individuals referred for overnight polysomnography from March 1 to August 30, 2015. Main Outcomes and Measures: Eyelid laxity and ocular surface disease were assessed on bedside ophthalmologic examination. The presence and severity of OSA were determined from polysomnography results. Initial correlation between OSA and ocular surface and eyelid markers was calculated through bivariate linear regression analysis, and the association between ocular symptoms was obtained through bivariate ordered logistic regression. Analysis was repeated adjusting for known associations between OSA and sex, age, body mass index, and medical comorbidities through multivariable analysis. Results: In total, 201 individuals (402 eyes) were enrolled in the study. Their mean (SD) age was 53.2 (13.5) years, 43.3% (n = 87) were female, 56.7% (n = 114) were of white race/ethnicity, 26.9% (n = 54) were black/African American, 4.0% (n = 8) were Asian, 8.0% (n = 16) were multiracial or other, and 4.5% (n = 9) were of unknown race/ethnicity, with 21.9% (n = 44) of all individuals self-identifying as Hispanic and 75.1% (n = 151) self-identifying as non-Hispanic. After adjustment, no association was observed between OSA severity and an eyelid laxity score (regression coefficient, 0.85; 95% CI, -0.33 to 0.62; P = .40) or an ocular surface score (regression coefficient, 1.09; 95% CI, -0.32 to 0.29; P = .93). Through subset analysis, male sex was associated with a higher ocular surface score, while older age and diabetes were associated with a higher eyelid laxity score. Only one patient (0.5%) exhibited findings of floppy eyelid syndrome. Conclusions and Relevance: Among individuals referred for overnight polysomnography, quantitative markers of eyelid laxity were not associated with the presence or severity of OSA. Subset analysis suggests that prior studies may have been limited by confounding variables or the technique of identifying eyelid laxity. PMID- 28880985 TI - Dietary Modifications in the Treatment of Laryngopharyngeal Reflux-Will "an Apple a Day" Keep the Laryngopharyngeal Reflux Away? PMID- 28880984 TI - Association of a Perioperative Education Program With Unplanned Readmission Following Total Laryngectomy. PMID- 28880986 TI - Association of Disease Location and Treatment With Survival in Diffuse Large B Cell Lymphoma of the Eye and Ocular Adnexal Region. AB - Importance: Primary diffuse large B-cell lymphoma (DLBCL) of the ocular region is rare, and the utility of surgery and radiation therapy remains unresolved. Objective: To explore the clinical characteristics and determine factors associated with overall survival in primary vitreoretinal lymphoma (PVRL) and ocular adnexal (OA)-uveal DLBCL. Design, Setting, and Participants: This retrospective analysis included 396 patients with ophthalmic DLBCL from January 1, 1973, through December 31, 2014, using the Surveillance, Epidemiology, and End Results database. The median follow-up was 39.0 months (interquartile range, 5.1 72.9 months). All patients diagnosed with primary DLBCL of the eye or retina (PVRL) or the eyelid, conjunctiva, choroid, ciliary body, lacrimal gland, or orbit (OA-uveal lymphoma) were included. Patients diagnosed at autopsy or with additional neoplastic disease were excluded. Main Outcomes and Measures: Patient demographic characteristics, disease location, treatment modalities, and overall survival. Results: Forty-seven patients with PVRL (24 women [51.1%] and 23 men [48.9%]) and 349 with OA-uveal DLBCL (192 women [55.0%] and 157 men [45.0%]) had a similar mean (SD) age at diagnosis (69.6 [12.3] vs 66.1 [17.7] years). No difference in the use of surgery or radiation therapy by location was found. For all PVRL and OA-uveal DLBCL, a Cox proportional hazards regression model affirmed that age older than 60 years was associated with increased risk for death (hazard ratio [HR], 2.7; 95% CI, 1.9-4.0; P < .001). Gross total resection was associated with a decreased risk for death (HR, 0.5; 95% CI, 0.3-0.9; P = .04), whereas radiation therapy was not. The 5-year overall survival among patients with PVRL was 41.4% (SE, 8.6%); among those with OA-uveal DLBCL, 59.1% (SE, 2.8%; Mantel Cox test, P = .007). Median overall survival was lower in PVRL (38.0 months; 95% CI, 14.2-61.8 months) than in OA-uveal DLBCL (96.0 months; 95% CI, 67.3-124.7 months; Mantel-Cox test, P = .007). In addition, median overall survival in ophthalmic-only disease was higher (84.0 months; 95% CI, 63.2-104.8 months) than that in primary DLBCL that occurred outside the central nervous system and ophthalmic regions (46.0 months; 95% CI, 44.4-47.6 months; Mantel-Cox test, P < .001). Conclusions and Relevance: The 5-year survival in PVRL vs OA-uveal DLBCL differed by 17.7%, and overall survival was greater in ophthalmic DLBCL than in DLBCL located outside the central nervous system and ophthalmic regions. Younger age (<=60 years) and gross total resection were associated with increased survival. PMID- 28880987 TI - Association of Mohs Reconstructive Surgery Timing With Postoperative Complications. AB - Importance: Same-day Mohs reconstructive surgery is not always possible; moreover, a delay can offer benefits such as improved surgical planning and increased blood supply to the cauterized wound bed. However, recent work found that delaying reconstruction by more than 2 days increases the postoperative complication rate. Objective: To review the outcomes of Mohs micrographic surgery (MMS) reconstruction with respect to patient- and surgery-specific variables, especially timing of repair. Design, Setting, and Participants: Retrospective, single-institution cohort study of patients who underwent Mohs reconstructive surgery by 1 of the 2 senior authors from January 2012 to March 2017 for cutaneous squamous cell carcinoma or basal cell carcinoma. No patients had to be excluded for inadequate follow-up or incomplete medical records. Main Outcomes and Measures: Postoperative complications including hematoma, infection, dehiscence, and partial or full graft or flap loss. Results: A total of 633 defects in 591 patients (median [range] age, 65 [21-96] years; 333 [56.3%] female) were identified over the 5-year period. Reconstructions occurred from less than 24 hours to 32 days after MMS, with 229 (36.2%) delayed longer than 48 hours. Patient-specific variables reviewed included comorbidities, age, smoking status, and use of anticoagulant or antiplatelet medications. Surgery-specific variables analyzed included location and size of defect, time interval between MMS and reconstruction, and reconstructive modalities. Single-variable analysis was performed to determine whether each variable was associated with postoperative complications. On multivariable binary logistic regression, smoking status (odds ratio [OR], 2.46; 95% CI, 1.29-4.71; P = .007), defect size (OR exp(B), 1.04; 95% CI, 1.01-1.06; P = .006), full-thickness defects (OR, 1.56; 95% CI, 1.08-2.25; P = .02), interpolated flaps with cartilage grafting (OR, 8.09; 95% CI, 2.65-24.73; P < .001), and composite grafts (OR, 6.35; 95% CI, 2.25 17.92; P < .001) were associated with an increased risk of postoperative complications. Conclusions and Relevance: We found no association between timing of Mohs reconstructive surgery and complications, indicating that a delayed repair did not increase the risk of infection or flap failure. Variables associated with an increased risk of postoperative complications include smoking status, size of the defect, full-thickness defects, interpolated flaps with cartilage grafting, and the use of composite grafts. Level of Evidence: 3. PMID- 28880988 TI - The 10-Item Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) for Functional and Cosmetic Rhinoplasty. AB - Importance: Rhinoplasty is a common operation in which shape and function are intimately related, whether the procedure is cosmetic, functional, or combined in nature. There is currently no properly developed and validated patient-reported outcome measure (PROM) to evaluate both functional and cosmetic components of rhinoplasty. Objective: To develop, validate, and field test the Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) to evaluate both functional and cosmetic outcomes of rhinoplasty. Design, Setting, and Participants: Survey development study between October 2016 and April 2017 in a tertiary referral facial plastic and reconstructive surgery clinic. Preoperative and postoperative adult patients undergoing rhinoplasty, whether cosmetic or reconstructive, were included. A fifth group of adult nonrhinoplasty patients (facial cosmetic or reconstructive) were also included for the field test. Main Outcomes and Measures: Generated and reduced items, psychometric validation measures of the SCHNOS, and differences on scales between groups. Results: For survey development, a total of 18 patients and 5 experts were interviewed. Of these patients, 5 were male, and 13 were female. Their mean (SD) age was 38 (14.8) years (range, 20-64 years). Field testing included 191 patients (67% were women and the mean [SD] age was 41.5 [15.8] years). A total of 10 items were included after generation, cognitive interviews, and item reduction. The 10 items represent 2 domains: nasal obstruction (first 4 items) and nasal cosmesis (last 6 items). For both domains, Cronbach alpha was excellent: 0.94 (95% CI, 0.92-0.95) for obstruction and 0.94 (95% CI, 0.93-0.95) for cosmesis. Exploratory factor analysis using scree plots for each domain showed that the domains are unidimensional in nature with each domain evaluating what it is intended to assess (nasal obstruction and cosmesis). The factor loading estimates were high for all the items, varying from 0.74 to 0.92. Kruskal-Wallis testing showed a significance level of P < .001 when evaluating the difference between groups (preoperative cosmetic, postoperative cosmetic, preoperative functional, postoperative functional, and nonrhinoplasty) for all individual questions, composite scores, and Nasal Obstruction Symptom Evaluation (NOSE) score. Correlations between the obstruction composite score and the NOSE scores were r = 0.943 (P < .001), which is very strong. The obstruction and cosmesis composite scores were only weakly correlated (r = 0.388; P < .001). Conclusions and Relevance: We have developed and validated a new PROM to evaluate both functional and cosmetic rhinoplasty patients. The domains of obstruction and cosmesis were found to be internally consistent and unidimensional. The SCHNOS provides a short, validated questionnaire that we recommend for use in all functional or cosmetic rhinoplasty patients. Level of Evidence: N/A. PMID- 28880989 TI - Blepharitis With Facial Numbness and Ocular Pain. PMID- 28880990 TI - Research Integrity, Academic Promotion, and Attribution of Authorship and Nonauthor Contributions. PMID- 28880991 TI - A Comparison of Alkaline Water and Mediterranean Diet vs Proton Pump Inhibition for Treatment of Laryngopharyngeal Reflux. AB - Importance: Laryngopharyngeal reflux (LPR) is a common disorder with protean manifestations in the head and neck. In this retrospective study, we report the efficacy of a wholly dietary approach using alkaline water, a plant-based, Mediterranean-style diet, and standard reflux precautions compared with that of the traditional treatment approach of proton pump inhibition (PPI) and standard reflux precautions. Objective: To determine whether treatment with a diet-based approach with standard reflux precautions alone can improve symptoms of LPR compared with treatment with PPI and standard reflux precautions. Design, Setting, and Participants: This was a retrospective medical chart review of 2 treatment cohorts. From 2010 to 2012, 85 patients with LPR that were treated with PPI and standard reflux precautions (PS) were identified. From 2013 to 2015, 99 patients treated with alkaline water (pH >8.0), 90% plant-based, Mediterranean style diet, and standard reflux precautions (AMS) were identified. The outcome was based on change in Reflux Symptom Index (RSI). Main Outcomes and Measures: Recorded change in the RSI after 6 weeks of treatment. Results: Of the 184 patients identified in the PS and AMS cohorts, the median age of participants in each cohort was 60 years (95% CI, 18-82) and 57 years (95% CI, 18-93), respectively (47 [56.3%] and 61 [61.7%] were women, respectively). The percentage of patients achieving a clinically meaningful (>=6 points) reduction in RSI was 54.1% in PS-treated patients and 62.6% in AMS-treated patients (difference between the groups, 8.05; 95% CI, -5.74 to 22.76). The mean reduction in RSI was 27.2% for the PS group and 39.8% in the AMS group (difference, 12.10; 95% CI, 1.53 to 22.68). Conclusions and Relevance: Our data suggest that the effect of PPI on the RSI based on proportion reaching a 6-point reduction in RSI is not significantly better than that of alkaline water, a plant-based, Mediterranean style diet, and standard reflux precautions, although the difference in the 2 treatments could be clinically meaningful in favor of the dietary approach. The percent reduction in RSI was significantly greater with the dietary approach. Because the relationship between percent change and response to treatment has not been studied, the clinical significance of this difference requires further study. Nevertheless, this study suggests that a plant-based diet and alkaline water should be considered in the treatment of LPR. This approach may effectively improve symptoms and could avoid the costs and adverse effects of pharmacological intervention as well as afford the additional health benefits associated with a healthy, plant-based diet. PMID- 28880993 TI - Trends in dental caries rates over 45 years (1971-2016) among schoolchildren in Florianopolis, southern Brazil. AB - OBJECTIVE: The present study aimed to estimate the prevalence and severity of dental caries in schoolchildren from Florianopolis, southern Brazil, in 2016, as well as to compare these findings with data obtained from six previous studies carried out in the same school since 1971. METHODS: A cross-sectional study was conducted with 133 schoolchildren, 12 and 13 years of age. Clinical data were collected by three previously calibrated examiners, according to the 2013 World Health Organization diagnostic criteria, in order to estimate the mean count of decayed, missing and filled teeth/surfaces (DMFT/DMFS indexes) and the Significant Caries Index (SiC). RESULTS: The study response rate was 87.2% (n = 116), and the prevalence of dental caries decreased from 98.0% (95% CI: 96.0 100.0) in 1971 to 39.6% (95% CI 30.7-49.2) in 2016. The mean DMFT index fell from 9.2 in 1971 to 0.9 in 2016, while the DMFS index ranged from 2.0 (95% CI: 1.2 2.8) in 2009 to 1.5 (95% CI: 1.0-1.9) in 2016. The SiC index, which was 3.4 (95% CI: 3.0-3.8) in 2002, reached 2.5 (95% CI: 2.0-2.9) in 2016. CONCLUSION: Over the 45 years of monitoring, a significant decline in rates of dental caries has been observed. However, the SiC index suggests that dental caries lesions are unequally distributed in the study sample, with one-third of the schoolchildren showing a significantly higher mean DMFT score compared with the entire sample. PMID- 28880992 TI - Innate lymphoid cells at the interface between obesity and asthma. AB - Obesity and asthma prevalence has dramatically and concomitantly increased over the last 25 years, and many epidemiological studies have highlighted obesity as an important risk factor for asthma. Although many studies have been performed, the underlying mechanisms remain poorly understood. Innate mechanisms have been involved in both diseases, in particular through the recently described innate lymphoid cells (ILCs). ILCs are subdivided into three groups that are defined by their cytokine production and by their master transcription factor expression, in sharp correlation with their T helper counterparts. However, unlike T helper cells, ILCs do not express antigen-specific receptors, but respond to damage induced signals. ILCs have been found in target tissues of both diseases, and data have implicated these cells in the pathogenesis of both diseases. In particular group 2 ILCs (ILC2) are activated in both the adipose and lung tissues under the effect of interleukin-33 and interleukin-25 expression. However, counter-intuitively to the well-known association between obesity and asthma, ILC2 are beneficial for obesity but deleterious for asthma. This review will examine the roles of ILCs in each disease and recent data highlighting ILCs as a putative link between obesity and asthma. PMID- 28880994 TI - Live long and prosper: plant-soil feedback, lifespan, and landscape abundance covary. AB - Plant soil feedbacks (PSFs) are thought to be important to plant growth and species coexistence, but most support for these hypotheses is derived from short term greenhouse experiments. Here we use a seven-year, common garden experiment to measure PSFs for seven native and six nonnative species common to the western United States. We use these long-term, field-based estimates to test correlations between PSF and plant landscape abundance, species origin, functional type, and lifespan. To assess potential PSF mechanisms, we also measured soil microbial community composition, root biomass, nitrogen cycling, bulk density, penetration resistance, and shear strength. Plant abundance on the landscape and plant lifespan were positively correlated with PSFs, though this effect was due to the relationships for native plants. PSFs were correlated with indices of soil microbial community composition. Soil nutrient and physical traits and root biomass differed among species but were not correlated with PSF. While results must be taken with caution because only 13 species were examined, these species represent most of the dominant plant species in the system. Results suggest that native plant abundance is associated with the ability of long-lived plants to create positive plant-soil microbe interactions, while short-lived nonnative plants maintain dominance by avoiding soil-borne antagonists, increasing nitrogen cycling and dedicating resources to aboveground growth and reproduction rather than to belowground growth. Broadly, results suggest that PSFs are correlated with a suite of traits that determine plant abundance. PMID- 28880995 TI - Vitamin A supplements for reducing mother-to-child HIV transmission. AB - BACKGROUND: Strategies to reduce the risk of mother-to-child transmission of the human immunodeficiency virus (HIV) include lifelong antiretroviral therapy (ART) for HIV-positive women, exclusive breastfeeding from birth for six weeks plus nevirapine or replacement feeding plus nevirapine from birth for four to six weeks, elective Caesarean section delivery, and avoiding giving children chewed food. In some settings, these interventions may not be practical, feasible, or affordable. Simple, inexpensive, and effective interventions (that could potentially be implemented even in the absence of prenatal HIV testing programmes) would be valuable. Vitamin A, which plays a role in immune function, is one low-cost intervention that has been suggested in such settings. OBJECTIVES: To summarize the effects of giving vitamin A supplements to HIV positive women during pregnancy and after delivery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to 25 August 2017, and checked the reference lists of relevant articles for eligible studies. SELECTION CRITERIA: We included randomized controlled trials conducted in any setting that compared vitamin A supplements to placebo or no intervention among HIV-positive women during pregnancy or after delivery, or both. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed study eligibility and extracted data. We expressed study results as risk ratios (RR) or mean differences (MD) as appropriate, with their 95% confidence intervals (CI), and conducted random-effects meta-analyses. This is an update of a review last published in 2011. MAIN RESULTS: Five trials met the inclusion criteria. These were conducted in Malawi, South Africa, Tanzania, and Zimbabwe between 1995 and 2005 and none of the participants received ART. Women allocated to intervention arms received vitamin A supplements at a variety of doses (daily during pregnancy; a single dose immediately after delivery, or daily doses during pregnancy plus a single dose after delivery). Women allocated to comparison arms received identical placebo (6601 women, 4 trials) or no intervention (697 women, 1 trial). Four trials (with 6995 women) had low risk of bias and one trial (with 303 women) had high risk of attrition bias.The trials show that giving vitamin A supplements to HIV-positive women during pregnancy, the immediate postpartum period, or both, probably has little or no effect on mother-to-child transmission of HIV (RR 1.07, 95% CI 0.91 to 1.26; 4428 women, 5 trials, moderate certainty evidence) and may have little or no effect on child death by two years of age (RR 1.06, 95% CI 0.92 to 1.22; 3883 women, 3 trials, low certainty evidence). However, giving vitamin A supplements during pregnancy may increase the mean birthweight (MD 34.12 g, 95% CI -12.79 to 81.02; 2181 women, 3 trials, low certainty evidence) and probably reduces the incidence of low birthweight (RR 0.78, 95% CI 0.63 to 0.97; 1819 women, 3 trials, moderate certainty evidence); but we do not know whether vitamin A supplements affect the risk of preterm delivery (1577 women, 2 trials), stillbirth (2335 women, 3 trials), or maternal death (1267 women, 2 trials). AUTHORS' CONCLUSIONS: Antepartum or postpartum vitamin A supplementation, or both, probably has little or no effect on mother-to-child transmission of HIV in women living with HIV infection and not on antiretroviral drugs. The intervention has largely been superseded by ART which is widely available and effective in preventing vertical transmission. PMID- 28880996 TI - Dravet syndrome and its mimics: Beyond SCN1A. AB - OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. Most cases are now known to be caused by pathogenic variants in the sodium channel gene SCN1A, but several other genes have also been implicated. This review examines current understanding of the role of non-SCN1A genes in DS, and what is known about phenotypic similarities and differences. We discuss whether these are best thought of as minority causes of DS, or as similar but distinct conditions. METHODS: Based on a review of literature, a list of genes linked to DS was compiled and PubMed was searched for reports of DS-like phenotypes arising from variants in each. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene. RESULTS: Genes that have been reported to cause DS-like phenotypes include SCN2A, SCN8A, SCN9A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2, and KCNA2. Many of these genes, however, appear to be associated with their own, different, clinical picture. Other candidate genes for DS have been reported, but there is currently an insufficient body of literature to support their causative role. SIGNIFICANCE: Although most cases of DS arise from SCN1A variants, numerous other genes cause encephalopathies that are clinically similar. Increasingly, a tendency is noted to define newly described epileptic disorders primarily in genetic terms, with clinical features being linked to genotypes. As genetic diagnosis becomes more readily available, its potential to guide pathophysiologic understanding and therapeutic strategy cannot be ignored. Clinical assessment remains essential; the challenge now is to develop a gene-based taxonomy that complements traditional syndromic classifications, allowing elements of both to inform new approaches to treatment. PMID- 28880997 TI - The role of the miR-148/-152 family in physiology and disease. AB - MicroRNAs (miRNAs) are endogenously encoded ~22 nt small non-coding RNAs. They function as key players of many cellular processes by base pairing with target mRNAs and thereby impairing gene expression at the post-transcriptional level. Recent findings demonstrate a critical role of many miRNAs in immune cell differentiation and immune responses, which is also associated with the development and progression of many tumor and non-tumor diseases. Here we review the multifaceted miRNA-148/-152 family members consisting of miR-148a, miR-148b and miR-152. Next to regulation mechanisms that control the expression of this miRNA family, we will focus on (i) the role of miR-148a in regulating B and T lymphocyte function and its role in associated diseases and (ii) the importance of miR-148/-152 family members for cancer initiation, tumor growth and metastasis formation. In addition, this review aims to highlight some selected targets of the miRNA-148/-152 family members, which are involved in the biology of cancer and maintenance of epigenetic patterns. In conclusion, members of the miR-148/ 152 family might represent prognostic markers and/or potential therapeutic targets for treatment of autoimmune disorders, chronic inflammatory diseases and multiple types of cancer. PMID- 28880998 TI - Impaired bone and muscle development in young people treated with antiepileptic drugs. AB - OBJECTIVE: Antiepileptic drugs (AEDs) are associated with reduced bone density, balance impairment, and increased fracture risk in adults. However, pediatric data are limited. Therefore, we aimed to examine bone, muscle, and balance outcomes in young patients taking AEDs. METHODS: We undertook a case-control study utilizing an AED exposure-discordant matched-pair approach. Subjects were aged 5-18 years with at least 12 months of AED exposure. Pairs were twins, nontwin siblings and first cousins, sex- and age-matched (to within 2 years), allowing for greater power than with unrelated control subjects. Dual energy x ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and muscle force/balance were tested, with questionnaires were administered for bone health and epilepsy details. RESULTS: Twenty-three pairs were recruited, (median age 12.9 years [subjects] and 13.5 years [controls])-7 twin, 14 sibling, and 2 cousin pairs. Those taking AEDs had an increased prevalence of fractures (15 fractures in 8 subjects, compared with 4 fractures in 3 controls, p < 0.01). Trabecular volumetric bone mineral density (vBMD) measured by pQCT at the 4% site (tibia) was reduced by 14% (p = 0.03) in subjects. Subjects exerted a decreased maximum force compared to body weight (Fmax total/g) at the tibia. There were no differences seen in either bone mineral parameters measured by DXA or balance measures. SIGNIFICANCE: Young people taking AEDs reported more fractures and had reductions in tibial vBMD and lower limb muscle force compared to their matched controls. These findings suggest that further exploration of bone health issues of young patients on AED therapy is required. Longitudinal studies are required to confirm these changes in the muscle-bone unit and to further explore the clinical outcomes. PMID- 28880999 TI - Stereo-EEG: Diagnostic and therapeutic tool for periventricular nodular heterotopia epilepsies. AB - OBJECTIVE: Periventricular nodular heterotopias (PNHs) are malformations of cortical development related to neuronal migration disorders, frequently associated with drug-resistant epilepsy (DRE). Stereo-electroencephalography (SEEG) is considered a very effective step of the presurgical evaluation, providing the recognition of the epileptogenic zone (EZ). At the same time, via the intracerebral electrodes it is possible to perform radiofrequency thermocoagulation (SEEG-guided RF-TC) with the aim of ablating and/or disrupting the EZ. The purpose of this study was to evaluate both the relationships between PNH and the EZ, and the efficacy of SEEG-guided RF-TC. METHODS: Twenty patients with DRE related to PNHs were studied. Inclusion criteria were the following: (1) patients with epilepsy and PNHs (unilateral or bilateral, single or multiple nodules) diagnosed on brain magnetic resonance imaging (MRI); (2) SEEG recordings available as part of the presurgical investigations, with at least one intracerebral electrode inside the heterotopia; (3) complete surgical workup with SEEG-guided RF-TC and/or with traditional neurosurgery, with a follow-up of at least 12 months. RESULTS: Complex and heterogenic epileptic networks were found in these patients. SEEG-guided RF-TC both into the nodules and/or the cortex was efficacious in the 76% of patients. Single or multiple, unilateral or bilateral PNHs are the most suitable for this procedure, whereas patients with PNHs associated with complex cortical malformations obtained excellent outcome only with traditional resective surgery. SIGNIFICANCE: Each patient had a specific epileptogenic network, independent from the number, size, or location of nodules and from the cortical malformation associated with. SEEG-guided RF-TC appears as a new and very effective diagnostic and therapeutic approach for DRE related to PNHs. PMID- 28881001 TI - Facial emotion recognition and eye movement behaviour in conduct disorder. AB - BACKGROUND: Conduct Disorder (CD) is associated with impairments in facial emotion recognition. However, it is unclear whether such deficits are explained by a failure to attend to emotionally informative face regions, such as the eyes, or by problems in the appraisal of emotional cues. METHOD: Male and female adolescents with CD and varying levels of callous-unemotional (CU) traits and age and sex-matched typically developing (TD) controls (aged 13-18) categorised the emotion of dynamic and morphed static faces. Concurrent eye tracking was used to relate categorisation performance to participants' allocation of overt attention. RESULTS: Adolescents with CD were worse at emotion recognition than TD controls, with deficits observed across static and dynamic expressions. In addition, the CD group fixated less on the eyes when viewing fearful and sad expressions. Across all participants, higher levels of CU traits were associated with fear recognition deficits and reduced attention to the eyes of surprised faces. Within the CD group, however, higher CU traits were associated with better fear recognition. Overall, males were worse at recognising emotions than females and displayed a reduced tendency to fixate the eyes. DISCUSSION: Adolescents with CD, and particularly males, showed deficits in emotion recognition and fixated less on the eyes when viewing emotional faces. Individual differences in fixation behaviour predicted modest variations in emotion categorisation. However, group differences in fixation were small and did not explain the much larger group differences in categorisation performance, suggesting that CD-related deficits in emotion recognition were not mediated by abnormal fixation patterns. PMID- 28881000 TI - How to survive the medical misinformation mess. AB - Most physicians and other healthcare professionals are unaware of the pervasiveness of poor quality clinical evidence that contributes considerably to overuse, underuse, avoidable adverse events, missed opportunities for right care and wasted healthcare resources. The Medical Misinformation Mess comprises four key problems. First, much published medical research is not reliable or is of uncertain reliability, offers no benefit to patients, or is not useful to decision makers. Second, most healthcare professionals are not aware of this problem. Third, they also lack the skills necessary to evaluate the reliability and usefulness of medical evidence. Finally, patients and families frequently lack relevant, accurate medical evidence and skilled guidance at the time of medical decision-making. Increasing the reliability of available, published evidence may not be an imminently reachable goal. Therefore, efforts should focus on making healthcare professionals, more sensitive to the limitations of the evidence, training them to do critical appraisal, and enhancing their communication skills so that they can effectively summarize and discuss medical evidence with patients to improve decision-making. Similar efforts may need to target also patients, journalists, policy makers, the lay public and other healthcare stakeholders. PMID- 28881002 TI - Clinician-targeted interventions to influence antibiotic prescribing behaviour for acute respiratory infections in primary care: an overview of systematic reviews. AB - BACKGROUND: Antibiotic resistance is a worldwide health threat. Interventions that reduce antibiotic prescribing by clinicians are expected to reduce antibiotic resistance. Disparate interventions to change antibiotic prescribing behaviour for acute respiratory infections (ARIs) have been trialled and meta analysed, but not yet synthesised in an overview. This overview synthesises evidence from systematic reviews, rather than individual trials. OBJECTIVES: To systematically review the existing evidence from systematic reviews on the effects of interventions aimed at influencing clinician antibiotic prescribing behaviour for ARIs in primary care. METHODS: We searched the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), MEDLINE, Embase, CINAHL, PsycINFO, and Science Citation Index to June 2016. We also searched the reference lists of all included reviews. We ran a pre-publication search in May 2017 and placed additional studies in 'awaiting classification'.We included both Cochrane and non-Cochrane reviews of randomised controlled trials evaluating the effect of any clinician-focussed intervention on antibiotic prescribing behaviour in primary care. Two overview authors independently extracted data and assessed the methodological quality of included reviews using the ROBIS tool, with disagreements reached by consensus or by discussion with a third overview author. We used the GRADE system to assess the quality of evidence in included reviews. The results are presented as a narrative overview. MAIN RESULTS: We included eight reviews in this overview: five Cochrane Reviews (33 included trials) and three non-Cochrane reviews (11 included trials). Three reviews (all Cochrane Reviews) scored low risk across all the ROBIS domains in Phase 2 and low risk of bias overall. The remaining five reviews scored high risk on Domain 4 of Phase 2 because the 'Risk of bias' assessment had not been specifically considered and discussed in the review Results and Conclusions. The trials included in the reviews varied in both size and risk of bias. Interventions were compared to usual care.Moderate-quality evidence indicated that C-reactive protein (CRP) point-of-care testing (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.66 to 0.92, 3284 participants, 6 trials), shared decision making (odds ratio (OR) 0.44, 95% CI 0.26 to 0.75, 3274 participants, 3 trials; RR 0.64, 95% CI 0.49 to 0.84, 4623 participants, 2 trials; risk difference -18.44, 95% CI -27.24 to -9.65, 481,807 participants, 4 trials), and procalcitonin-guided management (adjusted OR 0.10, 95% CI 0.07 to 0.14, 1008 participants, 2 trials) probably reduce antibiotic prescribing in general practice. We found moderate-quality evidence that procalcitonin-guided management probably reduces antibiotic prescribing in emergency departments (adjusted OR 0.34, 95% CI 0.28 to 0.43, 2605 participants, 7 trials). The overall effect of these interventions was small (few achieving greater than 50% reduction in antibiotic prescribing, most about a quarter or less), but likely to be clinically important.Compared to usual care, shared decision making probably makes little or no difference to reconsultation for the same illness (RR 0.87, 95% CI 0.74 to 1.03, 1860 participants, 4 trials, moderate-quality evidence), and may make little or no difference to patient satisfaction (RR 0.86, 95% CI 0.57 to 1.30, 1110 participants, 2 trials, low-quality evidence). Similarly, CRP testing probably has little or no effect on patient satisfaction (RR 0.79, 95% CI 0.57 to 1.08, 689 participants, 2 trials, moderate-quality evidence) or reconsultation (RR 1.08, 95% CI 0.93 to 1.27, 5132 participants, 4 trials, moderate-quality evidence). Procalcitonin-guided management probably results in little or no difference in treatment failure in general practice compared to normal care (adjusted OR 0.95, 95% CI 0.73 to 1.24, 1008 participants, 2 trials, moderate quality evidence), however it probably reduces treatment failure in the emergency department compared to usual care (adjusted OR 0.76, 95% CI 0.61 to 0.95, 2605 participants, 7 trials, moderate-quality evidence).The quality of evidence for interventions focused on clinician educational materials and decision support in reducing antibiotic prescribing in general practice was either low or very low (no pooled result reported) and trial results were highly heterogeneous, therefore we were unable draw conclusions about the effects of these interventions. The use of rapid viral diagnostics in emergency departments may have little or no effect on antibiotic prescribing (RR 0.86, 95% CI 0.61 to 1.22, 891 participants, 3 trials, low-quality evidence) and may result in little to no difference in reconsultation (RR 0.86, 95% CI 0.59 to 1.25, 200 participants, 1 trial, low-quality evidence).None of the trials in the included reviews reported on management costs for the treatment of an ARI or any associated complications. AUTHORS' CONCLUSIONS: We found evidence that CRP testing, shared decision making, and procalcitonin-guided management reduce antibiotic prescribing for patients with ARIs in primary care. These interventions may therefore reduce overall antibiotic consumption and consequently antibiotic resistance. There do not appear to be negative effects of these interventions on the outcomes of patient satisfaction and reconsultation, although there was limited measurement of these outcomes in the trials. This should be rectified in future trials.We could gather no information about the costs of management, and this along with the paucity of measurements meant that it was difficult to weigh the benefits and costs of implementing these interventions in practice.Most of this research was undertaken in high-income countries, and it may not generalise to other settings. The quality of evidence for the interventions of educational materials and tools for patients and clinicians was either low or very low, which prevented us from drawing any conclusions. High-quality trials are needed to further investigate these interventions. PMID- 28881003 TI - Drivers of synchrony of acorn production in the valley oak (Quercus lobata) at two spatial scales. AB - We investigated spatial synchrony of acorn production by valley oaks (Quercus lobata) among individual trees at the within-population, local level and at the among-population, statewide level spanning the geographic range of the species. At the local level, the main drivers of spatial synchrony were water availability and flowering phenology of individual trees, while proximity, temperature differences between trees, and genetic similarity failed to explain a significant proportion of variance in spatial synchrony. At the statewide level, annual rainfall was the primary driver, while proximity was significant by itself but not when controlling for rainfall; genetic similarity was again not significant. These results support the hypothesis that environmental factors, the Moran effect, are key drivers of spatial synchrony in acorn production at both small and large geographic scales. The specific environmental factors differed depending on the geographic scale, but were in both cases related to water availability. In addition, flowering phenology, potentially affecting either density-independent pollination failure (the pollination Moran effect) or density dependent pollination efficiency (pollen coupling), plays a key role in driving spatial synchrony at the local geographic scale. PMID- 28881004 TI - #colorectalsurgery. AB - BACKGROUND: The use of social media platforms among healthcare professionals is increasing. A Twitter social media campaign promoting the hashtag #colorectalsurgery was launched with the aim of providing a specialty-specific forum to collate discussions and science relevant to an engaged, global community of coloproctologists. This article reviews initial experiences of the early adoption, engagement and utilization of this pilot initiative. METHODS: The hashtag #colorectalsurgery was promoted via the online microblogging service Twitter across a 180-day interval. Data on all tweets containing the #colorectalsurgery hashtag were analysed using online analytical tools. Data included total number of tweets, number of views, and user engagement since registration and launch of the campaign. Content of tweet and user demographic analysis was undertaken. RESULTS: The number of tweets using #colorectalsurgery grew rapidly following the launch on 24 April 2016; #colorectalsurgery was used in 15 708 tweets, which resulted in 65 398 696 impressions and involved 1863 individual Twitter accounts. Increased volumes of #colorectalsurgery tweets were noted in association with the timing of three major international colorectal surgical conferences, and geographical trends were noted. Some 88.4 per cent of all posts were by male users. The top 25 users by volume of #colorectalsurgery tweets had considerable influence and posted 8023 tweets (51.1 per cent). CONCLUSION: Online global communities formed via healthcare-related hashtags, such as #colorectalsurgery, unify social media posts, scientists, surgeons and authors who have an interest in coloproctology. Furthermore, they facilitate greater connectivity among geographically separate users. PMID- 28881006 TI - Simple aspiration versus intercostal tube drainage for primary spontaneous pneumothorax in adults. AB - BACKGROUND: For management of pneumothorax that occurs without underlying lung disease, also referred to as primary spontaneous pneumothorax, simple aspiration is technically easier to perform than intercostal tube drainage. In this systematic review, we seek to compare the clinical efficacy and safety of simple aspiration versus intercostal tube drainage for management of primary spontaneous pneumothorax. This review was first published in 2007 and was updated in 2017. OBJECTIVES: To compare the clinical efficacy and safety of simple aspiration versus intercostal tube drainage for management of primary spontaneous pneumothorax. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1) in the Cochrane Library; MEDLINE (1966 to January 2017); and Embase (1980 to January 2017). We searched the World Health Organization (WHO) International Clinical Trials Registry for ongoing trials (January 2017). We checked the reference lists of included trials and contacted trial authors. We imposed no language restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of adults 18 years of age and older with primary spontaneous pneumothorax that compared simple aspiration versus intercostal tube drainage. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, assessed trial quality, and extracted data. We combined studies using the random-effects model. MAIN RESULTS: Of 2332 publications obtained through the search strategy, seven studies met the inclusion criteria; one study was ongoing and six studies of 435 participants were eligible for inclusion in the updated review. Data show a significant difference in immediate success rates of procedures favouring tube drainage over simple aspiration for management of primary spontaneous pneumothorax (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.69 to 0.89; 435 participants, 6 studies; moderate-quality evidence). Duration of hospitalization however was significantly less for patients treated by simple aspiration (mean difference (MD) -1.66, 95% CI -2.28 to -1.04; 387 participants, 5 studies; moderate-quality evidence). A narrative synthesis of evidence revealed that simple aspiration led to fewer adverse events (245 participants, 3 studies; low-quality evidence), but data suggest no differences between groups in terms of one-year success rate (RR 1.07, 95% CI 0.96 to 1.18; 318 participants, 4 studies; moderate-quality evidence), hospitalization rate (RR 0.60, 95% CI 0.25 to 1.47; 245 participants, 3 studies; very low-quality evidence), and patient satisfaction (median between group difference of 0.5 on a scale from 1 to 10; 48 participants, 1 study; low quality evidence). No studies provided data on cost-effectiveness. AUTHORS' CONCLUSIONS: Available trials showed low to moderate-quality evidence that intercostal tube drainage produced higher rates of immediate success, while simple aspiration resulted in a shorter duration of hospitalization. Although adverse events were reported more commonly for patients treated with tube drainage, the low quality of the evidence warrants caution in interpreting these findings. Similarly, although this review observed no differences between groups when early failure rate, one-year success rate, or hospital admission rate was evaluated, this too needs to be put into the perspective of the quality of evidence, specifically, for evidence of very low and low quality for hospitalization rate and patient satisfaction, respectively. Future adequately powered research is needed to strengthen the evidence presented in this review. PMID- 28881005 TI - Relationship between family history of type 2 diabetes and serum FGF21. AB - BACKGROUND: Determining predictive markers for the development of type 2 diabetes (T2D), particularly in young individuals, offers immense potential benefits in preventative medicine. Previous research examining serum fibroblast growth factor 21 (FGF21) in humans has revealed equivocal relationships with clinical markers of metabolic dysfunction. However, it is unknown to what extent, if any, first degree family history of T2D (mother or father of the participant diagnosed with T2D) level affects serum FGF21 levels. The aim of this study was to determine whether in healthy individuals with FH+ (n = 18) and without FH- (n = 17) a family history of T2D affects serum FGF21. MATERIALS AND METHODS: Fasting serum and clinical, metabolic and anthropometric measures were determined using a cross sectional design. RESULTS: Differences between groups for FGF21 were not significant (FH+ = 266 pg/mL +/- 51.4, FH = 180 pg/mL +/- 29; Z = 0.97, P = 0.33). Adiponectin values were lower in FH+ (8.81 MUg/mL +/- 2.14) compared to FH (10.65 MUg/mL +/- 1.44; F = 8.83, P = 0.01). Resistin was negatively correlated with FGF21 for all participants (r = -0.38, P = 0.03), but no other clinical, metabolic, or serum markers were predictive for serum FGF21 in FH+ or FH-. CONCLUSIONS: Serum FGF21 is not significantly different between FH+ and FH- in young, healthy individuals. Based upon the data of this pilot study, it is unclear whether serum FGF21 can be used as a stand-alone predictive marker for T2D in healthy subjects. PMID- 28881007 TI - Delayed antibiotic prescriptions for respiratory infections. AB - BACKGROUND: Concerns exist regarding antibiotic prescribing for respiratory tract infections (RTIs) owing to adverse reactions, cost, and antibacterial resistance. One proposed strategy to reduce antibiotic prescribing is to provide prescriptions, but to advise delay in antibiotic use with the expectation that symptoms will resolve first. This is an update of a Cochrane Review originally published in 2007, and updated in 2010 and 2013. OBJECTIVES: To evaluate the effects on clinical outcomes, antibiotic use, antibiotic resistance, and patient satisfaction of advising a delayed prescription of antibiotics in respiratory tract infections. SEARCH METHODS: For this 2017 update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 4, 2017), which includes the Cochrane Acute Respiratory Infection Group's Specialised Register; Ovid MEDLINE (2013 to 25 May 2017); Ovid Embase (2013 to 2017 Week 21); EBSCO CINAHL Plus (1984 to 25 May 2017); Web of Science (2013 to 25 May 2017); WHO International Clinical Trials Registry Platform (1 September 2017); and ClinicalTrials.gov (1 September 2017). SELECTION CRITERIA: Randomised controlled trials involving participants of all ages defined as having an RTI, where delayed antibiotics were compared to immediate antibiotics or no antibiotics. We defined a delayed antibiotic as advice to delay the filling of an antibiotic prescription by at least 48 hours. We considered all RTIs regardless of whether antibiotics were recommended or not. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Three review authors independently extracted and collated data. We assessed the risk of bias of all included trials. We contacted trial authors to obtain missing information. MAIN RESULTS: For this 2017 update we added one new trial involving 405 participants with uncomplicated acute respiratory infection. Overall, this review included 11 studies with a total of 3555 participants. These 11 studies involved acute respiratory infections including acute otitis media (three studies), streptococcal pharyngitis (three studies), cough (two studies), sore throat (one study), common cold (one study), and a variety of RTIs (one study). Five studies involved only children, two only adults, and four included both adults and children. Six studies were conducted in a primary care setting, three in paediatric clinics, and two in emergency departments.Studies were well reported, and appeared to be of moderate quality. Randomisation was not adequately described in two trials. Four trials blinded the outcomes assessor, and three included blinding of participants and doctors. We conducted meta-analysis for antibiotic use and patient satisfaction.We found no differences among delayed, immediate, and no prescribed antibiotics for clinical outcomes in the three studies that recruited participants with cough. For the outcome of fever with sore throat, three of the five studies favoured immediate antibiotics, and two found no difference. For the outcome of pain related to sore throat, two studies favoured immediate antibiotics, and three found no difference. One study compared delayed antibiotics with no antibiotic for sore throat, and found no difference in clinical outcomes.Three studies included participants with acute otitis media. Of the two studies with an immediate antibiotic arm, one study found no difference for fever, and the other study favoured immediate antibiotics for pain and malaise severity on Day 3. One study including participants with acute otitis media compared delayed antibiotics with no antibiotics and found no difference for pain and fever on Day 3.Two studies recruited participants with common cold. Neither study found differences for clinical outcomes between delayed and immediate antibiotic groups. One study favoured delayed antibiotics over no antibiotics for pain, fever, and cough duration (moderate quality evidence for all clinical outcomes - GRADE assessment).There were either no differences for adverse effects or results favoured delayed antibiotics over immediate antibiotics (low quality evidence - to GRADE assessment) with no significant differences in complication rates. Delayed antibiotics resulted in a significant reduction in antibiotic use compared to immediate antibiotics prescription (odds ratio (OR) 0.04, 95% confidence interval (CI) 0.03 to 0.05). However, a delayed antibiotic was more likely to result in reported antibiotic use than no antibiotics (OR 2.55, 95% CI 1.59 to 4.08) (moderate quality evidence - GRADE assessment).Patient satisfaction favoured delayed over no antibiotics (OR 1.49, 95% CI 1.08 to 2.06). There was no significant difference in patient satisfaction between delayed antibiotics and immediate antibiotics (OR 0.65, 95% CI 0.39 to 1.10) (moderate quality evidence - GRADE assessment).None of the included studies evaluated antibiotic resistance. AUTHORS' CONCLUSIONS: For many clinical outcomes, there were no differences between prescribing strategies. Symptoms for acute otitis media and sore throat were modestly improved by immediate antibiotics compared with delayed antibiotics. There were no differences in complication rates. Delaying prescribing did not result in significantly different levels of patient satisfaction compared with immediate provision of antibiotics (86% versus 91%) (moderate quality evidence). However, delay was favoured over no antibiotics (87% versus 82%). Delayed antibiotics achieved lower rates of antibiotic use compared to immediate antibiotics (31% versus 93%) (moderate quality evidence). The strategy of no antibiotics further reduced antibiotic use compared to delaying prescription for antibiotics (14% versus 28%). Delayed antibiotics for people with acute respiratory infection reduced antibiotic use compared to immediate antibiotics, but was not shown to be different to no antibiotics in terms of symptom control and disease complications. Where clinicians feel it is safe not to prescribe antibiotics immediately for people with respiratory infections, no antibiotics with advice to return if symptoms do not resolve is likely to result in the least antibiotic use while maintaining similar patient satisfaction and clinical outcomes to delaying prescription of antibiotics. Where clinicians are not confident in using a no antibiotic strategy, a delayed antibiotics strategy may be an acceptable compromise in place of immediate prescribing to significantly reduce unnecessary antibiotic use for RTIs, and thereby reduce antibiotic resistance, while maintaining patient safety and satisfaction levels.Editorial note: As a living systematic review, this review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review. PMID- 28881009 TI - Seeking a better landscape for therapy development in neuromuscular disorders. AB - Although the neuromuscular field has seen accelerated approval of a drug for Duchenne muscular dystrophy (DMD) and full approval of one for spinal muscular atrophy, these experiences have shown that objective data and an adequate level of effect are essential for drug approval and reimbursement. The appropriateness and validity of biomarkers and clinically meaningful endpoints and an understanding of disease progression rates all played essential roles in the levels of evidence for these drugs. Such tools are best developed through integration of clinical data. The siloing of clinical data for rare neuromuscular diseases represents a considerable barrier to achieving better care and novel therapies for patients living with neuromuscular diseases. We discuss a data sharing model implemented for DMD and urge cultural changes in the ways natural history and clinical trial data are collected and shared across all neuromuscular diseases in order to benefit the primary stakeholder, the patient. Muscle Nerve 57: 16-19, 2018. PMID- 28881008 TI - Drivers of nitrogen transfer in stream food webs across continents. AB - Studies of trophic-level material and energy transfers are central to ecology. The use of isotopic tracers has now made it possible to measure trophic transfer efficiencies of important nutrients and to better understand how these materials move through food webs. We analyzed data from thirteen 15 N-ammonium tracer addition experiments to quantify N transfer from basal resources to animals in headwater streams with varying physical, chemical, and biological features. N transfer efficiencies from primary uptake compartments (PUCs; heterotrophic microorganisms and primary producers) to primary consumers was lower (mean 11.5%, range <1% to 43%) than N transfer efficiencies from primary consumers to predators (mean 80%, range 5% to >100%). Total N transferred (as a rate) was greater in streams with open compared to closed canopies and overall N transfer efficiency generally followed a similar pattern, although was not statistically significant. We used principal component analysis to condense a suite of site characteristics into two environmental components. Total N uptake rates among trophic levels were best predicted by the component that was correlated with latitude, DIN:SRP, GPP:ER, and percent canopy cover. N transfer efficiency did not respond consistently to environmental variables. Our results suggest that canopy cover influences N movement through stream food webs because light availability and primary production facilitate N transfer to higher trophic levels. PMID- 28881010 TI - Multiple source feedback for teaching fellows. PMID- 28881011 TI - Sarcolemmal excitability in the myotonic dystrophies. AB - INTRODUCTION: Chloride conductance disturbances contribute to sarcolemmal dysfunction in myotonic dystrophy type 1 (DM1) and type 2 (DM2). Studies using muscle velocity recovery cycles (MVRCs) suggest Na+ /K+ -adenosine triphosphatase activation becomes defective in advanced DM1. We used MVRCs to investigate muscle excitability in DM1 and DM2. METHODS: MVRCs were measured for patients with mild (n = 8) and advanced (n = 11) DM1, DM2 (n = 4), and normal controls (n = 30). RESULTS: Residual supernormality after multiple conditioning stimuli was increased in DM2 and advanced DM1. Advanced DM1 was distinguished by increases in muscle relative refractory period (MRRP) and reduced early supernormality as well as peak amplitude decrements for the first and last responses in train during repetitive stimulation. DISCUSSION: Prolongation of the MRRP indicates that depolarization of the resting muscle membrane potential occurs in advanced DM1, with possible implications for future therapeutic approaches. Muscle Nerve 57: 595-602, 2018. PMID- 28881012 TI - Integrating residents with institutional quality improvement teams. PMID- 28881013 TI - Pencil graphite electrodes for improved electrochemical detection of oleuropein by the combination of Natural Deep Eutectic Solvents and graphene oxide. AB - A novel methodology is presented for the enhanced electrochemical detection of oleuropein in complex plant matrices by Graphene Oxide Pencil Grahite Electrode (GOPGE) in combination with a buffer modified with a Natural Deep Eutectic Solvent, containing 10% (v/v) of Lactic acid, Glucose and H2 O (LGH). The electrochemical behavior of oleuropein in the modified-working buffer was examined using differential pulse voltammetry. The combination of both modifications, NADES modified buffer and nanomaterial modified electrode, LGH GOPGE, resulted on a signal enhancement of 5.3 times higher than the bare electrode with unmodified buffer. A calibration curve of oleuropein was performed between 0.10 to 37 MUM and a good linearity was obtained with a correlation coefficient of 0.989. Detection and quantification limits of the method were obtained as 30 and 102 nM, respectively. In addition, precision studies indicated that the voltammetric method was sufficiently repeatable, %RSD 0.01 and 3.16 (n = 5) for potential and intensity, respectively. Finally, the proposed electrochemical sensor was successfully applied to the determination of oleuropein in an olive leaf extract prepared by ultrasound-assisted extraction. The results obtained with the proposed electrochemical sensor were compared with Capillary Zone Electrophoresis analysis with satisfactory results. PMID- 28881014 TI - Student driven production of high value online resources. PMID- 28881015 TI - Exposure to suicide in the family: Suicide risk and psychache in individuals who have lost a family member by suicide. AB - OBJECTIVE: The aim of the present study was to compare a sample of Portuguese individuals exposed to suicide in their families with a control group, for lifetime suicidality. This study also evaluated the incremental value of psychache (i.e., extreme psychological pain) in determining suicide risk beyond the contribution associated with having lost a family member by suicide. METHOD: A total of 225 community adults participated. Two groups were defined: a group exposed to suicide (n = 53), and a control group (n = 172). RESULTS: Results demonstrated that groups did significantly differ on the total score of the Suicide Behaviors Questionnaire-Revised (SBQ-R), on the four individual SBQ-R items, and on psychache. Results from a hierarchical multiple regression analysis demonstrated that having lost a family member by suicide and the construct of psychache each provided a significant unique contribution to explaining variance in suicide risk. The interaction between group membership and psychache also provided a further enhancement to the statistical prediction of suicide risk. CONCLUSION: Findings are discussed with regard to their implications for clinical intervention and postvention. PMID- 28881016 TI - An adult with a rare form of congenital fiber type disproportion. PMID- 28881018 TI - Urinary incontinence in bitches under primary veterinary care in England: prevalence and risk factors. AB - OBJECTIVES: To estimate prevalence and demographic risk factors for urinary incontinence in bitches under primary veterinary care in England. METHODS: The study population included all bitches within the VetCompass database from September 1, 2009 to July 7, 2013. Electronic patient records were searched for urinary incontinence cases and additional demographic and clinical information was extracted. RESULTS: Of 100,397 bitches attending 119 clinics in England, an estimated 3108 were diagnosed with urinary incontinence. The prevalence of urinary incontinence was 3.14% (95% confidence intervals: 2.97 to 3.33). Medical therapy was prescribed to 45.6% cases. Predisposed breeds included the Irish setter (odds ratio: 8.09; 95% confidence intervals: 3.15 to 20.80; P< 0.001) and Dobermann (odds ratio: 7.98; 95% confidence intervals: 4.38 to 14.54; P< 0.001). Increased odds of a diagnosis of urinary incontinence were associated with: (1) weight at or above the mean adult bodyweight for the breed (odds ratio: 1.31; 95% confidence intervals: 1.12 to 1.54; P< 0.001), (2) age 9 to 12 years (odds ratio: 3.86; 95% confidence intervals: 2.86 to 5.20, P< 0.001), (3) neuter status (odds ratio: 2.23; 95% confidence intervals: 1.52 to 3.25, P< 0.001) and (4) being insured (odds ratio: 1.59; 95% confidence intervals: 1.34 to 1.88, P< 0.001). CLINICAL IMPACT: Clinical Impact: Urinary incontinence affects just over 3% of bitches overall but affects more than 15% of bitches in high-risk breeds including the Irish setter, Dobermann, bearded collie, rough collie and Dalmatian. These results provide an evidence base for clinicians to enhance clinical recommendations on neutering and weight control, especially in high-risk breeds. PMID- 28881019 TI - Scientific Poster Abstracts Selected for the 2017 Congress on Cardiovascular Disease Prevention, Sept. 15-17, 2017, Fort Lauderdale, Florida. PMID- 28881017 TI - The body composition profile is associated with response to anti-TNF therapy in Crohn's disease and may offer an alternative dosing paradigm. AB - BACKGROUND: Anti-tumour necrosis factor (TNF)s form a major part of therapy in Crohn's disease and have a primary nonresponse rate of 10%-30% and a secondary loss of response rate of 5% per year. Myopenia is prevalent in Crohn's disease and is measured using body composition analysis tools. AIM: To test the hypothesis that body composition can predict outcomes of anti-TNF primary nonresponse and secondary loss of response. METHODS: Between January 2007 and June 2012, 106 anti-TNF naive patients underwent anti-TNF therapy for Crohn's disease with body composition parameters analysed using CT scans to estimate body fat-free mass. The outcome measures were primary nonresponse and secondary loss of response. COX-regression analysis was used with 3 year follow-up data. RESULTS: A total of 106 patients were included for analysis with 26 (24.5%) primary nonresponders and 29 (27.4%) with secondary loss of response to anti-TNF therapy. Sex-specific cut-offs for muscle and fat were ascertained by stratification analysis. On univariate analysis, primary nonresponse was associated with low albumin (OR 0.94; 0.88-0.99, P = .04) and presence of myopenia (OR 4.69; 1.83-12.01, P = .001) when taking into account patient's medical therapy, severity of disease and body composition. On multivariate analysis, presence of myopenia was associated with primary nonresponse (OR 2.93; 1.28-6.71, P = .01). Immunomodulator therapy was associated with decreased secondary loss of response (OR 0.48; 0.23-0.98, P = .04). BMI was poorly correlated with lean body mass (r2 = 0.15, P = .54). CONCLUSIONS: In this cohort study, body composition profiles did not correlate well with BMI. Myopenia was associated with primary nonresponse with potential implications for dosing and serves as an explanation for pharmacokinetic failure. PMID- 28881020 TI - Comments on assessment of polarization dependence of body shadow effect on dosimetry measurements in 2.4GHz band. PMID- 28881022 TI - Getting help from Frank and Starling (and Coats and Bowditch) to augment blood flow in heat-stressed older adults. PMID- 28881021 TI - Convergence of fMRI and ERP measures of emotional face processing in combat exposed U. S. military veterans. AB - The late positive potential (LPP) and fMRI blood-oxygen-level dependent (BOLD) activity can provide complementary measures of the processing of affective and social stimuli. Separate lines of research using these measures have often employed the same stimuli, paradigms, and samples; however, there remains relatively little understanding of the way in which individual differences in one of these measures relates to the other, and all prior research has been conducted in psychiatrically healthy samples and using emotional scenes (not faces). Here, 32 combat-exposed U. S. military veterans with varying levels of posttraumatic stress symptomatology viewed affective social stimuli (angry, fearful, and happy faces) and geometric shapes during separate EEG and fMRI BOLD recordings. Temporospatial principal component analysis was used to quantify the face elicited LPP in a data-driven manner, prior to conducting whole-brain correlations between resulting positivities and fMRI BOLD elicited by faces. Participants with larger positivities to fearful faces (> shapes) showed increased activation in the amygdala; larger positivities to angry and happy faces (> shapes) were associated with increased BOLD activation in the posterior fusiform gyrus and inferior temporal gyrus, respectively. Across all face types, larger positivities were associated with increased activation in the fusiform "face" area. Correlations using mean area amplitude LPPs showed an association with increased activation in the anterior insula for angry faces (> shapes). LPP BOLD associations were not moderated by PTSD. Findings provide the first evidence of correspondence between face-elicited LPP and BOLD activation across a range of (normal to disordered) psychiatric health. PMID- 28881023 TI - Double-outlet left ventricle with a bicuspid pulmonary valve and aortic coarctation. AB - A double-outlet left ventricle (DOLV) is a rare congenital cardiac malformation. Here, we describe a case of DOLV with bicuspid pulmonary valve, aortic coarctation, and a subpulmonary ventricular septal defect in which both ventricles were well developed. The anatomic features were observed with echocardiography, and the diagnosis was confirmed at surgery. Many variations of DOLV have been described. The features of our case expand the spectrum of this entity and may provide new insight into its complex anatomy. PMID- 28881024 TI - Responses to comments on assessment of polarization dependence of body shadow effect on dosimetry measurements in the 2.4 GHz band. PMID- 28881025 TI - Reprioritising transfusion medicine education for graduating medical students. PMID- 28881026 TI - Acing education: pilot curriculum on adverse childhood experiences. PMID- 28881027 TI - Meeting in difference: Revisiting the therapeutic relationship based on patients' and therapists' experiences in several clinical contexts. AB - Despite decades of research on the therapeutic relationship and the therapeutic alliance and their connection with therapeutic outcomes (Horvath, Del Re, Fluckiger, & Symonds, 2011), only a handful of studies have examined how they are experienced by the therapy participants. The aim of the present study is to describe the therapeutic relationship from the subjective perspective of the patients and therapists involved in 3 clinical cases: (a) a 7-year-old child diagnosed with attention deficit hyperactivity disorder, (b) a 29-year old woman diagnosed with a personality disorder, and (c) a 22-year-old man diagnosed with schizophrenia. We conducted semistructured interviews with patients and therapists that were later analyzed following grounded theory coding procedures (Corbin & Strauss, 2008). The results obtained reveal that the constitutive elements of the therapeutic relationship are linked to 2 dimensions of the patient-therapist meeting experience: the technical and role-related dimension, characterized by relational asymmetry, and the affective exchange dimension, characterized by relational symmetry. The article discusses the possible association between the asymmetrical technical dimension, whose roles are defined by the organization of the helping relationship, and the notion of therapeutic alliance as commonly conceptualized and assessed; on the other hand, the experience of the bidirectional and symmetrical patient-therapist affective exchange is linked with concepts such as real relationship and intersubjectivity. PMID- 28881028 TI - Specific rescue by ortho-hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB. AB - The statin atorvastatin (ATV) given as a post-treatment has been reported beneficial in stroke, although the mechanisms involved are not well understood so far. Here, we investigated in vitro the effect of post-treatment with ATV and its main bioactive metabolite ortho-hydroxy ATV (o-ATV) on neuroprotection after oxygen and glucose deprivation (OGD), and the role of the pro-survival cAMP response element-binding protein (CREB). Post-OGD treatment of primary cultures of rat cortical neurons with o-ATV, but not ATV, provided neuroprotection to a specific subset of cortical neurons that were large and positive for glutamic acid decarboxylase (large-GAD(+) neurons, GABAergic). Significantly, only these GABAergic neurons showed an increase in phosphorylated CREB (pCREB) early after neuronal cultures were treated post-OGD with o-ATV. We found that o-ATV, but not ATV, increased the neuronal uptake of glutamate from the medium; this provides a rationale for the specific effect of o-ATV on pCREB in large-GABAergic neurons, which have a higher ratio of synaptic (pCREB-promoting) vs extrasynaptic (pCREB reducing) N-methyl-D-aspartate (NMDA) receptors (NMDAR) than that of small-non GABAergic neurons. When we pharmacologically increased pCREB levels post-OGD in non-GABAergic neurons, through the selective activation of synaptic NMDAR, we observed as well long-lasting neuronal survival. We propose that the statin metabolite o-ATV given post-OGD boosts the intrinsic pro-survival factor pCREB in large-GABAergic cortical neurons in vitro, this contributing to protect them from OGD. PMID- 28881030 TI - The association between anticoagulation therapy, maternal characteristics, and a failed cfDNA test due to a low fetal fraction. AB - OBJECTIVES: The objective of this study was to identify maternal characteristics associated with a failed cell-free DNA (cfDNA) test due to a low fetal fraction (FF). METHOD: Retrospective cohort study of women with singleton pregnancies who had cfDNA screening at 10-25 weeks gestation between October 2011 and January 2016. cfDNA screening was performed using methylation techniques until October 2013; thereafter, samples were run with massively parallel sequencing. Multivariable logistic regression was performed to identify maternal characteristics associated with no cell free DNA result secondary to low FF. RESULTS: Thirty-three (1.2%) of 2890 eligible women had a failed cfDNA test, including 18 (0.6%) cases with a low FF. A failed cfDNA test due to a low FF was associated with obesity (aOR 1.11, CI 1.05-1.18, p = 0.0003) and treatment with enoxaparin (aOR 37.5, 11.19-125.87, p < 0.0001). 5 of 28 (18%, 95% CI: 6.1% 36.9%) women on enoxaparin had a failed cfDNA test secondary to a low FFx. CONCLUSION: Enoxaparin therapy and obesity were associated with an increased incidence of a failed cfDNA test due to low FF. Further research is needed to determine the mechanism by which anticoagulation therapy alters cfDNA test functionality and identify approaches to improve test performance in these women. PMID- 28881029 TI - ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine. AB - To identify neuropeptides that are regulated by cocaine, we used a quantitative peptidomic technique to examine the relative levels of neuropeptides in several regions of mouse brain following daily intraperitoneal administration of 10 mg/kg cocaine or saline for 7 days. A total of 102 distinct peptides were identified in one or more of the following brain regions: nucleus accumbens, caudate putamen, frontal cortex, and ventral tegmental area. None of the peptides detected in the caudate putamen or frontal cortex were altered by cocaine administration. Three peptides in the nucleus accumbens and seven peptides in the ventral tegmental area were significantly decreased in cocaine-treated mice. Five of these ten peptides are derived from proSAAS, a secretory pathway protein and neuropeptide precursor. To investigate whether proSAAS peptides contribute to the physiological effects of psychostimulants, we examined acute responses to cocaine and amphetamine in the open field with wild-type (WT) and proSAAS knockout (KO) mice. Locomotion was stimulated more robustly in the WT compared to mutant mice for both psychostimulants. Behavioral sensitization to amphetamine was not maintained in proSAAS KO mice and these mutants failed to sensitize to cocaine. To determine whether the rewarding effects of cocaine were altered, mice were tested in conditioned place preference (CPP). Both WT and proSAAS KO mice showed dose-dependent CPP to cocaine that was not distinguished by genotype. Taken together, these results suggest that proSAAS-derived peptides contribute differentially to the behavioral sensitization to psychostimulants, while the rewarding effects of cocaine appear intact in mice lacking proSAAS. PMID- 28881031 TI - Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C-infected patients treated with direct-acting antivirals. AB - BACKGROUND: In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. AIM: To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). METHODS: Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. RESULTS: A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). CONCLUSION: In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR. PMID- 28881032 TI - Startle reflex modulation during threat of shock and "threat" of reward. AB - During threat of shock, the startle reflex is potentiated, suggesting modulation by defensive mobilization. To determine whether startle potentiation is specific to aversive anticipation, startle reflexes were measured in the context of either aversive or appetitive anticipation in a between-subject study. Participants wore a device on the wrist that could deliver electrical shock (n = 49), or vibrotactile stimulation indicating monetary reward (n = 48). Cues signaling "threat" or "safe" periods were presented alone, or accompanied by presentation of affective and neutral pictures on half of the trials. Results indicated that the startle reflex was significantly potentiated when anticipating either shock or reward, compared to safe periods, both when no picture was presented, as well as during picture viewing. The difference between threat and safety in both reflex magnitude and skin conductance changes was larger for those anticipating shock, suggesting that the aversive context was more motivationally engaging. The pattern of reflex modulation as a function of picture valence varied under threat and safety, but was identical in the shock and reward groups, consistent with a hypothesis that anticipation of either aversive or appetitive events prompts heightened perceptual vigilance, potentiating the acoustic startle reflex. PMID- 28881033 TI - The conformational epitope for a new Abeta42 protofibril-selective antibody partially overlaps with the peptide N-terminal region. AB - Aggregation and accumulation of amyloid-beta peptide (Abeta) is a key component of Alzheimer's disease (AD). While monomeric Abeta appears to be benign, oligomers adopt a biologically detrimental structure. These soluble structures can be detected in AD brain tissue by antibodies that demonstrate selectivity for aggregated Abeta. Protofibrils are a subset of soluble oligomeric Abeta species and are described as small (< 100 nm) curvilinear assemblies enriched in beta sheet structure. Our own in vitro studies demonstrate that microglial cells are much more sensitive to soluble Abeta42 protofibrils compared to Abeta42 monomer or insoluble Abeta42 fibrils. Protofibrils interact with microglia, trigger Toll like receptor signaling, elicit cytokine transcription and expression, and are rapidly taken up by the cells. Because of the importance of this Abeta species, we sought to develop an antibody that selectively recognizes protofibrils over other Abeta species. Immunization of rabbits with isolated Abeta42 protofibrils generated a high-titer anti serum with a strong affinity for Abeta42 protofibrils. The antiserum, termed AbSL, was selective for Abeta42 protofibrils over Abeta42 monomers and Abeta42 fibrils. AbSL did not react with amyloid precursor protein and recognized distinct pathological features in AD transgenic mouse brain slices. Competition studies with an Abeta antibody that targets residues 1-16 indicated that the conformational epitope for AbSL involved the N terminal region of protofibrils in some manner. The newly developed antibody may have potential diagnostic and therapeutic uses in AD tissue and patients, and targeting of protofibrils in AD may have beneficial effects. Read the Editorial Highlight for this article on page 621. Cover Image for this issue: doi. 10.1111/jnc.13827. PMID- 28881035 TI - Protease-activated receptor 2 contributes to Toxoplasma gondii-mediated gut inflammation. AB - Toxoplasma gondii is a widespread intracellular parasite, which naturally enters the organism via the oral route and crosses the intestinal barrier to disseminate. In addition to neuronal and ocular pathologies, this pathogen also causes gut inflammation in a number of animals. This infection-triggered inflammation has been extensively studied in the C57BL/6 mice, highlighting the importance of the immune cells and their mediators in the development of gut pathology. However, despite their importance in inflammation, the role of protease-activated receptors (PAR) was never reported in the context of T.gondii mediated small intestine inflammation. Using genetically modified mice, we show that PAR2 plays a pathogenic role in the development of gut inflammatory lesions. We find that PAR2 controls the innate inflammatory mediators IL-6, KC/CXCL1, PGE2 as well as neutrophil infiltration in T. gondii-triggered gut damage. These results bring new knowledge on the mechanisms operating in the gut in response to T. gondii infection. PMID- 28881034 TI - MicroRNA-27a-3p suppression of peroxisome proliferator-activated receptor-gamma contributes to cognitive impairments resulting from sevoflurane treatment. AB - Sevoflurane is the most widely used anaesthetic administered by inhalation. Exposure to sevoflurane in neonatal mice can induce learning deficits and abnormal social behaviours. MicroRNA (miR)-27a-3p, a short, non-coding RNA that functions as a tumour suppressor, is up-regulated after inhalation of anaesthetic, and peroxisome proliferator-activated receptor gamma (PPAR-gamma) is one of its target genes. The objective of this study was to investigate how the miR-27a-3p-PPAR-gamma interaction affects sevoflurane-induced neurotoxicity. A luciferase reporter assay was employed to identify the interaction between miR 27a-3p and PPAR-gamma. Primary hippocampal neuron cultures prepared from embryonic day 0 C57BL/6 mice were treated with miR-27a-3p inhibitor or a PPAR gamma agonist to determine the effect of miR-27a-3p and PPAR-gamma on sevoflurane induced cellular damage. Cellular damage was assessed by a flow cytometry assay to detect apoptotic cells, immunofluorescence to detect reactive oxygen species, western blotting to detect NADPH oxidase 1/4 and ELISA to measure inflammatory cytokine levels. In vivo experiments were performed using a sevoflurane-induced anaesthetic mouse model to analyse the effects of miR-27a-3p on neurotoxicity by measuring the number of apoptotic neurons using the Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) method and learning and memory function by employing the Morris water maze test. Our results revealed that PPAR gamma expression was down-regulated by miR-27a-3p following sevoflurane treatment in hippocampal neurons. Down-regulation of miR-27a-3p expression decreased sevoflurane-induced hippocampal neuron apoptosis by decreasing inflammation and oxidative stress-related protein expression through the up-regulation of PPAR gamma. In vivo tests further confirmed that inhibition of miR-27a-3p expression attenuated sevoflurane-induced neuronal apoptosis and learning and memory impairment. Our findings suggest that down-regulation of miR-27a-3p expression ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-gamma signalling pathway. MicroRNA-27a-3p may, therefore, be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity. PMID- 28881036 TI - Characterization of a d-Lactate Dehydrogenase from Lactobacillus fermentum JN248 with High Phenylpyruvate Reductive Activity. AB - : Phenyllactic acid (PLA) is a novel antimicrobial compound. A novel NADH dependent d-lactate dehydrogenase (d-LDH), named as LF-d-LDH0653, with high phenylpyruvate (PPA) reducing activity was isolated from Lactobacillus fermentum JN248. Its optimum pH and temperature were 8.0 and 50 degrees C, respectively. The Michaelis-Menten constant (Km ), turnover number (kcat ), and catalytic efficiency (kcat /Km ) for NADH were 1.20 mmol/L, 67.39 s-1 , and 56.16 (mmol/L) 1 s-1 , respectively. The (Km ), (kcat ), and (kcat /Km ) for phenylpyruvate were 1.68 mmol/L, 122.66 s-1 , and 73.01 (mmol/L)-1 s-1 , respectively. This enzyme can catalyze phenylpyruvate and the product presented excellent optical purity (enantioselectivity >99%). The results suggest that LF-d-LDH0653 is a promising biocatalyst for the efficient synthesis of optically pure d-PLA. PRACTICAL APPLICATION: A novel d-LDH with phenylpyruvate reducing activity has been isolated and identified. It could be used as a reference for improving the production of optically pure d-PLA. d-PLA has a potential for application as antimicrobial an agent in dairy industry and baking industry, pharmaceutical agent in medicine and cosmetics. PMID- 28881037 TI - Comparison of vessel enhancement algorithms applied to time-of-flight MRA images for cerebrovascular segmentation. AB - PURPOSE: Vessel enhancement algorithms are often used as a preprocessing step for vessel segmentation in medical images to improve the overall segmentation accuracy. Each algorithm uses different characteristics to enhance vessels, such that the most suitable algorithm may vary for different applications. This paper presents a comparative analysis of the accuracy gains in vessel segmentation generated by the use of nine vessel enhancement algorithms: Multiscale vesselness using the formulas described by Erdt (MSE), Frangi (MSF), and Sato (MSS), optimally oriented flux (OOF), ranking orientations responses path operator (RORPO), the regularized Perona-Malik approach (RPM), vessel enhanced diffusion (VED), hybrid diffusion with continuous switch (HDCS), and the white top hat algorithm (WTH). METHODS: The filters were evaluated and compared based on time of-flight MRA datasets and corresponding manual segmentations from 5 healthy subjects and 10 patients with an arteriovenous malformation. Additionally, five synthetic angiographic datasets with corresponding ground truth segmentation were generated with three different noise levels (low, medium, and high) and also used for comparison. The parameters for each algorithm and subsequent segmentation were optimized using leave-one-out cross evaluation. The Dice coefficient, Matthews correlation coefficient, area under the ROC curve, number of connected components, and true positives were used for comparison. RESULTS: The results of this study suggest that vessel enhancement algorithms do not always lead to more accurate segmentation results compared to segmenting nonenhanced images directly. Multiscale vesselness algorithms, such as MSE, MSF, and MSS proved to be robust to noise, while diffusion-based filters, such as RPM, VED, and HDCS ranked in the top of the list in scenarios with medium or no noise. Filters that assume tubular shapes, such as MSE, MSF, MSS, OOF, RORPO, and VED show a decrease in accuracy when considering patients with an AVM, because vessels may vary from its tubular shape in this case. CONCLUSIONS: Vessel enhancement algorithms can help to improve the accuracy of the segmentation of the vascular system. However, their contribution to accuracy has to be evaluated as it depends on the specific applications, and in some cases it can lead to a reduction of the overall accuracy. No specific filter was suitable for all tested scenarios. PMID- 28881038 TI - Experience of the waiting area as perceived by haemodialysis patients and family carers. AB - AIM: To identify the meaning of the waiting area based on the experiences of haemodialysis patients and their carers and to develop an optimal social environment for meaningful nursing care. BACKGROUND: Haemodialysis patients require treatment three times a week and they and their carers spend much of their time in waiting areas, where they experience a unique culture. Limited qualitative research has focused on the culture of the waiting area among haemodialysis patients in South Korea. DESIGN: A qualitative study using an ethnographic approach. METHODS: Eighteen participants were recruited in a hospital waiting area. The data were collected via participant observations and interviews from 24 November 2015-21 April 2016. Spradley's research sequence was employed to analyse the data. RESULTS: Three themes were identified that describe the unique characteristics of the waiting area: sharing information and consoling, inhabiting a separate area of ease and discomfort and experiencing vigilance and unsure stillness. The overarching theme was a boundary space that presented antithetical and dynamic patterns. CONCLUSIONS: This study contributes to a better understanding of the distinct culture experienced by haemodialysis patients in the waiting area and the findings can help nurses deliver more meaningful care. Nursing interventions germane to psychological and emotional support and applicable nursing education should be seriously considered for haemodialysis waiting rooms. PMID- 28881039 TI - Dietary antioxidants and risk of Parkinson's disease in two population-based cohorts. AB - BACKGROUND: A neuroprotective effect of dietary antioxidants on Parkinson's disease (PD) risk has been suggested, but epidemiological evidence is limited. OBJECTIVES: To examine the associations between intake of dietary antioxidant vitamins and total antioxidant capacity and risk of PD. METHODS: We prospectively assessed the relationships of dietary antioxidant vitamins C and E, beta carotene, and total antioxidant capacity with PD risk in two population-based cohorts (38,937 women and 45,837 men). RESULTS: During a mean 14.9-year follow-up period, 1,329 PD cases were identified. Dietary intake of beta-carotene was associated with a lower risk of PD (hazard ratio: 0.86; 95% confidence interval: 0.78-0.95; Ptrend < 0.01 for women and hazard ratio: 0.91; 95% confidence interval: 0.84-0.99; Ptrend = 0.05 for men). An inverse association between dietary vitamin E and PD risk was found in women (hazard ratio: 0.87; 95% confidence interval: 0.79-0.96; Ptrend = 0.02). Dietary intake of vitamin C was inversely associated with PD risk in women at borderline significance (hazard ratio: 0.91; 95% confidence interval: 0.83-1.00; Ptrend = 0.04). There was no association between dietary total antioxidant capacity and PD risk in either women (hazard ratio: 0.93; 95% confidence interval: 0.84-1.02; Ptrend = 0.35) or men (hazard ratio: 1.00; 95% confidence interval: 0.93-1.07; Ptrend = 0.97). CONCLUSION: Intake of dietary vitamin E and beta-carotene was associated with a lower risk of PD. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 28881040 TI - Comprehensive histopathological comparison of epidermotropic/dermal metastatic melanoma and primary nodular melanoma. AB - AIMS: Metastatic melanoma involving the epidermis and/or upper dermis may show significant histological overlap with primary cutaneous melanoma, especially the nodular subtype. Proper histopathological classification is crucial to appropriate staging and management, but is often challenging. The aim of this study was to identify helpful histopathological features for differentiating epidermotropic/dermal metastatic melanoma (EDMM) and primary nodular melanoma (PNM). METHODS AND RESULTS: A cohort of EDMMs (n = 74) and PNMs (n = 75) was retrospectively reviewed for various histopathological features, and the data were compared between groups by the use of univariate analysis. Features significantly associated with EDMM included a tumour size of <2 mm, an absence of tumour-infiltrating lymphocytes and plasma cells, monomorphism, and involvement of adnexal epithelium. Features associated with PNM included a polypoid (exophytic) configuration, prominent tumour-infiltrating plasma cells (TIPs), a tumour size of >10 mm, ulceration, epidermal collarettes, a higher mitotic rate, necrosis, multiple phenotypes, significant pleomorphism, and lichenoid inflammation. In multivariate analysis, a logistic regression model including large tumour size, ulceration, prominent TIPs, lichenoid inflammation and epidermal collarettes was highly predictive of PNM. Six (8%) EDMMs from three patients showed an 'epidermal-only' or 'epidermal-predominant' pattern closely simulating in-situ or microinvasive melanoma. Two of these cases were tested by fluorescence in-situ hybridisation, which confirmed clonal relationships with their corresponding primary melanomas. CONCLUSIONS: This is the first comprehensive histopathological comparison of EDMM and PNM. Recognition of the above histopathological associations should aid in the correct classification and staging of cutaneous melanoma. Epidermotropic metastatic melanomas may occasionally show an epidermal-only/epidermal-predominant pattern; accurate diagnosis requires prudent clinical correlation and, when necessary, ancillary molecular tests. PMID- 28881041 TI - Evaluation of CT's ASIST program: Specialized services to divert higher risk defendants. AB - Some criminal defendants with mental illness may not be referred to traditional mental health jail diversion programs because they have a history of non compliance with treatment, or complex personal circumstances such as homelessness. To successfully divert such individuals, Connecticut has developed a specialized program called the Advanced Supervision and Intervention Support Team (ASIST), which offers criminal justice supervision in conjunction with mental health treatment and support services. An evaluation of the ASIST program included a six-month follow-up study of 111 program clients to examine mental health functioning and other outcomes, and a comparison of administrative data for 492 ASIST clients with a propensity-matched group to examine recidivism. Follow-up study clients showed improvements in mental health. Administrative data showed no change in arrest rates, but a significant reduction in re incarceration. These findings must be viewed with caution due to the quasi experimental design of the study, but it appears that greater attention to criminogenic needs in addition to defendants' mental illness may help jurisdictions to divert a wider variety of defendants. PMID- 28881042 TI - Nature, nurture, and capital punishment: How evidence of a genetic-environment interaction, future dangerousness, and deliberation affect sentencing decisions. AB - Research has shown that the low-activity MAOA genotype in conjunction with a history of childhood maltreatment increases the likelihood of violent behaviors. This genetic-environment (G * E) interaction has been introduced as mitigation during the sentencing phase of capital trials, yet there is scant data on its effectiveness. This study addressed that issue. In a factorial design that varied mitigating evidence offered by the defense [environmental (i.e., childhood maltreatment), genetic, G * E, or none] and the likelihood of the defendant's future dangerousness (low or high), 600 mock jurors read sentencing phase evidence in a capital murder trial, rendered individual verdicts, and half deliberated as members of a jury to decide a sentence of death or life imprisonment. The G * E evidence had little mitigating effect on sentencing preferences: participants who received the G * E evidence were no less likely to sentence the defendant to death than those who received evidence of childhood maltreatment or a control group that received neither genetic nor maltreatment evidence. Participants with evidence of a G * E interaction were more likely to sentence the defendant to death when there was a high risk of future dangerousness than when there was a low risk. Sentencing preferences were more lenient after deliberation than before. We discuss limitations and future directions. PMID- 28881043 TI - Human papillomavirus prevalence in lung carcinomas in Bulgaria. AB - A possible association between high-risk human papillomaviruses (HPV) and lung cancer has been investigated for decades with discrepant results. The aim of this study was to determine the prevalence of HPV16 and 18 in Bulgarian patients with lung cancer. Two hundred and nine biopsy specimens from patients with histologically proven lung cancer and without cancer were analyzed. Each sample was subjected to three parallel PCRs using broad spectrum GP5+/6+ primers and type-specific (TS) primers for HPV types 16 and 18. Of the 132 lung carcinoma samples, 33 (25%) were positive for HPV16 and/or HPV18 by TS PCR whereas only five (3.8%) samples were HPV positive by consensus PCR. All non-malignant controls were HPV negative. HPV18 was the more prevalent, being found in 11.4% of samples, followed by HPV16 in 9.1% samples; 4.5% of lesions were positive for both HPV16 and HPV18. HPV16/18 were most prevalent in small cell carcinoma (29.2%) and least prevalent in squamous cell carcinoma (23.3%). HPV was only detected in squamous cell carcinoma and adenosquamous carcinoma by consensus PCR. This study revealed a high HPV16/18 prevalence in lung carcinoma samples from Bulgarian patients when TS PCR was used to detect them. The difference between HPV positivity as detected by consensus and by TS PCR was significant, indicating the importance of methodological issues in explaining the discrepancies between previous studies. HPV18 was more common than HPV16. No association between HPV16/18 status and histopathological diagnosis was identified. PMID- 28881045 TI - Diagnostic accuracy of immunofluorescence versus immunoperoxidase staining to distinguish immune complex-mediated glomerulonephritis and C3 dominant glomerulopathy. AB - AIMS: The technique used for classification of membranoproliferative glomerulonephritis (MPGN) has been changed from an electron microscopy-based to an immunofluorescence (IF)-based semiquantitative technique with immunoperoxidase (IP) staining as a backup option when IF is not possible. Since data on that matter is lacking, our aims were to study the interobserver variability, the correlation and the reclassification of MPGN based on these two techniques. METHODS AND RESULTS: We retrospectively analysed cases of type 1 MPGN. We repeated IF staining and performed IP staining for IgG, kappa, lambda, C3c and C4d in 35 renal biopsies, among which 19 biopsies had matched IP and IF samples. We observed substantial to near-perfect agreement among the seven observers for both IF and IP (W coefficients from 0.66 for IF lambda to 0.89 for IF C4d). Of the 19 cases with matched IP and IF samples, five (26%) turned out to have different diagnoses on IF and on IP. Also, the ability of C4d to discriminate immune complex-mediated glomerulonephritis (ICGN) from C3 glomerulopathy (C3G) was poor, with areas under the curve of 0.44 [95% confidence interval (CI) 0.24 0.63] and 0.66 (95% CI 0.50-0.81) for the receiver operating characteristic curves of IF and IP respectively. Limitations include the fact that no clinical data regarding complement activation were available. CONCLUSION: The diagnosis of ICGN versus C3GN depends on the immunochemical technique used. Also, the use of C4d failed to discriminate ICGN from C3G in our study. Further validation studies are required to avoid misdiagnosis based on kidney biopsy. PMID- 28881044 TI - From large to small: the immunohistochemical panel in the diagnosis of early hepatocellular carcinoma. AB - AIMS: The aims of this study were to: validate the use of the immunohistochemical (IHC) markers glutamine synthetase (GS), glypican-3 (GPC3), heat shock protein-70 (HSP70) and enhancer of zeste homologue 2 (EZH2) in liver biopsies for the differential diagnosis between small hepatocellular carcinoma (HCC) and non neoplastic liver nodules, with special attention to <10-mm nodules; and assess the actual sensitivity and specificity of the single markers, and their combination, in needle biopsies. METHODS AND RESULTS: One hundred liver nodules, i.e. 66 HCCs and 34 non-neoplastic nodules, were prospectively collected from 43 consecutive orthotopic liver transplantation patients, and subjected to 'backtable' needle biopsies directly on surgical specimens. IHC evaluation was semi-automatically performed with a Benchmark Ultra immunostainer. The morphological and IHC diagnosis in surgical specimens was considered to be the gold standard. GS, GPC3, HSP70 and EZH2 showed 16.6%, 10.7%, 28.8% and 62.1% decreases in sensitivity, respectively, from surgical specimen to needle biopsy. Higher decreases were observed in <10-mm nodules. In 18 HCCs with no morphological diagnostic features of malignancy in biopsies, GPC3 or GS were positive in 16; in seven HCCs, neither morphology nor IHC evaluation ruled out the differential diagnosis made on the basis of needle biopsy. CONCLUSIONS: We present for the first time a direct comparison between surgical specimens and needle biopsies to confirm the usefulness and reproducibility of the most widely used antibodies for the diagnosis of small liver nodules. Our results support the use of IHC evaluation in biopsies for the diagnosis of small liver lesions, although the IHC panel could also give negative results in the presence of obvious HCC, and the possibility of false positives should always be considered. PMID- 28881046 TI - A meta-analysis of the effect on maternal health of upright positions during the second stage of labour, without routine epidural analgesia. AB - AIM: To detect the effect on maternal health of upright positions during the second stage of labour. BACKGROUND: Maternal position during labour has an important effect on maternal and foetal health. DESIGN: A meta-analysis was used based on the Cochrane Handbook. DATA SOURCES: Randomized/non-randomized clinical trials were searched with English and Turkish key words in databases (CINAHL, Medline, Science Direct, Springer Link, Ovid, Cochrane Central Register of Controlled Trials, Networked Digital Library of Theses & Dissertations, Proquest, ULAKBIM (Turkish Academic Network and Information Center) and YOK (Turkish Council of Higher Education) (1970-December 2015). REVIEW METHODS: According to inclusion criteria, eligible studies were identified. Data extraction was performed and the bias risks of the studies were assessed independently by two authors. The publication bias of the main outcomes was examined. The overall effect size was calculated by risk ratio with a random effects model. Statistical heterogeneity tests and sensitivity analyses were performed. RESULTS: The criteria for the meta-analysis were met by 22 articles. It was detected that the ratio of instrumental labour and episiotomy was lower but the haemorrhage ratio was higher in women. There was no statistical effect of upright position on the other maternal outcomes. CONCLUSION: The reductions in these ratios improved comfort. Due to methodological shortcomings of the studies, the increased ratio of postpartum haemorrhage should be interpreted with caution. Researchers are recommended to conduct studies rigorously. In addition, healthcare professionals are recommended to decide the appropriate birth position by considering the individual risk factors and preferences of the women. PMID- 28881047 TI - Podoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinoma. AB - AIMS: Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an unfavourable indicator in squamous cell carcinoma of the lung, but little is known about its clinical significance in early-stage lung adenocarcinoma. We evaluated the prognostic impact of podoplanin expression in patients with pathological stage (p-stage) IA lung adenocarcinoma as categorised by the 8th edition of the tumour-node-metastasis classification for lung cancer. METHODS AND RESULTS: Immunohistochemical analyses using anti-podoplanin antibody were performed on resected specimens from 158 patients with p-stage IA lung adenocarcinoma. When more than 10% of cancer cells or CAFs showed immunoreactivity with podoplanin, the specimens were classified as podoplanin positive. Podoplanin-positive status in cancer cells (n = 8) was not correlated with clinicopathological factors or with patient prognosis. Podoplanin-positive status in CAFs (n = 41) was correlated significantly with poorer tumour differentiation (P < 0.001), the presence of lymphatic invasion (P < 0.001) and high-grade (solid and/or micropapillary) components constituting >=1% of the entire tumour (P < 0.001). The log-rank test showed that podoplanin-positive status in CAFs was associated significantly with shorter disease-free survival (DFS) (P < 0.001) and disease-specific survival (P = 0.015). In Cox's multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DFS [hazard ratio (HR) = 4.411, P = 0.004], followed by the presence of high-grade components (HR = 3.581, P = 0.013). CONCLUSIONS: Podoplanin expression in CAFs could be an independent predictor of increased risk of recurrence in patients with p-stage IA lung adenocarcinoma. PMID- 28881048 TI - A novel technique for biobanking of large sections of radical prostatectomy specimens. AB - AIMS: Harvesting of unfixed tissue from radical prostatectomy specimens for research purposes is challenging. Many prostate cancers cannot be identified at gross inspection, and this tumour is notoriously multifocal and heterogeneous. We aimed to develop a technique to allow detailed topographic analysis and the sampling of a sufficient amount of tumour without jeopardising clinical reporting. METHODS AND RESULTS: A custom-made double-bladed knife was utilised for cutting a 4-mm-thick horizontal section of the prostate. The slices were split into segments that were frozen in gel, cryosections were cut, and RNA integrity numbers (RINs) were analysed. Sections were cut from all blocks of 20 cases, and the cutting time was monitored. Slides were scanned, and the slices were digitally reconstructed. Cutting frozen sections of an entire slice took 79 253 min (mean 162 min). Tumour was detected in frozen sections of 85% (17/20) of cases and in 46% (72/155) of blocks. The morphological quality was determined to be excellent, and RIN values were high (mean 8.9). CONCLUSIONS: This novel protocol for biobanking of fresh tissue from prostatectomy specimens provides sufficient tumour material for research purposes, while also enabling reporting of histopathology. The harvesting of a full tissue slice facilitates studies of tumour multifocality and heterogeneity. PMID- 28881049 TI - Classical gonadoblastoma: its relationship to the 'dissecting' variant and undifferentiated gonadal tissue. AB - Classical gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development. Approximately 40% of such neoplasms are bilateral. Almost all gonadoblastomas occur in patients who have a Y chromosome or part thereof; testis-specific protein Y-encoded 1 (TSPY1) is the putative gene. If a gonad in a patient who has a disorder of sex development contains germ cells with delayed maturation, and also harbours the TSPY1 gene, the cells can undergo transformation to classical gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements and hyaline basement membrane material surrounded by a variably cellular gonadal stroma that sometimes contains steroid cells. Classical gonadoblastoma can be interpreted as a non-invasive neoplasm that is the precursor of germinoma and, indirectly, other more aggressive germ cell neoplasms. Undifferentiated gonadal tissue is the precursor of classical gonadoblastoma and contains germ cells with delayed maturation that express octamer-binding transcription factor 4 (OCT4); however, other germ cells show normal maturation and express TSPY1. If all germ cells in a patient with undifferentiated gonadal tissue involute, the result is a secondary streak. Undifferentiated gonadal tissue is a non-neoplastic condition that should be distinguished clearly from 'dissecting gonadoblastoma', a neoplasm derived from classical gonadoblastoma that is the precursor of some germinomas. 'Dissecting gonadoblastoma' is a variant of classical gonadoblastoma that has unusual growth patterns and contains both sex cord and germ cell elements. Clonal expansion of germ cells is a characteristic of the late stage of 'dissecting gonadoblastoma'. PMID- 28881050 TI - Pulmonary sclerosing pneumocytoma remains a diagnostic challenge using frozen sections: a clinicopathological analysis of 59 cases. AB - AIMS: Using intraoperative frozen sections to diagnose pulmonary sclerosing pneumocytoma is always challenging. However, an accurate diagnosis is needed to guide surgical management and prevent unnecessary treatment. The aim of this study was to investigate the most frequently misdiagnosed histological patterns and evaluate the potential diagnostic pitfalls of using frozen sections. METHODS AND RESULTS: We reviewed retrospectively 59 cases of sclerosing pneumocytoma that underwent an intraoperative frozen section examination. All original frozen section slides and permanent section slides were reviewed. The rate of accurate diagnosis using frozen sections was 44.1%, the deferral rate was 15.3% and 10 cases (16.9%) were misdiagnosed as malignancy. A solid-predominant pattern is misdiagnosed more frequently than other growth patterns. We also summarised the five major diagnostic pitfalls, including hypercellularity, glandular spaces, desmoplasia-like sclerosis, cellular atypia and coagulative necrosis. CONCLUSIONS: In addition to evaluating the tumour circumscription and identifying the various growth patterns, we propose that the key to avoiding a misdiagnosis is to recognise the dual-cell populations in a tumour, i.e. cuboidal surface cells and stromal round cells. PMID- 28881051 TI - Heli(aza)cene: A Helical Molecular Tweezer with Tunable Intra- and Intermolecular Charge Transfer. AB - Non-planar fluorophores offer unique avenues of intra- and intermolecular energy transfer not available in their planar counterparts. We have rationally designed a molecular tweezer based on the pyridine-2,6-dicarboxamide framework having two structurally similar arms with extended pi-surface. We termed this molecular tweezer as Heli(aza)cene (HAC) due to its spontaneous adoption of helical conformation stabilized by the amide and imine moieties present in it. In the helical conformation, the two arms of HAC are twisted unequally. This asymmetry confers dissimilar electronic character to the two arms and results in intramolecular charge transfer interactions in HAC. Homochiral stacking of the P- and the M- helices in crystal, and profound redshifting of the emission at higher concentrations of HAC was attributed to intermolecular charge-transfer interactions in aggregated/crystal state. Exposure of HAC, in solution as well as in the solid state, to Lewis/Bronsted acids results in rapid and vibrant color changes. This is the first example of a pi-layered helical molecule exhibiting tunable intra-/intermolecular charge-transfer characteristics. PMID- 28881052 TI - Asunaprevir and daclatasvir for recurrent hepatitis C after liver transplantation: A Japanese multicenter experience. AB - The safety and efficacy of an IFN-free regimen using asunaprevir (ASV) and daclatasvir (DCV) for recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) have not been evaluated in Japan. A multicenter study of LT recipients (n = 74) with recurrent HCV genotype 1b infection treated with ASV-DCV for 24 weeks was performed. Medical history was positive for pegylated interferon and ribavirin (Peg-IFN/RBV) in 40 (54.1%) patients, and for simeprevir (SMV) with Peg-IFN/RBV in 12 (16.2%) patients. Resistance-associated variants (RAVs) were positive at D168 (n = 1) in the NS3, and at L31 (n = 4), Y93 (n = 4), and L31/Y93 (n = 1) in the NS5A region of the HCV genome. Sixty-one (82.4%) patients completed the 24-week treatment protocol. Although sustained viral response (SVR) was achieved in 49 (80.3%) patients, it was achieved in only two (16.7%) patients among those with histories of receiving SMV (n = 12). Univariate analysis showed that a history of SMV (P < .01) and the presence of mutations in NS5A (P = .02) were the significant factors for no-SVR. By excluding the patients with either a history of SMV-based treatment or RAVs in NS3/NS5A, the SVR rate was 96.4%. By excluding the patients with a history of SMV and those with RAVs in NS3/NS5A, viral clearance of ASV-DCV was favorable, with a high SVR rate. PMID- 28881053 TI - Lower percentage of allergic sensitization in children with Down syndrome. PMID- 28881054 TI - Facet-Specific Ligand Interactions on Ternary AgSbS2 Colloidal Quantum Dots. AB - Silver dimetal chalcogenide (Ag-V-VI2 ) ternary quantum dots (QDs) are emerging lead-free materials for optoelectronic devices due to their NIR band gaps, large absorption coefficients, and superior electronic properties. However, thin film based devices of the ternary QDs still lag behind due to the lack of understanding of the surface chemistry, compared to that of lead chalcogenide QDs even with the same crystal structure. Herein the surface ligand interactions of AgSbS2 QDs, synthesized with 1-dodecanethiol used as a stabilizer, are studied. For nonpolar (1 0 0) surfaces, it is suggested that the thiolate ligands are associated with the crystal lattices, thus preventing surface oxidation by protecting sulfur after air-exposure, as confirmed through optical and surface chemical analysis. Otherwise, silver rich (1 1 1) surfaces are passivated by thiolate ligands, allowing ligand exchange processes for the conductive films. This in-depth investigation of the surface chemistry of ternary QDs will prompt the performance enhancement of their optoelectronic devices. PMID- 28881055 TI - Individual healthcare plan for allergic children at school: Lessons from a 2015 2016 school year survey. AB - BACKGROUND: The individual healthcare plan (IHP) was implemented in schools in France in 2003 to improve management of allergic children. Our objectives were to assess the practical aspects of IHP (excluding asthma) and allergic reactions occurring at school. METHODS: Prospective study conducted in the North Department (France) during the 2015/2016 school year. Two questionnaires were developed: one for the school doctors (n = 67) and one for the school principals (n = 2372). RESULTS: Data from 336 (25%) of the 1325 IHPs (0.24% of children) were collected (mean age: 8 years; food allergy [FA]: 94% [peanut = 44%, nuts = 54%], venom: 4%). Wide variations in emergency kit (EK) medications were observed: antihistamines (84%), oral corticosteroids (79%), adrenaline auto-injectors (70%), and inhaled bronchodilators (65%). Six hundred and seventy (28%) school principals' responses, representing 81% of all IHPs, were analyzed. A total of 1935 EKs were stored (mean: 2.8/school), one or more with adrenaline, by 213 (32%) schools: in the class room (33%), the nursery (14%), or the principal's office (10%). Sixty, mainly, mild-to-moderate allergic reactions (adrenaline injection: 2) occurred in 44 schools (0.09/school/year), in children with previously undocumented allergy in 50%. FA was highly suspected in 92%. CONCLUSION: Individual healthcare plan is mainly implemented for FA. Anaphylaxis remains rare in the school setting, and FA is often a suspected cause of reaction. Staff training should be improved. Application of the recommendations regarding the content and accessibility of EK and a widespread emergency action plan is needed. PMID- 28881056 TI - Synthesis and Biological Evaluation of O-Methylated Glycolipids Related to PGLs via Direct Stereoselective Glycosidation and Sequential Suzuki-Miyaura Coupling using Boracyclane. AB - Synthesis of O-methylated glycolipids via direct stereoselective glycosidation whose sugar moieties are related to those in phenolic glycolipids (PGLs) is reported. Treatment of 2-O-methyl-rhamnosyl imidates with I2 and nBu4 NOTf resulted in their activation under low temperature and provided the alpha rhamnosides with excellent alpha-selectivity. nBu4 NOTf enhanced the electorophilicity of iodine. This methodology improved the efficiency of the synthesis of both PGL-1 and PGL-tb1 sugars. The process involved the formation of 2-O-naphthylmethyl-alpha-rhamnoside and 2-O-methyl-alpha-fucoside. Sequential Suzuki-Miyaura coupling using synthetic glycosides, boracyclane, and aryl bromides provided glycolipids related to PGL sugars, and was accomplished with a one-pot process. Finally, we elucidated the immunosuppressive activities of all these synthetic compounds and found that a phenyl 3-O-alpha-rhamnosyl-2-O-methyl alpha-rhamnoside possessing a 6-(2-naphthyl)hexyl group exhibited the strongest inhibitory effect. PMID- 28881057 TI - Efficient Sensitized Z->E Photoisomerization of an Iridium(III)-Azobenzene Complex over a Wide Concentration Range. AB - To improve the sensitized Z->E photoisomerization of azobenzenes, and circumvent the threshold concentration necessary for the bimolecular photoinduced electron transfer reaction to generate the rapidly isomerizing Z-azobenzene radical anion, an IrIII complex with a covalently tethered azobenzene fragment was synthesized. Selective irradiation of the 1 MLCT band of the IrIII complex induced an efficiently sensitized photoswitching of the dyad over a wide concentration range and even at high dilution. PMID- 28881058 TI - Increased regulatory T cells in pediatric acute appendicitis. PMID- 28881059 TI - Pancreas-preserving duodenectomy after living donor liver transplantation for invasive cytomegalovirus disease. AB - CMV infection plays an important role in the postoperative course following solid organ transplantation. We present the case of an 11-year-old male patient who underwent LDLT due to severe hepatopulmonary syndrome and biliary cirrhosis. Four weeks after LDLT, he developed persistent GI bleeding and was subjected to repeated endoscopic treatment and radiological arterial embolization to stop the bleeding from duodenal ulcers. Diagnostic workup was negative for CMV disease. Because the bleeding persisted, surgical treatment was indicated, and a pancreas preserving duodenectomy was performed. Immunohistochemical staining of the surgical specimen demonstrated diffuse endothelial infiltration by CMV. Despite ganciclovir treatment, the patient developed new erosions in the jejunal mucosa and melena; ganciclovir was discontinued, and foscarnet was started, resulting in clinical improvement and the cessation of bleeding. This case highlights the technical aspects of performing a complex upper GI resection in a patient recently subjected to LDLT, taking care to avoid injury to the previous liver graft anastomosis and restore GI continuity. Moreover, CMV tissue-invasive disease compartmentalized in the GI tract may be difficult to diagnose, as indicated by the negative results of antigenemia and PCR assays and endoscopic superficial mucosal biopsies. PMID- 28881060 TI - Outcome of kidney transplant in primary, repeat, and kidney-after-nonrenal solid organ transplantation: 15-year analysis of recent UNOS database. AB - The number of nonrenal solid-organ transplants increased substantially in the last few decades. Many of these patients develop renal failure and receive kidney transplantation. The aim of this study was to evaluate patient and kidney allograft survival in primary, repeat, and kidney-after-nonrenal organ transplantation using national data reported to United Network for Organ Sharing (UNOS) from January 2000 through December 2014. Survival time for each patient was stratified into the following: Group A (comparison group)-recipients of primary kidney transplant (178 947 patients), Group B-recipients of repeat kidney transplant (17 819 patients), and Group C-recipients of kidney transplant performed after either a liver, heart, or lung transplant (2365 patients). We compared survivals using log-rank test. Compared to primary or repeat kidney transplant, patient and renal allograft survival was significantly lower in those with previous nonrenal organ transplant. Renal allograft and patient survival after liver, heart, or lung transplants are comparable. Death was the main cause of graft loss in patients who had prior nonrenal organ transplant. PMID- 28881061 TI - Full breastfeeding and allergies from infancy until adolescence in the GINIplus cohort. PMID- 28881062 TI - The Brief Memory and Executive Test (BMET): A cognitive screening tool to detect and differentiate vascular cognitive impairment and Alzheimer's disease. AB - OBJECTIVE: While there are several cognitive screening tests available for the detection of cortical dementias such as Alzheimer's disease (AD), these are rarely designed to be sensitive to vascular cognitive impairment (VCI). The Brief Memory and Executive Test (BMET) is a screening measure designed to be sensitive to the cognitive profile of both VCI and AD. This study investigated the ability of the BMET to detect AD, and to differentiate between VCI and AD. METHODS: This study included 150 patients, with either SVD, both with (n = 48) and without VCI (n = 51), or AD (N = 51) and 51 healthy controls. Participants were aged between 40 and 90 years of age and completed both the BMET and the MMSE. RESULTS: Receiver operator characteristic (ROC) curve analysis showed as before the BMET is a good predictor SVD. Additionally, the BMET was a good predictor of AD (AUC = 0.96) and performed at least as well as the MMSE (AUC = 0.92) when differentiating AD patients from healthy controls. The BMET had a sensitivity of 86% and specificity of 100% for detecting AD patients from control subjects. Using the difference in cognitive profile between the AD and VCI group, we developed an index score which correctly classified 76% of patients as either having VCI or AD. CONCLUSION: The BMET is a brief and sensitive tool for the detection of cognitive impairment due to both SVD and AD and can be used to aid in the differentiation of the 2 diseases. PMID- 28881063 TI - Carbon-Rich Monolayers on ITO as Highly Sensitive Platforms for Detecting Polycyclic Aromatic Hydrocarbons in Water: The Case of Pyrene. AB - The determination of polycyclic aromatic hydrocarbons (PAHs) in water at low levels is a current challenge given their great impact on the health and safety of the public. Here, a novel pyrene-based self-assembled monolayer (SAM) platform is exploited as an electrochemical sensing recognition device. Interestingly, the formation of pi-pi sandwich complexes between PAHs and the recognition element switches the surface electron transfer capability. The unique supramolecular interaction between identical aromatic molecules provides a highly sensitive and selective sensor for pyrene in the order of part per trillion. Accordingly, and using pyrene as a proof-of-concept, this work presents the basis for an "at-point of-use" impedimetric sensor focused on a highly sensitive carbon-rich SAM for PAHs determination in water at ultra-trace levels. PMID- 28881064 TI - Misdiagnosis of hepatocellular carcinoma in patients receiving no local-regional therapy prior to liver transplant: An analysis of the Organ Procurement and Transplantation Network explant pathology form. AB - : Patients with T1 hepatocellular carcinoma (HCC) are not eligible for Model for End Stage Liver Disease (MELD) exception for liver transplant (LT) in part due to a high rate of misdiagnosis (no HCC on explant). The likelihood of misdiagnosis for T2 HCC and factors associated with misdiagnosis are unknown. We analyzed the Organ Procurement and Transplantation Network database including 5664 adults who underwent LT from 2012 to 2015 with MELD exception for T2 HCC, and searched for no evidence of HCC in the explant pathology file. We focused on those (n = 324) receiving no local-regional therapy (LRT) to evaluate the probability of no HCC found in explant. Median waiting time was short at 1.7 months, and 35 (11%) had no HCC on explant. On multivariable logistic regression, factors associated with no HCC on explant were age <50 (OR: 17.3, P < .001), non-HCV (OR: 5.4, P = .001), and alpha-fetoprotein <10 (OR: 2.9, P = .04). Tumor size and number were not different between groups. The proportion of misdiagnosis did not change significantly after implementation of Liver Imaging Reporting and Data System (LI RADS) for HCC diagnosis. CONCLUSION: The rate of misdiagnosis was 11% among T2 HCC patients who underwent LT without receiving LRT prior to LT and did not change significantly after implementation of LI-RADS. More efforts are needed to eliminate unnecessary LT for patients without HCC. PMID- 28881065 TI - The intergenerational transmission of at-risk/problem gambling: The moderating role of parenting practices. AB - BACKGROUND AND OBJECTIVES: Although parenting practices are articulated as underlying mechanisms or protective factors in several theoretical models, their role in the intergenerational transmission of gambling problems has received limited research attention. This study therefore examined the degree to which parenting practices (positive parenting, parental involvement, and inconsistent discipline) moderated the intergenerational transmission of paternal and maternal problem gambling. METHODS: Students aged 12-18 years (N = 612) recruited from 17 Australian secondary schools completed a survey measuring parental problem gambling, problem gambling severity, and parenting practices. RESULTS: Participants endorsing paternal problem gambling (23.3%) were 4.3 times more likely to be classified as at-risk/problem gamblers than their peers (5.4%). Participants endorsing maternal problem gambling (6.9%) were no more likely than their peers (4.0%) to be classified as at-risk/problem gamblers. Paternal problem gambling was a significant predictor of offspring at-risk/problem gambling after controlling for maternal problem gambling and participant demographic characteristics. The relationship between maternal problem gambling and offspring at-risk/problem gambling was buffered by parental involvement. DISCUSSION AND CONCLUSIONS: Paternal problem gambling may be important in the development of adolescent at-risk/problem gambling behaviours and higher levels of parental involvement buffers the influence of maternal problem gambling in the development of offspring gambling problems. Further research is therefore required to identify factors that attenuate the seemingly greater risk of transmission associated with paternal gambling problems. SCIENTIFIC SIGNIFICANCE: Parental involvement is a potential candidate for prevention and intervention efforts designed to reduce the intergenerational transmission of gambling problems. (Am J Addict 2017;26:707-712). PMID- 28881066 TI - Molecular screening of Vel-blood donors using DNA pools in Nanjing, China. PMID- 28881067 TI - The diversity and biogeography of abundant and rare intertidal marine microeukaryotes explained by environment and dispersal limitation. AB - Benthic microeukaryotes are key ecosystem drivers in marine sandy beaches, an important and dynamic environment; however, little is known about their diversity and biogeography on a large spatial scale. Here, we investigated the community composition and geographical distributions of benthic microeukaryotes using high throughput sequencing of the 18S rRNA gene and quantified the contributions of environmental factors and spatial separation on the distribution patterns of both rare and abundant taxa. We collected 36 intertidal samples at 12 sandy beaches from four regions that spanned distances from 0.001 to 12,000 km. We found 12,890 operational taxonomic units (OTUs; 97% sequence identity level) including members of all eukaryotic super-groups and several phyla of uncertain position. Arthropoda and Diatomeae dominated the sequence reads in abundance, but Ciliophora and Discoba were the most diverse groups across all samples. About one third of the OTUs could not be definitively classified at a similarity level of 80%, supporting the view that a large number of rare and minute marine species may have escaped previous characterization. We found generally similar geographical patterns for abundant and rare microeukaryotic sub-communities, and both showed a significant distance-decay similarity trend. Variation partitioning showed that both rare and abundant sub-communities exhibited a slightly stronger response to environmental factors than spatial (distance) factors. However, the abundant sub-community was strongly correlated with variations in spatial, environmental and sediment grain size factors (66% of variance explained), but the rare assemblage was not (16%). This suggests that different or more complex mechanisms generate and maintain diversity in the rare biosphere in this habitat. PMID- 28881069 TI - Person-centred discharge education following coronary artery bypass graft: A critical review. AB - AIMS AND OBJECTIVES: To examine the extent that individualised education helps reduce depression and anxiety and improves self-care for people who have undergone coronary artery bypass graft surgery. BACKGROUND: Individualised discharge planning is increasingly important following cardiac surgery due to recurrent admissions as well as the issue of anxiety and depression, often due to lack of preparation. The hospital to home transition is fundamental in the recovery process. Individualised education and person-centred care ensure that patients' educational needs are met. This empowers patients, increasing self efficacy or confidence, resulting in autonomy, a smoother discharge process and avoiding postdischarge problems and rehospitalisation. DESIGN: A critical review of published peer-reviewed literature was conducted. METHODS: Electronic databases searched included MEDLINE, CINAHL, the Cochrane Library and PsychInfo 2009-2015. RESULTS: Eight articles were identified for review, and a Critical Appraisal Skills Programme framework was used to determine the quality of the papers, all of the papers focussed on coronary artery bypass graft. The designs were typically experimental or quasi-experimental with two reviews. CONCLUSION: A greater understanding of the patients' needs allows tailored education to be provided, which promotes self-care management. This level of patient empowerment increases confidence and ultimately minimise anxiety and depression. Despite the varying teaching and learning methods associated with individualised education, patient-centred education has the potential to assist cardiac nurses in adequately preparing patients for discharge following their coronary artery bypass graft. RELEVANCE TO CLINICAL PRACTICE: Development of individualised education programmes is crucial in preparing patients for discharge. The reduction in readmission to hospital has a significant effect on already stretched resources, and the reduction in postoperative complications during the recovery period linked with depression and anxiety will have a positive effect on the individuals' ability to self-care, health and well-being. PMID- 28881070 TI - Identification of sialyl oligosaccharides including an oligosaccharide nucleotide in colostrum of an addax (Addax nasomaculatus) (Subfamily Antelopinae). AB - Mammalian milk/colostrum usually contains milk oligosaccharides along with the predominant lactose. Although milk oligosaccharides of a variety of Bovidae species including cow, sheep and goat have been characterized, those of the addax, an Antelopinae species of the Bovidae, have not as yet been clarified. In this study, several sialyl oligosaccharides were purified from a sample of addax colostrum and characterized as follows: Neu5Ac(alpha2-8)Neu5Ac(alpha2-3)Gal(beta1 4)Glc, Neu5Gc(alpha2-8)Neu5Gc(alpha2-3)Gal(beta1-4)Glc, Neu5Ac(alpha2-3)Gal(beta1 4)Glc, Neu5Ac(alpha2-6)Gal(beta1-4)GlcNAc, Neu5Gc(alpha2-3)Gal(beta1-4)Glc, Neu5Gc(alpha2-6)Gal(beta1-4)Glc, Neu5Gc(alpha2-6)Gal(beta1-4)GlcNAc. In addition, an oligosaccharide nucleotide Neu5Gc(alpha2-6)Gal(beta1-4)GlcNAcalpha1-UDP was characterized. Molecular species of a variety of sialyl oligosaccharides found in milk and colostrum of these Bovidae were compared. PMID- 28881071 TI - Quantity over quality-Findings from a systematic review and environmental scan of patient decision aids on early abortion methods. AB - BACKGROUND: The availability and effectiveness of decision aids (DAs) on early abortion methods remain unknown, despite their potential for supporting women's decision making. OBJECTIVE: To describe the availability, impact and quality of DAs on surgical and medical early abortion methods for women seeking induced abortion. SEARCH STRATEGY: For the systematic review, we searched MEDLINE, Cochrane Library, CINAHL, EMBASE and PsycINFO. For the environmental scan, we searched Google and App Stores and consulted key informants. INCLUSION CRITERIA: For the systematic review, we included studies evaluating an early abortion method DA (any format and language) vs a comparison group on women's decision making. DAs must have met the Stacey et al (2014). Cochrane review definition of DAs. For the environmental scan, we included English DAs developed for the US context. DATA EXTRACTION AND SYNTHESIS: We extracted study and DA characteristics, assessed study quality using the Effective Practice and Organization of Care risk of bias tool and assessed DA quality using International Patient Decision Aid Standards (IPDAS). RESULTS: The systematic review identified one study, which found that the DA group had higher knowledge and felt more informed. The evaluated DA met few IPDAS criteria. In contrast, the environmental scan identified 49 DAs created by non-specialists. On average, these met 28% of IPDAS criteria for Content, 22% for Development and 0% for Effectiveness. CONCLUSIONS: Research evaluating DAs on early abortion methods is lacking, and although many tools are accessible, they demonstrate suboptimal quality. Efforts to revise existing or develop new DAs, support patients to identify high-quality DAs and facilitate non-specialist developers' adoption of best practices for DA development are needed. PMID- 28881072 TI - Self-efficacy modulates the neural correlates of craving in male smokers and ex smokers: an fMRI study. AB - The regulation of cue-induced craving for cigarettes is a key factor in smoking cessation. Outcomes of smoking cessation have been linked to self-efficacy, faith in one's own ability, in smokers. However, no study has examined the neural basis of self-efficacy during the control of craving. We examined whether self-efficacy can affect the neural response to smoking cues in smokers and ex-smokers using functional magnetic resonance imaging. During scanning, participants were instructed (1) to view smoking-related images passively, (2) to view the smoking related images with a strategy focused on self-efficacy to control cue-induced craving or (3) to view neutral images. In smokers, the self-efficacy strategy significantly reduced self-reported craving. This strategy was related to increased activation in the rostral medial prefrontal cortex (rmPFC) and the pregenual anterior cingulate cortex in smokers compared with ex-smokers. Furthermore, smokers showed increased effective connectivity between rmPFC and hippocampus and between pregenual anterior cingulate cortex and parahippocampus gyrus when employing the self-efficacy strategy compared with ex-smokers. The magnitude of the rmPFC-hippocampus connectivity was positively correlated with self-reported self-efficacy. Our findings suggest that in smokers, self-efficacy is related to activation and connectivity in brain regions involved in regulating craving and self-assessment. The current study provides evidence for understanding the vunderlying cognitive and neurobiological mechanisms involved in the control of craving to smoke cigarettes. PMID- 28881068 TI - Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma. AB - Parathyroid carcinoma (PC) may occur as part of a complex hereditary syndrome or an isolated (i.e., non-syndromic) non-hereditary (i.e., sporadic) endocrinopathy. Studies of hereditary and syndromic forms of PC, which include the hyperparathyroidism-jaw tumor syndrome (HPT-JT), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), and familial isolated primary hyperparathyroidism (FIHP), have revealed some genetic mechanisms underlying PC. Thus, cell division cycle 73 (CDC73) germline mutations cause HPT-JT, and CDC73 mutations occur in 70% of sporadic PC, but in only ~2% of parathyroid adenomas. Moreover, CDC73 germline mutations occur in 20%-40% of patients with sporadic PC and may reveal unrecognized HPT-JT. This indicates that CDC73 mutations are major driver mutations in the etiology of PCs. However, there is no genotype-phenotype correlation and some CDC73 mutations (e.g., c.679_680insAG) have been reported in patients with sporadic PC, HPT-JT, or FIHP. Other genes involved in sporadic PC include germline MEN1 and rearranged during transfection (RET) mutations and somatic alterations of the retinoblastoma 1 (RB1) and tumor protein P53 (TP53) genes, as well as epigenetic modifications including DNA methylation and histone modifications, and microRNA misregulation. This review summarizes the genetics and epigenetics of the familial syndromic and non-syndromic (sporadic) forms of PC. PMID- 28881073 TI - Parental professional help-seeking for infant sleep. AB - AIMS AND OBJECTIVES: To explore the perceptions and experiences of parental professional help-seeking for infant sleep and sleep-related concerns. BACKGROUND: Infant sleep is a frequent concern for parents. However, very little is known about the reasons parents seek, do not seek or delay seeking professional attention about their concerns related to infant sleep. DESIGN AND METHODS: A qualitative study design was used. Twenty audio-taped interviews with parents of healthy 12-month-old infants were conducted at a university-affiliated hospital or parents' homes depending on where parents felt more comfortable discussing their personal views and medical help-seeking experiences. Thematic content analysis was performed to determine specific patterns and similarities within and between interview data. FINDINGS: Three main themes developed from the interviews were as follows: (i) uncertainty about infant sleep; (ii) I can handle infant sleep; and (iii) I am not satisfied with the professional services provided for infant sleep. Overall, parents knew little about or misunderstood infant sleep behaviours. Lack of proper information and knowledge about infant sleep influenced parents' motivation for professional help-seeking and help receiving. Parents who have consulted a healthcare professional but received unsatisfactory responses, such as an ambivalent attitude or insufficient assessment, reported being less motivated or unwilling to seek medical help again. CONCLUSION: Our study demonstrates the complexity of parental professional help-seeking and receiving for infant sleep. Findings suggest that parents perceive a wide range of barriers that influence the likelihood that they will seek professional advice for infant sleep. RELEVANCE TO CLINICAL PRACTICE: Reducing knowledge barriers and providing adequate attention at all well-infant visits would facilitate parental use of healthcare services to manage problematic infant sleep behaviours. PMID- 28881074 TI - Hospital passports, patient safety and person-centred care: A review of documents currently used for people with intellectual disabilities in the UK. AB - AIMS AND OBJECTIVES: To review hospital passports currently in use for people with intellectual disabilities in the UK and to make recommendations for practice. BACKGROUND: Hospital passports have been introduced internationally to address communication barriers that may limit access to appropriate health care for people with intellectual disabilities. They are viewed as promoting patient safety and person-centred care but their format may vary, they are not always used appropriately, and hence, their effectiveness may be limited. DESIGN: Qualitative content analysis. METHODS: Sixty hospital passports in use in the UK were reviewed against a coding frame by two members of the research team. Areas of interest included key patient and primary care information, support network details, consent and capacity, support required in relation to activities of daily living, length of the document and completion details. Results were entered into Excel. RESULTS: Considerable variation was found between documents in terms of terminology, length and format. Most included information regarding communication and support needs although some omitted important information such as allergies, risk assessment and need for reasonable adjustments. CONCLUSIONS: Considerable variation exists between current hospital passports, which may limit their effectiveness: key information required may not be included and/or it may not be easy to locate. Greater standardisation of documents is required, but this process should include input from all key stakeholders. RELEVANCE TO CLINICAL PRACTICE: Internationally nurses provide care for people with intellectual disabilities and others with communication difficulties. Hospital passports are one way of enhancing safety and person-centred care, need to be accessed and used as a basis for care planning. However, variation in format may limit this effectiveness and nurses should work with others to develop a more standardised approach, which better meets the needs of all stakeholders. PMID- 28881075 TI - Formation of Methane versus Benzene in the Reactions of (C5 Me5 )2 Th(CH3 )2 with [CH3 PPh3 ]X (X=Cl, Br, I) Yielding Thorium-Carbene or Thorium-Ylide Complexes. AB - The reaction of (C5 Me5 )2 Th(CH3 )2 with the phosphonium salts [CH3 PPh3 ]X (X=Cl, Br, I) was investigated. When X=Br and I, two equivalents of methane are liberated to afford (C5 Me5 )2 Th[CHPPh3 ]X, rare terminal phosphorano-stabilized carbenes with thorium. These complexes feature the shortest thorium-carbon bonds (~2.30 A) reported to date, and electronic structure calculations show some degree of multiple bonding. However, when X=Cl, only one equivalent of methane is lost with concomitant formation of benzene from an unstable phosphorus(V) intermediate, yielding (C5 Me5 )2 Th[kappa2 -(C,C')-(CH2 )(CH2 )PPh2 ]Cl. Density functional theory (DFT) investigations of the reaction energy profiles for [CH3 PPh3 ]X, X=Cl and I showed that in the case of iodide, thermodynamics prevents the production of benzene and favors formation of the carbene. PMID- 28881076 TI - The relationship between psychiatric patients' caregiver burden and anger expression styles. AB - AIMS AND OBJECTIVES: To examine the relationship between psychiatric patients' caregiver burden and anger expression styles. BACKGROUND: In the caregiving process, when coping with problems, caregivers may exhibit emotional and behavioural responses, which can produce distressful results. One of these responses is angry. Examining the relationship between psychiatric patients' caregiver burden and caregivers' anger expression styles is necessary for quality of care. DESIGN: A descriptive and relational study. METHODS: The sample for study included 60 family caregivers who were stayed with patient in psychiatry clinic during the treatment of inpatient setting of a university hospital. Data for the study were collected using the Caregiver Burden Inventory and the Trait Anger and Anger Expression Scale. The analysis of variance, Mann-Whitney U test, Kruskal-Wallis and Pearson correlation analysis were used. RESULTS: The caregivers' Caregiver Burden Inventory score was found to be 24.60 +/- 1.57. Gender, working status, level of intimacy with patient, status of whether or not caregiver was living with patient and status of whether or not caregiver experienced difficulties in providing care had a significant effect on the Caregiver Burden Inventory scale as a whole, as well as its subscales. This study found a positive relationship between caregiver burden and caregivers' anger expression styles (p < .05, p < .01). CONCLUSION: The total Caregiver Burden Inventory mean score of caregivers was concluded to be low, with some introductory characteristics and anger expression styles having an impact on the burden experienced by caregivers. RELEVANCE TO CLINICAL PRACTICE: Knowing the anger expression styles of caregivers is important for reducing caregiver burden and improving quality of care. PMID- 28881077 TI - Development of a rapid risk evaluation tool for herbs/drugs interactions in cancer patients: a multicentric experience in south of France. AB - Cancer patients use herbs in spite of severe interactions risks with major anticancer drugs. In daily practice, it is very difficult for oncologists to detect and define the risk of a herb-anticancer drug interaction (HDI). In this work, we realised a state of play in one of the most populated region of France by evaluating, through a specific questionnaire, the position of a representative panel of oncologists. About 80% of them thought that herbs interact with anticancer treatments whereas only 15.4% of them actually knew the real HDI. About 89.1% of them thought that a practical detection tool would be relevant and useful for their daily practice. Then, we constructed a tool in order to rapidly evaluate a HDI risk level. Based on experts' reviews and using a criticality matrix, we determined the HDI risk level between 11 herbs and 126 anticancer drugs. Then, we measured satisfactory of oncologists. All of them considered the tool as useful in their daily practice and then used it. This work highlighted that even if HDI has been integrated as a theoretical risk, its practical detection and risk evaluation is difficult to implement for oncologists in their daily practice. Thus, the tool we developed should answer to an unmet medical need. PMID- 28881078 TI - Effects of nurse-led clinical pathway in coronary artery bypass graft surgery: A quasi-experimental study. AB - AIMS AND OBJECTIVES: To develop and evaluate the effects of a nurse-led clinical pathway for patients undergoing coronary artery bypass graft surgery. BACKGROUND: A clinical pathway is a multidisciplinary care plan, based on evidence and guidelines to provide consistent, quality care to patients and improve outcomes. DESIGN: Prospective, quasi-experimental design. METHODS: Patients hospitalised for coronary artery bypass graft between April 2014-November 2015 in a hospital in Turkey were studied. First 42 usual care patients were enrolled to determine outcomes and plan for the development of the clinical pathway followed by 40 patients in the newly developed clinical pathway. The primary outcome was length of stay and secondary outcomes related to recovery from surgery (e.g., time to extubation, first feeding). RESULTS: The mean age for the clinical pathway group was 60 and for usual care was 63 years. Most were male (CP = 78%, UC = 69%). There were significant differences between groups for the primary outcome. Length of stay in the intensive care unit was 38.9 hr for CP and 50.7 hr for usual care patients p < .01. Total hospital time was 144.4 hr for clinical pathway and 162.2 hr for usual care, p < .05. For secondary measures, the following times were less for the clinical pathway group than for the usual care: time to extubation and nasogastric tube removal (5.7 vs. 8.6 hr, p < .01), first oral feeding (4.7 vs. 10.9 hr, p < .001), first mobilisation (8.4 vs. 22.9 hr, p < .001) and first bowel movement (69.8 vs. 85.9 hr, p < .01). There were no statistically significant differences in the 3-month readmission rates and complication rates between the groups, except the renal complication rates were higher in the usual care (n = 16, 38%) than in the clinical pathway (n = 7, 17.5%) (p < .05). CONCLUSION: The nurse-led clinical pathway was effective in improving length of stay in both the ICU and hospital as well as the secondary outcomes. RELEVANCE TO CLINICAL PRACTICE: This study contributes to previous studies supporting clinical pathway use can improve the length of stay and quality of care in patients undergoing coronary artery bypass graft surgery. PMID- 28881079 TI - Formyl Peptide Receptors in Mice and Men: Similarities and Differences in Recognition of Conventional Ligands and Modulating Lipopeptides. AB - The pattern recognition formyl peptide receptors (FPRs) belong to the class of G protein-coupled receptors (GPCRs), the largest group of cell surface receptors involved in a range of physiological processes and pathologies. The FPRs have regulatory function in the initiation as well as resolution of inflammatory reactions, making them highly interesting as targets for drug development. Recent research in the GPCR/FPR fields has uncovered novel receptor biology concepts, including biased signalling/functional selectivity, allosteric modulation, receptor reactivation and receptor cross-talk. When it comes to allosteric modulators, 'tailor-made' lipopeptides (pepducins and lipopeptoids) represent a novel concept of GPCR/FPR regulation. This MiniReview is focused on the basis for recognition of conventional ligands and immunomodulating lipopeptides, novel allosteric modulators for the FPRs, receptors that are highly expressed by both human and mouse neutrophils. The FPRs play key roles in host defence against microbial infections, tissue homeostasis and the initiation as well as resolution of inflammation but there are both similarities and differences in ligand recognition between mice and men. Thus, identification and functional characterization of activating and inhibiting ligands should provide insights into future design of FPR-based animal models of human diseases and development of therapeutics for treating inflammatory diseases. PMID- 28881082 TI - Molecular characterisation of the broad-spectrum resistance to powdery mildew conferred by the Stpk-V gene from the wild species Haynaldia villosa. AB - A key member of the Pm21 resistance gene locus, Stpk-V, derived from Haynaldia villosa, was shown to confer broad-spectrum resistance to wheat powdery mildew. The present study was planned to investigate the resistance mechanism mediated by Stpk-V. Transcriptome analysis was performed in Stpk-V transgenic plants and recipient Yangmai158 upon Bgt infection, and detailed histochemical observations were conducted. Chromosome location of Stpk-V orthologous genes in Triticeae species was conducted for evolutionary study and over-expression of Stpk-V both in barley and Arabidopsis was performed for functional study. The transcriptome results indicate, at the early infection stage, the ROS pathway, JA pathway and some PR proteins associated with the SA pathway were activated in both the resistant Stpk-V transgenic plants and susceptible Yangmai158. However, at the later infection stage, the genes up-regulated at the early stage were continuously held only in the transgenic plants, and a large number of new genes were also activated in the transgenic plants but not in Yangmai158. Results indicate that sustained activation of the early response genes combined with later-activated genes mediated by Stpk-V is critical for resistance in Stpk-V transgenic plants. Stpk-V orthologous genes in the representative grass species are all located on homologous group six chromosomes, indicating that Stpk-V is an ancient gene in the grasses. Over-expression of Stpk-V enhanced host resistance to powdery mildew in barley but not in Arabidopsis. Our results enable a better understanding of the resistance mechanism mediated by Stpk-V, and establish a solid foundation for its use in cereal breeding as a gene resource. PMID- 28881083 TI - Transcriptome analysis, using RNA-Seq of Lomandra longifolia roots infected with Phytophthora cinnamomi reveals the complexity of the resistance response. AB - The plant pathogen Phytophthora cinnamon the causal agent of disease in numerous species, is a major threat to natural vegetation and has economic impacts in agriculture. The pathogen principally invades the root system, which, in susceptible species, is rapidly colonised and functionally destroyed. Few species are resistant, however, where resistance is expressed the pathogen is restricted to small, localised lesions. The molecular mechanisms that underpin this response in resistant species are not well understood. Lomandra longifolia, an Australian native species, is highly resistant to P. cinnamomi. In an earlier study, we showed induction of resistance-related components such as callose, lignin and hydrogen peroxide (H2 O2 ) in L. longifolia roots that had been inoculated with P. cinnamomi. Here, in order to further identify, during the very early stages of infection, the molecular components and regulatory networks that may trigger resistance, a comprehensive root transcriptome analysis was performed using next generation sequencing. Overall, 18 cDNA libraries were produced generating 52.8 GB 126 base pair reads, which were de novo assembled into contigs. Differentially expressed genes (DEGs) were identified allowing the identification of infection responsive candidate genes that were putatively related to resistance, and from this set ten were selected for qRT-PCR to validate the RNA-Seq expression value. Further analysis of individual candidates revealed that many were involved in PAMP-triggered immunity (PTI; pattern recognition receptors, glutathione S transferase, callose synthases, pathogenesis-related protein-1, mitogen activated protein kinases) and effector-triggered immunity (ETI) (NBS-LRR, signalling genes, transcription factors and anti-pathogenic compound synthase genes). As these candidate genes or mediated components activate different defence signalling systems, they may have potential for investigation of novel approaches to disease control and in transgenic approaches for improvement, in susceptible species, of resistance to P. cinnamomi. PMID- 28881081 TI - A genetically inducible porcine model of intestinal cancer. AB - Transgenic porcine cancer models bring novel possibilities for research. Their physical similarities with humans enable the use of surgical procedures and treatment approaches used for patients, which facilitates clinical translation. Here, we aimed to develop an inducible oncopig model of intestinal cancer. Transgenic (TG) minipigs were generated using somatic cell nuclear transfer by handmade cloning. The pigs encode two TG cassettes: (a) an Flp recombinase inducible oncogene cassette containing KRAS-G12D, cMYC, SV40LT - which inhibits p53 - and pRB and (b) a 4-hydroxytamoxifen (4-OHT)-inducible Flp recombinase activator cassette controlled by the intestinal epithelium-specific villin promoter. Thirteen viable transgenic minipigs were born. The ability of 4-OHT to activate the oncogene cassette was confirmed in vitro in TG colonic organoids and ex vivo in tissue biopsies obtained by colonoscopy. In order to provide proof of principle that the oncogene cassette could also successfully be activated in vivo, three pigs were perorally treated with 400 mg tamoxifen for 2 * 5 days. After two months, one pig developed a duodenal neuroendocrine carcinoma with a lymph node metastasis. Molecular analysis of the carcinoma and metastasis confirmed activation of the oncogene cassette. No tumor formation was observed in untreated TG pigs or in the remaining two treated pigs. The latter indicates that tamoxifen delivery can probably be improved. In summary, we have generated a novel inducible oncopig model of intestinal cancer, which has the ability to form metastatic disease already two months after induction. The model may be helpful in bridging the gap between basic research and clinical usage. It opens new venues for longitudinal studies of tumor development and evolution, for preclinical assessment of new anticancer regimens, for pharmacology and toxicology assessments, as well as for studies into biological mechanisms of tumor formation and metastasis. PMID- 28881084 TI - A Ferroelectric Iron(II) Spin Crossover Material. AB - A dual-function material in which ferroelectricity and spin crossover coexist in the same temperature range has been obtained. Our synthetic strategy allows the construction of acentric crystal structures in a predictable way and is based on the high directionality of hydrogen bonds. The well-known iron(II) spin crossover complex [Fe(bpp)2 ]2+ (bpp=2,6-bis(pyrazol-3-yl)pyridine), a four-fold noncentrosymmetric H-bond donor, was combined with a disymmetric H-bond acceptor such as the isonicotinate (isonic) anion to afford [Fe(bpp)2 ](isonic)2 ?2 H2 O. This low-spin iron(II) compound crystallizes in the acentric nonpolar I4? space group and shows piezoelectricity and SHG properties. Upon dehydration, it undergoes a single-crystal to single-crystal structural rearrangement to a monoclinic polar Pc phase that is ferroelectric and exhibits spin crossover. PMID- 28881085 TI - Analysis of the Catalytic Mechanism of Bifunctional Triterpene/Sesquarterpene Cyclase: Tyr167 Functions To Terminate Cyclization of Squalene at the Bicyclic Step. AB - Onoceroids are a group of triterpenes biosynthesized from squalene or dioxidosqualene by cyclization from both termini. We previously identified a bifunctional triterpene/sesquarterpene cyclase (TC) that constructs a tetracyclic scaffold from tetraprenyl-beta-curcumene (C35 ) but a bicyclic scaffold from squalene (C30 ) in the first reaction. TC also accepts the bicyclic intermediate as a substrate and generates tetracyclic and pentacyclic onoceroids in the second reaction. In this study, we analyzed the catalytic mechanism of an onoceroid synthase by using mutated enzymes. TCY167A produced an unnatural tricyclic triterpenol, but TCY167L , TCY167F , and TCY167W formed small quantities of tricyclic compounds, which suggested that the bulk size at Y167 contributed to termination of the cyclization of squalene at the bicyclic step. Our findings provide insight into the unique catalytic mechanism of TC, which triggers different cyclization modes depending on the substrate. These findings may facilitate the large-scale production of an onoceroid for which natural sources are limited. PMID- 28881086 TI - Investigation on the Interface Modification of TiO2 Surfaces by Functional Co Adsorbents for High-Efficiency Dye-Sensitized Solar Cells. AB - The influence of interface modification of sensitized TiO2 surfaces by co adsorbents on photovoltaic performance is detailed. We investigated different functional groups of co-adsorbents, such as carboxylic (4-guanidino butyric acid, chenodeoxycholic acid), phosphinic (dineohexyl phosphinic acid), and phosphonic (dodecyl phosphonic acid), to better highlight their influence on the device performance and accurately classify them into de-aggregating agents or agents with both de-aggregating and co-adsorbing properties. By optimizing the type of co-adsorbent and its concentration in the dye solution, we reached an efficiency of 11.0 % using 4-guanidino butyric acid or dineohexyl phosphinic acid, compared to 10.6 % when the benchmark chenodeoxycholic acid was used. The presence of co adsorbents on the TiO2 surface was studied using ATR-FTIR spectroscopy. The role of these co-adsorbents on the band edge shift versus the recombination resistance is discussed. PMID- 28881087 TI - Organometallic DNA-B12 Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin-Transport Proteins. AB - The synthesis and structural characterization of Co-(dN)25 -Cbl (Cbl: cobalamin; dN: deoxynucleotide) and Co-(dN)39 -Cbl, which are organometallic DNA-B12 conjugates with single DNA strands consisting of 25 and 39 deoxynucleotides, respectively, and binding studies of these two DNA-Cbl conjugates to three homologous human Cbl transporting proteins, transcobalamin (TC), intrinsic factor (IF), and haptocorrin (HC), are reported. This investigation tests the suitability of such DNA-Cbls for the task of eventual in vivo oligonucleotide delivery. The binding of DNA-Cbl to TC, IF, and HC was investigated in competition with either a fluorescent Cbl derivative and Co-(dN)25 -Cbl, or radiolabeled vitamin B12 (57 Co-CNCbl) and Co-(dN)25 -Cbl or Co-(dN)39 -Cbl. Binding of the new DNA-Cbl conjugates was fast and tight with TC, but poorer with HC and IF, which extends a similar original finding with the simpler DNA-Cbl, Co (dN)18 -Cbl. The contrasting affinities of TC versus IF and HC for the DNA-Cbl conjugates are rationalized herein by a stepwise mechanism of Cbl binding. Critical contributions to overall affinity result from gradual conformational adaptations of the Cbl-binding proteins to the DNA-Cbl, which is first bound to the respective beta domains. This transition is fast with TC, but slow with IF and HC, with which weaker binding results. The invariably tight interaction of the DNA-Cbl conjugates with TC makes the Cbl moiety a potential natural vector for the specific delivery of oligonucleotide loads from the blood into cells. PMID- 28881088 TI - Ectopic thyroid cancer diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration. AB - We report a case of papillary carcinoma in a mediastinal ectopic thyroid diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). In this case, the tumor was adjacent to the central airway; therefore, we attempted to perform EBUS-TBNA to obtain specimens for a diagnosis of papillary thyroid carcinoma. Surgical resection was conducted, and histological evaluation of the resected specimen confirmed ectopic papillary thyroid carcinoma, consistent with the histology from the EBUS-TBNA specimen. As a safe and minimally invasive procedure, EBUS-TBNA may be considered for the diagnosis of mediastinal lesions, including papillary carcinoma in mediastinal ectopic thyroid. PMID- 28881089 TI - Intra- versus Intermolecular Hydrogen Bonding: Solvent-Dependent Conformational Preferences of a Common Supramolecular Binding Motif from 1 H NMR and Vibrational Circular Dichroism Spectra. AB - When predicting binding properties of small molecules or larger supramolecular aggregates, intra- and intermolecular hydrogen bonds are often considered the most important factor. Spectroscopic techniques such as 1 H NMR spectroscopy are typically utilized to characterize such binding events, but interpretation is often qualitative and follows chemical intuition. In this study, we compare the effects of intramolecular hydrogen bonding and solvation on two chiral 2,6 pyridinediyl-dialkylamides. In comparison with 1 H NMR spectroscopy, vibrational circular dichroism (VCD) spectroscopy proved to be more sensitive to conformational changes. In fact, the change of the solvent from CDCl3 to [D6 ]DMSO generates mirror-image VCD spectra for the same enantiomer. Here, the common sense that the sterically less hindered group is more prone to solvation proved to be wrong according predicted VCD spectra, which clearly show that both asymmetric amide hydrogens are equally likely to be solvated, but never simultaneously. The competition between intra- and intermolecular hydrogen bonding and their importance for a correct prediction of spectral properties are discussed. PMID- 28881090 TI - An activity transition from NADH dehydrogenase to NADH oxidase during protein denaturation. AB - A decrease in the specific activity of an enzyme is commonly observed when the enzyme is inappropriately handled or is stored over an extended period. Here, we reported a functional transition of an FMN-bound diaphorase (FMN-DI) that happened during the long-term storage process. It was found that FMN-DI did not simply lose its beta-nicotinamide adenine diphosphate (NADH) dehydrogenase activity after a long-time storage, but obtained a new enzyme activity of NADH oxidase. Further mechanistic studies suggested that the alteration of the binding strength of an FMN cofactor with a DI protein could be responsible for this functional switch of the enzyme. PMID- 28881092 TI - Improved Electrochemical Cycling Durability in a Nickel Oxide Double-Layered Film. AB - For the first time, a crystalline-amorphous double-layered NiOx film has been prepared by reactive radio frequency magnetron sputtering. This film has exhibited improved electrochemical cycling durability, whereas other electrochromic parameters have been maintained at the required level, namely, a short coloration/bleaching time (0.8 s/1.1 s) and an enhanced transmittance modulation range (62.2 %) at lambda=550 nm. Additionally, the double-layered film has shown better reversibility than that of amorphous and crystalline single layered films. PMID- 28881091 TI - Poor recovery from cystic fibrosis pulmonary exacerbations is associated with poor long-term outcomes. AB - RATIONALE: People with CF treated with IV antibiotics for a pulmonary exacerbation (PEx) frequently fail to recover to baseline FEV1 . The long-term impact of these events has not been studied. OBJECTIVES: To determine if a patient's spirometric recovery after a PEx is associated with time to next PEx within 1 year, the spirometric recovery after the next PEx, and/or the number of PEx episodes in the next 3 years. METHODS: We used data from the CF Foundation Patient Registry from 2004 to 2011. We randomly selected one PEx per patient that met inclusion/exclusion criteria. Patients were defined as Non-Responders if their best FEV1 (in liters) recorded in the 3 months after the PEx was <90% of the best FEV1 (in liters) in the 6 months before the PEx. We compared Responders and Non-Responders using multivariable regression models. RESULTS: We randomly chose 13 954 PEx episodes that met inclusion/exclusion criteria. A total of 2 762 (19.8%) patients were classified as Non-Responders. Non-Responders had a shorter median time to the next PEx, 235 (95%CI 218, 252) days, versus >365 days for Responders. Thirty-four percent of Non-Responders at the initial PEx were also Non-Reponders at the next PEx, versus 20% of Responders at the initial PEx. Non Responders had more PEx episodes over the next 3 years, 4.99 (95%CI 4.84, 5.13), than Responders, 3.46 (95%CI 3.41, 3.51). CONCLUSIONS: Poor recovery after a PEx is associated with a shorter time to the next PEx, increased risk of poor recovery at a second PEx, and more frequent subsequent PEx treatments. PMID- 28881093 TI - Expansion of Bone Marrow Mesenchymal Stromal Cells in Perfused 3D Ceramic Scaffolds Enhances In Vivo Bone Formation. AB - Bone marrow-derived mesenchymal stromal cells (BMSC), when expanded directly within 3D ceramic scaffolds in perfusion bioreactors, more reproducibly form bone when implanted in vivo as compared to conventional expansion on 2D polystyrene dishes/flasks. Since the bioreactor-based expansion on 3D ceramic scaffolds encompasses multiple aspects that are inherently different from expansion on 2D polystyrene, we aimed to decouple the effects of specific parameters among these two model systems. We assessed the effects of the: 1) 3D scaffold vs. 2D surface; 2) ceramic vs. polystyrene materials; and 3) BMSC niche established within the ceramic pores during in vitro culture, on subsequent in vivo bone formation. While BMSC expanded on 3D polystyrene scaffolds in the bioreactor could maintain their in vivo osteogenic potential, results were similar as BMSC expanded in monolayer on 2D polystyrene, suggesting little influence of the scaffold 3D environment. Bone formation was most reproducible when BMSC are expanded on 3D ceramic, highlighting the influence of the ceramic substrate. The presence of a pre-formed niche within the scaffold pores had negligible effects on the in vivo bone formation. The results of this study allow a greater understanding of the parameters required for perfusion bioreactor-based manufacturing of osteogenic grafts for clinical applications. PMID- 28881094 TI - Nontuberculous mycobacteria in cystic fibrosis: Updates and the path forward. AB - Nontuberculous mycobacteria (NTM) are troublesome pathogens that can cause significant pulmonary disease in patients with cystic fibrosis (CF). Diagnosis can be difficult in the setting of underlying CF and treatment regimens are burdensome on both patients and providers. Recent consensus guidelines for treatment of NTM in CF have provided a guide for the CF community, however research is lagging regarding accuracy of our diagnostic abilities and treatment efficacy. In this review, we provide new insights into the complexity of NTM from emerging whole genome sequencing data, a summary of current NTM diagnosis and treatment guidelines, highlight new treatment options, and discuss future research projects which aim to better define which patients to treat and timing and duration of treatment. PMID- 28881095 TI - Albumin-Assisted Method Allows Assessment of Release of Hydrophobic Drugs From Nanocarriers. AB - Polymeric nanoparticles have been extensively studied as drug delivery vehicles both in vitro and in vivo for the last two decades. In vitro methods to assess drug release profiles usually utilize degradation of nanoparticles in aqueous medium, followed by the measurement of the concentration of the released drug. This method, however, is difficult to use for drugs that are poorly water soluble. In this study, a protocol for measuring drug release kinetic using albumin solution as the medium is described. Albumin is a major blood transport protein, which mediates transport of many lipid soluble compounds including fatty acids, hormones, and bilirubin. The use of a dialysis-based system utilizing albumin dialysate solution allows hydrophobic drug release from a diverse set of drug delivery modalities is demonstrated. The method using liposomes and PLGA nanoparticles as drug carriers, and two model hydrophobic drugs, 17beta estradiol, and dexamethasone is validated. PMID- 28881096 TI - Integrated Chromatographic Platform for Simultaneous Separation of Charge Variants and Aggregates from Monoclonal Antibody Therapeutic Products. AB - Achieving consistent product quality of a biotherapeutic is a major target for any biopharmaceutical manufacturer, even more for a biosimilar producer as comparability with the innovator product is a regulatory expectation. The complexity of biotherapeutic products and their tedious manufacturing processes, however, make this a non-trivial exercise. The primary motivation of this work is to develop an integrated chromatographic platform for purification of monoclonal antibody (mAb) therapeutics that can deliver the desired separation of both charge variants and aggregates, in addition to the process related impurities like host cell proteins (HCP) and host cell DNA. To achieve the same, an integrated two-stage chromatographic process platform consisting of cation exchange chromatography and multimodal chromatography is being proposed. The versatility of the proposed platform has been successfully demonstrated for three different mAbs. It have been shown that in each case charge variant separation is achieved with the required clearance of aggregates (<1%), HCP (<10 ppm), and DNA (<5 ppb). Moreover, the proposed platform is conducive to use for development of a continuous process and offers smaller process time, lower buffer utilization, and decreased operational costs when compared to the conventional purification platforms. PMID- 28881098 TI - Identification and Engineering of Post-PKS Modification Bottlenecks for Ansamitocin P-3 Titer Improvement in Actinosynnema pretiosum subsp. pretiosum ATCC 31280. AB - The type-I polyketide ansamitocin P-3 (AP-3) is a potent antitumor agent. Its production is most likely hampered by the required multiple substrate supplies and complicated post-PKS modifications in Actinosynnema pretiosum subsp. pretiosum ATCC 31280. For titer improvement, gene ansa30, encoding for a glycosyltransferase competing for the N-demethyl-AP-3 (PND-3) intermediate for AP 3 biosynthesis, was initially inactivated. In the mutant NXJ-22, the AP-3 titer was increased by 66% along with an obvious accumulation of PND-3, indicating that the N-methylation is a rate-limiting step. Alternatively, when abundant upstream intermediate 19-chloroproansamitocin was fed into a PKS mutant, 3-O-acylation was further identified along with the N-methylation as the rate-limiting steps. Subsequent overexpression of N-methyltransferase gene asm10 in NXJ-22 resulted in a 93% increase of AP-3 and a corresponding 92% decrease of PND-3. Additional supplementation of L-methionine, the precursor for SAM biosynthesis, substantially decreased the accumulation of PND-3. In parallel, the 3-O-acylation bottleneck was relieved by feeding with L-valine to NXJ-22, resulting in a 126% increase of AP-3. Eventually, a combined asm10 overexpression and supplementation of L-methionine and L-valine resulted in a 5-fold increase of AP-3, from 42 +/- 2 mg L-1 to 246 +/- 6 mg L-1 , without any noticeable accumulation of PND-3. PMID- 28881099 TI - Renal-protective and ameliorating impacts of omega-3 fatty acids against aspartame damaged MDCK cells. AB - Aspartame is widely used artificial sweeteners as food additives. Several researchers have pointed that the controversial report on the use of aspartame over more than decades. Omega-3 fatty acids are essential and unsaturated fatty acids, and it plays a remarkable role in vision, intelligence, neural development, and metabolism of neurotransmitters. Therefore, the present study was aimed to investigate the effect of omega-3 fatty acids on aspartame treated renal cells. Experimental groups were divided into three such as sham control, aspartame treated, and aspartame with omega-3 fatty acids. Cell viability was determined by sulforhodamine-b assay and flow cytometric analysis. The experimental results showed that the aspartame induced altered cell viability were reduced following treatment of aspartame with omega-3 fatty acids. Altered cell morphology was recovered by omega-3 fatty acids. DNA damage appeared in the highest concentration of aspartame used in this study. DNA damage characteristics such as comet tail and tiny head sections did not appear in the omega-3 fatty acids treated cells. Several microvilli and vesicular structures were found in aspartame treated cells. Altered morphology such as rounding, microvilli, and formation of dome-like structures did not appear in the omega-3 fatty acids with aspartame treated cells. Caspase-3 mRNA and protein expression were increased in aspartame treated cells, and these levels were reduced following omega-3 fatty acids treatment. Taking all these data together, it is suggested that the omega-3 fatty acids may be a therapeutic agent to reduce the aspartame induced biochemical and morphological alterations in normal renal cells. (c) 2017 BioFactors, 43(6):847-857, 2017. PMID- 28881101 TI - Nasal high-frequency oscillatory ventilation impairs heated humidification: A neonatal bench study. AB - OBJECTIVE: Nasal high-frequency oscillatory ventilation (nHFOV) is a novel mode of non-invasive ventilation used in neonates. However, upper airway obstructions due to viscous secretions have been described as specific adverse effects. We hypothesized that high-frequency oscillations reduce air humidity in the oropharynx, resulting in upper airway desiccation. Therefore, we aimed to investigate the effects of nHFOV ventilatory settings on oropharyngeal gas conditions. METHODS: NHFOV or nasal continuous positive airway pressure (nCPAP) was applied, along with heated humidification, to a previously established neonatal bench model that simulates oropharyngeal gas conditions during spontaneous breathing through an open mouth. A digital thermo-hygro sensor measured oropharyngeal temperature (T) and humidity at various nHFOV frequencies (7, 10, 13 Hz), amplitudes (10, 20, 30 cmH2 O), and inspiratory-to-expiratory (I:E) ratios (25:75, 33:66, 50:50), and also during nCPAP. RESULTS: Relative humidity was always >99%, but nHFOV resulted in lower mean T and absolute humidity (AH) in comparison to nCPAP (P < 0.001). Specifically, decreasing the nHFOV frequency and increasing nHFOV amplitude caused a decline in T and AH (P < 0.001). Mean T and AH were highest during nCPAP (T 34.8 +/- 0.6 degrees C, AH 39.3 +/- 1.3 g . m-3 ) and lowest during nHFOV at a frequency of 7 Hz and an amplitude of 30 cmH2 O (T 32.4 +/- 0.3 degrees C, AH 34.7 +/- 0.5 g . m-3 ). Increasing the I:E ratio also reduced T and AH (P = 0.03). CONCLUSION: Intensified nHFOV settings with low frequencies, high amplitudes, and high I:E ratios may place infants at an increased risk of upper airway desiccation. Future studies should investigate strategies to optimize heated humidification during nHFOV. PMID- 28881097 TI - Toward inclusive therapy with CFTR modulators: Progress and challenges. AB - Cystic fibrosis is caused by gene mutations that result in an abnormal Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein on the surface of cells. CFTR modulators are a novel class of drugs that directly target the molecular defect. CFTR modulators include potentiators that result in improved activity of the channel; correctors that help the protein traffic to the cell surface properly; and readthrough agents that restore full-length CFTR by suppression of premature termination codons, among other novel classes more recently established. While some of these drugs, CFTR potentiators in particular, have provided remarkable improvements for CF patients, others have yet to achieve profoundly improved outcomes, and many CF patients are not yet impacted by CFTR modulators due to lack of knowledge regarding susceptibility of their mutations to treatment. One limitation to expanding these types of therapies to the maximum number of patients with CF is the lack of rigorously validated clinical biomarkers that can determine efficacy on an individual basis, as well as few pre clinical tools that can predict whether an individual with a rare combination of mutant alleles will respond to a particular CFTR modulator regimen. In this review, we discuss the various groups of CFTR modulators and their status in clinical development, as well as address the current literature on biomarkers, pre-clinical cell-based tools, and the role of pharmacometrics in creating therapeutic strategies to improve the lives of all patients with cystic fibrosis, regardless of their specific mutation. PMID- 28881100 TI - An Engineered Glycerol Dehydratase With Improved Activity for the Conversion of meso-2,3-butanediol to Butanone. AB - There is substantial interest in engineering microorganisms to produce industrial chemicals that are currently derived from petroleum. One of these petrochemicals is butanone, which could be produced from microbially synthesized 2,3-butanediol through the action of a suitable dehydratase enzyme. Unfortunately, however, there are no known enzymes that natively catalyze this reaction. In this work, the authors set out to engineer the B12 -dependent glycerol dehydratase from Klebsiella pneumoniae (KpGDHt), in order to increase its activity for the conversion of meso-2,3-butanediol into butanone. The authors began by fusing the alpha and beta subunits of the enzyme, to simplify downstream high-throughput screening protocols. Serendipitously, the fusion protein showed a 20 degrees C increase in its temperature optimum. Using this stabilized scaffold as a starting point, the authors employed the combinatorial active site saturation test and consensus-guided mutagenesis to randomize 28 residues within 12 A of the KpGDHt active site. By screening over 5500 variants, the authors discovered a single point mutation (T200S) that increased the catalytic efficiency of meso-2,3 butanediol dehydration by four-fold, to a value of kcat /KM = 5.1 * 103 M-1 s-1 . Thus the authors report what is, to date, the most comprehensive mutagenesis and the largest engineered increase in catalytic efficiency on the B12 -dependent glycerol dehydratase scaffold. PMID- 28881102 TI - Living with schizophrenia: Health-related quality of life among primary family caregivers. AB - AIMS AND OBJECTIVES: To examine influencing factors of health-related quality of life in primary family caregivers of people with schizophrenia receiving inpatient psychiatric rehabilitation services. BACKGROUND: Families, particularly primary family caregivers, have become more important than ever in mental health care. Yet, research on health-related quality of life among primarily family caregivers is limited. DESIGN: A correlational study design was used. METHODS: A convenience sample of 122 primary family caregivers participated in the study. Data were analysed with descriptive statistics, Pearson's product-moment correlation, t test, one-way analysis of variance and a hierarchical multiple regression analysis. RESULTS: Primary family caregivers who were parents, older, less educated, and had a lower monthly household income, increased affiliate stigma and decreased quality of family-centred care experienced poor health related quality of life. Particularly, monthly household income, affiliate stigma and quality of family-centred care appeared to be the most critical determinants of health-related quality of life. CONCLUSIONS: Efforts to enhance satisfaction of life should focus on reducing affiliate stigma as well as increasing monthly household income and strengthening the quality of family-centred care. RELEVANCE TO CLINICAL PRACTICE: Findings may assist in the development of culturally integrated rehabilitation programmes to decrease affiliate stigma and increase family engagement as a means of promoting quality of life for primary family caregivers living with people who have schizophrenia. PMID- 28881103 TI - HLA polymorphisms and risk of red blood cell alloimmunisation in polytransfused patients with sickle cell anaemia. AB - BACKGROUND: Red blood cell (RBC) alloimmunisation is an event that may occur due to factors such as numerous blood transfusions, age, gender and genetic factors such as human leukocyte antigen (HLA). AIMS/OBJECTIVES: The aim of the present study was to investigate the possibility of alloimmunisation to red blood cell group antigens associated with the HLA of individuals and to relate alloimmunisation to risk factors. METHODS: A total of 172 polytransfused patients with sickle cell anaemia (SCA) (44 alloimmunised, 128 non-alloimmunised) participated in this study. Blood group genotyping was performed by the DNA microarray method and HLA genotyping by polymerase chain reaction - specific sequence of oligonucleotides. RESULTS: The number of transfusions received directly influenced the incidence of alloimmunisation, and the most common alloantibodies were against Rh (48.8%) and Kell (17%) systems. The HLA-C*06 and HLA-DQB1*03 variants were significantly higher in alloimmunised patients. The HLA DRB1*04 and HLA-DRB1*11 were more often found in individuals who developed the alloantibodies anti-Fya and anti-K, respectively. CONCLUSION: This study suggests that polytransfused patients with SCA possessing the HLA-DQB1*03 and HLA-C*06 allele variants are more susceptible to alloimmunisation. In addition, HLA DRB1*04 and HLA-DRB1*11 alleles were seen to be associated with the production of anti-Fya and anti-K antibodies, respectively. PMID- 28881104 TI - Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint. AB - Blockade of the immunoinhibitory PD-1/PD-L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have now been approved for the treatment of a number of tumor types, whereas the development of small molecules targeting immune checkpoints lags far behind. We characterized two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclic compounds act by directly binding to PD-L1 and that they are capable of antagonizing PD-L1 signaling and, similarly to antibodies, can restore the function of T-cells. We also provide the crystal structures of two of these small molecule inhibitors bound to PD-L1. The structures provide a rationale for the checkpoint inhibition by these small molecules, and a description of their small molecule/PD-L1 interfaces provides a blueprint for the design of small-molecule inhibitors of the PD-1/PD-L1 pathway. PMID- 28881105 TI - Decision aid use during post-biopsy consultations for localized prostate cancer. AB - BACKGROUND: Decision Aids (DAs) effectively translate medical evidence for patients but are not routinely used in clinical practice. Little is known about how DAs are used during patient-clinician encounters. OBJECTIVE: To characterize the content and communicative function of high-quality DAs during diagnostic clinic visits for prostate cancer. PARTICIPANTS: 252 men newly diagnosed with localized prostate cancer who had received a DA, 45 treating physicians at 4 US Veterans Administration urology clinics. METHODS: Qualitative analysis of transcribed audio recordings was used to inductively develop categories capturing content and function of all direct references to DAs (booklet talk). The presence or absence of any booklet talk per transcript was also calculated. RESULTS: Booklet talk occurred in 55% of transcripts. Content focused on surgical procedures (36%); treatment choice (22%); and clarifying risk classification (17%). The most common function of booklet talk was patient corroboration of physicians' explanations (42%), followed by either physician or patient acknowledgement that the patient had the booklet. Codes reflected the absence of DA use for shared decision-making. In regression analysis, predictors of booklet talk were fewer years of patient education (P = .027) and more time in the encounter (P = .027). Patient race, DA type, time reading the DA, physician informing quality and physician age did not predict booklet talk. CONCLUSIONS: Results show that good decision aids, systematically provided to patients, appeared to function not to open up deliberations about how to balance benefits and harms of competing treatments, but rather to allow patients to ask narrow technical questions about recommended treatments. PMID- 28881106 TI - Quantitative assessment of airway dimensions in young children with cystic fibrosis lung disease using chest computed tomography. AB - OBJECTIVE: To evaluate lung disease progression using airway and artery (AA) dimensions on chest CT over 2-year interval in young CF patients longitudinally and compare to disease controls cross-sectionally. METHODS: Retrospective analysis of pressure controlled end-inspiratory CTs, 12 routine baseline (CT1 ) and follow up (CT2 ) from AREST CF cohort; 12 disease controls with normal CT. All visible AA-pairs were measured perpendicular to the airway axis. Inner and outer airway diameters and wall (outer-inner radius) thickness were divided by adjacent arteries to compute Ain A-, Aout A-, and AWT A-ratios, respectively. Differences between CF and control data were assessed using mixed effects models predicting AA-ratios per segmental generation (SG). Power calculations were performed with 80% power and alpha = 0.05. RESULTS: CF, median age CT1 2 years; CT2 3.9 years, 5 males. Controls, median age 2.9 years, 10 males. Total of 4798 AA-pairs measured. Cross-sectionally: Ain A-ratio showed no difference between controls and CF CT1 or CT2 . Aout A-ratio was significantly higher in CF CT1 (SG 2-4) and CT2 (SG 2-5) compared to controls. AWT A-ratio was increased for CF CT1 (SG 1-5) and CT2 (SG 2-6) compared to controls. CF longitudinally: Ain A-ratio was significantly higher at CT2 compared to CT1 . Increase in Aout A-ratio at CT2 compared to CT1 was visible in SG >=4. Sample sizes of 21 and 58 would be necessary for 50% and 30% Aout A-ratio reductions, respectively, between CF CT2 and controls. CONCLUSION: AA-ratio differences were present in young CF patients relative to disease controls. Aout A-ratio as an objective parameter for bronchiectasis could reduce sample sizes for clinical trials. PMID- 28881107 TI - Saddle nose deformity and septal perforation in granulomatosis with polyangiitis. AB - BACKGROUND: Patients who have granulomatosis with polyangiitis (GPA, syn. M. Wegener) often develop an external nose deformity which may have devastating psychological effects. Therefore, reconstruction of nasal deformities by rhinoplasty may become necessary to achieve a normal appearance. OBJECTIVE OF REVIEW: The aim of this systematic review was to investigate the efficacy and safety of surgical reconstruction in external nasal deformities and septal perforation in GPA patients. SEARCH STRATEGY: A systematic literature search with defined search terms was performed for scientific articles archived in the MEDLINE-Database up to 10 June 2016 (PubMed Advanced MEDLINE Search), describing management of cases or case series in GPA patients with saddle nose deformity and/or septal perforation. RESULTS: Eleven of 614 publications met the criteria for this analysis including 41 GPA patients undergoing external nasal reconstruction and/or septal reconstruction with a median follow-up of 2.6 years. Overall, saddle nose reconstruction in GPA patients is safe even if an increased rate of revision surgery has to be expected compared with individuals without GPA undergoing septorhinoplasty. Most implanted grafts were autografts of calvarial bone or costal cartilage. For septal perforation reconstruction, few studies were available. Therefore, based on the available data for surgical outcomes, it is impossible to make evidence-based recommendations. All included GPA patients had minimal or no local disease at the time of reconstructive surgery. Therefore, the relationship between disease activity and its impact on surgical outcomes remains unanswered. The potential impact of immune-modulating medications on increased complication rates and the impact of prophylactic antibiotics are unknown. CONCLUSIONS: This study systematically reviews the efficacy and safety of surgical reconstruction of external nasal deformities in GPA patients for the first time. Saddle nose reconstruction in GPA patients with minimal or no local disease is a safe procedure despite an increased rate of revision surgery. Further research is required regarding the impact of antibiotic prophylaxis, immune-modulating therapy, long-term outcomes and functional outcomes measured with subjective and objective parameters. PMID- 28881108 TI - Altered oesophageal mechanosensitivity of secondary peristalsis as a pathophysiological marker in patients with globus sensation. AB - OBJECTIVE: Secondary peristalsis is important for clearance of retained food bolus and refluxate from the oesophagus. We aimed to investigate whether patients with globus sensation have altered physiological characteristics of secondary peristalsis. DESIGN: Prospective case-controlled study SETTING: Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan. PARTICIPANTS: Seventeen globus patients and 18 healthy controls. MAIN OUTCOME MEASURES: After a baseline recording of primary peristalsis, secondary peristalsis was stimulated with slow and rapid mid-oesophageal injections of air. Distension thresholds and peristaltic activities of secondary peristalsis were analysed and compared between the patients and healthy controls. RESULTS: The threshold volume for generating secondary peristalsis during slow air distension did not differ between the patient and control groups (P = .55). The threshold volume for generating secondary peristalsis during rapid air distension was significantly greater in patients with globus than healthy controls (7.0 +/- 0.9 vs 5.0 +/- 0.3 mL, P = .04). Secondary peristalsis was triggered less frequently in globus patients as compared with healthy control after rapid air distension (40% [30% 65%] vs 60% [60%-83%], P = .001). There was no difference in any of peristaltic parameters for primary and secondary peristalsis between the groups. CONCLUSIONS: Our work identifies functional defects of oesophageal secondary peristalsis in patients with globus sensation and such defects are characterised with defective triggering of secondary peristalsis during rapid air distension. Whether current findings have therapeutic implication in the management of patients with globus sensation warrants further investigation. PMID- 28881109 TI - Cell-Surface Expression Levels Are Important for Fine-Tuning the Performance of Receptor Tyrosine Kinase-Based Signalobodies. AB - As receptor tyrosine kinases (RTKs) play important roles in cell-fate control of various cell types, engineered RTKs that could respond to inexpensive ligands might drastically reduce the cost of producing desired cells for various applications in regenerative medicine. We developed several engineered RTKs named "signalobodies" in which the ligand-recognition domain of RTKs is replaced by single-chain Fv for enabling recognition of a specific antigen. However, the remaining concern was the dysregulation of antigen-dependent on/off signaling of the signalobodies. This study aims at fine-tuning the performance of the signalobodies based on three RTKs (fibroblast growth factor receptor 1, insulin receptor, and c-fms). To this end, the cell-surface expression levels of the RTK based signalobodies were altered by locating their genes either upstream or downstream of the internal ribosomal entry site, and by inserting 1 to 3 alanine residue(s) at the intracellular juxtamembrane region. As a result, while the signaling response was different among the three signalobodies, the antigen dependent on/off regulation became tighter when the cell-surface expression levels of the signalobodies were lowered. Therefore, we successfully developed a method to diminish the leaky signaling of RTK-based signalobodies, which will be important for establishing the signalobody-based platform technology that can produce cells of interest for regenerative medicine. PMID- 28881110 TI - Endoscopic Spine Surgery. AB - Surgical treatment of the degenerative disc disease has evolved from traditional open spine surgery to minimally invasive spine surgery including endoscopic spine surgery. Constant improvement in the imaging modality especially with introduction of the magnetic resonance imaging, it is possible to identify culprit degenerated disc segment and again with the discography it is possible to diagnose the pain generator and pathological degenerated disc very precisely and its treatment with minimally invasive approach. With improvements in the optics, high resolution camera, light source, high speed burr, irrigation pump etc, minimally invasive spine surgeries can be performed with various endoscopic techniques for lumbar, cervical and thoracic regions. Advantages of endoscopic spine surgeries are less tissue dissection and muscle trauma, reduced blood loss, less damage to the epidural blood supply and consequent epidural fibrosis and scarring, reduced hospital stay, early functional recovery and improvement in the quality of life & better cosmesis. With precise indication, proper diagnosis and good training, the endoscopic spine surgery can give equally good result as open spine surgery. Initially, endoscopic technique was restricted to the lumbar region but now it also can be used for cervical and thoracic disc herniations. Previously endoscopy was used for disc herniations which were contained without migration but now days it is used for highly up and down migrated disc herniations as well. Use of endoscopic technique in lumbar region was restricted to disc herniations but gradually it is also used for spinal canal stenosis and endoscopic assisted fusion surgeries. Endoscopic spine surgery can play important role in the treatment of adolescent disc herniations especially for the persons who engage in the competitive sports and the athletes where less tissue trauma, cosmesis and early functional recovery is desirable. From simple chemonucleolysis to current day endoscopic procedures the history of minimally invasive spine surgery is interesting. Appropriate indications, clear imaging prior to surgery and preplanning are keys to successful outcome. In this article basic procedures of percutaneous endoscopic lumbar discectomy through transforaminal and interlaminar routes, percutaneous endoscopic cervical discectomy, percutaneous endoscopic posterior cervical foraminotomy and percutaneous endoscopic thoracic discectomy are discussed. PMID- 28881111 TI - Biomechanical Comparison of Inter-fragmentary Compression Pressures: Lag Screw versus Herbert Screw for Anterior Odontoid Screw Fixation. AB - OBJECTIVE: The purpose of the present study was to compare inter-fragmentary compression pressures after fixation of a simulated type II odontoid fracture with the headless compression Herbert screw and a half threaded cannulated lag screw. METHODS: We compared inter-fragmentary compression pressures between 40- and 45-mm long 4.5-mm Herbert screws (n=8 and n=9, respectively) and 40- and 45 mm long 4.0-mm cannulated lag screws (n=7 and n=10, respectively) after insertion into rigid polyurethane foam test blocks (Sawbones, Vashon, WA, USA). A washer load cell was placed between the two segments of test blocks to measure the compression force. Because the total length of each foam block was 42 mm, the 40 mm screws were embedded in the cancellous foam, while the 45-mm screws penetrated the denser cortical foam at the bottom. This enabled us to compare inter fragmentary compression pressures as they are affected by the penetration of the apical dens tip by the screws. RESULTS: The mean compression pressures of the 40- and 45-mm long cannulated lag screws were 50.48+/-1.20 N and 53.88+/-1.02 N, respectively, which was not statistically significant (p=0.0551). The mean compression pressures of the 40-mm long Herbert screw was 52.82+/-2.17 N, and was not statistically significant compared with the 40-mm long cannulated lag screw (p=0.3679). However, 45-mm Herbert screw had significantly higher mean compression pressure (60.68+/-2.03 N) than both the 45-mm cannulated lag screw and the 40-mm Herbert screw (p=0.0049 and p=0.0246, respectively). CONCLUSION: Our results showed that inter-fragmentary compression pressures of the Herbert screw were significantly increased when the screw tip penetrated the opposite dens cortical foam. This can support the generally recommended surgical technique that, in order to facilitate maximal reduction of the fracture gap using anterior odontoid screws, it is essential to penetrate the apical dens tip with the screw. PMID- 28881112 TI - Morphological and Hemodynamic Parameters for Middle Cerebral Artery Bifurcation Aneurysm Rupture Risk Assessment. AB - OBJECTIVE: To investigate the morphological and hemodynamic parameters associated with middle cerebral artery (MCA)bifurcation aneurysm rupture. METHODS: A retrospective study of 67 consecutive patients was carried out based on 3D digital subtraction angiography data. Morphological and hemodynamic parameters including aneurysm size parameters (dome width, height, and perpendicular height), longest dimension from the aneurysm neck to the dome tip, neck width, aneurysm area, aspect ratio, Longest dimension from the aneurysm neck to the dome tip (Dmax) to dome width, and height-width, Bottleneck factor, as well as wall shear stress (WSS), low WSS area (LSA), percentage of LSA (LSA%) and energy loss (EL) were estimated. Parameters between ruptured and un-ruptured groups were analyzed. Receiver operating characteristics were generated to check prediction performance of all significant variables. RESULTS: Sixty-seven patients with MCA bifurcation aneurysm were included (31 unruptured, 36 ruptured). Dmax (p=0.008) was greater in ruptured group than that in un-ruptured group. D/W (p<0.001) and the percentage of the low WSS area (0.09+/-0.13 vs. 0.01+/-0.03, p<0.001) were also greater in the ruptured group. Moreover, the EL in ruptured group was higher than that in un-ruptured group (6.39+/-5.04 vs. 1.53+/-0.86, p<0.001). Multivariate regression analysis suggested D/W and EL were significant predictors of rupture of MCA bifurcation aneurysms. Correlation analyses revealed the D/W value was positively associated with the EL (R=0.442, p<0.01). CONCLUSION: D/W and EL might be the most two favorable factors to predict rupture risk of MCA bifurcation aneurysms. PMID- 28881113 TI - Cerebral Arterial Stenosis in Patients with Spontaneous Intracerebral Hemorrhage. AB - OBJECTIVE: Spontaneous intracerebral hemorrhage (ICH) and ischemic stroke share common vascular risk factors such as aging and hypertension. Previous studies suggested that the rate of recurrent ICH and ischemic stroke might be similar after ICH. Presence of cerebral arterial stenosis is a potential risk factor for future ischemic stroke. This study investigated the prevalence and factors associated with cerebral arterial stenosis in Korean patients with spontaneous ICH. METHODS: A total of 167 patients with spontaneous ICH were enrolled. Intracranial arterial stenosis (ICAS) and extracranial arterial stenosis (ECAS) were assessed by computed tomography angiography. Presence of ICAS was defined if patients had arterial stenosis in at least one intracranial artery. ECAS was assessed in the extracranial carotid artery. More than 50% luminal stenosis was defined as presence of stenosis. Prevalence and factors associated with presence of ICAS and cerebral arterial stenosis (presence of ICAS and/or ECAS) were investigated by multivariable logistic regression analysis. RESULTS: Thirty-two (19.2%) patients had ICAS, 7.2% had ECAS, and 39 (23.4%) patients had any cerebral arterial stenosis. Frequency of ICAS and ECAS did not differ among ganglionic ICH, lobar ICH, and brainstem ICH. Age was higher in patients with ICAS (67.6+/-11.8 vs. 58.9+/-13.6 years p=0.004) and cerebral arterial stenosis (67.9+/-11.6 vs. 59.3+/-13.5 years, p<0.001) compared to those without stenosis. Patients with ICAS were older, more frequently had diabetes, had a higher serum glucose level, and had a lower hemoglobin level than those without ICAS. Patients with cerebral arterial stenosis were older, had diabetes and lower hemoglobin level, which was consistent with findings in patients with ICAS. However, patients with cerebral arterial stenosis showed higher prevalence of hypertension and decreased kidney function compared to those without cerebral arterial stenosis. Multivariable logistic regression analyses showed that aging and presence of diabetes independently predicted the presence of ICAS, and aging, diabetes, and hypertension were independently associated with presence of cerebral arterial stenosis. CONCLUSION: 19.2% of patients with spontaneous ICH had ICAS, but the prevalence of ECAS was relatively lower (7.2%) compared with ICAS. Aging and diabetes were independent factors for the presence of ICAS, whereas aging, hypertension, and diabetes were factors for the cerebral arterial stenosis. PMID- 28881114 TI - Intra-arterial and Intravenous Tirofiban Infusion for Thromboembolism during Endovascular Coil Embolization of Cerebral Aneurysm. AB - OBJECTIVE: Thromboembolism is the one of the most serious complications that can occur during endovascular coil embolization of cerebral aneurysm. We report on the effectiveness and safety of intra-arterial/intravenous (IA/IV) glycoprotein IIb/IIIa inhibitor (tirofiban) infusion for treating thromboembolism during endovascular coil embolization of cerebral aneurysm. METHODS: We performed a retrospective analysis of 242 patients with ruptured or unruptured cerebral aneurysms (n=264) who underwent endovascular coil embolization from January 2011 to June 2014. Thromboembolism occurred in 20 patients (7.4%), including 14 cases of ruptured aneurysms and 6 cases of unruptured aneurysms. The most common site of aneurysms was the anterior communicating artery (n=8), followed by middle cerebral artery (n=6). When we found an enlarged thromboembolism during coil embolization, we tried to dissolve it using tirofiban administered via IA and IV loading (5 MUg/kg, respectively) for 3-5 minutes followed by IV maintenance (0.08 MUg/kg/min) for approximately 4-24 hours. RESULTS: In 4 of 5 patients with total vessel occlusion, the vessel was recanalized to Thrombolysis in Cerebral Infarction Perfusion Scale (TICI) grade 3, and in 1 patient to TICI grade 2a. In 2 patients with partial vessel occlusion and 13 patients with minimal occlusion, the vessel recanalized to TICI grade 3. Irrelevant intracerebral hemorrhage was noted in 1 patient (5%), and thromboemboli-related cerebral infarction developed in 5 patients (25%), of which only 1 (5%) was symptomatic. CONCLUSION: IA/IV infusion and IV maintenance with tirofiban appear to be an effective rescue treatment for thromboembolism during endovascular coil embolization in patients with ruptured or unruptured cerebral aneurysms. PMID- 28881115 TI - The Role of Adjuvant Treatment in Patients with High-Grade Meningioma. AB - OBJECTIVE: To investigate the efficacy of adjuvant treatment in patients with high-grade meningioma. METHODS: A retrospective analysis was performed for patients with high-grade meningioma, World Health Organization grade 2 or 3, in a single center between 2003 and 2014. The patients were reviewed according to age at diagnosis, sex, the location of meningioma, degree of tumor resection, histological features, and type of adjuvant treatment. These factors were analyzed by Firth logistic regression analyses. RESULTS: Fifty-three patients with high-grade meningioma were enrolled. Thirty-four patients received adjuvant treatment; conventional radiotherapy or radiosurgery. Clinical follow-up ranged from 13-113 months with a median follow-up of 35.5 months. Gross total removal (GTR), Simpson grade 1 or 2, was achieved in 29 patients and, among them, 13 patients received adjuvant treatment. In the other 24 patients with non-GTR, conventional adjuvant radiotherapy and radiosurgery were performed in 11 and 10 patients, respectively. The other 3 patients did not receive any adjuvant treatment. Radiation-related complications did not occur. Of the 53 patients, 19 patients had suffered from recurrence. The recurrence rate in the adjuvant treatment group was 23.5% (8 out of 34). On the other hand, the rate for the non adjuvant treatment group was 57.9% (11 out of 19) (odds ratio [OR]=0.208, p=0.017). In the GTR group, the recurrence rate was 7.5% (1 out of 13) for patients with adjuvant treatment and 50% (8 out of 16) for patients without adjuvant treatment (OR=0.121, p=0.04). CONCLUSION: Adjuvant treatment appears to be safe and effective, and could lead to a lower recurrence rate in high-grade meningioma, regardless of the extent of removal. Our results might be used as a reference for making decisions when planning adjuvant treatments for patients with high-grade meningioma after surgery. PMID- 28881117 TI - Comparison of Root Images between Post-Myelographic Computed Tomography and Magnetic Resonance Imaging in Patients with Lumbar Radiculopathy. AB - OBJECTIVE: To evaluate the diagnostic value of computed tomography-myelography (CTM) compared to that of magnetic resonance imaging (MRI) in patients with lumbar radiculopathy. METHODS: The study included 91 patients presenting with radicular leg pain caused by herniated nucleus pulposus or lateral recess stenosis in the lumbar spine. The degree of nerve root compression on MRI and CTM was classified into four grades. The results of each imaging modality as assessed by two different observers were compared. Visual analog scale score for pain and electromyography result were the clinical parameters used to evaluate the relationships between clinical features and nerve root compression grades on both MRI and CTM. These relationships were quantified by calculating the receiver operating characteristic curves, and the degree of relationship was compared between MRI and CTM. RESULTS: McNemar's test revealed that the two diagnostic modalities did not show diagnostic concurrence (p<0.0001). Electromyography results did not correlate with grades on either MRI or CTM. The visual analog pain scale score results were correlated better with changes of the grades on CTM than those on MRI (p=0.0007). CONCLUSION: The present study demonstrates that CTM could better define the pathology of degenerative lumbar spine diseases with radiculopathy than MRI. CTM can be considered as a useful confirmative diagnostic tool when the exact cause of radicular pain in a patient with lumbar radiculopathy cannot be identified by using MRI. However, the invasiveness and potential complications of CTM are still considered to be pending questions to settle. PMID- 28881116 TI - Surgical Roles for Spinal Involvement of Hematological Malignancies. AB - OBJECTIVE: Patients with hematological malignancies frequently encounter spine related symptoms, which are caused by disease itself or process of treatment. However, there is still lack of knowledge on their epidemiology and clinical courses. The purpose of this article is to review clinical presentations and surgical results for spinal involvement of hematologic malignancies. METHODS: From January 2011 to September 2014, 195 patients (98 males and 97 females) suffering from hematological malignancies combined with spinal problems were retrospectively analyzed for clinical and radiological characteristics and their clinical results. RESULTS: The most common diagnosis of hematological malignancy was multiple myeloma (96 patients, 49.7%), followed by chronic myeloid leukemia (30, 15.2%), acute myeloid leukemia (22, 11.2%), and lymphoma (15, 7.56%). The major presenting symptoms were mechanical axial pain (132, 67.7%) resulting from pathologic fractures, and followed by radiating pain (49, 25.1%). Progressive neurologic deficits were noted in 15 patients (7.7%), which revealed as cord compression by epidural mass or compressive myelopathy combined with pathologic fractures. Reconstructive surgery for neurologic compromise was done in 16 patients. Even though surgical intervention was useful for early paralysis (Frankel grade D or E), neurologic recovery was not satisfactory for the progressed paralysis (Frankel grade A or B). CONCLUSION: Hematological malignancies may cause various spinal problems related to disease progression or consequences of treatments. Conservative and palliative treatments are mainstay for these lesions. However, timely surgical interventions should be considered for the cases of pathologic fractures with progressive neurologic compromise. PMID- 28881118 TI - The Effect of Uncinate Process Resection on Subsidence Following Anterior Cervical Discectomy and Fusion. AB - OBJECTIVE: Subsidence is a frequent complication of anterior cervical discectomy and fusion. Postoperative segmental micro-motion, thought to be a causative factor of subsidence, has been speculated to increase with uncinate process resection area (UPR). To evaluate the effect of UPR on micro-motion, we designed a method to measure UPR area based on pre- and postoperative computed tomography images and analyzed the relationship between UPR and subsidence as a proxy of micro-motion. METHODS: We retrospectively collected clinical and radiological data from January 2011 to June 2016. A total of 38 patients (53 segments) were included. All procedures included bilateral UPR and anterior plate fixation. UPR area was evaluated with reformatted coronal computer tomography images. To reduce level-related bias, we converted UPR area to the proportion of UPR to the pre operative UP area (pUPR). RESULTS: Subsidence occurred in 18 segments (34%) and positively correlated with right-side pUPR, left-side pUPR, and the sum of bilateral pUPR (sum pUPR) (R=0.310, 301, 364; p=0.024, 0.029, 0.007, respectively). Multiple linear regression analysis revealed that subsidence could be estimated with the following formula: subsidence=1.522+2.7*sum pUPR (R2=0.133, p=0.007). Receiver-operating characteristic analysis determined that sum pUPR>=0.38 could serve as a threshold for significantly increased risk of subsidence (p=0.005, area under curve=0.737, sensitivity=94%, specificity=51%). This threshold was confirmed by logistic regression analysis for subsidence (p=0.009, odds ratio=8.471). CONCLUSION: The UPR measurement method confirmed that UPR was correlated with subsidence. Particularly when the sum of pUPR is >=38%, the possibility of subsidence increased. PMID- 28881119 TI - Evaluation of Global Sagittal Balance in Koreans Adults. AB - OBJECTVIE: The global sagittal postural patterns as characterized by Roussouly classification have been previously described in various ethnicities, there were no studies investigated in Koreans. To analyze the distribution of the global sagittal postural patterns in Korean adults using Roussouly classification, the author prospectively studied. METHODS: 252 asymptomatic Korean adults was recruited. Data was obtained by reviewing the films for each subject. Spinopelvic parameters were measured and sagittal postural patterns were then determined according to Roussouly classification. We compared the data across different ethnicities from our study and a previous study to further characterize Korean sagittal postures. RESULTS: The subject included 151 males and 101 females, with mean age of 33.2+/-8.2 years. The average descriptive results were as below: thoracic kyphosis 28.6+/-7.7 degrees , lumbar lordosis 48.3+/-10.2 degrees , sacral slope 37.8+/-5.8 degrees , pelvic incidence 45.1+/-7.5 degrees , pelvic tilt 9.4+/-6.7 degrees , spinosacral angle 130.1+/-5.4 degrees , and sagittal vertical axis 16.25+/-22.5 mm. 125 subjects among 252 (49.6%) belonged to Roussouly type 3 (namely neutral). There were also 58 (23%), 33 (13.1%), and 36 (14.3) subjects in type 1, 2, and 4 (namely non-neutral), respectively. CONCLUSION: Enrolling 252 asymptomatic Korean adults, this prospective study found that 49.6% of asymptomatic Korean adults possessed a sagittal posture of Roussouly type 3. All radiologic parameters follows general concept of spinal sagittal balance pattern. Overall, this study might be a basis for further investigation of spinal sagittal balance. PMID- 28881120 TI - A Lower T1 Slope as a Predictor of Subsidence in Anterior Cervical Discectomy and Fusion with Stand-Alone Cages. AB - OBJECTIVE: Preoperative parameters including the T1 slope (T1S) and C2-C7 sagittal vertical axis (SVA) have been recognized as predictors of kyphosis after laminoplasty, which is accompanied by posterior neck muscle damage. The importance of preoperative parameters has been under-estimated in anterior cervical discectomy and fusion (ACDF) because there is no posterior neck muscle damage. We aimed to determine whether postoperative subsidence and pseudarthrosis could be predicted according to specific parameters on preoperative plain radiographs. METHODS: We retrospectively analyzed 41 consecutive patients (male: female, 22: 19; mean age, 51.15+/-9.25 years) who underwent ACDF with a stand alone polyether-ether-ketone (PEEK) cage (>1 year follow-up). Parameters including SVA, T1S, segmental angle and range of motion (ROM), C2-C7 cervical angle and ROM, and segmental inter-spinous distance were measured on preoperative plain radiographs. Risk factors of subsidence and pseudarthrosis were determined using multivariate logistic regression. RESULTS: Fifty-five segments (27 single segment and 14 two-segment fusions) were included. The subsidence and pseudarthrosis rates based on the number of segments were 36.4% and 29.1%, respectively. Demographic data and fusion level were unrelated to subsidence. A greater T1S was associated with a lower risk of subsidence (p=0.017, odds ratio=0.206). A cutoff value of T1S<28 degrees significantly predicted subsidence (sensitivity: 70%, specificity: 68.6%). There were no preoperative predictors of pseudarthrosis except old age. CONCLUSION: A lower T1S (T1S<28 degrees ) could be a risk factor of subsidence following ACDF. Surgeons need to be aware of this risk factor and should consider various supportive procedures to reduce the subsidence rates for such cases. PMID- 28881121 TI - The Predictable Factors of the Postoperative Kyphotic Change of Sagittal Alignment of the Cervical Spine after the Laminoplasty. AB - OBJECTIVE: Laminoplasty is an effective surgical method for treating cervical degenerative disease. However, postoperative complications such as kyphosis, restriction of neck motion, and instability are often reported. Despite sufficient preoperative lordosis, this procedure often aggravates the lordotic curve of the cervical spine and straightens cervical alignment. Hence, it is important to examine preoperative risk factors associated with postoperative kyphotic alignment changes. Our study aimed to investigate preoperative radiologic parameters associated with kyphotic deformity post laminoplasty. METHODS: We retrospectively reviewed the medical records of 49 patients who underwent open door laminoplasty for cervical spondylotic myelopathy (CSM) or ossification of the posterior longitudinal ligament (OPLL) at Pusan National University Yangsan Hospital between January 2011 and December 2015. Inclusion criteria were as follows: 1) preoperative diagnosis of OPLL or CSM, 2) no previous history of cervical spinal surgery, cervical trauma, tumor, or infection, 3) minimum of one-year follow-up post laminoplasty with proper radiologic examinations performed in outpatient clinics, and 4) cases showing C7 and T1 vertebral body in the preoperative cervical sagittal plane. The radiologic parameters examined included C2-C7 Cobb angles, T1 slope, C2-C7 sagittal vertical axis (SVA), range of motion (ROM) from C2-C7, segmental instability, and T2 signal change observed on magnetic resonance imaging (MRI). Clinical factors examined included preoperative modified Japanese Orthopedic Association scores, disease classification, duration of symptoms, and the range of operation levels. RESULTS: Mean preoperative sagittal alignment was 13.01 degrees lordotic; 6.94 degrees lordotic postoperatively. Percentage of postoperative kyphosis was 80%. Patients were subdivided into two groups according to postoperative Cobb angle change; a control group (n=22) and kyphotic group (n=27). The kyphotic group consisted of patients with more than 5 degrees kyphotic angle change postoperatively. There were no differences in age, sex, C2-C7 Cobb angle, T1 slope, C2-C7 SVA, ROM from C2-C7, segmental instability, or T2 signal change. Multiple regression analysis revealed T1 slope had a strong relationship with postoperative cervical kyphosis. Likewise, correlation analysis revealed there was a statistical significance between T1 slope and postoperative Cobb angle change (p=0.035), and that there was a statistically significant relationship between T1 slope and C2-C7 SVA (p=0.001). Patients with higher preoperative T1 slope demonstrated loss of lordotic curvature postoperatively. CONCLUSION: Laminoplasty has a high probability of aggravating sagittal balance of the cervical spine. T1 slope is a good predictor of postoperative kyphotic changes of the cervical spine. Similarly, T1 slope is strongly correlated with C2-C7 SVA. PMID- 28881122 TI - Traumatic Brain Injury in Children under Age 24 Months: Analysis of Demographic Data, Risk Factors, and Outcomes of Post-traumatic Seizure. AB - OBJECTIVE: Traumatic brain injury (TBI) in children under age 24 months has characteristic features because the brain at this age is rapidly growing and sutures are opened. Moreover, children this age are completely dependent on their parents. We analyzed the demographic data and risk factors for outcomes in TBI patients in this age group to elucidate their clinical characteristics. METHODS: We retrospectively reviewed the medical records and radiological films of children under 24 months who were admitted to Kyungpook National University Hospital from January 2004 to December 2013 for TBI. Specifically, we analyzed age, cause of injury, initial Glasgow coma scale (GCS) score, radiological diagnosis, seizure, hydrocephalus, subdural hygroma, and Glasgow outcome scale (GOS) score, and we divided outcomes into good (GOS 4-5) or poor (GOS 1-3). We identified the risk factors for post-traumatic seizure (PTS) and outcomes using univariate and multivariate analyses. RESULTS: The total number of patients was 60, 39 males and 21 females. Most common age group was between 0 to 5 months, and the median age was 6 months. Falls were the most common cause of injury (n=29, 48.3%); among them, 15 were falls from household furniture such as beds and chairs. Ten patients (16.7%) developed PTS, nine in one week; thirty-seven patients (61.7%) had skull fractures. Forty-eight patients had initial GCS scores of 13-15, 8 had scores of 12-8, and 4 had scored 3-7. The diagnoses were as follows: 26 acute subdural hematomas, 8 acute epidural hematomas, 7 focal contusional hemorrhages, 13 subdural hygromas, and 4 traumatic intracerebral hematomas larger than 2 cm in diameter. Among them, two patients underwent craniotomy for hematoma removal. Four patients were victims of child abuse, and all of them had PTS. Fifty-five patients improved to good-to-moderate disability. Child abuse, acute subdural hematoma, and subdural hygroma were risk factors for PTS in univariate analyses. Multivariate analysis found that the salient risk factor for a poor outcome was initial GCS on admission. CONCLUSION: The most common cause of traumatic head injury in individuals aged less than 24 months was falls, especially from household furniture. Child abuse, moderate to severe TBI, acute subdural hematoma, and subdural hygroma were risk factors for PTS. Most of the patients recovered with good outcomes, and the risk factor for a poor outcome was initial mental status. PMID- 28881123 TI - Significant Risk Factors for Postoperative Enlargement of Basal Ganglia Hematoma after Frameless Stereotactic Aspiration: Antiplatelet Medication and Concomitant IVH. AB - OBJECTIVE: Frameless stereotactic aspiration of a hematoma can be the one of the treatment options for spontaneous intracerebral hemorrhage in the basal ganglia. Postoperative hematoma enlargement, however, can be a serious complication of intracranial surgery that frequently results in severe neurological deficit and even death. Therefore, it is important to identify the risk factors of postoperative hematoma growth. METHODS: During a 13-year period, 101 patients underwent minimally invasive frameless stereotactic aspiration for basal ganglia hematoma. Patients were classified into two groups according to whether or not they had postoperative hematoma enlargement in a computed tomography scan. Baseline demographic data and several risk factors, such as hypertension, preoperative hematoma growth, antiplatelet medication, presence of concomitant intraventricular hemorrhage (IVH), were analysed via a univariate statistical study. RESULTS: Nine of 101 patients (8.9%) showed hematoma enlargement after frameless stereotactic aspiration. Among the various risk factors, concomitant IVH and antiplatelet medication were found to be significantly associated with postoperative enlargement of hematomas. CONCLUSION: In conclusion, our study revealed that aspirin use and concomitant IVH are factors associated with hematoma enlargement subsequent to frameless stereotactic aspiration for basal ganglia hematoma. PMID- 28881124 TI - Minimally Invasive Anterior Decompression Technique without Instrumented Fusion for Huge Ossification of the Posterior Longitudinal Ligament in the Thoracic Spine: Technical Note And Literature Review. AB - OBJECTIVE: Several surgical methods have been reported for treatment of ossification of the posterior longitudinal ligament (OPLL) in the thoracic spine. Despite rapid innovation of instruments and techniques for spinal surgery, the postoperative outcomes are not always favorable. This article reports a minimally invasive anterior decompression technique without instrumented fusion, which was modified from the conventional procedure. The authors present 2 cases of huge beak-type OPLL. Patients underwent minimally invasive anterior decompression without fusion. This method created a space on the ventral side of the OPLL without violating global thoracic spinal stability. Via this space, the OPLL and anterior lateral side of the dural sac can be seen and manipulated directly. Then, total removal of the OPLL was accomplished. No orthosis was needed. In this article, we share our key technique and concepts for treatment of huge thoracic OPLL. METHODS: Case 1. 51-year-old female was referred to our hospital with right lower limb radiating pain and paresis. Thoracic OPLL at T6-7 had been identified at our hospital, and conservative treatment had been tried without success. Case 2. This 54-year-old female with a 6-month history of progressive gait disturbance and bilateral lower extremity radiating pain (right>left) was admitted to our institute. She also had hypoesthesia in both lower legs. Her symptoms had been gradually progressing. Computed tomography scans showed massive OPLL at the T9-10 level. Magnetic resonance imaging of the thoracolumbar spine demonstrated ventral bony masses with severe anterior compression of the spinal cord at the same level. RESULTS: We used this surgical method in 2 patients with a huge beaked type OPLL in the thoracic level. Complete removal of the OPLL via anterior decompression without instrumented fusion was accomplished. The 1st case had no intraoperative or postoperative complications, and the 2nd case had 1 intraoperative complication (dural tear) and no postoperative complications. There were no residual symptoms of the lower extremities. CONCLUSION: This surgical technique allows the surgeon to safely and effectively perform minimally invasive anterior decompression without instrumented fusion via a transthoracic approach for thoracic OPLL. It can be applied at the mid and lower level of the thoracic spine and could become a standard procedure for treatment of huge beak type thoracic OPLL. PMID- 28881125 TI - Adjustable Ghajar Guide Technique for Accurate Placement of Ventricular Catheters: A Pilot Study. AB - OBJECTIVE: An adjustable Ghajar guide is presented to improve the accuracy of the original Ghajar guide technique. The accuracy of the adjustable Ghajar guide technique is also investigated. METHODS: The coronal adjustment angle from the orthogonal catheter trajectory at Kocher's point is determined based on coronal head images using an electronic picture archiving and communication system. For the adjustable Ghajar guide, a protractor is mounted on a C-shaped basal plate that is placed in contact with the margin of a burrhole, keeping the central 0 degrees line of the protractor orthogonal to the calvarial surface. A catheter guide, which is moved along the protractor and fixed at the pre-determined adjustment angle, is then used to guide the ventricular catheter into the frontal horn adjacent to the foramen of Monro. The adjustable Ghajar guide technique was applied to 20 patients, while a freehand technique based on the surface anatomy of the head was applied to another 47 patients. The accuracy of the ventricular catheter placement was then evaluated using postoperative computed tomography scans. RESULTS: For the adjustable Ghajar guide technique (AGT) patients, the bicaudate index ranged from 0.23 to 0.33 (mean+/-standard deviation [SD]: 0.27+/ 0.03) and the adjustment angle ranged from 0 degrees to 10 degrees (mean+/-SD: 5.2 degrees +/-3.2 degrees ). All the AGT patients experienced successful cerebrospinal fluid diversion with only one pass of the catheter. Optimal placement of the ventricular catheter in the ipsilateral frontal horn approximating the foramen of Monro (grade 1) was achieved in 19 patients (95.0%), while a suboptimal trajectory into a lateral corner of the frontal horn passing along a lateral wall of the frontal horn (grade 3) occurred in 1 patient (5.0%). Thus, the AGT patients experienced a significantly higher incidence of optimal catheter placement than the freehand catheterized patients (95.0% vs. 68.3%, p=0.024). Moreover, none of the AGT patients experienced any tract hemorrhages along the catheter or procedure-related complications. CONCLUSION: The proposed adjustable Ghajar guide technique, using angular adjustment in the coronal plane from the orthogonal trajectory at Kocher's point, facilitates accurate freehand placement of a ventricular catheter for hydrocephalic patients. PMID- 28881126 TI - In Situ Stringing of Metal Organic Frameworks by SiC Nanowires for High Performance Electromagnetic Radiation Elimination. AB - The design of novel hybrid nanostructures has been seen as an effective route to tune the properties of materials. Herein, we provide an in situ growth strategy to efficiently construct kebab-like hybrids, which are composed of one dimensional SiC nanowires stringing polyhedral metal organic frameworks (MOFs). Through a heat-treatment process regardless of under air or argon, these hybrids generate an excellent electromagnetic absorption (EMA) ability. We comprehensively explored the growth and calcination process of these hybrids as well as their EMA enhanced mechanism. The results indicate that the MOFs kept as shrunken polyhedrons under air but decomposed to small particles under argon, due to the different calcination mechanism. In addition, the enhanced EMA ability should be attributed to the combined influences of the reduced dielectric constant, enlarged aspect ratio, and enhanced interface polarization. This research opens up the rational designs and applications of novel materials by the hybridizing of nanomaterials in multidimensions. PMID- 28881127 TI - A New Strategy to Stabilize Capacity and Insight into the Interface Behavior in Electrochemical Reaction of LiNi0.5Mn1.5O4/Graphite System for High-Voltage Lithium-Ion Batteries. AB - The performance of CEI and SEI configuration and formation mechanism on the cathode and anode side for LiNi0.5Mn1.5O4/natural graphite (LNMO/NG) batteries is investigated, where series permutations of the NG electrodes modified with TEOS species as the anode for the LNMO full cells. It is believed that the excellent long-term cycling performance of LNMO/NG full cells at the high voltage is a result of alleviating the devastated reaction to form the CEI and SEI on the both electrodes with electrolyte, respectively. At a voltage range from 3.4 to 4.8 V for the LNMO full cells, 95.0% capacity retention after 100 cycles is achieved when cycled with TEOS-modifying NG anode. This mechanism may be explained that eliminating the HF and absorbing water impurities in the electrolyte by introducing the TEOS group, which can transform the SiO2 species that react with the acid of HF at the organic solvent environment instead of destroying/forming the anode SEI and attacking the LNMO spinel structure to form the dense and high resistance CEI, meanwhile the SiO2 species will absorb the water molecule and precipitate into the anode surface further stabilizing the SEI configuration during the cycling. PMID- 28881128 TI - Oxidation State-Dependent Intramolecular Electronic Interaction of Carbazole Based Azacyclophanes with 9,10-Anthrylene Units. AB - We designed an azacyclophane comprising 3,6-substituted carbazole and 9,10 anthrylene units to investigate the unique electronic properties of the oxidation states arising from the presence of multiple oxidizable azacyclophane. This compound and its analogue containing 1,4-phenylene in substitution of 9,10 anthrylene units were synthesized by Buchwald-Hartwig coupling reactions. Cyclic voltammograms of both the 9,10-anthrylene and 1,4-phenylene derivatives exhibited four quasi-reversible oxidation processes. The absorption spectra of the oxidation states of the 9,10-anthrylene derivative exhibited broad absorption bands in the near-infrared region arising from charge-resonance and intramolecular charge-transfer interactions. The photophysical and electrochemical properties of the 9,10-anthrylene derivative were compared with those of the corresponding 1,4-phenylene derivative on the basis of theoretical calculations to evaluate the intramolecular electronic interactions. PMID- 28881129 TI - Polymorphism of Lysozyme Condensates. AB - Protein condensates play essential roles in physiological processes and pathological conditions. Recently discovered mesoscopic protein-rich clusters may act as crucial precursors for the nucleation of ordered protein solids, such as crystals, sickle hemoglobin polymers, and amyloid fibrils. These clusters challenge settled paradigms of protein condensation as the constituent protein molecules present features characteristic of both partially misfolded and native proteins. Here we employ the antimicrobial enzyme lysozyme and examine the similarities between mesoscopic clusters, amyloid structures, and disordered aggregates consisting of chemically modified protein. We show that the mesoscopic clusters are distinct from the other two classes of aggregates. Whereas cluster formation and amyloid oligomerization are both reversible, aggregation triggered by reduction of the intramolecular S-S bonds is permanent. In contrast to the amyloid structures, protein molecules in the clusters retain their enzymatic activity. Furthermore, an essential feature of the mesoscopic clusters is their constant radius of less than 50 nm. The amyloid and disordered aggregates are significantly larger and rapidly grow. These findings demonstrate that the clusters are a product of limited protein structural flexibility. In view of the role of the clusters in the nucleation of ordered protein solids, our results suggest that fine-tuning the degree of protein conformational stability is a powerful tool to control and direct the pathways of protein condensation. PMID- 28881130 TI - Non-Noble Metal Nanoparticles Supported by Postmodified Porous Organic Semiconductors: Highly Efficient Catalysts for Visible-Light-Driven On-Demand H2 Evolution from Ammonia Borane. AB - From the viewpoint of controlling the visible-light-driven activities of catalysts containing metal nanoparticles (NPs) by tuning the microstructures of semiconducting supports, we employed a postsynthetic thermal modification approach to prepare carbon nitride (C3N4) species featuring different microstructures and then we synthesized Co and Ni NPs supported by these C3N4 species, which were used to catalyze the room-temperature H2 evolution from ammonia borane (NH3BH3). The systematic investigation showed that the catalysts had different activities under light irradiation. Compared with the pristine C3N4 based catalyst, all the modified C3N4-based catalysts had enhanced activities. The highest active Co catalyst with a total turnover frequency of 93.8 min-1 was successfully obtained, which exceeded the values of all the reported heterogeneous noble metal-free catalysts. The structure characterizations indicated that the postmodified porous C3N4 species had the different band structures, photoluminescence lifetime, and photocurrent density under visible light irradiation, leading to the different separation efficiency of photogenerated charge carriers. These characteristics helped us regulate the electronic characteristics of Co and Ni NPs in the supported catalysts and then led to the significantly different and enhanced activity in the visible-light driven H2 evolution. PMID- 28881131 TI - Where Ion Mobility and Molecular Dynamics Meet To Unravel the (Un)Folding Mechanisms of an Oligorotaxane Molecular Switch. AB - At the interface between foldamers and mechanically interlocked molecules, oligorotaxanes exhibit a spring-like folded secondary structure with remarkable mechanical and physicochemical properties. Among these properties, the ability of oligorotaxanes to act as molecular switches through controlled modulations of their spatial extension over (un)folding dynamics is of particular interest. The present study aims to assess and further characterize this remarkable feature in the gas phase using mass spectrometry tools. In this context, we focused on the [4]5NPR+12 oligorotaxane molecule complexed with PF6- counterion and probed its co-conformational states as a function of the in-source-generated charge states. Data were interpreted in light of electronic secondary structure computations at the PM6 and DFT levels. Our results highlight two major co-conformational groups associated either with folded compact structures, notably stabilized by intramolecular pi-pi interactions and predominant for low charge states or with fully stretched structures resulting from significant Coulombic repulsions at high charge states. Between, the oligorotaxane adopts intermediate folded co conformations, suggesting a stepwise unfolding pathway under increasing repulsive Coulombic constraints. The reversibility of this superstructural transition was next interrogated under electron-driven (nondissociative electron transfer) and heat-driven (collision-induced unfolding) activation stimuli. The outcomes support the feasibility to either unfold or (partially) refold the oligorotaxane foldamer on purpose in the gas phase. Our results show that the balance between the stabilizing pi-pi interactions and the versatile Coulomb interactions dictates the elongation state of the foldamer in the gas phase and emphasizes the adequacy of mass spectrometry tools for the superstructural characterization of desolvated prototypical artificial molecular machines. PMID- 28881132 TI - Multistate Complete-Active-Space Second-Order Perturbation Theory Based on Density Matrix Renormalization Group Reference States. AB - We present the development of the multistate multireference second-order perturbation theory (CASPT2) with multiroot references, which are described using the density matrix renormalization group (DMRG) method to handle a large active space. The multistate first-order wave functions are expanded into the internally contracted (IC) basis of the single-state single-reference (SS-SR) scheme, which is shown to be the most feasible variant to use DMRG references. The feasibility of the SS-SR scheme comes from two factors: first, it formally does not require the fourth-order transition reduced density matrix (TRDM) and second, the computational complexity scales linearly with the number of the reference states. The extended multistate (XMS) treatment is further incorporated, giving suited treatment of the zeroth-order Hamiltonian despite the fact that the SS-SR based IC basis is not invariant with respect to the XMS rotation. In addition, the state-specific fourth-order reduced density matrix (RDM) is eliminated in an approximate fashion using the cumulant reconstruction formula, as also done in the previous state-specific DMRG-cu(4)-CASPT2 approach. The resultant method, referred to as DMRG-cu(4)-XMS-CASPT2, uses the RDMs and TRDMs of up to third order provided by the DMRG calculation. The multistate potential energy curves of the photoisomerization of diarylethene derivatives with CAS(26e,24o) are presented to illustrate the applicability of our theoretical approach. PMID- 28881133 TI - Localized Charges Control Exciton Energetics and Energy Dissipation in Doped Carbon Nanotubes. AB - Doping by chemical or physical means is key for the development of future semiconductor technologies. Ideally, charge carriers should be able to move freely in a homogeneous environment. Here, we report on evidence suggesting that excess carriers in electrochemically p-doped semiconducting single-wall carbon nanotubes (s-SWNTs) become localized, most likely due to poorly screened Coulomb interactions with counterions in the Helmholtz layer. A quantitative analysis of blue-shift, broadening, and asymmetry of the first exciton absorption band also reveals that doping leads to hard segmentation of s-SWNTs with intrinsic undoped segments being separated by randomly distributed charge puddles approximately 4 nm in width. Light absorption in these doped segments is associated with the formation of trions, spatially separated from neutral excitons. Acceleration of exciton decay in doped samples is governed by diffusive exciton transport to, and nonradiative decay at charge puddles within 3.2 ps in moderately doped s-SWNTs. The results suggest that conventional band-filling in s-SWNTs breaks down due to inhomogeneous electrochemical doping. PMID- 28881134 TI - Modeling sigma-Bond Activations by Nickel(0) Beyond Common Approximations: How Accurately Can We Describe Closed-Shell Oxidative Addition Reactions Mediated by Low-Valent Late 3d Transition Metal? AB - Accurate modelings of reactions involving 3d transition metals (TMs) are very challenging to both ab initio and DFT approaches. To gain more knowledge in this field, we herein explored typical sigma-bond activations of H-H, C-H, C-Cl, and C C bonds promoted by nickel(0), a low-valent late 3d TM. For the key parameters of activation energy (DeltaE?) and reaction energy (DeltaER) for these reactions, various issues related to the computational accuracy were systematically investigated. From the scrutiny of convergence issue with one-electron basis set, augmented (A) basis functions are found to be important, and the CCSD(T)/CBS level with complete basis set (CBS) limit extrapolation based on augmented double zeta and triple-zeta basis pair (ADZ and ATZ), which produces deviations below 1 kcal/mol from the reference, is recommended for larger systems. As an alternative, the explicitly correlated F12 method can accelerate the basis set convergence further, especially after its CBS extrapolations. Thus, the CCSD(T) F12/CBS(ADZ-ATZ) level with computational cost comparable to the conventional CCSD(T)/CBS(ADZ-ATZ) level, is found to reach the accuracy of the conventional CCSD(T)/A5Z level, which produces deviations below 0.5 kcal/mol from the reference, and is also highly recommendable. Scalar relativistic effects and 3s3p core-valence correlation are non-negligible for achieving chemical accuracy of around 1 kcal/mol. From the scrutiny of convergence issue with the N-electron basis set, in comparison with the reference CCSDTQ result, CCSD(T) is found to be able to calculate DeltaE? quite accurately, which is not true for the DeltaER calculations. Using highest-level CCSD(T) results of DeltaE? in this work as references, we tested 18 DFT methods and found that PBE0 and CAM-B3LYP are among the three best performing functionals, irrespective of DFT empirical dispersion correction. With empirical dispersion correction included, omegaB97XD is also recommendable due to its improved performance. PMID- 28881135 TI - Ultrasensitive Detection of Viable Enterobacter sakazakii by a Continual Cascade Nanozyme Biosensor. AB - Recent outbreaks of life-threatening neonatal infections linked to Enterobacter sakazakii (ES) heightened the need to develop rapid and ultrasensitive detection strategies, especially those capable of determining the viable cells. This study introduced a continual cascade nanozyme biosensor for the detection of viable ES based on propidium monoazide (PMA), loop-mediated isothermal amplification (LAMP), and Nanozyme strip. The ompA gene of ES was determined using FITC modified and BIO-modified primers in the LAMP process. LAMP combined with PMA treatment was applied for distinguishing the viable from the dead state of ES. Then, using Fe3O4 magnetic nanoparticles as a nanozyme probe, a magnetic nanoparticle (MNP)-based immunochromatographic strip (Nanozyme strip) was further employed for amplifying signal to allow visual detection and quantification by a strip reader. The LAMP products were sandwiched between the anti-FITC and the anti-BIO, and the accumulation of the Fe3O4 magnetic nanoparticles enabled the visual detection of ES. The detection limit of the nanozyme biosensor was improved by 10 CFU/mL compared with previously reported techniques, and the whole manipulation process was much faster (within 1 h) and simpler (without specialist facilities). Hence, the developed continual cascade nanozyme biosensor has provided a rapid, ultrasensitive, and simple tool for on-site detection of viable ES. PMID- 28881136 TI - Coordination and Substitution of DNA Polymerases in Response to Genomic Obstacles. AB - The ability for DNA polymerases (Pols) to overcome a variety of obstacles in its path to maintain genomic stability during replication is a complex endeavor. It requires the coordination of multiple Pols with differing specificities through molecular control and access to the replisome. Although a number of contacts directly between Pols and accessory proteins have been identified, forming the basis of a variety of holoenzyme complexes, the dynamics of Pol active site substitutions remain uncharacterized. Substitutions can occur externally by recruiting new Pols to replisome complexes through an "exchange" of enzyme binding or internally through a "switch" in the engagement of DNA from preformed associated enzymes contained within supraholoenzyme complexes. Models for how high fidelity (HiFi) replication Pols can be substituted by translesion synthesis (TLS) Pols at sites of damage during active replication will be discussed. These substitution mechanisms may be as diverse as the number of Pol families and types of damage; however, common themes can be recognized across species. Overall, Pol substitutions will be controlled by explicit protein contacts, complex multiequilibrium processes, and specific kinetic activities. Insight into how these dynamic processes take place and are regulated will be of utmost importance for our greater understanding of the specifics of TLS as well as providing for future novel chemotherapeutic and antimicrobial strategies. PMID- 28881137 TI - Fabrication of a Self-Supported Nanoparticle-Decorated Amphipathic Film at a Liquid/Liquid Interphase. AB - The design and facile fabrication of an amphipathic, mechanically durable, nanoparticle (NP)-decorated film has been realized at a liquid/liquid interphase. The innovative film is prepared by applying a changing electric field across an organic-aqueous interphase in the presence of 1-2 nm metal NPs, with a specific focus on Ir NPs in this work, self-assembled at the interphase, where the organic phase consists of a dissolved hydrophobic polymer in a volatile solvent. The electrochemical process leads to the oxidation of the Ir to IrOx, forming a hydrous oxide matrix at the interphase. With evaporation of the residual volatile solvent and precipitation of the polymer backbone, an isolable Ir/IrOx-decorated film is realized. The novelty of this technique stems from the ability to fabricate a substrate material in situ around a nanoparticle matrix, as opposed to transferring the matrix onto a substrate. The subsequent film exhibits a hydrophobic and a hydrophilic surface, permitting the film to reside at a water/oil, water/air, or oil/air interphase. The differences in wettability are attributed to the differences in the chemical and physical properties of the two sides of the film. Interestingly, despite both sides of the film exhibiting different wettabilities, both sides are electrochemically accessible. Several potential applications exist for this film, including the separation and collection of oil from water, in biosensors, and as catalyst layers. PMID- 28881138 TI - Impact of Rotational Twin Boundaries and Lattice Mismatch on III-V Nanowire Growth. AB - Pseudomorphic planar III-V transition layers greatly facilitate the epitaxial integration of vapor-liquid-solid grown III-V nanowires (NW) on Si(111) substrates. Heteroepitaxial (111) layer growth, however, is commonly accompanied by the formation of rotational twins. We find that rotational twin boundaries (RTBs), which intersect the surface of GaP/Si(111) heterosubstrates, generally cause horizontal NW growth and may even suppress NW growth entirely. Away from RTBs, the NW growth direction switches from horizontal to vertical in the case of homoepitaxial GaP NWs, whereas heteroepitaxial GaAs NWs continue growing horizontally. To understand this rich phenomenology, we develop a model based on classical nucleation theory. Independent of the occurrence of RTBs and specific transition layers, our model can generally explain the prevalent observation of horizontal III-V NW growth in lattice mismatched systems and the high crystal quality of horizontal nanowires. PMID- 28881140 TI - Proton Capture Dynamics in Quinoline Photobases: Substituent Effect and Involvement of Triplet States. AB - Converting light into chemical energy often occurs through redox reactions that require transfer of several electrons and protons. Using light to control proton transfer has the potential for driving otherwise unfavorable protonation reactions or producing transient pH changes. Photoacids and photobases are fundamental functional elements that could serve this purpose. Previously, we have reported the thermodynamic drive for proton removal in a series of quinoline photobases using Forster cycle analysis of the singlet states. Because the existence of thermodynamic drive does not imply that the molecules can indeed capture protons in the excited state, in this work we report the kinetics of proton removal from water by 5-R-quinolines, R = {NH2, OCH3, H, Cl, Br, CN}, using ultrafast transient absorption spectroscopy. We found that the time constants and mechanisms of proton capture from water are highly sensitive to the substituent. In some cases, proton transfer occurs within the singlet manifold, whereas in some others intersystem crossing competes with this process. We have evidence that the triplet states are also capable of proton capture in two of the compounds. This renders the excited state proton transfer process more complicated than can be captured by the linear free energy relationships inferred from the energetics of the singlet states. We have measured proton capture times in this family to be in the range of several tens of picoseconds with no discernible trend with respect to the Hammett parameter of the substituents. This wide range of mechanisms is attributed to the high density of excited electronic states in the singlet and triplet manifolds. The ordering between these states is expected to change by substituent, solvent, and hydrogen bonding, thus making the rate of intersystem crossing and proton transfer very sensitive to these parameters. These results are necessary fundamental steps to assess the capabilities of photobases in prospective applications such as photomediated proton removal in redox reactions, steady state optical regulation of local pH, and pOH jump kinetics experiments. PMID- 28881139 TI - Fracture-Targeted Delivery of beta-Catenin Agonists via Peptide-Functionalized Nanoparticles Augments Fracture Healing. AB - Despite several decades of progress, bone-specific drug delivery is still a major challenge. Current bone-acting drugs require high-dose systemic administration which decreases therapeutic efficacy and increases off-target tissue effects. Here, a bone-targeted nanoparticle (NP) delivery system for a beta-catenin agonist, 3-amino-6-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-N-(pyridin-3 yl)pyrazine-2-carboxamide, a glycogen synthase kinase 3 beta (GSK-3beta) inhibitor, was developed to enhance fracture healing. The GSK-3beta inhibitor loading capacity was found to be 15 wt % within highly stable poly(styrene-alt maleic anhydride)-b-poly(styrene) NPs, resulting in ~50 nm particles with ~ -30 mV surface charge. A peptide with high affinity for tartrate-resistant acid phosphatase (TRAP), a protein deposited by osteoclasts on bone resorptive surfaces, was introduced to the NP corona to achieve preferential delivery to fractured bone. Targeted NPs showed improved pharmacokinetic profiles with greater accumulation at fractured bone, accompanied by significant uptake in regenerative cell types (mesenchymal stem cells (MSCs) and osteoblasts). MSCs treated with drug-loaded NPs in vitro exhibited 2-fold greater beta-catenin signaling than free drug that was sustained for 5 days. To verify similar activity in vivo, TOPGAL reporter mice bearing fractures were treated with targeted GSK-3beta inhibitor-loaded NPs. Robust beta-galactosidase activity was observed in fracture callus and periosteum treated with targeted carriers versus controls, indicating potent beta-catenin activation during the healing process. Enhanced bone formation and microarchitecture were observed in mice treated with GSK-3beta inhibitor delivered via TRAP-binding peptide-targeted NPs. Specifically, increased bone bridging, ~4-fold greater torsional rigidity, and greater volumes of newly deposited bone were observed 28 days after treatment, indicating expedited fracture healing. PMID- 28881141 TI - Elongated Plant Virus-Based Nanoparticles for Enhanced Delivery of Thrombolytic Therapies. AB - Thrombotic cardiovascular disease, including acute myocardial infarction, ischemic stroke, and venous thromboembolic disease, is the leading cause of morbidity and mortality worldwide. While reperfusion therapy with thrombolytic agents reduces mortality from acute myocardial infarction and disability from stroke, thrombolysis is generally less effective than mechanical reperfusion and is associated with fatal intracerebral hemorrhage in up to 2-5% of patients. To address these limitations, we propose the tobacco mosaic virus (TMV)-based platform technology for targeted delivery of thrombolytic therapies. TMV is a plant virus-based nanoparticle with a high aspect ratio shape measuring 300 * 18 nm. These soft matter nanorods have favorable flow and margination properties allowing the targeting of the diseased vessel wall. We have previously shown that TMV homes to thrombi in a photochemical mouse model of arterial thrombosis. Here we report the synthesis of TMV conjugates loaded with streptokinase (STK). Various TMV-STK formulations were produced through bioconjugation of STK to TMV via intervening PEG linkers. TMV-STK was characterized using SDS-PAGE and Western blot, transmission electron microscopy, cryo-electron microscopy, and cryo electron tomography. We investigated the thrombolytic activity of TMV-STK in vitro using static phantom clots, and in a physiologically relevant hydrodynamic model of shear-induced thrombosis. Our findings demonstrate that conjugation of STK to the TMV surface does not compromise the activity of STK. Moreover, the nanoparticle conjugate significantly enhances thrombolysis under flow conditions, which can likely be attributed to TMV's shape-mediated flow properties resulting in enhanced thrombus accumulation and dissolution. Together, these data suggest TMV to be a promising platform for the delivery of thrombolytics to enhance clot localization and potentially minimize bleeding risk. PMID- 28881142 TI - Thermal and cytokine responses to endotoxin challenge during early life. AB - Sudden infant death syndrome (SIDS) remains the leading cause of infant mortality beyond the neonatal period. An increase in body temperature as a result of high environmental temperature, overwrapping of infants, and (or) infection are associated with SIDS. Endotoxins such as lipopolysaccharide (LPS) and heat stress may perturb cardiorespiratory function and thermoregulation. Although LPS mediated body temperature and cytokine responses are well documented in older animals, the capacity of LPS to induce fever and cytokine response in young rats remains unclear. Therefore, we sought to investigate the acute effects of LPS on body temperature and cytokine concentrations in rat pups. Postnatal day 7 rat pups were divided into 3 groups: Group 1, rats were administered LPS intraperitoneally (200 MUg/kg); Group 2, rats received saline at volume equal to that administered in the LPS group; Group 3, rats received no treatment. Pups were placed in custom-made chambers maintained at ambient temperature of 33 degrees C. Body surface temperature was continuously monitored for 4 h. Thereafter, the rats were euthanized and serum was collected for cytokine analysis. We demonstrate that LPS treatment increased MIP-1alpha, IL-10, MCP-1, IP-10, fractalkine, and TNF-alpha with no concurrent rise in body surface temperature. Although neonatal rats produced an array of cytokines in response to LPS, there was no evidence of fever. PMID- 28881143 TI - Evaluation of the clinical effectiveness of fluocinolone acetonide 190 ug intravitreal implant in diabetic macular edema: a comparison between study and fellow eyes. AB - OBJECTIVES: To compare visual and anatomical outcomes between eyes treated with fluocinolone acetonide (FAc) 190 ug intravitreal implant for clinically significant chronic diabetic macular edema (DME) and fellow eyes not treated with FAc implant using data from the Iluvien Clinical Evidence study in the UK (ICE UK) study. METHODS: In this retrospective cohort study, data on people attending hospital eye services and treated with the FAc implant between April 1, 2013 and April 15, 2015 were collected. Changes in visual acuity (VA), central foveal thickness (CFT) and intraocular pressure (IOP) were compared between study eyes (intervention) and fellow eyes. RESULTS: A total of 208 people were selected. Mean age was 68.1 years and 62% were male. Mean change in VA was -0.09 LogMAR units for study eyes and 0.04 LogMAR units for fellow eyes at 12 months post implant (p < .001). Over the same period, >=5 letter, >=10 letter and >=15 letter improvements in Early Treatment Diabetic Retinopathy Study (ETDRS) score were achieved by more FAc treated eyes than by fellow eyes (41% versus 23%, p < .001; 28% versus 11%, p < .001; and 18% versus 4%, p < .001 at 12 months, respectively). Differences in the mean change in CFT (-113 um versus -13 um, p < .001) and IOP (3.2 mmHg versus -0.2 mmHg, p < .001) were also observed between study and fellow eyes at 12 months. CONCLUSION: Visual acuity improved in study eyes over the 12 months following FAc implant and worsened in fellow eyes. Over the same period, study eyes showed a larger improvement in central foveal thickness. Intraocular pressure worsened in study eyes only. Change in visual acuity, central foveal thickness and intraocular pressure between FAc implant and the end of the 12-month follow-up period differed significantly between study and fellow eyes. PMID- 28881144 TI - Studies on occurrence, characterisation and decontamination of emerging pathogenic Escherichia coli (STEC, ETEC and EIEC) in table eggs. AB - 1. Escherichia coli is one of the most common facultative anaerobic species present in the gastrointestinal tract of animals and human beings. Usually they occur as commensals, but some serotypes can cause significant illnesses in humans as well as mammals and birds. 2. The occurrence of E. coli in different categories of table eggs collected from markets was evaluated. Isolates were analysed for the presence of virulence genes, antibiotic susceptibility pattern and efficacy of peracetic acid and chlorine for the purpose of decontaminating table eggs. 3. Significant differences were observed in the occurrence of E. coli between different groups viz. processed (cleaned, washed, sanitised and packed eggs), unprocessed (un-cleaned, un-sanitised and loose eggs) and free range (eggs obtained from backyard poultry) table eggs. Overall, E. coli occurred in table eggs at 28.6% with 22.9, 29.2 and 50.0% occurrence in processed, unprocessed and free-range table eggs, respectively. 4. A total of 24 isolates of E. coli were obtained and screened for virulence genes viz. STH, SLT1/2 and INVE genes. Of the 24 isolates recovered, 10 typeable isolates belonged to O141, O119, O9, O120 and O101 serotypes, while the remaining 14 were untypeable. Antibiograms of the isolates showed multiple antimicrobial resistance (MAR) index in the range of 0.13-0.40. 5. Peracetic acid (PAA) and chlorine (CL) were studied for their sanitisation efficacy; concentrations of 100 mg/kg of PAA and 200 mg/kg of CL completely inactivated E. coli over the egg surface and also resulted in 2.58 and 2.38 log reduction in total viable counts (TVC), respectively. 6. The presence of virulence-associated shiga-like toxin (SLT1/2) and invasion E (INVE) genes and antimicrobial resistance among the emerging serotypes of pathogenic E. coli isolated from table eggs has public health implications. It underscores the need to implement better management practices across the production systems and marketing channels to produce E. coli-free wholesome eggs for consumers. PMID- 28881145 TI - Secondhand tobacco smoke and severity in wheezing children: Nasal oxidant stress and inflammation. AB - OBJECTIVES: Prenatal and postnatal smoke exposures are associated with many lung diseases in children due to impaired lung function, increased inflammation, and oxidative stress. We aimed to determine the influence of secondhand tobacco smoke exposure on the levels of nasal glutathione, IL-8, IL-17, MMP-9, and TIMP-1, as well as serum surfactant protein-D (SP-D) in wheezy children. METHODS: We enrolled 150 children with recurrent wheezing and recorded wheezing characteristics at enrollment. We measured the levels of serum cotinine, SP-D, nasal glutathione, IL-8, IL-17, MMP-9, and TIMP-1. Serum cotinine levels between 3 and 12 ng/mL, and above 12 ng/mL were defined as lower and higher level secondhand tobacco smoke exposure, respectively. The ANOVA test, Pearson's correlation analysis and multivariate analysis with a linear regression test were used for the statistical analysis. RESULTS: Ninety-one children had been exposed to lower level secondhand tobacco smoke, while 24 children were exposed to higher level secondhand tobacco smoke. Thirty-five children were not exposed to cigarette smoke. Wheezing symptom scores were higher in exposed children (p = 0.03). Levels of other biomarkers showed no significant difference. CONCLUSIONS: Secondhand tobacco smoke exposure is associated with more severe respiratory symptoms in wheezing children. However, levels of nasal or serum inflammatory markers fail to explain this association, either because of different mechanical factors in the process or due to low levels of the biomarkers especially in nasal secretions. PMID- 28881146 TI - Health-economic evaluation of fluocinolone acetonide 190 ug implant in people with diabetic macular edema. AB - OBJECTIVES: To assess healthcare resource use and costs of treating people with clinically significant diabetic macular edema (DME) with fluocinolone acetonide (FAc) 190 ug intravitreal implant in routine clinical practice. METHODS: The retrospective Iluvien Clinical Evidence (ICE-UK) study collected data on people prescribed the FAc implant in any one of 13 ophthalmology centers between April 1, 2013 and April 15, 2015. Data were collected for 12 months before and after implantation. Standard UK costs were attributed to healthcare resource use. RESULTS: In total, 208 people contributing 233 FAc-treated eyes were selected. Mean age was 68.1 years and 62% were male. The mean (standard deviation, SD) number of anti-vascular endothelial growth factor (anti-VEGF) injections per FAc treated eye in the 12 months prior to implant was 2.8 (2.5), decreasing to 0.6 (1.4) for the same period after implant (p < .001). The corresponding figures for other steroid injections (dexamethasone and triamcinolone) were 0.14 (0.4) before and 0.08 (0.4) after implant (p = .016). There was no statistically significant difference in the number of laser therapies required in the 12 months before and after FAc implant (mean = 0.12 vs 0.11, respectively; p = .626). Overall, mean (SD) healthcare costs were L2,691 (L1,850) before and L1,239 (L1,203) after FAc implant (p < .001). The unit drug and administration cost per FAc implant was L5,680. CONCLUSIONS: Excluding the cost of the FAc implant, healthcare costs were significantly reduced in the 12 months post-implant. FAc implant has a duration of 3 years. This needs to be considered when interpreting the cost associated with the FAc implant. PMID- 28881147 TI - Cardiorespiratory demand of acute voluntary cycling with functional electrical stimulation in individuals with multiple sclerosis with severe mobility impairment. AB - Exercise training is one strategy for improving cardiorespiratory fitness (CRF) in multiple sclerosis (MS); however, few modalities are accessible for those with severe mobility impairment. Functional electrical stimulation (FES) cycling is an adapted exercise modality with the potential for improving CRF in people with severe MS. The objective of this study was to characterize the cardiorespiratory response of acute voluntary cycling with FES in people with MS with severe mobility impairment, and to compare this response to passive leg cycling. Eleven participants with MS that required assistance for ambulation completed a single bout of voluntary cycling with FES or passive leg cycling. Oxygen consumption, heart rate (HR), work rate (WR), and ratings of perceived exertion (RPE) were recorded throughout the session. For the FES group, mean exercising oxygen consumption was 8.7 +/- 1.8 mL/(kg.min)-1, or 63.5% of peak oxygen consumption. Mean HR was 102 +/- 9.7 bpm, approximately 76.4% of peak HR. Mean WR was 27.0 +/- 9.2 W, or 57.3% of peak WR, and median RPE was 13.5 (interquartile range = 5.5). Active cycling with FES was significantly (p < 0.05) more intense than passive leg cycling based on oxygen consumption, HR, WR, and RPE during exercise. In conclusion, voluntary cycling with FES elicited an acute response that corresponded with moderate-to vigorous-intensity activity, suggesting that active cycling with FES can elicit a sufficient stimulus for improving CRF. PMID- 28881148 TI - Protective effect of (-)-alpha-bisabolol on rotenone-induced toxicity in Drosophila melanogaster. AB - (-)-alpha-Bisabolol (BISA) is a sesquiterpene alcohol, which has several recognized biological activities, including anti-inflammatory, anti-irritant, and antibacterial properties. In the present study, we investigated the influence of BISA (5, 25, and 250 MUmol/L) on rotenone (500 MUmol/L)-induced toxicity in Drosophila melanogaster for 7 days. BISA supplementation significantly decreased rotenone-induced mortality and locomotor deficits. The loss of motor function induced by rotenone correlated with a significant change in stress response factors; it decreased thiol levels, inhibited mitochondria complex I, and increased the mRNA expression of antioxidant marker proteins such as superoxide dismutase (SOD), catalase (CAT), and the keap1 gene product. Taken together, our findings indicate that the toxicity of rotenone is likely due to the direct inhibition of complex I activity, resulting in a high level of oxidative stress. Dietary supplementation with BISA affected the expression of SOD mRNA only at a concentration of 250 MUmol/L, and did not affect any other parameter measured. Our results showed a protective effect of BISA on rotenone-induced mortality and locomotor deficits in Drosophila; this effect did not correlate with mitochondrial complex I activity, but may be related to the antioxidant protection afforded by eliminating superoxide generated as a result of rotenone induced mitochondrial dysfunction. PMID- 28881150 TI - Patterns of retinal thickness prior to and following treatment with fluocinolone acetonide 190 ug intravitreal implant for diabetic macular edema. AB - OBJECTIVES: To compare retinal thickness before and after treatment with the fluocinolone acetonide (FAc) 190 ug intravitreal implant in people with diabetic macular edema (DME) using data from the Iluvien Clinical Evidence study in the UK (ICE-UK). METHODS: For this retrospective cohort study, data on people attending any one of 13 participating ophthalmology departments and treated with FAc intravitreal implant between April 1, 2013 and April 15, 2015 were collected for 12 months prior to and at least 12 months after implantation. Cross-sectional and longitudinal patterns of central foveal thickness (CFT) were compared before and after FAc implant. RESULTS: There were 208 people who contributed data from 233 individual eyes treated with the FAc implant. Mean age was 68.1 years and 62% were male. Median (interquartile range) CFT decreased from 462 um (354-603 um) at time of implant to 309 um (222-433 um) at 12 months post-implant (p < .001). Over the same period, a reduction of >=10%, >=25%, and >=50% in CFT was observed in 113 (65%), 87 (50%), and 37 (21%) treated eyes, respectively. Eyes with a CFT of >=400 um at the time of implant were significantly more likely to achieve a reduction in CFT of >=10%, >=25%, and >=50% at 12 months (all p < .001) compared with eyes with a CFT of <400 um at implant. Both retinal thickness and changes in retinal thickness were loosely correlated with visual acuity. CONCLUSION: A marked reduction in retinal thickness was observed in people following FAc intravitreal implant for DME. The response was related to the degree of retinal thickness prior to treatment. PMID- 28881149 TI - Evaluation of the clinical effectiveness in routine practice of fluocinolone acetonide 190 ug intravitreal implant in people with diabetic macular edema. AB - OBJECTIVE: The aim of the Iluvien Clinical Evidence study in the UK (ICE-UK) was to assess the real-world effectiveness of fluocinolone acetonide (FAc) 190 ug intravitreal implant for the treatment of clinically significant chronic diabetic macular edema (DME) in routine clinical practice. METHODS: This retrospective study collected data from patient medical records in 13 ophthalmology centers for people with DME prescribed FAc intravitreal implant between April 1, 2013 and April 15, 2015. Visual acuity (VA) and intraocular pressure (IOP) measurements were collected for 12 months prior to and after implant. RESULTS: Two hundred and eight people, contributing 233 eyes, treated with FAc implant were included. Mean age was 68.1 years and 62% were male. In the 12 months prior to FAc implant, VA declined. Median (interquartile range, IQR) VA was 0.66 (0.48-1.00) LogMAR units (equivalent to 52.0 ETDRS letters) at implant, improving to 0.60 (0.38-0.90) LogMAR units (55.0 letters) at 12 months post-implant (p < 0.001). In total, 44%, 30%, and 18% of people achieved an improvement in ETDRS score of >=5, >=10, and >=15 letters, respectively, over the same period. A small but significant (p < .001) increase in median IOP was observed (median = 15.0, IQR = 13.0-18.0 mmHg at implant to 18.0, 15.0-21.0 mmHg at 12 months). In the 12 months following implant, additional IOP-lowering therapy was prescribed in 15% of subjects previously not requiring such therapy. CONCLUSION: Following FAc implant, an overall significant improvement in VA was observed over a period of 12 months, accompanied by a significant but small increase in IOP. PMID- 28881151 TI - Jean Marian Purdy remembered - the hidden life of an IVF pioneer. AB - Jean Purdy is almost forgotten as one of the British trio that introduced clinical IVF to the world. An unlikely pioneer, she qualified as a nurse but through indefatigable effort and unstinting loyalty to a programme that faced vitriolic opposition she became the clinical embryologist for the first IVF baby. In 1980, she helped to launch fertility services as the 'Technical Director' of Bourn Hall Clinic, near Cambridge. Although Robert Edwards and Patrick Steptoe generously credited her role in research and clinical care, a premature death in 1985 at age 39 robbed her of the reward of witnessing the blossoming of assisted reproductive technologies for patients around the world. This commentary seeks to recognize her contribution and bring her name to the attention of professionals in reproductive medicine and the patients they care for. PMID- 28881152 TI - Determining the relative cost effectiveness of the fluocinolone acetonide intravitreal implant. PMID- 28881153 TI - A personal tribute to Terry Beveridge. PMID- 28881154 TI - Preconditioning with morphine protects hippocampal CA1 neurons from ischemia reperfusion injury via activation of the mTOR pathway. AB - The signaling pathway of chronic morphine treatment to prevent neuronal damage following transient cerebral ischemia is not clear. In this study, we examined the role of mammalian target of rapamycin (mTOR) to identify the neuroprotective effects of chronic morphine preconditioning on the hippocampus following ischemia reperfusion (I/R) injury. Morphine was administered for 5 days, twice a day, before inducing I/R injury. The possible role of mTOR was evaluated by the injection of rapamycin (5 mg/kg body weight, by intraperitoneal injection) before I/R was induced. The passive avoidance test was used to evaluate memory performance. Neuronal density and apoptosis were measured in the CA1 region, 72 h after I/R injury. The expressions of mTOR and phosphorylated mTOR (p-mTOR), as well as superoxide dismutase (SOD) activity were determined 24 h after I/R injury. Chronic morphine treatment attenuated apoptosis and neuronal loss in the hippocampus after I/R injury, which led to improvement in memory (P < 0.05 vs. untreated I/R) and increase in the expression of p-mTOR (P < 0.05 vs. untreated I/R) and SOD activity (P < 0.05 vs. untreated I/R) in the hippocampus. Pretreatment with rapamycin abolished all the above-mentioned protective effects. These results describe novel findings whereby chronic morphine preconditioning in hippocampal CA1 neurons is mediated by the mTOR pathway, and through increased phosphorylation of mTOR can alleviate oxidative stress and apoptosis, and eventually protect the hippocampus from I/R injury. PMID- 28881155 TI - Seasonal patterns of Asthma medication fills among diverse populations of the United States. AB - OBJECTIVE: Nonadherence to controller and overuse of reliever asthma medications are associated with exacerbations. We aimed to determine patterns of seasonal asthma medication use and to identify time period(s) during which interventions to improve medication adherence could reduce asthma morbidity. METHODS: We conducted a retrospective cohort study of asthmatics 4-50 years of age and enrolled in three diverse health insurance plans. Seasonal patterns of medications were reported by monthly prescription fill rates per 1000 individuals with asthma from 1998 to 2013, and stratified by healthcare plan, sex, and age. RESULTS: There was a distinct and consistent seasonal fill pattern for all asthma medications. The lowest fill rate was observed in the month of July. Fills increased in the autumn and remained high throughout the winter and spring. Compared with the month of May with high medication fills, July represented a relative decrease of fills ranging from 13% (rate ratio, RR: 0.87, 95% confidence interval, 95%CI: 0.72-1.04) for the combination of inhaled corticosteroids (ICS) + long acting beta agonists (LABA) to 45% (RR: 0.55, 95%CI: 0.49-0.61) for oral corticosteroids. Such a seasonal pattern was observed each year across the 16 year study period, among healthcare plans, sexes, and ages. LABA containing control medication (ICS+LABA and LABA) fill rates were more prevalent in older asthmatics, while leukotriene receptor antagonists were more prevalent in the younger population. CONCLUSIONS: A seasonal pattern of asthma medication fill rates likely represents a reactive response to a loss of disease control and increased symptoms. Adherence to and consistent use of asthma medications among individuals who use medications in reaction to seasonal exacerbations might be a key component in reducing the risk of asthma exacerbations. PMID- 28881156 TI - Nucleic acid-based vaccines targeting respiratory syncytial virus: Delivering the goods. AB - Respiratory syncytial virus (RSV) is a massive medical burden on a global scale. Infants, children and the elderly represent the vulnerable populations. Currently there is no approved vaccine to protect against the disease. Vaccine development has been hindered by several factors including vaccine enhanced disease (VED) associated with formalin-inactivated RSV vaccines, inability of target populations to raise protective immune responses after vaccination or natural viral infection, and a lack of consensus concerning the most appropriate virus associated target antigen. However, with recent advances in the molecular understanding of the virus, and design of highly characterized vaccines with enhanced immunogenicity there is new belief a RSV vaccine is possible. One promising approach is nucleic acid-based vaccinology. Both DNA and mRNA RSV vaccines are showing promising results in clinically relevant animal models, supporting their transition into humans. Here we will discuss this strategy to target RSV, and the ongoing studies to advance the nucleic acid vaccine platform as a viable option to protect vulnerable populations from this important disease. PMID- 28881157 TI - Identifying cost-effective screening algorithms for active hepatitis C virus infections in a high prevalence setting. AB - OBJECTIVE: To evaluate the cost-effectiveness of different screening patterns for active chronic hepatitis C virus (HCV) infections utilizing the hepatitis C core antigen test compared to standard care in the context of a general screening program in a high-prevalence country. METHODS: This study developed a decision analytic model to estimate the cost-effectiveness of four screening algorithms for the detection of active HCV infections among asymptomatic individuals with an unknown HCV status in a context of high (>5%) HCV prevalence. Three algorithms started with a serological test for antibodies (AB) followed by a nucleic acid test for HCV-RNA (RNA), the HCVAg (AG) assay, or both. An additional single marker screening strategy with AG was added to the analysis. By the example of the Republic of Georgia, strategies were compared in terms of total costs for screening and diagnosis of an active infection from a health system perspective. RESULTS: Replacing RNA with AG for confirmation of positive AB identified fewer active infections (-110 per 100,000 screened subjects) at significantly reduced total costs (-$2.74 per screened) and costs per diagnosed infection (-$44). Adding a subsequent RNA confirmatory test on AG negative results captured at least the same rate compared to the standard (AB followed by RNA) at still reduced costs (-$1.16 per subject screened, -$22 per case detected). Utilizing AG as the frontline test revealed the highest detection rate (97.9%) at the highest costs (+$3.80 per subject, +$323 per case detected vs standard). CONCLUSION: A combined pattern of HCV AB screening followed by sequential confirmation with AG and RNA on AG negatives would provide equal or better diagnostic performance at lower cost over a broad range of scenarios. Potential long-term consequences of screening strategies to patients and society have to be considered, since the latency period for HCV to develop into severe liver disease is long. PMID- 28881158 TI - Long noncoding RNA DLX6-AS1 promotes renal cell carcinoma progression via miR 26a/PTEN axis. AB - Recently, long non-coding RNAs (lncRNAs) have emerged as new gene regulators and prognostic markers in several types of cancer, including renal cell carcinoma (RCC). In this study, we identified an upregulated lncRNA, DLX6-AS1, in RCC tumor tissues compared with normal kidney tissues. Our data suggested that DLX6-AS1 promoted RCC cell growth and tumorigenesis via targeting miR-26a. In addition, we observed that PTEN overexpression restored the renal cancer cell growth and also rescued the RCC tumorigenesis. In summary, we conclude that DLX6-AS1 promotes renal cell carcinoma development via regulation of miR-26a/PTEN axis. PMID- 28881159 TI - Patent trend and competitive analysis of cancer immunotherapy in the United States. AB - Immunotherapy has brought high hopes for cancer treatment, and attracted tremendous resources from the biopharmaceutical community. Here we analyze cancer immunotherapy-related patents granted by the United States Patent and Trademark Office in the past decade (2006-2016). A total of 2,229 patents were identified in 13 subfields. The growth of patent number in this field has outpaced the background rate, with cytokine-related therapies, immune checkpoint inhibitors, and natural killer cell therapies growing the most rapidly. The top 15 assignees possess 27.6% (616) of the patents. Amgen is the largest patent holder, followed by Novartis, and then by Chugai Seiyaku. The top assignees have focused on different subfields, and collaborated with each other for technology development. Our competitive analysis reveals that Novartis, Chugai Seiyaku, and Abbvie lead in both patent number and average quality of patents. Meanwhile, Immunomedics owns a high-quality though relatively small patent portfolio in single-chain variable fragment technology, which is not the focus of the abovementioned forerunners. Overall, our analysis illustrates an ecosystem where industry giants and smaller-size players each occupies a niche. Selection and succession are expected to continue for years in this young ecosystem. PMID- 28881160 TI - Effective treatment of aggressive fibromatosis with celecoxib guided by genetic testing. AB - Aggressive fibromatosis (AF) or desmoid tumors is an aggressive fibroblastic proliferation which is locally invasive but can not metastasize. The treatment of AF is challenging. Surgery was the main treatment modality for AF in the past, other strategies including radiotherapy, systemic therapies and wait-and-see policy. The use of non-steroidal anti-inflammatory drugs (NSAIDs) and targeted therapies has demonstrated good results. In the case report, a 39-year-old man presented with progressive chest wall pain. Computed tomography (CT) showed an approximately 46* 13 mm soft-tissue mass between the inside of the fifth and sixth rib on the right side. The entire mass was excised and an AF was confirmed based on histopathology. Four months after surgery, magnetic resonance imaging (MRI) showed a soft-tissue mass in surgical areas and biopsy confirmed local recurrence. Therefore, Tomotherapy was administered. However, two months later, an (18)F-fluorodeoxyglucose (FDG) Positron Emission Tomography combined with CT (PET-CT) revealed the presence of an FDG-avid mass in the area of local recurrence. Genetic testing reported the presence of a p.T41A mutations on the CTNNB1 gene, which predicted that he is sensitive to the COX-2 inhibitor celecoxib. The tumor regressed rapidly after the application of celecoxib. Within the 20-month follow-up period, the patient showed remarkable regression without any signs and symptoms. Our case report provides further evidence for the efficacy of celecoxib in AF with CTNNB1 gene mutations. To our knowledge, this is the first report of AF treated with celecoxib under the guidance of the genetic testing. However, further studies are required. PMID- 28881161 TI - Leptomeningeal carcinomatosis from gastric cancer successfully treated by the intrathecal methotrexate plus temozolomide and simultaneous radiotherapy: Case report and literatures review. AB - Leptomeningeal carcinomatosis (LMC) from gastrointestinal cancer is rare. A 56 year-old man with complaint of upper abdominal pain exhibited adenocarcinoma upon histopathologic examination of biopsy specimens. At the end of adjuvant chemotherapy, the patient was affected by hearing loss. Malignant cells were observed by cerebrospinal fluid (CSF) cytology. Therefore, the patient received intrathecal methotrexate and oral temozolomide chemotherapy and radiotherapy. The progress-free survival was approximately 11 months. To our knowledge, such cases of LMC from gastric cancer are very rare. Here, we describe the case of a patient with LMC from gastric cancer and review the literature associated with treatment. We hope that the present report may be helpful when considering how to improve treatment of LMC in gastric cancer patients and offer some tips for the adjuvant treatment modality. PMID- 28881162 TI - Perioperative Vision Loss after Non-Ocular Surgery. AB - Perioperative vision loss (POVL) may cause devastating visual morbidity. A prompt anatomical and etiologic diagnosis is paramount to guide management and assess prognosis. Where possible, steps should be undertaken to minimize risk of POVL for vulnerable patients undergoing high-risk procedures. We review the specific risk factors, pathophysiology, and management and prevention strategies for various etiologies of POVL. PMID- 28881164 TI - Systemic Rosai-Dorfman disease with central nervous system involvement. AB - Rosai-Dorfman disease (RDD) is a rare idiopathic and lymphoproliferative disorder. Central nervous system (CNS) involvement is infrequent and typically manifests as an isolated lesion. In this article, we describe an unusual case of RDD with multiple lesions in the CNS, upper respiratory tract and lymph nodes. A literature review revealed 45 cases (including the one described herein) of systemic RDD with CNS involvement documented to date. Among these cases, 29 (64.4%) presented with intracranial lesions, 10 (22.2%) with spinal lesions and 6 (13.3%) with both. While the condition of most patients was stable, only four died from RDD or for other reasons. Prognosis is good for most patients, even those with extensive lesions. Although there are various treatments for RDD, surgery is preferred. Given the rarity of RDD, multicenter international collaborations are advocated in order to study disease pathogenesis and develop effective treatment strategies. PMID- 28881163 TI - Exploiting poly(I:C) to induce cancer cell apoptosis. AB - TLR3 belong to the Toll-like receptors family, it is mainly expressed on immune cells where it senses pathogen-associated molecular patterns and initiates innate immune response. TLR3 agonist poly(I:C) was developed to mimic pathogens infection and boost immune system activation to promote anti-cancer therapy. Accordingly, TLR agonists were included in the National Cancer Institute list of immunotherapeutic agents with the highest potential to cure cancer. Besides well known effects on immune cells, poly(I:C) was also shown, in experimental models, to directly induce apoptosis in cancer cells expressing TLR3. This review presents the current knowledge on the mechanism of poly(I:C)-induced apoptosis in cancer cells. Experimental evidences on positive or negative regulators of TLR3 mediated apoptosis induced by poly(I:C) are reported and strategies are proposed to successfully promote this event in cancer cells. Cancer cells apoptosis is an additional arm offered by poly(I:C), besides activation of immune system, for the treatment of various type of cancer. A further dissection of TLR3 signaling would contribute to greater resolution of the critical steps that impede full exploitation of the poly(I:C)-induced apoptosis. Experimental evidences about negative regulator of poly(I:C)-induced apoptotic program should be considered in combinations with TLR3 agonists in clinical trials. PMID- 28881165 TI - Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine in adults 50 to 65 years of age in India: An open-label trial. AB - Streptococcus pneumoniae infection is a major global public health concern in older adults, especially as life expectancy continues to increase in most countries, including India. Recently, a 13-valent pneumococcal conjugate vaccine (PCV13) with the ability to enhance immunity (immunologic memory) on natural exposure or revaccination has been shown to protect against community-acquired pneumonia and invasive pneumococcal disease in adults 65 years of age and older. An unconjugated 23-valent pneumococcal polysaccharide vaccine has been available for decades; however, data on protection against pneumonia are inconsistent. For the first time, a multicenter study has been conducted in India to assess the safety and immunogenicity of a single dose of PCV13 in adults aged 50 to 65 years. In this study, PCV13 elicited robust immune responses against all 13 pneumococcal serotypes as reflected by the magnitude of geometric mean fold rises (range, 6.6-102.7) in functional antibody levels from before to 1 month after vaccination. No serious adverse events occurred. These clinical trial findings support the safety and immunogenicity of PCV13 when administered to adults in India and indicate that a single dose of PCV13 has the potential to protect against vaccine-type pneumococcal disease in adults aged 50 to 65 years. ClinicalTrials.gov identifier: NCT02034877. PMID- 28881167 TI - Meeting report: The 12th European oral microbiology workshop (EOMW) in Stockholm, Sweden. PMID- 28881166 TI - Effect of combination vaccines on completion and compliance of childhood vaccinations in the United States. AB - Vaccination at age-appropriate intervals increases protection against morbidity and mortality; however, compliance rates among children remain low partly due to a complicated vaccination schedule. Use of combination vaccines reduces the number of injections per visit; however, there is limited evidence quantifying the effect of combination vaccines on vaccination rates. To examine how combination vaccines impact childhood completion (receipt of recommended doses) and compliance (receipt of age-appropriate vaccinations) rates, this study analyzed vaccination data from the 2012 National Immunization Survey (NIS), a nationally representative cross-sectional survey of caregivers of children aged 24 to 35 months in the United States. Vaccines were categorized as combination or single antigen. Vaccine completion was measured at ages 8, 18, and 24 months. Vaccine compliance and time undervaccinated were measured at 24 months. Children who received at least 1 combination vaccine (86%) had a higher completion rate (69%) and compliance with the full vaccine series (4:3:1:3:3:1:4 series) at 24 months (24%) than those who received only single-antigen vaccines (50% and 13%, respectively). Receipt of combination vaccine was associated with an increased likelihood of completing all recommended vaccinations at 24 months (odds ratio [OR] = 2.5; P < 0.001), receiving all vaccinations at age-appropriate times (OR = 2.2; P < 0.001), and less than 7 months undervaccinated (OR = 2.4; P < 0.001). Combination vaccines were associated with improved completion and compliance and should be encouraged among children who are undervaccinated or who received single-antigen vaccines only. PMID- 28881169 TI - Are orthodontic systematic reviews registered a priori in PROSPERO? AB - INTRODUCTION: Aim of this study was to assess the registration of orthodontic systematic reviews in PROSPERO. METHOD: Seven databases were searched for orthodontic systematic reviews published in 2012-2016. After duplicate study selection and data extraction, descriptive statistics, followed by chi square/Fisher exact tests were calculated. Finally, bivariable/multivariable regression with relative risks (RR) and 95% confidence intervals (CIs) was used. RESULTS: A total of 182 orthodontic systematic reviews were identified, 37 (20.3%) of which were registered in PROSPERO, with registration rates ranging from 4.3% in 2012 to 37.0% in 2016. Differences in review registration were found according to publication year, geographic origin, multicentre status, funding, and journal category. After controlling for confounders, each additional year was associated with increased registration probability (RR = 1.51; 95% CI = 1.19 1.93). Reviews from South America were more likely to be registered than reviews from Europe (RR = 1.49; 95% CI = 1.06-2.11). Finally, reviews published in orthodontic specialty journals were more likely to be registered than reviews in general dentistry journals (RR = 1.87; 95% CI = 1.02-3.49). CONCLUSIONS: A small percentage of orthodontic systematic reviews was registered a priori, although improvement signs have been seen since the initiation of PROSPERO. PMID- 28881168 TI - Proteomic analysis reveals that a global response is induced by subinhibitory concentrations of ampicillin. AB - In this study, a recipient-donor co-culture system was used to research the effect of subinhibitory concentrations of antibiotics on horizontal transmission in bacteria and the influence of antibiotics on protein expression. We employed two-dimensional gel electrophoresis combined with mass spectrometry to compare the protein expression profiles in systems with or without 0.5 * the minimum inhibitory concentration of ampicillin. RT-PCR was used to assess the transcriptional levels of the differentially expressed genes. Fifty-seven different proteins were induced or suppressed. The upregulated proteins were involved in transcription and translation, cell wall synthesis, bacterial SOS response, and detoxifying functions, and the downregulated proteins were involved in metabolism. These results indicated that a global response was induced in the recipient-donor co-culture system by the subinhibitory concentration of ampicillin. Further analysis revealed that a global regulatory network based on key pathways was induced in the system in response to the antibiotic pressure. These findings provide a new, more comprehensive view for research on antibiotic resistance mechanisms in recipient-donor co-culture. PMID- 28881170 TI - The Book Corner. PMID- 28881171 TI - Meetings & Symposia. PMID- 28881172 TI - From ideal occlusion to dentofacial deformity and back to ideal: an osteochondroma treatment with lingual orthodontics. AB - This original case report describes the morphologic changes caused by a mandibular condylar osteochondroma (OC) on a female patient and its treatment. The changes were identified by comparing her final records from a previous orthodontic treatment, without the presence of OC, to records taken before a second treatment, with a developed OC. The diagnostics and treatment for the OC and its consequences were described and discussed in this paper. Treatment included orthodontics with a lingual appliance, low condylectomy on the affected side, high condylectomy on the contralateral side, bilateral disc repositioning and orthognathic surgery. It was concluded that the OC caused a Class III subdivision malocclusion, midline deviation and an edge-to-edge bite on the left side, a cant of the occlusal plane on the Z-axis and a deviation of the pogonion to the left. Treatment was successful and stable long term (36 months) with good occlusal, aesthetical and functional results. PMID- 28881173 TI - ESTIMATION OF THE EXTENT OF LINKAGE DISEQUILIBRIUM IN SEVEN REGIONS OF THE PORCINE GENOME. AB - Linkage disequilibrium (LD) refers to the correlation among neighboring alleles, reflecting non-random patterns of association between alleles at (nearby) loci. A better understanding of LD in the porcine genome is of direct relevance for identification of genes and mutations with a certain effect on the traits of interest. Here, 215 SNPs in seven genomic regions were genotyped in individuals of three breeds. Pairwise linkage disequilibrium was calculated for all marker pairs. To estimate the extent of LD, all pairwise LD values were plotted against the distance between the markers. Based on SNP markers in four genomic regions analyzed in three panels from populations of Large White, Dutch Landrace, and Meishan origin, useful LD is estimated to extend for approximately 40 to 60 kb in the porcine genome. PMID- 28881176 TI - A HIERARCHICAL BINOMIAL-POISSON MODEL FOR THE ANALYSIS OF A CROSSOVER DESIGN FOR CORRELATED BINARY DATA WHEN THE NUMBER OF TRIALS IS DOSE-DEPENDENT. AB - The differential reinforcement of a low-rate 72-seconds schedule (DRL-72) is a standard behavioral test procedure for screening a potential antidepressant compound. The data analyzed in the article are binary outcomes from a crossover design for such an experiment. Recently, Shkedy et al. ( 2004 ) proposed to estimate the treatments effect using either generalized linear mixed models (GLMM) or generalized estimating equations (GEE) for clustered binary data. The models proposed by Shkedy et al. ( 2004 ) assumed the number of responses at each binomial observation is fixed. This might be an unrealistic assumption for a behavioral experiment such as the DRL-72 because the number of responses (the number of trials in each binomial observation) is expected to be influenced by the administered dose level. In this article, we extend the model proposed by Shkedy et al. ( 2004 ) and propose a hierarchical Bayesian binomial-Poisson model, which assumes the number of responses to be a Poisson random variable. The results obtained from the GLMM and the binomial-Poisson models are comparable. However, the latter model allows estimating the correlation between the number of successes and number of trials. PMID- 28881178 TI - GUEST EDITORS' NOTE. PMID- 28881177 TI - MODELING ANTI-KLH ELISA DATA USING TWO-STAGE AND MIXED EFFECTS MODELS IN SUPPORT OF IMMUNOTOXICOLOGICAL STUDIES. AB - During preclinical drug development, the immune system is specifically evaluated after prolonged treatment with drug candidates, because the immune system may be an important target system. The response of antibodies against a T-cell-dependent antigen is recommenced by the FDA and EMEA for the evaluation of immunosuppression/enhancement. For that reason, we developed a semiquantitative enzyme-linked immunosorbent assay to measure antibodies against keyhole limpet hemocyanin. To our knowledge, the analysis of this kind of data is at this moment not yet fully explored. In this article, we describe two approaches for modeling immunotoxic data using nonlinear models. The first is a two-stage model in which we fit an individual nonlinear model for each animal in the first stage, and the second stage consists of testing possible treatment effects using the individual maximum likelihood estimates obtained in the first stage. In the second approach, the inference about treatment effects is based on a nonlinear mixed model, which accounts for heterogeneity between animals. In both approaches, we use a three parameter logistic model for the mean structure. PMID- 28881180 TI - Giant Pilomatrix Carcinoma of the Face. AB - This case report describes an unusually large facial pilomatrix carcinoma (PC) in a 60-year-old man. This PC had been growing slowly for 11 months and had recently ulcerated. It measured 9 cm * 7 cm * 5 cm. Initial punch biopsy findings were inconclusive. The tumor was excised in total with 5-mm margins in a supra superficial musculoaponeurotic system plane. The defect was reconstructed with a cervicofacial bilobed rotational advancement flap. Histopathologic findings confirmed the diagnosis of PC. There was no lymph node spread or distant metastasis. The patient recovered with a good esthetic result. This case represents one of the largest facial PCs reported in the literature. Diagnostic challenges are discussed, and the literature is reviewed. PMID- 28881179 TI - Correlation of body mass index Z-scores with glucose and lipid profiles among overweight and obese children and adolescents. AB - OBJECTIVE: To evaluate the prevalence of abnormalities in plasma lipid and glucose profiles among overweight and obese children and adolescents, and to assess the presence of a correlation between body mass index Z-scores and indicators of comorbidities related to both profiles. METHODS: This was a multicenter cross-sectional study conducted at two outpatient clinics. The study included all 417 comers for the first visit from 2008 to 2012, aged between 7 and 18 years, with BMI above the Z-score +1. Anthropometry and blood sampling were obtained. The prevalence of dyslipidemias, hyperglycemia, and insulin resistance were evaluated, together with the correlations of these variables with the increase of Z-BMI. RESULTS: Dyslipidemia was observed in 43.4% of the boys and 66.1% of the girls, with no difference between genders. High glucose levels were detected in 6.2% of the individuals. Insulin resistance was present in 32.3% and 41.7% of the cases, with no statistical significance between boys and girls. Correlations between the Z-BMI were noted for triglycerides in the entire group and among girls; for HDL-c, only among girls; for glucose, a correlation was observed for the entire group, but not when stratified by gender. The indicators of insulin resistance were all correlated with Z-BMI, even when corrected for age. CONCLUSIONS: Overweight and obesity give origin to a high prevalence of dyslipidemia and insulin resistance. BMI Z-scores showed a weak positive correlation with glucose and triglyceride, and negative with HDL-c. In turn, the strongest positive correlation was found with insulin resistance indicators. PMID- 28881181 TI - Digital Workflow for Computer-Guided Implant Surgery in Edentulous Patients: A Case Report. AB - PURPOSE: The purpose of this article was to describe a fully digital workflow used to perform computer-guided flapless implant placement in an edentulous patient without the use of conventional impressions, models, or a radiographic guide. MATERIALS AND METHODS: Digital data for the workflow were acquired using an intraoral scanner and cone-beam computed tomography (CBCT). The image fusion of the intraoral scan data and CBCT data was performed by matching resin markers placed in the patient's mouth. RESULTS: The definitive digital data were used to design a prosthetically driven implant position, surgical template, and computer aided design and computer-aided manufacturing fabricated fixed dental prosthesis. CONCLUSION: The authors believe this is the first published case describing such a technique in computer-guided flapless implant surgery for edentulous patients. PMID- 28881182 TI - Surgical Staples: A Superior Alternative to Sutures for Skin Closure After Neck Dissection-A Single-Blinded Prospective Randomized Clinical Study. AB - PURPOSE: To evaluate the efficacy of staples in skin closure after neck dissection in patients with oral squamous cell carcinoma. The authors hypothesized that the use of staples would result in better wound closure compared with the use of nonabsorbable monofilament sutures. MATERIALS AND METHODS: A prospective single-blinded randomized clinical trial was performed to compare various parameters, including time for wound closure, inflammatory changes, pain, cost efficacy, complications, and esthetic outcome of skin closure with surgical staples versus nonabsorbable monofilament sutures and to determine their statistical relevance using chi2 and Mann-Whitney U tests. RESULT: In a study of 124 patients, the mean skin closure time was 29.2 +/- 4 minutes with sutures (n = 61) and 5.3 +/- 1.29 minutes with staples (n = 63), which was significant (P = .01). Mean pain scores during removal using the visual analog scale were 5.08 +/- 1.29 and 3.15 +/- 0.89 with sutures and staples, respectively. Postoperative complications, such as gapping and stitch abscess with purulent discharge, were noted. CONCLUSION: Staples provided better esthetics with fewer complications, faster closure, minimal pain at removal, and faster healing compared with sutures. The slowest closure time in the staples group was 4 times faster than the fastest closure time in the sutures group. However, staples cost 5 times more than sutures. PMID- 28881183 TI - From machine learning to deep learning: progress in machine intelligence for rational drug discovery. AB - Machine intelligence, which is normally presented as artificial intelligence, refers to the intelligence exhibited by computers. In the history of rational drug discovery, various machine intelligence approaches have been applied to guide traditional experiments, which are expensive and time-consuming. Over the past several decades, machine-learning tools, such as quantitative structure activity relationship (QSAR) modeling, were developed that can identify potential biological active molecules from millions of candidate compounds quickly and cheaply. However, when drug discovery moved into the era of 'big' data, machine learning approaches evolved into deep learning approaches, which are a more powerful and efficient way to deal with the massive amounts of data generated from modern drug discovery approaches. Here, we summarize the history of machine learning and provide insight into recently developed deep learning approaches and their applications in rational drug discovery. We suggest that this evolution of machine intelligence now provides a guide for early-stage drug design and discovery in the current big data era. PMID- 28881185 TI - The Usefulness of Serologic Testing for Epstein-Barr Virus Before Initiation of Therapy for Inflammatory Bowel Disease. PMID- 28881184 TI - Developmental Delay and Colon Polyposis. PMID- 28881186 TI - An Unusual Liver Tumor. PMID- 28881187 TI - An Atypical Coincidence of Colon Ischemia and Bilateral Distal Ureteral Strictures. PMID- 28881188 TI - RE: Steatorrhea, Hyperoxaluria and Colonic Hyperproliferation After Roux-en-Y Gastric Bypass. PMID- 28881189 TI - Screening for Epstein-Barr Virus Status and Risk of Hemophagocytic Lymphohistiocytosis in Children With Inflammatory Bowel Disease on Azathioprine. PMID- 28881190 TI - A Large Changing Mass in the Esophagus. PMID- 28881191 TI - A Rare Case of Chylous Ascites. PMID- 28881192 TI - A Rare Cause of Severe Hypokalemia and Back Pain. PMID- 28881193 TI - An Unusual Cause of Hepatic Dysfunction. PMID- 28881194 TI - An Unexpected Cause of Acute Abdomen. PMID- 28881195 TI - Detectable Viremia at the End of Treatment With Direct-Acting Antivirals Can Be Associated With Subsequent Clinical Cure in Patients With Chronic Hepatitis C: A Case Series. PMID- 28881196 TI - A Severe But Easily Treatable Dysphagia. PMID- 28881198 TI - Ecophysiological strategies for growth under varying light and organic carbon supply in two species of green microalgae differing in their motility. AB - Mixing events in stratified lakes result in microalgae being exposed to varying conditions in light and organic carbon concentrations. Stratified lakes consist of an upper illuminated strata and a lower, darker strata where organic carbon accumulates. Therefore, in this contribution we explore the importance of dissolved organic carbon for growth under various light intensities by measuring some ecophysiological adaptations in two green microalgae. We compared the non motile Chlorella vulgaris with the flagellated Chlamydomonas acidophila under auto-, mixo-, and heterotrophic growth conditions. In both algae the maximum photosynthetic and growth rates were highest under mixotrophy, and both algae appeared inhibited in their phosphorus acquisition under heterotrophy. Heterotrophic conditions provoked the largest differences as C. vulgaris produced chlorophyll a in darkness and grew as well as in autotrophic conditions, whereas Chl. acidophila bleached and could not grow heterotrophically. Although the fatty acid composition of both phytoplankton species differed, both species reacted in a similar way to changes in their growth conditions, mainly by a decrease of C18:3n-3 and an increase of C18:1n-9 from auto- to heterotrophic conditions. The two contrasting responses within the group of green microalgae suggest that dissolved organic carbon has a high deterministic potential to explain the survival and behaviour of green algae in the deeper strata of lakes. PMID- 28881197 TI - Oleanane-type triterpene saponins from Calendula stellata. AB - Five previously undescribed bisdesmosidic triterpenoid saponins named calendustellatosides A-E, along with fifteen known compounds were isolated from the 70% ethanol whole plant extract of Calendula stellata Cav. (Asteraceae). Their structures were determined by 1D- and 2D-NMR spectroscopy as well as high resolution mass spectrometry and acid hydrolysis. The saponins comprised oleanolic acid, echinocystic acid, morolic acid or mesembryanthemoidigenic acid as the aglycones and saccharide moieties at C-3 and C-28. Like most Calendula saponins, the sugar moiety linked at C-3 was either beta-d-glucose or beta-d glucuronic acid which could be substituted at C-3 by a beta-d-galactose and/or C 2 by a supplementary beta-d-galactose or a beta-d-glucose. The sugar moiety linked to C-28 was determined as beta-d-glucose. The antibacterial evaluation of compounds 1-20 by bioautography on Staphylococcus aureus followed by the determination of MIC values of active compounds by serial dilution technique against 5 bacteria revealed that; calendustellatoside D was the most active against Enterococcus faecalis with an antibacterial effect comparable to antibiotics. The cytotoxic activities of isolated compounds were evaluated against fibrosarcoma cell line (HT1080) and human lung cancer cell line (A549). Calendustellatosides B and D exhibited a low cytotoxic activity against HT1080 cell line with IC50 values of 47 +/- 0.6 and 39 +/- 0.5 MUM, respectively. PMID- 28881199 TI - Nitrogen-doped carbon nanotubes based on melamine-formaldehyde resin as highly efficient catalyst for oxygen reduction reaction. AB - The preparation of highly efficient and cheap electrocatalysts toward oxygen reduction reaction is significant for many electrochemical cells. Here we facilely synthesized nitrogen doped carbon nanotube by pyrolyzing melamine formaldehyde resin and Fe loading on MgO. There were mainly three morphologies observed, slender bamboo-like CNT, thick bamboo-like CNT, surface smooth, hollow CNT. The content of Fe loading on MgO had little influence on morphologies of CNT, however, when no MgO as support, only carbon ribbon obtained. The MgO as support was also significant for the formation of CNT. The samples with CNT formed represented better catalytic activity than control samples with no-CNT obtained, the morphology of CNT was beneficial for catalytic process. The sample C1-CNT with lowest content of Fe on support represented best catalytic activity which was competitive with 20% Pt/C in half-wave potential. The C1-CNT also showed outstanding stability and improved selectivity towards ORR, making it a promising alternative to Pt in application of fuel cells and metal-air batteries. PMID- 28881200 TI - Facile synthesis of bimetallic gold-palladium nanocrystals as effective and durable advanced catalysts for improved electrocatalytic performances of ethylene glycol and glycerol oxidation. AB - In this work, well-defined bimetallic AuPd alloyed nanocrystals (AuPd NCs) were facilely synthesized by a straightforward and controllable one-step wet-chemical strategy, using a biomolecule (L-hydroxyproline, L-Hyp) as the green stabilizer and the structure-directing agent. Their morphology, size, composition, crystal structures and growth mechanism were investigated by a series of techniques. The synthesized architectures exhibited enlarged electrochemically active surface area (ECSA), improved catalytic activity, enhanced durability and stability towards ethylene glycol oxidation reaction (EGOR) and glycerol oxidation reaction (GOR) in alkaline electrolytes in comparison with commercial Pd black catalyst. PMID- 28881202 TI - The effect of solvent polarity on wormlike micelles using dipropylene glycol (DPG) as a cosolvent in an anionic/zwitterionic mixed surfactant system. AB - HYPOTHESIS: The behavior/properties of micellar solutions are governed by Coulombic interactions that are influenced by the polarity of the surfactant head groups, hydrophobic tails, and solvent molecules. The addition of co-solvent should have a direct impact on solvent polarity and the size of the micelles are expected to decrease accordingly. EXPERIMENTS: In this study, a mixed surfactant system is studied composed of a common anionic surfactant, sodium laureth sulfate 1, modified by a zwitterionic surfactant, cocamidopropyl betaine in deuterated water. In this system, worm-like micelles (WLMs) are formed. The influence of a co-solvent, dipropylene glycol (DPG) in the present of high salt content, is investigated. DPG primarily modifies the dielectric constant of the solvent. FINDINGS: It was found that the addition of DPG slightly decreased the micelle radius, but dramatically reduced the persistence length as well as the contour length of the micelles. The relative dependence of contour length on salt concentration is not significantly changed. Thus, it is shown that the self assembled structure can be tuned by adjusting solvent polarity without affecting the relative tunability of the WLM/ellipsoidal structure through counter ion concentration. PMID- 28881201 TI - Double Z-scheme system of silver bromide@bismuth tungstate/tungsten trioxide ternary heterojunction with enhanced visible-light photocatalytic activity. AB - The ternary heterojunction of silver bromide@bismuth tungstate/tungsten trioxide (AgBr@Bi2WO6/WO3) was designed and synthesised by hydrothermal and deposition precipitation approaches. The composites were characterised by X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy (XPS). The photoabsorption range and bandgaps of the photocatalysts were analysed by ultraviolet-visible diffuse reflectance spectroscopy (UV-vis DRS). Compared with Bi2WO6/WO3 or AgBr alone, the AgBr@Bi2WO6/WO3 composites displayed higher visible light photocatalytic performance for degrading rhodamine B (RhB). AgBr@Bi2WO6/WO3 with 40% AgBr concentration was optimum for photocatalytic activity. Radical trapping experiments revealed that superoxide anion radicals (O2-) and holes (h+) were the active species during photocatalytic degradation and that O2- was the dominant active species. Therefore, the increased photocatalytic activity of AgBr@Bi2WO6/WO3 was attributed to the atypical double Z-scheme system, which effectively improved the transfer and separation of electron-hole pairs in ternary heterojunction structures. PMID- 28881203 TI - In situ silica coating-directed synthesis of orthorhombic methylammonium lead bromide perovskite quantum dots with high stability. AB - Luminescent perovskite quantum dots (QDs) had attracted great attention by virtue of the merits of color-tunable and narrow-band emissions. However, sofar reported perovskite QDs suffered from instability more or less. In this work, a type of silica-coated orthorhombic CH3NH3PbBr3 QDs (SiO2-QDs) with greatly improved stability was reported. The SiO2-QDs were one-pot synthesized using a reprecipitation-encapsulation method assisted with an amine functional silane, which not conly controlled the crystallization of QDs, but also encapsulated QDs with a silica layer simultaneously. More interestingly, the in situ encapsulation of silica shell induced the presence of orthorhombic perovskite that was thought to be unstable at room temperature. This is the first report of orthorhombic CH3NH3PbBr3 QDs, as far as we are concerned. The orthorhombic SiO2-QDs exhibited narrow-band green luminescence with a quantum yield of 78%, and a high production yield of ~70wt%. Moreover, stability of SiO2-QDs was considerably improved due to silica-coating. White-LEDs were also successfully fabricated with the green SiO2 QDs and a red commercial phosphors using a noncontact configuration. These results demonstrated that the orthorhombic SiO2-QDs held great promise for high performance display or lighting technology. PMID- 28881204 TI - Gelation mechanism of cellulose nanofibre gels: A colloids and interfacial perspective. AB - HYPOTHESIS: Nanocellulose gels form a new category of sustainable soft materials of industrial interest for a wide range of applications. There is a need to map the rheological properties and understand the mechanism which provides the colloidal stability and gelation of these nanofibre suspensions. EXPERIMENTS: TEMPO (2,2,6,6,-tetramethylpiperidine-1-oxyl)-oxidised cellulose nanofibre gels were investigated at different fibre concentrations, pH and ionic strength. Dynamic and cyclic rheological studies was performed to quantify gel behaviour and properties. Gels were produced at different pH and salt contents to map and understand colloidal stability of the nanocellulose gel. FINDINGS: Rheology indicates gelation asa transitionary state starting at a fibre concentration of 0.1wt.%. The colloidal stability of the nanocellulose gel network is controlled by pH and salt, whereas fibre concentration mainly dictates the dynamic rheological properties. Decreasing pH and adding salt destabilises the gel network by eluting bound water which is correlated with the decrease in electrostatic repulsion between fibres. The gelation and colloidal stability of these nanocellulose gels is driven by electrostatic forces and the entanglement ability of the fibrous system to overlap. PMID- 28881205 TI - Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells. AB - Previously, combination chemotherapy of doxorubicin (DOX) and quercetin (QUR) was developed to improve antitumor effects and reverse multidrug resistance and several biocompatible nanocarriers, such as liposomes and micelles, were validated for their targeted delivery. In this study, we report a near-infrared (NIR)-responsive drug delivery system based on DOX and QUR co-loaded gold nanocages (AuNCs) with biotin modification. The system was simply fabricated by filling the hollow interiors of AuNCs with tetradecanol (TD), a phase-change material with a melting point of 39 degrees C, to control the drug release. The main cause of multidrug resistance (MDR) of DOX is the overexpression of P glycoprotein (P-gp), which can be inhibited by QUR. Thus the combination chemotherapy of DOX and QUR may provide a promising strategy for MDR. The in vitro cytotoxicity of DOX and QUR at several fixed mass ratios was carried out and showed that the combination index (CI) was the smallest at the ratio of 1:0.2, indicating that the best synergistic effect was achieved. The resultant nanocomplex (abbreviated as BPQD-AuNCs) exhibited fast release (80% released in 20min) and strong cytotoxicity against MCF-7/ADR cells (IC50, 1.5MUg/mL) under NIR irradiation. Additionally, BPQD-AuNCs were found to generate a large amount of reactive oxygen species (ROS), to inhibit P-gp expression and ATP activity. Taken together, the results show that BPQD-AuNC is a prospective nano-delivery system for overcoming multidrug-resistant cancer. PMID- 28881206 TI - Polyglycerolated nanocarriers with increased ligand multivalency for enhanced in vivo therapeutic efficacy of paclitaxel. AB - Despite the excellent biocompatibility and antifouling effect of poly(ethylene glycol) (PEG), the high steric hindrance, limited chemical functionality, and low ligand multivalency of PEGylated nanocarriers often lead to inefficient cell targeting and intracellular trafficking. Hence, a new structure of hydrophilic corona allowing a higher ligand density without loss of excellent biocompatibility is highly desirable. Here we introduce tumor-targeted polyglycerolated (PGylated) nanocarriers that dramatically enhance the in vivo therapeutic efficacy of incorporated paclitaxel simply by increasing the surface density of hydrophobic tumor-targeting ligands. Linear polyglycerol-poly (epsilon caprolactone) block copolymer (PG-b-PCL) is used to prepare PGylated lipiodol nanoemulsions, where PG serves as a corona conjugated with a large number of folic acid (FA) for efficient tumor targeting. Unlike FA-PEGylated nanoemulsions, FA-PGylated nanoemulsions can display a larger number of FA without structural destabilization. This property enables excellent anti-cancer activities and effective tumor regression in a cervical cancer xenograft murine model at a cumulative drug dose of ~5 mg kg-1, which is about four fold smaller than that of commercial Taxol formulation. This study highlights the importance of surface chemistry of nanocarriers that enable multivalent ligand functionalization and high tolerance to the conjugation of hydrophobic ligands, which make PG as a very effective hydrophilic corona for in vivo drug delivery. PMID- 28881207 TI - Pathway from poor self-rated health to mortality: Explanatory power of disease diagnosis. AB - Poor self-rated health has been consistently demonstrated as a reliable predictor for mortality, often exceeding the predictive power of other "objective" medical factors. Drawing from a theoretical framework for the cognitive processes underlying the self-assessment of health, this study seeks to test the knowledge mechanisms that moderate the predictive power of poor self-rated health. Using nationally-representative longitudinal data from the Canadian National Population Health Survey (NPHS) from 1994 to 2010, this study tests the effects of physician diagnosed disease for the life course trajectory of self-rated health, and as a moderator for the power of poor self-rated health to predict proximate mortality. Disruptions to self-rated health trajectories are measured using an interrupted time-series analysis. Predictive power is modelled using generalized estimating equation (GEE) logistic regression. Findings show that physician-diagnosed diseases cause a negative shock to self-rated health, even accounting for endogeneity. Furthermore, a major portion of the predictive power of poor self rated health in the final years of life is explained by respondents' knowledge of the disease conditions which eventually cause their death. This novel finding supports one of the foremost theories putting cognition and knowledge at the root of why poor self-rated health is such a robust predictor of mortality. PMID- 28881208 TI - Differential item functioning in quality of life measurement: An analysis using anchoring vignettes. AB - Systematic differences in the ways that people use and interpret response categories (differential item functioning, DIF) can introduce bias when using self-assessments to compare health or quality of life across heterogeneous groups. This paper reports on an exploratory analysis involving the use of anchoring vignettes to identify DIF in a commonly used measure for assessing health-related quality of life - namely the EQ-5D. Using data from a bespoke (i.e. custom) survey that recruited a representative sample of 4300 respondents from the general Australian population in 2014 and 2015, we find that the assumptions of response consistency (RC) and vignette equivalence (VE) hold in a sub-sample of respondents aged 55-65 years (n = 914), which demonstrates that vignettes can appropriately identify DIF in EQ-5D reporting for this age group. We find that the EQ-5D is indeed subject to DIF, and that failure to account for DIF can lead to conclusions that are misleading when using the instrument to compare health or quality of life across heterogeneous groups. We also provide several important insights in terms of the identifying assumptions of RC and VE. We conclude that the implications of DIF could be of considerable importance, not only for outcomes research, but for funding decisions in healthcare more broadly given the strong reliance on patient-reported outcome measures in economic evaluations for health technology assessment. PMID- 28881209 TI - Use of gas chromatography-mass spectrometry-olfactometry and a conventional flask test to identify off-flavor compounds generated from phenylalanine during chlorination of drinking water. AB - Off-flavor in drinking water can be caused by transformation products (TPs) generated from organic compounds, such as amino acids, present during chlorination. However, the contributions of many of these TPs to overall off flavor have not been quantified, mainly because the lack of appropriate chemical standards prevents sensory evaluation by means of a conventional flask test. In the present study, we used gas chromatography-mass spectrometry-olfactometry (GC MS-O) to identify compounds responsible for the off-flavor generated by chlorination of an aqueous solution of the amino acid phenylalanine, and we propose a sensory evaluation procedure for quantification of the contributions of the identified TPs to the overall off-flavor, regardless of the availability of chemical standards of the TPs. GC-MS-O revealed that two TPs, N chlorophenylacetaldimine and 2-chloro-2-phenylacetaldehyde, for which chemical standards are not commercially available, were the main components responsible for the off-flavor of the chlorinated solution. By using a sensory evaluation procedure involving a combination of GC-MS-O and a conventional flask test, we quantified the contributions of TPs to the overall off-flavor of the chlorinated solution. Approximately 60% of the off-flavor was attributable to free chlorine (13%), 2-chloro-2-phenylacetaldehyde (13%), trichloramine (12%) phenylacetaldehyde (11%) phenylacetonitrile (8%), and N-chlorophenylacetaldimine (2%). Treatment with powdered activated carbon (PAC) removed the off-flavor. Experiments with chlorination of 15N-labeled phenylalanine suggested that PAC reductively decomposed trichloramine into N2 gas and adsorbed all of the other identified TPs. Superfine PAC (median diameter, 0.7 MUm) removed the off-flavor more rapidly than normal-size PAC (median diameter, 8.0 MUm). PMID- 28881210 TI - Total electron acceptor loading and composition affect hexavalent uranium reduction and microbial community structure in a membrane biofilm reactor. AB - Molecular microbiology tools (i.e., 16S rDNA gene sequencing) were employed to elucidate changes in the microbial community structure according to the total electron acceptor loading (controlled by influent flow rate and/or medium composition) in a H2-based membrane biofilm reactor evaluated for removal of hexavalent uranium. Once nitrate, sulfate, and dissolved oxygen were replaced by U(VI) and bicarbonate and the total acceptor loading was lowered, slow-growing bacteria capable of reducing U(VI) to U(IV) dominated in the biofilm community: Replacing denitrifying bacteria Rhodocyclales and Burkholderiales were spore producing Clostridiales and Natranaerobiales. Though potentially competing for electrons with U(VI) reducers, homo-acetogens helped attain steady U(VI) reduction, while methanogenesis inhibited U(VI) reduction. U(VI) reduction was reinstated through suppression of methanogenesis by addition of bromoethanesulfonate or by competition from SRB when sulfate was re-introduced. Predictive metagenome analysis further points out community changes in response to alterations in the electron-acceptor loading: Sporulation and homo acetogenesis were critical factors for strengthening stable microbial U(VI) reduction. This study documents that sporulation was important to long-term U(VI) reduction, whether or not microorganisms that carry out U(VI) reduction mediated by cytochrome c3, such as SRB and ferric-iron-reducers, were inhibited. PMID- 28881211 TI - The in situ bacterial production of fluorescent organic matter; an investigation at a species level. AB - Aquatic dissolved organic matter (DOM) plays an essential role in biogeochemical cycling and transport of organic matter throughout the hydrological continuum. To characterise microbially-derived organic matter (OM) from common environmental microorganisms (Escherichia coli, Bacillus subtilis and Pseudomonas aeruginosa), excitation-emission matrix (EEM) fluorescence spectroscopy was employed. This work shows that bacterial organisms can produce fluorescent organic matter (FOM) in situ and, furthermore, that the production of FOM differs at a bacterial species level. This production can be attributed to structural biological compounds, specific functional proteins (e.g. pyoverdine production by P. aeruginosa), and/or metabolic by-products. Bacterial growth curve data demonstrates that the production of FOM is fundamentally related to microbial metabolism. For example, the majority of Peak T fluorescence (> 75%) is shown to be intracellular in origin, as a result of the building of proteins for growth and metabolism. This underpins the use of Peak T as a measure of microbial activity, as opposed to bacterial enumeration as has been previously suggested. This study shows that different bacterial species produce a range of FOM that has historically been attributed to high molecular weight allochthonous material or the degradation of terrestrial FOM. We provide definitive evidence that, in fact, it can be produced by microbes within a model system (autochthonous), providing new insights into the possible origin of allochthonous and autochthonous organic material present in aquatic systems. PMID- 28881212 TI - Nanofiltration as tertiary treatment method for removing trace pharmaceutically active compounds in wastewater from wastewater treatment plants. AB - The ever-increasing occurrence and persistence of pharmaceutically active compounds (PhACs) in soils, sediments, drinking water supplies and wastewater effluents are a matter of serious environmental concern for governments and researchers worldwide. Nanofiltration as tertiary treatment method can be a viable and practical tool to remove these pollutants from aquatic environments. However, organic matter present in water sources can foul the membrane surface during operation, thus being potentially able to affect the membrane performance. Therefore, fouling mechanisms could heavily influence on the removal efficiencies. The purpose of this study was to investigate the implementation of three nanofiltration membranes (TFC-SR2, NF-270 and MPS-34) and to study both the rejection of trace PhACs and the fouling mechanisms for each membrane as a function of feed solution pH. Fouling mechanisms were predicted by Hermia's model adapted to cross-flow configurations. Results demonstrated that higher removals were obtained at slightly alkaline pH, especially for anionic trace PhACs. At the same conditions, more severe fouling was observed, which resulted in strong flux declines and an increase in hydrophobicity. This indicates that the attached organic matter on the membrane surface acts as a secondary selective barrier for separation. PMID- 28881213 TI - Trends in riverine element fluxes: A chronicle of regional socio-economic changes. AB - We show how concentrations of water solutes in the Vltava River (Czech Republic) and their riverine outputs from the catchment were modified by socio-economic changes, land use, and hydrology between 1960 and 2015. In the early 1960s, HCO3 and Ca were the dominant ions. During 1960-1989 (a period of planned economy with an over-use of synthetic fertilizers, excessive draining of agricultural land and little environmental protection), the riverine concentrations of strong acid anions (SAAs: SO4, NO3, and Cl) increased 2-4-fold and their leaching was accompanied for by a 1.4-1.8-fold increase in concentrations of Ca, Mg, K, and Na. SAAs mostly originated from diffuse agricultural sources (synthetic fertilizers and mineralization of organic matter in freshly drained and deeply tilled agricultural land) and their annual average concentrations (as well as those of Ca, Mg, and K) were positively correlated with discharge. During 1990 2015 (a period of a re-established market economy, reduced fertilization, ceased drainage, partial conversion of arable land to pastures, and increasing environmental protection), concentrations of SO4 and NO3 significantly decreased due to reduced agricultural production and atmospheric pollution, and their positive correlations with discharge disappeared. In contrast, Na and Cl concentrations increased due to more intensive road de-icing, and their concentrations became negatively correlated with discharge. Trends in phosphorus concentrations reflected changes in its input by both diffuse (fertilizers) and point (wastewater) sources and were discharge independent. PMID- 28881214 TI - The influence of online images on self-harm: A qualitative study of young people aged 16-24. AB - To date, research on the role of the Internet in self-harm has focused on young people's interaction via the medium of text, with limited consideration of the effect of images. This qualitative study explores how young people understand and use online images of self-harm. Semi-structured interviews were conducted with a community sample of 21 individuals aged 16-24 living in Wales, UK, with a previous history of self-harm. Interviewees reported the role of the Internet in normalising young people's self-harm. Images rather than textual interactions are the primary reason cited for using the Internet for self-harm purposes. Images invoke a physical reaction and inspire behavioural enactment, with Tumblr, which permits the sharing of images by anonymous individuals, being the preferred platform. Viewing online images serves a vital role in many young people's self harm, as part of ritualistic practice. Online prevention and intervention need to attend to the importance of images. PMID- 28881215 TI - A systemic approach to understanding mental health and services. AB - In the UK mental health and associated NHS services face considerable challenges. This paper aims to form an understanding both of the complexity of context in which services operate and the means by which services have sought to meet these challenges. Systemic principles as have been applied to public service organisations with reference to interpersonal relations, the wider social culture and its manifestation in service provision. The analysis suggests that the wider culture has shaped service demand and the approaches adopted by services resulting in a number of unintended consequences, reinforcing loops, increased workload demands and the limited value of services. The systemic modelling of this situation provides a necessary overview prior to future policy development. The paper concludes that mental health and attendant services requires a systemic understanding and a whole system approach to reform. PMID- 28881216 TI - Who provides inconsistent reports of their health status? The importance of age, cognitive ability and socioeconomic status. AB - Self-assessed health (SAH) measures are widely used in models of health and health inequalities. Such models assume that SAH is a reliable measure of health status. We utilise a unique feature of a national longitudinal survey to examine the consistency of responses to a standard SAH question that is asked twice to the same individual in close temporal proximity in up to three waves (2001, 2009, and 2013). In particular, we analyse whether the consistency of responses varies with personal characteristics. The main analysis sample includes 18,834 individual-year observations. We find that 57% of respondents provide inconsistent reports at least once. Characteristics that are associated with significantly higher inconsistencies are age, education, cognitive ability, and time between responses. The results suggest that there are systematic differences in the ability of individuals' to self-evaluate and summarise their own health. Consequently, failure to account for such error may lead to large estimation biases in models of health outcomes, particularly with respect to the relationship between education, cognitive ability, and health. PMID- 28881217 TI - Protein beta-sheet prediction using an efficient dynamic programming algorithm. AB - Predicting the beta-sheet structure of a protein is one of the most important intermediate steps towards the identification of its tertiary structure. However, it is regarded as the primary bottleneck due to the presence of non-local interactions between several discontinuous regions in beta-sheets. To achieve reliable long-range interactions, a promising approach is to enumerate and rank all beta-sheet conformations for a given protein and find the one with the highest score. The problem with this solution is that the search space of the problem grows exponentially with respect to the number of beta-strands. Additionally, brute-force calculation in this conformational space leads to dealing with a combinatorial explosion problem with intractable computational complexity. The main contribution of this paper is to generate and search the space of the problem efficiently to reduce the time complexity of the problem. To achieve this, two tree structures, called sheet-tree and grouping-tree, are proposed. They model the search space by breaking it into sub-problems. Then, an advanced dynamic programming is proposed that stores the intermediate results, avoids repetitive calculation by repeatedly uses them efficiently in successive steps and reduces the space of the problem by removing those intermediate results that will no longer be required in later steps. As a consequence, the following contributions have been made. Firstly, more accurate beta-sheet structures are found by searching all possible conformations, and secondly, the time complexity of the problem is reduced by searching the space of the problem efficiently which makes the proposed method applicable to predict beta-sheet structures with high number of beta-strands. Experimental results on the BetaSheet916 dataset showed significant improvements of the proposed method in both execution time and the prediction accuracy in comparison with the state-of-the-art beta-sheet structure prediction methods Moreover, we investigate the effect of different contact map predictors on the performance of the proposed method using BetaSheet1452 dataset. The source code is available at http://www.conceptsgate.com/BetaTop.rar. PMID- 28881218 TI - Downregulated expression of miR-223 promotes Toll-like receptor-activated inflammatory responses in macrophages by targeting RhoB. AB - Toll-like receptors (TLRs) induced-inflammatory response must be tightly regulated to avoid impairment in host itself. Numerous factors have been identified in regulation of TLR-triggered inflammatory response. Among these, microRNAs (miRNAs) are small non-coding RNA molecules which have got much attention. MiR-223, which highly expresses in myeloid cells of the bone marrow, has reported to participate in kinds of inflammatory responses by targeting inflammasome sensor-NLRP3 to repress production of IL-6 and IL-1beta, and thus attenuate inflammatory response. However, the function of miR-223 in TLRs activated inflammatory response of macrophages is not clear. Here we found miR 223 expression is dramatically reduced in macrophages by TLR ligand stimulation (e.g. LPS, CpG and poly (I:C)). The down-regulated miR-223 leads to the increase in the RhoB expression, which induce the activation of NF-kappaB and MAPK signaling, promoting TNF-alpha, IL-6 and IL-1beta production upon LPS stimulation. In addition, the histone deacetylase inhibitor trichostatin A increased miR-223 expression obviously in TLR-triggered macrophages, which in turn suppressed RhoB expression and downstream IL-6 production, suggesting that the inhibition of miR-223 by histone deacetylation may be involved in the regulation of TLR-activated inflammatory response. Herein, our findings suggest that miR-223-RhoB axis might be a novel target for the treatment of inflammatory diseases. PMID- 28881219 TI - 'It is not a quick fix' structural and contextual issues that affect implementation of integrated health and well-being services: a qualitative study from North East England. AB - OBJECTIVE: The objective of this article is to examine the factors affecting the design, commissioning and delivery of integrated health and well-being services (IHWSs), which seek to address multiple health-related behaviours, improve well being and tackle health inequalities using holistic approaches. STUDY DESIGN: Qualitative studies embedded within iterative process evaluations. METHODS: Semi structured interviews conducted with 16 key informants as part of two separate evaluations of IHWSs in North East England, supplemented by informal observations of service delivery. Transcripts and fieldnotes were analysed thematically. RESULTS: The study findings identify a challenging organisational context in which to implement innovative service redesign, as a result of budget cuts and changes in NHS and local authority capacity. Pressures to demonstrate outcomes affected the ability to negotiate the practicalities of joint working. Progress is at risk of being undermined by pressures to disinvest before the long-term benefits to population health and well-being are realised. The findings raise important questions about contract management and relationships between commissioners and providers involved in implementing these new ways of working. CONCLUSIONS: These findings provide useful learning in terms of the delivery and commissioning of similar IHWSs, contributing to understanding of the benefits and challenges of this model of working. PMID- 28881220 TI - Executive function predicts cognitive-behavioral therapy response in childhood obsessive-compulsive disorder. AB - Cognitive-behavioral therapy (CBT) is considered first-line treatment for childhood obsessive-compulsive disorder (OCD). Despite CBT's efficacy, too many children and adolescents do not fully respond to treatment, making the identification of predictors of treatment response highly relevant. Executive functions (EF) have been suggested to constitute such predictors, but studies with pediatric samples are scarce. In the present study, we investigated latent level EF test performance and ratings of daily life EF behavior as predictors of CBT response in pediatric OCD. We further examined the stability of EF from pre to post-treatment and the association of EF changes with OCD severity change. EF test performance significantly predicted exposure-based CBT outcome. Patients with better EF test performance had significantly elevated risk of non-response relative to patients with poorer performance. Daily life EF behavior in OCD probands improved after treatment relative to controls. The findings suggest that EF performance impacts CBT outcome, and that exposure-based CBT is well-suited for children and adolescents with OCD and poorer EF test performance. This study supports the relevance of EF in CBT for childhood OCD and denotes a possible need for development of enhanced treatments for children and adolescents with OCD and superior EF performance. PMID- 28881221 TI - Social anxiety in pre-adolescent children: What do we know about maintenance? AB - The cognitive theory of social anxiety disorder (SAD) is one of the most widely accepted accounts of the maintenance of the disorder in adults, yet it remains unknown if, or to what extent, the same cognitive and behavioral maintenance mechanisms that occur in adult SAD also apply to SAD among pre-adolescent children. In contrast to the adult literature, current models of SAD in children mostly account for etiology and maintenance processes are given limited attention. Consequently, their clinical utility for the treatment of SAD in children may be limited. This narrative review, first, critically examines the different theoretical conceptualizations of the maintenance of social anxiety in the child and adult literature and illustrates how these have resulted in different treatment approaches and clinical understanding. Second, it reviews the available evidence relating to hypotheses about the maintenance of SAD in children as derived from adult cognitive and etiological models. Third, it highlights the need to attend directly to child specific maintenance mechanisms in SAD, to draw on cognitive theory, and to account for the influence of childhood-specific contextual (e.g. family and school-based interactions) and developmental factors on children's social experiences. PMID- 28881222 TI - Immune checkpoint blockade for unresectable or metastatic uveal melanoma: A systematic review. AB - BACKGROUND: The use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM. METHODS: We performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies. RESULTS: Out of 1327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n=162), 4 phase II trials (n=171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3mg/kg in 5 trials (n=186) with a response rate of 0 to 5%. Two reports investigated ipilimumab at 10mg/kg (n=45) with radiological responses observed in 0 to 6.5%. The median progression-free survival (PFS) was below 3months and the median overall survival was 5.2-9.8months for ipilimumab monotherapy. Severe immune related adverse events occurred at a frequency comparable to cutaneous melanoma (6 to 36%). Two studies investigated pembrolizumab (2mg/kg) and nivolumab (3mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9months. CONCLUSIONS: UM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM. PMID- 28881223 TI - Efficacy of extended adjuvant therapy with aromatase inhibitors in early breast cancer among common clinicopathologically-defined subgroups: A systematic review and meta-analysis. AB - BACKGROUND: Randomized controlled trials (RCTs) have shown improvements in breast cancer outcomes from extending treatment with aromatase inhibitors (AIs) beyond the initial 5years after diagnosis. Consistency of this effect in common clinicopathologically defined subgroups was not been reported systematically. METHODS: We identified RCTs comparing extended AIs to placebo or no treatment using a systematic search of MEDLINE and a review of abstracts from key conferences between 2013 and 2016. Hazard ratios (HRs) and 95% confidence intervals (CI) for disease-free survival (DFS) were included in a meta-analysis using generic inverse variance and random effects modelling. Pre-specified subgroups included: age (<60+/-5years versus >=60+/-5 years), tumor size (>2cm versus <=2cm), nodal status (positive versus negative), hormone receptor status (double versus single receptor expression) and receipt of adjuvant chemotherapy (yes versus no). RESULTS: Seven trials comprising 16,349 patients were analyzed. Overall, the effect of extended AIs was similar in all subgroups. Non significantly greater effect sizes were seen in patients with larger tumors (HR for DFS 0.77 versus 0.88, p for difference=0.44), nodal involvement (HR=0.72 versus 0.83, p for difference=0.22), double hormone receptor expression (HR=0.68 versus 1.01, p for difference=0.31) and receipt of adjuvant chemotherapy (HR=0.71 versus 0.80, p for difference=0.51). CONCLUSIONS: Extended treatment with AIs is associated with similar relative improvements in DFS in all subgroups analyzed. The combination of greater effect size and higher absolute risk of recurrence in node positive and larger tumors will likely translate to higher absolute benefits from extended AIs in these groups. PMID- 28881224 TI - Accent modulates access to word meaning: Evidence for a speaker-model account of spoken word recognition. AB - Speech carries accent information relevant to determining the speaker's linguistic and social background. A series of web-based experiments demonstrate that accent cues can modulate access to word meaning. In Experiments 1-3, British participants were more likely to retrieve the American dominant meaning (e.g., hat meaning of "bonnet") in a word association task if they heard the words in an American than a British accent. In addition, results from a speeded semantic decision task (Experiment 4) and sentence comprehension task (Experiment 5) confirm that accent modulates on-line meaning retrieval such that comprehension of ambiguous words is easier when the relevant word meaning is dominant in the speaker's dialect. Critically, neutral-accent speech items, created by morphing British- and American-accented recordings, were interpreted in a similar way to accented words when embedded in a context of accented words (Experiment 2). This finding indicates that listeners do not use accent to guide meaning retrieval on a word-by-word basis; instead they use accent information to determine the dialectic identity of a speaker and then use their experience of that dialect to guide meaning access for all words spoken by that person. These results motivate a speaker-model account of spoken word recognition in which comprehenders determine key characteristics of their interlocutor and use this knowledge to guide word meaning access. PMID- 28881225 TI - The oxidative stress response of oxytetracycline in the ciliate Pseudocohnilembus persalinus. AB - Oxytetracycline (OTC) is commonly employed in fish farms to prevent bacterial infections in China, and because of their widely and intensive use, the potential harmful effects on organisms in aquatic environment are of great concern. Ciliates play an important role in aquatic food webs as secondary producers, and Pseudocohnilembus persalinus, is one kind of them which are easily found in fish farms, surviving in polluted water. Therefore, using P. persalinus as experimental models, this study investigated the effects of oxytetracycline (OTC) on the growth, antioxidant system and morphological damage in pollution-resistant ciliates species. Our results showed that the 96-h EC50 values for OTC of P. persalinus was 21.38mgL-1. The increased level of SOD and GSH during 96h OTC stress was related to an adaptive response under oxidative stress induced in ciliates. Additionally, sod1, sod2 and sod3 exhibited a significant increased expression level compared to control group at 24h treatment, indicating a promoting of dense system in ciliates at this exposure time. However, only sod1 and sod2 showed raised expression level at 48h stress, showing the different sensitive of gene isoforms to some extent. With OTC treatment, damage of regular wrinkles, shrunk, twisted on the cell surface, even forming cyst of scuticociliatid ciliate cells were firstly observed by SEM (scanning electron microscope) in this study. Overall, physiological, molecular and morphological information on the toxicological studies of ciliates and more information on possibility of ciliates as indicators of contamination were provided in this study. PMID- 28881226 TI - A comparison of the effects of copper nanoparticles and copper sulfate on Phaeodactylum tricornutum physiology and transcription. AB - Copper nanoparticles (CuNPs) have been used in a broad range of applications. However, they are inevitably released into the marine environment, making it necessary to evaluate their potential effects on marine phytoplankton. In this study, the short-term (96h) effects of CuNPs and CuSO4 on Phacodactylum tricornutum growth, photosynthesis, reactive oxygen species production and transcription were assessed. It was found that high concentrations (40MUM) of CuNPs and CuSO4 significantly inhibited the growth, photosynthesis and induced oxidative stress of P. tricornutum, while lower concentrations caused a hormetic response as indicated by a slight stimulation in algal growth. The high percentage of dissolved Cu (78-100%) in culture medium suggested that the dissolved Cu was the main driver of toxicity during CuNPs treatment. The algal cells upregulated electron transport chain-related genes to produce more energy and restore photosynthesis after 96h of treatment with CuNPs and CuSO4. This study delineates the cellular mechanism behind the toxicity of CuNPs and CuSO4 on marine diatoms. PMID- 28881227 TI - Test-retest reliability and smallest detectable change of the Bristol Impact of Hypermobility (BIoH) questionnaire. AB - OBJECTIVE: The Bristol Impact of Hypermobility (BIoH) questionnaire is a patient reported outcome measure developed in conjunction with adults with Joint Hypermobility Syndrome (JHS). It has demonstrated strong concurrent validity with the Short Form-36 (SF-36) physical component score but other psychometric properties have yet to be established. This study aimed to determine its test retest reliability and smallest detectable change (SDC). DESIGN: A test-retest reliability study. SETTING: Participants were recruited from the Hypermobility Syndromes Association, a patient organisation in the United Kingdom. PATIENTS: Recruitment packs were sent to 1080 adults who had given permission to be contacted about research. MAIN OUTCOME MEASURES: BIoH and SF-36 questionnaires were administered at baseline and repeated two weeks later. An 11-point global rating of change scale (-5 to +5) was also administered at two weeks. Test-retest analysis and calculation of the SDC was conducted on 'stable' patients (defined as global rating of change -1 to +1). RESULTS: 462 responses were received. 233 patients reported a 'stable' condition and were included in analysis (95% women; mean (SD) age 44.5 (13.9) years; BIoH score 223.6 (54.0)). The BIoH questionnaire demonstrated excellent test-retest reliability (ICC 0.923, 95% CI 0.900-0.940). The SDC was 42 points (equivalent to 19% of the mean baseline score). The SF-36 physical and mental component scores demonstrated poorer test-retest reliability and larger SDCs (as a proportion of the mean baseline scores). CONCLUSION: The results provide further evidence of the potential of the BIoH questionnaire to underpin research and clinical practice for people with JHS. PMID- 28881228 TI - Dendrimer-like amino-functionalized hierarchical porous silica nanoparticle: A host material for 2,4-dichlorophenoxyacetic acid imprinting and sensing. AB - In this work, a novel molecularly imprinted electrochemical sensor based on the amino-functionalized silica nanoparticles was built for the sensitive and selective detection of 2,4-dichlorophenoxyacetic acid (2,4-D). The hierarchical porous dendrimer-like silica nanoparticles (HPSNs-NH2) were synthesized by an ethyl ether emulsion method. The selective molecularly imprinted polymers (MIP) was prepared on the HPSNs-NH2 modified electrode via electropolymerization by using 2,4-D as the template and o-phenylenediamine (OPD) as the monomer. The porous structure of HPSNs-NH2 reduced the diffusion limitations of the analytes, enhanced the accessibility and increased the surface area of the sensor, while the MIP layer offered the ability to recognize and quantify target 2,4-D by using ferro/ferricyanide as probes. Several significant experimental parameters on the analytical performance of the MIP/HPSNs-NH2 sensor were explored and optimized. Under the optimized condition, the sensor displayed an appreciable selectivity over structurally related compounds and good sensitivity toward 2,4-D. The linear range of 2,4-D detection was from 1.00 * 10-10 to 2.50 * 10-8M and the detection limit was down to 1.17 * 10-11M according to the 3Sa/b criteria. This method has been applied to detect 2,4-D in bean sprout samples with satisfying results. PMID- 28881229 TI - A flow-based statistical model integrating spatial and nonspatial dimensions to measure healthcare access. AB - Assessing access to healthcare for an entire healthcare system involves accounting for demand, supply, and geographic variation. In order to capture the interaction between healthcare services and populations, various measures of healthcare access have been utilized, including the popular two-step floating catchment area (2SFCA) method. However, despite the many advantages of 2SFCA, the problems, such as inappropriate assumption of healthcare demand and failure to capture cascading effects across the system have not been satisfactorily addressed. In this paper, a statistical model for evaluating flows of individuals was added to the 2SFCA method (hereafter we refer to it as F2SFCA) in order to overcome limitations associated with its current restriction. The proposed F2SFCA model can incorporate both spatial and nonspatial dimensions and thus synthesizes them into one framework. Moreover, the proposed F2SFCA model can be easily adapted to measure access for different types of individuals, over different service provider types, or with capacity constraints in a healthcare system. We implemented the proposed model in a case study assessing access to healthcare for the elderly in Taipei City, Taiwan, and compared the weaknesses and strengths to the 2SFCA method and its variations. PMID- 28881230 TI - Investigation of the 5' flanking region and exon 3 polymorphisms of IGF-1 gene showed moderate association with semen quality in Sanjabi breed rams. AB - In this study, semen samples were collected from 96 Sanjabi rams in order to investigate the IGF-1 gene polymorphisms and their relationship with the characteristics of semen quality and testicular size. The dimensions of scrotal length, width and circumference were measured during autumn and spring over two years. Blood samples were simultaneously collected from jugular vein to extract DNA. PCR was performed using specific primers to amplify 294 and 272bp fragments including 5' regulatory region and exon 3 of IGF-1 gene, respectively. PCR products were digested by BFOI and Eco88l restriction enzymes, respectively. Two genotypes including AA (194 and 100bp), AB (294, 194 and 100bp) and all possible genotypes including CC (182 and 90bp), CT (272, 182, and 90bp) and TT (272bp) were observed for 5' flanking region and exon 3 of IGF-1 gene, respectively. The significant differences among IGF-1 genotypes for testicular dimensions were not observed. However, the polymorphism of 5' flanking region in the studied population had significant effect on individual motility and percent morphology traits. Animals with AB genotype had significantly higher individual motility compared with AA genotype (P < 0.05). Also, animals with AA genotype had significantly the highest percent morphology compared with AB genotype (P < 0.1). The exon 3 of IGF-1 gene had significant effect on individual motility, concentration, morphology and water test traits. Animals with CT genotype had the highest sperm concentration (P < 0.1) and water test (P < 0.05) compared to CC and TT genotypes. Moreover, animals with TT genotype had significantly the highest percent morphology compared with other genotypes (P < 0.05). Briefly, the results indicated that individual motility, concentration, percent morphology and water test traits could be in association with IGF-1 genotypes. It might be concluded that polymorphisms in IGF-1gene can be considered to develop male fertility in future and for using in selection process of better animals under masker assisted selection programs. PMID- 28881232 TI - Time-, spectral- and spatially resolved EPR spectroscopy enables simultaneous monitoring of diffusion of different guest molecules in nano-pores. AB - Diffusion in porous materials is under ongoing active investigation due to its major role in practical applications such as catalysis and chromatography. The complexity of these systems limits the use of the Einstein-Stokes diffusion theory, and it must be distinguished between the microscopic scale of diffusion at a molecular level, which is sensitive to the local surroundings of a diffusing molecule, and the macroscopic scale which takes into account diffusion spanning multiple pores, grain boundaries and inhomogeneity within the material. Here, we employ an in situ approach for quantitative measurements of the diffusion on a macroscopic length scale. For the first time, full time-resolved spectral spatial EPR imaging in combination with the simultaneous iterative reconstruction technique (SIRT) allows the simultaneous observation of the diffusion of two different molecular species inside of an aerogel in a single experiment. PMID- 28881231 TI - Follicles and gonadotropins during waves 2 and 3 in three-wave interovulatory intervals in Bos taurus heifers. AB - Observations were made on follicle dynamics and gonadotropin concentrations in anovulatory wave 2 and ovulatory wave 3 in three-wave interovulatory intervals (n = 15). Hypotheses were not used owing to inadequate availability of rationale. The future dominant follicles for waves 2 and 3 were designated DF2 and DF3 and the largest future subordinate follicles as SF2 and SF3, respectively. The day of expected diameter deviation (day 0) was defined as the day that DF2 or DF3 was closest to 8.5 mm. The first day that DF2 became smaller (P < 0.05) than DF3 was day 2 (10.7 +/- 0.2 mm vs 11.8 +/- 0.3 mm). The FSH surges 2 and 3 that stimulated waves 2 and 3 were similar at peak concentration, but the postsurge nadir of surge 2 occurred 1 day earlier than for surge 3. An LH increase was not temporally associated with deviation in wave 2, but an increase (P < 0.05) in LH in wave 3 began on day -1. Diameter of SF2 (6.5 +/- 0.2 mm) on day 0 was less (P < 0.005) than for SF3 (7.2 +/- 0.2 mm). Mean diameter of subordinate follicles in wave 2 did not differ among days. Diameter of subordinate follicles that attained >=6 mm in wave 3 was greater (interaction, P < 0.02) by day 3 when in the right ovary (RO, 7.4 +/- 0.2 mm) than when in the left ovary (LO, 5.6 +/- 0.2 mm). The frequency of a conventional classification of deviation (future SF greater than 7.0 mm on day 0) was less (P < 0.001) for wave 2 (1 of 15 waves) than for wave 3 (8 of 15 waves). Novel observations involving DF2 and DF3 were (1) before deviation, diameter of DF2 vs DF3 and an incline in FSH surge 2 vs surge 3 were similar and (2) after deviation, smaller diameter of DF2 vs DF3 by day 2 was associated with an earlier cessation (nadir) in FSH surge 2 vs surge 3 and an absence of an LH increase during deviation. Novel observations involving subordinate follicles >=6 mm were (1) before deviation, diameters were similar between waves 2 and 3 in association with the similar incline in FSH surges 2 vs 3 and (2) after deviation, a greater diameter increase of subordinates occurred in RO than in LO for wave 3, but an increase did not occur for either ovary in wave 2. The characteristics of diameter deviation were profoundly different between waves 2 and 3 owing to a smaller SF2 than SF3 at deviation but similar diameter of DF2 and DF3. PMID- 28881233 TI - A rapid magnetization preparation for MRI measurements of sprays. AB - The process of spray atomization, i.e., the transformation of a continuous liquid jet into MUm-sub-mm sized droplets, is ubiquitous in industry yet quite complex to analyze theoretically and study experimentally. One of the main strengths of MRI is its ability to sensitize spatially-resolved NMR signal to a wide variety of physical and chemical parameters. However, standard preparation schemes are difficult to employ for studies of sprays due to sprays' fast speeds (>10-20m/s). In addition, sprays are usually low-density systems, leading to a poor SNR and a need for massive signal averaging and long acquisition time. In this paper, we reduced the interval between the preparation and the readout stages by performing SPI encoding on the rising gradients. This also enabled the use of 90-degree flip angles to maximize the spray signal and saturate the stationary water signal while avoiding unwanted slice-selection. The use of gradients during preparation stage was eliminated due to their time-consuming rise and stabilization times limiting possible preparation schemes to a combination of RF pulses and delays. The two preparation schemes presented here are Time-of-Flight (TOF) and T1rho weighting schemes. The total duration of the sequence (without TR) was 240 1100MUs for the TOF and 410MUs for T1rho. The T1rho prepared images of the near atomization region (11 spin-locking frequencies, 0-15kHz) showed a strong signal attenuation at higher frequencies. In series of TOF images the clearly noticeable displacement of the liquid parcel can be utilized to measure spray speeds. PMID- 28881234 TI - Corrigendum to "Theoretical study of CP-VC: A simple, robust and accurate MAS NMR method for analysis of dipolar C-H interactions under rotation speeds faster than ca. 60kHz" [J. Magn. Reson. 252 (2015) 67-77]. PMID- 28881235 TI - MRI compatibility study of an integrated PET/RF-coil prototype system at 3T. AB - We have been working on the development of a PET insert for existing magnetic resonance imaging (MRI) systems for simultaneous PET/MR imaging, which integrates radiofrequency (RF)-shielded PET detector modules with an RF head coil. In order to avoid interferences between the PET detector circuits and the different MRI generated electromagnetic fields, PET detector circuits were installed inside eight Cu-shielded fiber-reinforced plastic boxes, and these eight shielded PET modules were integrated in between the eight elements of a 270-mm-diameter and 280-mm-axial-length cylindrical birdcage RF coil, which was designed to be used with a 3-T clinical MRI system. The diameter of the PET scintillators with a 12 mm axial field-of-view became 255mm, which was very close to the imaging region. In this study, we have investigated the effects of this PET/RF-coil integrated system on the performance of MRI, which include the evaluation of static field (Bo) inhomogeneity, RF field (B1) distribution, local specific absorption rate (SAR) distribution, average SAR, and signal-to-noise ratio (SNR). For the central 170-mm-diameter and 80-mm-axial-length of a homogenous cylindrical phantom (with the total diameter of 200mm and axial-length of 100mm), an increase of about a maximum of 3MUT in the Bo inhomogeneity was found, both in the central and 40-mm off-centered transverse planes, and a 5 percentage point increase of B1 field inhomogeneity was observed in the central transverse plane (from 84% without PET to 79% with PET), while B1 homogeneity along the coronal plane was almost unchanged (77%) following the integration of PET with the RF head coil. The average SAR and maximum local SAR were increased by 1.21 and 1.62 times, respectively. However, the SNR study for both spin-echo and gradient-echo sequences showed a reduction of about 70% and 60%, respectively, because of the shielded PET modules. The overall results prove the feasibility of this integrated PET/RF-coil system for using with the existing MRI system. PMID- 28881236 TI - Investigating detailed interactions between novel PAR1 antagonist F16357 and the receptor using docking and molecular dynamic simulations. AB - Currently, Vorapaxar is the only recently FDA-approved antiplatelet drug targeting Protease-activated receptor 1 (PAR1). However, a novel antagonist, F16357, has been shown to prevent painful bladder syndrome, also known as interstitial cystitis (IC). Unfortunately, there is no high resolution structure of the F16357-receptor complex, hindering its optimization as a therapeutic agent. In this study, we used docking and molecular dynamic (MD) simulations to investigate the detailed interactions between F16357 and PAR1 at a molecular level. The recently solved crystal structure of human PAR1 complexed with Vorapaxar was used in our docking of F16357 into the binding pocket of the receptor. To enhance binding pose selection, F16357 was docked first without constraints and then with a positional constraint to invert its orientation to become similar to that of Vorapaxar. The three systems, with crystal Vorapaxar, F16357 and an inverted F16357, were subjected to 3.0MUs MD simulations. The MM GBSA binding energy analysis showed that F16357 binds more strongly in a pose obtained from an unrestrained docking than in the inverted pose from a restrained docking; and Vorapaxar binds more strongly than F17357. This ordering is consistent with the experimental pIC50 values. Our structural data showed subtle changes in the binding pose between Vorapaxar and F16357. Transmembrane helices 1, 2, 5, and 7 were most significantly affected; most notably a large kink at F2795.47 in TM helix 5 of the Vorapaxar complex was completely absent in the F16357 complex. The results of this study facilitate the future development of other therapeutic PAR1 antagonists. PMID- 28881237 TI - Synthesis of a series of new glycoclusters and the evaluation of their anti adhesion activities. AB - According to our early researches, some glycoclusters having glucose, mannose, cellose and lactose residues showed good anti-adhesion activity of leukocytes to endothelial cells and exerted anti-inflammatory effects. Based on these results and combination principles of drugs, a series of new glycoclusters modifying with potentially anti-oxidant activity pharmacophores have been synthesized, and their anti-adhesion activities were assessed by static state cell-based adhesion assay. The results showed that some modified glycoclusters displayed better activities than their leading compound. PMID- 28881238 TI - In silico investigation of gas/particle partitioning equilibrium of polybrominated diphenyl ethers (PBDEs). AB - Polybrominated diphenyl ethers (PBDEs), a group of typical brominated flame retardants (BFRs), have drawn an increasing concern due to their widespread manufacture, usage and disposal around the world and the frequent detection in a variety of environmental media. In the present study, we investigated the molecular mechanism of the partitioning equilibrium of PBDEs between gas and atmospheric particles, and developed a new temperature-dependent predictive model for the gas/particle partition coefficient (KP) of these chemicals. Quantum chemical computations were implemented at B3LYP/6-31G (d,p) level of theory based on the neutral electronic ground state of PBDE congeners by Gaussian 09 software package. The model performance was assessed by different validation strategies and the application domain was defined by Williams Plot. Mechanism analysis indicated that the interactions of dispersion, electrostatic and hydrogen bond play crucial roles in the partitioning of PBDEs between the two phases. The developed model can be used to estimate the KP values of PBDEs for which experimental measurements are restricted. Therefore, this work provides an alternative method in a regulatory context of PBDEs. PMID- 28881239 TI - Comparing in situ colorimetric DET and DGT techniques with ex situ core slicing and centrifugation for measuring ferrous iron and dissolved sulfide in coastal sediment pore waters. AB - In productive coastal sediments the separation between different biogeochemical zones (e.g. oxic, iron(III)-reducing and sulfate-reducing) may be on the scale of millimetres. Conventional measurement techniques simply cannot resolve changes in pore water solute concentrations over such small distances. The diffusive equilibration in thin films (DET) and the diffusive gradients in thin films (DGT) techniques allow in situ determination of pore water solute concentration profiles with one-dimensional profiles and/or two-dimensional distributions on the millimetre scale. Here we compare measurements of pore water iron(II) and sulfide using conventional core sampling (slicing and centrifugation) and colorimetric DET-DGT techniques. DET-DGT samplers were deployed within replicate sediment cores from three different sites, which were processed by slicing and centrifugation following retrieval of the samplers, so that the measurements were approximately co-located. Iron(II) concentrations were determined by DET at all three sites (0.3-262 MUmol L-1), while dissolved sulfide was consistently measured by DGT at one site only (0.003-112 MUmol L-1). Pore water concentrations of iron(II) and sulfide determined conventionally following pore water extraction (iron(II); 0.4-88 MUmol L-1 and sulfide; 0.05-36 MUmol L-1), were systematically lower than the colorimetric DET and DGT measurements in the same sample. This underestimation was most likely due to the mixing of sediment from different biogeochemical zones during pore water extraction, which resulted in the precipitation of iron(II) and sulfide. This study shows that conventional pore water extraction methods can be unreliable for the determination of redox-active solutes due to artefacts associated with pore water mixing. PMID- 28881240 TI - Concentration and movement of neonicotinoids as particulate matter downwind during agricultural practices using air samplers in southwestern Ontario, Canada. AB - Atmospheric emissions of neonicotinoid seed treatment insecticides as particulate matter in field crops occur mainly for two reasons: 1) due to abraded dust of treated seed generated during planting using vacuum planters, and 2) as a result of disturbances (tillage or wind events) in the surface of parental soils which release wind erodible soil-bound residues. In the present study, concentration and movement of neonicotinoids as particulate matter were quantified under real conditions using passive and active air samplers. Average neonicotinoid concentrations in Total Suspended Particulate (TSP) using passive samplers were 0.48 ng/cm2, trace, trace (LOD 0.80 and 0.04 ng/cm2 for clothianidin and thiamethoxam, respectively), and using active samplers 16.22, 1.91 and 0.61 ng/m3 during planting, tillage and wind events, respectively. There was a difference between events on total neonicotinoid concentration collected in particulate matter using either passive or active sampling. Distance of sampling from the source field during planting of treated seed had an effect on total neonicotinoid air concentration. However, during tillage distance did not present an effect on measured concentrations. Using hypothetical scenarios, values of contact exposure for a honey bee were estimated to be in the range from 1.1% to 36.4% of the reference contact LD50 value of clothianidin of 44 ng/bee. PMID- 28881241 TI - Degradation of Acid Orange 7 using peroxymonosulfate catalyzed by granulated activated carbon and enhanced by electrolysis. AB - Electrochemistry coupled with granulated activated carbon catalysis of peroxymonosulfate (electro/GAC/PMS) as a novel wastewater treatment process was performed for the degradation of Acid Orange 7 (AO7) in aqueous solution. The decolorization of AO7 was compared under different permutations and combinations of electro-oxidation, GAC and PMS. It showed that the electro/GAC/PMS process was the most effective and the decolorization of AO7 followed pseudo-first order kinetics. The surface chemistry of GAC samples was analyzed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. Compared with the fresh samples, pi-electron density and hydroxyl group content decreased under the GAC/PMS system, but kept the similar values under the electro/GAC/PMS system. Electron paramagnetic resonance and radical scavenger studies were used to verify the formation of sulfate radicals (SO4-) and hydroxyl radicals (OH). The optimized conditions were found to be: current density 8 mA cm-2; PMS concentration 5 mM; GAC dosage 0.5 g L-1; and initial pH value 5.0. GAC recycling experiments over 4 runs showed some decrease in reactivity. Overall, the results indicate that 100% color removal was readily achieved and 50.4% of TOC was removed which shows high efficiency of the electro/GAC/PMS process. PMID- 28881242 TI - Comparison of three types of oil crop rotation systems for effective use and remediation of heavy metal contaminated agricultural soil. AB - Selecting suitable plants tolerant to heavy metals and producing products of economic value may be a key factor in promoting the practical application of phytoremediation polluted soils. The aim of this study is to further understand the utilization and remediation of seriously contaminated agricultural soil. In a one-year field experiment, we grew oilseed rape over the winter and then subsequently sunflowers, peanuts and sesame after the first harvest. This three rotation system produced high yields of dry biomass; the oilseed rape-sunflower, oilseed rape-peanut and oilseed rape-sesame rotation allowed us to extract 458.6, 285.7, and 134.5 g ha-1 of cadmium, and 1264.7, 1006.1, and 831.1 g ha-1 of lead from soil, respectively. The oilseed rape-sunflower rotation showed the highest phytoextraction efficiency (1.98%) for cadmium. Lead and cadmium in oils are consistent with standards after extraction with n-hexane. Following successive extractions with potassium tartrate, concentrations of lead and cadmium in oilseed rape and peanut seed meals were lower than levels currently permissible for feeds. Thus, this rotation system could be useful for local farmers as it would enable the generation of income during otherwise sparse phytoremediation periods. PMID- 28881243 TI - Assessing biological effects of fluoxetine in developing zebrafish embryos using gas chromatography-mass spectrometry based metabolomics. AB - Continuous low-dose exposure of pharmaceutically active compounds (PhACs) in aquatic ecosystems is a concern worldwide. In this study, we utilized a gas chromatography mass spectrometry (GC-MS) based metabolomics approach to assess endogenous metabolite changes in developing zebrafish embryos exposed to different concentrations of the widely used antidepressant, fluoxetine. Embryos were exposed from 2 h post fertilization (hpf) until 96 hpf. Using the Fiehn GC MS library, a total of 31 metabolites were positively identified in embryos. Statistical analyses revealed significant dysregulation of 11 metabolites in fluoxetine exposed embryos. Metabolite classes that were significantly altered included, amino acids, monosaccharides, glycerophosphates, fatty acids, carboxylic acid derivatives and sugars. Concentrations of amino acids, maltose, d malic acid, 3-phosphoglycerate and d-glucose were significantly reduced in exposed embryos. Conversely, concentrations of citric acid were in some cases significantly elevated in exposed embryos. Metabolic pathway analysis revealed perturbation of five main pathways, including (i) alanine, aspartate and glutamate metabolism, (ii) phenylalanine, tyrosine and tryptophan biosynthesis, (iii) phenylalanine metabolism. (iv) tyrosine metabolism and (v) starch and sucrose metabolism. The results indicate fluoxetine exposure causes perturbation of energy and amino acid metabolism, which may adversely impact embryogenesis due to depletion of energy reserves during this period. Also, the observed alterations in aspartic acid, phenylalanine and tyrosine in fluoxetine exposed embryos suggests potential disruption of normal neurobehavioral and liver function. The results further demonstrate that GC-MS based metabolomics is an effective approach for assessing toxicodynamics and threshold effect levels of environmental pollutants in aquatic organisms. PMID- 28881244 TI - Disinfection byproduct precursor dynamics and water treatability during an extreme flooding event in a coastal blackwater river in southeastern United States. AB - Coastal blackwater rivers, characterized by high concentrations of natural organic matter, are source water for millions of people in the southeastern US. In October 2015, large areas of coastal South Carolina were flooded by Hurricane Joaquin. This so-called "thousand-year" rainfall mobilized and flushed large amounts of terrestrial organic matter and associated pollutants (e.g. mercury) into source water, affecting water quality and safety of municipal water supply. To understand the dynamics of water quality and water treatability during this extreme flood, water samples were collected from Waccamaw River (a typical blackwater river in the southeastern US) during rising limb, peak discharge, falling limb, and base flow. Despite decreasing water flow after peak discharge, dissolved organic carbon (DOC) levels (increased by up to 125%), and formation potentials of trihalomethanes and haloacetic acids (increased by up to 150%) remained high for an extended period of time (>eight weeks after peak discharge), while variation in the N-nitrosodimethylamine (NDMA) FP was negligible. Coagulation with alum and ferric at optimal dosage significantly reduced concentrations of DOC by 51-76%, but up to 10 mg/L of DOC still remained in treated waters. For an extended period of time, elevated levels of THMs (71-448 MUg/L) and HAAs (88-406 MUg/L) were quantified in laboratory chlorination experiments under uniform formation conditions (UFC), exceeding the United States Environmental Protection Agency's (USEPA) maximum contaminant level of 80 and 60 MUg/L, respectively. Results demonstrated that populations in coastal cities are at high risk with disinfection by-products (DBPs) under the changing climate. PMID- 28881245 TI - The influence of thermal treatment on bioweathering and arsenic sorption capacity of a natural iron (oxyhydr)oxide-based adsorbent. AB - Adsorption plays a significant role in remediation of waters contaminated with arsenic, but the efficiency of the process varies depending on the sorbent properties. Bog iron ores (BIOs), characterized by high sorption capacity and widespread availability, seem to be an optimal sorbent of arsenic. However, the use of BIOs for arsenic removal from waters may be limited by the high amount of organic matter, which may stimulate microbial activity, and thus decomposition of the sorbent. The aim of this study was to determine the effect of organic matter removal by thermal transformation (roasting) on the bioavailability of BIOs and their arsenic sorption capacity. For this purpose, the influence of bacterial growth and activity on untreated and treated BIOs, unloaded and loaded with arsenic, was studied. Moreover, the chemical and physical properties (including FTIR and desorption of arsenic) of BIOs were investigated as well. The results show that the removal of organic matter increases the stability of BIOs, and thus reduces the bioavailability of the immobilized arsenic. PMID- 28881246 TI - Avoiding harm and supporting autonomy are under-prioritised in cancer-screening policies and practices. AB - The ethical principles of avoiding harm and supporting autonomy are relevant to cancer-screening policy. We argue that more attention needs to be given to implementing them. Cancer screening may deliver excessive harms due to low-value or outdated screening programs and from poorly communicated screening options that leave people with heavy burdens of decision-making. Autonomy is inadequately supported due to limited opportunities for people to understand downsides of screening and because of institutional and societal pressures in favour of screening. Members of screening policy committees may have differing ideas about the goals of screening or have conflicts of interest that prevent them from addressing policy questions in a neutral way. We recommend the following: 1. Committees should be required to discern and discuss the values of individual members and the wider public; 2. Committee membership and voting procedures should be more carefully constructed to reduce the likelihood that committee members' interests are placed above public interests; 3. Committees should explain their policy decisions with reference to values as well as evidence, so that values considered in decision-making can be interrogated and challenged if necessary. These changes would increase the likelihood that cancer-screening policy decisions are in keeping with public views about what is important. PMID- 28881248 TI - Value of a short-term imaging follow-up after a benign result in a one-stop breast unit: Is it still useful? AB - INTRODUCTION: A short-term radiologic follow-up after a benign breast biopsy or fine needle aspiration (FNA) is recommended in many guidelines. However, the current trend is to reduce imaging investigations, radiation dose and costs. The objectives of this study were to evaluate the cancer detection rate at short-term follow-up and to estimate its cost. METHODS: We retrospectively assessed all consecutive patients referred to our 'one-stop' breast unit between 2004 and 2012, with a benign histological or cytological result and at least one short term follow-up within 3-12 months after the initial diagnosis. We evaluated the number of cancers detected, as well as the mean cost to detect each cancer and per patient. RESULTS: About 1366 patients were eligible for this study. Ten patients were diagnosed with cancers (0.73%) at short-term follow-up; six of 10 were low-grade tumours or ductal carcinoma in situ. The cost for detecting one cancer was 19,043?, with mean cost per patient of 139?. CONCLUSION: The cancer detection rate at short-term follow-up after benign biopsy or FNA was low and was similar to that of most national screening programs. The cost of cancer detection appeared high, considering that most cancers were indolent. This suggests that radiologic follow-up could reasonably be carried out at a later point in time. PMID- 28881247 TI - Time trends (2006-2015) of quality indicators in EUSOMA-certified breast centres. AB - AIM OF THE STUDY: The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast centres to establish minimum standards and ensure specialist multidisciplinary care. Prospectively collected anonymous information on primary breast cancer cases diagnosed and treated in the units is transferred annually to a central EUSOMA data warehouse for continuous monitoring of quality indicators (QIs) to improve quality of care. Units have to comply with the EUSOMA Breast Centre guidelines and are audited by peers. The database was started in 2006 and includes over 110,000 cancers from breast centres located in Germany, Switzerland, Belgium, Austria, The Netherlands, Spain, Portugal and Italy. The aim of the present study is assessing time trends of QIs in EUSOMA-certified breast centres over the decade 2006-2015. MATERIALS AND METHODS: Previously defined QIs were calculated for 22 EUSOMA certified breast centres (46122 patients) during 2006-2015. RESULTS: On the average of all units, the minimum standard of care was achieved in 8 of 13 main EUSOMA QIs in 2006 and in all in 2015. All QIs, except removal of at least 10 lymph nodes at axillary clearance and oestrogen receptor-negative tumours (T > 1 cm or N+) receiving adjuvant chemotherapy, improved significantly in this period. The desirable target was reached for two QIs in 2006 and for 7 of 13 QIs in 2015. CONCLUSION: The EUSOMA model of audit and monitoring QIs functions well in different European health systems and results in better performance of QIs over the last decade. QIs should be evaluated and adapted on a regular basis, as guidelines change over time. PMID- 28881250 TI - Airborne radionuclides in the proglacial environment as indicators of sources and transfers of soil material. AB - A survey of artificial (137Cs, 238Pu, 239+240Pu, 241Am) and natural (226Ra, 232Th, 40K, 210Pb) radioactive isotopes in proglacial soils of an Arctic glacier have revealed high spatial variability of activity concentrations and inventories of the airborne radionuclides. Soil column 137Cs inventories range from below the detection limit to nearly 120 kBq m-2, this value significantly exceeding direct atmospheric deposition. This variability may result from the mixing of materials characterised by different contents of airborne radionuclides. The highest activity concentrations observed in the proglacial soils may result from the deposition of cryoconites, which have been shown to accumulate airborne radionuclides on the surface of glaciers. The role of cryoconites in radionuclide accumulation is supported by the concordant enrichment of the naturally occurring airborne 210Pb in proglacial soil cores showing elevated levels of artificial radionuclides. The lithogenic radionuclides show less variability than the airborne radionuclides because their activity concentrations are controlled only by the mixing of material derived from the weathering of different parent rocks. Soil properties vary little within and between the profiles and there is no unequivocal relationship between them and the radionuclide contents. The inventories reflect the pathways and time variable inputs of soil material to particular sites of the proglacial zone. Lack of the airborne radionuclides reflects no deposition of material exposed to the atmosphere after the 1950s or its removal by erosion. Inventories above the direct atmospheric deposition indicate secondary deposition of radionuclide-bearing material. Very high inventories indicate sites where transport pathways of cryoconite material terminated. PMID- 28881249 TI - Cost-effectiveness analysis of PET-CT-guided management for locally advanced head and neck cancer. AB - BACKGROUND: A recent large United Kingdom (UK) clinical trial demonstrated that positron-emission tomography-computed tomography (PET-CT)-guided administration of neck dissection (ND) in patients with advanced head and neck cancer after primary chemo-radiotherapy treatment produces similar survival outcomes to planned ND (standard care) and is cost-effective over a short-term horizon. Further assessment of long-term outcomes is required to inform a robust adoption decision. Here we present results of a lifetime cost-effectiveness analysis of PET-CT-guided management from a UK secondary care perspective. METHODS: Initial 6 month cost and health outcomes were derived from trial data; subsequent incidence of recurrence and mortality was simulated using a de novo Markov model. Health benefit was measured in quality-adjusted life years (QALYs) and costs reported in 2015 British pounds. Model parameters were derived from trial data and published literature. Sensitivity analyses were conducted to assess the impact of uncertainty and broader National Health Service (NHS) and personal social services (PSS) costs on the results. RESULTS: PET-CT management produced an average per-person lifetime cost saving of L1485 and an additional 0.13 QALYs. At a L20,000 willingness-to-pay per additional QALY threshold, there was a 75% probability that PET-CT was cost-effective, and the results remained cost effective over the majority of sensitivity analyses. When adopting a broader NHS and PSS perspective, PET-CT management produced an average saving of L700 and had an 81% probability of being cost-effective. CONCLUSIONS: This analysis indicates that PET-CT-guided management is cost-effective in the long-term and supports the case for wide-scale adoption. PMID- 28881251 TI - Registration and fusion quantification of augmented reality based nasal endoscopic surgery. AB - This paper quantifies the registration and fusion display errors of augmented reality-based nasal endoscopic surgery (ARNES). We comparatively investigated the spatial calibration process for front-end endoscopy and redefined the accuracy level of a calibrated endoscope by using a calibration tool with improved structural reliability. We also studied how registration accuracy was combined with the number and distribution of the deployed fiducial points (FPs) for positioning and the measured registration time. A physically integrated ARNES prototype was customarily configured for performance evaluation in skull base tumor resection surgery with an innovative approach of dynamic endoscopic vision expansion. As advised by surgical experts in otolaryngology, we proposed a hierarchical rendering scheme to properly adapt the fused images with the required visual sensation. By constraining the rendered sight in a known depth and radius, the visual focus of the surgeon can be induced only on the anticipated critical anatomies and vessel structures to avoid misguidance. Furthermore, error analysis was conducted to examine the feasibility of hybrid optical tracking based on point cloud, which was proposed in our previous work as an in-surgery registration solution. Measured results indicated that the error of target registration for ARNES can be reduced to 0.77 +/- 0.07 mm. For initial registration, our results suggest that a trade-off for a new minimal time of registration can be reached when the distribution of five FPs is considered. For in-surgery registration, our findings reveal that the intrinsic registration error is a major cause of performance loss. Rigid model and cadaver experiments confirmed that the scenic integration and display fluency of ARNES are smooth, as demonstrated by three clinical trials that surpassed practicality. PMID- 28881252 TI - Bone-derived exosomes. AB - Exosomes are endosomal-derived vesicles secreted by a wide range of cell types for transporting functional proteins, microRNAs (miRNAs) and messenger RNAs (mRNA) from their parental cells to affect the recipient cells. Emerging evidence indicates that exosomes also play an important role in the intercellular communication among the bone cells, that is, osteoblasts, osteoclasts and bone marrow stromal cells, within bone microenvironment. Here, we reviewed the local and systemic effects of bone-derived exosomes, and discussed the potential of exosomes as targeted delivery systems for molecular therapy in skeletal disorders. PMID- 28881253 TI - 5-Substituted 2-benzylidene-1-tetralone analogues as A1 and/or A2A antagonists for the potential treatment of neurological conditions. AB - Adenosine A1 and A2A receptors are attracting great interest as drug targets for their role in cognitive and motor deficits, respectively. Antagonism of both these adenosine receptors may offer therapeutic benefits in complex neurological diseases, such as Alzheimer's and Parkinson's disease. The aim of this study was to explore the affinity and selectivity of 2-benzylidene-1-tetralone derivatives as adenosine A1 and A2A receptor antagonists. Several 5-hydroxy substituted 2 benzylidene-1-tetralone analogues with substituents on ring B were synthesized and assessed as antagonists of the adenosine A1 and A2A receptors via radioligand binding assays. The results indicated that hydroxy substitution in the meta and para position of phenyl ring B, displayed the highest selectivity and affinity for the adenosine A1 receptor with Ki values in the low micromolar range. Replacement of ring B with a 2-amino-pyrimidine moiety led to compound 12 with an increase of affinity and selectivity for the adenosine A2A receptor. These substitution patterns led to enhanced adenosine A1 and A2A receptor binding affinity. The para-substituted 5-hydroxy analogue 3 behaved as an adenosine A1 receptor antagonists in a GTP shift assay performed with rat whole brain membranes expressing adenosine A1 receptors. In conclusion, compounds 3 and 12, showed the best adenosine A1 and A2A receptor affinity respectively, and therefore represent novel adenosine receptor antagonists that may have potential with further structural modifications as drug candidates for neurological disorders. PMID- 28881254 TI - Is literature data useful for identifying enzyme catalysts for new substrates? A case study on reduction of 1-aryl-2-alkanoates. AB - The use of literature data to identify catalysts for a novel transformation is a commonly used approach. Herein, we have evaluated if this is a viable strategy in enzyme catalysis, using asymmetric reduction of 1-aryl-2-alkanoates asa model system. The study, which includes data from 24 ketone substrates and 108 enzymes, clearly identifies pitfalls with this approach, but anyhow shows that literature data is highly useful for identification of enantioselective catalysts. By combining data for selectivity and rate useful catalyst for converting different substrates to their corresponding (R)- and (S)-enantiomers are highlighted. PMID- 28881255 TI - Synthesis, characterization and DNA binding studies of platinum(II) complexes with benzimidazole derivative ligands. AB - The aim of this study was to synthesize and evaluate plasmid DNA interaction of new platinum(II) complexes with some 2-substituted benzimidazole derivatives as carrier ligands which may have potent anticancer activity and low toxicity. Twelve benzimidazole derivatives carrying indole, 2-/or 3-/or 4-methoxyphenyl, 4 methylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-methoxybenzyl, 3,4,5 trimethoxybenzyl, 3,4,5-trimethoxystyryl, 3,4,5-trimethoxybenzylthio or dimethylamino ethyl groups in their position 2 and twelve platinum(II) complexes with these carrier ligands were synthesized. The chemical structure of the platinum complexes have been characterized by their elemental analysis and FIR, 1H NMR and mass spectra and their 1H NMR and FIR spectra were interpreted by comparison with those of the ligands. The interaction of all the ligands and their complexes with plasmid DNA and their restriction endonuclease reactions by BamHI and HindIII enzymes were studied by agarose gel electrophoresis. It was determined that complex 1 [dichloro-di(2-(1H-indole-3 yl)benzimidazole)platinum(II).2H2O] has stronger interaction than carboplatin and complex 10 [dichloro-di(2-(3,4,5 trimethoxystyryl)benzimidazole)platinum(II).2H2O] has stronger interaction than both carboplatin and cisplatin with plasmid DNA. PMID- 28881256 TI - Structural brain correlates of resilience to traumatic stress in Dutch police officers. AB - OBJECTIVE: Neurobiological research has traditionally focused on vulnerability rather than on resilience to severe stress. So far, only a few neuroimaging studies examining resilience have used designs that allow disentangling of the neural correlates of resilience from those related to psychopathology or trauma exposure. The aim of this study was to identify structural brain correlates of resilience, and their correlations with behavioral measures. METHOD: MRI scanning was performed in three groups of police officers: (1) a resilient group (N=29; trauma-exposed, no psychopathology), (2) a vulnerable group (N=33; trauma exposed, psychopathology), and (3) a control group (N=19; no trauma, no psychopathology). Using whole brain and region-of-interest approaches, we examined gray matter volume and shapes, and white matter integrity using software tools from the FSL-library. RESULTS: We did not find patterns of gray matter volumes or shape specific for the resilient group. In resilient police officers, we found an increase in structural connectivity in the corticopontine tract. White matter integrity in this location correlated with a coping style of positive reappraisal. CONCLUSIONS: Resilient police officers show a specific pattern of increased structural connectivity, which is associated to the use of higher order emotion regulation strategies. Given this finding in an area that has not been implicated in stress-related disorders before, as well as the null findings in areas repeatedly shown to be involved in stress-related disorders, the current study indicates that resilience is not simply the opposite of having psychiatric symptoms, but rather an independent construct. PMID- 28881257 TI - The length of pre-existing fissures effects on the mechanical properties of cracked red sandstone and strength design in engineering. AB - It is important to study the mechanical properties of cracked rock to understand the engineering behavior of cracked rock mass. Consequently, the influence of the length of pre-existing fissures on the strength, deformation, acoustic emission (AE) and failure characteristics of cracked rock specimen was analyzed, and the optimal selection of strength parameter in engineering design was discussed. The results show that the strength parameters (stress of dilatancy onset and uniaxial compressive strength) and deformation parameters (axial strain and circumferential strain at dilatancy onset and peak point) of cracked rock specimen decrease with the increase of the number of pre-existing fissures, and the relations which can use the negative exponential function to fit. Compared with the intact rock specimens, the different degrees of stress drop phenomena were produced in the process of cracked rock specimens when the stress exceeds the dilatancy onset. At this moment, the cracked rock specimens with the existence of stress drop are not instantaneous failure, but the circumferential strain, volumetric strain and AE signals increase burstingly. And the yield platform was presented in the cracked rock specimen with the length of pre existing fissure more than 23mm, the yield failure was gradually conducted around the inner tip of pre-existing fissure, the development of original fissures and new cracks was evolved fully in rock. However, the time of dilatancy onset is always ahead of the the time of that point with the existence of stress drop. It indicates that the stress of dilatancy onset can be as the parameter of strength design in rock engineering, which can effectively prevent the large deformation of rock. PMID- 28881258 TI - Time-frequency analysis to a particular type of scattering problems involving metallic-polymer tubing structures. AB - In this paper, recent studies of backscattered acoustic signals in thinner steel polymer tubing structures have been presented. Reassigned smoothed pseudo Wigner Ville (rspWV) analysis has been adopted in order to diminish the cross-term effect, and achieve high resolution spectral. Vibration modes, which are associated to the resonances of circumferential waves, have been determined by using the modal isolation plan representation. At normalized frequencies below 140, an appreciable influence from the polymer coating thickness on the A0+ and S0 modes has been noticed. Furthermore, the trajectory of the A0- wave has been modified in the normalized frequency band 40-42. Group velocity curves of the A0- wave have, then, been graphically illustrated. The findings have shown a particular curvature change at reduced frequency 41 in the case of an immersed two-layer tube in water. Studies of acoustic backscattering involving steel polymer tubing structures have confirmed the significant coupling of A0+ and S0 waves. Besides, the disappearance of the A0+ resonance trajectory has been observed; which is a very important phenomenon to understand. PMID- 28881259 TI - Sodium channel blockers in KCNQ2-encephalopathy: Lacosamide as a new treatment option. PMID- 28881260 TI - Activation Status of Receptor Tyrosine Kinases as an Early Predictive Marker of Response to Chemotherapy in Osteosarcoma. AB - Receptor tyrosine kinases (RTKs) are membrane receptors that play a vital role in various biological processes, in particular, cell survival, cell proliferation, and cell differentiation. These cellular processes are composed of multitiered signaling cascades of kinases starting from ligand binding to extracellular domains of RTKs that activate the entire pathways through tyrosine phosphorylation of the receptors and downstream effectors. A previous study reported that, based on proteomics data, RTKs were a major candidate target for osteosarcoma. In this study, activation profiles of six candidate RTKs, including c-Met, c-Kit, VEGFR2, HER2, FGFR1, and PDGFRalpha, were directly examined from chemonaive fresh frozen tissues of 32 osteosarcoma patients using a multiplex immunoassay. That examination revealed distinct patterns of tyrosine phosphorylation of RTKs in osteosarcoma cases. Unsupervised hierarchical clustering was calculated using Pearson uncentered correlation coefficient to classify RTKs into two groups-Group A (c-Met, c-Kit, VEGFR2, and HER2) and Group B (FGFR1 and PDGFRalpha)-based on tyrosine phosphorylation patterns. Nonactivation of all Group A RTKs was associated with shorter overall survival in stage IIB osteosarcoma patients. Percentages of tumor necrosis in patients with inactive Group A RTKs were significantly lower than those in patients with at least one active Group A RTK. Paired primary osteosarcoma cells with fresh osteosarcoma tissue were extracted and cultured for cytotoxicity testing. Primary cells with active Group A RTKs tended to be sensitive to doxorubicin and cisplatin. We also found that osteosarcoma cells with active Group A RTKs were more proliferative than cells with inactive Group A RTKs. These findings indicate that the activation pattern of Group A RTKs is a potential risk stratification and chemoresponse predictor and might be used to guide the optimum chemotherapy regimen for osteosarcoma patients. PMID- 28881261 TI - Cardiorenal syndrome in sepsis: A narrative review. AB - Multi-organ dysfunction is seen in nearly 40-60% of all patients presenting with sepsis, including renal and cardiac dysfunction. Cardiorenal syndrome type-5 reflects concomitant cardiac and renal dysfunction secondary to a systemic condition that primarily affects both organs, such as sepsis. There are limited data on the etiology, pathogenesis and clinical implications of cardiorenal syndrome in sepsis. Cardiac dysfunction and injury can be measured with cardiac biomarkers, echocardiographic dysfunction, and hemodynamic parameters. Acute kidney injury is systematically evaluated using serum creatinine and urine output criteria. This review seeks to systematically describe the epidemiology, risk factors, pathogenesis, diagnosis and management of cardiorenal syndrome type-5 in the setting of sepsis. PMID- 28881262 TI - Young children are more willing to accept group decisions in which they have had a voice. AB - People accept an unequal distribution of resources if they judge that the decision-making process was fair. In this study, 3- and 5-year-old children played an allocation game with two puppets. The puppets decided against a fair distribution in all conditions, but they allowed children to have various degrees of participation in the decision-making process. Children of both ages protested less when they were first asked to agree with the puppets' decision compared with when there was no agreement. When ignored, the younger children protested less than the older children-perhaps because they did not expect to have a say in the process-whereas they protested more when they were given an opportunity to voice their opinion-perhaps because their stated opinion was ignored. These results suggest that during the preschool years, children begin to expect to be asked for their opinion in a decision, and they accept disadvantageous decisions if they feel that they have had a voice in the decision-making process. PMID- 28881263 TI - Metagenetic analysis of the bacterial communities of edible insects from diverse production cycles at industrial rearing companies. AB - Despite the continuing development of new insect-derived food products, microbial research on edible insects and insect-based foods is still very limited. The goal of this study was to increase the knowledge on the microbial quality of edible insects by comparing the bacterial community composition of mealworms (Tenebrio molitor) and crickets (Acheta domesticus and Gryllodes sigillatus) from several production cycles and rearing companies. Remarkable differences in the bacterial community composition were found between different mealworm rearing companies and mealworm production cycles from the same company. In comparison with mealworms, the bacterial community composition of the investigated crickets was more similar among different companies, and was highly similar between both cricket species investigated. Mealworm communities were dominated by Spiroplasma and Erwinia species, while crickets were abundantly colonised by (Para)bacteroides species. With respect to food safety, only a few operational taxonomic units could be associated with potential human pathogens such as Cronobacter or spoilage bacteria such as Pseudomonas. In summary, our results implicate that at least for cricket rearing, production cycles of constant and good quality in terms of bacterial composition can be obtained by different rearing companies. For mealworms however, more variation in terms of microbial quality occurs between companies. PMID- 28881264 TI - Is endometrioma-associated damage to ovarian reserve progressive? Insights from IVF cycles. AB - OBJECTIVE: The relation between endometriomas and damage to ovarian reserve remains controversial. In this study, we hypothesized that this damage may not be present at the time of endometrioma formation but may conversely gradually develop over time. STUDY DESIGN: To investigate the possibility of a time-related detrimental effect of endometriomas on ovarian reserve, we retrospectively selected 29 women with unilateral cysts who underwent at least two IVF cycles at least 6 months apart and evaluated ovarian responsiveness over time. Women were excluded if they conceived, developed new endometriomas or necessitated new medical or surgical therapies for endometriosis during the interval between the two cycles, RESULTS: The mean+/-SD of the diameter of the endometriomas was 26+/ 8mm. Most women (n=25) had only one endometrioma. In the first cycle, the number of developing follicles in the affected and contralateral intact gonads was 4.9+/ 2.5 and 5.9+/-2.4, respectively (p=0.10). In the second cycle, it was 5.0+/-2.9 and 6.0+/-2.8, respectively (p=0.13). The median (Interquartile Range) proportion of follicles developing in the affected ovaries in the first and second cycles was 44% (31-58%) and 44% (35-55%), respectively (p=0.97). Subgroup analyses according to the duration of the time interval between the two assessments, the dimension of the endometriomas and the history of previous surgery for endometriosis did not show subgroups at significant risk of time-related damage. CONCLUSIONS: We failed to observe an endometrioma-related reduction of ovarian responsiveness with time. However, evidence from larger series obtained in women carrying larger cysts and enrolled for longer time period of time are required for a definitive conclusion. PMID- 28881265 TI - New variants near RHOJ and C2, HLA-DRA region and susceptibility to endometriosis in the Polish population-The genome-wide association study. AB - OBJECTIVE: Endometriosis is a common gynaecological disease, associated with severe pelvic pain and reduced fertility; however, molecular mechanisms remain largely unknown. Genome-wide association studies (GWAS) are able to identify genetic loci, which can play significant role during endometriosis development. AIM: The study aimed at localisation of new genes and chromosomal loci, the nucleotide variants of which determine the level of susceptibility to endometriosis. STUDY DESIGN: Blood samples from 171 patients with endometriosis were used as material for studies. The patients were recruited to the study at the Department of Operative Gynaecology of the Institute of the Polish Mother's Memorial Hospital in Lodz. A control group (n=2934) came from the POPULOUS collection registered at Biobank Lab, Department of Molecular Biophysics, University of Lodz. DNA of the patients with endometriosis was compared with DNA of women free from that disease, the comparison being supported by GWAS. RESULTS: Genome-wide significant correlation was identified between one new, not previously described, single nucleotide polymorphism (SNP), rs10129516, localised on chromosome 14 in intergenic region between PARP1P2 and RHOJ genes (p=1.44*10 10, OR=3.104, 95% CI=2.329-4.136) and endometriosis. We have also identified significant association with endometriosis of 18 SNPs localised on chromosome 6 in position range 31883957 - 32681631 (C2 and HLA-DRA genes region) with the lowest observed p value for rs644045 in C2 gene (p=2.04*10-8, OR=1.955, 95% CI=1.541-2.480). CONCLUSION: Reported GWAS identified the novel loci associated with endometriosis in Polish women, not previously reported. The most interesting observation shown in our study are regions associated with susceptibility to endometriosis of loci located near C2, HLA-DRA and RHOJ genes. RESULTS: of that study did not correspond to previously published data about polymorphism in that regions and further evaluations are necessary in groups with higher numbers of patients to explain whether the above-mentioned genetic variant may be the risk factor for pathogenesis of endometriosis. PMID- 28881266 TI - Lesion localization using the scroll bar on tomosynthesis: Why doesn't it always work? AB - The scroll bar on digital breast tomosynthesis (DBT) is an important tool that facilitates localization of lesions on the orthogonal view. While this works well most of the time, occasionally the location of the lesion as directed by the scroll bar is seemingly inaccurate. There are five important reasons why the scroll bar indicator may suggest a contradictory lesion location. Understanding specific scenarios when this may occur will aid the reader in reconciling these differences. PMID- 28881267 TI - Gamma-glutamyltransferase and cardiovascular mortality in Korean adults: A cohort study. AB - BACKGROUND AND AIMS: Insufficient evidence has been reported on the associations between gamma-glutamyltransferase (GGT) and cardiovascular disease (CVD) mortality from studies with an adequate number of participants. METHODS: 512,990 Korean adults who participated in routine health examinations during the period 2002-2003 were followed up until 2013. Hazard ratios (HRs) were calculated after adjusting for potential confounders. RESULTS: Each 1-unit higher natural-log transformed GGT (LogeGGT) level was associated with approximately 30-50% higher mortality risk of CVD (HR = 1.31): hypertensive diseases (HR = 1.31), ischemic heart diseases (IHD, HR = 1.29), total stroke (HR = 1.29), acute myocardial infarction (HR = 1.30), chronic IHD (HR = 1.27), heart failure (HR = 1.48), hemorrhagic stroke (HR = 1.42), and ischemic stroke (HR = 1.27). The associations with CVD mortality did not vary by sex, or alcohol use, whereas they were stronger in younger (<60 years), non-hypertensive (systolic blood pressure [SBP] <140 mmHg), physically more active, normal-weight (body mass index<25 kg/m2), and normocholesterolemic (total cholesterol <200 mg/dL) adults than in their respective counterparts. Adding LogeGGT to prediction models for CVD mortality increased AUC value (0.0020, p < 0.001), especially in persons aged <60 years (0.0055), with SBP <140 mmHg (0.0030), and with both age <60 years and SBP <140 mmHg (0.0086). CONCLUSIONS: Higher GGT significantly increased the risk of mortality due to CVD and its subtypes. The relative risks were greater in subjects with younger age, no hypertension, more physical activity, normal weight, and normocholesterolemia than in their respective counterparts. In the general population, adding GGT to conventional CVD risk factors may improve the prediction of CVD mortality, especially in subjects younger than 60 years and in those without hypertension. PMID- 28881268 TI - High-density lipoprotein cholesterol associated with change in coronary plaque lipid burden assessed by near infrared spectroscopy. AB - BACKGROUND AND AIMS: Little is known about the relation between serum lipid parameters and serial change in plaque composition using in vivo coronary imaging. The aim of this study was to examine the association between serum lipids and change in coronary plaque lipid burden assessed by near-infrared spectroscopy (NIRS). METHODS: We performed serial NIRS-intravascular ultrasound studies in 49 patients who underwent coronary angiography for an acute coronary syndrome (ACS) or stable ischemic symptoms. Univariable and multivariable linear regression analyses were applied to evaluate the relationship between serum lipid parameters and change in lipid core burden index at the 4-mm maximal segment (max LCBI4mm). RESULTS: Mean patient age was 61 +/- 9 y, 29% were women, 35% had an ACS clinical presentation, 78% received statin therapy at baseline, and median low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL C), total cholesterol and triglyceride levels were 101, 43, 174 and 133 mg/dL, respectively. During a median follow-up period of 13 months, max LCBI4mm significantly decreased from 277 to 194 (p = 0.001). On univariable analysis, the percent change in HDL-C negatively associated with the change in max LCBI4mm (beta = -3.19, p = 0.004). There were no significant associations between the other lipid parameters and change in max LCBI4mm. On multivariable analysis, percent change in HDL-C remained significantly associated with the change in max LCBI4mm (p = 0.002). CONCLUSIONS: Change in HDL-C, but not other lipids parameters, associated with changes in coronary plaque lipid burden assessed by NIRS. These findings highlight the potential therapeutic importance of high density lipoprotein on serial change in plaque composition. PMID- 28881269 TI - Coronary risk factors associated with OCT macrophage images and their response after CoCr everolimus-eluting stent implantation in patients with stable coronary artery disease. AB - BACKGROUND AND AIMS: The aim of this study was to evaluate the accumulation of optical coherence tomography (OCT)-macrophages and OCT findings after CoCr everolimus-eluting stent placement, in addition to coronary risk factors. METHODS: A total of 89 lesions in 89 patients were registered in the 1- and 3 month cohort of the multi-centre study. Lesion characteristics and post-procedure OCT images were evaluated immediately and 1 and 3 months after stenting. Patients were divided into low and high macrophage grade groups based on the median macrophage grade. RESULTS: Low-density lipoprotein cholesterol (LDL-C) levels, the prevalence of diabetes mellitus, HbA1c and blood glucose levels in the high macrophage grade group were significantly higher than in the low macrophage grade group (p = 0.025, p = 0.040, p = 0.032, and p = 0.010). Moreover, total lipid arc and length and number of thin-cap fibroatheromas (TCFAs) in the high macrophage grade group were significantly higher than in the low macrophage group (p = 0.008, p = 0.002, and p = 0.012). After CoCr everolimus-eluting stenting, there was a trend towards a greater number, height, and area of irregular protrusions in the high macrophage grade group compared to the low macrophage grade group (p = 0.091, p = 0.059, and p = 0.085). Multivariate logistic regression analysis showed that diabetes mellitus was a significant predictor of high macrophage grades (odds ratio: 2.8, 95% CI: 1.1-7.3, p = 0.030). CONCLUSIONS: The accumulation of OCT-macrophages was associated with diabetes mellitus in patients with coronary artery disease. Moreover, macrophage accumulation and diabetes mellitus may be associated with irregular protrusions just after stenting. PMID- 28881270 TI - Molecular and clinical characterization of a series of patients with childhood onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants. AB - BACKGROUND AND AIMS: Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D. METHODS: Data collected included clinical and laboratory investigations, liver imaging, liver biopsy and LIPA gene analysis. The response to lipid-lowering medications, liver transplantation and enzyme replacement therapy (ERT) was reported for some patients. RESULTS: LAL-D was suspected at 4.4 +/- 3.3 years of age for the presence of hepatomegaly, elevated serum transaminases and hypercholesterolemia, and was confirmed by liver biopsy/imaging and LAL assay. The follow up period ranged from 3 to 40 years (mean 7.8 +/- 4.0 years in 13 cases). Patients treated with statins with or without ezetimibe showed 28% reduction of plasma LDL-cholesterol without a tangible effect on liver enzymes; some patients receiving ERT showed normalized lipoprotein profile and transaminase levels. The common c.894G > A variant was observed in homozygosity or compound heterozygosity in 10 patients. We found seven previously reported variants: p.(Trp140*), p.(Arg218*), p.(Gly266*), p.(Thr288Ile), p.(Leu294Ser), p.(His295Tyr) and p.(Gly342Arg) and two novel variants: p.(Asp345Asn), affecting the LAL catalytic triad, and c.229+3A > C, affecting splicing. Homozygosity for p.(Thr288Ile) or c.229+3A > C was associated with a severe phenotype. CONCLUSIONS: This study provides additional data on the features of childhood-onset LAL-D and describes two novel pathogenic variants of the LIPA gene. PMID- 28881271 TI - Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and endothelial cells. AB - BACKGROUND AND AIMS: The factor VII activating protease (FSAP) knockout mice have a bigger neointima after vascular injury and a larger infarct volume after stroke. The Marburg I (MI) single nucleotide polymorphism (SNP) in the FSAP encoding gene is associated with an increased risk of stroke and carotid stenosis in humans. We hypothesize that the regulation of gene expression by FSAP in vascular cells accounts for its vasculo-regulatory properties. METHODS: Vascular smooth muscle cells (VSMC) and endothelial cells (EC) were stimulated with FSAP and a microarray-based expression analysis was performed. Selected genes were further investigated by qPCR. Receptor- and pathway-inhibitors were used to elucidate the mechanisms involved. RESULTS: Pathways significantly activated by FSAP include those related to inflammation, apoptosis and cell growth in VSMC and inflammation in EC. The key upregulated genes in VSMC were AREG, PTGS2 and IL6; and in EC these were SELE, VCAM1, and IL8. Secretion of IL6 in VSMC and IL8 in EC was also stimulated by FSAP. Recombinant wild type protease domain of FSAP, but not the MI-isoform, could recapitulate most of these effects. In VSMC, but not EC, gene expression by FSAP was impaired by PAR1 (protease-activated receptor1) receptor antagonists. In VSMC, FSAP-induced expression of AREG and IL6 was blocked by cAMP and MAPK pathway inhibitors indicating that multiple signalling pathways are likely to be involved. CONCLUSIONS: The stimulation of inflammation- and proliferative/apoptosis-related genes in VSMC and EC provides a comprehensive basis for understanding the role of FSAP in vascular diseases. PMID- 28881273 TI - Investigating the androgenic activity of ozonation transformation products of testosterone and androstenedione. AB - This study investigates the impact of ozonation on the concentration of two androgen steroid hormones, testosterone and androstenedione, and on androgenic activity as measured using the YAS assay. While these compounds are remarkably similar in chemical structure and showed comparable removal profiles in the presence and absence of a hydroxyl scavenger (isopropanol), large differences between percent removal of target compounds using chemical analysis and percent removal of bioactivity was observed when small ozone doses were applied. The dynamic change and initial increase in bioactivity during ozonation can be attributed to transformation products. These results demonstrate the importance of combining chemical analysis and bioanalytical techniques not only to perform a comprehensive assessment of environmental risks but also as a tool to optimize treatment technologies proposed as a mean to mitigate the impact of contaminants of emerging concern. PMID- 28881272 TI - A novel bioreactor system for simultaneous mutli-metal leaching from industrial pyrite ash: Effect of agitation and sulphur dosage. AB - Simultaneous multi-metal leaching from industrial pyrite ash is reported for the first time using a novel bioreactor system that allows natural diffusion of atmospheric O2 and CO2 along with the required temperature maintenance. The waste containing economically important metals (Cu, Co, Zn & As) was leached using an adapted consortium of meso-acidophilic Fe2+ and S oxidising bacteria. The unique property of the sample supported adequate growth and activity of the acidophiles, thereby, driving the (bio) chemical reactions. Oxido-reductive potentials were seen to improve with time and the system's pH lowered as a result of active S oxidation. Increase in sulphur dosage (>1g/L) and agitation speed (>150rpm) did not bear any significant effect on metal dissolution. The consortium was able to leach 94.01% Cu (11.75% dissolution/d), 98.54% Co (12.3% dissolution/d), 75.95% Zn (9.49% dissolution/d) and 60.80% As (7.6% dissolution/d) at 150rpm, 1g/L sulphur, 30 degrees C in 8days. PMID- 28881274 TI - Novel bacterial selenite reductase CsrF responsible for Se(IV) and Cr(VI) reduction that produces nanoparticles in Alishewanella sp. WH16-1. AB - Alishewanella sp. WH16-1 is a facultative anaerobic bacterium isolated from mining soil. Under aerobic conditions, this bacterium efficiently reduces selenite and chromate. A flavoprotein showing 37% amino acid identity to E. coli chromate reductase ChrR was identified from the genome (named CsrF). Gene mutation and complementation along with heterologous expression revealed the ability of CsrF to reduce selenite and chromate in vivo. The purified CsrF was yellow and showed an absorption spectra similar to that of FMN. The molecular weight of CsrF was 23,906 for the monomer and 47,960 for the dimer. In vitro, CsrF catalyzes the reduction of Se(IV) and Cr(VI) using NAD(P)H as cofactors with optimal condition of pH 7.0 and temperature of 30-37 degrees C. This enzyme also catalyze the reduction of sulfate and ferric iron but not arsenate and nitrate. Using NADPH as its electron donor, the Km for the reduction of Se(IV) and Cr(VI) was 204.1+/-27.91 and 250.6+/-23.46MUmol/L, respectively. Site-directed mutagenesis showed that Arg13 and Gly113 were essential for the reduction of Se(IV) and Cr(VI). The products of the reduction of Se(IV) and Cr(VI) were Se(0)- and Cr(III)-nanoparticles, respectively. To our knowledge, CsrF is a novel and well-characterized bacterial aerobic selenite reductase. PMID- 28881275 TI - Residence time effects on technetium reduction in slag-based cementitious materials. AB - A long-term disposal of technetium-99 (99Tc) has been considered in a type of cementitious formulation, slag-based grout, at the U.S. Department of Energy, Savannah River Site, Aiken SC, U.S.A. Blast furnace slag, which contains S and Fe electron donors, has been used in a mixture with fly ash, and Portland cement to immobilize 99Tc(VII)O4-(aq) in low level radioactive waste via reductive precipitation reaction. However the long-term stability of Tc(IV) species is not clearly understood as oxygen gradually diffuses into the solid structure. In this study, aging effects of Tc speciation were investigated as a function of depth (<2.5cm) in slag-based grout using X-ray absorption spectroscopy. All of Fe(II) in solids was oxidized to Fe(III) after 117d. However, elemental S, sulfide, and sulfoxide persists at the 0-8mm depths even after 485d, suggesting the presence of a reduced zone below the surface few millimeters. Pertechnetate was successfully reduced to Tc(IV) after 29d. Distorted hydrolyzed Tc(IV) octahedral molecules were partially sulfidized and or polymerized at all depths (0-8mm) and were stable in 485d aged sample. The results of this study suggest that variable S species contribute to stabilize the partially sulfidized Tc(IV) species in aged slag-based grout. PMID- 28881276 TI - Stress-induced changes of growth, yield and bioactive compounds in lemon balm cultivars. AB - The aim of the present study was to investigate the impact of water deficiency on five Melissa officinalis genotypes. For three months water supply of 70% (control) and 40% (stress) of soil water capacity treatments have been adjusted in a pot experiment. Considering the morphological data, the different genetic potentials of cultivars were manifested only under optimum water regimes while under drought they merged into one homogeneous basic population representing the species. The biomass data decreased for all cultivars under drought stress, but the degree of loss was genotype specific. Genotype dependence of the change in essential oil accumulation was clearly proved by the data. Three of the cultivars ('Gold Leaf', 'Lorelei' and 'Quedlinburger Niederliegende') showed the same essential oil content both in control and stress treatments. Under drought stress the cultivar 'Lemona' produced only 35% of its essential oil content, however cv. 'Soroksar' reacted with 58% increase of essential oil accumulation to drought treatment. Considering the non-volatile bioactive compounds a unique response of the investigated accessions to drought stress was demonstrated. Cultivar 'Lorelei' showed an increased accumulation of total hydroxicinnamic acid derivatives content while cv. 'Gold Leaf' and 'Soroksar' clearly reacted with higher accumulation of total flavonoid fraction. In the case of cv. 'Quedlinburger Niederliegende' the remarkable decline in total flavonoid content is the most obvious stress reaction. The rosmarinic acid content of all genotypes showed lower accumulation level in consequence of lower water supply. PMID- 28881277 TI - Functional identification of MdPIF1 as a Phytochrome Interacting Factor in Apple. AB - Light plays a central role in regulating both apple plant yield and fruit quality formation; however, the Phytochrome interacting factors (PIFs), which are the main components of Phytochrome-mediated light signal transduction in apple, have rarely been characterized. Here, we isolated and identified a PIF-like protein(MdPIF1) in apple, which is similar to AtPIF1. MdPIF1 was constitutively expressed at different levels in various apple tissues, and the transcription level of MdPIF1 was significantly induced during seed germination. A functional complementation assay in the Arabidopsis PIF1-deletion mutant pil5 suggested that MdPIF1 was a negative regulator in the Phy-mediated inhibition of hypocotyl elongation under far-red light conditions. MdPIF1-overexpression promoted hypocotyl elongation, while inhibiting seed germination and PIF1 deletion-induced the bleaching phenotype in the pil5 mutant. In addition, expression analysis indicated that MdPIF1 was involved in the germination of apple seeds and dormancy breaking of apple buds. Moreover, MdPIF1 inhibited the growth of apple calli via Phy-mediated pathways. These findings build a solid foundation for studies on Phytochrome-mediated light signal transduction and molecular breeding in apple. PMID- 28881278 TI - Deciphering the interplay among genotype, maturity stage and low-temperature storage on phytochemical composition and transcript levels of enzymatic antioxidants in Prunus persica fruit. AB - The aim of this study was to understand the antioxidant metabolic changes of peach (cvs. 'Royal Glory', 'Red Haven' and 'Sun Cloud') and nectarine fruits (cv. 'Big Top') exposed to different combinations of low-temperature storage (0, 2, 4 weeks storage at 0 degrees C, 90% R.H.) and additional ripening at room temperature (1, 3 and 5 d, shelf life, 20 degrees C) with an array of analytical, biochemical and molecular approaches. Initially, harvested fruit of the examined cultivars were segregated non-destructively at advanced and less pronounced maturity stages and qualitative traits, physiological parameters, phytochemical composition and antioxidant capacity were determined. 'Big Top' and 'Royal Glory' fruits were characterized by slower softening rate and less pronounced ripening-related alterations. The coupling of HPLC fingerprints, consisted of 7 phenolic compounds (chlorogenic, neochlorogenic acid, catechin, epicatechin, rutin, quecetin-3-O-glucoside, procyanidin B1) and spectrophotometric methods disclosed a great impact of genotype on peach bioactive composition, with 'Sun Cloud' generally displaying the highest contents. Maturity stage at harvest did not seem to affect fruit phenolic composition and no general guidelines for the impact of cold storage and shelf life on individual phenolic compounds can be extrapolated. Subsequently, fruit of less pronounced maturity at harvest were used for further molecular analysis. 'Sun Cloud' was proven efficient in protecting plasmid pBR322 DNA against ROO attack throughout the experimental period and against HO attack after 2 and 4 weeks of cold storage. Interestingly, a general down-regulation of key genes implicated in the antioxidant apparatus with the prolongation of storage period was recorded; this was more evident for CAT, cAPX, Cu/ZnSOD2, perAPX3 and GPX8 genes. Higher antioxidant capacity of 'Sun Cloud' fruit could potentially be linked with compounds other than enzymatic antioxidants that further regulate peach fruit ripening. PMID- 28881279 TI - Evaluation of risk change-point for novice teenage drivers. AB - The driving risk of novice teenagers is the highest during the initial period after licensure but decreases rapidly. This paper applies two recurrent-event change-point models to detect the time of change in driving risks. The models are based on a non-homogeneous Poisson process with piecewise constant intensity functions. We show that the maximum likelihood estimators of the change-points can only occur at the event times and they are consistent. A simulation study is conducted to demonstrate the model performance under different scenarios. The proposed models are applied to the Naturalistic Teenage Driving Study, which continuously recorded in situ driving behaviour of 42 novice teenage drivers for the first 18 months after licensure using sophisticated in-vehicle instrumentation. The results indicate that approximately half of the drivers have lower risk after 73.0h of independent driving after licensure while the risk for others increases. On the average the driving risk deceases after the change point. The results provide critical information for safety education, safety countermeasure development, and Graduated Driver Licensing policy making. PMID- 28881281 TI - Improvement of early functional outcomes in hospitalized geriatric patients after hip surgery. AB - Computer supported clinical practice has great potential to improve process performance and care outcomes. However, further research is needed to evaluate the efficiency of Health Information Technology (HIT) across the various clinical settings. This study focuses on the status of the patient as determined by various potential predicting factors for functional recovery during hospitalization after hip surgery. We assess the relations among patient's characteristics, (co)morbidities, surgical procedures, hospital courses and modified Salvati-Wilson's (SW) score on discharge. The aim is to improve decision making in clinical practice at General hospital "Djordje Joanovic" in Zrenjanin, Serbia, by applying the variation of the Johnson's algorithm for data reduction. The data are related to hospitalized geriatric patients after hip surgery. The second aim is to define the methodology for decision making based on data related to hospitalized geriatric patients after hip surgery in local environments. The SW score as a measure of results of early functional recovery, was affected by age, surgical procedure, the lowest postoperative value of red blood cells during hospitalization, haemoglobin level on discharge, length of hospitalization and length of rehabilitation. It is possible to improve decision making in clinical practice at General hospital "Djordje Joanovic" in Zrenjanin, Serbia, by applying the variation of the Johnson's algorithm for data reduction. The applied method is useful for any local environment for similar geriatric population, in effort to improve their own clinical practice. PMID- 28881280 TI - A computational study of the Fontan circulation with fenestration or hepatic vein exclusion. AB - Fontan patients may undergo additional surgical modifications to mitigate complications like protein-losing enteropathy, liver cirrhosis, and other issues in their splanchnic circulation. Recent case reports show promise for several types of modifications, but the subtle effects of these surgeries on the circulation are not well understood. In this paper, we employ mathematical modeling of blood flow to systematically quantify the impact of these surgical changes on extracardiac Fontan hemodynamics. We investigate two modifications: (1) the fenestrated Fontan and (2) the Fontan with hepatic vein exclusion. Closed loop hemodynamic models are used, which consist of one-dimensional networks for the major vessels and zero-dimensional models for the heart and organ beds. Numerical results suggest the hepatic vein exclusion has the greatest overall impact on the hemodynamics, followed by the largest sized fenestration. In particular, the hepatic vein exclusion drastically lowers portal venous pressure while the fenestration decreases pulmonary artery pressure. Both modifications increase flow to the intestines, a finding consistent with their utility in clinical practice for combating complications in the splanchnic circulation. PMID- 28881282 TI - Enlarge the biologic coating-induced absorbance enhancement of Au-Ag bimetallic nanoshells by tuning the metal composition. AB - Surface plasmon resonance (SPR) absorption properties of biologic layer-coated Au Ag core-shell nanoparticle have been studied theoretically. By comparing with pure Au and Ag nanoparticles, the absorption peak intensity of Au-Ag bimetallic nanoparticle is more dependent on the dielectric coating, and the longer wavelength peak corresponding to the Au-Ag interface is more sensitive to the coating thickness. As the Au-Ag composition ratio is increased, the dielectric coating-dependent peak intensity change is always non-monotonous, and the critical Au-Ag composition ratio corresponding to the greatest peak intensity increase could be further tuned by changing the dielectric constant of the coated dielectric layer. The physical mechanism of the non-monotonous sensitivity change has been attributed to the Au-Ag composition ratio-dependent separation and overlap of the two SPR peaks from Au-Ag interface and outer Ag surface. These results indicate that the plasmonic absorption intensity of Au-Ag core-shell nanoparticle could be used in refractive index sensing and biologic detection. PMID- 28881283 TI - Spectroscopic study of 2-methylindole and 3-methylindole: Solvents interactions and DFT studies. AB - The interaction between the 2- and 3-methylindole derivatives has been studied using spectroscopic technique and molecular modeling. Solvent polarity was found to play a great role in the interaction with acetonitrile showing greatest interaction with indole derivatives but less hydrogen bonding contribution. Good agreement was found between the models used for the analysis of experimental data and the theoretical calculations. Moreover, on the part of the quenching, benzonitrile was found to be better quencher over chlorobenzene, with 3 methylindole giving higher dynamic quenching constants. PMID- 28881284 TI - Multi-branched gold nanostars with fractal structure for SERS detection of the pesticide thiram. AB - The surface-enhanced Raman scattering (SERS) activity of multi-branched gold nanostars with fractal structure has been investigated for trace detection of pesticide thiram. Raman spectrum results show that the gold nanostars substrate can produce about 102 fold stronger signal than the thiram alone with the thiram concentration increase of 103 times and 1.4 fold stronger signal than the gold nanostars without fractal feature. In the detection procedure, the most prominent SERS peak at 1376cm-1 has been chosen to characterize and quantify the concentration of thiram. Experimental results indicate this Raman substrate based on fractal gold nanostars exhibits excellent selective probing performance for thiram with a detection limit as low as 10-10M in solution and 0.24ng/cm2 in apple peels. Interference experiment results show that the effects from the interfering pesticides could be neglected in the detection procedure. Therefore, the gold nanostars as a SERS substrate have excellent sensitivity and selectivity. PMID- 28881285 TI - Structures and biochemical evaluation of silver(I) 5,5-diethylbarbiturate complexes with bis(diphenylphosphino)alkanes as potential antimicrobial and anticancer agents. AB - New silver(I) 5,5-diethylbarbiturate (barb) complexes with a series of bis(diphenylphosphino)alkanes such as 1,1-bis(diphenylphosphino)methane (dppm), 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp) and 1,4-bis(diphenylphosphino)butane (dppb) were synthesized and characterized. [Ag2(barb)2(MU-dppm)2] (1), [Ag2(barb)2(MU-dppe)(DMSO)2] (2) and [Ag2(barb)2(MU dppp)2] (3) were binuclear, while [Ag(barb)(MU-dppb)]n (4) was a coordination polymer. 1-4 effectively bind to the G/C rich region of the major groove of DNA and interact with BSA via hydrophobic interactions in accordance with molecular docking studies. All complexes displayed significant DNA cleavage in the presence of H2O2. 1-4 exhibited more specificity against Gram-positive bacteria than Gram negative bacteria, but 2 targets both bacterial strains, being comparable to AgNO3 and silver sulfadiazine. Complex 1 has a strong growth inhibitory effect on A549 cells, while 2 and 3 exhibit considerable cytotoxicity against MCF-7 cells. The complexes showed high accumulation in the cytosol fraction of the cells. Mechanistic studies showed that 1 and 2 display effective cell growth inhibition by triggering S and G2/M phase arrest, induce apoptosis via mitochondrial pathways and also damage to DNA due to the overproduction of ROS. PMID- 28881286 TI - Synthesis and evaluation of asymmetric curcuminoid analogs as potential anticancer agents that downregulate NF-kappaB activation and enhance the sensitivity of gastric cancer cell lines to irinotecan chemotherapy. AB - NF-kappaB is a critical target for cancer treatment due to its central role in facilitating cancer progression and desensitizing cancer cells to chemotherapeutic drugs. In this study, a series of chemically modified asymmetric curcuminoid analogs named S01-S15 were synthesized and evaluated for NF-kappaB inhibitory activity in gastric cancer cell lines. Cell growth inhibition assays revealed that most of these analogs effectively inhibited the growth of BGC-823, SGC-7901, and MFC cells. S06 was selected for further research. MTT assay, clonogenic assay, Hoechst 33258 staining assay, and western blotting revealed that S06 could exert anti-gastric cancer effects by downregulating NF-kappaB activity. Moreover, via its effects on NF-kappaB, S06 effectively enhanced the sensitivity of the gastric cancer cells to irinotecan. Together, this study provide a series of new curcuminoid analogs as promising cancer therapeutic agents. PMID- 28881287 TI - Recent advances in polysaccharides for osteoarthritis therapy. AB - The polysaccharides used in the treatment of osteoarthritis (OA) mainly include sodium hyaluronate, chondroitin sulfate, chitosan, xanthan gum, Low molecular weight heparin, alginate and other polysaccharides. This review summarizes the recent advances in the chemistry and biological activities of polysaccharides for the treatment of OA. PMID- 28881288 TI - Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach. AB - The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in pi-pi staking interaction with Trp227 (partial overlapping) and in a T-shape pi-pi staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide. PMID- 28881289 TI - Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi. AB - The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples of 3-substituted 4 hydroxy-6-methyl alpha-pyrones were synthesized and their antiparasitic efficacy evaluated against Leishmania (L.) infantum and Trypanosoma cruzi in order to evaluate structure-activity relationships within the series. The mechanism of action and the in vivo efficacy of the most selective compound against T. cruzi were evaluated using different techniques. In vitro data indicated that compounds 8, 15, 25, 26 and 28 presented IC50 values in the range between 13 and 54 MUM against L. infantum intracellular amastigotes. Among them, hexanoyl substituted pyrone 8 was the most selective and potent, with a Selectivity Index (SI) > 14. Fifteen of the alpha-pyrones were effective against T. cruzi trypomastigotes, with 3-undecanoyl (11) and 3-tetradecanoyl (12) substituted pyrones being the most potent against trypomastigotes, with IC50 values of 1 and 2 MUM, respectively, and SI higher than 70. Using flow cytometry and fluorescent-based assays, pyrone 12 was found to induce hyperpolarization of the mitochondrial membrane potential of T. cruzi, without affecting plasma membrane permeability. An experimental acute phase-murine model, demonstrated that in vivo dosing of 12 (30 mg/kg/day; 5 days), had no efficacy at the first parasitemia onset of T. cruzi, but reduced the second onset by 55% (p < 0.05), suggesting a delayed action in BALB/c mice. Additionally, a histopathology study demonstrated no toxic effects to the treated mice. The finding that several 3-substituted alpha-pyrones have in vitro efficacy against both L. infantum and T. cruzi, and that one analogue exhibited moderate and non-toxic in vivo efficacy against T. cruzi is encouraging, and suggests that this compound class should be explored as long term treatments in experimental Chagas disease. PMID- 28881290 TI - Glycyrrhizic acid increases glucagon like peptide-1 secretion via TGR5 activation in type 1-like diabetic rats. AB - Glycyrrhizic acid (GA) is belonged to triterpenoid saponin that is contained in the root of licorice and is known to affect metabolic regulation. Recently, glucagon like peptide-1 (GLP-1) has widely been applied in diabetes therapeutics. However, the role of GLP-1 in GA-induced anti-diabetic effects is still unknown. Therefore, we are interested in understanding the association of GLP-1 with GA induced effects. In type 1-like diabetic rats induced by streptozotocin (STZ treated rats), GA increased the level of plasma GLP-1, which was blocked by triamterene at a dose sufficient to inhibit Takeda G-protein-coupled receptor 5 (TGR5). The direct effect of GA on TGR5 has been identified using the cultured Chinese hamster ovary cells (CHO-K1 cells) transfected TGR5 gene. Moreover, in intestinal NCI-H716 cells that secreted GLP-1, GA promoted GLP-1 secretion with a marked elevation of calcium levels. However, both effects of GA were reduced by ablation of TGR5 with siRNA in NCI-H716 cells. Therefore, we demonstrated that GA can enhance GLP-1 secretion through TGR5 activation. PMID- 28881291 TI - A practical guide for induction of type-2 diabetes in rat: Incorporating a high fat diet and streptozotocin. AB - Prevalence of diabetes, a serious public health problem is rapidly increasing worldwide. Type-2 diabetes is the common form of diabetes characterized by insulin resistance and abnormalities in insulin production. Despite the current development of therapeutic agents, there is no effective treatment without side effects; it is therefore necessary to find new prevention strategies and better treatments. For this purpose animal models of diabetes are appropriate tools, of which rodents due to the short generation time and economic considerations are the first choice. The aim of this review is to present features of a frequently used model of type-2 diabetes in rat, induced by a high fat diet and streptozotocin, taking into account its advantages/disadvantages and presenting a practical guide. PMID- 28881292 TI - Exceptionally high UBE2C expression is a unique phenomenon in basal-like type breast cancer and is regulated by BRCA1. AB - Ubiquitin-conjugating enzyme 2C (UBE2C) is overexpressed in various types of cancer, leading to poor outcomes and drug resistance. UBE2C may also have a critical role in phenotypes associated with poor prognosis in breast cancer; however, the relationship between UBE2C expression and clinical outcome in breast cancer subtypes has not previously been investigated. We firstly analyzed breast cancer patient data and immunohistochemistry of breast cancer patient samples. We demonstrated that UBE2C was associated with poor prognosis in breast cancer, particularly basal-like breast cancer, a subtype with aggressive clinical features. Interestingly, we found that there was a close relationship between the expression of BRCA1 and UBE2C in the MCF-7 and MDA-MB-231 breast cancer cell lines. Upregulation of BRCA1 could inhibit the expression of UBE2C. In cells with BRCA1 silenced down, expression of UBE2C was obviously increased, with a concurrent decrease in cellular sensitivity to doxorubicin. Suppression of UBE2C expression by RNA interference led to decrease the mRNA expressions of BCRP, MRP1 and P-gp in doxorubicin-treated MDA-MB-231 cells. Moreover, treatment with 1MUg/ml doxorubicin led to increased expression of UBE2C. The results show high expression of UBE2C is a potential prognostic factor of poor outcome in basal like breast cancer. Moreover, loss of BRCA1 function results in an increase in UBE2C expression and chemical resistance to doxorubicin in breast cancer cells. PMID- 28881293 TI - The anti-tumor effect of aspirin: What we know and what we expect. AB - Aspirin has been widely used as an antipyretic analgesic drug. More and more evidences have shown that aspirin may be play some role on anti-tumor. In this article, we reviewed the research history of aspirin in the treatment and prevention of cancer. Many epidemiological and clinical studies have shown that aspirin can reduce the risk of a variety of malignant tumors and reduce cancer mortality. In addition, we discuss the specific mechanisms of aspirin in the anti tumor effects. It has been found that aspirin mainly depends on the COX pathway and non-COX pathway to inhibit tumor cell growth and to curb tumor development. In this article, clinical studies and anti-tumor mechanism studies published in recent years are reviewed. PMID- 28881294 TI - Sleep disturbance may impact treatment outcome in bipolar disorder: A preliminary investigation in the context of a large comparative effectiveness trial. AB - BACKGROUND: Bipolar patients experience sleep disturbances during and between mood episodes. Yet the impact of sleep on treatment with different medications has not been fully explored. The purpose of this paper is to explore the potential impact of poor sleep at baseline on outcomes in a randomized effectiveness trial of quetiapine and lithium. METHODS: The Bipolar CHOICE study was a 6-month, parallel group, multisite randomized controlled trial. Participants with bipolar disorder (N = 482; 59% female and age 18-70 years) received quetiapine or lithium. Patients were allowed to also receive adjunctive personalized treatments, which were guideline-informed, empirically-based medications added to treatment as needed. Medication changes were recorded as necessary clinical adjustments (NCA). Fisher's exact tests, mixed-regression models, and Mann-Whitney U tests were used to assess demographic and clinical characteristics as well as whether sleep disturbance would predict outcomes. RESULTS: 63% of patients had baseline sleep disturbance. Individuals with sleep disturbance had worse bipolar illness severity, greater severity of depression, mania, anxiety, irritability, and psychosis, were less likely to have sustained response (17% vs. 29%; adjusted RR: 0.55, 95% CI: 0.38-0.78, p = 0.0006) and had more NCAs (median 0.71 vs. 0.59, p = 0.03). LIMITATIONS: Our findings were limited by how we defined sleep disturbance, and by how severity of sleep disturbance was assessed with one item with a non-sleep specific measure. CONCLUSIONS: Baseline sleep disturbance was associated with more severe bipolar symptoms and worse 6-month outcomes. Further research is warranted on improving sleep in bipolar disorder, especially the role of psychosocial interventions. PMID- 28881295 TI - Simultaneous quantitation of hydrazine and acetylhydrazine in human plasma by high performance liquid chromatography-tandem mass spectrometry after derivatization with p-tolualdehyde. AB - A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for simultaneous quantitative analysis of hydrazine and acetylhydrazine in human plasma based on the strategy of p-tolualdehyde derivatization. The derivatization reactions were easily realized by ultrasonic manipulation for 40min. Good separation of the derivatization products was achieved using a C18 column by gradient elution. The optimized mass transition ion-pairs (m/z) monitored for the two hydrazine derivatives were m/z 237.1?>119.9 and m/z 176.9?>117.8, respectively. The limit of detection (LOD) and limit of quantification (LOQ) for hydrazine were 0.002 and 0.005ngmL-1 separately. And they were 0.03 and 0.05ngmL-1 for acetylhydrazine, respectively. The linear range was 0.005-50ngmL-1 for hydrazine and 0.05-500ngmL-1 for acetylhydrazine with R2 greater than 0.999. The recovery range was determined to be 95.38-108.12% with the relative standard deviation (RSD) in the range of 1.24-14.89%. The method was successfully applied to detect 30 clinical plasma samples of pulmonary tuberculosis patients treated with isoniazid. The concentrations were from 0.04 1.99ngmL-1 for hydrazine and 0.06-142.43ngmL-1 for acetylhydrazine. The results indicated that our developed method had the potential for the detection of hydrazine toxicology in complex biological samples. Furthermore, the method has an important significance to clinical treatment with drugs. PMID- 28881296 TI - Folic Acid navigated Silver Selenide nanoparticles for photo-thermal ablation of cancer cells. AB - Photothermal ablation of the cancer cells is a non-invasive technique for cancer treatment, involving cellular assassination in presence of photothermal agent. We are reporting silver selenide (Ag2Se) nanoparticles for photothermal therapy using folic acid for selective targeting. The material, when exposed to 808nm laser, the temperature got boosted to 54 degrees C in 6.5min, thus proving its potential for photothermal ablation. The material was highly biocompatible (95%) at highest concentration (10MUg/mL) against A 549 cells. However, in presence of laser, the cellular killing was 55%. The mode of death was analyzed using MALDI TOF MS. PMID- 28881297 TI - In vitro evaluation of sunitinib loaded bioresorbable microspheres for potential application in arterial chemoembolization. AB - Drug-loadable bioresorbable microspheres (BRMS) are designed for treating hypervascular tumors through chemoembolization, thereby reducing systemic side effects via controllable local delivery. The present study investigated the degradation and loading capability of bioresorbable microspheres with an anti angiogenic agent, sunitinib, and then evaluated the release profiles in different media (PBS, 10MUg/mL and 4mg/mL lysozyme solutions), and tested catheter deliverability as well as potential antiangiogenic effects of the loaded microspheres. The dry weight of the BRMS showed a consistent decrease over the period of incubation in a 10MUg/mL lysozyme solution with 61.3% mass remaining on day 21. Sunitinib was loaded efficiently onto the microspheres, with smaller sizes exhibiting a slightly faster loading and release rate. At 2h, the loading percentages were 99.28%, 97.95%, and 94.39% for 100-300, 300-500, and 500-700MUm microspheres, respectively. At 8h, the percentage of drug released were 78.4+/ 5.8%, 71.7+/-0.3%, and 67.0+/-2.9% for 100-300, 300-500, and 500-700MUm microspheres under static medium conditions, respectively. Under replacing-medium conditions, the presence of 10MUg/mL lysozyme slightly delayed the drug release while 4mg/mL lysozyme significantly facilitated the drug release from the microspheres as compared with PBS solution. Confocal imaging revealed an even distribution of sunitinib throughout the microspheres. Drug loaded microspheres were delivered through microcatheters smoothly without any clogging. Sunitinib retained its efficacy at reducing the viability of human endothelial cells after elution from the microspheres. Thus, these bioresorbable microspheres are promising for arterial chemoembolization. PMID- 28881298 TI - Evaluation of hemocompatibility and hemostasis of a bioflocculant. AB - Bioflocculants are widely used in a large variety of applications, because of their wide range of flocculation. There is limited information in the literature about the ability of bioflocculants to perform beneficial functions without having adverse effects on blood components. In this study, general hemocompatibility of a bioflocculant (MBF-06) was investigated in an in vitro system, measuring flocculation of plasma proteins, red blood cell integrity, blood cell counts, platelet activation, clot formation, complement activation, cytotoxicity and inflammatory response. Effects of MBF-06 included low plasma protein flocculation, low platelet activation, low inflammatory response, no hemolysis or cytotoxicity and increased expression of coagulation markers, including prothrombin fragments 1+2. These findings suggested that the rapid hemostasis caused by MBF-06 resulted, essentially, from humoral coagulation. Overall, our observations revealed the great potential of MBF-06 as a novel hemostatic agent. PMID- 28881299 TI - Photo-responsive tetraether lipids based vesicles for prophyrin mediated vascular targeting and direct phototherapy. AB - Tetraether lipids (TELs) derived from the thermoacidophilic archaeon Sulfolobus acidocaldarius are dominated by polyisoprenoid skeleton. The unique molecular stability of TELs is attributed to the presence of cyclopentane rings, methyl side groups and sugar residues that create extensive hydrogen bond network. In addition, the presence of ether linkages and the lacking of double bonds make them an epitome candidate for photodynamic therapy (PDT). A subtle blend of formulation design to trigger efficient photo responses of protoporphyrin IX (PpIX) exploiting TELs was developed. The platform has demonstrated in principle a practical potential in PDT in terms of prompt Vascular Targeting Photodynamic therapy (VTP) in-ovo chick chorioallantoic membrane (CAM) model. Short PpIX-light interval was associated with thrombosis and massive vascular occlusion in and out the irradiated area after TEL9mol% liposomes have been intravenously injected. Profoundly, TEL62mol% liposomes have proved to be the most effective liposomes that demonstrated localized suppression of angiogenesis in the irradiated area without quiescent vasculature damage. The massive thrombotic effect was no longer observed and eventually the chick has survived. After long PpIX-light interval, TEL62mol% has deliberately gained metronomic PDT at low rate of PpIX dosimetry and the radiant exposure doses in human ovarian carcinoma (SKOV-3) cells as determined by PpIXIC50. These findings could be explained by the fact that TELs impart a remarkable stability to the liposomal bilayer that makes them a potential platform for photodynamic applications. PMID- 28881300 TI - Kinetics and thermodynamics of bovine serum albumin interactions with Congo red dye. AB - To optimize the therapeutic applications of Congo red (CR), a potential inhibitor of protein aggregation, the kinetics and thermodynamics of the interactions between CR and a model protein need to be understood. We used surface plasmon resonance (SPR) and fluorescence techniques to determine the dynamics and thermodynamic parameters for the formation of complexes between CR and bovine serum albumin (BSA). CR interacts with BSA through a transition complex; the activation energy for association (Eact(a)) was determined to be 35.88kJmol-1, while the activation enthalpy (DeltaH?), entropy (DeltaS?), and Gibbs free energy (DeltaG?) are 33.41kJmol-1, 0.18Jmol-1K-1, and 33.35kJmol-1, respectively. When this intermediate transforms into the final CR-BSA complex, the entropy of the system increases and part of the absorbed energy is released; this process is associated with a reverse activation energy (Eact(d)) of 20.17kJmol-1, and values of DeltaH?, DeltaS?, and DeltaG? of 17.69kJmol-1, -162.86Jmol-1K-1, and 66.25kJmol-1, respectively. A comparison of the SPR and fluorescence results suggests that there is more than one site where BSA interacts with CR. PMID- 28881301 TI - Surface immobilization of gelatin onto TiO2 nanotubes to modulate osteoblast behavior. AB - To improve the bioactivity of titanium implants, a homogeneous layer of TiO2 nanotubes with a diameter of approximately 110nm was prepared by anodization. Gelatin was immobilized onto TiO2 nanotubes through an intermediate layer of polydopamine. The surface characteristics of different substrates were evaluated using X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), atomic force microscopy (AFM) and contact angle measurements, respectively. These results demonstrate that gelatin was successfully immobilized onto TiO2 nanotubes. In vitro cell culture experiments including immunofluorescence staining, cell viability, alkaline phosphatase (ALP), mineralization and the expression of osteogenic genes including runt-related transcription factor 2 (Runx2), ALP, collagen type I (Col I), and osteopontin (OPN) confirm that cell spreading, proliferation and osteoblastic differentiation were improved when cells were seeded onto gelatin-immobilized TiO2 nanotubes. This resulting material shows great promise as a future material in titanium implant applications. PMID- 28881302 TI - Nanoparticulation of bovine serum albumin and poly-d-lysine through complex coacervation and encapsulation of curcumin. AB - Soluble coacervate nanoparticles were fabricated by mixing bovine serum albumin (BSA) and poly-d-lysine with low (LMW-PDL) and high molecular weights (HMW-PDL). The particle size was influenced by molecular weight, mass ratio of polyelectrolytes (PEs), and salt concentration. The smallest nanoparticles had a diameter of 212+/-11nm which was achieved with LMW-PDL dissolved with 0.1M NaCl at pH 7 and a mass ratio of 2.0 (BSA: PDL). SEM images showed that coacervate nanoparticles of LMW-PDL are relatively spherical in shape, while nanoparticles of HMW-PDL were irregular. Crosslinking of the protein/polypeptide with glutaraldehyde had variable impact on the stability and particle size over 21days at 4 and 25 degrees C. The encapsulation efficiency (EE) for curcumin to BSA molar ratio of 0.5 was 47%. The EE increased to 60% when the curcumin to BSA molar ratio was 10 with a loading capacity of 22MUg of curcumin per mg of coacervate nanoparticles. The average particle size of the loaded colloidal dispersions increased as the curcumin concentration was increased. For the colloidal dispersions with 0.5 molar ratio of curcumin to BSA, the particle size was around 204+/-14nm at day 1, while the nanoparticles with molar ratio of 10 showed a particle size around 316+/-43nm. The curcumin loaded BSA:LMW-PDL nanoparticles were pretty stable over a period of 21days. PMID- 28881303 TI - Randomized controlled trial of a parenting program to reduce the risk of child maltreatment in South Africa. AB - Parenting programs in high-income countries have been shown to reduce the risk of child maltreatment. However, there is limited evidence of their effectiveness in low- and middle-income countries. The objective of this study was to examine the initial effects of a parenting program in reducing the risk of child maltreatment in highly-deprived and vulnerable communities in Cape Town, South Africa. Low income parents (N=68) with children aged three to eight years were randomly assigned to either a group-based parenting program or a wait-list control group. Observational and parent-report assessments were taken at baseline and at immediate post-test after the intervention was delivered. Primary outcomes were parent-report and observational assessments of harsh parenting, positive parenting, and child behavior problems. Secondary outcomes were parent-report assessments of parental depression, parenting stress, and social support. Results indicated moderate treatment effects for increased frequency of parent-report of positive parenting (d=0.63) and observational assessments of parent-child play (d=0.57). Observational assessments also found moderate negative treatment effects for less frequent positive child behavior (d=-0.56). This study is the first randomized controlled trial design to rigorously test the effectiveness of a parenting program on reducing the risk of child maltreatment in sub-Saharan Africa using both observational and self-report assessments. Results provide preliminary evidence of effectiveness of reducing the risk of child maltreatment by improving positive parenting behavior. Further development is required to strengthen program components regarding child behavior management and nonviolent discipline strategies. Future research would benefit from a larger trial with sufficient power to determine program effectiveness. PMID- 28881304 TI - Biomarkers as indicators of fungal biomass in the atmosphere of Sao Paulo, Brazil. AB - The biogenic aerosol contribution to atmospheric particulate matter (PM) mass concentration is usually neglected due to the difficulty in identifying its components, although it can be significant. In the Metropolitan Area of Sao Paulo (MASP)-Brazil, several studies have been performed to identify sources for PM, revealing vehicular emissions and soil re-suspension as the main identified sources. The organic fraction has been related primarily to biomass burning (BB) and fuel combustion, although there is significant presence of green areas in the city which render biogenic emissions as an additional source of organic carbon (OC). The objectives of this work are to (i) characterise the composition of the PM10 (ii) estimate the relative mass contribution of fungal spores to PM concentrations with sizes smaller than 10MUm (PM10) in MASP and (iii) assess the main sources of PM10. To achieve these objectives, we measured markers of biogenic sources and BB, during the fall-winter transition, which along with other constituents, such as ions, organic/elemental carbon, elemental composition and fungal spore concentrations, help assess the PM10 sources. We used receptor models to identify distinct source-related PM10 fractions and conversion factors to convert biomarker concentrations to fungal mass. Our results show the mean contributions of fungal aerosol to PM10 and OC mass were 2% and 8%, respectively, indicating the importance of fungal spores to the aerosol burden in the urban atmosphere. Using specific rotation factor analysis, we identified the following factors contributing to PM: soil re-suspension, biogenic aerosol, secondary inorganic aerosol, vehicular emissions and BB/isoprene-related secondary organic aerosol (I-SOA). BB/I-SOA was the main source representing 28% of the PM10 mass, while biogenic aerosol explained a significant (11%) fraction of the PM10 mass as well. Our findings suggest that primary biogenic aerosol is an important fraction of PM10 mass, yet not considered in most studies. PMID- 28881305 TI - The association between cooking oil fume exposure during pregnancy and birth weight: A prospective mother-child cohort study. AB - Effects of indoor air pollution on neonatal birth weight has been studied for many years. In China, cooking oil fumes are important parts of indoor air pollution. However, whether cooking oil fume exposure during pregnancy affects birth weight in China remains poorly understood. The objective of this study was to examine the association between pregnancy exposure to cooking oil fumes and birth weight in a newly established prospective mother-child cohort in China. We finally included 1420 pregnant women from 2013 to 2015 and follow up for one year until the offspring was born. According to self-reported exposure status, we categorized mothers into non-exposure group and exposed group or three exposure time subgroups, including 0h/day, 0-1h/day and >1h/day respectively. By using multinomial logistics regression models, we found that pregnancy exposure to cooking oil fumes significantly increased the risk of large for gestational age (LGA, OR=1.58, 95% CI=1.15-2.18, P=4.88*10-3). Additionally, compared to pregnant women who were in non-exposure group, 0-1h/day exposure elevated the risk of LGA (OR=1.69, 95% CI=1.22-2.33, P=1.63*10-3), while >1h/day exposure elevated the risk of small for gestational age, but were not significant (SGA, OR=2.15, 95% CI=0.61-7.66, P=0.24). In the stratification analysis, women aged 25-29years and >=30years were predisposed to the influence of cooking oil fumes and have LGA newborns (OR=1.73, 95% CI=1.09-2.75, P=0.02; OR=1.72, 95% CI=1.07-2.77, P=0.02, respectively). In conclusion, the present study suggests inverse U-shape dose response association between maternal exposure to cooking oil fumes during pregnancy and birth weight, and further studies are needed to verify the effect of cooking oil fumes on the birth weight. PMID- 28881306 TI - Assessment of baseline ecotoxicity of sediments from a prospective mining area enriched in light rare earth elements. AB - Rare earth elements (REEs) disperse from indigenous rocks to the environment, thus making sediments one of the major sinks and sources of metal pollution. The emerging use of REEs and the subsequent opening of new mining areas may contribute to their release into surrounding ecosystems. For this reason, this study was performed in a natural area with geological material abundant in ferrocarbonatites and light REE. The aim of this work was to assess the natural REE availability and (eco)toxicity in freshwater sediments. Sediments showed high REE concentrations in samples with fine grain size fractions, and low in organic rich sediments. The enrichment in LREE was mostly from rocks and the obtained enrichment factors (EF) confirmed that the sediments are not anthropogenically polluted. To assess REE availability and ecotoxicity, four toxicity tests were performed. REEs measured as the dissolved concentration in the test media were very low compared to the potentially available total REE in sediments and showed positive or negative correlations with fine or coarse grain sizes, respectively, and positive correlations with the content in Mg, Fe and Al. In tests performed in media supplemented with salts, the availability of REEs decreased considerably. Only some toxic effects could be linked to the REE contents in the ostracodtox and luminotox tests. However, measurement of toxicity could be influenced by the sediment properties and lead to a potential overestimation of ecotoxicity if only REE are regarded. Our study reveals that the physicochemical properties of sediments are a key factor controlling both REE availability and toxicity, whereas the determination of REE effects from toxicity tests using liquid media with salt addition will decrease REE availability and could mask toxic effects. Our findings provide new knowledge about REE behaviour in sediments and are a starting point for understanding potential REE pollution around prospective mining areas. PMID- 28881307 TI - Using spatial-stream-network models and long-term data to understand and predict dynamics of faecal contamination in a mixed land-use catchment. AB - An 11year dataset of concentrations of E. coli at 10 spatially-distributed sites in a mixed land-use catchment in NE Scotland (52km2) revealed that concentrations were not clearly associated with flow or season. The lack of a clear flow concentration relationship may have been due to greater water fluxes from less contaminated headwaters during high flows diluting downstream concentrations, the importance of persistent point sources of E. coli both anthropogenic and agricultural, and possibly the temporal resolution of the dataset. Point sources and year-round grazing of livestock probably obscured clear seasonality in concentrations. Multiple linear regression models identified potential for contamination by anthropogenic point sources as a significant predictor of long term spatial patterns of low, average and high concentrations of E. coli. Neither arable nor pasture land was significant, even when accounting for hydrological connectivity with a topographic-index method. However, this may have reflected coarse-scale land-cover data inadequately representing "point sources" of agricultural contamination (e.g. direct defecation of livestock into the stream) and temporal changes in availability of E. coli from diffuse sources. Spatial stream-network models (SSNMs) were applied in a novel context, and had value in making more robust catchment-scale predictions of concentrations of E. coli with estimates of uncertainty, and in enabling identification of potential "hot spots" of faecal contamination. Successfully managing faecal contamination of surface waters is vital for safeguarding public health. Our finding that concentrations of E. coli could not clearly be associated with flow or season may suggest that management strategies should not necessarily target only high flow events or summer when faecal contamination risk is often assumed to be greatest. Furthermore, we identified SSNMs as valuable tools for identifying possible "hot spots" of contamination which could be targeted for management, and for highlighting areas where additional monitoring could help better constrain predictions relating to faecal contamination. PMID- 28881309 TI - In situ benthic flow-through chambers to determine sediment-to-water fluxes of legacy hydrophobic organic contaminants. AB - Contaminated sediment can release hydrophobic organic contaminants (HOCs) and thereby act as a secondary source of primarily legacy hazardous substances to the water column. There is therefore a need for assessments of the release of HOCs from contaminated sediment for prioritization of management actions. In situ assessment of HOC sediment-to-water flux is currently done with (closed) benthic flux chambers, which have a sampling time exceeding one month. During this time, the water inside the chamber is depleted of oxygen and the effect of bioturbation on the sediment-to-water release of HOCs is largely ignored. Here we present a novel benthic flux chamber, which measures sediment-to-water flux of legacy HOCs within days, and includes the effect of bioturbation since ambient oxygen levels inside the chamber are maintained by continuous pumping of water through the chamber. This chamber design allows for sediment-to-water flux measurements under more natural conditions. The chamber design was tested in a contaminated Baltic Sea bay. Measured fluxes were 62-2300 ng m-2 d-1 for individual polycyclic aromatic hydrocarbons (PAHs), and 5.5-150 ng m-2 d-1 for polychlorinated biphenyls (PCBs). These fluxes were 3-23 times (PAHs) and 12-74 times (PCBs) higher than fluxes measured with closed benthic chambers deployed in parallel at the same location. We hypothesize that the observed difference in HOC flux between the two chamber designs are partly an effect of bioturbation. This hypothesized effect of bioturbation was in accordance with literature data from experimental studies. PMID- 28881308 TI - Overexpression of Exportin-5 Overrides the Inhibitory Effect of miRNAs Regulation Control and Stabilize Proteins via Posttranslation Modifications in Prostate Cancer. AB - Although XPO5 has been characterized to have tumor-suppressor features in the miRNA biogenesis pathway, the impact of altered expression of XPO5 in cancers is unexplored. Here we report a novel "oncogenic" role of XPO5 in advanced prostate cancer. Using prostate cancer models, we found that excess levels of XPO5 override the inhibitory effect of the canoncial miRNA-mRNA regulation, resulting in a global increase in proteins expression. Importantly, we found that decreased expression of XPO5 could promote an increase in proteasome degradation, whereas overexpression of XPO5 leads to altered protein posttranslational modification via hyperglycosylation, resulting in cellular protein stability. We evaluated the therapeutic advantage of targeting XPO5 in prostate cancer and found that knocking down XPO5 in prostate cancer cells suppressed cellular proliferation and tumor development without significantly impacting normal fibroblast cells survival. To our knowledge, this is the first report describing the oncogenic role of XPO5 in overriding the miRNAs regulation control. Furthermore, we believe that these findings will provide an explanation as to why, in some cancers that express higher abundance of mature miRNAs, fail to suppress their potential protein targets. PMID- 28881310 TI - Multi-walled carbon nanotubes facilitated the removal of tetrabromobisphenol a mediated by horseradish peroxidase. AB - In this study, we systematically investigated the effect of multiwall carbon nanotubes (MWCNTs) on the removal of tetrabromobisphenol A (TBBPA) mediated by horseradish peroxidase (HRP) at varying important conditions. The results suggested that the presence of MWCNTs significantly enhanced the removal of TBBPA mediated by HRP and the reaction rate constant was linear with the MWCNTs dosage. The enhancement of MWCNTs on the HRP-mediated reaction was attributed to two facts, one is that MWCNTs protected HRP from inactivation, the other is that the presence of MWCNTs made the homogeneous reaction of TBBPA be heterogeneous reaction by adsorbing TBBPA on its surface. Moreover, the influence of MWCNTs on TBBPA products distribution was further elucidated. We found that the species of reaction product had no difference between the HRP-mediated systems with and without the presence of MWCNTs. However, the presence of MWCNTs significantly decreased the yields of each product. These results give insight into the role of MWCNTs in HRP-mediated TBBPA reactions and provide theoretical foundation for potential development of novel enzymatic methods to control TBBPA contamination. MWCNTs enhanced the removal of TBBPA mediated by HRP/H2O2, because it protected HRP from inactivation and adsorbed TBBPA on its surface to form a heterogeneous reaction process. PMID- 28881311 TI - Simultaneous determination of tenofovir alafenamide and its active metabolites tenofovir and tenofovir diphosphate in HBV-infected hepatocyte with a sensitive LC-MS/MS method. AB - Tenofovir (TFV), a first-line anti-viral agent, has been prepared as various forms of prodrugs for better bioavailability, lower systemic exposure and higher target cells loading of TFV to enhance efficacy and reduce toxicity. TFV undergoes intracellular phosphorylation to form TFV diphosphate (TFV-DP) in target cell to inhibit viral DNA replication. Hence, TFV-DP is the key active metabolite that exhibits anti-virus activity, its intracellular exposure and half life determine the final activity. Therefore, simultaneous monitoring prodrug, TFV and TFV-DP in target cells will comprehensively evaluate TFV prodrugs, both considering the stability of ester prodrug, and the intracellular exposure of TFV DP. Thus we intended to develop a convenient general analytical method, taking tenofovir alafenamide (TAF) as a representative of TFV prodrugs. A sensitive LC MS/MS method was developed, and TAF, TFV and TFV-DP were separated on a XSelect HSS T3 column (4.6mm*150mm, 3.5MUm, Waters) with gradient elution after protein precipitation. The method provided good linearity for all the compounds (2-500nM for TFV and TAF; 20-5000nM for TFV-DP) with the correlation coefficients (r) greater than 0.999. Intra- and inter-day accuracies (in terms of relative error, RE<10.4%) and precisions (in terms of coefficient of variation, CV<14.1%) satisfied the standard of validation. The matrix effect, recovery and stability were also within acceptable criteria. Finally, we investigated the intracellular pharmacokinetics of TAF and its active metabolites in HepG2.2.15 cells with this method. PMID- 28881312 TI - LC-MS/MS assay for the quantitation of the ribonucleotide reductase inhibitor triapine in human plasma. AB - The ribonucleotide reductase inhibitor and radiosensitizer triapine (3 aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), NSC 663249) is clinically being evaluated via the intravenous (IV) route for the treatment of cervical and vulvar cancer in combination with primary cisplatin chemoradiation. The need for a 2-h infusion and frequent administration of triapine is logistically challenging, prompting us to pursue oral (PO) administration. In support of the clinical trial investigating oral triapine in combination with chemoradiation, we developed and validated a novel LC-MS/MS assay for the quantification of triapine in 50MUL human plasma. After protein precipitation, chromatographic separation of the supernatant was achieved with a Shodex ODP2 column and an isocratic acetonitrile-water mobile phase with 10% ammonium acetate. Detection with an ABI 4000 mass spectrometer utilized electrospray positive mode ionization. The assay was linear from 3 to 3,000ng/mL and proved to be accurate (97.1-103.1%) and precise (<7.4% CV), and met the U.S. FDA guidance for bioanalytical method validation. This LC-MS/MS assay will be an essential tool to further define the pharmacokinetics and oral bioavailability of triapine. PMID- 28881313 TI - LC-MS/MS method for preclinical pharmacokinetic study of QX-OH, a novel long acting local anesthetic, in sciatic nerve blockade in rats. AB - QX-OH, a new synthetic local anesthetic, produced concentration-dependent, reversible, and long-acting local anesthesia in animal models, with moderate local toxicity. As part of preclinical research for drug development, we developed and validated a method for the determination of QX-OH in the plasma, muscle, and sciatic nerve using liquid chromatography-mass spectrometry. After a simple protein precipitation procedure, analysis was performed on an Extend C18 column (100mm*3mm, 3.5MUm) by isocratic elution with 0.05% formic acid/acetonitrile (78:22, v/v) at a flow rate of 0.3mL/min. A multiple-reaction monitoring mode at the transitions of m/z 279.1->102.1 for QX-OH and m/z 275.2 >126.1 for an internal standard (ropivacaine hydrochloride) was used for the quantification, with a positive electrospray ionization interface. The approach was validated as per the U.S. Food and Drug Administration guidelines and successfully used in a pharmacokinetic study of QX-OH after a sciatic nerve block with 0.2mL of 35mM QX-OH. The results demonstrated that the new local anesthetic, QX-OH, had a high concentration in tissue, low systemic exposure, and long duration in the sciatic nerve. PMID- 28881314 TI - Analytical characterization of human milk oligosaccharides - potential applications in pharmaceutical analysis. AB - Human breast milk is the gold standard for infant feeding and the best possible nourishment a new-born could have. Breastfeeding is the natural way to provide optimal nutritional, immunological and emotional nurturing for the healthy growth and development of infants. Human milk is a complex and dynamic biofluid comprised of many hundreds to thousands of distinct bioactive structures, among which one of the most abundant substances are the non-conjugated complex carbohydrates referred to as human milk oligosaccharides (HMOs). Due to their structural diversity and abundance, HMOs possess many beneficial biological functions. In order to understand human milk composition and HMO functions, state of-the-art glycomic methods are inevitable. The industrial, large scale chemoenzymatic production of the most abundant HMOs became a reality in the last years and it evokes the need for straightforward and genuine analytical procedures to monitor the synthetic process and the quality of the products. It is obvious, that HMOs represent the next breakthrough in infant nutrition, as the addition of HMOs (such as 2'-fucosyllactose or lacto-N-neotetraose) to infant- and follow-on formulas, processed cereal-based food and baby foods for infants and young children etc. will revolutionize this field. This review highlights the potential applications of HMOs in the (bio)pharmaceutical industry, also summarizes the analytical methods available for the characterization of HMOs. An overview of the structure and function of HMOs along with their determination methods in complex matrices are provided. Various separation methods including liquid- and gas chromatography and capillary electrophoresis for the characterization and novel approaches for the quantitation of HMOs are discussed. PMID- 28881315 TI - Double-Track Electrochemical Green Approach for Simultaneous Dissolution Profiling of Naproxen Sodium and Diphenhydramine Hydrochloride. AB - Acquisition of the dissolution profiles of more than single active ingredient in a multi-analyte pharmaceutical formulation is a mandatory manufacturing practice that is dominated by utilization of the off-line separation-based chromatographic methods. This contribution adopts a new "Double-Track" approach with the ultimate goal of advancing the in-line potentiometric sensors to their most effective applicability for simultaneous acquisition of the dissolution profiles of two active ingredients in a binary pharmaceutical formulation. The unique abilities of these sensors for real-time measurements is the key driver for adoption of "green analytical chemistry" (GAC) principles aiming to expand the application of eco-friendly analytical methods With the aim of performing a side-by-side comparison, this work investigates the degree of adherence of ISEs to the 12 principles of GAC in multicomponent dissolution profiling with respect to the HPLC. For the proof of concept, a binary mixture of naproxen sodium (NAPR) and diphenhydramine hydrochloride (DIPH) marketed as Aleve pm(r) tablets was selected as a model for which dissolution profiles were attained by two techniques. The first "Double-Track" in-line strategy depends on dipping two highly integrated membrane sensors for continuous monitoring of the dissolution of each active pharmaceutical ingredient (API) by tracing the e.m.f change over the time scale. For the determination of NAPR, sensor I was developed using tridodecyl methyl ammonium chloride as an anion exchanger, while sensor II was developed for the determination of DIPH using potassium tetrakis (4-chlorophenyl) borate as a cation exchanger. The second off-line strategy utilizes a separation-based HPLC method via off-line tracking the increase of peak area by UV detection at 220nm over time using a mobile phase of acetonitrile: water (90:10) pH 3. The advantages of the newly introduced "Double-Track" approach regarding GAC principles are highlighted, and the merits of these benign real-time analyzers (ISEs) that can deliver equivalent analytical results as HPLC while significantly reducing solvent consumption/waste generation are described. PMID- 28881316 TI - Development and validation of a sensitive LC-MS/MS method without derivatization/ion-pairing agents for etimicin quantification in rat plasma, internal ear and kidney. AB - Etimicin (ETM), which belongs to the newest generation of aminoglycosides (AGs), has been proven to not only maintain but also strengthen the advantages of former AGs with relatively less toxicity. Now, it is widely applied for the treatment of bacterial infections in the clinic. Nevertheless, nephrotoxicity and ototoxicity are unavoidable issues for AGs, and while ETM is no exception, the seriousness of these issues is different. To explore the reason why ETM exhibits less toxicity and to better direct the optimization and development of new AGs, it is of great necessity and importance to monitor the pharmacokinetic behaviors of ETM in its potential toxicity target organs, the kidney and internal ear, as well as in plasma. Therefore, a novel, sensitive and efficient LC-MS/MS method without derivatization or ion-pairing agents had been developed and validated for quantification of ETM in rat plasma, kidney and internal ear for the first time. This method showed good linearity over the range of 50-2000ng/mL for rat plasma/internal ear and 100-5000ng/mL for rat kidney. The precision was less than 4.4% and the accuracy was below 4.8%. Recovery and matrix effects were 71.3% 82.8% and 97.6%-108.5%, respectively. After intravenous administration of a single dose of ETM, plasma drug concentrations fit well with a two-compartmental model, and the AUC0-infinity, t1/2alpha, t1/2beta, MRT and CL were 127.96+/ 5.52MUg*h/mL, 0.53+/-0.03h, 3.32+/-1.11h, 1.01+/-0.03h and 234.80+/-10.05mL/h/kg, respectively. Particularly, ETM showed a considerably long half-life in kidney and internal ear, up to 155.96+/-19.95h and 83.11+/-26.60h, respectively, which might contribute greatly to its toxicity. PMID- 28881317 TI - Modulation of antioxidative defense expression and osmolyte content by co application of 24-epibrassinolide and salicylic acid in Pb exposed Indian mustard plants. AB - The study focuses on potential of combined pre-soaking treatment of 24 Epibrassinolide (EBL) and Salicylic acid (SA) in alleviating Pb phytotoxicity in Brassica juncea L. plants. The seeds after treatment with combination of both the hormones were sown in mixture of soil, sand and manure (3:1:1) and were exposed to Pb concentrations (0.25mM, 0.50mM and 0.75mM). After 30 days of growth, the plants were harvested and processed, for quantification of various metabolites. It was found that pre-sowing of seeds in combination of EBL and SA, mitigated the adverse effects of metal stress by modulating antioxidative defense response and enhanced osmolyte contents. Dry matter content and heavy metal tolerance index were enhanced in response to co-application of EBL and SA. The levels of superoxide anions, hydrogen peroxide and malondialdehyde were lowered by the combined treatment of hormones. Enhancement in activities of guaiacol peroxidase, catalase, glutathione reductase and glutathione-s-transferase were recorded. Contents of glutathione, tocopherol and ascorbic acid were also enhanced in response to co-application of both hormones. Expression of POD, CAT, GR and GST1 genes were up-regulated whereas SOD gene was observed to be down-regulated. Contents of proline, trehalose and glycine betaine were also reported to be elevated as a result of treatment with EBL+SA. The results suggest that co application of EBL+SA may play an imperative role in improving the antioxidative defense expression of B. juncea plants to combat the oxidative stress generated by Pb toxicity. PMID- 28881318 TI - Alcohol and substance use diagnoses among HIV-positive patients receiving care in NYC clinic settings. AB - BACKGROUND: Substance use among HIV-positive persons exacerbates health problems. This study sought to estimate the prevalence of alcohol and drug-use diagnoses and examined hypothesized predictors associated with alcohol and drug-use diagnoses among HIV-positive patients in New York City (NYC). METHODS: This cohort study reviewed electronic medical records (EMRs) of 4965 HIV-positive patients based on diagnostic codes. These patients attended a comprehensive care clinic in NYC in 2012. Multinomial logistic regression was used to predict the odds of classification into substance use diagnosis grouping. RESULTS: Of the full sample, only 12.7% of patients had an alcohol use diagnosis documented in their EMR compared with more than one-quarter (26.4%) of patients having a recorded drug use diagnosis (p<0.001). Compared with the No Alcohol or Drugs group, the regression model showed that older age and having a recent inpatient hospital stay independently predicted being in the Alcohol Only group; years living with HIV, having an unsuppressed viral load, and having a recent inpatient hospital stay were associated with higher odds of being in the Drugs Only and Alcohol and Drugs groups; and being women and men who have sex with men (MSM) were associated with decreased odds of being in the Drugs Only and Alcohol and Drugs groups. CONCLUSIONS: Substance use diagnosis was associated with viremia and low CD4 counts and hospital stays. This implies that providers should screen for substance use in HIV-positive patients with poor health. Further examination of the extent of such comorbidity is instrumental for intervention efforts. PMID- 28881320 TI - Frequency and predictors of psychological distress after a diagnosis of epilepsy: A community-based study. AB - OBJECTIVE: The objective of the study was to determine the frequency and predictors of psychological distress after a diagnosis of epilepsy. METHODS: The Sydney Epilepsy Incidence Study to Measure Illness Consequences (SEISMIC) was a prospective, multicenter, community-based study of people of all ages with newly diagnosed epilepsy in Sydney, Australia. Analyses involved multivariate logistic regression and multinomial logit regression to identify predictors of psychological distress, assessed using the Hospital Anxiety and Depression Scale (HADS) and the Strengths and Difficulties Questionnaire (SDQ), as part of structured interviews. RESULTS: Psychological distress occurred in 33% (95% confidence interval [CI] 26 to 40%) and 24% (95% CI 18 to 31%) of 180 adults at baseline and 12months, respectively, and 23% (95% CI 14 to 33%) of 77 children at both time points. Thirty adults and 7 children had distress at baseline who recovered at 12months, while 15 adults and 7 children had new onset of distress during this period. History of psychiatric or behavioral disorder (for adults, odds ratio [OR] 6.82, 95% CI 3.08 to 15.10; for children, OR 28.85, 95% CI 2.88 to 288.60) and higher psychosocial disability (adults, OR 1.17, 95% CI 1.07 to 1.27) or lower family functioning (children, OR 1.80, 95% CI 1.08 to 3.02) were associated with psychological distress (C statistics 0.80 and 0.78). CONCLUSIONS: Psychological distress is common and fluctuates in frequency after a diagnosis of epilepsy. Those with premorbid psychological, psychosocial, and family problems are at high risk of this adverse outcome. PMID- 28881319 TI - Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses. AB - BACKGROUND: Food intake and use of drugs of abuse like cocaine share common central and peripheral physiological pathways. Appetitive hormones play a major role in regulating food intake; however, little is known about the effects of acute cocaine administration on the blood concentrations of these hormones in cocaine users. METHODS: We evaluated serum concentrations of six appetitive hormones: ghrelin (total and acyl-ghrelin), amylin, glucagon-like peptide-1 (GLP 1), insulin, leptin and peptide YY (PYY), as well as acute cardiorespiratory and subjective responses of 8 experienced cocaine users who received 25mg intravenous (IV) cocaine. RESULTS: Serum concentrations of GLP-1 (p=0.014) and PYY (p=0.036) were significantly decreased one hour following IV cocaine administration; there was a trend towards a decrease for insulin (p=0.055) and amylin (p=0.063) concentrations, while no significant IV cocaine effect was observed for ghrelin (total or acyl-ghrelin) or leptin concentrations (p's?>0.5). We also observed associations between hormone concentrations acutely affected by IV cocaine (GLP 1, PYY, insulin, amylin) and some cocaine-related cardiorespiratory and subjective responses (e.g., increased heart and respiratory rates; feeling high and anxious). DISCUSSION: These findings show a significant effect of acute IV cocaine administration on some appetitive hormones and suggest potential associations between these hormones and cocaine-related cardiorespiratory and subjective responses. Additional research is needed to further investigate the potential mechanisms underlining these associations. PMID- 28881321 TI - Health-related quality of life and emotional wellbeing improve in parents after their children have undergone epilepsy surgery - A prospective population-based study. AB - The objective was to compare parental health-related quality of life (HRQoL), anxiety, and depression at baseline and 2years after epilepsy surgery in a population-based series of children and young people who underwent surgery between 1995 and 1999 and to compare with population norms. Fifty mothers and 44 fathers of 50 children and young people (age: 1-20years) completed the Medical Outcome Study 36-item Short Form Health Survey (SF-36) and Hospital Anxiety and Depression (HAD) scale at baseline and at follow-up. Changes in SF-36 and HAD scores between baseline and follow-up were compared using Wilcoxon signed rank test. Scores on the SF-36 were compared with a reference sample from the Swedish population using the Mann Whitney U test. Factors associated with changes in SF 36 and HAD scores were analyzed using regression analysis. On the SF-36, the Physical Component Summary (PCS) scores were not significantly different between baseline and follow-up for mothers (p=0.177) or fathers (p=0.054). Mental Component Summary (MCS) scores improved significantly for mothers (p=0.008) and fathers (p<0.001). Mothers' baseline scores on seven of eight SF-36 domains were significantly lower than reference values. Scores at follow-up improved on these seven domains, but on three domains (primarily mental health domains), scores remained significantly lower than reference values. Fathers' baseline scores on four of eight SF-36 domains were significantly lower than reference values, and scores at follow-up remained significantly lower on the four primarily mental health domains. The proportions of mothers and fathers classified as HAD-A and HAD-D cases decreased at follow-up but did not reach statistical significance. Child epilepsy variables were in the main not associated with parental outcomes, but a greater reduction in AEDs was associated with a greater reduction in PCS scores. Parents of young people/children with seizure-free outcome were significantly more likely to have a reduction in depression scores than parents of young people/children with continued seizures. Many aspects of HRQoL and emotional wellbeing improved at 2-year follow-up for parents after epilepsy surgery on their children. There is a need to comprehensively identify factors associated with changes in parental HRQoL and emotional wellbeing to provide adequate support. PMID- 28881322 TI - The use of a game-based learning platform to engage nursing students: A descriptive, qualitative study. AB - Baccalaureate nursing programs require students to complete a research course, and faculty find it challenging to engage students. Educational gaming has recently gained attention as a technique to motivate students and enhance learning. The purpose of this pilot study was to describe undergraduate nursing students' reflections of their experiences with 3D Gamelab(c), a game-based learning platform. A descriptive qualitative research design was used to elicit students' reflections of their experiences. Educational content such as handouts, videos, activities, and recommended resources for a required junior level nursing research course was organized into quests for use in 3D GameLab(c). At the end of the semester, students were invited to give their feedback through a survey with open-ended questions. Thematic analysis resulted in the following components of the game-based learning experience: navigation, motivation, gaming concept, knowledge, technology, and target population. Although the overall response to 3D GameLab(c) in this course was negative, game-based learning does have the potential to engage students and enhance learning. To better understand how educational gaming could be used in nursing, further research should be conducted to determine the most motivating elements and the types of course content best delivered in this manner. PMID- 28881323 TI - A systematic review comparing open-book and closed-book examinations: Evaluating effects on development of critical thinking skills. AB - The advantages of using traditional closed-book examinations are closely compared to the advantages of using open-book examinations for the development of critical thinking skills in nursing students. The use of critical thinking skills is vital among nurses to assess patient needs and modify standard approaches to individualize care for better patient outcomes. The following areas are compared and contrasted for both closed-book and open-book examinations: examination preparation, rote memorization versus active learning, intellectual engagement, simulation of working environment, higher order thinking skills, anxiety reduction and student satisfaction. During investigation of closed-book examinations and open-book examinations, the use of collaborative testing was unveiled. Collaborative testing combines areas from both closed-book and open book examinations. Based on the systematic review of literature, the recommendation is to use a mixed method of examination types throughout the course of the nursing program. Each type of examination helps develop different skill sets in the nursing student. PMID- 28881324 TI - Assessment of undergraduate nursing students from an Irish perspective: Decisions and dilemmas? AB - Assessment of clinical competence plays a pivotal role in the education of undergraduate nursing students in preparation for registration. The challenges that face preceptors are represented in the international literature yet few studies have focused on the factors that influence the decision-making process by preceptors when students under-perform or appear to be borderline status in relation to clinical practice. This study explored the lived experiences of the preceptors during the assessment process using a phenomenological approach. This was a qualitative study that utilised a phenomenological approach to explore the lived experiences of the preceptors in relation to student assessment of those students who were incompetent and underperformed in clinical practice. Three categories emerged from the findings: First impressions, Emotional turmoil of failing a clinical assessment and competing demands in the workplace. It is proposed that employing a tripartite approach would enhance the assessment process to ensure a more robust and decision-sharing mechanism. This would support decisions that are made in the cases of incompetent or borderline nursing students and increase the objectivity of the competency assessment to ameliorate the emotional turmoil that is experienced by preceptors. PMID- 28881325 TI - Biodegradation of high doses of commercial pesticide products in pilot-scale biobeds using olive-oil agroindustry wastes. AB - Biobeds systems containing soil, peat and straw (SPS) are used worldwide to eliminate pesticide point-source contamination, but implantation is difficult when peat and/or straw are not available. Novel biobeds composed of soil, olive pruning and wet olive mill cake (SCPr) or its vermicompost (SVPr) were assayed at pilot scale for its use in olive grove areas. Their removal efficiency for five pesticides applied at high concentration was compared with the biobed with SPS. The effect of a grass layer on the efficiency of these biobeds was also evaluated. Pesticides were retained mainly in the upper layer. In non-planted biobeds with SCPr and SVPr, pesticides dissipation was higher than in SPS, except for diuron. In the biobed with SVPr, with the highest pesticide dissipation capacity, the removed amount of dimethoate, imidacloprid, tebuconazole, diuron and oxyfluorfen was 100, 80, 73, 75 and 50%, respectively. The grass layer enhanced dehydrogenase and diphenol-oxidase activities, modified the pesticides dissipation kinetics and favored the pesticide downward movement. One metabolite of imidacloprid, 3 of oxyfluorfen and 4 of diuron were identified by GC-MS. These novel biobeds represent an alternative to the traditional one and a contribution to promote a circular economy for the olive-oil production. PMID- 28881326 TI - Remediation of electronic waste polluted soil using a combination of persulfate oxidation and chemical washing. AB - Laboratory experiments were conducted to investigate the efficiency of a simultaneous chemical extraction and oxidation for removing persistent organic pollutants (POPs) and toxic metals from an actual soil polluted by the recycling activity of electronic waste. Various chemicals, including hydroxypropyl-beta cyclodextrin (HPCD), citric acid (CA) and sodium persulfate (SP) were applied synchronously with Fe2+ activated oxidation to enhance the co-removal of both types of pollutants. It is found that the addition of HPCD can enhance POPs removal through solubilization of POPs and iron chelation; while the CA-chelated Fe2+ activation process is effective for extracting metals and degrading residual POPs. Under the optimized reagent conditions, 69.4% Cu, 78.1% Pb, 74.6% Ni, 97.1% polychlorinated biphenyls, 93.8% polycyclic aromatic hydrocarbons, and 96.4% polybrominated diphenylethers were removed after the sequential application of SP HPCD-Fe2+ and SP-CA-Fe2+ processes with a duration of 180 and 240 min, respectively. A high dehalogenation efficiency (84.8% bromine and 86.2% chlorine) is observed, suggesting the low accumulation of halogen-containing organic intermediates. The remediated soil can satisfy the national soil quality standard of China. Collectively, co-contaminated soil can be remediated with reasonable time and capital costs through simultaneous application of persulfate oxidation and chemical extraction. PMID- 28881327 TI - Solving multi-objective water management problems using evolutionary computation. AB - Water as a resource is becoming increasingly more valuable given the changes in global climate. In an agricultural sense, the role of water is vital to ensuring food security. Therefore the management of it has become a subject of increasing attention and the development of effective tools to support participative decision-making in water management will be a valuable contribution. In this paper, evolutionary computation techniques and Pareto optimisation are incorporated in a model-based system for water management. An illustrative test case modelling optimal crop selection across dry, average and wet years based on data from the Murrumbidgee Irrigation Area in Australia is presented. It is shown that sets of trade-off solutions that provide large net revenues, or minimise environmental flow deficits can be produced rapidly, easily and automatically. The system is capable of providing detailed information on optimal solutions to achieve desired outcomes, responding to a variety of factors including climate conditions and economics. PMID- 28881328 TI - Photocatalytic removal of Congo red dye using MCM-48/Ni2O3 composite synthesized based on silica gel extracted from rice husk ash; fabrication and application. AB - MCM-48 mesoporous silica was successfully synthesized from silica gel extracted from rice husk ash and loaded by nickel oxide (Ni2O3). The resulted composite was characterized using X-ray diffraction, scanning electron microscope, and UV-vis spectrophotometer. The role of MCM-48 as catalyst support in enhancing the photocatalytic properties of nickel oxide was evaluated through the photocatalytic degradation of Congo red dye under visible light source. MCM-48 as catalyst support for Ni2O3 shows considerable enhancement in the adsorption capacity by 17% and 29% higher than the adsorption capacity of MCM-48 and Ni2O3, respectively. Additionally, the photocatalytic degradation percentage increased by about 64% relative to the degradation percentage using Ni2O3 as a single component. The adsorption mechanism of MCM-48/Ni2O3 is chemisorption process of multilayer form. The using of MCM-48 as catalyst support for Ni2O3 enhanced the adsorption capacity and the photocatalytic degradation through increasing the surface area and prevents the nickel oxide particles from agglomeration. This was done through fixing nickel oxide particles throughout the porous structure which providing more exposed active adsorption sites and active photocatalyst sites for the incident photons. Based on the obtained results, supporting of nickel oxide particles onto MCM-48 are promising active centers for the degradation of Congo red dye molecules. PMID- 28881329 TI - A reusable adsorbent polyethylenimine/polyvinyl chloride crosslinked fiber for Pd(II) recovery from acidic solutions. AB - In this study, a mixture of polyethylenimine (PEI) and polyvinyl chloride (PVC) was reacted at 80 degrees C for 6 h to synthesize crosslinked PEI/PVC polymer solution, which was injected to produce the PEI/PVC-crosslinked fiber (PEI/PVC CF). PEI/PVC-CF was investigated as an adsorbent to remove and recover Pd(II) from acidic solutions. In order to examine the adsorption characteristics and usability of PEI/PVC-CF for Pd(II) recycling, several experiments such as isotherm, kinetics, desorption and reuse were conducted. The adsorption isotherms were fitted using the Langmuir and Freundlich models, respectively. The maximum adsorption capacity was estimated as 146.03 mg/g according to the Langmuir model. The kinetic experiments demonstrated that adsorbent reaches adsorption equilibrium within 60 min for initial Pd(II) concentrations of 25-100 mg/L. After adsorption, Pd(II) on PEI/PVC-CF was easily desorbed using acidified thiourea solution, and the desorption efficiency increased with the thiourea concentration. It was also demonstrated that PEI/PVC-CF can be used repeatedly for at least five cycles without reduction in adsorption capacity. PMID- 28881330 TI - From declared asset retirement obligations to a decommissioning cost estimate for onshore crude oil fields in Nigeria. AB - As in most mature crude oil producing regions, asset divestment has commenced in Nigeria. Decommissioning and associated environmental liabilities are expected to become important problems requiring attention. Public and government engagement on decommissioning will be ineffective without information on cost of decommissioning liabilities, which are held confidential by oil companies. This study demonstrates a method to determine generic aggregate cost of decommissioning liabilities for Nigeria onshore fields, using non-proprietary data from annual financial reports of operating companies in Nigeria. The results can be used as basis for negotiation with operators and to help government in preparation for decommissioning risk. PMID- 28881332 TI - Reverse shoulder arthroplasty for deltoid-deficient shoulder following latissimus dorsi flap transfer. Case report. AB - INTRODUCTION: The usual indication for reverse shoulder arthroplasty is glenohumeral arthritis with inadequate rotator cuff and intact deltoid muscle. We report here a case of reverse shoulder arthroplasty using a lattisimus dorsi flap in a patient with deltoid-deficient shoulder following a gunshot injury. PRESENTATION OF THE CASE: The patient was an otherwise healthy 51-year-old male with a history of gunshot injury of the left shoulder 2006. Upon presentation in 2011, the patient had a loss of most of his shoulder bony and muscular structures. Due to deltoid muscle deficiency, the patient underwent Lattisimus Dorsi muscle flap followed by reverse shoulder arthroplasty in order to establish an upper limb function. Upon discharge, 11days after the surgery, the patient was able to achieve 150 degrees flexion and 90 degrees abduction while in the supine position and 45 degrees in each direction, while sitting. He was able to perform internal rotation (behind back) up to the level of the L1 vertebra, assisted active abduction of 90 degrees , and external rotation of 20 degrees . Power tests showed power of grade 4/5 for both shoulder flexion and extension and grade 2+/5 for both abduction and adduction. At the last follow up one year after the operation, The patient still had passive pain-free full range of motion, but no progress in active range of motion beyond that upon discharge. CONCLUSION: Reverse shoulder arthroplasty after Latissmus dori flap in patient with deltoid deficient shoulders can be a successful and reproducible approach to treat such conditions. PMID- 28881331 TI - Breaking down barriers: the evolution of cell invasion. AB - Cell invasion is a specialized cell behavior that likely co-evolved with the emergence of basement membranes in metazoans as a mechanism to break down the barriers that separate tissues. A variety of conserved and lineage-specific biological processes that occur during development and homeostasis rely on cell invasive behavior. Recent innovations in genome editing and live-cell imaging have shed some light on the programs that mediate acquisition of an invasive phenotype; however, comparative approaches among species are necessary to understand how this cell behavior evolved. Here, we discuss the contexts of cell invasion, highlighting both established and emerging model systems, and underscore gaps in our understanding of the evolution of this key cellular behavior. PMID- 28881333 TI - Long-term survival of a patient with advanced gastric cancer with paraaortic lymph node metastasis who attained pathological complete response after S-1/CDDP chemotherapy: A case report. AB - INTRODUCTION: Gastric cancer with paraaortic lymph node (PAN) metastasis have unfavorable prognosis. There are no evidence-based preoperative chemotherapy regimens available. CASE PRESENTATION: A 62-year-old female was diagnosed with advanced gastric cancer and PAN metastasis. We attempted S-1/CDDP chemotherapy in six coursed and total gastrectomy as well as systematic dissection of regional lymph nodes and PAN. Histologically, no cancerous cells were detected in specimens. The patient has been disease-free for 5 years since the surgery. DISCUSSION: Long-term survival case of gastric cancer with PAN metastasis attaining pathologically complete response is extremely rare. It is possible that preoperative S1/CDDP with surgery might be a standard treatment strategy for gastric cancer with PANs. CONCLUSION: We report herein a rare case of gastric cancer with PAN metastases who achieved a 5-year survival after S-1/CDDP chemotherapy and surgery. PMID- 28881334 TI - Antegrade jejunojejunal intussusception inside a retrograde jejunogastric intussusception (double intussusception)-A rare case report. AB - INTRODUCTION: Jejunogastric intussusception through a gastrojejunal stoma along with a jejunojejunal intussusception (intussusception within an intussusception) is a rare but serious complication of previous gastric surgery such as gastrojejunostomy and Billroth II gastrectomy. The incidence of which is less than 0.1%. CASE PRESENTATION: An elderly male presented with an abdominal lump, diffuse abdominal pain and vomiting for one-day duration. Ultrasound and CECT abdomen revealed dilated stomach with jejunojejunal intussusception herniating into stomach. Emergency laparotomy was done with manual reduction of intussusception loops and roux- en-y anastomosis. DISCUSSION: The number of cases reported in literature involving a jejunogastric intussusception following gastric surgery was about 300.Furthermore, there have been only two reported cases of jejunogastric intussusception along with jejunojejunal intussusception. The rarity of this clinical event makes it imperative for a high index of suspicion in patients presenting with abdominal pain following gastric surgery. CONCLUSION: The mortality of this condition ranges from 10% to 50%. Hence prompt diagnosis and early surgical intervention prevents vascular compromise and bowel gangrene. PMID- 28881335 TI - The great mimicker at thoracolumbar spine: Non-Hodgkin's lymphoma. AB - PURPOSE: To report two cases with Non-Hodgkin's Lymphoma (NHL) in thoracolumbar spine with very different presentation. METHODS: Case 1; An 84-year-old female patient was admitted to our emergency clinic with paraparesis in both lower extremities. Magnetic resonance imaging (MRI) revealed an epidural mass at the level of the T12 vertebrae. She was operated immediately with wide laminectomy and posterior instrumentation because of the paraparesis of both lower extremities. Case 2; An 70-year-old female patient was admitted to our clinic with thoracolumbar back pain. There was a T12 vertebra compression fracture view in the X-ray imaging. MRI revealed multiple infiltrations in medullar canale at thoracolumbar spine with lytic lesion. She underwent eight cycles of chemotherapy. RESULTS: Multiple bone involvement was detected in both cases in PET-CT (Positron emission tomography-computed tomography) scans. Additionally it was found that there were nodal involvements accompanying these involvements in case 1. Because radiological examinations were not spesific enough to diagnose, it was necessary to perform a biopsy. The histopathological diagnosis of these patients revealed diffuse large B cell non-Hodgkin's lymphoma. CONCLUSIONS: Diagnosis of the non-Hodgkin's lymphomas that are localized in thoracolumbar spine is often missed or delayed due to lack of specific findings and presence similarities to other diseases. Diagnosis is made by histopathologic examination. Although the main treatment is chemotherapy for these patients, surgery is necessary for patients with neurological deficite. PMID- 28881336 TI - Perianal pseudolymphoma: A case report and review of the literature. AB - INTRODUCTION: Perianal pseudolymphoma is a rare lymphoproliferative disorder that can mimic cutaneous lymphoma. The condition can present acutely with concerns of perianal sepsis. The purpose of this case review is to review the current literature on perianal pseudolymphoma and emphasise to the surgical community its presentation, suggested aetiology and management. CASE PRESENTATION: In this case report, we detail the case of a 28-year-old female who presented with perianal pseudolymphoma. Malignant lymphoproliferative diseases required exclusion. Conservative management of this rare condition was successful. DISCUSSION: We highlight the differential diagnoses, investigations and treatment options for a rare condition. A review of the literature on the limited published data on perianal pseudolymphoma is briefly discussed. CONCLUSION: The aim of this case report is to highlight the existence of such a rare condition that can imitate an acute surgical presentation and its successful conservative management. PMID- 28881337 TI - Surgical management of a De Garengeot's hernia using a biologic mesh: A case report and review of literature. AB - INTRODUCTION: A De Garengeot hernia is a rare form of femoral hernia, where the appendix is found in the herniated sac. This feature is important to report, as both the diagnosis and the treatment are quite challenging in this particular condition. PRESENTATION OF CASE: We report the case of a 77-year-old female presenting with a femoral hernia, containing an incarcerated necrotic vermiform appendix (De Garengeot hernia). A laparoscopic appendectomy was performed and the herniated defect was repaired according to Rives technique, using a biological mesh. DISCUSSION: The De Garengeot hernia is often unexpected and diagnosed intra operatively. A pre-operative diagnosis is quite difficult, as it often presents clinically as a strangled femoral hernia. In patients without peritoneal signs, a contrast-enhanced Computed Tomography (CT) of the abdomen is useful for the diagnosis. Many surgical techniques have been discussed in literature, but there is no consensus. We show the feasibility and safety of the hernia repair according to Rives technique, through an inguinotomy with a biologic mesh. A laparoscopic approach was used to remove the necrotic appendix. CONCLUSION: The De Garengeot hernia is an uncommon differential diagnosis for patients presenting with clinical signs of strangled femoral hernia. Although hernia repairs with a synthetic mesh in the presence of appendicitis have been reported, we describe a case of femoral hernia repair using a biologic mesh, in a patient with a De Garengot hernia. PMID- 28881338 TI - Simple Age Specific Cutoff Value for Sarcopenia Evaluated by Computed Tomography. AB - OBJECTIVE: Until now, cutoff values of low skeletal muscle mass using computed tomography (CT) were driven by optimal stratification to predict mortality in cancer patients. The aim of the present study was to investigate the simple, age specific, cutoff value of low skeletal muscle mass by CT in healthy adults. DESIGN: This is a retrospective, observational, single-center study. SETTING: This study was performed in the health screening department of a university affiliated hospital during a 10-year period. PATIENTS: Medical records of 1,422 patients presenting to the health screening department were reviewed. Cross sectional area of psoas muscle at the level of the third lumbar vertebra on abdominal CT was measured and adjusted by height (mm2/m2). This value (psoas muscle index [PMI]) was assumed to represent whole skeletal muscle mass. We divided the patients according to age, sex, and defined cutoff value of low skeletal muscle mass as 2 SDs below the mean. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Among 1,422 patients, 550 patients (38.6%) were male. The mean PMI was 896.60 (mm2/m2) for men and 570.54 (mm2/m2) for women. Cutoff values of PMI for men were 592.3 mm2/m2 for 20-39 years, 474.0 mm2/m2 for 40-49 years, 422.2 mm2/m2 for 50-59 years, 374.4 mm2/m2 for 60-69 years, and 331.5 mm2/m2 for 70-89 years. The values for women were 399.9 mm2/m2 for 20-39 years, 287.7 mm2/m2 for 40-49 years, 242.5 mm2/m2 for 50-59 years, 220.4 mm2/m2 for 60-69 years, and 147.6 mm2/m2 for 70-89 years. CONCLUSIONS: Cutoff values of low skeletal muscle mass using CT differed in healthy adults as age increased. Further studies on the effect of sarcopenia intervention using this cutoff value are needed. PMID- 28881339 TI - Interstitial Immunostaining and Renal Outcomes in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis. AB - BACKGROUND: Immunopathologic features predict renal function at baseline and follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). The interstitial infiltrate consists predominantly of T lymphocytes, but their pathophysiologic significance is unclear, especially in light of the success of B-cell-directed therapy. METHODS: Renal biopsies from 33 patients treated with cyclophosphamide (CYC; n = 17) or rituximab (RTX; n = 16) in the RTX in ANCA-associated vasculitis (RAVE) trial were classified according to the new ANCA GN classification. T- and B-cell infiltration in the interstitium was assessed by immunostaining for CD3 and CD20. Correlations of clinical and histologic parameters with renal function at set time points were examined. RESULTS: The mean (SD) baseline estimated glomerular filtration rate was 36 (20) mL/min/1.73 m2. ANCA GN class distribution was 46% focal, 33% mixed, 12% sclerotic and 9% crescentic. The interstitial infiltrate consisted of >50% CD3 positive cells in 69% of biopsies, but >50% CD20 positive cells only in 8% of biopsies. In a multiple linear regression model, only baseline glomerular filtration rate (GFR) correlated with GFR at 6, 12, and 18 months. Interstitial B and T-cell infiltrates had no significant impact on long-term prognosis, independent of the treatment limb. A differential effect was noted only at 6 months, where a dense CD3 positive infiltrate predicted lower GFR in the RTX group and a CD20 positive infiltrate predicted higher GFR in the CYC group. CONCLUSIONS: In ANCA-associated GN, the interstitial infiltrate contains mainly T lymphocytes. However, it is neither reflecting baseline renal function nor predictive of response to treatment, regardless of the immunosuppression regimen employed. PMID- 28881340 TI - Additional Benefits of Routine Drugs on Gastrointestinal Cancer: Statins, Metformin, and Proton Pump Inhibitors. AB - BACKGROUND: Commonly used medications including statins, metformin, and proton pump inhibitors (PPIs) effectively reduce the risk of esophageal, gastric, and colorectal cancer (CRC). SUMMARY: A number of observational studies and meta analyses have shown that long-term statin use significantly reduces the incidence of gastrointestinal (GI) cancer. Moreover, statin use after GI cancer diagnosis has been significantly associated with better prognosis in large-scale cohort studies. Metformin was rigorously evaluated in a population-based study and meta analysis, and was found to have an unexpected benefit in the prevention and prolonged survival of CRC patients with type 2 diabetes mellitus. In contrast, few studies have demonstrated the chemopreventive effect of metformin for esophageal and gastric cancer. Recent observational studies have demonstrated that PPIs effectively reduce the progression of nondysplastic Barrett's esophagus into esophageal adenocarcinoma in a dose-dependent manner. However, the association between chronic PPI use and CRC or gastric cancer risk is still controversial. It was expected that these 3 routinely used medicines would show a synergistic effect with conventional systemic chemotherapy in advanced GI cancers. However, recent phase III studies failed to show significantly better outcomes. Key Messages: Further studies are needed to identify "additional" anticancer effects of these commonly used medicines. PMID- 28881341 TI - The Association of Combined Total Kidney and Liver Volume with Pain and Gastrointestinal Symptoms in Patients with Later Stage Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND: There is an ongoing debate if and how kidney and liver volume are associated with pain and gastrointestinal (GI) symptoms in autosomal dominant polycystic kidney disease (ADPKD) patients. Since both kidney and liver volume could interact, we investigated whether combined total kidney and liver volume had stronger associations with ADPKD-related pain and GI symptoms than the volumes of the organs separately. METHODS: We used baseline data from the DIPAK-1 study, which included ADPKD patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2. MR imaging was performed to measure height-adjusted total kidney volume (hTKV), height-adjusted total liver volume (hTLV) and the combination of both (height-adjusted total kidney liver volume [hTKLV]). RESULTS: Three hundred nine ADPKD patients were included with a mean age of 48 +/- 7 years, 53% female, eGFR 50 +/- 11 mL/min/1.73 m2 and median hTKV, hTLV and hTKLV of 1,095 (758-1,669), 1,173 (994-1,523) and 2,496 (1,972-3,352) mL/m, respectively. ADPKD-related pain and GI symptoms were present in, respectively, 27.5 and 61.2% of patients. Gender was no effect modifier in the association between kidney and/or liver volume, and symptom burden, indicating that all models could be tested in the overall study population. hTKLV and hTLV were significantly associated with pain and GI symptoms, whereas hTKV was not. Model testing revealed that the associations of pain and GI symptoms with hTKLV were significantly stronger than with hTKV (p = 0.04 and p = 0.04, respectively) but not when compared to hTLV (p = 0.2 and p = 0.5, respectively). CONCLUSIONS: This study indicates that combined kidney and liver volume was associated with the presence and severity of pain and GI symptoms in ADPKD, with a more prominent role for hTLV than for hTKV. PMID- 28881342 TI - Clinical Significance of Area of Psoas Major Muscle on Computed Tomography after Gastrectomy in Gastric Cancer Patients. AB - BACKGROUND: The measurement of a single abdominal image on computed tomography (CT) can provide an estimate of the total body skeletal muscle. We evaluate the change of the area of the psoas major muscle (PMMA) in a CT which was performed routinely after gastrectomy in gastric cancer. METHODS: A total of 119 gastric cancer patients who underwent gastrectomy were enrolled for the study. A CT image at the top of the iliac crest level was obtained at the following times: 3 postoperative months (POM), 6 POM, 1 postoperative year (POY), 2 POY, 3 POY, and 5 POY. We analyzed the change rate of PMMA after gastrectomy and before or after recurrence. RESULTS: PMMA change after gastrectomy was approximately between -8 and -10% over the 5-year observation period. PMMA in the R2 (macroscopic residual tumor)/recurrence group was lower than that in the no recurrence group, and a significant difference was observed at 2 POY (-21.7 +/- 3.6% vs. -7.9 +/- 2.3%, p < 0.01). PMMA after freshly diagnosed recurrence had decreased significantly by 14.1 +/- 1.8% (p < 0.01). CONCLUSIONS: Evaluation of PMMA change by CT after gastrectomy could assist in the diagnosis of the progression of cancer state in gastric cancer patients. PMID- 28881343 TI - The Edinburgh Feeding Evaluation in Dementia Scale: A Longitudinal Study in Nursing Home Residents. AB - AIMS/BACKGROUND: The Edinburgh Feeding Evaluation in Dementia (EdFED) scale has been shown to have good psychometric properties using a range of methods including Mokken scaling. We aimed to study the Italian version of the EdFED using Mokken scaling. METHODS: Data were gathered at 7 time points from 401 nursing home residents affected by dementia in the course of a 6-month intervention study using analysis of variance, Mokken scaling, and person-item fit statistics. RESULTS: The properties of the EdFED-I scale were stable over the course of the study with 4 items showing invariant item ordering at all time points. Some items behaved differently at different levels of difficulty in the scale and also depending on the mean level of feeding difficulty. The test information function showed a dip in the mid-range of difficulty scores. PMID- 28881344 TI - Long-Term Outcomes of Two Different Initial Dosing Regimens of Intravitreal Ranibizumab Used to Treat Myopic Choroidal Neovascularization. AB - PURPOSE: To compare two different initial dosing regimens of intravitreal ranibizumab used to treat myopic choroidal neovascularization. METHODS: A total of 61 eyes of 56 patients were treated: 26 eyes received a single injection followed by treatment pro re nata (1+ PRN), while 35 eyes first received 3 consecutive monthly injections (3+ PRN). RESULTS: The mean follow-up was 53 +/- 16 months. The visual acuities were 51.9 +/- 16.2 letters with 3+ PRN and 53 +/- 22.4 letters with 1+ PRN at baseline (p = 0.824); 69.5 +/- 12.3 and 69 +/- 15.1 letters, respectively, at 12 months; and 67.1 +/- 16.2 and 66.4 +/- 19.7 letters, respectively, at the end of follow-up (p = 0.877). Mean survival until first retreatment after the loading dose was 36.9 +/- 6.1 months with 3+ PRN and 19.2 +/- 5.4 months with 1+ PRN (p < 0.001). CONCLUSIONS: Both dosing regimens led to similar visual outcomes. For eyes given a single injection in the first quarter, retreatment was needed appreciably earlier. PMID- 28881345 TI - Difference in Mortality Risk in Elderly People with Bronchial Obstruction Diagnosed Using a Fixed Cutoff or the Lower Limit of Normal of the FEV1/FVC Ratio. AB - BACKGROUND: Whether a fixed cutoff or the lower limit of normal of the FEV1/FVC ratio should be used to diagnose bronchial obstruction is still a matter of debate. This issue is particularly important for elderly people. OBJECTIVES: We used equations applicable up to 90 years of age to evaluate the mortality of elderly people diagnosed with bronchial obstruction using either a fixed cutoff of 0.7 or the lower limit of normal (LLN). METHODS: Participants in the SaRA (Salute Respiratoria nell'Anziano, Italian for "Respiratory Health in the Elderly") study were grouped as follows: FEV1/FVC >=0.7 and >= LLN (n = 535: F-/L ), FEV1/FVC <0.7 but >= LLN (n = 118: F+/L-), and FEV1/FVC <0.7 and < LLN (n = 229: F+/L+). We estimated the mortality risk in the three groups over 15 years of follow-up. RESULTS: The mean age was 73 years (58% men). The hazard ratio (HR) for mortality was 1.427 (95% CI: 1.09-1.868) in the F+/L- group and 2.143 (95% CI: 1.13-1.995) in the F+/L+ group. After adjustment for potential confounders, we found no increased mortality in the F+/L- group (HR: 1.007, 95% CI: 0.755 1.342), while the HR in the F+/L+ group was still sizeable (1.474, 95% CI: 1.136 1.911). CONCLUSIONS: As expected, using a fixed cutoff translates in a larger number of people to be classified as having bronchial obstruction. In our sample the increased mortality in the F+/L- group is due to the confounding effect of age and sex. Our study lends support to the use of LLN in elderly people. PMID- 28881346 TI - Hyponatremia and Bone Fractures: An Intriguing and Often Overlooked Association. PMID- 28881347 TI - Benefits of Curcumin Supplementation on Antioxidant Status in beta-Thalassemia Major Patients: A Double-Blind Randomized Controlled Clinical Trial. AB - BACKGROUND: beta-Thalassemia major, the most common inherited anemia in the world, is associated with imbalance in the oxidant-antioxidant system. The objective of this study was to evaluate the efficacy of curcumin supplementation on markers of oxidative stress in patients with beta-Thalassemia. METHODS: This double-blind randomized controlled clinical trial was performed on 61 beta thalassemia major patients. Subjects in the curcumin group received two 500 mg curcumin capsules daily and patients in the placebo group took 2 placebo capsules daily for 12 weeks. Dietary intakes and biochemical parameters were assessed at the beginning and the end of intervention. RESULTS: At the end of the study, serum malondialdehyde (MDA), total and direct bilirubin significantly decreased (p = 0.002, p < 0.001, and p < 0.001, respectively) and total antioxidant capacity significantly increased (p = 0.005) in the curcumin group. Based on the analysis of covariance, a significant reduction in MDA, total and direct bilirubin was also detected in the curcumin group when compared to the placebo group (p = 0.001, p = 0.039, and p = 0.013, respectively). Changes in hemoglobin, serum iron, ferritin, catalase, and vitamin E were not significant in any of the 2 groups. CONCLUSIONS: Curcumin supplementation in combination with deferoxamin improved the antioxidant status in beta-thalassemia major patients. Curcumin may be useful for the relief of metabolic complications in these patients. PMID- 28881348 TI - Accelerating Topical Anaesthesia Using Microneedles. AB - BACKGROUND/AIMS: Topical anaesthetics reduce pain during venous access procedures in children. However, clinical use is hindered by a significant anaesthetic onset time. Restricted diffusion of the topical anaesthetic through the stratum corneum barrier is the principal reason for the delayed onset. Microneedles can painlessly pierce the skin. This study evaluated microneedle pre-treatment of ex vivo human skin as a means to increase the rate of tetracaine permeation, in order to accelerate the onset of anaesthesia. METHODS: Franz-type diffusion cells were used to determine permeation of a commercial tetracaine formulation, Ametop gel, through human skin epidermis. Microneedle-assisted permeation was compared to untreated epidermis. Upon completion of the permeation studies, the epidermal membranes were visually characterised. RESULTS: At 30 min, 5.43 ug/cm2 of tetracaine had permeated through the untreated membrane compared to 12.13 ug/cm2 through the microneedle-treated membrane. Insertion of a hypodermic needle created a large single channel in the epidermis (approx. 4,250 MUm2) whilst the punctured surface area following microneedle treatments was estimated to be 75,000 MUm2. CONCLUSION: Pre-treatment of skin with microneedles significantly enhances the permeation of tetracaine. Microneedles have the potential to more than halve the onset time for anaesthesia when applying Ametop gel. PMID- 28881349 TI - Reduced Serum Phosphorus Levels Were Associated with Metabolic Syndrome in Men But Not in Women: A Cross-Sectional Study among the Japanese Population. AB - BACKGROUND: Reduced serum phosphorus (SP) levels are reported to be associated with insulin resistance and metabolic syndrome (MetS). However, there have been a few gender-specific studies although SP levels are substantially different between men and women. METHODS: This is a cross-sectional study. A total of 16,041 subjects (9,076 men and 6,965 women) were analyzed. The subjects were divided into 3 groups of gender-specific tertiles based on phosphorus levels: the lowest (T1), middle (T2), and the highest (T3). RESULTS: SP levels were significantly lower in subjects with MetS than in those without MetS in men but not in women. Waist circumference and fasting plasma glucose were negatively and high-density lipoprotein cholesterol was positively correlated with SP levels both in men and women. Blood pressure (BP) and triglycerides (TG) were negatively correlated with SP levels in men, while they were positively correlated with SP levels in women. Lower SP levels were associated with the prevalence of MetS in men (T1; 19.9%, T2; 16.9%, and T3; 14.3%; p < 0.001) but not in women (T1; 14.1%, T2; 16.6%, and T3; 15.3%; p = 0.282). CONCLUSION: BP and TG were unexpectedly positively correlated with SP levels in women. Reduced SP levels were associated with MetS in men but not in women. PMID- 28881350 TI - Comparing Modified with Conventional Parotidectomy for Benign Parotid Tumors. AB - PURPOSE: We conducted a study to compare the functional outcomes and surgical complications of patients with benign parotid tumors treated with conventional parotidectomy and modified parotidectomy. METHODS: This study retrospectively analyzed 99 patients who had benign parotid lesions and underwent parotidectomy using either conventional or modified parotidectomy. The operation time, cosmetic outcome, great auricular nerve anesthesia, incidence of Frey syndrome, and secretory function with the two techniques were compared. RESULTS: The mean operation time was shorter and the total complication rate was obviously lower in the modified surgery group (p < 0.001). In the modified surgery group, the incision was more cosmetic (p < 0.001), the sensory deficit rate was low (p < 0.001), and the sensory recovery rate was high, and transient facial paralysis and Frey syndrome were rare. Furthermore, glandular function was preserved in patients with a conserved Stensen duct. There was no tumor recurrence in the two groups during a mean follow-up of 29.8 months. CONCLUSION: Modified surgical techniques for benign parotid neoplasms significantly reduced the surgery time and improved the surgery outcomes compared with the conventional approach. This adds to the evidence to support the effectiveness of modified parotidectomy in selected patients with benign parotid tumors. PMID- 28881351 TI - Mild Cognitive Impairment and Progression to Dementia in Progressive Supranuclear Palsy. AB - BACKGROUND: Cognitive deficits are common in progressive supranuclear palsy (PSP), but their relevance and the progression to dementia are still poorly described. The recently revised criteria for PSP consider cognitive dysfunction in the diagnostic work-up. METHODS: The study retrospectively evaluated a series of 99 PSP patients with Richardson syndrome (PSP-RS), subgrouped according to cognitive and behavioural performances into PSP with normal cognition (PSP-NC), PSP with mild cognitive impairment (PSP-MCI), and PSP with dementia (PSP-D). The progression to dementia at the 3-year follow-up was assessed. RESULTS: At baseline, 15.2% of patients were classified as PSP-NC, 43.4% as PSP-MCI, and 41.4% as PSP-D. During the 3-year follow-up, 21 out of 29 patients, previously classified as PSP-NC or PSP-MCI, converted to dementia, with an incidence rate of 241 per 1,000 patients/year. Nineteen out of 21 PSP patients (90%) developed the behavioural variant frontotemporal dementia phenotype. The only factor associated with conversion to dementia was MCI diagnosis at baseline (p = 0.023). CONCLUSION: Cognitive decline occurs in a great proportion of PSP-RS patients early during the disease course. In the absence of a specific phenotype, the diagnosis of MCI might identify PSP patients at greatest risk of developing dementia and should be considered further in the diagnostic assessment. PMID- 28881353 TI - Variance Formulae for Correlation Measures of Linkage Disequilibrium. AB - BACKGROUND: Linkage disequilibrium (LD) is the non-random association between alleles at different loci and remains important for disease mapping studies in humans. A common measure of LD is the sample correlation between indicator variables for alleles at the 2 loci. Knowledge of LD estimate precision may help inform biomedical decisions based on those estimates. OBJECTIVES AND METHODS: Variance formulae are obtained for correlation measures of LD in 4 scenarios. These scenarios include data in the form of gametic and genotypic counts, with different assumptions used to simplify the analysis. RESULTS: The formulae are expressed as polynomials (or ratios of polynomials) in higher-order disequilibrium coefficients with constants which are functions of the allele frequencies and Hardy-Weinberg disequilibrium coefficients. With genotypic data, the variance is the same as with gametic data when the phase is known and there is random mating. When the phase is unknown, the correlation LD has variance which is twice as large. CONCLUSIONS: Symbolic computation proved to be effective in facilitating algebraic derivations which would otherwise have been intractable. PMID- 28881352 TI - Current Practice of Airway Stenting in the Adult Population in Europe: A Survey of the European Association of Bronchology and Interventional Pulmonology (EABIP). AB - BACKGROUND: Airway stenting (AS) commenced in Europe circa 1987 with the first placement of a dedicated silicone airway stent. Subsequently, over the last 3 decades, AS was spread throughout Europe, using different insertion techniques and different types of stents. OBJECTIVES: This study is an international survey conducted by the European Association of Bronchology and Interventional Pulmonology (EABIP) focusing on AS practice within 26 European countries. METHODS: A questionnaire was sent to all EABIP National Delegates in February 2015. National delegates were responsible for obtaining precise and objective data regarding the current AS practice in their country. The deadline for data collection was February 2016. RESULTS: France, Germany, and the UK are the 3 leading countries in terms of number of centres performing AS. These 3 nations represent the highest ranked nations within Europe in terms of gross national income. Overall, pulmonologists perform AS exclusively in 5 countries and predominately in 12. AS is performed almost exclusively in public hospitals. AS performed under general anaesthesia is the rule for the majority of institutions, and local anaesthesia is an alternative in 9 countries. Rigid bronchoscopy techniques are predominant in 20 countries. Amongst commercially available stents, both Dumon and Ultraflex are by far the most commonly deployed. Finally, 11 countries reported that AS is an economically viable activity, while 10 claimed that it is not. CONCLUSION: This EABIP survey demonstrates that there is significant heterogeneity in AS practice within Europe. Therapeutic bronchoscopy training and economic issues/reimbursement for procedures are likely to be the primary reasons explaining these findings. PMID- 28881354 TI - Preoperative Capecitabine, Oxaliplatin, and Irinotecan in Resectable Gastric or Gastroesophageal Junction Cancer: Pathological Response as Primary Endpoint and FDG-PET Predictions. AB - OBJECTIVES: This phase II trial was aimed at assessing the safety and activity of capecitabine, oxaliplatin, and irinotecan (COI regimen) as a preoperative treatment for resectable gastric cancer (GC) or gastroesophageal junction (GEJ) cancer. METHODS: Patients affected by T3-T4/N0-N+/M0 GC/GEJ cancer were treated with the COI regimen for 4 cycles followed by restaging and gastroresection with D2 lymphadenectomy. Four postoperative cycles were scheduled. The primary endpoint was pathological response rate according to Becker et al. [Cancer 2003;98:1521-1530]. The potential role of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) as a predictive biomarker of pathological tumor response was assessed in a subgroup of 19 evaluable patients. RESULTS: Between January 2011 and October 2015, a total of 40 patients were enrolled. After the preoperative phase, 36 out of 40 patients (90%) were considered eligible for surgery: 12 patients (30%) achieved a pathological response. The most frequent grade 3/4 adverse events were diarrhea (27%), nausea (25%), and fatigue (17%). Grade 3 neutropenia occurred in 7.5% of patients. A lower standard uptake value at baseline FDG-PET/CT was associated with pathological response. CONCLUSION: COI combination is active with a manageable toxicity profile in patients with resectable GC or GEJ cancer. FDG-PET/CT imaging as a surrogate biomarker of pathological response in this setting appears fascinating but should be further investigated. PMID- 28881355 TI - Presurgical weight loss affects tumour traits and circulating biomarkers in men with prostate cancer. AB - BACKGROUND: Obesity is associated with aggressive prostate cancer. To explore whether weight loss favourably affects tumour biology and other outcomes, we undertook a presurgical trial among overweight and obese men with prostate cancer. METHODS: This single-blinded, two-arm randomised controlled trial explored outcomes of a presurgical weight loss intervention (WLI) that promoted ~1 kg per week loss via caloric restriction and increased physical activity (PA). Forty overweight/obese men with clinically confirmed prostate cancer were randomised to the WLI presurgery or to a control arm; changes in weight, body composition, quality-of-life, circulating biomarkers, gene expression, and immunohistochemical markers in tumour and benign prostatic tissue were evaluated. RESULTS: The study period averaged 50 days. Mean (s.d.) change scores for the WLI vs control arms were as follows: weight: -4.7 (3.1) kg vs -2.2 (4.4) kg (P=0.0508); caloric intake: -500 (636) vs -159 (600) kcal per day (P=0.0034); PA: +0.9 (3.1) vs +1.7 (4.6) MET-hours per day (NS); vitality: +5.3 (7.l4) vs -1.8 (8.1) (P=0.0491); testosterone: +55.1 (86.0) vs -48.3 (203.7) ng dl-1 (P=0.0418); sex hormone-binding globulin: +14.0 (14.6) vs +1.8 (7.6) nmol l-1 (P=0.0023); and leptin: -2.16 (2.6) vs -0.03 (3.75) (P=0.0355). Follow-up Ki67 was significantly higher in WLI vs control arms; median (interquartile range): 5.0 (2.5,10.0) vs 0.0 (0.0,2.5) (P=0.0061) and several genes were upregulated, for example, CTSL, GSK3B, MED12, and LAMC2. CONCLUSIONS: Intentional weight loss shows mixed effects on circulating biomarkers, tumour gene expression, and proliferative markers. More study is needed before recommending weight loss, in particular rapid weight loss, among men with prostate cancer. PMID- 28881356 TI - Aldehyde dehydrogenase 1B1: a novel immunohistological marker for colorectal cancer. AB - BACKGROUND: Aldehyde dehydrogenase (ALDH) 1A1 is an immunohistological biomarker of various solid tumours, but has not been successfully proved as a colorectal cancer (CRC) marker. We recently reported that ALDH1B1, which has functional roles in tumourigenesis, may be a better CRC marker than ALDH1A1. METHODS: Human CRC explants and cell lines were analysed to identify candidate CRC markers from eight ALDH isozymes including ALDH1A1 and ALDH1B1. A tissue microarray, including paired specimens of normal and tumour tissues, was subsequently analysed to determine if candidate ALDHs could distinguish CRC from normal tissue. RESULTS: Based on mRNA analysis, ALDH1B1 and ALDH2 were selected as suitable candidates. These were strongly and regularly expressed in tumour tissue and cell lines, including highly tumourigenic cell populations (ALDH+CD44+ cells), while other ALDHs, including ALDH1A1, showed differential or low expression. No genetic alteration of ALDH1B1 in CRC was suggested by the relationships between mRNA and protein levels/enzymatic activities, and cDNA sequences of CRC cell lines. Tissue microarray findings showed that ALDH1B1, but not ALDH2, could distinguish CRC from normal tissue. Furthermore, ratios of ALDH1B1 to ALDH1A1 or ALDH2 were found to be powerful CRC indicators. CONCLUSIONS: These results suggest that ALDH1B1 is a novel human CRC biomarker. PMID- 28881359 TI - HPV-positive women with normal cytology remain at increased risk of CIN3 after a negative repeat HPV test. AB - BACKGROUND: In human papillomavirus (HPV)-based screening, a repeat HPV test is often recommended for HPV-positive women with normal cytology (HPV-pos/cyt-neg), but its absolute risk of cervical precancer (CIN3+) over two screening rounds needs to be assessed. METHODS: We compared the 5-year risk of HPV infection and CIN3+ in HPV-pos/cyt-neg women with a negative repeat HPV test to the risk in HPV negative women with normal cytology (double negatives) in the POBASCAM cohort. We obtained histology data from the Dutch pathology registry (PALGA). RESULTS: Human papillomavirus infection risk was 20.4% (19 of 93) in HPV-pos/cyt-neg, repeat HPV negative women and 3.2% (294 of 9186; P<0.001) in double negatives. Corresponding CIN3+ risks were 2.0% (4 of 199) and 0.2% (41 of 18 562; P<0.001). Infection risks were also increased in type-specific analyses of HPV16, 31, 33, 39, 52, 56 and 58. CONCLUSIONS: HPV-pos/cyt-neg women continue to have an increased CIN3+ risk, also when the repeat HPV test is negative. Therefore, intervals in primary HPV screening should be determined separately for HPV-positive and -negative women. PMID- 28881357 TI - A novel inhibitory anti-invasive MAb isolated using phenotypic screening highlights AnxA6 as a functionally relevant target protein in pancreatic cancer. AB - BACKGROUND: Discovery and validation of new antibody tractable targets is critical for the development of new antibody therapeutics to address unmet needs in oncology. METHODS: A highly invasive clonal variant of the MDA-MB-435S cell line was used to generate monoclonal antibodies (MAbs), which were screened for anti-invasive activity against aggressive cancer cells in vitro. The molecular target of selected inhibitory MAb 9E1 was identified using immunoprecipitation/liquid chromatography-tandem mass spectrometry. The potential anti-tumour effects of MAb 9E1 were investigated in vitro together with immunohistochemical analysis of the 9E1 target antigen in normal and cancer tissues. RESULTS: MAb 9E1 significantly decreases invasion in pancreatic, lung squamous and breast cancer cells and silencing of its target antigen, which was revealed as AnxA6, leads to markedly reduced invasive capacity of pancreatic and lung squamous cancer in vitro. IHC using MAb 9E1 revealed that AnxA6 exhibits a high prevalence of membrane immunoreactivity across aggressive tumour types with restricted expression observed in the majority of normal tissues. In pancreatic ductal adenocarcinoma, high AnxA6 IHC score correlated with the presence of tumour budding at the invasive front of tumours (P=0.082), the presence of perineural invasion (P= <0.0001) and showed a weak correlation with reduced survival (P=0.2242). CONCLUSIONS: This study highlights the use of phenotypic hybridoma screening as an effective strategy to select a novel function-blocking MAb, 9E1 with anti-cancer activity in vitro. Moreover, through characterisation of the 9E1 target antigen, AnxA6, our findings support further investigation of AnxA6 as a potential candidate target for antibody-mediated inhibition of pancreatic cancer. PMID- 28881360 TI - [Is the theoretical support for the improvement of brain plasiticity in schizophrenic psychoses adequate?] PMID- 28881361 TI - [Practicals in a psychiatric clinic for occupational orientation in pupils]. AB - This pilot study investigates the implementation of a practical program for pupils including psychoeducation aimed to educate them about professions in psychiatry. 29 persons aged between 16-21 years were included in the program for vocational orientation at the Department of Psychiatry and Psychotherapy, University of Munich, from 2013-2016. The 1-2-week program provides information about job descriptions of psychologists and physicians. On average the pupils performed at M=2.75, SD=0.64 and they were motivated. At the end of their practical course, they reported that their fear of contact with inpatients decreased. Their knowledge in psychiatry and psychotherapy increased. 59 % of the participants reported that they plan to study medicine or psychology. All young adolescents reported that they satisfied with the program. Enhancing contact with patients and their caretakers may serve to decrease anxiety and prejudices as well as to increase interest and knowledge in this area. PMID- 28881358 TI - Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands. AB - BACKGROUND: Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood. METHODS: The expression of HH ligands was studied by qPCR, western blot and immunohistochemistry. Functional and animal model studies were carried out with cells transduced with shRNAs against HH ligands or treated with HH-specific inhibitors (Vismodegib and MEDI-5304). Finally, the molecular characterisation of an off-target effect of Vismodegib was also made. RESULTS: The results showed a prominent expression of HH ligands supporting an autocrine ligand-dependent activation of the pathway. A comparison of pharmacologic Smoothened inhibition (Vismodegib) and HH ligand blocking (MEDI-5304) is also provided. Interestingly, a first description of pernicious off-target effect of Vismodegib is also reported. CONCLUSIONS: The clarification of the HH pathway activation mechanism in RMS opens a door for targeted therapies against HH ligands as a possible alternative in the future development of better treatment protocols. Moreover, the description of a pernicious off-target effect of Vismodegib, via unfolded protein response activation, may mechanistically explain its previously reported inefficiency in several ligand-dependent cancers. PMID- 28881362 TI - [Sensory Inventory (SI): self-assessment of sensory sensitivity for adults and adolescents]. AB - An adequate perception of the environment is one of the main foundations of adaptive behavior. Furthermore, sensory sensitivity varies from person to person and can play a central role in the development and course of mental disorders. The objective was the development of a questionnaire for the multidimensional assessment of sensory sensitivity. A total of 1417 persons were evaluated with the Sensory Inventory (SI). The factorial validity was tested with exploratory factor analyses and exploratory structural equation modeling. A 6-factorial structure was established. High internal consistency and retest reliability were shown, as well as increased sensory sensitivity and lower body perception in participants with mental disorders. The SI is a short instrument with good test characteristics that can easily be integrated in a clinical or research environment. PMID- 28881363 TI - [Motivational interviewing with alcohol-dependent patients]. AB - Motivational interviewing with alcohol-dependent patients Alcohol-dependent patients do not need to be motivated from the outside. They are mostly ambivalent, and the inner voice, which already speaks for change (change talk), is heard through motivational interviewing, carefully strengthened and developed together with the patient. The practitioner has to deal with the human spirit of motivational interviewing and should be able to communicate with empathy, respect, congruence, and openness. The patient's autonomy should always be maintained. Advice is only given upon request. The conversation style is directive-guiding instead of authoritariansteering. OARS and the EPE principle are the motivational interviewing basics, which are consistently applied over 4 processes of motivational interviewing: engaging, focusing, evocing, and planning. The likelihood of change talk increases as soon as discrepancies between life goals and alcohol consumption emerge. An increased rate of change talk makes a change in behavior more likely. If a patient argues against change (sustain talk), one should not confront, but should consistently work with reflections, reframing, and an emphasis on autonomy. Motivational interviewing can be applied in different settings and populations, should be learned by the entire team (best professional guidance) in teamwork, and be subjected to a critical and constant evaluation. PMID- 28881364 TI - [Editor's Comment]. PMID- 28881365 TI - ? PMID- 28881366 TI - ? PMID- 28881367 TI - ? PMID- 28881368 TI - [Overcoming the papilla for sialendoscopy]. PMID- 28881370 TI - ? PMID- 28881369 TI - [Molecular Pathogenesis of Thyroid Nodules: Relevance for Clinical Care]. AB - Thyroid nodules represent heterogeneous tumors with distinct molecular signatures. While benign thyroid nodules correspond to poly- or monoclonal tumors, thyroid carcinomas are monoclonal and thus "real" neoplasms. These are caused by somatic mutations that lead to the constitutive activation of specific signaling cascades and determine the corresponding histology and also partly the functional phenotype of the thyroid tumor. Dedifferentiation of thyroid carcinomas is accompanied by the occurrence of additional mutations in the tumors. The mutation load of thyroid carcinomas correlates with their biological behavior. In clinical practice, detection of somatic mutations can help in the cytological differential diagnosis. In the prognostic assessment of thyroid tumors, proof of classical oncogene mutations (BRAF, RAS) has little relevance. Other genetic alterations, especially TERT promoter mutations that occur with increasing frequency in advanced thyroid carcinomas, probably have a prognostic significance. The molecular signature, however, is of great relevance for the development and application of targeted therapies in advanced carcinomas (radioactive iodine-refractory DTC, PDTC and ATC, metastatic medullary carcinoma). For this, there is increasing evidence from clinical studies and case reports that underline the concept of "oncogene addiction" as a pathogenetically relevant mechanism of thyroid tumorigenesis and carcinogenesis. PMID- 28881371 TI - ? PMID- 28881372 TI - [From the Expert's Office: Adaptation of the 3-Frequency-Table of Roser (1980) to the importance of hearing in the contemporary working environment]. PMID- 28881373 TI - [Not Available]. PMID- 28881374 TI - ? PMID- 28881375 TI - ? PMID- 28881376 TI - The 2014-2015 National Impact of the 2014 American Academy of Pediatrics Guidance for Respiratory Syncytial Virus Immunoprophylaxis on Preterm Infants Born in the United States. AB - OBJECTIVE: This article aims to compare respiratory syncytial virus (RSV) immunoprophylaxis (IP) use and RSV hospitalization rates (RSVH) in preterm and full-term infants without chronic lung disease of prematurity or congenital heart disease before and after the recommendation against RSV IP use in preterm infants born at 29 to 34 weeks' gestational age (wGA). STUDY DESIGN: Infants in commercial and Medicaid claims databases were followed from birth through first year to assess RSV IP and RSVH, as a function of infant's age and wGA. RSV IP was based on pharmacy or outpatient medical claims for palivizumab. RSVH was based on inpatient medical claims with a diagnosis of RSV. RESULTS: Commercial and Medicaid infants 29 to 34 wGA represented 2.9 to 3.5% of all births. RSV IP use in infants 29 to 34 wGA decreased 62 to 95% (p < 0.01) in the 2014-2015 season relative to the 2013-2014 season. Compared with the 2013-2014 season, RSVH increased by 2.7-fold (p = 0.02) and 1.4-fold (p = 0.03) for infants aged <3 months and 29 to 34 wGA in the 2014-2015 season with commercial and Medicaid insurance, respectively. In the 2014-2015 season, RSVH for infants 29 to 34 wGA were two to seven times higher than full-term infants without high-risk conditions. CONCLUSION: Following the 2014 RSV IP guidance change, RSV IP use declined and RSVH increased among infants born at 29 to 34 wGA and aged <3 months. PMID- 28881377 TI - Comparison of unilateral versus bilateral intensity-modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil. AB - BACKGROUND: The authors hypothesized that unilateral intensity-modulated radiotherapy (IMRT) would decrease toxicity compared with bilateral IMRT for patients with lateralized palatine tonsillar cancer and a neck classification of N0 to N2b, with similar oncological outcomes. METHODS: A total of 154 patients were treated with postoperative IMRT from 1997 through 2013. Data were collected prospectively from 2005 to 2013 and retrospectively collected before 2005. Of those patients with lateralized primary and N0 to N2b disease, 48 received unilateral IMRT (group 1) and 59 received bilateral IMRT (group 2); a total of 47 patients had nonlateralized primary or N2c to N3 disease and received bilateral IMRT (group 3). RESULTS: The median follow-up was 5.5 years. The 5-year locoregional control rates were similar in group 1, group 2, and group 3 (100%, 96%, and 94%, respectively; pooled comparison: P = .39 and group 1 vs group 2 comparison: P = .19). The 5-year overall survival rates were similar in group 1, group 2, and group 3 (85%, 79%, and 76%, respectively; pooled comparison: P = .60 and group 1 vs group 2 comparison: P = .25). There were no contralateral neck recurrences noted among unilaterally treated patients. Unilateral IMRT reduced acute toxicity and improved patient-reported quality of life compared with bilateral IMRT. CONCLUSIONS: Unilateral IMRT appears to reduce acute toxicity and achieves oncological outcomes similar to those of bilateral IMRT in selected patients with lateralized palatine tonsillar cancer with a neck classification of N0 to N2b. Cancer 2017;123:4594-4607. (c) 2017 American Cancer Society. PMID- 28881378 TI - Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects. AB - Istradefylline, a selective adenosine A2A inhibitor, is under development for the treatment of Parkinson's disease. The effect of oral steady-state rifampin 600 mg/day, a potent cytochrome P450 (CYP) 3A4 inducer, on the disposition of a single oral dose of istradefylline 40 mg was determined in a crossover study in 20 healthy subjects by measuring plasma concentrations of istradefylline and its M1 and M8 metabolites and their derived pharmacokinetic parameters. Based on the geometric mean ratio of log-transformed data, rifampin reduced istradefylline exposure: Cmax , 0.55 (90%CI, 0.49-0.62); AUClast , 0.21 (90%CI, 0.19-0.22); and AUCinf , 0.19 (90%CI, 0.18-0.20), indicating nonequivalence. These changes were primarily because of the effect of rifampin on the elimination parameters of istradefylline; mean CL/F was increased from 4.0 to 20.6 L/h, and mean t1/2 was reduced from 94.8 to 31.5 hours. The effect of rifampin coadministration on the disposition of the istradefylline M1 and M8 metabolites was inconsistent and variable. Furthermore, as exposure of the istradefylline M1 and M8 metabolites in plasma was generally <9% of total drug exposure, it would be expected to have a negligible impact on the pharmacodynamic effect of istradefylline. Caution should be exercised when istradefylline is administered concurrently with strong CYP3A4 inducers and dose adjustment considered. PMID- 28881379 TI - Trends in major upper abdominal surgery for cancer in octogenarians: Has there been a change in patient selection? AB - BACKGROUND: Although there is a general perception that, as the older population grows in number, more are undergoing surgery, there are few data on trends in major resections for cancer and short-term outcomes in this group. METHODS: The Nationwide Inpatient Sample was (NIS) used to estimate the national trends of major upper abdominal resections (esophagus, stomach, liver, pancreas) for cancer in octogenarians (aged >=80 years) from 2001 to 2011. Resection rates performed per year were incidence-adjusted within this age group for each cancer type as determined by the NIS database. Joinpoint regression was used to calculate average annual percentage changes (AAPC) when evaluating trends over time. RESULTS: During the study period, octogenarians underwent an estimated 30,356 upper abdominal organ resections for cancer in the United States, representing 3.8% of all cancer admissions among octogenarians. Resection rates in octogenarians increased significantly over time (AAPC, 2.54; P < .001) secondary to increasing trends in pancreatic (AAPC, 11.52; P < .001) and hepatic (AAPC, 6.67; P < .001) resections. Elixhauser comorbidity index scores increased from a mean of 3.61 to 4.20 (AAPC, 1.31; P < .001), whereas inpatient mortality during this time decreased from 13.6% to 8.2% (AAPC, 5.58; P < .001). CONCLUSIONS: Overall rates of major upper abdominal cancer resections in octogenarians are increasing over time, driven by increases in liver and pancreatic resections. These increases were observed despite a less favorable patient morbidity profile over time. These patterns may suggest shifting selection criteria for octogenarians undergoing major abdominal surgery over time in the context of diminishing postoperative mortality. Cancer 2018;124:125-35. (c) 2017 American Cancer Society. PMID- 28881380 TI - Missed therapeutic and prevention opportunities in women with BRCA-mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling and BRCA testing: A review of the literature. AB - Answer questions and earn CME/CNE Fifteen percent of women with epithelial ovarian cancer have inherited mutations in the BRCA breast cancer susceptibility genes. Knowledge of her BRCA status has value both for the woman and for her family. A therapeutic benefit exists for the woman with cancer, because a new family of oral drugs, the poly ADP-ribose polymerase (PARP) inhibitors, has recently been approved, and these drugs have the greatest efficacy in women who carry the mutation. For her family, there is the potential to prevent ovarian cancer in those carrying the mutation by using risk-reducing surgery. Such surgery significantly reduces the chance of developing this, for the most part, incurable cancer. Despite these potential benefits, referral rates for genetic counseling and subsequent BRCA testing are low, ranging from 10% to 30%, indicating that these therapeutic and prevention opportunities are being missed. The authors have reviewed the relevant available literature. Topics discussed are BRCA and its relation to ovarian cancer, the rates of referral for genetic counseling/BRCA testing, reasons for these low rates, potential strategies to improve on those rates, lack of effectiveness of current screening strategies, the pros and cons of risk-reducing surgery, other prevention options, and the role and value of PARP inhibitors. CA Cancer J Clin 2017;67:493-506. (c) 2017 American Cancer Society. PMID- 28881382 TI - Cancer risk among Holocaust survivors in Israel. PMID- 28881381 TI - Muscle mass at the time of diagnosis of nonmetastatic colon cancer and early discontinuation of chemotherapy, delays, and dose reductions on adjuvant FOLFOX: The C-SCANS study. AB - BACKGROUND: For many chemotherapy regimens dosed based on body surface area (BSA), patients experience dose reductions or delays or discontinue treatment, thereby reducing survival. Consideration of body composition may be useful in individualizing chemotherapy dosing, but to the authors' knowledge few studies to date have examined the association of body composition with chemotherapy tolerance in patients with colon cancer. METHODS: The authors identified patients with nonmetastatic colon cancer who were diagnosed from 2006 through 2011 at Kaiser Permanente and who received leucovorin calcium/calcium folinate, 5 fluorouracil, and oxaliplatin (FOLFOX) as initial adjuvant chemotherapy (533 patients). Patients' muscle mass was quantified using clinically acquired computed tomography scans. The authors quantified chemotherapy doses, treatment dates, and related toxicities using the electronic medical record. In logistic regression models adjusting for age, sex, and American Joint Committee on Cancer stage of disease, the authors examined associations of muscle tertiles with early treatment discontinuation (<6 cycles), treatment delay (>3 days off schedule for >=3 times), and/or dose reduction (relative dose intensity <= 0.70, based on planned treatment). RESULTS: The average age of the patients at the time of diagnosis was 58.7 years; BSA was 1.9 m2 and body mass index was 28.7 kg/m2 . Compared with the highest sex-specific tertile of muscle mass, patients in the lowest tertile were more likely to experience toxicities and had twice the risk of adverse outcomes while receiving FOLFOX; for early discontinuation, the odds ratio (OR) was 2.34 (95% confidence interval [95% CI], 1.04-5.24; P for trend = .03), whereas the ORs were 2.24 (95% CI, 1.37-3.66; P for trend = .002) for treatment delay and 2.28 (95% CI, 1.19-4.36; P for trend = .01) for dose reduction. CONCLUSIONS: Lower muscle mass is associated with greater toxicity and poor chemotherapy adherence among patients receiving FOLFOX. Many chemotherapy drugs are dosed based on BSA, but treatment may be better individualized if muscle mass is considered. Cancer 2017;123:4868-77. (c) 2017 American Cancer Society. PMID- 28881383 TI - Processes of code status transitions in hospitalized patients with advanced cancer. AB - BACKGROUND: Although hospitalized patients with advanced cancer have a low chance of surviving cardiopulmonary resuscitation (CPR), the processes by which they change their code status from full code to do not resuscitate (DNR) are unknown. METHODS: We conducted a mixed-methods study on a prospective cohort of hospitalized patients with advanced cancer. Two physicians used a consensus driven medical record review to characterize processes that led to code status order transitions from full code to DNR. RESULTS: In total, 1047 hospitalizations were reviewed among 728 patients. Admitting clinicians did not address code status in 53% of hospitalizations, resulting in code status orders of "presumed full." In total, 275 patients (26.3%) transitioned from full code to DNR, and 48.7% (134 of 275 patients) of those had an order of "presumed full" at admission; however, upon further clarification, the patients expressed that they had wished to be DNR before the hospitalization. We identified 3 additional processes leading to order transition from full code to DNR acute clinical deterioration (15.3%), discontinuation of cancer-directed therapy (17.1%), and education about the potential harms/futility of CPR (15.3%). Compared with discontinuing therapy and education, transitions because of acute clinical deterioration were associated with less patient involvement (P = .002), a shorter time to death (P < .001), and a greater likelihood of inpatient death (P = .005). CONCLUSIONS: One-half of code status order changes among hospitalized patients with advanced cancer were because of full code orders in patients who had a preference for DNR before hospitalization. Transitions due of acute clinical deterioration were associated with less patient engagement and a higher likelihood of inpatient death. Cancer 2017;123:4895-902. (c) 2017 American Cancer Society. PMID- 28881384 TI - Quality of life from the perspective of the patient with acute myeloid leukemia. AB - BACKGROUND: Although outcomes for acute myeloid leukemia (AML) have improved over time, they remain poor overall, and toxicity from both the disease and its treatment can affect quality of life (QOL). One barrier to including QOL endpoints in clinical trials is the lack of a disease-specific QOL instrument that can efficiently capture the major QOL deficits in this population. METHODS: A cross-sectional study was performed to elicit concepts for inclusion in a new AML-specific QOL instrument called the AML-QOL. Eighty-two patients at various stages of disease were interviewed about sources of support (positive concepts) and problems and symptoms (negative concepts) experienced over the past week, and they were asked to grade how much each affected their QOL. In addition, patients were asked to complete 2 validated instruments: the Functional Assessment of Cancer Therapy with the leukemia and transplant modules and the 29-item Patient Reported Outcomes Measurement Information System questionnaire. RESULTS: With data from the open-ended and questionnaire-based portions of the interview, 7 positive concepts and 64 negative concepts were elicited. From these, 5 positive concepts and 21 negative concepts were selected for inclusion in the preliminary AML-QOL on the basis of concept prevalence and the impact on QOL. CONCLUSIONS: These concepts will form the basis of a new QOL instrument specific to AML. Cancer 2018;124:145-52. (c) 2017 American Cancer Society. PMID- 28881385 TI - Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance. AB - Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES. PMID- 28881386 TI - Heterogeneous impact of smoking on major salivary gland cancer according to histopathological subtype: A case-control study. AB - BACKGROUND: Major salivary gland cancers (M-SGCs) are rare, and have distinct heterogeneous histopathological subtypes. To the authors' knowledge, no consistent evidence of an association between cigarette smoking and the risk of M SGCs has appeared to date. Furthermore, evidence of potential heterogeneity in the impact of smoking on histopathological subtypes is scarce, despite the fact that the histopathological subtypes of M-SGC exhibit different genetic features. METHODS: The authors conducted a case-control study to investigate the association between smoking and M-SGC by histopathological subtype. Cases were 81 patients with M-SGCs and the controls were 810 age-matched and sex-matched first visit outpatients without cancer treated at Aichi Cancer Center Hospital from 1988 to 2005. Odds ratios (OR) and 95% confidence intervals (95% CI) were assessed by conditional logistic regression analysis with adjustment for potential confounders. RESULTS: Smoking was found to be associated with a significantly increased risk of M-SGC overall, with an OR of 3.45 (95% CI, 1.58 7.51; P =.001) for heavy smokers compared with never-smokers. A significant dose response relationship was observed (P for trend, .001). When stratified by histological subtype, no obvious impact of smoking was observed among patients with mucoepidermoid carcinoma (MEC). In contrast, smoking demonstrated a significantly increased risk of M-SGCs other than MEC, with an OR of 5.15 (95% CI, 2.06-12.87; P<.001) for heavy smokers compared with never-smokers. The authors observed possible heterogeneity with regard to the impact of smoking on risk between MEC and M-SGCs other than MEC (P for heterogeneity, .052). CONCLUSIONS: The results of the current study demonstrate a significant positive association between cigarette smoking and the risk of M-SGC overall. However, the impact of smoking appeared to be limited to M-SGCs other than MEC. Cancer 2018;124:118-24. (c) 2017 American Cancer Society. PMID- 28881387 TI - Effects of lactoferrin and lactoperoxidase-containing food on the oral microbiota of older individuals. AB - The oral microbiota influences health and disease states. Some gram-negative anaerobic bacteria play important roles in tissue destruction associated with periodontal disease. Lactoferrin (LF) and lactoperoxidase (LPO) are antimicrobial proteins found in saliva; however, their influence on the whole oral microbiota currently remains unknown. In this randomized, double-blinded, placebo-controlled study, the effects of long-term ingestion of LF and LPO-containing tablets on the microbiota of supragingival plaque and tongue coating were assessed. Forty-six older individuals ingested placebo or test tablets after every meal for 8 weeks. The relative abundance of bacterial species was assessed by 16S rRNA gene high throughput sequencing. Most of the bacterial species in supragingival plaque and tongue coating that exhibited significant decreases in the test group were gram negative bacteria, including periodontal pathogens. Decreases in the total relative abundance of gram-negative organisms in supragingival plaque and tongue coating correlated with improvements in assessed variables related to oral health, such as oral malodor and plaque accumulation. Furthermore, there was significantly less microbiota diversity in supragingival plaque at 8 weeks in the test group than in the placebo group and low microbiota diversity correlated with improvements in assessed variables related to oral health. These results suggest that LF and LPO-containing tablets promote a shift from a highly diverse and gram negative-dominated to a gram-positive-dominated community in the microbiota of supragingival plaque and tongue coating. This microbial shift may contribute to improvements in oral health, including oral malodor and state of the gingiva. PMID- 28881388 TI - Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21. AB - INTRODUCTION: A calpain-3 (CAPN3) gene heterozygous deletion (c.643_663del21) was recently linked to autosomal dominant (AD) limb-girdle muscular dystrophy. However, the possibility of digenic disease was raised. We describe 3 families with AD calpainopathy carrying this isolated mutation. METHODS: Probands heterozygous for CAPN3 c.643_663del21 were identified by targeted next generation or whole exome sequencing. Clinical findings were collected for probands and families. Calpain-3 muscle Western blots were performed in 3 unrelated individuals. RESULTS: Probands reported variable weakness in their 40s or 50s, with myalgia, back pain, or hyperlordosis. Pelvic girdle muscles were affected with adductor and hamstring sparing. Creatine kinase was normal to 1,800 U/L, independent of weakness severity. Imaging demonstrated lumbar paraspinal muscle atrophy. Electromyographic findings and muscle biopsies were normal to mildly myopathic. Muscle calpain-3 expression was reduced. DISCUSSION: This study provides further evidence for AD calpainopathy associated with CAPN3 c.643_663del21. No pathogenic variants in other genes known to cause myopathy were detected. Muscle Nerve 57: 679-683, 2018. PMID- 28881389 TI - Comparisons in fluctuation of muscle strength and function in patients with immune-mediated neuropathy treated with intravenous versus subcutaneous immunoglobulin. AB - INTRODUCTION: Variations in muscle strength and function have not been studied in patients with chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy whose treatment regimen has been changed from intravenous to subcutaneous immunoglobulin (IVIg to SCIg). METHODS: In a prospective, open-label study, patients were changed from monthly IVIg to weekly SCIg. The primary endpoint was variation in isokinetic muscle strength (cIKS). Secondary endpoints were variations in Medical Research Council (MRC) score, grip strength (GS), 9 hole-peg test (9-HPT), and 40-meter-walk test (40-MWT). RESULTS: The coefficient of variance of cIKS during the IVIg and SCIg treatment periods was unchanged (mean +/- SD: 6.97 +/- 4.83% vs. 5.50 +/- 3.13%, P = 0.21). The variations in the 9-HPT and 40-MWT were significantly lower in the SCIg group (P = 0.01 and P = 0.005, respectively). DISCUSSION: When therapy was changed from IVIg to SCIg, fluctuation of muscle strength was unchanged, but performance fluctuations were diminished. Muscle Nerve 57: 610-614, 2018. PMID- 28881391 TI - RNA meets DNA: The Potential for gene expression to produce short RNA molecules capable of generating DNA mutation and driving genome evolution (Comment on DOI: 10.1002/bies.201700069). PMID- 28881390 TI - Prenatal Alcohol Exposure in Relation to Autism Spectrum Disorder: Findings from the Study to Explore Early Development (SEED). AB - BACKGROUND: Prenatal alcohol exposure can affect neurodevelopment, but few studies have examined associations with autism spectrum disorder (ASD). METHODS: We assessed the association between maternal alcohol use and ASD in the Study to Explore Early Development, a multi-site case-control study of children born between September 2003 and August 2006 in the US Regression analyses included 684 children with research clinician-confirmed ASD, 869 children with non-ASD developmental delays or disorders (DDs), and 962 controls ascertained from the general population (POP). Maternal alcohol exposure during each month from 3 months prior to conception until delivery was assessed by self-report. RESULTS: Mothers of POP children were more likely to report any prenatal alcohol use than mothers of children with ASD or DD. In trimester one, 21.2% of mothers of POP children reported alcohol use compared with 18.1% and 18.2% of mothers of children with ASD or DD, respectively (adjusted OR for ASD vs. POP 0.8, 95% confidence interval 0.6, 1.1). During preconception and the first month of pregnancy, one to two drinks on average per week was inversely associated with ASD risk. CONCLUSIONS: These results do not support an adverse association between low-level alcohol exposure and ASD, although these findings were based on retrospective self-reported alcohol use. Unmeasured confounding or exposure misclassification may explain inverse associations with one to two drinks per week. Pregnant or potentially pregnant women should continue to follow recommendations to avoid alcohol use because of other known effects on infant health and neurodevelopment. PMID- 28881392 TI - On the road to replacing invasive testing with cell-based NIPT: Five clinical cases with aneuploidies, microduplication, unbalanced structural rearrangement, or mosaicism. AB - OBJECTIVE: Trophoblastic fetal cells harvested from maternal blood have the capacity to be used for copy number analyses in a cell-based non-invasive prenatal test (cbNIPT). Potentially, this will result in increased resolution for detection of subchromosomal aberrations due to high quality DNA not intermixed with maternal DNA. We present 5 selected clinical cases from first trimester pregnancies where cbNIPT was used to demonstrate a wide range of clinically relevant aberrations. METHOD: Blood samples were collected from high risk pregnancies in gestational week 12 + 1 to 12 + 5. Fetal trophoblast cells were enriched and stained using fetal cell specific antibodies. The enriched cell fraction was scanned, and fetal cells were picked using a capillary-based cell picking instrument. Subsequently, whole genome amplification (WGA) was performed on fetal cells, and the DNA was analyzed blindly by array comparative genomic hybridization (aCGH). RESULTS: We present 5 cases where non-invasive cell-based prenatal test results are compared with aCGH results on chorionic villus samples (CVS), demonstrating aneuploidies including mosaicism, unbalanced translocations, subchromosomal deletions, or duplications. CONCLUSION: Aneuploidy and subchromosomal aberrations can be detected using fetal cells harvested from maternal blood. The method has the future potential of being offered as a cell based NIPT with large high genomic resolution. PMID- 28881393 TI - Outcomes of Gallstone Disease during Pregnancy: a Population-based Data Linkage Study. AB - BACKGROUND: Gallstone disease is a leading indication for non-obstetric abdominal surgery during pregnancy. There are limited whole population data on maternal and neonatal outcomes. This population-based study aims to describe the outcomes of gallstone disease during pregnancy in an Australian setting. METHODS: Linked hospital, birth, and mortality data for all women with singleton pregnancies in New South Wales, Australia, 2001-2012 were analysed. Exposure of interest was gallstone disease (acute biliary pancreatitis, gallstones with/without cholecystitis). Outcomes including preterm birth (spontaneous and planned), readmission, morbidity and mortality (maternal and neonatal) were compared between pregnancies with and without gallstone disease. Adjusted risk ratios (aRRs) and 99% confidence intervals were estimated using modified Poisson regression and adjusted for maternal and pregnancy factors. RESULTS: Among 1 064 089 pregnancies, 1882 (0.18%) had gallstone disease. Of these, 239 (12.7%) had an antepartum cholecystectomy and 1643 (87.3%) were managed conservatively. Of those managed conservatively, 319 (19.0%) had a postpartum cholecystectomy. Gallstone disease was associated with increased risk of preterm birth (aRR 1.3, 99% CI 1.1, 1.6), particularly planned preterm birth (aRR 1.6, 99% CI 1.2, 2.1), maternal morbidity (aRR 1.6, 99% CI 1.1, 2.3), maternal readmission (aRR 4.7, 99% CI 4.2, 5.3), and neonatal morbidity (aRR 1.4, 99% CI 1.1, 1.7). Surgery was associated with decreased risk of maternal readmission (aRR 0.4, 99% CI 0.2, 0.7). CONCLUSIONS: Gallstone disease during pregnancy was associated with adverse maternal and neonatal outcomes. Most women with gallstone disease during pregnancy are managed conservatively. Surgical management was associated with decreased risk of readmission. PMID- 28881395 TI - Long-standing Challenges to Exposure Measurement and Outcome Definitions: the Case of Alcohol and Autism Spectrum Disorder. PMID- 28881394 TI - The Effect of Vaccination Against Human Papillomavirus on Fecundability. AB - BACKGROUND: The human papillomavirus (HPV) vaccine was developed to prevent infection with strains of HPV that cause cervical cancer. While HPV infection has been associated with reduced semen quality and lower pregnancy rates in some studies, no studies have examined the relationship between HPV vaccination and fecundability. We hypothesize that HPV prevention via vaccination will protect fecundity. METHODS: We analysed data from Pregnancy Study Online (PRESTO), a preconception cohort of North American pregnancy planners. Between 2013 and 2017, we followed 3483 female pregnancy planners and 1022 of their male partners for 12 months or until reported pregnancy, whichever came first. At baseline, participants reported whether they had been vaccinated against HPV and their age at vaccination. We estimated fecundability ratios (FR) and 95% confidence intervals (CI) using proportional probabilities models adjusted for sociodemographics, smoking, and abnormal Pap test before HPV vaccination (females only). RESULTS: HPV vaccination was more prevalent among females (33.9%) than males (5.2%). There was little overall association between female vaccination (FR 0.98, 95% CI 0.90, 1.08) or male vaccination (FR 1.07, 95% CI 0.79, 1.46) and fecundability. Among females with a history of sexually transmitted infections or pelvic inflammatory disease (i.e. a group at high risk of exposure to HPV infection), those vaccinated against HPV had higher fecundability than those not vaccinated (FR 1.35, 95% CI 0.99, 1.86). CONCLUSION: Although HPV vaccination had little effect on fecundability overall, HPV vaccination was positively associated with fecundability among women with a history of sexually transmitted infections. PMID- 28881396 TI - Guidelines on radiographic imaging as part of root canal treatment: a systematic review with a focus on review imaging after treatment. AB - AIM: To identify guidelines on endodontics which make recommendations relating to post-root canal treatment radiological review imaging, to make an objective assessment of their quality using the AGREE tool and to examine the evidence cited in support of their recommendations. METHODOLOGY: The primary sources to identify published guidelines were MEDLINE (Ovid(r) ) and EMBASE. The search aim was to identify guidelines pertaining to the post-root canal treatment follow-up recommendations published from 1946 with the final search date being 26 June 2016. The primary search was supplemented by searching Internet search engines and several websites that might have guidelines. The guidelines obtained from the search end-result were assessed for quality and scientific evidence using the AGREE II instrument. Similarities and differences in the recommendations were identified. RESULTS: Thirty guidelines were identified, seven of which met the inclusion criteria. Two guidelines used and clearly described the methods for obtaining scientific evidence from which the recommendations were set. The recommendations varied, particularly as regards the timing of the first review radiograph. Some guidelines lacked supporting evidence. CONCLUSIONS: The recommendations for post-root canal treatment radiographic follow-up varied amongst the identified guidelines. However, the methodology for obtaining the scientific evidence was poorly described in most of the guidelines. Guideline development groups should use the AGREE II instrument as a guide to produce higher quality guidelines. PMID- 28881397 TI - Cholesterol-imprinted macroporous monoliths: Preparation and characterization. AB - The development of sorbents for selective binding of cholesterol, which is a risk factor for cardiovascular disease, has a great importance for analytical science and medicine. In this work, two series of macroporous cholesterol-imprinted monolithic sorbents differing in the composition of functional monomers (methacrylic acid, butyl methacrylate, 2-hydroxyethyl methacrylate and ethylene dimethacrylate), amount of a template (4, 6 and 8 mol%) used for molecular imprinting, as well as mean pore size were synthesized by in situ free-radical process in stainless steel housing of 50 mm * 4.6 mm i.d. All prepared materials were characterized regarding to their hydrodynamic permeability and porous properties, as well as examined by BET and SEM methods. Imprinting factors, apparent dynamic dissociation constants, the maximum binding capacity, the number of theoretical plates and the height equivalent to a theoretical palate of MIP monoliths at different mobile phase flow rates were determined. The separation of a mixture of structural analogues, namely, cholesterol and prednisolone, was demonstrated. Additionally, the possibility of using the developed monoliths for cholesterol solid-phase extraction from simulated biological solution was shown. PMID- 28881399 TI - Heavy-Atom Tunneling Calculations in Thirteen Organic Reactions: Tunneling Contributions are Substantial, and Bell's Formula Closely Approximates Multidimensional Tunneling at >=250 K. AB - Multidimensional tunneling calculations are carried out for 13 reactions, to test the scope of heavy-atom tunneling in organic chemistry, and to check the accuracy of one-dimensional tunneling models. The reactions include pericyclic, cycloaromatization, radical cyclization and ring opening, and SN 2. When compared at the temperatures that give the same effective rate constant of 3*10-5 s-1 , tunneling accounts for 25-95 % of the rate in 8 of the 13 reactions. Values of transmission coefficients predicted by Bell's formula, kappaBell , agree well with multidimensional tunneling (canonical variational transition state theory with small curvature tunneling), kappaSCT . Mean unsigned deviations of kappaBell vs. kappaSCT are 0.08, 0.04, 0.02 at 250, 300 and 400 K. This suggests that kappaBell is a useful first choice for predicting transmission coefficients in heavy-atom tunnelling. PMID- 28881398 TI - Acquired Arnold-Chiari malformation in a 16-year-old patient with hereditary angioedema. PMID- 28881400 TI - Quality specification and status of internal quality control of cardiac biomarkers in China from 2011 to 2016. AB - BACKGROUND: This study aimed to investigate the status of internal quality control (IQC) for cardiac biomarkers from 2011 to 2016 so that we can have overall knowledge of the precision level of measurements in China and set appropriate precision specifications. METHODS: Internal quality control data of cardiac biomarkers, including creatinine kinase MB (CK-MB) (MUg/L), CK-MB(U/L), myoglobin (Mb), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and homocysteines (HCY), were collected by a web-based external quality assessment (EQA) system. Percentages of laboratories meeting five precision quality specifications for current coefficient of variations (CVs) were calculated. Then, appropriate precision specifications were chosen for these six analytes. Finally, the CVs and IQC practice were further analyzed with different grouping methods. RESULTS: The current CVs remained nearly constant for 6 years. cTnT had the highest pass rates every year against five specifications, whereas HCY had the lowest pass rates. Overall, most analytes had a satisfactory performance (pass rates >80%), except for HCY, if one-third TEa or the minimum specification were employed. When the optimal specification was applied, the performance of most analytes was frustrating (pass rates < 60%) except for cTnT. The appropriate precision specifications of Mb, cTnI, cTnT and HCY were set as current CVs less than 9.20%, 9.90%, 7.50%, 10.54%, 7.63%, and 6.67%, respectively. The data of IQC practices indicated wide variation and substantial progress. CONCLUSION: The precision performance of cTnT was already satisfying, while the other five analytes, especially HCY, were still frustrating; thus, ongoing investigation and continuous improvement for IQC are still needed. PMID- 28881402 TI - Should there be an app for that? The case for text messaging in mHealth interventions. PMID- 28881401 TI - Generation of T follicular helper cells in vitro: requirement for B-cell receptor cross-linking and cognate B- and T-cell interaction. AB - The minimum requirements for in vitro modelling of natural CD4+ T-cell differentiation into T follicular helper (Tfh) cells are still under investigation. We co-cultured wild-type and T-cell receptor (TCR) transgenic CD4+ T cells from naive mice with dendritic cells and B-cell receptor (BCR) transgenic B cells in the presence of HIV-derived virus-like particles containing matched B cell and T-cell epitopes. This co-culturing induced co-expression of Tfh-master regulator transcription factor BCL-6 and CXCR5 in up to 10% of the wild-type and up to 40% of the TCR-transgenic CD4+ T cells. Phenotypic markers, production of interleukin-21 and isotype switching of the B cells to IgG1 further indicated a helper function of the induced Tfh cells in vitro. Dendritic cells supported the generation of functional Tfh cells, but were unable to induce them without cognate B cells. Hence, our study presents a robust experimental system for efficient generation of functionally active Tfh cells in vitro and confirms the importance of cognate B- and T-cell cross-talk for the Tfh differentiation process. PMID- 28881403 TI - Differentiation of movement behaviour in an adaptively diverging salamander population. AB - Dispersal is considered to be a species-specific trait, but intraspecific variation can be high. However, when and how this complex trait starts to differentiate during the divergence of species/lineages is unknown. Here, we studied the differentiation of movement behaviour in a large salamander population (Salamandra salamandra), in which individual adaptations to different habitat conditions drive the genetic divergence of this population into two subpopulations. In this system, salamanders have adapted to the deposition and development of their larvae in ephemeral ponds vs. small first-order streams. In general, the pond habitat is characterized as a spatially and temporally highly unpredictable habitat, while streams provide more stable and predictable conditions for the development of larvae. We analysed the fine-scale genetic distribution of larvae, and explored whether the adaptation to different larval habitat conditions has in turn also affected dispersal strategies and home range size of adult salamanders. Based on the genetic assignment of adult individuals to their respective larval habitat type, we show that pond-adapted salamanders occupied larger home ranges, displayed long-distance dispersal and had a higher variability of movement types than the stream-adapted individuals. We argue that the differentiation of phenotypically plastic traits such as dispersal and movement characteristics can be a crucial component in the course of adaptation to new habitat conditions, thereby promoting the genetic divergence of populations. PMID- 28881404 TI - Heptazine: an Electron-Deficient Fluorescent Core for Discotic Liquid Crystals. AB - Herein, room-temperature discotic liquid crystals based on heptazine, an electron deficient central core, are reported for the first time. Mesomorphic behaviors of the materials are also investigated. Supramolecular assembly of the mesophase derivatives were confirmed by X-ray scattering experiments. Heptazine-based solid thin films are strong blue light emitters, whereas in the solution state, they are weakly emissive or non-emissive. The band gap energy is found to be low in this class of compounds. Formation of room-temperature mesophases, low band-gap behavior, and strong blue-light emission in the solid state are promising attributes for optoelectronic applications of the materials. PMID- 28881405 TI - Fabrication of Photocontrolled Surfaces for Oil/Water Separation through Sulfur(VI) Fluoride Exchange. AB - Smart surfaces with controllable wettability have attracted substantial interest owing to the potential use of these materials for the separation of oil from oily water caused by frequent oil-spill accidents. Because there are few separation materials on the market that are capable of switching between hydrophobicity and hydrophilicity, this work reports an efficient and low-cost method to fabricate a photoresponsive membrane through the sulfur(VI) fluoride exchange reaction (SuFEx) between poly(4-vinylphenol sulfofluoridate) and (E)-1-(4-(tert butoxy)phenyl)-2-(4-(trifluoromethoxy)phenyl)diazene. The resulting material displays switchable wettability between hydrophobic and hydrophilic states when subjected to ultraviolet or visible irradiation. This membrane can be recycled (greater than five times) and features superior efficiency (up to 97.9 %) for the separation of oils that have both higher and lower densities than water. This work is the first proof-of-concept application of SuFEx to fabricate functional materials for environmental remediation. PMID- 28881406 TI - The Circadian expression of Piezo1, TRPV4, Connexin26, and VNUT, associated with the expression levels of the clock genes in mouse primary cultured urothelial cells. AB - AIMS: To investigate circadian gene expressions in the mouse bladder urothelium to establish an experimental model and study the functions of the circadian rhythm. METHODS: The gene expression rhythms of the clock genes, mechano-sensors such as Piezo1 and TRPV4, ATP release mediated molecules (ARMM) such as Cx26 and VNUT were investigated in mouse primary cultured urothelial cells (UCs) of wild type (WT) and Clock mutant (ClockDelta19/Delta19 ) mice using quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting analysis. The long-term oscillation of the clock genes in UC was investigated by measuring bioluminescence from UC isolated from Period2luciferase knock-in mice (Per2::luc) and Per2::luc with ClockDelta19/Delta19 using a luminometer. The mRNA expression rhythms after treatment with Clock short interfering RNA (siRNA) were also measured to compare differences between Clock point mutations and Clock deficiency. RESULTS: The UCs from WT mice showed the time-dependent gene expressions for clock genes, mechano-sensors, and ARMM. The abundances of the products of these genes also correlated with the mRNA expression rhythms in UCs. The bioluminescence of Per2::Luc in UCs showed a circadian rhythm. By contrast, all the gene expressions rhythms observed in WT mice were abrogated in the ClockDelta19/Delta19 mice. Transfection with Clock siRNA in UCs had the same effect as the Clock mutation. CONCLUSIONS: We demonstrated that the time-dependent gene expressions, including clock genes, mechano-sensors, and ARMM, were reproducible in UCs. These findings demonstrated that UCs have the potential to progress research into the circadian functions of the lower urinary tract regulated by clock genes. PMID- 28881408 TI - Hydrogen Bond versus Halogen Bond in Cation-Cation Complexes: Effect of the Solvent. AB - Competition between hydrogen- (HB) and halogen-bonded (XB) 4-ammoniumpyridine and halogenammonium (NHn F3-n X+ ; n=0-3; X=F, Cl, Br, and I) cation-cation complexes are explored by means of DFT calculations. HB and XB minima structures are found for all systems in the gas phase. As the number of fluorine atoms increases, the HB complexes are more favored than those of XB. Proton transfer is generally observed in complexes with two, three, or four halogen atoms. The XB complexes evolve from traditional halogen bonds, to halogen-shared complexes, and to ionic complexes as the number of fluorine atoms increases. The dissociation transition states and their corresponding barriers are also characterized; the barriers increase as the number of fluorine atoms increases. The results if solvent effects are considered indicate that, even in an apolar solvent, such as n hexane, most of the complexes have favorable binding energies. Atoms-in-molecules theory is used to analyze the complexes, and results in good correlations between electron density and total electron energy density (Eta) values with the intermolecular bond length. According to the Eta values obtained, the covalency of these interactions starts to manifest at distances around 72-74 % the sum of the van der Waals radii of the interacting atoms. PMID- 28881407 TI - Quantification of AKBA in Boswellia sacra Using NIRS Coupled with PLSR as an Alternative Method and Cross-Validation by HPLC. AB - INTRODUCTION: 3-O-Acetyl-11-keto-beta-boswellic acid (AKBA), one of the pentacyclic triterpenoids, is the main biologically active constituent in the resin of Boswellia sacra and has received significant pharmacological interest in recent years. OBJECTIVE: It was aimed to develop a robust method to quantify the AKBA content in methanolic extracts of different parts of B. sacra plants and in various fractions of its resin exudates through near-infrared spectroscopy (NIRS) coupled with partial least squares regression (PLSR). MATERIAL AND METHODS: The near-infrared (NIR) spectra were used to measure the AKBA standards and B. sacra samples at a wavelength range between 700 and 2500 nm in absorption mode. A PLSR model was built from the obtained spectral data using 70% of the AKBA working standard solutions (training set), ranging from 0.1 ppm to 100 ppm. The final PLSR showed a R2 value of 99% with a root mean square error of cross-validation (RMSECV) value of 0.39% and a R2 value of 99%. RESULTS: The results showed that a 50% CHCl3 /n-hexane sub-fraction has the highest concentration of AKBA (14.8%), followed by 55% CHCl3 /n-hexane (13.6%), and 40% CHCl3 /n-hexane (6.1%). CONCLUSION: As the results achieved with the proposed NIRS methodology are in close agreement to the results of AKBA analysis using HPLC, we suggest that our proposed NIRS method is a fast alternative and non-destructive method for the analysis of AKBA in different samples of B. sacra. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28881409 TI - An Emerging New Risk Analysis Science: Foundations and Implications. AB - To solve real-life problems-such as those related to technology, health, security, or climate change-and make suitable decisions, risk is nearly always a main issue. Different types of sciences are often supporting the work, for example, statistics, natural sciences, and social sciences. Risk analysis approaches and methods are also commonly used, but risk analysis is not broadly accepted as a science in itself. A key problem is the lack of explanatory power and large uncertainties when assessing risk. This article presents an emerging new risk analysis science based on novel ideas and theories on risk analysis developed in recent years by the risk analysis community. It builds on a fundamental change in thinking, from the search for accurate predictions and risk estimates, to knowledge generation related to concepts, theories, frameworks, approaches, principles, methods, and models to understand, assess, characterize, communicate, and (in a broad sense) manage risk. Examples are used to illustrate the importance of this distinct/separate risk analysis science for solving risk problems, supporting science in general and other disciplines in particular. PMID- 28881410 TI - How alcohol industry organisations mislead the public about alcohol and cancer. AB - INTRODUCTION AND AIMS: Alcohol consumption increases the risk of several types of cancer, including several common cancers. As part of their corporate social responsibility activities, the alcohol industry (AI) disseminates information about alcohol and cancer. We examined the information on this which the AI disseminates to the public through its 'social aspects and public relations organizations' and related bodies. The aim of the study was to determine its comprehensiveness and accuracy. DESIGN AND METHODS: Qualitative analysis of websites and documents from 27 AI organisations. All text relating to cancer was extracted and analysed thematically. RESULTS: Most of the organisations were found to disseminate misrepresentations of the evidence about the association between alcohol and cancer. Three main industry strategies were identified: (i) denial/omission: denying, omitting or disputing the evidence that alcohol consumption increases cancer risk; (ii) distortion: mentioning cancer, but misrepresenting the risk; and (iii) distraction: focussing discussion away from the independent effects of alcohol on common cancers. Breast cancer and colorectal cancer appeared to be a particular focus for this misrepresentation. DISCUSSION AND CONCLUSIONS: The AI appears to be engaged in the extensive misrepresentation of evidence about the alcohol-related risk of cancer. These activities have parallels with those of the tobacco industry. This finding is important because the industry is involved in developing alcohol policy in many countries, and in disseminating health information to the public, including schoolchildren. Policymakers, academics, public health and other practitioners should reconsider the appropriateness of their relationships to these AI bodies. PMID- 28881411 TI - Are cataract surgery referrals to public hospitals in Australia poorly targeted? AB - IMPORTANCE: Referral letters constitute the first step on the pathway to cataract surgery; however, little is known on how effective referral letters are in providing adequate information to triage patients and inform surgical prioritization. BACKGROUND: Benchmarking exercises are important to document referral processes and to identify areas where improvements can be made. DESIGN: Cross-sectional study with longitudinal follow-up conducted at two metropolitan public hospitals in New South Wales, Australia. PARTICIPANTS: A total of 400 sequential cataract referral letters. METHODS: An audit of cataract referral letters was performed and content benchmarked against international prioritization tools. Medical records were reviewed 1 year following referral. MAIN OUTCOME MEASURES: Referral quality and waiting times. RESULTS: Two-thirds of patients referred for cataract surgery were yet to have their initial hospital appointment in the year following referral (65%, 245/376). One half of referrals seen in clinic (49%, 64/113) were not listed for cataract surgery. Multivariate analysis revealed referral letter content was not indicative of surgical booking, with the major predictors being hospital-recorded visual acuity and grading of cataract (P < 0.0001). Referral content lacked sufficient detail to apply prioritization tools developed in other settings. CONCLUSION AND RELEVANCE: This audit highlights a disconnect between referral letter content and hospital assessment of patients. Current referrals to public hospitals are poorly targeted, with high numbers of referred patients not proceeding to surgery. Patients commonly waited over 1 year to have their ophthalmic assessment at these public hospital eye clinics, revealing lengthy 'wait-for-waits' as a barrier to care. Standardized referral templates may facilitate improvement of referral pathways and shorten waiting times. PMID- 28881412 TI - Benefits of extracurricular participation in dissection in a prosection-based medical anatomy program. AB - The purpose of this study was to evaluate the extracurricular cadaveric dissection program available to medical students at an institution with a modern (time-compressed, student-centered, and prosection-based) approach to medical anatomy education. Quantitative (Likert-style questions) and qualitative data (thematic analysis of open-ended commentary) were collated from a survey of three medical student cohorts who had completed preclerkship. Perceived benefits of dissection included the hands-on learning style and the development of anatomy expertise, while the main barrier that limited participation was the time intensive nature of dissection. Despite perceived benefits, students preferred that dissection remain optional. Analysis of assessments for the MD2016 cohort revealed that dissection participation was associated with enhanced performance on anatomy items in each systems-based unit examination, with the largest benefits observed on discriminating items that assessed knowledge application. In conclusion, this study revealed that there are academic and perceived benefits of extracurricular participation in dissection. While millennial medical students recognized these benefits, these students also indicated strong preference for having flexibility and choice in their anatomy education, including the choice to participate in cadaveric dissection. Anat Sci Educ 11: 294-302. (c) 2017 American Association of Anatomists. PMID- 28881413 TI - Low expression of SEMA6C accelerates the primordial follicle activation in the neonatal mouse ovary. AB - The primordial follicle assembly, activation and the subsequent development are critical processes for female reproduction. A limited number of primordial follicles are activated to enter the growing follicle pool each wave, and the primordial follicle pool progressively diminishes over a woman's life-time. The number of remaining primordial follicles represents the ovarian reserve. Identification and functional investigation of the factors involved in follicular initial recruitment will be of great significance to the understanding of the female reproduction process and ovarian ageing. In this study, we aimed to study whether and how semaphorin 6C (Sema6c) regulated the primordial follicle activation in the neonatal mouse ovary. The attenuation of SEMA6C expression by SiRNA accelerated the primordial follicle activation in the in vitro ovary culture system. PI3K-AKT-rpS6 pathway was activated when SEMA6C expression was down-regulated. And the LY294002 could reverse the effect of low SEMA6C expression on primordial follicle activation. Our findings revealed that Sema6c was involved in the activation of primordial follicles, and the down-regulation of SEMA6C led to massive primordial follicle activation by interacting with the PI3K-AKT-rpS6 pathway, which might also provide valuable information for understanding premature ovarian failure and ovarian ageing. PMID- 28881414 TI - Changes in field dose-response curves for demethylation inhibitor (DMI) and quinone outside inhibitor (QoI) fungicides against Zymoseptoria tritici, related to laboratory sensitivity phenotyping and genotyping assays. AB - BACKGROUND: Insensitivity of Zymoseptoria tritici to demethylation inhibitor (DMI) and quinone outside inhibitor (QoI) fungicides has been widely reported from laboratory studies, but the relationships between laboratory sensitivity phenotype or target site genotype and field efficacy remain uncertain. This article reports field experiments quantifying dose-response curves, and investigates the relationships between field performance and in vitro half maximal effective concentration (EC50 ) values for DMIs, and the frequency of the G143A substitution conferring QoI resistance. RESULTS: Data were analysed from 83 field experiments over 21 years. Response curves were fitted, expressed as percentage control, rising towards an asymptote with increasing dose. Decline in DMI efficacy over years was associated with a decrease in the asymptote, and reduced curvature. Field ED50 values were positively related to in vitro EC50 values for isolates of Z. tritici collected over a 14-year period. Loss of QoI efficacy was expressed through a change in asymptote. Increasing frequency of G143A was associated with changes in field dose-response asymptotes. CONCLUSION: New resistant strains are often detected by resistance monitoring and laboratory phenotyped/genotyped before changes in field performance are detected. The relationships demonstrated here between laboratory tests and field performance could aid translation between laboratory and field for other fungicide groups. (c) 2017 Society of Chemical Industry. PMID- 28881415 TI - Uterine massage as part of active management of the third stage of labour for preventing postpartum haemorrhage during vaginal delivery: a systematic review and meta-analysis of randomised trials. PMID- 28881416 TI - Improved fruit alpha-tocopherol, carotenoid, squalene and phytosterol contents through manipulation of Brassica juncea 3-HYDROXY-3-METHYLGLUTARYL-COA SYNTHASE1 in transgenic tomato. AB - 3-Hydroxy-3-methylglutaryl-coenzyme A synthase (HMGS) in the mevalonate (MVA) pathway generates isoprenoids including phytosterols. Dietary phytosterols are important because they can lower blood cholesterol levels. Previously, the overexpression of Brassica juncea wild-type (wt) and mutant (S359A) BjHMGS1 in Arabidopsis up-regulated several genes in sterol biosynthesis and increased sterol content. Recombinant S359A had earlier displayed a 10-fold higher in vitro enzyme activity. Furthermore, tobacco HMGS overexpressors (OEs) exhibited improved sterol content, plant growth and seed yield. Increased growth and seed yield in tobacco OE-S359A over OE-wtBjHMGS1 coincided with elevations in NtSQS expression and sterol content. Herein, the overexpression of wt and mutant (S359A) BjHMGS1 in a crop plant, tomato (Solanum lycopersicum), caused an accumulation of MVA-derived squalene and phytosterols, as well as methylerythritol phosphate (MEP)-derived alpha-tocopherol (vitamin E) and carotenoids, which are important to human health as antioxidants. In tomato HMGS OE seedlings, genes associated with the biosyntheses of C10, C15 and C20 universal precursors of isoprenoids, phytosterols, brassinosteroids, dolichols, methylerythritol phosphate, carotenoid and vitamin E were up-regulated. In OE S359A tomato fruits, increased squalene and phytosterol contents over OE wtBjHMGS1 were attributed to heightened SlHMGR2, SlFPS1, SlSQS and SlCYP710A11 expression. In both tomato OE-wtBjHMGS1 and OE-S359A fruits, the up-regulation of SlGPS and SlGGPPS1 in the MEP pathway that led to alpha-tocopherol and carotenoid accumulation indicated cross-talk between the MVA and MEP pathways. Taken together, the manipulation of BjHMGS1 represents a promising strategy to simultaneously elevate health-promoting squalene, phytosterols, alpha-tocopherol and carotenoids in tomato, an edible fruit. PMID- 28881418 TI - Population Pharmacokinetic Evaluation and Missed-Dose Simulations for Eslicarbazepine Acetate Monotherapy in Patients With Partial-Onset Seizures. AB - Given the potential consequences of antiepileptic therapy nonadherence, missed dose scenarios of 12- to 48-hour dose delays (4-hour intervals) for eslicarbazepine acetate monotherapy were evaluated using simulated plasma concentrations of a population pharmacokinetic model (representing 493 subjects). When 1600-mg doses were delayed 12 to <16 or 36 to <44 hours, simulations showed immediate administration of 1600 mg followed by the same dose at the scheduled time maintained plasma concentrations within the target concentration range. With 16- to 24- or 44- to 48-hour delays, administration of 2400 mg at the scheduled time followed by resumption of 1600 mg/day maintained plasma concentrations within the target concentration range. For exploratory purposes, the population pharmacokinetic model was refined to predict (n = 6 subjects) and also to allow for simulation of cerebrospinal fluid concentrations. Based on the plasma concentration simulations conducted herein, potential dosing recommendations were developed that suggest a missed ESL dose should be taken when remembered, and the usual dose regimen resumed. If it is remembered within 4 hours of the next dose, 1.5 times the usual dose should be taken immediately, the scheduled dose for that day should be skipped, and the usual regimen resumed the next day. PMID- 28881417 TI - Central and non-central networks, cognition, clinical symptoms, and polygenic risk scores in schizophrenia. AB - Schizophrenia is a complex disorder that may be the result of aberrant connections between specific brain regions rather than focal brain abnormalities. Here, we investigate the relationships between brain structural connectivity as described by network analysis, intelligence, symptoms, and polygenic risk scores (PGRS) for schizophrenia in a group of patients with schizophrenia and a group of healthy controls. Recently, researchers have shown an interest in the role of high centrality networks in the disorder. However, the importance of non-central networks still remains unclear. Thus, we specifically examined network-averaged fractional anisotropy (mean edge weight) in central and non-central subnetworks. Connections with the highest betweenness centrality within the average network (>75% of centrality values) were selected to represent the central subnetwork. The remaining connections were assigned to the non-central subnetwork. Additionally, we calculated graph theory measures from the average network (connections that occur in at least 2/3 of participants). Density, strength, global efficiency, and clustering coefficient were significantly lower in patients compared with healthy controls for the average network (pFDR < 0.05). All metrics across networks were significantly associated with intelligence (pFDR < 0.05). There was a tendency towards significance for a correlation between intelligence and PGRS for schizophrenia (r = -0.508, p = 0.052) that was significantly mediated by central and non-central mean edge weight and every graph metric from the average network. These results are consistent with the hypothesis that intelligence deficits are associated with a genetic risk for schizophrenia, which is mediated via the disruption of distributed brain networks. Hum Brain Mapp 38:5919-5930, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28881419 TI - A 55-Year-Old Male Presenting With Altered Mental Status: A Complicated Case of Intracranial Aneurysm. PMID- 28881420 TI - Lethal Effect of Photodynamic Treatment on Persister Bacteria. AB - Persister bacteria tolerate bactericidal antibiotics due to transient and reversible phenotypic changes. As these bacteria can limit the effectiveness of antibiotics to eradicate certain infections, their elimination is a relevant issue. Photodynamic therapy seems suitable for this purpose, but phenotypic tolerance to it has also been reported for Pseudomonas aeruginosa. To test whether any phenotypic feature could confer tolerance against both antibiotics and photoinactivation, survivors from exposures to light in the presence of methylene blue were treated with ofloxacin, an antibiotic effective on nongrowing bacteria. Susceptibility to ofloxacin was normal in these bacteria in spite of their increased ability to survive photodynamic inactivation, suggesting the absence of cross-tolerance. It thus seemed possible to use one of these treatments to eliminate bacteria which had phenotypic tolerance to the other. To test this strategy, persister bacteria emerging from ofloxacin treatments were submitted to the action of light and methylene blue while the antibiotic remained in the bacterial suspension. Persisters lost their clonogenic ability under these conditions and the effects of the treatments seemed to be synergistic. These observations suggest that photodynamic antimicrobial therapy could be used as a complement to antibiotic treatments to eliminate persister bacteria from localized infections. PMID- 28881421 TI - Reply. PMID- 28881422 TI - Could Autophagy Induced by Misfolded Mutant alpha1 -Antitrypsin Z in Synovitis Explain the Association of alpha1 -Antitrypsin Z With Increased Anti Citrullinated Protein Antibody Production in Rheumatoid Arthritis? Comment on the Article by McCarthy et al. PMID- 28881424 TI - Anatomic relationship of the first olfactory neuron and trochlea: cadaveric study with surgical implications. AB - BACKGROUND: Iatrogenic injury to the trochlea is a potential complication of the Draf III or endoscopic modified Lothrop procedure; however, the location of the trochlea from within the sinus cavity has yet to be clearly characterized. We performed the first cadaveric study assessing the position of the trochlea in relation to the first olfactory neuron, a commonly identified landmark during the Draf III procedure. METHODS: Thirteen external dissections of the trochlea were performed on 7 disarticulated cadaveric heads via an extended Lynch type incision. An endoscopic Draf III procedure was then performed on all cadavers. A burr hole was then created at the trochlear fovea. A straight vector between the trochlear attachment and the ipsilateral first olfactory neuron was then created. The vector was then viewed from within the sinuses using a 30-degree endoscope. The endoscope was maneuvered to create an upright midline view centered on the olfactory neurons. An image was subsequently captured and analyzed using ImageJ software to calculate a vector angle. The linear distance between the 2 structures was also recorded. RESULTS: Relative to the first olfactory neuron, the trochlea was found to be 19.52 +/- 4.68 mm away and at an angle of 39.42 +/- 8.54 degrees in the anterolateral, superior direction along the frontal bone. CONCLUSION: We report the first anatomical dissection characterizing the position of the trochlea relative to the ipsilateral first olfactory neuron. Intraoperative recognition of this relationship during Draf III procedures can prevent potential injury to the trochlea. PMID- 28881423 TI - Thyroid cancer mortality is higher in Filipinos in the United States: An analysis using national mortality records from 2003 through 2012. AB - BACKGROUND: Well-differentiated thyroid carcinoma has a favorable prognosis, but patients with multiple recurrences have drastically lower survival. Filipinos in the United States are known to have high rates of thyroid cancer incidence and disease recurrence. To the authors' knowledge, it is unknown whether Filipinos also have higher thyroid cancer mortality rates. METHODS: The authors studied thyroid cancer mortality in Filipino, non-Filipino Asian (NFA), and non-Hispanic white (NHW) adults using US death records (2003-2012) and US Census data. Age adjusted mortality rates and proportional mortality ratios (PMRs) were calculated. Sex, nativity status, age at death, and educational attainment also were examined. RESULTS: The authors examined 19,940,952 deaths. The age-adjusted mortality rates due to thyroid cancer were highest in Filipinos (1.72 deaths per 100,000 population; 95% confidence interval [95% CI], 1.51-1.95) compared with NFAs (1.03 per 100,000 population; 95% CI, 0.95-1.12) and NHWs (1.17 per 100,000 population; 95% CI, 1.16-1.18). Compared with NHWs, higher proportionate mortality was observed in Filipino women (3-5 times higher) across all age groups, and among Filipino men, the PMR was 2 to 3 times higher in the subgroup aged >55 years. Filipinos who completed a higher educational level had a notably higher PMR (5.0) compared with their counterparts who had not (3.5). CONCLUSIONS: Negative prognostic factors for thyroid cancer traditionally include age >45 years and male sex. The results of the current study demonstrate that Filipinos die of thyroid cancer at higher rates than NFA and NHW individuals of similar ages. Highly educated Filipinos and Filipino women may be especially at risk of poor thyroid cancer outcomes. Filipino ethnicity should be factored into clinical decision making in the management of patients with thyroid cancer. Cancer 2017;123:4860-7. (c) 2017 American Cancer Society. PMID- 28881425 TI - In Vitro Microfluidic Models for Neurodegenerative Disorders. AB - Microfluidic devices enable novel means of emulating neurodegenerative disease pathophysiology in vitro. These organ-on-a-chip systems can potentially reduce animal testing and substitute (or augment) simple 2D culture systems. Reconstituting critical features of neurodegenerative diseases in a biomimetic system using microfluidics can thereby accelerate drug discovery and improve our understanding of the mechanisms of several currently incurable diseases. This review describes latest advances in modeling neurodegenerative diseases in the central nervous system and the peripheral nervous system. First, this study summarizes fundamental advantages of microfluidic devices in the creation of compartmentalized cell culture microenvironments for the co-culture of neurons, glial cells, endothelial cells, and skeletal muscle cells and in their recapitulation of spatiotemporal chemical gradients and mechanical microenvironments. Then, this reviews neurodegenerative-disease-on-a-chip models focusing on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Finally, this study discusses about current drawbacks of these models and strategies that may overcome them. These organ-on-chip technologies can be useful to be the first line of testing line in drug development and toxicology studies, which can contribute significantly to minimize the phase of animal testing steps. PMID- 28881426 TI - Reply. PMID- 28881427 TI - Active site geometry of a novel aminopropyltransferase for biosynthesis of hyperthermophile-specific branched-chain polyamine. AB - : Branched-chain polyamines are found exclusively in thermophilic bacteria and Euryarchaeota and play essential roles in survival at high temperatures. In the present study, kinetic analyses of a branched-chain polyamine synthase from the hyperthermophilic archaeon Thermococcus kodakarensis (Tk-BpsA) were conducted, showing that N4 -bis(aminopropyl)spermidine was produced by sequential additions of decarboxylated S-adenosylmethionine (dcSAM) aminopropyl groups to spermidine, through bifunctional catalytic action. Tk-BpsA catalyzed the aminopropylation of the linear-chain polyamines spermidine, spermine, norspermidine, and the tertiary branched polyamines N4 -aminopropylspermidine and N4 -aminopropylnorspermidine, but not of short-chain diamines, putrescine, and cadaverine, suggesting that Tk BpsA does not catalyze the aminopropylation of primary amino groups of diamines. X-ray structural analyses of Tk-BpsA in the presence or absence of the substrates spermidine and dcSAM revealed that a large, negatively charged cavity is responsible for the binding of branched-chain substrates. The binding is different from that in the active site of linear polyamine spermidine/spermine synthases, and loop-closures occur upon the binding of spermidine. Based on structural analyses, further kinetic studies were carried out for various mutants, revealing that Asp159, positioned between the reactive secondary amino group of the substrate polyamine and a sulfur atom of the product 5' methylthioadenosine and in a Gly-Asp-Asp-Asp motif, functions as a catalytic center, with reactions proceeding via a ping-pong mechanism. Our study provides a novel aminopropyltransfer reaction mechanism, distinct from the SN 2 displacement mechanism found in other known linear spermidine/spermine synthases. DATABASE: Atomic coordinates and structure factors have been deposited in the Protein Data Bank with PDB codes 5XNF for apo-Tk-BpsA, 5XNH for the binary complex, and 5XNC for the ternary complex. PMID- 28881429 TI - Pulmonary Sarcoidosis Revealed by Ulcerating Nodules Within Tattoos. PMID- 28881430 TI - Distinctive effects between cognitive stimulation and reminiscence therapy on cognitive function and quality of life for different types of behavioural problems in dementia. AB - BACKGROUND: Among the various complementary therapies for patients with dementia (PwD), cognitive stimulation therapy (CST) and reminiscence therapy (RT) are frequently used to improve cognitive function and quality of life. However, no studies have examined the use of complementary therapies applied to different types of behavioural and psychological symptoms of dementia in PwD. AIMS: The purpose of this study was to investigate the distinctive effects of CST and RT on cognitive function and quality of life for PwD with three types of behavioural problems - the dispute, return and dissociate types. METHODS: A quasi experimental design was employed. A total of PwD residing in 10 long-term care institutions participated in the study and were divided into three groups. The CST and RT groups received 50-minute sessions of intervention therapy once a week for 10 continuous weeks, and the control group participated in regular activities. The pretest (week 1), post-test (week 12) and follow-up (week 24) data were collected using the Mini-Mental State Examination and Quality of Life Alzheimer's Disease. Two-way analysis of variance was used for data analysis. RESULTS: The results of our study revealed CST and RT interventions had positive effects on cognition and quality of life of PwD. For short-term effects on cognitive function, CST was the most positive intervention for the dispute type. With regard to short-term effects on quality of life, CST was greater than RT for PwD. For follow-up effects, CST and RT may have potentially sustained effects. CONCLUSION: This study suggests that CST and RT could be applied to improve the cognitive function and quality of life for PwD, as well as contribute to the effectiveness of nonpharmacological approaches to PwD with certain types of behavioural problems. PMID- 28881428 TI - Densification of Type I Collagen Matrices as a Model for Cardiac Fibrosis. AB - Cardiac fibrosis is a disease state characterized by excessive collagenous matrix accumulation within the myocardium that can lead to ventricular dilation and systolic failure. Current treatment options are severely lacking due in part to the poor understanding of the complexity of molecular pathways involved in cardiac fibrosis. To close this gap, in vitro model systems that recapitulate the defining features of the fibrotic cellular environment are in need. Type I collagen, a major cardiac extracellular matrix protein and the defining component of fibrotic depositions, is an attractive choice for a fibrosis model, but demonstrates poor mechanical strength due to solubility limits. However, plastic compression of collagen matrices is shown to significantly increase its mechanical properties. Here, confined compression of oligomeric, type I collagen matrices is utilized to resemble defining hallmarks seen in fibrotic tissue such as increased collagen content, fibril thickness, and bulk compressive modulus. Cardiomyocytes seeded on compressed matrices show a strong beating abrogation as observed in cardiac fibrosis. Gene expression analysis of selected fibrosis markers indicates fibrotic activation and cardiomyocyte maturation with regard to the existing literature. With these results, a promising first step toward a facile heart-on-chip model is presented to study cardiac fibrosis. PMID- 28881431 TI - Fractional CO2 laser of the vagina for genitourinary syndrome of menopause: Is the out-of-pocket cost worth the outcome of treatment? AB - OBJECTIVES: The purpose of this study is to assess patient's satisfaction treatment outcomes and out-of-pocket expense for the fractional CO2 laser (SmartXide) in the treatment of genitourinary symptoms of menopause (GSM). MATERIALS AND METHODS: A multicenter retrospective cohort study of patients who completed a course of three vaginal treatments with the SmartXide11 Fractional CO2 laser. Patients contacted via telephone and asked to participate in questionnaires to evaluate for adverse outcomes since last treatment, symptom severity before and after treatment, patient satisfaction with treatment, patient satisfaction with out-of-pocket expense, and sexual function. RESULTS: Of the 368 patients contacted, 122 agreed to be interviewed. No patients reported seeking emergent medical treatment. Patient reported vaginal dryness significantly improved following treatment (P < 0.05). The frequency of intercourse increased from "once a month" to "few times a month" (P < 0.001). The vast majority of patients reported being satisfied with their treatment results (86%) and with the cost of treatment (78%). Satisfaction with the out-of-pocket expense did not correlate with household income (P = 0.07). CONCLUSION: The SmartXide Fractional CO2 laser is a safe and efficacious treatment for GSM. This treatment is associated with a high level of patient satisfaction with both treatment results and out-of-pocket expense. Lasers Surg. Med. 49:882-885, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28881432 TI - Protein 4.1R is Involved in the Transport of 5-Aminolevulinic Acid by Interaction with GATs in MEF Cells. AB - 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT) has been successfully used in the treatment of cancers. However, the mechanism of 5-ALA transportation into cancer cells is still not fully elucidated. Previous studies have confirmed that the efficiency of 5-ALA-PDT could be affected by the membrane skeleton protein 4.1R. In this study, we investigated the role of 4.1R in the transport of 5-ALA into cells. Wild-type (4.1R+/+ ) and 4.1R gene knockout (4.1R /- ) mouse embryonic fibroblast (MEF) cells were incubated with 1 mm 5-ALA and different concentrations of specific inhibitors of GABA transporters GAT (1-3). Our results showed that the inhibition of GAT1 and GAT2 in particular markedly attenuated the intracellular PpIX production, reactive oxygen species (ROS) level and 5-ALA-induced photodamage. However, the inhibition of GAT3 did not show such effects. Further research showed that 4.1R-/- MEF cells had a lower expression of GAT1 and GAT2 than 4.1R+/+ MEF cells. Additionally, 4.1R directly bound to GAT1 and GAT2. Taken together, GAT1 and GAT2 transporters are involved in the uptake of 5-ALA in MEF cells. 4.1R plays an important role in transporting 5-ALA into cells via at least partly interaction with GAT1 and GAT2 transporters in 5-ALA PDT. PMID- 28881433 TI - Structural connectivity-defined thalamic subregions have different functional connectivity abnormalities in multiple sclerosis patients: Implications for clinical correlations. AB - In spite of the well-known importance of thalami in multiple sclerosis (MS), only limited data on whole and subregional thalamic functional connectivity (FC) changes are available. Using diffusion tensor imaging, we performed a structural connectivity based thalamic parcellation and investigated subregional thalamic resting-state (RS) FC alterations and their relationship with clinical/cognitive measures in MS. MRI data from a reference set of healthy controls (HC) were used to parcellate the thalami into five subregions, according to their structural connectivity. For each thalamic subregion, a seed-based RS FC analysis was performed in 187 MS patients and 94 HC. Correlations between thalamic RS FC and clinical/cognitive variables were assessed. Compared to HC, MS patients showed increased intra- and inter-thalamic RS FC for almost all thalamic subregions, and increased RS FC between all thalamic subregions and the left insula. Frontal and motor thalamic subregions also showed reduced RS FC with the caudate nucleus. For the temporal thalamic subregion, we observed reduced RS FC with the ipsilateral thalamus, anterior and middle cingulate cortex, and cerebellum. Compared to cognitively preserved, cognitively impaired MS patients had higher thalamic RS FC with several temporal areas. In MS patients, lower RS FC between thalamic subregions and the caudate and cingulate cortex correlated with worse motor performance, whereas higher RS FC with the insula correlated with better motor performance. The main thalamic subregions have different RS-FC abnormalities in MS patients. Increased thalamic RS FC with the insula may have a compensatory role, whereas increased RS FC with temporal areas, observed in patients with cognitive impairment may reflect maladaptive mechanisms. Hum Brain Mapp 38:6005 6018, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28881434 TI - Prevalence and causes of musculoskeletal impairment in Fundong District, North West Cameroon: results of a population-based survey. AB - OBJECTIVES: Epidemiological data on musculoskeletal conditions such as degenerative joint diseases and bone fractures are lacking in low- and middle income countries. This survey aimed to estimate the prevalence and causes of musculoskeletal impairment in Fundong Health District, North-West Cameroon. METHODS: Fifty-one clusters of 80 people (all ages) were selected using probability proportionate to size sampling. Households within clusters were selected by compact segment sampling. Six screening questions were asked to identify participants likely to have a musculoskeletal impairment (MSI). Participants screening positive to any screening question underwent a standardised examination by a physiotherapist to assess presence, cause, diagnosis and severity of impairment. RESULTS: In total, 3567 of 4080 individuals enumerated for the survey were screened (87%). The all-age prevalence of MSI was 11.6% (95% CI: 10.1-13.3). Prevalence increased with age, from 2.9% in children to 41.2% in adults 50 years and above. The majority of MSI cases (70.4%) were classified as mild, 27.2% as moderate and 2.4% as severe. Acquired non-trauma comprised 67% of the diagnoses. The remainder included trauma (14%), neurological (11%), infection (5%) and congenital (3%). The most common individual diagnosis was degenerative joint disease (43%). Over one-third (38%) of individuals with MSI had never received medical care or rehabilitation for their condition. CONCLUSIONS: This survey contributes to the epidemiological data on MSI in low- and middle-income countries. Nearly half of adults aged over 50 years had an MSI. There is a need to address the treatment and rehabilitative service gap for people with MSI in Cameroon. PMID- 28881435 TI - Versatile Method for the Site-Specific Modification of DNA with Boron Clusters: Anti-Epidermal Growth Factor Receptor (EGFR) Antisense Oligonucleotide Case. AB - A general and convenient approach for the incorporation of different types of boron clusters into specific locations of the DNA-oligonucleotide chain based on the automated phosphoramidite method of oligonucleotide synthesis and post synthetic "click chemistry" modification has been developed. Pronounced effects of boron-cluster modification on the physico- and biochemical properties of the antisense oligonucleotides were observed. The silencing activity of antisense oligonucleotides bearing a single boron cluster modification in the middle of the oligonucleotide chain was substantially higher than that of unmodified oligonucleotides. This finding may be of importance for the design of therapeutic nucleic acids with improved properties. The proposed synthetic methodology broadens the availability of nucleic acid-boron cluster conjugates and opens up new avenues for their potential practical use. PMID- 28881436 TI - Rational Design of Sulfur-Doped Copper Catalysts for the Selective Electroreduction of Carbon Dioxide to Formate. AB - The selective electroreduction of CO2 to formate (or formic acid) is of great interest in the field of renewable-energy utilization. In this work, we designed a sulfur-doped Cu2 O-derived Cu catalyst and showed that the presence of sulfur can tune the selectivity of Cu significantly from the production of various CO2 reduction products to almost exclusively formate. Sulfur is doped into the Cu catalysts by dipping the Cu substrates into ammonium polysulfide solutions. Catalyst films with the highest sulfur content of 2.7 at % showed the largest formate current density (jHCOO- ) of -13.9 mA cm-2 at -0.9 V versus the reversible hydrogen electrode (RHE), which is approximately 46 times larger than that previously reported for Cu(110) surfaces. At -0.8 V versus RHE, the faradaic efficiency of formate was maintained at approximately 75 % for 12 h of continuous electrolysis. Through the analysis of the evolution of the jHCOO- and jH2 values with the sulfur content, we show that sulfur doping increases formate production and suppresses the hydrogen evolution reaction. Ag-S and Cu-Se catalysts did not exhibit any significant enhancement towards the reduction of CO2 to formate. This demonstrates clearly that sulfur and copper acted synergistically to promote the selective formation of formate. A hypothesis about the role of sulfur is proposed and discussed. PMID- 28881437 TI - Older people's experiences of nurse-patient telephone communication in the primary healthcare setting. AB - AIM: To determine which aspects of primary nurse-patient telephone communication are viewed positively or negatively in terms of meeting the older persons' needs. BACKGROUND: Health professionals are increasingly being called on to develop different ways of working and increase their capacity to meet the needs of an ageing population. In some countries, telephone communication between primary nurses and patients in General Practice is already seen as a routine practice, but determining the value of this type of communication as a specific health service needs more understanding. DESIGN: A qualitative exploratory study as the aim was to explore the older person's experiences. METHODS: Semi-structured interviews were conducted with 21 older people from General Practices in New Zealand during 2014-2015. Thematic analysis was informed by a constructivist grounded theory approach. FINDINGS: The overarching theme was the difficulties older people face in making decisions about whether to contact a health professional by telephone and whether this should be the Primary nurse. Accounting for some of their symptoms as age related added to the uncertainty of decision-making. Importantly, some older people were not raising concerns e.g. emotional state. CONCLUSION: Decision-making by older people around treatment seeking is complex. Increasing the awareness of the nurse role in the General Practice is integral to creating a health system which will meet the needs of a growing older population. Primary care practices can review their systems to better inform older people how the nurse-telephone role as a specific health service works and what they can expect when using this service. PMID- 28881438 TI - Host-induced gene silencing of an important pathogenicity factor PsCPK1 in Puccinia striiformis f. sp. tritici enhances resistance of wheat to stripe rust. AB - Rust fungi are devastating plant pathogens and cause a large economic impact on wheat production worldwide. To overcome this rapid loss of resistance in varieties, we generated stable transgenic wheat plants expressing short interfering RNAs (siRNAs) targeting potentially vital genes of Puccinia striiformis f. sp. tritici (Pst). Protein kinase A (PKA) has been proved to play important roles in regulating the virulence of phytopathogenic fungi. PsCPK1, a PKA catalytic subunit gene from Pst, is highly induced at the early infection stage of Pst. The instantaneous silencing of PsCPK1 by barley stripe mosaic virus (BSMV)-mediated host-induced gene silencing (HIGS) results in a significant reduction in the length of infection hyphae and disease phenotype. These results indicate that PsCPK1 is an important pathogenicity factor by regulating Pst growth and development. Two transgenic lines expressing the RNA interference (RNAi) construct in a normally susceptible wheat cultivar displayed high levels of stable and consistent resistance to Pst throughout the T3 to T4 generations. The presence of the interfering RNAs in transgenic wheat plants was confirmed by northern blotting, and these RNAs were found to efficiently down-regulate PsCPK1 expression in wheat. This study addresses important aspects for the development of fungal-derived resistance through the expression of silencing constructs in host plants as a powerful strategy to control cereal rust diseases. PMID- 28881439 TI - Natural disturbances are spatially diverse but temporally synchronized across temperate forest landscapes in Europe. AB - Natural disturbance regimes are changing substantially in forests around the globe. However, large-scale disturbance change is modulated by a considerable spatiotemporal variation within biomes. This variation remains incompletely understood particularly in the temperate forests of Europe, for which consistent large-scale disturbance information is lacking. Here, our aim was to quantify the spatiotemporal patterns of forest disturbances across temperate forest landscapes in Europe using remote sensing data and determine their underlying drivers. Specifically, we tested two hypotheses: (1) Topography determines the spatial patterns of disturbance, and (2) climatic extremes synchronize natural disturbances across the biome. We used novel Landsat-based maps of forest disturbances 1986-2016 in combination with landscape analysis to compare spatial disturbance patterns across five unmanaged forest landscapes with varying topographic complexity. Furthermore, we analyzed annual estimates of disturbances for synchronies and tested the influence of climatic extremes on temporal disturbance patterns. Spatial variation in disturbance patterns was substantial across temperate forest landscapes. With increasing topographic complexity, natural disturbance patches were smaller, more complex in shape, more dispersed, and affected a smaller portion of the landscape. Temporal disturbance patterns, however, were strongly synchronized across all landscapes, with three distinct waves of high disturbance activity between 1986 and 2016. All three waves followed years of pronounced drought and high peak wind speeds. Natural disturbances in temperate forest landscapes of Europe are thus spatially diverse but temporally synchronized. We conclude that the ecological effect of natural disturbances (i.e., whether they are homogenizing a landscape or increasing its heterogeneity) is strongly determined by the topographic template. Furthermore, as the strong biome-wide synchronization of disturbances was closely linked to climatic extremes, large-scale disturbance episodes are likely in Europe's temperate forests under climate changes. PMID- 28881440 TI - Injectable Mussel-Inspired Immobilization of Platelet-Rich Plasma on Microspheres Bridging Adipose Micro-Tissues to Improve Autologous Fat Transplantation by Controlling Release of PDGF and VEGF, Angiogenesis, Stem Cell Migration. AB - Platelets-rich plasma (PRP) can produce growth factors (GFs) to improve angiogenesis. However, direct injection of PRP does not lead to highly localized GFs. The current study employs a mussel-inspired polydopamine to immobilize PRP on gelatin microspheres (GMs) with the purpose of bridging adipose micro-tissues to help implanted fat survive (GM-pDA-PRP). Enhanced PRP adhesion leads to a prolonged and localized production of GFs, which is verified by platelet counting and by ELISA of vascular endothelial growth factors (VEGFs) and of platelet derived growth factors (PDGFs). The GM-pDA-PRP "hatches" a microenvironment for the proliferation of adipose-derived stem cells. After the adipose micro-tissue has bridged with GM-pDA-PRP after 16 weeks, triple-fluorescence staining reveals that the mature adipocytes, blood vessels, and capillaries are arranged like in normal adipose tissue. The survival fat increases significantly compared to that in control, PRP, and GM-PRP groups (84.8 +/- 11.4% versus 47.8 +/- 8.9%, 56.9 +/- 9.7%, and 60.2 +/- 10.5%, respectively). Both histological assessments and CD31 immunofluorescence indicate that the improvement of angiogenesis in GM-pDA-PRP is higher than in the fat graft group (6.4-fold in quantitative CD31 positive cells). The CD34 positive cells in the GM-pDA-PRP group are around 3.5-fold the amount in the fat graft group, which suggests that more stem cells migrate to the implant area. Cell proliferation staining shows that the number of Ki67 positive cells is around five times as high as that in the fat graft group. PMID- 28881441 TI - Effects of Self-Assembled Monolayer Modification of Nickel Oxide Nanoparticles Layer on the Performance and Application of Inverted Perovskite Solar Cells. AB - Entirely low-temperature solution-processed (<=100 degrees C) planar p-i-n perovskite solar cells (PSCs) offer great potential for commercialization of roll to-roll fabricated photovoltaic devices. However, the stable inorganic hole transporting layer (HTL) in PSCs is usually processed at high temperature (200 500 degrees C), which is far beyond the tolerant temperature (<=150 degrees C) of roll-to-roll fabrication. In this context, inorganic NiOx nanoparticles (NPs) are an excellent candidate to serve as the HTL in PSCs, owing to their excellent solution processability at room temperature. However, the low-temperature processing condition is usually accompanied with defect formation, which deteriorates the film quality and device efficiency to a large extent. To suppress this setback, we used a series of benzoic acid selfassembled monolayers (SAMs) to passivate the surface defects of the NiOx NPs and found that 4 bromobenzoic acid could effectively play the role of the surface passivation. This SAM layer reduces the trap-assisted recombination, minimizes the energy offset between the NiOx NPs and perovskite, and changes the HTL surface wettability, thus enhancing the perovskite crystallization, resulting in more stable PSCs with enhanced power conversion efficiency (PCE) of 18.4 %, exceeding the control device PCE (15.5 %). Also, we incorporated the above-mentioned SAMs into flexible PSCs (F-PSCs) and achieved one of the highest PCE of 16.2 % on a polyethylene terephthalate (PET) substrate with a remarkable power-per-weight of 26.9 W g-1 . This facile interfacial engineering method offers great potential for the large-scale manufacturing and commercialization of PSCs. PMID- 28881442 TI - Many-to-one form-to-function mapping weakens parallel morphological evolution. AB - Evolutionary ecologists aim to explain and predict evolutionary change under different selective regimes. Theory suggests that such evolutionary prediction should be more difficult for biomechanical systems in which different trait combinations generate the same functional output: "many-to-one mapping." Many-to one mapping of phenotype to function enables multiple morphological solutions to meet the same adaptive challenges. Therefore, many-to-one mapping should undermine parallel morphological evolution, and hence evolutionary predictability, even when selection pressures are shared among populations. Studying 16 replicate pairs of lake- and stream-adapted threespine stickleback (Gasterosteus aculeatus), we quantified three parts of the teleost feeding apparatus and used biomechanical models to calculate their expected functional outputs. The three feeding structures differed in their form-to-function relationship from one-to-one (lower jaw lever ratio) to increasingly many-to-one (buccal suction index, opercular 4-bar linkage). We tested for (1) weaker linear correlations between phenotype and calculated function, and (2) less parallel evolution across lake-stream pairs, in the many-to-one systems relative to the one-to-one system. We confirm both predictions, thus supporting the theoretical expectation that increasing many-to-one mapping undermines parallel evolution. Therefore, sole consideration of morphological variation within and among populations might not serve as a proxy for functional variation when multiple adaptive trait combinations exist. PMID- 28881443 TI - Preference Functions for Spatial Risk Analysis. AB - When outcomes are defined over a geographic region, measures of spatial risk regarding these outcomes can be more complex than traditional measures of risk. One of the main challenges is the need for a cardinal preference function that incorporates the spatial nature of the outcomes. We explore preference conditions that will yield the existence of spatial measurable value and utility functions, and discuss their application to spatial risk analysis. We also present a simple example on household freshwater usage across regions to demonstrate how such functions can be assessed and applied. PMID- 28881445 TI - The expression of Spodoptera exigua P450 and UGT genes: tissue specificity and response to insecticides. AB - Cytochrome P450 and UDP-glucosyltransferase (UGT) as phase I and phase II metabolism enzymes, respectively, play vital roles in the breakdown of endobiotics and xenobiotics. Insects can increase the expression of detoxification enzymes to cope with the stress from xenobiotics including insecticides. However, the molecular mechanisms for insecticide detoxification in Spodoptera exigua remain elusive, and the genes conferring insecticide metabolisms in this species are less well reported. In this study, 68 P450 and 32 UGT genes were identified. Phylogenetic analysis showed gene expansions in CYP3 and CYP4 clans of P450 genes and UGT33 family of this pest. P450 and UGT genes exhibited specific tissue expression patterns. Insecticide treatments in fat body cells of S. exigua revealed that the expression levels of P450 and UGT genes were significantly influenced by challenges of abamectin, lambda-cyhalothrin, chlorantraniliprole, metaflumizone and indoxacarb. Multiple genes for detoxification were affected in expression levels after insecticide exposures. The results demonstrated that lambda-cyhalothrin, chlorantraniliprole, metaflumizone and indoxacarb induced similar responses in the expression of P450 and UGT genes in fat body cells; eight P450 genes and four UGT genes were co-up regulated significantly, and no or only a few CYP/UGT genes were down-regulated significantly by these four insecticides. However, abamectin triggered a distinct response for P450 and UGT gene expression; more P450 and UGT genes were down regulated by abamectin than by the other four compounds. In conclusion, P450 and UGT genes from S. exigua were identified, and different responses to abamectin suggest a different mechanism for insecticide detoxification. PMID- 28881444 TI - GABAergic inhibition gates excitatory LTP in perirhinal cortex. AB - The perirhinal cortex (PRh) is a key region downstream of auditory cortex (ACx) that processes familiarity linked mnemonic signaling. In gerbils, ACx-driven EPSPs recorded in PRh neurons are largely shunted by GABAergic inhibition (Kotak et al., 2015, Frontiers in Neural Circuits, 9). To determine whether inhibitory shunting prevents the induction of excitatory long-term potentiation (e-LTP), we stimulated ACx-recipient PRh in a brain slice preparation using theta burst stimulation (TBS). Under control conditions, without GABA blockers, the majority of PRh neurons exhibited long-term depression. A very low concentration of bicuculline increased EPSP amplitude, but under this condition TBS did not significantly increase e-LTP induction. Since PRh synaptic inhibition included a GABAB receptor-mediated component, we added a GABAB receptor antagonist. When both GABAA and GABAB receptors were blocked, TBS reliably induced e-LTP in a majority of PRh neurons. We conclude that GABAergic transmission is a vital mechanism regulating e-LTP induction in the PRh, and may be associated with auditory learning. PMID- 28881447 TI - Combination of Histopathology and FT-Raman Spectroscopy for the Study of Experimental Paracoccidioidomycosis in the Spleen. AB - Paracoccidioides brasiliensis (Pb) can disseminate through the lymphatic and hematogenic pathways. As a result the spleen and other lymphoid organs are targets of paracoccidioidomycosis. There are few studies describing this disease in the spleen and more detailed descriptions are required. This study combines Histopathology and Fourier Transform Raman Spectroscopy (FT-Raman) methods to study spleen infected by Pb. The Swiss mice were euthanized after 1, 2, 4 and 8 weeks of infection with Pb, and their spleens were removed for ex vivo analyzes. Histopathological evaluation revealed that the red pulp was the area most affected, presenting the highest concentration of yeasts, inflammatory cells and cells in apoptosis, with no observation of typical granuloma formation. The main physical-chemical changes were detected in the spectral ranges between 1730-1590 cm-1 and 1390-1280 cm-1 attributed to amide I and vibrational deformation mode of CH3 and CH2 molecules, respectively. The amide I was correlated to total protein content and CH3 and CH2 molecules to collagen of the spleen. The association between histological and physical-chemical methods enabled detection of several alterations in the spleen, including apoptosis, contributing to a better understanding of paracoccidioidomycosis, a tropical neglected disease. PMID- 28881448 TI - Reply to cancer risk among Holocaust survivors in Israel. PMID- 28881446 TI - The Epidemiology of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis in Olmsted County, Minnesota: A Twenty-Year US Population-Based Study. AB - OBJECTIVE: To estimate the annual incidence, prevalence, and mortality of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) and its subsets, granulomatosis with polyangiitis (Wegener's) (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg Strauss) (EGPA), in a US-based adult population. METHODS: All medical records of patients with a diagnosis of, or suspicion of having, AAV in Olmsted County, Minnesota from January 1, 1996 to December 31, 2015 were reviewed. AAV incidence rates were age- and sex-adjusted to the 2010 US white population. Age- and sex adjusted prevalence of AAV was calculated on January 1, 2015. Survival rates observed in the study cohort were compared with expected rates in the Minnesota population. RESULTS: Of the 58 incident cases of AAV in Olmsted County during the study period, 23 (40%) were cases of GPA, 28 (48%) were cases of MPA, and 7 (12%) were cases of EGPA. Overall, 28 (48%) of the patients with AAV were women and 57 (98%) were white. The mean +/- SD age at diagnosis was 61.1 +/- 16.5 years. Thirty-four patients (61%) had myeloperoxidase (MPO)-ANCAs, and 17 (30%) were positive for proteinase 3 (PR3)-ANCAs; 5 (9%) were ANCA-negative. The annual incidence of AAV was 3.3 per 100,000 population (95% confidence interval [95% CI] 2.4-4.1). The incidence rates of GPA, MPA, and EGPA were 1.3 (95% CI 0.8-1.8), 1.6 (95% CI 1.0-2.2), and 0.4 (95% CI 0.1-0.6), respectively. The overall prevalence of AAV was 42.1 per 100,000 (95% CI 29.6-54.6). The mortality rate among AAV patients overall, and among patients with EGPA, those with MPA, and those with MPO-ANCAs, was increased in comparison to the Minnesota general population (each P < 0.05), whereas mortality rates among patients with GPA, those with PR3-ANCAs, and ANCA-negative patients did not differ from that in the general population. CONCLUSION: The annual incidence of AAV in Olmsted County, Minnesota over the 20 years of the study was 3.3 per 100,000, with a prevalence of 42.1 per 100,000, which is substantially higher than the rates reported in other areas worldwide. The incidence of GPA was similar to that of MPA. Patients with MPA and those with EGPA, but not patients with GPA, experienced higher rates of mortality than that in the Minnesota general population. MPO-ANCAs were a marker of poor survival in this population of patients with AAV. PMID- 28881449 TI - Theoretical Study on the Substituent Effect on the Excited-State Proton Transfer in the 7-Azaindole-Water Derivatives. AB - The first excited-state proton transfer (ESPT) in 7AI-H2 O complex and its derivatives, in which the hydrogen atom at the C2 position in pyrrole ring was replaced by halogen atom X (X = F, Cl, Br), were studied at the TD-M06-2X/6-31 + G(d, p) level. The double proton transfer took place in a concerted but asynchronous protolysis pathway. The vibrational-mode selectivity of excited state double proton transfer in the model system was confirmed. The specific vibrational-mode could shorten the reaction path and accelerate the reaction rate. The substituent effects on the excited-state proton transfer process were discussed. When the H atom at C2 position in 7AI-H2 O complex was replaced by halogen atom, some geometrical parameters changed obviously, the barrier height of ESDPT reduced, and the asynchronicity of proton transfer enlarged. The above changes correlated with the Pauling electronegativity of halogen atom. PMID- 28881450 TI - Translation and field testing of the family functioning, family health and social support questionnaire in Danish outpatients with heart failure. AB - BACKGROUND: Valid and reliable instruments to assess family functioning, health and social support in families with heart failure constitute a cornerstone in the detection of the families' needs, in improving their functioning and in evaluating the effects of nursing interventions. AIM: To translate the three scales of the Family Functioning, Family Health and Social Support (FAFHES) questionnaire from Finnish into Danish, to test validity and reliability of the Danish version among outpatients with heart failure and to add to previous studies by reconstructing scales using confirmatory factor analysis. METHODS: A cross-sectional design was used to study a sample of 330 patients with heart failure who completed the FAFHES. The validity (dimensionality) and reliability (internal consistency and test-retest) were assessed for each of the three scales. The scales were constructed using confirmatory factor analysis. RESULTS: Patients were primarily men (76%) with a mean age of 66.5 (SD 12.5), categorised as New York Heart Association (NYHA) classification II (80%) and NYHA III (20%) for clinical severity of symptoms. In all three modified scales, construct validity was supported by the analysis. There were strong correlations within the factors, with Cronbach's alpha ranging from 0.73 to 0.95 across the three scales, and significant, though weak, correlations between most of the factors. None of the revised scales showed good model fit according to the goodness-of-fit indices used. The test-retest showed interclass correlation coefficients ranging between 0.69 and 0.86, indicating acceptable test-retest reliability. CONCLUSION: The Danish version of the FAFHES is an instrument that can be used to measure family functioning, family health and social support from the perspective of the patient with heart failure. Further testing is recommended. PMID- 28881451 TI - Validation of a pediatric early warning system for hospitalized pediatric oncology patients in a resource-limited setting. AB - BACKGROUND: Pediatric oncology patients are at high risk of clinical deterioration, particularly in hospitals with resource limitations. The performance of pediatric early warning systems (PEWS) to identify deterioration has not been assessed in these settings. This study evaluates the validity of PEWS to predict the need for unplanned transfer to the pediatric intensive care unit (PICU) among pediatric oncology patients in a resource-limited hospital. METHODS: A retrospective case-control study comparing the highest documented and corrected PEWS score before unplanned PICU transfer in pediatric oncology patients (129 cases) with matched controls (those not requiring PICU care) was performed. RESULTS: Documented and corrected PEWS scores were found to be highly correlated with the need for PICU transfer (area under the receiver operating characteristic, 0.940 and 0.930, respectively). PEWS scores increased 24 hours prior to unplanned transfer (P = .0006). In cases, organ dysfunction at the time of PICU admission correlated with maximum PEWS score (correlation coefficient, 0.26; P = .003), patients with PEWS results >=4 had a higher Pediatric Index of Mortality 2 (PIM2) (P = .028), and PEWS results were higher in patients with septic shock (P = .01). The PICU mortality rate was 17.1%; nonsurvivors had higher mean PEWS scores before PICU transfer (P = .0009). A single-point increase in the PEWS score increased the odds of mechanical ventilation or vasopressors within the first 24 hours and during PICU admission (odds ratio 1.3-1.4). CONCLUSIONS: PEWS accurately predicted the need for unplanned PICU transfer in pediatric oncology patients in this resource-limited setting, with abnormal results beginning 24 hours before PICU admission and higher scores predicting the severity of illness at the time of PICU admission, need for PICU interventions, and mortality. These results demonstrate that PEWS aid in the identification of clinical deterioration in this high-risk population, regardless of a hospital's resource-level. Cancer 2017;123:4903-13. (c) 2017 American Cancer Society. PMID- 28881452 TI - Hypertensive Disorders in Pregnancy and Future Maternal Cardiovascular Disease: The Challenges of Looking Beyond First Pregnancy. PMID- 28881453 TI - The content of nurse unit managers' work: a descriptive study using daily activity diaries. AB - BACKGROUND: NUMs' job description in Icelandic hospitals has been revised and now also includes managerial and financial responsibilities. AIM: To describe the actual work activities of nurse unit managers (NUMs) in surgical and internal medicine services as self-documented and reflected in their job description. DESIGN: Prospective exploratory study. METHOD: The study's setting was the largest hospital in Iceland. Data were collected over 7 days from NUMs working on surgical and medical units with an activity diary listing five domains and 41 activities: 'management and planning' (seven activities), 'staff responsibility (seven activities), 'direct clinical work' (five activities), 'service' (12 activities) and 'other' (nine activities). RESULTS: The managers' spent most of their time within the 'other' domain (32% of their time), then the next significant amount of time on 'management and planning' and 'clinical nursing' (19%), and the least amount of time on 'service' (14%). All reported working on two or more activities simultaneously. NUMs made erroneous estimations approximately half of the time about the domain they spent most of their time in and their satisfaction with their work each day varied greatly. CONCLUSION: The work of NUMs is highly diverse, including undefined miscellaneous tasks and clinical work beyond their job description. PMID- 28881454 TI - Hypersensitivity to low intensity fearful faces in autism when fixation is constrained to the eyes. AB - Previous studies that showed decreased brain activation in people with autism spectrum disorder (ASD) viewing expressive faces did not control that participants looked in the eyes. This is problematic because ASD is characterized by abnormal attention to the eyes. Here, we collected fMRI data from 48 participants (27 ASD) viewing pictures of neutral faces and faces expressing anger, happiness, and fear at low and high intensity, with a fixation cross between the eyes. Group differences in whole brain activity were examined for expressive faces at high and low intensity versus neutral faces. Group differences in neural activity were also investigated in regions of interest within the social brain, including the amygdala and the ventromedial prefrontal cortex (vmPFC). In response to low intensity fearful faces, ASD participants showed increased activation in the social brain regions, and decreased functional coupling between the amygdala and the vmPFC. This oversensitivity to low intensity fear coupled with a lack of emotional regulation capacity could indicate an excitatory/inhibitory imbalance in their socio-affective processing system. This may result in social disengagement and avoidance of eye-contact to handle feelings of strong emotional reaction. Our results also demonstrate the importance of careful control of gaze when investigating emotional processing in ASD. Hum Brain Mapp 38:5943-5957, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28881455 TI - The impact of enhancing perceived self-efficacy in torture survivors. AB - BACKGROUND: Perceived self-efficacy (SE) is an important factor underlying psychological well-being. Refugees suffer many experiences that can compromise SE. This study tested the impact of enhancing perceived SE on coping with trauma reminders and distress tolerance in tortured refugees. METHODS: Torture survivors (N = 40) were administered a positive SE induction in which they retrieved mastery-related autobiographical memories, or a non-SE (NSE) induction, and then viewed trauma-related images. Participants rated their distress following presentation of each image. Participants then completed a frustration-inducing mirror-tracing task to index distress tolerance. RESULTS: Participants in the SE condition reported less distress and negative affect, and improved coping in relation to viewing the trauma-related images than those in the NSE condition. The SE induction also led to greater persistence with the mirror-tracing task than the NSE induction. CONCLUSIONS: These findings provide initial evidence that promoting SE in tortured refugees can assist with managing distress from trauma reminders, and promoting greater distress tolerance. Enhancing perceived SE in tortured refugees may increase their capacity to tolerate distress during therapy, and may be a useful means to improve treatment response. PMID- 28881457 TI - Ocular presentation of myasthenia gravis: A natural history cohort. AB - INTRODUCTION: There are limited data on the natural history of untreated myasthenia gravis (MG) with ocular presentation. METHODS: We analyzed 93 patients from symptom onset who presented to the Birmingham Midlands Eye Centre (BMEC) between January 2004 and July 2015. We used multiple stepwise logistic regression to identify predictive factors of generalization and Kaplan-Meier analysis on time to generalization. RESULTS: Forty-six percent of patients developed generalized symptoms during the study period. Median time to generalization was 7 months. Time to generalization was earlier in patients seropositive for acetylcholine receptor (AChR) antibody (median 5 months vs. 21 months, P < 0.0001) and bilateral ptosis at onset (P = 0.015). Multivariate analysis identified AChR seropositivity [hazard ratio (HR) 5.03; 95% confidence interval (CI) 1.48-17.14; P = 0.001] and disease onset < 50 years (HR 3.58; 95% CI 1.18 10.90; P = 0.035) as risk factors for generalization. DISCUSSION: As patients were steroid-naive before generalization, our cohort approximated the natural history of the condition. Muscle Nerve 57: 622-627, 2018. PMID- 28881456 TI - Improvement in sexual function after ovarian cancer: Effects of sexual therapy and rehabilitation after treatment for ovarian cancer. AB - BACKGROUND: Sexual dysfunction is a distressing long-term effect after gynecological cancer and affects the majority of survivors for years after the completion of therapy. Despite its prevalence, treatment-related sexual dysfunction is underrecognized and undertreated for survivors. Thus, the aim of this study was to develop and test a brief psychoeducational intervention for managing sexual dysfunction for women who have undergone treatment for ovarian cancer (OC). METHODS: Forty-six OC survivors with documented, treatment-related sexual dysfunction received a single half-day group intervention that included sexual health education and rehabilitation training, relaxation and cognitive behavioral therapy skills to address sexual symptoms, and a single tailored booster telephone call 4 weeks after the group. Assessment measures were completed at the baseline (baseline 1), after an 8-week no-treatment run-in period (baseline 2), and then again 2 and 6 months after the intervention. The Female Sexual Function Index (FSFI) was used to assess sexual functioning, and the Brief Symptom Inventory 18 (BSI-18) was used to capture psychological distress. RESULTS: Between baseline 1 and baseline 2, there were no significant changes in the study measures, and this indicated no natural improvement during the run-in period. In contrast, the total FSFI scores improved significantly from baseline 1 to the 2- (n = 45; P < .0005) and 6-month time points (n = 42; P < .05). The BSI-18 scores were also significantly improved at the 2- (P < .005) and 6-month time points (P < .01) in comparison with baseline 1. CONCLUSIONS: This brief behavioral intervention led to significant improvements in overall sexual functioning and psychological distress that were maintained at the 6-month follow up. The results demonstrate the feasibility of this brief, low-intensity behavioral intervention and support the development of a larger randomized controlled trial. Cancer 2018;124:176-82. (c) 2017 American Cancer Society. PMID- 28881458 TI - Functional Hyper-Crosslinkers. AB - Crosslinking is an essential architecture for polymers to improve mechanical and thermal properties and to form three-dimensional (3D) structures. Although conventional synthetic crosslinkers usually only serve as bridges between different polymeric chains, biological crosslinkers are multifunctional. Recently, crosslinkers with active functionality after polymerization are promising a new dimension of molecular design for generating smart materials as they may exhibit dramatic changes in structures and properties in response to external stimuli. This concept article introduces several different designs of hyper-crosslinkers (i.e., multifunctional crosslinkers that provide three or more sites for generating networks) and their applications in tailoring stimuli responsive and self-healing soft materials. Particularly, the polymeric materials that contain functional hyper-crosslinkers are exhibiting anti-intuitive redox or thermal-pH responses. The goal of this article is to illustrate the concept that functional hyper-crosslinkers not only improve the physical and chemical performance of the polymers, but more importantly, may introduce new architectures and functionalities for soft materials. PMID- 28881459 TI - Synthesis and Microbiological Evaluation of Novel Tetracyclic Fluoroquinolones. AB - Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression. PMID- 28881460 TI - Endogenous oxytocin is associated with the experience of compassion and recalled upbringing in Borderline Personality Disorder. AB - BACKGROUND/OBJECTIVE: The role of the neuropeptide oxytocin (OT) in Borderline Personality Disorder (BPD) is poorly understood. It is particularly unknown how early experiences with caregivers moderate the action of OT in BPD. Here, we examined the association of plasma OT levels in BPD patients with the experience of compassion and recalled parental behavior during childhood. METHODS: Fifty seven BPD patients and 43 healthy controls participated in the study. OT plasma levels were analyzed by radioimmunoassay. Subjects additionally completed questionnaires focusing on fears of compassion (FOC) and recalled upbringing ("Questionnaire of Recalled Parental Rearing Behavior/Fragebogen zum erinnerten elterlichen Erziehungsverhalten," FEE). RESULTS: BPD patients had significantly lower OT plasma levels than healthy controls and differed significantly on all FOC and FEE scales; BPD patients had higher FOC scores (indicating more aversion of being compassionate to themselves and others and receiving compassion from others). They also differed in recalled parenting. In the BPD group, scores of the FOC scale "fear of compassion from others" were significantly negatively correlated with OT levels. Moreover, recalled "emotional warmth" of their parents during childhood was positively correlated with OT plasma levels of BPD subjects. No such correlations were found in the control group. CONCLUSION: Our results corroborate findings from previous studies reporting lower OT levels in patients with BPD. Moreover, peripheral OT seems to be linked with the tolerance of compassionate feelings and early experiences with caregivers. This is consistent with other findings that OT is an important mediator of the experience of emotional warmth from others. PMID- 28881461 TI - Overdoses with Aripiprazole: Signs, Symptoms and Outcome in 239 Exposures Reported to the Danish Poison Information Centre. AB - The aim of this study was to characterize the clinical signs and symptoms of exposures to aripiprazole overdoses. We retrospectively identified all aripiprazole exposures reported to the Danish Poison Information Centre (DPIC) from June 2007 to May 2015. Information concerning demographics, ingested dose and symptoms was extracted from the DPIC database and medical records. Information on death and admission to hospital was obtained from Danish national registers. We analysed 239 cases, 86 concerning single-drug exposures to aripiprazole, and 153 cases where aripiprazole had been taken with at least one other substance (mixed-drug). The median ingested aripiprazole dose was 105 mg (IQR: 50-1680 mg) in the single-drug exposure group and 120 mg (IQR: 60-225 mg) in the mixed-drug exposure group. The most commonly reported symptom was light sedation, reported in 63% of the single-drug group and 50% of the mixed-drug exposure group. There were no malignant arrhythmias or ECG abnormalities after single-drug exposures. No deaths were recorded in relation to the intake. We found a long-term mortality rate of 13 deaths per 1000 person-years (95% CI: 7; 23 per 1000 person-years), which is significantly higher than in an age- and gender-matched background population. In conclusion, we found that aripiprazole overdoses had few and mild symptoms predominantly related to the sedative properties. We detected a benign cardiovascular safety profile and no new safety concerns. Our findings may support an increased threshold of 300 mg for hospital admission after a single-drug exposure with aripiprazole and symptoms not worse than light sedation. PMID- 28881462 TI - Impact of ixekizumab on facial psoriasis and related quality of life measures in moderate-to-severe psoriasis patients: 12-week results from two phase III trials. AB - BACKGROUND: Facial psoriasis was reported in 17-68% of patients with psoriasis and shown to have a negative impact on patients' personal and health-related quality of life (HRQoL). OBJECTIVES: To explore the association of facial psoriasis with patients' HRQoL and to assess the relationship between ixekizumab (IXE) and improvement in facial psoriasis and changes in HRQoL. METHODS: This work reports the combined results of two phase III multicentre, randomized, double-blind, placebo-controlled, active-comparator trials in patients with moderate-to-severe psoriasis. Patients received placebo, etanercept (ETN; 50 mg twice weekly) or IXE [80 mg every 4 weeks (Q4W) or every 2 weeks (Q2W)] for up to 12 weeks following an initial 160-mg dose. HRQoL parameters were analysed based on facial psoriasis status at baseline using analysis of covariance models. Improvement was assessed as percentage of patients with no facial psoriasis. RESULTS: The combined database included 1133 patients with facial psoriasis and 1437 without. Patients treated with IXE whose facial psoriasis cleared had improved Dermatology Life Quality Index 0.1 responses (P < 0.01) compared with patients with facial psoriasis at Week 12. At Week 12, clearance of facial psoriasis compared with the presence of facial psoriasis was independently associated with significantly better improvement in Psoriasis Skin Appearance Bothersomeness scores in the IXE Q2W treatment group (P < 0.01). At Week 12, facial clearance and overall Psoriasis Area Severity Index (PASI) improvement were observed in significant numbers of patients treated with IXE compared with ETN and placebo. Facial psoriasis clearance at Week 12 in patients treated with IXE or ETN was positively associated with PASI75 and PASI90 achievement. CONCLUSION: Facial psoriasis had a larger negative impact on HRQoL than no facial psoriasis. Facial psoriasis clearance was associated with improved HRQoL. Significantly more IXE-treated patients had rapid facial clearance vs. ETN and PBO, which led to better clinical outcomes. PMID- 28881464 TI - Immediate Postpartum Contraception: A Survey Needs Assessment of a National Sample of Midwives. AB - INTRODUCTION: Immediate postpartum long-acting, reversible contraception (LARC) providing intrauterine devices (IUDs) and contraceptive implants immediately following birth-is an effective strategy to prevent unintended pregnancies and improve birth spacing. We measured US certified nurse-midwives' (CNMs') and certified midwives' (CMs') knowledge, training needs, current practice, and perceived barriers to providing immediate postpartum LARC. METHODS: We invited currently practicing CNM and CM members of the American College of Nurse-Midwives to complete an online survey about their knowledge and experience with the use of LARC and analyzed eligible questionnaires using descriptive statistics. RESULTS: Of 4609 eligible midwives, 794 responded (17% response rate). Most were female (99.5%) and non-Hispanic white (92.1%), with 45.0% attending births in urban settings. Responses revealed multiple knowledge gaps related to IUD expulsion rates and appropriateness of immediate postpartum LARC in certain clinical scenarios. Only 10.1% of respondents reported feeling confident to insert an immediate postpartum IUD and 43.3% an implant. Many reported desiring additional training in immediate postpartum IUD (63.5%) and implant (22.8%) insertion; few reported access to such training (IUD, 19.9%; implant, 15.2%). Most respondents had never inserted an immediate postpartum IUD (90.7%) or implant (86.8%). The most commonly cited barriers to immediate postpartum LARC provision were that it is not standard practice (IUD, 40.9%; implant, 39.0%) or is not available (IUD, 27.8%; implant, 34.8%) at one's institution and feeling inadequately trained (IUD, 26.5%; implant, 10.7%). DISCUSSION: Nine in 10 midwife respondents have never inserted an IUD or implant immediately postpartum, but more than half indicated they would like the opportunity to provide these services. Our findings highlight opportunities to enhance the immediate postpartum LARC-related knowledge and skills of the midwife workforce. They also suggest that logistic and institutional barriers to immediate postpartum LARC access must be removed in order to make this evidence-based reproductive health service available to all women who desire it. PMID- 28881463 TI - A Family Based Study of Carbon Monoxide and Nitric Oxide Signalling Genes and Preeclampsia. AB - BACKGROUND: Preeclampsia is thought to originate during placentation, with incomplete remodelling and perfusion of the spiral arteries leading to reduced placental vascular capacity. Nitric oxide (NO) and carbon monoxide (CO) are powerful vasodilators that play a role in the placental vascular system. Although family clustering of preeclampsia has been observed, the existing genetic literature is limited by a failure to consider both mother and child. METHODS: We conducted a nested case-control study within the Norwegian Mother and Child Birth Cohort of 1545 case-pairs and 995 control-pairs from 2540 validated dyads (2011 complete pairs, 529 missing mother or child genotype). We selected 1518 single nucleotide polymorphisms (SNPs) with minor allele frequency >5% in NO and CO signalling pathways. We used log-linear Poisson regression models and likelihood ratio tests to assess maternal and child effects. RESULTS: One SNP met criteria for a false discovery rate Q-value <0.05. The child variant, rs12547243 in adenylate cyclase 8 (ADCY8), was associated with an increased risk (relative risk [RR] 1.42, 95% confidence interval [CI] 1.20, 1.69 for AG vs. GG, RR 2.14, 95% CI 1.47, 3.11 for AA vs. GG, Q = 0.03). The maternal variant, rs30593 in PDE1C was associated with a decreased risk for the subtype of preeclampsia accompanied by early delivery (RR 0.45, 95% CI 0.27, 0.75 for TC vs. CC; Q = 0.02). None of the associations were replicated after correction for multiple testing. CONCLUSIONS: This study uses a novel approach to disentangle maternal and child genotypic effects of NO and CO signalling genes on preeclampsia. PMID- 28881466 TI - A hot lunch for herbivores: physiological effects of elevated temperatures on mammalian feeding ecology. AB - Mammals maintain specific body temperatures (Tb ) across a broad range of ambient temperatures. The energy required for thermoregulation ultimately comes from the diet, and so what animals eat is inextricably linked to thermoregulation. Endothermic herbivores must balance energy requirements and expenditure with complicated thermoregulatory challenges from changing thermal, nutritional and toxicological environments. In this review we provide evidence that plant-based diets can influence thermoregulation beyond the control of herbivores, and that this can render them susceptible to heat stress. Notably, herbivorous diets often require specialised digestive systems, are imbalanced, and contain plant secondary metabolites (PSMs). PSMs in particular are able to interfere with the physiological processes responsible for thermoregulation, for example by uncoupling mitochondrial oxidative phosphorylation, binding to thermoreceptors, or because the pathways required to detoxify PSMs are thermogenic. It is likely, therefore, that increased ambient temperatures due to climate change may have greater and more-specific impacts on herbivores than on other mammals, and that managing internal and external heat loads under these conditions could drive changes in feeding ecology. PMID- 28881465 TI - WNK Signaling Inhibitors as Potential Antihypertensive Drugs. AB - Since the discovery of WNK mutations that cause an inherited form of hypertension in humans, there has been increasing interest in targeting WNK signaling as a novel strategy for modulating blood pressure. This notion is now supported by numerous mouse models with impaired WNK signaling that exhibit reduced blood pressure. Biochemical analyses of the various protein components that make up this signaling pathway have identified a number of plausible molecular targets that are amenable to targeting by small molecules. To date, a selection of small molecule WNK signaling inhibitors have been identified and have shown promise in suppressing the activity of WNK signaling in cells and in animals. In this Minireview, we briefly discuss the WNK signaling pathway and provide an overview of the various druggable targets within this cascade, as well as the different WNK signaling inhibitors discovered to date. PMID- 28881467 TI - Important factors affecting the choice of an oral anticoagulant may be missed in database studies. PMID- 28881469 TI - Biomimicry, Biofabrication, and Biohybrid Systems: The Emergence and Evolution of Biological Design. AB - The discipline of biological design has a relatively short history, but has undergone very rapid expansion and development over that time. This Progress Report outlines the evolution of this field from biomimicry to biofabrication to biohybrid systems' design, showcasing how each subfield incorporates bioinspired dynamic adaptation into engineered systems. Ethical implications of biological design are discussed, with an emphasis on establishing responsible practices for engineering non-natural or hypernatural functional behaviors in biohybrid systems. This report concludes with recommendations for implementing biological design into educational curricula, ensuring effective and responsible practices for the next generation of engineers and scientists. PMID- 28881468 TI - Parallel folding pathways of Fip35 WW domain explained by infrared spectra and their computer simulation. AB - We present a calculation of the amide I' infrared (IR) spectra of the folded, unfolded, and intermediate states of the WW domain Fip35, a model system for beta sheet folding. Using an all-atom molecular dynamics simulation in which multiple folding and unfolding events take place we identify six conformational states and then apply perturbed matrix method quantum-mechanical calculations to determine their amide I' IR spectra. Our analysis focuses on two states previously identified as Fip35 folding intermediates and suggests that a three-stranded core similar to the folded state core is the main source of the spectroscopic differences between the two intermediates. In particular, we propose a hypothesis for why folding via one of these intermediates was not experimentally observed by IR T-jump. PMID- 28881470 TI - Solvothermal Synthesis of Cs0.33 WO3 /LDHs Composite as a Novel Visible-Light Driven Photocatalyst. AB - A novel Cs0.33 WO3 /LDHs (CWLDH) composite was synthesized by simple two steps solvothermal method and first investigated as the photocatalyst for tetracycline (TC) and Congo red (CR) degradation under visible light irradiation. The CWLDH heterostructures catalysts were characterized by XRD, UV-Vis, SEM, XPS and BET. The composite CWLDH showed enhanced photocatalytic activity compared with pure Cs0.33 WO3 and NiAl-LDH under identical experimental conditions. The enhanced photocatalytic activity was mainly attributed to the higher visible light absorbing ability, efficient electron-hole separation and prolonged lifetimes of photogenerated charges. The photocatalyst presented a high photocatalytic activity (92%) at the optimum of CWLDH-3 and initial TC concentration of 40 mg L 1 . Besides, the degradation efficiency of TC is higher than 75% for reused CWLDH after four cycles, demonstrating that it could be used as a potential catalyst with good photocatalytic activity, stability and reusability. According to the experimental results, a possible photocatalytic mechanism of CWLDH was discussed. PMID- 28881472 TI - Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Domagrozumab (PF 06252616), an Antimyostatin Monoclonal Antibody, in Healthy Subjects. AB - Safety, tolerability, anabolic effects, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses of domagrozumab, an antimyostatin monoclonal antibody, were assessed following intravenous (IV) and subcutaneous (SC) administration in healthy subjects. A range of single ascending dose levels between 1 and 40 mg/kg IV and multiple doses (3 doses) of 10 mg/kg IV were tested (n = 8 per cohort). Additionally, a 3 mg/kg SC (n = 8) cohort also received domagrozumab. Magnetic resonance imaging and whole-body dual-energy x-ray absorptiometry imaging were conducted to investigate the anabolic effects of domagrozumab. Domagrozumab was well tolerated with no severe and 1 non-treatment related serious adverse event. The most commonly reported adverse events were headache (21 subjects) and fatigue, upper respiratory tract infections, and muscle spasms (10 subjects each). Domagrozumab demonstrated typical IgG1 pharmacokinetics, with slow SC absorption and slow clearance, low volume of distribution, and a long half-life. Target engagement was observed with an increase in extent of myostatin modulation, plateauing at the 20 mg/kg IV dose. Downstream pharmacology following myostatin binding by domagrozumab was only observed in the 10 mg/kg single IV cohort (increase in whole-body lean mass of 5.38% using dual-energy x-ray absorptiometry) and the 10 mg/kg repeat-dose cohort (muscle volume increase of 4.49% using magnetic resonance imaging). PMID- 28881471 TI - Strategic recruitment of an ethnically diverse cohort of overweight survivors of breast cancer with lymphedema. AB - BACKGROUND: Black women are more likely to experience adverse effects from cancer treatment such as lymphedema. Thus, black women may particularly benefit from research regarding interventions to improve lymphedema. Herein, the authors report the challenges and strategies related to the recruitment of minority survivors of breast cancer and to the recruitment of survivors of breast cancer with lymphedema into the Women In Steady Exercise Research (WISER) Survivor Clinical Trial. METHODS: Subjects for this community-based trial were recruited from the Philadelphia area through active (mailings) and passive (printed materials and Web site) recruitment strategies. In addition, education sessions coordinated through partner hospitals in communities with a predominantly minority population were conducted to increase awareness of lymphedema in survivors of breast cancer. Women who were interested in the study were screened for lymphedema via telephone questionnaire and invited to see a study-related certified lymphedema therapist to confirm the presence of lymphedema. RESULTS: Screening was conducted among 2295 women: 628 were eligible, 450 consented, and 351 were randomized. Minority women comprised 38% of the study population. Letters to women on state and hospital registries resulted in a 0.4% randomization rate; education sessions yielded a 10% randomization rate. The authors observed that approximately 23.6% of the study sample had no previous diagnosis of lymphedema. CONCLUSIONS: The WISER Survivor Clinical Trial faced multiple recruitment challenges and used unique strategies to successfully enroll minority survivors of breast cancer into a lifestyle intervention. Cancer 2018;124:95-104. (c) 2017 American Cancer Society. PMID- 28881473 TI - The classic signalling and trans-signalling of interleukin-6 are both injurious in podocyte under high glucose exposure. AB - Interleukin-6 (IL-6) is a multifunctional cytokine that employs IL-6 classic and trans-signalling pathways, and these two signal channels execute different or even opposite effects in certain diseases. As a cardinal event of diabetic kidney disease (DKD), whether the podocyte abnormalities are associated with IL-6 signalling, especially classic or trans-signalling respectively, remains unclear. In this study, we identified that the circulatory IL-6, soluble IL-6R (sIL-6R) and soluble glycoprotein 130 (sgp130) levels are elevated in patients with DKD. The expressions of membrane-bound IL-6R (mIL-6R), sIL-6R and gp130 are enhanced in kidney cortex of diabetic mice accompanying with activated STAT3 by tyrosine 705 residue phosphorylation, while not serine 727. Above data infer both classic signalling and trans-signalling of IL-6 are activated during DKD. In cultured podocyte, high glucose (HG) up-regulates the expression of mIL-6R and gp130, as well as STAT3 tyrosine 705 phosphorylation, in a time-dependent manner. Entirely blocking IL-6 signalling by gp130 shRNA, gp130 or IL-6 neutralizing antibodies attenuates HG-induced podocyte injury. Interestingly, either inhibiting IL-6 classic signalling by mIL-6R shRNA or suppressing its trans-signalling using sgp130 protein dramatically alleviates HG-induced podocyte injury, suggesting both IL-6 classic signalling and trans-signalling play a detrimental role in HG induced podocyte injury. Additionally, activation of IL-6 classic or trans signalling aggravates podocyte damage in vitro. In summary, our observations demonstrate that the activation of either IL-6 classic or trans-signalling advances podocyte harming under hyperglycaemia. Thus, suppressing IL-6 classic and trans-signalling simultaneously may be more beneficial in podocyte protection and presents a novel therapeutic target for DKD. PMID- 28881474 TI - Assessment of Instructions on Protection Against Food Contaminated with Radiocesium in Japan in 2011. AB - The Japan Ministry of Health, Labour and Welfare (MHLW) has published instructions for radiological protection against food after the Fukushima Daiichi nuclear power plant accident in 2011. Following the instructions, the export and consumption of food items identified as being contaminated were restricted for a certain period. We assessed the validity of the imposed restriction periods for two representative vegetables (spinach and cabbage) grown in Fukushima Prefecture from two perspectives: effectiveness for reducing dietary dose and economic efficiency. To assess effectiveness, we estimated the restriction period required to maintain consumers' dose below the guidance dose levels. To assess economic efficiency, we estimated the restriction period that maximizes the net benefit to taxpayers. All estimated restriction periods were shorter than the actual restriction periods imposed on spinach and cabbage from Fukushima in 2011, which indicates that the food restriction effectively maintained consumers' dietary dose below the guidance dose level, but in an economically inefficient manner. We also evaluated the response of the restriction period to the sample size for each weekly food safety test and the instructions for when to remove the restriction. Stringent MHLW instructions seemed to sufficiently reduce consumers' health risk even when the sample size for the weekly food safety test was small, but tended to increase the economic cost to taxpayers. PMID- 28881475 TI - The Cancer of the Bladder Risk Assessment (COBRA) score: Estimating mortality after radical cystectomy. AB - BACKGROUND: Risk stratification of patients with urothelial carcinoma of the bladder (UCB) after cystectomy has important clinical and research implications. The authors assessed the relative effect of tumor stage and lymph node status on cancer-specific survival (CSS) after cystectomy and developed a simplified risk assessment tool. METHODS: In total, 14,828 patients who underwent cystectomy with lymph node dissection for UCB were identified from the Surveillance, Epidemiology, and End Results database (1988-2011). The relative importance of tumor stage and lymph node status with regard to CSS was assessed using stratified Kaplan-Meier and Cox proportional-hazards analyses. The patients were split randomly into development and validation cohorts. Additional validation using overall survival was performed on 19,362 patients from the National Cancer Data Base. The Cancer of Bladder Risk Assessment (COBRA) tool was created using a Cox model incorporating age, tumor stage, and lymph node density. Performance was validated using observed versus expected survival plots and the Harrell concordance index. RESULTS: Patients with muscle invasive (T2), lymph node positive disease had a survival curve similar to that in patients with extravesical (T3 and T4), lymph node-negative disease (2-year CSS, 67% and 70%, respectively). Each point increase in the COBRA score (range, 0-7) was associated with a 1.61-fold increase (95% confidence interval, 1.56-fold to 1.65-fold increase) in the risk of bladder cancer death in the development cohort. The model accurately stratified patients across risk levels in the development cohort and the 2 validation cohorts (C-index, 0.712, 0.705, and 0.68, respectively). CONCLUSIONS: The COBRA score offers a straightforward, validated risk stratification tool that incorporates the relative contribution of tumor stage and lymph node involvement to patient prognosis after cystectomy for UCB. Cancer 2017;123:4574-4582. (c) 2017 American Cancer Society. PMID- 28881476 TI - Supporting patients in reducing postoperative constipation: fundamental nursing care - a quasi-experimental study. AB - BACKGROUND: The prevalence of constipation in the general population is 2-28%. Patients with constipation report symptoms of abdominal pain, bloating, nausea, straining to defecate and general discomfort. Strategies for preventing constipation include laxatives, exercise and increased fluid and fibre intake, but life style adjustments, such as exercise, eating more fibres and drinking more fluids, were not considered a solution by older patients. Previous studies have shown that actively involving patients through individualised care and support increases patients' outcome. AIM: To test the efficacy of a nursing intervention based on active patient involvement including individualised nursing care plans and daily dialogues for patients with hip fractures in preventing constipation after surgery. METHODS: A quasi-experimental design was applied. Inclusion criteria hip fracture needing surgery, understand Danish. Exclusion criteria dementia, gastrointestinal disease. A total of 186 patients were included and 155 completed. An admission interview including Constipation Risk Assessment Scale was undertaken. On that basis an individualised nursing care plan was made. At admission, discharge and 30 days after surgery constipation, intake of fibres and fluid were measured. The Bristol Stool Scale and Rasmussen's scale were used to measure constipation. Patients in the control group received standard care of the ward. RESULTS: After 30 days constipation rates for patients in the intervention group were significantly lower than for patients in the control group (p = 0.042). The fibre intakes and fluid intakes were significantly higher in the intervention group (p <= 0.001). The effect of liquid intake was statistically significant (OR = 1.1, 95% CI: 1.0-1.2). Likewise, the effect of fibre intake was statistically significant; the odds of constipation decreased with increasing fibre intake (OR = 0.4, 95% CI: 0.2-0.8). CONCLUSION: Patients with hip fractures that were actively involved in their own care in preventing constipation were significantly less constipated 30 days after surgery than control patients. Increases in fluid and fibre intakes had significant effects on reducing the risk of developing constipation. PMID- 28881477 TI - Multimodal quantitative examination of nerve function in colorectal cancer patients prior to chemotherapy. AB - INTRODUCTION: Given recent findings of subclinical sensory deficits in colorectal cancer patients before oxaliplatin treatment, in the current study we aimed to identify evidence of subclinical peripheral neuropathy on multimodal testing before chemotherapy commencement. METHODS: Clinical, functional, and neurophysiological assessments were undertaken in 93 colorectal cancer patients before chemotherapy. RESULTS: There was no neurophysiological evidence of neuropathy, with 92 of 93 sural sensory values within normative reference values for age and no significant abnormalities detected in nerve conduction or nerve excitability studies. Clinical neurological assessment revealed 75.9% of patients with no signs or symptoms, 10.3% with reduction in distal vibration or pinprick sensitivity, and 6.9% with reduction in ankle reflexes only. There was no difference in manual dexterity (using the 9-hole peg-board test) compared with normative data. DISCUSSION: The present study has established a low likelihood of significant distal symmetrical polyneuropathy in colorectal cancer patients before initiation of chemotherapy. Muscle Nerve 57: 615-621, 2018. PMID- 28881479 TI - Response to the American College of Physicians Osteoporosis Guideline, 2017 Update. PMID- 28881478 TI - Properties of BioRoot RCS, a tricalcium silicate endodontic sealer modified with povidone and polycarboxylate. AB - AIM: To evaluate the chemical and physical properties of a tricalcium silicate root canal sealer containing povidone and polycarboxylate (BioRoot RCS), a calcium silicate MTA-based sealer containing a salicylate resin (MTA Fillapex), a traditional eugenol-containing sealer (Pulp Canal Sealer) and an epoxy resin based root canal sealer (AH Plus). METHODOLOGY: Calcium release, pH, setting time, water sorption, volume of open pores, volume of impervious portion, apparent porosity and weight loss were measured. The ability to nucleate calcium phosphates (CaP) after ageing 28 days in a simulated body fluid was evaluated using ESEM-EDX and micro-Raman spectroscopy. Data were statistically analysed (P = 0.05) using one-way anova (setting time, radiopacity, solubility, water sorption, porosity) or two-way anova (ion release tests). RESULTS: BioRoot RCS had a final setting time of 300 min and adequate radiopacity (5.2 mm Al). It demonstrated the highest (P < 0.05) and more prolonged ability to release calcium ions (721 ppm at 3 h) and to increase the pH (11-12) (P < 0.05); B-type carbonated apatite deposits were found on aged BioRoot RCS (biointeractivity related CaP-forming ability). A final setting time of 270 min and good calcium release (17.4 ppm at 3 h) were measured for MTA Fillapex; apatite deposits were present on aged samples. No calcium release and no alkalizing activity were measured for Pulp Canal Sealer and AH Plus; no CaP nucleation was detected on aged Pulp Canal Sealer, and some apatite deposits were found on aged AH Plus (chemi/physisorption-related CaP-deposition). Higher and significantly different (P < 0.05) porosity, water sorption and solubility were measured for the two calcium silicate sealers, especially for BioRoot RCS. CONCLUSIONS: BioRoot RCS had bioactivity with calcium release, strong alkalizing activity and apatite forming ability, and adequate radiopacity. PMID- 28881480 TI - Hypomineralized second primary molars: prevalence, defect characteristics and relationship with dental caries in Melbourne preschool children. AB - BACKGROUND: Dental caries and enamel defects (DDE) are prevalent amongst children. The presence of DDE, especially enamel hypomineralization, may increase caries experience. The reported prevalence of hypomineralized second primary molars (HSPM) is 2.7-21.8%, although the occurrence in Australian children remains unknown. These HSPM represent a potential predictive factor for molar incisor hypomineralization (MIH). METHODS: In total, 623 children aged 3-5 years from 30 randomly selected kindergartens participated. The HSPM were recorded using an index combining the European Academy of Paediatric Dentistry MIH Judgment Criteria and modified DDE Index. Caries was recorded using International Caries Detection and Assessment System criteria. RESULTS: In total, 144 HSPM were observed in 88 of the 623 (14.1%) children, a tooth-level prevalence of 5.8%. The prevalence of dentinal carious lesions was 13.2%, and caries prevalence (d2-6 mft > 0) was 36.4%. Cavitated carious lesions affected 30.7% of HSPM. CONCLUSIONS: The relationship between an increase in HSPM lesion extent and increasing number of HSPM per child was statistically significant. A positive association between HSPM severity and extent at tooth level existed (P < 0.05). There was a positive relationship between the extent of HSPM and carious lesion severity (P < 0.05). In this population, children with HSPM did not have overall greater caries experience. PMID- 28881481 TI - Oxaliplatin induces muscle loss and muscle-specific molecular changes in Mice. AB - INTRODUCTION: Muscle wasting is a frequent, debilitating complication of cancer. The impact of colorectal cancer chemotherapeutic oxaliplatin on the development of muscle loss and associated molecular changes is of clinical importance. METHODS: C57BL/6J male mice were treated with oxaliplatin. Total body weights were measured and behavioral studies performed. Hindlimb muscle weights (gastrocnemius and soleus) were recorded in conjunction with gene and protein expression analysis. RESULTS: Oxaliplatin-treated mice displayed reduced weight gain and behavioral deficits. Mice treated over a shorter course had significantly increased STAT3 phosphorylation in gastrocnemius muscles. Mice receiving extended oxaliplatin treatment demonstrated reduced hindlimb muscle mass with upregulation of myopathy-associated genes Foxo3, MAFbx, and Bnip3. DISCUSSION: The findings suggest that oxaliplatin treatment can directly disrupt skeletal muscle homeostasis and promote muscle loss, which may be clinically relevant in the context of targeting fatigue and weakness in cancer patients. Muscle Nerve 57: 650-658, 2018. PMID- 28881483 TI - Meta-analysis: Risk of hyperhidrosis with second-generation antidepressants. AB - BACKGROUND: Our goal was to quantify the risk of hyperhidrosis associated with commonly used antidepressant agents and examine the impact of medication class, pharmacodynamics, and dose on risk of hyperhidrosis. METHODS: We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of second-generation antidepressant medications in the treatment of adults with a depressive disorder, anxiety disorders, or obsessive compulsive disorder. We used a random-effects meta-analysis to examine the pooled risk ratio of hyperhidrosis reported as a side effect in adults treated with second-generation antidepressants compared to placebo. We used stratified subgroup analysis and metaregression to examine the effects of medication type, class, dosage, indication, and receptor affinity profile on the measured risk of hyperhidrosis. RESULTS: We identified 76 trials involving 28,544 subjects. There was no significant difference in the risk of hyperhidrosis between serotonin norepinephrine reuptake inhibitors (SNRI) [risk ratio (RR) = 3.17, 95% CI: 2.63 3.82] and selective serotonin reuptake inhibitors (SSRI) (RR = 2.93, 95% CI: 2.46 3.47) medications compared to placebo. All antidepressant medications were associated with a significantly increased risk of hyperhidrosis except fluvoxamine (RR = 0.56, 95% CI: 0.12-2.53), bupropion (RR = 1.23, 95% CI: 0.57 2.67), and vortioxetine (RR = 1.35, 95% CI: 0.79-2.33). The dose of SSRI/SNRI medications was not significantly associated with the risk of hyperhidrosis. Increased risk of hyperhidrosis was associated with increased affinity of SSRI/SNRI medications to the dopamine transporter. CONCLUSION: Risk of hyperhidrosis was significantly increased with most antidepressant medications but was associated with dopamine transporter affinity. PMID- 28881482 TI - Altered expression of antigen-specific memory and regulatory T-cell subsets differentiate latent and active tuberculosis. AB - Although one-third of the world population is infected with Mycobacterium tuberculosis, only 5-10% of the infected individuals will develop active tuberculosis (TB) disease and the rest will remain infected with no symptoms, known as latent TB infection (LTBI). Identifying biomarkers that differentiate latent and active TB disease enables effective TB control, as early detection, treatment of active TB and preventive treatment of individuals with LTBI are crucial steps involved in TB control. Here, we have evaluated the frequency of antigen-specific memory and regulatory T (Treg) cells in 15 healthy household contacts (HHC) and 15 pulmonary TB patients (PTB) to identify biomarkers for differential diagnosis of LTBI and active TB. Among all the antigens tested in the present study, early secretory antigenic target-6 (ESAT-6) -specific CD4+ and CD8+ central memory (Tcm) cells showed 93% positivity in HHC and 20% positivity in PTB. The novel test antigens Rv0753c and Rv0009 both displayed 80% and 20% positivity in HHC and PTB, respectively. In contrast to Tcm cells, effector memory T (Tem) cells showed a higher response in PTB than HHC; both ESAT-6 and Rv0009 showed similar positivity of 80% in PTB and 33% in HHC. PTB patients have a higher proportion of circulating antigen-reactive Treg cells (CD4+ CD25+ FoxP3+ ) than LTBI. Rv2204c-specific Treg cells showed maximum positivity of 73% in PTB and 20% in HHC. Collectively, our data conclude that ESAT-6-specific Tcm cells and Rv2204c-specific Treg cells might be useful biomarkers to discriminate LTBI from active TB. PMID- 28881484 TI - Primary cells in BCR/FGFR1-positive 8p11 myeloproliferative syndrome are sensitive to dovitinib, ponatinib, and dasatinib. AB - OBJECTIVES: Translocations involving the fibroblast growth factor receptor 1 (FGFR1) gene are associated with the 8p11 myeloproliferative syndrome (EMS), a rare neoplasm that following a usually short chronic phase progresses into acute myeloid or lymphoid leukemia. The treatment commonly involves chemotherapy and, if possible, allogeneic stem cell transplantation which is the only therapeutic option for long-term survival. Given the aggressive course of EMS, we here evaluated tyrosine kinase inhibitors as treatment options to delay disease progression. METHODS: We described a new case of EMS and used chromosome analyses, PCR, and sequencing to investigate the underlying genetic aberrations. The sensitivity to several tyrosine kinase inhibitors was tested in vitro on the EMS cell line KG1 and on primary cells from the newly diagnosed EMS patient. RESULTS: A translocation involving chromosomes 8 and 22 was detected, and a BCR/FGFR1 fusion gene was confirmed and characterized by sequencing. KG1 cells and primary EMS cells displayed distinct sensitivity to dovitinib, ponatinib, and dasatinib as compared to normal bone marrow control cells. CONCLUSIONS: These results suggest that treatment with tyrosine kinase inhibitors may be beneficial for patients with EMS during the search for a suitable stem cell donor and for those not eligible for transplantation. PMID- 28881485 TI - Indices of anti-dengue immunoglobulin G subclasses in adult Mexican patients with febrile and hemorrhagic dengue in the acute phase. AB - Heterologous secondary infections are at increased risk of developing dengue hemorrhagic fever (DHF) because of antibody-dependent enhancement (ADE). IgG subclasses can fix and activate complement and bind to Fcgamma receptors. These factors may also play an important role in the development of ADE and thus in the pathogenesis of DHF. The aim of this study was to analyze the indices of anti dengue IgG subclasses in adult patients with febrile and hemorrhagic dengue in the acute phase. In 2013, 129 patients with dengue fever (DF) and 57 with DHF in Veracruz, Mexico were recruited for this study and anti-dengue IgM and IgG determined by capture ELISA. Anti-dengue IgG subclasses were detected by indirect ELISA. Anti-dengue IgG2 and IgG3 subclasses were detected in patients with dengue. IgG1 increased significantly in the sera of patients with both primary and secondary infections and DHF, but was higher in patients with secondary infections. The IgG4 subclass index was significantly higher in the sera of patients with DHF than in that of those with DF, who were in the early and late acute phase of both primary and secondary infection. In conclusion, indices of subclasses IgG1 and IgG4 were higher in patients with DHF. PMID- 28881486 TI - How USP18 deals with ISG15-modified proteins: structural basis for the specificity of the protease. AB - The ubiquitin-specific protease 18 (USP18) has two major functions: (a) it is a highly specific protease that cleaves the ubiquitin-like modifier ISG15 (interferon-stimulated gene 15) from proteins, and (b) independent from its enzymatic activity USP18 interacts with the type I interferon receptor and shuts off downstream signaling. The structures of USP18 and a USP18-ISG15 complex revealed the molecular basis of the unique specificity of the protease and might shed some light into its interaction with the interferon receptor. PMID- 28881487 TI - Improving properties of silk sericin membranes via enzymatic oxidation with laccase and TEMPO. AB - Silk sericin has excellent features of antioxidant ability and good cytocompatibility; however, high water solubility and poor mechanical properties have restricted its application in biomedical fields. In this study, aimed at improving the mechanical properties of a regenerated silk sericin, the primary hydroxy groups in silk sericin were enzymatically oxidized by using laccase and 2,2',6,6'-tetramethylpiperidine-N-oxyl (TEMPO), and the generated reactive groups then reacted further with the amino groups in the sericin chains. The efficacy of the enzymatic cross-linking was evaluated by means of determination of amino groups, SDS polyacrylamide gel electrophoresis, Fourier transform infrared (FTIR) spectroscopy, and size exclusion chromatography. The results indicated that either laccase/TEMPO incubation or laccase treatment alone incurred a noticeable increase in the molecular weight of the sericin. FTIR analysis revealed that there was small change in the structure of the silk sericin after laccase/TEMPO treatment, and the obtained air-dried sericin membrane exhibited remarkably improved mechanical properties relative to those of the uncross-linked sericin membrane. In addition, the biocompatibility of the sericin membrane was at an acceptable level according to the cell viability of NIH/3T3 cells. The present work provides a novel method for the preparation of sericin-based biomaterials. PMID- 28881488 TI - Case series of pleomorphic carcinomas of the lung treated with nivolumab. AB - Pleomorphic carcinoma (PC) of the lung is a rare type of non-small cell lung cancer, exhibiting aggressive behavior and resistance to chemotherapy and radiotherapy. A previous study reported that PCs expressed high levels of PD-L1, suggesting the potential efficacy of immune checkpoint inhibitors in these tumors. We retrospectively reviewed the clinical records of three patients with PC of the lung treated with nivolumab: a 59-year-old woman (Case 1), a 66-year old man (Case 2), and an 83-year-old man (Case 3). PD-L1 was highly expressed in their tumor cells. Two cases showed a partial response with long progression-free survival. However, in Case 2, brain and bone metastases progressed during nivolumab treatment in spite of high PD-L1 expression. This case series indicates that nivolumab is effective to some extent for PC of the lung. However, the clinical course of patients treated with nivolumab should be carefully observed, even when PD-L1 is highly expressed. PMID- 28881489 TI - Behavioral Modeling of Adversaries with Multiple Objectives in Counterterrorism. AB - Attacker/defender models have primarily assumed that each decisionmaker optimizes the cost of the damage inflicted and its economic repercussions from their own perspective. Two streams of recent research have sought to extend such models. One stream suggests that it is more realistic to consider attackers with multiple objectives, but this research has not included the adaption of the terrorist with multiple objectives to defender actions. The other stream builds off experimental studies that show that decisionmakers deviate from optimal rational behavior. In this article, we extend attacker/defender models to incorporate multiple objectives that a terrorist might consider in planning an attack. This includes the tradeoffs that a terrorist might consider and their adaption to defender actions. However, we must also consider experimental evidence of deviations from the rationality assumed in the commonly used expected utility model in determining such adaption. Thus, we model the attacker's behavior using multiattribute prospect theory to account for the attacker's multiple objectives and deviations from rationality. We evaluate our approach by considering an attacker with multiple objectives who wishes to smuggle radioactive material into the United States and a defender who has the option to implement a screening process to hinder the attacker. We discuss the problems with implementing such an approach, but argue that research in this area must continue to avoid misrepresenting terrorist behavior in determining optimal defensive actions. PMID- 28881490 TI - Diabetic retinopathy screening using deep neural network. AB - IMPORTANCE: There is a burgeoning interest in the use of deep neural network in diabetic retinal screening. BACKGROUND: To determine whether a deep neural network could satisfactorily detect diabetic retinopathy that requires referral to an ophthalmologist from a local diabetic retinal screening programme and an international database. DESIGN: Retrospective audit. PARTICIPANTS: Diabetic retinal photos from Otago database photographed during October 2016 (485 photos), and 1200 photos from Messidor international database. METHODS: Receiver operating characteristic curve to illustrate the ability of a deep neural network to identify referable diabetic retinopathy (moderate or worse diabetic retinopathy or exudates within one disc diameter of the fovea). MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve, sensitivity and specificity. RESULTS: For detecting referable diabetic retinopathy, the deep neural network had an area under receiver operating characteristic curve of 0.901 (95% confidence interval 0.807-0.995), with 84.6% sensitivity and 79.7% specificity for Otago and 0.980 (95% confidence interval 0.973-0.986), with 96.0% sensitivity and 90.0% specificity for Messidor. CONCLUSIONS AND RELEVANCE: This study has shown that a deep neural network can detect referable diabetic retinopathy with sensitivities and specificities close to or better than 80% from both an international and a domestic (New Zealand) database. We believe that deep neural networks can be integrated into community screening once they can successfully detect both diabetic retinopathy and diabetic macular oedema. PMID- 28881491 TI - In Vivo X-ray Imaging of Transport of Renal Clearable Gold Nanoparticles in the Kidneys. AB - With more and more engineered nanoparticles (NPs) being designed renal clearable for clinical translation, fundamental understanding of their transport in the different compartments of kidneys becomes increasingly important. Here, we report noninvasive X-ray imaging of renal clearable gold NPs (AuNPs) in normal and nephropathic kidneys. By quantifying the transport kinetics of the AuNPs in cortex, medulla and pelvis of the normal and injured kidneys, we found that ureteral obstruction not just blocked the NP elimination through the ureter but also slowed down their transport from the medulla to pelvis and enhanced the cellular uptake. Moreover, the transport kinetics of the NPs and renal anatomic details can be precisely correlated with local pathological lesion. These findings not only advance our understandings of the nano-bio interactions in kidneys but also offer a new pathway to noninvasively image kidney dysfunction and local injuries at the anatomical level. PMID- 28881492 TI - Brief Report: A Novel ELANE Mutation Associated With Inflammatory Arthritis, Defective NETosis, and Recurrent Parvovirus Infection. AB - OBJECTIVE: We describe a 38-year-old woman who presented with a history of inflammatory arthritis, rash, and daily fevers. She was noted to have chronic parvovirus infection with persistently detectable viral titers and a novel mutation in the ELANE gene. ELANE encodes neutrophil elastase, a neutrophil serine protease with important antimicrobial effects, and is found as part of neutrophil extracellular trap (NET) complexes. Pathogenic ELANE mutations have been identified in forms of hereditary neutropenia. However, our patient never had neutropenia. Because of the striking clinical scenario, we investigated this mutation functionally. METHODS: NET formation by neutrophils was assessed by scanning electron microscopy. Neutrophil activation and neutrophil elastase production were evaluated by flow cytometry and fluorescent substrate-based functional assay, respectively. A multiplex assay was used to quantitate neutrophil inflammatory cytokine production. PyMOL software was used to generate 3-dimensional models of mutant elastase. RESULTS: Activated neutrophils from the patient demonstrated a significantly decreased ability to form NETs on scanning electron microscopy, as well as quantitative defects in neutrophil activation and neutrophil elastase activity. The patient's neutrophils showed altered levels of interleukin-12 (IL-12) and IL-8, which are key cytokines for antiviral immunity and neutrophil chemotaxis. Three-dimensional mapping revealed that the mutation could alter protein folding and surface charge distribution, potentially perturbing protein trafficking. Thus, the mutation could affect neutrophil function by decreasing NETosis and altering key antiviral activities of neutrophils. CONCLUSION: This is the first report of a human pathogenic ELANE mutation associated with a defect in NETosis and a distinct syndrome of recurrent viral infection and chronic inflammation. PMID- 28881493 TI - Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Multiple-Ascending-Dose Study. AB - This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUCtau,ss of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400 and 600 mg/day, whereas the Cmax,ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2 fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported >=1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study. PMID- 28881494 TI - Pituitary and skull-base lesions and the litigious patient. AB - BACKGROUND: The objective of this research was to evaluate litigation relating to the diagnosis and management of pituitary and ventral skull base lesions and delineate allegations involved in the decision to pursue medicolegal proceedings. METHODS: Publically available federal and court records were accessed via the Westlaw Next database. Jury verdict and settlement reports relevant to pituitary and anterior skull-base lesions were accessed, and litigation was reviewed for alleged injuries, defendant specialty, patient demographics, and other factors raised in proceedings. RESULTS: Of 75 cases included, 50.7% were resolved in the defendant's favor. The most frequent physician specialties cited as defendants included primary care (20%), neurosurgery (17%), and radiology (16%), while otolaryngologists were defendants in only 5% of cases. Fifty-two (69%) did not involve surgical intervention; the most common allegations in these proceedings were misdiagnosis, permanent injury (19%), requiring additional procedures as a result of misdiagnosis (17%), permanent endocrine dysfunction (14%), and visual sequelae (12%). Among surgical cases, the most common allegations raised included permanent injury (17%), postoperative complications (14%), intraoperative complications (13%), and death (10%). Among cases resolved with payment, there was no statistical difference in payment between surgical cases ($5.7M) and nonsurgical cases ($4.8M). CONCLUSION: Misdiagnosis of endocrinopathy, failure to appropriately workup patients presenting with neurologic complaints, and radiologic misdiagnosis play important roles in the pursuit of litigation in nonsurgical cases. Sustaining permanent sequelae including endocrine and visual injury play an important role in surgical cases. Postoperative management appears to play just as important a role in the decision to pursue litigation as intraoperative considerations. PMID- 28881495 TI - Anatase TiO2 as a Cheap and Sustainable Buffering Filler for Silicon Nanoparticles in Lithium-Ion Battery Anodes. AB - The design of effective supporting matrices to efficiently cycle Si nanoparticles is often difficult to achieve and requires complex preparation strategies. In this work, we present a simple synthesis of low-cost and environmentally benign aAnatase TiO2 nanoparticles as buffering filler for Si nanoparticles (Si@TiO2 ). The average anatase TiO2 crystallite size was approximately 5 nm. A complete structural, morphological, and electrochemical characterization was performed. Electrochemical test results show very good specific capacity values of up to 1000 mAh g-1 and cycling at several specific currents, ranging from 500 to 2000 mA g-1 , demonstrating a very good tolerance to high cycling rates. Postmortem morphological analysis shows very good electrode integrity after 100 cycles at 500 mA g-1 specific current. PMID- 28881496 TI - Xk-related protein 8 regulates myoblast differentiation and survival. AB - Xk-related protein 8 (Xkr8) is a scramblase and responsible for phosphatidylserine (PS) exposure on the cell surface in a caspase-dependent manner. Although PS exposure is found to be important for myotube formation during myoblast differentiation, the role of Xkr8 during myogenesis has not been elucidated. Here we show that Xkr8 contributes to myoblast differentiation. Xkr8 overexpression induced the formation of large myotubes during early differentiation, but this phenotype was not related to caspase-dependent cleavage of Xkr8. Furthermore, forced Xkr8 expression accelerated myoblast differentiation and conferred cell-death resistance after the induction of differentiation. Consistent with these results, Xkr8-knocked-down myoblasts exhibited impaired differentiation and more apoptotic cells during differentiation, implying the involvements of Xkr8 in the survival and proliferation of myoblasts. Taken together, the study shows Xkr8 influences myogenesis by acting as a positive regulator of terminal differentiation and myoblast survival. PMID- 28881497 TI - Therapies for advanced stage hepatocellular carcinoma with macrovascular invasion or metastatic disease: A systematic review and meta-analysis. AB - : Hepatocellular carcinoma (HCC) is a complex disease most commonly arising in the background of chronic liver disease. In the past two decades, there has been a significant increase in our understanding of both the clinical and molecular heterogeneity of HCC. There has been a robust increase in clinical trial activity in patients with poor prognostic factors, such as macrovascular invasion and extrahepatic spread (EHS). We aimed to synthesize the evidence for the treatment of patients with advanced HCC based on these baseline characteristics, including patients with both Child-Pugh (CP) scores of A and B. A comprehensive search of several databases from each database inception to February 15, 2016 any language was conducted. We included 14 studies (three randomized controlled studies [RCTs] and 11 observational studies). We included studies that compared sorafenib, transarterial bland embolization/transarterial chemoembolization, yttrium 90/radiation therapy, ablation (or combination), and no therapy. Two RCTs comparing sorafenib to best supportive care demonstrated a consistent improvement in overall survival (OS) for patients with advanced HCC and metastatic vascular invasion (MVI) and/or EHS and CP A liver disease (hazard ratio, 0.66 [95% confidence interval, 0.51-0.87]; I2 = 0%). Several observational studies evaluated locoregional therapies alone or in combination with other treatments and were limited by very-low-quality of evidence. This was true for both patients with EHS and MVI. CONCLUSION: In patients with advanced HCC and CP A liver function, sorafenib is the only treatment that has been shown to improve OS in randomized studies. High-quality data supporting the use of other treatment modalities in this setting, or in the setting of patients with less compensated (CP B) liver disease, are lacking. (Hepatology 2018;67:422-435). PMID- 28881499 TI - Immortal Time Bias: Comment on the Article by Gwinnutt et al. PMID- 28881498 TI - Local environment rather than past climate determines community composition of mountain stream macroinvertebrates across Europe. AB - Community assembly is determined by a combination of historical events and contemporary processes that are difficult to disentangle, but eco-evolutionary mechanisms may be uncovered by the joint analysis of species and genetic diversity across multiple sites. Mountain streams across Europe harbour highly diverse macroinvertebrate communities whose composition and turnover (replacement of taxa) among sites and regions remain poorly known. We studied whole-community biodiversity within and among six mountain regions along a latitudinal transect from Morocco to Scandinavia at three levels of taxonomic hierarchy: genus, species and haplotypes. Using DNA barcoding of four insect families (>3100 individuals, 118 species) across 62 streams, we found that measures of local and regional diversity and intraregional turnover generally declined slightly towards northern latitudes. However, at all hierarchical levels we found complete (haplotype) or high (species, genus) turnover among regions (and even among sites within regions), which counters the expectations of Pleistocene postglacial northward expansion from southern refugia. Species distributions were mostly correlated with environmental conditions, suggesting a strong role of lineage- or species-specific traits in determining local and latitudinal community composition, lineage diversification and phylogenetic community structure (e.g., loss of Coleoptera, but not Ephemeroptera, at northern sites). High intraspecific genetic structure within regions, even in northernmost sites, reflects species specific dispersal and demographic histories and indicates postglacial migration from geographically scattered refugia, rather than from only southern areas. Overall, patterns were not strongly concordant across hierarchical levels, but consistent with the overriding influence of environmental factors determining community composition at the species and genus levels. PMID- 28881500 TI - The Different Resistance of Two Astragalus Plants to UV-B Stress is Tightly Associated with the Organ-specific Isoflavone Metabolism. AB - In this work, the changes in isoflavone levels and the expression of genes involved in their biosynthesis were studied in two Astragalus by UPLC-MS and real time PCR after 10 days of UV-B treatment (lambdamax = 313 nm, 804 J m-2 ). Isoflavones were significantly induced by UV-B irradiation. The influence might be activated by the regulation of these target genes. Our results indicate that (1) the resistance of Astragalus membranaceus might not be as good as Astragalus mongholicus in the enhanced UV-B radiation environment; (2) the enhanced accumulation of calycosin and calycosin-7-glucoside with UV-B treatment in roots of A. mongholicus might be derived from formononetin which is synthesized in the leaves; (3) the glycosylation process could be stimulated and activated by the enhanced UV-B radiation in both A. mongholicus and A. membranaceus. In other words, glycosylation of isoflavones might play a crucial role for two Astragalus plants in response to UV-B stress. Overall, this study offered a feasible elicitation strategy to understand the accumulation pattern of isoflavone in A. mongholicus and A. membranaceus, and also provided a reference for the changes in isoflavone levels of Astragalus in UV-B enhanced environment in the future. PMID- 28881502 TI - Biochemical and aerosol characterization of ricin for use in non-clinical efficacy studies. AB - Ricin toxin may be used as a biological warfare agent and no medical countermeasures are currently available. Here, a well-characterized lot of ricin was aerosolized to determine the delivered dose for future pre-clinical efficacy studies. Mouse intraperitoneal (IP) median lethal dose (LD50 ) bioassay measured potency at 5.62 and 7.35 MUg/kg on Days 0 and 365, respectively. Additional analyses included total protein, sodium dodecyl sulfate polyacrylamide gel electrophoresis, Western blotting, and rabbit reticulocyte lysate activity assay. The nebulizer aerosol produced consistent concentrations (2.5 * 103 , 5.0 * 103 , 1.0 * 104 , and 1.5 * 104 MUg/mL) and spray factor values. The aerosol particle size distribution was of sufficient size to deposit in lung alveoli (1.12-1.43 MUm). Ricinus communis Agglutinin II (RCA 60), prepared at 19 mg/mL in phosphate buffered saline, pH 7.8, and stored at -70 degrees C, maintained attributes for toxicity following 1-year storage and aerosolized consistently. PMID- 28881501 TI - Drug-drug interaction potential in men treated with enzalutamide: Mind the gap. AB - AIMS: Metastatic castration-resistant prostate cancer (mCRPC) patients are generally older patients with several co-morbidities and are therefore at increased risk of complications due to drug-drug interactions (DDIs). We assessed the prevalence of potential DDIs in a cohort of mCRPC patients treated with enzalutamide. METHODS: We conducted a retrospective review of pharmacy records to retrieve individual drug histories of mCRPC patients who started enzalutamide therapy in a tertiary care setting. Potential DDIs were analysed using two international drug interaction compendia: Lexicomp(r) and Micromedex(r) , and the Dutch drug database. Two potential pharmacodynamic DDIs were analysed. RESULTS: A total of 105 records were evaluated for potential DDIs with enzalutamide. Of 205 different co-medications, 56 were flagged by at least one of the three compendia: Lexicomp, Micromedex and the Dutch drug database flagged for potential DDIs in 85%, 54% and 32%, respectively. Eighty-five per cent of DDIs were classified as major. The median number of co-medications per patient was 11 (range 1-26). The median (range) number of interactions per patient was 4 (0-10), 1 (0-5) and 0 (0 2) for Lexicomp, Micromedex and the Dutch drug database, respectively. In 23% and 45% of all patients, a potential DDI was found with PPIs and CNS depressants, respectively. CONCLUSIONS: A high prevalence of potential DDIs was found. The inclusion and grading of potential DDIs was highly variable between the three drug interaction compendia. Physicians, nurses and pharmacists should be aware of this potential problem, which might require intensive monitoring or alternative treatment strategies to prevent suboptimal treatment of the co-morbidities in patients treated with enzalutamide. PMID- 28881503 TI - Identification of CEA-interacting proteins in colon cancer cells and their changes in expression after irradiation. AB - PURPOSE: The serum carcinoembryonic antigen (CEA) level has been recognized as a prognostic factor in colorectal cancer, and associated with response of rectal cancer to radiotherapy. This study aimed to identify CEA-interacting proteins in colon cancer cells and observe post-irradiation changes in their expression. MATERIALS AND METHODS: CEA expression in colon cancer cells was examined by Western blot analysis. Using an anti-CEA antibody or IgG as a negative control, immunoprecipitation was performed in colon cancer cell lysates. CEA and IgG immunoprecipitates were used for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Proteins identified in the CEA immunoprecipitates but not in the IgG immunoprecipitates were selected as CEA-interacting proteins. After radiation treatment, changes in expression of CEA-interacting proteins were monitored by Western blot analysis. RESULTS: CEA expression was higher in SNU-81 cells compared with LoVo cells. The membrane localization of CEA limited the immunoprecipitation results and thus the number of CEA-interacting proteins identified. Only the Ras-related protein Rab-6B and lysozyme C were identified as CEA-interacting proteins in LoVo and SNU-81 cells, respectively. Lysozyme C was detected only in SNU-81, and CEA expression was differently regulated in two cell lines; it was down-regulated in LoVo but up-regulated in SNU-81 in radiation dosage-dependent manner. CONCLUSION: CEA-mediated radiation response appears to vary, depending on the characteristics of individual cancer cells. The lysozyme C and Rab subfamily proteins may play a role in the link between CEA and tumor response to radiation, although further studies are needed to clarify functional roles of the identified proteins. PMID- 28881504 TI - Low-dose radiation therapy for massive chylous leakage after subtotal gastrectomy. AB - Massive chylous leakage is a rare postoperative complication that can prolong hospital stay and cause secondary morbidities. Conservative management strategies are the treatment of choice; however, radiation therapy (RT) can be used as an alternative for cases that are refractory to conservative treatment. Herein, we report a 69-year-old female patient who suffered from massive chylous leakage after subtotal gastrectomy. Due to persistent massive chylous leakage, she was scheduled to undergo low-dose RT. Radiation was delivered with a daily dose of 1 Gy, using an anterior-posterior and posterior-anterior beam arrangement. The clinical target volume encompassed the entire lymph node area of the D2 dissection. RT was completed at the total dose of 8 Gy because the amount of chylous leakage declined rapidly. Percutaneous drainage tube was removed after 3 days of RT. The patient did not complain of any symptoms related to massive chylous leakage 2 years after the completion of RT. PMID- 28881505 TI - [Consideration on the revision of evidence based guidelines of childhood renal diseases]. PMID- 28881507 TI - [Evidence-based guideline for diagnosis and treatment of Henoch-Schonlein purpura nephritis (2016)]. PMID- 28881506 TI - [Evidence-based guidelines for diagnosis and treatment of primary IgA nephropathy (2016)]. PMID- 28881508 TI - [Interpretation of evidence-based guidelines for diagnosis and treatment of primary IgA nephropathy (2016)]. PMID- 28881509 TI - [Interpretation of evidence-based guideline for diagnosis and treatment of Henoch Schonlein prupura nephritis 2016]. PMID- 28881510 TI - [Clinical phenotypes of hepatocyte nuclear factor 1 homeobox b-associated disease]. AB - Objective: Hepatocyte nuclear factor 1 homeobox b (HNF1B) -associated disease is an autosomal dominant inherited disorder with a variable, multi-systemic phenotype. In China, five adult probands and one child proband with HNF1B associated disease had been reported, whereas few fetuses are described. The aims of this retrospective study were to understand about the clinical manifestations of HNF1B-associated disease and to further improve the recognition of this disorder. Method: Four patients (3 males, 1 female) and three fetuses with HNF1B mutations were included in this study. They were admitted to our hospital from January 2013 to March 2017. HNF1B mutations were detected using targeted next generation sequencing and quantitative real-time PCR or Sanger sequencing. HNF1B heterozygous deletion of exons 1-9 was found in 4 patients and 2 fetuses, and HNF1B heterozygous missense mutation in 1 fetus. These two mutations had been reported. Two patients and 1 fetus had de novo mutations. Results of renal ultrasonography with or without magnetic resonance imaging, biochemical investigations, urine routine examination and other necessary investigations in 7 cases were analyzed. Result: Three patients were Han Chinese ethnicity, and one patient was Mongolian. In patients 1 and 4, abnormal fetal kidneys were discovered by routine ultrasonography, and the age at first feature identified in Patients 2 and 3 were 13 years and 28 years. Patient 3 had normal renal function and the remainder had reduced glomerular filtration rate. In addition, patient 4 presented with nephrotic syndrome and glycosuria, patient 2 with early onset hyperparathyroidism and renal osteodystrophy, and patient 3 with diabetes mellitus. All the 4 patients had renal structural abnormalities including bilateral multiple renal cysts, dysplasia and hyperechogenic kidneys. Only patient 3 had a positive family history of renal diseases, the remainder had a negative family history of renal diseases. In 3 fetuses, prenatal ultrasound anomalies were detected during the second trimester. These 3 fetuses had hyperechogenic kidneys with or without renal cysts. Polyhydramnios was detected in only one of the 3 fetuses. Two of the 3 fetuses had a positive family history of renal diseases. Conclusion: Clinical phenotypes of HNF1B-related disease are heterogeneous, renal malformations clearly appear to be the most common manifestation, multiple renal cysts are characteristic, and patients can progress to impaired kidney function during childhood; HNF1B mutation is a differential diagnosis of fetal hyperechogenic kidneys or multiple renal cysts. PMID- 28881511 TI - [Role of IgG antibody to galactose-deficient IgA1 in children with IgA nephropathy]. AB - Objective: In order to learn the serum level of galactose-deficient IgA1 (GdIgA1), IgG antibody to galactose-deficient IgA1(GdIgA1-IgG) and the clinical role of them in IgA nephropathy(IgAN) children. Method: We compared blood levels of GdIgA1, GdIgA1-IgG in 33 children with IgAN, 38 children with other renal disease (including focal segmental glomerular nephritis, minimal change disease, Alport syndrome and thin basement membrane nephropathy) as disease controls, 35 healthy children as normal controls with enzyme-linked immunosorbent assay(ELISA). Twenty-four-hour urine protein content and Lee's pathological classification were collected in IgAN cases. The difference among the three groups were examined by analysis of variance. The specificity and sensitivity of GdIgA1, GdIgA1-IgG to IgA nephropathy were evaluated by ROC curve.The correlations were analyzed by correlation analysis among GdIgA1, GdIgA1-IgG and urine protein content and pathological classification . All statistical analyses were performed by SPSS 18.0. P value of <0.05 was considered statistically significant. Result: The levels of GdIgA1 and GdIgA1-IgG significantly elevated in children with IgAN compared to disease controls and normal controls. GdIgA1(mg/L): 1.728+/-0.456, 1.123+/-0.461, 1.410+/-0.905 (F=15.04, P<0.001); GdIgA1-IgG(g/L): 1.299+/-0.499, 1.111+/-0.549, 0.628+/-0.142 (F=76.96, P<0.001). Area under the curve of ROC of GdIgA1 between IgAN and normal controls was 0.765, with specificity 0.943 and sensitivity 0.697, while the area under the curve of GdIgA1-IgG was 0.969, with specificity 0.971 and sensitivity 0.939.The blood level of GdIgA1-IgG was mildly correlated with both 24-hour urine protein(r=0.364, ) and renal pathological grading(r=0.392) in children with IgAN. Conclusion: The levels of GdIgA1 and GdIgA1-IgG significantly elevated in children with IgAN compared to disease controls and normal controls. GdIgA1-IgG had higher sensitivity in distinguishing IgAN from normal controls, GdIgA1-IgG was mildly correlated with 24-hour urine protein volume and pathological grading in children with IgAN. PMID- 28881512 TI - [Multicenter investigation of the correlation between supraventricular tachycardia and tachycardia-induced cardiomyopathy in children]. AB - Objective: This study aimed to investigate the correlation between supraventricular tachycardia (SVT) and tachycardia-induced cardiomyopathy(TIC) in children and assess the risk factors for the development of TIC. Method: One hundred and eighty-three patients were recruited in four hospitals of Beijing diagnosed as SVT were divided into two groups depending on whether or not complicated with TIC. The age, gender, tachycardia type, ventricular rate during tachycardia, frequency of tachycardia episodes and duration of tachycardia were compared between the two groups and risk factors associated with TIC were analyzed. Statistical analyses were performed using t test, Mann-Whitney U and chi(2) test. Result: Totally 183 patients were included in this study (paroxysmal supraventricular tachycardia, PSVT, n=149; atrial tachycardia, AT, n=34). The incidence of TIC was 13.1%. There was significant difference regarding the incidence of TIC between children with AT and children with PSVT (26.5% vs. 10.1%, chi(2)=6.537, P=0.011). The percentage of AT in patients with TIC was significantly higher than patients without TIC (37.5% vs. 15.7%, chi(2)=6.537, P=0.011). Patients with TIC had a higher frequency of tachycardia episodes(2.5(1.0-4.8) beats/year vs 4.0(1.0-10.0) beats/year, Z=-2.223, P=0.026)and longer duration of tachycardia(11.0(1.1-36.0) h vs 2.5(1.0-12.0) h, Z=-2.154, P=0.031)compared with patients without TIC. Multivariate predictors of TIC was longer duration of tachycardia (OR=2.041, P=0.028). Conclusion: TIC occurs in 13.1% of children with SVT. The incidence of TIC in children with AT is higher than in children with PSVT. Risk factor for the development of TIC is longer duration of tachycardia. PMID- 28881513 TI - [Effect of docosahexenoic acid microalgae oil supplementation during pregnancy and lactation on levels of serum polyunsaturated fatty acid and tolerance to ovalbumin in suckling mice]. AB - Objective: To study the tolerance to ovalbumin (OVA) in suckling mice whose mothers had different doses of docosahexenoic acid (DHA) microalgae oil (DMO) supplementation during pregnancy and lactation. Method: According to different doses of DMO fed to mother mice during pregnancy and lactation, 66 suckling mice were divided into four groups. Suckling mice whose mothers were fed with 0.7% DMO were designated as low dose group (group L) (n=16), 2.1% DMO as middle dose group (group M) (n=16), 3.5% DMO as high dose group (group H) (n=17) and no DMO as control group (n=17). Before exposing to OVA, 8 suckling mice were killed in each group at 21-day-old. Remaining suckling mice were killed at 59-day-old after repeated OVA exposure. The serum polyunsaturated fatty acid (PUFA) levels of suckling mice were analyzed by high performance liquid chromatography (HPLC) at the age of 21- and 59-day.Histological examinations of jejunum were performed by HE staining and the mast cells in jejunum were observed by toluidine blue staining. OVA-IgE in serum, total IgA and OVA-IgA in the feces and IL-4 and IFN gamma in the supernatants of splenic mononuclear cells (SMC) were measured by ELISA. Real time PCR was performed to identify the gene expression of IL-10, TGF beta1 mRNA in SMC. Differences among groups were compared by one-way AVOVA and that between each group were compared by LSD. Result: In group M and H, the serum levels of n-3DHA (108+/-29)MUg/ml; (102+/-34)MUg/ml vs.(40+/-19)MUg/ml (F=12.052, P=0.000)and n-3 eicosapentaenoic acid (6.7+/-2.3)MUg/ml; (7.7+/-2.0)MUg/ml vs. (3.9+/-1.1)MUg/ml(F=9.573, P=0.000) were significantly higher than that in control group at the age of 21-day. The serum levels of n-3DHA were higher in group H (17.1+/-2.9)MUg/ml than that in control group (5.9+/-3.3) MUg/ml after repeated OVA exposure at the age of 59-day (F=10.339, P<0.000). Compared with control group (53+/-12) pg/ml, the levels of IL-4 in SMC in group H (42+/-9)pg/ml were lower (F=2.484, P<0.05). Conclusion: The serum levels of DHA in baby mice, whose mothers was fed with DMO during pregnancy and lactation, were significantly increased till adulthood. However, the effect on tolerance to OVA was limited. PMID- 28881514 TI - [Phenotypic and genotypic features of twenty children with classic pantothenate kinase-associated neurodegeneration]. AB - Objective: To explore the phenotypic and genotypic characteristics in Chinese children with classic pantothenate kinase-associated neurodegeneration (PKAN). Method: The clinical, radiographic and genetic data of all PKAN patients diagnosed at pediatric department of Peking University First Hospital from November 2006 to December 2016 were retrospectively collected and analyzed. Result: Twenty patients with classic PKAN were included in the study. The median age at onset was 3.5 years (ranging from 1.0 to 10.0 years), and the most common initial symptom was gait disturbance (16 cases). At the last evaluation, the clinical features were limbs dystonia (20 cases), dysarthria (16 cases), dysphagia (11 cases), pyramidal sign (7 cases), mental regression (3 cases) and pigmentary retinopathy (5 cases). For those classic PKAN patients, the median time from onset of disease to loss of independent ambulation was 6.9 years (ranging from 2.0 to 12.0 years). Imaging data showed, except "eye of tiger" in MRI (19 cases), globus pallidus calcification in CT was also found in four patients. In gene testing, 26 different mutations in PANK2 gene were identified, and 16 of 26 were novel mutations. Moreover, c. 1502T>C (p.Ile501Asn) was the most common mutation (4 cases). Conclusion: Dystonia is the major neurologic feature of classic PKAN. Disease progression is rapid, with loss of independent ambulation within 10 years after onset. Except "eye of tiger" in MRI, globus pallidus calcification in CT may be another imaging feature of PKAN.Sixteen novel mutations of PANK2 gene were identified in the study. PMID- 28881515 TI - [Characteristics of epidemiology and antimicrobial resistance of gram-negative bacterial bloodstream infections in children]. AB - Objective: To study the epidemiology and antimicrobial resistance of Gram negative bacterial bloodstream infections in children, and to guide the choice of antimicrobials and the control of nosocomial infection. Method: Clinical data, bacteriology and antimicrobial susceptibility test results were collected retrospectively in hospitalized children who were diagnosed with gram-negative bacterial bloodstream infections in Yuying Children's Hospital of Wenzhou Medical University from January, 2010 to December, 2015. Result: A total of 399 cases (253 male and 146 female) were identified. The age ranged from 16 hours to 16 years (median age 10.1 months). The majority of cases were collected from division of neonatology (n=261, 65.4%), followed by 31 cases (7.8%) from pediatric intensive care unit and 29 cases (7.3%) from Gastroenterology Department; 275 cases (68.9%) had underlying diseases, mainly including preterm birth(n=172), neonatal respiratory distress syndrome(n=67) and newborn asphyxia(n=53). Eighty cases had received invasive procedures and 20 had surgical operation; 149 cases (37.3%) were community-acquired and 250 cases (62.7%) were hospital acquired. Fifty cases had complications, among those, 40 cases had septic shock, 32 cases had multiple organ dysfunction syndrome and 7 cases had disseminated intravascular coagulation; 288 cases were cured, 48 improved, 17 gave up treatment and discharged, and 46 died; totally 408 strains were isolated from 399 children, including Enterobacteriaceae (346, 84.8%), non-fermentative Gram-negative bacteria (49, 12.0%) and other gram-negative bacteria (13, 3.2%). The resistance rates of Escherichia coli (n=175) and Klebsiella pneumoniae (n=106) to carbapenems, beta-lactams enzyme and its inhibitors, amikacin and cefoxitin were all lower than 10%. Totally 245 multi-drug resistant strains (60.1%) were isolated, including 225 strains of Enterobacteriaceae and 18 strains of non-fermentative Gram-negative bacteria (P<0.01) . Nine strains of Carbapenem resistant Enterobacteriaceae were isolated, which were all sensitive to amikacin and the sensitive rates to fluoroquinolone reached 88.9%. Five strains which were detected sensitive to tigecycline were all sensitive. The proportion of Klebsiella sp in Gram-negative bacteria between 2013-2015 and 2010-2012 were 32.9% and 21.2%, respectively. The resistance rates of Escherichia coli and Klebsiella pneumoniae to beta-lactams and its enzyme inhibitors and carbapenems had no significant change. Conclusion: Gram-negative bacterial bloodstream infections occur more frequently in newborns. Most children had combined underlying diseases. Escherichia coli and Klebsiella pneumoniae are the most common pathogens. beta-Lactams and its enzyme inhibitors and carbapenems are the empirical choice of antimicrobial therapy for severe Enterobacteriaceae bloodstream bacterial infections. PMID- 28881516 TI - [Effectiveness and safety of rituximab for children with autoimmune diseases of the nervous system]. AB - Objective: To assess the effectiveness and safety of rituximab in Chinese children with autoimmune diseases of the nervous system. Method: An ambispective cohort study enrolled patients with refractory and(or) relapse autoimmune diseases of nervous system from June 2010 to June 2016 in Peking University First Hospital.These patients failed to respond to steroids and(or)intravenous immunoglobulin (IVIG) were treated with rituximab and seen for follow-up visits once every 3 months.The effectiveness was assessed by modified Rankin scale (mRs) and the annualized relapse rate.B cell was repeatedly counted after the treatment.Side effects attributed to rituximab were recorded.Paired rank test and chi-square test were used to compare the mRs score and the recurrence rate (time/year) before and after the treatment. Result: A total of 38 patients (15 males and 23 females) with mean age of (6+/-4) years were treated with rituximab.Among those patients, 4 cases were in multiple sclerosis, 5 in neuromyelitis optica, 6 in opsoclonus myoclonus syndrome, 9 in myasthenia gravis, and 14 in autoimmune encephalitis and other nervous system autoimmune diseases.The course of the disease before rituximab treatment was from two months to 7.25 years, with the average of (21+/-19) months.The patients had been followed up for 2-52 months. The mRs score and recurrence rate of 38 patients before receiving rituximab was 3 points (3, 4) and 2.56 (1.80, 4.75) times per year, respectively, while patients after receiving rituximab were mRs score of 0 (0, 2) and had a recurrence rate of 0 (0, 0.17) per year.There was statistical difference before and after treatment (Z=-4.51 and -4.71, P<0.01). Rituximab had a definite benefit in 23 patients, probable benefit in 2 patients, possible benefit in 3 patients, no benefit in one patient, and the disease worsened in 2 patients.Therefore the total effective rate was 74%, except for 6 undetermined cases because of the short follow-up time, and one patient withdrew from the study due to allergic reaction.During the follow-up, only one patient with severe allergy gave up the rituximab treatment. And only one patient was found severe infection with Pneumocystis carinii pneumonia. Conclusion: Rituximab is an effective and safe treatment strategy for patients with refractory and relapse autoimmune diseases of CNS, especially in neuromyelitis optica and myasthenia gravis.The adverse events including infection and allergy during infusion are not common. PMID- 28881517 TI - [Thoracoscopy in diagnosis and treatment of pleural diseases in children]. AB - Objective: To investigate the value of thoracoscopy in diagnosis and treatment of pleural diseases in children. Method: Clinical manifestations and treatment outcomes of 19 patients who had refractory pleural diseases treated with thoracosocy during May 2011 to August 2016 in Hunan Provincial People's Hospital were retrospectively analyzed. In 19 cases, 15 were male and 4 were female, with an average age of (4.8+/-2.0) years. Thirteen patients had left pleural lesion, while 5 patients had right lesion, and 1 had bilateral lesions. Result: All cases were successfully treated with thoracoscopy without emergent thoracotomy. Pre- and post operative diagnosis was compatible in 10 cases, including 8 cases of empyema (Streptococcus pneumoniae infection in 6 cases, and Staphylococcus Aureus infection in 2 cases), and 2 cases of tuberculous pleuritis. Nine patients who had not been clearly diagnosed before surgery were diagnosed to be empyema (4 case), tuberculous pleuritic (3 cases), mycoplasma infection (1 case), and foreign body with infection (1 case) by thoracoscopy. The average duration of post-op closed thoracic drainage was (4.7+/-2.3) days. The average time to get normal temperature was (2.4+/-2.6) days. And the average length of hospital stay was (6.7+/-1.8) days. No hemothorax, chylothorax, or need for analgesic occurred. Conclusion: Thoracoscopy can be recommended for diagnosis and treatment of refractory pleural lesions diseases in children, with minimal trauma and complications. PMID- 28881518 TI - [Refractory kaposiform hemangioendothelioma with Kasabach-Merritt syndrome: clinical analysis of 10 cases]. AB - Objective: To analyze the clinical value of sirolimus plus prednisone for the treatment of the refractory kaposiform hemangioendothelioma(RKHE) and Kasabach Merritt syndrome(KMS). Method: Clinical retrospective analysis was carried out for 10 patients recruited in Children's Hospital Affiliated to Capital Institute of Paediatrics from January 2014 to January 2017 who were non responders to or relapsers after the treatment of propranolol, prednisone, pingyangmycin and lauromacrogol(5 cases RKHE, 5 cases RKHE plus KMS, age ranged from 6 days to 9 years); patients were treated with sirolimus at the dosage of 0.035 ml/(kg.d), once a day, for 6-410 days; the diagnosis of 10 patients were confirmed by pathological biopsy and immunohistochemical examination(IHC); the difference of the coagulation parameters and the platelet counts, the size of tumor and ecchymosis at different stages of treatment were recorded and measured by scale and ultrasonography; the side effects of sirolimus were recorded as well. Result: Clinical characteristics of 10 cases (6 male and 4 female) RKHE with KMS were refractory dark red hard hemangioma or ecchymosis, the platelet counts were lower than 30.0*10(9)/L, (15+/-7)*10(9)/L, coagulation tests were obviously abnormal, fibrinogens were significantly decreased(0.8+/-0.5)g/L, the fibrin lysates and D dimer were significantly increased(100+/-23)mg/L, (10 000+/-2 200)ng/L, the prothrombin time and activated partial thromboplastin time were prolonged(25.0+/ 2.1)s, (58.0+/-3.4)s. The pathologic characteristics of the tumors were similar: spindle tumor cells, mass distribution and deeply stained nuclei tumor cells. IHC revealed positive staining for D2-40, CD31 and CD34. Stainings for factor VIII and GLUT-1 were negative. In five cases RKHE plus KMS were treated with sirolimus and prednisone, after (6.5+/-0.7) days treatment, the platelet counts were obviously increased(72.0+/-0.6)*10(9)/L, coagulation parameters were obviously improved, fibrinogen significantly increased(1.5+/-0.2)g/L, the fibrinlysates and D-dimer significantly decreased(7+/-3)mg/L, (2 300+/-200)ng/L, the prothrombin time and activated partial thromboplastin time were prolonged(15+/-2.3)s, (42+/ 3.4) s, and the sizes of tumor and ecchymosis were slightly shrunken 18%+/-3%, 38%+/-5%; after (30+/-5.7) days treatment, the platelet counts and coagulation parameters returned to normal(146+/-36)*10(9)/L, and the size of tumor and ecchymosis were obviously shrunken 73%+/-3%, 97%+/-3%; after (3+/-0.4) months treatment, the tumor was obviously shrunken by 93%+/-2% and no longer palpable. In five cases with RKHE without KMS manifested stubborn dark red hard hemangiomatous plaques, coagulation tests and platelet were obviously normal, these patients were treated with sirolimus, after (2.0+/-0.6) months treatment, the tumor became shrunken 8%+/-3%, with continuous treatment the tumor shrunk gradually, after (4.0+/-3.2)months(2-18 mouths) the tumor was not eliminated 51%+/-7%. Conclusion: RKHE and KMS have typical clinical, laboratory and pathological characteristics, sirolimus plus prednisone have remarkable efficacy and minor side effects, it should be recommended for the treatment of KHE with KMS. PMID- 28881520 TI - [A new somatic mosaicism for a KIT D816F mutation results in congenital diffuse cutaneous mastocytosis: a rare monozygotic twins]. PMID- 28881519 TI - [Splenic infarction in a child with Mycoplasma pneumoniae pneumonia]. PMID- 28881521 TI - [Diagnostic analysis of glanzmann thrombasthenia caused by two novel ITGA2B gene mutations]. PMID- 28881522 TI - [DMGDH gene-related dimethylglycine dehydrogenase deficiency in a case]. PMID- 28881524 TI - [Warfarin therapy in children with cardiovascular diseases]. PMID- 28881523 TI - [Further understanding of membranoproliferative glomerulonephritis]. PMID- 28881525 TI - [Progress in gene therapy for Duchenne muscular dystrophy]. PMID- 28881526 TI - [Current and ongoing applications of Robotics-assisted spinal surgery]. PMID- 28881527 TI - [Factors correlated with height gain after posterior spinal correction surgery in lenke 1 adolescent idiopathic scoliosis]. AB - Objective: To investigate the correlated factors of height gain (DeltaSH) after posterior spinal correction surgery in Lenke 1 adolescent idiopathic scoliosis (AIS), and to propose the predictive model of DeltaSH. Methods: From 2013 to 2015, a total of 150 Lenke 1 AIS patients undergoing posterior spinal correction surgery were included in the study, with the age of (14.3+/-2.9) years. The Cobb angle of major curve, thoracic kyphosis (TK) and lumbar lordosis (LL) were measured on both pre-op and post-op standing whole spine x-rays. The change in Cobb angle, TK and LL were calculated. The difference between pre-operation and post-operation was compared and the linear regression analysis was used for the predictive model of DeltaSH. Results: The pre-op and post-op values were (41.6+/ 3.0)cm and (43.9+/-2.7)cm for spinal height (SH)[DeltaSH=(2.4+/-0.8)cm, P=0.000]; (50.5+/-10.4) degrees and (14.6+/-6.4) degrees for Cobb angle (P=0.000). The Pearson correlation analysis showed that DeltaSH was significantly correlated with pre-op SH (P=0.000), pre-op Cobb angle (P=0.000), pre-op TK (P=0.000), post op SH (P=0.020), post-op Cobb angle (P=0.000), change in Cobb angle (P=0.000) and change in TK (P=0.000). The linear regression model 1 revealed that DeltaSH was linearly correlated with change in Cobb angle (P=0.000) as well as change in TK (P=0.000); the linear regression model 2 showed that the pre-op Cobb angle (P=0.000) and pre-op TK (P=0.020) could be used for the pre-op prediction of DeltaSH. Conclusions: The positively correlated factors of DeltaSH include pre-op and post-op Cobb angle, TK, change in Cobb angle and change in TK. High pre-op Cobb angle and TK indicates high height gain in Lenke 1 AIS patients. PMID- 28881528 TI - [Clinical research of minimally invasive spine surgery with Vesselplasty]. AB - Objective: To evaluate the efficacy and safety of Vesselplasty in the treatment of osteoporotic vertebral fractures and vertebral metastases. Methods: From June 2010 to December 2016, data of 81 patients with spinal diseases treated with Vesselplasty in Department of Spinal Surgery, Beijing Friendship hospital, Capital Medical University were retrospectively analyzed. There are 49 cases of vertebral fractures with age (70.2+/-8.2) years. Among them, 16 cases have posterior vertebral wall breakage, but no symptoms of nerve injury. Clinical result were evaluated with Visual Analogue Scale(VAS) , the kyphotic angle(Cobb's angle) and Oswestry disability index(ODI) was measured preoperatively, postoperatively and follow-up. At the same time, the operation time and cement leakage were recorded. There were 32 patients with vertebral metastases, with age of (69.6+/-11.1) years old. The posterior wall of the vertebral body was damaged in 22 cases. The VAS scores were recorded and compared preoperatively and postoperatively. The operation time was recorded also. Results: All patients were completed the operation safely and with no complications. Compared with preoperative VAS, postoperative VAS was significantly decreased in all subjects(P<0.05). The average operation time of each vertebral body was 16.2+/ 4.6 min, and the postoperative VAS score significantly decreased (P<0.05), Cobb 's angle from preoperative (13.9+/-6.0) degrees to( 5.2+/-4.0) degrees (P<0.05) in 49 cases of vertebral fracture(58 vertebrae). The clinical results were still satisfied in follow-up . In 32 cases of vertebral metastases(38 vertebrae), the average operation time was (17.6+/-5.4) min. The postoperative VAS score was obviously decreased also(P<0.05). A small amount of bone cement leakage occurred in 4 cases of 4 vertebrae. The rate of bone cement leakage was 4.2%, but there were no clinical symptoms in these cases. Conclusion: Vesselplasty is a safe and effective treatment of osteoporotic vertebral fractures and vertebral metastases. It can lead to satisfactory clinical effect, partial recovery of vertebral height. Besides, the bone filling mesh can reduce the risk of bone cement leakage, which can provide a new choice for minimally invasive treatment of vertebral fracture and metastases. PMID- 28881529 TI - [Results for the treatment of fresh type thoracolumbar vertebral fracture according to the intraoperative CT scan]. AB - Objective: To evaluate the value of intraoperative CT scanning in the treatment of fresh thoracolumbar burst fractures. Methods: From January 2008 to January 2015 , 161 patients with thoracolumbar fractures in Department of Orthopedics, Luohe City Central Hospital, were divided into two groups: 79 cases were treatment group which were treated with intraoperative CT scan and decompression mode was determined according to CT scan results during the period from October 2012 to January 2015. 82 patients as the observation group were treated without intraoperative CT scan and direct laminectomy were performed during the period. In the treatment group, it is no further decompression of the spinal canal when the CT showed a reduction of the fracture block into the spinal canal, if the intraoperative CT showed that the fractures still occupied the spinal dura mater according to the three-dimensional CT information, the position and the size of the fracture of the spinal canal were determined, and the unilateral laminectomy was performed corresponding to the position of the lamina and intervertebral ligamentum flavum. The operative time, bleeding volume, neurological function, height of the anterior vertebral compression and Cobb angle were compared between the two groups. Results: In the treatment group, CT scan showed 48 cases (60.8%) entered the spinal canal fracture completely or basically reset.31 cases (39.2%) still occupied the spinal canal compression spinal dura mater. There were significant differences in the operation time and bleeding volume between the two groups. The treatment group was less than the control group. There was no infection, secondary spinal cord injury, loose fixation and other complications. There was no difference in the ASIA classification before and after operation(chi(2)=0.268 vs chi(2)=1.372, P>0.05). The anterior vertebral height and COBB angle of the two groups were significantly improved compared with those before operation. There was no significant difference between the two groups in the postoperative height and COBB angle[(40.3+/-11.8) degrees vs(82.1+/-4.2) degrees , (-10.3+/-2.6) degrees vs(6.9+/-3.3) degrees , P<0.05], but after 2 years the difference was statistically significant between the two groups, to retain the rear ligament complex treatment group was significantly better than the control group. Conclusions: Patients of thoracolumbar vertebral fracture in hyperextension position combined with internal fixation can achieve good correction effect. Orthopedic postoperative CT scan and according to the results of the scan precision treatment can simplify the operation, there was no difference in clinical efficacy compared with total laminectomy, but some patients avoid the spinal canal decompression and part were treated by small fenestration laminectomy decompression, which is conducive to the protection of spinouts ligament complex integrity. PMID- 28881530 TI - [Analysis of factors of elder patients with lumbar vertebrae fractures caused by low-energy injury in plateau area]. AB - Objective: To analyse the factors of elder patients with lumbar vertebrae fractures caused by low-energy injury in plateau area. Methods: From March 2013 to September 2016, 124 elder patients with lumbar vertebrae fractures caused by low-energy injury in our hospital were selected as observation group, in the corresponding period, 98 elderly patients who had no fractures were considered as control group .The bone mineral density (BMD) was examined by whole body bone mineral density tester, and univariate analysis and multivariate Logistic regression analysis were used to analyze the influencing factors of lumbar fractures caused by low-energy injury. Results: BMD and T value of lateral projection of lumbar vertebrae in observation group were significantly lower than those in control group (P<0.05). Single factor analysis showed that the age, body mass index, past history, bone mineral density and calcium supplementation had a significant effect on lumbar fractures caused by low-energy injury. Logistic regression analysis showed that age (OR=1.215), bone mineral density (OR=3.215) and calcium supplementation (OR=4.904) were independent risk factors for lumbar fractures caused by low-energy injury (P<0.05). Conclusion: Bone mineral density of elderly population in plateau area is lower. Age, bone mineral density and calcium supplementation are independent risk factors of lumbar fractures caused by low-energy injury, and individual medical intervention is needed. PMID- 28881531 TI - [Gene expression profiles of long non-coding RNAs in human degenerated intervertebral disc tissue]. AB - Objective: To investigate the gene expression profiles of long non-coding RNAs (lncRNA)in human degenerated intervertebral disc degeneration (IDD). Methods: An lncRNA-mRNA microarray analysis of human nucleus pulposus (NP) was employed. Bioinformatics prediction was also applied to delineate the functional roles of the differentially expressed lncRNAs. Several lncRNAs and mRNAs were chosen for quantitative real-time PCR (qRT-PCR) validation. Results: A total of 1 570 lncRNAs expressed in degenerate group compared with the nondegenerate group. Of these, the expression level of 428 lncRNAs was upregulated >2-fold compared with nondegenerate group while that of 584 was downregulated. Bioinformatics analysis (GO and pathway analyses) revealed that some classical pathways participating in extracellular matrix (ECM) and cell apoptosis were aberrantly expressed in the intervertebral disc (P<0.05). Enhancer-like lncRNAs and their nearby coding genes were analyzed. Three lncRNAs were identified as potential enhancers. Several lncRNAs were validated in the intervertebral disc using RT-qPCR. Conclusion: The lncRNAs express differentially in the intervertebral disc. LncRNAs may therefore be novel candidate biomarkers and potential targets for intervertebral disc degeneration therapy in the future. PMID- 28881532 TI - [Safety analysis of carotid endarterectomy without shunting in carotid artery stenosis patients with contralateral carotid occlusion]. AB - Objective: To investigate the safety of carotid endarterectomy (CEA) without shunting in carotid artery stenosis (CAS) patients with contralateral carotid occlusion (CAO) under the protection of monitoring of cerebral blood oxygen saturation. Methods: A total of 71 patients with CAS was enrolled in our research during 2013 to 2016. They were divided into two groups which were group A: 20 CAS patients with contralateral CAO, and group B: 51 CAS patients without contralateral CAO. All patients were given CEA without shunting during operation.One and 6 months following up was carried to observe the incidence of newly hemorrhage and infarction on operation side and adverse cardiac events. Results: There was none adverse cardiac event and newly infarction. But there was 1 (5.00%) newly hemorrhage in group A during the 1 month following up. None adverse event was found in group B. During the 3 months following up, none adverse event was found in group A and 3 (5.88%) newly infarction patients were found in group B. However, there was no significant difference between group A and group B. Conclusion: CEA without shunting in CAS patients with contralateral carotid occlusion under the protection of monitoring of cerebral blood oxygen saturation is an efficient and safe way to improve the patients, living quality. PMID- 28881533 TI - [Efficacy and safety of Rivaroxaban anticoagulant therapy in the treatment of atrial fibrillation cryoablation]. AB - Objective: To observe the efficacy and safety of the novel oral anticoagulant Rivaroxaban for anticoagulation therapy in patients with nonvalvular atrial fibrillation (AF) during cryoablation. Methods: A total of 137 AF patients from October 2013 to December 2016 underwent cryoablation were divided into two groups according to the application of anticoagulant drugs: Rivaroxaban group (65 cases) and Heparin group (72 cases). Rivaroxaban group: oral administration of Rivaroxaban 20 mg, once a day, was started 3 days before the cryoablation, no anticoagulant was additionally added during cryoablation, the activated clotting time (ACT) was measured, and oral administration of Rivaroxaban was continued for 3 months after cryoablation. Heparin group: oral administration of Rivaroxaban 20 mg, once a day, was stopped 24 hours before the cryoablation, heparin (100 U/kg) anticoagulation was given during cryoablation, ACT was controlled between 250 and 300 seconds, and oral administration of Rivaroxaban was continued for 3 months after cryoablation. The ACT results, the incidence of bleeding and thromboembolic events between the two groups were compared. Results: The ACT result between the two groups were with statistically significance[(110+/-16) vs (323+/-61) seconds, P=0.000)]. The bleeding events for Rivaroxaban group were two cases of local hematoma of the femoral vein puncture site, with the incidence rate of 3.1%(2/65); Heparin group were two cases of local hematoma of the femoral vein puncture site, and one case of epistaxis, with the incidence rate of 4.2%(3/72), with no statistical significance(P=0.549) between the two groups. No thromboembolic event occurred in the Rivaroxaban group, one cerebellar thromboembolic event occurred in the Heparin group during anticoagulant bridging phase after cryoablation. Conclusion: Rivaroxaban is safe and effective for anticoagulation therapy in patients with atrial fibrillation cryoablation. PMID- 28881534 TI - [Tracheobronchial segmental resection and reconstruction applied to surgical treatment of esophageal cancer with airway involvement]. AB - Objective: To evaluate the efficacy of tracheobronchial segmental resection and reconstruction applied to surgical treatment in the patients with esophageal cancer with airway invasion. Methods: From January 2004 to April 2014, 13 patients in our center underwent radical esophagectomy combined with tracheobronchial segmental resection and reconstruction. Patient characteristics, operative procedures, postoperative complications and long-term survival were retrospectively reviewed. Results: All patients received complete resection (R0) with an average length of resected airway 2.77+/-0.73 cm. In addition, carinal resection plus lobar resection (including carinal pneumonectomy) was accomplished in 2 patients; 1 patient underwent aortic replacement. Complications were noted in 5 patients (39%) and 2 patients (15.38%) died within 30 days after operation. 4 patients (30.76%) suffered from airway anastomosis stenosis and all 3 of them died within 2 years after operation due to refusing bronchoscopy interventions. The overall 1-, 2-, and 5-year survival rates were 72.7%, 45.5%, and 24.2%, respectively, with a median survival time of 2 years (0.5-10 years). Conclusion: Tracheobronchial segmental resection and reconstruction can provide an opportunity of complete resection and a survival benefit for patients with esophageal cancer invading airway with acceptable morbidity and mortality. Postoperative airway anastomosis stenosis needs active treatment. PMID- 28881535 TI - [Diagnostic value of combination of US and MRI in preoperative prediction for the extrathyroidal extension of papillary thyroid carcinoma]. AB - Objective: The purpose of the present study was to evaluate the diagnostic performance of preoperative ultrasonography(US), magnetic resonance imaging(MRI) and US combined with MRI in the prediction of extrathyroidal extension(ETE) in patients with papillary thyroid carcinoma(PTC). Methods: Between January 2013 and December 2016, a total of 83 consecutive patients underwent surgery for pathologically confirmed PTCs with ETE. We analyzed all patients with PTC with ETE who received preoperative combination of US and MRI scan to evaluate ETE. Results: For minimal ETE, the accuracy was 92.2%(47/51) of US, 74.5%(38/51) of MRI, and their combination was 98.0%(50/51). The differences of the three methods for minimal ETE were statistically significantly different(P=0.000). For extensive ETE, the accuracy was 62.5%(20/32) of US, 87.5%(28/32) of MRI, and their combination was 93.8%(30/32). The different of the three methods for extensive ETE was statistically significantly different(P=0.000). For the total accuracy of ETE, US was 80.7%(67/83), MRI was 79.5% (66/83), and their combination was 96.4%(80/83). The difference of the three methods for ETE was statistically significantly different(P=0.001). Conclusion: The combination of US and MRI can improve the preoperative diagnostic accuracy of ETE for PTC. PMID- 28881536 TI - [MR imaging of flexor tendon and pulley system of the fingers: normal anatomy and injury]. AB - Objective: To explore the magnetic resonance imaging (MRI) features of the anatomy and injuries of flexor tendon and pulley system of the fingers. Methods: Clinical and imaging data of 20 healthy volunteers without injuries and 36 patients from Beijing Jishuitan Hospital with flexor tendon and pulley system injuries in the fingers between March 2013 and March 2016 were retrospectively analyzed. All subjects underwent magnetic resonance imaging (MRI) examination. The MRI findings of patients were compared with healthy volunteers. In addition, imaging findings of patients were compared with the surgical results and confirmed by double-blinded method. Results: Twenty volunteers without flexor tendon and pulley system injures showed homogeneous hypointensity on both T1 weighted and Proton Density-weighted images with fat saturation (PD-FS). There were 36 patients with finger injures, including 21 cases of flexor tendon injury, 10 cases of pulley system injury, 5 cases of compound injury, which demonstrated unclear signal, discontinuity on T1-weighted images and heterogeneously increased signal intensity of the involved structures on PD-FS images. Edema was detected in the soft tissues surrounding the injured sites. Conclusions: MRI is an accurate method for evaluation of the anatomy and pathologic conditions of flexor tendon and pulley system of the fingers and a useful tool for diagnosis and treatment of flexor tendon and pulley system injuries. PMID- 28881537 TI - [The relationship between autoimmune thyroiditis and pregnancy outcomes of patients with PCOS following in vitro fertilization and embryo transfer IVF-ET]. AB - Objective: To investigate the impact of autoimmune thyroiditis (AIT) on pregnancy outcomes in patients with polycystic ovary syndrome (PCOS) following the in vitro fertilization and embryo transfer (IVF-ET) by analyzing their pregnancy outcomes. Methods: The patients undergoing IVF-ET treatment diagnosed with PCOS in Peking University Third Hospital from May 2010 to December 2014 were investigated. According to the anti-thyroid antibodies (TPOAb or TGAb), patients were divided into AIT group and non-AIT group. The pregnancy outcomes of two groups were analysed for investigate the effect of AIT on pregnancy outcomes. Results: Four hundred and ninety patients with PCOS were enrolled, 119 (24.3%) of AIT group and 371 (75.7%) of non-AIT group. Patients with PCOS had a higher incidence (24.3%) of AIT. There was no correlation between AIT and the different pregnancy outcomes.TSH was negatively correlated with pregnancy as a risk factor. Hyperandrogenemia was negatively correlated with clinical pregnancy as a risk factor. Hyperprolactinemia was negatively correlated with delivery as a risk factor, while TSH was positively correlated with delivery. Conclusions: The incidence of AIT was higher in patients with PCOS. AIT was not the risk factor of adverse pregnancy outcomes for PCOS women undergoing IVF. The metabolic disorders (including hyperinsulinemia, hyperandrogenemia and hyperprolactinemia) were the risk factors of adverse pregnancy outcomes. Patients in AIT group had the high TSH level. They should be received more care and monitoring to make it conducive to delivery. PMID- 28881538 TI - [Co-culture with endometrial stromal cells promotes the differentiation of menstrual blood-derived mesenchymal stem cells into endometrial epithelial cells]. AB - Objective: To study the potential of differentiation of menstrual blood-derived mesenchymal stem cells (MenSC) into endometrial epithelial cells (EEC) in vitro. Methods: Endometrial stromal cells (ESC) and MenSC were cultured and identified by certain methods.MenSC were co-cultured with ESC, added 10 ng/ml TGF-beta1, 10 ng/ml EGF, 10 ng/ml PDGF-BB and 1*10(-7) mol/L 17-beta-estradiol.The expression of cytokeratin, which was marker of EEC, was tested by immunofluorescence in differentiated MenSC. Results: MenSC proliferated quickly in vitro, and showed fusiform shape and clear structure within 10 generations.The expression rate of superficial markers of MenSC, CD44, CD90, CD73, and CD29, were 98.4%, 90.77%, 94.75% and 97.01% respectively.The expression of vimentin, which was stromal marker, was positive in cultured ESC (P3). After co-cultured with ESC for 3 weeks, MenSC morphology changed from fibroblast-like cells into epithelial-like cells.Immunofluorescence assay showed that the differentiated MenSC expressed cytokeratin. Conclusion: Under the condition of co-culture with ESC, MenSC has the ability to differentiate into endometrial epithelial cells. Cell growth factor and estrogen play the important roles in this process. PMID- 28881539 TI - [Analysis of carotid atherosclerosis and related risk factors in a university physical examination population in Beijing]. AB - Objective: To explore the incidence of carotid atherosclerosis in staffs of Tsinghua university according to the different age groups, the possible risk factors and conduct a follow-up survey. Methods: Detailed information about physical examination and carotid ultrasound from 832 staffs of Tsinghua University between 2014 to 2016 were reviewed to observe the occurrence and development of atherosclerosis according to different age groups; the correlation between conventional risk factors and carotid arteriosclerosis was studied by multivariate Logistic regression analysis.The process of different degrees of arteriosclerosis in the population was observed one year later. Results: In the past three years, there were 2 024 cases of carotid examination. Among them, there were 832 staffs who had been followed up for more than 6 months. There were 517 cases of carotid atherosclerosis, with 289 males (55.9%) and 228 females (44.1%), and the incidence of atherosclerosis in male was higher than that in female (P<0.05). The 50 to 59 years old, 60 to 69 years old, 70 to79 years old were the age group with high incidence of pure carotid intima-media thickening, atherosclerosis plaque formation and stenosis or occlusion, respectively. After multivariate Logistic regression analysis, hypertension, diabetes and hyperlipidemia were found the independent risk factors for carotid intimal thickening. The follow-up of 832 staffs with ultrasound showed that there was no significant difference in intima-media thickening, plaque formation, stenosis or occlusion after one year (P>0.05). Conclusions: This research suggests that the incidence of atherosclerosis in male is higher than that in female, and hypertension, diabetes and hyperlipidemia are important influencing factors of arteriosclerosis for staffs of Tsinghua University. Early screening, identification of high-risk patients and comprehensive treatment should be done to delay the process of atherosclerosis.In addition, long-term follow-up is necessary in the context of no significant changes within the short-term. PMID- 28881540 TI - [Health promoting in adolescents and youths across the life span]. PMID- 28881541 TI - [Investigation of influencing factors associated with neck-shoulder symptoms among middle school students in three cities in China]. AB - Objective: The aim of this study was to describe the distribution of neck shoulder symptoms among middle school students, and to explore its influence factors. Methods: A cross-sectional survey was conducted on 24 middle schools in Shenyang, Zhengzhou and Shenzhen by purposive sampling method. In each middle school, 3 to 4 classes were selected from each grade all the students in the selected class would be recruited to the survey to investigate the demographic characteristics, neck-shoulder symptoms, physical exercise time, academic stress, screen behavior, sedentary behavior and other information by questionnaire. A total of 10 566 questionnaires were issued and 10 270 valid questionnaires were withdrawn. The prevalence of neck-shoulder symptoms among students were compared by different characteristics. Logistic regression models were applied to examine influencing factors associated with neck-shoulder symptoms. Results: The prevalence of neck-shoulder symptoms among middle school students was 19.2% (1 968/10 270), while it was 22.6% (1 137/5 039) among girls and 15.9% (831/5 231) among boys; the difference showed statistical significance (P<0.001). The prevalence of neck-shoulder symptoms was separately 13.3% (253/1 901) in seventh grade, 16.8% (326/1 942) in eighth grade, 18.5% (299/1 617) in ninth grade, 21.8% (417/1 915) in sophomore, 21.4% (345/1 611) in junior, 25.5% (328/1 284) in senior; the difference showed statistical significance (P<0.001). The multivariate logistic regression analysis showed that in the last 3 months, students who always playing mobile phone >=40 min continuously (OR=4.66, 95%CI: 3.95-5.49), watching TV >=40 min continuously (OR=4.01, 95%CI: 3.39-4.73), using computer >=40 min continuously (OR=3.61, 95%CI: 3.09-4.23), doing homework >=60 min continuously (OR=3.25, 95%CI: 2.79-3.79), the average daily sitting time >=10 h (OR=4.95, 95%CI: 4.25-5.77), and always sitting >=90 min continuously (OR=5.18, 95%CI: 4.42-6.06) were risk factors of neck-shoulder symptoms. Conclusion: The prevalence of neck-shoulder symptoms was high among middle school students in China, especially girls in senior grades. Long time, high frequency video behaviors and sedentary behaviors were related to the occurrence of neck-shoulder symptoms among middle school students. PMID- 28881542 TI - [Study of association between adverse experiences in childhood, social support, and physical and psychological sub-health status among middle school students in 3 cities in China]. AB - Objective: To explore the relationship between adverse experience in childhood, social support, and physical and psychological sub-health status among middle school students in 3 cities in China. Methods: 15 278 adolescents were selected as subjects from 20 junior and senior middle schools located in 3 cities of China by stratified cluster sampling method. The survey collected the demographic information, ACEs, social support and physical-psychological status. A total of 14 820 valid questionnaires were retained for analysis. We assessed ACE score (count of six categories of childhood adversity), social support (adolescent social support questionnaire), and the prevalence of two outcomes: physiological and psychological sub-health status. Logistic regression was used to analyze the relationship between adverse childhood experiences, social support, and physiological and psychological sub-health status. Results: The prevalence of physiological and psychological sub-health status were 26.4% (3 917/14 820) and 24.1%(3 572/14 820), respectively. A total of 89.4% (13 247/14 820) reported at least 1 adverse childhood experiences. The rates of physiological and psychological sub-health status were higher among girls (28.1%(2 092/7 443), 26.0%(1 932/7 443)) than boys (24.7%(1 825/7 377), 22.2%(1 640/7 377)). Among adolescents without ACEs, the rate of physiological and psychological sub-health status were 15.4%(243/1 573) and 10.4%(163/1 573), for those with 5-6 ACEs, the rate were 40.9%(636/1 556) and 43.6%(678/1 556). Among adolescents with higher social support, the rate of physiological and psychological sub-health status were 19.9%(724/3 635) and 13.0%(474/3 635) for those with lower social support, the rate of physiological and psychological sub-health status were 35.9%(1 403/3 913) and 39.0%(1 528/3 913). The rates of physiological and psychological sub health status were higher with more ACE exposure or less social support. At each level of ACE exposure, physiological and psychological sub-health status were less in those with greater social support. For example, among adolescents reporting 5-6 ACEs, those in the lowest tertile of social support increased the risk of physiological sub-health status than those in the highest tertile (adjusted prevalence ratio (95%CI)=1.79 (1.23-2.56)); for those reporting no ACEs, the ratio was 3.04 (1.91-4.83). Among adolescents reporting 5-6 ACEs, those in the lowest tertile of social support increased the risk of psychological sub health status than those in the highest tertile (adjusted prevalence ratio (95%CI)=3.77 (2.57-5.52)); for those reporting no ACEs, the ratio was 3.97(2.33 6.76). Conclusion: The findings suggest that ACEs should be considered as risk factors for physiological and psychological sub-health status among middle school students. Across a range of exposures to ACEs, less social support was associated with more physiological and psychological sub-health status. Identifying those with ACE exposure who also have lower social support could be used to improve the health of adolescents. PMID- 28881543 TI - [Associations between overweight-obesity and puberty timing in children with different genders in China]. AB - Objective: To understand the associations between overweight-obesity and puberty timing in children with different genders. Methods: The girls in grade 2, 3, 7, 8 and boys in grade 3, 4, 7, 8 were recruited from primary and middle schools in North new area of Shenyang, Yanqing district of Beijing, Erqi district of Zhengzhou and Jiulongpo district of Chongqing by purposive sampling method between October and December 2014, respectively. The information of demographic characteristics of the respondents were collected and the pubertal development status was evaluated by Pubertal Development Scale (PDS). A total of 6 701 students were recruited; 6 137 out of which were valid with complete questionnaires. The associations between overweight-obesity and puberty timing were estimated by multivariate logistic regression analysis. Results: The prevalence of overweight-obesity in primary schools were 34.8% (522/1 499) among boys and 24.2% (341/1 409) among girls, respectively. The prevalence of overweight-obesity in middle schools were 31.3% (591/1 658) among boys and 21.8% (342/1 571) among girls, respectively. The prevalence of premature puberty in primary schools were 15.0% (225/1 499) among boys and 14.2% (200/1 409) among girls, respectively. The prevalence of delayed puberty in middle schools were 14.3% (237/1 658) among boys and 14.9% (234/1 571) among girls, respectively. After adjusting the effects of region, age, one-child, family income and the parents' educational levels, multivariate logistic regression analysis showed that overweight-obesity had significantly positive association with premature puberty (OR=2.16, 95%CI: 1.56-2.99) among girls in primary schools, and significantly negative association with delayed puberty (OR=0.54, 95%CI: 0.36 0.80) among girls in middle schools when compared with students with normal weights, both P values were <0.05. There was no significant associations among boys in primary and middle schools between overweight-obesity and puberty timing, and the corresponding OR(95%CI) were 1.08(0.80-1.45) and 0.93(0.69-1.27) respectively, both P values >0.05. Conclusion: There was significantly positive association between overweight-obesity and premature puberty among girls, and significantly negative association with delayed puberty among girls in middle schools; but the association was not found among boys. PMID- 28881544 TI - [Prospective association between early adiposity rebound and adolescent development in girls]. AB - Objective: To determine possible relations between early adiposity rebound and adolescent development. Methods: Prospective children cohort from 2 kindergartens selected through clustering convenience sampling method in Anhui Province was established since Sep. 2010. Participants were classified as Cohort 1 (2010), Cohort 2 (2011) and Cohort 3 (2012) according to the recruiting year. Till Sep. 2015, a toal of 802 girls were included in this study, and received follow-up till primary school. During kindergarten period, physical examination was carried out every 3 months, 8 times in total. In primary school, physical examination was carried out annually; till Sep.2015, the cohort 1, 2, 3 took physical examination for 12, 11, 10 times, respectively. Information on household economic status and child physical activity was acquired through parents questionnaire survey, and breast development were assessed through visual inspection and palpation. Adiposity rebound was determined according to Rolland-Cachera's method for each girl. Differences between early adiposity rebound and normal adiposity rebound groups were compared by using t test and chi(2) test. Multivariate regression analysis was applied to explore the association between early adiposity rebound and breast development. Results: The average age of participants was (8.90+/ 0.87) years old and the BMI was (17.48+/-2.70) kg/m(2). The average age at adiposity rebound was (6.16+/-0.90) years old and the BMI was (15.33+/-1.82) kg/m(2). Premature breast development was found significantly higher in girls in early adiposity rebound group (27.8%, 54/802) than it in normal adiposity rebound group (13.7%) (P<0.001). After current adiposity, age, household economic status, childhood physical activity adjusted, the OR of premature beast development in early adiposity rebound group was 2.41(95%CI: 1.41-4.12). Conclusion: Early adiposity rebound increases the risk of premature puberty in girls. PMID- 28881545 TI - [Study on relationship between outdoor activities and self-reported myopia among middle school students]. AB - Objective: To examine the relationship between the prevalence of self-reported myopia and outdoor activities among middle school students and to explore the influence factors of the self-reported myopia. Methods: A total of 12 979 participants were recruited from junior and senior middle school students in in Shenzhen, Nanchang, Zhengzhou and Shenyang by random cluster sampling method between December 2015 and March 2016. All participants completed an anonymous questionnaire to collect the information of demographic characteristics, self reported myopia, outdoor activities, etc. 12 603 out of 12 979 copies of questionnaire were valid. The prevalence of self-reported myopia was compared among middle school students with different characteristics. Logistic regression models were used to analyze the relationship between myopia and outdoor activities. Results: The prevalence of self-reported myopia among middle school students was 69.6% (8 766/12 603); which was separately 52.1% (1 216/2 335) in seventh grader, 61.6% (1 459/2 369) in eighth grader, 69.0%(1 470/2 129) in ninth grader, 80.0% (1 812/2 265) in freshmen, 79.4% (1 622/2 042) in sophomore, and 81.1%(1 187/1 463) in junior. The prevalence of self-reported myopia showed an increasing trend with the increase of grade (chi(2)=639.67, P<0.001). The prevalence of self-reported myopia was separately 63.5%(4 927/7 756) in non myopic parents group, 78.0%(2 664/3 415)in either myopic parent group, and 82.1%(1 175/1 432) in both myopic parents group(chi(2)=328.28, P<0.001). Outdoor activities were associated with self-reported myopia. Binary logistic regression analysis showed that the risk of self-reported myopia was significantly increased by always staying at home in extracurricular time among the middle school students (OR=1.58, 95%CI: 1.36-1.82). The risk of self-reported myopia were significantly decreased by always physical exercise and recreational activities after school among middle school students: the ORs were separately 0.67 (95%CI: 0.57-0.78) for physical exercise and 0.77 (95%CI: 0.64-0.92) for recreational activities. After stratified analysis by the parents' myopia status, in non myopic parents group, exercise and recreational activities after school among middle school students decreased the risk of myopia: the ORs were separately 0.68 (95%CI: 0.55-0.82) for physical exercise and 0.76 (95%CI: 0.61-0.95) for recreational activities; in either myopic parent group, OR(95%CI) were separately 0.65 (0.47-0.90) and 0.68 (0.47-0.98). Conclusion: Outdoor activities was negatively associated with self-reported myopia among middle school students. However, the parents' myopia status may affect the protective effect. PMID- 28881546 TI - [Effect of breastfeeding on the behavioral development of infants and children: a birth cohort study in Ma'anshan]. AB - Objective: To discuss the relationship between breastfeeding and the behavioral development of infants and children. Methods: Based on the Ma'anshan Birth Cohort Study, there were 3 474 pregnant women recruited from Ma'anshan Maternal and Child Care Center between May 2013 and September 2014, including 3 273 singleton live births. Follow up the infants to the age of 18 months old. Excluded the infants with incomplete information of breastfeeding and who did not finish the ASQ-3 evaluation in 6 months old and 18 months old, 2 404 valid subjects were included in the study. The information of demographic characteristics, deliver, infants and breastfeeding was collected. The behavioral development were evaluated by the third edition of Ages and Stages Questionnaire (ASQ-3) at 6 months old and 18 months old, and the effect of breastfeeding on behavioral development among infants and children were analyzed by multivariable logistic regression model. Results: The intensity of breastfeeding of infants within 6 months old was (26.56+/-10.56). The rate of breastfeeding as pure or major intake for infants between 0-5 months old were separately 54.2% (1 303), 54.0% (1 298). 54.0% (1 297), 50.5% (1 213), 34.4% (827) and 9.9% (237). After age, pre-pregnant BMI, intelligence, delivery mode, gender, gestational age, birth weight and family economic status adjusted, compared to never-breastfeeding, continuous breastfeeding for 1-3 months could protect children from severe developmental delay in fine motor domain aged 6 months old (RR=0.36, 95%CI: 0.17-0.79), communication domain aged 18 months old (RR=0.27, 95%CI: 0.08-0.88), and social domain aged 18 months old (RR=0.36, 95%CI: 0.21-0.63). Compared to never breastfeeding, continuous breastfeeding for more than 4 months could protect children from severe developmental delay in fine motor domain aged 6 months old (RR=0.58, 95%CI: 0.34-0.97), communication domain (RR=0.57, 95%CI: 0.39-0.83) and mild developmental delay (RR=0.65, 95%CI: 0.48-0.87) aged 18 months old and fine motor domain (RR=0.57, 95%CI: 0.39-0.83) aged 18 months old and social domain aged 18 months old (RR=0.57, 95%CI: 0.39-0.83). With the breastfeeding intensity rising, there were less children evaluated as severe development delay in communication domain aged 6 months old, communication, fine motor and problem solving domains aged 18 months old, with RR (95%CI) at 0.98 (0.96-1.00), 0.96 (0.93-0.99), 0.98 (0.97-1.00) and 0.98 (0.96-1.00); and less children evaluated as mild development delay in communication domain aged 18 months old with RR (95%CI) at 0.99 (0.98-1.00). Conclusion: Breastfeeding with longer duration and increased intensity could promote better development in children. PMID- 28881547 TI - [Health economic evaluation of bivalent human papilloma virus vaccine in China: based on the dynamic model]. AB - Objective: This study aims to evaluate the prevention effect and cost effectiveness of a prophylactic bivalent human papilloma virus (HPV) vaccine. Methods: A multiple health status dynamic model was developed, including natural history of diseases and prevention strategies. We built 19 prevention strategies including visual inspection with acetic acid/lugol's iodine (VIA/VILI) and/or 3 does prophylactic bivalent HPV vaccine administered to adolescent girls at the age of 15 years old every year under the assumption that vaccine coverage and screening coverage were 70%. The incremental cost-effectiveness ratio (ICER), optimal price of 3 does vaccine and cost-effectiveness frontier of these strategies were analyzed compared with no-intervention. The ICER threshold is 152 087 CNY. Results: Compared with no-intervention, Routine vaccination reduced the incidence of cervical cancer by 69.5%, superior to 5 strategies including VIA/VILI screening only. The range of effect was between 9.0% and 69.2%, and the effect of strategy increased significantly with the increase of screening frequency. Combination vaccination with screening at ages of 35 reduced the incidence of cervical cancer by 72.0%, and the effect increased with the increase of screening frequency. Combination vaccination with screening every 3 years between (35-64) years old reduced the incidence by 89.4%. Compared with no intervention, the ICER of combination vaccination with screening twice between 35 years and 64 years was 121 292 CNY/life-year, which was cost-effective. The price of vaccine had a significant impact on the ICER of the strategy; when the vaccine price was less than 600 CNY, only routine vaccination or supplementary vaccination between 16-39 years old after routine vaccination was cost-effective; when the vaccine price was less than 1 200 CNY, supplementary vaccination between 16-19 years old plus VIA/VILI was cost-effective. Conclusion: Ther prevention strategy was cost-effective, which could effectively reduce the incidence of cervical cancer by implementation of HPV vaccination combined with VIA/VILI in suitable aging females. PMID- 28881548 TI - [Quality of case report of Japanese Encephalitis after the establishment of surveillance on acute meningitis and encephalitis syndrome in Baoji]. AB - Objective: To evaluate the quality of Japanese Encephalitis (JE) case reports based on the establishment of surveillance on acute meningitis and encephalitis syndrome (AMES) in Baoji. Methods: A surveillance network on AMES cases was set up in Baoji city of Shaanxi province between July 2013 and December 2016. All the cases met the surveillance definition of AMES cases were conducted a questionnaire, collected serum and/or cerebrospinal fluid (CSF) specimens to test JE immunoglobulin M antibodies by using enzyme-linkedimmunosorbent assay methods.The information of the incidence of JE in Shaanxi and Baoji from 2009 to 2016 originated from the China information system for disease control and prevention. Chi square test was used to compare the difference in JE incidence in Baoji, Shaanxi before and after the implementation of AMES monitoring project. Results: 75 out of 855 collected cases were laboratory confirmed as JE, Including 42 suspected JE cases and 33 other suspected cases diagnosed after hospitalization. Except 1 case occurring in December, all the other cases occurred between July and October, especially in August with a peak of 55 cases (73.3%), and 6 cases (8.0%) in July, 11 cases (14.7%) in September, 2 cases (2.7%) in October. The proportion of patients aging 0-6, 7-14 and >=15 years old were respectively 4.0% (3 cases), 8.0% (6 cases) and 88.0% (66 cases). The biochemical test showed the cerebrospinal fluid in 13 cases (17.3%) were slightly turbid, the white blood cell in 31 cases (41.3%) elevated, the glucose levels in 24 cases (32.0%) were abnormal, and the chloride level in 23 cases (30.7%) were abnormal. A total of 103 cases of JE were diagnosed in Baoji from 2009 to 2016, with an average annual incidence rate at 0.34/100 000. The average incidence of JE in 2009-2012 and 2013-2016 was 0.21/100 000 and 0.48/100 000 respectively. From 2013 to 2016, the proportion of JE cases in Baoji, Shaanxi was 19.3% (71/369), and it was 8.9% (32/362) between 2009 and 2012 (chi(2)=4.15, P=0.040). Conclusion: The AMES surveillance project improved the quality of the JE case report in Baoji. Changes appeared in biochemistrical and epidemiological characteristics of cerebrospinal fluid. The incidence of JE was seriously underestimated in Shaanxi province and therefore the sensitivity of Japanese encephalitis surveillance cases should be further improved. PMID- 28881549 TI - [Study on the immunogenicity and safety of recombinant B-subunit/whole cell cholera vaccine infused with antacids in healthy population at ages of 2-6 years]. AB - Objective: To assess the immunogenicity and safety of recombinant B-subunit/whole cell cholera vaccine (rBS/WC) oral cholera vaccine (Ora Vacs) infused with antacids in healthy population at ages of 2-6 years. Methods: Between December 2009 and January 2010, we recruited 900 volunteers aged 2-6 years od through giving out recruitment notice for the eligible children's parents from different vaccination clinics of Chongzuo city in Guangxi Zhuang Autonomous Region. This study was a randomized, double-blind, placebo-controlled trial, and subjects were randomly (2?1) assigned to receive Cholera vaccine infused with antacids or placebo, and observed for safety. Serum samples of 300 subjects in immunogenicity subgroups (200 for vaccine groups, 100 for control groups) before the 1st dose and 49 d (+/-3 d) after immunization were collected, and determined for antibody levels against the cholera toxin (anti-CT) and cholera vibriocidal (anti-Vab) with Enzyme-linked immunosorbent assays (ELISA), based on which the GMT was calculated. There were 266 cases paired with the serum samples before and after immunization (177 for vaccine groups, 89 for control groups). The comparison of subjects' age at enrollment and the level of GMT before and after immunization between groups were analyzed by t test. The superiority test for the difference between seroconversion rates of vaccine groups and control groups were analyzed by chi(2) test. Results: Of 900 subjects enrolled, the number of males and females were 503 and 397 respectively (vaccine groups 335 vs. 265, control groups 168 vs. 132), the average ages of vaccine groups and control groups at enrollment were (4.8+/-1.2) years and (4.9+/-1.2) years respectively. There were no significant differences between groups in terms of gender and age (chi(2)=0.00, P=1.000; t=0.55, P=0.585). The 2 times increase rates of anti-CT and anti-Vab in vaccine groups after inoculation were 90.96% and 57.63% respectively, which were superiority to those of control groups (15.73% and 29.21%), and significant differences were observed between groups (chi(2)=15.89, chi(2)=3.85, P<0.001). There were significant differences between vaccine groups and control groups after inoculation in terms of GMTs of anti-CT (1?647.56 vs. 1?99.49) and anti-Vab antibodies (1?16.19 vs. 1?11.27) (t values were 15.82 and 3.43, respetively; both P values were<0.05), significant differences were observed in the growth rates when compared the GMTs of anti-CT (6.63 vs. 1.11) and anti-Vab antibodies (1.64 vs. 1.16) before inoculation between vaccine groups and control groups (t'=17.85 and 4.96, P<0.001). In terms of safety, the adverse reaction rates in vaccine groups and control groups were 37.67% (226/600) and 36.67% (110/300), respectively,the common adverse reaction including fever, nausea, vomiting, abdominal pain, diarrhea, headache, fatigue, allergies, rash, etc; and the severity degree were mainly for level 1. Conclusion: Ora Vacs infused with antacids could produce an positive effect on immune response and safety. PMID- 28881550 TI - [The epidemiological characteristics and drug resistance of mycoplasma pneumoniae in patients with community-acquired pneumonia during 2011-2015 in 5 sentinel hospitals in Beijing]. AB - Objective: To analyze the prevalence and drug resistance of mycoplasma pneumoniae in patients with community-acquired pneumonia during 2011-2015 in Beijing. Methods: Totally 2 272 mycoplasma pneumoniae samples were collected from patients with community-acquired pneumonia in 5 sentinel hospitals during 2011-2015. Mycoplasma pneumoniae were detected by real-time PCR. 142 copies of positive samples with Ct value under 30 were cultured to get the strains so that the genotypes based on the P1 gene sequence and the drug resistance based on the in vitro drug resistance test could be conducted. chi(2) test was used to compare the detection rates of mycoplasma pneumoniae among different age groups and different onset-phase. Results: The positive rate of mycoplasma pneumoniae was 13.6%(308 cases). The positive rate in groups aging (5-14), (15-24) and >=60 years old were separately 24.4% (67/275), 24.4% (38/156) and 3.9% (28/727) (chi(2)=1.22, P<0.001). The annual detection rate of mycoplasma pneumoniae in 2011-2015 were 14.6% (73/501), 10.2% (36/353), 26.4% (101/383), 10.3% (41/398), 9.0% (57/637),respectively (chi(2)=72.65, P<0.001). Seasonally, the peak of positive rate was between October and December (17.5%, 122/699) and the lowest positive rate was between April and June (8.6%, 43/502). 36 strains were isolated from 142 swabs and 23 (63.9%) were P1-I and 13 (36.1%) were P1-II by genotyping. All isolates were susceptible to the fluoroquinolones (levofloxacin, ciprofloxacin, and gatifloxacin) and tetracycline. All P1-II strains were susceptible to macrolides while most of the P1-I strains (22 strains) were macrolide-resistant. Conclusion: People aging (5-14) and (15-24) years old were more susceptible to mycoplasma pneumoniae in patients with community-acquired pneumonia in Beijing between 2011 and 2015. The highest positive rate of mycoplasma pneumoniae was in 2013 and the case distributed in all seasons. The major popular genotype was P1-I, whose strains were mostly macrolide-resistant. PMID- 28881551 TI - [The prevalence and related factors of HBV infection among adults in Mianyang]. AB - Objective: To analyze the prevalence and related factors of HBV infection among people aged 18 years old and above in Mianyang city. Methods: A total of 260 950 residents, living in Mianyang city more than 6 months, aging 18 years old and above were employed by multi-stage random sampling method from November 2014 to September 2015. Questionnaire survey was conducted on participants using a self designed questionnaire, including general demographic characteristics, family history of Hepatitis B, history of Hepatitis B vaccination and history of present illness, etc. 5ml blood was collected from all participants, and the blood samples were detected for HBsAg by enzyme-linked immunosorbent assay (ELISA). The multivariate unconditional logistic regression was performed to identify the related factors of positive HBsAg. Results: Among the 260 950 subjects, 113 184 were males (43.37%), 147 766 were females (56.63%), and the average age was (47.68+/-17.36) years old. The positive rate of HBsAg was 6.10%(15 822 cases). Subjects who were 25-34 years old (OR=1.23), 35-44 years old (OR=1.26), 45-54 years old (OR=1.23), and 55-64 years old (OR=1.34) were more likely to be HBsAg positive,65 years and older (OR=0.88) were less likely to be, compared with subjects aging 18-24 years old; males were more likely to be HBsAg positive compared with females (OR=1.35); people living in Fucheng district were more likely to be HBsAg positive compared with who living in Jiangyou district(OR=1.91); married people were more likely to be HBsAg positive compared with unmarried ones (OR=1.36); medical staff were less likely to be HBsAg positive compared with non-medical staff (OR=0.61); subjects with a surgery history were more likely to HBsAg positive compared with who without (OR=1.13); subjects with trauma history were more likely to HBsAg positive compared with who without (OR=1.13); people with history of Hepatitis B were more likely to HBsAg positive compared with who without (OR=4.21); people with Hepatitis B vaccination history were less likely to be HBsAg positive compared with who without (OR=0.48); all the P values above were less than 0.05. Conclusion: The positive rate of HBsAg among adults in Mianyang city was very high, and we should pay more attention to people aging between 25 and 64 years old, male, medical staff, with surgery history, trauma history, and a family history of Hepatitis B and Hepatitis B vaccination history. PMID- 28881552 TI - [Analysis on the exposure level and geographic distribution trend of toxicological indicators in rural drinking water, Shandong Province, in 2015]. AB - Objective: To analyze the exposure level and the geographical distribution trend of toxicological indicators of rural drinking water in Shandong Province. Methods: The drawing method was used to randomly select no less than 60% villages and towns from 137 counties (cities, districts) of 17 cities in Shandong Province in 2015, and then 1-3 rural centralized water supply units were selected according to the circumstance of rural centralized water supply units in each village and town. In total, 735 villages and towns, 1 473 rural centralized water supply units were selected, and 1 473 water samples were collected. The water treatment process, water supply population and other circumstances of the rural centralized water supply units were investigated, the water quality was monitored, the content of toxicological indicators of drinking water in different areas was compared, and the trend surface isogram of excessive toxicological indicators was drawn. Results: The qualified rate of toxicological indicators in 1 473 water samples was 83.64% (n=1 232). The main toxicological indicators that affected the qualified rate of toxicological indicators of drinking water in rural areas in Shandong Province were nitrate and fluoride. The excessive rate of fluoride was 5.70% (n=84) and the exposed population was 1 736 709 (4.22%). The excessive rate of nitrate (as nitrogen) was 12.29% (n=181) and the exposed population was 1 393 612 (3.39%). The P(5)0 content of fluoride in the eastern, middle and western regions was 0.24, 0.29 and 0.59 mg/L, respective;which was higher in the western region than in the east and the middle regions (P<0.05). There was no significant difference between the eastern and the middle regions (P>0.05). The P(50) content of nitrate (as nitrogen) in the eastern, middle and western regions was 8.00, 7.48, and 2.00 mg/L, which was higher in the eastern and middle regions than in the west region (P<0.05), there was no significant difference between the eastern and the middle regions (P>0.05). The trend surface isogram of nitrate and fluoride content showed that the content of nitrate (as nitrogen) in rural drinking water in the eastern region was significantly higher than that in the western region, especially there was a high peak area in the northeastern region, and this high content distribution extended diagonally to the central region, while the other regions were in a relatively low range. The content of fluoride in rural drinking water in the western region was significantly higher than that in the eastern region, and there were high peaks in the southwest and northwest regions, and the other regions were in a relatively low range. Conclusion: The high exposed toxicological indicators in rural drinking water in Shandong Province were nitrate (as nitrogen) and fluoride, and their distribution showed obvious geographical distribution trend. PMID- 28881554 TI - [Study on quality of life and its related factors among patients with chronic hepatitis C in rural area]. PMID- 28881553 TI - [Association between A-kinase anchor proteins 12 methylation and recurrence of hepatocellular carcinoma]. AB - Objective: To study the association between the AKAP12 promoter methylation and recurrence of hepatocellular carcinoma. Methods: A total of 142 primary liver cancer patients underwent surgery in department of Hepatobiliary surgery in Peking University Cancer Hospital from 2003 to 2009 were selected as subjects in the survey; with the inclusion criteria as hepatocellular carcinoma, no cancer cells were observed in the surgical margin(SM) samples. All patients had neither lymph nor distant metastasis at the time of surgery, and receiving complete follow-up data for at least 3 years. By the end of May 2014, a total of 75 patients had relapsed of whom 71 died and there were no lost. All samples were acquired from the frozen surgical tissues. Genomic DNA was extracted using phenol/chloroform method and performed bisulfite modification following with polymerase chain reaction (PCR). AKAP12 methylation in hepatoma and the corresponding SM samples from 142 patients was determined by denature high performance liquid chromatography (DHPLC) and bisulfite clone sequencing. Kaplan Meier and Cox proportion hazard regression model were used to identify the factors related to the survival time. Results: In 142 cases, 125 patients (88.0%) were male and 17 (12.0%) cases were female. The median age was 52.5 years, ranging from 34 years to 76 years. AKAP12 methylation-positive rate was significantly higher in hepatomas than SMs (54.9% vs. 10.2%, P<0.001). Patients with AKAP12 methylation-positive had less risk of the recurrence (HR=0.62, 95%CI: 0.39-0.99); with tumor diameter more than 5 cm (HR=1.53, 95%CI: 1.00-2.50),portal vein invasion(HR=4.53, 95% CI:2.69-7.64) increased the recurrence risk. Moreover, portal vein invasion had a higher risk of death (HR=2.98, 95% CI: 1.73-4.98). Conclusion: There was significant association between AKAP12 DNA methylation and low risk of recurrence and long progression-free survival of hepatocellular carcinoma patients. PMID- 28881555 TI - [Molecular characteristics of the first imported case of dengue-2 virus at Yuxi city in Yunnan Province]. PMID- 28881556 TI - [Epidemiological analysis of pertussis in Jinan, 2005-2015]. PMID- 28881557 TI - [Early adiposity rebound: prevalence and the effect on metabolic risk in children]. AB - The timing of the adiposity rebound (AR) gradually shifted to earlier ages throughout the world; early AR has a great effect on children's health, especially is possible associated with the development of metabolic disease for life, while the special mechanism isn't very clear. Metabolic diseases(MD) are common in adults, and the establishment of MD is the result of pathological chronic processes that can start in early life stages. If the metabolic risk factors and its predictive factors can be found in early childhood, it can bring forward the prevention and control of adult diseases. This paper is a review of the prevalence of early AR around the world, the factors that influence the timing of the AR, the significance of early detection and prevention of MD, the associations between timing of AR and metabolic risk in children and explored the possible mechanism. It aims to raise public awareness about the harm of early AR and provide new perspective to prevent and control of the metabolic syndrome. PMID- 28881558 TI - [Developmental pattern of hypothalamic-pituitary-adrenal axis during pubertal transition and implications for emotional disorders]. AB - During an individual's life, puberty is not only a crucial phase for physical development, but a key period for neuroendocrine transformation. As a major neuroendocrine axis, the influence of hypothalamic-pituitary-adrenal (HPA) axis's changes during puberty on mental and physical health, as well as emotional symptoms, is causing a growing attention. However, information of its developing pattern and circadian variation is limited. Recent research has demonstrated that certain developing pattern of HPA axis in puberty is closely related to the adolescent emotional disorders, which highlights the recognition of HPA functions developing paths under both resting and stress state and the evaluation of its prediction effect for the adolescent emotional disorders. Generally, cortisol awakening response is utilised to assess HPA functions. Elaborating the variation of HPA axis functions from the puberty to the later developing process provides much guiding significance for the early screening, intervention and treatment of adolescent emotional disorders. PMID- 28881559 TI - [Minutes of the 8(th) Forum on Basic Science & Applied Technology for Prevention and Control of infectious Diseases]. PMID- 28881561 TI - Multi-story Parkin. PMID- 28881560 TI - Sequential Objective Structured Clinical Examination based on item response theory in Iran. AB - PURPOSE: In a sequential objective structured clinical examination (OSCE), all students initially take a short screening OSCE. Examinees who pass are excused from further testing, but an additional OSCE is administered to the remaining examinees. Previous investigations of sequential OSCE were based on classical test theory. We aimed to design and evaluate screening OSCEs based on item response theory (IRT). METHODS: We carried out a retrospective observational study. At each station of a 10-station OSCE, the students' performance was graded on a Likert-type scale. Since the data were polytomous, the difficulty parameters, discrimination parameters, and students' ability were calculated using a graded response model. To design several screening OSCEs, we identified the 5 most difficult stations and the 5 most discriminative ones. For each test, 5, 4, or 3 stations were selected. Normal and stringent cut-scores were defined for each test. We compared the results of each of the 12 screening OSCEs to the main OSCE and calculated the positive and negative predictive values (PPV and NPV), as well as the exam cost. RESULTS: A total of 253 students (95.1%) passed the main OSCE, while 72.6% to 94.4% of examinees passed the screening tests. The PPV values ranged from 0.98 to 1.00, and the NPV values ranged from 0.18 to 0.59. Two tests effectively predicted the results of the main exam, resulting in financial savings of 34% to 40%. CONCLUSION: If stations with the highest IRT based discrimination values and stringent cut-scores are utilized in the screening test, sequential OSCE can be an efficient and convenient way to conduct an OSCE. PMID- 28881562 TI - NF-kappaB-mediated astrocyte dysfunction initiates neurodegeneration. PMID- 28881563 TI - Immunosuppression by viral N proteins. PMID- 28881564 TI - Targeting APP/AICD in Down syndrome. PMID- 28881565 TI - Reversibility of Abeta oligomer neurotoxicity. PMID- 28881566 TI - PPARs as determinants of the estrogen receptor lineage: use of synthetic lethality for the treatment of estrogen receptor-negative breast cancer. AB - THE DILEMMA: Estrogen receptora-negative (ER-) breast cancer lacks a specific critical target to control tumor progression. THE OBJECTIVE: To identify mechanisms that enable increased expression of the ER+ lineage in an otherwise ER breast cancer. PREFACE: The nuclear receptor superfamily members PPARgamma and PPARdelta regulate gene expression associated with a multitude of pathways, including intermediary metabolism, angiogenesis, proliferation and inflammation (see reviews [1-3]). Recent developments using transgenic and knockout mice, as well as pharmacologic intervention with PPARgamma and PPARdelta agonists, have revealed a previously unknown relationship between PPARgamma suppression and PPARdelta activation that leads to the appearance of ER+ tumors, enabling a synthetic lethality approach by anti-ER therapy. The ability to selectively affect the ER+ lineage by modulating PPARgamma and PPARdelta activity represents a new clinical paradigm and opportunity to treat ER- cancer with PPARgamma and PPARdelta modulating agents, ultimately rendering them more responsive to adjuvant therapy. PMID- 28881567 TI - Restoration of immune surface molecules in Kaposi sarcoma-associated herpes virus infected cells by lenalidomide and pomalidomide. AB - Kaposi sarcoma-associated herpesvirus (KSHV) is the cause of several tumors, including Kaposi sarcoma and primary effusion lymphoma (PEL). Most viruses have evolved means of escaping immune recognition. KSHV downregulates MHC-I expression during lytic infection, and expression of ICAM-1 and B7-2 (CD86) during latent infection, allowing evasion of T cell and natural killer immunity respectively. These effects are largely mediated by two KSHV-encoded proteins, K3 and K5. We show here that lenalidomide (Len) and pomalidomide (Pom) prevent down-regulation of MHC-I during lytic activation, and restore ICAM-1 and B7-2 surface expression in latently infected PEL cells. Importantly, these changes occurred at clinically achievable concentrations and prior to any cytotoxic effects. Exploration of the mechanism revealed that Pom blocked lytic down-regulation of MHC-I induced by transfection with K3 but not K5. Although Pom alone did not significantly increase HLA mRNA expression in PEL cells, it did blunt the butyrate-induced decrease in MHC-I mRNA expression and decreased the upregulation of K3 mRNA in lytic cells. Virus-induced tumors express foreign antigens, but immunotherapy can be thwarted by viral strategies to evade immune recognition. The effects of Pom and Len described here can prevent these strategies and support the use of these drugs to treat KSHV-induced tumors. PMID- 28881568 TI - Modulation of estrogen related receptor alpha activity by the kinesin KIF17. AB - Estrogen-related receptor alpha (ERR1) is an orphan nuclear receptor that can bind transcriptional co-activators constitutively. ERR1 expression correlates with poor patient outcomes in breast cancer, heightening interest in this nuclear receptor as a therapeutic target. Because ERR1 has no known regulatory ligand, a major challenge in targeting its activity is to find cellular or synthetic modulators of its function. We identified an interaction between ERR1 and KIF17, a kinesin-2 family microtubule motor, in a yeast-2-hybrid screen. We confirmed the interaction using in vitro biochemical assays and determined that binding is mediated by the ERR1 ligand-binding/AF2 domain and the KIF17 C-terminal tail. Expression of KIF17 tail domain in either ER-negative or ER-positive breast cancer epithelial cells attenuated nuclear accumulation of newly synthesized ERR1 and inhibited ERR1 transcriptional activity. Conversely, ERR1 transcriptional activity was elevated significantly in KIF17 knock-out cells. Sequence analysis of the KIF17 tail domain revealed it contains a nuclear receptor box with a conserved LXXLL motif found in transcriptional co-activators. Expression of a 12 amino-acid peptide containing this motif was sufficient to inhibit ERR1 transcriptional activity and cell invasion, while deletion of this region from the KIF17 tail resulted in increased ERR1 activity. Together, these data suggest KIF17 modifies ERR1 function by two possible, non-exclusive mechanisms: (i) by regulating nuclear-cytoplasmic distribution or (ii) by competing with transcriptional co-activators for binding to ERR1. Thus targeting the ERR1-KIF17 interaction has potential as a novel strategy for treating breast cancer. PMID- 28881569 TI - Aurora A kinase regulates non-homologous end-joining and poly(ADP-ribose) polymerase function in ovarian carcinoma cells. AB - Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a better understanding of signaling pathways important for ovarian cancer progression. Aurora A kinase (AURKA) plays an important role in ovarian cancer progression by mediating mitosis and chromosomal instability. In the current study, we investigated the role of AURKA in regulating the DNA damage response and DNA repair in ovarian carcinoma cells. We discovered that AURKA modulated the expression and activity of PARP, a crucial mediator of DNA repair that is a target of therapeutic interest for the treatment of ovarian and other cancers. Further, specific inhibition of AURKA activity with the small molecule inhibitor, alisertib, stimulated the non-homologous end-joining (NHEJ) repair pathway by elevating DNA PKcs activity, a catalytic subunit required for double-strand break (DSB) repair, as well as decreased the expression of PARP and BRCA1/2, which are required for high-fidelity homologous recombination-based DNA repair. Further, AURKA inhibition stimulates error-prone NHEJ repair of DNA double-strand breaks with incompatible ends. Consistent with in vitro findings, alisertib treatment increased phosphorylated DNA-PKcs(pDNA-PKcsT2609) and decreased PARP levels in vivo. Collectively, these results reveal new non-mitotic functions for AURKA in the regulation of DNA repair, which may inform of new therapeutic targets and strategies for treating ovarian cancer. PMID- 28881570 TI - Diagnostic performance of gait speed, G8 and G8 modified indices to screen for vulnerability in older cancer patients: the prospective PF-EC cohort study. AB - BACKGROUND: The diagnostic performance of tools used to screen vulnerability in older cancer patients varies widely. We assessed the diagnostic performance of gait speed (GS) for assessing vulnerability in such patients. METHODS: All consecutive outpatients 65 years and older were referred for geriatric oncology assessment (GA) before a therapeutic decision between November 2013 and April 2016 in a bicentric observational and prospective cohort study. Vulnerability was defined as impaired score on at least one of the 6 domains of the GA. GS and the G8 index and G8 modified index were assessed at the first geriatric oncology visit during the GA. Sensitivity, specificity, positive and negative predictive value and positive and negative likelihood ratio were estimated. The accuracy of the three tools was analysed by the area under the receiver operating characteristic curve (AUC). RESULTS: Among 269 included patients (mean [SD] age, 81.3 years [5.9]; 55% women, 94.4% solid tumors; 39.4% with metastasis), 252 (93.7%) had impaired GA. With the GS threshold of 1 m/s, sensitivity was 79.4% (95% CI, 73.8-84.2), specificity 64.7% (38.3-85.8), and AUC 82.0 (74.0-90.0). The corresponding values for the G8 index were 90.1% (85.7-93.5), 35.3% (14.2-61.7), and 79.0 (70.0-88.0) and G8 modified index were 89.3% (84.8-92.8), 64.7% (38.3 85.8), and 84.0 (74.0-92.0). CONCLUSIONS: GS < 1 m/s with a single measure could be used as a new screening tool for detecting vulnerability in older cancer outpatients. This first external validation of the G8 modified index was very good. PMID- 28881571 TI - Phospho-AXL is widely expressed in glioblastoma and associated with significant shorter overall survival. AB - Receptor tyrosine kinase AXL (RTK-AXL) is regarded as a suitable target in glioblastoma (GBM) therapy. Since AXL kinase inhibitors are about to get approval for clinical use, patients with a potential benefit from therapy targeting AXL need to be identified. We therefore assessed the expression pattern of Phospho AXL (P-AXL), the biologically active form of AXL, in 90 patients with newly diagnosed GBM, which was found to be detectable in 67 patients (corresponding to 74%). We identified three main P-AXL expression patterns: i) exclusively in the tumor vasculature (13%), ii) in areas of hypercellularity (35%), or iii) both, in the tumor vasculature and in hypercellular areas of the tumor tissue (52%). Pattern iii) is associated with significant decrease in overall survival (Hazard ratio 2.349, 95% confidence interval 1.069 to 5.162, *p=0.03). Our data suggest that P-AXL may serve as a therapeutic target in the majority of GBM patients. PMID- 28881572 TI - A single nucleotide polymorphism in the interferon-gamma gene (IFNG +874 T/A) is associated with susceptibility to tuberculosis. AB - Interferon-gamma (Interferon gamma, IFNG) is an important cytokine involved in providing resistance to mycobacterial diseases. Common variants of IFNG, such as IFNG +874 T/A(rs2430561), may be related to tuberculosis susceptibility, but this association has not been consistently observed. We performed an updated meta analysis to evaluate the association between the IFNG +874 T/A (rs2430561) polymorphism and tuberculosis susceptibility. PubMed and SinoMed databases were searched up to October 2016, and odds ratios (OR) and 95% confidence intervals (CI) were used to assess the association strength. Based on search criteria for manuscripts reporting tuberculosis susceptibility and its relationship with the IFNG +874 T/A(rs2430561)polymorphism, 42 case-control studies from 39 different articles were retrieved. Significantly positive, decreased, and protective associations were found between the IFNG +874 T/A(rs2430561)polymorphism and tuberculosis risk in five genetic models. Moreover, in the stratified subgroup analysis, a protective relationship was detected in four different ethnicities and sources of the control groups. Furthermore, the IFNG +874 T/A(rs2430561)polymorphism played an important role in protecting individuals from both pulmonary tuberculosis and extra-pulmonary tuberculosis. Our meta analysis suggests that the IFNG +874 T/A(rs2430561)polymorphism is potentially associated with tuberculosis susceptibility and may be used as a predictive biomarker. Further studies with larger sample sizes and consideration of gene environment interactions should be conducted to elucidate the role of IFNG +874 T/A(rs2430561) polymorphism in tuberculosis susceptibility. PMID- 28881573 TI - Histopathological findings of renal tissue induced by oxidative stress due to different concentrations of fluoride. AB - It has been reported that excessive intake of fluoride can induce renal lesions. However, its pathogenesis is still less understood. Therefore, this study was conducted to investigate oxidative damage and the relationships between the oxidative damage and renal lesions in fluoride-treated mice by using the methods of histopathology, biochemistry, flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR). A total of 240 ICR mice were randomly divided into four equal groups (sodium fluoride was given orally at the dose of 0, 12, 24 and 48 mg/kg body weight for 42 days, respectively). We found that fluoride in excess of 12 mg/kg induced renal oxidative damage, which was characterized by increasing the levels of reactive oxygen species (ROS) production and contents of malondialdehyde (MDA) and protein carbonyls (PC), and decreasing the abilities of anti-superoxide anion (ASA) and anti-hydroxyl radical (AHR), glutathione (GSH) content, as well as activities and mRNA expression levels of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GSH-Px). Concurrently, fluoride caused degeneration and necrosis of the tubular cells, renal tubular hyaline casts and glomeruli swelling, which were consistent with the alteration of renal function parameters including elevated contents of serum creatinine (Cr), serum uric acid (UA), blood urea nitrogen (BUN), and the activities of urinary N-acetyl-b-D-glucosaminidase (NAG), renal lactate dehydrogenase (LDH), and reduced activities of sodium potassium adenosine triphosphatase (Na+/K+-ATPase) and acid phosphatase (ACP) in the kidney. The above-mentioned results showed that fluoride in excess of 12 mg/kg induced renal oxidative damage, which then caused renal lesions and dysfunctions. These findings also clearly demonstrated that oxidative damage is one of the mechanisms of fluoride-induced renal lesions and dysfunctions. PMID- 28881574 TI - Prevention of colitis-associated cancer by selective targeting of immunoproteasome subunit LMP7. AB - Chronic inflammation is a well-known risk factor in development of intestinal tumorigenesis, although the exact mechanisms underlying development of colitis associated cancer (CAC) still remain obscure. The activity and function of immunoproteasome has been extensively analyzed in the context of inflammation and infectious diseases. Here, we show that the proteasomal immunosubunit LMP7 plays an essential role in development of CAC. Mice devoid of LMP7 were resistant to chronic inflammation and formation of neoplasia, and developed virtually no tumors after AOM/DSS treatment. Our data reveal that LMP7 deficiency resulted in reduced expression of pro-tumorigenic chemokines CXCL1, CXCL2 and CXCL3 as well as adhesion molecule VCAM-1. As a consequence, an impaired recruitment and activity of tumor-infiltrating leukocytes resulting in decreased secretion of cytokines IL-6 and TNF-alpha was observed. Further, the deletion or pharmacological inhibition of LMP7 and consequent blockade of NF-kappaB abrogated the production of IL-17A, which possesses a strong carcinogenic activity in the gut. Moreover, in vivo administration of the selective LMP7 inhibitor ONX-0914 led to a marked reduction of tumor numbers in wild-type (WT) mice. Collectively, we identified the immunoproteasome as a crucial mediator of inflammation-driven neoplasia highlighting a novel potential therapeutic approach to limit colonic tumorigenesis. PMID- 28881575 TI - Overexpression of C16orf74 is involved in aggressive pancreatic cancers. AB - Clinical outcome of pancreatic ductal adenocarcinoma (PDAC) has not been improved in the last three decades due to the lack of effective molecular-targeted drugs. To identify a novel therapeutic target for PDAC, we have performed genome-wide anamysis and found that Homo sapienschromosome 16 open reading frame 74 (C16orf74) was up-regulated in the vast majority of PDAC. Overexpression of C16orf74protein detected by immunohistochemical analysis was an independent prognostic factor for patients with PDAC. The knockdown of endogenous C16orf74 expression in the PDAC cell lines KLM-1 and PK-59 by vector-based small hairpin RNA (shRNA) drastically attenuated the growth of those cells, whereas ectopic C16orf74 overexpression in HEK293T and NIH3T3 cells promoted cell growth and invasion, respectively. More importantly, the endogenous threonine 44 (T44) phosphorylated form of C16orf74 interacted with the protein phosphatase 3 catalytic subunit alpha (PPP3CA) via the PDIIIT sequence in the PPP3CA-binding motif within the middle portion of C16orf74 in PDAC cells. The overexpression of mutants of C16orf74 lacking the PDIIIT sequence or T44 phosphorylation resulted in the suppression of invasive activity compared with wild-type C16orf74, indicating that their interaction should be indispensable for PDAC cell invasion. These results suggest that C16orf74 plays an important role for PDAC invasion and proliferation, and is a promising target for a specific treatment for patients with PDAC. PMID- 28881576 TI - Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis. AB - In sporadic colon cancer, colon cancer stem cells (CCSCs) initiate tumorigenesis and may contribute to late disease recurrences and metastases. We previously showed that aldehyde dehydrogenase (ALDH) activity (as indicated by the ALDEFLUOR(r) assay) is an effective marker for highly enriching CCSCs for further evaluation. Here, we used comparative transcriptome and proteome approaches to identify signaling pathways overrepresented in the CCSC population. We found overexpression of several components of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway, including PI3KR2, a regulatory subunit of PI3K. LY294002, a PI3K inhibitor, defined the contribution of the PI3K/Akt/mTOR signaling pathway in CCSCs. LY294002-treated CCSCs showed decreases in proliferation, sphere formation and self-renewal, in phosphorylation-dependent activation of Akt, and in expression of cyclin D1. Inhibition of PI3K in vivo reduced tumorigenicity, increased detection of cleaved caspase 3, an indicator of apoptosis, and elevated expression of the inflammatory chemokine, CXCL8. Collectively, these results indicate that PI3K/Akt/mTOR signaling controls CCSC proliferation and CCSC survival, and suggests that it would be useful to develop therapeutic agents that target this signaling pathway. PMID- 28881577 TI - A comprehensively characterized cell line panel highly representative of clinical ovarian high-grade serous carcinomas. AB - Recent literature suggests that most widely used ovarian cancer (OVCA) cell models do not recapitulate the molecular features of clinical tumors. To address this limitation, we generated 18 cell lines and 3 corresponding patient-derived xenografts predominantly from high-grade serous carcinoma (HGSOC) peritoneal effusions. Comprehensive genomic characterization and comparison of each model to its parental tumor demonstrated a high degree of molecular similarity. Our characterization included whole exome-sequencing and copy number profiling for cell lines, xenografts, and matched non-malignant tissues, and DNA methylation, gene expression, and spectral karyotyping for a subset of specimens. Compared to the Cancer Genome Atlas (TCGA), our models more closely resembled HGSOC than any other tumor type, justifying their validity as OVCA models. Our meticulously characterized models provide a crucial resource for the OVCA research community that will advance translational findings and ultimately lead to clinical applications. PMID- 28881578 TI - The establishment of a growth-controllable orthotopic bladder cancer model through the down-regulation of c-myc expression. AB - To properly evaluate the biological effects of immunotherapy, it is critical to utilize a model of cancer in immune-competent mice. Currently, MBT-2 is the most common murine bladder cancer cell line used in orthotopic bladder cancer models, even though this cell type often has an inappropriate genetic mutation landscape. In these models, after tumors are detected with in vivo imaging, the mouse usually dies within two to three weeks due to post-renal azotemia caused by the rapidly growing mass. This event prohibits the evaluation of tumor behavior upon intravesical drug treatment. We explored whether an shRNA-induced decrease in the expression of the c-myc oncogene in MBT-2 cells could slow down their in vitro proliferation and in vivo tumor growth. We transduced MBT-2 cells with shRNA lentiviruses that bound c-myc, established MBT2.cMYCshRNA and confirmed the retardation of the growth of tumors implanted in C3H/He mice. Accordingly, this study suggests that this novel orthotopic bladder cancer model in immune competent mice may be more appropriate for the analysis of the effects of the intravesical instillation of immunotherapeutic agents. PMID- 28881579 TI - Methylation of HPV and a tumor suppressor gene reveals anal cancer and precursor lesions. AB - We studied DNA methylation patterns of human papillomavirus (HPV) and tumor suppressor gene EPB41L3 in 148 anal and perianal biopsies to determine whether high levels of methylation would be associated with anal intraepithelial neoplasia (AIN). The most prevalent HPV type was HPV16, detected in 54% of the 30 benign biopsies, 33% of the 43 low-grade AIN (lgAIN), 82% of the 59 high grade AIN (hgAIN) and 4 of the 5 anal cancers. A methylation score was developed (0.561*HPV16me+0.439*EPB41L3) which had increasing values with severity of disease: the mean was 8.1% in benign, 13.2% in lgAIN, 22.3% in hgAIN and 49.3% in cancers (p < 0.0001). The methylation score as a triage classifier at a cut-off of 8.8 gave a sensitivity of 90.6% (95% CI: 82.8, 96.9), specificity of 50.7% (95% CI: 39.7, 61.6) and area under the curve of 0.82 (95% CI: 0.75-0.89) for separating hgAIN and cancer from benign and lgAIN biopsies. We conclude that methylation of HPV16 and EPB41L3 show highly significant association with increasing severity of AIN and cancer and may be useful as biomarkers in anal disease. PMID- 28881580 TI - Selective compounds enhance osteoblastic activity by targeting HECT domain of ubiquitin ligase Smurf1. AB - The HECT-type ubiquitin ligase Smurf1 (Smad ubiquitination regulatory factor-1) plays the prominent role in regulation of bone formation, embryonic development, and tumorigenesis by directing the ubiquitin-proteasomal degradation of specific targets. In contrast with RING-type E3s, the catalytic HECT domain of Smurf1 firstly binds to and then transfers ubiquitin (Ub) molecules onto the substrates. The Smurf1-Ub interaction is required for Smurf1 catalytic ligase activity to promote substrate degradation. However, so far specific regulators or compounds controlling Smurf1-Ub interaction and the ligase activity have not been identified. Here we report two small molecule compounds targeting Ub binding region of HECT domain interrupt Smurf1-Ub contact, inhibit Smurf1 ligase activity and stabilize BMP signal components Smad1/5 protein level. Furthermore, these compounds increase BMP signal responsiveness and enhance osteoblastic activity in cultured cells. These findings provide a novel strategy through targeting Smurf1 ligase activity to potentially treat bone disorders such as osteoporosis. PMID- 28881581 TI - A molecular pathology method for sequential fluorescence in situ hybridization for multi-gene analysis at the single-cell level. AB - Multi-gene detection at the single-cell level is desirable to enable more precise genotyping of heterogeneous hematology and oncology samples. This study aimed to establish a single-cell multi-gene fluorescence in situ hybridization (FISH) method for use in molecular pathology analyses. Five fluorochromes were used to label different FISH gene probes, and 5 genes were detected using a five-color FISH protocol. After the first hybridization, the previous FISH probe set was stripped, and a second set of five-color FISH probes was used for rehybridization. After each hybridization, the fluorescence signals were recorded in 6 fluorescence filter channels that included DAPI, Spectrum GreenTM, Cy3TM v1, Texas Red, Cy5, and PF-415. A digital automatic relocation procedure was used to ensure that exactly the same microscopic field was studied in each stripping and hybridization cycle. By using this sequential stripping and rehybridization strategy, up to 20 genes can be detected within a single nucleus. In conclusion, a practical molecular pathology method was developed for analyzing multiple genes at the single-cell level. PMID- 28881583 TI - Troy is expressed in human stomach mucosa and a novel putative prognostic marker of intestinal type gastric cancer. AB - Epithelial stem cells of gastrointestinal tissues are characterized and controlled by an active Wnt signaling. Recently, the Wnt target gene Troy has been proposed as a neoplastic marker in the murine intestine. In this study, we explored the putative tumor biological significance of Troy in humans by using immunohistochemistry (104 cases), quantitative RT-PCR (50 cases) and cell culture experiments (MKN45, MKN74). In the non-neoplastic gastric mucosa, Troy was expressed by Muc5AC-positive foveolar epithelium, parietal cells, chief cells and cells of the intestinal metaplasia. In gastric cancer, Troy was found in the desmoplastic stroma and tumor cells. The overall staining intensity of the tumor cells was lower compared with the adjacent non-neoplastic mucosa, Troy was found significantly more commonly in intestinal compared with diffuse type gastric cancer (p=0.001) and correlated inversely with tumor grade (p<0.001) and nodal spread (p=0.025). In the intestinal type, loss of Troy-expression was associated with a significantly worse overall survival (p=0.006). Subsequent cell culture experiments showed a Wnt dependent expression of Troy and a reduced colony formation ability of Troy-overexpressing MKN45-cells. Our results lead to the conjecture that Troy is also a negative regulator of WNT signaling in gastric cancer, which affects patient outcome. PMID- 28881582 TI - Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells. AB - Metformin inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which is frequently upregulated in hepatocellular carcinoma (HCC). Metformin has also been shown to induce apoptosis in this cancer. Here, we investigate whether metformin-induced apoptosis in HCC is mediated by the downstream mTORC1 effectors eukaryotic initiation factor 4E and (eIF4E)-binding proteins (4E-BPs). Further, we ask whether changes in 4E-BPs activity during metformin treatment negatively regulate translation of the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) mRNA. A genetic HCC mouse model was employed to assess the ability of metformin to reduce tumor formation, induce apoptosis, and control 4E-BP1 activation and Mcl-1 protein expression. In parallel, the HCC cell line Huh7 was transduced with scrambled shRNA (control) or shRNAs targeting 4E-BP1 and 4E-BP2 (4E-BP knock-down (KD)) to measure differences in mRNA translation, apoptosis, and Mcl-1 protein expression after metformin treatment. In addition, immunohistochemical staining of eIF4E and 4E-BP1 protein levels was addressed in a HCC patient tissue microarray. We found that metformin decreased HCC tumor burden, and tumor tissues showed elevated apoptosis with reduced Mcl-1 and phosphorylated 4E-BP1 protein levels. In control but not 4E-BP KD Huh7 cells, metformin induced apoptosis and repressed Mcl-1 mRNA translation and protein levels. Immunostaining of HCC patient tumor tissues revealed a varying ratio of eIF4E/4E-BP1 expression. Our results propose that metformin induces apoptosis in mouse and cellular models of HCC through activation of 4E-BPs, thus tumors with elevated expression of 4E-BPs may display improved clinical chemopreventive benefit of metformin. PMID- 28881584 TI - Dimerization of EGFR and HER2 induces breast cancer cell motility through STAT1 dependent ACTA2 induction. AB - The dimerization of EGFR and HER2 is associated with poor prognosis such as induction of tumor growth and cell invasion compared to when EGFR remains as a homodimer. However, the mechanism for events after dimerization in breast cancer models is not clear. We found that expressions of alpha-smooth muscle actin (ACTA2) and signal transducer and activator of transcription 1 (STAT1) significantly increased with transient or stable overexpression of HER2 in EGFR positive breast cancer cells. ACTA2 and STAT1 expression was also increased in HER2-positive breast cancer patients. In contrast, ACTA2 expression was decreased by HER2 siRNA. Next, we investigated the co-relation between STAT1 and ACTA2 expression. Basal ACTA2 expression was significantly decreased by treatment with the STAT1 inhibitor fludarabine or the JAK2 inhibitor AG490. In contrast, ACTA2 expression was increased by STAT1 overexpression. Levels of ACTA2, STAT1, and HER2 were increased and relapse free survival was decreased in high-risk breast cancer patients. We also investigated the effect of ACTA2 on cell motility, which was suppressed by ACTA2 shRNA overexpression in MDA-MB231 HER2 and 4T1 mammary carcinoma cells. The number of lung metastatic nodules was significantly decreased in ACTA2 knockdown mice. Taken together, these results demonstrated that induction of ACTA2 by EGFR and HER2 dimerization was regulated through a JAK2/STAT1 signaling pathway, and aberrant ACTA2 expression accelerated the invasiveness and metastasis of breast cancer cells. PMID- 28881585 TI - C/EBP-delta positively regulates MDSC expansion and endothelial VEGFR2 expression in tumor development. AB - Vascular endothelial cells and Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) are two important components that constitute the tumor microenvironment. Targeting these cells offers the potential to halt tumor growth. In this study, we report a common mediator in C/EBP-delta that regulates both components and aids in tumor development. C/EBP-delta is elevated in tumor derived MDSCs. Interestingly, genetic deletion of C/EBP-delta in mice significantly impaired MDSC expansion in response to tumor progression, but it had no effect on Gr 1+CD11b+ cell production in normal development. It suggests a specific role of C/EBP-delta in emergency myelopoiesis under tumor conditions. Consistent with the pro tumor functions of MDSCs, loss of C/EBP-delta resulted in reduced tumor angiogenesis and tumor growth. Moreover, we found expression of C/EBP-delta in vascular endothelial cells. C/EBP-delta regulated cell motility, endothelial network formation and vascular sprouting. Notably, inactivation of C/EBP-delta in endothelial cells specifically inhibited the expression of VEGFR2 but not VEGFR1. Ectopic expression of C/EBP-delta increased and knockdown of the gene decreased VEGFR2 expression. C/EBP-delta is recruited to the promoter region of VEGFR2, indicative of transcriptional regulation. Collectively, this study has identified a positive mediator in C/EBP-delta, which regulates tumor induced MDSC expansion and VEGFR2 expression in endothelium. Considering the importance of MDSCs and endothelial cells in tumor progression, targeting C/EBP-delta may provide an interesting means for cancer therapy, killing two birds with one stone. PMID- 28881586 TI - Identification of KANSARL as the first cancer predisposition fusion gene specific to the population of European ancestry origin. AB - Gene fusion is one of the hallmarks of cancer. Recent advances in RNA-seq of cancer transcriptomes have facilitated the discovery of fusion transcripts. In this study, we report identification of a surprisingly large number of fusion transcripts, including six KANSARL (KANSL1-ARL17A) transcripts that resulted from the fusion between the KANSL1 and ARL17A genes using a RNA splicingcode model. Five of these six KANSARL fusion transcripts are novel. By systematic analysis of RNA-seq data of glioblastoma, prostate cancer, lung cancer, breast cancer, and lymphoma from different regions of the World, we have found that KANSARL fusion transcripts were rarely detected in the tumors of individuals from Asia or Africa. In contrast, they exist in 30 - 52% of the tumors from North Americans cancer patients. Analysis of CEPH/Utah Pedigree 1463 has revealed that KANSARL is a familially-inherited fusion gene. Further analysis of RNA-seq datasets of the 1000 Genome Project has indicated that KANSARL fusion gene is specific to 28.9% of the population of European ancestry origin. In summary, we demonstrated that KANSARL is the first cancer predisposition fusion gene associated with genetic backgrounds of European ancestry origin. PMID- 28881587 TI - MGMT and CALCA promoter methylation are associated with poor prognosis in testicular germ cell tumor patients. AB - Testicular germ cell tumors (TGCT) represent the second main cause of cancer related death in young men. Despite high cure rates, refractory disease results in poor prognosis. Epigenetic reprogramming occurs during the development of seminomas and non-seminomas. Understanding the molecular and genetic basis of these tumors would represent an important advance in the search for new TGCT molecular markers. Hence the frequency of methylation of a gene panel (VGF, MGMT, ADAMTS1, CALCA, HOXA9, CDKN2B, CDO1 and NANOG) was evaluated in 72 primary TGCT by quantitative methylation specific PCR. A high frequency of MGMT (90.9%, 20/22; p=0.019) and CALCA (90.5%, 19/21; p<0.026) methylation was associated with non seminomatous tumors while CALCA methylation was also associated with refractory disease (47.4%, 09/19; p=0.005). Moreover, promoter methylation of both genes predicts poor clinical outcome for TGCT patients (5-year EFS: 50.5% vs 77.1%; p=0.032 for MGMT and 51.3% vs 77.0%; p=0.029 for CALCA). The findings of this study indicate that methylation of MGMT and CALCA are frequent and could be used as new molecular markers of prognosis in TGCT. PMID- 28881588 TI - Experimental study of brachial plexus and vessel compression: evaluation of combined central and peripheral electrodiagnostic approach. AB - INTRODUCTION: We sought to investigate the reliability of a new electrodiagnostic method for identifying Electrodiagnosis of Brachial Plexus & Vessel Compression Syndrome (BPVCS) in rats that involves the application of transcranial electrical stimulation motor evoked potentials (TES-MEPs) combined with peripheral nerve stimulation compound muscle action potentials (PNS-CMAPs). RESULTS: The latencies of the TES-MEP and PNS-CMAP were initially elongated in the 8-week group. The amplitudes of TES-MEP and PNS-CMAP were initially attenuated in the 16-week group. The isolateral amplitude ratio of the TES-MEP to the PNS-CMAP was apparently decreased, and spontaneous activities emerged at 16 weeks postoperatively. MATERIALS AND METHODS: Superior and inferior trunk models of BPVCS were created in 72 male Sprague Dawley (SD) rats that were divided into six experimental groups. The latencies, amplitudes and isolateral amplitude ratios of the TES-MEPs and PNS-CMAPs were recorded at different postoperative intervals. CONCLUSIONS: Electrophysiological and histological examinations of the rats' compressed brachial plexus nerves were utilized to establish preliminary electrodiagnostic criteria for BPVCS. PMID- 28881589 TI - Decreased calpain activity in chronic myeloid leukemia impairs apoptosis by increasing survivin in myeloid progenitors and xiap1 in differentiating granulocytes. AB - Chronic Myeloid Leukemia (CML) is characterized by translocations between chromosomes 9 and 22, resulting in expression of Bcr-abl oncogenes. Although the clinical course of CML was revolutionized by development of Bcr-abl-directed tyrosine kinase inhibitors (TKIs), CML is not cured by these agents. Specifically, the majority of subjects relapsed in clinical trials attempting TKI discontinuation, suggesting persistence of leukemia stem cells (LSCs) even in molecular remission. Identifying mechanisms of CML-LSC persistence may suggest rationale therapeutic targets to augment TKI efficacy and lead to cure. Apoptosis resistance is one proposed mechanism. In prior studies, we identified increased expression of Growth Arrest Specific 2 (Gas2; a Calpain inhibitor) in Bcr-abl+ bone marrow progenitor cells. A number of previously described Calpain substrates might influence apoptosis in CML, including betacatenin and the X-linked Inhibitor of Apoptosis Protein 1 (Xiap1). We previously found Gas2/Calpain dependent stabilization of betacatenin in CML, and increased expression of betacatenin target genes, including Survivin (also an IAP). In the current work, we investigate contributions of Survivin and Xiap1 to Fas-resistance in Bcr-abl+ bone marrow cells. Inhibitors of these proteins are currently in clinical trials for other malignancies, but a role for either IAP in CML-LSC persistence is unknown. PMID- 28881590 TI - Upregulation of microRNA-125b by G-CSF promotes metastasis in colorectal cancer. AB - Although there are reports of miR-125b being dysregulated in colorectal cancer (CRC) and associated with CRC progression, little is known about its intrinsic regulatory mechanisms. Here we detected the expression of miR-125b in CRC tissues, subsequently investigated the effect of miR-125b on the proliferation, apoptosis, cell cycle and metastasis on CRC cells. Our results showed that the expression of miR-125b was significantly decreased in CRC tissues comparing to adjacent tissues. However, with the stimulation of Granulocyte colony-stimulating factor (G-CSF), which was highly expressed in CRC tissues, the expression of miR 125b could be improved. Analysis of patient samples revealed that miR-125b presented a clear association with poor differentiation, positive lymph node metastasis, and advanced TNM stage. Overexpression of miR-125b inhibited cell proliferation, triggered G2/M cell cycle arrest, induced subsequent apoptosis, and promoted cell migration and invasion. Moreover, luciferase reporter assays and western blot clarified that the myeloid cell leukemia 1 (MCL1) was a direct target of miR-125b. Thus overexpression of MCL1 attenuated the pro-metastasis function of miR-125b in CRC cell lines. In addition, the protein expression level of MCL1 was decreased in CRC tissues from patients with positive lymph node metastasis, which had high miR-125b expression. Collectively, our study suggested that miR-125b induced by G-CSF plays a promoting role in the metastasis of CRC by targeting MCL1, which may serve as a novel therapeutic target for CRC metastasis. PMID- 28881591 TI - Usp5 functions as an oncogene for stimulating tumorigenesis in hepatocellular carcinoma. AB - As deubiquitinases, several ubiquitin specific protease members have been reported to mediate tumorigenesis. Although ubiquitin specific protease 5 (Usp5) was previously demonstrated to suppress p53 transcriptional activity and DNA repair, its role in carcinogenesis remains elusive. In this study, we sought to define a novel role of Usp5 in tumorigenesis. It was found that Usp5 was significantly upregulated in hepatocellular carcinoma (HCC) cells and most clinical specimens. Further functional investigation also showed that Usp5 knockdown suppressed cell proliferation, migration, drug resistance and induced apoptosis; on the other hand, Usp5 overexpression promoted colony formation, migration, drug resistance and tumorigenesis. Additionally, the inactivated p14ARF-p53 signaling was observed in Usp5 overexpressed HCC cells, while this signaling was activated by Usp5 knockdown. Therefore, our data demonstrated that Usp5 contributed to hepatocarcinogenesis by acting as an oncogene, which provides new insights into the pathogenesis of HCC and explores a promising molecular target for HCC diagnosis and therapy. PMID- 28881592 TI - Associations between LMO1 gene polymorphisms and Wilms' tumor susceptibility. AB - Wilms' tumor is the most common childhood renal malignancy. A genome-wide association study identified LIM domain only 1 (LMO1) as having oncogenic potential. We examined the associations between LMO1 gene polymorphisms and susceptibility to Wilms' tumor. In this hospital-based, case-control study, we recruited 145 children with Wilms' tumor and 531 cancer-free children. Four polymorphisms (rs110419 A>G, rs4758051 G>A, rs10840002 A>G and rs204938 A>G) were genotyped using Taqman methodology. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to measure the associations between selected polymorphisms and Wilms' tumor susceptibility. Only rs110419 AG was found to be protective against Wilms' tumor (adjusted OR = 0.62, 95% CI = 0.41-0.94, P = 0.024) when compared to rs110419 AA. Wilms' tumor risk was markedly greater in children with 1-4 risk genotypes (nucleotide alterations) than in those with no risk genotypes (adjusted OR = 1.84, 95% CI = 1.25-2.69, P = 0.002). In a stratified analysis, the protective effect of rs110419 AG/GG was predominant in males. The association of 1-4 risk genotypes with Wilms' tumor risk was limited to subgroups of children who were >18 months old, female, and in clinical stages III+IV. Thus, LMO1 gene polymorphisms may contribute to Wilms' tumor risk, but this conclusion should be validated in other populations and larger studies. PMID- 28881593 TI - Association of genetic polymorphisms in IL-1R1 and IL-1R2 genes with IgA nephropathy in the Han Chinese population. AB - AIM: IgA nephropathy (IgAN) is the major cause of end-stage renal disease(ESRD) in Asia and its pathogenesis is influenced by both genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in IL1R1 and IL-1R2 may be associated with susceptibility to IgAN. In this study, we study the association between genetic variants of IL-1R1 and IL-1R2 and IgA nephropathy risk in the Chinese Han population. RESULT: In the allelic model analysis, the rs10490571 and rs3917225 were associated with a 1.40-fold, and 1.31-fold increased risk of IgA nephropathy, respectively. In the genetic model analysis, the rs10490571 in IL1R1 was associated with a 1.46-fold increased risk of IgAN in the dominant model and 1.36-fold increased risk in the Log-additive model, respectively. However, the rs3218977 in IL1R2 was associated with a 0.71-fold decrease risk of IgAN in the dominant model and a 0.71-fold decrease risk in the over-dominant model, respectively. We found four SNPs (rs11674595, rs4851521, rs719250, and rs3218896) constructed four haplotypes in the IL1R2 gene and none of the haplotype was significantly associated with risk of IgAN. MATERIALS AND METHODS: A case-control study was conducted including 426 nephropathy patients and 463 healthy controls. Chi-squared tests and genetic model were used to evaluate associations. >CONCLUSIONS: These findings suggested that IL-1R1 and IL-1R2 polymorphisms may contribute to the development of IgAN. PMID- 28881594 TI - The miR-106a~363Xpcl1 miRNA cluster induces murine T cell lymphoma despite transcriptional activation of the p27Kip1 cell cycle inhibitor. AB - The miR-106a~363 cluster encodes 6 miRNAs on the X-chromosome which are abundant in blood cells and overexpressed in a variety of malignancies. The constituent miRNA of miR-106a~363 have functional activities in vitro that are predicted to be both oncogenic and tumor suppressive, yet little is known about their physiological functions in vivo. Mature miR-106a~363 (Mirc2) miRNAs are processed from an intragenic, non-protein encoding gene referred to as Xpcl1 (or Kis2), situated at an X-chromosomal locus frequently targeted by retroviruses in murine lymphomas. The oncogenic potential of miR-106a~363 Xpcl1 has not been proven, nor its potential role in T cell development. We show that miR106a~363 levels normally drop at the CD4+/CD8+ double positive (DP) stage of thymocyte development. Forced expression of Xpcl1 at this stage impairs thymocyte maturation and induces T-cell lymphomas. Surprisingly, miR-106a~363 Xpcl1 also induces p27 transcription via Foxo3/4 transcription factors. As a haploinsufficient tumor suppressor, elevated p27 is expected to inhibit lymphomagenesis. Consistent with this, concurrent p27 Kip1 deletion dramatically accelerated lymphomagenesis, indicating that p27 is rate limiting for tumor development by Xpcl1. Whereas down-regulation of miR-106a~363 is important for normal T cell differentiation and for the prevention of lymphomas, eliminating p27 reveals Xpcl1's full oncogenic potential. PMID- 28881595 TI - Effects of increased Kindlin-2 expression in bladder cancer stromal fibroblasts. AB - Kindlin-2 is a focal adhesion protein highly expressed in bladder cancer stromal fibroblasts. We investigated the prognostic significance of Kindlin-2 in bladder cancer stromal fibroblasts and evaluated the effects of Kindlin-2 on the malignant behaviors of tumor cells. Immunohistochemical staining of 203 paraffin embedded bladder cancer tissues showed that Kindlin-2 expression correlated with advanced stage, high grade, and relapse of bladder cancer. Kaplan-Meier survival analysis demonstrated that patients exhibiting high Kindlin-2 expression had shorter survival times than those with low Kindlin-2 expression (p < 0.01). Multivariate analysis revealed that high Kindlin-2 expression leads to poor prognosis in bladder cancer. Using cancer-associated fibroblasts (CAFs) isolated from human bladder cancer tissue, we observed that Kindlin-2 knockdown decreased CAFs activation, resulting in decreased expression of alpha-smooth muscle actin (alpha-SMA) and the extracellular matrix protein fibronectin. Kindlin-2 suppression also reduced CAF-induced bladder cancer cell migration and invasion. Moreover, we found that Kindlin-2 activates CAFs and promotes the invasiveness of bladder cancer cells by stimulating TGF-beta-induced epithelial-mesenchymal transition. These results support targeting Kindlin-2 and the corresponding activated CAFs in bladder cancer therapy. PMID- 28881596 TI - A prediction model for distinguishing lung squamous cell carcinoma from adenocarcinoma. AB - Accurate classification of squamous cell carcinoma (SCC) from adenocarcinoma (AC) of non-small cell lung cancer (NSCLC) can lead to personalized treatments of lung cancer. We aimed to develop a miRNA-based prediction model for differentiating SCC from AC in surgical resected tissues and bronchoalveolar lavage (BAL) samples. Expression levels of seven histological subtype-associated miRNAs were determined in 128 snap-frozen surgical lung tumor specimens by using reverse transcription-polymerase chain reaction (RT-PCR) to develop an optimal panel of miRNAs for acutely distinguishing SCC from AC. The biomarkers were validated in an independent cohort of 112 FFPE lung tumor tissues, and a cohort of 127 BAL specimens by using droplet digital PCR for differentiating SCC from AC. A prediction model with two miRNAs (miRs-205-5p and 944) was developed that had 0.988 area under the curve (AUC) with 96.55% sensitivity and 96.43% specificity for differentiating SCC from AC in frozen tissues, and 0.997 AUC with 96.43% sensitivity and 96.43% specificity in FFPE specimens. The diagnostic performance of the prediction model was reproducibly validated in BAL specimens for distinguishing SCC from AC with a higher accuracy compared with cytology (95.69 vs. 68.10%; P < 0.05). The prediction model might have a clinical value for accurately discriminating SCC from AC in both surgical lung tumor tissues and liquid cytological specimens. PMID- 28881597 TI - TGFbeta and miRNA regulation in familial and sporadic breast cancer. AB - The term 'BRCAness' was introduced to identify sporadic malignant tumors sharing characteristics similar to those germline BRCA-related. Among all mechanisms attributable to BRCA1 expression silencing, a major role has been assigned to microRNAs. MicroRNAs role in familial and sporadic breast cancer has been explored but few data are available about microRNAs involvement in homologous recombination repair control in these breast cancer subgroups. Our aim was to seek microRNAs associated to pathways underlying DNA repair dysfunction in breast cancer according to a family history of the disease. Affymetrix GeneChip microRNA Arrays were used to perform microRNA expression analysis in familial and sporadic breast cancer. Pathway enrichment analysis and microRNA target prediction was carried out using DIANA miRPath v.3 web-based computational tool and miRWalk v.2 database. We analyzed an external gene expression dataset (E-GEOD-49481), including both familial and sporadic breast cancers. For microRNA validation, an independent set of 19 familial and 10 sporadic breast cancers was used. Microarray analysis identified a signature of 28 deregulated miRNAs. For our validation analyses by real time PCR, we focused on miR-92a-1*, miR-1184 and miR 943 because associated to TGF-beta signalling pathway, ATM and BRCA1 genes expression. Our results highlighted alterations in miR-92a-1*, miR-1184 and miR 943 expression levels suggesting their involvement in repair of DNA double-strand breaks through TGF-beta pathway control. PMID- 28881598 TI - TRAIL-R1 as a novel surface marker for circulating giant cell tumor of bone. AB - Giant cell tumor of bone (GCT), which frequently occurs in the patients' spine, is relatively prevalent in Chinese population. A group of GCT invades into vessels and appears to be circulating tumor cells (CTCs) responsible for the distal metastasis of the primary tumor. So far the cell surface markers of GCT have not been determined. In the current study, we aimed to identify a novel CTC marker with higher specificity in GCT. TRAIL-R1+ cells were purified from GCT cell lines. The TRAIL-R1+ cells were compared with total GCT cells for tumor sphere formation, chemo-resistance, tumor formation in nude mice, and frequency of developing distal metastases. We found that TRAIL-R1+ GCT cells appeared to be highly enriched for CTCs in GCT. Compared to total GCT cells, TRAIL-R1+ GCT cells generated significantly more tumor spheres in culture, were higher chemo resistant, and had a higher frequency of being detected in the circulation after subcutaneous transplantation as well as development of distal metastases. Thus, we conclude that TRAIL-R1+ may be a novel CTC marker in GCT. Selective elimination of TRAIL-R1+ GCT cells may improve the current GCT therapy. PMID- 28881599 TI - Macrophages promote the progression of premalignant mammary lesions to invasive cancer. AB - Breast cancer initiation, progression and metastasis rely on a complex interplay between tumor cells and their surrounding microenvironment. Infiltrating immune cells, including macrophages, promote mammary tumor progression and metastasis; however, less is known about the role of macrophages in early stage lesions. In this study, we utilized a transplantable p53-null model of early progression to characterize the immune cell components of early stage lesions. We show that macrophages are recruited to ductal hyperplasias with a high tumor-forming potential where they are differentiated and polarized toward a tumor-promoting phenotype. These macrophages are a unique subset of macrophages, characterized by pro-inflammatory, anti-inflammatory and immunosuppressive factors. Macrophage ablation studies showed that macrophages are required for both early stage progression and primary tumor formation. These studies suggest that therapeutic targeting of tumor-promoting macrophages may not only be an effective strategy to block tumor progression and metastasis, but may also have critical implications for breast cancer prevention. PMID- 28881600 TI - Curcumin induces G2/M cell cycle arrest and apoptosis of head and neck squamous cell carcinoma in vitro and in vivo through ATM/Chk2/p53-dependent pathway. AB - Studies have demonstrated that curcumin (CUR) exerts its tumor suppressor function in a variety of human cancers including head and neck squamous cell carcinoma (HNSCC). However, the exact underlying molecular mechanisms remain obscure. Here, we aim to test whether CUR affects ATM/Chk2/p53 signaling pathway, leading to the induction of cell cycle arrest, inhibition of angiogenesis of HNSCC in vitro and in vivo. To this end, we conducted multiple methods such as MTT assay, Invasion assay, Flow cytometry, Western blotting, RT-PCR, and transfection to explore the functions and molecular insights of CUR in HNSCC. We observed that CUR significantly induced apoptosis and cell cycle arrest, inhibited angiogenesis in HNSCC. Mechanistically, we demonstrated that CUR markedly up-regulated ATM expression and subsequently down-regulated HIF-1alpha expression. Blockage of ATM production totally reversed CUR induced cell cycle arrest as well as anti-angiogenesis in HNSCC. Moreover, our results demonstrated that CUR exerts its antitumor activity through targeting ATM/Chk2/p53 signal pathway. In addition, the results of xenograft experiments in mice were highly consistent with in vitro studies. Collectively, our findings suggest that targeting ATM/Chk2/p53 signal pathway by CUR could be a promising therapeutic approach for HNSCC prevention and therapy. PMID- 28881601 TI - Identification of a RNA-Seq based prognostic signature with five lncRNAs for lung squamous cell carcinoma. AB - Long non-coding RNAs (lncRNAs) expression profile signature for survival assessment in lung squamous cell carcinoma (LUSC) are largely inconsistent due to distinct detecting approaches and small sample size. Systematic and integrative investigation of RNA-Seq based data from The Cancer Genome Atlas (TCGA) herein was performed to determine candidate lncRNAs for prognosis evaluation of LUSC. A total of 60483 genes, including 7589 lncRNAs were assessed in a cohort including 478 LUSC cases with follow-up data. Firstly, 4225 differentially expressed lncRNAs were obtained via R packages. Next, univariate and multivariate Cox proportional hazards regression revealed that 41 lncRNAs were closely related to the survival of LUSC. Finally, lncRNA based prognosis index (PI) could predict overall survival of LUSC with high accuracy (AUC = 0.652, CI: 0.598, 0.705), PI = expCYP4F26P*betaCYP4F26P+expRP11-108M12.3*betaRP11-108M12.3+expRP11 38M8.1*betaRP11-38M8.1+expRP11-54H7.4*betaRP11-54H7.4+expZNF503-AS1*betaZNF503 AS1. Furthermore, it was confirmed that the five-lncRNA signature could act as an independent prognostic indicator for LUSC (HR = 2.068, p < 0.001 with univariate analysis, HR = 1.928, p = 0.038 with multivariate). Besides, we constructed a weighted gene co-expression network analysis (WGCNA) of key lncRNA RP11-54H7.4 according to the p-value of related genes' weight. This study provides a RNA-Seq based prognostic signature with five lncRNAs for further clinical application to LUSC patients. PMID- 28881602 TI - Correlation between hormone receptor status and depressive symptoms in patients with metastatic breast cancer. AB - Individual differences in depressive symptoms correlate with morbidity and outcomes in breast cancer patients. We evaluated the effect of hormone receptor (HR) status on depressive symptoms in 176 women with metastatic breast cancer at diagnosis. To assess depression, the women completed Self-Rating Depression Scale (SDS) questionnaires at baseline examination (T1), after 4 chemotherapy cycles (T2) and after 6 months (T3). At baseline examination, 45/176 (25.6%) patients were found to be at high or medium risk for depression (SDS score >=0.6). Among these, depression was both prevalent in HR-positive patients and in HR-negative patients (64.4% versus 51.4%, P = 0.001). In multivariate model, HR positivity and higher depression risk were associated with poorer overall survival (25.0 months versus 32.0 months, P < 0.05). Patients at high/medium risk of depression were treated with the antidepressant agent fluoxetine (N = 23) or no drug (N = 22). SDS scores in patients treated with fluoxetine were lower after 4 chemotherapy cycles and after 6 months than in the control group (mean scores: T2, 0.61 versus 0.67, P = 0.001; T3, 0.56 versus 0.65, P < 0.001). No difference on SDS scores was found between patients with positive or negative HR status during fluoxetine treatment. These findings suggest hormone receptor status is associated with depressive symptoms in patients with metastatic breast cancer. Fluoxetine relieves depressive symptoms in these patients, regardless of hormone receptor status. PMID- 28881603 TI - PD-1 mRNA expression in peripheral blood cells and its modulation characteristics in cancer patients. AB - Immune checkpoint inhibitors that block the PD-1/PD-L1 signaling pathway have been used to treat a wide variety of cancers. Although results have been promising, significant inter-individual and inter-tumor variability has been observed. It is believed that better clinical outcome could be achieved if the treatment was individually designed based on the functional status of the PD-1/PD L1 signaling and the cellular immunity. In this study, we analyzed the mRNA expression of PD-1 and other immunomodulatory genes in peripheral blood from cancer patients, and immunomodulatory gene expression during radiotherapy and immunomodulation therapy with cytokines. Our results show that the PD-1 mRNA expression is significantly increased in peripheral blood in cancer patients. Anti-cancer treatments can significantly modulate the PD-1 expression, but this is largely dependent on the initial immune status. Moreover, the PD-1 expression on peripheral lymphocytes can be immunoactivation-derived. These results suggest that the regulation and expression pattern of PD-1/PD-L1 signal is complicated which will influence the effect of blockade of the PD-1/PD-L1 signaling pathway for cancer treatment. Through combined analysis of PD-1, CTLA-4, and other immune markers in peripheral blood, we may accurately evaluate the functional status of PD-1/PD-L1 signaling and cellular immunity, thereby providing clues for guiding anti-PD-1 or anti-PD-L1 treatment. PMID- 28881604 TI - Impact of country of birth on genetic testing of metastatic lung adenocarcinomas in France: African women exhibit a mutational spectrum more similar to Asians than to Caucasians. AB - BACKGROUND: Limited data are available on the prevalence of oncogenic driver mutations in Caucasian populations, and especially in Europeans. AIM: To evaluate the targetable mutational spectra in unselected patients with lung adenocarcinoma in routine clinical practice from several French hospitals, using the same molecular platform. PATIENTS AND METHODS: Samples from 2,219 consecutive patients with histologically-proven advanced lung adenocarcinoma were centrally analysed at a referenced and certified diagnostic platform in order to test for activating and resistance mutations in EGFR, KRAS, BRAF, ERBB2 and PI3KCA. Demographic and clinical features were retrieved from the medical charts. Multivariate binary logistic regression was used to determine the independent predictive factors for the occurrence of specific mutations, in the whole study population or in selected subgroups. FINDINGS: The overall respective incidence of EGFR, KRAS, BRAF, ERBB2 and PI3KCA mutations was 10.5%, 0.9%, 25%, 1.5%, 2.1% and 1.4%, in our study sample including 87.4% white Caucasians, 10.8% Africans and 1.8% Asians; 60.6% men, 30.7% never smoker (median age: 68.3 years). Ethnicity was an independent predictor for EGFR, KRAS and ERBB2 gene abnormalities. In all cases, a significantly higher prevalence of targetable EGFR and ERBB2, and a lower prevalence of resistance KRAS mutations were observed in African women as compared to African men or Caucasians. CONCLUSIONS: In real life conditions of routine genetic testing, we have identified subsets of patients with specific targetable activating somatic mutations according to ethnicity, who could preferentially benefit from anti-EGFR and anti-ERBB2 targeted therapies. PMID- 28881605 TI - Low PCA3 expression is a marker of poor differentiation in localized prostate tumors: exploratory analysis from 12,076 patients. AB - BACKGROUND: Prostate cancer antigen 3 (PCA3) is a prostate cancer diagnostic biomarker that has been clinically validated. The limitations of the diagnostic role of PCA3 in initial biopsy and the prognostic role are not well established. Here, we elucidate the limitations of tissue PCA3 to predict high grade tumors in initial biopsy. RESULTS: PCA3 has a bimodal distribution in both biopsy and radical prostatectomy (RP) tissues, where low PCA3 expression was significantly associated with high grade disease (p<0.001). PCA3 had a poor performance of predicting high grade disease in initial biopsy (GS>=8) with 55% sensitivity and high false negative rates; 42% of high Gleason (>=8) samples had low PCA3. In RP, low PCA3 is associated with adverse pathological features, clinical recurrence outcome and greater probability of metastatic progression (p<0.001). MATERIALS AND METHODS: A total of 1,694 expression profiles from biopsy and 10,382 from RP patients with high risk tumors were obtained from the Decipher Genomic Resource Information Database (GRIDTM)prostate cancer database. The primary clinical endpoint was distant metastasis-free survival for RP and high Gleason grade for biopsy. Logistic regression analyses and Cox proportional hazards models were used to evaluate the association of PCA3 with clinical variables and risk of metastasis. CONCLUSIONS: There is high prevalence of high grade tumors with low PCA3 expression in the biopsy setting. Therefore, urologists should be warned that using PCA3 as stand-alone test may lead to high rate of under-diagnosis of high grade disease in initial biopsy setting. PMID- 28881606 TI - GSK1059615 kills head and neck squamous cell carcinoma cells possibly via activating mitochondrial programmed necrosis pathway. AB - This study tested the anti-head and neck squamous cell carcinoma (HNSCC) cell activity by GSK1059615, a novel PI3K and mTOR dual inhibitor. GSK1059615 inhibited survival and proliferation of established (SCC-9, SQ20B and A253 lines) and primary human HNSCC cells. GSK1059615 blocked PI3K-AKT-mTOR activation in HNSCC cells. Intriguingly, GSK1059615 treatment in HNSCC cells failed to provoke apoptosis, but induced programmed necrosis. The latter was tested by mitochondria depolarization, ANT-1-cyclophilin-D mitochondrial association and lactate dehydrogenase (LDH) release. Reversely, mPTP blockers (sanglifehrin A, cyclosporin A and bongkrekic acid) or cyclophilin-D shRNA dramatically alleviated GSK1059615-induced SCC-9 cell death. Further studies demonstrated that GSK1059615 i.p. injection suppressed SCC-9 tumor growth in nude mice, which was compromised with co-administration with cyclosporin A. Thus, targeting PI3K-AKT-mTOR pathway by GSK1059615 possibly provokes programmed necrosis pathway to kill HNSCC cells. PMID- 28881607 TI - Lack of association between the pancreatitis risk allele CEL-HYB and pancreatic cancer. AB - CEL-HYB is a hybrid allele that arose from a crossover between the 3' end of the Carboxyl ester lipase (CEL) gene and the nearby CEL pseudogene (CELP) and was recently identified as a risk factor for chronic pancreatitis. Since chronic pancreatitis is a risk factor for the development of pancreatic cancer, we compared the prevalence of the CEL-HYB allele in patients with pancreatic ductal adenocarcinoma to spousal controls and disease controls. The CEL-HYB allele was detected using Sanger and next generation sequencing. There was no significant difference in the prevalence of the CEL-HYB allele between cases with pancreatic ductal adenocarcinoma compared to controls; 2.6% (22/850) vs. 1.8% (18/976) (p=0.35). CEL-HYB carriers were not more likely to report a history of pancreatitis. Patients with pancreatic cancer are not more likely than controls to be carriers of the CEL-HYB allele. PMID- 28881608 TI - Anti-tumor efficacy of theliatinib in esophageal cancer patient-derived xenografts models with epidermal growth factor receptor (EGFR) overexpression and gene amplification. AB - Targeted therapy is not yet approved for esophageal cancer (EC). In this study, we first evaluated EGFR gene and protein expression in 70 Chinese EC patient tumor samples collected during surgery. We then established 23 patient-derived EC xenograft (PDECX) models and assessed the efficacy of theliatinib, a potent and highly selective EGFR inhibitor currently in Phase I clinical study, in 9 PDECX models exhibiting various EGFR expression levels. Immunohistochemical analysis showed that 50 patient tumor samples (71.4%) had high EGFR expression. Quantitative PCR showed that eight tumors (11.6%) had EGFR gene copy number gain, and fluorescence in situ hybridization (FISH) revealed that four tumors had EGFR gene amplification. These results suggest that EGFR protein may be overexpressed in many EC tumors without gene amplification. Also detected were rare hot-spot mutations in EGFR and PIK3CA, whereas no mutations were found in K-Ras or B-Raf. Theliatinib exhibited strong antitumor activity in PDECX models with high EGFR expression, including remarkable tumor regression in two PDECX models with both EGFR gene amplification and protein overexpression. However, the efficacy of theliatinib was diminished in models with PI3KCA mutations or FGFR1 overexpression in addition to high EGFR expression. This study demonstrates that theliatinib could potentially benefit EC patients with high EGFR protein expression without mutations or aberrant activities of associated factors, such as PI3KCA or FGFR1. PMID- 28881609 TI - Grape seed extracts modify the outcome of oxaliplatin in colon cancer cells by interfering with cellular mechanisms of drug cytotoxicity. AB - Grape seed extracts are commonly utilized as dietary supplements for their antioxidant properties, even from cancer patients. However, whether these natural extracts interfere with chemotherapeutics utilized in colon cancer treatment is still poorly investigated. The cytotoxicity of extracts from Italia and Palieri cultivars either alone or in combination with oxaliplatin was evaluated in colon cancer cells. Grape seed extracts displayed anti-proliferative activity depending on the concentration utilized through apoptosis induction. In combination, they affected the activation of Erk1/2 and counteracted the intrinsic and the extrinsic pathway of apoptosis, the DNA damage and the generation of ROS induced by oxaliplatin. Noteworthy grape seed extracts strongly enhanced the uptake of oxaliplatin into all cells, by affecting the cell transport system of platinum. The addition of these natural extracts to oxaliplatin strongly reduced the cellular response to oxaliplatin and allowed a huge accumulation of platinum into cells. Here, we shed light on the chemical biology underlying the combination of grape seed extracts and oxaliplatin, demonstrating that they might be detrimental to oxaliplatin effectiveness in colon cancer therapy. PMID- 28881610 TI - Association between rs2853669 in TERT gene and the risk and prognosis of human cancer: a systematic review and meta-analysis. AB - The polymorphism rs2853669 within the promoter of telomerase reverse transcriptase gene (TERTp) has been debated about its role in cancer risk and prognosis. Additionally, several studies report inconsistent results concerning the modifying effect of rs2853669 on the prognostic value of TERTp mutations in cancer patients. Here, we performed this meta-analysis to comprehensively evaluate the role of rs2853669 in the risk and prognosis of human cancer, and further assess its modifying impact on TERTp mutations in the survival of cancer patients. We systematically searched literature via PubMed, Web of Science, and EMBASE through July 2016, and included 22 eligible studies. The overall analysis (64,119 cases and 78,988 controls) demonstrated that rs2853669 did not increase or decrease the overall cancer risk. Subsequent analyses also did not reveal any association between rs2853669 and overall cancer prognosis. However, we identified a modifying effect of rs2853669 on TERTp mutations in that, among cancer patients with TERTp mutations, only those carrying the TT genotype had a poor survival (Hazard ratio = 1.56, 95% confidence interval = 1.06-2.28); subgroup analyses by cancer type also supported these results. In conclusion, our findings suggest that rs2853669 could be important for assessing the prognostic value of TERTp mutations. Future large studies are required to further validate our results. PMID- 28881611 TI - Inhibition and deficiency of the immunoproteasome subunit LMP7 suppress the development and progression of colorectal carcinoma in mice. AB - New treatment options and drug targets for colorectal carcinoma are a pressing medical need. Inflammation and pro-inflammatory cytokines produced by Th1 and Th17 cells like IL-6, TNF, IL-17 and IL-23 promote the development and growth of colorectal cancer (CRC). The immunoproteasome is a proteasome subtype highly expressed in immune cells but also in the intestine. Since the immunoproteasome promotes Th1 and Th17 differentiation and pro-inflammatory cytokine production, we investigated here whether deficiency or inhibition of the immunoproteasome subunit LMP7 would interfere with CRC development and exacerbation in preventive and therapeutic mouse models. Treatment with the LMP7 inhibitor ONX 0914 blocked tumor initiation and progression in either chemically-induced (AOM/DSS) or transgenic mouse models (ApcMin/+) of colon carcinogenesis. ONX 0914 treatment strongly reduced tumor numbers and CRC-associated loss of body weight while the survival rates were significantly enhanced. Moreover, genetic LMP7 deficiency markedly reduced the tumor burden in AOM/DSS induced wild type and ApcMin/+ mice. In conclusion, we show that the immunoproteasome is involved in CRC development and progression and we identify LMP7 as a new potential drug target for the treatment of CRC. PMID- 28881612 TI - The B-box module of CYLD is responsible for its intermolecular interaction and cytoplasmic localization. AB - The tumor suppressor protein cylindromatosis (CYLD), as a microtubule-associated deubiquitinase, plays a pivotal role in a wide range of cellular activities, including innate immunity, cell division, and ciliogenesis. Structural characterization reveals a small zinc-binding B-box inserted within the ubiquitin specific protease (USP) domain of CYLD; however, the exact role for this module remains yet to be elucidated. Here we identify a critical role for the B-box in facilitating the intermolecular interaction and subcellular localization of CYLD. By co-immunoprecipitation assays we uncover that CYLD has the ability to form an intermolecular complex. Native gel electrophoresis analysis and pull down assays show that the USP domain of CYLD is essential for its intermolecular interaction. Further investigation reveals that deletion of the B-box from the USP domain disrupts the intermolecular interaction of CYLD. Importantly, although loss of the B-box has no obvious effect on the deubiquitinase activity of CYLD, it abolishes the USP domain-mediated retention of CYLD in the cytoplasm. Collectively, these data demonstrate an important role for the B-box module of CYLD in mediating its assembly and subcellular distribution, which might be related to the functions of CYLD in various biological processes. PMID- 28881613 TI - LGR5 promotes hepatocellular carcinoma metastasis through inducting epithelial mesenchymal transition. AB - The purpose of the present study was to investigate the prognostic value of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) in hepatocellular carcinoma (HCC) and its role in promoting HCC metastasis. The expression level of LGR5 in liver tumor tissues and adjacent non-tumor tissues were detected adopting immunohistochemistry (IHC), real-time PCR (RT-PCR) and western blot assays. Chi-square test was used to evaluate the correlation between LGR5 expression and clinicopathological characteristics. In addition, we assessed the relationship between LGR5 and two epithelial-mesenchymal transition (EMT) markers (E-cadherin and N-cadherin) in HCC tissues and cell lines. Our results showed that the expression of LGR5 was significantly higher in liver tumor tissues than in adjacent non-tumor tissues. Moreover, up-regulated LGR5 was associated with larger tumor diameter (>5cm, P=0.001), higher TNM stage (P=0.021), increased recurrence (P=0.023) and growing metastasis (P=0.030). Besides, we found that the expression level of LGR5 was correlated with E cadherin and N-cadherin. In conclusion, up-regulated LGR5 in HCC patients is associated with malignant clinicopathological characteristics. LGR5 may promote HCC metastasis through inducting EMT process, and thus can be regarded as a candidate biomarker for prognosis and as a target in therapy. PMID- 28881614 TI - Autophagy deactivation is associated with severe prostatic inflammation in patients with lower urinary tract symptoms and benign prostatic hyperplasia. AB - Autophagy is a conserved evolutionary process that allows cells to maintain macromolecular synthesis and energy homeostasis during starvation and stressful conditions. We prospectively evaluated the relationship between autophagy and prostatic inflammation in a series of transurethral prostatic resection samples. Inflammatory infiltrates were defined according to the standardized classification of chronic prostatitis of the National Institute of Health. The inflammatory score (IS score) was calculated. High IS score was defined as >=7. Each sample was stained for anti-LC3B and for anti-P62/SQSTM1 and scored. High p62 or LC3B percentage was defined as >25%, whereas low was defined as <25% of cells with dots. We analyzed 94 specimens. Overall, 18/94 (19%) showed no sign of prostatic inflammation, whereas 76/94 (81%) presented inflammatory infiltrates. Inflammation was mild in 61/76 (80%), moderate/severe in 15/76 (20%). Patients with high p62 percentage were 62/94 (66%) while 32 (34%) showed low p62 percentage. Patients with high LC3B percentage were 37/94 (39%) while 57(61%) showed low LC3B percentage. Overall 42/94 (44%) patients presented a high p62 percentage and concomitant a low LC3B percentage. IS score was significantly higher in patients with a with high p62 percentage (median IS 7 (6/8) vs 5 (3/7); p= 0.04) and in patients with a low LC3B percentage (median IS 7 (6/8) vs 5 (3/7); p= 0.004) when compared to patients with a low p62 percentage or a high LC3B percentage respectively. On multivariate analysis, p62 (OR: 10.1, 95%CI: 2.6 38.6; p= 0,001) and LC3B expression (OR: 0.319; 95%CI: 0.112-0.907; p= 0.032) were independent predictors of a high IS. Here we present the first evidence of autophagy deregulation in prostatic inflammation. These results raise many questions about the mechanisms mediating the autophagy dysfunction and the links to prostatic inflammation that need to be addressed. PMID- 28881615 TI - Perfluorodecanoic acid (PFDA) promotes gastric cell proliferation via sPLA2-IIA. AB - The association of perfluorodecanoicacid (PFDA) with tumor promotion and associated effects is not clear. Given that PDFA is mostly consumed with food and drinking water, we evaluated the effects of PFDA on a gastric cell line. When added to cell cultures, PFDA significantly increased growth rate and colony forming ability compared with control treatment. We found that suppression of cell senescence, but not apoptosis or autophagy was associated with PFDA-induced promotion of cell amount. To determine the molecular mechanism that was involved, DNA microarray assays was used to analyze changes in gene expression in response to PFDA treatment. Data analysis demonstrated that the vascular endothelial growth factor signaling pathway had the lowest p-value, with sPLA2-IIA (pla2g2a) exhibits the most altered expression pattern within the pathway. Moreover, sPLA2 IIA and its transcription factor TCF4, known as a direct target and a binding partner of Wnt/beta-catenin signaling in gastric cells respectively, were the third and second most varied genes globally. Cells transfected with expression plasmids pENTER-tcf4 and pENTER-pla2g2a show reduced cell proliferation by more than 60% and 30% respectively. Knockdown with sPLA2-IIA siRNA provided additional evidence that sPLA2-IIA was a mediator of PFDA-induced cell senescence suppression. The results suggest for the first time that PFDA induced suppression of cell senescence through inhibition of sPLA2-IIA protein expression and might increased the proliferative capacity of an existing tumor. PMID- 28881616 TI - Repetitive transcranial magnetic stimulation for treatment of lactacystin-induced Parkinsonian rat model. AB - The dysfunction of ubiquitin-proteasome system is an important pathogenesis in the neurodegenerative process of Parkinson's disease. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive and potential method in treating Parkinson's disease. To investigate whether rTMS has neuroprotective effects in parkinsonian rat model induced by ubiquitin-proteasome system impairment, we gave rTMS daily for 4 weeks to proteasome inhibitor, lactacystin-induced parkinsonian rat model. Rotational behavior test demonstrated that rTMS obviously reduced apomorphine-induced turning number in parkinsonian rats. rTMS could significantly alleviate the loss of tyrosine hydroxylase-positive dopaminergic neurons in lactacystin-lesioned substantia nigra and prevent the loss of striatal dopamine levels. Furthermore, rTMS also reduced the levels of apoptotic protein (cleaved caspase-3) and inflammatory factors (cyclooxygenase-2 and tumor necrosis factor alpha) in lesioned substantia nigra. These results suggest that rTMS can protect nigral dopaminergic neurons against the ubiquitin-proteasome system impairment induced degeneration by anti-apoptotic and anti-inflammatory molecular mechanism. PMID- 28881618 TI - The prognostic role of pretreatment epidermal growth factor receptor T790M mutation in advanced non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitors. AB - PURPOSE: The outcome of pretreatment epidermal growth factor receptor (EGFR) T790M mutation in EGFR mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) is controversial, this study aimed to evaluate the prognostic role of pretreatment T790M in advanced NSCLC patients treated with EGFR TKIs. RESULTS: A total of 7 eligible studies containing 179 cases and 281 controls were included in the meta-analysis. The pooled hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were 2.21 (95% CI 1.49-3.29, P<0.001) and 1.24 (95% CI 0.90-1.71, P=0.186), respectively. We also did subgroup analyses on OS and PFS according to patients from various districts. METHODS: Identified literatures from various databases were reviewed. A meta-analysis was performed to evaluate the prognostic role of pretreatment EGFR T790M in advanced EGFR mutant patients treated with EGFR TKIs. CONCLUSIONS: Pretreatment T790M may be a poor prognostic factor for PFS in advanced NSCLC patients treated with EGFR TKIs. However, no significant prognostic effect was found between pretreatment T790M mutation and OS. More studies are needed to demonstrate the prognostic role of pretreatment T790M mutation in advanced NSCLC patients. PMID- 28881617 TI - Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene. AB - We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8*10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality. PMID- 28881619 TI - mRNA in exosomas as a liquid biopsy in non-Hodgkin Lymphoma: a multicentric study by the Spanish Lymphoma Oncology Group. AB - PURPOSE: To determine the feasibility of mRNAs (C-MYC, BCL-XL, BCL-6, NF kappabeta, PTEN and AKT) in exosomes of plasma as a liquid biopsy method for monitoring and prognostic evolution in B-cell lymphomas. PATIENTS AND METHODS: Exosomes were isolated from 98 patients with B-cell Lymphoma and 68 healthy controls. mRNAs were analyzed by quantitative PCR. An additional 31 post treatment samples were also studied. RESULTS: In the general and follicular lymphoma series, the presence of AKT mRNA was associated with poor response to rituximab-based treatment. Patients with first relapse or disease progression showed a lower percentage of PTEN and BCL-XL mRNA. The presence of BCL-6 mRNA was associated with a high death rate. The absence of PTEN mRNA in the general series, and presence of C-MYC mRNA in follicular lymphomas, were associated with short progression-free survival. BCL-6 and C-MYC mRNA were independent prognostic variables of overall survival. C-MYC mRNA may provide prognostic information with respect to overall survival. BCL-XL mRNA and increase of BCL-6 mRNA in post treatment samples could serve as molecular monitoring markers. CONCLUSIONS: This is the first large study to evaluate the prognostic and predictive values of pretreatment tumor-associated mRNA in exosomes. BCL-6 and C-MYC mRNA positivity in pretreatment samples were predictors of worse PFS compared to patients with mRNA negativity. C-MYC mRNA positivity was also a statistically significant predictor of inability to obtain complete response with first-line therapy. PMID- 28881620 TI - EETs reduces LPS-induced hyperpermeability by targeting GRP78 mediated Src activation and subsequent Rho/ROCK signaling pathway. AB - Integrity of endothelial barrier is a determinant of the prognosis in the acute lung injury caused by sepsis. The epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, exhibit protective effects in various pathogenic states, however, whether EETs play a role in endothelial barrier enhancement and the involved mechanisms remain to be investigated. Here, we show that increased EETs level by endothelial specific cytochrome P450 epoxygenase 2J2 over-expression and soluble epoxide hydrolase (sEH) inhibitor TPPU reduced lipopolysaccharide-induced endothelial hyper-permeability in vivo, accompanied by improved survival of septic mice. In addition, sEH inhibitor AUDA and 11,12-EET also decreased endothelial hyper-permeability in the in-vitro study. Importantly, the relative mechanisms were associated with reduced GRP78-Src interaction and ROS production, and subsequently reduced RhoA/ROCK activation, and eventually decreased VE cadherin and myosin light chain (MLC) phosphorylation. Thus CYP2J2-EETs is crucial for RhoA-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability, which may contribute to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability. PMID- 28881621 TI - Connexin40 controls endothelial activation by dampening NFkappaB activation. AB - Connexins are proteins forming gap junction channels for intercellular communication. Connexin40 (Cx40) is highly expressed by endothelial cells (ECs) of healthy arteries but this expression is lost in ECs overlying atherosclerotic plaques. Low/oscillatory shear stress observed in bends and bifurcations of arteries is atherogenic partly through activation of the pro-inflammatory NFkappaB pathway in ECs. In this study, we investigated the relation between shear stress, Cx40 and NFkappaB. Shear stress-modifying casts were placed around carotid arteries of mice expressing eGFP under the Cx40 promoter (Cx40+/eGFP ). We found that Cx40 expression is decreased in carotid regions of oscillatory shear stress but conserved in high and low laminar shear stress regions. These results were confirmed in vitro. Using phage display, we retrieved a binding motif for the intracellular regulatory Cx40 C-terminus (Cx40CT), i.e. HS[I, L, V][K, R]. One of the retrieved peptides (HSLRPEWRMPGP) showed a 58.3% homology with amino acids 5-to-16 of IkappaBalpha, a member of the protein complex inhibiting NFkappaB activation. Binding of IkappaBalpha (peptide) and Cx40 was confirmed by crosslinking and en face proximity ligation assay on carotid arteries. TNFalpha-induced nuclear translocation of NFkappaB in ECs was enhanced after reducing Cx40 with siRNA. Transfection of HeLa cells with either full length Cx40 or Cx40CT demonstrated that Cx40CT was sufficient for inhibition of TNFalpha-induced NFkappaB phosphorylation. Finally, Tie2CreTgCx40fl/flApoe-/- mice showed exaggerated shear stress-induced atherosclerosis and enhanced NFkappaB nuclear translocation. Our data show a novel functional IkappaBalpha Cx40 interaction that may be relevant for the control of NFkappaB activation by shear stress in atherogenesis. PMID- 28881622 TI - Is FTO gene variant related to cancer risk independently of adiposity? An updated meta-analysis of 129,467 cases and 290,633 controls. AB - Previous studies have examined the association between the fat mass and obesity associated (FTO) gene variant and risk of cancer in diverse populations. However, the results have been inconsistent. PubMed and Embase databases were searched for the eligible publications in English language by July, 2016. The associations of FTO variants with cancer risk were estimated by calculating the pooled odds ratios and 95% confidence intervals by meta-analyses. A total of 27 publications (129,467 cancer cases and 290,633 normal controls) were included in our meta analysis. Overall, FTO rs9939609 variant (or its proxy) was not associated with cancer risk without adjustment for body mass index, as well as additional adjustment for body mss index. However, FTO rs9939609 variant was associated with some types of cancer in the subgroup analysis. In addition, overall, there was no significant association between FTO rs1477196 variant and cancer risk regardless of adjustment for body mass index. However, FTO rs11075995 variant risk allele was associated with breast cancer risk without adjustment for body mass index, but the association disappeared with further adjustment for body mass index. This study overall does not support that the FTO variant is associated with cancer risk independently of the adiposity. PMID- 28881623 TI - Peptide-based PET imaging of the tumor restricted IL13RA2 biomarker. AB - Peptides that target cancer cell surface receptors are promising platforms to deliver diagnostic and therapeutic payloads specifically to cancer but not normal tissue. IL13RA2 is a tumor-restricted receptor found to be present in several aggressive malignancies, including in the vast majority of high-grade gliomas and malignant melanoma. This receptor has been successfully targeted for diagnostic and therapeutic purposes using modified IL-13 ligand and more recently using a specific peptide, Pep-1L. In the current work, we establish the in vitro and in vivo tumor binding properties of radiolabeled Pep-1L, designed for tumor imaging. We radiolabeled Pep-1L with Copper-64 and demonstrated specific cell uptake in the IL13RA2-over expressing G48 glioblastoma cell line having abundant IL13RA2 expression. [64Cu]Pep-1L binding was blocked by unlabeled ligand, demonstrating specificity. To demonstrate in vivo tumor uptake, we intravenously injected into tumor-bearing mice and demonstrated that [64Cu]Pep-1L specifically bound tumors at 24 hours, which was significantly blocked (3-fold) by pre-injecting unlabeled peptide. To further demonstrate specificity of Pep-1L towards IL13RA2 in vivo, we exploited an IL13RA2-inducible melanoma tumor model that does not express receptor at baseline but expresses abundant receptor after treatment with doxycycline. We injected [64Cu]Pep-1L into mice bearing IL13RA2-inducible melanoma tumors and performed in vivo PET/CT and post-necropsy biodistribution studies and found that tumors that were induced to express IL13RA2 receptor by doxycycline pretreatment bound radiolabeled Pep-1L 3-4 fold greater than uninduced tumors, demonstrating receptor specificity. This work demonstrates that [64Cu]Pep-1L selectively binds hIL13RA2-expressing tumors and validates Pep-1L as an effective platform to deliver diagnostics and therapeutics to IL13RA2 expressing cancers. PMID- 28881624 TI - Ascites promotes cell migration through the repression of miR-125b in ovarian cancer. AB - Interactions between ovarian cancer cells and the surrounding tumor microenvironment are not well characterized. Here, we investigated the molecular mechanisms by which malignant ascites promote the metastasis of ovarian cancer. It was found that ovarian cancer ascites promoted ovarian cancer cell migration which was attenuated by either heat inactivation or antibody blockade of TGF beta. High level (at ng/ml level) of TGF-beta was detected in the ascites. In addition, ascites repressed the expression of miRNA-125b in a TGF-beta-dependent manner. Mimic of miR-125b blocked ascites-induced cell migration. Furthermore, Gab2 (a target gene of miR-125b) was elevated by ascites in a TGF-beta-dependent manner. And forced expression of Gab2 reversed the inhibition of migration induced by miR-125b mimic. Most importantly, the expression of miR-125b and Gab2 mRNA was negatively correlated in ovarian cancer specimens. Taken together, our finding suggested that TGF-beta in ascites promoted cancer cell migration through repression of miR-125b in ovarian cancer. This might provide a novel therapeutic target for ovarian cancer in the future. PMID- 28881625 TI - The influence of marital status on the survival of patients with Hodgkin lymphoma. AB - Marital status is viewed as an independent prognostic factor for survival in various cancers. But, little is known about the relationship between marital status and Hodgkin lymphoma (HL) outcomes. To investigate the impact of marital status on the survival of patients with HL, we identified 37884 cases from 1988 to 2013 in the Surveillance, Epidemiology and End Results (SEER) database. The Kaplan-Meier method and multivariate Cox regression model were used for analyzing the influence of marital status on cause-specific survival (CSS). We found patients in widowed group had a higher proportion of women and a higher incidence of older (>60 years) patients; all of these parameters were found to be statistically significant in within-group comparisons. Marital status was demonstrated to be an independent prognostic factor. Widowed individuals were at greater risk of cancer specific mortality relative to other groups. Similar associations in subgroup analyses were observed according to SEER stage. In conclusion, widowed patients suffered survival disadvantages relative to other groups, and marital status had significant prognostic value in HL. PMID- 28881626 TI - Relevance of CCL3/CCR5 axis in oral carcinogenesis. AB - The chemokine CCL3 is a chemotactic cytokine crucial for inflammatory cell recruitment in homeostatic and pathological conditions. CCL3 might stimulate cancer progression by promoting leukocyte accumulation, angiogenesis and tumour growth. The expression of CCL3 and its receptors CCR1 and CCR5 was demonstrated in oral squamous cell carcinoma (OSCC), but their role was not defined. Here, the functions of CCL3 were assessed using a model of chemically induced tongue carcinogenesis with 4-nitroquinoline-1-oxide (4NQO). Lineages of OSCC were used to analyse the effects of CCL3 in vitro. The 4NQO-induced lesions exhibited increased expression of CCL3, CCR1 and CCR5. CCL3-/- and CCR5-/- mice presented reduced incidence of tongue tumours compared to wild-type (WT) and CCR1-/- mice. Consistently, attenuated cytomorphological atypia and reduced cell proliferation were observed in lesions of CCL3-/- and CCR5-/- mice. OSCC from CCL3-/- mice exhibited lower infiltration of eosinophils and reduced expression of Egf, Fgf1, Tgf-beta1, Vegfa, Vegfb, Itga-4, Vtn, Mmp-1a, Mmp-2 and Mmp-9 than WT mice. In vitro, CCL3 induced invasion and production of CCL5, IL-6, MMP -2, -8, -9. Blockage of CCL3 in vitro using alpha-CCL3 or Evasin-1 (a CCL3-binding protein) impaired tumour cell invasion. In conclusion, CCL3/CCR5 axis has pro-tumourigenic effects in oral carcinogenesis. The induction of inflammatory and angiogenic pathways and eosinophils recruitment appear to be the underlying mechanism explaining these effects. These data reveal potential protective effects of CCL3 blockade in oral cancer. PMID- 28881627 TI - Structural basis of a novel heterodimeric Fc for bispecific antibody production. AB - Bispecific antibodies provide an efficient tool for combinational clinical therapy. Here we have engineered a heterodimeric Fc for bispecific antibodies production by combining the knob-into-hole and electrostatic steering strategies where a bulky hydrophobic residue Phe405 of the IgG CH3 interface is mutated to a charged residue Lys and Lys409 of the corresponding CH3 domain is mutated to Ala. The crystal structure of this Fc heterodimer solved here at 2.7A resolution revealed how these two mutations resulted a complementary binding interface and explained why F405K mutation could effectively inhibit Fc homodimer formation during protein expression. An anti-HER2 bispecific antibody derived from trastuzumab and pertuzumab was generated by this heterodimeric Fc. It showed comparable or improved efficacy than the combination of trastuzumab and pertuzumab in inhibiting proliferation of cancer cells in vitro and in vivo. Overall this study shows that the heterodimeric Fc engineered here provides an efficient platform for generating active bispecific antibody for cancer treatment. PMID- 28881628 TI - Establishment of a mouse xenograft model of metastatic adrenocortical carcinoma. AB - Adrenocortical carcinoma is a rare neoplasm with a poor prognosis. Very important advances have been made in the identification of the genetic determinants of adrenocortical carcinoma pathogenesis but our understanding is still limited about the mechanisms that determine cancer spread and metastasis. One major problem hindering preclinical experimentation for new therapies for adrenocortical carcinoma is represented by the lack of suitable animal models for metastatic disease. With the aim to overcome these limitations, in this study we tested several protocols in order to establish a mouse xenograft model of metastatic adrenocortical carcinoma. The most efficient method, based upon intrasplenic injection followed by splenectomy, produced metastases with high efficiency, whose development could be followed over time by bioluminescence measurements. We expect that the availability of this model will greatly improve the possibilities for preclinical testing of new treatments for advanced-stage disease. PMID- 28881629 TI - Up-regulation of long non-coding RNA SPRY4-IT1 promotes tumor cell migration and invasion in lung adenocarcinoma. AB - Long non-coding RNAs (lncRNAs) play important role in a variety of biological processes, and are tightly associated with tumorigenesis and cancer prognosis. However, the potential power of lncRNA signatures in predicting survival of patients with lung adenocarcinoma (LUAD) has not been investigated. Here, we identified a four-lncRNA signature (SPRY4-IT1, LINC00941,GPR158-AS1 and KCNK15 AS1) displaying prognostic values for LUAD using The Cancer Genome Atlas (TCGA) dataset. Based on the four-lncRNA signature, the LUAD patients can be classified into high-risk and low-risk groups with significantly different survival. We further validated the expression of SPRY4-IT1 in LUAD tissues and corresponding normal lung tissues using quantitative real-time PCR in Chinese LUAD patients. The results showed that SPRY4-IT1 was significantly up-regulated in LUAD tissues. Further analysis indicated that LUAD patients with high SPRY4-IT1 expression have significantly poorer overall survival in Chinese LUAD patients. Moreover, knock down of SPRY4-IT1 can inhibit the lung cancer cell migration and invasion. The present work indicated that SPRY4-IT1 may play a pivotal role in promoting tumor migration and invasion in LUAD. Our work implicates the promising effect of SPRY4 IT1 on the prognosis of LUAD. PMID- 28881630 TI - Protective effect of madecassoside on H2O2-induced oxidative stress and autophagy activation in human melanocytes. AB - BACKGROUND: Centella asiatica (L.) Urb. is a traditional Chinese medicine that has many medical applications, including wound healing and anti-oxidation. Some traditional Chinese Medicine doctors have found that it has therapeutic effects for external use in the repigmentation of vitiligo and post-inflammatory hypopigmentation. This study was designed to evaluate the effects of madecassoside, a major bioactive component of C. asiatica, on oxidative stress in human melanocytes and its possible mechanism of action. RESULTS: In H2O2-induced oxidative conditions, madecassoside inhibited melanocyte dendrite retraction, improved MMP and reduced the accumulation of [Ca2+]i in a concentration-dependent manner. Observations by TEM showed that madecassoside attenuated the damage of mitochondria in human melanocytes caused by oxidative stress. Furthermore, autophagy activation was demonstrated by AO staining and an increased LC3-II/LC3 I ratio. MATERIALS AND METHODS: Normal human melanocytes were treated with 0.01 mM H2O2 and varying concentrations of madecassoside (0, 10, 50, 100 MUg/mL). Subsequently, the retraction velocity of melanocyte dendrites was assessed. Determination of mitochondrial membrane potential (MMP, DeltaPsim) was performed by flow cytometry and intracellular calcium ([Ca2+]i) level were measured. Alterations of mitochondrial ultrastructure were observed by transmission electron microscopy (TEM). Acridine orange (AO) staining was used to measure autophagy. The LC3-II/LC3-I ratio, an indicator of autophagosome formation, was analyzed by western blot. CONCLUSIONS: These results demonstrate the antioxidative effect of madecassoside on human melanocytes subjected to oxidative damage via the activation of autophagy. Moreover, madecassoside could be a promising treatment for vitiligo mainly caused by oxidative stress. PMID- 28881631 TI - Comparison of long-term outcome between hemicolectomy and partial colectomy in the elderly: a large population-based study. AB - Due to large progress has been achieved in surgical techniques, anesthesia and perioperative care, it is accepted that the very elderly colon cancer (CC) patient is not contraindication for surgery. However, it is a controversy that an extended or a less aggressive surgical approach should be performed for this population. Here, we identified 28110 CC patients aged >=80 from Surveillance, Epidemiology, and End-Results (SEER) database. The surgical approaches included extended hemicolectomy (HC) and partial colectomy (PC). 5-year cancer specific survival (CSS) was obtained. Kaplan-Meier methods and Cox regression models were used to assess the correlations between prognostic factors and long-term survival. The 5-year CSS for patients treated with HC were 45.6%, which were similar to patients who received PC (44.8%), the survival difference has no statistical significance (P=0.087). The result following propensity score matching further confirmed long-term survival were equal between HC and PC. However, patients in AJCC T3/T4 stage and with tumor size >=5cm could obtain survival benefit from the extended surgery. In conclusion, most of elderly CC patients could not obtain survival benefit from extended resection. Partial colectomy should also be considered as an alternative approach for this group of patients. PMID- 28881632 TI - Preliminary biological evaluation of 18F-AlF-NOTA-MAL-Cys-Annexin V as a novel apoptosis imaging agent. AB - A novel annexin V derivative (Cys-Annexin V) with a single cysteine residue at its C-terminal has been successfully labeled site-specifically with NOTA maleimide aluminum [18F]fluoride complexation and evaluated it as a novel apoptosis agent in vitro and in vivo. The total synthesis time of 18F-AlF-NOTA MAL-Cys-Annexin V from [18F]fluoride was about 65 min. The tracer was stable in vitro and it was excreted through renal in normal mice. The rate of the tracer bound to erythrocytes with exposed phosphatidylserine was 89.36+/-0.61% and this binding could be blocked by unlabeled Cys-Annexin V. In rats treated with cycloheximide, there were 6.23+/-0.23 times (n=4) increase in hepatic uptake of the tracer as compared to normal rats at 1h p.i. The uptake of the tracer in liver also could be blocked by co-injection of unlabeled Cys-Annexin V. These results indicated the favorable characterizations such as convenient synthesis and specific apoptotic cells targeting of18F-AlF-NOTA-MAL- Cys-Annexin V were suitable for its further investigation in clinical apoptosis imaging. PMID- 28881633 TI - Peroxiredoxin 6 overexpression attenuates lipopolysaccharide-induced acute kidney injury. AB - Peroxiredoxin 6 (PRDX6) is a member of the PRDX family of antioxidant enzymes and correlated with inflammatory response. Therefore, we investigated the role of PRDX6 during lipopolysaccharide (LPS)-induced acute kidney injury. Both 3 months aged PRDX6-overexpressing transgenic mice (PRDX6 mice) and wild type (WT) mice had acute renal injury induced by intraperitoneal injection of LPS (10 mg/kg)., PRDX6 mice showed decreased mortality and renal injury following LPS challenge compared to WT mice. Furthermore, infiltration of macrophages, T-cells and neutrophils, and the number of apoptotic cells were more decreased by LPS treatment in PRDX6 mice than in WT mice. Because LPS induces reactive oxygen species (ROS) production which induces inflammation through c-Jun N-terminal Kinase (JNK) and p38 MAPK activation, we investigated ROS concentration and MAPK signaling pathway in the kidney of PRDX6 mice. As expected, LPS-induced oxidative stress was attenuated, and p38 MAPK and JNK activation was decreased in the kidney of PRDX6 mice. Inhibitory effect of PRDX6 on LPS-induced apoptosis and MAPK activation in the primary renal proximal tubular cells were overcome by treatment with PRDX6 inhibitor or hydrogen peroxide. These results suggest that PRDX6 overexpression inactivates p38 MAPK and JNK pathway through decrease LPS induced ROS concentration in the kidney, resulting in inhibition of renal apoptosis and leukocyte infiltration and led to attenuation of LPS-induced acute kidney injury. PMID- 28881634 TI - Heterogeneous nuclear ribonucleoprotein (hnRNP) L promotes DNA damage-induced cell apoptosis by enhancing the translation of p53. AB - The tumor suppressor p53 is an essential gene in the induction of cell cycle arrest, DNA repair, and apoptosis. p53 protein is induced under cellular stress, blocking cell cycle progression and inducing DNA repair. Under DNA damage conditions, it has been reported that post-transcriptional regulation of p53 mRNA contributes to the increase in p53 protein level. Here we demonstrate that heterogeneous nuclear ribonucleoprotein (hnRNP) L enhances p53 mRNA translation. We found that hnRNP L is increased and binds to the 5'UTR of p53 mRNA in response to DNA damage. Increased hnRNP L caused enhancement of p53 mRNA translation. Conversely, p53 protein levels were decreased following hnRNP L knock-down, rendering them resistant to apoptosis and arrest in the G2/M phase after DNA damage. Thus, our findings suggest that hnRNP L functions as a positive regulator of p53 translation and promotes cell cycle arrest and apoptosis. PMID- 28881635 TI - HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor kappaB signaling. AB - Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-kappaB (NF kappaB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV 1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-kappaB binding site in the EGR1 promotor or inhibition of NF-kappaB activation reduced Tax induced EGR1 upregulation. Tax mutants unable to activate NF-kappaB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-kappaB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-kappaB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF kappaB activation in HTLV-1-infected and Tax-expressing cells. Both NF-kappaB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-kappaB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target. PMID- 28881636 TI - The landscape of DNA methylation-mediated regulation of long non-coding RNAs in breast cancer. AB - Although systematic studies have identified a host of long non-coding RNAs (lncRNAs) which are involved in breast cancer, the knowledge about the methyla tion-mediated dysregulation of those lncRNAs remains limited. Here, we integrated multi-omics data to analyze the methylated alteration of lncRNAs in breast invasive carcinoma (BRCA). We found that lncRNAs showed diverse methylation patterns on promoter regions in BRCA. LncRNAs were divided into two categories and four subcategories based on their promoter methylation patterns and expression levels be-tween tumor and normal samples. Through cis-regulatory analysis and gene ontology network, abnormally methylated lncRNAs were identified to be associated with can-cer regulation, proliferation or expression of transcription factors. Competing endog-enous RNA network and functional enrichment analysis of abnormally methylated lncRNAs showed that lncRNAs with different methylation patterns were involved in several hallmarks and KEGG pathways of cancers significantly. Finally, survival analysis based on mRNA modules in networks revealed that lncRNAs silenced by high methylation were associated with prognosis significantly in BRCA. This study enhances the understanding of aberrantly methylated patterns of lncRNAs and pro-vides a novel insight for identifying cancer biomarkers and potential therapeutic tar-gets in breast cancer. PMID- 28881637 TI - CD147 functions as the signaling receptor for extracellular divalent copper in hepatocellular carcinoma cells. AB - Elevated copper levels in tumor microenvironment are directly correlated to cancer progression in a variety of malignancies. Copper is required in angiogenesis, and promotes the proliferation and metastasis of cancer cells. However, the molecular mechanism of copper in promoting cancer progression remains elusive. Here we report that CD147 serves as a signaling receptor for extracellular Cu2+ in hepatocellular carcinoma (HCC) cells. Cu2+ binds to the extracellular membrane-proximal domain of CD147 and mediates its self association. Cu2+-mediated self-association of CD147 activates PI3K/Akt signaling pathway leading to the up-regulation of matrix metalloproteinase MMP-2 and MMP-14 in HCC cells. Cu2+-induced CD147 self-association also enhances the ability of HCC cells to stimulate MMP-2 expression from neighboring fibroblasts, as well as increases the invasiveness of HCC cells which is abolished by the copper chelator tetrathiomolybdate. We have mapped the interfaces and identified the key residues of CD147 involved in the Cu2+ induced self-association. The Cu2+ binding deficient CD147 mutant abolishes the stimulating effects of Cu2+ on HCC cells. Our study reveals a novel extracellular signaling role of copper in promoting cancer cell metastasis, which implies that targeting the Cu2+-induced self association of CD147 is a new strategy for cancer treatment. PMID- 28881638 TI - The oxido-metabolic driver ATF4 enhances temozolamide chemo-resistance in human gliomas. AB - Malignant gliomas are devastating neoplasia with limited curative treatment options. Temozolomide (TMZ, Temcat(r), Temodal(r) or Temodar(r)) is a first-line treatment for malignant gliomas but the development of drug resistance remains a major concern. Activating transcription factor 4 (ATF4) is a critical oxido metabolic regulator in gliomas, and its role in the pathogenesis of TMZ resistance remains elusive. We investigated the effect of TMZ on human glioma cells under conditions of enhanced ATF4 expression (ATF4OE) and ATF4 knock down (ATF4KD). We monitored cell survival, ATF4 mRNA expression of ATF4 and xCT (SLC7a11) regulation within human gliomas. TMZ treatment induces a transcriptional response with elevated expression of ATF4, xCT and Nrf2, as a sign of ER stress and toxic cell damage response. ATF4 overexpression (ATF4OE) fosters TMZ resistance in human gliomas and inhibits TMZ-induced autophagy. Conversely, ATF4 suppression by small interfering RNAs (ATF4KD) leads to increased TMZ susceptibility and autophagy in comparison to wild type gliomas. ATF4OE gliomas show reduced cell cycle shift and apoptotic cell death, whereas ATF4KD gliomas reveal higher susceptibility towards cell cycle rearrangements. Hence, the migration capacity of ATF4OE glioma cells is almost not affected by TMZ treatment. In contrast, ATF4KD gliomas show a migratory stop following TMZ application. Mechanistically, xCT elevation is a consequence of ATF4 activation and increased levels of xCT amplifies ATF4-induced TMZ resistance. Our data show that ATF4 operates as a chemo-resistance gene in gliomas, and the tumor promoting function of ATF4 is mainly determined by its transcriptional target xCT. Therefore, therapeutic inactivation of ATF4 can be a promising strategy to overcome chemo-resistance and promote drug efficacy in human gliomas. PMID- 28881639 TI - Netrin-1 promotes gastric cancer cell proliferation and invasion via the receptor neogenin through PI3K/AKT signaling pathway. AB - Netrin-1 is a laminin-related protein found to promote proliferation and invasion in multiple types of cancers. Recent studies have identified the function role of netrin-1 in several cancers; however, the influence of netrin-1 in human gastric cancer(GC) remains largely unknown. In this study, we found netrin-1 was upregulated in human GC tissues, where its expression correlated inversely with cancer stage and lymph node metastasis. We detected netrin-1 and its receptor knockdown significantly suppressed GC cells proliferation and invasion, while overexpression netrin-1 reversed these effects. Xenografted analyses using GC cells displayed significantly inhibition of tumor growth and metastasis by netrin 1 depletion. Furthermore, we identified that netrin-1 as a regulator of PI3K/AKT pathway to modulate GC cells proliferation and invasion abilities via its receptor neogenin. Taken together, our findings argued that netrin-1 and its receptor neogenin might act synergistically in promoting GC cells proliferation and invasion through the PI3K/AKT signaling pathway. It is conceivable that netrin-1 could be new therapeutic target to GC therapy. PMID- 28881640 TI - MicroRNA-200c as a prognostic and sensitivity marker for platinum chemotherapy in advanced gastric cancer. AB - We examined microRNA-200c (miR-200c) expression in tumor tissues and plasma of patients with advanced gastric cancer and correlated miR-200c expression with treatment efficacy of platinum chemotherapy and patient prognosis. Tumor tissues were collected from 51 patients with advanced gastric cancer who received platinum-containing chemotherapies. The plasma was collected from the same group of patients and 51 subjects with chronic superficial gastritis. Quantitative RT PCR was used to evaluate miR-200c expression, and its correlation with treatment efficacy and patient prognosis was analyzed. The results showed that the miR-200c expression in gastric cancer tissues and in plasma were significantly lower than tumor-adjacent tissues and in patients with chronic superficial gastritis (both p <0.05). No significant correlation was found between miR-200c expression in tumors or plasma and clinical characteristics. Patients with higher miR-200c expression had better treatment outcomes with platinum chemotherapy and longer progression-free survival and overall survival than patients with lower miR-200c expression. Receiver-operating characteristic curve analysis showed that miR-200c expression in gastric cancer tissues and plasma distinguished patients' treatment outcomes. Multivariate analyses confirmed that over expression of miR-200c both in gastric cancer tissue and plasma is associated with longer progression-free survival and overall survival. Taken together, our study indicated that miR-200c expression in gastric cancer tissues and plasma of patients with advanced gastric cancer is associated with better treatment efficacy and prognosis with platinum chemotherapy, suggesting that expression of miR-200c may be predictive for chemotherapy and prognosis in advanced gastric cancer patients. PMID- 28881641 TI - Colorectal cancer at high risk of peritoneal metastases: long term outcomes of a pilot study on adjuvant laparoscopic HIPEC and future perspectives. AB - OBJECTIVE: Early detection of peritoneal metastases (PM) of colorectal cancer (CRC) is difficult and treatment options at a clinically overt stage are limited. Potentially, adjuvant laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) is of value. The aim of this study was to present long term oncological outcomes of a pilot study on adjuvant HIPEC to reduce development of PMCRC, with systematic review of literature. METHODS: Long term oncological outcomes of ten patients who underwent laparoscopic HIPEC within eight weeks after resection of primary CRC in the pilot study were retrospectively collected. A systematic search of literature was performed on studies describing the use of HIPEC in patients with CRC at high risk of developing PM. RESULTS: The median follow-up was 54 months (range 49-63). All patients were alive at the last follow-up moment and none of them had developed PM. Two patients had developed pulmonary metastases. Systematic review revealed five small cohort studies, including two matched comparisons. Peritoneal recurrences were found in 0% to 9% after adjuvant HIPEC, which was 28% and 43% in the two control groups, respectively. Disease free and overall survival were significantly higher in favour of HIPEC. CONCLUSION: Long term follow-up of ten patients included in a pilot study on adjuvant HIPEC revealed no peritoneal recurrences. This result is in line with other published pilot studies, a promising observation. However, the outcomes of the Dutch randomized COLOPEC trial and similar trials worldwide should be awaited for definitive conclusions on the effectiveness of adjuvant HIPEC. PMID- 28881642 TI - PD-1 and PD-L1 expression in 132 recurrent nasopharyngeal carcinoma: the correlation with anemia and outcomes. AB - The expression of Programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) has been reported to be reliable prognostic factors in various malignances including primary nasopharyngeal carcinoma (NPC). However, the exact role of PD 1/PD-L1 in recurrent NPC remains unclear. In this study, we aimed to investigate the relationship between the expression of PD-1 / PD-L1 and the clinical pathology as well the outcomes of recurrent NPC patients (n = 132). The expression of PD-1 and PD-L1 was measured by immunohistochemistry staining. The relationship between PD-1 / PD-L1 and factors involved in clinic-pathology and outcomes of patients with NPC was assessed by correlation analysis. To further explore the association between PD-L1 and anemia, immunofluorescence analysis was performed to investigate the correlation of PD-L1 with hypoxia inducible factor 1alpha (HIF-1alpha). We observed that advanced rT classification and anemia status before salvage treatment was associated with high level of PD-L1 in recurrent NPC patients, and PD-L1 and was co-located with HIF-1alpha in recurrent tumors by immunofluorescence analysis. Moreover, our result suggested that PD-L1 might be a negative indicator for recurrent NPC patients as well as age, rT classification, anemia and tumor necrosis at diagnose of recurrence. Taken together, our results revealed that PD-L1 might be a potential prognostic biomarker for recurrent NPC patients, and advanced re-stage, anemia might represent as candidate biomarkers for evaluating patients' response to anti-PD-1 / PD-L1-treatment. However, further studies are needed to clarify the underlying mechanism of hypoxia in immunosuppression process induced by PD-1 / PD-L1 axis. PMID- 28881643 TI - Critical analysis of the major and ancillary imaging features of LI-RADS on 127 proven HCCs evaluated with functional and morphological MRI: Lights and shadows. AB - PURPOSE: To report a critical analysis of major and ancillary MR imaging features in assessment of HCC. METHODS: Retrospectively we evaluated 70 cirrhotic patients with 173 nodules, which were subjected to MR study at 0 time (MR0), after 3 (MR3) and 6 months (MR6) using two different contrast media. EOB-GD-DTPA was injected at MR0 and MR6, while Gd-BT-DO3A at MR3. Three expert hepatic radiologists reviewed all images, recording, according to LI-RADS, the size, the presence and quality of arterial-phase hyperenhancement, washout and capsule appearance, threshold growth. Additionally, we recorded signal intensity (SI) on T2-W images, on DWI, on apparent diffusion coefficient (ADC) maps and SI on T1-W images of EOB GD-BPTA hepatospecific phase. Median value of ADC and of Intravoxel incoherent motion related parameters were assessed. RESULTS: 127 HCCs and 24 dysplastic nodules were assessed. Hypervascular on arterial phase was found in 84 HCCs, washout appearance in 124, capsule appearance in 111, hypointensity on hepatospecific phase in 127, hyperintensity on T2-W sequences and restricted diffusion in 107. Hyper vascular on arterial phase was found in 17 dysplastic nodules, wash-out appearance in 2, hypointensity on hepatospecific phase in 7 while no dysplastic nodules showed capsule appearance, hyperintensity on T2-W and restricted diffusion. Highest accuracy was obtained by washout appearance and hypointense signal on hepatospecific phase (97% and 95%). CONCLUSIONS: Hypointensity on hepatospecific phase and washout appearance are the most relevant diagnostic sign for differentiating low-risk from high-risk HCC nodules. The capsule appearance, T2-W hyperintensity and restricted diffusion have high positive predictive value. PMID- 28881644 TI - Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design. AB - Cluster of differentiation 24 (CD24) is a specific surface marker involved in the tumorigenesis and progression of hepatocellular carcinoma (HCC). However, all reported anti-CD24 antibodies are murine ones with inevitable immunogenicity. To address this, a method using both molecular structure and docking-based complementarity determining region (CDR) grafting was employed for humanization. After xenogeneic CDR grafting into a human antibody, three types of canonical residues (in the VL/VH interface core, in the loop foundation, and interaction with loop residues) that support loop conformation and residues involved in the antigen-binding interface were back-mutated. Four engineered antibodies were produced, among which hG7-BM3 has virtually identical 3-D structure and affinity parameters with the parental chimeric antibody cG7. In vitro, hG7-BM3 demonstrated superior immunogenicity and serum stability to cG7. Antibody dependent cellular cytotoxicity (ADCC), tumor cell internalization and in vivo targeting assays indicate that hG7-BM3 has the potential for development as an antibody-drug conjugate (ADC). We therefore generated the hG7-BM3-VcMMAE conjugate, which was shown to induce tumor cell apoptosis and effectively suppress nude mice bearing HCC xenografts. In conclusion, our study provides new inspiration for antibody humanization and an ADC candidate for laboratory study and clinical applications. PMID- 28881645 TI - Spatial function of the oxidative DNA damage response in radiation induced bystander effects in intra- and inter-system of Caenorhabditis elegans. AB - Though the signaling events involved in radiation induced bystander effects (RIBE) have been investigated both in vitro and in vivo, the spatial function of these communications, especially the related signaling pathways, is not fully elucidated. In the current study, significant increases of DNA damage were clearly observed in C. elegans germline upon irradiation to both intra-system of posterior pharynx and inter-system of vulva, in which more severe damage, even to F1 generation worms, was shown for vulva irradiation. Spatial function assay indicated the DDR key components of mrt-2/hus-1/cep-1/ced-4 were indispensable in germ cells for both sites irradiation, while those components in somatic cells were either not (cep-1/ced-4) or partially (mrt-2/hus-1) required to promote apoptosis. Moreover, production of reactive oxygen species (ROS) indicated by the superoxide dismutase expression and the unfolded protein response of the mitochondria was found systemically involved in the initiation of these processes for both two site irradiation. These results will give a better understanding of the RIBE mechanisms in vivo, and invaluable to assess the clinical relevance to radiotherapy. PMID- 28881646 TI - Modeling African American prostate adenocarcinoma by inducing defined genetic alterations in organoids. AB - Genomic studies are rapidly identifying genetic alterations in human cancer, but functional validation of such alterations has been slow. Here, using human prostate cancer as a model, we have assessed the feasibility of engineering defined genetic alterations in well-known cancer driver genes to transform benign prostate epithelial organoids derived from African American men. Benign human prostate organoids were transduced with lentiviruses expressing MYC, shPTEN, shTP53 and AR, alone and in various combinations, to recapitulate prostate cancer development. Organoids expressing MYC, shPTEN, shTP53 and AR (denoted MPPA); MYC, shPTEN and shTP53 (MPP); or MYC (M) were significantly larger, had higher proliferation rates and demonstrated pathologically transformed morphology compared to organoids transduced with control lentivirus. Alterations in MYC, PTEN and TP53 also affected the rate of organoid basal-to-luminal differentiation in vitro. MPPA and MPP organoids expressed the clinical prostate cancer marker AMACR and developed prostate adenocarcinoma when grafted under the renal capsule in mice. These data indicate that genetic alterations commonly observed in human prostate cancer can be rapidly modeled in human organoid culture. Prostate cancer organoids provide a useful pre-clinical model for the evaluation of new candidate cancer genes, cancer disparities, and potentially for testing of novel therapeutic agents. PMID- 28881647 TI - Ocular Behcet's disease is associated with aberrant methylation of interferon regulatory factor 8 (IRF8) in monocyte-derived dendritic cells. AB - Aberrant methylation of interferon regulatory factor 8 (IRF8) has been noted in various tumors. IRF8 has also been reported to be involved in many autoimmune diseases, including Behcet's disease (BD). However, the methylation status of IRF8 in BD has not been reported. To address this issue, we investigated whether the degree of methylation of IRF8 in dendritic cells (DCs) plays a role in the development of BD. We found a lower mRNA expression and a higher methylation level of IRF8 in active ocular BD patients as compared to normal subjects and inactive patients. Treatment with a demethylation agent, 5-Aza-2'-deoxycytidine (DAC) resulted in an increase of mRNA expression and a reduction of the IRF8 methylation level. It also down-regulated the expression of the co-stimulatory molecules CD86, CD80, CD40, and reduced the production of IL-6, IL-1beta, IL-23 and IL-12. An inhibition of Th1/Th17 responses was observed as evidenced by a decreased production of IFN-gamma, IL-17, and a reduction of IFN-gamma/IL-17- producing CD4+ T cells following treatment with DAC. This study shows that active ocular BD patients have an aberrant IRF8 methylation status. These findings suggest that epigenetic control of IRF8 expression may offer a future target in the treatment of ocular BD. PMID- 28881648 TI - Correlation between microRNA-143 in peripheral blood mononuclear cells and disease severity in patients with psoriasis vulgaris. AB - This study aims to explore the correlation between microRNA-143 (miR-143) expression in peripheral blood mononuclear cells (PBMCs) and disease severity in patients with psoriasis vulgaris. From March 2014 to November 2015, 194 patients with psoriasis vulgaris (102 patients in progressive stage and 92 patients in stable stage) were selected as the case group and 175 healthy people as a control group were enrolled in this study. ELISA was used to detect the levels of IL-17 and VEGF in serum. The qRT-PCR assay was performed to detect the relative expression of miR-143 in PBMCs. Disease severity in psoriasis vulgaris patients was graded with Psoriasis Lesions Area and Severity Index (PASI). The value of miR-143 expression in PBMCs for the diagnosis of psoriasis vulgaris was evaluated using receiver operating characteristic (ROC) curve. The correlation between miR 143 expression in PBMCs and PASI scores was measured using Spearman rank correlation analysis. Compared with the control group, serum levels of IL-17 and VEGF were higher and miR-143 expression in PBMCs was lower in the case group. Furthermore, miR-143 expression in PBMCs was lower in patients in progressive stage than that in patients with stable stage. The relative expression of miR-143 in PBMCs was negatively correlated with PASI scores of patients with psoriasis vulgaris. ROC curve showed that miR-143 was a reliable and accurate biomarker of psoriasis vulgaris. Our findings suggest that miR-143 expression in PBMCs is negatively correlated the disease severity in psoriasis vulgaris. PMID- 28881650 TI - APEX2-enhanced electron microscopy distinguishes sigma-1 receptor localization in the nucleoplasmic reticulum. AB - The sigma-1 receptor (Sig1R) is an endoplasmic reticulum chaperonin that is attracting tremendous interest as a potential anti-neurodegenerative target. While this membrane protein is known to reside in the inner nuclear envelope (NE) and influences transcription, apparent Sig1R presence in the nucleoplasm is often observed, seemingly contradicting its NE localization. We addressed this confounding issue by applying an antibody-free approach of electron microscopy (EM) to define Sig1R nuclear localization. We expressed APEX2 peroxidase fused to Sig1R-GFP in a Sig1R-null NSC34 neuronal cell line generated with CRISPR-Cas9. APEX2-catalyzed gold/silver precipitation markedly improved EM clarity and confirmed an apparent intra-nuclear presence of Sig1R. However, serial sectioning combined with APEX2-enhanced EM revealed that Sig1R actually resided in the nucleoplasmic reticulum (NR), a specialized nuclear compartment formed via NE invagination into the nucleoplasm. NR cross-sections also indicated Sig1R in ring shaped NR membranes. Thus, this study distinguishes Sig1R in the NR which could otherwise appear localized in the nucleoplasm if detected with low-resolution methods. Our finding is important for uncovering potential Sig1R regulations in the nucleus. PMID- 28881649 TI - Identification of deubiquitinase targets of isothiocyanates using SILAC-assisted quantitative mass spectrometry. AB - Cruciferous vegetables such as broccoli and kale have well documented chemopreventative and anticancer effects that are attributed to the presence of isothiocyanates (ITCs). ITCs modulate the levels of many oncogenic proteins, but the molecular mechanisms of ITC action are not understood. We previously reported that phenethyl isothiocyanate (PEITC) inhibits two deubiquitinases (DUBs), USP9x and UCH37. DUBs regulate many cellular processes and DUB dysregulation is linked to the pathogenesis of human diseases including cancer, neurodegeneration, and inflammation. Using SILAC assisted quantitative mass spectrometry, here we identify 9 new PEITC-DUB targets: USP1, USP3, USP10, USP11, USP16, USP22, USP40, USP48 and VCPIP1. Seven of these PEITC-sensitive DUBs have well-recognized roles in DNA repair or chromatin remodeling. PEITC both inhibits USP1 and increases its ubiquitination and degradation, thus decreasing USP1 activity by two mechanisms. The loss of USP1 activity increases the level of mono-ubiquitinated DNA clamp PCNA, impairing DNA repair. Both the inhibition/degradation of USP1 and the increase in mono-ubiquitinated PCNA are new activities for PEITC that can explain the previously recognized ability of ITCs to enhance cancer cell sensitivity to cisplatin treatment. Our work also demonstrates that PEITC reduces the mono ubiquityl histones H2A and H2B. Understanding the mechanism of action of ITCs should facilitate their use as therapeutic agents. PMID- 28881651 TI - Expression and clinical significance of CD147 in renal cell carcinoma: a meta analysis. AB - OBJECTIVE: To assess clinical significance of CD147 in renal cell carcinoma. METHODS: Collect case-control studies which focus on CD147's expression in renal cell carcinoma. Trails were retrieved from CBM, CNKI, Wan-fang database, PubMed, Cochrane Library and Embase. According to the inclusion and exclusion criteria, data extraction and quality assessment were done by two researchers independently, and outcomes were pooled with Revman5.3 and STATA14.0. RESULTS: A total of 11 studies were confirmed, among which renal cell carcinoma 887 cases, non-cancer 505cases. As for the positive rate of CD147, there are statistical differences among survival, renal cell carcinoma tissue vs. non-cancer tissues [OR= 8.19, P= 0.0002], with vs. without lymph node metastases [OR= 6.52, P= 0.001], clinical stage III~IV vs. II~I [OR= 4.07, P< 0.00001], histopathological stage III~IV vs. II [OR= 3.01, P= 0.002], histopathological stage III~IV vs. I [OR= 7.50, P< 0.00001], tumor size [OR= 5.01, P= 0.0007]. No significant difference was tested among different age, gender, histological types and Position of cancer. CONCLUSION: As shown in our results, CD 147 may participate the whole course of carcinogenesis of renal cell carcinoma, which might be valuable for the diagnosis, treatment and prognosis. PMID- 28881652 TI - Predictors of acute kidney injury after paraquat intoxication. AB - Paraquat intoxication is characterized by multi-organ failure, causing substantial mortality and morbidity. Many paraquat patients experience acute kidney injury (AKI), sometimes requiring hemodialysis. We observed 222 paraquat intoxicated patients between 2000 and 2012, and divided them into AKI (n = 103) and non-AKI (n = 119) groups. The mortality rate was higher for AKI than non-AKI patients (70.1% vs. 40.0%, P < 0.001). Patients with AKI had a longer time to hospital arrival (P = 0.003), lower PaO2 (P = 0.006) and higher alveolar-arterial O2 difference (P < 0.001) 48 h after admission, higher sequential organ failure assessment 48-h score (P < 0.001), higher severity index of paraquat poisoning (SIPP) score (P = 0.016), lower PaCO2 at admission (P = 0.031), higher PaO2 at admission (P = 0.015), lower nadir PaCO2 (P = 0.001) and lower nadir HCO3 (P = 0.004) than non-AKI patients. Multivariate logistic regression indicated that acute hepatitis (P < 0.001), a longer time to hospital arrival (P < 0.001), higher SIPP score (P = 0.026) and higher PaO2 at admission (P = 0.014) were predictors of AKI. The area under the receiver operating characteristic curve confirmed that an Acute Kidney Injury Network 48-hour score >= 2 predicted AKI necessitating hemodialysis with a sensitivity of 0.6 and specificity of 0.832. AKI is common (46.4%) following paraquat ingestion, and acute hepatitis, the time to hospital arrival, SIPP score and PaO2 at admission were powerful predictors of AKI. Larger studies with longer follow-up durations are warranted. PMID- 28881653 TI - Identification of novel small molecule Beclin 1 mimetics activating autophagy. AB - Anti-apoptotic proteins Bcl-2 and Bcl-xL could block autophagy by binding to Beclin 1 protein, an essential inducer of autophagy. Compounds mimicking Beclin 1 might be able to disrupt Bcl-xL/2-Beclin 1 interaction, free out Beclin 1, and thus trigger autophagy. In order to identify small molecule Beclin 1 mimetics, a fluorescence polarization-based high-throughput screening of 50,316 compounds was carried out with a Z' score of 0.82 +/- 0.05, and an outcome of 58 hits. After the structure analysis, three acridine analogues were unveiled and confirmed using the fluorescence polarization assay and the surface plasmon resonance assay. Moreover, a set of 17 additional acridine analogues was prepared and tested. Compound 7 showed selectivity for Bcl-xL (KD = 6.5 MUM) over Bcl-2 (KD = 160 MUM) protein, and potent cytotoxicity (nanomolar scale) in PC-3, PC-3a and DU145 prostate cancer cells. Furthermore, induction of autophagy was also demonstrated in PC-3 and PC-3a cells treated with some acridine compounds by LC3 conversion immunoblotting and LC3 fluorescence microscopy. These Beclin 1 mimetics will be invaluable tools for developing novel autophagy inducers, better understanding the roles of autophagy in cancer, and will contribute to cancer therapy. PMID- 28881654 TI - Fusion between M2-macrophages and cancer cells results in a subpopulation of radioresistant cells with enhanced DNA-repair capacity. AB - Cell fusion is a natural biological process in normal development and tissue regeneration. Fusion between cancer cells and macrophages results in hybrids that acquire genetic and phenotypic characteristics from both maternal cells. There is a growing body of in vitro and in vivo data indicating that this process also occurs in solid tumors and may play a significant role in tumor progression. However, investigations of the response of macrophage:cancer cell hybrids to radiotherapy have been lacking. In this study, macrophage:MCF-7 hybrids were generated by spontaneous in vitro cell fusion. After irradiation, both hybrids and their maternal MCF-7 cells were treated with 0 Gy, 2.5 Gy and 5 Gy gamma radiation and examined by clonogenic survival and comet assays at three time points (0 h, 24 h, and 48 h). Compared to maternal MCF-7 cells, the hybrids showed increased survival fraction and plating efficiency (colony formation ability) after radiation. The hybrids developed less DNA-damage, expressed significantly lower residual DNA-damage, and after higher radiation dose showed less heterogeneity in DNA-damage compared to their maternal MCF-7 cells. To our knowledge this is the first study that demonstrates that macrophage:cancer cell fusion generates a subpopulation of radioresistant cells with enhanced DNA-repair capacity. These findings provide new insight into how the cell fusion process may contribute to clonal expansion and tumor heterogeneity. Furthermore, our results provide support for cell fusion as a mechanism behind the development of radioresistance and tumor recurrence. PMID- 28881655 TI - DNA hypomethylation of CBS promoter induced by folate deficiency is a potential noninvasive circulating biomarker for colorectal adenocarcinomas. AB - Aberrant DNA methylation patterns, which induced by folate deficiency, play important roles in tumorigenesis of colorectal cancer (CRC). Some DNA methylation alterations can also be detected in cell-free DNA (cfDNA) of patients' plasma, making cfDNA an ideal noninvasive circulating biomarker. However, exact DNA methylation alterations induced by folate deficiency in tumorigenesis of CRC and exact potential circulating cfDNA methylation biomarker are still unclear. Therefore, DNA methylation patterns of the normal human colon mucosal epithelial cell line (NCM460), cultured with normal or low folate content, were screened and the DNA hypomethylation of cystathionine-beta-synthase (CBS) promoter was further validated in vitro and vivo. Then, the correlation analysis between folate level, DNA methylation alteration in promoter and expression of CBS was carried out in vitro and vivo. Further, the methylation patterns of CBS promoter in plasma cfDNA were detected and statistically correlated with pathological parameters and clinical outcome. Our study showed that DNA hypomethylation in CBS promoter, induced by folate deficiency, would lead to up-regulation of CBS both in vitro and vivo. Patients with cfDNA hypomethylation of CBS promoter in plasma were correlated with high tumor stage and poor clinical outcome. In addition, cfDNA hypomethylation of CBS promoter in plasma was shown to be an independent prognostic factor for recurrence and cancer-related death in CRC. Our results indicated that DNA hypomethylation of CBS promoter induced by folate deficiency could serve as a potential noninvasive circulating biomarker and may be helpful in developing more effective prognostic markers for CRC. PMID- 28881656 TI - BRD4 facilitates DNA damage response and represses CBX5/Heterochromatin protein 1 (HP1). AB - Ovarian cancer (OC) is a heterogeneous disease characterized by defective DNA repair. Very few targets are universally expressed in the high grade serous (HGS) subtype. We previously identified that CHK1 was overexpressed in most of HGSOC. Here, we sought to understand the DNA damage response (DDR) to CHK1 inhibition and increase the anti-tumor activity of this pathway. We found BRD4 suppression either by siRNA or BRD4 inhibitor JQ1 enhanced the cytotoxicity of CHK1 inhibition. Interestingly, BRD4 was amplified and/or upregulated in a subset of HGSOC with statistical correlation to overall survival. BRD4 inhibition increased CBX5 (HP1alpha) level. CHK1 inhibitor induced DDR marker, gamma-H2AX, but BRD4 suppression did not. Furthermore, nuclear localization of CBX5 and gamma-H2AX was mutually exclusive in BRD4-and CHK1-inhibited cells, suggesting BRD4 facilitates DDR by repressing CBX5. Our results provide a strong rationale for clinical investigation of CHK1 and BRD4 co-inhibition, especially for HGSOC patients with BRD4 overexpression. PMID- 28881658 TI - Decitabine-Vorinostat combination treatment in acute myeloid leukemia activates pathways with potential for novel triple therapy. AB - Despite advancements in cancer therapeutics, acute myeloid leukemia patients over 60 years old have a 5-year survival rate of less than 8%. In an attempt to improve this, epigenetic modifying agents have been combined as therapies in clinical studies. In particular combinations with Decitabine and Vorinostat have had varying degrees of efficacy. This study therefore aimed to understand the underlying molecular mechanisms of these agents to identify potential rational epi-sensitized combinations. Combined Decitabine-Vorinostat treatment synergistically decreased cell proliferation, induced apoptosis, enhanced acetylation of histones and further decreased DNMT1 protein with HL-60 cells showing a greater sensitivity to the combined treatment than OCI-AML3. Combination therapy led to reprogramming of unique target genes including AXL, a receptor tyrosine kinase associated with cell survival and a poor prognosis in AML, which was significantly upregulated following treatment. Therefore targeting AXL following epi-sensitization with Decitabine and Vorinostat may be a suitable triple combination. To test this, cells were treated with a novel triple combination therapy including BGB324, an AXL specific inhibitor. Triple combination increased the sensitivity of OCI-AML3 cells to Decitabine and Vorinostat as shown through viability assays and significantly extended the survival of mice transplanted with pretreated OCI-AML3 cells, while bioluminescence imaging showed the decrease in disease burden following triple combination treatment. Further investigation is required to optimize this triple combination, however, these results suggest that AXL is a potential marker of response to Decitabine-Vorinostat combination treatment and offers a new avenue of epigenetic combination therapies for acute myeloid leukemia. PMID- 28881659 TI - SIRT1 inhibition promotes atherosclerosis through impaired autophagy. AB - SIRT1, a highly conserved NAD+-dependent protein deacetylase, plays a pivotal role in the pathogenesis and therapy of atherosclerosis (AS). The aim of this study is to investigate the potential effects of SIRT1 on AS in ApoE-/- mice and the underlying mechanisms of autophagy in an ox-LDL-stimulated human monocyte cell line, THP-1. In vivo, the accelerated atherosclerotic progression of mice was established by carotid collar placement; then, mice were treated for 4 weeks with a SIRT1-specific inhibitor, EX-527. The atherosclerotic lesion size of EX 527-treated mice was greatly increased compared to that of the mice in the control group. Immunostaining protocols confirmed that the inhibition of SIRT1 during plaque initiation and progression enhanced the extent of intraplaque macrophage infiltration and impaired the autophagy process. In vitro cultured THP 1 macrophages exposed to ox-LDL were utilized to study the link between the SIRT1 function, autophagy flux, pro-inflammatory cytokine secretion, and foam cell formation using different methods. Our data showed that ox-LDL markedly suppressed SIRT1 protein expression and the autophagy level, while it elevated the MCP-1 production and lipid uptake. Additionally, the application of the SIRT1 inhibitor EX-527 or SIRT1 siRNA further attenuated ox-LDL-induced autophagy inhibition. In conclusion, our results show that the inhibition of SIRT1 promoted atherosclerotic plaque development in ApoE-/- mice by increasing the MCP-1 expression and macrophage accumulation. In particular, we demonstrate that blocking SIRT1 can exacerbate the acetylation of key autophagy machinery, the Atg5 protein, which further regulates the THP-1 macrophage-derived foam cell formation that is triggered by ox-LDL. PMID- 28881657 TI - Tumor biomarker conversion between primary and metastatic breast cancer: mRNA assessment and its concordance with immunohistochemistry. AB - Biomarker changes between primary (PT) and metastatic tumor (MT) site may be significant in individualizing treatment strategies and can result from actual clonal evolution, biomarker conversion, or technical limitations of diagnostic tests. This study explored biomarker conversion during breast cancer (BC) progression in 67 patients with different tumor subtypes and metastatic sites via mRNA quantification and subsequently analyzed the concordance between real-time qPCR and immunohistochemistry (IHC). Immunostaining for estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 was performed on formalin-fixed, paraffin-embedded PT and MT tissue sections. RT-qPCR was performed using a multiplex RT-qPCR kit for ESR1, PGR, ERBB2, and MKI67 and the reference genes B2M and CALM2. Subsequent measurement of tumor biomarker mRNA expression to detect conversion revealed significant decreases in ESR1 and PGR mRNA and MKI67 upregulation (all p < 0.001) in MT compared to PT of all tumor subtypes and ERBB2 upregulation in MT from triple-negative PT patients (p = 0.023). Furthermore, ERBB2 mRNA was upregulated in MT brain biopsies, particularly those from triple negative PTs (p = 0.023). High concordance between RT-qPCR and IHC was observed for ER/ESR1 (81%(kappa 0.51) in PT and 84%(kappa 0.34) in MT, PR/PGR (70%(kappa 0.10) in PT and 78% (kappa -0.32) in MT), and for HER2/ERBB2 (100% in PT and 89% in MT). Discordance between mRNA biomarker assessments of PT and MT resulting from receptor conversion calls for dynamic monitoring of BC tumor biomarkers. Overall, RT-qPCR assessment of BC target genes and their mRNA expression is highly concordant with IHC protein analysis in both primary and metastatic tumor. PMID- 28881660 TI - Activation of PERK branch of ER stress mediates homocysteine-induced BKCa channel dysfunction in coronary artery via FoxO3a-dependent regulation of atrogin-1. AB - The molecular mechanism of endoplasmic reticulum (ER) stress in vascular pathophysiology remains inadequately understood. We studied the role of ER stress in homocysteine-induced impairment of coronary dilator function, with uncovering the molecular basis of the effect of ER stress on smooth muscle large-conductance Ca2+-activated K+ (BKCa) channels. The vasodilatory function of BKCa channels was studied in a myograph using endothelium-denuded porcine small coronary arteries. Primary cultured porcine coronary artery smooth muscle cells were used for mRNA and protein measurements and current recording of BKCa channels. Homocysteine inhibited vasorelaxant response to the BKCachannel opener NS1619, lowered BKCa beta1 subunit protein level and suppressed BKCa current. Inhibition of ER stress restored BKCa beta1 protein level and NS1619-evoked vasorelaxation. Selective blockade of the PKR-like ER kinase (PERK) yielded similarly efficient restoration of BKCa beta1, preserving BKCa current and BKCa-mediated vasorelaxation. The restoration of BKCa beta1 by PERK inhibition was associated with reduced atrogin 1 expression and decreased nuclear localization of forkhead box O transcription factor 3a (FoxO3a). Silencing of atrogin-1 prevented homocysteine-induced BKCa beta1 loss and silencing of FoxO3a prevented atrogin-1 upregulation induced by homocysteine, accompanied by preservation of BKCa beta1 protein level and BKCa current. ER stress mediates homocysteine-induced BKCa channel inhibition in coronary arteries. Activation of FoxO3a by PERK branch underlies the ER stress mediated BKCa inhibition through a mechanism involving ubiquitin ligase-enhanced degradation of the channel beta1 subunit. PMID- 28881661 TI - Combination of Fe/Cu -chelators and docosahexaenoic acid: an exploration for the treatment of colorectal cancer. AB - Colorectal cancer (CRC) is one of the major causes of cancer deaths in the world. 5-fluorouracil (5-FU) -based chemotherapy is a common choice for patients with CRC; unfortunately, the benefit is rather limited due to the acquisition of drug resistance. Therefore, the alternative therapeutic strategies are required. The activation of autophagic mechanism was considered as the main cause of the acquisition of drug resistance in 5-FU treatment. Docosahexaenoic acid (DHA), a fatty acid, has been regarded as an efficient anticancer agent and can improve the drug resistance in conventional cancer therapy by a low basal level of autophagy in colon cancer cells. Moreover, removal of iron or copper by metal chelators could cause ROS levels increase and mediate cancer cell cytotoxicity led by autophagy. In the present study, we constructed a combination of 5-FU, 1:1 mixture of metal chelators di-2-pyridylketone 4-cyclohexyl-4-methyl-3 thiosemicarbazone hydrochloride (DpC) and N, N, N', N'-tetrakis-[2-pyridylmethyl] ethylenediamine (TPEN) named DTN, and DHA to evaluate the anticancer effect of this combination, compared to the traditional 5-FU-based chemotherapy; further we investigated the underlying mechanism. Through inducing ROS-mediated degradation of Mcl-1 ubiquitination, the triple combination of 5-FU, DTN and DHA resulted in the elevated apoptosis in CRC cells, thus to reduce the tumor size and weight. Taken together, this study suggests the triple combination of 5-FU+DTN+DHA exhibits an effective anticancer activity of overcoming drug resistance in colorectal cancer, mechanism as the elevated apoptosis mediated by an increase of ROS and Mcl-1 ubiquitination, may be a novel strategy for clinical colon cancer treatment. PMID- 28881662 TI - Bevacizumab significantly increases the risks of hypertension and proteinuria in cancer patients: A systematic review and comprehensive meta-analysis. AB - Published data regarding the overall risks and incidence of hypertension and proteinuria associated with bevacizumab were still unclear. To quantify the precise risks and incidence, we performed this comprehensive meta-analysis of 72 published clinical trials including 21902 cases and 20608 controls. The overall incidence, risk ratios (RRs), and 95% confidence intervals (95% CIs) were calculated using a fixed or random-effect model based on the heterogeneity. The incidence of all-grade and high-grade hypertension were 25.3% (95% CI: 21.5% 29.5%) and 8.2% (95% CI: 7%-9.8%) for patients treated with bevacizumab. And the incidence of all-grade and high-grade proteinuria were 18% (95% CI: 11.7%-26.6%) and 2.4% (95% CI: 1.8%-3.2%), respectively. Compared with controls, bevacizumab significantly increased the risks of all-grade (RR: 3.595, 95% CI: 2.952-4.378) and high-grade hypertension (RR: 5.173, 95% CI: 4.188-6.390). Obviously increased risks of all-grade (RR: 3.369, 95% CI: 2.492-4.556) and high-grade proteinuria (RR: 5.494, 95% CI: 3.991-7.564) were also observed. In the subgroup analysis, the risks of hypertension and proteinuria may significantly vary with bevacizumab dosage, cancer types and concomitant drugs. Whereas, no obvious difference were discovered when stratified based on phase of trials, age of patients, treatment line and duration. So, close monitor and effective management were highly recommended for the safe use of bevacizumab. PMID- 28881663 TI - Bisphenol A exposure promotes HTR-8/SVneo cell migration and impairs mouse placentation involving upregulation of integrin-beta1 and MMP-9 and stimulation of MAPK and PI3K signaling pathways. AB - In this study, we investigated the effect of Bisphenol A (BPA), an endocrine disrupting chemical, on the migration of human trophoblasts and mouse placentation by using the primary extravillous trophoblast (EVT) and its cell line HTR-8/SVneo, villous explant cultures, and pregnant mice. BPA increased EVT motility and the outgrowth of villous explants in a dose-dependent manner. BPA also increased the protein levels of integrin-beta1 and matrix metalloproteinase (MMP)-9 in human EVTs. Low-dose BPA (<=50 mg) increased the protein levels of MMP 9 and MMP-2 as well as integrin-beta1 and integrin-alpha5 in mouse placenta and decreased the proportion of the labyrinth and spongiotrophoblast layers. Inhibitors of mitogen-activated protein kinase (MAPK) U0126 and phosphatidylinositol-3-kinases (PI3K) LY294002 reversed the protein levels of integrin-beta1 and MMP-9 as well as the migratory ability induced by BPA. In conclusion, these results indicated that BPA can enhance trophoblast migration and impair placentation in mice by a mechanism involving upregulation of integrin(s) and MMP(s) as well as the stimulation of MAPK and PI3K/Akt (protein kinase B) signaling pathways. PMID- 28881664 TI - Prognostic microRNAs in upper tract urothelial carcinoma: multicenter and international validation study. AB - OBJECTIVE: To validate previously discovered miRNAs (miR-31-5p and miR-149-5p) as prognostic factors for UTUC in an independent cohort of UTUC patients. PATIENTS AND METHODS: Multicenter, international and retrospective study of formalin-fixed paraffin-embedded tissue samples from 103 UTUC patients (45 progressing and 58 non-progressing) who underwent radical nephroureterectomy. Total RNA was isolated and reverse transcribed. The expression of target miRNAs (miR-31-5p and miR-149 5p) and the endogenous control miR-218-5p was evaluated in all samples by reverse transcription quantitative PCR. Normalized miRNA expression values were evaluated by multivariate forward stepwise Cox regression analysis. Kaplan Meier curves were used to discriminate between two groups of patients with a different probability of tumour progression. RESULTS: The mean age (range) of the series was 67 (33-94) years. Overall, 45 patients (43.7%) developed tumour progression and 32 patients (31.2%) died, 20 of these (62.5%) due to their UTUC, after a median follow-up of 36 months. The mean time for tumour progression and cancer specific survival were 15 and 20 months, respectively. Five year tumour progression free survival and cancer-specific survival were 58% for <= pT2, 36% for pT3 and 0% for pT4 and 67.8% for <= pT2, 50.6% for pT3 and 0% for pT4, respectively. In the multivariate analysis, expression of miR-31-5p was found to be an independent prognostic factor of tumour progression (HR 1.1; 95% CI 1.039 1.273; p=0.02). Kaplan Meier curve shows that miR-31-5p expression values are able to discriminate between two groups of UTUC patients with a different probability of tumour progression (p=0.007). CONCLUSIONS: We have been able to validate our previous results in an independent multicentre international cohort of UTUC patients, suggesting that miRNA-31-5p could be a useful prognostic marker of UTUC progression. The application of miRNA expression values to clinical practice could refine the currently used clinicopathological-based approach for predicting UTUC patients' outcome. PMID- 28881665 TI - HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer. AB - HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption. HPV-negative cells express HIF1alpha and its downstream mediators of glucose metabolism such as hexokinase II (HKII) and carbonic anhydrase IX (CAIX) at higher levels, while the expression level of cytochrome c oxidase (COX) was noticeably higher in HPV positive HNSCC. In addition, the expression levels of pyruvate dehydrogenase kinases (PDKs), which inhibit pyruvate dehydrogenase activity, thereby preventing entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle, were much higher in HPV-negative HNSCC compared to those in HPV-positive cells. Importantly, a PDK inhibitor, dichloroacetate, effectively sensitized HPV negative cells to irradiation. Lastly, we found positive interactions between tonsil location and HPV positivity for COX intensity and COX/HKII index ratio as determined by immunohistochemical analysis. Overall survival of patients with HNSCC at the tonsil was significantly improved with an increased COX expression. Taken together, the present study provides molecular insights into the mechanistic basis for the differential responses to radiotherapy between HPV driven vs. spontaneous or chemically induced oropharyngeal cancer. PMID- 28881666 TI - More precise prediction in Chinese patients with penile squamous cell carcinoma: protein kinase CK2alpha catalytic subunit (CK2alpha) as a poor prognosticator. AB - PURPOSE: In this study, we assess the CK2alpha expression in human penile squamous cell carcinoma (SCC) and its clinical significance. METHODS: A total of 157 human penile SCC tissue samples were immunohistochemically analyzed. In addition, 12 human penile SCC and adjacent normal tissues were examined for CK2alpha protein and mRNA expression by Western blotting and real-time quantitative PCR, respectively. Survival was analyzed using the Kaplan-Meier test and the log-rank test. Multivariate Cox proportional hazard regression analysis was performed to determine the impacts of CK2alpha expression and the clinicopathological features on patient disease-specific survival (DSS). Likelihood ratios (LRs), Akaike information criterion (AIC) values, and concordance indexes (C-indexes) were investigated to evaluate the accuracies of the factors. Bootstrap-corrected C-indexes were used for internal validation (with sampling 1000 times). RESULTS: A significant difference in the distribution of CK2alpha was observed between the normal and penile carcinoma tissues (P<0.001). CK2alpha expression was associated with the pathological T and N stages in the penile cancer tissues (P<0.001). High CK2alpha expression was with significantly poorer DSS compared with low expression one (P<0.001). Western blotting and real-time quantitative PCR also confirmed that CK2alpha expression was increased in the penile cancer tissues. In multivariate Cox regression analysis, CK2alpha overexpression still was one of independent prognostic factors for penile SCC (P=0.005). The predictive accuracy of CK2alpha was verified by analysis of the C-indexes. CONCLUSION: High protein kinase CK2alpha expression is associated with several prognostic factors and is thus a significant indicator of poor prognosis for penile cancer. PMID- 28881667 TI - A high plasma D-dimer level predicts poor prognosis in gynecological tumors in East Asia area: a systematic review and meta-analysis. AB - High pre-treatment plasma D-dimer levels have been reported as a factor associated with a poor prognosis in different types of malignancies, including pancreatic, gastric, colorectal, lung, and nasopharyngeal carcinoma. Here, we performed a meta-analysis to determine the association of plasma D-dimer levels and long term survival in gynecological cancers, including ovarian, cervical and endometrial carcinoma. We searched all eligible publications in PubMed and Web of Science Databases up to August 2016. Primary outcomes, including overall survival (OS), disease-free survival and hazard ratios (HR) of were extracted and analyzed. Heterogeneity and publication bias were also assessed. A total of 7 eligible studies with 1112 cases were included in this study and all included studies are conducted in East Asia area. We found that gynecological cancer patients with high D-dimer demonstrates a much lower 5-year survival rate than those with low D-dimer levels (OR 4.12, 95% CI 3.04-5.58, P<0.00001). No significant heterogeneity is found (I2 = 10 %; P = 0.35). Importantly, pooled analysis showed that high plasma D-dimer levels are predictive of a shorter OS in gynecological cancers (HR 2.09, 95% CI 1.59-2.74). No heterogeneity is observed (I2=5%, P=0.39). Additionally, a subgroup analysis of ovarian cancer is conducted. In conclusion, this meta-analysis showed that a high plasma D-dimer level predicts poor prognosis in gynecological tumors. PMID- 28881668 TI - The metastasis suppressor CD82/KAI1 regulates cell migration and invasion via inhibiting TGF-beta 1/Smad signaling in renal cell carcinoma. AB - The tetraspanin KAI1/CD82 was identified as a tumor metastasis suppressor that downregulated in various malignant cell types. However, the function of CD82 and its underlying anti-metastasis role in renal cell carcinoma (RCC) is still unraveled. Here, we investigated the expression of CD82 in RCC and explored its regulatory mechanism in RCC cell lines. We found that CD82 was down-regulated in RCC tissues and cells and its expression was significantly associated with histological grade(p=0.041), tumour stage (p=0.036) and tumor size(p=0.020) by analyzing tissue microarrays. After upregulation of CD82 through lentivirus, reduced ability of migration and invasion in Caki-1 cells were detected. In contrast, gene silencing of CD82 by small interfering RNA promoted metastatic and invasive potential of 786-O cells. Furthermore, Western blot was performed to identify the influence of CD82 on MMP family and TGF-beta1/Smad pathway in RCC. Subsequently, upregulating protein level of TGF-beta1 with the overexpression of CD82 could rescue the malignant behaviors inhibited by CD82 which indicated that CD82 played its inhibitory role in RCC partially by attenuating the expression of TGF-beta1. Taken together, CD82 played a prominent role in migration and invasion of RCC cells and it might exhibit its inhibitory role in RCC metastasis via block TGF-beta1/Smad signaling pathway. PMID- 28881669 TI - Genetic evaluations of Chinese patients with odontohypophosphatasia resulting from heterozygosity for mutations in the tissue-non-specific alkaline phosphatase gene. AB - BACKGROUND: Hypophosphatasia is a rare heritable metabolic disorder characterized by defective bone and tooth mineralization accompanied by a deficiency of tissue non-specific (liver/bone/kidney) isoenzyme of alkaline phosphatase activity, caused by a number of loss-of-function mutations in the alkaline phosphatase liver type gene. We seek to explore the clinical manifestations and identify the mutations associated with the disease in a Chinese odonto- hypophosphatasia family. RESULTS: The proband and his younger brother affected with premature loss of primary teeth at their 2-year-old. They have mild abnormal serum alkaline phosphatase and 25-hydroxy vitamin D values, but the serum alkaline phosphatase activity of their father, mother and grandmother, who showed no clinical symptoms of hypophosphatasia, was exhibited significant decreased. In addition to premature loss of primary teeth, the proband and his younger brother showed low bone mineral density, X-rays showed that they had slight metaphyseal osteoporosis changes, but no additional skeletal abnormalities. Deoxyribonucleic acid sequencing and analysis revealed a single nucleotide polymorphism c.787T>C (p.Y263H) in exon 7 and/or a novel mutation c.-92C>T located at 5'UTR were found in the affected individuals. MATERIALS AND METHODS: We examined all individuals of an odonto- hypophosphatasia family by clinical and radiographic examinations as well as laboratory assays. Furthermore, all 12 exons and the exon-intron boundaries of the alkaline phosphatase liver type gene were amplified and directly sequenced for further analysis and screened for mutations. CONCLUSION: Our present findings suggest the single nucleotide polymorphism c.787T>C and c. 92C>T should be responsible for the odonto- hypophosphatasia disorders in this family. PMID- 28881670 TI - G-CSF inhibits LFA-1-mediated CD4+ T cell functions by inhibiting Lck and ZAP-70. AB - In this study, we showed that G-CSF mobilization increased the frequency of T cells, specifically CD3+CD4+ T cells. G-CSF mobilization decreased the secretion of inflammatory cytokines of CD4+ T cells through the LFA-1/ICAM-1 signaling pathway, whereas it did not alter the TH1/TH2 ratio. We found that G-CSF mobilization inhibited LFA-1-mediated CD4+ T cell polarization and motility. In vitro, G-CSF stimulation also attenuated the polarization and adhesiveness of CD4+ T cells through the LFA-1/ICAM-1 interaction. Further investigation revealed that G-CSF mobilization suppressed LFA-1 signaling by down-regulating Lck and ZAP 70 expression in CD4+ T cells, similar results was also confirmed by in-vitro studies. These findings suggested that G-CSF directly suppressed LFA-1-mediated CD4+ T cell functions through the down-regulation of Lck and ZAP-70. The immunosuppressive effect of G-CSF mobilization deepened our understanding about peripheral blood hematopoietic stem cell transplantation. LFA-1/ICMA-1 pathway may become a potential target for graft-versus-host disease prophylaxis. PMID- 28881671 TI - Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis. AB - Angiogenesis promotes tumor development. Understanding the crucial factors regulating tumor angiogenesis may reveal new therapeutic targets. Human GT198 (PSMC3IP or Hop2) is an oncoprotein encoded by a DNA repair gene that is overexpressed in tumor stromal vasculature to stimulate the expression of angiogenic factors. Here we show that pericytes expressing GT198 give rise to tumor cells through angiogenesis. GT198+ pericytes and perivascular cells are commonly present in the stromal compartment of various human solid tumors and rodent xenograft tumor models. In human oral cancer, GT198+ pericytes proliferate into GT198+ tumor cells, which migrate into lymph nodes. Increased GT198 expression is associated with increased lymph node metastasis and decreased progression-free survival in oral cancer patients. In rat brain U-251 glioblastoma xenografts, GT198+ pericytes of human tumor origin encase endothelial cells of rat origin to form mosaic angiogenic blood vessels, and differentiate into pericyte-derived tumor cells. The net effect is continued production of glioblastoma tumor cells from malignant pericytes via angiogenesis. In addition, activation of GT198 induces the expression of VEGF and promotes tube formation in cultured U251 cells. Furthermore, vaccination using GT198 protein as an antigen in mouse xenograft of GL261 glioma delayed tumor growth and prolonged mouse survival. Together, these findings suggest that GT198-expressing malignant pericytes can give rise to tumor cells through angiogenesis, and serve as a potential source of cells for distant metastasis. Hence, the oncoprotein GT198 has the potential to be a new target in anti-angiogenic therapies in human cancer. PMID- 28881672 TI - MB4-2/MB4-3 transcripts of IGH-MMSET fusion gene in t(4;14)pos multiple myeloma indicate poor prognosis. AB - Multiple myeloma (MM) patients with t(4;14) is a heterogeneous group. Prognostic tools capable of predicting the outcome of patients are currently lacking. The MM SET domain (MMSET) protein is universally overexpressed and has been suggested to have an important tumorigenic role. This study analyzed whether the overexpression of full-length (MB4-1) or truncated forms (MB4-2 and MB4-3) of MMSET influence the prognosis of t(4;14)pos MM patients. A total of 53 symptomatic t(4;14)pos MM patients were retrospectively analyzed. RT-PCR was performed using cDNA from purified CD138+ bone marrow plasma cells to analyze expression and clinical significance of the IGH-MMSET fusion transcripts corresponding to MB4-1, MB4-2 and MB4-3 breakpoints. Among the patients, 25 (47.2%), 12 (22.6%) and 16 (30.2%) had the MB4-1, MB4-2 and MB4-3 breakpoints, respectively. When adjusted to the established prognostic variables including del(17p), ISS stage, serum LDH and serum calcium levels, the pooled MB4-2/MB4-3 subgroup remained a powerful independent adverse factor for PFS (P=0.013) and OS (P=0.029). Bortezomib-based therapy significantly improved the survival of the MB4-1 subgroup but could not overcome the negative effect of the MB4-2/MB4-3 breakpoints. Our results indicate that MB4-2/MB4-3 breakpoints with truncated forms of MMSET define a subset of t(4;14)posMM with poor prognosis. PMID- 28881673 TI - Bromodomain inhibition shows antitumoral activity in mice and human luminal breast cancer. AB - BET bromodomain inhibitors, which have an antitumoral effect against various solid cancer tumor types, have not been studied in detail in luminal breast cancer, despite the prevalence of this subtype of mammary malignancy. Here we demonstrate that the BET bromodomain inhibitor JQ1 exerts growth-inhibitory activity in human luminal breast cancer cell lines associated with a depletion of the C-MYC oncogene, but does not alter the expression levels of the BRD4 bromodomain protein. Interestingly, expression microarray analyses indicate that, upon JQ1 administration, the antitumoral phenotype also involves downregulation of relevant breast cancer oncogenes such as the Breast Carcinoma-Amplified Sequence 1 (BCAS1) and the PDZ Domain-Containing 1 (PDZK1). We have also applied these in vitro findings in an in vivo model by studying a transgenic mouse model representing the luminal B subtype of breast cancer, the MMTV-PyMT, in which the mouse mammary tumor virus promoter is used to drive the expression of the polyoma virus middle T-antigen to the mammary gland. We have observed that the use of the BET bromodomain inhibitor for the treatment of established breast neoplasms developed in the MMTV-PyMT model shows antitumor potential. Most importantly, if JQ1 is given before the expected time of tumor detection in the MMTV-PyMT mice, it retards the onset of the disease and increases the survival of these animals. Thus, our findings indicate that the use of bromodomain inhibitors is of great potential in the treatment of luminal breast cancer and merits further investigation. PMID- 28881674 TI - Prognostic significance of PD-L1 expression and 18F-FDG PET/CT in surgical pulmonary squamous cell carcinoma. AB - Programmed cell death-ligand 1 (PD-L1) expression is commonly observed in non small cell lung cancer (NSCLC). The prognostic value of PD-L1 expression and the maximum standardized uptake value (SUVmax) on 18F-Fluorodeoxyglucose positron emission tomography (18FDG-PET) in surgical pulmonary squamous cell carcinoma(SCC)remains unclear. Furthermore, the correlation between the SUVmax and PD-L1 expression has not been assessed. Thus, the purpose of this study was to investigate the correlation between PD-L1 expression and the SUVmax on 18FDG PET and to examine the prognostic significance of PD-L1 expression and the SUVmax in surgical pulmonary SCC. Expression of PD-L1 was examined in 84 patients with resected SCC using immunohistochemistry. Positive PD-L1 expression in tumour cells was observed in 58.3% (49/84) of patients with SCC. High PD-L1 expression levels were significantly correlated with histological differentiation (P=0.006), and a high SUVmax was associated with histological differentiation (P=0.037), and lymph node metastasis (P=0.025). Spearman's test showed that there was a significant correlation between PD-L1 expression levels and the SUVmax. High PD L1 expression levels and a high SUVmax were both independent risks factors for poor overall survival. Our results suggested that high PD-L1 expression levels and a high SUVmax was associated with poor prognosis in surgical pulmonary SCC. The existence of a statistically significant correlation between the SUVmax and PD-L1 expression levels justifies exploring the usefulness of the SUVmax as a predictor of PD-1/PD-L1 inhibitor activity. PMID- 28881675 TI - PD-L1 and intratumoral immune response in breast cancer. AB - PURPOSE: PD-L1 is thought to play an important role in the antitumor immune response. In this study, we investigated the expression of PD-L1 within breast tumor subsets to better define its prognostic significance. METHODS: Immunohistochemistry was performed to determine PD-L1 tumor cell expression and to enumerate CD8, CD4 and CD68 tumor-infiltrating leucocytes (TIL) in a cohort of 443 breast cancers categorized by molecular subtype. RESULTS: Across the entire cohort, PD-L1 tumor cell expression was observed in 73/443 (16.5%) cases and associated with known indicators of poor prognosis, including low patient age, high tumor grade, ER/PR negative status, but not with outcome. However, in the Triple Negative breast cancer subset PD-L1 was associated with better recurrence free survival (RFS) especially within the Basal-like subset (Hazard ratio = 0.39, 95% CI = 0.22 - 0.86, p = 0.018). Combined PD-L1/epithelial CD8 positive status was also strongly associated with better RFS and OS (Hazard ratio = 0.12, 95% CI = 0.10 - 0.71, p = 0.010 and Hazard ratio = 0.11, 95% CI = 0.11 - 0.68, p = 0.006 respectively) in the Basal-like subgroup. CONCLUSIONS: PD-L1 expression is associated with better patient survival in Basal-like breast cancer. PMID- 28881676 TI - Experimental study on the therapeutic effect and underlining mechanisms of positron in pancreatic cancer cells. AB - The purpose of this study was to assess the potential therapeutic effect of positrons emitted by 18F-2-Deoxy-2-Fluoro-D-Glucose (18F-FDG) on pancreatic cancer cells and elucidate its underlying mechanisms. Pancreatic cancer cells were incubated with different radioactive concentrations of 18F-FDG and evaluated for anti-cancer properties and underlining mechanisms. In addition, three groups of tumor-bearing mice were treated with different doses of 18F-FDG weekly, the tumor growth rate was calculated, and the mice were imaged by positron emission tomography (PET) with 18F-FDG before and after treatment. The presence of apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stain and immunohistochemistry analysis. All treated groups exhibited positron-inhibited proliferation and positron-induced apoptosis compared with the control group in vitro. Further, we noted that higher treatment dose correlated with a better treatment response. In vivo, the high dose administration of 18F-FDG reduced tumor growth and prolonged the survival of treated mice compared with the control group with no change in the behavior or normal tissues of the mice. Immunohistochemical analysis and TUNEL stain showed more apoptotic cells than that in control group. The results demonstrated that positron radiation inhibited the proliferation and induced apoptosis of pancreatic cancer cells in vitro and in vivo, via an endogenous mitochondria mediated signaling pathway. PMID- 28881677 TI - Impact of insurance status on the survival of gallbladder cancer patients. AB - The prognostic significance of insurance status has been investigated in many types of malignancies, however, its impact on gallbladder cancer is yet not known. The purpose of this study was to determine the relationship between insurance status and gallbladder cancer survival. We searched the Surveillance, Epidemiology, and End Results dataset, and identified 1,729 gallbladder cancer cases. Kaplan-Meier methods and multivariable Cox regression models were used to analyze survival outcomes and risk factors. We found that individuals who had non Medicaid insurance were more likely to be male, older, from wealthier area, and better-educated. Insurance status was confirmed as an independent prognostic factor for gallbladder cancer patients. Stratified analysis revealed that the uninsured status independently predicted unfavorable survival outcome at localized tumor stage and in white individuals. To conclude, insurance status is an important predictive factor for gallbladder cancer, and uninsured individuals are at the highest risk of death. PMID- 28881678 TI - Autophagy is required for crizotinib-induced apoptosis in MET-amplified gastric cancer cells. AB - MET amplification has been clinically credentialed as a therapeutic target in gastric cancer, but the molecular mechanisms underlying sensitivity and resistance to MET inhibitors are still not well understood. Using whole-genome mRNA expression profiling, we identified autophagy as a top molecular pathway that was activated by the MET inhibitor crizotinib in drug-sensitive human gastric cancer cells, and functional studies confirmed that crizotinib increased autophagy levels in the drug-sensitive cells in a concentration-dependent manner. We then used chemical and molecular approaches to inhibit autophagy in order to define its role in cell death. The clinically available inhibitor of autophagy, chloroquine, or RNAi-mediated knockdown of two obligate components of the autophagy pathway (ATG5 and ATG7) blocked cell death induced by crizotinib or RNAi-mediated knockdown of MET, and mechanistic studies localized the effects of autophagy to cytochrome c release from the mitochondria. Overall, the data reveal a novel relationship between autophagy and apoptosis in gastric cancer cells exposed to MET inhibitors. The observations suggest that autophagy inhibitors should not be used to enhance the effects of MET inhibitors in gastric cancer patients. PMID- 28881679 TI - miR-487b mitigates chronic heart failure through inhibition of the IL-33/ST2 signaling pathway. AB - We investigated the effects of microRNA-587b (miR-487b) in a rat model of chronic heart failure (CHF). Wistar rats were assigned to 10 groups (n=8 per group). Expression of interleukin-33 (IL-33), somatostatin 2 (ST2), IL-6, and TNF-alpha was higher in the CHF group than the control group. In the CHF, negative control (NC) for si-IL-33, NC for miR-487b mimic, NC for miR-487b inhibitor, and miR-487b inhibitor + si IL-33 groups, as compared to the blank and sham groups: steroid binding protein (SBP), D binding protein (DBP), left ventricular systolic pressure (LVSP), +/- dp/dtmax, and superoxide dismutase (SOD) were all lower; myocardial fibrosis, MDA, left ventricular end-diastolic pressure (LVEDP), myocardial apoptosis rate, IL-6, and TNF-alpha were all higher; levels of IL-33 and ST2 mRNA and protein were higher; and levels of miR-487b were lower. Levels of IL-33 and ST2 mRNA and protein were lower, and SBP, DBP, LVSP, +/- dp/dtmax, and SOD were higher in the miR-487b mimic and si-IL-33 groups than the CHF group. Expression of miR-487b was increased in the miR-487b mimic group, and expression of IL-33 and ST2 were increased and expression of miR-487b was decreased in the miR-487b inhibitor group. MiR-487b reduces apoptosis, inflammatory responses, and fibrosis in CHF by suppressing IL-33 through inhibition the IL-33/ST2 signaling pathway. PMID- 28881680 TI - Identification of dysregulated long non-coding RNAs/microRNAs/mRNAs in TNM I stage lung adenocarcinoma. AB - Lung adenocarcinoma (LUAD) is the primary subtype in lung cancer, which is the leading cause of cancer-related death worldwide. This study aimed to investigate the aberrant expression profiling of long non-coding RNA (lncRNA) in TNM I stage (stage I) LUAD. The lncRNA/mRNA/miRNA expression profiling of stage I LUAD and adjacent non-tumor tissues from 4 patients were measured by RNA-sequencing. Total of 175 differentially expressed lncRNAs (DELs), 1321 differentially expressed mRNAs (DEMs) and 94 differentially expressed microRNAs (DEMIs) were identified in stage I LUAD. DEMI-DEM regulatory network consisted of 544 nodes and 1123 edge; miR-200 family members had high connectivity with DEMs. In DEL-DEM co-expression network, CDKN2B-AS1, FENDRR and LINC00312 had the high connectivity with DEMs, which co-expressed with 105, 63 and 61 DEMs, respectively. DEL-DEMI-DEM network depicted the links among DELs, DEMI and DEMs. Identified DEMs were significantly enriched in cell adhesion molecules, focal adhesion and tight junction of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways; and enriched in cell adhesion, angiogenesis and regulation of cell proliferation of Gene Ontology biological processes. Quantitative real-time polymerase chain reaction results were generally consistent with our bioinformatics analyses. LINC00312 and FENDRR had diagnostic value for LUAD patients in The Cancer Genome Atlas database. Our study might lay the foundation for illumination of pathogenesis of LUAD and identification of potential therapeutic targets and novel diagnosis biomarkers for LUAD patients. PMID- 28881681 TI - Insulin-like growth factor-1 is a negative modulator of glucagon secretion. AB - Glucagon secretion involves a combination of paracrine, autocrine, hormonal, and autonomic neural mechanisms. Type 2 diabetes often presents impaired glucagon suppression by insulin and glucose. Insulin-like growth factor-I (IGF-1) has elevated homology with insulin, and regulates pancreatic beta-cells insulin secretion. Insulin and IGF-1 receptors share considerable structure homology and function. We hypothesized the existence of a mechanism linking the inhibition of alpha-cells glucagon secretion to IGF-1. Herein, we evaluated the association between plasma IGF-1 and glucagon levels in 116 nondiabetic adults. After adjusting for age gender and BMI, fasting glucagon levels were positively correlated with 2-h post-load glycaemia, HOMA index and fasting insulin, and were negatively correlated with IGF-1 levels. In a multivariable regression, the variables independently associated to fasting glucagon were circulating IGF-1 levels, HOMA index and BMI, explaining 20.7% variation. To unravel the molecular mechanisms beneath IGF-1 and glucagon association, we investigated whether IGF-1 directly modulates glucagon expression and secretion in an in vitro model of alpha-cells. Our data showed that IGF-1 inhibits the ability of low glucose concentration to stimulate glucagon expression and secretion via activation of the phosphatidylinositol-3-kinase/Akt/FoxO1 pathway. Collectively, our results suggest a new regulatory role of IGF-1 on alpha-cells biological function. PMID- 28881682 TI - Inhibition of FAK kinase activity preferentially targets cancer stem cells. AB - Because cancer stem cells (CSCs) have been implicated in chemo-resistance, metastasis and tumor recurrence, therapeutic targeting of CSCs holds promise to address these clinical challenges to cancer treatment. VS-4718 and VS-6063 are potent inhibitors of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that mediates cell signals transmitted by integrins and growth factor receptors. We report here that inhibition of FAK kinase activity by VS-4718 or VS-6063 preferentially targets CSCs, as demonstrated by a panel of orthogonal CSC assays in cell line models and surgically resected primary breast tumor specimens cultured ex vivo. Oral administration of VS-4718 or VS-6063 to mice bearing xenograft models of triple-negative breast cancer (TNBC) significantly reduced the proportion of CSCs in the tumors, as evidenced by a reduced tumor-initiating capability upon re-implantation in limiting dilutions of cells prepared from these tumors. In contrast, the cytotoxic chemotherapeutic agents, paclitaxel and carboplatin, enriched for CSCs, consistent with previous reports that these cytotoxic agents preferentially target non-CSCs. Importantly, VS-4718 and VS-6063 attenuated the chemotherapy-induced enrichment of CSCs in vitro and delayed tumor regrowth following cessation of chemotherapy. An intriguing crosstalk between FAK and the Wnt/beta-catenin pathway was revealed wherein FAK inhibition blocks beta catenin activation by reducing tyrosine 654 phosphorylation of beta-catenin. Furthermore, a constitutively active mutant form of beta-catenin reversed the preferential targeting of CSCs by FAK inhibition, suggesting that this targeting is mediated, at least in part, through attenuating beta-catenin activation. The preferential targeting of cancer stem cells by FAK inhibitors provides a rationale for the clinical development of FAK inhibitors aimed to increase durable responses for cancer patients. PMID- 28881683 TI - Inhibition of COX2 enhances the chemosensitivity of dichloroacetate in cervical cancer cells. AB - Dichloroacetate (DCA), a traditional mitochondria-targeting agent, has shown promising prospect as a sensitizer in fighting against malignancies including cervical cancer. But it is unclear about the effect of DCA alone on cervical tumor. Moreover, previous reports have demonstrated that the increased cyclooxygenase-2 (COX2) expression is associated with chemoresistance and poor prognosis of cervical cancer. However, it is still unknown whether COX2 can affect the sensitivity of DCA in cervical cancer cells. In this study, we found that cervical cancer cells were insensitive to DCA. Furthermore, we for the first time revealed that DCA could upregulate COX2 which impeded the chemosensitivity of DCA in cervical cancer cells. Mechanistic study showed that DCA reduced the level of RNA binding protein quaking (QKI), leading to the decay suppression of COX2 mRNA and the subsequent elevation of COX2 protein. Inhibition of COX2 using celecoxib could sensitize DCA in repressing the growth of cervical cancer cells both in vitro and in vivo. These results indicate that COX2 is a novel resistance factor of DCA, and combination of celecoxib with DCA may be beneficial to the treatment of cervical cancer. PMID- 28881684 TI - Efficacy and safety of long-term therapy for high-grade glioma with temozolomide: A meta-analysis. AB - Further treatments are warranted in preventing recurrence or progression for high grade glioma (HGG) patients having achieved stable disease with tolerable toxicity after the Stupp regimen (6 cycles of temozolomide). This meta-analysis aims to extensively evaluate the safety, feasibility, and efficacy of long-term therapy with temozolomide (>6 cycles) for these patients. We systematically searched the pubmed, Embase and Chinese Biomedical (CBM) databases using the strategy of combination of free-text words and MeSH terms. The efficacy indicators are hazard ratio (HR) for the pooled analysis of overall survival (OS) and progression free survival (PFS). The safety indicator is risk ratio (RR) for the pooled analysis of adverse effects. Six studies comprising a total number of 396 patients met all inclusion and exclusion criteria were included. No heterogeneity and publication bias were observed across each study. It was found that patients could obtain benefits from long-term administration of temozolomide both in OS (HR 2.39, 95% CI 1.82-3.14) and PFS (HR 2.12, 95% CI 1.56-2.89). In addition, the results showed that the patients receiving long-term administration of temozolomide did not experience additional toxicity over that of the Stupp regimen (6 cycles of temozolomide). It could be concluded that it's efficacious and safe for HGG patients to receive long-term therapy with temozolomide. Nevertheless, more randomized controlled trials (RCTs) should be carried out to verify this conclusion. PMID- 28881686 TI - Survival benefit of immune checkpoint inhibitors according to the histology in non-small-cell lung cancer: A meta-analysis and review. AB - Immune checkpoint inhibitors (ICIs) have been approved for patients with advanced non-small-cell lung cancer (NSCLC), regardless of histology. However, histologic subtypes of NSCLC may influence treatment outcomes of ICIs. We conducted this meta-analysis to investigate if there is difference in survival benefits of ICIs between squamous (SQ) and non-squamous (non-SQ) NSCLC. We searched PubMed, MEDLINE, EMBASE and ESMO databases. We included randomized controlled trials with the data of survival outcomes in advanced NSCLC patients treated with ICIs. From 7 eligible studies, 998 patients with SQ NSCLC and 2,769 with non-SQ NSCLC were included in the meta-analysis. ICIs improved progression-free survival (PFS) significantly in patients with SQ NSCLC (HR = 0.68 [95% confidence interval (CI), 0.51-0.91], P = 0.01), compared to chemotherapy. For patients with non-SQ NSCLC, however, ICIs were not associated with significant improvement of PFS (HR = 0.88 [95% CI, 0.67-1.16], P = 0.37). In terms of overall survival (OS), ICIs prolonged OS significantly in both SQ (HR = 0.71 [95% CI, 0.60-0.83], P < 0.0001) and non SQ NSCLC (HR = 0.77 [95% CI, 0.63-0.94], P = 0.01). In conclusion, this meta analysis indicates that ICIs significantly prolong OS in both SQ and non-SQ NSCLC. PMID- 28881685 TI - Association between PSCA gene polymorphisms and the risk of cancer: an updated meta-analysis and trial sequential analysis. AB - Previous studies have investigated the relationships between PSCA rs2294008 C>T and rs2976392 G>A polymorphisms and cancer susceptibility. However, the available findings remained inconsistent and even controversial. Thus, the aim of this meta analysis was performed to clarify such associations. The online databases PubMed, EMBASE and Web of Science searched for relevant studies, covering all the papers published until September 1st, 2016. Data were pooled by odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of such associations. Then, trial sequential analysis was performed to estimate whether the evidence of the results was firm. Overall, a significant increased risk of cancer was associated with PSCA rs2294008 C>T and rs2976392 G>A polymorphisms. For the PSCA rs2294008 polymorphism, when stratified by type of cancer, the results were significant especially in gastric cancer and bladder cancer. Moreover, in the subgroup analysis by ethnicity, significant results were detected in both Asian and Caucasian populations. Similarly, for the PSCA rs2976392 polymorphism, the stratification analyses by type of cancer showed that the results were significant only in gastric cancer. In addition, the stratification analyses by ethnicity detected that this polymorphism increased cancer risk only in Asian populations. Then, trial sequential analyses demonstrated that the results of the meta-analysis were based on sufficient evidence. Therefore, this meta-analysis suggested that the PSCA rs2294008 C>T and rs2976392 G>A polymorphisms might be associated with cancer susceptibility, which might act as a potential predicted biomarker for genetic susceptibility to cancer, especially in gastric cancer and bladd er cancer. PMID- 28881687 TI - OGTT 1h serum C-peptide to plasma glucose concentration ratio is more related to beta cell function and diabetes mellitus. AB - OBJECTIVE: To clarify the association between C-peptide index and pancreatic beta cell function and diabetes. MATERIALS AND METHODS: We carried out a retrospective analysis of 1021 patients aged 27 to 80 without diabetes from January 2012 to January 2016. All subjects underwent a 75-g oral glucose tolerance test. Blood samples were drawn at 0, 30, 60, 120 and 180 min after the glucose load. Plasma glucose concentrations, serum insulin levels, C-peptide levels, hemoglobin A1c (HbA1c), and other biochemical indicators were determined. C-peptide index was calculated as the ratio of C-peptide to plasma glucose. Disposition index was calculated as the result of the insulin sensitivity * insulin secretion. Area under the receiver operating characteristic curve was used to compare the diagnostic ability of C-peptide index for type 2 diabetes. RESULTS: C-peptide index 1h was the most related one to disposition index (r = 647, p<0.001) and C peptide release (r = 0.879, p<0.001). Both C-peptide index 1h (Exp(beta) = 0.28, p<0.001) and 2h (Exp(beta) = 0.42, p<0.001) were independently associated with disposition index, but the OR of C-peptide index 1h for diabetes was much lower. Area under the receiver operating characteristic curve of both C-peptide index 1h and 2h were all above 0.9, but the area of C-peptide index 1h was the highest one (0.937 vs 0.917). C-peptide index 1h has the highest diagnostic value (sensitivity = 90%, specificy = 85.2% vs sensitivity = 83.5%, specificy = 87.9%). CONCLUSION: C-peptide index after oral glucose ingestion may reflect the maximal beta-cell function and is more related to diabetes. C-peptide index 1h is the most relevant one. PMID- 28881688 TI - The clinical utility and outcomes of microwave ablation for colorectal cancer liver metastases. AB - In recent years, the microwave ablation (MWA) has been reported to play an important role in the treatment of patients with colorectal liver metastases (CRLM). In this work, 62 cases of patients who received MWA for liver metastases from colon or rectal cancer between Jan 2012 and Jan 2014 were enrolled in this trial. 28 underwent MWA, and 34 were treated with liver resection as control. Perioperative and 60 months of follow-up data were collected to analyze potential adverse effects, concurrent conditions and survival status. Here, we found there were no significant differences between both groups in the baseline level, including gender, size, number and pathological type (all p>0.05). In those patients, the mean hospitalization duration of patients with MWA is 5.9+/-0.9d, which is significantly different from control (11.8+/-6.9 d) (p<0.001). Little severe complication was observed in MWA group, while 26.5% (9/34) of patients developed severe complications (p=0.003). Besides, the mean hospitalization cost of patients with MWA was significantly less than that of control (p<0.000). Additionally, we found no statistically significant differences in disease-free survival (DFS) (p=0.156) or overall survival (OS) (p=0.580). In conclusion, MWA may be a safe, economical and competent way to treat inoperable CRLM patients, which has more advantages than liver resection in some degree. PMID- 28881689 TI - Cause of death in patients diagnosed with esophageal cancer in Sweden: a population-based study. AB - BACKGROUND: Esophageal cancer carries a poor prognosis with an overall 5-year survival of less than 20%. However, the causes of death in patients with esophageal cancer have not been well described. METHODS: This nationwide, population-based cohort study included 18 229 esophageal cancer patients who were diagnosed between 1961 and 2014 in Sweden. We assessed the distribution of main causes of death in patients with esophageal cancer and used competing-risks regression to compare the cause-specific risks of death across sexes, ages at diagnosis, and calendar periods of diagnosis. RESULTS: A total of 16 938 (92.9%) patients died during follow-up. Esophageal cancer accounted for 79.5% of all reported deaths. Other major causes of death were non-esophageal cancers (9.8%), ischemic heart disease or cerebrovascular disease (4.2%) and respiratory diseases (1.3%). Female patients had a lower risk of death from esophageal cancer (sub hazard ratio [SHR]=0.90, 95% confidence interval [CI]: 0.87, 0.94), which was more pronounced in patients with squamous cell carcinoma (SHR=0.85, 95% CI: 0.81, 0.89). Risks of death from esophageal cancer and other cancers in patients who were diagnosed in more recent calendar periods were lower than in those diagnosed in earlier periods. CONCLUSIONS: Patients diagnosed with esophageal cancer are more likely to die from this cancer than from other causes. However, these patients also face considerable risk of death from other cancers, ischemic heart disease, cerebrovascular disease, and respiratory diseases. These common causes of death should be taken into consideration in esophageal cancer management. PMID- 28881690 TI - Perioperative entecavir for patients with HBV-related hepatocellular carcinoma and low levels of viral DNA: analysis using propensity score matching. AB - The safety and efficacy of perioperative antiviral therapy for patients with hepatitis B virus related hepatocellular carcinoma and low serum levels of hepatitis B virus DNA are unknown. This retrospective study compared serum levels of hepatitis B virus DNA, liver function, morbidity, and length of hospital stay between patients who underwent hepatic resection alone and patients who received entecavir therapy before and after resection (n = 44 in each group). Propensity score matching was used to reduce confounding due to baseline differences between the groups. Hepatitis B virus reactivation during follow-up, which lasted a median of 6.1 months, occurred in one patient in the entecavir group (2.3%) and 11 patients in the resection-only group (25%; P = 0.02). Liver function, especially alanine aminotransferase levels, recovered much faster in the entecavir group. This group also showed a slightly lower rate of morbidity (P = 0.081) as well as significantly shorter overall hospital stay (20.1 +/- 4.9 vs 24.9 +/- 13.2 days; P = 0.028) and postoperative hospital stay (11.4 +/- 1.9 vs 16.8 +/- 13.1 days; P = 0.008). These results from this pilot study suggest that patients with hepatitis B virus related hepatocellular carcinoma and low levels of hepatitis B virus DNA are at risk of hepatitis B virus reactivation following resection, and that perioperative entecavir therapy can safely and effectively reduce this risk. Such therapy also appears to improve liver function and shorten hospitalization. PMID- 28881691 TI - Critical role of matrix metallopeptidase 9 in postoperative cognitive dysfunction and age-dependent cognitive decline. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is a significant clinical syndrome. Neuroinflammation is an important pathological process for POCD. However, it is not clear how systemic inflammation induced by surgery on peripheral tissues or organs is transmitted into the brain. We determined whether matrix metallopeptidase 9 (MMP9), a protein that can increase blood-brain barrier permeability, is critical in this transmission. The role of MMP9 in age-dependent cognitive decline was also determined. METHODS: Two-month old male C57BL/6J wild type mice and MMP9-/- mice were randomly assigned to control or surgery groups. The surgery was right carotid artery exposure under isoflurane anesthesia. Cognitive function was tested from one week after the surgery by Barnes maze and fear conditioning. Cognitive function of 2-month old C57BL/6J mice was compared with that of 18-month old mice. RESULTS: Surgery increased the expression of interleukin 1beta, interleukin 6 and ionized calcium binding adapter molecule 1, inflammation indicators, in the brain of the wild-type mice. Blood-brain barrier permeability was increased by surgery. Surgery also impaired the learning and memory of these mice. These surgical effects were absent in the MMP9-/- mice. Eighteen-month old wild-type mice had poorer performance in Barnes maze and fear conditioning tests and lower MMP9 protein expression and activity than did the 2 month old mice. CONCLUSION: MMP9 is critical for transmission of systemic inflammation into the brain for POCD. MMP9 may also play a role in age-dependent cognitive decline. PMID- 28881692 TI - Cabazitaxel in recurrent/metastatic squamous cell carcinoma of the head and neck: phase II UNICANCER trial ORL03. AB - Treatments are limited after platinum Cetuximab or anti-PD1 failure for patients with recurrent/metastatic head and neck squamous cell carcinoma. Cabazitaxel has increased overall survival in hormone-refractory metastatic prostate cancer after failure of Docetaxel. Our aim was to detect a signal of activity with Cabazitaxel in patients with head and neck cancer who had failed platinum-, Cetuximab- and taxanes-based chemotherapy. This multicenter phase II trial included progressive patients with an ECOG <=2. Cabazitaxel was given at 25 mg/m2/3 weeks (maximum of 10 cycles), with growth factors support. Efficacy was centralized and assessed every 6 weeks. The primary endpoint was control rate at six-weeks. A Simon's two stage optimal design (P0=0.10; P1=0.30) required 29 evaluable patients. At the end of trial, at least 6 non-progressions were required to consider the drug worthy of further study. Out of the 31 enrolled patients, 29 were eligible; 42% had received at least three previous lines of chemotherapy. For the primary end point, 8 patients (27.6%; 95%CI 12.7%-47.2%) had a stable disease at six weeks. Median progression-free survival was 1.05 months (95%CI 0.69-2.07). All patients were analyzed for toxicity: 6 patients had febrile neutropenia. During the 81 cycles administered, 49 grade 3-5 events were observed concerning 81% of the patients, including 35 severe adverse events of which 15 were related to Cabazitaxel. Although Cabazitaxel met its primary endpoint to deserve further investigations, its toxicity makes it difficult to use in frail patients and new schemes are needed (20 mg/m2 for example) if further investigations are launched. PMID- 28881693 TI - Predictive factors of para-aortic lymph nodes metastasis in cervical cancer patients: a retrospective analysis based on 723 para-aortic lymphadenectomy cases. AB - Para-aortic lymph node (PALN) dissection is optional and controversial in patients with stage IB1-IIA2 cervical cancer. This retrospective study investigated PALN involvement patterns and evaluated preoperative clinical factors. A total of 723 consecutive FIGO stage IB1-IIA2 cervical cancer patients were included in the study. All patients underwent radical hysterectomy/radical trachelectomy, pelvic lymph node dissection, and PALN dissection. PALN metastasis was found in 101 (14.0%) patients, and the positive PALN rates of stage IB1, IB2, IIA1, and IIA2 were 8.4%, 11.1%, 17.2% and 21.7%, respectively. A multivariate model suggested age > 46 years (OR: 1.67, 95% confidence interval (CI): 1.08 2.58), tumor size > 3.5 cm (OR: 1.79, 95% CI: 1.12-2.87), and FIGO stage IIA (vs. IB) (OR: 1.97, 95% CI: 1.25-3.11) all positively correlated with PALN metastasis. When squamous cervical cancer cases were categorically analyzed, a multivariate model indicated age > 46 years (OR: 1.67, 95% CI: 1.00-2.80), FIGO stage IIA (vs. IB) (OR: 1.76, 95% CI: 1.02-3.02), and squamous cell carcinoma antigen (SCCA) > 6.5 ng/ml (OR: 5.20, 95% CI: 3.07-8.81) all positively correlated with PALN metastasis. Age, tumor size, and FIGO stage correlated with PALN metastasis in cervical cancer, while age, FIGO stage, and SCCA level were predictive in squamous cell carcinoma. PMID- 28881694 TI - Individual isotoxic radiation dose escalation based on V20 and advanced technologies benefits unresectable stage III non-small cell lung cancer patients treated with concurrent chemoradiotherapy: long term follow-up. AB - Under the assumption that the highest therapeutic ratio could be achieved by increasing the total tumor dose (TTD) to the limits of normal tissues, the phase I trial was conducted in patients with unresectable stage III non-small cell lung cancer treated with concurrent chemoradiotherapy, to determine the feasibility and effects of individual isotoxic radiation dose escalation based on bilateral lung V20 and advanced technologies. Consecutive eligible patients were assigned to cohorts of eight. V20 of each cohort was increased from 27% to 30%, 33%, 35%, 37%, and so on. The criterion for cessation of dose escalation was defined as >= 2 patients in each cohort experienced dose limiting toxicity. Isotoxic dose escalation was based on V20, functional imaging was used to improve the accuracy of radiotherapy. To test the power of escalation dose, patients with TTD over 66 Gy were assigned to the higher dose group (HD), while the others to the standard dose one (SD). In result, the recommended value of V20 was 35%. For all patients, follow-up ranged from 1 to 112 months, median overall and progression free survivals were 25.0 and 13.0 months, respectively. The 1-, 3-, 5- and 8-year overall survival (OS) rates were 72.5%, 22.5%, 17.5%, and 10.0%, respectively. Especially, the OS and local recurrence-free survival of patients in HD group were significantly longer than those in SD one (P=0.035, P=0.007, respectively) without increasing severe toxicity. Thus, individual isotoxic dose escalation based on V20 with advanced technologies was feasible and effective. PMID- 28881695 TI - Correlation of HAMP gene polymorphisms and expression with the susceptibility and length of hospital stays in Taiwanese children with Kawasaki disease. AB - Kawasaki disease (KD) is a form of systemic vasculitis. Regarding its pathogenesis, HAMP gene encoding hepcidin, which is significant for iron metabolism, has a vital function. In this study, we recruited a total of 381 KD patients for genotyping. Data from 997 subjects (500 subjects from cohort 1; 497 subjects from cohort 2) were used for analysis. Using TaqMan allelic discrimination, we determined five tag SNPs (rs916145, rs10421768, rs3817623, rs7251432, and rs2293689). Treatment outcome data related to such clinical phenotypes as coronary artery lesions (CAL), coronary artery aneurysms (CAA), and intravenous immunoglobulin (IVIG) effects were also collected. Furthermore, we measured plasma hepcidin levels with an enzyme-linked immunosorbent assay. We found that HAMP gene polymorphism (rs7251432, and rs2293689) was significantly correlated with KD risk and that plasma hepcidin levels both before and after IVIG treatment had a significantly positive correlation with length of hospital stays (R = 0.217, p = 0.046 and R = 0.381, p < 0.0001, respectively). In contrast, plasma hepcidin levels has a negative correlation with KD patients' albumin levels (R = -0.27, p < 0.001) prior to IVIG treatment. This study's findings indicate that HAMP might have a role in the disease susceptibility, as well as its expressions correlated length of hospital stays, and albumin levels in Taiwanese children with KD. PMID- 28881696 TI - The effect of intraperitoneal chemotherapy on early pain hyperalgesia in patients following elective laparoscopic transabdominal resection of rectal cancer. AB - BACKGROUND: Chemotherapy has been associated with hyperalgesia. This prospective study was designed to investigate the effect of intraperitoneal chemotherapy with lobaplatin on post-operative pain intensity and sufentanil requirements after laparoscopic transabdominal resection of rectal cancer. METHODS: Eighty subjects (40 subjects treated with intraperitoneal chemotherapy and 40 subjects without chemotherapy treatment) scheduled for laparoscopic transabdominal resection of rectal cancer were included in this study. All subjects received standardized anesthetic and patient-controlled analgesia using sufentanil for 72 h post surgery, as the only analgesics. Pain intensity scores, cumulative sufentanil requirements and side effects were recorded until 72 h post-surgery. RESULTS: Following intraperitoneal chemotherapy, patients had a significantly higher total post-operative sufentanil requirement (193 MUg vs. 142 MUg; P = 0.008), significantly higher verbal rating scale post-surgery pain intensity scores at rest and with coughing (P < 0.05), and a significantly worse functional activity score (P < 0.05) over 72 h, compared with those without intraperitoneal chemotherapy. There were no post-operative differences in the incidence of side effects (post-operative nausea [P = 0.189], vomiting [P = 0.311], pruritus [P = 0.263], respiratory depression [P = 1.000], and dizziness [P = 0.712]) between the two groups. CONCLUSION: Intraperitoneal chemotherapy is associated with significantly increased post-operative sufentanil requirements and pain intensity, suggesting chemotherapy-associated hyperalgesia. PMID- 28881697 TI - Feasibility of laparoscopic gastrectomy for elderly gastric cancer patients: meta analysis of non-randomized controlled studies. AB - The aim of this meta-analysis was to determine the feasibility of laparoscopic gastrectomy (LG) for elderly gastric cancer patients by comparing laparoscopic and conventional open gastrectomies (OG). Comprehensive search of the PubMed, EMBASE, and Cochrane Library databases revealed nine non-randomized controlled studies that compared LG and OG in elderly gastric cancer patients We then analyzed dichotomous or continuous parameters using odds ratios (ORs) or weighted mean differences (WMDs). Overall survival was estimated using hazard ratios (HRs) with a fixed effects or random effects model. We observed that the age distribution was similar between the LG and OG patient groups (WMD -0.22 95% CI, 1.26-0.82). LG patients experienced less blood loss (WMD -119.14 95% CI, -204.17- 34.11) and had shorter hospital stays (WMD -3.48 95% CI, -5.41--1.56), but endured longer operation times (WMD 10.87 95% CI, 2.50-19.24). Postoperatively, LG patients exhibited lower incidences of postoperative morbidities (OR 0.59 95% CI, 0.43-0.79), surgery related morbidities (OR 0.58 95% CI, 0.41-0.81) and systemic morbidities (OR 0.56 95% CI, 0.38-0.82). We observed no differences between the LG and OG patient groups regarding anastomotic leakage (OR 0.69 95% CI, 0.34-1.41), mental disease (OR 0.72 95% CI, 0.37-1.41) and long term effects (HR 0.98 95% CI, 0.74-1.32). We therefore conclude that laparoscopic gastrectomy might be technically feasible for elderly gastric cancer patients. PMID- 28881698 TI - Reduction-oxidation pathways involved in cancer development: a systematic review of literature reviews. AB - Oxidative stress results from an imbalance of the reactive oxygen species/reactive nitrogen species (ROS/RNS) production and the oxidants defense system. Extensive research during the last decades has revealed that oxidative stress can mediate cancer initiation and development by leading not only to molecular damage but also to a disruption of reduction-oxidation (redox) signaling. In order to provide a global overview of the redox signaling pathways, which play a role in cancer formation, we conducted a systematic literature search in PubMed and ISI Web of Science and identified 185 relevant reviews published in the last 10 years. The 20 most frequently described pathways were selected to be presented in this systematic review and could be categorized into 3 groups: Intracellular ROS/RNS generating organelles and enzymes, signal transduction cascades kinases/phosphatases and transcription factors. Intracellular ROS/RNS generation organelles are mitochondria, endoplasmic reticulum and peroxisomes. Enzymes, including NOX, COX, LOX and NOS, are the most prominent enzymes generating ROS/RNS. ROS/RNS act as redox messengers of transmembrane receptors and trigger the activation or inhibition of signal transduction kinases/phosphatases, such as the family members of protein tyrosine kinases and protein tyrosine phosphatases. Furthermore, these reactions activate downstream signaling pathways including protein kinase of the MAPK cascade, PI3K and PKC. The kinases and phosphatases regulate the phosphorylation status of transcription factors including APE1/Ref-1, HIF-1alpha, AP-1, Nrf2, NF-kappaB, p53, FOXO, STAT, and beta-catenin. Finally, we briefly discuss cancer prevention and treatment opportunities, which address redox pathways and further research needs. PMID- 28881699 TI - Thymoquinone, as an anticancer molecule: from basic research to clinical investigation. AB - Thymoquinone is an anticancer phytochemical commonly found in black cumin. In this review, we discuss the potential of thymoquinone as anticancer molecule, its mechanism of action and future usage in clinical applications. Thymoquinone exhibits anticancer activity via numerous mechanisms of action, specifically by showing selective antioxidant and oxidant activity, interfering with DNA structure, affecting carcinogenic signaling molecules/pathways and immunomodulation. In vitro activity of thymoquinone has been further implicated in animal models of cancer; however, no clinical application has been proven yet. This is the optimum time to focus on clinical trials for developing thymoquinone as a future drug in cancer therapeutics. PMID- 28881700 TI - SETBP1 dysregulation in congenital disorders and myeloid neoplasms. AB - Myeloid malignancies are characterized by an extreme molecular heterogeneity, and many efforts have been made in the past decades to clarify the mechanisms underlying their pathogenesis. In this scenario SET binding protein 1 (SETBP1) has attracted a lot of interest as a new oncogene and potential marker, in addition to its involvement in the Schinzel-Giedon syndrome (SGS). Our review starts with the analysis of the structural characteristics of SETBP1, and extends to its corresponding physiological and pathological functions. Next, we describe the prevalence of SETBP1 mutations in congenital diseases and in hematologic malignancies, exploring how its alterations might contribute to tumor development and provoke clinical effects. Finally, we consider to understand how SETBP1 activation could be exploited in molecular medicine to enhance the cure rate. PMID- 28881701 TI - PD1 signal transduction pathways in T cells. AB - The use of immune checkpoint inhibitors for the treatment of cancer is revolutionizing oncology. Amongst these therapeutic agents, antibodies that block PD-L1/PD1 interactions between cancer cells and T cells are demonstrating high efficacies and low toxicities. Despite all the recent advances, very little is yet known on the molecular intracellular signaling pathways regulated by either PD-L1 or PD1. Here we review the current knowledge on PD1-dependent intracellular signaling pathways, and the consequences of disrupting PD1 signal transduction. PMID- 28881703 TI - Current status of lymph node micrometastasis in gastric cancer. AB - Lymph node metastasis is one of the most important prognostic factors in patients with gastric cancer. An inadequate number of dissected lymph nodes is an independent risk factor affecting recurrence, even in patients who are node negative. Oddly, certain early-stage patients still experience recurrence or metastasis within a short time, even if they have undergone standard radical mastectomy. Many researchers have attributed these adverse events to lymph node micrometastasis (LNM), which is defined as a microscopic deposit of malignant cells of less than 2 mm in diameter. With the development of diagnostic tools such as immunohistochemistry and reverse transcription-polymerase chain reaction, the rate of detection of LNM has been constantly increasing. Although there is no clear consensus about risk factors for or the definitive clinical significance of LNM, the clinical impact of LNM is remarkable in gastric cancer. For minimally invasive treatment in particular, such as endoscopic submucosal dissection and laparoscopic surgery, accurate diagnosis of LNM is regarded as the potential key to maintaining the balance between curability and safety. This review provides an overview of the definition, detection and significance of LNM in gastric cancer. We also summarize several attention-drawing controversies regarding the treatment of patients who may have LNM. PMID- 28881702 TI - The epigenetic integrator UHRF1: on the road to become a universal biomarker for cancer. AB - Cancer is one of the deadliest diseases in the world causing record number of mortalities in both developed and undeveloped countries. Despite a lot of advances and breakthroughs in the field of oncology still, it is very hard to diagnose and treat the cancers at early stages. Here in this review we analyze the potential of Ubiquitin-like containing PHD and Ring Finger domain 1 (UHRF1) as a universal biomarker for cancers. UHRF1 is an important epigenetic regulator maintaining DNA methylation and histone code in the cell. It is highly expressed in a variety of cancers and is a well-known oncogene that can disrupt the epigenetic code and override the senescence machinery. Many studies have validated UHRF1 as a powerful diagnostic and prognostic tool to differentially diagnose cancer, predict the therapeutic response and assess the risk of tumor progression and recurrence. Highly sensitive, non-invasive and cost effective approaches are therefore needed to assess the level of UHRF1 in patients, which can be deployed in diagnostic laboratories to detect cancer and monitor disease progression. PMID- 28881705 TI - A summary of relationships between alternative splicing and breast cancer. AB - Alternative splicing (AS) is the process of combinatorial rearrangement of parts of exons, and/or parts of introns into mature RNA to result in a multitude of transcripts. AS is a biological process through which organisms produce as many protein variants as possible by a limited genetic resource. It plays an important role in growth and development of the organisms. Over the past few years, alternative splicing has been discovered to be critical for genesis and development of malignant tumors, including breast cancer. If the relationships between AS and breast cancer can be discussed more deeply, it will be helpful for better diagnosis, judging prognosis and intervening with breast cancer. In this paper, the relationships between AS and breast cancer are elaborated from different angles, in hope that this summary is beneficial for readers to understand the roles of AS and breast cancer. PMID- 28881706 TI - Associations between two common single nucleotide polymorphisms (rs2241766 and rs1501299) of ADIPOQ gene and coronary artery disease in type 2 diabetic patients: a systematic review and meta-analysis. AB - ADIPOQ gene polymorphisms were indicated to be associated with coronary artery disease (CAD) in diabetic patients, however, published studies reported inconsistent results. We performed this meta-analysis to reach a more accurate estimation of the relationship between two common ADIPOQ genetic polymorphisms (rs2241766 and rs1501299) and CAD risk in diabetic patients. Eligible studies were retrieved by searching PubMed, Embase, Wangfang, VIP database and China National Knowledge Infrastructure databases. Included and excluded criteria were formulated. The case group was diabetic patients with CAD, and the control group was diabetic subjects without CAD. Summary odds rations (ORs) and 95% confidence intervals (CIs) were used to evaluate ADIPOQ polymorphisms associations with CAD risk in diabetic group. Heterogeneity was evaluated by Q statistic and I2 statistic. A total of twelve published articles, involving 3996 cases and 8876 controls were included in this meta-analysis. The pooled results from rs1501299 polymorphism showed decreased risk in homozygote model (TT VS GG: OR=0.67, 95%CI=0.54-0.83). Heterogeneity was detected in our study. Sensitivity analysis and subgroup analysis were conducted in the meta-analysis. For rs2241766 polymorphism, an increased risk was detected in Caucasian subgroup in heterozygote model (CT VS TT: OR=1.19, 95%CI=1.00-1.42). In genotyping method (PCR-RFLP) subgroup, an increased risk was found in recessive model (GG VS GT+TT: OR=2.05, 95%CI=1.23-3.39). In the sensitivity analysis of rs1501299, decreased risk was detected in allelic model (T VS G: OR=0.86, 95%CI=0.76-0.98) and recessive model (TT VS TG+GG: OR=0.47, 95%CI=0.33-0.67). Publication bias is not observed in our results. Our meta-analysis suggests that the rs1501299 polymorphism may play a protective role in CAD in diabetic patients. The rs2241766 polymorphism is found to be associated with a significant increase in CAD risk in Caucasian and genotyping method (PCR-RFLP) subgroups. Further studies are needed to confirm the prediagnostic effect of the two gene polymorphisms in CAD risk in diabetic patients. PMID- 28881704 TI - Chaperone-mediated autophagy substrate proteins in cancer. AB - All intracellular proteins undergo continuous synthesis and degradation. Chaperone-mediated autophagy (CMA) is necessary to maintain cellular homeostasis through turnover of cytosolic proteins (substrate proteins). This degradation involves a series of substrate proteins including both cancer promoters and suppressors. Since activating or inhibiting CMA pathway to treat cancer is still debated, targeting to the CMA substrate proteins provides a novel direction. We summarize the cancer-associated substrate proteins which are degraded by CMA. Consequently, CMA substrate proteins catalyze the glycolysis which contributes to the Warburg effect in cancer cells. The fact that the degradation of substrate proteins based on the CMA can be altered by posttranslational modifications such as phosphorylation or acetylation. In conclusion, targeting to CMA substrate proteins develops into a new anticancer therapeutic approach. PMID- 28881707 TI - Intratumoral coagulation by radiofrequency ablation facilitated the laparoscopic resection of giant hepatic hemangioma: a surgical technique report of two cases. AB - BACKGROUND: Traditionally, open hepatic resection is the first choice of treatment for symptomatic enlarging hepatic hemangiomas, which requires a large abdominal incision and is associated with substantial recovery time and morbidity. Minimally invasive laparoscopic resection has been used recently in liver surgery for treating selected hepatic hemangiomas. However, laparoscopic liver surgery poses the significant technical challenges and high rate of conversion. Radiofrequency (RF) ablation has been proved feasible in the treatment of hepatic hemangiomas with a size range of 5.0-9.9 cm. It is controversial to treat giant hepatic hemangiomas (>=10.0 cm) by means of RF ablation, due to the low technique success rate and high incidence of ablation related complications. We aimed to assess the safety and efficacy of combined laparoscopic resection with intratumoral RF-induced coagulation for giant hepatic hemangiomas. METHODS: We treated 2 patients with giant subcapsular hepatic hemangioma (12.0 cm and 13.1 cm in diameters respectively) by laparoscopic resection following intratumoral coagulation of the tumor with RF ablation. RESULTS: Blood loss during resection was 100 ml (case 1) and 300ml (case 2) respectively. No blood transfusion and dialysis were needed during perioperative period. The two patients were discharged 6 days (case 1) and 12 days (case 2) after surgery without any complications, respectively. Postoperative contrast enhanced CT follow up showed there was no residual tumor. CONCLUSIONS: It is feasible to treat giant subcapsular hepatic hemangioma by laparoscopic tumor resection boosted by intratumoral coagulation using RF ablation, which may open a new avenue for treating giant hemangioma. PMID- 28881708 TI - Targeting TRIB3 and PML-RARalpha interaction against APL. PMID- 28881709 TI - Indole microbial metabolites: expanding and translating target(s). PMID- 28881710 TI - Experimental African trypanosome infection suppresses the development of multiple myeloma in mice by inducing intrinsic apoptosis of malignant plasma cells. AB - Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Recently, several studies have highlighted the role of pathogens in either promoting or dampening malignancies of unrelated origin. Trypanosoma brucei is an extracellular protozoan parasite which causes sleeping sickness. Our group has previously demonstrated that trypanosome infection affects effector plasma B cells. Therefore, we hypothesized that T. brucei infection could have an impact on MM development. Using the immunocompetent 5T33MM model, we demonstrated a significant reduction in BM plasmacytosis and M-protein levels in mice infected with T. brucei, resulting in an increased survival of these mice. Blocking IFNgamma could only partially abrogate these effects, suggesting that other mechanisms are involved in the destruction of malignant plasma cells. We found that T. brucei induces intrinsic apoptosis of 5T33MM cells in vivo, and that this was associated with reduced endogenous unfolded protein response (UPR) activation. Interestingly, pharmacological inhibition of IRE1alpha and PERK was sufficient to induce apoptosis in these cells. Together, these results demonstrate that trypanosome infections can interfere with MM development by suppressing endogenous UPR activation and promoting intrinsic apoptosis. PMID- 28881711 TI - Characterization of midostaurin as a dual inhibitor of FLT3 and SYK and potentiation of FLT3 inhibition against FLT3-ITD-driven leukemia harboring activated SYK kinase. AB - Oncogenic FLT3 kinase is a clinically validated target in acute myeloid leukemia (AML), and both multi-targeted and selective FLT3 inhibitors have been developed. Spleen tyrosine kinase (SYK) has been shown to be activated and increased in FLT3 ITD-positive AML patients, and has further been shown to be critical for transformation and maintenance of the leukemic clone in these patients. Further, over-expression of constitutively activated SYK causes resistance to highly selective FLT3 tyrosine kinase inhibitors (TKI). Up to now, the activity of the multi-targeted FLT3 inhibitor, midostaurin, against cells expressing activated SYK has not been explored in the context of leukemia, although SYK has been identified as a target of midostaurin in systemic mastocytosis. We compared the ability of midostaurin to inhibit activated SYK in mutant FLT3-positive AML cells with that of inhibitors displaying dual SYK/FLT3 inhibition, targeted SYK inhibition, and targeted FLT3 inhibition. Our findings suggest that dual FLT3/SYK inhibitors and FLT3-targeted drugs potently kill oncogenic FLT3-transformed cells, while SYK-targeted small molecule inhibition displays minimal activity. However, midostaurin and other dual FLT3/SYK inhibitors display superior anti proliferative activity when compared to targeted FLT3 inhibitors, such as crenolanib and quizartinib, against cells co-expressing FLT3-ITD and constitutively activated SYK-TEL. Interestingly, additional SYK suppression potentiated the effects of dual FLT3/SYK inhibitors and targeted FLT3 inhibitors against FLT3-ITD-driven leukemia, both in the absence and presence of activated SYK. Taken together, our findings have important implications for the design of drug combination studies in mutant FLT3-positive patients and for the design of future generations of FLT3 inhibitors. PMID- 28881712 TI - Tumor antigen CA125 suppresses antibody-dependent cellular cytotoxicity (ADCC) via direct antibody binding and suppressed Fc-gamma receptor engagement. AB - Cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of tumor-shed antigen CA125/MUC16 on suppressing IgG1-mediated antibody-dependent cellular cytotoxicity (ADCC). This evidence stems from prespecified subgroup analysis of a Phase 3 clinical trial testing farletuzumab, a monoclonal antibody to folate receptor alpha, plus standard-of-care carboplatin taxane chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low serum CA125 levels treated with farletuzumab demonstrated improvements in progression free survival (HR 0.49, p = 0.0028) and overall survival (HR 0.44, p = 0.0108) as compared to placebo. Farletuzumab's pharmacologic activity is mediated in part through ADCC. Here we show that CA125 inhibits ADCC by directly binding to farletuzumab that in turn perturbs Fc-gamma receptor engagement on effector cells. PMID- 28881713 TI - Therapeutic vaccine to cure large mouse hepatocellular carcinomas. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Here we report the development of a therapeutic vaccination regimen (shortened as 'TheraVac') consisting of intratumoral delivery of high-mobility group nucleosome-binding protein 1 (HMGN1), R848/resiquimod, and one of the checkpoint inhibitors (e.g. anti-CTLA4, anti-PD-L1, or low dose of Cytoxan). C57BL/6 mice harboring large (approximately 1 cm in diameter) established subcutaneous Hepa1-6 hepatomas were cured by intratumoral injections of TheraVac and became tumor-free long-term survivors. Importantly, the resultant tumor-free mice were resistant to re-challenge with Hepa1-6 hepatoma, not B16 melanoma, demonstrating the acquisition of hepatoma-specific immunity in the absence of any administered tumor antigen. Mechanistic studies showed that upon treatment with TheraVac, Hepa1-6-bearing mice generated increased Hepa1-6 specific CTLs in the draining lymph nodes and showed greatly upregulated expression of CXCL9, CXCL10, and IFN-gamma and elevated infiltration of T lymphocytes in tumor tissues. Treatment of large Hepa1-6 hepatomas on one mouse flank also eliminated smaller (approximately 0.5 cm in diameter) hepatomas implanted on the other flank. Thus, TheraVac has potential as a curative immunotherapeutic regimen for the treatment of human HCC. PMID- 28881714 TI - The "4 plus 2" rituximab protocol makes maintenance treatment unneeded in patients with refractory ANCA-associated vasculitis: A 10 years observation study. AB - BACKGROUND: ANCA associated vasculitides (AAV) often present with a chronic relapsing course. Relapse leads to increased immunosuppressive exposure and consequent toxicity. While two randomized controlled trials have shown rituximab (RTX) to be the most effective induction treatment in patients with relapsing disease, the optimal treatment duration and RTX dose remain debated. Whether to administer a maintenance dose to every patient, at a fixed time interval or on the basis of B cell count and ANCA titre or only when disease manifestations do occur is still debated as well. METHODS: 11 patients (5 with granulomatosis with polyangiitis, 4 with microscopic polyangiitis-MPA-, and 2 with eosinophilic granulomatosis with polyangiitis -EGPA-) intolerant or refractory to conventional therapies including cyclophosphamide were enrolled. All patients received the so called "improved 4+2" RTX scheme as a rescue therapy. Following RTX administration, immunosuppressive drugs were rapidly tapered and no immunosuppressive maintenance therapy had been given. RESULTS: After a mean follow-up of 85 months since the "4+2" RTX protocol: four out of 11 patients (37%, 1 EGPA and 3 MPA, all MPO-positive) remained in remission after one cycle of "4+2" RTX infusion protocol with no relapse for a median 66 months [60-108]). Seven relapsing patients were re-treated once with RTX (again as monotherapy with the same protocol) after a median of 54 months (24-96). Following re-treatment, they again showed complete remission over a median of 32 months (12-96) of observation. CONCLUSION: In one of the longest-term observation (85 months) studies, sustained clinical remission without immunosuppressive maintenance therapy (and a negligible dose of prednisone since the 5thmonth) was obtained by the "4 + 2" RTX infusion protocol in patients with ANCA-associated vasculitis intolerant or refractory to conventional therapy. PMID- 28881715 TI - Activation of the Nrf2/ARE signaling pathway by probucol contributes to inhibiting inflammation and neuronal apoptosis after spinal cord injury. AB - The nuclear erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway plays an essential role in the cellular antioxidant and anti-inflammatory responses. Spinal cord injury (SCI) results in a massive release of inflammatory factors and free radicals, which seriously compromise nerve recovery and axon regeneration. In this study, we examined the efficacy of probucol on anti-inflammatory responses and functional recovery after SCI by activating the Nrf2/ARE signaling pathway. We also investigated the mechanism by which inflammation is inhibited in this process. We found that treatment of injured rats with probucol significantly increased levels of Nrf2, heme oxygenase 1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 (NQO1), while levels of inflammatory cytokines, interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were decreased. This was associated with a reduction in neural cell apoptosis and promotion of nerve function recovery. These results demonstrate that the neuroprotective effects of probucol after SCI are mediated by activation of the Nrf2/ARE signaling pathway. These findings indicate that the anti-inflammatory effects of probucol represent a viable treatment for improving functional recovery following SCI. PMID- 28881716 TI - Prognostic value of a systemic inflammatory response index in metastatic renal cell carcinoma and construction of a predictive model. AB - Inflammation act as a crucial role in carcinogenesis and tumor progression. In this study, we aim to investigate the prognostic significance of systemic inflammatory biomarkers in metastatic renal cell carcinoma (mRCC) and develop a survival predictive model. One hundred and sixty-one mRCC patients who had undergone cytoreductive nephrectomy were enrolled from January 2006 to December 2013. We created a systemic inflammation response index (SIRI) basing on pretreatment hemoglobin and lymphocyte to monocyte ratio (LMR), and evaluated its associations with overall survival (OS) and clinicopathological features. Pretreatment hemoglobin and LMR both remained as independent factors adjusted for other markers of systemic inflammation responses and conventional clinicopathological parameters. A high SIRI seems to be an independent prognosis predictor of worse OS and was significantly correlated with aggressive tumor behaviors. Inclusion of the SIRI into a prognostic model including Fuhrman grade, histology, tumor necrosis and targeted therapy established a nomogram, which accurately predicted 1-year survival for mRCC patients. The SIRI seems to be a prognostic biomarker in mRCC patients. The proposed nomogram can be applied to predict OS of patients with mRCC after nephrectomy. PMID- 28881717 TI - 5-aza-2'-deoxycytidine (DAC) treatment downregulates the HPV E6 and E7 oncogene expression and blocks neoplastic growth of HPV-associated cancer cells. AB - High-risk human papillomaviruses (hr HPVs) may cause various human cancers and associated premalignant lesions. Transformation of the host cells is triggered by overexpression of the viral oncogenes E6 and E7 that deregulate the cell cycle and induce chromosomal instability. This process is accompanied by hypermethylation of distinct CpG sites resulting in silencing of tumor suppressor genes, inhibition of the viral E2 mediated control of E6 and E7 transcription as well as deregulated expression of host cell microRNAs. Therefore, we hypothesized that treatment with demethylating agents might restore those regulatory mechanisms. Here we show that treatment with 5-aza-2'-deoxycytidine (DAC) strongly decreases the expression of E6 and E7 in a panel of HPV-transformed cervical cancer and head and neck squamous cell carcinoma cell lines. Reduction of E6 and E7 further resulted in increased target protein levels including p53 and p21 reducing the proliferation rates and colony formation abilities of the treated cell lines. Moreover, DAC treatment led to enhanced expression of tumor the suppressive miRNA-375 that targets and degrades E6 and E7 transcripts. Therefore, we suggest that DAC treatment of HPV-associated cancers and respective precursor lesions may constitute a targeted approach to subvert HPV oncogene functions that deserves testing in clinical trials. PMID- 28881718 TI - Quercetin inhibits Cr(VI)-induced malignant cell transformation by targeting miR 21-PDCD4 signaling pathway. AB - Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Inhibition of Cr(VI)-induced carcinogenesis by a dietary antioxidant is a novel approach. Quercetin is one of the most abundant dietary flavonoids widely present in many fruits and vegetables, possesses potent antioxidant and anticancer properties. MicroRNA-21 (miR-21) is a key oncomiR significantly elevated in the majority of human cancers that exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the effect of quercetin on the inhibition of Cr(VI)-induced malignant cell transformation and the role of miR-21 PDCD4 signaling involved. Our results showed that quercetin decreased ROS generation induced by Cr(VI) exposure in BEAS-2B cells. Chronic Cr(VI) exposure induced malignant cell transformation, increased miR-21 expression and caused inhibition of PDCD4, which were significantly inhibited by the treatment of quercetin in a dose dependent manner. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of quercetin showed reduced tumor incidence compared to Cr(VI) alone treated group. Stable knockdown of miR-21 and overexpression of PDCD4 or catalase in BEAS-2B cells suppressed Cr(VI)-induced malignant transformation and tumorigenesis. Taken together, these results demonstrate that quercetin is able to protect BEAS-2B cells from Cr(VI)-induced carcinogenesis by targeting miR-21-PDCD4 signaling. PMID- 28881719 TI - Combined CT-guided radiofrequency ablation with systemic chemotherapy improves the survival for nasopharyngeal carcinoma with oligometastasis in liver: Propensity score matching analysis. AB - The aim of this study was to retrospectively compare the treatment efficacy of systemic chemotherapy combined with sequential CT-guided radiofrequency ablation (Chemo-RFA) to chemotherapy alone (Chemo-only) in the management of nasopharyngeal carcinoma (NPC) with liver metastasis. Between 2003 and 2011, 328 NPC patients diagnosed with liver metastasis at Sun Yat-sen University Cancer Center were enrolled. One-to-one matched pairs between Chemo-RFA group with the Chemo-only group were generated using propensity score matching. The associations of treatment modality with overall survival (OS) and progression-free survival (PFS) were determined by Cox regression. Of the patients enrolled, 37 patients (11.8 %) received combined treatment, 291 (82.2) received chemotherapy alone. The patients in Chemo-RFA group were more frequently classified as lower number (<=3) of liver metastatic lesions (P<0.001), had lower rates of bi-lobar liver metastasis (P<0.001) and extra-hepatic metastasis (P<0.001) than patients in Chemo-only group. After propensity score matching, 37 pairs of well-matched liver metastatic NPC patients were selected from different treatment groups. The adjusted hazard ratio in OS and PFS of the choice for Chemo-RFA approach to Chemo only was 0.53 (95%CI, 0.30-0.93) and 0.60 (95%CI, 0.36-0.97), respectively. In conclusion, combined CT-guided RFA and chemotherapy approach offer the chance of improved survival for NPC patients with oligometastasis in liver, and should be considered if the ablation is technically feasible. PMID- 28881720 TI - Analysis of ESR1 and PIK3CA mutations in plasma cell-free DNA from ER-positive breast cancer patients. AB - BACKGROUND: The measurement of ESR1 and PIK3CA mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive method to quickly assess and monitor endocrine therapy (ET) resistant metastatic breast cancer (MBC) patients. METHODS: The subjects of this retrospective study were a total of 185 plasma samples from 86 estrogen receptor-positive BC patients, of which 151 plasma samples were from 69 MBC patients and 34 plasma samples were from 17 primary BC (PBC) patients. We developed multiplex droplet digital PCR assays to verify the clinical significance of ESR1 and PIK3CA mutations both in a snapshot and serially in these patients. RESULTS: cfDNA ESR1 and PIK3CA mutations were found in 28.9% and 24.6 % of MBC patients, respectively. The relation between ESR1 or PIK3CA mutations and clinical features showed that ESR1 mutations occurred mostly in patients previously treated by ET, which was not the case for PIK3CA mutations. The analysis of the clinical impact of those mutations on subsequent lines of treatment for the 69 MBC patients revealed that both ESR1 and PIK3CA mutations detection were related to a shorter duration of ET effectiveness in univariate analysis but only for ESR1 mutations in multivariate analysis. The monitoring of cfDNA in a subset of 52 patients showed that loss of ESR1 mutations was related to a longer duration of response, which was not the case for PIK3CA mutations. CONCLUSIONS: We have demonstrated the clinical significance of on treatment ESR1 mutations both in a snapshot and serially in comparison with PIK3CA mutations. PMID- 28881721 TI - Lower Beclin 1 downregulates HER2 expression to enhance tamoxifen sensitivity and predicts a favorable outcome for ER positive breast cancer. AB - Tamoxifen(TAM) is one of the most effective endocrine treatment for estrogen receptor(ER)-positive breast cancer, however drug resistance greatly limits benefit of it. Our purpose is to uncover the role of Beclin 1 in tamoxifen resistance and prognosis of ER positive breast cancer. We established a tamoxifen resistant ER-positive breast cancer cell subline MCF-7R presenting with higher Beclin 1 and human epidermal growth factor receptor 2(HER2) levels than MCF-7. Silencing Beclin 1 decreased levels of HER2 and significantly promoted TAM sensitivity of MCF-7 and MCF-7R in vitro. Overexpression of HER2 could reverse TAM sensitivity, which was formerly increased in Beclin 1 downregulated cell. Beclin 1 level was not only positively correlated with level of HER2 but also negatively correlated with overall survival of ER-positive breast cancer patients. Using bioinformatic methods, Beclin 1 mRNA was found to be negatively correlated with overall survival in breast cancer patients receiving TAM treatment. This study indicated for the first time that lower HER2 expression by Beclin 1 downregulation contributes to alteration of tamoxifen sensitivity and low Beclin 1 predicts favorable outcome in ER-positive breast cancer. PMID- 28881722 TI - Hepatic NK cell-mediated hypersensitivity to ConA-induced liver injury in mouse liver expressing hepatitis C virus polyprotein. AB - The role of hepatic NK cells in the pathogenesis of HCV-associated hepatic failure is incompletely understood. In this study, we investigated the effect of HCV on ConA-induced immunological hepatic injury and the influence of HCV on hepatic NK cell activation in the liver after ConA administration. An immunocompetent HCV mouse model that encodes the entire viral polyprotein in a liver-specific manner based on hydrodynamic injection and phiC31o integrase was used to study the role of hepatic NK cells. Interestingly, the frequency of hepatic NK cells was reduced in HCV mice, whereas the levels of other intrahepatic lymphocytes remained unaltered. Next, we investigated whether the reduction in NK cells within HCV mouse livers might elicit an effect on immune mediated liver injury. HCV mice were subjected to acute liver injury models upon ConA administration. We observed that HCV mice developed more severe ConA-induced immune-mediated hepatitis, which was dependent on the accumulated intrahepatic NK cells. Our results indicated that after the administration of ConA, NK cells not only mediated liver injury through the production of immunoregulatory cytokines (IFN-gamma, TNF-alpha and perforin) with direct antiviral activity, but they also killed target cells directly through the TRAIL/DR5 and NKG2D/NKG2D ligand signaling pathway in HCV mice. Our findings suggest a critical role for NK cells in oversensitive liver injury during chronic HCV infection. PMID- 28881723 TI - Association of high microvessel alphavbeta3 and low PTEN with poor outcome in stage 3 neuroblastoma: rationale for using first in class dual PI3K/BRD4 inhibitor, SF1126. AB - Neuroblastoma (NB) is the most common extracranial solid tumor in children. Our previous studies showed that the angiogenic integrin alphavbeta3 was increased in high-risk metastatic (stage 4) NB compared with localized neuroblastomas. Herein, we show that integrin alphavbeta3 was expressed on 68% of microvessels in MYCN amplified stage 3 neuroblastomas, but only on 34% (means) in MYCN-non-amplified tumors (p < 0.001; n = 54). PTEN, a tumor suppressor involved in alphavbeta3 signaling, was expressed in neuroblastomas either diffusely, focally or not at all (immunohistochemistry). Integrin alphavbeta3 was expressed on 60% of tumor microvessels when PTEN was negative or focal, as compared to 32% of microvessels in tumors with diffuse PTEN expression (p < 0.001). In a MYCN transgenic mouse model, loss of one allele of PTEN promoted tumor growth, illustrating the potential role of PTEN in neuroblastoma pathogenesis. Interestingly, we report the novel dual PI-3K/BRD4 activity of SF1126 (originally developed as an RGD conjugated pan PI3K inhibitor). SF1126 inhibits BRD4 bromodomain binding to acetylated lysine residues with histone H3 as well as PI3K activity in the MYCN amplified neuroblastoma cell line IMR-32. Moreover, SF1126 suppressed MYCN expression and MYCN associated transcriptional activity in IMR-32 and CHLA136, resulting in overall decrease in neuroblastoma cell viability. Finally, treatment of neuroblastoma tumors with SF1126 inhibited neuroblastoma growth in vivo. These data suggest integrin alphavbeta3, MYCN/BRD4 and PTEN/PI3K/AKT signaling as biomarkers and hence therapeutic targets in neuroblastoma and support testing of the RGD integrin alphavbeta3-targeted PI-3K/BRD4 inhibitor, SF1126 as a therapeutic strategy in this specific subgroup of high risk neuroblastoma. PMID- 28881724 TI - The pseudogene derived long noncoding RNA DUXAP8 promotes gastric cancer cell proliferation and migration via epigenetically silencing PLEKHO1 expression. AB - Gastric cancer (GC) is the third leading cause of cancer death due to its poor prognosis and limited treatment options. Evidence indicates that pseudogene derived long noncoding RNAs (lncRNAs) may be important players in human cancer progression, including GC. In this paper, we report that a newly discovered pseudogene-derived lncRNA named DUXAP8, a 2107-bp RNA, was remarkably upregulated in GC. Additionally, a higher level of DUXAP8 expression in GC was significantly associated with greater tumor size, advanced clinical stage, and lymphatic metastasis. Patients with a higher level of DUXAP8 expression had a relatively poor prognosis. Further experiments revealed that knockdown of DUXAP8 significantly inhibited cell proliferation and migration, as documented in the SGC7901 and BGC823 cell lines. Furthermore, RNA immunoprecipitation and chromatin immunoprecipitation assays demonstrated that DUXAP8 could epigenetically suppress the expression of PLEKHO1 by binding to EZH2 and SUZ12 (two key components of PRC2), thus promoting GC development. Taken together, our findings suggest that the pseudogene-derived lncRNA DUXAP8 promotes the progression of GC and is a potential therapeutic target for GC intervention. PMID- 28881725 TI - Nurse-like cells promote CLL survival through LFA-3/CD2 interactions. AB - In the tumoral micro-environment (TME) of chronic lymphocytic leukemia (CLL), nurse-like cells (NLC) are tumor-associated macrophages which play a critical role in the survival and chemoresistance of tumoral cells. This pro-survival activity is known to involve soluble factors, but few data are available on the relative role of cells cross-talk. Here, we used a transcriptome-based approach to systematically investigate the expression of various receptor/ligand pairs at the surface of NLC/CLL cells. Their relative contribution to CLL survival was assessed both by fluorescent microscopy to identify cellular interactions and by the use of functional tests to measure the impact of uncoupling these pairs with blocking monoclonal antibodies. We found for the first time that lymphocyte function-associated antigen 3 (LFA-3), expressed in CLL at significantly higher levels than in healthy donor B-cells, and CD2 expressed on NLC, were both key for the specific pro-survival signals delivered by NLC. Moreover, we found that NLC/CLL interactions induced the shedding of soluble LFA-3. Importantly, in an exploratory cohort of 60 CLL patients receiving frontline immunochemotherapy, increased levels of soluble LFA-3 were found to correlate with shorter overall survival. Altogether, these data suggest that LFA-3/CD2 interactions promote the survival of CLL cells in the tumor microenvironment. PMID- 28881726 TI - Modulation of paracrine signaling by CD9 positive small extracellular vesicles mediates cellular growth of androgen deprived prostate cancer. AB - Proliferation and maintenance of both normal and prostate cancer (PCa) cells is highly regulated by steroid hormones, particularly androgens, and the extracellular environment. Herein, we identify the secretion of CD9 positive extracellular vesicles (EV) by LNCaP and DUCaP PCa cells in response to dihydrotestosterone (DHT) and use nano-LC-MS/MS to identify the proteins present in these EV. Subsequent bioinformatic and pathway analyses of the mass spectrometry data identified pathologically relevant pathways that may be altered by EV contents. Western blot and CD9 EV TR-FIA assay confirmed a specific increase in the amount of CD9 positive EV in DHT-treated LNCaP and DUCaP cells and treatment of cells with EV enriched with CD9 after DHT exposure can induce proliferation in androgen-deprived conditions. siRNA knockdown of endogenous CD9 in LNCaPs reduced cellular proliferation and expression of AR and prostate specific antigen (PSA) however knockdown of AR did not alter CD9 expression, also implicating CD9 as an upstream regulator of AR. Moreover CD9 positive EV were also found to be significantly higher in plasma from prostate cancer patients in comparison with benign prostatic hyperplasia patients. We conclude that CD9 positive EV are involved in mediating paracrine signalling and contributing toward prostate cancer progression. PMID- 28881727 TI - Adult T cell leukemia aggressivenness correlates with loss of both 5 hydroxymethylcytosine and TET2 expression. AB - Mutations in TET2, encoding one of the TET members responsible for the conversion of DNA cytosine methylation to hydroxymethylation (5-hmc), have been recently described in Human T-lymphotropic virus type 1-associated adult T-cell leukemia/lymphoma (ATLL). However, neither the amount of genomic 5-hmc in ATLL tumor cells nor TET2 expression has been studied yet. In this study, we analyzed these two parameters as well as the mutational status of TET2 in ATLL patients. By employing a direct in situ approach, we documented that tumor T cells infiltrating lymph nodes exhibit low level of 5-hmc compared to residual normal T cells. Furthermore, this 5-hmc defect was more pronounced in tumor T cells from acute patients than from chronic ones and correlated with reduced expression of TET2 protein. TET2 variations were found in 14 patients (20%), including 13 with aggressive forms. Strikingly, 9 of the 14 patients showed the same variation (SNP rs72963007), whose frequency in ATLL patients was significantly higher than that of an ethnically matched control population (13% vs. 5%). However, no reduction of 5-hmc was found in PBMC from individuals possessing the variant rs72963007 TET2 allele, as compared to wild-type individuals. In contrast, a robust correlation was observed between 5-hmc and the levels of TET2 mRNA. Finally, loss of 5-hmc and TET2 downregulation both correlated with poor survival. These findings demonstrate that ATLL progression coincides with loss of genomic 5-hmc and indicate that downregulation of TET2, rather than TET2 mutations, is the key mechanism involved in 5-hmc modulation during ATLL progression. PMID- 28881728 TI - The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study. AB - Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5-21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1-5 and 8-9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73%), thrombocytopenia (67%), mucositis (24%) and febrile neutropenia (19%). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5%. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50% vs. 16%, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML. PMID- 28881729 TI - The type I insulin-like growth factor regulates the liver stromal response to metastatic colon carcinoma cells. AB - Hepatic stellate cells (HSC) play a major role in initiating the liver fibrogenic (wounding) response of the liver and can also orchestrate a pro-metastatic microenvironment in the liver in response to invading cancer cells. Here we explored the role of the hepatic stellate cells in colon carcinoma liver metastasis with emphasis on the contribution of the insulin-like growth factor (IGF) axis to their activation and function. To this end, we used mice with a Tamoxifen inducible liver IGF-I deficiency. We found that in mice with a sustained IGF-I deficiency, recruitment and activation of HSC into tumor infiltrated areas of the liver were markedly diminished, resulting in decreased collagen deposition and reduced tumor expansion. In addition, IGF-I could rescue HSC from apoptosis induced by pro-inflammatory factors such as TNF-alpha known to be upregulated in the early stages of liver metastasis. Moreover, in surgical specimens, activated IGF-IR was observed on HSC-like stromal cells surrounding colorectal carcinoma liver metastases. Finally, IGF-targeting in vivo using an IGF-Trap caused a significant reduction in HSC activation in response to metastatic colon cancer cells. Therefore, our data identify IGF as a survival factor for HSC and thereby, a promoter of the pro-metastatic microenvironment in the liver. IGF-targeting could therefore provide a strategy for curtailing the pro-metastatic host response of the liver during the early stages of liver metastasis. PMID- 28881730 TI - Suppression of microRNA-205-5p in human mesenchymal stem cells improves their therapeutic potential in treating diabetic foot disease. AB - Diabetes is a prevalent disease endangering human health, while diabetic foot disease (DF) is one of the most severe complications of diabetes. Mesenchymal stem cells (MSCs) have been used in DF treatment, taking advantage of the differentiation potential of MSCs into endothelial cells and their production and secretion of trophic factors like vascular endothelial growth factor (VEGF). Molecular modification of MSCs to improve their therapeutic effects has been recently applied in treating other diseases, but not yet in DF. Here, we found that micoRNA-205-5p (miR-205-5p) is expressed in human MSCs, and miR-205-5p inhibits protein translation of VEGF through its interaction with 3'-UTR of the VEGF mRNA. Expression of antisense of miR-205-5p (as-miR-205-5p) significantly increased both cellular and secreted VEGF by MSCs, which significantly improved the therapeutic effects of MSCs on DF-associated wound healing in diabetic NOD/SCID mice. Together, our data suggest that miR-205-5p suppression in MSCs may improve their therapeutic effects on DF, seemingly through augmentation of VEGF mediated vascularization. PMID- 28881731 TI - Detection of BRAF, NRAS, KIT, GNAQ, GNA11 and MAP2K1/2 mutations in Russian melanoma patients using LNA PCR clamp and biochip analysis. AB - Target inhibitors are used for melanoma treatment, and their effectiveness depends on the tumor genotype. We developed a diagnostic biochip for the detection of 39 clinically relevant somatic mutations in the BRAF, NRAS, KIT, GNAQ, GNA11, MAP2K1 and MAP2K2 genes. We used multiplex locked nucleic acid (LNA) PCR clamp for the preferable amplification of mutated over wild type DNA. The amplified fragments were labeled via the incorporation of fluorescently labeled dUTP during PCR and were hybridized with specific oligonucleotides immobilized on a biochip. This approach could detect 0.5% of mutated DNA in the sample analyzed. The method was validated on 253 clinical samples and six melanoma cell lines. Among 253 melanomas, 129 (51.0%) BRAF, 45 (17.8%) NRAS, 6 (2.4%) KIT, 4 (1.6%) GNAQ, 2 (0.8%) GNA11, 2 (0.8%) MAP2K1 and no MAP2K2 gene mutations were detected by the biochip assay. The results were compared with Sanger sequencing, next generation sequencing and ARMS/Scorpion real-time PCR. The specimens with discordant results were subjected to LNA PCR clamp followed by sequencing. The results of this analysis were predominantly identical to the results obtained by the biochip assay. Infrequently, we identified rare somatic mutations. In the present study we demonstrate that the biochip-based assay can effectively detect somatic mutations in approximately 70% of melanoma patients, who may require specific targeted therapy. PMID- 28881732 TI - Oncogenic secretory clusterin in hepatocellular carcinoma: Expression at early staging and emerging molecular target. AB - Secretory clusterin (sCLU) is associated with hepatocellular carcinoma (HCC) progression by contributing to angiogenesis, chemoresistance, cell survival, and metastasis. However, the sCLU expression at early stage of HCC progression remains to be clarified. In this study, the alteration of sCLU oncogenicity was firstly evaluated in HCC- and their para-cancerous- tissues. The incidence of sCLU expression in HCC was significantly higher than that in their non-tumorous tissues at message RNA (mRNA) or protein level, gradually increasing with tumor node-metastasis (TNM) staging. Abnormal sCLU expression was associated with the poor differentiation, TNM stage, and considered as an independent prognostic factor for HCC patients. Furthermore, silencing sCLU gene transcription inhibited the colony formation and proliferation of HCC cells, with decreasing phosphorylation level of AKT and GSK-3beta in HCCLM3 cells in vitro and significantly suppressed the HCC xenograft growth in vivo, suggesting that sCLU with oncogenicity should be not only an early indicator but also novel potential molecular-targeted therapy for HCC. PMID- 28881733 TI - Positive regulation of TAZ expression by EBV-LMP1 contributes to cell proliferation and epithelial-mesenchymal transition in nasopharyngeal carcinoma. AB - The Epstein-Barr virus latent membrane protein 1 (LMP1) is an integral membrane protein. LMP1 has been reported to activate the NF-kappaB and mitogen-activated protein kinase pathways. However, these effects alone are unable to account for the profound oncogenic properties of LMP1. TAZ is one of the nuclear effectors of Hippo-related pathways and highly expressed in many human tumors. Here, we reported that TAZ was frequently expressed in LMP1-positive nasopharyngeal carcinoma. In NPC cell lines, we showed that LMP1 promoted TAZ expression. Gelsolin is an important inhibitor of TAZ activity. Our studies showed that LMP1 interacted with gelsolin, resulting in inhibition of Lats1/2 phosphorylation and improvement of TAZ stability. Furthermore, we revealed that TAZ is important for LMP1-mediated cell proliferation, cancer stem cell-like properties and epithelial mesenchymal transition. These findings provide new insights into the carcinogenic roles of LMP1 and contribute to further understanding of its oncogenic mechanism. PMID- 28881734 TI - Targeting aldehyde dehydrogenase activity in head and neck squamous cell carcinoma with a novel small molecule inhibitor. AB - Chemoresistant cancer cells express high levels of aldehyde dehydrogenases (ALDHs), particularly in head and neck squamous cell carcinoma (HNSCC). The ALDH family of enzymes detoxify both exogenous and endogenous aldehydes. Since many chemotherapeutic agents, such as cisplatin, result in the generation of cytotoxic aldehydes and oxidative stress, we hypothesized that cells expressing high levels of ALDH may be more chemoresistant due to their increased detoxifying capacity and that inhibitors of ALDHs may sensitize them to these drugs. Here, we show that overall ALDH activity is increased with cisplatin treatment of HNSCC and that ALDH3A1 protein expression is particularly enriched in cells treated with cisplatin. Activation of ALDH3A1 by a small molecule activator (Alda-89) increased survival of HNSCC cells treated with cisplatin. Conversely, treatment with a novel small molecule ALDH inhibitor (Aldi-6) resulted in a marked decrease in cell viability, and the combination of Aldi-6 and cisplatin resulted in a more pronounced reduction of cell viability and a greater reduction in tumor burden in vivo than what was observed with cisplatin alone. These data indicate that ALDH3A1 contributes to cisplatin resistance in HNSCC and that the targeting of ALDH, specifically, ALDH3A1, appears to be a promising strategy in this disease. PMID- 28881735 TI - Prognostic and clinicopathologic significance of SIRT1 expression in hepatocellular carcinoma. AB - The clinical value of SIRT1 in hepatocellular carcinoma (HCC) remains controversial. This meta-analysis was performed to investigate the prognostic and clinicopathological significance of the histone deacetylase SIRT1 in HCC. Pooled hazard ratios (HRs) for survival outcomes and pooled odds ratios (ORs) for clinical parameters associated with SIRT1 were calculated in nine studies using Review Manager. Meta-analysis showed that increased SIRT1 expression is associated with poor overall survival (OS) (HR=1.82, 95% confidence interval (CI): 1.49-2.22, P<0.00001) and disease-free survival (DFS) (HR=1.44, 95%CI: 1.06 1.96, P=0.02) in HCC. Increased expression of SIRT1 is more common in female than male HCC patients (OR=0.47, 95%CI: 0.32-0.70, P=0.0001). The increased SIRT1 expression correlates with hepatitis B virus (HBV) infection (OR=1.63, 95%CI: 1.04-2.57, P=0.03), large tumor size (OR=1.81, 95%CI: 1.05-3.13, P=0.03), high p53 expression (OR=2.71, 95%CI: 1.39-5.29, P=0.003), high levels of alpha fetoprotein (AFP; cutoff value: 400 ng/ml, OR=1.84, 95%CI: 1.26-2.69, P=0.002), and tumor stage (OR=1.72, 95%CI: 1.27-2.32, P=0.0004). Re-sampling statistics for 5,000,000 samples revealed that increased SIRT1 expression is associated with higher TNM stage (OR=1.70, 95%CI: 1.69-1.70, P<0.00001). These results indicate that SIRT1 is a new biomarker off HCC as well as a potentially effective therapeutic target. PMID- 28881736 TI - Comparisons of short-term and survival outcomes of laparoscopy-assisted versus open total gastrectomy for gastric cancer patients. AB - OBJECTIVES: The safety and surgical oncology of laparoscopy-assisted total gastrectomy (LATG) remain inconclusive and challenging. This study aimed to compare the short-term and long-term outcomes between LATG and open total gastrectomy (OTG) procedures. RESULTS: In the all-included analyses, there were 69 patients in the LATG group and 268 in the OTG group. LATG was as safe as OTG without increasing postoperative morbidity and mortality. Stage imbalance might introduce differences in the numbers of harvested lymph nodes in LATG (34.4 +/- 12.0) and OTG (40.9 +/- 16.9), whereas 95.7% of patients underwent D2/D2+ dissection during the LATG procedure. After a median 31 months of follow-up, the overall survival outcomes were comparable between the LATG and OTG procedures (HR = 1.16, 95% CI 0.68-1.97). Sensitivity analysis found comparable node retrieval and stage-specific or treatment-specific overall survival. MATERIALS AND METHODS: A retrospective case-control study was conducted among gastric cancer patients who underwent either LATG or OTG with curative intention between June 2006 and December 2015. Data retrieval was based on the Surgical Gastric Cancer Patient Registry in the West China Hospital. The primary outcome was overall survival. The secondary outcomes were postoperative complication incidence and severity, operation duration, blood loss, number of harvested lymph nodes, and postoperative hospital stay. Matched pairwise case-control comparisons were performed as a sensitivity analysis. CONCLUSIONS: LATG by experienced surgeons possibly has comparable short-term surgical outcomes and long-term survival outcomes compared with OTG for gastric cancer patients. However, high-quality RCTs are necessary before confirmative judgment and recommendation as an optional treatment in general practice. PMID- 28881737 TI - Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice. AB - Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-kappaB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC. Galeterone (gal), a multi target, agent in phase III clinical development for prostate cancer has also shown effects on the aforementioned pathways. We show for the first time, that gal/analogs (VNPT55, VNPP414 and VNPP433-3beta) profoundly inhibited cell viability of gemcitabine-naive/resistance PDAC cell lines and strongly synergized with gemcitabine in gemcitabine-resistant PDAC cells. In addition, to inducing G1 cell cycle arrest, gal/analogs induced caspase 3-mediated cell-death of PDAC cells. Gal/analogs caused profound downregulation of Mnk1/2, peIF4E and NF-kappaB (p-p65), metastatic inducing factors (N-cadherin, MMP-1/-2/-9, Slug, Snail and CXCR4) and putative stem cell factors, (beta-Catenin, Nanog, BMI-1 and Oct-4). Gal/analog also depleted EZH2 and upregulated E-Cadherin. These effects resulted in significant inhibition of PDAC cell migration, invasion and proliferation. Importantly, we also observed strong MiaPaca-2 tumor xenograft growth inhibition (61% to 92%). Collectively, these promising findings strongly support further development of gal/analogs as novel therapeutics for PDAC. PMID- 28881738 TI - Expression analysis of microRNA as prognostic biomarkers in colorectal cancer. AB - microRNA (miRNA) based biomarkers have unique advantages due to their critical regulatory function, superior stability, and relatively small number compared to mRNAs. A number of miRNAs play key roles in colon cancer stem cell chemoresistance and have clinical potential as prognostic biomarkers. The purpose of this study is to systematically validate the prognostic potential of miRNAs in colorectal cancer. In this study, we validated the prognostic potential of a panel of miRNAs using 205 stage II, III, and IV colorectal cancer specimens by qRT-PCR analysis. We cross validated our results using The Cancer Genome Atlas (TCGA) database. Many of the miRNAs we investigated have been functionally validated to be important in contributing to chemoresistance to 5-fluorouracil (5 FU) based chemotherapy. We determined that miR-16 is the most consistent miRNA for expression normalization in colorectal cancer. We have validated several miRNAs (miR-15b, miR-215, miR-145, miR-192, let-7g) that are significantly associated with progression free survival (PFS) and/or overall survival (OS) of colorectal cancer patients independent of tumor stage and age at diagnosis. These 5 miRNAs are significantly associated with OS of colorectal cancer even after tumor location (left side vs. right side) is adjusted for. Furthermore, the prognostic value of let-7g for overall survival was independently validated using the RNA-Seq results from TCGA colorectal cancer database. These results, taken together, establish a solid foundation towards miRNA based precision management of colorectal cancer. PMID- 28881739 TI - A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors. AB - BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC), an albumin binding protein, is downregulated by hypermethylation in many cancers. Hypomethylating agents such as azacitidine can upregulate SPARC in tumors, which may enhance the accumulation of albumin-bound drugs at tumor site. The objectives of this phase I trial was to determine the safety and maximum tolerated dose and to assess any clinical activity of the combination of azacytidine and weekly nanoparticle-albumin-bound (nab(r)) paclitaxel. METHODS: Patients received escalating azacytidine doses daily for 5 days, followed by nab-paclitaxel at the standard 100mg/m2 weekly dose for 3 weeks in 4-week cycles. Dose-limiting toxicities (DLTs) were monitored during the first cycle. Serum was obtained at baseline, during and after treatment for correlative study. RESULTS: All sixteen total patients enrolled were evaluable for toxicity, while 13 patients were evaluable for response. Two of five patients treated with 100mg/m2 of azacytidine had DLT of prolonged grade 4 neutropenia. Therefore, the MTD of azacitidine in this regimen is 75 mg/m2. Three additional patients were treated with no grade 4 toxicity in cycle 1. Clinical activity included 1 complete response (CR) in refractory DLBCL, 2 CR in ovarian cancer, 4 partial responses (PR) in ovarian and endometrial cancer, 4 stable diseases (SD) in lung, sarcoma and pancreatic cancer, 1 unconfirmed PR in breast cancer, and 1 progression of disease in CLL/SLL. CONCLUSIONS: Priming with azacitidine 75 mg/m2 daily for 5 days, followed by weekly nab-paclitaxel 100 mg/m2 weekly was well tolerated and results in dramatic responses pre-treated cancer patients. PMID- 28881740 TI - Unit resection of buccal squamous cell carcinoma: Description of a new surgical technique. AB - This study characterized the infiltration of primary tumors along the muscles, fascia and spaces of the maxillofacial region in buccal squamous cell carcinoma (BSCC) and suggested a new surgical strategy that is suitable for most stages. Based on the anatomic characteristics and infiltration of the primary tumor a new surgical approach - unit resection buccal surgery (URBS) - was developed. We evaluated this new surgical strategy, across a cohort of 127 BSCCs: 60 cases treated with URBS and 67 cases treated with conventional surgery. Notably there was no statistical difference in the clinicopathological variables between the two groups. After initial treatment with curative intent, the patients were regularly followed-up with clinical examination and imaging. URBS proved suitable for almost all stages of BSCC, and was particularly advantageous for advanced stages of BSCC. At 2 years post-treatment, the rates of overall survival were 83.3% in the URBS group and 60.1% in the conventional surgery group, respectively (hazard ratio 0.38; 95% CI 0.20 to 0.75; P=0.005). Similarly, the rates of disease-free survival were 76.6% and 51.9% in the URBS group and the conventional surgery group, respectively (hazard ratio 0.42; 95% CI 0.23 to 0.75; P=0.003). The principles of URBS are suitable for almost all stages of BSCC, especially advanced stages. URBS may improve the prognosis of BSCC patients. PMID- 28881741 TI - CRABP-II enhances pancreatic cancer cell migration and invasion by stabilizing interleukin 8 expression. AB - Our previous study shows that cellular retinoic acid binding protein II (CRABP II) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and pre-cancerous lesions, but not detected in normal pancreatic tissues. In this study, we show that deletion of CRABP-II in PDAC cells by CRISPR/Cas9 does not affect cancer cell proliferation, but decreases cell migration and invasion. Gene expression microarray analysis reveals that IL-8 is one of the top genes whose expression is down-regulated upon CRABP-II deletion, while expression of MMP-2 and MMP-14, two targets of IL-8 are also significantly down-regulated. Moreover, we found that CRABP-II is able to form a complex with HuR, which binds to the 3'UTR of IL-8 messenger RNA (mRNA) and enhances IL-8 mRNA stability. Ectopic expression of flag CRABP-II in CRABP-II knockout cells is able to rescue the expression of IL-8, MMP 2/MMP-14 and recovers cell migration. Using the orthotopic xenograft model, we further demonstrate that CRABP-II deletion impairs tumor metastasis to nearby lymph nodes. Taken together, our results reveal a novel pathway linking CRABP-II expression to enhanced PDAC metastasis, and hence we propose CRABP-II may serve as a new PDAC therapeutic target. PMID- 28881742 TI - Eribulin alone or in combination with the PLK1 inhibitor BI 6727 triggers intrinsic apoptosis in Ewing sarcoma cell lines. AB - In this study, we investigated the molecular mechanisms of eribulin-induced cell death and its therapeutic potential in combination with the PLK1 inhibitor BI 6727 in Ewing sarcoma (ES). Here, we show that eribulin triggers cell death in a dose-dependent manner in a panel of ES cell lines. In addition, eribulin at subtoxic, low nanomolar concentrations acts in concert with BI 6727 to induce cell death and to suppress long-term clonogenic survival. Mechanistic studies reveal that eribulin monotherapy at cytotoxic concentrations and co-treatment with eribulin at subtoxic concentrations together with BI 6727 arrest cells in the M phase of the cell cycle prior to the onset of cell death. This mitotic arrest is followed by increased phosphorylation of BCL-2 and BCL-xL as well as downregulation of MCL-1, suggesting inactivation of these antiapoptotic BCL-2 family proteins. Consistently, eribulin monotherapy and eribulin/BI 6727 co treatment trigger activation of BAX, a key proapoptotic BCL-2 family protein, and increase proteolytic activation of caspase-9 and -3. Importantly, overexpression of BCL-2 or addition of the broad-range caspase inhibitor zVAD.fmk significantly rescue eribulin- as well as eribulin/BI 6727-induced cell death. Together, these findings demonstrate that eribulin induces cell death via the intrinsic pathway of apoptosis in ES cells, both alone at cytotoxic concentrations and in combination with BI 6727 at subtoxic concentrations. Thus, our study highlights the therapeutic potential of eribulin for the treatment of ES alone or in rational combination therapies. PMID- 28881743 TI - Prognostic role of podocalyxin-like protein expression in various cancers: A systematic review and meta-analysis. AB - Several studies were conducted to explore the prognostic significance of podocalyxin-like protein (PODXL) expression in various cancers, with contradictory. This study aims to summarize the prognostic significance of PODXL expression in cancers. PubMed, the Cochrane Library and Embase were completely retrieved. The prospective or retrospective studies focusing on the prognostic role of PODXL expression in cancers were eligible. The endpoints were overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS).12 studies involving a total of 5,309 patients were identified. The results indicated that high PODXL expression was significantly associated with worse OS when compared to the low PODXL expression (HR=1.76, 95%CI=1.53-2.04, p<0.00001; I2=41%, p=0.08). And similar results were detected in the subgroup analysis of analysis model, ethnicity, sample size, tumor type and antibody type. And the results also showed that high PODXL expression was obviously related to shorter DSS (HR=2.47, 95%CI=1.53-3.99, p=0.0002; I2=66%, p=0.03) and DFS (HR=2.12, 95%CI=1.58-2.85, p<0.00001; I2=19%, p=0.29). In conclusion, it was revealed that high PODXL expression is an unfavorable predictor of OS, DSS and DFS in patients with cancers, and high PODXL expression is a promising prognostic biomarker for cancers, especially for patients in European. PMID- 28881744 TI - MiR-199a-3p suppresses proliferation and invasion of prostate cancer cells by targeting Smad1. AB - OBJECTIVES: This study was intended to analyze effects of miR-199a-3p and Smad1 on proliferation, migration and invasion of prostate cancer (PCa) cells. RESULTS: MiR-199a-3p was significantly decreased in PCa tissues in comparison to that in adjacent normal tissues (P < 0.05). Over-expressed miR-199a-3p markedly suppressed proliferation and invasion of PCa cells (P < 0.05). MiR-199a-3p was negatively correlated with Smad1 expression, and overexpression of Smad1 could antagonize the effects of miR-199a-3p on PCa cells. MATERIALS AND METHODS: The PCa tissues and their adjacent normal tissues were collected from 54 PCa patients. Expressions of miR-199a-3p and Smad1 mRNA in tissues and cells were evaluated with real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemistry assay was used to detect Smad1 protein expressions. The target relationship between miR-199a-3p and Smad1 was assessed by luciferase reporter assay. The PCa cell lines (i.e. PC-3 cells) were transfected with miR 199a-3p mimics and Smad1-cDNA. MTT and Transwell assays were applied to detect proliferative, migratory and invasive abilities of PCa cells. CONCLUSIONS: MiR 199a-3p suppressed proliferation and invasion of PCa cells by targeting Smad1. PMID- 28881745 TI - Whole tumor RNA-sequencing and deconvolution reveal a clinically-prognostic PTEN/PI3K-regulated glioma transcriptional signature. AB - The concept that solid tumors are maintained by a productive interplay between neoplastic and non-neoplastic elements has gained traction with the demonstration that stromal fibroblasts and immune system cells dictate cancer development and progression. While less studied, brain tumor (glioma) biology is likewise influenced by non-neoplastic immune system cells (macrophages and microglia) which interact with neoplastic glioma cells to create a unique physiological state (glioma ecosystem) distinct from that found in the normal tissue. To explore this neoplastic ground state, we leveraged several preclinical mouse models of neurofibromatosis type 1 (NF1) optic glioma, a low-grade astrocytoma whose formation and maintenance requires productive interactions between non neoplastic and neoplastic cells, and employed whole tumor RNA-sequencing and mathematical deconvolution strategies to characterize this low-grade glioma ecosystem as an aggregate of cellular and acellular elements. Using this approach, we demonstrate that optic gliomas generated by altering the germline Nf1 gene mutation, the glioma cell of origin, or the presence of co-existing genetic alterations represent molecularly-distinct tumors. However, these optic glioma tumors share a 25-gene core signature, not found in normal optic nerve, that is normalized by microglia inhibition (minocycline), but not conventional (carboplatin) or molecularly-targeted (rapamycin) chemotherapy. Lastly, we identify a genetic signature conferred by Pten reduction and corrected by PI3K inhibition. This signature predicts progression-free survival in patients with either low-grade or high-grade glioma. Collectively, these findings support the concept that gliomas are composite ecological systems whose biology and response to therapy may be best defined by examining the tumor as a whole. PMID- 28881746 TI - Prostate-derived ETS factor improves prognosis and represses proliferation and invasion in hepatocellular carcinoma. AB - Prostate-derived E-twenty-six (ETS) factor (PDEF), an epithelium-specific ETS transcription factor, regulates carcinogenesis and tumor progression. The prognostic importance and biologic functions in hepatocellular carcinoma (HCC) have not been established. We investigated PDEF expression in 400 HCC patients using quantitative real-time polymerase chain reaction, western blot and immunohistochemistry analysis. PDEF expression was significantly lower in tumors than in peritumoral tissues. Lower PDEF levels were associated with poorer prognosis in patients. PDEF was an independent predictor of overall survival in multivariate analysis. PDEF expression was suppressed in highly metastatic HCC cell lines, and shRNA-mediated down-regulation of PDEF in low-metastatic HCC cell lines (with high PDEF) significantly increased cellular proliferative and invasive capacity in vitro and in vivo. RNA sequencing analysis indicated that PDEF may mediate transcription of several genes involved in apoptosis and the cell cycle. PDEF modulated epithelial-mesenchymal transition by up-regulating E cadherin expression and down-regulating Slug and Vimentin expression, thereby lowering migration and invasion abilities of HCC cells. In conclusion, PDEF is associated with proliferation and invasiveness of HCC cells. It may serve as an independent predictor of prognosis in patients with HCC. PMID- 28881747 TI - Excessive matrix metalloprotease-mediated degradation of interstitial tissue (type I collagen) independently predicts short-term survival in an observational study of postmenopausal women diagnosed with cancer. AB - Extensive tissue remodeling mediated by matrix metalloproteases (MMPs) is an important part of cancer. The aim of this study was to investigate whether serum biomarkers reflecting MMP-mediated degradation of type I collagen (C1M), type IV collagen (C4M) and citrullinated vimentin (VICM) were predictive of cancer specific mortality. Between 1999 and 2001, 5855 Danish postmenopausal women participated in The Prospective Epidemiologic Risk Factor (PERF I) study. Demographics and serum samples were collected at enrolment. Cancer diagnosis, and cause and time of death were obtained from Danish registries. C1M, C4M and VICM were measured by ELISA. Hazard ratios (HR) and Kaplan-Meier curves were applied to assess mortality at 3 and 12 years of follow-up for women diagnosed with cancer within 3 years from blood sampling. Within 3 years from blood sampling, 250 women had been diagnosed with cancer. C1M and VICM were associated with survival over time at 3 years of follow-up. Only C1M was predictive of mortality at 3 years follow-up: the adjusted HR was 2.65 [95% CI: 1.08-6.51]. In conclusion, C1M and VICM are associated with survival in postmenopausal women with cancer, and C1M is an independent risk factor for cancer-specific mortality. Thus, quantification of tissue remodeling is important in cancer. PMID- 28881748 TI - Api5 a new cofactor of estrogen receptor alpha involved in breast cancer outcome. AB - Api5 (Apoptosis inhibitor 5) is an anti-apoptotic factor that confers resistance to genotoxic stress in human cancer. Api5 is also expressed in endothelial cells and participates to the Estrogen Receptor alpha (ERalpha) signaling to promote cell migration. In this study, we found an over expression of Api5 in human breast cancer. Given that we show that high expression of Api5 in breast cancer patients is associated with shorter recurrence free survival, we investigated the relationship between ERalpha and Api5 at the molecular level. We found that Api5 Nuclear Receptor box (NR box) drives a direct interaction with the C domain of ERalpha. Furthermore, Api5 participates to gene transcription activation of ERalpha target genes upon estrogen treatment. Besides, Api5 expression favors tumorigenicity and migration and is necessary for tumor growth in vivo in mice xenografted model of breast cancer cell line. These finding suggest that Api5 is a new cofactor of ERalpha that functionally participates to the tumorigenic phenotype of breast cancer cells. In ERalpha breast cancer patients, Api5 overexpression is associated with poor survival, and may be used as a predictive marker of breast cancer recurrence free survival. PMID- 28881749 TI - Effects of microRNA-126 on cell proliferation, apoptosis and tumor angiogenesis via the down-regulating ERK signaling pathway by targeting EGFL7 in hepatocellular carcinoma. AB - This study intends to explore the effects of microRNA-126 (miR-126) on cell proliferation, apoptosis, and tumor angiogenesis in hepatocellular carcinoma (HCC) by regulating epidermal growth factor-like domain 7 (EGFL7) through extracellular signal-regulated kinase (ERK) signaling. HCC tissues and adjacent normal tissues were obtained from 184 HCC patients. HCC cells were separately transfected with recombinant plasmids. Western blotting and qRT-PCR were applied to detect miR-126 and EGFL7, ERK, Fas/FasL, Bcl-2, Caspase mRNA and protein levels. CCK8 and TUNEL were performed to determinate cell proliferation and apoptosis. Flow cytometry was used to analyze cell cycle distribution. Rats model of HCC was constructed, and tumor weight and the number of new blood vessels were recorded after 3 weeks of tumor transplantation. Compared with the adjacent normal tissues, HCC tissues exhibited lower miR-126 expression, and higher EGFL7, and ERK mRNA and protein levels. Overexpression of miR-126 in HCC cell lines suppressed EGFL7, ERK, Bcl-2, and P-ERK, and increased apoptotic-associated proteins Fas/FasL and Caspase-3, and it inhibited cell proliferation and induced cell apoptosis. Overexpression of miR-126 in nude mice resulted in reduced tumor weight and less new blood vessels in tumors. The inhibition of miR-126 decreased cell apoptosis, and enhanced cell proliferation and tumor angiogenesis. This study demonstrates that miR-126 might decrease cell proliferation, induce apoptosis, and inhibit tumor angiogenesis in HCC by inhibiting EGFL7 via down regulating the ERK signaling pathway. PMID- 28881750 TI - New in vivo avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis. AB - Diffuse Instrinsic Pontine Glioma is the most aggressive form of High Grade Gliomas in children. The lack of biological material and the absence of relevant models have hampered the development of new therapeutics. Their extensive infiltration of the brainstem renders any surgical resection impossible and until recently biopsies were considered not informative enough and therefore not recommended. Thus, most models were derived from autopsy material. We aimed to develop relevant in vivo DIPG models that mimic this specific disease and its molecular diversity from tumor material obtained at diagnosis. Eight patient derived orthotopic xenograft models were obtained after direct stereotactic injection of a mixed cell suspension containing tumor cells and stromal cells in the brainstem or thalamus of nude mice and serially passaged thereafter. In parallel, we developed 6 cell-derived xenograft models after orthotopic injection of tumor-initiating cells cultured from stereotactic biopsies. Cells were modified to express luciferase to enable longitudinal tumor growth monitoring, and fluorescent reporter proteins to trace the tumor cells in the brain. These models do not form a tumor mass, they are invasive, show the H3K27 trimethylation loss in vivo and the tumor type diversity observed in patients in terms of histone H3 mutations and lineage markers. Histological and MRI features at 11.7 Tesla show similarities with treatment naive human DIPG, and in this respect, both direct and indirect orthotopic xenograft looked alike. These DIPG models will therefore constitute valuable tools for evaluating new therapeutic approaches in this devastating disease. PMID- 28881751 TI - Hepatitis B virus surface proteins accelerate cholestatic injury and tumor progression in Abcb4-knockout mice. AB - : Understanding of the pathophysiology of cholestasis associated carcinogenesis could challenge the development of new personalized therapeutic approaches and thus improve prognosis. Simultaneous damage might aggravate hepatic injury, induce chronic liver disease and even promote carcinogenesis. We aimed to study the effect of Hepatitis B virus surface protein (HBsAg) on cholestatic liver disease and associated carcinogenesis in a mouse model combining both impairments. Hybrids of Abcb4-/- and HBsAg transgenic mice were bred on fibrosis susceptible background BALB/c. Liver injury, serum bile acid concentration, hepatic fibrosis, and carcinogenesis were enhanced by the combination of simultaneous damage in line with activation of c-Jun N-terminal kinase (JNK), proto-oncogene c-Jun, and Signal transducer and activator of transcription 3 (STAT3). Activation of Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) and Eukaryotic translation initiation factor 2A (eIF2alpha) indicated unfolded protein response (UPR) in HBsAg-expressing mice and even in Abcb4-/- without HBsAg-expression. CONCLUSION: Cholestasis-induced STAT3- and JNK-pathways may predispose HBsAg-associated tumorigenesis. Since STAT3- and JNK-activation are well characterized critical regulators for tumor promotion, the potentiation of their activation in hybrids suggests an additive mechanism enhancing tumor incidence. PMID- 28881752 TI - Integrated expression profiles analysis reveals novel predictive biomarker in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is the most lethal human malignant tumor, with a dismal 5-year survival rate of less than 5%. The lack of specific symptoms at early tumor stages and the paucity of biomarkers contribute to the poor diagnosis of pancreatic ductal adenocarcinoma. To improve prognosis, a screening biomarker for early diagnosis of pancreatic cancer is in urgent need. We searched the databases of expression profiling by array on GEO, aiming at comparing gene expression profile of matched pairs of pancreatic tumor and adjacent non-tumor tissues, and we screen out 4 suitable series of gene expression microarray data ("GSE15471", "GSE18670", "GSE28735" and "GSE58561"). After carefully analyzing, 13 DEGs (MYOF, SLC6A6, S100P, HK2, IFI44L, OSBPL3, IGF2BP3, PDK4, IL1R2, ERO1A, EGLN3, PLAC8 and ACSL5) are significantly differentially expressed in four microarray databases in common. After analyzing mRNA expression data and clinical follow-up survey provided in the TCGA database and clinicopathological data of 137 pancreatic ductal adenocarcinoma patients, we carefully demonstrated that three of these differentially expressed genes (ERO1A, OSBPL3 and IFI44L) are correlated with poor prognosis of pancreatic ductal adenocarcinoma patients. In addition, we revealed that cell-matrix adhesion and extracellular matrix were top significantly regulated pathways in pancreatic ductal adenocarcinoma and depicted two protein-protein interactions networks of extracellular matrix related Genes which are dysregulated according to 4 gene expression microarray data mentioned above ("GSE15471", "GSE18670", "GSE28735" and "GSE58561"), hoping to shed light on the etiology of PDAC and mechanisms of drug resistance in PDAC in this study. PMID- 28881753 TI - siRNA-mediated inactivation of HER3 improves the antitumour activity and sensitivity of gefitinib in gastric cancer cells. AB - The human EGFR family consists of four type-1 transmembrane tyrosine kinase receptors: HER1 (EGFR, ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). HER3 can dimerize with EGFR, HER2 and even c-Met and likely plays a central role in the response to EGFR-targeted therapy. Because HER3 lacks significant kinase activity and cannot be inhibited by tyrosine kinase inhibitors, neutralizing antibodies and alternative inhibitors of HER3 have been sought as cancer therapeutics. Here, we describe the stable suppression of HER3 mRNA and protein using siRNA. The inhibition of HER3 expression decreased cell proliferation, suppressed cell cycle progression, induced apoptosis and inhibited cell motility, migration, invasiveness, and soft agar growth. In addition, we found that gefitinib treatment increased the HER3 and HER2 mRNA levels. The administration of various concentrations of gefitinib to HER3-knockdown cells enhanced antitumour activity and sensitivity due to the downregulation of protein phosphorylation via PI3K/AKT and ERK signalling. Our results support the use of combined treatments targeting multiple EGFR receptors, particularly the use of HER3 inhibitors combined with EGFR inhibitors, such as gefitinib. PMID- 28881754 TI - Intercellular adhesion molecule 1 rs5498 polymorphism is associated with the risk of myocardial infarction. AB - Several studies addressed the association between Intercellular adhesion molecule 1 (ICAM-1) rs5498 polymorphism and Myocardial Infarction (MI) risk. However, they addressed conflicting findings. Therefore, the aim of this study was to explore whether ICAM-1 gene rs5498 polymorphism plays an important role in modifying the risk of MI. A meta-analysis was conducted on the association between ICAM-1 rs5498 polymorphism and MI. 12 eligible studies involving 1,696 cases and 3,039 controls were included in the meta-analysis. Meta-analysis revealed that ICAM-1 rs5498 polymorphism showed a strongly positive correlation with MI and could be viewed as a protective factor for MI. Furthermore, subgroup analysis according to ethnicity indicated that ICAM-1 rs5498 polymorphism decreased the risk of MI among Caucasian and Asian populations. In conclusion, ICAM-1 rs5498 polymorphism was associated with the decreased risk of MI. Larger sample size studies with more diverse ethnic populations are needed to confirm these findings. PMID- 28881755 TI - Identification of long non-coding RNAs biomarkers associated with progression of endometrial carcinoma and patient outcomes. AB - Endometrial carcinoma is a complex disease characterized by both genetic, epigenetic and environmental factors. Increasing evidence has suggested that long non-coding RNAs (lncRNAs) play important roles in the development and progression of cancers. In this study, we performed a comparison analysis for lncRNA expression between patients with early-stage (stage I/II) and those with advanced stage (stage III/IV) derived from The Cancer Genome Atlas (TCGA) project and identified 17 differentially expressed lncRNAs using student t-test. Five of the 17 differentially expressed lncRNAs were selected as optimal biomarkers that are significantly associated with progression of UCEC using random forest feature selection procedure. A risk classifier of five lncRNAs was developed to as a molecular signature that identifies patients at high risk for progression using support vector machine. Results of five-lncRNA risk classifier achieved high discriminatory performance in distinguishing advanced stage from early stage with 78% prediction accuracy, 96.6% sensitivity and 76.6% specificity. Functional analysis suggested that these five lncRNA biomarkers may play critical roles in the progression of UCEC by participating in important cancer-related biological processes. Our study will help to improve our understanding of underlying mechanisms in the progression of UCEC and provide novel lncRNAs as candidate predictive biomarkers for the identification of patients with high risk for progression. PMID- 28881756 TI - MM-BMSCs induce naive CD4+ T lymphocytes dysfunction through fibroblast activation protein alpha. AB - BACKGROUND: The tumor microenvironment plays a major role in multiple myelomas (MM). MM-BMSCs (bone marrow mesenchymal stromal cells) can support tumor growth and immune surveillance escape. On the other hand, fibroblast activation protein alpha, expressed by cancer stroma cells including BMSCs, has been shown to potentiate epithelial cancers growth and immune suppression. RESULTS: MM-BMSC inhibited proliferation of T cells (P = 0.0138), promoted senescence of T cells (P < 0.001), consistent with decreased CD28 and hTERT expression (P < 0.001), Treg/Th17 was down-regulated by MM-BMSC (P = 0.031). After treatment with FAPalpha inhibitor PT-100, senescent rate was decreased (P = 0.001), Treg/Th17 was up-regulated (P = 0.024). FAPalpha was up-regulated by TCCM (P = 0.02). p-AKT was increased in MM-BMSC co-cultured T cells (P = 0.021) and decreased by PT-100 (P = 0.017). Higher level of TGF-beta was observed in MM-BMSC co-cultured medium (P < 0.001), and down-regulated by PT-100 (P = 0.038). p-AKT was upregulated as compared to T-cells without MM-BMSCs (P = 0.021). The abnormal p-AKT level was distinctly decreased by PT-100 (P = 0.017). MATERIALS AND METHODS: The expression of FAPalpha was analyzed by western blot and RT-PCR. The proliferation and senescence of CD4+ T cells was examined by cck-8 and beta-gal staining, and Treg/Th17, CD28 expression was analyzed by FCM. The FAPalpha and PI3K pathway was analyzed by western blot and their relationship with T cell function was detected by FCM and RT-PCR. The level of IL-10, IL-17 and TGF-beta was detected by ELISA. CONCLUSIONS: MM-BMSCs inhibit T-cell proliferation and drive Th17 differentiation through FAPalpha/TGF-beta axis, leading to the progression of myeloma. FAPalpha induced T-cell senescence is mediated by the PI3K signaling pathway. PMID- 28881757 TI - Antagonistic effects of selenium on cadmium-induced apoptosis by restoring the mitochondrial dynamic equilibrium and energy metabolism in chicken spleens. AB - The aim of this study was to investigate the mechanism of cadmium-induced apoptosis in chicken spleens and the antagonistic effects of selenium. We duplicated the selenium-cadmium interaction model and examined the expression of apoptosis-, immune-, mitochondrial dynamics- and energy metabolism-related genes. The results demonstrated that after treatment with cadmium, the frequency of apoptosis was significantly increased, and the morphological characteristics of apoptosis were observed. The expression of pro-apoptotic genes was increased, and that of anti-apoptotic genes was decreased. The mRNA levels of tumor necrosis factor-alpha and interlenkin-1beta were observably increased, but the interlenkin 2 and interferon-gamma levels were markedly decreased. Furthermore, the mRNA and protein levels of dynamin-related protein 1 and mitochondrial fission factor were significantly enhanced, whereas mitofusin 1, mitofusin 2, and optic atrophy 1 were markedly decreased. The expression of hexokinase 1, hexokinase 2, aconitase 2, lactate dehydrogenase A, lactate dehydrogenase B, succinatedehydrogenase B, pyruvate kinase and phosphofructokinase were also reduced. Selenium supplements remarkably attenuated cadmium-induced effects (p < 0.05). Based on the above results, conclude that the cadmium treatment promoted a mitochondrial dynamic imbalance and reduced energy metabolism, leading to apoptosis and immune dysfunction in chicken spleens, and selenium had an antagonistic effect on Cd induced apoptosis. PMID- 28881758 TI - Suppression of pyruvate dehydrogenase kinase-2 re-sensitizes paclitaxel-resistant human lung cancer cells to paclitaxel. AB - Despite impressive initial clinical responses, the majority of lung cancer patients treated with paclitaxel eventually develop resistance to the drug. Pyruvate dehydrogenase kinase-2 (PDK2) is a key regulator of glycolysis and oxidative phosphorylation, and its expression is increased in a variety of tumors. In this study, the role of PDK2 in mediating paclitaxel resistance in lung cancer cells was investigated using biochemical and isotopic tracing methods. Increased expression of PDK2 was observed in paclitaxel-resistant cells ascompared totheir parental cells. Down-regulation of PDK2 usingsiRNA increased the sensitivity to paclitaxel of resistant lung cancer cells. Targeting paclitaxel-resistant cells throughPDK2 knockdown was associated with reduced glycolysis rather than increased oxidative phosphorylation (OXPHOS). Moreover, combining paclitaxel withthe specific PDK2 inhibitor dichloroacetate had a synergistic inhibitory effect on the viability of paclitaxel-resistant lung cancer cells. These results indicate that paclitaxel-induced expression of PDK2 serves as an important mechanism for acquired paclitaxel resistance of lung cancer cells. They also highlight the importance of PDK2 for potential therapeutic interventions in patients who have developed a resistance to paclitaxel. PMID- 28881759 TI - Combination treatment with transarterial chemoembolization, radiotherapy, and hyperthermia (CERT) for hepatocellular carcinoma with portal vein tumor thrombosis: Final results of a prospective phase II trial. AB - BACKGROUND & AIMS: This study was designed to evaluate the efficacy and safety of combination transarterial chemoembolization (TACE) followed by radiotherapy (RT) and hyperthermia (CERT) in hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). METHODS: This single-institution, single-arm, prospective phase II study was performed from October 2013 to February 2016. The objective response rate (ORR) was evaluated at 3 months after CERT completion, and overall ORR was the primary end point. RESULTS: During the study period, 69 of 77 patients who consented to participate underwent at least one session of hyperthermia and RT. More than half of the patients (39, 56.5%) complained of severe hyperthermia-related pain. The overall ORR was 43.5% (30/69), and the ORR of the RT target area was 69.6% (48/69). Liver function status was not significantly affected by CERT. Overall survival, local progression-free survival, and progression-free survival of all enrolled patients at 2 years was 62.9%, 47.6%, and 14.3%, respectively. CONCLUSIONS: An overall ORR of 43.5% was observed after CERT, but a promising ORR of 69.6% was achieved in the RT target area. Toxicities related to CERT were manageable, and pain intolerance to hyperthermia was the main obstacle to treatment maintenance. PMID- 28881760 TI - Prognostic value of Flotillin-1 expression in patients with solid tumors. AB - BACKGROUND: In numerous studies, Flotillin-1 was reported to be involved in tumor progression, indicating prognosis in various types of cancer. However, the results were inconsistent. RESULTS: A total of 2473 patients from 13 articles were included. The results indicated that: (1) Patients detected with high expression level of Flotillin-1 protein had a significantly shorter OS (HR =1.64; 95%CI: 1.39-1.88), statistical significance was also observed in subgroup meta analyses stratified by the cancer type, nationality, detecting method, cutoff value, analysis type, sample size and publication date. (2) Patients with high Flotillin-1 protein expression level had a poorer DFS (HR = 2.49; 95%CI: 1.64 3.35), a worse RFS(HR = 3.26; 95%CI: 1.10-5.43) and a potential shorter PFS(HR = 1.84; 95%CI: 0.81-2.87). (3) The pooled odds ratios (ORs) showed that increased Flotillin-1 level was also related to lymph node metastasis (OR =6.30; 95% CI: 3.15-12.59), distant metastasis (OR =6.02; 95% CI: 1.50-24.06) and more advanced TNM stage (OR =4.69; 95% CI: 2.74-8.03). MATERIALS AND METHODS: A comprehensive retrieval was performed in multiple databases, including PubMed, Embase, Web of Science and CNKI. The relevant articles were screened for investigating the association between increased Flotillin-1 expression level and prognosis. Additionally, clinicopathological features data was also extracted from these studies. CONCLUSIONS: High expression level of Flotillin-1 protein was correlated with poorer clinical outcome. It might serve as a prognostic biomarker and a potential predictive factor of clinicopathology in various tumors. Further well designed clinical studies should be performed to verify the clinical utility of Flotillin-1 in human solid tumors. PMID- 28881761 TI - Transcription factor c-Rel is indispensable for generation of thymic but not of peripheral Foxp3+ regulatory T cells. AB - The transcription factor c-Rel has been shown to be crucial for development of regulatory T cells (Tregs). Recent studies have reported that the expression of transcription factor Helios in Foxp3+ Tregs correlates with thymic origin of these cells (tTregs). Notably, we found that only the Helios+Foxp3+ Treg cell population was substantially reduced in c-Rel deficient mice. In contrast to a defective tTreg development, we observed an expansion of mucosal Tregs during the induction of acute colitis in rel-/- mice. Furthermore, we found a preferential accumulation of Helios-Foxp3+ Tregs in aged c-Rel deficient mice. This unexpected finding, together with the observation that naive CD4+ T cells convert into Tregs in vitro in the absence of c-Rel and presence of IL-2, provide an evidence that extra-thymic generation of induced and peripheral Tregs (iTregs and pTregs) is independent of c-Rel. Moreover, the treatment with IL-2/anti-IL-2 mAb (JES6-1) resulted in a widespread increase of Helios+Foxp3+ Tregs in both wild-type (WT) and rel-/- mice. These data suggest that exogenous IL-2 administration compensates for defective IL-2 production and reduced tTreg numbers in c-Rel deficient mice. Our findings reveal that c-Rel is essential for the generation of tTregs but not for that of pTregs and iTregs. PMID- 28881762 TI - Erectile dysfunction and the risk of prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed malignancy and the third leading cause of cancer death among men in developed countries. Because some risk factors are common between erectile dysfunction (ED) and PCa, we investigated the association between ED and subsequent PCa. METHODS: This nationwide population-based cohort study used data from the Taiwan National Health Insurance Research Database for the period 2000-2010. We identified patients newly diagnosed with ED by using codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. RESULTS: In total, 5858 and 23432 patients were enrolled in the ED and non-ED cohorts, respectively. After adjustment for age, sex, and comorbidities, the overall incidence densities of PCa were significantly higher in the ED cohort than in the non-ED cohort, with an adjusted hazard ratio (aHR) of 1.19. The age-specific relative risk of PCa was significantly higher for all age groups in the ED cohort than in the non-ED cohort. Compared with patients without ED, those with organic ED had a 1.27-fold higher risk of PCa. CONCLUSION: ED is a harbinger of PCa in some men. Physicians should consider the possibility of occult PCa in patients with ED regardless of age and comorbidities. PMID- 28881763 TI - TBX2 over-expression promotes nasopharyngeal cancer cell proliferation and invasion. AB - TBX2 is a member of the T box transcription factor family. Its expression and potential biological functions in nasopharyngeal cancer (NPC) cells are studied here. We showed that TBX2 mRNA and protein expression was significantly elevated in multiple human NPC tissues, as compared with that in adjacent normal tissues. Knockdown of TBX2 by targeted-siRNA significantly inhibited proliferation and invasion of NPC cells (CNE-1 and HONE-1 lines). Meanwhile, TBX2 knockdown also induced G1-phase cell cycle arrest. At the molecular level, we discovered that expressions of several tumor suppressor genes, including p21, p27, phosphatase with tensin homology (PTEN) and E-Cadherin, were increased dramatically after TBX2 knockdown in above NPC cells. Collectively, our results imply that TBX2 over expression promotes NPC cell proliferation and invasion, possibly via silencing several key tumor suppressor genes. PMID- 28881764 TI - Detection of nasopharyngeal carcinoma susceptibility with single nucleotide polymorphism analysis using next-generation sequencing technology. AB - Nasopharyngeal carcinoma (NPC) is a head and neck cancer with high incidence in South China and East Asia. To provide a theoretical basis for NPC risk screening and early prevention, we conducted a meta-analysis of relevant literature on the association of single nucleotide polymorphisms (SNP)s with NPC susceptibility. Further, expression of 15 candidate SNPs identified in the meta-analysis was evaluated in a cohort of NPC patients and healthy volunteers using next generation sequencing technology. Among the 15 SNPs detected in the meta analysis, miR-146a (rs2910164, C>G), HCG9 (rs3869062, A>G), HCG9 (rs16896923, T>C), MMP2 (rs243865, C>T), GABBR1 (rs2076483, T>C), and TP53 (rs1042522, C>G) were associated with decreased susceptibility to NPC, while GSTM1 (+/DEL), IL-10 (rs1800896, A>G), MDM2 (rs2279744, T>G), MDS1-EVI1 (rs6774494, G>A), XPC (rs2228000, C>T), HLA-F (rs3129055, T>C), SPLUNC1 (rs2752903, T>C; and rs750064, A>G), and GABBR1 (rs29232, G>A) were associated with increased susceptibility to NPC. In our case-control study, an association with increased risk for NPC was found for the AG vs AA genotype in HCG9 (rs3869062, A>G). In addition, heterozygous deletion of the GSTM1 allele was associated with increased susceptibility to NPC, while an SNP in GABBR1 (rs29232, G>A) was associated with decreased risk, and might thus have a protective role on NPC carcinogenesis. This work provides the first comprehensive assessment of SNP expression and its relationship to NPC risk. It suggests the need for well-designed, larger confirmatory studies to validate its findings. PMID- 28881765 TI - Mitral isthmus ablation using a circular mapping catheter positioned in the left atrial appendage as a reference for conduction block. AB - BACKGROUND: For perimitral atrial flutter (PMFL) developing after catheter ablation of atrial fibrillation (AF), to create a complete conduction block at the mitral isthmus (MI) is mandatory to terminate it, however, it is still challenging. METHODS: This study consisted of 80 patients (74 male, 61 +/- 8.1 years) undergoing MI ablation. After a circular mapping catheter was positioned at the neck of the left atrial appendage (LAA), the MI ablation was performed on the MI line just below the LAA neck targeting the earliest activation recording site of the LAA catheter during pacing from the coronary sinus (CS). When ablation during CS pacing was not successful, an RF delivery during LAA pacing was applied targeting the earliest activation site just below the MI line. If the endocardial approach failed, an RF application inside the CS was attempted. RESULTS: With the endocardial approach, acute success was achieved in 51/80 patients (64%). Additional epicardial ablation from the CS was performed in 26/29 (90%) endocardially unsuccessful patients and conduction block at the MI was achieved in 21/26 (81%). Overall, complete conduction block at the MI was achieved in 72/80 patients (90%). At a mean follow-up of 16 +/- 6 months, 20 patients (25%) had recurrence of atrial arrhythmias (AT: 12, AF: 8), and 10 (AT: 7, AF : 3) underwent a second procedure in which an LMI block line was completed in 3 (33%). PMFL was diagnosed in 6 out of 7 AT patients. No complications were observed. CONCLUSIONS: Creating linear lesions just beneath the neck of the LAA was highly successful under the guidance of a circular mapping catheter in the LAA using a steerable sheath. An RF application from the CS was needed in less than half of the cases. PMID- 28881766 TI - NFATc3 mediates the sensitivity of gastric cancer cells to arsenic sulfide. AB - Arsenic sulfide (As4S4) is the main component of Realgar which is widely used in traditional Chinese medicine. Previously we showed that As4S4 inhibited the proliferation of colon cancer cells through regulating nuclear factor of activated T cells (NFAT) pathway. Here we explore the role of NFAT in gastric cancer. We showed that As4S4 inhibited the expression of NFATc1, NFATc3, and NFATc4, and modulated the expression of NFATc2 accompanying with p53. The baseline expression of NFATc3 varied distinctly in gastric cancer cell lines (AGS, MGC803, MKN28, MKN45, and SGC7901) and the sensitivity of these cells to As4S4 was dissimilar, with AGS and MGC803 cells showing higher sensitivity while the SGC7901 cells relatively resistant. Interestingly, the sensitivity to As4S4 was correlated with the level of expression of NFATc3, and the cells relatively sensitivity just showing higher expression of NFATc3. Furthermore, NFATc3 expression was significantly higher in gastric cancer tissues compared with the adjacent normal tissues. Our data also showed that, NFATc3 promoted the proliferation of gastric cancer cells by regulating c-Myc. In conclusion, As4S4 inhibited the proliferation of gastric cancer cells through NFATc3/c-Myc pathway and the diverse sensitivity among different cell lines correlated with the expression level of NFATc3 indicating that NFATc3 may be a potential therapeutic target in gastric cancer. PMID- 28881767 TI - Transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model. AB - This project was undertaken to address a critical cancer biology question: Is overexpression of the pluripotency molecule Nanog sufficient to initiate tumor development in a somatic tissue? Nanog1 is critical for the self-renewal and pluripotency of ES cells, and its retrotransposed homolog, NanogP8 is preferentially expressed in somatic cancer cells. Our work has shown that shRNA mediated knockdown of NanogP8 in prostate, breast, and colon cancer cells inhibits tumor regeneration whereas inducible overexpression of NanogP8 promotes cancer stem cell phenotypes and properties. To address the key unanswered question whether tissue-specific overexpression of NanogP8 is sufficient to promote tumor development in vivo, we generated a NanogP8 transgenic mouse model, in which the ARR2PB promoter was used to drive NanogP8 cDNA. Surprisingly, the ARR2PB-NanogP8 transgenic mice were viable, developed normally, and did not form spontaneous tumors in >2 years. Also, both wild type and ARR2PB-NanogP8 transgenic mice responded similarly to castration and regeneration and castrated ARR2PB-NanogP8 transgenic mice also did not develop tumors. By crossing the ARR2PB-NanogP8 transgenic mice with ARR2PB-Myc (i.e., Hi-Myc) mice, we found that the double transgenic (i.e., ARR2PB-NanogP8; Hi-Myc) mice showed similar tumor incidence and histology to the Hi-Myc mice. Interestingly, however, we observed white dots in the ventral lobes of the double transgenic prostates, which were characterized as overgrown ductules/buds featured by crowded atypical Nanog expressing luminal cells. Taken together, our present work demonstrates that transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model. PMID- 28881768 TI - Downregulated long noncoding RNA ALDBGALG0000005049 induces inflammation in chicken muscle suffered from selenium deficiency by regulating stearoyl-CoA desaturase. AB - Long non-coding RNAs (lncRNAs) have been demonstrated to play a pivotal role in proliferation and differentiation of muscles. However, the study on the roles of lncRNAs in Selenium (Se) deficiency induced muscle injury is still unclear. In this study, deep sequencing was performed to profile lncRNAs and mRNAs of the muscles from the Se deficiency (-Se group) and control (C group) chickens. The results revealed that 38 lncRNAs (23 up-regulated and 15 down-regulated) and 687 mRNAs (285 up-regulated and 402 down-regulated) were significantly dysregulated expressed, and the significantly dysregulated pathway including Phagosome, Cardiac muscle contraction, and Peroxisome Proliferator-Activated Receptor (PPAR) in -Se group. The regulatory relationship between ALDBGALG0000005049 and stearoyl CoA desaturase (SCD), which involved in PPAR pathway was verified. The results also showed that the decreased expressions of SCD, PPARalpha, PPARbeta and PPARgamma, and the increased expressions of interleukin (IL)-1beta, IL-6, IL-8, and chemokine (C-C motif) ligand 4 (CCL4) along with silencing of ALDBGALG0000005049 in chicken myoblasts. Moreover, increased expressions of IL 1beta, IL-6, IL-8, and CCL4 and inflammatory cell infiltration in microstructure of chicken muscles treated with Se deficiency were observed. This study displayed an overview of aberrantly expressed lncRNAs and mRNAs profiles and PPAR pathway, and revealed that downregulation of ALDBGALG0000005049 caused inflammation by regulating SCD in chicken muscle resulted from Se deficiency. PMID- 28881769 TI - Middle-distance running acutely influences the concentration and composition of serum bile acids: Potential implications for cancer risk? AB - BACKGROUND: This study was aimed to investigate the acute effect of medium distance running on bile acids concentration and composition, in order to verify whether the positive impact of physical exercise on cancer risk may also be mediated by variation of bile acids concentration and composition in serum. METHODS: The concentration and composition of serum bile acids was analyzed in 30 middle-aged and healthy recreational athletes with a reference liquid chromatography-mass spectrometry technique, immediately before and shortly after the end of the running trial. The concentration of bile acids after the run was adjusted for plasma volume change. RESULTS: All athletes successfully completed the trial. After correction of values for the individual plasma volume change calculated after the run, the serum concentration of total bile acids was found to be significantly reduced by approximately 46%. A statistically significant decrease was observed for cholic, deoxycholic, chenodeoxycholic, ursodeoxycholic, glycoursodeoxycholic and hyodeoxycholic acids, whereas the concentration of the remaining compounds remained unvaried after the run. A considerable variation of bile acids profile was also observed. No significant association was found between running performance and variation of bile acids concentrations. CONCLUSION: These results show that middle distance running acutely decreases the concentration of total bile acids in serum, especially that of the more mutagenic and carcinogenic compounds, so providing an intriguing support to the favorable effects of physical exercise for lowering the risk of many gastrointestinal cancers. PMID- 28881770 TI - Toxicarioside O induces protective autophagy in a sirtuin-1-dependent manner in colorectal cancer cells. AB - Colorectal cancer is the most common cancer. It has high morbidity and mortality worldwide, and more effective treatment strategies need to be developed. Toxicarioside O (TCO), a natural product derived from Antiaris toxicaria, has been shown to be a potential anticancer agent. However, the molecular mechanisms involved remain poorly understood. In this study, our results demonstrated that TCO can induce both apoptosis and autophagy in colorectal cancer cells. Moreover, TCO-induced autophagy was due to the increase of the expression and activity of the enzyme sirtuin-1 (SIRT1), and subsequent inhibition of the Akt/mTOR pathway. Inhibition of SIRT1 activity by its inhibitor, EX-527, attenuated TCO-induced autophagy. Of interest, inhibition of autophagy by chloroguine, an autophagy inhibitor, enhanced TCO-induced apoptotic cell death, suggesting that autophagy plays a protective role in TCO-induced apoptosis. Together, these findings suggest that combination of TCO and autophagy inhibitor may be a novel strategy suitable for potentiating the anticancer activity of TCO for treatment of colorectal cancer. PMID- 28881771 TI - Prediction of EGFR and KRAS mutation in non-small cell lung cancer using quantitative 18F FDG-PET/CT metrics. AB - This study investigated the relationship between epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in non small-cell lung cancer (NSCLC) and quantitative FDG-PET/CT parameters including tumor heterogeneity. 131 patients with NSCLC underwent staging FDG-PET/CT followed by tumor resection and histopathological analysis that included testing for the EGFR and KRAS gene mutations. Patient and lesion characteristics, including smoking habits and FDG uptake parameters, were correlated to each gene mutation. Never-smoker (P < 0.001) or low pack-year smoking history (p = 0.002) and female gender (p = 0.047) were predictive factors for the presence of the EGFR mutations. Being a current or former smoker was a predictive factor for the KRAS mutations (p = 0.018). The maximum standardized uptake value (SUVmax) of FDG uptake in lung lesions was a predictive factor of the EGFR mutations (p = 0.029), while metabolic tumor volume and total lesion glycolysis were not predictive. Amongst several tumor heterogeneity metrics included in our analysis, inverse coefficient of variation (1/COV) was a predictive factor (p < 0.02) of EGFR mutations status, independent of metabolic tumor diameter. Multivariate analysis showed that being a never-smoker was the most significant factor (p < 0.001) for the EGFR mutations in lung cancer overall. The tumor heterogeneity metric 1/COV and SUVmax were both predictive for the EGFR mutations in NSCLC in a univariate analysis. Overall, smoking status was the most significant factor for the presence of the EGFR and KRAS mutations in lung cancer. PMID- 28881772 TI - High-resolution dynamic imaging and quantitative analysis of lung cancer xenografts in nude mice using clinical PET/CT. AB - Considering the general application of dedicated small-animal positron emission tomography/computed tomography is limited, an acceptable alternative in many situations might be clinical PET/CT. To estimate the feasibility of using clinical PET/CT with [F-18]-fluoro-2-deoxy-D-glucose for high-resolution dynamic imaging and quantitative analysis of cancer xenografts in nude mice. Dynamic clinical PET/CT scans were performed on xenografts for 60 min after injection with [F-18]-fluoro-2-deoxy-D-glucose. Scans were reconstructed with or without SharpIR method in two phases. And mice were sacrificed to extracting major organs and tumors, using ex vivo gamma-counting as a reference. Strikingly, we observed that the image quality and the correlation between the all quantitive data from clinical PET/CT and the ex vivo counting was better with the SharpIR reconstructions than without. Our data demonstrate that clinical PET/CT scanner with SharpIR reconstruction is a valuable tool for imaging small animals in preclinical cancer research, offering dynamic imaging parameters, good image quality and accurate data quatification. PMID- 28881773 TI - Apatinib inhibits VEGFR-2 and angiogenesis in an in vivo murine model of nasopharyngeal carcinoma. AB - Angiogenesis is initiated by the activation of the vascular epidermal growth factor receptor-2 (VEGFR-2) by the vascular epidermal growth factor (VEGF) ligand. Overexpression of VEGFR-2 increases the growth of nasopharyngeal carcinomas (NPC). Apatinib (YN968D1) is a highly-selective inhibitor of VEGFR-2, but its effects on NPC have not been hitherto investigated. In the present study, CNE-2 NPC cells were xenografted into 132 nude mice, which were treated with one of 6 drug regimens of apatinib administered alone or in combination with cisplatin (DDP). The impact of treatment regimens on the growth, microvascularization, apoptosis, and metabolic response of tumors, as well as mouse survival was determined by histopathology, immunohistochemistry (VEGFR-2 and CD31), terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL), micro 18F-FDG PET/CT imaging and survival curves. Administration of apatinib alone inhibited tumor growth, reduced microvascular density, and facilitated the apoptosis of tumors. Tumors treated simultaneously with apatinib and cisplatin exhibited significantly-increased inhibition of tumor growth, prolonged survival time, decreased expression of VEGFR-2, reduced microvascular density, and frequency of apoptosis over standalone and sequential administration therapy. Tumors treated simultaneously with apatinib and cisplatin had the lowest uptake of FDG. Taken together, the simultaneous administration of apatinib and cisplatin improves the therapeutic efficacy over standalone treatments, which also led to improved efficacy over sequential administration regimens. VEGFR-2 is an important predictive marker for efficacy of apatinib treatment of NPC. PMID- 28881774 TI - Chromatin remodeling modulates radiosensitivity of the daughter cells derived from cell population exposed to low- and high-LET irradiation. AB - Radiation effects are dependent of linear energy transfer (LET), but it is still obscure whether the daughter cells (DCs) derived from irradiated population are radioresistance and much less the underlying mechanism. With the measurements of survival, proliferation and gammaH2AX foci, this study shows that the DCs from gamma-ray irradiated cells (DCs-gamma) became more radioresistant than its parent control without irradiation, but the radiosensitivity of DCs from alpha-particle irradiated cells (DCs-alpha) was not altered. After irradiation with equivalent doses of gamma-rays and alpha-particles, the foci number of histone H3 lysine 9 dimethylation (H3K9me3) and the activity of histone deacetylase (HDAC) in DCs gamma was extensively higher than these in DCs-alpha and its parent control, indicating that a higher level of heterochromatin was formed in DCs-gamma but not in DCs-alpha. Treatment of cells with SAHA (an inhibitor of HDAC) decreased the level of heterochromatin domains by inhibiting the expressions of H3K9m3 and HP 1a proteins and triggering the expression of acetylated core histone H3 (Ac-H3). When cells were treated with SAHA, the radioresistance phenotype of DCs-gamma was eliminated so that the radiosensitivities of DCs-gamma, DCs-alpha and their parent cells approached to same levels. Our current results reveal that gamma rays but not alpha-particles could induce chromatin remodeling and heterochromatinization which results in the occurrence of radioresistance of DCs, indicating that the combination treatment of irradiation and HDAC inhibitor could serve as a potential cancer therapy strategy, especially for the fraction radiotherapy of low-LET irradiation. PMID- 28881775 TI - Uridine diphosphate-glucuronosyltransferase 2B15 D85Y gene polymorphism is associated with lower prostate cancer risk: a systematic review and meta analysis. AB - UGT2B15 (uridine diphosphate-glucuronosyltransferase 2B15) catalyzes the conversion of lipophilic C19 steroid androgens such as dihydrotestosterone (DHT) into water-soluble metabolites that can be excreted. Studies of the association between the UGT2B15 gene D85Y polymorphism and prostate cancer have yielded contradictory results. We therefore systematically searched in the PubMed, EMBASE, Science Direct/Elsevier, CNKI, and Cochrane Library databases, and identified six relevant studies with which to perform a meta-analysis of the relation between UGT2B15 D85Y polymorphism and prostate cancer risk. Our meta analysis revealed a significant association between UGT2B15 D85Y gene polymorphism and prostate cancer in all genetic models (P<0.05). The combined odds ratios and 95% confidence intervals were as follows: additive model, 0.53 and 0.32-0.88; dominant model, 0.51 and 0.33-0.79; recessive model, 0.76 and 0.60 0.96; co-dominant model, 0.55 and 0.35-0.86; and allele model, 0.70 and 0.55 0.89. These results are consistent with the idea that the UGT2B15 D85Y enzyme variant reduces the risk of prostate cancer by efficiently metabolizing dihydrotestosterone (DHT), which is associated with prostate cancer progression. PMID- 28881776 TI - Changing trends in the prevalence of anencephaly in Liaoning province of Northeast China from 2006-2015: data from a population-based birth defects registry. AB - The goal of this study was to assess the prevalence and trends of anencephaly on the basis of a large population-based cases identified by the Liaoning Birth Defects Registry, which included 14 cities over a 10-year period. Anencephaly prevalence, percent change, average changeand the contribution rates of each city were calculated. Statistical analysis was undertaken on the basis of a Poisson regression model. A total of 1600 anencephaly cases were collected during the observational period (4.92/10,000 live births). On average, the prevalence decreased 10.15% each year; this overall time trend was statistically significant (P<0.01). The top three leading cities were Huludao (10.33 per 10,000 live births), Chaoyang (8.56 per 10,000 live births) and Fuxin (6.36 per 10,000 live births). In contrast, Anshan (2.64 per 10,000 live births), Dalian (2.79 per 10,000 live births) and Yingkou (3.46 per 10,000 live births) were the cities with the lowest prevalence. Of note, significantly decreasing trends were observed in half of these cities (n=7). Additionally, Benxi, Yingkou and Dalian were the major cities contributing to over one third of the decreasing trend in Liaoning province. In conclusion, this study provided evidence of the decreasing prevalence of anencephaly from 2006 to 2015 in Liaoning province. In the future, prevention efforts should be strengthened to further reduce the risk of anencephaly in areas with high rates. PMID- 28881777 TI - OVA12 promotes tumor growth by regulating p53 expression in human cancer cells. AB - Ovarian cancer-associated antigen 12 (OVA12) was first identified in an ovarian carcinoma complementary DNA (cDNA) expression library and has been shown to play an important role in tumor growth. Here, we found that overexpression of OVA12 accelerated tumor growth in different tumor cells, whereas OVA12 depletion was associated with the opposite effect. Moreover, knocking down OVA12 led to a significant increase in the protein levels of p53, and the overexpression of OVA12 significantly decreased endogenous p53 levels. In addition, OVA12 stimulated p53 polyubiquitination and degradation by the proteasome and promoted tumor growth at least partially through the p53 pathway. Taken together, these results indicate that OVA12 is a negative regulator of p53 and that inhibition of OVA12 expression might serve as a therapeutic target to restore tumor suppression. PMID- 28881778 TI - Treatment of hepatocellular carcinoma with a GPC3-targeted bispecific T cell engager. AB - There are limited strategies for the treatment of hepatocellular carcinoma (HCC). In this study, we prepared a Bispecific T cell engager (BiTE) targeting Glypican 3 (GPC3) and CD3. The GPC3/CD3 BiTE was prepared by fusing the single-chain variable fragment (scFv) of the humanized anti-GPC3 antibody (9F2) with the scFv of the anti-CD3 antibody (OKT3). The in vitro and in vivo cytotoxic activities of the GPC3/CD3 BiTE were evaluated against various HCC cell lines. The GPC3/CD3 BiTE could efficiently mediate the T cell killing of GPC3-positive HCC in vitro, which was dependent on GPC3 expression on the surface of HCC cells. Moreover, our study indicates that, in the presence of the GPC3/CD3 BiTE, T cells could efficiently destroy GPC3-positive human HCC cells in vitro and in vivo. Additionally, our study further proved that GPC3 is not expressed in normal tissues. Thus, GPC3 may be a cancer-specific antigen. Collectively, these findings suggest that this anti-GPC3 BiTE might be a promising anti-tumor reagent for patients with GPC3-positive HCC. PMID- 28881779 TI - The anti-ErbB2 antibody H2-18 and the pan-PI3K inhibitor GDC-0941 effectively inhibit trastuzumab-resistant ErbB2-overexpressing breast cancer. AB - Trastuzumab, an anti-ErbB2 humanized antibody, brings benefit to patients with ErbB2-amplified metastatic breast cancers. However, the resistance to trastuzumab is common. Our previously reported H2-18, an anti-ErbB2 antibody, potently induced programmed cell death in trastuzumab-resistant breast cancer cells. Here, we aim to investigate the antitumor efficacy of H2-18 in combination with the pan PI3K inhibitor GDC-0941 in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and GDC-0941 synergistically inhibited the in vitro proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cells. H2-18 plus GDC-0941 showed significantly enhanced programmed cell death-inducing activity compared with each drug used alone. The combination of H2-18 and GDC 0941 did not increase the effect of single agent on ROS production, cell cycle and ErbB2 signaling. Importantly, the in vivo antitumor efficacy of H2-18 plus GDC-0941 was superior to that of single agent. Thus, the enhanced in vivo antitumor efficacy of H2-18 plus GDC-0941 may mainly be attributable to its increased programmed cell death-inducing activity. Collectively, H2-18 plus GDC 0941 could effectively inhibit tumor growth, suggesting the potential to be translated into clinic as an efficient strategy for ErbB2-overexpressing breast cancers. PMID- 28881780 TI - PD-L1: a novel prognostic biomarker in head and neck squamous cell carcinoma. AB - BACKGROUND: The PD-1 receptor and its ligands PD-L1 and PD-L2 are known to be significantly involved in T-cell regulation. Recent studies suggest that PD-L1 expression in malignant tumors contributes to an immunosuppressive microenvironment and disruption of antitumoral immune response. Drugs targeting this pathway are already tested in clinical trials against several tumor entities with promising results. However, until now comprehensive data with regard to PD L1 and PD-L2 expression in head and neck squamous cell carcinoma (HNSCC) is still lacking. PATIENTS AND METHODS: We assessed PD-L1 and PD-L2 expression via immunohistochemistry in two independent cohorts of 293 HNSCC patients. RESULTS: A significant subset of HNSCC showed high expression levels of PD-L1. Most remarkable, we detected a strong correlation between PD-L1 expression and overall survival time in both HNSCC cohorts. Further, in multivariate cox proportional hazard models, PD-L1 dominates as the strongest prognostic factor of patient's outcome in HNSCC, leaving even tumor stage and distant metastasis behind. Moreover, strong PD-L1 expression was associated with the presence of distant metastases in a subset of cases. CONCLUSIONS: In summary, while the significance of PD-L2 in HNSCC seems to minor, we show that PD-L1 expression is common in HNSCC and, more importantly, a both robust and strong prognostic biomarker. In this respect, our results provide hints on further application of therapies targeting the PD-1/PD-L1 pathway in HNSCC. Investigation of response and outcome of patients receiving anti-PD-1/PD-L1 containing therapies in correlation with PD L1 expression analysis should be an important task for the future. STATEMENT OF TRANSLATIONAL RELEVANCE: In spite of improved treatment options and increasing knowledge of molecular alterations in HNSCC, the survival rate has not been dramatically changed in the past decades. Pies are missing in HNSCC. One promising candidate in cancer immune therapy is PD-L1. Drugs targeting PD-L1 or its receptor PD-1 are subject of several clinical studies in different cancer entities. However, comprehensive data about PD-L1 expression in HNSCC and therefore a rational basis for anti PD-L1/PD-1 therapy in HNSCC is lacking. Here, we provide wide-ranging data about PD-L1 expression in HNSCC of all major localizations. We observed a strong correlation between expression of PD-L1 and reduced overall survival time. Furthermore, high PD-L1 expression was identified as a strong prognostic factor of patient's outcome when verified together with recognized prognostic factors. PMID- 28881781 TI - Twist1 confers multidrug resistance in colon cancer through upregulation of ATP binding cassette transporters. AB - Multidrug resistance is a major problem in colon cancer treatment. However, its molecular mechanisms remain unclear. Recently, the epithelial-mesenchymal transition (EMT) in anticancer drug resistance has attracted increasing attention. This study investigated whether vincristine treatment induces EMT and promotes multidrug resistance in colon cancer. The result showed that vincristine treatment increases the expression of several ATP-binding cassette transporters in invasive human colon adenocarcinoma cell line (HCT-8). Vincristine-resistant HCT-8 cells (HCT-8/V) acquire a mesenchymal phenotype, and thus its migratory and invasive ability are increased both in vitro and in vivo. The master transcriptional factors of EMT, especially Twist1, were significantly increased in the HCT-8/V cell line. Moreover, the ectopic expression of Twist1 increased the chemoresistance of HCT-8 cells to vincristine and increased the expression levels and promoter activities of ABCB1 and ABCC1. Furthermore, Twist1 silencing reverses the EMT phenotype, enhances the chemosensitivity of HCT-8/ V cells to anticancer agents in vitro and in vivo, and downregulates the expression of ABCB1 and ABCC1. Twist1-mediated promotion of ABCB1 and ABCC1 expression levels plays an important role in the drug resistance of colon cancer cells. PMID- 28881782 TI - miR-106b regulates the 5-fluorouracil resistance by targeting Zbtb7a in cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma (CCA) is highly resistant to chemo-therapy, including 5-fluorouracil (5-FU) treatment. MicroRNAs are endogenous and short non coding RNAs that can regulate multiple genes expression. Many microRNAs have shown functional roles in the chemo-resistance of tumors. Here, we examined the relationship between microRNAs expression and the sensitivity of CCA cells to 5 FU. METHODS: Microarray analysis was used to determine the aberrantly expressed microRNAs in two 5-FU resistant CCA cell lines, KKU-M139 and KKU-M214 cells. To determine the effect of candidate microRNAs on 5-FU sensitivity, expression of candidate was modified via either transfection of a microRNA mimic or transfection of an antagonist. Ontology-based programs were also used to investigate the potential targets of microRNAs that were confirmed to affect the 5-FU sensitivity of CCA cells. RESULTS: The microRNA-106b (miR-106b) was significantly down-regulated in 5-FU resistant CCA cells. Instead, over expression of miR-106b could re-sensitize resistant CCA cells to 5-FU through down-regulation of Zbtb7a. Moreover, decreased expression of miR-106b is related to poor prognosis in patients with CCA, suggesting its potential role as a new prognostic marker in CCA. CONCLUSION: Our study demonstrates that miR-106b can reverse 5-FU resistance via Zbtb7a suppression, thus offer a novel and powerful strategy for CCA chemotherapy. PMID- 28881783 TI - Effect and mechanism of inhibition of PI3K/Akt/mTOR signal pathway on chronic neuropathic pain and spinal microglia in a rat model of chronic constriction injury. AB - OBJECTIVE: To explore the effects of inhibition of PI3K/Akt/mTOR signal pathway on chronic neuropathic pain (CNP) and spinal microglia in a rat model of chronic constriction injury (CCI). METHODS: Male SD rats were assigned into control, sham, CCI, wortmannin, dimethyl sulfoxide (DMSO) and wortmannin-positive control groups. Paw withdrawal mechanical threshold (PWMT) and thermal withdrawal latency (TWL) were recorded. qRT-PCR and Western blotting were used to detect PI3K, Akt and mTOR expressions and their phosphorylation. OX-4 expression was detected by immunohistochemistry and glial fibrillary acidic protein (GFAP) and nerve growth factor (NGF) expressions by immunofluorescence. RESULTS: PWMT and TWL decreased in the CCI group than in the sham group on the 7th and 14th day after operation. Compared with the control and sham groups, the CCI group showed increased PI3K, Akt and mTOR mRNA expressions and elevated PI3K, p-Akt, p-mTOR and P70S6K protein expressions. More OX-42-positive cells and higher integrated optical density (IOD) of GFAP and NGF were found in the CCI group than the sham group at the 14th day after operation. Compared with the DMSO group, the wortmannin group had higher PWMT and TWL, decreased PI3K, Akt and mTOR mRNA expressions and reduced PI3K, p-Akt, p-mTOR and P70S6K protein expressions. Less OX-42-positive cells and lower IOD of GFAP and NGF were found in the wortmannin group than the DMSO group 14th day after operation. CONCLUSION: Inhibition of PI3K/Akt/mTOR signal pathway may alleviate CNP and reduce microglia and GFAP and NGF expressions in marrow in a rat model of CCI. PMID- 28881784 TI - Selective Inhibitors of Nuclear Export (SINE) compounds block proliferation and migration of triple negative breast cancer cells by restoring expression of ARRDC3. AB - Arrestin-related domain-containing protein-3 (ARRDC3) is one of 6 mammalian arrestins, which suppresses metastasis by inducing degradation of phosphorylated beta2-adrenergic receptor (beta2 AR) and integrin beta4 (ITG beta4). Our previous studies demonstrated that expression of ARRDC3 is epigentically silenced in Triple Negative Breast Cancer (TNBC) cells, and the forced expression of ARRDC3 significantly reduced the invasive potential of TNBC cells. In the current study, we found that Selective Inhibitors of Nuclear Export (SINE) compounds (KPT-185 and selinexor (KPT-330)) restore ARRDC3 expression in TNBC cell lines (MDA-MB-231 and MDA-MB-468) at both the mRNA and protein level in a dose and time course dependent manner. SINE compounds inhibit the proliferation, pro-invasive migration and anchorage independent growth of the TNBC cells by restoring ARRDC3 expression. We found that ARRDC3 expression is lower in TNBC cell lines than those of luminal breast cancer cell lines, and inversely correlated with IC50s of selinexor. Analysis of tissue microarray confirmed that ARRDC3 expression in patient samples is significantly lower in the majority of TNBC tumors relative to normal tissue. In vivo, selinexor inhibited the tumor growth of MDA-MB-231 xenografts by nearly 100% compared with vehicle treated animals. Furthermore, immunohistochemical analysis of TNBC tumors from selinexor treated mice revealed increased ARRDC3 expression versus vehicle treated animals. Our results suggest that restoration of ARRDC3 expression is an important antineoplastic mechanism of SINE compounds in TNBC, and therefore selinexor could be an effective treatment option for breast tumors with down-regulated ARRDC3. PMID- 28881785 TI - MiR-486-5p negatively regulates oncogenic NEK2 in hepatocellular carcinoma. AB - NEK2 is a member of the NIMA-related family of serine/threonine centrosomal kinases. We analyzed the relationship between differential expression of NEK2 and hepatocellular carcinoma (HCC) patient outcomes after liver transplants. We also studied the microRNAs that affect NEK2 expression. Analysis of multiple microarrays in the Oncomine database revealed that NEK2 expression was higher in HCC tissues than adjacent normal liver tissues. High NEK2 expression correlated with tumor size, pathological grade and macro- and microvascular invasion. Consequently, patients exhibiting high NEK2 expression had poorer prognosis. This was corroborated by our multivariate analysis that showed NEK2 to be an independent prognostic factor for HCC patient survival. Further, high NEK2 expression promoted proliferation, colony formation, migration and invasion of HCC cell lines. Tumor xenograft data from Balb/c nude mice demonstrated that HCC cells with high NEK2 expression formed larger tumors than those with low NEK2 expression. Finally, we showed that miR-486-5p suppressed NEK2 by directly binding to its transcript 3'UTR. We also demonstrated an inverse relationship between miR-486-5p and NEK2 expression in HCC patients. These findings suggest miR-486-5p negatively regulates NEK2, which is a critical prognostic indicator of HCC patient survival after liver transplantation. PMID- 28881786 TI - TUSC3 induces autophagy in human non-small cell lung cancer cells through Wnt/beta-catenin signaling. AB - We investigated the effects of tumor suppressor candidate 3 (TUSC3) on autophagy in human non-small cell lung cancer (NSCLC) cells. A total of 118 NSCLC patients (88 males and 30 females) who underwent surgery at our institute were enrolled in the study. Immunohistochemical analysis revealed that TUSC3 protein expression was lower in NSCLC specimens than adjacent normal tissue. Correspondingly, there was greater methylation of TUSC3 in NSCLC than adjacent normal tissue. After transient transfection of A549 NSCLC cells with constructs designed to up regulate or down-regulate TUSC3 expression, we analyzed the effects of inhibiting the Wnt pathway (XAV939) and autophagy (chloroquine, CQ) on the behavior of NSCLC cells. We also performed TOP/FOP-Flash reporter assays, MTT assays, Annexin V FITC/propidium iodide staining, and acridine orange staining to evaluate Wnt/beta catenin signaling, cell proliferation, apoptosis, and autophagy, respectively. Expression of Wnt/beta-catenin pathway components and autophagy-related proteins was analyzed using qRT-PCR and Western blotting. We found that TUSC3 inhibited cell proliferation and promoted both apoptosis and autophagy in A549 cells. In addition, TUSC3 increased expression of autophagy-related proteins. It also increased expression of Wnt/beta-catenin signaling pathway components and promoted nuclear transfer of beta-catenin, resulting in activation of Wnt/beta catenin signaling. TUSC3 thus induces autophagy in human NSCLC cells through activation of the Wnt/beta-catenin signaling pathway. PMID- 28881787 TI - Mitochondrial DNA sequencing and large-scale genotyping identifies MT-ND4 gene mutation m.11696G>A associated with idiopathic oligoasthenospermia. AB - Genetic variants of mitochondrial DNA (mtDNA) were implicated to be associated with male infertility. Our previous whole mitochondrial genome sequencing and association study has identified two susceptibility mtDNA variants for oligoasthenospermia in Han Chinese men. In this study, we tested promising associations in an extended validation using 670 idiopathic oligoasthenospermia cases and 793 healthy controls to identify additional risk variants. We found that the genetic variant of m.11696G>A showed significantly higher frequency in the case group than that in the control group (odds ratio (OR) 2.21, 95% CI 1.21 4.04) (P=7.90*10-3). To elucidate the exact role of the genetic variants in spermatogenesis, two main sperm parameters (sperm count and motility) were taken into account. We found that m.11696G>A was associated with low sperm motility, with the OR of 2.38 (95 % CI 1.27-4.46) (P =5.22*10-3). These results advance our understanding of the genetic susceptibility to oligoasthenospermia and more functional studies are needed to provide insights into its pathogenic mechanism. PMID- 28881788 TI - miR-133b down-regulates ABCC1 and enhances the sensitivity of CRC to anti-tumor drugs. AB - Multidrug resistance (MDR) is the main cause of failed chemotherapy treatments. Therefore, preventing MDR is pivotal in treating colorectal cancer (CRC). In a previous study miR-133b was shown to be a tumor suppressor. Additionally, in CRC cells transfected with miR-133b, ATP-binding cassette (ABC) subfamily C member 1(ABCC1) was shown to be significantly down regulated. Whether miR-133b also enhances the chemosensitivity of drugs used to treat CRC by targeting ABCC1 is still unclear. Here, we utilized flow cytometry and high-performance liquid chromatography (HPLC) analysis to identify the ability of miR-133b to reserve MDR in CRC. We then used a dual-luciferase reporter assay to validate that miR-133b targets ABCC1. Further in vivo experiments were designed to validate the method in which miR-133b reversed MDR in CRC cells. The results demonstrated that the level of miR-133b was down-regulated and the expression of ABCC1 was up-regulated in drug-resistant CRC cells compared to non-drug-resistant CRC cells. The restoration of miR-133b expression in CRC drug-resistant cells in vitro resulted in reduced IC50s to chemotherapeutic drugs, significantly induced G1 accumulation, inhibited growth and promoted necrosis in combination with either 5 fluorouracil (5-FU) or vincristine (VCR), and decreased the expression of ABCC1. The dual-luciferase assay demonstrated that miR-133b directly targets ABCC1. The combination of agomiRNA-133b with chemotherapeutic drugs in vivo inhibited tumor growth induced by CRC drug-resistant cells. A xenograft from the in vivo model resulted in up-regulated levels of miR-133b and down-regulated levels of ABCC1. Therefore, miR-133b enhances the chemosensitivity of CRC cells to anti-tumor drugs by directly down-regulating ABCC1. This discovery provides a therapeutic strategy in which miR-133b is used as a potential sensitizer for drug-resistant CRC. PMID- 28881790 TI - MicroRNA profiles involved in trifluridine resistance. AB - Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil, which is approved for the treatment of patients with metastatic colorectal cancer refractory to standard chemotherapies. A microRNA analysis of three colorectal cell lines was conducted to investigate causes of FTD resistance. Drug resistant sublines of DLD-1, HCT-116, and RKO cells were developed by continuous administration of increasing doses of FTD for 5 months. The let-7d-5p gene, which maps to chromosome 9q22.32, was downregulated in the FTD-resistant DLD-1 sublines. DLD-1 cells became more resistant to FTD when let 7d-5p was knocked down and more sensitive when let-7d-5p was overexpressed. The FTD-resistant sublines were not cross-resistant to 5-fluorouracil (5-FU); 5-FU sensitivity was affected only slightly when let-7d-5p as overexpressed or knocked down. These data indicate that let-7d-5p increases sensitivity of FTD but not 5 FU and that let-7d-5p is a potential clinical marker of treatment sensitivity. PMID- 28881789 TI - Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation. DNA was extracted from cultured PEC from idiopathic PAH (n = 11), heritable PAH (n = 10) and controls (n = 18). DNA methylation was assessed using the Illumina HumanMethylation450 Assay. After normalization, samples and probes were clustered according to their methylation profile. Differential clusters were functionally analyzed using bioinformatics tools. Unsupervised hierarchical clustering allowed the identification of two clusters of probes that discriminates controls and PAH patients. Among 147 differential methylated promoters, 46 promoters coding for proteins or miRNAs were related to lipid metabolism. Top 10 up and down-regulated genes were involved in lipid transport including ABCA1, ABCB4, ADIPOQ, miR-26A, BCL2L11. NextBio meta-analysis suggested a contribution of ABCA1 in PAH. We confirmed ABCA1 mRNA and protein downregulation specifically in PAH PEC by qPCR and immunohistochemistry and made the proof-of-concept in an experimental model of the disease that its targeting may offer novel therapeutic options. In conclusion, DNA methylation analysis identifies a set of genes mainly involved in lipid transport pathway which could be relevant to PAH pathophysiology. PMID- 28881791 TI - Dipeptidyl peptidase 4 inhibitor use is associated with a lower risk of incident acute kidney injury in patients with diabetes. AB - OBJECTIVES: Dipeptidyl peptidase 4 inhibitor (DPP4i) use potentially slows the progression of diabetic kidney disease, but its effects on the risk of acute kidney injury (AKI) are unclear. We aimed to assess the association between DPP4i use and incident AKI episodes from a nationally representative cohort in Taiwan. MATERIALS AND METHODS: All patients newly diagnosed with diabetes mellitus (DM) between 2008, when DPP4i use was first approved in Taiwan, and mid-2013 were enrolled. Propensity score-matched diabetic DPP4i users, who received DPP4i for at least 90 days, and nonusers were selected. The primary and secondary outcomes were incident AKI and dialysis-requiring AKI during follow-up. Cox proportional hazard analyses were performed to examine the effect of DPP4i on the risk of AKI. RESULTS: We enrolled 923,936 diabetic patients; of these, 83,638 DPP4i users (75.7% sitagliptin, 14.6% vildagliptin, and 9.7% saxagliptin) were propensity score-matched to 83,638 non-users. After an average 3.6-year follow-up, 1.56% and 0.35% of DPP4i users and 2.53% and 0.56% of non-users developed incident AKI and dialysis-requiring AKI, respectively. DPP4i use was significantly associated with lower risk of incident AKI (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.53-0.61) and risk of dialysis-requiring AKI (HR 0.57, 95% CI 0.49-0.66). The risk reduction was consistent regardless of DPP4i type, the presence of chronic kidney disease, the previous acute kidney injury, and age. CONCLUSIONS: DPP4i use is associated with reduced risk of mild and severe forms of AKI among patients with incident DM. DPP4i may be an important class of anti-glycaemic agent with reno-protective effects. PMID- 28881792 TI - Long working hours, job satisfaction, and depressive symptoms: a community-based cross-sectional study among Japanese employees in small- and medium-scale businesses. AB - Although long working hours have been suspected to be a risk factor for depressive symptoms (DS), it is not well understood the conditions under which long working hours are associated with it. This study investigated the moderating effect of job satisfaction on the relationship between working hours and DS. A total of 2,375 full-time non-shift day workers (73% men), aged 18-79 (mean 45) years, in 296 small- and medium-scale businesses were surveyed using a self administered questionnaire evaluating working hours, job satisfaction, DS and covariates. The Center for Epidemiologic Studies Depression scale (CES-D) was used to assess DS. Risk of DS (CES-D >= 16) by working hours, job satisfaction, and both combined was estimated by multivariable logistic regression analysis. Compared to participants working 6-8 hrs/day, those working 12+ hrs/day had significantly higher odds of DS (adjusted odds ratio [aOR] 1.49), while participants with low satisfaction, as opposed to high satisfaction, had increased odds of DS (aOR 1.81). Furthermore, compared to those working 6-8 hrs/day with high satisfaction (reference group), participants working 6-8 hrs/day, > 8 to 10 hrs/day, and > 10 hrs/day combined with low satisfaction had dose-response increase of DS (aOR 1.48, 2.21 and 2.31, respectively, p < 0.05), whereas those working > 8 to 10 hrs/day and > 10 hrs/day combined with high satisfaction had not (aOR 0.93 and 1.39, respectively, p > 0.10). The results suggest that long working hours are associated with increased risk of DS only under reduced job satisfaction condition, which highlights the importance of improving job satisfaction, particularly among those working excessive hours. PMID- 28881793 TI - Lenalidomide increases human dendritic cell maturation in multiple myeloma patients targeting monocyte differentiation and modulating mesenchymal stromal cell inhibitory properties. AB - The use of Lenalidomide (LEN), to reverse tumor-mediated immune suppression and amplify multiple myeloma-specific immunity is currently being explored. Particularly, LEN effects on dendritic cells (DCs) are still unclear. In this study, we investigated the potential effect of LEN on DC differentiation and activity. DCs were differentiated either from CD14+ cells obtained from patients with multiple myeloma or from a human monocytic cell line. LEN, at the concentration range reached in vivo, significantly increased the median intensity expression of HLA-DR, CD86 and CD209 by DCs derived from both bone marrow and peripheral myeloma monocytes and enhanced the production of Interleukin-8, C-C motif chemokine ligand (CCL) 2, CCL5 and tumor necrosis factor-alpha. Consistently, LEN pre-treated DCs showed an increased ability to stimulate autologous CD3+ cell proliferation. LEN effect on dendritic differentiation was associated with the degradation of the Cereblon-related factors Ikaros and Aiolos. Moreover, we showed that LEN also blunted mesenchymal stromal cell inhibitory effect on dendritic differentiation, inhibiting Casein Kinase-1alpha levels. Finally, in vitro data were confirmed in ex vivo cultures obtained from relapsed myeloma patients treated with LEN, showing a significant increase of DC differentiation from peripheral blood monocytes. In conclusion, LEN increased the expression of mature dendritic markers both directly and indirectly and enhanced DC ability to stimulate T cell proliferation and to release chemokines. This suggests a new possible mechanism by which LEN could exert its anti-myeloma activity. PMID- 28881794 TI - Enhanced efficacy of AKT and FAK kinase combined inhibition in squamous cell lung carcinomas with stable reduction in PTEN. AB - Squamous cell lung carcinoma (SCC) accounts for 30% of patients with NSCLC and to date, no molecular targeted agents are approved for this type of tumor. However, recent studies have revealed several oncogenic mutations in SCC patients, including an alteration of the PI3K/AKT pathway, i.e. PI3K point mutations and amplification, AKT mutations and loss or reduced PTEN expression. Prompted by our observation of a correlation between PTEN loss and FAK phosphorylation in a cohort of patients with stage IV SCC, we evaluated the relevance of PTEN loss in cancer progression as well as the efficacy of a new combined treatment with the pan PI3K inhibitor buparlisip and the FAK inhibitor defactinib. An increase in AKT and FAK phosphorylation, associated with increased proliferation and invasiveness, paralleled by the acquisition of mesenchymal markers, and overexpression of the oncomir miR-21 were observed in SKMES-1-derived cell clones with a stable reduction of PTEN. Notably, the combined treatment induced a synergistic inhibition of cell proliferation, and a significant reduction in cell migration and invasion only in cells with reduced PTEN. The molecular mechanisms underlying these findings were unraveled using a specific RTK array that showed a reduction in phosphorylation of key kinases such as JNK, GSK-3 alpha/beta, and AMPK-alpha2, due to the concomitant decrease in AKT and FAK activation. In conclusion, the combination of buparlisib and defactinib was effective against cells with reduced PTEN and warrants further studies as a novel therapeutic strategy for stage IV SCC patients with loss of PTEN expression. PMID- 28881795 TI - RNase alleviates neurological dysfunction in mice undergoing cardiac arrest and cardiopulmonary resuscitation. AB - Cardiac arrest (CA) is one of the leading lethal factors. Despite cardiopulmonary resuscitation (CPR) procedure has been consecutively improved and lots of new strategies have been developed, neurological outcome of the patients experienced CPR is still disappointing. Ribonuclease (RNase) has been demonstrated to have neuroprotective effects in acute stroke and postoperative cognitive impairment, possibly through acting against endogenous RNA that released from damaged tissue. However, the role of RNase in post-cardiac arrest cerebral injury is unknown. In the present study, we investigated the role of RNase in neurological outcome of mice undergoing 5 minutes of CA and followed by CPR. RNase or the same dosage of normal saline was administrated. We found that RNase administration could: 1) improve neurologic score on day 1 and day 3 after CA/CPR performance; 2) improve memory and learning ability on day 3 after training in contextual fear conditioning test; 3) reduce extracellular RNA (exRNA) level in plasma and hippocampus tissue, and hippocampal cytokines mRNA production on day 3 after CA/CPR procedure; 4) attenuate autophagy levels in hippocampus tissue on day 3 after CA/CPR procedure. In conclusion, RNase could improve neurological function by reducing inflammation response and autophagy in mice undergoing CA/CPR. PMID- 28881796 TI - Discriminating patients with early-stage breast cancer from benign lesions by detection of oxidative DNA damage biomarker in urine. AB - Breast cancer is one of the most commonly diagnosed and death-related cancers in women worldwide. Mammography is routinely used for screening and invasive examinations such as painful tissue biopsies were recommended for patients with abnormal screening outcomes. However, a considerable proportion of these cases turn out to be benign lesions. Thus, novel non-invasive approach for discriminating breast cancer from benign lesions is desirable. Herein, we applied a high-throughput ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) analysis to determine the oxidative DNA damage biomarker, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine samples from 60 patients with early-stage breast cancer (stage I, II), 51 patients with benign breast diseases and 73 healthy volunteers. We demonstrated that the concentration of urinary 8-oxodG in patients with early-stage breast cancer was significantly higher not only than that in healthy controls, but also than that in patients with benign breast diseases, whereas no significant difference of urinary 8-oxodG level was observed between benign breast diseases group and healthy control group. Moreover, there was significant difference between early stage breast cancer group and non-cancerous group which consisted of benign breast diseases patients and healthy controls. Besides, logistic regression analysis and receiver operator characteristic (ROC) curve analysis were also performed. Our findings indicate that the marked increase of 8-oxodG in urine may serve as a potential biomarker for the risk estimation, early screening and detection of breast cancer, particularly for discriminating early-stage breast cancer from benign lesions. PMID- 28881797 TI - Upregulation of long noncoding RNA HOXA-AS3 promotes tumor progression and predicts poor prognosis in glioma. AB - Long noncoding RNAs (lncRNAs) have recently emerged as new potentially promising therapeutic targets in many cancers. However, their prognostic value and biological functions associated with glioma remain to be elucidated. Here, High throughput RNAseq was performed to detect the expression profiles of lncRNAs in 325 human glioma tissues. It was shown that a novel lncRNA HOXA-AS3 was one of the most significantly upregulated lncRNAs in glioma tissues. Quantitative PCR further verified the increased expression of HOXA-AS3 in patient samples and glioma cell lines. Uni and Multivariate Cox regression analysis revealed that HOXA-AS3 was an independent prognostic factor in glioma patients. Gene set enrichment analysis indicated that the gene sets correlated with HOXA-AS3 expression were involved in cell cycle progression and E2F targets. Functionally, HOXA-AS3 silencing resulted in proliferation arrest by altering cell cycle progression and promoting cell apoptosis, and impaired cell migration in glioma cells. Furthermore, the growth-inhibiting effect of HOXA-AS3 knockdown was also demonstrated in Xenograft mouse model. Our results highlight the important role of HOXA-AS3 in glioma progression, and indicate that HOXA-AS3 may be served as a valuable prognostic biomarker for glioma. PMID- 28881798 TI - Role of A-Kinase anchor protein (AKAP4) in growth and survival of ovarian cancer cells. AB - Ovarian cancer represents one of the most common malignancies among women with very high mortality rate worldwide. A-kinase anchor protein 4 (AKAP4), a unique cancer testis (CT) antigen has been shown to be associated with various malignant properties of cancer cells. However, its involvement in various molecular pathways in ovarian cancer remains unknown. In present investigation, employing gene silencing approach, we examined the role of AKAP4 in cell cycle, apoptosis and epithelial-mesenchymal transition (EMT). Further, we also investigated the effect of ablation of AKAP4 on tumor growth in SCID mice ovarian cancer xenograft mouse model. Our results showed that ablation of AKAP4 resulted in increased reactive oxygen species (ROS) generation, DNA damage, cell cycle arrest and apoptosis in ovarian cancer cells. AKAP4 knockdown lead to degradation of protien kinase A (PKA) which was rescued by proteosome inhibitor MG-132. ROS quencher N acetyl cysteine (NAC) treatment rescued cell cycle arrest and resumed cell division. Subsequently, increased expression of pro-apoptotic molecules and decreased expression of pro-survival/anti-apoptotic factors was observed. As a result of AKAP4 depletion, DNA damage response proteins p-gammaH2AX, p-ATM and p21 were upregulated. Also, knockdown of CREB resulted in similar findings. Further, PKA inhibitor (H89) and oxidative stress resulted in similar phenotype of ovarian cancer cells as observed in AKAP4 ablated cells. Collectively, for the first time our data showed the involvement of AKAP4 in PKA degradation and perturbed signaling through PKA-CREB axis in AKAP4 ablated ovarian cancer cells. PMID- 28881799 TI - Prognostic values of tissue factor and its alternatively splice transcripts in human gastric cancer tissues. AB - We have previously reported that the higher expression of TF in human esophageal cancer tissues was significantly associated with tumor invasion, intratumoral microvessel density and patients' postoperative prognoses. Besides its trans membranous form, TF also has alternatively spliced transcripts. In the present study, the transcripts of the two TF isoforms, flTF and asTF, in human gastric cancer tissues were determined by real-time PCR, and the correlation between the expression of TF isoforms and patient's clinicopathological features was also analyzed. Our results showed that the relative mRNA expression levels of flTF and asTF in human gastric cancer tissues was significantly higher than those in normal tissues (P=0.035 and P=0.006, respectively). The relative mRNA expression level of asTF was significantly associated with age (P=0.018), meanwhile, we could not find that flTF or asTF expression level was correlated with any other characteristics of the patients, including gender, TNM stage, pathological grade, tumor size, histological type, or chemotherapy sensitivity. Univariate analysis demonstrated that the overall survival rate of gastric cancer patients with lower flTF or asTF expression level was greater than those with higher expression level (P=0.018 and =0.038, respectively). Multivariate COX model analysis also demonstrated that flTF expression (P=0.048) or asTF expression (P=0.002) could be used as independent prognostic predictors in human gastric cancer. Thus, both flTF and asTF mRNA expression levels in cancer tissues could be used as useful risk factors for evaluating the prognoses of patients suffering from gastric cancer. PMID- 28881800 TI - Menstrual pattern after abdominal radical trachelectomy. AB - To assess changes of menstrual patterns, their causes, preventions and treatment methods after abdominal radical trachelectomy (ART), we recorded patients' menstrual patterns after surgery and compared them with the conditions before surgery. Patients were divided into 3 groups based on their menstrual status post trachelectomy:Group 1: menstrual patterns unchanged; Group 2: menstrual patterns changed without amenorrhea; and Group 3: amenorrhea. One hundred and twenty-nine patients were included: 39 (30.2%) women belonged to Group 1, 74 (57.4%) to Group 2 and 16 (12.4%) to Group 3. For patients in Group 2, the most common presenting symptom was decrease of menstrual volume (59, 79.7%), followed by a prolonged (33, 44.6%) menstrual bleeding. All of the changes in Group 2 and 12 cases in Group 3 were due to narrow of the remaining cervical os. Additionally, 9 and 12 patients, respectively, in Group 2 and 3, developed cervical stenosis. To maintain regular menstruation and prevent isthmic stenosis, 99 patients had tailed intrauterine devices (IUDs) placed in the uterine cavity. Incidence of cervical stenosis all happened in patients without IUDs placed in the uterine cavity. Menstrual condition improved in all patients except one after dilation of the new-cervix. Our results demonstrated that the majority of patients suffered from changes in menstrual patterns after ART. Narrowing of the remaining cervical canal was the main reason and could be treated by cervical dilation. The use of a tailed IUD was effective in the prevention of this complication. PMID- 28881801 TI - A screen for inducers of bHLH activity identifies pitavastatin as a regulator of p21, Rb phosphorylation and E2F target gene expression in pancreatic cancer. AB - The average survival for patients with Pancreatic Ductal Adenocarcinoma (PDA) is merely 6 months, underscoring the need for new therapeutic approaches. During PDA progression, pancreatic acinar cells lose activity of the ClassI/II bHLH factors that regulate quiescence. We previously found that promoting transcriptional activity of the Class I bHLH factor E47 in highly aggressive PDA cells induced stable growth arrest in vitro and in vivo. To translate these findings for clinical utility, we developed a high throughput screening platform to identify small molecule inducers of Class I/II bHLH activity. A screen of 4,375 known drugs identified 70 bHLH activators. Prominent among the hits were members of the statin class of HMG-CoA reductase inhibitors, cholesterol lowering drugs that are also being evaluated in cancer. Studies with pitavastatin in primary patient derived tumor cells and established PDA lines, revealed dose dependent growth inhibition. At the molecular level, pitavastatin induced expression of the cyclin dependent kinase (CDK) inhibitor p21 in a cholesterol independent manner, blocked repressive phosphorylation of the Retinoblastoma tumor suppressor protein at CDK targeted sites, and reduced expression of E2F target genes required for progression through the G1/S boundary. Together, the data provide new insight into mechanisms by which statins constrain proliferation in cancer and establish the effectiveness of a novel screening platform to identify small molecules of clinical relevance in pancreatic cancer. PMID- 28881802 TI - MEK inhibition enhances efficacy of bacillus Calmette-Guerin on bladder cancer cells by reducing release of Toll-like receptor 2-activated antimicrobial peptides. AB - Bacillus Calmette-Guerin (BCG) is one of the standard treatment options for non muscle-invasive bladder cancer. The details of the biological defense mechanisms against BCG remain unclear. Here, we investigated whether BCG-induced release of antimicrobial peptides (AMPs; e.g., human beta-defensin-2, -3, and cathelicidin) is involved with mitogen-activated protein kinase (MAPK) pathways, and investigated the enhanced anticancer effect of BCG through the down-regulation of Toll-like receptors (TLRs) and MAPK pathways in bladder cancer cells. BCG infected bladder cancer cells produced AMPs as a defense mechanism against BCG, which were reduced by MEK inhibitors by blocking phosphorylation of extracellular signal-regulated kinase (ERK1/2 or MEK) and c-Jun. MEK inhibitors enhanced inhibition of bladder cancer cell growth by decreased binding of c-Jun, p65 and Pol II to the activated protein-1 promoter. Knockdown of TLR2 and TLR4 reduced ERK phosphorylation. Knockdown of TLR 2 decreased release of AMPs, which was similar to the efficacy of MEK inhibitor on BCG-infected cells. BCG-infected bladder cancer cells were more prone to induction of AMP release following TLR2 activation via ERK and c-Jun pathway mediators. In conclusion, our data suggest that the BCG-induced release of AMPs in bladder cancer cells is a promising molecular target for enhancing the immunotherapeutic efficacy of BCG in bladder cancer patients. PMID- 28881803 TI - Regulation of actin-binding protein ANLN by antitumor miR-217 inhibits cancer cell aggressiveness in pancreatic ductal adenocarcinoma. AB - Analysis of our microRNA (miRNA) expression signature of pancreatic ductal adenocarcinoma (PDAC) revealed that microRNA-217 (miR-217) was significantly reduced in cancer tissues. The aim of this study was to investigate the antitumor roles of miR-217 in PDAC cells and to identify miR-217-mediated molecular pathways involved in PDAC aggressiveness. The expression levels of miR-217 were significantly reduced in PDAC clinical specimens. Ectopic expression of miR-217 significantly suppressed cancer cell migration and invasion. Transcription of actin-binding protein Anillin (coded by ANLN) was detected by our in silico and gene expression analyses. Moreover, luciferase reporter assays showed that ANLN was a direct target of miR-217 in PDAC cells. Overexpression of ANLN was detected in PDAC clinical specimens by real-time PCR methods and immunohistochemistry. Interestingly, Kaplan-Meier survival curves showed that high expression of ANLN predicted shorter survival in patients with PDAC by TCGA database analysis. Silencing ANLN expression markedly inhibited cancer cell migration and invasion capabilities of PDAC cell lines. We further investigated ANLN-mediated downstream pathways in PDAC cells. "Focal adhesion" and "Regulation of actin binding protein" were identified as ANLN-modulated downstream pathways in PDAC cells. Identification of antitumor miR-217/ANLN-mediated PDAC pathways will provide new insights into the potential mechanisms underlying the aggressive course of PDAC. PMID- 28881804 TI - Altered erythropoiesis and decreased number of erythrocytes in children with neuroblastoma. AB - Neuroblastoma (NB) is a pediatric tumor presenting at diagnosis either as localized or metastatic disease, which mainly involves the bone marrow (BM). The physical occupancy of BM space by metastatic NB cells has been held responsible for impairment of BM function. Here, we investigated whether localized or metastatic NB may alter hematopoietic lineages' maturation and release of mature cells in the periphery, through gene expression profiling, analysis of BM smears, cell blood count and flow cytometry analysis. Gene ontology and disease associated analysis of the genes significantly under-expressed in BM resident cells from children with localized and metastatic NB, as compared to healthy children, indicated anemia, blood group antigens, and heme and porphyrin biosynthesis as major functional annotation clusters. Accordingly, in children with NB there was a selective impairment of erythrocyte maturation at the ortho chromic stage that resulted in reduced erythrocyte count in the periphery, regardless of the presence of metastatic cells in the BM. By considering all NB patients, low erythrocyte count at diagnosis associated with worse survival. Moreover, in the subset of metastatic patients, low erythrocyte count, hemoglobin and hematocrit and high red cell distribution width at follow-up also associated with worse outcome. These observations provide an alternative model to the tenet that infiltrating cells inhibit BM functions due to physical occupancy of space and may open a new area of research in NB to understand the mechanism(s) responsible for such selective impairment. PMID- 28881805 TI - Down regulation of human positive coactivator 4 suppress tumorigenesis and lung metastasis of osteosarcoma. AB - Osteosarcoma is a kind of primary malignant bone tumor with the highest incidence and an extraordinarily poor prognosis and early pulmonary metastasis formation as a frequent occurrence. Transcriptional positive coactivator 4 (PC4) has multiple functions in DNA replication, transcription, repair and chromatin organization, even in tumorigenesis. However, the precise function of PC4 in osteosarcoma is still unclear and controversial. In this paper we found PC4 was upregulated in patient-derived osteosarcoma tissues compared to normal. Moreover, higher expression of PC4 was correlated with poorer overall survival and advanced clinicopathological tumor staging. Down regulation of PC4 in the highly metastatic osteosarcoma cells reduced the malignant behaviors in vitro and in vivo. Analyzing the downstream genes affected obviously by shPC4 with RNA sequencing, we found knocking down PC4 will inhibit the propensity for lung metastasis through transcriptional suppression of MMPs pathways. Taken together, PC4 may be an attractive therapeutic strategy for osteosarcoma, especially in preventing lung metastasis formation. PMID- 28881806 TI - Increased p16 and p53 protein expression predicts poor prognosis in mucosal melanoma. AB - Primary mucosal melanoma (MM) is a rare, and aggressive, neoplasm with a poor prognosis. To date, few prognostic markers of MM have been well-defined. The aim of this study is to clarify the prognostic value of p53 and p16 proteins in predicting the clinical outcome of Chinese patients with MM. A total of 59 MM samples were contained from biopsy specimens, and, expressions of p53 and p16 proteins were assessed by immunohistochemistry. Cox regression analysis was performed to investigate the association of these proteins with the overall survival of MM patients. Increased p16 expression was significantly associated with reduced survival at three years (P=0.039). Increased p53 expression correlates with reduced one-year (P=0.025), and, two-year survival (P=0.037). Increased p53 and p16 protein expression may be helpful prognostic indicators for the management of these patients. PMID- 28881807 TI - Associations of high altitude polycythemia with polymorphisms in EPHA2 and AGT in Chinese Han and Tibetan populations. AB - High altitude polycythemia (HAPC) refers to the long-term living in the plateau of the hypoxia environment is not accustomed to cause red blood cell hyperplasia. The pathological changes are mainly the various organs and tissue congestion, blood stasis and hypoxia damage. Although chronic hypoxia is the main cause of HAPC, the related molecular mechanisms remain largely unclear. This study aims to explore the genetic basis of HAPC in the Chinese Han and Tibetan populations. We enrolled 100 patients (70 Han, 30 Tibetan) with HAPC and 100 healthy control subjects (30 Han, 70 Tibetan). To explore the hereditary basis of HAPC and investigate the association between EPHA2 with AGT and HAPC in Chinese Han and Tibetan populations. Using the Chi-squared test and analyses of genetic models, rs2291804, rs2291805, rs3768294, rs3754334, rs6603856, rs6669624, rs11260742, rs13375644 and rs10907223 in EPHA2, and rs699, rs4762 and rs5051 in AGT showed associations with reduced HAPC susceptibility in Han populations. Additionally, in Tibetan populations, rs2478523 in AGT showed an increased the risk of HAPC. Our study suggest that polymorphisms in the EPHA2 and AGT correlate with susceptibility to HAPC in Chinese Han and Tibetan populations. PMID- 28881808 TI - CXCL13 is androgen-responsive and involved in androgen induced prostate cancer cell migration and invasion. AB - Androgen receptor (AR) is a key transcription factor playing a critical role in prostate cancer (PCa) initiation and progression. However, the molecular mechanisms of AR action in prostate cancer are not very clear. CXCL13, known as B cell attracting chemokine1 (BCA-1), is a member of CXC chemokine family and relevant to cancer metastasis. This study shows that CXCL13 is an androgen responsive gene and involved in AR-induced PCa cell migration and invasion. In clinical specimens, expression of CXCL13 in PCa tissues is markedly higher than that in adjacent normal tissues. In cultures, expression of CXCL13 is up regulated by androgen-AR axis at both mRNA and protein levels. Furthermore, Chip Seq assay identifies canonical androgen responsive elements (ARE) at CXCL13 enhancer and dual-luciferase reporter assays reveals that the ARE is highly responsive to androgen while mutations of the ARE abolish the reporter activity. Additional chromatin immunoprecipitation (ChIP) assays also identify that the ARE presents androgen responsiveness. In addition, CXCL13 promotes G2/M phase transition by increasing Cyclin B1 levels in PCa cells. Functional studies demonstrate that reducing endogenous CXCL13 expression in LNCaP cells largely weakens androgen-AR axis induced cell migration and invasion. Taken together, our study implicates for the first time that CXCL13 is an AR target gene and involved in AR-mediated cell migration and invasion in primary PCa. PMID- 28881809 TI - Jagged-2 (JAG2) enhances tumorigenicity and chemoresistance of colorectal cancer cells. AB - Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality. Recent studies have stated that NOTCH signaling plays an important role in the development and progression of CRC. However, the role of Jagged-2 (JAG2), one of the NOTCH ligands, has not been delineated in colorectal tumorigenesis and drug resistance. In the present study, we have examined the impact of targeting JAG2 on CRC cells. Among all the members of NOTCH ligands, only the expression of JAG2 was found up-regulated in the intestinal tumors of Apc Min /+ mice as compared to the nearby normal mucosa. JAG2 expression was also observed in a panel of human CRC cell lines. Pharmacological inhibition or genetic knockdown of beta-catenin in CRC cell lines suppressed JAG2 expression, suggesting Wnt/beta-catenin regulation of JAG2 expression. In addition, deletion of Apc gene in the intestinal cells of Apc conditional knockout mice resulted in up-regulation of JAG2 expression. Modulation of JAG2 expression significantly affected in vivo tumorigenicity of CRC cell lines. Moreover, knockdown of JAG2 sensitized CRC cells to chemotherapeutic agents, while ectopic expression of JAG2 increased chemoresistance of the CRC cells. Significant down-regulation of p21 was observed in JAG2-knockdown cells. Forced expression of p21 rescued the sensitivity of JAG2 knockdown cells to doxorubicin. In addition, the chemosensitivity of p21-null cells was not affected by JAG2 knockdown. These results suggest that JAG2 modulates the sensitivity of CRC cells to chemotherapeutic agents through p21. Our study identifies JAG2 as a novel target for therapeutic intervention of CRC. PMID- 28881810 TI - Infiltrating macrophages in diabetic nephropathy promote podocytes apoptosis via TNF-alpha-ROS-p38MAPK pathway. AB - Macrophage infiltration has been linked to the pathogenesis of diabetic nephropathy (DN). However, how infiltrating macrophages affect the progression of DN is unknown. Although infiltrating macrophages produce pro-inflammatory mediators and induce apoptosis in a variety of target cells, there are no studies in podocytes. Therefore, we tested the contribution of macrophages to podocytes apoptosis in DN. in vivo experiments showed that apoptosis in podocytes was increased in streptozocin (STZ)-induced diabetic rats compared with control rats and that this apoptosis was accompanied by increased macrophages infiltration in the kidney. Then, we established a co-culture system to study the interaction between macrophages and podocytes in the absence or presence of high glucose. Macrophages did not trigger podocytes apoptosis when they were co-cultured in the absence of high glucose in a transwell co-culture system. Additionally, although podocyte apoptosis was increased after high glucose stimulation, there was a further enhancement of podocyte apoptosis when podocytes were co-cultured with macrophages in the presence of high glucose compared with podocytes cultured alone in high glucose. Mechanistically, we found that macrophages were activated when they were exposed to high glucose, displaying pro-inflammatory M1 polarization. Furthermore, conditioned media (CM) from such high glucose activated M1 macrophages (HG-CM) trigged podocytes apoptosis in a reactive oxygen species (ROS)-p38mitogen-activated protein kinases (p38MAPK) dependent manner, which was abolished by either a ROS inhibitor (Tempo) or a p38MAPK inhibitor (SB203580). Finally, we identified tumor necrosis factor (TNF-alpha) as a key mediator of high glucose-activated macrophages to induce podocytes apoptosis because an anti-TNF-alpha neutralizing antibody blunted the apoptotic response, excess ROS generation and p38MPAK activation in podocytes induced by HG-CM. Moreover, addition of recombinant TNF-alpha similarly resulted in podocytes apoptosis. In summary, the TNF-alpha that was released by high glucose-activated macrophages promoted podocytes apoptosis via ROS-p38MAPK pathway. Blockade of TNF alpha secretion from high glucose activated macrophages and ROS-p38MAPK pathway might be effective therapeutic options to limit podocytes apoptosis and delay the progression of diabetic nephropathy. PMID- 28881811 TI - AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors. AB - Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) tumors. Cetuximab is the first targeted (anti-EGFR) therapy approved for the treatment of HNSCC patients. However, its efficacy is limited due to primary and secondary resistance, and there is no predict biomarkers of response. New generation of EGFR inhibitors with pan HER targeting and irreversible action, such as afatinib and allitinib, represents a significant therapeutic promise. In this study, we intend to compare the potential cytotoxicity of two anti-EGFR inhibitors (afatinib and allitinib) with cetuximab and to identify potential predictive biomarkers of response in a panel of HNSCC cell lines. The mutational analysis in the eight HNSCC cell lines revealed an EGFR mutation (p.H773Y) and gene amplification in the HN13 cells. According to the growth inhibition score (GI), allitinib was the most cytotoxic drug, followed by afatinib and finally cetuximab. The higher AKT phosphorylation level was associated with resistance to anti-EGFR agents. Therefore, we further performed drug combinations with anti-AKT agent (MK2206) and AKT1 gene editing, which demonstrated afatinib and allitinib sensitivity restored. Additionally, in silico analysis of TCGA database showed that AKT1 overexpression was present in 14.7% (41/279) of HNSCC cases, and was associated with perineural invasion in advanced stage. In conclusion, allitinib presented a greater cytotoxic profile when compared to afatinib and cetuximab. AKT pathway constitutes a predictive marker of allitinib response and combination with AKT inhibitors could restore response and increase treatment success. PMID- 28881812 TI - A combination of valproic acid sodium salt, CHIR99021, E-616452, tranylcypromine, and 3-Deazaneplanocin A causes stem cell-like characteristics in cancer cells. AB - Many studies are based on the hypothesis that recurrence and drug resistance in lung carcinoma are due to a subpopulation of cancer stem-like cells (CSLCs) in solid tumors. Therefore it is crucial to screen for and recognize lung CSLCs. In this study, we stimulated non-small cell lung cancer (NSCLC) A549 cells to display stem cell-like characteristics using a combination of five small molecule compounds. The putative A549 stem cells activated an important CSLC marker, CD133 protein, as well multiple CSLC-related genes including ATP-binding cassette transporter G2 (ABCG2), C-X-C chemokine receptor type 4 (CXCR4), NESTIN, and BMI1. The A549 stem-like cells displayed resistance to the chemotherapeutic drugs etoposide and cisplatin, epithelial-to-mesenchymal transition properties, and increased protein expression levels of NOTCH1 and Hes Family bHLH Transcription Factor 1 (HES1). When A549 cells were pretreated with a NOTCH signaling pathway inhibitor before compound induction, expression of the NOTCH1 target gene HES1 was reduced. This demonstrated that the NOTCH signaling pathway in the putative A549 stem-like cells had been activated. Together, the results of our study showed that a combination of five small molecule agents could transform A549 cells into putative stem-like cells, and that these compounds could also elevate CD133 and ABCG2 protein expression levels in H460 cells. This study provides a convenient method for obtaining lung CSLCs, which may be an effective strategy for developing lung carcinoma treatments. PMID- 28881813 TI - Differential metabonomic profiles of primary hepatocellular carcinoma tumors from alcoholic liver disease, HBV-infected, and HCV-infected cirrhotic patients. AB - Our objective was to comparatively profile the metabolite composition of primary hepatocellular carcinoma (HCC) tumors from alcoholic liver disease (ALD), hepatitis B virus (HBV)-infected, and hepatitis C virus (HCV)-infected cirrhotic patients. Primary HCC tumors were collected from ALD, HBV-infected, and HCV infected cirrhotic patients (n=20 each). High-resolution magic-angle spinning proton nuclear magnetic resonance spectroscopy and metabonomic data analysis were performed to compare HCC tumors from the three groups. Sensitivity analyses were performed to determine the effects of diabetes, high body mass index, and smoking status. Metabonomic pathway analyses were conducted to identify dysregulated pathways. Three metabolites were significantly differentiated between ALD and HBV infected patients, which were distinguishable by changes in ketone body, glycerolipid, and phenylalanine metabolism. Five metabolites were significantly differentiated between ALD and HCV-infected patients, which were distinguishable by changes in ketone body, alanine/aspartate/glutamate, and phenylalanine metabolism. Six metabolites were significantly differentiated between HBV infected and HCV-infected patients, which were distinguishable by changes in ketone body, tyrosine, and alanine/aspartate/glutamate metabolism. In conclusion, this is the first study to demonstrate that the metabolic phenotypes of primary HCC tumors vary significantly across ALD, HBV-infected, and HCV-infected cirrhotic patients. PMID- 28881814 TI - Diagnostic and prognostic values of cerebrospinal fluid CYFRA 21-1 in patients with leptomeningeal carcinomatosis. AB - OBJECTIVES: To investigate the diagnostic and prognostic values of cerebrospinal fluid (CSF) CYFRA 21-1 in patients with leptomeningeal carcinomatosis (LMC). METHODS: Concentration of CSF CYFRA 21-1 was detected using electro chemiluminescent immunoassay. The difference in level of CYFRA 21-1 between 61 patients with LMC and 200 patients with other neurological disease was evaluated, and diagnostic performance of CSF CYFRA 21-1 was investigated. In LMC patients treated with ventriculo-lumbar perfusion (VLP) chemotherapy, prognostic performance of CSF CYFRA 21-1 was evaluated. RESULTS: The CSF CYFRA 21-1 was significantly higher in LMC patients than that in patients with other neurological diseases (p<0.001). The sensitivity, specificity, accuracy, and positive and negative predictive values were 80.3%, 95.0%, 91.6%, 83.1%, and 94.1% for CSF CYFRA 21-1, and 65.6%, 100%, 92.0%, 100%, and 90.5% for CSF cytology, respectively. The use of high CSF CYFRA 21-1 and/or positive CSF cytology findings resulted in an increased sensitivity of 85.3%, without compromising specificity. LMC patients with high CSF CYFRA 21-1 were more frequently accompanied by positive CSF cytology results than those with low CSF CYFRA 21-1. The median overall survival was longer in LMC patients with low CSF CYFRA 21-1 than in those with high CSF CYFRA 21-1 (p=0.031). During VLP chemotherapy, the clinical responses were found to be correlated with the biological responses, including the level of CSF CYFRA 21-1 and intracranial pressure. CONCLUSIONS: CSF CYFRA 21-1 might be regarded as an additional diagnostic tool for LMC and a potential significant prognostic biomarker in LMC patients treated with VLP chemotherapy. PMID- 28881815 TI - Clinicopathological characteristics of ROS1- and RET-rearranged NSCLC in caucasian patients: Data from a cohort of 713 non-squamous NSCLC lacking KRAS/EGFR/HER2/BRAF/PIK3CA/ALK alterations. AB - Targeted therapies have substantially changed the management of non-small cell lung cancer (NSCLC) patients with driver oncogenes. Given the high frequency, EGFR and ALK aberrations were the first to be detected and paved the way for tyrosine kinase inhibitor (TKI) treatments. Other kinases such as ROS1 and more recently RET have emerged as promising targets, and ROS1 and RET TKIs are already available for precision medicine. We screened a large cohort of 713 Caucasian non squamous NSCLC patients lacking EGFR/KRAS/BRAF/HER2/PI3KCA/ALK aberrations for ROS1 and RET rearrangements using fluorescence in situ hybridization to determine the frequency and clinicopathological characteristics of ROS1- and RET-positive patients. Frequencies of ROS1 and RET rearrangements were 2.1% and 2.52%, respectively. Contrary to common belief, both ROS1 and RET rearrangements were detected in patients with a history of smoking, and the RET-positive patients were not younger than the negative patients. Moreover, RET but not ROS1 rearrangement was associated with the female gender. Nearly half of the ROS1 rearranged patients were successfully treated with ROS1 TKIs. In contrast, only 5/18 RET-positive patients received off-label RET TKIs. Two patients had stable disease, and three experienced disease progression. In addition to the 18 RET positive cases, 10 showed isolated 5' signals. The clinical relevance is unknown but if the frequency is confirmed by other groups, the question whether these patients are eligible to TKIs will arise. More potent RET TKIs are under development and may improve the response rate in RET-positive patients. Therefore, we recommend the routine implementation of RET testing in non-squamous NSCLC patients, including those with a history of smoking. PMID- 28881816 TI - Autophagy-related genes are induced by histone deacetylase inhibitor suberoylanilide hydroxamic acid via the activation of cathepsin B in human breast cancer cells. AB - Autophagy is involved in modulating tumor cell motility and invasion, resistance to epithelial-to-mesenchymal transition, anoikis, and escape from immune surveillance. We have previous shown that SAHA is capable to induce several apoptosis and autophagy-related gene expression in breast cancers. However, the exact mechanisms of autophagy activation in this context have not been fully identified. Our results showed that the expression and the activity of Cathepsin B (CTSB), one of the major lysosomal cysteine proteases, were significantly increased in MDA-MB- 231 and MCF-7 cells upon SAHA treatment. We confirmed that Cystatin C, a protease inhibitor, significantly inhibited the expression of CTSB induced by SAHA on breast cancer cells. We demonstrated that SAHA is able to promote the expression of LC3II, a key member in the maturation of the autophagosome, the central organelle of autophagy in breast cancer cells. However, SAHA induced LC3II expression is effectively suppressed after the addition of Cystatin C to the cell culture. In addition, we identified a number of genes, as well as the mitogen-activated protein kinase (MAPK) signaling that is potentially involved in the action of SAHA and CTSB in the breast cancer cells. Overall, our results revealed that the autophagy-related genes are induced by SAHA via the activation of CTSB in breast cancer cells. An improved understanding of SAHA molecular mechanisms in breast cancer may facilitate SAHA clinical use and the selection of suitable combinations. PMID- 28881817 TI - Dectin-1 signaling inhibits osteoclastogenesis via IL-33-induced inhibition of NFATc1. AB - Abnormal osteoclast activation contributes to osteolytic bone diseases (OBDs). It was reported that curdlan, an agonist of dectin-1, inhibits osteoclastogenesis. However, the underlying mechanisms are not fully elucidated. In this study, we found that curdlan potently inhibited RANKL-induced osteoclast differentiation and the resultant bone resorption. Curdlan inhibited the expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), the key transcriptional factor for osteoclastogenesis. Notably, dectin-1 activation increased the expression of MafB, an inhibitor of NFATc1, and IL-33 in osteoclast precursors. Mechanistic studies revealed that IL-33 enhanced the expression of MafB in osteoclast precursors and inhibited osteoclast precursors to differentiate into mature osteoclasts. Furthermore, blocking ST2, the IL-33 receptor, partially abrogated curdlan-induced inhibition of NFATc1 expression and osteoclast differentiation. Thus, our study has provided new insights into the mechanisms of dectin-1-induced inhibition of osteoclastogenesis and may provide new targets for the therapy of OBDs. PMID- 28881818 TI - 20(S)-Rg3 blocked epithelial-mesenchymal transition through DNMT3A/miR-145/FSCN1 in ovarian cancer. AB - Epithelial-mesenchymal transition (EMT) is one of the key mechanisms mediating cancer progression. MicroRNAs (miRs) are essential regulators of gene expression by suppressing translation or causing degradation of target mRNA. Growing evidence illustrates the crucial roles of miRs dysregulation in cancer development and progression. Here, we have found for the first time that the ginsenoside 20(S)-Rg3, a pharmacologically active component of Panax ginseng, potently increases miR-145 expression by downregulating methyltransferase DNMT3A to attenuate the hypermethylation of the promoter region in the miR-145 precursor gene. Restoration of DNMT3A reverses the inhibitory effect of 20(S)-Rg3 on EMT. FSCN1 is verified as the target of miR-145 to suppress EMT in human ovarian cancer cells. The results from nude mouse xenograft models further demonstrate the suppressive effect of miR-145 on malignant progression of ovarian cancer. Taken together, our results show that 20(S)-Rg3 blocks EMT by targeting DNMT3A/miR-145/FSCN1 pathway in ovarian cancer cells, highlighting the potentiality of 20(S)-Rg3 to be used as a therapeutic agent for ovarian cancer. PMID- 28881819 TI - APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model. AB - Esophageal cancer (EC) is one of the most aggressive malignancies of the upper aerodigestive tract. Over the past three decades, with advances in surgical techniques and treatment, the prognosis of esophageal cancer has only slowly improved. Thus identifying novel molecular targets and developing therapeutic agents are critical. Aurora kinases play a crucial role in mitosis and selective inhibitors might provide an effective therapeutic treatment for cancer. However, the role of Aurora kinases in EC is still inadequately studied. Here, we identified a novel compound, referred to as APIO-EE-9, which inhibits growth and colony formation and induces apoptosis of esophageal cancer cells. Using computer modeling, we found that APIO-EE-9 interacted with both Aurora A and B in the ATP binding pocket. APIO-EE-9 inhibited both Aurora A and B kinase activities in a dose-dependent manner. Treatment with APIO-EE-9 substantially reduced the downstream Aurora kinase phosphorylation of histone H3 (Ser10), resulting in formation of multiple nuclei and centrosomes. Additionally, esophageal cancer cells expressing shAurora A or shAurora B kinase exhibited a dramatic reduction in proliferation and colony formation. Injection of these cells as xenografts in mice reduced tumor formation compared to wildtype cells. Importantly, APIO-EE-9 significantly decreased the size of esophageal patient-derived xenograft (PDX) tumors implanted in SCID mice. These results demonstrated that APIO-EE-9 is a specific Aurora kinase inhibitor that could be developed as a therapeutic agent against esophageal cancer. PMID- 28881820 TI - Brain metastases in patients with non-small cell lung cancer: the role of mutated EGFRs with an exon 19 deletion or L858R point mutation in cancer cell dissemination. AB - Non-small cell lung cancer (NSCLC) patients tend to develop brain metastases (BM), but the link between BM occurrence and driver mutations in NSCLC is not very clear. We explored whether activating mutations of epidermal growth factor receptors (EGFRs) in exon 19 deletion or L858R predict BM in NSCLC. A retrospective multivariable logistic regression analysis of 384 patients demonstrated that the presence of mutated-EGFRs was associated with overall BM (OR=2.24, P=0.001) compared to that of wild-type EGFR (WT-EGFR). Moreover, the time-to-event analysis model considering death as a competing risk revealed that, irrespective of survival, mutated-EGFRs predicted subsequent BM (SBM) in stage IIIB-IV patients (37.1% vs. 10.6%, HR=2.98, P=0.002) after adjusting for age (HR=2.00, P=0.012), gender, histological subtype, and smoking history. Notably, the younger mutated-EGFR subgroup was at a higher risk for SBM compared to the older WT-EGFR one (58.1% vs.10.9%, HR=6.57, P<0.001). Additionally, EGFR exon 19 deletion, despite having a slightly longer overall survival (20.6 vs. 14.2 months, P=0.368), was comparable to L858R mutation in predicting SBM (39.5% vs. 34.5%, HR=0.91, P=0.770). In vitro, the overexpression of mutated-EGFRs induced morphological changes towards a mesenchymal-like phenotype and promoted mobility in lung cancer cells. Clinically, mutated-EGFR NSCLC displayed a higher proportion of vimentin-positive expression (75.3% vs. 51.2%; P=0.007) and a shorter median time to SBM (23.5 months vs. not reached, P=0.017) than WT-EGFR NSCLC. These results suggest that NSCLC patients carrying mutated-EGFRs may require a higher frequency of brain imaging assessments than those with WT-EGFR to facilitate earlier SBM detection during follow-up. PMID- 28881821 TI - Radial artery intima-media thickness regresses after secondary prevention interventions in patients' post-acute coronary syndrome and is associated with cardiac and kidney biomarkers. AB - BACKGROUND: Radial artery intima-media thickness (rIMT) measured by ultra-high resolution ultrasound is associated with increased cardiovascular risk and predicts outcomes. We performed non-invasive high-resolution ultrasound of the radial artery to investigate vascular changes in subjects presenting with acute coronary syndrome (ACS) and who had undergone percutaneous coronary intervention (PCI). PURPOSE: In the present work, we aimed to follow rIMT change over time post-acute coronary syndrome as a tool to monitor potential response to intensified medical therapy. METHODS: We examined 256 subjects who underwent PCI due to ACS and healthy controls (n= 39) and we measured a number of biomarkers, which are known to be associated with cardiovascular disease. Images of radial artery were acquired bilaterally in the longitudinal view using a 50 MHz transducer (Vevo 2100 VisualSonics, Inc, Toronto, Ontario, Canada). Carotid IMT (cIMT) and rIMT were measured at <1 month after index PCI followed by a repeated measurement of rIMT at 4 months from the ACS in a sub-set (n=117). RESULTS: rIMT measured within 1 month post ACS was significantly higher than rIMT after 4 months from ACS, (p < 0.0001), mean +/- SD (rIMT right 0.35 +/- 0.08; rIMT left 0.37 +/- 0.08) vs. (rIMT right 0.29 +/- 0.08; rIMT left 0.31 +/- 0.09) respectively. There was no statistically significant change in cIMT. In healthy controls there were no changes in rIMT or cIMT overtime. High levels of CX3CL1 and myeloperoxidase measured within one month post ACS are associated with increase of rIMT, r=0.38 (p< 0.0001) and r=0.41 (p< 0.0001) respectively. CONCLUSIONS: rIMT seem to decrease systemically after ACS and is accompanied with corresponding biomarker change. The cause and clinical implications of the observed decrement in rIMT after ACS need further studies. PMID- 28881822 TI - An epigenetic signature of adhesion molecules predicts poor prognosis of ovarian cancer patients. AB - DNA methylation is a promising biomarker for cancer. The epigenetic effects of cell adhesion molecules may affect the therapeutic outcome and the present study examined their effects on survival in ovarian cancer. We integrated methylomics and genomics datasets in The Cancer Genome Atlas (n = 391) and identified 106 highly methylated adhesion-related genes in ovarian cancer tissues. Univariate analysis revealed the methylation status of eight genes related to progression free survival. In multivariate Cox regression analysis, four highly methylated genes (CD97, CTNNA1, DLC1, HAPLN2) and three genes (LAMA4, LPP, MFAP4) with low methylation were significantly associated with poor progression-free survival. Low methylation of VTN was an independent poor prognostic factor for overall survival after adjustment for age and stage. Patients who carried any two of CTNNA1, DLC1 or MFAP4 were significantly associated with poor progression-free survival (hazard ratio: 1.59; 95% confidence interval: 1.23, 2.05). This prognostic methylation signature was validated in a methylomics dataset generated in our lab (n = 37, hazard ratio: 16.64; 95% confidence interval: 2.68, 103.14) and in another from the Australian Ovarian Cancer Study (n = 91, hazard ratio: 2.43; 95% confidence interval: 1.11, 5.36). Epigenetics of cell adhesion molecules is related to ovarian cancer prognosis. A more comprehensive methylomics of cell adhesion molecules is needed and may advance personalized treatment with adhesion molecule-related drugs. PMID- 28881823 TI - Hypertriglyceridemia in female rats during pregnancy induces obesity in male offspring via altering hypothalamic leptin signaling. AB - Maternal obesity influence the child's long-term development and health. Though, the mechanism concerned in this process is still uncertain. In the present study, we explored whether overfeeding of a high-fat diet during pregnancy in female rats altered metabolic phenotypes in an F1 generation and authenticated the contribution of hypothalamic leptin signaling. Leptin responsiveness and the number of immunopositive neurons for phosphorylated signal transducer and activator transcription 3 (pSTAT3) were analyzed. Neuropeptide Y in the arcuate nucleus of the hypothalamus and in nucleus tractus solitaries was examined. Triglycerides and leptin levels were increased in the high-fat diet mother. The number of neuropeptide Y positive cell bodies and neurons was significantly increased in the high-fat diet-F1 offspring (HDF-F1) as compared to Chow-F1. Leptin administration significantly decreased the food intake and increased the pSTAT3 expression levels in neurons in the arcuate nucleus of Chow-F1. However, leptin did not show any effect on food intake and had a reduced effect on pSTAT3 expression levels in neurons in the arcuate nucleus of HDF-F1. From the present domino effect, we conclude that mothers exposed to high-fat diet during pregnancy may pass the obese phenotype to the succeeding generation via altering hypothalamic leptin signaling. PMID- 28881824 TI - Differential gene and lncRNA expression in the lower thoracic spinal cord following ischemia/reperfusion-induced acute kidney injury in rats. AB - We used high-throughput RNA sequencing to analyze differential gene and lncRNA expression patterns in the lower thoracic spinal cord during ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) in rats. We observed that of 32662 mRNAs, 4296 out were differentially expressed in the T8-12 segments of the spinal cord upon I/R-induced AKI. Among these, 62 were upregulated and 34 were downregulated in response to I/R (FDR < 0.05, |log2FC| > 1). Further, 52 differentially expressed lncRNAs (35 upregulated and 17 downregulated) were identified among 3849 lncRNA transcripts. The differentially expressed mRNAs were annotated as "biological process," "cellular components" and "molecular functions" through gene ontology enrichment analysis. KEGG pathway enrichment analysis showed that cell cycle and renin-angiotensin pathways were upregulated in response to I/R, while protein digestion and absorption, hedgehog, neurotrophin, MAPK, and PI3K Akt signaling were downregulated. The RNA-seq data was validated by qRT-PCR and western blot analyses of select mRNAs and lncRNAs. We observed that Bax, Caspase 3 and phospho-AKT were upregulated and Bcl-2 was downregulated in the spinal cord in response to renal injury. We also found negative correlations between three lncRNAs (TCONS_00042175, TCONS_00058568 and TCONS_00047728) and the degree of renal injury. These findings provide evidence for differential expression of lncRNAs and mRNAs in the lower thoracic spinal cord following I/R-induced AKI in rats and suggest potential clinical applicability. PMID- 28881825 TI - Development of hepatocellular cancer induced by long term low fat-high carbohydrate diet in a NAFLD/NASH mouse model. AB - Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease. It can progress to nonalcoholic steatohepatitis (NASH) and, in a percentage of cases, to hepatocarcinogenesis. The strong incidence in western countries of obesity and metabolic syndrome, whose NAFLD is the hepatic expression, is thought to be correlated to consumption of diets characterized by processed food and sweet beverages. Previous studies described high-fat diet-induced liver tumors. Conversely, the involvement of low-fat/high-carbohydrate diet in the progression of liver disease or cancer initiation has not been described yet. Here we show for the first time hepatic cancer formation in low-fat/high-carbohydrate diet fed NAFLD/NASH mouse model. Animals were long term high-fat, low-fat/high carbohydrate or standard diet fed. We observed progressive liver damage in low fat/high-carbohydrate and high-fat animals after 12 and, more, 18 months. Tumors were detected in 20% and 50% of high-fat diet fed mice after 12 and 18 months and, interestingly, in 30% of low-fat/high-carbohydrate fed animals after 18 months. No tumors were detected in standard diet fed mice. Global increase of hepatic interleukin-1beta, interleukin-6, tumor necrosis factor-alpha and hepatocyte growth factor was detected in low-fat/high-carbohydrate and high-fat with respect to standard diet fed mice as well as in tumor with respect to non tumor bearing mice. A panel of 15 microRNAs was analyzed: some of them revealed differential expression in low-fat/high-carbohydrate with respect to high-fat diet fed groups and in tumors. Data here shown provide the first evidence of the involvement of low-fat/high-carbohydrate diet in hepatic damage leading to tumorigenesis. PMID- 28881827 TI - Structural basis of mutant-selectivity and drug-resistance related to CO-1686. AB - Non-small-cell lung cancers (NSCLCs) caused by activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) initially respond to first generation reversible drugs gefitinib and erlotinib. However, clinical efficacy is limited due to the development of drug-resistance that in more than half of the cases are driven by the secondary T790M mutation. CO-1686 is one of the third generation irreversible inhibitors that inhibits EGFR activating mutants, including those with concurrent T790M, while avoiding the off-target toxicity owing to inhibition of wild-type EGFR in treating EGFR mutation-positive NSCLCs. Despite the remarkable success, the experimentally determined structure of this agent in complex with EGFR T790M remains unknown. In this study, we determined crystal structures of EGFR T790M or L858R mutants covalently bound by CO-1686. Based on these structural data, we can explain why CO-1686 irreversibly inhibits EGFR and selectively prefers T790M, which may help improving this or similar compounds, and explain why EGFR L718Q and L844V mutations incur resistance to this agent. PMID- 28881826 TI - TLR4 interaction with LPS in glioma CD133+ cancer stem cells induces cell proliferation, resistance to chemotherapy and evasion from cytotoxic T lymphocyte induced cytolysis. AB - Despite advances in treatment modalities, 5-year survival among glioma patients remains poor. Glioma cancer stem cells (CSCs) exhibit high tumorigenic activity and are associated with resistance to treatment and tumor recurrence. Because overexpression of toll-like receptor 4 (TLR4) correlated with cancer development, we investigated LPS-induced TLR4 signaling in glioma CD133-positive (CD133+) CSCs. The proliferation of CD133+ CSCs isolated from CSCs derived from the U251 and SF295 glioma cell lines and from human glioma samples was upregulated on a time- and concentration-dependent basis by LPS stimulation, with increases in CD133, NANOG, and NESTIN mRNA and protein levels. Also elevated was cytokine expression, which was coupled to phosphorylation of mitogen-activated protein kinase, and activation of cyclins and cyclin-dependent kinase complexes. TLR4 knockdown reduced LPS-induced CD133+ CSC proliferation, whereas Adriamycin induced CD133+ CSC apoptosis was moderately inhibited by treatment with LPS, implying a protective effect of LPS. The capacity of glioma CD133+ CSC-reactive cytotoxic T lymphocyte to selectively kill CD133+ CSCs was reduced by LPS, and this effect was not apparent after TLR4 knockdown in CD133+ CSCs. These data suggest TLR4 signaling is a factor in CD133+ CSC immune evasion, and thus disruption of TLR4 signaling is a potential therapeutic strategy in glioma. PMID- 28881828 TI - SHP2 negatively regulates HLA-ABC and PD-L1 expression via STAT1 phosphorylation in prostate cancer cells. AB - Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitous protein tyrosine phosphatase that activates the signal transduction pathways of several growth factors and cytokines. In our study, SHP2 expression was very high in prostate cancer (PCa) cell lines, and the expression of phospho signal transducer and activator of transcription 1 (p-STAT1) and STAT1 was very low. SHP2 knockdown upregulated the expression of p-STAT1 and downregulated phospho-extracellular signal regulated kinase (p-ERK). SHP2 depletion also increased the expression of human leukocyte antigen (HLA)-ABC and programmed death ligand 1 (PD-L1). When tumor cells were pretreated with Janus kinase 2 (JAK2) inhibitor, SHP2 depletion failed to induce HLA-ABC and PD-L1 expression. Furthermore, treating tumor cells with the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitor PD0325901 did not upregulate HLA-ABC and PD-L1. SHP2 depletion was associated with increased T-cell activation (CD25 MFI of CD8+) by coculture of allogeneic healthy donor peripheral blood monocytes (PBMC) with SHP2 siRNA pretreated PCa cell lines. These results show that SHP2 targeting upregulates HLA-ABC and PD-L1 expression via STAT1 phosphorylation in PCa cells and SHP2 depletion could increase T-cell activation. PMID- 28881829 TI - Compliance with the enhanced recovery after surgery protocol and prognosis after colorectal cancer surgery: A prospective cohort study. AB - We explored the effects of different levels of compliance with an enhanced recovery after surgery (ERAS) protocol on the short-term prognosis of patients who underwent colorectal cancer surgery. We conducted a single-center prospective cohort study in which 254 patients who received surgical treatment in a teaching tertiary care hospital were enrolled from March 2016 to November 2016. The patients were divided into four groups (I, II, III, and IV) based on individual compliance rates; the corresponding range of compliance rates was 0-60%, 60-70%, 70-80%, and 80-100%, and the number of patients in each group was 66, 63, 53, and 72, respectively. In the four groups from low to high compliance with ERAS (group I, II, III, and IV), the incidence of surgical site infections was 24.2%, 20.6%, 9.4%, and 6.9% (P < 0.05); the overall incidence of postoperative complications was 41.3%, 33.3%, 26.4%, and 16.7% (P < 0.05); the median length of postoperative hospital stay (in days) was 12.5, 10, 9, 8 (P < 0.05); and the median total hospital cost (Chinese Yuan) was 71,733, 73,632, 65,861, and 63,289 (P < 0.05), respectively. These results suggest that higher compliance with the ERAS protocol was associated with a lower incidence of surgical site infections, lower overall postoperative complication rate, shorter postoperative hospital stays, and lower total hospital costs. PMID- 28881830 TI - Value of quantitative magnetic resonance imaging T1-relaxometry in predicting contrast-enhancement in glioblastoma patients. AB - SUMMARIZING THE IMPORTANCE OF THE STUDY: The repetitive usage of gadolinium-based contrast agents (GBCA) is critical for magnetic resonance imaging (MRI) evaluation of tumor burden in glioblastoma patients. It is also a crucial tool for determination of radiographical response to treatment. GBCA injection, however, comes with a 2.4% rate of adverse events including life-threatening conditions such as nephrogenic systemic fibrosis (NSF). Moreover, GBCA have been shown to be deposited in brain tissue of patients even with an intact blood-brain barrier (BBB). The present study explores quantitative T1 relaxometry as an alternative non-invasive imaging technique detection of tumor burden and determination of radiographical response. This technique exploits specific properties of brain tissue with impaired BBB. With a sensitivity and specificity as high as 86% and 80%, respectively, quantitative T1-relaxometry allows for detecting contrast-enhancing areas without the use of GBCA. This method could make it unnecessary to subject patients to the risk of adverse events associated with the use of GBCA. Nonetheless, a large-scale analysis is needed to confirm our findings. BACKGROUND: Gadolinium-based contrast agents (GBCA) are crucial for magnetic resonance imaging (MRI)-based evaluation of tumor burden in glioblastoma (GBM). Serious adverse events of GBCA, even though uncommon, and gadolinium deposition in brain tissue could be avoided by novel imaging techniques not requiring GBCA. Altered tissue composition in areas with impaired blood-brain barrier also alters the quantified T1 relaxation time (qT1), so that qT1 analysis could replace GBCA-based MRI for the analysis of tumor burden and response. METHODS: As a part of a prospective pilot MRI-relaxometry trial, patients with newly-diagnosed GBM who relapsed under standard radiochemotherapy were selected for this study. At recurrence, subtraction of qT1 maps pre and post-GBCA application (DeltaqT1 maps) was used to determine areas of contrast-enhancement. With the contrast-enhancement on DeltaqT1 maps as reference, ROC analysis served to detect an optimal qT1 cut-off on qT1 maps prior to GBCA to distinguish between contrast-enhancing tissue and its surroundings. RESULTS: Ten patients were included. A qT1 value >2051ms predicted contrast-enhancing tumor tissue with a sensitivity of 86% and specificity of 80% (AUC, 0.92; p<0.0001). Interestingly, qT1 prolongation >2051 ms that did not overlap with contrast-enhancing area transformed into contrast-enhancement later on (n=4). CONCLUSION: T1-relaxometry may be a useful technique to assess tissue properties equivalent to contrast enhancement without the need for GBCA application. It may also provide information on sites with future tumor progression. Nonetheless, large-scale studies are needed to confirm these findings. PMID- 28881831 TI - A vitamin D receptor agonist converts CD4+ T cells to Foxp3+ regulatory T cells in patients with ulcerative colitis. AB - One of the pathological features of ulcerative colitis (UC) is the dysfunction of immune regulatory T cells (Treg cells); the pathogenesis is unclear and needs to be further investigated. Vitamin D has immune regulatory functions. This study tests a hypothesis that vitamin D receptor (VDR) regulates Treg cell differentiation. Peripheral blood samples were collected from UC patients and healthy subjects. The correlation between VDR expression and T helper (Th)2 cell differentiation in peripheral CD4+ T cells was analyzed. We observed that the expression of VDR was lower, the expression of interleukin (IL)-4 was higher, in peripheral CD4+ T cells of UC patients than that in healthy controls. Naive CD4+ T cells from VDR deficient mice were prone to differentiating into Th2 cells, which could be adjusted by the presence of VDR agonists. The Th2 polarization status in the peripheral CD4+ T cells of UC patients could be converted to regulatory T cells in the culture in the presence of VDR agonists. In conclusion, the peripheral Th2 cells in UC patients can be converted to regulatory T cells by VDR agonists in the culture. The results suggest that administration of VDR agonists at proper dosages may improve the immunity of UC patients. PMID- 28881832 TI - The novel sphingosine-1-phosphate receptors antagonist AD2900 affects lymphocyte activation and inhibits T-cell entry into the lymph nodes. AB - Sphingolipid derivatives play key roles in immune cell migration and function. Synthetic sphingolipid analogues are used as therapeutics to intervene various inflammatory and malignant conditions. We hypothesize that different analogs have different effects on immune cells and therefore can be used as treatment for specific diseases. This study examines the properties of the novel synthetic sphingolipid analog, AD2900, and its effects on immune cell activation and lymphocyte localization in homeostasis. AD2900 is an antagonist for all sphingosine-1-phosphate (S1P) receptors. It demonstrates a significant inhibitory effect on the proliferation of activated human peripheral blood mononuclear cells, which is dependent on cAMP reduction and calcium signal transduction but not on phospholipase C activation. AD2900 causes a significant but reversible downregulation of S1P1 expression on the cell surface. AD2900 administration to C57BL/6J mice leads to the accumulation of T cells in the blood and spleen and in turn reduces T-cell number in the lymph nodes. Moreover, AD2900 treatment shows significant effects on the localization of T-cell subpopulations. These results demonstrate the key roles of S1P in T-cell trafficking in a steady state and suggest a potential clinical application for AD2900. Notably, this sphingolipid analog does not cause a severe lymphopenia. The clinical effect of AD2900 in hemato-oncologic diseases and immune-related diseases needs further investigation. PMID- 28881834 TI - Selective ATP hydrolysis inhibition in F1Fo ATP synthase enhances radiosensitivity in non-small-cell lung cancer cells (A549). AB - BACKGROUND: F1Fo-ATP synthase (F1Fo-ATPase) is a reversibly rotary molecular machine whose dual functions of synthesizing or hydrolyzing ATP switch upon the condition of cell physiology. The robust ATP-hydrolyzing activity occurs in ischemia for maintaining the transmembrane proton motive force of mitochondria inner membrane, but the effect of F1Fo-ATPase on X-ray response of non-small-cell lung cancer (NSCLC) cells is unknown. METHODS AND FINDINGS: We studied whether ATP hydrolysis affected X-ray radiation induced cell death. NSCLC cells (A549) were pretreated with BTB06584 (BTB), an elective ATP hydrolysis inhibitor, followed by X-ray radiation. Cell viability and clonogenic survival were markedly decreased, clear indications of enhanced radiosensitivity through BTB incubation. Additionally, ATP5alpha1 was upregulated in parallel with elevated ATP hydrolytic activity after X-ray radiation, showing an increased mitochondrial membrane potential (DeltaPsim). ATP hydrolysis inhibition led to collapse of DeltaPsim suggesting ATP hydrolytic activity could enhance DeltaPsim after X-ray radiation. Furthermore, we also demonstrated that apoptosis was pronounced with the prolonged collapse of DeltaPsim due to hydrolysis inhibition by BTB incubation. CONCLUSION: Overall, these findings supported that ATP hydrolysis inhibition could enhance the radiosensitivity in NSCLC cells (A549) after X-ray radiation, which was due to the collapse of DeltaPsim. PMID- 28881835 TI - XPG gene rs751402 C>T polymorphism and cancer risk: Evidence from 22 publications. AB - The Xeroderma pigmentosum group G (XPG) gene promotes recognition and excision of damaged DNA during the DNA repair process. We conducted a comprehensive search of the MEDLINE, EMBASE, and Chinese Biomedical databases for publications evaluating the association XPG gene rs751402 C>T polymorphism and overall cancer risk. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were adopted to assess the strength of the association. A total of 22 publications encompassing 10538 cases and 10511 control subjects were included in the final meta-analysis. We found the polymorphism to be associated with increased cancer risk (TT vs. CC: OR = 1.18, 95% CI = 1.01-1.38, P = 0.040; CT vs. CC: OR = 1.12, 95% CI = 1.01 1.24, P = 0.040; and CT/TT vs. CC: OR = 1.12, 95% CI = 1.002-1.26, P = 0.045). Stratification by cancer type indicated that this polymorphism may increase the risk of gastric cancer and hepatocellular carcinoma, which was further confirmed by a false-positive report probability analysis. Genotype-based mRNA expression provides further evidence that this polymorphism is associated with altered XPG mRNA expression. This meta-analysis suggests XPG gene rs751402 C>T polymorphism correlates with overall cancer risk, especially for gastric cancer and hepatocellular carcinoma. PMID- 28881833 TI - lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling. AB - Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can undergo self-renewal and differentiate into multiple lineages. Osteogenic differentiation from MSCs is a well-orchestrated process and regulated by multiple signaling pathways. We previously demonstrated that BMP9 is one of the most potent osteogenic factors. However, molecular mechanism through which BMP9 governs osteoblastic differentiation remains to be fully understood. Increasing evidence indicates noncoding RNAs (ncRNAs) may play important regulatory roles in many physiological and/or pathologic processes. In this study, we investigate the role of lncRNA H19 in BMP9-regulated osteogenic differentiation of MSCs. We demonstrated that H19 was sharply upregulated at the early stage of BMP9 stimulation of MSCs, followed by a rapid decease and gradual return to basal level. This process was correlated with BMP9-induced expression of osteogenic markers. Interestingly, either constitutive H19 expression or silencing H19 expression in MSCs significantly impaired BMP9-induced osteogenic differentiation in vitro and in vivo, which was effectively rescued by the activation of Notch signaling. Either constitutive H19 expression or silencing H19 expression led to the increased expression of a group of miRNAs that are predicted to target Notch ligands and receptors. Thus, these results indicate that lncRNA H19 functions as an important mediator of BMP9 signaling by modulating Notch signaling-targeting miRNAs. Our findings suggest that the well-coordinated biphasic expression of lncRNA H19 may be essential in BMP9-induced osteogenic differentiation of MSCs, and that dysregulated H19 expression may impair normal osteogenesis, leading to pathogenic processes, such as bone tumor development. PMID- 28881836 TI - The prevalence of depression in rheumatoid arthritis in China: A systematic review. AB - This systematic review is to explore the prevalence of depression in patients with rheumatoid arthritis (RA) in China. Articles of prevalence rates for depression in adult RA patients published before October 2015 were identified from PubMed, Embase, The Cochrane Library, CNKI, CBM, VIP, and Wanfang database and other internet databases. Relevant journals and the recommendations of expert panels were also searched manually. Two independent reviewers searched and assessed the literature. Therelevant data were applied with Meta-Analyst 3.13 software, and the forest plot and funnel plot were performed. 21 studies with a total of 4447 patients were selected to be enrolled in this study. The prevalence of depression by analyzing the effect size was 48% [95% CI (41%, 56%)]. The prevalence of minor depression and dysthymic disorder was 30% [95%CI (23%, 38%)], and the moderate or major depression was 18% [95%CI (11%, 29%)], respectively. Subgroup analysis showed that the depression rate of female RA patients was higher than male. The depression rate in the central and western areas were higher than that of the eastern region of China, the prevalence level estimated by the Geriatric Depression Scale (GDS) was higher than estimated by other tools. Sensitivity analysis showed that the pooled effect size had good stability and reliability, To be conclusive, the prevalence rate of depression in RA patients is 48%, which suggesting that medical staff should pay more attention to depression in adult patients with RA. PMID- 28881837 TI - The impact of primary tumor location on efficacy of cetuximab in metastatic colorectal cancer patients with different Kras status: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the prognostic role of primary tumor location along with Kras status in metastatic colorectal cancer (mCRCs) treated with cetuximab. MATERIALS AND METHODS: Databases of EMBASE, Pubmed, the Cochrane library, China National Knowledge Infrastructure and other databases from inception to July 2016 were searched. Randomized controlled trial (RCT) and/or retrospective studies of influence of primary tumor location on efficacy of cetuximab in patients with mCRC were identified. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), overall response rate (ORR) and disease control rate (DCR). RESULTS: Ten studies including 2977 cases were finally included. The results of meta-analysis were in favor of cetuximab to patients with left-sided colorectal cancer in terms of OS (HR = 0.52, 95% CI: 0.40-0.66; p < 0.01), PFS (HR = 0.64, 95% CI: 0.58-0.70; p < 0.01), and ORR (OR = 2.17, 95% CI: 1.57-2.99; p < 0.01). Patients with right-sided CRC gained less benefit from cetuximab in terms of OS (HR = 1.89, 95% CI: 1.43-2.50; p < 0.01), compared with left-sided CRC. Regarding Kras status, left-sided mCRC with wild type Kras had better PFS (HR = 0.61, 95% CI: 0.51-0.74; p < 0.01) and OS (HR = 0.49, 95% CI: 0.35-0.69; p < 0.01) than right-sided cases when treated with cetuximab. We also found that cetuximab was both significantly effective in different treatment lines and regions when comparing by primary tumor locations (p < 0.01). CONCLUSIONS: mCRC Patients with left-sided, wild type Kras have a better prognosis than those with right-sided diseases when treated with cetuximab. The clinical application of cetuximab should be determined by the primary tumor location and molecular gene mutation status. PMID- 28881838 TI - Prognostic value of molecular events from negative surgical margin of non-small cell lung cancer. AB - It is hypothesized that the molecular status in negative surgical margin (NSM) is associated with prognosis of cancer patients. In this study, the prognostic relevance of Epithelial-to-Mesenchymal Transition (EMT) molecular events in NSMs in patients with NSCLC was investigated. EMT model was developed, in which the mesenchymal transition of human immortalized bronchial epithelial cell line was induced by TGF-beta1. Gene expression of EMT-induced cells and NSMs from 60 lung squamous cell carcinoma (SCC) patients was profiled by microarray and validated by quantitative RT-PCR. Two independent cohorts (lung SCC, n = 50; NSCLC, n = 54) were employed to validate the prognostic value of candidate genes. A set of 1490 genes were identified in EMT model in vitro. An EMT-like gene-expression pattern by 33 essential genes was optimized in NSMs, and was significantly associated with tumor progression. The 33 genes also exhibited a site-dependent field cancerization effect in the normal-appearing airways adjacent to NSCLCs. In the independent lung SCC cohort, the EMT-like active pattern indicated poor outcome of patients (n = 50, log-rank p = 0.009). Furthermore, in the NSCLC cohort, patients with EMT-like active pattern had shorter predictive survival time (n = 54, log-rank p = 0.02). In conclusion, the existence of EMT-like gene expression in NSMs, may play critical role in tumor progression and be a potential biomarker for prognosis in patients with NSCLC. PMID- 28881839 TI - Decitabine-based chemotherapy followed by haploidentical lymphocyte infusion improves the effectiveness in elderly patients with acute myeloid leukemia. AB - In this study, we first initiated a multicenter, single-arm, phase-II clinical trial using decitabine (DAC) (20mg/m2 for five days) based chemotherapy, followed by haploidentical lymphocyte infusion (HLI) that was applied as induction therapy for elderly patients with AML. Furthermore, the role of HLI infusion was explored in a mouse model. The clinical trial included 29 elderly patients (median age: 64, range 57-77) with AML. Sixteen cases achieved complete remission (CR) and 9 cases achieved partial remission (PR) after the first treatment cycle. Of the patients with PR, 5 subjects achieved remission after the second induction, which brings the overall CR rate to 72.4%. The 2-year overall survival (OS) and disease free survival (DFS) was 59.6% and 36.9% respectively. The treatment regimen was well tolerated with only one patient died of severe pneumonia one month after the first treatment. In the mouse experiment, we found that DAC/HLI significantly enhanced the survival of leukemic mice. These results suggested that DAC-based chemotherapy combined with HLI is an alternative first line induction therapy for elderly patients with AML. This trial is registered at ClinicalTrials.gov (NCT01690507). PMID- 28881840 TI - Tumor heterogeneity assessed by texture analysis on contrast-enhanced CT in lung adenocarcinoma: association with pathologic grade. AB - Objectives To investigate whether texture features on contrast-enhanced computed tomography (CECT) images of lung adenocarcinoma have association with pathologic grade. Methods A cohort of 148 patients with surgically operated adenocarcinoma was retrospectively reviewed. Fifty-four CT features of the primary lung tumor were extracted from CECT images using open-source 3D Slicer software; meanwhile, enhancement homogeneity was evaluated by two radiologists using visual assessment. Multivariate logistic regression analysis was performed to determine significant image indicator of pathologic grade. Results Tumors of intermediate grade were more likely to be never smokers (P=0.020). Enhancement heterogeneity by visual assessment showed no statistical difference between intermediate grade and high grade (P=0.671). Among those 54 features, 29 of them were significantly associated with pathologic grade. Multivariate logistic regression analyses identified F33 (Homogeneity 1) (P=0.005) and F38 (Inverse Variance) (P=0.032) as unique independent image indicators of pathologic grade, and the AUC calculated from this model (AUC=0.834) was higher than clinical model (AUC=0.615) (P=0.0001). Conclusions Our study revealed that texture analysis on CECT images could be helpful in predicting pathologic grade of lung adenocarcinoma. PMID- 28881841 TI - Efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in targeted therapy of lung squamous cell carcinoma patients with EGFR mutation: a pooled analysis. AB - PURPOSE: This pooled analysis aims to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in lung squamous cell carcinoma with EGFR mutation. METHODS: Advanced stage (IIIB/IV) lung squamous cell carcinoma patients with EGFR mutations treated with EGFR-TKIs were extracted from the publications searched from the databases of EMBASE, Medline (Ovid SP), Web of Science, Cochrane library, PubMed Publisher, ASCO meeting abstract and Google Scholar before August 2016, or identified from the database of Shanghai Chest Hospital from July 2014 to August 2016. Pooled objective response rate, disease control rate and median progression-free survival were accessed directly or by Kaplan-Meier method and combined in different studies by Comprehensive Meta Analysis software via one-group dichotomous or continuous analysis functions. RESULTS: The combined objective response rate, disease control rate and median progression-free survival were 31.6% (95%CI, 24.1%~40.2%), 72.0% (95% CI, 63.5%~79.2%) and 3.08 months (95% CI, 2.31-3.84 months) in lung squamous cell carcinoma patients with EGFR mutation. CONCLUSION: The EGFR-TKIs had a modest response for EGFR mutated lung squamous cell carcinoma patients and might be a selective option for those patients. PMID- 28881842 TI - Effect of age on long-term outcomes after stroke with atrial fibrillation: a hospital-based follow-up study in China. AB - Atrial fibrillation (AF) is an established predictor of poor outcomes after stroke. We aimed to assess the effect of age on outcomes at 1 year and 3 years in stroke patients with AF. We recruited acute ischemic stroke patients with AF between January 2006 and September 2014 in Tianjin, China. Clinical features and outcomes at 1 year and 3 years after stroke were compared between younger group and elderly group. Overall, 951 consecutive stroke patients with AF were included in this study. There was a higher mortality and dependency rate in the elderly group than in the young group at both 1 and 3 years after stroke. Recurrence rates were significantly higher in the elderly group than in the young group at 3 years after stroke. The higher risks of mortality and dependency in elderly patients remained unchanged, but disappeared in recurrence rates after adjusting for stroke subtype, severity, risk factors, and lifestyle. These findings suggest that it is crucial to highlight the treatment of elderly stroke patients with AF in order to reduce poor outcomes and to reduce the burden of AF in China. PMID- 28881843 TI - Dynamic changes in serum cytokine levels and their clinical significance in predicting acute GVHD. AB - To explore the clinical significance of cytokines and biochemical tests in acute graft-versus-host disease (aGVHD), we detected the concentrations of 8 cytokines and 19 conventional biochemical markers in the sera of aGVHD and non-GVHD patients throughout the process of allogeneic hematopoietic stem cell transplantation and the onset of aGVHD. Predictive models were then established using the 27 indices, and models were verified by a prospective trial. The 27 indices showed significant differences between aGVHD patients and non-GVHD control subjects (two-tailed p<0.05) prior to transplantation and before the onset of aGVHD. Our models, established by binary logistic regression on days +7 and +14, showed a significant absolute capacity of predicting grade 2~4 aGVHD with positive and negative predictive values of at least 70%. Our data showed that the progression of aGVHD could induce dynamic changes in the levels of serum cytokines and biochemical markers. Because most of these tests were less specific for aGVHD, these changes were easily neglected in clinical work. However, by combining cytokine and biochemical tests, the established prediction model can greatly improve the ability of these biomarkers to predict the development of aGVHD one or two weeks earlier. PMID- 28881844 TI - Methotrexate plus idarubicin improves outcome of patients with primary central nervous system lymphoma. AB - Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with poor long-term survival. This study assessed methotrexate (MTX) plus idarubicin (IDA) in treating patients of PCNSL comparing to MTX alone therapy. A total of 100 patients were retrospectively enrolled and subjected to MTX alone (n = 52) and MTX plus IDA (n = 48). The completed response (CR) rate in patients treated with MTX plus IDA was 62.50%, and overall response (OR) rate was 79.17%, which in MTX alone cohort were 42.31% and 63.46% respectively. Median progression-free survival (PFS) of patients treated with MTX plus IDA was significantly better than those treated with MTX alone (18.35 months vs.8.45months, P = 0.000). The MTX plus IDA regimen exhibited a significantly better control of PCNSL. Further studies would be needed to confirm these results. PMID- 28881845 TI - Gender differences in fibrosis remodeling in patients with long-standing persistent atrial fibrillation. AB - The success rate of catheter ablation in atrial fibrillation (AF) is known to be lower in females than in males. However, while the exact mechanism for this phenomenon remains to be elucidated, tissue fibrosis may play an important role in this regard. It has been shown that fibrosis promotes AF and its recurrence, thereby substantially reducing the efficacy of catheter ablation in AF patients. Thus, we hypothesized that fibrosis may contribute to gender differences in the outcomes of AF catheter ablation. Here we systematically assessed pulmonary vein sleeves obtained from 166 patients with and without long-standing persistent-AF (LSP-AF) in order to identify gender-specific mechanistic differences in fibrosis remodeling of AF patients. Histological analysis revealed that the female LSP-AF group, rather than its male counterpart, had a higher degree of fibrosis when compared to the NON-AF group. Further analysis using microarray, immunohistochemistry and Western Blot displayed that gender differences in fibrosis remodeling of LSP-AF were mainly due to the inherent differential expression of fibrosis-related genes (n=32) and proteins (n=6). Especially, those related to the TGFbeta/Smad3 pathway appeared to be up-regulated in the female LSP-AF group thus promoting an aggravation of fibrosis remodeling. In summary, our data suggest that the aggravation of fibrosis remodeling in women may be an important reason for the low success rate of AF catheter ablation when compared to men. Therefore, inhibiting the TGFbeta/Smad3 pathway-mediated fibrosis could represent an interesting target for future therapeutic concepts to improve the success rate of AF catheter ablation in women. PMID- 28881846 TI - Safety and efficacy of p62 DNA vaccine ELENAGEN in a first-in-human trial in patients with advanced solid tumors. AB - Elenagen is a plasmid encoding p62/SQSTM1, the first DNA vaccine possessing two mutually complementing mechanisms of action: it elicits immune response against p62 and mitigates systemic chronic inflammation. Previously, Elenagen demonstrated anti-tumor efficacy and safety in rodent tumor models and spontaneous tumors in dogs. This multicenter I/IIa trial evaluated safety and clinical activity of Elenagen in patients with advanced solid tumors. Fifteen patients were treated with escalating doses of Elenagen (1- 5 mg per doses, 5 times weekly) and additional 12 patients received 1 mg dose. Ten patients with breast and ovary cancers that progressed after Elenagen were then treated with conventional chemotherapy. Adverse events (AE) were of Grade 1; no severe AE were observed. Cumulatively twelve patients (44%) with breast, ovary, lung, renal cancer and melanoma achieved stable disease for at least 8 wks, with 4 of them (15%) had tumor control for more than 24 wks, with a maximum of 32 wks. The patients with breast and ovary cancers achieved additional tumor stabilization for 12-28 wks when treated with chemotherapy following Elenagen treatment. Therefore, Elenagen demonstrated good safety profile and antitumor activity in advanced solid tumors. Especially encouraging is its ability to restore tumor sensitivity to chemotherapy. PMID- 28881847 TI - To predict the radiosensitivity of nasopharyngeal carcinoma using intravoxel incoherent motion MRI at 3.0 T. AB - PURPOSE: To investigate intravoxel incoherent motion (IVIM) MRI for evaluating the sensitivity of radiotherapy on nasopharyngeal carcinoma (NPC). RESULTS: The reproducibility between intra-observer and inter-observer was relatively good. D (0.72*10-3 mm2/s+/-0.14 vs. 0.54*10-3 mm2/s+/-0.23; P < 0.001) and D* (157.92*10 3 mm2/s+/-15.21 vs. 120.36*10-3 mm2/s+/-10.22; P < 0.0001) were significantly higher in effective group than poor-effective group, whereas the difference of f (18.79%+/-2.51 vs. 16.47%+/-1.51) and ADC (1.21*10-3 mm2/s+/-0.11 vs. 1.33*10-3 mm2/s+/-0.23) could not reach statistical significant between the 2 groups (P > 0.05). CONCLUSIONS: IVIM may be potentially useful in assessing the radiosensitivity of NPC. The higher D value combining with higher D* value might indicate the more radiosensitive of NPC, and increased D* might reflect increased blood vessel generation and parenchymal perfusion in NPC. MATERIALS AND METHODS: Sixty consecutive patients (20 female, range, 27-83 years, mean age, 52 years) newly diagnosed NPC in the stage of T3 or T4 were enrolled. Forty-two of them were divided into effective group clinically after a standard radiotherapy according to the RECIST criteria. IVIM with 13 b-values (range, 0-800 s/mm2) and general MRI were performed at 3.0T MR scanner before and after radiotherapy. The parameters of IVIM including perfusion fraction (f), perfusion-related diffusion (D*), pure molecular diffusion (D) and apparent diffusion coefficient (ADC) were calculated. Two radiologists major in MRI diagnose analyzed all images independently and placed regions of interest (ROIs). Intra-class correlation coefficient (ICC) was used to evaluate intra-observer and inter-observer agreement. And Mann-Whitney test was used to assess the differences between the two groups. PMID- 28881848 TI - Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moonshot? AB - Early diagnosis of malignant pleural mesothelioma (MPM) is a challenge for clinicians. The disease is usually detected in an advanced stage which precludes curative treatment. We assume that only new and non-invasive biomarkers allowing earlier detection will result in better patient management and outcome. Many efforts have already been made to find suitable biomarkers in blood and pleural effusions, but have not yet resulted in a valid and reproducible diagnostic one. In this review, we will highlight the strengths and shortcomings of blood and fluid based biomarkers and highlight the potential of breath analysis as a non invasive screening tool for MPM. This method seems very promising in the early detection of diverse malignancies, because exhaled breath contains valuable information on cell and tissue metabolism. Research that focuses on breath biomarkers in MPM is in its early days, but the few studies that have been performed show promising results. We believe a breathomics-based biomarker approach should be further explored to improve the follow-up and management of asbestos exposed individuals. PMID- 28881849 TI - Advances in single-cell RNA sequencing and its applications in cancer research. AB - : Unlike population-level approaches, single-cell RNA sequencing enables transcriptomic analysis of an individual cell. Through the combination of high throughput sequencing and bioinformatic tools, single-cell RNA-seq can detect more than 10,000 transcripts in one cell to distinguish cell subsets and dynamic cellular changes. After several years' development, single-cell RNA-seq can now achieve massively parallel, full-length mRNA sequencing as well as in situ sequencing and even has potential for multi-omic detection. One appealing area of single-cell RNA-seq is cancer research, and it is regarded as a promising way to enhance prognosis and provide more precise target therapy by identifying druggable subclones. Indeed, progresses have been made regarding solid tumor analysis to reveal intratumoral heterogeneity, correlations between signaling pathways, stemness, drug resistance, and tumor architecture shaping the microenvironment. Furthermore, through investigation into circulating tumor cells, many genes have been shown to promote a propensity toward stemness and the epithelial-mesenchymal transition, to enhance anchoring and adhesion, and to be involved in mechanisms of anoikis resistance and drug resistance. This review focuses on advances and progresses of single-cell RNA-seq with regard to the following aspects: 1. Methodologies of single-cell RNA-seq 2. Single-cell isolation techniques 3. Single-cell RNA-seq in solid tumor research 4. Single cell RNA-seq in circulating tumor cell research 5. PERSPECTIVES: PMID- 28881850 TI - Transforming growth factor beta: A potential biomarker and therapeutic target of ventricular remodeling. AB - Transforming growth factor beta (TGF-beta) is a multifunctional cytokine that is synthesized by many types of cells and regulates the cell cycle. Increasing evidence has led to TGF-beta receiving increased and deserved attention in recent years because it may play a potentially novel and critical role in the development and progression of myocardial fibrosis and the subsequent progress of ventricular remodeling (VR). Numerous studies have highlighted a crucial role of TGF-beta in VR and suggest potential therapeutic targets of the TGF-beta signaling pathways for VR. Changes in TGF-beta activity may elicit anti-VR activity and may serve as a novel therapeutic target for VR therapy. This review we discusses the smad-dependent signaling pathway, such as TGF-beta/Smads, TGF beta/Sirtuins, TGF-beta/BMP, TGF-beta/miRNAs, TGF-beta/MAPK, and Smad-independent signaling pathway of TGF-beta, such as TGF-beta/PI3K/Akt, TGF-beta/Rho/ROCK,TGF beta/Wnt/beta-catenin in the cardiac fibrosis and subsequent progression of VR. Furthermore, agonists and antagonists of TGF-beta as potential therapeutic targets in VR are also described. PMID- 28881851 TI - The involvement of DARPP-32 in the pathophysiology of schizophrenia. AB - Schizophrenia is one of the most devastating heterogeneous psychiatric disorders. The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia based on neurochemical evidences of elevated brain striatal dopamine synthesis capacity and increased dopamine release in response to stress. Dopamine and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000 (DARPP-32) is a cytosolic protein highly enriched in the medium spiny neurons of the neostriatum, considered as the most important integrator between the cortical input and the basal ganglia, and associated with motor control. Accumulating evidences has indicated the involvement of DARPP-32 in the development of schizophrenia; i. DARPP-32 phosphorylation is regulated by several neurotransmitters, including dopamine and glutamate, neurotransmitters implicated in schizophrenia pathogenesis; ii. decrease of both total and phosphorylated DARPP-32 in the prefrontal cortex are observed in schizophrenic animal models; iii. postmortem brain studies indicated decreased expression of DARPP-32 protein in the superior temporal gyrus and dorsolateral prefrontal cortex in patients with schizophrenia; iv. DARPP-32 phosphorylation is increased upon therapy with antipsychotic drugs, such as haloperidol and risperidone which improve behavioral performance in experimental animal models and patients; v. Genetic analysis of the gene coding for DARPP-32 propose an association with schizophrenia. Cumulatively, these findings implicate DARPP-32 protein in schizophrenia and propose it as a potential therapeutic target. Here, we summarize the possible roles of DARPP-32 during the development of schizophrenia and make some recommendations for future research. We propose that DARPP-32 and its interacting proteins may serve as potential therapeutic targets in the treatment of schizophrenia. PMID- 28881852 TI - Epigenetic dynamics and interplay during spermatogenesis and embryogenesis: implications for male fertility and offspring health. AB - Mapping epigenetic modifications and identifying their roles in the regulation of spermatogenesis and embryogenesis are essential for gaining fundamental medical understandings and for clinical applications. More and more evidence has shown that specific epigenetic modifications are established during spermatogenesis, which will be transferred into oocyte via fertilisation, and play an important role in the early embryo development. Defects in epigenetic patterns may increase the risk of abnormal spermatogenesis, fertilisation failure, early embryogenesis abnormality and several other complications during pregnancy. This review mainly discusses the relationship between altered epigenetic profiles and reproductive diseases, highlighting how epigenetic defects affect the quality of sperm and embryo. PMID- 28881853 TI - Succinate: An initiator in tumorigenesis and progression. AB - As an intermediate metabolite of the tricarboxylic acid cycle in mitochondria, succinate is widely investigated for its role in metabolism. In recent years, an increasing number of studies have concentrated on the unanticipated role of succinate outside metabolism, acting as, for instance, an inflammatory signal or a carcinogenic initiator. Actually, succinate dehydrogenase gene mutations and abnormal succinate accumulation have been observed in a battery of hereditary and sporadic malignancies. In this review, we discuss the unexpected role of succinate and possible mechanisms that may contribute to its accumulation. Additionally, we describe how the high concentration of succinate in the tumor microenvironment acts as an active participant in tumorigenesis, rather than a passive bystander or innocent victim. Focusing on mechanism-based research, we summarize some targeted therapies which have been applied to the clinic or are currently under development. Furthermore, we posit that investigational drugs with different molecular targets may expand our horizon in anticancer therapy. PMID- 28881854 TI - Microbiota-gut-brain axis and the central nervous system. AB - The gut and brain form the gut-brain axis through bidirectional nervous, endocrine, and immune communications. Changes in one of the organs will affect the other organs. Disorders in the composition and quantity of gut microorganisms can affect both the enteric nervous system and the central nervous system (CNS), thereby indicating the existence of a microbiota-gut-brain axis. Due to the intricate interactions between the gut and the brain, gut symbiotic microorganisms are closely associated with various CNS diseases, such as Parkinson's disease, Alzheimer's disease, schizophrenia, and multiple sclerosis. In this paper, we will review the latest advances of studies on the correlation between gut microorganisms and CNS functions & diseases. PMID- 28881855 TI - The role of Notch signaling in gastric carcinoma: molecular pathogenesis and novel therapeutic targets. AB - Notch signaling, an evolutionarily conserved signaling cascade system, is involved in promoting the progression of different types of cancers. Within the past decades, the Notch signaling pathway has increasingly been shown to have a primary role in deciding the fate of cancer cells and cancer stem cells in the stomach. Most components of Notch signaling are strongly expressed at different levels in gastric carcinoma tissue samples and are associated with a considerable number of clinical parameters. Moreover, crosstalk signaling between the Notch pathway and the Wnt, Ras, and NF-kappaB pathways promotes the process of gastric carcinogenesis. Consequently, this increases proliferation and prevents apoptosis in gastric cancer cells, and it contributes to the induction of angiogenesis and accelerates the progression of the epithelial-to-mesenchymal transition. Although the Notch signaling pathway presents novel therapeutic targets for cancer therapeutic intervention, there is still a dearth of in-depth understanding of the molecular mechanisms of Notch signaling in gastric carcinoma. In this review, we summarize the landscape of the Notch signaling pathway and recent findings on Notch signaling in gastric cancer. Furthermore, advanced studies and clinical treatments targeting the Notch signaling pathway arediscussed. PMID- 28881856 TI - Strategies targeting angiogenesis in advanced non-small cell lung cancer. AB - Tumor angiogenesis is a frequent event in the development and progression of non small cell lung cancer (NSCLC) and has been identified as a promising therapeutic target. The vascular endothelial growth factor (VEGF) family and other angiogenic factors, including fibroblast growth factor and platelet-derived growth factor, promote the growth of newly formed vessels from preexisting vessels and change the tumor microenvironment. To date, two antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab, which target VEGF-A and its receptor VEGF receptor 2, respectively, have been approved for the treatment of locally advanced or metastatic NSCLC when added to first-line standard chemotherapy. Numerous oral multitargeting angiogenic small molecule tyrosine kinase inhibitors (TKIs) have been widely evaluated in advanced NSCLC, but only nintedanib in combination with platinum-based doublet chemotherapy has demonstrated a survival benefit in the second-line setting. Additionally, small-molecule TKIs remain the standard of care for patients with mutated EGFR, ALK or ROS1. Moreover, immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) are changing the current strategy in the treatment of advanced NSCLC without driver gene mutations. The potential synergistic activity of antiangiogenic agents and TKIs or immunotherapy is an interesting topic of research. This review will summarize the novel antiangiogenic agents, antiangiogenic monotherapy, as well as potential combination therapeutic strategies for the clinical management of advanced NSCLC. PMID- 28881857 TI - Genetic association between TNF-alpha promoter polymorphism and susceptibility to squamous cell carcinoma, basal cell carcinoma, and melanoma: A meta-analysis. AB - Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional pro-inflammatory cytokine that plays an important role in cancer development. We performed a meta analysis to assess the relationship between single nucleotide polymorphisms in the TNF-alpha promoter region (rs1800629 and rs361525) and susceptibility to squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. After database retrieval, article selection, data extraction, and quality assessment, 20 articles comprising 4865 cases and 6329 controls were included in this study. rs1800629 was associated with an increased overall risk of SCC, lung SCC, and oral SCC in the AA vs G and AA vs GG+GA genetic models (all OR>1, Passociation <0.05). No increased risk of skin SCC, skin BCC or melanoma was observed (all Passociation >0.05). Rs361525 was not associated with overall SCC risk in the allele, heterozygote, dominant, recessive, or carrier model (all Passociation >0.05). Begg's and Egger's tests (PBegg>0.05; PEgger>0.05) demonstrated there was no significant publication bias. These data indicate that the AA genotype of TNF alpha rs1800629, but not rs361525, is associated with an increased risk of SCC, suggesting it could potentially serve as a prognostic marker for predicting SCC risk. PMID- 28881858 TI - Correction: Deciphering the role of nuclear and cytoplasmic IKKalpha in skin cancer. AB - [This corrects the article DOI: 10.18632/oncotarget.8792.]. PMID- 28881859 TI - Correction: IKKalpha regulates the stratification and differentiation of the epidermis: implications for skin cancer development AB - [This corrects the article DOI: 10.18632/oncotarget.12527.] PMID- 28881861 TI - International travel and blood donation: risks and restrictions. PMID- 28881862 TI - Use of antimicrobial agents for treatment and prevention of travellers' diarrhoea in the face of enhanced risk of transient fecal carriage of multi-drug resistant enterobacteriaceae: setting the stage for consensus recommendations. AB - Background: The recommendation that antibiotics should be used for routine therapy of travellers' diarrhoea is being reconsidered in view of growing evidence that the therapy may lead to intestinal carriage of multi-drug resistant (MDR) colonic microbiota. This review attempts to put the issues of therapy and MDR acquisition in perspective to help in the establishment of therapeutic recommendations for travellers' diarrhoea. Methods: The existing literature showing the risk and consequences of acquisition of MDR microbiota in antibiotic treated travellers was reviewed. Issues important to the development of firm evidence-based recommendations for antibiotics use for treatment and prevention of travellers' diarrhoea were researched. Results: Six areas of research needed to allow the development of evidence-based recommendations for antibiotic treatment and -prevention of travellers' diarrhoea were identified. Conclusions: Increasing worldwide occurrence of antibiotic resistance should alert public health officials of the importance of encouraging local antibiotic stewardship guidelines. Six areas to research are identified in this review to allow the development of evidence-based recommendations for use of antibiotics for treatment and selective prevention of travellers' diarrhoea. An interdisciplinary ISTM Consensus group will consider the data available and develop current recommendations for therapy and chemoprevention of travellers' diarrhoea considering groups who would benefit the most from antimicrobials while recognizing the hazards associated with broad use of these drugs. With interim recommendations and ultimately evidence-based recommendations, guidelines can be developed for management of travellers' diarrhoea considering populations and destinations. PMID- 28881863 TI - Disrupting IGF Signaling in Adult Mice Conditions Leanness, Resilient Energy Metabolism, and High Growth Hormone Pulses. AB - Growth hormone (GH) and insulinlike growth factor (IGF) promote aging and age related pathologies. Inhibiting this pathway by targeting IGF receptor (IGF-1R) is a promising strategy to extend life span, alleviate age-related diseases, and reduce tumor growth. Although anti-IGF-1R agents are being developed, long-term effects of IGF-1R blockade remain unknown. In this study, we used ubiquitous inducible IGF-1R knockout (UBIKOR) to suppress signaling in all adult tissues and screened health extensively. Surprisingly, UBIKOR mice showed no overt defects and presented with rather inconspicuous health, including normal cognition. Endocrine GH and IGF-1 were strongly upregulated without causing acromegaly. UBIKOR mice were strikingly lean with coordinate changes in body composition and organ size. They were insulin resistant but preserved physiological energy expenditure and displayed enhanced fasting metabolic flexibility. Thus, long-term IGF-1R blockade generated beneficial effects on aging-relevant metabolism, but exposed to high GH. This needs to be considered when targeting IGF-1R to protect from neurodegeneration, retard aging, or fight cancer. PMID- 28881864 TI - Ghrelin: A Link Between Energy Homeostasis and the Immune System. PMID- 28881865 TI - Insulinotropic Actions of GLP-1: How Much in the Brain and How Much in the Periphery? PMID- 28881866 TI - CRISPR Fish Reel in Novel Roles for Estrogen Receptors in Reproduction. PMID- 28881867 TI - Estrogen Deficiency Plus Type 1 Diabetes: A Double-Dip for Bone Loss. PMID- 28881868 TI - PGC1alpha Promoter Methylation and Nucleosome Repositioning: Insights Into Exercise and Metabolic Regulation in Skeletal Muscle. PMID- 28881869 TI - Female Fertility: It Takes Two to Tango. PMID- 28881870 TI - Corrigendum for "Misfolding Ectodomain Mutations of the Lutropin Receptor Increase Efficacy of Hormone Stimulation". PMID- 28881871 TI - Secretory Granules Tell (Almost) All in Enteroendocrine Cells. PMID- 28881873 TI - Corrigendum. PMID- 28881872 TI - Hypertension and cardiac arrhythmias: a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE). AB - Hypertension is a common cardiovascular risk factor leading to heart failure (HF), coronary artery disease, stroke, peripheral artery disease and chronic renal insufficiency. Hypertensive heart disease can manifest as many cardiac arrhythmias, most commonly being atrial fibrillation (AF). Both supraventricular and ventricular arrhythmias may occur in hypertensive patients, especially in those with left ventricular hypertrophy (LVH) or HF. Also, some of the antihypertensive drugs commonly used to reduce blood pressure, such as thiazide diuretics, may result in electrolyte abnormalities (e.g. hypokalaemia, hypomagnesemia), further contributing to arrhythmias, whereas effective control of blood pressure may prevent the development of the arrhythmias such as AF. In recognizing this close relationship between hypertension and arrhythmias, the European Heart Rhythm Association (EHRA) and the European Society of Cardiology (ESC) Council on Hypertension convened a Task Force, with representation from the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE), with the remit to comprehensively review the available evidence to publish a joint consensus document on hypertension and cardiac arrhythmias, and to provide up-to-date consensus recommendations for use in clinical practice. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and the patient in light of all of the circumstances presented by that patient. PMID- 28881874 TI - Oncopression: gene expression compendium for cancer with matched normal tissues. AB - Motivation: Expression profile of normal tissue is primary source to find genes showing aberrant expression pattern specific in matched cancer tissue, but sample number of normal control in public gene expression repositories is disproportionally small compared to cancer and scattered in several datasets. Results: We built oncopression by integrating several datasets into one large dataset for comprehensive analysis about 25 types of human cancers including 20 640 cancer samples and 6801 normal control profiles. Expression profiles in cancers can be directly compared to normal tissue counterparts. Validity of the integration was tested using immunohistochemical staining results and principal component analysis. We have utilized the pre-release version of oncopression to identify cancer-specific genes in several studies. Availability and Implementation: Free access at http://www.oncopression.com and all expression data are available for download at the site. Contacts: cchoi@kaist.ac.kr or jungsullee@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881877 TI - Ten Years of the Journal of Crohn's and Colitis. PMID- 28881875 TI - Efficacy, Safety, and Long-term Outcome of Serial Endoscopic Balloon Dilation for Upper Gastrointestinal Crohn's Disease-associated Strictures-A Cohort Study. AB - Background : Gastric and duodenal Crohn's disease [CD]-associated strictures are rare. Evidence on endoscopic balloon dilation [EBD] of upper gastrointestinal [GI] CD strictures is limited, in particular in respect to serial dilations. Methods : Prospective short- and long-term outcome data as well as complication rates on a cohort of upper GI CD-associated stricture dilations [stomach and duodenum] were collected from 1999 to 2015. Factors linked with clinical and technical success, long-term efficacy and complication rates were investigated. Results : A total of 35 CD patients with symptomatic CD-associated upper GI strictures [20% gastric, 67% duodenal, 11% both; mean age at diagnosis 25 years; mean CD duration to stricture 79.9 months; median post-dilation follow-up 22.1 months] underwent a total of 96 pneumatic dilations [33 gastric and 63 duodenal]. The median maximal dilation diameter was 15 mm. Technical success was achieved in 93% and clinical success in 87%, with a complication rate of 4% per procedure. The mean time to re-dilation was 2.2 months and mean time to stricture-related surgery after first dilation was 2.8 months. There was no difference in short term efficacy, safety, or long-term outcome between the first and any later dilation procedure in the same patient. Conclusions : Pneumatic dilation of upper GI CD-associated strictures has a high rate of short-term technical and clinical success, with moderate long-term efficacy and acceptable complication rates. Serial dilations do not change the efficacy and could be a feasible option to delay or prevent surgical intervention. PMID- 28881876 TI - Accuracy of Faecal Immunochemical Test to Predict Endoscopic and Histological Healing in Ulcerative Colitis: A Prospective Study Based on Validated Histological Scores. AB - Background and Aims: Endoscopic and histological healing are associated with improved clinical outcomes in ulcerative colitis [UC]. We aimed to investigate the predictive value of faecal immunochemical test [FIT] for endoscopic and histological healing in UC. Methods: We measured quantitative FIT and faecal calprotectin [FC] in 140 consecutive UC patients who underwent colonoscopy. We assessed the diagnostic accuracy of FIT for predicting endoscopic healing using the Mayo endoscopic subscore [MES 0/1] and for histological healing using the Geboes score [< 2.0] and Nancy index [grade <= 1]. The predictive abilities of FIT were compared with those of FC. Results: FIT had an area under the curve [AUC] of 0.77 (95% confidence interval [CI] 0.67-0.86, p < 0.001) for endoscopic healing, an AUC of 0.77 [95% CI 0.67-0.86, p < 0.001] using the Geboes score, and 0.77 [95% CI 0.66-0.85, p < 0.001] using the Nancy Index for histological healing. The AUC of FIT was comparable to that of FC for endoscopic healing [p = 0.773] and histological healing [p = 0.767-0.960], and was comparable to colonoscopy for histological healing [p = 0.384-0.673]. FIT < 50 ng/ml predicted endoscopic healing with a sensitivity, specificity, and positive predictive value [PPV] of 72%, 68%, and 82%, respectively, and for histological healing with a sensitivity, specificity, and PPV of 73-75%, 67%, and 78-80%, respectively. Combining FIT with FC led to a higher specificity [90%] for histological healing. Over 85% of patients with FIT < 50 ng/ml and FC < 50 MUg/g achieved histological healing. Conclusions: FIT is highly sensitive and accurate to predict endoscopic and histological healing in UC. It represents a promising non-invasive tool for monitoring mucosal healing in UC. PMID- 28881878 TI - Management of esophageal gastrointestinal stromal tumor: review of one hundred seven patients. AB - Gastrointestinal stromal tumors (GIST) are the most common type of gastrointestinal mesenchymal tumor, but are rarely found in the thoracic esophagus. There is no clear consensus about the optimal treatment of this rare disease. A systematic search of the literature was performed for localized esophageal GIST that was resected between 2000 and 2015, and individual patients were included from two major academic institutions. We obtained information on demographics, tumor size and location, mitotic rate, treatment method, and time to recurrence or death. We performed univariate and multivariate Cox regression analyses to evaluate the factors associated with recurrence or death. A total of 28 studies met our inclusion and exclusion criteria, and with two patients from two academic institutions, we had a total of 107 patients in the study. Due to lack of uniformity among studies, there were several missing data for different variables. The average patient age was 56 (n = 98) with mostly males (60%, n = 91). The average tumor size on the CT scan was 7.9 +/- 5.4 cm (n = 91), located mostly in the distal esophagus (81%, n = 74). A similar number of patients underwent enucleation (n = 47) compared to esophagectomy (n = 42). Approximately half of the patients had a mitotic rate of 0-4 mitosis per 50 high-powered field (48%, n = 80). The median survival time was 73 months with a 5-year disease free survival of 57% (n = 97). Univariate Cox regression analyses showed that a large tumor, undergoing esophagectomy, and a high mitotic rate were associated with poor survival or recurrence control. We found that patients with a lesion smaller than or equal to 5 cm on the CT scan had a better disease-free survival rate than those with a size greater than 5 cm (HR = 12.41, p = 0.014) and had a 5-year survival rate of 92% with 90% of those patients undergoing enucleation (n = 29). Esophageal GIST is a very rare malignancy. The tumor size and mitotic rate of the tumor are associated with poor survival. However, patients with esophageal GIST measuring 5 cm or smaller may be safely treated with esophageal enucleation. PMID- 28881879 TI - Spectrum of esophageal dysmotility in systemic sclerosis on high-resolution esophageal manometry as defined by Chicago classification. AB - The classic manometric findings in systemic sclerosis are aperistalsis of the esophageal body with hypotensive lower esophageal sphincter. These changes contribute to gastroesophageal reflux disease in these patients. With widespread use of high-resolution esophageal manometry, diverse abnormalities are seen. The aim of this study is to characterize esophageal dysmotility in patients with systemic sclerosis undergoing high-resolution esophageal manometry and compare demographic features and diagnostic test results among patients with varying degrees of esophageal dysmotility. Patients with systemic sclerosis who underwent high-resolution esophageal manometry between January 2008 and October 2014 at our institution were identified. High-resolution esophageal manometry studies were reinterpreted using the Chicago Classification, v3.0 criteria. We also reviewed the patient charts for demographic data, indications for manometry, esophagogastroduodenoscopy findings, pH studies, medication use, and autoantibody panel. The cohort consisted of 122 patients with a mean age of 53.3 +/- 15.3 years. High-resolution esophageal manometry was normal in 23, showed ineffective esophageal motility in 22, absent contractility in 73, and one case each of type II achalasia, esophagogastric junction outflow obstruction, hypercontractile esophagus, and distal esophageal spasm. Patients with absent contractility were younger and more likely to have erosive esophagitis, hiatal hernia, and esophageal strictures than patients with ineffective esophageal motility or normal manometry. There were no statistically significant differences in the groups based on autoantibodies or indications for manometry. Diverse esophageal motility abnormalities were noted in systemic sclerosis with ineffective esophageal motility or absent contractility observed in over three-fourth of the patients. Patients with absent contractility were younger and had more severe reflux. The severity of gastroesophageal reflux disease related endoscopic findings correlated with the degree of esophageal dysmotility on high-resolution esophageal manometry. PMID- 28881880 TI - Trends in diagnoses after implementation of the Chicago classification for esophageal motility disorders (V3.0) for high-resolution manometry studies. AB - To determine trends in the diagnostic distribution of esophageal motility disorders after implementation of the Chicago Classification Version 3.0 (CC V3.0) for interpretation of high-resolution manometry (HRM) studies compared to non-Chicago Classification criteria. Retrospective trends analysis of patients with an HRM study conducted at a single center from January 1, 2013 to September 30, 2015. The implementation of the CC V3.0 for manometry interpretation occurred in September 2014. Patient charts were manually reviewed for data collection including demographics and HRM diagnoses. The prevalence and relative risks (RR) of CC V3.0 diagnostic categories (i.e. normal, indeterminate, achalasia, and EGJ outflow obstruction [EJGOO], and major and minor motility disorders) were calculated before and after CC V3.0 implementation. Four hundred sixty-five HRM studies were included in the study including 268 before and 179 after CC V3.0 implementation. The mean +/- SD age was 54 +/- 15.4 years and 59.8% were female (n = 278). The percentage with indeterminate diagnosis decreased from 35.3% before CC V3.0 implementation to 16.8% after implementation (adjusted RR 0.5, 95%CI 0.30-0.70, p < 0.001). The percentage with a major motility disorders decreased from 13.9% to 7.3% (adjusted RR 0.5, 95%CI 0.2-1.0, p < 0.001). The percentage with EJGOO and minor diagnoses increased from 1.4% to 14.5% and 11.9% to 22.9%, respectively. The percentage with achalasia and normal diagnosis did not change over the study period. Implementation of CCV3.0 was associated with changes in the distribution of esophageal motility diagnoses in clinical practice. The percentage of indeterminate and major diagnosis decreased and EGJOO and minor diagnoses increased. The decrease in the number of indeterminate studies suggests that the CC V3.0 may clarify the criteria for the interpreting physician. The increase in studies with a diagnosis of EGJ outflow obstruction may reflect the heterogeneity of disorders with clinically relevant outflow obstruction. PMID- 28881881 TI - Clinicopahological features of superficial basaloid squamous cell carcinoma of the esophagus. AB - Basaloid squamous cell carcinoma (BSC) of the esophagus is classified as an epithelial malignant tumor and is a rare variant of squamous cell carcinoma (SCC). Most previous reports have suggested that advanced BSC has a poorer prognosis than typical SCC because of its high biological malignancy, but the biological activity of superficial BSC remains unclear. Twenty cases of superficial BSC, which underwent surgical resection in Tokai University Hospital between January 2004 and December 2013, were analyzed retrospectively. Among these cases, 19 cases with a T1 depth of invasion (BSC group) were compared with 180 cases of SCC that were resected during the same period and were pathologically diagnosed as T1 (SCC group). The frequency of lymph node metastasis in the T1 BSC group was significantly lower (2 patients, 11%) than that in the SCC group (84 patients, 47%) (P = 0.005). The frequency of lymphatic invasion in the BSC group was also lower (9 patients, 47%) than that in the SCC group (131 patients, 73%) (P = 0.021). The pathological type of the metastatic lymph node was BSC in all the superficial BSC cases with lymph node metastasis. This study demonstrated that lymph node metastasis was less likely to occur in cases with superficial BSC than in cases with superficial SCC. PMID- 28881882 TI - Long-term functional outcomes after replacement of the esophagus with gastric, colonic, or jejunal conduits: a systematic literature review. AB - It is generally recognized that in patients with an intact stomach diagnosed with esophageal cancer, gastric tubulization and pull-up shall always be the preferred technique for reconstruction after an esophageal resection. However, in cases with extensive gastroesophageal junction (GEJ) cancer with aboral spread and after previous gastric surgery, alternative methods for reconstruction have to be pursued. Moreover, in benign cases as well as in those with early neoplastic lesions of the esophagus and the GEJ that are associated with long survival, it is basically unclear which conduit should be recommended. The aim of this study is to determine the long-term functional outcomes of different conduits used for esophageal replacement, based on a comprehensive literature review. Eligible were all clinical studies reporting outcomes after esophagectomy, which contained information on at least three years of follow-up after the operation in patients who were older than 18 years of age at the time of the operation. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic web-based search using MEDLINE, the Cochrane Library, and EMBASE databases was performed, reviewing medical literature published between January 2006 and December 2015. The scientific quality of the data was generally low, which allowed us to incorporate only 16 full text articles for the final analyses. After a gastric pull-up, the proportion of patients who suffered from dysphagia varied substantially but seemed to decrease over time with a mild dysphagia remaining during long-term follow-up. When reflux-related symptoms and complications were addressed, roughly two third of patients experienced mild to moderate reflux symptoms a long time after the resection. Following an isoperistaltic colonic graft, the functional long-term outcomes regarding swallowing difficulties were sparsely reported, while three studies reported reflux/regurgitation symptoms in the range of 5% to 16%, one of which reported the symptom severity as being mild. Only one report was available after the use of a long jejunal segment, which contained only six patients, who scored the severity of dysphagia and reflux as mild. Very few if any data were available on a structured assessment of dumping and disturbed bowel functions. Few high-quality data are available on the long-term functional outcomes after esophageal replacement irrespective of the use of a gastric tube, the right or left colon or a long jejunal segment. No firm conclusions regarding the advantages of one graft over the other can presently be drawn. PMID- 28881883 TI - The clinical significance of hypercontractile peristalsis: comparison of high resolution manometric features, demographics, symptom presentation, and response to therapy in patients with Jackhammer esophagus versus Nutcracker esophagus. AB - The Chicago Classification version 3.0 (CC v 3.0) defines hypercontractile peristalsis as Jackhammer esophagus (JE); Nutcracker esophagus (NE) is no longer recognized. Data regarding patient characteristics and treatment response for JE versus NE are limited. We aimed to compare demographic characteristics, high resolution manometry (HRM) features, clinical presentation, management strategies, and treatment outcomes in patients with JE versus NE. We performed a retrospective analysis of adult patients diagnosed with NE (CC v 2.0) or JE (CC v 3.0) by HRM from January 2012 to August 2015. Demographics, symptoms, treatments, and response to therapy (none or partial/complete) were ascertained by chart review, for statistical comparisons. In 45 patients with JE and 29 with NE, there was no significant difference in rate of dysphagia (73% and 59%) or chest pain (44% and 59%). Treatment data were available in 29 JE (smooth muscle relaxants in 4, pain modulators in 3, botulinum toxin injection (BTX) in 10, endoscopic dilation in 5, multimodal treatment in 7), and 20 NE patients (smooth muscle relaxants in 2, pain modulators in 2, (BTX) in 6, endoscopic dilation in 3, multimodal treatment in 7). Follow-up data on 26/29 JE and 20/20 NE patients showed similar treatment response (96.4% vs. 82.1%, p= 0.08) after mean follow-up of 11.2 and 11 months, respectively. There were no major differences for JE versus NE in demographics, symptoms, or type of and response to therapy. Larger prospective, controlled trials are needed to clarify the clinical significance and response to treatment in JE and NE. PMID- 28881884 TI - Clinical outcomes and benefits for staging of surgical lymph node mapping after esophagectomy. AB - Dissection of lymph nodes (LN) immediately after esophagectomy is utilized by some surgeons to aid determination of LN stations involved in esophageal cancer. Some suggest that this increases LN yield and gives information regarding the pattern of lymphatic spread, others feel that this may compromise a circumferential resection margin (CRM) assessment. The aim of this study is to evaluate the effect of ex vivo dissection on the assessment of the CRM and the pattern of lymph node dissemination in patients with adenocarcinoma of the esophagus and gastroesophageal junction (GEJ) undergoing radical surgery after neoadjuvant chemotherapy and their prognostic impact. Data from consecutive patients with potentially curable adenocarcinoma of the distal esophagus and GEJ who received neoadjuvant treatment followed by surgery were analyzed. Clinical and pathological findings were reviewed and LN burden and location correlated with clinical outcome. Pathology specimens were dissected into individual LN groups 'ex-vivo' by the surgeon. A total of 301 patients were included: 295 had a radical proximal and distal resection margin however in 62(20.6%) CRM could not be assessed. A median of 33(10-77) nodes were recovered. A 117(38.9%) patients were ypN0 while 184(61.1%) were LN positive (ypN1-N3). LN stations close to the tumor were most frequently involved. Twenty-seven (14.7%) patients had only thoracic stations involved, 48(26.1%) only abdominal stations and 109 (59.2%) had both. Median survival for yN0 patients was 171 months compared to 24 months for those LN positive (P< 0.001). Multivariate analyses identified ypT-category, ypN category, male gender, and nonradical resection (proximal or distal) margin as significant prognostic factors. Surgical dissection of nodes after esophagectomy enables accurate LN assessment, but may compromise CRM assessment in up to 20% of cases. It also provides valuable information regarding the pattern of nodal spread. PMID- 28881885 TI - IgG4-related disease involving the esophagus: a clinicopathological study. AB - Immunoglobulin G4 (IgG4)-related disease is a recently coined systemic disease characterized by specific histopathologic findings of an intense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis in the presence of predominant IgG4-positive plasma cells. Although IgG4-related disease has been described in many organs, involvement of the esophagus is very rare. In this study, we describe the clinicopathologic characteristics of eight patients with IgG4-related esophagitis. We evaluated chronic esophagitis specimens with lymphoplasmacytic infiltrate obtained over the past 6 years (from January 2011 to February 2017) using a chart review, pathologic examination, and IgG4 immunohistochemical staining. The diagnoses of the specimens were either confirmed as IgG4-related esophagitis (IgG4-RE) or chronic esophagitis, not otherwise specified (CENOS), and the clinicopathologic data from each group were compared. Eight patients were diagnosed with IgG4-RE and 10 controls were identified and diagnosed with CENOS. In the IgG4-RE group, esophageal strictures were identified in three patients, two patients had postmyotomy treated achalasia, one patient had erosive esophagitis and another presented with an esophageal nodule. Only one patient had an unremarkable mucosa on endoscopy. In the CENOS group, four patients had esophageal strictures, six had erosive esophagitis, one patient had mild esophagitis. The IgG4-RE group had significantly higher numbers of IgG4-positive plasma cells (66.9 +/- 21.9 vs. 4.7 +/- 2.4 per high power field; P< 0.001) and a greater IgG4: IgG ratio 0.76 +/- 0.13 vs. 0.06 +/- 0.05; P< 0.001) when compared to CENOS patients. Two of the patients with recurrent esophageal strictures in the IgG4-RE group showed initial response to steroid therapy and are currently on immunosuppressive therapy which has significantly reduced the need for multiple esophageal dilatations. The presentation of IgG4-related esophageal disease can vary and the key to diagnosis is dependent on histopathology. These observations highlight the need for IgG4 immunohistochemical staining of esophageal biopsies especially in patients with mucosal ulceration, chronic inflammation, and plasmacytosis on biopsy. This will prevent unwarranted esophagectomies and failed medical treatment due to lack of recognition of this entity. PMID- 28881886 TI - Monitoring sputum culture in resected esophageal cancer patients with preoperative treatment. AB - Pneumonia is a major cause of postesophagectomy mortality and worsens the long term survival in resected esophageal cancer patients. Moreover, preoperative treatments such as chemotherapy or chemoradiotherapy (which have recently been applied worldwide) might affect the bacterial flora of the sputum. To investigate the association among preoperative treatments, the bacterial flora of sputum, and the clinical and pathological features in resected esophageal cancer patients, this study newly investigates the effect of preoperative treatments on the bacterial flora of sputum. We investigated the association among preoperative treatments, the bacterial flora of sputum, and clinical and pathological features in 163 resected esophageal cancer patients within a single institution. Pathogenic bacteria such as Candida (14.1%), Staphylococcus aureus (6.7%), Enterobacter cloacae (6.1%), Haemophilus parainfluenzae (4.9%), Klebisiella pneumoniae (3.7%), Methicillin-resistant Staphylococcus aureus (MRSA) (3.7%), Pseudomonas aeruginosa (2.5%), Escherichia coli (1.8%), Streptococcus pneumoniae (1.8%), and Haemophilus influenzae (1.2%) were found in the sputum. The pathogen detection rate in the present study was 34.3% (56/163). In patients with preoperative chemotherapy and chemoradiotherapy, the indigenous Neisseria and Streptococcus species were significantly decreased (P= 0.04 and P= 0.04). However, the detection rates of pathogenic bacteria were not associated with preoperative treatments (all P> 0.07). There was not a significant difference of hospital stay between the sputum-monitored patients and unmonitored patients (35.5 vs. 49.9 days; P= 0.08). Patients undergoing preoperative treatments exhibited a significant decrease of indigenous bacteria, indicating that the treatment altered the bacterial flora of their sputum. This finding needs to be confirmed in large-scale independent studies or well-designed multicenter studies. PMID- 28881887 TI - Learning curve for robotic esophagectomy and dissection of bilateral recurrent laryngeal nerve nodes for esophageal cancer. AB - Dissection of bilateral recurrent laryngeal nerve (RLN) nodes is a technically demanding procedure, but robotic systems have been useful for RLN node dissection. This retrospective study investigated the learning curve for bilateral RLN node dissection in esophageal-cancer patients using a robotic system for esophageal cancer. We retrospectively reviewed 33 consecutive patients who received a robotic esophagectomy and total lymphadenectomy by single surgeon. The patients were divided into either group 1 (initial 20 cases) or group 2 (later 13 cases). The mean patient age was 61.88 +/- 9.03 years and 28 (84.8%) patients were male. Most cases were pathologically diagnosed as squamous cell carcinoma. The lesion locations included 3 (9.1%) in the upper esophagus, 12 (63.6%) in the mid esophagus, and 9 (27.3%) in the lower esophagus. Eleven (33.3%) cases were stage I, 7 (21.2%) were stage II, and 15 (45.5%) were stage III. One case in group 2 (3%) suffered operative mortality. Operation time, robot console time, and blood loss were similar between the two groups. The timing of right and left RLN node dissection, the number of total dissected lymph nodes, and the percentage of dissected right and left RLN nodes were also comparable. However, the incidence of vocal cord palsy was significantly lower in group 2 (55% vs. 0%, p= 0.02). The incidence of other operative complications did not vary between the two groups. Even though operative outcomes and incidence of other complications were comparable between the two groups, the incidence of vocal cord palsy decreased significantly after 20 cases. Thus, we conclude that a minimum of 20 cases is required before a surgeon is experienced enough to perform safe dissection of bilateral RLN nodes. PMID- 28881888 TI - High-resolution esophageal manometry findings in malignant pseudoachalasia. PMID- 28881889 TI - Fully robotic da Vinci Ivor-Lewis esophagectomy in four-arm technique-problems and solutions. AB - The aim of this technical note is a step-by-step description of a fully robotic abdominothoracic esophagectomy with an intrathoracic esophagogastrostomy. We report on our technique and short-term results of 75 patients undergoing an Ivor Lewis esophagectomy using a fully robotic 4-arm approach in the abdominal and thoracic phase with a hand-sewn intrathoracic anastomosis. There are several important steps and differences to consider compared to the conventional minimal invasive approach (patient's positioning, anaesthesiological set up, port placement, gastric conduit pull up, technique of esophagostrostomy). Mean operative time was 392 minutes (240-610) with a 94% R0 resection status. Conversion to open procedure occurred in 2 (2.6%) in the abdominal, and 14 (18.2%) in the thoracic phase. Main reasons for conversion were problems during the lifting of the gastric conduit and difficulties in the construction of the esophagogastrostomy. The rate dropped during the last 20 patients (1/20 (10%). Our results suggest that the reported technique is safe and feasible. It satisfies the oncological principles and provides the advantages of robotic assisted minimal invasive surgery. PMID- 28881890 TI - Active surveillance in clinically complete responders after neoadjuvant chemoradiotherapy for esophageal or junctional cancer. AB - Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is standard of care for locally advanced esophageal cancer in many countries. After nCRT up to one third of all patients have a pathologically complete response in the resection specimen, posing an ethical imperative to reconsider the necessity of standard surgery in all operable patients after nCRT. An active surveillance strategy following nCRT, in which patients are subjected to frequent clinical investigations after the completion of neoadjuvant therapy, has been evaluated in other types of cancer with promising results. In esophageal cancer, both patients who are cured by neoadjuvant therapy alone as well as patients with subclinical disseminated disease at the time of completion of neoadjuvant therapy may benefit from such an organ sparing approach. Active surveillance is currently applied in selected patients with esophageal cancer who refuse surgery or are medically unfit for major surgery after completion of nCRT, but this strategy is not (yet) adopted as an alternative to standard surgery or definitive chemoradiation. The available literature is scarce, but suggests that long-term oncological outcomes after active surveillance are noninferior compared to standard surgical resection, providing justification for comparison of both treatments in a phase III trial. This review gives an overview of the current knowledge regarding active surveillance after completion of nCRT in esophageal cancer and outlines future research perspectives. PMID- 28881891 TI - Induction therapy before surgery improves survival in patients with clinical T3N0 esophageal cancer: a nationwide study in Taiwan. AB - The utility of induction therapy (IT) in patients with resectable esophageal cancer remains controversial, especially when clinical evidence of nodal metastases is lacking. We sought to compare the survival impact of IT versus upfront surgery (US) in patients with cT3N0 esophageal cancer. We searched the Taiwan Cancer Registry for patients with cT3N0 esophageal cancer who underwent US or IT between 2008 and 2013. Multivariate Cox regression analysis was used to analyze the potential benefits of IT in terms of overall survival (OS) and disease-free survival (DFS). Of the 11752 patients with esophageal cancer included in the nationwide database, 762 (6.5%) had cT3N0 disease. Most cases (720 [94.5%]) had a histological diagnosis of squamous cell carcinoma. Of them, 135 received IT (the IT group) and 237 received surgery first (the US group). In the US group, pretreatment clinical staging was accurate in 47.9% of patients. Twenty-one (8.97%) were clinically overstaged (pT1-2N0), whereas 101 (43.17%) were clinically understaged (pT4N0 or pTanyN1-3). The presence of unexpected nodal metastases was identified in 92.1% of clinically understaged patients. In the IT group, 28 (20.74%) patients did not proceed to surgery after IT. The use of IT was associated with higher R0 resection rates and fewer pathological nodal metastases, despite unexpected M1 disease being more common (all P< 0.05). The 5 year OS rate was significantly higher (42%) in the IT group than in the US group (33%, P= 0.032). Similar findings were observed in terms of 5-year DFS (37% in the IT group versus 29% in the US group, P= 0.009). Multivariate analysis identified US (hazard ratio: 1.42, P= 0.03) and non-R0 resection (hazard ratio: 1.58, P= 0.03) as independent adverse prognostic factors. We found that 43.17% of patients with cT3N0 disease undergoing primary surgery had their disease understaged. The use of IT before esophagectomy significantly improves OS and DFS in patients with clinical T3N0 esophageal squamous cell carcinoma. PMID- 28881892 TI - Influence of esophagectomy on the gastroesophageal reflux in patients with esophageal cancer. AB - This study aims to assess the influence of esophagectomy with gastric transposition on the gastroesophageal reflux (GER) and gastric acidity in patients with esophageal cancer. Data on 53 esophageal cancer patients who underwent 24-hour impedance-pH monitoring after esophagectomy were retrospectively analyzed. We used a solid-state esophageal pH probe in which the esophageal pH sensor is placed 1.5 cm distal to the upper esophageal sphincter and the gastric pH sensor is located 15 cm distal to the esophageal pH channel. 24-hour impedance-pH monitoring data and other clinical data including anastomosis site stricture and incidence of pneumonia were collected. We defined pathologic reflux with reference to known normative data. Stricture was defined when an intervention such as bougienage or balloon dilatation was required to relieve dysphagia. The esophageal and gastric mean pH were 5.47 +/- 1.51 and 3.33 +/- 1.64, respectively. The percent time of acidic pH (<4) was 6.66 +/- 12.49% in the esophagus and 70.53 +/- 32.19% in the stomach. Esophageal pathologic acid reflux was noticed in 32.1%, 20.8%, and 35.8% during total, upright, and recumbent time, respectively. Esophageal pathologic bolus reflux was noted in 83.0%, 77.4%, and 64.2% during total, upright, and recumbent time, respectively. Gastric acidity increased with time after esophagectomy. Esophageal acid exposure time correlated with intragastric pH. However, esophageal pathologic acid reflux was not associated with anastomosis site stricture or pneumonia. In conclusion, GER frequently occurs after esophagectomy. Thus, strict lifestyle modifications and acid suppression would be necessary in patients following esophagectomy. PMID- 28881893 TI - C-reactive protein to albumin ratio is a prognostic factor for patients with cStage II/III esophageal squamous cell cancer. AB - C-reactive protein to albumin (CRP/Alb) ratio, a novel inflammation-based prognostic score, was first developed as a prognostic score for septic patients. Recent reports show that CRP/Alb ratio is also a prognostic score for cancer patients, including esophageal cancer. However, the role of CRP/Alb ratio for those with neoadjuvant chemotherapy (NAC) and the changes of CRP/Alb ratio around NAC have never been discussed. The aim of this study is to evaluate the significance of CRP/Alb ratio around NAC for patients with cStage II/III esophageal squamous cell cancer (ESCC). A total of 149 patients who were diagnosed as cStage II/III ESCC were enrolled between February 2007 and December 2014. We retrospectively investigated the relation between pre-NAC and post-NAC CRP/Alb ratio and short and long outcomes. The optimal cutoff level for pre-NAC and post-NAC CRP/Alb ratio was 0.030 and 0.048, respectively. There was no relation between CRP/Alb ratio level and postoperative outcomes. Post-NAC CRP/Alb ratio < 0.048 had a significantly higher overall survival rate than CRP/Alb ratio >=0.048 (P< 0.001). Univariate analysis showed that cT, cN, pre-NAC CRP/Alb ratio < 0.030 and post-NAC CRP/Alb ratio < 0.048 was prognostic factors (P= 0.003, P= 0.022, P= 0.033, and P< 0.001, respectively). Multivariate analysis showed that cT and post-NAC CRP/Alb ratio < 0.048 was independent prognostic factors (P= 0.030 and P< 0.001, respectively). Post-NAC CRP/Alb ratio is an independent prognostic factor in patients with cStage II/III ESCC. PMID- 28881894 TI - Outcomes following the main treatment options in patients with a leaking esophagus: a systematic literature review. AB - Leakage from the esophagus and gastroesophageal junction can be lethal due to uncontrolled contamination of the mediastinum. The most predominant risk factors for the subsequent clinical outcome are the patients' delay as well as the delay of diagnosis. Two major therapeutic concepts have been advocated: either prompt closure of the leakage by insertion of a self-expandable metal stent (SEMS) or more traditionally, surgical exploration. The objective of this review is to carefully scrutinize the recent literature and assess the outcomes of these two therapeutic alternatives in the management of iatrogenic perforation-spontaneous esophageal rupture as separated from those with anastomotic leak. A systematic web-based search using PubMed and the Cochrane Library was performed, reviewing literature published between January 2005 and December 2015. Eligible studies included all studies that presented data on the outcome of SEMS or surgical exploration in case of esophageal leak (including >3 patients). Only patients older than 15 years of age by the time of admission were included. Articles in other languages but English were excluded. Treatment failure was defined as a need for change in therapeutic strategy due to uncontrolled sepsis and mediastinitis, which usually meant rescue esophagectomy with end esophagostomy, death occurring as a consequence of the leakage or development of an esophagorespiratory fistula and/or other serious life threatening complications. Accordingly, the corresponding success rate is composed of cases where none of the failures above occurred. Regarding SEMS treatment, 201 articles were found, of which 48 were deemed relevant and of these, 17 articles were further analyzed. As for surgical management, 785 articles were retrieved, of which 82 were considered relevant, and 17 were included in the final analysis. It was not possible to specifically extract detailed clinical outcomes in sufficient numbers, when we tried to separately analyze the data in relation to the cause of the leakage: i.e. iatrogenic perforation-spontaneous esophageal rupture and anastomotic leak. As for SEMS treatment, originally 154 reports focused on iatrogenic perforation, 116 focused on spontaneous ruptures, and only four described the outcome following trauma and foreign body management. Only five studies used a prospective protocol to assess treatment efficacy. Regarding a leaking anastomosis, 80 reports contained information about the outcome after treatment of esophagogastrostomies and 35 reported the clinical course after an esophagojejunostomy. An overall success rate of 88% was reported among the 371 SEMS-treated patients, where adequate data were available, with a reported in hospital mortality amounting to 7.5%. Regarding the surgical exploration strategy, the vast majority of patients had an attempt to repair the defect by direct or enforced suturing. This surgical approach also included procedures such as patching with pleura or with a diaphragmatic flap. The overall reported success rate was 83% (305/368) and the in-hospital mortality was 17% (61/368). The current literature suggests that a SEMS-based therapy can be successfully applied as an alternative therapeutic strategy in esophageal perforation rupture. PMID- 28881895 TI - Balloon-based esophageal cryoablation with a novel focal ablation device: dose finding and safety in porcine and human models. AB - The new Cryoballoon Focal Ablation System (CbFAS), a through-the-scope catheter with battery-powered handle that delivers cryogenic fluid into an inflated balloon, differs from current cryotherapy methods used for treatment of Barrett's epithelium. In this dose-finding study, short- and long-term histopathological effects and safety of the CbFAS were evaluated. Cryoablations with (supra)therapeutic durations (4-24 seconds) were performed in pigs that survived for 12 or 48 hours or 4 or 28 days. Next, cryoablations (durations based on animal data) were performed in normal mucosa of esophageal cancer patients scheduled to undergo esophagectomy. The outcome parameters, the occurrence of any bleeding or perforation, the histological presence of edema, inflammation, and necrosis throughout the esophageal wall layers, were evaluated. A total of 60 cryoablations were performed in 11 pigs. 48 hour cryoablations with therapeutic durations (4-10 seconds) resulted in edema/inflammation as deep as the serosa and necrosis ranging from submucosa to serosa with a median depth of 3.2 mm. In 4 day cryoablations this was in the serosa, and muscularis tunica to serosa at a median depth of 4.5 mm, respectively. No necrosis or inflammation remained after 28 days, not even after supratherapeutic cryoablation (12-24 seconds). No acute or delayed bleeding or perforation was observed. Next, eight 6-second cryoablations were performed in four patients. Direct postablation mucosal necrosis was observed; after 4 days necrosis and inflammation was limited to the submucosa. CbFAS cryoablation penetrates deeply into the esophageal wall layers resulting in severe early ablation. After 4 weeks, little injury and no fibrosis remain, even after supratherapeutic durations of administration, suggesting that CbFAS combines deep ablation with a potentially favorable safety profile. PMID- 28881896 TI - Development of a risk prediction model for Barrett's esophagus in an Australian population. AB - Esophageal adenocarcinoma has poor 5-year survival rates. Increased survival might be achieved with earlier treatment, but requires earlier identification of the precursor, Barrett's esophagus. Population screening is not cost effective, this may be improved by targeted screening directed at individuals more likely to have Barrett's esophagus. To develop a risk prediction tool for Barrett's esophagus, this study compared individuals with Barrett's esophagus against population controls. Participants completed a questionnaire comprising 35 questions addressing medical history, symptom history, lifestyle factors, anthropomorphic measures, and demographic details. Statistical analysis addressed differences between cases and controls, and entailed initial variable selection, checking of model assumptions, and establishing calibration and discrimination. The area under the curve (AUC) was used to assess overall accuracy. One hundred and twenty individuals with Barrett's esophagus and 235 population controls completed the questionnaire. Significant differences were identified for age, gender, reflux history, family reflux history, history of hypertension, alcoholic drinks per week, and body mass index. These were used to develop a risk prediction model. The AUC was 0.82 (95% CI 0.78-0.87). Good calibration between predicted and observed risk was noted (Hosmer-Lemeshow test P = 0.67). At the point minimizing false positives and false negatives, the model achieved a sensitivity of 84.96% and a specificity of 66%. A well-calibrated risk prediction model with good discrimination has been developed to identify patients with Barrett's esophagus. The model needs to be externally validated before consideration for clinical practice. PMID- 28881897 TI - Comparative evaluation of new and conventional classifications of magnifying endoscopy with narrow band imaging for invasion depth of superficial esophageal squamous cell carcinoma. AB - A new classification of magnifying endoscopy with narrow band imaging (ME-NBI) for diagnosing and staging superficial esophageal squamous cell carcinoma (SESCC) was proposed by the Japan Esophageal Society in 2011. This study aimed to compare the new classification with the conventional classifications (Inoue's classification and Arima's classification). This was a prospective analysis of data from a single cancer center involving 151 consecutive patients with 156 SESCCs that were endoscopically or surgically resected. Initially, only ME-NBI images were selected and reviewed independently by three experienced endoscopists. White light imaging (WLI) was then evaluated separately after an interval. The diagnostic performance of each classification and interobserver agreement were assessed, and the WLI findings that affect the diagnosis by the new classification were identified. The specificity for classifying invasive depth as epithelium (EP)/lamina propria mucosae (LPM) confined was higher with the new classification than with Inoue's classification (0.512 vs. 0.349; P = 0.02) and Arima's classification (0.512 vs. 0.279; P < 0.01). However, the sensitivity was lower (0.902 vs. 1.000; P < 0.01) compared with Arima's classification. The concordance rates of three evaluators (kappa values) were 0.52 for the new classification, 0.50 for Inoue's classification, and 0.23 for Arima's classification. On multivariate analysis, thickness on WLI independently affected the accuracy of diagnosis with the new classification (OR 3.23; 95%CI, 1.30-8.03). The new classification is superior to conventional classifications with respect to specificity for diagnosing SESCC with depth EP/LPM. Thickness on WLI was a factor negatively affecting the diagnostic performance of the new classification. PMID- 28881898 TI - Performance characteristics of optical coherence tomography in assessment of Barrett's esophagus and esophageal cancer: systematic review. AB - Optical coherence tomography (OCT) can generate high-resolution images of the esophagus that allows cross-sectional visualization of esophageal wall layers. We conducted a systematic review to assess the utility of OCT for diagnosing of esophageal intestinal metaplasia (IM; Barrett's esophagus BE)), dysplasia, cancer and staging of early esophageal cancer. English language human observational studies and clinical trials published in PubMed and Embase were included if they assessed any of the following: (i) in-vivo features and accuracy of OCT at diagnosing esophageal IM, sub-squamous intestinal metaplasia (SSIM), dysplasia, or cancer, and (ii) accuracy of OCT in staging esophageal cancer. Twenty-one of the 2,068 retrieved citations met inclusion criteria. In the two prospective studies that assessed accuracy of OCT at identifying IM, sensitivity was 81%-97%, and specificity was 57%-92%. In the two prospective studies that assessed accuracy of OCT at identifying dysplasia and early cancer, sensitivity was 68% 83%, and specificity was 75%-82%. Observational studies described significant variability in the ability of OCT to accurately identify SSIM. Two prospective studies that compared the accuracy of OCT at staging early squamous cell carcinoma to histologic resection specimens reported accuracy of >90%. Risk of bias and applicability concerns was rated as low among the prospective studies using the QUADAS-2 questionnaire. OCT may identify intestinal metaplasia and dysplasia, but its accuracy may not meet recommended thresholds to replace 4 quadrant biopsies in clinical practice. OCT may be more accurate than EUS at staging early esophageal cancer, but randomized trials and cost-effective analyses are lacking. PMID- 28881899 TI - Polyglycolic acid sheet and fibrin glue for preventing esophageal stricture after endoscopic submucosal dissection: a historical control study. AB - There have been several reports that steroid administration is effective at preventing strictures after endoscopic submucosal dissection (ESD). However, adverse events after steroid use are of great concern. We have reported that shielding with a polyglycolic acid (PGA) sheet and fibrin glue can be useful for prevention of stricture after ESD. We conducted a retrospective analysis of efficiency of shielding with a PGA sheet and fibrin glue for prevention of esophageal stricture compared with intralesional steroid injection. ESD was performed on a total of 489 lesions in 400 patients for superficial esophageal cancer from January 2012 to July 2016. Of these, 39 lesions were enrolled in the study group (PGA sheet and fibrin glue) and 31 lesions were enrolled in the control group. The incidence of postoperative stricture at 6 weeks and the number of sessions of endoscopic balloon dilatation (EBD) required to resolve any strictures were evaluated. The post-ESD stricture rate was 9.1% in the study group (3/33 patients), which was not significantly lower than the stricture rate of 10.3% in the historical control group (3/29 patients; p = 1.00). The mean number of EBD was 0.057 +/- 0.24 in the study group and 1.9 +/- 5.1 in the control group, which was not significant (P = 0.95). PGA sheet and fibrin glue appear to be a promising option for the prevention of esophageal stricture similar to the effect of intralesional steroid injection. PMID- 28881900 TI - Changes in esophageal motility after endoscopic submucosal dissection for superficial esophageal cancer: a high-resolution manometry study. AB - The effect of endoscopic submucosal dissection (ESD) on esophageal motility remains unknown. Therefore, the aim of this study is to elucidate changes in esophageal motility after ESD along with the cause of dysphagia using high resolution manometry (HRM). This is a before-and-after trial of the effect of ESD on the esophageal motility. Twenty patients who underwent ESD for superficial esophageal carcinoma were enrolled in this study. Patients filled out a questionnaire about dysphagia and underwent HRM before and after ESD. Results before and after ESD were compared. Data were obtained from 19 patients. The number of patients who complained of dysphagia before and after ESD was 1/19 (5.3%) and 6/19 (31.6%), respectively (P = 0.131). Scores from the five-point Likert scale before and after ESD were 0.1 +/- 0.5 and 1.0 +/- 1.6, respectively (P = 0.043). The distal contractile integral (DCI) before and after ESD and the number of failed, weak, or fragmented contractions were not significantly different. However, in five patients with circumferential ESD, DCI was remarkably decreased and the frequency of fail, weak, or fragmented contractions increased. Univariate regression analysis showed a relatively strong inverse correlation of DeltaDCI with the circumferential mucosal defect ratio {P < 0.01, standardized regression coefficient (r) = -0.65}, the number of stricture preventions (P < 0.01, r = -0.601), and the number of stricture resolutions (P < 0.01, r = -0.77). This HRM study showed that impairment of esophageal motility could be caused by ESD. The impairment of esophageal motility was conspicuous, especially in patients with circumferential ESD and subsequent procedures such as endoscopic triamcinolone injection and endoscopic balloon dilatation. Impaired esophageal motility after ESD might explain dysphagia. PMID- 28881901 TI - Digital microscopy as valid alternative to conventional microscopy for histological evaluation of Barrett's esophagus biopsies. AB - Management of Barrett's esophagus (BE) relies heavily on histopathological assessment of biopsies, associated with significant intra- and interobserver variability. Guidelines recommend biopsy review by an expert in case of dysplasia. Conventional review of biopsies, however, is impractical and does not allow for teleconferencing or annotations. An expert digital review platform might overcome these limitations. We compared diagnostic agreement of digital and conventional microscopy for diagnosing BE +/- dysplasia. Sixty BE biopsy glass slides (non-dysplastic BE (NDBE); n = 25, low-grade dysplasia (LGD); n = 20; high grade dysplasia (HGD); n = 15) were scanned at *20 magnification. The slides were assessed four times by five expert BE pathologists, all practicing histopathologists (range: 5-30 years), in 2 alternating rounds of digital and conventional microscopy, each in randomized order and sequence of slides. Intraobserver and pairwise interobserver agreement were calculated, using custom weighted Cohen's kappa, adjusted for the maximum possible kappa scores. Split into three categories (NDBE, IND, LGD+HGD), the mean intraobserver agreement was 0.75 and 0.84 for digital and conventional assessment, respectively (p = 0.35). Mean pairwise interobserver agreement was 0.80 for digital and 0.85 for conventional microscopy (p = 0.17). In 47/60 (78%) of digital microscopy reviews a majority vote of >=3 pathologists was reached before consensus meeting. After group discussion, a majority vote was achieved in all cases (60/60). Diagnostic agreement of digital microscopy is comparable to that of conventional microscopy. These outcomes justify the use of digital slides in a nationwide, web-based BE revision platform in the Netherlands. This will overcome the practical issues associated with conventional histologic review by multiple pathologists. PMID- 28881902 TI - Frequency of endoscopic surveillance for Barrett's esophagus is influenced by health insurance status: results from a population-based analysis. AB - Factors that influence the frequency of surveillance endoscopy for nondysplastic Barrett's esophagus are not well understood. The objective of this study is to assess factors which influence the frequency of endoscopic surveillance for Barrett's esophagus, including health insurance/third-party payer status. Cases of nondysplastic Barrett's esophagus undergoing esophagogastroduodenoscopy with biopsy were identified using longitudinal data from the Healthcare Utilization Project database in 2005-2006 and followed through 2011. The threshold for appropriate surveillance utilization was defined as two to four surveillance esophagogastroduodenoscopies over a standardized 5-year period. Patients' insurance status was designated as either Medicare, Medicaid, private, or noninsured. 36,676 cases of nondysplastic Barrett's esophagus were identified. Among these, 4,632 patients (12.6%) underwent between two and four surveillance esophagogastroduodenoscopies in 5 years of follow-up versus 31,975 patients (87.3%) who underwent fewer than two esophagogastroduodenoscopies during follow up. Multivariate analysis found that Barrett's patients insured through Medicaid (OR 1.273; 95% CI = 1.065-1.522) or without insurance (OR = 2.453; 95% CI = 1.67 3.603) were at increased likelihood of being under-surveilled. This study identified a difference in frequency of surveillance esophagogastroduodenoscopy for Barrett's esophagus by payer status. Patients without health insurance and those whose primary insurance was Medicaid were at increased odds for under surveillance. These data suggest that a more robust system for tracking and ensuring longitudinal follow-up of patients with Barrett's esophagus, with attention to the uninsured and underinsured population, may be needed to ensure optimal surveillance. PMID- 28881903 TI - Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer. AB - Although surgery is traditionally the standard of care for esophageal cancer, esophagectomy carries significant morbidity. Alternative endoscopic therapies are needed for patients who are not candidates for conventional treatment. The objective of this study is to assess the safety, efficacy, and tolerability of spray cryotherapy of esophageal adenocarcinoma. This study includes patients with esophageal adenocarcinoma who had failed or were not candidates for conventional therapy enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from 11 academic and community practices. Endoscopic spray cryotherapy was performed until biopsy proven local tumor eradication or until treatment was halted due to progression of disease, patient withdrawal or comorbidities. Eighty-eight patients with esophageal adenocarcinoma (median age 76, 80.7% male, mean length 5.1 cm) underwent 359 treatments (mean 4.4 per patient). Tumor stages included 39 with T1a, 25 with T1b, 9 with unspecified T1, and 15 with T2. Eighty-six patients completed treatment with complete response of intraluminal disease in 55.8%, including complete response in 76.3% for T1a, 45.8% for T1b, 66.2% for all T1, and 6.7% for T2. Mean follow up was 18.4 months. There were no deaths or perforations related to spray cryotherapy. Strictures developed in 12 of 88 patients (13.6%) but were present before spray cryotherapy in 3 of 12. This study suggests that endoscopic spray cryotherapy is a safe, well-tolerated, and effective treatment option for early esophageal adenocarcinoma. PMID- 28881904 TI - Human papillomavirus does not play a role in the Barrett esophagus: a French cohort. AB - The role of human papillomavirus (HPV) in Barrett's esophagus (BE) has been examined but remains unclear. The purpose of the study is to dispute the connection between HPV and BE in a prospective case-control study. Biopsies were performed above and inside the Barrett's segment for BE patients and in the distal third of the esophagus for control patients for histological interpretation and for virological analysis. Biopsies for virological analysis were placed in a virus transport medium and immediately frozen in liquid nitrogen. Virological analysis involved real-time PCR using the SyBr(r) green protocol with modified SPF10 general primers. A total of 180 patients (119 control and 61 BE, respectively) were included. In BE patients, 31, 18, and 12 patients had, respectively, no dysplasia, low-grade dysplasia, and high grade dysplasia. Overall, nine were found to be HPV positive: five were control patients and four BE patients. HPV positive status was not associated with BE. No factors were associated with HPV, in particular the degree of BE dysplasia. HPV infection appears unlikely to be significant in the etiology of BE compared with control patients. (ClinicalTrials.gov, Number NCT02549053). PMID- 28881905 TI - Perforated esophageal intervention focus (PERF) study: a multi-center examination of contemporary treatment. AB - The treatment of esophageal perforation (EP) remains a significant clinical challenge. While a number of investigators have previously documented efficient approaches, these were mostly single-center experiences reported prior to the introduction of newer technologies: specifically endoluminal stents. This study was designed to document contemporary practice in the diagnosis and management of EP at multiple institutions around the world and includes early clinical outcomes. A five-year (2009-2013) multicenter retrospective review of management and outcomes for patients with thoracic or abdominal esophageal perforation was conducted. Demographics, etiology, diagnostic modalities, treatments, subsequent early outcomes as well as morbidity and mortality were captured and analyzed. During the study period, 199 patients from 10 centers in the United States, Canada, and Europe were identified. Mechanisms of perforation included Boerhaave syndrome (60, 30.1%), iatrogenic injury (65, 32.6%), and penetrating trauma (25, 12.6%). Perforation was isolated to the thoracic segment alone in 124 (62.3%), with 62 (31.2%) involving the thoracoabdominal esophagus. Mean perforation length was 2.5 cm. Observation was selected as initial management in 65 (32.7%), with only two failures. Direct operative intervention was initial management in 65 patients (32.6%), while 29 (14.6%) underwent esophageal stent coverage. Compared to operative intervention, esophageal stent patients were significantly more likely to be older (61.3 vs. 48.3 years old, P < 0.001) and have sustained iatrogenic mechanisms of esophageal perforation (48.3% vs.15.4%). Secondary intervention requirement for patients with perforation was 33.7% overall (66). Complications included sepsis (56, 28.1%), pneumonia (34, 17.1%) and multi-organ failure (23, 11.6%). Overall mortality was 15.1% (30). In contemporary practice, diagnostic and management approaches to esophageal perforation vary widely. Despite the introduction of endoluminal strategies, it continues to carry a high risk of mortality, morbidity, and need for secondary intervention. A concerted multi-institutional, prospectively collected database is ideal for further investigation. PMID- 28881906 TI - Comparison of short-term outcomes between 2- and 3-field lymph node dissection for esophageal cancer. AB - Although 3-field lymph node dissection (3-FLD) is often performed for thoracic esophageal squamous cell carcinoma (ESCC), the clinical effects of cervical lymph node dissection in addition to mediastinal and abdominal dissections on postoperative complications remain unclear. A total of 367 ESCC patients who underwent curative esophagectomy for thoracic esophageal cancer in our hospital from 2010 to 2015 were included in the study: 157 patients who underwent 2-field lymph node dissection (2-FLD) and 210 patients who underwent 3-FLD. Clinicopathological parameters and postoperative complications based on the Clavien-Dindo classification were compared between the two groups. We performed propensity score matching (PSM) analyses to compare the groups with well-balanced backgrounds. In terms of patient background, clinical T (p < 0.001), N (p < 0.001), and M (p = 0.002) stage of tumor was significantly more advanced; therefore, preoperative treatment was more frequently performed in the 3-FLD group than in the 2-FLD group (91.0% vs. 79.0%, P< 0.001). However, perioperative parameters including operation time, blood loss, and the number of dissected mediastinal and abdominal lymph nodes did not differ between the groups. In terms of postoperative complications, the occurrence rate of pneumonia increased significantly in patients with 3-FLD compared to 2-FLD (grade III or higher: 10.5% vs. 3.2%, P= 0.025). Although the duration of systemic inflammatory response syndrome (SIRS) was longer in the 3-FLD group than in the 2-FLD group (median 3 days vs. 2 days, P= 0.025), other postoperative parameters (including the highest level of postoperative serum C-reactive protein, intensive care unit stay, re-operation rate, and postoperative hospital stay) were similar between the groups. After PSM, the differences in the background between the groups disappeared. PSM analysis showed that there was no significant difference in each complication between the groups. The duration of SIRS tended to be longer in the 3-FLD group than in the 2-FLD group, but the difference was not significant. The field of lymphadenectomy negatively impacted the short-term outcome in ESCC patients in terms of pneumonia and inflammatory response. However, because the results of the PSM analyses indicate that the short-term outcome was similar between the two groups, 3-FLD could be as feasible as 2-FLD in ESCC patients. PMID- 28881907 TI - Pilot-study on the feasibility of sentinel node navigation surgery in combination with thoracolaparoscopic lymphadenectomy without esophagectomy in early esophageal adenocarcinoma patients. AB - High-risk submucosal esophageal adenocarcinoma's might be treated curatively by means of radical endoscopic resection, followed by thoracolaparoscopic lymphadenectomy without concomitant esophagectomy. A preclinical study has shown the feasibility and safety of this approach; however, no studies are performed in a clinical setting. In addition, sentinel node navigation surgery could be valuable in tailoring the extent of the lymphadenectomy. This study aimed to evaluate the feasibility and safety of thoracolaparoscopic lymphadenectomy without esophagectomy (phase I) and sentinel node navigation surgery (phase II) in patients with early esophageal adenocarcinoma. Patients with T1N0M0 early esophageal adenocarcinoma scheduled for esophagectomy without neoadjuvant therapy were included. Phase I: Two-field, esophagus preserving, thoracolaparoscopic lymphadenectomy was performed, followed by esophagectomy in the same session. Primary outcome parameters were the number of lymph nodes resected, and number of retained lymph nodes in the esophagectomy specimen. Phase II: A radioactive tracer was injected endoscopically the day before surgery. Static imaging was performed 15 and 120 minutes after injection. The day of surgery, sentinel node navigation surgery followed by esophagectomy was performed. Primary outcome parameters were the percentage of patients with a detectable sentinel node, and the concordance between static imaging and probe-based detection of sentinel node. Phase I: Five patients were included, and a median of 30 (IQR: 25-46) lymph nodes was resected. A median of 6 (IQR: 2-9) retained lymph nodes was found in the esophagectomy specimen. No acute adverse events occurred, but near the end of lymphadenectomy esophageal discoloration was observed, possibly indicating ischemia. Phase II: In all five included patients sentinel nodes could be visualized and resected, at a median of 3 (IQR: 2-5) locations. There was a high concordance between imaging and probe-based detection of sentinel nodes. In conclusion, sentinel node navigation surgery followed by lymphadenectomy without concomitant esophagectomy seems feasible in patients with high-risk submucosal early esophageal adenocarcinoma. More evidence is however needed before applying this technique in clinical practice. PMID- 28881908 TI - Does physical activity protect against the development of gastroesophageal reflux disease, Barrett's esophagus, and esophageal adenocarcinoma? A review of the literature with a meta-analysis. AB - Physical activity affects the functioning of the gastrointestinal system through both local and systemic effects and may play an important role in reducing the risk of esophageal adenocarcinoma. This review assesses the biological mechanisms and epidemiological evidence for the relationship between physical activity and the development of esophageal adenocarcinoma and its precursor diseases: gastroesophageal reflux disease (GORD) and Barrett's esophagus. A search of PubMed, Medline, Embase, and CINAHL was conducted from their inceptions to 25th March 2017 for analytical studies that examined associations between recreational and/or occupational levels of physical activity and the risk of GORD, Barrett's esophagus, and esophageal adenocarcinoma. Where appropriate, a meta-analysis of effects was undertaken. Seven studies were included (2 cohort, 5 case control). For GORD, there were three case-control studies with 10 200 cases among 78 034 participants, with a pooled estimated OR of 0.67 (95% CI 0.57-0.78) for high versus low levels of recreational physical activity. In Barrett's esophagus, there was a single case-control study, which reported no association, OR 1.19 (95% CI 0.82-1.73). For esophageal adenocarcinoma, there were three studies (two prospective cohort, one case control) with 666 cases among 910 376 participants. The largest cohort study reported an inverse association for high versus low levels of recreational physical activity, RR 0.68, 95% CI 0.48-0.96. The remaining two studies reported no associations with either occupational or combined recreational and occupational activity. Heterogeneity in the measurement of exposure (recreational, occupational, and both) made a pooled estimate for esophageal adenocarcinoma inappropriate. Although limited, there is some evidence that higher levels of recreational physical activity may reduce the risk of both GORD and esophageal adenocarcinoma, but further large cohort studies examining the type, intensity and duration of activities that may be beneficial are needed. PMID- 28881909 TI - Outcomes of nutritional interventions to treat dysphagia in esophageal cancer: a population-based study. AB - Esophageal cancer (EC) is increasing in prevalence due to rising incidence and improved treatment strategies. Dysphagia is a significant morbidity in patients with EC requiring nutritional intervention. We sought to evaluate outcomes of nutritional interventions for EC patients hospitalized with dysphagia at a population level. The National Inpatient Sample (2002-2012) was utilized to include all adult inpatients (>=18 years of age) with EC and presence of dysphagia and stricture that underwent nutritional interventions including feeding tube (FT) placement, esophageal stenting, or parenteral nutrition (PN). Temporal trends were examined with multivariate analysis performed for mortality, length of stay (LOS), and cost of hospitalization. A total of 509,593 EC patients had 12,205 hospitalizations related to dysphagia. The hospitalization rates doubled over the study period (1.52% vs. 3.28%, p < 0.001). The most common nutritional intervention was FT (27%), followed by esophageal stenting (13%), and PN (11%). PN was more frequently associated with a diagnosis of sepsis (6.1%, p = 0.023) compared to FT (2.5%) or esophageal stenting (1.8%). Multivariate analysis demonstrated FT and esophageal stenting had comparable mortality (OR 1.06, 95% CI: 0.49, 2.32); however, PN was associated with higher mortality (OR 2.37, 95% CI: 1.22, 4.63), cost of hospitalization ($5,510, 95% CI: 2,262, 8,759), and LOS (2.13 days, 95% CI: 0.72, 3.54). This study shows that hospitalizations for EC with dysphagia and related nutritional interventions are increasing. As a single modality, parenteral nutrition should be avoided. Among our esophageal stent and FT population, further studies are necessary to determine adequate interventions based on disease stage. PMID- 28881910 TI - Effect of polaprezinc on experimental corrosive esophageal burns in rats. AB - Unconsciously caustic ingestion is one of the most common causes of serious esophageal strictures in children. The aim of this study is to determine the efficiency of polaprezinc in preventing stricture formation after corrosive esophageal burns (CEB); this was the first time it has been used to treat experimental CEB in rats. Twenty-four rats were divided into four groups, three of which received CEB by the instillation of 1 mL of 10% NaOH solution into their isolated esophageal segments for three minutes. Group C (control) was uninjured and untreated. Group B (esophageal burn) received CEB but were left untreated. Groups PT1 and PT2 had CEB and received 100 mg/kg/day and 200 mg/kg/day, respectively, of intraperitoneal polaprezinc treatment (PT) for the first two weeks, then oral PT for another two weeks. We assessed the treatment's efficiency of the treatment after the fourth week by evaluating the stenosis index (SI) and the histopathological damage score, determining tissue hydroxyproline content (HP), and measuring the weight of the rats before and after the experiment. Mean SI was statistically lower in the groups PT1 and PT2 when compared with Group B (p = 0.006, 0.004, respectively). HP levels were highest in Group B, but it was insignificant (P> 0.05). In terms of histopathological damage score, treatment groups demonstrated less collagen deposition, mucosal, and submucosal damage than both Group B (p = 0.01) and Group C (p = 0.02). Group PT1 and Group PT2 (P> 0.05) showed similar results, indicating the treatment's effectiveness was independent of dosage. Outside of Group C, weight gain was detected only in Group PT2, though it was statistically insignificant. In Group PT1, weight loss was lower than in Group B. Polaprezinc, with its antifibrotic, antioxidant, anti-inflammatory, wound-healing and antiapoptotic effects, was efficient in reducing stricture formation by decreasing HP levels and histopathologic damage, preventing stenosis, and weight gain in higher dosages in the treatment group. PMID- 28881911 TI - Vascular density of superficial esophageal squamous cell carcinoma determined by direct observation of resected specimen using narrow band imaging with magnifying endoscopy. AB - Observation of the microvasculature using narrow band imaging (NBI) with magnifying endoscopy is useful for diagnosing superficial squamous cell carcinoma. Increased vascular density is indicative of cancer, but not many studies have reported differences between cancerous and noncancerous areas based on an objective comparison. We observed specimens of endoscopic submucosal dissection (ESD) using NBI magnification, and determined the vascular density of cancerous and noncancerous areas. A total of 25 lesions of esophageal squamous cell carcinoma that were dissected en bloc by ESD between July 2013 and December 2013 were subjected to NBI magnification. We constructed a device that holds an endoscope and precisely controls the movement along the vertical axis in order to observe submerged specimens by NBI magnification. NBI image files of both cancerous (pathologically determined invasion depth, m1/2) and surrounding noncancerous areas were created and subjected to vascular density assessment by two endoscopists who were blinded to clinical information. The invasion depth was m1/2 in 20, m3/sm1 in four and sm2 in one esophageal cancer lesion. Mean vascular density was significantly increased in cancerous areas (37.6 +/- 16.3 vessels/mm2) compared with noncancerous areas (17.6 +/- 10.0 vessels/mm2) (P < 0.05). The correlation coefficients between vascular density determined by two endoscopists were 0.86 and 0.81 in cancerous and noncancerous areas, respectively. Receiver operating curve (ROC) analysis revealed that the area under the curve (AUC) of vascular density was 0.895 (95% CI, 0.804-0.986). For this ROC curve, sensitivity was 78.3% and specificity was 87.0% when the cutoff value of vascular density was 26 vessels/mm2. NBI magnification confirmed significant increases in vascular density in cancerous areas compared with noncancerous areas in esophageal squamous cell carcinoma. The rates of agreement between vascular density values determined by two independent operators were high. PMID- 28881912 TI - Letter to the Editor: Parameters, Characteristics, and Criteria for Defining the Term "FGF21 Resistance". PMID- 28881913 TI - Erratum for "Anti-Opioid Effects of RFRP-3 on Magnocellular Neuron Activity in Morphine-Naive and Morphine-Treated Female Rats?" PMID- 28881914 TI - Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. PMID- 28881915 TI - Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 28881916 TI - Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 28881918 TI - Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 28881917 TI - EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. PMID- 28881919 TI - Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 28881920 TI - Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 28881921 TI - Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 28881922 TI - Appendix 1: Renal cell carcinoma: MCBS eUpdate published online 10 April 2017(www.esmo.org/Guidelines/Genitourinary-Cancers). PMID- 28881923 TI - Appendix 2: Advanced breast cancer: MCBS eUpdate published online 25 April 2017 (www.esmo.org/Guidelines/Breast-Cancer). PMID- 28881924 TI - Appendix 3: Soft tissue sarcoma: MCBS eUpdate published online 5 May 2017(www.esmo.org/Guidelines/Sarcoma-and-GIST). PMID- 28881925 TI - Appendix 4: Chronic lymphocytic leukaemia: eUpdate published online 27 June 2017 (www.esmo.org/Guidelines/Haematological-Malignancies). PMID- 28881926 TI - Appendix 5: Endometrial cancer: eUpdate published online 8 June 2017 (www.esmo.org/Guidelines/Gynaecological-Cancers). PMID- 28881927 TI - Appendix 6: Cancer of the pancreas: MCBS eUpdate published online 20 June 2017 (www.esmo.org/Guidelines/Gastrointestinal-Cancers). PMID- 28881928 TI - Appendix 7: Metastatic non-small-cell lung cancer (1): MCBS eUpdate published online 28 June 2017 (www.esmo.org/Guidelines/Lung-and-Chest-Tumours). PMID- 28881929 TI - Appendix 8: Metastatic non-small-cell lung cancer (2): eUpdate published online 28 June 2017 (www.esmo.org/Guidelines/Lung-and-Chest-Tumours). PMID- 28881930 TI - Appendix 9: Testicular seminoma and non-seminoma: eUpdate published online 29 June 2017 (www.esmo.org/Guidelines/Genitourinary-Cancers). PMID- 28881931 TI - Corrigendum. PMID- 28881933 TI - Incorporating Context Dependency of Species Interactions in Species Distribution Models. AB - SYNOPSIS: Species distribution models typically use correlative approaches that characterize the species-environment relationship using occurrence or abundance data for a single species. However, species distributions are determined by both abiotic conditions and biotic interactions with other species in the community. Therefore, climate change is expected to impact species through direct effects on their physiology and indirect effects propagated through their resources, predators, competitors, or mutualists. Furthermore, the sign and strength of species interactions can change according to abiotic conditions, resulting in context-dependent species interactions that may change across space or with climate change. Here, we incorporated the context dependency of species interactions into a dynamic species distribution model. We developed a multi species model that uses a time-series of observational survey data to evaluate how abiotic conditions and species interactions affect the dynamics of three rocky intertidal species. The model further distinguishes between the direct effects of abiotic conditions on abundance and the indirect effects propagated through interactions with other species. We apply the model to keystone predation by the sea star Pisaster ochraceus on the mussel Mytilus californianus and the barnacle Balanus glandula in the rocky intertidal zone of the Pacific coast, USA. Our method indicated that biotic interactions between P. ochraceus and B. glandula affected B. glandula dynamics across >1000 km of coastline. Consistent with patterns from keystone predation, the growth rate of B. glandula varied according to the abundance of P. ochraceus in the previous year. The data and the model did not indicate that the strength of keystone predation by P. ochraceus varied with a mean annual upwelling index. Balanus glandula cover increased following years with high phytoplankton abundance measured as mean annual chlorophyll-a. M. californianus exhibited the same pattern to a lesser degree, although this pattern was not significant. This work bridges the disciplines of biogeography and community ecology to develop tools to better understand the direct and indirect effects of abiotic conditions on ecological communities. PMID- 28881932 TI - Health facility management and access: a qualitative analysis of challenges to seeking healthcare for children under five in Uganda. AB - While several studies have documented the various barriers that caretakers of children under five routinely confront when seeking healthcare in Uganda, few have sought to capture the ways in which caretakers themselves prioritize their own barriers to seeking services. To that end, we asked focus groups of caretakers to list their five greatest challenges to seeking care on behalf of children under five. Using qualitative content analysis, we grouped responses according to four categories: (1) geographical access barriers; (2) facility supplies, staffing, and infrastructural barriers; (3) facility management and administration barriers (e.g. health worker professionalism, absenteeism and customer care); and (4) household barriers related to financial circumstances, domestic conflicts with male partners and a stated lack of knowledge about health related issues. Among all focus groups, caretakers mentioned supplies, staffing and infrastructure barriers most often and facility management and administration barriers the least. Caretakers living furthest from public facilities (8-10 km) more commonly mentioned geographical barriers to care and barriers related to financial and other personal circumstances. Caretakers who lived closest to health facilities mentioned facility management and administration barriers twice as often as those who lived further away. While targeting managerial barriers is vitally important-and increasingly popular among national planners and donors-it should be done while recognizing that alleviating such barriers may have a more muted effect on caretakers who are geographically harder to reach - and by extension, those whose children have an increased risk of mortality. In light of calls for greater equity in child survival programming - and given the limited resource envelopes that policymakers often have at their disposal - attention to the barriers considered most vital among caretakers in different settings should be weighed. PMID- 28881934 TI - Broadening Participation in the Society for Integrative and Comparative Biology. AB - SYNOPSIS: The goal of the Society for Integrative and Comparative Biology's Broadening Participation Committee (SICB BPC) is to increase the number of underrepresented group (URG) members within the society and to expand their capabilities as future researchers and leaders within SICB. Our short-term 10 year goal was to increase the recruitment and retention of URG members in the society by 10%. Our long-term 25-year goal is to increase the membership of URG in the society through recruitment and retention until the membership demographic mirrors that of the US Census. Our plans to accomplish this included establishment of a formal standing committee, establishment of a moderate budget to support BPC activities, hosting professional development workshops, hosting diversity and mentor socials, and obtaining grant funds to supplement our budget. This paper documents broadening participation activities in the society, discusses the effectiveness of these activities, and evaluates BPC goals after 5 years of targeted funded activities. Over the past 5 years, the number of URG members rose by 5.2% to a total of 16.2%, members who report ethnicity and gender increased by 25.2% and 18%, respectively, and the number of members attending BPC activities has increased to 33% by 2016. SICB has made significant advances in broadening participation, not only through increased expenditures, but also with a commitment by its members and leadership to increase diversity. Most members realize that increasing diversity will both improve the Society's ability to develop different approaches to tackling problems within integrative biology, and help solve larger global issues that are evident throughout science and technology fields. In addition, having URG members as part of the executive committee would provide other URG members role models within the society, as well as have a voice in the leadership that represents diversity and inclusion for all scientists. PMID- 28881936 TI - Searching for Biotic Multipliers of Climate Change. AB - SYNOPSIS: As climates change, biologists need to prioritize which species to understand, predict, and protect. One way is to identify key species that are both sensitive to climate change and that disproportionately affect communities and ecosystems. These "biotic multipliers" provide efficient targets for research and conservation. Here, we propose eight mechanistic hypotheses related to impact and sensitivity that suggest that top consumers might often act as biotic multipliers of climate change. For impact, top consumers often affect communities and ecosystems through strong top-down effects. For sensitivity, metabolic theory and data suggest that photosynthesis and respiration differ in temperature responses, potentially increasing the sensitivity of consumers relative to plants. Larger-bodied organisms are typically more thermally sensitive than smaller ones, suggesting how large top consumers might be more sensitive than their smaller prey. In addition, traits related to predation are more sensitive than defensive traits to temperature. Top consumers might also be more sensitive because they often lag behind prey in phenological responses. The combination of low population sizes and demographic traits of top consumers could make them more sensitive to disturbances like climate change, which could slow their recovery. As top consumers are positioned at the top of the food chain, many small effects can accumulate from other trophic levels to affect top consumers. Finally, top consumers also often disperse more frequently and farther than prey, potentially leading to greater sensitivity to climate-induced changes in ranges and subsequent impacts on invaded communities. Overall, we expect that large, ectothermic top consumers and mobile predators might frequently be biotic multipliers of climate change. However, this prediction depends on the particular features of species, habitats, and ecosystems. In specific cases, herbivores, plants, or pathogens might be more sensitive than top consumers or have greater community impacts. To predict biotic multipliers, we need to compare sensitivities and impacts across trophic groups in a broader range of ecosystems as well as perform experiments that uncouple proposed mechanisms. Overall, the biotic multiplier concept offers an alternative prioritization scheme for research and conservation that includes impacts on communities and ecosystems. PMID- 28881935 TI - Species as Stressors: Heterospecific Interactions and the Cellular Stress Response under Global Change. AB - SYNOPSIS: Anthropogenic global change is predicted to increase the physiological stress of organisms through changes in abiotic conditions such as temperature, pH, and pollution. However, organisms can also experience physiological stress through interactions with other species, especially parasites, predators, and competitors. The stress of species interactions could be an important driver of species' responses to global change as the composition of biological communities change through factors such as distributional and phenological shifts. Interactions between biotic and abiotic stressors could also induce non-linear physiological stress responses under global change. One of the primary means by which organisms deal with physiological stress is through the cellular stress response (CSR), which is broadly the upregulation of a conserved set of genes that facilitate the removal and repair of damaged macromolecules. Here, we present data on behavioral interactions and CSR gene expression for two competing species of intertidal zone porcelain crab (Petrolisthes cinctipes and Petrolisthes manimaculis). We found that P. cinctipes and P. manimaculis engage in more agonistic behaviors when interacting with heterospecifics than conspecifics; however, we found no evidence that heterospecific interactions induced a CSR in these species. In addition to our new data, we review the literature with respect to CSR induction via species interactions, focusing on predator-prey systems and heterospecific competition. We find extensive evidence for predators to induce cellular stress and aspects of the CSR in prey, even in the absence of direct physical contact between species. Effects of heterospecific competition on the CSR have been studied far less, but we do find evidence that agonistic interactions with heterospecifics can induce components of the CSR. Across all published studies, there is clear evidence that species interactions can lead to cellular stress and induction of the CSR. Nonetheless, our understanding of species-induced cellular stress lags far behind our understanding of abiotic cellular stress. PMID- 28881937 TI - Using a Sound Field to Reduce the Risks of Bird-Strike: An Experimental Approach. AB - SYNOPSIS: Each year, billions of birds collide with large human-made structures, such as building, towers, and turbines, causing substantial mortality. Such bird strike, which is projected to increase, poses risks to populations of birds and causes significant economic costs to many industries. Mitigation technologies have been deployed in an attempt to reduce bird-strike, but have been met with limited success. One reason for bird-strike may be that birds fail to pay adequate attention to the space directly in front of them when in level, cruising flight. A warning signal projected in front of a potential strike surface might attract visual attention and reduce the risks of collision. We tested this idea in captive zebra finches (Taeniopygia guttata) that were trained to fly down a long corridor and through an open wooden frame. Once birds were trained, they each experienced three treatments at unpredictable times and in a randomized order: a loud sound field projected immediately in front of the open wooden frame; a mist net (i.e., a benign strike surface) placed inside the wooden frame; and both the loud sound and the mist net. We found that birds slowed their flight approximately 20% more when the sound field was projected in front of the mist net compared with when the mist net was presented alone. This reduction in velocity would equate to a substantial reduction in the force of any collision. In addition to slowing down, birds increased the angle of attack of their body and tail, potentially allowing for more maneuverable flight. Concomitantly, the only cases where birds avoided the mist net occurred in the sound-augmented treatment. Interestingly, the sound field by itself did not demonstrably alter flight. Although our study was conducted in a limited setting, the alterations of flight associated with our sound field has implications for reducing bird-strike in nature and we encourage researchers to test our ideas in field trials. PMID- 28881938 TI - Indirect Effects of Global Change: From Physiological and Behavioral Mechanisms to Ecological Consequences. AB - SYNOPSIS: A major focus of current ecological research is to understand how global change makes species vulnerable to extirpation. To date, mechanistic ecophysiological analyses of global change vulnerability have focused primarily on the direct effects of changing abiotic conditions on whole-organism physiological traits, such as metabolic rate, locomotor performance, cardiac function, and critical thermal limits. However, species do not live in isolation within their physical environments, and direct effects of climate change are likely to be compounded by indirect effects that result from altered interactions with other species, such as competitors and predators. The Society for Integrative and Comparative Biology 2017 Symposium "Indirect Effects of Global Change: From Physiological and Behavioral Mechanisms to Ecological Consequences" was designed to synthesize multiple approaches to investigating the indirect effects of global change by bringing together researchers that study the indirect effects of global change from multiple perspectives across habitat, type of anthropogenic change, and level of biological organization. Our goal in bringing together researchers from different backgrounds was to foster cross-disciplinary insights into the mechanistic bases and higher-order ecological consequences of indirect effects of global change, and to promote collaboration among fields. PMID- 28881939 TI - Data Management Rubric for Video Data in Organismal Biology. AB - SYNOPSIS: Standards-based data management facilitates data preservation, discoverability, and access for effective data reuse within research groups and across communities of researchers. Data sharing requires community consensus on standards for data management, such as storage and formats for digital data preservation, metadata (i.e., contextual data about the data) that should be recorded and stored, and data access. Video imaging is a valuable tool for measuring time-varying phenotypes in organismal biology, with particular application for research in functional morphology, comparative biomechanics, and animal behavior. The raw data are the videos, but videos alone are not sufficient for scientific analysis. Nearly endless videos of animals can be found on YouTube and elsewhere on the web, but these videos have little value for scientific analysis because essential metadata such as true frame rate, spatial calibration, genus and species, weight, age, etc. of organisms, are generally unknown. We have embarked on a project to build community consensus on video data management and metadata standards for organismal biology research. We collected input from colleagues at early stages, organized an open workshop, "Establishing Standards for Video Data Management," at the Society for Integrative and Comparative Biology meeting in January 2017, and then collected two more rounds of input on revised versions of the standards. The result we present here is a rubric consisting of nine standards for video data management, with three levels within each standard: good, better, and best practices. The nine standards are: (1) data storage; (2) video file formats; (3) metadata linkage; (4) video data and metadata access; (5) contact information and acceptable use; (6) camera settings; (7) organism(s); (8) recording conditions; and (9) subject matter/topic. The first four standards address data preservation and interoperability for sharing, whereas standards 5-9 establish minimum metadata standards for organismal biology video, and suggest additional metadata that may be useful for some studies. This rubric was developed with substantial input from researchers and students, but still should be viewed as a living document that should be further refined and updated as technology and research practices change. The audience for these standards includes researchers, journals, and granting agencies, and also the developers and curators of databases that may contribute to video data sharing efforts. We offer this project as an example of building community consensus for data management, preservation, and sharing standards, which may be useful for future efforts by the organismal biology research community. PMID- 28881940 TI - Predation in High CO2 Waters: Prey Fish from High-Risk Environments are Less Susceptible to Ocean Acidification. AB - SYNOPSIS: Most studies investigating the effects of anthropogenic environmental stressors do so in conditions that are often optimal for their test subjects, ignoring natural stressors such as competition or predation. As such, the quantitative results from such studies may often underestimate the lethality of certain toxic compounds. A well-known example of this concept is illustrated by the marked increase in the lethality of pesticides when larval amphibians are concurrently exposed to the odor of potential predators. Here, we investigated the interaction between background levels of environmental predation risk (high vs. low) and ocean acidification (ambient vs. elevated CO2) in 2 * 2 design. Wild caught juvenile damselfish, Pomacentrus amboinensis, were exposed in the laboratory to the different risk and CO2 conditions for 4 days and released onto coral reef patches. Using a well-established field assay, we monitored the in situ behavior and mortality of the damselfish for 2 days. We predicted that juvenile fish exposed to elevated CO2 and high-risk conditions would display more severe behavioral impairments and increased mortality compared to fish exposed to elevated CO2 maintained under low-risk conditions. As expected, elevated CO2 exposure led to impaired antipredator responses and increased mortality in low risk fish compared to ambient CO2 controls. However, we failed to find an effect of elevated CO2 on the behavior and survival of the high-risk fish. We hypothesized that the results may stem from either a behavioral compensation or a physiological response to high risk. Our results provide insights into the interactive nature of environmental and natural stressors and advance our understanding of the predicted effect of ocean acidification on aquatic ecosystems. PMID- 28881941 TI - Awards, Scholarships, and Grants Awarded at the SICB Meeting in January 2017. PMID- 28881942 TI - eComment. Uniportal VATS: the great potential of the technique. PMID- 28881943 TI - eComment. Neoadjuvant treatment for advanced thymomas: Is downstaging realistic when opting for thoracoscopic surgery? PMID- 28881944 TI - eComment. The quest for elusive causative microbiological agents of infectious ascending aortitis. PMID- 28881945 TI - eComment. Management of deep sternal wound infections after cardiac surgery: Towards development of new substrates for sustained multiagent delivery release profiles. PMID- 28881946 TI - Soil and Foliar Arthropod Abundance and Diversity in Five Cropping Systems in the Coastal Plains of North Carolina. AB - Soil and foliar arthropod populations in agricultural settings respond to environmental disturbance and degradation, impacting functional biodiversity in agroecosystems. The objective of this study was to evaluate system level management effects on soil and foliar arthropod abundance and diversity in corn and soybean. Our field experiment was a completely randomized block design with three replicates for five farming systems which included: Conventional clean till, conventional long rotation, conventional no-till, organic clean till, and organic reduced till. Soil arthropod sampling was accomplished by pitfall trapping. Foliar arthropod sampling was accomplished by scouting corn and sweep netting soybean. Overall soil arthropod abundance was significantly impacted by cropping in corn and for foliar arthropods in soybeans. Conventional long rotation and organic clean till systems were highest in overall soil arthropod abundance for corn while organic reduced till systems exceeded all other systems for overall foliar arthropod abundance in soybeans. Foliar arthropod abundance over sampling weeks was significantly impacted by cropping system and is suspected to be the result of in-field weed and cover crop cultivation practices. This suggests that the sum of management practices within production systems impact soil and foliar arthropod abundance and diversity and that the effects of these systems are dynamic over the cropping season. Changes in diversity may be explained by weed management practices as sources of disturbance and reduced arthropod refuges via weed reduction. Furthermore, our results suggest agricultural systems lower in management intensity, whether due to organic practices or reduced levels of disturbance, foster greater arthropod diversity. PMID- 28881947 TI - Bacterial Inoculant Treatment of Bermudagrass Alters Ovipositional Behavior, Larval and Pupal Weights of the Fall Armyworm (Lepidoptera: Noctuidae). AB - Nonpathogenic soil bacteria can colonize the rhizosphere and induce unique plant phenotypes that may influence plant-insect interactions. However, few studies have considered the influences of bacteria-plant interactions on insect feeding and oviposition. The objective of this study was to determine how rhizobacterial inoculation of bermudagrass affects larval development and ovipositional behaviors of the fall armyworm (Spodoptera frugiperda J.E. Smith). Eight blends of rhizobacteria known to induce root or shoot growth in grasses were applied weekly to hybrid bermudagrass for 5 wk. Oviposition was evaluated in two no choice trials with bacteria-treated, fertilized, or nontreated grass. Grass blades from these treatments were extracted in polar and nonpolar solvents and assayed for oviposition responses. Another experiment compared the development of fall armyworm larvae on bermudagrass treated with each of the eight rhizobacterial blends for 5 wk to larvae fed nontreated bermudagrass. Females deposited more eggs on nontreated and fertilized grass and <=34% of eggs on grass treated with rhizobacterial blends. Moths exposed to polar and nonpolar extracts were unable to reproduce these results. Larval and pupal weights at days 10 and 12 and the number of adults to eclose were lower for larvae fed some, but not all, bacteria-treated bermudagrass relative to controls. This is one of the few studies to investigate plant-microbe-insect interactions in an economically important system. Although the effects noted with fall armyworm are limited, induced changes in roots also reported for these bacteria may have greater utility than foliar changes for mediating interactions with biotic or abiotic stresses. PMID- 28881948 TI - Cohabiting With the Enemy: Comparative Population Ecology of Two Mantid Species in a Successional Old Field. AB - Two praying mantids, Tenodera aridifolia sinensis Saussure and Tenodera angustipennis Saussure, are commonly found in the same old-field habitats in the eastern United States and in much of temperate zone Asia. Naturally established populations of these two species were studied intensively over two consecutive years (2010 and 2011) in an old field in southeastern Virginia, to compare life history features relevant to how they coexist, or whether one or the other of them is likely to be more successful in the same habitat. Populations of both species declined about 50% from 2010 to 2011 (adults from 47 to 21 for T. a. sinensis; 37 to 20 for T. angustipennis), but T. a. sinensis oviposited 10 oothecae and T. angustipennis only one in 2011. Tenodera a. sinensis was more abundant in the study site in both years, hatched earlier, and matured and oviposited earlier than T. angustipennis. Fewer females of both species survived to maturity in 2011 than in 2010, possibly indicating a reduction in prey or habitat suitability in 2011. We suggest that T. angustipennis will always be at a disadvantage as a result of its smaller body size, because of interspecific predation (and potentially competition) from its congener, lower clutch size, and susceptibility to egg parasitism. Further, environmental variability across field habitats and years profoundly affects populations of both species in successional old fields. PMID- 28881949 TI - Heat Tolerance Induction of the Indian Meal Moth (Lepidoptera: Pyralidae) Is Accompanied by Upregulation of Heat Shock Proteins and Polyols. AB - The Indian meal moth, Plodia interpunctella, causes massive damage to stored grains and processed foods. Heat treatment has been widely used to control insect pests infesting stored grains. However, heat treatment may result in unsatisfactory control owing to heat tolerance of target insects. This study quantified the heat tolerance and analyzed its induction in P. interpunctella. Susceptibility of P. interpunctella to different high temperatures was assessed in all developmental stages. Heat treatment at 44 degrees C for 1 h caused significant mortalities to all developmental stages, with late-instar larvae exhibiting the highest tolerance. However, the survivorship to heat treatment was significantly increased by pre-exposure to 37 degrees C for 30 min. The induction of heat tolerance was accompanied by upregulation of two heat shock proteins of Hsc70 and Hsp90. Trehalose and glycerol concentrations in the hemolymph also increased after pre-exposure to 37 degrees C for 30 min. RNA interference (RNAi) by specific double-stranded RNAs effectively suppressed the inducible expressions of both Hsc70 and Hsp90 in response to 37 degrees C for 30 min. Either RNAi of Hsc70 or Hsp90 significantly impaired the heat tolerance induction of P. interpunctella. These results suggest that the induction of heat tolerance in P. interpunctella involves the upregulation of these heat shock proteins and hemolymph polyol levels. PMID- 28881951 TI - Monitoring Temporal Variation to Assess Changes in the Structure of Subtropical Atlantic Forest Butterfly Communities. AB - The study of fauna through long-term surveys is important in unveiling how temporal patterns shape the structure of communities in tropical habitats. The butterfly assemblage of the subtropical Atlantic Forest may be considered highly diverse and shows changes in diversity and composition over time, highlighting the importance of long-term inventories. This work assessed temporal diversity patterns in the distribution and composition of butterfly assemblages in an Atlantic Forest site in southern Brazil using combined data from three years of standardized sampling with entomological nets, increasing the knowledge on this group in the Neotropics for monitoring and conservation. The butterfly fauna was analyzed in terms of richness, abundance, and composition. The inventories reached 401 species, with 14,442 butterfly individuals sampled. All the diversity parameters evaluated show significant differences between the first year of sampling compared to the second and third years. The latter had higher values of richness and abundance, followed by the first and second years. Hesperiidae was the richest family, followed by Nymphalidae and Lycaenidae, indicating a good representation of the assemblage as a whole. The results of this work are important for developing conservation programs in the Atlantic Forest and other forested environments in the neotropics, especially concerning reliable diversity assessments for the monitoring and management of protected areas. Decision making and public policy might also benefit from knowledge on temporal patterns of diversity regarding the maintenance of native habitats and integrity of biomes and their associated fauna. PMID- 28881950 TI - Susceptibility, Oviposition Preference, and Biology of Grapholita molesta (Lepidoptera: Tortricidae) in Prunus Spp. Rootstock Genotypes. AB - Studying the susceptibility of peach trees to Grapholita molesta (Busck) is one of the major steps in the development of pest-resistant peach varieties. This work evaluated the susceptibility of 55 genotypes of the "Prunus Rootstock Collection" ("Colecao Porta-enxerto de Prunus") of Embrapa Temperate Climate (Pelotas, Rio Grande do Sul, Brazil) to the natural infestation of G. molesta, assessed the oviposition preference of G. molesta in choice and no-choice bioassays, and estimated the biological parameters and the fertility life table on different Prunus spp. genotypes in the laboratory. Genotypes Prunus kansuensis (Rehder), I-67-52-9, and I-67-52-4 were the most susceptible to G. molesta infestation in the field (>60% of branches infested), while 'Sharpe' (Prunus angustifolia x Prunus spp.) and Prunus sellowii (Koehne) were the least infested (0% of branches infested). In choice and no-choice bioassays, G. molesta preferred to oviposit on P. kansuensis when compared with Sharpe. The Sharpe genotype also showed an antibiosis effect, resulting in negative effects on the fertility life table parameters when compared with the genotypes P. kansuensis and 'Capdeboscq.' The results found in the present study can provide information to initiate a long-term breeding program moving desired G. molesta resistance traits from the rootstock into the Prunus spp. cultivars. PMID- 28881952 TI - Effects of Temperature on Development of Lymantria dispar asiatica and Lymantria dispar japonica (Lepidoptera: Erebidae). AB - Periodic introductions of the Asian subspecies of gypsy moth, Lymantria dispar asiatica Vnukovskij and Lymantria dispar japonica Motschulsky, in North America are threatening forests and interrupting foreign trade. Although Asian gypsy moth has similar morphology to that of European and North American gypsy moth, it has several traits that make it a greater threat, the most important being the flight capability of females. Asian gypsy moth is not yet established in North America; however, infestations have been detected multiple times in Canada and the United States. To facilitate detection and eradication efforts, we evaluated the effect of a range of temperatures on development time, survivorship, and fertility of eight populations of Asian gypsy moth. There were significant impacts of temperature and population on these life history characteristics. The larval developmental rate increased with temperature until it reached an optimum at 29 degrees C. Larvae experienced significant molting problems at the highest and lowest temperatures tested (10 degrees C and 30 degrees C). At 30 degrees C, female fitness was markedly compromised, as evidenced by reduced fecundity and fertility. This suggests that development and survival of Asian gypsy moth may be limited by summer temperature extremes in the Southern United States. We also determined the degree-day requirements for two critical life stages and two populations of Asian gypsy moth, which represent the extremes in latitude, to predict the timing for biopesticide application and adult trap deployment. Our data will benefit pest managers in developing management strategies, pest risk assessments, and timing for implementation of management tactics. PMID- 28881953 TI - Wireworm in Quebec Field Crops: Specific Community Composition in North America. AB - Wireworms are important economic pests that attack the seeds and roots of numerous vegetable and field crops worldwide. A 5-yr study was conducted in the main agricultural regions of the province of Quebec (Canada), to identify and characterize the wireworm communities (Coleoptera: Elateridae) that occur in fields planted with economically important crops (maize, soybean, cereals, canola, and grasslands). Bait traps were used to collect wireworms each spring from 2011 to 2015. More than 600 sites were sampled in total, involving ca. 14,000 traps. Wireworms were found in 69% of the sites and 73% of the traps. A total of 6,014 wireworms were collected and identified to genus, or to species when possible. The results show that nine genera occur in Quebec and that Hypnoidus abbreviatus (Say) is currently the most abundant species in arable land in Quebec, representing 72% of all collected wireworms. The other genera collected were Melanotus (8% of all wireworms collected), Ampedus (7%), Limonius (6%), and Agriotes (4%). Wireworms from the genera Aeolus, Dalopius, Hemicrepidius, and Oestodes constituted ca. 3% together. The predominance of H. abbreviatus appeared to be specific to Quebec compared with the other Canadian provinces and the rest of North America. We observed differences in the relative abundance of wireworm genera among the agricultural regions sampled. However, no effect of current and preceding crops was observed in this study. Our results suggest that integrated pest management strategies for managing wireworms in Quebec fields should take into consideration the species present in each agronomical region. PMID- 28881954 TI - Within-Plant Distribution and Susceptibility of Hazelnut Cultivars to Mikomya coryli (Diptera: Cecidomyiidae). AB - The Mikomya coryli (Kieffer) (Diptera: Cecidomyiidae) is widespread in Europe and the most important cecidomyiid pest of hazelnut. Within-plant distribution, susceptibility of 18 Turkish hazelnut cultivars ('Aci,' 'Allahverdi,' 'Cakildak,' 'Cavcava,' 'Fosa,' 'Incekara,' 'Kalinkara,' 'Kan,' 'Karafindik,' 'Kargalak,' 'Kus,' 'Mincane,' 'Palaz,' 'Sivri,' 'Tombul,' 'Uzunmusa,' 'Yassi Badem,' and 'Yuvarlak Badem'), and the phenology of larvae of this pest in hazelnut leaves and involucres were assessed in 2014 and 2015 in Giresun (Turkey). Mikomya coryli distribution differed significantly within different parts of the hazelnut plant. The highest gall numbers of M. coryli were found in the middle part (0.70-1.40 m) of the plant in both years. Total gall numbers varied between years: 1,779 and 2,588 galls were counted in 2014 and 2015, respectively. Susceptibility to M. coryli damage varied significantly among the cultivars. The highest leaf gall densities and total numbers of galls were found on leaves and involucres of Allahverdi, Yuvaklak Badem, and Yassi Badem cultivars in both years. Mikomya coryli larvae were detected between April and June in the leaf galls. The number of larvae in the involucres changed between April and mid-June. Results of the within-plant distribution, M. coryli larval phenology, and cultivar pest susceptibility analyses are presented to enable effective control of the pest as a part of hazelnut integrated pest management. PMID- 28881955 TI - Calling Behavior, Copulation Time, and Reproductive Compatibility of Corn-Strain Fall Armyworm (Lepidoptera: Noctuidae) From Populations in Mexico. AB - The calling behavior, mating time, and the reproductive compatibility of virgin adults of fall armyworms, Spodoptera frugiperda (J. E. Smith), were studied in this work. Larvae were collected on maize (Zea mays L.) from six states located on the Pacific coast (Chiapas, Michoacan, and Sinaloa), on the Gulf of Mexico (Veracruz and Yucatan), and in central Mexico (Morelos). Before the experiments, insects were reared under laboratory conditions for one generation. We recorded the age at which females called for the first time, the onset time of calling, the duration of calling, the onset time of copulation, and the duration of copulation. The calling rhythms of the six populations were dissimilar. Females from all populations began to call in the second or third scotophase. The time for onset of calling and the duration of calling were significantly different among the S. frugiperda populations studied. Spodoptera frugiperda pairs from Sinaloa, Veracruz, Yucatan, and Morelos started to copulate earlier than the pairs from Chiapas and Michoacan. Pairs from Veracruz and Yucatan copulated longer than those from Michoacan, Morelos, Chiapas, and Sinaloa. Our crossing experiment using females and males from the six populations showed that individuals from different populations could copulate and produce fertile offspring. Thus, although the S. frugiperda populations showed variability in the timing of reproduction, the populations were not reproductively incompatible, which indicated that geographic distance has not led to reproductive isolation in corn-strain populations of S. frugiperda in Mexico. PMID- 28881956 TI - Geostatistical Characterization of Cereal Leaf Beetle (Coleoptera: Chrysomelidae) Distributions in Wheat. AB - A 3-yr study was conducted in wheat, Triticum aestivum L., in South Carolina to characterize the spatial distribution of Oulema melanopus (L.) adults, eggs, and larvae using semivariograms, which provides a measure of spatial dependence among sampling data. Moran's I coefficients for peak densities of each life stage indicated significant positive autocorrelation for seven (two for eggs, one for larvae, and four for adults) of the 16 datasets. Aggregation was detected in 13 of these 16 datasets when analyzed by semivariogram modeling, with spherical, Gaussian, and exponential models best fitting for eight, four, and one dataset, respectively, and with models for two datasets having only one parameter (nugget) significantly different from zero. The nugget-to-sill ratios ranged from 0.043 to 0.774, and indicated strong spatial dependence in six models (three for adults, two for eggs, and one for larvae), moderate spatial dependence in six models (three for adults and six for eggs), and weak spatial dependence in one model (adults). Range values varied from 39.1 m to 234.1 m, with an average of 120.1 +/ 14.0 m. Average range values were 104.9, 135.2, and 161.2 m for adults, eggs, and larvae, respectively. Because the majority of semivariogram models in our study indicated aggregated distributions, spatial sampling will provide more information than nonspatial random sampling. Developing our understanding of spatial dependence of crop pests is needed to optimize sampling plans and can provide a basis for exploring site-specific management tactics. PMID- 28881957 TI - Fermentation for Disinfesting Fruit Waste From Drosophila Species (Diptera: Drosophilidae). AB - Economic losses in a range of fruit crops due to the Drosophila suzukii (Matsumura) have become severe. Removal and treatment of fruit waste, which may harbor D. suzukii, is a key step in preventing reinfestation of fruit production. Natural fermentation for disinfesting fruit wastes from D. suzukii was examined at ambient air temperatures of 12-20 degrees C. Soft and stone fruit wastes infested with eggs, larvae, and pupae of Drosophila melanogaster (Meigen) or D. suzukii were placed in sealed vessels containing fruit wastes, and samples were retrieved at intervals and tested for the emergence of adults. Mean temperatures of the fruit waste in the sealed vessels during fermentation were 15-23 degrees C. Fermentation for 3 d was effective in disinfesting waste from different life stages of D. suzukii. Treatment for 4 d also ensured that the waste was free of viable life stages of D. melanogaster, which could be used as an indicator species for disinfestation of waste from D. suzukii owing to its greater tolerance of fermentation. The O2 concentration of the headspace air in the vessels became undetectable after 13-16 h, with a corresponding increase in CO2 concentration, which exceeded 80% vol/vol. The resulting hypoxia and hypercapnia may explain the efficacy of the fermentation treatment in disinfesting the waste. Fermented fruit remained attractive to D. suzukii and retained its capacity to rear a life cycle. Covering or mixing fermented fruit with a sufficient depth (0.1 m) or volume (*9) of soil or coir prevented the reinfestation of treated waste. PMID- 28881958 TI - Influence of Host Quality and Temperature on the Biology of Diaeretiella rapae (Hymenoptera: Braconidae, Aphidiinae). AB - Biological features of Diaeretiella rapae (McIntosh), an aphid parasitoid, are conditioned by temperature and host. However, studies of host quality changes due to temperature adaptability have not been performed previously. Therefore, this study evaluated the adaptability of Lipaphis pseudobrassicae (Davis) and Myzus persicae (Sulzer) to high temperature, high temperature effect on their quality as hosts for D. rapae, and on parasitoid's thermal threshold. Aphid development, survivorship, fecundity, and longevity were compared at 19 degrees C and 28 degrees C. Host quality in different temperatures was determined through evaluation of parasitoid biology. Thermal threshold of D. rapae was determined using development time data. At 28 degrees C, development time, rate of immature survival, and total fecundity rates were greater in L. pseudobrassicae than in M. persicae. Development time of D. rapae in L. pseudobrassicae was shorter than that in M. persicae at 28 degrees C and 31 degrees C for females and at 31 degrees C for males. The thermal threshold of D. rapae was 6.38 degrees C and 3.33 degrees C for females and 4.45 degrees C and 3.63 degrees C for males developed on L. pseudobrassicae and M. persicae, respectively. Diaeretiella rapae size gain was greater in L. pseudobrassicae than that in M. persicae at 25 degrees C and 28 degrees C. Lipaphis pseudobrassicae showed better adaptation than M. persicae to elevated temperatures, which resulted in a better quality host for D. rapae at temperatures of 28 degrees C and 31 degrees C and a higher lower thermal threshold when the parasitoid developed within L. pseudobrassicae. The host's adaptation to high temperatures is a determinant of host quality for the parasitoid at that same climatic condition. PMID- 28881959 TI - MaBoSS 2.0: an environment for stochastic Boolean modeling. AB - Motivation: Modeling of signaling pathways is an important step towards the understanding and the treatment of diseases such as cancers, HIV or auto-immune diseases. MaBoSS is a software that allows to simulate populations of cells and to model stochastically the intracellular mechanisms that are deregulated in diseases. MaBoSS provides an output of a Boolean model in the form of time dependent probabilities, for all biological entities (genes, proteins, phenotypes, etc.) of the model. Results: We present a new version of MaBoSS (2.0), including an updated version of the core software and an environment. With this environment, the needs for modeling signaling pathways are facilitated, including model construction, visualization, simulations of mutations, drug treatments and sensitivity analyses. It offers a framework for automated production of theoretical predictions. Availability and Implementation: MaBoSS software can be found at https://maboss.curie.fr , including tutorials on existing models and examples of models. Contact: gautier.stoll@upmc.fr or laurence.calzone@curie.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881960 TI - Message from the ISCB: 2017 ISCB Innovator Award Given to Aviv Regev. PMID- 28881961 TI - Rectified factor networks for biclustering of omics data. AB - Motivation: Biclustering has become a major tool for analyzing large datasets given as matrix of samples times features and has been successfully applied in life sciences and e-commerce for drug design and recommender systems, respectively. actor nalysis for cluster cquisition (FABIA), one of the most successful biclustering methods, is a generative model that represents each bicluster by two sparse membership vectors: one for the samples and one for the features. However, FABIA is restricted to about 20 code units because of the high computational complexity of computing the posterior. Furthermore, code units are sometimes insufficiently decorrelated and sample membership is difficult to determine. We propose to use the recently introduced unsupervised Deep Learning approach Rectified Factor Networks (RFNs) to overcome the drawbacks of existing biclustering methods. RFNs efficiently construct very sparse, non-linear, high dimensional representations of the input via their posterior means. RFN learning is a generalized alternating minimization algorithm based on the posterior regularization method which enforces non-negative and normalized posterior means. Each code unit represents a bicluster, where samples for which the code unit is active belong to the bicluster and features that have activating weights to the code unit belong to the bicluster. Results: On 400 benchmark datasets and on three gene expression datasets with known clusters, RFN outperformed 13 other biclustering methods including FABIA. On data of the 1000 Genomes Project, RFN could identify DNA segments which indicate, that interbreeding with other hominins starting already before ancestors of modern humans left Africa. Availability and implementation: https://github.com/bioinf-jku/librfn. Contact: djork-arne.clevert@bayer.com or hochreit@bioinf.jku.at. PMID- 28881962 TI - Applying meta-analysis to genotype-tissue expression data from multiple tissues to identify eQTLs and increase the number of eGenes. AB - Motivation: There is recent interest in using gene expression data to contextualize findings from traditional genome-wide association studies (GWAS). Conditioned on a tissue, expression quantitative trait loci (eQTLs) are genetic variants associated with gene expression, and eGenes are genes whose expression levels are associated with genetic variants. eQTLs and eGenes provide great supporting evidence for GWAS hits and important insights into the regulatory pathways involved in many diseases. When a significant variant or a candidate gene identified by GWAS is also an eQTL or eGene, there is strong evidence to further study this variant or gene. Multi-tissue gene expression datasets like the Gene Tissue Expression (GTEx) data are used to find eQTLs and eGenes. Unfortunately, these datasets often have small sample sizes in some tissues. For this reason, there have been many meta-analysis methods designed to combine gene expression data across many tissues to increase power for finding eQTLs and eGenes. However, these existing techniques are not scalable to datasets containing many tissues, like the GTEx data. Furthermore, these methods ignore a biological insight that the same variant may be associated with the same gene across similar tissues. Results: We introduce a meta-analysis model that addresses these problems in existing methods. We focus on the problem of finding eGenes in gene expression data from many tissues, and show that our model is better than other types of meta-analyses. Availability and Implementation: Source code is at https://github.com/datduong/RECOV . Contact: eeskin@cs.ucla.edu or datdb@cs.ucla.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881963 TI - Deep learning with word embeddings improves biomedical named entity recognition. AB - Motivation: Text mining has become an important tool for biomedical research. The most fundamental text-mining task is the recognition of biomedical named entities (NER), such as genes, chemicals and diseases. Current NER methods rely on pre defined features which try to capture the specific surface properties of entity types, properties of the typical local context, background knowledge, and linguistic information. State-of-the-art tools are entity-specific, as dictionaries and empirically optimal feature sets differ between entity types, which makes their development costly. Furthermore, features are often optimized for a specific gold standard corpus, which makes extrapolation of quality measures difficult. Results: We show that a completely generic method based on deep learning and statistical word embeddings [called long short-term memory network-conditional random field (LSTM-CRF)] outperforms state-of-the-art entity specific NER tools, and often by a large margin. To this end, we compared the performance of LSTM-CRF on 33 data sets covering five different entity classes with that of best-of-class NER tools and an entity-agnostic CRF implementation. On average, F1-score of LSTM-CRF is 5% above that of the baselines, mostly due to a sharp increase in recall. Availability and implementation: The source code for LSTM-CRF is available at https://github.com/glample/tagger and the links to the corpora are available at https://corposaurus.github.io/corpora/ . Contact: habibima@informatik.hu-berlin.de. PMID- 28881964 TI - Orthologous Matrix (OMA) algorithm 2.0: more robust to asymmetric evolutionary rates and more scalable hierarchical orthologous group inference. AB - Motivation: Accurate orthology inference is a fundamental step in many phylogenetics and comparative analysis. Many methods have been proposed, including OMA (Orthologous MAtrix). Yet substantial challenges remain, in particular in coping with fragmented genes or genes evolving at different rates after duplication, and in scaling to large datasets. With more and more genomes available, it is necessary to improve the scalability and robustness of orthology inference methods. Results: We present improvements in the OMA algorithm: (i) refining the pairwise orthology inference step to account for same-species paralogs evolving at different rates, and (ii) minimizing errors in the pairwise orthology verification step by testing the consistency of pairwise distance estimates, which can be problematic in the presence of fragmentary sequences. In addition we introduce a more scalable procedure for hierarchical orthologous group (HOG) clustering, which are several orders of magnitude faster on large datasets. Using the Quest for Orthologs consortium orthology benchmark service, we show that these changes translate into substantial improvement on multiple empirical datasets. Availability and Implementation: This new OMA 2.0 algorithm is used in the OMA database ( http://omabrowser.org ) from the March 2017 release onwards, and can be run on custom genomes using OMA standalone version 2.0 and above ( http://omabrowser.org/standalone ). Contact: christophe.dessimoz@unil.ch or adrian.altenhoff@inf.ethz.ch. PMID- 28881965 TI - Deep learning-based subdivision approach for large scale macromolecules structure recovery from electron cryo tomograms. AB - Motivation: Cellular Electron CryoTomography (CECT) enables 3D visualization of cellular organization at near-native state and in sub-molecular resolution, making it a powerful tool for analyzing structures of macromolecular complexes and their spatial organizations inside single cells. However, high degree of structural complexity together with practical imaging limitations makes the systematic de novo discovery of structures within cells challenging. It would likely require averaging and classifying millions of subtomograms potentially containing hundreds of highly heterogeneous structural classes. Although it is no longer difficult to acquire CECT data containing such amount of subtomograms due to advances in data acquisition automation, existing computational approaches have very limited scalability or discrimination ability, making them incapable of processing such amount of data. Results: To complement existing approaches, in this article we propose a new approach for subdividing subtomograms into smaller but relatively homogeneous subsets. The structures in these subsets can then be separately recovered using existing computation intensive methods. Our approach is based on supervised structural feature extraction using deep learning, in combination with unsupervised clustering and reference-free classification. Our experiments show that, compared with existing unsupervised rotation invariant feature and pose-normalization based approaches, our new approach achieves significant improvements in both discrimination ability and scalability. More importantly, our new approach is able to discover new structural classes and recover structures that do not exist in training data. Availability and Implementation: Source code freely available at http://www.cs.cmu.edu/~mxu1/software . Contact: mxu1@cs.cmu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881966 TI - DextMP: deep dive into text for predicting moonlighting proteins. AB - Motivation: Moonlighting proteins (MPs) are an important class of proteins that perform more than one independent cellular function. MPs are gaining more attention in recent years as they are found to play important roles in various systems including disease developments. MPs also have a significant impact in computational function prediction and annotation in databases. Currently MPs are not labeled as such in biological databases even in cases where multiple distinct functions are known for the proteins. In this work, we propose a novel method named DextMP, which predicts whether a protein is a MP or not based on its textual features extracted from scientific literature and the UniProt database. Results: DextMP extracts three categories of textual information for a protein: titles, abstracts from literature, and function description in UniProt. Three language models were applied and compared: a state-of-the-art deep unsupervised learning algorithm along with two other language models of different types, Term Frequency-Inverse Document Frequency in the bag-of-words and Latent Dirichlet Allocation in the topic modeling category. Cross-validation results on a dataset of known MPs and non-MPs showed that DextMP successfully predicted MPs with over 91% accuracy with significant improvement over existing MP prediction methods. Lastly, we ran DextMP with the best performing language models and text-based feature combinations on three genomes, human, yeast and Xenopus laevis , and found that about 2.5-35% of the proteomes are potential MPs. Availability and Implementation: Code available at http://kiharalab.org/DextMP . Contact: dkihara@purdue.edu. PMID- 28881967 TI - HopLand: single-cell pseudotime recovery using continuous Hopfield network-based modeling of Waddington's epigenetic landscape. AB - Motivation: The interpretation of transcriptional dynamics in single-cell data, especially pseudotime estimation, could help understand the transition of gene expression profiles. The recovery of pseudotime increases the temporal resolution of single-cell transcriptional data, but is challenging due to the high variability in gene expression between individual cells. Here, we introduce HopLand, a pseudotime recovery method using continuous Hopfield network to map cells to a Waddington's epigenetic landscape. It reveals from the single-cell data the combinatorial regulatory interactions among genes that control the dynamic progression through successive cell states. Results: We applied HopLand to different types of single-cell transcriptomic data. It achieved high accuracies of pseudotime prediction compared with existing methods. Moreover, a kinetic model can be extracted from each dataset. Through the analysis of such a model, we identified key genes and regulatory interactions driving the transition of cell states. Therefore, our method has the potential to generate fundamental insights into cell fate regulation. Availability and implementation: The MATLAB implementation of HopLand is available at https://github.com/NetLand-NTU/HopLand . Contact: zhengjie@ntu.edu.sg. PMID- 28881968 TI - SnapDock-template-based docking by Geometric Hashing. AB - Motivation: A highly efficient template-based protein-protein docking algorithm, nicknamed SnapDock, is presented. It employs a Geometric Hashing-based structural alignment scheme to align the target proteins to the interfaces of non-redundant protein-protein interface libraries. Docking of a pair of proteins utilizing the 22 600 interface PIFACE library is performed in < 2 min on the average. A flexible version of the algorithm allowing hinge motion in one of the proteins is presented as well. Results: To evaluate the performance of the algorithm a blind re-modelling of 3547 PDB complexes, which have been uploaded after the PIFACE publication has been performed with success ratio of about 35%. Interestingly, a similar experiment with the template free PatchDock docking algorithm yielded a success rate of about 23% with roughly 1/3 of the solutions different from those of SnapDock. Consequently, the combination of the two methods gave a 42% success ratio. Availability and implementation: A web server of the application is under development. Contact: michaelestrin@gmail.com or wolfson@tau.ac.il. PMID- 28881969 TI - Chromatin accessibility prediction via convolutional long short-term memory networks with k-mer embedding. AB - Motivation: Experimental techniques for measuring chromatin accessibility are expensive and time consuming, appealing for the development of computational approaches to predict open chromatin regions from DNA sequences. Along this direction, existing methods fall into two classes: one based on handcrafted k mer features and the other based on convolutional neural networks. Although both categories have shown good performance in specific applications thus far, there still lacks a comprehensive framework to integrate useful k -mer co-occurrence information with recent advances in deep learning. Results: We fill this gap by addressing the problem of chromatin accessibility prediction with a convolutional Long Short-Term Memory (LSTM) network with k -mer embedding. We first split DNA sequences into k -mers and pre-train k -mer embedding vectors based on the co occurrence matrix of k -mers by using an unsupervised representation learning approach. We then construct a supervised deep learning architecture comprised of an embedding layer, three convolutional layers and a Bidirectional LSTM (BLSTM) layer for feature learning and classification. We demonstrate that our method gains high-quality fixed-length features from variable-length sequences and consistently outperforms baseline methods. We show that k -mer embedding can effectively enhance model performance by exploring different embedding strategies. We also prove the efficacy of both the convolution and the BLSTM layers by comparing two variations of the network architecture. We confirm the robustness of our model to hyper-parameters by performing sensitivity analysis. We hope our method can eventually reinforce our understanding of employing deep learning in genomic studies and shed light on research regarding mechanisms of chromatin accessibility. Availability and implementation: The source code can be downloaded from https://github.com/minxueric/ismb2017_lstm . Contact: tingchen@tsinghua.edu.cn or ruijiang@tsinghua.edu.cn. Supplementary information: Supplementary materials are available at Bioinformatics online. PMID- 28881970 TI - Improving the performance of minimizers and winnowing schemes. AB - Motivation: The minimizers scheme is a method for selecting k -mers from sequences. It is used in many bioinformatics software tools to bin comparable sequences or to sample a sequence in a deterministic fashion at approximately regular intervals, in order to reduce memory consumption and processing time. Although very useful, the minimizers selection procedure has undesirable behaviors (e.g. too many k -mers are selected when processing certain sequences). Some of these problems were already known to the authors of the minimizers technique, and the natural lexicographic ordering of k -mers used by minimizers was recognized as their origin. Many software tools using minimizers employ ad hoc variations of the lexicographic order to alleviate those issues. Results: We provide an in-depth analysis of the effect of k -mer ordering on the performance of the minimizers technique. By using small universal hitting sets (a recently defined concept), we show how to significantly improve the performance of minimizers and avoid some of its worse behaviors. Based on these results, we encourage bioinformatics software developers to use an ordering based on a universal hitting set or, if not possible, a randomized ordering, rather than the lexicographic order. This analysis also settles negatively a conjecture (by Schleimer et al. ) on the expected density of minimizers in a random sequence. Availability and Implementation: The software used for this analysis is available on GitHub: https://github.com/gmarcais/minimizers.git . Contact: gmarcais@cs.cmu.edu or carlk@cs.cmu.edu. PMID- 28881971 TI - Modelling haplotypes with respect to reference cohort variation graphs. AB - Motivation: Current statistical models of haplotypes are limited to panels of haplotypes whose genetic variation can be represented by arrays of values at linearly ordered bi- or multiallelic loci. These methods cannot model structural variants or variants that nest or overlap. Results: A variation graph is a mathematical structure that can encode arbitrarily complex genetic variation. We present the first haplotype model that operates on a variation graph-embedded population reference cohort. We describe an algorithm to calculate the likelihood that a haplotype arose from this cohort through recombinations and demonstrate time complexity linear in haplotype length and sublinear in population size. We furthermore demonstrate a method of rapidly calculating likelihoods for related haplotypes. We describe mathematical extensions to allow modelling of mutations. This work is an important incremental step for clinical genomics and genetic epidemiology since it is the first haplotype model which can represent all sorts of variation in the population. Availability and Implementation: Available on GitHub at https://github.com/yoheirosen/vg . Contact: benedict@soe.ucsc.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881972 TI - Abundance estimation and differential testing on strain level in metagenomics data. AB - Motivation: Current metagenomics approaches allow analyzing the composition of microbial communities at high resolution. Important changes to the composition are known to even occur on strain level and to go hand in hand with changes in disease or ecological state. However, specific challenges arise for strain level analysis due to highly similar genome sequences present. Only a limited number of tools approach taxa abundance estimation beyond species level and there is a strong need for dedicated tools for strain resolution and differential abundance testing. Methods: We present DiTASiC ( fferential axa bundance including milarity orrection) as a novel approach for quantification and differential assessment of individual taxa in metagenomics samples. We introduce a generalized linear model for the resolution of shared read counts which cause a significant bias on strain level. Further, we capture abundance estimation uncertainties, which play a crucial role in differential abundance analysis. A novel statistical framework is built, which integrates the abundance variance and infers abundance distributions for differential testing sensitive to strain level. Results: As a result, we obtain highly accurate abundance estimates down to sub-strain level and enable fine-grained resolution of strain clusters. We demonstrate the relevance of read ambiguity resolution and integration of abundance uncertainties for differential analysis. Accurate detections of even small changes are achieved and false positives are significantly reduced. Superior performance is shown on latest benchmark sets of various complexities and in comparison to existing methods. Availability and Implementation: DiTASiC code is freely available from https://rki_bioinformatics.gitlab.io/ditasic . Contact: renardB@rki.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881973 TI - BIOSSES: a semantic sentence similarity estimation system for the biomedical domain. AB - Motivation: The amount of information available in textual format is rapidly increasing in the biomedical domain. Therefore, natural language processing (NLP) applications are becoming increasingly important to facilitate the retrieval and analysis of these data. Computing the semantic similarity between sentences is an important component in many NLP tasks including text retrieval and summarization. A number of approaches have been proposed for semantic sentence similarity estimation for generic English. However, our experiments showed that such approaches do not effectively cover biomedical knowledge and produce poor results for biomedical text. Methods: We propose several approaches for sentence-level semantic similarity computation in the biomedical domain, including string similarity measures and measures based on the distributed vector representations of sentences learned in an unsupervised manner from a large biomedical corpus. In addition, ontology-based approaches are presented that utilize general and domain specific ontologies. Finally, a supervised regression based model is developed that effectively combines the different similarity computation metrics. A benchmark data set consisting of 100 sentence pairs from the biomedical literature is manually annotated by five human experts and used for evaluating the proposed methods. Results: The experiments showed that the supervised semantic sentence similarity computation approach obtained the best performance (0.836 correlation with gold standard human annotations) and improved over the state-of-the-art domain-independent systems up to 42.6% in terms of the Pearson correlation metric. Availability and implementation: A web-based system for biomedical semantic sentence similarity computation, the source code, and the annotated benchmark data set are available at: http://tabilab.cmpe.boun.edu.tr/BIOSSES/ . Contact: gizemsogancioglu@gmail.com or arzucan.ozgur@boun.edu.tr. PMID- 28881974 TI - Large-scale structure prediction by improved contact predictions and model quality assessment. AB - Motivation: Accurate contact predictions can be used for predicting the structure of proteins. Until recently these methods were limited to very big protein families, decreasing their utility. However, recent progress by combining direct coupling analysis with machine learning methods has made it possible to predict accurate contact maps for smaller families. To what extent these predictions can be used to produce accurate models of the families is not known. Results: We present the PconsFold2 pipeline that uses contact predictions from PconsC3, the CONFOLD folding algorithm and model quality estimations to predict the structure of a protein. We show that the model quality estimation significantly increases the number of models that reliably can be identified. Finally, we apply PconsFold2 to 6379 Pfam families of unknown structure and find that PconsFold2 can, with an estimated 90% specificity, predict the structure of up to 558 Pfam families of unknown structure. Out of these, 415 have not been reported before. Availability and Implementation: Datasets as well as models of all the 558 Pfam families are available at http://c3.pcons.net/ . All programs used here are freely available. Contact: arne@bioinfo.se. PMID- 28881975 TI - Molecular signatures that can be transferred across different omics platforms. AB - Motivation: Molecular signatures for treatment recommendations are well researched. Still it is challenging to apply them to data generated by different protocols or technical platforms. Results: We analyzed paired data for the same tumors (Burkitt lymphoma, diffuse large B-cell lymphoma) and features that had been generated by different experimental protocols and analytical platforms including the nanoString nCounter and Affymetrix Gene Chip transcriptomics as well as the SWATH and SRM proteomics platforms. A statistical model that assumes independent sample and feature effects accounted for 69-94% of technical variability. We analyzed how variability is propagated through linear signatures possibly affecting predictions and treatment recommendations. Linear signatures with feature weights adding to zero were substantially more robust than unbalanced signatures. They yielded consistent predictions across data from different platforms, both for transcriptomics and proteomics data. Similarly stable were their predictions across data from fresh frozen and matching formalin fixed paraffin-embedded human tumor tissue. Availability and Implementation: The R-package 'zeroSum' can be downloaded at https://github.com/rehbergT/zeroSum . Complete data and R codes necessary to reproduce all our results can be received from the authors upon request. Contact: rainer.spang@ur.de. PMID- 28881976 TI - Increasing the power of meta-analysis of genome-wide association studies to detect heterogeneous effects. AB - Motivation : Meta-analysis is essential to combine the results of genome-wide association studies (GWASs). Recent large-scale meta-analyses have combined studies of different ethnicities, environments and even studies of different related phenotypes. These differences between studies can manifest as effect size heterogeneity. We previously developed a modified random effects model (RE2) that can achieve higher power to detect heterogeneous effects than the commonly used fixed effects model (FE). However, RE2 cannot perform meta-analysis of correlated statistics, which are found in recent research designs, and the identified variants often overlap with those found by FE. Results : Here, we propose RE2C, which increases the power of RE2 in two ways. First, we generalized the likelihood model to account for correlations of statistics to achieve optimal power, using an optimization technique based on spectral decomposition for efficient parameter estimation. Second, we designed a novel statistic to focus on the heterogeneous effects that FE cannot detect, thereby, increasing the power to identify new associations. We developed an efficient and accurate p -value approximation procedure using analytical decomposition of the statistic. In simulations, RE2C achieved a dramatic increase in power compared with the decoupling approach (71% vs. 21%) when the statistics were correlated. Even when the statistics are uncorrelated, RE2C achieves a modest increase in power. Applications to real genetic data supported the utility of RE2C. RE2C is highly efficient and can meta-analyze one hundred GWASs in one day. Availability and implementation: The software is freely available at http://software.buhmhan.com/RE2C . Contact: buhm.han@amc.seoul.kr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881977 TI - Denoising genome-wide histone ChIP-seq with convolutional neural networks. AB - Motivation: Chromatin immune-precipitation sequencing (ChIP-seq) experiments are commonly used to obtain genome-wide profiles of histone modifications associated with different types of functional genomic elements. However, the quality of histone ChIP-seq data is affected by many experimental parameters such as the amount of input DNA, antibody specificity, ChIP enrichment and sequencing depth. Making accurate inferences from chromatin profiling experiments that involve diverse experimental parameters is challenging. Results: We introduce a convolutional denoising algorithm, Coda, that uses convolutional neural networks to learn a mapping from suboptimal to high-quality histone ChIP-seq data. This overcomes various sources of noise and variability, substantially enhancing and recovering signal when applied to low-quality chromatin profiling datasets across individuals, cell types and species. Our method has the potential to improve data quality at reduced costs. More broadly, this approach-using a high-dimensional discriminative model to encode a generative noise process-is generally applicable to other biological domains where it is easy to generate noisy data but difficult to analytically characterize the noise or underlying data distribution. Availability and implementation: https://github.com/kundajelab/coda . Contact: akundaje@stanford.edu. PMID- 28881978 TI - Incorporating interaction networks into the determination of functionally related hit genes in genomic experiments with Markov random fields. AB - Motivation: Incorporating gene interaction data into the identification of 'hit' genes in genomic experiments is a well-established approach leveraging the 'guilt by association' assumption to obtain a network based hit list of functionally related genes. We aim to develop a method to allow for multivariate gene scores and multiple hit labels in order to extend the analysis of genomic screening data within such an approach. Results: We propose a Markov random field-based method to achieve our aim and show that the particular advantages of our method compared with those currently used lead to new insights in previously analysed data as well as for our own motivating data. Our method additionally achieves the best performance in an independent simulation experiment. The real data applications we consider comprise of a survival analysis and differential expression experiment and a cell-based RNA interference functional screen. Availability and implementation: We provide all of the data and code related to the results in the paper. Contact: sean.j.robinson@utu.fi or laurent.guyon@cea.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881979 TI - Identification of associations between genotypes and longitudinal phenotypes via temporally-constrained group sparse canonical correlation analysis. AB - Motivation: Neuroimaging genetics identifies the relationships between genetic variants (i.e., the single nucleotide polymorphisms) and brain imaging data to reveal the associations from genotypes to phenotypes. So far, most existing machine-learning approaches are widely used to detect the effective associations between genetic variants and brain imaging data at one time-point. However, those associations are based on static phenotypes and ignore the temporal dynamics of the phenotypical changes. The phenotypes across multiple time-points may exhibit temporal patterns that can be used to facilitate the understanding of the degenerative process. In this article, we propose a novel temporally constrained group sparse canonical correlation analysis (TGSCCA) framework to identify genetic associations with longitudinal phenotypic markers. Results: The proposed TGSCCA method is able to capture the temporal changes in brain from longitudinal phenotypes by incorporating the fused penalty, which requires that the differences between two consecutive canonical weight vectors from adjacent time points should be small. A new efficient optimization algorithm is designed to solve the objective function. Furthermore, we demonstrate the effectiveness of our algorithm on both synthetic and real data (i.e., the Alzheimer's Disease Neuroimaging Initiative cohort, including progressive mild cognitive impairment, stable MCI and Normal Control participants). In comparison with conventional SCCA, our proposed method can achieve strong associations and discover phenotypic biomarkers across multiple time-points to guide disease-progressive interpretation. Availability and implementation: The Matlab code is available at https://sourceforge.net/projects/ibrain-cn/files/ . Contact: dqzhang@nuaa.edu.cn or shenli@iu.edu. PMID- 28881980 TI - Alignment of dynamic networks. AB - Motivation: Network alignment (NA) aims to find a node mapping that conserves similar regions between compared networks. NA is applicable to many fields, including computational biology, where NA can guide the transfer of biological knowledge from well- to poorly-studied species across aligned network regions. Existing NA methods can only align static networks. However, most complex real world systems evolve over time and should thus be modeled as dynamic networks. We hypothesize that aligning dynamic network representations of evolving systems will produce superior alignments compared to aligning the systems' static network representations, as is currently done. Results: For this purpose, we introduce the first ever dynamic NA method, DynaMAGNA ++. This proof-of-concept dynamic NA method is an extension of a state-of-the-art static NA method, MAGNA++. Even though both MAGNA++ and DynaMAGNA++ optimize edge as well as node conservation across the aligned networks, MAGNA++ conserves static edges and similarity between static node neighborhoods, while DynaMAGNA++ conserves dynamic edges (events) and similarity between evolving node neighborhoods. For this purpose, we introduce the first ever measure of dynamic edge conservation and rely on our recent measure of dynamic node conservation. Importantly, the two dynamic conservation measures can be optimized with any state-of-the-art NA method and not just MAGNA++. We confirm our hypothesis that dynamic NA is superior to static NA, on synthetic and real-world networks, in computational biology and social domains. DynaMAGNA++ is parallelized and has a user-friendly graphical interface. Availability and implementation: http://nd.edu/~cone/DynaMAGNA++/ . Contact: tmilenko@nd.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881981 TI - TITER: predicting translation initiation sites by deep learning. AB - Motivation: Translation initiation is a key step in the regulation of gene expression. In addition to the annotated translation initiation sites (TISs), the translation process may also start at multiple alternative TISs (including both AUG and non-AUG codons), which makes it challenging to predict TISs and study the underlying regulatory mechanisms. Meanwhile, the advent of several high throughput sequencing techniques for profiling initiating ribosomes at single nucleotide resolution, e.g. GTI-seq and QTI-seq, provides abundant data for systematically studying the general principles of translation initiation and the development of computational method for TIS identification. Methods: We have developed a deep learning-based framework, named TITER, for accurately predicting TISs on a genome-wide scale based on QTI-seq data. TITER extracts the sequence features of translation initiation from the surrounding sequence contexts of TISs using a hybrid neural network and further integrates the prior preference of TIS codon composition into a unified prediction framework. Results: Extensive tests demonstrated that TITER can greatly outperform the state-of-the-art prediction methods in identifying TISs. In addition, TITER was able to identify important sequence signatures for individual types of TIS codons, including a Kozak sequence-like motif for AUG start codon. Furthermore, the TITER prediction score can be related to the strength of translation initiation in various biological scenarios, including the repressive effect of the upstream open reading frames on gene expression and the mutational effects influencing translation initiation efficiency. Availability and Implementation: TITER is available as an open-source software and can be downloaded from https://github.com/zhangsaithu/titer . Contact: lzhang20@mail.tsinghua.edu.cn or zengjy321@tsinghua.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881982 TI - Association testing of bisulfite-sequencing methylation data via a Laplace approximation. AB - Motivation: Epigenome-wide association studies can provide novel insights into the regulation of genes involved in traits and diseases. The rapid emergence of bisulfite-sequencing technologies enables performing such genome-wide studies at the resolution of single nucleotides. However, analysis of data produced by bisulfite-sequencing poses statistical challenges owing to low and uneven sequencing depth, as well as the presence of confounding factors. The recently introduced Mixed model Association for Count data via data AUgmentation (MACAU) can address these challenges via a generalized linear mixed model when confounding can be encoded via a single variance component. However, MACAU cannot be used in the presence of multiple variance components. Additionally, MACAU uses a computationally expensive Markov Chain Monte Carlo (MCMC) procedure, which cannot directly approximate the model likelihood. Results: We present a new method, Mixed model Association via a Laplace ApproXimation (MALAX), that is more computationally efficient than MACAU and allows to model multiple variance components. MALAX uses a Laplace approximation rather than MCMC based approximations, which enables to directly approximate the model likelihood. Through an extensive analysis of simulated and real data, we demonstrate that MALAX successfully addresses statistical challenges introduced by bisulfite sequencing while controlling for complex sources of confounding, and can be over 50% faster than the state of the art. Availability and Implementation: The full source code of MALAX is available at https://github.com/omerwe/MALAX . Contact: omerw@cs.technion.ac.il or ehalperin@cs.ucla.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881983 TI - A scalable moment-closure approximation for large-scale biochemical reaction networks. AB - Motivation: Stochastic molecular processes are a leading cause of cell-to-cell variability. Their dynamics are often described by continuous-time discrete-state Markov chains and simulated using stochastic simulation algorithms. As these stochastic simulations are computationally demanding, ordinary differential equation models for the dynamics of the statistical moments have been developed. The number of state variables of these approximating models, however, grows at least quadratically with the number of biochemical species. This limits their application to small- and medium-sized processes. Results: In this article, we present a scalable moment-closure approximation (sMA) for the simulation of statistical moments of large-scale stochastic processes. The sMA exploits the structure of the biochemical reaction network to reduce the covariance matrix. We prove that sMA yields approximating models whose number of state variables depends predominantly on local properties, i.e. the average node degree of the reaction network, instead of the overall network size. The resulting complexity reduction is assessed by studying a range of medium- and large-scale biochemical reaction networks. To evaluate the approximation accuracy and the improvement in computational efficiency, we study models for JAK2/STAT5 signalling and NF kappa B signalling. Our method is applicable to generic biochemical reaction networks and we provide an implementation, including an SBML interface, which renders the sMA easily accessible. Availability and implementation: The sMA is implemented in the open-source MATLAB toolbox CERENA and is available from https://github.com/CERENADevelopers/CERENA . Contact: jan.hasenauer@helmholtz muenchen.de or atefeh.kazeroonian@tum.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881984 TI - Estimation of time-varying growth, uptake and excretion rates from dynamic metabolomics data. AB - Motivation: Technological advances in metabolomics have made it possible to monitor the concentration of extracellular metabolites over time. From these data, it is possible to compute the rates of uptake and excretion of the metabolites by a growing cell population, providing precious information on the functioning of intracellular metabolism. The computation of the rate of these exchange reactions, however, is difficult to achieve in practice for a number of reasons, notably noisy measurements, correlations between the concentration profiles of the different extracellular metabolites, and discontinuties in the profiles due to sudden changes in metabolic regime. Results: We present a method for precisely estimating time-varying uptake and excretion rates from time-series measurements of extracellular metabolite concentrations, specifically addressing all of the above issues. The estimation problem is formulated in a regularized Bayesian framework and solved by a combination of extended Kalman filtering and smoothing. The method is shown to improve upon methods based on spline smoothing of the data. Moreover, when applied to two actual datasets, the method recovers known features of overflow metabolism in Escherichia coli and Lactococcus lactis , and provides evidence for acetate uptake by L. lactis after glucose exhaustion. The results raise interesting perspectives for further work on rate estimation from measurements of intracellular metabolites. Availability and implementation: The Matlab code for the estimation method is available for download at https://team.inria.fr/ibis/rate-estimation-software/ , together with the datasets. Contact: eugenio.cinquemani@inria.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881985 TI - popFBA: tackling intratumour heterogeneity with Flux Balance Analysis. AB - Motivation: Intratumour heterogeneity poses many challenges to the treatment of cancer. Unfortunately, the transcriptional and metabolic information retrieved by currently available computational and experimental techniques portrays the average behaviour of intermixed and heterogeneous cell subpopulations within a given tumour. Emerging single-cell genomic analyses are nonetheless unable to characterize the interactions among cancer subpopulations. In this study, we propose popFBA , an extension to classic Flux Balance Analysis, to explore how metabolic heterogeneity and cooperation phenomena affect the overall growth of cancer cell populations. Results: We show how clones of a metabolic network of human central carbon metabolism, sharing the same stoichiometry and capacity constraints, may follow several different metabolic paths and cooperate to maximize the growth of the total population. We also introduce a method to explore the space of possible interactions, given some constraints on plasma supply of nutrients. We illustrate how alternative nutrients in plasma supply and/or a dishomogeneous distribution of oxygen provision may affect the landscape of heterogeneous phenotypes. We finally provide a technique to identify the most proliferative cells within the heterogeneous population. Availability and implementation: the popFBA MATLAB function and the SBML model are available at https://github.com/BIMIB-DISCo/popFBA . Contact: chiara.damiani@unimib.it. PMID- 28881987 TI - Efficient simulation of intrinsic, extrinsic and external noise in biochemical systems. AB - Motivation: Biological cells operate in a noisy regime influenced by intrinsic, extrinsic and external noise, which leads to large differences of individual cell states. Stochastic effects must be taken into account to characterize biochemical kinetics accurately. Since the exact solution of the chemical master equation, which governs the underlying stochastic process, cannot be derived for most biochemical systems, approximate methods are used to obtain a solution. Results: In this study, a method to efficiently simulate the various sources of noise simultaneously is proposed and benchmarked on several examples. The method relies on the combination of the sigma point approach to describe extrinsic and external variability and the tau -leaping algorithm to account for the stochasticity due to probabilistic reactions. The comparison of our method to extensive Monte Carlo calculations demonstrates an immense computational advantage while losing an acceptable amount of accuracy. Additionally, the application to parameter optimization problems in stochastic biochemical reaction networks is shown, which is rarely applied due to its huge computational burden. To give further insight, a MATLAB script is provided including the proposed method applied to a simple toy example of gene expression. Availability and implementation: MATLAB code is available at Bioinformatics online. Contact: flassig@mpi-magdeburg.mpg.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881986 TI - Predicting multicellular function through multi-layer tissue networks. AB - Motivation: Understanding functions of proteins in specific human tissues is essential for insights into disease diagnostics and therapeutics, yet prediction of tissue-specific cellular function remains a critical challenge for biomedicine. Results: Here, we present OhmNet , a hierarchy-aware unsupervised node feature learning approach for multi-layer networks. We build a multi-layer network, where each layer represents molecular interactions in a different human tissue. OhmNet then automatically learns a mapping of proteins, represented as nodes, to a neural embedding-based low-dimensional space of features. OhmNet encourages sharing of similar features among proteins with similar network neighborhoods and among proteins activated in similar tissues. The algorithm generalizes prior work, which generally ignores relationships between tissues, by modeling tissue organization with a rich multiscale tissue hierarchy. We use OhmNet to study multicellular function in a multi-layer protein interaction network of 107 human tissues. In 48 tissues with known tissue-specific cellular functions, OhmNet provides more accurate predictions of cellular function than alternative approaches, and also generates more accurate hypotheses about tissue specific protein actions. We show that taking into account the tissue hierarchy leads to improved predictive power. Remarkably, we also demonstrate that it is possible to leverage the tissue hierarchy in order to effectively transfer cellular functions to a functionally uncharacterized tissue. Overall, OhmNet moves from flat networks to multiscale models able to predict a range of phenotypes spanning cellular subsystems. Availability and implementation: Source code and datasets are available at http://snap.stanford.edu/ohmnet . Contact: jure@cs.stanford.edu. PMID- 28881988 TI - Discovery and genotyping of novel sequence insertions in many sequenced individuals. AB - Motivation: Despite recent advances in algorithms design to characterize structural variation using high-throughput short read sequencing (HTS) data, characterization of novel sequence insertions longer than the average read length remains a challenging task. This is mainly due to both computational difficulties and the complexities imposed by genomic repeats in generating reliable assemblies to accurately detect both the sequence content and the exact location of such insertions. Additionally, de novo genome assembly algorithms typically require a very high depth of coverage, which may be a limiting factor for most genome studies. Therefore, characterization of novel sequence insertions is not a routine part of most sequencing projects. Result: Here, we present Pamir, a new algorithm to efficiently and accurately discover and genotype novel sequence insertions using either single or multiple genome sequencing datasets. Pamir is able to detect breakpoint locations of the insertions and calculate their zygosity (i.e. heterozygous versus homozygous) by analyzing multiple sequence signatures, matching one-end-anchored sequences to small-scale de novo assemblies of unmapped reads, and conducting strand-aware local assembly. We test the efficacy of Pamir on both simulated and real data, and demonstrate its potential use in accurate and routine identification of novel sequence insertions in genome projects. Availability and implementation: Pamir is available at https://github.com/vpc-ccg/pamir . Contact: fhach@{sfu.ca, prostatecentre.com } or calkan@cs.bilkent.edu.tr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881989 TI - Direct AUC optimization of regulatory motifs. AB - Motivation: The discovery of transcription factor binding site (TFBS) motifs is essential for untangling the complex mechanism of genetic variation under different developmental and environmental conditions. Among the huge amount of computational approaches for de novo identification of TFBS motifs, discriminative motif learning (DML) methods have been proven to be promising for harnessing the discovery power of accumulated huge amount of high-throughput binding data. However, they have to sacrifice accuracy for speed and could fail to fully utilize the information of the input sequences. Results: We propose a novel algorithm called CDAUC for optimizing DML-learned motifs based on the area under the receiver-operating characteristic curve (AUC) criterion, which has been widely used in the literature to evaluate the significance of extracted motifs. We show that when the considered AUC loss function is optimized in a coordinate wise manner, the cost function of each resultant sub-problem is a piece-wise constant function, whose optimal value can be found exactly and efficiently. Further, a key step of each iteration of CDAUC can be efficiently solved as a computational geometry problem. Experimental results on real world high throughput datasets illustrate that CDAUC outperforms competing methods for refining DML motifs, while being one order of magnitude faster. Meanwhile, preliminary results also show that CDAUC may also be useful for improving the interpretability of convolutional kernels generated by the emerging deep learning approaches for predicting TF sequences specificities. Availability and Implementation: CDAUC is available at: https://drive.google.com/drive/folders/0BxOW5MtIZbJjNFpCeHlBVWJHeW8 . Contact: dshuang@tongji.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881991 TI - Exploiting sequence-based features for predicting enhancer-promoter interactions. AB - Motivation: A large number of distal enhancers and proximal promoters form enhancer-promoter interactions to regulate target genes in the human genome. Although recent high-throughput genome-wide mapping approaches have allowed us to more comprehensively recognize potential enhancer-promoter interactions, it is still largely unknown whether sequence-based features alone are sufficient to predict such interactions. Results: Here, we develop a new computational method (named PEP) to predict enhancer-promoter interactions based on sequence-based features only, when the locations of putative enhancers and promoters in a particular cell type are given. The two modules in PEP (PEP-Motif and PEP-Word) use different but complementary feature extraction strategies to exploit sequence based information. The results across six different cell types demonstrate that our method is effective in predicting enhancer-promoter interactions as compared to the state-of-the-art methods that use functional genomic signals. Our work demonstrates that sequence-based features alone can reliably predict enhancer promoter interactions genome-wide, which could potentially facilitate the discovery of important sequence determinants for long-range gene regulation. Availability and Implementation: The source code of PEP is available at: https://github.com/ma-compbio/PEP . Contact: jianma@cs.cmu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881990 TI - A new method to study the change of miRNA-mRNA interactions due to environmental exposures. AB - Motivation: Integrative approaches characterizing the interactions among different types of biological molecules have been demonstrated to be useful for revealing informative biological mechanisms. One such example is the interaction between microRNA (miRNA) and messenger RNA (mRNA), whose deregulation may be sensitive to environmental insult leading to altered phenotypes. The goal of this work is to develop an effective data integration method to characterize deregulation between miRNA and mRNA due to environmental toxicant exposures. We will use data from an animal experiment designed to investigate the effect of low dose environmental chemical exposure on normal mammary gland development in rats to motivate and evaluate the proposed method. Results: We propose a new network approach-integrative Joint Random Forest (iJRF), which characterizes the regulatory system between miRNAs and mRNAs using a network model. iJRF is designed to work under the high-dimension low-sample-size regime, and can borrow information across different treatment conditions to achieve more accurate network inference. It also effectively takes into account prior information of miRNA-mRNA regulatory relationships from existing databases. When iJRF is applied to the data from the environmental chemical exposure study, we detected a few important miRNAs that regulated a large number of mRNAs in the control group but not in the exposed groups, suggesting the disruption of miRNA activity due to chemical exposure. Effects of chemical exposure on two affected miRNAs were further validated using breast cancer human cell lines. Availability and implementation: R package iJRF is available at CRAN. Contacts: pei.wang@mssm.edu or susan.teitelbaum@mssm.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881992 TI - Image-based spatiotemporal causality inference for protein signaling networks. AB - Motivation: Efforts to model how signaling and regulatory networks work in cells have largely either not considered spatial organization or have used compartmental models with minimal spatial resolution. Fluorescence microscopy provides the ability to monitor the spatiotemporal distribution of many molecules during signaling events, but as of yet no methods have been described for large scale image analysis to learn a complex protein regulatory network. Here we present and evaluate methods for identifying how changes in concentration in one cell region influence concentration of other proteins in other regions. Results: Using 3D confocal microscope movies of GFP-tagged T cells undergoing costimulation, we learned models containing putative causal relationships among 12 proteins involved in T cell signaling. The models included both relationships consistent with current knowledge and novel predictions deserving further exploration. Further, when these models were applied to the initial frames of movies of T cells that had been only partially stimulated, they predicted the localization of proteins at later times with statistically significant accuracy. The methods, consisting of spatiotemporal alignment, automated region identification, and causal inference, are anticipated to be applicable to a number of biological systems. Availability and implementation: The source code and data are available as a Reproducible Research Archive at http://murphylab.cbd.cmu.edu/software/2017_TcellCausalModels/. Contact: murphy@cmu.edu. PMID- 28881993 TI - Genomes as documents of evolutionary history: a probabilistic macrosynteny model for the reconstruction of ancestral genomes. AB - Motivation: It has been argued that whole-genome duplication (WGD) exerted a profound influence on the course of evolution. For the purpose of fully understanding the impact of WGD, several formal algorithms have been developed for reconstructing pre-WGD gene order in yeast and plant. However, to the best of our knowledge, those algorithms have never been successfully applied to WGD events in teleost and vertebrate, impeded by extensive gene shuffling and gene losses. Results: Here, we present a probabilistic model of macrosynteny (i.e. conserved linkage or chromosome-scale distribution of orthologs), develop a variational Bayes algorithm for inferring the structure of pre-WGD genomes, and study estimation accuracy by simulation. Then, by applying the method to the teleost WGD, we demonstrate effectiveness of the algorithm in a situation where gene-order reconstruction algorithms perform relatively poorly due to a high rate of rearrangement and extensive gene losses. Our high-resolution reconstruction reveals previously overlooked small-scale rearrangements, necessitating a revision to previous views on genome structure evolution in teleost and vertebrate. Conclusions: We have reconstructed the structure of a pre-WGD genome by employing a variational Bayes approach that was originally developed for inferring topics from millions of text documents. Interestingly, comparison of the macrosynteny and topic model algorithms suggests that macrosynteny can be regarded as documents on ancestral genome structure. From this perspective, the present study would seem to provide a textbook example of the prevalent metaphor that genomes are documents of evolutionary history. Availability and implementation: The analysis data are available for download at http://www.gen.tcd.ie/molevol/supp_data/MacrosyntenyTGD.zip , and the software written in Java is available upon request. Contact: yoichiro.nakatani@tcd.ie or aoife.mclysaght@tcd.ie. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881995 TI - deBGR: an efficient and near-exact representation of the weighted de Bruijn graph. AB - Motivation: Almost all de novo short-read genome and transcriptome assemblers start by building a representation of the de Bruijn Graph of the reads they are given as input. Even when other approaches are used for subsequent assembly (e.g. when one is using 'long read' technologies like those offered by PacBio or Oxford Nanopore), efficient k -mer processing is still crucial for accurate assembly, and state-of-the-art long-read error-correction methods use de Bruijn Graphs. Because of the centrality of de Bruijn Graphs, researchers have proposed numerous methods for representing de Bruijn Graphs compactly. Some of these proposals sacrifice accuracy to save space. Further, none of these methods store abundance information, i.e. the number of times that each k -mer occurs, which is key in transcriptome assemblers. Results: We present a method for compactly representing the weighted de Bruijn Graph (i.e. with abundance information) with essentially no errors. Our representation yields zero errors while increasing the space requirements by less than 18-28% compared to the approximate de Bruijn graph representation in Squeakr. Our technique is based on a simple invariant that all weighted de Bruijn Graphs must satisfy, and hence is likely to be of general interest and applicable in most weighted de Bruijn Graph-based systems. Availability and implementation: https://github.com/splatlab/debgr . Contact: rob.patro@cs.stonybrook.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881994 TI - Multiple network-constrained regressions expand insights into influenza vaccination responses. AB - Motivation: Systems immunology leverages recent technological advancements that enable broad profiling of the immune system to better understand the response to infection and vaccination, as well as the dysregulation that occurs in disease. An increasingly common approach to gain insights from these large-scale profiling experiments involves the application of statistical learning methods to predict disease states or the immune response to perturbations. However, the goal of many systems studies is not to maximize accuracy, but rather to gain biological insights. The predictors identified using current approaches can be biologically uninterpretable or present only one of many equally predictive models, leading to a narrow understanding of the underlying biology. Results: Here we show that incorporating prior biological knowledge within a logistic modeling framework by using network-level constraints on transcriptional profiling data significantly improves interpretability. Moreover, incorporating different types of biological knowledge produces models that highlight distinct aspects of the underlying biology, while maintaining predictive accuracy. We propose a new framework, Logistic Multiple Network-constrained Regression (LogMiNeR), and apply it to understand the mechanisms underlying differential responses to influenza vaccination. Although standard logistic regression approaches were predictive, they were minimally interpretable. Incorporating prior knowledge using LogMiNeR led to models that were equally predictive yet highly interpretable. In this context, B cell-specific genes and mTOR signaling were associated with an effective vaccination response in young adults. Overall, our results demonstrate a new paradigm for analyzing high-dimensional immune profiling data in which multiple networks encoding prior knowledge are incorporated to improve model interpretability. Availability and implementation: The R source code described in this article is publicly available at https://bitbucket.org/kleinstein/logminer . Contact: steven.kleinstein@yale.edu or stefan.avey@yale.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881996 TI - Improved data-driven likelihood factorizations for transcript abundance estimation. AB - Motivation: Many methods for transcript-level abundance estimation reduce the computational burden associated with the iterative algorithms they use by adopting an approximate factorization of the likelihood function they optimize. This leads to considerably faster convergence of the optimization procedure, since each round of e.g. the EM algorithm, can execute much more quickly. However, these approximate factorizations of the likelihood function simplify calculations at the expense of discarding certain information that can be useful for accurate transcript abundance estimation. Results: We demonstrate that model simplifications (i.e. factorizations of the likelihood function) adopted by certain abundance estimation methods can lead to a diminished ability to accurately estimate the abundances of highly related transcripts. In particular, considering factorizations based on transcript-fragment compatibility alone can result in a loss of accuracy compared to the per-fragment, unsimplified model. However, we show that such shortcomings are not an inherent limitation of approximately factorizing the underlying likelihood function. By considering the appropriate conditional fragment probabilities, and adopting improved, data driven factorizations of this likelihood, we demonstrate that such approaches can achieve accuracy nearly indistinguishable from methods that consider the complete (i.e. per-fragment) likelihood, while retaining the computational efficiently of the compatibility-based factorizations. Availability and implementation: Our data driven factorizations are incorporated into a branch of the Salmon transcript quantification tool: https://github.com/COMBINE-lab/salmon/tree/factorizations . Contact: rob.patro@cs.stonybrook.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881997 TI - Predicting phenotypes from microarrays using amplified, initially marginal, eigenvector regression. AB - Motivation: The discovery of relationships between gene expression measurements and phenotypic responses is hampered by both computational and statistical impediments. Conventional statistical methods are less than ideal because they either fail to select relevant genes, predict poorly, ignore the unknown interaction structure between genes, or are computationally intractable. Thus, the creation of new methods which can handle many expression measurements on relatively small numbers of patients while also uncovering gene-gene relationships and predicting well is desirable. Results: We develop a new technique for using the marginal relationship between gene expression measurements and patient survival outcomes to identify a small subset of genes which appear highly relevant for predicting survival, produce a low-dimensional embedding based on this small subset, and amplify this embedding with information from the remaining genes. We motivate our methodology by using gene expression measurements to predict survival time for patients with diffuse large B-cell lymphoma, illustrate the behavior of our methodology on carefully constructed synthetic examples, and test it on a number of other gene expression datasets. Our technique is computationally tractable, generally outperforms other methods, is extensible to other phenotypes, and also identifies different genes (relative to existing methods) for possible future study. Availability and Implementation: All of the code and data are available at http://mypage.iu.edu/~dajmcdon/research/ . Contact: dajmcdon@indiana.edu. Supplementary information: Supplementary material is available at Bioinformatics online. PMID- 28881998 TI - Systematic identification of feature combinations for predicting drug response with Bayesian multi-view multi-task linear regression. AB - Motivation: A prime challenge in precision cancer medicine is to identify genomic and molecular features that are predictive of drug treatment responses in cancer cells. Although there are several computational models for accurate drug response prediction, these often lack the ability to infer which feature combinations are the most predictive, particularly for high-dimensional molecular datasets. As increasing amounts of diverse genome-wide data sources are becoming available, there is a need to build new computational models that can effectively combine these data sources and identify maximally predictive feature combinations. Results: We present a novel approach that leverages on systematic integration of data sources to identify response predictive features of multiple drugs. To solve the modeling task we implement a Bayesian linear regression method. To further improve the usefulness of the proposed model, we exploit the known human cancer kinome for identifying biologically relevant feature combinations. In case studies with a synthetic dataset and two publicly available cancer cell line datasets, we demonstrate the improved accuracy of our method compared to the widely used approaches in drug response analysis. As key examples, our model identifies meaningful combinations of features for the well known EGFR, ALK, PLK and PDGFR inhibitors. Availability and Implementation: The source code of the method is available at https://github.com/suleimank/mvlr . Contact: muhammad.ammad-ud-din@helsinki.fi or suleiman.khan@helsinki.fi. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28882000 TI - Integrative deep models for alternative splicing. AB - Motivation: Advancements in sequencing technologies have highlighted the role of alternative splicing (AS) in increasing transcriptome complexity. This role of AS, combined with the relation of aberrant splicing to malignant states, motivated two streams of research, experimental and computational. The first involves a myriad of techniques such as RNA-Seq and CLIP-Seq to identify splicing regulators and their putative targets. The second involves probabilistic models, also known as splicing codes, which infer regulatory mechanisms and predict splicing outcome directly from genomic sequence. To date, these models have utilized only expression data. In this work, we address two related challenges: Can we improve on previous models for AS outcome prediction and can we integrate additional sources of data to improve predictions for AS regulatory factors. Results: We perform a detailed comparison of two previous modeling approaches, Bayesian and Deep Neural networks, dissecting the confounding effects of datasets and target functions. We then develop a new target function for AS prediction in exon skipping events and show it significantly improves model accuracy. Next, we develop a modeling framework that leverages transfer learning to incorporate CLIP Seq, knockdown and over expression experiments, which are inherently noisy and suffer from missing values. Using several datasets involving key splice factors in mouse brain, muscle and heart we demonstrate both the prediction improvements and biological insights offered by our new models. Overall, the framework we propose offers a scalable integrative solution to improve splicing code modeling as vast amounts of relevant genomic data become available. Availability and implementation: Code and data available at: majiq.biociphers.org/jha_et_al_2017/. Contact: yosephb@upenn.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28881999 TI - DeepBound: accurate identification of transcript boundaries via deep convolutional neural fields. AB - Motivation: Reconstructing the full-length expressed transcripts ( a.k.a. the transcript assembly problem) from the short sequencing reads produced by RNA-seq protocol plays a central role in identifying novel genes and transcripts as well as in studying gene expressions and gene functions. A crucial step in transcript assembly is to accurately determine the splicing junctions and boundaries of the expressed transcripts from the reads alignment. In contrast to the splicing junctions that can be efficiently detected from spliced reads, the problem of identifying boundaries remains open and challenging, due to the fact that the signal related to boundaries is noisy and weak. Results: We present DeepBound, an effective approach to identify boundaries of expressed transcripts from RNA-seq reads alignment. In its core DeepBound employs deep convolutional neural fields to learn the hidden distributions and patterns of boundaries. To accurately model the transition probabilities and to solve the label-imbalance problem, we novelly incorporate the AUC (area under the curve) score into the optimizing objective function. To address the issue that deep probabilistic graphical models requires large number of labeled training samples, we propose to use simulated RNA-seq datasets to train our model. Through extensive experimental studies on both simulation datasets of two species and biological datasets, we show that DeepBound consistently and significantly outperforms the two existing methods. Availability and implementation: DeepBound is freely available at https://github.com/realbigws/DeepBound . Contact: mingfu.shao@cs.cmu.edu or realbigws@gmail.com. PMID- 28882001 TI - Efficient approximations of RNA kinetics landscape using non-redundant sampling. AB - Motivation: Kinetics is key to understand many phenomena involving RNAs, such as co-transcriptional folding and riboswitches. Exact out-of-equilibrium studies induce extreme computational demands, leading state-of-the-art methods to rely on approximated kinetics landscapes, obtained using sampling strategies that strive to generate the key landmarks of the landscape topology. However, such methods are impeded by a large level of redundancy within sampled sets. Such a redundancy is uninformative, and obfuscates important intermediate states, leading to an incomplete vision of RNA dynamics. Results: We introduce RNANR, a new set of algorithms for the exploration of RNA kinetics landscapes at the secondary structure level. RNANR considers locally optimal structures, a reduced set of RNA conformations, in order to focus its sampling on basins in the kinetic landscape. Along with an exhaustive enumeration, RNANR implements a novel non-redundant stochastic sampling, and offers a rich array of structural parameters. Our tests on both real and random RNAs reveal that RNANR allows to generate more unique structures in a given time than its competitors, and allows a deeper exploration of kinetics landscapes. Availability and implementation: RNANR is freely available at https://project.inria.fr/rnalands/rnanr . Contact: yann.ponty@lix.polytechnique.fr. PMID- 28882002 TI - Tumor phylogeny inference using tree-constrained importance sampling. AB - Motivation: A tumor arises from an evolutionary process that can be modeled as a phylogenetic tree. However, reconstructing this tree is challenging as most cancer sequencing uses bulk tumor tissue containing heterogeneous mixtures of cells. Results: We introduce P robabilistic A lgorithm for S omatic Tr ee I nference (PASTRI), a new algorithm for bulk-tumor sequencing data that clusters somatic mutations into clones and infers a phylogenetic tree that describes the evolutionary history of the tumor. PASTRI uses an importance sampling algorithm that combines a probabilistic model of DNA sequencing data with a enumeration algorithm based on the combinatorial constraints defined by the underlying phylogenetic tree. As a result, tree inference is fast, accurate and robust to noise. We demonstrate on simulated data that PASTRI outperforms other cancer phylogeny algorithms in terms of runtime and accuracy. On real data from a chronic lymphocytic leukemia (CLL) patient, we show that a simple linear phylogeny better explains the data the complex branching phylogeny that was previously reported. PASTRI provides a robust approach for phylogenetic tree inference from mixed samples. Availability and Implementation: Software is available at compbio.cs.brown.edu/software. Contact: braphael@princeton.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28882003 TI - miniMDS: 3D structural inference from high-resolution Hi-C data. AB - Motivation: Recent experiments have provided Hi-C data at resolution as high as 1 kbp. However, 3D structural inference from high-resolution Hi-C datasets is often computationally unfeasible using existing methods. Results: We have developed miniMDS, an approximation of multidimensional scaling (MDS) that partitions a Hi C dataset, performs high-resolution MDS separately on each partition, and then reassembles the partitions using low-resolution MDS. miniMDS is faster, more accurate, and uses less memory than existing methods for inferring the human genome at high resolution (10 kbp). Availability and implementation: A Python implementation of miniMDS is available on GitHub: https://github.com/seqcode/miniMDS . Contact: mahony@psu.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28882006 TI - Update in Infectious Diseases 2017. AB - Antimicrobial resistance in complex models of continuous infection is a current issue. The update 2017 course addresses about microbiological, epidemiological and clinical aspects useful for a current approach to infectious disease. During the last year, nosocomial pneumonia approach guides, recommendations for management of yeast and filamentous fungal infections, review papers on the empirical approach to peritonitis and extensive guidelines on stewardship have been published. HIV infection is being treated before and more intensively. The implementation of molecular biology, spectrometry and inmunology to traditional techniques of staining and culture achieve a better and faster microbiological diagnosis. Finally, the infection is increasingly integrated, assessing non antibiotic aspects in the treatment. PMID- 28882004 TI - When loss-of-function is loss of function: assessing mutational signatures and impact of loss-of-function genetic variants. AB - Motivation: Loss-of-function genetic variants are frequently associated with severe clinical phenotypes, yet many are present in the genomes of healthy individuals. The available methods to assess the impact of these variants rely primarily upon evolutionary conservation with little to no consideration of the structural and functional implications for the protein. They further do not provide information to the user regarding specific molecular alterations potentially causative of disease. Results: To address this, we investigate protein features underlying loss-of-function genetic variation and develop a machine learning method, MutPred-LOF, for the discrimination of pathogenic and tolerated variants that can also generate hypotheses on specific molecular events disrupted by the variant. We investigate a large set of human variants derived from the Human Gene Mutation Database, ClinVar and the Exome Aggregation Consortium. Our prediction method shows an area under the Receiver Operating Characteristic curve of 0.85 for all loss-of-function variants and 0.75 for proteins in which both pathogenic and neutral variants have been observed. We applied MutPred-LOF to a set of 1142 de novo vari3ants from neurodevelopmental disorders and find enrichment of pathogenic variants in affected individuals. Overall, our results highlight the potential of computational tools to elucidate causal mechanisms underlying loss of protein function in loss-of-function variants. Availability and Implementation: http://mutpred.mutdb.org. Contact: predrag@indiana.edu. PMID- 28882005 TI - CATS (Coordinates of Atoms by Taylor Series): protein design with backbone flexibility in all locally feasible directions. AB - Motivation: When proteins mutate or bind to ligands, their backbones often move significantly, especially in loop regions. Computational protein design algorithms must model these motions in order to accurately optimize protein stability and binding affinity. However, methods for backbone conformational search in design have been much more limited than for sidechain conformational search. This is especially true for combinatorial protein design algorithms, which aim to search a large sequence space efficiently and thus cannot rely on temporal simulation of each candidate sequence. Results: We alleviate this difficulty with a new parameterization of backbone conformational space, which represents all degrees of freedom of a specified segment of protein chain that maintain valid bonding geometry (by maintaining the original bond lengths and angles and omega dihedrals). In order to search this space, we present an efficient algorithm, CATS, for computing atomic coordinates as a function of our new continuous backbone internal coordinates. CATS generalizes the iMinDEE and EPIC protein design algorithms, which model continuous flexibility in sidechain dihedrals, to model continuous, appropriately localized flexibility in the backbone dihedrals phi and psi as well. We show using 81 test cases based on 29 different protein structures that CATS finds sequences and conformations that are significantly lower in energy than methods with less or no backbone flexibility do. In particular, we show that CATS can model the viability of an antibody mutation known experimentally to increase affinity, but that appears sterically infeasible when modeled with less or no backbone flexibility. Availability and implementation: Our code is available as free software at https://github.com/donaldlab/OSPREY_refactor . Contact: mhallen@ttic.edu or brd+ismb17@cs.duke.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28882007 TI - Epidemiology of antibiotic resistance in Pseudomonas aeruginosa. Implications for empiric and definitive therapy. AB - Pseudomonas aeruginosa is one of the major pathogens causing hospital-acquired infections. It can easily develop antibiotic resistance through chromosomal mutations or by horizontal acquisition of resistant determinants. The increasing prevalence of multi-drug-resistant (MDR) or extensively-drug-resistant (XDR) P. aeruginosa isolates is associated with the dissemination of the so-called high risk-clones, such as ST175. Infections caused by MDR/XDR are a cause of concern as they compromise the selection of appropriate empiric and definitive antimicrobial treatments. Introduction of new antibiotics with potent activity against MDR/XDR P. aeruginosa opens new horizons in the treatment of these infections. PMID- 28882008 TI - Highlights in HIV, 2016. AB - Research in HIV-infection continues to grow every year. Reports published in journals or presented at conferences in 2016-2017 have brought light to some issues that had been highly debated. We have selected three conceptual publications, which we find include important information for clinicians taking care of HIV-infected patients. PMID- 28882009 TI - Update on the diagnosis of invasive fungal infection. AB - The number of patients at risk of suffering invasive fungal infection (IFI) is increasing. Because of its high mortality, new rapid and accurate diagnostic tools are needed. Last advances in invasive candidiasis diagnosis comprise Peptide Nucleic Acid Fluorescent In-Situ Hybridization (PNA-FISH), direct MALDI TOF or multiplex acid nucleic testing. While all of them rely in positive blood cultures, T2Candida uses PCR coupled with T2Magnetic resonance detection directly in whole blood, allowing detection of 1-3 UFC/mL of Candida in about four hours. Beyond galactomannan (GM), novelties in IFI caused by molds include the international standardization of PCR techniques, with several commercial kits available. A combination of GM and PCR appears to be a good diagnostic strategy for invasive aspergillosis. PCR coupled to electrospray ionization/mass spectrometry and detection of volatile organic compounds in exhaled air by gas chromatography/mass spectrometry are other promising approaches to IFI diagnostic that still need to be validated. PMID- 28882010 TI - Invasive candidiasis in the neutropenic patient. AB - There are major differences in the epidemiology and prognosis of invasive candidiasis and candidemia in the neutropenic patient; however, a recent study performed in Spanish hospitals (Candipop) confirmed that mortality at 1 month is 30%, which is similar to that observed in the general population. Although Candida albicans is the most frequently isolated species, C. tropicalis, C. glabrata, and C. krusei are more prevalent than in non-neutropenic patients. The benefit of neutrophil transfusion is unclear, and catheter withdrawal must be tailored and based on confirmation of the diagnosis. Echinocandins are the first line option for therapy and have a better safety profile than other agents. PMID- 28882011 TI - Comments on practice guidelines for the diagnosis and management of aspergillosis made by the IDSA in 2016. AB - We sought to review the most important updates in the treatment of aspergillosis after the publication of the clinical practice guidelines for the diagnosis and management of invasive aspergillosis (IA) by the Infectious Diseases Society of America. Our aim is to discuss some of the key aspects concerning the following topics: early initiation of antifungal therapy, antifungal agent of choice, follow-up of patients with IA, and breakthrough aspergillosis. PMID- 28882012 TI - Empirical treatment of adults with hospital-acquired pneumonia: lights and shadows of the 2016 Clinical Practice ATS/IDSA Guidelines. AB - Hospital-acquired pneumonia (HAP) is a common cause of nosocomial infection associated with significant morbidity and mortality. New clinical practice guidelines for the management of adults with hospital-acquired pneumonia have been published in 2016 by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS). This review focuses on the recent recommendations and their limitations. We also focus on new therapeutic options that might improve the treatment and outcomes of these patients. PMID- 28882013 TI - Antimicrobial management in nosocomial peritonitis: microbiota, drug and time. AB - Complicated intra-abdominal infection requires surgical treatment and broad spectrum empiric antibiotic treatment used early. The rapid spread of multidrug resistant bacteria has become a serious threat, especially in critical care units. The excessive use of carbapenems has led to carbapenemase-producing Enterobacteriaceae, leaving tigecycline and colistin as therapeutical options. The new antimicrobials, ceftazidime-avibactam and ceftolozane-tazobactam open new horizons in the treatment of multi-drug resistant Enterobacteriaceae. Candida peritonitis causes a high mortality in the critical patient. Diagnosis and early treatment are associated with a better prognosis, the administration of an echinocandin being of choice in these patients. PMID- 28882014 TI - Urinary tract infections in inpatients: that challenge. AB - Urinary tract infection (UTI) is one of the major nosocomial infections. In more than 80% of cases it is related to the use of urological devices, especially linked to the misuse of urinary catheters. Empirical treatment should be based on local epidemiology, severity criteria and risk of multiresistant bacteria. This review shows the most important aspects of nosocomial UTI, as well as the recommendations for correct treatment adjustment; both empirical and definitive, that is the great challenge to avoid multiresistance, as well as to avoid unnecessary treatments. PMID- 28882016 TI - New sepsis criteria: do they replace or complement what is known in the approach to the infectious patient? AB - There have recently been profound changes in both the definitions of sepsis and septic shock and the diagnostic criteria established for daily clinical practice. In addition, a new screening tool known as qSOFA has been introduced to identify patients at risk of a poor short-term outcome. This score has been accompanied by some controversy due to presenting a lower sensitivity than the systemic inflammatory response criteria previously used to identify such patients. In this article, we shall summarise and analyse the most important recently published studies in relation to these new criteria. PMID- 28882015 TI - Non-valvular intravascular device and endovascular graft-related infection. AB - In the last few years there has been an increase of implantable cardiac electronic device and vascular graft related infections. This is due in part to a higher complexity of some of these procedures and an increase in patient's comorbidities. Despite wide diagnosis methods availability, early stage diagnosis usually constitutes a challenge as often patients only denote insidious symptoms. In most confirmed cases, removal of the infected device is required to resolve the infection. This is mostly explainable because of bacterial ability to grow as biofilms on biomaterial surfaces, conferring them antimicrobial resistance. If removal is not possible, chronic suppressive antimicrobial therapy could be an option. PMID- 28882017 TI - Utility of rapid microbiological techniques for the diagnosis of severe infections. AB - Rapid diagnostic microbiological techniques and antimicrobial susceptibility testing are necessary for early and adequate treatment. The utility of old (Gram stain, antigen detection, direct antimicrobial susceptibility testing, chromogenic media) and new techniques (molecular assays, MALDI-TOF) is summarized for the rapid diagnosis of bacteraemia and fungaemia, catheter-related bloodstream infections, pneumonia, meningitis, skin and soft-tissue infections, urinary tract infection, Clostridium difficile infection, viral infections, and tuberculosis. PMID- 28882018 TI - Optimizing antimicrobial prescribing: a practical decalogue. AB - Increasing antibiotic resistance is one of the leading problems in the Public Agenda worldwide. In the last 20 years, the pace of antimicrobial drug development has markedly slowed leading to a dramatic world situation. Infections with antibiotic-resistant microorganisms have been associated with increased length of stay, mortality and costs. Improving antimicrobial prescribing is one of the tools in our hands to optimize the outcomes of patients with moderate to severe infections and control the emerging of resistance. Several clues to improve antimicrobial prescribing are provided as a key-messages decalogue. PMID- 28882019 TI - Usefulness of Hospital at Home in nosocomial infections: advantages and limitations. AB - Hospital at Home units allows ambulatory treatment and monitoring of complex and serious infections. Nosocomial infections produce an extension of the stay in hospital often specifying long intravenous treatments without any effective oral alternatives. Daily dosing of antimicrobial are easier to administer at home. The use of portable programmable pump infusion and elastomeric devices allow efficient and safe infu-sions for most antimicrobials at home. Some antibiotics against multidrug-resistant organisms of recent introduction have a suitable profile for outpatient intravenous treatment. PMID- 28882020 TI - Non-antibiotic treatment for infectious diseases. AB - The abuse and uncontrolled use of antibiotics has resulted in the emergence and spread of resistant bacteria. The utility of conventional antibiotics for the treatment of bacterial infections has become increasingly strained due to increased rates of resistance coupled with reduced rates of development of new agents. As a result, multidrug-resistant, extensively drug-resistant, and pan drug-resistant bacterial strains are now frequently encountered. This has led to fears of a "post-antibiotic era" in which many bacterial infections could be untreatable. Alternative non-antibiotic treatment strategies need to be explored to ensure that a robust pipeline of effective therapies is available to clinicians. The new therapeutic approaches for bacterial infections (beyond antibiotics) may provide a way to extend the usefulness of current antibiotics in an era of multidrug-resistant (MDR) bacterial infections. PMID- 28882021 TI - Sarcopenia Predicts Prognosis in Patients with Newly Diagnosed Hepatocellular Carcinoma, Independent of Tumor Stage and Liver Function. AB - Purpose: The purpose of this study was to demonstrate the prognostic significance of changes in body composition in patients with newly diagnosed hepatocellular carcinoma (HCC). Materials and Methods: Patients (n=178) newly diagnosed with HCC participated in the study between 2007 and 2012. Areas of skeletal muscle and abdominal fat were directly measured using a three-dimensional workstation. Cox proportional-hazards modes were used to estimate the effect of baseline variables on overall survival. The inverse probability of treatmentweighting (IPTW) method was used to minimize confounding bias. Results: Cutoff values for sarcopenia, obtained from receiver-operating characteristic curves, were defined as skeletal muscle index at the third lumbar vertebra of <= 45.8 cm/m2 for males and <= 43.0 cm/m2 for females. Sarcopenia patients were older, more likely to be female, and had lower body mass index. Univariable analysis showed that the presence of sarcopenia and visceral to subcutaneous fat area ratio (VSR) were significantly associatedwith prognosis. The multivariable analyses revealed that VSR was predictive of overall survival. However, in the multivariable Cox model adjusted by IPTW, sarcopenia, not VSR, were associated with overall survival. Conclusion: The presence of sarcopenia at HCC diagnosis is independently associated with survival. PMID- 28882022 TI - Trend Analysis for the Choice and Cost of Lung Cancer Treatment in South Korea, 2003-2013. AB - Purpose: Our study aimed to report the annual changes in lung cancer statistics and analyze trends in sociodemographic, medical, and financial factors from 2003 to 2013 in the national database from the Korean National Health Insurance (KNHI). Materials and Methods: Among 7,489 patients with code C34 in KNHI database, only lung cancer patients newly diagnosed after 2003 were included in the study population, for a total of 4,582 patients. Descriptive statistics were used to characterize treatment patterns and medical costs according to sociodemographic factors. Results: Approximately 70% of subjects were male, and the mean age was 67 years. Around 46% of patients were over 70 years old, and 12% were over 80 years old. The medical costs were highest for patients younger than 60 and lowest for those over 80 years old. Surgery was more common in younger patients, while "no treatment" increased greatly with age. In trend analysis, the proportions of aging (p for trend < 0.001), female (p for trend=0.003), metropolitan/urban (p for trend=0.041), and lowest or highest-income patients (p for trend=0.004) increased over time, along with the prevalence of surgery as the primary treatment (p for trend < 0.001). There was also a trend with regard to change in medical costs (p for trend < 0.001), in that those of surgery and radiotherapy increased. Conclusion: Surgery as a curative treatment has increased over the past decade. However, the elderly, suburban/rural residents, and low income patients were more likely to be untreated. Therefore, active measures are required for these increasingly vulnerable groups. PMID- 28882024 TI - Higher glucagon-to-insulin ratio is associated with elevated glycated hemoglobin levels in type 2 diabetes patients. AB - Background/Aims: The importance of alpha-cell dysfunction in the pathogenesis of type 2 diabetes has re-emerged recently. However, data on whether relative glucagon excess is present in clinical settings are scarce. We aimed to investigate associations between glucagon-to-insulin ratio and various metabolic parameters. Methods: A total of 451 patients with type 2 diabetes naive to insulin treatment were recruited. Using glucagon-to-insulin ratio, we divided subjects into quartiles according to both fasting and postprandial glucagon-to insulin ratios. Results: The mean age of the subjects was 58 years, with a mean body mass index of 25 kg/m2 . The patients in the highest quartile of glucagon-to insulin ratio had higher glycated hemoglobin (HbA1c) levels. HbA1c levels were positively correlated with both fasting and postprandial glucagon-to-insulin ratios. Subjects in the highest quartile of postprandial glucagon-to-insulin ratio were more likely to exhibit uncontrolled hyperglycemia, even after adjusting for confounding factors (odds ratio, 2.730; 95% confidence interval, 1.236 to 6.028; p for trend < 0.01). Conclusions: Hyperglucagonemia relative to insulin could contribute to uncontrolled hyperglycemia in type 2 diabetes patients. PMID- 28882023 TI - APEX1 Polymorphism and Mercaptopurine-Related Early Onset Neutropenia in Pediatric Acute Lymphoblastic Leukemia. AB - Purpose: Mercaptopurine (MP) is one of the main chemotherapeutics for acute lymphoblastic leukemia (ALL). To improve treatment outcomes, constant MP dose titration is essential to maintain steady drug exposure, while minimizing myelosuppression. We performed two-stage analyses to identify genetic determinants of MP-related neutropenia in Korean pediatric ALL patients. Materials and Methods: Targeted sequencing of 40 patients who exhibited definite MP intolerance was conducted using a novel panel of 211 pharmacogenetic-related genes, and subsequent analysis was performed with 185 patients. Results: Using bioinformatics tools and genetic data, four functionally interesting variants were selected (ABCC4, APEX1, CYP1A1, and CYP4F2). Including four variants, 23 variants in 12 genes potentially linked to MP adverse reactions were selected as final candidates for subsequent analysis in 185 patients. Ultimately, a variant allele in APEX1 rs2307486was found to be strongly associated with MP-induced neutropenia that occurred within 28 days of initiating MP (odds ratio, 3.44; p=0.02). Moreover, the cumulative incidence of MP-related neutropenia was significantly higher in patients with APEX1 rs2307486 variants, as GG genotypes were associated with the highest cumulative incidence (p < 0.01). NUDT15 rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01). Conclusion: We have identified that APEX1 rs2307486 variants conferred an increased risk of MP-related early onset neutropenia. APEX1 and NUDT15 both contribute to cell protection from DNA damage or misincorporation, so alleles that impair the function of either gene may affect MP sensitivities, thereby inducing MP-related neutropenia. PMID- 28882025 TI - Relationship between shipping amounts of olive flounder aquacultured from Jejudo and the reported events of acute food poisoning by Kudoa septempunctata in 2015, South Korea: an ecological study. AB - OBJECTIVES: Confirmation of Kudoa septempunctata (K. septempunctata) as the pathogenic agent causing acute food poisoning remains under debate owing to inconsistencies in the reproducibility of experimental evidence. Higher intake of olive flounder infected with K. septempunctata would result in increased diagnosis of food poisoning by K. septempunctata, if the latter was one of the causal agents of acute food poisoning. The aim was to evaluate the relationship between the shipping amount of olive flounder aquacultured from Jejudo and the incidence of K. septempunctata food poisoning in 2015, Korea. METHODS: Data of shipping amounts between March 2014 and February 2016 and of monthly reported events of Kudoa food poisoning were taken from Jejudo Fish-Culture Fisheries Cooperatives and Korea Centers for Disease Control and Prevention, respectively. Non-parametric correlation analyses were conducted. RESULTS: Shipping amounts indicated the seasonal changes according to variation of consumption. Spearman's rho and Kendall's tau-a between the monthly shipping amounts and the reported events in 2015 were 0.39 (p=0.21) and 0.27 (p=0.20), respectively. CONCLUSIONS: An independent relationship was noted between the shipping amount and the reported events, which contrasted with the claim that the virulence of K. septempunctata caused acute food poisoning. PMID- 28882027 TI - Promoting physical activity for children: an audit among Italian family paediatricians. AB - BACKGROUND: This survey aimed to investigate the perception of Italian Paediatricians regarding the promotion of physical activity. METHODS: From January to May 2015, a survey was conducted among family paediatricians working in Puglia, interviewed by a standardised questionnaire, that investigated demographic information, participation in sporting activity by the paediatrician, opinion on obesity and the promotion of physical activity, and attitude towards enquiring about the physical activity of patients with and without chronic diseases. RESULTS: We collected 200 questionnaires (35.7% of target population). 51.5% of enrolled paediatricians stated that they were participating in sporting activities at the time of the survey. The average opinion regarding the relevance of the obesity was 9+/-1.4/10 and about the promotion of physical activity 9.6+/ .8. All enrolled paediatricians asked for their patients' physical activity and encouraged inactive children to begin an appropriate activity. Paediatricians who took part in sport had a high probability of encouraging physical activity, in particular among patients affected by chronic diseases. CONCLUSIONS: Family Paediatricians declared a good attitude regarding the promotion of physical activity for their patients according to national and international recommendations. The main concern emerging from our results is the risk of an "inappropriate interdiction" of physical activity in children affected by chronic diseases, in particular physicians that have never participated in a sport. PMID- 28882026 TI - Epidemiology and risk factors of voluntary pesticide poisoning in Morocco (2008 2014). AB - OBJECTIVES: To determine the epidemiological profile and risk factors of voluntary poisoning by pesticides. METHODS: A retrospective analysis was conducted of all cases of voluntary poisoning by pesticides registered at the AntiPoison and Pharmacovigilance Center of Morocco between January 2008 and December 2014. RESULTS: During the study period, 2,690 cases of acute pesticide poisoning were registered. The region of Rabat-Sale-Zemmour-Zaer accounted for the largest proportion, with 598 cases. The average age of the patients was 24.63+/-10.29 years. The sex ratio (female-to-male) was 0.45. Adults and teenagers were most affected by this type of poisoning, with 1,667 cases (62.0%) and 806 cases (30.0%), respectively. Suicide attempts accounted for 98.4% of the cases (2,469 cases). Pesticide poisoning occurred more often in urban zones (64.8%). Insecticides were incriminated in 14.0% of cases, with a mortality rate of 4.2%. Among the 1,635 patients for whom the outcomes were known, 154 died, corresponding to a mortality rate of 5.7%. CONCLUSIONS: Voluntary intoxication by pesticides presents a real scourge that affects public health, and in this study, we developed an epidemiological profile of this phenomenon. Nevertheless, this study has limitations in that it did not evaluate the impact of the socioeconomic and psychological factors that are important contributors to this type of poisoning. PMID- 28882028 TI - Cochlear malformation and sensorineural hearing loss in the Silver-Russell syndrome. PMID- 28882029 TI - Clinical observation of umbilical cord mesenchymal stem cell transplantation for treating patients receiving peritoneal dialysis. AB - BACKGROUND: This study aims to observe the outcome and safety of umbilical cord mesenchymal stem cell (UC-MSC) treatment for continuous ambulatory peritoneal dialysis (CAPD) patients. METHODS: A total of 24 CAPD patients, who underwent UC MSC treatment from June 2011 to December 2012, were selected for this study. These patients were followed up until June 2015. RESULTS: Results revealed a significant increase in hemoglobin, erythropoietin and albumin levels, a decrease in C-reactive protein levels, and marked improvement in cystatin C and urine volume within three months after UC-MSC transplantation; and the difference was statistically significant (P<0.05). However, the difference in residual glomerular filtration rate, serum creatinine, peritoneal KT/V and remnant kidney KT/V was not statistically significant (P>0.05). CONCLUSIONS: Clinical indicators of patients with CAPD can be partially improved through UC-MSC treatment. PMID- 28882030 TI - Outcomes following robotic-assisted laparoscopic prostatectomy: Pentafecta and Trifecta achievements. AB - BACKGROUND: Functional and oncologic outcomes following radical prostatectomy play a major role in patient satisfaction after treatment. This study was designed to assess the functional and oncologic outcome after robotic assisted radical prostatectomy (RARP) in a single surgeon series of patients. METHODS: A prospectively maintained database of patients undergoing robotic radical prostatectomy in a referral academic center was queried for functional and oncologic outcome. Patients undergoing RARP between 2010 and 2013 were included. Analysis was performed with SPSS and SAS, chi2, Mann-Whitney and t-test were used when appropriate. RESULTS: Overall, 566 patients were included in the analysis. The Trifecta and Pentafecta was 73.9% and 64.1%, respectively. Patients achieving Pentafecta were younger (P<0.001), had lower PSA level (P=0.04), lower Biopsy Gleason (P<0.01), lower risk prostate cancer (P<0.01) and fewer comorbidities (P=0.03). The patients were followed up for a median of 27.4 months in Trifecta and 20.6 months in Pentafecta group. At 12-month follow-up the continence and potency rate was 90.6% and 84.1%, respectively. CONCLUSIONS: Although preoperative counseling for RARP surgery using Pentafecta criteria offers more precise information and reasonable expectations than using the Trifecta, further research is required to prepare a standard reporting outline. PMID- 28882032 TI - Efficacy and safety of single-shot vs. continuous regional analgesia in ambulatory orthopedic surgery: when is a systematic review appropriate? PMID- 28882031 TI - A multiregional Italian cohort of 24-hour urine metabolic evaluation in renal stone formers. AB - BACKGROUND: Nephrolithiasis is a common condition with several studies documenting an increased prevalence over the past four decades. EAU and AUA guidelines recommend 24-hour urine metabolic evaluation in high-risk stone formers. Aim of this study is to retrospectively evaluate the first three years of experience with LithoTest(r) (Biohealth Italia Srl, Turin, Italy) through the analysis of demographic, clinical and biochemical data collected from a large cohort of patients with kidney stones. METHODS: We retrospectively analyzed data from the LithoCenter database, including data from outpatient consultations, between January 2007 and December 2009 from all over Italy. LithoTest(r) was performed through a 24-hour urine collection and included measurements of urine volume and pH, 24-hour excretion of creatinine as well as main cations and anions, including calcium, magnesium sodium potassium, ammonium, uric acid, oxalate, citrate, phosphate, inorganic sulphate and chloride. Urine state of saturation for calcium oxalate (betaCaOx), calcium hydrogen phosphate or brushite (betabsh) and uric acid (betaUA) were also calculated by means of the computer program LithoRisk. Brand's test for cystinuria was also carried out. Statistical analysis was performed using the S-PSS software v. 22.0. RESULTS: The number of patients with data available for analysis was 435, of whom 236 were male (54%) and 199 female (46%). Complete 24-hour urine measurements were available for all 435 patients. Compared to men, women had significantly lower values for creatinine, urate, oxalate, phosphate, sodium, potassium, magnesium and chloride excretion, whereas 24-hour pH and citrate excretion were higher. No significant differences were found for the other examined variables. betaCaOx and betaUA were significantly higher in men than women, whereas no significant difference was found for betabsh. There was a direct relationship between calcium and sodium urine excretion. Excessive sodium excretion was recorded in 191 patients (44%) and low urine volumes in 201 (46.2%). Hyperoxaluria was observed in 118 patients (27.3%), hypercalciuria in 115 (26.6%), hyperuricosuria in 153 (35.4%), hypomagnesuria in 96 (22.2%), and hypocitraturia in 134 patients (31%). Hyperexcretion of sodium, hypocitraturia and hyperoxaluria were most frequent in males. betaCaOx was significantly higher in the setting of hypercalciuria, hypocitraturia, hyperoxaluria and urine pH below 5.5. CONCLUSIONS: Our findings in a large cohort of high-risk stone-forming patients show significant differences in urinary metabolic profiles between men and women. Carrying on the collection and analysis of data by LithoTest(r) from 2009 to 2015 and matching urinary and dietary data could eventually improve our understanding on the metabolic profile of stone-formers in Italy. PMID- 28882033 TI - Visible Light-Induced Plasticity of Shape Memory Polymers. AB - Plasticity of thermoset polymers has been realized by introducing exchangeable bonds, and the plasticity is mostly triggered via heat or UV light. Visible light is a relatively mild trigger that has not been used to induce plasticity in polymer materials. Herein, thermoset polyurethanes (PUs) containing diselenide bonds are fabricated that possess visible light-induced plasticity along with shape memory behavior. A series of PUs with different diselenide bond contents were tested and their shape memory properties and plasticity varied. With a higher diselenide bond content, both shape memory and light-induced plasticity are achieved. By combining these two properties, reshaping the permanent shapes of the PUs is easier. Compared with heat or UV light, visible light has the advantage of spatial control. For instance, a pattern of visible light was introduced by a commercial projector to demonstrate facile reshaping of the materials. Because visible light can be introduced via various methods, PUs with visible light-induced plasticity have great potential applications. PMID- 28882034 TI - One-Step Fast Synthesis of Nanoparticles for MRI: Coating Chemistry as the Key Variable Determining Positive or Negative Contrast. AB - Iron oxide nanomaterial is a typical example of a magnetic resonance imaging probe for negative contrast. It has also been shown how this nanomaterial can be synthesized for positive contrast by modification of the composition and size of the core. However, the role of the organic coating in the relaxometric properties is largely unexplored. Here, maghemite nanoparticles with either excellent positive or very good negative contrast performance are obtained by modifying coating thickness while the core is kept unchanged. Different nanoparticles with tailored features as contrast agent according to the coating layer thickness have been obtained in a single-step microwave-driven synthesis by heating at different temperatures. A comprehensive analysis is conducted of how the composition and structure of the coating affects the final magnetic, relaxometric, and imaging performance. These results show how the organic coating plays a fundamental role in the intrinsic relaxometric parameters of iron oxide-based contrast media. PMID- 28882035 TI - Reactive Compatibilization: Formation of Double-Grafted Copolymers by In Situ Binary Grafting and Their Compatibilization Effect. AB - Reactive compatibilizers are usually used to enhance the compatibility of immiscible polymer blends. However, reactive linear compatibilizers containing reactive groups on the main chains form graft copolymers during reactive blending, and such graft copolymers with an asymmetric molecular structure are often "pulled in" or "pulled out" under mechanical shear. Double-grafted compatibilizers have a symmetric structure, and they usually exhibit higher compatibilizing efficiency. In this work, we propose a binary grafting strategy during melt blending to form compatibilizers located at the interface of an immiscible polymer blend. Specifically, poly(methyl methacrylate) (PMMA) oligomer with carboxylic end groups (PMMA-COOH) and poly(styrene-co-glycidyl methacrylate) (SG) copolymer were simultaneously incorporated into immiscible poly(vinylidene fluoride)/poly(l-lactic acid) (PVDF/PLLA) blends. The carboxylic acid groups of both the PMMA oligomer and PLLA can react with the epoxide groups on the SG main chains. Therefore, novel compatibilizing polymers with both PMMA and PLLA chains grafted onto the SG main chains form in situ. The grafted PMMA chains can entangle with PVDF, and the grafted PLLA chains are embedded in the PLLA phase, so the double-grafted copolymers act as effective compatibilizers for the PVDF/PLLA blends. Moreover, the effects of the PMMA molecular weight and PMMA loading (number of grafted PMMA side chains) on the compatibilization efficiency were investigated. The compatibilizing efficiency increases with increasing molecular weight and number of side chains in the ranges considered in this study. This one-pot synthesis of double-grafted compatibilizers by in situ grafting provides a new and simple method to prepare double-comb compatibilizers, and it offers the possibility of high-efficiency compatibilization. PMID- 28882036 TI - Micropatternable Double-Faced ZnO Nanoflowers for Flexible Gas Sensor. AB - Micropatternable double-faced (DF) zinc oxide (ZnO) nanoflowers (NFs) for flexible gas sensors have been successfully fabricated on a polyimide (PI) substrate with single-walled carbon nanotubes (SWCNTs) as electrode. The fabricated sensor comprises ZnO nanoshells laid out on a PI substrate at regular intervals, on which ZnO nanorods (NRs) were grown in- and outside the shells to maximize the surface area and form a connected network. This three-dimensional network structure possesses multiple gas diffusion channels and the micropatterned island structure allows the stability of the flexible devices to be enhanced by dispersing the strain into the empty spaces of the substrate. Moreover, the micropatterning technique on a flexible substrate enables highly integrated nanodevices to be fabricated. The SWCNTs were chosen as the electrode for their flexibility and the Schottky barrier they form with ZnO, improving the sensing performance. The devices exhibited high selectivity toward NO2 as well as outstanding sensing characteristics with a stable response of 218.1, fast rising and decay times of 25.0 and 14.1 s, respectively, and percent recovery greater than 98% upon NO2 exposure. The superior sensing properties arose from a combination of high surface area, numerous active junction points, donor point defects in the ZnO NRs, and the use of the SWCNT electrode. Furthermore, the DF ZnO NF gas sensor showed sustainable mechanical stability. Despite the physical degradation observed, the devices still demonstrated outstanding sensing characteristics after 10 000 bending cycles at a curvature radius of 5 mm. PMID- 28882037 TI - Reusable Silicon-Based Surface-Enhanced Raman Scattering Ratiometric Aptasensor with High Sensitivity, Specificity, and Reproducibility. AB - Rapid, sensitive, and accurate detection of adenosine triphosphate (ATP), the primary energy molecule, is critical for the elucidation of its unique roles in cell signaling and many cellular reactions. Up to date, a major challenge is still remaining for fabricating surface-enhanced Raman scattering (SERS) aptamer sensors (aptasensors) suitable for accurate and reliable quantification of ATP. Herein, we develop the ratiometric silicon SERS aptasensor for ATP detection, which is made of uniform silver nanoparticles (Ag NPs)-modified silicon wafer (Ag NPs@Si), followed by the functionalization with double-stranded DNA (dsDNA I). The dsDNA I is formed by the aptamer and its complementary DNA (cDNA), which contains two independent segments (e.g., 5'-Cy3-labeled DNA-C1, 3'-ROX-labeled DNA-C2). In the presence of ATP, ROX-DNA-C2 is dissociated from dsDNA I due to the formation of aptamer/ATP complex, leading to the attenuation of ROX signals, and meanwhile, Cy3 signals remain constant ascribed to the formation of dsDNA II caused by the supplementation of aptamer. As a result, ratiometric signals of the ratio of ROX intensity to Cy3 intensity (IROX/ICy3) can be achieved. Of particular significance, the developed ATP aptasensor features excellent reproducibility [e.g., the relative standard deviation (RSD) is less than ~4%, comparable or superior to that of previously reported aptasensors], ultrahigh sensitivity [e.g., the detection of limit (LOD) reaches 9.12 pM, lower than that of other reported ATP SERS aptasensors], as well as good recyclability (e.g., ~9.3% of RSD values of ratiometric signals within three cycles). PMID- 28882038 TI - Ultradeep Lysine Crotonylome Reveals the Crotonylation Enhancement on Both Histones and Nonhistone Proteins by SAHA Treatment. AB - Lysine crotonylation is a newly discovered protein post-translational modification and was reported to share transferases and deacylases with lysine acetylation. The acetyltransferase p300 was reported to also contain crotonyltransferase activity, and class I histone deacetylases were demonstrated to be the major histone decrotonylases. However, the decrotonylases for nonhistone proteins are unclear. Moreover, because of the lack of high-quality pan-antibodies, large-scale analysis of crotonylome still remains a challenge. In this work, we comprehensively studied lysine crotonylome on both histones and nonhistone proteins upon SAHA treatment and dramatically identified 10 163 lysine crotonylation sites in A549 cells. This is the first identification of tens of thousands of lysine crotonylation sites and also the largest lysine crotonylome data set up to now. Moreover, a parallel-reaction-monitoring-based experiment was performed for validation, which presented highly consistent results with the SILAC experiments. By intensive bioinformatic analysis, it was found that lysine crotonylation participates in a wide range of biological functions and processes. More importantly, it was revealed that both the crotonylation and acetylation levels of most core histones sites and a number of nonhistone proteins as well as some known substrates of class IIa and IIb HDACs were up-regulated after SAHA treatment. These results suggest that SAHA may have decrotonylation inhibitory activities on both histones and nonhistone proteins by inhibiting HDACs. PMID- 28882039 TI - Metabolic Profiling on Alternaria Toxins and Components of Xinjiang Jujubes Incubated with Pathogenic Alternaria alternata and Alternaria tenuissima via Orbitrap High-Resolution Mass Spectrometry. AB - Xinjiang jujubes (Zizyphus rhamnaceae) are important agro-economical foods with the highest planting area and yields in China; however, black spot disease and contaminated Alternaria toxins have unfortunately caused a decline or loss of jujube nutritional quality in recent years. In this study, we used ultrahigh performance liquid chromatography coupled to Orbitrap high-resolution mass spectrometry to profile both Alternaria toxins and components in three representative Xinjiang jujubes, Hami Huang, Hetian Jun, and Ruoqiang Hui. Before liquid chromatography-mass spectrometry analysis, jujubes were inoculated with two main pathogens of Alternaria alternata (Aa) and Alternaria tenuissima (At). Different combinations of jujube varieties with pathogenic isolates display different metabolic profiles, as expected. Moreover, four major Alternaria toxins, alternariol, alternariol monomethyl ether, altenuene, and tenuazonic acid, were detected in all samples. The inoculation of both pathogens significantly decreased the levels of nutrients and metabolites in jujube, including four saponins, three organic acids, and three alkaloids, whereas it increased the level of several glycerol phosphates. The flavonoid profiles are diverse. Lastly, inoculation of Aa changes more metabolites in jujubes than At. Our data provide insights to better understand the detrimental contamination of Alternaria pathogens in Xinjiang jujubes and improve food safety of jujubes. PMID- 28882040 TI - Visualizing Breast Cancer Cell Proliferation and Invasion for Assessing Drug Efficacy with a Fluorescent Nanoprobe. AB - Hard-to-treat cancers are closely relative to uncontrolled cell proliferation, invasion, and metastasis. Assessing proliferation and invasion properties of tumor cells both in vitro and in vivo is especially important for acquiring reliable information for cancer pathogenesis, drug screening, and therapeutic effect evaluation. Herein, we developed a multicolor fluorescent nanoprobe for simultaneously monitoring breast cancer cells' proliferation marker Ki-67 and invasion marker urokinase plasminogen activator (uPA). After treated with the anticancer drugs tamoxifen and curcumin, the changes in cancer cell proliferation and invasion properties were visually detected and therapeutic effects of corresponding drugs were further assessed in vitro and in vivo. The design of the fluorescent nanoprobe opens up an avenue for investigating unscheduled proliferation, invasion, and metastasis in living cells and in vivo and as such will be a promising tool to screen antitumor drugs and evaluate drug efficiency in an extremely efficient manner. PMID- 28882041 TI - Dynamics of Silver Nanoparticles in Aqueous Solution in the Presence of Metal Ions. AB - Using a combined UV-vis, DLS, and electrochemical approach, this work experimentally studies the physical origin of the observed colorimetric sensitivity of aqueous silver nanoparticles toward divalent metal ions. In the presence of Pb2+, AgNPs are slow to reversibly form agglomerates (the time scale of the reverse deagglomeration process is of the order of hours). This agglomeration is shown to be induced by complex formation between Pb2+ and citrate groups localized on the AgNPs, reducing surface charges (zeta-potential) and hence electrostatic repulsion between the AgNPs. Other divalent metal ions including Ca2+, Cd2+, Zn2+, Ni2+, Co2+, and Sn2+ are also studied, and the resulting sizes of the AgNPs clusters and the extents of the UV-vis spectrum red shift in lambdamax have a strong positive correlation with the metal-ligand (citrate) complex formation constant (Kf). This work thus serves as a guide for the selection of capping agents on the basis of Kf and demonstrates the correlation between sizes and spectrophotometric as well as electrochemical responses of the AgNPs clusters. Importantly, we give further physical insights into the size-dependent properties of AgNPs and emphasize the difference between theoretical and experimental values of extinction coefficients, where the latter is affected by the angle-dependent scattering intensities and the measurement technique used. PMID- 28882042 TI - All-Aqueous Assemblies via Interfacial Complexation: Toward Artificial Cell and Microniche Development. AB - In nature, the environment surrounding biomolecules and living cells can dictate their structure, function, and properties. Confinement is a key means to define and regulate such environments. For example, the confinement of appropriate constituents in compartments facilitates the assembly, dynamics, and function of biochemical machineries as well as subcellular organelles. Membraneless organelles, in particular, are thought to form via thermodynamic cues defined within the interior space of cells. On larger length scales, the confinement of living cells dictates cellular function for both mammalian and bacterial cells. One promising class of artificial structures that can recapitulate these multiscale confinement effects is based on aqueous two-phase systems (ATPSs). This feature article highlights recent developments in the production and stabilization of ATPS-droplet-based systems, with a focus on interfacial complexation. These systems enable structure formation, modulation, and triggered (dis)assembly, thereby allowing structures to be tailored to fit the desired function and designed for particular confinement studies. Open issues for both synthetic cells and niche studies are identified. PMID- 28882043 TI - Water Adsorption Isotherms on Fly Ash from Several Sources. AB - In this study, horizontal attenuated total reflection (HATR) Fourier-transform infrared (FT-IR) spectroscopy was combined with quartz crystal microbalance (QCM) gravimetry to investigate the adsorption isotherms of water on fly ash, a byproduct of coal combustion in power plants. Because of composition variability with the source region, water uptake was studied at room temperature as a function of relative humidity (RH) on fly ash from several regions: United States, India, The Netherlands, and Germany. The FT-IR spectra show water features growth as a function of RH, with water absorbing on the particle surface in both an ordered (ice-like) and a disordered (liquid-like) structure. The QCM data was modeled using the Brunauer, Emmett, and Teller (BET) adsorption isotherm model. The BET model was found to describe the data well over the entire range of RH, showing that water uptake on fly ash takes place mostly on the surface of the particle, even for poorly combusted samples. In addition, the source region and power-plant efficiency play important roles in the water uptake and ice nucleation (IN) ability of fly ash. The difference in the observed water uptake and IN behavior between the four samples and mullite (3Al2O3.2SiO2), the aluminosilicate main component of fly ash, is attributed to differences in composition and the density of OH binding sites on the surface of each sample. A discussion is presented on the RH required to reach monolayer coverage on each sample as well as a comparison between surface sites of fly ash samples and enthalpies of adsorption of water between the samples and mullite. PMID- 28882045 TI - The transition to integrate palliation in cancer care. PMID- 28882046 TI - Do what I couldn't...and go save your life. PMID- 28882044 TI - Host-Guest Tethered DNA Transducer: ATP Fueled Release of a Protein Inhibitor from Cucurbit[7]uril. AB - Host-guest complexes are emerging as powerful components in functional systems with applications ranging from materials to biomedicine. In particular, CB7 based host-guest complexes have received much attention for the controlled release of drugs due to the remarkable ability of CB7 toward binding input molecules in water with high affinity leading to displacement of CB7 from included pharmacophores (or from drug loaded porous particles). However, the release of bound guests from CB7 in response to endogenous biological molecules remains limited since the input biomolecule needs to have the appropriate chemical structure to bind tightly into the CB7 cavity. Herein we describe a synthetic transducer based on self-assembling DNA-small molecule chimeras (DCs) that is capable of converting a chosen biological input, adenosine triphosphate (ATP; that does not directly bind to the CB7 host), into functional displacement of a protein inhibitor that is bound within the CB7 host. Our system-which features the first example of a covalent CB-DNA conjugate-is highly modular and can be adapted to enable responsiveness to other biologically/clinically relevant stimuli via its split DNA aptamer architecture. PMID- 28882047 TI - Transitions in cancer care-moving from crisis intervention to care planning and management. PMID- 28882048 TI - Project ECHO: an effective means of increasing palliative care capacity. PMID- 28882049 TI - The carrot or stick? integrating palliative care into oncology practice. PMID- 28882050 TI - Transitions of care in patients with cancer. PMID- 28882051 TI - Temperament, coping, and involuntary stress responses in preadolescent children: the moderating role of achievement goal orientation. AB - BACKGROUND AND OBJECTIVES: Developmental theorists posit that temperament contributes to preadolescent's stress response styles. Findings from empirical studies, however, have yielded mixed results, thus indicating a need to consider moderators of this relation. Utilizing an analytic framework guided by resiliency theory [Zimmerman, M. A. (2013). Resiliency theory: A strengths-based approach to research and practice for adolescent health. Health Education & Behavior, 40, 381 383], this study examined achievement goal orientation as a moderator of the relation between temperament and stress response styles. METHODS: 96 preadolescent-parent dyads (Mage = 10.30 years, range = 9-12 years) participated in the study. Preadolescents reported on their achievement goal orientation, coping and involuntary stress responses (ISRs) styles and a parent reported on children's temperament. RESULTS: Multiple regressions revealed that effortful control positively predicted preadolescent's predominant use of engagement coping and negatively predicted predominance of ISRs, but only for children with a predominant mastery goal orientation. For preadolescents with a predominant performance goal orientation, effortful control negatively predicted the predominant use of engagement coping and positively predicted predominance of ISRs. Negative affectivity and its interaction with goal orientation did not predict coping or ISR styles. CONCLUSIONS: Findings suggest that a predominant mastery goal orientation may function as a promotive factor by enhancing the contribution of effortful control to engagement coping styles and buffering against unmanaged reactivity. PMID- 28882053 TI - Naphthoquinone rich Onosma visianii Clem (Boraginaceae) root extracts induce apoptosis and cell cycle arrest in HCT-116 and MDA-MB-231 cancer cell lines. AB - In the present study, five root extracts of Onosma visianii Clem were investigated for their in vitro cytotoxic activity. On the basis of HPLC-PDA analysis, these extracts have proved to be a rich source of naphthoquinones as natural colourants for food and cosmetic industry. All investigated root extracts contain acetylshikonin, isobutyrylshikonin and alpha-methylbutyrylshikonin as major compounds. As the most abundant source of active compounds for antitumour therapy, acetone, chloroform and ethyl acetate extracts showed strong cytotoxic activity towards HCT-116 and MDA-MB-231 cancer cell lines. Also, these extracts induced apoptosis and cell cycle arrest in HCT-116 and MDA-MB-231 cancer cell lines. PMID- 28882052 TI - An Optimized and Validated Method for Isolation and Characterization of Lymphocytes from HIV+ Human Gut Biopsies. AB - The gastrointestinal (GI) tract harbors most of the body's immune cells and is also a major HIV reservoir in ART-treated patients. To achieve a cure, most HIV infected cells must be identified and eliminated. While obtaining gut biopsies is a relatively noninvasive method of sampling relevant tissue for monitoring HIV activity, immune cell isolation from these limited tissue samples has proven to be challenging. Enzymatic tissue digestion is required for maximal immune cell isolation from gut biopsies. However, these enzymatic digestions can also be detrimental for preservation of cellular surface markers that are required for accurate identification of various subsets of leukocytes. In this study, we describe an optimized protocol for isolation of lymphocytes from human gut biopsies. We also discuss our validation results, which show that compared with several other collagenase preparations, the use of CSLPA maintains high lymphocyte recovery while preserving the integrity of most cellular surface antigens that we tested. Importantly, chemokine receptors that are used to characterize various subsets of T cells, which are notorious for being digested during a typical enzymatic tissue digestion, are highly preserved using this protocol. PMID- 28882054 TI - Determination of the Problems Experienced by Patients Post-Thyroidectomy. AB - This descriptive, cross-sectional study investigated problems experienced by patients after undergoing a thyroidectomy. The study included 60 first-time, post thyroidectomy patients diagnosed with benign thyroid disease from a university hospital's general surgery clinic in Ankara, Turkey. The data were collected in two stages: interviews with patients on the first day following surgery and postoperative follow-up telephone interviews in each of the first 4 weeks following surgery. The follow-ups revealed that patients principally experienced varying degrees of pain and difficulties in connection with work and recreation, communication, body image, and movement, for up to 4 weeks after surgery. These results showed that patients were particularly prone to problems on the first day and during the first week of the postoperative period; therefore, patients should be provided with follow-up telephone interviews to facilitate easier recovery and to help them overcome any problems experienced during the postoperative period. PMID- 28882055 TI - Comparison of neuroprotective effect of Forsythia suspensa leaf extract and forsythiaside, one of its metabolites. AB - As one of authentic Chinese medicinal materials in Shanxi Province, leaves of Forsythia suspensa (Thunb.) Vahl (F. suspensa, Lianqiao in Chinese) have been used as alternative for the relief or treatment of inflammation. The study aimed to compare the neuroprotective effects of extract from F. suspensa leaves and forsythiaside against inflammation and apoptosis induced by lipopolysaccharide (LPS) on hippocampal slices. The cultured hippocampal slices were treated with extract (5 and 50 MUg/mL) and forsythiaside (5 and 50 MUg/mL), respectively, followed by LPS treatment for 24 h. The present study showed that 60% ethanol extract of F. suspensa leaves exhibited better neuroprotective effect than equivalent forsythiaside. PMID- 28882056 TI - Multiscale Imaging of HIV-1 Transmission in Humanized Mice. PMID- 28882057 TI - Interethnic DNA methylation difference and its implications in pharmacoepigenetics. AB - AIM: This is the first systematic study to examine the population differentiation effect of DNA methylation on the treatment response and drug absorption, distribution, metabolism and excretion in multiple tissue types and cancer types. MATERIALS & METHODS: We analyzed the whole methylome and transcriptome data of primary tumor tissues of four cancer types (breast, colon, head & neck and uterine corpus) and lymphoblastoid cell lines for African and European ancestry populations. RESULTS: Ethnicity-associated CpG sites exhibited similar methylation patterns in the two studied populations, but the patterns differed between tumor tissues and lymphoblastoid cell lines. Ethnicity-associated CpG sites may have triggered gene expression, influenced drug absorption, distribution, metabolism and excretion, and showed tumor-specific patterns of methylation and gene regulation. CONCLUSION: Ethnicity should be carefully accounted for in future pharmacoepigenetics research. PMID- 28882058 TI - Role of acoustic radiation force impulse and shear wave velocity in prediction of preterm birth: a prospective study. AB - Background Preterm birth is one of the important causes of neonatal morbidity where we rely on subjective criteria such as modified Bishop's scoring and contemporary sonographic measurement of cervical length. Acoustic radiation force impulse (ARFI) is a technological advancement in elastography that can be employed in prediction of cervical softening and preterm labor. Purpose To evaluate the role of ARFI technique and shear wave velocity (SWV) estimates as a predictor of preterm birth and its comparison with other clinical and sono elastographic measures. Material and Methods Thirty-four pregnant women (gestation age = 28-37 weeks age) showing features suggestive of preterm labor were included and evaluated with modified Bishop's score, cervical length by ultrasound (US), ARFI to derive Elastography index (EI), and SWV of the cervix. The patients were later divided into two groups, using the clinical outcome of preterm or term delivery. Results Twenty patients delivered at term (gestational age > 37 weeks) and 14 were preterm. Receiver operating characteristics (ROC) curves showed SWV with highest sensitivity and specificity (93% and 90%, respectively) for the prediction of preterm birth at a cutoff value of 2.83 m/s. EI and modified Bishop's score were comparable to each other, but were less sensitive techniques. Conclusion Elastographic assessment of antenatal cervix is a novel technique of virtual palpation of internal os and can be utilized as an objective criterion for preterm birth prediction. PMID- 28882059 TI - MRI evaluation of ligaments and tendons of foot arch in talar dome osteochondral lesions. AB - Background There are no publications in literature describing an association between disorders of the ligaments and tendons supporting the foot arch and osteochondral lesions of the talus (OCLT). We believe there may be a correlation between the damage of these structures. Purpose To investigate the pathologies of main ligaments and tendons that support the foot arch in sprained ankles, by reviewing magnetic resonance imaging (MRI) studies and comparing the results in two groups of patients, with and without OCLT. Material and Methods MR images from 316 patients examined in the orthopedic clinic for ankle sprain were evaluated for pathologic findings of the plantar fascia, short and long plantar ligaments, spring ligament, sinus tarsi, and ankle tendons supporting the foot arch. Findings were compared between two groups of patients: 158 patients with OCLT and 158 patients without OCLT. Results Plantar fascia, short plantar ligament, and spring ligament abnormalities were seen in 50 (31.6%), 28 (17.7%), and 60 (38%) patients with OCLT, and in nine (5.6%), three (1.9%), and 18 (11.4%) patients without OCLT, respectively ( P < 0.05). Sinus tarsi and tendon abnormalities were seen in 11 (6.7%) and nine (5.7%) patients with OCLT, and in eight (5%) and eight (5%) patients without OCLT, respectively ( P > 0.05). Two or more associated abnormalities were present in 50 (31.6%) patients with OCLT and in 11 (6.7%) without OCLT ( P < 0.05). Conclusion Plantar fascia, short plantar ligament, and spring ligament abnormalities were commonly seen in patients with OCLT on MRI, while sinus tarsi and tendon abnormalities were not. Concomitant pathologies have an increased incidence in patients with OCLT. PMID- 28882060 TI - MRI assessment of pituitary iron accumulation by using pituitary-R2 in beta thalassemia patients. AB - Background Patients with thalassemia major (TM) require repeated blood transfusions, which leads to accumulation of iron in a wide variety of tissues. Accumulation of iron in the pituitary gland can lead to irreversible hypogonadotropic hypogonadism (HH) in this group of patients. Purpose To investigate the reliability of pituitary-R2 as a marker to estimate the extent of pituitary iron load by comparing the pituitary magnetic resonance imaging (MRI) findings with hepatic iron load and serum ferritin levels. Material and Methods A total of 38 beta-TM patients were classified into HH (group A, n = 18) and non-HH (group B, n = 17) groups. A third group, group C, consisted of 17 healthy participants. Each participant underwent 1.5-T MRI examinations. Pituitary gland heights (PGH), pituitary-R2 values, and liver-R2 values were measured by using multi-echo spin-echo sequences. Results Pituitary-R2 values were significantly higher in group A compared with group B ( P < 0.05). A positive correlation was detected between the pituitary-R2 values and serum ferritin levels in TM patients ( P < 0.01). A threshold value of 14.1 Hz for pituitary-R2 was found to give a high specificity and sensitivity in distinguishing the TM patients with HH from those with normal pituitary functions. PGH measurements were significantly lower in group A compared with group B ( P < 0.05). Conclusion MRI-assessed pituitary R2 seems to be a reliable marker for differentiating the TM patients with normal pituitary function from those with secondary hypogonadism due to iron toxicity. PMID- 28882061 TI - Feasibility of a home-based exercise intervention with remote guidance for patients with stable grade II and III gliomas: a pilot randomized controlled trial. AB - OBJECTIVE: In this pilot study, we investigated the feasibility of a home-based, remotely guided exercise intervention for patients with gliomas. DESIGN: Pilot randomized controlled trial (RCT) with randomization (2:1) to exercise or control group. SUBJECTS: Patients with stable grade II and III gliomas. INTERVENTION: The six-month intervention included three home-based exercise sessions per week at 60%-85% of maximum heart rate. Participants wore heart rate monitors connected to an online platform to record activities that were monitored weekly by the physiotherapist. MAIN MEASURES: Accrual, attrition, adherence, safety, satisfaction, patient-reported physical activity, VO2 peak (by maximal cardiopulmonary exercise testing) and body mass index (BMI) at baseline and at six-month follow-up. RESULTS: In all, 34 of 136 eligible patients (25%) were randomized to exercise training ( N = 23) or the control group ( N = 11), of whom 19 and 9, respectively, underwent follow-up. Mean adherence to prescribed sessions was 79%. Patients' experiences were positive. There were no adverse events. Compared to the control group, the exercise group showed larger improvements in absolute VO2 peak (+158.9 mL/min; 95% CI: -44.8 to 362.5) and BMI (-0.3 kg/m2; 95% CI: -0.9 to 0.2). The median increase in physical activity was 1489 metabolic equivalent of task (MET) minutes higher in the exercise group. The most reported reasons for non-participation were lack of motivation or time. CONCLUSION: This innovative and intensive home-based exercise intervention was feasible in a small subset of patients with stable gliomas who were interested in exercising. The observed effects suggest that the programme may improve cardiorespiratory fitness. These results support the need for large-scale trials of exercise interventions in brain tumour patients. PMID- 28882063 TI - Increased serum concentrations of NE-carboxymethyllysine are related to the presence and the severity of rheumatoid arthritis. AB - Background There are limited data regarding the contribution of advanced glycation end products in the presence of rheumatoid arthritis. We investigated whether serum NE-carboxymethyllysine and pentosidine were related to the presence and the severity of rheumatoid arthritis. Methods Eighty patients with rheumatoid arthritis and 30 control subjects were included in a cross-sectional study. The severity of rheumatoid arthritis was assessed using the disease activity score for 28 joints. Serum NE-carboxymethyllysine and pentosidine were measured by enzyme-linked immunosorbent assay. Results Serum NE-carboxymethyllysine and pentosidine concentrations were significantly higher in patients with rheumatoid arthritis vs. control subjects ( P < 0.001). Serum NE-carboxymethyllysine and pentosidine concentrations were significantly higher in rheumatoid arthritis patients with high disease activity vs. rheumatoid arthritis patients with moderate disease activity ( P < 0.001, P = 0.019, respectively). A multiple logistic regression analysis demonstrated that NE-carboxymethyllysine was independently associated with the presence of rheumatoid arthritis (OR = 1.21, 95% CI: 1.05-1.39, P = 0.006). Furthermore, in a multivariate stepwise regression analysis, NE-carboxymethyllysine was independently correlated with disease activity score for 28 joints (standardized beta = 0.43, P = 0.001). Conclusion Serum NE-carboxymethyllysine and pentosidine were increased during rheumatoid arthritis, and NE-carboxymethyllysine was independently associated with the presence and the severity of rheumatoid arthritis. PMID- 28882064 TI - Development of a novel fluorescent activity assay for lecithin:cholesterol acyltransferase. AB - Background Lecithin:cholesterol acyltransferase (LCAT) is a plasma enzyme that esterifies cholesterol. Recombinant human LCAT (rhLCAT) is now being developed as an enzyme replacement therapy for familial LCAT deficiency and as a possible treatment for acute coronary syndrome. The current 'gold standard' assay for LCAT activity involves the use of radioisotopes, thus making it difficult for routine clinical use. Methods We have developed a novel and more convenient LCAT activity assay using fluorescence-labelled cholesterol (BODIPY-cholesterol), which is incorporated into proteoliposomes as a substrate instead of radiolabelled cholesterol. Results The apparent Km and Vmax were 31.5 umol/L and 55.8 nmol/h/nmoL, rhLCAT, respectively, for the 3H-cholesterol method and 103.1 umol/L and 13.4 nmol/h/nmol rhLCAT, respectively, for the BODIPY-cholesterol method. Although the two assays differed in their absolute units of LCAT activity, there was a good correlation between the two test assays ( r = 0.849, P < 1.6 * 10-7, y = 0.1378x + 1.106). The BODIPY-cholesterol assay had an intra assay CV of 13.7%, which was superior to the intra-assay CV of 20.8% for the radioisotopic assay. The proteoliposome substrate made with BODIPY-cholesterol was stable to storage for at least 10 months. The reference range ( n = 20) for the fluorescent LCAT activity assay was 4.6-24.1 U/mL/h in healthy subjects. Conclusions In summary, a novel fluorescent LCAT activity assay that utilizes BODIPY-cholesterol as a substrate is described that yields comparable results to the radioisotopic method. PMID- 28882065 TI - Serum high-sensitive C-reactive protein is associated with dietary intakes in diabetic patients with and without hypertension: a cross-sectional study. AB - Background Serum high-sensitive C-reactive protein (hs-CRP) concentrations independently predict the development of diabetes, metabolic syndrome and cardiovascular disease. However, the impact of dietary factors on serum high sensitive C-reactive protein concentrations in diabetic patients has received limited attention. We aimed to investigate the association between dietary factors and high-sensitive C-reactive protein , among diabetic patients with and without hypertension and healthy subjects. Methods In this cross-sectional study, diabetics with ( n = 325) and without hypertension ( n = 599) and healthy individuals ( n = 1220) were recruited in Mashhad, Iran. Dietary intake was assessed by 24-h recall. Biochemical parameters including serum high-sensitive C reactive protein were measured using standard protocols. Stepwise multiple regression analysis was used to predict whether serum high-sensitive C-reactive protein concentration was associated with dietary constituents. Results High sensitive C-reactive protein was significantly higher among hypertensive and non hypertensive diabetic patients compared with healthy subjects ( P < 0.001). The dietary intake of zinc + 6.4% and calcium -3.4% and body mass index +3.9% explained approximately 13.7% of the variation in serum high-sensitive C-reactive protein among diabetic hypertensive patients. Approximately 9.7% of the variation in serum high-sensitive C-reactive protein in diabetic non-hypertensive patients could be explained by body mass index, and intake of sodium, iron and cholesterol. In the healthy subjects, approximately 4.4% of the total variation in serum high-sensitive C-reactive protein concentration could be explained by cholesterol consumption and waist circumference. Conclusion Serum high-sensitive C-reactive protein concentrations were found to be a significant predictor for hypertensive and non-hypertensive diabetic subjects. There was a significant association between dietary factors include zinc, iron, sodium and cholesterol and serum high-sensitive C-reactive protein, while there was an inverse association between dietary calcium and serum high-sensitive C-reactive protein in diabetic hypertensive individuals. PMID- 28882062 TI - Remodeling of Sensorimotor Brain Connectivity in Gpr88-Deficient Mice. AB - Recent studies have demonstrated that orchestrated gene activity and expression support synchronous activity of brain networks. However, there is a paucity of information on the consequences of single gene function on overall brain functional organization and connectivity and how this translates at the behavioral level. In this study, we combined mouse mutagenesis with functional and structural magnetic resonance imaging (MRI) to determine whether targeted inactivation of a single gene would modify whole-brain connectivity in live animals. The targeted gene encodes GPR88 (G protein-coupled receptor 88), an orphan G protein-coupled receptor enriched in the striatum and previously linked to behavioral traits relevant to neuropsychiatric disorders. Connectivity analysis of Gpr88-deficient mice revealed extensive remodeling of intracortical and cortico-subcortical networks. Most prominent modifications were observed at the level of retrosplenial cortex connectivity, central to the default mode network (DMN) whose alteration is considered a hallmark of many psychiatric conditions. Next, somatosensory and motor cortical networks were most affected. These modifications directly relate to sensorimotor gating deficiency reported in mutant animals and also likely underlie their hyperactivity phenotype. Finally, we identified alterations within hippocampal and dorsal striatum functional connectivity, most relevant to a specific learning deficit that we previously reported in Gpr88-/- animals. In addition, amygdala connectivity with cortex and striatum was weakened, perhaps underlying the risk-taking behavior of these animals. This is the first evidence demonstrating that GPR88 activity shapes the mouse brain functional and structural connectome. The concordance between connectivity alterations and behavior deficits observed in Gpr88-deficient mice suggests a role for GPR88 in brain communication. PMID- 28882066 TI - Programmatic Moderators of CBT Correctional Treatment for Whites and African Americans. AB - A recent experimental evaluation of a cognitive behavioral intervention ( Reasoning and Rehabilitation) reported significantly greater reductions in recidivism for White male parolees than African American male parolees. These results prompted the present examination of whether specific program conditions may have differentially impacted program outcomes (returns to prison) for White ( n = 141) and African American ( n = 318) participants. Study participants were tracked for up to 33 months on parole. Discrete-time event history analysis tested for race interactions with the following program attributes: facilitator gender, facilitator race, number of facilitators, class size, and the facilitators' evaluations of parolee participation on measures pertaining to level of participation, enjoyment, understanding, atmosphere and use of skills in the program. The gender of the facilitator, the number of facilitators, and sizes of the classes differentially affected success rates for African Americans compared with Whites. African American participants achieved more favorable outcomes with female facilitators than male facilitators, and when class sizes and the number of facilitators conformed to program guidelines. No statistically significant interaction effects were found for race of the facilitator, or facilitator evaluations of parolee participation. PMID- 28882068 TI - Self-esteem and hope mediate the relations between social support and post traumatic stress disorder and growth in adolescents following the Ya'an earthquake. AB - BACKGROUND AND OBJECTIVE: Although posttraumatic stress disorders (PTSD) and posttraumatic growth (PTG) can co-exist, and several theories suggest that social support, self-esteem, and hope can predict both PTSD and PTG, no study to date has examined the combined role of social support, self-esteem, and hope in PTSD and PTG. The present study aimed to simultaneously examine the mediating roles of self-esteem and hope in the relations between social support and PTSD, and between social support and PTG. DESIGN: This study included 397 adolescents living in Lushan County, China, who were affected by the Ya'an earthquake. METHOD: The participants completed the self-report questionnaires at two and a half years after the earthquake. Structural equation models were built to examine the roles of social support, self-esteem, and hope in PTSD and PTG. RESULTS: Social support directly and negatively predicted PTSD and positively predicted PTG. Moreover, social support negatively predicted PTSD via self-esteem, and positively predicted PTG via hope. In addition, social support positively predicted PTG through multiple mediating paths from self-esteem to hope. CONCLUSIONS: PTSD and PTG had different predictive paths. Specifically, social support reduced PTSD through enhanced self-esteem and promoted PTG through hope, or through the path from self-esteem to hope. PMID- 28882069 TI - ORCID Identifiers: Personalized Authorship. PMID- 28882070 TI - Isolation of a larvicidal compound from Piper solmsianum C.DC. (Piperaceae). AB - The Aedes aegypti mosquito is one of the major vectors of arboviruses. These diseases have re-emerged and the insecticides used nowadays are toxic to mammals and environment and have only been effective in the short-term. In this context, natural products are an alternative. The genus Piper has many active compounds against arthropods, including neolignans. The present study evaluated the larvicidal potential of the n-hexanic extract of Piper solmsianum and eupomatenoid-6, identified by GC-MS and NMR techniques, from this extract against Ae. aegypti. The crude extract (100 MUg/mL) killed 80% and 98.3% of larvae in the first and third day, respectively. Eupomatenoid-6 exhibited LD50 of 19.33 MUM and LD90 of 28.68 MUM and was then assayed in human fibroblast cells (MRC5), showing an IC50 of 39.30 MUM with estimated LD50 of 42.26 mmol/kg. Our results indicate eupomatenoid-6 as a potent insecticide with relatively low toxicity for mammals. PMID- 28882071 TI - "Wearing My Spiritual Jacket": The Role of Spirituality as a Coping Mechanism Among African American Youth. AB - There is growing evidence in the theoretical literature regarding the importance of religion and religiosity in people's lives, particularly concerning their health and well-being. Spirituality, a related but different concept, has been less well studied, especially empirically, but shows promise as a mechanism for coping with deleterious social and health circumstances. This article details a qualitative exploration of the role of spiritual coping in the lives of urban African American youth. Data were gathered through in-depth, semistructured interviews with 20 African American youth, ages 12 to 20 years. The findings indicate that urban African American youth have multifaceted dimensions of their spirituality, including the role of prayer in their lives, an unwavering faith in a higher power, and the importance of giving back to their communities. Such findings offer counterstories, generated through ethnographic research, to the dominant discourses regarding urban African American youth. Ultimately, this study's findings have implications for research and practice related to the mechanisms of both ill-health and wellness among youth. PMID- 28882072 TI - Women's experiences of exercise as a treatment for their postnatal depression: A nested qualitative study. AB - Women with postnatal depression are often reluctant to take medication postnatally and access to psychological therapies is limited. Exercise offers a freely available treatment option but depressed mothers' experience of exercise has not been investigated. We conducted a qualitative study nested within a randomised trial of an exercise intervention for women with postnatal depression. Women described deterioration in their sense of identity postnatally and through experiencing depression and described the positive impact exercise had on their sense of self. Views of exercise as treatment for postnatal depression ranged from doubts about its practicality to positive comparisons with other traditional treatments and to improved recovery. PMID- 28882073 TI - Qualitative Research Methods to Advance Research on Health Inequities Among Previously Incarcerated Women Living With HIV in Alabama. AB - Justice-involved HIV-positive women have poor health outcomes that constitute health inequities. Researchers have yet to embrace the range of qualitative methods to elucidate how psychosocial histories are connected to pathways of vulnerability to HIV and incarceration for this key population. We used life course narratives and intersubjectivity-predicated on interview dialogue-to investigate how familial and social settings established their social patterning of HIV, incarceration risk, and poor health. Working with two Alabama community based organizations, we recruited and interviewed 24 HIV-positive cisgender women with cyclical incarceration. We analyzed the data by charting women's life histories and conducting iterative content analyses. Participants described chaotic home environments, marked by exposure to trauma in childhood. The majority experienced repeated sexual and physical abuse that went undiagnosed and untreated until adulthood. Adolescence and young adulthood were characterized by onset of substance use, violent intimate partnerships, and subsequent behavioral and mental health problems. In adulthood, risk behaviors persisted for decades and women lacked mental health treatment and social support. Life course narratives and intersubjectivity contributed to knowledge by affording agency to marginalized participants to reflect on and narrate their life stories; instilling needed trust for researchers to investigate the complex risk pathways and psychosocial histories with this population; illuminating the nature, timing, sequence, and frequency of events underlying women's vulnerability and exposure to HIV and incarceration; and clarifying that early shaping events in childhood are connected to later risk environments and behaviors in adolescence and adulthood, suggesting the need for earlier interventions than are typically proposed. PMID- 28882074 TI - Body appreciation, anxiety, and depression among a racially diverse sample of women. AB - This study aims to explore correlates between body appreciation and mental health among a racially and ethnically diverse sample of adult women using validated measures. The sample included racially and ethnically diverse women ( N = 497) from various socioeconomic levels. Linear regression results indicated that body appreciation was significantly and inversely associated with depression ( b = 3.68; p < 0.001). In this sample, as body appreciation increased, depression scores decreased. Similarly, body appreciation was significantly and inversely associated with anxiety among this sample ( b = -1.78; p < 0.001). This article concludes with a discussion of findings and implications. PMID- 28882067 TI - Differentiating Immune Cell Targets in Gut-Associated Lymphoid Tissue for HIV Cure. AB - The single greatest challenge to an HIV cure is the persistence of latently infected cells containing inducible, replication-competent proviral genomes, which constitute only a small fraction of total or infected cells in the body. Although resting CD4+ T cells in the blood are a well-known source of viral rebound, more than 90% of the body's lymphocytes reside elsewhere. Many are in gut tissue, where HIV DNA levels per million CD4+ T cells are considerably higher than in the blood. Despite the significant contribution of gut tissue to viral replication and persistence, little is known about the cell types that support persistence of HIV in the gut; importantly, T cells in the gut have phenotypic, functional, and survival properties that are distinct from T cells in other tissues. The mechanisms by which latency is established and maintained will likely depend on the location and cytokine milieu surrounding the latently infected cells in each compartment. Therefore, successful HIV cure strategies require identification and characterization of the exact cell types that support viral persistence, particularly in the gut. In this review, we describe the seeding of the latent HIV reservoir in the gut mucosa; highlight the evidence for compartmentalization and depletion of T cells; summarize the immunologic consequences of HIV infection within the gut milieu; propose how the damaged gut environment may promote the latent HIV reservoir; and explore several immune cell targets in the gut and their place on the path toward HIV cure. PMID- 28882075 TI - Comparative treatment-related adverse event cost burden in immune thrombocytopenic purpura. AB - AIMS: Real-world evidence on the safety profile and costs associated with immune thrombocytopenic purpura (ITP) treatment in adults is lacking. This study quantifies and compares adverse event (AE) crude rates and costs associated with ITP treatments as found in claims data. MATERIALS AND METHODS: A retrospective claims-based analysis was conducted using IMS Pharmetrics Plus database. Included patients were >=18 years old, with a diagnosis of ITP (2007-2012); an ITP-related claim for anti-D, intravenous immunoglobulin (IVIG), rituximab, romiplostim, or eltrombopag; and 1-year continuous enrollment (3-years for rituximab) during follow-up. AEs and event costs were identified during active treatment, defined from the first claim of each drug to a pre-defined treatment gap or end of study period. Descriptive statistics were reported with Wilcoxon rank-sum significance tests. RESULTS: A total of 2,518 patients were identified (mean age = 50.8 (+/ 16.3 years); 55.8% male). Of all patients, 22.8% experienced any AE. Significantly fewer anti-D patients had any AE (13.8% vs IVIG: 21.1%, rituximab: 29.4%, romiplostim: 28.1%, eltrombopag: 22.4%). Nausea/vomiting and arthralgia/musculoskeletal pain were most common across treatments, and hemolytic events did not differ significantly across treatments. Most costly AEs were urinary tract infection, aseptic meningitis, and fever ($5000+/case); headache, nasal congestion, and hemolytic event were $4,000-5,000/case. Cost per AE did not differ by treatment. LIMITATIONS AND CONCLUSIONS: Although lower than trial-based AE rates, claims for ITP treatment-related AEs are common, with higher numbers for rituximab and lower numbers for anti-D. This disparity suggests a possible differential cost burden overall that future analysis should explore. PMID- 28882076 TI - Assessing Health Promotion Interventions: Limitations of Traditional Research Methods in Community-Based Studies. AB - Most low-income Americans fail to meet physical activity recommendations. Inactivity and poor diet contribute to obesity, a risk factor for multiple chronic diseases. Health promotion activities have the potential to improve health outcomes for low-income populations. Measuring the effectiveness of these activities, however, can be challenging in community settings. A "Biking for Health" study tested the impact of a bicycling intervention on overweight or obese low-income Latino and African American adults to reduce barriers to cycling and increase physical activity and fitness. A randomized controlled trial was conducted in Milwaukee, Wisconsin, in summer 2015. A 12-week bicycling intervention was implemented at two sites with low-income, overweight, or obese Latino and African American adults. We found that randomized controlled trial methodology was suboptimal for use in this small pilot study and that it negatively affected participation. More discussion is needed about the effectiveness of using traditional research methods in community settings to assess the effectiveness of health promotion interventions. Modifications or alternative methods may yield better results. The aim of this article is to discuss the effectiveness and feasibility of using traditional research methods to assess health promotion interventions in community-based settings. PMID- 28882077 TI - Review: the potential impact of surface crystalline states of titanium for biomedical applications. AB - In many biomedical applications, titanium forms an interface with tissues, which is crucial to ensure its long-term stability and safety. In order to exert control over this process, titanium implants have been treated with various methods that induce physicochemical changes at nano and microscales. In the past 20 years, most of the studies have been conducted to see the effect of topographical and physicochemical changes of titanium surface after surface treatments on cells behavior and bacteria adhesion. In this review, we will first briefly present some of these surface treatments either chemical or physical and we explain the biological responses to titanium with a specific focus on adverse immune reactions. More recently, a new trend has emerged in titanium surface science with a focus on the crystalline phase of titanium dioxide and the associated biological responses. In these recent studies, rutile and anatase are the major two polymorphs used for biomedical applications. In the second part of this review, we consider this emerging topic of the control of the crystalline phase of titanium and discuss its potential biological impacts. More in-depth analysis of treatment-related surface crystalline changes can significantly improve the control over titanium/host tissue interface and can result in considerable decreases in implant-related complications, which is currently a big burden on the healthcare system. PMID- 28882078 TI - Detection of fetal duplication 16p11.2q12.1 by next-generation sequencing of maternal plasma and invasive diagnosis. AB - OBJECTIVE: The objective of study is to report the feasibility of non-invasive prenatal screening (NIPS) combined with invasive detection by chromosomal analysis in identifying fetal duplication, providing clinical performance of NIPS on copy number variations (CNVs) detection. MATERIAL AND METHODS: NIPS was offered to a 35-year-old pregnant woman. Amniocentesis was performed to confirm the positive screening result. Fetal sample was detected by karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray (CMA). Parental karyotyping was also conducted. RESULTS: NIPS result was positive for chromosome 16, indicating an extra copy of chromosome 16. FISH and chromosomal karyotyping revealed that the fetus had a marker chromosome derived from chromosome 16. CMA further demonstrated an approximately 19-Mb duplication in chromosome 16. The final fetal karyotype was 47,XY,+mar. ish der (16)(D16Z3+).arr 16p11.2q12.1 (30 624 186-49 696 337 * 3). Ultrasound scan and MRI showed some structure malformations. CONCLUSIONS: A protocol for CNVs detection by combining a series of genetic methods was presented in this study and a novel marker duplication 16p11.2q12.1 was reported. With the ability to identify subchromosomal deletions and duplications in fetus, NIPS could reduce the possibility of invasive diagnosis. The followed confirmation test for positive sample is necessary and ensures the accuracy of the diagnosis. PMID- 28882079 TI - Using Qualitative Methods to Understand Perceptions of Risk and Condom Use in African American College Women: Implications for Sexual Health Promotion. AB - BACKGROUND: Young African American women are disproportionately affected with sexually transmitted infections (STIs) and unintentional pregnancies. Despite adequate knowledge, assertiveness, and negotiation skills, consistent condom use remains low. AIMS: We sought to assess the role of pregnancy and STI risk perception in condom decision making among African American women. METHOD: We conducted a phenomenological qualitative study. Utilizing a purposive sampling strategy, 100 African American women (18-24 years) were recruited from a historically Black college and university for an open discussion of condom use. Thirteen focus groups were conducted via a semistructured interview guide and analyzed with an inductive thematic approach. RESULTS: Uniformly women perceived pregnancy as a greater threat than STIs which appears to be maintained by (a) their sense of fertility, (b) self-care concept, and (c) experiences with condom failure. Thus, women were skeptical about using condoms as a form of contraception. Women perceived casual sex as having the greatest HIV/STI risk and emphasized the importance of assertiveness and self-respect to negotiate condom use. However, condom use in monogamous relationships is less likely due to (a) testing/knowing partner's status, (b) relationship trust, and (c) the use of hormonal contraception for pregnancy prevention. Perceived threat of infidelity increases condom use. CONCLUSION: The implications of these findings suggest sexual health promotion programs may focus on improving women's estimate of the effectiveness of condoms to prevent pregnancy and addressing women's reliance on testing for STI prevention. PMID- 28882080 TI - Use of the Nellix Endovascular Aneurysm Sealing System in Combination With Parallel Grafts for the Treatment of a Symptomatic Type V Thoracoabdominal Aortic Aneurysm. AB - PURPOSE: To report endovascular treatment of a symptomatic type V thoracoabdominal aortic aneurysm (TAAA) using the combined techniques of endovascular aneurysm sealing and parallel stent-grafts. CASE REPORT: A 70-year old man was referred with a symptomatic type V TAAA. The Nellix EndoVascular Aneurysm Sealing (EVAS) System was used in combination with 2 chimney grafts for the celiac artery (CA) and the superior mesenteric artery (SMA); one periscope graft perfused the right renal artery. Completion angiography showed exclusion of the aneurysm and patency of all 3 parallel grafts but occlusion of the left renal artery (LRA) due to unintentional coverage of its ostium by the Nellix endobags. Antegrade catheterization of the LRA failed, requiring implantation of an aortorenal vein bypass. The postoperative course was complicated by acute kidney injury. Imaging at 6 months showed sustained exclusion of the aneurysm, patency of the CA and SMA parallel grafts and left aortorenal bypass but occlusion of the right renal artery periscope graft. Serum creatinine at 6 months was 1.5 mg/dL. CONCLUSION: The combination of EVAS with parallel grafts for preservation of the visceral vessels may be a feasible technique to treat selected TAAAs in the acute setting when other options are not applicable. PMID- 28882081 TI - Assessment of time management skills: psychometric properties of the Swedish version. AB - BACKGROUND: Persons with impaired time management skills are often in need of occupational therapy. Valid and reliable instruments to assess time management and organizational skills are needed for the evaluation of intervention. The purpose of this study was to evaluate the psychometric properties of a Swedish version of the Assessment of Time Management Skills (ATMS-S) for persons with and without impaired time management skills. METHOD: A total of 238 persons participated in the study, of whom 94 had self-reported impaired time management skills due to mental disorders such as schizophrenic spectrum or neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and mild intellectual disabilities, and 144 persons had no reported impaired time management skills. Rasch analysis was used to analyze data. RESULTS: Three subscales were detected: the time management subscale with 11 items, the organization & planning subscale with 11 items, and the subscale of regulation of emotions with 5 items, with excellent to acceptable psychometric properties. The conclusions were that: ATMS-S is a valid instrument for self-rating of time management, organization & planning and for the regulation of emotions. ATMS-S can be useful for persons with mental disorders including mild neurodevelopmental disorders. PMID- 28882082 TI - Changes in hepatic phase I and phase II biotransformation enzyme expression and glutathione levels following atrazine exposure in female rats. AB - 1. To determine the effects of repeated atrazine (ATR) treatment on hepatic phase I and II enzymes, adult female rats were treated with vehicle or 100 mg/kg of ATR for 1, 2, 3 or 4 days. Glutathione-s-transferases (GST) mRNA expression, protein levels (mu, pi, alpha, omega), and activity (cytosolic and microsomal), along with bioavailable glutathione (GSH) were assayed. 2. GST expression, concentrations and activity were increased, along with GSH levels, in animals treated with ATR for 3 and 4 days. 3. A subsequent study was performed with animals treated with vehicle, 6.5, 50 or 100 mg/kg/day for 4, 8 or 14 days. Expression of hepatic phase I CYP 450 enzymes was evaluated in conjugation with GST expression, protein and activity. Nineteen of the 45 CYP enzymes assayed displayed increased mRNA levels after eight days of treatment in animals treated with 50 or 100 mg/kg/day. After 14 days of treatment, all CYP expression levels returned to control levels except for CYP2B2, CYP2B3, CYP2C7, CYP2C23, CYP2E1, CYP3A9, CYP4A3 and CYP27A1, which remained elevated. 4. Results indicate that there may be a habituation or adaptation of liver phase I and phase II expression following repeated ATR treatment. PMID- 28882083 TI - Regulation of MAPK signaling and implications in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is a heterogeneous B cell malignancy that still remains incurable. Recent studies have highlighted cellular and non cellular components of the tissue microenvironment in CLL that help nurture the growth of leukemic cells by providing the necessary stimuli for their proliferation and survival. The diverse stimuli in the specialized tissue microenvironment of CLL lead to constitutive activation of several signaling pathways that includes B cell receptor signaling and the associated mitogen activated protein kinase (MAPK) signaling. Recent findings have described aberrant activation of MAPK signaling and its interactions with other cellular signaling pathways in the pathogenesis of CLL. These studies have shed light on the deregulated molecular mechanisms contributing to hyperactivation of MAPK signaling and provided avenues for therapeutic options for aggressive CLL. In this review, we describe and discuss the current status of our understanding into the role of MAPK signaling in the pathogenesis of CLL. PMID- 28882084 TI - Genomic characterization of chromosome translocations in patients with T/myeloid mixed-phenotype acute leukemia. AB - Mixed-phenotype acute leukemia (MPAL) is a progenitor type of leukemia with ambiguous expression of lineage markers. The diagnosis of MPAL is based on flow cytometric analysis of immunophenotype, which commonly identifies myeloid lineage markers as well as B- or T- lymphoid lineage markers on leukemic blasts. Due to the rare occurrence of this disease, few studies have delineated the molecular bases of MPAL. Combining conventional karyotyping with whole genomic sequencing (WGS) and RNA sequencing (RNA-seq), we report here our identification and characterization of chromosome translocations, gene mutations and gene expression profile in four patients with T/Myeloid MPAL, including two t(6;14)(q25;q32) one t(8;14)(q24.2;q32) and one t(7;8)(p14;q24.2). Notably, seven of the eight translocation breakpoints reside in the non-coding regions and their locations appear to be shared by two or more patients. Gene expression analysis of matched diagnostic vs. remission samples provided evidence of transcriptomes alteration involving nucleosome organization and chromatin assembly. PMID- 28882085 TI - Psychotherapeutic and vocational interventions among young adults with work disability due to mental disorders in Finland. AB - : Backround: Little is known about treatment and rehabilitation received and planned among young adults with work disability due to a mental disorder. AIMS: To examine the implemented psychotherapeutic and vocational interventions and treatment plans among young adults with work disability due to a mental disorder. MATERIAL AND METHODS: Data were collected from medical records of young Finnish adults aged 18-34 with a long-term work disability history due to a mental disorder (N = 1163). The participant characteristics associated with four types of interventions were analyzed using log-binomial regression analysis. RESULTS: In total, 34% had participated in a psychotherapeutic intervention. Of the non students, 26% had participated in vocational intervention. For 46% of the non students, neither type of intervention was planned. Both implemented and planned psychotherapeutic interventions were associated with female sex, high education, attachment to employment, and absence of substance abuse. Low education and childhood adversity were associated with implemented vocational interventions and absence of substance abuse with planned vocational interventions. CONCLUSION AND SIGNIFICANCE: There is an unmet need for psychotherapeutic interventions among men, among those with lower socio-economic status, and among those with poor attachment to labor market. In addition, there is a lack of vocational interventions for those with high education. People with substance abuse are largely excluded from both types of interventions. PMID- 28882087 TI - Racial/Ethnic Disparities in Quality of Care for Cardiovascular Disease in Ambulatory Settings: A Review. AB - Racial and ethnic disparities in cardiovascular disease (CVD) outcomes are widely reported, but research has largely focused on differences in quality of inpatient and urgent care to explain these disparate outcomes. The objective of this review is to synthesize recent evidence on racial and ethnic disparities in management of CVD in the ambulatory setting. Database searches yielded 550 articles of which 25 studies met the inclusion criteria. Reviewed studies were categorized into non interventional studies examining the association between race and receipt of ambulatory CVD services with observational designs, and interventional studies evaluating specific clinical courses of action intended to ameliorate disparities. Based on the Donabedian framework, this review demonstrates that significant racial/ethnic disparities persist in process and outcome measures of quality of ambulatory CVD care. Multimodal interventions were most effective in reducing disparities in CVD outcomes. PMID- 28882086 TI - Improving gold nanorod delivery to the central nervous system by conjugation to the shuttle Angiopep-2. AB - AIM: To improve the in vivo delivery of gold nanorods (GNRs) to the central nervous system of rats, these gold nanoparticles were conjugated to Angiopep-2, a shuttle peptide that can cross the blood-brain barrier. MATERIALS & METHODS: GNRs were synthesized and modified using polyethylene glycol and Angiopep-2 (GNR-PEG Angiopep-2). The physicochemical properties, in vitro cytotoxicity and ex vivo biodistribution of the conjugate were examined. RESULTS: GNR-PEG-Angiopep-2 was stable over the following days, and the different concentrations that were tested did not affect the viability of microvascular endothelial cells. The conjugation of Angiopep-2 to GNRs enhanced the endocytosis of these particles (in vitro) and the accumulation in brains (in vivo), when compared with GNRs modified only with PEG. CONCLUSION: This study provides evidence that Angiopep-2 improves the delivery of GNRs to the brain parenchyma. This property is highly relevant for future applications of GNRs as platforms for photothermal and theranostic purposes. PMID- 28882088 TI - Slc7a11 (xCT) protein expression is not altered in the depressed brain and system xc- deficiency does not affect depression-associated behaviour in the corticosterone mouse model. AB - OBJECTIVES: The cystine/glutamate antiporter (system xc-) is believed to contribute to nonvesicular glutamate release from glial cells in various brain areas. Although recent investigations implicate system xc- in mood disorders, unambiguous evidence has not yet been established. Therefore, we evaluated the possible role of system xc- in the depressive state. METHODS: We conducted a protein expression analysis of the specific subunit of system xc- (xCT) in brain regions of the corticosterone mouse model, Flinders Sensitive Line rat model and post-mortem tissue of depressed patients. We next subjected system xc- deficient mice to the corticosterone model and analysed their behaviour in several tests. Lastly, we subjected additional cohorts of xCT-deficient and wild-type mice to N acetylcysteine treatment to unveil whether the previously reported antidepressant like effects are dependent upon system xc-. RESULTS: We did not detect any changes in xCT expression levels in the animal models or patients compared to proper controls. Furthermore, loss of system xc- had no effect on depression- and anxiety-like behaviour. Finally, the antidepressant-like effects of N acetylcysteine are not mediated via system xc-. CONCLUSIONS: xCT protein expression is not altered in the depressed brain and system xc- deficiency does not affect depression-associated behaviour in the corticosterone mouse model. PMID- 28882089 TI - The Default Mode Network as a Biomarker of Persistent Complaints after Mild Traumatic Brain Injury: A Longitudinal Functional Magnetic Resonance Imaging Study. AB - The objective of this study was to examine longitudinal functional connectivity of resting-state networks in patients with and without complaints after uncomplicated mild traumatic brain injury (mTBI). Second, we aimed to determine the value of network connectivity in predicting persistent complaints, anxiety, depression and long-term outcome. Thirty mTBI patients with three or more post traumatic complaints at 2 weeks post-injury, 19 without complaints, and 20 matched healthy controls were selected for this study. Resting-state functional MRI (fMRI) was performed in patients at 1 month and 3 months post-injury, and once in healthy controls. Independent component analysis (ICA) was used to investigate the default mode, executive and salience networks. Persistent post traumatic complaints, anxiety, and depression were measured at 3 months post injury, and outcome was determined at 1 year post-injury. Within the group with complaints, higher functional connectivity between the anterior and posterior components of the default mode network at 1 month post-injury was associated with a greater number of complaints at 3 months post-injury (rho = 0.59, p = 0.001). Minor longitudinal changes in functional connectivity were found for patients with and without complaints after mTBI, which were limited to connectivity within the precuneus component of the default mode network. No significant results were found for the executive and salience networks. Current results suggest that the default mode network may serve as a biomarker of persistent complaints in patients with uncomplicated mTBI. PMID- 28882090 TI - Stenosis length of middle cerebral artery and branch atheromatous disease associated infarct. AB - BACKGROUND: We analyzed the relationship between the characteristics of branch atheromatous disease associated infarct (BAI) and stenosis length (SL) of relevant middle cerebral artery (MCA) M1 segment. METHODS: Ninety-five patients with BAI were recruited from 1024 consecutive acute ischemic stroke patients. Among them, 59 patients (62.11%) had concurrent relative stenosis of MCA M1 segment. The neurologic deficit severity at admission was assessed by National Institutes of Health Stroke Scale (NIHSS) and the infarct size by infarct lesion thickness and maximum diameter. The SL and the distance from the carotid terminal segment to stenosis (DT) were measured on coronary projection on 3D TOF MRA. The correlations between SL and NIHSS, SL and infarct lesion maximum diameter were analyzed. RESULTS: There was no difference between BAI patients with or without M1 stenosis in image markers for infarct etiological subtype. SL was significant difference in patients with NIHSS >3 vs. <= 3 (p = 0.032) at admission. Further analysis showed that SL correlated with NIHSS at admission (rs = 0.613, p = 0.000) and maximum diameter (rs = 0.621, p = 0.000) significantly. CONCLUSION: SL is a significant moderate predictor for infarct lesion diameter and neurologic deficit severity. PMID- 28882091 TI - Measles Lymphadenopathy in a Child With PFAPA Syndrome. AB - Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a common cause of periodic fever in children. The pathogenesis of PFAPA is unknown but likely involves immune system dysregulation and may be initiated by an environmental trigger. Tonsillectomy resolves or improves symptoms in some patients, but the reason for this is unknown; moreover, specific abnormalities in tonsillectomy specimens from PFAPA patients have not been described. Here, we report measles virus in tonsil from a child with PFAPA. Measles-type viral cytopathic effect was discovered on histological examination of tonsillar tissue after therapeutic tonsillectomy for PFAPA. Molecular testing showed the left tonsil was positive for measles RNA by reverse transcription polymerase chain reaction (RT-PCR) while the right tonsil was inconclusive (weakly positive). Real-time RT-PCR specific for measles vaccine strain RNA (genotype A) was weakly reactive in the left tonsil tissue when tested in 3 independent replicates, but this result could not be confirmed with conventional genotyping by sequencing. The relationship and clinical significance between measles virus and PFAPA in this case is unclear but may be related to PFAPA associated immune dysregulation. Additional investigation of measles virus in PFAPA patients would be helpful in further exploring this potential association. PMID- 28882092 TI - Bayesian sensitivity analysis for unmeasured confounding in causal mediation analysis. AB - Causal mediation analysis techniques enable investigators to examine whether the effect of the exposure on an outcome is mediated by some intermediate variable. Motivated by a data example from epidemiology, we consider estimation of natural direct and indirect effects on a survival outcome. An important concern is bias from confounders that may be unmeasured. Estimating natural direct and indirect effects requires an elaborate series of assumptions in order to identify the target quantities. The analyst must carefully measure and adjust for important predictors of the exposure, mediator and outcome. Omitting important confounders may bias the results in a way that is difficult to predict. In recent years, several methods have been proposed to explore sensitivity to unmeasured confounding in mediation analysis. However, many of these methods limit complexity by relying on a handful of sensitivity parameters that are difficult to interpret, or alternatively, by assuming that specific patterns of unmeasured confounding are absent. Instead, we propose a simple Bayesian sensitivity analysis technique that is indexed by four bias parameters. Our method has the unique advantage that it is able to simultaneously assess unmeasured confounding in the mediator-outcome, exposure-outcome and exposure-mediator relationships. It is a natural Bayesian extension of the sensitivity analysis methodologies of VanderWeele, which have been widely used in the epidemiology literature. We present simulation findings, and additionally, we illustrate the method in an epidemiological study of mortality rates in criminal offenders from British Columbia. PMID- 28882093 TI - Sample size considerations for n-of-1 trials. AB - N-of-1 trials are trials in which patients are treated with two or more treatments on multiple occasions. They can have many different purposes and can be analysed in different frameworks. In this note, five different criteria for planning sample sizes for n-of-1 trials are identified, and formulae and advice to address the associated tasks are provided. The basic design addressed is that of randomisation to treatment and control within cycles of pairs of episodes and the model assumed is that of a Normal-Normal mixture with variance components corresponding to within-cycle within-patient variation and treatment-by-patient interaction. The code to accomplish the tasks has been written in GenStat(r), SAS(r) and R(r) and the application of the approaches is illustrated. PMID- 28882094 TI - Competing risks modeling of cumulative effects of time-varying drug exposures. AB - An accurate assessment of drug safety or effectiveness in pharmaco-epidemiology requires defining an etiologically correct time-varying exposure model, which specifies how previous drug use affects the hazard of the event of interest. An additional challenge is to account for the multitude of mutually exclusive events that may be associated with the use of a given drug. To simultaneously address both challenges, we develop, and validate in simulations, a new approach that combines flexible modeling of the cumulative effects of time-varying exposures with competing risks methodology to separate the effects of the same drug exposure on different outcomes. To account for the dosage, duration and timing of past exposures, we rely on a spline-based weighted cumulative exposure modeling. We also propose likelihood ratio tests to test if the cumulative effects of past exposure on the hazards of the competing events are the same or different. Simulation results indicate that the estimated event-specific weight functions are reasonably accurate, and that the proposed tests have acceptable type I error rate and power. In real-life application, the proposed method indicated that recent use of antihypertensive drugs may reduce the risk of stroke but has no effect on the hazard of coronary heart disease events. PMID- 28882095 TI - Intra-demographic birth risk assessment scheme and infant mortality in Nigeria. AB - BACKGROUND: Infant mortality (IM) is high in Nigeria. High-risk birth can limit a newborn's survival chances to the first year of life. The approach used in investigating the relationship between high-risk birth and IM in this study is yet to be documented in Nigeria. OBJECTIVES: The Intra-Demographic Birth Risk Assessment Scheme (IDBRAS) was generated and its relationship with IM was examined. METHODS: 2013 Nigeria demographic and health survey data were used. Mothers who gave birth in the 5 years before the survey were investigated (n = 31,155). IDBRAS was generated from information on maternal age at childbirth, parity and preceding birth interval and was disaggregated into low, medium and high. Data were analysed using the Cox proportional hazard and Brass 1-parameter models (alpha = 0.05). RESULTS: Infant mortality rate was 88.4, 104.7 and 211.6 per 1000 live births among women with low, medium and high level of IDBRAS respectively. The rate of increase of reported infant deaths between low and high IDBRAS was 0.1932 (R2 = 0.5326; p < 0.001). The prevalence of medium- and high risk birth was 24.6 and 4.2% respectively. The identified predictors of IM were place of residence, marital status and size of the child at birth. The hazard ratio of IM was higher among women with medium (HR = 1.35; 95% CI = 1.22-1.48, p < 0.001) and high IDBRAS (HR = 1.73; 95% CI = 1.48-2.02, p < 0.001) than among those with low IDBRAS. Controlling for other correlates barely changed this pattern. CONCLUSIONS: The risk and level of IM increased as the level of IDBRAS increases in Nigeria. IDBRAS was an important predictor of IM. Maintaining a low level of IDBRAS will facilitate a reduction in IM rate in Nigeria. PMID- 28882096 TI - Delivering perinatal depression care in a rural obstetric setting: a mixed methods study of feasibility, acceptability and effectiveness. AB - OBJECTIVES: Universal screening for depression during pregnancy and postpartum is recommended, yet mental health treatment and follow-up rates among screen positive women in rural settings are low. We studied the feasibility, acceptability and effectiveness of perinatal depression treatment integrated into a rural obstetric setting. METHODS: We conducted an open treatment study of a screening and intervention program modified from the Depression Attention for Women Now (DAWN) Collaborative Care model in a rural obstetric clinic. Depression screen-positive pregnant and postpartum women received problem-solving therapy (PST) with or without antidepressants. A care manager coordinated communication between patient, obstetrician and psychiatric consultant. We measured change in the Patient Health Questionnaire 9 (PHQ-9) score. We used surveys and focus groups to measure patient and provider satisfaction and analyzed focus groups using qualitative analysis. RESULTS: The intervention was well accepted by providers and patients, based on survey and focus group data. Feasibility was also evidenced by recruitment (87.1%) and retention (92.6%) rates and depression outcomes (64% with >50% improvement in PHQ 9) which were comparable to clinical trials in similar urban populations. Conclusions for practice: DAWN Collaborative Care modified for treatment of perinatal depression in a rural obstetric setting is feasible and acceptable. Behavioral health services integrated into rural obstetric settings could improve care for perinatal depression. PMID- 28882097 TI - Access and Utilization of Prenatal Health Care Services in Rural Communities: A Study of Isiekenesi in Imo State. AB - Pregnancy and childbirth complications are leading causes of death and disability among women of reproductive age, especially in developing countries, with Nigeria experiencing 576 deaths in every 100,000 births. This is particularly worrisome when most of these deaths could be prevented if pregnant women seek prenatal health care services. It is in the light of the foregoing that this research investigates the level of access and factors that influence use of prenatal health care services in Isiekenesi. Secondary and primary data were used for this study. The study adopted questionnaire, IDI, and FGD as data collection instruments. The data was analyzed at univariate and bivariate levels. The high cost of prenatal health care services was identified as a major factor that influences a woman's decision not to use prenatal health care services. Finally, while all stakeholders should intensify awareness of the importance of using prenatal health care services, concerted effort should be channeled toward reduction of cost or outright free services at least in government-owned health centers in rural areas. PMID- 28882098 TI - Angels of Courage: The Experiences of Mothers Who Have Been Bereaved by Suicide. AB - Despite the increasing number of people being bereaved by suicide, little is understood concerning the experiences of those bereaved by suicide as they struggle to make sense of a loved one's death. The current study explored the experiences of four mothers who had been bereaved by suicide and the role of support groups in the meaning-making process following bereavement by suicide. Participants were interviewed and transcribed interviews were then analysed from an interpretative phenomenological perspective. Four main themes were identified: Continuing role of the mother; A never-ending quest; Finding sanctuary; and Rising up from the ashes. These themes relate to a range of emotions following bereavement by suicide, the meaning-making process, the social context and the role of the support group. Clinical implications are discussed in relation to these findings. PMID- 28882100 TI - Low-dose cyclosporine in treatment of membranous nephropathy with nephrotic syndrome: effectiveness and renal safety. AB - BACKGROUND: To observe effectiveness and renal safety of long-term low-dose cyclosporine in idiopathic membranous nephropathy (IMN). METHODS: Sixty-eight patients were enrolled in this prospective cohort study. Renal endpoint was defined as a decrease in eGFR >=50% from baseline and a development of eGFR <=60 ml/min/1.73m2. RESULTS: A cyclosporine dose of 2.0 +/- 0.5 mg/kg/d and a prednisone of 0.3 +/- 0.2 mg/kg/d were prescribed. The duration of cyclosporine treatment was 27 (3-80) months. The overall remission rate was 91% with a relapse rate of 42%. Fourteen patients had cyclosporine-related acute renal injury (CsA ARI) within the first three months, and 16 patients had cyclosporine related chronic renal injury (CsA-CRI) within the first year. At the end of follow-up (50 +/- 18 months), 16 patients (24%) reached renal endpoint. Presence of intimal fibrosis of small artery and higher time-averaged proteinuria were identified as independent risk factors for renal endpoint. RAS inhibition treatment decreased the risk of poor renal outcome. Patients in CsA-ARI group had the highest proteinuria at the third month, the highest time-average proteinuria and the highest proportion of cases reaching renal endpoint. Patients with CsA-CRI were of the oldest age and with the lowest baseline eGFR. CONCLUSIONS: Low-dose cyclosporine is effective in treating IMN. CsA-ARI and no response in proteinuria during the first three months of cyclosporine treatment had the lowest benefit/risk ratio, and these patients should be switched to non-calcineurin inhibitor based regimen. Patients of older age, with lower baseline eGFR, or having intimal sclerosis of small artery, are more likely to develop progressive renal dysfunction. PMID- 28882101 TI - Perceptions about the cultural practices of male partners during postpartum care in rural Tanzania: a qualitative study. AB - BACKGROUND: Men play an important role in maternal health. The postpartum period is a critical stage, yet there is a scarcity of research that explores men's involvement during this stage. OBJECTIVE: The aim of the study was to explore male partners' perceptions of the cultural practices during postpartum care in rural Tanzania. METHODS: Fourteen focus group discussions were conducted with 93 men, with an age range of 19-65 years, in August 2013. The study was conducted in the Kongwa District, located in the Dodoma region in central Tanzania. Qualitative data were digitally recorded, transcribed verbatim and analyzed using content analysis. RESULTS: Four categories emerged, namely: 'Men as providers and, occasionally, care takers', 'Men as decision makers', 'Diverse perceptions of sexual abstinence' and 'Barriers for men in using/accompanying partners to use reproductive and child healthcare services'. The cross-category theme 'Men during postpartum: remaining powerful but excluded' refers to how men are in a powerful position above women in different aspects of life. Elderly women played an important role in caring for postpartum mothers and their newborns, but men were the ones making the final decision about where to seek care. Traditional practices isolated men from their partners for a certain period, and enforced sexual abstinence for the women during the postpartum period. However, cultural norms permitted men to engage in extramarital relations. Reproductive and child healthcare services were perceived by men as not welcoming the male partners, and local gender norms discouraged men from accompanying their partners to seek services. CONCLUSIONS: In this study, we found that men perceived their role during the postpartum period as financial providers, decision makers and, occasionally, care givers. Men also held diverse perceptions with regard to sexual abstinence and felt excluded from participating in maternal healthcare services. PMID- 28882102 TI - Monte Carlo simulation-based estimation for the minimum mortality temperature in temperature-mortality association study. AB - BACKGROUND: Rich literature has reported that there exists a nonlinear association between temperature and mortality. One important feature in the temperature-mortality association is the minimum mortality temperature (MMT). The commonly used approach for estimating the MMT is to determine the MMT as the temperature at which mortality is minimized in the estimated temperature mortality association curve. Also, an approximate bootstrap approach was proposed to calculate the standard errors and the confidence interval for the MMT. However, the statistical properties of these methods were not fully studied. METHODS: Our research assessed the statistical properties of the previously proposed methods in various types of the temperature-mortality association. We also suggested an alternative approach to provide a point and an interval estimates for the MMT, which improve upon the previous approach if some prior knowledge is available on the MMT. We compare the previous and alternative methods through a simulation study and an application. In addition, as the MMT is often used as a reference temperature to calculate the cold- and heat-related relative risk (RR), we examined how the uncertainty in the MMT affects the estimation of the RRs. RESULTS: The previously proposed method of estimating the MMT as a point (indicated as Argmin2) may increase bias or mean squared error in some types of temperature-mortality association. The approximate bootstrap method to calculate the confidence interval (indicated as Empirical1) performs properly achieving near 95% coverage but the length can be unnecessarily extremely large in some types of the association. We showed that an alternative approach (indicated as Empirical2), which can be applied if some prior knowledge is available on the MMT, works better reducing the bias and the mean squared error in point estimation and achieving near 95% coverage while shortening the length of the interval estimates. CONCLUSIONS: The Monte Carlo simulation-based approach to estimate the MMT either as a point or as an interval was shown to perform well particularly when some prior knowledge is incorporated to reduce the uncertainty. The MMT uncertainty also can affect the estimation for the MMT-referenced RR and ignoring the MMT uncertainty in the RR estimation may lead to invalid results with respect to the bias in point estimation and the coverage in interval estimation. PMID- 28882104 TI - Dysphoric symptoms in relation to other behavioral and psychological symptoms of dementia, among elderly in nursing homes. AB - BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are common and varied in the elderly. The aim of the current study was to explore associations between BPSD and dysphoric symptoms at different levels of cognitive impairment. METHODS: Assessments of 4397 elderly individuals living in nursing homes in Sweden were performed. Data on cognitive function and BPSD were collected using the Multi-Dimensional Dementia Assessment Scale (MDDAS). The relationships between dysphoria and eight BPSD factors were plotted against cognitive function to investigate how dysphoria affects BPSD throughout the dementia disease. RESULTS: Overall, dysphoric symptoms were most prevalent in persons with moderate cognitive impairment. However, moderate to severe dysphoric symptoms showed no clear variation with cognitive impairment. Furthermore, aggressive behavior, verbally disruptive/attention-seeking behavior, hallucinatory symptoms and wandering behavior were more common with concurrent dysphoria regardless of cognitive function. In contrast, passiveness was more common with concurrent dysphoria in mild cognitive impairment but not in moderate to severe cognitive impairment. CONCLUSIONS: BPSD, including aggressive behavior and hallucinations, were more common with concurrent dysphoric symptoms, providing insight into behavioral and psychological symptoms among individuals with cognitive impairment. Apathy was more commonly associated with concurrent dysphoria at early stages of cognitive decline but not at later stages, indicating that apathy and dysphoria represent separate syndromes among elderly patients with moderate to severe cognitive impairment. PMID- 28882103 TI - Low serum vitamin D levels in type 2 diabetes patients are associated with decreased mycobacterial activity. AB - BACKGROUND: Concurrent diabetes mellitus and tuberculosis represent a significant health problem worldwide. Patients with diabetes mellitus have a high risk of tuberculosis, which may be mediated by an abnormal innate immune response due to hyperglycaemia or low vitamin D levels. METHODS: In the present study, we evaluated inactive vitamin D serum levels and the monocyte response to infection with M. tuberculosis, including phagocytosis of M. tuberculosis, antimycobacterial activity, LL-37, human beta defensin-2 and IL-10 gene expression and nitric oxide production, between type 2 diabetes mellitus patients (n = 51) and healthy volunteers (n = 38). RESULTS: Twenty-seven type 2 diabetes mellitus patients had inadequate inactive vitamin D levels (<50 nM). The percentages of M. tuberculosis phagocytosis between monocytes were similar across groups according to microscopy. Intracellular mycobacterial growth was similar in infected monocytes from both groups. However, M. tuberculosis growth was significantly higher in monocytes obtained from type 2 diabetes mellitus patients and lower vitamin D levels after 1-h (D0) and 72-h (D3) post-infection (p <= 0.05). LL-37, human beta defensin-2 and IL-10 mRNA expression were similar between monocytes across groups; vitamin D serum levels and LL-37, human beta defensin-2 and IL-10 expression were not correlated. Nitric oxide production was significantly higher in healthy volunteers than in type 2 diabetes mellitus patients with low vitamin D serum levels at D3 post-infection (p <= 0.05). CONCLUSIONS: Our results show that monocytes from type 2 diabetes mellitus patients and low vitamin D serum levels show an impaired ability to control the intracellular growth of M. tuberculosis, which is not associated with significant decrease of LL-37 or human beta defensin-2 expression. Vitamin D could be the link between diabetes and tuberculosis susceptibility. PMID- 28882105 TI - Addressing data privacy in matched studies via virtual pooling. AB - BACKGROUND: Data confidentiality and shared use of research data are two desirable but sometimes conflicting goals in research with multi-center studies and distributed data. While ideal for straightforward analysis, confidentiality restrictions forbid creation of a single dataset that includes covariate information of all participants. Current approaches such as aggregate data sharing, distributed regression, meta-analysis and score-based methods can have important limitations. METHODS: We propose a novel application of an existing epidemiologic tool, specimen pooling, to enable confidentiality-preserving analysis of data arising from a matched case-control, multi-center design. Instead of pooling specimens prior to assay, we apply the methodology to virtually pool (aggregate) covariates within nodes. Such virtual pooling retains most of the information used in an analysis with individual data and since individual participant data is not shared externally, within-node virtual pooling preserves data confidentiality. We show that aggregated covariate levels can be used in a conditional logistic regression model to estimate individual-level odds ratios of interest. RESULTS: The parameter estimates from the standard conditional logistic regression are compared to the estimates based on a conditional logistic regression model with aggregated data. The parameter estimates are shown to be similar to those without pooling and to have comparable standard errors and confidence interval coverage. CONCLUSIONS: Virtual data pooling can be used to maintain confidentiality of data from multi-center study and can be particularly useful in research with large-scale distributed data. PMID- 28882106 TI - Sumoylation in p27kip1 via RanBP2 promotes cancer cell growth in cholangiocarcinoma cell line QBC939. AB - BACKGROUND: Cholangiocarcinoma is one of the deadly disease with poor 5-year survival and poor response to conventional therapies. Previously, we found that p27kip1 nuclear-cytoplasmic translocation confers proliferation potential to cholangiocarcinoma cell line QBC939 and this process is mediated by crm-1. However, no other post-transcriptional regulation was found in this process including sumoylation in cholangiocarcinoma. RESULTS: In this study, we explored the role of sumoylation in the nuclear-cytoplasmic translocation of p27kip1 and its involvement of QBC939 cells' proliferation. First, we identified K73 as the sumoylation site in p27kip1. By utilizing plasmid flag-p27kip1, HA-RanBP2, GST RanBP2 and His-p27kip1 and immunoprecipitation assay, we validated that p27kip1 can serve as the sumoylation target of RanBP2 in QBC939. Furthermore, we confirmed crm-1's role in promoting nuclear-cytoplasmic translocation of p27kip1 and found that RanBP2's function relies on crm-1. However, K73R mutated p27kip1 can't be identified by crm-1 or RanBP2 in p27kip1 translocation process, suggesting sumoylation of p27kip1 via K73 site is necessary in this process by RanBP2 and crm-1. Phenotypically, the overexpression of either RanBP2 or crm-1 can partially rescue the anti-proliferative effect brought by p27kip1 overexpression in both the MTS and EdU assay. For the first time, we identified and validated the K73 sumoylation site in p27kip1, which is critical to RanBP2 and crm-1 in p27kip1 nuclear-cytoplasmic translocation process. CONCLUSION: Taken together, targeted inhibition of sumoylation of p27kip1 may serve as a potentially potent therapeutic target in the eradication of cholangiocarcinoma development and relapses. PMID- 28882107 TI - Statistical classifiers for diagnosing disease from immune repertoires: a case study using multiple sclerosis. AB - BACKGROUND: Deep sequencing of lymphocyte receptor repertoires has made it possible to comprehensively profile the clonal composition of lymphocyte populations. This opens the door for novel approaches to diagnose and prognosticate diseases with a driving immune component by identifying repertoire sequence patterns associated with clinical phenotypes. Indeed, recent studies support the feasibility of this, demonstrating an association between repertoire level summary statistics (e.g., diversity) and patient outcomes for several diseases. In our own prior work, we have shown that six codons in VH4-containing genes in B cells from the cerebrospinal fluid of patients with relapsing remitting multiple sclerosis (RRMS) have higher replacement mutation frequencies than observed in healthy controls or patients with other neurological diseases. However, prior methods to date have been limited to focusing on repertoire-level summary statistics, ignoring the vast amounts of information in the millions of individual immune receptors comprising a repertoire. We have developed a novel method that addresses this limitation by using innovative approaches for accommodating the extraordinary sequence diversity of immune receptors and widely used machine learning approaches. We applied our method to RRMS, an autoimmune disease that is notoriously difficult to diagnose. RESULTS: We use the biochemical features encoded by the complementarity determining region 3 of each B cell receptor heavy chain in every patient repertoire as input to a detector function, which is fit to give the correct diagnosis for each patient using maximum likelihood optimization methods. The resulting statistical classifier assigns patients to one of two diagnosis categories, RRMS or other neurological disease, with 87% accuracy by leave-one-out cross-validation on training data (N = 23) and 72% accuracy on unused data from a separate study (N = 102). CONCLUSIONS: Our method is the first to apply statistical learning to immune repertoires to aid disease diagnosis, learning repertoire-level labels from the set of individual immune repertoire sequences. This method produced a repertoire based statistical classifier for diagnosing RRMS that provides a high degree of diagnostic capability, rivaling the accuracy of diagnosis by a clinical expert. Additionally, this method points to a diagnostic biochemical motif in the antibodies of RRMS patients, which may offer insight into the disease process. PMID- 28882108 TI - General practitioners' perspectives on a proposed new model of service delivery for primary care management of knee osteoarthritis: a qualitative study. AB - BACKGROUND: Effective management of people with knee osteoarthritis (OA) requires development of new models of care, and successful implementation relies on engagement of general practitioners (GPs). This study used a qualitative methodology to identify potential factors influencing GPs' engagement with a proposed new model of service delivery to provide evidence-based care for patients with knee OA and achieve better patient outcomes. METHODS: Semi structured telephone interviews with 11 GPs were conducted. Based on a theoretical model of behaviour, interview questions were designed to elicit perspectives on a remotely-delivered (telephone-based) service to support behaviour change and self-management for patients with knee OA, with a focus on exercise and weight loss. Transcripts were analysed using an inductive thematic approach, and GPs' opinions were organised using the APEASE (affordability, practicability, effectiveness, acceptability, safety/side effects and equity) criteria as themes. RESULTS: GPs expressed concerns about potential for confusion, incongruence of information and advice, disconnect with other schemes and initiatives, loss of control of patient care, lack of belief in the need and benefits of proposed service, resistance to change because of lack of familiarity with the procedures and the service, and reluctance to trust in the skills and abilities of the health professionals providing the care support. GPs also recognised the potential benefits of the extra support for patients, and improved access for remote patients to clinicians with specialist knowledge. CONCLUSION: The findings can be used to optimise implementation and engagement with a remotely-delivered 'care support team' model by GPs. PMID- 28882109 TI - Obstetric care providers' knowledge, practice and associated factors towards active management of third stage of labor in Sidama Zone, South Ethiopia. AB - BACKGROUND: Active management of third stage of labor played a great role to prevent child birth related hemorrhage. However, maternal morbidity and mortality related to hemorrhage is high due to lack of knowledge and skill of obstetric care providers 'on active management of third stage of labor. Our study was aimed to assess knowledge, practice and associated factors of obstetric care providers (Midwives, Nurses and Health officers) on active management of third stage of labor in Sidama Zone, South Ethiopia. METHODS: An institution based cross sectional study design was conducted from December 1-30 /2015 among midwives, nurses and health officers. Simple random sampling technique was used to get the total of 528 participants. Data entry was done using EPI Info 3.5.1 and exported to SPSS version 20.0 software package for analysis. The presence of association between independent and dependent variables was assessed using odds ratio with 97% confidence interval by applying logistic regression model. RESULTS: Of the 528 obstetric care providers 37.7% and 32.8% were knowledgeable and skilled to manage third stage of labor respectively. After controlling for possible confounding factors, the result showed that pre/in service training, being midwife and graduation year were found to be the major predictors of proper active management of third stage of labor. CONCLUSION: The knowledge and practice of obstetric care providers towards active management of third stage of labor can be improved with appropriate interventions like in-service trainings. This study also clearly showed that the level of knowledge and practice of obstetric care providers to wards active management of third stage of labor needs immediate attention of Universities and health science colleges better to revise their obstetrics course contents, health institutions and zonal health bureau should arrange trainings for their obstetrics care providers to enhance skill. PMID- 28882110 TI - Serum osteoprotegerin in prevalent hemodialysis patients: associations with mortality, atherosclerosis and cardiac function. AB - BACKGROUND: To assess whether serum osteoprotegerin (OPG) and/or fetuin-A predict mortality and cardiovascular (CV) morbidity and mortality in hemodialysis patients. METHODS: Multicenter, observational, prospective study that included 220 hemodialysis patients followed up for up to 6 years. Serum OPG and fetuin-A levels were measured at baseline and their possible association with clinical characteristics, CV risk biomarkers, carotid ultrasonographic findings, as well as their association with overall and CV mortality and CV events were assessed. RESULTS: During a mean follow-up of 3.22 +/- 1.91 years, there were 74 deaths (33.6%) and 86 new cardiovascular events. In the Kaplan-Meier survival analysis, the highest tertile of OPG levels was associated with higher overall mortality (p = 0.005), as well as a higher, although non-significant, incidence of CV events and CV mortality. In contrast, fetuin-A levels did not predict any of these events. OPG levels were directly associated with age, the Charlson comorbidity index (CCI), prevalent cardiovascular disease, carotid intima-media thickness, adiponectin, troponin-I and brain natriuretic peptide (BNP). OPG showed a negative correlation with left ventricular ejection fraction (LVEF) and phosphate levels. In the multivariate Cox proportional hazard analysis, all-cause mortality was associated with the highest tertile of OPG (HR:1.957, p = 0.018), age (HR:1.031, p = 0.036), smoking history (HR:2.122, p = 0.005), the CCI (HR:1.254, p = 0.004), troponin-I (HR:3.894, p = 0.042), IL-18 (HR:1.061, p < 0.001) and albumin levels (HR:0.886, p < 0.001). In the bootstrapping Cox regression analysis, the best cut-off value of OPG associated with mortality was 17.69 pmol/L (95%CI: 5.1-18.02). CONCLUSIONS: OPG, but not fetuin-A levels, are independently associated with overall mortality, as well as clinical and subclinical atherosclerosis and cardiac function, in prevalent hemodialysis patients. PMID- 28882111 TI - TSH cut off point based on depression in hypothyroid patients. AB - BACKGROUND: The prevalence of depressive symptoms in hypothyroidism is high. Considering that hypothyroidism and depression share some clinical features, some researchers use the "brain hypothyroidism" hypothesis to explain the pathogenesis of depression. We aimed to detect a new TSH cut-off value in hypothyroidism based on depression symptoms. METHODS: A cross-sectional study was conducted on hypothyroid patients referred to endocrine clinics. Individuals who had developed euthyroid state under treatment with levothyroxine with TSH levels of 0.5-5 MIU/L with no need for dosage change were included in the study. After comprehensive history taking, laboratory tests including TSH, T4 and T3 were performed. Beck depression questionnaire was completed for all patients by trained interviewers. TSH cut-off values based on depression was determined by Roc Curve analysis. RESULTS: The participants were 174 hypothyroid patients (Female; 116: 66.7%, Male; 58: 33.3%) with mean age 45.5 +/- 11.7 (19-68) years old. Based on Beck depression test, scores less than 10 was considered healthy and more than 10 were considered depressed. According to Roc curve analysis, the optimal cut- off value of TSH was 2.5 MIU/L with 89.66% sensitivity. The optimal TSH cut- off based on severe depression was 4 MIU/L. CONCLUSION: The present study suggests that a clinically helpful TSH cut-off value for hypothyroidism should be based on associated symptoms, not just in population studies. Based on the assessment of depression, our study concludes that a TSH cutofff value of 2.5 MIU/L is optimal. PMID- 28882112 TI - Identification of adenylyl cyclase isoforms mediating parathyroid hormone- and calcitonin-stimulated cyclic AMP accumulation in distal tubule cells. AB - BACKGROUND: The distal convoluted tubule (DCT) is an important nephron site for parathyroid hormone (PTH) and calcitonin regulation of urinary divalent cation excretion. These hormones exert their effects on the DCT in substantial part through activation of adenylyl cyclase (AC); however, it is unknown which AC isoforms are involved. METHODS: To examine this, two mouse DCT cell lines were studied: 209 and D1 cells. AC isoform mRNA expression was analyzed by real-time PCR. Cyclic AMP was measured using enzyme immunoassay. RESULTS: Calcitonin, but not PTH, stimulated cAMP accumulation in 209 cells, while PTH, but not calcitonin, increased cAMP content in D1 cells. Both cell types expressed AC3, AC4, AC6, AC7, and AC9 mRNA; in both cell types, AC6 mRNA was most abundant, followed by AC9, then AC3 and AC7, with relatively very small amounts of AC4 mRNA. Microdissected mouse DCT had a similar pattern of AC isoform mRNA expression although AC5 mRNA was detected. Individual siRNA knockdown of AC6 and AC9 reduced calcitonin-stimulated cAMP accumulation in 209 cells and PTH-induced cAMP levels in D1 cells. Knockdown of AC3 had no effect on hormonal augmentation of cAMP in either cell line. Surprisingly, knockdown of AC7 increased calcitonin induced cAMP accumulation in 209 cells as well as PTH-stimulated cAMP content in D1 cells. CONCLUSIONS: Taken together, these findings indicate that AC6 and AC9 mediate calcitonin- and PTH-stimulated cAMP accumulation in DCT cells, while activation of AC7 may paradoxically reduce the stimulatory effects of PTH and calcitonin on cultured DCT cAMP levels. PMID- 28882113 TI - New use of low-dose aspirin and risk of colorectal cancer by stage at diagnosis: a nested case-control study in UK general practice. AB - BACKGROUND: Evidence from clinical trial populations suggests low-dose aspirin reduces the risk of colorectal cancer (CRC). Part of this reduction in risk might be due to protection against metastatic disease. METHODS: We investigated the risk of CRC among new-users of low-dose aspirin (75-300 mg), including risk by stage at diagnosis. Using The Health Improvement Network, we conducted a cohort study with nested case-control analysis. Two cohorts (N = 170,336 each) aged 40 89 years from 2000 to 2009 and free of cancer were identified: i) new-users of low-dose aspirin, ii) non-users of low-dose aspirin, at start of follow-up, matched by age, sex and previous primary care practitioner visits. Patients were followed for up to 12 years to identify incident CRC. 10,000 frequency-matched controls were selected by incidence density sampling where the odds ratio is an unbiased estimator of the incidence rate ratio (RR). RRs with 95% confidence intervals were calculated. Low-dose aspirin use was classified 'as-treated' independent from baseline exposure status to account for changes in exposure during follow-up. RESULTS: Current users of low-dose aspirin (use on the index date or in the previous 90 days) had a significantly reduced risk of CRC, RR 0.66 (95% CI 0.60-0.74). The reduction in risk was apparent across all age groups, and was unrelated to dose, indication, gender, CRC location or case-fatality status. Reduced risks occurred throughout treatment duration and with all low-dose aspirin doses. RRs by aspirin indication were 0.71 (0.63-0.79) and 0.60 (0.53 0.68) for primary and secondary cardiovascular protection, respectively. Among cases with staging information (n = 1421), RRs for current use of low-dose aspirin were 0.94 (0.66-1.33) for Dukes Stage A CRC, 0.54 (0.42-0.68) for Dukes B, 0.71 (0.56-0.91) for Dukes C, and 0.60 (0.48-0.74) for Dukes D. After 5 years' therapy, the RR for Dukes Stage A CRC was 0.53 (0.24-1.19). CONCLUSIONS: Patients starting low-dose aspirin therapy have a reduced risk of Stages B-D CRC, suggesting a role for low-dose aspirin in the progression of established CRC; a substantial reduction in the risk of Dukes A CRC may occur after 5 years' therapy. PMID- 28882114 TI - Associations of genetic variants of endothelin with cardiovascular complications in patients with renal failure. AB - BACKGROUND: Cardiovascular (CV) complications are the main cause of death in end stage renal disease (ESRD) patients. The high CV risks are attributable to the additive effects of multiple factors. Endothelin (EDN) is a potent vasoconstrictor and plays a role in regulating vascular homeostasis. However, whether variants of the EDN gene are associated with risks of CV events is not known. We conducted a study to investigate associations of variants of the EDN gene with CV events in ESRD patients. METHODS: A cohort of 190 ESRD patients was recruited, and 19 tagged single-nucleotide polymorphisms within the EDN gene family were selected for genotyping through a TaqMan assay. Data on clinical characteristics and hospitalizations for CV events were collected. Associations of genetic variants of the EDN gene with CV events were analyzed. RESULTS: In this cohort, 62% (n = 118) of patients were hospitalized for a CV event. The EDN1 rs4714384 (CC/TC vs. TT) polymorphism was associated with an increased risk of a CV event after multiple testing (p < 0.001). Further functional exploration showed that it was a quantitative trait locus which may significantly alter gene expression in the tibial artery. CONCLUSIONS: EDN1 rs4714384 is very likely an important biomarker of CV events in ESRD patients. PMID- 28882115 TI - Caught in a no-win situation: discussions about CCSVI between persons with multiple sclerosis and their neurologists - a qualitative study. AB - BACKGROUND: In recent years, shared decision making (SDM) has been promoted as a model to guide interactions between persons with MS and their neurologists to reach mutually satisfying decisions about disease management - generally about deciding treatment courses of prevailing disease modifying therapies. In 2009, Dr. Paolo Zamboni introduced the world to his hypothesis of Chronic Cerebrospinal Venous Insufficiency (CCSVI) as a cause of MS and proposed venous angioplasty ('liberation therapy') as a potential therapy. This study explores the discussions that took place between persons with MS (PwMS) and their neurologists about CCSVI against the backdrop of the recent calls for the use of SDM to guide clinical conversations. METHODS: In 2012, study researchers conducted focus groups with PwMS (n = 69) in Winnipeg, Canada. Interviews with key informants were also carried out with 15 participants across Canada who were stakeholders in the MS community: advocacy organizations, MS clinicians (i.e. neurologists, nurses), clinical researchers, and government health policy makers. RESULTS: PwMS reported a variety of experiences when attempting to discuss CCSVI with their neurologist. Some found that there was little effort to engage in desired discussions or were dissatisfied with critical or cautious stances of their neurologist. This led to communication breakdowns, broken relationships, and decisions to autonomously access alternative opinions or liberation therapy. Other participants were appreciative when clinicians engaged them in discussions and were more receptive to more critical appraisals of the evidence. Key informants reported that they too had heard of neurologists who refused to discuss CCSVI with patients and that neurology as a whole had been particularly vilified for their response to the hypothesis. Clinicians indicated that they had shared information as best they could but recommended against seeking liberation therapy. They noted that being respectful of patient emotions, values, and hope were also key to maintaining good relationships. CONCLUSIONS: While CCSVI proved a challenging context to carry out patient-physician discussions and brought numerous tensions to the surface, following the approach of SDM can minimize the potential for unfortunate outcomes as much as possible because it is based on principles of respect and more two-way communication. PMID- 28882116 TI - THISTLE: trial of hands-on Interprofessional simulation training for local emergencies: a research protocol for a stepped-wedge clustered randomised controlled trial. AB - BACKGROUND: Many adverse pregnancy outcomes in the UK could be prevented with better intrapartum care. Training for intrapartum emergencies has been widely recommended but there are conflicting data about their effectiveness. Observational studies have shown sustained local improvements in perinatal outcomes associated with the use of the PRactical Obstetric Multi-Professional Training - (PROMPT) training package. However this effect needs to be investigated in the context of randomised study design in settings other than enthusiastic early adopter single-centres. The main aim of this study is to determine the effectiveness of PROMPT to reduce the rate of term infants born with low APGAR scores. METHODS: THISTLE (Trial of Hands-on Interprofessional Simulation Training for Local Emergencies) is a multi-centre stepped-wedge clustered randomised controlled superiority trial conducted across 12 large Maternity Units in Scotland. On the basis of prior observational findings all Units have been offered the intervention and have been randomly allocated in groups of four Units, to one of three intervention time periods, each six months apart. Teams of four multi-professional clinicians from each participating Unit attended a two-day PROMPT Train the Trainers (T3) programme prior to the start of their allocated intervention step. Following the T3 training, the teams commenced the implementation of local intrapartum emergency training in their own Units by the start of their allocated intervention period. Blinding has not been possible due to the nature of the intervention. The aim of the study is to follow up each Unit for at least 12-months after they have commenced their local courses. The primary outcome for the study is the proportion of Apgar scores <7 at 5 min for term vaginal or emergency caesarean section births (>=37 weeks) occurring in each of the study Units. These data will be extracted from the Information Services Division Scottish Morbidity Record 02, a national routine data collection on pregnancy and births. Mixed or marginal logistic regression will be employed for the main analysis. DISCUSSION: THISTLE is the first stepped wedge cluster randomised trial to evaluate the effectiveness of an intrapartum emergencies training programme. The results will inform training, trainers and policy going forward. TRIAL REGISTRATION: ISRCTN11640515 (registered on 09/09/2013). PMID- 28882117 TI - Awareness and practices regarding eye diseases among patients with diabetes: a cross sectional analysis of the CoDiab-VD cohort. AB - BACKGROUND: The increasing prevalence of diabetes is leading to a rise of eye diseases, augmenting the risk of sight-threatening complications. The aim of this study was to evaluate prevalence, awareness and practices regarding eye diseases among patients with diabetes in the canton of Vaud, Switzerland. METHODS: A cohort of 323 patients with diabetes completed a self-administered questionnaire assessing prevalence, awareness and practices regarding eye diseases, besides health status and quality of care measures. Descriptive analyses followed by exploratory subgroup analyses and linear regressions were performed to investigate factors associated with awareness and practices. RESULTS: While diabetic retinopathy was reported by 40.9% of patients with type 1 diabetes and 9.8% of patients with type 2 diabetes, 35.8% and 12.6% of all participants reported cataract and glaucoma, respectively. Awareness that diabetes could damage the eyes was reported by almost all participants; the majority was also aware of the importance of glycemic control and regular eye examination in preventing eye diseases. In contrast, only 70.5% of participants underwent an eye examination by an ophthalmologist during the past year. Eye examination was associated with better patients' awareness. Barriers mentioned by patients revealed a lack of knowledge about screening guidelines, in particular regarding the preventive nature of eye examinations. CONCLUSIONS: Despite high levels of awareness regarding diabetic eye diseases, a significant proportion of patients with diabetes did not report annual eye examination. Both healthcare strategic efforts targeting the promotion of regular eye examination and initiatives aiming at improving knowledge of screening guidelines should be encouraged. TRIAL REGISTRATION: ClinicalTrials.gov on 9th July 2013, identifier NCT01902043 (retrospectively registered). PMID- 28882118 TI - Separating obsessive-compulsive disorder from the self. A qualitative study of family member perceptions. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a condition which can have major effects on the life of both the sufferer and their family members. Previous research has shown that the impact of illness on family members is related to their conceptualisation of the illness. In the present study we used qualitative methods to explore illness perceptions in family members of people with OCD. METHOD: Fourteen family members of people meeting diagnostic criteria for OCD within the previous year took part in a semi-structured interview. Transcribed interviews were analysed using thematic analysis. RESULTS: OCD was viewed as originating from non-modifiable endogenous factors, particularly personal characteristics. Ambiguity about the boundary between OCD and the person was further heightened by a lack of distinction in family members' interpretations about which behaviours were a problematic symptom of a mental health problem and which were behaviours performed for enjoyment or the purposeful pursuit of a goal. The perceived close relationship between OCD and the person appeared to lead to pessimism regarding the likelihood of recovery. Some individuals viewed OCD as presenting on a continuum such that individuals with sub-clinical symptoms exist on the same spectrum as those with the mental health problem. For some however, labelling of sub-clinical symptoms as OCD by members of the public was a source of frustration for families, who felt that the severity of OCD was unrecognised. CONCLUSIONS: Family members' perceptions of the link between OCD and the person and of a spectrum of OCD presentation within the general population, may represent important dimensions of illness perception, which are not currently represented within existing models or assessment measures of illness perception. The perceptions that individuals hold about a health problem have been shown to be important in determining their coping responses to that condition. Further study using larger samples and quantitative methods are needed to understand whether these novel perceptions are associated with coping responses and outcomes in family members and people with OCD. If linked, clinicians may need to identify and challenge unhelpful family member perceptions as part of psychological therapy for families living with OCD. PMID- 28882119 TI - Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model. AB - BACKGROUND: Alexander disease (AxD) is an astrogliopathy that predominantly affects the white matter of the central nervous system (CNS), and is caused by a mutation in the gene encoding the glial fibrillary acidic protein (GFAP), an intermediate filament primarily expressed in astrocytes and ependymal cells. The main pathologic feature of AxD is the presence of Rosenthal fibers (RFs), homogeneous eosinophilic inclusions found in astrocytes. Because of difficulties in procuring patient' CNS tissues and the presence of RFs in other pathologic conditions, there is a need to develop an in vivo assay that can determine whether a mutation in the GFAP results in aggregation and is thus disease causing. METHODS: We found a GFAP mutation (c.382G > A, p.Asp128Asn) in a 68-year old man with slowly progressive gait disturbance with tendency to fall. The patient was tentatively diagnosed with AxD based on clinical and radiological findings. To develop a vertebrate model to assess the aggregation tendency of GFAP, we expressed several previously reported mutant GFAPs and p.Asp128Asn GFAP in zebrafish embryos. RESULTS: The most common GFAP mutations in AxD, p.Arg79Cys, p.Arg79His, p.Arg239Cys and p.Arg239His, and p.Asp128Asn induced a significantly higher number of GFAP aggregates in zebrafish embryos than wild-type GFAP. CONCLUSIONS: The p.Asp128Asn GFAP mutation is likely to be a disease-causing mutation. Although it needs to be tested more extensively in larger case series, the zebrafish assay system presented here would help clinicians determine whether GFAP mutations identified in putative AxD patients are disease-causing. PMID- 28882120 TI - Clinical and radiological characteristics of patients with late-onset severe restrictive lung defect after hematopoietic stem cell transplantation. AB - BACKGROUND: Late-onset noninfectious pulmonary complications (LONIPCs), which occur more than 3 months after allogeneic hematopoietic stem cell transplantation (HSCT), are major causes of morbidity and mortality after transplantation. Among LONIPCs, we occasionally treat patients with late-onset severe restrictive lung defect after HSCT; however, its clinical features have not been fully elucidated. METHODS: A retrospective chart review of a single center on cases of late-onset severe restrictive lung defect after HSCT was performed. Among 453 patients who survived longer than 100 days after allogeneic HSCT with evaluable spirometry data, 12 patients (2.6%) developed late-onset severe restrictive lung defect (i.e., vital capacity percent of predicted less than 60%). RESULTS: Median duration from transplantation to diagnosis of late-onset severe restrictive lung defect cases was 44.5 months. Major computed tomography (CT) finding was pleuroparenchymal thickening with volume loss, an evidence of fibrosis, predominantly in upper lobes (n = 7), which was consistent with pleuroparenchymal fibroelastosis. The remaining patients showed unclassifiable interstitial pneumonia pattern (n = 2) and airway-predominant pattern (n = 3). The diffusing capacity for carbon oxide tended to decrease, while the residual volume/total lung capacity ratio tended to increase after HSCT. Of 12 patients, 8 patients died and the median month from diagnosis to death was 33.5 months. Seven patients died of pulmonary or systemic infection, and one patient died due to relapse of the primary disease. CONCLUSION: Severe restrictive lung defect could develop in selected cases in the late-phase after HSCT and could be a unique clinical entity with specific radiographical findings. PMID- 28882121 TI - Evaluation of a peer education program on student leaders' energy balance-related behaviors. AB - BACKGROUND: Few studies have reported energy balance-related behavior (EBRB) change for peer leaders delivering health promotion programs to younger students in secondary schools. Our study assessed the impact of the Students As LifeStyle Activists (SALSA) program on SALSA peer leaders' EBRBs, and their intentions regarding these behaviors. METHODS: We used a pre-post study design to assess changes in EBRBs and intentions of Year 10 secondary school students (15-16 year olds) who volunteered to be peer leaders to deliver the SALSA program to Year 8 students (13-14 year olds). This research is part of a larger study conducted during 2014 and 2015 in 23 secondary schools in Sydney, Australia. We used an online questionnaire before and after program participation to assess Year 10 peer leaders' fruit and vegetable intake, daily breakfast eating, sugar sweetened beverage (SSB) intake, moderate-to-vigorous physical activity (MVPA) participation and school-day recreational screen time behaviors and intentions regarding these EBRBs. Generalized estimating equations with a robust variance structure and exchangeable correlation structure were used to estimate the individual-level summary statistics and their 95% CIs, adjusted for clustering. We further assessed the effect of covariates on EBRB changes. RESULTS: There were significant increases in the proportion of Year 10 peer leaders (n = 415) who reported eating >=2 serves fruit/day fruit from 54 to 63% (P < 0.01); eating >=5 serves vegetables/day from 8 to 12% (P < 0.01); and drinking <1 cup/day of SSBs from 56 to 62% (P < 0.01). Change in >=60 min MVPA participation/day depended on gender (P < 0.01): Boys increased 14% while girls decreased -2%. Changes in eating breakfast daily also depended on gender (P < 0.004): Boys increased 13% while girls decreased -0.4%. The change in peer leaders recreational screen time differed by socio-economic status (P < 0.05): above average communities decreased by -2.9% while below average communities increased 6.0%. Significant shifts were seen in peer leaders' intentions, except MVPA which remained stable. CONCLUSIONS: The SALSA program had a positive impact on peer leaders' EBRBs, with gender and socio-economic status moderating some outcomes. TRIAL REGISTRATION: ACTRN12617000712303 retrospectively registered. PMID- 28882122 TI - Prevalence and predictors of early gestational weight gain associated with obesity risk in a diverse Australian antenatal population: a cross-sectional study. AB - BACKGROUND: Excess gestational weight gain (GWG) leads to adverse short- and long term consequences for women and their offspring. Evidence suggests that excess GWG in early pregnancy may be particularly detrimental, contributing to the intergenerational cycle of obesity. The primary outcome was to investigate the prevalence and predictors of excess GWG in early pregnancy, and if women understand the risks to themselves and their offspring stratified by maternal body mass index (BMI). METHODS: This was a secondary analysis (n = 2131) of a cross-sectional study (n = 2338) conducted over 6 months in 2015 of pregnant women attending antenatal clinics at four maternity hospitals across Sydney, Australia before 22 completed weeks gestation An self-completed questionnaire was used to investigate knowledge of expected weight gain in pregnancy, understanding of risks associated with excess GWG, self-reported anthropometric measures and socio-demographic data. RESULTS: One third (34.2%) of women gained weight in excess of the recommendations by 22 completed weeks gestation. Women who were overweight (OR: 1.69, 95% CI: 1.33-2.14) or obese (OR: 1.64, 95% CI: 1.20-2.24) pre-pregnancy were more likely to gain excess weight in early pregnancy compared to normal weight women; as were women from lower socio-economic areas (OR: 1.89, 95% CI: 1.49-2.41). Half (51%) the women were unsure about the effect of excess GWG on their baby; 11% did not believe that excess GWG would affect the weight of the baby and 14% did not believe that excess GWG would affect longer term outcomes for their baby. Women who gained weight above the recommendations were significantly more likely to believe that excessive GWG in pregnancy would not have any adverse future effect on health outcomes or weight of their baby. CONCLUSIONS: The women at particular risk of excess early GWG are those who are overweight and obese and/or residing in lower socio-economic areas. These women need to be targeted for appropriate counselling preconception or in early pregnancy. Given the significant adverse outcomes associated with excess GWG in early pregnancy, preconception or early pregnancy counselling with respect to GWG and intervention research regarding best approach remains a public health priority. PMID- 28882123 TI - Electronic cigarette use behaviors and motivations among smokers and non-smokers. AB - BACKGROUND: The use of electronic cigarettes (EC) has risen exponentially over the past decade, including among never smokers, and ECs are now the most popular tobacco product among teenagers in the US. While, EC manufacturers utilize numerous marketing strategies to target both smokers and non-smokers, it is unclear how perceptions and behaviors differ between these two groups. METHODS: We conducted a survey of 320 adults either via online surveys or in Baltimore vape shops to determine demographics, behaviors, perceptions, and motivations underlying use of ECs. RESULTS: Our survey respondents were predominantly young, Caucasian males, 74% of whom identified themselves as former smokers, while 20% identified as current smokers and 6% were never smokers. Former smokers reported a longer history of EC use and higher nicotine concentrations than current smokers. For former and current smokers, the primary motivation for EC use was assistance to quit smoking, and nearly half indicated that they plan to reduce their nicotine concentration and eventually quit using ECs. Among former smokers, self-reports on use and measures of dependence were consistent with nicotine replacement as their primary motivation. The majority of former and current smokers also reported that their respiratory health had improved as a result of EC use, although this effect was stronger for former smokers. Never smokers reported less frequent EC use and dependence compared to former and current smokers. Their motivations for use were more commonly for enjoyment and popularity, and they displayed a reduced desire to eventually quit using ECs. CONCLUSIONS: These responses provide insight into the underlying thoughts and behaviors of smoking and non-smoking EC users and also suggest that never smoking EC users are an emerging demographic with different motivations and perceptions than those of current and former smokers. PMID- 28882124 TI - Phenotypic expressions of hereditary Transthyretin Ala97Ser related Amyloidosis (ATTR) in Taiwanese. AB - BACKGROUND: The disease course and early signs specific to ATTR Ala97Ser, the most common endemic mutation in Taiwan, have not been well described. Since new medications can slow down the rate of disease progression, the early diagnosis of this heterogeneous and fatal disease becomes critical. METHODS: We retrospectively reviewed the characteristics of genetically confirmed ATTR Ala97Ser patients at a tertiary referral medical center. RESULTS: Eight patients from 7 different families were enrolled (61.7 +/- 5.5 years). Gastrointestinal symptoms, dyspnea or chest tightness, rather than sensory symptoms, were the initial symptoms in two patients (2/7 = 29%). Body weight loss (3/7 = 43%), muscle wasting (4/7 = 57%), or dysphagia (3/7 = 43%) were the consecutive symptoms. Orthostatic symptoms including orthostatic hypotension (7/7 = 100%), dizziness (6/7 = 86%) and syncope (5/7 = 71%) tended to develop in the late phase of the disease. Autonomic dysfunction was conspicuous. Cardiographic findings included a combination of ventricular wall thickening and pericardial effusion (7/7 = 100%), a granular sparkling appearance of the ventricular myocardium (4/7 = 57%), or conduction abnormalities (5/7 = 71%). CONCLUSIONS: This study broadens the recognition of the initial signs and symptoms, including cardiographic findings and longitudinal manifestations in Taiwanese individuals with ATTR Ala97Ser mutation. These manifestations should prompt doctors to perform further studies and make an early diagnosis. PMID- 28882125 TI - Evidence mapping based on systematic reviews of therapeutic interventions for gastrointestinal stromal tumors (GIST). AB - BACKGROUND: Gastrointestinal Stromal Tumours (GISTs) are the most common mesenchymal tumours. Currently, different pharmacological and surgical options are used to treat localised and metastatic GISTs, although this research field is broad and the body of evidence is scattered and expanding. Our objectives are to identify, describe and organise the current available evidence for GIST through an evidence mapping approach. METHODS: We followed the methodology of Global Evidence Mapping (GEM). We searched Pubmed, EMBASE, The Cochrane Library and Epistemonikos in order to identify systematic reviews (SRs) with or without meta analyses published between 1990 and March 2016. Two authors assessed eligibility and extracted data. Methodological quality of the included systematic reviews was assessed using AMSTAR. We organised the results according to identified PICO questions and presented the evidence map in tables and a bubble plot. RESULTS: A total of 17 SRs met eligibility criteria. These reviews included 66 individual studies, of which three quarters were either observational or uncontrolled clinical trials. Overall, the quality of the included SRs was moderate or high. In total, we extracted 14 PICO questions from them and the corresponding results mostly favoured the intervention arm. CONCLUSIONS: The most common type of study used to evaluate therapeutic interventions in GIST sarcomas has been non experimental studies. However, the majority of the interventions are reported as beneficial or probably beneficial by the respective authors of SRs. The evidence mapping is a useful and reliable methodology to identify and present the existing evidence about therapeutic interventions. PMID- 28882126 TI - Predictors of Acute Renal Injury Study (PARIS) among HIV-positive individuals: design and methods. AB - BACKGROUND: Acute kidney injury (AKI), which is common among HIV-positive individuals, may contribute to the excess burden of chronic kidney disease (CKD) in this patient population; however, conventional clinical methods to detect AKI do not capture kidney injury sufficiently early to prevent irreversible damage. Further, large observational and interventional studies of AKI generally exclude HIV-positive persons in spite of their disproportionate risk. METHODS: The Predictors of Acute Renal Injury Study (PARIS) is a prospective observational cohort study among HIV-positive individuals established to determine the ability of candidate kidney injury biomarkers to predict future hospitalized clinical AKI, to characterize hospitalized subclinical AKI, and to discern the risk of progressive kidney disease following subclinical and clinical AKI. Among the candidate kidney injury markers, we will select the most promising to translate into a clinically viable, multiplex panel of urinary biomarkers which we will integrate with clinical factors to develop a model prognostic of risks for AKI and subsequent kidney function decline. This study has a targeted enrollment of 2000 participants. The overall follow-up of participants consists of two phases: 1) a 5-year active follow-up phase which involves serial evaluations at enrollment, annual clinic visits, and among participants who are hospitalized during this period, an evaluation at index hospitalization and 3 and 12 months post-hospitalization; and 2) a subsequent passive follow-up phase for the duration that the participant receives medical care at The Johns Hopkins Hospital. DISCUSSIONS: This study will serve as an important resource for future studies of AKI by establishing a repository with both ambulatory and inpatient biospecimens, a resource that is currently lacking in existing HIV clinical cohorts and studies of AKI. Upon completion of this study, the resulting prognostic model which will incorporate results from the multiplex HIV-AKI Risk Pane could serve as a pharmacodynamic endpoint for early phase therapeutic candidates for AKI. PMID- 28882127 TI - Derivation of a frailty index from the resident assessment instrument - home care adapted for Switzerland: a study based on retrospective data analysis. AB - BACKGROUND: The screening of frail individuals at risk for functional health decline and adverse health outcomes lies in the evolving agenda of home care providers. Such a screening can be based on a frailty index (FI) derived from data collected with interRAI instruments used in clinical routines to define care plans. The objective of this study was to assess the feasibility of deriving an FI from the Resident Assessment Instrument - Home Care adapted for Switzerland (Swiss RAI-HC). METHODS: Data were collected by the Geneva Institution for Homecare and Assistance in clinical routines. The sample consisted of 3714 individuals aged 65 or older (67.7% females) who had each received a Swiss RAI-HC upon admission in the year of 2015. The FI was derived from 52 variables identified and scored according to published guidelines. Adverse health outcomes were either assessed during follow-up assessments (falls, hospitalizations) or documented from administrative records (mortality). RESULTS: The results showed that the FI was distributed normally, with a mean of 0.24 (+/- 0.13), an interquartile range of 0.16, and values of 0.04 at percentile 1 and 0.63 at percentile 99. The effect of Age was significant (R2 = 0.011) with a slope of beta = 0.002, 95% CI = [0.001-0.002]. Sex as well as the Age * Sex interaction were not significant. The FI predicted deaths (OR = 9.99, 95% CI = [3.20-29.99]), hospitalizations (OR = 3.40, 95% CI = [1.78-6.32]), and falls (OR = 5.00, 95% CI = [2.68-9.38]). CONCLUSIONS: The results support the feasibility of an FI derivation from the Swiss RAI-HC, hence replicating previous demonstrations based on interRAI instruments. The results also replicated findings showing that the FI is a good predictor of adverse health outcomes. Yet, the results suggest that home care recipients demonstrate a frailty pattern different from the one reported in community dwellers but comparable to clinical samples. Further work is needed to assess the characteristics of the proposed index in community dwelling, non-clinical samples for comparability with the existing literature and external validation TRIAL REGISTRATION: ClinicalTrials.gov NCT03139162 . Retrospectively registered May 2, 2017. PMID- 28882128 TI - Institutional maternal and perinatal deaths: a review of 40 low and middle income countries. AB - BACKGROUND: Understanding the magnitude and clinical causes of maternal and perinatal mortality are basic requirements for positive change. Facility-based information offers a contextualized resource for clinical and organizational quality improvement. We describe the magnitude of institutional maternal mortality, causes of death and cause-specific case fatality rates, as well as stillbirth and pre-discharge neonatal death rates. METHODS: This paper draws on secondary data from 40 low and middle income countries that conducted emergency obstetric and newborn care assessments over the last 10 years. We reviewed 6.5 million deliveries, surveyed in 15,411 facilities. Most of the data were extracted from reports and aggregated with excel. RESULTS: Hemorrhage and hypertensive diseases contributed to about one third of institutional maternal deaths and indirect causes contributed another third (given the overrepresentation of sub-Saharan African countries with large proportions of indirect causes). The most lethal obstetric complication, across all regions, was ruptured uterus, followed by sepsis in Latin America and the Caribbean and sub Saharan Africa. Stillbirth rates exceeded pre-discharge neonatal death rates in nearly all countries, possibly because women and their newborns were discharged soon after birth. CONCLUSIONS: To a large extent, facility-based findings mirror what population-based systematic reviews have also documented. As coverage of a skilled attendant at birth increases, proportionally more deaths will occur in facilities, making improvements in record-keeping and health management information systems, especially for stillbirths and early neonatal deaths, all the more critical. PMID- 28882129 TI - IGF1R activation and the in vitro antiproliferative efficacy of IGF1R inhibitor are inversely correlated with IGFBP5 expression in bladder cancer. AB - BACKGROUND: The insulin growth factor (IGF) pathway has been proposed as a potential therapeutic target in bladder cancer. We characterized the expression of components of the IGF pathway - insulin growth factor receptors (INSR, IGF1R, IGF2R), ligands (INS, IGF1, IGF2), and binding proteins (IGFBP1-7, IGF2BP1-3) - in bladder cancer and its correlation with IGF1R activation, and the anti proliferative efficacy of an IGF1R kinase inhibitor in this setting. METHODS: We analyzed transcriptomic data from two independent bladder cancer datasets, corresponding to 200 tumoral and five normal urothelium samples. We evaluated the activation status of the IGF pathway in bladder tumors, by assessing IGF1R phosphorylation and evaluating its correlation with mRNA levels for IGF pathway components. We finally evaluated the correlation between inhibition of proliferation by a selective inhibitor of the IGF1R kinase (AEW541), reported in 13 bladder cancer derived cell lines by the Cancer Cell Line Encyclopedia Consortium and mRNA levels for IGF pathway components. RESULTS: IGF1R expression and activation were stronger in non-muscle-invasive than in muscle-invasive bladder tumors. There was a significant inverse correlation between IGF1R phosphorylation and IGFBP5 expression in tumors. Consistent with this finding, the inhibition of bladder cell line viability by IGF1R inhibitor was also inversely correlated with IGFBP5 expression. CONCLUSION: The IGF pathway is activated and therefore a potential therapeutic target for non muscle-invasive bladder tumors and IGFBP5 could be used as a surrogate marker for predicting tumor sensitivity to anti-IGF therapy. PMID- 28882130 TI - The hemorrhagic transformation index score: a prediction tool in middle cerebral artery ischemic stroke. AB - BACKGROUND: We aimed to develop a tool, the hemorrhagic transformation (HT) index (HTI), to predict any HT within 14 days after middle cerebral artery (MCA) stroke onset regardless of the intravenous recombinant tissue plasminogen activator (IV rtPA) use. That is especially important in the light of missing evidence-based data concerning the timing of anticoagulant resumption after stroke in patients with atrial fibrillation (AF). METHODS: We retrospectively analyzed 783 consecutive MCA stroke patients. Clinical and brain imaging data at admission were recorded. A follow-up period was 2 weeks after admission. The patients were divided into derivation (DC) and validation (VC) cohorts by generating Bernoulli variates with probability parameter 0.7. Univariate/multivariate logistic regression, and factor analysis were used to extract independent predictors. Validation was performed with internal consistency reliability and receiver operating characteristic (ROC) analysis. Bootstrapping was used to reduce bias. RESULTS: The HTI was composed of 4 items: Alberta Stroke Program Early CT score (ASPECTS), National Institutes of Health Stroke Scale (NIHSS), hyperdense MCA (HMCA) sign, and AF on electrocardiogram (ECG) at admission. According to the predicted probability (PP) range, scores were allocated to ASPECTS as follows: 10 7 = 0; 6-5 = 1; 4-3 = 2; 2-0 = 3; to NIHSS: 0-11 = 0; 12-17 = 1; 18-23 = 2; >23 = 3; to HMCA sign: yes = 1; to AF on ECG: yes = 1. The HTI score varied from 0 to 8. For each score, adjusted PP of any HT with 95% confidence intervals (CI) was as follows: 0 = 0.027 (0.011-0.042); 1 = 0.07 (0.043-0.098); 2 = 0.169 (0.125 0.213); 3 = 0.346 (0.275-0.417); 4 = 0.571 (0.474-0.668); 5 = 0.768 (0.676 0.861); 6 = 0.893 (0.829-0.957); 7 = 0.956 (0.92-0.992); 8 = 0.983 (0.965-1.0). The optimal cutpoint score to differentiate between HT-positive and negative groups was 2 (95% normal-based CI, 1-3) for the DC and VC alike. ROC area/sensitivity/specificity with 95% normal-based CI for the DC and VC were 0.85 (0.82-0.89)/0.82 (0.73-0.9)/0.89 (0.8-0.97) and 0.83 (0.78-0.88)/0.8 (0.66 0.94)/0.87 (0.73-1.0) respectively. McDonald's categorical omega with 95% bias corrected and accelerated CI for the DC and VC was 0.81 (0.77-0.84) and 0.82 (0.76-0.86) respectively. CONCLUSIONS: The HTI is a simple yet reliable tool to predict any HT within 2 weeks after MCA stroke onset regardless of the IV rtPA use. PMID- 28882131 TI - An evaluation of Interprofessional group antenatal care: a prospective comparative study. AB - BACKGROUND: Maternal and neonatal outcomes are influenced by the nature of antenatal care. Standard pregnancy care is provided on an individual basis, with one-on-one appointments between a client and family doctor, midwife or obstetrician. A novel, group-based antenatal care delivery model was developed in the United States in the 1990s and is growing in popularity beyond the borders of the USA. The purpose of this study was to evaluate outcomes in clients receiving interprofessional group perinatal care versus interprofessional individual care in a Canadian setting. METHODS: Clients attending the South Community Birth Program (SCBP), an interprofessional, collaborative, primary care maternity program, offering both individual and group care, were invited to participate in the study. Pregnancy knowledge and satisfaction scores, and perinatal outcomes were compared between those receiving group versus individual care. Chi-square tests, general linear models and logistic regression were used to compare the questionnaire scores and perinatal outcomes between cohorts. RESULTS: Three hundred three clients participated in the study. Group care was comparable to individual care in terms of mode of birth, gestational age at birth, infant birth weight, breastfeeding rates, pregnancy knowledge, preparedness for labour and baby care, and client satisfaction. The rates of adverse perinatal outcomes were extremely low amongst SCBP clients, regardless of the type of care received (preterm birth rates ~5%). Breastfeeding rates were very high amongst all study participants (> 78% exclusive breastfeeding), as were measures of pregnancy knowledge and satisfaction. CONCLUSIONS: This is the first Canadian study to compare outcomes in clients receiving interprofessional group care versus individual care. Our observation that interprofessional group care outcomes and satisfaction were as good as interprofessional individual care has important implications for the antenatal care of clients and for addressing the projected maternity provider crisis facing Canada, particularly in small and rural communities. Further study of group-based care including not only client satisfaction, but also provider satisfaction, is needed. In addition, research into the role of interprofessional care in meeting the needs and improving perinatal outcomes of different populations is necessary. PMID- 28882132 TI - Hospital volume and the risk of revision in Oxford unicompartmental knee arthroplasty in the Nordic countries -an observational study of 14,496 cases. AB - BACKGROUND: High procedure volume and dedication to unicompartmental knee arthroplasty (UKA) has been suggested to improve revision rates. This study aimed to quantify the annual hospital volume effect on revision risk in Oxfordu nicompartmental knee arthroplasty in the Nordic countries. METHODS: 14,496 cases of cemented medial Oxford III UKA were identified in 126 hospitals in the four countries included in the Nordic Arthroplasty Register Association (NARA) database from 2000 to 2012. Hospitals were divided by quartiles into 4 annual procedure volume groups (<=11, 12-23, 24-43 and >=44). The outcome was revision risk after 2 and 10 years calculated using Kaplan Meier method. Multivariate Cox regression analysis was used to assess the Hazard Ratio (HR) of any revision due to specific reasons with 95% confidence intervals (CI). RESULTS: The implant survival was 80% at 10 years in the volume group <=11 procedures per year compared to 83% in other volume groups. The HR adjusted for age category, sex, year of surgery and nation was 0.87 (95% CI: 0.76-0.99, p = 0.036) for the group 12-23 procedures per year, 0.78 (95% CI: 0.68-0.91, p = 0.002) for the group 24 43 procedures per year and 0.82 (95% CI: 0.70-0.94, p = 0.006) for the group >=44 procedures per year compared to the low volume group. Log-rank test was p = 0.003. The risk of revision for unexplained pain was 40-50% higher in the low compared with other volume groups. CONCLUSION: Low volume hospitals performing <=11 Oxford III UKAs per year were associated with an increased risk of revision compared to higher volume hospitals, and unexplained pain as revision cause was more common in low volume hospitals. PMID- 28882134 TI - A conceptual framework for patient-centered fertility treatment. AB - BACKGROUND: Patient-centered care is a pillar of quality health care and is important to patients experiencing infertility. In this study we used empirical, in-depth data on couples' experiences of infertility treatment decision making to inform and revise a conceptual framework for patient-centered fertility treatment that was developed based on health care professionals' conceptualizations of fertility treatment, covering effectiveness, burden, safety, and costs. METHODS: In this prospective, longitudinal mixed methods study, we collected data from both members (separately) of 37 couples who scheduled an initial consult with a reproductive specialist. Data collection occurred 1 week before the initial consultation, 1 week after the initial consultation, and then roughly 2, 4, 8, and 12 months later. Data collection included semi-structured qualitative interviews, self-reported questionnaires, and medical record review. Interviews were recorded, transcribed, and content analyzed in NVivo. A single coder analyzed all transcripts, with > 25% of transcripts coded by a second coder to ensure quality control and consistency. RESULTS: Content analysis of the interview transcripts revealed 6 treatment dimensions: effectiveness, physical and emotional burden, time, cost, potential risks, and genetic parentage. Thus, the revised framework for patient-centered fertility treatment retains much from the original framework, with modification to one dimension (from safety to potential risks) and the addition of two dimensions (time and genetic parentage). For patients and their partners making fertility treatment decisions, tradeoffs are explicitly considered across dimensions as opposed to each dimension being considered on its own. CONCLUSIONS: Patient-centered fertility treatment should account for the dimensions of treatment that patients and their partners weigh when making decisions about how to add a child to their family. Based on the lived experiences of couples seeking specialist medical care for infertility, this revised conceptual framework can be used to inform patient-centered treatment and research on infertility and to develop decision support tools for patients and providers. PMID- 28882133 TI - Is a motivational interviewing based lifestyle intervention for obese pregnant women across Europe implemented as planned? Process evaluation of the DALI study. AB - BACKGROUND: Process evaluation is an essential part of designing and assessing complex interventions. The vitamin D and lifestyle intervention study (DALI) study is testing different strategies to prevent development of gestational diabetes mellitus among European obese pregnant women with a body mass index >=29 kg/m2. The intervention includes guidance on physical activity and/or healthy eating by a lifestyle coach trained in motivational interviewing (MI). The aim of this study was to assess the process elements: reach, dose delivered, fidelity and satisfaction and to investigate whether these process elements were associated with changes in gestational weight gain (GWG). METHODS: Data on reach, dose delivered, fidelity, and satisfaction among 144 participants were collected. Weekly recruitment reports, notes from meetings, coach logs and evaluation questionnaires (n = 110) were consulted. Fidelity of eight (out of twelve) lifestyle coach practitioners was assessed by analysing audio recorded counselling sessions using the MI treatment integrity scale. Furthermore, associations between process elements and GWG were assessed with linear regression analyses. RESULTS: A total of 20% of the possible study population (reach) was included in this analysis. On average 4.0 (of the intended 5) face-to face sessions were delivered. Mean MI fidelity almost reached 'expert opinion' threshold for the global scores, but was below 'beginning proficiency' for the behavioural counts. High variability in quality of MI between practitioners was identified. Participants were highly satisfied with the intervention, the lifestyle coach and the intervention materials. No significant associations were found between process elements and GWG. CONCLUSION: Overall, the intervention was well delivered and received by the study population, but did not comply with all the principles of MI. Ensuring audio recording of lifestyle sessions throughout the study would facilitate provision of individualized feedback to improve MI skills. A larger sample size is needed to confirm the lack of association between process elements and GWG. TRIAL REGISTRATION: ISRCTN registry: ISRCTN70595832 ; Registered 12 December 2011. PMID- 28882135 TI - Wait time management strategies for total joint replacement surgery: sustainability and unintended consequences. AB - BACKGROUND: In Canada, long waiting times for core specialized services have consistently been identified as a key barrier to access. Governments and organizations have responded with strategies for better access management, notably for total joint replacement (TJR) of the hip and knee. While wait time management strategies (WTMS)are promising, the factors which influence their sustainable implementation at the organizational level are understudied. Consequently, this study examined organizational and systemic factors that made it possible to sustain waiting times for TJR within federally established limits and for at least 18 months or more. METHODS: The research design is a multiple case study of WTMS implementation. Five cases were selected across five Canadian provinces. Three success levels were pre-defined: 1) the WTMS maintained compliance with requirements for more than 18 months; 2) the WTMS met requirements for 18 months but could not sustain the level thereafter; 3) the WTMS never met requirements. For each case, we collected documents and interviewed key informants. We analyzed systemic and organizational factors, with particular attention to governance and leadership, culture, resources, methods, and tools. RESULTS: We found that successful organizations had specific characteristics: 1) management of the whole care continuum, 2) strong clinical leadership; 3) dedicated committees to coordinate and sustain strategy; 4) a culture based on trust and innovation. All strategies led to relatively similar unintended consequences. The main negative consequence was an initial increase in waiting times for TJR and the main positive consequence was operational enhancement of other areas of specialization based on the TJR model. CONCLUSIONS: This study highlights important differences in factors which help to achieve and sustain waiting times. To be sustainable, a WTMS needs to generate greater synergies between contextual-level strategy (provincial or regional) and organizational objectives and constraints. Managers at the organizational level should be vigilant with regard to unintended consequences that a WTMS in one area can have for other areas of care. A more systemic approach to sustainability can help avoid or mitigate undesirable unintended consequences. PMID- 28882136 TI - Lessons learned on recruitment and retention in hard-to-reach families in a phase III randomised controlled trial of preparatory information for children undergoing general anaesthesia. AB - BACKGROUND: Recruitment and retention are documented as two of the most difficult elements of conducting clinical trials. These issues are even more challenging in paediatric trials, particularly when the families being recruited and retained are deemed 'hard to reach'. METHODS: Through the authors' own reflection on the conduct of the trial this paper examines recruitment and retention with hard to reach families from the perspective of a recently completed clinical trial on preparatory information for children undergoing general anaesthesia for tooth extractions in which approximately 83% of those approached and eligible agreed to participate. RESULTS: The lessons learned for recruitment include: the importance of children's assent; maximising limited resources when screening and approaching potential participants; valuing families' time; and developing effective professional relationships. The retention rate was 83-85.5% at follow up time points up to 3.5 weeks following recruitment, insights into how this was accomplished include: ensuring continuity of care; determination to connect via telephone; valuing families' time; and close monitoring of appointment date changes. CONCLUSIONS: Implications for future paediatric trials with hard to reach families are discussed. TRIAL REGISTRATION: ISRCTN18265148 ; NIHR Portfolio 10,006. Date of Registration: 29 November 2013. The trial was registered after commencement but before completion of data collection. PMID- 28882137 TI - Methodology for the assessment of brucellosis management practices and its vaccination campaign: example in two Argentine districts. AB - BACKGROUND: In Argentina, vaccination with Brucella abortus Strain 19 vaccine is mandatory. The objective of the study was to develop and test a method for evaluating, in an innovative way, some farmers' and veterinarians' management practices in relation to brucellosis and to assess the vaccination campaign and coverage. The work took place in Brandsen and Navarro districts. Four questionnaires were designed (for officials from Local Sanitary Entities, vaccinators, vet practitioners and farmers). Responses were coded as "ideal" (0) and "not ideal" (1). To assess the relative weight of each question ("item"), experts ranked the items according to their impact on management practices and vaccination. A weighted score was then calculated. A higher weighted score was assigned to the worse practices. Farmers obtaining a global weighted score above the third quartile were classified as "inappropriately managed farms", to be compared per type of production system and district. To assess the immunization coverage, female calves were sampled 30 to 50 days post vaccination; they were expected to react positively to serological diagnostic tests (DT+). RESULTS: There were significantly more inappropriately managed farms and higher global scores among beef farmers and in Brandsen. Eighty three percent (83%) of female calves were DT+, significantly under the ideal immunization coverage (95%). Only 48% of farms were considered well vaccinated. DT+ results were positively associated with the Brandsen district (OR = 25.94 [4.60-1146.21] and with the farms having more than 200 cow heads ((OR = 78.34 [4.09-1500.00]). On the contrary, DT+ were less associated with vaccinators being veterinary practitioners (OR = 0.07 [0.006-0.78]). Farmers are well advised by their veterinary practitioners but they should improve some management practices. CONCLUSIONS: The vaccination campaign is globally well implemented, but the immunization coverage and some vaccinators' practices should be improved. This study leads to a better understanding of the most common used management and control practices regarding brucellosis, which affect its epidemiology. Any vaccination campaign should be periodically assessed to highlight possible fails. The described methodology can be extrapolated to other countries and different contexts. PMID- 28882138 TI - A dual therapy of off-pump temporary left ventricular extracorporeal device and amniotic stem cell for cardiogenic shock. AB - BACKGROUND: Temporary mechanical circulatory support device without sternotomy has been highly advocated for severe cardiogenic shock patient but little is known when coupled with amniotic stem cell therapy. CASE PRESENTATION: This case reports the first dual therapy of temporary left ventricular extracorporeal device CentriMag with distal banding technique and human amniotic stem cell injection for treating a severe refractory cardiogenic shock of an 68-year-old female patient. A minimally-invasive off-pump LVAD was established by draining from the left ventricle and returning to the right axillary artery with distal arterial banding to prevent right upper extremity hyperperfusion. Amniotic stem cells were injected intramyocardially at the left ventricular apex, lateral wall, inferior wall, and right subclavian vein. CONCLUSION: The concomitant use of the temporary minimally-invasive off-pump CentriMag placement and stem cell therapy not only provided an alternative to cardiopulmonary bypass and full-median sternotomy procedures but may have also synergistically enhanced myocardial reperfusion and regeneration. PMID- 28882139 TI - The influence of institutional discourses on the work of informal carers: an institutional ethnography from the perspective of informal carers. AB - BACKGROUND: The growing numbers of seniors worldwide and the need for support and services that follow from a higher standard of living have led to an increased focus on scarce benefits and limited human resources. At the same time, many western countries have had to make welfare cuts to balance budgets. This has brought the contributions of informal carers to the fore. Thus far, the focus has generally been on the need for the informal carers to receive information and support; to enable them to contribute. METHODS: The study is designed as an institutional ethnography. The article describes the social processes of informal caregiving and how it interacts with formal caregiving, from the perspective of informal carers. The research question for the study is How do institutional discourses on the work of informal carers influence informal carework? Data for the article comes from qualitative semi-structured interviews with 26 informal carers caring for persons with dementia in Norway, and with 7 administrators working in the allocation divisions of five different municipalities. RESULTS: The results demonstrate how three institutional discourses of informal carers' work influence the allocation divisions' practices and the work of informal carers in caring for their next of kin. The three discourses are categorised as moral and family obligation, shared care and task specificity. The informal carers want to contribute, as they feel a family and moral obligation to their next of kin. In the interaction with the allocation division, they find that the expectation that they will share in the carework and perform specific tasks forces them to perform care within a framework set by the public services. CONCLUSIONS: The findings suggest that further research should challenge how services are distributed and allocated rather than focus on how to enable informal carers to fulfil their role better. Because of their moral and family obligation, the informal carers do not have to be forced to perform certain tasks or parts of the shared care. To maintain the informal carers' carework and to fully utilise their contributions, public services would benefit from collaborating with the informal carers to fulfil the total care need of the person with dementia. PMID- 28882140 TI - Role of mitochondrial dysfunction and dysregulation of Ca2+ homeostasis in the pathophysiology of insulin resistance and type 2 diabetes. AB - Metabolic diseases such as obesity, type 2 diabetes (T2D) and insulin resistance have attracted great attention from biomedical researchers and clinicians because of the astonishing increase in its prevalence. Decrease in the capacity of oxidative metabolism and mitochondrial dysfunction are a major contributor to the development of these metabolic disorders. Recent studies indicate that alteration of intracellular Ca2+ levels and downstream Ca2+-dependent signaling pathways appear to modulate gene transcription and the activities of many enzymes involved in cellular metabolism. Ca2+ uptake into mitochondria modulates a number of Ca2+ dependent proteins and enzymes participating in fatty acids metabolism, tricarboxylic acid cycle, oxidative phosphorylation and apoptosis in response to physiological and pathophysiological conditions. Mitochondrial calcium uniporter (MCU) complex has been identified as a major channel located on the inner membrane to regulate Ca2+ transport into mitochondria. Recent studies of MCU complex have increased our understanding of the modulation of mitochondrial function and retrograde signaling to the nucleus via regulation of the mitochondrial Ca2+ level. Mitochondria couple cellular metabolic state by regulating not only their own Ca2+ levels, but also influence the entire network of cellular Ca2+ signaling. The mitochondria-associated ER membranes (MAMs), which are specialized structures between ER and mitochondria, are responsible for efficient communication between these organelles. Defects in the function or structure of MAMs have been observed in affected tissue cells in metabolic disease or neurodegenerative disorders. We demonstrated that dysregulation of intracellular Ca2+ homeostasis due to mitochondrial dysfunction or defects in the function of MAMs are involved in the pathogenesis of insulin insensitivity and T2D. These observations suggest that mitochondrial dysfunction and disturbance of Ca2+ homeostasis warrant further studies to assist the development of therapeutics for prevention and medication of insulin resistance and T2D. PMID- 28882141 TI - 3-dimensional versus conventional laparoscopy for benign hysterectomy: protocol for a randomized clinical trial. AB - BACKGROUND: Hysterectomy is one of the most common surgical procedures for women of reproductive age. Laparoscopy was introduced in the 1990es and is today one of the recommended routes of surgery. A recent observational study showed that operative time for hysterectomy was significantly lower for 3-dimensional compared to conventional laparoscopy. Complication rates were similar for the two groups. No other observational studies or randomized clinical trials have compared 3-dimensional to conventional laparoscopy in patients undergoing total hysterectomy for benign disease. The objective of the study is to determine if 3D laparoscopy gives better quality of life, less postoperative pain, less per- and postoperative complications, shorter operative time, or a shorter stay in hospital and a faster return to work or normal life, compared to conventional laparoscopy for benign hysterectomy. METHODS/DESIGN: The design is a randomised multicentre clinical trial. Participants will be 400 women referred for laparoscopic hysterectomy for benign indications. Patients will be randomized to 3-dimensional or conventional laparoscopic hysterectomy. Operative procedures will follow the same principles and the same standard whether the surgeon's vision is 3-dimensional or conventional laparoscopy. Primary outcomes will be the impact of surgery on quality of life, assessed by the SF 36 questionnaire, and postoperative pain, assessed by a Visual Analogue scale for pain measurement. With a standard deviation of 12 points on SF 36 questionnaire, a risk of type I error of 3.3% and a risk of type II error of 10% a sample size of 190 patients in each arm of the trial is needed. Secondarily, we will investigate operative time, time to return to work, length of hospital stay, and - and postoperative complications. DISCUSSION: This trial will be the first randomized clinical trial investigating the potential clinical benefits and harms of 3-dimensional compared to conventional laparoscopy. The results may provide more evidence regarding the future place of 3-dimensional laparoscopy in the range of endoscopic approaches for benign hysterectomy. TRIAL REGISTRATION: This study is registered at ClinicalTrial.gov: NCT02610985 November 16th 2015. November 2015. The regional Ethical committee approved it on the 12. November 2015, approval number: SJ-498. Data handling was approved by the Danish Data Protection Agency: REG-109-2015 on the 13. November 2015. PMID- 28882142 TI - Prospective associations of psychosocial adversity in childhood with risk factors for cardiovascular disease in adulthood: the MRC National Survey of Health and Development. AB - BACKGROUND: Studies assessing associations of childhood psychosocial adversity (e.g. sexual abuse, physical neglect, parental death), as opposed to socioeconomic adversity, with cardiovascular disease (CVD) risk factors in adulthood are scarce. We aimed to assess associations of various forms of psychosocial adversity and cumulative adversity in childhood, with multiple CVD risk factors in mid-life. METHODS: Participants were from the MRC National Survey of Health and Development. Childhood psychosocial risk factors were reported prospectively by parents from 1950-1957, and retrospectively by participants at mean age 43 years in 1989. CVD risk factors were assessed at mean age 60-64 years in 2006-2011. Associations of a summary score of total psychosocial adversity and CVD risk in adulthood were assessed. RESULTS: There was no consistent evidence that cumulative psychosocial adversity, nor any specific form of psychosocial adversity in childhood, was associated with CVD risk factors in late adulthood. There was some evidence that parental death in the first 15 years was associated with higher SBP (Beta: 0.23, 95% confidence interval: 0.06 to 0.40, P=0.01) and DBP (Beta: 0.15, 95% confidence interval: -0.01 to 0.32, P=0.07). CONCLUSIONS: We found no evidence that exposure to greater psychosocial adversity, or specific forms of psychosocial adversity during childhood is associated with adult CVD risk factors. Further large population studies are needed to clarify whether parental death is associated with higher systolic and diastolic blood pressure. PMID- 28882144 TI - Sutureless aortic valve replacement in a calcified homograft combined with mitral valve replacement. AB - BACKGROUND: Aortic valve replacement in a patient with an aortic homograft can be very challenging, especially when concomitant mitral valve surgery needs to be performed. CASE PRESENTATION: We report a case of implantation of a sutureless aortic valve bioprosthesis combined with mitral valve replacement in a patient with a severely calcified aortic homograft where conventional valve replacement was technically unfeasible. CONCLUSIONS: We believe that sutureless AVR is a viable option especially for young patients with a high surgical risk where conventional valve replacement cannot be achieved. PMID- 28882143 TI - Characteristics of persons who inject drugs and who witness opioid overdoses in Vietnam: a cross-sectional analysis to inform future overdose prevention programs. AB - BACKGROUND: Persons who use opioids have a high risk of overdose and associated mortality. In Vietnam, little is known about the characteristics of this population and the persons who are witness to those overdoses. One approach to combatting fatal overdose has been the use of peer interventions in which a friend or injecting partner administers overdose reversal medication, but availability in Vietnam of these medications is limited to pilot programs with aims to expand in the future (Le Minh and V.F. Go, Personal Communication, 2016). The primary objective of this paper is to explore the characteristics associated with witnessing three or more overdoses in a lifetime. METHODS: This cross sectional analysis used baseline data from a four-arm randomized control trial conducted in Thai Nguyen, Vietnam, known as the Prevention for Positives project. One thousand six hundred seventy-three PWID were included in the analysis. We conducted bivariable and multivariable logistic regression to identify characteristics associated with witnessing three or more overdoses in a lifetime. Characteristics explored included education, employment, marital status, risky drug use behaviors, locations for accessing syringes, recent overdose, history of incarceration, drug treatment, and having slept outside in the past 3 months. RESULTS: Seventy-two percent (n = 1203) of participants had witnessed at least one overdose in their lifetime, and 46% had witnessed three or more overdoses (n = 765). In the multivariable model, having less than secondary education (AOR 0.70; 95% CI 0.57, 0.86), having slept outside in the past 3 months (AOR 1.77; 95% CI 1.31, 2.40), having a history of incarceration (AOR 1.33; 95% CI 1.07, 1.65), having a history of drug treatment (AOR 1.41; 95% CI 1.12, 1.77), experiencing a recent non-fatal overdose (AOR 3.84; 95% CI 2.36, 6.25), injecting drugs daily (AOR 1.79; 95% CI 1.45, 2.20), receptive needle sharing (AOR 1.30; 95% CI 1.04, 1.63), and number of years injecting (AOR 1.04; 95% CI 1.02, 1.07) were significantly associated with witnessing three or more overdoses. CONCLUSIONS: Targeted interventions are needed to train persons witnessing an overdose to administer overdose-reversal medication. This includes targeting persons prior to release from prisons, drug treatment centers, and those accessing syringe exchange programs. Additional research should assess the burden of witnessing an overdose as well as locations for medication distribution. Assessments of the training capacity and needs for implementing these programs among drug using peers in Vietnam are of the utmost importance. PMID- 28882145 TI - Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome. AB - BACKGROUND: Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13 mutations. In the 2017 EDS nosology, minimal criteria (general and gene-specific) for a clinical suspicion of spEDS have been proposed, but molecular analysis is required to reach a definite diagnosis. The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity and/or its complications. To date only 7 patients with beta4GALT7-deficiency (spEDS-B4GALT7) have been described and their clinical data suggested that, in addition to short stature and muscle hypotonia, radioulnar synostosis, hypermetropia, and delayed cognitive development might be a hallmark of this specific type of spEDS. Additional 22 patients affected with an overlapping phenotype, i.e., Larsen of Reunion Island syndrome, all carrying a homozygous B4GALT7 mutation, are also recognized. RESULTS: Herein, we report on a 30-year-old Moroccan woman who fitted the minimal criteria to suspect spEDS, but lacked radioulnar synostosis and intellectual disability and presented with neurosensorial hearing loss and limb edema of lymphatic origin. Sanger sequencing of B4GALT7 was performed since the evaluation of the spEDS gene-specific minor criteria suggested this specific subtype. Mutational screening revealed the homozygous c.829G>T, p.Glu277* pathogenetic variant leading to aberrant splicing. CONCLUSIONS: Our findings expand both the clinical and mutational spectrum of this ultrarare connective tissue disorder. The comparison of the patient's features with those of the other spEDS and Larsen of Reunion Island syndrome patients reported up to now offers future perspectives for spEDS nosology and clinical research in this field. PMID- 28882147 TI - Unexpected collateral impact after out of hospital resuscitation using LUCAS system. AB - BACKGROUND: Mechanical chest compression using a piston device during reanimation is often the only way to ensure stable chest compression at a constant rate and force. However, its use can be associated with severe fractures of the thoracic rib cage and endanger the clinical course of the patient. Thus, the usage of such a piston device during the reanimation has currently been classified as a mere Class IIB indication. CASE PRESENTATION: We present a case of a 66-year-old male who underwent emergent CABG surgery after receiving out-of-hospital resuscitation as a result of myocardial infarction using the LUCAS system. Due to severe bilateral rib fractures a concomitant emergency chest-wall stabilization surgery had to be performed to ensure uncompromised graft flow to obtain stable cardiac function and hemodynamics. CONCLUSIONS: Reanimation using LUCAS-System might enable stable resuscitation conditions. However, it is crucial not to underestimate potential collateral damage which can in turn aggravate patient's clinical condition. PMID- 28882146 TI - Does mosquito mass-rearing produce an inferior mosquito? AB - BACKGROUND: The success of the sterile insect technique depends, among other things, on continuous releases of sexually competitive sterile males within the target area. Several factors (including high rearing density and physical manipulation, such as larvae and pupae separation) can influence the quality of males produced in mass-rearing facilities. The different steps in mass production in the laboratory may modify the behaviour of mosquitoes, directly or through loss of natural characters as a result of adaptation to lab rearing, and lead to the competitiveness of sterile male being reduced. In the present study, the objective was to evaluate the effect of mass-rearing conditions on sterile male sexual competitiveness in semi-field cages compared to routine small scale laboratory rearing methods. METHODS: Anopheles arabiensis immature stages were reared both on a large scale using a rack and tray system developed by the FAO/IAEA (MRS), and on a small scale using standard laboratory rearing trays (SRS). Mosquito life history traits such as pupation rate, emergence rate, adult size as well as the effect of irradiation on adult longevity were evaluated. Moreover, 5-6 day old mosquitoes were released into field cages and left for two nights to mate and the mating competitiveness between sterile mass-reared males and fertile males reared on a small scale when competing for small scale reared virgin females was investigated. Resulting fertility in a treatment ratio of 1:1:1 (100 irradiated males: 100 non-irradiated males: 100 virgin females) was compared to control cages with 0:100:100 (non-irradiated control) and 100:0:100 (irradiated control). RESULTS: No significant differences in life history parameters were observed between rearing methods. The competitiveness index of mass reared males (0.58) was similar to males reared on a small scale (0.59). A residual fertility rate of 20% was observed in the irradiated control (100:0:100), measured as the percentage of eggs collected from the cages which developed to adulthood. No significant difference was observed (t = 0.2896, df = 4, P = 0.7865) between the rearing treatments (MRS and SRS) in the fertility rate, a measure of mating competitiveness. CONCLUSIONS: The results showed that the FAO/IAEA mass-rearing process did not affect mosquito life history parameters or the mating competitiveness of males. PMID- 28882148 TI - Environmental radon exposure and breast cancer risk in the Nurses' Health Study II. AB - BACKGROUND: Radon and its decay products, a source of ionizing radiation, are primarily inhaled and can deliver a radiation dose to breast tissue, where they may continue to decay and emit DNA damage-inducing particles. Few studies have examined the relationship between radon and breast cancer. METHODS: The Nurses' Health Study II (NHSII) includes U.S. female registered nurses who completed biennial questionnaires since 1989. Self-reported breast cancer was confirmed from medical records. County-level radon exposures were linked with geocoded residential addresses updated throughout follow-up. Time-varying Cox regression models adjusted for established breast cancer risk factors were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: From 1989 to 2013, 3966 invasive breast cancer cases occurred among 112,639 participants. Increasing radon exposure was not associated with breast cancer risk overall (adjusted HR comparing highest to lowest quintile = 1.06, 95% CI: 0.94, 1.21, p for trend = 0.30). However, women in the highest quintile of exposure (>=74.9 Bq/m3) had a suggested elevated risk of ER-/PR- breast cancer compared to women in the lowest quintile (<27.0 Bq/m3) (adjusted HR = 1.38, 95% CI: 0.97, 1.96, p for trend = 0.05). No association was observed for ER+/PR+ breast cancer. CONCLUSIONS: Although we did not find an association between radon exposure and risk of overall or ER+/PR+ breast cancer, we observed a suggestive association with risk of ER-/PR- breast cancer. PMID- 28882149 TI - Cost-effectiveness analysis of quadrivalent seasonal influenza vaccines in England. AB - BACKGROUND: As part of the national seasonal influenza vaccination programme in England and Wales, children receive a quadrivalent vaccine offering protection against two influenza A strains and two influenza B strains. Healthy children receive a quadrivalent live attenuated influenza vaccine (QLAIV), whilst children with contraindications receive the quadrivalent inactivated influenza vaccine (QIIV). Individuals aged younger than 65 years in the clinical risk populations and elderly individuals aged 65+ years receive either a trivalent inactivated influenza vaccine (TIIV) offering protection from two A strains and one B strain or the QIIV at the choice of their general practitioner. The cost-effectiveness of quadrivalent vaccine programmes is an open question. The original analysis that supported the paediatric programme only considered a trivalent live attenuated vaccine (LAIV). The cost-effectiveness of the QIIV to other patients has not been established. We sought to estimate the cost-effectiveness of these programmes, establishing a maximum incremental total cost per dose of quadrivalent vaccines over trivalent vaccines. METHODS: We used the same mathematical model as the analysis that recommended the introduction of the paediatric influenza vaccination programme. The incremental cost of the quadrivalent vaccine is the additional cost over that of the existing trivalent vaccine currently in use. RESULTS: Introducing quadrivalent vaccines can be cost effective for all targeted groups. However, the cost-effectiveness of the programme is dependent on the choice of target cohort and the cost of the vaccines: the paediatric programme is cost-effective with an increased cost of L6.36 per dose, though an extension to clinical risk individuals younger than 65 years old and further to all elderly individuals means the maximum incremental cost is L1.84 and L0.20 per dose respectively. CONCLUSIONS: Quadrivalent influenza vaccines will bring substantial health benefits, as they are cost effective in particular target groups. PMID- 28882150 TI - Care-managers' professional choices: ethical dilemmas and conflicting expectations. AB - BACKGROUND: Care-managers are responsible for the public administration of individual healthcare decisions and decide on the volume and content of community healthcare services given to a population. The purpose of this study was to investigate the conflicting expectations and ethical dilemmas these professionals encounter in their daily work with patients and to discuss the clinical implications of this. METHODS: The study had a qualitative design. The data consisted of verbatim transcripts from 12 ethical reflection group meetings held in 2012 at a purchaser unit in a Norwegian city. The participants consist of healthcare professionals such as nurses, occupational therapists, physiotherapists and social workers. The analyses and interpretation were conducted according to a hermeneutic methodology. This study is part of a larger research project. RESULTS: Two main themes emerged through the analyses: 1. Professional autonomy and loyalty, and related subthemes: loyalty to whom/what, overruling of decisions, trust and obligation to report. 2. Boundaries of involvement and subthemes: private or professional, care-manager or provider and accessibility. CONCLUSIONS: Underlying values and a model illustrating the dimensions of professional responsibility in the care-manager role are suggested. The study implies that when allocating services, healthcare professionals need to find a balance between responsibility and accountability in their role as care managers. PMID- 28882151 TI - Retraction Note: Astragalus saponins affect proliferation, invasion and apoptosis of gastric cancer BGC-823 cells. PMID- 28882152 TI - Impact of the Supporting Physical Activity in the Childcare Environment (SPACE) intervention on preschoolers' physical activity levels and sedentary time: a single-blind cluster randomized controlled trial. AB - BACKGROUND: Physical activity levels among preschoolers in childcare are low and sedentary time high. The Supporting Physical Activity in the Childcare Environment (SPACE) intervention had three components: 1. portable play equipment; 2. staff training; and, 3. modified outdoor playtime (i.e., shorter, more frequent periods). This study aimed to examine the effectiveness of the SPACE intervention on preschoolers' physical activity levels and sedentary time during childcare hours (compared to standard care). METHODS: Via a single-blind cluster randomized controlled trial, 338 preschoolers (39.86 +/- 7.33 months; 52% boys) from 22 centre-based childcare facilities (11 experimental, 11 control) were enrolled. Preschoolers wore an ActicalTM accelerometer for 5 days during childcare hours at baseline, post-intervention, and 6- and 12-month follow-up, and were included in the analyses if they had a minimum of two valid days (5 h each day) at baseline and one additional time point. Intervention effectiveness was tested using a linear mixed effects model for each of the four outcome variables (i.e., sedentary time, light physical activity [LPA], moderate-to vigorous physical activity [MVPA], and total physical activity [TPA]). Fixed effects were further evaluated with t-tests, for which degrees of freedom were estimated using a Satterthwaite approximation. RESULTS: One hundred and ninety five preschoolers were retained for analyses. The intervention did not significantly impact LPA. MVPA was significantly greater among children in the experimental group when comparing post-intervention to pre-intervention, t(318) = 3.50, p = .0005, but no intervention effects were evident at 6- or 12-month follow-up. TPA was significantly greater for children in the intervention group at post-intervention when compared to pre-intervention, t(321) = 2.70, p = .007, with no intervention effects evident at later time periods. Finally, sedentary time was significantly lower among preschoolers in the experimental group when comparing post-intervention to pre-intervention, t(322) = 2.63, p = .009, with no significant effects at follow-up. CONCLUSIONS: The SPACE intervention was effective at increasing MVPA and TPA among preschoolers, while simultaneously decreasing sedentary time. The ability of the SPACE intervention to target higher intensity activity is promising, as MVPA levels have been documented to be low in centre-based childcare. The changes in physical activity were not sustained long term (6- or 12-month follow-up). TRIAL REGISTRATION: ISRCTN70604107 (October 8, 2014). PMID- 28882153 TI - Susceptibility of Moroccan sheep and goat breeds to peste des petits ruminants virus. AB - BACKGROUND: Peste des petits ruminants (PPR) is a highly contagious viral disease of small ruminants in Asia and Africa. In 2008, a PPR outbreak was reported for the first time in Morocco and a mass vaccination campaign allowed control of the disease. In this study, the susceptibility of four Moroccan local breeds of small ruminants to PPR virus was investigated by experimental infections. The objective was to make recommendations for improved epidemiological surveillance in Morocco by evaluating the susceptibility of the dominant Moroccan small ruminant breeds. Three parameters were studied: hyperthermia, clinical scoring and virus excretion. The outcome was compared to Alpine goats, which are considered one of the most sensitive breeds. RESULTS: The study showed that the local goat breed was the most sensitive breed with a susceptibility rate of 67%, followed by Timahdit, Beni Guil and Sardi sheep with 48, 29 and 26%, respectively. Serological testing including enzyme-linked immunosorbent assay and viral neutralization showed that the Timahdit breed developed a stronger antibody response compared to the other breeds. Although the clinical signs observed in the sheep were mild, evidence of viral excretion was detected by means of a polymerase chain reaction assay. CONCLUSIONS: It is recommended that effective surveillance should focus on susceptible breeds complemented with serological surveillance of the sheep population. PMID- 28882154 TI - Evaluation of continuing education of family health strategy teams for the early identification of suspected cases of cancer in children. AB - BACKGROUND: This study evaluated the influence of continuing education of family health strategy teams by the Ronald McDonald Institute program on the early diagnosis of cancer in children and adolescents. METHODS: The study applied Habicht's model to evaluate the adequacy and plausibility of continuing education by using as outcome the number of children with suspected cancer who were referred to the hospital of references in the 1 year before and 1 year after intervention and the number of patients referred by intervention group and control group family health strategy teams. Medical records from each hospital of reference were used to collect information of suspect cases of cancer. Descriptive analyses were performed using frequencies and mean values. Chi-square tests were used to assess statistically significant differences between the groups and periods by using p-values < 0.05. RESULTS: The results showed a 30.6% increase in the number of children referred to the hospital of reference for suspected cancer in the post-intervention period; in addition, the family health strategy teams that underwent the intervention referred 3.6 times more number of children to hospital of references than did the control group. Only the intervention group showed an increase in the number of confirmed cases. CONCLUSIONS: This evaluation of a continuing education program for early identification of pediatric cancer showed that the program was adequate in achieving the established goals and that the results could be attributed to the program. PMID- 28882155 TI - Barriers to retention in methadone maintenance therapy among people who inject drugs in Bangkok, Thailand: a mixed-methods study. AB - BACKGROUND: Methadone maintenance therapy (MMT) is a mainstay for treating opioid use disorder and preventing and managing HIV among people who inject drugs (PWID). While previous research suggested low dosing of methadone and high rates of discontinuation of MMT among PWID in Thailand, little is known about patients' lived experiences with MMT in this setting. Therefore, we conducted a mixed methods study to examine barriers to retention in MMT among PWID in Bangkok, Thailand, with particular attention to methadone dosing. METHODS: Bivariate statistics were used to analyze quantitative survey data collected from methadone treated PWID between July and October 2011. Qualitative data collected through semi-structured interviews with 16 methadone-treated PWID between July 2011 and June 2012 were analyzed thematically, with a focus on individual-level, social structural, and environmental barriers to accessing MMT. RESULTS: Among 158 survey participants, a median dosage of methadone was 30 mg/day (interquartile range 20-50). Of these, 15.8% reported having acquired street methadone due to low prescribed dosages of methadone and 19.0% reported recent syringe sharing. Qualitative interview data indicated some methadone provider-related barriers, including discouraging patients from using methadone due to it being a Western medicine, difficulty negotiating higher doses of methadone, and abrupt dose reductions without patient consultation (involving the provision of non-medicated "syrup" in some cases). Social-structural and environmental barriers to optimal MMT access included intense police surveillance of methadone clinics; and frequent incarceration of PWID and a lack of access to methadone in prisons. CONCLUSIONS: Among our sample of methadone-treated PWID, methadone dosages were suboptimal according to the international guidelines. Poor adherence to international guidelines for opioid agonist therapies, aggressive law enforcement, and a lack of methadone in prisons need to be addressed to optimize MMT and reduce harms associated with untreated opioid use disorder in Thailand. PMID- 28882156 TI - Comparative safety and efficacy of pharmacological and non-pharmacological interventions for the behavioral and psychological symptoms of dementia: protocol for a systematic review and network meta-analysis. AB - BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in patients with dementia. Both pharmacological and non-pharmacological strategies are commonly used to treat these symptoms, but their comparative safety and efficacy is unknown. METHODS: We will conduct a systematic review of the published and unpublished literature to retrieve all articles pertaining to outcomes of safety and efficacy associated with pharmacological and non pharmacological treatments of BPSD for patients living in the community and institutionalized care settings. Our primary outcome of efficacy is a change in aggression. Our primary outcome of safety will be risk of fracture. These primary outcomes were chosen by stakeholders involved in the care of patients experiencing BPSD. Possible secondary outcomes of efficacy will include a change in agitation, depressive symptoms, and night-time behaviors. Possible secondary outcomes of safety will include the risk of stroke, falls, and mortality. All article screening, data abstraction, and risk of bias appraisal will be completed independently by two reviewers. If the assumption of transitivity is valid and the evidence forms a connected network, Bayesian random-effects pairwise and network meta-analyses (NMAs) will be conducted. Relative treatment rankings will be reported with mean ranks and the surface under the cumulative ranking curve. DISCUSSION: We will identify the safest and most efficacious treatment strategies for patients with BPSD from among our most highly ranked treatments. The results of this study will be used to guide decision-making and improve patient care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number CRD42017050130. PMID- 28882157 TI - Symptom management in complex post-traumatic stress disorder (ICD-11), view and experience of patients and their relatives: a mixed methods approach (Research Proposal). AB - OBJECTIVE: Using the framework of IDC-11, complex post-traumatic stress disorder will be diagnosed using the core criteria of a post-traumatic stress disorder and the presence of at least one symptom from the following three domains: symptoms of emotional dysregulation, negative self-concept, and problems in interpersonal relationships. In the literature, these symptoms are discussed as a common reason for seeking treatment. The symptoms can influence and impair the quality of life. This article describes a mixed methods study with a sequential exploratory design. The aim is to describe specific patient characteristics, levels of symptom burden and perspectives of adult inpatients and to describe the experiences, views and needs of patients' relatives. The study will also investigate facilitators of and barriers to symptom management. The research will be conducted in four phases. The first phase will assess patients' symptom burdens. The second phase will use semi-structured interviews to explore attitudes to symptom management and perceptions of patients and their relatives. The third phase will statistically explore hypotheses generated after the qualitative interviews. The fourth phase will mix the quantitative and qualitative results and interpret critically. RESULTS: The present study will add new results to the growing literature on complex post-traumatic stress disorder. These results could serve as the basis for further research into the development of interventions to improve symptom management. Trial registration Ethical approval has been obtained from the Swiss cantonal ethic commission (Nr. 201500096). This research was also registered to the World Health Organization Clinical Trials Search Portal through the German Clinical Trial Register, Trial DRKS00012268 (21/04/2017). PMID- 28882158 TI - International tuberculosis research collaborations within Asia. AB - BACKGROUND: Asia bears more than half the global tuberculosis (TB) burden. Economic development in the region has increased available funding for biomedical research and opportunity for collaboration. We explored the extent of international tuberculosis research collaborations between institutions within Asia. METHODS: We conducted a Pubmed search for all articles with tuberculosis in the title published during a 12 month period with at least one author affiliation listed in Asia, then identified international collaborations from institution websites and internet searches. RESULTS: We identified 99 international collaborations involving an institution within Asia, of which only 8 (8.1%) were collaborations between Asian institutions. The remainder were with institutions outside of Asia. CONCLUSIONS: The paucity of intra-Asian international research collaboration represents a lost opportunity to optimise regional research funding, capacity building and the development of an Asia-relevant TB research agenda. PMID- 28882159 TI - Estrogen attenuates the spondyloarthritis manifestations of the SKG arthritis model. AB - BACKGROUND: Ankylosing spondylitis (AS) is a male-predominant disease, and radiographic evidence of damage is also more severe in males. Estrogen modulates immune-related processes such as T cell differentiation and cytokine production. This study aimed to evaluate the effect of estrogen on the disease activity of spondyloarthritis (SpA). METHODS: The effects of estrogen on the development of arthritis were evaluated by performing ovariectomy and 17beta-estradiol (E2) pellet implantation in zymosan-treated SKG mice. Clinical arthritis scores were measured, and 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography performed to quantify joint inflammation. The expression of inflammatory cytokines in joint tissue was measured. RESULTS: E2 treated mice showed remarkable suppression of arthritis clinically and little infiltration of inflammatory cells in the Achilles tendon and intervertebral disc. 18F-FDG uptake was significantly lower in E2-treated mice than in sham operated (sham) and ovariectomized mice. Expression of TNF, interferon-gamma, and IL-17A was significantly reduced in E2-treated mice, whereas expression of sclerostin and Dickkopf-1 was increased in E2-treated mice compared with sham and ovariectomized mice. CONCLUSIONS: Estrogen suppressed arthritis development in SKG mice, a model of SpA. Results of this study suggest that estrogen has an anti inflammatory effect on the spondyloarthritis manifestations of the SKG arthritis model. PMID- 28882161 TI - General Anesthesia versus Local Anesthesia in StereotaXY (GALAXY) for Parkinson's disease: study protocol for a randomized controlled trial. AB - BACKGROUND: The aim of the study is to investigate if deep brain stimulation (DBS) in the subthalamic nucleus (STN) for Parkinson's disease (PD) under general anesthesia further improves outcome by lessening postoperative cognitive, mood, and behavioral adverse effects; shorten surgical time and hospital admittance; and produce comparable symptomatic and functional improvement to surgery under local anesthesia. METHODS/DESIGN: The study will be a single-center, prospective, randomized, open-label, blinded endpoint trial comparing DBS under general anesthesia with DBS under local anesthesia. The primary outcome measure is a composite score of the postoperative cognitive, mood, and behavioral adverse effects and will be measured 6 months after surgery. The secondary outcome measures consist of changes in motor symptoms, adverse effects of stimulation and surgical complications, surgical time, functional health, quality of life, patient satisfaction with the outcome of treatment, patient evaluation of the burden of therapy, and medication. A total of 110 patients with advanced PD who are candidates for DBS will be randomized during a 2.5-year period. DISCUSSION: The aim of this trial is to further enhance the effectiveness of DBS treatment in PD while reducing the burden of DBS surgery by studying if DBS surgery under general anesthesia results in less cognitive, mood, and behavioral adverse effects compared with surgery under local anesthesia. TRIAL REGISTRATION: Netherlands Trial Register, NTR5809 . Registered on 23 April 2016. PMID- 28882162 TI - Factors influencing the practice of exclusive breastfeeding among nursing mothers in a peri-urban district of Ghana. AB - BACKGROUND: Exclusive breastfeeding (EBF) is one of the optimal infant and young child feeding practices. Globally, <40% of infants under 6 months of age are exclusively breastfed. In Ghana, 63% of children <6 months are exclusively breastfed which is far less than the 100% recommended by the United Nation Children Emergency Fund. This study was carried out to find out the factors that influence the practice of exclusive breastfeeding in the district. METHODS: A cross-sectional quantitative study was conducted using structured questionnaires. A convenience sampling technique was employed to select 380 nursing mothers who attended postnatal care at the postnatal clinic in all the 13 health facilities with child welfare clinics (both public and private) and were available on the day of data collection. Data were analysed using frequency and CHISQ tables. RESULTS: There was a significant association between socio-demographic characteristics of mothers such as age (p = 0.129), religion (p = 0.035) type of employment (p = 0.005) and the practice of exclusive breastfeeding. Again, there was significant relationship between mothers' knowledge on EBF in terms of sources of information about EBF (p = 0.000), steps taken by mothers who perceived not to have breast milk (p = 0.000), some medical conditions of nursing mothers (p = 0.000) and the practice of EBF. CONCLUSION: Most nursing mothers use infant formula feeds as either supplement or substitute for breast milk based on their perception that breast milk may not be sufficient for the babies despite the high cost of these artificial milk. This puts the babies at a higher risk of compromised health and malnutrition which has the potential of increasing infant mortality. Most mothers are not practicing exclusive breastfeeding because their spouses and family members do not allow them. PMID- 28882160 TI - Intrinsic fluorescence of the clinically approved multikinase inhibitor nintedanib reveals lysosomal sequestration as resistance mechanism in FGFR-driven lung cancer. AB - BACKGROUND: Studying the intracellular distribution of pharmacological agents, including anticancer compounds, is of central importance in biomedical research. It constitutes a prerequisite for a better understanding of the molecular mechanisms underlying drug action and resistance development. Hyperactivated fibroblast growth factor receptors (FGFRs) constitute a promising therapy target in several types of malignancies including lung cancer. The clinically approved small-molecule FGFR inhibitor nintedanib exerts strong cytotoxicity in FGFR driven lung cancer cells. However, subcellular pharmacokinetics of this compound and its impact on therapeutic efficacy remain obscure. METHODS: 3-dimensional fluorescence spectroscopy was conducted to asses cell-free nintedanib fluorescence properties. MTT assay was used to determine the impact of the lysosome-targeting agents bafilomycin A1 and chloroquine combined with nintedanib on lung cancer cell viability. Flow cytometry and live cell as well as confocal microscopy were performed to analyze uptake kinetics as well as subcellular distribution of nintedanib. Western blot was conducted to investigate protein expression. Cryosections of subcutaneous tumor allografts were generated to detect intratumoral nintedanib in mice after oral drug administration. RESULTS: Here, we report for the first time drug-intrinsic fluorescence properties of nintedanib in living and fixed cancer cells as well as in cryosections derived from allograft tumors of orally treated mice. Using this feature in conjunction with flow cytometry and confocal microscopy allowed to determine cellular drug accumulation levels, impact of the ABCB1 efflux pump and to uncover nintedanib trapping into lysosomes. Lysosomal sequestration - resulting in an organelle specific and pH-dependent nintedanib fluorescence - was identified as an intrinsic resistance mechanism in FGFR-driven lung cancer cells. Accordingly, combination of nintedanib with agents compromising lysosomal acidification (bafilomycin A1, chloroquine) exerted distinctly synergistic growth inhibitory effects. CONCLUSION: Our findings provide a powerful tool to dissect molecular factors impacting organismal and intracellular pharmacokinetics of nintedanib. Regarding clinical application, prevention of lysosomal trapping via lysosome alkalization might represent a promising strategy to circumvent cancer cell intrinsic nintedanib resistance. PMID- 28882163 TI - Prevalence and significance of Mycoplasma genitalium in women living with HIV in Denmark. AB - OBJECTIVE: Mycoplasma genitalium (M. genitalium) is a sexually transmitted pathogen associated with urethritis, cervicitis, and pelvic inflammatory disease. Previous studies have shown a strong association between M. genitalium and HIV infection, therefore screening and treatment for M. genitalium has been suggested as part of HIV prevention strategies. The objective of this study was to determine the prevalence of M. genitalium in women living with HIV (WLWH) in Denmark, and to compare the result with data on symptoms from the lower abdomen, sexual habits and immune status. 234 women, recruited from Danish HIV centres as part of a larger observational study on aspects of living with HIV as a woman (the SHADE study), were included. RESULTS: We tested cervical samples for M. genitalium by specific PCR. We found three samples positive (1.3%). The women were between 30 and 50 years old, all were of Asian origin, sexually active, and on antiretroviral treatment with supressed HIV RNA and CD4 count >350 cells/uL. None reported symptoms from the lower abdomen. The prevalence of M. genitalium infection in WLWH in Denmark is low, thus systematic screening for M. genitalium in this group does not seem relevant. PMID- 28882164 TI - The role of phospholipase C signaling in bovine herpesvirus 1 infection. AB - Bovine herpesvirus 1 (BoHV-1) infection enhanced the generation of inflammatory mediator reactive oxidative species (ROS) and stimulated MAPK signaling that are highly possibly related to virus induced inflammation. In this study, for the first time we show that BoHV-1 infection manipulated phospholipase C (PLC) signaling, as demonstrated by the activation of PLCgamma-1 at both early stages [at 0.5 h post-infection (hpi)] and late stages (4-12 hpi) during the virus infection of MDBK cells. Viral entry, and de novo protein expression and/or DNA replication were potentially responsible for the activation of PLCgamma-1 signaling. PLC signaling inhibitors of both U73122 and edelfosine significantly inhibited BoHV-1 replication in both bovine kidney cells (MDBK) and rabbit skin cells (RS-1) in a dose-dependent manner by affecting the virus entry stage(s). In addition, the activation of Erk1/2 and p38MAPK signaling, and the enhanced generation of ROS by BoHV-1 infection were obviously ameliorated by chemical inhibition of PLC signaling, implying the requirement of PLC signaling in ROS production and these MAPK pathway activation. These results suggest that the activation of PLC signaling is a potential pathogenic mechanism for BoHV-1 infection. PMID- 28882165 TI - Successful treatment of acute renal failure secondary to complicated infective endocarditis by peritoneal dialysis: a case report. AB - BACKGROUND: Infective endocarditis is one of the most common infections among intravenous drug addicts. Its complications can affect many systems, and these can include acute renal failure. There is a scarcity of cases in the literature related to acute renal failure secondary to infective endocarditis treated with peritoneal dialysis. In this paper, the case of a 48-year-old Saudi male is reported, who presented with features suggestive of infective endocarditis and who developed acute kidney injury that was treated successfully with high tidal volume automated peritoneal dialysis. To our knowledge, this is the second report of such an association in the literature. CASE PRESENTATION: A 48-year-old Saudi gentleman diagnosed to have a glucose-6-phosphate dehydrogenase deficiency and hepatitis C infection for the last 9 years, presented to the emergency department with a history of fever of 2 days' duration. On examination: his temperature = 41 degrees C, there was clubbing of the fingers bilaterally and a pansystolic murmur in the left parasternal area. The results of the blood cultures and echocardiogram were supportive of the diagnosis of infective endocarditis, and the patient subsequently developed acute kidney injury, and his creatinine reached 5.2 mg/dl, a level for which dialysis is essential for the patient to survive. CONCLUSION: High tidal volume automated peritoneal dialysis is highly effective as a renal replacement therapy in acute renal failure secondary to infective endocarditis if no contraindication is present. PMID- 28882166 TI - Social determinants of common metabolic risk factors (high blood pressure, high blood sugar, high body mass index and high waist-hip ratio) of major non communicable diseases in South Asia region: a systematic review protocol. AB - BACKGROUND: Prevalence of non-communicable diseases has been increasing at a greater pace in developing countries and, in particular, the South Asia region. Various behavioral, social and environmental factors present in this region perpetuate common metabolic risk factors of non-communicable diseases. This study will identify social determinants of common metabolic risk factors of major non communicable diseases in the context of the South Asian region and map their causal pathway. METHODS: A systematic review of selected articles will be carried out following Cochrane guidelines. Review will be guided by Social Determinants of Health Framework developed by the World Health Organization to extract social determinants of metabolic risk factors of non-communicable diseases from studies. A distinct search strategy will be applied using key words to screen relevant studies from online databases. Primary and grey literature published from the year 2000 to 2016 and studies with discussion on proximal and distal determinants of non-communicable risk factors among adults of the South Asia region will be selected. They will be further checked for quality, and a matrix illustrating contents of selected articles will be developed. Thematic content analysis will be done to trace social determinants and their interaction with metabolic risk factors. Findings will be illustrated in causal loop diagrams with social determinants of risk factors along with their interaction (feedback mechanism). DISCUSSION: The review will describe the interplay of social determinants of common NCD metabolic risk factors in the form of causal loop diagram. Findings will be structured in two parts: the first part will explain the linkage between proximal determinants with the metabolic risk factors and the second part will describe the linkage among the risk factors, proximal determinants and distal determinants. Evidences across different regions will be discussed to compare and validate and/or contrast the findings. Possible bias and limitations of this study will also be discussed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017067212. PMID- 28882167 TI - Implementation and results of an integrated data quality assurance protocol in a randomized controlled trial in Uttar Pradesh, India. AB - BACKGROUND: There are few published standards or methodological guidelines for integrating Data Quality Assurance (DQA) protocols into large-scale health systems research trials, especially in resource-limited settings. The BetterBirth Trial is a matched-pair, cluster-randomized controlled trial (RCT) of the BetterBirth Program, which seeks to improve quality of facility-based deliveries and reduce 7-day maternal and neonatal mortality and maternal morbidity in Uttar Pradesh, India. In the trial, over 6300 deliveries were observed and over 153,000 mother-baby pairs across 120 study sites were followed to assess health outcomes. We designed and implemented a robust and integrated DQA system to sustain high quality data throughout the trial. METHODS: We designed the Data Quality Monitoring and Improvement System (DQMIS) to reinforce six dimensions of data quality: accuracy, reliability, timeliness, completeness, precision, and integrity. The DQMIS was comprised of five functional components: 1) a monitoring and evaluation team to support the system; 2) a DQA protocol, including data collection audits and targets, rapid data feedback, and supportive supervision; 3) training; 4) standard operating procedures for data collection; and 5) an electronic data collection and reporting system. Routine audits by supervisors included double data entry, simultaneous delivery observations, and review of recorded calls to patients. Data feedback reports identified errors automatically, facilitating supportive supervision through a continuous quality improvement model. RESULTS: The five functional components of the DQMIS successfully reinforced data reliability, timeliness, completeness, precision, and integrity. The DQMIS also resulted in 98.33% accuracy across all data collection activities in the trial. All data collection activities demonstrated improvement in accuracy throughout implementation. Data collectors demonstrated a statistically significant (p = 0.0004) increase in accuracy throughout consecutive audits. The DQMIS was successful, despite an increase from 20 to 130 data collectors. CONCLUSIONS: In the absence of widely disseminated data quality methods and standards for large RCT interventions in limited-resource settings, we developed an integrated DQA system, combining auditing, rapid data feedback, and supportive supervision, which ensured high-quality data and could serve as a model for future health systems research trials. Future efforts should focus on standardization of DQA processes for health systems research. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02148952 . Registered on 13 February 2014. PMID- 28882168 TI - Detection of Cryptosporidium parvum and Cyclospora cayetanensis infections among people living in a slum area in Kathmandu valley, Nepal. AB - OBJECTIVE: The aim of this study is to determine the prevalence of Cyclospora cayetanensis and Cryptosporidium parvum infections among people living a slum in Kathmandu valley, Nepal. RESULTS: Ten different parasites were detected in the stool samples; the prevalence of any parasite was in 27.1% (71/262). The prevalence of C. cayetanensis and C. parvum were 14.1% (10/71) and 5.6% (4/71), respectively. This study showed high prevalence of intestinal parasitic infections along with the coccidian parasites in the slum area of Kathmandu Valley. PMID- 28882169 TI - Targeted therapeutic mild hypercapnia after cardiac arrest: a part of the bundle of care for mitigating secondary injury after cardiac arrest. PMID- 28882170 TI - Prognostic value of platelet-to-lymphocyte ratios among critically ill patients with acute kidney injury. AB - BACKGROUND: Inflammation plays an important role in the initiation and progression of acute kidney injury (AKI). However, evidence regarding the prognostic effect of the platelet-to-lymphocyte ratio (PLR), a novel systemic inflammation marker, among patients with AKI is scarce. In this study, we investigated the value of the PLR in predicting the outcomes of critically ill patients with AKI. METHODS: Patient data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care Database III version 1.3. PLR cutoff values were determined using smooth curve fitting or quintiles and were used to categorize the subjects into groups. The clinical outcomes were 30-day and 90-day mortality in the intensive care unit (ICU). Cox proportional hazards models were used to evaluate the association between the PLR and survival. RESULTS: A total of 10,859 ICU patients with AKI were enrolled. A total of 2277 thirty-day and 3112 ninety-day deaths occurred. A U-shaped relationship was observed between the PLR and both 90-day and 30-day mortality, with the lowest risk being at values ranging from 90 to 311. The adjusted HR (95% CI) values for 90-day mortality given risk values < 90 and > 311 were 1.25 (1.12-1.39) and 1.19 (1.08-1.31), respectively. Similar trends were observed for 30-day mortality or when quintiles were used to group patients according to the PLR. Statistically significant interactions were found between the PLR and both age and heart rate. Younger patients (aged < 65 years) and those with more rapid heart rates (>=89.4 beats per minute) tended to have poorer prognoses only when the PLR was < 90, whereas older patients (aged >= 65 years) and those with slower heart rates (<89.4 beats per minute) had higher risk only when the PLR was > 311 (P < 0.001 for age and P < 0.001 for heart rate). CONCLUSIONS: The preoperative PLR was associated in a U shaped pattern with survival among patients with AKI. The PLR appears to be a novel, independent prognostic marker of outcomes in critically ill patients with AKI. PMID- 28882171 TI - Application of random survival forests in understanding the determinants of under five child mortality in Uganda in the presence of covariates that satisfy the proportional and non-proportional hazards assumption. AB - BACKGROUND: Uganda just like any other Sub-Saharan African country, has a high under-five child mortality rate. To inform policy on intervention strategies, sound statistical methods are required to critically identify factors strongly associated with under-five child mortality rates. The Cox proportional hazards model has been a common choice in analysing data to understand factors strongly associated with high child mortality rates taking age as the time-to-event variable. However, due to its restrictive proportional hazards (PH) assumption, some covariates of interest which do not satisfy the assumption are often excluded in the analysis to avoid mis-specifying the model. Otherwise using covariates that clearly violate the assumption would mean invalid results. METHODS: Survival trees and random survival forests are increasingly becoming popular in analysing survival data particularly in the case of large survey data and could be attractive alternatives to models with the restrictive PH assumption. In this article, we adopt random survival forests which have never been used in understanding factors affecting under-five child mortality rates in Uganda using Demographic and Health Survey data. Thus the first part of the analysis is based on the use of the classical Cox PH model and the second part of the analysis is based on the use of random survival forests in the presence of covariates that do not necessarily satisfy the PH assumption. RESULTS: Random survival forests and the Cox proportional hazards model agree that the sex of the household head, sex of the child, number of births in the past 1 year are strongly associated to under-five child mortality in Uganda given all the three covariates satisfy the PH assumption. Random survival forests further demonstrated that covariates that were originally excluded from the earlier analysis due to violation of the PH assumption were important in explaining under five child mortality rates. These covariates include the number of children under the age of five in a household, number of births in the past 5 years, wealth index, total number of children ever born and the child's birth order. The results further indicated that the predictive performance for random survival forests built using covariates including those that violate the PH assumption was higher than that for random survival forests built using only covariates that satisfy the PH assumption. CONCLUSIONS: Random survival forests are appealing methods in analysing public health data to understand factors strongly associated with under-five child mortality rates especially in the presence of covariates that violate the proportional hazards assumption. PMID- 28882172 TI - Meta-analyses of the proportion of Japanese encephalitis virus infection in vectors and vertebrate hosts. AB - BACKGROUND: Japanese encephalitis (JE) is a zoonosis in Southeast Asia vectored by mosquitoes infected with the Japanese encephalitis virus (JEV). Japanese encephalitis is considered an emerging exotic infectious disease with potential for introduction in currently JEV-free countries. Pigs and ardeid birds are reservoir hosts and play a major role on the transmission dynamics of the disease. The objective of the study was to quantitatively summarize the proportion of JEV infection in vectors and vertebrate hosts from data pertaining to observational studies obtained in a systematic review of the literature on vector and host competence for JEV, using meta-analyses. METHODS: Data gathered in this study pertained to three outcomes: proportion of JEV infection in vectors, proportion of JEV infection in vertebrate hosts, and minimum infection rate (MIR) in vectors. Random-effects subgroup meta-analysis models were fitted by species (mosquito or vertebrate host species) to estimate pooled summary measures, as well as to compute the variance between studies. Meta-regression models were fitted to assess the association between different predictors and the outcomes of interest and to identify sources of heterogeneity among studies. Predictors included in all models were mosquito/vertebrate host species, diagnostic methods, mosquito capture methods, season, country/region, age category, and number of mosquitos per pool. RESULTS: Mosquito species, diagnostic method, country, and capture method represented important sources of heterogeneity associated with the proportion of JEV infection; host species and region were considered sources of heterogeneity associated with the proportion of JEV infection in hosts; and diagnostic and mosquito capture methods were deemed important contributors of heterogeneity for the MIR outcome. CONCLUSIONS: Our findings provide reference pooled summary estimates of vector competence for JEV for some mosquito species, as well as of sources of variability for these outcomes. Moreover, this work provides useful guidelines when interpreting vector and host infection proportions or prevalence from observational studies, and contributes to further our understanding of vector and vertebrate host competence for JEV, elucidating information on the relative importance of vectors and hosts on JEV introduction and transmission. PMID- 28882173 TI - Risk factors for chronic periodontitis in Sri Lankan adults: a population based case-control study. AB - OBJECTIVE: To determine risk factors for chronic periodontitis in 30-60 year olds in Sri Lanka. Cases and controls for this population based unmatched case-control study were identified from a broader cross-sectional study which was conducted to determine the prevalence of chronic periodontitis in 30-60 year old adults in Colombo district Sri Lanka. The study included 694 cases and 706 controls. Data were collected by means of a pre-tested interviewer administered questionnaire to obtain information about socio-demographic and behavioural factors, a physical examination to record anthropometric measurements and an oral examination. RESULTS: Being a male, a Muslim, belonging to the 45-60 year old age group, having less than 12 years of education, using the finger to clean teeth, current smoking, current betel quid chewing, self-reported diabetes and hypertension emerged as risk factors for chronic periodontitis. CONCLUSIONS: Several socio demographic and behavioural factors as well as co-morbid conditions emerged as independent risk factors for chronic periodontits in this population. The findings could be used for planning programmes to reduce the burden of chronic periodontits in Colombo district Sri Lanka. PMID- 28882174 TI - Molecular phylogeny of Anopheles hyrcanus group members based on ITS2 rDNA. AB - BACKGROUND: The Anopheles hyrcanus group includes 25 species, and is widely distributed in the Oriental and Palaearctic regions. Several species within this group are vectors of malaria, lymphatic filariasis and Japanese encephalitis. It is difficult or impossible to identify cryptic species based on their morphological characteristics, with some closely related species of the Hyrcanus Group have similar adult morphological characteristics. Thus, their molecular identification has been an important complementary method to traditional morphological taxonomy. METHODS: We used 461 ribosomal DNA (rDNA) internal transcribed spacer 2 (ITS2) sequences relating to 19 species to reconstruct the molecular phylogeny of the Hyrcanus Group across its range. In addition, we compared the performance of rDNA ITS2 to that of mitochondrial DNA (mtDNA) cytochrome c oxidase subunit 1 gene (cox1) to assess the genetic divergence of Hyrcanus Group sibling species. RESULTS: Based on Kimura's 2-parameter (K2P) distance model, the average conspecific ITS2 divergence was 0.003, whereas sequence divergence between species averaged 0.480. Average ITS2 sequence divergences were almost 160 times higher among the Hyrcanus Group members than within each species. Two sets of sibling species, An. lesteri Baisas & Hu, 1936 and An. paraliae Sandosham, 1959; and An. sinensis Wiedemann, 1828, An. belenrae Rueda, 2005, and An. kleini Rueda, 2005, were resolved by ITS2. Each of these species was represented as an independent lineage in the phylogenetic tree. Results suggest that An. pseudopictus Grassi, 1899 and An. hyrcanus (Pallas, 1771) are most likely a single species. We uncovered two new ITS2 lineages that require further study before resolving their true taxonomic status, and designed a diagnostic polymerase chain reaction (PCR) assay to distinguish five morphologically similar species. CONCLUSIONS: Nuclear and mitochondrial genes generally provided consistent results for subgroup division. Compared to cox1, ITS2 is a more reliable tool for studying phylogenetic relationships among closely related mosquito taxa. Based on species-specific differences in ITS2 sequences, the multiplex PCR assay developed here can be used to improve the efficiency of vector identification. Thus, this research will promote the progress of malaria vector surveillance in both epidemic and non-epidemic areas of South and East Asia. PMID- 28882175 TI - Strategies to improve the quality of life of persons post-stroke: protocol of a systematic review. AB - BACKGROUND: While many outcomes post-stroke (e.g., depression) have been previously investigated, there is no complete data on the impact of a variety of quality improvement strategies on the quality of life and physical and psychological well-being of individuals post-stroke. The current paper outlines a systematic review protocol on the impact of quality improvement strategies on quality of life as well as physical and psychological well-being of individuals with stroke. METHODS: MEDLINE, CINAHL, EMBASE, and PsycINFO databases will be searched. Two independent reviewers will conduct all levels of screening, data abstraction, and quality appraisal. Only randomized controlled trials that report on the impact of quality improvement strategies on quality of life outcomes in people with stroke will be included. The secondary outcomes will be physical and psychological well-being. Quality improvement strategies include audit and feedback, case management, team changes, electronic patient registries, clinician education, clinical reminders, facilitated relay of clinical information to clinicians, patient education, (promotion of) self-management, patient reminder systems, and continuous quality improvement. Studies published since 2000 will be included to increase the relevancy of findings. Results will be grouped according to the target group of the varying quality improvement strategies (i.e., health system, health care professionals, or patients) and/or by any other noteworthy grouping variables, such as etiology of stroke or by sex. DISCUSSION: This systematic review will identify those quality improvement strategies aimed at the health system, health care professionals, and patients that impact the quality of life of individuals with stroke. Improving awareness and utilization of such strategies may enhance uptake of stroke best practices and reduce inappropriate health care utilization costs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42017064141. PMID- 28882176 TI - Use of the mice passive protection test to evaluate the humoral response in goats vaccinated with Sterne 34F2 live spore vaccine. AB - The Sterne live spore vaccine (34F2) is the most widely used veterinary vaccine against anthrax in animals. Antibody responses to several antigens of Bacillus anthracis have been described with a large focus on those against protective antigen (PA). The focus of this study was to evaluate the protective humoral immune response induced by the live spore anthrax vaccine in goats. Boer goats vaccinated twice (week 0 and week 12) with the Sterne live spore vaccine and naive goats were used to monitor the anti-PA and toxin neutralizing antibodies at week 4 and week 17 (after the second vaccine dose) post vaccination. A/J mice were passively immunized with different dilutions of sera from immune and naive goats and then challenged with spores of B. anthracis strain 34F2 to determine the protective capacity of the goat sera. The goat anti-PA ELISA titres indicated significant sero-conversion at week 17 after the second doses of vaccine (p = 0.009). Mice receiving undiluted sera from goats given two doses of vaccine (twice immunized) showed the highest protection (86%) with only 20% of mice receiving 1:1000 diluted sera surviving lethal challenge. The in vitro toxin neutralization assay (TNA) titres correlated to protection of passively immunized A/J mice against lethal infection with the vaccine strain Sterne 34F2 spores using immune goat sera up to a 1:10 dilution (rs >= 0.522, p = 0.046). This study suggests that the passive mouse protection model could be potentially used to evaluate the protective immune response in livestock animals vaccinated with the current live vaccine and new vaccines. PMID- 28882178 TI - Differential lung ventilation via tracheostomy using two endotracheal tubes in an infant: a case report. AB - BACKGROUND: This case report presents differential lung ventilation in an infant. The aim is to define an alternative technique for performing differential lung ventilation in children. To the best of our knowledge, this is the first report of this kind. CASE PRESENTATION: A 4.2-kg, 2.5-month-old Asian boy was referred to our facility with refractory hypoxemia and hypercarbia due to asymmetric lung disease with atelectasis of the left lung and hyperinflation of the right lung. He was unresponsive to conventional ventilator strategies; different ventilator settings were required. To perform differential lung ventilation, two separate single-lumen endotracheal tubes were inserted into the main bronchus of each lung by tracheotomy; the tracheal tubes were attached to discrete ventilators. The left lung was ventilated with a lung salvage strategy using high-frequency oscillatory ventilation, and the right lung was ventilated with a lung-protective strategy using pressure-regulated volume control mode. Differential lung ventilation was performed successfully with this technique without complications. CONCLUSIONS: Differential lung ventilation may be a lifesaving procedure in select patients who have asymmetric lung disease. Inserting two single-lumen endotracheal tubes via tracheotomy for differential lung ventilation can be an effective and safe alternative method. PMID- 28882177 TI - AmpC and extended spectrum beta-lactamases production among urinary isolates from a tertiary care hospital in Lalitpur, Nepal. AB - BACKGROUND: Production of AmpC and extended spectrum beta-lactamases among urinary isolates has created a serious problem to the successful management of the urinary tract infection. The main purpose of this study was to determine the rates of the extended spectrum beta-lactamase (ESBL) production and AmpC beta lactamase (ABL) production among urinary isolates. RESULTS: Among total 564 urinary isolates, 514 (91.1%) were gram negative bacilli and 50 (8.9%) were gram positive cocci. E. coli (76.1%) was the most common bacteria isolated. Staphylococcus aureus (6.7%) was the predominant gram positive bacteria isolated. 35 (6.8%) of the 514 gram negative bacilli were ESBL producers. Similarly, 14 (2.7%) of the gram negative bacilli were ABL producers. Only one isolate was ESBL and ABL co-producer. Highest rate of susceptibility of gram negative bacteria was seen toward amikacin (97.3%) followed by imipenem (94.4%). Similarly, highest rate of susceptibility among gram positive cocci was seen toward vancomycin (100%) followed by amikacin (93.5%). CONCLUSIONS: Low rates of AmpC and extended spectrum beta-lactamases production in comparison to other previous studies were reported. On the basis of the antimicrobial susceptibility patterns of the bacteria we reported in our study, amikacin, imipenem and nitrofurantoin can be used for the preliminary treatment of urinary tract infections caused by gram negative bacteria and vancomycin and amikacin for treatment of urinary tract infections caused by gram positive bacteria. PMID- 28882179 TI - Medical expenditure for esophageal cancer in China: a 10-year multicenter retrospective survey (2002-2011). AB - BACKGROUND: Esophageal cancer is associated with substantial disease burden in China, and data on the economic burden are fundamental for setting priorities in cancer interventions. The medical expenditure for the diagnosis and treatment of esophageal cancer in China has not been fully quantified. This study aimed to examine the medical expenditure of Chinese patients with esophageal cancer and the associated trends. METHODS: From 2012 to 2014, a hospital-based multicenter retrospective survey was conducted in 37 hospitals in 13 provinces/municipalities across China as a part of the Cancer Screening Program of Urban China. For each esophageal cancer patient diagnosed between 2002 and 2011, clinical information and expense data were extracted by using structured questionnaires. All expense data were reported in Chinese Yuan (CNY; 1 CNY = 0.155 USD) based on the 2011 value and inflated using the year-specific health care consumer price index for China. RESULTS: A total of 14,967 esophageal cancer patients were included in the analysis. It was estimated that the overall average expenditure per patient was 38,666 CNY, and an average annual increase of 6.27% was observed from 2002 (25,111 CNY) to 2011 (46,124 CNY). The average expenditures were 34,460 CNY for stage I, 39,302 CNY for stage II, 40,353 CNY for stage III, and 37,432 CNY for stage IV diseases (P < 0.01). The expenditure also differed by the therapy type, which was 38,492 CNY for surgery, 27,933 CNY for radiotherapy, and 27,805 CNY for chemotherapy (P < 0.05). Drugs contributed to 45.02% of the overall expenditure. CONCLUSIONS: These conservative estimates suggested that medical expenditures for esophageal cancer in China substantially increased in the last 10 years, treatment for early-stage esophageal cancer costs less than that for advanced cases, and spending on drugs continued to account for a considerable proportion of the overall expenditure. PMID- 28882180 TI - High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods. AB - BACKGROUND: Next generation sequencing (NGS) is being increasingly applied for assisting cancer molecular diagnosis. However, it is still needed to validate NGS accuracy on detection of DNA alternations based on a large number of clinical samples, especially for DNA rearrangements and copy number variations (CNVs). This study is to set up basic parameters of targeted NGS for clinical diagnosis and to understand advantage of targeted NGS in comparison with the conventional methods of molecular diagnosis. METHODS: Genomic DNA from 1000 Genomes Project and DNA from cancer cell lines have been used to establish the basic parameters for targeted NGS. The following confirmation was conducted by clinical samples. The multiple variants tested by amplification-refractory mutation system (ARMS), fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were evaluated by targeted NGS to determine the sensitivity. Furthermore, the multiple variants detected by targeted NGS were confirmed by current conventional methods to elucidate the specificity. RESULTS: At sequencing depth of 500*, the maximal sensitivities on detecting single nucletic variances (SNVs) and small insertions/deletions (Indels) can reach 99% and 98.7% respectively, and in 20% of cancer cells, CNV detection can reach to the maximal level. The following confirmation of the sensitivity and specificity was conducted by a large cohort of clinical samples. For SNV and indel detection in clinical samples, targeted NGS can identify all hotspot mutations with 100% sensitivity and specificity. On ALK fusion detection, about 86% IHC-identified cases could be identified by targeted NGS and all ALK fusion detected by targeted NGS were confirmed by IHC. For HER2-amplification, 14 HER2-amplification cases identified by target NGS were all confirmed by FISH and about 93.3% of Her-2 IHC (3+) cases were identified by targeted NGS. Finally, the targeted NGS platform developed here has accurately detected EGFR hotspot mutations in 215 NSCLC patients. CONCLUSIONS: DNA from cancer cell lines is better than standard DNA as a reference to establish basic parameters for targeted NGS. Comparison of the conventional methods using a large cohort of patient samples confirmed the high preformance of targeted NGS on detecting DNA alterations. PMID- 28882181 TI - Is cytotoxicity a determinant of the different in vitro and in vivo effects of bioactives? AB - BACKGROUND: Foodstuffs of both plant and animal origin contain a wide range of bioactive compounds. Although human intervention studies are mandatory to assess the health effects of bioactives, the in vitro approach is often used to select the most promising molecules to be studied in vivo. To avoid misleading results, concentration and chemical form, exposure time, and potential cytotoxicity of the tested bioactives should be carefully set prior to any other experiments. METHODS: In this study the possible cytotoxicity of different bioactives (docosahexaenoic acid, propionate, cyanidin-3-O-glucoside, protocatechuic acid), was investigated in HepG2 cells using different methods. Bioactives were supplemented to cells at different concentrations within the physiological range in human blood, alone or in combination, considering two different exposure times. RESULTS: Reported data clearly evidence that in vitro cytotoxicity is tightly related to the exposure time, and it varies among bioactives, which could exert a cytotoxic effect even at a concentration within the in vivo physiological blood concentration range. Furthermore, co-supplementation of different bioactives can increase the cytotoxic effect. CONCLUSIONS: Our results underline the importance of in vitro cytotoxicity screening that should be considered mandatory before performing studies aimed to evaluate the effect of bioactives on other cellular parameters. Although this study is far from the demonstration of a toxic effect of the tested bioactives when administered to humans, it represents a starting point for future research aimed at verifying the existence of a potential hazard due to the wide use of high doses of multiple bioactives. PMID- 28882182 TI - (S)-crizotinib induces apoptosis in human non-small cell lung cancer cells by activating ROS independent of MTH1. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancers and is usually diagnosed at an advanced stage with poor prognosis. Targeted therapy has produced unprecedented outcomes in patients with NSCLC as a number of oncogenic drivers have been found. Crizotinib, a selective small-molecule inhibitor, has been widely used for the treatment of NSCLC patients with ALK gene rearrangements. A recent study has also shown that (S) enantiomer of crizotinib exhibits anticancer activity by targeting the protein mutT homologue (MTH1). Since this discovery, contradictory studies have cast a doubt on MTH1 as a therapeutic target of (S)-crizotinib. METHODS: NCI-H460, H1975, and A549 cells and immunodeficient mice were chosen as a model to study the (S)-crizotinib treatment. The changes induced by (S)-crizotinib treatment in cell viability, apoptosis as well as ROS, and endoplasmic reticulum stress pathway in the cells were analyzed by MTT assay, FACSCalibur, Western blotting, ROS imaging and electron microscopy. RESULTS: Here, we report that MTH1 does not affect survival of NSCLC cells. We found that (S)-crizotinib induces lethal endoplasmic reticulum stress (ER) response in cultured NSCLC cells by increasing intracellular levels of reactive oxygen species (ROS). Blockage of ROS production markedly reversed (S)-crizotinib-induced ER stress and cell apoptosis, independent of MTH1. We confirmed these findings in NSCLC xenograft studies and showed that (S)-crizotinib-induced ER stress and cell apoptosis. CONCLUSIONS: Our results reveal a novel antitumor mechanism of (S)-crizotinib in NSCLC which involves activation of ROS-dependent ER stress apoptotic pathway and is independent of MTH1 inhibition. PMID- 28882183 TI - miR-22 suppresses tumorigenesis and improves radiosensitivity of breast cancer cells by targeting Sirt1. AB - BACKGROUND: miR-22 has been shown to be frequently downregulated and act as a tumor suppressor in multiple cancers including breast cancers. However, the role of miR-22 in regulating the radioresistance of breast cancer cells, as well as its underlying mechanism is still not well understood. METHODS: The expressions of miR-22 and sirt1 at mRNA and protein levels were examined by qRT-PCR and Western Blot. The effects of miR-22 overexpression and sirt1 knockdown on cell viability, apoptosis, radiosensitivity, gamma-H2AX foci formation were evaluated by CCK-8 assay, flow cytometry, colony formation assay, and gamma-H2AX foci formation assay, respectively. Luciferase reporter assay and qRT-PCR analysis were performed to confirm the interaction between miR-22 and sirt1. RESULTS: miR 22 was downregulated and sirt1 was upregulated at both mRNA and protein levels in breast cancer cells. miR-22 overexpression or sirt1 knockdown significantly suppressed viability, induced apoptosis, reduced survival fraction, and increased the number of gamma-H2AX foci in breast cancer cells. Sirt1 was identified as a target of miR-22 and miR-22 negatively regulated sirt1 expression. Ectopic expression of sirt1 dramatically reversed the inhibitory effect of miR-22 on cell viability and promotive effect on apoptotic rates and radiosensitivity in breast cancer cells. CONCLUSIONS: miR-22 suppresses tumorigenesis and improves radiosensitivity of breast cancer cells by targeting sirt1, providing a promising therapeutic target for breast cancer. PMID- 28882184 TI - Modified task-based learning program promotes problem-solving capacity among Chinese medical postgraduates: a mixed quantitative survey. AB - BACKGROUND: Despite great advances, China's postgraduate education faces many problems, for example traditional lecture-based learning (LBL) method provides fewer oppotunities to apply knowledge in a working situation. Task-based learning (TBL) is an efficient strategy for increasing the connections among skills, knowledge and competences. This study aimed to evaluate the effect of a modified TBL model on problem-solving abilities among postgraduate medical students in China. METHODS: We allocated 228 first-year postgraduate students at Third Military Medical University into two groups: the TBL group and LBL group. The TBL group was taught using a TBL program for immunohistochemistry. The curriculum consisted of five phases: task design, self-learning, experimental operations, discussion and summary. The LBL group was taught using traditional LBL. After the course, learning performance was assessed using theoretical and practical tests. The students' preferences and satisfaction of TBL and LBL were also evaluated using questionnaires. RESULTS: There were notable differences in the mean score rates in the practical test (P < 0.05): the number of high scores (>80) in the TBL group was higher than that in the LBL group. We observed no substantial differences in the theoretical test between the two groups (P > 0.05). The questionnaire results indicated that the TBL students were satisfied with teaching content, teaching methods and experiment content. The TBL program was also beneficial for the postgraduates in completing their research projects. Furthermore, the TBL students reported positive effects in terms of innovative thinking, collaboration, and communication. CONCLUSIONS: TBL is a powerful educational strategy for postgraduate education in China. Our modified TBL imparted basic knowledge to the students and also engaged them more effectively in applying knowledge to solve real-world issues. In conclusion, our TBL established a good foundation for the students' future in both medical research and clinical work. PMID- 28882185 TI - Effect of housing arrangement on fecal-oral transmission of avian hepatitis E virus in chicken flocks. AB - BACKGROUND: Avian hepatitis E virus (HEV) infection is common in chicken flocks in China, as currently no measures exist to prevent the spread of the disease. In this study, we analyzed the effect of caged versus cage-free housing arrangements on avian HEV transmission. First, 127 serum and 110 clinical fecal samples were collected from 4 chicken flocks including the two arrangements in Shaanxi Province, China and tested for HEV antibodies and/or virus. Concurrently, 36 specific-pathogen-free chickens were divided equally into four experimental living arrangement groups, designated cage-free (Inoculated), caged (Inoculated), cage-free (Negative) and caged (Negative) groups. In caged groups, three cages contained 3 chickens each. Three chickens each from cage-free (Inoculated) and caged (Inoculated) groups (one chicken of each cage) were inoculated by cutaneous ulnar vein with the same dose of avian HEV, respectively. The cage-free (Negative) and caged (Negative) groups served as negative control. Serum and fecal samples were collected at 1 to 7 weeks post-inoculation (wpi) and liver lesions were scored at 7 wpi. RESULTS: The results of serology showed that the avian HEV infection rate (54.10%) of the cage-free chickens was significantly higher than the one (12.12%) for caged chickens (P < 0.05). Also, the rate of detection of avian HEV RNA in the clinical fecal samples was significantly higher in the cage-free (22.80%, 13/57) than caged birds (5.66%, 3/53). Moreover, under experimental conditions, the infected number of uninoculated cage-free chickens (6) was significantly higher than the one for the uninoculated caged birds (2), as evidenced by seroconversion, fecal virus shedding, viremia and gross and microscopic liver lesions. CONCLUSIONS: These results suggest that reduction of contact with feces as seen in the caged arrangement of housing chickens can reduce avian HEV transmission. This study provides insights for prevention and control of avian HEV infection in chicken flocks. PMID- 28882186 TI - More fishers and fewer martens due to cumulative effects of forest management and climate change as evidenced from local knowledge. AB - BACKGROUND: Monitoring of fur-bearing species populations is relatively rare due to their low densities. In addition to catch data, trappers' experience provides information on the ecology and status of the harvested species. Fisher (Pekania pennanti) and American marten (Martes americana) are mustelids that are sensitive to forest management and therefore considered to be ecological indicators of forest health. Fisher populations have increased in eastern North America since the early 2000s and this could have resulted in a northeastern extension of the species' range and increased overlap with marten's range. Moreover, habitats of both species are subject to natural and anthropogenic disturbances. The objective of this study was to document the knowledge held by local trappers in the northern area of sympatry between fisher and marten to identify factors that could explain variation in populations of the two species and interactions between them. METHOD: Forty-one semi-directed interviews with Indigenous and non Indigenous trappers in the Abitibi-Temiscamingue region of western Quebec (Canada), at the northern limit of the overlapping ranges of the two mustelid species. RESULTS: Trappers highlighted the lack of exclusivity of marten and fisher to coniferous forests, although marten is more closely associated with them than is fisher. Fisher apparently also takes advantage of open environments, including agroforestry systems. Moreover, climate change increases the frequency of freeze-thaw events that cause the formation of an ice crust on the snow surface, which favors fisher movements. CONCLUSION: The fisher was identified as a competitor and even a predator of the marten. Furthermore, the fisher is less affected than the marten by forest management, and it also seems to benefit from climate change to a greater extent. PMID- 28882187 TI - Nadir PSA is a strong predictor of treatment outcome in intermediate and high risk localized prostate cancer patients treated by definitive external beam radiotherapy and androgen deprivation. AB - BACKGROUND: The aim of this study is to investigate the effect of tumor characteristics and parameters of treatment response in predicting biochemical disease-free survival (BFS) for patients with intermediate or high risk prostate cancer treated by combined definitive external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT). METHODS: Between June 1995 and January 2015, 375 patients with localized prostate cancer and a National Comprehensive Cancer Network (NCCN) intermediate or high risk categories were treated by definitive EBRT and ADT. Median duration of androgen blockade was 10 months (range: 3-36 months); Median radiation dose was 72 Gy (Range: 70-78 Gy). Median follow-up time was 5.8 years (range: 0.8-16.39 years). The main study endpoint was biochemical disease free survival (BFS). RESULTS: Forty seven patients (12.5%) developed biochemical recurrence (BCR) during the observation period. Monovariate analysis identified baseline PSA (bPSA) (p = 0.024), T-stage (p = 0.001), Gleason's score (GS) (p = 0.042), radiation dose (p = 0.045), PSA pre-radiation therapy (p = 0.048), and nadir PSA (nPSA), (p < 0.001) as significant variables affecting BCR. The receiver operating characteristic (ROC) curve identified a nPSA of 0.06 ng/ml as optimal cut-off value significantly predicting the patients' risk of BCR (p < 0.001). Multivariate cox regression analysis revealed T-stage, GS, and nPSA as independent variable affecting BFS, while bPSA, age, and radiation dose were not. CONCLUSION: Nadir PSA at 0.06 is a strong independent predictor of BFS in patients with intermediate or high risk prostate cancer treated by definitive EBRT and ADT. PMID- 28882188 TI - Unifying a fragmented effort: a qualitative framework for improving international surgical teaching collaborations. AB - BACKGROUND: Access to adequate surgical care is limited globally, particularly in low- and middle-income countries (LMICs). To address this issue, surgeons are becoming increasingly involved in international surgical teaching collaborations (ISTCs), which include educational partnerships between surgical teams in high income countries and those in LMICs. The purpose of this study is to determine a framework for unifying, systematizing, and improving the quality of ISTCs so that they can better address the global surgical need. METHODS: A convenience sample of 68 surgeons, anesthesiologists, physicians, residents, nurses, academics, and administrators from the U.S., Canada, and Norway was used for the study. Participants all had some involvement in ISTCs and came from multiple specialties and institutions. Qualitative methodology was used, and participants were interviewed using a pre-determined set of open-ended questions. Data was gathered over two months either in-person, over the phone, or on Skype. Data was evaluated using thematic content analysis. RESULTS: To organize and systematize ISTCs, participants reported a need for a centralized/systematized process with designated leaders, a universal data bank of current efforts/progress, communication amongst involved parties, full-time administrative staff, dedicated funds, a scholarly approach, increased use of technology, and more research on needs and outcomes. CONCLUSION: By taking steps towards unifying and systematizing ISTCs, the quality of ISTCs can be improved. This could lead to an advancement in efforts to increase access to surgical care worldwide. PMID- 28882189 TI - Competencies for first year residents - physicians' views from medical schools with different undergraduate curricula. AB - BACKGROUND: Frameworks like the CanMEDS model depicting professional roles and specific professional activities provide guidelines for postgraduate education. When medical graduates start their residency, they should possess certain competencies related to communication, management and professionalism while other competencies will be refined during postgraduate training. Our study aimed to evaluate the relevance of different competencies for a first year resident required for entrustment decision from the perspective of physicians from medical faculties with different undergraduate medical curricula. METHODS: Nine hundred fifty-two surgeons and internists from three medical schools with different undergraduate medical curricula were invited to rank 25 competencies according to their relevance for first year residents. The rankings were compared between universities, specialties, physicians' positions, and gender. RESULTS: Two hundred two physicians participated, 76 from Hamburg University, 44 from Oldenburg University, and 82 from Technical University Munich. No significant differences were found regarding the top 10 competencies relevant for first year residents between the universities. 'Responsibility' was the competency with the highest rank overall. Internists ranked 'Structure, work planning and priorities' higher while surgeons ranked 'Verbal communication with colleagues and supervisors' higher. Consultants evaluated 'Active listening to patients' more important than department directors and residents. Female physicians ranked 'Verbal communication with colleagues and supervisors' and 'Structure, work planning and priorities' significantly higher while male physicians ranked 'Scientifically and empirically grounded method of working' significantly higher. CONCLUSIONS: Physicians from universities with different undergraduate curricula principally agreed on the competencies relevant for first year residents. Some differences between physicians from different positions, specialties, and gender were found. These differences should be taken into account when planning competence-based postgraduate education training programs. PMID- 28882190 TI - Traversing the valley of glycemic control despair. PMID- 28882192 TI - Satisfaction with quality of ICU care for patients and families: the euroQ2 project. AB - BACKGROUND: Families' perspectives are of great importance in evaluating quality of care in the intensive care unit (ICU). This Danish-Dutch study tested a European adaptation of the "Family Satisfaction in the ICU" (euroFS-ICU). The aim of the study was to examine assessments of satisfaction with care in a large cohort of Danish and Dutch family members and to examine the measurement characteristics of the euroFS-ICU. METHODS: Data were from 11 Danish and 10 Dutch ICUs and included family members of patients admitted to the ICU for 48 hours or more. Surveys were mailed 3 weeks after patient discharge from the ICU. Selected patient characteristics were retrieved from hospital records. RESULTS: A total of 1077 family members of 920 ICU patients participated. The response rate among family members who were approached was 72%. "Excellent" or "Very good" ratings on all items ranged from 58% to 96%. Items with the highest ratings were concern toward patients, ICU atmosphere, opportunities to be present at the bedside, and ease of getting information. Items with room for improvement were management of patient agitation, emotional support of the family, consistency of information, and inclusion in and support during decision-making processes. Exploratory factor analysis suggested four underlying factors, but confirmatory factor analysis failed to yield a multi-factor model with between-country measurement invariance. A hypothesis that this failure was due to misspecification of causal indicators as reflective indicators was supported by analysis of a factor representing satisfaction with communication, measured with a combination of causal and reflective indicators. CONCLUSIONS: Most family members were moderately or very satisfied with patient care, family care, information and decision-making, but areas with room for improvement were also identified. Psychometric assessments suggest that composite scores constructed from these items as representations of either overall satisfaction or satisfaction with specific sub-domains do not meet rigorous measurement standards. The euroFS-ICU and other similar instruments may benefit from adding reflective indicators. PMID- 28882193 TI - Fragile X mental retardation protein regulates skeletal muscle stem cell activity by regulating the stability of Myf5 mRNA. AB - BACKGROUND: Regeneration of adult tissues relies on adult stem cells that are primed to enter a differentiation program, while typically remaining quiescent. In mouse skeletal muscle, these features are reconciled by multiple translational control mechanisms that ensure primed muscle stem cells (MuSCs) are not activated. In quiescent MuSCs, this concept is illustrated by reversible microRNA silencing of Myf5 translation, mediated by microRNA-31 and fragile X mental retardation protein (FMRP). METHODS: In this work, we take advantage of FMRP knockout (Fmr1 -/- ) mice to support the role for FMRP in maintaining stem cell properties of the MuSC. We compare the activity of MuSCs in vivo after acute injury and engraftment, as well as ex vivo during culture. We use RNA immunoprecipitation and 3'UTR poly-adenine (poly(A)) length assays to assess the impact of FMRP on the stability of transcripts for myogenic regulatory factors. RESULTS: We show that RNA-binding FMRP is required to maintain the MuSC pool. More specifically, FMRP is required for stem cell properties of muscle stem cells, which include MuSC capacity to prime the myogenic program, their self renewal, and their capacity to efficiently regenerate muscle. We provide evidence that FMRP regulation of MuSC activity occurs in part by the capacity of FMRP to directly bind Myf5 transcripts and impact rates of Myf5 deadenylation. CONCLUSIONS: Our results provide further evidence supporting a role for post transcriptional silencing platforms by RNA-binding proteins in maintaining stemness properties of adult stem cells. In addition, deregulated MuSC activity in the absence of Fmr1 may have implications for fragile X syndrome, which is associated with muscle hypotonia during infancy. PMID- 28882191 TI - Effects of sustained i.c.v. infusion of lupus CSF and autoantibodies on behavioral phenotype and neuronal calcium signaling. AB - Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that is often accompanied by brain atrophy and diverse neuropsychiatric manifestations of unknown origin. More recently, it was observed that cerebrospinal fluid (CSF) from patients and lupus-prone mice can be neurotoxic and that acute administration of specific brain-reactive autoantibodies (BRAs) can induce deficits in isolated behavioral tasks. Given the chronic and complex nature of CNS SLE, the current study examines broad behavioral performance and neuronal Ca2+ signaling in mice receiving a sustained infusion of cerebrospinal fluid (CSF) from CNS SLE patients and putative BRAs (anti-NR2A, anti-ribosomal P, and anti-alpha-tubulin). A 2-week intracerebroventricular (i.c.v.) infusion of CSF altered home-cage behavior and induced olfactory dysfunction, excessive immobility in the forced swim test, and perseveration in a learning task. Conversely, sustained administration of purified BRAs produced relatively mild, both inhibitory and stimulatory effects on olfaction, spatial learning/memory, and home-cage behavior. In vitro studies revealed that administration of some CSF samples induces a rapid influx of extracellular Ca2+ into murine neurons, an effect that could be partially mimicked with the commercial anti-NR2A antibody and blocked with selective N-methyl-D-aspartate (NMDA) receptor antagonists. The current findings confirm that the CSF from CNS SLE patients can be neuroactive and support the hypothesis that intrathecal BRAs induce synergistically diverse effects on all domains of behavior. In addition, anti-NMDA receptor antibodies may alter Ca2+ homeostasis of central neurons, thus accounting for excitotoxicity and contributing to the heterogeneity of psychiatric manifestations in CNS SLE and other autoantibody-related brain disorders. PMID- 28882194 TI - GPs' and child and adolescent psychiatry specialists' experiences of joint consultations in the GP's office: a qualitative study. AB - BACKGROUND: The study is an exploration of a joint consultation model, a collaboration between general practitioners (GPs) and specialists from child and adolescent mental health services (CAMHS) in Lillehammer, Norway. METHODS: A qualitative study based on two focus group interviews, one with participating GPs and one with participating specialists from the local CAMHS. Participants were five GPs, with work experience varying from 6 months to 20 years (four of them specialists in general medicine) and two CAMHS specialists-a psychiatrist and a psychologist-both with more than 20 years of experience. RESULTS: The focus group discussions revealed that both GPs and CAMHS specialists saw the joint consultations as a good teaching method for improving GPs' skills in child and adolescent psychiatry. Both groups believed that this low-threshold service benefits the patients and that the joint consultation is especially suited to sort problems and determine the level of help required. CONCLUSIONS: The GPs and CAMHS specialists shared the impression that the collaboration model is beneficial for both patients and health care providers. Close collaboration with primary health care is recommended in the guidelines for child and adolescent psychiatry outpatient clinics. We suggest that the joint consultation model could be a good way for GPs and CAMHS specialists to collaborate. PMID- 28882196 TI - Simultaneous Determination of Acetylsalicylic Acid, Hydrochlorothiazide, Enalapril, and Atorvastatin in a Polypill-Based Quaternary Mixture by TLC. AB - A new chromatographic-densitometric method has been developed for the qualitative and quantitative determination of the active ingredients in a simulated mixture corresponding to the PolyIran polypill, composed of acetylsalicylic acid, hydrochlorothiazide (HCT), enalapril (ENA), and atorvastatin (ATR), whose efficacy in the treatment and prevention of cardiovascular disease has been documented in clinical trials. Chromatographic separation was performed using TLC silica gel 60 plates with fluorescent indicator F254 as the stationary phase and a mixture of n-hexane-ethyl acetate-methanol-water-acetic acid (8.4 + 8 + 3 + 0.4 + 0.2, v/v/v/v/v) as the mobile phase. Densitometric measurements were carried out at lambda = 210 nm when determining ENA and at lambda = 265 nm in the case of the other drugs. Peaks of examined substances were well separated in the recorded chromatograms, enabling the evaluation of the results in terms of both qualitative and quantitative analysis. The method was specific for the analyzed components and was characterized by high sensitivity. The LOD was between 0.043 and 0.331 MUg/spot, and LOQ was between 0.100 and 0.942 MUg/spot. Recovery was in the range of 97.02-101.34%. The linearity range was broad and ranged from 0.600 to 6.000 MUg/spot for acetylsalicylic acid, from 0.058 to 1.102 MUg/spot for HCT, from 0.505 to 6.560 MUg/spot for ENA, and from 0.100 to 1.000 MUg/spot for ATR. The method was characterized by good precision, with RSD values that ranged from 0.10 to 2.26%. PMID- 28882195 TI - Treating vitamin D deficiency in children with type I diabetes could improve their glycaemic control. AB - BACKGROUND AND AIMS: The relationship between vitamin D deficiency and type I DM is an ongoing area of interest. The study aims to identify the prevalence of vitamin D deficiency in children and adolescents with T1DM and to assess the impact of treatment of vitamin D deficiency on their glycaemic control. METHODS: Retrospective data was collected from 271 children and adolescents with T1DM. The vitamin D deficient (25(OH)D <30 nmol/L) and insufficient (25(OH)D 30-50 nmol/L) patients were treated with 6000 units of cholecalciferol and 400 units of cholecalciferol, once daily for 3 months respectively. HbA1c and 25(OH)D concentrations were measured before and at the end of the vitamin D treatment. RESULTS: 14.8% from the whole cohort (n = 271) were vitamin D deficient and 31% were insufficient. Among the children included in the final analysis (n = 73), the mean age and plasma 25(OH)D concentration (+/-SD) were 7.7 years (+/-4.4) and 32.2 nmol/l (+/-8.2) respectively. The mean 25(OH)D concentration post-treatment was 65.3 nmol/l (+/-9.3). The mean HbA1c (+/-SD) before and after cholecalciferol was 73.5 mmol/mol (+/-14.9) and 65 mmol/mol (+/-11.2) respectively (p < 0.001). Children with higher pre-treatment HbA1c had greater reduction in HbA1c (p < 0.001) and those with lower 25(OH)D concentration showed higher reduction in HbA1c (p = 0.004) after treatment. CONCLUSIONS: Low 25(OH)D concentrations are fairly prevalent in children and adolescents with T1DM, treatment of which, can potentially improve the glycaemic control. PMID- 28882197 TI - Kinetic Profiling of the Hydrolytic Reaction of Benazepril: Metabolic Pathway Simulation. AB - A simple, specific, and rapid kinetic study of benazepril (BNZ) hydrolysis was developed and validated using HPLC. BNZ was degraded using 0.1 N sodium hydroxide at room temperature to produce benazeprilat, which is an active metabolite of BNZ and acts as an angiotensin-converting enzyme inhibitor. Analysis was carried out using an Athena C18 column (4.6 * 250 mm, 5 um particle size). The mobile phase consists of a mixture of phosphate buffer (pH 4.5) and acetonitrile (53 + 47, v/v) at a flow rate of 1 mL/min. UV detection was accomplished at 242 nm using moexipril as the internal standard. The method was validated according to International Conference on Harmonization guidelines, and the calibration curve was linear over the range 10-100 ug/mL, with acceptable accuracy and precision. Kinetic profiling of the hydrolysis was shown to follow pseudo-first-order kinetics. The method was applied to the assay of BNZ in combined dosage form with no interference from other ingredients. The obtained results were statistically compared with those of the official method, showing no significant difference. PMID- 28882198 TI - Genetic, Biochemical, and Biophysical Methods for Studying FeS Proteins and Their Assembly. AB - FeS clusters containing proteins are structurally and functionally diverse and present in most organisms. Our understanding of FeS cluster production and insertion into polypeptides has benefited from collaborative efforts between in vitro and in vivo studies. The former allows a detailed description of FeS containing protein and a deep understanding of the molecular mechanisms catalyzing FeS cluster assembly. The second allows to include metabolic and environmental constraints within the analysis of FeS homeostasis. The interplay and the cross talk between the two approaches have been a key strategy to reach a multileveled integrated understanding of FeS cluster homeostasis. In this chapter, we describe the genetic and biochemical/biophysical strategies that were used in the field of FeS cluster biogenesis, with the aim of providing the reader with a critical view of both approaches. In addition to the description of classic tricks and a series of recommendations, we will also discuss models as well as spectroscopic techniques useful to characterize FeS clusters such as UV visible, Mossbauer, electronic paramagnetic resonance, resonance Raman, circular dichroism, and nuclear magnetic resonance. PMID- 28882199 TI - Defining the Architecture of the Core Machinery for the Assembly of Fe-S Clusters in Human Mitochondria. AB - Although Fe-S clusters may assemble spontaneously from elemental iron and sulfur in protein-free systems, the potential toxicity of free Fe2+, Fe3+, and S2- ions in aerobic environments underscores the requirement for specialized proteins to oversee the safe assembly of Fe-S clusters in living cells. Prokaryotes first developed multiprotein systems for Fe-S cluster assembly, from which mitochondria later derived their own system and became the main Fe-S cluster suppliers for eukaryotic cells. Early studies in yeast and human mitochondria indicated that Fe S cluster assembly in eukaryotes is centered around highly conserved Fe-S proteins (human ISCU) that serve as scaffolds upon which new Fe-S clusters are assembled from (i) elemental sulfur, provided by a pyridoxal phosphate-dependent cysteine desulfurase (human NFS1) and its stabilizing-binding partner (human ISD11), and (ii) elemental iron, provided by an iron-binding protein of the frataxin family (human FXN). Further studies revealed that all of these proteins could form stable complexes that could reach molecular masses of megadaltons. However, the protein-protein interaction surfaces, catalytic mechanisms, and overall architecture of these macromolecular machines remained undefined for quite some time. The delay was due to difficulties inherent in reconstituting these very large multiprotein complexes in vitro or isolating them from cells in sufficient quantities to enable biochemical and structural studies. Here, we describe approaches we developed to reconstitute the human Fe-S cluster assembly machinery in Escherichia coli and to define its remarkable architecture. PMID- 28882200 TI - Fe-S Cluster Hsp70 Chaperones: The ATPase Cycle and Protein Interactions. AB - Hsp70 chaperones and their obligatory J-protein cochaperones function together in many cellular processes. Via cycles of binding to short stretches of exposed amino acids on substrate proteins, Hsp70/J-protein chaperones not only facilitate protein folding but also drive intracellular protein transport, biogenesis of cellular structures, and disassembly of protein complexes. The biogenesis of iron sulfur (Fe-S) clusters is one of the critical cellular processes that require Hsp70/J-protein action. Fe-S clusters are ubiquitous cofactors critical for activity of proteins performing diverse functions in, for example, metabolism, RNA/DNA transactions, and environmental sensing. This biogenesis process can be divided into two sequential steps: first, the assembly of an Fe-S cluster on a conserved scaffold protein, and second, the transfer of the cluster from the scaffold to a recipient protein. The second step involves Hsp70/J-protein chaperones. Via binding to the scaffold, chaperones enable cluster transfer to recipient proteins. In eukaryotic cells mitochondria have a key role in Fe-S cluster biogenesis. In this review, we focus on methods that enabled us to dissect protein interactions critical for the function of Hsp70/J-protein chaperones in the mitochondrial process of Fe-S cluster biogenesis in the yeast Saccharomyces cerevisiae. PMID- 28882201 TI - B. subtilis as a Model for Studying the Assembly of Fe-S Clusters in Gram Positive Bacteria. AB - Complexes of iron and sulfur (Fe-S clusters) are widely distributed in nature and participate in essential biochemical reactions. The biological formation of Fe-S clusters involves dedicated pathways responsible for the mobilization of sulfur, the assembly of Fe-S clusters, and the transfer of these clusters to target proteins. Genomic analysis of Bacillus subtilis and other Gram-positive bacteria indicated the presence of only one Fe-S cluster biosynthesis pathway, which is distinct in number of components and organization from previously studied systems. B. subtilis has been used as a model system for the characterization of cysteine desulfurases responsible for sulfur mobilization reactions in the biogenesis of Fe-S clusters and other sulfur-containing cofactors. Cysteine desulfurases catalyze the cleavage of the C-S bond from the amino acid cysteine and subsequent transfer of sulfur to acceptor molecules. These reactions can be monitored by the rate of alanine formation, the first product in the reaction, and sulfide formation, a byproduct of reactions performed under reducing conditions. The assembly of Fe-S clusters on protein scaffolds and the transfer of these clusters to target acceptors are determined through a combination of spectroscopic methods probing the rate of cluster assembly and transfer. This chapter provides a description of reactions promoting the assembly of Fe-S clusters in bacteria as well as methods used to study functions of each biosynthetic component and identify mechanistic differences employed by these enzymes across different pathways. PMID- 28882202 TI - Structural Characterization of Poised States in the Oxygen Sensitive Hydrogenases and Nitrogenases. AB - The crystallization of FeS cluster-containing proteins has been challenging due to their oxygen sensitivity, and yet these enzymes are involved in many critical catalytic reactions. The last few years have seen a wealth of innovative experiments designed to elucidate not just structural but mechanistic insights into FeS cluster enzymes. Here, we focus on the crystallization of hydrogenases, which catalyze the reversible reduction of protons to hydrogen, and nitrogenases, which reduce dinitrogen to ammonia. A specific focus is given to the different experimental parameters and strategies that are used to trap distinct enzyme states, specifically, oxidants, reductants, and gas treatments. Other themes presented here include the recent use of Cryo-EM, and how coupling various spectroscopies to crystallization is opening up new approaches for structural and mechanistic analysis. PMID- 28882203 TI - Nitrogenase Assembly: Strategies and Procedures. AB - Nitrogenase is a metalloenzyme system that plays a critical role in biological nitrogen fixation, and the study of how its metallocenters are assembled into functional entities to facilitate the catalytic reduction of dinitrogen to ammonia is an active area of interest. The diazotroph Azotobacter vinelandii is especially amenable to culturing and genetic manipulation, and this organism has provided the basis for many insights into the assembly of nitrogenase proteins and their respective metallocofactors. This chapter will cover the basic procedures necessary for growing A. vinelandii cultures and subsequent recombinant transformation and protein expression techniques. Furthermore, protocols for nitrogenase protein purification and substrate reduction activity assays are described. These methods provide a solid framework for the assessment of nitrogenase assembly and catalysis. PMID- 28882205 TI - De Novo Design of Iron-Sulfur Proteins. AB - Iron-sulfur proteins are one of the most abundant and functionally pliable redox proteins found in all living organisms. Because of their crucial role in mediating electron transfer processes, minimalist model systems have been developed as a proxy to study natural Fe-S redox proteins and to dissect rules to enable tuning of their redox and electron transfer activities. This goal has been pursued through computational design, mutagenesis in the first and second coordination sphere, metal substitution, cofactor replacement, and the use of unnatural amino acids to stabilize a given cluster. In this chapter, we discuss the most recent design strategies to introduce various Fe-S clusters into natural and artificial protein scaffolds. Practical approaches for the cluster reconstitution, hydrogen production, and electrochemical characterization are mentioned. PMID- 28882204 TI - TsrM as a Model for Purifying and Characterizing Cobalamin-Dependent Radical S Adenosylmethionine Methylases. AB - Cobalamin-dependent radical S-adenosylmethionine (SAM) methylases play vital roles in the de novo biosynthesis of many antibiotics, cofactors, and other important natural products, yet remain an understudied subclass of radical SAM enzymes. In addition to a [4Fe-4S] cluster that is ligated by three cysteine residues, these enzymes also contain an N-terminal cobalamin-binding domain. In vitro studies of these enzymes have been severely limited because many are insoluble or sparingly soluble upon their overproduction in Escherichia coli. This solubility issue has led a number of groups either to purify the protein from inclusion bodies or to purify soluble protein that often lacks proper cofactor incorporation. Herein, we use TsrM as a model to describe methods that we have used to generate soluble protein that is purified in an active form with both cobalamin and [4Fe-4S] cluster cofactors bound. Additionally, we highlight the methods that we developed to characterize the enzyme following purification. PMID- 28882206 TI - Mechanism-Based Strategies for Structural Characterization of Radical SAM Reaction Intermediates. AB - X-ray crystallographic characterization of enzymes at different stages in their reaction cycles can provide unique insight into the reaction pathway, the number and type of intermediates formed, and their structural context. The known mechanistic diversity in the radical S-adenosylmethionine (SAM) superfamily of enzymes makes it an appealing target for such studies as more than 100,000 sequences have been identified to date with wide-ranging reactivities that share a pattern of complex radical-mediated chemistry. Here, we review selected examples of radical SAM enzyme crystal structures representative of reactant, product, and intermediate state complexes with a particular emphasis on the strategies employed to capture these states. Broader application of structural characterization techniques to analyze mechanism and substrate specificity is certain to play an important role as more members of this family become tractable for biochemical study. PMID- 28882207 TI - A Polymerase With Potential: The Fe-S Cluster in Human DNA Primase. AB - Replication of DNA in eukaryotes is primarily executed by the combined action of processive DNA polymerases delta and E. These enzymes cannot initiate synthesis of new DNA without the presence of a primer on the template ssDNA. The primers on both the leading and lagging strands are generated by DNA polymerase alpha primase (pol-prim). DNA primase is a DNA-dependent RNA polymerase that synthesizes the first ~10 nucleotides and then transfers the substrate to polymerase alpha to complete primer synthesis. The mechanisms governing the coordination and handoff between primase and polymerase alpha are largely unknown. Isolated DNA primase contains a [4Fe-4S]2+ cluster that has been shown to serve as a redox switch modulating DNA binding affinity. This discovery suggests a mechanism for modulating the priming activity of primase and handoff to polymerase alpha. In this chapter, we briefly discuss the current state of knowledge of primase structure and function, including the role of its iron sulfur cluster. This is followed by providing the methods for expressing, purifying, and biophysically/structurally characterizing primase and its iron sulfur cluster-containing domain, p58C. PMID- 28882208 TI - In Vitro Studies of Cellular Iron-Sulfur Cluster Biosynthesis, Trafficking, and Transport. AB - Iron-sulfur clusters are metal cofactors that comprise the largest class of metalloproteins and are utilized for a wide variety of functions ranging from electron transport to DNA repair. These clusters and their respective cluster binding proteins are highly conserved and are produced in the mitochondria via an evolutionarily conserved process for export to the cytosol and delivery to other organelles, including the nucleus. Disruption of the biosynthetic pathway results in a number of disease conditions that reflect the essential requirements of cluster function and trafficking within the cell. In vivo studies are limited in their ability to examine the detailed molecular mechanisms of protein-protein interactions, since they often focus on the downstream effects of protein depletion or mutation. As such, in vitro analyses are essential for defining the roles of specific Fe-S proteins in trafficking events and supporting in vivo analyses of disease conditions arising from aberrant Fe-S assembly and trafficking. In this chapter, we describe a variety of methods for the analysis of structure-function relationships in holo Fe-S cluster proteins, as well as monitoring the kinetics and molecular mechanisms of Fe-S cluster transfer. PMID- 28882210 TI - Preface. PMID- 28882209 TI - Combined Biochemical, Biophysical, and Cellular Methods to Study Fe-S Cluster Transfer and Cytosolic Aconitase Repair by MitoNEET. AB - MitoNEET is the first identified Fe-S protein anchored to mammalian outer mitochondrial membranes with the vast majority of the protein polypeptide located in the cytosol, including its [2Fe-2S] cluster-binding domain. The coordination of the cluster is unusual and involves three cysteines and one histidine. MitoNEET is capable of transferring its redox-active Fe-S cluster to a bacterial apo-ferredoxin in vitro even under aerobic conditions, unlike other Fe-S transfer proteins such as ISCU. This specificity suggests its possible involvement in Fe-S repair after oxidative and/or nitrosative stress. Recently, we identified cytosolic aconitase/iron regulatory protein 1 (IRP1) as the first physiological protein acceptor of the mitoNEET Fe-S cluster in an Fe-S repair process. This chapter describes methods to study in vitro mitoNEET Fe-S cluster transfer/repair to a bacterial ferredoxin used as a model aporeceptor and in a more comprehensive manner to cytosolic aconitase/IRP1 after a nitrosative stress using in vitro, in cellulo, and in vivo methods. PMID- 28882211 TI - Introduction to Northeast Pacific Shark Biology, Ecology, and Conservation. AB - Sharks are iconic, sometimes apex, predators found in every ocean and, as a result, they have featured prominently in the mythology, history, and fisheries of diverse human cultures around the world. Because of their regional significance to fisheries and ecological role as predators, and as a result of concern over long-term stability of their populations, there has been an increasing amount of work focused on shark conservation in recent decades. This volume highlights the biodiversity and biological attributes of, and conservation efforts targeted at, populations of sharks that reside in the Northeast Pacific Ocean bordering the west coast of the United States and Canada, one of the most economically and ecologically important oceanic regions in the world. A companion volume addresses details of fisheries and ecotourism in the same region, as well as delving into the relationship between captive husbandry of sharks and education/outreach efforts aimed at fostering a conservation mindset in the public at large. Together, these volumes provide readers a detailed backdrop against which to consider their own actions, and those of resource managers, academics, and educators, as they relate to the long-term conservation of sharks and their relatives. PMID- 28882212 TI - Diet Composition and Trophic Ecology of Northeast Pacific Ocean Sharks. AB - Although there is a general perception of sharks as large pelagic, apex predators, most sharks are smaller, meso- and upper-trophic level predators that are associated with the seafloor. Among 73 shark species documented in the eastern North Pacific (ENP), less than half reach maximum lengths >200cm, and 78% occur in demersal or benthic regions of the continental shelf or slope. Most small (<=200cm) species (e.g., houndsharks) and demersal, nearshore juveniles of larger species (e.g., requiem sharks) consume small teleosts and decapod crustaceans, whereas large species in pelagic coastal and oceanic environments feed on large teleosts and squids. Several large, pelagic apex predator species occur in the ENP, but the largest species (i.e., Basking Shark, Whale Shark) consume zooplankton or small nekton. Size-based dietary variability is substantial for many species, and segregation of juvenile and adult foraging habitats also is common (e.g., Horn Shark, Shortfin Mako). Temporal dietary differences are most pronounced for temperate, nearshore species with wide size ranges, and least pronounced for smaller species in extreme latitudes and deep water regions. Sympatric sharks often occupy various trophic positions, with resource overlap differing by space and time and some sharks serving as prey to other species. Most coastal species remain in the same general region over time and feed opportunistically on variable prey inputs (e.g., season migrations, spawning, or recruitment events), whereas pelagic, oceanic species actively seek hot spots of prey abundance that are spatiotemporally variable. The influence of sharks on ecosystem structure and regulation has been downplayed compared to that of large teleosts species with higher per capita consumption rates (e.g., tunas, billfishes). However, sharks also exert indirect influences on prey populations by causing behavioural changes that may result in restricted ranges and reduced fitness. Except for food web modelling efforts in Alaskan waters, the trophic impacts of sharks are poorly incorporated into current ecosystem approaches to fisheries management in the NEP. PMID- 28882213 TI - Stable Isotope Applications for Understanding Shark Ecology in the Northeast Pacific Ocean. AB - Stable isotopes are used to address a wide range of ecological questions and can help researchers and managers better understand the movement and trophic ecology of sharks. Here, we review how shark studies from the Northeast Pacific Ocean (NEP) have employed stable isotopes to estimate trophic level and diet composition and infer movement and habitat-use patterns. To date, the number of NEP shark studies that have used stable isotopes is limited, suggesting that the approach is underutilized. To aid shark researchers in understanding the strengths and limitations of the approach, we provide a brief overview of carbon and nitrogen stable isotope trophic discrimination properties (e.g., change in delta15N between predator and prey), tissue sample preparation methods specific to elasmobranchs, and methodological considerations for the estimation of trophic level and diet composition. We suggest that stable isotopes are a potentially powerful tool for addressing basic questions about shark ecology and are perhaps most valuable when combined and analysed with other data types (e.g., stomach contents, tagging data, or other intrinsic biogeochemical markers). PMID- 28882214 TI - Age and Growth of Elasmobranchs and Applications to Fisheries Management and Conservation in the Northeast Pacific Ocean. AB - In addition to being an academic endeavour, the practical purpose of conducting age and growth studies on fishes is to provide biological data to stock assessment scientists and fisheries managers so they may better understand population demographics and manage exploitation rates. Age and size data are used to build growth models, which are a critical component of stock assessments. Though age determination of elasmobranchs in the northeast Pacific Ocean (NEP) began in the 1930s, the field has evolved substantially in recent years, allowing scientists to incorporate age data into assessments for more species than ever before. Owing to the highly diverse biology of this group of fishes, each species has its own set of challenges with regard to age determination. Age determination methods typically rely on semicalcified hard structures that form regular growth patterns; however, the structure selected and preparation method used is often species specific. New staining techniques have improved the ability to assess age and improve ageing precision for some species, and advances in microchemical methods have allowed for independent means of estimating age and validating age determination accuracy. Here we describe current age determination methods for NEP elasmobranchs. While the library of available techniques is increasing, there are still some NEP species for which reliable ageing methods have yet to be defined; we discuss these challenges and potential avenues of future research. Finally, we conclude by describing how age estimates are used in growth models and subsequently in stock assessments of selected NEP elasmobranchs. PMID- 28882215 TI - Review of Current Conservation Genetic Analyses of Northeast Pacific Sharks. AB - Conservation genetics is an applied science that utilizes molecular tools to help solve problems in species conservation and management. It is an interdisciplinary specialty in which scientists apply the study of genetics in conjunction with traditional ecological fieldwork and other techniques to explore molecular variation, population boundaries, and evolutionary relationships with the goal of enabling resource managers to better protect biodiversity and identify unique populations. Several shark species in the northeast Pacific (NEP) have been studied using conservation genetics techniques, which are discussed here. The primary methods employed to study population genetics of sharks have historically been nuclear microsatellites and mitochondrial (mt) DNA. These markers have been used to assess genetic diversity, mating systems, parentage, relatedness, and genetically distinct populations to inform management decisions. Novel approaches in conservation genetics, including next-generation DNA and RNA sequencing, environmental DNA (eDNA), and epigenetics are just beginning to be applied to elasmobranch evolution, physiology, and ecology. Here, we review the methods and results of past studies, explore future directions for shark conservation genetics, and discuss the implications of molecular research and techniques for the long-term management of shark populations in the NEP. PMID- 28882216 TI - Biodiversity, Life History, and Conservation of Northeastern Pacific Chondrichthyans. AB - The sharks, batoids, and chimaeras, collectively the class Chondrichthyes, are one of the most successful groups of fishes, with over 1250 species globally. Recent taxonomic revisions have increased their diversity by about 20% over the past 17 years (2000-2016). The Northeast Pacific Ocean is one of the top 20 most diverse regions/countries on the globe with 77 chondrichthyan species, a number less than a quarter that of the most species-rich area (Australia) but that has increased by 10% since 2000 to include three new species (two skates and a chimaera). In this chapter we discuss the species richness of chondrichthyans occurring in the Northeast Pacific Ocean, characterize their life histories, briefly review several fisheries, and summarize the conservation status of those chondrichthyans occurring in the region. Detailed descriptions and evaluations of fisheries can be found in Chapter 7 of AMB Volume 78. PMID- 28882217 TI - Preface: Molecular Mechanisms, Novel Modes of Regulation, and Therapeutic Strategies. PMID- 28882219 TI - MicroRNAs and Cancer: A Long Story for Short RNAs. AB - More than six decades ago Watson and Crick published the chemical structure of DNA. This discovery revolutionized our approach to medical science and opened new perspectives for the diagnosis and treatment of many diseases including cancer. Since then, progress in molecular biology, together with the rapid advance of technologies, allowed to clone hundreds of protein-coding genes that were found mutated in all types of cancer. Normal and aberrant gene functions, interactions, and mechanisms of mutations were studied to identify the intricate network of pathways leading to cancer. With the acknowledgment of the genetic nature of cancer, new diagnostic, prognostic, and therapeutic strategies have been attempted and developed, but very few have found their way in the clinical field. In an effort to identify new translational targets, another great discovery has changed our way to look at genes and their functions. MicroRNAs have been the first noncoding genes involved in cancer. This review is a brief chronological history of microRNAs and cancer. Through the work of few of the greatest scientists of our times, this chapter describes the discovery of microRNAs from C. elegans to their debut in cancer and in the medical field, the concurrent development of technologies, and their future translational applications. The purpose was to share the exciting path that lead to one of the most important discoveries in cancer genetics in the past 20 years. PMID- 28882220 TI - Cancer Hallmarks and MicroRNAs: The Therapeutic Connection. AB - Human cancers are characterized by a number of hallmarks, including sustained proliferative signaling, evasion of growth suppressors, activated invasion and metastasis, replicative immortality, angiogenesis, resistance to cell death, and evasion of immune destruction. As microRNAs (miRNAs) are deregulated in virtually all human cancers, they show involvement in each of the cancer hallmarks as well. In this chapter, we describe the involvement of miRNAs in cancer from a cancer hallmarks and targeted therapeutics point of view. As no miRNA-based cancer therapeutics are available to date, and the only clinical trial on miRNA-based cancer therapeutics (MRX34) was terminated prematurely due to serious adverse events, we are focusing on protein-coding miRNA targets for which targeted therapeutics in oncology are already approved by the FDA. For each of the cancer hallmarks, we selected major protein-coding players and describe the miRNAs that target them. PMID- 28882221 TI - microRNAs in Cancer Susceptibility. AB - microRNAs (miRNAs) are a small RNA species without protein-coding potential. However, they are key modulators of protein translation. Many studies have linked miRNAs with cancer initiation, progression, diagnosis, and prognosis, and recent studies have also linked them with cancer etiology and susceptibility, especially through single-nucleotide polymorphisms (SNPs). This review discusses some of the recent advances in miRNA-SNP literature-including SNPs in miRNA genes, miRNA target sites, and the processing machinery. In addition, we highlight some emerging areas of interest, including isomiRs and non-3'UTR focused miRNA-binding mechanisms that could provide further novel insight into the relationship between miR-SNPs and cancer. Finally, we note that additional epidemiological and experimental research is needed to close the gap in our understanding of the genotype-phenotype relationship between miRNA-SNPs and cancer. PMID- 28882222 TI - Role of the tRNA-Derived Small RNAs in Cancer: New Potential Biomarkers and Target for Therapy. AB - Noncoding RNAs are untranslated RNA molecules that can be divided into two main types: infrastructural, including transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), and regulatory, including long ncRNAs (lncRNAs) and small ncRNAs (sRNA). Among small ncRNA, the role of microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs) in cancer is well documented. Recently, other small ncRNAs have been described. In particular, tRNA-derived small RNAs (tsRNA) have been found to be frequently dysregulated in cancer. Since tsRNAs can be considered unique sequences and are able to bind both Argonaute proteins (like miRNAs) and Piwi proteins (like piRNAs), their dysregulation could play a critical role in cancer by interfering with gene expression regulation at different levels. Like microRNAs, ts-53 (previously known as miR-3676) interacts with the 3'UTR of TCL1, therefore supporting a role for tsRNAs on the posttranscriptional regulation of gene expression. Like piRNAs, tsRNAs are produced as single-stranded molecules and can interact with DNA and histone methylation machinery, suggesting a role in the pretranscriptional regulation of gene expression. Herein, we describe the most recent findings about the role of tsRNAs in cancer. PMID- 28882223 TI - MicroRNAs and Epigenetics. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression mainly at the posttranscriptional level. Similar to protein-coding genes, their expression is also controlled by genetic and epigenetic mechanisms. Disruption of these control processes leads to abnormal expression of miRNAs in cancer. In this chapter, we discuss the supportive links between miRNAs and epigenetics in the context of carcinogenesis. miRNAs can be epigenetically regulated by DNA methylation and/or specific histone modifications. However, they can themselves (epi-miRNAs) repress key enzymes that drive epigenetic remodeling and also bind to complementary sequences in gene promoters, recruiting specific protein complexes that modulate chromatin structure and gene expression. All these issues affect the transcriptional landscape of cells. Most important, in the cancer clinical scenario, knowledge about miRNAs epigenetic dysregulation can not only be beneficial as a prognostic biomarker, but can also help in the design of new therapeutic approaches. PMID- 28882224 TI - The Enigma of miRNA Regulation in Cancer. AB - MicroRNAs (miRNAs or miRs) are small 19-22 nucleotide long, noncoding, single stranded, and multifunctional RNAs that regulate a diverse assortment of gene and protein functions that impact on a vast network of pathways. Lin-4, a noncoding transcript discovered in 1993 and named miRNA, initiated the exploration of research into these intriguing molecules identified in almost all organisms. miRNAs interfere with translation or posttranscriptional regulation of their target gene and regulate multiple biological actions exerted by these target genes. In cancer, they function as both oncogenes and tumor suppressor genes displaying differential activity in various cellular contexts. Although the role of miRNAs on target gene functions has been extensively investigated, less is currently known about the upstream regulatory molecules that regulate miRNAs. This chapter focuses on the factors and processes involved in miRNA regulation. PMID- 28882226 TI - Preface. PMID- 28882228 TI - Is Atrial Fibrillation a Necessary Component of the Thrombogenic Atrium? PMID- 28882227 TI - Left Atrial Fibrosis and Risk of Cerebrovascular and Cardiovascular Events in Patients With Atrial Fibrillation. AB - BACKGROUND: Severity of left atrial (LA) fibrosis is a strong predictor of atrial fibrillation (AF) ablation success and has been associated with a history of stroke, hypertension, and heart failure (HF). However, it is unclear whether more severe LA fibrosis independently increases the risk of major adverse cardiovascular and cerebrovascular events (MACCE) among those with AF. OBJECTIVES: The goal of this study was to evaluate the occurrence and frequency of MACCE by strata of LA fibrosis severity in patients with AF. METHODS: This was a retrospective cohort study of 1,228 patients with AF who underwent late gadolinium enhancement (LGE)-cardiac magnetic resonance imaging to quantify LA fibrosis severity between January 2007 and June 2015. Patients were stratified according to Utah stage of LA LGE criteria, and observed for the occurrence of MACCE, which included a composite of stroke or transient ischemic attack (TIA), myocardial infarction, acute decompensated HF, or cardiovascular death. Disease risk score (DRS) stratification was used to control for between-group differences in baseline characteristics and risk. RESULTS: During follow-up, 62 strokes or TIAs, 42 myocardial infarctions, 156 HF events, and 38 cardiovascular deaths occurred. In DRS stratified analysis, the hazard ratio comparing patients with stage IV versus stage I LA LGE was 1.67 (95% confidence interval: 1.01 to 2.76) for the composite MACCE outcome. The only individual component of the MACCE outcome to remain significantly associated with advanced LGE following DRS stratification was stroke or TIA (hazard ratio: 3.94; 95% confidence interval: 1.72 to 8.98). CONCLUSIONS: This retrospective analysis demonstrated that more severe LA LGE is associated with increased MACCE risk, driven primarily by increased risk of stroke or TIA. PMID- 28882229 TI - Care Patterns and Outcomes in Atrial Fibrillation Patients With and Without Diabetes: ORBIT-AF Registry. AB - BACKGROUND: Diabetes is a well-established risk factor for thromboembolism in patients with atrial fibrillation (AF), but less is known about how diabetes influences outcomes among AF patients. OBJECTIVES: This study assessed whether symptoms, health status, care, and outcomes differ between AF patients with and without diabetes. METHODS: The cohort study included 9,749 patients from the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, a prospective, nationwide, outpatient registry of patients with incident and prevalent AF. Outcomes included symptoms, health status, and AF treatment, as well as 2-year risk of death, hospitalization, thromboembolic events, heart failure (HF), and AF progression. RESULTS: Patients with diabetes (29.5%) were younger, more likely to have hypertension, chronic kidney disease, HF, coronary heart disease, and stroke. Compared to patients without diabetes, patients with diabetes also had a lower Atrial Fibrillation Effects on Quality of Life score of 80 (interquartile range [IQR]: 62.5 to 92.6) versus 82.4 (IQR: 67.6 to 93.5; p = 0.025) and were more likely to receive anticoagulation (p < 0.001). Diabetes was associated with higher mortality risk, including overall (adjusted hazard ratio [aHR]: 1.63; 95% confidence interval [CI]: 1.04 to 2.56, for age <70 years vs. aHR: 1.25; 95% CI: 1.09 to 1.44, for age >=70 years) and cardiovascular (CV) mortality (aHR: 2.20; 95% CI: 1.22 to 3.98, for age <70 years vs. 1.24; 95% CI: 1.02 to 1.51 for age >=70 years). Diabetes conferred a higher risk of non-CV death, sudden cardiac death, hospitalization, CV hospitalization, and non-CV and nonbleeding-related hospitalization, but no increase in risks of thromboembolic events, bleeding-related hospitalization, new-onset HF, and AF progression. CONCLUSIONS: Among AF patients, diabetes was associated with worse AF symptoms and lower quality of life, and increased risk of death and hospitalizations, but not thromboembolic or bleeding events. PMID- 28882230 TI - Concomitant Diabetes and Atrial Fibrillation: No Sugarcoating the Bittersweet Reality. PMID- 28882225 TI - Animal Models to Study MicroRNA Function. AB - The discovery of the microRNAs, lin-4 and let-7 as critical mediators of normal development in Caenorhabditis elegans and their conservation throughout evolution has spearheaded research toward identifying novel roles of microRNAs in other cellular processes. To accurately elucidate these fundamental functions, especially in the context of an intact organism, various microRNA transgenic models have been generated and evaluated. Transgenic C. elegans (worms), Drosophila melanogaster (flies), Danio rerio (zebrafish), and Mus musculus (mouse) have contributed immensely toward uncovering the roles of multiple microRNAs in cellular processes such as proliferation, differentiation, and apoptosis, pathways that are severely altered in human diseases such as cancer. The simple model organisms, C. elegans, D. melanogaster, and D. rerio, do not develop cancers but have proved to be convenient systesm in microRNA research, especially in characterizing the microRNA biogenesis machinery which is often dysregulated during human tumorigenesis. The microRNA-dependent events delineated via these simple in vivo systems have been further verified in vitro, and in more complex models of cancers, such as M. musculus. The focus of this review is to provide an overview of the important contributions made in the microRNA field using model organisms. The simple model systems provided the basis for the importance of microRNAs in normal cellular physiology, while the more complex animal systems provided evidence for the role of microRNAs dysregulation in cancers. Highlights include an overview of the various strategies used to generate transgenic organisms and a review of the use of transgenic mice for evaluating preclinical efficacy of microRNA-based cancer therapeutics. PMID- 28882231 TI - Hemodynamic Response to Nitroprusside in Patients With Low-Gradient Severe Aortic Stenosis and Preserved Ejection Fraction. AB - BACKGROUND: Low-gradient severe aortic stenosis (LGSAS) with preserved ejection fraction (EF) is incompletely understood. The influence of arterial afterload and diastolic dysfunction on the hemodynamic presentation of LGSAS remains unknown. OBJECTIVES: The authors sought to determine the acute hemodynamic response to sodium nitroprusside in LGSAS with preserved EF. METHODS: Symptomatic patients with LGSAS and preserved EF underwent cardiac catheterization with comparison of hemodynamic measurements before and after nitroprusside. RESULTS: Forty-one subjects (25 with low flow [LF], stroke volume index [SVI] <=35 ml/m2, 16 with normal flow [NF]) were included. At baseline, LF patients had lower total arterial compliance (0.36 +/- 0.12 ml/m2/mm Hg vs. 0.48 +/- 0.16 ml/m2/mm Hg; p = 0.01) and greater effective arterial elastance (2.77 +/- 0.84 mm Hg . m2/ml vs. 1.89 +/- 0.82 mm Hg . m2/ml; p = 0.002). In all patients, nitroprusside reduced elastance, left ventricular filling pressures, and pulmonary artery pressures and improved compliance (p < 0.05). Aortic valve area increased to >=1.0 cm2 in 6 LF (24%) and 4 NF (25%) subjects. Change in SVI with nitroprusside varied inversely to baseline SVI and demonstrated improvement in LF only (3 +/- 6 ml/m2; p = 0.02). CONCLUSIONS: Nitroprusside reduces afterload and left ventricular filling pressures in patients with LGSAS and preserved EF, enabling reclassification to moderate stenosis in 25% of patients. An inverse relationship between baseline SVI and change in SVI with afterload reduction was observed, suggesting that heightened sensitivity to afterload is a significant contributor to LF-LGSAS pathophysiology. These data highlight the utility of afterload reduction in the diagnostic assessment of LGSAS. PMID- 28882232 TI - Evaluating Resistance in Our Assessing Patients With Aortic Stenosis: OHM Sweet OHM. PMID- 28882233 TI - Prognostic Significance of Central Apneas Throughout a 24-Hour Period in Patients With Heart Failure. AB - BACKGROUND: Large trials using noninvasive mechanical ventilation to treat central apnea (CA) occurring at night ("sleep apnea") in patients with systolic heart failure (HF) have failed to improve prognosis. The prevalence and prognostic value of CA during daytime and over an entire 24-h period are not well described. OBJECTIVES: This study evaluated the occurrence and prognostic significance of nighttime, daytime, and 24-h CA episodes in a large cohort of patients with systolic HF. METHODS: Consecutive patients receiving guideline recommended treatment for HF (n = 525; left ventricular ejection fraction [LVEF] of 33 +/- 9%; 66 +/- 12 years of age; 77% males) underwent prospective evaluation, including 24-h respiratory recording, and were followed-up using cardiac mortality as an endpoint. RESULTS: The 24-h prevalence of predominant CAs (apnea/hypopnea index [AHI] >=5 events/h, with CA of >50%) was 64.8% (nighttime: 69.1%; daytime: 57.0%), whereas the prevalence of predominant obstructive apneas (OA) was 12.8% (AHI >=5 events/h with OAs >50%; nighttime: 14.7%; daytime: 5.9%). Episodes of CA were associated with neurohormonal activation, ventricular arrhythmic burden, and systolic/diastolic dysfunction (all p < 0.05). During a median 34-month follow-up (interquartile range [IQR]: 17 to 36 months), 50 cardiac deaths occurred. Nighttime, daytime, and 24-h moderate-to-severe CAs were associated with increased cardiac mortality (AHI of =15 events/h; log-rank: 6.6, 8.7, and 5.3, respectively; all p < 0.05; central apnea index [CAI] of =10 events/h; log-rank 8.9, 11.2, and 10.9, respectively; all p < 0.001). Age, B-type natriuretic peptide level, renal dysfunction, 24-h AHI, CAI, and time with oxygen saturation of <90% were independent predictors of outcome. CONCLUSIONS: In systolic HF patients, CAs occurred throughout a 24-h period and were associated with a neurohormonal activation, ventricular arrhythmic burden, and worse prognosis. PMID- 28882234 TI - Ambulatory Apnea Monitoring in Heart Failure: Proceed With Caution. PMID- 28882236 TI - Using Absolute Event Rates to See What Works in Cardiovascular Medicine. PMID- 28882235 TI - Efficacy and Safety of Ticagrelor Over Time in Patients With Prior MI in PEGASUS TIMI 54. AB - BACKGROUND: Ticagrelor reduces ischemic risk in patients with prior myocardial infarction (MI). It remains unclear whether ischemic risk and the benefits of prolonged P2Y12 inhibition in this population remain consistent over time. OBJECTIVES: The study sought to investigate the pattern of ischemic risk over time and whether the efficacy and safety of ticagrelor were similar early and late after randomization. METHODS: The PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction) 54 trial randomized patients with prior MI (median 1.7 years prior) to ticagrelor 90 mg, ticagrelor 60 mg, or placebo on a background of aspirin. The rates of cardiovascular (CV) death, MI, and stroke as well as TIMI major bleeding were analyzed at yearly landmarks (years 1, 2, and 3). RESULTS: A total of 21,162 patients were randomized and followed for 33 months (median), with 28% of patients >=5 years from MI at trial conclusion. The risk of CV death, MI, or stroke in the placebo arm remained roughly constant over the trial at an ~3% annualized rate. The benefit of ticagrelor 60 mg was consistent at each subsequent landmark (year 1 hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.67 to 0.99; year 2 HR: 0.90; 95% CI: 0.74 to 1.11; and year 3 HR: 0.79; 95% CI: 0.62 to 1.00). TIMI major bleeding was increased with ticagrelor 60 mg at each landmark, but with the greatest hazard in the first year (year 1 HR: 3.22; year 2 HR: 2.07; year 3 HR: 1.65). CONCLUSIONS: Patients with a history of MI remain at persistent high risk for CVD, MI, and stroke as late as 5 years after MI. The efficacy of low-dose ticagrelor is consistent over time with a trend toward less excess bleeding. (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562). PMID- 28882237 TI - The Evolving Future of Instantaneous Wave-Free Ratio and Fractional Flow Reserve. AB - In this review, the authors reflect upon the role of coronary physiology in the modern management of coronary artery disease. They critically appraise the scientific background of the instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR), from early experimental studies to validation studies against indexes of ischemia, to clinical trials assessing outcome. At this important juncture for the field, the authors make predictions for the future of physiological stenosis assessment, outlining developments for both iFR and FFR in new clinical domains beyond the confines of stable angina. With a focus on the evolving future of iFR and FFR, the authors describe how physiological assessment with iFR may advance its application from simply justifying to guiding revascularization. PMID- 28882239 TI - Bridge to Transplantation: Advanced Heart Failure and Transplant Cardiology Training for Cardiovascular Disease Fellows. PMID- 28882240 TI - Father's Day. PMID- 28882241 TI - Sudden Cardiac Death in Professional Soccer Players. PMID- 28882238 TI - Unraveling Vascular Inflammation: From Immunology to Imaging. AB - Inflammation is a critical factor in early atherosclerosis and its progression to myocardial infarction. The search for valid surrogate markers of arterial vascular inflammation led to the increasing use of positron emission tomography/computed tomography. Indeed, vascular inflammation is associated with future risk for myocardial infarction and can be modulated with short-term therapies, such as statins, that mitigate cardiovascular risk. However, to better understand vascular inflammation and its mechanisms, a panel was recently convened of world experts in immunology, human translational research, and positron emission tomographic vascular imaging. This contemporary review first strives to understand the diverse roles of immune cells implicated in atherogenesis. Next, the authors describe human chronic inflammatory disease models that can help elucidate the pathophysiology of vascular inflammation. Finally, the authors review positron emission tomography-based imaging techniques to characterize the vessel wall in vivo. PMID- 28882243 TI - Early Revascularization in NSTE-ACS: Insights From the ICTUS Long-Term Follow-Up. PMID- 28882242 TI - A Collaborative Cardiologist-Intensivist Management Model Improves Cardiac Intensive Care Unit Outcomes. PMID- 28882244 TI - Reply: Early Revascularization in NSTE-ACS: Insights From the ICTUS Long-Term Follow-Up. PMID- 28882245 TI - Potent P2Y12 Inhibitor Therapy for All?: But What About Ethnicity? PMID- 28882246 TI - Reply: Potent P2Y12 Inhibitor Therapy for All? But What About Ethnicity? PMID- 28882247 TI - Vascular Disorders in the Athlete: A Call for Vascular Sports Medicine Clinics. PMID- 28882248 TI - Demonstrated value in the public health arena: Operation protect yourself. PMID- 28882249 TI - Demonstrated value in the public health arena: Pharmacist roles in addressing the current opioid crisis. PMID- 28882250 TI - Demonstrated value in the public health arena: Overcoming societal-level barriers to vaccination through patient relationships. PMID- 28882251 TI - Influenza vaccine formulation and effectiveness. PMID- 28882252 TI - Crisaborole, Dupilumab, and Sarilumab. PMID- 28882253 TI - EMERGE from reporting inconsistencies on pharmacy adherence intervention. PMID- 28882254 TI - Validation and models in computational biomedical sciences: Philosophy, science, engineering. PMID- 28882255 TI - Improvement of the performance of animal crossing warning signs. AB - INTRODUCTION: Animal-vehicle collisions (AVCs) can result in serious injury and death to drivers, animals' death, and significant economic costs. However, the cost effectiveness of the majority of AVC mitigation measures is a significant issue. METHOD: A mobile-based data collection effort was deployed to measure signs under the Utah Department of Transportation's (UDOT) jurisdiction. The crash data were obtained from the UDOT risk management database. ArcGIS was employed to link these two data sets and extract animal-related crashes and signs. An algorithm was developed to process the data and identify AVCs that occurred within sign recognition distance. Kernel density estimation (KDE) technique was applied to identify potential crash hotspots. RESULTS: Only 2% of AVCs occurred within the recognition distance of animal crossing signs. Almost 58% of animal-related crashes took place on the Interstate and U.S. highways, wherein only 30% of animal crossing signs were installed. State routes with a higher average number of signs experienced a lower number of AVCs per mile. The differences between AVCs that occurred within versus outside of sign recognition distance were not statistically significant regarding crash severity, time of crash, weather condition, driver age, vehicle speed, and type of animal. It is more likely that drivers become accustomed to deer crossing signs than cow signs. CONCLUSIONS: Based on the historical crash data and landscape structure, with attention given to the low cost safety improvement methods, a combination of different types of AVC mitigation measures can be developed to reduce the number of animal-related crashes. After an in-depth analysis of AVC data, warning traffic signs, coupled with other low cost mitigation countermeasures can be successfully placed in areas with higher priority or in critical areas. Practical applications: The findings of this study assist transportation agencies in developing more efficient mitigation measures against AVCs. PMID- 28882256 TI - Workers' compensation loss prevention representative contact and risk of lost time injury in construction policyholders. AB - INTRODUCTION: Insurance loss prevention (LP) representatives have access and contact with businesses and employees to provide targeted safety and health resources. Construction firms, especially those smaller in size, are a high-risk population. This research evaluated the association between LP rep contact and risk for lost-time injuries in construction policyholders. METHODS: Workers' compensation data were utilized to track LP rep contact with policyholders and incidence of lost-time injury over time. Survival analysis with repeated events modeling calculated hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Compared no LP contact, one contact was associated with a 27% reduction of risk (HR=0.73, CI=0.65-0.82), two with a 41% (HR=0.59, CI=0.51-0.68), and three or more contacts with a 28% reduction of risk (HR=0.72, CI=0.65-0.81). CONCLUSIONS: LP reps appear to be a valuable partner in efforts to reduce injury burden. Their presence or contact with policyholders is consistent with reduction in overall incidence of lost-time injuries. PRACTICAL APPLICATIONS: Reduction in lost-time injuries, resulting in reduced workers' compensation costs for policyholders and insurance companies, builds a business-case for safety and injury prevention. LP reps are often a low or no-cost benefit for insurance policyholders and may be an important injury prevention resource for small firms and/or those with lack of safety resources and staff. PMID- 28882257 TI - Safety climate and firefighting: Focus group results. AB - BACKGROUND: Firefighting is a hazardous occupation and there have been numerous calls for fundamental changes in how fire service organizations approach safety and balance safety with other operational priorities. These calls, however, have yielded little systematic research. METHODS: As part of a larger project to develop and test a model of safety climate for the fire service, focus groups were used to identify potentially important dimensions of safety climate pertinent to firefighting. RESULTS: Analyses revealed nine overarching themes. Competency/professionalism, physical/psychological readiness, and that positive traits sometimes produce negative consequences were themes at the individual level; cohesion and supervisor leadership/support at the workgroup level; and politics/bureaucracy, resources, leadership, and hiring/promotion at the organizational level. A multi-level perspective seems appropriate for examining safety climate in firefighting. CONCLUSIONS: Safety climate in firefighting appears to be multi-dimensional and some dimensions prominent in the general safety climate literature also seem relevant to firefighting. These results also suggest that the fire service may be undergoing transitions encompassing mission, personnel, and its fundamental approach to safety and risk. PRACTICAL APPLICATIONS: These results help point the way to the development of safety climate measures specific to firefighting and to interventions for improving safety performance. PMID- 28882258 TI - Effects of red light running camera systems installation and then deactivation on intersection safety. AB - INTRODUCTION: The primary objective of this paper is to evaluate the safety impacts of red-light running camera (RLC) system installation and then deactivation at 48 intersections in Houston, Texas. The second objective is to evaluate the spillover effect at nearby non-treated intersections in Houston after the deactivation. METHODS: To accomplish study objectives, an Empirical Bayes (EB) before-after analysis was used. RESULTS: The results indicate statistically significant collision reductions on all red-light running (RLR) crash types (37 percent) as well as right-angle RLR crashes (47 percent) at the treated intersections after RLC activation. By way of comparison, the RLC deactivation analysis indicated that crashes increased by 20 percent for all RLR crash types and by 23 percent in right-angle RLR crashes at the formerly treated intersections. After deactivation, all severity RLR crashes increased more than expected at nearby non-treated intersections, which indicates the possibility of an adverse spillover effect. However, fatal/injury crashes associated with rear end decreased after deactivation at both formerly treated and non-treated intersections, although those rear-end crashes account for smaller proportions when compared to all crash types/right-angle crashes. PRACTICAL APPLICATIONS: Overall, removing RLC treatments results in a negative reaction to the safety benefits that the treatment provides when it is in place and actively working and to the nearby intersections where the treatment has not been implemented. This study helps define the effects that RLCs have on safety at signalized intersections after installation and deactivation. PMID- 28882259 TI - Determinants of safety outcomes and performance: A systematic literature review of research in four high-risk industries. AB - INTRODUCTION: In spite of increasing governmental and organizational efforts, organizations still struggle to improve the safety of their employees as evidenced by the yearly 2.3 million work-related deaths worldwide. Occupational safety research is scattered and inaccessible, especially for practitioners. Through systematically reviewing the safety literature, this study aims to provide a comprehensive overview of behavioral and circumstantial factors that endanger or support employee safety. METHOD: A broad search on occupational safety literature using four online bibliographical databases yielded 27.527 articles. Through a systematic reviewing process 176 online articles were identified that met the inclusion criteria (e.g., original peer-reviewed research; conducted in selected high-risk industries; published between 1980 2016). Variables and the nature of their interrelationships (i.e., positive, negative, or nonsignificant) were extracted, and then grouped and classified through a process of bottom-up coding. RESULTS: The results indicate that safety outcomes and performance prevail as dependent research areas, dependent on variables related to management & colleagues, work(place) characteristics & circumstances, employee demographics, climate & culture, and external factors. Consensus was found for five variables related to safety outcomes and seven variables related to performance, while there is debate about 31 other relationships. Last, 21 variables related to safety outcomes and performance appear understudied. CONCLUSIONS: The majority of safety research has focused on addressing negative safety outcomes and performance through variables related to others within the organization, the work(place) itself, employee demographics, and-to a lesser extent-climate & culture and external factors. PRACTICAL APPLICATIONS: This systematic literature review provides both scientists and safety practitioners an overview of the (under)studied behavioral and circumstantial factors related to occupational safety behavior. Scientists could use this overview to study gaps, and validate or falsify relationships. Safety practitioners could use the insights to evaluate organizational safety policies, and to further development of safety interventions. PMID- 28882260 TI - Crash risk factors for interstate large trucks in North Carolina. AB - INTRODUCTION: Provide an updated examination of risk factors for large truck involvements in crashes resulting in injury or death. METHODS: A matched case control study was conducted in North Carolina of large trucks operated by interstate carriers. Cases were defined as trucks involved in crashes resulting in fatal or non-fatal injury, and one control truck was matched on the basis of location, weekday, time of day, and truck type. The matched-pair odds ratio provided an estimate of the effect of various driver, vehicle, or carrier factors. RESULTS: Out-of-service (OOS) brake violations tripled the risk of crashing; any OOS vehicle defect increased crash risk by 362%. Higher historical crash rates (fatal, injury, or all crashes) of the carrier were associated with increased risk of crashing. Operating on a short-haul exemption increased crash risk by 383%. Antilock braking systems reduced crash risk by 65%. All of these results were statistically significant at the 95% confidence level. Other safety technologies also showed estimated benefits, although not statistically significant. CONCLUSIONS: With the exception of the finding that short-haul exemption is associated with increased crash risk, results largely bolster what is currently known about large truck crash risk and reinforce current enforcement practices. Results also suggest vehicle safety technologies can be important in lowering crash risk. This means that as safety technology continues to penetrate the fleet, whether from voluntary usage or government mandates, reductions in large truck crashes may be achieved. Practical application: Results imply that increased enforcement and use of crash avoidance technologies can improve the large truck crash problem. PMID- 28882261 TI - Factors contributing to commercial vehicle rear-end conflicts in China: A study using on-board event data recorders. AB - INTRODUCTION: In the last 30years, China has undergone a dramatic increase in vehicle ownership and a resulting escalation in the number of road crashes. Although crash figures are decreasing today, they remain high; it is therefore important to investigate crash causation mechanisms to further improve road safety in China. METHOD: To shed more light on the topic, naturalistic driving data was collected in Shanghai as part of the evaluation of a behavior-based safety service. The data collection included instrumenting 47 vehicles belonging to a commercial fleet with data acquisition systems. From the overall sample, 91 rear-end crash or near-crash (CNC) events, triggered by 24 drivers, were used in the analysis. The CNC were annotated by three researchers, through an expert assessment methodology based on videos and kinematic variables. RESULTS: The results show that the main factor behind the rear-end CNC was the adoption of very small safety margins. In contrast to results from previous studies in the US, the following vehicles' drivers typically had their eyes on the road and reacted quickly in response to the evolving conflict in most events. When delayed reactions occurred, they were mainly due to driving-related visual scanning mismatches (e.g., mirror checks) rather than visual distraction. Finally, the study identified four main conflict scenarios that represent the typical development of rear-end conflicts in this data. CONCLUSIONS: The findings of this study have several practical applications, such as informing the specifications of in-vehicle safety measures and automated driving and providing input into the design of coaching/training procedures to improve the driving habits of drivers. PMID- 28882262 TI - Application of Bayesian informative priors to enhance the transferability of safety performance functions. AB - INTRODUCTION: Safety performance functions (SPFs) are essential tools for highway agencies to predict crashes, identify hotspots and assess safety countermeasures. In the Highway Safety Manual (HSM), a variety of SPFs are provided for different types of roadway facilities, crash types and severity levels. Agencies, lacking the necessary resources to develop own localized SPFs, may opt to apply the HSM's SPFs for their jurisdictions. Yet, municipalities that want to develop and maintain their regional SPFs might encounter the issue of the small sample bias. Bayesian inference is being conducted to address this issue by combining the current data with prior information to achieve reliable results. It follows that the essence of Bayesian statistics is the application of informative priors, obtained from other SPFs or experts' experiences. METHOD: In this study, we investigate the applicability of informative priors for Bayesian negative binomial SPFs for rural divided multilane highway segments in Florida and California. An SPF with non-informative priors is developed for each state and its parameters' distributions are assigned to the other state's SPF as informative priors. The performances of SPFs are evaluated by applying each state's SPFs to the other state. The analysis is conducted for both total (KABCO) and severe (KAB) crashes. RESULTS, CONCLUSIONS AND PRACTICAL APPLICATIONS: As per the results, applying one state's SPF with informative priors, which are the other state's SPF independent variable estimates, to the latter state's conditions yields better goodness of fit (GOF) values than applying the former state's SPF with non-informative priors to the conditions of the latter state. This is for both total and severe crash SPFs. Hence, for localities where it is not preferred to develop own localized SPFs and adopt SPFs from elsewhere to cut down on resources, application of informative priors is shown to facilitate the process. PMID- 28882263 TI - Evaluating the stability of a freestanding Mast Climbing Work Platform. AB - Mast Climbing Work Platforms (MCWPs) are becoming more common at construction sites and are being used as an alternative to traditional scaffolding. Although their use is increasing, little to no published information exists on the potential safety hazards they could pose for workers. As a last line of defense, a personal fall-arrest system can be used to save a worker in a fall incident from the platform. There has been no published information on whether it is safe to use such a personal fall-arrest system with MCWPs. In this study, the issues of concern for occupational safety included: (a) the overall stability of the freestanding mast climber during a fall-arrest condition and (b) whether that fall-arrest system could potentially present safety hazards to other workers on the platform during a fall-arrest condition. This research project investigated those safety concerns with respect to the mast climber stability and the workers using it by creating fall-arrest impact forces that are transmitted to the equipment and by subsequently observing the movement of the mast climber and the working deck used by the workers. This study found that when the equipment was erected and used according to the manufacturer's recommendations during a fall arrest condition, destabilizing forces were very small and there were no signs of potential of MCWP collapse. However, potential fall hazards could be presented to other workers on the platform during a fall arrest. Workers near an open platform are advised to wear a personal fall-arrest system to reduce the risk of being ejected. Due to the increasing use of MCWPs at construction sites, there is a corresponding need for evidence and science-based safety guidelines or regulations and further research should be conducted to continue to fill the knowledge gap with MCWP equipment. PMID- 28882264 TI - Development of a multilevel health and safety climate survey tool within a mining setting. AB - INTRODUCTION: This study aimed to design, implement and evaluate the reliability and validity of a multifactorial and multilevel health and safety climate survey (HSCS) tool with utility in the Australian mining setting. METHODS: An 84-item questionnaire was developed and pilot tested on a sample of 302 Australian miners across two open cut sites. RESULTS: A 67-item, 10 factor solution was obtained via exploratory factor analysis (EFA) representing prioritization and attitudes to health and safety across multiple domains and organizational levels. Each factor demonstrated a high level of internal reliability, and a series of ANOVAs determined a high level of consistency in responses across the workforce, and generally irrespective of age, experience or job category. Participants tended to hold favorable views of occupational health and safety (OH&S) climate at the management, supervisor, workgroup and individual level. CONCLUSION: The survey tool demonstrated reliability and validity for use within an open cut Australian mining setting and supports a multilevel, industry specific approach to OH&S climate. Findings suggested a need for mining companies to maintain high OH&S standards to minimize risks to employee health and safety. Future research is required to determine the ability of this measure to predict OH&S outcomes and its utility within other mine settings. PRACTICAL APPLICATIONS: As this tool integrates health and safety, it may have benefits for assessment, monitoring and evaluation in the industry, and improving the understanding of how health and safety climate interact at multiple levels to influence OH&S outcomes. PMID- 28882265 TI - Trends in teen driver licensure, driving patterns and crash involvement in the United States, 2006-2015. AB - INTRODUCTION: The Monitoring the Future (MTF) survey provides nationally representative annual estimates of licensure and driving patterns among U.S. teens. A previous study using MTF data reported substantial declines in the proportion of high school seniors that were licensed to drive and increases in the proportion of nondrivers following the recent U.S. economic recession. METHOD: To explore whether licensure and driving patterns among U.S. high school seniors have rebounded in the post-recession years, we analyzed MTF licensure and driving data for the decade of 2006-2015. We also examined trends in teen driver involvement in fatal and nonfatal injury crashes for that decade using data from the Fatality Analysis Reporting System and National Automotive Sampling System General Estimates System, respectively. RESULTS: During 2006-2015, the proportion of high school seniors that reported having a driver's license declined by 9 percentage points (11%) from 81% to 72% and the proportion that did not drive during an average week increased by 8 percentage points (44%) from 18% to 26%. The annual proportion of black seniors that did not drive was consistently greater than twice the proportion of nondriving white seniors. Overall during the decade, 17- and 18-year-old drivers experienced large declines in fatal and nonfatal injury crashes, although crashes increased in both 2014 and 2015. CONCLUSIONS: The MTF data indicate that licensure and driving patterns among U.S. high school seniors have not rebounded since the economic recession. The recession had marked negative effects on teen employment opportunities, which likely influenced teen driving patterns. Possible explanations for the apparent discrepancies between the MTF data and the 2014 and 2015 increases in crashes are explored. PRACTICAL APPLICATIONS: MTF will continue to be an important resource for clarifying teen driving trends in relation to crash trends and informing strategies to improve teen driver safety. PMID- 28882266 TI - Effects of organizational complexity and resources on construction site risk. AB - INTRODUCTION: Our research is aimed at studying the relationship between risk level and organizational complexity and resources on constructions sites. Our general hypothesis is that site complexity increases risk, whereas more resources of the structure decrease risk. A Structural Equation Model (SEM) approach was adopted to validate our theoretical model. METHOD: To develop our study, 957 building sites in Spain were visited and assessed in 2003-2009. All needed data were obtained using a specific tool developed by the authors to assess site risk, structure and resources (Construction Sites Risk Assessment Tool, or CONSRAT). This tool operationalizes the variables to fit our model, specifically, via a site risk index (SRI) and 10 organizational variables. Our random sample is composed largely of small building sites with general high levels of risk, moderate complexity, and low resources on site. CONCLUSIONS: The model obtained adequate fit, and results showed empirical evidence that the factors of complexity and resources can be considered predictors of site risk level. PRACTICAL APPLICATIONS: Consequently, these results can help companies, managers of construction and regulators to identify which organizational aspects should be improved to prevent risks on sites and consequently accidents. PMID- 28882267 TI - Work-related injuries among commercial janitors in Washington State, comparisons by gender. AB - INTRODUCTION: We analyzed workers' compensation (WC) data to identify characteristics related to workers' compensation claim outcomes among janitorial service workers in Washington State. METHOD: We analyzed WC data from the Washington State Department of Labor & Industries (L&I) State Fund (SF) from January 1, 2003 through December 31, 2013, for janitorial service workers employed in the National Occupational Research Agenda (NORA) Services Sector. We constructed multivariable models to identify factors associated with higher medical costs and increased time lost from work. RESULTS: There were 2,390 janitorial service compensable claims available for analysis. There were significant differences in injury type and other factors by gender, age, and language preference. Linguistic minority status was associated with longer time loss and higher median medical costs. Women were estimated to account for 35% of janitorial service workers but made up 55% of the compensable claims in this study. CONCLUSIONS: Janitorial service workers comprise a large vulnerable occupational group in the U.S. workforce. Identifying differences by injury type and potential inequitable outcomes by gender and language is important to ensuring equal treatment in the workers' compensation process. PRACTICAL APPLICATIONS: There were significant differences in injury and individual characteristics between men and women in this study. Women had twice the estimated rate of injury to men, and were more likely to require Spanish language materials. Improving communication for training and knowledge about the workers' compensation system appear to be high priorities in this population of injured janitorial service workers. PMID- 28882268 TI - Role of sensation seeking and attitudes as mediators between age of driver and risky driving of Powered Two Wheelers. AB - INTRODUCTION: This study examines the effect of age of driver on risky driving of Powered Two-Wheelers (PTW) employing sensation seeking and safety attitudes as mediators. METHODS: A survey was conducted with 1299 PTW drivers (1089 males and 210 females) within the age of 18 and 63years, living in the state of Kerala, India. The questionnaire consisted of 31 items to measure sensation seeking, safety attitude, and risky driving of the drivers. RESULTS: Mediation models were examined using sensation seeking as mediator and secondly safety attitudes as mediators. The relationship between the driver's age and risky driving was fully mediated by all the three variables. PRACTICAL APPLICATIONS: Results of this study suggest that safety strategies should be employed to reduce risky driving tendencies that could be achieved by shaping or adapting the mediators (reducing sensation seeking and enhancing safety attitudes). This goal could be reached by starting to educate children about this at an early stage when they are at school as well as by social learning and safety awareness campaigns. PMID- 28882269 TI - The construction FACE database - Codifying the NIOSH FACE reports. AB - INTRODUCTION: The National Institute for Occupational Safety and Health (NIOSH) has published reports detailing the results of investigations on selected work related fatalities through the Fatality Assessment and Control Evaluation (FACE) program since 1982. METHOD: Information from construction-related FACE reports was coded into the Construction FACE Database (CFD). Use of the CFD was illustrated by analyzing major CFD variables. RESULTS: A total of 768 construction fatalities were included in the CFD. Information on decedents, safety training, use of PPE, and FACE recommendations were coded. Analysis shows that one in five decedents in the CFD died within the first two months on the job; 75% and 43% of reports recommended having safety training or installing protection equipment, respectively. CONCLUSION: Comprehensive research using FACE reports may improve understanding of work-related fatalities and provide much needed information on injury prevention. PRACTICAL APPLICATION: The CFD allows researchers to analyze the FACE reports quantitatively and efficiently. PMID- 28882270 TI - Pedestrian falls: A review of the literature and future research directions. AB - INTRODUCTION: Pedestrian falls (PFs) - falls in public spaces without collisions with other road users - are a significant cause of serious transport-related injuries, amounting to three-quarters of all pedestrians admitted to hospital. METHODS: This scoping review examined peer-reviewed research on PFs published between 1995 and 2015. Electronic databases (Scopus, SafetyLit, and PubMed) were used to find studies identifying PFs or outdoor falls (the latter also including falls in gardens). RESULTS: We identified only 28 studies reporting relevant information on PFs (i.e., 15 prospective, 10 retrospective, and 3 intervention studies). The results show that more walking is related to a lower risk of PFs. Older people, especially older women, have a higher risk of (injurious) PFs. Outdoor fall victims have equally good or better health characteristics and scores on balance tests compared to those who have not experienced such falls. Road factors such as uneven surfaces, busy junctions, stairs, and slippery surfaces seem to play an important role in PFs, but much of the research on these factors is of a qualitative nature. CONCLUSIONS: PF victims are generally in good health (apart from normal age-related problems) but at risk due to road factors. PRACTICAL APPLICATIONS: We recommend to adopt a human factors approach. The road system should be adapted to human capabilities and limitations including those of pedestrians. Measures such as preventing uneven surfaces and good winter maintenance seem to be effective. However, we advise more quantitative research on road factors to inform design guidelines and standards for public space authorities given the qualitative nature of current research on road factors. PMID- 28882271 TI - Association between safety leading indicators and safety climate levels. AB - OBJECTIVES: The aim of this study was to evaluate the association of leading indicators for occupational health and safety, particularly safety inspections and non-compliances, with safety climate levels. METHODS: Nordic Occupational Safety Climate Assessment Questionnaire was employed to evaluate safety climate in cross-sectional design. The geographically diverse population of the inspection body made it possible to conduct the survey across 10 provinces in Iran. 89 completed questionnaires were obtained with a response rate of 47%. Except for management safety justice, the internal consistency of other six dimensions was found to be acceptable (alpha>=0.7). RESULTS: Mean scores of dimensions ranged from 3.50 in trust in the efficacy of safety systems (SD=0.38) to 2.98 in workers' safety priority and risk non-acceptance (SD=0.47). Tukey HSD tests indicated a statistically significant difference of mean scores among groups undergoing different number of safety inspections and those receiving different number of non-compliances (p<0.05), with no significant differences based on safety training man-hours and sessions (p>0.05). Spearman's rank-order correlation showed no relationship between work experience and number of non compliances (correlation coefficient=-0.04, p>0.05) and between safety training man-hours and number of non-compliances (correlation coefficient=-0.15, p>0.05). CONCLUSIONS: Our results indicate that safety climate levels are influenced by number of safety inspections and the resultant non-compliances. PRACTICAL APPLICATIONS: Findings suggest that safety non-compliances detected as a result of conducting safety inspections could be used to monitor the safety climate state. Establishing plans to conduct scheduled safety inspections and recording findings in the form of safety non-compliance and monitoring their trend could be used to monitor levels of safety climate. PMID- 28882272 TI - Using interactive virtual presence to support accurate installation of child restraints: Efficacy and parental perceptions. AB - INTRODUCTION: Child restraint systems (car seats) reduce injury risk for young children involved in motor-vehicle crashes, but parents experience significant difficulty installing child restraints correctly. Installation by certified child passenger safety (CPS) technicians yields more accurate installation, but is impractical for broad distribution. A potential solution is use of interactive virtual presence via smartphone application (app), which permits "hands on" teaching through simultaneous and remote joint exposure to 3-dimensional images. METHOD: In two studies, we examined the efficacy of remote communication via interactive virtual presence to help parents install child restraints. Study 1 was conducted at existing car seat checkpoints and Study 2 at preschools/daycare centers. In both cases, existing installations were assessed by certified CPS technicians using an objective coding scheme. Participants then communicated with remotely-located certified CPS technicians via a smartphone app offering interactive virtual presence. Technicians instructed participants to install child restraints and then the installation was inspected by on-site technicians. Both before and after the remote interaction, participants completed questionnaires concerning perception of child restraints and child restraint installation, self-efficacy to install child restraints, and perceived risk of injury to children if they were in a crash. RESULTS: In both studies, accuracy of child restraint installations improved following the remote interaction between participants and certified CPS technicians. Together, the two samples achieved a weighted average of 90% correct installations across a multi-point inspection. Both samples reported increased self-efficacy to install child restraints and altered perceptions about the accuracy of the child restraint installations in their vehicles. CONCLUSIONS: Findings support use of interactive virtual presence as a strategy to realize accurate installation of child restraints. PRACTICAL APPLICATIONS: Interactive virtual presence between certified CPS technicians and the public via smartphone app has potential to improve proper child restraint installations broadly, including to vulnerable and underserved rural populations. PMID- 28882273 TI - School transportation mode, by distance between home and school, United States, ConsumerStyles 2012. AB - INTRODUCTION: Motor-vehicle crashes are a leading cause of death among children in the United States, and almost one-fourth of all trips by school-aged children are trips to and from school. This study sought to determine how children (5 18years) travel to and from school and, among those living <=1mile of school, to explore the role of school bus service eligibility on school travel mode. METHODS: We used national 2012 survey data to determine prevalence of usual school travel mode, stratified by distance from school. For those living <=1mile of school, multivariable regression was conducted to assess the association between bus service eligibility and walking or bicycling. RESULTS: Almost half (46.6%) of all children rode in passenger vehicles (PV) to school and 41.8% did so for the trip home. Results were similar among those living <=1mile (48.1%, PV to school; 41.3%, PV to home). Among those living <=1mile, 21.9% and 28.4% of children walked or bicycled to and from school, respectively. Ineligibility for school bus service was strongly associated with walking or bicycling to school [adjusted prevalence ratio (aPR: 5.36; p<0.001)] and from school (aPR: 5.36; p<0.001). CONCLUSIONS: Regardless of distance from school, passenger vehicles were a common mode of travel. For children who live close to school, the role that school bus service eligibility plays in walking or bicycling deserves further consideration. PRACTICAL APPLICATIONS: Given the large proportion of children who use passenger vehicles for school travel, effective interventions can be adopted to increase proper child restraint and seat belt use and reduce crash risks among teen drivers. Better understanding of conditions under which bus service is offered to children who live close to school could inform efforts to improve pedestrian and bicyclist safety for school travel. PMID- 28882274 TI - CDC's efforts to improve traumatic brain injury surveillance. AB - INTRODUCTION: Youth sports concussion has become a prominent public health issue due to growing concern about the risk of long-term health effects. METHOD: A broad spectrum of stakeholders has convened to propose solutions, including a committee of the National Academy of Sciences (NAS) who systematically examined the issue and, in a 2014 report, made a series of recommendations to better address this public health problem. RESULTS: Among these recommendations, the NAS committee called for CDC to develop a plan for a comprehensive surveillance system to better quantify the incidence and outcomes of youth sports concussion among children 5 to 21years of age. Since the release of the NAS report, CDC has taken action to address this recommendation and, in the process, develop strategies to improve traumatic brain injury (TBI) surveillance more broadly. The challenges outlined by the NAS committee with respect to producing comprehensive incidence estimates of youth sports concussion are not exclusive to youth sports concussion, but also apply to TBI surveillance overall. In this commentary, we will discuss these challenges, the process CDC has undertaken to address them and describe our plan for improving TBI and youth sports concussion surveillance. PMID- 28882276 TI - Economic and statistical perspectives on traffic safety in Louisiana, 2005-2015. AB - INTRODUCTION: This study examine and applies recent empirical evidence from Mississippi and Alabama on fatal crashes and its relationship with gasoline prices and alcohol consumptions using the Louisiana Crash Data Reports between January 2005 and December 2015. METHOD: The negative binomial models is the preferred specification for the Louisiana Crash Data. The marginal effects and related elasticities were calculated to facilitate the interpretation of the results. RESULTS: Findings suggest that higher gasoline prices reduce fatalities among young drivers. A fewer number of young drivers on the roads are believed to reduce the likelihood of fatal crashes. Underage drinking is still prominent in Louisiana. Extreme temperatures are positively associated with youth and other types of fatal crashes. PRACTICAL APPLICATIONS: This study highlights a huge toll on society in terms of social and economic costs, wealth destruction, and unfulfilled potential of the deceased or incapacitated. PMID- 28882275 TI - Using SHRP 2 naturalistic driving data to assess drivers' speed choice while being engaged in different secondary tasks. AB - INTRODUCTION: The engagement in secondary tasks while driving has been found to result in considerable impairments of driving performance. Texting has especially been suspected to be associated with an increased crash risk. At the same time, there is evidence that drivers use various self-regulating strategies to compensate for the increased demands caused by secondary task engagement. One of the findings reported from multiple studies is a reduction in driving speed. However, most of these studies are of experimental nature and do not let the drivers decide for themselves to (not) engage in the secondary task, and therefore, eliminate other strategies of self-regulation (e.g., postponing the task). The goal of the present analysis was to investigate if secondary task engagement results in speed adjustment also under naturalistic conditions. METHOD: Our analysis relied on data of the SHRP 2 naturalistic driving study. To minimize the influence of potentially confounding factors on drivers' speed choice, we focused on episodes of free flow driving on interstates/highways. Driving speed was analyzed before, during, and after texting, smoking, eating, and adjusting/monitoring radio or climate control; in a total of 403 episodes. RESULTS: Data show some indication for speed adjustment for texting, especially when driving with high speed. However, the effect sizes were small and behavioral patterns varied considerably between drivers. The engagement in the other tasks did not influence drivers' speed behavior significantly. CONCLUSIONS AND PRACTICAL APPLICATIONS: While drivers might indeed reduce speed slightly to accommodate for secondary task engagement, other forms of adaptation (e.g., strategic decisions) might play a more important role in a natural driving environment. The use of naturalistic driving data to study drivers' self regulatory behavior at an operational level has proven to be promising. Still, in order to obtain a comprehensive understanding about drivers' self-regulatory behavior, a mixed-method approach is required. PMID- 28882277 TI - The need for detailed gender-specific occupational safety analysis. AB - INTRODUCTION: The female work in population is growing in the United States, therefore the occupational health and safety entities must start to analyze gender-specific data related to every industry, especially to nontraditional occupations. Women working in nontraditional jobs are often exposed to extreme workplace hazards. These women have their safety and health threatened because there are no adequate policies to mitigate gender-specific risks such as discrimination and harassment. Employers tend to aggravate this situation because they often fail to provide proper reporting infrastructure and support. According to past studies, women suffered from workplace injuries and illnesses that were less prominent among men. Statistics also confirmed that men and women faced different levels of risks in distinct work environments. For example, the rates of workplace violence and murders by personal acquaintances were significantly higher among women. METHODS: In this paper, the authors analyze prior public data on fatal and nonfatal injuries to understand why we need to differentiate genders when analyzing occupational safety and health issues. RESULTS: The analyses confirmed that women dealt with unique workplace hazards compared to men. CONCLUSIONS: It is urgent that public agencies, such as the U.S. Department of Labor, record gender-specific data in details and by occupations and industries. PRACTICAL APPLICATION: The reader will become aware of the current lack - and need - of data and knowledge about injuries and illnesses separated by gender and industry. Finally, safety and health researchers are encouraged to investigate the gender-specific data in all industries and occupations, as soon as they become available. PMID- 28882278 TI - Urban street structure and traffic safety. AB - INTRODUCTION: This paper reports the influence of road type and junction density on road traffic fatality rates in U.S. cities. METHOD: The Fatality Analysis Reporting System (FARS) files were used to obtain fatality rates for all cities for the years 2005-2010. A stratified random sample of 16 U.S. cities was taken, and cities with high and low road traffic fatality rates were compared on their road layout details (TIGER maps were used). Statistical analysis was done to determine the effect of junction density and road type on road traffic fatality rates. RESULTS: The analysis of road network and road traffic crash fatality rates in these randomly selected U.S. cities shows that, (a) higher number of junctions per road length was significantly associated with a lower motor- vehicle crash and pedestrian mortality rates, and, (b) increased number of kilometers of roads of any kind was associated with higher fatality rates, but an additional kilometer of main arterial road was associated with a significantly higher increase in total fatalities. When compared to non-arterial roads, the higher the ratio of highways and main arterial roads, there was an association with higher fatality rates. CONCLUSIONS: These results have important implications for road safety professionals. They suggest that once the road and street structure is put in place, that will influence whether a city has low or high traffic fatality rates. A city with higher proportion of wider roads and large city blocks will tend to have higher traffic fatality rates, and therefore in turn require much more efforts in police enforcement and other road safety measures. PRACTICAL APPLICATIONS: Urban planners need to know that smaller block size with relatively less wide roads will result in lower traffic fatality rates and this needs to be incorporated at the planning stage. PMID- 28882279 TI - Benefit-cost analysis of lane departure warning and roll stability control in commercial vehicles. AB - INTRODUCTION: This paper presents the cost benefits of two different onboard safety systems (OSS) installed on trucks as they operated during normal revenue deliveries. Using a formal economic analysis approach, the study quantified the costs and benefits associated with lane departure warning (LDW) systems and roll stability control (RSC) systems. METHODS: The study used data collected from participating carriers (many of these crashes were not reported to state or Federal agencies), and the research team also reviewed each crash file to determine if the specific OSS would have mitigated or prevented the crash. The deployment of each OSS was anticipated to increase the safety of all road users, but impact different sectors of society in different ways. Benefits that were inherent in each group (e.g., industry, society) were considered, and different benefit-cost analyses (BCAs) were performed. RESULTS: This paper presents two BCAs: a BCA focused on the costs and benefits in the carrier industry by implementing each OSS, and a BCA that measured the societal benefits of each OSS. In addition, a BCA for a theoretical mandatory deployment option for each OSS is presented. CONCLUSIONS: BCA results for LDW and RSC clearly showed their benefits outweighed their costs for the carrier and society. Practical applications: Cost information is a crucial factor in purchasing decisions in carriers; similarly, regulators must consider the cost burden prior to mandating technologies. The results in this study provide carrier decision makers and regulators with information necessary to make an informed decision regarding RSC and LDW. PMID- 28882280 TI - Estimating the value of life and injury for pedestrians using a stated preference framework. AB - INTRODUCTION: The incidence of pedestrian death over the period 2010 to 2014 per 1000,000 in North Cyprus is about 2.5 times that of the EU, with 10.5 times more pedestrian road injuries than deaths. With the prospect of North Cyprus entering the EU, many investments need to be undertaken to improve road safety in order to reach EU benchmarks. METHOD: We conducted a stated choice experiment to identify the preferences and tradeoffs of pedestrians in North Cyprus for improved walking times, pedestrian costs, and safety. The choice of route was examined using mixed logit models to obtain the marginal utilities associated with each attribute of the routes that consumers chose. These were used to estimate the individuals' willingness to pay (WTP) to save walking time and to avoid pedestrian fatalities and injuries. We then used the results to obtain community-wide estimates of the value of a statistical life (VSL) saved, the value of an injury (VI) prevented, and the value per hour of walking time saved. RESULTS: The estimate of the VSL was ?699,434 and the estimate of VI was ?20,077. These values are consistent, after adjusting for differences in incomes, with the median results of similar studies done for EU countries. The estimated value of time to pedestrians is ?7.20 per person hour. CONCLUSIONS: The ratio of deaths to injuries is much higher for pedestrians than for road accidents, and this is completely consistent with the higher estimated WTP to avoid a pedestrian accident than to avoid a car accident. The value of time of ?7.20 is quite high relative to the wages earned. PRACTICAL APPLICATIONS: Findings provide a set of information on the VRR for fatalities and injuries and the value of pedestrian time that is critical for conducing ex ante appraisals of investments to improve pedestrian safety. PMID- 28882281 TI - The state of the residential fire fatality problem in Sweden: Epidemiology, risk factors, and event typologies. AB - INTRODUCTION: Residential fires represent the largest category of fatal fires in Sweden. The purpose of this study was to describe the epidemiology of fatal residential fires in Sweden and to identify clusters of events. METHOD: Data was collected from a database that combines information on fatal fires with data from forensic examinations and the Swedish Cause of Death-register. Mortality rates were calculated for different strata using population statistics and rescue service turnout reports. Cluster analysis was performed using multiple correspondence analysis with agglomerative hierarchical clustering. RESULTS: Male sex, old age, smoking, and alcohol were identified as risk factors, and the most common primary injury diagnosis was exposure to toxic gases. Compared to non fatal fires, fatal residential fires more often originated in the bedroom, were more often caused by smoking, and were more likely to occur at night. Six clusters were identified. The first two clusters were both smoking-related, but were separated into (1) fatalities that often involved elderly people, usually female, whose clothes were ignited (17% of the sample), (2) middle-aged (45 64years old), (often) intoxicated men, where the fire usually originated in furniture (30%). Other clusters that were identified in the analysis were related to (3) fires caused by technical fault, started in electrical installations in single houses (13%), (4) cooking appliances left on (8%), (5) events with unknown cause, room and object of origin (25%), and (6) deliberately set fires (7%). CONCLUSIONS: Fatal residential fires were unevenly distributed in the Swedish population. To further reduce the incidence of fire mortality, specialized prevention efforts that focus on the different needs of each cluster are required. PRACTICAL APPLICATIONS: Cooperation between various societal functions, e.g. rescue services, elderly care, psychiatric clinics and other social services, with an application of both human and technological interventions, should reduce residential fire mortality in Sweden. PMID- 28882283 TI - The Impact of IMPACT-Contemporary Outcomes With Balloon Aortic Valvuloplasty: Are We Doing the Right Thing? PMID- 28882282 TI - Acute Success of Balloon Aortic Valvuloplasty in the Current Era: A National Cardiovascular Data Registry Study. AB - OBJECTIVES: The aim of this study was to evaluate practice patterns and outcomes of a contemporary group of patients undergoing balloon aortic valvuloplasty (BAV) for congenital aortic stenosis (AS). BACKGROUND: BAV is the most common treatment for isolated congenital AS. METHODS: Within the IMPACT (Improving Pediatric and Adult Congenital Treatments) Registry, all BAV procedures performed between January 2011 and March 2015 were identified. Procedures were separated into those performed for critical versus noncritical AS. Outcomes were stratified into optimal, adequate, and inadequate, with optimal and adequate outcomes defining "successful" procedures. Multivariate logistic regression was used to identify patient and procedural characteristics associated with unsuccessful BAV. Mortality and adverse events rates were compared across patient cohorts. RESULTS: Of the 1,026 isolated BAV procedures captured in IMPACT, 718 (70%) were "successful." Success rates were 70.9% for noncritical AS (n = 916) and 62.7% for critical AS (n = 110). Multivariate analysis revealed that prior cardiac catheterization, mixed valve disease, baseline aortic valve gradient >60 mm Hg, baseline aortic insufficiency greater than mild, presence of a trainee, and multiple balloon inflations were associated with unsuccessful BAV in the noncritical AS cohort. There were no factors associated with unsuccessful procedures in the critical AS group. No procedural deaths occurred, but 2.4% of patients did not survive to hospital discharge. Adverse events occurred in 15.8% of all cases and were more frequent in procedures performed for critical AS (30.0% vs. 14.1%; p < 0.001). CONCLUSIONS: BAV is an effective treatment for congenital AS with low rates of mortality and adverse events. Patients with critical AS have a higher risk for procedure-related adverse events. PMID- 28882284 TI - Harmony Feasibility Trial: Acute and Short-Term Outcomes With a Self-Expanding Transcatheter Pulmonary Valve. AB - OBJECTIVES: This study sought to obtain in vivo data to confirm assumptions on device loading conditions and assess procedural feasibility, safety, and valve performance. BACKGROUND: The Harmony transcatheter pulmonary valve (Medtronic, Minneapolis, Minnesota) was designed for patients with severe pulmonary regurgitation who require pulmonary valve replacement. METHODS: Three sites participated in this first Food and Drug Administration-approved early feasibility study using an innovative device design to accommodate the complex anatomy of the right ventricular outflow tract. Potentially eligible patients underwent review by a screening committee to determine implant eligibility. Six month outcomes are reported. RESULTS: Between May 2013 and May 2015, 66 subjects were enrolled, and 21 were approved for implant and underwent catheterization; 20 were implanted. Catheterized patients had a median age of 25 years, were predominantly diagnosed with tetralogy of Fallot (95%), had severe pulmonary regurgitation (95%), and had trivial or mild stenosis. The device was delivered in the desired location in 19 of 20 (95%) patients. Proximal migration occurred in 1 patient during delivery system removal. Two devices were surgically explanted. Premature ventricular contractions related to the procedure were reported in 3 patients; 2 were resolved without treatment. One patient had ventricular arrhythmias that required treatment and later were resolved. At 1 month, echocardiography revealed none or trivial pulmonary regurgitation in all and a mean right ventricular outflow tract gradient of 16 +/- 8 mm Hg (range 6 to 31 mm Hg). CONCLUSIONS: In this feasibility study of the Harmony transcatheter pulmonary valve device, there was high procedural success and safety, and favorable acute device performance. PMID- 28882286 TI - When Opportunity Knocks on the Front Door. PMID- 28882285 TI - Stenting of the Right Ventricular Outflow Tract Promotes Better Pulmonary Arterial Growth Compared With Modified Blalock-Taussig Shunt Palliation in Tetralogy of Fallot-Type Lesions. AB - OBJECTIVES: This study sought to compare pulmonary arterial (PA) growth during palliation after right ventricular outflow tract (RVOT) stenting versus modified Blalock-Taussig shunt (mBTS) in patients coming forward for complete repair of tetralogy of Fallot-type lesions. BACKGROUND: RVOT stenting is a recent alternative to mBTS in the initial palliation of selected patients with Fallot type lesions. METHODS: This was a retrospective, single-center study of nonrandomized, consecutive palliated Fallot patients over a 10-year period. Differential left PA (LPA) and right PA (RPA) growth was assessed by serial echocardiograms in 67 patients after mBTS (n = 28) or RVOT stent (n = 39). Statistical data analysis was performed using mixed model analysis. RESULTS: RPA z-scores in the mBTS group improved from median -2.41 (interquartile range [IQR]: -2.97 to -1.32) to -1.13 (IQR: -1.68 to -0.59). LPA z-scores improved from -1.89 (IQR: -2.33 to -1.12) to -0.32 (IQR: -0.88 to -0.05). In the RVOT stenting group RPA z-scores improved from -2.28 (IQR: -3.28 to -1.82) to -0.72 (IQR: -1.27 to +0.48), and LPA z-scores from -2.08 (IQR: -2.90 to -0.61) to -0.05 (IQR: -0.88 to +0.48). Mixed model analysis showed significantly better RPA and LPA growth after RVOT stenting. The benefit of RVOT stenting versus mBTS was 0.599 z-scores for the LPA and 0.749 z-scores for the RPA. Rise in oxygen saturations was greater with RVOT stenting (p = 0.012). Median time to complete repair was shorter in the RVOT stent group (227 [142 to 328] days) compared with the mBTS group (439 [300 to 529] days; p < 0.0003). CONCLUSIONS: RVOT stenting promotes better pulmonary arterial growth and oxygen saturations compared with mBTS in the initial palliation of Fallot-type lesions. PMID- 28882287 TI - The Effect of Strut Protrusion on Shear Stress Distribution: Hemodynamic Insights From a Prospective Clinical Trial. PMID- 28882288 TI - Early Initiation of Impella in Acute Myocardial Infarction Complicated by Cardiogenic Shock Improves Survival: A Meta-Analysis. PMID- 28882289 TI - Little Kids, Little Problems-Big Kids, Big Problems. PMID- 28882291 TI - Impact of End-Stage Renal Disease on Left and Right Ventricular Mechanics: Does Kidney Transplantation Reverse the Abnormalities? PMID- 28882292 TI - ROC Cutpoints May Help Clinicians Predict the Need for Pacemakers Prior to TAVR. PMID- 28882290 TI - The Potential of Clinical Phenotyping of Heart Failure With Imaging Biomarkers for Guiding Therapies: A Focused Update. AB - The need for noninvasive assessment of cardiac volumes and ejection fraction (EF) ushered in the use of cardiac imaging techniques in heart failure (HF) trials that investigated the roles of pharmacological and device-based therapies. However, in contrast to HF with reduced EF (HFrEF), modern HF pharmacotherapy has not improved outcomes in HF with preserved EF (HFpEF), largely attributed to patient heterogeneity and incomplete understanding of pathophysiological insights underlying the clinical presentations of HFpEF. Modern cardiac imaging methods offer insights into many sets of changes in cardiac tissue structure and function that can precisely link cause with cardiac remodeling at organ and tissue levels to clinical presentations in HF. This has inspired investigators to seek a more comprehensive understanding of HF presentations using imaging techniques. This article summarizes the available evidence regarding the role of cardiac imaging in HF. Furthermore, we discuss the value of cardiac imaging techniques in identifying HF patient subtypes who share similar causes and mechanistic pathways that can be targeted using specific HF therapies. PMID- 28882293 TI - The Authors' Reply. PMID- 28882294 TI - Distinguishing Active Vasculitis From Sterile Inflammation and Graft Infection: A Call for a More Specific Imaging Target. PMID- 28882296 TI - Correction. PMID- 28882295 TI - Correction. PMID- 28882297 TI - ERRATUM. PMID- 28882298 TI - Measuring Tau-microtubule affinity through cosedimentation assays. AB - Microtubule cosedimentation assays have long been used to study the affinity of interactions between Tau protein and microtubules. While these assays are very useful for characterizing and comparing the effects of alterations to either Tau or the microtubule filaments, they can also be problematic. We provide a set of straightforward instructions for performing these assays and point out a number of challenges and pitfalls that can complicate their interpretation. PMID- 28882299 TI - Single-molecule imaging of Tau dynamics on the microtubule surface. AB - The microtubule-associated protein Tau is primarily expressed in neurons and plays an integral role in the regulation of multiple functions within the axon. In the adult brain, the six Tau isoforms are expressed allowing for a complex system of control. Despite Tau's central role, the mechanisms by which Tau acts are not fully understood. We have used single-molecule total internal reflection fluorescence (TIRF) microscopy and the methods described in this chapter to further our knowledge of Tau's behavior and function. We have demonstrated that Tau's dynamic binding behavior allows for regulation of motor protein motility and microtubule dynamics in an isoform-specific manner. The continued use and refinement of the single-molecule techniques detailed here can only further our knowledge of Tau and other proteins integral to the maintenance of axonal transport. PMID- 28882300 TI - Synchrotron small-angle X-ray scattering and electron microscopy characterization of structures and forces in microtubule/Tau mixtures. AB - Tau, a neuronal protein known to bind to microtubules and thereby regulate microtubule dynamic instability, has been shown recently to not only undergo conformational transitions on the microtubule surface as a function of increasing microtubule coverage density (i.e., with increasing molar ratio of Tau to tubulin dimers) but also to mediate higher-order microtubule architectures, mimicking fascicles of microtubules found in the axon initial segment. These discoveries would not have been possible without fine structure characterization of microtubules, with and without applied osmotic pressure through the use of depletants. Herein, we discuss the two primary techniques used to elucidate the structure, phase behavior, and interactions in microtubule/Tau mixtures: transmission electron microscopy and synchrotron small-angle X-ray scattering. While the former is able to provide striking qualitative images of bundle morphologies and vacancies, the latter provides angstrom-level resolution of bundle structures and allows measurements in the presence of in situ probes, such as osmotic depletants. The presented structural characterization methods have been applied both to equilibrium mixtures, where paclitaxel is used to stabilize microtubules, and also to dissipative nonequilibrium mixtures at 37 degrees C in the presence of GTP and lacking paclitaxel. PMID- 28882301 TI - A TIRF microscopy assay to decode how tau regulates EB's tracking at microtubule ends. AB - Tau is a major microtubule-associated protein (MAP) mainly expressed in the brain. Tau binds the lattice of microtubules and favors their elongation and bundling. Recent studies have shown that tau is also a partner of end-binding proteins (EBs) in neurons. EBs belong to the protein family of the plus-end tracking proteins that preferentially associate with the growing plus-ends of microtubules and control microtubule end behavior and anchorage to intracellular organelles. Reconstituted cell-free systems using purified proteins are required to understand the precise mechanisms by which tau influences EB localization on microtubules and how the concerted activity of these two MAPs modulates microtubule dynamics. We developed an in vitro assay combining TIRF microscopy and site-directed mutagenesis to dissect the interaction of tau with EBs and to study how this interaction affects microtubule dynamics. Here, we describe the detailed procedures to purify proteins (tubulin, tau, and EBs), prepare the samples for TIRF microscopy, and analyze microtubule dynamics, and EB binding at microtubule ends in the presence of tau. PMID- 28882302 TI - TIRF assays for real-time observation of microtubules and actin coassembly: Deciphering tau effects on microtubule/actin interplay. AB - Microtubule and actin cytoskeletons are key players in vital processes in cells. Although the importance of microtubule-actin interaction for cell development and function has been highlighted for years, the properties of these two cytoskeletons have been mostly studied separately. Thus we now need procedures to simultaneously assess actin and microtubule properties to decipher the basic mechanisms underlying microtubule-actin crosstalk. Here we describe an in vitro assay that allows the coassembly of both filaments and the real-time observation of their interaction by TIRF microscopy. We show how this assay can be used to demonstrate that tau, a neuronal microtubule-associated protein, is a bona fide actin-microtubule cross-linker. The procedure relies on the use of highly purified proteins and chemically passivated perfusion chambers. We present a step by-step protocol to obtain actin and microtubule coassembly and discuss the major pitfalls. An ImageJ macro to quantify actin and microtubule interaction is also provided. PMID- 28882303 TI - Digital quantification of neurite outgrowth and retraction by phase-contrast microscopy: A tau perspective. AB - The proper organization and function of the mammalian nervous system relies on neuronal processes or "neurites," extended morphological projections that include axons and dendrites. Tau is a structural microtubule-associated protein that is widely expressed in the nervous system that mediates the establishment of cell polarity, neurite outgrowth, and axonal transport. A useful model for studying the establishment and maintenance of these neuronal structures are rat neuronal PC12 cells, which can be induced to express tau and project neurites by treating the cells with nerve growth factor. Here, we present a simple method for continuously measuring the rate of neurite outgrowth and retraction over time by neurite length and neurite area analyses. This method uses freely available ImageJ software and widely available phase-contrast imaging. PMID- 28882304 TI - Assessing the degradation of tau in primary neurons: The role of autophagy. AB - Tau is a neuronal cytosolic, highly regulated protein. Although first identified as a protein that binds and stabilizes microtubules, it is now clear that tau plays numerous other roles in neurons. In addition to its key physiological roles in neuronal structure and function, tau is also involved in the pathogenesis of Alzheimer's disease and numerous other neurodegenerative disorders. In all tauopathies, there are pathogenic accumulations of tau. Given that tau homeostasis requires a balance of synthesis and degradation, understanding the pathways that mediate tau clearance and regulate this process in the disease state is of fundamental importance. In neurons, macroautophagy (referred to as autophagy in this chapter) plays a pivotal role in clearing damaged or misfolded proteins under normal conditions. However, in the disease state autophagy is impaired and tau may not be efficiently targeted for degradation which contributes to the increases in pathological tau species. Therefore, establishing model systems that allow for the analysis of tau clearance by autophagy and quantitative assessment of interventions that increase autophagy and tau clearance are needed. Of particular importance is the use of primary neurons as a model system, as they are more reflective of the relevant in vivo autophagy pathway than clonal or immortalized cell models. In this chapter we present detailed methods for the preparation of neurons, immunoblotting and imaging analyses, genetic and pharmacological manipulation of autophagy with analyses, and methods to quantitatively measure changes in tau and phospho-tau levels. PMID- 28882305 TI - Methods related to studying tau fragmentation. AB - Several tau posttranslational modifications have been implicated in neuronal degeneration. Among them, tau fragmentation has been identified not only in brain samples obtained from Alzheimer's disease (AD) and related disorder subjects but also in AD culture and animal models. Some of these tau fragments have not been extensively studied. In contrast, data obtained recently showed that tau fragmentation mediated by enhanced or abnormal calpain, caspase 2, caspase 3, and asparagine endopeptidase activity results in the formation of toxic fragments. These cleaved tau forms induce neuronal death, synapse loss, and/or behavioral deficits. Here, we described protease activity assays and methods to study the effects of tau fragments on neuronal viability. PMID- 28882306 TI - The Drosophila model system to study tau action. AB - The fruit fly, Drosophila melanogaster, is a powerful model system for applying molecular, cellular, and genetic approaches to understanding human tauopathies, including Alzheimer's disease. Here, we provide an introduction to using Drosophila as a tauopathy model system and describe several protocols that we use to analyze human tau protein expressed in flies. Methods to detect tau expression include light and scanning electron microscopy in the fly eye, confocal microscopy of primary neuronal cultures, and preparation of tissue homogenates for separation by sodium dodecyl sulfate polyacrylamide gel electrophoresis with analysis by Western blotting. PMID- 28882307 TI - Insights into tau function and dysfunction through single-molecule fluorescence. AB - Fluorescence correlation spectroscopy and single-molecule Forster resonance energy transfer are powerful and versatile techniques to quantify and describe molecular interactions. They are particularly well suited to the study of dynamic proteins and assemblies, as they can overcome some of the challenges that stymie more conventional ensemble approaches. In this chapter, we describe the application of these methods to study the interaction of tau with the molecular aggregation inducer, heparin, and the functional binding partner, soluble tubulin. Specifically, we outline the practical aspects of both techniques to characterize the critical first steps of tau aggregation and tau-mediated microtubule polymerization. The information gained from these measurements provides unique insight into tau function and its role in disease. PMID- 28882308 TI - The use of mouse models to study cell-to-cell transmission of pathological tau. AB - Tau protein aggregates are found in a variety of neurodegenerative diseases known as tauopathies. Emerging evidence shows tau can propagate from cell-to-cell by seeding endogenous tau to aggregate. Studies in tau transgenic mice showed intracerebrally injecting misfolded tau seeds initiates and transmits tau pathology across the mouse brain. However, transgenic mice that overexpress human tau with disease-associated mutations do not fully recapitulate sporadic tauopathies. Here, we present our method for developing a sporadic tauopathy model using pathological tau extracted from human Alzheimer's disease (AD) brains. We describe a novel method for sequentially extracting tau pathologies from human AD brain in high yield and purity. We then describe how to intracerebrally inject this extract into a nontransgenic mouse brain and analyze the transmission of tau pathology. This novel sporadic tauopathy model can be used to study the transmission of tau aggregates and test new tau-directed therapies. PMID- 28882309 TI - Expression and isolation of recombinant tau. AB - In this chapter, we describe methods for the purification of both untagged and polyhistidine-tagged tau protein. These protocols utilize a bacterial expression system to produce the tau isoform of interest, followed by heat treatment and column chromatography to separate tau from impurities. These techniques yield a biochemically pure protein with which to pursue any number of questions regarding the mechanisms of tau action. PMID- 28882310 TI - Studying tau protein propagation and pathology in the mouse brain using adeno associated viruses. AB - The progressive spread of pathological brain lesions containing aggregated tau protein is a hallmark of Alzheimer's disease and other neurodegenerative diseases. In AD, this process follows a distinct pattern along neuronal connections from the entorhinal cortex to hippocampal areas and further on through the limbic system. In other tauopathies, the spread of tau appears less hierarchical throughout the brain, and also nonpathological tau is reported to cross-synaptic connections in the brain. To be able to study the process of cell to-cell transport of tau and the associated neurotoxicity in the brain in vivo, adeno-associated virus-mediated expression of tau can be used to express different forms of tau in distinct brain areas in rodent models. As an example, we describe how the expression of FTD-mutant human tauP301L in the entorhinal cortex of wild-type mice can be used to study the propagation of tau to connected neurons and to determine pathological consequences such as tau hyperphosphorylation, misfolding, and gliosis. The approach described can easily be translated to study other aggregating and/or propagating proteins in the brain such as synuclein, Abeta, or SOD1. PMID- 28882311 TI - Production of recombinant tau oligomers in vitro. AB - The pathological aggregation of the tau protein is a common characteristic of many neurodegenerative diseases. There is strong interest in characterizing the potentially toxic nature of tau oligomers. These nonfibrillar, soluble multimers appear to be more toxic than neurofibrillary tangles made up of filamentous tau. However, reliable production, purification, and verification of tau oligomers can provide certain challenges. Here, we provide a series of methods that address these issues. First, recombinant tau is produced using Escherichia coli, purified through affinity, size-exclusion, and anion-exchange chromatography steps and quantified using an SDS Lowry protein quantitation assay. Aggregation of tau is induced using arachidonic acid, and oligomers are purified by centrifugation over a sucrose step gradient. Finally, we describe a sandwich enzyme-linked immunosorbent assay that utilizes the tau oligomer-specific TOC1 antibody to confirm the presence of oligomeric tau. Together, these steps provide a very simple and reliable method for producing tau oligomers that can be used in downstream applications. PMID- 28882313 TI - Conformation-based assay of tau protein aggregation. AB - Amyloid fiber-forming proteins are predominantly intrinsically disordered proteins (IDPs). The protein tau, present mostly in neurons, is no exception. There is a significant interest in the study of tau protein aggregation mechanisms, given the direct correlation between the deposit of beta-sheet structured neurofibrillary tangles made of tau and pathology in several neurodegenerative diseases, including Alzheimer's disease. Among the core unresolved questions is the nature of the initial step triggering aggregation, with increasing attention placed on the question whether a conformational change of the IDPs plays a key role in the early stages of aggregation. Specifically, there is growing evidence that a shift in the conformation ensemble of tau is involved in its aggregation pathway, and might even dictate structural and pathological properties of mature fibers. Yet, because IDPs lack a well-defined 3D structure and continuously exchange between different conformers, it has been technically challenging to characterize their structural changes on-pathway to aggregation. Here, we make a case that double spin labeling of the beta-sheet stacking region of tau combined with pulsed double electron-electron resonance spectroscopy is a powerful method to assay conformational changes occurring during the course of tau aggregation, by probing intramolecular distances around aggregation-prone domains. We specifically demonstrate the potential of this approach by presenting recent results on conformation rearrangement of the beta sheet stacking segment VQIINK (known as PHF6*) of tau. We highlight a canonical shift of the conformation ensemble, on-pathway and occurring at the earliest stage of aggregation, toward an opening of PHF6*. We expect this method to be applicable to other critical segments of tau and other IDPs. PMID- 28882312 TI - Optimization of in vitro conditions to study the arachidonic acid induction of 4R isoforms of the microtubule-associated protein tau. AB - The microtubule-associated protein tau exists in six different isoforms that accumulate as filamentous aggregates in a wide spectrum of neurodegenerative diseases classified as tauopathies. One potential source of heterogeneity between these diseases could arise from differential tau isoform aggregation. in vitro assays employing arachidonic acid as an inducer of aggregation have been pivotal in gaining an understanding of the longest four repeat tau isoform (2N4R). These approaches have been less successful for modeling the shorter 1N4R and 0N4R tau isoforms in vitro. Through a careful analysis of in vitro conditions for aggregation, we found that the differences in the acidity of tau isoform N terminal projection domains determine whether tau filaments cluster into larger assemblies in solution. Beyond the potential biological implications of filament clustering, we provide optimized conditions for the arachidonic acid induction of shorter 4R tau isoforms aggregation in vitro that greatly reduce filament clustering and improved modeling results. PMID- 28882314 TI - Preface. PMID- 28882315 TI - Is atherosclerosis imaging the most sensitive way to assess patients' risk and the best way to conduct future drug trials? A pros-and-cons debate. AB - Atherosclerosis imaging has been the focus of intense debate and research for several decades. Among its primary applications are risk stratification of asymptomatic individuals and follow-up of atherosclerosis progression under a variety of treatments designed to retard or regress the development of arterial disease. Although endorsed and supported by many, this approach has been fiercely opposed by several key opinion leaders over the years. Similarly, regulatory agencies have raised a number of objections to resist the approval of new drugs and devices based on surrogate imaging markers. However, there is a large body of evidence in the medical literature that shows that risk stratification is improved with implementation of atherosclerosis imaging. Additionally, numerous lipid-modifying agents have been tested as far as their ability to affect progression of atherosclerosis, and in many cases the information obtained with imaging was in line with the outcome of subsequent clinical trials. This pros-and cons debate was staged to bring up in a fun and provoking way the main arguments in favour or against the application of atherosclerosis imaging in the main settings described above. PMID- 28882316 TI - Death From Opioid Overdose After Deep Brain Stimulation: A Case Report. PMID- 28882318 TI - Adaptive-gain fast super-twisting sliding mode fault tolerant control for a reusable launch vehicle in reentry phase. AB - In this paper, a novel adaptive-gain fast super-twisting (AGFST) sliding mode attitude control synthesis is carried out for a reusable launch vehicle subject to actuator faults and unknown disturbances. According to the fast nonsingular terminal sliding mode surface (FNTSMS) and adaptive-gain fast super-twisting algorithm, an adaptive fault tolerant control law for the attitude stabilization is derived to protect against the actuator faults and unknown uncertainties. Firstly, a second-order nonlinear control-oriented model for the RLV is established by feedback linearization method. And on the basis a fast nonsingular terminal sliding mode (FNTSM) manifold is designed, which provides fast finite time global convergence and avoids singularity problem as well as chattering phenomenon. Based on the merits of the standard super-twisting (ST) algorithm and fast reaching law with adaption, a novel adaptive-gain fast super-twisting (AGFST) algorithm is proposed for the finite-time fault tolerant attitude control problem of the RLV without any knowledge of the bounds of uncertainties and actuator faults. The important feature of the AGFST algorithm includes non overestimating the values of the control gains and faster convergence speed than the standard ST algorithm. A formal proof of the finite-time stability of the closed-loop system is derived using the Lyapunov function technique. An estimation of the convergence time and accurate expression of convergence region are also provided. Finally, simulations are presented to illustrate the effectiveness and superiority of the proposed control scheme. PMID- 28882317 TI - Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior. AB - BACKGROUND: Chronic stress-induced inflammatory responses occur in part via danger-associated molecular pattern (DAMP) molecules, such as high mobility group box 1 protein (HMGB1), but the receptor(s) underlying DAMP signaling have not been identified. METHODS: Microglia morphology and DAMP signaling in enriched rat hippocampal microglia were examined during the development and expression of chronic unpredictable stress (CUS)-induced behavioral deficits, including long term, persistent changes after CUS. RESULTS: The results show that CUS promotes significant morphological changes and causes robust upregulation of HMGB1 messenger RNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent upregulation of receptor for advanced glycation end products (RAGE) messenger RNA, but not toll-like receptor 4 in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia as determined by flow cytometry and returned to basal levels 5 weeks after CUS. Importantly, exposure to short-term stress was sufficient to increase RAGE surface expression as well as anhedonic behavior, reflecting a primed state that results from a persistent increase in RAGE messenger RNA expression. Further evidence for DAMP signaling in behavioral responses is provided by evidence that HMGB1 infusion into the hippocampus was sufficient to cause anhedonic behavior and by evidence that RAGE knockout mice were resilient to stress-induced anhedonia. CONCLUSIONS: Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure. PMID- 28882319 TI - Behavioural variant frontotemporal dementia: At the interface of interoception, emotion and social cognition? PMID- 28882320 TI - Judges' delivery of ground rules to child witnesses in Australian courts. AB - Ground rules directions are given to children in forensic interviews to explain what is expected of them, and to reduce their tendency to acquiesce to erroneous or incomprehensible questions. Ground rules may also be necessary when children provide testimony in court. Drawing on research conducted for the Australian Royal Commission into Institutional Responses to Child Sexual Abuse, the present study examined the use of ground rules directions delivered in court in 52 trials by 24 presiding judges in three jurisdictions to 57 child complainants (aged 7 17.5 years). Eleven categories of rules were identified. The number of words spoken to deliver each rule was counted, and grade-level readability scores were calculated as a proxy for the complexity of the ground rules. When judges asked comprehension or practice questions, the question types were coded. More than one third of the children (35%) received no ground rules directions from the judge; the remaining 65% received directions on an average of 3.5 types of ground rules out of a maximum of 11 types. While comprehension questions were common, practice questions were rare. Comprehension questions were most often presented in a yes/no format that implied the expected response, although this form of question is unlikely to provide an effective assessment of a child's comprehension. Neither the number of rules delivered nor the number of words used was related to children's age. Implications for children's court testimony are discussed. PMID- 28882321 TI - Pyrimidinylacetamide-based 2-pyridylureas as Angiogenesis Inhibitors: Design, Synthesis and Biological Evaluation. AB - BACKGROUND: VEGFR-2 inhibitors have been widely used in the treatment of cancer. In our continued efforts to search for potent and novel VEGFR-2 inhibitors as antitumor agents, we have identified a series of ureas and amides bearing a oxazolopyrimidine scaffold. AIM OF THE STUDY: To discover more potent VEGFR-2 inhibitors with stronger binding affinity and better physical and chemical properties. METHODS: 23 pyrimidinylacetamide-based ureas were designed and synthesized. Replacement of oxazolopyrimidine with a pyrimidinylacetamide generated a series of novel VEGFR-2 inhibitors. RESULTS AND CONCLUSIONS: In HUVEC inhibition assay, the most potent compound (compound 16) possessed an IC50 value of 0.43 MUM. Compound 16 also inhibited the migration and capillary like tube formation of HUVECs with inhibition rate at 22% (1 MUM) and 17.5% (0.8 MUM) respectively. These results support the further investigation of compound 16 as a potential anti-cancer agent. PMID- 28882322 TI - Who Can Diagnose Parkinson's Disease First? Role of Pre-motor Symptoms. AB - In 1817, James Parkinson described the disease which bears his name. The disease was defined as a neurological syndrome characterized by tremor, rigidity, and slowness of movements. Almost one hundred years later, degeneration of neurons in the substantia nigra and low levels of dopamine were identified as the putative cause of the disease, thus the disease remained as a pure neurological disorder. In the late 1990s, non-motor symptoms of the disease began to gain interest because of their clinical relevance, as well as for their potential role in broadening the understanding of the pathophysiological mechanisms involved. In the last decade, focus has shifted to the pre-motor symptoms, those non-motor symptoms that present years before the motor onset of the disease. The main premotor symptoms include rapid eye movement sleep behavior disorder, hyposmia, constipation and depression. Subjects with these symptoms usually are not initially seen by a neurologist, and by the time they are consulted neuronal loss in the substantia nigra is over 50%. This review summarizes the overall relevance of non-motor symptoms, their frequency and their pathophysiological implications. Also, the importance of pre-motor symptoms, and the role of specialists other than neurologists in diagnosing subjects with Parkinson's disease is discussed. Two hundred years after the first description of the disease, it is now evident that Parkinson's disease is a systemic disease and a multispecialty team approach is mandatory. PMID- 28882323 TI - Left atrial appendage closure for prevention of death, stroke, and bleeding in patients with nonvalvular atrial fibrillation. AB - Nonvalvular atrial fibrillation (AF) is the most frequent arrhythmia with a prevalence of 1%-2% in the general population. Its prevalence increases with age and its diagnosis benefits of improvement and simplification of technologies for its detection. Today, AF affects approximately 7% of individuals age>65years and 15%-20% of octogenarians. Due to stasis and activation of coagulation in a fibrillating atrium, patients are at increased risk of thromboembolism, in particular ischemic stroke, with an overall stroke risk of 5% per year. Since the left atrium itself is round and smooth-walled, thrombi typically do not form there, but almost exclusively in the left atrial appendage (LAA), a blind sac like heterogeneous structure trabeculated by pectinate muscles. In the past five decades, oral anticoagulation (OAC) with vitamin K antagonists (VKA) has been the state-of-the art treatment to prevent stroke and systemic embolism from thrombi in AF. In the last decade, nonvitamin K dependant oral anticoagulants (NOAC) have been shown to be overall superior to VKA with respect to efficacy and safety in large trials and registries. Given the safety issues of indefinite OAC with either VKA or NOAC, it is plausible to consider left atrial appendage closure (LAAC) as an alternative strategy for prevention of all three catastrophes for patients with AF on anticoagulation: death, stroke or other systemic embolization, and bleeding. In the past years, LAAC has been compared to VKA in prospective randomized trials, yielding superior results regarding efficacy and non-inferiority regarding safety in the mid-term. Today, the decision to provide the most appropriate treatment for a patient with AF (OAC, NOAC, or LAAC) is complex and needs to be individualized. This review provides a comprehensive update on the current state of LAAC in the field of prevention of death, stroke and bleedings in patients suffering from nonvalvular AF. We describe the pathophysiology of the LAA with regard to stroke, elucidate the evidence and limitations of anticoagulation as the classical treatment paradigm, and review devices and techniques for LAAC. Most importantly, the current clinical evidence on efficacy and safety is outlined and finally, contemporary recommendations for patient selection are provided. PMID- 28882324 TI - Extracorporeal membrane oxygenation to resuscitate a 14-year-old boy after 43min drowning. PMID- 28882325 TI - Antimicrobial stewardship programme in critical care medicine: A prospective interventional study. AB - OBJECTIVE: Hospital antimicrobial stewardship programmes have achieved savings and a more rational use of antimicrobial treatments in general wards. The purpose of this report is to evaluate the experience of an antimicrobial stewardship programme in an intensive care unit (ICU). DESIGN: Prospective interventional, before-and-after study. SCOPE: 24-bed medical ICU in a tertiary hospital. INTERVENTION: Prospective audit and feedback antimicrobial stewardship programme. ENDPOINTS: Antimicrobial consumption, antimicrobial related costs, multi-drug resistant microorganisms (MDRM) prevalence, nosocomial infections incidence, ICU length of stay, and ICU mortality rates were compared before and after one-year intervention. RESULTS: A total of 218 antimicrobial episodes of 182 patients were evaluated in 61 team meetings. Antimicrobial stewardship suggestions were accepted in 91.5% of the cases. Total antimicrobial DDD/100 patient-days consumption was reduced from 380.6 to 295.2 (-22.4%; p=0.037). Antimicrobial stewardship programme was associated with a significant decrease in the prescription of penicillins plus b-lactamase inhibitors, linezolid, cephalosporins, and aminoglycosides. Overall antimicrobial spending was reduced by ?119,636. MDRM isolation and nosocomial infections per 100 patient-days did not change after the intervention period. No changes in length of stay or mortality rate were observed. CONCLUSIONS: An ICU antimicrobial stewardship programme significantly reduced antimicrobial use without affecting inpatient mortality and length of stay. Our results further support the implementation of an antimicrobial stewardship programme in critical care units. PMID- 28882326 TI - Avoid mitochondrion-toxic antiepileptic drugs in glycine encephalopathy. PMID- 28882327 TI - Erectile Function and Oncologic Outcomes Following Open Retropubic and Robot assisted Radical Prostatectomy: Results from the LAParoscopic Prostatectomy Robot Open Trial. AB - BACKGROUND: Whether surgeons perform better utilising a robot-assisted laparoscopic technique compared with an open approach during prostate cancer surgery is debatable. OBJECTIVE: To report erectile function and early oncologic outcomes for both surgical modalities, stratified by prostate cancer risk grouping. DESIGN, SETTING, AND PARTICIPANTS: In a prospective nonrandomised trial, we recruited 2545 men with prostate cancer from seven open (n=753) and seven robot-assisted (n=1792) Swedish centres (2008-2011). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinometrically-validated questionnaire-based patient reported erectile function was collected before, 3 mo, 12 mo, and 24 mo after surgery. Surgeon-reported degree of neurovascular-bundle preservation, pathologist-reported positive surgical margin (PSM) rates, and 2-yr prostate specific antigen-relapse rates were measured. RESULTS AND LIMITATIONS: Among 1702 preoperatively potent men, we found enhanced erectile function recovery for low/intermediate-risk patients in the robot-assisted group at 3 mo. For patients with high-risk tumours, point estimates for erectile function recovery at 24 mo favoured the open surgery group. The degree of neurovascular bundle preservation and erectile function recovery were greater correlated for robot-assisted surgery. In pT2 tumours, 10% versus 17% PSM rates were observed for open and robot-assisted surgery, respectively; corresponding rates for pT3 tumours were 48% and 33%. These differences were associated with biochemical recurrence in pT3 but not pT2 disease. The study is limited by its nonrandomised design and relatively short follow-up. CONCLUSIONS: Earlier recovery of erectile function in the robot-assisted surgery group in lower-risk patients is counterbalanced by lower PSM rates for open surgeons in organ-confined disease; thus, both open and robotic surgeons need to consider this trade-off when determining the plane of surgical dissection. Robot-assisted surgery also facilitates easier identification of nerve preservation planes during radical prostatectomy as well as wider dissection for pT3 cases. PATIENT SUMMARY: For prostate cancer surgery, an open operation reduces erection problems in high-risk cancers but has higher relapse rates than robotic surgery. Relapse rates appear similar in low/intermediate-risk cancers and the robot appears better at preserving erections in these cases. PMID- 28882328 TI - Refining insulin concentrations in culture medium containing growth factors BMP15 and GDF9: An in vitro study of the effects on follicle development of goats. AB - The aim of the present study was to investigate the influence of two insulin concentrations (10ng/mL and 10MUg/mL) combined or in the absence of BMP15 and/or GDF9, on the in vitro survival and development of preantral follicles of goat ovarian tissue. Ovarian slices from the same goat ovary pair were randomly assigned to a non-cultured control treatment or to be in vitro cultured for 1 or 7days in alpha-MEM containing 10ng/mL (Low) or 10MUg/mL (High) of insulin in the absence or presence of BMP15 and/or GDF9. With the low insulin treatment, there was a greater percentage of normal follicles than with the high insulin treatment. The addition of BMP15 alone or in association with GDF9 to the medium containing low insulin resulted in a lesser percentage of normal follicles (P<0.05). The addition of BMP15 and GDF9 separately or in combination with the high insulin concentration enhanced the percentage of normal follicles. On day 7 of culture, the use of medium containing low insulin alone or high insulin supplemented with BMP15 and BMP15+GDF9 resulted in a greater percentage of secondary follicles than the non-cultured control, although follicles cultured with low insulin were smaller than those from the control group and had greater rates of oxidative stress. In conclusion, in the presence of physiological concentrations of insulin (10ng/mL), medium supplementation with GDF9 and BMP15 alone or in combination is unnecessary for normal follicle development in vitro. PMID- 28882329 TI - Targeted temperature management in Kounis syndrome following cardiac arrest with anaphylaxis. PMID- 28882330 TI - Combining muscle synergies and biomechanical analysis to assess gait in stroke patients. AB - The understanding of biomechanical deficits and impaired neural control of gait after stroke is crucial to prescribe effective customized treatments aimed at improving walking function. Instrumented gait analysis has been increasingly integrated into the clinical practice to enhance precision and inter-rater reliability for the assessment of pathological gait. On the other hand, the analysis of muscle synergies has gained relevance as a novel tool to describe the neural control of walking. Since muscle synergies and gait analysis capture different but equally important aspects of walking, we hypothesized that their combination can improve the current clinical tools for the assessment of walking performance. To test this hypothesis, we performed a complete bilateral, lower limb biomechanical and muscle synergies analysis on nine poststroke hemiparetic patients during overground walking. Using stepwise multiple regression, we identified a number of kinematic, kinetic, spatiotemporal and synergy-related features from the paretic and non-paretic side that, combined together, allow to predict impaired walking function better than the Fugl-Meyer Assessment score. These variables were time of peak knee flexion, VAFtotal values, duration of stance phase, peak of paretic propulsion and range of hip flexion. Since these five variables describe important biomechanical and neural control features underlying walking deficits poststroke, they may be feasible to drive customized rehabilitation therapies aimed to improve walking function. This paper demonstrates the feasibility of combining biomechanical and neural-related measures to assess locomotion performance in neurologically injured individuals. PMID- 28882331 TI - Demonstration of extended field-of-view ultrasound's potential to increase the pool of muscles for which in vivo fascicle length is measurable. AB - Static, B-mode ultrasound is the most common method of measuring fascicle length in vivo. However, most forearm muscles have fascicles that are longer than the field-of-view of traditional ultrasound (T-US). As such, little work has been done to quantify in vivo forearm muscle architecture. The extended field-of-view ultrasound (EFOV-US) method, which fits together a sequence of B-mode images taken from a continuous ultrasound scan, facilitates direct measurements of longer, curved fascicles. Here, we test the validity and reliability of the EFOV US method for obtaining fascicle lengths in the extensor carpi ulnaris (ECU). Fascicle lengths from images of the ECU captured in vivo with EFOV-US were compared to lengths from a well-established method, T-US. Images were collected in a joint posture that shortens the ECU such that entire fascicle lengths were captured within a single T-US image. Resulting measurements were not significantly different (p=0.18); a Bland-Altman test demonstrated their agreement. A novice sonographer implemented EFOV-US in a phantom and in vivo on the ECU. The novice sonographer's measurements from the ultrasound phantom indicate that the combined imaging and analysis method is valid (average error=2.2+/-1.3mm) and the in vivo fascicle length measurements demonstrate excellent reliability (ICC=0.97). To our knowledge, this is the first study to quantify in vivo fascicle lengths of the ECU using any method. The ability to define a muscle's architecture in vivo using EFOV-US could lead to improvements in diagnosis, model development, surgery guidance, and rehabilitation techniques. PMID- 28882332 TI - Improving stress shielding following total hip arthroplasty by using a femoral stem made of beta type Ti-33.6Nb-4Sn with a Young's modulus gradation. AB - Stress shielding-related bone loss occurs after total hip arthroplasty because the stiffness of metallic implants differs from that of the host femur. Although reducing stem stiffness can ameliorate the bone resorption, it increases stress at the bone-implant interface and can inhibit fixation. To overcome this complication, a novel cementless stem with a gradient in Young's modulus was developed using Ti-33.6Nb-4Sn (TNS) alloy. Local heat treatment applied at the neck region for increasing its strength resulted in a gradual decrease in Young's modulus from the proximal to the distal end, from 82.1 to 51.0GPa as calculated by a heat transfer simulation. The Young's modulus gradient did not induce the excessive interface stress which may cause the surface debonding. The main purpose of this study was to evaluate bone remodeling with the TNS stem using a strain-adaptive bone remodeling simulation based on finite element analysis. Our predictions showed that, for the TNS stem, bone reduction in the calcar region (Gruen zone 7) would be 13.6% at 2years, 29.0% at 5years, and 45.8% at 10years postoperatively. At 10 years, the bone mineral density for the TNS stem would be 42.6% higher than that for the similar Ti-6Al-4V alloy stem. The stress-strength ratio would be lower for the TNS stem than for the Ti-6Al-4V stem. These results suggest that although proximal bone loss cannot be eliminated completely, the TNS stem with a Young's modulus gradient may have bone-preserving effects and sufficient stem strength, without the excessive interface stress. PMID- 28882333 TI - Trends and Outcomes of Aortic Valve Replacement in Patients With End-Stage Renal Disease on Hemodialysis. AB - Hemodialysis (HD) patients with aortic stenosis are less likely to undergo aortic valve replacement (AVR) due to their excess perioperative mortality. We aimed to evaluate contemporary utilization and outcomes of combined and isolated AVR in HD patients. The Nationwide Inpatient Sample was used to identify 142,046 patients who underwent AVR in 2005 to 2014, of whom 2,264 (1.6%) were on HD. Crude and adjusted in-hospital outcomes and costs were assessed in unmatched and propensity matched cohorts of HD and non-HD patients, respectively. The utilization of AVR in HD patients increased significantly (p = 0.047), with a significant decrease in mortality (p = 0.013). Compared with patients not on HD, crude in-hospital mortality in HD patients was twice higher (11.8% vs 6.2%, p <0.0001). HD patients had more blood transfusion and a trend toward more strokes. Lengths of stay and hospital charges, and rates of nonhome discharges were also higher in the HD group. In the propensity-matched cohorts of HD versus non-HD patients, in hospital mortality rates after AVR remained twofold higher in the HD group (8.1% vs 3.9%, p <0.001). Rates of blood transfusion, cardiac tamponade, length of stay, hospital charges, and nonhome discharges were also higher in HD patients. In conclusion, AVR utilization in HD patients increased and its associated mortality decreased over the last decade. However, AVR mortality in HD patients remained twofold higher compared with non-HD patients. Also, AVR in HD patients was associated with higher cost, longer hospitalizations, and more frequent nonhome discharges. PMID- 28882334 TI - Meta-Analysis of Safety and Efficacy of Uninterrupted Non-Vitamin K Antagonist Oral Anticoagulants Versus Vitamin K Antagonists for Catheter Ablation of Atrial Fibrillation. AB - This meta-analysis sought to assess the safety and efficacy of uninterrupted non vitamin K antagonist oral anticoagulants (NOACs) versus uninterrupted vitamin K antagonists in atrial fibrillation (AF) patients undergoing catheter ablation. Electronic databases were searched for randomized trials (RCTs) and observational studies that compared uninterrupted NOACs versus uninterrupted vitamin K antagonists in the catheter ablation of AF. Safety outcomes included major bleeding, total bleeding, minor bleeding, and cardiac tamponade. Efficacy outcomes were symptomatic thromboembolism and symptomatic stroke/transient ischemic attack. Summary estimate risk ratios (RRs) were constructed primarily with a DerSimonian-Laird model. Thirteen studies (3 RCTs and 10 observational studies) with 4,878 patients were included. The risk of major bleeding (RR 0.83, 95% confidence interval [CI] 0.46 to 1.50, p = 0.53), total bleeding (RR 0.90, 95% CI 0.71 to 1.15, p = 0.41), minor bleeding (RR 0.98, 95% CI 0.80 to 1.21, p = 0.85), cardiac tamponade (RR 0.85, 95% CI 0.43 to 1.69, p = 0.65), symptomatic thromboembolism (RR 0.92, 95% CI 0.26 to 3.31, p = 0.90), and symptomatic stroke/transient ischemic attack (RR 1.03, 95% CI 0.29 to 3.65, p = 0.97) was similar in both groups. The quality of evidence for both major bleeding and symptomatic thromboembolism was moderate for RCTs and very low for observational studies. In conclusion, the use of uninterrupted NOACs in AF catheter ablation appears to be safe and efficacious. The evidence is not of high quality; thus, further high-quality RCTs are needed to confirm these findings. PMID- 28882335 TI - Usefulness of Speckle Tracking Strain Echocardiography for Assessment of Risk of Ventricular Arrhythmias After Placement of a Left Ventricular Assist Device. AB - Patients with continuous-flow left ventricular assist devices (LVADs) are at elevated risk of developing ventricular arrhythmias (VA), which can result in right ventricular dysfunction and abnormal LVAD function. Predictors of postoperative VA after LVAD placement are unclear. We hypothesized that global left ventricular circumferential strain (LVCS), a marker of transmural impairment in myocardial function, would independently predict postoperative VA in patients who underwent LVAD implantation. We studied 98 consecutive patients (57 +/- 11 years, 83% men) who underwent HeartMate II axial flow LVAD placement. Speckle tracking-derived global circumferential strain was assessed from mid-left ventricular short-axis images. The primary composite end point was defined as any ventricular tachycardia that required intervention (anti-arrhythmic medication, cardioversion, implantable cardioverter defibrillator placement, implantable cardioverter defibrillator shock) or any ventricular fibrillation. A total of 33 patients (34%) experienced the primary end point (median follow-up: 7 months). Reduced LVCS was statistically significantly related to the primary end point (hazard ratio 1.77, 95% confidence interval 1.09 to 2.87 per 1 standard deviation reduction in LVCS, p = 0.02). LVCS above a cut-off value of -9.7% was associated with significantly reduced arrhythmia-free survival (log-rank p = 0.001). In conclusion, global LVCS is an independent predictor of ventricular arrhythmias after LVAD placement. PMID- 28882336 TI - Comparison of In-Hospital Outcomes and Readmission Rates in Acute Pulmonary Embolism Between Systemic and Catheter-Directed Thrombolysis (from the National Readmission Database). AB - There are sparse comparative data on in-hospital outcomes and readmission rates in patients with acute pulmonary embolism (PE) who receive systemic thrombolytics versus catheter-directed thrombolysis (CDT). The study cohort was derived from the National Readmission Database 2013 to 2014, subset of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality. Systemic and CDT were identified using appropriate International Classification of Diseases, 9th Revision, Clinical Modification codes. The co-primary outcomes were in-hospital mortality and 30-day readmissions and secondary outcome was combined in-hospital mortality + gastrointestinal bleed + intracranial hemorrhage. We used propensity score match analysis without replacement using Greedy's algorithm to adjust for possible confounders. We identified a total of 4,426 patients (3,107: systemic thrombolysis and 1,319: CDT) with acute PE who were treated with thrombolysis. In our 2:1 propensity score algorithm, in hospital mortality was lower in the CDT group (6.12%) versus systemic thrombolytics (14.94%) (odds ratio 0.37, 95% confidence interval 0.28 to 0.49, p <0.001). There was also a lower composite secondary outcome (in-hospital mortality + gastrointestinal bleed + intracranial hemorrhage) in patients who received CDT (8.42%) versus those who received systemic thrombolytics (18.13%) (odds ratio 0.41, 95% confidence interval 0.33 to 0.53, p <0.001). Thirty-day readmission was lower in patients with CDT group (7.65%) compared with systemic thrombolytics (10.58%, p = 0.009). In conclusion, in-hospital mortality, as well as bleeding during primary admission was significantly lower with CDT compared with systemic thrombolytics for patients with acute PE. There was also significant decrease in rate of readmissions among patients receiving CDT compared with systemic thrombolytics. PMID- 28882337 TI - Meta-Analysis Comparing Metoprolol and Carvedilol on Mortality Benefits in Patients With Acute Myocardial Infarction. AB - Although carvedilol, a nonselective beta-blocker with alpha-adrenergic blocking and multiple ancillary activities, has been demonstrated to be superior to metoprolol in chronic heart failure, it remains unclear whether the superiority of carvedilol still exists in myocardial infarction (MI). Therefore, we performed a network meta-analysis of randomized controlled trials (RCTs) to compare the 2 drugs in patients with MI. All RCTs that compared either 2 of the following interventions, carvedilol, metoprolol, and placebo, for the treatment of MI were included. The Cochrane Collaboration Central Register of Controlled Trials, Embase, and PubMed were searched thoroughly for potential eligible studies. Finally, 12 RCTs involving 61,081 patients were included. Pooled results showed that compared with placebo, carvedilol and metoprolol significantly reduced composite cardiovascular events (risk ratio [RR] 0.63; 95% credible interval [CrI] 0.41, 0.85 for carvedilol; RR 0.78; 95% CrI 0.65, 0.93 for metoprolol) and re-infarction (RR 0.57; 95% CrI 0.37, 0.84 for carvedilol; RR 0.77; 95% CrI 0.62, 0.91 for metoprolol) in patients with MI. However, neither carvedilol nor metoprolol showed significant benefits on all-cause death, cardiovascular death, revascularization, and rehospitalization. Also, no obvious difference was found when comparing carvedilol and metoprolol on primary or secondary outcomes. In conclusion, there is insufficient evidence supporting the superiority of carvedilol over metoprolol for the treatment of MI. Further studies are needed to confirm our findings. PMID- 28882338 TI - Relationship of Cardiorespiratory Fitness and Adiposity With Left Ventricular Strain in Middle-Age Adults (from the Dallas Heart Study). AB - Low cardiorespiratory fitness (CRF) and obesity are significant risk factors for heart failure (HF). However, given the inverse association between CRF and obesity, the independent contributions of low CRF and adiposity toward HF risk are not well established. We evaluated the association of CRF and measures of adiposity with left ventricular (LV) peak systolic strain-a subclinical measure of LV dysfunction-among the Dallas Heart Study phase II participants without cardiovascular disease who had CRF estimated using a submaximal treadmill test and LV systolic circumferential strain assessment by tissue-tagged cardiac magnetic resonance imaging. Peak midwall systolic circumferential strain (Ecc) was determined by harmonic phase imaging. Associations of CRF and adiposity measures with Ecc were determined using adjusted linear regression analysis. A total of 1,617 participants were included in the analysis. After adjustment for baseline risk factors, higher waist circumference (WC) and lower CRF were associated with higher Ecc (WC: beta = 0.07; p = 0.01; CRF: beta = -0.17; p = < 0.0001), whereas % body fat and body mass index were not associated with Ecc. The relationship between WC and Ecc was attenuated completely after additional adjustment for CRF. In contrast, the association between CRF and Ecc did not attenuate after additional adjustment for WC and other measures of LV structure and function (beta = -0.18; p = < 0.0001). Taken together, our study findings suggest that lower CRF, but not measures of adiposity, is associated with greater impairment in LV strain independent of LV mass and ejection fraction. PMID- 28882339 TI - Generic gas chromatography-flame ionization detection method for quantitation of volatile amines in pharmaceutical drugs and synthetic intermediates. AB - Volatile amines are among the most frequently used chemicals in organic and pharmaceutical chemistry. Synthetic route optimization often involves the evaluation of several different amines requiring the development and validation of analytical methods for quantitation of residual amine levels. Herein, a simple and fast generic GC-FID method on an Agilent J&W CP-Volamine capillary column (using either He or H2 as the carrier gas) capable of separating over 25 volatile amines and other basic polar species commonly used in pharmaceutical chemistry workflows is described. This 16min method is successfully applied to the analysis and quantitation of volatile amines in a variety of pharmaceutically-related drugs and synthetic intermediates. Method validation experiments showed excellent analytical performance in linearity, recovery, repeatability, and limit of quantitation and detection. In addition, diverse examples for the application of this method to the simultaneous determination of other amine-related chemicals in reaction mixtures are illustrated, thereby indicating that these GC-FID method conditions can be effectively used as starting point during method development for the analysis of other basic polar species beyond the validated list of amines described in this study. PMID- 28882340 TI - An automated and self-cleaning nano liquid chromatography mass spectrometry platform featuring an open tubular multi-hole crystal fiber solid phase extraction column and an open tubular separation column. AB - An open tubular (OT) sample preparation/separation platform was developed. A multi-channel polymer layer open tubular (mPLOT) solid phase extraction (SPE) column was prepared by wall-coating the 126 channels (8MUm inner diameter (ID) each) of a crystal fiber capillary with an organic polymer, namely poly(styrene co-octadecene-co-divinylbenzene) (PS-OD-DVB). The mPLOT SPE was coupled on-line with a 10MUm*2m poly(styrene-co-divinylbenzene) (PS-DVB) OT liquid chromatography column with nanospray mass spectrometry (OTLC-MS). Compared to using monolithic/particle-packed SPEs, mPLOT-SPE-OTLC allowed both fast loading and sufficient refocusing on the OT analytical column of small model compounds (sulfonamides~300Da). Using automatic filtration/filter back-flushing (AFFL) plumbing, the mPLOT SPE column gave a constant and low back-pressure ~35bar at 0.5MUL/min. Surprisingly large sample volumes (10MUL) were possible to be injected using a 12cm mPLOT. PMID- 28882341 TI - Comparison of micellar extraction combined with ionic liquid based vortex assisted liquid-liquid microextraction and modified quick, easy, cheap, effective, rugged, and safe method for the determination of difenoconazole in cowpea. AB - Two simple sample pretreatment for the determination of difenoconazole in cowpea was developed including micellar extraction combined with ionic liquid based vortex-assisted liquid-liquid microextraction (ME-IL-VALLME) prior to high performance liquid chromatography (HPLC), and modified quick, easy, cheap, effective, rugged, and safe method (QuEChERS) coupled with HPLC-MS/MS. In ME-IL VALLME method, the target analyte was extracted by surfactant Tween 20 micellar solution, then the supernatant was diluted with 3mL water to decrease the solubility of micellar solution. Subsequently, the vortex-assisted liquid-liquid microextraction (VALLME) procedure was performed in the diluted extraction solution by using the ionic liquid of 1-hexyl-3-methylimidazolium hexafluorophosphate ([HMIM]PF6) as the extraction solvent and Tween 20 as an emulsifier to enhance the dispersion of the water-immiscible ionic liquid into the aqueous phase. Parameters that affect the extraction have been investigated in both methods Under the optimum conditions, the limits of quantitation were 0.10 and 0.05mgkg-1, respectively. And good linearity was achieved with the correlation coefficient higher than 0.9941. The relative recoveries ranged from 78.6 to 94.8% and 92.0 to 118.0% with the relative standard deviations (RSD) of 7.9-9.6% and 1.2-3.2%, respectively. Both methods were quick, simple and inexpensive. However, the ME-IL-VALLME method provides higher enrichment factor compared with conventional QuEChERS method. The ME-IL-VALLME method has a strong potential for the determination of difenoconazole in complex vegetable matrices with HPLC. PMID- 28882342 TI - The analysis of aroma/flavor compounds in green tea using ice concentration linked with extractive stirrer. AB - Worldwide, green tea is one of the most popular beverages. It promotes blood circulation, liver function, and lowers the risk of cancer and cardiovascular diseases. This drink is characterized by the distinctive odors and flavors produced by its constituent compounds, with its value predicated on the amount and type of constituents extracted from the tea leaves during brewing. Ice concentration linked with extractive stirrer (ICECLES) is a novel sample preparation technique, especially applicable for the extraction of relatively polar compounds while retaining excellent extraction efficiencies for non-polar compounds. In this study, ICECLES was used to prepare green tea for analysis of aroma/flavor compounds by gas chromatography-mass spectrometry (GC-MS). ICECLES performed very well, revealing 301 constituents as compared to 245 for SBSE (i.e., 56 more constituents were detected via ICECLES). Moreover, ICECLES produced stronger signal to noise ratios for all except 4 of 301 constituents, with a maximum signal enhancement of 19. Of the constituents which were only detectable using ICECLES, some very important aroma/flavor and/or medicinal compounds were easily identified, including furfural, furfural alcohol, maltol, eugenol, 2-methylpyrazine, phenethyl alcohol, 2,6-dimethoxyphenol, and alpha terpineol. Overall, we confirmed that ICECLES sample preparation followed by GC MS consistently allowed more complete green tea aroma/flavor analysis, especially for relatively polar compounds, some of which are critical for flavor quality. PMID- 28882343 TI - A retention index system for comprehensive two-dimensional gas chromatography using polyethylene glycols. AB - The characterization and identification of compounds in complex real-world samples is quite difficult and new concepts and workflows are highly desirable. Retention indices (RIs) are widely used in gas chromatography (GC) to support the identification of unknown compounds. Several attempts have been made to introduce a similar concept for the second dimension in comprehensive two-dimensional (2D) GC (GC * GC) but, an easily applicable and robust system remains elusive. In the present study, a new RI system for GC * GC was developed. Polyethylene glycols (PEGs) were used in combination with a simple linear regression, with n-alkanes as reference points for virtually unretained compounds and PEG homologs as reference compounds for second-dimension RIs (PEG-2I). The n-alkanes were assigned a PEG-2I of zero and the distance between consecutive PEG homologs from PEG-2 (diethylene glycol) and higher were assigned a PEG-2I value of 10. We used ethylene glycol and PEG-2 through PEG-10 as reference compounds, thereby covering a PEG-2I range from 20.0 for ethylene glycol, over 50.0 for diethylene glycol (PEG-2) to 130.0 for decaethylene glycol (PEG-10); additional PEGs can be added to cover a wider polarity range. The PEG-2I system was initially evaluated using a 30 m * 0.25 mm non-polar (5% phenyl, 0.25 MUm film thickness) first-dimension column and a 1.6 m * 0.18 mm polar (50% phenyl, 0.18 MUm film thickness) second dimension column. This system was validated for use with non-polar first dimension columns and a semi-polar (50% phenyl) second-dimension column, and exhibited robustness to changes in the carrier gas flow velocity, oven temperature ramping rate, and secondary oven temperature offset. An average relative standard deviation of 2.7%, equal to a 95% confidence interval of 1.27 PEG-2I units, was obtained for the PEG-2I values of 72 environmental pollutants. Additionally, the system was found to be applicable over a wide range of boiling points (in the current case, from n-heptane to n-dotriacontane (C7-C32)) and can be used with various column dimensions. Changing the second-dimension column to either a narrower 0.1 mm column or a wider 0.25 mm column, yielded similar 95% percentiles to that of the 0.18 mm column, differing by only 3.20 and 2.80 PEG-2I units, respectively. Moreover, methods for improving the system were suggested. PMID- 28882344 TI - A multiple-dimension liquid chromatography coupled with mass spectrometry data strategy for the rapid discovery and identification of unknown compounds from a Chinese herbal formula (Er-xian decoction). AB - It is very important to rapidly discover and identify the multiple components of traditional Chinese medicine (TCM) formula. High performance liquid chromatography with high resolution tandem mass spectrometry (HPLC-HRMS/MS) has been widely used to analyze TCM formula and contains multiple-dimension data including retention time (RT), high resolution mass (HRMS), multiple-stage mass spectrometric (MSn), and isotope intensity distribution (IID) data. So it is very necessary to exploit a useful strategy to utilize multiple-dimension data to rapidly probe structural information and identify chemical compounds. In this study, a new strategy to initiatively use the multiple-dimension LC-MS data has been developed to discover and identify unknown compounds of TCM in many styles. The strategy guarantees the fast discovery of candidate structural information and provides efficient structure clues for identification. The strategy contains four steps in sequence: (1) to discover potential compounds and obtain sub structure information by the mass spectral tree similarity filter (MTSF) technique, based on HRMS and MSn data; (2) to classify potential compounds into known chemical classes by discriminant analysis (DA) on the basis of RT and HRMS data; (3) to hit the candidate structural information of compounds by intersection sub-structure between MTSF and DA (M,D-INSS); (4) to annotate and confirm candidate structures by IID data. This strategy allowed for the high exclusion efficiency (greater than 41%) of irrelevant ions in er-xian decoction (EXD) while providing accurate structural information of 553 potential compounds and identifying 66 candidates, therefore accelerating and simplifying the discovery and identification of unknown compounds in TCM formula. PMID- 28882345 TI - Editorial. PMID- 28882346 TI - Current Evidence Regarding the Treatment of Pediatric Lumbar Spondylolisthesis: A Report From the Scoliosis Research Society Evidence Based Medicine Committee. AB - STUDY DESIGN: Structured literature review. OBJECTIVES: The Scoliosis Research Society requested an assessment of the current state of peer-reviewed evidence regarding pediatric lumbar spondylolisthesis to identify what is known and what research remains essential to further understanding. SUMMARY OF BACKGROUND DATA: Pediatric lumbar spondylolisthesis is common, yet no formal synthesis of the published literature regarding treatment has been previously performed. METHODS: A comprehensive literature search was performed. From 6600 initial citations with abstract, 663 articles underwent full-text review. The best available evidence regarding surgical and medical/interventional treatment was provided by 51 studies. None of the studies were graded Level I or II evidence. Eighteen of the studies were Level III, representing the current best available evidence. Thirty three of the studies were Level IV. RESULTS: Although studies suggest a benign course for "low grade" (<50% slip) isthmic spondylolisthesis, extensive literature suggests that a substantial number of patients present for treatment with pain and activity limitations. Pain resolution and return to activity is common with both medical/interventional and operative treatment. The role of medical/interventional bracing is not well established. Uninstrumented posterolateral fusion has been reported to produce good clinical results, but concerns regarding nonunion exist. Risk of slip progression is a specific concern in the "high grade" or dysplastic type. Although medical/interventional observation has been reported to be reasonable in a small series of asymptomatic high-grade slip patients, surgical treatment is commonly recommended to prevent progression. There is Level III evidence that instrumentation and reduction lowers the risk of nonunion, and that circumferential fusion is superior to posterior-only or anterior-only fusion. There is Level III evidence that patients with a higher slip angle are more likely to fail medical/interventional treatment of high-grade spondylolisthesis. CONCLUSIONS: The current "best available" evidence to guide the treatment of pediatric spondylolisthesis is presented. LEVEL OF EVIDENCE: Level III; review of Level III studies. PMID- 28882347 TI - Systematic Review of School Scoliosis Screening. AB - OBJECTIVES: The aim of this study was to review the literature on school screening and its reported effectiveness. SUMMARY OF BACKGROUND DATA: There is no worldwide consensus concerning the mandating of school screening for scoliosis. This remains a controversial issue. METHODS: The following databases were employed: Medline, Premedline, CINAHL, CENTRAL, AMED, Embase, SCOPUS, Ovid nursing, and Web of Science. These data were generated from the Forward Bend Test, the angle of trunk rotation and Moire topography. The first and second authors each independently screened titles and abstracts for potential studies. Fulltext papers of potential studies were also independently read by the first two authors to identify studies to be included based on strict inclusion/exclusion criteria. A heterogeneity test was performed by testing for the significance of the between-study variance. Publication bias was examined by a funnel plot. RESULTS: We found 20 studies that met our inclusion criteria. The pooled estimate of prevalence of scoliosis curves in the population was 1.1% for curves greater than 10 degrees , and 0.2% for curves greater than 20 degrees . The pooled referral rate to radiography during the screening process was 6.6%. The pooled positive predictive values for detecting curves >10 degrees and >20 degrees were 32.3% and 6.5% respectively. Analysis of data demonstrated significant heterogeneity between studies but was not suggestive of the presence of publication bias. CONCLUSIONS: We support the implementation of scoliosis screening as a means of detecting curves at an early treatable stage. The current available evidence in the literature for routine scoliosis screening is low to moderate. Challenges exist to the school scoliosis screening including a high referral rate to radiology. PMID- 28882348 TI - Hemostasis and Safety of a Novel Fibrin Dressing Versus Standard Gauze in Bleeding Cancellous Bone in a Caprine Spine Surgery Model. AB - BACKGROUND: Decorticated bone is a significant source of blood loss in scoliosis surgery. Current hemostatic methods include packed gauze (GS), physical barriers such as bone wax, and xenograft collagen-based materials. We assessed the safety and efficacy of a novel fibrin dressing (dextran-thrombin-fibrinogen [DTF]) compared to GS. This dressing comprises lyophilized thrombin and fibrinogen embedded in an elastic electrospun nanofiber dextran matrix. PURPOSE: The study tests the hypothesis that DTF is more efficacious than GS in control of bleeding from cancellous bone. STUDY DESIGN: A preclinical Good Laboratory Practices (GLP) study. METHODS: We enrolled 10 goats that were followed for 28 +/- 1 days. Each animal was randomly assigned to the test or control group. Both test and control animals had 4 cancellous bone injuries. Test animal injuries were treated with DTF, whereas standard GS was used to control bleeding in the control animals. Bleeding at the bone injury site was characterized as either none, oozing, flowing, or pulsatile and was assessed at 4 and 8 minutes after dressing application. Goats were survived 28 +/- 1 days and then necropsied. RESULTS: Application of the fibrin dressing to bleeding cancellous bone, both posterior spinal lamina, and iliac crest graft sites, resulted in control of bleeding within 4 minutes at all injury sites. Eighty percent of control injury sites continued to bleed after 8 minutes and required application of bone wax to control bleeding. There were no differences in prothrombin time, partial thromboplastin time, or fibrinogen levels between test and control animals at 1 or 28 days. We observed no adverse histologic reactions at 28 days. CONCLUSION: The fibrin dressing is an efficacious and safe method of controlling blood loss from cancellous bone in a spine surgery model. PMID- 28882349 TI - Spine Growth Modulation in Early Adolescent Idiopathic Scoliosis: Two-Year Results of Prospective US FDA IDE Pilot Clinical Safety Study of Titanium Clip Screw Implant. AB - STUDY DESIGN: Prospective pilot clinical safety study of novel treatment, consecutive case series from first human use in patients with early adolescent idiopathic scoliosis (AIS). OBJECTIVE: The primary purpose was to determine the initial safety of a titanium clip-screw implant system for spine growth modulation. The secondary aim was to document curvatures to 2 years postoperatively. SUMMARY OF BACKGROUND DATA: Spinal growth modulation was documented in preclinical studies. A prospective pilot clinical safety study was then performed under a Food and Drug Administration (FDA) Investigational Device Exemption (IDE) (www.clinicaltrials.gov Identifier: NCT01465295). METHODS: Six subjects with early AIS underwent thoracoscopic placement of titanium clip-screw devices. Eligibility criteria included only patients at high risk for progression to 50 degrees : single major thoracic curve 25 degrees -40 degrees , age >=10 years, skeletally immature (Risser 0 plus open triradiate cartilages), and if female, premenarchal. Adverse events (AEs), clinical outcomes, and radiographic measures were documented using Good Clinical Practices. RESULTS: Six consecutive subjects were enrolled, three females and three males aged 12.1 years (+/-1.7). AEs included one that was device related-mild device migration at 18 months in the most rapidly progressive curve. Procedure-related AEs were mostly pulmonary. A chylous effusion that met the clinical protocol definition of a serious AE resolved after minimally invasive interventions. Major thoracic curves were 34 degrees (+/-3 degrees ) preoperatively and 38 degrees (+/-18 degrees ) at two years (intrasubject change, 4 degrees +/- 18 degrees ). At 24 months, curves in 3 patients were >45 degrees and 3 were <40 degrees . CONCLUSIONS: A spine growth modulation system undergoing study under an FDA IDE was determined to be safe. Variability in curve response to the implant was high, ranging from progression to correction. Investigational approval was granted by the US FDA for the next cohort of 30 subjects. PMID- 28882350 TI - Preoperative Norepinephrine Levels in Cerebrospinal Fluid and Plasma Correlate With Pain Intensity After Pediatric Spine Surgery. AB - PURPOSE: Catecholamines were found to be involved in descending pain modulation and associated with perioperative pain. The purpose of the present study was to investigate the relationship between preoperative concentrations of catecholamines and postoperative pain intensity of pediatric patients. METHODS: Fifty adolescents with idiopathic scoliosis scheduled for elective spinal fusion surgery were enrolled in this prospective cohort study. Preoperative plasma and cerebrospinal fluid (CSF) samples were collected and analyzed by mass spectrometry. Pain intensity was assessed during the acute postoperative period and in the intermediate period. RESULTS: Preoperative plasma concentrations of norepinephrine (NE) and normetanephrine (NME), as well as the CSF concentration of NE, were significantly correlated with the presence of pain six weeks after surgery (r = 0.48, 0.50, and 0.50, respectively; p < .002). We also found that preoperative NE levels in CSF were significantly higher in patients reporting moderate to severe pain intensity than in patients with mild pain during the first day following surgery (0.268 +/- 0.29 ng/mL vs. 0.121 +/- 0.074 ng/mL, p = .01), as well as between patients reporting pain and painless patients at 6 weeks postsurgery (0.274 +/- 0.282 ng/mL vs. 0.103 +/- 0.046 ng/mL respectively, U = 69.5, p = .002). CONCLUSIONS: These results support the potential role of catecholamine levels in predicting postoperative pain intensity. PMID- 28882351 TI - Psychological Profile of Children Who Require Repetitive Surgical Procedures for Early Onset Scoliosis: Is a Poorer Quality of Life the Cost of a Straighter Spine? AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: Assess the psychosocial status of children with early-onset scoliosis (EOS) undergoing multiple procedures and evaluate associations with other variables. SUMMARY OF BACKGROUND DATA: EOS may require repetitive surgical procedures to control deformity and preserve growth. These procedures impact patients' psychosocial status because of the repetitive surgeries. METHODS: EOS patients 6-18 years, undergoing traditional growing rod treatment with more than 5 surgical procedures, and neurologically/mentally intact were included. Patients were screened for psychiatric disorders before inclusion. The Quality of Life Scale for Children (PedsQL), Strengths and Difficulties Questionnaire (SDQ) self-report form, Beck Depression Inventory, Children Depression Inventory (CDI), Beck Anxiety Inventory (BAI), and the Self Report for Childhood Anxiety Related Disorders (SCARED) were completed by the children. PedsQL Parental Form and SDQ Parent Form were completed by their parents. RESULTS: Twenty-one patients (9 male, 12 female) met the inclusion criteria. Average age was 6.4 years (4-10.5) at index surgery, and 13.5 years (8 17) at final follow-up. The mean number of procedures was 13 (6-18). Mean follow up was 83.9 months (36-122). Depression was observed in 23.8% of patients, and generalized anxiety disorder in 42.8%. Patients in the study group were more likely than the general population to have a psychiatric diagnosis. Number of procedures undergone was found to correlate negatively with BAI, SCARED, and the behavioral difficulties domain of SDQ parent form score and positively with emotional functioning, psychosocial health summary score, PedsQL total score, and increased social and physical functioning. Nonidiopathic etiology was found to be related to increased behavioral difficulties and lower functioning. CONCLUSION: A higher prevalence of depressive and anxiety symptoms was observed in patients with EOS along with dysfunctional areas of daily life. Other comorbidities may also contribute to dysfunction and difficulties. Determination of the aspects of EOS treatment that have a negative impact on psychosocial functioning may allow for more competent help for these patients. PMID- 28882352 TI - Adult Spinal Deformity: National Trends in the Presentation, Treatment, and Perioperative Outcomes From 2003 to 2010. AB - STUDY DESIGN: Retrospective review of a prospective database. OBJECTIVES: To investigate adult spinal deformity (ASD) surgery outcome trends on a nationwide scale using the Nationwide Inpatient Sample (NIS) from 2003 to 2010. METHODS: ASD patients >=25 years from 2003 to 2010 in the NIS undergoing anterior, posterior, or combined surgical approaches were included. Fractures, 9+ levels fused, or any cancer were excluded. Patient demographics, hospital data, and procedure-related complications were evaluated. Yearly trends were analyzed using univariate analysis and linear regression modeling. RESULTS: Of 10,966 discharges, 1,952 were anterior, 6,524 were posterior, and 1,106 were combined. The total surgical ASD volume increased by 112.5% (p = .029), and both the average patient age (p < .001) and number of patients >65 years old significantly increased from 2003 to 2010 (p = .009). Anterior approach case volume decreased by 13.7% (p = .019), whereas that of combined increased by 22.7% (p = .047). Posterior case volume increased by 38.9% from 2003 to 2010, though insignificantly (p = .084). Total hospital charges for all approaches increased over the interval (p < .001). Total length of stay for all approaches decreased over the time interval (p < .005). Although the overall morbidity for all approaches increased by 22.7% (p < .001), mortality did not change (p = .817). The most common morbidities in 2003 were hemorrhagic anemia, accidental cut, puncture, perforation, or laceration during a procedure, and device-related complications, which persisted in 2010 with the exception of increased acute respiratory distress syndrome and pulmonary-related complications. CONCLUSIONS: For ASD surgery from 2003 to 2010, the volume of anterior approaches decreased, whereas posterior procedures did not change, and combined approaches increased. Total hospital charges increased for all considered procedures, length of hospital stay decreased, whereas operative patients were increasingly elderly, and more procedures were observed for patients >65 years old. For all approaches, morbidity increased whereas mortality did not change. Future study is required to develop methods to reduce morbidity and costs, thereby optimizing patient outcomes. PMID- 28882353 TI - Neurophysiological Monitoring in Radiofrequency Ablation of Spinal Osteoid Osteoma With a Progressive Time and Temperature Protocol in Children. AB - STUDY DESIGN: Retrospective. Level IV Evidence. OBJECTIVE: To assess the utility of intraoperative neurophysiological monitoring (IONM) to detect and eventually prevent impending neurovascular damage during computed tomography (CT)-guided radiofrequency ablation (RFA) of spinal osteoid osteoma (OO) in children. SUMMARY AND BACKGROUND DATA: To our knowledge, this is the first case series of spinal OO in pediatric patients treated at a single center employing IONM during RFA. METHODS: This is a retrospective study of seven consecutive patients (3 girls and 4 boys, mean age: 9 years 4 months) with imaging and clinical signs compatible with spinal OO who underwent CT-guided RFA, under general anesthesia, and IONM in a single center between 2011 and 2015. Before the RFA procedure, a CT-guided percutaneous biopsy of the nidus was performed in the same setting. RFA was divided into four cycles of increasing time and temperature and performed under IONM in every patient. RESULTS: Two patients had lesions located in the thoracic spine and five patients had lumbar involvement. The RFA technical and clinical success was 85.7%. Six patients presented with reversible neurophysiological changes either during biopsy needle positioning or RFA cycles. In the remaining case, as IONM changes did not improve after several minutes of neuroprotective hypertension, the procedure was interrupted. Neither neurologic nor vascular complications were observed after RFA treatment. In only one biopsy sample, OO was confirmed by histopathologic studies. CONCLUSION: CT-guided RFA is an accepted minimally invasive technique for the treatment of spinal OO in children. IONM may be a helpful tool that requires minimal additional time and provides feedback on the state of the spinal cord and nerves at risk during the procedure. We promote the use of IONM during these procedures to detect and possibly prevent impending neurologic damage. LEVEL OF EVIDENCE: Level IV. PMID- 28882354 TI - Surgical Treatment With Pedicle Screws of Scoliosis Associated With Osteogenesis Imperfecta in Children. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To assess results of posterior instrumented fusion using pedicle screws in 12 children with osteogenesis imperfecta (OI) with spinal deformity at a single institution from 2001 to 2012. SUMMARY OF BACKGROUND DATA: This is the first case series of OI patients who underwent non-cement augmented screw-rod instrumented fusion published in the literature. METHODS: Of a total of 54 children with spinal deformity associated with OI, 12 (22.2%) were submitted to posterior spinal fusion with pedicle screws (80% density) because of severe spinal deformity. Here we reported the results in seven females and five males. RESULTS: Five thoracic (41.7%), five double (thoracic and lumbar 41.7%), and two lumbar (16.7%) curves were considered. The mean number of fused levels was 11.8 (range: 5 to 16). Mean age at surgery was 13 years 8 months. Mean follow-up was 7 years 11 months (range: 3 years 7 months to 16 years 1 month). The mean preoperative scoliosis angle was 75.6 degrees , whereas the postoperative angle was 31.4 degrees (58.5% correction rate). The mean preoperative kyphosis angle was 57.4 degrees and the postoperative angle was 42.3 degrees . We observed one superficial infection, one dural tear, and three cases of proximal junctional kyphosis; two patients required one revision surgery each (2 years and 4 months postoperatively on average). CONCLUSIONS: To our knowledge, this is the first case series published in the literature regarding OI with instrumented fusion with non-cement augmented pedicle screws exclusively in children with spinal deformity. We found that posterior spinal fusion with the screw-rod system in OI deformity in children is feasible and reliable, and has acceptable clinical and imaging results in the long-term follow up. LEVEL OF EVIDENCE: Level IV. PMID- 28882355 TI - Letter to the Editor Concerning: Parvaresh, K.C., Osbom, E.J., Reighard, F.G., Doan, J., Bastrom, T.P., Newton, P.O. Spine Deformity 5(2017):159-165. PMID- 28882356 TI - Response to Schlosser et al. PMID- 28882357 TI - Evaluation of negative pressure wound therapy to closed laparotomy incisions in acute care surgery. AB - BACKGROUND: Surgical site complications in the form of wound infections are a major burden to the healthcare system. Negative pressure wound therapy (NPWT) as delivered by a surgical incision management system (SIMS) is a novel approach to improve wound healing when applied to closed incisions. However, data is limited in its application to laparotomy incisions in the acute care surgery setting. METHODS: A retrospective case-control study was performed to evaluate the outcomes of SIMS with regard to surgical site infections in a series of 48 consecutive patients in which SIMS was applied to closed laparotomy incisions in the acute care surgery setting. RESULTS: 48 cases were matched with equivalent controls without significant differences between groups. Patients who received the SIMS had significantly lower rates of surgical site infection and readmission rates. CONCLUSIONS: Negative pressure surgical incision management systems may be a novel approach to reduce surgical site infections in acute care surgery. PMID- 28882358 TI - Impact of screening for metabolic syndrome on the evaluation of obese living kidney donors. AB - BACKGROUND: We report our experience with metabolic syndrome screening for obese living kidney donor candidates to mitigate the long-term risk of CKD. METHODS: We retrospectively reviewed 814 obese (BMI>=30) and 993 nonobese living kidney donor evaluations over 12 years. Using logistic regression, we explored interactions between social/clinical variables and candidate acceptance before and after policy implementation. RESULTS: Obese donor candidate acceptance decreased after metabolic syndrome screening began (56.3%, 46.3%, p < 0.01), while nonobese candidate acceptance remained similar (59.6%, 59.2%, p = 0.59). Adjusting for age, gender, race, BMI, and number of prior evaluations, acceptance of obese candidates decreased significantly more than nonobese (p = 0.025). In candidates without metabolic syndrome, there was no significant change in how age, sex, race, or BMI affected a donor candidate's probability of acceptance. CONCLUSION: Metabolic syndrome screening is a simple stratification tool for centers with liberal absolute BMI cut-offs to exclude potentially higher-risk obese candidates. PMID- 28882359 TI - Integrating technical and non-technical skills coaching in an acute trauma surgery team training: Is it too much? AB - OBJECTIVE: Research on effective integration of technical and non-technical skills in surgery team training is sparse. In a previous study we found that surgical teachers predominantly coached on technical and hardly on non-technical skills during the Definitive Surgical and Anesthetic Trauma Care (DSATC) integrated acute trauma surgery team training. This study aims to investigate whether the priming of teachers could increase the amount of non-technical skills coaching during such a training. DESIGN: Coaching activities of 12 surgical teachers were recorded on audio and video. Six teachers were primed on non technical skills coaching prior to the training. Six others received no priming and served as controls. Blind observers reviewed the recordings of 2 training scenario's and scored whether the observed behaviors were directed on technical or non-technical skills. We compared the frequency of the non-technical skills coaching between the primed and the non-primed teachers and analyzed for differences according to the trainees' level of experience. SETTING: Surgical teachers coached trainees during the highly realistic DSATC integrated acute trauma surgery team training. Trainees performed damage control surgery in operating teams on anesthetized porcine models during 6 training scenario's. PARTICIPANTS: Twelve experienced surgical teachers participated in this study. RESULTS: Coaching on non-technical skills was limited to about 5%. The primed teachers did not coach more often on non-technical skills than the non-primed teachers. We found no differences in the frequency of non-technical skills coaching based on the trainees' level of experience. CONCLUSION: Priming experienced surgical teachers does not increase the coaching on non-technical skills. The current DSATC acute trauma surgery team training seems too complex for integrating training on technical and non-technical skills. COMPETENCIES: Patient care, Practice based learning and improvement. PMID- 28882360 TI - Local parastomal hernia repair with biological mesh is safe and effective. AB - PURPOSE: The goal of this study was to evaluate the efficacy, morbidity and safety of local parastomal hernia repair using biological mesh. PATIENTS AND METHODS: A retrospective analysis of a prospectively maintained database was performed for parastomal hernia repairs. All patients who underwent local parastomal hernia repair with biological mesh between July 2006 and July 2015 were included in the study. Non-local (laparoscopic or midline incision) procedures were excluded. The type of repair, incision used, mesh placement and morbidity were analyzed. Time to recurrence was measured as an independent variable. RESULTS: 58 procedures with a median follow up of 3.8 years were analyzed. The majority (91%) of repairs were performed on an elective basis. Underlay technique was used in 24 patients (39%), overlay in 4 (7%) and both overlay and underlay (sandwich technique) in 33 (54%) of the cases. Overall, 11 patients (18.1%) experienced recurrence. Recurrence occurred in 8 patients in the underlay group (33%), 1 in the overlay group (25%), with 2 recurrences identified in the sandwich technique group (6%; p = 0.02). There was one occurrence of 30 day morbidity in our study population (0.016%). No difference was observed for recurrence or morbidity according to the type of biologic mesh used (human, bovine, or porcine). CONCLUSION: Our results demonstrate that local parastomal hernia repairs are associated with moderate recurrence rates, very low morbidity and consistent with the current literature. The sandwich technique was found to have a significantly lower recurrence rate compared to underlay or overlay techniques. Keyhole incisions were associated with less recurrence than traditional circular incisions. Our findings further reveal biologic mesh type was not associated with any difference in outcomes. Local parastomal hernia repair with biologic mesh is a safe procedure with very low morbidity and acceptable recurrence rate, especially using the sandwich repair technique. PMID- 28882361 TI - Relation between parental psychopathology and posttraumatic growth after a child's admission to intensive care: Two faces of the same coin? AB - OBJECTIVES: Confronted with the potentially traumatic experience of a child's admission to a paediatric intensive care unit, parents may experience psychopathological post-trauma symptoms as well as posttraumatic growth. The aim of this cross-sectional study was to explore the relation between psychopathology symptoms, namely, posttraumatic stress disorder), anxiety and depression, as well as post traumatic growth in parents following their child's hospitalisation in a paediatric intensive care unit. METHODS: Six months after their child's discharge, 143 parents completed the questionnaire, which assessed post traumatic growth (Posttraumatic Growth Inventory), post traumatic stress disorder (Davidson Trauma Scale), depression and anxiety (Hospital Anxiety and Depression Scale). RESULTS: Of the 143 parents, 23.1% reported symptoms of post traumatic stress disorder, 21% reported symptoms of moderate to severe anxiety, 9.1% reported symptoms of moderate to severe depression and 37.1% reported at least a medium degree of post traumatic growth. There was a moderate, direct association between post traumatic stress disorder, depression and anxiety with post traumatic growth. Higher scores in anxiety, depression and post traumatic stress disorder were associated with higher levels of post traumatic growth, contradicting the notion of an inverted U-shaped relationship between psychopathology symptoms and post traumatic growth. CONCLUSIONS: Given that positive and negative outcomes after a child's critical admission tend to co-occur, it is surmised that parents who indicate post traumatic growth do not deny the difficulties. While not negating the negative impact on the mental health of a parent with a child admitted to intensive care, including the assessment of post traumatic growth as an outcome following this event has important implications for research and clinical practice. PMID- 28882362 TI - Independent association of joint space narrowing, cyst formation and health related quality of life of patients with hip osteoarthritis in Japan. AB - INTRODUCTION: This study clarified individual associations of joint space narrowing (JSN) and radiographic features (RF) of hip osteoarthritis (HOA), i.e., cyst and osteophyte formation and subchondral sclerosis, with quality of life (QOL) in Japanese HOA patients. METHODS: This cross-sectional study comprised 117 Japanese HOA patients (98 women, 17 men; mean age, 61.2 years). We recorded locations and the size of each RF and measured JSN on the acetabular side (Ace) or femoral head (FH). We evaluated pain with the Visual Analog Scale (VAS) and assessed QOL with the physical component summary (PCS) and mental component summary (MCS) of the Medical Outcomes Study Short Form-36. We compared QOL with/without the RF on the Ace, FH or both and analyzed relationships between each RF and VAS, PCS and MCS with linear regression analysis. We assessed independent associations of each RF with PCS and MCS with multiple regression analysis using various independent variables. RESULTS: VAS values with the cyst on the Ace only were significantly lower than those with the cyst at both locations. PCS values with the cyst on the Ace only were significantly higher than those for both locations. Independent associations existed for maximum cyst length on the Ace and FH with VAS and for JSN with PCS, but none existed for MCS. CONCLUSIONS: Our study suggested that the location and the size of the cyst formation were associated with both VAS and QOL in Japanese HOA patients. The JSN was independently associated with the PCS. PMID- 28882363 TI - Editorial commentary: Leadless pacemaker: A pacemaker revolution or a simply new alternative solution? PMID- 28882364 TI - Editorial commentary: QTdrugs: From electrocardiographic intervals to prevention of sudden cardiac death. PMID- 28882365 TI - Editorial commentary: TAVR-Is there a path to an all-surgical-risk indication? PMID- 28882366 TI - Editorial commentary: Let it snow-Emerging roles for snoRNAs in cardiovascular disease. PMID- 28882367 TI - Defining the phenotype of antibody-mediated rejection in kidney transplantation: Advances in diagnosis of antibody injury. AB - The diagnostic criteria for antibody-mediated rejection (ABMR) are constantly evolving in light of the evidence. Inclusion of C4d-negative ABMR has been one of the major advances in the Banff Classification in recent years. Currently Banff 2015 classification requires evidence of donor specific antibodies (DSA), interaction between DSA and the endothelium, and acute tissue injury (in the form of microvasculature injury (MVI); acute thrombotic microangiopathy; or acute tubular injury in the absence of other apparent cause). In this article we review not only the ABMR phenotypes acknowledged in the most recent Banff classification, but also the phenotypes related to novel pathogenic antibodies (non-HLA DSA, antibody isoforms and subclasses, complement-binding functionality) and molecular diagnostic tools (gene transcripts, metabolites, small proteins, cytokines, and donor-derived cell-free DNA). These novel tools are also being considered for the prognosis and monitoring of treatment response. We propose that improved classification of ABMR based on underlying pathogenic mechanisms and outcomes will be an important step in identifying patient-centered therapies to extend graft survival. PMID- 28882368 TI - The epigenetic promise to improve prognosis of heart failure and heart transplantation. AB - Heart transplantation is still the only possible life-saving treatment for end stage heart failure, the critical epilogue of several cardiac diseases. Epigenetic mechanisms are being intensively investigated because they could contribute to establishing innovative diagnostic and predictive biomarkers, as well as ground-breaking therapies both for heart failure and heart transplantation rejection. DNA methylation and histone modifications can modulate the innate and adaptive immune response by acting on the expression of immune related genes that, in turn, are crucial determinants of transplantation outcome. Epigenetic drugs acting on methylation and histone-modification pathways may modulate Treg activity by acting as immunosuppressive agents. Moreover, the identification of non-invasive and reliable epigenetic biomarkers for the prediction of allograft rejection and for monitoring immunosuppressive therapies represents an attractive perspective in the management of transplanted patients. MiRNAs seem to fit particularly well to this purpose because they are differently expressed in patients at high and low risk of rejection and are detectable in biological fluids besides biopsies. Although increasing evidence supports the involvement of epigenetic tags in heart failure and transplantation, further short and long-term clinical studies are needed to translate the possible available findings into clinical setting. PMID- 28882370 TI - Caudal epidural anesthesia in mares after bicarbonate addition to a lidocaine epinephrine combination. AB - OBJECTIVE: To investigate the nociceptive and clinical effects of buffering a lidocaine-epinephrine solution with sodium bicarbonate in caudal epidural block in mares. STUDY DESIGN: Prospective randomized controlled trial. ANIMALS: Six mixed-breed mares weighing 350-440 kg. METHODS: Each animal was administered two caudal epidural injections, 72 hours apart, using different solutions prepared immediately before injection. The control solution was 7 mL 2% lidocaine hydrochloride with epinephrine hemitartrate (1:200,000) added to 3 mL sterile water for injection (pH 2.9). The alkalinized solution was 7 mL of lidocaine epinephrine solution added to 2.3 mL sterile water for injection and 0.7 mL 8.4% sodium bicarbonate (pH 7.4). Nociception was evaluated by response to skin pinching at 31 sites in the sacral region and around the perimeter of the anogenital area (distances of 10, 15 and 20 cm) before, and 5, 10 and 15 minutes after epidural injection, then every 15 minutes until the return of nociception in all evaluated sites. The onset and duration times, and intensity of ataxia (grades 0 to 3) were recorded. The paired t test was used to compare the onset and duration of anesthesia and ataxia (p<0.05). RESULTS: Alkalization of the solution resulted in significant decreases in the average time of onset of loss of nociception in the sacral region (40%) and around the perimeter of the anogenital area extending up to 5 cm (36%) and from 5 to 10 cm (32%) from the anus and vulva. Alkalization also decreased the average duration of ataxia (33%), without affecting the duration and extent of anesthesia or the degree of ataxia. CONCLUSIONS AND CLINICAL RELEVANCE: Alkalization of lidocaine-epinephrine solution is advantageous in shortening the duration of ataxia and hastening the onset of anesthesia in areas adjacent to the anogenital area, without reducing the duration of epidural anesthesia, in mares. PMID- 28882369 TI - 3D printed TCP-based scaffold incorporating VEGF-loaded PLGA microspheres for craniofacial tissue engineering. AB - OBJECTIVE: Vascularization is a critical process during bone regeneration/repair and the lack of tissue vascularization is recognized as a major challenge in applying bone tissue engineering methods for cranial and maxillofacial surgeries. The aim of our study is to fabricate a vascular endothelial growth factor (VEGF) loaded gelatin/alginate/beta-TCP composite scaffold by 3D printing method using a computer-assisted design (CAD) model. METHODS: The paste, composed of (VEGF loaded PLGA)-containing gelatin/alginate/beta-TCP in water, was loaded into standard Nordson cartridges and promptly employed for printing the scaffolds. Rheological characterization of various gelatin/alginate/beta-TCP formulations led to an optimized paste as a printable bioink at room temperature. RESULTS: The in vitro release kinetics of the loaded VEGF revealed that the designed scaffolds fulfill the bioavailability of VEGF required for vascularization in the early stages of tissue regeneration. The results were confirmed by two times increment of proliferation of human umbilical vein endothelial cells (HUVECs) seeded on the scaffolds after 10 days. The compressive modulus of the scaffolds, 98+/-11MPa, was found to be in the range of cancellous bone suggesting their potential application for craniofacial tissue engineering. Osteoblast culture on the scaffolds showed that the construct supports cell viability, adhesion and proliferation. It was found that the ALP activity increased over 50% using VEGF loaded scaffolds after 2 weeks of culture. SIGNIFICANCE: The 3D printed gelatin/alginate/beta-TCP scaffold with slow releasing of VEGF can be considered as a potential candidate for regeneration of craniofacial defects. PMID- 28882371 TI - Comparison of subcutaneous dexmedetomidine-midazolam versus alfaxalone-midazolam sedation in leopard geckos (Eublepharis macularius). AB - OBJECTIVE: To compare dexmedetomidine-midazolam with alfaxalone-midazolam for sedation in leopard geckos (Eublepharis macularius). STUDY DESIGN: Prospective, randomized, blinded, complete crossover study. ANIMALS: Nine healthy adult leopard geckos. METHODS: Geckos were administered a combination of dexmedetomidine (0.1 mg kg-1) and midazolam (1.0 mg kg-1; treatment D-M) or alfaxalone (15 mg kg-1) and midazolam (1.0 mg kg-1; treatment A-M) subcutaneously craniodorsal to a thoracic limb. Heart rate (HR), respiratory rate (fR), righting reflex, palpebral reflex, superficial and deep pain reflexes, jaw tone and escape response were assessed every 5 minutes until reversal. Conditions for intubation and response to needle prick were evaluated. Antagonist drugs [flumazenil (0.05 mg kg-1) +/- atipamezole (1.0 mg kg-1)] were administered subcutaneously, craniodorsal to the contralateral thoracic limb, 45 minutes after initial injection, and animals were monitored until recovery. RESULTS: HR, but not fR, decreased significantly over time in both treatments. HR was significantly lower than baseline at all time points in D-M and for all but the 5 and 10 minute time points in A-M. HR was significantly higher in A-M at all time points after drug administration when compared with D-M. Sedation scores between protocols were similar for most time points. All animals in A-M lost righting reflex compared with seven out of nine (78%) geckos in D-M. Geckos in A-M lost righting reflex for significantly longer time. Mean +/- standard deviation time to recovery after antagonist administration was 6.1 +/- 2.2 minutes for D-M and 56 +/- 29 minutes for A-M, and these times were significantly different. CONCLUSIONS AND CLINICAL RELEVANCE: Combination D-M or A-M provided sedation of a level expected to allow physical examinations and venipuncture in leopard geckos. A-M provided a faster onset of sedation compared with D-M. Recovery was significantly faster following antagonist reversal of D-M, compared with A-M. PMID- 28882372 TI - Reduced survival for uncemented compared to cemented total hip arthroplasty after operatively treated acetabular fractures. AB - BACKGROUND: Post traumatic arthritis and avascular necrosis of the femoral head are common complications after operatively treated acetabular fractures. This may cause severe disabilities for the patient, necessitating a total hip arthroplasty. Even though an arthroplasty may provide good symptomatic relief, the long-term results are more uncertain and no consensus exists according to preferred prosthetic designs. With this cohort study, we aimed to investigate the medium to long term arthroplasty survival and clinical results of total hip arthroplasty after operatively treated acetabular fractures. METHODS: We included 52 patients treated with a secondary total hip arthroplasty at a median of 2.4 (0.1-14.1) years after an operatively treated acetabular fracture. The median age was 54 (11-82) years. Cemented arthroplasty was used for 33 patients, 10 patients had an uncemented arthroplasty and 9 patients received a hybrid arthroplasty. Average follow up was 8.0 (SD 5.0) years. RESULTS: Ten-year revision free arthroplasty survival was 79%. Uncemented arthroplasties had a significantly worse 10-year survival of 57%. Arthroplasties performed at a centre without a pelvic fracture service also had a significantly worse 10-years survival of 51%. Cox regression showed similar results with an 8-fold increase in risk of revision for both uncemented arthroplasties and operations performed at a non-pelvic trauma centre. CONCLUSION: Total hip arthroplasty secondary to an operatively treated acetabular fracture provides good symptomatic relief. These patients are, however, complex cases and are probably best treated at specialist centres with both pelvic trauma surgeons and arthroplasty surgeons proficient in complex revisions present. PMID- 28882373 TI - A paradigm shift in surgical planning and simulation using 3Dgraphy: Experience of first 50 surgeries done using 3D-printed biomodels. AB - INTRODUCTION: Preoperative planning is an important aspect of any orthopedic surgery. Traditionally, surgeons mentally rehearse the operation and anticipate problems based on data available from "radiography" like MRI and CT. 3D printed bio-models and tools, or "3Dgraphy" can simplify this mental exercise and provide a realistic and user-friendly portrayal of this radiographic data. METHODS: Five surgeons participated in this multicenter study. 3D printed biomodels were obtained for 50 surgical cases that included periarticular trauma (24), pelvic trauma (11), complex primary (7), and revision arthroplasty (8). CT scan data was used to generate computer models which were then 3D printed in real size. These models were used to understand pathoanatomy and conduct simulated surgery as a part of preoperative planning. The models were sterilized and were used for intraoperative referencing. Following each case, the operating surgeon was asked to fill out a structured questionnaire to report on the perceived benefits of these tools. RESULTS: All surgeons reported that the biomodels provided additional information to conventional imaging that enhanced their knowledge of the complex pathoanatomy. It was useful in preoperative planning, rehearsing the operation, surgical simulation, intraoperative referencing, surgical navigation, preoperative implant selection, and inventory management. This probably reduced surgical time and improved accuracy of the surgery. All surgeons reported that they would not only use it themselves but also recommend it to other surgeons. CONCLUSION: 3Dgraphy was found to be a valuable tool in orthopedic surgeries that involve complex pathoanatomy like pelvic trauma, revision arthroplasty, and periarticular fracture. As the technology evolves and improves, they are likely to become a standard component of many orthopedic procedures. PMID- 28882374 TI - Does concomitant ulnar styloid fracture and distal radius fracture portend poorer outcomes? A meta-analysis of comparative studies. AB - PURPOSE: An ulnar styloid fracture often occur in association with a distal radial fracture. Whether an ulnar styloid fracture interfere with the results of a distal radial fracture still remains controversial. The aim of this study was to analyse the effects of an accompanying ulnar styloid fracture on clinical outcomes in patients with distal radial fractures. METHODS: A meta-analysis of published studies comparing outcomes of distal radial fractures with an ulnar styloid fracture versus isolated distal radial fractures was performed. Outcomes of function results, radiological evaluation, and patient reported scores were analyzed. RESULTS: Ten studies including 1403 distal radius fractures were identified fitting inclusion criteria. There was no significant difference in wrist motion, grip strength, radial height, volar angle, ulnar variance, pain score, PRWE score, or SF-36 score for distal radial fractures associated with an ulnar styloid fracture versus isolated distal radial fractures. In final follow up, patients with associated an ulnar styloid fracture had lower radial inclination and higher DASH scores. But there was no significant clinical difference. In addition, we found there was no significant difference of outcomes between union and non-union ulnar styloid fractures. CONCLUSIONS: Based on this meta-analysis, we suggest that an associated ulnar styloid fracture does not affect the outcomes of a distal radial fracture and clinicians should be caution in electing operative treatment for patients with an ulnar styloid fracture. PMID- 28882375 TI - Surgical treatment of osteoporotic fractures: An update on the principles of management. AB - The treatment of osteoporotic fractures continues to challenge orthopedic surgeon. The fragility of the underlying bone in conjunction with the need for specific implants led to the development of explicit surgical techniques in order to minimize implant failure related complications, morbidity and mortality. From the patient's perspective, the existence of frailty, dementia and other medical related co-morbidities induce a complex situation necessitating high vigilance during the perioperative and post-operative period. This update reviews current principles and techniques essential to successful surgical treatment of these injuries. PMID- 28882376 TI - A novel approach to improving the interpretation of CT brain in trauma. AB - BACKGROUND: Computed tomography of the brain (CTB) has a fundamental role in the diagnosis and management of traumatic brain injury (TBI). There may be substantial discordance between initial CTB interpretation by emergency clinicians and the final radiology report. This study aimed to assess the utility of a structured reporting template in improving the accuracy of CTB interpretation by emergency clinicians. METHOD: A prospective pre- and post intervention cohort study was undertaken using a study population of emergency medicine trainees. The CTB reporting template was created with consultation from radiology, emergency medicine and trauma specialists. Participants reported on a set of randomly selected trauma CTBs first without, and then with, the reporting template. Each case was independently assessed for concordance with the radiology report by two blinded assessors (including a radiologist) and the proportion of concordant reports in each phase calculated. RESULTS: There were 26 participants recruited to the study who reported on a total of 320 CTBs. In the pre intervention phase, 121 (76%) cases were concordant with the radiology report compared to 147 (92%) post-intervention (p<0.01). The AUROC was 0.84 (95% CI: 0.78-0.89) pre-intervention and improved to 0.94 (95% CI: 0.88-0.99) with the intervention (p=0.01). A higher level of baseline accuracy was observed in advanced trainees (78%) compared to basic trainees (72%), but both improved to a similar level of 92% with the use of the CTB reporting template. There was a marked reduction in false negative errors, with increased identification of critical diagnoses such as cerebral herniation and diffuse axonal injury. CONCLUSION: The use of the CTB reporting template significantly increased the accuracy of emergency medicine trainees and reduced the number of missed critical diagnoses. Reporting templates may represent an effective strategy to improve CTB interpretation and enhance the initial care of head injured patients. PMID- 28882378 TI - Changes in cortical microarchitecture are independent of areal bone mineral density in patients with fragility fractures. AB - Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) are commonly used to assess the areal bone mineral density (aBMD) and peripheral microstructure, respectively. While DXA is the standard to diagnose osteoporosis, HR-pQCT provides information about the cortical and trabecular architecture. Many fragility fractures occur in patients who do not meet the osteoporosis criterion (i.e., T-score<=-2.5). We hypothesize that patients with T-score above -2.5 and fragility fracture may have abnormal bone microarchitecture. Therefore, in this retrospective clinical study, HR-pQCT data obtained from patients with fragility fractures and T-scores>=-2.5 (n=71) were compared to corresponding data from patients with fragility fractures and T-scores<=-3.5 (n=56). Types of secondary osteoporosis were excluded from the study. To verify the dependency of alterations in bone microarchitecture and T score, the association between HR-pQCT values and aBMD as reflected by the T score at both proximal femora, was assessed. At the distal tibia, cortical thickness was lower (p<0.001), cortical porosity was similar (p=0.61), trabecular number was higher (p<0.001), and bone volume fraction (BV/TV) was higher (p<0.001) in patients with T-scores>=-2.5 than in patients with T-scores<=-3.5. Trabecular number and BV/TV correlated with T-score (r=0.68, p<0.001; r=0.61, p<0.001), whereas the cortical values did not. Our results thus demonstrate the importance of bone structure, as assessed by HR-pQCT, in addition to the standard DXA T-score in the diagnosis of osteoporosis. PMID- 28882379 TI - Reliable anatomical landmarks for minimizing leg-length discrepancy during hip arthroplasty using the lateral transgluteal approach for femoral neck fracture. AB - BACKGROUND: The purpose of this study was to describe our experience of a preoperative templating technique, and to investigate the most reliable anatomical reference to minimize leg length discrepancy (LLD) during hip arthroplasty using the lateral transgluteal approach for femoral neck fractures. We hypothesized that the medial fracture tip and greater trochanter would be viable alternative anatomical References METHODS: A total of 156 hip arthroplasty cases were enrolled in the present study (103 women, 114 hemiarthroplasties, 42 total hip arthroplasties). Preoperative acetate overlay templating was conducted based on pelvic anteroposterior radiographs. Three different anatomical references were used to determine the bony resection level, including the uppermost point of the lesser trochanter, uppermost point of the greater trochanter, and medial fracture tip. The accuracy of preoperative templating and the reliability of each anatomical reference for minimizing LLD were assessed. RESULTS: Significant differences in postoperative LLD after hip arthroplasty between the three groups were identified. Post-hoc analysis showed that postoperative LLD in group A was significantly larger than that in groups B or C in hip arthroplasty. CONCLUSION: The results of this study suggest that the use of the lesser trochanter as an anatomical reference to determine the level of femoral neck osteotomy should be discouraged, and that the medial fracture tip and greater trochanter may be better alternatives when using the lateral transgluteal approach. PMID- 28882377 TI - Lasting impression of violence: Retained bullets and depressive symptoms. AB - BACKGROUND: Over 70,000 nonfatal firearm injuries occur in the US annually, frequently leaving victims injured with retained bullets. The long-term psychological risks associated with retained bullets remains unstudied. By serving as a constant reminder of injury, we hypothesized that the presence of retained bullets after firearm injury is associated with increased PTSD and depression symptom severity. METHODS: We conducted a prospective cohort study (2013-2015) of Black male survivors of firearm injury at an urban Level I trauma center. Interviews, questionnaires and validated survey tools for PTSD (PCL-5) and depression (QIDS-SR16) to assess severity of symptoms were administered 3 months post-injury. Clinical characteristics and symptom severity scores were compared with respect to retained bullets using Wilcoxon Rank Sum tests and linear regression. RESULTS: Of 139 participants, 101(73%) had retained bullets. The cohort was young (mean age 26 years), educated (82% high school or greater) yet unemployed (53%) and with multiple injuries (median [IQR] no. of GSWs 2 [1 3]). There was no difference in age, education, employment status, number of gunshot wounds, operative procedures, pain, hospital or ICU LOS between groups (p>0.05). Patients with retained bullets less often rated their health as "very good" or "excellent" (10% vs 29%, p=0.046). Of those working prior to injury (n=47), 61% with retained bullets had not returned to work compared to 33% without retained bullets (p=0.027). No difference in PCL-5 scores [30.9 (SD 18.9) vs 27.9 (SD 18.6), p=0.470] was observed, but patients with retained bullets had greater mean QIDS-SR16 scores [10.7 (SD 6.2) vs 7.8 (SD 6.1), p=0.038] than those without. After controlling for injury severity, number of wounds, marital status and education level, multiple linear regression analysis determined that retained bullets (beta=3.52; p=0.017) were associated with more severe depressive symptoms. CONCLUSION: Retained bullets are associated with adverse psychological consequences after firearm injury. To improve recovery and to aid in clinical management decisions, clinicians should consider both the psychological and physical effects of retained bullets in survivors of firearm injury. PMID- 28882380 TI - Differences between orthopaedic evaluation and radiological reports of conventional radiographs in patients with minor trauma admitted to the emergency department. AB - INTRODUCTION: During night and on weekends, in our emergency department there is no radiologist on duty or on call: thus, X-ray examinations (XR) are evaluated by the orthopaedic surgeon on duty and reported the following morning/monday by radiologists. The aim of our study was to examine the discrepancy rate between orthopaedists and radiologists in the interpretation of imaging examinations performed on patients in our tertiary level orthopaedic institution and the consequences of delayed diagnosis in terms of patient management and therapeutic strategy. MATERIALS AND METHODS: We retrospectively reviewed all cases of discrepancy between orthopaedists and radiologists, which were categorized according to anatomical location of injury, initial diagnosis and treatment, change in diagnosis and treatment. We used the Chi square test to compare the frequencies of discrepancies between patients <=14 and >14years of age. RESULTS: From January to December 2016, 19,512 patients admitted to our emergency department performed at least an imaging examination; among these patients, 13,561 underwent XR in absence of an attending radiologist. A discrepant diagnosis was found in 337/13,561 (2.5%; 184 males; mean age: 36.7+/-23.7, range 2-95); 151/337 (45%) discrepancies were encountered in the lower limbs, with ankle being the most common site of misdiagnosis (64/151), and 103/337 (30%) in the upper limbs, with the elbow being the most frequent site in this district (35/103). We found 293/337 false negatives (87%) and 44/337 false positives (13%), with 134 and 13 patients needing treatment change, respectively. We found 85/337 discrepancies (25%) in patients <=14 years of age, and 252/337 (75%) in those >14years. The distribution of discrepancies per anatomic district was significantly different (P<0.001) in these two groups of patients. CONCLUSIONS: A low rate of discrepancy between orthopaedists and radiologists in evaluating images of patients admitted to our emergency department was found, although treatment change occurred in about half of cases. A thorough and accurate clinical evaluation is crucial to provide a correct treatment and prognosis. PMID- 28882381 TI - Trunk muscle activation pattern in parkinsonian camptocormia as revealed with surface electromyography. AB - INTRODUCTION: Camptocormia is frequently seen in Parkinson's disease (PD) and multiple system atrophy. It is characterized by a pathological forward bending of the trunk during standing, often combined with a lateral trunk deviation. The etiology of camptocormia in PD is still unknown. Muscle MRI studies show abnormalities mainly of the erector spinae confirmed by muscle biopsies. Quantitative electromyographic examination of trunk muscle activity is missing. METHODS: Ventral (rectus and obliquus externus abdominis) and dorsal (iliocostalis lumborum, longissimus, multifidus) trunk muscles and the rectus femoris were recorded bilaterally with surface electromyography in standing PD patients with camptocormia (n = 10) and matched healthy controls (n = 10) who mimicked the patients' posture. EMG amplitudes were compared quantitatively. In controls, the relation between varying degrees of trunk flexion and EMG was established systematically. RESULTS: Increasing forward trunk flexion was associated with increasing back muscle activity in controls, while abdominal muscle activity was negligible. During anterolateral trunk flexion, back muscle activity increased particularly on the contralateral side. The patients showed a similar pattern. However, normalized EMG activity of their trunk extensors was significantly higher than in controls, often reaching half-maximal amplitudes. Their rectus femoris and oblique abdominal muscles were overactive, but to a lesser extent. CONCLUSIONS: PD patients with camptocormia must use the functional reserve of their lumbar trunk muscles to counteract gravity. We interpret this as a weakness of the paravertebral muscles. Compared to the other examined muscles the paravertebral muscles are most affected. The increased EMG activity of the rectus femoris warrants further research. PMID- 28882382 TI - Soil-transmitted helminth infections. AB - More than a quarter of the world's population is at risk of infection with the soil-transmitted helminths Ascaris lumbricoides, hookworm (Ancylostoma duodenale and Necator americanus), Trichuris trichiura, and Strongyloides stercoralis. Infected children and adults present with a range of medical and surgical conditions, and clinicians should consider the possibility of infection in individuals living in, or returning from, endemic regions. Although safe and effective drugs are donated free to endemic countries, only half of at-risk children received treatment in 2016. This Seminar describes the epidemiology, lifecycles, pathophysiology, clinical diagnosis, management, and public health control of soil-transmitted helminths. Previous work has questioned the effect of population-level deworming; however, it remains beyond doubt that treatment reduces the severe consequences of soil-transmitted helminthiasis. We highlight the need for refined diagnostic tools and effective control options to scale up public health interventions and improve clinical detection and management of these infections. PMID- 28882383 TI - Serial Dependence in Audition: Free, Fast, and Featureless? PMID- 28882384 TI - Two-ion theory of energy coupling in ATP synthesis rectifies a fundamental flaw in the governing equations of the chemiosmotic theory. AB - The vital coupled processes of oxidative phosphorylation and photosynthetic phosphorylation synthesize molecules of adenosine-5'-triphosphate (ATP), the universal biological energy currency, and sustain all life on our planet. The chemiosmotic theory of energy coupling in oxidative and photophosphorylation was proposed by Mitchell >50years ago. It has had a contentious history, with part of the accumulated body of experimental evidence supporting it, and part of it in conflict with the theory. Although the theory was strongly criticized by many prominent scientists, the controversy has never been resolved. Here, the mathematical steps of Mitchell's original derivation leading to the principal equation of the chemiosmotic theory are scrutinized, and a fundamental flaw in them has been identified. Surprisingly, this flaw had not been detected earlier. Discovery of such a defect negates, or at least considerably weakens, the theoretical foundations on which the chemiosmotic theory is based. Ad hoc or simplistic ways to remedy this defect are shown to be scientifically unproductive and sterile. A novel two-ion theory of biological energy coupling salvages the situation by rectifying the fundamental flaw in the chemiosmotic theory, and the governing equations of the new theory have been shown to accurately quantify and predict extensive recent experimental data on ATP synthesis by F1FO-ATP synthase without using adjustable parameters. Some major biological implications arising from the new thinking are discussed. The principles of energy transduction and coupling proposed in the new paradigm are shown to be of a very general and universal nature. It is concluded that the timely availability after a 25-year research struggle of Nath's torsional mechanism of energy transduction and ATP synthesis is a rational alternative that has the power to solve the problems arising from the past, and also meet present and future challenges in this important interdisciplinary field of research. PMID- 28882385 TI - Lung deposition and systemic bioavailability of different aerosol devices with and without humidification in mechanically ventilated patients. AB - BACKGROUND: During mechanical ventilation medical aerosol delivery has been reported to be upto two fold greater with dry inhaled gas than with heated humidity. Urine levels at 0.5 h post dose (URSAL0.5%) has been confirmed as an index of lung deposition and 24 h (URSAL24%) as index of systemic absorption. Our aim was to determine the effect of humidification and aerosol device type on drug delivery to ventilated patients using urine levels. METHODS: In a randomized crossover design, 36 (18female) mechanically ventilated patients were assigned to one of three groups. Groups 1 and 2 received 5000 MUg salbutamol using vibrating mesh (VM) and jet nebulizers (JN), respectively, while group 3 received 1600 MUg (16 puffs) of salbutamol via metered dose inhaler with AeroChamber Vent (MDI-AV). All devices were placed in the inspiratory limb of ventilator downstream from the humidifier. Each subject received aerosol with and without humidity at >24 h intervals with >12 h washout periods between salbutamol doses. Patients voided urine 15 min before each study dose and urine samples were collected at 0.5 h post dosing and pooled for the next 24 h. RESULTS: The MDI-AV and VM resulted in a higher percentage of urinary salbutamol levels compared to the JN (p < 0.05). Urine levels were similar between humidity and dry conditions. CONCLUSIONS: Our findings suggest that in-vitro reports overestimate the impact of dry vs. heated humidified conditions on the delivery of aerosol during invasive mechanical ventilation. PMID- 28882386 TI - Knowledge of medical students on National Health Care System: A French multicentric survey. AB - BACKGROUND: Education on national health care policy and costs is part of our medical curriculum explaining how our health care system works. Our aim was to measure French medical students' knowledge about national health care funding, costs and access and explore association with their educational and personal background. METHODS: We developed a web-based survey exploring knowledge on national health care funding, access and costs through 19 items and measured success score as the number of correct answers. We also collected students' characteristics and public health training. The survey was sent to undergraduate medical students and residents from five medical universities between July and November 2015. RESULTS: A total of 1195 students from 5 medical universities responded to the survey. Most students underestimated the total amount of annual medical expenses, hospitalization costs and the proportion of the general population not benefiting from a complementary insurance. The knowledge score was not associated with medical education level. Three students' characteristics were significantly associated with a better knowledge score: male gender, older age, and underprivileged status. CONCLUSION: Medical students have important gaps in knowledge regarding national health care funding, coverage and costs. This knowledge was not associated with medical education level but with some of the students' personal characteristics. All these results are of great concern and should lead us to discussion and reflection about medical and public health training. PMID- 28882387 TI - Reducing the data-deficiency of threatened European habitats: Spatial variation of sabellariid worm reefs and associated fauna in the Sicily Channel, Mediterranean Sea. AB - Biogenic reefs, such as those produced by tube-dwelling polychaetes of the genus Sabellaria, are valuable marine habitats which are a focus of protection according to European legislation. The achievement of this goal is potentially hindered by the lack of essential empirical data, especially in the Mediterranean Sea. This study addresses some of the current knowledge gaps by quantifying and comparing multi-scale patterns of abundance and distribution of two habitat forming species (Sabellaria alveolata and S. spinulosa) and their associated fauna along 190 km of coast on the Italian side of the Sicily Channel. While the abundance of the two sabellariids and the total number of associated taxa did not differ at any of the examined scales (from tens of centimetres to tens-100 of kilometres), the structure (composition in terms of both the identity and the relative abundance of constituting taxa) of the associated fauna and the abundance of several taxa (the polychaetes Eulalia ornata, Syllis pulvinata, S. garciai, Nereis splendida and Arabella iricolor, and the amphipods Apolochus neapolitanus, Tethylembos viguieri and Caprella acanthifera) varied among locations established ~50-100 km apart. Syllis pulvinata also showed significant variation between sites (hundreds of metres apart), analogously to the other syllid polychaetes S. armillaris and S. gracilis, the nereidid polychaete Nereis rava, and the amphipod Gammaropsis ulrici. The largest variance of S. spinulosa, of the structure of the whole associated fauna and of 56% of taxa analysed individually occurred at the scale of replicates (metres apart), while that of the dominant bio-constructor S. alveolata and of 25% of taxa occurred at the scale of sites. The remaining 19% and the total richness of taxa showed the largest variance at the scale of locations. Present findings contribute to meet a crucial requirement of any future effective protection strategy, i.e., identifying relevant scales of variation to be included in protection schemes aiming at preserving representative samples not only of target habitats and organisms, but also of the processes driving such variability. PMID- 28882388 TI - Laparoscopic liver resection using the silicone band uplift technique for tumors in segments 8 and 7 (with video). PMID- 28882389 TI - Pore-scale simulations of concentration tails in heterogeneous porous media. AB - The retention of contaminants in the finest and less-conductive regions of natural aquifer is known to strongly affect the decontamination of polluted aquifers. In fact, contaminant transfer from low to high mobility regions at the back end of a contaminant plume (i.e. back diffusion) is responsible for the long term release of contaminants during remediation operation. In this paper, we perform pore-scale calculations for the transport of contaminant through heterogeneous porous media composed of low and high mobility regions with two objectives: (i) study the effect of permeability contrast and solute transport conditions on the exchange of solutes between mobile and immobile regions and (ii) estimate the mass of contaminants sequestered in low mobility regions based on concentration breakthrough curves. PMID- 28882390 TI - [Patients' quality of life after cataract surgery]. AB - INTRODUCTION: Our goal is to assess the Quality of Life (QL) of our patients after cataract surgery. MATERIALS AND METHODS: We performed a multicenter prospective study from July 2012 to December 2013 including patients undergoing cataract surgery, aged 18 and older. A survey sheet with sociodemographic data, clinical data and QL survey (VF-14) was given to each patient after surgery at day 7 (D7), one month (M1) and two months (M2) postoperatively. The final score was obtained by the following formula: QL=V (%)=(F __/__ C)*25. The data analysis was performed using SPSS software. RESULTS: A total of 100 patients were included, 56 men, and 61 years was the mean age. The mean QL score was 29.86% at D7, 73.97% at M1 and 81.21% at M2. Subjects between 18 and 30 years of age had a score of 90.15% vs. 82.52% at M2 for older patients. After optical correction, the quality of life scores increased from 83.22% at D7 to 93.18% at M2. Patients who did not have functional signs had a QL score of 83.94%. Anxious patients had a QL score of 44% at D7, 61.23% at M1 and 52.67% at M2. CONCLUSION: Good surgical outcomes require, in addition to clinical success, good quality of life. Several factors may influence this quality of life. PMID- 28882391 TI - [Evaluation of surgical simulation sessions of the French society of ophthalmology. A new surgical instruction method]. AB - INTRODUCTION: Since 2013, at the French society of ophthalmology (FSO) meetings, two simulators for intraocular surgeries have been available. The goal of this study was to assess the satisfaction of the participants in these organized training sessions. MATERIALS AND METHODS: A questionnaire was mailed to participants in the FSO sessions as well as those carried out during the annual congress. This questionnaire collected data on the participants and the practical modalities of the sessions, and assessed participants' feelings and satisfaction with these sessions. RESULTS: The participants in the SFO sessions were young members of the SFO (31.8+/-12.3 years). 53.8 % were in training, looking to improve a problematic surgical step (capsulorhexis in 51.5 %). They spent nearly 5hours on simulators (4.8hours) and were alone on a simulator 50 % of the time. The sessions held during the annual congress were used by older physicians (41.9+/-26.4 years) already in practice (66.6 %). The goal of such training was curiosity in a third of the cases (to try the simulators). The majority spent less than an hour on the devices and were at least two participants per machine. Despite these differences, participants cited a role for their surgical learning curve and recommended such training to their colleagues. CONCLUSIONS: The participants' enthusiasm for this new training technique is highlighted by the results of this study. PMID- 28882392 TI - Fundus autofluorescence in retinal artery occlusion: A more precise diagnosis. AB - IMPORTANCE: Retinal artery occlusion (RAO) is a medical emergency associated with a high risk of cerebral vascular accident and other cardiovascular events. Among patients with non-arteritic RAO, a retinal embolus is observed in approximately 40% of cases. Fundus examination and retinography are not reliable to predict the nature of the emboli. OBSERVATIONS: We report three consecutive cases of central and branch RAO that were investigated with fundus autofluorescence, fluorescein angiography and color retinal photographs. All patients underwent complete neurological and cardiovascular workups, with brain imaging, cardiac Doppler ultrasound, carotid Dopplers and Holter ECG's, to determine the underlying mechanism of retinal embolism. In the three cases, aged 77.7+/-4 years (2 women and 1 man), fundus autofluorescence demonstrated hyperautofluorescent emboli. In two cases, it allowed visualization of emboli that were not detected with fundus examination or retinography. The cardiovascular work-up demonstrated atheromatous carotid or aortic plaques in all patients. In one case, it permitted the diagnosis of RAO. Two of the three cases were considered to be of atherosclerotic origin and one of undefined origin. CONCLUSION AND RELEVANCE: Fundus autofluorescence may help to detect and characterize retinal emboli. Since lipofuscin, which is present in large quantity in atherosclerotic plaques, is the main fluorophore detected with fundus autofluorescence, this non-invasive and simple examination may give information about the underlying mechanism of retinal embolism, and thus impact the etiologic assessment of RAO. Additional studies are necessary to confirm this potential role of autofluorescence. PMID- 28882393 TI - [Prognostic factors in uveitis]. AB - PURPOSE: To evaluate prognostic factors of vision loss among patients with uveitis. MATERIAL AND METHODS: This descriptive and retrospective study included all patients diagnosed with uveitis who were seen at the teaching hospital of Rabat, Morocco, over a 5-year period. Information regarding demographic data, uveitis type, bilaterality of the disease, etiology and complications were gathered from patients' records. Statistical analysis was performed using SPSS software. RESULTS: One hundred and thirty-nine eyes of 89 patients were included. There were 60.7 % men and 39.3 % women. The mean age (years) was 31.1+/-16.8. Median follow-up was 11 months. Median visual acuity (logMAR) on admission was 1.7 [0.7-2] and 1 [0.4-1.7] on the last visit (P<0.001). Fifty-nine percent of eyes had final visual acuity (VA) equal to or less than 1/10. Panuveitis (85.4 %) and posterior uveitis (72.7 %) were responsible for final VA equal to or less than 1/10 (P<0.001). Cataract, posterior synechiae, vitreous opacities, epimacular membrane (ERM) and cystoid macular edema (CME) were the most frequent complications. Using multivariate logistic regression, the prognostic factors associated with severe vision loss were the type of uveitis (posterior and panuveitis), CME, ERM, macular scarring and optic atrophy (P<0.05). CONCLUSION: Although this study included a limited number of subjects, the results showed that final VA was equal or less than 1/10 in 59 % of eyes diagnosed with uveitis and was associated with risk factors including posterior segment involvement (panuveitis and posterior uveitis), CME and ERM. PMID- 28882394 TI - The Thesaurus Medicinae practicae by Thomas Burnet. PMID- 28882395 TI - Genetic variant of Stickler's syndrome. AB - CASES REPORTS: Three myopic components of a same family came for study because presented severely degraded vitreous, equatorial membranes, retinal pigment epithelium hyperplasia, vascular sheathed and sclerosis of peripheral predominance. A genetic study confirmed the diagnosis of Stickler syndrome with a variant in the mutation of the COL2A1 gene. DISCUSSION: Stickler's syndrome should be suspected in families with a characteristic phenotype with vitreous syneresis and alterations in the retina, but there may be genetic variants that do not express the classic phenotype. PMID- 28882396 TI - 7-Year follow-up of a lifestyle intervention in overweight children: Comparison to an untreated control group. AB - BACKGROUND & AIMS: We present the 7-year follow-up analysis in overweight children and adolescents, who had participated originally in a randomized control trial of a lifestyle intervention. We compared them to an untreated population based control group to demonstrate the effectiveness of the intervention. METHODS: Degree of overweight (BMI-SDS) was determined in 32 overweight children (mean age 11.5 +/- 1.5yrs, 65.6% females, mean BMI 23.7 +/- 1.5 kg/m2) at onset of intervention (T0), end of 6-month intervention (T1), 12 months (T2) and 7 years after end of intervention (T3). A total of 76 overweight children derived from a representative national population survey served as control group. RESULTS: The participants in the intervention group reduced significantly their BMI-SDS between T0-T1 (mean +/- standard deviation -0.28 +/- 0.28, p < 0.001) and demonstrated no significant changes between T1-T2 (mean +/- standard deviation 0.10 +/- 0.34) and between T2-T3 (median +0.07; interquartile range: -0.54-0.62). BMI-SDS at T3 was significantly (p = 0.015) lower compared to T0. At T3, 46.8% of the participants in the intervention were normal-weight. The reduction in BMI-SDS between T0-T3 was significantly (p = 0.043) greater in the intervention group (median -0.26; interquartile range -0.87-0.23 BMI-SDS) compared to the control group (mean +/- standard deviation -0.05 +/- 0.77). CONCLUSIONS: The lifestyle intervention led to a significant reduction of overweight in the 7-year follow-up period. This decrease in BMI-SDS was significantly greater than the changes in BMI-SDS in a control group. This study is registered at clinicaltrials.gov (NCT00422916). PMID- 28882397 TI - Sex difference in the effect of the fasting serum glucose level on the risk of coronary heart disease. AB - OBJECTIVE: Diabetic women have a greater relative risk of coronary heart disease than diabetic men. However, the sex difference in the effect of fasting serum glucose levels below the diabetic range on the risk of coronary heart disease is unclear. We investigated whether the association between nondiabetic blood glucose levels and the incident risk of coronary heart disease is different between men and women. METHODS: The fasting serum glucose levels and other cardiovascular risk factors at baseline were measured in 159,702 subjects (100,144 men and 59,558 women). Primary outcomes were hospital admission and death due to coronary heart disease during the 11-year follow-up. RESULTS: The risk for coronary heart disease in women significantly increased with impaired fasting glucose levels (>=110mg/dL) compared to normal glucose levels (<100mg/dL), whereas the risk for coronary heart disease in men was significantly increased at a diabetic glucose range (>=126mg/dL). Women had a higher hazard ratio of coronary heart disease associated with the fasting serum glucose level than men (p for interaction with sex=0.021). CONCLUSIONS: The stronger effect of the fasting serum glucose levels on the risk of coronary heart disease in women than in men was significant from a prediabetic range (>=110mg/dL). PMID- 28882398 TI - Cystic fibrosis complicated by cor pulmonale: The first case report in Taiwan. PMID- 28882399 TI - Risky pleasures and drugged assemblages: Young people's consumption practices of AOD in Madrid. AB - BACKGROUND: Drawing on a research project that we carried out on the functionality of "excessive" consumption practices in the lifestyles of young people in Madrid, this article aims to understand how (dis)pleasurable states emerge during young people's consumption of alcohol and other drugs. METHODS: This article claims that these states derive from "drugged assemblages," that is, a set of (human and non-human) actants that intra-act to produce different effects. Although pleasure can be one of these effects, it is not always guaranteed: consumption practices are assemblages that fluctuate between pleasure and displeasure, and the former can be reached or not depending on the characteristics acquired by the assemblage. It is this fluctuation that makes pleasures "risky." Drugged assemblages also configure and are configured by specific spatial-temporal and material apparatuses or dispositifs. We will analyse botellones, night-clubs and raves as examples of this kind of dispositif, focusing on how they work as a holistic frame where drugged assemblages emerge. RESULTS: Finally, we will focus on the different strategies and practices that young people, in constant intra-action with other agencies, develop in order to achieve and keep a "controlled loss of control" within the limits and potentials offered by these contexts, in a constant effort to avoid the risks that may result from the blurred line that divides pleasure and displeasure. CONCLUSION: In this sense, we will argue that, despite the criticisms it has received, it is possible to make Measham's concept of "controlled loss of control" compatible with a post-humanist theoretical framework. PMID- 28882400 TI - Histone modifications: A review about the presence of this epigenetic phenomenon in carcinogenesis. AB - Among the epigenetic changes, histone acetylation has been recognized as a fundamental process that strongly affects gene expression regulation. Disrupt of this phenomenon has been linked to carcinogenesis. In this review, we analysed studies reporting the process of histone modification, the enzymes associated and affected genes concerning human malignancies and histone enzyme inhibitor drugs used in cancer treatment. Variable degrees of expression of HDACs (histone deacetylases) and HATs (histone acetyltransferases) are found in many human malignant tissues and the histones acetylation seems to influence different processes including the progression of cell cycle, the dynamics of chromosomes, DNA recombination, DNA repair and apoptosis. Thus, the control of aberrant activity and/or expression of these proteins have been favorable in treatment of diseases as cancer. HDACi have shown efficacy in clinical trials in solid and hematological malignancies. Therefore, the development and use of HDACs inhibitors are increasing, leading to continue studying these enzyme expressions and behavior, aiming to determine tumors that will respond better to this type of treatment. PMID- 28882401 TI - Loss and gain of cone types in vertebrate ciliary photoreceptor evolution. AB - Ciliary photoreceptors are a diverse cell type family that comprises the rods and cones of the retina and other related cell types such as pineal photoreceptors. Ciliary photoreceptor evolution has been dynamic during vertebrate evolution with numerous gains and losses of opsin and phototransduction genes, and changes in their expression. For example, early mammals lost all but two cone opsins, indicating loss of cone receptor types in response to nocturnal lifestyle. Our review focuses on the comparison of specifying transcription factors and cell type-specific transcriptome data in vertebrate retinae to build and test hypotheses on ciliary photoreceptor evolution. Regarding cones, recent data reveal that a combination of factors specific for long-wavelength sensitive opsin (Lws)- cones in non-mammalian vertebrates (Thrb and Rxrg) is found across all differentiating cone photoreceptors in mice. This suggests that mammalian ancestors lost all but one ancestral cone type, the Lws-cone. We test this hypothesis by a correlation analysis of cone transcriptomes in mouse and chick, and find that, indeed, transcriptomes of all mouse cones are most highly correlated to avian Lws-cones. These findings underscore the importance of specifying transcription factors in tracking cell type evolution, and shed new light on the mechanisms of cell type loss and gain in retina evolution. PMID- 28882403 TI - Biochemical comparison of four commercially available human alpha1-proteinase inhibitors for treatment of alpha1-antitrypsin deficiency. AB - Intravenous therapy with purified plasma-derived alpha1-proteinase inhibitor (alpha1-PI) concentrates is the only specific treatment for alpha1-PI deficiency. For the therapy to be safe and efficacious, alpha1-PI concentrates should be highly pure and contain high amounts of functional protein. This study compared the four plasma-derived alpha1-PI products commercially available in Europe (Respreeza, Prolastin, Alfalastin, Trypsone) by biochemical methods with respect to function, purity, structure, and chemical modifications. Respreeza had the highest level of functional protein (48.8 mg/mL) and the highest specific activity (0.862 mg active alpha1-PI per mg total protein). By size exclusion chromatography, Respreeza was 97.4% pure, followed by Alfalastin 88.1%, Prolastin 76.9%, and Trypsone 70.8%. By reversed phase chromatography, Respreeza had an alpha1-PI purity of 97.7%, followed by Trypsone 88.0%, Prolastin 78.0%, and Alfalastin 69.5%. The main protein band by sodium dodecyl sulphate-polyacrylamide gel electrophoresis was found for all products at approximately 50 kDa. Additional protein bands were found for Prolastin, Alfalastin, and Trypsone. The alpha1-PI products differed in cysteine oxidation state and C-terminal lysine status. alpha1-PI products tested differ in purity, concentration, and chemical variation. Respreeza has the highest level of purity. The impact of the non therapeutic proteins identified has not been evaluated. PMID- 28882404 TI - Health Related Quality of Life Following Radical Cystectomy: Comparative Analysis from the Medicare Health Outcomes Survey. AB - PURPOSE: Health related quality of life after radical cystectomy and ileal conduit is not well quantified at the population level. We evaluated health related quality of life in patients with bladder cancer compared with noncancer controls and patients with colorectal cancer using data from SEER (Surveillance, Epidemiology and End Results)-MHOS (Medicare Health Outcomes Survey). MATERIALS AND METHODS: SEER-MHOS data from 1998 to 2013 were used to identify patients with bladder cancer and those with colorectal cancer who underwent extirpative surgery with ileal conduit or colostomy creation, respectively. A total of 166 patients with bladder cancer treated with radical cystectomy were propensity matched 1:5 to 830 noncancer controls and compared with 154 patients with colorectal cancer. Differences in Mental and Physical Component Summary scores as well as component subscores were determined between patients with bladder cancer, patients with colorectal cancer and noncancer controls. RESULTS: SEER-MHOS patients were more commonly male and white with a mean +/- SD age of 77 +/- 6 years. Patients treated with radical cystectomy had significantly lower Physical Component Summary scores, select physical subscale scores and all mental subscale scores compared with noncancer controls. These findings were similar in the subset of 40 patients treated with radical cystectomy who had available preoperative and postoperative survey data. Global Mental Component Summary scores did not differ significantly between the groups. No significant differences were observed in global Mental Component Summary, Physical Component Summary or subscale scores between patients with bladder cancer and patients with colorectal cancer. CONCLUSIONS: Patients with bladder cancer who undergo radical cystectomy have significant declines in multiple components of physical and mental health related quality of life vs noncancer controls, which mirror those of patients with colorectal cancer. Further longitudinal study is required to better codify the effectors of poor health related quality of life after radical cystectomy to improve patient expectations and outcomes. PMID- 28882402 TI - Visceral endoderm and the primitive streak interact to build the fetal-placental interface of the mouse gastrula. AB - Hypoblast/visceral endoderm assists in amniote nutrition, axial positioning and formation of the gut. Here, we provide evidence, currently limited to humans and non-human primates, that hypoblast is a purveyor of extraembryonic mesoderm in the mouse gastrula. Fate mapping a unique segment of axial extraembryonic visceral endoderm associated with the allantoic component of the primitive streak, and referred to as the "AX", revealed that visceral endoderm supplies the placentae with extraembryonic mesoderm. Exfoliation of the AX was dependent upon contact with the primitive streak, which modulated Hedgehog signaling. Resolution of the AX's epithelial-to-mesenchymal transition (EMT) by Hedgehog shaped the allantois into its characteristic projectile and individualized placental arterial vessels. A unique border cell separated the delaminating AX from the yolk sac blood islands which, situated beyond the limit of the streak, were not formed by an EMT. Over time, the AX became the hindgut lip, which contributed extensively to the posterior interface, including both embryonic and extraembryonic tissues. The AX, in turn, imparted antero-posterior (A-P) polarity on the primitive streak and promoted its elongation and differentiation into definitive endoderm. Results of heterotopic grafting supported mutually interactive functions of the AX and primitive streak, showing that together, they self-organized into a complete version of the fetal-placental interface, forming an elongated structure that exhibited A-P polarity and was composed of the allantois, an AX-derived rod-like axial extension reminiscent of the embryonic notochord, the placental arterial vasculature and visceral endoderm/hindgut. PMID- 28882405 TI - Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the control of subthreshold symptoms of bipolar disorder: Results from a pilot, randomized controlled trial. AB - Patients with bipolar disorder (BD) do not always achieve full remission between episodes. Subthreshold symptoms (depressive, manic or mixed) represent a major cause of relapse and disability in these patients. Immediate release (IR) and extended release (XR) formulations of quetiapine are both indicated for short and long-term treatment of BD. The aim of this study was to evaluate the efficacy of quetiapine XR vs placebo in subthreshold symptomatology when added to previous mood stabilizer treatment. A pilot phase IIIB, multicentre, prospective, placebo controlled, randomized, double blinded study of 12 weeks follow-up was performed (NCT01197846). Patients were randomized to quetiapine XR 300mg or placebo once daily. The primary outcome was the mean change between quetiapine XR and placebo from baseline to study endpoint (week 6) in the Montgomery-Asberg Depression Rating Scale (MADRS). Quetiapine XR 300mg (n=16) significantly improved depressive subthreshold symptoms compared with placebo (n=16) after 6 weeks (P=0.021). Early response (reduction of at least the 20% of the MADRS total score) and remission rate (reduction in MADRS total score <8 and YMRS<8) did not show differences between groups. Quetiapine XR did not show superiority vs placebo when evaluating subthreshold manic symptoms, instead it was superior when evaluating functioning (GAF score) in BD type I patients (P=0.005). The most common adverse events were somnolence (9.1%), increased appetite, dry mouth and dizziness (6.8%). Quetiapine XR 300mg once daily was significantly more effective than placebo in depressive subthreshold symptoms. Adverse events were consistent with the known side effects of quetiapine. PMID- 28882406 TI - Process model economics of xanthan production from confectionery industry wastewaters. AB - In this research a process and cost model for a xanthan production facility was developed using process simulation software (SuperPro Designer(r)). This work represents a novelty in the field for two reasons. One is that xanthan gum has been produced from several wastes but never from wastewaters from confectionery industries. The other more important is that the aforementioned software, which in intended exclusively for bioprocesses, is used for generating a base case, i.e. starting point for transferring the technology to industrial scales. Previously acquired experimental knowledge about using confectionery wastewaters from five different factories as substitutes for commercially used cultivation medium have been incorporated into the process model in order to obtain an economic viability of implementing such substrates. A lower initial sugar content in the medium based on wastewater (28.41 g/L) compared to the synthetic medium (30.00 g/L) gave a lower xanthan content at the end of cultivation (23.98 and 26.27 g/L, respectively). Although this resulted in somewhat poorer economic parameters, they were still in the range of being an investment of interest. Also the possibility of utilizing a cheap resource (waste) and reducing pollution that would result from its disposal has a positive effect on the environment. PMID- 28882407 TI - Isolated Palmaris Brevis Spasm in a 16-Year-Old. PMID- 28882408 TI - Dental and oropharyngeal lesions in rats with chronic acid reflux esophagitis. AB - OBJECTIVE: In this study, we evaluated pathological changes in the tooth and pharynx of GERD rats to elucidate the association between gastric acid reflux and oral and pharyngeal diseases. METHODS: An experimental rat model of chronic acid reflux esophagitis was surgically created. The oral cavities were observed histologically every 2 weeks until 20 weeks after surgery. RESULTS: At 10 weeks after surgery, molar crown heights in GERD rats were shorter than that in control rats, and inflammatory cell infiltration by gastric acid reflux was found in the periodontal mucosa of GERD rats. Furthermore, dental erosion progressed in GERD rats at 20 weeks after surgery, and enamel erosion and dentin exposure were observed. During the same period, inflammatory cell infiltration was observed in the mucosa of the posterior part of the tongue. These findings suggest that gastric acid reflux may be one of the exacerbating factors of dental erosion, periodontitis and glossitis. CONCLUSION: We investigated oral changes in an experimental rat model of GERD and observed development of dental erosion, periodontitis and glossitis. Our findings suggested chronic gastric acid reflux may be involved in the pathogenesis of oral disease. PMID- 28882409 TI - Assessment of growth of Aspergillus spp. from agricultural soils in the presence of glyphosate. AB - Agriculture is one of the bases of the Argentine economy. Glyphosate is undoubtedly one of the most important herbicides used. The increasing consumption and the efficiency of glyphosate-based herbicides have encouraged several studies on their persistence in soils, their effects on soil microbiota and their degradation processes. Fungi have been reported as being the main herbicide degrading microorganisms as well as the most tolerant to environmental stress conditions. This study evaluated the growth performance of Aspergillus section Flavi and Aspergillus niger aggregate strains on Czapek Dox media supplied with a commercial glyphosate formulation as sole source of carbon (CZC), phosphorus (CZP) or nitrogen (CZN). Six Aspergillus spp. strains were evaluated. Each medium was stab-inoculated with fungal spores from 7-day old cultures. Two measures of colony radii were taken daily. All of the Aspergillus section Flavi strains showed a significant increase (from 24 to 44%) in growth rate on the CZN medium, as compared to controls. The A. niger aggregate strains exhibited the same behavioral pattern under all the conditions tested, except on the CZN medium. Velutinous or slightly floccose colonies with abundant sporulation were observed on CZP. Moreover, the colonies produced sparse sporulation on CZC or CZN media, being their appearances completely different from those on the CZP medium. This study establishes that A. section Flavi and A. niger aggregate strains can grow in vitro in the presence of glyphosate, especially when it is used as a sole source of phosphorus or nitrogen. PMID- 28882410 TI - Radiological protection of foetuses and breast-fed children of occupationally exposed women in nuclear medicine - Challenges for hospitals. AB - This paper describes issues of concern for protecting foetuses and breast-fed children of occupationally exposed women in nuclear medicine from unnecessary exposure of ionising radiation. The protection principle is to ensure the same level of protection for the foetus and child as for the general public. Therefore international radiation protection standards recommend a dose constraint of 1mSv to a foetus during the remaining time of pregnancy after it is known/declared and a yearly dose constraint of 1mSv to a breast-fed child. It is not self-evident how to guarantee this level of radiation protection. The exposure situation in nuclear medicine is complex. Exploring existing reported occupational exposure levels suggests great variability between work tasks and facilities. The standards and guidelines found give no detailed advice. Therefore each facility needs to systematically review external and internal exposure levels in order to plan appropriate protection measures and issue their own guidelines and rules. One strategy might be that each facility defines tasks that do not require any restrictions and lists such duties that are not suitable to do when pregnant or breastfeeding, taking also potential exposure levels into consideration. This paper gives examples of such types of work. Information to the staff about the necessity of declaring pregnancy or breastfeeding is of fundamental importance. The internal policies issued by the hospital management should make clear the basis for taking care of pregnant and breastfeeding employees. PMID- 28882411 TI - Prenatal stress-induced impairments of cognitive flexibility and bidirectional synaptic plasticity are possibly associated with autophagy in adolescent male offspring. AB - Prenatal stress (PS) brings numerous outcomes on offspring, including anxiety, depression-like behavior and other cognitive disorder. In this study, a rat model of PS was established by using restraint stress for 45min three times per day from the 15th to 21st day of pregnancy. Behavioral tests, including open field test (OPT), elevated plus-maze (EPM) and Morris water-maze (MWM), were performed in adolescent male-offspring. The bidirectional synaptic plasticity, including long-term potential (LTP) and depotentiation (DEP), from the hippocampal Schaffer collaterals to CA1 region was subsequently measured. Furthermore, Western blot assay, immunofluorescence staining and hematoxylin-eosin (HE) staining were employed. The MWM test showed that the cognitive flexibility was remarkably damaged in PS offspring. Meanwhile, PS considerably aggravated the anxiety and depression-like behavior in OPT and EPM. Both LTP and DEP were significantly inhibited by PS. Furthermore, PS considerably altered the expression of synaptic related proteins NR2A, NR2B and PSD-95 in adolescent male-offspring. Interestingly, PS significantly elevated the autophagy level in the hippocampus of male-offspring. In order to investigate the role of autophagy on the negative impacts of PS in adolescent male-offspring, both in vitro and in vivo studies were performed. It was found that autophagy inhibitors significantly eliminated the alterations in gene expression induced by corticosterone. The results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by PS in adolescent male-offspring. PMID- 28882412 TI - A flavonoid agonist of the TrkB receptor for BDNF improves hippocampal neurogenesis and hippocampus-dependent memory in the Ts65Dn mouse model of DS. AB - Intellectual disability is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Reduced neurogenesis and impaired neuron maturation are considered major determinants of altered brain function in DS. Since the DS brain starts at a disadvantage, attempts to rescue neurogenesis and neuron maturation should take place as soon as possible. The brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a key role in brain development by specifically binding to tropomyosin-related kinase receptor B (TrkB). Systemic BDNF administration is impracticable because BDNF has a poor blood-brain barrier penetration. Recent screening of a chemical library has identified a flavone derivative, 7,8-dihydroxyflavone (7,8-DHF), a small-molecule that crosses the blood-brain barrier and binds with high affinity and specificity to the TrkB receptor. The therapeutic potential of TrkB agonists for neurogenesis improvement in DS has never been examined. The goal of our study was to establish whether it is possible to restore brain development in the Ts65Dn mouse model of DS by targeting the TrkB receptor with 7,8-DHF. Ts65Dn mice subcutaneously injected with 7,8-DHF in the neonatal period P3-P15 exhibited a large increase in the number of neural precursor cells in the dentate gyrus and restoration of granule cell number, density of dendritic spines and levels of the presynaptic protein synaptophysin. In order to establish the functional outcome of treatment, mice were treated with 7,8-DHF from P3 to adolescence (P45-50) and were tested with the Morris Water Maze. Treated Ts65Dn mice exhibited improvement of learning and memory, indicating that the recovery of the hippocampal anatomy translated into a functional rescue. Our study in a mouse model of DS provides novel evidence that treatment with 7,8-DHF during the early postnatal period restores the major trisomy-linked neurodevelopmental defects, suggesting that therapy with 7,8-DHF may represent a possible breakthrough for Down syndrome. PMID- 28882413 TI - cGAS Conducts Micronuclei DNA Surveillance. AB - DNA damage elicits a potent proinflammatory immune response. A collection of four papers now reveals that micronuclear DNA is a new cell intrinsic immunostimulatory molecule, and that accumulation of the immune sensor cyclic GMP AMP synthase (cGAS) in micronuclei leads to a cell-cycle-dependent proinflammatory response following DNA damage. PMID- 28882414 TI - Proinflammatory Signals as Fuel for the Fire of Hematopoietic Stem Cell Emergence. AB - Hematopoietic stem cells (HSCs) have the extraordinary ability to both self-renew and generate all mature blood cell lineages. The ability to produce or expand patient-derived HSCs in vitro would greatly improve the outcome for patients with blood disorders that are currently treated with allogeneic HSC transplantation. Many laboratories have been working to identify the signals required for HSC emergence in their native environments to apply this knowledge in vitro. Recently, several signals traditionally known to underlie classical inflammation have emerged as essential regulators of HSC development. In this review we synthesize the findings that have established inflammatory cues as key regulators of HSC development. PMID- 28882415 TI - Anaesthesia for abnormally invasive placenta: a single-institution case series. PMID- 28882416 TI - Determining Cellular Responses: Phytoglobins May Direct the Traffic. AB - How stem cells retain their undifferentiated state or how differentiated cells are capable of having dissimilar responses to perturbations are major open questions in plant biology. Cell-specific phytoglobin expression may be one mechanism determining cell fate by the modulation of nitric oxide (NO), affecting cellular hormonal responses and processes such as cell differentiation. PMID- 28882417 TI - Derivation and validation model for hospital hypoglycemia. AB - BACKGROUND: An objective and simple prognostic model for hospitalized patients with hypoglycemia could be helpful in guiding initial intensity of treatment. METHODS: We carried out a derivation rule for hypoglycemia using data from a nationwide retrospective cohort study of patients with diabetes or hyperglycemia carried out in 2014 (n=839 patients). The rule for hypoglycemia was validated using a second data set from a nationwide retrospective cohort study carried out in 2016 (n=561 patients). We derived our prediction rule using logistic regression with hypoglycemia (glucose less than 70mg/dL) as the primary outcome. RESULTS: The incidence of hypoglycemia in the derivation cohort was 10.3%. Patient's characteristics independently associated with hypoglycemia included episodes of hypoglycemia during the previous three months (odds ratio [OR]: 6.29, 95% confidence interval [95%CI]: 3.37-11.79, p<0.001) estimated glomerular filtration rate lower than 30mL/min/1.73m2 (OR: 2.32, 95%CI: 1.23-4.35, p=0.009), daily insulin dose greater than 0.3units per Kg (OR: 1.74, 95%CI: 1.06-2.85, p=0.028), and days of hospitalization (OR: 1.03, 95%CI: 1.01-1.04, p=0.001). The model showed an area under the curve (AUC): 0.72 (95%CI: 0.66-0.78, p<0.001). The AUC in the validation cohort was: 0.71 (95%CI: 0.63-0.79, p<0.001). CONCLUSIONS: The rule showed fair accuracy to predict hypoglycemia. Implementation of the rule into computer systems could be used in guiding initial insulin therapy. PMID- 28882418 TI - Epidemiological trends of inflammatory bowel disease (IBD) in Split-Dalmatia County, Croatia from 2006 to 2014. PMID- 28882419 TI - Carcinoma in situ of the breast in New South Wales, Australia: Current status and trends over the last 40 year. AB - BACKGROUND: The incidence of non-invasive breast cancer has increased substantially over time. We aim to describe temporal trends in the incidence of carcinoma in situ of the breast in New South Wales (NSW), Australia. METHODS: Descriptive study of trends in the incidence of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) in women who received a diagnosis from 1972 to 2012, recorded in the NSW Cancer Registry. RESULTS: Carcinoma in situ as a proportion of all breast cancer was 0.4% during the prescreening period 1972 to 1987 and is currently 14.1% (2006 to 2012). Among 10,810 women diagnosed with DCIS, incidence across all ages rose from 0.15 per 100,000 during 1972 to 1983 to 16.81 per 100,000 over 2006 to 2012, representing a 100-fold increase (IRR 113.10; 95% CI 81.94 to 156.08). Among women in the target age group for screening (50-69 years) incidence rose from 0.27 per 100,000 to 51.96 over the same period (IRR 195.50; 95% CI 117.26 to 325.89). DCIS incidence peaks in women aged 60-69 years. DCIS incidence has not stabilized despite screening being well established for over 20 years, and participation rates in the target age range remaining stable. CONCLUSIONS: Our findings raise questions about the value of the increasing detection of DCIS and aggressive treatment of these lesions, especially among older women, and support trials of de-escalated treatment. PMID- 28882420 TI - Age-related differences in the topological efficiency of the brain structural connectome in amnestic mild cognitive impairment. AB - Amnestic mild cognitive impairment (aMCI) is accompanied by the accelerated cognitive decline and rapid brain degeneration with aging. However, the age related alterations of the topological organization of the brain connectome in aMCI patients remained largely unknown. In this study, we constructed the brain structural connectome in 51 aMCI patients and 51 healthy controls by diffusion magnetic resonance imaging and deterministic tractography. The different age related alteration patterns of the global and regional network metrics between aMCI patients and healthy controls were assessed by a linear regression model. Compared with healthy controls, significantly decreased global and local network efficiency in aMCI patients were found. When correlating network efficiency with age, we observed a significant decline in network efficiency with aging in the aMCI patients, while not in the healthy controls. The age-related decreases of nodal efficiency in aMCI patients were mainly distributed in the key regions of the default-mode network, such as precuneus, anterior cingulate gyrus, and parahippocampal gyrus. In addition, age-related decreases in the connection strength of the edges between peripheral nodes were observed in aMCI patients. Moreover, the decreased regional efficiency of the parahippocampal gyrus was correlated with impaired memory performances in patients. The present study suggests an age-related disruption of the topological organization of the brain structural connectome in aMCI patients, which may provide evidence for different neural mechanisms underlying aging in aMCI and may serve as a potential imaging marker for the early diagnosis of Alzheimer's disease. PMID- 28882421 TI - 18F-FDG PET hypometabolism patterns reflect clinical heterogeneity in sporadic forms of early-onset Alzheimer's disease. AB - Until now, hypometabolic patterns and their correlations with neuropsychological performance have not been assessed as a function of the various presentations of sporadic early-onset Alzheimer's disease (EOAD). Here, we processed and analyzed the patients' metabolic maps at the vertex and voxel levels by using a nonparametric, permutation method that also regressed out the effects of cortical thickness and gray matter volume, respectively. The hypometabolism patterns in several areas of the brain were significantly correlated with the clinical manifestations. These areas included the paralimbic regions for typical presentations of sporadic EOAD. For atypical presentations, the hypometabolic regions included Broca's and Wernicke's areas and the pulvinar in language forms, bilateral primary and higher processing visual regions (with right predominance) in visuospatial forms, and the bilateral prefrontal cortex in executive forms. Similar hypometabolism patterns were also observed in a correlation analysis of the 18F-FDG PET data versus domain-specific, neuropsychological test scores. These heterogeneities might reflect different underlying pathophysiological processes in particular clinical presentations of sporadic EOAD and should be taken into account in future longitudinal and therapeutic studies. PMID- 28882422 TI - Associations between dynamic functional connectivity and age, metabolic risk, and cognitive performance. AB - Advanced age is associated with reduced within-network functional connectivity, particularly within the default mode network. Most studies to date have examined age differences in functional connectivity via static indices that are computed over the entire blood-oxygen-level dependent time series. Little is known about the effects of age on short-term temporal dynamics of functional connectivity. Here, we examined age differences in dynamic connectivity as well as associations between connectivity, metabolic risk, and cognitive performance in healthy adults (N = 168; age, 18-83 years). A sliding-window k-means clustering approach was used to assess dynamic connectivity from resting-state functional magnetic resonance imaging data. Three out of 8 dynamic connectivity profiles were associated with age. Furthermore, metabolic risk was associated with the relative amount of time allocated to 2 of these profiles. Finally, the relative amount of time allocated to a dynamic connectivity profile marked by heightened connectivity between default mode and medial temporal regions was positively associated with executive functions. Thus, dynamic connectivity analyses can enrich understanding of age-related differences beyond what is revealed by static analyses. PMID- 28882423 TI - Hepatitis B virus-related mortality in rheumatoid arthritis patients undergoing long-term low-dose glucocorticoid treatment: A population-based study. AB - BACKGROUND/PURPOSE: Glucocorticoids (GC) are commonly used in rheumatoid arthritis (RA) patients which bears a risk of hepatitis B virus (HBV) reactivation. The purpose of this study was to investigate the risk of HBV related mortality under long-term low-dose GCs in Taiwanese RA patients. METHODS: We retrospectively analyzed 45,423 RA patients using National Health Insurance Research Database from January 1999 to December 2011. Of them, 2204 patients had the diagnosis of HBV and were classified into four groups according to GCs regimens. Outcome comparison by Cox model analysis for liver-related mortality was performed. RESULTS: In this cohort, 90.5% were older than 40. One hundred and five patients had been treated with short-term large-dose GCs (Group A); 862 patients received GCs >=20 mg/day for >=3 days or a variable dose but did not meet Group C criteria (Group B); 689 patients were continuously treated with low dose (<20 mg/day) GCs for >=3 months for at least one session (Group C); and 548 patients had never been exposed to GCs (Group D). Two hundred and sixty-one patients had been exposed to antiviral agents, which was significantly higher in Group C. Fifty-eight patients (2.63%) died of acute hepatic failure, while no statistically significant difference between each groups (p = 0.074). Groups C and D comparison by two-sample test showed that long-term low-dose GC treatment was not associated with liver-related death after adjusting for malignancy. CONCLUSION: Long-term low-dose GC treatment was not associated with liver-related mortality in RA with concomitant HBV patients probably due to commonly applied antiviral therapy by rheumatologists. PMID- 28882424 TI - Too sweet to eat: Exploring the effects of cuteness on meat consumption. AB - Although daily meat consumption is a widespread habit, many individuals at the same time put a high value on the welfare of animals. While different psychological mechanisms have been identified to resolve this cognitive tension, such as dissociating the animal from the consumed meat or denying the animal's moral status, few studies have investigated the effects of the animal's appearance on the willingness to consume its meat. The present article explored how the perception of cuteness influences hypothetical meat consumption. We hypothesized that cuter animals would reduce the willingness to consume meat, and that this relationship would be mediated by empathy felt towards the animal. Across four pre-registered studies sampling 1074 US and Norwegian participants, we obtained some support for this prediction in the US but to a lesser degree in Norway. However, in all studies an indirect mediation effect of cuteness on meat consumption going through empathy towards the animal was observed. We also explored possible moderating and additional mediating mechanisms of trait pro social orientation, caretaking intentions and sex effects for which we found mixed evidence. Theoretical and practical implications of the findings are discussed. PMID- 28882425 TI - Presence of pups suppresses hunger-induced feeding in virgin adult mice of both sexes. AB - Despite recent progress on neural pathways underlying individual behaviors, how an animal balances and prioritizes behavioral outputs remains poorly understood. While studying the relationship between hunger-induced feeding and pup-induced maternal behaviors in virgin female mice, we made the unexpected discovery that presence of pups strongly delayed and decreased food consumption. Strikingly, presence of pups also suppressed feeding induced by optogenetic activation of Agrp neurons. Such a suppressive effect inversely correlated with the extents of maternal behaviors, but did not rely on the display of these behaviors, and was also present in virgin males. Furthermore, chemogenetic activation of Vglut2+ neurons in the medial preoptic area (mPOA), a region critical for maternal behaviors and motivation, was sufficient to suppress hunger-induced feeding. However, muscimol inhibition of the mPOA, while disrupting maternal behaviors, did not prevent pup suppression of feeding, indicating that neural pathways in other brain regions may also mediate such an effect. Together, these results provide novel insights into neural coordination of pup care and feeding in mice and organizations of animal behaviors in general. PMID- 28882426 TI - Statistical analysis of solid waste composition data: Arithmetic mean, standard deviation and correlation coefficients. AB - Data for fractional solid waste composition provide relative magnitudes of individual waste fractions, the percentages of which always sum to 100, thereby connecting them intrinsically. Due to this sum constraint, waste composition data represent closed data, and their interpretation and analysis require statistical methods, other than classical statistics that are suitable only for non constrained data such as absolute values. However, the closed characteristics of waste composition data are often ignored when analysed. The results of this study showed, for example, that unavoidable animal-derived food waste amounted to 2.21+/-3.12% with a confidence interval of (-4.03; 8.45), which highlights the problem of the biased negative proportions. A Pearson's correlation test, applied to waste fraction generation (kg mass), indicated a positive correlation between avoidable vegetable food waste and plastic packaging. However, correlation tests applied to waste fraction compositions (percentage values) showed a negative association in this regard, thus demonstrating that statistical analyses applied to compositional waste fraction data, without addressing the closed characteristics of these data, have the potential to generate spurious or misleading results. Therefore, compositional data should be transformed adequately prior to any statistical analysis, such as computing mean, standard deviation and correlation coefficients. PMID- 28882427 TI - Plastic waste to liquid oil through catalytic pyrolysis using natural and synthetic zeolite catalysts. AB - This study aims to examine the catalytic pyrolysis of various plastic wastes in the presence of natural and synthetic zeolite catalysts. A small pilot scale reactor was commissioned to carry out the catalytic pyrolysis of polystyrene (PS), polypropylene (PP), polyethylene (PE) and their mixtures in different ratios at 450 degrees C and 75min. PS plastic waste resulted in the highest liquid oil yield of 54% using natural zeolite and 50% using synthetic zeolite catalysts. Mixing of PS with other plastic wastes lowered the liquid oil yield whereas all mixtures of PP and PE resulted in higher liquid oil yield than the individual plastic feedstocks using both catalysts. The GC-MS analysis revealed that the pyrolysis liquid oils from all samples mainly consisted of aromatic hydrocarbons with a few aliphatic hydrocarbon compounds. The types and amounts of different compounds present in liquid oils vary with some common compounds such as styrene, ethylbenzene, benzene, azulene, naphthalene, and toluene. The FT-IR data also confirmed that liquid oil contained mostly aromatic compounds with some alkanes, alkenes and small amounts of phenol group. The produced liquid oils have high heating values (HHV) of 40.2-45MJ/kg, which are similar to conventional diesel. The liquid oil has potential to be used as an alternative source of energy or fuel production. PMID- 28882428 TI - The effect of mianserin on the severity of psychosis and dyskinesia in the parkinsonian marmoset. PMID- 28882430 TI - Reproductive outcomes in recipients are not associated with oocyte donor body mass index up to 28 kg/m2: a cohort study of 2722 cycles. AB - The effect of increasing donor body mass index (BMI) on clinical pregnancies was retrospectively analysed in a cohort of consecutive 2722 donor oocyte IVF cycles. The relationship between donor BMI and clinical pregnancies was assessed after adjusting for recipient BMI. Clinical pregnancy rates and live birth rates (LBR) were no different with increasing donor BMI (up to donor BMI <=28 kg/m2). The odds of pregnancy did not vary with donor BMI. Compared with donor BMI quartile 1, OR 95% CI of clinical pregnancy was 1.01 (0.82 to 1.25), 1.01 (0.82 to 1.25) and 0.90 (0.73 to 1.12) for quartiles 2, 3 and 4 respectively. A statistically significant reduction of cumulative LBR (P = 0.036) and LBR (P = 0.011) was observed in the results of donation cycles according to recipient BMI quartiles. A reduced odds of clinical pregnancy was observed with increasing recipient BMI. Compared with recipient BMI quartile 1, OR 95% CI of clinical pregnancy was 0.84 (0.68 to 1.03), 0.79 (0.63 to 00.97) and 0.78 (0.63 to 0.971) for quartiles 2, 3 and 4, respectively. A negative effect on oocyte donation cycle outcomes with increased donor BMI was not found after adjusting oocyte donor and recipient BMI. PMID- 28882431 TI - Abnormal retention of nuclear lamina and disorganization of chromatin-related proteins in spermatozoa from DPY19L2-deleted globozoospermic patients. AB - The aim of this study was to characterize the nuclear lamina (NL) and lamin chromatin-partners in spermatozoa from four DPY19L2-deleted globozoospermic patients. We tested for spermatid transcripts encoding lamins and their chromatin partners emerin, LAP2alpha, BAF and BAF-L, by reverse transcriptase-PCR using spermatozoa RNA. We also determined the localization of lamin B1, BAF and BAF-L by immunofluorescent analysis of spermatozoa from all patients. In RNA from globozoospermic and control spermatozoa we detected transcripts encoding lamin B1, lamin B3, emerin, LAP2alpha and BAF-L, but not A-type lamins. In contrast, BAF transcripts were detected in globozoospermic but not control spermatozoa. The NL was immature in human globozoospermic spermatozoa: lamin B1 signal was detected in the nuclei of globozoospermic spermatozoa in significantly higher proportions than the control (P < 0.05; 56-91% versus 40%) and was predominantly observed at the whole nuclear periphery, not polarized as in control spermatozoa. Conversely, BAF and BAF-L were detected in control, but not globozoospermic spermatozoa. Our results strongly emphasize the importance of the NL and associated proteins during human spermiogenesis. In globozoospermia, the lack of maturation of the NL, and the modifications in expression and location of chromatin-partners, could explain the chromatin defects observed in this rare phenotype. PMID- 28882432 TI - Analysis of ambient pH stress response mediated by iron and copper intake in Schizosaccharomyces pombe. AB - The molecular mechanism of tolerance to alkaline pH is well studied in model fungi Aspergillus nidulans and Saccharomyces cerevisiae. However, how fission yeast Schizosaccharomyces pombe survives under alkaline stress remains largely unknown, as the genes involved in the alkaline stress response pathways of A. nidulans and S. cerevisiae were not found in the genome of this organism. Since uptake of iron and copper into cells is important for alkaline tolerance in S. cerevisiae, here we examined whether iron and copper uptake processes were involved in conferring tolerance to alkaline stress in S. pombe. We first revealed that S. pombe wild-type strain could not grow at a pH higher than 6.7. We further found that the growths of mutants harboring disruption in the iron uptake-related gene frp1+, fio1+ or fip1+ were severely inhibited under ambient pH stress condition. In contrast, derepression of these genes, by deletion of their repressor gene fep1+, caused cells to acquire resistance to pH stress. Together, these results suggested that uptake of iron is essential for ambient pH tolerance in S. pombe. We also found that copper is required for the pH stress response because disruptants of ctr4+, ctr5+, ccc2+ and cuf1+ genes, all of which are needed for regulating intracellular Cu+, displayed ambient pH sensitivity. Furthermore, supplementing Fe2+ and Cu2+ ions to the culture media improved growth under ambient pH stress. Taken together, our results suggested that uptake of iron and copper is the crucial factor needed for the adaptation of S. pombe to ambient pH stress. PMID- 28882433 TI - Reporting of three-dimensional echocardiography-derived left ventricular volumes comes of age. PMID- 28882429 TI - Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy. AB - Natural killer (NK) cells have long been known to mediate anti-tumor responses without prior sensitization or recognition of specific tumor antigens. However, the tumor microenvironment can suppress NK cell function resulting in tumor escape and disease progression. Despite recent advances in cytokine therapy and NK cell adoptive transfer, tumor expression of ligands to NK - expressed checkpoint receptors can still suppress NK mediated tumor lysis. This review will explore many of the checkpoint receptors tumors utilize to manipulate the NK cell response as well as some of the current and upcoming pharmacological solutions to limit tumor suppression of NK cell function. Furthermore, we will discuss the potential to use these drugs in combinational therapies with novel antibody reagents such as bi- and tri-specific killer engagers (BiKEs and TriKEs) against tumor-specific antigens to enhance NK cell-mediated tumor rejection. PMID- 28882434 TI - Associations of age, aerobic fitness, and body mass index with injury in an operational Army brigade. AB - OBJECTIVES: To investigate the effects of age, aerobic fitness, and body mass index (BMI) on injury risk in operational Army soldiers. DESIGN: Retrospective cohort study. METHODS: Male soldiers from an operational Army brigade were administered electronic surveys regarding personal characteristics, physical fitness, and injuries occurring over the last 12 months. Injury risks were stratified by age, 2-mile run time, and BMI. Analyses included descriptive incidence, a Mantel-Haenszel chi2 test to determine trends, a multivariable logistic regression to determine factors associated with injury, and a one-way analysis of variance (ANOVA). RESULTS: Forty-seventy percent of 1099 respondents reported at least one injury. A linear trend showed that as age, 2-mile run time, and BMI increased, so did injury risk (p<0.01). When controlling for BMI, the most significant independent injury risk factors were older age (odd ratio (OR) 30years-35years/<=24years=1.25, 95%CI: 1.08-2.32), (OR>=36years/<=24years=2.05, 95%CI: 1.36-3.10), and slow run times (OR>=15.9min/<=13.9min=1.91, 95%CI: 1.28 2.85). An ANOVA showed that both run times and BMI increased with age. CONCLUSIONS: The stratified analysis and the multivariable logistic regression suggested that older age and poor aerobic fitness are stronger predictors of injury than BMI. PMID- 28882435 TI - Validation of HeadCount-2w for estimation of two-week heading: Comparison to daily reporting in adult amateur player. AB - OBJECTIVES: To validate the HeadCount-2w questionnaire for estimation of 2-week soccer heading by comparison to daily electronic diary reporting over the same two-week period. DESIGN: Prospective observational study. METHODS: Adult amateur soccer players completed HeadCount-daily, comprising 14 daily at-home assessments of soccer play and heading via a tablet PC. Following the 14day period, players completed HeadCount-2w, a web-based two-week-recall questionnaire on soccer and heading. intraclass correlation coefficient (ICC) was estimated between HeadCount daily, the reference standard, and HeadCount-2w estimates of heading during the same 2-week period. RESULTS: 53 participants (38 men) reported a mean of 24.36 (median=11.76) headers during 2 weeks via HeadCount-daily and a mean of 38.34 (median=15.0) headers for the same 2 weeks via HeadCount-2w. The ICC comparing 2 week heading from HeadCount-daily and HeadCount-2w was 0.85. Linear regression of the log-transformed Headcount-daily on HeadCount-2w data yielded a slope of 0.71 (p<0.001; 95% CI 0.54-0.82), suggesting that heading tends to be over-estimated by HeadCount-2w relative to HeadCount-daily. Slope estimates for men (0.65) and women (0.71) were similar. CONCLUSIONS: HeadCount, a self-administered web-based survey, is valid for self-reporting 2-week heading in adult amateur players, supporting its use in future research and as a simple and low-cost technique for exposure monitoring. PMID- 28882436 TI - Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2. AB - OBJECTIVE: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). METHODS: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600mg BID, irrespective of BRCA1/2 mutation status and prior treatments. RESULTS: In the efficacy population (n=106), ORR was 53.8% (95% confidence interval [CI], 43.8-63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2months (95% CI, 6.6-11.6). In the safety population (n=377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade >=3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. CONCLUSIONS: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile. PMID- 28882437 TI - DNA vaccines against leptospirosis: A literature review. AB - Leptospirosis is an infectious disease caused by pathogenic Leptospira species. The vaccines that are currently available for leptospirosis are composed of whole cell preparations and suffer from limitations such as low efficacy, multiple side effects, poor immunological memory and lack of cross-protection against different serovars of Leptospira spp. In light of the global prevalence of this disease, the development of a more effective vaccine against leptospirosis is of paramount importance. Genetic immunization is a promising alternative to conventional vaccine development. In the last 25years, several novel strategies have been developed for increasing the efficacy of DNA vaccines. Examples of such strategies include the introduction of novel plasmid vectors, adjuvants, alternate delivery routes, and prime-boost regimens. Herein we discuss the latest and most promising advances that have been made in developing DNA vaccines against leptospirosis. We also deliberate over the future directions that must be undertaken in order to improve results in this field. PMID- 28882438 TI - Biodistribution and safety of a live attenuated tetravalent dengue vaccine in the cynomolgus monkey. AB - BACKGROUND: The first licensed dengue vaccine is a recombinant, live, attenuated, tetravalent dengue virus vaccine (CYD-TDV; Sanofi Pasteur). This study assessed the biodistribution, shedding, and toxicity of CYD-TDV in a non-human primate model as part of the nonclinical safety assessment program for the vaccine. METHODS: Cynomolgus monkeys were given one subcutaneous injection of either one human dose (5log10 CCID50/serotype) of CYD-TDV or saline control. Study endpoints included clinical observations, body temperature, body weight, food consumption, clinical pathology, immunogenicity, and post-mortem examinations including histopathology. Viral load, distribution, persistence, and shedding in tissues and body fluids were evaluated by quantitative reverse transcriptase polymerase chain reaction. RESULTS: The subcutaneous administration of CYD-TDV was well tolerated. There were no toxicological findings other than expected minor local reactions at the injection site. A transient low level of CYD-TDV viral RNA was detected in blood and the viral genome was identified primarily at the injection site and in the draining lymph nodes following immunization. CONCLUSIONS: These results, together with other data from repeat-dose toxicity and neurovirulence studies, confirm the absence of toxicological concern with CYD-TDV and corroborate clinical study observations. PMID- 28882439 TI - Erratum to "Phase I, randomized, observer-blind, placebo-controlled studies to evaluate the safety, reactogenicity and immunogenicity of an investigational non typeable Haemophilus influenzae (NTHi) protein vaccine in adults" [Vaccine 34 (2016) 3156-3163]. PMID- 28882440 TI - Determinants of under-immunization and cumulative time spent under-immunized in a Quebec cohort. AB - BACKGROUND: Under-immunization refers to a state of sub-optimal protection against vaccine preventable diseases. Vaccine coverage for age may not capture intentional or non-intentional spacing of vaccines in the recommended provincial immunization guidelines. We aimed to identify factors associated with coverage and under-immunization and to determine the number of days during which children were under-immunized during their first 24months of life. METHODS: Secondary analysis of children <=3years recruited through active surveillance for gastroenteritis from three Quebec pediatric emergency departments from 2012 to 2014. Vaccination status for children at least 24months of age was determined using provincial immunization guidelines. Cumulative days under-immunized were calculated for DTaP-VPI-Hib, PCV, MMR, and Men-C-C. Factors associated with up-to date (UTD) status at 24months of life and for under-immunization >=6months were analyzed using logistic regression. RESULTS: Of 246 eligible children, 180 (73%) were UTD by 24months of life. The mean cumulative days under-immunized for MMR was 107days, for PCV 209days, for Men-C-C 145days, and for DTaP-VPI-Hib 227days. Overall, 149 children (60%) experienced delay for at least 1 vaccine. Factors associated with both an UTD status at 24months and concurrently associated with being under-immunization >=6months, included timely initiation of immunization (OR=5.85; 95% CI: 2.80-12.22) and (OR=0.13; 95% CI: 0.07-0.24), failure to co administer 18-month vaccines (OR=0.15; 95% CI: 0.10-0.21) and (OR=3.29; 95% CI: 2.47-4.39), and having a household with >=3 children under 18years ((OR=0.50; 0.28-0.86) and (OR=2.99; 1.45-6.22), respectively. CONCLUSION: Paired with an unexpected low level of coverage at 24months of life, the majority of our cohort also experienced a state of under-immunization for a least one vaccine. Estimates of coverage do not capture intentional or non-intentional gaps in protection from vaccine preventable illnesses. Timely preventive care should be prioritized. PMID- 28882441 TI - Generation of a novel live rabies vaccine strain with a high level of safety by introducing attenuating mutations in the nucleoprotein and glycoprotein. AB - The current live rabies vaccine SAG2 is attenuated by only one mutation (Arg-to Glu) at position 333 in the glycoprotein (G333). This fact generates a potential risk of the emergence of a pathogenic revertant by a back mutation at this position during viral propagation in the body. To circumvent this risk, it is desirable to generate a live vaccine strain highly and stably attenuated by multiple mutations. However, the information on attenuating mutations other than that at G333 is very limited. We previously reported that amino acids at positions 273 and 394 in the nucleoprotein (N273/394) (Leu and His, respectively) of fixed rabies virus Ni-CE are responsible for the attenuated phenotype by enhancing interferon (IFN)/chemokine gene expressions in infected neural cells. In this study, we found that amino acid substitutions at N273/394 (Phe-to-Leu and Tyr-to-His, respectively) attenuated the pathogenicity of the oral live vaccine ERA, which has a virulent-type Arg at G333. Then we generated ERA-N273/394-G333 attenuated by the combination of the above attenuating mutations at G333 and N273/394, and checked its safety. Similar to the ERA-G333, which is attenuated by only the mutation at G333, ERA-N273/394-G333 did not cause any symptoms in adult mice after intracerebral inoculation, indicating a low level of residual pathogenicity of ERA-N273/394-G333. Further examination revealed that infection with ERA-N273/394-G333 induces IFN-beta and CXCL10 mRNA expressions more strongly than ERA-G333 infection in a neuroblastoma cell line. Importantly, we found that the ERA-N273/394-G333 stain has a lower risk for emergence of a pathogenic revertant than does the ERA-G333. These results indicate that ERA-N273/394-G333 has a potential to be a promising candidate for a live rabies vaccine strain with a high level of safety. PMID- 28882442 TI - Polio immunity and the impact of mass immunization campaigns in the Democratic Republic of the Congo. AB - BACKGROUND: In order to prevent outbreaks from wild and vaccine-derived poliovirus, maintenance of population immunity in non-endemic countries is critical. METHODS: We estimated population seroprevalence using dried blood spots collected from 4893 children 6-59months olds in the 2013-2014 Demographic and Health Survey in the Democratic Republic of the Congo (DRC). RESULTS: Population immunity was 81%, 90%, and 70% for poliovirus types 1, 2, and 3, respectively. Among 6-59-month-old children, 78% reported at least one dose of polio in routine immunization, while only 15% had three doses documented on vaccination cards. All children in the study had been eligible for at least two trivalent oral polio vaccine campaigns at the time of enrollment; additional immunization campaigns seroconverted 5.0%, 14%, and 5.5% of non-immune children per-campaign for types 1, 2, and 3, respectively, averaged over relevant campaigns for each serotype. CONCLUSIONS: Overall polio immunity was high at the time of the study, though pockets of low immunity cannot be ruled out. The DRC still relies on supplementary immunization campaigns, and this report stresses the importance of the quality and coverage of those campaigns over their quantity, as well as the importance of routine immunization. PMID- 28882443 TI - Debate on vaccines and autoimmunity: Do not attack the author, yet discuss it methodologically. AB - Since Jenner, vaccines and vaccinations have stirred a hot, highly polarized debate, leading to contrasting positions and feelings, ranging from acritical enthusiasm to blind denial. On the one hand, we find anti-vaccination movements which divulge and disseminate misleading information, myths, prejudices, and even frauds, with the main aim of denying that vaccination practices represent a major public health measure, being effective in controlling infectious diseases and safeguarding the wellbeing of entire communities. Recently, the authors of many vaccine safety investigations are being personally criticized rather than the actual science being methodologically assessed and critiqued. Unfortunately, this could result in making vaccine safety science a "hazardous occupation". Critiques should focus on the science and not on the authors and on the scientists that publish reasonably high-quality science suggesting a problem with a given vaccine. These scientists require adequate professional protection so there are not disincentives to publish and to carry out researches in the field. The issues for vaccine safety are not dissimilar to other areas such as medical errors and drug safety. PMID- 28882444 TI - Tetanus Toxoid carrier protein induced T-helper cell responses upon vaccination of middle-aged adults. AB - INTRODUCTION: Vaccines frequently induce suboptimal immune responses in the elderly, due to immunological ageing. Timely vaccination may be a strategy to overcome this problem, which classifies middle-aged adults asan interesting target group for future vaccine interventions. However, the immunological fitness of the middle-aged population is ill-defined. It is currently unknown whether effective T-cell help towards B-cells is initiated by conjugate-carrier vaccines at middle-age. AIM: We characterized systemic Tetanus Toxoid (TT) specific T helper cell responses in the circulation of middle-aged adults (50-65years of age, n=31) having received the MenACWY-TT vaccination. METHODS: Blood samples were taken pre- as well as 7days, 28days, and 1year post-vaccination. TT-specific T-cell responses were determined by IFNgamma Elispot and by the secretion of IFNgamma, IL13, IL10, IL17, and IL21 in cell culture supernatants. Circulating CD4+CXCR5+ICOS+IL21+ cells were analyzed by flow cytometry, and meningococcal and TT-specific IgG responses by bead-based immunoassays. The correlation between the T-cell help and humoral responses was evaluated. RESULTS: Vaccination with a TT carrier protein induced a mixed TT-specific Th1 (IFNgamma), Th2 (IL13, IL10), and Th17 (IL17) response in most participants. Additionally, circulating CD4+CXCR5+ICOS+IL21+ cells were significantly increased 7days post-vaccination. Pre-vaccination TT-specific cytokine production and post-vaccination Th2 responses correlated positively with the increase of CD4+CXCR5+ICOS+IL21+ cells. No correlation between T-cell help and antibody responses was found. CONCLUSION: The characteristics of the T-cell response upon a TT-carrier vaccination suggests effective T-cell help towards B-cells in response to meningococcal polysaccharides, although the absence of a correlation with the antibody responses warrants further clarification. However, the robust T-helper cell response in middle-aged adults, decades after previous TT vaccinations, strengthens the classification of this age group for future vaccine interventions in the context of population ageing. PMID- 28882445 TI - Strong influence of human leukocyte antigen-DP variants on response to hepatitis B vaccine in a Japanese population. AB - Genome-wide association studies (GWASs) have reported that human leukocyte antigen (HLA) variants are associated with chronic hepatitis B, spontaneous hepatitis B virus (HBV) clearance, and response to hepatitis B vaccine. Single nucleotide polymorphisms (SNPs) in HLA-DP (rs9277535 and rs3077) and HLA-DQ (rs2856718 and rs7453920) have been repeatedly associated with chronic hepatitis B and spontaneous HBV clearance. However, the data on the SNPs associated with response to hepatitis B vaccine are inconclusive. The objective of this study was to determine whether these four HLA SNPs that have been identified as risk loci for chronic HBV infection are associated with response to hepatitis B vaccine in a Japanese population. We enrolled 278 medical students who received hepatitis B vaccination and measured anti-hepatitis B surface (HBs) antibody titers 1month after a three-dose vaccination series. We found that rs9277535 and rs3077 in HLA DP were strongly associated with response to hepatitis B vaccine (odds ratio [OR]=0.31 and 0.32, P=0.004 and 0.010, respectively). These two SNPs were significantly associated with anti-HBs titers in an allele-dependent manner. On the other hand, rs2856718 and rs7453920 in HLA-DQ were not associated with response to hepatitis B vaccine. These results indicate that rs9277535 and rs3077 in HLA-DP are the major determinants of response to hepatitis B vaccine, whereas rs2856718 and rs7453920 in HLA-DQ have little effect on the immune response to hepatitis B vaccine. PMID- 28882446 TI - Relationship between Mixed Donor-Recipient Chimerism and Disease Recurrence after Hematopoietic Cell Transplantation for Sickle Cell Disease. AB - Mixed donor chimerism after hematopoietic cell transplantation for sickle cell disease (SCD) can result in resolution of disease symptoms, but symptoms recur when donor chimerism is critically low. The relationship between chimerism, hemoglobin S (HbS) level, and symptomatic disease was correlated retrospectively in 95 patients who had chimerism reports available at day 100 and at 1 and 2 years after transplantation. Recurrent disease was defined as recurrence of vaso occlusive crises, acute chest syndrome, stroke, and/or HbS levels > 50%. Thirty five patients maintained full donor chimerism (myeloid or whole blood) through 2 years. Donor chimerism was less than 10% (defined as graft failure) in 13 patients during this period. Mixed chimerism was reported in the remaining 47 patients (range, 10% to 94%). The lowest documented donor chimerism without symptomatic disease was 26%. Of 12 surviving patients with recurrent disease, 2 had recurrence of symptoms before documented graft failure (donor chimerism of 11% and 17%, respectively). Three patients underwent second transplantation for graft failure. None received donor leukocyte infusion to maintain mixed chimerism or prevent graft failure. We conclude stable donor chimerism greater than 25% is associated with resolution of SCD-related symptoms, and HbS levels in transplant recipients should be interpreted in context of the sickle trait status of the donors. PMID- 28882447 TI - Improving the Informed Consent Process in Hematopoietic Cell Transplantation: Patient, Caregiver, and Provider Perspectives. AB - One of the significant modifications to the Common Rule is the requirement that prospective participants be given information sufficient for a "reasonable person." However, research is limited on what types of information patients, caregivers, and providers consider "key information." Although certain aspects of informed consent (IC) may be considered standard, considering the individualized needs and preferences of patients is necessary for patient-centered consent. In this study, we qualitatively examined the specific types of information that patients and caregivers involved in hematopoietic cell transplantation (HCT), as well as their providers, believe to be important and necessary as part of the IC process to make a decision about participating in clinical research; and further, how these perspectives are aligned. Our findings suggest opportunities for improving the IC document and process by emphasizing information of importance to patients, such as the benefits to others and contributions to science that are associated with participation in clinical research. Furthermore, increasing patient engagement during the IC process may allow providers to streamline information that is aligned with patient information needs and preferences. PMID- 28882448 TI - Paenibacillus ihbetae sp. nov., a cold-adapted antimicrobial producing bacterium isolated from high altitude Suraj Tal Lake in the Indian trans-Himalayas. AB - The assessment of bacterial diversity and bioprospection of the high-altitude lake Suraj Tal microorganisms for potent antimicrobial activities revealed the presence of two Gram-stain-variable, endospore-forming, rod-shaped, aerobic bacteria, namely IHBB 9852T and IHBB 9951. Phylogenetic analysis based on 16S rRNA gene sequence showed the affiliation of strains IHBB 9852T and IHBB 9951 within the genus Paenibacillus, exhibiting the highest sequence similarity to Paenibacillus lactis DSM 15596T (97.8% and 97.7%) and less than 95.9% similarity to other species of the genus Paenibacillus. DNA-DNA relatedness among strains IHBB 9852T and IHBB 9951 was 90.2%, and with P. lactis DSM 15596T, was 52.7% and 52.4%, respectively. The novel strains contain anteiso-C15:0, iso-C15:0, C16:0 and iso-C16:0 as major fatty acids, and phosphatidylglycerol, phosphatidylethanolamine and diphosphatidylglycerol were predominant polar lipids. The DNA G+C content for IHBB 9852T and IHBB 9951 was 52.1 and 52.2mol%. Based on the results of phenotypic and genomic characterisations, we concluded that strains IHBB 9852T and IHBB 9951 belong to a novel Paenibacillus species, for which the name Paenibacillus ihbetae sp. nov. is proposed. The type strain is IHBB 9852T (=MTCC 12459T=MCC 2795T=JCM 31131T=KACC 19072T; DPD TaxonNumber TA00046) and IHBB 9951 (=MTCC 12458=MCC 2794=JCM 31132=KACC 19073) is a reference strain. PMID- 28882449 TI - Contribution of backward and forward wave pressures to age-related increases in aortic pressure in a community sample not receiving antihypertensive therapy. AB - Reports on the contribution of aortic forward (Pf) and backward (Pb) wave pressures to age-related increases in central aortic pulse pressure (PPc) have been confounded by the use of participants receiving antihypertensive therapy. We assessed the relative contribution of Pf and Pb to age-related increases in PPc (radial applanation tonometry and SphygmoCor software using an assumed triangular wave for wave separation analysis) in 892 community participants not receiving antihypertensive therapy. We validated our results using aortic flow waves (echocardiography) for wave separation analysis in 254 of these participants. In multivariate regression models in those aged <50 years, adjustments for both Pb and a Pf-independent measure of reflected wave function (RM = Pb/Pf), but not Pf abolished the impact of age on PPc. However, in those aged >50 years, adjustments for Pf (beta-coefficient: 0.25 +/- 0.06 vs. 0.74 +/- 0.08; P < .0001) and Pb (0.04 +/- 0.04 vs. 0.74 +/- 0.08; P < .0001), but not RM markedly decreased the relationship between age and PPc. On product of coefficient mediation analysis, whether assessed in men or in women, in those participants aged <50 years, independent of several confounders and mean arterial pressure, Pb (P < .005), but not Pf contributed to age-related increases in PPc. In contrast, in those participants aged >=50 years, independent of several confounders and mean arterial pressure, Pb (P < .005) and Pf (P < .01) contributed to age-related increases in PPc, and Pb effects were markedly diminished by adjustments for Pf (0.26 +/- 0.002 vs. 0.52 +/- 0.003 mm Hg per year, P < .0001 for comparison). In conclusion, independent of the effects of antihypertensive therapy, aortic backward waves contribute to age-related increases in aortic PPc across the adult lifespan, but at an older age, this effect may be attributed in part to the impact of forward on backward wave pressures. PMID- 28882450 TI - The 8-oxo-deoxyguanosine glycosylase increases its migration to mitochondria in compensated cardiac hypertrophy. AB - Cardiac hypertrophy is a compensatory mechanism maladapted because it presents an increase in the oxidative stress which could be associated with the development of the heart failure. A mechanism proposed is by mitochondrial DNA (mtDNA) oxidation, which evolved to a vicious cycle because of the synthesis of proteins encoded in the genome is committed. Therefore, the aim of the present work was to evaluate the mtDNA damage and enzyme repairing the 8-oxo-deoxyguanosine glycosylase mitochondrial isoform 1-2a (OGG1-2a) in the early stage of compensated cardiac hypertrophy induced by abdominal aortic constriction (AAC). Results showed that after 6 weeks of AAC, hearts presented a compensated hypertrophy (22%), with an increase in the cell volume (35%), mitochondrial mass (12%), and mitochondrial membrane potential (94%). However, the increase of oxidative stress did not affect mtDNA most probably because OGG1-2a was found to increase 3.2 times in the mitochondrial fraction. Besides, mitochondrial function was not altered by the cardiac hypertrophy condition but in vitro mitochondria from AAC heart showed an increased sensibility to stress induced by the high Ca2+ concentration. The increase in the oxidative stress in compensated cardiac hypertrophy induced the OGG1-2a migration to mitochondria to repair mtDNA oxidation, as a mechanism that allows maintaining the cardiac function in the compensatory stage. PMID- 28882451 TI - Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer. AB - Small activating RNAs (saRNAs) are short double-stranded oligonucleotides that selectively increase gene transcription. Here, we describe the development of an saRNA that upregulates the transcription factor CCATT/enhancer binding protein alpha (CEBPA), investigate its mode of action, and describe its development into a clinical candidate. A bioinformatically directed nucleotide walk around the CEBPA gene identified an saRNA sequence that upregulates CEBPA mRNA 2.5-fold in human hepatocellular carcinoma cells. A nuclear run-on assay confirmed that this upregulation is a transcriptionally driven process. Mechanistic experiments demonstrate that Argonaute-2 (Ago2) is required for saRNA activity, with the guide strand of the saRNA shown to be associated with Ago2 and localized at the CEBPA genomic locus using RNA chromatin immunoprecipitation (ChIP) assays. The data support a sequence-specific on-target saRNA activity that leads to enhanced CEBPA mRNA transcription. Chemical modifications were introduced in the saRNA duplex to prevent activation of the innate immunity. This modified saRNA retains activation of CEBPA mRNA and downstream targets and inhibits growth of liver cancer cell lines in vitro. This novel drug has been encapsulated in a liposomal formulation for liver delivery, is currently in a phase I clinical trial for patients with liver cancer, and represents the first human study of an saRNA therapeutic. PMID- 28882452 TI - AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy. AB - The lack of technology for direct global-scale targeting of the adult mouse nervous system has hindered research on brain processing and dysfunctions. Currently, gene transfer is normally achieved by intraparenchymal viral injections, but these injections target a restricted brain area. Herein, we demonstrated that intravenous delivery of adeno-associated virus (AAV)-PHP.B viral particles permeated and diffused throughout the neural parenchyma, targeting both the central and the peripheral nervous system in a global pattern. We then established multiple procedures of viral transduction to control gene expression or inactivate gene function exclusively in the adult nervous system and assessed the underlying behavioral effects. Building on these results, we established an effective gene therapy strategy to counteract the widespread accumulation of alpha-synuclein deposits throughout the forebrain in a mouse model of synucleinopathy. Transduction of A53T-SCNA transgenic mice with AAV PHP.B-GBA1 restored physiological levels of the enzyme, reduced alpha-synuclein pathology, and produced significant behavioral recovery. Finally, we provided evidence that AAV-PHP.B brain penetration does not lead to evident dysfunctions in blood-brain barrier integrity or permeability. Altogether, the AAV-PHP.B viral platform enables non-invasive, widespread, and long-lasting global neural expression of therapeutic genes, such as GBA1, providing an invaluable approach to treat neurodegenerative diseases with diffuse brain pathology such as synucleinopathies. PMID- 28882453 TI - Molecular cloning, biochemical characterization, and expression analysis of two glutathione S-transferase paralogs from the big-belly seahorse (Hippocampus abdominalis). AB - Glutathione S-transferases (GSTs, EC 2.5.1.18) are important Phase II detoxifying enzymes that catalyze hydrophobic, electrophilic xenobiotic substance with the conjugation of reduced glutathione (GSH). In this study, GSTMU and GSTrho paralogs of GST in the big belly seahorse (Hippocampus abdominalis; HaGSTrho, HaGSTMU) were biochemically, molecularly, functionally characterized to determine their detoxification range and protective capacities upon different pathogenic stresses. HaGSTrho and HaGSTMU are composed of coding sequences of 681bp and 654bp, which encode proteins 225 and 217 amino acids, with predicted molecular masses of 26.06kDa and 25.74kDa respectively. Sequence analysis revealed that both HaGSTs comprise the characteristic GSH-binding site in the thioredoxin-like N-terminal domain and substrate binding site in the C-terminal domain. The recombinant HaGSTrho and HaGSTMU proteins catalyzed the model GST substrate 1 chloro-2, 4-dinitrobenzene (CDNB). Enzyme kinetic analysis revealed different Km and Vmax values for each rHaGST, suggesting that they have different conjugation rates. The optimum conditions (pH, temperature) and inhibitory assays of each protein demonstrated different optimal ranges. However, HaGSTMU was highly expressed in the ovary and gill, whereas HaGSTrho was highly expressed in the gill and pouch. mRNA expression of HaGSTrho and HaGSTMU was significantly elevated upon lipopolysaccharide, Poly (I:C), and Edwardsiella tarda challenges in liver and in blood cells as well as with Streptococcus iniae challenge in blood cells. From these collective experimental results, we propose that HaGSTrho and HaGSTMU are effective in detoxifying xenobiotic toxic agents, and importantly, their mRNA expression could be stimulated by immunological stress signals in the aquatic environment. PMID- 28882455 TI - Assessment of the discriminating value of the 8th AJCC stage grouping for hepatocellular carcinoma. AB - BACKGROUND: This study seeks to validate the discriminating value of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for Hepatocellular carcinoma (HCC) amongst patients registered within the surveillance, epidemiology and end results (SEER) database. METHODS: Through SEER*Stat program, SEER database (2010-2013) was queried and 8th AJCC stage groups were reconstructed. Overall and cancer-specific survival analyses according to both 7th and 8th editions were conducted through Kaplan-Meier analysis/log-rank testing and multivariate analysis was conducted through a Cox proportional model. RESULTS: For overall and cancer-specific survival assessment according to the 8th edition, P values for pair wise comparisons among different stages were significant (<0.001) in all comparisons except for stage IB vs. II/stage IIIB vs. stage IVA. A modified AJCC 8th staging system was suggested through collapsing stages IB/II into one stage and stages IIIB/IVA into one stage. Overall and cancer-specific survivals were compared according to this modified system and pair wise P value was significant in all comparisons (P < 0.001). CONCLUSION: There is a minimal improvement in discriminating value for the 8th edition compared to the 7th edition; however, notable overlap in outcomes is still observed between stages IB/II and IIIB/IVA. A modified AJCC 8th system collapsing these overlapping stages may be more clinically relevant. PMID- 28882454 TI - Understanding Immunity through the Lens of Disease Ecology. AB - As we describe the immune system in ever more exquisite detail, we might find that no matter how successful, this approach will not be sufficient to understand the spread of infectious agents, their susceptibility to vaccine therapy, and human disease resistance. Compared with the strict reductionism practiced as a means of characterizing most biological processes, I propose that the progression and outcome of disease-causing host-parasite interactions will be more clearly understood through a focus on disease ecology. PMID- 28882456 TI - Predicting adverse events in patients undergoing hepatectomy-validation of preoperative nomogram and risk score. AB - BACKGROUND/PURPOSE: Much research exists on preoperative measures of postoperative mortality in the surgical treatment of liver malignancies, but little on morbidity, a more common outcome. This study aims (i) to validate the published calculations as acceptable measures of postoperative mortality and (ii) to assess the value of these published measures in predicting postoperative morbidity. METHODS: Data were collected from a prospectively managed dataset of 1059 hepatectomies performed in Louisville, Kentucky from December 1990 to April 2014. Preoperative data were used to assign scores for each of two published measures and the scores were sorted into clinically relevant groups with corresponding ordinal scores, according to the previously published literature (Dhir nomogram and Simons risk score). RESULTS: After selection, 851 hepatectomies were analyzed. Both the Dhir nomogram (p = 0.0004) and Simons risk score (p = 0.0017) were acceptable predictors of postoperative mortality. In the analysis of morbidity, Dhir scores were a poor predictor of morbidity. The Simons ordinal risk score was predictive of complications (p = 0.0029), the number of complications (p = 0.0028), complication grade (p = 0.0033), and hepatic-specific complications (p = 0.0003). CONCLUSION: The Simons ordinal risk score can be useful in assessing postoperative morbidity among hepatectomy patients. PMID- 28882457 TI - Characterization of dermal myofibroblast differentiation in pseudoxanthoma elasticum. AB - Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder which is caused by ABCC6 (ATP-binding cassette subfamily C member 6) gene mutations. Characteristic hallmarks of PXE are progressive calcification and degradation of the elastic fibers in skin, cardiovascular system and ocular fundus. Since the underlying pathomechanisms of PXE remain unidentified, the aim of this study was to get new insights into PXE pathophysiology by characterizing dermal myofibroblast differentiation. Fibroblasts are the key cells of extracellular matrix (ECM) remodeling and, therefore, participate not only in physiological processes, such as calcification or wound healing, but also in pathologic events, such as fibrotization. We revealed that human dermal PXE fibroblasts possess exaggerated migration capability in wound healing and attenuated myofibroblast contractility in comparison to controls. Subsequent analyses reinforced these observations and indicated a diminished induction of the myofibroblast differentiation markers alpha-smooth muscle actin and xylosyltransferase-I as well as poor transforming growth factor-beta1 responsiveness in PXE fibroblasts. In summary, we describe pathological deviations of dermal myofibroblast differentiation in PXE which might be mediated by aberrant supramolecular ECM organization. These results not only improve our insights into cellular PXE pathophysiology, but might also qualify us to interfere with ECM remodeling in the future. PMID- 28882458 TI - Opioid Prescribing Education in Surgical Residencies: A Program Director Survey. AB - BACKGROUND: Opioid abuse and misuse is a public health crisis. A national effort to reduce this phenomenon is ongoing. Residents represent a large pool of opioid prescribers but, are often not the target for opioid prescribing education (OPE). We developed a survey to assess current opioid prescribing practices and education among surgical residents. STUDY DESIGN: An Institutional Review Board and Association of Program Directors in Surgery approved survey was electronically mailed to surgical program directors (PDs). The survey included questions regarding residency type, location, number of graduates per year, perceived value of OPE, residency policy on prescribing outpatients controlled substances, presence of OPE, and preferred method of OPE. MATERIALS AND METHODS: A total of 248 PDs were e-mailed the survey with 110 complete responses (44.4%). Of all 104 (94.5%) allow residents to prescribe outpatient opioids with 24 (23.1%) limiting the opioid class prescribed. A total of 29 (27.9%) programs require residents to obtain their own Drug Enforcement Administration registration. Only 22 (20.0%) programs had in place mandatory OPE, 7 (6.4%) PDs were unsure if OPE was a mandatory educational requirement. Furthermore, 70 (79.5%) of programs currently without OPE are considering adding it. Didactic lecture (18, 81.8%) is the most common modality for OPE. The mode time dedicated to OPE was 1 hour. When PDs were asked about which method would be best to deliver OPE, the most common response was case-based scenarios (39, 35.5%). Bivariate statistics were performed and no association was found between OPE and program characteristics'. CONCLUSIONS: Most surgical residency programs allow residents to prescribe outpatient opioids, very few require OPE. The most common method of OPE was didactic lectures. To enhance a resident's knowledge in prescribing opioids, programs should incorporate OPE into their curriculum. PMID- 28882459 TI - Compliance of secondary production and eco-exergy as indicators of benthic macroinvertebrates assemblages' response to canopy cover conditions in Neotropical headwater streams. AB - Riparian vegetation cover influences benthic assemblages structure and functioning in headwater streams, as it regulates light availability and autochthonous primary production in these ecosystems.Secondary production, diversity, and exergy-based indicators were applied in capturing how riparian cover influences the structure and functioning of benthic macroinvertebrate assemblages in tropical headwater streams. Four hypotheses were tested: (1) open canopy will determine the occurrence of higher diversity in benthic macroinvertebrate assemblages; (2) streams with open canopy will exhibit more complex benthic macroinvertebrate communities (in terms of information embedded in the organisms' biomass); (3) in streams with open canopy benthic macroinvertebrate assemblages will be more efficient in using the available resources to build structure, which will be reflected by higher eco-exergy values; (4) benthic assemblages in streams with open canopy will exhibit more secondary productivity. We selected eight non-impacted headwater streams, four shaded and four with open canopy, all located in the Neotropical savannah (Cerrado) of southeastern Brazil. Open canopy streams consistently exhibited significantly higher eco-exergy and instant secondary production values, exemplifying that these streams may support more complex and productive benthic macroinvertebrate assemblages. Nevertheless, diversity indices and specific eco exergy were not significantly different in shaded and open canopy streams. Since all the studied streams were selected for being considered as non-impacted, this suggests that the potential represented by more available food resources was not used to build a more complex dissipative structure. These results illustrate the role and importance of the canopy cover characteristics on the structure and functioning of benthic macroinvertebrate assemblages in tropical headwater streams, while autochthonous production appears to play a crucial role as food source for benthic macroinvertebrates. This study also highlights the possible application of thermodynamic based indicators as tools to guide environmental managers in developing and implementing policies in the neotropical savannah. PMID- 28882460 TI - Elemental and radiological characterization of commercial Cetraria islandica (L.) Acharius pharmaceutical and food supplementation products. AB - An elemental and radiological characterization was performed on Cetraria islandica (L.) Ach. pharmaceutical and food supplementation products purchased in local specialty shops in Italy. Essential elements (K, Ca, P, S, Cl, Mn, Fe, Cu, Zn, Ni, Br, I) and nonessential or toxic elements (Al, Ti, Si, Rb, Sr, As, Cd, Sn, and Pb) were determined by Energy Dispersive Polarized X-Ray Fluorescence Spectrometry; natural radionuclides (238U, 234U, 230Th, 210Po, 232Th, and 228Th) were determined by alpha spectrometry. The results show that C. islandica, whose nutritional value was assessed referring to recommended nutrient intakes, could serve as an important source of essential elements. Moreover, as expected, lichens concentrate airborne 210Po, whose activity ranged from 132 to 489Bqkg 1dw. This value was much higher than those reported by UNSCEAR for leafy vegetables in the world. In addition, total As and Cd were <1mgkg-1dw and Pb mean concentration was 9.25mgkg-1dw. Health risks associated with the toxic elements contained in C. islandica (L.) products were calculated using risk estimators. Their contribution to total elemental intake does not appear to pose a threat, but the concentrations of these elements should be continuously monitored to protect consumers against potential adverse health effects. PMID- 28882461 TI - A rare giant chronic polypoidal endocervicits in a premenopausal woman; case report. PMID- 28882462 TI - Successful management of a severe anti-M alloimmunization during pregnancy. AB - We report the successful outcome of a patient with anti-M antibodies with a previous history of severe hemolysis of erythrocytes. Serial plasma exchange from the first trimester combined with ultrasound monitoring of the fetal middle cerebral artery blood velocity was implemented. This management allowed a favorable pregnancy outcome of an infant born by an elective caesarean section at 32 weeks 6/7 with a normal Apgar score at 8/9/10. The other therapeutic alternatives such as intravenous immunoglobulin and in utero fetal blood transfusions are discussed. PMID- 28882463 TI - Neonatal outcomes after failed tracheal intubation during obstetric general anaesthesia for caesarean section: Secondary analysis of a UKOSS case-control study. PMID- 28882464 TI - Metacarpophalangeal joint of the thumb arthrodesis using intramedullary interlocking screws XMCPTM. AB - The study objective was to assess the results of a thumb metacarpophalangeal joint (MCPJ) arthrodesis using intramedullary interlocking screws at 25 degrees , XMCP TM (Extremity Medical, Parsippany, NJ). Radiographs evaluated the angle of arthrodesis, time of fusion and fixation of the implant. Clinical and functional outcomes were assessed using the DASH questionnaire and the VAS scale. Any complications found during surgery or the follow-up period were noted. We studied 9 patients. The mean follow-up was 27.6 months. Patients showed clinical and radiological evidence of fusion in an average of 8 weeks, the angle of fusion was 25 degrees . There were no complications and no implant had to be removed. The XMCPTM system provides a reliable method for MCPJ arthrodesis for several indications and can be used with other procedures in the complex hand. PMID- 28882465 TI - Remote cerebellar hemorrhage caused by undetected dural tear after lumbar spinal surgery. AB - Remote cerebellar haemorrhage is a rare but serious complication after spinal surgery. Although the mechanism is not well known, it always occurs after loss of cerebrospinal fluid due to dural tear, not always identified, which produces remote venous bleeding. Prognosis depends largely on the severity of this bleeding. We report a case of 67-year-old female who suffered a cerebellar and subarachnoid haemorrhage and subdural haematoma after elective lumbar fusion surgery and eventually required decompressive craniectomy. PMID- 28882466 TI - A low degree of high ambient temperature decreased food intake and activated median preoptic and arcuate nuclei. AB - High ambient temperature (HTa) activates both behavioral and autonomic responses. Decreased food intake (FI) is a well-known behavioral response under HTa. In general, this behavioral response seems to be mediated under the activation of the stress axis. The present study, however, revealed that decreased FI after a low degree of HTa appeared to be activated earlier than stress axis activation. By comparing low and high levels of HTa exposure in rats, the present experiment demonstrated that the HTa-induced decrease in FI was clear in both conditions. However, only the high degree HTa rats showed prominent physiological responses to HTa. The results indicated that low degree HTa exposure decreased FI earlier than activated physiological responses. Using the low degree HTa condition, the next experiment revealed that only the median preoptic nucleus (MnPO) and arcuate nucleus (Arc) were activated. These results suggested that the MnPO and Arc (MnPO Arc) are apparently involved in the low degree HTa effect on FI and that the paraventricular hypothalamic nucleus, which is the upper part of the stress axis, was not associated with this effect. A separate experiment also showed no differences in the corticotropin-releasing factor (CRF) concentrations from many selected nuclei. This result suggested that the effect of HTa to decrease FI via the MnPO-Arc was not associated with CRF. The current findings introduce a new behavioral aspect of the HTa effect on FI, representing important information to explain the mechanism of obesity relative to environmental conditions. PMID- 28882467 TI - Muscle activation behavior in a swimming exergame: Differences by experience and gaming velocity. AB - The effects of playing intensity and prior exergame and sport experience on the activation patterns of upper limb muscles during a swimming exergame were investigated. Surface electromyography of Biceps Brachii, Triceps Brachii, Latissimus Dorsi, Upper Trapezius, and Erector Spinae of twenty participants was recorded, and the game play was divided into normal and fast. Mean muscle activation, normalized to maximum voluntary isometric contraction (MVIC), ranged from 4.9 to 95.2%MVIC and differed between normal and fast swimming for all techniques (p<0.05), except for Latissimus Dorsi during backstroke. After normalizing the %MVIC to playing velocity, selective behaviors were observed between muscles which were sufficient for pragmatic game play. Moreover, prior exergame and real sport experience did not have any effect on the muscle activation changes between normal and fast swimming. These behaviors are likely to happen when players understand the game mechanics, even after a short exposure. Such evaluation might help in adjusting the physical demands of sport exergames, for safe and meaningful experiences. PMID- 28882468 TI - Inclusive design in architectural practice: Experiential learning of disability in architectural education. AB - BACKGROUND: The built environment can facilitate or impede an individual's ability to participate in society. This is particularly so for people with disability. Architects are well placed to be advocates for design that enhances societal equality. OBJECTIVE: This qualitative study explored architectural design students' perceptions of inclusive design, their reflections resulting from an experiential learning module and the subsequent influence of these on their design practice. METHODS: Twenty four architectural design students participated in focus groups or individual interviews. Data were analyzed thematically. RESULTS: Three themes were evident: 1) Inclusive design was perceived as challenging, 2) Appreciation for the opportunity to learn about the perspectives of people with disabilities, and 3) Change of attitude toward inclusive design. Experiential learning had fostered reflection, changes in attitude and the realization that inclusive design, should begin at the start of the design process. CONCLUSIONS: For equitable access for all people to become reality, experiential learning, coupled with positive examples of inclusive design should be embedded in architectural education. PMID- 28882469 TI - Inverse association between excessive alcohol drinking and cardiometabolically healthy status in middle-aged men with and without overweight and obesity. AB - AIMS: The aim of this study was to clarify the relationship between drinking and metabolically healthy status in men with normal weight, overweight and obesity. METHODS: The subjects were Japanese men aged from 35 to 60 years (n=31781) and they were divided by daily amount of drinking (g ethanol) into light (< 22), moderate (>=22 and <44), heavy (>=44 and <66) and very heavy (>=66) drinkers. Metabolically healthy subjects were defined as those without hypertension, dyslipidemia and diabetes. RESULTS: The percentage of metabolically healthy subjects was much lower in the overweight (BMI>=25 and <30) and obese (BMI>=30) groups than in the normal weight group (BMI>=18.5 and <25) and was much lower in the obese group than in the overweight group. In each of the normal weight and overweight groups, percentages of metabolically healthy subjects were significantly lower in heavy and very heavy drinkers than in nondrinkers and were marginally significantly higher in light drinkers than in nondrinkers. The above associations between drinking and metabolically healthy status were confirmed by logistic regression analysis. In the obese group, the percentage of metabolically healthy subjects was significantly lower in regular drinkers (including all drinker categories) than in nondrinkers, and metabolically healthy subjects were rare (0.56%) among regular drinkers. CONCLUSIONS: Regardless of absence and presence of overweight or obesity, excessive alcohol drinking is inversely associated with metabolically healthy status and should be avoided for prevention of cardiovascular disease. PMID- 28882470 TI - An observational study of vitamin b12 levels and peripheral neuropathy profile in patients of diabetes mellitus on metformin therapy. AB - METHODS: A descriptive, observational study was completed in a tertiary care hospital between November 2014 and March 2016. Fifty consecutive patients of Type 2-Diabetes Mellitus who had been on metformin therapy for at least three months were included in our study. Several Parameters were compared with vitamin B12 levels and severity of peripheral neuropathy (using Toronto Clinical Scoring System (TCSS) and Nerve Conduction Velocity). These included the duration of diabetes, duration of metformin usage, dietary history, and HbA1c levels. Definite B12 deficiency was defined as B12<150pg/ml and possible B12 deficiency as <220pg/ml. RESULTS: In our study, we found a negative correlation between duration of metformin use and Vitamin B12 levels(r=-0.40). The mean Vitamin B12 levels seen in our study was 212.3pg/mL. There is a positive correlation between the duration of metformin therapy and peripheral neuropathy (r=0.40). The mean TCSS score was 6.8. The percentage of patients with mild neuropathy was 28%, with moderate neuropathy was 20% and severe neuropathy in 12% of the patients. The average duration of metformin use in patients without peripheral neuropathy was 5.5yrs whereas the average length of metformin use in patients with peripheral neuropathy was 10.4 yrs. CONCLUSION: Patients on long-term metformin therapy are at a high risk for Vitamin B12 deficiency and peripheral neuropathy. Interval Screening for peripheral neuropathy is recommended for patients on metformin even if Vitamin B12 levels appear to be normal. PMID- 28882471 TI - Arginine vasopressin improves the memory deficits in Han Chinese patients with first-episode schizophrenia. AB - The memory impairment is a core deficit in the first-episode schizophrenia patients. Arginine vasopressin (AVP) in the brain can improve learning and memory. We performed multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial to study the cognitive functioning in Han Chinese first-episode schizophrenic patients in a 12-week treatment regime with the intranasal administration of AVP (128 cases) or placebo (131 cases) in addition to the conventional treatment. The methods of positive and negative syndrome scale (PANSS), Wechsler memory scale-4th edition (WMS-IV) and event-related potential (ERP) were used to study the effects of AVP on the cognitive function. The results showed that (1) AVP concentration decreased in cerebrospinal fluid (CSF) of the right-handed Han Chinese first-episode schizophrenic patients comparing with that of the health volunteers (7.1+/-1.5pg/ml vs 13.3+/-1.9pg/ml, p<0.01), and did not change in plasma; (2) AVP significantly improved PANSS scores including total scores, positive symptoms, negative symptoms and general psychopathology comparing with those of the placebo group; (3) AVP elevated WMS IV scores including the long-term memory (accumulation), short-term memory (recognition, comprehension), immediate memory (number recitation) and memory quotient 4, 8 and 12 weeks after treatment; and (4) AVP did not influence the latency and wave amplitude of target stimulus of P300 of right-handed Han Chinese first-episode schizophrenic patients. The data suggested that AVP might improve cognitive process, such as memorizing and extraction of the information although there were many changes of cognitive functions in the right-handed Han Chinese first-episode schizophrenic patients. PMID- 28882472 TI - Overwhelming Streptococcus pyogenes sepsis in an elderly patient with septic arthritis. AB - INTRODUCTION: The signs of Streptococcus pyogenes, group A streptococci (GAS) bacteremia are non-specific and patients can have wide presentations ranging from flu-like symptoms to life-threatening toxic-shock syndrome in just a few hours. CASE PRESENTATION: We report a case of fulminant S. pyogenes sepsis in an elderly woman with septic arthritis and remarkable past medical history/risk factors. She was febrile, hypotensive and had a swollen and tender right knee. Multiple blood cultures and the synovial fluid culture yielded S. pyogenes. Despite adequate antimicrobial therapy with penicillin and clindamycin the patient succumbed to her infection within 4days of presentation in our hospital. CONCLUSION: GAS remains penicillin sensitive most of the time but prompt appropriate antibiotic therapy is very crucial to survival. PMID- 28882474 TI - Postpartum inhibition of ovarian steroid action increases aspects of maternal caregiving and reduces medial preoptic area progesterone receptor expression in female rats. AB - The rapid peripartum onset of maternal caregiving involves progesterone synergizing with estradiol, but prolonging progesterone exposure past this time can prevent the emergence of mothering. Interestingly, there is a 7-10day-long rise in progesterone during mid-lactation, but its effects on mothering are unknown. Given progesterone's potential to inhibit mothering onset, this mid lactational rise may contribute to the normal attenuation of caregiving behaviors across lactation. To evaluate this, recently-parturient rats were ovariectomized and caregiving observed from postpartum days (PPD) 7-18. Ovariectomized dams were found to lick, hover over, and nurse in kyphosis more frequently than controls. Ovariectomy also decreased medial preoptic area (mPOA) progesterone receptor (PR) mRNA, which was negatively correlated with pup licking and kyphosis, but it did not affect mPOA levels of oxytocin receptor or vasopressin V1a receptor mRNAs. In a second study, gonadally intact dams were given the PR antagonist, RU 486, and were found to display more kyphosis and less supine nursing compared to controls. Finally, progesterone sensitivity across lactation was examined by measuring numbers of PR immunoreactive (PR-ir) cells in the mPOA, ventral bed nucleus of the stria terminalis (BSTv) and periaqueductal gray (PAG). PR-ir was higher in the mPOA at parturition compared to virgins, while PR-ir in the mPOA and BSTv dropped from parturition to PPD 7 and remained low through PPD 18. The number of PR-ir cells in the PAG was constant. Thus, in addition to their well-known prepartum effects, ovarian hormones limit the display of some maternal behaviors during mid-to-late lactation and contribute to their decline as weaning approaches. PMID- 28882473 TI - Age-related changes in sexual function and steroid-hormone receptors in the medial preoptic area of male rats. AB - Testosterone is the main circulating steroid hormone in males, and acts to facilitate sexual behavior via both reduction to dihydrotestosterone (DHT) and aromatization to estradiol. The mPOA is a key site involved in mediating actions of androgens and estrogens in the control of masculine sexual behavior, but the respective roles of these hormones is not fully understood. As males age they show impairments in sexual function, and a decreased facilitation of behavior by steroid hormones compared to younger animals. We hypothesized that an anatomical substrate for these behavioral changes is a decline in expression and/or activation of hormone receptor-sensitive cells in the mPOA. We tested this by quantifying and comparing numbers of AR- and ERalpha-containing cells, and Fos as a marker of activated neurons, in the mPOA of mature (4-5months) and aged (12 13months) male rats, assessed one hour after copulation to one ejaculation. Numbers of AR- and ERalpha cells did not change with age or after sex, but the percentage of AR- and ERalpha-cells that co-expressed Fos were significantly up regulated by sex, independent of age. Age effects were found for the percentage of Fos cells that co-expressed ERalpha (up-regulated in the central mPOA) and the percentage of Fos cells co-expressing AR in the posterior mPOA. Interestingly, serum estradiol concentrations positively correlated with intromission latency in aged but not mature animals. These data show that the aging male brain continues to have high expression and activation of both AR and ERalpha in the mPOA with copulation, raising the possibility that differences in relationships between hormones, behavior, and neural activation may underlie some age-related impairments. PMID- 28882476 TI - [Upper lip lift]. AB - The author revisits an old technique of shortening of the upper lip. He shows the interest of systematically analyzing the length of the upper lip in any consultation of face and especially of rejuvenation. He develops indications based on the visibility of the upper incisors at the half-open mouth rest. He details the technique and shows results. PMID- 28882475 TI - [Use of Harmonic blade in face lifting]. AB - INTRODUCTION: Rapid recovery and return to social activities are what every patient wishes when considering to undergo a face lifting procedure. In our practice, the use of the Harmonic scalpel in order to achieve this goal has greatly improved the postoperative period. PATIENTS AND METHODS: We have performed 920 face lifting procedures exclusively using the Harmonic scalpel from 2001 to May 2017. RESULTS: A retrospective chart review was performed. Mean operative time was 110minutes for facelift involving SMAS plication only, and 180minutes for facelift involving SMAS plication with the addition of submental approach for anterior platysma plasty. Return to normal social life was achieved on the 8th postoperative day for the majority of cases. CONCLUSION: The use of the Harmonic scalpel, once properly integrated in the face lifting procedure, significantly reduces postoperative ecchymosis and oedema and allows a prompt return to normal social life. PMID- 28882477 TI - Possible role of tropomyosin-receptor kinase fused gene on skin collagen remodeling. PMID- 28882478 TI - Corrigendum to "The expression of Death Inducer-Obliterator (DIDO) variants in Myeloproliferative Neoplasms" [Blood Cells Mol. Dis. 59 (2016) 25-30]. PMID- 28882479 TI - Improved accuracy of lesion to symptom mapping with multivariate sparse canonical correlations. AB - Lesion to symptom mapping (LSM) is a crucial tool for understanding the causality of brain-behavior relationships. The analyses are typically performed by applying statistical methods on individual brain voxels (VLSM), a method called the mass univariate approach. Several authors have shown that VLSM suffers from limitations that may decrease the accuracy and reliability of the findings, and have proposed the use of multivariate methods to overcome these limitations. In this study, we propose a multivariate optimization technique known as sparse canonical correlation analysis for neuroimaging (SCCAN) for lesion to symptom mapping. To validate the method and compare it with mass-univariate results, we used data from 131 patients with chronic stroke lesions in the territory of the middle cerebral artery, and created synthetic behavioral scores based on the lesion load of 93 brain regions (putative functional units). LSM analyses were performed with univariate VLSM or SCCAN, and the accuracy of the two methods was compared in terms of both overlap and displacement from the simulated functional areas. Overall, SCCAN produced more accurate results - higher dice overlap and smaller average displacement - compared to VLSM. This advantage persisted at different sample sizes (N = 20-131) and different multiple comparison corrections (false discovery rate, FDR; Bonferroni; permutation-based family wise error rate, FWER). These findings were replicated with a fully automated SCCAN routine that relied on cross-validated predictive accuracy to find the optimal sparseness value. Simulations of one, two, and three brain regions showed a systematic advantage of SCCAN over VLSM; under no circumstance could VLSM exceed the accuracy obtained with SCCAN. When considering functional units composed of multiple brain areas VLSM identified fewer areas than SCCAN. The investigation of real scores of aphasia severity (aphasia quotient and picture naming) showed that SCCAN could accurately identify known language-critical areas, while VLSM either produced diffuse maps (FDR correction) or few scattered voxels (FWER correction). Overall, this study shows that a multivariate method, such as, SCCAN, outperforms VLSM in a number of scenarios, including functional dependency on single or multiple areas, different sample sizes, different multi-area combinations, and different thresholding mechanisms (FWER, Bonferroni, FDR). These results support previous claims that multivariate methods are in general more accurate than mass univariate approaches, and should be preferred over traditional VLSM approaches. All the methods described in this study are available in the newly developed LESYMAP package for R. PMID- 28882481 TI - Synergistic antiproliferative effect of chemo-phototherapy: Synthesis and photodynamic activity evaluation of novel Chlorin e6-artesunate conjugates as antiproliferative agents. AB - In order to increase the photodynamic effect of Chlorin e6, four Chlorin e6 artesunate conjugates were designed and synthesized. Among them, three conjugates (3, 6, 9) contained single artesunate side chain at 152, 173 and 131 of Chlorin e6, respectively, and one conjugate (11) contained three artesunate side chains. In the in vitro evaluation of photodynamic effect, the four conjugates showed more potent phototoxicity against HepG2 cells than Chlorin e6. The introduction of artesunate side chain significantly increased the intracellular ROS production, although the production of singlet oxygen was not improved. Compound 11 exhibited much more potent phototoxicity than the other conjugates because the three artesunate side chains greatly enhanced the ROS production and cellular uptake. The results demonstrated that the conjugation of Chlorin e6 and artesunate could accomplish synergistic effects of chemo-phototherapy, and finally enhanced their antiproliferative effects. PMID- 28882480 TI - Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure. AB - Heart failure is associated with mitochondrial dysfunction so that restoring or improving mitochondrial health is of therapeutic importance. Recently, reduction in NAD+ levels and NAD+-mediated deacetylase activity has been recognized as negative regulators of mitochondrial function. Using a cardiac specific KLF4 deficient mouse line that is sensitive to stress, we found mitochondrial protein hyperacetylation coupled with reduced Sirt3 and NAD+ levels in the heart before stress, suggesting that the KLF4-deficient heart is predisposed to NAD+ associated defects. Further, we demonstrated that short-term administration of Nicotinamide Mononucleotide (NMN) successfully protected the mutant mice from pressure overload-induced heart failure. Mechanically, we showed that NMN preserved mitochondrial ultrastructure, reduced ROS and prevented cell death in the heart. In cultured cardiomyocytes, NMN treatment significantly increased long chain fatty acid oxidation despite no direct effect on pyruvate oxidation. Collectively, these results provide cogent evidence that hyperacetylation of mitochondrial proteins is critical in the pathogenesis of cardiac disease and that administration of NMN may serve as a promising therapy. PMID- 28882483 TI - Profiling of in vitro activities of urea-based inhibitors against cysteine synthases from Mycobacterium tuberculosis. AB - CysK1 and CysK2 are two members of the cysteine/S-sulfocysteine synthase family in Mycobacterium tuberculosis, responsible for the de novo biosynthesis of l cysteine, which is subsequently used as a building block for mycothiol. This metabolite is the first line defense of this pathogen against reactive oxygen and nitrogen species released by host macrophages after phagocytosis. In a previous medicinal chemistry campaign we had developed urea-based inhibitors of the cysteine synthase CysM with bactericidal activity against dormant M. tuberculosis. In this study we extended these efforts by examination of the in vitro activities of a library consisting of 71 urea compounds against CysK1 and CysK2. Binding was established by fluorescence spectroscopy and inhibition by enzyme assays. Several of the compounds inhibited these two cysteine synthases, with the most potent inhibitor displaying an IC50 value of 2.5uM for CysK1 and 6.6uM for CysK2, respectively. Four of the identified molecules targeting CysK1 and CysK2 were also among the top ten inhibitors of CysM, suggesting that potent compounds could be developed with activity against all three enzymes. PMID- 28882482 TI - Ester-prodrugs of ethambutol control its antibacterial activity and provide rapid screening for mycobacterial hydrolase activity. AB - M. tuberculosis contains an unusually high number of serine hydrolases by proteome percentage compared to other common bacteria or humans. This letter describes a method to probe the global substrate specificity of mycobacterial serine hydrolases with ester-protected prodrugs of ethambutol, a first-line antibiotic treatment for TB. These compounds were synthesized directly from ethambutol using a selective o-acylation to yield products in high yield and purity with minimal workup. A library of derivatives was screened against M. smegmatis, a non-infectious model for M. tuberculosis, which displayed significantly lowered biological activity compared to ethambutol. Incubation with a general serine hydrolase reactivated each derivative to near-ethambutol levels, demonstrating that esterification of ethambutol should provide a simple screen for mycobacterial hydrolase activity. PMID- 28882486 TI - Polymeric micelles: Basic research to clinical practice. AB - Rapidly developing polymeric micelles as potential targeting carriers has intensified the need for better understanding of the underlying principles related to the selection of suitable delivery materials for designing, characterizing, drug loading, improving stability, targetability, biosafety and efficacy. The emergence of advanced analytical tools such as fluorescence resonance energy transfer and dissipative particle dynamics has identified new dimensions of these nanostructures and their behavior in much greater details. This review summarizes recent efforts in the development of polymeric micelles with respect to their architecture, formulation strategy and targeting possibilities along with their preclinical and clinical aspects. Literature of the past decade is discussed critically with special reference to the chemistry involved in the formation and clinical applications of these versatile materials. Thus, our main objective is to provide a timely update on the current status of polymeric micelles highlighting their applications and the important parameters that have led to successful delivery of drugs to the site of action. PMID- 28882484 TI - Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma. AB - Alternatives of treatments for multiple myeloma (MM) have become increasingly available with the advent of new drugs such as proteasome inhibitors, thalidomide derivatives, histone deacetylase inhibitors, and antibody drugs. However, high risk MM cases that are refractory to novel drugs remain, and further optimization of chemotherapeutics is urgently needed. We had achieved asymmetric total synthesis of komaroviquinone, which is a natural product from the plant Dracocephalum komarovi. Similar to several leading antitumor agents that have been developed from natural compounds, we describe the antitumor activity and cytotoxicity of komaroviquinone and related compounds in bone marrow cells. Our data suggested that komaroviquinone-related agents have potential as starting compounds for anticancer drug development. PMID- 28882485 TI - Zinc chloride rapidly stimulates efflux transporters in renal proximal tubules of killifish (Fundulus heteroclitus). AB - Multidrug resistance-related protein 2 (Mrp2) is an ATP-driven efflux pump at the luminal membrane in renal proximal tubules. It acts as detoxification mechanism by transporting xenobiotics and metabolic products into urine. The trace element zinc is essential for cellular growth, differentiation and survival. It modulates immune response and is used as dietary supplement. Here, we found that 0.1-10MUM ZnCl2 rapidly stimulated transport of the Mrp2 probe substrate Texas Red (TR) in isolated killifish renal proximal tubules, which provide an established model system to measure efflux transporter activity by using fluorescent probe substrates, confocal microscopy and image analysis. This stimulation was insensitive to the translation inhibitor cycloheximide (CHX), but it was quickly reversed by removing ZnCl2 from the incubation medium. ZnCl2-induced transport stimulation was abolished by inhibitors and antagonists of the endothelin receptor type B (ETB)/nitric oxide synthase (NOS)/protein kinase C (PKC) pathway. Moreover, ZnCl2-induced effects were blocked by inhibition of PKCalpha using Go6976 and PKCalpha inhibitor peptide C2-4. Both the phosphatidylinositol 3 kinase (PI3K) inhibitor LY 294002 and the mammalian target of rapamycin (mTOR) inhibitor rapamycin abolished ZnCl2-induced transport stimulation. Furthermore, the stimulating effects of ZnCl2 were blocked by GSK650394, an inhibitor of the downstream target serum- and glucocorticoid-inducible kinase 1 (SGK1). ZnCl2 also stimulated transport mediated by P-glycoprotein (P-gp) and Breast cancer resistance protein (Bcrp). This is the first report about zinc affecting efflux transporter activity and demonstrates that ZnCl2 triggers a suite of signaling events to evoke a rapid stimulation of ABC transporter-mediated efflux in killifish proximal tubules. PMID- 28882487 TI - Modeling drug release through stimuli responsive polymer hydrogels. AB - There is a rising interest in stimuli-responsive hydrogels to achieve controlled and self-regulated drug delivery. Stimuli responsive polymer hydrogels with their ability to swell/de-swell under varying pH conditions present themselves as a potential candidate for controlled drug delivery. It is important to develop a mechanistic understanding of the underlying phenomena that will help suggest ways to control the drug release from a polymer hydrogel. We present a mathematical model that couples Nernst-Planck, Poisson and force balance equations to incorporate diffusion of ionic species and drug along with deformation of hydrogel under osmotic pressure. The model can be used to simulate swelling behaviour of the hydrogel along with the kinetics of drug release. It has been validated with published experimental data for swelling of polyhydroxyl methacrylate-co-methacrylic acid (pHEMA-co-MA) gels and release kinetics of Phenylpropanolamine from these gels. Effect of formulation parameters such as polymer concentration and cross-linker concentration has also been evaluated. The model can be used to reduce the number of exploratory experiments required during design of a drug delivery system. PMID- 28882488 TI - Association between serum periostin concentrations and outcome after acute spontaneous intracerebral hemorrhage. AB - BACKGROUND: Higher serum periostin concentrations are associated with mortality after head trauma. We further determined the relationship between periostin concentrations, severity, and clinical outcome in patients with intracerebral hemorrhage (ICH). METHODS: We prospectively included 128 controls and 128 consecutive patients with acute ICH within the first 24h after onset. At admission, we measured serum periostin concentrations. RESULTS: Serum periostin concentrations were significantly higher in the patients than in the controls. Serum periostin concentrations were positively related to National Institutes of Health Stroke Scale (NIHSS) score (r=0.526) and hematoma volume (r=0.586). An unfavorable outcome (defined as modified Rankin scale >2) was observed in 65 (50.8%) patients. Serum periostin [odds ratio (OR), 1.008; 95% confidence interval (CI), 1.002-1.013], NIHSS score (OR, 1.462; 95% CI, 1.209-1.767), hematoma volume (OR, 1.134; 95% CI, 1.047-1.227) and age (OR, 1.060; 95% CI, 1.015-1.108) emerged as independent predictors for 6-month unfavorable outcome. In terms of ROC AUC, serum periostin concentrations had significantly higher predictive value compared with age and showed similar predictive value compared with NIHSS score and hematoma volume. CONCLUSIONS: High concentrations of serum periostin in acute ICH patients are associated with increasing severity and a poor functional prognosis. PMID- 28882489 TI - Folate and microRNA: Bidirectional interactions. AB - Low folate status is linked to increased risk of a number of conditions, including developmental disorders, some cancers, neurodegenerative and cardiovascular diseases. Some of the mechanisms of these associations are known, but much remains to be elucidated. Aberrant microRNA (miRNA) profiles are also signatures of these conditions, and as such, the association between folate status and miRNA are now being investigated. Potential associations are bidirectional, with miRNA linked to regulation of folate-mediated pathways, and folate linked to modulation of miRNA expression. miRNA are short non-coding RNA, involved in post-transcriptional regulation of gene expression via complementary binding to mRNA. Evidence is emerging that links folate levels to the regulation of miRNA levels, and miRNA to the regulation of the expression of enzymes involved in folate mediated one carbon metabolism. One carbon metabolism is the source of methyl groups for methylation reactions, including DNA methylation and is important in DNA synthesis and repair. miRNA may be modulated by DNA methylation and other epigenetic mechanisms directly, or indirectly via modulation of upstream signalling pathways. As such, there may be bi-directional associations between folate status and miRNA profiles. miRNA may also act as biomarkers for diagnosis or prognosis of conditions associated with folate status. PMID- 28882490 TI - Patient-rated long-term results after complete denervation of the wrist. AB - The aim of this study was to examine the long-term results after the denervation of the wrist. Between 1977 and 2001, we treated 375 patients in our clinic. The mean age was 43.5 years; 81% were male and 19% female. The long-term results were assessed by a questionnaire assessing pain on a visual analog scale and patient satisfaction and by the DASH questionnaire. After a mean follow-up of 12.23 years, we found an overall pain reduction of 52.1%. In 67.7% of the patients, we found a relief of pain: of these, 44% are free of pain until today and 56% were temporarily asymptomatic. Patients with a painful osteoarthritic condition without dynamic instability and good range of motion are ideal candidates to benefit from the denervation. The complete denervation of the wrist is an effective treatment option in patients with painful wrist conditions to reduce pain and improve the overall function. PMID- 28882491 TI - Anatomic and high-resolution computed tomographic angiography study of the lateral femoral condyle flap: Implications for surgical dissection. AB - BACKGROUND: The lateral femoral condyle (LFC) flap is a vascularized bone flap based on the superior lateral genicular artery (SLGA). Harvest technique for this flap has not yet been demonstrated. The purpose of this study was to better delineate the blood supply to the bone and skin of this flap to allow for a safe and effective harvest. MATERIALS AND METHODS: Twenty-three lower extremities were injected with latex or a mixture of latex and barium sulfate. The SLGA was identified and dissected, documenting the course, diameter, anatomical relations, length, and branches. In the mixture group, high-resolution CT scanning was performed prior to dissection. Two additional specimens were dissected to illustrate the harvest technique. RESULTS: The SLGA originated from the popliteal artery at an average of 44.3 mm proximal to the knee joint line. The SLGA had an average diameter of 1.9 mm at origin and length of 56 mm. It coursed posterior to the femur, reaching the lateral intermuscular septum (IMS), dividing into superficial (patellar) and deep (condylar) branches, which coursed toward and gave branches to the patella and the LFC, respectively. At least one (average 1.4) septocutaneous skin perforator >5 mm emerged and ran posterior to the IMS. 3D reconstructions of the CT scans were used to confirm anatomic findings and describe a standard harvest technique. CONCLUSIONS: The SLGA has consistent anatomy, adequate length, suitable diameter at origin for microvascular anastomosis, and constant perforators to bone and skin. The LFC flap provides a useful alternative to flaps from the medial knee or iliac crest. PMID- 28882492 TI - Assessing the effort associated with teaching residents. AB - BACKGROUND: Intraoperative resident education is an integral mission of academic medical centers and serves as the basis for training the next generation of surgeons. The actual effort associated with teaching residents is unknown as it pertains to additional operative time. Using a large validated multi institutional dataset, this study aims to quantify the effect of having a resident present in common plastic surgery procedures on operative time. Future directions for developing standardized methods to record and report teaching time are proposed, which can help inform prospective studies. STUDY DESIGN: The 2006 2012 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried to identify seven isolated plastic surgical procedures that were categorized based on resident involvement and supervision. Linear regression models were used to calculate the difference in operative time with respect to resident participation while controlling for patient and operative factors. RESULTS: Resident involvement was associated with longer operative times for muscle flap trunk procedures (53 min, 95% CI = [25, 80], p value = 0.0002) and breast reconstruction procedures with a latissimus dorsi flap (55 min, 95% CI = [22, 88], p-value = 0.001). For six of the seven surgeries evaluated, resident involvement was associated with longer operative times, as compared to no resident involvement. CONCLUSION: Resident involvement is associated with an increase in operative time for certain plastic surgery procedures. This finding underscores the need for a mechanism to quantify the time and effort that the attending surgeons allocate toward intraoperative resident education. Further study is also necessary to determine the causal impact on patient care. PMID- 28882493 TI - Delaying implant-based mammary reconstruction after radiotherapy does not decrease capsular contracture: An in vitro study. PMID- 28882494 TI - The merits of decision modelling in the earliest stages of the IDEAL framework: An innovative case in DIEP flap breast reconstructions. AB - BACKGROUND: The IDEAL framework aims at improving the evidence base of available surgical innovations. However, the development of such innovations and collection of evidence is costly. Surgical innovation can provide more value for money if innovations are evaluated at an early stage, where evaluations can inform the decision whether to stop or to further develop an innovation. We illustrate how decision modelling can be readily adopted at the earliest stages (0-1) of the IDEAL framework, using an innovation in bilateral DIEP flap breast reconstruction as an example. METHODS: We quantified expected costs and quality-adjusted life years (QALYs) of the current treatment and compared them with an innovation aimed at reducing complications and surgery time. The maximum effect of eliminating all complications (headroom analysis) was explored. Moreover, three scenarios with varying complications and surgery time reductions were modelled. Furthermore, the maximum price of the innovation was estimated in a threshold analysis according to its impact and societal willingness to pay. RESULTS: The headroom analysis showed that when all complications associated with the current treatment are prevented, up to ?889 per patient is saved. Scenario analysis showed cost savings between ?256 and ?828 per patient. When surgery time is reduced by 15 min and complications by 50%, the innovation will remain cost-effective at ?671 per patient. CONCLUSION: In a field struggling with cost containment, decision modelling can help to separate promising innovations from costly failures at an early stage. In this example, decision modelling showed that it seems worthwhile to further develop the innovation. PMID- 28882495 TI - Prevalence of Zinc Deficiency in Cardiac Surgery Patients. AB - BACKGROUND: The aim of this study was to define the status of preoperative zinc levels in patients with heart disease presenting for cardiac surgery and to identify any predictors for and any clinical consequences of low zinc levels. METHODS: Adult patients presenting for elective surgery, either coronary artery bypass graft surgery and/or valve replacement, provided a fasting blood sample on the day of admission for surgery. Plasma and erythrocyte zinc levels were analysed and the levels correlated with the patient's characteristics and clinical outcomes. RESULTS: Of 56 patients 53% (n=30) had abnormally low plasma zinc levels (<12MUmol/L) and 5.5% (n=3) had abnormally low erythrocyte zinc levels (<160MUmol/L), indicative of deficiency. There were significant associations between lower plasma zinc levels and the presence of hypertension (p=0.02), hypercholesteraemia (p=0.02) and higher body mass index (BMI) (p=0.034) but no effect on major postoperative clinical outcomes. CONCLUSIONS: This small study shows that zinc deficiency is common in cardiac surgery patients, especially in the presence of hypertension, hypercholesterolaemia or obesity. The effects of zinc deficiency in cardiac surgery need to be further investigated. PMID- 28882496 TI - The Echocardiographic Characteristics and Prognostic Significance of Pericardial Effusions in Eisenmenger Syndrome. AB - BACKGROUND AND OBJECTIVES: Pericardial effusion (PE) confers a poor prognosis in non-congenital pulmonary arterial hypertension (PAH). The clinical significance and prognostic implications of PE in Eisenmenger syndrome (ES) is much less well characterised. Accordingly, we aimed to define the frequency, echocardiographic characteristics, natural history and clinical sequelae of PE in those with ES. PATIENTS AND METHODS: We retrospectively studied 55 consecutive individuals presenting since 2000, age >18 years, with ES. Analysis of clinical notes, transthoracic echocardiograms and vital status was undertaken via local records and the National Death Index. RESULTS: Mean age was 38 years (11.4SD), 22% had Down syndrome and the mean follow-up time was 14.7 years (13.4SD). Nine patients (16%) had a PE during their follow-up period with the majority being small (56%). No PE exhibited clinical or echocardiographic signs of tamponade and none required pericardiocentesis. At the time of last review, 42% of individuals had died. The presence of PE was not associated with mortality (p=0.83). CONCLUSIONS: Pericardial effusion occurs relatively frequently in ES but is usually small and with no evidence of haemodynamic compromise. Pericardial effusion in this setting is not related to mortality. PMID- 28882497 TI - Pulmonary Vein Isolation for Atrial Fibrillation Can Be Achieved With Low Radiation Exposure. AB - BACKGROUND: Atrial fibrillation is common and management by pharmacotherapy is limited by modest efficacy and significant toxicities. Pulmonary vein isolation (PVI) is a safe and effective alternative in select patients with atrial fibrillation. However, prolonged procedure time raises concerns of health risks from radiation exposure. This study aims to determine the significance of radiation exposure from PVI. METHODS: In this study, we retrospectively reviewed patient demographics, fluoroscopy time, entrance skin dose and dose area product in 80 cases of PVI, radiofrequency ablation for atrial flutter and diagnostic coronary angiogram performed in our institution. RESULTS: Compared to other procedures, patients who underwent PVI were younger (age, mean+/-standard error of mean, 59.4+/-1.1 years old, p<0.0001) and were more likely to be male (82%, p<0.001). Body mass index was similar between the three groups. The median (and interquartile range) fluoroscopy time was similar between PVI (20.8 and 13.1 30.7mins) and flutter ablation (17.6 and 11.1-26.1mins) but longer than diagnostic angiography (4.2 and 2.3-6.7mins, p<0.0001). Entrance skin dose was similar between PVI and flutter ablation groups but significantly higher in the diagnostic angiography group, with median and IQR for PVI vs. flutter ablation vs. diagnostic angiography, 100.4 (52.8-179.9) vs. 73.2 (37.0-142.1) vs. 393.5 (276.1-555.6) mGy (p<0.0001). Dose area product in PVI (1831.2 and 887.7 3460.8cGycm2) was higher than flutter ablation (1077.8 and 452.9-2410.2cGycm2, p<0.05) but lower than the diagnostic angiography group (3446.8 and 2341.9 5283.1cGycm2, p<0.0001). The fluoroscopy time and entrance skin dose for PVI decreased over time, likely due to increased operator experience. CONCLUSIONS: Despite prolonged procedure time, radiation exposure from PVI was comparable to, or lower than, other fluoroscopy-guided cardiac procedures. PMID- 28882498 TI - Reproducibility of the dynamics of facial expressions in unilateral facial palsy. AB - The aim of this study was to assess the reproducibility of non-verbal facial expressions in unilateral facial paralysis using dynamic four-dimensional (4D) imaging. The Di4D system was used to record five facial expressions of 20 adult patients. The system captured 60 three-dimensional (3D) images per second; each facial expression took 3-4seconds which was recorded in real time. Thus a set of 180 3D facial images was generated for each expression. The procedure was repeated after 30min to assess the reproducibility of the expressions. A mathematical facial mesh consisting of thousands of quasi-point 'vertices' was conformed to the face in order to determine the morphological characteristics in a comprehensive manner. The vertices were tracked throughout the sequence of the 180 images. Five key 3D facial frames from each sequence of images were analyzed. Comparisons were made between the first and second capture of each facial expression to assess the reproducibility of facial movements. Corresponding images were aligned using partial Procrustes analysis, and the root mean square distance between them was calculated and analyzed statistically (paired Student t test, P<0.05). Facial expressions of lip purse, cheek puff, and raising of eyebrows were reproducible. Facial expressions of maximum smile and forceful eye closure were not reproducible. The limited coordination of various groups of facial muscles contributed to the lack of reproducibility of these facial expressions. 4D imaging is a useful clinical tool for the assessment of facial expressions. PMID- 28882499 TI - Secondary surgical management of osteoradionecrosis using three-dimensional isodose curve visualization: a report of three cases. AB - Osteoradionecrosis is defined as bone death secondary to radiotherapy. There is a relationship between the radiation dose received and the occurrence of osteoradionecrosis of the jaws, with the risk increasing above a dose of 60Gy. In cases of class III mandibular osteoradionecrosis, a segmental resection can be indicated. Current practice is to completely remove the affected bone up to the point where the bone looks healthy and is bleeding. Exact resection planning and the use of guided surgery based on imaging of the bone changes have not been reported so far. This article describes a method whereby the radiotherapy dose information is incorporated into the imaging of the affected bone in order to plan a three-dimensional (3D) virtual guided resection and reconstruction of the mandible in osteoradionecrosis. The method enables 3D visualization of each desired dose field in relation to the 3D model of the affected bone. Two types of application - for resection and reconstruction - are described. PMID- 28882500 TI - Pediatric ophthalmology and childhood reading difficulties: Convergence insufficiency: relationship to reading and academic performance. AB - Patients with convergence insufficiency (CI) are often symptomatic during activities that require near fixation, such as reading. Indeed, CI has been associated with reading impairment and poor academic performance. However, these associations do not prove a causal relationship between these conditions. The current evidence regarding the relationship between CI and its treatment, reading ability, and academic performance is discussed. PMID- 28882501 TI - Pediatric ophthalmology and childhood reading difficulties: Overview of reading development and assessments for the pediatric ophthalmologist. AB - Reading difficulties are common in the pediatric population, and large socioeconomic disparities exist. In the United States 46% of white children achieved expected reading proficiency by the end of fourth grade, while only 21% of Hispanic and 18% of African American children were reading at the expected level. Reading is an involved cognitive process with many subskills; likewise, development of reading proficiency is a complex and continuous process. Failure to achieve reading proficiency or even early difficulty with reading can affect a child's academic performance for years to come. Some studies suggest reading proficiency may be related to later success in life. Although many problems with reading are not related to vision, a vision assessment is recommended for children with reading difficulties and a suspected vision problem. The process of reading development as well as the varied educational assessments of reading are presented here for pediatric ophthalmologists. PMID- 28882502 TI - Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents. AB - Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor alpha (ERalpha) and ERbeta (IC50 < MUM), while binding to the estrogen-related receptor gamma (ERRgamma), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs). PMID- 28882503 TI - Synthesis and beta-sheet propensity of constrained N-amino peptides. AB - The stabilization of beta-sheet secondary structure through peptide backbone modification represents an attractive approach to protein mimicry. Here, we present strategies toward stable beta-hairpin folds based on peptide strand N amination. Novel pyrazolidinone and tetrahydropyridazinone dipeptide constraints were introduced via on-resin Mitsunobu cyclization between alpha-hydrazino acid residues and a serine or homoserine side chain. Acyclic and cyclic N-amino peptide building blocks were then evaluated for their effect on beta-hairpin stability in water using a GB1-derived model system. Our results demonstrate the strong beta-sheet stabilizing effect of the peptide N-amino substituent, and provide useful insights into the impact of covalent dipeptide constraint on beta sheet folding. PMID- 28882504 TI - Peroral peptide delivery: Peptidase inhibition as a key concept for commercial drug products. PMID- 28882505 TI - [Ablative therapy: Urology is underway!] PMID- 28882506 TI - Association of skin autofluorescence with arterial properties: A closer look at AGE Reader and EndoPAT 2000 commercial devices. PMID- 28882507 TI - Stochastic noncooperative and cooperative evolutionary game strategies of a population of biological networks under natural selection. AB - We review current static and dynamic evolutionary game strategies of biological networks and discuss the lack of random genetic variations and stochastic environmental disturbances in these models. To include these factors, a population of evolving biological networks is modeled as a nonlinear stochastic biological system with Poisson-driven genetic variations and random environmental fluctuations (stimuli). To gain insight into the evolutionary game theory of stochastic biological networks under natural selection, the phenotypic robustness and network evolvability of noncooperative and cooperative evolutionary game strategies are discussed from a stochastic Nash game perspective. The noncooperative strategy can be transformed into an equivalent multi-objective optimization problem and is shown to display significantly improved network robustness to tolerate genetic variations and buffer environmental disturbances, maintaining phenotypic traits for longer than the cooperative strategy. However, the noncooperative case requires greater effort and more compromises between partly conflicting players. Global linearization is used to simplify the problem of solving nonlinear stochastic evolutionary games. Finally, a simple stochastic evolutionary model of a metabolic pathway is simulated to illustrate the procedure of solving for two evolutionary game strategies and to confirm and compare their respective characteristics in the evolutionary process. PMID- 28882509 TI - Clinical Benefits of Joint Mobilization on Ankle Sprains: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To assess the clinical benefits of joint mobilization for ankle sprains. DATA SOURCES: MEDLINE, MEDLINE In-Process, Embase, AMED, PsycINFO, CINAHL, Cochrane Library, PEDro, Scopus, SPORTDiscus, and Dissertations and Theses were searched from inception to June 2017. STUDY SELECTION: Studies investigating humans with grade I or II lateral or medial sprains of the ankle in any pathologic state from acute to chronic, who had been treated with joint mobilization were considered for inclusion. Any conservative intervention was considered as a comparator. Commonly reported clinical outcomes were considered such as ankle range of movement, pain, and function. After screening of 1530 abstracts, 56 studies were selected for full-text screening, and 23 were eligible for inclusion. Eleven studies on chronic sprains reported sufficient data for meta-analysis. DATA EXTRACTION: Data were extracted using the participants, interventions, comparison, outcomes, and study design approach. Clinically relevant outcomes (dorsiflexion range, proprioception, balance, function, pain threshold, pain intensity) were assessed at immediate, short-term, and long-term follow-up points. DATA SYNTHESIS: Methodological quality was assessed independently by 2 reviewers, and most studies were found to be of moderate quality, with no studies rated as poor. Meta-analysis revealed significant immediate benefits of joint mobilization compared with comparators on improving posteromedial dynamic balance (P=.0004), but not for improving dorsiflexion range (P=.16), static balance (P=.96), or pain intensity (P=.45). Joint mobilization was beneficial in the short-term for improving weight-bearing dorsiflexion range (P=.003) compared with a control. CONCLUSIONS: Joint mobilization appears to be beneficial for improving dynamic balance immediately after application, and dorsiflexion range in the short-term. Long-term benefits have not been adequately investigated. PMID- 28882508 TI - Recovery of marine Conus (Mollusca: Caenogastropoda) from imposex at Rottnest Island, Western Australia, over a quarter of a century. AB - Imposex is a reproductive abnormality in which female snails begin to transform to males, but do not become functional. It was caused by tributyltin (TBT) used as an antifoulant in boat paints. Imposex was first recorded marine snails (Conus) (Mollusca: Caenogastropoda) at Rottnest Island, Western Australia, in January 1991, where 88% of individuals at the west end were affected. Most were at moderate Stages 3 and 4 on a scale of 0 (no affect) to 6 (death). TBT was banned on boats <25m long in late 1991 in WA. In 1996, imposex had declined to 69% of females with Stages 3 and 4 still the most common. By 2007 only 35% of females exhibited imposex; Stage 3 was the highest level recorded. TBT was below detection limits. TBT was banned on vessels >25m in September 2013. In February 2017 only 4% of Conus had imposex, at Stage 1. PMID- 28882510 TI - Interdisciplinary Approach to the Development of Accessible Computer-Administered Measurement Instruments. AB - Principles of fairness in testing require that all test takers, including people with disabilities, have an equal opportunity to demonstrate their capacity on the construct being measured. Measurement design features and assessment protocols can pose barriers for people with disabilities. Fairness in testing is a fundamental validity issue at all phases in the design, administration, and interpretation of measurement instruments in clinical practice and research. There is limited guidance for instrument developers on how to develop and evaluate the accessibility and usability of measurement instruments. This article describes a 6-stage iterative process for developing accessible computer administered measurement instruments grounded in the procedures implemented across several major measurement initiatives. A key component of this process is interdisciplinary teams of accessibility experts, content and measurement experts, information technology experts, and people with disabilities working together to ensure that measurement instruments are accessible and usable by a wide range of users. The development of accessible measurement instruments is not only an ethical requirement, it also ensures better science by minimizing measurement bias, missing data, and attrition due to mismatches between the target population and test administration platform and protocols. PMID- 28882511 TI - [Doses to organs at risk for conformational and stereotactic radiotherapy: Bladder]. AB - Bladder dose constraints in case of conformational radiotherapy/intensity modulated radiotherapy and stereotactic radiotherapy are reported from the literature, in particular from the French radiotherapy society RECORAD recommendations, according to the treated pelvic tumor sites. The dose-volume effect on urinary toxicity is not clearly demonstrated, making difficult to establish absolute dose constraints for the bladder. In case of high-dose prostate cancer radiotherapy, the bladder dose constraints are: V60Gy<50% and maximum dose<80Gy for standard fractionation and V60Gy<5%, V48Gy<25% and V41Gy<50% for moderate hypofractionation (20 fractions of 3Gy). In case of prostate stereotactic radiotherapy (five fractions of 7.25Gy), the most frequent dose constraints in the literature are V37Gy<10cm3 and V18Gy<40%. In case of conformational radiotherapy of cervix cancer, postoperative endometrium, anal canal and rectum, the recommendations are V40Gy<40% and D2% lower than the prescribed dose. PMID- 28882512 TI - Epidemiology of Babesia, Anaplasma and Trypanosoma species using a new expanded reverse line blot hybridization assay. AB - Vector-borne hemoparasitic infections are a major problem that affects livestock industries worldwide, particularly in tropical and subtropical regions. In this work, a reverse line blot (RLB) hybridization assay was developed for the simultaneous detection and identification of Anaplasma, Babesia and bovine trypanosomes, encompassing in this way the most relevant hemoparasites that affect cattle. A total of 186 bovine blood samples collected from two different ecoepidemiological regions of northeast Argentina, with and without tick control, were analyzed with this new RLB. High diversity of parasites, such as Babesia bovis, B. bigemina, Anaplasma marginale and three different Trypanosoma species, was found. High rates of coinfections were also detected, and significant differences were observed not only in the prevalence of parasites but also in the level of coinfections between the two analyzed areas. Regarding the Trypanosoma genus, we provide molecular evidence of the presence of T. vivax and T. theileri for the first time in Argentina. Besides, since the RLB is a prospective tool, it allowed the identification of a yet unknown bovine trypanosome which could not be assigned to any of the bovine species known so far. In the present study we provide new insights on the prevalence of several pathogens that directly impact on livestock production in Argentina. The RLB assay developed here allows to identify simultaneously numerous pathogenic species which can also be easily expanded to detect other blood borne pathogens. These characteristics make the RLB hybridization assay an essential tool for epidemiological survey of all vector-borne pathogens. PMID- 28882513 TI - Enhanced detection of Rickettsia species in Ixodes pacificus using highly sensitive fluorescence in situ hybridization coupled with Tyramide Signal Amplification. AB - Ixodes pacificus is a host of many bacteria including Rickettsia species phylotypes G021 and G022. As part of the overall goal of understanding interactions of phylotypes with their tick host, this study focused on molecular detection of rickettsiae in ovarian and midgut tissue of I. pacificus by fluorescent in situ hybridization (FISH), PCR, and ultrastructural analysis. Of three embedding media (Technovit 8100, Unicryl, and paraffin) tested for generating thin sections, tissues embedded in paraffin resulted in the visualization of bacteria with low autofluorescence in FISH. Digoxigenin-labeled probes were used in FISH to intensify bacterial hybridization signals using Tyramide Signal Amplification reaction. Using this technique, rickettsiae were detected in the cytoplasm of oocytes of I. pacificus. The presence of rickettsiae in the ovary and midgut was further confirmed by PCR and transmission electron microscopic analysis. Overall, the methods in this study can be used to identify locations of tick-borne bacteria in tick tissues and understand transmission routes of bacterial species in ticks. PMID- 28882514 TI - Re: "Systematic Review and Meta-analysis of the Association between C-reactive Protein and Major Cardiovascular Events in Patients with Peripheral Artery Disease: Do Not Ignore Patients with Critical Limb Ischaemia". PMID- 28882515 TI - How Quickly Do Asymptomatic Infrarenal Abdominal Aortic Aneurysms Grow and What Factors Affect Aneurysm Growth Rates? Analysis of a Single Centre Surveillance Cohort Database. AB - OBJECTIVE/BACKGROUND: Abdominal aortic aneurysm (AAA) maximum antero-posterior diameter (MAPD) is the parameter most commonly used to inform the timing of surgical intervention. However, other factors, such as growth rates and patient comorbidities are likely to be important considerations as they may influence AAA related complications including rupture, operative outcomes, and the clinical and cost effectiveness of continued surveillance. METHODS: This was a retrospective analysis of a 20 year period of a single centre AAA surveillance database. In total, 5363 AAA measurements in 692 patients were analysed for patient demographics, including comorbidity and drug history, growth and rupture rates, and cause of death. RESULTS: A significant proportion of patients (n = 73; 11%) were kept under surveillance despite having a MAPD < 30 mm. Overall, mean aneurysm growth rate was 2.3 mm/year. Elective repair was undertaken in 20.1% and those who required surgical intervention had significantly faster growth rates. Only 3.9% of patients in surveillance ruptured, 40.7% of whom had a MAPD <55 mm at their last scan. Of the 214 deaths recorded, only 11.7% were related to AAA. The majority of patients who died in surveillance did so from malignancy. Patients with larger AAA (MAPD > 40 mm) on entry into surveillance were significantly more likely to receive surgical intervention, as were those whose AAA expanded >4 mm/year. Females had significantly higher growth rates, and those with diabetes had significantly smaller growth rates. Other comorbidities and drug history were not associated with AAA growth, or 5 and 10 year surgery free survival. CONCLUSION: The results highlight several areas for service improvement. Specifically, it is important not to maintain surveillance in patients who are very unlikely to ever grow to a point where AAA surgery would be contemplated on grounds or age and/or comorbidity. Similarly, patients should be discharged from surveillance when this likelihood becomes apparent. PMID- 28882516 TI - Genetic characterization of the glycoprotein G of Chandipura viruses in India with emphasis on an outbreak of 2015. AB - Chandipura virus (CHPV) is found to be associated with sporadic encephalitis outbreaks in humans in India since 1965. We report here, the investigation of CHPV activity during the period of June-August 2015 in the state of Gujarat, which revealed 24.44% positivity among 45 referred encephalitis cases. Phylogenetic study of the G gene sequences of strains from Gujarat 2015 along with available sequences of additional strains from different geographical locations and isolation years (1965-2015), indicated the relatedness of the 2015 strain to a group of the CHPV prototype strain of 1965 and the earliest outbreak strains of 2003. Analyses of selection pressure in the G gene revealed positively selected sites within the signal peptide region and a putative CHPV epitope. These results indicate a probable role of G protein-based immune selection and underline the need for continued surveillance to monitor genetic and antigenic variations in the CHPV. PMID- 28882517 TI - Diagnosis and genetic analysis of the worldwide distributed Rattus-borne Trypanosoma (Herpetosoma) lewisi and its allied species in blood and fleas of rodents. AB - Trypanosoma (Herpetosoma) lewisi is a cosmopolitan parasite of rodents strongly linked to the human dispersal of Rattus spp. from Asia to the rest of the world. This species is highly phylogenetically related to trypanosomes from other rodents (T. lewisi-like), and sporadically infects other mammals. T. lewisi may opportunistically infect humans, and has been considered an emergent rat-borne zoonosis associated to poverty. We developed the THeCATL-PCR based on Cathepsin L (CATL) sequences to specifically detect T. (Herpetosoma) spp., and assess their genetic diversity. This method exhibited high sensitivity using blood samples, and is the first molecular method employed to search for T. lewisi in its flea vectors. THeCATL-PCR surveys using simple DNA preparation from blood preserved in ethanol or filter paper detected T. lewisi in Rattus spp. from human dwellings in South America (Brazil and Venezuela), East Africa (Mozambique), and Southeast Asia (Thailand, Cambodia and Lao PDR). In addition, native rodents captured in anthropogenic and nearby human settlements in natural habitats harbored T. (Herpetosoma) spp. PCR-amplified CATL gene fragments (253bp) distinguish T. lewisi and T. lewisi-like from other trypanosomes, and allow for assessment of genetic diversity and relationships among T. (Herpetosoma) spp. Our molecular surveys corroborated worldwide high prevalence of T. lewisi, incriminating Mastomys natalensis as an important carrier of this species in Africa, and supported its spillover from invader Rattus spp. to native rodents in Brazil and Mozambique. THeCATL-PCR provided new insights on the accurate diagnosis and genetic repertoire of T. (Herpetosoma) spp. in rodent and non-rodent hosts, revealing a novel species of this subgenus in an African gerbil. Phylogenetic analysis based on CATL sequences from T. (Herpetosoma) spp. and other trypanosomes (amplified using pan-trypanosome primers) uncovered rodents harboring, beyond mammal trypanosomes of different subgenera, some species that clustered in the lizard-snake clade of trypanosomes. PMID- 28882518 TI - Viability qPCR, a new tool for Legionella risk management. AB - BACKGROUND: Viability quantitative Polymerase Chain Reaction (v-qPCR) is a recent analytical approach for only detecting live microorganisms by DNA amplification based methods This approach is based on the use of a reagent that irreversibly fixes dead cells DNA. In this study, we evaluate the utility of v-qPCR versus culture method for Legionellosis risk management. METHODS: The present study was performed using 116 real samples. Water samples were simultaneously analysed by culture, v-qPCR and qPCR methods. Results were compared by means of a non parametric test. RESULTS: In 11.6% of samples using both methods (culture method and v-qPCR) results were positive, in 50.0% of samples both methods gave rise to negative results. As expected, equivalence between methods was not observed in all cases, as in 32.1% of samples positive results were obtained by v-qPCR and all of them gave rise to negative results by culture. Only in 6.3% of samples, with very low Legionella levels, was culture positive and v-qPCR negative. In 3.5% of samples, overgrowth of other bacteria did not allow performing the culture. When comparing both methods, significant differences between culture and v-qPCR were in the samples belonging to the cooling towers-evaporative condensers group. The v-qPCR method detected greater presence and obtained higher concentrations of Legionella spp. (p<0.001). Otherwise, no significant differences between methods were found in the rest of the groups. CONCLUSIONS: The v-qPCR method can be used as a quick tool to evaluate Legionellosis risk, especially in cooling towers-evaporative condensers, where this technique can detect higher levels than culture. The combined interpretation of PCR results along with the ratio of live cells is proposed as a tool for understanding the sample context and estimating the Legionellosis risk potential according to 4 levels of hierarchy. PMID- 28882519 TI - Re: "Ultrasound Findings on Hands and Wrists of Patients with Systemic Lupus Erythematosus: Relationship with Physical Examination". PMID- 28882520 TI - Dynamic foraminal dimensions during neck extension and rotation in fusion and artificial disc replacement: an observational study. AB - BACKGROUND: Changes in the dimensions of the cervical neural foramina (CNF) are considered to be a key factor in nerve root compression and development of cervical radiculopathy. However, to what extent foraminal geometry differs between patients who underwent anterior cervical discectomy and fusion (ACDF) and those who underwent total disc arthroplasty with an artificial disc (AD) during physiological motion is largely unknown. PURPOSE: The objective of this study is to compare CNF dimensions during physiological neck motion between ACDF and AD. STUDY DESIGN/SETTING: This is a retrospective comparative analysis of prospectively collected, consecutive, non-randomized series of patients at a single institution. PATIENT SAMPLE: A total of 16 single-level C5-C6 ACDF (4 males, 12 females; 28-71 years) and 7 single-level C5-C6 cervical arthroplasty patients (3 males, 4 females; 38-57 years), at least 12 months after surgery (23.6+/-6.8 months) were included. OUTCOME MEASURES: Patient demographics, preoperative magnetic resonance imaging (MRI)-based measurements of cervical spine degeneration, and 2-year postoperative measurements of dynamic foraminal geometry were the outcome measures. METHODS: Biplane X-ray images were acquired during axial neck rotation and neck extension. A computed tomography scan was also acquired from C3 to the first thoracic vertebrae. The subaxial cervical vertebrae (C3-C7) were reconstructed into three-dimensional (3D) bone models for use with model-based tracking. Foraminal height (FH) was calculated as the 3D distance between the superior point of the inferior pedicle and the inferior point of the superior pedicle using custom software. Foraminal width (FW) was similarly calculated as the 3D distance between the anterolateral aspect of the superior vertebral body inferior notch and the posterolateral aspect of the inferior vertebral body superior notch. Dynamic foraminal dimensions were quantified as the minimum (FH.Min, FW.Min), the range (FH.Range, FW.Range), and the median (FH.Med, FW.Med) of each trial and then averaged over trials. Mixed model analysis of variance framework was used to examine the differences between ACDF and AD groups. The initial severity of disc degeneration as determined from preoperative MRI images was introduced as covariates in the models. RESULTS: At the operated level (C5-C6), FH.Med and FH.Range were smaller in ACDF than in AD during axial rotation and neck extension (p<.003 to p<.05). At the superior adjacent level (C4-C5), no significant difference was found. At the inferior adjacent level (C6-C7), FW.Range was greater in ACDF than in AD during axial rotation and extension (p<.05). At the non-adjacent level (C3-C4), FW.Range was greater in ACDF than in AD during extension (p<.008). CONCLUSIONS: This study demonstrated decreases in foraminal dimensions and their range for ACDF compared with AD at the operated level. In contrast, it demonstrated increases in the range of foraminal dimensions during motion for ACDF compared with AD at the non operated segments. Together, these data support the notion that increased mobility at the non-operated segments after ACDF may contribute to a greater risk for adjacent segment degeneration. Because of the significant presence of range variables in the findings, the current data also indicate that a dynamic evaluation is likely more appropriate for evaluation of the differences in foramina between ACDF and AD than a static evaluation. PMID- 28882521 TI - Reliability of physical functioning tests in patients with low back pain: a systematic review. AB - PURPOSE: The aim of this study was to provide a comprehensive overview of physical functioning tests in patients with low back pain (LBP) and to investigate their reliability. DATA SOURCES: A systematic computerized search was finalized in four different databases on June 24, 2017: PubMed, Web of Science, Embase, and MEDLINE. STUDY SELECTION: Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed during all stages of this review. Clinical studies that investigate the reliability of physical functioning tests in patients with LBP were eligible. The methodological quality of the included studies was assessed with the use of the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist. To come to final conclusions on the reliability of the identified clinical tests, the current review assessed three factors, namely, outcome assessment, methodological quality, and consistency of description. DATA SYNTHESIS: A total of 20 studies were found eligible and 38 clinical tests were identified. Good overall test-retest reliability was concluded for the extensor endurance test (intraclass correlation coefficient [ICC]=0.93-0.97), the flexor endurance test (ICC=0.90-0.97), the 5-minute walking test (ICC=0.89-0.99), the 50-ft walking test (ICC=0.76-0.96), the shuttle walk test (ICC=0.92-0.99), the sit-to-stand test (ICC=0.91-0.99), and the loaded forward reach test (ICC=0.74-0.98). For inter-rater reliability, only one test, namely, the Biering-Sorensen test (ICC=0.88-0.99), could be concluded to have an overall good inter-rater reliability. None of the identified clinical tests could be concluded to have a good intrarater reliability. CONCLUSIONS: Further investigation should focus on a better overall study methodology and the use of identical protocols for the description of clinical tests. The assessment of reliability is only a first step in the recommendation process for the use of clinical tests. In future research, the identified clinical tests in the current review should be further investigated for validity. Only when these clinimetric properties of a clinical test have been thoroughly investigated can a final conclusion regarding the clinical and scientific use of the identified tests be made. PMID- 28882522 TI - Hospital competitive intensity and perioperative outcomes following lumbar spinal fusion. AB - BACKGROUND CONTEXT: Interhospital competition has been shown to influence the adoption of surgical techniques and approaches, clinical patient outcomes, and health care resource use for select surgical procedures. However, little is known regarding these dynamics as they relate to spine surgery. PURPOSE: This investigation sought to examine the relationship between interhospital competitive intensity and perioperative outcomes following lumbar spinal fusion. STUDY DESIGN/SETTING: This study used the Nationwide Inpatient Sample dataset, years 2003, 2006, and 2009. PATIENT SAMPLE: Patients were included based on the presence of the International Classification of Disease, Ninth Edition, Clinical Modification (ICD-9-CM) codes corresponding to lumbar spinal fusion, as well as on the presence of data on the Herfindahl-Hirschman Index (HHI). OUTCOME MEASURES: The outcome measures are perioperative complications, defined using an ICD-9-CM coding algorithm. MATERIALS AND METHODS: The HHI, a validated measure of competition within a market, was used to assess hospital market competitiveness. The HHI was calculated based on the hospital cachement area. Multiple regression was performed to adjust for confounding variables including patient age, gender, primary payer, severity of illness score, primary versus revision fusion, anterior versus posterior approach, national region, hospital bed size, location or teaching status, ownership, and year. Perioperative clinical outcomes were assessed based on ICD-9-CM codes with modifications. RESULTS: In total, 417,520 weighted patients (87,999 unweighted records) were analyzed. The mean cachement area HHI was 0.31 (range 0.099-0.724). The average patient age was 55.4 years (standard error=0.194), and the majority of patients were female (55.8%, n=232,727). The majority of procedures were primary spinal fusions (92.7%, n=386,998) and fusions with a posterior-only technique (81.5%, n=340,271). Most procedures occurred in the South (42.5%, n=177,509) or the Midwest (27.0%, n=112,758) regions. In the multiple regression analysis, increased hospital competitive intensity was associated with an increased total complication rate (odds ratio [OR] 1.52, p<.0001), device-related complications (OR 1.46, p=.0294), genitourinary complications (OR 2.15, p=.0091), infection (OR 3.48, p<.0001), neurologic complications (OR 1.69, p=.0422), total charges (+29%, p=.0034), and inpatient hospital length of stay (LOS) (+16%, p=.0012). The likelihood of complications at state-owned hospitals (OR 2.81, p=.0001) was more highly associated with HHI than at private, non-profit hospitals (OR 1.39, p=.0050). The occurrence of complications at urban teaching hospitals (OR 2.14, p<.0001) was generally more associated with HHI than at urban non-teaching hospitals (OR 1.19, p=.2457). CONCLUSIONS: Increased interhospital competitive intensity is associated with increased odds of complications, increased total charges, and prolonged LOS following lumbar spine fusion. These differences are generally highest among state-owned and urban teaching hospitals. Differences in outcome related to hospital competition may be due to suboptimal resource allocation. Identifying differences in perioperative outcomes associated with hospital market competition is important in the contemporary environment of health care reimbursement reform and hospital consolidation. Perioperative outcome disparities between highly competitive and minimally competitive areas should be monitored and further studied. PMID- 28882523 TI - Role of intraoperative radiotherapy in the treatment of sacral chordoma. AB - BACKGROUND CONTEXT: Sacral chordoma is a rare entity with high local recurrence rates when complete resection is not achieved. To date, there are no series available in literature combining surgery and intraoperative radiotherapy (IORT). PURPOSE: The objective of this study was to report the experience of our center in the management of sacral chordoma combining radical resection with both external radiotherapy and IORT. STUDY DESIGN: This is a retrospective case series. PATIENT SAMPLE: The patient sample included 15 patients with sacral chordoma resected in our center from 1998 to 2015. OUTCOME MEASURES: The outcome measures were overall survival (OS), disease-free survival (DFS), and rates of local and distant recurrences. METHODS: We retrospectively reviewed the records of all the patients with sacral chordoma resected in our center from 1998 to December 2015. Overall survival, DFS, and rates of local and distant recurrences were calculated. Results between patients treated with or without IORT were compared. RESULTS: A total of 15 patients were identified: 8 men and 7 women. The median age was 59 years (range 28-77). Intraoperative radiotherapy was applied in nine patients and six were treated with surgical resection without IORT. In 13 patients, we performed the treatment of the primary tumor, and in two patients, we performed the treatment of recurrence disease. A posterior approach was used in four patients. Wide surgical margins (zero residue) were achieved in six patients, marginal margins (microscopic residue) were achieved in seven patients, and there were no patients with intralesional (R2) margins. At a median follow-up of 38 months (range 11-209 months), the 5-year OS in the IORT group was 100% versus 53% in the group of non-IORT (p=.05). The median DFS in the IORT group was 85 months, and that in the non-IORT group was 41 months. In the group without IORT, two patients died and nobody died during the follow-up in the group treated with IORT. High-sacrectomy treated patients had a median survival of 41 months, and low-sacrectomy treated patients had a median survival of 90 months. Disease free survival in patients without gluteal involvement was 100% at 5 years, and that in patients with gluteal involvement was 40%. All patients with a recurrence in our study had gluteal involvement. CONCLUSIONS: Multidisciplinary management of sacral chordoma seems to improve local control. The use of IORT, in our experience, is associated with an increase in OS and DFS. The level of resection and gluteal involvement seems to affect survival. The posterior approach is useful in selected cases. Multicenter studies should be performed to confirm the utility of IORT. PMID- 28882524 TI - Activities performed and treatments conducted before consultation with a spine surgeon: are patients and clinicians following evidence-based clinical practice guidelines? AB - BACKGROUND CONTEXT: Clinical practice guidelines (CPGs) are designed to ensure that evidence-based treatment is easily put into action. Whether patients and clinicians follow these guidelines is equivocal. PURPOSE: The objectives of this study were to examine how many patients complaining of low back pain (LBP) underwent evidence-based medical interventional treatment in line with CPG recommendations before consultation with a spine surgeon, and to evaluate any associations between adherence to CPG recommendations and baseline factors. STUDY DESIGN/SETTING: This is a cross-sectional cohort analysis at a tertiary care center. PATIENT SAMPLE: A total of 229 patients were referred for surgical consultation for an elective lumbar spinal condition. OUTCOME MEASURES: The outcome measures include the number of CPG-recommended treatments undertaken by patients at or before the time of referral, the validated pain score, the EuroQol 5D (EQ-5D) health status, and the Oswestry Disability Index (ODI) score. METHODS: Questionnaires assessing demographic and functional characteristics as well as overall health care use were sent to patients immediately after their referral was received by the surgeon's office. RESULTS: Medications were the most common modality before consultation (74.2% of patients), of which 46.3% received opioids. The number of medications taken was significantly related to a higher ODI score (R=0.23, p=.0004), a higher pain score (R=0.15, p=.026), and a lower EQ 5D health status (R=-0.15, p=.024). In contrast, a lower pain score (7.2 vs. 7.7, p=.037) and a lower ODI score (26.6 vs. 29.9, p=.0023) were associated with performing adequate amounts of exercise. There was a significant association between lower numbers of treatments received and higher numerical pain rating scores (R=-0.14, p=.035). The majority (61.1%) of patients received two or less forms of treatment. CONCLUSIONS: Evidence-based medical interventional treatments for patients with LBP are not being taken advantage of before spine surgery consultation. If more patients were to undertake CPG-endorsed conservative modalities, it may result in fewer unnecessary referrals from primary care physicians, and patients might not deteriorate as much while lingering on long wait lists. Further studies incorporating knowledge translation or health system pathway changes are necessary. PMID- 28882525 TI - Multilevel posterior foraminotomy with laminoplasty versus laminoplasty alone for cervical spondylotic myelopathy with radiculopathy: a comparative study. AB - BACKGROUND CONTEXT: Conventional laminoplasty is useful for expanding a stenotic spinal canal. However, it has limited use for the decompression of accompanying neural foraminal stenosis. As such, an additional posterior foraminotomy could be simultaneously applied, although this procedure carries a risk of segmental kyphosis and instability. PURPOSE: The aim of this study was to elucidate the long-term surgical outcomes of additional posterior foraminotomy with laminoplasty (LF) for cervical spondylotic myelopathy (CSM) with radiculopathy. STUDY DESIGN/SETTING: A retrospective comparative study was carried out. PATIENT SAMPLE: Ninety-eight consecutive patients who underwent laminoplasty for CSM with radiculopathy between January 2006 and December 2012 were screened for eligibility. This study included 66 patients, who were treated with a laminoplasty of two or more levels and followed up for more than 2 years after surgery. OUTCOME MEASURES: The Neck Disability Index (NDI), Japanese Orthopedic Association (JOA) scores, JOA recovery rates, and visual analog scale (VAS) were used to evaluate clinical outcomes. The C2-C7 sagittal vertical axis distance, cervical lordosis, range of motion (ROM), and angulation and vertebral slippage at the foraminotomy level were used to measure radiological outcomes using the whole spine anterioposterior or lateral and dynamic lateral radiographs. METHODS: Sixty-six patients with CSM with radiculopathy involving two or more levels were consecutively treated with laminoplasty and followed up for more than 2 years after surgery. The first 26 patients underwent laminoplasty alone (LA group), whereas the next 40 patients underwent an additional posterior foraminotomy at stenotic neural foramens with radiating symptoms in addition to laminoplasty (LF group). In the LF group, the foraminotomy with less resection than 50% of facet joint to avoid segmental kyphosis and instability was performed at 78 segments (unilateral-to-bilateral ratio=57:21) and 99 sites. Clinical and radiographic data were assessed preoperatively and at 2-year follow-up and compared between the groups. RESULTS: The NDI, JOA scores, JOA recovery rates, and VAS for neck and arm pain were improved significantly in both groups after surgery. The improvement in the VAS for arm pain was significantly greater in the LF group (from 5.55+/-2.52 to 1.85+/-2.39) than the LA group (from 5.48+/-2.42 to 3.40+/ 2.68) (p<.001). Although cervical lordosis and ROM decreased postoperatively in both groups, there were no significant differences in the degree of reduction between the LF and LA groups. Although the postoperative focal angulation and slippage were slightly increased in the LF group, this was not to a significant degree. Furthermore, segmental kyphosis and instability were not observed in the LF group, regardless of whether the patient underwent a unilateral or bilateral foraminotomy. CONCLUSIONS: Additional posterior foraminotomy with laminoplasty is likely to improve arm pain more significantly than laminoplasty alone by decompressing nerve roots. Also, performing posterior foraminotomy via multiple levels or bilaterally did not significantly affect segmental malalignment and instability. Therefore, when a laminoplasty is performed for CSM with radiculopathy, an additional posterior foraminotomy could be an efficient and safe treatment that improves both myelopathy symptoms and radicular arm pain. PMID- 28882526 TI - Extraforaminal microscopic assisted percutaneous nucleotomy for foraminal and extraforaminal lumbar disc herniations. AB - BACKGROUND: Foraminal and extraforaminal lumbar disc herniations are uncommon. The main presentation is radicular pain related to the exiting nerve root at the affected level. Different approaches for surgical intervention have been described. PURPOSE: This study aimed to evaluate the clinical outcome, complications recurrence, and reoperation rate of extraforaminal microscopic assisted percutaneous nucleotomy, with literature review focusing on complications and recurrence rate. STUDY DESIGN: This is a prospective cohort study done in a high-flow spine center in Germany. PATIENT SAMPLE: Between October 2012 and October 2015, 76 patients (35 women and 41 men) with foraminal or extraforaminal lumbar disc prolapse were operated on. OUTCOME MEASURES: The following were the outcome measures: (1) self-report measures: Visual Analogue Scale (VAS) for leg pain and back pain; (2) physiological measures: standing plain X-rays (anterioposterior, lateral, and dynamic views); and (3) functional measures: Oswestry Disability Index (ODI) (validated German version) and Odom's criteria. METHODS: All patients were operated upon with trans-tubular extraforaminal microscopic-assisted percutaneous nucleotomy (EF-MAPN) technique. Preoperative clinical and neurologic evaluations were done. The mean follow-up period was 38 months (range 12-54). The study has not received funding for research from any organization. All authors do not have any conflict of interest. RESULTS: The mean age was 54 years. The most commonly affected level was L4/L5 (34 patients). The mean preoperative VAS for leg pain was 7.6 (3-10), which improved to 1.4 (0-4) postoperatively. The average operative time was 57.5 minutes. There were no intraoperative complications. One patient had temporary postoperative quadriceps weakness (L4 radiculopathy) that was completely improved at 3 months' follow-up. Another patient had deep venous thrombosis after discharge. Two patients had recurrences that necessitated another operation within the first 6 months postoperatively. Both were followed up for 1 year without a second recurrence. CONCLUSION: Trans-tubular percutaneous extraforaminal microscopic-assisted nucleotomy is effective for foraminal and extraforaminal disc herniations. It is a muscle-splitting minimally invasive approach with minimal morbidity. Complications, recurrence, and reoperation rate are not different compared with microsurgical open or endoscopic techniques. PMID- 28882527 TI - Successful lumbar surgery results in improved psychological well-being: a longitudinal assessment of depressive and anxiety symptoms. AB - BACKGROUND CONTEXT: Preoperative psychological symptoms predict surgical outcomes. The impact of surgical outcomes on psychological well-being, however, has not been delineated. PURPOSE: This study aimed to compare pre- with postoperative depressive and anxiety symptoms based on success of surgery, defined as fulfilled expectations and improvement in disability and pain. STUDY DESIGN/SETTING: A prospective 2-year longitudinal study in a tertiary care center was carried out. PATIENT SAMPLE: The sample consisted of 276 patients who underwent lumbar surgery. OUTCOME MEASURES: The Geriatric Depression Scale (GDS) and the Spielberger State-Trait Anxiety Inventory (STAI) were the outcome measures. METHODS: Patients completed the following validated surveys several days before and again 2 years after surgery: the GDS with a set threshold for a positive screen for depression; the STAI with population norms used as threshold values; the Oswestry Disability Index (ODI); a numerical pain rating; and the Expectations Survey measuring amount of improvement expected. Dependent variables were pre- to postoperative within-patient change in GDS and STAI scores. Independent variables were three outcomes of surgery: proportion of expectations fulfilled, and changes in ODI scores and pain ratings. Analyses were conducted with GDS and STAI scores as continuous variables and according to threshold values, and for expectations, ODI and pain according to minimum clinically important differences (MCIDs). RESULTS: Mean age was 55, 56% were men, and 78% had degenerative diagnoses. For depressive symptoms, 41% screened positive preoperatively and 16% screened positive postoperatively; 72% had some improvement. In multivariable analysis adjusted for age, gender, comorbidity, diagnosis, and surgical invasiveness, depressive symptoms improved more for more expectations fulfilled (p<.0001), more ODI improvement (p<.0001), and more pain improvement (p=.001). For anxiety symptoms: 59% were worse than population norms preoperatively and 26% were worse postoperatively; 73% had some improvement. In adjusted multivariable analyses, anxiety symptoms improved more for more expectations fulfilled (p=.0002), more ODI improvement (p<.0001), and more pain improvement (p=.03). Similar results were obtained according to threshold values and MCIDs. CONCLUSION: Substantial improvements in psychological well-being resulted after surgery among patients with favorable spine-specific outcomes. PMID- 28882528 TI - Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency. AB - OBJECTIVE: We investigated metabolism and physiological responses to exercise in an 18-year-old woman with multiple congenital abnormalities and exertional muscle fatigue, tightness, and rhabdomyolysis. METHODS: We studied biochemistry in muscle and fibroblasts, performed mutation analysis, assessed physiological responses to forearm and cycle-ergometer exercise combined with stable-isotope techniques and indirect calorimetry, and evaluated the effect of IV glucose infusion and oral sucrose ingestion on the exercise response. RESULTS: Phosphoglucomutase type 1 (PGM1) activity in muscle and fibroblasts was severely deficient and PGM1 in muscle was undetectable by Western blot. The patient was compound heterozygous for missense (R422W) and nonsense (Q530X) mutations in PGM1. Forearm exercise elicited no increase in lactate, but an exaggerated increase in ammonia, and provoked a forearm contracture. Comparable to patients with McArdle disease, the patient developed a 'second wind' with a spontaneous fall in exercise heart rate and perceived exertion. Like in McArdle disease, this was attributable to an increase in muscle oxidative capacity. Carbohydrate oxidation was blocked during exercise, and the patient had exaggerated oxidation of fat to fuel exercise. Exercise heart rate and perceived exertion were lower after IV glucose and oral sucrose. Muscle glycogen level was low normal. CONCLUSIONS: The second wind phenomenon has been considered to be pathognomonic for McArdle disease, but we demonstrate that it can also be present in PGM1 deficiency. We show that severe loss of PGM1 activity causes blocked muscle glycogenolysis that mimics McArdle disease, but may also limit glycogen synthesis, which broadens the phenotypic spectrum of this disorder. PMID- 28882530 TI - [Confusional state in an octogenarian patient with a recent implantation of pacemaker]. PMID- 28882529 TI - Proteomic features of delayed ocular symptoms caused by exposure to sulfur mustard: As studied by protein profiling of corneal epithelium. AB - Exposure to mustard gas can lead to variations in the proteome of corneal epithelium cells and after a latency period produces delayed symptoms in the eyes of chemical victims. Hence, a comparative proteome analysis was conducted between the corneal epithelial cells of chemical victims from Iran-Iraq war (1980-1988) and healthy donors. To this end, corneal epithelium samples from victims and healthy individuals were collected, and the proteome of these samples were prepared for two-dimensional electrophoresis and the analysis of spots by statistical software. Selected spots were further analyzed by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry. Twenty four proteins were identified of which eighteen proteins showed downregulation while six proteins were upregulated in the victims in comparison to the normal individuals. Also, six protein spots were confirmed by western-blot analysis. In conclusion, all the twenty-four identified proteins are involved in pathways which their up- or down-regulation leads to the accumulation of undesired substrates, cell death and apoptosis. Bioinformatics' tools indicated that these identified proteins were involved in various metabolic processes, DNA damage response, immune response and etc. The present study provides a suitable platform for further clinical studies. PMID- 28882531 TI - Primary cardiac tumor presenting as left ventricular outflow tract obstruction and complex arrhythmia. AB - An adult female mixed breed dog presented for recurrent collapsing episodes over several weeks. Holter evaluation revealed periods of sinus arrest and echocardiography identified a soft tissue mass with subsequent severe dynamic obstruction of the left ventricular outflow tract. The patient was euthanized five days after presentation for severe dyspnea. Necropsy revealed an irregular mass circumferentially lining the left ventricular outflow tract as well as multiple myocardial metastases. The final diagnosis was an undifferentiated pleomorphic endocardial sarcoma. PMID- 28882532 TI - Helminthic infections in returning travelers and migrants with eosinophilia: Diagnostic value of medical history, eosinophil count and IgE. AB - OBJECTIVES: Eosinophilia in travelers and migrants returning from the tropics is often associated with invasive helminthic infections. Total IgE is considered a useful additional diagnostic parameter; however, both parameters are also increased in various other non-helminthic diseases. METHODS: We retrospectively evaluated travelers and migrants seen at our department between September 2007 and May 2014. Patients with an absolute eosinophil count >=500 cells/MUl were considered for further analyses. RESULTS: Among 6618 returned travelers and migrants, 154 (2.3%) had a total eosinophil count >=500 cells/MUL. Of these, 71 patients (46%) were diagnosed with helminthic infection. In an additional 62 patients (40%) with eosinophilia a final diagnosis was found, including non helminthic infections in 34 patients and non-infectious causes in 28 patients, while in 21 patients (14%) no diagnosis was made. Patients with helminthic infections had higher eosinophil counts than travelers and migrants with other diagnoses (median 981 vs. 710 cells/MUl; p = 0.001), while total IgE levels (n = 70; 172 vs. 152 kU/l; p = 0.731) were similar in both groups. CONCLUSION: Eosinophil count but not total IgE levels are associated with helminthic infections in returning travelers and migrants with eosinophilia. Our results do not support the use of total IgE to differentiate helminthic infections from other causes of eosinophilia in this population. PMID- 28882533 TI - Swelling of the right cheek in an Israeli traveler returning from Columbia: A diagnostic challenge. PMID- 28882534 TI - Corrigendum to "The SAH Score: A Comprehensive Communication Tool" Journal of Stroke & Cerebrovascular Diseases 23 (2014) 902-909. PMID- 28882535 TI - GeDDiS: insight into frontline therapy in soft tissue sarcoma. PMID- 28882536 TI - Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. AB - BACKGROUND: For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. METHODS: The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m2 on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m2 on days 1 and 8 and intravenous docetaxel 75 mg/m2 on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (<=18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009-014907-29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. FINDINGS: Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15.7 29.3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46.3% [95% CI 37.5-54.6] vs 46.4% [37.5-54.8]); median progression-free survival (23.3 weeks [95% CI 19.6-30.4] vs 23.7 weeks [18.1 20.0]; hazard ratio [HR] for progression-free survival 1.28, 95% CI 0.99-1.65, p=0.06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. INTERPRETATION: Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. FUNDING: Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen. PMID- 28882538 TI - Clinicopathologic factors associated with recurrence in parotid carcinoma. AB - INTRODUCTION: Parotid carcinomas have varying histological types and diverse biologic behaviors. Establishing an adequate treatment plan and predicting recurrence is important. OBJECTIVE: To analyze the risk factors associated with recurrence in our 5 year experience with 30 cases of primary parotid carcinoma undergoing surgery at a single institute. METHODS: From January 2009 to December 2013, 30 patients with surgical treatment of parotid carcinoma were identified based on their medical records. RESULTS: The 30 patients were comprised of 17 males and 13 females. Among 11 patients with T4 tumors, seven patients had recurrence. Among seven patients with cervical nodal metastasis, all patient except one had recurrence. Clinically late stages (stage III and IV) showed more common recurrence than early stage (stage I and II) lesions. Lymphovascular invasion was seen in 5 patients, and all patients had recurrence. Among 11 patients with extracapsular spread, 7 patients had recurrence. In 17 patients with high grade carcinomas, ten patients had recurrence. In 13 patients with low grade carcinomas, no patients experienced recurrence. CONCLUSION: T- and N-stage, clinical stage, lymphovascular invasion, extracapsular spread, and histopathologic grade correlate significantly with recurrence in parotid carcinoma. PMID- 28882539 TI - Multidimensional effects of voice therapy in patients affected by unilateral vocal fold paralysis due to cancer. AB - INTRODUCTION: Patients with unilateral vocal fold paralysis may demonstrate different degrees of voice perturbation depending on the position of the paralyzed vocal fold. Understanding the effectiveness of voice therapy in this population may be an important coefficient to define the therapeutic approach. OBJECTIVE: To evaluate the voice therapy effectiveness in the short, medium and long-term in patients with unilateral vocal fold paralysis and determine the risk factors for voice rehabilitation failure. METHODS: Prospective study with 61 patients affected by unilateral vocal fold paralysis enrolled. Each subject had voice therapy with an experienced speech pathologist twice a week. A multidimensional assessment protocol was used pre-treatment and in three different times after voice treatment initiation: short-term (1-3 months), medium term (4-6 months) and long-term (12 months); it included videoendoscopy, maximum phonation time, GRBASI scale, acoustic voice analysis and the portuguese version of the voice handicap index. RESULTS: Multiple comparisons for GRBASI scale and VHI revealed statistically significant differences, except between medium and long term (p<0.005). The data suggest that there is vocal improvement over time with stabilization results after 6 months (medium term). From the 28 patients with permanent unilateral vocal fold paralysis, 18 (69.2%) reached complete glottal closure following vocal therapy (p=0.001). The logistic regression method indicated that the Jitter entered the final model as a risk factor for partial improvement. For every unit of increased Jitter, there was an increase of 0.1% (1.001) of the chance for partial improvement, which means an increase on no full improvement chance during rehabilitation. CONCLUSION: Vocal rehabilitation improves perceptual and acoustic voice parameters and voice handicap index, besides favor glottal closure in patients with unilateral vocal fold paralysis. The results were also permanent during the period of 1 year. The Jitter value, when elevated, is a risk factor for the voice therapy success. PMID- 28882537 TI - Bevacizumab-induced hypertension: Clinical presentation and molecular understanding. AB - Bevacizumab is a vascular endothelial growth factor-A-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of several types of cancer. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy and lead to other cardiovascular complications. The factors that contribute to interindividual variability in blood pressure response to bevacizumab treatment are not well understood. In this review, we outline research efforts to understand the mechanisms and pathophysiology of hypertension resulting from bevacizumab treatment. Moreover, we highlight current knowledge of the pharmacogenetics of bevacizumab-induced hypertension, which may be used to develop strategies to prevent or minimize this toxicity. PMID- 28882540 TI - Symptoms of anxiety and depression are independently associated with inflammatory bowel disease-related disability. AB - BACKGROUND: Inflammatory bowel disease (IBD) frequently results in disability. The relevance of psychological effects in causing disability, and whether disability occurs similarly in non-Western cohorts is as yet unknown. AIM: We assessed the relationship between symptoms of anxiety and depression, quality of life and disability in a Singaporean IBD cohort and their predictors. METHODS: Cross-sectional study. We assessed consecutive IBD subjects' IBD-Disability Index (IBD-DI), Hospital Anxiety and Depression Scale (HADS), and IBD questionnaire (IBDQ). Clinical and demographic variables were collected. Non-parametric statistical analyses were performed. Independent predictors of disability were identified through multivariate logistic regression. RESULTS: 200 consecutive subjects were recruited (males: 69%; median age: 43.8 (+/-15.4) years; 95 had Crohn's disease (CD), 105 had ulcerative colitis (UC); median IBD duration: 10.8 (+/-9.0) years.) 27% of the cohort had anxiety and/or depression, which worsened disability (IBD-DI: -9 (+/-14) with anxiety vs 6 (+/-13) without anxiety, P<0.001; -12 (+/-16) with depression vs 5 (+/-13) without depression, P<0.001). Age at diagnosis, use of prednisolone, stricturing CD and active IBD were significant predictors of disability. IBDQ strongly correlated with IBD DI(rs=0.82, P<0.01). CONCLUSION: Symptoms of anxiety and depression were common in this Asian cohort of IBD and were strongly associated with IBD-related disability. Recognizing psychological issues contributing to disability in IBD is important to ensure holistic care and appropriate treatment. PMID- 28882542 TI - Applications of Optobiology in Intact Cells and Multicellular Organisms. AB - Temporal kinetics and spatial coordination of signal transduction in cells are vital for cell fate determination. Tools that allow for precise modulation of spatiotemporal regulation of intracellular signaling in intact cells and multicellular organisms remain limited. The emerging optobiological approaches use light to control protein-protein interaction in live cells and multicellular organisms. Optobiology empowers light-mediated control of diverse cellular and organismal functions such as neuronal activity, intracellular signaling, gene expression, cell proliferation, differentiation, migration, and apoptosis. In this review, we highlight recent developments in optobiology, focusing on new features of second-generation optobiological tools. We cover applications of optobiological approaches in the study of cellular and organismal functions, discuss current challenges, and present our outlook. Taking advantage of the high spatial and temporal resolution of light control, optobiology promises to provide new insights into the coordination of signaling circuits in intact cells and multicellular organisms. PMID- 28882543 TI - Longitudinal study of a NoGo-P3 event-related potential component following mild traumatic brain injury in adults. AB - BACKGROUND: Event-related potentials have repeatedly revealed electrophysiological markers of cognitive dysfunction associated with Mild Traumatic Brain Injury (MTBI) and may represent a sensitive tool to guide cognitive rehabilitative interventions. We previously found patients with symptomatic MTBI characterized by smaller P300 (or P3) wave amplitudes in a NoGo P3 subcomponent in the acute phase of the injury. The goal of this longitudinal study was to investigate whether this early NoGo-P3 subcomponent differs over time in symptomatic MTBI patients and healthy controls. METHODS: We included adults with a diagnosis of MTBI and individually matched healthy controls tested at 1 week, 3 months, and 1 year after the MTBI. Symptoms were assessed by the Rivermead Post-Concussion Symptoms Questionnaire. NoGo-P3 was collected by using a cued Go/NoGo task and the relevant subcomponent was extracted by independent component analysis. RESULTS: Among 53 adults with a diagnosis of MTBI and 53 controls, we included 35 with symptomatic MTBI and 35 matched healthy controls (18 females each group; mean age 34.06+/-13.15 and 34.26+/-12.98 years). Amplitudes for the early NoGo-P3 subcomponent were lower for symptomatic MTBI patients than controls (P<0.05) at 1 week post-injury. Furthermore, mixed ANOVA revealed a significant time by group interaction (P<0.05), so the effect of time differed for symptomatic MTBI patients and healthy controls. The amplitudes for MTBI patients normalized from 1 week to 3 months post-injury and were comparable to those of controls from 3 months to 1 year post-injury. However, amplitudes for 3 MTBI patients with particularly severe complaints 1 year post-injury did not normalize and were lower than those for the remaining MTBI sample (P<0.05). CONCLUSIONS: Selected event-related potentials can be used as a sensitive and objective tool to illustrate the cognitive consequences of and recovery after MTBI. PMID- 28882541 TI - Structures of Leishmania Fructose-1,6-Bisphosphatase Reveal Species-Specific Differences in the Mechanism of Allosteric Inhibition. AB - The gluconeogenic enzyme fructose-1,6-bisphosphatase has been proposed as a potential drug target against Leishmania parasites that cause up to 20,000-30,000 deaths annually. A comparison of three crystal structures of Leishmania major fructose-1,6-bisphosphatase (LmFBPase) along with enzyme kinetic data show how AMP acts as an allosteric inhibitor and provides insight into its metal-dependent reaction mechanism. The crystal structure of the apoenzyme form of LmFBPase is a homotetramer in which the dimer of dimers adopts a planar conformation with disordered "dynamic loops". The structure of LmFBPase, complexed with manganese and its catalytic product phosphate, shows the dynamic loops locked into the active sites. A third crystal structure of LmFBPase complexed with its allosteric inhibitor AMP shows an inactive form of the tetramer, in which the dimer pairs are rotated by 18 degrees relative to each other. The three structures suggest an allosteric mechanism in which AMP binding triggers a rearrangement of hydrogen bonds across the large and small interfaces. Retraction of the "effector loop" required for AMP binding releases the side chain of His23 from the dimer-dimer interface. This is coupled with a flip of the side chain of Arg48 which ties down the key catalytic dynamic loop in a disengaged conformation and also locks the tetramer in an inactive rotated T-state. The structure of the effector site of LmFBPase shows different structural features compared with human FBPases, thereby offering a potential and species-specific drug target. PMID- 28882544 TI - Gene2DisCo: Gene to disease using disease commonalities. AB - OBJECTIVE: Finding the human genes co-causing complex diseases, also known as "disease-genes", is one of the emerging and challenging tasks in biomedicine. This process, termed gene prioritization (GP), is characterized by a scarcity of known disease-genes for most diseases, and by a vast amount of heterogeneous data, usually encoded into networks describing different types of functional relationships between genes. In addition, different diseases may share common profiles (e.g. genetic or therapeutic profiles), and exploiting disease commonalities may significantly enhance the performance of GP methods. This work aims to provide a systematic comparison of several disease similarity measures, and to embed disease similarities and heterogeneous data into a flexible framework for gene prioritization which specifically handles the lack of known disease-genes. METHODS: We present a novel network-based method, Gene2DisCo, based on generalized linear models (GLMs) to effectively prioritize genes by exploiting data regarding disease-genes, gene interaction networks and disease similarities. The scarcity of disease-genes is addressed by applying an efficient negative selection procedure, together with imbalance-aware GLMs. Gene2DisCo is a flexible framework, in the sense it is not dependent upon specific types of data, and/or upon specific disease ontologies. RESULTS: On a benchmark dataset composed of nine human networks and 708 medical subject headings (MeSH) diseases, Gene2DisCo largely outperformed the best benchmark algorithm, kernelized score functions, in terms of both area under the ROC curve (0.94 against 0.86) and precision at given recall levels (for recall levels from 0.1 to 1 with steps 0.1). Furthermore, we enriched and extended the benchmark data to the whole human genome and provided the top-ranked unannotated candidate genes even for MeSH disease terms without known annotations. PMID- 28882545 TI - How patients' use of social media impacts their interactions with healthcare professionals. AB - INTRODUCTION: Patients are increasingly accessing online health information and have become more participatory in their engagement with the advent of social media (SM). This study explored how patients' use of SM impacted their interactions with healthcare professionals (HCPs). METHODS: Focus groups (n=5) were conducted with 36 patients with chronic conditions and on medication who used SM for health-related purposes. The discussions lasted 60-90min, were audio recorded, transcribed verbatim, and thematically analysed. RESULTS: Participants did not interact with HCPs on SM and were not expecting to do so as they used SM exclusively for peer interactions. Most reported improvement in the patient-HCP relationship due to increased knowledge, better communication, and empowerment. Participants supplemented HCP-provided information with peer interactions on SM, and prepared themselves for consultations. They shared online health information with HCPs, during consultations, to validate it and to actively participate in the decision-making. Although some participants reported HCP support for their online activities, most perceived overt or tacit opposition. CONCLUSION: Participants perceived that their SM use positively impacted relationships with HCPs. They felt empowered and were more assertive in participating in decision making. PRACTICE IMPLICATIONS: HCPs should be aware of patients' activities and expectations, and support them in their online activities. PMID- 28882546 TI - Patient-centered communication between adolescent and young adult cancer survivors and their healthcare providers: Identifying research gaps with a scoping review. AB - OBJECTIVE: To conduct a scoping literature review to identify practices or programs that promote AYA patient-centered communication. METHODS: Between January and May of 2016, we applied standard scoping review methodology to systematically review articles. We considered peer-reviewed, English language articles written at any phase of intervention research. Both qualitative and quantitative studies were eligible, and no additional search restrictions were applied. We retained articles that included explicit or implicit outcomes for one of the six functions of patient-centered communication in cancer care. At least two independent reviewers assessed the articles. RESULTS: We screened a total of 4072 titles and abstracts, retaining 27 for full-text review. Ultimately, eight titles met the review's inclusion criteria. We categorized each publication by the action or setting used to improve patient-centered communication, resulting in five categories. Most studies were not included because they did not include a patient-centered communication outcome. CONCLUSION: This area of research is still emerging, as indicated by the small number of eligible studies and predominance of qualitative, descriptive, pilot, and feasibility studies with small sample sizes. PRACTICE IMPLICATIONS: Our results suggest a clear need to develop and evaluate interventions focused on improving patient-centered communication between AYA survivors and their healthcare providers. PMID- 28882548 TI - Pleistocene fossil woods from the Okote Member, site FwJj 14 in the Ileret region, Koobi Fora Formation, northern Kenya. AB - On the eastern side of Lake Turkana in northern Kenya are extensive Plio Pleistocene deposits containing a rich diversity of fossil mammals, hominins and flora within the radiometrically dated tuffaceous, lacustrine and fluvial sequence. Reconstruction of this landscape and paleoenvironment are part of an ongoing multinational and multidisciplinary human evolution project in the eastern Turkana Basin. Today there is a huge lake in the Rift Valley but it has fluctuated since the early Pliocene. Silicified wood is fairly common in some areas of the Koobi Fora Formation. One such site is FwJj 14E, alongside one of the tributaries of the Ileret River. Hominin hand and arm bones have been excavated from here in the Okote Member and dated at 1.56-1.36 Ma. The fossils are associated with hominin and bovid footprints. Sixty of the over 100 wood specimens collected have been sectioned and studied. In general the woods have large vessels and an average vulnerability index of 40, which implies a mesic megathermal environment with no water stress. Taxonomically the woods belong to large African families: Caesalpiniaceae (Didelotia idae), Combretaceae (Anogeissus sp.), Putranjivaceae (Euphorbiaceae; Drypetes sp.), Lamiaceae (cf Premna sp.), Malvaceae (Heritiera sp.) and Sapindaceae (Sapindoxylon sp.). Most of these taxa do not occur in the area today because now it is much drier and the local vegetation is predominantly Acacia-Commiphora-Salvadora shrubland. The reconstruction of the paleovegetation supports the interpretation from the fauna, namely, a tall riverine forest with shady refuge trees, possibly some edible fruits, and wooded grassland and more open bushland in the vicinity. PMID- 28882547 TI - Molecular dynamics simulations of ether- and ester-linked phospholipids. AB - Dissimilarities in the bulk structure of bilayers composed of ether- vs ester linked lipids are well-established; however, the atomistic interactions responsible for these differences are not well known. These differences are important in understanding of why archaea have a different bilayer composition than the other domains of life and why humans have larger concentrations of plasmalogens in specialized membranes? In this paper, we simulate two lipid bilayers, the ester linked dipalmitoylphosphatidylcholine (DPPC) and the ether lined dihexadecylphosphatidylcholine (DHPC), to study these variations. The structural analysis of the bilayers reveals that DPPC is more compressible than DHPC. A closer examination of dipole potential shows DHPC, despite having a smaller dipole potential of the bilayer, has a higher potential barrier than DPPC at the surface. Analysis of water order and dynamics suggests DHPC has a more ordered, less mobile layer of water in the headgroup. These results seem to resolve the issue as to whether the decrease in permeability of DHPC is due to of differences in minimum area per lipid (A0) or diffusion coefficient of water in the headgroup region (Dhead) (Guler et al., 2009) since we have shown significant changes in the order and mobility of water in that region. PMID- 28882549 TI - Effect of Knowledge of Self-removability of Intrauterine Contraceptives on Uptake, Continuation, and Satisfaction. AB - OBJECTIVE: Preference for control over use is a consideration in choosing a contraceptive method. Counseling women on the possibility of intrauterine device (IUD) self-removal may increase interest in the method. This study tests whether counseling on self-removability as a stated feature of IUDs affects uptake, satisfaction, and continuation. STUDY DESIGN: We monitored clinic-level data on IUD uptake at clinics in Michigan, Missouri, New Jersey, and Utah over 6 months. During the first 3 months, counselors provided standard contraceptive counseling. During the second 3 months, they added information about IUD self-removal. Women who initiated IUD use in both periods were recruited and asked to complete baseline and follow up surveys at 3 and 6 months after insertion. Among 361 women who had IUDs inserted during the study, we compared outcomes for women who did and did not receive information about self-removability during contraceptive counseling. We conducted descriptive analyses to test for differences by group and used logistic regression and survival analysis to assess discontinuation. RESULTS: There were no differences in IUD uptake, satisfaction, or discontinuation by receipt of self-removal information. Those who did not receive information about self-removal were more likely to report considering discontinuing use of the IUD. One-third of participants who considered discontinuation faced barriers to IUD removal. Knowledge of self-removability before the study was high in both groups, reducing our ability to find group differences. CONCLUSIONS: Counseling women on the possibility of self-removal may empower women when they face barriers to removal at facilities. More research is needed to understand whether knowledge of self-removal increases uptake and continuation. PMID- 28882552 TI - Prognostic and predictive biomarkers in breast cancer: Past, present and future. AB - Following a diagnosis of breast cancer, the most immediate challenges in patient management are the determination of prognosis and identification of the most appropriate adjuvant systemic therapy. Determining prognosis can best be addressed with a combination of traditional clinicopathological prognostic factors, biomarkers such as HER2/neu and specific multigene genes tests. Amongst the best validated prognostic multigene tests are uPA/PAI1, Oncotype DX and MammaPrint. Oncotype DX and MammaPrint, may be used for predicting outcome and aiding adjunct therapy decision making in patients with ER-positive, HER2 negative breast cancers that are either lymph node-negative or node positive (1-3 metastatic nodes), while uPA/PAI-1 may be similarly used in ER-positive, lymph node-negative patients. For selecting likely response to endocrine therapy, both estrogen receptors (ER) and progesterone receptors (PR) should be measured. On the other hand, for identifying likely response to anti-HER2 therapy, determination of HER2 gene amplification or overexpression is necessary. To identify new prognostic and predictive biomarkers for breast cancer, current research is focusing on tumor and circulating DNA (ctDNA) and RNA (e.g., micro RNAs) and circulating tumor cells. A promising ctDNA biomarker is the mutational status of ER (ESR1) for predicting the emergence of resistance to aromatase inhibitors. Challenges for future research include the identification of biomarkers for predicting response to radiotherapy and specific forms of chemotherapy. PMID- 28882550 TI - Partner Relationships and Injection Sharing Practices among Rural Appalachian Women. AB - BACKGROUND: The role of relationships in initiating and maintaining women's risk behaviors has been established. However, understanding factors that may underlie partner relationships and women's risky drug use, particularly in rural contexts, is limited. This study is the first to examine the association between injecting partners and women's risky injection practices as a function of relationship power perception. METHODS: Female participants were recruited from three rural jails in the Appalachian region. Women were selected randomly, provided informed consent, and screened for study eligibility criteria. This cross-sectional analysis focuses on women who inject drugs during the year before entering jail (n = 199). MAIN FINDINGS: Approximately three-quarters (76%) reported having a recent main male sexual partner with a history of injection drug use. Although having a risky partner independently increased the likelihood of women reporting shared injection practices, perceptions of relationship power significantly moderated the effect on shared needle (adjusted odds ratio, 0.02; 95% CI, 0.003 0.23; p = .001) and shared works (adjusted odds ratio, 0.17; 95% CI, 0.03-0.95; p = .04) use. CONCLUSIONS: This interaction indicated that, for women who inject drugs with a recent injecting male partner, greater perception of relationship power was associated with a decreased likelihood of shared injection practices. Implications for clinical assessment and intervention are discussed. PMID- 28882551 TI - What Women Want from Their Health Care Providers about Pregnancy Options Counseling: A Qualitative Study. AB - OBJECTIVES: Unintended pregnancy is common in the United States, yet scant research has evaluated women's preferences on pregnancy options counseling. This study explores pregnant women's preferences for pregnancy options counseling from health care providers. METHODS: We conducted semistructured interviews with pregnant women at a prenatal clinic and an abortion clinic. We asked women about recent discussions-or lack thereof-about pregnancy options (parenting, adoption, and abortion) with a clinician, and what they would want their provider to discuss about pregnancy options. We analyzed transcripts using modified grounded theory. FINDINGS: We interviewed 10 women in prenatal care and 18 women seeking abortion. In both settings, most said clinicians should discuss pregnancy options with pregnant women and 1) respect patient autonomy, 2) avoid assumptions about a woman's desired pregnancy outcome, and 3) consider the patient-including her health and fertility intentions-beyond her pregnancy. Participants wanted their doctors to assess a pregnancy's individual circumstances to determine the appropriateness of options counseling. A few participants, including women who did and did not receive options counseling, reported they personally preferred not to receive such counseling. Explaining this preference, they cited preservation of privacy, having already made a decision for the pregnancy, or just not wanting to discuss abortion. Regarding best practices for providing options counseling, participants said it should be done in a routine manner, with discretion, and early in pregnancy. CONCLUSIONS: Pregnant women seeking both prenatal and abortion care broadly support options counseling. IMPLICATIONS: Discussion of pregnancy options, including abortion, provides patient-centered care and supports women's preferences. PMID- 28882553 TI - Non-parametric estimation of low-concentration benzene metabolism. AB - Two apparently contradictory findings in the literature on low-dose human metabolism of benzene are as follows. First, metabolism is approximately linear at low concentrations, e.g., below 10 ppm. This is consistent with decades of quantitative modeling of benzene pharmacokinetics and dose-dependent metabolism. Second, measured benzene exposure and metabolite concentrations for occupationally exposed benzene workers in Tianjin, China show that dose-specific metabolism (DSM) ratios of metabolite concentrations per ppm of benzene in air decrease steadily with benzene concentration, with the steepest decreases below 3 ppm. This has been interpreted as indicating that metabolism at low concentrations of benzene is highly nonlinear. We reexamine the data using non parametric methods. Our main conclusion is that both findings are correct; they are not contradictory. Low-concentration metabolism can be linear, with metabolite concentrations proportional to benzene concentrations in air, and yet DSM ratios can still decrease with benzene concentrations. This is because a ratio of random variables can be negatively correlated with its own denominator even if the mean of the numerator is proportional to the denominator. Interpreting DSM ratios that decrease with air benzene concentrations as evidence of nonlinear metabolism is therefore unwarranted when plots of metabolite concentrations against benzene ppm in air show approximately straight-line relationships between them, as in the Tianjin data. Thus, an apparent contradiction that has fueled heated discussions in the recent literature can be resolved by recognizing that highly nonlinear, decreasing DSM ratios are consistent with linear metabolism. PMID- 28882555 TI - Treatment-induced changes in the androgen receptor axis: Liquid biopsies as diagnostic/prognostic tools for prostate cancer. AB - Prostate cancer progression and treatment relapse is associated with changes in the androgen receptor axis, and analysis of alternations of androgen receptor signaling is valuable for prognostics and treatment optimization. The profile of androgen receptor axis is currently obtained from biopsy specimens, which are not always easy to obtain. Moreover, the information acquired only provides a snapshot of the tumor biology, with strict spatial and temporal limitations. On the other hand, circulation is easily accessible source of both circulating tumor cells and circulating tumor DNA, which can be sampled at numerous time points. This Review will explore the potential use of androgen receptor axis alternations detectable in the blood in therapeutic decision-making and precision medicine for advancing metastatic castration-resistant prostate cancer. PMID- 28882556 TI - Role of the microbiota in skin immunity and atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15-20% of children and 2-5% of adults in industrialized countries. The pathogen Staphylococcus aureus selectively colonizes the lesional skin of AD patients while this bacterium is absent in the skin of the majority of healthy individuals. However, the role of S. aureus in the pathogenesis of AD remains poorly understood. In addition to S. aureus, recent studies show a contribution of the skin microbiota to the regulation of immune responses in the skin as well as to the development of inflammatory skin disease. This review summarizes current knowledge about the role of the microbiota in skin immune responses and the role of S. aureus virulent factors in the pathogenesis of AD. PMID- 28882554 TI - The impact of androgen actions in neurons on metabolic health and disease. AB - The male hormone testosterone exerts different effects on glucose and energy homeostasis in males and females. Testosterone deficiency predisposes males to visceral obesity, insulin resistance and type 2 diabetes. However, testosterone excess predisposes females to similar metabolic dysfunction. Here, we review the effects of testosterone actions in the central nervous system on metabolic function in males and females. In particular, we highlight changes within the hypothalamus that control glucose and energy homeostasis. We distinguish the organizational effects of testosterone in the programming of neural circuitry during development from the activational effects of testosterone during adulthood. Finally, we explore potential sites where androgen might be acting to impact metabolism within the central nervous system. PMID- 28882557 TI - Exposure amount and timing of solar irradiation during pregnancy and the risk of sensitization in children. AB - BACKGROUND: Solar irradiation affects sensitization to aeroallergens and the prevalence of allergic diseases. Little is known, however, about how the time and amount of solar irradiation during pregnancy affects such risks in children. We aimed to find out how solar irradiation during pregnancy affects sensitization to aero-allergens and the prevalence of allergic diseases in children. METHODS: This population-based cross-sectional study involved 7301 aged 6 years and aged 12 years children. Maternal exposure to solar irradiation during pregnancy was evaluated using data from weather stations closest to each child's birthplace. Monthly average solar irradiation during the second and third trimesters was calculated with rank by quartiles. Risks of allergic sensitization and allergic disease were estimated. RESULTS: Relative to the first (lowest) quartile, the adjusted odds ratio (aOR) for allergic sensitization in the fourth (highest) quartile was lowest within solar irradiation during pregnancy months 5-6 (aOR = 0.823, 95% CI 0.720-0.942, p < 0.05). During months 9-10, the aOR for allergic sensitization for the fourth was higher than the first quartile of solar irradiation (aOR = 1.167, 95% CI 1.022-1.333, p < 0.05). Similar results were observed when solar irradiation was analyzed as a continuous variable during months 5 (aOR = 0.975, 95% CI 0.962-0.989, p < 0.001) and month 9 (aOR = 1.018, 95% CI 1.004-1.031, p = 0.003). Increased solar irradiation during months 7-8 increased the risk of asthma (aOR = 1.309, 95% CI 1.024-1.674, p = 0.032). CONCLUSIONS: Maternal exposure to solar irradiation during the second trimester of pregnancy associated with reduced aeroallergen sensitization, whereas solar irradiation during the third trimester was related to increased sensitization to aeroallergens. PMID- 28882558 TI - Cinnamaldehyde protects human dental pulp cells against oxidative stress through the Nrf2/HO-1-dependent antioxidant response. AB - Cinnamaldehyde (CA) has various functional properties, such as anti-cancer, anti microbial, anti-inflammatory, and anti-oxidant activities. This study examined the intracellular signaling mechanisms of CA on the oxidative stress response in human dental pulp cells (hDPCs). The results showed that CA did not have any cell cytotoxicity or cause morphological changes at concentrations up to 50uM. A CA treatment strongly up-regulated the cellular protein level of heme oxygenase-1 (HO-1) and promoted Nrf2 translocation to the nucleus. CA-mediated Nrf2/HO-1 activation reduced the level of reactive oxygen species and protected the hDPCs from H2O2-induced oxidative stress, which induces apoptosis. Moreover, HO-1 depletion by siRNA attenuated the CA-mediated cell protection against oxidative stress. These results indicate that CA protects hDPCs dysfunction under oxidative stress conditions, and this effect is mediated by Nrf2 activation and the up regulation of HO-1. Overall, these observations suggest that CA is a potential therapeutic agent for cell protection against oxidative stress. PMID- 28882559 TI - Enhancement of S1P-induced contractile response in detrusor smooth muscle of rats having cystitis. AB - Interstitial cystitis is a chronic disease characterized by lower abdominal pain and some nonspecific symptoms including an increase in urinary frequency and urgency. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that controls smooth muscle tone via G-protein coupled receptors (S1P1-3 receptors). S1P production is known to take place both in physiological states and some pathological situations, such as in overactive bladder syndrome. The intracellular mechanism of S1P-induced contractile response was investigated in beta-escin permeabilized detrusor smooth muscle of rats having cyclophosphamide induced cystitis. The bladder was isolated from rats and detrusor smooth muscle strips were permeabilized with beta-escin. S1P (50uM)-induced contraction and calcium sensitization response were significantly increased in cystitis. S1P induced augmented contractile response was inhibited by S1P2 receptor antagonist JTE-013 and S1P3 receptor antagonist suramin. S1P2 receptor protein expressions were increased in cystitis, where no change was observed in S1P3 expressions between control and cystitis groups. S1P-induced contraction was reduced by Rho kinase (ROCK) inhibitor Y-27632 and protein kinase C (PKC) inhibitor GF-109203X in both control and cystitis group. S1P-induced increased calcium sensitization response was decreased by ROCK inhibitor and PKC inhibitor in cystitis. Our findings provide the first evidence that interstitial cystitis triggers S1P induced increase in intracellular calcium in permeabilized detrusor smooth muscle of female rats. Both S1P2 and S1P3 receptors are involved in S1P mediated enhanced contractile response. The augmentation in S1P-induced contraction in interstitial cystitis involves both PKC and ROCK pathways of calcium sensitization. PMID- 28882560 TI - Plan B (-cell) in atherosclerosis. AB - Atherosclerosis is a leading cause of death worldwide. It is a complex chronic inflammatory disease involving interactions between vascular, circulating and immune cells. B cells play an important role in chronic inflammation producing antibodies and regulating T and natural killer (NKT) cell activation. The role of B cells in atherosclerosis is complex, with atherogenic and protective roles assigned for distinct B cell subsets. Drugs that deplete B cells or modulate their functions are now used in the treatment of various autoimmune diseases in humans. Here, we briefly review the roles of B cell subsets in atherogenesis, and emphasize the potential impact of B cell targeted therapies on the cardiovascular risk of treated patients. Developing more B cell subset-specific therapies would lead to more effective treatments with enhanced safety profile. PMID- 28882561 TI - Locomotor and reinforcing effects of pentedrone, pentylone and methylone in rats. AB - The broad diversity of synthetic cathinone psychostimulant drugs that are available to users complicates research efforts to provide understanding of health risks. Second generation cathinones pentedrone and pentylone are distinguished from each other by the 3,4-methylenedioxy structural motif (which distinguishes methamphetamine from 3,4-methylenedioxymethamphetamine) and each incorporates the alpha-alkyl chain motif contained in the transporter-inhibitor cathinones (3,4-methylenedioxypyrovalerone (MDPV), alpha-pyrrolidinopentiophenone (alpha-PVP)) but not in the monoamine releasers (mephedrone, methylone). Studies were conducted in male and female Wistar rats to compare locomotor and thermoregulatory effects of pentedrone, pentylone and methylone using an implanted radiotelemetry system. Reinforcing effects were assessed in female Wistar rats trained in the intravenous self-administration (IVSA) procedure and subjected to dose-substitution (0.025-0.3 m/gkg/inf) under a fixed-ratio 1 response contingency. Pentedrone, pentylone and methylone dose-effect curves were contrasted with those for alpha-PVP and alpha-pyrrolidinohexiophenone (alpha PHP). Dose dependent increases in locomotion were observed after intraperitoneal injection of pentylone (0.5-10.0 mg/kg), pentedrone (0.5-10.0 mg/kg) or mephedrone (0.5-10.0 mg/kg) in male and female rats. The maximum locomotor effect was similar across drugs but lasted longest after pentedrone. Mean body temperature did not vary systematically more than 0.5 degrees C after pentedrone or pentylone in either sex. A sustained hyperthermia (0.4-0.8 degrees C) was observed for four hours after 10.0 mg/kg methylone in male rats. More infusions of pentedrone or pentylone were self-administered compared with methylone, but all three were less potent than alpha-PVP or alpha-PHP. These studies support the inference that second generation cathinones pentylone and pentedrone have abuse liability greater than that of methylone. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 28882562 TI - Candesartan prevents resiniferatoxin-induced sensory small-fiber neuropathy in mice by promoting angiotensin II-mediated AT2 receptor stimulation. AB - Sensory defects associated with small-fiber neuropathy (SFN) can lead to profound disabilities. The relationship between the sensory nervous system and modulation of the renin-angiotensin system (RAS) has been described and focused on pain and neurodegeneration in several animal models. We have recently developed an experimental model of functional sensory neuropathy showing thermal hypoalgesia and neuropeptide depletion without nerve fiber degeneration. Here, we aimed to determine whether the modulation of angiotensin II (Ang II) activity could prevent sensory neuropathy induced by RTX. Control and RTX mice received ramipril, an Ang II converting enzyme (ACE) inhibitor, (0.5 mg/kg/day) or candesartan, an Ang II type 1 receptor (AT1R) blocker (0.5 mg/kg/day), one day before vehicle or RTX administration, and each day for the next seven days. Ramipril did not have a beneficial effect in RTX mice, whereas candesartan prevented thermal hypoalgesia and reduced neuropeptide depletion in intraepidermal nerve fibers and dorsal root ganglion neurons. The preventive effect of candesartan was not observed in mice deficient for the Ang II type 2 receptor (AT2R) and was counteracted in wild type mice by EMA200, an AT2R antagonist (3 mg/kg/day). Thus, candesartan may promote AT2R activation by blocking AT1R and increasing Ang II production and enhance its mechanisms of neuroprotection in our RTX model. Our finding that candesartan prevents nociception deficits and neuropeptide depletion encourages the evaluation of its therapeutic potential in patients presenting SFN, particularly those who experience chemotherapy-induced SFN. PMID- 28882563 TI - Adenosine A1 receptor potentiated glycinergic transmission in spinal cord dorsal horn of rats after peripheral inflammation. AB - Adenosine is present at the extracellular space within spinal cord dorsal horn and engaged in the processing of nociceptive sensory signals. Systemic or spinal administration of exogenous adenosine produces a potent analgesia against pathological pain. Here we found that inhibitory glycinergic neurotransmission was an important target for adenosine regulation. In spinal cord slices from intact rats, adenosine increased the inhibitory postsynaptic currents mediated by glycine receptors (GlyRs). In spinal slices from Complete Freund's Adjuvant injected rats, adenosine potentiated glycinergic transmission to a more degree than in control rats. This synaptic potentiation was dependent on the activation of adenosine A1 receptor (A1R), and attributed to the modification of postsynaptic GlyRs function. The Gi protein-coupled A1R typically signals through Galphai/cAMP-dependent protein kinase (PKA) and Gbetagamma pathways. We found that blockade of either Galphai/PKA or Gbetagamma signaling attenuated the ability of adenosine to increase glycinergic synaptic responses in inflamed rats. To identify which GlyRs subunit was subjected to A1R regulation, we recorded glycine-evoked whole-cell currents in HEK293T cells co-transfected with A1R and distinct GlyRs subunit. We found that alpha1, the most abundant functional GlyRs subunit in adult spinal cord, was insensitive to A1R activation. However, when GlyRs alpha3 subunit or alpha1ins subunit, a longer alpha1 isoform, was co expressed with A1R, adenosine caused a significant increase of glycinergic currents. Inhibition of PKA and Gbetagamma abolished the stimulatory effects of A1R on alpha3 and alpha1ins, respectively. These data suggested that A1R might potentiate glycinergic transmission through Galphai/PKA/alpha3 and Gbetagamma/alpha1ins pathways in inflamed rat. PMID- 28882564 TI - Searching for synergy: Identifying optimal antiviral combination therapy using Hepatitis C virus (HCV) agents in a replicon system. AB - Direct acting antiviral agents (DAAs) are potent inhibitors of Hepatitis C virus (HCV) that have revolutionized the treatment landscape for this important viral disease. There are currently four classes of DAAs that inhibit HCV replication via distinct mechanisms of action: nonstructural protein (NS) 3/4a protease inhibitors, NS5A inhibitors, NS5B nucleoside polymerase inhibitors, and NS5B non nucleoside polymerase inhibitors. Combination therapy with two or more DAAs has great potential to further enhance antiviral potency. The purpose of this study was to identify optimal combinations of DAAs against genotype 1 HCV replicons that maximized the inhibition of replicon replication. All possible two-drug combinations were evaluated against genotype 1a and 1b HCV replicons using a 96 well plate luciferase-based assay in triplicate. The Greco Universal Response Surface Area mathematical model was fit to the luciferase data to identify drug drug interactions (i.e.: synergy, additivity, and antagonism) for antiviral effect against both genotypes. This information was used to rank-order combinations of DAAs based on their ability to inhibit replicon replication against genotype 1a and 1b HCV. These preclinical findings can provide information as to which antiviral regimens should move on in the development process. PMID- 28882566 TI - Genetic variations in UGT2B28, UGT2B17, UGT2B15 genes and the risk of prostate cancer: A case-control study. AB - Glucuronidation is a major pathway for elimination of exogenous and endogenous compounds such as environmental carcinogens and androgens from the body. This biochemical pathway is mediated by enzymes called uridine diphosphoglucuronosyltransferases (UGTs). Null (del/del) genes polymorphisms in UGT2B17, and UGT2B28 and D85Y single-nucleotide polymorphism (SNP) of UGT2B15 have been reported to increase the risk of prostate cancer. The goal of this study was to determine the association of mentioned genetic variants with the risk of prostate cancer. We investigated the copy number variations (CNVs) of UGT2B17 and UGT2B28 loci and the association between rs1902023 polymorphism of UGT2B15 gene in 360 subjects consisted of 120 healthy controls, 120 prostate cancer (PC) patients and 120 benign prostatic hyperplasia (BPH) patients. No association was detected for the mentioned polymorphisms and the risk of PC. However, a significant association was detected between UGT2B17 copy number variation and BPH risk (OR=2.189; 95% CI, 1.303-3.675; p=0.003). Furthermore, we observed that the D85Y polymorphism increases the risk of BPH when analyzed in combination with the copy number variation of UGT2B17 gene (OR=0.135; 95% CI, 0.036-0.512; p=0.003). Our findings suggest that the D85Y polymorphism of UGT2B15 and CNVs in UGT2B28 and UGT2B17 genes is not associated with prostate cancer risk in Iranian patients. To our knowledge, this is the first report that implicates the role of CNV of UGT2B17 gene in BPH. PMID- 28882565 TI - Evidence of disordered calcium metabolism in adolescent girls with type 1 diabetes: An observational study using a dual-stable calcium isotope technique. AB - Type 1 diabetes (T1D) is associated with skeletal abnormalities including low bone density and increased fracture risk. The pathophysiology underlying T1D related skeletal fragility remains unknown. The objective of this study was to use a dual-stable calcium isotope method to investigate the effects of T1D on calcium absorption and estimated calcium retention in adolescent females. Twenty adolescent females with T1D were admitted for a 24-h calcium absorption study using oral (44Ca) and intravenous (42Ca) stable isotopes for determination of percent gastrointestinal calcium absorption and estimated calcium retention. Five out of twenty participants were found to have negative estimated calcium retention. Participants with negative calcium retention had greater urinary calcium excretion [202mg/d (IQR: 178-213)] compared to those with positive calcium retention [101.5mg/d (IQR: 82-122)], p=0.01, but similar calcium intake and percent calcium absorption. With the exception of one outlier, 24-h urine calcium was significantly associated with hemoglobin A1c (Pearson's r=0.55, p=0.02). 50% of participants consumed less than the RDA for calcium; fractional calcium absorption was inversely correlated with calcium intake in participants not meeting the RDA (Spearman's rho -0.65, p=0.04). In conclusion, one-quarter of adolescent girls with T1D were found to have negative estimated calcium retention at a time when bone mineral accrual should be ongoing. This appeared to be the result of excess urinary calcium excretion as opposed to diminished gastrointestinal calcium absorption. Insufficient calcium availability for bone deposition during adolescence could impair bone mineral accrual and contribute to skeletal fragility. Trial registered: ClinicalTrials.gov Reg No. NCT03156179. PMID- 28882567 TI - Anaerobic sulfatase maturase AslB from Escherichia coli activates human recombinant iduronate-2-sulfate sulfatase (IDS) and N-acetylgalactosamine-6 sulfate sulfatase (GALNS). AB - Maturation of type I sulfatases requires the conversion of the cysteine (Cys) or serine (Ser) present in the active site to formylglycine (FGly). This activation represents a limiting step during the production of recombinant sulfatases in bacteria and eukaryotic hosts. AslB, YdeM and YidF have been proposed to participate in the activation of sulfatases in Escherichia coli. In this study, we combined in-silico and experimental approaches to study the interaction between Escherichia coli BL21(DE3) AslB and human sulfatases, more specifically iduronate-2-sulfate sulfatase (IDS) and N-acetylgalactosamine-6-sulfate sulfatase (GALNS). In-silico results show that AslB has a higher affinity for the residual motif of GALNS (-9.4kcalmol-1), Cys- and Ser-type, than for the one of IDS ( 8.0kcalmol-1). However, the distance between the AslB active residue and the target motif favors the interaction with IDS (4.4A) more than with GALNS (5.5A). Experimental observations supported in-silico results where the co-expression of AslB with GALNS Cys- and Ser-type presented an activity increment of 2.0- and 1.5 fold compared to the control cultures, lacking overexpressed AslB. Similarly, IDS activity was increased in 4.6-fold when co-expressed with AslB. The higher sulfatase activity of AslB-IDS suggests that the distance between the AslB active residue and the motif target is a key parameter for the in-silico search of potential sulfatase activators. In conclusion, our results suggest that AslB is involve in the maturation of heterologous human sulfatases in E. coli BL21(DE3), and that it can have important implications in the production of recombinant sulfatases for therapeutic purposes and research. PMID- 28882568 TI - Identification of pathogenic genes related to rheumatoid arthritis through integrated analysis of DNA methylation and gene expression profiling. AB - The purpose of our study was to identify new pathogenic genes used for exploring the pathogenesis of rheumatoid arthritis (RA). To screen pathogenic genes of RA, an integrated analysis was performed by using the microarray datasets in RA derived from the Gene Expression Omnibus (GEO) database. The functional annotation and potential pathways of differentially expressed genes (DEGs) were further discovered by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Afterwards, the integrated analysis of DNA methylation and gene expression profiling was used to screen crucial genes. In addition, we used RT-PCR and MSP to verify the expression levels and methylation status of these crucial genes in 20 synovial biopsy samples obtained from 10 RA model mice and 10 normal mice. BCL11B, CCDC88C, FCRLA and APOL6 were both up regulated and hypomethylated in RA according to integrated analysis, RT-PCR and MSP verification. Four crucial genes (BCL11B, CCDC88C, FCRLA and APOL6) identified and analyzed in this study might be closely connected with the pathogenesis of RA. PMID- 28882569 TI - miR-130a regulates differential lipid accumulation between intramuscular and subcutaneous adipose tissues of pigs via suppressing PPARG expression. AB - To investigate the molecular mechanism underlying differential lipid deposition between intramuscular (IM) and subcutaneous (SC) fat tissues of pigs, peroxisome proliferator-activated receptor gamma (PPARG) expression levels were compared in these two types of adipose tissues. The results showed that both mRNA and protein levels of PPARG were significantly higher in SC fat than in IM fat. Correspondingly, the expression levels of miR-128 and miR-130a, which potentially targeting PPARG 3'-untranslated region (3'-UTR), in IM fat were 8.37 and 2.30 fold of those in SC fat respectively. Further dual luciferase activity assay showed that only miR-130a directly targeting PPARG. Moreover, over-expression of miR-130a in preadipocytes significantly inhibited its differentiation by suppressing PPARG expression. In conclusion, tissue variance of miR-130a levels results in the diverse of PPARG, and might be the reason for differential fat deposition between IM and SC fat tissues in pigs. Our study would provide the molecular foundation for IM fat deposition increase and therefore contribute to pork quality improvement. PMID- 28882570 TI - Taurine restores the exploratory behavior following alcohol withdrawal and decreases BDNF mRNA expression in the frontal cortex of chronic alcohol-treated rats. AB - Alcohol use disorder is an alarming health problem, and the withdrawal symptoms increase the risk of relapse. We have hypothesized that taurine, a multitarget substance acting as a gamma-aminobutyric acid A receptor (GABAAR) positive modulator and a partial inhibitor of N-methyl-d-aspartate (NMDA) glutamate receptors, may reduce the withdrawal symptoms or modify behaviors when combined with alcohol. Therefore, we investigated the effects of taurine on behavior in the open field test (OFT), the GABAAR alpha2 subunit and BDNF mRNA expression in the frontal cortex of rats after chronic alcohol treatment or upon withdrawal. Rats received alcohol 2g/kg (alcohol and withdrawal groups) or water (control group) twice daily by oral gavage for 28days. On day 29, the withdrawal rats received water instead of alcohol, and all groups were reallocated to receive 100mg/kg taurine or vehicle intraperitoneally, once a day for 5days. On day 33, the rats were exposed to OFT; 18h later, they were euthanized, and the frontal cortex was dissected for GABAAR alpha2 subunit detection and BDNF mRNA expression determination by real-time quantitative PCR. Taurine administration restored rearing behavior to the control levels in the withdrawal rats. Taurine also showed anxiolytic-like effects in control rats and did not change the behaviors in the chronic alcohol group. Chronic alcohol treatment or withdrawal did not change the GABAAR alpha2 subunit or BDNF mRNA expression in the frontal cortex, but taurine decreased the alpha2 subunit level in control rats and to the BDNF levels in the alcohol rat group. We conclude that taurine restored exploratory behavior after alcohol withdrawal but that this effect was not related to the GABAAR alpha2 subunit or BDNF mRNA expression in the frontal cortex of the rats. PMID- 28882571 TI - Genome shuffling improved the nucleosides production in Cordyceps kyushuensis. AB - Genome shuffling was first applied to improve the production of nucleosides in Cordyceps kyushuensis. Six improved strains were selected for genome shuffling by UV and HNO2 mutagenesis. Ten improved genome shuffling strains with good genetic stability were obtained, among which, the production of cordycepin in R6 was 9.624 times higher than that of the ancestor. While in R18 and R19, the yield of cordycepin, adenosine, guanosine and uridine were all increased greatly compared with the ancestor. Based on the four phenotypes of the content of cordycepin, adenosine, guanosine and uridine, hierarchical clustering analysis (HCA) and principal component analysis (PCA) were applied to infer the relationships between genome shuffling strains and mutants. PMID- 28882572 TI - Identification of essential transcription factors for adequate DNA damage response after benzo(a)pyrene and aflatoxin B1 exposure by combining transcriptomics with functional genomics. AB - DNA damage mediates widespread changes in transcription through activation or repression of transcription factors (TFs). However, the consequences of regulating specific TFs for the outcome of the DNA repair process remain incompletely understood. Here, we combined transcriptomics and TF binding prediction with functional genomics to identify TFs essential for adequate DNA repair in HepG2 liver cells after a non-cytotoxic dose of carcinogens benzo(a)pyrene (BaP) (2MUM) and aflatoxin B1 (AFB1) (5MUM). BaP and AFB1 induced a largely common transcriptional response, mediated by similar TFs. A lentiviral shRNA screen knocking down the top31 identified TFs, was performed to determine their effect on DNA repair by assessing phosphorylation of H2AX (gamma-H2AX). In addition to the top candidate p53, we identified several other interesting TFs that modulated gamma-H2AX after BaP and AFB1 treatment. Validation studies confirmed the role of p53 in reducing gamma-H2AX formation and DNA breaks measured by COMET assay after BaP and AFB1 exposure. Expression of the cell cycle inhibitor p21 was profoundly impaired upon p53 knock-down. In addition, the expression of 2 genes involved in nucleotide exchange repair, DDB2 and XPC was significantly reduced in p53 knock-down cells. Although p63 knock-down affected DNA damage upon BaP treatment this was not associated with altered expression of DDB2 or XPC. Finally, knock-down of ARNT reduced gamma-H2AX in response to BaP, which was associated with reduced CYP1A1 expression. Importantly, our results suggest a new role for ARNT and its dimerization partner AHR in the occurrence of H2AX phosphorylation after AFB1 treatment. These data show that modulation of TF activity impacts on the repair of BaP- and AFB1-induced DNA damage. Our study also demonstrates the potential of combining functional genomics with genome-wide expression analysis to identify yet unknown causal relationships, thereby aiding in the interpretation of complex biological systems. PMID- 28882573 TI - Scientific and ethical obligations to publish tobacco industry-funded research on nicotine delivery systems of reduced risk. PMID- 28882574 TI - Kupffer cells activation promoted binge drinking-induced fatty liver by activating lipolysis in white adipose tissues. AB - Kupffer cells (KCs) have been suggested to play critical roles in chronic ethanol induced early liver injury, but the role of KCs in binge drinking-induced hepatic steatosis remains unclear. This study was designed to investigate the roles of KCs inhibitor (GdCl3) and TNF-alpha antagonist (etanercept) on binge drinking induced liver steatosis and to explore the underlying mechanisms. C57BL/6 mice were exposed to three doses of ethanol (6g/kg body weight) to mimic binge drinking-induced fatty liver. The results showed that both GdCl3 and etanercept partially but significantly alleviated binge drinking-induced increase of hepatic triglyceride (TG) level, and reduced fat droplets accumulation in mice liver. GdCl3 but not etanercept significantly blocked binge drinking-induced activation of KCs. However, neither GdCl3 nor etanercept could affect binge drinking-induced decrease of PPAR-alpha, ACOX, FAS, ACC and SCD protein levels, or increase of the LC3 II/LC3 I ratio and p62 protein level. Interestingly, both GdCl3 and etanercept significantly suppressed binge drinking-induced phosphorylation of HSL in epididymal adipose tissues. Results of in vitro studies with cultured epididymal adipose tissues showed that TNF-alpha could increase the phosphorylation of HSL in adipose tissues and upgrade the secretion of free fatty acid (FFA) in the culture medium. Taken together, KCs inhibitor and TNF-alpha antagonist could partially attenuate binge drinking-induced liver steatosis, which might be attributed to the suppression of mobilization of white adipose tissues. These results suggest that KCs activation may promote binge drinking induced fatty liver by TNF-alpha mediated activation of lipolysis in white adipose tissues. PMID- 28882575 TI - Cohort study comparing the diagnostic yields of 2 different EUS fine-needle biopsy needles. AB - BACKGROUND AND AIMS: Two second-generation, flexible EUS fine-needle biopsy (FNB) needles have been marketed recently in the United States. Thus far, there have been no comparative studies of the diagnostic yield of these needles. The aim of this study was to compare the diagnostic yield achieved with FNB by using 1 needle during 1 time period and the other needle during a second time period. METHODS: Consecutive patients with solid lesions undergoing EUS-FNB by using 1 of two 22-gauge FNB needles (Franseen needle or fork-tip) at 2 different time intervals were included. The final diagnosis was based on positive pathology results. In cases of a negative pathology result, the final diagnosis was based on clinical and imaging follow-up. RESULTS: A total of 194 lesions (97 in each group) were sampled in 179 patients. Rapid on-site evaluation (ROSE) was used in 12% of cases. The overall diagnostic yield was lower in the Franseen needle group compared with the fork-tip needle group (61/97 [63%] vs 75/97 [77%], odds ratio (OR) 2.01, 1.07-3.8; P = .027). Similarly, subanalysis of the yield for solid pancreatic masses demonstrated a lower yield with the Franseen needle (34/53 [64%] vs 40/47 [85%], OR 3.4, 9.1-8.9; P = .017). Multivariate analysis controlling for the number of passes, site, and lesion size did not have any effect on diagnostic yield. There were no adverse events in either group. CONCLUSION: In this first, large, single-center comparative cohort study of 2 new, second-generation EUS-FNB needles of different design, the diagnostic yield when used primarily without ROSE was high in both groups but was significantly higher when a fork-tip needle was used. PMID- 28882576 TI - Endoscopic features and clinical outcomes of colorectal mucosa-associated lymphoid tissue lymphoma. AB - BACKGROUND AND AIMS: Colorectal mucosa-associated lymphoid tissue (MALT) lymphoma is a rare disease. The purpose of this study was to investigate the clinical and endoscopic features of colorectal MALT lymphoma. METHODS: Patients diagnosed with colorectal MALT lymphoma at Asan Medical Center from 2002 to 2016 were eligible. Medical records were reviewed to investigate clinical features and treatment outcomes. Endoscopic pictures were assessed to characterize the endoscopic features of colorectal MALT lymphoma. RESULTS: A total of 51 patients were enrolled. The median age was 60 years (interquartile range, 55-71), and 21 (41%) were men. Twenty-six patients (51%) were asymptomatic. Forty-four patients (86%) were in early disease stages, namely Lugano stages I, II, and IIE. Endoscopic appearances were classified as 4 distinct types: subepithelial tumor type (26 patients, 51%), polyposis type (10 patients, 20%), epithelial mass type (7 patients, 14%), and ileitis type (8 patients, 16%). The rectum (20 patients, 39%) was the most common location, followed by the ileocecal area (15 patients, 30%). An initial endoscopic impression of lymphoma was made in only 7 patients. Forceps biopsy sampling as the initial tissue acquisition method could histologically diagnose MALT lymphoma in 28 of 35 patients (80%). Polypectomy as the initial histologic diagnosis could diagnose MALT lymphoma in 16 of 16 patients. Progression-free and overall survival rates at 5 years were 92% and 94%, respectively. CONCLUSIONS: Colorectal MALT lymphomas show various endoscopic appearances, complicating the endoscopic suspicion of colorectal MALT lymphoma. The prognosis of colorectal MALT lymphoma was excellent. PMID- 28882577 TI - Assessing colon polypectomy competency and its association with established quality metrics. AB - BACKGROUND AND AIMS: Inadequate polypectomy leads to incomplete resection, interval colorectal cancer, and adverse events. However, polypectomy competency is rarely reported, and quality metrics are lacking. The primary aims of this study were to assess polypectomy competency among a cohort of gastroenterologists and to measure the correlation between polypectomy competency and established colonoscopy quality metrics (adenoma detection rate and withdrawal time). METHODS: We conducted a prospective observational study to assess polypectomy competency among 13 high-volume screening colonoscopists at an academic medical center. Over 6 weeks, we made video recordings of >=28 colonoscopies per colonoscopist and randomly selected 10 polypectomies per colonoscopist for evaluation. Two raters graded the polypectomies by using the Direct Observation of Polypectomy Skills, a polypectomy competency assessment tool, which assesses individual polypectomy skills and overall competency. RESULTS: We evaluated 130 polypectomies. A total of 83 polypectomies (64%) were rated as competent, which was more likely for diminutive (70%) than small and/or large polyps (50%, P = .03). Overall Direct Observation of Polypectomy Skills competency scores varied significantly among colonoscopists (P = .001), with overall polypectomy competency rates ranging between 30% and 90%. Individual skills scores, such as accurately directing the snare over the lesion (P = .02) and trapping an appropriate amount of tissue within the snare (P = .001) varied significantly between colonoscopists. Polypectomy competency rates did not significantly correlate with the adenoma detection rate (r = 0.4; P = .2) or withdrawal time (r = 0.2; P = .5). CONCLUSIONS: Polypectomy competency varies significantly among colonoscopists and does not sufficiently correlate with established quality metrics. Given the clinical implications of suboptimal polypectomy, efforts to educate colonoscopists in polypectomy techniques and develop a metric of polypectomy quality are needed. PMID- 28882578 TI - Surgery versus surveillance in ulcerative colitis patients with endoscopically invisible low-grade dysplasia: a cost-effectiveness analysis. AB - BACKGROUND AND AIMS: There is uncertainty regarding the optimal management of endoscopically invisible (flat) low-grade dysplasia in ulcerative colitis. Such a finding does not currently provide an automatic indication for colectomy; however, a recommendation of surveillance instead of surgery is controversial. The aim of this study was to determine the clinical and cost-effectiveness of colonoscopic surveillance versus colectomy for endoscopically invisible low-grade dysplasia of the colon in ulcerative colitis. METHODS: A Markov model was used to evaluate the costs and health outcomes of surveillance and surgery over a 20-year timeframe. Outcomes evaluated were life years gained and quality-adjusted life years (QALYs). Cohorts of patients aged 25 to 75 were modeled, including estimates from a validated surgical risk calculator and considering none, 1, or both of 2 key comorbidities: heart failure and obstructive airway disease. RESULTS: Surveillance is associated with more life years and QALYs compared with surgery from age 61 for those with no comorbidities, age 51 for those with 1 comorbidity and age 25 for those with 2 comorbidities. At the current United Kingdom National Institute for Health and Care Excellence threshold of $25,800 per QALY, ongoing surveillance was cost-effective at age 65 in those without comorbidities and at age 60 in those with either 1 or more comorbidities. CONCLUSIONS: Surveillance can be recommended from age 65 for those with no comorbidities; however, in younger patients with typical postsurgical quality of life, colectomy may be more effective clinically and more cost-effective. The results were sensitive to the colorectal cancer incidence rate in patients under surveillance and to quality of life after surgery. PMID- 28882579 TI - Accelerator Mass Spectrometry (AMS) in Radioecology. AB - Accelerator Mass Spectrometry (AMS) provides with an excellent sensitivity for the determination of radionuclides in the environment. In fact, conventional radiometric techniques can hardly compete with AMS in the solution of many problems involving the measurement of very low levels of radioactivity in Nature. For that reason, during the last years AMS has become a powerful tool for Radioecology studies. In this paper a review is done on the evolution of AMS applications to the measurement of environmental radioactivity and, therefore, its contribution to the understanding of radionuclide behavior in Nature. For that, the advantages of using AMS to determine key nuclides as 129I, 14C, Pu isotopes and others in different natural compartments will be discussed. The content of the paper is illustrated with the contributions to these studies of the Spanish National Center for Accelerators (CNA) AMS systems. PMID- 28882580 TI - Lotus birth, a holistic approach on physiological cord clamping. AB - BACKGROUND: The positive effects of delayed cord clamping (DCC) has been extensively researched. DCC means: waiting at least one minute after birth before clamping and cutting the cord or till the pulsation has stopped. With physiological clamping and cutting (PCC) the clamping and cutting can happen at the earliest after the pulsation has stopped. With a Lotus birth, no clamping and cutting of the cord is done. A woman called Clair Lotus Day imitated the holistic approach of PCC from an anthropoid ape in 1974. The chimpanzee did not separate the placenta from the newborn. AIM: The aim of this case report is to discuss and learn a different approach in the third stage of labour. METHOD: Three cases of Lotus birth by human beings were observed. All three women gave birth in an out of-hospital setting and had ambulant postnatal care. FINDINGS: The placenta was washed, salted and herbs were put on 2-3h post partum. The placenta was wrapped in something that absorbs the moisture. The salting was repeated with a degreasing frequency depending on moistness of the placenta. On life day six all three Lotus babies experiences a natural separation of the cord. All three Lotus birth cases were unproblematic, no special incidence occurred. CONCLUSIONS: One should differentiate between early cord clamping (ECC), delayed cord clamping (DCC) and physiological cord clamping (PCC). Lotus birth might lead to an optimisation of the bonding and attachment. Research is needed in the areas of both PCC and Lotus birth. PMID- 28882582 TI - Group B Streptococcal infection in neonates and colonization in pregnant women: An epidemiological retrospective analysis. AB - BACKGROUND: Group B Streptococcus (GBS) infection is one of the major causes of neonatal morbidity and mortality. Universal GBS screening with intrapartum antibiotic prophylaxis (IAP) in pregnant women were initiated in 2012 in Taiwan. This study aimed to analyze the most recent maternal GBS colonization rate and the changes in neonatal GBS infection rate from 2011 to 2016. METHODS: All pregnant women and their live born neonates between January 2011 and June 2016 were retrospectively reviewed. Whether GBS screening was done, screening results, presence of risk factors, the use of antibiotics, and neonatal outcome were analyzed. In addition, hospitalized neonates diagnosed with GBS infections were retrieved for comparison of early onset disease (EOD) (<7 days) and late onset disease (LOD) (>=7 days). RESULTS: A total of 9535 women delivered babies during the study period. The maternal GBS screening rate was 71.0% and the colonization rate was 22.6%. The overall neonatal invasive GBS infection rate was 0.81 per 1000 live births and the vertical transmission rate was 1.2%. After 2012, the invasive neonatal GBS infection rate declined from 1.1-1.60/00 to 0.6-0.70/00 in 2014 and thereafter, the GBS EOD incidence rate declined from 2.80/00 to 0.0 0.60/00, but the LOD incidence rate remained approximately 0.70/00. Infants with EOD had strong association with obstetric risk factors. CONCLUSIONS: Taiwan's universal GBS screening with IAP program reduced the incidence rate of neonatal GBS EOD to be lower than 10/00 after 2012. Pediatricians still should pay attention to infants with GBS LOD since its incidence rate remained unchanged. PMID- 28882581 TI - Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV. AB - BACKGROUND & AIMS: Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+. METHODS: Three different groups were studied: (1) Clinical cohort: 100 women who were HCV+ and also had chronic liver disease (CLD), age matched with 50 women who were HBV+ with CLD and with 100 healthy women; all women were consecutively observed in three gastroenterology units in hospitals in Italy; (2) 1,998 women who were HCV+ and enrolled in the Italian Platform for the Study of Viral Hepatitis Therapies (PITER); (3) 6,085 women, who were mono-infected with HCV, and 20,415 women, who were HCV-, from a large de-identified insurance database from the USA. MEASUREMENTS: total fertility rate (TFR) defined as the average number of children that a woman would bear during her lifetime. To define the reproductive stage of each participant, levels of anti-Mullerian hormone (AMH) and 17beta estradiol were measured. RESULTS: Clinical cohort: women who were either HCV+ or HBV+ had similar CLD severity and age at first pregnancy. Based on a multivariate analysis, women who were HCV+ had a higher risk of miscarriage than those who were HBV+ (odds ratio [OR] 6,905; 95% CI 1.771-26.926). Among women who were HCV+, incidence of miscarriage was correlated with median AMH level (1.0 ng/ml). Achieving a sustained virologic response (SVR) after antiviral treatment reduced the risk of miscarriage (OR 0.255; 95% CI 0.090-0.723). In the PITER-HCV cohort, miscarriage occurred in 42.0% of women (44.6% had multiple miscarriages). TFR for women who were HCV+ and between 15 and 49 years of age was 0.7 vs. 1.37 of Italian population of the same age range. In the US cohort: compared with women who were HCV-, women who were HCV+ positive were significantly more likely to have infertility (OR 2.439; 95% CI 2.130-2.794), premature birth (OR 1.34; 95% CI 1.060-1.690), gestational diabetes (OR 1.24; 95% CI 1.020-1.510), and pre eclampsia (OR 1.206; 95% CI 0.935-1.556), and were less likely to have a live birth (OR 0.754; 95% CI 0.622-0.913). CONCLUSIONS: Ovarian senescence in women of childbearing age who are HCV+ is associated with a lower chance of live birth, greater risk of infertility, gestational diabetes, pre-eclampsia and miscarriage. Such risks could be positively influenced by successful HCV cure. LAY SUMMARY: Most new cases of HCV infection are among people who inject drugs, many of whom are young women in their childbearing years. Women of reproductive age who are HCV+ display markers of ovarian senescence. This is associated with an increased burden in terms of infertility and adverse pregnancy outcomes, including stillbirth, miscarriage, fewer live births, and gestational diabetes. Early viral suppression with therapy is likely to mitigate these risks. PMID- 28882583 TI - Clinical and epidemiological characteristics in hospitalized young children with acute gastroenteritis in southern Taiwan: According to major pathogens. AB - BACKGROUND: Acute gastroenteritis (AGE) can be caused by a wide array of pathogens, including bacteria, viruses, and parasites. A prospective study to investigate the epidemiology and clinical presentation in young children hospitalized with AGE was conducted in a medical center in southern Taiwan. METHODS: Patients aged less than 5 years who was hospitalized due to AGE in National Cheng Kung University Hospital were enrolled from July 2014 to June 2016. The demographic information, clinical features and laboratory data were collected by chart reviews, and stool samples were sent to Centers of Disease Control, Taiwan (Taiwan CDC) for a panel of pathogen identification consisting of two viruses, nine bacteria, and five parasites. RESULTS: Totally 441 patients were enrolled in this study. Salmonella spp. was the leading cause of disease (21.8%), followed by norovirus (17.0%), Clostridium difficile (9.5%), and rotavirus (9.3%). Norovirus identification rate was the highest among patients less than 6 months of age, while Salmonella was highest among patients between 2 and 3 years old. Patients with Salmonella infection frequently presented with fever, lethargy, bloody stool, and elevated serum level of C-reactive protein (CRP); norovirus and rotavirus infection frequently presented with vomiting. Salmonella gastroenteritis also resulted in longer hospitalization and more frequent antibiotics administration. C. difficile could be isolated from both gastroenteritis patients and control children. CONCLUSION: Salmonella spp. was the most common pathogen of AGE in hospitalized children in southern Taiwan during 2014-2016, followed by norovirus and rotavirus. Further monitoring of epidemiology characteristics among cardinal pathogens of pediatric gastroenteritis is necessary. PMID- 28882584 TI - Prophylactic Cranial Irradiation (PCI) versus Active MRI Surveillance for Small Cell Lung Cancer: The Case for Equipoise. AB - Prophylactic cranial irradiation (PCI) for SCLC offers a consistent reduction in the incidence of brain metastases at the cost of measurable toxicity to neurocognitive function and quality of life, in the setting of characteristic pathologic changes to the brain. The sequelae of PCI have historically been justified by the perception of an overall survival advantage specific to SCLC. This rationale has now been challenged by a randomized trial in extensive-stage SCLC demonstrating equivalent progression-free survival and a trend toward improved overall survival with PCI omission in the context of modern magnetic resonance imaging (MRI) staging and surveillance. In this article, we critically examine the randomized trials of PCI in extensive-stage SCLC and discuss their implications on the historical data supporting PCI for limited-stage SCLC from the pre-MRI era. Further, we review the toxicity of moderate doses of radiation to the entire brain that underlie the growing interest in active MRI surveillance and PCI omission. Finally, the evidence supporting prospective investigation of radiosurgery for limited brain metastases in SCLC is reviewed. Overall, our aim is to provide an evidence-based assessment of the debate over PCI versus active MRI surveillance and to highlight the need for contemporary trials evaluating optimal central nervous system management in SCLC. PMID- 28882585 TI - Prognostic Impact of Margin Distance and Tumor Spread Through Air Spaces in Limited Resection for Primary Lung Cancer. AB - OBJECTIVES: The aim of this study was to investigate the relationship between clinicopathological prognostic factors, including surgical margin distance and tumor spread through air spaces (STAS), and recurrence after limited resection for primary lung cancer. METHODS: We identified 508 cases of limited resection (12.8%) and examined their clinicopathological features. Using Cox regression analysis, we examined the significant prognostic factors for recurrence of limited resection. Finally, we conducted a histopathological evaluation of tumor STAS. RESULTS: Multivariate Cox analysis showed that the risk for local recurrence was significantly associated with STAS (hazard ratio = 12.24, p = 0.001) and a tumor margin less than 1.0 cm (hazard ratio = 6.36, p = 0.02). However, the presence of tumor STAS was not significantly associated with distant recurrence (p = 0.98). This lack of association of STAS with distant recurrence may be due to the small number of distant recurrences. In all, 76 cases (15.0%) (60 adenocarcinomas, nine squamous cell carcinomas, and seven others) were positive for STAS. The morphological STAS patterns were 12 single cells, 45 small cell clusters, and 19 large nests. There was no significant relationship between the recurrence rate and morphological STAS pattern. The STAS-positive group was associated with the presence of micropapillary (p = 0.002) and/or solid components (p = 0.008) in patients with adenocarcinoma and with lymphovascular and pleural invasion (p < 0.001). CONCLUSIONS: The presence of STAS and tumor margins less than 1.0 cm are significant risk factors for local recurrence in early-stage lung cancer after limited resection. Thus, the presence of tumor STAS might be a pathological prognostic factor for patients with lung cancer who have undergone limited resection. However, the pathological and molecular significance of STAS remain to be clarified. PMID- 28882586 TI - PCBs and measures of attention and impulsivity on a continuous performance task of young adults. AB - The present study examines the relationship between current body burden of persistent PCBs and attention and impulsivity in 140 Akwesasne Mohawk young adults aged 17 to 21 whose environment has been contaminated by industrial effluent. Attention and impulsivity were measured by errors of omission, errors of commission, and patterns of reaction time responses on the Conners Continuous Performance Test. The PCB measure was the sum of those persistent PCB congeners detected in 50% of the participants. After adjusting for multiple covariates, regression analyses showed a significant positive relationship between PCB levels and omission scores, but only for males. PMID- 28882587 TI - Low levels of apolipoprotein-CII in normotriglyceridemic patients with very premature coronary artery disease: Observations from the MISSION! Intervention study. AB - BACKGROUND: While the overall acute myocardial infarction rates declined in women and men, premature acute myocardial infarction rates remained stable in men and increased in women. OBJECTIVE: The purpose of this study was to assess whether baseline apolipoprotein (apo) levels, clinical characteristics, and follow-up of patients with very premature coronary artery disease (CAD) could provide novel clues for the identification of high-risk individuals. METHODS: Apos were measured with a validated quantification liquid chromatography-mass spectrometry method in a well-defined cohort of 38 patients aged <=45 years admitted with acute ST-segment elevation myocardial infarction. RESULTS: Mean age was 39.8 +/- 4.6 years and 24% was female. Four of these patients (11%) had apoCII levels <=5.0 mg/L. Compared with the very premature CAD group with apoCII > 5 mg/L, the patients with apoCII levels <=5.0 mg/L were all females, tended to be younger (35.8 +/- 8.4 years vs 40.3 +/- 3.9 years, P = .063), had more often a family history of cardiovascular disease <=65 years (P = .034) and a significantly lower Framingham risk score (P = .001). They presented with normal triglyceride levels, and had lower low-density lipoprotein cholesterol, apoB100, and apoE levels. Corrected for differences in risk profile, apoCII <= 5 mg/L was associated with increased risk of 10-years reinfarction or revascularization (hazard ratio 7.9 [95% confidence interval 1.5-41.6], P = .015). CONCLUSIONS: In 38 patients with very premature CAD, 11% were found to have low apoCII levels (<=5.0 mg/L) with normal triglyceride levels. Despite their low a priori risk for CAD, these patients presented with ST-segment elevation myocardial infarction and had a high relative risk of 10-year reinfarction or revascularization. This particular phenotype of relatively young female patients with CAD is not recognized earlier and deserves further study. PMID- 28882588 TI - ASK1 in neurodegeneration. AB - Neurodegenerative diseases (NDDs) such as glaucoma, multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are characterized by the progressive loss of neurons, causing irreversible damage to patients. Longer lifespans may be leading to an increase in the number of people affected by NDDs worldwide. Among the pathways strongly impacting the pathogenesis of NDDs, oxidative stress, a condition that occurs because of an imbalance in oxidant and antioxidant levels, has been known to play a vital role in the pathophysiology of NDDs. One of the molecules activated by oxidative stress is apoptosis signal-regulating kinase 1 (ASK1), which has been shown to play a role in NDDs. ASK1 activation is regulated by multiple steps, including oligomerization, phosphorylation, and protein protein interactions. In the oxidative stress state, reactive oxygen species (ROS) induce the dissociation of thioredoxin, a protein regulating cellular reduction and oxidation (redox), from the N-terminal region of ASK1, and ASK1 is subsequently activated by the oligomerization and phosphorylation of a critical threonine residue, leading to cell death. Here, we review experimental evidence that links ASK1 signaling with the pathogenesis of several NDDs. We propose that ASK1 may be a new point of therapeutic intervention to prevent or treat NDDs. PMID- 28882589 TI - Leucine-induced localization of Leucyl-tRNA synthetase in lysosome membrane. AB - Leucyl-tRNA synthetase (LRS) plays major roles in providing leucine-tRNA and activating mechanistic target of rapamycin complex 1 (mTORC1) through intracellular leucine sensing. mTORC1 activated by amino acids affects the influence on physiology functions including cell proliferation, protein synthesis and autophagy in various organisms. Biochemical results demonstrating leucine sensing have been published, but visual results are lacking. Therefore, we observed the location of LRS with and without leucine using stimulated emission depletion (STED) microscopy one of the super-resolution microscopy and transmission electron microscopy (TEM). This revealed that LRS was translocated to the lysosome on addition of leucine. The translocation was inhibited by treatment with compound BC-LI-0186, disrupting the interaction between RagD and LRS. Immuno-TEM revealed a clear decrease in LRS translocation to the lysosome on addition of the inhibitor. This direct visualization of leucine sensing and LRS translocation to the lysosome was related to mTORC1 activation. To study the relationship between mTORC1 activation and LRS translocation, we monitored the change in autophagy for each condition using TEM and CLSM. The results showed a decrease in autophagy on addition of leucine, demonstrating crosstalk between leucine sensing, LRS translocation, RagD interaction, and mTORC1 activation. PMID- 28882590 TI - Targeted deletion of RANKL in M cell inducer cells by the Col6a1-Cre driver. AB - The gut-associated lymphoid tissues (GALTs), including Peyer's patches (PPs), cryptopatches (CPs) and isolated lymphoid follicles (ILFs), establish a host microbe symbiosis by the promotion of immune reactions against gut microbes. Microfold cell inducer (MCi) cells in GALTs are the recently identified mesenchymal cells that express the cytokine RANKL and initiate bacteria-specific immunoglobulin A (IgA) production via induction of microfold (M) cell differentiation. In the previous study, the Twist2-Cre driver was utilized for gene deletion in mesenchymal cells including MCi cells. In order to investigate MCi cells more extensively, it will be necessary to develop experimental tools in addition to the Twist2-Cre driver mice and characterize such drivers in specificity and efficiency. Here we show that M cell differentiation and IgA production are impaired in the targeted deletion of RANKL by the Col6a1-Cre driver. We compared Col6a1-Cre with Twist2-Cre in terms of the specificity for mesenchymal cells in GALTs. Col6a1-Cre CAG-CAT-EGFP mice exhibited EGFP expression in podoplanin+CD31- cells including MCi cells, while Twist2-Cre mice were shown to target endothelial cells and podoplanin+CD31- cells. Tnfsf11fl/DeltaCol6a1-Cre mice exhibited the absence of M cells and severe IgA reduction together with an alteration in gut microbial composition. Moreover, we analyzed germ free mice to test whether changes in the microbiota are the cause of M cell deficiency. M cell differentiation was normal in the CPs/ILFs of germ free mice, indicating that MCi cells induce M cells independently of microbial colonization. This study demonstrates that Col6a1-Cre driver mice are as useful as Twist2-Cre driver mice for functional analyses of GALT-resident mesenchymal cells, including MCi cells. PMID- 28882591 TI - The POZ-ZF transcription factor Znf131 is implicated as a regulator of Kaiso mediated biological processes. AB - Znf131 belongs to the family of POZ-ZF transcription factors, but, in contrast to most other characterized POZ-ZF proteins that function as transcriptional repressors, Znf131 acts as a transcriptional activator. Znf131 heterodimerizes with the POZ-ZF protein Kaiso, which itself represses a subset of canonical Wnt target genes, including the cell cycle regulator Cyclin D1. Herein, we report a possible role for Znf131 in Kaiso-mediated processes. Notably, we found that Znf131 associates with several Kaiso target gene promoters, including that of CCND1. ChIP analysis revealed that Znf131 indirectly associates with the CCND1 promoter in HCT116 and MCF7 cells via a region that encompasses the previously characterized +69 Kaiso Binding Site, hinting that the Znf131/Kaiso heterodimer may co-regulate Cyclin D1 expression. We also demonstrate that Kaiso inhibits Znf131 expression, raising the possibility that Kaiso and Znf131 act to fine-tune target gene expression. Together, our findings implicate Znf131 as a co-regulator of Kaiso-mediated biological processes. PMID- 28882592 TI - Polyunsaturated fatty acids induce ovarian cancer cell death through ROS dependent MAP kinase activation. AB - Free fatty acids not only play a role in cell membrane construction and energy production but also exert diverse cellular effects through receptor and non receptor mechanisms. Moreover, epidemiological and clinical studies have so far suggested that polyunsaturated fatty acids (PUFAs) could have health benefits and the advantage as therapeutic use in cancer treatment. However, the underlying mechanisms of PUFA-induced cellular effects remained to be cleared. Here, we examined the effects of omega-3 and omega-6 PUFAs on cell death in ovarian cancer cell lines. omega-3 PUFA, docosahexaenoic acid (DHA) and omega-6 PUFA, gamma linolenic acid (gamma-LNA) induced cell death in KF28 cells at the levels of physiological concentrations, but not HAC2 cells. Pharmacological and biochemical analyses demonstrated that cell death induced by DHA and gamma-LNA was correlated with activation of JNK and p38 MAP kinases, and further an upstream MAP kinase kinase, apoptosis signal-regulating kinase 1, which is stimulated by reactive oxygen species (ROS). Furthermore, an antioxidant vitamin E attenuated PUFA induced cell death and MAP kinase activation. These findings indicate that PUFA induced cell death involves ROS-dependent MAP kinase activation and is a cell type-specific action. A further study of the underlying mechanisms for ROS dependent cell death induced by PUFAs will lead to the discovery of a new target for cancer therapy or diagnosis. PMID- 28882593 TI - Real-time subpixel-accuracy tracking of single mitochondria in neurons reveals heterogeneous mitochondrial motion. AB - Mitochondria are essential for cellular survival and function. In neurons, mitochondria are transported to various subcellular regions as needed. Thus, defects in the axonal transport of mitochondria are related to the pathogenesis of neurodegenerative diseases, and the movement of mitochondria has been the subject of intense research. However, the inability to accurately track mitochondria with subpixel accuracy has hindered this research. Here, we report an automated method for tracking mitochondria based on the center of fluorescence. This tracking method, which is accurate to approximately one-tenth of a pixel, uses the centroid of an individual mitochondrion and provides information regarding the distance traveled between consecutive imaging frames, instantaneous speed, net distance traveled, and average speed. Importantly, this new tracking method enables researchers to observe both directed motion and undirected movement (i.e., in which the mitochondrion moves randomly within a small region, following a sub-diffusive motion). This method significantly improves our ability to analyze the movement of mitochondria and sheds light on the dynamic features of mitochondrial movement. PMID- 28882594 TI - Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3. AB - Two-pore domain potassium channels (K2Ps) are characterized by their four transmembrane domain and two-pore topology. They carry background (or leak) potassium current in a variety of cell types. Despite a number of important roles there is currently a lack of pharmacological tools with which to further probe K2P function. We have developed a cell-based thallium flux assay, using baculovirus delivered TASK3 (TWIK-related acid-sensitive K+ channel 3, KCNK9, K2P9.1) with the aim of identifying novel, selective TASK3 activators. After screening a library of 1000 compounds, including drug-like and FDA approved molecules, we identified Terbinafine as an activator of TASK3. In a thallium flux assay a pEC50 of 6.2 ( +/-0.12) was observed. When Terbinafine was screened against TASK2, TREK2, THIK1, TWIK1 and TRESK no activation was observed in thallium flux assays. Several analogues of Terbinafine were also purchased and structure activity relationships examined. To confirm Terbinafine's activation of TASK3 whole cell patch clamp electrophysiology was carried out and clear potentiation observed in both the wild type channel and the pathophysiological, Birk-Barel syndrome associated, G236R TASK3 mutant. No activity at TASK1 was observed in electrophysiology studies. In conclusion, we have identified the first selective activator of the two-pore domain potassium channel TASK3. PMID- 28882595 TI - Upregulation of SOX2 activated LncRNA PVT1 expression promotes breast cancer cell growth and invasion. AB - Increasing evidences indicated that Long noncoding RNAs (lncRNAs) played pivotal roles during tumorigenesis in multiple types of cancers, including breast cancer. This study aimed to investigate the role and function of long noncoding RNA PVT1 in the progression of breast cancer and explore the transcription factor which contributes to the regulation of PVT1 in breast cancer. Our results indicated that the expression of PVT1 was significantly upregulated in breast cancer tissues, compared with adjacent normal tissues (ANTs). And the increasing expression of PVT1 was associated with clinical stage, lymph nodes metastasis, and overall survival in breast cancer patients. Using computational screening, a transcriptional factor binding site was found between SOX2 and PVT1 promoter and the interaction between each other was further verified by chromatin immunoprecipitation (ChIP) analysis. In addition, ectopically overexpression of SOX2 can enhance breast cancer cell proliferation and invasion, while knockdown of SOX2 or PVT1 can severely attenuate this effect both in epithelial and mesenchymal types of breast cancer cells. Further evidences confirmed that overexpression of SOX2 can promote breast cancer cell EMT process; while silencing SOX2 or PVT1 expression can undermine this effect. These data suggest that elevated expression of SOX2 can activate lncRNA PVT1 expression promoted breast cancer tumorigenesis and progression. PVT1 may be a prognostic predictive biomarker for breast cancer, and the interaction of PVT1-SOX2 could be a therapeutic target in breast cancer. PMID- 28882596 TI - Insulin treatment augments KCNQ1/KCNE1 currents but not KCNQ1 currents, which is associated with an increase in KCNE1 expression. AB - Diabetes mellitus affects ion channel physiology. We have previously reported that acute application of insulin suppresses the KCNQ1/KCNE1 currents that play an important role in terminating ventricular action potential. In this study, we investigated the effect of long-term insulin treatment on KCNQ1/KCNE1 currents using the Xenopus oocyte expression system. Insulin treatment with a duration longer than 6 h had an opposite effect to acute insulin application, that is, it augmented the KCNQ1/KCNE1 currents. Inhibitors of PI3K, wortmannin and LY294002, and a MEK inhibitor, U0126, abolished the potentiating effect of long-term insulin treatment. The long-term treatment with insulin had no effect on KCNQ1 currents indicating an essential role of KCNE1 in the insulin effect, which is similar to the acute insulin effect. Cycloheximide, an inhibitor of protein synthesis, and brefeldin A, an inhibitor of protein transport from endoplasmic reticulum, suppressed the long-term insulin effect. Western blotting analysis combined with these pharmacological data suggest that long-term insulin treatment augments KCNQ1/KCNE1 currents by increasing KCNE1 protein expression. PMID- 28882597 TI - The acute and chronic effects of intravitreal anti-vascular endothelial growth factor injections on intraocular pressure: A review. AB - The acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields. PMID- 28882598 TI - Iris cysts: A comprehensive review on diagnosis and treatment. AB - Iris cysts, both primary and secondary, are a diagnostic and treatment challenge. Primary cysts arise either from the iris pigment epithelium or the iris stroma. Posterior pigment epithelial cysts are subdivided according to their location as central, midzonal, and peripheral. Iris stromal cysts are classified either as congenital or acquired. Free-floating cysts are usually dislodged pigment epithelial cysts. Secondary cysts are classified according to the underlying cause as implantation cysts, drug-induced, uveitic, tumor-induced, parasitic, or as cysts associated with systemic disorders. Differential diagnosis is based on the clinical presentation and imaging. Ultrasound biomicroscopy is the gold standard for the imaging of iris cysts, combining excellent resolution with sufficient tissue penetration. Treatment of iris cysts depends largely on whether they become symptomatic or not. Symptoms include obstruction of the visual axis, corneal decompensation, secondary uveitis, and secondary glaucoma. Treatment options cover a range from simple observation to fine-needle aspiration (with or without intracystic injection of absolute alcohol or antimitotic agents), laser (argon, Nd:YAG), or surgical excision. In the past, the prevailing notion was that of a radical surgical intervention in the form of iridectomy or iridocyclectomy. Given the high rate of recurrence, a stepwise conservative approach is currently favored by most clinicians. PMID- 28882599 TI - A network-level approach of cognitive flexibility impairment after surgery of a right temporo-parietal glioma. AB - OBJECTIVE: The right "non-dominant" temporo-parietal junction is usually not considered as a highly eloquent area. This contrasts with its mirrored left "dominant" counterpart, which is known as highly eloquent regarding language function. The question arises about which functions should be monitored when operating lesions of the right temporo-parietal junction under awake conditions. METHODS: We report the case of a patient who underwent a surgical resection of a glioma located in the right temporo-parietal junction. Cognitive evaluations were performed preoperatively and 4 months after surgery, as well as resting state fMRI and diffusion-based tractography. RESULTS: Long-term postoperative cognitive examination revealed an important deterioration of cognitive control abilities, especially regarding set-shifting abilities as measured by Trail making test part B. Based on pre- and postoperative resting state fMRI and diffusion-based tractography, we demonstrate that surgical resection massively impacted structural and functional connectivity of the right fronto-parieto-temporal network, a network that is classically involved in cognitive control, reasoning and working memory. CONCLUSION: This case clearly illustrates how a white matter focal lesion can generate a neuropsychological deficit by remotely disconnecting distant cortical areas belonging to a functional network. Furthermore, our observation strongly supports the use of intraoperative cognitive control tests during surgery of the right temporo-parietal junction and promote the interest of pre and postoperative resting state functional connectivity to explore the potential mechanisms causing cognitive deficits. PMID- 28882600 TI - Lesson to be remembered from a skull base tumor. AB - The natural history of giant prolactinomas is not known. While it is commonly accepted that the enlargement of microadenoma is rare and more limited than macroadenoma, it is so far uncommon that macroadenoma progress to giant adenoma. Thus, spontaneous enlargement of adenomas is poorly documented. We report the unusual history of undiagnosed microprolactinoma, revealed 12years later at the stage of a giant adenoma presenting as a skull base tumor. This unique observation provides information on the natural history of giant adenomas and arguments for particular attention to microadenomas with signs of invasion. Moreover, this clinical case highlights the need for a prolactin dosage for all midline skull base tumors. PMID- 28882601 TI - Extradural resection of the anterior clinoid process: How I do it. AB - BACKGROUND: The anterior clinoid process shares a close relationship with the optic canal, the internal carotid artery, the superior orbital fissure and the cavernous sinus. These structures may be involved in diseases whose surgical exposure requires prior clinoid process resection. METHOD: Based on operative cases we describe the different steps of this surgical technique and illustrate our surgical procedure with a video. Dividing the orbito-temporal periosteal fold is a key-step in order to optimize the elevation of the periosteal dural layer at the level of the superior orbital fissure to expose the contours of the anterior clinoid process. The clinoid tip is removed after "debulking" the bony content inside the anterior clinoid process in order to leave only a thin shell of bony contour. The bony shell is then detached from the dura, twisted and pulled out. The indications and limitations of the technique are presented. CONCLUSION: The extradural approach of the anterior clinoid process totally provides a full resection of the anterior clinoid process and safety for the paraclinoid space structures. Meticulous stepwise bony resection and optimized dura opening contribute to reduce the risk inherent to this technique. PMID- 28882602 TI - Neurosurgical aspects of dialysis-related spinal amyloidosis: Report of three cases and a review of the literature. AB - BACKGROUND AND PURPOSE: Osteoarticular manifestations of beta-2 microglobulin amyloidosis are often diagnosed in long-term dialyzed patients. However, spinal involvement is rare (10-25% of patients), and generally not associated with neurological deterioration. Compression of the spinal cord or roots is extremely rare, and probably under-recognized. METHODS: The authors describe three cases of spinal stenosis presenting with neurological signs in long-term dialyzed patients, prospectively collected over 2 years in two different institutions and treated by surgical decompression. In all three cases, the main cause of neural compression was amyloid deposition in the spine, either extradurally in the ligamentum flavum or intradurally. RESULTS: All patients improved after surgery and did not present any postoperative complications. However, two out of three patients with amyloid in the cervical spine required surgical revision to obtain a satisfactory decompression of the spinal cord. DISCUSSION: The authors discuss spinal amyloidosis which is a well-known complication of long-term dialysis. However, neurological complications such as spinal cord or radicular symptoms have been rarely reported and, when present in dialyzed patients, are symptoms that are often attributed to other causes. To our knowledge, this is the first case series that demonstrates the relationship between neurological deterioration and amyloid depositions in the spinal canal that occur in long-term dialyzed patients. The prevalence of spinal stenosis related to the presence of amyloid in this specific subgroup of patients is probably underestimated. PMID- 28882603 TI - Gamma Knife surgery for a hemangioma of the cavernous sinus in an adult: Case report and short review of the literature. AB - Cavernous sinus hemangiomas (CSH) are rare benign extra-axial vascular lesions. Both radiological and clinical aspects are important, for deciding a therapeutic modality, including medical treatment, radiation therapy or microsurgery. In the particular case of CSH, a radical removal of the tumor often cannot be achieved and is associated with a considerable risk for intraoperative uncontrollable bleeding. An alternative treatment modality is radiosurgery. Here we report the case of a 45-year-old patient, who presented with diplopia due to left abducens nerve palsy. A left-sided cavernous sinus lesion was found, initially considered to be a meningioma. However, after serial MR acquisitions, a progressive and heterogeneous enhancement was observed. In order to clarify the diagnosis between meningioma and hemangioma, a diagnostic Tc-99m labeled red blood cells (RBC) scintigraphy (Tc-99m RBC scintigraphy) was performed and showed a typical perfusion blood pool mismatch, with accumulation of the RBC at the level of the left CS, which is typical for a hemangioma. The patient underwent Gamma Knife surgery. The CSH showed a significant reduction in size starting 6 months after treatment and a full regression of the left abducens nerve palsy was observed within 1 year. These clinical and radiological results persisted over the next 3 years. PMID- 28882604 TI - [Contribution of temozolomide chemotherapy for intramedullary grade II spinal cord astrocytomas in adults: Our experience]. AB - INTRODUCTION: Grade II intramedullary astrocytomas are rare tumors. Despite a well-defined role of adjuvant temozolomide chemotherapy for brain gliomas, the contribution of this therapy for intramedullary gliomas is not yet clearly defined. METHOD: We retrospectively analyzed the data of 5 adult patients treated with temozolomide between 2008 and 2015 for a grade II intramedullary astrocytoma with progression after surgery. RESULTS: Five patients from 19 to 70 years of age (median, 37years) underwent a second surgery for the progression of a grade II intramedullary astrocytoma (median progression-free survival 26months [8-90]). All tumors remained grade II. Due to a second clinical or/and radiological tumor progression, the patients were treated with temozolomide after a 37months median progression-free survival (5-66). All patients received at minimum 12 cycles (mean 14 +/- 5; range 12-24) of temozolomide (150-200mg/m2/day, 5days/28days). All patients were alive after a 10-year median follow-up after diagnosis (6-13). All patients were able to walk except one, who was previously in McCormick autonomy grade IV before chemotherapy. The McCormick autonomy rating after temozolomide was stable for 4 patients and improved for 1 patient. The treatment was delayed once for hematological toxicity. CONCLUSION: Temozolomide stabilized all 5 patients without any major toxicity. Based on this experience that needs to be confirmed, we consider that temozolomide should be envisaged within the therapeutic arsenal for progressive intramedullary grade II astrocytomas. PMID- 28882605 TI - Cervical pedicular agenesis: Case report and a review of the literature. AB - Cervical pedicular agenesis, an unusual disorder, is a rare clinical and radiological finding, which can lead to misdiagnosis, moreover in a traumatic situation. The authors report the case of a young woman with a C3 right congenital absence of the cervical pedicle. A systematic review of literature found more than 70 reported cases. In patients with congenital agenesis of the cervical pedicle, the two most common levels of this congenital absence are C6 and C5. The three radiological findings were: the false appearance of an enlarged ipsilateral neural foramen due to the absent pedicle; a dysplastic, dorsally displaced ipsilateral articular pillar and lamina; and a dysplastic ipsilateral transverse process. These pedicle ageneses are a stable congenital anomaly. PMID- 28882606 TI - Managing spine surgery referrals: The consultation of neurosurgery and its nuances. AB - INTRODUCTION: Spinal disorders, particularly low back pain, are among the most common reasons for general practitioner (GP) consultation and can sometimes be a source of professional friction. Despite their frequency and published guidelines, many patients are still mistakenly referred by their GP to specialists for spinal surgery consultation which can create colleague relationship problems, suboptimal or unnessary delayed care, as well as the financial implications for patients. PURPOSE: To assess the management of GP lumbar spine referrals made to 4 neurosurgeons from 3 neurosurgical teams specialized in spinal surgery. METHODS: All patient's medical records relating to 672 primary consultants over a period of two months (January and February 2015) at three institutions were retrospectively reviewed. Medical referral letters, clinical evidence and imaging data were analyzed and the patients were classified according the accuracy of surgical assessment. The final decisions of the surgeons were also considered. RESULTS: Of the 672 patients analyzed, 198 (29.5%) were considered unsuitable for surgical assessment: no spinal pathology=10.6%, no surgical conditions=35.4%, suboptimal medical treatment=31.3%, suboptimal radiology=18.2% and asymptomatic patients=4.5%. CONCLUSION: Unnecessary referrals to our consultation centers highlight the gap between the reason for the consultation and the indications for spinal surgery. Compliance with the guidelines, the creation of effective multidisciplinary teams, as well as the "hands on" involvement of surgeons in primary and continuing education of physicians are the best basis for a reduction in inappropriate referrals and effective patient care management. PMID- 28882607 TI - Efficacy and safety in frameless robot-assisted stereo-electroencephalography (SEEG) for drug-resistant epilepsy. AB - INTRODUCTION: Stereo-electroencephalography (SEEG) is an invasive procedure, used to identify the epileptogenic zone that can be surgically removed in order to treat drug-resistant epilepsy. Frameless robot-assisted positioning of depth electrodes permits a 3D approach with different obliquities and trajectories. The objective of the present study was to evaluate the morbidity and the accuracy related to this frameless procedure. PATIENTS AND METHODS: Sixty-six patients were managed wherein 901 electrodes were implanted during a 6-year-period. All patients had a postoperative CT-scan that was fused with preoperative MRI planning. In order to assess the accuracy of the procedure, the Euclidian distance was calculated between the coordinates of the planned trajectory and the actual position of the electrode at the entry point and at the target point for 857 electrodes. RESULTS: Among the 66 patients, one (1.5%) experienced a symptomatic brain haematoma and one (1.5%) a stroke-like migraine after radiation therapy (SMART) syndrome. There was no permanent morbidity or mortality. Compared to the classical SEEG approach, a higher rate of asymptomatic postoperative bleeding was found on the CT-scan in 8 patients (12.1%). Any infectious events were recorded. The median accuracy of frameless robotic SEEG procedure was equivalent to a 1.1mm error deviation (0.15-2.48) at the entry point and 2.09mm (1.06-3.72) at the target point respectively, with no differences for double obliquity trajectories. CONCLUSION: Frameless robot-assisted SEEG appears to be a safe procedure, providing sufficient accuracy in order to delineate the epileptogenic zone and represents a helpful tool in the pre-surgical management of refractory epilepsy. PMID- 28882608 TI - [Intracranial hemorrhage and oral anticoagulants of patients treated between 2011 and 2013 at the Nancy Regional University Hospital]. AB - OBJECTIVE: To perform a descriptive analysis of intracranial hemorrhages of patients treated with an antivitamin K (fluindione, acenocoumarol or warfarin) or a direct oral anticoagulant (dabigatran, rivaroxaban or apixaban) at the Nancy Regional University Hospital. MATERIAL AND METHOD: The study period was from January 2011 to December 2013 and the computerized data (Programme de Medicalisation des Systemes d'Information) of our hospital was accessed to identify the patients. Clinical data were obtained from the patients' files. Regional healthcare system was queried for reimbursement data. RESULTS: Among the 157 identified cases of intracranial hemorrhage, 153 were related to antivitamin K, primarily fluindione (n=127), and only 4 to a direct oral anticoagulant (3 dabigatran and 1 rivaroxaban). During the same period, regional data indicated that 65,345 patients had had at least one reimbursement of antivitamin K and 20,983 patients one reimbursement of an oral direct anticoagulant. In our series, the most frequent intracranial hemorrhages were subdural hematoma (chronic in 65 cases, acute in 50 cases) and intraparenchymal hemorrhage (20 cases). The global mortality rate was 20.2% but varied with the site of hemorrhage. In multivariate analysis, the two risk factors of fatal outcome were coma on admission (OR 6.2; 95%CI: 2.6-15.0) and a history of previous intracranial hemorrhage (OR 13,4; 95% CI: 1,6-114,9). CONCLUSION: During the 2011-2013 period, antivitamin K, especially fluindione, was the most frequently involved anticoagulants in intracranial hemorrhages with hospitalization at our Regional University Hospital. Coma on admission and a history of previous intracranial hemorrhage were the two main risk factors for fatal outcome. PMID- 28882609 TI - Atypical meningioma. A study on recurrence and disease-specific survival. AB - BACKGROUND: To analyse the outcome of patients with WHO grade II meningioma and identify factors that may influence recurrence and survival. MATERIAL AND METHODS: Between January 2000 and October 2016, a retrospective search identified 215 WHO grade II meningiomas operated on at our institution. A survival analysis was conducted on clinical and histological criteria. RESULTS: Eighteen patients (8.4%) had a previous history of grade I meningioma. The cohort underwent a total of 302 surgical resections and 29.7% received radiotherapy. Forty-one patients (19.1%) had been re-operated on for a WHO grade II meningioma relapse. Median follow-up was 4.5 years. At the end of the study, 105 patients (53.6%) had no residual tumour on the last scan. Surgical recurrence-free survival at 5 years was 82%, 95% CI [75.9-88.5]. Secondary grade II meningioma (HR=4.27, P=0.001), Simpson resection grade 1 and 2 vs. 3, 4 and 5 (HR=0.25, P=0.001) and, Ki-67 index (HR=0.22, P<0.001) were independently associated with the surgical recurrence-free survival. Forty-four patients died from their tumours (20.5%). Cause-specific survival probability at 5 years was 83.2%, 95% CI [77.6-89.1]. Age at diagnosis (HR=0.31, P<0.001), Simpson resection grade 1 and 2 vs. 3, 4 and 5 (HR=0.32, P<0.001) and, redo surgery for recurrence (HR=2.39, P=0.010) were independently associated with the cause-specific survival. Patients who received radiotherapy did not demonstrate either a reduced risk of recurrence or a longer survival (P=0.280). CONCLUSION: In this large series, atypical meningioma recurrence correlated with progression from grade I to II, incomplete resection and high Ki-67 index; shorter survival with an older age, incomplete resection, and redo surgery for recurrence. We did not observe a significant improvement in any of the clinical outcomes after radiotherapy. PMID- 28882610 TI - Aspergillus fumigatus alkaline protease 1 (Alp1/Asp f13) in the airways correlates with asthma severity. PMID- 28882611 TI - Generation and CRISPR/Cas9 editing of transformed progenitor B cells as a pseudo physiological system to study DNA repair gene function in V(D)J recombination. AB - Antigen receptor gene assembly is accomplished in developing lymphocytes by the V(D)J recombination reaction, which can be separated into two steps: DNA cleavage by the recombination-activating gene (RAG) nuclease and joining of DNA double strand breaks (DSBs) by components of the nonhomologous end joining (NHEJ) pathway. Deficiencies for NHEJ factors can result in immunodeficiency and a propensity to accumulate genomic instability, thus highlighting the importance of identifying all players in this process and deciphering their functions. Bcl2 transgenic v-Abl kinase-transformed pro-B cells provide a pseudo-physiological cellular system to study V(D)J recombination. Treatment of v-Abl/Bcl2 pro-B cells with the Abl kinase inhibitor Imatinib leads to G1 cell cycle arrest, the rapid induction of Rag1/2 gene expression and V(D)J recombination. In this system, the Bcl2 transgene alleviates Imatinib-induced apoptosis enabling the analysis of induced V(D)J recombination. Although powerful, the use of mouse models carrying the Bcl2 transgene for the generation of v-Abl pro-B cell lines is time and money consuming. Here, we describe a method for generating v-Abl/Bcl2 pro-B cell lines from wild type mice and for performing gene knock-out using episomal CRISPR/Cas9 targeting vectors. Using this approach, we generated distinct NHEJ-deficient pro B cell lines and quantified V(D)J recombination levels in these cells. Furthermore, this methodology can be adapted to generate pro-B cell lines deficient for any gene suspected to play a role in V(D)J recombination, and more generally DSB repair. PMID- 28882612 TI - Proposed panel of diagnostic tools for accurate temporal classification of symptomatic T. gondii infection. AB - Serological tests available for the diagnosis of acute Toxoplasma gondii infection have limitations in establishing the temporal diagnosis of acute toxoplasmosis. The present analytical-descriptive investigation comprises of a prospective longitudinal cohort study to search for accurate biomarkers to distinguish acute, early and late convalescent T. gondii infection. Classic methods (immunofluorescence-IFA along with Enzyme-linked immunosorbent-ELISA and fluorescent-ELFA assays) for IgM, IgA, IgG and IgG avidity were employed in parallel with flow cytometry-based anti-fixed T. gondii tachyzoites serology (FC AFTA-IgM, IgG, IgG avidity and IgG subclasses). The results reemphasized the limitations of IgM & IgG IFA, IgG ELFA, IgG & IgG subclasses FC as well as IgA ELISA biomarkers for the temporal diagnosis of acute toxoplasmosis. Receiver Operating-characteristics features (ROC-curves) were employed to adjust conventional cut-offs aiming at establishing a novel protocol to discriminate more accurately the different phases of toxoplasmosis. Conversely, IgM presented high diagnostic co-positivity for acute toxoplasmosis (97% for ELISA, 96% for ELFA and 95% for FC-AFTA) along with moderate co-negativity for detection of late convalescent toxoplasmosis (82%, 76% and 79%, respectively). IgG avidity (ELFA and FC-AFTA) outstand with the highest performance indices with 91% and 96% co negativity for assessing acute toxoplasmosis and 91% and 98% co-positivity for late convalescent toxoplasmosis, respectively. Multivariate analysis generated a three-step algorithm comprising IgM ELFA screening followed by ELFA and FC-AFTA IgG avidity with high accuracy in discriminating acute from late convalescent infection. Together, these findings demonstrate the applicability of the proposed panel of diagnostic tools for accurate temporal classification of T. gondii infection. PMID- 28882613 TI - Average Overlap Frequency: A simple metric to evaluate staining quality and community identification in high dimensional mass cytometry experiments. AB - High dimensional cytometry now allows measurement of over 50 parameters in a single sample, and is typically visualized using sophisticated dimensionality reducing methods and analyzed with automated clustering algorithms. While these tools facilitate the identification and presentation of key findings, it remains challenging to effectively monitor and report the staining quality of individual markers. We present the Average Overlap Frequency (AOF), a simple and efficient metric to evaluate and quantify the robustness of staining and clustering quality in high-dimensional data. We leverage the AOF to compare and determine the optimal storage conditions for stained whole blood samples prior to mass cytometry analysis. We also show that the AOF can be easily incorporated as part of automated analysis pipelines in large scale immune monitoring studies and used to flag and exclude samples with poor staining quality. We propose that the AOF may be incorporated as an essential quality control metric to better identify and report the underlying sample quality in all CyTOF and other high-dimensional cytometry experiments. PMID- 28882614 TI - Triple pancreatic lesion in a patient with Von Hippel-Lindau disease. PMID- 28882615 TI - Fluoroscopy-assisted vs fluoroless endoscopic ultrasound-guided transmural drainage of pancreatic fluid collections: A comparative study. AB - INTRODUCTION: The need for fluoroscopy guidance in patients undergoing endoscopic ultrasound-guided transmural drainage (EUS-TMD) of peripancreatic fluid collections (PFCs) remains unclear. AIMS: The aim of this study was to compare general outcomes of EUS-TMD of PFCs under fluoroscopy (F) vs fluoroless (FL). METHODS: This is a comparative study with a retrospective analysis of a prospective and consecutive inclusion database at a tertiary centre, from 2009 to 2015. All patients were symptomatic pseudocyst (PSC) and walled-off pancreatic necrosis (WON). Two groups were assigned depending on availability of fluoroscopy. The groups were heterogeneous in terms of their demographic characteristics, PFCs and procedure. The main outcome measures included technical and clinical success, incidences, adverse events (AEs), and follow-up. RESULTS: Fifty EUS-TMD of PFCs from 86 EUS-guided drainages were included during the study period. Group F included 26 procedures, PSC 69.2%, WON 30.8%, metal stents 61.5% (46.1% lumen-apposing stent) and plastic stents 38.5%. Group FL included 24 procedures, PSC 37.5%, WON 62.5%, and metal stents 95.8% (lumen-apposing stents). Technical success was 100% in both groups, and clinical success was similar (F 88.5%, FL 87.5%). Technical incidences and intra-procedure AEs were only described in group F (7.6% and 11.5%, respectively) and none in group FL. Procedure time was less in group FL (8min, p=0.0341). CONCLUSIONS: Fluoroless in the EUS-TMD of PFCs does not involve more technical incidences or intra-procedure AEs. Technical and clinical success was similar in the two groups. PMID- 28882617 TI - Trends in Skin and Soft Tissue-Related Injuries in NOLS Wilderness Expeditions from 1984 to 2012. AB - OBJECTIVE: Wilderness expeditions inevitably involve risk to participants. Understanding of expedition-related illnesses and injuries allows institutions and individuals to develop strategies to mitigate risk. We describe findings and trends in soft tissue injuries, the second-most common type of injury, among participants in the National Outdoor Leadership School expeditions from 1984 to 2012. METHODS: Injuries and illnesses sustained by students and staff have been recorded continuously since 1984 in the extensive National Outdoor Leadership School database. We performed a retrospective analysis of incidence of soft tissue injuries in this population. Data before 1996 were standardized in order to make use of the entire dataset. RESULTS: Of 9734 total reported incidents, 2151 (22%) were soft tissue related, 707 (33%) of which required evacuation. The sex distribution of incidents was similar to the sex distribution of participants. The largest incidence of soft tissue injuries occurred independent of activity (711 incidents, 33%). The most commonly associated activities were hiking (528 incidents, 25%), camping (301 incidents, 14%), and cooking (205 incidents, 10%). Over the study period, rates of injury declined overall and in every individual category except cooking. CONCLUSIONS: Over this 28-year period, the incidence of soft tissue injuries associated with the most common activities decreased. Incidence of activity-independent injuries did not change significantly, but reported severity decreased. These data provide unique insights to help improve wilderness risk management for institutions and individuals and suggest areas in which educational efforts may further reduce risk. PMID- 28882616 TI - Screening of Inflammatory Bowel Disease and Spondyloarthritis for Referring Patients Between Rheumatology and Gastroenterology. AB - OBJECTIVE: To define clinical screening criteria for spondyloarthritis (SpA) in patients with inflammatory bowel disease (IBD) and vice versa, which can be used as a reference for referring them to the rheumatology or gastroenterology service. METHOD: Systematic literature review and a two-round Delphi method. The scientific committee and the expert panel were comprised of 2 rheumatologists and 2 gastroenterologists, and 7 rheumatologists and 7 gastroenterologists, respectively. The scientific committee defined the initial version of the criteria, taking into account sensitivity, specificity, standardization and ease of application. Afterwards, members of the expert panel assessed each item in a two-round Delphi survey. Items that met agreement in the first or second round were included in the final version of the criteria. RESULTS: Positive screening for SpA if at least one of the following is present: onset of chronic low back pain before 45 years of age; inflammatory low back pain or alternating buttock pain; HLA-B27 positivity; sacroiliitis on imaging; arthritis; heel enthesitis; dactylitis. Positive screening for IBD in the presence of one of the major criteria or at least two minor criteria. Major: rectal bleeding; chronic diarrhea with organic characteristics; perianal disease. Minor: chronic abdominal pain; iron deficiency anemia or iron deficiency; extraintestinal manifestations; fever or low grade fever, of unknown origin and duration >1week; unexplained weight loss; family history of IBD. CONCLUSION: Screening criteria for IBD in patients with SpA, and vice versa, have been developed. These criteria will be useful for early detection of both diseases. PMID- 28882618 TI - DOCK8 and STAT3 dependent inhibition of IgE isotype switching by TLR9 ligation in human B cells. PMID- 28882619 TI - Variable domain glycosylation of ACPA-IgG: A missing link in the maturation of the ACPA response? AB - Anti-citrullinated Protein Antibodies (ACPA) are excellent markers for Rheumatoid arthritis (RA) and are postulated to have a pathogenic role in the disease process. A multistep model for the evolution of the ACPA response in RA was proposed in which an initial break of tolerance causes, as "first hit", "silent" production of ACPA without any clinical symptoms. The model further proposes that the ACPA immune response matures upon a certain (unknown) trigger, a "second hit", which leads to epitope spreading, an increase in ACPA titres and extended isotype usage before clinical RA manifestations. These occurrences are indicative of an expansion of the citrulline-specific B cell response, though ACPA remain of low avidity even in established disease. This persistence of low avidity is puzzling, as the typical signs of maturation of the immune response seem to be uncoupled from the classical process of affinity maturation. In fact, it suggests that B cells expressing ACPA could bypass selection mechanisms that otherwise control the expansion of auto-reactive B cells. In the established, chronic phase, we recently found that ACPA-IgG are extensively glycosylated in the variable (Fab) domain. More than 90% of ACPA-IgG molecules carry Fab glycans that are highly sialylated. This molecular feature is striking and may provide a missing link in our understanding of the maturation of the ACPA immune response. This review, therefore, describes the current knowledge about ACPA Fab glycosylation in the pathogenesis of RA. PMID- 28882620 TI - HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the prognosis of malignant melanoma patients. AB - HLA class Ia (HLA-ABC) and HLA class Ib (HLA-E, -F and -G) molecules and FOXP3+ tumor-infiltrating lymphocytes (TILs) are often reported as relevant factors of tumor immune regulation. We investigated their expression as prognostic factors in 200 patients with primary cutaneous melanoma (PCM). In our cohort, patients with tumors showing upregulation of HLA-ABC molecules had significantly thicker tumors (32% vs 7%, P<0.001), frequent ulceration (20% vs 6%, P=0.007) and frequent nodular melanomas (20% vs 4%, P=0.001). Additionally, high expression of HLA-G in the tumor was a sign of bad prognosis for the patients, being associated with thick tumors (30% vs 12%, P=0.017), ulceration (24% vs 5%, P<0.001) and positive sentinel node (13% vs 6%, P=0.015). HLA-E, HLA-F and FOXP3+ TILs were not indicative of the prognosis in PCM. High HLA-ABC and HLA-G were associated with tumor aggressiveness and could be relevant predictive markers for effective immunotherapy of melanoma tumors. PMID- 28882622 TI - [Weight loss and fever]. PMID- 28882621 TI - Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade. AB - Persistent stimulation with antigens derived from viruses that establish chronic infections or tumour antigens results in the exhaustion of T cells. Coinhibitory receptors like PD-1 and CTLA-4 function as immune checkpoints on exhausted T cells. Blocking these molecules with antibodies improve immunity to cancer cells. Immune checkpoint inhibitors targeting other coinhibitory receptors might have a similar role in improving T cell function and thus also utility in cancer therapy. Using HIV-specific T cells as a model for exhaustion we have evaluated the capacity of antibodies targeting TIM-3, BTLA, CD160, LAG-3 and CTLA-4 alone or in combination with a PD-1 antibody to enhance proliferation and cytokine production in response to Gag and Nef peptides. Antibodies targeting BTLA and TIM 3 enhanced CD8 T cell proliferation. Moreover, our results indicate that blocking BTLA and TIM-3 in combination with PD-1 might be especially effective in enhancing responses of exhausted human T cells. PMID- 28882623 TI - [Patients' assessment of their chronic illness care]. AB - OBJECTIVE: The aim of this study is to assess the care received by chronic patients from their point of view and objectify the factors related with a better assessment of care. DESIGN: Cross-sectional descriptive study realized between September 2014 and April 2015. LOCATION: Nine Health Centers of Navarra (6 urban and 3 rural), Spain. PARTICIPANTS: Sampling opportunity of 196 patients aged over 65years presenting at least one chronic disease. MAIN MEASURES: Outcome variable: Evaluation of the care received through the Patient Assessment of Chronic Illness Care (PACIC) test (score 1 to 5, higher values indicate better perception about quality of care). Explanatory variables: quality of life employing the EQ5D instrument, Katz index and Gijon's socio-family evaluation scale. Other variables studied were: sex, age, education, Charlson index and number of chronic diseases. The association between the PACIC numerical value with the rest of the variables was calculated. RESULTS: The assessment of the care received according to the PACIC was higher with more chronic diseases (rho: 0.196; p=0.006), with less autonomy (mild or no disability: mean 2.9; SD: 0.6 vs. moderate or severe disability: mean 3.3; SD: 0.2; P=.003), in those with worse quality of life (EQ5D5L Index value rho: -0.227; P=.001. EQ VAS rho: -0.145; P=.043), and in those with a more favorable social situation (rho: -0.167; P=.022). CONCLUSIONS: The perception of chronic patients about the received care is better with an increased number of chronic diseases and with less autonomy and quality of life. The social environment influences the care perception of the patient, being this worse in environments with higher social risk. PMID- 28882624 TI - Network pharmacology analysis of the anti-cancer pharmacological mechanisms of Ganoderma lucidum extract with experimental support using Hepa1-6-bearing C57 BL/6 mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (GL) is an oriental medical fungus, which was used to prevent and treat many diseases. Previously, the effective compounds of Ganoderma lucidum extract (GLE) were extracted from two kinds of GL, [Ganoderma lucidum (Leyss. Ex Fr.) Karst.] and [Ganoderma sinense Zhao, Xu et Zhang], which have been used for adjuvant anti-cancer clinical therapy for more than 20 years. However, its concrete active compounds and its regulation mechanisms on tumor are unclear. AIM OF THE STUDY: In this study, we aimed to identify the main active compounds from GLE and to investigate its anti cancer mechanisms via drug-target biological network construction and prediction. MATERIALS AND METHODS: The main active compounds of GLE were identified by HPLC, EI-MS and NMR, and the compounds related targets were predicted using docking program. To investigate the functions of GL holistically, the active compounds of GL and related targets were predicted based on four public databases. Subsequently, the Identified-Compound-Target network and Predicted-Compound Target network were constructed respectively, and they were overlapped to detect the hub potential targets in both networks. Furthermore, the qRT-PCR and western blot assays were used to validate the expression levels of target genes in GLE treated Hepa1-6-bearing C57 BL/6 mice. RESULTS: In our work, 12 active compounds of GLE were identified, including Ganoderic acid A, Ganoderenic acid A, Ganoderic acid B, Ganoderic acid H, Ganoderic acid C2, Ganoderenic acid D, Ganoderic acid D, Ganoderenic acid G, Ganoderic acid Y, Kaemferol, Genistein and Ergosterol. Using the docking program, 20 targets were mapped to 12 compounds of GLE. Furthermore, 122 effective active compounds of GL and 116 targets were holistically predicted using public databases. Compare with the Identified Compound-Target network and Predicted-Compound-Target network, 6 hub targets were screened, including AR, CHRM2, ESR1, NR3C1, NR3C2 and PGR, which was considered as potential markers and might play important roles in the process of GLE treatment. GLE effectively inhibited tumor growth in Hepa1-6-bearing C57 BL/6 mice. Finally, consistent with the results of qRT-PCR data, the results of western-blot assay demonstrated the expression levels of PGR and ESR1 were up regulated, as well as the expression levels of NR3C2 and AR were down-regulated, while the change of NR3C1 and CHRM2 had no statistical significance. CONCLUSIONS: The results indicated that these 4 hub target genes, including NR3C2, AR, ESR1 and PGR, might act as potential markers to evaluate the curative effect of GLE treatment in tumor. And, the combined data provide preliminary study of the pharmacological mechanisms of GLE, which may be a promising potential therapeutic and chemopreventative candidate for anti-cancer. PMID- 28882625 TI - Drug-induced bile duct injury. AB - Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug induced bile duct injury is characterized by the destruction of the biliary epithelium following exposure to a drug. Most of the drugs associated with bile duct injury cause immune-mediated lesions to the epithelium of interlobular ducts. These share common histopathological features with primary biliary cholangitis, such as inflammation and necrosis at the expense of cholangiocytes and, if the insult persists, bile duct loss and biliary cirrhosis. Some drugs selectively target larger ducts. Such injury is often dose-dependent and thought to be the result of intrinsic drug toxicity. The histological changes resemble those seen in primary sclerosing cholangitis. This overview focuses on the clinical and pathological features of bile duct injury associated with drug treatment and on the immunological and biochemical effects that drugs exert on the biliary epithelium. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28882626 TI - Epinecidin-1 protects mice from LPS-induced endotoxemia and cecal ligation and puncture-induced polymicrobial sepsis. AB - The antimicrobial peptide, epinecidin-1 (Epi), was identified from Epinephelus coioides and may have clinical application for treating sepsis. Epi has been shown to ameliorate antibiotic-resistant bacteria-induced sepsis in mice, but further evaluation in mixed-flora models and a description of the protective mechanisms are essential to establish this peptide as a potential therapeutic. Therefore, we first tested the protective effects of Epi against polymicrobial sepsis-induced bactericidal infection, inflammation and lung injury that result from cecal ligation and puncture in mice. Furthermore, since lipopolysaccharide (LPS) is a key inducer of inflammation during bacterial infection and sepsis, we also tested the LPS-antagonizing activity and related mechanisms of Epi-mediated protection in mice with LPS-induced endotoxemia and LPS-treated Raw264.7 mouse macrophage cells. Epi rescued mice from both polymicrobial sepsis and endotoxemia after delayed administration and suppressed both lung and systemic inflammatory responses, while attenuating lung injury and diminishing bacterial load. In vitro studies revealed that Epi suppressed LPS-induced inflammatory cytokine production. Mechanistically, Epi disrupted the interaction between LPS and LPS binding protein, competed with LPS for binding on the cell surface, and inhibited Toll-like receptor 4 endocytosis, resulting in inhibition of LPS-induced reactive oxygen species/p38/Akt/NF-kappaB signaling and subsequent cytokine production. Overall, our results demonstrate that Epi is a promising therapeutic agent for endotoxemia and polymicrobial sepsis. PMID- 28882627 TI - Selection and characterization of DNA aptamers for detection of glutamate dehydrogenase from Clostridium difficile. AB - Rapid and accurate diagnosis of Clostridium difficile infections (CDI) is crucial for patient treatment, infection control and epidemiological monitoring. As an important antigen, glutamate dehydrogenase (GDH) has been proposed as a preliminary screening test target for CDI. However, current assays based on GDH activity or GDH immunoassays have suboptimal sensitivity and specificity. Herein, we describe the selection and characterization of single-stranded DNA aptamers that specifically target GDH. After 10 rounds of selection, high-throughput sequencing was used to identify enriched aptamer candidates. Of 10 candidates, three aptamers for GDH were identified. Gel shift assays showed that these aptamers exhibited low nanomolar affinities. One aptamer was optimized based on structural analysis and further engineered into a structure-switching fluorescence signaling aptamer, wherein desorption from reduced graphene oxide (RGO) upon binding of GDH led to an increase in fluorescence emission. This method allowed for quantitative detection of GDH with a detection limit of 1 nM, providing great potential for its further application in CDI diagnosis. PMID- 28882628 TI - An exemplar-based approach to individualized parcellation reveals the need for sex specific functional networks. AB - Recent work with functional connectivity data has led to significant progress in understanding the functional organization of the brain. While the majority of the literature has focused on group-level parcellation approaches, there is ample evidence that the brain varies in both structure and function across individuals. In this work, we introduce a parcellation technique that incorporates delineation of functional networks both at the individual- and group-level. The proposed technique deploys the notion of "submodularity" to jointly parcellate the cerebral cortex while establishing an inclusive correspondence between the individualized functional networks. Using this parcellation technique, we successfully established a cross-validated predictive model that predicts individuals' sex, solely based on the parcellation schemes (i.e. the node-to network assignment vectors). The sex prediction finding illustrates that individualized parcellation of functional networks can reveal subgroups in a population and suggests that the use of a global network parcellation may overlook fundamental differences in network organization. This is a particularly important point to consider in studies comparing patients versus controls or even patient subgroups. Network organization may differ between individuals and global configurations should not be assumed. This approach to the individualized study of functional organization in the brain has many implications for both neuroscience and clinical applications. PMID- 28882630 TI - Spatial gene expression analysis of neuroanatomical differences in mouse models. AB - MRI is a powerful modality to detect neuroanatomical differences that result from mutations and treatments. Knowing which genes drive these differences is important in understanding etiology, but candidate genes are often difficult to identify. We tested whether spatial gene expression data from the Allen Brain Institute can be used to inform us about genes that cause neuroanatomical differences. For many single-gene-mutation mouse models, we found that affected neuroanatomy was not strongly associated with the spatial expression of the altered gene and there are specific caveats for each model. However, among models with significant neuroanatomical differences from their wildtype controls, the mutated genes had preferential spatial expression in affected neuroanatomy. In mice exposed to environmental enrichment, candidate genes could be identified by a genome-wide search for genes with preferential spatial expression in the altered neuroanatomical regions. These candidates have functions related to learning and plasticity. We demonstrate that spatial gene expression of single genes is a poor predictor of altered neuroanatomy, but altered neuroanatomy can identify candidate genes responsible for neuroanatomical phenotypes. PMID- 28882631 TI - Neurochemical dynamics of acute orofacial pain in the human trigeminal brainstem nuclear complex. AB - The trigeminal brainstem sensory nuclear complex is the first central relay structure mediating orofacial somatosensory and nociceptive perception. Animal studies suggest a substantial involvement of neurochemical alterations at such basal CNS levels in acute and chronic pain processing. Translating this animal based knowledge to humans is challenging. Human related examining of brainstem functions are challenged by MR related peculiarities as well as applicability aspects of experimentally standardized paradigms. Based on our experience with an MR compatible human orofacial pain model, the aims of the present study were twofold: 1) from a technical perspective, the evaluation of proton magnetic resonance spectroscopy at 3 T regarding measurement accuracy of neurochemical profiles in this small brainstem nuclear complex and 2) the examination of possible neurochemical alterations induced by an experimental orofacial pain model. Data from 13 healthy volunteers aged 19-46 years were analyzed and revealed high quality spectra with significant reductions in total N acetylaspartate (N-acetylaspartate + N-acetylaspartylglutamate) (-3.7%, p = 0.009) and GABA (-10.88%, p = 0.041) during the pain condition. These results might reflect contributions of N-acetylaspartate and N-acetylaspartylglutamate in neuronal activity-dependent physiologic processes and/or excitatory neurotransmission, whereas changes in GABA might indicate towards a reduction in tonic GABAergic functioning during nociceptive signaling. Summarized, the present study indicates the applicability of 1H-MRS to obtain neurochemical dynamics within the human trigeminal brainstem sensory nuclear complex. Further developments are needed to pave the way towards bridging important animal based knowledge with human research to understand the neurochemistry of orofacial nociception and pain. PMID- 28882632 TI - Spatial specificity of the functional MRI blood oxygenation response relative to neuronal activity. AB - Previous attempts at characterizing the spatial specificity of the blood oxygenation level dependent functional MRI (BOLD fMRI) response by estimating its point-spread function (PSF) have conventionally relied on retinotopic spatial representations of visual stimuli in area V1. Consequently, their estimates were confounded by the width and scatter of receptive fields of V1 neurons. Here, we circumvent these limits by instead using the inherent cortical spatial organization of ocular dominance columns (ODCs) to determine the PSF for both Gradient Echo (GE) and Spin Echo (SE) BOLD imaging at 7 Tesla. By applying Markov chain Monte Carlo sampling on a probabilistic generative model of imaging ODCs, we quantified the PSFs that best predict the spatial structure and magnitude of differential ODCs' responses. Prior distributions for the ODC model parameters were determined by analyzing published data of cytochrome oxidase patterns from post-mortem histology of human V1 and of neurophysiological ocular dominance indices. The average PSF full-widths at half-maximum obtained from differential ODCs' responses following the removal of voxels influenced by contributions from macroscopic blood vessels were 0.86 mm (SE) and 0.99 mm (GE). Our results provide a quantitative basis for the spatial specificity of BOLD fMRI at ultra-high fields, which can be used for planning and interpretation of high-resolution differential fMRI of fine-scale cortical organizations. PMID- 28882633 TI - Probabilistic inference under time pressure leads to a cortical-to-subcortical shift in decision evidence integration. AB - Real-life decision-making often involves combining multiple probabilistic sources of information under finite time and cognitive resources. To mitigate these pressures, people "satisfice", foregoing a full evaluation of all available evidence to focus on a subset of cues that allow for fast and "good-enough" decisions. Although this form of decision-making likely mediates many of our everyday choices, very little is known about the way in which the neural encoding of cue information changes when we satisfice under time pressure. Here, we combined human functional magnetic resonance imaging (fMRI) with a probabilistic classification task to characterize neural substrates of multi-cue decision making under low (1500 ms) and high (500 ms) time pressure. Using variational Bayesian inference, we analyzed participants' choices to track and quantify cue usage under each experimental condition, which was then applied to model the fMRI data. Under low time pressure, participants performed near-optimally, appropriately integrating all available cues to guide choices. Both cortical (prefrontal and parietal cortex) and subcortical (hippocampal and striatal) regions encoded individual cue weights, and activity linearly tracked trial-by trial variations in the amount of evidence and decision uncertainty. Under increased time pressure, participants adaptively shifted to using a satisficing strategy by discounting the least informative cue in their decision process. This strategic change in decision-making was associated with an increased involvement of the dopaminergic midbrain, striatum, thalamus, and cerebellum in representing and integrating cue values. We conclude that satisficing the probabilistic inference process under time pressure leads to a cortical-to-subcortical shift in the neural drivers of decisions. PMID- 28882634 TI - Learning stage-dependent effect of M1 disruption on value-based motor decisions. AB - The present study aimed at characterizing the impact of M1 disruption on the implementation of implicit value information in motor decisions, at both early stages (during reinforcement learning) and late stages (after consolidation) of action value encoding. Fifty subjects performed, over three consecutive days, a task that required them to select between two finger responses according to the color (instruction) and to the shape (implicit, undisclosed rule) of an imperative signal: considering the implicit rule in addition to the instruction allowed subjects to earn more money. We investigated the functional contribution of M1 to the implementation of the implicit rule in subjects' motor decisions. Continuous theta burst stimulation (cTBS) was applied over M1 either on Day 1 or on Day 3, producing a temporary lesion either during reinforcement learning (cTBSLearning group) or after consolidation of the implicit rule, during decision making (cTBSDecision group), respectively. Interestingly, disrupting M1 activity on Day 1 improved the reliance on the implicit rule, plausibly because M1 cTBS increased dopamine release in the putamen in an indirect way. This finding corroborates the view that cTBS may affect activity in unstimulated areas, such as the basal ganglia. Notably, this effect was short-lasting; it did not persist overnight, suggesting that the functional integrity of M1 during learning is a prerequisite for the consolidation of implicit value information to occur. Besides, cTBS over M1 did not impact the use of the implicit rule when applied on Day 3, although it did so when applied on Day 2 in a recent study where the reliance on the implicit rule declined following cTBS (Derosiere et al., 2017). Overall, these findings indicate that the human M1 is functionally involved in the consolidation and implementation of implicit value information underlying motor decisions. However, M1 contribution seems to vanish as subjects become more experienced in using the implicit value information to make their motor decisions. PMID- 28882629 TI - Intracranial markers of conscious face perception in humans. AB - Investigations of the neural basis of consciousness have greatly benefited from protocols that involve the presentation of stimuli at perceptual threshold, enabling the assessment of the patterns of brain activity that correlate with conscious perception, independently of any changes in sensory input. However, the comparison between perceived and unperceived trials would be expected to reveal not only the core neural substrate of a particular conscious perception, but also aspects of brain activity that facilitate, hinder or tend to follow conscious perception. We take a step towards the resolution of these confounds by combining an analysis of neural responses observed during the presentation of faces partially masked by Continuous Flash Suppression, and those responses observed during the unmasked presentation of faces and other images in the same subjects. We employed multidimensional classifiers to decode physical properties of stimuli or perceptual states from spectrotemporal representations of electrocorticographic signals (1071 channels in 5 subjects). Neural activity in certain face responsive areas located in both the fusiform gyrus and in the lateral-temporal/inferior-parietal cortex discriminated seen vs. unseen faces in the masked paradigm and upright faces vs. other categories in the unmasked paradigm. However, only the former discriminated upright vs. inverted faces in the unmasked paradigm. Our results suggest a prominent role for the fusiform gyrus in the configural perception of faces, and possibly other objects that are holistically processed. More generally, we advocate comparative analysis of neural recordings obtained during different, but related, experimental protocols as a promising direction towards elucidating the functional specificities of the patterns of neural activation that accompany our conscious experiences. PMID- 28882635 TI - Impact of tissue correction strategy on GABA-edited MRS findings. AB - Tissue composition impacts the interpretation of magnetic resonance spectroscopy metabolite quantification. The goal of applying tissue correction is to decrease the dependency of metabolite concentrations on the underlying voxel tissue composition. Tissue correction strategies have different underlying assumptions to account for different aspects of the voxel tissue fraction. The most common tissue correction is the CSF-correction that aims to account for the cerebrospinal fluid (CSF) fraction in the voxel, in which it is assumed there are no metabolites. More recently, the alpha-correction was introduced to account for the different concentrations of GABA+in gray matter and white matter. In this paper, we show that the selected tissue correction strategy can alter the interpretation of results using data from a healthy aging cohort with GABA+ measurements in a frontal and posterior voxel. In a frontal voxel, we show an age related decline in GABA+ when either no tissue correction (R2 = 0.25, p < 0.001) or the CSF-correction is applied (R2 = 0.08, p < 0.01). When applying the alpha correction to the frontal voxel data, we find no relationship between age and GABA+ (R2 = 0.02, p = 0.15). However, with the alpha-correction we still find that cognitive performance is correlated with GABA+ (R2 = 0.11, p < 0.01). These data suggest that in healthy aging, while there is normal atrophy in the frontal voxel, GABA+ in the remaining tissue is not decreasing on average. This indicates that the selection of tissue correction can significantly impact the interpretation of MRS results. PMID- 28882637 TI - Successful Retrograde Intubation After Failed Fiberoptic Intubation and Percutaneous Cricothyrotomy. AB - BACKGROUND: An obstructive neck lesion presents an airway challenge for any emergency physician. Retrograde intubation is an infrequently used airway alternative that can be employed in the difficult airway algorithm that requires little training and is less invasive than surgical cricothyrotomy. CASE REPORT: We report a case of a 31-year-old male patient who presented with respiratory distress progressing to respiratory failure from upper airway obstruction. The patient had significant tracheal thickening at the level of the thyroid gland based on a computed tomography report from 3 weeks prior to his presentation. Awake upright fiberoptic intubation and subsequent percutaneous cricothyrotomy were unsuccessful secondary to obstructive neck mass. We performed a retrograde intubation via tracheal approach and secured the airway via manipulation of a small-diameter endotracheal tube over the guidewire using visualization with video laryngoscopy. This case describes a combination of difficult airway techniques utilizing retrograde intubation with a Glidescope (Verathon Inc., Bothell, WA) as a rescue maneuver for a difficult airway secondary to a tracheal obstruction and supraglottic and subglottic stenosis. Follow-up confirmed the patient's diagnosis as granulomatosis with polyangiitis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In cases of supraglottic and subglottic narrowing or mass lesions, retrograde intubation can be a life-saving technique that is an important consideration in the difficult airway algorithm. This technique may be combined with other difficult airway techniques and is especially relevant and potentially life-saving for patients in whom an open cricothyrotomy is undesirable, such as patients with a potentially vascular neck mass, subglottic stenosis, localized neck trauma, or morbid obesity. PMID- 28882636 TI - Bisphenol A and estrogen induce proliferation of human thyroid tumor cells via an estrogen-receptor-dependent pathway. AB - OBJECTIVE: To determine the relationship between papillary thyroid carcinoma and environmental exposure to bisphenol A (BPA) or 17-beta estrogen (E2) by assessing the effects of these compounds on estrogen receptor expression and AKT/mTOR signaling. METHODS: The effects of low levels of BPA (1mM-10nM) and 17beta estradiol (E2, 0.1mM-1nM) on ER expression and cellular proliferation were determined in human thyroid papillary cancer BHP10-3 cells. Protein and mRNA levels of estrogen nuclear receptors (ERalpha/ERbeta) and membrane receptors (GPR30) were determined by immunofluorescence assay, Western blotting, and RT PCR, respectively, and proliferation was assessed by CCK-8 assay. RESULTS: The proliferative effects of BPA and E2 were both concentration- and time-dependent. Expression of ERalpha/ERbeta and GPR30 were enhanced by BPA and E2. BPA and E2 could quickly phosphorylate AKT/mTOR. Moreover, ICI suppressed ERalpha expression and activated GPR30 as did G-1. G-15 reversed the effects of E2 on GPR30 and AKT/mTOR, but did not alter the effect of BPA. CONCLUSIONS: BPA influences thyroid cancer proliferation by regulating expression of ERs and GPR30, a mechanism that differs from E2. In addition, ICI and G-15 may have the potential to be used as anti-thyroid cancer agents. PMID- 28882638 TI - Delayed Onset of Atrial Fibrillation and Ventricular Tachycardia after an Automobile Lightning Strike. AB - BACKGROUND: Lightning strike is a rare medical emergency. The primary cause of death in lightning strike victims is immediate cardiac arrest. The mortality rate from lightning exposure can be as high as 30%, with up to 70% of patients left with significant morbidity. CASE REPORT: An 86-year-old male was struck by lightning while driving his vehicle and crashed. On initial emergency medical services evaluation, he was asymptomatic with normal vital signs. During his transport, he lost consciousness several times and was found to be in atrial fibrillation with intermittent runs of ventricular tachycardia during the unconscious periods. In the emergency department, atrial fibrillation persisted and he experienced additional episodes of ventricular tachycardia. He was treated with i.v. amiodarone and admitted to cardiovascular intensive care unit, where he converted to a normal sinus rhythm on the amiodarone drip. He was discharged home without rhythm-control medications and did not have further episodes of dysrhythmias on follow-up visits. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Lightning strikes are one of the most common injuries suffered from natural phenomenon, and short-term mortality ordinarily depends on the cardiac effects. This case demonstrates that the cardiac effects can be multiple, delayed, and recurrent, which compels the emergency physician to be vigilant in the initial evaluation and ongoing observation of patients with lightning injuries. PMID- 28882639 TI - Effects of residual levels of tetracycline on the barrier functions of human intestinal epithelial cells. AB - Tetracyclines are frequently used in food-producing animals to treat, control, and prevent microbial diseases. Concerns are raised regarding the effects of residual levels of tetracycline, which may be present in the food supply, for emergence of drug-resistance and transfer of antibiotic-resistance gene in intestinal microbiota. In contrast, no information is available regarding the possible effects of residual tetracycline on the gastrointestinal epithelial layer barrier-disruption. This study investigates the outcome of tetracycline treatment on intestinal epithelial cells integrity. Intestinal epithelial cells (T84) were treated at concentrations of 0.015, 0.15, 1.5, 15 and 150 MUg/ml for 48 h in an in vitro cell culture model. The permeability study revealed that 15 and 150 MUg/ml of tetracycline causes barrier disruption. Whereas the altered mRNA expression of notch-3, notch-4, claudin-2, claudin-8, claudin-10, claudin 15, gap junction alpha 8 and delta 2 and integrin, alpha 3 and alpha L, which are cell-integrity-related genes starts at 1.5 MUg/ml tetracycline after 48 h treatment. Translocation of GFP-labeled bacteria from apical to basal comportment provides proof of concept to intestinal barrier disruption. This study is the first to evaluate whether residual concentrations of tetracycline impact epithelial cell integrity. PMID- 28882640 TI - Toxicity of the main electronic cigarette components, propylene glycol, glycerin, and nicotine, in Sprague-Dawley rats in a 90-day OECD inhalation study complemented by molecular endpoints. AB - While the toxicity of the main constituents of electronic cigarette (ECIG) liquids, nicotine, propylene glycol (PG), and vegetable glycerin (VG), has been assessed individually in separate studies, limited data on the inhalation toxicity of them is available when in mixtures. In this 90-day subchronic inhalation study, Sprague-Dawley rats were nose-only exposed to filtered air, nebulized vehicle (saline), or three concentrations of PG/VG mixtures, with and without nicotine. Standard toxicological endpoints were complemented by molecular analyses using transcriptomics, proteomics, and lipidomics. Compared with vehicle exposure, the PG/VG aerosols showed only very limited biological effects with no signs of toxicity. Addition of nicotine to the PG/VG aerosols resulted in effects in line with nicotine effects observed in previous studies, including up regulation of xenobiotic enzymes (Cyp1a1/Fmo3) in the lung and metabolic effects, such as reduced serum lipid concentrations and expression changes of hepatic metabolic enzymes. No toxicologically relevant effects of PG/VG aerosols (up to 1.520 mg PG/L + 1.890 mg VG/L) were observed, and no adverse effects for PG/VG/nicotine were observed up to 438/544/6.6 mg/kg/day. This study demonstrates how complementary systems toxicology analyses can reveal, even in the absence of observable adverse effects, subtoxic and adaptive responses to pharmacologically active compounds such as nicotine. PMID- 28882641 TI - Clinical factors influencing mortality risk in hospital-acquired sepsis. AB - BACKGROUND: Identification of factors that confer an increased risk of mortality in hospital-acquired sepsis (HAS) is necessary to help prevent, and improve the outcome of, this condition. AIM: To evaluate the clinical characteristics and factors associated with mortality in patients with HAS. METHODS: Retrospective study of patients with HAS in a major Spanish Hospital from 2011 to 2015. Data from adults receiving any of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes associated with sepsis were collected. Those fulfilling the SEPSIS-2 definition with no evidence of infection during the first 48 h following hospitalization were included (N = 196). Multivariate analysis was employed to identify the risk factors of mortality. FINDINGS: HAS patients were found to have many of the risk factors associated with cardiovascular disease (male sex, ageing, antecedent of cardiac disease, arterial hypertension, dyslipidaemia, smoking habit) and cancer. Vascular disease or chronic kidney disease were associated with 28-day mortality. Time from hospital admission to sepsis diagnosis, and the presence of organ failure were risk factors for 28-day and hospital mortality. Experiencing more than one episode of sepsis increased the risk of hospital mortality. 'Sepsis code' for the early identification of sepsis was protective against hospital mortality. CONCLUSION: This study identifies several major factors associated with mortality in patients suffering from HAS. Implementation of surveillance programmes for the early identification and treatment of sepsis translate into a clear benefit. PMID- 28882642 TI - Risk factors for acquisition of OXA-48-producing Klebsiella pneumonia among contact patients: a multicentre study. AB - BACKGROUND: Cohorting carbapenemase-producing Enterobacteriaceae (CPE) carriers during hospitalization limits in-hospital spreading. AIM: To identify risk factors for CPE acquisition among contacts of an index patient in non-cohorted populations. METHODS: A multicentre retrospective matched case-control study was conducted in five hospitals. Each contact patient (case) who acquired Klebsiella pneumoniae (KP)-OXA-48 from an index patient was compared to three contact (controls) with the same index patients matched with hospitalization in the same unit and similar exposure times. FINDINGS: Fifty-one secondary cases and 131 controls were included. By univariate analysis, exposure time (odds ratio: 1.06; 95% confidence interval: 1.02-1.1; P = 0.006), concomitant infection at admission (3.23; 1.42-7.35; P = 0.005), antimicrobial therapy within the last month before hospitalization (2.88; 1.34-6.2; P = 0.007), antimicrobial therapy during the exposure time (5.36; 2.28-12.6; P < 0.001), use of at least one invasive procedure (2.99; 1.25-7.15; P = 0.014), number of invasive procedures (1.52; 1.05 2.19; P = 0.025), and geographical proximity (2.84; 1.15-7.00; P = 0.023) were associated with CPE acquisition. By multivariate analysis, antimicrobial therapy during the exposure time (odds ratio: 6.36; 95% confidence interval: 2.46-16.44; P < 0.001), at least one invasive procedure (2.92; 1.04-8.17; P = 0.041), and geographical proximity (3.69; 1.15-11.86; P = 0.028) were associated with acquisition. CONCLUSION: In this study, geographical proximity, invasive procedure, and antimicrobial therapy during exposure time were significantly associated with KP-OXA-48 acquisition. PMID- 28882643 TI - Efficacy of ethanol against viruses in hand disinfection. AB - Ethanol is used worldwide in healthcare facilities for hand rubbing. It has been reported to have a stronger and broader virucidal activity compared with propanols. The aim of this review was to describe the spectrum of virucidal activity of ethanol in solution or as commercially available products. A systematic search was conducted. Studies were selected when they contained original data on reduction of viral infectivity from suspension tests (49 studies) and contaminated hands (17 studies). Ethanol at 80% was highly effective against all 21 tested, enveloped viruses within 30 s. Murine norovirus and adenovirus type 5 are usually inactivated by ethanol between 70% and 90% in 30 s whereas poliovirus type 1 was often found to be too resistant except for ethanol at 95% (all test viruses of EN 14476). Ethanol at 80% is unlikely to be sufficiently effective against poliovirus, calicivirus (FCV), polyomavirus, hepatitis A virus (HAV) and foot-and-mouth disease virus (FMDV). The spectrum of virucidal activity of ethanol at 95%, however, covers the majority of clinically relevant viruses. Additional acids can substantially improve the virucidal activity of ethanol at lower concentrations against, e.g. poliovirus, FCV, polyomavirus and FMDV although selected viruses such as HAV may still be too resistant. The selection of a suitable virucidal hand rub should be based on the viruses most prevalent in a unit and on the user acceptability of the product under frequent-use conditions. PMID- 28882644 TI - Postsynaptic N-type or P/Q-type calcium channels mediate long-term potentiation by group I metabotropic glutamate receptors in the trigeminal oralis. AB - AIMS: Both N-type and P/Q-type voltage-gated Ca2+ channels (VGCCs) are involved in the induction of long-term potentiation (LTP), the long-lasting increase of synaptic strength, in the central nervous system. To provide further information on the roles of N-type and P/Q-type VGCCs in the induction of LTP at excitatory synapses of trigeminal primary afferents in the spinal trigeminal subnucleus oralis (Vo), we investigated whether they contribute to the induction of LTP by activation of group I metabotropic glutamate receptors (mGluRs). MAIN METHODS: (S)-3,5-Dihydroxyphenylglycine (DHPG; 10MUM for 5min), the group I mGluR agonist, was used to induce LTP of excitatory postsynaptic currents that were evoked in the Vo neurons by stimulating the trigeminal track. KEY FINDINGS: Weak blockade of the N-type or P/Q-type VGCCs by omega-conotoxin GVIA or omega-agatoxin IVA, respectively, which inhibited only 20-40% of Ca2+ currents recorded in isolated trigeminal ganglion neurons but had no effect on the basal excitatory synaptic transmission, completely blocked the induction of LTP. In contrast, stronger blockade of the channels, which inhibited >50% of Ca2+ currents and about 30% of basal synaptic transmission, resulted in the development of long-term depression (LTD), the long-lasting decrease of synaptic strength. Interestingly, the postsynaptic mechanism of DHPG-induced LTP, which was determined by paired-pulse ratio, disappeared when LTP was blocked, or LTD occurred, while a presynaptic mechanism still remained. SIGNIFICANCE: Our data suggest that postsynaptic N-type and P/Q-type VGCCs mediate the DHPG-induced LTP at the trigeminal afferent synapses in the Vo. PMID- 28882645 TI - MiR-770 inhibits tumorigenesis and EMT by targeting JMJD6 and regulating WNT/beta catenin pathway in non-small cell lung cancer. AB - AIMS: MicroRNAs (miRNAs) plays important role in development and disease, especially in cancer including non-small cell lung cancer (NSCLC). However, the role of miR-770 in NSCLC remains unclear. In this study, we aimed to study the function and mechanism of miR-770 in tumorigenesis of NSCLC. MAIN METHODS: RT qPCR was used to measure the expression levels of miR-770 in NSCLC tissues and cells. MTT assay, colony formation assay, flow cytometric analysis and transwell migration and invasion assays were performed to investigate the role of miR-770 in NSCLC cells. Bioinformatics and luciferase reporter analyses were used to demonstrate that whether the Jumonji domain-containing 6 (JMJD6) as a direct target of miR-770. The function of JMJD6 in NSCLC was also investigated. Finally, in vivo animal experiment was used to study whether miR-770 was capable of inhibiting tumor growth by inhibiting JMJD6. KEY FINDINGS: We first showed that miR-770 was downregulated in NSCLC tissues and cell lines, and the low expression of miR-770 was correlated with poor patient survival in NSCLC patients. miR-770 acted on a tumor suppressor by binding to the 3'UTR of JMJD6 and downregulated its expression in NSCLC cells. This study also demonstrated that JMJD6 played as an oncogene in NSCLC cells. miR-770 overexpression was capable of inhibiting NSCLC tumor growth by inhibiting JMJD6 and its downstream WNT/beta-catenin pathway both in vitro and in vivo. SIGNIFICANCE: The present study indicated that miR-770 functioned as a tumor suppressor and it might be a potential biomarker and therapeutic target in NSCLC. PMID- 28882646 TI - Protective effect of miR-200b/c by inhibiting vasohibin-2 in human retinal microvascular endothelial cells. AB - AIMS: Proliferative diabetic retinopathy (PDR), characterized by angiogenesis, can cause serve vision loss and even blindness. Recent studies have suggested a pivotal role of vasohibin-2 (VASH2) in the promotion of angiogenesis in tumor tissues. Here we further investigated the role of VASH2 in the proliferation and migration of retinal endothelial cells. MAIN METHODS: The expression of VASH2 in vascular endothelial cells of epiretinal fibrovascular membranes (FVMs) from PDR patients were detected by immunofluorescence. VASH2 gene interfering lentiviral vectors (VASH2-shRNA) and miR-200b/c were constructed for the evaluation of the VASH2 effect on high glucose induced human retinal microvascular endothelial cell line (HRMECs). Cell proliferation, cell cycle and cell migration were carried out subsequently. The relationship between VASH2 and miR-200b/c was determined by luciferase reporter gene assays. KEY FINDINGS: A positive expression of VASH2 was identified in vascular endothelial cells of FVMs from PDR patients. In HRMECs, cells transfected with shRNA or miR-200b/c mimics showed a significantly reduced VASH2 expression compared with negative control group by real time-polymerase chain reaction and western-blot analysis. Inhibition of VASH2 was demonstrated to suppress cell proliferation and migration from Day 2 to Day 4. The luciferase reporter gene assays confirmed the post-transcriptional regulation of VASH2 by miR-200b/c in HRMECs. SIGNIFICANCE: The present study suggests a protective effect of miR-200b/c on high glucose induced HRMECs dysfunction by inhibiting VASH2. It could be a potential therapeutic strategy to inhibit angiogenesis for the treatment of retinal vascular disease. PMID- 28882647 TI - Acute and chronic exposure to high levels of glucose modulates tight junction associated epithelial barrier function in a renal tubular cell line. AB - AIMS: Type 2 diabetes mellitus (T2DM) is one of the most prevalent diseases worldwide. Diabetic nephropathy (DN) is a complication of diabetes and the mechanisms underlying onset and progression of this disease are not fully understood. It has been shown that hyperglycemia is an independent factor to predict the development of DN in individuals with T2DM, however, a link between high plasma glucose levels and renal tubular injuries in DN remains unknown. In this study, we investigated the effect of high levels of glucose (i.e. 180 or 360mg/dL) for up to 24h (acute) or over 72h (chronic) upon tight junction (TJ) mediated epithelial barrier integrity of the kidney tubular cell line, MDCK. METHODS/KEY FINDINGS: High levels of glucose (180 and 360mg/dL) induced a decrease in transepithelial electrical resistance associated with an increase in TJ cation selectivity at 24h or in TJ permeability to a paracellular marker, Lucifer Yellow, at 72h-exposure when compared to control group (exposed to 100mg/dL glucose). Immunofluorescence analyses showed that glucose treatment induced a significant decrease in the tight junctional content of claudins-1 and 3 as well as a significant increase in claudin-2 (particularly at 24h-exposure) and a time-dependent change in occludin/ZO-1 junctional content. The analyses of total cell content of these junctional proteins by Western blot did not reveal significant changes, except in claudin-2 expression. SIGNIFICANCE: Our data suggest that high levels of glucose induce time-dependence changes in TJ structure in MDCK monolayers, suggesting a possible link between hyperglycemia induced tubular epithelial barrier disruption and diabetic nephropathy. PMID- 28882648 TI - MiR-598: A tumor suppressor with biomarker significance in osteosarcoma. AB - AIMS: Osteosarcoma is the most frequent primary malignant bone tumor in children and adolescents. Identifying specific and sensitive biomarkers is beneficial to early detection and improvement of life qualities and overall survival rates of osteosarcoma patients. MATERIALS AND METHODS: Realtime PCR was used to detect the expression of miR-598. CCK-8 assay was employed to detect the proliferation of osteosarcoma cells, while transwell assays were used to examine the migration and invasion. Tumor xenograft experiments were performed to test the in vivo malignancy of osteosarcoma cells. Co-culture experiment was used to study the relationship between osteosarcoma cells and osteoblast. Realtime PCR, Western Blotting and luciferase report assays were conducted for the target genes analysis. KEY FINDINGS: Using a cohort of 20 cases of osteosarcoma and paired adjacent tissue samples, we found that miR-598 expression was decreased in osteosarcoma tissues and serum, as well as the osteosarcoma cell lines. Over expression of miR-598 suppressed the proliferation, migration, and invasion of osteosarcoma cells, while inhibition of miR-598 expression stimulated the proliferation, migration, and invasion. However, MiR-598 had no effect on osteosarcoma cell apoptosis. Data from nude mice further demonstrated the inhibitory role of miR-598 in osteosarcoma progression in vivo. Mechanically, miR 598 played its role by modulating osteoblastic differentiation in the microenvironment and targeting PDGFB and MET. SIGNIFICANCE: Our findings enrich the knowledge of miR-598 in osteosarcoma progression, and reveal miR-598 as a promising diagnostic, prognostic, therapeutic biomarker for osteosarcoma. PMID- 28882649 TI - Carpal tunnel syndrome due to a tophus: Low-field magnetic resonance image. PMID- 28882650 TI - Does Access to Green Space Impact the Mental Well-being of Children: A Systematic Review. AB - PROBLEM: An increasing body of research is showing associations between green space and overall health. Children are spending more time indoors while pediatric mental and behavioral health problems are increasing. A systematic review of the literature was done to examine the association between access to green space and the mental well-being of children. ELIGIBILITY CRITERIA: Articles were limited to English language, ages 0-18 years, and publish date 2012-2017. SAMPLE: The search yielded 341 articles in Ovid, 81 in Pub Med and 123 in Scopus. Articles that were not original research and that were not a pediatric population were excluded. Twelve articles fit the selection criteria. RESULTS: Twelve articles relating to green space and the mental well-being of children were reviewed. Three articles outside the date criteria were included as they are cited often in the literature as important early research on this topic. CONCLUSIONS: Access to green space was associated with improved mental well-being, overall health and cognitive development of children. It promotes attention restoration, memory, competence, supportive social groups, self-discipline, moderates stress, improves behaviors and symptoms of ADHD and was even associated with higher standardized test scores. IMPLICATIONS: Scientific evidence demonstrating the mental health benefits of access to nature for children can guide policy and urban planning, while nursing interventions and initiatives can enhance health by promoting outdoor play, educating patients and families, advocating for recess times and green environments at school as well as healing gardens in hospital settings. PMID- 28882651 TI - In cystic fibrosis, lung clearance index is sensitive to detecting abnormalities appearing at exercise in children with normal spirometry. AB - Symptom-limited incremental cardiopulmonary exercise test was performed in school age children with clinically stable cystic fibrosis (CF), all with normal spirometry. Physiological parameters were compared between patients with normal lung clearance index (LCI; n=6) and patients with elevated LCI (n=6). Dyspnoea ratings during exercise were similar in both groups. Although no patient had significant dynamic hyperinflation, end-expiratory lung volumes were higher throughout exercise in patients with elevated LCI. In addition, alveolar-arterial oxygen gradient at peak exercise was higher, and SpO2 was lower in patients with elevated LCI. LCI can thus be regarded as a test performed at rest that predicts some abnormalities appearing at exercise in CF children with normal spirometry. PMID- 28882652 TI - Measuring Olfactory Processes in Mus musculus. AB - This paper briefly reviews the literature that describes olfactory acuity and odour discrimination learning. The results of current studies that examined the role of the neurotransmitters noradrenalin and acetylcholine in odour discrimination learning are discussed as are those that investigated pattern recognition and models of human disease. The methodology associated with such work is also described and its role in creating disparate results assessed. Recommendations for increasing the reliability and validity of experiments so as to further our understanding of olfactory processes in both healthy mice and those modelling human disease are made throughout the paper. PMID- 28882653 TI - Behavioural responses of two-spotted spider mites induced by predator-borne and prey-borne cues. AB - Applying predatory mites as biological control agents is a well established method against spider mites which are major pests worldwide. Although antipredator responses can influence the outcome of predator-prey interactions, we have limited information about what cues spider mites use to adjust their behavioural antipredator responses. We experimentally exposed two-spotted spider mites (Tetranychus urticae) to different predator-borne cues (using a specialist predator, Phytoseiulus persimilis, or a generalist predator, Amblyseius swirskii), conspecific prey-borne cues, or both, and measured locomotion and egg laying activity. The reactions to predator species compared to each other manifested in reversed tendencies: spider mites increased their locomotion activity in the presence of P. persimilis, whereas they decreased it when exposed to A. swirskii. The strongest response was triggered by the presence of a killed conspecific: focal spider mites decreased their locomotion activity compared to the control group. Oviposition activity was not affected by either treatment. Our results point out that spider mites may change their behaviour in response to predators, and also to the presence of killed conspecifics, but these effects were not enhanced when both types of cues were present. The effect of social contacts among prey conspecifics on predator-induced behavioural defences is discussed. PMID- 28882654 TI - Larviculture of a carnivorous freshwater catfish, Lophiosilurus alexandri, screened by personality type. AB - Considering that each personality type in animals presents distinct physiological and behavioural responses, this study evaluated the efficiency of the Novel Environment test to classify larvae of Lophiosilurus alexandri into bold and shy individuals, which were then investigated for growth, cannibalism and mortality in larviculture of pure and mixed groups. Larvae with an average weight of 24.0+/ 1.7mg and length of 14.1+/-0.4mm, were subjected to a Novel Environment test to classify their personality type (bold and shy larvae). After the larvae were classified according to personality type, they were subjected to larviculture for 15days. Three treatments were tested: only bold larvae, only shy larvae, and a mixed treatment (bold larvae+shy larvae) at a density for 16 larvae/L, which were fed 3 times a day with Artemia nauplii. After larviculture, there were no differences in the final lengths of larvae of the bold, shy, and mixed treatments (26.9+/-0.76mm, 26.7+/-1.00mm, and 26.8+/-1.24mm, respectively); however, shy larvae possessed weighed less (0.22+/-0.01g) than the bold and mixed treatments, which did not differ significantly (0.25+/-0.02g and 0.27+/-0.02g, respectively). The bold and mixed treatments had the highest cannibalism rate (11.2+/-5.1% and 23.1+/-12.3%, respectively). Overall survival was lowest in the mixed treatment (62.5+/-13.0%), while that of the bold and shy treatments were similar (82.5+/ 9.2% and 86.2+/-9.2%, respectively). The separation of L. alexandri larvae by traits can ensure a decrease in cannibalism and hence, more productive larviculture. PMID- 28882655 TI - Brief psychological intervention in phase I of cardiac rehabilitation after acute coronary syndrome. AB - INTRODUCTION: Acute coronary syndrome (ACS) is an important cause of mortality and significant personal and financial costs. Cardiac rehabilitation (CR) programs have shown positive effects in reducing cardiovascular mortality and improving functional capacity. However, adherence is low and appears to be influenced by psychosocial factors, such as patients' cognitions and emotional state. The objective was to evaluate the efficacy of a brief in-hospital psychological intervention to promote cognitive and emotional adaptation after ACS. METHODS: One hundred and twenty-one patients with ACS, admitted to a coronary care unit in a central hospital, were randomized to an experimental group (EG, n=65) and a control group (CG, n=56). Portuguese versions of the HADS and BIPQ were used to measure emotional well-being and illness cognitions. Two 1 h 15 min sessions were conducted 2-3 days after hospital admission, and a 20 minute follow-up session took place one month after discharge. Patients were assessed at four different time points: pre-test, post-test, and at 1- and 2 month follow-up. RESULTS: The intervention had significant effects on anxiety, depression and illness cognitions. Anxiety and depression were significantly reduced and illness cognitions improved significantly in the EG compared to the control group. For the EG, these changes were maintained or enhanced at 1- and 2 month follow-up, whereas for the CG there was a deterioration in psychosocial adjustment. CONCLUSIONS: These results indicate that a brief psychological intervention program delivered during hospitalization for ACS and combined with standard medical care can have positive effects in terms of psychosocial outcomes that have proven impact on cardiac rehabilitation and prognosis. PMID- 28882656 TI - Fetal giant cardiac tumor. PMID- 28882657 TI - The diagnostic accuracy of DetermineTM TB LAM antigen in detection of extra pulmonary tuberculosis (EPTB). PMID- 28882658 TI - Increased Risk for Unfavorable Outcome in Patients with Pre-Existing Disability Undergoing Endovascular Therapy. AB - INTRODUCTION: Most studies evaluating endovascular therapy (EVT) for stroke only included patients without pre-existing disabilities. However, in real life many patients have pre-existing disabilities, and whether they can benefit from EVT remains unknown. METHODS: Patients with emergent large vessel occlusions undergoing EVT were prospectively enrolled. Patients with no or mild pre-existing disabilities (modified Rankin Scale [mRS], 0-2) were compared with patients presenting with pre-existing moderate disability (mRS >= 3). Baseline demographics and risk factors, stroke severity (studied with the National Institutes of Health Stroke Scale [NIHSS]), imaging data including pretreatment Alberta Stroke Program Early Computerized Tomography Score (ASPECTS) and ASPECTS collateral scores, as well as procedure-related variables were accrued. Unfavorable outcome was defined as mRS >= 4 at day 90. RESULTS: Of 131 enrolled patients, 108 had a baseline mRS of 2 or lower, and 23 had a prestroke mRS score of 3 or higher. Patients with pre-existing mRS scores of 3 or higher were significantly older (80.3 +/- 10 versus 66.9 +/- 13.7; P = .001) and more often had previous strokes (39% versus 16%; P = .02). Patients with mRS scores of 3 or higher were more likely to have poor outcomes or death (odds ratio [OR], 4.4; 95% confidence interval [CI], 1.3-15.0). Of the 23 patients with pre-existing moderate disability, 8 (35%) maintained their previous degree of disability. On multivariate analysis, age (OR, .92; 95% CI, .88-.97; P = .001), admission NIHSS (OR, .92; 95% CI, .85-.99; P = .042) and pretreatment ASPECTS (OR, 6.4; 95% CI, 1.4-29.5; P = .017) remained significant modifiers of favorable outcome. DISCUSSION AND CONCLUSIONS: Patients with pre-existing moderate disabilities have higher chances of sustaining unfavorable outcomes despite EVT. Nevertheless, some patients maintain the same level of moderate disabilities, and therefore, patients with pre-existing moderate disabilities should not be excluded from EVT. PMID- 28882659 TI - Review of Protocols Used in Ultrasound Thrombolysis. AB - OBJECTIVES: This paper focuses on the review of protocols used in thrombolysis studies with ultrasound. MATERIALS AND METHODS: Data from peer-review articles were acquired. RESULTS: The protocols of several published reports are summarized in 3 tables (in vitro, in vivo, and clinical), providing detailed information concerning clot model, thrombolytic drug, treatment mode, sonication parameters, evaluation method, thrombolysis outcome, side effects, and conclusions. CONCLUSIONS: The aim of this review was to give an overview of the different protocols used so far in the field of sonothrombolysis and investigate the impact of several aspects involved on sonothrombolysis outcome. PMID- 28882660 TI - A Masked Marauder: Hepatitis C Neuropathy. PMID- 28882661 TI - IgG4 Isolated Retroperitoneal Fibrosis and Aneurysmal Periaortitis. PMID- 28882662 TI - The Hyperlipidemia Effect: Pseudohyponatremia in Pancreatic Cancer. PMID- 28882663 TI - Dangerous Waters? Chronic Arsenic Exposure. PMID- 28882664 TI - Spatial distribution of West Nile virus in humans and mosquitoes in Israel, 2000 2014. AB - OBJECTIVES: Israel has a long history of West Nile virus (WNV) morbidity, and the rate of detection of WNV in mosquitoes has been high since 2000. The aim of this study was to integrate several WNV datasets in order to gain an insight into the geographical distribution of WNV in Israel. METHODS: Three choropleth maps were generated showing WNV human morbidity, WNV prevalence in mosquitoes, and the results of a nationwide serological survey, based on the division of Israel into 15 sub-districts. RESULTS: The maps show a high endemicity of WNV in Israel. In respect to the morbidity map, the population residing in the central part of the country and in Arava Region is at higher risk of developing the disease than the population of the rest of Israel. Interestingly, high prevalence rates of both WNV serology and WNV-infected mosquitoes were detected in Arava Region, but lower prevalence rates were detected in most areas of the coastal region, suggesting that other factors might also be important in the development of symptomatic WNV infections. CONCLUSIONS: These results underline the high prevalence of WNV in Israel and point to specific risk areas for WNV infections across the country. PMID- 28882665 TI - Human gastric hyperinfection by Anisakis simplex: A severe and unusual presentation and a brief review. AB - Anisakiasis is an emerging marine food-borne zoonosis resulting from the accidental ingestion of Anisakis larvae, through the consumption of raw or undercooked infected seafood products. The first case of human gastric hyperinfection by Anisakis simplex with an unusual and severe presentation, occurring in a Portuguese woman, is described in this article. Over 140 anisakid larvae were removed by gastroscopy. Massive infection is uncommon in areas where the consumption of raw fish is not part of the traditional diet, as is the case in Portugal. The increased consumption of raw seafood products is considered a health determinant in the rise in cases of anisakiasis. However, clinicians should be aware of the emergence of these infections, not only because of the new dietary habits of the population, but also because of the high prevalence of Anisakis larvae in the different fish species usually consumed by the population, collected on the Portuguese coast. PMID- 28882666 TI - Clinical features for 89 deaths of hand, foot and mouth disease in Guangxi, China, 2014. AB - OBJECTIVES: The aim of this study is to summarize the risk factors of severe Hand, foot and mouth disease (HFMD) and explore the clinical characteristics of pulmonary edema (PE) and non-PE in the deceased patients with HFMD. METHODS: We identified 89 HFMD deaths which were separated into the PE group or non-PE group. Next, patients were divided based on their initial admission to hospitals as stage 1, 2, 3, or 4; at this point, their clinical manifestations were compared. RESULTS: There were 87 cases in the PE group, and 2 cases in the non-PE group. In the PE group, the difference in median time for patients at different stages from onset to symptoms, showed no significant difference (p>0.05). The etiology was detected as a positive rate for enterovirus 71 (EV71) of 89.19%, which showed a more severe course than other etiologies. The white blood cell (WBC) counts, lymphocyte (LYM) counts and creatine kinase MB (CK-MB) counts of patients admitted in different stages increased significantly with severity (p<0.05). CONCLUSIONS: There may be two clinical subtypes, mostly PE and rarely non-PE, in the deceased patients with HMFD. EV71 and risk factors such as an increased WBC count are associated with a severe course of HMFD. PMID- 28882667 TI - Clinical evaluation of early acquisition of Staphylococcus aureus carriage by newborns. AB - BACKGROUND: Little is known about neonatal Staphylococcus aureus carriage. Sites and clinical outcomes of S. aureus colonization during the first month of life were evaluated in this study. METHODS: A cohort of 279 infants born at term to 277 mothers was included. Maternal S. aureus colonization status was examined before labor. Newborns were screened for nasal, auricular, umbilical, and rectal colonization, one to three times within 100h after birth, and infants of carrier mothers were re-screened at 1 month. Medical data were recorded from the medical charts at discharge and at the 1-month follow-up interview. RESULTS: Overall 43 out of 279 (15.4%) infants acquired S. aureus within the first days of life. The only two predictors of S. aureus carriage in the postnatal period were maternal S. aureus carriage (odds ratio 7.905, 95% confidence interval 3.182-19.638) and maternal antibiotic treatment during labor (odds ratio 0.121, 95% confidence interval 0.016-0.949). Among colonized children, the nose (56%) and rectum (40%) were more frequently colonized, while ear (26%) and umbilicus (16%) colonization were less common. Co-colonization at two sites was rare (4%), but always predicted carriage at 1 month of age. Maternal and neonatal characteristics, including neonatal outcomes, were similar between S. aureus carrier and non carrier infants during the first month of life. CONCLUSIONS: Maternal carriage is the major predictor of neonatal S. aureus carriage. The nose and rectum are the main sites of neonatal carriage. S. aureus carriage was not associated with neonatal complications throughout the first month of life. The long-term significance of early S. aureus carriage is yet to be determined. PMID- 28882668 TI - Performance evaluation of the Cobas TaqMan MTB assay on respiratory specimens according to clinical application. AB - OBJECTIVE: To evaluate the performance of the Cobas TaqMan MTB assay (Cobas assay) with respect to its clinical application. METHODS: This was a retrospective analysis of 1154 results from 1034 patients for whom mycobacterial cultures and the Cobas assay were performed simultaneously. Based on the patient medical records, two categories of clinical application were defined: (1) the diagnosis of patients with a high probability of pulmonary tuberculosis according to clinical and radiological features (n=128), and (2) the exclusion of tuberculosis in clinically indeterminate patients (n=1026). Standard culture was used as the reference method. RESULTS: The sensitivity of the Cobas assay for the detection of Mycobacterium tuberculosis was 70.4% (95% confidence interval (CI) 49.7-85.5%) for category 1, but only 25.0% (95% CI 4.5-64.4%) for category 2. The specificity was >=95.0% for both categories. The positive predictive value was 79.2% (95% CI 57.3-92.1%) for category 1 and 33.3% (95% CI 6.0-75.9%) for category 2, while the negative predictive value was 92.3% (95% CI 85.0-96.4%) for category 1 and 99.4% (95% CI 98.7-99.8%) for category 2. CONCLUSIONS: The results of this study indicate that Cobas assay results must be interpreted carefully according to the clinical purpose of the assay. PMID- 28882669 TI - Real-time visualization of distinct nitric oxide generation of nitric oxide synthase isoforms in single cells. AB - The members of the nitric oxide synthase (NOS) family, eNOS, nNOS and iNOS, are well-characterized enzymes. However, due to the lack of suitable direct NO sensors, little is known about the kinetic properties of cellular NO generation by the different nitric oxide synthase isoenzymes. Very recently, we developed a novel class of fluorescent protein-based NO-probes, the geNOps, which allow real time measurement of cellular NO generation and fluctuation. By applying these genetic NO biosensors to nNOS-, eNOS- and iNOS-expressing HEK293 cells we were able to characterize the respective NO dynamics in single cells that exhibited identical Ca2+ signaling as comparable activator of nNOS and eNOS. Our data demonstrate that upon Ca2+ mobilization nNOS-derived NO signals occur instantly and strictly follow the Ca2+ elevation while NO release by eNOS occurs gradually and sustained. To detect high NO levels in cells expressing iNOS, a new ratiometric probe based on two fluorescent proteins was developed. This novel geNOp variant allows the measurement of the high NO levels in cells expressing iNOS. Moreover, we used this probe to study the L-arginine-dependency of NO generation by iNOS on the level of single cells. Our experiments highlight that the geNOps technology is suitable to detect obvious differences in the kinetics, amplitude and substrate-dependence of cellular NO signals-derived from all three nitric oxide synthase isoforms. PMID- 28882671 TI - Five new chromone glycosides from Scindapsus officinalis (Roxb.) Schott. AB - Five new chromone glycosides, officinalisides A (1), B (2), C (3), D (4) and E (5) were isolated from Scindapsus officinalis (Roxb.) Schott., along with six known chromone derivatives, 7-O-alpha-l-rhamnosyl-nereugenin (6), undulatoside A (7), drynachromoside A (8), drynachromoside B (9), 5,7-dihydroxy-2-methyl chromone(10), 5,7-dihydroxy-2-hydroxymethyl chromone (11). Structural elucidation of the isolated compounds was established by spectroscopic analysis, especially 2D NMR techniques and comparison with literatures. The isolates were evaluated for anti-inflammatory activities in a LPS-stimulated RAW 264.7 model using inhibition of nitric oxide (NO) production as an indicator. Compounds 2, 4 and 10 demonstrated potential anti-inflammatory activity with IC50 values of 16.1, 19.1, and 13.4MUM, respectively, compared to the positive control dexamethasone. PMID- 28882670 TI - Bi- and bisbibenzyls from the roots of Dichapetalum heudelotii and their antiproliferative activities. AB - Two new bisbibenzyls, heudelotol A (1) and B (2), along with the known bibenzyls, (E)-combretastatin A-1 (3) and combretastatin B-1 (4) have been isolated from the ethyl acetate extract of the roots of Dichapetalum heudelotii. Structure elucidation of all four isolated compounds was achieved using UV, IR, 1D and 2D NMR spectroscopy and HR-Mass Spectrometry. The compounds exhibited varying antiproliferative activity against six cancer cell lines using the CellTiter Glo(r) Luminiscent Cell Viability Assay. Compound 3 was found to be the most active with sub-micromolar growth inhibition concentrations against all the cell lines (GI50 0.03-0.72MUM). However, it was about ten-fold less active than the positive control, taxol. The new bisbibenzyls heudelotol A and B exhibited good activity against human pancreatic adenocarcinoma (GI50 9.04MUM) and Burkitt's lymphoma (GI50 4.67MUM) respectively, and average activity against the other cancer cell lines. PMID- 28882672 TI - Contemporary survival trends in penile cancer: Results from the National Cancer Database. AB - OBJECTIVE: To investigate contemporary survival trends in penile cancer. METHODS: The National Cancer Database was queried for men with penile cancer diagnosed between 1998 and 2009. Patient, tumor, treatment, and facility characteristics were obtained. Overall survival (OS) was analyzed using the Kaplan-Meier method and multivariable Cox proportional hazards regression model for all cases and stratified by stage. RESULTS: A total of 8,122 cases of penile cancer were reported from 1998 to 2009 in the National Cancer Database. Complete staging, survival, and covariate data were available for 5,043 cases. The estimated crude 5-year OS for the entire cohort was 61.0%. For all patients, no significant differences in crude 5-year OS were detected between 2006 to 2009 and 2002 to 2005 compared to 1998 to 2001. On multivariable analysis, OS did not significantly differ across all eras. Regional lymph node dissection was associated with improved OS (hazard ratio [HR] = 0.777, P <= 0.0001). In patients who underwent lymph node dissection, dissection of >=8 nodes significantly improved survival (HR = 0.672; P = 0.0011). Additional modeling stratified by stage revealed that OS for stage II cancers increased significantly in 2006 to 2009 compared to 1998 to 2001 (HR = 0.714; P = 0.0034). CONCLUSIONS: Survival in penile cancer has remained unchanged as a whole and for each stage, except for stage II disease. An improved survival trend was detected in stage II penile cancer. Performing a lymph node dissection, especially extensive dissections, may benefit long-term survival. PMID- 28882674 TI - Liposome accumulation in irradiated tumors display important tumor and dose dependent differences. AB - Radiation therapy may affect several important parameters in the tumor microenvironment and thereby influence the accumulation of liposomes by the enhanced permeability and retention (EPR)-effect. Here we investigate the effect of single dose radiation therapy on liposome tumor accumulation by PET/CT imaging using radiolabeled liposomes. Head and neck cancer xenografts (FaDu) and syngenic colorectal (CT26) cancer models were investigated. Radiotherapy displayed opposite effects in the two models. FaDu tumors displayed increased mean accumulation of liposomes for radiation doses up to 10 Gy, whereas CT26 tumors displayed a tendency for decreased accumulation. Tumor hypoxia was found negatively correlated to microregional distribution of liposomes. However, liposome distribution in relation to hypoxia was improved at lower radiation doses. The study reveals that the heterogeneity in liposome tumor accumulation between tumors and different radiation protocols are important factors that need to be taken into consideration to achieve optimal effect of liposome based radio sensitizer therapy. PMID- 28882675 TI - Gold nanoparticles: Distribution, bioaccumulation and toxicity. In vitro and in vivo studies. AB - Concerns about the bioaccumulation and toxicity of gold nanoparticles inside humans have recently risen. HT-29 and HepG2 cell lines and Wistar rats were exposed to 10, 30 or 60 nm gold nanoparticles to determine their tissue distribution, subcellular location and deleterious effects. Cell viability, ROS production and DNA damage were evaluated in vitro. Lipid peroxidation and protein carbonylation were determined in liver. ICP-MS measurements showed the presence of gold in intestine, kidney, liver, spleen, feces and urine. Subcellular locations of gold nanoparticles were observed in colon cells and liver samples by transmission electron microscopy. Inflammatory markers in liver and biochemical parameters in plasma were measured to assess the inflammatory status and presence of tissue damage. The size of the nanoparticles determined differences in the biodistribution and the excretion route. The smallest nanoparticles showed more deleterious effects, confirmed by their location inside the cell nucleus and the higher DNA damage. PMID- 28882673 TI - Predictive factors for local recurrence after glansectomy and neoglans reconstruction for penile squamous cell carcinoma. AB - OBJECTIVES: To investigate predictive pathological factors for local recurrence (LR) after glansectomy for penile squamous cell carcinoma (SCC) and to develop a risk score for prediction of LR after glansectomy. PATIENTS AND METHODS: In this retrospective study, we analyzed 117 patients operated between February 2005 and January 2016 in a supraregional penile cancer center in the UK for LR after glansectomy and glans reconstruction. Univariate and multivariate Cox proportional hazards regression was used to identify 4 prognostic indicators for LR. The hazard ratio (HR) of LR was estimated in Kaplan-Meier analysis, and based on these data, we designed a postoperative model for prediction of LR based on 3 risk groups. RESULTS: Median follow-up period was 33.7 (95% CI: 26.8-40.3) months; 12.8% of the patients experienced LR. Univariate Cox proportional hazards regression revealed that the risk factors for recurrence were the presence of perineural invasion, carcinoma in situ, positive margin on definitive pathology, and high-grade disease. Based on Kaplan-Meier analysis stratified by number of factors present, we defined 3 risk groups for LR: low (0,1 risk factors) as reference, intermediate (2,3 risk factors) with HR of 13.9 (95% CI: 1.81-107.04, P = 0.0115), or high risk (all 4 risk factors present) with a HR of 34.2 (95% CI: 3.07-381.81, P = 0,0041). Limitations include the retrospective design and low number of events inherent to the rare nature of penile SCC. CONCLUSIONS: Perineural invasion, carcinoma in situ, positive definitive margins, and the presence of high-grade SCC predict LR following glansectomy. These factors can be used to stratify patients into low-, intermediate-, and high-risk groups for recurrence which may be used to tailor follow-up. PMID- 28882676 TI - Malonylome analysis in developing rice (Oryza sativa) seeds suggesting that protein lysine malonylation is well-conserved and overlaps with acetylation and succinylation substantially. AB - : In recent years, lysine malonylation has garnered wide spread interest due to its potential regulatory roles. While studies have been performed in bacteria, mouse, and human, the involvement and the biological function of this modification in plant are still largely unknown. We examined the global proteome profile of lysine malonylation in developing rice seeds using affinity enrichment followed by LC-MS/MS analysis. We identified 421 malonylated lysine sites across 247 proteins. Functional analyses showed predominant presence of malonylated proteins in metabolic processes, including carbon metabolism, glycolysis/gluconeogenesis, TCA cycle, as well as photosynthesis. Malonylation was also detected on enzymes in starch biosynthesis pathway in developing rice seeds. In addition, we found a remarkable overlap among the malonylated, succinylated and acetylated sites identified in rice. Furthermore, malonylation at conserved sites of homologous proteins was observed across organisms of different kingdoms, including mouse, human, and bacteria. Finally, distinct motifs were identified when the rice malonylation sites were analyzed and conserved motifs were observed from bacterium to human and rice. Our results provide an initial understanding of the lysine malonylome in plants. The study has critical reference value for future understanding of the biological function of protein lysine malonylation in plants. BIOLOGICAL SIGNIFICANCE: Lysine malonylation is a newly discovered acylation with functional potential in regulating cellular metabolisms and activities. However, the malonylation status has not been reported in plants. Grain yield and quality, mainly determined during cereal seed development, are closely related to food security, human health and economic value. To evaluate malonylation level in plants and the possible regulatory functions of malonylation in seed development, we conducted comprehensive analyses of malonylome in developing rice seeds. A total of 421 malonylated lysine sites from 247 proteins were identified, which involved in multiple critical metabolic processes, including central carbon metabolism, lipid metabolism, photosynthesis, and starch biosynthesis. We found that charged amino acids, lysine and arginine, were the preferred residues in positions flanking the modified lysines. Highly conserved modification sites on both histone and non histone proteins were observed among different organisms through sequence alignment analysis. More interestingly, a large number of modification sites shared by malonylation, acetylation and succinylation were identified in rice. The study presents a comprehensive understanding of malonylome in plants, which will serve as an initial platform for further investigation of the functions of lysine malonylation, especially in cereal seeds development. PMID- 28882677 TI - Protein biomarkers for early detection of diseases: The decisive contribution of combinatorial peptide ligand libraries. AB - : The present review deals with biomarker discovery, especially in regard to sample treatment via combinatorial peptide ligand libraries, perhaps the only technique at present allowing deep exploration of biological fluids and tissue extracts in search for low- to very-low-abundance proteins, which could possibly mark the onset of most pathologies. Early-stage biomarkers, in fact, might be the only way to detect the beginning of most diseases thus permitting proper intervention and care. The following cancers are reviewed, with lists of potential biomarkers suggested in various reports: hepatocellular carcinoma, ovarian cancer, breast cancer and pancreatic cancer, together with some other interesting applications. Although panels of proteins have been presented, with robust evidence, as potential early-stage biomarkers in these different pathologies, their approval by FDA as novel biomarkers in routine clinical chemistry settings would require plenty of additional work and efforts from the pharma industry. The science environment in universities could simply not afford such heavy monetary investments. SIGNIFICANCE: After more than 16years of search for novel biomarkers, to be used in a clinical chemistry set-up, via proteomic analysis (mostly in biological fluids) it was felt a critical review was due. In the present report, though, only papers reporting biomarker discovery via combinatorial peptide ligand libraries are listed and assessed, since this methodology seems to be the most advanced one for digging in depth into low-to very-low-abundance proteins, which might represent important biomarkers for the onset of pathologies. In particular, a large survey has been made for the following diseases, since they appear to have a large incidence on human population and/or represent fatal diseases: ovarian cancer, breast cancer, pancreatic cancer and hepatocellular carcinoma. PMID- 28882679 TI - Measuring oral contraceptive adherence using self-report versus pharmacy claims data. AB - OBJECTIVE: Proportion of Days Covered (PDC) is a measure of medication adherence that uses prescription claims data to describe the proportion of days that the patient possessed medication. The objective of this study is to compare PDC and self-report as measures of oral contraceptive pills (OCPs) adherence and to identify individual-level predictors of adherence. STUDY DESIGN: In a sample of 384 OCP users, self-report was compared with PDC as measures of adherence over the past 3 months. Patient-level variables were examined for associations with adherence using multivariable logistic regression models. RESULTS: High adherence, defined as missing <=1 pill per month, was 76%, 68% and 54% as measured by self-report, PDC and both measures, respectively. Younger women (ages 18-25 and 26-33 years) were significantly less likely to have high adherence on both measures than women in the 34-40 age group [adjusted odds ratio (OR) 0.20, 95% confidence interval (CI) 0.08-0.51 and adjusted OR 0.26, 95% CI 0.11-0.62, respectively). Other predictors of high adherence on both self-report and PDC measures included being in a relationship (adjusted OR 2.30, 95% CI 1.14-4.64, compared with unpartnered women), Protestant religion (adjusted OR 2.08, 95% CI 1.07-4.06, compared with women with no religious affiliation) and higher contraceptive self-efficacy (adjusted OR 1.63, 95% CI 1.03-2.58). CONCLUSION: PDC derived from pharmacy claims, or a combination of PDC and self-report measures, may be an alternative to self-report alone for measuring OCP adherence. IMPLICATIONS: PDC may be a potential tool for measuring women's adherence to OCPs and should be validated in future studies. PMID- 28882678 TI - RNA interference-mediated knockdown of SIRT1 and/or SIRT2 in melanoma: Identification of downstream targets by large-scale proteomics analysis. AB - : Melanoma is the most notorious and fatal of all skin cancers and the existing treatment options have not been proven to effectively manage this neoplasm, especially the metastatic disease. Sirtuin (SIRT) proteins have been shown to be differentially expressed in melanoma. We have shown that SIRTs 1 and 2 were overexpressed in melanoma and inhibition of SIRT1 imparts anti-proliferative responses in human melanoma cells. To elucidate the impact of SIRT 1 and/or 2 in melanoma, we created stable knockdowns of SIRTs 1, 2, and their combination using shRNA mediated RNA interference in A375 human melanoma cells. We found that SIRT1 and SIRT1&2 combination knockdown caused a decreased cellular proliferation in melanoma cells. Further, the knockdown of SIRT 1 and/or 2 resulted in a decreased colony formation in melanoma cells. To explore the downstream targets of SIRTs 1 and/or 2, we employed a label-free quantitative nano-LC-MS/MS proteomics analysis using the stable lines. We found aberrant levels of proteins involved in many vital cellular processes, including cytoskeletal organization, ribosomal activity, oxidative stress response, and angiogenesis. These findings provide clear evidence of cellular systems undergoing alterations in response to sirtuin inhibition, and have unveiled several excellent candidates for future study. SIGNIFICANCE: Melanoma is the deadliest form of skin cancer, due to its aggressive nature, metastatic potential, and a lack of sufficient treatment options for advanced disease. Therefore, detailed investigations into the molecular mechanisms of melanoma growth and progression are needed. In the search for candidate genes to serve as therapeutic targets, the sirtuins show promise as they have been found to be upregulated in melanoma and they regulate a large number of proteins involved in cellular processes known to affect tumor growth, such as DNA damage repair, cell cycle arrest, and apoptosis. In this study, we used a large-scale label-free comparative proteomics system to identify novel protein targets that are affected following knockdown of SIRT1 and/or 2 in A375 metastatic melanoma cell line. Our study offers important insight into the potential downstream targets of SIRTs 1 and/or 2. This may unravel new potential areas of exploration in melanoma research. PMID- 28882680 TI - Perfect-use and typical-use Pearl Index of a contraceptive mobile app. AB - OBJECTIVES: The Natural Cycles application is a fertility awareness-based contraceptive method that uses dates of menstruation and basal body temperature to inform couples whether protected intercourse is needed to prevent pregnancies. Our purpose with this study is to investigate the contraceptive efficacy of the mobile application by evaluating the perfect- and typical-use Pearl Index. STUDY DESIGN: In this prospective observational study, 22,785 users of the application logged a total of 18,548 woman-years of data into the application. We used these data to calculate typical- and perfect-use Pearl Indexes, as well as 13-cycle pregnancy rates using life-table analysis. RESULTS: We found a typical-use Pearl Index of 6.9 pregnancies per 100 woman-years [95% confidence interval (CI): 6.5 7.2], corrected to 6.8 (95% CI: 6.4-7.2) when truncating users after 12months. We estimated a 13-cycle typical-use failure rate of 8.3% (95% CI: 7.8-8.9). We found that the perfect-use Pearl Index was 1.0 pregnancy per 100 woman-years (95% CI: 0.5-1.5). Finally, we estimated that the rate of pregnancies from cycles where the application erroneously flagged a fertile day as infertile was 0.5 (95% CI: 0.4-0.7) per 100 woman-years. We estimated a discontinuation rate over 12months of 54%. CONCLUSIONS: This study shows that the efficacy of a contraceptive mobile application is higher than usually reported for traditional fertility awareness based methods. The application may contribute to reducing the unmet need for contraception. IMPLICATIONS: The measured typical- and perfect-use efficacies of the mobile application Natural Cycles are important parameters for women considering their contraceptive options as well as for the clinicians advising them. The large available data set in this paper allows for future studies on acceptability, for example, by studying the efficacy for different cohorts and geographic regions. PMID- 28882681 TI - Provider communication with adolescent and young females during sexual and reproductive health visits: findings from the 2011-2015 National Survey of Family Growth. AB - OBJECTIVE: This study assesses provider communication with adolescent and young women about birth control, emergency contraception and condoms during sexual and reproductive health visits. STUDY DESIGN: Using data from sexually active 15-24 year-old women in the 2011-2015 National Survey of Family Growth, we examined provider communication about contraception and condoms at sexual and reproductive health services in the past year and assessed differences by demographics, sexual behavior and source of care. RESULTS: Approximately two thirds of women received provider communication about condoms (65.0%) and birth control (64.0%-66.8%). Communication was higher among Title-X-funded clinic vs. private providers. Differences by age, race/ethnicity, mother's education, number of partners and condom use were also found. CONCLUSION: Most sexually active young women attending sexual and reproductive health visits received provider communication about condoms and birth control, but communication is not universal and varies by source of care, demographics and sexual behavior. PMID- 28882682 TI - Management of the Pressure Injury Patient with Osteomyelitis: An Algorithm. PMID- 28882683 TI - Structured Operative Autonomy: An Institutional Approach to Enhancing Surgical Resident Education Without Impacting Patient Outcomes. AB - BACKGROUND: Although barriers to granting surgical residents autonomy in the operating room are well described, few have proposed practical strategies to overcome these barriers. Our department adopted a multidisciplinary approach to develop a rotation that aimed to grant chief residents structured operative autonomy. In this study, we assess the feasibility of implementation, impact on patient safety, and educational benefit to residents after the program's pilot year. STUDY DESIGN: During a 1-month rotation, chief residents began cases alone using their own operative block time. The attending surgeon was notified when the critical portion of the operation was reached and supervised its completion. Postoperative complications, intraoperative adverse events, readmissions, operation duration, and length of stay in a subset of patients that underwent a cholecystectomy or appendectomy were compared with patients operated on by standard resident services. Follow-up surveys were administered to residents 1 year after graduation. RESULTS: One hundred and twenty-four operations, which ranged in complexity, were performed by chief residents. Unadjusted subset analysis comparing the structured operative autonomy (n = 54) and standard resident (n = 718) services outcomes for appendectomies and cholecystectomies revealed no significant differences in 30-day postoperative complications (5.6% vs 4.0%; p = 0.59), major intraoperative adverse events, or readmissions (3.7% vs 3.8%; p = 1.00), respectively. Multivariate analysis performed for 30-day complications (odds ratio 0.8; 95% CI 0.2 to 3.2; p = 0.76) and readmissions (odds ratio 0.4; 95% CI 0.1 to 2.1; p = 0.3) corroborated unadjusted findings. All participants (n = 8) strongly agreed that the rotation eased their transition to fellowship or independent practice. CONCLUSIONS: Structured operative autonomy overcomes known barriers to granting chief residents autonomy in the operating room. When used for select general surgery cases, resident education is enhanced without impacting patient outcomes. This training model has the potential to improve the surgical independence of graduating residents. PMID- 28882684 TI - Concerns of Quality and Safety in Public Domain Surgical Education Videos: An Assessment of the Critical View of Safety in Frequently Used Laparoscopic Cholecystectomy Videos. AB - BACKGROUND: Online videos are among the most common resources for case preparation. Using crowd sourcing, we evaluated the relationship between operative quality and viewing characteristics of online laparoscopic cholecystectomy videos. STUDY DESIGN: We edited 160 online videos of laparoscopic cholecystectomy to 60 seconds or less. Crowd workers (CW) rated videos using Global Objective Assessment of Laparoscopic Skills (GOALS), the critical view of safety (CVS) criteria, and assigned overall pass/fail ratings if CVS was achieved; linear mixed effects models derived average ratings. Views, likes, dislikes, subscribers, and country were recorded for subset analysis of YouTube videos. Spearman correlation coefficient (SCC) assessed correlation between performance measures. RESULTS: One video (0.06%) achieved a passing CVS score of >=5; 23%, >=4; 44%, >=3; 79%, >=2; and 100% >=1. Pass/fail ratings correlated to CVS, SCC 0.95 (p < 0.001) and to GOALS, SCC 0.79 (p < 0.001). YouTube videos (n = 139) with higher views, likes, or subscribers did not correlate with better quality. The average CVS and GOALS scores were no different for videos with >20,000 views (22%) compared with those with <20,000 (78%). CONCLUSIONS: There is an incredibly low frequency of CVS and average GOALS technical performance in frequently used online surgical videos of LC. Favorable characteristics, such as number of views or likes, do not translate to higher quality. PMID- 28882685 TI - Hemoencephalography self-regulation training and its impact on cognition: A study with schizophrenia and healthy participants. AB - BACKGROUND: Cognitive impairments in schizophrenia are strongly correlated to functional outcome and recovery rates, with no pharmacological agent approved for its treatment. Neurofeedback has emerged as a non-pharmacological approach to enhance neuroplasticity, which consists in inducing voluntary control of brain responses through operant conditioning. METHOD: The effects of hemoencephalography neurofeedback (HEG-NFBK) in 4 brain sites (F7, Fp1, Fp2 and F8) was studied in 8 patients with schizophrenia (SCH, mean age 36.5+/-9.98) and 12 health controls (mean age 32.17+/-5.6). We analyzed groups' performance (10 sessions) and cognitive differences in 3 time points (baseline, after training and follow-up) with generalized estimated equations. For SCH we also evaluate the impact on psychopathology. RESULTS: We found a group*time interaction for HEG NFBK performance in the left hemisphere sites (F7 an Fp1) and a near-to significant in the right frontotemporal region (F8), with no group differences and a significant time effect. Most of cognitive domains improved after intervention, including information processing speed, attention processing, working memory, executive functioning, verbal and visual learning. No group*time interaction was found. Results suggest that both groups benefit from HEG-NFBK training regardless of cognitive differences at baseline. No significant time effects were found for Calgary and PANSS total scale and subscales (positive, negative neither general). CONCLUSION: To our knowledge, this is the first controlled trial showing effects of NFBK on cognitive performance improvement in schizophrenia. Further research investigating the effects of HEG-NFBK training in schizophrenia should be performed. PMID- 28882686 TI - Effects of peer social interaction on performance during computerized cognitive remediation therapy in patients with early course schizophrenia: A pilot study. AB - BACKGROUND: Recent studies show that computer-based training enhances cognition in schizophrenia; furthermore, socialization has also been found to improve cognitive functions. It is generally believed that non-social cognitive remediation using computer exercises would be a pre-requisite for therapeutic benefits from social cognitive training. However, it is also possible that social interaction by itself enhances non-social cognitive functions; this possibility has scarcely been explored in schizophrenia patients. This pilot study examined the effects of computer-based neurocognitive training, along with social interaction either with a peer (PSI) or without one (N-PSI). We hypothesized that PSI will enhance cognitive performance during computerized exercises in schizophrenia, as compared with N-PSI. METHODS: Sixteen adult participants diagnosed with schizophrenia or schizoaffective disorder participating in an ongoing trial of Cognitive Enhancement Therapy completed several computerized neurocognitive remediation training sessions (the Orientation Remedial Module(c), or ORM), either with a peer or without a peer. RESULTS: We observed a significant interaction between the effect of PSI and performance on the different cognitive exercises (p<0.05). More precisely, when patients performed the session with PSI, they demonstrated better cognitive performances than with N-PSI in the ORM exercise that provides training in processing speed, alertness, and reaction time (the standard Attention Reaction Conditioner, or ARC) (p<0.01, corrected). PSI did not significantly affect other cognitive domains such as target detection and spatial attention. CONCLUSION: Our findings suggest that PSI could improve cognitive performance, such as processing speed, during computerized cognitive training in schizophrenia. Additional studies investigating the effect of PSI during cognitive remediation are needed to further evaluate this hypothesis. PMID- 28882687 TI - Sodium valproate and clozapine induced neutropenia: A case control study using register data. AB - BACKGROUND: The use of clozapine is limited due to the occurrence of neutropenia, and the rare but life threatening adverse event of agranulocytosis. There is little epidemiological research into clinical factors that may impact on this risk. We conducted a case control study examining the clinical risk factors for neutropenia patients treated with clozapine. METHOD: A case-control study was conducted within a database of anonymised electronic clinical records. All patients who discontinued clozapine due to a neutropenic event were included as cases. Matched controls were selected from patients with a documented clozapine exposure at the time of the clozapine neutropenic event of the case patient, matched by duration of clozapine treatment. RESULTS: 136 cases and 136 controls were included. In multivariable analysis, the concurrent use of sodium valproate was associated with neutropenia (Odds Raito (OR) 2.28, 95%CI: 1.27-4.11, p=0.006). There was a dose-response effect, with greater associations for higher doses. Patients who discontinued clozapine due to neutropenia were more likely to be of black ethnicity (OR 2.99, p<0.001), were younger (t=5.86, df=267, p<0.001), and received lower doses of clozapine (t=-2.587, p=0.01) than those who did not develop neutropenia. CONCLUSION: We identified an association between the concurrent use of sodium valproate and an increased risk of clozapine associated neutropenia. These results, taken in combination with the results from previous case series, suggest that the risk of clozapine associated neutropenia could be reduced by avoiding concurrent valproate treatment. PMID- 28882688 TI - Short Sleep Duration Is Associated With Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease. PMID- 28882689 TI - Timing of Endoscopy in Acute Nonvariceal Gastrointestinal Bleeding: Still Looking for the Answer. PMID- 28882690 TI - Toxicogenomic and bioinformatics platforms to identify key molecular mechanisms of a curcumin-analogue DM-1 toxicity in melanoma cells. AB - Melanoma is a highly invasive and metastatic cancer with high mortality rates and chemoresistance. Around 50% of melanomas are driven by activating mutations in BRAF that has led to the development of potent anti-BRAF inhibitors. However resistance to anti-BRAF therapy usually develops within a few months and consequently there is a need to identify alternative therapies that will bypass BRAF inhibitor resistance. The curcumin analogue DM-1 (sodium 4-[5-(4-hydroxy-3 methoxy-phenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) has substantial anti tumor activity in melanoma, but its mechanism of action remains unclear. Here we use a synthetic lethal genetic screen in Saccharomyces cerevisiae to identify 211 genes implicated in sensitivity to DM-1 toxicity. From these 211 genes, 74 had close human orthologues implicated in oxidative phosphorylation, insulin signaling and iron and RNA metabolism. Further analysis identified 7 target genes (ADK, ATP6V0B, PEMT, TOP1, ZFP36, ZFP36L1, ZFP36L2) with differential expression during melanoma progression implicated in regulation of tumor progression, cell differentiation, and epithelial-mesenchymal transition. Of these TOP1 and ADK were regulated by DM-1 in treatment-naive and vemurafenib-resistant melanoma cells respectively. These data reveal that the anticancer effect of curcumin analogues is likely to be mediated via multiple targets and identify several genes that represent candidates for combinatorial targeting in melanoma. PMID- 28882691 TI - Is that disgust I see? Political ideology and biased visual attention. AB - Considerable evidence suggests that political liberals and conservatives vary in the way they process and respond to valenced (i.e., negative versus positive) information, with conservatives generally displaying greater negativity biases than liberals. Less is known about whether liberals and conservatives differentially prioritize certain forms of negative information over others. Across two studies using eye-tracking methodology, we examined differences in visual attention to negative scenes and facial expressions based on self-reported political ideology. In Study 1, scenes rated high in fear, disgust, sadness, and neutrality were presented simultaneously. Greater endorsement of socially conservative political attitudes was associated with less attentional engagement (i.e., lower dwell time) of disgust scenes and more attentional engagement toward neutral scenes. Socially conservative political attitudes were not significantly associated with visual attention to fear or sad scenes. In Study 2, images depicting facial expressions of fear, disgust, sadness, and neutrality were presented simultaneously. Greater endorsement of socially conservative political attitudes was associated with greater attentional engagement with facial expressions depicting disgust and less attentional engagement toward neutral faces. Visual attention to fearful or sad faces was not related to social conservatism. Endorsement of economically conservative political attitudes was not consistently associated with biases in visual attention across both studies. These findings support disease-avoidance models and suggest that social conservatism may be rooted within a greater sensitivity to disgust-related information. PMID- 28882692 TI - Hippocampal theta phase-contingent memory retrieval in delay and trace eyeblink conditioning. AB - Hippocampal theta oscillations (3-12Hz) play a prominent role in learning. It has been suggested that encoding and retrieval of memories are supported by different phases of the theta cycle. Our previous study on trace eyeblink conditioning in rabbits suggests that the timing of the conditioned stimulus (CS) in relation to theta phase affects encoding but not retrieval of the memory trace. Here, we directly tested the effects of hippocampal theta phase on memory retrieval in two experiments conducted on adult female New Zealand White rabbits. In Experiment 1, animals were trained in trace eyeblink conditioning followed by extinction, and memory retrieval was tested by presenting the CS at troughs and peaks of the theta cycle during different stages of learning. In Experiment 2, animals were trained in delay conditioning either contingent on a high level of theta or at a random neural state. Conditioning was then followed by extinction conducted either at a random state, contingent on theta trough or contingent on theta peak. Our current results indicate that the phase of theta at CS onset has no effect on the performance of the behavioral learned response at any stage of classical eyeblink conditioning or extinction. In addition, theta-contingent trial presentation does not improve learning during delay eyeblink conditioning. The results are consistent with our earlier findings and suggest that the theta phase alone is not sufficient to affect learning at the behavioral level. It seems that the retrieval of recently acquired memories and consequently performing a learned response is moderated by neural mechanisms other than hippocampal theta. PMID- 28882693 TI - Different effects of running wheel exercise and skilled reaching training on corticofugal tract plasticity in hypertensive rats with cortical infarctions. AB - The approaches that facilitate white matter plasticity may prompt functional recovery after a stroke. The effects of different exercise methods on motor recovery in stroke rats have been investigated. However, it is not clear whether their effects on axonal plasticity different. The aim of this study was to compare the effects of the forced running wheel exercise (RWE) and skilled reaching training (SRT) on axonal plasticity and motor recovery. Cortical infarctions were generated in stroke-prone renovascular hypertensive rats. The rats were randomly divided into the following three groups: the control (Con) group, the RWE group, and the SRT group. A sham group was also included. The mNSS and forelimb grip strength tests were performed on days 3, 7, 14, 21, 28, 35, and 42 after ischemia. The anterograde tract tracer biotinylated dextran amine (BDA) was injected into the rats to trace the axonal plasticity of the contralesional corticofugal tracts. Compared with the Con group, the mNSS scores in the SRT and RWE groups decreased on day 28 (P<0.05) and on days 35 and 42 (P<0.01). The grip strength in the SRT group increased relative to that in the RWE group at 42day post-ischemia (P<0.01). Both the RWE and SRT groups exhibited enhanced plasticity of the contralesional corticofugal tract axons at the level of the red nucleus (P<0.01) and the cervical enlargement (P<0.01). More contralateral corticorubral tract remodeling was observed at the red nucleus level in the SRT group than in the RWE group (P<0.001). Taken together, these results suggest that SRT may enhance axon plasticity in the corticorubral tract more effectively than the forced RWE and is associated with better motor recovery after cerebral ischemia. PMID- 28882694 TI - Embryonic alcohol exposure leading to social avoidance and altered anxiety responses in adult zebrafish. AB - Fetal Alcohol Spectrum Disorders (FASD) is a syndrome characterized by neurological and behavioral impairments. A recently discovered hallmark of FASD is impaired social behavior. Avoidance of social interaction typical of FASD may be the result of increased anxiety. Previously, the zebrafish was successfully used to model embryonic alcohol induced social abnormalities. Here, we analyzed both anxiety and social responses using a zebrafish FASD model, in adult fish. We exposed zebrafish embryos to low concentrations of ethanol (0.1%; 0.25%; 0.5% and 1% v/v) for 2h at, 24h post-fertilization, to mimic the most prevalent milder FASD cases, and investigated the ensuing alterations in adult, 4-month-old, zebrafish. We studied social interaction in the social preference task and anxiety in the novel tank task. We observed an ethanol dose dependent reduction of time spend in the conspecific zone compared to control, corroborating prior findings. We also found significant changes in the novel tank (e.g. increased bottom dwell time, increased distance to top) suggesting elevated anxiety to control, but we also found, using an anxiolytic drug buspirone, that reduction of anxiety is associated with reduced shoaling. Our results confirm that embryonic alcohol exposure disrupts social behavior, and also show that its effects on anxiety related phenotypes may be genotype, alcohol administration method, experimental procedure and test-context dependent. PMID- 28882695 TI - Effects of an acute therapeutic or rewarding dose of amphetamine on acquisition of Pavlovian autoshaping and ventral striatal dopamine signaling. AB - Rewarding doses of amphetamine increase the amplitude, duration, and frequency of dopamine transients in the ventral striatum. Debate continues at the behavioral level about which component of reward, learning or incentive salience, is signaled by these dopamine transients and thus altered in addiction. The learning hypothesis proposes that rewarding drugs result in pathological overlearning of drug-predictive cues, while the incentive sensitization hypothesis suggests that rewarding drugs result in sensitized attribution of incentive salience to drug predictive cues. Therapeutic doses of amphetamine, such as those used to treat attention-deficit hyperactivity disorder, are hypothesized to enhance the ventral striatal dopamine transients that are critical for reward-related learning and to enhance Pavlovian learning. However, the effects of therapeutic doses of amphetamine on Pavlovian learning are poorly understood, and the effects on dopamine transients are completely unknown. We determined the effects of an acute pre-training therapeutic or rewarding amphetamine injection on the acquisition of Pavlovian autoshaping in the intact rat. We also determined the effects of these doses on electrically evoked transient-like dopamine signals using fast-scan cyclic voltammetry in the anesthetized rat. The rewarding dose enhanced the amplitude and duration of DA signals, caused acute task disengagement, impaired learning for several days, and triggered incentive sensitization. The therapeutic dose produced smaller enhancements in DA signals but did not have similar behavioral effects. These results underscore the necessity of more studies using therapeutic doses, and suggest a hybrid learning/incentive sensitization model may be required to explain the development of addiction. PMID- 28882696 TI - Histone deacetylases inhibition: a potential diagnostic and therapeutic target for cancers. PMID- 28882697 TI - Clinicopathologic and gene expression analysis of initial biopsies from patients with eosinophilic esophagitis refractory to therapy. AB - Some patients with eosinophilic esophagitis (EoE) do not respond to therapy. The clinicopathologic characteristics and gene expression profile at time of presentation could help predict response to therapy. Refractory EoE was defined as persistence of symptoms and biopsies with histologic features of EoE after 6 months of therapy with proton pump inhibitors and topical corticosteroids. Initial biopsies from refractory EoE patients (n=21), responder to therapy (n=8), patients who relapsed (n=6), and reflux controls (n=24) were studied. RNA was isolated from a subset of cases, and gene expression analysis of 285 genes involved in inflammation was performed using NanoString technology. There was no difference in the presenting symptoms among groups. The number of eosinophils/high-power field among nonresponders was higher (66+/-15) than responders (39+/-8; P<.0001) and similar to patients who relapsed (62+/-11). Six genes were expressed by at least 4-fold compared with reflux at a false discovery rate < 0.05, including overexpression of ALOX15, CCL26, FCER2, RTNLB, and RNASE2, and underexpression of DSG1. EoE patients refractory to therapy or who relapsed showed a trend toward higher ALOX15 expression compared with patients with good response to therapy (364.4- and 425-fold change, P=.097 and P=.07). RTNLB was significantly overexpressed in patients who were refractory to therapy versus those who responded favorably (10-fold versus 3-fold; P<.01). In conclusion, the number of eosinophils/high-power field in the initial biopsy inversely correlates with therapy response. Overexpression of RTNLB in refractory-to-therapy patients and overexpression of ALOX15 and CCL26 suggest that they are critical in the EoE pathogenesis. PMID- 28882698 TI - Prognostic value of microRNA-9 and microRNA-155 expression in triple-negative breast cancer. AB - MicroRNAs (miRNAs) are involved in regulation of epithelial-mesenchymal transition (EMT) during breast cancer progression. The purpose of this study was to analyze the clinicopathologic significance of expression of EMT-related miRNAs, miR-9 and miR-155, in triple-negative breast cancers (TNBCs). We analyzed relative expression levels of miR-9 and miR-155 in 190 surgically resected TNBC specimens using quantitative real-time polymerase chain reaction. Then we analyzed the relationship between these miRNA expression levels and EMT marker expression (vimentin, smooth muscle actin [SMA], osteonectin, N-cadherin, E cadherin, CD146, and ZEB1) assessed by immunohistochemistry. We also evaluated the prognostic significance of these miRNA expression levels. While miR-9 expression level showed a positive correlation with pT category, miR-155 expression level did not correlate with any clinicopathologic features of TNBCs. In relation to EMT phenotype, miR-9 expression was not associated with EMT marker expression except for SMA. However, miR-155 expression level correlated inversely with the expression of several EMT markers including SMA, osteonectin, and CD146. We observed that both miR-9 and miR-155 could be prognostic markers in TNBC in opposite ways; high level of miR-9 expression showed significant association with poor disease-free survival and distant metastasis-free survival (DMFS) in TNBC, while high level of miR-155 expression was associated with better DMFS. Our study suggests that expression levels of both miR-9 and miR-155 can serve as candidates for prognostic biomarkers in TNBCs. PMID- 28882700 TI - Net1, a therapeutic potential target for cancer. PMID- 28882699 TI - Neutrophil infiltration is a favorable prognostic factor in early stages of colon cancer. AB - The tumor immune response has been proven critical to prognosis in colorectal cancer (CRC), but studies on the prognostic role of neutrophil infiltration have shown contradictory results. The aim of this study was to elucidate the prognostic role of infiltrating neutrophils at different intratumoral subsites and in different molecular subgroups of CRC. The relations between neutrophil infiltration and infiltration of other immune cells (T-cell and macrophage subsets) were also addressed. Expression of the neutrophil marker CD66b was assessed by immunohistochemistry in 448 archival human tumor tissue samples from patients surgically resected for CRC. The infiltration of CD66b-positive cells was semi-quantitatively evaluated along the tumor invasive front, in the tumor center, and within the tumor epithelium (intraepithelial expression). We found that poor infiltration of CD66b-positive cells in the tumor front indicated a worse patient prognosis. The prognostic significance of CD66b infiltration was found to be mainly independent of tumor molecular characteristics and maintained significance in multivariable analysis of stage I-II colon cancers. We further analyzed the prognostic impact of CD66b-positive cells in relation to other immune markers (NOS2, CD163, Tbet, FOXP3, and CD8) and found that neutrophil infiltration, even though strongly correlated to infiltration of other immune cell subsets, had additional prognostic value. In conclusion, we find that low infiltration of neutrophils in the tumor front is an independent prognostic factor for a poorer patient prognosis in early stages of colon cancers. Further studies are needed to elucidate the biological role of neutrophils in colorectal carcinogenesis. PMID- 28882701 TI - Diagnostic value of histone 3 mutations in osteoclast-rich bone tumors. AB - Differentiating osteoclast-rich lesions of bone (giant cell tumor of bone [GCTB], chondroblastoma [CBA], and aneurysmal bone cyst [ABC]) can be challenging, especially in small biopsies or fine-needle aspirations. Mutations affecting codons 34 and 36 of either H3 Histone Family Member 3A (H3F3A) and/or 3B (H3F3B) are characteristically seen in GCTB and CBAs. We devised a simple assay to identify these mutations and evaluated its applicability for routine clinical diagnosis. One hundred twenty-four tissue specimens from 108 patients (43 GCTBs, 38 CBAs and 27 ABCs) were collected from the archives of the Calgary Laboratory Services/University of Calgary and Vanderbilt University Medical Center. Histology was reviewed by an expert orthopedic pathologist. A single base extension assay (SNaPshot) is used to interrogate each nucleotide in codons 34 and 36 of H3F3A and codon 36 of H3F3B. Final diagnoses were generated after re reviewing cases and incorporating molecular findings. Of 43 GCTBs, 38 (88%) had an H3F3A G34W mutation; 35 of 38 CBAs (92%) had a K36M mutation in either H3F3B (N = 31; 82%) or H3F3A (N = 4; 11%); none of 27 ABCs had a tested mutation. Molecular findings changed the histomorphologic diagnosis in 5 cases (3 GCTB changed to ABC, and 2 ABC changed to GCTB). These findings support the diagnostic utility of mutational analysis for this differential diagnosis in certain challenging cases when clinicoradiologic and histomorphologic features are not definitive, particularly for distinguishing cellular ABC versus GCTB with secondary ABC. PMID- 28882702 TI - Tumoral FOXP3 expression is associated with favorable clinicopathological variables and good prognosis in gastric adenocarcinoma: the tumor suppressor function of tumoral FOXP3 is related with the P21 expression in gastric adenocarcinoma. AB - The function and contribution of tumoral FOXP3 in gastric cancer development remain poorly understood. Thus, we studied the expression of tumoral FOXP3 and its relationship with the well-known tumor suppressor proteins P21 and P53 in gastric adenocarcinoma. The tissue microarray was constructed from 182 cases of gastric adenocarcinoma. The immunohistochemistry was performed on 4-MUm tissue sections from each tissue microarray block. We found that positive tumoral FOXP3 expression was significantly correlated with a lower T category, a lower N category, a lower recurrence rate, and less lymphatic invasion. Furthermore, the survival analysis revealed that the tumoral FOXP3-positive group had significantly increased overall survival and disease-free survival rates compared with the tumoral FOXP3-negative group. Additionally, P21 expression showed a significant positive correlation with tumoral FOXP3 expression in gastric adenocarcinoma cells. Taken together, these findings demonstrate that tumoral FOXP3 expression is associated with favorable clinicopathological variables and good prognosis in gastric adenocarcinoma through increased expression of the tumor suppression protein P21. PMID- 28882703 TI - PEGylation for enhancing nanoparticle diffusion in mucus. AB - The viscoelastic mucus secretions coating exposed organs such as the lung airways and the female reproductive tract can trap and quickly eliminate not only foreign pathogens and ultrafine particles but also particle-based drug delivery systems, thus limiting sustained and targeted drug delivery at mucosal surfaces. To improve particle distribution across the mucosa and enhance delivery to the underlying epithelium, many investigators have sought to develop nanoparticles capable of readily traversing mucus. The first synthetic nanoparticles shown capable of rapidly penetrating physiological mucus secretions utilized a dense coating of polyethylene glycol (PEG) covalently grafted onto the surface of preformed polymeric nanoparticles. In the decade since, PEG has become the gold standard in engineering mucus-penetrating drug carriers for sustained and targeted drug delivery to the lungs, gastrointestinal tract, eyes, and female reproductive tract. This review summarizes the history of the development of various PEG-based mucus-penetrating particles, and highlights the key physicochemical properties of PEG coatings and PEGylation strategies to achieve muco-inert PEG coatings on nanoparticle drug carriers for improved drug and gene delivery at mucosal surfaces. PMID- 28882704 TI - Bioluminescent enzyme inhibition-based assay to predict the potential toxicity of carbon nanomaterials. AB - A bioluminescent enzyme inhibition-based assay was applied to predict the potential toxicity of carbon nanomaterials (CNM) presented by single- and multi walled nanotubes (SWCNT and MWCNT) and aqueous solutions of hydrated fullerene S60 (C60HyFn). This assay specifically detects the influence of substances on parameters of the soluble or immobilised coupled enzyme system of luminescent bacteria: NAD(P)N:FMN-oxidoreductase+luciferase (Red+Luc). A protocol based on the optical properties of CNM for correcting the results of the bioluminescent assay was also developed. It was shown that the inhibitory activity of CNM on Red+Luc decreased in the following order: MWCNT>SWCNT>C60HyFn. The soluble enzyme system Red+Luc had high sensitivity to MWCNT and SWCNT, with values of the inhibition parameter IC50 equal to 0.012 and 0.16mg/L, respectively. The immobilised enzyme system was more vulnerable to C60HyFn than its soluble form, with an IC50 equal to 1.4mg/L. Due to its technical simplicity, rapid response time and high sensitivity, this bioluminescent method has the potential to be developed as a general enzyme inhibition-based assay for a wide variety of nanomaterials. PMID- 28882705 TI - Prediction of skin sensitization potency sub-categories using peptide reactivity data. AB - While the skin sensitization hazard of substances can already be identified using non-animal methods, the classification of potency sub-categories GHS-1A and 1B is still challenging. Potency can be measured by the dose at which an effect is observed; since the protein-adduct formation is determining the dose of the allergen in the skin, peptide reactivity was used to assess the potency. The Direct Peptide Reactivity Assay (DPRA; one concentration and reaction-time) did not sufficiently discriminate between sub-categories 1A and 1B (56% accuracy compared to LLNA data, n=124). An extended protocol termed 'quantitative DPRA' (three concentrations and one reaction-time), discriminated sub-categories GHS 1A and 1B with an accuracy of 81% or 57% compared to LLNA (n=36) or human (n=14) data, respectively. The analysis of the Cys-adducts was already sufficient; additional analysis of Lys-adducts did not improve the predictivity. An additional modification, the 'kinetic DPRA' (several concentrations and reaction times) was used to approximate the rate constant of Cys-peptide-adduct formation. 35 of 38 substances were correctly assigned to the potency sub-categories (LLNA data), and the predictivity for 14 human data was equally high. These results warrant the kinetic DPRA for further validation in order to fully replace in vivo testing for assessing skin sensitization including potency sub-classification. PMID- 28882706 TI - Can functional connectivity diagnose autoantibody-associated encephalitides? PMID- 28882707 TI - Functional connectivity of large-scale brain networks in patients with anti-NMDA receptor encephalitis: an observational study. AB - BACKGROUND: In anti-NMDA receptor (NMDAR) encephalitis, antibody-mediated dysfunction of NMDARs causes severe neuropsychiatric symptoms, including psychosis, memory deficits, and movement disorders. However, it remains elusive how antibody-mediated NMDAR dysfunction leads to these symptoms, and whether the symptoms arise from impairment in specific brain regions and the interactions between impaired regions. METHODS: In this observational study, we recruited 43 patients with anti-NMDAR encephalitis from a tertiary university hospital and 43 age-matched and sex-matched healthy controls without a history of neurological or psychiatric disorders, who were recruited from the general population of Berlin. We used structural and resting-state functional MRI to investigate alterations in connectivity in all participants. We did functional connectivity analyses, including large-scale network analysis, whole-brain pair-wise connectivity, and machine-learning classification, and compared the results with patients' functional impairment. FINDINGS: Although structural MRI was normal in 31 (72%) of the 43 patients, we observed widespread alterations of functional connectivity that correlated with clinical measures. These alterations included impaired hippocampal functional connectivity, decoupling of the medial temporal and the default-mode networks, and an overall impairment of frontotemporal connections. Furthermore, functional connectivity was impaired within distributed large-scale networks, including sensorimotor, frontoparietal, lateral-temporal, and visual networks. Memory impairment correlated with hippocampal and medial-temporal-lobe network connectivity, whereas schizophrenia-like symptoms were associated with functional connectivity changes in frontoparietal networks. Machine-learning analyses corroborated these findings and identified frontoparietal and frontotemporal connections as reliably discriminating features between patients and controls, yielding an overall accuracy of 81%. INTERPRETATION: This study reveals a characteristic pattern of whole-brain functional connectivity alterations in anti-NMDAR encephalitis that is well suited to explain the major clinical symptoms of the disorder. These observations advance the pathophysiological understanding of NMDAR dysfunction in the human brain and could be similarly relevant for other neuropsychiatric disorders, such as schizophrenia. FUNDING: Deutsche Forschungsgemeinschaft, Israeli National Science Foundation, Ministry of Science and Technology of Israel, Orion Foundation, and the Agnes Ginges Center for Neurologenetics. PMID- 28882708 TI - Fermentation properties of isomaltooligosaccharides are affected by human fecal enterotypes. AB - Isomaltooligosaccharides (IMOs) are enzymatically synthesized oligosaccharides that have potential prebiotic effects. Five IMO substrates with 2-16 degrees of polymerization (DP) were studied for their fermentation capacities using human microbiomes in an in vitro batch fermentation model. Eleven fecal slurries belonging to three enterotypes, including the Bacteroides-, Prevotella- and Mixed type, exhibited different degradation rates for long chain IMOs (DP 7 to 16). In contrast, the degradation rates for short chain IMOs (DP 2 to 6) were not affected by enterotypes. Both 16S rRNA gene sequencing and quantitative PCR demonstrated that, after fermentation, the Bifidobacterium growth with IMOs was primarily detected in the Bacteroides- and Mixed-type (non-Prevotella-type), and to a lesser degree in the Prevotella-type. Interestingly, the Prevotella-type microbiome had higher levels of propionic acid and butyric acid production than non-Prevotella-type microbiome after IMOs fermentation. Moreover, principal coordinate analysis (PCoA) of both denaturing gradient gel electrophoresis (DGGE) profiling and 16S rRNA sequencing data demonstrated that the microbiome community compositions were separately clustered based on IMO chain length, suggesting significant impact of DP on the bacterial community structure. The current results clearly demonstrated that the IMO chain length could modulate the structure and composition of the human colonic microbiome. Different responses to short and long chain IMOs were observed from three human enterotypes, indicating that IMOs may be used as therapeutic substrates for directly altering human colonic bacteria. PMID- 28882709 TI - Short-Term Outcome Comparison Between Full-Endoscopic Interlaminar Approach and Open Minimally Invasive Microsurgical Technique for Treatment of Lumbar Disc Herniation. AB - OBJECTIVE: To compare postoperative pain control and functional outcome between full-endoscopic interlaminar approach (FEIA) and open minimally invasive microsurgical technique (MMST) for lumbar discectomy. METHODS: All consecutive patients treated with FEIA were prospectively followed. Clinical outcome parameters (low back and leg numeric rating scale and Quebec Back Pain Disability Scale) were measured. Analgesics use after surgery was quantified. Results were compared with a cohort of patients treated in the same period with MMST. The decision regarding which surgical technique to use was based on endoscope availability only. RESULTS: There were 26 patients treated with FEIA and 18 treated with MMST. Baseline patient characteristics were comparable. Sciatic pain was treated in both groups. Postoperative back pain was significantly lower in the FEIA group (numeric rating scale scores 1.5, 0.3, and 0.2 at 1, 2, and 4 weeks after FEIA vs. 3.6, 2.4, and 1.6 after MMST). In the FEIA group, 61.5% of patients did not take any pain medication. The average number of analgesics taken within 30 days was 4.0 in the FEIA group and 27.2 in the MMST group. The average Quebec Back Pain Disability Scale score decreased from 57.7 to 25.0, 18.0, and 14.2 at 1, 2, and 4 weeks after FEIA compared with a decrease from 58.8 to 41.1, 34.7, and 23.0 in the MMST group. No approach-related complications were reported. CONCLUSIONS: With less analgesic use, back and leg pain relief after 1 week in the FEIA group was comparable to that achieved in the MMST group after 1 month. This was also true for overall ability of patients to perform daily activities. PMID- 28882710 TI - Quantitative Analysis of Intracranial Vertebrobasilar Dissecting Aneurysm with Intramural Hematoma After Endovascular Treatment Using 3-T High-Resolution Magnetic Resonance Imaging. AB - OBJECTIVE: Quantitative measurements of intracranial vessel walls are reliable in 3-T high-resolution magnetic resonance imaging (HR-MRI). However, few reports have assessed the arterial wall after endovascular treatment (EVT) by 3-T HR-MRI. This study aimed to quantitatively analyze vessel walls in vertebrobasilar artery dissecting aneurysms after EVT. METHODS: From May 2012 to December 2015, a total of 21 patients with 21 intracranial vertebrobasilar dissecting aneurysms (VBDAs) were enrolled in this consecutive study. All the VBDAs were characterized by intramural hematomas (IMHs >=5 mm) and treated with reconstructive EVT. Images of preoperative and follow-up 3-T HR-MRI were used to evaluate the arterial wall. The relative signal intensity (RSI) of IMHs was quantified on T1-weighted imaging (T1WI) and magnetization-prepared rapid acquisition gradient-echo (MPRAGE). RESULTS: Angiographic follow-up was performed for a mean of 9.19 +/- 3.22 months. According to angiographic results at follow-up, 21 patients were divided into 2 groups (progressive group, n = 6; stable group, n = 15). In the progressive group, RSI of IMHs was significantly increased on MPRAGE of follow-up 3-T HR-MRI compared with that before treatment (P < 0.05), and the difference was not significant on T1WI. However, in the stable group, RSI of IMHs was significantly reduced after treatment (P < 0.05). CONCLUSIONS: Persistent high signal intensity of IMHs in VBDAs after reconstructive EVT may be associated with the progression of VBDAs. It may also indicate an unsteady state of the aneurysm, which suggests that reconstruction of the parent artery is not satisfactory. PMID- 28882711 TI - Stereotactic Radiosurgery of Central Skull Base Meningiomas-Volumetric Evaluation and Long-Term Outcomes. AB - BACKGROUND AND OBJECTIVE: Complete resection of a central skull base meningioma (CSM) is possible, but it is often associated with high morbidity. Stereotactic radiosurgery (SRS) plays an appreciable role in the management of skull base meningiomas. This study aims to apply volumetric methods to assess the CSM response after SRS and correlate it with clinical outcomes. MATERIALS AND METHODS: The cohort consisted of 219 patients, of whom 73.9% were female (n = 162), with a median age of 55 years (19-88). SRS was the primary treatment for 45.7% (n = 100), while 37.9% (n = 83) underwent treatment for residual tumors, 14.2% (n = 31) for recurrence, and in 5 with others reasons. The median tumor volume was 4.9 cm3 (0.3-105 cm3) to a median margin dose of 14 Gy (5-35 Gy). Volumetric analysis of CSM was performed on the SRS scan and each available magnetic resonance image thereafter. RESULTS: The median clinical and imaging follow-ups of the cohort were 72 (24-298) and 66 (18-298) months, respectively. The overall tumor control rate was 83.4% (n = 183) at last follow-up with tumor regression 72.1% (n = 158). Neurologic symptoms were improved after SRS in 6.8% (n = 15), stable in 72.6% (n = 159), and worsened in 20.5% (n = 45). The clinical deterioration usually occurred in the patients with tumor progression (P < 0.001). Following SRS, the volumetric analysis confirmed that tumor response at 3 years reliably projected volumetric change and tumor control at 5 years (R2 = 0.694) with P < 0.001 and 10 years (R2 = 0.571) with P = 0.001. CONCLUSION: SRS affords effective tumor volumetric control and neurologic stability or improvement in the majority of patients with CSMs. The radiologic response of CSM as determined by volumetry at 3 years post-SRS is predictive of long-term tumor response at 5 and 10 years following SRS. PMID- 28882712 TI - Joint Capsule-Like Intracranial Osteochondroma Mimicking Cystic Meningioma. AB - This report provides the first representative images of an intracranial osteochondroma with a cystic component mimicking cystic meningioma. A 40-year-old male presented at our outpatient clinic with decreased sensation in his right upper extremity. Preoperative computed tomography showed a tumor with a cystic meningioma-like appearance and prominent calcifications. On magnetic resonance imaging, calcification of the lesion was suggested by the T2-weighted image; weak enhancement was seen on the T1-weighted image. Following surgical removal of the tumor, the pathologic examination showed findings consistent with osteochondroma. Cystic meningioma is a rare tumor with a cystic component. Intracranial osteochondroma is also a rare, benign tumor that can mimic meningioma when presenting in the dural convexity. Our report describes the joint capsule-like appearance of a convex cystic osteochondroma including a calcified cap, bonelike structure, and fluid-containing intracapsular space. The tumor was evaluated by imaging and pathologic studies. PMID- 28882713 TI - A Systematic Review of Radiosurgery Versus Surgery for Neurofibromatosis Type 2 Vestibular Schwannomas. AB - OBJECTIVE: Neurofibromatosis type 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas (VSs). NF2-associated VSs (NF2 VSs) are routinely treated with microsurgery; however, stereotactic radiosurgery (SRS) has emerged as an effective alternative in recent decades. To elucidate the role of SRS in NF2-VSs, a systematic review of the literature was conducted to compare outcomes of SRS versus surgery. METHODS: PubMed, Web of Science, Scopus, Embase, and Cochrane databases were queried using relevant search terms. Retrospective studies investigating outcomes of NF2-VS patients treated with either SRS or surgery were included. Single-patient case reports were excluded. Outcome measures between the SRS and surgery groups were compared using chi2 2 sample tests for equality of proportions on the pooled patient data. RESULTS: A total of 974 patients (485 SRS, 489 surgery) were identified. The mean 5-year local control rate for SRS was 75.1%, and the mean recurrence rate for surgery was 8.1%. The mean hearing and facial nerve preservation rates were 40.1% and 92.3%, respectively, for SRS and 52.0% and 75.7%, respectively, for surgery. Rates of hearing preservation were higher after surgery than after SRS (P = 0.006), whereas rates of facial nerve preservation were higher after SRS than after surgery (P < 0.001). CONCLUSIONS: SRS appears to be a safe and effective alternative to surgery for NF2-VS. Although rates of hearing preservation were higher in the surgery cohorts, SRS demonstrated high rates of local control and significantly lower facial nerve complications. Certain patients may therefore benefit more from SRS than surgery. PMID- 28882714 TI - Combined Minimally Invasive Supraciliary and Transfacial Approach for Large Tumors with Skull Base and Sinonasal Involvement. AB - BACKGROUND: Tumors invading both the anterior skull base and the sinonasal area have traditionally been accessed via largely invasive open craniofacial approaches. Minimally invasive extended endoscopic endonasal approaches have recently become increasingly available but have anatomical limitations and require incremental experience and thus high patient volume. Our objective was to assess the applicability of a novel combination of the minimally invasive supraciliary incision and the limited maxillofacial osteotomy as a combined surgical approach for large tumors invading both the anterior skull base and the sinonasal area. METHODS: The well-established technique of supraciliary incision with a 2.5 * 3.0-cm craniotomy was combined for the first time with limited facial translocation approach. RESULTS: This series involves 11 cases (female/male ratio 4:7; ranging in age from 6 to 61 years). Intracranial tumor propagation with intranasal and ethmoidal extension was detected in all patients. The pathologic diagnoses included adenocarcinomas, esthesioneuroblastoma, rhabdomyosarcoma, sinonasal papilloma, meningioma, and neurofibroma. The postoperative approach-related mortality rate was zero. No case of cerebrospinal fluid leak was detected. The 3-year survival rate was 70%. CONCLUSIONS: The limited transfacial approach in combination with a supraciliary extension is associated with minimal mortality and morbidity and facilitates gross total tumor removal. We highly recommend this approach for the surgical treatment of large tumors invading both the anterior skull base and the sinonasal area, especially for those being out of indication for extended endoscopic endonasal surgery. PMID- 28882715 TI - Motor Cortex Stimulation in Patients Suffering from Chronic Neuropathic Pain: Summary of Expert Meeting and Premeeting Questionnaire, Combined with Literature Review. AB - BACKGROUND: Motor cortex stimulation (MCS) was introduced in the early 1990s by Tsubokawa and his group for patients diagnosed with drug-resistant, central neuropathic pain. Inconsistencies concerning the details of this therapy and its outcomes and poor methodology of most clinical essays divide the neuromodulation society worldwide into "believers" and "nonbelievers." A European expert meeting was organized in Brussels, Belgium by the Benelux Neuromodulation Society in order to develop uniform MCS protocols in the preoperative, intraoperative, and postoperative courses. METHODS: An expert meeting was organized, and a questionnaire was sent out to all the invited participants before this expert meeting. An extensive literature research was conducted in order to enrich the results. RESULTS: Topics that were addressed during the expert meeting were 1) inclusion and exclusion criteria, 2) targeting and methods of stimulation, 3) effects of MCS, and 4) results from the questionnaire. CONCLUSIONS: Substantial commonalities but also important methodologic divergencies emerged from the discussion of MCS experts from 7 European Centers. From this meeting and questionnaire, all participants concluded that there is a need for more homogenous standardized protocols for MCS regarding patient selection, implantation procedure, stimulation parameters, and follow-up-course. PMID- 28882716 TI - Remote Thoracic Myelopathy From a Spinal Dural Arteriovenous Fistula at the Craniocervical Junction: Case Report and Review of Literature. AB - BACKGROUND: The craniocervical junction is a rare location for spinal dural arteriovenous fistulas (dAVFs). Typically, fistulas at this location present with findings related to intracranial cortical venous reflux or cervical myelopathy. We present a case of craniocervical junction dAVF with isolated clinical and radiographic findings of thoracolumbar myelopathy. CASE DESCRIPTION: A 54-year old man presented with subacute onset of lower extremity weakness, paresthesias, and gait dysfunction. Routine spine magnetic resonance imaging demonstrated edema of the conus medullaris and distal thoracic spinal cord and prominent dorsal venous flow voids, suggestive of a thoracolumbar dAVF. Spinal angiography performed at an outside institution failed to demonstrate a fistula. Noninvasive spinal angiographic imaging with time-resolved magnetic resonance angiography (TR MRA) performed at our institution was able to demonstrate presence of the fistula at the craniocervical junction. Subsequent cerebral angiography identified feeding vessels arising from the posterior meningeal artery and ascending pharyngeal artery on the right side. The fistula was successfully embolized with onyx embolic material, with rapid resolution of his clinical symptoms. CONCLUSIONS: Isolated lower extremity myelopathic symptoms are a rarely reported finding in patients harboring craniocervical junction dAVFs. At our institution, noninvasive imaging with TR-MRA is routinely used to aid localization of dAVFs. This results in decreased contrast dose and radiation exposure, and inclusion of the cervical spine should be performed when thoracolumbar imaging fails to identify a dAVF prior to proceeding to invasive angiography. PMID- 28882717 TI - The Effects of Combined Intraoperative Monitoring of Abnormal Muscle Response and Z-L Response for Hemifacial Spasm. AB - BACKGROUND: Microvascular decompression (MVD) is the most effective treatment for hemifacial spasm (HFS). During MVD surgery, abnormal muscle response (AMR) is widely used. Z-L response (ZLR) is a new monitoring method for HFS. We compared the effectiveness of AMR plus ZLR and simple AMR. METHODS: In a retrospective study of 1868 cases of HFS treated using intraoperative monitoring between January 2013 and December 2015, 896 patients underwent simple AMR monitoring and 972 underwent combined intraoperative monitoring of AMR and ZLR. RESULTS: AMR waveforms were observed in 837 (93.42%) patients in the AMR group and in 898 (92.39%) patients in the AMR plus ZLR group (P > 0.05). During MVD, AMR waveforms disappeared in 772 patients in the AMR group and 854 patients in the AMR plus ZLR group (P < 0.05). The efficacy rate of MVD in the AMR plus ZLR group was higher compared with the AMR group when AMR was not detected or disappeared during the operation (P < 0.05). When AMR persisted during the operation, there was no significant difference between the 2 groups in efficacy of the operation (P > 0.05). CONCLUSIONS: Regardless of whether the compression vessels of the facial nerve are simple or complicated, combined intraoperative monitoring of AMR plus ZLR monitoring provides more valuable neurosurgical guidance than simple AMR during MVD for HFS. PMID- 28882718 TI - Nontraumatic Multiple Vertebral Compression Fractures Induced by Primary Hyperparathyroidism: A Case Report and Literature Review. AB - BACKGROUND: Primary hyperparathyroidism (PHPT) is one of the causes of osteoporosis and is known to increase the fracture risk of bone. However, multiple vertebral compression fracture because of PHPT is extremely rare. CASE DESCRIPTION: A case of acute multiple vertebral compression fracture in a patient with PHPT is described. The fracture occurred suddenly without trauma. The patient had a low T score (-4.4), and serum hypercalcemia and phosphatemia were evident. On examination, serum parathyroid hormone was found to be elevated, and PHPT was diagnosed by neck sonography and technetium-99m methoxyisobutylisonitrile scan. Once the patient was diagnosed with PHPT, we performed subtotal parathyroidectomy and corrective spinal surgery for multiple compression fractures. CONCLUSIONS: When a patient has multiple compression fractures without any trauma history and a very low T score, the presence of other underlying diseases should be investigated. PMID- 28882719 TI - Lessons from culturally contrasted alternative methods of inquiry and styles of comprehension for the new foundations in the study of life. AB - Contemporary scientific approaches to Biology are the result of some cultural ideas considered as universal by Western reductionist traditions. The study of the cultural, symbolic and historical approaches to reality and Life provides us important lessons about the necessity of integrating Eastern holistic views into the study of Life. This is both an epistemological and ontological enhancement which provides more powerful and insightful ways to deal with Life and its understanding. PMID- 28882720 TI - The European Association of Epilepsy Centers (EAEC): Just Old Europe or a modern model? PMID- 28882721 TI - Clinical presentation of neurocysticercosis-related epilepsy. AB - Neurocysticercosis (NCC) is the most common parasitic infection of the central nervous system and a major risk factor for seizures and epilepsy. Seizure types in NCC vary largely across studies and seizure semiology is poorly understood. We discuss here the studies regarding seizure types and seizure semiology in NCC, and examine the clinical presentation in patients with NCC and drug-resistant epilepsy. We also provide evidence of the role of MRI and EEG in the diagnosis of NCC-related epilepsy. Focal seizures are reported in 60-90% of patients with NCC related epilepsy, and around 90% of all seizures registered prospectively are focal not evolving to bilateral tonic-clonic seizures. A great number of cases suggest that seizure semiology is topographically related to NCC lesions. Patients with hippocampal sclerosis and NCC have different clinical and neurophysiological characteristics than those with hippocampal sclerosis alone. Different MRI protocols have allowed to better differentiate NCC from other etiologies. Lesions' stages might account on the chances of finding an interictal epileptiform discharge. Studies pursuing the seizure onset in patients with NCC are lacking and they are specially needed to determine both whether the reported events of individual cases are seizures, and whether they are related to the NCC lesion or lesions. This article is part of a Special Issue entitled "Neurocysticercosis and Epilepsy". PMID- 28882722 TI - Cognition in patients with benign epilepsy with centrotemporal spikes: A study with long-term VEEG and RS-fMRI. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between alterations of functional brain network and cognition in patients with benign epilepsy with centrotemporal spikes (BECTS) as a function of spike-wave index (SWI) during slow wave sleep. METHODS: Resting-state functional magnetic resonance imaging (RS-fMRI) data and Intelligence Quotient (IQ) were collected from two groups of patients with BECTS, including a SWI<50% group (5 cases) and a SWI>=50% group (7 cases). The SWI was calculated from the long-term video electroencephalogram monitoring (one sleep cycle was included at least). The RS fMRI data were analyzed by regional homogeneity (ReHo) method. RESULTS: There were three main findings. Firstly, Full Intelligence Quotient (FIQ), Verbal Intelligence Quotient (VIQ), and Performance Intelligence Quotient (PIQ) of the SWI>=50% group were significantly lower than SWI<50% group (p<0.05). Secondly, there was a negative correlation between the FIQ, VIQ, PIQ, and SWI (p<0.05), and the FIQ, VIQ, and PIQ were not dependent on age, age of onset, disease course, years of education, and total number of seizures (p>0.05). Finally, compared with the SWI<50% group, the SWI>=50% group showed increased ReHo in the bilateral precentral gyrus, bilateral premotor area, bilateral subcortical structure, right temporal lobe, and bilateral insular lobe, while they showed decreased ReHo in the posterior cingulate cortex and posterior of right inferior temporal lobe. CONCLUSIONS: The alterations of functional brain network caused by the frequent discharges during slow wave sleep could affect cognition in patients with BECTS. PMID- 28882723 TI - Antibiotic stewardship: update and perspectives. PMID- 28882724 TI - Evaluation of the scientific impact of the Ebola epidemic: a systematic review. AB - OBJECTIVES: The Ebola outbreak prompted an extensive number of scientific publications, but little attention has been paid to the involvement of local scientists, distribution of research funding and related publications. We sought to systematically review publicly available information on the scientific impact of the Ebola epidemic. METHODS: A systematic review of literature on the Ebola outbreak was performed. Extracted information included origins of the authors, type and distribution of funding, and impact factors (IF) of related publications between 6 December 2013, and 22 December 2015. RESULTS: We identified 460 relevant articles out of 3281 references, which were mostly authored by American (46.6%) and European (28.4%) institutions; only 13.4% of authors were affiliated with African institutions. Most IF can be attributed to the Americas and Europe, with 43% (25 030.8 IF) and 34.5% (20 074.2 IF), respectively, compared with 17.9% (10 436.5 IF) in Africa. Funds were provided mainly by the Americas (31.8% of all funded studies) and Europe (17%). American and European funds were also distributed back, mainly to American (77.8%) and European (85.2%) institutions, respectively. CONCLUSIONS: The Ebola outbreak had a significant scientific impact and resulted in numerous publications in high IF journals. The main impact could be measured in the Americas and Europe, and was directly related to funding. African researchers were only marginally involved in the scientific processing (86.6% of all researchers were not African), probably because major research centres are located in America and Europe. Our results suggest the importance of promoting closer cooperation between regions. PMID- 28882725 TI - What is antimicrobial stewardship? AB - BACKGROUND: The use of the term 'antimicrobial stewardship' has grown exponentially in recent years, typically referring to programmes and interventions that aim to optimize antimicrobial use. Although antimicrobial stewardship originated within human healthcare, it is increasingly applied in broader contexts including animal health and One Health. As the use of the term 'antimicrobial stewardship' becomes more common, it is important to consider what antimicrobial stewardship is, as well as what it is not. AIMS: To review the emergence and evolution of the term 'antimicrobial stewardship'. SOURCES: We searched and reviewed existing literature and official documents, which mostly focused on antibiotics. We contacted the authors of the first publications that mentioned antimicrobial stewardship. CONTENT: We describe the historical background behind how antimicrobial stewardship came into use in clinical settings. We discuss challenges emerging from the varied descriptions of antimicrobial stewardship in the literature, including an over-emphasis on individual prescriptions, an under-emphasis on the societal implications of antimicrobial use, and language translation problems. IMPLICATIONS: To help address these challenges, we suggest viewing antimicrobial stewardship as a strategy, a coherent set of actions which promote using antimicrobials responsibly. We stress the continuous need for 'responsible use' to be defined and translated into context-specific and time-specific actions. Furthermore, we present examples of actions that can be undertaken within antimicrobial stewardship across human and animal health. PMID- 28882726 TI - Methanobrevibacter oralis detected along with Aggregatibacter actinomycetemcomitans in a series of community-acquired brain abscesses. PMID- 28882727 TI - Newer glycopeptide antibiotics for treatment of complicated skin and soft tissue infections: systematic review, network meta-analysis and cost analysis. AB - OBJECTIVES: Skin and soft tissue infections (SSTIs) carry significant economic burden, as well as morbidity and mortality, especially when caused by methicillin resistant Staphylococcus aureus (MRSA). Several new MRSA-active antibiotics have been developed, including semisynthetic glycopeptides (telavancin, dalbavancin and oritavancin). Of these, dalbavancin and oritavancin offer extended dosing intervals. METHODS: We performed a systematic review, network meta-analysis and cost analysis to compare the newer glycopeptides to standard care and to each other for the treatment of complicated SSTIs (cSSTI). A search for randomized controlled trials (RCTs) was conducted in Medline, Embase and the Cochrane Central Register of Controlled Trials. We also developed a model to evaluate the costs associated with dalbavancin and oritavancin from the third-party payer perspective. RESULTS: Seven RCTs met the inclusion criteria. Network meta analyses suggested that the clinical response to telavancin, dalbavancin and oritavancin was similar to standard care (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.90-1.33; OR 0.78, 95% CI 0.52-1.18; and OR 1.06, 95% CI 0.85 1.33, respectively). Head-to-head comparisons showed no difference in clinical response between oritavancin and dalbavancin (OR 1.36; 95% CI 0.85-2.18), oritavancin and telavancin (OR 0.98; 95% CI 0.72-1.31) or dalbavancin and telavancin (OR 0.72; 95% CI 0.45-1.13). Telavancin had a higher incidence of overall adverse events compared to standard care (OR 1.33; 95% CI 1.10-1.61). Compared to telavancin, there were fewer overall adverse events with dalbavancin (OR 0.58; 95% CI 0.45-0.76) and oritavancin (OR 0.71; 95% CI 0.55-0.92). Studies were of high quality overall. Our cost analyses demonstrated that dalbavancin and oritavancin were less costly compared to standard care under baseline assumptions and many scenarios evaluated. The use of dalbavancin could save third-party payers $1442 to $4803 per cSSTI, while the use of oritavancin could save $3571 to $6932 per cSSTI. CONCLUSIONS: Dalbavancin and oritavancin demonstrate efficacy and safety comparable to standard care in well-designed RCTs and result in cost savings when standard care is treatment that covers MRSA. PMID- 28882729 TI - Tumor markers and mature cystic teratoma of the ovary. PMID- 28882728 TI - Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of Pseudomonas aeruginosa pneumonia. AB - OBJECTIVES: Pseudomonas aeruginosa is a common cause of pneumonia in patients with cystic fibrosis with the property to generate multidrug resistance against clinically used antibiotics. Antimicrobial peptides (AMPs) are a diverse group of effector molecules of the innate immune system that protect the host against pathogens. However, the lack of activity in common biological matrices has hampered efforts towards clinical development. In this study, we evaluated the therapeutic potential of the engineered AMP WLBU2 via direct airway delivery in a murine model of P. aeruginosa infection. METHODS: The human AMPs LL37 and WLBU2 were compared for (i) antibiofilm activity using P. aeruginosa on polarized human bronchial epithelial cells, and (ii) efficacy in P. aeruginosa pneumonia in mice using intratracheal instillation of bacteria and AMPs. RESULTS: WLBU2 (16 MUM) prevents biofilm formation by up to 3-log compared with 1-log reduction by LL37. With a single dose of 1 MUg (0.05 mg/kg) delivered intratracheally, the initial effect of LL37 was moderate and transitory, as bacterial load and inflammatory cytokines increased at 24 h with observed signs of disease such as lethargy and hypothermia, consistent with moribund state requiring euthanasia. In sharp contrast, WLBU2 reduced bacterial burden (by 2 logs) and bacteria-induced inflammation (leucocytic infiltrates, cytokine and chemokine gene expression) at 6 h and 24 h post-exposure, with no observed signs of disease or host toxicity. CONCLUSION: These promising results now establish a much lower minimum therapeutic dose of WLBU2 (a net gain of 80-fold) compared with the previously reported 4 mg/kg systemic minimum therapeutic dose, with significant implications for clinical development. PMID- 28882730 TI - Complete genome sequence of the first human parechovirus type 3 isolated in Taiwan. AB - The first human parechovirus 3 (HPeV3 VGHKS-2007) in Taiwan was identified from a clinical specimen from a male infant. The entire genome of the HPeV3 isolate was sequenced and compared to known HPeV3 sequences. Genome alignment data showed that HPeV3 VGHKS-2007 shares the highest nucleotide identity, 99%, with the Japanese strain of HPeV3 1361K-162589-Yamagata-2008. All HPeV3 isolates possess at least 97% amino acid identity. The analysis of the genome sequence of HPeV3 VGHKS-2007 will facilitate future investigations of the epidemiology and pathogenicity of HPeV3 infection. PMID- 28882731 TI - Danggui Buxue decoction promotes angiogenesis by up-regulation of VEGFR1/2 expressions and down-regulation of sVEGFR1/2 expression in myocardial infarction rat. AB - BACKGROUND: The traditional herbal compound Danggui Buxue decoction (DBD), has long been used for the prevention and treatment of cardiovascular diseases, however, the underlying molecular mechanism for its effect remains still unknown. So this study would to investigate the effect of DBD on cardiac damage induced by myocardial infarction (MI) challenge. METHODS: SD Rats with ligation of left anterior descending (LAD) coronary artery were randomly divided into MI, MI plus Betaloc Zok, MI plus DBD high dose, and MI plus DBD low dose group, together with sham-operated group. After corresponding treatment for consecutive 4 weeks, cardiac function was evaluated by hemodynamics with the method of pressure-volume conduit system. Cardiac histological morphology, microvascular density and the expressions of VEGF and VEGFR1/2 mRNA and their relative protein including VEGF, membranous VEGFR1 (VEGFR1), soluble VEGFR1 (sVEGFR1), VEGFR2, and sVEGFR2 were examined by hematoxylin & eosin staining, immunohistochemical staining and quantitative polymerase chain reaction and western blot assay, respectively. RESULTS: It showed that a significant impaired cardiac function and a remarkably inducible increase in fibrotic scar formation, microvascular density and VEGF mRNA expressions in MI rats. While DBD treatment could markedly boost cardiac angiogenesis further, hinder fibrotic scar formation, and improve declined cardiac function. Apart from the up-regulation of VEGF mRNA and VEGF and the down regulation of sVEGFR1/2, high dose of DBD dedicated to increasing VEGFR1 mRNA and VEGFR1 expression, while low dose to elevating VEGFR2 mRNA and VEGFR2 expression. CONCLUSION: The present study demonstrated that DBD could accelerate cardiac angiogenesis, restrain fibrous scar formation and thus ameliorate cardiac function in post-MI, via the active regulation of VEGF/VEGFRs signaling pathway. PMID- 28882733 TI - [Risk of fatal/non-fatal events in patients with previous coronary heart disease/acute myocardial infarction and treatment with non-steroidal anti inflammatory drugs]. AB - BACKGROUND: Primary Care is the fundamental axis of our health system and obliges us to be consistent with our prescriptions. The non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk and increased risk of all causes of death, as well as acute myocardial infarction (AMI) in patients with a previous myocardial infarction. Pain and cardiac patient management are 2 basic pillars in our daily activity, and we must know the limitations of NSAIDs in patients with established cardiovascular risk. OBJECTIVES: We present a review of the scientific literature with primary interest in the role of NSAIDs and cardiovascular risk. The objective is to determine the relationship between the consumption of different NSAIDs and the fatal and non-fatal events among patients with known coronary disease. METHOD: This is a review of the scientific literature with primary interest in the role of NSAIDs and cardiovascular risk. The literature review was conducted in PubMed search engines like Tripdatabase and with certain keywords. Of the 15 original papers found, 9 did not correspond completely to the central focus, so the approach was decided from 6 original articles from the past 5 years, which address the central focus of increased cardiovascular risk found (fatal and non fatal events) in patients with prior cardiovascular disease or AMI being prescribed NSAIDs for any reason. The risk of fatal/non-fatal events in each of the studies is expressed by the odds ratio (OR)/hazard ratio (HR), defined as the probability of an event occurring. RESULTS: A moderate risk was observed for ibuprofen. It increases the risk of acute coronary syndrome after 5 years of cardiovascular event, especially in the 2nd year (OR 1.63; 95% CI 1.42-1.87). It also increases the risk of stroke (HR 1.23; 95% IC 1.10-1.38). Cyclo-oxygenase-2 inhibitors were the third risk group, after nabumetone and diclofenac. Celecoxib increases risk from the 14th day of treatment (HR 2.3; 95% CI 1.79-3.02), having an OR of 1.47 (95% CI 1.05-2.07) for new AMI. Rofecoxib shows a risk of fatal cardiovascular events, even at low doses, and after 7 days of treatment (HR 2.5; 95% CI 1.91-3.46), with an OR of 2.30 (95% CI 1.76-2.99) for new AMI. Naproxen had a lower risk of cardiovascular death and new cardiovascular events, but no significant results except for treatment longer than 90 days (HR 1.55; 95% CI 1.10-2.17), with increased gastrointestinal bleeding and associated comorbidity during the first year of treatment (HR 1.44; 95% CI 1.07-1.94). Ketorolac is seen as the drug of greatest risk for new AMI: Oral treatment (OR 3.91; 95% CI 2.02 7.58). The review highlights the cardio-protective factor of certain drugs, such as antiplatelet agents and statins in patients, with NSAIDs use. For example, in patients with greater comorbidity, differences were observed in the OR, with antiplatelet agents consumption giving an OR of 1.37 (95% CI 0.68-2.74), compared to the non-consumption, OR 1.79 (95% CI 1.16-2.78). CONCLUSIONS: The consumption of various NSAIDs and their relationship to increased risk of fatal and non-fatal acute coronary syndrome is classified by years. Consumption increases the risk regardless of the time elapsed in relation to those that did not take them, with the figures remaining virtually stable for five years. Diclofenac and cyclooxygenase-2 inhibitors (especially Rofecoxib) showed an increased risk, unlike naproxen, which had a lower risk. However, naproxen, and because of its greater capacity to generate gastrointestinal bleeding, increased for this reason, fatal events and comorbidity in these patients. Despite this, it still has the best cardiovascular safety profile. PMID- 28882732 TI - Mesenchymal stem cells and their conditioned medium can enhance the repair of uterine defects in a rat model. AB - BACKGROUND: Our aim was to examine the roles of mesenchymal stem cell (MSC) transplantation in the repair of large uterine defects. METHODS: Uterine defects were created in both uterine horns of female rats by a punch instrument, and bone marrow-derived MSCs, MSC-conditioned medium (MSC-CM) or vehicle were injected into the myometrium around the defect. The rate of uterine defect repair was monitored on day 2 and 4 after operation. Cytokine array of MSC-CM was performed, followed by neutralizing antibody experiments to clarify the exact cytokine participating in the MSC-CM-enhanced wound repair. RESULTS: Transplantation of MSCs, but not myometrial cells, significantly enhanced uterine defect repair. The transplanted MSCs were detected in the uterine horn with no signs of rejection on day 4 after transplantation, when the MSC-transplanted uterine wound was nearly healed. Moreover, uterine defect repair was also accelerated by injection of MSC CM, indicating the paracrine effects of MSCs on uterine wound healing. Cytokine array analysis further revealed that MSC-CM contained abundant cytokines and chemokines, among which high levels of interleukin-6 (IL-6) were found. Additionally, antibodies against IL-6 were shown to block MSC-CM-enhanced uterine defect repair. CONCLUSION: This study demonstrated that transplantation of MSCs could enhance uterine defect repair by paracrine effects involving IL-6, which are findings that may be applied to facilitate uterine wound healing in the removal of huge intramural masses. PMID- 28882734 TI - [Control of blood pressure by using an intelligent telephone application with feedback and competitiveness strategy. HTApp Control project]. AB - INTRODUCTION AND OBJECTIVE: Arterial hypertension is a highly important cardiovascular risk factor, with low control percentages. New technologies can help to obtain a better control of this disease. The intention is to know if a mobile application can help achieve this goal. METHOD: A mobile phone application is used to give feedback to physicians with the aim of generate competitiveness in achieving objectives. The application could, at any time, determine the rate of controlled patients (<140/90mmHg) by each physician, and compare them with the mean number of the patients controlled by the group. The possible changes in the therapeutic attitude of physicians are also analysed and the differences in achieving objectives are compared based on specific characteristics of patients. RESULTS: The study included 220 patients aged 18-80 years, with mean blood pressure>140/90mmHg, despite medical treatment, tracked for 4 visits. At the end of the follow-up, 69.03% achieved good control, compared to 12.8% in the baseline study (P<.001), with no differences between gender (control of 68.6 and 69.29% of women and men, respectively), nor among the different levels of cardiovascular risk. CONCLUSIONS: The use of interactive tools that allow the dynamic process of feedback on the results fosters the motivation and improves the therapeutic inertia in the control of blood pressure. PMID- 28882735 TI - Integrative factor analysis - An unsupervised method for quantifying cross-study consistency of gene expression data. AB - Integrative analyses of multiple gene expression studies are frequently performed. In the setting of two studies, integrative correlation (IGC) can be used to assess the consistency of co-expression of a given gene. For three or more studies, an extension of IGC gives a global score per gene. We propose to extend IGC and use factor analysis to assess the study-specific consistency of co expression of genes when there are three or more studies, possibly on different platforms. Our method is able to identify studies whose expression patterns are different from others. Filtering genes based on our score is shown to improve the concordance of association with phenotype across studies. PMID- 28882736 TI - Gene-centric metegenome analysis reveals diversity of Pseudomonas aeruginosa biofilm gene orthologs in fresh water ecosystem. AB - Metagenomic analysis of biofilm forming bacteria in environmental samples remains challenging due to the non-availability of gene sequences of most of the uncultivable bacteria. Sequences of Pseudomonas aeruginosa PAO1-UW genes involved either directly or indirectly in biofilm formation were analyzed using BLASTn to obtain matching sequences from different strain, species and genus. Conserved regions in the functional domain of the amino acid sequences were used to design common primers for direct PCR analysis of freshwater metagenomes. Seven key genes such as aceA, clpP, typA, cbrA, phoR, rpoS and gacA involved in biofilm formation were validated. The ortholog genes belonged to wide range of Pseudomonas sp. indicating the diversity of biofilm genes and the conservation of protein functional domains. The approach would also help in analyzing the expression of biofilm genes in different bacteria of freshwater systems for monitoring toxic contaminations such as organic or inorganic pollutants. PMID- 28882737 TI - Five-year Survival of Patients With Metastatic Renal Cell Carcinoma in the Russian Federation: Results From the RENSUR5 Registry. AB - BACKGROUND: The 5-year overall survival (OS) of patients with metastatic renal cell carcinoma (mRCC) has been rarely reported. The aim of the RENSUR5 registry study was to obtain real-world data on the use of therapy for mRCC and assess the 5-year OS in the Russian population. PATIENT AND METHODS: Patients were retrospectively identified at 11 cancer centers in different regions of Russia (Astrakhan, Barnaul, Ekaterinburg, Kazan, Krasnoyarsk, Obninsk, Omsk, Rostov-on Don, Samara, St. Petersburg, and Ufa). Patients were included if mRCC had been diagnosed from January 2010 to January 2011. Anonymized data were collected through an online registry covering the demographic data, treatments, and outcomes. RESULTS: A total of 439 adult mRCC patients were included in the present study for analysis. The mean age at diagnosis of mRCC was 60.9 years (range, 33-90 years; with 9% of patients aged >= 75 years). The patients were predominantly men (70.2%) and 67.7% had nephrectomy. Clear cell and non-clear cell tumors were detected in 61.1% and 7.7% of patients, respectively. A total of 271 patients (62%) received systemic therapy. The median duration of therapy was 11 months (95% confidence interval, 9.5-12.5 months). Most treatment was with interferon only (n = 145); 105 patients (23.9%) received targeted therapy, and 69 patients (15.7%) received >= 2 treatment lines. The 1-, 3-, and 5-year OS rate was 49.4%, 18.9%, and 8.2%, respectively. The median OS from the start of treatment was 12 months (95% confidence interval, 9.7-14.4 months). CONCLUSION: RENSUR5 is a large real-world database assessing the mRCC treatment patterns and 5-year OS in Russia. According to the first results of the present study, we believe that 5-year OS should improve with novel therapies. The limited administration of targeted therapies was reflected by the results of the 5-year survival rate. The treatment of mRCC has changed in the past years with new treatment options significantly improving OS. The 5-year OS of patients treated with immunotherapy and targeted therapy should be analyzed in the real world. PMID- 28882738 TI - Testosterone Reduction of >= 480 ng/dL Predicts Favorable Prognosis of Japanese Men With Advanced Prostate Cancer Treated With Androgen-Deprivation Therapy. AB - INTRODUCTION: Reductions in testosterone concentration play a significant role in the treatment of prostate cancer. We studied the role of testosterone as a prognostic marker for advanced prostate cancer (stage C or higher) treated with primary androgen-deprivation therapy (ADT). PATIENTS AND METHODS: A total of 348 patients were treated using ADT as first-line therapy for prostate cancer at Chiba University Hospital between 1999 and 2016. Of these, 222 patients with advanced prostate cancer (stage C or higher) were enrolled onto this study. The prognostic values of serum testosterone level and other clinical factors were evaluated in association with prostate-specific antigen (PSA), progression-free survival during first-line therapy, and overall survival. RESULTS: Median age was 73 years. PSA at baseline was 86 ng/mL. Gleason scores of <= 6, 7, 8, and >= 9 were seen in 2.3%, 19.4%, 21.2%, and 41.9%, respectively. Mean follow-up was 60.5 months. Median testosterone at baseline was 482 ng/dL and nadir testosterone was 13 ng/dL. No variable associated with testosterone predicted progression-free survival. With regard to overall survival, multivariate analysis identified nadir testosterone <= 20 ng/dL (hazard ratio = 0.44, P = .026) and testosterone reduction >= 480 ng/dL (hazard ratio = 0.35, P = .030) as independent prognostic factors. With regard to progression-free survival, multivariate analysis identified nadir PSA <= 0.1 ng/mL (hazard ratio = 3.07, P < .001), presence of lymph node metastasis (hazard ratio = 1.67, P = .017), and time to nadir PSA (hazard ratio = 0.30, P < .001) as independent prognostic factors. CONCLUSION: Our data suggested both nadir testosterone (< 20 ng/dL; P = .026) and testosterone reduction (>= 480 ng/dL; P = .030) to be key prognostic factors for primary ADT in advanced prostate cancer in Japanese men. PMID- 28882739 TI - Autoimmune hepatitis - update on clinical management in 2017. AB - Autoimmune hepatitis (AIH) is a progressive immune mediated liver disease of unknown origin. Key diagnostic features include hypergammaglobulinemia/elevated serum-IgG, characteristic circulating autoantibodies, periportal hepatitis with interface activity on liver biopsy and the exclusion of hepatotropic viruses. However, the diagnosis is challenging in cholestatic and severe presentations. It can be difficult to differentiate AIH from drug-induced liver injury. Although many patients initially respond to standard immunosuppressive therapy, a significant proportion experiences intolerable side effects or insufficient treatment response. This underlines the need for effective alternative treatment options, which are still very limited and based on rather poor evidence. This review summarises core aspects of the clinical management of AIH with focus on recent achievements and unmet needs. PMID- 28882740 TI - Effect of sleep deprivation after a night shift duty on simulated crisis management by residents in anaesthesia. A randomised crossover study. AB - BACKGROUND: Sleep deprivation has been associated with an increased incidence of medical errors and can jeopardise patients' safety during medical crisis management. The aim of the study was to assess the effect of sleep deprivation on the management of simulated anaesthesia crisis by residents in anaesthesiology. METHODS: A randomised, comparative, monocentric crossover study involving 48 residents in anaesthesia was performed on a high fidelity patient simulator. Each resident was evaluated in a sleep-deprived state (deprived group, after a night shift duty) and control state (control group, after a night of sleep). Performance was assessed through points obtained during crisis scenario 1 (oesophageal intubation followed by anaphylactic shock) and scenario 2 (anaesthesia-related bronchospasm followed by ventricular tachycardia). Sleep periods were recorded by actigraphy. Two independent observers assessed the performances. The primary endpoint of the study was the score obtained for each scenario. RESULTS: Resident's crisis management performance is associated with sleep deprivation (scenario 1: control=39 [33-42] points vs. deprived=26 [19-40] points, P=0.02; scenario 2: control=21 [17-24] vs. deprived=14 [12-19], P=0.01). The main errors observed were: error in drug administration and dose, delay in identification of hypotension, and missing communication with the surgical team about situation. CONCLUSIONS: The present study showed that sleep deprivation is associated with impairment of performance to manage crisis situations by residents in anaesthesia. PMID- 28882741 TI - Tracheal extubation with suction vs. positive pressure during emergence from general anaesthesia in adults: A randomised controlled trial. AB - BACKGROUND: After general anaesthesia (GA) in adults, the optimal tracheal extubation technique (positive pressure or suctioning) remains debated. The primary endpoint of this study was to assess the effects of these techniques on onset time of desaturation (SpO2<92%). METHODS: Sixty-nine patients with a body mass index<30 scheduled for elective orthopaedic surgery were allocated to positive pressure (PP) or suctioning (SUC) group. GA was standardised with propofol and remifentanil via target-controlled infusion. A morphine bolus of 0.15mg/kg was administered 20-30mins before the end of surgery. The effect of extubation technique on onset time of desaturation (T92) was assessed during the first 10mins after extubation during the spontaneous air breathing. Secondary endpoints included: frequency of desaturation, respiratory complications, need to use oxygen therapy and SpO2 at the end of the first hour while breathing in air (ClinicalTrials.gov identifier: NCT01323049). RESULTS: Baseline patient characteristics and intraoperative management data for the 68 patients included had no relevant clinical difference between groups. T92 (sec) after tracheal extubation was 214 (168) vs. 248 (148) in the PP and SUC groups, respectively (P=0.44). In the PP and SUC groups, 50 and 43% reached a SpO2<92% within the first 10mins after extubation respectively (P=0.73). There were no statistically significant differences between groups for any secondary endpoints. CONCLUSIONS: Positive pressure extubation as compared with suctioning extubation did not seem to delay onset time of desaturation after GA in standard weight adult patients. PMID- 28882742 TI - To vape or not to vape? Effects of exposure to conflicting news headlines on beliefs about harms and benefits of electronic cigarette use: Results from a randomized controlled experiment. AB - News coverage of novel tobacco products including e-cigarettes has framed the use of these products with both positive and negative slants. Conflicting information may shape public knowledge, perceptions of e-cigarettes, and their harms. The objective of this study is to assess effects of exposure to conflicting news coverage on US adults' beliefs about harms and benefits of e-cigarette use. We conducted a one-way between-subjects randomized controlled experiment in 2016 to compare the effects of viewing either 1) positive, 2) negative, 3) both positive and negative (conflicting) news headlines about the safety of using e-cigarettes, or 4) no-message. Participants were 2056 adults aged 18 and older from an online survey panel. Outcomes were beliefs about harms (3-item scale, alpha=0.76) and benefits (3-item scale, alpha=0.82) of using e-cigarettes. Participants who viewed negative headlines reported increased beliefs about harms (B=0.164, p=0.039) and lower beliefs about benefits of e-cigarette use (B=-0.216, p=0.009), compared with those in the positive headlines condition. These differences were replicated in subgroup analyses among never e-cigarette users. In addition, never e-cigarette users who viewed conflicting headlines reported lower beliefs about benefits of e-cigarette use (B=-0.221, p=0.030) than the positive headlines condition. Valence of news coverage about e-cigarettes (positive, negative, or conflicting) could influence people's beliefs about harms and benefits of e cigarette use. PMID- 28882743 TI - Effectiveness of mobile health (mHealth) interventions for promoting healthy eating in adults: A systematic review. AB - Unhealthy eating is a major risk factor for chronic disease. However, many current strategies to promote healthy eating are not sustainable over the longer term. More cost-effective wide-reaching initiatives are urgently needed. Mobile health (mHealth) interventions, delivered via mobile devices, could provide a solution. This systematic review summarized the evidence on the effect of mHealth interventions for promoting healthy eating in adults. A comprehensive systematic search of five scientific databases was conducted using methods adapted from the Cochrane Handbook. Eligible studies were randomized controlled trials (RCTs), published up to 1 July 2016, which examined healthy eating interventions delivered via mobile device. Of 879 articles identified, 84 full text articles were potentially eligible and further assessed, and 23 included. Narrative review results indicated small positive effects of mHealth interventions on healthy eating (5/8 trials) and weight loss (5/13 trials). However, the current evidence base is insufficient (studies are of poor quality) to determine conclusive positive effects. More rigorous RCTs with longer-term (>6months) follow-up are warranted to determine if effects are maintained. PMID- 28882744 TI - Local health and social services expenditures: An empirical typology of local government spending. AB - The conceptual importance of social services to health outcomes is well known and recent empirical evidence has linked social services spending to better population health outcomes. Yet little research has been devoted to what social services spending actually entails as it relates to population health and whether broadly similar spending patterns may exist across communities. The purpose of this study was to identify empirical patterns in spending, and explore health status and outcome correlates with social services spending. Spending data come from the 2012 U.S. Census Bureau's Census of Governments, which includes spending data for 14 social services within 3129 U.S. counties. Additional 2012 demographic, socioeconomic, and population health data were obtained and analyzed at the county-level in 2017. Hierarchical cluster analysis revealed 5 clusters of counties according to local government spending. One group had significantly lower income, social services spending, health indicators, and health outcomes than other counties. Two other groups had relatively high income, high social services spending, and strong health outcomes and indicators. Yet these latter two groups invested differently, with one spreading spending across a larger number of social services and the other concentrating spending in a smaller number of services such as education. Determining the extent to which spending approaches contribute to population health may offer communities guidance for maximizing population health. While it cannot establish causality, this study adds to the literature regarding the ways in which communities invest in both health care and social services to prevent disease and promote population health. PMID- 28882746 TI - Contributing to helping to achieve the UN Sustainable Development Goals: Truly shifting from niche to norm. PMID- 28882747 TI - A novel method of multiple nucleic acid detection: Real-time RT-PCR coupled with probe-melting curve analysis. AB - A novel method, real-time reverse transcription PCR (real-time RT-PCR) coupled with probe-melting curve analysis, has been established to detect two kinds of samples within one fluorescence channel. Besides a conventional TaqMan probe, this method employs another specially designed melting-probe with a 5' terminus modification which meets the same label with the same fluorescent group. By using an asymmetric PCR method, the melting-probe is able to detect an extra sample in the melting stage effectively while it almost has little influence on the amplification detection. Thus, this method allows the availability of united employment of both amplification stage and melting stage for detecting samples in one reaction. The further demonstration by simultaneous detection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in one channel as a model system is presented in this essay. The sensitivity of detection by real time RT-PCR coupled with probe-melting analysis was proved to be equal to that detected by conventional real-time RT-PCR. Because real-time RT-PCR coupled with probe-melting analysis can double the detection throughputs within one fluorescence channel, it is expected to be a good solution for the problem of low throughput in current real-time PCR. PMID- 28882748 TI - Method to minimize ozone effect on Cy5 fluorescent intensity in DNA microarrays. AB - Cyanine 5 (Cy5) is an established fluorescent dye in microarray analysis. It is degraded rapidly when exposed to atmospheric ozone during post-hybridization washes, which leads to loss of fluorescent intensity. To minimize this undesirable effect, we coated microarray slides with sodium dodecyl sulfate (SDS) solution at post-hybridization washes. The fluorescent intensities on coated slides were more stable than those on uncoated slide. We also performed the microarrays with SDS solution for a year to check the solution's effectiveness along with seasonal changes of atmospheric ozone level. Consistent results in microarray analysis were obtained using Cy5 dye under atmospheric ozone. PMID- 28882749 TI - The consequences of violence against nurses working in the emergency department: A qualitative study. AB - BACKGROUND: Workplace violence (WPV) in healthcare organizations can lead to serious consequences that negatively affect nurses' lives and patient care. There is limited research on the deeper, underlying consequences of WPV for emergency nurses, particularly among emergency nurses in Iran. METHODS: A qualitative exploratory design was utilized. Semi-structured interviews were conducted with sixteen nurses working in emergency departments in five hospitals in west and east Azerbaijan of Iran. Data were analyzed using conventional content analysis. RESULTS: "Suffering nurses" emerged as a primary theme of underlying consequences of WPV for emergency nurses. Four sub-themes of suffering were revealed: "mental health risks"; "physical health risks"; "threats to professional integrity"; and "threats to social integrity." CONCLUSION: Emergency nurses suffer from consequences following WPV. These consequences may not be addressed by staff health and safety programs, putting nurses at further risk. The findings of this study can help policy makers, healthcare leadership, and managers better understand the consequences of WPV so they can advocate for and establish WPV prevention programs and support for nurses who have experienced WPV. Preventing violence and providing support for nurses will ensure a safe workplace and safer patient care. PMID- 28882745 TI - The effects of yoga among adults with type 2 diabetes: A systematic review and meta-analysis. AB - The purpose of this meta-analysis was to examine the effects of yoga for glycemic control among adults with type 2 diabetes (T2DM). Comprehensive electronic databases searches located 2559 unique studies with relevant key terms. Studies were included if they (1) evaluated a yoga intervention to promote T2DM management, (2) used a comparison group, (3) reported an objective measure of glycemic control at post-intervention, and (4) had follow-up length or post-test of at least 8weeks from baseline. Independent raters coded participant, design and methodological characteristics and intervention content. Summary effect sizes and 95% confidence intervals (CI) were calculated. Twenty-three studies with 2473 participants (mean age=53years; 43% women) met eligibility criteria. Compared with controls, yoga participants were successful in improving their HbA1c (d+=0.36, 95% CI=0.16, 0.56; k=16), FBG (d+=0.58, 95% CI=0.40, 0.76; k=20), and PPBG (d+=0.40, 95% CI=0.23, 0.56; k=14). Yoga was also associated with significant improvements in lipid profile, blood pressure, body mass index, waist/hip ratio and cortisol levels. Overall, studies satisfied an average of 41% of the methodological quality (MQ) criteria; MQ score was not associated with any outcome (Ps >0.05). Yoga improved glycemic outcomes and other risk factors for complications in adults with T2DM relative to a control condition. Additional studies with longer follow-ups are needed to determine the long-term efficacy of yoga for adults with T2DM. PMID- 28882750 TI - Grey areas: New Zealand ambulance personnel's experiences of challenging resuscitation decision-making. AB - INTRODUCTION: When faced with a patient in cardiac arrest, ambulance personnel must rapidly make complex decisions with limited information. Much of the research examining decisions to commence, continue, withhold or terminate resuscitation has used retrospective audits of registry data and clinical documentation. This study offers a provider-perspective which characterises uncertainty and highlights clinical, cognitive, emotional and physical demands associated with decision-making in the cardiac arrest context. METHOD: Semi structured interviews with a purposive sample of sixteen demographically diverse ambulance personnel, currently employed in a variety of emergency ambulance response roles across New Zealand. RESULTS: All participants readily identified clinical, cognitive, emotional and ethical challenges associated with resuscitation decision-making. Four main themes were identified: grey areas; exceptional cases; scene challenges; and personal responses. A lack of information or a mix of favourable and unfavourable prognostic factors created decision-making uncertainty or "grey areas". Exceptional cases such as first encounters also increased uncertainty and presented emotional, ethical and clinical challenges. Cardiac arrest scenes were often challenging, and participants described managing bystander expectations and responses and logistical limitations including adverse environmental conditions, fatigue and task-overload, and crew resource management. CONCLUSION: This unique research presents a provider-perspective on the challenges faced by ambulance personnel deciding to commence, continue, withhold or terminate resuscitation efforts. Knowledge of personal values and strategies for managing personal responses appear to be central to certainty and coping. Simulated training should move beyond resuscitation task performance, to incorporate challenging elements and encourage ambulance personnel to explore their personal values, stressors and coping strategies. PMID- 28882751 TI - C2K77 ELISA detects cleavage of type II collagen by cathepsin K in equine articular cartilage. AB - OBJECTIVES: Develop a species-specific ELISA for a neo-epitope generated by cathepsin K cleavage of equine type II collagen to: (1) measure cartilage type II collagen degradation by cathepsin K in vitro, (2) identify cytokines that upregulate cathepsin K expression and (3) compare cathepsin K with matrix metalloproteinase (MMP) collagenase activity in stimulated cartilage explants and freshly isolated normal and osteoarthritic (OA) articular cartilages. DESIGN: A new ELISA (C2K77) was developed and tested by measuring the activity of exogenous cathepsin K on equine articular cartilage explants. The ELISA was then employed to measure endogenous cathepsin K activity in cultured cartilage explants with or without stimulation by interleukin-1 beta (IL-1beta), tumour necrosis-alpha (TNF alpha), oncostatin M (OSM) and lipopolysaccharide (LPS). Cathepsin K activity in cartilage explants (control and osteoarthritic-OA) and freshly harvested cartilage (control and OA) was compared to that of MMPs employing C2K77 and C1,2C immunoassays. RESULTS: The addition of Cathepsin K to normal cartilage caused a significant increase (P < 0.01) in the C2K77 epitope release. Whereas the content of C1,2C, that reflects MMP collagenase activity, was increased in media by the addition to cartilage explants of TNF-alpha and OSM (P < 0.0001) or IL-1beta and OSM (P = 0.002), no change was observed in C2K77 which also unchanged in OA cartilages compared to normal. CONCLUSIONS: The ELISA C2K77 measured the activity of cathepsin K in equine cartilage which was unchanged in OA cartilage. Cytokines that upregulate MMP collagenase activity had no effect on endogenous cathepsin K activity, suggesting a different activation mechanism that requires further study. PMID- 28882752 TI - Mechanosensitive ion channels in articular nociceptors drive mechanical allodynia in osteoarthritis. AB - OBJECTIVE: Osteoarthritis (OA) is a disabling and highly prevalent condition affecting millions worldwide. Pain is the major complaint of OA patients and is presently inadequately managed. It manifests as mechanical allodynia, a painful response to innocuous stimuli such as joint movement. Allodynia is due in part to the sensitization of articular nociceptors to mechanical stimuli. These nociceptors respond to noxious mechanical stimuli applied to their terminals via the expression of depolarizing high-threshold mechanosensitive ion channels (MSICs) that convert painful mechanical forces into electrical signals. In this study, we examined the contribution of MSICs to mechanical allodynia in a mouse model of OA. METHOD: Sodium mono-iodoacetate (MIA) was injected in the left knee of adult male Trpv1:Cre; GFP mice. Primary mechanical allodynia was monitored using the knee-bend test. Single-channel patch clamp electrophysiology was performed on visually-identified knee-innervating nociceptors. Dorsal horn neuronal activation was assessed by Fos immunoreactivity. RESULTS: In examining the gating properties of MSICs of naive and OA mice, we discovered that their activation threshold is greatly reduced, causing their opening at significantly lower stimuli intensities. Consequently, nociceptors are activated by mild mechanical stimuli. These channels are reversibly inhibited by the selective MSIC inhibitor GsMTx4, and the intra-articular injection of this peptide significantly reduced the activation of dorsal horn nociceptive circuits and primary mechanical allodynia in OA mice. CONCLUSIONS: These results suggest that MSICs are sensitized during OA and directly contribute to mechanical allodynia. They therefore represent potential therapeutic targets in the treatment of OA pain. PMID- 28882753 TI - Knee internal contact force in a varus malaligned phenotype in knee osteoarthritis (KOA). AB - PURPOSE: Multiple phenotypes characterized by different disease mechanisms have been hypothesized to explain the large variability in the knee osteoarthritis (KOA) population. The purpose of this study was: to estimate and compare the medial and lateral knee compression forces (CF) during gait of three subgroups of KOA subjects characterized by different alignment and cartilage disruption patterns. METHODS: A secondary data analysis was conducted on a sample of 39 KOA subjects and 18 controls (C). The patients were classified in the different groups according to the following criteria: Varus medial disease (VMD) (12): varus alignment and predominant medial cartilage degeneration Varus generalized disease (VGD) (17): varus alignment and cartilage degeneration that extends to the lateral compartment. Neutral alignment (NA) (10): neutral alignment. The total, medial and lateral CF corrected for body weight were estimated using an inverse dynamics model (AnyBody Modeling System, AnyBody Technology) during stance. RESULTS: The impulse of the medial compressive force (MCF) (overall effect of the CF over the stance) was significantly higher (P < 0.01) in the VMD compared to all the other groups. Peak MCF was higher in the VMD compared to all the other groups, but the difference reached significance only when compared to the VGD group (P < 0.05). The results of the regression analysis showed a significant relationship in the VMD group between alignment and impulse of the MCF (R2 = 0.62; P < 0.01). This relationship disappears in the other groups. CONCLUSIONS: These findings suggest the existence of a phenotype characterized by increased MCF. PMID- 28882754 TI - Mini-review: Far peripheral vision. AB - The region of far peripheral vision, beyond 60 degrees of visual angle, is important to the evaluation of peripheral dark shadows (negative dysphotopsia) seen by some intraocular lens (IOL) patients. Theoretical calculations show that the limited diameter of an IOL affects ray paths at large angles, leading to a dimming of the main image for small pupils, and to peripheral illumination by light bypassing the IOL for larger pupils. These effects are rarely bothersome, and cataract surgery is highly successful, but there is a need to improve the characterization of far peripheral vision, for both pseudophakic and phakic eyes. Perimetry is the main quantitative test, but the purpose is to evaluate pathologies rather than characterize vision (and object and image regions are no longer uniquely related in the pseudophakic eye). The maximum visual angle is approximately 1050, but there is limited information about variations with age, race, or refractive error (in case there is an unexpected link with the development of myopia), or about how clear cornea, iris location, and the limiting retina are related. Also, the detection of peripheral motion is widely recognized to be important, yet rarely evaluated. Overall, people rarely complain specifically about this visual region, but with "normal" vision including an IOL for >5% of people, and increasing interest in virtual reality and augmented reality, there are new reasons to characterize peripheral vision more completely. PMID- 28882755 TI - Binocular contrast, stereopsis, and rivalry: Toward a dynamical synthesis. AB - It is well known that small orientation differences between two monocular gratings fuse to generate a stereoscopic perception of tilt, while large differences trigger binocular rivalry. In addition, unequal monocular contrasts combine nonlinearly to generate binocular contrast. A nonlinear neural model is developed here to account for binocular contrast, fusion at small orientation differences, and rivalry at large differences. The model also accounts for hysteresis in the transition between fusion and rivalry. Finally, the model predicts that interocular contrast differences between fusible gratings will produce a reduced tilt percept, and experiments reported here support this. Key to the model is the presence of two classes of inhibitory interneurons: one operating on similar orientations to normalize interocular contrast (IN), and one operating across large orientation differences to generate rivalry (IR). Critically, the IN neurons switch off the IR neurons driven by the other eye, thus permitting fusion of binocular plaids. PMID- 28882756 TI - Opening a Can of Worms: Leprosy Reactions and Complicit Soil-Transmitted Helminths. AB - BACKGROUND: >94% of new annual leprosy cases are diagnosed in populations co endemic for soil-transmitted helminths (STH). STH can profoundly dysregulate host immune responses towards Th2 bias, which can be restored over time after deworming. We hypothesize that STH co-infection is associated with leprosy reaction (denoted as simply "reaction" herein) occurrence within a co-endemic population. METHODS: A cohort study was performed on a cohort of Nepalese leprosy patients across treatment and diagnostic classifications who were screened by routine fecal smear microscopy and multiplex quantitative PCR (qPCR) for Ascaris lumbricoides (Al), Strongyloides stercoralis (Ss), Ancyclostoma duodenale (Ad) and Necator americanus (Na). RESULTS: Among 145 patients, 55% were positive for >=1 STH (STH+): 34% Al+, 18% Ss+, 17% Ad+and 5% Na+. Significant inverse STH and reaction relationships were evidenced by the bulk of cases: 63% reaction-negative were STH+ of total cases (p=0.030) while 65% reaction-positive were STH- in new cases (96; p=0.023). Strikingly, the majority of STH+ were reaction-negative, even when considering each species: 59% Al+, 60% Ss+, 62% Ad+and 67% Na+of new leprosy cases. CONCLUSIONS: Absence of STH co-infection is associated with leprosy reaction at diagnosis within a co-endemic population. This is likely due to immune reconstitution effects after deworming or interruption of chronic STH mediated immune dysregulation. PMID- 28882757 TI - Ion channel functional protein kinase TRPM7 regulates Mg ions to promote the osteoinduction of human osteoblast via PI3K pathway: In vitro simulation of the bone-repairing effect of Mg-based alloy implant. AB - : Mg-based alloys, as the potential orthopaedic implant, can self-degrade to avoid second operation for its remove, and enable to promote bone repair; however, the underlying molecular mechanisms remain unclear. In the present study, we examined the effect of Mg ions on osteogenesis, chemotaxis and anti alkaline stress in hFOB1.19 human osteoblast cells to simulate bone-repairing effect of a biodegradable Mg-based alloy implant in vitro, and explored the regulatory role of the transient receptor potential melastatin 7 (TRPM7)/phosphoinositide 3-kinase (PI3K) signalling pathway in the process of Mg ion-induced bone repair by knockdown of TRPM7 and antagonizing PI3K activity. Results indicate that Mg ions up-regulated the expression of Runx2 and alkaline phosphatase (ALP) through TRPM7/PI3K signalling pathway, which could significantly enhance the osteogenic activity of human osteoblasts. Furthermore, the expression levels of MMP2, MMP9 and vascular endothelial growth factor (VEGF) were increased by TRPM7/PI3K signalling pathway, which recruits osteoblasts from low- to high-Mg ion environments by inducing cell migration. Although an alkaline environment has antibacterial effects, alkaline stress can cause cytotoxicity and induce cell death. Finally, we found that Mg ions could activate PI3K phosphorylation to promote cell growth and survival, protecting cells against the alkaline-stress-induced cytotoxicity caused by the degradation of Mg-based alloy implants. Our study not only revealed the molecular mechanism of Mg in promoting bone repair but also explained the protective effects of Mg ions on osteoblasts in an alkaline environment, which provides a theoretical basis and new directions for the application of Mg-based alloy implant material in orthopaedics fixations and osteosarcoma treatment. STATEMENTS OF SIGNIFICANCE: As a potential biomaterial for orthopaedic implant, biodegradable magnesium has several advantages including self-degradation and bone repair promotion; however, the underlying mechanisms and effective concentration by which molecular regulates the bone repair remain unclear. The present study revealed that Mg ion and its effective concentration for activating PI3K phosphorylation via TRPM7, which causes three processes affecting bone repair, namely, osteoblast recruitment, osteogenesis and resistance to alkaline stress in human osteoblast. Therefore, our results have provided insight into the underlying molecular biological basis, and guidance for manipulating degradation rate, such as surface modification, of orthopaedic Mg-based implants. PMID- 28882758 TI - Formation and characterization of polyelectrolyte complex synthesized by chitosan and carboxylic curdlan for 5-fluorouracil delivery. AB - In this study, negatively charged carboxylic curdlan (Cc) bearing a beta-1,3 polyglucuronic acid structure was employed to fabricate nanosized polyelectrolyte complexes (PECs) with positively charged chitosan (CS) in aqueous solution as potential carriers for 5-fluorouracil (5Fu) delivery. Nanosized CS/Cc PECs were formed by the addition of 0.5mg/mL solutions of CS and Cc with a mixing ratio of 1:1 (w/w) at pH 3.0. Under optimized conditions, the prepared CS/Cc PECs showed spherical morphology with an average size of about 180nm and a zeta potential of around 41mV. The 5Fu drug was incorporated into the nanosized CS/Cc PECs and showed excellent encapsulation efficiency (86.47%) and loading content (10.81%). The drug release data in vitro indicated that the nanosized CS/Cc PECs are promising carriers for the sustained release of 5Fu with an anomalous transport mechanism following the Ritger-Peppas model. Besides, the CS/Cc PECs exhibited low cytotoxic activity against SPCA-1 and HeLa cell lines in vitro. This finding suggested that the development of the nanosized CS/Cc PECs offered great promise as an antitumor drug platform. PMID- 28882759 TI - The preparation and study of regenerated cellulose fibers by cellulose carbamate pathway. AB - In this work, using cotton pulps and urea as raw materials, cellulose carbamates (CCs) were successfully prepared by liquid-solid phase in the high-boiling aprotic and polar solvent (DMAc). Regenerated cellulose (RC) fibers were successfully spun from cellulose carbamate in a NaOH aqueous solution by wet spinning on a conventional viscose filament device. And the structures and properties of products were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffractometry (XRD), Thermal gravimetric analysis (TG) and Scanning electron microscopy (SEM), rheology measurement and dye testing. The results showed that the CC can be quickly dissolved in 9%NaOH solution. RC fibers exhibited a bright surface and an approximately circular cross section. There was no lobulate shape and contained obvious pores and voids in the internal sections. RC fibers demonstrated a typical cellulose II crystal structure and a good thermal stability. And tensile strength of the RC fibers was 1.4 cN/dtex, and their elongation at break was 6.8%. Furthermore, the RC fibers showed excellent dyeing properties compared with viscose rayon and Yingli Lyocell. So, the described carbamate pathway provided a simple and environmentally friendly method to overcome the environmental drawbacks of the traditional viscose process. PMID- 28882760 TI - Biochemical and spectroscopic characterization of dinuclear Mn-sites in artificial four-helix bundle proteins. AB - To better understand metalloproteins with Mn-clusters, we have designed artificial four-helix bundles to have one, two, or three dinuclear metal centers able to bind Mn(II). Circular dichroism measurements showed that the Mn-proteins have substantial alpha-helix content, and analysis of electron paramagnetic resonance spectra is consistent with the designed number of bound Mn-clusters. The Mn-proteins were shown to catalyze the conversion of hydrogen peroxide into molecular oxygen. The loss of hydrogen peroxide was dependent upon the concentration of protein with bound Mn, with the proteins containing multiple Mn clusters showing greater activity. Using an oxygen sensor, the oxygen concentration was found to increase with a rate up to 0.4MUM/min, which was dependent upon the concentrations of hydrogen peroxide and the Mn-protein. In addition, the Mn-proteins were shown to serve as electron donors to bacterial reaction centers using optical spectroscopy. Similar binding of the Mn-proteins to reaction centers was observed with an average dissociation constant of 2.3MUM. The Mn-proteins with three metal centers were more effective at this electron transfer reaction than the Mn-proteins with one or two metal centers. Thus, multiple Mn-clusters can be incorporated into four-helix bundles with the capability of performing catalysis and electron transfer to a natural protein. PMID- 28882762 TI - Estimation of the diagnostic performance of two ELISAs to detect PCV2 antibodies in pig sera using a Bayesian method. AB - This study was designed to assess the diagnostic characteristics of two PCV2 ELISAs without a gold standard. Four hundred and sixty-five serum samples from finishing pigs (25 herds) not vaccinated against PCV2 were used. Samples were tested by two ELISAs: an in-house ELISA (I-ELISA) and the commercial SERELISA(r)PCV2 Ab Mono Blocking kit (S-ELISA). A ROC curve was used to assess the S-ELISA's optimal threshold by taking the I-ELISA as a reference and using the cut-off previously determined by comparison to an cccmonolayer assay (IPMA). This led to an S-ELISA result >=170 being considered as positive. The sensitivity (Se) and specificity (Sp) of each ELISA were then estimated without a gold standard using a Bayesian approach. The mean Se and Sp values of the I-ELISA were slightly higher than those of the S-ELISA (mean Se I-ELISA=0.90 vs. mean Se S ELISA=0.86; mean Sp I-ELISA=0.92 vs. mean Sp S-ELISA=0.85). However, the 95% credibility intervals (CI95%) overlapped (Se I-ELISA CI95%=0.85-0.95 vs. Se S ELISA CI95%=0.82-0.90; Sp I-ELISA CI95%=0.82-0.98 vs. Sp S-ELISA CI95%=0.75 0.94). Both ELISAs appeared to be valuable tools for detecting PCV2 antibodies. PMID- 28882761 TI - Decorin and biglycan are necessary for maintaining collagen fibril structure, fiber realignment, and mechanical properties of mature tendons. AB - The small leucine-rich proteoglycans (SLRPs), decorin and biglycan, are key regulators of collagen fibril and matrix assembly. The goal of this work was to elucidate the roles of decorin and biglycan in tendon homeostasis. Our central hypothesis is that decorin and biglycan expression in the mature tendon would be critical for the maintenance of the structural and mechanical properties of healthy tendons. Defining the function(s) of these SLRPs in tendon homeostasis requires that effects in the mature tendon be isolated from their influence on development. Thus, we generated an inducible knockout mouse model that permits genetic ablation of decorin and biglycan expression in the mature tendon, while maintaining normal expression during development. Decorin and biglycan expression were knocked out in the mature patellar tendon with the subsequent turnover of endogenous SLRPs deposited prior to induction. The acute absence of SLRP expression was associated with changes in fibril structure with a general shift to larger diameter fibrils in the compound knockout tendons, together with fibril diameter heterogeneity. In addition, tendon mechanical properties were altered. Compared to wild-type controls, acute ablation of both genes resulted in failure of the tendon at lower loads, decreased stiffness, a trend towards decreased dynamic modulus, as well as a significant increase in percent relaxation and tissue viscosity. Collagen fiber realignment was also increased with a delayed and slower in response to load in the absence of expression. These structural and functional changes in response to an acute loss of decorin and biglycan expression in the mature tendon demonstrate a significant role for these SLRPs in adult tendon homeostasis. PMID- 28882763 TI - Antimicrobial resistance of Enterococcus isolates in Turkey: A meta-analysis of current studies. AB - OBJECTIVES: In this study, a meta-analysis of Enterococcus isolates collected in 2000-2015 in Turkey and their susceptibility/resistance to antibiotics, clinical indications for initial drug treatment, and identification of alternative treatments was conducted. METHODS: The meta-analysis examined antibiotic susceptibility/resistance in Enterococcus spp. isolates. The study was planned and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Statements on antimicrobial resistance were grouped according to the antimicrobial stewardship programme (ASP). RESULTS: The mean resistance rates of Enterococcus faecalis to vancomycin (VAN) and linezolid (LNZ) were 1.0+/-2.2% and 1.9+/-2.6%, respectively, whereas the mean resistance rates of Enterococcus faecium to VAN and LNZ were 10.3+/-11.3% and 2.4+/-0%, respectively. CONCLUSIONS: This study is the first meta-analysis of the resistance of clinical Enterococcus isolates in Turkey to antimicrobial agents, which is a major problem stemming from the excessive usage of antibiotics. The development of antibiotic resistance in Turkey has changed over time. To support the practice of evidence-based medicine, more notifications about Enterococcus resistance status are needed, especially notifications following ASP rules. PMID- 28882764 TI - Clarithromycin-based therapy of Helicobacter pylori in Iran. PMID- 28882765 TI - Multivariate pharmacokinetic/pharmacodynamic (PKPD) analysis with metabolomics shows multiple effects of remoxipride in rats. AB - The study of central nervous system (CNS) pharmacology is limited by a lack of drug effect biomarkers. Pharmacometabolomics is a promising new tool to identify multiple molecular responses upon drug treatment. However, the pharmacodynamics is typically not evaluated in metabolomics studies, although being important properties of biomarkers. In this study we integrated pharmacometabolomics with pharmacokinetic/pharmacodynamic (PKPD) modeling to identify and quantify the multiple endogenous metabolite dose-response relations for the dopamine D2 antagonist remoxipride. Remoxipride (vehicle, 0.7 or 3.5mg/kg) was administered to rats. Endogenous metabolites were analyzed in plasma using a biogenic amine platform and PKPD models were derived for each single metabolite. These models were clustered on basis of proximity between their PKPD parameter estimates, and PKPD models were subsequently fitted for the individual clusters. Finally, the metabolites were evaluated for being significantly affected by remoxipride. In total 44 metabolites were detected in plasma, many of them showing a dose dependent decrease from baseline. We identified 6 different clusters with different time and dose dependent responses and 18 metabolites were revealed as potential biomarker. The glycine, serine and threonine pathway was associated with remoxipride pharmacology, as well as the brain uptake of the dopamine and serotonin precursors. This is the first time that pharmacometabolomics and PKPD modeling were integrated. The resulting PKPD cluster model described diverse pharmacometabolomics responses and provided a further understanding of remoxipride pharmacodynamics. Future research should focus on the simultaneous pharmacometabolomics analysis in brain and plasma to increase the interpretability of these responses. PMID- 28882766 TI - Pharmacologic studies on ET-26 hydrochloride in a rat model of lipopolysaccharide induced sepsis. AB - BACKGROUND: ET-26 hydrochloride (ET-26 HCl) is a promising sedation-hypnotic compound with stable hemodynamic features that elicits virtually no adrenocortical suppression. However, whether it preserves better pharmacologic characteristics in a rat model of sepsis is not known. This study compared the survival rate, levels of corticosterone and pro-inflammatory cytokines, and histologic injury in the lungs and kidneys of rats suffering from sepsis treated with ET-26 HCl, etomidate, or normal saline (NS). METHODS: Rats were given lipopolysaccharide (1mg/kg body weight, i.v.) to establish a sepsis model. Thirty minutes after lipopolysaccharide administration, ET-26 HCl, etomidate or NS were given as a bolus injection at equivalent doses. Plasma levels of corticosterone, interleukin-1beta, interleukin-6, interleukin-10, and tumor necrosis factor-alpha were measured 1, 2, 4, 6 and 24h after administration. Histologic injury was observed at the time of death or 24h after drug administration. RESULTS: The survival rate for rats in the etomidate, ET-26 HCl and NS groups was 40%, 90% and 90%, respectively. Corticosterone concentrations in the etomidate group were lower than those in the other groups 1h after administration of hypnotic compounds. Concentrations of pro-inflammatory cytokines in the ET-26 HCl group and NS group were not significantly different, but were significantly lower than those in the etomidate group. The injury scores of kidneys and lungs in the etomidate group were higher than those in ET-26 HCl and NS groups. CONCLUSIONS: ET-26 HCl showed virtually no suppression of corticosterone synthesis, lower concentrations of pro-inflammatory cytokines, higher survival rate, and less organ injury in rats suffering from sepsis compared with the etomidate group. It may be safer to induce anesthesia using ET-26 HCl, rather than etomidate, in patients suffering from sepsis. PMID- 28882767 TI - Optimization of alginate microcapsules containing cells overexpressing alpha-l iduronidase using Box-Behnken design. AB - Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease caused by deficiency of alpha-l-iduronidase (IDUA), which results in the lysosomal accumulation of glycosaminoglycans (GAG) leading to widespread clinical manifestations. The microencapsulation of IDUA overexpressing recombinant cells has been considered as a promising strategy for the treatment of MPS I. This study aimed at the optimization of alginate microcapsules containing recombinant BHK (Baby Hamster Kidney) cells (rBHK) overexpressing IDUA produced by electrostatic extrusion technique. The alginate microcapsule (MC-A) optimization study was carried out by means of an experimental Box-Behnken Design that allowed the simultaneous evaluation of the influence of voltage (kV), alginate/cell suspension flow (mL/h), and alginate concentration (%) on size and IDUA activity. The optimal conditions of voltage (10kV), flow (25mL/h), and alginate concentration (1.3%) made possible to obtain the smallest microcapsules showing the highest IDUA activity. After optimization, the microcapsules were sequentially coated with PLL and alginate (MC-APA) to increase their stability. MC-A and MC-APA presented monodisperse populations (span<1.22) with an average diameter of less than 350MUm. The coating increased the mechanical stability of MC-APA by about 6-fold and modulated the permeability to the enzyme. Surface analyzes of MC-APA showed the presence of PLL bands, suggesting that the last alginate layer appears to have only partially coated the PLL. After 30days of subcutaneous implantation of the MC-APA microcapsules containing rBHK cells in a MPS I murine model, a significant increase in IDUA activity was observed in the skin near the implant. Histological analysis revealed an inflammatory infiltrate at the application site, which did not prevent the release of the enzyme under the conditions evaluated. Taken together, the overall results demonstrate the feasibility of MC-APA as a potential alternative for local treatment of MPS I. PMID- 28882768 TI - Long-term outcome of laparoscopic Nissen fundoplication in a regional hospital setting. AB - BACKGROUND: Laparoscopic Nissen fundoplication is considered to be the standard approach for the surgical treatment of gastroesophageal reflux disease. Various trials have assessed the outcome of the operation performed in high-volume centers, but the existing evidence regarding peripheral, low-volume hospitals is scarce. The purpose of this study is to investigate the late outcome of laparoscopic Nissen fundoplication with regard to symptom control and postoperative quality of life in a community-hospital setting. METHODS: 376 patients underwent laparoscopic Nissen fundoplication in our hospital during the period of 1997-2012. Patients were asked to subjectively; assess the pre- and postoperative severity of their symptoms and quality of life. Follow-up was conducted by means of a mailed questionnaire. RESULTS: Respondents had a median follow-up of 8.8 years (range: 1.4-17). 60.8% (101/166) patients reported complete control of heartburn. Ten patients (6%) had undergone revisional surgery. 31 respondents (18.6%) reported a new-onset dysphagia postoperatively. 85% (138/166) of the respondents would have; the operation again, if necessary. 73.6% (120/166) reported a lasting improvement of their overall quality of life. CONCLUSION: Laparoscopic Nissen fundoplication is a safe method with significant long-term efficacy in terms of symptom control and quality of life, even when; performed in a low-volume, community-hospital setting. PMID- 28882769 TI - Adjuvant hepatic artery infusion chemotherapy after hemihepatectomy for gastric cancer liver metastases. AB - BACKGROUND: The most frequent pattern of recurrence is remnant liver after hepatectomy for gastric cancer liver metastases (GLM). The evidence of adjuvant hepatic artery infusion chemotherapy (HAIC) after hepatectomy for GLM is lacking. The aim of this study was to evaluate the efficacy of adjuvant HAIC after hemihepatectomy for GLM. METHODS: Between 2001 and 2012, 14 patients who underwent hemihepatectomy for GLM were included in this study. Adjuvant HAIC to the remnant hemiliver was the FEM regimen (333 mg/m2 5-fluorouracil each week, 30 mg/m2 epirubicin once every 4 weeks, and 2.7 mg/m2 mitomycin-C once every 2 weeks) and was administered for 6 months after hemihepatectomy. Clinicopathological prognostic factors for survival were analyzed using a prospectively collected database. RESULTS: Nine patients had solitary GLM, and 5 patients had multiple GLM before surgery. The median period from hemihepatectomy to HAIC was 30 days. The 6-month HAIC completion rate was 79% (n = 11/14). Reasons of HAIC failure included liver dysfunction (n = 1), catheter infection (n = 1), and development of multiple recurrence (n = 1). The median follow-up was 29 (range 8-166) months. Recurrences were detected in 8 patients (57%). The site of recurrences included lung (n = 1), lymph nodes (n = 1), peritoneal dissemination (n = 1), brain (n = 1), pleural (n = 1), and multiple sites (n = 3). The overall 5-year survival rate was 43%. The pathological T4 classification and the preoperative CEA >=5 ng/mL were significant prognostic factors for overall survival. CONCLUSIONS: Adjuvant HAIC after hemihepatectomy for GLM prevents remnant liver recurrence and may contribute to long-term survival. PMID- 28882770 TI - Video-Assisted Anal Fistula Treatment (VAAFT) in Cryptoglandular fistula-in-ano: A systematic review and proportional meta-analysis. AB - BACKGROUND: Video-Assisted Anal Fistula Treatment (VAAFT) is a relatively new minimally invasive videoendoscopic procedure for treating fistula-in-ano. We reviewed and performed metaanalysis to evaluate the efficacy of this procedure. METHODS: Studies from the period 2010 to 2016 were searched in PubMed, Medline, Scopus, Embase, Ovid, SCI database, Cochrane Central Register of Controlled Trials (CENTRAL) & Google Scholar database. All studies which utilized VAAFT to treat fistula-in-ano were extracted. The studies in which the Cryptoglandular fistula were treated were included. Procedure's done in patients with Crohn's disease, pediatric patients and associated malignancy were excluded from the study. The primary outcome parameter was success rate in fistula healing and the secondary outcome parameters were operating time, hospital stay, return to work, incontinence rate and complication rate. RESULTS: A total of 1378 studies were screened. Out of these, eight studies were finally included for meta-analysis. The analysis (n = 786) demonstrated a net Proportion Meta-analysis pooled rate of 76.01% (95% CI = 68.1 to 83.9) for success rate, 16.2% (95% CI = 12.1 to 20.2) for complications, 44.7 min (95% CI = 38.3 to 51.2) for operating time, 1-4.1 days for mean hospital stay and 1-11 days for return to work. None of the studies reported worsening of continence levels. CONCLUSIONS: VAAFT is a safe videoendoscopic method to treat fistula-in-ano with an overall success rate of 76% (net Proportion Meta-analysis pooled rate). The main benefit of the procedure is minimal risk to incontinence, minimal hospital stay and early return to work. PMID- 28882772 TI - Early elective versus delayed elective surgery in acute recurrent diverticulitis: A systematic review and meta-analysis. AB - OBJECTIVES: To investigate outcomes of early versus delayed surgery in patients with acute recurrent diverticulitis. METHODS: We performed a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta Analyses statement standards. We conducted a search of electronic information sources, including MEDLINE; EMBASE; CINAHL; the Cochrane Central Register of Controlled Trials (CENTRAL); the World Health Organization International Clinical Trials Registry; ClinicalTrials.gov; and ISRCTN Register, and bibliographic reference lists to identify all randomised controlled trials (RCTs) and observational studies investigating outcomes of early versus delayed surgery in patients with acute recurrent diverticulitis. We used the Newcastle-Ottawa scale to assess the risk of bias of included studies. Random-effects models were applied to calculate pooled outcome data. RESULTS: We identified three retrospective and one prospective cohort studies enrolling a total of 1046 patients. The included patients were comparable in terms of age, ASA score and Hinchey classifications (Hinchey I and II). The results of our analyses suggested that there was no difference between two groups in surgical site infection [Odds ratio (OR) 1.61, 95% CI 0.79-3.27, P = 0.19], intra-abdominal abscess (OR 0.92, 95% CI 0.21-4.00, P = 0.91), anastomotic leak (OR1.27, 95% CI 0.50-3.25, P = 0.61), 30-day mortality [Risk difference (RD) 0.00 95% CI -0.01-0.01, P = 0.80], postoperative ileus (OR 1.35, 95% CI 0.50-3.66, P = 0.55), postoperative bleeding (OR 0.93, 95% CI 0.32-2.69, P = 0.89), ureteric injury (OR 0.62, 95% CI 0.08 5.07, P = 0.65), and overall morbidity (OR 1.42 95% CI 0.76-2.66, P = 0.27). The early surgery was associated with longer operative time [Mean Difference (MD) 12.8, 95% CI 5.08-20.53, P = 0.001] and length of stay (MD 4.41, 95% CI -0.34 8.53, P = 0.03). Among those undergoing laparoscopic surgery, conversion to open surgery was higher in the early surgery group (OR 2.71, 95% CI 1.36-5.40, P = 0.005). CONCLUSIONS: The best available evidence suggests that there is no difference between early elective and delayed elective surgery for acute recurrent diverticulitis in terms of clinical outcomes. However, longer operative time and length of stay and higher conversion rate to open surgery associated with early elective surgery may make the delayed elective surgery more cost effective. The best available evidence is derived from non-randomised studies; therefore, high quality randomised controlled trials are required to provide more robust basis for definite conclusions. PMID- 28882773 TI - Shockwave treatment for medial tibial stress syndrome in military cadets: A single-blind randomized controlled trial. AB - : Medial tibial stress syndrome (MTSS) is a common injury in athletes and soldiers. Several studies have demonstrated the effectiveness of extracorporeal shockwave treatment (ESWT) in athletes with MTSS. OBJECTIVE: To assess whether one session of focused ESWT is effective in the treatment of military cadets with MTSS. DESIGN: A randomized, prospective, controlled, single-blind, parallel-group clinical study. LEVEL OF EVIDENCE: Ib. SETTING: Military School of Cadets of the Colombian Army. METHODS: Forty-two military cadets with unilateral chronic MTSS were randomly assigned to either one session of focused electromagnetic ESWT (1500 pulses at 0.20 mJ/mm2) plus a specific exercise programme (muscle stretching and strengthening exercises) or the exercise programme alone. The primary endpoint was change in asymptomatic running test (RT) duration at four weeks from baseline. Secondary endpoints were changes in the visual analogue scale (VAS) after running and modified Roles and Maudsley (RM) score also at four weeks from baseline. RESULTS: ESWT patients were able to run longer. Mean RT after four weeks was 17 min 33 s (SE: 2.36) compared to 4 min 48 s (SE: 1.03) in the exercise-only group (p = 0.000). Mean VAS after running was 2.17 (SE: 0.44) in the ESWT group versus 4.26 (SE: 0.36) in the exercise-only group (p = 0.001). The ESWT group had a significantly higher RM score, with excellent or good results for 82.6% of patients vs. 36.8% in the exercise-only group (p = 0.002). No significant adverse effects of ESWT were observed. CONCLUSION: A single application of focused shockwave treatment in combination with a specific exercise programme accelerates clinical and functional recovery in military cadets with MTSS. PMID- 28882771 TI - Eccentric technique for foraminoplasty in percutaneous endoscopic transforaminal procedure: A technical note. AB - OBJECTIVE: To describe a modified technique usied for foraminoplasty in percutaneous endoscopic transforaminal procedure. METHODS: 58 patients (20 males and 38 females, average age 52.5 years) underwent percutaneous endoscopic transforaminal procedure by using our modified technique. Under the guidance of C arm fluoroscopy, a kirschner wire was inserted into targeted superior articular process. After expanding the soft tissues, a trepan with the largest diameter was located through the kirschner wire and the angle of trepan was flexible enough to adjust to different operative conditions. This technique could help to avoided using step-by-step larger diameters of trepans without slippage during foraminoplasty. RESULTS: With our modified technique, the mean operation time was 65 min (range 50-80 min) and mean estimated blood loss was 12 ml (range 10-30 ml). Fluoroscopy was less (the mean duration of fluoroscopy was 20.4 +/- 9.2 s and the mean radiation dose was 0.9 +/- 0.2 mSv) and no complications occurred. All foraminoplasties were excellent via CT scans after surgery and all patients were discharged on 2nd day after operation. The results of 58 patients with an average follow-up of 18 (6-36) months demonstrated our eccentric technique to be effective. CONCLUSION: Our eccentric technique could help to avoid step-by-step larger diameters of trepans during foraminoplasty to shorten operation time and reduced the number of fluoroscopy intraoperative. PMID- 28882774 TI - How Prospective Physical Medicine and Rehabilitation Trainees Rank Residency Training Programs. AB - BACKGROUND: Since the inception of the National Resident Matching Program, multiple studies have investigated the factors applicants consider important to ranking prospective residency programs. However, only 2 previous studies focused on prospective physical medicine and rehabilitation (PM&R) trainees, and the most recent of these studies was published in 1993. It is unknown whether these previous studies are reflective of current prospective PM&R residents. OBJECTIVE: To assess various factors that contribute to prospective PM&R residents' decision making in choosing a residency program and compare these findings with previous studies. DESIGN: An anonymous, voluntary questionnaire. SETTING: A single PM&R residency program. PARTICIPANTS: All applicants to a single PM&R residency program. METHODS: All applicants to our PM&R residency program were invited to participate in a 44-item, 5-point Likert-based questionnaire. Applicants were asked to rate the importance of various factors as they related to constructing their residency rank list. MAIN OUTCOME MEASUREMENTS: Means and standard deviations were calculated for items included in the survey. RESULTS: A response rate of 26% was obtained, with the responses of 98 applicants (20%) ultimately analyzed. The highest rated factors included "perceived happiness of current residents," "opportunities for hands-on procedure training," "perceived camaraderie among current residents," "perceived camaraderie among faculty and current residents," "perceived quality of current residents," and "perceived work/life balance among current residents." Although male and female respondents demonstrated similar ranking preferences, an apparent difference was detected between how genders rated the importance of "whether the program projects a favorable environment for women" and "whether the program projects a favorable environment for minorities." As compared with previous PM&R applicants, current prospective trainees seem to place greater importance on skill acquisition over didactic teaching. CONCLUSION: Prospective PM&R residents highly value subjective perceptions of prospective PM&R training programs and the ability to obtain hands on procedural experience. LEVEL OF EVIDENCE: Not applicable. PMID- 28882775 TI - Premenstrual Dysphoric Disorder in a Patient With Traumatic Brain Injury: A Case Presentation. AB - : We present a case of a 17-year-old girl who developed premenstrual dysphoric disorder (PMDD) after sustaining a severe traumatic brain injury (TBI), and we review the diagnosis of PMDD. The patient developed symptoms of severe depression surrounding her menses months after sustaining severe TBI and was diagnosed with PMDD by a psychiatrist. She ultimately required antipsychotics for optimal symptom resolution. PMDD is a severe form of premenstrual syndrome with symptoms including irritability, anxiety, and nonfatal suicidal behavior. We discuss other potential causes of mood disturbance that are important to screen for after TBI, including depression, anxiety, and hypothalamic-pituitary axis disorders. Rehabilitation medicine providers need to be aware of PMDD in postpubertal female patients with TBI because it can lead to nonfatal suicidal behaviors. LEVEL OF EVIDENCE: V. PMID- 28882776 TI - Immunosuppressant Medication-Induced Lower Extremity Pain After Combined Liver and Kidney Transplant: A Case Report. AB - : Calcineurin inhibitors are imperative in the success of a transplanted organ. However, these immunosuppressants can lead to a rare complication known as calcineurin inhibitor-induced pain syndrome, which may not be recognized early and managed appropriately. We present a case of a 35-year-old woman who underwent a combined liver/kidney transplant and developed lower extremity pain while being maintained on tacrolimus. This case illustrates a patient with previously reported characteristic clinical features of calcineurin inhibitor-induced pain syndrome in addition to uncharacteristic neuropathic symptoms and imaging findings. The patient was treated successfully with gabapentin, calcitonin nasal spray, and acupuncture. Early recognition of this syndrome can help improve a patient's quality of life. LEVEL OF EVIDENCE: V. PMID- 28882777 TI - Secondary Urethral Malignancies Following Prostate Brachytherapy. AB - OBJECTIVE: To understand urethral secondary malignancies among patients treated with brachytherapy (BRT) for primary prostate cancer. PATIENTS AND METHODS: Institutional retrospective review identified 13 patients evaluated from 2003 to 2014 with urethral cancer and history of BRT monotherapy for prostate cancer. All patients were biochemically free of their primary disease and radiation associated secondary malignancies (RASMs) were confirmed pathologically to be histologically distinct from primary tumor. BRT characteristics, patient age, presentation, staging workup, and clinical course were evaluated. RESULTS: The mean time from BRT to presenting symptoms of hematuria, urinary retention, and/or renal failure was 71 months. Symptom onset to RASM diagnosis interval was 24 months. Mean time from BRT to RASM diagnosis was 95 months. Eighty-five percent of patients had an undetectable prostate-specific antigen level (<0.2 ng/mL) at last follow-up. Types of RASM included sarcomatoid carcinoma (6), small cell carcinoma (2), urothelial carcinoma with squamous differentiation (2), squamous cell carcinoma (1), rhabdomyosarcoma (1), and urothelial carcinoma (1). A majority of patients were diagnosed with advanced disease with either distant metastases (54%) or local progression (23%). Ten patients died during this study period with median time to death after RASM diagnosis of 6 months. CONCLUSION: RASMs localized to the posterior urethra displayed advanced disease and high mortality rates. Refractory lower urinary tract symptoms, hematuria, and history of prostate BRT should raise suspicion for urethral RASMs. Further studies are warranted to determine patient and disease characteristics that correlate with disease-specific mortality of secondary urethral malignancies. PMID- 28882778 TI - The Efficacy of Tadalafil Daily vs on Demand in the Treatment of Erectile Dysfunction: A Systematic Review and Meta-analysis. AB - We present a review comparing the use of tadalafil daily vs on-demand for erectile dysfunction. We examined randomized controlled trials and observational studies that examined the use of tadalafil for at least 8 weeks of follow-up with the primary outcome of International Index for Erectile Dysfunction-Erectile Function domain. Eight studies that examined the desired dosing regimens were identified. Of these, 6 studies included the primary end point of 12 weeks. Those patients taking tadalafil daily for 12 weeks scored on average 1.82 points higher in International Index for Erectile Dysfunction-Erectile Function domain scores, although the difference may not be clinically significant (Fig. 1). PMID- 28882779 TI - Safety and Effectiveness of Holmium Laser Enucleation of the Prostate Using a Low power Laser. AB - OBJECTIVE: To assess the safety and effectiveness of holmium laser enucleation of the prostate (HoLEP) using a low-power 30-W holmium laser with an en bloc enucleation technique. MATERIALS AND METHODS: We retrospectively analyzed 74 patients with a diagnosis of benign prostatic hyperplasia treated with HoLEP using a 30-W laser set at 1.5 J with a frequency of 20 Hz, as a low-power setting. The enucleation process was performed using the en bloc technique. Forty four patients were operated on by an experienced surgeon, whereas 30 patients were operated on by 2 less experienced surgeons. We evaluated the surgical parameters and practicality of the low-power laser. RESULTS: All patients underwent successful HoLEP with the low-power setting; it was not necessary to increase the output of the laser in any case. Mean preoperative estimated prostate volume was 94.5 mL (range 22-489 mL). Mean total operating time and enucleation time were 91.9 minutes (range 30-232 minutes) and 45.4 minutes (range 13-101 minutes), respectively. No patient required blood transfusion postoperatively. Other intraoperative complications, including capsular perforation and ureteral orifice injury, did not occur. In 55 patients without preoperative stress urinary incontinence (SUI), postoperative SUI was observed in 7 patients (12.7%) at 1 month postoperatively, and in 3 patients (5.5%) at 3 months postoperatively. CONCLUSION: HoLEP using a low-power 30-W holmium laser can be performed safely and without any technical problems; this low-power setting is thought to be sufficient for performing HoLEP. As the introduction costs can be reduced by using a low-power laser, HoLEP could become widespread. PMID- 28882780 TI - Reply by the Authors. PMID- 28882782 TI - Prostate Cancer in Transgender Women: Incidence, Etiopathogenesis, and Management Challenges. AB - OBJECTIVE: To critically analyze the available evidence regarding the incidence, etiopathogenesis, and management of prostate cancer (CaP) in transgender women. In addition, this article aims to present a recent case report of a transgender woman with a unique presentation at the author's institution. MATERIALS AND METHODS: An electronic nonsystematic literature search was performed to identify pertinent studies. PubMed search engine was queried by using the following search terms: "prostate cancer," "male to female transsexual," "transgender patient," "androgen + prostate cancer," "estrogen therapy + prostate cancer," and "health care barrier." In addition, a clinical case managed at our institution was reviewed and critically discussed. RESULTS: Including our case, there have been only 10 documented cases of CaP in transgender women. Additionally, an emerging body of literature has questioned the role of androgens in the development of CaP and suggested that estrogen therapy may not be as protective as initially thought. Therefore, the current evidence suggests that the transgender woman should be screened for CaP the same as a nontransgender men. Barriers to care in the transgender female population include accessing resources, medical knowledge deficits, ethics of transition-related medical care, diagnosing vs pathologizing transgender patients, financial restrictions of the patient, and health system determinants. CONCLUSION: Although rare, CaP in transgender women has been documented. Both the mechanism and the impact of receiving a bilateral orchiectomy on disease development are unclear. Future study is needed to examine these factors, and to further shape the treatment and screening regimen for these patients. PMID- 28882781 TI - Ureteroscopic Urinary Stone Treatment Among Patients With Renal Anomalies: Patient Characteristics and Treatment Outcomes. AB - OBJECTIVE: To evaluate patients' characteristics, surgical procedure data, and outcomes of ureterorenoscopy (URS) stone treatment in patients with a horseshoe kidney (HSK), ectopic kidney (EK), and malrotated kidney (MK). MATERIALS AND METHODS: This study is a subanalysis of the Clinical Research Office of the Endourological Society URS Global Study, which was a prospective multicenter observational study, collecting data on URS stone treatment from consecutive patients over a 1-year period. A total of 114 centers in 32 countries participated. This analysis acuminated on URS stone treatment in the specified renal anomalies: HSK, EK, and MK. For each group, patient characteristics, operation data, and treatment outcomes were evaluated. RESULTS: Of the 11,885 patients included in the Clinical Research Office of the Endourological Society URS study, 43 patients had HSK, 27 EK, and 16 MK. The stone-free rate (SFR) in the HSK group was 77% for renal stones and 85% for ureteral stones. In the HSK group, the intraoperative complication rate was 11.6% and the postoperative complication rate was 7%, including 1 Clavien grade IIIa and 1 IIIb complication. In the EK group, the SFR was 20% for renal stones and 94% for ureteral stones, with an intraoperative complication rate of 14.8% and a postoperative complication rate of 7.4%. One Clavien IVa complication was reported. In the MK group, the SFR was 71% for renal stones and 88% for ureteral stones, with an intraoperative complication rate of 6.3%. No postoperative complications occurred in this group. CONCLUSION: URS is an effective and safe treatment modality to remove ureteral and renal stones in patients with HSK and MK. The effectiveness of URS for renal stones in EK was low. PMID- 28882783 TI - ramR is not involved in the regulation of ramA associated antibiotic resistance in Salmonella enterica serovar Typhi. AB - RamA, a global transcriptional activator, belongs to the AraC/XylS family of regulatory proteins and can regulate multidrug resistance through activating the expression of AcrAB. In Salmonella spp., Klebsiella pneumonia, Enterobacter cloacae and Enterobacter aerogenes, RamR represses the transcription of gene ramA through binding to the upstream sequences of ramA. In this study, we found that the locus and transcription directions of ramA-ramR in S. Typhi GIFU10007 are different from that in S. Typhimurium (SL1344). To study the role of RamR involved in regulation of ramA in S. Typhi, we constructed ramA over-expression strain and ramR deletion mutant, and detected the expression level of ramA, and measured the growth curve of these strain in the presence of ampicillin. The results showed that RamR in S. Typhi neither repressed the expression of ramA, nor affected the bacterial resistance to ampicillin. In summary, RamR is not the repressor of RamA in S. Typhi, which is different from its role in other bacteria, such as S. Typhimurium and K. pneumoniae. PMID- 28882784 TI - High prevalence of diverse vancomycin resistance Enterococcus faecium isolates in clinical and environmental sources in ICU wards in southwest of Iran. AB - This study aimed at determining the prevalence, antibiotic resistance patterns, and genetic linkage of Vancomycin Resistant Enterococcus faecium (VREfm) from different sources in the southwest of Iran. A total of 51 VREfm isolates were obtained and subjected to antibiotic susceptibility testing, carriage of virulence genes, and pulsed-field gel electrophoresis (PFGE) method. All the VRE isolates exhibited a high level of resistance to teicoplanin, ampicillin, erythromycin, ciprofloxacin, and gentamicin, also carried the vanA gene. A total of 59% and 34% of the VREfm strains harbored esp and hyl genes, respectively. The results from PFGE showed 31 PFGE patterns including 10 common types (CT) and 21 single types (ST) among the VRE isolates. Furthermore, isolates from different sources in each common type revealed cross transmission between clinical and environmental sources. Overall, the study showed a high prevalence of diverse VRE faecium strains with threatening resistance phenotypes in the environment and clinical sections among different ICU wards of Ahvaz hospitals. PMID- 28882785 TI - Orlistat treatment induces apoptosis and arrests cell cycle in HSC-3 oral cancer cells. AB - The present study was aimed to investigate the effect of orlistat on an oral squamous cancer line HSC-3 as well as the underlying mechanism. Cell Counting Kit 8 (CCK-8) (Dojindo, Shanghai, China) was used for the analysis of proliferation, Annexin V-FITC and propidium iodide staining for apoptosis and flow cytometry for cell cycle distribution. Western blot assay was used to determine the alteration in the expression of cyclin D1, B1, E and CDK1. The results revealed a concentration and time-dependent decrease in the proliferation of HSC-3 cells by orlistat. The viability of HSC-3 cells was reduced to 23.4 +/- 2.5 and 15.7 +/- 1.6% at 40 and 50 MUM concentration of orlistat after 48 h. Treatment of HSC-3 cells with orlistat resulted induction of apoptosis significantly (p < 0.05). Orlistat treatment led to the increase in proportion of apoptotic cells to 38.6 +/- 2.5% after 48 h compared to 0.85 +/- 0.34% in the control. Analysis of cell cycle showed that population of cells in G2/M phase in the cultures treated with orlistat for 48 h increased to 59.7 +/- 5% compared to 10.2 +/- 1.2% in the control. However, the population of cells in the G0/G1 and S phases was subsequently decreased. The expression of cyclin D1 and E was decreased and phosphorylation of CDK1 was increased by orlistat treatment in HSC-3 cells. Thus, orlistat induces apoptosis and cell cycle arrest in G2/M phase in HSC-3 cells through decrease in expression of cyclin D1 and E and increase in phosphorylation of CDK1. Therefore, orlistat can be used for the treatment of oral squamous cancer. PMID- 28882788 TI - Efficient detection of chromosome imbalances and single nucleotide variants using targeted sequencing in the clinical setting. AB - We evaluated an approach to detect copy number variants (CNVs) and single nucleotide changes (SNVs), using a clinically focused exome panel complemented with a backbone and SNP probes that allows for genome-wide copy number changes and copy-neutral absence of heterozygosity (AOH) calls; this approach potentially substitutes the use of chromosomal microarray testing and sequencing into a single test. A panel of 16 DNA samples with known alterations ranging from megabase-scale CNVs to single base modifications were used as positive controls for sequencing data analysis. The DNA panel included CNVs (n = 13) of variable sizes (23 Kb to 27 Mb), uniparental disomy (UPD; n = 1), and single point mutations (n = 2). All DNA sequence changes were identified by the current platform, showing that CNVs of at least 23 Kb can be properly detected. The estimated size of genomic imbalances detected by microarrays and next generation sequencing are virtually the same, indicating that the resolution and sensitivity of this approach are at least similar to those provided by DNA microarrays. Accordingly, our data show that the combination of a sequencing platform comprising focused exome and whole genome backbone, with appropriate algorithms, enables a cost-effective and efficient solution for the simultaneous detection of CNVs and SNVs. PMID- 28882787 TI - Steering Against Wind: A New Network of NamiRNAs and Enhancers. AB - MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs with regulatory functions. Traditionally, miRNAs are thought to play a negative regulatory role in the cytoplasm by binding to the 3'UTR of target genes to degrade mRNA or inhibit translation. However, it remains a challenge to interpret the potential function of many miRNAs located in the nucleus. Recently, we reported a new type of miRNAs present in the nucleus, which can activate gene expression by binding to the enhancer, and named them nuclear activating miRNAs (NamiRNAs). The discovery of NamiRNAs showcases a complementary regulatory mechanism of miRNA, demonstrating their differential roles in the nucleus and cytoplasm. Here, we reviewed miRNAs in nucleus to better understand the function of NamiRNAs in their interactions with the enhancers. Accordingly, we propose a NamiRNA-enhancer target gene activation network model to better understand the crosstalk between NamiRNAs and enhancers in regulating gene transcription. Moreover, we hypothesize that NamiRNAs may be involved in cell identity or cell fate determination during development, although further study is needed to elucidate the underlying mechanisms in detail. PMID- 28882786 TI - Exosomal biomarkers in Down syndrome and Alzheimer's disease. AB - Every person with Down syndrome (DS) has the characteristic features of Alzheimer's disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population. PMID- 28882789 TI - Litopenaeus vannamei activating transcription factor 6 alpha gene involvement in ER-stress response and white spot symptom virus infection. AB - A previous study found that inositol-requiring enzyme-1-X-box binding protein 1 (IRE1-XBP1) pathway and the protein kinase RNA (PKR)-like ER kinase-eIF2alpha (PERK-eIF2alpha) pathway of shrimp play roles in the unfolded protein response (UPR). And they also be proved that was involved in white spot symptom virus (WSSV) infection. Yet the functions of the third branch in shrimp UPR are still unclear. In this study, we showed that upon UPR activation, activating transcription factor 6 alpha (LvATF6alpha) of Litopenaeus vannamei was cleaved and transferred from the cytoplasm to the nucleus in 293T cells, indicating that the ATF6 pathway in shrimp is also a branch of UPR. Furthermore, LvATF6alpha could reduce the apoptosis rate of Drosophila Schneider 2 (S2) cells treated with actinomycin, and knock-down expression of LvATF6alpha increased the apoptosis rate of shrimp hemocytes. In vivo testing revealed that the short from LvATF6alpha (LvATF6alpha-s) was obviously increased after UPR activation or WSSV infection, indicating that the ATF6 pathway was activated in L. vannamei gills under such circumstances. Moreover, knock-down expression of LvATF6alpha could reduce the cumulative mortality and WSSV copy number in WSSV-infected shrimp. Further study revealed that WSSV may profit from shrimp ATF6 pathway activation in two aspects. First, LvATF6alpha-s significantly upregulated the expression of the WSSV genes (wsv023, wsv045, wsv083, wsv129, wsv222, wsv249, and wsv343). Second, LvATF6alpha-s inhibited apoptosis by negatively regulating the apoptosis signal-regulating kinase 1 - (c-Jun N-terminal kinase) pathway. All of these evidences suggested that the ATF6 pathway is a member of the L. vannamei UPR, and it is also engaged in WSSV infection. PMID- 28882790 TI - Molecular characterization, expression and functional analysis of two Kazal-type serine protease inhibitors from Venerupis philippinarum. AB - Kazal-type serine protease inhibitors (KSPIs) act as negative regulators in immune signaling pathway by controlling the extent of serine protease (SP) activities. In this study, the full-length cDNA of two KSPIs (designed as VpKSPI 1 and VpKSPI-2) were identified from Venerupis philippinarum by rapid amplification of cDNA ends (RACE) approaches. The open reading frame (ORF) of VpKSPI-1 and VpKSPI-2 was of 552 bp and 402 bp, encoding a polypeptide of 183 and 133 amino acids, respectively. The transcripts of VpKSPI-1 and VpKSPI-2 were ubiquitously expressed in all tissues tested with the highest expression level in hepatopancreas. After Vibrio anguillarum challenge, the relative mRNA expression of VpKSPI-1 and VpKSPI-2 in hepatopancreas was both up-regulated within 96 h. The recombinant VpKSPI-1 (rVpKSPI-1) displayed weak activities towards chymotrypsin, moderate inhibitory activity to trypsin, while rVpKSPI-2 showed significant inhibitory activities against chymotrypsin and trypsin. When the molar ratio of rVpKSPI-2 to chymotrypsin and trypsin reached 1:4 and 1:2, the protease activities could be almost entirely inhibited. All these results suggested that both VpKSPI-1 and VpKSPI-2 perhaps play a vital role in the innate immunity of V. philippinarum. PMID- 28882791 TI - Effects of organic acids and essential oils blend on growth, gut microbiota, immune response and disease resistance of Pacific white shrimp (Litopenaeus vannamei) against Vibrio parahaemolyticus. AB - An 8-week feeding trial was undertaken to evaluate supplemental effects of AviPlus(r) (AP), a blend of organic acids [citric acid, 25%; sorbic acid, 16.7%] and essential oils [thymol, 1.7%; vanillin, 1.0%], on growth, gut microbiota, innate immunity and disease resistance of Pacific white shrimp (Litopenaeus vannamei) against Vibrio parahaemolyticus. A basal experimental diet was formulated and supplemented with 0, 0.3, 0.6, 0.9 and 1.2 g kg-1 AP to produce five test diets (Con, AP0.3, AP0.6, AP0.9 and AP1.2). Each diet was fed to triplicate groups of shrimp (0.2 +/- 0.01 g, mean +/- SE) to apparent satiation three times daily. Growth performance and survival rate were not significantly influenced by AP supplementation (P > 0.05). Significantly (P < 0.05) higher serum total protein was found in groups fed >= 0.6 g kg-1 AP compared to control. Serum alkaline phosphatase and phenoloxidase activities were significantly increased in AP0.9 and AP1.2 groups. Also, the group received AP0.6 diet showed significantly higher glutathione peroxidase activity than control. Expression of gut pro-inflammatory genes including TNF-alpha, LITAF and RAB6A were down regulated by AP administration. Gut microbiota analysis showed the significant enhancement of the operational taxonomic unit (OTU) diversity and richness indices by AP application. AP supplementation led to increased abundance of Firmicutes and a reduction in abundance of Proteobacteria. Also, dietary inclusion of 1.2 g kg-1 AP led to a significant increase in the abundance of Lactobacillus in shrimp gut. The group offered AP0.3 diet showed significantly higher disease resistance than control group. Furthermore, AP application significantly enhanced relative expression of immune related genes including lysozyme, penaeidin and catalase at 48 h post challenge. In conclusion, these findings show that the tested organic acids and essential oils mixture beneficially affects intestinal microflora and improves immune response and disease resistance of L. vannamei. PMID- 28882792 TI - Hypothermal stress induced differential expression profiles of the immune response gene, warm-temperature-acclimation associated 65-kDa protein (Wap65), in the liver of fresh water and seawater milkfish, Chanos chanos. AB - The milkfish (Chanos chanos), an important aquaculture species, is intolerant to cold environments. Temperature fluctuations in the environment affect the physiological response, behavior, and survival rate of the fish. The warm temperature-acclimation associated 65-kDa protein (Wap65) of teleosts was identified after heat shock treatment and has two isoforms. Both the isoforms were involved in the induction of immune responses in fish. They showed high degree of sequence conservation with the mammalian hemopexin and had high affinity for heme, which helped in the neutralization of free-heme and its transport to the liver. In this study, we isolated and characterized the two isoforms of wap65 genes (Ccwap65-1 and Ccwap65-2) from the liver of milkfish. The Ccwap65-1 and Ccwap65-2 are mainly expressed in livers of milkfish. In hypothermal treatment, the expression levels of Ccwap65-2 in the livers of SW and FW milkfish were up-regulated after exposure to low temperature (18 degrees C) for 12 h and 96 h compared to those in the normal temperature (28 degrees C) group, respectively. After intraperitoneal injection of lipopolysaccharide (LPS), the expression of Ccwap65-2 was elevated in both SW and FW milkfish, whereas that of Ccwap65-1 was not affected in both the groups. Thus, Ccwap65-2 expressed in the milkfish liver under hypothermal stress was identified as a novel immune biomarker. In addition, according to the transcriptome database, up-regulation of the other immune-response genes indicated increased pathogen infection status under hypothermal stress. Acute increase in the expression of hepatic Ccwap65-2 in response to pathogen infection might lead to better cold tolerance of SW milkfish compared to that of the FW individuals upon cold challenge. PMID- 28882793 TI - Regulation mechanism of oxidative stress induced by high glucose through PI3K/Akt/Nrf2 pathway in juvenile blunt snout bream (Megalobrama amblycephala). AB - This study was conducted to investigate the effects of oral administration of a high concentration of glucose on the respiratory burst, antioxidant status, and hepatic gene expression of heme oxygenase-1 (ho1) and PI3K/Akt/Nrf2-related signaling molecules in juvenile blunt snout bream (Megalobrama amblycephala). Blunt snout bream juveniles with an initial body weight of 19.94 +/- 0.58 g were orally fed with a high concentration of glucose (3 g/kg body weight). The results indicated that plasma glucose exhibited a biphasic response. Acute and persistent hyperglycemia due to the oral glucose administration significantly reduced (P < 0.05) the white blood cell count, red blood cell count, and hemoglobin content and caused oxidative stress (significantly increased alanine aminotransferase, aspartate transaminase, alkaline phosphatase, and glucose levels) and early apoptosis of hepatocytes in the fish. Hepatic superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities increased rapidly (P < 0.05) as protection from oxidative stress and were downregulated (P < 0.05) because of persistent hyperglycemia. Blood respiratory burst was significantly reduced (P < 0.05) because of hyperglycemia and showed a trend that was opposite to that of plasma glucose. Slight upregulation of nrf2 mRNA and antioxidants acts as a compensative protection mechanism, and the downregulated PI3K/Akt pathway blocked this function of Nrf2. In conclusion, the PI3K/Akt pathway and Nrf2 mediated the antioxidative mechanism independently in the blunt snout bream juveniles subjected to the oral administration of a high glucose concentration. PMID- 28882794 TI - Local immune response of two mucosal surfaces of the European seabass, Dicentrarchus labrax, fed tryptophan- or methionine-supplemented diets. AB - Immune responses relies on an adequate provision of multiple nutrients that sustain the synthesis of key effector molecules. These needs are depicted in the already reported increase of circulating free amino acids in fish under stressful conditions. Since aquaculture and the inherent fish welfare are an emergent call, the immunomodulatory effects of amino acids on gut- and skin-associated lymphoid tissues of the European seabass (Dicentrarchus labrax) were studied under unstressed conditions and after an inflammatory insult. To achieve this goal, fish were distributed in duplicate tanks (fifteen fish per tank) and were fed for 14 days with methionine or tryptophan-supplemented diets at 2* dietary requirement level (MET and TRP, respectively) or a control diet meeting the amino acids requirement levels (CTRL). Afterwards, samples of skin and posterior gut were collected from 6 fish per dietary treatment for the assessment of the immune status while the remaining animals were intraperitoneally-injected with inactivated Photobacterium damselae subsp. piscicida and subsequently sampled either 4 or 24 h post-injection. The immune status of both mucosal surfaces was poorly affected, although a tryptophan effect was denoted after bacterial inoculation, with several immune-related genes up-regulated in the gut at 4 h post-injection, which seems to suggest a neuroendocrine-immune systems interaction. In contrast, skin mucosal immunity was inhibited by tryptophan dietary supplementation. Regarding methionine, results were often statistically non-significant, though increasing trends were denoted in a few parameters. Overall, dietary methionine did not significantly affect neither gut nor skin immunity, whereas tryptophan supplementation seems to induce modulatory mechanisms that might be tissue-specific. PMID- 28882795 TI - Effects of Cordyceps militaris spent mushroom substrate and Lactobacillus plantarum on mucosal, serum immunology and growth performance of Nile tilapia (Oreochromis niloticus). AB - An 8-weeks feeding trial was performed to investigate the possible effects of supplementation of Nile tilapia diet with Cordyceps militaris spent mushroom substrate (SMS) single or combined with Lactobacillus plantarum on immune parameters and growth performance. For this aim, Nile tilapia fingerlings were fed with four experimental diets namely: Diet 1 (0 - control), Diet 2 (10 g kg-1 SMS), Diet 3 (108 CFU g-1L. plantarum), and Diet 4 (10 g kg-1 SMS + 108 CFU g-1L. plantarum). At the end of feeding trial, skin mucus parameters, serum immune parameters, and growth performance were measured. The results indicated that supplementations SMS + L. plantarum or/and resulted in a significant increase in skin mucus lysozyme and peroxidase activities compared with the control group after 8 weeks of feeding trial (P < 0.05). The highest values of these parameters were recorded for fish fed both SMS + L. plantarum supplementations. Nonetheless, no significant difference was recorded between other supplemented groups (P < 0.05). For serum immunology, the results showed that serum lysozyme activity, alternative complement, phagocytosis, serum peroxidase, and respiratory burst activities were significantly higher in supplemented groups compared to the control (P < 0.05). The highest values were recorded in fish fed both SMS and L. plantarum with respect to the individual application. No significant differences were observed between fish fed SMS and L. plantarum (P < 0.05). Results on growth performance indicated that fish fed supplemented diets showed a statistically significant increase in the specific growth rate (SGR), weight gain (WG), final weight (FW) compared to the control group (P < 0.05). The highest SGR and WG values were observed in fish fed both dietary SMS and L. plantarum. However, no significant differences in these parameters were observed in fish fed SMS or L. plantarum alone (P > 0.05). The FCR was significantly lower in fish fed 10 g kg-1 SMS + 108 CFU g-1L. plantarum than in other groups, while control group presented the highest values (P < 0.05). The present results suggested that the combination of these natural substances could be considered as potential feed-additives for aquaculture farmed fish. PMID- 28882796 TI - Protective effect of glutamine and arginine against soybean meal-induced enteritis in the juvenile turbot (Scophthalmus maximus). AB - Soybean meal can induce enteritis in the distal intestine (DI) and decrease the immunity of several cultured fish species, including turbot Scophthalmus maximus. Glutamine and arginine supplementation have been used to improve immunity and intestinal morphology in fish. This study was conducted to investigate the effects of these two amino acids on the immunity and intestinal health of turbot suffering from soybean meal-induced enteritis. Turbots (initial weight 7.6 g) were fed one of three isonitrogenous and isolipidic diets for 8 weeks: SBM (control diet), with 40% soybean meal; GLN, SBM diet plus 1.5% glutamine; ARG, the SBM diet plus 1.5% arginine. Symptoms that are typical of soybean meal induced enteritis, including swelling of the lamina propria and subepithelial mucosa and a strong infiltration of various inflammatory cells was observed in fish that fed the SBM diet. Glutamine and arginine supplementation significantly increased (1) the weight gain and feed efficiency ratio; (2) the height and vacuolization of villi and the integrity of microvilli in DI; (3) serum lysozyme activity, and the concentrations of C3, C4, and IgM. These two amino acids also significantly decreased the infiltration of leucocytes in the lamina propria and submucosa and the expression of inflammatory cytokines including il-8, tnf-alpha, and tgf-beta. For the mucosal microbiota, arginine supplementation significantly increased microbiota community richness and diversity, and glutamine supplementation significantly increased the relative abundance of Lactobacillus and Bacillus. These results indicate that dietary glutamine and arginine improved the growth performance, feed utilization, and distal intestinal morphology, activated the innate and adaptive immune systems, changed the intestinal mucosal microbiota community, and relieved SBMIE possibly by suppression of the inflammation response. PMID- 28882797 TI - Modification of the plasma complement protein profile by exogenous estrogens is indicative of a compromised immune competence in marine medaka (Oryzias melastigma). AB - Growing evidence suggests that the immune system of teleost is vulnerable to xenoestrogens, which are ubiquitous in the marine environment. This study detected and identified the major circulatory immune proteins deregulated by 17alpha-ethinylestradiol (EE2), which may be linked to fish susceptibility to pathogens in the marine medaka, Oryzias melastigma. Fish immune competence was determined using a host resistance assay to pathogenic bacteria Edwardsiella tarda. Females were consistently more susceptible to infection-induced mortality than males. Exposure to EE2 could narrow the sex gap of mortality by increasing infection-induced death in male fish. Proteomic analysis revealed that the major plasma immune proteins of adult fish were highly sexually dimorphic. EE2 induced pronounced sex-specific changes in the plasma proteome, with the male plasma composition clearly becoming "feminised". Male plasma was found to contain a higher level of fibrinogens, WAP63 and ependymin-2-like protein, which are involved in coagulation, inflammation and regeneration. For the first time, we demonstrated that expression of C1q subunit B (C1Q), an initiating factor of the classical complement pathway, was higher in males and was suppressed in both sexes in response to EE2 and bacterial challenge. Moreover, cleavage and post translational modification of C3, the central component of the complement system, could be altered by EE2 treatment in males (C3dg down; C3g up). Multiple regression analysis indicated that C1Q is possibly an indicator of fish survival, which warrants further confirmation. The findings support the potential application of plasma immune proteins for prognosis/diagnosis of fish immune competence. Moreover, this study provides the first biochemical basis of the sex differences in fish immunity and how these differences might be modified by xenoestrogens. PMID- 28882798 TI - Modulatory in vitro effect of stress hormones on the cytokine response of rainbow trout and gilthead sea bream head kidney stimulated with Vibrio anguillarum bacterin. AB - In fish, the stress response and their consequences in the immune system have been widely described. Recently, a differential cytokine regulation between rainbow trout (Oncorhynchus mykiss) and gilthead sea bream (Sparus aurata) was reported after treatment with stress hormones together with their receptor antagonists. Nevertheless, there is no evidence of whether antagonists for stress hormone receptors may influence the interaction between hormones and cytokines after bacterial administration. Thus, the aim of our study was to evaluate the cytokine expression in the presence of stress hormones (cortisol, ACTH, adrenaline), hormone receptor antagonists and inactivated Vibrio anguillarum bacterin in rainbow trout and gilthead sea bream head kidney primary cell culture (HKPCC). Mifepristone, spironolactone, propranolol and phentolamine were used to block GR, MR, MC2R, and beta-/alpha-adrenoreceptors. Our results showed an expected increase of the pro-inflammatory and anti-inflammatory response after inactivated V. anguillarum bacterin treatment in both species. Cortisol, ACTH and adrenaline did not modulate the expression of immune-related genes in rainbow trout, while in sea bream cortisol was able to reduce the stimulated gene expression of all cytokines. This effect was only restored to basal expression level in IL-1beta and TNF-alpha by mifepristone. ACTH reduced both pro inflammatory and anti-inflammatory cytokine expression, excluding IL-1beta, only in sea bream. Adrenaline enhanced the expression of IL-1beta and TGF-beta1 stimulated by inactivated V. anguillarum in sea bream, and the effect was diminished by propranolol. In sum, our results confirm that the immunoendocrine differences reported at gene expression profile between two teleost species are also observed after exposure to inactivated V. anguillarum bacterin, suggesting that stress hormones would differentially modulate the immune response against pathogens in teleost species. PMID- 28882799 TI - Transcriptomic profiling of Tibetan highland fish (Gymnocypris przewalskii) in response to the infection of parasite ciliate Ichthyophthirius multifiliis. AB - Gymnocypris przewalskii is a native cyprinid in the Lake Qinghai of the Qinghai Tibetan Plateau. G. przewalskii is highly susceptible to the infection of a parasite, Ichthyophthirius multifiliis, in the artificial propagation and breeding. To better understand the host immune reaction to I. multifiliis infection, we characterize the gene expression profiles in the spleen of healthy and I. multifiliis infected G. przewalskii by RNA-seq. Totally, the transcriptomic analysis produces 463,031,110 high quality reads, which are assembled to 213,538 genes with N50 of 1918 bp and the average length of 1205 bp. Of assembled genes, 90.52% are annotated by public databases. The expression analysis shows 744 genes are significantly changed by the infection of I. multifiliis, which are validated by qRT-PCR with the correlation coefficient of 0.896. The differentially expressed genes are classified into 689 GO terms and 230 KEGG pathways, highlighting the promoted innate immunity in I. multifiliis infected G. przewalskii at 2 days post infection. Our results pinpoint that the up-regulated genes are enriched in TLR signaling pathway, inflammatory response and activation of immune cell migration. On the contrary, complement genes are down-regulated, indicating the evasion of host complement cascades by I. multifiliis. The repressed genes are also enriched in the pathways related to metabolism and endocrine, suggesting the metabolic disturbance in I. multifiliis treated G. przewalskii. In summary, the present study profiles the gene expression signature of G. przewalskii in the responses to I. multifiliis infection, and improves our understanding on molecular mechanisms of host parasite interaction in G. przewalskii, which focuses the crucial function of TLRs, cytokines and complement components in the host defense against I. multifiliis. PMID- 28882800 TI - C1r and C1s from Nile tilapia (Oreochromis niloticus): Molecular characterization, transcriptional profiling upon bacterial and IFN-gamma inductions and potential role in response to bacterial infection. AB - The complement components C1r and C1s play a vital role in immunity with the activation of C1 complex in the classical complement pathway against pathogen infection. In this study, Nile tilapia (Oreochromis niloticus) C1r and C1s orthologs (OnC1r and OnC1s) were identified and characterized. The cDNA of OnC1r and OnC1s ORFs consisted of 1902 bp and 2100 bp of nucleotide sequence encoding polypeptides of 633 and 699 amino acids, respectively. The deduced OnC1r and OnC1s proteins both possessed CUB, EGF, CCP and SP domains, which were significantly homology to teleost. Spatial mRNA expression analysis revealed that the OnC1r and OnC1s were highly expressed in liver. After the in vivo challenges of Streptococcus agalactiae (S. agalactiae) and lipopolysaccharide (LPS), the mRNA expressions of OnC1r and OnC1s were significantly up-regulated in liver and spleen, which were consistent with immunohistochemical detection at the protein level. The up-regulation of OnC1r and OnC1s expressions were also demonstrated in head kidney monocytes/macrophages in vitro stimulated with LPS, S. agalactiae, and recombinant OnIFN-gamma. Taken together, the results of this study indicated that OnC1r and OnC1s were likely to get involved in the immune response of Nile tilapia against bacterial infection. PMID- 28882801 TI - Effect of immune gene silencing in WSSV infected tiger shrimp Penaeus monodon. AB - White spot syndrome virus, continues to cause huge economic loss to aquaculture industry. In the absence of effective therapeutics to control WSSV, it is important to understand the host pathogen interaction at the molecular level. Suppression subtractive hybridization (SSH) cDNA library was constructed which led to identification of several differentially expressed genes in response to WSSV infection in Penaeus monodon. The genes expressed in SSH cDNA library of shrimp gill and gut tissues belonged to a wide range of biological functions. The three differentially expressed genes, Single von Willebrand factor type C domain protein (pmSVC), P53 protein gene (pmP53) and ADP ribosylation factor (pmArf) were up-regulated against WSSV infection and were further characterized by gene silencing to study the role of these shrimp immune genes on WSSV multiplication. The sequence-specific knock down of pmSVC, pmP53 and pmArf using the dsRNA revealed that in pmSVC-dsRNA inoculated shrimps WSSV replication was more with increased viral copy numbers when compared with pmP53-dsRNA and pmArf -dsRNA inoculated shrimps. The varied response of immune genes to WSSV infection, indicated that host genes may either inhibit virus replication to some extent or might act as a target to facilitate viral pathogenesis. PMID- 28882802 TI - Identification of the functional regions of the viral haemorrhagic septicaemia virus (VHSV) NV protein: Variants that improve function. AB - Non-virion (NV) protein is essential for an efficient replication increasing the pathogenicity of the Salmonid novirhabdovirus (formerly IHNV), Piscine novirhabdovirus (formerly VHSV), and Hirame novirhabdovirus (HIRV). The interferon system, apoptosis, and other immune-related genes are modulated by NV to finally induce a deficient antiviral state in the cell. However, little is known about the VHSV NV regions involved in function and location. Here, eight different NV 07.71 fragments and eleven NV 07.71 mutants derived from the region between the two first alpha-helices have been studied in order to establish the mx and il8 transcript levels in ZF4 cells and the subcellular location. As a result, we determined that the N-terminal part of NV preserves the same ability as the wild-type (wt) NV in mx/il8 modulation and it also shares the subcellular location. Among NV mutants, some induced mx upregulation (N34A, C35A, D38A, and S40A) but maintained the il8 levels stable when compared to wt-NV in ZF4. Four NV mutants (D28A, N31A, L33A, and F37A) were not affected by the mutation and showed mx and il8 transcript levels similar to wt-NV. Surprisingly, mutants D36A, R39A, and D41A induced a stronger downregulation of both mx and il8 transcript levels than wt-NV, suggesting that a more stable structure and an improved interaction with ligands could be achieved through these mutations. Amino acids at positions 36 and 39 are conserved among known VHSV NV proteins whereas at position 41 two different amino acids have been described. To date, no natural NV proteins with alanine at positions 36, 39, and 41 have been found. In addition, wt-NV, all NV mutants, and one N-terminal NV fragment were located at cytoplasm with a characteristic pattern, which might support that cytoplasm is the site for interaction with candidate ligands such as PPM1Bb. Taken together, the data presented in this work indicated that NV function relies on the first part of the molecule and is dependent on tertiary structure rather than on the linear one. This study could lead to a better knowledge of VHSV escape from fish antiviral mechanisms as well as to future studies on immune targets. PMID- 28882803 TI - Involvement of the Macrobrachium nipponense rhodanese homologue 2, MnRDH2 in innate immunity and antioxidant defense. AB - In Macrobrachium nipponense, the rhodanese homologue 2 (MnRDH2) gene codes for a single rhodanese domain protein. Considering the lack of information on the biological role of the ubiquitous rhodaneses in invertebrate, we examined the functions of MnRDH2 using both in silico and in vitro approaches. Quantitative PCR analysis of different tissues indicated that expression of MnRDH2 was enriched in hepatopancreas, in which bacterial challenge by Aeromonas hydrophila induced MnRDH2 expression. Knocking down MnRDH2 by RNA interference caused significant accumulations of reactive oxygen species and malondialdehyde (MDA). Using Escherichia coli (DE3), we expressed MnRDH2 and the mutant MnRDH2C78A, in which the predicted catalytic cysteine was mutated to alanine, and found significant rodanese activity of the recombinant MnRDH2 in vitro, but not for the mutant rMnRDH2C78A. We observed that rMnRDH2 was able to significantly increase tolerance of the host bacteria to oxidative stressor phenazine methosulfate. These results suggest that MnRDH2 might have the potential to buffer general levels of oxidants via regulation of redox reactions. In conclusion, our study begins to hint a possible biological functionality of MnRDH2 as a redox switch to activate defensive activities against oxidative damage, which helps host in maintaining the cellular redox balance. These characteristics will facilitate future investigations into the physiological functions for invertebrate rhodanese family genes. PMID- 28882804 TI - ABCB1 and ABCC1-like transporters in immune system cells from sea urchins Echinometra lucunter and Echinus esculentus and oysters Crassostrea gasar and Crassostrea gigas. AB - ABC transporters activity and expression have been associated with the multixenobiotic resistance phenotype (MXR). The activity of these proteins leads to a reduction in the intracellular concentration of several xenobiotics, thus reducing their toxicity. However, little attention has been given to the expression of ABC transporters in marine invertebrates and few studies have investigated their role in immune system cells of sea urchins and shellfish bivalves. The aim of the present study was to investigate the activity of the ABC transporters ABCB1 and ABCC1 in immune system cells of sea urchins (coelomocytes) and oysters (hemocytes) from different climatic regions (Brazil and France). Sea urchins and oysters were collected at Paraiba coast; Brazil (Echinometra lucunter and Crassostrea gasar) and Rade of Brest; France (Echinus esculentus and Crassostrea gigas). Coelomocytes and hemocytes were stained with the ABC transporter substrate calcein-AM and dye accumulation analyzed under flow cytometry. Reversin 205 (ABCB1 transporter blocker) and MK571 (ABCC1 transporter blocker) were used as pharmacological tools to investigate ABC transporter activity. A different pattern of calcein accumulation was observed in coelomocytes: phagocytes > colorless spherulocytes > vibrate cells > red spherulocytes. The treatment with MK571 increased calcein fluorescence levels in coelomocytes from both species. However, reversin 205 treatment was not able to increase calcein fluorescence in E. esculentus coelomocytes. These data suggest that ABCC1-like transporter activity is present in both sea urchin species, but ABCB1-like transporter activity might only be present in E. lucunter coelomocytes. The activity of ABCC1-like transporter was observed in all cell types from both bivalve species. However, reversin 205 only increased calcein accumulation in hyalinocytes of the oyster C. gasar, suggesting the absence of ABCB1-like transporter activity in all other cell types, including hyalinocytes from the oyster C. gigas. Additionally, our results showed that C. gigas exhibited higher activity of ABCC1-like transporter in all hemocyte types than C. gasar. The present work is the first to characterize ABCB1 and ABCC1-like transporter activity in the immune system cells of sea urchins E. lucunter and E. esculentus and oysters. Our findings encourage the performing studies regarding ABC transporters activity/expression in immune system cells form marine invertebrates under stress conditions and the possible use of ABC transporters as biomarkers. PMID- 28882805 TI - Suppressor of cytokine signaling 3 (SOCS3) is related to pro-inflammatory cytokine production and triglyceride deposition in turbot (Scophthalmus maximus). AB - Turbot (Scophthalmus maximus) is an economically important fish that is farmed by aquaculture for human consumption. Aquacultured turbot are commonly fed a high lipid diet; however, this diet causes excessive lipid deposition and the overexpression of pro-inflammatory cytokines. Studies in mammals have indicated that a relationship exists between pro-inflammatory cytokine overexpression and altered lipid metabolism through the activation of suppressor of cytokine signaling 3 (SOCS3). In this study, we investigated the relationship between SOCS3 and triglyceride (TG) deposition and mechanism of SOCS3 activation in farmed turbot fed high-lipid diet (HLD). TG content increased with SOCS3 production, mediated by toll-like receptor-nuclear transcription factor kappa-B (TLR-NFkappaB) signaling in the liver of turbot fed a HLD and in turbot primary liver cells incubated with oleic acid (OA). Overexpression of SOCS3 increased TG deposition via the increased production of mature sterol regulatory element binding protein 1 (m-SREBP-1). Knockdown of SOCS3 in turbot primary liver cells resulted in normalized TG deposition and decreased m-SREBP-1 production. These results suggest that the HLD and OA can induce cytokine expression by activating the TLR-NFkappaB signaling pathways, resulting in increased SOCS3 expression. It is proposed that SOCS3 enhances m-SREBP-1 production, leading to TG deposition. These findings provide important new insights into the relationship between cytokine expression and TG deposition and mechanism of HLD-induced pro inflammatory response, which could help to improve the health of farmed turbot and a better understanding of fish immunity. PMID- 28882806 TI - Modulatory effect of different doses of beta-1,3/1,6-glucan on the expression of antioxidant, inflammatory, stress and immune-related genes of Oreochromis niloticus challenged with Streptococcus iniae. AB - beta-glucans are widely-known immunostimulants that are profusely used in aquaculture industry. The present study was conducted to evaluate the effect of different in-feed doses of beta-1,3/1,6-glucans on the expression of antioxidant and stress-related genes (GST, HSP-70, Vtg), inflammation related genes (Il-8, TNFalpha, CXC-chemokine and CAS) and adaptive immune-related genes (MHC-IIbeta, TLR-7, IgM-H, and Mx) of Oreochromis niloticus challenged and non-challenged with Streptococcus iniae. Six experimental groups were established: non-challenged control (non-supplemented diet), challenged control (non-supplemented diet), non challenged supplemented with 0.1% beta-glucan, challenged supplemented with 0.1% beta-glucan, non-challenged supplemented with 0.2% beta-glucan and challenged supplemented with 0.2% beta-glucan. Fish were fed with beta-glucan for 21 days prior challenge and then sampled after 1, 3 and 7 days post-challenge. In non challenged group, variable effects of the two doses of beta-Glucans on the expression of the studied genes were observed; 0.1% induced higher expression of HSP70, CXC chemokine, MHC-IIbeta and MX genes. Meanwhile, 0.2% induced better effect on the expression of Vtg, TNF-alpha, CAS and IgM-H, and almost equal effects of both doses on GST and IL8. However, with the challenged group, 0.2% beta-Glucans showed better effect than 0.1% at day one post challenge through significant up-regulation of GST, HSP, IL8, TNF-alpha, CXC, and MHC-IIbeta, meanwhile, the effect of 0.1% was only on the expression of HSP70, MHC-IIbeta, and TLR7 at day 3 post challenge. No stimulatory role for both doses of beta Glucans on the expression of almost all genes at day 7 post-challenge. We conclude that both doses of beta-glucan can modulate the antioxidant, inflammation, stress and immune-related genes in Nile tilapia, moreover, 0.2% beta-Glucans showed better protective effect with Streptococcus iniae challange. PMID- 28882807 TI - Atlantic salmon endothelial cells from the heart were more susceptible than fibroblasts from the bulbus arteriosus to four RNA viruses but protected from two viruses by dsRNA pretreatment. AB - Heart diseases caused by viruses are major causes of Atlantic salmon aquaculture loss. Two Atlantic salmon cardiovascular cell lines, an endothelial cell line (ASHe) from the heart and a fibroblast cell line (BAASf) from the bulbus arteriosus, were evaluated for their response to four fish viruses, CSV, IPNV, VHSV IVa and VHSV IVb, and the innate immune agonist, double-stranded RNA mimic poly IC. All four viruses caused cytopathic effects in ASHe and BAASf. However, ASHe was more susceptible to all four viruses than BAASf. When comparing between the viruses, ASHe cells were found to be moderately susceptible to CSV and VHSV IVb, but highly susceptible to IPNV and VHSV IVa induced cell death. All four viruses were capable of propagating in the ASHe cell line, leading to increases in virus titre over time. In BAASf, CSV and IPNV produced more than one log increase in titre from initial infection, but VHSV IVb and IVa did not. When looking at the antiviral response of both cell lines, Mx proteins were induced in ASHe and BAASf by poly IC. All four viruses induced Mx proteins in BAASf, while only CSV and VHSV IVb induced Mx proteins in ASHe. IPNV and VHSV IVa suppressed Mx proteins expression in ASHe. Pretreatment of ASHe with poly IC to allow for Mx proteins accumulation protected the culture from subsequent infections with IPNV and VHSV IVa, resulting in delayed cell death, reduced virus titres and reduced viral proteins expression. These data suggest that endothelial cells potentially can serve as points of infections for viruses in the heart and that two of the four viruses, IPNV and VHSV IVa, have mechanisms to avoid or downregulate antiviral responses in ASHe cells. Furthermore, the high susceptibility of the ASHe cell line to IPNV and VHSV IVa can make it a useful tool for studying antiviral compounds against these viruses and for general detection of fish viruses. PMID- 28882808 TI - Mobile Phone Interventions for Sleep Disorders and Sleep Quality: Systematic Review. AB - BACKGROUND: Although mobile health technologies have been developed for interventions to improve sleep disorders and sleep quality, evidence of their effectiveness remains limited. OBJECTIVE: A systematic literature review was performed to determine the effectiveness of mobile technology interventions for improving sleep disorders and sleep quality. METHODS: Four electronic databases (EBSCOhost, PubMed/Medline, Scopus, and Web of Science) were searched for articles on mobile technology and sleep interventions published between January 1983 and December 2016. Studies were eligible for inclusion if they met the following criteria: (1) written in English, (2) adequate details on study design, (3) focus on sleep intervention research, (4) sleep index measurement outcome provided, and (5) publication in peer-reviewed journals. RESULTS: An initial sample of 2679 English-language papers were retrieved from five electronic databases. After screening and review, 16 eligible studies were evaluated to examine the impact of mobile phone interventions on sleep disorders and sleep quality. These included one case study, three pre-post studies, and 12 randomized controlled trials. The studies were categorized as (1) conventional mobile phone support and (2) utilizing mobile phone apps. Based on the results of sleep outcome measurements, 88% (14/16) studies showed that mobile phone interventions have the capability to attenuate sleep disorders and to enhance sleep quality, regardless of intervention type. In addition, mobile phone intervention methods (either alternatively or as an auxiliary) provide better sleep solutions in comparison with other recognized treatments (eg, cognitive behavioral therapy for insomnia). CONCLUSIONS: We found evidence to support the use of mobile phone interventions to address sleep disorders and to improve sleep quality. Our findings suggest that mobile phone technologies can be effective for future sleep intervention research. PMID- 28882809 TI - The User Knows What to Call It: Incorporating Patient Voice Through User Contributed Tags on a Participatory Platform About Health Management. AB - BACKGROUND: Body listening, described as the act of paying attention to the body's signals and cues, can be an important component of long-term health management. OBJECTIVE: The aim of this study was to introduce and evaluate the Body Listening Project, an innovative effort to engage the public in the creation of a public resource-to leverage collective wisdom in the health domain. This project involved a website where people could contribute their experiences of and dialogue with others concerning body listening and self-management. This article presents an analysis of the tags contributed, with a focus on the value of these tags for knowledge organization and incorporation into consumer-friendly health information retrieval systems. METHODS: First, we performed content analysis of the tags contributed, identifying a set of categories and refining the relational structure of the categories to develop a preliminary classification scheme, the Body Listening and Self-Management Taxonomy. Second, we compared the concepts in the Body Listening and Self-Management Taxonomy with concepts that were automatically identified from an extant health knowledge resource, the Unified Medical Language System (UMLS), to better characterize the information that participants contributed. Third, we employed visualization techniques to explore the concept space of the tags. A correlation matrix, based on the extent to which categories tended to be assigned to the same tags, was used to study the interrelatedness of the taxonomy categories. Then a network visualization was used to investigate structural relationships among the categories in the taxonomy. RESULTS: First, we proposed a taxonomy called the Body Listening and Self-Management Taxonomy, with four meta-level categories: (1) health management strategies, (2) concepts and states, (3) influencers, and (4) health-related information behavior. This taxonomy could inform future efforts to organize knowledge and content of this subject matter. Second, we compared the categories from this taxonomy with the UMLS concepts that were identified. Though the UMLS offers benefits such as speed and breadth of coverage, the Body Listening and Self-Management Taxonomy is more consumer-centric. Third, the correlation matrix and network visualization demonstrated that there are natural areas of ambiguity and semantic relatedness in the meanings of the concepts in the Body Listening and Self-Management Taxonomy. Use of these visualizations can be helpful in practice settings, to help library and information science practitioners understand and resolve potential challenges in classification; in research, to characterize the structure of the conceptual space of health management; and in the development of consumer-centric health information retrieval systems. CONCLUSIONS: A participatory platform can be employed to collect data concerning patient experiences of health management, which can in turn be used to develop new health knowledge resources or augment existing ones, as well as be incorporated into consumer-centric health information systems. PMID- 28882810 TI - Study of Methods for Assessing Research Topic Elicitation and pRioritization (SMARTER): Study Protocol to Compare Qualitative Research Methods and Advance Patient Engagement in Research. AB - BACKGROUND: Involving patients as partners in research is a defining characteristic of patient-centered outcomes research (PCOR). While patients' experiential knowledge of a health condition or treatment may yield research priorities not reflected by researchers and policy makers, the methods for identifying and effectively collaborating with patients are still evolving. Patient registries and crowdsourcing may offer ease of access and convenience to both researchers and patients. Surveys and focus groups, including online modalities, have been described for prioritizing research topics. However, little is known about how these different methods compare in producing consistent priorities and similar perceptions of engagement quality among participants. OBJECTIVE: The aims of this study are (1) to compare how different engagement methods used to elicit patient priorities for research perform as measured by rankings for priorities generated and participant satisfaction; and (2) to determine characteristics of individuals choosing to participate in research prioritization activities. METHODS: Participants in the Back pain Outcomes using Longitudinal Data (BOLD) patient registry, established to evaluate the natural history of back pain among individuals 65 years and older, and participants on the Amazon Mechanical Turk (MTurk) crowdsourcing platform, to provide input on priorities for research via a questionnaire, are invited. For BOLD participants, we subsequently randomize interested respondents to 1 of 3 interactive prioritization activities to further develop priorities: a Delphi panel, an online crowd voting activity, or an in-person facilitated prioritization activity using nominal group technique (NGT). Participants involved in each activity complete a survey to evaluate the quality of the experience and a subset of these participants discuss their experience further in an interview. Descriptive statistics are used to characterize the rankings produced by each method and compare the top 5 rated topics resulting from each prioritization activity. We use rank-ordered logistic regression models to identify associations of the ranked priority topics with baseline patient characteristics. We analyze responses to the evaluation using a mixed-methods approach wherein we tabulate responses to Likert-scale questions and use content analysis to enumerate themes emerging from interviews for the 3 activities. RESULTS: In Phase I, we invite approximately 3000 BOLD participants and 500 Amazon MTurk workers to complete a research topic prioritization survey. Based on these results, we include additional topics into a subsequent prioritization survey. In Phase II, we invite BOLD participants to join 1 of 3 activities: 90 participants for Delphi panel, 100 participants for crowd voting, and 60 participants for focus groups. Of the Phase II participants, 30 will be interviewed to evaluate the activities. CONCLUSIONS: This study informs decisions about how to conduct outreach to patient registry participants for providing input on research priorities, how individuals 65 years and older wish to participate in engagement activities, and how different research prioritization methods compare in terms of rankings generated and participant satisfaction. PMID- 28882811 TI - Effect of Caffeine on Attention and Alertness Measured in a Home-Setting, Using Web-Based Cognition Tests. AB - BACKGROUND: There is an increasing interest among nutritional researchers to perform lifestyle and nutritional intervention studies in a home setting instead of testing subjects in a clinical unit. The term used in other disciplines is 'ecological validity' stressing a realistic situation. This becomes more and more feasible because devices and self-tests that enable such studies are more commonly available. Here, we present such a study in which we reproduced the effect of caffeine on attention and alertness in an at-home setting. OBJECTIVE: The study was aimed to reproduce the effect of caffeine on attention and alertness using a Web-based study environment of subjects, at home, performing different Web-based cognition tests. METHODS: The study was designed as a randomized, placebo-controlled, double-blind, crossover study. Subjects were provided with coffee sachets (2 with and 2 without caffeine). They were also provided with a written instruction of the test days. Healthy volunteers consumed a cup of coffee after an overnight fast. Each intervention was repeated once. Before and 1 hour after coffee consumption subjects performed Web-based cognitive performance tests at home, which measured alertness and attention, established by 3 computerized tests provided by QuantifiedMind. Each test was performed for 5 minutes. RESULTS: Web-based recruitment was fast and efficient. Within 2 weeks, 102 subjects applied, of whom 70 were eligible. Of the 66 subjects who started the study, 53 completed all 4 test sessions (80%), indicating that they were able to perform the do it yourself tests, at home, correctly. The Go-No Go cognition test performed at home showed the same significant improvement in reaction time with caffeine as found in controlled studies in a metabolic ward (P=.02). For coding and N-back the second block was performed approximately 10% faster. No effect was seen on correctness. CONCLUSIONS: The study showed that the effects of caffeine consumption on a cognition test in an at-home setting revealed similar results as in a controlled setting. The Go-No Go test applied showed improved results after caffeine intake, similar as seen in clinical trials. This type of study is a fast, reliable, economical, and easy way to demonstrate effectiveness of a supplement and is rapidly becoming a viable alternative for the classical randomized control trial to evaluate life style and nutritional interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02061982; https://clinicaltrials.gov/ct2/show/NCT02061982 (Archived by WebCite at https://clinicaltrials.gov/ct2/show/NCT02061982). PMID- 28882812 TI - Health Information Technology (HIT) Adaptation: Refocusing on the Journey to Successful HIT Implementation. AB - In past years, policies and regulations required hospitals to implement advanced capabilities of certified electronic health records (EHRs) in order to receive financial incentives. This has led to accelerated implementation of health information technologies (HIT) in health care settings. However, measures commonly used to evaluate the success of HIT implementation, such as HIT adoption, technology acceptance, and clinical quality, fail to account for complex sociotechnical variability across contexts and the different trajectories within organizations because of different implementation plans and timelines. We propose a new focus, HIT adaptation, to illuminate factors that facilitate or hinder the connection between use of the EHR and improved quality of care as well as to explore the trajectory of changes in the HIT implementation journey as it is impacted by frequent system upgrades and optimizations. Future research should develop instruments to evaluate the progress of HIT adaptation in both its longitudinal design and its focus on adaptation progress rather than on one cross sectional outcome, allowing for more generalizability and knowledge transfer. PMID- 28882813 TI - Perceptions of Health-Related Information on Facebook: Cross-Sectional Study Among Vietnamese Youths. AB - BACKGROUND: While health information websites may have previously been the core source of information about health-related conditions on the Internet, social networking sites are increasingly replacing those websites as a source of health related information. The increasingly popularity of social networking sites among the general population has consequential impact on health policies as well as health-related interventions. To date, there remains a paucity of research conducted in developing countries like Vietnam looking at the influence of social networking sites. OBJECTIVE: Our goal is to establish the baseline use of Facebook among Vietnamese youths and establish their perception of the reliability and usefulness of health-related information that they previously encountered while using the social networking site. METHODS: An online cross sectional study was conducted from August 2015 to October 2015. Respondent-driven sampling (RDS) technique was used in the recruitment of participants. Sociodemographic, health status, behaviors, Facebook use and belief of information on Facebook, and interpersonal influence of social network sites were collected via an online structured questionnaire. RESULTS: Among 1080 participants, 72.87% (787/1080) reported being interested in health information on Facebook, and 50.74% (548/1080) and 17.50% (189/1080) perceived the information to be reliable and useful, respectively. A total of 10.93% (118/1080) of the participants also reported that they would follow the health advice they obtained from Facebook. Of significance, 7.13% (77/1080) of the participants also reported peer influences on their behavior. Factors that mediate Vietnamese perceptions of the information online include gender, level of perceived stress, age, educational level, and interpersonal influences from Facebook. CONCLUSIONS: Our study is perhaps one of the first conducted in Vietnam that looks at the relationship between health information on Facebook and factors that might influence young Vietnamese perceptions of the information and the consequential use of that information. PMID- 28882814 TI - Opsin 3 and 4 mediate light-induced pulmonary vasorelaxation that is potentiated by G protein-coupled receptor kinase 2 inhibition. AB - We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the nonvisual G protein-coupled receptor melanopsin (Opsin 4; Opn4). Here we tested the hypothesis that nonvisual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G protein-coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2, as demonstrated with a proximity ligation assay. Light elicited an intensity-dependent relaxation of PAs preconstricted with phenylephrine (PE), with a maximum response between 400 and 460 nm (blue light). Wavelength-specific photorelaxation was attenuated in PAs from Opn4-/- mice and further reduced following shRNA-mediated knockdown of Opn3. Inhibition of GRK2 amplified the response and prevented physiological desensitization to repeated light exposure. Blue light also prevented PE-induced constriction in isolated PAs, decreased basal tone, ablated PE-induced single-cell contraction of PASMCs, and reversed PE-induced depolarization in PASMCs when GRK2 was inhibited. The photorelaxation response was modulated by soluble guanylyl cyclase but not by protein kinase G or nitric oxide. Most importantly, blue light induced significant vasorelaxation of PAs from rats with chronic pulmonary hypertension and effectively lowered pulmonary arterial pressure in isolated intact perfused rat lungs subjected to acute hypoxia. These findings show that functional Opn3 and Opn4 in PAs represent an endogenous "optogenetic system" that mediates photorelaxation in the pulmonary vasculature. Phototherapy in conjunction with GRK2 inhibition could therefore provide an alternative treatment strategy for pulmonary vasoconstrictive disorders. PMID- 28882816 TI - Do patients at risk of infective endocarditis need antibiotics before dental procedures? PMID- 28882815 TI - Childhood tolerance of severe influenza: a mortality analysis in mice. AB - During the 1918 influenza pandemic, children experienced substantially lower mortality than adults, a striking but unexplained finding. Whether this was due to enhanced resistance (reduced virus load) or better tolerance (reduced impact of infection) has not been defined. We found that prepubertal mice infected with H1N1 influenza virus also showed greater survival than infected pubertal mice, despite similar virus loads. Transcriptome profiling of infected lungs identified estrogen as a regulator of susceptibility in both sexes and also linked better survival to late expression of IL-1beta. Blocking puberty with gonadectomy or a gonadotropin-releasing hormone antagonist improved survival. Estrogen or testosterone (which can be converted to estrogen) restored susceptibility of gonadectomized pubertal mice to influenza mortality, but dihydrotestosterone (which cannot be converted to estrogen) did not. Estrogen receptor blockade with fulvestrant in both male and female pubertal mice resulted in improved survival, even when given 3 days after infection. Moreover, late, but not early, IL-1beta neutralization after infection was also protective. These findings indicate that pubertal increases in estrogen in both sexes are associated with increased mortality during influenza. This helps explain the reduced mortality of children seen with influenza in 1918 and might also be relevant to childhood tolerance to many other infectious diseases. PMID- 28882817 TI - Dental procedures, antibiotic prophylaxis, and endocarditis among people with prosthetic heart valves: nationwide population based cohort and a case crossover study. AB - Objective To assess the relation between invasive dental procedures and infective endocarditis associated with oral streptococci among people with prosthetic heart valves.Design Nationwide population based cohort and a case crossover study.Setting French national health insurance administrative data linked with the national hospital discharge database.Participants All adults aged more than 18 years, living in France, with medical procedure codes for positioning or replacement of prosthetic heart valves between July 2008 and July 2014.Main outcome measures Oral streptococcal infective endocarditis was identified using primary discharge diagnosis codes. In the cohort study, Poisson regression models were performed to estimate the rate of oral streptococcal infective endocarditis during the three month period after invasive dental procedures compared with non exposure periods. In the case crossover study, conditional logistic regression models calculated the odds ratio and 95% confidence intervals comparing exposure to invasive dental procedures during the three month period preceding oral streptococcal infective endocarditis (case period) with three earlier control periods.Results The cohort included 138 876 adults with prosthetic heart valves (285 034 person years); 69 303 (49.9%) underwent at least one dental procedure. Among the 396 615 dental procedures performed, 103 463 (26.0%) were invasive and therefore presented an indication for antibiotic prophylaxis, which was performed in 52 280 (50.1%). With a median follow-up of 1.7 years, 267 people developed infective endocarditis associated with oral streptococci (incidence rate 93.7 per 100 000 person years, 95% confidence interval 82.4 to 104.9). Compared with non exposure periods, no statistically significant increased rate of oral streptococcal infective endocarditis was observed during the three months after an invasive dental procedure (relative rate 1.25, 95% confidence interval 0.82 to 1.82; P=0.26) and after an invasive dental procedure without antibiotic prophylaxis (1.57, 0.90 to 2.53; P=0.08). In the case crossover analysis, exposure to invasive dental procedures was more frequent during case periods than during matched control periods (5.1% v 3.2%; odds ratio 1.66, 95% confidence interval 1.05 to 2.63; P=0.03).Conclusion Invasive dental procedures may contribute to the development of infective endocarditis in adults with prosthetic heart valves. PMID- 28882818 TI - Prospective Association of Physical Activity and Heart Failure Hospitalizations Among Black Adults With Normal Ejection Fraction: The Jackson Heart Study. AB - BACKGROUND: Given high rates of obesity, hypertension, and diabetes mellitus, black persons are at risk to develop heart failure. The association of moderate to vigorous physical activity (MVPA) and heart failure in black adults is underresearched. The purpose of this study was to explore whether greater MVPA was associated with lower risk of heart failure hospitalizations (HFHs) among black adults with normal ejection fractions. METHODS AND RESULTS: We performed a prospective analysis of 4066 black adults who participated in the Jackson Heart Study and who had physical activity measured, had normal ejection fraction on 2 dimensional echocardiograms, and were followed for 7 years for incident HFH. We used Cox proportional regression analyses adjusted for age, sex, body mass index, smoking status, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, coronary heart disease, atrial fibrillation, and chronic kidney disease and examined effect modification by sex and body mass index. Of the eligible population, 1925 participants, according to the duration of MVPA, had poor health (0 minutes/week), 1332 had intermediate health (1-149 minutes/week), and 809 had ideal health (>=150 minutes/week). There were 168 incident HFHs. MVPA for intermediate and ideal health was associated with decreasing risk of incident HFH (hazard ratio: 0.70 [95% confidence interval, 49-1.00] and 0.35 [95% confidence interval, 0.19-0.64], respectively; Ptrend=0.003). The full model revealed hazard ratios of 0.74 [95% confidence interval, 0.52-1.07] and 0.41 [95% confidence interval, 0.22-0.74], respectively. There was no effect modification between MVPA and body mass index or sex on incident HFH. CONCLUSIONS: A dose-response relationship between increasing levels of MVPA and protection from incident HFH was found in black men and women with normal ejection fractions. PMID- 28882819 TI - Cardiomyocyte-Specific Telomere Shortening is a Distinct Signature of Heart Failure in Humans. AB - BACKGROUND: Telomere defects are thought to play a role in cardiomyopathies, but the specific cell type affected by the disease in human hearts is not yet identified. The aim of this study was to systematically evaluate the cell type specificity of telomere shortening in patients with heart failure in relation to their cardiac disease, age, and sex. METHODS AND RESULTS: We studied cardiac tissues from patients with heart failure by utilizing telomere quantitative fluorescence in situ hybridization, a highly sensitive method with single-cell resolution. In this study, total of 63 human left ventricular samples, including 37 diseased and 26 nonfailing donor hearts, were stained for telomeres in combination with cardiomyocyte- or alpha-smooth muscle cell-specific markers, cardiac troponin T, and smooth muscle actin, respectively, and assessed for telomere length. Patients with heart failure demonstrate shorter cardiomyocyte telomeres compared with nonfailing donors, which is specific only to cardiomyocytes within diseased human hearts and is associated with cardiomyocyte DNA damage. Our data further reveal that hypertrophic hearts with reduced ejection fraction exhibit the shortest telomeres. In contrast to other reported cell types, no difference in cardiomyocyte telomere length is evident with age. However, under the disease state, telomere attrition manifests in both young and older patients with cardiac hypertrophy. Finally, we demonstrate that cardiomyocyte-telomere length is better sustained in women than men under diseased conditions. CONCLUSIONS: This study provides the first evidence of cardiomyocyte-specific telomere shortening in heart failure. PMID- 28882821 TI - Government needs coherent policy to tackle rising clinical negligence costs, says financial watchdog. PMID- 28882820 TI - High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease. AB - BACKGROUND: Atherosclerosis is an inflammatory lipid disorder and the main underlying pathology of acute ischemic events. Despite a vast amount of data from murine atherosclerosis models, evidence of B-cell involvement in human atherosclerotic disease is limited. We therefore investigated the association of circulating B-cell subtypes with the occurrence of secondary cardiovascular events in advanced atherosclerotic disease. METHODS AND RESULTS: This cohort study consists of 168 patients who were included in the Athero-Express biobank between 2009 and 2011. Before surgery, peripheral blood mononuclear cells were isolated and stored in liquid nitrogen. After gentle thawing of the peripheral blood mononuclear cells, different B-cell subtypes including naive, (un)switched memory, and CD27+CD43+ B1-like B cells, were analyzed by flow cytometry. Univariable and multivariable Cox proportional hazard models were used to analyze associations between B-cell subtypes, circulating antibodies and secondary cardiovascular manifestations during the 3-year follow-up period. Mean age was 70.1+/-9.6 years, males represented 62.8% of the population, and 54 patients had secondary manifestations during follow-up. High numbers of unswitched memory cells were protective against secondary outcome (hazard ratio, 0.30 [95% CI, 0.13 0.69]; P<0.01). Similar results were obtained for the switched memory cells that also showed to be protective against secondary outcome (hazard ratio, 0.33 [95% CI, 0.14-0.77]; P=0.01). CONCLUSIONS: A high number of (un)switched memory B cells is associated with better outcome following carotid artery endarterectomy. These findings suggest a potential role for B-cell subsets in prediction and prevention of secondary cardiovascular events in patients with atherosclerosis. PMID- 28882822 TI - Both NHERF3 and NHERF2 are necessary for multiple aspects of acute regulation of NHE3 by elevated Ca2+, cGMP, and lysophosphatidic acid. AB - The intestinal epithelial brush border Na+/H+ exchanger NHE3 accounts for a large component of intestinal Na absorption. NHE3 is regulated during digestion by signaling complexes on its COOH terminus that include the four multi-PDZ domain containing NHERF family proteins. All bind to NHE3 and take part in different aspects of NHE3 regulation. Because the roles of each NHERF appear to vary on the basis of the cell model or intestinal segment studied and because of our recent finding that a NHERF3-NHERF2 heterodimer appears important for NHE3 regulation in Caco-2 cells, we examined the role of NHERF3 and NHERF2 in C57BL/6 mouse jejunum using homozygous NHERF2 and NHERF3 knockout mice. NHE3 activity was determined with two-photon microscopy and the dual-emission pH-sensitive dye SNARF-4F. The jejunal apical membrane of NHERF3-null mice appeared similar to wild-type (WT) mice in surface area, microvillus number, and height, which is similar to results previously reported for jejunum of NHERF2-null mice. NHE3 basal activity was not different from WT in either NHERF2- or NHERF3-null jejunum, while d-glucose stimulated NHE3 activity was reduced in NHERF2, but similar to WT in NHERF3 KO. LPA stimulation and UTP (elevated Ca2+) and cGMP inhibition of NHE3 were markedly reduced in both NHERF2- and NHERF3-null jejunum. Forskolin inhibited NHE3 in NHERF3-null jejunum, but the extent of inhibition was reduced compared with WT. The forskolin inhibition of NHE3 in NHERF2-null mice was too inconsistent to determine whether there was an effect and whether it was altered compared with the WT response. These results demonstrate similar requirement for NHERF2 and NHERF3 in mouse jejunal NHE3 regulation by LPA, Ca2+, and cGMP. The explanation for the similarity is not known but is consistent with involvement of a brush border NHERF3-NHERF2 heterodimer or sequential NHERF-dependent effects in these aspects of NHE3 regulation. NEW & NOTEWORTHY NHERF2 and NHERF3 are apical membrane multi-PDZ domain-containing proteins that are involved in regulation of intestinal NHE3. This study demonstrates that NHERF2 and NHERF3 have overlapping roles in NHE3 stimulation by LPA and inhibition by elevated Ca2+ and cGMP. These results are consistent with their role being as a NHERF3-NHERF2 heterodimer or via sequential NHERF-dependent signaling steps, and they begin to clarify a role for multiple NHERF proteins in NHE3 regulation. PMID- 28882823 TI - The antioxidant glutathione protects against enteric neuron death in situ, but its depletion is protective during colitis. AB - Enteric glia play an important neuroprotective role in the enteric nervous system (ENS) by producing neuroprotective compounds such as the antioxidant reduced glutathione (GSH). The specific cellular pathways that regulate glial production of GSH and how these pathways are altered during, or contribute to, neuroinflammation in situ and in vivo are not fully understood. We investigated this issue using immunohistochemistry to localize GSH synthesis enzymes within the myenteric plexus and tested how the inhibition of GSH synthesis with the selective inhibitor l-buthionine sulfoximine impacts neuronal survival and inflammation. Both enteric glia and neurons express the cellular machinery necessary for GSH synthesis. Furthermore, glial GSH synthesis is necessary for neuronal survival in isolated preparations of myenteric plexus. In vivo depletion of GSH does not induce colitis but alters myenteric plexus neuronal phenotype and survival. Importantly, global depletion of glutathione is protective against some macroscopic and microscopic measures of colonic inflammation. Together, our data highlight the heterogeneous roles of GSH in the myenteric plexus of the ENS and during gastrointestinal inflammation. NEW & NOTEWORTHY Our results show that both enteric glia and neurons express the cellular machinery necessary for glutathione (GSH) synthesis and that glial GSH synthesis is necessary for neuronal survival in isolated enteric nervous system (ENS) preparations. In vivo depletion of GSH with the selective inhibitor l-buthionine sulfoximine is not sufficient to induce inflammation but does alter neuronal neurochemical composition and survival. Together, our data highlight novel heterogeneous roles for GSH in the ENS and during gastrointestinal inflammation. PMID- 28882824 TI - A physics-based model for maintenance of the pH gradient in the gastric mucus layer. AB - It is generally accepted that the gastric mucus layer provides a protective barrier between the lumen and the mucosa, shielding the mucosa from acid and digestive enzymes and preventing autodigestion of the stomach epithelium. However, the precise mechanisms that contribute to this protective function are still up for debate. In particular, it is not clear what physical processes are responsible for transporting hydrogen protons, secreted within the gastric pits, across the mucus layer to the lumen without acidifying the environment adjacent to the epithelium. One hypothesis is that hydrogen may be bound to the mucin polymers themselves as they are convected away from the mucosal surface and eventually degraded in the stomach lumen. It is also not clear what mechanisms prevent hydrogen from diffusing back toward the mucosal surface, thereby lowering the local pH. In this work we investigate a physics-based model of ion transport within the mucosal layer based on a Nernst-Planck-like equation. Analysis of this model shows that the mechanism of transporting protons bound to the mucus gel is capable of reproducing the trans-mucus pH gradients reported in the literature. Furthermore, when coupled with ion exchange at the epithelial surface, our analysis shows that bicarbonate secretion alone is capable of neutralizing the epithelial pH, even in the face of enormous diffusive gradients of hydrogen. Maintenance of the pH gradient is found to be robust to a wide array of perturbations in both physiological and phenomenological model parameters, suggesting a robust physiological control mechanism.NEW & NOTEWORTHY This work combines modeling techniques based on physical principles, as well as novel numerical simulations to test the plausibility of one hypothesized mechanism for proton transport across the gastric mucus layer. Results show that this mechanism is able to maintain the extreme pH gradient seen in in vivo experiments and suggests a highly robust regulation mechanism to maintain this gradient in the face of dynamic lumen composition. PMID- 28882825 TI - Hepatocyte nuclear factor 4alpha regulates the expression of intestinal epithelial Na+/H+ exchanger isoform 3. AB - Na+/H+ exchanger isoform 3 (NHE3) plays a key role in coupled electroneutral NaCl absorption in the mammalian intestine. Reduced NHE3 expression or function has been implicated in the pathogenesis of diarrhea associated with inflammatory bowel disease (IBD) or enteric infections. Our previous studies revealed transcriptional regulation of NHE3 by various agents such as TNF-alpha, IFN gamma, and butyrate involving transcription factors Sp1 and Sp3. In silico analysis revealed that the NHE3 core promoter also contains a hepatocyte nuclear factor 4alpha (HNF-4alpha) binding site that is evolutionarily conserved in several species suggesting that HNF-4alpha has a role in NHE3 regulation. Nhe3 mRNA levels were reduced in intestine-specific Hnf4alpha-null mice. However, detailed mechanisms of NHE3 regulation by HNF-4alpha are not known. We investigated the regulation of NHE3 gene expression by HNF-4alpha in vitro in the human intestinal epithelial cell line C2BBe1 and in vivo in intestine-specific Hnf4alpha-null ( Hnf4alphaDeltaIEpC) and control ( Hnf4alphafl/fl) mice. HNF 4alpha knockdown by short interfering RNA in C2BBe1 cells significantly decreased NHE3 mRNA and NHE3 protein levels. Gel mobility shift and chromatin immunoprecipitation assays revealed that HNF-4alpha directly interacts with the HNF-4alpha motif in the NHE3 core promoter. Site-specific mutagenesis on the HNF 4alpha motif decreased, whereas ectopic overexpression of HNF-4alpha increased, NHE3 promoter activity. Furthermore, loss of HNF-4alpha in Hnf4alphaDeltaIEpC mice decreased colonic Nhe3 mRNA and NHE3 protein levels. Our results demonstrate a novel role for HNF-4alpha in basal regulation of NHE3 expression. These studies represent an important and novel target for therapeutic intervention in IBD associated diarrhea. NEW & NOTEWORTHY Our studies for the first time show that hepatocyte nuclear factor 4alpha directly regulates NHE3 promoter activity and its basal expression in the intestine. PMID- 28882827 TI - Treatment of depression in schizophrenia: systematic review and meta-analysis. AB - BackgroundDepression in schizophrenia predicts poor outcomes, including suicide, yet the effectiveness of antidepressants for its treatment remains uncertain.AimsTo synthesise the evidence of the effectiveness of antidepressants for the treatment of depression in schizophrenia.MethodMultiple databases were searched and inclusion criteria included participants aged over 18 years with schizophrenia or related psychosis with a depressive episode. Papers were quality assessed used the Cochrane risk bias tool. Meta-analyses were performed for risk difference and standardised mean difference of all antidepressants, antidepressant class and individual antidepressant where sufficient studies allowed.ResultsA total of 26 moderate- to low-quality trials met inclusion criteria. In meta-analysis a significant risk difference was found in favour of antidepressant treatment, with a number needed to treat of 5 (95% CI 4-9). Studies using tools specifically designed to assess depression in schizophrenia showed a larger effect size. However, after sensitivity analysis standardised mean difference of all antidepressants did not show a statistically significant improvement in depression score at end-point, neither did any individual antidepressant class.ConclusionsAntidepressants may be effective for the treatment of depression in schizophrenia, however, the evidence is mixed and conclusions must be qualified by the small number of low- or moderate-quality studies. Further sufficiently powered, high-quality studies are needed. PMID- 28882826 TI - Improving life expectancy in people with serious mental illness: should we place more emphasis on primary prevention? AB - People with serious mental illness have a reduced life expectancy that is partly attributable to increased cardiovascular disease. One approach to address this is regular physical health monitoring. However, physical health monitoring is poorly implemented in everyday clinical practice and there is little evidence to suggest that it improves physical health. We argue that greater emphasis should be placed on primary prevention strategies such as assertive smoking cessation, dietary and exercise interventions and more judicious psychotropic prescribing. PMID- 28882828 TI - Systematic review and meta-analysis of factors that help or hinder treatment decision-making capacity in psychosis. AB - BackgroundThe evidence on factors that may influence treatment decisional capacity ('capacity') in psychosis has yet to be comprehensively synthesised, which limits the development of effective strategies to improve or support it.AimsTo determine the direction, magnitude and reliability of the relationship between capacity in psychosis and a range of clinical, demographic and treatment related factors, thus providing a thorough synthesis of current knowledge.MethodWe conducted a systematic review, meta-analytical and narrative synthesis of factors that help or hinder treatment decision-making capacity in psychosis, assessing the direction, magnitude, significance and reliability of reported associations.ResultsWe identified 23 relevant studies (n = l823). Psychotic symptoms had small, moderate and strong associations with appreciation, understanding and reasoning respectively. Both verbal cognitive functioning and duration of education had small to moderate correlations with understanding and reasoning. Better capacity was also associated with better insight, better metacognitive ability, higher anxiety and lower perceived coercion. No linear relationship with depression was observed. Interventions linked to improved capacity over time were in-patient care, information simplification, shared decision-making and metacognitive training.ConclusionsAlthough much is known about the role of symptoms and other clinical variables, effective and acceptable psychological interventions to support capacity in this group are lacking. PMID- 28882829 TI - Childhood cognitive development in 22q11.2 deletion syndrome: case-control study. AB - Background22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of childhood as well as adult psychiatric disorders, in particular schizophrenia. Childhood cognitive deterioration in 22q11.2DS has previously been reported, but only in studies lacking a control sample.AimsTo compare cognitive trajectories in children with 22q11.2DS and unaffected control siblings.MethodA longitudinal study of neurocognitive functioning (IQ, executive function, processing speed and attention) was conducted in children with 22q11.2DS (n = 75, mean age time 1 (T1) 9.9, time 2 (T2) 12.5) and control siblings (n = 33, mean age T1 10.6, T2 13.4).ResultsChildren with 22q11.2DS exhibited deficits in all cognitive domains. However, mean scores did not indicate deterioration. When individual trajectories were examined, some participants showed significant decline over time, but the prevalence was similar for 22q11.2DS and control siblings. Findings are more likely to reflect normal developmental fluctuation than a 22q11.2DS-specific abnormality.ConclusionsChildhood cognitive deterioration is not associated with 22q11.2DS. Contrary to previous suggestions, we believe it is premature to recommend repeated monitoring of cognitive function for identifying individual children with 22q11.2DS at high risk of developing schizophrenia. PMID- 28882830 TI - Autobiographical memory: a candidate latent vulnerability mechanism for psychiatric disorder following childhood maltreatment. AB - BackgroundAltered autobiographical memory (ABM) functioning has been implicated in the pathogenesis of depression and post-traumatic stress disorder and may represent one mechanism by which childhood maltreatment elevates psychiatric risk.AimsTo investigate the impact of childhood maltreatment on ABM functioning.MethodThirty-four children with documented maltreatment and 33 matched controls recalled specific ABMs in response to emotionally valenced cue words during functional magnetic resonance imaging.ResultsChildren with maltreatment experience showed reduced hippocampal and increased middle temporal and parahippocampal activation during positive ABM recall compared with peers. During negative ABM recall they exhibited increased amygdala activation, and greater amygdala connectivity with the salience network.ConclusionsChildhood maltreatment is associated with altered ABM functioning, specifically reduced activation in areas encoding specification of positive memories, and greater activation of the salience network for negative memories. This pattern may confer latent vulnerability to future depression and post-traumatic stress disorder. PMID- 28882831 TI - Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study. AB - Objective To determine if drugs approved through the Food and Drug Administration's expedited development and review pathways have different rates of safety related label changes after approval compared with drugs approved through standard non-expedited pathways.Design Retrospective cohort study.Setting FDA public records, January 1997 to April 2016.Participants 382 FDA approved drugs.Main outcome measures The number of times a particular safety section of a label (boxed warning, contraindication, warning, precaution, or adverse reaction) was changed during a drug's time on the market. The relative rate of safety related label changes per year for expedited pathway and non-expedited pathway drugs was compared by forming matched pairs of drugs in the same therapeutic class that were approved within three years of each other.Results Among the 382 eligible new drugs, 135 (35%) were associated with an expedited development or review pathway, and matches were available for 96 (71%). The matched pairs were associated with a total of 1710 safety related label changes during the study period. Expedited pathway drugs were characterized by a rate of 0.94 safety related label changes for each drug per year, compared with 0.68 safety related label changes per year for non-expedited pathway drugs (rate ratio 1.38, 95% confidence interval 1.25 to 1.52). Compared with non-expedited pathway drugs, expedited pathway drugs had a 48% higher rate of changes to boxed warnings and contraindications, the two most clinically important categories of safety warnings (1.48, 95% confidence interval 1.07 to 2.06). A qualitative review of changes to the boxed warning sections revealed that less than 5% (3/67) were changed to describe reduced risks for patients.Conclusions Expedited development and regulatory review pathways can accelerate the availability of new drugs, but drugs approved through these pathways are associated with increased safety related label changes after approval, particularly for the types of changes representing the highest risk warnings. To inform appropriate policy interventions, additional research should explore the causal factors contributing to these different rates. PMID- 28882832 TI - Checking in: T cells against multiple myeloma. PMID- 28882833 TI - Ticagrelor breaks up the tumor-platelet party. PMID- 28882834 TI - Anemia and bleeding in thrombocytopenic patients. PMID- 28882835 TI - Haplo, we have a problem. PMID- 28882836 TI - The beauty and the beast: lymphoma-like morphology of myeloid blast phase in CML. PMID- 28882837 TI - Sickle cell trait with beta-thalassemia, elliptocytosis, and thrombocytosis. PMID- 28882838 TI - New settlement procedures: changing the way the NHS resolves negligence claims. PMID- 28882839 TI - Preparing for what the reporting checklists will not tell you: the PREPARE Trial guide for planning clinical research to avoid research waste. PMID- 28882840 TI - Influence of a GSK3beta phosphorylation site within the proximal C-terminus of Neurofilament-H on neurofilament dynamics. AB - Phosphorylation of the C-terminal tail of the heavy neurofilament subunit (NF-H) impacts neurofilament (NF) axonal transport and residence within axons by fostering NF-NF associations that compete with transport. We tested the role of phosphorylation of a GSK-3beta consensus site (S493) located in the proximal portion of the NF-H tail in NF dynamics by transfection of NB2a/d1 cells with NF H, where S493 was mutated to aspartic acid (S493D) or to alanine (S493A) to mimic constitutive phosphorylation and non-phosphorylation. S493D underwent increased transport into axonal neurites, while S493A displayed increased perikaryal NF aggregates that were decorated by anti-kinesin. Increased levels of S493A co precipitated with anti-kinesin indicating that reduced transport of S493A was not due to reduced kinesin association but due to premature NF-NF interactions within perikarya. S493D displayed increased phospho-immunoreactivity within axonal neurites at downstream C-terminal sites attributable to mitogen-activated protein kinase and cyclin-dependent kinase 5. However, S493D was more prone to proteolysis following kinase inhibition, suggesting that S493 phosphorylation is an early event that alters sidearm configuration in a manner that promotes appropriate NF distribution. We propose a novel model for sidearm configuration. PMID- 28882841 TI - Quantitative analysis of mechanical force required for cell extrusion in zebrafish embryonic epithelia. AB - When cells in epithelial sheets are damaged by intrinsic or extrinsic causes, they are eliminated by extrusion from the sheet. Cell extrusion, which is required for maintenance of tissue integrity, is the consequence of contraction of actomyosin rings, as demonstrated by both molecular/cellular biological experimentation and numerical simulation. However, quantitative evaluation of actomyosin contraction has not been performed because of the lack of a suitable direct measurement system. In this study, we developed a new method using a femtosecond laser to quantify the contraction force of the actomyosin ring during cell extrusion in zebrafish embryonic epithelia. In this system, an epithelial cell in zebrafish embryo is first damaged by direct femtosecond laser irradiation. Next, a femtosecond laser-induced impulsive force is loaded onto the actomyosin ring, and the contraction force is quantified to be on the order of kPa as a unit of pressure. We found that cell extrusion was delayed when the contraction force was slightly attenuated, suggesting that a relatively small force is sufficient to drive cell extrusion. Thus, our method is suitable for the relative quantitative evaluation of mechanical dynamics in the process of cell extrusion, and in principle the method is applicable to similar phenomena in different tissues and organs of various species. PMID- 28882843 TI - Stop bombarding public with offers of bigger portions, say campaigners. PMID- 28882845 TI - Abnormalities on computed tomography of the pancreas. PMID- 28882846 TI - People who face the bereavement of a partner with dementia have poorer mental health than those whose partners are dying from other diseases. PMID- 28882847 TI - Epigenetic regulation of left-right asymmetry by DNA methylation. AB - DNA methylation is a major epigenetic modification; however, the precise role of DNA methylation in vertebrate development is still not fully understood. Here, we show that DNA methylation is essential for the establishment of the left-right (LR) asymmetric body plan during vertebrate embryogenesis. Perturbation of DNA methylation by depletion of DNA methyltransferase 1 (dnmt1) or dnmt3bb.1 in zebrafish embryos leads to defects in dorsal forerunner cell (DFC) specification or collective migration, laterality organ malformation, and disruption of LR patterning. Knockdown of dnmt1 in Xenopus embryos also causes similar defects. Mechanistically, loss of dnmt1 function induces hypomethylation of the lefty2 gene enhancer and promotes lefty2 expression, which consequently represses Nodal signaling in zebrafish embryos. We also show that Dnmt3bb.1 regulates collective DFC migration through cadherin 1 (Cdh1). Taken together, our data uncover dynamic DNA methylation as an epigenetic mechanism to control LR determination during early embryogenesis in vertebrates. PMID- 28882849 TI - Pediatric Hospitalist Comanagement Survey of Clinical and Billing Practices. AB - Surgical comanagement is an increasingly common practice in pediatric hospital medicine. Information about the structure and financing of such care is limited. The aim of the researchers for this study was to investigate pediatric hospitalist surgical comanagement models and to assess pediatric hospitalist familiarity with and patterns of billing for surgical patients. We conducted a cross-sectional cohort web-based survey of pediatric hospitalists using the American Academy of Pediatrics' Section on Hospital Medicine listserv. In our study (N = 133), we found wide variation in our cohort in surgical patient practice management, including program structure, individual billing practices, and knowledge regarding billing practices. Even for pediatric hospitalists with comanagement service agreements between surgeons and pediatric hospitalists, there was no increased awareness or knowledge about reimbursement or billing for surgical patients. This global lack of knowledge in our small but diverse sample suggests that billing resources and training for pediatric hospitalists practicing comanagement of surgical patients are needed. PMID- 28882848 TI - Orbital recurrence of iris melanoma 21 years after enucleation. AB - We present the case of a 56-year-old man who developed a neoplasm of epithelioid histology in his anophthalmic left orbit 21 years after he underwent enucleation for a spindle cell iris melanoma. The recurrent tumour was managed by orbital exenteration. Neither further recurrence nor metastasis was diagnosed over a 5 year follow-up period. This case, along with five other similar cases in the literature,1-3 emphasises the importance of long-term follow-up after treatment of iris melanoma. PMID- 28882850 TI - Two new drugs for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease that causes inflammation and destruction of the joints.1-3 It can also affect the eyes, the heart and the lungs and is associated with significant disability and increased mortality. RA is estimated to affect just under 1% of the population aged over 16 years, equating to more than 400,000 people in the UK.4 ?Baricitinib (Olumiant) and ?tofacitinib (Xeljanz) were launched in the UK in April 2017 and represent a new therapeutic class of medicines known as targeted synthetic disease modifying antirheumatic drugs.5,6 Here, we review the evidence for the safety and effectiveness of these new oral agents. PMID- 28882851 TI - Managing scarlet fever. AB - Scarlet fever, an infection caused by toxin-producing strains of Streptococcus pyogenes, was associated with high levels of morbidity and mortality when epidemics were common in the 18th and 19th centuries throughout Europe and the USA.1 Although this disease nearly disappeared during the 20th century, several countries, including the UK, have recently experienced a re-emergence of scarlet fever.1-3 However, the reason for these new outbreaks remains unclear.1,4 Despite a general move to reduce the use of antibiotics for many mild self-limiting infections (e.g. tonsillitis, sinusitis), national guidance recommends treating people with scarlet fever with antibiotics regardless of severity of illness to speed recovery, to reduce the length of time the infection is contagious and to reduce the risk of complications.5,6 Here, we discuss the management of scarlet fever in the UK. PMID- 28882852 TI - Human seroprevalence of Borrelia miyamotoi in Manitoba, Canada, in 2011-2014: a cross-sectional study. AB - BACKGROUND: Hard tick-borne relapsing fever caused by Borrelia miyamotoi has been reported in Russia, the Netherlands, Germany, Japan and the northeastern and upper midwestern United States. We sought to investigate the presence of B. miyamotoi infection in humans in Manitoba, Canada. METHODS: Two hundred fifty sera collected from residents of Manitoba with suspected Lyme disease between 2011 and 2014 were tested for Borrelia burgdorferi antibody using a C6 peptide enzyme-linked immunosorbent assay (ELISA) followed by Western blot. Residual sera were then anonymized, stored at -80 degrees C and subsequently thawed and tested for B. miyamotoi antibody using a 2-step glycerosphosphodiester phosphodiesterase based ELISA and Western blot assay. RESULTS: Twenty-four of the 250 (9.6%) sera tested positive for B. miyamotoi immunoglobulin G. Participants who were B. miyamotoi seropositive were predominantly male (54%) and younger on average than those who were seronegative (32 and 44 yr of age, respectively). Participants who were seropositive for B. burgdorferi were significantly more likely to be B. miyamotoi seropositive than those who were B. burgdorferi seronegative (20.3% v. 6.6%, respectively, odds ratio 3.6, 95% confidence interval 1.5-8.5). INTERPRETATION: This initial report of human B. miyamotoi infection in Canada should raise awareness of hard tick-borne relapsing fever among clinicians and residents of areas in Canada and western North America where Lyme disease is endemic. PMID- 28882853 TI - Neuronal inhibition of the autophagy nucleation complex extends life span in post reproductive C. elegans. AB - Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen. From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4 Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1, strongly extend both life span and health span. Furthermore, our data demonstrate that the improvements in health and longevity are mediated through the neurons, resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction. PMID- 28882855 TI - Over half of GPs are prepared to close their lists to new patients, says BMA. PMID- 28882854 TI - Mutation of Arabidopsis SMC4 identifies condensin as a corepressor of pericentromeric transposons and conditionally expressed genes. AB - In eukaryotes, transcriptionally inactive loci are enriched within highly condensed heterochromatin. In plants, as in mammals, the DNA of heterochromatin is densely methylated and wrapped by histones displaying a characteristic subset of post-translational modifications. Growing evidence indicates that these chromatin modifications are not sufficient for silencing. Instead, they are prerequisites for further assembly of higher-order chromatin structures that are refractory to transcription but not fully understood. We show that silencing of transposons in the pericentromeric heterochromatin of Arabidopsis thaliana requires SMC4, a core subunit of condensins I and II, acting in conjunction with CG methylation by MET1 (DNA METHYLTRANSFERASE 1), CHG methylation by CMT3 (CHROMOMETHYLASE 3), the chromatin remodeler DDM1 (DECREASE IN DNA METHYLATION 1), and histone modifications, including histone H3 Lys 27 monomethylation (H3K27me1), imparted by ATXR5 and ATXR6. SMC4/condensin also acts within the mostly euchromatic chromosome arms to suppress conditionally expressed genes involved in flowering or DNA repair, including the DNA glycosylase ROS1, which facilitates DNA demethylation. Collectively, our genome-wide analyses implicate condensin in the suppression of hundreds of loci, acting in both DNA methylation dependent and methylation-independent pathways. PMID- 28882856 TI - Contemporary Management of Hepatitis C in Patients with CKD. PMID- 28882858 TI - WEB Treatment of Ruptured Intracranial Aneurysms: A Single-Center Cohort of 100 Patients. AB - BACKGROUND AND PURPOSE: The Woven EndoBridge device was recently introduced for the intrasaccular treatment of wide-neck aneurysms without the need for adjunctive devices. We present our results of the primary treatment of ruptured aneurysms with the Woven EndoBridge regardless of location or neck size. MATERIALS AND METHODS: Between February 2015 and April 2017, 100 ruptured aneurysms were selectively treated with the Woven EndoBridge. No supporting stents or balloons were used. There were 71 women treated (mean patient age, 59 years; median age, 60 years; range, 23-82 years). RESULTS: The mean aneurysm size was 5.6 mm (range, 3-13 mm), and 42 aneurysms were <=4 mm. Sixty-six aneurysms (66%) had a wide neck, defined as >=4 mm or a dome-neck ratio <=1.5. There was 1 procedural rupture without sequelae. In 9 patients (9%), thromboembolic complications occurred. One poor grade patient died; neurologic deficits remained in 3. Overall treatment-related morbidity-mortality was 4% (4 of 100; 95% CI, 1.2%-10.2%).Two of 100 aneurysms were initially incompletely occluded and were additionally treated early after initial intervention. Of 80 eligible patients, 74 (93%) had 3-month angiographic follow-up. Fifty-four aneurysms (73%) were completely occluded, 17 (23%) had a small neck remnant, and 3 (4%) were incompletely occluded. One patient was additionally treated with a second Woven EndoBridge, and in 2 patients, additional treatment is scheduled. The overall reopening/retreatment rate was 6.8% (5 of 74; 95% CI, 2.6%-15.2%). There were no rebleeds during follow-up. CONCLUSIONS: Treatment of small ruptured aneurysms with the Woven EndoBridge was safe and effective. The Woven EndoBridge proved to be a valuable alternative to coils without the need for stents or balloons. PMID- 28882857 TI - Effect of Sofosbuvir-Based Hepatitis C Virus Therapy on Kidney Function in Patients with CKD. AB - BACKGROUND AND OBJECTIVES: Hepatitis C virus infection is common in patients with CKD and leads to accelerated progression to ESRD. Sofosbuvir is a potent direct acting antiviral therapy against hepatitis C virus; however, there are concerns about its safety in patients with CKD. The objective of our study was to determine the safety and efficacy of sofosbuvir in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied a retrospective observational cohort of patients with CKD defined by eGFR<60 ml/min per 1.73 m2, >=30 mg albuminuria per 1 g creatinine, or >=200 mg proteinuria per 1 g creatinine who received sofosbuvir-based therapy in a large health care system. Regression models were constructed to predict likelihood of sustained virologic response, detect adverse events, and examine changes in eGFR from baseline to follow-up. RESULTS: Ninety-eight patients with CKD (42% stage 1 or 2 CKD and 58% stage 3 CKD) were included. Mean age was 62 years old, 78% were men, and 65% were white. Additionally, 49% of patients had diabetes, 38% of patients had cirrhosis, and 33% of patients had prior solid organ transplant. Overall sustained virologic response was 81% and varied by regimen used and viral genotype. Average baseline eGFR was equivalent to average on-treatment eGFR, but seven patients experienced a rise in creatinine >=1.5 times baseline while taking sofosbuvir; all but one recovered. In patients with eGFR<60 ml/min per 1.73 m2 at baseline (stage 3 CKD), regression models showed that hepatitis C cure was associated with a 9.3 (95% confidence interval, 0.44 to 18) ml/min per 1.73 m2 improvement in eGFR during the 6-month post-treatment follow-up period. Adverse events were common (81%), but serious adverse events (17%) and treatment discontinuations (8%) were uncommon. CONCLUSIONS: Sofosbuvir-based direct-acting antiviral therapy is safe and effective in a cohort of patients with CKD infected with hepatitis C. PMID- 28882860 TI - WEB Device: Ready for Ruptured Aneurysms? PMID- 28882859 TI - Flow Diversion with Low-Profile Braided Stents for the Treatment of Very Small or Uncoilable Intracranial Aneurysms at or Distal to the Circle of Willis. AB - BACKGROUND AND PURPOSE: The endovascular treatment of aneurysms located at or distal to the circle of Willis and not amenable to coiling remains a challenge. We report our experience with flow-diversion treatment using low-profile braided stents as a stent monotherapy procedure for treating distally located very small or uncoilable aneurysms. MATERIALS AND METHODS: We retrospectively reviewed our data bases to identify patients with aneurysms located at or distal to the circle of Willis who were treated with stent monotherapy using low-profile braided stents. The immediate and follow-up angiographic findings and clinical status of the patients were assessed. RESULTS: Twenty aneurysms in 19 patients were included in the study. The mean size of the aneurysms was 4.7 +/- 2.4 mm. Patients were treated via telescopic implantation of 2 stents for 11 aneurysms; single-stent placement was used for the remaining aneurysms. The technical success rate was 95%. We observed a technical complication in 1 case (5.3%) and a late ischemic event in another (5.3%). The final angiographies during a mean follow-up of 14.7 months showed complete aneurysm occlusion in 73.7%. The complete occlusion rate of the aneurysms treated with telescopic stent placement was 81.8%. The modified Rankin scale scores of all patients at the last follow-up were between 0 and 2. CONCLUSIONS: Flow diversion with low-profile braided stents as a stent monotherapy procedure for very small or uncoilable intracranial aneurysms located at or beyond the circle of Willis is a promising, relatively safe, and durable endovascular procedure. PMID- 28882861 TI - Real-Time Motor Cortex Mapping for the Safe Resection of Glioma: An Intraoperative Resting-State fMRI Study. AB - BACKGROUND AND PURPOSE: Resting-state functional MR imaging has been used for motor mapping in presurgical planning but never used intraoperatively. This study aimed to investigate the feasibility of applying intraoperative resting-state functional MR imaging for the safe resection of gliomas using real-time motor cortex mapping during an operation. MATERIALS AND METHODS: Using interventional MR imaging, we conducted preoperative and intraoperative resting-state intrinsic functional connectivity analyses of the motor cortex in 30 patients with brain tumors. Factors that may influence intraoperative imaging quality, including anesthesia type (general or awake anesthesia) and tumor cavity (filled with normal saline or not), were studied to investigate image quality. Additionally, direct cortical stimulation was used to validate the accuracy of intraoperative resting-state fMRI in mapping the motor cortex. RESULTS: Preoperative and intraoperative resting-state fMRI scans were acquired for all patients. Fourteen patients who successfully completed both sufficient intraoperative resting-state fMRI and direct cortical stimulation were used for further analysis of sensitivity and specificity. Compared with those subjected to direct cortical stimulation, the sensitivity and specificity of intraoperative resting-state fMRI in localizing the motor area were 61.7% and 93.7%, respectively. The image quality of intraoperative resting-state fMRI was better when the tumor cavity was filled with normal saline (P = .049). However, no significant difference between the anesthesia types was observed (P = .102). CONCLUSIONS: This study demonstrates the feasibility of using intraoperative resting-state fMRI for real time localization of functional areas during a neurologic operation. The findings suggest that using intraoperative resting-state fMRI can avoid the risk of intraoperative seizures due to direct cortical stimulation and may provide neurosurgeons with valuable information to facilitate the safe resection of gliomas. PMID- 28882862 TI - Detection of Volume-Changing Metastatic Brain Tumors on Longitudinal MRI Using a Semiautomated Algorithm Based on the Jacobian Operator Field. AB - BACKGROUND AND PURPOSE: Accurate follow-up of metastatic brain tumors has important implications for patient prognosis and management. The aim of this study was to develop and evaluate the accuracy of a semiautomated algorithm in detecting growing or shrinking metastatic brain tumors on longitudinal brain MRIs. MATERIALS AND METHODS: We used 50 pairs of successive MR imaging datasets, 30 on 1.5T and 20 on 3T, containing contrast-enhanced 3D T1-weighted sequences. These yielded 150 growing or shrinking metastatic brain tumors. To detect them, we completed 2 major steps: 1) spatial normalization and calculation of the Jacobian operator field to quantify changes between scans, and 2) metastatic brain tumor candidate segmentation and detection of volume-changing metastatic brain tumors with the Jacobian operator field. Receiver operating characteristic analysis was used to assess the detection accuracy of the algorithm, and it was verified with jackknife resampling. The reference standard was based on detections by a neuroradiologist. RESULTS: The areas under the receiver operating characteristic curves were 0.925 for 1.5T and 0.965 for 3T. Furthermore, at its optimal performance, the algorithm achieved a sensitivity of 85.1% and 92.1% and specificity of 86.7% and 91.3% for 1.5T and 3T, respectively. Vessels were responsible for most false-positives. Newly developed or resolved metastatic brain tumors were a major source of false-negatives. CONCLUSIONS: The proposed algorithm could detect volume-changing metastatic brain tumors on longitudinal brain MRIs with statistically high accuracy, demonstrating its potential as a computer-aided change-detection tool for complementing the performance of radiologists, decreasing inter- and intraobserver variability, and improving efficacy. PMID- 28882863 TI - Patient Outcomes and Cerebral Infarction after Ruptured Anterior Communicating Artery Aneurysm Treatment. AB - BACKGROUND AND PURPOSE: Anterior communicating artery aneurysm rupture and treatment is associated with high rates of dependency, which are more severe after clipping compared with coiling. To determine whether ischemic injury might account for these differences, we characterized cerebral infarction burden, infarction patterns, and patient outcomes after surgical or endovascular treatment of ruptured anterior communicating artery aneurysms. MATERIALS AND METHODS: We performed a retrospective cohort study of consecutive patients with ruptured anterior communicating artery aneurysms. Patient data and neuroimaging studies were reviewed. A propensity score for outcome measures was calculated to account for the nonrandom assignment to treatment. Primary outcome was the frequency of frontal lobe and striatum ischemic injury. Secondary outcomes were patient mortality and clinical outcome at discharge and at 3 months. RESULTS: Coiled patients were older (median, 55 versus 50 years; P = .03), presented with a worse clinical status (60% with Hunt and Hess Score >2 versus 34% in clipped patients; P = .02), had a higher modified Fisher grade (P = .01), and were more likely to present with intraventricular hemorrhage (78% versus 56%; P = .03). Ischemic frontal lobe infarction (OR, 2.9; 95% CI, 1.1-8.4; P = .03) and recurrent artery of Heubner infarction (OR, 20.9; 95% CI, 3.5-403.7; P < .001) were more common in clipped patients. Clipped patients were more likely to be functionally dependent at discharge (OR, 3.2; P = .05) compared with coiled patients. Mortality and clinical outcome at 3 months were similar between coiled and clipped patients. CONCLUSIONS: Frontal lobe and recurrent artery of Heubner infarctions are more common after surgical clipping of ruptured anterior communicating artery aneurysms, and are associated with poorer clinical outcomes at discharge. PMID- 28882864 TI - MR Neurography of Greater Occipital Nerve Neuropathy: Initial Experience in Patients with Migraine. AB - BACKGROUND AND PURPOSE: MR imaging of peripheral nerves (MR neurography) allows improved assessment of nerve anatomy and pathology. The objective of this study was to evaluate patients with unilateral occipital neuralgia using MR neurography and to assess the differences in greater occipital nerve signal and size between the symptomatic and asymptomatic sides. MATERIALS AND METHODS: In this case control evaluation using MR neurography, bilateral greater occipital nerve caliber, signal intensity, signal-to-noise ratios, and contrast-to-noise ratios were determined by 2 observers. RESULTS: Among 18 subjects with unilateral occipital migraines, the average greater occipital nerve diameter for the symptomatic side was significantly greater at 1.77 +/- 0.4 mm than for the asymptomatic side at 1.29 +/- 0.25 mm (P = .001). The difference in nerve signal intensity between the symptomatic and asymptomatic sides was statistically significant at 269.06 +/- 170.93 and 222.44 +/- 170.46, respectively (P = .043). The signal-to-noise ratios on the symptomatic side were higher at 15.79 +/- 4.59 compared with the asymptomatic nerve at 14.02 +/- 5.23 (P = .009). Contrast-to noise ratios were significantly higher on the symptomatic side than on the asymptomatic side at 2.57 +/- 4.89 and -1.26 +/- 5.02, respectively (P = .004). Intraobserver performance was good to excellent (intraclass coefficient correlation, 0.68-0.93), and interobserver performance was fair to excellent (intraclass coefficient correlation, 0.54-0.81). CONCLUSIONS: MR neurography can be reliably used for the diagnosis of greater occipital nerve neuropathy in patients with unilateral occipital migraines with a good correlation of imaging findings to the clinical presentation. PMID- 28882865 TI - Prevalence of Intracranial Aneurysms in Patients with Aortic Dissection. AB - BACKGROUND AND PURPOSE: There is an uncertainty about the association between intracranial aneurysms and aortic dissection. We aimed to determine the prevalence of intracranial aneurysms in patients with aortic dissection and evaluate the independent risk factors for the presence of intracranial aneurysms in these patients. MATERIALS AND METHODS: Seventy-one patients with a confirmed aortic dissection who underwent additional brain imaging were enrolled as the aortic dissection group, and 2118 healthy individuals with brain imaging, as controls. Demographic data were obtained from their medical records, including age, sex, comorbidities, and arch vessel involvement of aortic dissection. Two readers reviewed all brain images independently regarding the presence, morphology, size, and location of intracranial aneurysms. Baseline characteristics were compared between the aortic dissection group and controls by propensity score matching, and logistic regression analysis was performed for independent risk factors for the presence of intracranial aneurysms. RESULTS: The prevalence of intracranial aneurysms was 12.96% in the aortic dissection group and 1.85% in controls (P = .022). The mean diameter of intracranial aneurysms was significantly larger in the aortic dissection group (5.79 +/- 3.26 mm in aortic dissection versus 3.04 +/- 1.57 mm in controls; P = .008), and intracranial aneurysms of >7 mm were also more common in the aortic dissection group (28.6% in aortic dissection versus 5.3% in controls, P = .003). On multivariate analysis, arch vessel involvement of aortic dissection was an independent risk factor for the presence of intracranial aneurysms (odds ratio, 6.246; 95% confidence interval, 1.472-26.50; P = .013). CONCLUSIONS: Patients with aortic dissection have a high prevalence of intracranial aneurysms, and selective screening for brain vessels could be considered in these patients with arch vessel involvement. A further prospective study is needed to demonstrate a substantial prevalence of intracranial aneurysms. PMID- 28882866 TI - Yield of Image-Guided Needle Biopsy for Infectious Discitis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Image-guided biopsy is routinely conducted in patients with suspected discitis, though the sensitivity reported in the literature ranges widely. PURPOSE: We applied a systematic review and meta-analysis to estimate the yield of image-guided biopsy for infectious discitis. DATA SOURCES: We performed a literature search of 4 data bases: PubMed, Cochrane CENTRAL Register of Controlled Trials, Embase.com, and Scopus from data base inception to March 2016. STUDY SELECTION: A screen of 1814 articles identified 88 potentially relevant articles. Data were extracted for 33 articles, which were eligible if they were peer-reviewed publications of patients with clinical suspicion of discitis who underwent image-guided biopsy. DATA ANALYSIS: Patients with positive cultures out of total image-guided biopsy procedures were pooled to estimate yield with 95% confidence intervals. Hypothesis testing was performed with an inverse variance method after logit transformation. DATA SYNTHESIS: Image-guided biopsy has a yield of approximately 48% (793/1763), which is significantly lower than the open surgical biopsy yield of 76% (152/201; P < .01). Biopsy in patients with prior antibiotic exposure had a yield of 32% (106/346), which was not significantly different from the yield of 43% (336/813; P = .08) in patients without prior antibiotic exposure. LIMITATIONS: The conclusions of this meta-analysis are primarily limited by the heterogeneity of the included studies. CONCLUSIONS: Image-guided biopsy has a moderate yield for the diagnosis of infectious discitis, which is significantly lower than the yield of open surgical biopsy. This yield is not significantly affected by prior antibiotic use. PMID- 28882867 TI - Diagnostic Accuracy of Neuroimaging to Delineate Diffuse Gliomas within the Brain: A Meta-Analysis. AB - BACKGROUND: Brain imaging in diffuse glioma is used for diagnosis, treatment planning, and follow-up. PURPOSE: In this meta-analysis, we address the diagnostic accuracy of imaging to delineate diffuse glioma. DATA SOURCES: We systematically searched studies of adults with diffuse gliomas and correlation of imaging with histopathology. STUDY SELECTION: Study inclusion was based on quality criteria. Individual patient data were used, if available. DATA ANALYSIS: A hierarchic summary receiver operating characteristic method was applied. Low- and high-grade gliomas were analyzed in subgroups. DATA SYNTHESIS: Sixty-one studies described 3532 samples in 1309 patients. The mean Standard for Reporting of Diagnostic Accuracy score (13/25) indicated suboptimal reporting quality. For diffuse gliomas as a whole, the diagnostic accuracy was best with T2-weighted imaging, measured as area under the curve, false-positive rate, true-positive rate, and diagnostic odds ratio of 95.6%, 3.3%, 82%, and 152. For low-grade gliomas, the diagnostic accuracy of T2-weighted imaging as a reference was 89.0%, 0.4%, 44.7%, and 205; and for high-grade gliomas, with T1-weighted gadolinium enhanced MR imaging as a reference, it was 80.7%, 16.8%, 73.3%, and 14.8. In high grade gliomas, MR spectroscopy (85.7%, 35.0%, 85.7%, and 12.4) and 11C methionine PET (85.1%, 38.7%, 93.7%, and 26.6) performed better than the reference imaging. LIMITATIONS: True-negative samples were underrepresented in these data, so false positive rates are probably less reliable than true-positive rates. Multimodality imaging data were unavailable. CONCLUSIONS: The diagnostic accuracy of commonly used imaging is better for delineation of low-grade gliomas than high-grade gliomas on the basis of limited evidence. Improvement is indicated from advanced techniques, such as MR spectroscopy and PET. PMID- 28882868 TI - Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is an increasingly prevalent and ultimately fatal disease with no effective pharmacological treatment. Because matrix degradation induced by vascular inflammation is the major pathophysiology of AAA, attenuation of this inflammation may improve its outcome. Previous studies suggested that miR-33 (microRNA-33) inhibition and genetic ablation of miR-33 increased serum high-density lipoprotein cholesterol and attenuated atherosclerosis. APPROACH AND RESULTS: MiR-33a-5p expression in central zone of human AAA was higher than marginal zone. MiR-33 deletion attenuated AAA formation in both mouse models of angiotensin II- and calcium chloride-induced AAA. Reduced macrophage accumulation and monocyte chemotactic protein-1 expression were observed in calcium chloride-induced AAA walls in miR-33-/- mice. In vitro experiments revealed that peritoneal macrophages from miR-33-/- mice showed reduced matrix metalloproteinase 9 expression levels via c-Jun N-terminal kinase inactivation. Primary aortic vascular smooth muscle cells from miR-33-/- mice showed reduced monocyte chemotactic protein-1 expression by p38 mitogen-activated protein kinase attenuation. Both of the inactivation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were possibly because of the increase of ATP-binding cassette transporter A1 that is a well-known target of miR-33. Moreover, high-density lipoprotein cholesterol derived from miR-33-/- mice reduced expression of matrix metalloproteinase 9 in macrophages and monocyte chemotactic protein-1 in vascular smooth muscle cells. Bone marrow transplantation experiments indicated that miR-33-deficient bone marrow cells ameliorated AAA formation in wild-type recipients. MiR-33 deficiency in recipient mice was also shown to contribute the inhibition of AAA formation. CONCLUSIONS: These data strongly suggest that inhibition of miR-33 will be effective as a novel strategy for treating AAA. PMID- 28882869 TI - Extracellular Vesicles Secreted by Atherogenic Macrophages Transfer MicroRNA to Inhibit Cell Migration. AB - OBJECTIVE: During inflammation, macrophages secrete vesicles carrying RNA, protein, and lipids as a form of extracellular communication. In the vessel wall, extracellular vesicles (EVs) have been shown to be transferred between vascular cells during atherosclerosis; however, the role of macrophage-derived EVs in atherogenesis is not known. Here, we hypothesize that atherogenic macrophages secrete microRNAs (miRNAs) in EVs to mediate cell-cell communication and promote proinflammatory and proatherogenic phenotypes in recipient cells. APPROACH AND RESULTS: We isolated EVs from mouse and human macrophages treated with an atherogenic stimulus (oxidized low-density lipoprotein) and characterized the EV miRNA expression profile. We confirmed the enrichment of miR-146a, miR-128, miR 185, miR-365, and miR-503 in atherogenic EVs compared with controls and demonstrate that these EVs are taken up and transfer exogenous miRNA to naive recipient macrophages. Bioinformatic pathway analysis suggests that atherogenic EV miRNAs are predicted to target genes involved in cell migration and adhesion pathways, and indeed delivery of EVs to naive macrophages reduced macrophage migration both in vitro and in vivo. Inhibition of miR-146a, the most enriched miRNA in atherogenic EVs, reduced the inhibitory effect of EVs on macrophage migratory capacity. EV-mediated delivery of miR-146a repressed the expression of target genes IGF2BP1 (insulin-like growth factor 2 mRNA-binding protein 1) and HuR (human antigen R or ELAV-like RNA-binding protein 1) in recipient cells, and knockdown of IGF2BP1 and HuR using short interfering RNA greatly reduced macrophage migration, highlighting the importance of these EV-miRNA targets in regulating macrophage motility. CONCLUSIONS: EV-derived miRNAs from atherogenic macrophages, in particular miR-146a, may accelerate the development of atherosclerosis by decreasing cell migration and promoting macrophage entrapment in the vessel wall. PMID- 28882870 TI - CRISPR/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages-Brief Report. AB - OBJECTIVE: To gain mechanistic insights into the role of LIPA (lipase A), the gene encoding LAL (lysosomal acid lipase) protein, in human macrophages. APPROACH AND RESULTS: We used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) technology to knock out LIPA in human induced pluripotent stem cells and then differentiate to macrophage (human induced pluripotent stem cells-derived macrophage [IPSDM]) to explore the human macrophage LIPA loss-of-function phenotypes. LIPA was abundantly expressed in monocyte-derived macrophages and was markedly induced on IPSDM differentiation to comparable levels as in human monocyte-derived macrophage. IPSDM with knockout of LIPA (LIPA-/-) had barely detectable LAL enzymatic activity. Control and LIPA-/- IPSDM were loaded with [3H]-cholesteryl oleate-labeled AcLDL (acetylated low density lipoprotein) followed by efflux to apolipoprotein A-I. Efflux of liberated [3H]-cholesterol to apolipoprotein A-I was abolished in LIPA-/- IPSDM, indicating deficiency in LAL-mediated lysosomal cholesteryl ester hydrolysis. In cells loaded with [3H]-cholesterol-labeled AcLDL, [3H]-cholesterol efflux was, however, not different between control and LIPA-/- IPSDM. ABCA1 (ATP-binding cassette, subfamily A, member 1) expression was upregulated by AcLDL loading but to a similar extent between control and LIPA-/- IPSDM. In nonlipid loaded state, LIPA-/- IPSDM had high levels of cholesteryl ester mass compared with minute amounts in control IPSDM. Yet, with AcLDL loading, overall cholesteryl ester mass was increased to similar levels in both control and LIPA-/- IPSDM. LIPA-/- did not impact lysosomal apolipoprotein-B degradation or expression of IL1B, IL6, and CCL5. CONCLUSIONS: LIPA-/- IPSDM reveals macrophage-specific hallmarks of LIPA deficiency. CRISPR/Cas9 and IPSDM provide important tools to study human macrophage biology and more broadly for future studies of disease-associated LIPA genetic variation in human macrophages. PMID- 28882871 TI - Independent and Synergistic Associations of Biomarkers of Vitamin D Status With Risk of Coronary Heart Disease. AB - OBJECTIVE: To comprehensively evaluate the independent associations and potential interactions of vitamin D-related biomarkers including total and bioavailable 25 hydroxyvitamin D (25OHD), VDBP (vitamin D binding protein), and parathyroid hormone (PTH) with risk of coronary heart disease (CHD). APPROACH AND RESULTS: We prospectively identified incident cases of nonfatal myocardial infarction and fatal CHD among women in the Nurses' Health Study during 20 years of follow-up (1990-2010). Using risk-set sampling, 1 to 2 matched controls were selected for each case. The analysis of 25OHD and PTH included 382 cases and 575 controls; the analysis of VDBP included 396 cases and 398 controls. After multivariate adjustment, plasma levels of total 25OHD, bioavailable 25OHD, and PTH were not significantly associated with CHD risk. VDBP was associated with a lower CHD risk with an extreme-quartile odds ratio of 0.60 (95% confidence interval, 0.39-0.92; P trend=0.02). When examining the biomarkers jointly, a significant, inverse association between 25OHD and CHD was observed among participants with higher PTH levels (P for interaction=0.02). The odds ratio (95% confidence interval) comparing the highest quartile of 25OHD to lowest was 0.43 (0.23-0.82; P trend=0.003) when PTH levels were above population median (35.3 pg/mL), whereas among the rest of participants the corresponding odds ratio (95% confidence interval) was 1.28 (0.70-2.36; P trend=0.43). CONCLUSIONS: Our data suggest that higher 25OHD levels were associated with a lower CHD risk when PTH levels were high, whereas no association was observed for participants with low PTH levels. VDBP but not bioavailable 25OHD was independently associated with lower CHD risk. PMID- 28882872 TI - Mechanical Activation of Hypoxia-Inducible Factor 1alpha Drives Endothelial Dysfunction at Atheroprone Sites. AB - OBJECTIVE: Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and inflammation that promote lesion initiation. The transcription factor HIF1alpha (hypoxia-inducible factor 1alpha) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1alpha activation and the contribution of this noncanonical pathway to lesion initiation. APPROACH AND RESULTS: Quantitative polymerase chain reaction and en face staining revealed that HIF1alpha was expressed preferentially at low shear stress regions of porcine and murine arteries. Low shear stress induced HIF1alpha in cultured EC in the presence of atmospheric oxygen. The mechanism involves the transcription factor nuclear factor-kappaB that induced HIF1alpha transcripts and induction of the deubiquitinating enzyme Cezanne that stabilized HIF1alpha protein. Gene silencing revealed that HIF1alpha enhanced proliferation and inflammatory activation in EC exposed to low shear stress via induction of glycolysis enzymes. We validated this observation by imposing low shear stress in murine carotid arteries (partial ligation) that upregulated the expression of HIF1alpha, glycolysis enzymes, and inflammatory genes and enhanced EC proliferation. EC-specific genetic deletion of HIF1alpha in hypercholesterolemic apolipoprotein E-defecient mice reduced inflammation and endothelial proliferation in partially ligated arteries, indicating that HIF1alpha drives inflammation and vascular dysfunction at low shear stress regions. CONCLUSIONS: Mechanical low shear stress activates HIF1alpha at atheroprone regions of arteries via nuclear factor-kappaB and Cezanne. HIF1alpha promotes atherosclerosis initiation at these sites by inducing excessive EC proliferation and inflammation via the induction of glycolysis enzymes. PMID- 28882873 TI - ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels. AB - OBJECTIVE: High-density lipoproteins (HDL) are considered to protect against atherosclerosis in part by facilitating the removal of cholesterol from peripheral tissues. However, factors regulating lipid efflux are incompletely understood. We previously identified a variant in adenosine triphosphate-binding cassette transporter A8 (ABCA8) in an individual with low HDL cholesterol (HDLc). Here, we investigate the role of ABCA8 in cholesterol efflux and in regulating HDLc levels. APPROACH AND RESULTS: We sequenced ABCA8 in individuals with low and high HDLc and identified, exclusively in low HDLc probands, 3 predicted deleterious heterozygous ABCA8 mutations (p.Pro609Arg [P609R], IVS17-2 A>G and p.Thr741Stop [T741X]). HDLc levels were lower in heterozygous mutation carriers compared with first-degree family controls (0.86+/-0.34 versus 1.17+/-0.26 mmol/L; P=0.005). HDLc levels were significantly decreased by 29% (P=0.01) in Abca8b-/- mice on a high-cholesterol diet compared with wild-type mice, whereas hepatic overexpression of human ABCA8 in mice resulted in significant increases in plasma HDLc and the first steps of macrophage-to-feces reverse cholesterol transport. Overexpression of wild-type but not mutant ABCA8 resulted in a significant increase (1.8-fold; P=0.01) of cholesterol efflux to apolipoprotein AI in vitro. ABCA8 colocalizes and interacts with adenosine triphosphate-binding cassette transporter A1 and further potentiates adenosine triphosphate-binding cassette transporter A1-mediated cholesterol efflux. CONCLUSIONS: ABCA8 facilitates cholesterol efflux and modulates HDLc levels in humans and mice. PMID- 28882875 TI - Class III PI3K Positively Regulates Platelet Activation and Thrombosis via PI(3)P Directed Function of NADPH Oxidase. AB - OBJECTIVE: Class III phosphoinositide 3-kinase, also known as VPS34 (vacuolar protein sorting 34), is a highly conserved enzyme regulating important cellular functions such as NADPH oxidase (NOX) assembly, membrane trafficking, and autophagy. Although VPS34 is expressed in platelets, its involvement in platelet activation remains unclear. Herein, we investigated the role of VPS34 in platelet activation and thrombus formation using VPS34 knockout mice. APPROACH AND RESULTS: Platelet-specific VPS34-deficient mice were generated and characterized. VPS34 deficiency in platelets did not influence tail bleeding time. In a ferric chloride-induced mesenteric arteriolar thrombosis model, VPS34-/- mice exhibited a prolonged vessel occlusion time compared with wild-type mice (42.05+/-4.09 versus 18.30+/-2.47 minutes). In an in vitro microfluidic whole-blood perfusion assay, thrombus formation on collagen under arterial shear was significantly reduced for VPS34-/- platelets. VPS34-/- platelets displayed an impaired aggregation and dense granule secretion in response to low doses of collagen or thrombin. VPS34 deficiency delayed clot retraction but did not influence platelet spreading on fibrinogen. We also demonstrated that VPS34 deficiency altered the basal level of autophagy in resting platelets and hampered NOX assembly and mTOR (mammalian target of rapamycin) signaling during platelet activation. Importantly, we identified the NOX-dependent reactive oxygen species generation as the major downstream effector of VPS34, which in turn can mediate platelet activation. In addition, by using a specific inhibitor 3-methyladenine, VPS34 was found to operate through a similar NOX-dependent mechanism to promote human platelet activation. CONCLUSIONS: Platelet VPS34 is critical for thrombosis but dispensable for hemostasis. VPS34 regulates platelet activation by influencing NOX assembly. PMID- 28882874 TI - Haploid Mammalian Genetic Screen Identifies UBXD8 as a Key Determinant of HMGCR Degradation and Cholesterol Biosynthesis. AB - OBJECTIVE: The cellular demand for cholesterol requires control of its biosynthesis by the mevalonate pathway. Regulation of HMGCR (3-hydroxy-3 methylglutaryl coenzyme A reductase), a rate-limiting enzyme in this pathway and the target of statins, is a key control point herein. Accordingly, HMGCR is subject to negative and positive regulation. In particular, the ability of oxysterols and intermediates of the mevalonate pathway to stimulate its proteasomal degradation is an exquisite example of metabolically controlled feedback regulation. To define the genetic determinants that govern this process, we conducted an unbiased haploid mammalian genetic screen. APPROACH AND RESULTS: We generated human haploid cells with mNeon fused to endogenous HMGCR using CRISPR/Cas9 and used these cells to interrogate regulation of HMGCR abundance in live cells. This resulted in identification of known and new regulators of HMGCR, and among the latter, UBXD8 (ubiquitin regulatory X domain-containing protein 8), a gene that has not been previously implicated in this process. We demonstrate that UBXD8 is an essential determinant of metabolically stimulated degradation of HMGCR and of cholesterol biosynthesis in multiple cell types. Accordingly, UBXD8 ablation leads to aberrant cholesterol synthesis due to loss of feedback control. Mechanistically, we show that UBXD8 is necessary for sterol-stimulated dislocation of ubiquitylated HMGCR from the endoplasmic reticulum membrane en route to proteasomal degradation, a function dependent on its UBX domain. CONCLUSIONS: We establish UBXD8 as a previously unrecognized determinant that couples flux across the mevalonate pathway to control of cholesterol synthesis and demonstrate the feasibility of applying mammalian haploid genetics to study metabolic traits. PMID- 28882876 TI - Post-Up Study: Postpartum Depression Screening in Well-Child Care and Maternal Outcomes. AB - OBJECTIVES: Postpartum depression often remains unaddressed. Screening in well child care (WCC) may improve early detection, promote maternal recovery, and reduce effects on child development. We assessed the effectiveness of screening for postpartum depression in WCC compared with care as usual (CAU) on outcomes at mother and child levels. METHODS: In a prospective, quasiexperimental, comparative design, mothers visiting Dutch WCC centers were exposed either to screening at 1, 3, and 6 months postpartum (n = 1843) or to CAU (n = 1246). Assessments were at 3 weeks (baseline), 9 months (the Mini International Neuropsychiatric Interview), and 12 months (the Spielberger State-Trait Anxiety Inventory, the Short-Form 12-Item Health Survey, the Maternal Self-Efficacy in the Nurturing Role questionnaire, and the Ages and Stages Questionnaire-Social Emotional) postpartum. RESULTS: Significantly fewer mothers in the intervention group were depressed at 9 months postpartum compared with the CAU group (0.6% vs 2.5% for major depression). The adjusted odds ratio was 0.28 (95% confidence interval, 0.12 to 0.63; Cohen's d, 0.70). For minor and major depression, figures were 3.0% vs 8.4%, and the adjusted odds ratio was 0.40 (95% confidence interval, 0.27 to 0.58; Cohen's d, 0.51). For parenting, anxiety symptoms, and mental health functioning, the intervention resulted in effect sizes ranging from 0.23 to 0.27. The effect on the child's socioemotional development was negligible. CONCLUSIONS: Implementation of screening for postpartum depression in WCC should be seriously considered given its positive effects on maternal mental health. The benefits of optimizing the trajectory after screening on maternal and child outcomes need further attention. PMID- 28882877 TI - Clinical Pathway Produces Sustained Improvement in Acute Gastroenteritis Care. AB - BACKGROUND AND OBJECTIVES: Despite widespread use of the rotavirus vaccine in the last decade, dehydrating illnesses impact almost 2 billion children worldwide annually. Evidence supports oral rehydration therapy as a first-line treatment of mild to moderate dehydration. Ondansetron has proven to be a safe and effective adjunct in children with vomiting. We implemented a clinical pathway in our pediatric emergency department (ED) in January 2005 to improve care for this common condition. Our objective in this study was to determine the long-term impact of the pathway for acute gastroenteritis (AGE) on the proportion of patients receiving intravenous (IV) fluids and ED length of stay (LOS) for discharged patients. METHODS: Cases were identified by using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. We used statistical process control to analyze process and outcome measures for 2 years before and 10 years after pathway implementation. RESULTS: We included 30 519 patients. We found special cause variation with a downward shift in patients receiving IV fluids after initiation of the pathway and later with addition of ondansetron to the pathway from 48% to 26%. Mean ED LOS for discharged patients with AGE decreased from 247 to 172 minutes. These improvements were sustained over time. CONCLUSIONS: Implementation of a clinical pathway emphasizing oral rehydration therapy and ondansetron for children with AGE led to decreased IV fluid use and LOS in a pediatric ED. Improvements were sustained over a 10-year period. Our results suggest that quality-improvement interventions for AGE can have long-term impacts on care delivery. PMID- 28882878 TI - Autoimmune disease variants regulate GSDMB gene expression in human immune cells and whole blood. PMID- 28882879 TI - Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile. AB - Several small-molecule Bruton tyrosine kinase (BTK) inhibitors are in development for B cell malignancies and autoimmune disorders, each characterized by distinct potency and selectivity patterns. Herein we describe the pharmacologic characterization of BTK inhibitor acalabrutinib [compound 1, ACP-196 (4-[8-amino 3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-(2 pyridyl)benzamide)]. Acalabrutinib possesses a reactive butynamide group that binds covalently to Cys481 in BTK. Relative to the other BTK inhibitors described here, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine-mediated covalent binding potential. Acalabrutinib demonstrated higher biochemical and cellular selectivity than ibrutinib and spebrutinib (compounds 2 and 3, respectively). Importantly, off target kinases, such as epidermal growth factor receptor (EGFR) and interleukin 2 inducible T cell kinase (ITK), were not inhibited. Determination of the inhibitory potential of anti-immunoglobulin M-induced CD69 expression in human peripheral blood mononuclear cells and whole blood demonstrated that acalabrutinib is a potent functional BTK inhibitor. In vivo evaluation in mice revealed that acalabrutinib is more potent than ibrutinib and spebrutinib. Preclinical and clinical studies showed that the level and duration of BTK occupancy correlates with in vivo efficacy. Evaluation of the pharmacokinetic properties of acalabrutinib in healthy adult volunteers demonstrated rapid absorption and fast elimination. In these healthy individuals, a single oral dose of 100 mg showed approximately 99% median target coverage at 3 and 12 hours and around 90% at 24 hours in peripheral B cells. In conclusion, acalabrutinib is a BTK inhibitor with key pharmacologic differentiators versus ibrutinib and spebrutinib and is currently being evaluated in clinical trials. PMID- 28882880 TI - Slow fusion pore expansion creates a unique reaction chamber for co-packaged cargo. AB - A lumenal secretory granule protein, tissue plasminogen activator (tPA), greatly slows fusion pore dilation and thereby slows its own discharge. We investigated another outcome of the long-lived narrow fusion pore: the creation of a nanoscale chemical reaction chamber for granule contents in which the pH is suddenly neutralized upon fusion. Bovine adrenal chromaffin cells endogenously express both tPA and its primary protein inhibitor, plasminogen activator inhibitor 1 (PAI). We found by immunocytochemistry that tPA and PAI are co-packaged in the same secretory granule. It is known that PAI irreversibly and covalently inactivates tPA at neutral pH. We demonstrate with zymography that the acidic granule lumen protects tPA from inactivation by PAI. Immunocytochemistry, total internal reflection fluorescence (TIRF) microscopy, and polarized TIRF microscopy demonstrated that co-packaged PAI and tPA remain together in granules for many seconds in the nanoscale reaction chamber, more than enough time to inhibit tPA and create a new secreted protein species. PMID- 28882881 TI - Respiratory manifestations of gastro-oesophageal reflux in children. AB - Gastro-oesophageal reflux disease (GORD) is a complex problem in children. Suspected respiratory manifestations of GORD, such as asthma, chronic cough and laryngitis, are commonly encountered in the paediatric practice, but continue to be entities with more questions than answers. The accuracy of diagnostic tests (ie, pH or pH-impedance monitoring, laryngoscopy, endoscopy) for patients with suspected extraoesophageal manifestations of GORD is suboptimal and therefore whether there is a causal relationship between these conditions remains largely undetermined. An empiric trial of proton pump inhibitors can help individual children with undiagnosed respiratory symptoms and suspicion of GORD, but the response to therapy is unpredictable, and in any case what may be being observed is spontaneous improvement. Furthermore, the safety of these agents has been called into question. Poor response to antireflux therapy is an important trigger to search for non-gastro-oesophageal reflux causes for patients' symptoms. Evidence for the assessment of children with suspected extraoesophageal manifestations of GORD is scanty and longitudinal studies with long-term follow up are urgently required. PMID- 28882882 TI - How I treat patients with HIV-related hematological malignancies using hematopoietic cell transplantation. AB - Hematopoietic cell transplantation (HCT) has now been shown to be safe and effective for selected HIV-infected patients with hematological malignancies. Autologous HCT is now the standard of care for patients with HIV-related lymphomas who otherwise meet standard transplant criteria. Limited data also support use of allogeneic HCT (alloHCT) in selected HIV-infected patients who meet standard transplant criteria. We recommend enrolling patients in clinical trials that offer access to CCR5Delta32 homozygous donors, if available. HIV infected patients requiring HCT may also be considered for participation in trials evaluating the activity of gene-modified hematopoietic stem cells in conferring resistance to HIV infection. To be considered for HCT, patients must have HIV infection that is responsive to combination antiretroviral therapy (cART). Careful planning for the peri-HCT management of the cART can avoid risk of significant drug interactions and development of cART-resistant HIV. In general, we recommend against the use of boosted proteasome inhibitors and nonnucleotide reverse transcriptase inhibitors in the cART regimen, in favor of nucleoside reverse transcriptase inhibitors and integrase inhibitors (without cobicistat). After HCT, patients must be closely monitored for development of opportunistic infections (OI), such as cytomegalovirus. Prevention of OI should include prophylactic and pre-emptive antimicrobials. PMID- 28882884 TI - Government pledges strong research links with EU after Brexit. PMID- 28882883 TI - Cytoprotective activated protein C averts Nlrp3 inflammasome-induced ischemia reperfusion injury via mTORC1 inhibition. AB - Cytoprotection by activated protein C (aPC) after ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation, and hence, cell-death forms disjunct from immunologically silent apoptosis are, in theory, more likely to be relevant. Because pyroptosis (ie, cell death resulting from inflammasome activation) is typically observed in IRI, we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRIs. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3A350V mutation abolished the protective effect of aPC, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via proteinase-activated receptor 1 (PAR-1) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Accordingly, inhibiting PAR-1 signaling, but not the anticoagulant properties of aPC, abolished the ability of aPC to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficiently as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression after IRI was corroborated in renal IRI, where the tissue protective effect of aPC was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1-dependent inflammasome activation and that mimicking biased aPC PAR-1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI. PMID- 28882885 TI - Modeling Major Adverse Outcomes of Pediatric and Adult Patients With Congenital Heart Disease Undergoing Cardiac Catheterization: Observations From the NCDR IMPACT Registry (National Cardiovascular Data Registry Improving Pediatric and Adult Congenital Treatment). AB - BACKGROUND: Risk standardization for adverse events after congenital cardiac catheterization is needed to equitably compare patient outcomes among different hospitals as a foundation for quality improvement. The goal of this project was to develop a risk-standardization methodology to adjust for patient characteristics when comparing major adverse outcomes in the NCDR's (National Cardiovascular Data Registry) IMPACT Registry (Improving Pediatric and Adult Congenital Treatment). METHODS: Between January 2011 and March 2014, 39 725 consecutive patients within IMPACT undergoing cardiac catheterization were identified. Given the heterogeneity of interventional procedures for congenital heart disease, new procedure-type risk categories were derived with empirical data and expert opinion, as were markers of hemodynamic vulnerability. A multivariable hierarchical logistic regression model to identify patient and procedural characteristics predictive of a major adverse event or death after cardiac catheterization was derived in 70% of the cohort and validated in the remaining 30%. RESULTS: The rate of major adverse event or death was 7.1% and 7.2% in the derivation and validation cohorts, respectively. Six procedure-type risk categories and 6 independent indicators of hemodynamic vulnerability were identified. The final risk adjustment model included procedure-type risk category, number of hemodynamic vulnerability indicators, renal insufficiency, single-ventricle physiology, and coagulation disorder. The model had good discrimination, with a C-statistic of 0.76 and 0.75 in the derivation and validation cohorts, respectively. Model calibration in the validation cohort was excellent, with a slope of 0.97 (standard error, 0.04; P value [for difference from 1] =0.53) and an intercept of 0.007 (standard error, 0.12; P value [for difference from 0] =0.95). CONCLUSIONS: The creation of a validated risk standardization model for adverse outcomes after congenital cardiac catheterization can support reporting of risk-adjusted outcomes in the IMPACT Registry as a foundation for quality improvement. PMID- 28882886 TI - Potential Cardiovascular and Total Mortality Benefits of Air Pollution Control in Urban China. AB - BACKGROUND: Outdoor air pollution ranks fourth among preventable causes of China's burden of disease. We hypothesized that the magnitude of health gains from air quality improvement in urban China could compare with achieving recommended blood pressure or smoking control goals. METHODS: The Cardiovascular Disease Policy Model-China projected coronary heart disease, stroke, and all cause deaths in urban Chinese adults 35 to 84 years of age from 2017 to 2030 if recent air quality (particulate matter with aerodynamic diameter <=2.5 um, PM2.5) and traditional cardiovascular risk factor trends continue. We projected life years gained if urban China were to reach 1 of 3 air quality goals: Beijing Olympic Games level (mean PM2.5, 55 MUg/m3), China Class II standard (35 MUg/m3), or World Health Organization standard (10 MUg/m3). We compared projected air pollution reduction control benefits with potential benefits of reaching World Health Organization hypertension and tobacco control goals. RESULTS: Mean PM2.5 reduction to Beijing Olympic levels by 2030 would gain ~241,000 (95% uncertainty interval, 189 000-293 000) life-years annually. Achieving either the China Class II or World Health Organization PM2.5 standard would yield greater health benefits (992 000 [95% uncertainty interval, 790 000-1 180 000] or 1 827 000 [95% uncertainty interval, 1 481 00-2 129 000] annual life-years gained, respectively) than World Health Organization-recommended goals of 25% improvement in systolic hypertension control and 30% reduction in smoking combined (928 000 [95% uncertainty interval, 830 000-1 033 000] life-years). CONCLUSIONS: Air quality improvement in different scenarios could lead to graded health benefits ranging from 241 000 life-years gained to much greater benefits equal to or greater than the combined benefits of 25% improvement in systolic hypertension control and 30% smoking reduction. PMID- 28882887 TI - Cut Points for Identifying Clinically Significant Diabetes Distress in Adolescents With Type 1 Diabetes Using the PAID-T: Results From Diabetes MILES Youth-Australia. AB - OBJECTIVE: To establish cut point(s) for the Problem Areas in Diabetes-teen version (PAID-T) scale to identify adolescents with clinically meaningful, elevated diabetes distress. RESEARCH DESIGN AND METHODS: Data were available from the Diabetes Management and Impact for Long-term Empowerment and Success (MILES) Youth-Australia Study, a national survey assessing various psychosocial indicators among self-selected National Diabetes Services Scheme registrants. Participants in the current study (n = 537) were (mean +/- SD) 16 +/- 2 years old, had type 1 diabetes for 6 +/- 4 years, and 62% (n = 334) were girls. They completed measures of diabetes distress (PAID-T) and depressive symptoms (Patient Health Questionnaire for Adolescents) and self-reported their most recent HbA1c and frequency of self-monitoring of blood glucose (SMBG). Relationships between the PAID-T and the psychological and clinical variables were examined to identify a clinically meaningful threshold for elevated diabetes distress. ANOVA was used to test whether these variables differed by levels of distress. RESULTS: Two cut points distinguished none-to-mild (<70), moderate (70-90), and high (>90) diabetes distress. Moderate distress was experienced by 18% of adolescents and high distress by 36%. Mean depressive symptoms, self-reported HbA1c, and SMBG differed significantly across the three levels of diabetes distress (all P < 0.001), with moderate-to-large effect sizes. CONCLUSIONS: Using the PAID-T, this study defined two clinically meaningful cut points to distinguish none-to-mild, moderate, and high diabetes distress in adolescents (aged 13-19). Based on these cut points, most respondents experienced at least moderate diabetes distress, which was clinically significant. Establishing thresholds for elevated diabetes distress will aid clinicians and researchers to interpret PAID-T scores, prompt discussion and intervention for those with unmet needs, and enable the effectiveness of interventions to be evaluated. PMID- 28882888 TI - Microbiome-Based Diagnostics: Ready for Applications in Laboratory Medicine? PMID- 28882889 TI - The Rho ADP-ribosylating C3 exoenzyme binds cells via an Arg-Gly-Asp motif. AB - The Rho ADP-ribosylating C3 exoenzyme (C3bot) is a bacterial protein toxin devoid of a cell-binding or -translocation domain. Nevertheless, C3 can efficiently enter intact cells, including neurons, but the mechanism of C3 binding and uptake is not yet understood. Previously, we identified the intermediate filament vimentin as an extracellular membranous interaction partner of C3. However, uptake of C3 into cells still occurs (although reduced) in the absence of vimentin, indicating involvement of an additional host cell receptor. C3 harbors an Arg-Gly-Asp (RGD) motif, which is the major integrin-binding site, present in a variety of integrin ligands. To check whether the RGD motif of C3 is involved in binding to cells, we performed a competition assay with C3 and RGD peptide or with a monoclonal antibody binding to beta1-integrin subunit and binding assays in different cell lines, primary neurons, and synaptosomes with C3-RGD mutants. Here, we report that preincubation of cells with the GRGDNP peptide strongly reduced C3 binding to cells. Moreover, mutation of the RGD motif reduced C3 binding to intact cells and also to recombinant vimentin. Anti-integrin antibodies also lowered the C3 binding to cells. Our results indicate that the RGD motif of C3 is at least one essential C3 motif for binding to host cells and that integrin is an additional receptor for C3 besides vimentin. PMID- 28882890 TI - C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation. AB - Voltage-gated Na+ (NaV) channels are key regulators of myocardial excitability, and Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent alterations in NaV1.5 channel inactivation are emerging as a critical determinant of arrhythmias in heart failure. However, the global native phosphorylation pattern of NaV1.5 subunits associated with these arrhythmogenic disorders and the associated channel regulatory defects remain unknown. Here, we undertook phosphoproteomic analyses to identify and quantify in situ the phosphorylation sites in the NaV1.5 proteins purified from adult WT and failing CaMKIIdeltac-overexpressing (CaMKIIdeltac-Tg) mouse ventricles. Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIdeltac-Tg compared with the WT ventricles. We then tested the hypothesis that phosphorylation at these two sites impairs fibroblast growth factor 13 (FGF13)-dependent regulation of NaV1.5 channel inactivation. Whole-cell voltage-clamp analyses in HEK293 cells demonstrated that FGF13 increases NaV1.5 channel availability and decreases late Na+ current, two effects that were abrogated with NaV1.5 mutants mimicking phosphorylation at both sites. Additional co-immunoprecipitation experiments revealed that FGF13 potentiates the binding of calmodulin to NaV1.5 and that phosphomimetic mutations at both sites decrease the interaction of FGF13 and, consequently, of calmodulin with NaV1.5. Together, we have identified two novel native phosphorylation sites in the C terminus of NaV1.5 that impair FGF13-dependent regulation of channel inactivation and may contribute to CaMKIIdeltac-dependent arrhythmogenic disorders in failing hearts. PMID- 28882891 TI - Identification of optineurin as an interleukin-1 receptor-associated kinase 1 binding protein and its role in regulation of MyD88-dependent signaling. AB - Upon stimulation of toll-like receptors with various microbial ligands, induction of a variety of inflammatory genes is elicited by activation of a myeloid differentiation primary-response protein 88 (MyD88)-dependent signaling pathway. Interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK1) plays an essential role in this pathway by activating nuclear factor kappaB (NF-kappaB) and mitogen activated kinases (MAPKs). Here, we identified optineurin (OPTN) as an IRAK1 binding protein by yeast two-hybrid screening using IRAK1 as bait. A C-terminal fragment of OPTN harboring a ubiquitin-binding domain was co-immunoprecipitated with IRAK1. In reporter analyses, overexpression of OPTN inhibited IL-1beta-, IRAK1-, and LPS-induced NF-kappaB activation. Consistently, OPTN deficiency resulted in increased NF-kappaB activation in response to IL-1beta/LPS stimulation. To address the mechanisms underlying the inhibitory effect of OPTN on NF-kappaB signaling, we focused on tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6), which is an adaptor protein of IRAK1 and upon polyubiquitination plays a crucial role during NF-kappaB activation. Overexpression of OPTN prevented TRAF6 polyubiquitination. Furthermore, OPTN H486R mutant, which is unable to recruit the deubiquitinase CYLD, failed to inhibit IRAK1-induced NF-kappaB activation. These results suggest that the IRAK1 binding protein OPTN negatively regulates IL-1beta/LPS-induced NF-kappaB activation by preventing polyubiquitination of TRAF6. PMID- 28882892 TI - Structural features of human inositol phosphate multikinase rationalize its inositol phosphate kinase and phosphoinositide 3-kinase activities. AB - Human inositol phosphate multikinase (HsIPMK) critically contributes to intracellular signaling through its inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) 3 kinase and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) 3-kinase activities. This catalytic profile is not conserved; orthologs from Arabidopsis thaliana and Saccharomyces cerevisiae are predominantly Ins(1,4,5)P3 6-kinases, and the plant enzyme cannot phosphorylate PtdIns(4,5)P2 Therefore, crystallographic analysis of the yeast and plant enzymes, without bound inositol phosphates, do not structurally rationalize HsIPMK activities. Here, we present 1.6-A resolution crystal structures of HsIPMK in complex with either Ins(1,4,5)P3 or PtdIns(4,5)P2 The Ins(1,4,5)P3 headgroup of PtdIns(4,5)P2 binds in precisely the same orientation as free Ins(1,4,5)P3 itself, indicative of evolutionary optimization of 3-kinase activities against both substrates. We report on nucleotide binding between the separate N- and C-lobes of HsIPMK. The N-lobe exhibits a remarkable degree of conservation with protein kinase A (root mean square deviation = 1.8 A), indicating common ancestry. We also describe structural features unique to HsIPMK. First, we observed a constrained, horseshoe shaped substrate pocket, formed from an alpha-helix, a 310 helix, and a recently evolved tri-proline loop. We further found HsIPMK activities rely on a preponderance of Gln residues, in contrast to the larger Lys and Arg residues in yeast and plant orthologs. These conclusions are supported by analyzing 14 single site HsIPMK mutants, some of which differentially affect 3-kinase and 6-kinase activities. Overall, we structurally rationalize phosphorylation of Ins(1,4,5)P3 and PtdIns(4,5)P2 by HsIPMK. PMID- 28882894 TI - Zinc oxide nanoparticles provide anti-cholera activity by disrupting the interaction of cholera toxin with the human GM1 receptor. AB - Vibrio cholerae causes cholera and is the leading cause of diarrhea in developing countries, highlighting the need for the development of new treatment strategies to combat this disease agent. While exploring the possibility of using zinc oxide (ZnO) nanoparticles (NPs) in cholera treatment, we previously found that ZnO NPs reduce fluid accumulation in mouse ileum induced by the cholera toxin (CT) protein. To uncover the mechanism of action of ZnO NPs on CT activity, here we used classical (O395) and El Tor (C6706) V. cholerae biotypes in growth and biochemical assays. We found that a ZnO NP concentration of 10 MUg/ml did not affect the growth rates of these two strains, nor did we observe that ZnO NPs reduce the expression levels of CT mRNA and protein. It was observed that ZnO NPs form a complex with CT, appear to disrupt the CT secondary structure, and block its interaction with the GM1 ganglioside receptor in the outer leaflet of the plasma membrane in intestinal (HT-29) cells and thereby reduce CT uptake into the cells. In the range of 2.5-10 MUg/ml, ZnO NPs exhibited no cytotoxicity on kidney (HEK293) and HT-29 cells. We conclude that ZnO NPs prevent the first step in the translocation of cholera toxin into intestinal epithelial cells without exerting measurable toxic effects on HEK293 and HT-29 cells. PMID- 28882893 TI - Kinetic signatures of myosin-5B, the motor involved in microvillus inclusion disease. AB - Myosin-5B is a ubiquitous molecular motor that transports cargo vesicles of the endomembrane system in intracellular recycling pathways. Myosin-5B malfunction causes the congenital enteropathy microvillus inclusion disease, underlining its importance in cellular homeostasis. Here we describe the interaction of myosin-5B with F-actin, nucleotides, and the pyrazolopyrimidine compound myoVin-1. We show that single-headed myosin-5B is an intermediate duty ratio motor with a kinetic ATPase cycle that is rate-limited by the release of phosphate. The presence of a second head generates strain and gating in the myosin-5B dimer that alters the kinetic signature by reducing the actin-activated ADP release rate to become rate limiting. This kinetic transition into a high-duty ratio motor is a prerequisite for the proposed transport function of myosin-5B in cellular recycling pathways. Moreover, we show that the small molecule compound myoVin-1 inhibits the enzymatic and functional activity of myosin-5B in vitro Partial inhibition of the actin-activated steady-state ATPase activity and sliding velocity suggests that caution should be used when probing the effect of myoVin-1 on myosin-5-dependent transport processes in cells. PMID- 28882895 TI - Peptide array-based screening reveals a large number of proteins interacting with the ankyrin-repeat domain of the zDHHC17 S-acyltransferase. AB - zDHHC S-acyltransferases are enzymes catalyzing protein S-acylation, a common post-translational modification on proteins frequently affecting their membrane targeting and trafficking. The ankyrin repeat (AR) domain of zDHHC17 (HIP14) and zDHHC13 (HIP14L) S-acyltransferases, which is involved in both substrate recruitment and S-acylation-independent functions, was recently shown to bind at least six proteins, by specific recognition of a consensus sequence in them. To further refine the rules governing binding to the AR of zDHHC17, we employed peptide arrays based on zDHHC AR-binding motif (zDABM) sequences of synaptosomal associated protein 25 (SNAP25) and cysteine string protein alpha (CSPalpha). Quantitative comparisons of the binding preferences of 400 peptides allowed us to construct a position-specific scoring matrix (PSSM) for zDHHC17 AR binding, with which we predicted and subsequently validated many putative zDHHC17 interactors. We identified 95 human zDABM sequences with unexpected versatility in amino acid usage; these sequences were distributed among 90 proteins, of which 62 have not been previously implicated in zDHHC17/13 binding. These zDABM-containing proteins included all family members of the SNAP25, sprouty, cornifelin, ankyrin, and SLAIN-motif containing families; seven endogenous Gag polyproteins sharing the same binding sequence; and several proteins involved in cytoskeletal organization, cell communication, and regulation of signaling. A dozen of the zDABM-containing proteins had more than one zDABM sequence, whereas isoform specific binding to the AR of zDHHC17 was identified for the Ena/VASP-like protein. The large number of zDABM sequences within the human proteome suggests that zDHHC17 may be an interaction hub regulating many cellular processes. PMID- 28882896 TI - Transcriptional fidelities of human mitochondrial POLRMT, yeast mitochondrial Rpo41, and phage T7 single-subunit RNA polymerases. AB - Single-subunit RNA polymerases (RNAPs) are present in phage T7 and in mitochondria of all eukaryotes. This RNAP class plays important roles in biotechnology and cellular energy production, but we know little about its fidelity and error rates. Herein, we report the error rates of three single subunit RNAPs measured from the catalytic efficiencies of correct and all possible incorrect nucleotides. The average error rates of T7 RNAP (2 * 10-6), yeast mitochondrial Rpo41 (6 * 10-6), and human mitochondrial POLRMT (RNA polymerase mitochondrial) (2 * 10-5) indicate high accuracy/fidelity of RNA synthesis resembling those of replicative DNA polymerases. All three RNAPs exhibit a distinctly high propensity for GTP misincorporation opposite dT, predicting frequent A->G errors in RNA with rates of ~10-4 The A->C, G->A, A->U, C->U, G->U, U->C, and U->G errors mostly due to pyrimidine-purine mismatches were relatively frequent (10-5-10-6), whereas C->G, U->A, G->C, and C->A errors from purine-purine and pyrimidine-pyrimidine mismatches were rare (10-7-10-10). POLRMT also shows a high C->A error rate on 8-oxo-dG templates (~10-4). Strikingly, POLRMT shows a high mutagenic bypass rate, which is exacerbated by TEFM (transcription elongation factor mitochondrial). The lifetime of POLRMT on terminally mismatched elongation substrate is increased in the presence of TEFM, which allows POLRMT to efficiently bypass the error and continue with transcription. This investigation of nucleotide selectivity on normal and oxidatively damaged DNA by three single-subunit RNAPs provides the basic information to understand the error rates in mitochondria and, in the case of T7 RNAP, to assess the quality of in vitro transcribed RNAs. PMID- 28882899 TI - Glucose-Induced Changes in Gene Expression in Human Pancreatic Islets: Causes or Consequences of Chronic Hyperglycemia. AB - Dysregulation of gene expression in islets from patients with type 2 diabetes (T2D) might be causally involved in the development of hyperglycemia, or it could develop as a consequence of hyperglycemia (i.e., glucotoxicity). To separate the genes that could be causally involved in pathogenesis from those likely to be secondary to hyperglycemia, we exposed islets from human donors to normal or high glucose concentrations for 24 h and analyzed gene expression. We compared these findings with gene expression in islets from donors with normal glucose tolerance and hyperglycemia (including T2D). The genes whose expression changed in the same direction after short-term glucose exposure, as in T2D, were considered most likely to be a consequence of hyperglycemia. Genes whose expression changed in hyperglycemia but not after short-term glucose exposure, particularly those that also correlated with insulin secretion, were considered the strongest candidates for causal involvement in T2D. For example, ERO1LB, DOCK10, IGSF11, and PRR14L were downregulated in donors with hyperglycemia and correlated positively with insulin secretion, suggesting a protective role, whereas TMEM132C was upregulated in hyperglycemia and correlated negatively with insulin secretion, suggesting a potential pathogenic role. This study provides a catalog of gene expression changes in human pancreatic islets after exposure to glucose. PMID- 28882897 TI - The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain. AB - T-cell lymphoma invasion and metastasis 1 (Tiam1) is a Dbl-family guanine nucleotide exchange factor (GEF) that specifically activates the Rho-family GTPase Rac1 in response to upstream signals, thereby regulating cellular processes including cell adhesion and migration. Tiam1 contains multiple domains, including an N-terminal pleckstrin homology coiled-coiled extension (PHn-CC-Ex) and catalytic Dbl homology and C-terminal pleckstrin homology (DH-PHc) domain. Previous studies indicate that larger fragments of Tiam1, such as the region encompassing the N-terminal to C-terminal pleckstrin homology domains (PHn-PHc), are auto-inhibited. However, the domains in this region responsible for inhibition remain unknown. Here, we show that the PHn-CC-Ex domain inhibits Tiam1 GEF activity by directly interacting with the catalytic DH-PHc domain, preventing Rac1 binding and activation. Enzyme kinetics experiments suggested that Tiam1 is auto-inhibited through occlusion of the catalytic site rather than by allostery. Small angle X-ray scattering and ensemble modeling yielded models of the PHn-PHc fragment that indicate it is in equilibrium between "open" and "closed" conformational states. Finally, single-molecule experiments support a model in which conformational sampling between the open and closed states of Tiam1 contributes to Rac1 dissociation. Our results highlight the role of the PHn-CC-Ex domain in Tiam1 GEF regulation and suggest a combinatorial model for GEF inhibition and activation of the Rac1 signaling pathway. PMID- 28882898 TI - Switch I-dependent allosteric signaling in a G-protein chaperone-B12 enzyme complex. AB - G-proteins regulate various processes ranging from DNA replication and protein synthesis to cytoskeletal dynamics and cofactor assimilation and serve as models for uncovering strategies deployed for allosteric signal transduction. MeaB is a multifunctional G-protein chaperone, which gates loading of the active 5' deoxyadenosylcobalamin cofactor onto methylmalonyl-CoA mutase (MCM) and precludes loading of inactive cofactor forms. MeaB also safeguards MCM, which uses radical chemistry, against inactivation and rescues MCM inactivated during catalytic turnover by using the GTP-binding energy to offload inactive cofactor. The conserved switch I and II signaling motifs used by G-proteins are predicted to mediate allosteric regulation in response to nucleotide binding and hydrolysis in MeaB. Herein, we targeted conserved residues in the MeaB switch I motif to interrogate the function of this loop. Unexpectedly, the switch I mutations had only modest effects on GTP binding and on GTPase activity and did not perturb stability of the MCM-MeaB complex. However, these mutations disrupted multiple MeaB chaperone functions, including cofactor editing, loading, and offloading. Hence, although residues in the switch I motif are not essential for catalysis, they are important for allosteric regulation. Furthermore, single-particle EM analysis revealed, for the first time, the overall architecture of the MCM-MeaB complex, which exhibits a 2:1 stoichiometry. These EM studies also demonstrate that the complex exhibits considerable conformational flexibility. In conclusion, the switch I element does not significantly stabilize the MCM-MeaB complex or influence the affinity of MeaB for GTP but is required for transducing signals between MeaB and MCM. PMID- 28882901 TI - Chronic Intermittent Hypoxia Impairs Insulin Sensitivity but Improves Whole-Body Glucose Tolerance by Activating Skeletal Muscle AMPK. AB - Obstructive sleep apnea syndrome is a highly prevalent disease resulting in transient respiratory arrest and chronic intermittent hypoxia (cIH). cIH is associated with insulin resistance and impaired metabolic homeostasis in rodents and humans, but the exact underlying mechanisms remain unclear. In the current study, we investigated the effects of 2 weeks of cIH (1-min cycle, fraction of inspired oxygen 21-5%, 8 h/day) on whole-body insulin sensitivity and glucose tolerance in lean mice. Although food intake and body weight were reduced compared with normoxia, cIH induced systemic insulin resistance in a hypoxia inducible factor 1-independent manner and impaired insulin signaling in liver, white adipose tissue, and skeletal muscle. Unexpectedly, cIH improved whole-body glucose tolerance independently of changes in body weight and glucose-induced insulin response. This effect was associated with elevated phosphorylation of Thr172-AMPK and Ser237-TBC1 domain family member 1 (TBC1D1) in skeletal muscle, suggesting a tissue-specific AMPK-dependent increase in TBC1D1-driven glucose uptake. Remarkably, although food intake, body weight, and systemic insulin sensitivity were still affected, the improvement in glucose tolerance by cIH was abolished in muscle-specific AMPKalpha1alpha2-deficient mice. We conclude that cIH impairs insulin sensitivity while improving whole-body glucose tolerance by promoting specific activation of the skeletal muscle AMPK pathway. PMID- 28882900 TI - Adipocyte Liver Kinase b1 Suppresses Beige Adipocyte Renaissance Through Class IIa Histone Deacetylase 4. AB - Uncoupling protein 1+ beige adipocytes are dynamically regulated by environment in rodents and humans; cold induces formation of beige adipocytes, whereas warm temperature and nutrient excess lead to their disappearance. Beige adipocytes can form through de novo adipogenesis; however, how "beiging" characteristics are maintained afterward is largely unknown. In this study, we show that beige adipocytes formed postnatally in subcutaneous inguinal white adipose tissue lost thermogenic gene expression and multilocular morphology at the adult stage, but cold restored their beiging characteristics, a phenomenon termed beige adipocyte renaissance. Ablation of these postnatal beige adipocytes inhibited cold-induced beige adipocyte formation in adult mice. Furthermore, we demonstrated that beige adipocyte renaissance was governed by liver kinase b1 and histone deacetylase 4 in white adipocytes. Although neither presence nor thermogenic function of uncoupling protein 1+ beige adipocytes contributed to metabolic fitness in adipocyte liver kinase b1-deficient mice, our results reveal an unexpected role of white adipocytes in maintaining properties of preexisting beige adipocytes. PMID- 28882902 TI - Increasing organ donation rates by revealing recipient details to families of potential donors. AB - Many families refuse to consent to donation from their deceased relatives or over rule the consent given before death by the patient, but giving families more information about the potential recipients of organs could reduce refusal rates. In this paper, we analyse arguments for and against doing so, and conclude that this strategy should be attempted. While it would be impractical and possibly unethical to give details of actual potential recipients, generic, realistic information about the people who could benefit from organs should be provided to families before they make a decision about donation or attempt to over-rule it. PMID- 28882903 TI - The structure of ethics review: expert ethics committees and the challenge of voluntary research euthanasia. PMID- 28882904 TI - Frontline Science: Proliferation of Ly6C+ monocytes during urinary tract infections is regulated by IL-6 trans-signaling. AB - Ly6C+ monocytes are important components of the innate immune defense against infections. These cells have been shown to proliferate in the bone marrow of mice with systemic infections. However, the proliferative capacity of Ly6C+ monocytes in infected peripheral tissues as well as the associated regulatory mechanisms remain unclear. In this study, we analyzed the proliferative capacity of Ly6C+ monocytes in the urinary bladder after infection with uropathogenic E. coli, one of the most prevalent pathogen worldwide, and in LPS-induced peritonitis. We show that Ly6C+ monocytes proliferated in the bladder after infection with uropathogenic E. coli and in the peritoneum after intraperitoneal injection of LPS. We identified IL-6, a molecule that is highly expressed in infections, as a crucial regulator of Ly6C+ monocyte proliferation. Inhibition of IL-6 via administration of antibodies against IL-6 or gp130 impeded Ly6C+ monocyte proliferation. Furthermore, repression of IL-6 trans-signaling via administration of soluble gp130 markedly reduced the proliferation of Ly6C+ monocytes. Overall, this study describes the proliferation of Ly6C+ monocytes using models of urinary tract infection and LPS-induced peritonitis. IL-6 trans-signaling was identified as the regulator of Ly6C+ monocyte proliferation. PMID- 28882905 TI - Cost comparison of orthopaedic fracture pathways using discrete event simulation in a Glasgow hospital. AB - OBJECTIVE: Healthcare faces the continual challenge of improving outcome while aiming to reduce cost. The aim of this study was to determine the micro cost differences of the Glasgow non-operative trauma virtual pathway in comparison to a traditional pathway. DESIGN: Discrete event simulation was used to model and analyse cost and resource utilisation with an activity-based costing approach. Data for a full comparison before the process change was unavailable so we used a modelling approach, comparing a virtual fracture clinic (VFC) with a simulated traditional fracture clinic (TFC). SETTING: The orthopaedic unit VFC pathway pioneered at Glasgow Royal Infirmary has attracted significant attention and interest and is the focus of this cost study. OUTCOME MEASURES: Our study focused exclusively on patients with non-operative trauma attending emergency department or the minor injuries unit and the subsequent step in the patient pathway. Retrospective studies of patient outcomes as a result of the protocol introductions for specific injuries are presented in association with activity costs from the models. RESULTS: Patients are satisfied with the new pathway, the information provided and the outcome of their injuries (Evidence Level IV). There was a 65% reduction in the number of first outpatient face-to-face (f2f) attendances in orthopaedics. In the VFC pathway, the resources required per day were significantly lower for all staff groups (p<=0.001). The overall cost per patient of the VFC pathway was L22.84 (95% CI 21.74 to 23.92) per patient compared with L36.81 (95% CI 35.65 to 37.97) for the TFC pathway. CONCLUSIONS: Our results give a clearer picture of the cost comparison of the virtual pathway over a wholly traditional f2f clinic system. The use of simulation-based stochastic costings in healthcare economic analysis has been limited to date, but this study provides evidence for adoption of this method as a basis for its application in other healthcare settings. PMID- 28882906 TI - Hospital comparison of stroke care in Sweden: a register-based study. AB - BACKGROUND AND PURPOSE: The objective of this study was to estimate the level of health outcomes and resource use at a hospital level during the first year after a stroke, and to identify any potential differences between hospitals after adjusting for patient characteristics (case mix). METHOD: Data from several registries were linked on individual level: seven regional patient administrative systems, Swedish Stroke Register, Statistics Sweden, National Board of Health and Welfare and Swedish Social Insurance Agency. The study population consisted of 14 125 patients presenting with a stroke during 2010. Case-mix adjusted analysis of hospital differences was made on five aspects of health outcomes and resource use, 1 year post-stroke. RESULTS: The results indicated that 26% of patients had died within a year of their stroke. Among those who survived, almost 5% had a recurrent stroke and 40% were left with a disability. On average, the patients had 22 inpatient days and 23 outpatient visits, and 13% had moved into special housing. There were significant variations between hospitals in levels of health outcomes achieved and resources used after adjusting for case mix. CONCLUSION: Differences in health outcomes and resource use between hospitals were substantial and not entirely explained by differences in patient mix, indicating tendencies of unequal stroke care in Sweden. Healthcare organisation of regions and other structural features could potentially explain parts of the differences identified. PMID- 28882907 TI - Protocol for a systematic review of psychological treatment for methamphetamine use: an analysis of methamphetamine use and mental health symptom outcomes. AB - INTRODUCTION: People who use methamphetamine (MA) regularly, often experience symptoms of mental ill health associated with the use of the drug. These include symptoms of psychosis, depression, anxiety and also cognitive deficits. Accordingly, psychological treatments aim to reduce MA use and related problems, including symptoms of mental ill health. Although there has been a substantial body of research reporting on the evidence of effectiveness of psychological treatments for MA use, there is a paucity of research addressing the effectiveness of these treatments for coexisting symptoms of mental ill health. We aim to address this gap by providing a comprehensive overview of the evidence for psychological treatments for MA use and associated symptoms of mental ill health in experimental/controlled clinical studies. In addition, a critical evaluation of study methods and the outcomes of psychological interventions on MA use and symptoms of mental ill health will be conducted. METHODS AND ANALYSIS: The Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement will be used to inform the methods of this review. Eight electronic peer-reviewed databases will be searched. Pilot searches have been conducted for MA literature considering controlled clinical trials only. Eligible articles will be independently assessed against inclusion criteria. Before final analyses are completed, searches will be rerun and if eligible, additional studies will be retrieved for inclusion. A quantitative synthesis of the findings will be reported where possible, and 'summary of findings' tables will be generated for each comparison. Risk ratios and 95% CI (dichotomous outcomes) will be calculated and/or effect size according to Cohen's formula (continuous outcomes) for the primary outcome of each trial. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Findings will be disseminated widely to clinicians and researchers via journal publication and conference presentation(s). TRIAL REGISTRATION NUMBER: CRD42016043657. PMID- 28882908 TI - What are the key contextual factors when preparing for successful implementation of assistive living technology in primary elderly care? A case study from Norway. AB - OBJECTIVE: To identify contextual factors at different organisational levels to guide the implementation of an assistive living technology intervention in Norwegian primary home care. DESIGN: A single embedded case study design was carried out in an urban municipality in Western Norway to get an overview of key contextual factors from the municipality's perspective. DATA COLLECTION AND ANALYSIS: The data collection was based on a triangulation of methods involving document analysis, semi-structured individual interviews and focus group interviews to get a broad insight when preparing for an intervention. Data were collected on three levels of the healthcare system: (1) national policy documents and regulations (macro), (2) five individual interviews with senior managers and municipal strategy documents (meso) and (3) two focus group interviews with nurses and nurse managers in direct patient care (micro). The Model for Understanding Success in Quality framework was used as a guide in the data analysis. RESULTS: The main contextual factors identified were external motivators and project sponsorship (macro level); leadership, workforce focus and maturity (meso level);and motivation to change and maturity (micro level). Strategies developed in policy documents affected upper management in the municipality, but healthcare personnel at the micro level were not so familiar with strategies and emphasis on assistive living technologies. Healthcare personnel in our study were motivated to use technological solutions, but lack of data infrastructure and resource availability hindered this. CONCLUSIONS: Aligning interests across multiple stakeholders remain a challenge when planning for an assistive living technology intervention in primary care. In the studied municipality, integration of technological solutions into healthcare services was more a vision than a reality because of a low level of organisational readiness. PMID- 28882909 TI - Effect of time and day of admission on hospital care quality for patients with chronic obstructive pulmonary disease exacerbation in England and Wales: single cohort study. AB - OBJECTIVE: To evaluate if observed increased weekend mortality was associated with poorer quality of care for patients admitted to hospital with chronic obstructive pulmonary disease (COPD) exacerbation. DESIGN: Prospective case ascertainment cohort study. SETTING: 199 acute hospitals in England and Wales, UK. PARTICIPANTS: Consecutive COPD admissions, excluding subsequent readmissions, from 1 February to 30 April 2014 of whom 13 414 cases were entered into the study. MAIN OUTCOMES: Process of care mapped to the National Institute for Health and Care Excellence clinical quality standards, access to specialist respiratory teams and facilities, mortality and length of stay, related to time and day of the week of admission. RESULTS: Mortality was higher for weekend admissions (unadjusted OR 1.20, 95% CI 1.00 to 1.43), and for case-mix adjusted weekend mortality when calculated for admissions Friday morning through to Monday night (adjusted OR 1.19, 95% CI 1.00 to 1.43). Median time to death was 6 days. Some clinical processes were poorer on Mondays and during normal working hours but not weekends or out of hours. Specialist respiratory care was less available and less prompt for Friday and Saturday admissions. Admission to a specialist ward or high dependency unit was less likely on a Saturday or Sunday. CONCLUSIONS: Increased mortality observed in weekend admissions is not easily explained by deficiencies in early clinical guideline care. Further study of out-of-hospital factors, specialty care and deaths later in the admission are required if effective interventions are to be made to reduce variation by day of the week of admission. PMID- 28882910 TI - Crossover trial to test the acceptability of a locally produced lipid-based nutrient supplement (LNS) for children under 2 years in Cambodia: a study protocol. AB - INTRODUCTION: The acceptability and efficacy of existing ready-to-use supplementary and therapeutic foods has been low in Cambodia, thus limiting success in preventing and treating malnutrition among Cambodian children. In that context, UNICEF and IRD have developed a locally produced, multiple micronutrient fortified lipid-based nutrient supplement. This food is innovative, in that it uses fish instead of milk as the animal source food. Very few supplementary foods have non-milk animal source foods, and in addition they have not been widely tested. This trial will assess the novel food's acceptability to children and caregivers. METHODS AND ANALYSIS: This is a cluster-randomised, incomplete block, 4*4 crossover design with no blinding. It will take place in four sites in a community setting in periurban Phnom Penh. Healthy children aged 9-23 months (n=100) will eat each of four foods for 3 days at a time. The amount they consume will be measured, and at the end of each 3-day set, caregivers will assess how well their child liked the food. After 12 days, caregivers themselves will do a sensory test of the 4 foods and will rank them in terms of preference. ETHICS AND DISSEMINATION: Ethical clearance was received from the University of Queensland Medical Research Ethics Committee (2014001070) and from Cambodia's National Ethics Committee for Health Research (03/8 NECHR). REGISTRATION: ClinicalTrials.gov, identifier: LNS-CAMB-INFANTS; NCT02257437. Pre-results. PMID- 28882911 TI - Predictors of HIV virological failure and drug resistance in Chinese patients after 48 months of antiretroviral treatment, 2008-2012: a prospective cohort study. AB - OBJECTIVE: To explore factors associated with HIV virological failure (VF) and HIV drug resistance (HIVDR) among HIV-positive Chinese individuals 4 years after initiating first-line lamivudine-based antiretroviral treatment (ART) in 2008 at five sentinel sites. DESIGN: First-line ART initiators who were previously treatment naive were selected using consecutive ID numbers from the 2008 National Surveillance Database into a prospective cohort study. Questionnaires and blood samples were collected in 2011 and 2012 to assess the outcomes of interest: VF (defined as viral load >=1000 copies/mL) and HIVDR (defined as VF with genetic drug-resistant mutations). Questionnaires and data from National Surveillance Database assessed demographics and drug adherence data. RESULTS: 536 individuals with HIV were analysed; the 4-year risk of VF was 63 (11.8%) and HIVDR was 27 (5.0%). Female participants initiating stavudine (D4T)-based regimens were more susceptible to both VF (adjusted OR (aOR)=2.5, 95% CI 1 to 6.1, p=0.04) and HIVDR (aOR=3.6, 95% CI 1 to 12.6, p=0.05) versus zidovudine-based regimens. Male participants missing doses in past month were more susceptible to both VF (aOR=2.8, 95% CI 1.1 to 7, p=0.03) and HIVDR (aOR=9.7, 95% CI 2.1 to 44.1, p<0.01). Participants of non-Han nationality were of increased risk for HIVDR (aOR from 4.8 to 12.2, p<0.05) and non-Han men were at increased risk for VF (aOR=2.9, 95% CI 1.1 to 7.3, p=0.02). All 27 participants detected with HIVDR had non-nucleoside reverse-transcriptase inhibitor mutations, 21 (77.8%) also had nucleoside reverse-transcriptase inhibitor mutations, and no protease inhibitor mutations were detected. CONCLUSIONS: Our findings suggest successful treatment outcomes at 4 years for roughly 90% of patients. We suggest conducting further study on whether and when to change ART regimen for women initiated with D4T based regimen, and reinforcing adherence counselling for men. Increased VF and HIVDR risk among non-Han minorities warrants further exploration, and ethnic minorities may be an important group to tailor adherence-focused interventions. PMID- 28882912 TI - What is the test-retest reliability of the Malay version of the Hypertension Self Care Profile self efficacy assessment tool? A validation study in primary care. AB - OBJECTIVES: Self-efficacy and self-care measures are key attributes to optimal control of essential hypertension. Self-efficacy can be measured by the Hypertension Self-Care Profile (HTN-SCP) tool but its utility is dependent on the literacy and understanding of the subjects. A Malay version of the HTN-SCP Tool was developed to assess self-efficacy of Malay-literate patients with hypertension in the multi-ethnic Asian population in Singapore. The study aimed to determine the test-retest reliability of this tool which has been translated in Malay language. METHODS AND MATERIAL: 145 Malay-literate patients, aged 41-70 years, with essential hypertension were recruited in a polyclinic (primary care clinic) in Singapore. Forty-three percent of them completed both the first and second HTN SCP tool online, with a period of two weeks in between. The Cronbach's alpha and Intra-class correlation coefficient (ICC) were computed to assess its test-retest reliability and internal consistency. RESULTS: The Cronbach's alpha/ICC for "Behavior" (0.851/0.664)), "Motivation" (0.928/0.655) and "Self efficacy" (0.945/0.682) domains showed high internal consistency, fair to good reliability and stability. No floor or ceiling effect was found for the "behavior" and "motivation" domains. However, the borderline ceiling effect (15.2) for "self-efficacy" suggested limited discriminating power of the tool for patients with high self-efficacy. Positive association was shown between the HTN SCP score and reported self-care measures but it was not statistically significant. CONCLUSION: Overall, the translated HTN-SCP tool showed satisfactory test-retest reliability and internal consistency amongst the Malay-literate study population. Further research is needed for its application in general practice to identify patients with low self-efficacy for possible intervention. PMID- 28882913 TI - Hospital volume and mortality for 25 types of inpatient treatment in German hospitals: observational study using complete national data from 2009 to 2014. AB - OBJECTIVES: To explore the existence and strength of a relationship between hospital volume and mortality, to estimate minimum volume thresholds and to assess the potential benefit of centralisation of services. DESIGN: Observational population-based study using complete German hospital discharge data (Diagnosis Related Group Statistics (DRG Statistics)). SETTING: All acute care hospitals in Germany. PARTICIPANTS: All adult patients hospitalised for 1 out of 25 common or medically important types of inpatient treatment from 2009 to 2014. MAIN OUTCOME MEASURE: Risk-adjusted inhospital mortality. RESULTS: Lower inhospital mortality in association with higher hospital volume was observed in 20 out of the 25 studied types of treatment when volume was categorised in quintiles and persisted in 17 types of treatment when volume was analysed as a continuous variable. Such a relationship was found in some of the studied emergency conditions and low-risk procedures. It was more consistently present regarding complex surgical procedures. For example, about 22 000 patients receiving open repair of abdominal aortic aneurysm were analysed. In very high-volume hospitals, risk-adjusted mortality was 4.7% (95% CI 4.1 to 5.4) compared with 7.8% (7.1 to 8.7) in very low volume hospitals. Theminimum volume above which risk of death would fall below the average mortality was estimated as 18 cases per year. If all hospitals providing this service would perform at least 18 cases per year, one death among 104 (76 to 166) patients could potentially be prevented. CONCLUSIONS: Based on complete national hospital discharge data, the results confirmed volume-outcome relationships for many complex surgical procedures, as well as for some emergency conditions and low-risk procedures. Following these findings, the study identified areas where centralisation would provide a benefit for patients undergoing the specific type of treatment in German hospitals and quantified the possible impact of centralisation efforts. PMID- 28882914 TI - Procedural Pain Scale Evaluation (PROPoSE) study: protocol for an evaluation of the psychometric properties of behavioural pain scales for the assessment of procedural pain in infants and children aged 6-42 months. AB - INTRODUCTION: Infants and children are frequently exposed to painful medical procedures such as immunisation, blood sampling and intravenous access. Over 40 scales for pain assessment are available, many designed for neonatal or postoperative pain. What is not well understood is how well these scales perform when used to assess procedural pain in infants and children. AIM: The aim of this study was to test the psychometric and practical properties of the Face, Legs, Activity, Cry and Consolability (FLACC) scale, the Modified Behavioural Pain Scale (MBPS) and the Visual Analogue Scale (VAS) observer pain scale to quantify procedural pain intensity in infants and children aged from 6-42 months to determine their suitability for clinical and research purposes. METHODS AND ANALYSIS: A prospective observational non-interventional study conducted at a single centre. The psychometric and practical performance of the FLACC scale, MBPS and the VAS observer pain scale and VAS observer distress scale used to assess children experiencing procedural pain will be assessed. Infants and young children aged 6-42 months undergoing one of four painful and/or distressing procedures were recruited and the procedure digitally video recorded. Clinicians and psychologists will be recruited to independently apply the scales to these video recordings to establish intrarater and inter-rater reliability, convergent validity responsiveness and specificity. Pain score distributions will be presented descriptively; reliability will be assessed using the intraclass correlation coefficient and Bland-Altman plots. Spearman correlations will be used to assess convergence and linear mixed modelling to explore the responsiveness of the scales to pain and their capacity to distinguish between pain and distress. ETHICS AND DISSEMINATION: Ethical approval was provided by the Royal Children's Hospital Human Research Ethics Committee, approval number 35220B. The findings of this study will be disseminated via peer-reviewed journals and presented at international conferences. PMID- 28882915 TI - Patient experience and perceived acceptability of whole-body magnetic resonance imaging for staging colorectal and lung cancer compared with current staging scans: a qualitative study. AB - OBJECTIVE: To describe the experience and acceptability of whole-body magnetic resonance imaging (WB-MRI) staging compared with standard scans among patients with highly suspected or known colorectal or lung cancer. DESIGN: Qualitative study using one-to-one interviews with thematic analysis. SETTING: Patients recruited from 10 hospitals in London, East and South East England between March 2013 and July 2014. PARTICIPANTS: 51 patients (31 male, age range 40-89 years), with varying levels of social deprivation, were recruited consecutively from two parallel clinical trials comparing the diagnostic accuracy and cost-effectiveness of WB-MRI with standard scans for staging colorectal and lung cancer ('Streamline C' and 'Streamline-L'). WB-MRI was offered as an additional scan as part of the trials. RESULTS: In general WB-MRI presented a greater challenge than standard scans, although all but four patients completed the WB-MRI. Key challenges were enclosed space, noise and scan duration; reduced patient tolerance was associated with claustrophobia, pulmonary symptoms and existing comorbidities. Coping strategies facilitated scan tolerance and were grouped into (1) those intended to help with physical and emotional challenges, and (2) those focused on motivation to complete the scan, for example focusing on health benefit. Our study suggests that good staff communication could reduce anxiety and boost coping strategies. CONCLUSIONS: Although WB-MRI was perceived as more challenging than standard scans, it was sufficiently acceptable and tolerated by most patients to potentially replace them if appropriate. TRIAL REGISTRATION NUMBER: ISRCTN43958015 and ISRCTN50436483. PMID- 28882916 TI - Incidence of laboratory-confirmed influenza disease among infants under 6 months of age: a systematic review. AB - OBJECTIVES: The aim of this systematic review was to assess incidence rates of laboratory-confirmed influenza (LCI) outcomes among infants under 6 months of age. DESIGN: Systematic literature search and review of indexed studies in PubMed, EMBASE, the Cochrane Library and CINAHL Plus from inception to 19 April 2017. SETTING: Population-based estimates from community or hospital settings. PARTICIPANTS: Infants under 6 months of age. PRIMARY AND SECONDARY OUTCOME MEASURES: LCI illness in ambulatory care settings, LCI hospitalisation, LCI intensive care unit admission and LCI death. Only studies with population-based incidence data were included. RESULTS: We identified 27 primary studies, 11 of which were from the USA, four were from other non-US high-income settings and the remaining were from lower-middle-income or upper-middle-income countries. Most studies (n=23) assessed incidence of LCI hospitalisation, but meta-analysis to pool study-specific rates was not possible due to high statistical and methodological heterogeneity. Among US studies, the reported incidence of LCI hospitalisation ranged from 9.3 to 91.2 per 10 000 infants under 6 months for seasonal influenza, while the only US-based estimate for pandemic H1N1 influenza was 20.2 per 10 000 infants. Reported rates for LCI hospitalisation for seasonal influenza from other countries ranged from 6.2 to 73.0 per 10 000 infants under 6 months, with the exception of one study with an estimated rate of 250 per 10 000 infants. No events were reported in five of the nine studies that evaluated LCI death among infants under 6 months. CONCLUSION: Our review of published studies found limited data on LCI outcomes for infants under 6 months, particularly from non-US settings. Globally representative and reliable incidence data are necessary to fully evaluate influenza disease burden and the potential impact of maternal influenza immunisation programme on morbidity and mortality in young infants. PMID- 28882917 TI - Effects of cerebral near-infrared spectroscopy on the outcome of patients undergoing cardiac surgery: a systematic review of randomised trials. AB - OBJECTIVES: Goal-directed optimisation of cerebral oxygenation using near infrared spectroscopy (NIRS) during cardiopulmonary bypass is widely used. We tested the hypotheses that the use of NIRS cerebral oximetry results in reductions in cerebral injury (neurocognitive function, serum biomarkers), injury to other organs including the heart and brain, transfusion rates, mortality and resource use. DESIGN: Systematic review and meta-analysis. SETTING: Tertiary cardiac surgery centres in North America, Europe and Asia. PARTICIPANTS: A search of Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature Plus from inception to November 2016 identified 10 randomised trials, enrolling a total of 1466 patients, all in adult cardiac surgery. INTERVENTIONS: NIRS-based algorithms designed to optimise cerebral oxygenation versus standard care (non NIRS-based) protocols in cardiac surgery patients during cardiopulmonary bypass. OUTCOME MEASURES: Mortality, organ injury affecting the brain, heart and kidneys, red cell transfusion and resource use. RESULTS: Two of the 10 trials identified in the literature search were considered at low risk of bias. Random-effects meta analysis demonstrated similar mortality (risk ratio (RR) 0.76, 95% CI 0.30 to 1.96), major morbidity including stroke (RR 1. 08, 95% CI 0.40 to 2.91), red cell transfusion and resource use in NIRS-treated patients and controls, with little or no heterogeneity. Grades of Recommendation, Assessment, Development and Evaluation of the quality of the evidence was low or very low for all of the outcomes assessed. CONCLUSIONS: The results of this systematic review did not support the hypotheses that cerebral NIRS-based algorithms have clinical benefits in cardiac surgery. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015027696. PMID- 28882918 TI - Prevalence and clinical characteristics of apparent therapy-resistant hypertension in patients with cardiovascular disease: a cross-sectional cohort study in secondary care. AB - OBJECTIVES: Our aim was to investigate the prevalence of apparent therapy resistant hypertension (aTRH) in patients with clinical manifest cardiovascular disease (CVD), and to study clinical characteristics related to aTRH in this population. SETTING: The SMART (Second Manifestations of ARTerial disease) study is a large, single-centre cohort study in secondary care. PARTICIPANTS: Office blood pressure (BP) at inclusion was used to evaluate BP control in 6191 hypertensive patients with clinical manifest (cardio)vascular disease. Therapy resistant hypertension was defined as BP >=140/90 mm Hg despite use of antihypertensive drugs from >=3 drug classes including a diuretic or use of >=4 antihypertensive drugs irrespective of BP. Logistic regression analysis was used to explore the relationship between clinical characteristics measured at baseline and presence of aTRH. RESULTS: The prevalence of aTRH was 9.1% (95% CI 8.4 to 9.8). Prevalence increased with age and when albuminuria was present and was higher in patients with lower estimated glomerular filtration rate (eGFR). Presence of aTRH was related to diabetes, female sex, duration and multiple locations of vascular disease, body mass index and waist circumference. Carotid intima-media thickness was higher (0.99+/-0.28 vs 0.93+/-0.28 mm) and ankle brachial index lower (1.07+/-0.20 vs 1.10+/-0.19) in patients with aTRH compared with patients without aTRH. CONCLUSION: aTRH is prevalent in patients with clinical manifest CVD and is related to clinical factors known to be related with increased vascular risk, and with lower eGFR. PMID- 28882919 TI - A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity. AB - INTRODUCTION: Stroke is the most disabling neurological disorder and often causes spasticity. Transmucosal cannabinoids (tetrahydrocannabinol and cannabidiol (THC:CBD), Sativex) is currently available to treat spasticity-associated symptoms in patients with multiple sclerosis. Cannabinoids are being considered useful also in the treatment of pain, nausea and epilepsy, but may bear and increased risk for cardiovascular events. Spasticity is often assessed with subjective and clinical rating scales, which are unable to measure the increased excitability of the monosynaptic reflex, considered the hallmark of spasticity. The neurophysiological assessment of the stretch reflex provides a precise and objective method to measure spasticity. We propose a novel study to understand if Sativex could be useful in reducing spasticity in stroke survivors and investigating tolerability and safety by accurate cardiovascular monitoring. METHODS AND ANALYSIS: We will recruit 50 patients with spasticity following stroke to take THC:CBD in a double-blind placebo-controlled cross-over study. Spasticity will be assessed with a numeric rating scale for spasticity, the modified Ashworth scale and with the electromyographical recording of the stretch reflex. The cardiovascular risk will be assessed prior to inclusion. Blood pressure, heart rate, number of daily spasms, bladder function, sleep disruption and adverse events will be monitored throughout the study. A mixed-model analysis of variance will be used to compare the stretch reflex amplitude between the time points; semiquantitative measures will be compared using the Mann-Whitney test (THC:CBD vs placebo) and Wilcoxon test (baseline vs treatment). ETHICS AND DISSEMINATION: The study was registered on the EudraCT database with number 2016 001034-10 and approved by both the Italian Medicines Agency (Agenzia Italiana del Farmaco) and local Ethics Committee 'Comitato Etico Regionale della Liguria'. Data will be made anonymous and uploaded to a open access repository. Results will be disseminated by presentations at national and international conferences and by publication in journals of clinical neuroscience and neurology. PMID- 28882920 TI - The HAT TRICK programme for improving physical activity, healthy eating and connectedness among overweight, inactive men: study protocol of a pragmatic feasibility trial. AB - INTRODUCTION: Physical activity, healthy eating and maintaining a healthy weight are associated with reduced risk of cardiovascular disease, type 2 diabetes and cancer and with improved mental health. Despite these benefits, many men do not meet recommended physical activity guidelines and have poor eating behaviours. Many health promotion programmes hold little appeal to men and consequently fail to influence men's health practices. HAT TRICK was designed as a 12-week face-to face, gender-sensitised intervention for overweight and inactive men focusing on physical activity, healthy eating and social connectedness and was delivered in collaboration with a major junior Canadian ice hockey team (age range 16-20 years). The programme was implemented and evaluated to assess its feasibility. This article describes the intervention design and study protocol of HAT TRICK. METHODS AND ANALYSIS: HAT TRICK participants (n=60) were men age 35 years, residing in the Okanagan Region of British Columbia, who accumulate 150 min of moderate to vigorous physical activity a week, with a body mass index of >25 kg/m2 and a pant waist size of >38'. Each 90 min weekly session included targeted health education and theory-guided behavioural change techniques, as well as a progressive (ie, an increase in duration and intensity) group physical activity component. Outcome measures were collected at baseline, 12 weeks and 9 months and included the following: objectively measured anthropometrics, blood pressure, heart rate, physical activity and sedentary behaviour, as well as self-reported physical activity, sedentary behaviour, diet, smoking, alcohol consumption, sleep habits, risk of depression, health-related quality of life and social connectedness. Programme feasibility data (eg, recruitment, satisfaction, adherence, content delivery) were assessed at 12 weeks via interviews and self report. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of British Columbia Okanagan Behavioural Research Ethics Board (reference no H1600736). Study findings will be disseminated through academic meetings, peer-reviewed publication, web-based podcasts, social media, plain language summaries and co-delivered community presentations. TRIAL REGISTRATION NUMBER: ISRCTN43361357,Pre results. PMID- 28882921 TI - Women's decision-making autonomy and utilisation of maternal healthcare services: results from the Bangladesh Demographic and Health Survey. AB - OBJECTIVES: The aim of this study was to determine the association between women's decision-making power and utilisation of maternal healthcare services (MHS) among Bangladeshi women. SETTINGS: This is a nationally representative survey that encompassed Dhaka, Rajshahi, Rangpur, Chittagong, Khulna, Barisal and Sylhet in Bangladesh. Sample households were selected by a two-stage stratification technique. First, 207 clusters in urban areas and 393 in rural areas were selected for 600 enumeration areas with proportional probability. In the second stage, on average 30 households were selected systematically from the enumeration areas. Finally, 17 989 households were selected for the survey of which 96% were interviewed successfully. PARTICIPANTS: Cross-sectional data on 4309 non-pregnant women were collected from Bangladesh demographic and health survey 2014. Decision-making status on respondent's own healthcare, large household purchases, having a say on child's healthcare and visiting to family or relatives were included in the analysis. RESULTS: Prevalence of at least four antenatal attendance, facility delivery and postnatal check-up were respectively 32.6% (95% CI 31.2 to 34), 40.6% (95% CI 39.13 to 42.07) and 66.3% (95% CI 64.89 to 67.71). Compared with women who could make decisions alone, women in the urban areas who had to decide on their healthcare with husband/partner had 20% (95% CI 0.794 to 1.799) higher odds of attending at least four antenatal visits and those in rural areas had 35% (95% CI 0.464 to 0.897) lower odds of attending at least four antenatal visits. Women in urban and rural areas had respectively 43% (95% CI 0.941 to 2.169) and 28% (95% CI 0.928 to 1.751) higher odds of receiving postnatal check-up when their health decisions were made jointly with their husband/partner. CONCLUSION: Neither making decisions alone, nor deciding jointly with husband/partner was always positively associated with the utilisation of all three types of MHS. This study concludes that better spousal cooperation on household and health issues could lead to higher utilisation of MHS services. PMID- 28882922 TI - Rectal water contrast transvaginal ultrasound versus double-contrast barium enema in the diagnosis of bowel endometriosis. AB - OBJECTIVES: The aim of study was to compare the accuracy between rectal water contrast transvaginal ultrasound (RWC-TVS) and double-contrast barium enema (DCBE) in evaluating the bowel endometriosis presence as well as its extent. DESIGN AND SETTING: 198 patients at reproductive age with suspicious bowel endometriosis were included. Physicians in two groups specialised at endometriosis performed RWC-TVS as well as DCBE before laparoscopy and both groups were blinded to other groups' results. Findings from RWC-TVS or DCBE were compared with histological results. The severity of experienced pain severity through RWC-TVS or DCBE was assessed by an analogue scale of 10 cm. RESULTS: In total, 110 in 198 women were confirmed to have endometriosis nodules in the bowel by laparoscopy as well as histopathology. For bowel endometriosis diagnosis, DCBE and RWC-TVS demonstrated sensitivities of 96.4% and 88.2%, specificities of 100% and 97.3%, positive prediction values of 100% and 98.0%, negative prediction values of 98.0% and 88.0%, accuracies of 98.0% and 92.4%, respectively. DCBE was related to more tolerance than RWC-TVS. CONCLUSIONS: RWC-TVS and DCBE demonstrated similar accuracies in the bowel endometriosis diagnosis; however, patients showed more tolerance for RWC-TVS than those with DCBE. PMID- 28882923 TI - 'Reframing Healthcare Services through the Lens of Co-Production' (RheLaunCh): a study protocol for a mixed methods evaluation of mechanisms by which healthcare and social services impact the health and well-being of patients with COPD and CHF in the USA and The Netherlands. AB - INTRODUCTION: The USA lags behind other high-income countries in many health indicators. Outcome differences are associated with differences in the relative spending between healthcare and social services at the national level. The impact of the ratio and delivery of social and healthcare services on the individual patient's health is however unknown. 'Reframing Healthcare Services through the Lens of Co-Production' (RheLaunCh) will be a cross-Atlantic comparative study of the mechanisms by which healthcare and social service delivery may impact patient health with chronic conditions. Insight into these mechanisms is needed to better and cost-effectively organise healthcare and social services. METHODS: We designed a mixed methods study to compare the socioeconomic background, needs of and service delivery to patients with congestive heart failure and chronic obstructive pulmonary disease in the USA and the Netherlands. We will conduct: (1) a literature scan to compare national and regional healthcare and social service systems; (2) a retrospective database study to compare patient's socioeconomic and clinical characteristics and the service use and spending at the national, regional and hospital level; (3) a survey to compare patient perceived quality of life, receipt and experience of service delivery and ability of these services to meet patient needs; and (4) multiple case studies to understand what patients need to better govern their quality of life and how needs are met by services. ETHICS AND DISSEMINATION: Ethics approval was granted by the ethics committee of the Radboud University Medical Center (2016-2423) in the Netherlands and by the Human Subjects Research Committee of the Hennepin Health Care System, Inc. (HSR #16-4230) in the USA. Multiple approaches will be used for dissemination of results, including (inter)national research presentations and peer-reviewed publications. A website will be established to support the development of a community of practice. PMID- 28882924 TI - Factors associated with mortality due to neonatal pneumonia in India: a protocol for systematic review and planned meta-analysis. AB - INTRODUCTION: India contributes to the highest number of neonatal deaths globally. It also has the greatest number of pneumonia-related neonatal deaths in the developing world. We aim to systematically review the evidence for the factors associated with mortality due to neonatal pneumonia in the Indian context, to address the lack of consolidated evidence on this important issue. METHODS AND ANALYSIS: This protocol is part of a series of three reviews on neonatal pneumonia in India. Observational studies reporting on outcome of neonatal pneumonia in the Indian context, and published in English in peer reviewed and indexed journals will be eligible for inclusion. Outcomes of this review will be the factors determining mortality due to neonatal pneumonia. A total of nine databases will be searched. Electronic and hand searching of published and grey literature will be performed. Selection of studies will be done in title, abstract and full text screening stages. Risk of bias, independently assessed by two authors, will be evaluated. Meta-analysis will be performed and heterogeneity assessed. Pooled effect estimates will be stated with 95% confidence intervals. Narrative synthesis will be done where meta-analysis cannot be performed. Publication bias will be evaluated and sensitivity analysis performed according to study quality. Quality of this review will be evaluated using AMSTAR (Assessing the Methodological quality of Systematic Reviews) and GRADE (Grades of Recommendation, Assessment, Development & Evaluation). A summary of findings table will be reported using GRADEPro. ETHICS AND DISSEMINATION: Since this is a review involving analysis of secondary data which is available in the public domain, and does not involve human participants, ethical approval was not required. The findings of the study will be shared with all stakeholders of this research. Knowledge dissemination workshops will be conducted with relevant stakeholders to transfer the evidence, tailored to the stakeholder (eg, policy briefs, publications, information booklets, etc). PMID- 28882925 TI - SNAP-2 EPICCS: the second Sprint National Anaesthesia Project-EPIdemiology of Critical Care after Surgery: protocol for an international observational cohort study. AB - INTRODUCTION: The admission of high-risk patients to critical care after surgery is a recommended standard of care. Nevertheless, poor compliance against this recommendation has been repeatedly demonstrated in large epidemiological studies. It is unclear whether this is due to reasons of capacity, equipoise, poor quality clinical care or because hospitals are working creatively to create capacity for augmented care on normal surgical wards. The EPIdemiology of Critical Care after Surgery study aims to address these uncertainties. METHODS AND ANALYSIS: One-week observational cohort study in the UK and Australasia. All patients undergoing inpatient (overnight stay) surgery will be included. All will have prospective data collection on risk factors, surgical procedure and postoperative outcomes including the primary outcome of morbidity (measured using the Postoperative Morbidity Survey on day 7 after surgery) and secondary outcomes including length of stay and mortality. Data will also be collected on critical care referral and admission, surgical cancellations and critical care occupancy. The epidemiology of patient characteristics, processes and outcomes will be described. Inferential techniques (multilevel multivariable regression, propensity score matching and instrumental variable analysis) will be used to evaluate the relationship between critical care admission and postoperative outcome. ETHICS AND DISSEMINATION: The study has received ethical approval from the National Research Ethics Service in the UK and equivalent in Australasia. The collection of patient identifiable data without prior consent has been approved by the Confidentiality Advisory Group (England and Wales) and the Public Privacy and Patient Benefit Panel (Scotland). In these countries, patient identifiable data will be used to link prospectively collected data with national registers of death and inpatient administrative data. The study findings will be disseminated using a multimedia approach with the support of our lay collaborators, to patients, public, policy-makers, clinical and academic audiences. PMID- 28882926 TI - Digital technology to facilitate Proactive Assessment of Obesity Risk during Infancy (ProAsk): a feasibility study. AB - OBJECTIVE: To assess the feasibility and acceptability of using digital technology for Proactive Assessment of Obesity Risk during Infancy (ProAsk) with the UK health visitors (HVs) and parents. DESIGN: Multicentre, pre- and post intervention feasibility study with process evaluation. SETTING: Rural and urban deprived settings, UK community care. PARTICIPANTS: 66 parents of infants and 22 HVs. INTERVENTION: ProAsk was delivered on a tablet device. It comprises a validated risk prediction tool to quantify overweight risk status and a therapeutic wheel detailing motivational strategies for preventive parental behaviour. Parents were encouraged to agree goals for behaviour change with HVs who received motivational interviewing training. OUTCOME MEASURES: We assessed recruitment, response and attrition rates. Demographic details were collected, and overweight risk status. The proposed primary outcome measure was weight-for age z-score. The proposed secondary outcomes were parenting self-efficacy, maternal feeding style, infant diet and exposure to physical activity/sedentary behaviour. Qualitative interviews ascertained the acceptability of study processes and intervention fidelity. RESULTS: HVs screened 324/589 infants for inclusion in the study and 66/226 (29%) eligible infants were recruited. Assessment of overweight risk was completed on 53 infants and 40% of these were identified as above population risk. Weight-for-age z-score (SD) between the infants at population risk and those above population risk differed significantly at baseline (-0.67 SD vs 0.32 SD). HVs were able to collect data and calculate overweight risk for the infants. Protocol adherence and intervention fidelity was a challenge. HVs and parents found the information provided in the therapeutic wheel appropriate and acceptable. CONCLUSION: Study recruitment and protocol adherence were problematic. ProAsk was acceptable to most parents and HVs, but intervention fidelity was low. There was limited evidence to support the feasibility of implementing ProAsk without significant additional resources. A future study could evaluate ProAsk as a HV-supported, parent-led intervention. TRIAL REGISTRATION NUMBER: NCT02314494 (Feasibility Study Results). PMID- 28882927 TI - Sharp instrument injuries among hospital healthcare workers in mainland China: a cross-sectional study. AB - OBJECTIVES: To determine the prevalence of sharp instrument injuries in hospital based healthcare workers (HCWs) in mainland China and the contributing factors. DESIGN: Cross-sectional study. SETTING: The data were derived from public hospitals. PARTICIPANTS: A total of 360 hospitals were recruited in the study, including 289 general hospitals and 71 specialised hospitals. Among them, 194 are tertiary-level hospitals and 166 are secondary level. The study population finally consisted of 223 149 hospital HCWs. PRIMARY OUTCOME MEASURES: A questionnaire was designed based on the aim of the study. Profession of HCWs, workplace, circumstance and medical apparatus and instrument were covered in the survey. HCWs completed a self-administered questionnaire regarding details of sharp instrument injuries within the previous month. Prevalence estimates for the injuries were calculated for the overall HCWs and for subgroups according to profession, workplace, circumstance or instrument. RESULTS: Within the included HCWs, the prevalence of sharp instrument injuries was 0.08 per person-month. Only 4.6% of the HCWs reported to their hospitals after injury. The highest number of injuries occurred in nursing staff (10.3%). Injuries took place most frequently on general wards (44.5%). The circumstances that involved most frequent injuries include surgical needle insertion, removing an arteriovenous needle from a patient and recapping the needle. Single-use syringe caused more injuries incidents than other instruments. CONCLUSIONS: These results indicate that sharp instrument injuries have become a major occupational problem of HCWs in mainland China. Attentions need to be paid to the issue and strategies for preventing such injuries are needed. PMID- 28882928 TI - Psychological and support interventions to reduce levels of stress, anxiety or depression on women's subsequent pregnancy with a history of miscarriage: an empty systematic review. AB - OBJECTIVE: The aim of this systematic review was to assess the effect of interventions to reduce stress in pregnant women with a history of miscarriage. DESIGN: A systematic review of randomised controlled trials (RCTs). DATA SOURCE: A total of 13 medical, psychological and social electronic databases were searched from January 1995 to April 2016 including PUBMED, CENTRAL, Web of Science and EMBASE. ELIGIBILITY CRITERIA: This review focused on women in their subsequent pregnancy following miscarriage. All published RCTs which assessed the effect of non-medical interventions such as counselling or support interventions on psychological and mental health outcomes such as stress, anxiety or depression when compared with a control group were included. Stress, anxiety or depression had to be measured at least preintervention and postintervention. RESULTS: This systematic review found no RCT which met our initial inclusion criteria. Of the 4140 titles screened, 17 RCTs were identified. All of them were excluded. One RCT, which implemented a caring-based intervention, included pregnant women in their subsequent pregnancy; however, miscarriage was analysed as a composite variable among other pregnancy losses such as stillbirth and neonatal death. Levels of perceived stress were measured by four RCTs. Different types of non medical interventions, time of follow-up and small sample sizes were found. CONCLUSION: Cohort studies and RCTs in non-pregnant women suggest that support and psychological interventions may improve pregnant women's psychological well being after miscarriage. This improvement may reduce adverse pregnancy-related outcomes in subsequent pregnancies. However, this review found no RCTs which met our criteria. There is a need for targeted RCTs that can provide reliable and conclusive results to determine effective interventions for this vulnerable group. PMID- 28882931 TI - Livedoid eruption in a patient affected by T-gammadelta large granular lymphocyte leukaemia. AB - Livedo is an ischaemic dermopathy characterised by a reddish-blue to violaceous mottling of the skin with a net-like reticular appearance. Livedo has been described in association with several medical conditions including lymphoproliferative disorders. Here, we describe the case of a 60-year-old woman who was presented with asymptomatic and persistent livedoid eruption on her trunk, lower and upper extremities as manifestation of an indolent form of T gammadelta large granular lymphocyte leukaemia. To the best of our knowledge, this is the first report describing the association between livedo reticularis and T-gammadelta large granular lymphocyte leukaemia. It is plausible that a pathogenetic role of the neoplastic process is based on a cytotoxic antiendothelial activity. PMID- 28882929 TI - RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus. AB - During the development of autoimmune disease, a switch occurs in the antibody repertoire of B cells so that the production of pathogenic rather than non pathogenic autoantibodies is enabled. However, there is limited knowledge concerning how this pivotal step occurs. Here, we present genetic and pharmacological evidence of a positive modifier function for the vesicular small GTPase RhoB in specifically mediating the generation of pathogenic autoantibodies and disease progression in the K/BxN preclinical mouse model of inflammatory arthritis. Genetic deletion of RhoB abolished the production of pathogenic autoantibodies and ablated joint inflammation in the model. Similarly, administration of a novel RhoB-targeted monoclonal antibody was sufficient to ablate autoantibody production and joint inflammation. In the MRL/lpr mouse model of systemic lupus erythematosus (SLE), another established preclinical model of autoimmune disease associated with autoantibody production, administration of the anti-RhoB antibody also reduced serum levels of anti-dsDNA antibodies. Notably, the therapeutic effects of RhoB blockade reflected a selective deficiency in response to self-antigens, insofar as RhoB-deficient mice and mice treated with anti-RhoB immunoglobulin (Ig) both mounted comparable productive antibody responses after immunization with a model foreign antigen. Overall, our results highlight a newly identified function for RhoB in supporting the specific production of pathogenic autoantibodies, and offer a preclinical proof of concept for use of anti-RhoB Ig as a disease-selective therapy to treat autoimmune disorders driven by pathogenic autoantibodies. PMID- 28882932 TI - Hickam's dictum: Myasthenia Gravis presenting concurrently with Graves' disease. AB - We present two patients with Graves' disease and concurrent myasthenia gravis. The impact of the dual diagnosis on the clinical course and the potential for a delayed diagnosis of myasthenia gravis is discussed. Patient 1, a 28-year-old man was diagnosed with Graves' disease following his second respiratory arrest. His history was strongly suggestive of a second pathology. Patient 2, a 66-year-old Cantonese woman with established Graves' disease presented with thionamide related neutropaenia. Examination revealed bilateral ptosis and right lateral rectus palsy. Both patients had thyrotoxicosis secondary to Graves' disease with concurrent myasthenia gravis. Although neuromuscular weakness is common in Graves' disease, coexisting myasthenia gravis (MG) is rare and can cause profound morbidity. Ocular signs in both diseases may cause diagnostic confusion although ptosis suggests coexisting MG. In both cases, the thyrotoxicosis delayed the diagnosis of MG. PMID- 28882930 TI - Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis. AB - We present a new preclinical model to study treatment, resolution and sequelae of severe ascending pyelonephritis. Urinary tract infection (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), is a common disease in children. Severe pyelonephritis is the primary cause of acquired renal scarring in childhood, which may eventually lead to hypertension and chronic kidney disease in a small but important fraction of patients. Preclinical modeling of UTI utilizes almost exclusively females, which (in most mouse strains) exhibit inherent resistance to severe ascending kidney infection; consequently, no existing preclinical model has assessed the consequences of recovery from pyelonephritis following antibiotic treatment. We recently published a novel mini-surgical bladder inoculation technique, with which male C3H/HeN mice develop robust ascending pyelonephritis, highly prevalent renal abscesses and evidence of fibrosis. Here, we devised and optimized an antibiotic treatment strategy within this male model to more closely reflect the clinical course of pyelonephritis. A 5-day ceftriaxone regimen initiated at the onset of abscess development achieved resolution of bladder and kidney infection. A minority of treated mice displayed persistent histological abscess at the end of treatment, despite microbiological cure of pyelonephritis; a matching fraction of mice 1 month later exhibited renal scars featuring fibrosis and ongoing inflammatory infiltrates. Successful antibiotic treatment preserved renal function in almost all infected mice, as assessed by biochemical markers 1 and 5 months post-treatment; hydronephrosis was observed as a late effect of treated pyelonephritis. An occasional mouse developed chronic kidney disease, generally reflecting the incidence of this late sequela in humans. In total, this model offers a platform to study the molecular pathogenesis of pyelonephritis, response to antibiotic therapy and emergence of sequelae, including fibrosis and renal scarring. Future studies in this system may inform adjunctive therapies that may reduce the long-term complications of this very common bacterial infection. PMID- 28882933 TI - Caecal cancer presenting as leg erythema and a lung opacity. AB - Necrotising infection of the lower limb is a rare presentation for colorectal malignancy. We report a case of a perforated caecal adenocarcinoma presenting with right leg erythema, pain and swelling in the presence of a right lower lobe lung opacity. Following initial debridement and washout, CT imaging demonstrated a thickened terminal ileum, caecum and appendix, in keeping with primary malignancy. This fed the right-sided lower limb sepsis tracking down from the medial aspect of the psoas muscle to give rise to the multiloculated collection seen in the adductor compartment. The lung lesion measured 16 mm and was metastatic. The patient was successfully managed with a subtotal colectomy and an end ileostomy. The biopsy confirmed an adenocarcinoma (T4N1M1). We highlight the importance of perforated colonic carcinoma as a leading differential for lower limb abscesses. Suspicions should be raised further if accompanied by rounded opacifications on plain film radiography of the lungs. PMID- 28882934 TI - Bowel perforation presenting three months after suprapubic catheter insertion. AB - An 82-year-old male with multiple comorbidities, including previous laparotomies, had a suprapubic catheter (SPC) inserted under guidance with ultrasound and a flexible cystoscope. Three months following the procedure, having returned for a flexible cystoscopy for ongoing bladder pain syndrome, he became peritonitic postoperatively.A CT scan and subsequent laparotomy confirmed the SPC to be passing through a section of terminal ileum. The bowel was resected and he recovered well after a long hospital admission. A literature search found this delayed presentation of bowel perforation following SPC insertion to be rare, with only a few other cases reported. In particular, previous abdominal surgery increases the risk of this complication. This case serves as a reminder of the rare but potentially significant risk of SPC insertion and unusually highlights that this may not present immediately. PMID- 28882935 TI - A case of De Garengeot hernia and literature review. AB - Femoral hernia accounts for only 3% of all the hernias and in only 0.5%-5% of the events, the appendix can travel through the femoral hernia which is called De Garengeot hernia, and the incidence of appendicitis in this type of hernia is as low as 0.08%-0.13%. We present a case of a 69-year-old healthy woman who was referred to the emergency department by her general practitioner for CT-proven appendicitis in the femoral canal. On initial assessment, she was found to have a hard, tender lump in her right groin below the inguinal ligament, and open appendectomy and herniorrhaphy were performed. Surgery is the mainstay of treatment of this type of hernia but due to the rarity of this condition, there is no specific guideline as for the surgical procedure. This article demonstrated a case of De Garengeot hernia which was diagnosed preoperatively and managed surgically. PMID- 28882936 TI - Ganglioneuroma of the retropharyngeal space in a patient with glottic cancer. AB - We describe the case of a 71-year-old man with a ganglioneuroma of the retropharyngeal space. The patient presented with a submucosal bulge of the left oropharyngeal wall during follow-up examination of a treated vocal cord carcinoma. CT and MRI revealed a non-specific, well-defined retropharyngeal soft tissue lesion. Positron emission tomography-CT did not show relevant metabolic activity, excluding the hypothesis of metastatic nodal disease. Surgical biopsy of the lesion was compatible with ganglioneuroma. Ganglioneuromas are well differentiated tumours composed of mature sympathetic ganglion cells that account for approximately 1% of spinal and paraspinal tumours. Peripherally, ganglioneuromas are predominantly found in the posterior mediastinum and retroperitoneal space. Only nine ganglioneuromas of the retropharyngeal space have been reported in the English literature since the early 1980s. PMID- 28882937 TI - Granulomatous hepatitis in a patient with Crohn's disease and cholestasis. AB - We describe a case of a 23-year-old woman with a history of Crohn's disease (CD), who initially presented with sepsis-like symptoms, subsequently developed severe cholestasis and following extensive inpatient workup was found to have non caseating granulomas on her liver biopsy. Infectious aetiologies were excluded and the patient was treated with oral corticosteroids, which ameliorated but did not completely reverse the cholestasis. We review the differential diagnosis of hepatic granulomas and discuss the potential difficulties in establishing their exact aetiology in patients with CD. PMID- 28882938 TI - Imatinib dramatically alleviates pulmonary tumour thrombotic microangiopathy induced by gastric cancer. AB - Pulmonary tumour thrombotic microangiopathy (PTTM) is a rare complication of cancer, which can be lethal due to progressive pulmonary hypertension (PH). Several case reports have demonstrated that imatinib, a platelet-derived growth factor receptor-tyrosine kinase inhibitor, can improve severe PH in patients with PTTM.We describe the case of a 56-year-old woman. Her mean pulmonary arterial pressure (mPAP) was 47 mm Hg, and her dyspnoea worsened rapidly over several days. Although pulmonary embolism was not observed on CT, enlargement of the para aortic lymph nodes was detected. Gastro-oesophageal endoscopy revealed signet ring cell carcinoma. We diagnosed her as having PTTM based on her clinical course, and started treatment with imatinib. Five days after its administration, her mPAP decreased dramatically. She was discharged and lived without symptoms of PH until her death due to systemic metastasis of carcinoma. In some cases of PTTM, imatinib may be an effective therapeutic option for PH. PMID- 28882940 TI - Varicella complicated by cellulitis and deep vein thrombosis. AB - We report a 16-month-old girl with varicella complicated by cellulitis, invasive Group A Streptococcus (GAS) infection and deep vein thrombosis. She presented with varicella lesions, fever and a painful firm tumefaction on the right lower leg (RLL). Ultrasound showed a local subcutaneous tissue thickening suggestive of cellulitis and antibiotics were initiated. Further swelling of the RLL motivated a second ultrasound that showed an obstructive thrombus for which she was started on enoxaparin. The blood culture confirmed GAS infection leading to directed antibiotherapy. Additional studies showed positive lupus anticoagulant, decreased protein S and antithrombin. She completed a 2-week course of intravenous antibiotics and anticoagulation therapy with clinical and laboratory markers improvement. However, 3 days later, a recrudescence of symptoms occurred and the ultrasound revealed a local abscess. Further amoxicillin treatment resulted on a complete resolution of symptoms. Doppler ultrasound after 1 month showed markedly increased vein patency. PMID- 28882939 TI - Wasp sting induced STEMI with complete coronary artery occlusion: a case of Kounis syndrome. AB - A 45-year-old previously healthy man with minimal coronary artery disease on imaging presented with an acute MI after sustaining a wasp sting following previous non-eventful exposures throughout his life. This is the first case of Kounis syndrome with optical coherence tomography imaging and proven IgE wasp venom hypersensitivity. The Hymenoptera venom is composed of allergenic proteins and vasoactive amines which are responsible for venom toxicity. This patient also has a history of atopy giving a predisposition for developing IgE-mediated allergic reactions. Hymenoptera stings can be severe in atopic individuals and anaphylaxis may ensue. However, it is a rare cause of myocardial infarction (MI) (Kounis syndrome). Multiple wasp stings in the past may have contributed to sensitisation. Kounis syndrome is a rare clinical manifestation which should remain in the minds of physicians, especially with younger patients with no history of ischaemic heart disease or few risk factors. PMID- 28882941 TI - Anomalous left anterior descending artery arising from the pulmonary trunk: a rare cause of angina. AB - A 60-year-old man with a medical history of hypertension and dyslipidaemia presented to our rapid access chest pain clinic with a 2-month history of chest pain on exertion. An exercise stress test was arranged, which showed electrical evidence of inducible ischaemia. Subsequently, a coronary angiogram revealed an anomalous left anterior descending artery arising from the main pulmonary artery that received grade 3 collaterals from a large right coronary artery arising from the aorta. The circumflex arises from the right coronary sinus with a retroaortic course and provided collaterals to the anomalous left anterior descending artery. The patient was managed medically with the recommended pharmacological measures for stable angina and responded well with complete resolution of his symptoms, and he is currently under regular follow-up in the cardiology outpatient department. PMID- 28882942 TI - Tamoxifen maculopathy in a male patient. PMID- 28882943 TI - Tissue-directed Implantation Using Ultrasound Visualization for Development of Biologically Relevant Metastatic Tumor Xenografts. AB - BACKGROUND: Advances in cancer therapeutics depend on reliable in vivo model systems. To develop biologically relevant xenografts, ultrasound was utilized for tissue-directed implantation of neuroblastoma (NB) cell line and patient-derived tumors in the adrenal gland, and for renal subcapsular engraftment of Ewing's sarcoma (ES). MATERIALS AND METHODS: NB xenografts were established by direct adrenal injection of luciferase-transfected NB cell lines (IMR32, SH-SY5Y, SK-N BE2) or NB patient-derived tumor cells (UMNBL001, UMNBL002). ES xenografts were established by renal subcapsular injection of TC32, A673, CHLA-25, or A4573 cells. Progression was monitored by in vivo imaging. RESULTS: Tumors progressed to local disease with metastasis evident by 5 weeks. Metastatic sites included cortical bone, lung, liver, and lymph nodes. Xenografted tumors retained immunochemical features of the original cancer. CONCLUSION: Human NB adrenal xenografts, including two patient-derived orthotopic, and ES renal subcapsular xenografts were established by ultrasound without open surgery. Tissue-directed implantation is an effective technique for developing metastatic preclinical models. PMID- 28882944 TI - Netrin-4 Promotes Differentiation and Migration of Osteoblasts. AB - BACKGROUND/AIM: While netrin-4 plays a vital role in the vascular system, the role of netrin-1 in osteoblast differentiation is not well understood. In this study we explored whether netrin-4 has functional roles in osteoblasts. MATERIALS AND METHODS: Quantitative reverse-transcriptase polymerase chain reaction (PCR), RNA interference, the generation of plasmids, transfections, measurement of alkaline phosphatase activity, a mineralization assay, a migration assay and a cell proliferation assay were performed. RESULTS: Netrin-4 expression was up regulated during osteoblast differentiation and an RNA interference experiment showed that small interfering RNA used to silence netrin-4 inhibited osteoblast differentiation. Recombinant mouse netrin-4 promoted alkaline phosphatase (ALP) activity of osteoblasts and enhancement of calcium deposits. Moreover, we constructed a vector containing the netrin-4 gene on the basis of the plasmid pcDNA3.1/V5-His. Overexpression of netrin-4 enhanced differentiation of osteoblasts. Finally, recombinant mouse netrin-4 promoted cell migration of osteoblasts. CONCLUSION: Netrin-4 promotes differentiation and migration of osteoblasts. PMID- 28882946 TI - Pharmacokinetics of Morphine in Rats with Adjuvant-induced Arthritis. AB - We investigated the in vivo dynamics and analgesic effect of morphine using an adjuvant-induced arthritis (AA) rat as a model of chronic inflammation. Morphine generally binds to MU-opioid receptors in the brain to exert its effects. After several minutes, it is metabolized by glucuronidation via a UDP glucuronosyltransferase (UGT). Here, we showed that in AA rats, UGT activity in liver microsomes was reduced. Morphine-free serum fractions in AA rats were also decreased (control, 84.9%; AA, 63.9%) and the expression of ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1), which plays a crucial role in morphine bile excretion, decreased to 23.0% that of the control group. However, we observed no significant difference between the AA and control groups regarding blood concentrations of morphine and morphine-3-glucuronide. In contrast, the analgesic effect of morphine increased 4-fold in AA rats. Our results showed that the pharmacokinetics of morphine is not changed, but the pharmacodynamics of morphine is enhanced in chronic inflammation. PMID- 28882945 TI - Melatonin Synergizes the Chemotherapeutic Effect of Cisplatin in Ovarian Cancer Cells Independently of MT1 Melatonin Receptors. AB - BACKGROUND/AIM: Melatonin (MLT), through the interaction with membrane melatonin receptors MT1, can improve the effectiveness of cytostatic agents, including cisplatin (CP). The aim of this study was to examine the synergistic effect of MLT and CP in three cell lines: IOSE 364, SK-OV-3 and OVCAR-3, as well as to assess the role of MT1 receptors in this mechanism. MATERIALS AND METHODS: Using the SRB assay we investigated the effect of different concentrations of CP and MLT on cell viability. Tests, using luzindole - MT1 inhibitor, allowed us to assess the potential involvement of MT1 in the mechanism of MLT action. RESULTS: MLT at certain concentrations demonstrated a synergistic effect in combination with CP. The addition of luzindole did not affect the action of MLT in combination with CP. CONCLUSION: In summary, the synergistic effect of MLT with CP seems to be independent of membrane MT1 receptors. PMID- 28882947 TI - Expression of Cyclooxygenase-2, Nitric Oxide Synthase 2 and Heme Oxygenase-1 mRNA Induced by Bis-Eugenol in RAW264.7 Cells and their Antioxidant Activity Determined Using the Induction Period Method. AB - BACKGROUND/AIM: To clarify the mechanisms responsible for the anti inflammatory/proinflammatory activities of eugenol-related compounds, we investigated the cytotoxicity and up-regulatory/down-refgulatory effects of the biphenols curcumin, bis-eugenol, magnolol and honokiol, and the monophenols eugenol and isoeugenol, on major regulators of cyclooxygenase-2 (Cox-2), nitric oxide synthase 2 (Nos2) and heme oxygenase-1 (HO-1) mRNA in RAW264.7 cells. MATERIALS AND METHODS: mRNA expression was investigated using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), and the theoretical parameters were calculated using the DFT/B3LYP/6-31* method. Also, the antioxidant activity of eugenol-related compounds in combination with 2-mercapto-1-methylimidazole (MMI, as a model for glutathione (GSH)) was investigated using the induction period method for polymerization of methyl methacrylate initiated by benzoyl peroxide (BPO). RESULTS: The cytotoxicity of eugenol-related compounds showed a linear relationship with their softness (sigma) and electrophilicity (omega). At a concentration of 50 MUM, biphenols except for bis-eugenol elicited the expression of mRNA for both Cox-2 and Nos2, but monophenols did not. In contrast, bis-eugenol elicited Cox-2 gene expression, but down-regulated Nos2 gene expression. bis-Eugenol alone induced the expression of HO-1 mRNA, and when combined with MMI it showed a potent antagonistic effect on BPO-induced antioxidant activity. The ability of methoxyphenols to inhibit LPS-stimulated Cox 2 gene expression declined in the order curcumin >> isoeugenol > bis-eugenol >> eugenol, and the rank of ability was related to their omega value. CONCLUSION: Most eugenol-related compounds had proinflammatory activity at high concentrations. However, they had also anti-inflammatory activity at lower concentrations. Eugenol-related compounds may exert antioxidant and anti inflammatory activity in LPS-stimulated RAW264.7 cells possibly by inhibiting the activation of nuclear factor-kappa B (Nf-KB), whereas bis-eugenol requires induction of HO-1 expression. bis-Eugenol as well as curcumin, may have anti inflammatory and anticancer therapeutic applications. PMID- 28882948 TI - RUNX3 as a Potential Predictor of Metastasis in Human Pancreatic Cancer. AB - BACKGROUND/AIM: In genetically engineered murine models of pancreatic ductal adenocarcinomas (PDAC), high levels of Runx3 increase the metastatic potential of cancer cells. In this study we evaluated the role of Runx3 in human pancreatic cancer. MATERIALS AND METHODS: Runx3 was retrospectively assessed by immunohistochemistry in seventy-eight tumor samples of patients who underwent surgical resection for PDCA and were followed at least for 24 months. RESULTS: Thirty-two cases resulted completely negative for Runx3; forty-six showed highly variable expression. We established an optimal cut-off value of Runx3 in predicting distant metastasis equal to 0.04. The odds ratio (ORs) for development of distant metastases at multivariate analysis for patients having Runx3 >=0.04 was 4.26 (p=0.043) and 4.68 (p=0.032) after adjusting for residual tumor and treatment, respectively; OR for development of metastases in multiple sites was 4.28 (p=0.025) for Runx3 >=0.04. CONCLUSION: Our results support the ability of Runx3 to contribute to the dissemination of human PDAC thus confirming the observations from murine models. PMID- 28882949 TI - Phe354Leu Polymorphism of LKB1 Is a Potential Prognostic Factor for Cytogenetically Normal Acute Myeloid Leukemia. AB - BACKGROUND/AIM: Liver kinase B1 (LKB1) is a major activator of the AMP-dependent kinase/mammalian target of rapamycin pathway. The prevalence and the specificity of LKB1 gene mutation in acute myeloid leukemia (AML) have not been well established. This study aimed to examine mutation of LKB1 in AML and its clinical and pathological implications. PATIENTS AND METHODS: Eighty-five patients newly diagnosed with cytogenetically normal AML were analyzed using polymerase chain reaction followed by direct sequencing. RESULTS: A silent mutation (837C>T) of LKB1 was detected in one patient and a pathogenic polymorphism Phe354Leu which diminishes LKB1 ability to maintain cell polarity was detected in six (7%) patients. The Phe354Leu polymorphism occurred concurrently with mutations of nucleophosmin 1 (NPM1), fms-related tyrosine kinase 3 (FLT3) and CCAAT/enhancer binding protein alpha (CEBPA), but not with metabolism-related genes, isocitrate dehydrogenase [nicotinamide adenine dinucleotide phosphate (+)]1 (IDH1) and IDH2. Patients with Phe354Leu polymorphism diagnosed at younger ages had a worse overall survival. CONCLUSION: LKB1 may be involved in the leukemogenesis and progression of cytogenetically normal AML. PMID- 28882950 TI - Cytocompatibility of Direct Laser Interference-patterned Titanium Surfaces for Implants. AB - In an effort to generate titanium surfaces for implants with improved osseointegration, we used direct laser interference patterning (DLIP) to modify the surface of pure titanium grade 4 of four different structures. We assessed in vitro cytoxicity and cell attachment, as well as the viability and proliferation of cells cultured directly on the surfaces. Attachment of the cells to the modified surfaces was comparably good compared to that of cells on grit-blasted and acid-etched reference titanium surfaces. In concordance with this, viability and proliferation of the cells directly cultured on the specimens were similar on all the titanium surfaces, regardless of the laser modification, indicating good cytocompatibility. PMID- 28882951 TI - The Immunoreactivity of PI3K/AKT Pathway After Prenatal Hypoxic Damage. AB - BACKGROUND/AIM: There is no consensus on the effect of hypoxia on neurogenesis. In this study, we investigated the immunoreactivity of BDNF and PI3K/Akt signaling after uterine artery ligation in pregnant rats. MATERIALS AND METHODS: Unilateral uterine artery ligation was performed at 16 days of gestation (dg). Fetuses from one horn with ligated artery were allocated to the hypoxic group. Immunohistochemistry was performed with primary antibodies; NeuN, BDNF, PI3K, Akt and phospho-Akt (pAkt). RESULTS: The densities of NeuN- and BDNF-immunoreactive (IR) cells in the cerebral cortex were lower in the hypoxic fetuses than in the controls at 21 dg. The density of PI3K and pAkt-IR cells in the cortex of the hypoxic group significantly decreased. The results in dentate gyrus were similar to the results in the cerebral cortex. CONCLUSION: Prenatal hypoxia reduced Akt phosphorylation, which affected neuronal survival in the cortex and dentate gyrus. PMID- 28882952 TI - Comparing the Organs and Vasculature of the Head and Neck in Five Murine Species. AB - BACKGROUND/AIM: The purpose of the present study was to delineate the cervical and facial vascular and associated anatomy in five murine species, and compare them for optimal use in research studies focused on understanding the pathology and treatment of diseases in humans. MATERIALS AND METHODS: The specific adult male animals examined were mice (C57BL/6J), rats (F344), mongolian gerbils (Merionesunguiculatus), hamsters (Syrian), and guinea pigs (Hartley). To stain the vasculature and organs, of the face and neck, each animal was systemically perfused using the vital stain, Trypan Blue. Following this step, the detailed anatomy of the head and neck could be easily visualized in all species. RESULTS: Unique morphological characteristics were demonstrated by comparing the five species, including symmetry of the common carotid origin bilaterally in the Mongolian Gerbil, a large submandibular gland in the hamster and an enlarged buccal branch in the Guinea Pig. In reviewing the anatomical details, this staining technique proves superior for direct surgical visualization and identification. CONCLUSION: The anatomical details provided through these five species atlas will help experimental researchers in the future to select the most appropriate animal model for specific laboratory studies aimed to improve our understanding and treatment of diseases in patients. PMID- 28882953 TI - SCARB1 Gene Polymorphisms and HDL Subfractions in Coronary Artery Disease. AB - BACKGROUND/AIM: Cardiovascular diseases are a leading cause of mortality and morbidity worldwide. Polymorphisms in the SCARB1 gene are known to be related to plasma lipids. PATIENTS AND METHODS: Real time-polymerase chain reaction (RT-PCR) was used for identification of SCARB1 polymorphisms and the Lipoprint Quantimetrix System was employed in identification of HDL subfractions. RESULTS: According to allelic distribution, in both groups SCARB1 AA genotype led to a two fold decrease in the risk of developing cardiovascular disease (p=0.04), while the GA genotype increased the risk two-fold (p=0.03). According to the HDL subfraction analysis results, the AA genotype had higher levels of big-sized HDL subfraction (p=0.02). CONCLUSION: The SCARB1AA genotype decreased cardiovascular risk and carrying GA genotype and G allele increased the risk of CAD. AA genotype carriers had higher levels of big-sized HDL subfraction. PMID- 28882954 TI - Antrodia Cinnamomea Reduces Carbon Tetrachloride-induced Hepatotoxicity In Male Wister Rats. AB - BACKGROUND/AIM: Antrodia cinnamomea is found with polysaccharides, lipids, vitamins, fibers and ash (minerals) and is well known in Taiwan as a traditional Chinese medicine. Its biological activities have been reported to have anti inflammatory, anti-fatigue, anti-tumor and immunomodulatory effects, but its protective effects on liver function are still unclear. MATERIALS AND METHODS: We determined if Antrodia cinnamomea was hepatoprotective against carbon tetrachloride (CCl4) toxicity in Wistar rats. Six groups were used in the study: 1) control (no induction by CCl4); 2) negative control (CCl4-induction and no treatment); 3) positive control (silymarin treatment); 4) groups 4-6 were treated with CC14 and different concentrations (350 mg/kg, 1,400 mg/kg, 3,150 mg/kg) of Antrodia cinnamomea. Blood and liver samples of rats were harvested and then detected by biochemical and tissue histochemical analysis. Activity of the antioxidative enzymes glutathione peroxidase, superoxide dismutase and catalase in the liver were also monitored. RESULTS: Only the high-dose treatment was able to decrease serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels and improve liver function. High and medium doses increased total liver protein and reduced hydroxyproline. It was also observed that the high dose treatment reduced lipid peroxidation. Liver sections of CC14 treated animals receiving Antrodia cinnamomea showed less fibrosis compared to the CCl4 control group. CONCLUSION: This finding suggested that Antrodia cinnamomea can either enhance liver recovering from CCl4 damage or attenuate CCl4 toxicity in rats. PMID- 28882955 TI - Differential Expression of Aquaporins in Experimental Models of Acute Lung Injury. AB - AIM: The mammalian lung expresses at least three aquaporin (AQP) water channels whose precise role in lung injury or inflammation is still controversial. MATERIALS AND METHODS: Three murine models of lung inflammation and corresponding controls were used to evaluate the expression of Aqp1, Aqp4, Aqp5 and Aqp9: lipopolysaccharide (LPS)-induced lung injury; HCl-induced lung injury; and ventilation-induced lung injury (VILI). RESULTS: All models yielded increased lung vascular permeability, and inflammatory cell infiltration in the broncho alveolar lavage fluid; VILI additionally produced altered lung mechanics. Lung expression of Aqp4 decreased in the models that targeted primarily the alveolar epithelium, i.e. acid aspiration and mechanical ventilation, while Aqp5 expression decreased in the model that appeared to target both the capillary endothelium and alveolar epithelium, i.e. LPS. CONCLUSION: Participation of aquaporins in the acute inflammatory process depends on localization and the type of lung injury. PMID- 28882956 TI - Osteochondral Repair Using Porous Three-dimensional Nanocomposite Scaffolds in a Rabbit Model. AB - AIM: To evaluate the utility of a novel nanocomposite biomaterial consisting of poly-L/D-lactide, and hydroxyapatite bioceramics, enriched with sodium alginate in articular cartilage defect treatment. MATERIALS AND METHODS: The biomaterial was prepared using the method of solvent casting and particle leaching. The study was conducted on 20 New Zealand White rabbits. Experimental osteochondral defects were created in the femoral trochlear grooves and filled with biomaterials. In control groups, the defects were left to spontaneously heal. The quality of newly formed tissue was evaluated on the basis of macroscopic and histological assessment. Additionally the level of osteogenic and cartilage degradation markers were measured. RESULTS: The majority of the defects from the treatment group were covered with tissue similar in structure and colour to healthy cartilage, whereas in the control group, tissue was uneven, and not integrated into the surrounding cartilage. CONCLUSION: The results obtained validate the choice of biomaterial used in this study as well as the method of its application. PMID- 28882957 TI - 5-Aminolevulinic-acid-mediated Photodynamic Diagnosis Enhances the Detection of Peritoneal Metastases in Biliary Tract Cancer in Mice. AB - BACKGROUND/AIM: Previous studies on the accuracy of 5-aminolevulinic-acid mediated photodynamic diagnosis (5-ALA PDD) have been reported for various cancers and brain surgery. However, biliary tract cancer is rare. Therefore, 5 ALA PDD has not been fully evaluated in biliary tract cancers. Small biliary tract cancer lesions such as peritoneal dissemination, liver metastases, and lymph node metastases are negative prognosticators in patients with biliary cancer. The purpose of this exploratory study was to determine if 5-ALA PDD could detect small biliary tract cancer lesions in murine models of biliary cancers. MATERIALS AND METHODS: Biliary cancer cell lines (TFK-1, HuCCT-1, G415, HuH28, SSP25, RBE, KKU055 and KKU100) and Normal human dermal fibroblast cells were used to evaluate protoporphyrin IX (PpIX) accumulation in vitro. Subcutaneous tumor mice were established using two cell lines (TFK-1 and HuCCT-1). 5-ALA (250 mg/kg) was administered intraperitoneally, and fluorescent 5ALA-PDD was performed 3 h later to evaluate tumoral PpIX accumulation. A murine peritoneal disseminated nodule model was established by intraperitoneal injection of TFK-1 cells. Four weeks later, 5-ALA was administered intraperitoneally, and 5-ALA-PDD was performed 3 h post administration to evaluate PpIX accumulation in the disseminated nodules. The presence of tumor cells in tumors and nodules was confirmed by haematoxylin and eosin staining. RESULTS: Compared TO non-cancerous cell lines, PpIX accumulation was increased in biliary tract cancer cell lines. PpIX accumulation led to a strong fluorescent signal in all subcutaneous tumors. In the murine model of peritoneal dissemination, microdisseminated nodules (<1 mm) that could not be detected under white light were clearly visible using 5-ALA PDD. CONCLUSION: 5-ALA PDD was useful for diagnosis of biliary tract cancer and detection of small peritoneal metastatic lesions in murine models of biliary cancers. Clinical studies and applications of 5-ALA PDD for biliary tract cancer are expected in the future. PMID- 28882958 TI - Treatment of Squamous Cell Carcinoma of the Esophagus Synchronously Associated with Head and Neck Cancer. AB - BACKGROUND/AIM: The aim of this study was to clarify the treatment strategy for synchronous squamous cell carcinoma of the esophagus (ESCC) and head and neck cancer (HNC). PATIENTS AND METHODS: Treatment outcomes of 91 patients with synchronous ESCC and HNC were evaluated. Thirty-eight patients received simultaneous definitive chemoradiotherapy (CRT) and 15 patients underwent simultaneous resection. RESULTS: Among the patients who received simultaneous CRT, adverse events (grade 3-5) were recognized in 14 patients (40%), including one case of death due to aspiration pneumonia. Complete response was observed in 22 patients with ESCC (58%) and 19 patients with HNC (50%). The five-year survival rate was 44%. There were no in-hospital deaths after simultaneous resection; however, postoperative complications were recognized in 4 patients. The five-year OS was 70%. CONCLUSION: The treatment of synchronous ESCC and HNC must be decided by adopting a strategy that is appropriate for each case. Both simultaneous CRT and simultaneous resection are feasible and effective treatment options. PMID- 28882959 TI - Comparison of the Grip Strength Using the Martin-Vigorimeter and the JAMAR Dynamometer: Establishment of Normal Values. AB - BACKGROUND/AIM: The JAMAR-Dynamometer and the Martin-Vigorimeter are frequently used tools in a hand surgeon's daily routine. This survey is primarily concerned with the establishment of valid conversion factors for measured values of both instruments, as well as the investigation of influence of anatomical characteristics and age and sex on maximal measured grip strength. PATIENTS AND METHODS: We registered anamnestic data and specific anatomical conditions in 339 patients, maximal grip strength was measured using all notches of both instruments. RESULTS: We found moderate to very high correlation comparing all 28 settings in both instruments. The influence of the hand's anatomy on the grip strength was greater using the JAMAR-Dynamometer than it was using the Martin Vigorimeter. CONCLUSION: The high reproducibility allowed us to calculate multiplying factors for the conversion of measured data for all settings of both tools. Therefore, the amount of data for meta-analyses relating to hand surgical issues can be significantly increased. PMID- 28882961 TI - Efficacy of N-acetylcysteine, D-mannose and Morinda citrifolia to Treat Recurrent Cystitis in Breast Cancer Survivals. AB - BACKGROUND/AIM: Breast cancer survivors in adjuvant therapy, frequently experience the estrogen deficiency with genitourinary symptoms mostly represented by recurrent bacterial cystitis. The objective of the present study was to evaluate the effectiveness of N-acetylcysteine, D-mannose and Morinda citrifolia fruit extract (NDM), when associated to antibiotic therapy, in reducing the persistence of recurrent cystitis in this risk population. PATIENTS AND METHODS: Sixty breast cancer survived women with recurrent cystitis were retrospectively examined. Group 1, comprised of 40 patients treated with antibiotic therapy associated with NDM lasting for six months, Group 2 comprised of 20 patients treated with antibiotics alone. RESULTS: The use of NDM in combination with antibiotic therapy showed a significant reduction in positive urine cultures, compared to antibiotics alone. Subjects of Group 1 rather than those of Group 2, showed improvement in symptoms score of urgency, frequency, urge incontinence, recurrent cystitis, bladder and urethral pain. CONCLUSION: In breast cancer survived women affected by genitourinary discomfort, the combination of NDM and antibiotic therapy showed a greater efficacy in reducing urinary tract infections and urinary discomfort with respect to antibiotic use only. PMID- 28882960 TI - Parathyroid Carcinoma in Patients that Have Undergone Surgery for Primary Hyperparathyroidism. AB - BACKGROUND/AIM: Parathyroid carcinoma is a rare clinical entity, which represents one of the main reasons, why surgery should be performed in specialized centres. Preoperatively, it is very difficult to distinguish between benign and malignant hyperparathyroidism. PATIENTS AND METHODS: During the years 1996-2016, we performed 2,220 operations in 2,075 patients with a diagnosis of primary hyperparathyroidism. RESULTS: Among these 2,220 operations, there were 16 operations for parathyroid carcinoma. These 16 operations, including reoperations, were performed in four patients. Two patients had no reoperation, but another 2 patients required 14 reoperations in total. Parathyroid carcinoma was described in 0.2% of all patients with a diagnosis of primary hyperparathyroidism. The number of operations was 0.73% of all operations of primary hyperparathyroidism in years 1996-2016. CONCLUSION: Prognosis of parathyroid carcinoma is quite favourable, patients evidence a long-term survival rate after the primary operation. However, every reoperation increases the number of possible complications, including recurrent laryngeal nerve injury. PMID- 28882962 TI - Prospective Analysis of a Sterile, Semi-automated Tissue Biopsy Homogenization Method in the Diagnosis of Prosthetic Joint Infections. AB - BACKGROUND/AIM: Prosthetic joint infection (PJI) remains a serious complication of total joint arthroplasty. To effectively treat PJI, it is essential to identify the microorganism causing it and be able to combine correct surgical and anti-infective treatments. This cannot always be achieved with the currently employed diagnostic methods. The aim of this study was to evaluate a semi automated tissue biopsy bead milling method (Ultra-TurrAX, Axonlab AG; Reichenbach, Germany) based on the hypothesis that the results are more sensitive for microbe detection and less prone to contamination. MATERIALS AND METHODS: We included 35 consecutive patients undergoing 38 hip or knee arthroplasty revisions in this study. In addition to manually processed biopsies, we processed tissue specimens harvested intraoperatively using a semi-automated method. The sensitivity and specificity of both methods were calculated using MSIS criteria and sonication results as gold standards. RESULTS: For total hip arthroplasty samples were evaluated separately based on MSIS criteria as the reference standard, Ultra-TurrAX processing yielded 81% (62-100%) sensitivity and 100% specificity. Using sonication as the gold standard, a sensitivity of 80% (60 100%) and specificity of 80% (45-100%) were calculated. In total knee arthroplasty, Ultra-TurrAX processing yielded 27% (1-54%) sensitivity and 57% (20 94%) specificity when using MSIS criteria as the gold standard. Using sonication as the gold standard, a sensitivity of 60% (17-100%) and specificity of 77% (54 100%) were calculated. CONCLUSION: This is the first study to analyze bead mill processing in total hip and knee arthroplasty revisions in a consecutive patient series. The method's sensitivity was comparable to and its specificity superior to regular sample processing results reported in the literature with respect to hip arthroplasties and to both hip and knee arthroplasties collectively. With respect to total knee arthroplasties, the method fared worse in our collective, most likely due to the small number of patients in the sample. Integrating the method into the clinical workflow allowed for speedier and more efficient sample handling and processing. The theoretical advantage of a lower risk of contamination because of fewer manual processing steps is, in our opinion, valid. PMID- 28882963 TI - Risk Factors for Transumbilical Wound Complications in Laparoscopic Gastric and Colorectal Surgery. AB - AIM: To investigate the risk factors of transumbilical incision for organ removal in laparoscopic surgery. PATIENTS AND METHODS: We enrolled 643 consecutive patients undergoing laparoscopic surgery from 2010 to 2013. Superficial surgical site infection (SSI) and transumbilical port site hernia were recorded. RESULTS: The participants underwent gastric (n=253) and colorectal (n=390) resections. SSI was observed in 17 cases (colorectal in 15; gastric in two) (2.64%) with colorectal resection having a high rate of SSI [odds ratio (OR)=5.020; p=0.022]. Hernia occurred in 23 cases (colorectal in 22; gastric in one) (3.53%), with a significantly higher rate for colorectal resection (OR=13.052; p<0.001). Female (OR=5.410; p=0.021) and history of diabetes mellitus (OR=4.437; p=0.009) contributed to the risk for developing a hernia. CONCLUSION: Especially in relation to hernia, being female and having diabetes mellitus were considered independent risk factors. PMID- 28882964 TI - Impact of Time Factors on Outcome in Patients with Head and Neck Cancer Treated with Definitive Radio(Chemo)Therapy. AB - AIM: To evaluate treatment-related factors such as overall treatment time (OTT) and radiation treatment time (RTT) in head-and-neck cancer. PATIENTS AND METHODS: A total of 216 patients with locoregionally advanced inoperable head and neck cancer were treated with definitive radio(chemo)therapy. Mean follow-up was 37 months. RESULTS: Median time from diagnosis to start of radiotherapy (total waiting time) was 34 days, and comprised of referral waiting time and time for preparatory work. Median RTT was 40 days, and median OTT was 91 days. At 6, 12 and 24 months local recurrence-free survival (LRFS) was 75%, 65% and 60%; metastasis-free survival (MFS) was 84%, 77% and 70%; overall survival (OS) was 72%, 58% and 40%. Tumor stage, boost and chemotherapy were significant for OS, waiting time for preparatory work and RTT were significant for MFS, and referral waiting time and total radiotherapy dose for LRFS. CONCLUSION: RTT <=40 days was a prognostic factor for better MFS. Prolonged waiting time had a converse effect for radiotherapy with better outcome on MFS and LRFS. PMID- 28882965 TI - Rotating Gamma System Irradiation: A Promising Treatment for Low-grade Brainstem Gliomas. AB - AIM: To evaluate the role of rotating gamma system (RGS) radiosurgery for low grade brainstem gliomas. PATIENTS AND METHODS: Thirty-seven patients undergoing RGS radiosurgery at the Bach Mai Hospital Hanoi for low-grade brainstem glioma were included in this prospective interventional study. The median RGS dose was 12 Gy (range=8-16 Gy). Endpoints included response to RGS radiosurgery given as change in glioma size (maximum diameter), survival and adverse events. Follow-up was performed for 36 months. Three dose-groups (<13, 13-14 and >14 Gy) were compared for survival. RESULTS: Mean glioma size decreased from 1.87 cm before RGS irradiation to 1.15 cm at 36 months. Mean survival was 39.5 months. Mean survival after <13, 13-14 and >14 Gy were 22.7, 66.7 and 49 months, respectively (p<0.05). Adverse events, mainly reduced appetite, sleep disturbances, headache and edema, were not associated with RGS dose and were easily managed. CONCLUSION: RGS radiosurgery led to promising results with acceptable toxicity in patients with low-grade brainstem gliomas. PMID- 28882966 TI - Predictive Factors of Late-onset Rectal Mucosal Changes After Radiotherapy of Prostate Cancer. AB - BACKGROUND/AIM: The Vienna Rectoscopy Score (VRS; from 0, absence of rectal mucosal changes, to 5) assessed 1 year after radiotherapy is a surrogate end point of late rectal toxicity. The aim of this study was to investigate the association between treatment-related factors and 1-year VRS. PATIENTS AND METHODS: We performed a retrospective analysis of prospectively collected data. Patients with prostate adenocarcinoma treated with definitive or postoperative radiotherapy (RT) underwent endoscopy 1 year after RT. Relationships between VRS of 2 or more and treatment parameters were investigated by univariate and multivariate logistic analyses. RESULTS: One hundred and ninety-five patients (mean age=69 years; range=43-81 years) were considered eligible for the study. At univariate analysis, patients treated with hypofractionation plus radiosurgery boost (p<0.001) and an equivalent dose in 2 Gy per fraction (EQD2) (alpha/beta=3) >=75 Gy (p<0.001) was associated with a significantly higher incidence of VRS >=2 after 1 year of follow-up. At multivariate analysis, radiosurgery boost was an independent risk factor for developing rectal mucosal lesions (VRS >=2), yielding an odds ratio (OR) of 4.14 (95% confidence interval (CI)=1.2-13.8), while pelvic surgery was inversely associated with VRS >=2 (OR=0.39; 95% CI=0.17-0.94). CONCLUSION: Hypofractionation followed by radiosurgery boost significantly increased the risk of developing late-onset rectal mucosal changes. Therefore, special care and preventative treatment strategies are needed when using radiosurgery boost after hypofractionated RT. PMID- 28882967 TI - Influenza Among Breast Cancer Survivors in South Korea: A Nationwide Population Based Study. AB - BACKGROUND/AIM: In this study, we analyzed the prevalence of influenza disease in breast cancer survivors using claims data from the Health Insurance Review and Assessment Service (HIRA) in South Korea. PATIENTS AND METHODS: We defined influenza among a nationwide cohort of 87,843 patients who were diagnosed with breast cancer and underwent surgery from January 1, 2010 to December 31, 2014, based on HIRA claim data. Descriptive statistics were calculated to estimate the frequency of influenza disease using diagnostic code and utilization pattern at medical institutions. RESULTS: Two thousand four hundred breast cancer survivors (2.7%) were diagnosed with influenza. The overall frequency of influenza increased from November (n=98) and peaked in February (n=1,745). Over 60% (2,693) of claims for influenza disease treatment were in the clinic, whereas general hospitals accounted for 22.0% (873). Among 3,967 claims, admission rate was 7.6% (n=301) and the average length of hospitalization was 4.7 days. Elderly breast cancer survivors over 70 years old had the longest length of hospitalization at 5.9 days. CONCLUSION: Breast cancer survivors are more susceptible to influenza than non-cancer survivors. It is important not only to raise the vaccination rate among young cancer survivors, but also to quickly identify symptoms and begin treatment for flu in elderly cancer survivors. PMID- 28882968 TI - Rectosigmoidian Involvement in Advanced-stage Ovarian Cancer - Intraoperative Decisions. AB - BACKGROUND/AIM: Ovarian cancer remains one of the most commonly encountered malignancies affecting women worldwide, that is unfortunately commonly diagnosed in advanced stages of the disease. In these stages, the tumoral process usually involves the surrounding viscera throughout contiguity or induces the apparition of distant metastases via peritoneal, lymphatic or hematogenous spread, multiple resections being needed in order to achieve a good control of the disease. PATIENTS AND METHODS: In the present study, we present a case series of 12 patients in whom various surgical procedures on the rectosigmoidian loop were performed in order to achieve debulking surgery to no residual disease. RESULTS: Digestive tract resections consisted of rectosigmoidian resection with left colostomy in three cases, low rectosigmoidian resections with anastomosis in eight cases and a stripping procedure of the peritoneal layer in one case. CONCLUSION: Due to the close proximity of the digestive and gynecological tract, advanced-stage ovarian tumors frequently involve the rectosigmoidian loop, imposing association of digestive tract surgical procedures. PMID- 28882969 TI - Successful Resection and Vascular Ligation of a Large Hepatic Artery Aneurysm - A Case Report and Literature Review. AB - The occurrence of hepatic artery aneurysms is rare and might be incidentally diagnosed, as the patient remains asymptomatic for a long period of time. However, due to the fact that these lesions are associated with a high risk of developing life threatening complications, such as intraperitoneal rupture, it has been stated that all cases should be submitted to treatment by endovascular or surgical approach. We present the case of a 68-year-old patient, who presented with recurrent upper digestive tract bleedings and was diagnosed with a large aneurysm of the common and the proper hepatic artery, and the gastroduodenal artery. The preoperative angiography revealed an anatomic variation consisting of the common hepatic artery originating from the celiac trunk, and the left hepatic artery originating from the left gastric artery. A percutaneous right portal vein embolization was performed in order to induce hypertrophy of the left lobe and prepare the patient for a right hepatectomy and aneurysmal resection. However, at the time of surgery, after performing the aneurysmal resection and arterial ligation, the vascular supply of the entire liver was efficiently provided by the left hepatic artery and its collaterals. Concluding, hepatic resection was no longer necessary. PMID- 28882970 TI - Management of a Fulminant Upper Gastrointestinal Bleeding Exteriorized Through Hemobilia Due to Arteriobiliary Fistula Between the Common Bile Duct and a Right Hepatic Artery Aneurysm - A Case Report. AB - Right hepatic artery aneurysms are rare events that might remain asymptomatic for a long period of time. However, in cases presenting large lesions, symptoms might develop especially due to the association of compression of the surrounding elements. Most often these symptoms and signs include diffuse abdominal pain, jaundice or portal vein compression signs. In rare cases life-threatening complications might develop due to the aneurysmal erosion of the biliary duct, portal vein or due to the aneurysmal rupture in the peritoneal cavity. In all these cases emergency surgery is imposed. We present the case of a 66-year-old patient diagnosed with a partially thrombosed right hepatic artery aneurysm compressing the common bile duct who was initially submitted to a percutaneous arterial embolization of the aneurysm in association with an external biliary drainage; three weeks later the patient presented a fulminant upper gastrointestinal bleeding exteriorized through the external biliary drainage, hematemesis and hematochezia. The patient was successfully submitted to surgery, intraoperatively a synchronous rupture of the portal vein being revealed. The right hepatic artery aneurysm was resected en bloc with common bile duct resection and segmental portal vein resection. The continuity of the portal vein was re-established through the interposition of a cadaveric allograft, the common bile duct was anastomosed with en Roux en Y limb while the right hepatic artery aneurysm was ligated and resected, the arterial vascularization of the liver being provided by the left hepatic artery. PMID- 28882971 TI - Mouse Hemokinin-1 Decapeptide Subjected to a Brain-specific Post-translational Modification. AB - BACKGROUND/AIM: The tachykinin mouse hemokinin-1, expressed by the mouse Tac4 gene, produces either analgesia or nociception, interacting with the neurokinin 1 receptor. TAC4 precursor processing is not identical to the processing of the TAC1 precursor, for the release of substance P (amidated undecapeptide). The characterization of the mouse hemokinin-1 sequence was required. MATERIALS AND METHODS: We developed anti-tachykinin-specific antibodies for the immunoaffinity purification of tachykinins. RESULTS: Using MALDI-ToF, we identified mouse hemokinin-1 as an amidated decapeptide expressed in murine brain and periphery. Furthermore, we interestingly observed an additional mass peak corresponding to acetylated mouse hemokinin-1 and this post-translational modification is brain specific, not detected in the periphery. CONCLUSION: We suggest that the N terminal acetylation of the peptide provides greater potency for ligand-receptor interactions during neural cell signaling. PMID- 28882972 TI - Ileocecal Obstruction Due to Endometriosis - A Case Report and Literature Review. AB - Endometriosis is a common finding in premenopausal women and a significant number of cases presenting digestive tract involvement at the time of diagnosis. However, most of these patients present pelvic nodules involving the rectosigmoidian junction, other digestive tract segments being less commonly affected. We present the case of a 37-year-old nulliparous woman who presented for diffuse abdominal pain and vomiting; she was diagnosed with complete ileocecal obstruction due to an endometriosis nodule in association with bilateral ovarian endometriosis lesions invading the rectosigmodian wall. A right colectomy with ileocolic anastomosis in association with bilateral cystectomy and rectosigmodian resection was successfully performed. The histopathological examination confirmed the endometriosic origin of the nodules invading the rectosigmodian and ileocecal wall, that was similar to the one described at the level of the ovarian cysts. PMID- 28882973 TI - Elevated Serum AA/EPA Ratio as a Predictor of Skeletal Muscle Depletion in Cachexic Patients with Advanced Gastro-intestinal Cancers. AB - BACKGROUND: In recent years, the number of cancer patients has increased. Cancer patients are prone to sarcopenia as a result of the decrease in muscle mass and muscle weakness which occurs in cancer cachexia. Attention has been given on the effects of fatty acid administration on cancer patients. MATERIALS AND METHODS: We conducted a retrospective chart-review study of consecutive patients with unresectable advanced GI cancer (stage IV) (n=46) receiving chemotherapy treatment in an outpatient or in-hospital setting between December 2012 and September 2015 at our Institution. The collected data were characteristics, psoas muscle area as measured by computed tomography (CT), and biochemical blood test and serum fatty acid profiles. Three methods of analysis were evaluated: (i) Comparison of biomarkers between two groups: psoas muscle index change rate (DeltaPMI) decrease group vs. DeltaPMI increase group. (ii) Correlation between DeltaPMI and biomarkers. (iii) Multiple regression of DeltaPMI and biomarkers Results: In the DeltaPMI decrease group, n-6/n-3 ratio and AA/EPA ratio in the decrease group were significantly higher than those in the increase group. Among all parameters, serum EPA was positively and significantly related to DeltaPMI (CC=0.443, p=0.039). In contrast, serum CRP, AA/EPA ratio and n-6/n-3 ratio were negatively related to DeltaPMI (CC=-0.566, CC=-0.501, CC=-0.476, p=0.006, p=0.018, p=0.025, respectively). On multiple regression analysis, serum CRP value was strongly related to DeltaPMI (r2=0.421, beta=-0.670, p=0.001). CONCLUSION: Higher n-6/n-3 and AA/EPA ratios were associated with a decrease in psoas muscle area, that lead to diagnosis of sarcopenia. Higher CRP was also associated with a decrease in psoas muscle area, suggesting that this might be an indicator of cachexic skeletal muscle depletion in cachexic patients with advanced gastro intestinal cancers. PMID- 28882974 TI - Lymph Node Size on Computed Tomography Images Is a Predictive Indicator for Lymph Node Metastasis in Patients with Colorectal Neuroendocrine Tumors. AB - BACKGROUND: Colorectal neuroendocrine tumors (NET) are a rare manifestation of colorectal neoplasia, requiring for radical dissection of the regional lymph nodes along with colorectal resection similar to that required for colorectal cancer. However, thus far, no reports have described the ability of computed tomography (CT) to predict lymph node involvement. In this study, we revealed the prediction rate of lymph node metastasis using contrast-enhanced CT. PATIENTS AND METHODS: A total of 21 patients with colorectal NET undergoing colorectal resection were recruited from January 2010 to June 2016. We compared the CT findings between samples with or without pathologically proven lymph node metastasis, in each field (pericolic/perirectal and intermediate nodes). RESULTS: Within the pericolic/perirectal field, any lymph node larger than 5 mm in the CT images was a predictive indicator of lymph node metastasis with a sensitivity, specificity, and area under ROC curve (AUC) of 66.7%, 87.5%, and 0.844, respectively. Within the intermediate field, any visible lymph node on the CT was a predictive indicator of lymph node metastasis with a sensitivity, specificity, and AUC of 100%, 76.4%, and 0.890, respectively. In addition, when we observed lymph nodes larger than 3 mm on the CT images, the sensitivity and specificity were 100% and 82.4%, respectively, with an AUC of 0.8971. CONCLUSION: CT images provide predictive information for lymph node metastasis with a high rate of accuracy. PMID- 28882975 TI - Gastric Tube Reconstruction with Superdrainage Using Indocyanine Green Fluorescence During Esophagectomy. AB - We report a case of gastric tube reconstruction with superdrainage using indocyanine green fluorescence during esophagectomy for esophageal cancer. A 53 year-old man with a history of early esophageal cancer treated with endoscopic mucosal dissection experienced esophageal cancer recurrence. There was no evidence of lymph node involvement or distant metastasis on computed tomography; therefore, we performed thoracoscopic esophagectomy. After thoracoscopic esophagectomy, we created a gastric tube. When pulling up the gastric tube through the post-mediastinum route, a root of the right gastroepiploic vein was injured. We subsequently performed superdrainage to avoid congestion of the gastric tube with omental vein and pre-tracheal vein anastomosis at the neck, and confirmed venous flow using the indocyanine green fluorescence method. No postoperative anastomotic leakage was observed, and the patient was discharged 22 days after surgery. Thus, we recommend the indocyanine green fluorescence method in cases involving superdrainage during esophagectomy. PMID- 28882976 TI - Endobronchial Carcinoid Tumor Totally Occluding the Left Main Bronchus Without Producing Symptoms of Bronchial Obstruction. AB - BACKGROUND: Bronchial carcinoid tumors (BCTs) are rare neuroendocrine neoplasms of the lung that mainly have a central distribution. They are classified as typical and atypical, with the former variant generally conferring a more favorable survival. Central tumors are usually symptomatic with features of bronchial obstruction, whereas peripheral tumors may remain silent. CASE REPORT: A 36-year-old woman presented to our hospital due to an episode of massive hemoptysis 5 days prior to admission. She had experienced another episode of hemoptysis 4 years before, for which a chest x-ray had shown no pathological findings. A new chest x-ray showed complete collapse of the left lung, with remarkable tracheal deviation. Computed tomography revealed a large endobronchial lesion causing occlusion of the left main bronchus and significant mediastinal shift to the left. Despite the collapse of the left lung, no symptoms of bronchial obstruction were evident. The patient underwent a successful left pneumonectomy and pathology of the resected specimen revealed a typical stage pT2b N1 Mx endobronchial carcinoid tumor. CONCLUSION: Central tumors are usually symptomatic with features of bronchial obstruction, whereas peripheral tumors may remain silent. Although a significant amount of bronchial occlusion may be present, symptoms of obstruction might not be apparent. Hemoptysis should always be thoroughly investigated, as it may be the only sign of a severe underlying disease. PMID- 28882977 TI - Influence of Diabetes on Circulating Apoptotic Microparticles in Patients with Chronic Hepatitis C. AB - BACKGROUND/AIM: Type 2 diabetes mellitus (DM) frequently occurs in patients with chronic hepatitis C (CHC) and is associated with atherosclerosis, in which circulating microparticles (MPs) play an important role. We asked whether the presence of DM affects endothelial-derived (EMPs) and platelet-derived microparticles (PMPs) levels; and whether MPs levels associate with biomarkers of inflammation and oxidative stress in patients with CHC. MATERIALS AND METHODS: Overall, 136 patients were enrolled in the study, 86 CHC patients (41 with DM with moderate glycemic control), 20 outpatients with DM and 30 controls. Circulating MPs were phenotyped by flow cytometry. RESULTS: When the MPs levels were analyzed individually in CHC patients, there was a positive association of plasma apoptotic MPs with oxidative stress markers. We report a hitherto undescribed relationship between diabetes prevalence and apoptotic MPs-associated inflammation in patients with CHC. CONCLUSION: The presence of apoptotic MPs in the plasma of CHC patients, with increased levels being found in patients with DM and moderate glycemic control was herein demonstrated. The simultaneous monitoring of plasma apoptotic MPs, oxidative stress markers and inflammatory biomarkers can be helpful for the cardiovascular disease control in diabetic patients with CHC. PMID- 28882979 TI - Multiple Sclerosis and Subsequent Human Immunodeficiency Virus Infection: A Case with the Rare Comorbidity, Focus on Novel Treatment Issues and Review of the Literature. AB - BACKGROUND: The comorbidity between Multiple Sclerosis (MS) and Human Immunodeficiency Virus (HIV) infection is particularly rare. Only a few cases of comorbidity of Clinically Definite(CD)-MS and HIV have been documented worldwide, while the potential beneficial role of antiretroviral therapy regarding MS activity has long been an area of debate. CASE REPORT: We present a 36-year old male, bearing a diagnosis of CD-MS for twelve years. He had been treated for ten years with interferon-beta-1b, when he voluntarily discontinued therapy, claiming clinical stability. One year later he was diagnosed positive for HIV and he started and continued only on efavirenz/emricitabine/tenofovir-disoproxil fumarate (ATRIPLA(r)), remaining relapse-free until today. CONCLUSION: This fact, in combination with the unique pharmaceutical composition of the drug, which contains a component similar to a newly-approved agent for MS, dimethyl fumarate, prompted us to review the literature regarding this rare comorbidity and to suggest that the role of the antiretroviral therapy should be further explored in MS. PMID- 28882978 TI - Predictive Factors of Nivolumab-induced Hypothyroidism in Patients with Non-small Cell Lung Cancer. AB - BACKGROUND/AIM: Although immune checkpoint inhibitors play an important role in the therapy of lung cancer, they are associated with various immune-related adverse events and predictive factors of them are unclear. In this study, we investigated predictive factors of nivolumab-induced hypothyroidism which is one of the adverse events in patients with lung cancer. PATIENTS AND METHODS: Patients with non-small-cell lung cancer who were administered nivolumab at our hospital between December 2015 and May 2016 were retrospectively enrolled. The thyroid-stimulating hormone, free triiodothyronine, free thyroxine, thyroid peroxidase (TPO) antibody, and thyroglobulin antibody levels of each patient were analyzed. RESULTS: Of the 64 patients enrolled, 5 (7.8%) developed hypothyroidism after treatment with nivolumab. The TPO and thyroglobulin antibodies were significantly positive in patients who developed primary hypothyroidism. CONCLUSION: TPO and thyroglobulin antibody levels at baseline may be predictive of hypothyroidism. PMID- 28882980 TI - The metabolic syndrome and its components in 178 patients treated for craniopharyngioma after 16 years of follow-up. AB - OBJECTIVE: Patients with craniopharyngioma are at an increased risk for cardio- and cerebrovascular mortality. The metabolic syndrome (MetS) is an important cardiometabolic risk factor, but barely studied in patients with craniopharyngioma. We aimed to investigate the prevalence of and risk factors for the MetS and its components in patients with craniopharyngioma. DESIGN: Cross sectional study with retrospective data. METHODS: We studied the prevalence of and risk factors for the MetS and its components in 110 Dutch (median age 47 years, range 18-92) and 68 Swedish (median age 50 years, range 20-81) patients with craniopharyngioma with >=3 years of follow-up (90 females (51%); 83 patients with childhood-onset craniopharyngioma (47%); median follow-up after craniopharyngioma diagnosis 16 years (range 3-62)). In Dutch patients aged 30-70 years and Swedish patients aged 45-69 years, we examined the prevalence of the MetS and its components relative to the general population. RESULTS: Sixty-nine (46%) of 149 patients with complete data demonstrated the MetS. Prevalence of the MetS was significantly higher in patients with craniopharyngioma compared with the general population (40% vs 26% (P < 0.05) for Dutch patients; 52% vs 15% (P < 0.05) for Swedish patients). Multivariable logistic regression analysis identified visual impairment as a borderline significant predictor of the MetS (OR 2.54, 95% CI 0.95-6.81; P = 0.06) after adjustment for glucocorticoid replacement therapy and follow-up duration. Age, female sex, tumor location, radiological hypothalamic damage, 90Yttrium brachytherapy, glucocorticoid replacement therapy and follow-up duration significantly predicted components of the MetS. CONCLUSIONS: Patients with craniopharyngioma are at an increased risk for the MetS, especially patients with visual impairment. PMID- 28882982 TI - Peri-orificial rash in an infant. PMID- 28882983 TI - The practice of radiology needs to change. PMID- 28882981 TI - Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH). AB - OBJECTIVE: Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation. DESIGN: Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals. METHODS: We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8). RESULTS: 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann's syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH. CONCLUSIONS: Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families. PMID- 28882985 TI - Reply to Newland et al.: The dominant phenolic pathway for atmospheric toluene oxidation. PMID- 28882984 TI - Transient apoptosis inhibition in donor stem cells improves hematopoietic stem cell transplantation. AB - During hematopoietic stem cell transplantation, a substantial number of donor cells are lost because of apoptotic cell death. Transplantation-associated apoptosis is mediated mainly by the proapoptotic BCL-2 family proteins BIM and BMF, and their proapoptotic function is conserved between mouse and human stem and progenitor cells. Permanent inhibition of apoptosis in donor cells caused by the loss of these BH3-only proteins improves transplantation outcome, but recipients might be exposed to increased risk of lymphomagenesis or autoimmunity. Here, we address whether transient inhibition of apoptosis can serve as a safe but efficient alternative to improve the outcome of stem cell transplantation. We show that transient apoptosis inhibition by short-term overexpression of prosurvival BCL-XL, known to block BIM and BMF, is not only sufficient to increase the viability of hematopoietic stem and progenitor cells during engraftment but also improves transplantation outcome without signs of adverse pathologies. Hence, this strategy represents a promising and novel therapeutic approach, particularly under conditions of limited donor stem cell availability. PMID- 28882986 TI - Elucidating the fate of the OH-adduct in toluene oxidation under tropospheric boundary layer conditions. PMID- 28882987 TI - Reply to HU et al.: On the interpretation of gasdermin-B expression quantitative trait loci data. PMID- 28882988 TI - Autosomal Trisomy and Triploidy Are Corrected During Female Meiosis in Caenorhabditis elegans. AB - Trisomy and triploidy, defined as the presence of a third copy of one or all chromosomes, respectively, are deleterious in many species including humans. Previous studies have demonstrated that Caenorhabditis elegans with a third copy of the X chromosome are viable and fertile. However, the extra X chromosome was shown to preferentially segregate into the first polar body during oocyte meiosis to produce a higher frequency of euploid offspring than would be generated by random segregation. Here, we demonstrate that extra autosomes are preferentially eliminated by triploid C. elegans and trisomy IV C. elegans Live imaging of anaphase-lagging chromosomes and analysis of REC-8 staining of metaphase II spindles revealed that, in triploids, some univalent chromosomes do not lose cohesion and preferentially segregate intact into the first polar body during anaphase I, whereas other autosomes segregate chromatids equationally at anaphase I and eliminate some of the resulting single chromatids during anaphase II. We also demonstrate asymmetry in the anaphase spindle, which may contribute to the asymmetric segregation. This study reveals a pathway that allows aneuploid parents to produce euploid offspring at higher than random frequency. PMID- 28882989 TI - Apico-basal Polarity Determinants Encoded by crumbs Genes Affect Ciliary Shaft Protein Composition, IFT Movement Dynamics, and Cilia Length. AB - One of the most obvious manifestations of polarity in epithelia is the subdivision of the cell surface by cell junctions into apical and basolateral domains. crumbs genes are among key regulators of this form of polarity. Loss of crumbs function disrupts the apical cell junction belt and crumbs overexpression expands the apical membrane size. Crumbs proteins contain a single transmembrane domain and localize to cell junction area at the apical surface of epithelia. In some tissues, they are also found in cilia. To test their role in ciliogenesis, we investigated mutant phenotypes of zebrafish crumbs genes. In zebrafish, mutations of three crumbs genes, oko meduzy/crb2a, crb3a, and crb2b, affect cilia length in a subset of tissues. In oko meduzy (ome), this is accompanied by accumulation of other Crumbs proteins in the ciliary compartment. Moreover, intraflagellar transport (IFT) particle components accumulate in the ciliary shaft of ome;crb3a double mutants. Consistent with the above, Crb3 knockdown in mammalian cells affects the dynamics of IFT particle movement. These findings reveal crumbs-dependent mechanisms that regulate the localization of ciliary proteins, including Crumbs proteins themselves, and show that crumbs genes modulate intraflagellar transport and cilia elongation. PMID- 28882991 TI - Artificial stone-associated silicosis: a rapidly emerging occupational lung disease. AB - INTRODUCTION: Artificial stone is an increasingly popular material used to fabricate kitchen and bathroom benchtops. Cutting and grinding artificial stone is associated with generation of very high levels of respirable crystalline silica, and the frequency of cases of severe silicosis associated with this exposure is rapidly increasing. AIM: To report the characteristics of a clinical series of Australian workers with artificial stone-associated silicosis. METHODS: Respiratory physicians voluntarily reported cases of artificial stone-associated silicosis identified in their clinical practices. Physicians provided information including occupational histories, respiratory function tests, chest radiology and histopathology reports, when available. RESULTS: Seven male patients were identified with a median age of 44 years (range 26-61). All were employed in small kitchen and bathroom benchtop fabrication businesses with an average of eight employees (range 2-20). All workplaces primarily used artificial stone, and dust control measures were poor. All patients were involved in dry cutting artificial stone. The median duration of exposure prior to symptoms was 7 years (range 4-10). Six patients demonstrated radiological features of progressive massive fibrosis. These individuals followed up over a median follow-up period of 16 months (IQR 21 months) demonstrated rapid decline in prebronchodilator forced expiratory volume in 1 s of 386 mL/year (SD 204 mL) and forced vital capacity of 448 mL/year (SD 312 mL). CONCLUSIONS: This series of silicosis in Australian workers further demonstrates the risk-associated high-silica content artificial stone. Effective dust control and health surveillance measures need to be stringently implemented and enforced in this industry. PMID- 28882990 TI - Extended Synaptotagmin Localizes to Presynaptic ER and Promotes Neurotransmission and Synaptic Growth in Drosophila. AB - The endoplasmic reticulum (ER) is an extensive organelle in neurons with important roles at synapses including the regulation of cytosolic Ca2+, neurotransmission, lipid metabolism, and membrane trafficking. Despite intriguing evidence for these crucial functions, how the presynaptic ER influences synaptic physiology remains enigmatic. To gain insight into this question, we have generated and characterized mutations in the single extended synaptotagmin (Esyt) ortholog in Drosophila melanogaster Esyts are evolutionarily conserved ER proteins with Ca2+-sensing domains that have recently been shown to orchestrate membrane tethering and lipid exchange between the ER and plasma membrane. We first demonstrate that Esyt localizes to presynaptic ER structures at the neuromuscular junction. Next, we show that synaptic growth, structure, and homeostatic plasticity are surprisingly unperturbed at synapses lacking Esyt expression. However, neurotransmission is reduced in Esyt mutants, consistent with a presynaptic role in promoting neurotransmitter release. Finally, neuronal overexpression of Esyt enhances synaptic growth and the sustainment of the vesicle pool during intense activity, suggesting that increased Esyt levels may modulate the membrane trafficking and/or resting Ca2+ pathways that control synapse extension. Thus, we identify Esyt as a presynaptic ER protein that can promote neurotransmission and synaptic growth, revealing the first in vivo neuronal functions of this conserved gene family. PMID- 28882992 TI - Novel Pathways of Ponatinib Disposition Catalyzed By CYP1A1 Involving Generation of Potentially Toxic Metabolites. AB - Ponatinib, a pan-BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML), causes severe side effects including vascular occlusions, pancreatitis, and liver toxicity, although the underlying mechanisms remain unclear. Modifications of critical proteins through reactive metabolites are thought to be responsible for a number of adverse drug reactions. In vitro metabolite screening of ponatinib with human liver microsomes and glutathione revealed unambiguous signals of ponatinib-glutathione (P-GSH) adducts. Further profiling of human cytochrome P450 (P450) indicated that CYP1A1 was the predominant P450 enzyme driving this reaction. P-GSH conjugate formation paralleled the disappearance of hydroxylated ponatinib metabolites, suggesting the initial reaction was epoxide generation. Mouse glutathione S-transferase p1 (mGstp1) further enhanced P-GSH adduct formation in vitro. Ponatinib pharmacokinetics were determined in vivo in wild-type (WT) mice and mice humanized for CYP1A1/2 and treated with the CYP1A1 inducers 2,3,7,8 tetrachlorodibenzodioxin or 3-methylcholanthrene. Ponatinib exposure was significantly decreased in treated mice compared with controls (7.7- and 2.2-fold for WT and humanized CYP1A1/2, respectively). Interestingly, the P-GSH conjugate was only found in the feces of CYP1A1-induced mice, but not in control animals. Protein adducts were also identified by liquid chromatography-tandem mass spectrometry analysis of mGstp1 tryptic digests. These results indicate that not only could CYP1A1 be involved in ponatinib disposition, which has not been previously reported, but also that electrophilic intermediates resulting from CYP1A1 metabolism in normal tissues may contribute to ponatinib toxicity. These data are consistent with a recent report that CML patients who smoke are at greater risk of disease progression and premature death. PMID- 28882994 TI - Synthesis of mixed hypermetallic oxide BaOCa+ from laser-cooled reagents in an atom-ion hybrid trap. AB - Hypermetallic alkaline earth (M) oxides of formula MOM have been studied under plasma conditions that preclude insight into their formation mechanism. We present here the application of emerging techniques in ultracold physics to the synthesis of a mixed hypermetallic oxide, BaOCa+ These methods, augmented by high level electronic structure calculations, permit detailed investigation of the bonding and structure as well as the mechanism of its formation via the barrierless reaction of Ca (3PJ) with BaOCH3+ Further investigations of the reaction kinetics as a function of collision energy over the range 0.005 kelvin (K) to 30 K and of individual Ca fine-structure levels compare favorably with calculations based on long-range capture theory. PMID- 28882993 TI - The condensin complex is a mechanochemical motor that translocates along DNA. AB - Condensin plays crucial roles in chromosome organization and compaction, but the mechanistic basis for its functions remains obscure. We used single-molecule imaging to demonstrate that Saccharomyces cerevisiae condensin is a molecular motor capable of adenosine triphosphate hydrolysis-dependent translocation along double-stranded DNA. Condensin's translocation activity is rapid and highly processive, with individual complexes traveling an average distance of >=10 kilobases at a velocity of ~60 base pairs per second. Our results suggest that condensin may take steps comparable in length to its ~50-nanometer coiled-coil subunits, indicative of a translocation mechanism that is distinct from any reported for a DNA motor protein. The finding that condensin is a mechanochemical motor has important implications for understanding the mechanisms of chromosome organization and condensation. PMID- 28882995 TI - Aqueous Au-Pd colloids catalyze selective CH4 oxidation to CH3OH with O2 under mild conditions. AB - The selective oxidation of methane, the primary component of natural gas, remains an important challenge in catalysis. We used colloidal gold-palladium nanoparticles, rather than the same nanoparticles supported on titanium oxide, to oxidize methane to methanol with high selectivity (92%) in aqueous solution at mild temperatures. Then, using isotopically labeled oxygen (O2) as an oxidant in the presence of hydrogen peroxide (H2O2), we demonstrated that the resulting methanol incorporated a substantial fraction (70%) of gas-phase O2 More oxygenated products were formed than the amount of H2O2 consumed, suggesting that the controlled breakdown of H2O2 activates methane, which subsequently incorporates molecular oxygen through a radical process. If a source of methyl radicals can be established, then the selective oxidation of methane to methanol using molecular oxygen is possible. PMID- 28882996 TI - Fibril structure of amyloid-beta(1-42) by cryo-electron microscopy. AB - Amyloids are implicated in neurodegenerative diseases. Fibrillar aggregates of the amyloid-beta protein (Abeta) are the main component of the senile plaques found in brains of Alzheimer's disease patients. We present the structure of an Abeta(1-42) fibril composed of two intertwined protofilaments determined by cryo electron microscopy (cryo-EM) to 4.0-angstrom resolution, complemented by solid state nuclear magnetic resonance experiments. The backbone of all 42 residues and nearly all side chains are well resolved in the EM density map, including the entire N terminus, which is part of the cross-beta structure resulting in an overall "LS"-shaped topology of individual subunits. The dimer interface protects the hydrophobic C termini from the solvent. The characteristic staggering of the nonplanar subunits results in markedly different fibril ends, termed "groove" and "ridge," leading to different binding pathways on both fibril ends, which has implications for fibril growth. PMID- 28882998 TI - Transplantation of iPS-Derived Tumor Cells with a Homozygous MHC Haplotype Induces GRP94 Antibody Production in MHC-Matched Macaques. AB - Immune surveillance is a critical component of the antitumor response in vivo, yet the specific components of the immune system involved in this regulatory response remain unclear. In this study, we demonstrate that autoantibodies can mitigate tumor growth in vitro and in vivo We generated two cancer cell lines, embryonal carcinoma and glioblastoma cell lines, from monkey-induced pluripotent stem cells (iPSC) carrying a homozygous haplotype of major histocompatibility complex (MHC, Mafa in Macaca fascicularis). To establish a monkey cancer model, we transplanted these cells into monkeys carrying the matched Mafa haplotype in one of the chromosomes. Neither Mafa-homozygous cancer cell line grew in monkeys carrying the matched Mafa haplotype heterozygously. We detected in the plasma of these monkeys an IgG autoantibody against GRP94, a heat shock protein. Injection of the plasma prevented growth of the tumor cells in immunodeficient mice, whereas plasma IgG depleted of GRP94 IgG exhibited reduced killing activity against cancer cells in vitro These results indicate that humoral immunity, including autoantibodies against GRP94, plays a role in cancer immune surveillance. Cancer Res; 77(21); 6001-10. (c)2017 AACR. PMID- 28882997 TI - Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. AB - Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and alpha-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or alpha-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis. PMID- 28882999 TI - miR-193b-Regulated Signaling Networks Serve as Tumor Suppressors in Liposarcoma and Promote Adipogenesis in Adipose-Derived Stem Cells. AB - Well-differentiated and dedifferentiated liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo Deep RNA sequencing on 93 WDLS, 145 DDLS, and 12 normal fat samples demonstrated that miR 193b was significantly underexpressed in DDLS compared with normal fat. Reintroduction of miR-193b induced apoptosis in liposarcoma cells and promoted adipogenesis in human adipose-derived stem cells (ASC). Integrative transcriptomic and proteomic analysis of miR-193b-target networks identified novel direct targets, including CRK-like proto-oncogene (CRKL) and focal adhesion kinase (FAK). miR-193b was found to regulate FAK-SRC-CRKL signaling through CRKL and FAK. miR-193b also stimulated reactive oxygen species signaling by targeting the antioxidant methionine sulfoxide reductase A to modulate liposarcoma cell survival and ASC differentiation state. Expression of miR-193b in liposarcoma cells was downregulated by promoter methylation, resulting at least in part from increased expression of the DNA methyltransferase DNMT1 in WDLS/DDLS. In vivo, miR-193b mimetics and FAK inhibitor (PF-562271) each inhibited liposarcoma xenograft growth. In summary, miR-193b not only functions as a tumor suppressor in liposarcoma but also promotes adipogenesis in ASC. Furthermore, this study reveals key tyrosine kinase and DNA methylation pathways in liposarcoma, some with immediate implications for therapeutic exploration. Cancer Res; 77(21); 5728 40. (c)2017 AACR. PMID- 28883000 TI - Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non-Small Cell Lung Carcinoma. AB - The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and -extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. Cancer Res; 77(21); 5963-76. (c)2017 AACR. PMID- 28883001 TI - KDM4 Inhibition Targets Breast Cancer Stem-like Cells. AB - Traditional treatments for breast cancer fail to address therapy-resistant cancer stem-like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem-like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900 12. (c)2017 AACR. PMID- 28883002 TI - Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation. AB - Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic, and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC "knockout" (KO) animals, the long-term regenerative potential of hepatocytes was unimpaired, and growth of aggressive experimental hepatoblastomas was only modestly slowed in the face of 80%-90% reductions in AcCoA and significant alterations in the levels of key tricarboxylic acid (TCA) cycle intermediates and amino acids. Overall, oxphos activity in KO livers and hepatoblastoma was comparable with that of control counterparts, with evidence that metabolic substrate abnormalities were compensated for by increased mitochondrial mass. These findings demonstrate that the biochemical link between glycolysis and the TCA cycle can be completely severed without affecting normal or neoplastic proliferation, even under the most demanding circumstances. Cancer Res; 77(21); 5795-807. (c)2017 AACR. PMID- 28883003 TI - Discovery of Human-Similar Gene Fusions in Canine Cancers. AB - Canine cancers represent a tremendous natural resource due to their incidence and striking similarities to human cancers, sharing similar clinical and pathologic features as well as oncogenic events, including identical somatic mutations. Considering the importance of gene fusions as driver alterations, we explored their relevance in canine cancers. We focused on three distinct human-comparable canine cancers representing different tissues and embryonic origins. Through RNA Seq, we discovered similar gene fusions as those found in their human counterparts: IGK-CCND3 in B-cell lymphoma, MPB-BRAF in glioma, and COL3A1-PDGFB in dermatofibrosarcoma protuberans-like. We showed not only similar partner genes but also identical breakpoints leading to oncogene overexpression. This study demonstrates similar gene fusion partners and mechanisms in human-dog corresponding tumors and allows for selection of targeted therapies in preclinical and clinical trials with pet dogs prior to human trials, within the framework of personalized medicine. Cancer Res; 77(21); 5721-7. (c)2017 AACR. PMID- 28883005 TI - FSTL1 Promotes Metastasis and Chemoresistance in Esophageal Squamous Cell Carcinoma through NFkappaB-BMP Signaling Cross-talk. AB - Esophageal squamous cell carcinoma (ESCC) has a generally poor prognosis, and molecular markers to improve early detection and predict outcomes are greatly needed. Here, we report that the BMP-binding follistatin-like protein FSTL1 is overexpressed in ESCCs, where it correlates with poor overall survival. Genetic amplification of FSTL1 or chromosome 3q, where it is located, occurred frequently in ESCC, where FSTL1 copy number correlated positively with higher FSTL1 protein expression. Elevating FSTL1 levels by various means was sufficient to drive ESCC cell proliferation, clonogenicity, migration, invasion, self-renewal, and cisplatin resistance in vitro and tumorigenicity and distant metastasis in vivo Conversely, FSTL1 attenuation by shRNA or neutralizing antibody elicited the opposite effects in ESCC cells. mRNA profiling analyses suggested that FSTL1 drives ESCC oncogenesis and metastasis through various pathways, with deregulation of NFkappaB and BMP signaling figuring prominently. Cross-talk between the NFkappaB and BMP pathways was evidenced by functional rescue experiments using inhibitors of NFkappaB and TLR4. Our results establish the significance of FSTL1 in driving oncogenesis and metastasis in ESCC by coordinating NFkappaB and BMP pathway control, with implications for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in this disease setting. Cancer Res; 77(21); 5886-99. (c)2017 AACR. PMID- 28883004 TI - CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer. AB - The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT+ was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T cell metabolism and IFNgamma production, whereas CD155 overexpression inhibited T cell metabolism and IFNgamma production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice. Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer. Cancer Res; 77(22); 6375-88. (c)2017 AACR. PMID- 28883006 TI - Acute fibrinous and organising pneumonia. AB - Acute fibrinous and organising pneumonia (AFOP) is a rare histological pattern of interstitial lung disease. The authors describe a 60-year-old woman admitted to the hospital for sustained fever, presenting with an alveolar opacity on chest X ray, with the presumed diagnosis of community-acquired pneumonia and the onset of antibiotics. Since serological results suggested that Legionella pneumophila was the infectious agent, she was discharged on levofloxacin. A week later, she was again admitted with fever. CT scan showed opacities with crescentic morphology and a central ground-glass area suggestive of cryptogenic organising pneumonia. Microbiological, serological and autoimmunity tests were negative. She underwent surgical lung biopsy that revealed inflammatory infiltrate, macrophage desquamation, fibroblasts proliferation and fibrin deposition in the alveolar spaces, consistent with AFOP. She started corticotherapy with good response. Disease relapsed after prednisolone discontinuation, 10 months later. Currently, the patient is on prednisolone 5 mg/day without clinical and radiological recurrence. PMID- 28883007 TI - Bilateral tarsal tunnel syndrome attributed to bilateral fibrous tarsal coalition and symmetrical hypertrophy of the sustentaculum tali. AB - Tarsal tunnel syndrome (TTS) is one of the frequently encountered entrapment neuropathies of the lower limb. Most often the aetiology is considered to be idiopathic. However, it has to be thoroughly investigated to rule out diverse extrinsic and intrinsic causes. The sustentaculum tali (ST) forms the superior part of the distal tarsal tunnel, and any increase in its size may result in irritation of the tibial nerve or its branches, the medial and lateral plantar nerves or decrease the overall volume of the tarsal tunnel culminating to clinical features of TTS. A hypertrophied ST is an extremely rare cause for TTS, and we report perhaps a first case of bilateral TTS in a young adult due to bilateral symmetrical hypertrophied ST which in turn was a result of bilateral fibrous tarsal coalition. Staged bilateral surgical excision of the hypertrophied part of ST and the underlying fibrous tarsal coalition ensured prompt symptomatic relief. PMID- 28883008 TI - Nasogastric tube knotting: a rare and potentially overlooked complication among healthcare professionals. AB - Nasogastric tube placement is a common procedure performed in surgical and medical specialities. The occurrence of knot formation is perhaps one of the least well-recognised complications associated with its usage. We present a case of nasogastric tube knotting to remind colleagues of this rare but important complication. A 75-year-old woman with adhesional bowel obstruction was admitted under the general surgery team. A wide bore nasogastric tube was inserted for drainage and decompression. Although placement of the tube was deemed to be successful, there was no drainage of gastric content evident. On removal of the 'non-functioning' tube a simple knot was seen at its proximal end. A further nasogastric tube was placed and the patient's symptoms resolved with conservative management. Nasogastric tube knotting is a rare and often overlooked complication with the potential to cause significant trauma on tube removal if unrecognised. PMID- 28883009 TI - Total knee prosthesis infected with Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (MTB) infection of a prosthetic joint is rarely reported in developed countries.1 Typically, MTB infection involves the hips or knees, and the infection can occur secondary to crushing and degradation of the granuloma during surgery or, less commonly, from distant foci spreading through the blood. In the present case, MTB infection likely resulted from haematogenous spread since multiple hot spots suggestive of MTB infection were noted in other sites. Early diagnosis allows for antitubercular therapy with retention of the prosthesis, while late diagnosis frequently results in removal and reimplantation of the joint. To avoid major surgery, a high index of suspicion is required to diagnose prosthetic joint tuberculosis. PMID- 28883010 TI - Laparoscopic adrenalectomy as an effective approach to massive bilateral pheochromocytomas. AB - Pheochromocytomas are catecholamine-secreting neoplasms, arising from adrenomedullary chromaffin cells. In type 2 multiple endocrine neoplasia (MEN2) syndrome, pheochromocytomas are usually benign but with predisposition to be bilateral (50%-80% of cases).The authors present the case of a young patient diagnosed with uncommonly large bilateral cystic pheochromocytomas and simultaneous detection of medullary thyroid carcinoma. Molecular testing confirmed germline RET codon C634 mutation, consistent with MEN2A syndrome. The patient underwent bilateral laparoscopic adrenalectomy plus total thyroidectomy with central lymph node dissection without associated complications. The histopathological study of the surgical specimens revealed bilateral benign pheochromocytomas (Ki67 of 2%) and a medullary carcinoma of the thyroid T1bN0M0; R0, respectively. One year after surgery, the patient was considered free of disease.This case demonstrates that bilateral laparoscopic adrenalectomy can be a safe and feasible approach for phechromocytomas in MEN2 syndrome, even in lesions with large diameter. However, due to elevated possibility of recurrence, patients should maintain lifelong follow-up. PMID- 28883011 TI - Rare case of massive bilateral chylothorax. AB - We present a case of a 48-year-old woman who was referred from an outside hospital. There, she had initially underwent hysterectomy and left salpingo oophorectomy for tubo-ovarian abscess. She later developed a colovaginal fistula and perforation of sigmoid colon and underwent Hartmann's procedure along with drainage of a left subphrenic abscess. Subsequently, she had to be intubated for acute respiratory failure and was transferred to our hospital. At our hospital, she was found to have massive bilateral pleural effusions. Bilateral small-bore chest tubes were inserted that drained milky fluid. Pleural fluid analysis was consistent with bilateral chylothorax. Thereafter, patient's respiratory status improved and she was extubated. The mechanism of chylothorax was thought be either secondary to the multiple abdominal procedures or alternatively as a complication of the right subclavian catheter that was placed at the outside hospital. Her chest tubes were removed eventually, and she had a slow but definite recovery. PMID- 28883012 TI - Fibular insufficiency fracture: an under-reported complication of advanced tibialis posterior dysfunction. AB - We present a case of fibular insufficiency (stress) fracture in a patient with pre-existing asymptomatic advanced tibialis posterior dysfunction. The patient had severe planovalgus (flat foot) deformity but no pain before the injury; hence had never sought any treatment. She was first treated conservatively for the fracture which failed to control the deformity and had ongoing symptoms. She eventually required tibio-talo-calcaneal fusion. To the best of our knowledge, this is the first case report of this condition in the English literature. In patients with severe tibialis posterior dysfunction, weight-bearing axis passes directly from calcaneum to fibula making it vulnerable to fracture. Patients should be made aware of this risk even if they are asymptomatic and encouraged to use orthotic support for protection against insufficiency fractures. PMID- 28883013 TI - Abbott Laboratories offers fix for 745 000 pacemakers vulnerable to hacking. PMID- 28883014 TI - Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies. AB - It is now a decade since human induced pluripotent stem cells (hiPSCs) were first described. The reprogramming of adult somatic cells to a pluripotent state has become a robust technology that has revolutionised our ability to study human diseases. Crucially, these cells capture all the genetic aspects of the patient from which they were derived. Combined with advances in generating the different cell types present in the human heart, this has opened up new avenues to study cardiac disease in humans and investigate novel therapeutic approaches to treat these pathologies. Here, we provide an overview of the current state of the field regarding the generation of cardiomyocytes from human pluripotent stem cells and methods to assess them functionally, an essential requirement when investigating disease and therapeutic outcomes. We critically evaluate whether treatments suggested by these in vitro models could be translated to clinical practice. Finally, we consider current shortcomings of these models and propose methods by which they could be further improved. PMID- 28883015 TI - Mouse models of metastasis: progress and prospects. AB - Metastasis is the spread of cancer cells from a primary tumor to distant sites within the body to establish secondary tumors. Although this is an inefficient process, the consequences are devastating as metastatic disease accounts for >90% of cancer-related deaths. The formation of metastases is the result of a series of events that allow cancer cells to escape from the primary site, survive in the lymphatic system or blood vessels, extravasate and grow at distant sites. The metastatic capacity of a tumor is determined by genetic and epigenetic changes within the cancer cells as well as contributions from cells in the tumor microenvironment. Mouse models have proven to be an important tool for unraveling the complex interactions involved in the metastatic cascade and delineating its many stages. Here, we critically appraise the strengths and weaknesses of the current mouse models and highlight the recent advances that have been made using these models in our understanding of metastasis. We also discuss the use of these models for testing potential therapies and the challenges associated with the translation of these findings into the provision of new and effective treatments for cancer patients. PMID- 28883018 TI - NICE urges GPs to diagnoses endometriosis more quickly. PMID- 28883017 TI - NFkappaB signaling in alveolar rhabdomyosarcoma. AB - Alveolar rhabdomyosarcoma (aRMS) is a pediatric soft tissue cancer commonly associated with a chromosomal translocation that leads to the expression of a Pax3:Foxo1 or Pax7:Foxo1 fusion protein, the developmental underpinnings of which may give clues to its therapeutic approaches. In aRMS, the NFkappaB-YY1-miR-29 regulatory circuit is dysregulated, resulting in repression of miR-29 and loss of the associated tumor suppressor activity. To further elucidate the role of NFkappaB in aRMS, we first tested 55 unique sarcoma cell lines and primary cell cultures in a large-scale chemical screen targeting diverse molecular pathways. We found that pharmacological inhibition of NFkappaB activity resulted in decreased cell proliferation of many of the aRMS tumor cultures. Surprisingly, mice that were orthotopically allografted with aRMS tumor cells exhibited no difference in tumor growth when administered an NFkappaB inhibitor, compared to control. Furthermore, inhibition of NFkappaB by genetically ablating its activating kinase inhibitor, IKKbeta, by conditional deletion in a mouse model harboring the Pax3:Foxo1 chimeric oncogene failed to abrogate spontaneous tumor growth. Genetically engineered mice with conditionally deleted IKKbeta exhibited a paradoxical decrease in tumor latency compared with those with active NFkappaB. However, using a synthetic-lethal approach, primary cell cultures derived from tumors with inactivated NFkappaB showed sensitivity to the BCL-2 inhibitor navitoclax. When used in combination with an NFkappaB inhibitor, navitoclax was synergistic in decreasing the growth of both human and IKKbeta wild-type mouse aRMS cells, indicating that inactivation of NFkappaB alone may not be sufficient for reducing tumor growth, but, when combined with another targeted therapeutic, may be clinically beneficial. PMID- 28883016 TI - Mitochondrial dynamics in Parkinson's disease: a role for alpha-synuclein? AB - The distinctive pathological hallmarks of Parkinson's disease are the progressive death of dopaminergic neurons and the intracellular accumulation of Lewy bodies enriched in alpha-synuclein protein. Several lines of evidence from the study of sporadic, familial and pharmacologically induced forms of human Parkinson's disease also suggest that mitochondrial dysfunction plays an important role in disease progression. Although many functions have been proposed for alpha synuclein, emerging data from human and animal models of Parkinson's disease highlight a role for alpha-synuclein in the control of neuronal mitochondrial dynamics. Here, we review the alpha-synuclein structural, biophysical and biochemical properties that influence relevant mitochondrial dynamic processes such as fusion-fission, transport and clearance. Drawing on current evidence, we propose that alpha-synuclein contributes to the mitochondrial defects that are associated with the pathology of this common and progressive neurodegenerative disease. PMID- 28883019 TI - Suppression of Striatal Prediction Errors by the Prefrontal Cortex in Placebo Hypoalgesia. AB - Classical learning theories predict extinction after the discontinuation of reinforcement through prediction errors. However, placebo hypoalgesia, although mediated by associative learning, has been shown to be resistant to extinction. We tested the hypothesis that this is mediated by the suppression of prediction error processing through the prefrontal cortex (PFC). We compared pain modulation through treatment cues (placebo hypoalgesia, treatment context) with pain modulation through stimulus intensity cues (stimulus context) during functional magnetic resonance imaging in 48 male and female healthy volunteers. During acquisition, our data show that expectations are correctly learned and that this is associated with prediction error signals in the ventral striatum (VS) in both contexts. However, in the nonreinforced test phase, pain modulation and expectations of pain relief persisted to a larger degree in the treatment context, indicating that the expectations were not correctly updated in the treatment context. Consistently, we observed significantly stronger neural prediction error signals in the VS in the stimulus context compared with the treatment context. A connectivity analysis revealed negative coupling between the anterior PFC and the VS in the treatment context, suggesting that the PFC can suppress the expression of prediction errors in the VS. Consistent with this, a participant's conceptual views and beliefs about treatments influenced the pain modulation only in the treatment context. Our results indicate that in placebo hypoalgesia contextual treatment information engages prefrontal conceptual processes, which can suppress prediction error processing in the VS and lead to reduced updating of treatment expectancies, resulting in less extinction of placebo hypoalgesia.SIGNIFICANCE STATEMENT In aversive and appetitive reinforcement learning, learned effects show extinction when reinforcement is discontinued. This is thought to be mediated by prediction errors (i.e., the difference between expectations and outcome). Although reinforcement learning has been central in explaining placebo hypoalgesia, placebo hypoalgesic effects show little extinction and persist after the discontinuation of reinforcement. Our results support the idea that conceptual treatment beliefs bias the neural processing of expectations in a treatment context compared with a more stimulus driven processing of expectations with stimulus intensity cues. We provide evidence that this is associated with the suppression of prediction error processing in the ventral striatum by the prefrontal cortex. This provides a neural basis for persisting effects in reinforcement learning and placebo hypoalgesia. PMID- 28883022 TI - A visit to Brookwood Aslyum in the 19th century. PMID- 28883020 TI - Increased GSNOR Expression during Aging Impairs Cognitive Function and Decreases S-Nitrosation of CaMKIIalpha. AB - As the population ages, an increasing number of people suffer from age-related cognitive impairment. However, the mechanisms underlying this process remain unclear. Here, we found that S-nitrosoglutathione reductase (GSNOR), the key enzyme that metabolizes intracellular nitric oxide (NO) and regulates S nitrosation, was significantly increased in the hippocampus of both aging humans and mice. Transgenic mice overexpressing GSNOR exclusively in neurons showed cognitive impairment in behavioral tests, including the Morris water maze, fear conditioning, and the Y-maze test. We also found that GSNOR transgenic mice have LTP defects and lower dendrite spine density, whereas GSNOR knock-out mice rescued the age-related cognitive impairment. Analysis of S-nitrosation showed significantly decreased hippocampal CaMKIIalpha S-nitrosation in naturally aged mice and GSNOR transgenic mice. Consistent with the change in CaMKIIalpha S nitrosation, the accumulation of CaMKIIalpha in the hippocampal synaptosomal fraction, as well as its downstream signaling targets p(S831)-GLUR1, was also significantly decreased. All these effects could be rescued in the GSNOR knock out mice. We further verified that the S-nitrosation of CaMKIIalpha was responsible for the CaMKIIalpha synaptosomal accumulation by mutating CaMKIIalpha S-nitrosated sites (C280/C289). Upregulation of the NO signaling pathway rescued the cognitive impairment in GSNOR transgenic mice. In summary, our research demonstrates that GSNOR impairs cognitive function in aging and it could serve as a new potential target for the treatment of age-related cognitive impairment. In contrast to the free radical theory of aging, NO signaling deficiency may be the main mediator of age-related cognitive impairment.SIGNIFICANCE STATEMENT This study indicated that S-nitrosoglutathione reductase (GSNOR), a key protein S nitrosation metabolic enzyme, is a new potential target in age-related cognitive impairment; and in contrast to the free radical theory of aging, NO signaling deficiency may be the main cause of this process. In addition, increased GSNOR expression during aging decreases S-nitrosation of CaMKIIalpha and reduces CaMKIIalpha synaptosomal accumulation. To our knowledge, it is for the first time to show the cellular function regulation of CaMKIIalpha by GSNOR-dependent S nitrosation as a new post-translational modification after its phosphorylation was explored. These findings elucidate a novel mechanism of age-related cognitive impairment and may provide a new potential target and strategy for slowing down this process. PMID- 28883023 TI - Time to consider a targeted HPV vaccination programme for male military recruits. AB - Human papillomaviruses (HPV) are the most common type of sexually transmitted infection in men but also related to high-risk cancers. This article considers the epidemiology of HPV in the male military population, the UK vaccination programme and the current UK Joint Committee on Vaccination and Immunisation recommendations. Military men may not benefit from HPV herd immunity and may have a different risk profile; vaccination may in turn reduce the operational burden of HPV-related disease within this population. Military men may benefit from a targeted vaccination programme, and the paper calls for urgent consideration of approaches that could protect them from acquiring HPV. PMID- 28883024 TI - Hearing threshold shifts among military pilots of the Israeli Air Force. AB - BACKGROUND: Military aviators are potentially at risk for developing noise induced hearing loss. Whether ambient aircraft noise exposure causes hearing deficit beyond the changes attributed to natural ageing is debated. The aim of this research was to assess changes in hearing thresholds of Israeli Air Force (IAF) pilots over 20 years of military service and identify potential risk factors for hearing loss. METHODS: A retrospective cohort analysis was conducted of pure-tone air conduction audiograms of pilots, from their recruitment at 18 years of age until the last documented medical check-up. Mean hearing thresholds were analysed in relation to age, total flight hours and aircraft platform. Comparisons were made to the hearing thresholds of air traffic controllers (ATCs) who were not exposed to the noise generated by aircraft while on duty. RESULTS: One hundred and sixty-three pilots were included, with flying platforms ranging from fighter jets (n=54), combat helicopters (n=27), transport helicopters (n=52) and transport aircraft (n=30). These were compared with the results from 17 ATCs. A marked notch in the frequency range of 4-6 kHz was demonstrated in the mean audiograms of all platforms pilots, progressing with ageing. Hearing threshold shifts in relation to measurements at recruitment were first noted at the age of 30 years, particularly at 4 kHz (mean shift of 2.97 dB, p=0.001). There was no statistical association between flying variables and hearing thresholds adjusted for age by logistic regression analysis. CONCLUSIONS: The audiometric profile of IAF pilots has a pattern compatible with noise exposure, as reflected by characteristic noise notch. However, no flight variable was associated with deterioration of hearing thresholds, and no significant difference from non flying controls (ATCs) was seen. PMID- 28883025 TI - Do air-gaps behind soft body armour affect protection? AB - INTRODUCTION: Body armour typically comprises a fabric garment covering the torso combined with hard armour (ceramic/composite). Some users wear only soft armour which provides protection from sharp weapons and pistol ammunition. It is usually recommended that body armour is worn against the body with no air-gaps being present between the wearer and the armour. However, air-gaps can occur in certain situations such as females around the breasts, in badly fitting armour and where manufacturers have incorporated an air-gap claiming improvements in thermophysiological burden. The effect of an air-gap on the ballistic protection and the back face signature (BFS) as a result of a non-perforating ballistic impact was determined. METHODS: Armour panels representative of typical police armour (400x400 mm) were mounted on calibrated Roma Plastilina No 1 and impacted with 9 mm Luger FMJ (9*19 mm; full metal jacket; Dynamit Nobel DM11A1B2) ammunition at 365+/-10 m/s with a range of air-gaps (0-15 mm). Whether or not the ammunition perforated the armour was noted, the BFS was measured and the incidence of pencilling (a severe, deep and narrow BFS) was identified. RESULTS: For 0 degrees impacts, a critical air-gap size of 10 mm is detrimental to armour performance for the armour/ammunition combination assessed in this work. Specifically, the incidences of pencilling were more common with a 10 mm air-gap and resulted in BFS depth:volume ratios >=1.0. For impacts at 30 degrees the armour was susceptible to perforation irrespective of air-gap. CONCLUSIONS: This work suggested that an air-gap behind police body armour might result in an increased likelihood of injury. It is recommended that body armour is worn with no air-gap underneath. PMID- 28883026 TI - Group O low titre only emergency donor panels for small combat teams. AB - INTRODUCTION: Military elements increasingly operate in small teams in remote areas with no immediate blood product support. Planners and operators may endorse collection of fresh whole blood from pretested donors in emergency situations. The biggest risk of transfusion is the accidental use of ABO incompatible blood which can be fatal. The risk may be mitigated by using only group O LOw (OLO) titre donors with plasma containing low levels of the naturally occurring antibody to group A and B red cells. This paper reviews the ABO blood group distribution in potential blood donors from a high readiness UK medical regiment and explores the feasibility of using only group OLO donors in small teams. METHODS: A retrospective review of routine volunteer blood donor samples was undertaken at 6 monthly intervals during a 2-year period. Personnel were tested in groups when available during training to create multiple donor panels to simulate small teams. RESULTS: 206 donation samples were collected from 157 potential donors. All donors were acceptable based on the lifestyle questionnaire, serology and microbiology screen. Of the 206 samples reviewed, 85 (41%) were group O (D pos and D neg). 14 group O (16.5%) were shown to have high titre of anti-A or B. Therefore, 71, that is, 34% overall were suitable as OLO donors. The donor panel size varied from 15 to 44. The absolute number of OLO donors in each panel ranged from 4 to 17 and the number of O neg donors was 0-3. CONCLUSION: A third of samples were suitable as OLO donors; however, there were insufficient 'universal' donors within smaller subgroups (<10). In this situation, we recommend the careful use of both group O and group A donors or the use of a buddy-buddy blood group matrix. PMID- 28883027 TI - Addressing the knowledge gap: sexual violence and harassment in the UK Armed Forces. AB - Despite media interest in alleged sexual violence and harassment in the UK military, there remains a paucity of UK-based peer-reviewed research in this area. Ministry of Defence and service-specific reports support the suggestion that UK service personnel may be at risk of experiencing sexual harassment. These reports however highlight a reluctance by service personnel to report sexual harassment through official channels. In this article, we discuss the paucity of UK-based research pertaining to the prevalence and impact of sexual harassment in the military, explore potential reasons for this gap in knowledge and outline future directions and priorities for academic research. PMID- 28883028 TI - Exploring the health risks of help-seeking military veterans living in different parts of the UK. AB - BACKGROUND: Little is known about the mental and physical health differences of treatment-seeking military veterans across the different nations that make up the UK. The aim of this research was to explore potential health differences in order to support better service planning. METHODS: A random cross-sectional sample of treatment-seeking veterans residing in England, Scotland, Wales and Northern Ireland was identified from a national mental health charity. 403 veterans completed a questionnaire highlighting their demographics, mental health and physical health difficulties. The data were analysed using a multinomial logistic regression with England as the baseline comparison. RESULTS: Help-seeking veterans residing in Northern Ireland tended to be older, have experienced less childhood adversity, joined the military after the age of 18 and took longer to seek help. Additionally, veterans from Northern Ireland had higher levels of obesity, sensory, mobility and systemic problems and a greater number of physical health conditions. Scottish and Welsh veterans had a higher risk of smoking and alcohol misuse. No differences were found in mental health presentations. CONCLUSION: The findings from this paper suggest that a greater focus needs to be placed on treating physical problems in Northern Irish veterans. Alcohol misuse should be addressed in more detail in treatment programmes, particularly in Scotland and Wales. As few differences were found in the mental health presentations, this suggests that standardised services are adequate. PMID- 28883029 TI - The Centre for Defence Healthcare Engagement: a focus for Defence Engagement by the Defence Medical Services. AB - The 2015 Strategic Defence and Security Review committed the government to an ambitious programme of Defence Engagement. This paper provides a short summary of the medical contribution to UK Defence Engagement. It then describes the intentions behind the creation of the Centre for Defence Health Engagement. PMID- 28883030 TI - An exertional heat illness triage tool for a jungle training environment. AB - This article introduces a practical triage tool designed to assist commanders, jungle training instructors (JTIs) and medical personnel to identify Defence Personnel (DP) with suspected exertional heat illness (EHI). The challenges of managing suspected EHI in a jungle training environment and the potential advantages to stratifying the urgency of evacuation are discussed. This tool has been designed to be an adjunct to the existing MOD mandated heat illness recognition and first aid training. PMID- 28883031 TI - Neuropathic pain treatment and research: experiences from the United Kingdom mission to Afghanistan and future prospects. AB - The Defence Medical Services (DMS) of the United Kingdom (UK) assumed command of the Role 3 Medical Treatment Facility field hospital during Operation HERRICK in Afghanistan from April 2006 until the final drawdown in November 2014. The signature injury sustained by coalition personnel during this period was traumatic amputation from improvised explosive devices. Many patients who had suffered extensive tissue damage experienced both nociceptive and neuropathic pain (NeuP). This presented as a heterogeneous collection of symptoms that are resistant to treatment. This paper discusses the relationship of NeuP in the context of ballistic injury, drawing in particular on clinical experience from the UK mission to Afghanistan, Operation HERRICK. The role of this paper is to describe the difficulties of assessment, treatment and research of NeuP and make recommendations for future progress within the DMS. PMID- 28883032 TI - Screening for atrial fibrillation in hospitalised geriatric patients. AB - OBJECTIVES: To assess whether daily short-term rhythm strip recordings on top of routine clinical care could increase the atrial fibrillation (AF) detection rate in the hospitalised elderly. METHODS: A hand-held device storing a bipolar ECG during 1 min was used for daily rhythm recording in hospitalised elderly patients. RESULTS: During 2 months, all patients admitted to the Department of Geriatric Medicine were screened (n=327). Five patients refused to participate in the study and 70 patients were unable to hold the device due to severe mental (n=46) or motor impairment (n=24). In the remaining 252 patients, 1582 recordings were successfully obtained after 1624 attempts with a median acquisition time of 1 min (min 1, max 9, IQR 1-2 min). The rhythm strips were not reliable interpretable due to artefacts in three patients or an implantable cardiac pulse generator in another 28 patients. Detailed clinical information was available in 214/221 patients. Mean age was 84+/-6 years. On top of 71 (33%) patients with AF identified by routine clinical care (history, n=64 or de novo detected during current hospitalisation, n=7), review of all rhythm strips identified another 28 patients (13%) with AF. All these patients had a CHA2DS2VASc score >=2. A contraindication for anticoagulation was present in only 8/28 (25%) of identified patients. CONCLUSIONS: On top of routine clinical care, daily short-term rhythm strip recordings identified another 13% of elderly hospitalised patients with AF, leading to an overall prevalence of 46% in hospitalised patients. This can have significant therapeutic implications with respect to initiation of anticoagulation. PMID- 28883033 TI - Transseptal puncture for structural heart intervention: an old technique with new indications. PMID- 28883034 TI - Aortic stenosis: treat the patient not the numbers. PMID- 28883035 TI - Non-surgical septal reduction therapy in hypertrophic cardiomyopathy. PMID- 28883036 TI - How to interpret an echocardiography report (for the non-imager)? PMID- 28883037 TI - Ischaemic heart disease in the former Soviet Union 1990-2015 according to the Global Burden of Disease 2015 Study. AB - OBJECTIVE: The objective of this study was to compare ischaemic heart disease (IHD) mortality and risk factor burden across former Soviet Union (fSU) and satellite countries and regions in 1990 and 2015. METHODS: The fSU and satellite countries were grouped into Central Asian, Central European and Eastern European regions. IHD mortality data for men and women of any age were gathered from national vital registration, and age, sex, country, year-specific IHD mortality rates were estimated in an ensemble model. IHD morbidity and mortality burden attributable to risk factors was estimated by comparative risk assessment using population attributable fractions. RESULTS: In 2015, age-standardised IHD death rates in Eastern European and Central Asian fSU countries were almost two times that of satellite states of Central Europe. Between 1990 and 2015, rates decreased substantially in Central Europe (men -43.5% (95% uncertainty interval 45.0%, -42.0%); women -42.9% (-44.0%, -41.0%)) but less in Eastern Europe (men 5.6% (-9.0, -3.0); women -12.2% (-15.5%, -9.0%)). Age-standardised IHD death rates also varied within regions: within Eastern Europe, rates decreased -51.7% in Estonian men (-54.0, -47.0) but increased +19.4% in Belarusian men (+12.0, +27.0). High blood pressure and cholesterol were leading risk factors for IHD burden, with smoking, body mass index, dietary factors and ambient air pollution also ranking high. CONCLUSIONS: Some fSU countries continue to experience a high IHD burden, while others have achieved remarkable reductions in IHD mortality. Control of blood pressure, cholesterol and smoking are IHD prevention priorities. PMID- 28883038 TI - Yeast silencing factor Sir4 and a subset of nucleoporins form a complex distinct from nuclear pore complexes. AB - Interactions occurring at the nuclear envelope (NE)-chromatin interface influence both NE structure and chromatin organization. Insights into the functions of NE chromatin interactions have come from the study of yeast subtelomeric chromatin and its association with the NE, including the identification of various proteins necessary for tethering subtelomeric chromatin to the NE and the silencing of resident genes. Here we show that four of these proteins-the silencing factor Sir4, NE-associated Esc1, the SUMO E3 ligase Siz2, and the nuclear pore complex (NPC) protein Nup170-physically and functionally interact with one another and a subset of NPC components (nucleoporins or Nups). Importantly, this group of Nups is largely restricted to members of the inner and outer NPC rings, but it lacks numerous others including cytoplasmically and nucleoplasmically positioned Nups. We propose that this Sir4-associated Nup complex is distinct from holo-NPCs and that it plays a role in subtelomeric chromatin organization and NE tethering. PMID- 28883039 TI - Disease-associated mutations in human BICD2 hyperactivate motility of dynein dynactin. AB - Bicaudal D2 (BICD2) joins dynein with dynactin into a ternary complex (termed DDB) capable of processive movement. Point mutations in the BICD2 gene have been identified in patients with a dominant form of spinal muscular atrophy, but how these mutations cause disease is unknown. To investigate this question, we have developed in vitro motility assays with purified DDB and BICD2's membrane vesicle partner, the GTPase Rab6a. Rab6a-GTP, either in solution or bound to artificial liposomes, released BICD2 from an autoinhibited state and promoted robust dynein dynactin transport. In these assays, BICD2 mutants showed an enhanced ability to form motile DDB complexes. Increased retrograde transport by BICD2 mutants also was observed in cells using an inducible organelle transport assay. When overexpressed in rat hippocampal neurons, the hyperactive BICD2 mutants decreased neurite growth. Our results reveal that dominant mutations in BICD2 hyperactivate DDB motility and suggest that an imbalance of minus versus plus end-directed microtubule motility in neurons may underlie spinal muscular atrophy. PMID- 28883040 TI - Genome-wide siRNA screen identifies UNC50 as a regulator of Shiga toxin 2 trafficking. AB - Shiga toxins 1 and 2 (STx1 and STx2) undergo retrograde trafficking to reach the cytosol. Early endosome-to-Golgi transport allows the toxins to evade degradation in lysosomes. Targeting this trafficking step has therapeutic promise, but the mechanism of trafficking for the more potent toxin STx2 is unclear. To identify host factors required for early endosome-to-Golgi trafficking of STx2, we performed a viability-based genome-wide siRNA screen in HeLa cells. 564, 535, and 196 genes were found to be required for toxicity induced by STx1 only, STx2 only, and both toxins, respectively. We focused on validating endosome/Golgi-localized hits specific for STx2 and found that depletion of UNC50 blocked early endosome to-Golgi trafficking and induced lysosomal degradation of STx2. UNC50 acted by recruiting GBF1, an ADP ribosylation factor-guanine nucleotide exchange factor (ARF-GEF), to the Golgi. These results provide new information about STx2 trafficking mechanisms and may advance efforts to generate therapeutically viable toxin-trafficking inhibitors. PMID- 28883041 TI - Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor growths. AB - ATP fuels the removal of metabolic end-products, including H+ ions that profoundly modulate biological activities. Energetic resources in hypoxic tumor regions are constrained by low-yielding glycolysis, and any means of reducing the cost of acid extrusion, without compromising pH homeostasis, would therefore be advantageous for cancer cells. Some cancers express connexin channels that allow solute exchange between cells, and we propose that, via this route, normoxic cells supply hypoxic neighbors with acid-neutralizing HCO3- ions. This hypothesis was tested by imaging cytoplasmic pH in spheroidal tissue growths of connexin43 positive pancreatic cancer Colo357 cells during light-controlled H+ uncaging at the hypoxic core. Cytoplasmic acid retention at the core was halved in the presence of CO2/HCO3-, but this process requires a restorative HCO3- flux. The effect of CO2/HCO3- was ablated by connexin43 inhibition or knockdown. In connexin-decoupled spheroids, 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), an inhibitor of HCO3- uptake, had no effect on cytoplasmic [H+] in the H+ uncaging region, indicating that DIDS-sensitive transport is not an adequate pH regulatory strategy therein. With intact connexin-coupling, acid retention at the core increased upon DIDS treatment, indicating that HCO3- ions are taken up actively by peripheral cells and then transmitted passively to cells at the hypoxic core. Thus, the energetic burden of pH regulation is offloaded from hypoxic cells onto metabolically altruistic normoxic neighbors.-Dovmark, T. H., Hulikova, A., Niederer, S. A., Vaughan-Jones, R. D., Swietach, P. Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin coupled tumor growths. PMID- 28883042 TI - Real-time acquisition of transendothelial electrical resistance in an all-human, in vitro, 3-dimensional, blood-brain barrier model exemplifies tight-junction integrity. AB - The blood-brain barrier (BBB) consists of endothelial cells, astrocytes, and pericytes embedded in basal lamina (BL). Most in vitro models use nonhuman, monolayer cultures for therapeutic-delivery studies, relying on transendothelial electrical resistance (TEER) measurements without other tight-junction (TJ) formation parameters. We aimed to develop reliable, reproducible, in vitro 3 dimensional (3D) models incorporating relevant human, in vivo cell types and BL proteins. The 3D BBB models were constructed with human brain endothelial cells, human astrocytes, and human brain pericytes in mono-, co-, and tricultures. TEER was measured in 3D models using a volt/ohmmeter and cellZscope. Influence of BL proteins-laminin, fibronectin, collagen type IV, agrin, and perlecan-on adhesion and TEER was assessed using an electric cell-substrate impedance-sensing system. TJ protein expression was assessed by Western blotting (WB) and immunocytochemistry (ICC). Perlecan (10 ug/ml) evoked unreportedly high, in vitro TEER values (1200 Omega) and the strongest adhesion. Coculturing endothelial cells with astrocytes yielded the greatest resistance over time. ICC and WB results correlated with resistance levels, with evidence of prominent occludin expression in cocultures. BL proteins exerted differential effects on TEER, whereas astrocytes in contact yielded higher TEER values and TJ expression. Maherally, Z., Fillmore, H. L., Tan, S. L., Tan, S. F., Jassam, S. A., Quack, F. I., Hatherell, K. E., Pilkington, G. J. Real-time acquisition of transendothelial electrical resistance in an all-human, in vitro, 3-dimensional, blood-brain barrier model exemplifies tight-junction integrity. PMID- 28883044 TI - Beneficial effects of exercise training in heart failure are lost in male diabetic rats. AB - Exercise training has been demonstrated to have beneficial effects in patients with heart failure (HF) or diabetes. However, it is unknown whether diabetic patients with HF will benefit from exercise training. Male Wistar rats were fed either a standard (Sham, n = 53) or high-fat, high-sucrose diet ( n = 66) for 6 mo. After 2 mo of diet, the rats were already diabetic. Rats were then randomly subjected to either myocardial infarction by coronary artery ligation (MI) or sham operation. Two months later, heart failure was documented by echocardiography and animals were randomly subjected to exercise training with treadmill for an additional 8 wk or remained sedentary. At the end, rats were euthanized and tissues were assayed by RT-PCR, immunoblotting, spectrophotometry, and immunohistology. MI induced a similar decrease in ejection fraction in diabetic and lean animals but a higher premature mortality in the diabetic group. Exercise for 8 wk resulted in a higher working power developed by MI animals with diabetes and improved glycaemia but not ejection fraction or pathological phenotype. In contrast, exercise improved the ejection fraction and increased adaptive hypertrophy after MI in the lean group. Trained diabetic rats with MI were nevertheless able to develop cardiomyocyte hypertrophy but without angiogenic responses. Exercise improved stress markers and cardiac energy metabolism in lean but not diabetic-MI rats. Hence, following HF, the benefits of exercise training on cardiac function are blunted in diabetic animals. In conclusion, exercise training only improved the myocardial profile of infarcted lean rats fed the standard diet. NEW & NOTEWORTHY Exercise training is beneficial in patients with heart failure (HF) or diabetes. However, less is known of the possible benefit of exercise training for HF patients with diabetes. Using a rat model where both diabetes and MI had been induced, we showed that 2 mo after MI, 8 wk of exercise training failed to improve cardiac function and metabolism in diabetic animals in contrast to lean animals. PMID- 28883043 TI - FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing. AB - Free fatty acid receptors 2 and 3 (FFAR2/FFA2/GPR43 and FFAR3/FFA3/GPR41) are mammalian receptors for gut microbiota-derived short-chain fatty acids (SCFAs). These receptors are promising drug targets for obesity, colitis, colon cancer, asthma, and arthritis. Here, we demonstrate that FFAR2 and FFAR3 interact to form a heteromer in primary human monocytes and macrophages via proximity ligation assay, and during heterologous expression in HEK293 cells via bimolecular fluorescence complementation and fluorescence resonance energy transfer. The FFAR2-FFAR3 heteromer displayed enhanced cytosolic Ca2+ signaling (1.5-fold increase relative to homomeric FFAR2) and beta-arrestin-2 recruitment (30-fold increase relative to homomeric FFAR3). The enhanced heteromer signaling was attenuated by FFAR2 antagonism (CATPB), Galphaq inhibition (YM254890), or Galphai inhibition (pertussis toxin). Unlike homomeric FFAR2/3, the heteromer lacked the ability to inhibit cAMP production but gained the ability to induce p38 phosphorylation in HEK293 and inflammatory monocytes via a CATPB- and YM254890 sensitive mechanism. Our data, taken together, reveal that FFAR2 and FFAR3 may interact to form a receptor heteromer with signaling that is distinct from the parent homomers-a novel pathway for drug targeting.-Ang, Z., Xiong, D., Wu, M., Ding, J. L. FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing. PMID- 28883045 TI - Breath-to-breath variability of exhaled CO2 as a marker of lung dysmaturity in infancy. AB - The concept of diffusional screening implies that breath-to-breath variations in CO2 clearance, when related to the variability of breathing, may contain information on the quality and utilization of the available alveolar surface. We explored the validity of the above hypothesis in a cohort of young infants of comparable postmenstrual age but born at different stages of lung maturity, namely, in term-born infants ( n = 128), preterm-born infants without chronic lung disease of infancy (CLDI; n = 53), and preterm infants with moderate/severe CLDI ( n = 87). Exhaled CO2 volume (VE,CO2) and concentration (FE,CO2) were determined by volumetric capnography, whereas their variance was assessed by linear and nonlinear variability metrics. The relationship between relative breath-to-breath change of VE,CO2 (DeltaVE,CO2) and the corresponding change of tidal volume (DeltaVT) was also analyzed. Nonlinear FE,CO2 variability was lower in CLDI compared with term and non-CLDI preterm group ( P < 0.001 for both comparisons). In CLDI infants, most of the VE,CO2 variability was attributed to the variability of VT ( r2 = 0.749), whereas in term and healthy preterm infants this relationship was weaker ( r2 = 0.507 and 0.630, respectively). The DeltaVE,CO2 - DeltaVT slope was less steep in the CLDI group (1.06 +/- 0.07) compared with non-CLDI preterm (1.16 +/- 0.07; P < 0.001) and term infants (1.20 +/- 0.10; P < 0.001), suggesting that the more dysmature the infant lung, the less efficiently it eliminates CO2 under tidal breathing conditions. We conclude that the temporal variation of CO2 clearance may be related to the degree of lung dysmaturity in early infancy. NEW & NOTEWORTHY Young infants exhibit appreciable breath-to-breath CO2 variability that can be quantified by nonlinear variability metrics and may reflect the degree of lung dysmaturity. In infants with moderate/severe chronic lung disease of infancy (CLDI), the variability of the exhaled CO2 is mainly driven by the variability of breathing, whereas in term born and healthy preterm infants this relationship is less strong. The slope of the relative CO2-to-volume change is less steep in CLDI infants, suggesting that dysmature lungs are less efficient in eliminating CO2 under tidal breathing conditions. PMID- 28883046 TI - Skeletal muscle mitochondrial protein synthesis and respiration in response to the energetic stress of an ultra-endurance race. AB - The 2016 Colorado Trail Race (CTR) was an ultra-endurance mountain bike race in which competitors cycled for up to 24 h/day between altitudes of 1,675 and 4,025 m to complete 800 km and 21,000 m of elevation gain. In one athlete, we had the unique opportunity to characterize skeletal muscle protein synthesis and mitochondrial respiration in response to a normal activity control period (CON) and the CTR. We hypothesized that mitochondrial protein synthesis would be elevated and mitochondrial respiration would be maintained during the extreme stresses of the CTR. Titrated and bolus doses of ADP were provided to determine substrate-specific oxidative phosphorylation (OXPHOS) and electron transport system (ETS) capacities in permeabilized muscle fibers via high-resolution respirometry. Protein synthetic rates were determined by daily oral consumption of deuterium oxide (2H2O). The endurance athlete had OXPHOS (226 pmol.s-1.mg tissue-1) and ETS (231 pmol.s-1.mg tissue-1) capacities that rank among the highest published to date in humans. Mitochondrial (3.2-fold), cytoplasmic (2.3 fold), and myofibrillar (1.5-fold) protein synthesis rates were greater during CTR compared with CON. With titrated ADP doses, the apparent Km of ADP, OXPHOS, and ETS increased after the CTR. With provision of ADP boluses after the CTR, the addition of fatty acids (-12 and -14%) mitigated the decline in OXPHOS and ETS capacity during carbohydrate-supported respiration (-26 and -31%). In the face of extreme stresses during the CTR, elevated rates of mitochondrial protein synthesis may contribute to rapid adaptations in mitochondrial bioenergetics. NEW & NOTEWORTHY The mechanisms that maintain skeletal muscle function during extreme stresses remain incompletely understood. In the current study, greater rates of mitochondrial protein synthesis during the energetic demands of ultra-endurance exercise may contribute to rapid adaptations in mitochondrial bioenergetics. The endurance athlete herein achieved mitochondrial respiratory capacities among the highest published for humans. Greater mitochondrial protein synthesis during ultra-endurance exercise may contribute to improved mitochondrial respiration and serve as a mechanism to resist cellular energetic stresses. PMID- 28883047 TI - Intrinsic exercise capacity in rats influences dopamine neuroplasticity induced by physical training. AB - The study evaluates whether the intrinsic capacity for physical exercise influences dopamine neuroplasticity induced by physical training. Male rats were submitted to three progressive tests until fatigue. Based on the maximal time of exercise (TE), rats were considered as low performance (LP), standard performance (SP) or high performance (HP) to exercise. Eight animals from each group (LP, SP, and HP) were randomly subdivided in sedentary (SED) or trained (TR). Physical training was performed for 6 wk. After that, concentrations of dopamine (DA), serotonin (5-HT), and their metabolites and mRNA levels of D1 receptor ( Drd1), D2 receptor ( Drd2), dopamine transporter ( Dat), tyrosine hydroxylase ( Th), glia cell line neurotrophic factor ( Gdnf), and brain-derived neurotrophic factor ( Bdnf) were determined in the caudate-putamen (CPu). TE was increased with training in all performance groups. However, the relative increase was markedly higher in LP rats, and this was associated with a training-induced increase in dopaminergic activity in the CPu, which was determined by the 3,4 dihydroxyphenylacetic acid (DOPAC)/DA ratio. An opposite monoamine response was found in HP-TR rats, in which physical training decreased the DOPAC/DA ratio in the CPu. Moreover, LP-SED rats displayed higher levels of Drd2 in the CPu compared with the other SED groups, and this higher expression was decreased by physical training. Physical training also decreased Dat and increased Gdnf in the CPu of LP rats. Physical training decreased Bdnf in the CPu only in HP rats. Thus, we provide evidence that the intrinsic capacity to exercise affects the neuroplasticity of the dopaminergic system in response to physical training. NEW & NOTEWORTHY The findings reported reveal that dopaminergic neuroplasticity in caudate-putamen induced by physical training is influenced by the intrinsic capacity to exercise in rats. To evaluate the dopaminergic neuroplasticity, we analyzed mRNA levels of D1 receptor, D2 receptor, dopamine transporter, tyrosine hydroxylase, glia cell line neurotrophic factor, and brain-derived neurotrophic factor as well as concentrations of dopamine, serotonin, and their metabolites. These results expand our knowledge about the interrelationship between genetic background, physical training, and dopaminergic neuroplasticity. PMID- 28883049 TI - Postdocs power research. PMID- 28883051 TI - Record storm puts gulf resilience to the test. PMID- 28883052 TI - NIH's massive health study is off to a slow start. PMID- 28883048 TI - CORP: Ultrasound assessment of vascular function with the passive leg movement technique. AB - As dysfunction of the vascular system is an early, modifiable step in the progression of many cardiovascular diseases, there is demand for methods to monitor the health of the vascular system noninvasively in clinical and research settings. Validated by very good agreement with more technical assessments of vascular function, like intra-arterial drug infusions and flow-mediated dilation, the passive leg movement (PLM) technique has emerged as a powerful, yet relatively simple, test of peripheral vascular function. In the PLM technique, the change in leg blood flow elicited by the passive movement of the leg through a 90 degrees range of motion is quantified with Doppler ultrasound. This relatively easy-to-learn test has proven to be <=80% dependent on nitric oxide bioavailability and is especially adept at determining peripheral vascular function across the spectrum of cardiovascular health. Indeed, multiple reports have documented that individuals with decreased cardiovascular health such as the elderly and those with heart failure tend to exhibit a substantially blunted PLM induced hyperemic response (~50 and ~85% reduction, respectively) compared with populations with good cardiovascular health such as young individuals. As specific guidelines have not yet been put forth, the purpose of this Cores of Reproducibility in Physiology (CORP) article is to provide a comprehensive reference for the assessment and interpretation of vascular function with PLM with the aim to increase reproducibility and consistency among studies and facilitate the use of PLM as a research tool with clinical relevance. PMID- 28883053 TI - Billionaire's gift pushes ocean sensors deeper. PMID- 28883054 TI - Oklahoma politician picked to lead NASA back to the moon. PMID- 28883055 TI - In Colombia, peace dividend for science proves elusive. PMID- 28883056 TI - Panel urges steps to boost evidence-based policy. PMID- 28883057 TI - Zapping cocaine addiction. PMID- 28883058 TI - A looming tragedy of the sand commons. PMID- 28883059 TI - Meet the primordial asteroid family. PMID- 28883060 TI - The balance between immunity and inflammation. PMID- 28883061 TI - Wire together, fire apart. PMID- 28883062 TI - The road to Crohn's disease. PMID- 28883063 TI - How glass fronts deceive bats. PMID- 28883064 TI - Science in litigation, the third branch of U.S. climate policy. PMID- 28883065 TI - Mitigating coastal landslide damage. PMID- 28883066 TI - The EU's ecological risk assessments. PMID- 28883067 TI - Manipulating ultracold matter. PMID- 28883068 TI - Trapped in orbit. PMID- 28883069 TI - Probing the frontiers of particle physics with tabletop-scale experiments. AB - The field of particle physics is in a peculiar state. The standard model of particle theory successfully describes every fundamental particle and force observed in laboratories, yet fails to explain properties of the universe such as the existence of dark matter, the amount of dark energy, and the preponderance of matter over antimatter. Huge experiments, of increasing scale and cost, continue to search for new particles and forces that might explain these phenomena. However, these frontiers also are explored in certain smaller, laboratory-scale "tabletop" experiments. This approach uses precision measurement techniques and devices from atomic, quantum, and condensed-matter physics to detect tiny signals due to new particles or forces. Discoveries in fundamental physics may well come first from small-scale experiments of this type. PMID- 28883070 TI - Quantum simulations with ultracold atoms in optical lattices. AB - Quantum simulation, a subdiscipline of quantum computation, can provide valuable insight into difficult quantum problems in physics or chemistry. Ultracold atoms in optical lattices represent an ideal platform for simulations of quantum many body problems. Within this setting, quantum gas microscopes enable single atom observation and manipulation in large samples. Ultracold atom-based quantum simulators have already been used to probe quantum magnetism, to realize and detect topological quantum matter, and to study quantum systems with controlled long-range interactions. Experiments on many-body systems out of equilibrium have also provided results in regimes unavailable to the most advanced supercomputers. We review recent experimental progress in this field and comment on future directions. PMID- 28883071 TI - Cold molecules: Progress in quantum engineering of chemistry and quantum matter. AB - Cooling atoms to ultralow temperatures has produced a wealth of opportunities in fundamental physics, precision metrology, and quantum science. The more recent application of sophisticated cooling techniques to molecules, which has been more challenging to implement owing to the complexity of molecular structures, has now opened the door to the longstanding goal of precisely controlling molecular internal and external degrees of freedom and the resulting interaction processes. This line of research can leverage fundamental insights into how molecules interact and evolve to enable the control of reaction chemistry and the design and realization of a range of advanced quantum materials. PMID- 28883072 TI - Behavioral time scale synaptic plasticity underlies CA1 place fields. AB - Learning is primarily mediated by activity-dependent modifications of synaptic strength within neuronal circuits. We discovered that place fields in hippocampal area CA1 are produced by a synaptic potentiation notably different from Hebbian plasticity. Place fields could be produced in vivo in a single trial by potentiation of input that arrived seconds before and after complex spiking. The potentiated synaptic input was not initially coincident with action potentials or depolarization. This rule, named behavioral time scale synaptic plasticity, abruptly modifies inputs that were neither causal nor close in time to postsynaptic activation. In slices, five pairings of subthreshold presynaptic activity and calcium (Ca2+) plateau potentials produced a large potentiation with an asymmetric seconds-long time course. This plasticity efficiently stores entire behavioral sequences within synaptic weights to produce predictive place cell activity. PMID- 28883073 TI - Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death. AB - Humans inhale mold conidia daily and typically experience lifelong asymptomatic clearance. Conidial germination into tissue-invasive hyphae can occur in individuals with defects in myeloid function, although the mechanism of myeloid cell-mediated immune surveillance remains unclear. By monitoring fungal physiology in vivo, we demonstrate that lung neutrophils trigger programmed cell death with apoptosis-like features in Aspergillus fumigatus conidia, the most prevalent human mold pathogen. An antiapoptotic protein, AfBIR1, opposes this process by inhibiting fungal caspase activation and DNA fragmentation in the murine lung. Genetic and pharmacologic studies indicate that AfBIR1 expression and activity underlie conidial susceptibility to NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-dependent killing and, in turn, host susceptibility to invasive aspergillosis. Immune surveillance exploits a fungal apoptosis-like programmed cell death pathway to maintain sterilizing immunity in the lung. PMID- 28883075 TI - Choose a program, have a life. PMID- 28883074 TI - Acoustic mirrors as sensory traps for bats. AB - Sensory traps pose a considerable and often fatal risk for animals, leading them to misinterpret their environment. Bats predominantly rely on their echolocation system to forage, orientate, and navigate. We found that bats can mistake smooth, vertical surfaces as clear flight paths, repeatedly colliding with them, likely as a result of their acoustic mirror properties. The probability of collision is influenced by the number of echolocation calls and by the amount of time spent in front of the surface. The echolocation call analysis corroborates that bats perceive smooth, vertical surfaces as open flyways. Reporting on occurrences with different species in the wild, we argue that it is necessary to more closely monitor potentially dangerous locations with acoustic mirror properties (such as glass fronts) to assess the true frequency of fatalities around these sensory traps. PMID- 28883079 TI - Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis. AB - While dietary folate deficiency is associated with increased risk for birth defects and other diseases, evidence suggests that supplementation with folic acid can contribute to predisposition to some diseases, including immune dysfunction and cancer. Herein, we show that diets supplemented with folic acid both below and above the recommended levels led to significantly altered metabolism in multiple tissues in mice. Surprisingly, both low and excessive dietary folate induced similar metabolic changes, which were particularly evident for nucleotide biosynthetic pathways in B-progenitor cells. Diet-induced metabolic changes in these cells partially phenocopied those observed in mice treated with anti-folate drugs, suggesting that both deficiency and excessive levels of dietary folic acid compromise folate-dependent biosynthetic pathways. Both folate deficiency and excessive dietary folate levels compromise hematopoiesis, resulting in defective cell cycle progression, persistent DNA damage, and impaired production of lymphocytes. These defects reduce the reconstitution potential in transplantation settings and increase radiation induced mortality. We conclude that excessive folic acid supplementation can metabolically mimic dietary folate insufficiency, leading to similar functional impairment of hematopoiesis. PMID- 28883078 TI - Human leukocyte antigen-E mismatch is associated with better hematopoietic stem cell transplantation outcome in acute leukemia patients. AB - The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53% vs 38%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95%=0.48-0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50% vs 18%, P=0.005; HR=0.40, CI 95%=0.22-0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post-transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs. PMID- 28883080 TI - Phenotype in combination with genotype improves outcome prediction in acute myeloid leukemia: a report from Children's Oncology Group protocol AAML0531. AB - Diagnostic biomarkers can be used to determine relapse risk in acute myeloid leukemia, and certain genetic aberrancies have prognostic relevance. A diagnostic immunophenotypic expression profile, which quantifies the amounts of distinct gene products, not just their presence or absence, was established in order to improve outcome prediction for patients with acute myeloid leukemia. The immunophenotypic expression profile, which defines each patient's leukemia as a location in 15-dimensional space, was generated for 769 patients enrolled in the Children's Oncology Group AAML0531 protocol. Unsupervised hierarchical clustering grouped patients with similar immunophenotypic expression profiles into eleven patient cohorts, demonstrating high associations among phenotype, genotype, morphology, and outcome. Of 95 patients with inv(16), 79% segregated in Cluster A. Of 109 patients with t(8;21), 92% segregated in Clusters A and B. Of 152 patients with 11q23 alterations, 78% segregated in Clusters D, E, F, G, or H. For both inv(16) and 11q23 abnormalities, differential phenotypic expression identified patient groups with different survival characteristics (P<0.05). Clinical outcome analysis revealed that Cluster B (predominantly t(8;21)) was associated with favorable outcome (P<0.001) and Clusters E, G, H, and K were associated with adverse outcomes (P<0.05). Multivariable regression analysis revealed that Clusters E, G, H, and K were independently associated with worse survival (P range <0.001 to 0.008). The Children's Oncology Group AAML0531 trial: clinicaltrials.gov Identifier: 00372593. PMID- 28883082 TI - The clinical and prognostic value of CXCL8 in cervical carcinoma patients: immunohistochemical analysis. AB - Cysteine-X-cysteine ligand 8 (CXCL8) was originally discovered as a proinflammatory chemokine. Recently, CXCL8 has been shown to act as an oncogene in several types of human cancers. However, the clinical and prognostic significance of CXCL8 in cervical cancer is poorly understood. In our study, we found that CXCL8 was highly expressed in cervical cancer tissues compared with normal cervical tissues in microarray datasets (GSE9750 and GSE7803). CXCL8 mRNA and protein expressions were increased in cervical cancer tissues and cell lines compared with normal cervical tissues and cervical epithelial cell lines. CXCL8 protein expression was significantly correlated with clinical stage, distant metastasis, histological type, and histological grade. CXCL8 high expression was a poor independent prognostic parameter for cervical cancer patients. In conclusion, CXCL8 is highly expressed in cervical cancer tissues and cell lines, and correlated with malignant status and prognosis in cervical cancer patients. PMID- 28883081 TI - Haploidentical hematopoietic cell transplantation for adult acute myeloid leukemia: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. AB - Allogeneic blood or marrow hematopoietic cell transplantation continues to be the most potent anti-leukemic treatment for adult patients with standard, high-risk, or chemo-refractory acute myeloid leukemia. Until recently, this procedure was generally limited to those recipients who had an available matched-sibling donor or matched-unrelated donor. Technical advances in graft cell processing and manipulation, control of bidirectional T cell alloreactivity, graft-versus-host disease prophylaxis, and other supportive measures in haploidentical transplantation now enable nearly all patients with acute myeloid leukemia to benefit from the graft-versus-leukemia effect with substantial reduction in procedure-related mortality. Over recent years, haploidentical donors have been increasingly adopted as a valid donor source in allogeneic hematopoietic cell transplantation for acute myeloid leukemia in the absence of an HLA-matched donor. Among centers of the European Society for Blood and Marrow Transplantation, the use of haploidentical related donor transplantation has increased by 250% since 2010, and 291% since 2005. On behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize recent utilization trends in haploidentical transplantation for acute myeloid leukemia and describe the transformative changes in haploidentical hematopoietic cell transplantation techniques over the past decade, which have led to the current widespread use of this procedure. Furthermore, we review the efficacy of haploidentical hematopoietic cell transplantation for acute myeloid leukemia from available studies, including preliminary comparative studies, and bring attention to remaining unanswered questions and directions for future research. We conclude this report with our recommendations for the role of haploidentical hematopoietic cell transplantation in acute myeloid leukemia. PMID- 28883084 TI - Advances in risk-oriented surgery for multiple endocrine neoplasia type 2. AB - Genetic association studies hinge on definite clinical case definitions of the disease of interest. This is why more penetrant mutations were overrepresented in early multiple endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went underrepresented. Enrichment of genetic association studies with advanced disease may produce a flawed understanding of disease evolution, precipitating far-reaching surgical strategies like bilateral total adrenalectomy and 4-gland parathyroidectomy in MEN2. The insight into the natural course of the disease gleaned over the past 25 years caused a paradigm shift in MEN2: from the removal of target organs at the expense of greater operative morbidity to close biochemical surveillance and targeted resection of adrenal tumors and hyperplastic parathyroid glands. The lead time provided by early identification of asymptomatic MEN2 carriers under biochemical surveillance delimits a 'window of opportunity', within which (i) pre-emptive total thyroidectomy alone is adequate, circumventing morbidity attendant to central node dissection; (ii) subtotal 'tissue-sparing' adrenalectomy is sufficient, trading the risk of steroid dependency for the risk of a second pheochromocytoma in the adrenal remnant and (iii) parathyroidectomy is limited to enlarged glands, trading the risk of postoperative hypoparathyroidism for the risk of leaving behind hyperactive parathyroid glands. Future research should delineate further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism to refine the risk-oriented approach to MEN2. The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our lifetime. PMID- 28883083 TI - Neupogen and mesenchymal stem cells are the novel therapeutic agents in regeneration of induced endometrial fibrosis in experimental rats. AB - Endometrial fibrosis is the presence of intrauterine adhesions (IUAs) after any uterine surgery or curettage and it results in infertility and recurrent pregnancy loss. We evaluated the role of human mesenchymal stem cells (hMSCs) as a therapeutic agent of endometrial fibrosis. We also compared the effect of MSCs with the effect of estrogen and neupogen either each alone or as a combined therapy with MSCs. This experimental study was performed on 84 albino rats which were divided into seven groups (n=12 rats/group) as follows, group1: normal control rats, group 2: induced fibrosis, group 3: induced fibrosis that received oral estrogen, group 4: induced fibrosis that received hMSCs, group 5: induced fibrosis that received hMSCs and estrogen, group 6: induced fibrosis that received neupogen, and group 7: induced fibrosis that received hMSCs and neupogen. The extent of fibrosis, vascularization, and inflammation were evaluated by; qRT-PCR for interleukin 1 (IL-1), interleukin 6 (IL-6), TNF, vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF beta), and RUNX; ELISA for connective tissue growth factor (CTGF); Western blotting for collagen-I; immunohistochemistry examination for VEGF and RUNX-2; and histopathological assessment. In therapeutic groups either by hMSCs alone or combined with estrogen or neupogen; fibrosis and inflammation (IL-1, IL-6, TNF, TGF-beta, RUNX, CTGF, and collagen-I) were significantly decreased but vascularization (VEGF) was significantly increased (P<0.05) compared with induced fibrosis group. The most significant result was obtained in fibrosis that received combined therapy of hMSCs and neupogen (P=0.000). Stem cells and neupogen are a highly effective alternative regenerative agents in endometrial fibrosis. PMID- 28883085 TI - Hydrodynamic function of dorsal fins in spiny dogfish and bamboo sharks during steady swimming. AB - A key feature of fish functional design is the presence of multiple fins that allow thrust vectoring and redirection of fluid momentum to contribute to both steady swimming and maneuvering. A number of previous studies have analyzed the function of dorsal fins in teleost fishes in this context, but the hydrodynamic function of dorsal fins in freely swimming sharks has not been analyzed, despite the potential for differential functional roles between the anterior and posterior dorsal fins. Previous anatomical research has suggested a primarily stabilizing role for shark dorsal fins. We evaluated the generality of this hypothesis by using time-resolved particle image velocimetry to record water flow patterns in the wake of both the anterior and posterior dorsal fins in two species of freely swimming sharks: bamboo sharks (Chiloscyllium plagiosum) and spiny dogfish (Squalus acanthias). Cross-correlation analysis of consecutive images was used to calculate stroke-averaged mean longitudinal and lateral velocity components, and vorticity. In spiny dogfish, we observed a velocity deficit in the wake of the first dorsal fin and flow acceleration behind the second dorsal fin, indicating that the first dorsal fin experiences net drag while the second dorsal fin can aid in propulsion. In contrast, the wake of both dorsal fins in bamboo sharks displayed increased net flow velocity in the majority of trials, reflecting a thrust contribution to steady swimming. In bamboo sharks, fluid flow in the wake of the second dorsal fin had higher absolute average velocity than that for first dorsal fin, and this may result from a positive vortex interaction between the first and second dorsal fins. These data suggest that the first dorsal fin in spiny dogfish has primarily a stabilizing function, while the second dorsal fin has a propulsive function. In bamboo sharks, both dorsal fins can contribute thrust and should be considered as propulsive adjuncts to the body during steady swimming. The function of shark dorsal fins can thus differ considerably among fins and species, and is not limited to a stabilizing role. PMID- 28883086 TI - Characterizing Chilean blue whale vocalizations with DTAGs: a test of using tag accelerometers for caller identification. AB - Vocal behavior of blue whales (Balaenoptera musculus) in the Gulf of Corcovado, Chile, was analysed using both audio and accelerometer data from digital acoustic recording tags (DTAGs). Over the course of three austral summers (2014, 2015 and 2016), seventeen tags were deployed, yielding 124 h of data. We report the occurrence of Southeast Pacific type 2 (SEP2) calls, which exhibit peak frequencies, durations and timing consistent with previous recordings made using towed and moored hydrophones. We also describe tonal downswept (D) calls, which have not been previously described for this population. As being able to accurately assign vocalizations to individual whales is fundamental for studying communication and for estimating population densities from call rates, we further examine the feasibility of using high-resolution DTAG accelerometers to identify low-frequency calls produced by tagged blue whales. We cross-correlated acoustic signals with simultaneous tri-axial accelerometer readings in order to analyse the phase match as well as the amplitude of accelerometer signals associated with low-frequency calls, which provides a quantitative method of determining if a call is associated with a detectable acceleration signal. Our results suggest that vocalizations from nearby individuals are also capable of registering accelerometer signals in the tagged whale's DTAG record. We cross-correlate acceleration vectors between calls to explore the possibility of using signature acceleration patterns associated with sounds produced within the tagged whale as a new method of identifying which accelerometer-detectable calls originate from the tagged animal. PMID- 28883087 TI - Modulation of muscle-tendon interaction in the human triceps surae during an energy dissipation task. AB - The compliance of elastic elements allows muscles to dissipate energy safely during eccentric contractions. This buffering function is well documented in animal models but our understanding of its mechanism in humans is confined to non specific tasks, requiring a subsequent acceleration of the body. The present study aimed to examine the behaviour of the human triceps surae muscle-tendon unit (MTU) during a pure energy dissipation task, under two loading conditions. Thirty-nine subjects performed a single-leg landing task, with and without added mass. Ultrasound measurements were combined with three-dimensional kinematics and kinetics to determine instantaneous length changes of MTUs, muscle fascicles, Achilles tendon and combined elastic elements. Gastrocnemius and soleus MTUs lengthened during landing. After a small concentric action, fascicles contracted eccentrically during most of the task, whereas plantar flexor muscles were activated. Combined elastic elements lengthened until peak ankle moment and recoiled thereafter, whereas no recoil was observed for the Achilles tendon. Adding mass resulted in greater negative work and MTU lengthening, which were accompanied by a greater stretch of tendon and elastic elements and a greater recruitment of the soleus muscle, without any further fascicle strain. Hence, the buffering action of elastic elements delimits the maximal strain and lengthening velocity of active muscle fascicles and is commensurate with loading constraints. In the present task, energy dissipation was modulated via greater MTU excursion and more forceful eccentric contractions. The distinct strain pattern of the Achilles tendon supports the notion that different elastic elements may not systematically fulfil the same function. PMID- 28883088 TI - Humeral loads during swimming and walking in turtles: implications for morphological change during aquatic reinvasions. AB - During evolutionary reinvasions of water by terrestrial vertebrates, ancestrally tubular limb bones often flatten to form flippers. Differences in skeletal loading between land and water might have facilitated such changes. In turtles, femoral shear strains are significantly lower during swimming than during walking, potentially allowing a release from loads favoring tubular shafts. However, flipper-like morphology in specialized tetrapod swimmers is most accentuated in the forelimbs. To test whether the forelimbs of turtles also experience reduced torsional loading in water, we compared strains on the humerus of river cooters (Pseudemys concinna) between swimming and terrestrial walking. We found that humeral shear strains are also lower during swimming than during terrestrial walking; however, this appears to relate to a reduction in overall strain magnitude, rather than a specific reduction in twisting. These results indicate that shear strains show similar reductions between swimming and walking for forelimb and hindlimb, but these reductions are produced through different mechanisms. PMID- 28883089 TI - CCL2 and T cells in pulmonary fibrosis: an old player gets a new role. PMID- 28883090 TI - Validity, responsiveness and minimum clinically important difference of the incremental shuttle walk in idiopathic pulmonary fibrosis: a prospective study. AB - : The incremental shuttle walk (ISW) is well validated in COPD but limited psychometric data restrict its use in idiopathic pulmonary fibrosis (IPF). Study 1: 50 patients performed the ISW and 6 min walk test (6MWT). Study 2: 72 patients completed the ISW before and after pulmonary rehabilitation (PR). The ISW correlated strongly with 6MWT distance (r=0.81,p<0.0001). Mean (95% confidence interval) improvement in ISW with PR was 54 (38 to 70) m with an effect size of 0.29. Distribution-based and anchor-based minimum clinically important difference (MCID) estimates ranged from 31 to 46 m. The ISW is valid and responsive in IPF, with an anchor-based MCID estimate similar to that observed in chronic obstructive pulmonary disease. TRIAL REGISTRATION NUMBER: Pre-results; NCT02530736, NCT02436278. PMID- 28883091 TI - Change in FVC and survival in chronic fibrotic hypersensitivity pneumonitis. AB - The predictive value of the decline in FVC by >=10% on survival in patients with fibrotic hypersensitivity pneumonitis is unknown. Of 112 patients included, 66 (59%) had surgical lung biopsies. Patients with >=10% decline in predicted FVC after 6-12 months had a significantly increased risk of all-cause mortality (median survival 53 months, 95% CI 37 to 69 vs 139 months, 95% CI 66 to 212 months, p=0.007). On multivariate analysis remained associated with increasing mortality: decline in FVC by >=10% (HR 4.13, 95% CI 1.96 to 8.70, p=0.005), lower FVC% (HR 1.03, 95% CI 1.01 to 1.05, p=0.003) and with decreasing mortality improvement with antigen avoidance (HR 0.18, 95% CI 0.04 to 0.77, p=0.021). PMID- 28883092 TI - Human microcephaly ASPM protein is a spindle pole-focusing factor that functions redundantly with CDK5RAP2. AB - Nonsense mutations in the ASPM gene have been most frequently identified among familial microcephaly patients. Depletion of the Drosophila orthologue (asp) causes spindle pole unfocusing during mitosis in multiple cell types. However, it remains unknown whether human ASPM has a similar function. Here, by performing CRISPR-based gene knockout (KO) and RNA interference combined with auxin inducible degron, we show that ASPM functions in spindle pole organisation during mitotic metaphase redundantly with another microcephaly protein, CDK5RAP2 (also called CEP215), in human tissue culture cells. Deletion of the ASPM gene alone did not affect spindle morphology or mitotic progression. However, when the pericentriolar material protein CDK5RAP2 was depleted in ASPM KO cells, spindle poles were unfocused during prometaphase, and anaphase onset was significantly delayed. The phenotypic analysis of CDK5RAP2-depleted cells suggested that the pole-focusing function of CDK5RAP2 is independent of its known function to localise the kinesin-14 motor HSET (also known as KIFC1) or activate the gamma tubulin complex. Finally, a hypomorphic mutation identified in ASPM microcephaly patients similarly caused spindle pole unfocusing in the absence of CDK5RAP2, suggesting a possible link between spindle pole disorganisation and microcephaly. PMID- 28883093 TI - Role of the ECM in notochord formation, function and disease. AB - The notochord is a midline structure common to all chordate animals; it provides mechanical and signaling cues for the developing embryo. In vertebrates, the notochord plays key functions during embryogenesis, being a source of developmental signals that pattern the surrounding tissues. It is composed of a core of vacuolated cells surrounded by an epithelial-like sheath of cells that secrete a thick peri-notochordal basement membrane made of different extracellular matrix (ECM) proteins. The correct deposition and organization of the ECM is essential for proper notochord morphogenesis and function. Work carried out in the past two decades has allowed researchers to dissect the contribution of different ECM components to this embryonic tissue. Here, we will provide an overview of these genetic and mechanistic studies. In particular, we highlight the specific functions of distinct matrix molecules in regulating notochord development and notochord-derived signals. Moreover, we also discuss the involvement of ECM synthesis and its remodeling in the pathogenesis of chordoma, a malignant bone cancer that originates from remnants of notochord remaining after embryogenesis. PMID- 28883094 TI - Integrin alpha8 and Pcdh15 act as a complex to regulate cilia biogenesis in sensory cells. AB - The way an organism perceives its surroundings depends on sensory systems and the highly specialized cilia present in the neurosensory cells. Here, we describe the existence of an integrin alpha8 (Itga8) and protocadherin-15a (Pcdh15a) ciliary complex in neuromast hair cells in a zebrafish model. Depletion of the complex via downregulation or loss-of-function mutation leads to a dysregulation of cilia biogenesis and endocytosis. At the molecular level, removal of the complex blocks the access of Rab8a into the cilia as well as normal recruitment of ciliary cargo by centriolar satellites. These defects can be reversed by the introduction of a constitutively active form of Rhoa, suggesting that Itga8-Pcdh15a complex mediates its effect through the activation of this small GTPase and probably by the regulation of actin cytoskeleton dynamics. Our data points to a novel mechanism involved in the regulation of sensory cilia development, with the corresponding implications for normal sensory function. PMID- 28883095 TI - Lipopolysaccharide modulates p300 and Sirt1 to promote PRMT1 stability via an SCFFbxl17-recognized acetyldegron. AB - E3 ubiquitin ligase recognizes its protein substrates via specific molecular signatures for ubiquitin proteasomal degradation. However, the role of acetylation/deacetylation in the process of E3 ubiquitin ligase recognizing its protein substrates is not fully studied. Here, we report that a tandem IK motif in protein arginine methyltransferase 1 (PRMT1) forms an acetyldegron to recruit the F-box/LRR-repeat protein 17 (FBXL17), a component of the SKP1-CUL1-F-box protein (SCF)-type E3 ubiquitin ligase complex. PRMT1 is polyubiquitylated for proteasome degradation with a half-life of approximately 4 h in lung epithelial cells. SCFFbxl17 mediates PRMT1 polyubiquitylation at K117. SCFFbxl17 specifically binds PRMT1 via a unique motif IKxxxIK. Strikingly, the acetylation/deacetylation status of the lysine residues within the motif determines Fbxl17 binding. Deacetylation on both K200 and K205 by Sirtuin 1 (Sirt1) and acetylation of p300 (EP300) on K205 collaboratively prepare the motif for SCFFbxl17 binding thereby triggering PRMT1 protein degradation. Pathogen derived lipopolysaccharide (LPS) downregulates Sirt1 and p300 to protect PRMT1 from degradation. This study demonstrates that LPS promotes PRMT1 stability by blockade of PRMT1 and SCFFbxl17 binding via an acetylation/deacetylation-modified acetyldegron; and LPS-elevated levels of PRMT1 lead to bronchial epithelial cell overgrowth in pulmonary inflammatory diseases. PMID- 28883097 TI - Survival of very preterm infants admitted to neonatal care in England 2008-2014: time trends and regional variation. AB - OBJECTIVE: To analyse survival trends and regional variation for very preterm infants admitted to neonatal care. SETTING: All neonatal units in England. PATIENTS: Infants born at 22+0-31+6 weeks+daysgestational age (GA) over 2008-2014 and admitted to neonatal care; published data for admitted infants 22+0-25+6 weeks+days GA in 1995 and 2006, and for live births at 22+0-31+6 weeks+days GA in 2013. METHODS: We obtained data from the National Neonatal Research Database. We used logistic regression to model survival probability with birth weight, GA, sex, antenatal steroid exposure and multiple birth included in the risk adjustment model and calculated annualpercentage change (APC) for trends using joinpoint regression. We evaluated survival over a 20-year period for infants <26 weeks' GA using additional published data from the EPICure studies. RESULTS: We identified 50 112 eligible infants. There was an increase in survival over 2008 2014 (2008: 88.0%; 2014: 91.3%; adjusted APC 0.46% (95% CI 0.30 to 0.62) p<0.001). The greatest improvement was at 22+0-23+6 weeks (APC 6.03% (95% CI 2.47 to 3.53) p=0.002). Improvement largely occurred in London and South of England (APC: London 1.26% (95% CI 0.60 to 1.96); South of England 1.09% (95% CI 0.36 to 1.82); Midlands and East of England 0.15% (95% CI -0.56 to 0.86); and North of England 0.26% (95% CI -0.54 to 1.07)). Survival at the earliest gestations improved at a similar rate over 1995-2014 (22+0-25+6 weeks, APC 2.73% (95% CI 2.35 to 3.12), p value for change=0.25). CONCLUSIONS: Continued national improvement in the survival of very preterm admissions masks important regional variation. Timely assessment of preterm survival is feasible using electronic records. PMID- 28883099 TI - Criticism remains for RSA's referral network despite cost of claims falling. PMID- 28883096 TI - COG7 deficiency in Drosophila generates multifaceted developmental, behavioral and protein glycosylation phenotypes. AB - Congenital disorders of glycosylation (CDG) comprise a family of human multisystemic diseases caused by recessive mutations in genes required for protein N-glycosylation. More than 100 distinct forms of CDGs have been identified and most of them cause severe neurological impairment. The Conserved Oligomeric Golgi (COG) complex mediates tethering of vesicles carrying glycosylation enzymes across the Golgi cisternae. Mutations affecting human COG1, COG2 and COG4-COG8 cause monogenic forms of inherited, autosomal recessive CDGs. We have generated a Drosophila COG7-CDG model that closely parallels the pathological characteristics of COG7-CDG patients, including pronounced neuromotor defects associated with altered N-glycome profiles. Consistent with these alterations, larval neuromuscular junctions of Cog7 mutants exhibit a significant reduction in bouton numbers. We demonstrate that the COG complex cooperates with Rab1 and Golgi phosphoprotein 3 to regulate Golgi trafficking and that overexpression of Rab1 can rescue the cytokinesis and locomotor defects associated with loss of Cog7. Our results suggest that the Drosophila COG7-CDG model can be used to test novel potential therapeutic strategies by modulating trafficking pathways. PMID- 28883101 TI - Wales launches voluntary BVD screening programme in bid to eradicate disease. PMID- 28883098 TI - Randomised trial of estimating oral endotracheal tube insertion depth in newborns using weight or vocal cord guide. AB - BACKGROUND: When intubating newborns, clinicians aim to position the endotracheal tube (ETT) tip in the midtrachea. The depth to which ETTs should be inserted is often estimated using the infant's weight. ETTs are frequently incorrectly positioned in newborns, most often inserted too far. Using the vocal cord guide (a mark at the distal end of the ETT) to guide insertion depth has been recommended. OBJECTIVE: To determine whether estimating ETT insertion depth using the vocal cord guide rather than weight results in more correctly positioned ETT tips. DESIGN: Single-centre randomised controlled trial. SETTING: Level III neonatal intensive care unit (NICU) at a university maternity hospital (National Maternity Hospital, Dublin, Ireland). PATIENTS: Newborn infants without congenital anomalies intubated in the NICU. INTERVENTIONS: Participants were randomised to have ETT insertion depth estimated using weight [insertion depth (cm) = weight (kg) +6] or vocal cord guide. MAIN OUTCOME MEASURE: Correct ETT position, that is, tip between the upper border of the first thoracic vertebra (T1) and the lower border of the second thoracic vertebra (T2) on a chest X-ray as determined by one paediatric radiologist masked to group assignment. RESULTS: 136 participants were randomised. The proportion of correctly positioned ETTs was similar in both groups (weight 30/69 (44%) vs vocal cord guide 27/67 (40%), p=0.731). Most incorrectly positioned ETT (69/79, 87%) were too low. CONCLUSION: Estimating ETT insertion depth using the vocal cord guide did not result in more correctly positioned ETT tips. TRIAL REGISTRATION NUMBER: ISRCTN39654846. PMID- 28883102 TI - Tackling Nipah virus: L2.36 million grant awarded to Pirbright to create vaccine. PMID- 28883103 TI - Helping animals affected by Hurricane Harvey in Texas. PMID- 28883105 TI - Disease surveillance in England and Wales, August 2017. AB - Current and emerging issues: psoroptic mange in cattleHighlights from the scanning surveillance networkUpdate on international disease threatsAfrican swine fever in eastern Europe and the risk to the UKThese are among matters discussed in the Animal and Plant Health Agency's (APHA's) disease surveillance report for August 2017. PMID- 28883106 TI - African swine fever in eastern Europe: the risk to the UK. AB - This article has been prepared by Helen Roberts of the Defra/APHA International Disease Monitoring team. PMID- 28883107 TI - Anaemia and oxidative stress in calves: an ironclad problem? PMID- 28883108 TI - Foot bathing dairy cows with antibiotics. PMID- 28883109 TI - Ducks and the control of liver fluke in sheep. PMID- 28883110 TI - Reviewing the Practice Standards Scheme. PMID- 28883111 TI - Veterinary research in clinical practice. PMID- 28883112 TI - Death notice. PMID- 28883113 TI - Spencer Norman Bayer. AB - Spencer Bayer cared about people; his legacy is one of hard work and high moral and ethical standards. PMID- 28883114 TI - Elizabeth Adam Blyth. AB - Elizabeth Blyth worked as a small animal vet and was married to a vet. PMID- 28883121 TI - A life with horses. AB - Ben Jacklin is equine director and consultant veterinary surgeon at CVS UK. He is a diplomate of the European College of Veterinary Surgeons and an RCVS and ECVS Specialist in equine surgery. PMID- 28883122 TI - On course. AB - Harry Carslake, equine medicine specialist at the Philip Leverhulme Equine Hospital, Liverpool, reviews a fiveday course on advanced cardiac ultrasound scanning that he completed recently. PMID- 28883124 TI - Debating the future of mandatory vaccination. PMID- 28883123 TI - Post-translational modification of the interferon-gamma receptor alters its stability and signaling. AB - The IFN gamma receptor 1 (IFNGR1) binds IFN-gamma and activates gene transcription pathways crucial for controlling bacterial and viral infections. Although decreases in IFNGR1 surface levels have been demonstrated to inhibit IFN gamma signaling, little is known regarding the molecular mechanisms controlling receptor stability. Here, we show in epithelial and monocytic cell lines that IFNGR1 displays K48 polyubiquitination, is proteasomally degraded, and harbors three ubiquitin acceptor sites at K277, K279, and K285. Inhibition of glycogen synthase kinase 3 beta (GSK3beta) destabilized IFNGR1 while overexpression of GSK3beta increased receptor stability. We identified critical serine and threonine residues juxtaposed to ubiquitin acceptor sites that impacted IFNGR1 stability. In CRISPR-Cas9 IFNGR1 generated knockout cell lines, cellular expression of IFNGR1 plasmids encoding ubiquitin acceptor site mutations demonstrated significantly impaired STAT1 phosphorylation and decreased STAT1 dependent gene induction. Thus, IFNGR1 undergoes rapid site-specific polyubiquitination, a process modulated by GSK3beta. Ubiquitination appears to be necessary for efficient IFNGR1-dependent gamma gene induction and represents a relatively uncharacterized regulatory mechanism for this receptor. PMID- 28883126 TI - Genome Sequences of a Novel Picorna-Like Virus from Pacific Abalone (Haliotis discus hannai) in South Korea. AB - We report the draft genome sequences of a novel member of the Picornavirales isolated from Pacific abalone (Haliotis discus hannai). The full length of the assembled draft genome sequences, obtained by use of a next-generation sequencing technique, were 8,019 nucleotides, including an RNA-dependent RNA polymerase gene (5,088 nucleotides) and a capsid protein gene (2,553 nucleotides). This genome sequence will be useful for understanding viral disease of Pacific abalone. PMID- 28883127 TI - Draft Genome Sequence of Lactobacillus brevis Strain 3M004, a Probiotic with Potential Quorum-Sensing Regulation. AB - We present here the draft genome sequence of Lactobacillus brevis strain 3M004, a probiotic that has potential for regulating quorum sensing. The strain was obtained from a type of aquafeed. The assembly consists of 2,459,326 bp and contains 33 contigs, with a G+C content of 45.10%. PMID- 28883128 TI - Draft Genome Sequence of Cercospora cf. sigesbeckiae, a Causal Agent of Cercospora Leaf Blight on Soybean. AB - Cercospora cf. sigesbeckiae is an ascomycete fungal pathogen that infects various plants, including important agricultural commodities, such as soybean. Here, we report the first draft genome sequence and assembly of this pathogen. PMID- 28883129 TI - Draft Genome Sequence of Zobellia sp. Strain OII3, Isolated from the Coastal Zone of the Baltic Sea. AB - Zobellia sp. strain OII3 was isolated from a marine environmental sample due to its heterotrophic lifestyle, i.e., using Escherichia coli cells as prey. It shows strong agar-lytic activity. The genome was assembled into 41 contigs with a total size of 5.4 Mb, revealing the genetic basis for natural product biosynthesis. PMID- 28883125 TI - Defining Optimal Brain Health in Adults: A Presidential Advisory From the American Heart Association/American Stroke Association. AB - Cognitive function is an important component of aging and predicts quality of life, functional independence, and risk of institutionalization. Advances in our understanding of the role of cardiovascular risks have shown them to be closely associated with cognitive impairment and dementia. Because many cardiovascular risks are modifiable, it may be possible to maintain brain health and to prevent dementia in later life. The purpose of this American Heart Association (AHA)/American Stroke Association presidential advisory is to provide an initial definition of optimal brain health in adults and guidance on how to maintain brain health. We identify metrics to define optimal brain health in adults based on inclusion of factors that could be measured, monitored, and modified. From these practical considerations, we identified 7 metrics to define optimal brain health in adults that originated from AHA's Life's Simple 7: 4 ideal health behaviors (nonsmoking, physical activity at goal levels, healthy diet consistent with current guideline levels, and body mass index <25 kg/m2) and 3 ideal health factors (untreated blood pressure <120/<80 mm Hg, untreated total cholesterol <200 mg/dL, and fasting blood glucose <100 mg/dL). In addition, in relation to maintenance of cognitive health, we recommend following previously published guidance from the AHA/American Stroke Association, Institute of Medicine, and Alzheimer's Association that incorporates control of cardiovascular risks and suggest social engagement and other related strategies. We define optimal brain health but recognize that the truly ideal circumstance may be uncommon because there is a continuum of brain health as demonstrated by AHA's Life's Simple 7. Therefore, there is opportunity to improve brain health through primordial prevention and other interventions. Furthermore, although cardiovascular risks align well with brain health, we acknowledge that other factors differing from those related to cardiovascular health may drive cognitive health. Defining optimal brain health in adults and its maintenance is consistent with the AHA's Strategic Impact Goal to improve cardiovascular health of all Americans by 20% and to reduce deaths resulting from cardiovascular disease and stroke by 20% by the year 2020. This work in defining optimal brain health in adults serves to provide the AHA/American Stroke Association with a foundation for a new strategic direction going forward in cardiovascular health promotion and disease prevention. PMID- 28883130 TI - Draft Genome Sequence of a Pseudomonas aeruginosa NA04 Bacterium Isolated from an Entomopathogenic Nematode. AB - We report the draft genome sequence of Gram-negative bacterium Pseudomonas aeruginosa NA04, isolated from the entomopathogenic nematode Heterorhabditis indica MOR03. The draft genome consists of 54 contigs, a length of 6.37 Mb, and a G+C content 66.49%. PMID- 28883131 TI - Genome Sequence of an Unusual Reassortant H1N1 Swine Influenza Virus Isolated from a Pig in Russia, 2016. AB - We report here the genome sequence of the influenza A virus strain A/swine/Siberia/1sw/2016, isolated from a swine in Russia. On the basis of sequence analysis, A/swine/Siberia/1sw/2016 is characterized by unusual surface glycoproteins phylogenetically distinct from those of swine A(H1N1)pdm09 influenza virus. PMID- 28883132 TI - Draft Genome Sequence of Natranaerobius trueperi DSM 18760T, an Anaerobic, Halophilic, Alkaliphilic, Thermotolerant Bacterium Isolated from a Soda Lake. AB - The anaerobic, halophilic, alkaliphilic, thermotolerant bacterium Natranaerobius trueperi was isolated from a soda lake in Wadi An Natrun, Egypt. It grows optimally at 3.7 M Na+, pH 9.5, and 43 degrees C. The draft genome consists of 2.63 Mb and is composed of 2,681 predicted genes. Genomic analysis showed that various genes are potentially involved in the adaptation mechanisms for osmotic stress, pH homeostasis, and high temperatures. PMID- 28883133 TI - Draft Genome Sequence of the Iridescent Marine Bacterium Cellulophaga lytica CECT 8139. AB - Some species of the genus Cellulophaga have been reported as having biotechnological interests and noteworthy physiological properties. We report here the draft genome sequence of Cellulophaga lytica CECT 8139, a bacterium that produces an intensely iridescent colony biofilm on agar surfaces. PMID- 28883134 TI - First Complete Genome Sequences of Xanthomonas citri pv. vignicola Strains CFBP7111, CFBP7112, and CFBP7113 Obtained Using Long-Read Technology. AB - Xanthomonas citri pv. vignicola strains cause bacterial blight of the legume crop cowpea. We report whole-genome sequences of three X. citri pv. vignicola strains obtained using PacBio single-molecule real-time sequencing. Such genomic data provide new information on pathogenicity factors, such as transcription activator like effectors. PMID- 28883135 TI - Insights into the Draft Genome Sequence of a Haitian Variant Vibrio cholerae Strain Isolated from a Clinical Setting in Kerala, South India. AB - We report here the draft genome sequence of a Haitian variant Vibrio cholerae strain, W4-13, isolated from Kerala, South India, possessing cholera toxin gene in chromosomes I and II. The sequence will be useful to achieve a profound understanding on its evolution, with emphasis on its pathogenesis and antibiotic resistance. PMID- 28883136 TI - Draft Genome Sequence of Comamonas testosteroni R2, Consisting of Aromatic Compound Degradation Genes for Phenol Hydroxylase. AB - Comamonas testosteroni strain R2 was isolated from a continuous culture enriched by a low concentration of phenol-oxygenating activities with low Ks values (below 1 MUM). The draft genome sequence of C. testosteroni strain R2 reported here may contribute to determining the phenol degradation gene cluster. PMID- 28883137 TI - Draft Genome Sequences of Three Sub-Antarctic Rhodococcus spp., Including Two Novel Psychrophilic Genomospecies. AB - The draft genome sequences of three sub-Antarctic Rhodococcus sp. strains-1159, 1163, and 1168-are reported here. The estimated genome sizes were 7.09 Mb with a 62.3% GC content for strain 1159, 4.45 Mb with a 62.3% GC content for strain 1163, and 5.06 Mb with a 62.10% GC content for strain 1168. PMID- 28883138 TI - Draft Genome Sequence of the Type Strain Sphingopyxis witflariensis DSM 14551. AB - Here, we present the draft genome sequence of Sphingopyxis witflariensis strain DSM 14551. The assembly consists of 38 contigs and contains 4,306,761 bp, with a GC content of 63.3%. PMID- 28883139 TI - Complete Genome Sequences of Four Extensively Drug-Resistant Pseudomonas aeruginosa Strains, Isolated from Adults with Ventilator-Associated Pneumonia at a Tertiary Referral Hospital in Mexico City. AB - Four extensively drug-resistant Pseudomonas aeruginosa strains, isolated from patients with pneumonia, were sequenced using PacBio RS-II single-molecule real time (SMRT) technology. Genome sequence analysis identified great variability among mobile genetic elements, as well as some previously undescribed genomic islands and new variants of class 1 integrons (In1402, In1403, In1404, and In1408). PMID- 28883140 TI - Draft Genome Sequences of Listeria monocytogenes Strains from Listeriosis Outbreaks Linked to Soft Cheese in Washington State. AB - Listeria monocytogenes has caused listeriosis outbreaks linked to soft cheese. Here, we report the draft genome sequences of seven L. monocytogenes isolates from two possibly related outbreaks caused by soft cheese products in Washington State. PMID- 28883141 TI - Metagenome-Assembled Genome Sequences of Acetobacterium sp. Strain MES1 and Desulfovibrio sp. Strain MES5 from a Cathode-Associated Acetogenic Microbial Community. AB - Draft genome sequences of Acetobacterium sp. strain MES1 and Desulfovibrio sp. strain MES5 were obtained from the metagenome of a cathode-associated community enriched within a microbial electrosynthesis system (MES). The draft genome sequences provide insight into the functional potential of these microorganisms within an MES and a foundation for future comparative analyses. PMID- 28883142 TI - Genome Sequence of Bradyrhizobium mercantei Strain SEMIA 6399T, Isolated from Nodules of Deguelia costata in Brazil. AB - SEMIA 6399T is the type strain of Bradyrhizobium mercantei, a nitrogen-fixing symbiont of Deguelia costata Its draft genome contains 8,842,857 bp with 8,246 predicted coding sequences (CDS), several related to amino acids and derivatives and to stress tolerance, with an emphasis on oxidative stress, in addition to symbiotic genes. PMID- 28883143 TI - Draft Genome Sequence of Zobellella denitrificans ZD1 (JCM 13380), a Salt Tolerant Denitrifying Bacterium Capable of Producing Poly(3-Hydroxybutyrate). AB - Zobellella denitrificans ZD1, isolated from sediments of an estuarine mangrove ecosystem in Taiwan, exhibits growth-associated production of biopolymer poly(3 hydroxybutyrate) (PHB). This work reports the 4.05-Mbp draft genome sequence of Z. denitrificans ZD1, consisting of 217 contigs with a G+C content of 63.8% and 3,672 protein-coding sequences. PMID- 28883144 TI - Complete Genome Sequence of a blaOXA-58-Producing Acinetobacter baumannii Strain Isolated from a Mexican Hospital. AB - In this study, we present the complete genome sequence of a blaOXA-58-producing Acinetobacter baumannii strain, sampled from a Mexican hospital and not related to the international clones. PMID- 28883146 TI - Draft Genome Sequence of the Gluten-Hydrolyzing Bacterium Bacillus subtilis GS 188, Isolated from Wheat Sourdough. AB - The draft genome sequence of Bacillus subtilis GS 188, a novel spore-forming probiotic bacterium with gluten-hydrolyzing potential, was isolated from wheat sourdough and provides deep insights into the beneficial features of this strain for its use in the preparation of gluten-reduced wheat foods for humans with celiac disease. PMID- 28883145 TI - Draft Genome Sequence of the Endophytic Bacterium Variovorax paradoxus KB5, Which Has Antagonistic Activity against a Phytopathogen, Pseudomonas syringae pv. tomato DC3000. AB - Variovorax paradoxus KB5, isolated from the inside of Arabidopsis thaliana leaves, showed antibacterial activity against the phytopathogen Pseudomonas syringae pv. tomato DC3000. Here, we report a draft genome sequence of V. paradoxus KB5, which contains a delftibactin-like nonribosomal peptide biosynthetic gene cluster. PMID- 28883147 TI - Draft Genome Sequences of 64 Salmonella enterica Serotype Enteritidis Isolates Obtained from Wild Mice. AB - Salmonella enterica serotype Enteritidis is a foodborne pathogen of global concern, because it is frequently isolated from foods and patients. Draft genome sequences are reported here for 64 S Enteritidis strains isolated from the intestines and spleens of mice caught live on chicken farms in the U.S. Northeast. The availability of these genomes provides baseline information on the genomic diversity of S Enteritidis during the 1990s, when foodborne outbreaks traced to internal contamination of eggs were prevalent. PMID- 28883148 TI - Complete Genome Sequence of Staphylococcus epidermidis ATCC 12228 Chromosome and Plasmids, Generated by Long-Read Sequencing. AB - Staphylococcus epidermidis ATCC 12228 was sequenced using a long-read method to generate a complete genome sequence, including some plasmid sequences. Some differences from the previously generated short-read sequence of this nonpathogenic and non-biofilm-forming strain were noted. The assembly size was 2,570,371 bp with a total G+C% content of 32.08%. PMID- 28883149 TI - Erratum for Edwards et al., "Draft Genome Sequence of Uncultured Upland Soil Cluster Gammaproteobacteria Gives Molecular Insights into High-Affinity Methanotrophy". PMID- 28883150 TI - Genome Sequence of Ralstonia pseudosolanacearum Strains with Compatible and Incompatible Interactions with the Major Tomato Resistance Source Hawaii 7996. AB - We report here the complete genome sequences of two Ralstonia pseudosolanacearum strains, isolated from the warm northeast region of Brazil. They display divergent (compatible versus incompatible) interactions with the resistant tomato line Hawaii 7996. Polymorphisms were detected in a subset of effector genes that might be associated with these contrasting phenotypes. PMID- 28883151 TI - Genome Sequence of Oceanimonas doudoroffii ATCC 27123T. AB - Oceanimonas doudoroffii ATCC 27123T is an obligately aerobic Gram-negative rod of the class Gammaproteobacteria It was first isolated from surface seawater off the coast of Oahu, HI, USA, in 1972. The predicted genome size is 3,832,938 bp (G+C content, 60.03%), which contains 3,524 predicted coding sequences. PMID- 28883152 TI - Complete Genome Sequences of Seven Strains Composing a Model Bacterial Community of Maize Roots. AB - Previously, we assembled a model bacterial community of maize roots. Here, we report the complete genome sequences of the seven strains composing the community. PMID- 28883153 TI - Genome Sequence of a Novel Picorna-Like RNA Virus from Feces of the Antarctic Fur Seal (Arctocephalus gazella). AB - A novel RNA virus was detected in a fecal sample collected from the Antarctic fur seal (Arctocephalus gazella) in King George Island, Antarctica. The almost complete genome sequence reveals two open reading frames and a dicistrovirus-like gene order. PMID- 28883154 TI - Draft Genome Sequence of the Marine Bacterium Oceanimonas baumannii ATCC 700832T. AB - The aerobic phenol-degrading Gram-negative rod Oceanimonas baumannii ATCC 700832T was first isolated from estuary mud from the River Wear, United Kingdom, in 1983. Information on the draft genome sequence for O. baumannii ATCC 700832T is included in this announcement. The predicted genome size is 3,809,332 bp, with 55.88% G+C content. PMID- 28883155 TI - Is Brazil going to achieve the road traffic deaths target? An analysis about the sustainable development goals. AB - OBJECTIVE: To describe the temporal relationship between the road traffic mortality rate and gross domestic product (GDP) per capita in Brazil, and make an annual prediction of the evolution of both indicators until 2020, the end of the Sustainable Development Goals (SDGs) monitoring period. METHODS: Brazilian road traffic mortality rate official data were described from 2000 to 2015, while the GDP per capita official data were described from 2000 to 2013. GDP per capita and traffic mortality rate predictions were performed until 2020 using fractional polynomial analysis. Correlations were assessed using Pearson's correlation coefficient. RESULTS: From 2000 to 2015, there were over 446 000 road crashes fatal victims in Brazil. The road traffic mortality rate was positively related to the Brazilian GDP per capita, with a strong correlation (r=0.89; p<0.001) from 2000 to 2013 and a mild correlation (r=0.55; p<0.001) considering the whole period (2000-2020). The predictions show a reduction on the road traffic mortality rates in Brazil; however, if this same reduction pace continues, we estimate that the country will reach 12.4 road crash deaths per 100 000 inhabitants in 2020, a reduction of only 13.4% compared with 2015. CONCLUSION: If the same mortality reduction pace continues in Brazil, the country will not reach the proposed SDG, which is to reduce by half the number of deaths per 100 000 inhabitants. In addition, an intertwined conciliation between economical growth, sustainable development and public policies is needed in order to meet such an overwhelming goal. PMID- 28883158 TI - How to Teach Health IT Evaluation: Recommendations for Health IT Evaluation Courses. AB - Systematic health IT evaluation studies are needed to ensure system quality and safety and to provide the basis for evidence-based health informatics. Well trained health informatics specialists are required to guarantee that health IT evaluation studies are conducted in accordance with robust standards. Also, policy makers and managers need to appreciate how good evidence is obtained by scientific process and used as an essential justification for policy decisions. In a consensus-based approach with over 80 experts in health IT evaluation, recommendations for the structure, scope and content of health IT evaluation courses on the master or postgraduate level have been developed, supported by a structured analysis of available courses and of available literature. The recommendations comprise 15 mandatory topics and 15 optional topics for a health IT evaluation course. PMID- 28883159 TI - Developing and Evaluating Collaborative Online-Based Instructional Designs in Health Information Management. AB - The number of students enrolled in online courses is increasing steadily. Distance education offers many advantages, but also has inherent challenges. Successful distance education needs a thoughtfully designed instructional strategy where students are supported to actively create knowledge. We present the design and evaluation of three online-based courses in health informatics. The courses were based on a collaborative instructional strategy. The evaluation comprised workload analysis, student evaluation, student interviews and student reflections. Students expressed high satisfaction with online learning, despite a high workload, and high perceived learning outcomes. Using the Community of Inquiry framework as reference, we found very high levels of teaching presence, social presence and cognitive presence. Summarizing, we found that the chosen instructional strategy supported student-centered, collaborative learning. We conclude by presenting lesson learned for online-based instructional design. PMID- 28883156 TI - Structural insights into the interaction of the nuclear exosome helicase Mtr4 with the preribosomal protein Nop53. AB - The nuclear exosome and the associated RNA helicase Mtr4 participate in the processing of several ribonucleoprotein particles (RNP), including the maturation of the large ribosomal subunit (60S). S. cerevisiae Mtr4 interacts directly with Nop53, a ribosomal biogenesis factor present in late pre-60S particles containing precursors of the 5.8S rRNA. The Mtr4-Nop53 interaction plays a pivotal role in the maturation of the 5.8S rRNA, providing a physical link between the nuclear exosome and the pre-60S RNP. An analogous interaction between Mtr4 and another ribosome biogenesis factor, Utp18, directs the exosome to an earlier preribosomal particle. Nop53 and Utp18 contain a similar Mtr4-binding motif known as the arch interacting motif (AIM). Here, we report the 3.2 A resolution crystal structure of S. cerevisiae Mtr4 bound to the interacting region of Nop53, revealing how the KOW domain of the helicase recognizes the AIM sequence of Nop53 with a network of hydrophobic and electrostatic interactions. The AIM-interacting residues are conserved in Mtr4 and are not present in the related cytoplasmic helicase Ski2, rationalizing the specificity and versatility of Mtr4 in the recognition of different AIM-containing proteins. Using nuclear magnetic resonance (NMR), we show that the KOW domain of Mtr4 can simultaneously bind an AIM-containing protein and a structured RNA at adjacent surfaces, suggesting how it can dock onto RNPs. The KOW domains of exosome-associated helicases thus appear to have evolved from the KOW domains of ribosomal proteins and to function as RNP-binding modules in the context of the nuclear exosome. PMID- 28883160 TI - User Experience Evaluations in Rehabilitation Video Games for Children: A Systematic Mapping of the Literature. AB - BACKGROUND: In recent years, the interest in user experience (UX) evaluation methods for assessing technology solutions, especially in health systems for children with special needs like cognitive disabilities, has increased. OBJECTIVE: Conduct a systematic mapping study to provide an overview in the field of UX evaluations in rehabilitation video games for children. METHODS: The definition of research questions, the search for primary studies and the extraction of those studies by inclusion and exclusion criteria lead to the mapping of primary papers according to a classification scheme. RESULTS: Main findings from this study include the detection of the target population of the selected studies, the recognition of two different ways of evaluating UX: (i) user evaluation and (ii) system evaluation, and UX measurements and devices used. CONCLUSIONS: This systematic mapping specifies the research gaps identified for future research works in the area. PMID- 28883161 TI - The Implementation of Medical Informatics in the National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM). AB - INTRODUCTION: The National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) describes medical skills and attitudes without being ordered by subjects or organs. Thus, the NKLM enables systematic curriculum mapping and supports curricular transparency. In this paper we describe where learning objectives related to Medical Informatics (MI) in Hannover coincide with other subjects and where they are taught exclusively in MI. METHODS: An instance of the web-based MERLIN-database was used for the mapping process. RESULTS: In total 52 learning objectives overlapping with 38 other subjects could be allocated to MI. No overlap exists for six learning objectives describing explicitly topics of information technology or data management for scientific research. Most of the overlap was found for learning objectives relating to documentation and aspects of data privacy. DISCUSSION: The identification of numerous shared learning objectives with other subjects does not mean that other subjects teach the same content as MI. Identifying common learning objectives rather opens up the possibility for teaching cooperations which could lead to an important exchange and hopefully an improvement in medical education. CONCLUSION: Mapping of a whole medical curriculum offers the opportunity to identify common ground between MI and other medical subjects. Furthermore, in regard to MI, the interaction with other medical subjects can strengthen its role in medical education. PMID- 28883163 TI - Implications of Low Levels of the UV Index for Sun Protection. AB - A Global Solar Ultraviolet Index (UVI) value of 2 is generally linked to the health message 'You can safely stay outside!' To examine whether this is sound advice for all skin types and even for prolonged periods spent outside we used erythemal irradiance data of all 136 days during the study period from 2014 till 2016 with such a UVI measured by the German Federal Office for Radiation Protection (BfS) in Munich, Germany. A comparison between the ambient erythemal doses calculated for various time intervals and minimal erythemal doses (MEDs) of the Caucasian skin types I-IV led us to a critical reappraisal of the above health message. Specifically, the message might be misleading if people with a fair complexion want to spend several hours outside, because without any protective measures the doses received can be sufficient to induce erythema. We thus recommend an amendment of the health message related to a safe level of the UVI and, moreover, generally tailoring UVI-related health messages to different skin types. Currently, these messages do not seem to be strictly evidence based, which might be one reason for the unexpected result of our analysis. PMID- 28883164 TI - Routine Data Analyses to Compare Outpatient Depression Treatment Regimens. AB - BACKGROUND: Routine data analyses are becoming increasingly important for health policy decision making. However such databases often vary in data quality, completeness and accessibility. The aim of this study is to describe the quality of a large outpatient healthcare database, the process of data extraction and to give a brief overview of data-structure with focusing on provider-type and disease severity in an example of the treatment of depressive disorders. METHOD: The quality of the database is described and diagnosis rates of depression in outpatient care (ICD-10 diagnoses F32/33) in relation to the provider-type (i.e. general or somatic physician vs. physicians specialized in mental-health vs. psychotherapist) were calculated using Cramers V as a measure for effect size. RESULTS: The database consisted of 2,383,672 cases from 2015. Most depressive patients were diagnosed and treated by general or somatic physicians. A clear relationship between the severity of depression and provider-type is shown. In contrast to psychotherapists or physicians specialized in mental-health, general or somatic physicians diagnose a higher rate of unspecified depressive episodes. PMID- 28883166 TI - Standards-Based Procedural Phenotyping: The Arden Syntax on i2b2. AB - Phenotyping, or the identification of patient cohorts, is a recurring challenge in medical informatics. While there are open source tools such as i2b2 that address this problem by providing user-friendly querying interfaces, these platforms lack semantic expressiveness to model complex phenotyping algorithms. The Arden Syntax provides procedural programming language construct, designed specifically for medical decision support and knowledge transfer. In this work, we investigate how language constructs of the Arden Syntax can be used for generic phenotyping. We implemented a prototypical tool to integrate i2b2 with an open source Arden execution environment. To demonstrate the applicability of our approach, we used the tool together with an Arden-based phenotyping algorithm to derive statistics about ICU-acquired hypernatremia. Finally, we discuss how the combination of i2b2's user-friendly cohort pre-selection and Arden's procedural expressiveness could benefit phenotyping. PMID- 28883167 TI - On-The-Fly Query Translation Between i2b2 and Samply in the German Biobank Node (GBN) Prototypes. AB - Information retrieval is a major challenge in medical informatics. Various research projects have worked on this task in recent years on an institutional level by developing tools to integrate and retrieve information. However, when it comes down to querying such data across institutions, the challenge persists due to the high heterogeneity of data and differences in software systems. The German Biobank Node (GBN) project faced this challenge when trying to interconnect four biobanks to enable distributed queries for biospecimens. All biobanks had already established integrated data repositories, and some of them were already part of research networks. Instead of developing another software platform, GBN decided to form a bridge between these. This paper describes and discusses a core component from the GBN project, the OmniQuery library, which was implemented to enable on-the-fly query translation between heterogeneous research infrastructures. PMID- 28883168 TI - Evaluation of the IT Infrastructure of the RESIST Study with the Evidence-Based CIPROS Checklist. AB - Efficient and powerful information systems are substantial to perform medical research projects successfully. Especially, translational medicine poses specific challenges to the corresponding IT infrastructure. The RESIST study is a translational research project in oncology where xenografts inform about patients second-line treatment. DBFORM, an in-house developed system, was used as EDC system. It was enhanced with project specific features. We demonstrate how the CIPROS checklist has the potential to optimize the related requirements engineering process. The CIPROS checklist consists of 72 items, organized within 12 Aspects/Topics and was developed to assess such patient registry software systems. In this paper we use the CIPROS checklist (1) to elucidate the projects requirements and (2) to assess systems features. The application of the CIPROS checklist to fix the RESIST project requirements and system features was successful. The interplay between (1) and (2) helped to accelerate the requirements engineering process and to set up a system suitable to perform the translational research project successful. PMID- 28883169 TI - Analysis of Age and Gender Structures for ICD-10 Diagnoses in Outpatient Treatment Using Shannon's Entropy. AB - INTRODUCTION: Diagnostic diversity has been in the focus of several studies of health services research. As the fraction of people with statutory health insurance changes with age and gender it is assumed that diagnostic diversity may be influenced by these parameters. METHODS: We analyze fractions of patients in Schleswig-Holstein with respect to the chapters of the ICD-10 code in outpatient treatment for quarter 2/2016 with respect to age and gender/sex of the patient. In a first approach we analyzed which diagnose chapters are most relevant in dependence of age and gender. To detect diagnostic diversity, we finally applied Shannon's entropy measure. Due to multimorbidity we used different standardizations. RESULTS: Shannon entropy strongly increases for women after the age of 15, reaching a limit level at the age of 50 years. Between 15 and 70 years we get higher values for women, after 75 years for men. DISCUSSION: This article describes a straight forward pragmatic approach to diagnostic diversity using Shannon's Entropy. From a methodological point of view, the use of Shannon's entropy as a measure for diversity should gain more attraction to researchers of health services research. PMID- 28883170 TI - Markov Model of the Outpatient Classification System Morbidity Related Groups (MRG). AB - BACKGROUND: Benchmarking and guidance of outpatient physicians in Germany are almost always based on one year data. This also holds true for morbidity related groups, a classification system applied in northern Germany since 2017. A study of the markov properties of prescription based grouping algorithms is reported here. RESULTS: There is a strongly connected graph for almost all components and the resulting markov chain has a unique stationary solution. CONCLUSIONS: Target values based on the status quo of prescription behavior can provide stable guidelines for outpatient physicians. Every set of partitions converging like MRG should be considered for controlling measures. PMID- 28883172 TI - IT Infrastructure for Biomedical Research in North-West Germany. AB - The efficient use of routine data for biomedical research presupposes an IT infrastructure designed for health care facilities. The objective of this study was to analyse which IT infrastructure is used in hospitals and by general practitioners' (GP) practices in the region Oldenburg-Bremen and to examine how well this supports research projects. To this end, IT managers and GPs were interviewed. The usage of hospital information systems (HIS) and data warehouse systems (DWS) in hospitals is of major importance for the study. Over 90 % use DWS for administration, 42 % for clinical research. None of the hospitals implemented consent for the use of routine data for research. Only a third of the GPs have participated in studies. The GPs' offices based EHR systems in use offer virtually no support for research projects. The study results demonstrate that technical and organisational measures are required for the further usage of routine data in the region. PMID- 28883173 TI - Data Collection of Medication - Impact of Autocompletion in eCRFs on Efficiency and Data Quality. AB - OBJECTIVE: Openclinica Input Completion (OIC) was developed to increase the efficiency to enter drugs in eCRF in OpenClinica(r). The aim of the study was to evaluate the impact on efficiency and data quality as well as usability. METHODS: 20 participants were asked to input 15 drugs with the new tool and by hand. RESULTS: The mean input time got decreased from 16:12m to 3:59m. 31 of 300 (10%) of manual entered medication data sets had one or more errors versus 10 of 300 (3,3%) data sets entered with OIC. CONCLUSION: OIC was able to increase efficiency and data quality. We conclude that new additions to the graphical user interface in electronical Case-Report-Form (eCRF) systems should be validated before usage in research projects. PMID- 28883174 TI - A Decentralized IT Architecture for Locating and Negotiating Access to Biobank Samples. AB - There is a need among researchers for the easy discoverability of biobank samples. Currently, there is no uniform way for finding samples and negotiate access. Instead, researchers have to communicate with each biobank separately. We present the architecture for the BBMRI-CS IT platform, whose goal is to facilitate sample location and access. We chose a decentral approach, which allows for strong data protection and provides the high flexibility needed in the highly heterogeneous landscape of European biobanks. This is the first implementation of a decentral search in the biobank field. With the addition of a Negotiator component, it also allows for easy communication and a follow-through of the lengthy approval process for accessing samples. PMID- 28883175 TI - Semi-Automatic Terminology Generation for Information Extraction from German Chest X-Ray Reports. AB - Extraction of structured data from textual reports is an important subtask for building medical data warehouses for research and care. Many medical and most radiology reports are written in a telegraphic style with a concatenation of noun phrases describing the presence or absence of findings. Therefore a lexico syntactical approach is promising, where key terms and their relations are recognized and mapped on a predefined standard terminology (ontology). We propose a two-phase algorithm for terminology matching: In the first pass, a local terminology for recognition is derived as close as possible to the terms used in the radiology reports. In the second pass, the local terminology is mapped to a standard terminology. In this paper, we report on an algorithm for the first step of semi-automatic generation of the local terminology and evaluate the algorithm with radiology reports of chest X-ray examinations from Wurzburg university hospital. With an effort of about 20 hours work of a radiologist as domain expert and 10 hours for meetings, a local terminology with about 250 attributes and various value patterns was built. In an evaluation with 100 randomly chosen reports it achieved an F1-Score of about 95% for information extraction. PMID- 28883176 TI - Implementing a Data Management Platform for Longitudinal Health Research. AB - Health IT adoption research is rooted in Rogers' Diffusion of Innovation theory, which is based on longitudinal analyses. However, many studies in this field use cross-sectional designs. The aim of this study therefore was to design and implement a system to (i) consolidate survey data sets originating from different years (ii) integrate additional secondary data and (iii) query and statistically analyse these longitudinal data. Our system design comprises a 5-tier architecture that embraces tiers for data capture, data representation, logics, presentation and integration. In order to historicize data properly and to separate data storage from data analytics a data vault schema was implemented. This approach allows the flexible integration of heterogeneous data sets and the selection of comparable items. Data analysis is prepared by compiling data in data marts and performed by R and related tools. IT Report Healthcare data from 2011, 2013 and 2017 could be loaded, analysed and combined with secondary longitudinal data. PMID- 28883177 TI - A Customizable Importer for the Clinical Data Warehouses PaDaWaN and I2B2. AB - In recent years, clinical data warehouses (CDW) storing routine patient data have become more and more popular to support scientific work in the medical domain. Although CDW systems provide interfaces to import new data, these interfaces have to be used by processing tools that are often not included in the systems themselves. In order to establish an extraction-transformation-load (ETL) workflow, already existing components have to be taken or new components have to be developed to perform the load part of the ETL. We present a customizable importer for the two CDW systems PaDaWaN and I2B2, which is able to import the most common import formats (plain text, CSV and XML files). In order to be run, the importer only needs a configuration file with the user credentials for the target CDW and a list of XML import configuration files, which determine how already exported data is indented to be imported. The importer is provided as a Java program, which has no further software requirements. PMID- 28883178 TI - Automated Transformation of CDISC ODM to OpenClinica. AB - Due to the increasing use of electronic data capture systems for clinical research, the interest in saving resources by automatically generating and reusing case report forms in clinical studies is growing. OpenClinica, an open source electronic data capture system enables the reuse of metadata in its own Excel import template, hampering the reuse of metadata defined in other standard formats. One of these standard formats is the Operational Data Model for metadata, administrative and clinical data in clinical studies. This work suggests a mapping from Operational Data Model to OpenClinica and describes the implementation of a converter to automatically generate OpenClinica conform case report forms based upon metadata in the Operational Data Model. PMID- 28883179 TI - Proof-of-Concept Integration of Heterogeneous Biobank IT Infrastructures into a Hybrid Biobanking Network. AB - Cross-institutional biobank networks hold the promise of supporting medicine by enabling the exchange of associated samples for research purposes. Various initiatives, such as BBMRI-ERIC and German Biobank Node (GBN), aim to interconnect biobanks for enabling the compilation of joint biomaterial collections. However, building software platforms to facilitate such collaboration is challenging due to the heterogeneity of existing biobank IT infrastructures and the necessary efforts for installing and maintaining additional software components. As a remedy, this paper presents the concept of a hybrid network for interconnecting already existing software components commonly found in biobanks and a proof-of-concept implementation of two prototypes involving four biobanks of the German Biobank Node. Here we demonstrate the successful bridging of two IT systems found in many German biobanks - Samply and i2b2. PMID- 28883181 TI - Alarm Fatigue: Causes and Effects. AB - The term "Alarm fatigue" is commonly used to describe the effect which a high number of alarms can have on caregivers: Frequent alarms, many of which are avoidable, can lead to inadequate responses, severely impacting patient safety. In the first step of a long-term effort to address this problem, both the direct and indirect impact of alarms, as well as possible causes of unnecessary alarms were focused. Models of these causes and impacts were developed using a scoping review which included guided interviews with experts from medical informatics, clinicians and medical device manufacturers. These models can provide the methodical grounds for the definition of targeted interventions and the assessment of their effects. PMID- 28883182 TI - IT Decision Making in German Hospitals - Do CEOs Open the Black Box? AB - Health IT and communication systems are indispensable in German hospitals for clinical as well as administrative process support. However, IT is often regarded as a "black box" for hospital CEOs. Thus, the question arises how can CEOs decide if they do not know what is in the box? In order to answer this question, half structured interviews with 14 German hospital CEOs were conducted. They revealed three principle decision processes: the supported decision, the joint decision and the corporate level decision. In all cases, the hospital CEO and the CIO interacted to reach the final decision, most strongly in the joint decision mode and least strongly in the corporate decision mode. Only the joint decision mode definitely forced the CEO to open the "black box" of IT. In the era of digitalisation, however, CEOs must develop better competencies to decide over complex matters. PMID- 28883183 TI - Cognitive Performance of Users Is Affected by Electronic Handovers Depending on Role, Task and Human Factors. AB - Patient handovers are cognitively demanding, crucial for information continuity and patient safety, but error prone. This study investigated the effect of an electronic handover tool, i.e. the handoverEHR, on the memory and care planning performance of nurse students (n=32) in a randomised, controlled cross-over design with the factors handover task and handover role. On a descriptive level, handover recipients could improve their memory performance with electronic support, handover givers their performance of writing care plans. Statistically meaningful differences occurred, however, only when the participants were givers. Without handover experience and with low fluency to word problems, givers performed badly in the most demanding of the handover tasks. Final recommendations, however, can only be made after replicating this study in a clinical setting with mixed groups. PMID- 28883184 TI - Technical Environment for Developing the SNIK Ontology of Information Management in Hospitals. AB - The SNIK project converts textbooks about information management in hospitals to a domain ontology that provides a shared vocabulary for institutions to model and integrate processes, data and infrastructure. To accommodate user groups with different requirements and technical backgrounds, and to support incremental and cooperative development, we create a system architecture to publish, visualize, browse and query the ontology, as well as to evaluate and improve the data quality. PMID- 28883185 TI - Factors Influencing the Implementation and Distribution of Clinical Decision Support Systems (CDSS). AB - Clinical Decision Support Systems (CDSS) can have positive effects on quality of care measures, yet have not gained widespread traction in healthcare. This study sought to determine and evaluate barriers and facilitators to CDSS implementation and distribution. Based on 768 systems identified in a literature review we conducted semi-structured telephone interviews with 54 system developers in 16 countries. Qualitative analysis led to the identification of 66 key factors influencing implementation. Central issues evolved around CDSS properties, quality and integration, as well as usability, user related factors, internal marketing, resource issues and collaborations with emphasis partly on topics differing from existing research. Additionally, evidence pointed to regional differences regarding implementation hurdles. Recent regulatory requirements were deemed less of a barrier to system adoption than expected, even though lacking expertise in this area was surprisingly common among interview partners. PMID- 28883186 TI - Disseminating a Standard for Medical Records in Emergency Departments Among Different Software Vendors Using HL7 CDA. AB - A standardized medical record for the emergency department (GEDMR) was released in Germany, but only sparsely and randomly implemented by emergency department (ED) electronic health record (EHR) vendors. A reason for this may be a lacking common language between the medical and the Health Information Technology (HIT) domain. HL7 clinical document architecture (CDA) may leverage this communication gap. This paper reports on the effects of a professional medical association record standard on EHR vendors and the German ED-EHR market. Standard records and data standards are developed and published by different institutions either on governmental, healthcare agency or medical association level. There are some standard records, especially by US cardiology associations, transformed into HL7 C-CDA. GEDMR was modeled as HL7 CDA with the use of interoperable terminologies like LOINC and SNOMED CT. Being part of an emergency department data registry development project, local deployment at 15 project hospitals receiving sufficient funding was performed. Two major ED-EHR vendors adapted GEDMR within their product including CDA export. 106,868 CDAs were produced in six hospitals until now. Four local implementations with four different ED-EHRs were developed, producing 42,256 CDAs. Five additional vendors are adapting or developing an ED EHR. The GEDMR-CDA implementation guide with funding for implementation in project hospitals had a significant impact on the German ED-EHR market. Within two years after release, a broadening and increasingly self-enforcing support by German ED-EHR vendors is notable. PMID- 28883187 TI - Requirements Analysis for a Clinical Decision Support System Aiming at Improving the Artificial Nutrition of Critically Ill Patients. AB - BACKGROUND: Nutrition support is an important aspect regarding the care of critically ill patients. Malnutrition affects the recovery process negatively. However, the impact on the clinical outcome is often underestimated in complex clinical settings due to several factors hindering optimization of nutrition. OBJECTIVE: To identify the requirements for a clinical decision support system that enables the medical staff to improve its patients' nutritional status. METHODS: A literature review and interviews with two senior physicians were conducted to refine the requirements for the support system as well as to determine the inclusion criteria for a subsequent intervention study. RESULTS: The analysis resulted in: (i) the identification of 4 measurement parameters for the assessment of the nutrition status; (ii) the graphical layout in adherence to the standards-based implementation approach for the creation of multi-patient dashboards; (iii) the definition of the study group. The nutrition dashboard will be implemented and integrated based on the set requirements, followed by an intervention study evaluating the dashboard's efficacy. PMID- 28883188 TI - Antecedents of CIOs' Innovation Capability in Hospitals: Results of an Empirical Study. AB - CIOs' innovation capability is regarded as a precondition of successful HIT adoption in hospitals. Based on the data of 142 CIOs, this study aimed at identifying antecedents of perceived innovation capability. Eight features describing the status quo of the hospital IT management (e.g. use of IT governance frameworks), four features of the hospital structure (e.g. functional diversification) and four CIO characteristics (e.g. duration of employment) were tested as potential antecedents in an exploratory stepwise regression approach. Perceived innovation capability in its entirety and its three sub-dimensions served as criterion. The results show that CIOs' perceived innovation capability could be explained significantly (R2=0.34) and exclusively by facts that described the degree of formalism and structure of IT management in a hospital, e.g. intensive and formalised strategic communication, the existence of an IT strategy and the use of IT governance frameworks. Breaking down innovation capability into its constituents revealed that "innovative organisational culture" contributed to a large extent (R2=0.26) to the overall result sharing several predictors. In contrast, "intrapreneurial personality" (R2=0.11) and "openness towards users" (R2=0.18) could be predicted less well. These results hint at the relationship between working in a well-structured, formalised and strategy oriented environment and the overall feeling of being capable to promote IT innovation. PMID- 28883189 TI - Identification of Measures and Indicators for the IT Security of Networked Medical Devices: A Delphi Study. AB - The networking of medical devices or systems in a hospital network is the foundation for modern medical diagnostics and therapy. This, however, makes possible numerous hazards that could lead to risks for patients, clinical processes or data and information. The aim of the work was to develop a catalogue of measures and indicators for the effective support of the IT risk management process in a health facility. Through a qualitative and quantitative Delphi study among 21 experts, it was possible to identify an initial 51 practice-relevant measures of IT risk management that a hospital should implement. Additionally, 27 indicators were defined which can be used to measure the impact of these measures. Of the 51 measures, 35 were seen as especially important, particularly organizational measures. Of the 27 indicators, six were seen as especially important, particularly indicators to measure networking effectiveness. The study also investigated the impact of the measures on the indicators. A case study is planned to investigate the practicability of the identified measures and indicators. PMID- 28883190 TI - Extending the Query Language of a Data Warehouse for Patient Recruitment. AB - Patient recruitment for clinical trials is a laborious task, as many texts have to be screened. Usually, this work is done manually and takes a lot of time. We have developed a system that automates the screening process. Besides standard keyword queries, the query language supports extraction of numbers, time-spans and negations. In a feasibility study for patient recruitment from a stroke unit with 40 patients, we achieved encouraging extraction rates above 95% for numbers and negations and ca. 86% for time spans. PMID- 28883191 TI - Implementation of Task-Tracking Software for Clinical IT Management. AB - Often in clinical IT departments, many different methods and IT systems are used for task-tracking and project organization. Based on managers' personal preferences and knowledge about project management methods, tools differ from team to team and even from employee to employee. This causes communication problems, especially when tasks need to be done in cooperation with different teams. Monitoring tasks and resources becomes impossible: there are no defined deliverables, which prevents reliable deadlines. Because of these problems, we implemented task-tracking software which is now in use across all seven teams at the University Hospital Erlangen. Over a period of seven months, a working group defined types of tasks (project, routine task, etc.), workflows, and views to monitor the tasks of the 7 divisions, 20 teams and 340 different IT services. The software has been in use since December 2016. PMID- 28883193 TI - Expert2OWL: A Methodology for Pattern-Based Ontology Development. AB - The formalization of expert knowledge enables a broad spectrum of applications employing ontologies as underlying technology. These include eLearning, Semantic Web and expert systems. However, the manual construction of such ontologies is time-consuming and thus expensive. Moreover, experts are often unfamiliar with the syntax and semantics of formal ontology languages such as OWL and usually have no experience in developing formal ontologies. To overcome these barriers, we developed a new method and tool, called Expert2OWL that provides efficient features to support the construction of OWL ontologies using GFO (General Formal Ontology) as a top-level ontology. This method allows a close and effective collaboration between ontologists and domain experts. Essentially, this tool integrates Excel spreadsheets as part of a pattern-based ontology development and refinement process. Expert2OWL enables us to expedite the development process and modularize the resulting ontologies. We applied this method in the field of Chinese Herbal Medicine (CHM) and used Expert2OWL to automatically generate an accurate Chinese Herbology ontology (CHO). The expressivity of CHO was tested and evaluated using ontology query languages SPARQL and DL. CHO shows promising results and can generate answers to important scientific questions such as which Chinese herbal formulas contain which substances, which substances treat which diseases, and which ones are the most frequently used in CHM. PMID- 28883194 TI - Light-Weighted Automatic Import of Standardized Ontologies into the Content Management System Drupal. AB - The amount of ontologies, which are utilizable for widespread domains, is growing steadily. BioPortal alone, embraces over 500 published ontologies with nearly 8 million classes. In contrast, the vast informative content of these ontologies is only directly intelligible by experts. To overcome this deficiency it could be possible to represent ontologies as web portals, which does not require knowledge about ontologies and their semantics, but still carries as much information as possible to the end-user. Furthermore, the conception of a complex web portal is a sophisticated process. Many entities must be analyzed and linked to existing terminologies. Ontologies are a decent solution for gathering and storing this complex data and dependencies. Hence, automated imports of ontologies into web portals could support both mentioned scenarios. The Content Management System (CMS) Drupal 8 is one of many solutions to develop web presentations with less required knowledge about programming languages and it is suitable to represent ontological entities. We developed the Drupal Upper Ontology (DUO), which models concepts of Drupal's architecture, such as nodes, vocabularies and links. DUO can be imported into ontologies to map their entities to Drupal's concepts. Because of Drupal's lack of import capabilities, we implemented the Simple Ontology Loader in Drupal (SOLID), a Drupal 8 module, which allows Drupal administrators to import ontologies based on DUO. Our module generates content in Drupal from existing ontologies and makes it accessible by the general public. Moreover Drupal offers a tagging system which may be amplified with multiple standardized and established terminologies by importing them with SOLID. Our Drupal module shows that ontologies can be used to model content of a CMS and vice versa CMS are suitable to represent ontologies in a user-friendly way. Ontological entities are presented to the user as discrete pages with all appropriate properties, links and tags. PMID- 28883195 TI - Mapping Equivalence of German Emergency Department Medical Record Concepts with SNOMED CT After Implementation with HL7 CDA. AB - INTRODUCTION: The German Emergency Department Medical Record (GEDMR) was created by medical domain experts and healthcare providers providing a dataset as well as a form. The trauma module of GEDMR was syntactically standardized using HL7 CDA and semantically standardized using different terminologies including SNOMED CT, LOINC and proprietary coding systems. This study depicts the mapping accuracy with aforementioned syntactical and semantical standards in general and especially the content coverage of SNOMED CT. METHODS: The specification of GEDMR (V2015.1) concepts with eHealth-standards HL7-CDA, LOINC, SNOMED CT was analyzed. A content coverage assessment was made using the ISO TR 12300 rating scheme, following descriptive analysis. RESULTS: The trauma module of GEDMR contains 489 concepts, with 202 concepts expressed via HL7 CDA structure. It is possible to code 89 % of the remaining concepts via SNOMED CT. 79 % provide an advanced level of semantic interoperability, as they represent the source information either lexically or as an approved synonym. DISCUSSION: The terminology binding problem is relevant when combining different standards for syntactic and semantic interoperability with best practice documents and reference specifications providing guidance. A national license and extension for SNOMED CT in Germany as well as an ongoing effort in contributing to the International Version of SNOMED CT would be necessary to gain full coverage for concepts in German Emergency Medicine and to leverage the associated standardization process. PMID- 28883196 TI - From a Content Delivery Portal to a Knowledge Management System for Standardized Cancer Documentation. AB - Heterogeneous tumor documentation and its challenges of interpretation of medical terms lead to problems in analyses of data from clinical and epidemiological cancer registries. The objective of this project was to design, implement and improve a national content delivery portal for oncological terms. Data elements of existing handbooks and documentation sources were analyzed, combined and summarized by medical experts of different comprehensive cancer centers. Informatics experts created a generic data model based on an existing metadata repository. In order to establish a national knowledge management system for standardized cancer documentation, a prototypical tumor wiki was designed and implemented. Requirements engineering techniques were applied to optimize this platform. It is targeted to user groups such as documentation officers, physicians and patients. The linkage to other information sources like PubMed and MeSH was realized. PMID- 28883197 TI - An Abstraction Layer to Facilitate Technical Interoperability Between Medical Records and Knowledge Modules. AB - Integrating clinical decision support (CDS) functions into an existing hospital information system (HIS) is often a tedious task. This problem area is so pervasive that the Arden Syntax, a widely used standard for CDS functions, assigned a specific designation, the so-called "curly braces problem". It derives from a pair of curly braces used to encapsulate any parameters required for the interactions with a HIS. The traditional approach is to leave the problem area of technical interoperability entirely to the specific institution, possibly entailing a considerable amount of initial programming work. This study describes a reusable and expandable solution to this problem in the form of an abstraction layer. Our study comprised an analytical phase in which we investigated the data source access capabilities of five Arden Syntax environments. Building on the results, we implemented a working prototype that is capable of querying heterogeneous data sources, which facilitates a straightforward connection of new data sources with existing and future communication protocols and standards. From our point of view, the technical aspects of the "curly braces problem" with respect to data source access have changed over the years, insofar as technical progress lead to defacto standards for data storage, data querying and inter system communication. An agreement on such a convention, together with the supply of commonly used data source adapters could promote the further dissemination of the Arden Syntax as a standard for representing and sharing medical knowledge. PMID- 28883198 TI - Analysis of Annotated Data Models for Improving Data Quality. AB - The public Medical Data Models (MDM) portal with more than 9.000 annotated forms from clinical trials and other sources provides many research opportunities for the medical informatics community. It is mainly used to address the problem of heterogeneity by searching, mediating, reusing, and assessing data models, e. g. the semi-interactive curation of core data records in a special domain. Furthermore, it can be used as a benchmark for evaluating algorithms that create, transform, annotate, and analyse structured patient data. Using CDISC ODM for syntactically representing all data models in the MDM portal, there are semi automatically added UMLS CUIs at several ODM levels like ItemGroupDef, ItemDef, or CodeList item. This can improve the interpretability and processability of the received information, but only if the coded information is correct and reliable. This raises the question how to assure that semantically similar datasets are also processed and classified similarly. In this work, a (semi-)automatic approach to analyse and assess items, questions, and data elements in clinical studies is described. The approach uses a hybrid evaluation process to rate and propose semantic annotations for under-specified trial items. The evaluation algorithm operates with the commonly used NLM MetaMap to provide UMLS support and corpus-based proposal algorithms to link datasets from the provided CDISC ODM item pool. PMID- 28883200 TI - Optimizing a Query by Transformation and Expansion. AB - In the biomedical sector not only the amount of information produced and uploaded into the web is enormous, but also the number of sources where these data can be found. Clinicians and researchers spend huge amounts of time on trying to access this information and to filter the most important answers to a given question. As the formulation of these queries is crucial, automated query expansion is an effective tool to optimize a query and receive the best possible results. In this paper we introduce the concept of a workflow for an optimization of queries in the medical and biological sector by using a series of tools for expansion and transformation of the query. After the definition of attributes by the user, the query string is compared to previous queries in order to add semantic co occurring terms to the query. Additionally, the query is enlarged by an inclusion of synonyms. The translation into database specific ontologies ensures the optimal query formulation for the chosen database(s). As this process can be performed in various databases at once, the results are ranked and normalized in order to achieve a comparable list of answers for a question. PMID- 28883201 TI - Deep Learning for Magnetic Resonance Fingerprinting: A New Approach for Predicting Quantitative Parameter Values from Time Series. AB - The purpose of this work is to evaluate methods from deep learning for application to Magnetic Resonance Fingerprinting (MRF). MRF is a recently proposed measurement technique for generating quantitative parameter maps. In MRF a non-steady state signal is generated by a pseudo-random excitation pattern. A comparison of the measured signal in each voxel with the physical model yields quantitative parameter maps. Currently, the comparison is done by matching a dictionary of simulated signals to the acquired signals. To accelerate the computation of quantitative maps we train a Convolutional Neural Network (CNN) on simulated dictionary data. As a proof of principle we show that the neural network implicitly encodes the dictionary and can replace the matching process. PMID- 28883202 TI - Evaluation of an Interactive Visualization Tool for the Interpretation of Pediatric Laboratory Test Results. AB - The physiological age-related development of pediatric laboratory results interferes with pathological derangements, which can complicate the interpretation of test results. Recently proposed continuous reference intervals (RIs) promise to be beneficial, although their clinical use may depend on graphical presentations. To estimate the clinical utility of continuous RIs, we developed and evaluated an interactive visualization tool, and examined the differentiation of hemoglobinopathies that is attainable based on the underlying innovative RI model. The implemented web application allows users to easily enter laboratory test results, and displays various visualizations in conjunction with the corresponding RIs, such as charts and personalized Z-scores. To evaluate the usability of the visualization tool, we conducted concurrent think-aloud sessions with four physicians, who were prompted to solve a set of typical interpretation tasks, and acquired additional information through a questionnaire including the System Usability Scale (SUS). We used 85 de-identified clinical cases for an exemplified assessment of how well model-based interpretations of blood count parameters reproduced previously diagnosed hemoglobinopathies. Usability tests as well as questionnaire responses indicated that the developed tool was well received by the physicians. Results from the think-aloud evaluation revealed only minor problems and the tool reached an average SUS score of 86.9, suggesting good usability. Hemoglobinopathy discrimination depended on the considered subtype, although the overall performance of the novel method rivaled the one of the conventional approach. The interactive visualization of innovative continuous reference intervals demonstrated promising results, which justifies further testing on the path towards clinical routine. PMID- 28883203 TI - Machine Learning Models of Post-Intubation Hypoxia During General Anesthesia. AB - Fine-meshed perioperative measurements are offering enormous potential for automatically investigating clinical complications during general anesthesia. In this study, we employed multiple machine learning methods to model perioperative hypoxia and compare their respective capabilities. After exporting and visualizing 620 series of perioperative vital signs, we had ten anesthesiologists annotate the subjective presence and severity of temporary post-intubation oxygen desaturation. We then applied specific clustering and prediction methods on the acquired annotations, and evaluated their performance in comparison to the inter rater agreement between experts. When reproducing the expert annotations, the sensitivity and specificity of multi-layer neural networks substantially outperformed clustering and simpler threshold-based methods. The achieved performance of our best automated hypoxia models thereby approximately equaled the observed agreement between different medical experts. Furthermore, we deployed our classification methods for processing unlabeled inputs to estimate the incidence of hypoxic episodes in another sizeable patient cohort, which attests to the feasibility of using the approach on a larger scale. We interpret that our machine learning models could be instrumental for computerized observational studies of the clinical determinants of post-intubation oxygen deficiency. Future research might also investigate potential benefits of more advanced preprocessing approaches such as automated feature learning. PMID- 28883204 TI - Considering Information Up-to-Dateness to Increase the Accuracy of Therapy Decision Support Systems. AB - During the diagnostic process a lot of information is generated. All this information is assessed when making a final diagnosis and planning the therapy. While some patient information is stable, e.g., gender, others may become outdated, e.g., tumor size derived from CT data. Quantifying this information up to-dateness and deriving consequences are difficult. Especially for the implementation in clinical decision support systems, this has not been studied. When information entities tend to become outdated, in practice, clinicians intuitively reduce their impact when making decisions. Therefore, in a system's calculations their impact should be reduced as well. We propose a method of decreasing the certainty of information entities based on their up-to-dateness. The method is tested in a decision support system for TNM staging based on Bayesian networks. We compared the actual N-state in records of 39 patients to the N-state calculated with and without decreasing data certainty. The results under decreased certainty correlated better with the actual states (r=0.958, p=0.008). We conclude that the up-to-dateness must be considered when processing clinical information to enhance decision making and ensure more patient safety. PMID- 28883205 TI - Processual Reasoning over Sequences of Situations in Endoscopic Surgery. AB - Minimally invasive surgery is a highly complex and technically demanding alternative to open surgery. Surgical procedures based on this method are characterized by small incisions and allow for a fast recovery of the patient. Such techniques are challenging for surgeons since they do not have a direct view of the surgical area. Systems that provide surgical navigation are well established in clinical practice but depend on external markers allowing a mapping between a surgeon's tools and a patient's medical images. As of today, these systems are prone to inaccuracies, the reasons of which lie in their extensive technical requirements. The BIOPASS project aims to develop an alternative that works without external markers and indirect computation of locations. An ontology has been used to provide an adequate vocabulary describing situations and their temporal relationship. This ontology is expected to relate real time multimodal sensor data and static surgical process models in order to infer movement directions, subsequent actions and hidden anatomical structures that inhere risk for surgical interventions. However, the Web Ontology Language is not capable of modelling temporal conditions, which are necessary to provide such exhaustive situational descriptions as expected by a surgeon. This paper concerns an ontology design pattern developed to overcome this issue by the integration of dynamic ontological classes that are assigned according to the temporal relations between situations. PMID- 28883208 TI - Basic study of intratracheal instillation study of nanomaterials for the estimation of the hazards of nanomaterials. AB - In order to examine the usefulness of intratracheal instillation of nanoparticles for the screening of the harmful effects of nanoparticles, we performed intratracheal instillation studies of nanomaterials on rats using different delivery devices and postures as a basic study. Multiwall carbon nanotubes (MWCNTs) with a geometric mean length and secondary diameter of 2.16 MUm and 752 nm, respectively, were used as the nanomaterials. Male F344 rats were intratracheally exposed to 0.04 or 0.2 mg/rat of MWCNT, were dissected at 1 d and 3 d, and cell analyses of the bronchoalveolar lavage fluid (BALF) were analyzed. Two delivery devices were used for the intratracheal instillation of the MWCNTs: a gavage needle and a microsprayer aerolizer. Both induced neutrophil influx in the lung at 1 and 3 d, and there were no significant differences in neutrophil inflammation between the two delivery devices. The main distribution of pulmonary inflammation by both delivery devices was in the centrilobular spaces in the lung. Two postures were used: an angle of approximately 45 degrees and a standing posture on a board, both of which also induced pulmonary influx in BALF and pulmonary inflammation mainly in the centrilobular spaces, with no large difference in pulmonary inflammation between the two postures. Taken together, the differences in the delivery devices and postures of the rats in the intratracheal instillation did not affect the acute pulmonary toxicity of the nanomaterials. PMID- 28883209 TI - Is Anatomic Lung Resection Necessary in Surgical Treatment of Giant Lung Hydatid Cysts in Childhood? AB - PURPOSE: The aim of this study is to evaluate the results of parenchymal saving methods for giant lung hydatid cysts and to discuss the necessity of anatomic lung resection in childhood. METHODS: The patients under the age of 16 years who were operated between January 2000 and January 2017 due to pulmonary hydatid cyst were evaluated retrospectively (n = 200). In all, 32 patients who had giant hydatid cyst were included in this study. Parenchymal saving methods (cystotomy capitonnage) were preferred and decortication was also performed for pleural thickening if needed. No lung resections were applied. RESULTS: Male patients were 53.1%. The mean age was 11.3 +/- 3.2 years. The total number of giant cysts was 32. The average size of the cysts was 11 cm. Thirty seven point five percent of the cysts were perforated. Postoperative complication rate was 31.3%. No recurrence and mortality were seen during follow-up period. CONCLUSION: Considering the high recovery capacity of lung tissue, a chance should be given to recover the existing infection, atelectasis, and parenchymal damage. Especially in areas where hydatid disease is endemic, children may be infected with the parasite again. For these reasons, we do not recommend resection with any indications. PMID- 28883210 TI - Developmental changes in hypothalamic SF-1, POMC, and ERalpha mRNA expression and their sensitivity to fasting in male and female rats. AB - Estrogen plays pivotal roles in body weight regulation through its effects on central estrogen receptor-alpha (ERalpha) expression. ERalpha is found on neurons that express the hypothalamic anorexigenic factors steroidogenic factor-1 (SF-1) and pro-opiomelanocortin (POMC) mediate these effects of estrogen. As the gonadal hormonal milieu is drastically altered during the developmental period, the expression levels of SF-1 and POMC might also change during this period. In this study, we showed that hypothalamic SF-1 and ERalpha mRNA expression did not change during the neonatal to pre-pubertal period (from postnatal day 10 to 30), and there were no significant differences in the hypothalamic mRNA expression levels of these molecules between males and females at any examined age. On the other hand, hypothalamic POMC mRNA expression and the serum estradiol (E2) level increased during development in both males and females. Significant positive correlations were detected between the serum E2 level and hypothalamic POMC mRNA expression in both males and females. Hypothalamic ERalpha and POMC mRNA expression were decreased by fasting in male rats at all examined ages, whereas fasting had no effect on hypothalamic ERalpha or POMC mRNA expression in the female rats. These results indicate that the regulatory system involving E2 and hypothalamic POMC expression might already be established in the neonatal period and that the roles of POMC and ERalpha in body weight regulation during development might differ slightly between males and females. PMID- 28883212 TI - [Verification of Learning Effects by Team-based Learning]. AB - It has been recommended that active learning methods, such as team-based learning (TBL) and problem-based learning (PBL), be introduced into university classes by the Central Council for Education. As such, for the past 3 years, we have implemented TBL in a medical therapeutics course for 4-year students. Based upon our experience, TBL is characterized as follows: TBL needs fewer teachers than PBL to conduct a TBL module. TBL enables both students and teachers to recognize and confirm the learning results from preparation and reviewing. TBL grows students' responsibility for themselves and their teams, and likely facilitates learning activities through peer assessment. PMID- 28883211 TI - CIDE Family-Mediated Unique Lipid Droplet Morphology in White Adipose Tissue and Brown Adipose Tissue Determines the Adipocyte Energy Metabolism. AB - White adipose tissue (WAT) stores energy as triacylglycerol in preparation for fasting state. In contrast, brown adipose tissue (BAT) consumes energy and produces heat in a cold environment. One of the major differences between these two adipose tissues is the morphology of the intracellular lipid droplet (LD), which is large and unilocular in WAT and small and multilocular in BAT. Although the fat-specific protein 27 alpha (FSP27alpha), belonging to the cell death inducing DNA fragmentation factor A (DFFA)-like effector (Cide) family, was known to be indispensable for large unilocular LD formation in WAT, the mechanism that regulated small multilocular LD formation in BAT remained unknown. We recently uncovered that FSP27beta, a novel isoform of FSP27 abundantly expressed in BAT, plays a crucial role in small multilocular LD formation by inhibiting the homodimerization of CideA in BAT. We speculate that unilocular LD formation is ideal for efficient lipid storage in WAT because lipolysis from the LD surface is restricted due to the minimum LD surface area. In addition, hydrolyzed free fatty acid (FFA) and glycerol can efficiently flow out into the circulation from the cell surface. In contrast, small multilocular LD formation is ideal for efficient intracellular lipolysis from the LD surface and the subsequent facilitation of FFA transport to mitochondria that are adjacent to LDs for beta-oxidation in BAT. Thus, intracellular LD morphology is closely related to the functions and characteristics of adipose tissues. Given that the browning of adipose tissue leads to enhanced energy expenditure and the prevention of obesity, clarification of the mechanism with respect to intracellular LD formation is very meaningful. PMID- 28883213 TI - [Present Status of Displaying Pharmaceutical Products for Sale on Flea Market Applications for Smartphones and the Responses to Illicit Selling by Service Providers]. AB - In Japan, a pharmacy or drug store license is required for selling pharmaceutical products. However, civilians without a pharmacy or drug store license are displaying pharmaceutical products for sale on a flea market application, which is illegal dealing. This study discussed the modality for implementing countermeasures for the illicit selling of pharmaceutical products. We extracted pharmaceutical products displayed for sale on three flea market applications (Mercari, Rakuma, Fril) on one day. One hundred and eighty-one pharmaceutical products were displayed (49 on Mercari, 86 on Rakuma, and 46 on Fril). There were 6.1% (11/181) domestically prescribed drugs, 69.1% (125/181) domestic OTC drugs, 23.8% (43/181) foreign-made prescribed drugs, and 1.1% (2/181) foreign-made OTC drugs. The seller could display the product for sale without confirming whether it is prohibited. We alerted the service providers of this illicit selling at flea markets at three different instances. The pharmaceutical product displays were deleted by the service providers at a rate of 55.1% (27/49) for Mercari and 51.2% (44/86) for Rakuma. The average number of drugs that were displayed for sale by each seller was 1.4 and the average number of total products that were displayed for sale by each seller was 100. The seller could have unintentionally displayed the pharmaceutical products for sale, without the knowledge that it is illegal. The service providers of flea market applications should create mechanisms to alert the sellers that displaying pharmaceutical products for sale is an illicit act and regulate these violations. PMID- 28883214 TI - The Incidence of Atypical Femoral Fractures in Patients with Rheumatic Disease: Yamagata Prefectural Committee of Atypical Femoral Fractures (YamaCAFe) Study. AB - Atypical femoral fractures (AFFs) have been reported to occur with minimal or spontaneous subtrochanteric and femoral shaft fractures with a characteristic transverse pattern, compared with typical femoral fractures in young patients with high-energy trauma. AFFs are related to long-term use of bisphosphonates (BPs), glucocorticoids and rheumatic diseases. We have estimated a blind analysis of AFFs in rheumatic patients receiving BPs and glucocorticoids ordinary over a long time in all Yamagata prefectural area through radiographic examination. The 123 AFFs including suspected cases over six years were collected and reviewed by two independent orthopedic surgeons. We found 86 patients with a total of 99 AFFs between 2009 and 2014 (1.43 cases/100,000 person/year). Of these 99 AFFs, 11 were in 8 rheumatic patients including three patients with bilateral AFFs. The incidence of AFFs in rheumatic patients had trend to increase from 2012. The mean age of all 8 patients was 54.9 years. All 8 patients received BPs and 7/8 received prednisolone (PSL). The mean dose of PSL was 14 mg/day. Compared to patients with unilateral AFFs, those with bilateral AFFs in rheumatic patients were on a higher dose of PSL (20 mg/day vs. 7 mg/day) and had less femoral neck shaft angle (129 degrees vs. 136 degrees , p < 0.05). In conclusion, the incidence of AFFs in rheumatic patients showed a trend to increase from 2012 to 2014 in Yamagata prefecture. Careful management of AFFs is of particular importance in rheumatic patients who have taken high doses of PSL and have small femoral neck-shaft angle. PMID- 28883216 TI - Impact of Speed-Eating Habit on Subsequent Body Mass Index and Blood Pressure Among Schoolchildren - The Ibaraki Children's Cohort Study (IBACHIL). AB - BACKGROUND: Habitual speed eating is a risk factor of obesity but evidence of this in children is limited. We examined the association between speed-eating habit and subsequent body mass index (BMI) and blood pressure (BP) among Japanese children.Methods and Results:The community-based study comprised 1,490 Japanese boys and girls who were born in 1989, involved in the Ibaraki Children's Cohort Study at age 3 years, and had returned questionnaires at both ages 6 and 12 years. In a subsample, we measured BP (n=263). Speed-eating habit was categorized into 4 groups: Never, Quit, Newly, and Continuous. Sex-specific mean values of questionnaire-based BMI and measured BPs at age 12 were examined according to speed-eating habit. Children with continuous speed eating had a higher BMI at age 12 than those who had never had a speed-eating habit (20.0 vs. 17.9 kg/m2for boys (P<0.001); 20.0 vs. 18.4 kg/m2(P<0.001) for girls). Systolic BP at age 12 was higher in boys with continuous speed eating than in those without (117 vs. 110 mmHg, P=0.01), but such a difference was not observed in girls (112 vs. 111 mmHg, P=0.95). CONCLUSIONS: Habitualspeed eating was positively associated with subsequent BMI among boys and girls as well as with systolic BP among boys. PMID- 28883215 TI - Cytokine Response to Diet and Exercise Affects Atheromatous Matrix Metalloproteinase-2/9 Activity in Mice. AB - BACKGROUND: The aim of this study is to identify the principal circulating factors that modulate atheromatous matrix metalloproteinase (MMP) activity in response to diet and exercise.Methods and Results:Apolipoprotein-E knock-out (ApoE-/-) mice (n=56) with pre-existing plaque, fed either a Western diet (WD) or normal diet (ND), underwent either 10 weeks of treadmill exercise or had no treatment. Atheromatous MMP activity was visualized using molecular imaging with a MMP-2/9 activatable near-infrared fluorescent (NIRF) probe. Exercise did not significantly reduce body weight, visceral fat, and plaque size in either WD-fed animals or ND-fed animals. However, atheromatous MMP-activity was different; ND animals that did or did not exercise had similarly low MMP activities, WD animals that did not exercise had high MMP activity, and WD animals that did exercise had reduced levels of MMP activity, close to the levels of ND animals. Factor analysis and path analysis showed that soluble vascular cell adhesion molecule (sVCAM)-1 was directly positively correlated to atheromatous MMP activity. Adiponectin was indirectly negatively related to atheromatous MMP activity by way of sVCAM-1. Resistin was indirectly positively related to atheromatous MMP activity by way of sVCAM-1. Visceral fat amount was indirectly positively associated with atheromatous MMP activity, by way of adiponectin reduction and resistin elevation. MMP-2/9 imaging of additional mice (n=18) supported the diet/exercise-related anti-atherosclerotic roles for sVCAM-1. CONCLUSIONS: Diet and exercise affect atheromatous MMP activity by modulating the systemic inflammatory milieu, with sVCAM-1, resistin, and adiponectin closely interacting with each other and with visceral fat. PMID- 28883217 TI - Safety and Efficacy of Long-Term Use of Tolvaptan in Patients With Heart Failure and Chronic Kidney Disease. AB - BACKGROUND: We assessed the long-term safety and efficacy of tolvaptan in 102 patients with heart failure (HF) and chronic kidney disease (CKD). Median follow up duration was 1.6 years (1.0-4.4 years).Methods and Results:One patient discontinued tolvaptan because of hypernatremia. There were no changes in renal function or electrolytes during the 1-year follow-up. The cardiac-related death free or HF-related hospitalization-free survival rate was significantly higher in patients receiving tolvaptan than in propensity score-matched patients who did not receive tolvaptan. CONCLUSIONS: In patients with HF and CKD, long-term administration of tolvaptan was well-tolerated, relatively safe and effective, suggesting its utility for long-term management of these conditions. PMID- 28883218 TI - Genesis and the Risk Score of Atrial Fibrillation for Personalized Management. PMID- 28883219 TI - High-dose chemotherapy with autologous stem cell transplantation following systemic chemotherapy, prophylactic intrathecal methotrexate, and radiotherapy prevents relapse and improves the outcome of advanced stage primary testicular lymphoma even with cardiac involvement. AB - Primary testicular lymphoma (PTL) is a rare but aggressive disease. Although most patients present in the early stage, their prognosis is poor. Similar with PTL, cardiac lymphoma is also an uncommon disease characterized by its aggressive clinical course and poor prognosis. We herein report an extremely rare case of advanced stage PTL with cardiac involvement, treated by high-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT) followed by systemic chemotherapy, prophylactic intrathecal methotrexate (IT-MTX), and radiotherapy. A 48-year-old man presented with painless left scrotal swelling. He was diagnosed with PTL after orchiectomy, and the histological type was diffuse large B-cell lymphoma. For staging of lymphoma, positron emission tomography was performed, which revealed uptake in the right atrium and early cardiac metastasis within just 2 months after orchiectomy. He underwent 6 cycles of systemic chemotherapy that consisted of rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone (R-CHOP). He also received central nervous system prophylaxis 4 times with weekly IT-MTX during the first 2 cycles of R-CHOP. He achieved complete response after 6 cycles of R-CHOP, and underwent HDT-ASCT and radiotherapy as consolidation therapy without irreversible adverse effects. He is currently doing well, with a progression-free survival of 31 months. The above treatment strategy including HDT-ASCT may be one of the treatment options for advanced stage PTL with cardiac metastasis in patients younger than 65 years old. PMID- 28883220 TI - A case of Waldenstrom Macroglobulinemia in which intermittent one-day administration cycles of bendamustine were effective for alleviation of nausea and maintenance of remission. PMID- 28883221 TI - Welder's pulmonary hemosiderosis associated with systemic iron overload following exacerbation of acute adult T-cell leukemia/lymphoma. AB - Herein, we describe a 61-year-old man diagnosed with pulmonary hemosiderosis following chemotherapy for acute adult T-cell leukemia/lymphoma (ATLL). Liver and heart biopsy confirmed hemosiderosis. ATLL progressed, and the patient died from multiorgan damage. Welder's lung may have been involved in hemosiderosis and systemic iron overload. Abnormal iron metabolism or immune reactions may have influenced the clinical course, but these were not validated. Detailed analyses of family medical and lifestyle histories, and genetic examination should be performed in cases of systemic iron overload. PMID- 28883222 TI - Temporal Changes in Platelet Response in Acute Coronary Syndrome Patients With Prasugrel and Clopidogrel After Stent Implantation. AB - BACKGROUND: Prasugrel has been shown to provide more potency and less variability than clopidogrel, but its potential temporal variability has not been described.Methods and Results:We conducted a prospective open-label study, evaluating platelet reactivity overtime in acute coronary syndrome (ACS) patients on aspirin and clopidogrel (n=60) or prasugrel (n=61), after a percutaneous coronary intervention (PCI). Blood samples were taken at discharge and at 3 and 6 months. Platelet function tests included VerifyNow (VN-P2Y12), and Multiplate Aggregometry (MEA). By means of VN-P2Y12, prasugrel patients displayed significantly (P<0.001) higher platelet inhibition than clopidogrel patients over time, although there were not significant differences using MEA. Prasugrel patients showed higher platelet inhibition at baseline than at 3 months (59.3+/ 8.1 vs. 105.0+/-49.2; P<0.001), without significant change at 6 months (107.9+/ 72.0; P=0.919 vs. 3 months). Clopidogrel patients showed a similar trend (160.1+/ 65.1, 184.8+/-62.7 and 185.0+/-53.3; baseline vs. 3 months P=0.060; 3 months vs. 6 months P=0.974). High platelet reactivity (HPR) was shown in 16.3% prasugrel patients, with no patient consistently remaining in HPR over time. HPR was detected in 36.6% of the clopidogrel patients, being consistently observed in 15.0% of them. Low platelet reactivity (LPR) was detected in 60.5% prasugrel and 9.8% clopidogrel patients. CONCLUSIONS: Prasugrel patients showed less temporal variation than patients on clopidogrel in terms of HPR. In contrast, higher variability in LPR was detected in prasugrel patients for up to 6 months' follow up. PMID- 28883223 TI - Exercise Ischemia Induced by Essential Thrombocytemia Diagnosed on Treadmill Test - Transcutaneous Oxygen Pressure Measurement of Foot Ischemia. PMID- 28883224 TI - Time Trend in Interest and Satisfaction Towards Clinical Training and Academic Activities Among Early-Career Cardiologists - The Japanese Circulation Society Post-Graduate Training Survey. AB - BACKGROUND: Satisfaction among early-career cardiologists is a key performance metric for cardiovascular (CV) educational programs. To assess the time trend in the interest and activities of early-career cardiologists regarding their training, we conducted web-based surveys in 2011 and 2015.Methods and Results:Early-career cardiologists were defined as physicians who planned to attend Japanese Circulation Society (JCS) annual meetings within 10 years of graduation. A total of 272 and 177 participants completed the survey for the years 2011 and 2015, respectively. Survey questions were designed to obtain core insights into the workplace, research interests, and demographic profile of respondents. Main outcome measures were satisfaction levels with their training program. The overall satisfaction rate for training was lower in 2015 than 2011; this was largely affected by decreases in the rates of satisfaction for valvular heart disease, ischemic heart disease, advanced heart failure, and congenital heart disease. Moreover, satisfaction with CV training was associated with the volume of invasive procedures such as coronary angiography and percutaneous coronary interventions in 2011 but not 2015. CONCLUSIONS: Early-career cardiologists' satisfaction with their training decreased during the study period, especially in the field of evolving subspecialties (e.g., valvular heart disease or advanced heart failure), suggesting that prompt reevaluation of the current educational curriculum is needed to properly adapt to progress in cardiology. PMID- 28883225 TI - Anemia Is Associated With Blunted Response to beta-Blocker Therapy Using Carvedilol - Insights From Japanese Chronic Heart Failure (J-CHF) Study. AB - BACKGROUND: Anemia portends a poor clinical outcome in patients with chronic heart failure (CHF). However, its mechanism remains unknown. We sought to elucidate the effect of anemia on patients with HF with reduced ejection fraction (HFrEF) who receive carvedilol therapy.Methods and Results:J-CHF study was a prospective, randomized, multicenter trial that assigned 360 HFrEF patients to 2.5 mg/5 mg/20 mg carvedilol groups according to the target dose. At baseline 70 patients (19%) had anemia ([A]) defined as hemoglobin level (Hb) <13 g/dL (male) or <12 g/dL (female) and the remaining 290 did not ([N]). Allocated and achieved doses of carvedilol were similar. Left ventricular ejection fraction (LVEF) and plasma B-type natriuretic peptide (BNP) level significantly improved in both groups over 56 weeks, but they were smaller in [A] than in [N] (LVEF, P=0.046; BNP, P<0.0001 by ANOVA). Baseline Hb was an independent predictor of absolute change in LVEF (beta=0.13, P=0.047) and BNP (beta=-0.10, P=0.01). Presence of chronic kidney disease defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2at baseline was not associated with differential response to carvedilol therapy. During 3.8+/-1.4 years follow-up, group [A] had a higher incidence of the composite endpoint of death, hospitalization for cardiovascular causes including HF compared with [N] (P=0.006). Baseline Hb was an independent predictor of the composite endpoint (hazard ratio 0.86, P=0.04), whereas baseline eGFR was not. CONCLUSIONS: Our data suggested that anemia was associated with a blunted response to carvedilol in HFrEF patients. PMID- 28883226 TI - Rapid Globalization of Medical Device Clinical Development Programs in Japan - The Case of Drug-Eluting Stents. AB - Delays in the introduction to the Japanese market of drug-eluting stents (DES) developed overseas (i.e., "device lag") decreased sharply between 2004 and 2012. The reduction accompanied a shift in clinical development from a succession pattern (initial product development and approval overseas followed by eventual entrance into the Japanese market) to parallel development (employing multiregional clinical trials (MRCTs)). Although resource-intensive in the short term, MRCTs are proving to be an effective tool in simultaneous global product development. Creative study designs and the absence of significant ethnic differences in Japanese subjects regarding DES safety and efficacy and the pharmacokinetic behavior of their coating drugs propel this process. More general factors such as medical need and industry incentivization also encourage this shift. Physicians' preference for DES over other percutaneous coronary interventions, the expanding global DES market, and streamlined development and approval prospects each motivate industry to continue investing in DES product development. The efforts of various stakeholders were also integral to overcoming practical obstacles, and contributions by 'Harmonization by Doing' and a premarket collaboration initiative between the USA and Japan were particularly effective. Today, USA/Japan regulatory cooperation is routine, and Japan is now integrated into global medical device development. MRCTs including Japanese subjects, sites, and investigators are now commonplace. PMID- 28883227 TI - Utilization of Anticoagulant and Antiplatelet Agents Among Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention - Retrospective Cohort Study Using a Nationwide Claims Database in Japan. AB - BACKGROUND: The European Society of Cardiology recommends a risk-based antithrombotic strategy for patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) based on CHA2DS2-VASc and HAS-BLED scores. However, because it is unclear if that strategy can be generalized to Asians, we aimed to describe antithrombotic therapies among Japanese patients.Methods and Results:Using a nationwide claims database in Japan, this retrospective cohort study identified AF patients who underwent PCI from April 1, 2014 to March 31, 2015. The primary outcome was utilization of anticoagulant and antiplatelet agents before PCI, at discharge, and 6, 9, and 12 months after PCI. The secondary outcome was incidence of stroke after PCI. We identified 10,862 patients and 87.5% of them had high CHA2DS2-VASc and HAS-BLED scores. There were no significant differences in antithrombotic therapies across the risk strata. More than 30% of patients at high risk of thrombosis did not receive oral anticoagulant prescriptions at discharge. The hazard ratio of incidence of stroke in patients with prior stroke compared with patients without prior stroke was 9.09 (95% confidence interval 7.86-10.50, P<0.01). CONCLUSIONS: Among Japanese AF patients who underwent PCI, prescriptions for antiplatelet agents were more common than those for anticoagulant agents. The majority of study participants were classified as high risk, suggesting a need for a new risk classification that reflects the risk profiles of Japanese patients. PMID- 28883228 TI - Paget-Schroetter Syndrome Resulting from Thoracic Outlet Syndrome and KAATSU Training. AB - A 29-year-old woman who worked as a KAATSU (a type of body exercise that involves blood flow restriction) instructor visited our emergency room with a chief complaint of swelling and left upper limb pain. Chest computed tomography (CT) showed non-uniform contrast images corresponding to the site from the left axillary vein to the left subclavian vein; vascular ultrasonography of the upper limb revealed a thrombotic obstruction at the same site, leading to a diagnosis of Paget-Schroetter syndrome (PSS). We herein report our experience with a case of PSS derived from thoracic outlet syndrome (TOS), in a patient who was a KAATSU instructor. PMID- 28883229 TI - Efficacy and Patient Satisfaction of the Weekly DPP-4 Inhibitors Trelagliptin and Omarigliptin in 80 Japanese Patients with Type 2 Diabetes. AB - Objective We investigated the efficacy, safety, and patient satisfaction of once weekly DPP-4 inhibitors (DPP-4Is). Methods Either of two once-weekly DPP-4Is, trelagliptin or omarigliptin, was administered alone or in combination with other antidiabetic drugs in 80 outpatients with type 2 diabetes mellitus for 3 months. The HbA1c, glycoalbumin (GA), body weight, and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) scores were evaluated. Results Patients switching from other daily DPP-4Is (n=29) showed no significant changes in the HbA1c or GA levels. However, the HbA1c and GA levels of patients who had been naive to DPP-4Is (n=37) significantly improved from 9.31+/-2.53% to 7.02+/-1.20% (p<0.001) and 26.7+/-11.8% to 17.3+/-5.7% (p<0.001), respectively. Several non serious adverse events were reported, including nausea (n=1), abdominal distension (n=1), and constipation (n=1). In the DTSQs, the total score for six questions on the primary factors representing patient treatment satisfaction was not markedly changed in patients switching from daily to weekly DPP-4Is but was significantly improved from 21.0 to 28.0 (p<0.001) in patients naive to DPP-4Is. Conclusion These findings suggest that the use of a once-weekly DPP-4I is effective and well-tolerated in diabetes treatment and improves treatment satisfaction. PMID- 28883230 TI - The Endovascular Management of an Iatrogenic Superior Gluteal Artery Rupture Following Bone Marrow Biopsy. AB - We herein report an uncommon case of a life-threatening retroperitoneal hematoma after a bone marrow biopsy. Two hours after iliac crest bone harvesting, the patient experienced syncope and severe hypotension. Urgent contrast-enhanced computed tomography demonstrated extravasation from the superior gluteal artery. Transcatheter coil embolization was performed successfully, without complications. Life-threatening complications caused by retroperitoneal bleeding after bone marrow biopsy are very rare. There are few reports on the use of endovascular treatment in the management of life-threatening hemorrhagic complications after bone marrow biopsy. PMID- 28883231 TI - The Assessment of the Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Patients with Glucocorticoid-induced Diabetes by Continuous Glucose Monitoring. AB - Objective The administration of glucocorticoids usually causes a mild increase in fasting glucose levels and a greater dose-dependent increase in postprandial values in patients without pre-existing diabetes mellitus. Patients with persistent hyperglycemia due to glucocorticoid therapy sometimes require insulin therapy, which might result in increased weight gain and more episodes of hypoglycemia, some of which are severe. On the other hand, scant evidence is available on the efficacy of oral hypoglycemic agents in treating glucocorticoid induced diabetes. In this study, we evaluated the efficacy of dipeptidyl peptidase (DPP)-4 inhibitors in patients with glucocorticoid-induced diabetes by continuous glucose monitoring (CGM). Methods We examined the glycemic profiles using CGM at baseline and 1-4 weeks after initiating DPP-4 inhibitor treatment in patients with newly developed glucocorticoid-induced diabetes. Results Eleven patients who had been diagnosed with kidney disease or other diseases with renal involvement were recruited for the present retrospective study. After starting DPP-4 inhibitors, the mean and standard deviation (SD) of the glucose level, and the mean amplitude of glycemic excursion (MAGE) were significantly improved in comparison to baseline. Furthermore, the area over the curve (AOC) for the glucose levels <70 mg/dL was not increased in comparison to baseline after the initiation of DPP-4 inhibitor treatment. The results indicate that the treatment of patients with glucocorticoid-induced diabetes using DPP-4 inhibitors can minimize the risk of hypoglycemia and reduce glucose variability. Conclusion DPP 4 inhibitors are potentially useful for blood glucose control in patients with glucocorticoid-induced diabetes. PMID- 28883233 TI - Aortic Valve Stenosis and Atheromatous Ascending Aorta. PMID- 28883232 TI - Severe Hypertriglyceridemia Possibly Masked Acute Pancreatitis and Led to a Difficult Diagnosis in an Obese Patient with Ketoacidosis-onset Type 2 Diabetes. AB - A young obese man with ketoacidosis-onset type 2 diabetes mellitus, associated with severe hypertriglyceridemia, was admitted to a local hospital complaining of abdominal pain. Although the abdominal pain worsened, his serum amylase level remained normal with persistent severe hypertriglyceridemia until the second day of hospitalization. The next day, computed tomography showed severe acute pancreatitis (AP) with serum amylase elevation, while the patient's triglyceride level decreased to 558 mg/dL. He was transferred to our hospital and recovered after intensive care. AP accompanied by diabetic ketoacidosis is not rare but an early diagnosis can be difficult to make due to normal amylase levels in the presence of severe hypertriglyceridemia. PMID- 28883234 TI - Crowned Dens Syndrome Associated with Bowel Cleaning for Colonoscopy. AB - A 77-year-old man was admitted with posterior cervical pain, lumbago, a low-grade fever, and anorexia after bowel cleaning with polyethylene glycol for colonoscopy. Computed tomography of the neck showed calcification of the transverse ligament of the atlas. He was diagnosed with crowned dens syndrome (CDS). His condition improved following treatment with corticosteroids. This represents a rare case of CDS after endoscopy with polypectomy. We should consider CDS in the differential diagnosis of patients with unexplained fever and posterior cervical pain after bowel preparation for colonoscopy. PMID- 28883235 TI - A Patient with Hepatocellular Carcinoma with Isolated Right Atrial Metastases. AB - Hepatocellular carcinoma (HCC) with isolated right atrial metastasis is extremely rare; most cases are considered inoperable. We herein report the case of a 74 year-old man with HCC with isolated right atrial metastases without hepatic vein invasion; the right atrial lesion was resected because of the risk of heart failure and sudden death. Postoperatively, he underwent transcatheter arterial chemoembolization and radiofrequency ablation for intrahepatic HCC. He recovered completely, with a long-term survival of 36 months. This is the first report of an HCC patient with isolated right atrial metastases without hepatic vein invasion. Tumorectomy for solitary atrial metastasis is effective for HCC patients. PMID- 28883236 TI - Amyand's Hernia Diagnosed by Computed Tomography. PMID- 28883237 TI - Chronic Intestinal Pseudo-obstruction and Orthostatic Hypotension Associated with Small Cell Lung Cancer that Improved with Tumor Reduction after Chemoradiotherapy. AB - Chronic intestinal pseudo-obstruction (CIPO) is a rare disease with symptoms of ileus without obstruction. Most cases of CIPO are idiopathic, and CIPO as a paraneoplastic neurological syndrome (PNS) associated with small cell lung cancer (SCLC) is rare. A 63-year-old man was diagnosed with functional ileus and confined to bed due to orthostatic hypotension. Chest computed tomography revealed a right hilar mass suspected of being lung cancer. Based on detailed examinations, he was diagnosed with limited-stage SCLC. His symptoms were confirmed as PNS because his serum anti-Hu antibody was positive. His PNS was improved with complete tumor reduction by chemoradiotherapy. PMID- 28883238 TI - Hemoptysis Is a Critical Sign of Aortobronchial Fistula. PMID- 28883239 TI - Superior Mesenteric Artery Syndrome May Be Overlooked in Women with Functional Dyspepsia. AB - Objective Superior mesenteric artery (SMA) syndrome is characterized by the compression of the third segment of the duodenum between the SMA and aorta, resulting in duodenal obstruction. Because the symptoms of the syndrome are similar to those of functional dyspepsia (FD), this study aimed to examine whether or not patients with SMA syndrome were present among those diagnosed with FD. Methods Patients with an FD diagnosis underwent measurement of the angle and distance between the SMA and aorta by ultrasonography or computed tomography. Patients with an angle of <=22 degrees or with a distance of <=8 mm between the SMA and aorta were diagnosed with SMA syndrome. Bacterial culture of the duodenal aspirate was also performed. Results Of the 46 FD patients, 5 (11%) met the criteria. All 5 were women with a body mass index significantly lower than the remaining 41 patients (18.7 vs. 24.0 kg/m2, p=0.003). In addition, all 5 patients had 105/mL or more bacteria in the duodenum. The symptoms of these five patients were treated through dietary and postprandial posture counselling with or without medication. Conclusion Patients with SMA syndrome were observed among underweight women diagnosed with FD. Their symptoms may be associated with bacterial overgrowth. PMID- 28883240 TI - Listeria Monocytogenes Septicemia and Meningitis Caused by Listeria Enteritis Complicating Ulcerative Colitis. AB - An 80-year-old man, who had been diagnosed with ulcerative colitis, was admitted due to a fever and bloody diarrhea and was treated with a glucocorticoid and azathioprine. After 5 days, he developed an impaired consciousness, headache, and neck stiffness. A sample of the colonic mucosa, blood cultures, and cerebrospinal fluid revealed Listeria monocytogenes infection. Intravenous ampicillin improved the symptoms of fever, bloody diarrhea, and headache without any neurological sequelae. Physicians should consider that Listeria enteritis complicating ulcerative colitis can cause septicemia and meningitis in immunosuppressed patients. A patient's central nervous system can avoid the effects of Listeria meningitis by an early diagnosis and appropriate treatment. PMID- 28883241 TI - Ketoacidosis due to a Low-carbohydrate Diet in an Elderly Woman with Dementia and Abnormal Eating Behavior. AB - Strict restriction of carbohydrates can induce symptomatic ketoacidosis. We herein report a 76-year-old demented woman who developed ketoacidosis after 1 month of abnormal eating behavior involving selectively eating hamburger steak (estimated carbohydrate =12.7 g/day). Laboratory tests showed high-anion-gap metabolic acidosis with elevated blood ketone levels. She was successfully treated with intravenous fluids followed by oral intake of a regular diet. She remained relapse-free after correcting her eating habits. Healthcare providers should know that abnormal eating behavior in demented people can lead to an extremely-low-carbohydrate diet and cause atypical ketoacidosis unexplained by diabetes, heavy alcohol intake, or starvation conditions. PMID- 28883242 TI - Cardiac Tamponade Provoked by a Subphrenic Abscess. PMID- 28883243 TI - An HIV-positive Case of Obstructive Jaundice Caused by Immune Reconstitution Inflammatory Syndrome of Tuberculous Lymphadenitis Successfully Treated with Corticosteroids. AB - A 60-year-old man was admitted to our hospital because of a persistent fever with enlargement of multiple lymph nodes in the mediastinum and around the pancreatic head. He was diagnosed with tuberculosis and human immunodeficiency virus infection. We started antiretroviral therapy three weeks after the initiation of anti-tuberculous therapy. Two weeks later, jaundice appeared with dilatation of the biliary tract due to further enlargement of the lymph nodes, which seemed to be immune reconstitution inflammatory syndrome (IRIS). The administration of corticosteroids resolved the obstructive jaundice without surgical treatment or endoscopic drainage. Obstructive jaundice caused by IRIS should first be treated with corticosteroids before invasive treatment. PMID- 28883244 TI - The Association between Tobacco Smoke and Serum Immunoglobulin E Levels in Korean Adults. AB - Objective Smoking is common in patients with allergic diseases. The aim of this study was to evaluate the cross-sectional association between the current smoking status and total and specific Immunoglobulin E (IgE) levels in Korean adults. Methods Data were obtained from the 2010 Korean National Health and Nutrition Examination Survey, a national cross-sectional study. We analyzed the data of subjects whose smoking status and serum IgE levels were of acceptable quality. Results A total of 1,963 subjects (1,118 never smokers, 340 ex-smokers, and 505 current smokers) were included. The total IgE levels and specific IgE levels to house dust mite Dermatophagoides farinae (Df), cockroach, and dog allergens in never smokers were significantly (p<0.0001) lower than in ex-smokers or current smokers. After adjusting for other variables, current smokers independently had significantly higher levels of total IgE and cockroach-specific IgE than ex smokers or never smokers. The proportions of subjects with total IgE >=150 kU/L and specific IgE >=0.35 kU/L to Df-specific IgE were significantly (p value for trend <0.05) increased in ex-smokers and current smokers. The total IgE levels and IgE levels specific to Df, cockroaches, and dogs significantly (p value for trend <0.05) and proportionally increased with increasing numbers of cigarettes smoked daily. Conclusion Smoking was associated with elevated total IgE levels and IgE levels specific to Df, cockroach, and dog allergens in a cumulative, dose dependent manner. Furthermore, current smoking status was an independent risk factor for elevated total IgE levels and IgE levels specific to cockroach allergen. PMID- 28883245 TI - The Sequential Development of Antiglomerular Basement Membrane Nephritis and Myeloperoxidase-antineutrophil Cytoplasmic Antibody-associated Vasculitis. AB - A 55-year-old woman presented with deafness, increased levels of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA), and renal insufficiency with proteinuria and hematuria. Renal biopsy revealed crescentic glomerulonephritis with the linear deposition of immunoglobulin G along the glomerular basement membrane (GBM) and peritubular capillaritis. The anti-GBM antibody levels on admission and 10 days after admission were 11.7 U/mL and 127 U/mL, respectively. These results indicated the sequential development of anti-GBM nephritis and MPO ANCA-associated vasculitis. This report shows that anti-GBM nephritis may be caused by MPO-ANCA-associated vasculitis because of preceding otitis media, the sequential anti-GBM antibody titers, and the findings of peritubular capillaritis. PMID- 28883246 TI - Dacryoadenitis with Ptosis and Diplopia as the Initial Presentation of Granulomatosis with Polyangiitis. AB - A 77-year-old Japanese woman presented to an ophthalmologist with an erythematous swollen upper eyelid and diplopia which was initially diagnosed to be idiopathic dacryoadenitis on the basis of a histological evaluation of an orbital mass that was in remission following a 3.5-month period of systemic corticosteroid therapy. She subsequently developed respiratory symptoms, and was finally diagnosed with systemic granulomatosis with polyangiitis (GPA) based on the clinical and histological features. She was successfully treated with corticosteroids and azathioprine. Dacryoadenitis in the form of an orbital inflammatory pseudotumor may be an initial presenting feature of GPA, sometimes as the limited phenotype, and occasionally progressing to systemic disease. PMID- 28883247 TI - Hepatic and Gastric Involvement in a Case of Systemic Sarcoidosis Presenting with Rupture of Esophageal Varices. AB - A 46-year-old woman presented with massive hematemesis, caused by the rupture of esophageal varices. The laboratory investigations showed pancytopenia, and imaging tests revealed hepatosplenomegaly and ascites. A diagnosis of systemic sarcoidosis was made based on biopsies of the liver, stomach, lungs, heart, and skin. Although fat deposition was predominant, non-caseating granuloma and cirrhotic changes were found in the liver. Non-caseating granuloma was also identified in a biopsy specimen from minute depressions of the gastric folds. This case illustrates the rare involvement of the digestive system in a case of systemic sarcoidosis. PMID- 28883248 TI - The Development of Yellow Nail Syndrome after the Implantation of a Permanent Cardiac Pacemaker. AB - Yellow nail syndrome (YNS) is characterized by yellowish nails, lymphedema, sinusitis, and pulmonary involvement and can be triggered by various underlying conditions, such as sinusitis or titanium exposure from an artificial joint or dental implant. Since YNS is potentially treatable, its timely diagnosis is important. The authors recently experienced a case of YNS in a patient who developed sinusitis, yellowish nails, bilateral edema of the extremities, and subclinical rheumatoid arthritis after the implantation of a cardiac pacemaker made from titanium. This case may be the first report of YNS induced by a titanium cardiac pacemaker. PMID- 28883249 TI - Pneumonitis with Diffuse Alveolar Hemorrhage Induced by Sho-seiryu-to. AB - A 78-year-old man presented with acute-onset fever and dyspnea. He had been taking Sho-seiryu-to for allergic rhinitis. A chest radiograph showed diffuse bilateral ground-glass opacities with subpleural sparing, crazy-paving pattern, and traction bronchiectasis. The patient's bronchoalveolar lavage fluid was bloody and transbronchial lung biopsy specimens showed alveolitis, organizing pneumonia, and type 2 alveolar epithelial cell proliferation. There were no clinical and laboratory findings suggestive of respiratory tract infection or connective tissue disease. Based on the clinical course and the exclusion of other etiologies, Sho-seiryu-to-induced pneumonitis with diffuse alveolar hemorrhage was considered. The patient's pneumonitis resolved after the discontinuation of the drug and the administration of systemic corticosteroid therapy. PMID- 28883250 TI - Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) due to a m.10158T>C ND3 Mutation with a Normal Muscle Biopsy. PMID- 28883251 TI - Ossification of the Posterior Atlantoaxial Membrane: An Atypical Presentation. PMID- 28883252 TI - Switching Therapy from Intravenous Landiolol to Transdermal Bisoprolol in a Patient with Thyroid Storm Complicated by Decompensated Heart Failure and Gastrointestinal Dysfunction. AB - Thyroid storm is a life-threatening disorder that remains a therapeutic challenge. Although beta-blockers are the mainstay for treatment, their use can be challenging in cases complicated by rapid atrial fibrillation and decompensated heart failure. We present a case of thyroid storm-associated atrial fibrillation and decompensated heart failure complicated by gastrointestinal dysfunction secondary to diffuse peritonitis that was successfully managed by a switching therapy, in which the continuous intravenous administration of landiolol was changed to bisoprolol via transdermal patch, in the acute phase treatment. This switching therapy may offer a promising therapeutic option for this potentially lethal disorder. PMID- 28883253 TI - Interstitial Lung Disease as an Initial Manifestation of Giant Cell Arteritis. AB - Interstitial lung disease (ILD) has rarely been reported as a manifestation of giant cell arteritis (GCA). We herein report a unique case of GCA in a 76-year old woman who presented with ILD as an initial manifestation of GCA. Ten years before admission, she had been diagnosed with granulomatous ILD of unknown etiology. Corticosteroid therapy induced remission. One year after the cessation of corticosteroid therapy, she was admitted with a persistent fever. After admission, she developed left oculomotor paralysis. Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) proved extremely useful in establishing the diagnosis. Our case promotes awareness of GCA as a possible diagnosis for granulomatous ILD with unknown etiology. PMID- 28883255 TI - Critical Leg Ischemia Following Abdominal Aortic Aneurysm Occlusion. PMID- 28883254 TI - Naratriptan in the Prophylactic Treatment of Cluster Headache. AB - Objective Naratriptan has been reported to reduce the frequency of cluster headache. The purpose of this study was to determine whether naratriptan is effective as a prophylactic treatment for cluster headache in Japan. Methods We retrospectively reviewed all 43 patients with cluster headache who received preventive treatment with naratriptan from April 2009 to April 2015. The International Classification of Headache Disorders, 3rd Edition (beta version) (ICHD-3 beta) was used to diagnose cluster headache. This study was conducted at 3 centers (Department of Neurology, Saitama Medical University; Saitama Neuropsychiatric Institute; Saitama Medical University International Medical Center). Patients were recruited from these specialized headache outpatient centers. Naratriptan was taken before the patient went to bed. Results The study population included 30 men (69.8%) and 13 women (30.2%). Twenty-two cases received other preventive treatments (51.2%), while 21 cases only received naratriptan (48.8%). Among the 43 cases, 37 patients (86.0%) achieved an improvement of cluster headache on naratriptan. Conclusion Naratriptan has been suggested as a preventive medicine for cluster headache because of the longer the biological half-life in comparison to other triptans. The internal use of naratriptan 2 hours before attacks appears to achieve a good response in patients with cluster headache. PMID- 28883256 TI - Atrial Involvement in Pleomorphic Carcinoma of the Lung. PMID- 28883257 TI - Buried Bumper Syndrome Leading to Peritonitis and Ileus. PMID- 28883258 TI - Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) due to a m.10158T>C ND3 Mutation with a Normal Muscle Biopsy. PMID- 28883259 TI - Naratriptan May Become an Alternative Prophylactic Option for Patients with Cluster Headache. PMID- 28883260 TI - A case of metastatic follicular thyroid carcinoma complicated with Graves' disease after total thyroidectomy. AB - Thyroid cancer and Graves' disease may present simultaneously in one patient. The incidence of the development of hyperthyroidism from metastatic differentiated thyroid carcinoma is rare. We herein report a case of metastatic follicular carcinoma complicated with Graves' disease after total thyroidectomy. A 57-year old woman underwent right hemithyroidectomy for follicular carcinoma. Metastatic lesions appeared in the lungs and skull two years after the first surgery, and remnant thyroidectomy was performed for radioactive iodine-131 (RAI) therapy, during which the TSH receptor antibody (TRAb) was found to be negative. The patient was treated with RAI therapy four times for four years and was receiving levothyroxine suppressive therapy. Although radioiodine uptake was observed in the lesions after the fourth course of RAI therapy, metastatic lesions had progressed. Four years after the second surgery, she had heart palpitations and tremors. Laboratory data revealed hyperthyroidism and positive TRAb. She was diagnosed with Graves' disease and received a fifth course of RAI therapy. 131I scintigraphy after RAI therapy showed strong radioiodine uptake in the metastatic lesions. As a result, the sizes and numbers of metastatic lesions decreased, and thyroid function improved. Metastatic lesions produced thyroid hormone and caused hyperthyroidism. RAI therapy was effective for Graves' disease and thyroid carcinoma. PMID- 28883261 TI - Fine-needle aspiration cytology for medullary thyroid carcinoma: a single institutional experience in Japan. AB - Many cytological studies on medullary thyroid carcinoma (MTC) have been reported; however, such studies in large series of patients with MTC have not been performed. We investigated MTC at a single institution in Japan using fine-needle aspiration cytology (FNAC), and aimed to establish a preoperative diagnostic algorithm for MTC. FNAC was performed in 119 of 149 patients with MTC (79.9%) who ultimately underwent surgical resection. Moreover, 22 of 56 hereditary MTC (39.3%) were diagnosed preoperatively without FNAC by their high serum calcitonin levels or increased response to calcium stimulation (11 cases each), as well as RET mutation analysis. On FNAC, 76.5% of nodules were categorized as 'malignancy' or 'suspicious for malignancy'. The sensitivity and specificity of calcitonin measurement in aspiration needle wash-out fluid and in immunocytochemical staining for calcitonin were 96.3% and 92.3% respectively. We proposed an algorithm for preoperative diagnosis of MTC utilizing FNAC: When thyroid nodules are highly suspicious for MTC by their clinical and ultrasonographic features, serum calcitonin measurement with or without a calcium stimulation test is required. Furthermore, FNAC should be performed for patients who do not have those findings. When there is a possibility of MTC at the time of FNAC, calcitonin measurement using needle wash-out fluid is a reliable diagnostic tool. When MTC is suspected on cytological examination, immunocytochemical staining for calcitonin is useful for confirming MTC diagnosis. PMID- 28883262 TI - Retraction: Transcription Factor SOX9 Promotes Osteosarcoma Cell Growth by Repressing Claudin-8 Expression. AB - We reported "Transcription Factor SOX9 Promotes Osteosarcoma Cell Growth by Repressing Claudin-8 Expression" in Tohoku J. Exp. Med., 2017, 241 (1), 55-63; doi: 10.1620/tjem.241.55. After publication of the paper, we have become aware of the ethical violation in collecting the samples from some patients. We therefore wish to retract the paper and apologize for any inconvenience caused by the retraction. PMID- 28883263 TI - Combination therapy with monoclonal antibodies for treatment of newly diagnosed multiple myeloma. AB - Monoclonal antibodies (mAbs) with new mechanisms of action are emerging as promising agents for patients with multiple myeloma (MM). Of these, anti-CD38 antibodies and anti-signaling lymphocytic activation molecule F7 (SLAMF7) antibody have demonstrated efficacy for relapsed and refractory myeloma (RRMM). Two CD38-targeting antibodies, daratumumab and isatuximab had significant activity as single agents, whereas the SLAMF7-targeting antibody, elotuzumab, did not. Patients with RRMM treated with 16 mg/kg daratumumab achieved at least PR of 36% and 29% in two distinct phase 2 studies. More favorable results of phase 3 study of 16 mg/kg daratumumab with lenalidomide and dexamethasone revealed that 92.9% of patients with RRMM achieved at least partial response (PR), with a 43.1% complete response (CR) rate. The median PFS was better in daratumumab arm (Not Reached) than control arm (18.4 months). When combined with lenalidomide plus dexamethasone, elotuzumab, at a dose of 10 mg/kg, improved the median PFS from 14.9 months to 19.4 months in a phase 3 study named ELOQUENT-2. In addition to IMiDs, bortezomib was a hopeful partner. Regarding toxicity, these mAbs are tolerable even in elderly patients. The most common adverse event is an infusion related reaction. Based on several published reports, we suggest that mAbs combined with standard agents could be successfully adapted for the treatment of newly diagnosed patients with MM. PMID- 28883264 TI - Treatment algorithms for multiple myeloma in Japan. AB - Recent progress in the development of novel therapeutic agents has remarkably improved the treatment outcome for multiple myeloma (MM). Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib; immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide; the histone deacetylase (HDAC) inhibitor panobinostat; and the monoclonal antibody, elotuzumab, have all been approved in Japan, although only bortezomib and lenalidomide have been approved for initial therapy. Accordingly, the Japanese Society of Hematology has released updated treatment guidelines for MM. Initial treatments with bortezomib based 2-3 drug regimens and lenalidomide+dexamethasone are recommended for patients eligible for autologous stem cell transplantation (ASCT), while bortezomib+melphalan+prednisolone and lenalidomide+dexamethasone are recommended for patients who are not eligible for ASCT. These novel agents provide us with wider therapeutic options for relapsed or refractory patients. Consequently, treatment paradigms for MM continue to rapidly evolve, and it is important to select the optimal treatment strategy for each patient. PMID- 28883265 TI - Acute lymphoblastic leukemia in adolescents and young adults: from the viewpoint of pediatricians. AB - Patients with acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) generation are treated by both pediatricians and adult hematologists. Because their participation rate in clinical trials has been low, the treatment results have been unsatisfactory. However, with a recent widespread adaptation of pediatric-based regimen in adult ALL trials, their prognosis has dramatically improved. Moreover, their characteristic biology is being rapidly elucidated. For further improvement of AYA-ALL prognosis and quality of life, the collaboration between pediatricians and adult hematologists is essential and multidisciplinary approach is necessary. PMID- 28883266 TI - Acute lymphoblastic leukemia of adolescents and young adults: from the viewpoint of physicians. AB - Fusion genes found in cases of acute lymphoblastic leukemia (ALL) are reported to be associated with age, such as MLL rearrangements in neonates and BCR-ABL1 in adults. However, the pathogenesis of ALL in adolescents and young adults (AYA) remains largely unknown. To investigate the potential role of fusion genes, we performed RNA-sequencing on 73 BCR-ABL1-negative ALL patients who were all AYA. Interestingly, DUX4-IGH was the most frequent fusion gene detected in B-ALL (18.5%) and was preferentially detected in the AYA generation. ZNF384 and MEF2D genes were also recurrently identified as functionally relevant fusion genes in 16.7% and 9.3% of AYA with B-ALL, respectively. Patients with DUX4 and ZNF384 fusion genes displayed better prognosis, while those with the MEF2D fusion gene displayed a worse outcome. To improve treatment outcome, the fusion genes detected in this study will be useful for risk stratification and target therapy. PMID- 28883267 TI - Acute myeloid leukemia in adolescents and young adults: from the viewpoint of pediatricians. AB - It is well known that adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) should be treated based on pediatric ALL protocol, which could yield better survival rates. However, an optimal treatment strategy for AYAs with acute myeloid leukemia (AML) is not yet established and corresponding data are limited. Compared with ALL, clinical and biological characteristics of pediatric and adult AML are relatively similar. Moreover, treatment strategy is quite similar, although pediatric protocols are more intensive and transplant indications are narrower. Previous reports show that AYAs with AML have similar to relatively lower survival rates and higher treatment-related mortality than children with AML. These results indicated that intensive pediatric chemotherapy is effective for preventing AML relapse in AYAs but higher toxicity rates compensates overall survival. To improve the outcomes of AYAs with AML, it is essential to develop optimal intensive chemotherapy, introduce novel targeted therapies, and adopt better risk stratification, particularly to determine appropriate transplant indications. These strategies should be accomplished by close cooperation between pediatric hematologists/oncologists and adult hematologists. PMID- 28883268 TI - Acute myeloid leukemia in adolescents and young adults: from the viewpoint of physicians. AB - Based on various studies, the survival of adolescent and young adults (AYAs) with acute myeloid leukemia (AML) was reportedly similar to or worse than younger children. AYAs with AML treated in adult institutions are usually offered the same treatment as that of the older adults. Although pediatric protocols generally include intensified regimens compared with adult protocols, it is still controversial whether an intensified pediatric AML regimen results in an improved survival for the AYA population. Somatic mutations have proven to be significantly prognostic in AML. Although such molecular markers are becoming increasingly important as a means of risk stratification for both children and adults with AML, the prevalence and significance of somatic mutations remain largely unknown in AYAs with AML. In addition to the biological characteristics of cancer, non-biological factors, such as compliance with treatment, may influence the treatment outcomes of AYAs. AYAs have specific and unique needs that are different from children and older adults such as psychosocial care, transition from the pediatric to adult care environment, and fertility considerations among long-term survivors. A further multidisciplinary approach for AYAs with AML is still an issue among adult institutes. PMID- 28883269 TI - Malignant lymphoma of adolescents and young adults: from the viewpoint of pediatricians. AB - Since adolescents and young adults (AYAs) with lymphoma began to be treated by pediatric hematologists and hematology physicians, few data have been collected regarding lymphoma in this generation of patients in Japan. We analyzed the number of pediatric hospitals that have treated hematological AYA patients. In half of the pediatric facilities, patients >15 years of age had been treated, and 40% of those facilities treated >1 AYA every year. A past lymphoma study by the Japanese Pediatric Leukemia/Lymphoma Study Group included some AYA patients. However, only the B-NHL03 study analyzed the difference between children and AYAs. In that study, 25 AYAs (7.8%) were treated among all 321 study patients. The 5-year overall survival rates of patients aged <10, 10-14, >14 years, were 88.7%, 87.0%, and 79.3%, respectively. However, this difference was not statistically significant because of the less number of patients. We analyzed data of stem cell transplantation in patients with non-Hodgkin lymphoma (NHL). Of the allogeneic transplant patients, children and AYAs did not significantly differ in treatment results. However, the 5-year transplant-related mortality after autologous transplantation was significantly higher in children than in AYAs. In NHL patients, the survival rate of AYAs after transplantation was not inferior to that of children. PMID- 28883270 TI - Malignant lymphoma in adolescents and young adults: from the viewpoint of physicians. AB - Malignant lymphoma (ML) is one of the most common malignancies among adolescents and young adults (AYA), accounting for approximately 20% of newly diagnosed cancers in this group. Although Hodgkin lymphoma represents only approximately 4% 5% of all cancers in children younger than 15 years of age, its incidence increases to approximately 16% in AYA. In non-Hodgkin lymphoma, the common malignancies affecting AYA include diffuse large B-cell lymphoma, Burkitt lymphoma, and anaplastic large cell lymphoma. Although it is generally accepted that AYA with ML experience outcomes that are worse than those experienced by children with ML, there are several critical issues. Hemato-oncologists and pediatric oncologists often follow diverse treatment strategies for ML, and it is unclear as to which treatment strategy is more suitable for AYA. Considering other aspects, tumor biology may explain the different outcomes. In Japan, there are no detailed data regarding the incidence, biology, treatment, prognosis, and long-term outcomes of ML in AYA. In future clinical trials, it will be important to determine whether the different outcomes result from the differences between the therapeutic approaches in pediatric and adult regimens or they are attributable to other factors such as variation in tumor biology and aging. PMID- 28883271 TI - Picture in Clinical Hematology No. 106. PMID- 28883272 TI - Peripheral T-cell lymphoma, not otherwise specified: a retrospective single center analysis. AB - We retrospectively analyzed clinical and pathological features, treatments, and prognoses in 28 patients with newly diagnosed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in Niigata University Medical and Dental Hospital. Of them, 16 were males and 12 were females, and their median age was 62.5 (range, 26-88) years. The International Prognostic Index was high-intermediate/high in 68% of patients. Twelve patients were treated with CHOP/THP-COP and nine with third-generation chemotherapy regimens. At a median follow-up period of 30 (range: 1-164) months, the 2-year overall survival and progression-free survival rates were 61% and 44%, respectively. Further investigation of novel agents for treating PTCL-NOS is warranted. PMID- 28883273 TI - Regression of uterine cervical diffuse large B-cell lymphoma transformed from mucosa-associated lymphoid tissue lymphoma subsequent to Chlamydia trachomatis eradication. AB - A 37-year-old-woman was referred to our center after her uterine cervix health screening presented abnormal findings. We performed a biopsy of the uterine cervix to examine for cervical dysplasia, and diagnosed a diffuse large B-cell lymphoma transformed from mucosa-associated lymphoid tissue (MALT) lymphoma of the cervix. The patient presented with concurrent chlamydial cervicitis and received eradication therapy for Chlamydia trachomatis. Four months later, the CD20 positive abnormal lymphocyte disappeared and complete remission was achieved. MALT lymphoma is considered to correlate with infection and inflammation. Particularly, the relationship between gastric MALT lymphoma and Helicobacter pylori is well known. MALT lymphoma of the uterine cervix is rare, and its relationship with C.trachomatis infection is unknown. Further studies are warranted to investigate this association. PMID- 28883274 TI - Successful long-term management with low-dose prednisolone in an adult patient with Diamond-Blackfan anemia. AB - Diamond-Blackfan anemia (DBA) is a rare congenital disease caused by mutations in ribosomal protein genes and is characterized by pure red cell aplasia. While the prognosis is relatively favorable, quality of life (QOL) among DBA patients is negatively impacted by the adverse effects of long-term prednisolone (PSL) therapy and blood transfusions. We describe a 43-year-old man who was diagnosed with DBA (Hb of 2.18 g/dl) at the age of two months. He was initially treated with PSL and blood transfusions, followed by cyclosporine and low-dose (6 mg/day) PSL, which resulted in a sustained hemoglobin level of 9 g/dl without severe adverse events or loss of QOL. High levels of eADA and GSH as well as a RPS19 gene mutation were confirmed. The only curative therapy is hematopoietic stem cell transplantation, which is associated with significant mortality. However, using low-dose PSL to maintain a stable hemoglobin level may improve QOL for patients who receive curative treatment. PMID- 28883275 TI - Successful management of intraperitoneal bleeding with platelet apheresis and von Willebrand factor supplementation in a patient with essential thrombocythemia and acquired von Willebrand syndrome. AB - A 36-year-old woman with essential thrombocythemia (ET) was admitted to our hospital for acute lower abdominal pain. Given no family history of bleeding disorder, she was diagnosed with acquired von Willebrand syndrome. Despite having a medical history of venous thrombosis, she had never been treated for ET because of her preferences. On admission, CT scan revealed massive hemorrhage in the ascending colon with the leakage of a contrast agent. Furthermore, a delayed enhancement of fluid collection in the Douglas fossa followingcontrast CT indicated bloody ascites. Laboratory data revealed elevated platelets (1,569*103/ul) and reduced von Willebrand factor (VWF) :RCo (32%) and VWF:Ag (48%). Platelet apheresis was initiated, combined with the infusion of VWF containing concentrates and cytoreductive therapy with hydroxyurea. Three days after admission, her platelet count decreased to 992*103/ul after the second round of platelet apheresis. CT scan revealed no hemorrhage, which implied hemostasis. Because of the absence of symptoms, she was discharged 23 days after admission. These results suggest that platelet apheresis, combined with infusion of VWF-containing concentrates and cytoreductive therapy with hydroxyurea, is an effective approach for the treatment of acquired von Willebrand syndrome characterized by emergent bleeding concomitant with ET. PMID- 28883276 TI - Acute exacerbation of organizing pneumonia leading to sudden death in a patient with sarcoidosis-lymphoma syndrome. AB - The subject was an 83-year-old female; she had a history of Propionibacterium acnes-related sarcoidosis at the age of 79 years. At diagnosis, she was treated with clarithromycin and achieved remission. Four years later, during a routine physical check-up, she presented with pulmonary opacities and swelling of multiple lymph nodes. A definitive diagnosis of lymphoma could not be made by inguinal lymph node biopsy. The patient's general condition was good, and we observed her clinical course. Oh the 56th day of her illness, she died suddenly. Autopsy revealed diffuse large B-cell lymphoma (DLBCL). Sarcoidosis-lymphoma syndrome (SLS) was diagnosed after sampling hyalinized nodules from both lungs. The cause of death was organizing pneumonia around an epithelioid granuloma and cor pulmonale. Organization markedly increased around the DLBCL. These findings might be associated with cor pulmonale. Although SLS often appears during chronic active sarcoidosis, sudden death is rare and there are few reports on SLS in Japan. We report this case along with a review of the literature. PMID- 28883277 TI - Siblings with congenital thrombotic thrombocytopenic purpura. AB - Congenital thrombotic thrombocytopenic purpura (TTP) is a rare hereditary deficiency of ADAMTS13 (von Willebrand factor-cleaving protease) characterized by thrombocytopenia and microangiopathic hemolytic anemia. The spectrum of the clinical phenotype is wide, ranging from asymptomatic episodes of thrombocytopenia to life-threatening multiorgan failure. Reportedly, some patients develop isolated thrombocytopenia during childhood. We herein report sibling cases of congenital TTP. An 11-year-old boy with thrombocytopenia accompanied by influenza virus infection was referred to our hospital. He had a history of severe neonatal jaundice. His 15-year-old brother also had recurrent thrombocytopenia with approximately 10 episodes of recurrence since 3 years of age. Their ADAMTS13 activities were low and ADAMTS13 inhibitors were negative, and a gene analysis confirmed the diagnosis of congenital TTP. Notably, congenital TTP should be included in the differential diagnosis, and it is essential to determine the ADAMTS13 activity for pediatric patients with thrombocytopenia of unknown etiology. PMID- 28883278 TI - Loss of CD45 expression at relapse of acute myeloid leukemia. AB - A 49-year-old female was initially diagnosed with acute myeloid leukemia (AML) M4 with a CD45+CD13+CD33+CD34-HLA-DR+ immunophenotype. She underwent allogeneic bone marrow transplantation, but the disease recurred. The bone marrow was infiltrated with 87.0% blasts negative for myeloperoxidase (MPO) staining. Immunophenotyping by flow cytometry identified the presence of a CD45-negative blast population. These blasts exhibited a CD13+CD33+CD19-CD10-CD34-HLA-DR- immunophenotype. The lack of CD45 expression is often observed in B-cell acute lymphoblastic leukemia, whereas CD45-negative AML is extremely rare; only one older male with AML-M0 has been reported. In the present case, the CD45-negative blasts had an MPO CD13+CD33+ phenotype, which is similar to AML-M0. PMID- 28883279 TI - Functional analysis of Protection of Telomeres 1a (Pot1a) in regulation of hematopoietic stem cell aging. AB - Repeated cell divisions induce DNA damage accumulation, which impairs stem cell function during aging. However, the general molecular mechanisms by which this occurs remain unclear. Herein, we show that the expression of protection of telomeres 1a (Pot1a), a component of shelterin, is crucial for prevention of telomeric DNA damage response (DDR) and maintenance of hematopoietic stem cell (HSC) activity during aging. We observed that HSCs express high levels of Pot1a during development, and this expression declines with aging. Knockdown of Pot1a induced an age-related phenotype, characterized by increased telomeric DDR and reduced long-term reconstitution activity. In contrast, treatment with exogenous Pot1a protein prevented telomeric DDR, which decreased stem cell activity and partially rejuvenated HSC activity. These results highlight a general, reversible mechanism by which aging compromises mammalian stem cell activity, with widespread implications for regenerative medicine. PMID- 28883280 TI - Susceptibility to 6-mercaptopurine toxicity related with NUDT15 and ABCC4 variants in Japanese childhood acute lymphoblastic leukemia. AB - 6-Mercaptopurine (6-MP) is one of the main components for the treatment of childhood acute lymphoblastic leukemia (ALL). However, many patients require a dose reduction of 6-MP due to its severe toxicities. NUDT15 variants are one of the factors that cause 6-MP intolerability in Asians. In each patient with heterozygous variants of NUDT15, 6-MP intolerability differs. Therefore, we hypothesized that the combination of NUDT15 genotype with ABCC4 genotype, which is associated with 6-MP efflux, might enable to accurately predict 6-MP intolerability. We analyzed the association between 6-MP-related events and the genotypes of NUDT15 and ABCC4. All patients with both NUDT15 rs116855232 heterozygous variants and ABCC4 rs3765534 variants suffered from severe leukopenia and required 6-MP dose reduction to less than 35 mg/m2/day. In conclusion, genotyping NUDT15 and ABCC4 facilitates the prediction of 6-MP intolerability. The results of this study will improve personalized medicines in Japanese patients with childhood ALL. PMID- 28883281 TI - Novel mechanism of immune evasion in cancer via structural variations of the PD L1 gene. AB - Cancer cells are thought to circumvent immune surveillance through PD-1/PD-L1 signaling. However, the genetic basis for PD-L1-PD-L1-mediated immune escape has not been completely understood, with the exception of elevated PD-L1 expression by gene amplification and the utilization of an ectopic promoter by translocation. Recently, we demonstrated a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' part of the PD-L1 gene. These SVs invariably cause a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR), and thereby widely affect multiple common cancer types, including adult T cell leukemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and adenocarcinoma of the stomach (2%). All SVs invariably result in a prominent increase of aberrant PD-L1 transcripts commonly lacking an intact 3'-UTR, which most typically generate gene fusions with ectopic sequences including integrated viral genomes. In this review, the critical role of 3'-UTR disruption is briefly summarized. PMID- 28883282 TI - Development of immune checkpoint inhibitors. AB - Immune checkpoint inhibitors are the most striking innovation in the clinical development of immunotherapy. Monoclonal antibodies (mAbs) restore and augment the antitumor immune activities of cytotoxic T cells by mainly blocking immune checkpoint molecules on T cells or their ligands on antigen-presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies of mAb in various cancers. The A first in-class approved immune checkpoint inhibitor is ipilimumab, which is a fully humanized mAb that blocks the immunosuppressive signal by cytotoxic T-lymphocyte antigen 4. In 2011, the US Food and Drug Administration approved the use of ipilimumab for the treatment of advanced metastatic melanoma. Then, nivolumab, which is a humanized mAb that blocks programmed death-1 (PD-1), was approved for use in the treatment of advanced melanoma in 2014 and of advanced non-small-cell lung carcinoma (NSCLC) in 2015 in Japan. Pembrolizumab, which is another anti-PD 1 antibody, was approved for use in the treatment of advanced melanoma and advanced NSCLC as the first-line therapy in 2016 in Japan. Thereafter, nivolumab was also approved for use in the treatment of advanced renal cell cancer in August 2016, of Hodgkin's lymphoma in December 2016, and of head and neck cancer in March 2017 in Japan. Moreover, phase III trials of anti-PD-1 mAb and anti-PD ligand 1 mAb for use in the treatment of cancers, such as gastric, ovarian, bladder, and esophageal cancers, are ongoing. Several clinical trials have investigated new agents, alone and in combination, for use in the treatment of various cancers. Current advances in tumor immunology have unveiled the importance of immunosuppressive cells, such as regulatory T cells, myeloid derived suppressor cells, and tumor-associated macrophages, especially in a tumor microenvironment (TME). Some data from basic research in mouse models and the immunomonitoring of cancer patients suggest that the inhibition of immunosuppressive cells and the cytokines related to them activate and infiltrate cytotoxic T cells and in TME, which could be one of the next combination strategies. The current clinical development of, translational research on, and future challenges in utilizing immune checkpoint inhibitors are described. PMID- 28883284 TI - Pediatric acute myeloid leukemia with genetic alterations. AB - Annually, it is estimated that approximately 150-200 children aged 0-16 years are diagnosed with acute myeloid leukemia (AML). In Japan, clinical studies with ANLL91, AML99, CCLSG-AML9805, and JPLSG-AML05 protocols were performed historically, and the risk stratification with a combination of chemotherapy and hematopoietic stem cell transplantation resulted in the improvement of clinical outcomes. Regarding the onset of pediatric AML at the molecular level, mutations in FLT3-ITD or KIT (Class I mutation) showed a poor prognosis, but the ratio of mutations in Class III-V genes was smaller than that in adult AML. In contrast, several pediatric AML cases are complicated due to chromosome fragility syndrome or congenital bone marrow failure syndrome. To improve the clinical outcomes, clinical application of next generation sequencing may allow for personalized therapy in each patient in the future. PMID- 28883283 TI - Oncolytic coxsackievirus therapy as an immunostimulator. AB - Recently, the active development of oncolytic virotherapy has gathered attention. Enterovirus research seeks to better understand its pathogenicity. In particular, coxsackievirus A21 (CVA21) is a promising candidate for oncolytic virotherapy, and thus is the focus of many clinical trials. We have reported that coxsackievirus B3 (CVB3) had potent oncolytic activity for cancer, and induced immunogenic cell death of CVB3-infected cells. We then genetically engineered wild type CVB3 and successfully produced a novel recombinant CVB3-miRT, improving its safety by the introducing an organ-specific miRNA target sequence. We also developed the production method of CVB3 agent, and are conducting a clinical trial of CVB3 therapy for cancer patients. In this report, we review recent clinical progress in oncolytic virotherapy of CVA21 and clinical development of our CVB3. PMID- 28883285 TI - Genetic abnormalities in core binding factor acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a genetically heterogeneous disease, and its prognosis is stratified on the basis of chromosomal and genetic alterations. Core binding factor (CBF) leukemia consists of AML with t (8;21) (p22;q22) and inv16 (q16q16) /t (16;16) (q16;q16) and is included in AML with recurrent genetic abnormality according to WHO classification. Although CBF-AML is categorized as favorable-risk AML, approximately 40% of patients show relapse. The t (8;21) and inv16 (q16q16) /t (16;16) (q16;q16) result in RUNX1-RUNX1T1 and CBFB-MYH11 fusion genes, respectively; however, the fusion proteins encoded by these genes alone are insufficient for the development of leukemia. Activating kinase mutations in KIT, FLT3, and N-RAS have been frequently found, and their cooperation with RUNX1 RUNX1T1 or CBFB-MYH11 is thought to be crucial for leukemogenesis in CBF-AML. Recently, mutations in ASXL2, ZBTB7A, CCND2, and DHX15 have been frequently identified in t (8;21) AML, but their biological and clinical significance have not been elucidated. Thus, a combination of several genetic alterations is associated with the development of CBF-AML, and comprehensive genetic analysis is necessary for the stratification of this leukemia. CBF-AML is a still heterogeneous disease entity, and it is necessary to elucidate the combinations of genomic abnormalities and clonal evolutions for better understanding of the disease and to develop a new treatment strategy. PMID- 28883286 TI - Proteasome inhibitors in first-line treatment of transplant-ineligible multiple myeloma patients. AB - Since the turn of the century, many agents against multiple myeloma (MM) have been introduced into daily clinical practice. The development of further agents is ongoing and some of these will reach the point of use in clinical practice in the near future. As various treatment options become available, the selection of an appropriate treatment strategy for an individual patient becomes more important. Treatment selection and decision making are based on the following two apparently opposite factors: 1) generalized findings and evidence from clinical trials, and 2) disease risks and background of individuals, which are diverse among patients. Proteasome inhibitors (PIs) are central players in MM treatment. In this review, we summarize evidence for the efficacy and safety of a first generation PI, bortezomib, and discuss its advantages in controlling disease risks and myeloma-defining events in patients with transplant-ineligible, untreated, newly diagnosed MM (NDMM). We also highlight on recent knowledge regarding the use of second generation PIs such as carfilzomib and ixazomib in the treatment of transplant-ineligible, untreated NDMM. PMID- 28883287 TI - Current evidence and topics of diagnosis and treatment for hepatocellular carcinoma. PMID- 28883289 TI - Transcatheter arterial chemoembolization for hepatocellular carcinoma:current topics. PMID- 28883288 TI - The evidence and topics for the diagnosis of hepatocellular carcinoma. PMID- 28883290 TI - Evidence and topics of surgical treatment for hepatocellular carcinoma. PMID- 28883291 TI - Evidence and topics of chemotherapy for hepatocellular carcinoma. PMID- 28883292 TI - Reactive swelling of the regional lymph nodes in patients with stage II colorectal cancer as a prognostic factor. AB - The aim of this study was to examine the relationship between reactive swelling of regional lymph node (LN) and survival in colorectal carcinoma. We retrospectively studied 170 patients with surgically resected colorectal carcinoma histopathologically diagnosed as stage II (pStage II). These patients were classified into two groups:a) a "reactive LN swelling" group (clinically diagnosed as positive for LN metastasis, but pathologically negative) and b) a "no LN swelling" group. Survival analyses of the two groups showed that overall survival (OS) and disease-specific survival (DSS) were longer in the reactive LN swelling group than in the no LN swelling group in patients with total colorectal and right-sided colon cancer. Multivariate analyses revealed that reactive LN swelling was an independent prognostic factor in OS and DSS in patients with right-sided colon cancer. Reactive swelling of regional LN is regarded as an expression of local immune responses, which could explain the present results. PMID- 28883293 TI - Usefulness of a peripherally inserted central catheter for total parenteral nutrition in patients with inflammatory bowel disease. AB - BACKGROUNDS AND AIMS: Peripherally inserted central catheters (PICC) have been widely used as a blood access route for total parenteral nutrition (TPN) in recent years. However, there have been few reports that evaluated the usefulness of PICC for patients with inflammatory bowel disease (IBD). In this study, we compared the clinical courses in patients with IBD who received TPN during their hospitalization by conventional central venous catheters (CVC) and PICC. PATIENTS AND METHODS: A total of 137 IBD patients were enrolled. The CVC group and the PICC group included 56 and 81 patients, respectively. The clinical courses in both groups were compared retrospectively. RESULTS: As a complication of the puncture, pneumothorax occurred in two patients (3.6%) in the CVC group, but in none (0%) in the PICC group. The PICC group had significantly higher rates of achieving the scheduled TPN without removing the catheter, lower rates of catheter-related blood stream infection (CRBSI) and longer periods without CRBSI than the CVC group. CONCLUSION: PICC might be more useful than CVC in terms of safety and the ability to deliver scheduled TPN for IBD patients. PMID- 28883294 TI - Potential risk factors for postoperative complications and deaths after laparoscopic cholecystectomy in the elderly. AB - Laparoscopic cholecystectomy (LC) is performed for gallbladder stones and cholecystitis in a large number of elderly patients. However, the safety of LC in the elderly is questioned. The aim of this study was to investigate predictive factors for the incidence of postoperative complications and deaths after LC in patients aged 80 years and older. Data from 85 elderly patients who underwent LC between January 2005 and December 2015 were prospectively collected in a database at our hospital. The following factors were compared for the occurrence of postoperative complications and deaths:age, gender, Body Mass Index, laboratory date, severity grade of cholecystitis, comorbidity of choledocholithiasis, conversion to open cholecystectomy, early or delayed LC, amount of time from onset to LC, operative duration, blood loss, and the following scoring systems for predicting risk of surgery:ECOG-PS, ASA, SIRS, CONUT, POSSUM, SAS, E-PASS. The complication rate of LC was 14.1% in this cohort. WBC, CRP, BUN, Cre, Na, PT INR, severity of cholecystitis, conversion to open cholecystectomy, operative duration, early LC, ASA, SIRS, CONUT, POSSUM (PS, OS, complication rate), SAS, E PASS (PRS, SSS, CRS) showed significant variability in univariate analysis. A high POSSUM score of complication and moderate or severe cholecystitis were independent risk factors for postoperative complication. Analysis of the ROC showed that the best cut-off point for the POSSUM score of complication was 51.5. LC for gallbladder stones and cholecystitis in elderly is a reliable operation, but the procedure for cases with a high score of the POSSUM for complications, or moderate or severe cholecystitis, may have the risk of postoperative complications in elderly patients. PMID- 28883295 TI - A case of granulomatous inflammation of the sigmoid colon caused by a fish bone that resembled cancer. AB - This case involved a 76-year-old man. Total colonoscopy was performed as a second examination for colorectal cancer because of positive fecal occult blood results, revealing a neoplasm with ulceration in the sigmoid colon. We suspected type-3 colorectal cancer and performed a biopsy, but the biopsy diagnosis showed only an ulcer with active inflammation. Colonoscopic re-examination in a highly advanced medical institution revealed granulomatous inflammation of the sigmoid colon caused by a fish bone, and the fish bone was removed endoscopically. Granulomatous inflammation of the colon caused by a fish bone is very rare, but sometimes needs to be differentiated from cancer. Endoscopic therapy can also be an option, depending on abdominal findings and the penetration status of the fish bone into the large intestinal wall. PMID- 28883296 TI - Multifocal angiosarcoma of the gastrointestinal tract:a case report. AB - An 80-year-old man presented to our hospital with complaints of tarry stool and shortness of breath. A blood test confirmed marked anemia. On abdominal contrast enhanced computed tomography, neither hemorrhagic lesions nor tumorous lesions could be pointed out. Upper gastrointestinal endoscopy revealed multiple erythematous flat elevated lesions, which were about 10mm in diameter, located between the stomach and the horizontal part of the duodenum. Colonoscopy revealed similar lesions throughout the entire colon. Pathological examination of biopsy specimens demonstrated the proliferation of neoplastic cells positive for immunostaining of factor VIII-related antigen, CD31, and CD34. Accordingly, the patient was diagnosed with angiosarcoma of the gastrointestinal tract. Although the patient was transferred to another hospital for chemotherapy, he died shortly after the transfer because of deterioration of his bleeding symptoms. Angiosarcoma is a soft-tissue neoplasm of vascular endothelium origin, accounting for less than 2% of all sarcomas. It usually occurs in the skin of the head and neck and in soft tissues. Angiosarcoma of the gastrointestinal tract is rare and is described only in case reports and small series. These tumors are characterized by an extremely aggressive course, with a high tendency to metastasize, leaving patients with a poor prognosis. When angiosarcoma is found in multiple sites of the gastrointestinal tract, it is sometimes difficult to differentiate between primary and metastatic occurrences. We analyzed reported cases of multifocal angiosarcoma of the digestive tract, of which there are 43 so far. In 24 cases, the angiosarcoma was thought to originate from the gastrointestinal tract (primary angiosarcoma). In 13 cases, angiosarcoma of other organs metastasized to the digestive tract (metastatic angiosarcoma). In the remaining 6 cases, whether the multifocal angiosarcoma of the digestive tract was primary or metastatic was unclear. In the current case, no primary lesion was found outside the gastrointestinal tract. Therefore, he was diagnosed with primary multifocal angiosarcoma. PMID- 28883297 TI - A case of serous cystic neoplasm with form changes on an image obtained during long-term follow-up. AB - A 45-year-old man presented with a 24-mm macrocystic lesion at the pancreatic head, which was detected by computed tomography (CT). During six years of follow up, CT, MRI, and endosonographic images of the cystic lesion showed that the cystic lesion had enlarged to 42mm, with the appearance of a thick cyst wall. Since a cystic tumor could not be ruled out, surgery was performed. Pathological examination of the resected specimen revealed microcystic-type serous cystadenoma of the pancreas, with the presence of internal bleeding in the cyst and hemorrhage and thick fibrous tissue in the cyst wall. We could observe a serous cystic neoplasm with prismatic form changes on an image obtained during long-term follow-up. Thus, we considered this case to be useful for investigating the natural history of serous cystic neoplasm of the pancreas. PMID- 28883298 TI - In vitro study on the osteogenesis enhancement effect of BMP-2 incorporated biomimetic apatite coating on titanium surfaces. AB - To fabricate a sustained-release delivery system of bone morphogenetic protein (BMP-2) on titanium surface, explore the effect of BMP-2 concentration on the loading/release behavior of BMP-2 and evaluate the cell compatibility of the system in vitro, pure titanium specimens were immersed into supersaturated calcium phosphate solutions (SCP) containing 4 different concentrations of BMP-2: 0, 50, 100, 200 and 400 ng/mL. Biomimetic calcium phosphate coating was formed on titanium surface and BMP-2 was incorporated into the coating through co deposition. The release profile of BMP-2 suggested that BMP-2 were delivered sustainably up to 20 days. CCK-8 and ALP assay showed that 200 group and 400 ng/mL BMP-2 group have significant effect on promoting MC3T3-E1 cell proliferation and differentiation. The BMP-2 incorporated into the hybrid coating released in a sustained manner and significantly promoted the proliferation and differentiation of MC3T3-E1 on the titanium surface. PMID- 28883299 TI - Cast, milled and EBM-manufactured titanium, differences in porcelain shear bond strength. AB - The objectives were to analyze the oxide layer generated between titanium and porcelain during firing and compare it in different manufacturing techniques: cast, milled and EBM-technique. Seventy two specimens were manufactured, subdivided according to surface treatment: time of passivation (P) and no time of passivation (NP) before porcelain firing. Specimens from each group were analyzed with scanning electron microscopy: one only fired once, and one subjected to six firings. Remaining specimens were subjected to shear bond strength test. The EBM produced NP-group had highest mean value (25.0 MPa) and the milled P-group showed lowest mean value (18.5 MPa) when all factors were compared. No significant difference was detected according to time of passivation. SEM showed consistent and well-defined boundary between the different layers. Time of passivation and impact on oxide growth was not detected. The bond strength of porcelain to milled titanium is lower when compared to cast titanium and EBM-produced titanium. PMID- 28883300 TI - Irrigation effectiveness of continuous ultrasonic irrigation system: An ex vivo study. AB - This study evaluated the irrigation extrusion and smear layer (SL) removal of continuous ultrasonic irrigation (CUI). Forty root canals were shaped, embedded in warm sterile saline agar colored with 1% acid red, and distributed into four groups; three groups had the final irrigation sequence of sodium hypochlorite and EDTA solutions performed by using syringe irrigation (SI), EndoVac (EV), and CUI, respectively. Group 4 had the canals ultrasonically irrigated with saline (CUIS). Irrigant extrusion was verified by a color change of the agar. The SL was evaluated under scanning electron microscope. Irrigant extrusion was observed in two and four teeth in the CUI and SI, respectively, whilst none had irrigant extruded in the EV. In term of SL, the CUI was comparable to EV at 1 and 3 mm but different to SI at 1 mm. Although CUI might clean the root canal system effectively, it was unable to avoid irrigant extrusion. PMID- 28883301 TI - Changes in polymerization stress and elastic modulus of bulk-fill resin composites for 24 hours after irradiation. AB - The objective of this study was to investigate changes in polymerization stress and elastic modulus for light-cured bulk-fill resin composites following irradiation. Crack analysis was applied to obtain the stresses for 24 h after irradiation, which were calculated from the lengths of cracks in a glass mold bonded to the composites. The elastic modulus was repeatedly measured by nano indentation tests performed over 24 h. The lengths of the cracks, the interfacial stress, and the elastic modulus were significantly affected by the material and time after irradiation (p<0.01). The stress and elastic modulus continued to increase for more than 6 and 1 h, respectively (p<0.05). Strong relationships (r>0.85) were revealed between the stress and elastic modulus. The bulk-fill resin composites generated smaller stresses than a flowable resin composite reported to generate relatively low stress. Post-irradiation polymerization during the first 1 h is a major determinant for the magnitude of stress. PMID- 28883303 TI - Accentuating systolic aortic regurgitation during premature ventricular systole. PMID- 28883302 TI - Effect of framework design on fracture load after thermal cycling and mechanical loading of implant-supported zirconia-based prostheses. AB - This study evaluated the effect of zirconia framework design on fracture load of implant-supported zirconia-based prostheses after thermal cycling and mechanical loading. Three different zirconia framework designs were investigated: uniform thickness (UNI), anatomic (ANA), and supported anatomic (SUP) designs. Each framework was layered with feldspathic porcelain (ZAC group) or indirect composite material (ZIC group). The specimens then underwent fracture load testing after thermal cycling and cyclic loading. In the ZAC group, mean fracture load was significantly lower for UNI design specimens than for the other framework designs. In the ZIC group, there was no significant difference in mean fracture load between ANA design specimens and either UNI or SUP design specimens. To improve fracture resistance of implant-supported zirconia-based prostheses after artificial aging, uniformly thick layering material and appropriate lingual support with zirconia frameworks should be provided. PMID- 28883304 TI - Real-time three-dimensional echocardiography imaging of the main pulmonary artery pseudoaneurysm. PMID- 28883306 TI - Editorial, Issue: September 2017. PMID- 28883305 TI - Cor calcium: heart trapped in a pericardial cage. PMID- 28883307 TI - Tolvaptan in the very elderly with acute decompensated heart failure- a therapeutic option worth of consideration. PMID- 28883308 TI - Successful management of iatrogenic retrograde dissection into the aortic root. PMID- 28883309 TI - Preventing Kounis syndrome by stent implantation: a reciprocal process? PMID- 28883310 TI - Author's Reply. PMID- 28883311 TI - Patients' knowledge and perspectives on vitamin K antagonists for stroke prevention in atrial fibrillation: implications for treatment quality. PMID- 28883312 TI - Hydrothermal Synthesis of Metal Oxide Nanoparticles in Supercritical Water. AB - This paper summarizes specific features of supercritical hydrothermal synthesis of metal oxide particles. Supercritical water allows control of the crystal phase, morphology, and particle size since the solvent's properties, such as density of water, can be varied with temperature and pressure, both of which can affect the supersaturation and nucleation. In this review, we describe the advantages of fine particle formation using supercritical water and describe which future tasks need to be solved. PMID- 28883314 TI - Sintering of Fine Particles in Suspension Plasma Sprayed Coatings. AB - Suspension plasma spraying is a process that enables the production of finely grained nanometric or submicrometric coatings. The suspensions are formulated with the use of fine powder particles in water or alcohol with some additives. Subsequently, the suspension is injected into plasma jet and the liquid additives evaporate. The remaining fine solids are molten and subsequently agglomerate or remain solid, depending on their trajectory in the plasma jet. The coating's microstructure results from these two groups of particles arriving on a substrate or previously deposited coating. Previous experimental studies carried out for plasma sprayed titanium oxide and hydroxyapatite coatings enabled us to observe either a finely grained microstructure or, when a different suspension injection mode was used, to distinguish two zones in the microstructure. These two zones correspond to the dense zone formed from well molten particles, and the agglomerated zone formed from fine solid particles that arrive on the substrate in a solid state. The present paper focuses on the experimental and theoretical analysis of the formation process of the agglomerated zone. The experimental section establishes the heat flux supplied to the coating during deposition. In order to achieve this, calorimetric measurements were made by applying experimental conditions simulating the real coatings' growth. The heat flux was measured to be in the range from 0.08 to 0.5 MW/m2,depending on the experimental conditions. The theoretical section analyzes the sintering during the coating's growth, which concerns the fine particles arriving on the substrate in the solid state. The models of volume, grain boundary and surface diffusion were analyzed and adapted to the size and chemistry of the grains, temperature and time scales corresponding to the suspension plasma spraying conditions. The model of surface diffusion was found to best describe the sintering during suspension plasma spraying. The formation of necks having the relative size equal to 10% of particle diameter was found to be possible during the thermal cycles occurring at the coatings' deposition. Transmission electron microscopic observations of the agglomerated zone hydroxyapatite coating confirm the sintering of some of the fine grains. PMID- 28883313 TI - A Comprehensive Review on Separation Methods and Techniques for Single-Walled Carbon Nanotubes. AB - Structural control of single-walled carbon nanotubes (SWNTs) is attracting enormous interest in view of their applications to nanoelectronics and nanooptics. Actually, more than 200 papers regarding separation of SWNTs have been published since 1998. In this review, they are classified into the following five sections according to the separation methods; electrophoresis, centrifugation, chromatography, selective solubilization and selective reaction. In each method, all literature is summarized in tables showing the separated objects (metallic/semiconducting (M/S), length, diameter, (n, m) structure and/or handedness), the production process of the used SWNTs (CoMoCAT, HiPco, arc discharge and/or laser vaporization) and the employed chemicals, such as detergents and polymers. Changes in annual number of publications related to this subject are also discussed. PMID- 28883317 TI - Combustion Synthesis of Porous TiC/Ti Composite by a Self-Propagating Mode. AB - Porous titanium carbide (TiC) and TiC/Ti composites were synthesized by self propagating high-temperature synthesis (SHS). Titanium and carbon powders were blended by various Ti/C blending ratios. The heat of reaction between titanium and carbon was high enough to induce the self-sustaining reaction of TiC formation on condition that some processing parameters (Ti/C ratio and porosity of the precursor) were appropriately selected. When the Ti/C blending ratio was high, the excess amount of titanium absorbed the heat of reaction. Consequently, the heated zone was not heated up to the ignition temperature. On the other hand, when the Ti/C ratio was low, high thermal conductivity of the precursor prevented an ignition of the heated side of precursors. The pore morphology was controlled by changing the Ti/C ratio and the preheat temperature. PMID- 28883316 TI - Characterization of Biomaterials by Soft X-Ray Spectromicroscopy. AB - Synchrotron-based soft X-ray spectromicroscopy techniques are emerging as useful tools to characterize potentially biocompatible materials and to probe protein interactions with model biomaterial surfaces. Simultaneous quantitative chemical analysis of the near surface region of the candidate biomaterial, and adsorbed proteins, peptides or other biological species can be obtained at high spatial resolution via scanning transmission X-ray microscopy (STXM) and X-ray photoemission electron microscopy (X-PEEM). Both techniques use near-edge X-ray absorption fine structure (NEXAFS) spectral contrast for chemical identification and quantitation. The capabilities of STXM and X-PEEM for the analysis of biomaterials are reviewed and illustrated by three recent studies: (1) characterization of hydrophobic surfaces, including adsorption of fibrinogen (Fg) or human serum albumin (HSA) to hydrophobic polymeric thin films, (2) studies of HSA adsorption to biodegradable or potentially biocompatible polymers, and (3) studies of biomaterials under fully hydrated conditions. Other recent applications of STXM and X-PEEM to biomaterials are also reviewed. PMID- 28883315 TI - Bioactive Glass and Glass-Ceramic Scaffolds for Bone Tissue Engineering. AB - Traditionally, bioactive glasses have been used to fill and restore bone defects. More recently, this category of biomaterials has become an emerging research field for bone tissue engineering applications. Here, we review and discuss current knowledge on porous bone tissue engineering scaffolds on the basis of melt-derived bioactive silicate glass compositions and relevant composite structures. Starting with an excerpt on the history of bioactive glasses, as well as on fundamental requirements for bone tissue engineering scaffolds, a detailed overview on recent developments of bioactive glass and glass-ceramic scaffolds will be given, including a summary of common fabrication methods and a discussion on the microstructural-mechanical properties of scaffolds in relation to human bone (structure-property and structure-function relationship). In addition, ion release effects of bioactive glasses concerning osteogenic and angiogenic responses are addressed. Finally, areas of future research are highlighted in this review. PMID- 28883318 TI - Nanoscale "Quantum" Islands on Metal Substrates: Microscopy Studies and Electronic Structure Analyses. AB - Confinement of electrons can occur in metal islands or in continuous films grown heteroepitaxially upon a substrate of a different metal or on a metallic alloy. Associated quantum size effects (QSE) can produce a significant height-dependence of the surface free energy for nanoscale thicknesses of up to 10-20 layers. This may suffice to induce height selection during film growth. Scanning STM analysis has revealed remarkable flat-topped or mesa-like island and film morphologies in various systems. We discuss in detail observations of QSE and associated film growth behavior for Pb/Cu(111), Ag/Fe(100), and Cu/fcc-Fe/Cu(100) [A/B or A/B/A], and for Ag/NiAl(110) with brief comments offered for Fe/Cu3Au(001) [A/BC binary alloys]. We also describe these issues for Ag/5-fold i-Al-Pd-Mn and Bi/5-fold i Al-Cu-Fe [A/BCD ternary icosohedral quasicrystals]. Electronic structure theory analysis, either at the level of simple free electron gas models or more sophisticated Density Functional Theory calculations, can provide insight into the QSE-mediated thermodynamic driving force underlying height selection. PMID- 28883320 TI - Synthesis and Characterization of Multifunctional Chitosan- MnFe2O4 Nanoparticles for Magnetic Hyperthermia and Drug Delivery. AB - Multifunctional nanoparticles composed of MnFe2O4 were encapsulated in chitosan for investigation of system to combine magnetically-triggered drug delivery and localized hyperthermia for cancer treatment with the previously published capacity of MnFe2O4 to be used as an efficient MRI contrast agent for cancer diagnosis. This paper focuses on the synthesis and characterization of magnetic MnFe2O4 nanoparticles, their dispersion in water and their incorporation in chitosan, which serves as a drug carrier. The surface of the MnFe2O4 nanoparticles was modified with meso-2,3-di-mercaptosuccinic acid (DMSA) to develop stable aqueous dispersions. The nanoparticles were coated with chitosan, and the magnetic properties, heat generation and hydrodynamic size of chitosan coated MnFe2O4 were evaluated for various linker concentrations and in a range of pH conditions. PMID- 28883322 TI - Emission Properties, Solubility, Thermodynamic Analysis and NMR Studies of Rare Earth Complexes with Two Different Phosphine Oxides. AB - The paper proposes novel molecular designs for rare-earth complexes involving the introduction of two different phosphine oxide structures into one rare-earth ion. These designs are effective for improving solubility and emission intensity. Additionally, the complexes are indispensable for realizing high performances in LEDs and security media. The thermodynamic properties of Eu(III) complexes are correlated with the solubility. Correlations between coordination structures and emission intensity were explained by NMR analysis. The luminous flux of red LED devices with Eu(III) complexes is very high (20 mA, 870 m lumen). A new white LED has its largest spectra intensity in the red region and a human look much more vividly under this light. PMID- 28883321 TI - Synthesis of Polymer-Mesoporous Silica Nanocomposites. AB - Polymer nanocomposites show unique properties combining the advantages of the inorganic nanofillers and the organic polymers. The mesoporous silica nanofillers have received much attention due to their ordered structure, high surface area and ease for functionalization of the nanopores. To accommodate macromolecules, the nanopores lead to unusually intimate interactions between the polymer and the inorganic phase, and some unusual properties can be observed, when compared with nonporous fillers. Whereas many review articles have been devoted to polymer/nonporous nanofiller nanocomposites, few review articles focus on polymer/mesoporous silica nanocomposites. This review summarizes the recent development in the methods for synthesizing polymer/mesoporous silica nanocomposites based on the papers published from 1998 to 2009, and some unique properties of these composites are also described. PMID- 28883323 TI - Thin Film Deposition Using Energetic Ions. AB - One important recent trend in deposition technology is the continuous expansion of available processes towards higher ion assistance with the subsequent beneficial effects to film properties. Nowadays, a multitude of processes, including laser ablation and deposition, vacuum arc deposition, ion assisted deposition, high power impulse magnetron sputtering and plasma immersion ion implantation, are available. However, there are obstacles to overcome in all technologies, including line-of-sight processes, particle contaminations and low growth rates, which lead to ongoing process refinements and development of new methods. Concerning the deposited thin films, control of energetic ion bombardment leads to improved adhesion, reduced substrate temperatures, control of intrinsic stress within the films as well as adjustment of surface texture, phase formation and nanotopography. This review illustrates recent trends for both areas; plasma process and solid state surface processes. PMID- 28883324 TI - Large-Scale Synthesis of Carbon Nanomaterials by Catalytic Chemical Vapor Deposition: A Review of the Effects of Synthesis Parameters and Magnetic Properties. AB - The large-scale production of carbon nanomaterials by catalytic chemical vapor deposition is reviewed in context with their microwave absorbing ability. Factors that influence the growth as well as the magnetic properties of the carbon nanomaterials are discussed. PMID- 28883325 TI - Hydrothermal Synthesis of Nanostructured Vanadium Oxides. AB - A wide range of vanadium oxides have been obtained via the hydrothermal treatment of aqueous V(V) solutions. They exhibit a large variety of nanostructures ranging from molecular clusters to 1D and 2D layered compounds. Nanotubes are obtained via a self-rolling process while amazing morphologies such as nano-spheres, nano flowers and even nano-urchins are formed via the self-assembling of nano particles. This paper provides some correlation between the molecular structure of precursors in the solution and the nanostructure of the solid phases obtained by hydrothermal treatment. PMID- 28883319 TI - Functional Coatings or Films for Hard-Tissue Applications. AB - Metallic biomaterials like stainless steel, Co-based alloy, Ti and its alloys are widely used as artificial hip joints, bone plates and dental implants due to their excellent mechanical properties and endurance. However, there are some surface-originated problems associated with the metallic implants: corrosion and wear in biological environments resulting in ions release and formation of wear debris; poor implant fixation resulting from lack of osteoconductivity and osteoinductivity; implant-associated infections due to the bacterial adhesion and colonization at the implantation site. For overcoming these surface-originated problems, a variety of surface modification techniques have been used on metallic implants, including chemical treatments, physical methods and biological methods. This review surveys coatings that serve to provide properties of anti-corrosion and anti-wear, biocompatibility and bioactivity, and antibacterial activity. PMID- 28883326 TI - Charge-Transfer Interactions in Organic Functional Materials. AB - Our goal in this review is three-fold. First, we provide an overview of a number of quantum-chemical methods that can abstract charge-transfer (CT) information on the excited-state species of organic conjugated materials, which can then be exploited for the understanding and design of organic photodiodes and solar cells at the molecular level. We stress that the Composite-Molecule (CM) model is useful for evaluating the electronic excited states and excitonic couplings of the organic molecules in the solid state. We start from a simple polyene dimer as an example to illustrate how interchain separation and chain size affect the intercahin interaction and the role of the charge transfer interaction in the excited state of the polyene dimers. With the basic knowledge from analysis of the polyene system, we then study more practical organic materials such as oligophenylenevinylenes (OPVn), oligothiophenes (OTn), and oligophenylenes (OPn). Finally, we apply this method to address the delocalization pathway (through-bond and/or through-space) in the lowest excited state for cyclophanes by combining the charge-transfer contributions calculated on the cyclophanes and the corresponding hypothetical molecules with tethers removed. This review represents a step forward in the understanding of the nature of the charge-transfer interactions in the excited state of organic functional materials. PMID- 28883327 TI - STM, SECPM, AFM and Electrochemistry on Single Crystalline Surfaces. AB - Scanning probe microscopy (SPM) techniques have had a great impact on research fields of surface science and nanotechnology during the last decades. They are used to investigate surfaces with scanning ranges between several 100 mm down to atomic resolution. Depending on experimental conditions, and the interaction forces between probe and sample, different SPM techniques allow mapping of different surface properties. In this work, scanning tunneling microscopy (STM) in air and under electrochemical conditions (EC-STM), atomic force microscopy (AFM) in air and scanning electrochemical potential microscopy (SECPM) under electrochemical conditions, were used to study different single crystalline surfaces in electrochemistry. Especially SECPM offers potentially new insights into the solid-liquid interface by providing the possibility to image the potential distribution of the surface, with a resolution that is comparable to STM. In electrocatalysis, nanostructured catalysts supported on different electrode materials often show behavior different from their bulk electrodes. This was experimentally and theoretically shown for several combinations and recently on Pt on Au(111) towards fuel cell relevant reactions. For these investigations single crystals often provide accurate and well defined reference and support systems. We will show heteroepitaxially grown Ru, Ir and Rh single crystalline surface films and bulk Au single crystals with different orientations under electrochemical conditions. Image studies from all three different SPM methods will be presented and compared to electrochemical data obtained by cyclic voltammetry in acidic media. The quality of the single crystalline supports will be verified by the SPM images and the cyclic voltammograms. Furthermore, an outlook will be presented on how such supports can be used in electrocatalytic studies. PMID- 28883328 TI - Molecular Dynamics in Two-Dimensional Supramolecular Systems Observed by STM. AB - Since the invention of scanning tunneling microscopy (STM), 2D supramolecular architectures have been observed under various experimental conditions. The construction of these architectures arises from the balance between interactions at the medium-solid interface. This review summarizes molecular motion observed in 2D-supramolecular structures on surfaces using nanospace resolution STM. The observation of molecular motion on surfaces provides a visual understanding of intermolecular interactions, which are the major driving force behind supramolecular arrangement. PMID- 28883329 TI - Metal Dependence of Signal Transmission through MolecularQuantum-Dot Cellular Automata (QCA): A Theoretical Studyon Fe, Ru, and Os Mixed-Valence Complexes. AB - Dynamic behavior of signal transmission through metal complexes [L5M-BL-ML5]5+ (M=Fe, Ru, Os, BL=pyrazine (py), 4,4'-bipyridine (bpy), L=NH3), which are simplified models of the molecular quantum-dot cellular automata (molecular QCA), is discussed from the viewpoint of one-electron theory, density functional theory. It is found that for py complexes, the signal transmission time (tst) is Fe(0.6 fs) < Os(0.7 fs) < Ru(1.1 fs) and the signal amplitude (A) is Fe(0.05 e) < Os(0.06 e) < Ru(0.10 e). For bpy complexes, tst and A are Fe(1.4 fs) < Os(1.7 fs) < Ru(2.5 fs) and Os(0.11 e) < Ru(0.12 e) 20, preoperative hospitalization for over 2 weeks or intensive care unit admission and bacterial infection within 1 month before LDLT. Patients were classified into those with 0-1 risk factors (Group LR, n=44) and those with 2-3 risk factors (Group HR, n=22). RESULTS The overall survival (OS) rate after LDLT was significantly lower in Group HR than in Group LR (1-year: HR 83.9% vs. LR 93%, 3-year: HR 70.8% vs. LR 90.5%, 5-year: HR 62% vs. LR 87.6%; p=0.029). In Group LR, OS rates did not differ significantly by graft type or donor age. In Group HR, OS rates at 1 (93.8% vs. 66.7%), 3 (85.2% vs. 50%), and 5 (75.8% vs. 25%) years were significantly higher using right (n=16) vs. left (n=6) lobe grafts (p=0.046). CONCLUSIONS Proper graft selection is very important to improve the outcome of LDLT recipients in deteriorated preoperative condition. LDLT using right-lobe grafts may be recommended for high risk severely deteriorated patients. PMID- 28883388 TI - Retrospective Clinical Study of the Effects of T-Tube Placement for Bile Duct Stricture. AB - BACKGROUND T-tube placement in the common bile duct (CBD) is a surgical alternative to bile duct reconstruction in cholecystectomy for cholecysto choledocholithiasis, or gallstones. The aim of this retrospective clinical study was to investigate the incidence of late complications of T-tube placement. MATERIAL AND METHODS Retrospective review identified 35 patients who had T-tube placement during cholecystectomy. Clinical data were collected on surgical indications, patient demographics, and clinical symptoms. Ultrasound (US) was used measure the diameter of the common bile duct (CBD), intrahepatic ducts, and presence or absence of stones in the CBD. Data from laboratory investigations included the aspartate aminotransferase-to-platelet ratio index (APRI), which was used as a non-invasive method to evaluate both cholestasis and liver fibrosis. RESULTS Of the 35 patients included in the study, 33 (94.3%) underwent open cholecystectomy, CBD exploration, and T-tube placement due to cholecysto choledocholithiasis. The remaining two patients (5.7%) underwent primary CBD repair and T-tube placement secondary to CBD injury. The mean follow-up period after T-tube placement was 69 months. In patients with T-tube placement, the CBD diameters ranged from 4-21 mm, were normal in 20 patients (57.1%), dilated in 15 patients (42.9%), with the mean CBD diameter being 8.91+/-4.82 mm. No residual or recurrent CBD calculus and no clinical or laboratory evidence of cholangitis or cholestasis were found. CONCLUSIONS A retrospective clinical study at a single surgical center, showed that T-tube placement during open cholecystectomy and CBD exploration was a safe procedure that did not result in late complications. PMID- 28883389 TI - Septic Shock with Multi Organ Failure Due to Fluoroquinolones Resistant Campylobacter Jejuni. AB - BACKGROUND Campylobacter jejuni infections are typically self-limited, and severe extra-intestinal complications are uncommon. CASE REPORT We report a case of a man with septic shock due to fluoroquinolones resistant Campylobacter jejuni. CONCLUSIONS This manuscript emphasizes the potential lethality of fluorquinolones resistant Campylobacter jejuni bacteremia. PMID- 28883391 TI - Ultrawide thermal free-carrier tuning of dielectric antennas coupled to epsilon near-zero substrates. AB - The principal challenge for achieving reconfigurable optical antennas and metasurfaces is the need to generate continuous and large tunability of subwavelength, low-Q resonators. We demonstrate continuous and steady-state refractive index tuning at mid-infrared wavelengths using temperature-dependent control over the low-loss plasma frequency in III-V semiconductors. In doped InSb we demonstrate nearly two-fold increase in the electron effective mass leading to a positive refractive index shift (Deltan > 1.5) that is an order of magnitude greater than conventional thermo-optic effects. In undoped films we demonstrate more than 10-fold change in the thermal free-carrier concentration producing a near-unity negative refractive index shift. Exploiting both effects within a single resonator system-intrinsic InSb wires on a heavily doped (epsilon-near zero) InSb substrate-we demonstrate dynamically steady-state tunable Mie resonances. The observed line-width resonance shifts (Deltalambda > 1.7 MUm) suggest new avenues for highly tunable and steady-state mid-infrared semiconductor antennas.Achieving large tunability of subwavelength resonators is a central challenge in nanophotonics. Here the authors demonstrate refractive index tuning at mid-infrared wavelengths using temperature-dependent control over the low loss plasma frequency in III-V semiconductors. PMID- 28883390 TI - Prophage-triggered membrane vesicle formation through peptidoglycan damage in Bacillus subtilis. AB - Bacteria release membrane vesicles (MVs) that play important roles in various biological processes. However, the mechanisms of MV formation in Gram-positive bacteria are unclear, as these cells possess a single cytoplasmic membrane that is surrounded by a thick cell wall. Here we use live cell imaging and electron cryo-tomography to describe a mechanism for MV formation in Bacillus subtilis. We show that the expression of a prophage-encoded endolysin in a sub-population of cells generates holes in the peptidoglycan cell wall. Through these openings, cytoplasmic membrane material protrudes into the extracellular space and is released as MVs. Due to the loss of membrane integrity, the induced cells eventually die. The vesicle-producing cells induce MV formation in neighboring cells by the enzymatic action of the released endolysin. Our results support the idea that endolysins may be important for MV formation in bacteria, and this mechanism may potentially be useful for the production of MVs for applications in biomedicine and nanotechnology.It is unclear how Gram-positive bacteria, with a thick cell wall, can release membrane vesicles. Here, Toyofuku et al. show that a prophage-encoded endolysin can generate holes in the cell wall through which cytoplasmic membrane material protrudes and is released as vesicles. PMID- 28883392 TI - Tunable inverted gap in monolayer quasi-metallic MoS2 induced by strong charge lattice coupling. AB - Polymorphism of two-dimensional transition metal dichalcogenides such as molybdenum disulfide (MoS2) exhibit fascinating optical and transport properties. Here, we observe a tunable inverted gap (~0.50 eV) and a fundamental gap (~0.10 eV) in quasimetallic monolayer MoS2. Using spectral-weight transfer analysis, we find that the inverted gap is attributed to the strong charge-lattice coupling in two-dimensional transition metal dichalcogenides (2D-TMDs). A comprehensive experimental study, supported by theoretical calculations, is conducted to understand the transition of monolayer MoS2 on gold film from trigonal semiconducting 1H phase to the distorted octahedral quasimetallic 1T' phase. We clarify that electron doping from gold, facilitated by interfacial tensile strain, is the key mechanism leading to its 1H-1T' phase transition, thus resulting in the formation of the inverted gap. Our result shows the importance of charge-lattice coupling to the intrinsic properties of the inverted gap and polymorphism of MoS2, thereby unlocking new possibilities for 2D-TMD-based device fabrication.MoS2 exhibits multiple electronic properties associated with different crystal structures. Here, the authors observe inverted and fundamental gaps through a designed annealing-based strategy, to induce a semiconductor-to metal phase transition in monolayer-MoS2 on Au, facilitated by interfacial strain and electron transfer from Au to MoS2. PMID- 28883393 TI - Fas cell surface death receptor controls hepatic lipid metabolism by regulating mitochondrial function. AB - Nonalcoholic fatty liver disease is one of the most prevalent metabolic disorders and it tightly associates with obesity, type 2 diabetes, and cardiovascular disease. Reduced mitochondrial lipid oxidation contributes to hepatic fatty acid accumulation. Here, we show that the Fas cell surface death receptor (Fas/CD95/Apo-1) regulates hepatic mitochondrial metabolism. Hepatic Fas overexpression in chow-fed mice compromises fatty acid oxidation, mitochondrial respiration, and the abundance of mitochondrial respiratory complexes promoting hepatic lipid accumulation and insulin resistance. In line, hepatocyte-specific ablation of Fas improves mitochondrial function and ameliorates high-fat-diet induced hepatic steatosis, glucose tolerance, and insulin resistance. Mechanistically, Fas impairs fatty acid oxidation via the BH3 interacting-domain death agonist (BID). Mice with genetic or pharmacological inhibition of BID are protected from Fas-mediated impairment of mitochondrial oxidation and hepatic steatosis. We suggest Fas as a potential novel therapeutic target to treat obesity-associated fatty liver and insulin resistance.Hepatic steatosis is a common disease closely associated with metabolic syndrome and insulin resistance. Here Item et al. show that Fas, a member of the TNF receptor superfamily, contributes to mitochondrial dysfunction, steatosis development, and insulin resistance under high fat diet. PMID- 28883394 TI - A thiol probe for measuring unfolded protein load and proteostasis in cells. AB - When proteostasis becomes unbalanced, unfolded proteins can accumulate and aggregate. Here we report that the dye, tetraphenylethene maleimide (TPE-MI) can be used to measure cellular unfolded protein load. TPE-MI fluorescence is activated upon labelling free cysteine thiols, normally buried in the core of globular proteins that are exposed upon unfolding. Crucially TPE-MI does not become fluorescent when conjugated to soluble glutathione. We find that TPE-MI fluorescence is enhanced upon reaction with cellular proteomes under conditions promoting accumulation of unfolded proteins. TPE-MI reactivity can be used to track which proteins expose more cysteine residues under stress through proteomic analysis. We show that TPE-MI can report imbalances in proteostasis in induced pluripotent stem cell models of Huntington disease, as well as cells transfected with mutant Huntington exon 1 before the formation of visible aggregates. TPE-MI also detects protein damage following dihydroartemisinin treatment of the malaria parasites Plasmodium falciparum. TPE-MI therefore holds promise as a tool to probe proteostasis mechanisms in disease.Proteostasis is maintained through a number of molecular mechanisms, some of which function to protect the folded state of proteins. Here the authors demonstrate the use of TPE-MI in a fluorigenic dye assay for the quantitation of unfolded proteins that can be used to assess proteostasis on a cellular or proteome scale. PMID- 28883395 TI - Bio-degradable highly fluorescent conjugated polymer nanoparticles for bio medical imaging applications. AB - Conjugated polymer nanoparticles exhibit strong fluorescence and have been applied for biological fluorescence imaging in cell culture and in small animals. However, conjugated polymer particles are hydrophobic and often chemically inert materials with diameters ranging from below 50 nm to several microns. As such, conjugated polymer nanoparticles cannot be excreted through the renal system. This drawback has prevented their application for clinical bio-medical imaging. Here, we present fully conjugated polymer nanoparticles based on imidazole units. These nanoparticles can be bio-degraded by activated macrophages. Reactive oxygen species induce scission of the conjugated polymer backbone at the imidazole unit, leading to complete decomposition of the particles into soluble low molecular weight fragments. Furthermore, the nanoparticles can be surface functionalized for directed targeting. The approach opens a wide range of opportunities for conjugated polymer particles in the fields of medical imaging, drug-delivery, and theranostics.Conjugated polymer nanoparticles have been applied for biological fluorescence imaging in cell culture and in small animals, but cannot readily be excreted through the renal system. Here the authors show fully conjugated polymer nanoparticles based on imidazole units that can be bio-degraded by activated macrophages. PMID- 28883397 TI - Port-based teleportation in arbitrary dimension. AB - Port-based teleportation (PBT), introduced in 2008, is a type of quantum teleportation protocol which transmits the state to the receiver without requiring any corrections on the receiver's side. Evaluating the performance of PBT was computationally intractable and previous attempts succeeded only with small systems. We study PBT protocols and fully characterize their performance for arbitrary dimensions and number of ports. We develop new mathematical tools to study the symmetries of the measurement operators that arise in these protocols and belong to the algebra of partially transposed permutation operators. First, we develop the representation theory of the mentioned algebra which provides an elegant way of understanding the properties of subsystems of a large system with general symmetries. In particular, we introduce the theory of the partially reduced irreducible representations which we use to obtain a simpler representation of the algebra of partially transposed permutation operators and thus explicitly determine the properties of any port-based teleportation scheme for fixed dimension in polynomial time. PMID- 28883396 TI - In vivo quantitative imaging of tumor pH by nanosonophore assisted multispectral photoacoustic imaging. AB - Changes of physiological pH are correlated with several pathologies, therefore the development of more effective medical pH imaging methods is of paramount importance. Here, we report on an in vivo pH mapping nanotechnology. This subsurface chemical imaging is based on tumor-targeted, pH sensing nanoprobes and multi-wavelength photoacoustic imaging (PAI). The nanotechnology consists of an optical pH indicator, SNARF-5F, 5-(and-6)-Carboxylic Acid, encapsulated into polyacrylamide nanoparticles with surface modification for tumor targeting. Facilitated by multi-wavelength PAI plus a spectral unmixing technique, the accuracy of pH measurement inside the biological environment is not susceptible to the background optical absorption of biomolecules, i.e., hemoglobins. As a result, both the pH levels and the hemodynamic properties across the entire tumor can be quantitatively evaluated with high sensitivity and high spatial resolution in in vivo cancer models. The imaging technology reported here holds the potential for both research on and clinical management of a variety of cancers.Background optical absorption of several biomolecules impedes an effective in vivo pH imaging in tumors. Here, the authors developed a visible light-based in vivo pH mapping method by coupling photoacoustic imaging and pH responsive modified nanoparticles that selectively target tumor cells. PMID- 28883398 TI - Robustness and mode selectivity in parity-time (PT) symmetric lasers. AB - We investigate two important aspects of PT symmetric photonic molecule lasers, namely the robustness of their single longitudinal mode operation against instabilities triggered by spectral hole burning effects, and the possibility of more versatile mode selectivity. Our results, supported by numerically integrating the nonlinear rate equations and performing linear stability analysis, reveals the following: (1) In principle a second threshold exists after which single mode operation becomes unstable, signaling multimode oscillatory dynamics, (2) For a wide range of design parameters, single mode operation of PT lasers having relatively large free spectral range (FSR) can be robust even at higher gain values, (3) PT symmetric photonic molecule lasers are more robust than their counterpart structures made of single microresonators; and (4) Extending the concept of single longitudinal mode operation based on PT symmetry in millimeter long edge emitting lasers having smaller FSR can be challenging due to instabilities induced by nonlinear modal interactions. Finally we also present a possible strategy based on loss engineering to achieve more control over the mode selectivity by suppressing the mode that has the highest gain (i.e. lies under the peak of the gain spectrum curve) and switch the lasing action to another mode. PMID- 28883399 TI - Antibiotic treatment for Tuberculosis induces a profound dysbiosis of the microbiome that persists long after therapy is completed. AB - Mycobacterium tuberculosis, the cause of Tuberculosis (TB), infects one third of the world's population and causes substantial mortality worldwide. In its shortest format, treatment of TB requires six months of multidrug therapy with a mixture of broad spectrum and mycobacterial specific antibiotics, and treatment of multidrug resistant TB is longer. The widespread use of this regimen makes this one of the largest exposures of humans to antimicrobials, yet the effects of TB treatment on intestinal microbiome composition and long-term stability are unknown. We compared the microbiome composition, assessed by both 16S rDNA and metagenomic DNA sequencing, of TB cases during antimycobacterial treatment and following cure by 6 months of antibiotics. TB treatment does not perturb overall diversity, but nonetheless dramatically depletes multiple immunologically significant commensal bacteria. The microbiomic perturbation of TB therapy can persist for at least 1.2 years, indicating that the effects of TB treatment are long lasting. These results demonstrate that TB treatment has dramatic effects on the intestinal microbiome and highlight unexpected durable consequences of treatment for the world's most common infection on human ecology. PMID- 28883400 TI - Snapshot 3D Electron Imaging of Structural Dynamics. AB - In order to understand the physical properties of materials it is necessary to determine the 3D positions of all atoms. There has been significant progress towards this goal using electron tomography. However, this method requires a relatively high electron dose and often extended acquisition times which precludes the study of structural dynamics such as defect formation and evolution. In this work we describe a method that enables the determination of 3D atomic positions with high precision from single high resolution electron microscopic images of graphene that show dynamic processes. We have applied this to the study of electron beam induced defect coalescence and to long range rippling in graphene. The latter strongly influences the mechanical and electronic properties of this material that are important for possible future applications. PMID- 28883401 TI - Comparison of APACHE IV with APACHE II, SAPS 3, MELD, MELD-Na, and CTP scores in predicting mortality after liver transplantation. AB - The Acute Physiology and Chronic Health Evaluation (APACHE) IV score and Simplified Acute Physiology Score (SAPS) 3 include liver transplantation as a diagnostic category. The performance of APACHE IV-liver transplantation (LT) specific predicted mortality, SAPS 3, APACHE II, Model for End-stage Liver Disease (MELD)-Na, MELD, and CTP scores in predicting in-hospital and 1 year mortality in liver transplant patients was compared using 590 liver transplantations in a single university hospital. In-hospital mortality and 1 year mortality were 2.9% and 4.2%, respectively. The APACHE IV-LT specific predicted mortality showed better performance in predicting in-hospital mortality (AUC 0.91, 95% CI [0.86-0.96]) compared to SAPS 3 (AUC 0.78, 95% CI [0.66-0.90], p = 0.01), MELD-Na (AUC 0.74, 95% CI [0.57-0.86], p = 0.01), and CTP (AUC 0.68, 95% CI [0.54-0.81], p = 0.01). The APACHE IV-LT specific predicted mortality showed better performance in predicting 1 year mortality (AUC 0.83, 95% CI [0.76 0.9]) compared to MELD-Na (AUC 0.67, 95% CI [0.55-0.79], p = 0.04) and CTP (AUC 0.64, 95% CI [0.53-0.75], p = 0.03), and also in all MELD groups and in both living and deceased donor transplantation. The APACHE IV-LT specific predicted mortality showed better performance in predicting in-hospital and 1 year mortality after liver transplantation. PMID- 28883403 TI - New Late Permian tectonic model for South Africa's Karoo Basin: foreland tectonics and climate change before the end-Permian crisis. AB - Late Permian Karoo Basin tectonics in South Africa are reflected as two fining upward megacycles in the Balfour and upper Teekloof formations. Foreland tectonics are used to explain the cyclic nature and distribution of sedimentation, caused by phases of loading and unloading in the southern source areas adjacent to the basin. New data supports this model, and identifies potential climatic effects on the tectonic regime. Diachronous second-order subaerial unconformities (SU) are identified at the base and top of the Balfour Formation. One third-order SU identified coincides with a faunal turnover which could be related to the Permo-Triassic mass extinction (PTME). The SU are traced, for the first time, to the western portion of the basin (upper Teekloof Formation). Their age determinations support the foreland basin model as they coincide with dated paroxysms. A condensed distal (northern) stratigraphic record is additional support for this tectonic regime because orogenic loading and unloading throughout the basin was not equally distributed, nor was it in-phase. This resulted in more frequent non-deposition with increased distance from the tectonically active source. Refining basin dynamics allows us to distinguish between tectonic and climatic effects and how they have influenced ancient ecosystems and sedimentation through time. PMID- 28883402 TI - In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis. AB - The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1. First, we confirmed expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A high-throughput screen did not identify further specific agonists or positive allosteric modulators of RXFP1, affirming the low druggability of this receptor. As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery. PMID- 28883404 TI - Identification of 2-hydroxyisocaproic acid production in lactic acid bacteria and evaluation of microbial dynamics during kimchi ripening. AB - Lactic acid bacteria produce diverse functional metabolites in fermented foods. However, little is known regarding the metabolites and the fermentation process in kimchi. In this study, the culture broth from Leuconostoc lactis, a lactic acid bacterium isolated from kimchi, was analysed by liquid chromatography-tandem mass spectrometry and identified by the MS-DIAL program. The MassBank database was used to analyse the metabolites produced during fermentation. A mass spectrum corresponding to 2-hydroxyisocaproic acid (HICA) was validated based on a collision-induced dissociation (CID) fragmentation pattern with an identified m/z value of 131.07. HICA production by lactic acid bacteria was monitored and showed a positive correlation with hydroxyisocaproate dehydrogenases (HicDs), which play a key role in the production of HICA from leucine and ketoisocaproic acid. Interestingly, the HICA contents of kimchi varied with Leuconostoc and Lactobacillus content during the early stage of fermentation, and the addition of lactic acid bacteria enhanced the HICA content of kimchi. Our results suggest that HICA production in kimchi is dependent on the lactic acid bacterial composition. PMID- 28883406 TI - MiR-338-5p enhances the radiosensitivity of esophageal squamous cell carcinoma by inducing apoptosis through targeting survivin. AB - Radioresistance is a challenge in the treatment of esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) are known to play an important role in the functional modification of cancer cells and recent studies have reported miRNA mediated radiotherapy resistance. However, further research is necessary to reveal the regulation mechanisms, and treatment strategies using miRNA are yet to be established for ESCC. We compared the miRNA expression profiles of ESCC parental (TE-4) and acquired radioresistance (TE-4R) cell lines using a miRNA microarray and qRT-PCR. Our data showed that miR-338-5p, one of the target miRNA biomarkers, was significantly downregulated in TE-4R. Ectopic overexpression of miR-338-5p induced apoptosis and sensitivity to radiation treatment by interfering with survivin, which is a known inhibitor of apoptosis. Overexpression of survivin reversed miR-338-5p-induced apoptosis. Tumor xenograft experiments indicated that therapeutic delivery of the miR-338-5p mimics via direct injection into tumor mass increased sensitivity to radiation therapy. In conclusion, our findings suggest that miR-338-5p is a potential radiosensitizer and may be a therapeutic biomarker for radioresistant in ESCC. PMID- 28883405 TI - Modeling a linkage between blood transcriptional expression and activity in brain regions to infer the phenotype of schizophrenia patients. AB - : Hundreds of genetic loci participate to schizophrenia liability. It is also known that impaired cerebral connectivity is directly related to the cognitive and affective disturbances in schizophrenia. How genetic susceptibility and brain neural networks interact to specify a pathological phenotype in schizophrenia remains elusive. Imaging genetics, highlighting brain variations, has proven effective to establish links between vulnerability loci and associated clinical traits. As previous imaging genetics works in schizophrenia have essentially focused on structural DNA variants, these findings could be blurred by epigenetic mechanisms taking place during gene expression. We explored the meaningful links between genetic data from peripheral blood tissues on one hand, and regional brain reactivity to emotion task assayed by blood oxygen level-dependent functional magnetic resonance imaging on the other hand, in schizophrenia patients and matched healthy volunteers. We applied Sparse Generalized Canonical Correlation Analysis to identify joint signals between two blocks of variables: (i) the transcriptional expression of 33 candidate genes, and (ii) the blood oxygen level-dependent activity in 16 region of interest. Results suggested that peripheral transcriptional expression is related to brain imaging variations through a sequential pathway, ending with the schizophrenia phenotype. Generalization of such an approach to larger data sets should thus help in outlining the pathways involved in psychiatric illnesses such as schizophrenia. IMAGING: SEARCHING FOR LINKS TO AID DIAGNOSIS: Researchers explore links between the expression of genes associated with schizophrenia in blood cells and variations in brain activity during emotion processing. El Cherif Ibrahim and Eric Fakra at Aix-Marseille Universite, France, and colleagues have developed a method to relate the expression levels of 33 schizophrenia susceptibility genes in blood cells and functional magnetic resonance imaging (fMRI) data obtained as individuals carry out a task that triggers emotional responses. Although they found no significant differences in the expression of genes between the 26 patients with schizophrenia and 26 healthy controls they examined, variations in activity in the superior temporal gyrus were strongly linked to schizophrenia associated gene expression and presence of disease. Similar analyses of larger data sets will shed further light on the relationship between peripheral molecular changes and disease-related behaviors and ultimately, aid the diagnosis of neuropsychiatric disease. PMID- 28883407 TI - In situ characterization of mixed-wettability in a reservoir rock at subsurface conditions. AB - We used X-ray micro-tomography to image the in situ wettability, the distribution of contact angles, at the pore scale in calcite cores from a producing hydrocarbon reservoir at subsurface conditions. The contact angle was measured at hundreds of thousands of points for three samples after twenty pore volumes of brine flooding.We found a wide range of contact angles with values both above and below 90 degrees . The hypothesized cause of wettability alteration by an adsorbed organic layer on surfaces contacted by crude oil after primary drainage was observed with Scanning Electron Microscopy (SEM) and identified using Energy Dispersive X-ray (EDX) analysis. However, not all oil-filled pores were altered towards oil-wet conditions, which suggests that water in surface roughness, or in adjacent micro-porosity, can protect the surface from a strong wettability alteration. The lowest oil recovery was observed for the most oil-wet sample, where the oil remained connected in thin sheet-like layers in the narrower regions of the pore space. The highest recovery was seen for the sample with an average contact angle close to 90 degrees , with an intermediate recovery in a more water-wet system, where the oil was trapped in ganglia in the larger regions of the pore space. PMID- 28883409 TI - Revised version of the Cenozoic Collision along the Zagros Orogen, Insights from Cr-spinel and Sandstone Modal Analyses. AB - Geoscientists have always considered the Neyriz region, located along the Zagros Suture Zone, an important area of interest because of the outcrops of Neotethys ophiolitic rocks. We carried out a modal analysis of the Cenozoic sandstones and geochemistry of the detrital Cr-spinels at Neyriz region in order to determine their provenance and tectonic evolution in the proximal part of Zagros Basin. Our data shows a clear change in provenance from the Late Cretaceous onwards. As from the Late Cretaceous to Eocene, lithic grains are mostly chert and serpentinite; and higher Cr# values of the detrital Cr-spinel compositions indicate that they originate from the fore-arc peridotites and deposited in an accretionary prism setting during this period. From the Late Oligocene to the Miocene periods, volcaniclastic and carbonate lithic grains show an increasing trend, and in the Miocene, metasedimentary lithic grains appear in the sediments. Ophiolite obduction caused a narrow trough sub-basin to be formed parallel to the general trend of the Zagros Orogeny between the Arabian and Iranian plates in Oligocene. From the Miocene onwards, the axial metamorphic complex belt was uplifted in the upper plate. Therefore, the collision along the Zagros Suture Zone must have occurred in the Late Oligocene. PMID- 28883408 TI - Loss of brain inter-frequency hubs in Alzheimer's disease. AB - Alzheimer's disease (AD) causes alterations of brain network structure and function. The latter consists of connectivity changes between oscillatory processes at different frequency channels. We proposed a multi-layer network approach to analyze multiple-frequency brain networks inferred from magnetoencephalographic recordings during resting-states in AD subjects and age matched controls. Main results showed that brain networks tend to facilitate information propagation across different frequencies, as measured by the multi participation coefficient (MPC). However, regional connectivity in AD subjects was abnormally distributed across frequency bands as compared to controls, causing significant decreases of MPC. This effect was mainly localized in association areas and in the cingulate cortex, which acted, in the healthy group, as a true inter-frequency hub. MPC values significantly correlated with memory impairment of AD subjects, as measured by the total recall score. Most predictive regions belonged to components of the default-mode network that are typically affected by atrophy, metabolism disruption and amyloid-beta deposition. We evaluated the diagnostic power of the MPC and we showed that it led to increased classification accuracy (78.39%) and sensitivity (91.11%). These findings shed new light on the brain functional alterations underlying AD and provide analytical tools for identifying multi-frequency neural mechanisms of brain diseases. PMID- 28883410 TI - A minimal double quantum dot. AB - Double quantum dots (DQDs) are a versatile platform for solid-state physics, quantum computation and nanotechnology. The micro-fabrication techniques commonly used to fabricate DQDs are difficult to extend to the atomic scale. Using an alternative approach, which relies on scanning tunneling microscopy and spectroscopy, we prepared a minimal DQD in a wide band-gap semiconductor matrix. It is comprised of a pair of strongly coupled donor atoms that can each be doubly charged. The donor excitation diagram of this system mimicks the charge stability diagram observed in transport measurements of DQDs. We furthermore illustrate how the charge and spin degrees of freedom of the minimal DQD may be used to obtain a single quantum bit and to prepare a Bell state. The results open an intriguing perspective for quantum electronics with atomic-scale structures. PMID- 28883411 TI - Active Control of Charge Density Waves at Degenerate Semiconductor Interfaces. AB - We present an optoelectronic switch for functional plasmonic circuits based on active control of Surface Plasmon Polaritons (SPPs) at degenerate PN+-junction interfaces. Self-consistent multi-physics simulations of the electromagnetic, thermal and IV characteristics of the device have been performed. The lattice matched Indium Gallium Arsenide (In0.53Ga0.47As) is identified as a better semiconductor material compared to Si for the practical implementation of the proposed optoelectronic switch providing higher optical confinement, reduced size and faster operation. The optimal device is shown to operate at signal modulation surpassing -100 dB, responsivity in excess of -600 dB.V-1 and switching rates up to 50 GHz, thus potentially providing a new pathway toward bridging the gap between electronic and photonic devices. PMID- 28883412 TI - BMP-2 induced Dspp transcription is mediated by Dlx3/Osx signaling pathway in odontoblasts. AB - Dentin sialophosphoprotein (Dspp) as a differentiation marker of odontoblasts is regulated by BMP-2. However, the intimate mechanism is still unknown. Transcription factors Dlx3 and Osx are essential for odontoblasts differentiation. We hypothesized that BMP-2 regulation of Dspp transcription was mediated by Dlx3 and/or Osx in odontoblasts. In the present investigation, we found that BMP-2 stimulated expression and nuclear translocation of Dlx3 and Osx in odontoblasts both in vitro and in vivo. Osx was a downstream target of Dlx3 and both of them stimulated Dsp expression. Both Dlx3 and Osx were able to activate Dspp promoter from nucleotides (nt) -318 to +54 by transfections of luciferase reports containing different lengths of mouse Dspp promoters. The binding of Dlx3 and Osx with nt -318 to +54 of Dspp promoter was verified by chromatin immunoprecipitation in vivo. Two Dlx3 binding sites and one Osx binding site on Dspp promoter were found by EMSA. Furthermore, the exact biological function of these binding sites was confirmed by site-directed mutagenesis. At last, the protein-protein interaction between Dlx3 and Osx in odontoblasts was detected by co-immunoprecipitation. In conclusion, in this study we found a novel signaling pathway in which BMP-2 activates Dspp gene transcription via Dlx3/Osx pathway. PMID- 28883414 TI - A general mechanistic model enables predictions of the biological effectiveness of different qualities of radiation. AB - Predicting the responses of biological systems to ionising radiation is extremely challenging, particularly when comparing X-rays and heavy charged particles, due to the uncertainty in their Relative Biological Effectiveness (RBE). Here we assess the power of a novel mechanistic model of DNA damage repair to predict the sensitivity of cells to X-ray, proton or carbon ion exposures in vitro against over 800 published experiments. By specifying the phenotypic characteristics of cells, the model was able to effectively stratify X-ray radiosensitivity (R 2 = 0.74) without the use of any cell-specific fitting parameters. This model was extended to charged particle exposures by integrating Monte Carlo calculated dose distributions, and successfully fit to cellular proton radiosensitivity using a single dose-related parameter (R 2 = 0.66). Using these parameters, the model was also shown to be predictive of carbon ion RBE (R 2 = 0.77). This model can effectively predict cellular sensitivity to a range of radiations, and has the potential to support developments of personalised radiotherapy independent of radiation type. PMID- 28883413 TI - The Ca2+ influx through the mammalian skeletal muscle dihydropyridine receptor is irrelevant for muscle performance. AB - Skeletal muscle excitation-contraction (EC) coupling is initiated by sarcolemmal depolarization, which is translated into a conformational change of the dihydropyridine receptor (DHPR), which in turn activates sarcoplasmic reticulum (SR) Ca2+ release to trigger muscle contraction. During EC coupling, the mammalian DHPR embraces functional duality, as voltage sensor and L-type Ca2+ channel. Although its unique role as voltage sensor for conformational EC coupling is firmly established, the conventional function as Ca2+ channel is still enigmatic. Here we show that Ca2+ influx via DHPR is not necessary for muscle performance by generating a knock-in mouse where DHPR-mediated Ca2+ influx is eliminated. Homozygous knock-in mice display SR Ca2+ release, locomotor activity, motor coordination, muscle strength and susceptibility to fatigue comparable to wild-type controls, without any compensatory regulation of multiple key proteins of the EC coupling machinery and Ca2+ homeostasis. These findings support the hypothesis that the DHPR-mediated Ca2+ influx in mammalian skeletal muscle is an evolutionary remnant.In mammalian skeletal muscle, the DHPR functions as a voltage sensor to trigger muscle contraction and as a Ca2+ channel. Here the authors show that mice where Ca2+ influx through the DHPR is eliminated display no difference in skeletal muscle function, suggesting that the Ca2+ influx through this channel is vestigial. PMID- 28883415 TI - High expression FUT1 and B3GALT5 is an independent predictor of postoperative recurrence and survival in hepatocellular carcinoma. AB - Cancer may arise from dedifferentiation of mature cells or maturation-arrested stem cells. Previously we reported that definitive endoderm from which liver was derived, expressed Globo H, SSEA-3 and SSEA-4. In this study, we examined the expression of their biosynthetic enzymes, FUT1, FUT2, B3GALT5 and ST3GAL2, in 135 hepatocellular carcinoma (HCC) tissues by qRT-PCR. High expression of either FUT1 or B3GALT5 was significantly associated with advanced stages and poor outcome. Kaplan Meier survival analysis showed significantly shorter relapse-free survival (RFS) for those with high expression of either FUT1 or B3GALT5 (P = 0.024 and 0.001, respectively) and shorter overall survival (OS) for those with high expression of B3GALT5 (P = 0.017). Combination of FUT1 and B3GALT5 revealed that high expression of both genes had poorer RFS and OS than the others (P < 0.001). Moreover, multivariable Cox regression analysis identified the combination of B3GALT5 and FUT1 as an independent predictor for RFS (HR: 2.370, 95% CI: 1.505 3.731, P < 0.001) and OS (HR: 2.153, 95% CI: 1.188-3.902, P = 0.012) in HCC. In addition, the presence of Globo H, SSEA-3 and SSEA-4 in some HCC tissues and their absence in normal liver was established by immunohistochemistry staining and mass spectrometric analysis. PMID- 28883416 TI - Purple spot damage dynamics investigated by an integrated approach on a 1244 A.D. parchment roll from the Secret Vatican Archive. AB - Ancient parchments are commonly attacked by microbes, producing purple spots and detachment of the superficial layer. Neither standard cultivation nor molecular methods (DGGE) solved the issue: causative agents and colonization model are still unknown. To identify the putative causal agents, we describe the 16 S rRNA gene analysis (454-pyrosequencing) of the microbial communities colonizing a damaged parchment roll dated 1244 A.D. (A.A. Arm. I-XVIII 3328, Vatican Secret Archives). The taxa in damaged or undamaged areas of the same document were different. In the purple spots, marine halotolerant Gammaproteobacteria, mainly Vibrio, were found; these microorganisms are rare or absent in the undamaged areas. Ubiquitous and environmental microorganisms were observed in samples from both damaged and undamaged areas. Pseudonocardiales were the most common, representing the main colonizers of undamaged areas. We hypothesize a successional model of biodeterioration, based on metagenomic data and spectroscopic analysis of pigments, which help to relate the damage to a microbial agent. Furthermore, a new method (Light Transmitted Analysis) was utilized to evaluate the kind and entity of the damage to native collagen. These data give a significant advance to the knowledge in the field and open new perspectives to remediation activity on a huge amount of ancient document. PMID- 28883417 TI - The Deposition and Accumulation of Microplastics in Marine Sediments and Bottom Water from the Irish Continental Shelf. AB - Microplastics are widely dispersed throughout the marine environment. An understanding of the distribution and accumulation of this form of pollution is crucial for gauging environmental risk. Presented here is the first record of plastic contamination, in the 5 mm-250 MUm size range, of Irish continental shelf sediments. Sixty-two microplastics were recovered from 10 of 11 stations using box cores. 97% of recovered microplastics were found to reside shallower than 2.5 cm sediment depth, with the area of highest microplastic concentration being the water-sediment interface and top 0.5 cm of sediments (66%). Microplastics were not found deeper than 3.5 +/- 0.5 cm. These findings demonstrate that microplastic contamination is ubiquitous within superficial sediments and bottom water along the western Irish continental shelf. Results highlight that cores need to be at least 4-5 cm deep to quantify the standing stock of microplastics within marine sediments. All recovered microplastics were classified as secondary microplastics as they appear to be remnants of larger items; fibres being the principal form of microplastic pollution (85%), followed by broken fragments (15%). The range of polymer types, colours and physical forms recovered suggests a variety of sources. Further research is needed to understand the mechanisms influencing microplastic transport, deposition, resuspension and subsequent interactions with biota. PMID- 28883418 TI - Quantitative proteomics of Sf21 cells during Baculovirus infection reveals progressive host proteome changes and its regulation by viral miRNA. AB - System level knowledge of alterations in host is crucial to elucidate the molecular events of viral pathogenesis and to develop strategies to block viral establishment and amplification. Here, we applied quantitative proteomics approach to study global proteome changes in the host; Spodoptera frugiperda upon infection by a baculovirus, Spodoptera litura NPV at two stages i.e. 12 h and 72 h post infection. At 12 hpi, >95% of host proteins remained stable, however at 72 hpi, 52% host proteins exhibited downregulation of 2-fold or more. Functional analysis revealed significant upregulation of transposition and proteasomal machinery while translation, transcription, protein export and oxidative phosphorylation pathways were adversely affected. An assessment of perturbed proteome after viral infection and viral miRNA expression led to the identification of 117 genes that are potential targets of 10 viral miRNAs. Using miRNA mimics, we confirmed the down regulation of 9 host genes. The results comprehensively show dynamics of host responses after viral infection. PMID- 28883419 TI - Bio-fabrication of silver nanoparticles by phycocyanin, characterization, in vitro anticancer activity against breast cancer cell line and in vivo cytotxicity. AB - In recent decades, researchers were attracted towards cyanobacterial components which are potential low-cost biological reagents for silver nanoparticle biosynthesis. This article describes the biological synthesis of silver nanoparticles using a proteinaceous pigment phycocyanin extracted from Nostoc linckia as reducing agent. The synthesized silver nanoparticles have a surface plasmon resonance band centered at 425 nm. Face-centered central composite design used for optimization of silver nanoparticles (AgNPs) biosynthesis using phycocyanin. The maximum AgNPs biosynthesis obtained using the optimized four variables, initial pH level (10), AgNO3 concentration (5 mM), phycocyanin pigment concentration (1 mg/mL) and incubation period (24 h) was 1100.025 ug/mL. The TEM analysis of AgNPs showed spherical nanoparticles with mean size between 9.39 to 25.89 nm. FTIR spectra showed major peaks of proteins involved in AgNPs biosynthesis by identifying different functional groups involved in effective capping of AgNPs. The biosynthesized AgNPs significantly inhibited the growth of medically important pathogenic Gram-positive (Staphylococcus aureus), Gram negative bacteria (Pseudomonas aeruginosa, E. coli and Klebsiella pneumonia). The synthesized AgNPs exhibited effective cytotoxic activity against MCF-7 and the inhibitory concentration (IC50) was recorded at 27.79 +/- 2.3 ug/mL. The in vivo studies clearly indicated that AgNPs has a capacity to inhibit the growth of tumor in Ehrlich ascites carcinoma bearing mice. PMID- 28883420 TI - Personalized structural image analysis in patients with temporal lobe epilepsy. AB - Volumetric and morphometric studies have demonstrated structural abnormalities related to chronic epilepsies on a cohort- and population-based level. On a single-patient level, specific patterns of atrophy or cortical reorganization may be widespread and heterogeneous but represent potential targets for further personalized image analysis and surgical therapy. The goal of this study was to compare morphometric data analysis in 37 patients with temporal lobe epilepsies with expert-based image analysis, pre-informed by seizure semiology and ictal scalp EEG. Automated image analysis identified abnormalities exceeding expert determined structural epileptogenic lesions in 86% of datasets. If EEG lateralization and expert MRI readings were congruent, automated analysis detected abnormalities consistent on a lobar and hemispheric level in 82% of datasets. However, in 25% of patients EEG lateralization and expert readings were inconsistent. Automated analysis localized to the site of resection in 60% of datasets in patients who underwent successful epilepsy surgery. Morphometric abnormalities beyond the mesiotemporal structures contributed to subtype characterisation. We conclude that subject-specific morphometric information is in agreement with expert image analysis and scalp EEG in the majority of cases. However, automated image analysis may provide non-invasive additional information in cases with equivocal radiological and neurophysiological findings. PMID- 28883421 TI - Changes in specific leaf area of dominant plants in temperate grasslands along a 2500-km transect in northern China. AB - Specific leaf area (SLA) is a key trait with great ecological importance as it correlates with whole plant growth. We aimed to investigate how SLA varies with environmental factors at a geographical scale in temperate grasslands. We measured SLA and mass-based leaf nitrogen content (N mass) of four dominant plant genera along a 2500 km climatic gradient in northern China grassland, and correlated SLA with mean annual precipitation (MAP), mean annual temperature (MAT), soil nitrogen concentration (soil N), soil C:N and N mass. Climate accounts much more for SLA variation than soil variables for Stipa, Cleistogens and Carex. SLA of Stipa is negatively associated with MAP and soil N, while positively with MAT, but Cleistogenes and Carex show the opposite. For Leymus, soil N promotes SLA and accounts for largest fraction of SLA variation. Overall, SLA was positively correlated with N mass in semi-arid regions, but not significant in arid regions. The genus-dependent responses of SLA may have consequences on ecosystem functioning, thus may help to predict the community composition and ecosystem functions under future climate scenario. The finding of SLA-N mass trade-off and its susceptibility to precipitation will advance our understanding on plant resource use strategies. PMID- 28883422 TI - Effect of Metabolic Syndrome on the Functional Outcome of Corticosteroid Injection for Lateral Epicondylitis: Retrospective Matched Case-Control Study. AB - Both obesity and diabetes mellitus are well-known risk factors for tendinopathies. We retrospectively compared the efficacy of single corticosteroid injections in treating lateral epicondylitis in patients with and without metabolic syndrome (MetS). Fifty-one patients with lateral epicondylitis and MetS were age- and sex-matched with 51 controls without MetS. Pain severity, Disability of the Arm, Shoulder, and Hand score, and grip strength were assessed at base line and at 6, 12 and 24 weeks post-injection. The pain scores in the MetS group were greater than those in the control group at 6 and 12 weeks. The disability scores and grip strength in the MetS group were significantly worse than those of the control group at 6 weeks. However, there were no significant differences at 24 weeks between the groups in terms of pain, disability scores and grip strengths. After 24 weeks, three patients (6%) in the control group and five patients (10%) in the MetS group had surgical decompression (p = 0.46). Patients with MetS are at risk for poor functional outcome after corticosteroid injection for lateral epicondylitis in the short term, but in the long term there was no difference in outcomes of steroid injection in patients with and without MetS. PMID- 28883423 TI - Conductance through a helical state in an Indium antimonide nanowire. AB - The motion of an electron and its spin are generally not coupled. However in a one-dimensional material with strong spin-orbit interaction (SOI) a helical state may emerge at finite magnetic fields, where electrons of opposite spin will have opposite momentum. The existence of this helical state has applications for spin filtering and cooper pair splitter devices and is an essential ingredient for realizing topologically protected quantum computing using Majorana zero modes. Here, we report measurements of a quantum point contact in an indium antimonide nanowire. At magnetic fields exceeding 3 T, the 2 e 2/h conductance plateau shows a re-entrant feature toward 1 e 2/h which increases linearly in width with magnetic field. Rotating the magnetic field clearly attributes this experimental signature to SOI and by comparing our observations with a numerical model we extract a spin-orbit energy of approximately 6.5 meV, which is stronger than the spin-orbit energy obtained by other methods.Indium antimonide nanowires have large spin-orbit coupling, which can give rise to helical states that are an important part of proposals for topological quantum computing. Here the authors measure conductance through the helical states and extract a larger spin-orbit energy than obtained before. PMID- 28883424 TI - Efficient post-acceleration of protons in helical coil targets driven by sub-ps laser pulses. AB - The characteristics of laser driven proton beams can be efficiently controlled and optimised by employing a recently developed helical coil technique, which exploits the transient self-charging of solid targets irradiated by intense laser pulses. Here we demonstrate a well collimated (<1 degrees divergence) and narrow bandwidth (~10% energy spread) proton beamlet of ~107 particles at 10 +/- 0.5 MeV obtained by irradiating helical coil targets with a few joules, sub-ps laser pulses at an intensity of ~2 * 1019 W cm-2. The experimental data are in good agreement with particle tracing simulations suggesting post-acceleration of protons inside the coil at a rate ~0.7 MeV/mm, which is comparable to the results obtained from a similar coil target irradiated by a fs class laser at an order of magnitude higher intensity, as reported in S. Kar et al., Nat. Commun, 7, 10792 (2016). The dynamics of hot electron escape from the laser irradiated target was studied numerically for these two irradiation regimes, which shows that the target self-charging can be optimised at a pulse duration of few hundreds of fs. This information is highly beneficial for maximising the post-acceleration gradient in future experiments. PMID- 28883425 TI - Computational genome-wide survey of odorant receptors from two solitary bees Dufourea novaeangliae (Hymenoptera: Halictidae) and Habropoda laboriosa (Hymenoptera: Apidae). AB - Olfactory/odorant receptors (ORs) probably govern eusocial behaviour in honey bees through detection of cuticular hydrocarbons (CHCs) and queen mandibular gland pheromones (QMP). CHCs are involved in nest-mate recognition whereas QMP acts as sex pheromone for drones and as retinue pheromone for female workers. Further studies on the effect of eusociality on the evolution of ORs are hindered by the non-availability of comprehensive OR sets of solitary species. We report complete OR repertoires from two solitary bees Dufourea novaeangliae (112 ORs) and Habropoda laboriosa (151 ORs). We classify these ORs into 34 phylogenetic clades/subfamilies. Differences in the OR sets of solitary and eusocial bees are observed in individual subfamilies like subfamily 9-exon (putative CHC receptors) and L (contains putative QMP receptor group). A subfamily (H) including putative floral scent receptors is expanded in the generalist honey bees only, but not in the specialists. On the contrary, subfamily J is expanded in all bees irrespective of their degree of social complexity or food preferences. Finally, we show species-lineage specific and OR-subfamily specific differences in the putative cis-regulatory DNA motifs of the ORs from six hymenopteran species. Out of these, [A/G]CGCAAGCG[C/T] is a candidate master transcription factor binding site for multiple olfactory genes. PMID- 28883426 TI - Bioaccumulation and biomagnification of short and medium chain polychlorinated paraffins in different species of fish from Liaodong Bay, North China. AB - Chlorinated paraffins (CPs) are highly complex technical mixtures, and the short chain chlorinated paraffins (SCCPs) are classed as persistent and have been included in the Stockholm Convention. However, there have been few studies of SCCPs and medium chain chlorinated paraffins (MCCPs) and their bioaccumulation and biomagnification in different species of fish. The present study investigated the levels, congener group profiles, bioaccumulation, and biomagnification of SCCPs and MCCPs in different species of fish from Liaodong Bay, North China. The ranges for the SigmaSCCP and SigmaMCCP concentrations were 376.3-8596 ng/g lipid weight (lw) and 22.37-5097 ng/g lw, respectively. The logarithms of bioaccumulation factors of SigmaSCCPs ranged from 4.69 to 6.05, implying that SCCPs bioaccumulated in the fish. The trophic magnification factor of SigmaSCCPs was 2.57, indicating that SCCPs could biomagnify in fish. Carbon chain length, the numbers of chlorine atoms, and octanol/water partition coefficients of the SCCPs and MCCPs might be important factors affecting the bioaccumulation of these chemicals in fish. The risk posed to human health by consumption of fish containing SCCPs was low. New SCCPs with nine carbons (C9) were detected in fish in this study. PMID- 28883428 TI - Assessing SNP genotyping of noninvasively collected wildlife samples using microfluidic arrays. AB - Noninvasively collected samples are a common source of DNA in wildlife genetic studies. Currently, single nucleotide polymorphism (SNP) genotyping using microfluidic arrays is emerging as an easy-to-use and cost-effective methodology. Here we assessed the performance of microfluidic SNP arrays in genotyping noninvasive samples from grey wolves, European wildcats and brown bears, and we compared results with traditional microsatellite genotyping. We successfully SNP genotyped 87%, 80% and 97% of the wolf, cat and bear samples, respectively. Genotype recovery was higher based on SNPs, while both marker types identified the same individuals and provided almost identical estimates of pairwise differentiation. We found that samples for which all SNP loci were scored had no disagreements across the three replicates (except one locus in a wolf sample). Thus, we argue that call rate (amplification success) can be used as a proxy for genotype quality, allowing the reduction of replication effort when call rate is high. Furthermore, we used cycle threshold values of real-time PCR to guide the choice of protocols for SNP amplification. Finally, we provide general guidelines for successful SNP genotyping of degraded DNA using microfluidic technology. PMID- 28883427 TI - Tau exacerbates excitotoxic brain damage in an animal model of stroke. AB - Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau-/-) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau-/- mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.Excitotoxicity contributes to neuronal injury following stroke. Here the authors show that tau promotes excitotoxicity by a post-synaptic mechanism, involving site-specific control of ERK activation, in a mouse model of stroke. PMID- 28883429 TI - A method for estimating intracellular ion concentration using optical nanosensors and ratiometric imaging. AB - Optical nanoparticle (NP)-based sensors have been widely implemented as tools for detection of targeted ions and biomolecules. The NP sensing platform offer a modular design that can incorporate different sensing components for greater target specificity and the ability to tune the dynamic range, as well as encapsulation of multiple dyes to generate a ratiometric signal with varying spectra. Despite these advantages, demonstrating quantitative ion imaging for intracellular measurement still possess a major challenge. Here, we describe fundamentals that enable intracellular validation of this approach using ion selective nanosensors for investigating calcium (Ca2+) as a model ion. While conventional indicators can improve individual aspects of indicator performance such as Kd, wavelength, and ratiometric measurements, the use of NP sensors can achieve combined benefits of addressing these issues simultaneously. The nanosensor incorporates highly calcium-selective ionophores and two fluorescence indicators that act as signal transducers to facilitate quantitative ratiometric imaging. For intracellular Ca2+ application, the sensors are fine-tuned to physiological sensing range, and live-cell imaging and quantification are demonstrated in HeLa cells loaded with nanosensors and their responsiveness to carbachol-evoked store release (~400 nM). The current nanosensor design thus provides a promising sensing platform for real-time detection and optical determination of intracellular ions. PMID- 28883430 TI - Magneto-actuated cell apoptosis by biaxial pulsed magnetic field. AB - We report on a highly efficient magneto-actuated cancer cell apoptosis method using a biaxial pulsed magnetic field configuration, which maximizes the induced magnetic torque. The light transmissivity dynamics show that the biaxial magnetic field configuration can actuate the magnetic nanoparticles with higher responsiveness over a wide range of frequencies as compared to uniaxial field configurations. Its efficacy was demonstrated in in vitro cell destruction experiments with a greater reduction in cell viability. Magnetic nanoparticles with high aspect ratios were also found to form a triple vortex magnetization at remanence which increases its low field susceptibility. This translates to a larger magneto-mechanical actuated force at low fields and 12% higher efficacy in cell death as compared to low aspect ratio nanoparticles. PMID- 28883431 TI - Association Between Body Mass Index Combined with Albumin: creatinine Ratio and All-cause Mortality in Chinese Population. AB - The association between body mass index (BMI) combined with albumin: creatinine ratio (ACR) and all-cause mortality in the general population has not been established. To address this, we examined a representative sample from the general population of China. The study included 46,854 participants with a follow up of 4.6 years. Compared to the normal weight with ACR <10 mg/g group (the reference group), the crude hazard ratios (HRs) for all-cause mortality for the underweight with ACR >10 mg/g, normal weight with ACR >10 mg/g, overweight with ACR >10 mg/g, and obese with ACR >10 mg/g groups, were 2.22 (95% CI, 1.41 to 3.49), 1.70 (95% CI, 1.42 to 2.04), 1.52 (95% CI, 1.22 to 1.89), and 2.05 (95% CI, 1.45 to 2.89), respectively. After multivariable adjustments for age, race, comorbidities, and baseline eGFR, the HRs for the underweight with ACR >10 mg/g and normal weight with ACR >10 mg/g groups were 1.85 (95% CI, 1.17 to 2.91) and 1.36 (95% CI, 1.13 to 1.63), respectively. The results indicate that BMI combined with ACR can better predict all-cause mortality than BMI alone in the general Chinese population. Underweight and normal weight people with elevated ACR are at a higher risk of all-cause mortality than those in the same BMI category with ACR <10 mg/g. PMID- 28883432 TI - Quantitative Phosphoproteomic Analysis Reveals Key Mechanisms of Cellular Proliferation in Liver Cancer Cells. AB - Understanding the mechanisms of uncontrolled proliferation in cancer cells provides valuable insights into tumor development and is benefit for discovering efficient methods in cancer treatment. In this study, we identified and quantified 2,057 phosphoproteins and 9,824 unique phosphosites in three liver cell lines with high (QGY, Hep3B) and low (L02) proliferative potentials and disclosed the wide variations in phosphorylation sites and levels among them. We found that the number of identified phosphoproteins and phosphosites in these cells were negatively correlated with their proliferative abilities. The function analysis suggested that the aberrant phosphorylation of SR proteins and activation of MAPK pathway might be two critical factors to promote cancer cell proliferation. Meanwhile, the phosphorylation status of mini-chromosome maintenance (MCM) and nuclear pore (NPC) complexes are significantly different between cell lines with high and low proliferative potentials. Furthermore, the phosphosites targeted by kinase families of CDK, STE and HIPK in the proteins coded by cancer driver genes showed distinct profiles between caner and normal cell lines. These results present key phosphorylation networks involving in abnormal proliferation of cancer cells and uncovered potential molecular markers for estimating the proliferation ability of liver cancer cells. PMID- 28883433 TI - In situ wrapping of the cathode material in lithium-sulfur batteries. AB - While lithium-sulfur batteries are poised to be the next-generation high-density energy storage devices, the intrinsic polysulfide shuttle has limited their practical applications. Many recent investigations have focused on the development of methods to wrap the sulfur material with a diffusion barrier layer. However, there is a trade-off between a perfect preassembled wrapping layer and electrolyte infiltration into the wrapped sulfur cathode. Here, we demonstrate an in situ wrapping approach to construct a compact layer on carbon/sulfur composite particles with an imperfect wrapping layer. This special configuration suppresses the shuttle effect while allowing polysulfide diffusion within the interior of the wrapped composite particles. As a result, the wrapped cathode for lithium-sulfur batteries greatly improves the Coulombic efficiency and cycle life. Importantly, the capacity decay of the cell at 1000 cycles is as small as 0.03% per cycle at 1672 mA g-1.To suppress the polysulfide shuttling effect in Li-S batteries, here the authors report a carbon/sulfur composite cathode with a wrapping layer that overcomes the trade-off between limiting polysulfide diffusion and allowing electrolyte infiltration, and affords extraordinary cycling stability. PMID- 28883434 TI - Automated video-mosaicking approach for confocal microscopic imaging in vivo: an approach to address challenges in imaging living tissue and extend field of view. AB - We describe a computer vision-based mosaicking method for in vivo videos of reflectance confocal microscopy (RCM). RCM is a microscopic imaging technique, which enables the users to rapidly examine tissue in vivo. Providing resolution at cellular-level morphology, RCM imaging combined with mosaicking has shown to be highly sensitive and specific for non-invasively guiding skin cancer diagnosis. However, current RCM mosaicking techniques with existing microscopes have been limited to two -dimensional sequences of individual still images, acquired in a highly controlled manner, and along a specific predefined raster path, covering a limited area. The recent advent of smaller handheld microscopes is enabling acquisition of videos, acquired in a relatively uncontrolled manner and along an ad-hoc arbitrarily free-form, non-rastered path. Mosaicking of video images (video-mosaicking) is necessary to display large areas of tissue. Our video-mosaicking methods addresses this need. The method can handle unique challenges encountered during video capture such as motion blur artifacts due to rapid motion of the microscope over the imaged area, warping in frames due to changes in contact angle and varying resolution with depth. We present test examples of video-mosaics of melanoma and non-melanoma skin cancers, to demonstrate potential clinical utility. PMID- 28883435 TI - A massive tsunami promoted gene flow and increased genetic diversity in a near threatened plant species. AB - The magnitude and frequency of disturbances affect species diversity and spatial distributions, but the direct effects of large-scale disturbances on genetic diversity are poorly understood. On March 11, 2011, the Great Tohoku Earthquake in Japan caused a massive tsunami that resulted in substantial alteration of community compositions. Populations of a near-threatened tidal marsh Carex rugulosa inhabiting brackish sandbars was also affected. We found four out of six remnant C. rugulosa populations along the Pacific Ocean had become completely extinct. Newly emergent post-tsunami populations, however, had higher allelic numbers than pre-tsunami populations, indicating higher genetic diversity after the tsunami. In addition, genetic differentiation (Fst) between post-tsunami populations was significantly lower than that of pre-tsunami populations. We therefore conclude that the tsunami enhanced gene flow. Seeds of many Carex species persist for long periods in soil, which suggests that seed banks are important genetic resources for post-disturbance recovery of genetic diversity. When its brackish sandbar habitat is no longer subject to disturbance and changes to the land, C. rugulosa is outcompeted by terrestrial plant competitors and eliminated. Disturbance is a driving force for the recovery and maintenance of populations of species such as C. rugulosa-even after near-complete eradication. PMID- 28883437 TI - Alpha subunit-dependent glycine receptor clustering and regulation of synaptic receptor numbers. AB - Accumulation of glycine receptors at synapses requires the interaction between the beta subunit of the receptor and the scaffold protein gephyrin. Here, we questioned whether different alpha subunits could modulate the receptors' diffusion and propensity to cluster at spinal cord synapses. Using quantitative photoactivated localisation microscopy we found that alpha-1 and alpha-3 containing glycine receptors display the same alpha3:beta2 stoichiometry and gephyrin binding. Despite these similarities, alpha-3 containing receptors are less mobile and cluster at higher density compared to alpha-1, with 1500 versus 1100 complexes um-2, respectively. Furthermore, we identified a subunit-specific regulation of glycine receptor copy numbers at synapses: when challenged with interleukin 1beta, the synaptic occupancy of alpha-1 but not alpha-3 receptors was reduced. This mechanism may play a role in the cell-type dependent regulation of glycinergic currents in response to interleukin 1beta and highlights the capacity of the alpha subunits to affect receptor-gephyrin binding at synapses. PMID- 28883436 TI - Pandemic 2009 H1N1 Influenza Venus reporter virus reveals broad diversity of MHC class II-positive antigen-bearing cells following infection in vivo. AB - Although it is well established that Influenza A virus infection is initiated in the respiratory tract, the sequence of events and the cell types that become infected or access viral antigens remains incompletely understood. In this report, we used a novel Influenza A/California/04/09 (H1N1) reporter virus that stably expresses the Venus fluorescent protein to identify antigen-bearing cells over time in a mouse model of infection using flow cytometry. These studies revealed that many hematopoietic cells, including subsets of monocytes, macrophages, dendritic cells, neutrophils and eosinophils acquire influenza antigen in the lungs early post-infection. Surface staining of the viral HA revealed that most cell populations become infected, most prominently CD45neg cells, alveolar macrophages and neutrophils. Finally, differences in infection status, cell lineage and MHC class II expression by antigen-bearing cells correlated with differences in their ability to re-stimulate influenza-specific CD4 T cells ex vivo. Collectively, these studies have revealed the cellular heterogeneity and complexity of antigen-bearing cells within the lung and their potential as targets of antigen recognition by CD4 T cells. PMID- 28883438 TI - Stretchable Dual-Capacitor Multi-Sensor for Touch-Curvature-Pressure-Strain Sensing. AB - We introduce a new type of multi-functional capacitive sensor that can sense several different external stimuli. It is fabricated only with polydimethylsiloxane (PDMS) films and silver nanowire electrodes by using selective oxygen plasma treatment method without photolithography and etching processes. Differently from the conventional single-capacitor multi-functional sensors, our new multi-functional sensor is composed of two vertically-stacked capacitors (dual-capacitor). The unique dual-capacitor structure can detect the type and strength of external stimuli including curvature, pressure, strain, and touch with clear distinction, and it can also detect the surface-normal directionality of curvature, pressure, and touch. Meanwhile, the conventional single-capacitor sensor has ambiguity in distinguishing curvature and pressure and it can detect only the strength of external stimulus. The type, directionality, and strength of external stimulus can be determined based on the relative capacitance changes of the two stacked capacitors. Additionally, the logical flow reflected on a tree structure with its branches reaching the direction and strength of the corresponding external stimulus unambiguously is devised. This logical flow can be readily implemented in the sensor driving circuit if the dual-capacitor sensor is commercialized actually in the future. PMID- 28883439 TI - T cells display mitochondria hyperpolarization in human type 1 diabetes. AB - T lymphocytes constitute a major effector cell population in autoimmune type 1 diabetes. Despite essential functions of mitochondria in regulating activation, proliferation, and apoptosis of T cells, little is known regarding T cell metabolism in the progression of human type 1 diabetes. In this study, we report, using two independent cohorts, that T cells from patients with type 1 diabetes exhibited mitochondrial inner-membrane hyperpolarization (MHP). Increased MHP was a general phenotype observed in T cell subsets irrespective of prior antigen exposure, and was not correlated with HbA1C levels, subject age, or duration of diabetes. Elevated T cell MHP was not detected in subjects with type 2 diabetes. T cell MHP was associated with increased activation-induced IFNgamma production, and activation-induced IFNgamma was linked to mitochondria-specific ROS production. T cells from subjects with type 1 diabetes also exhibited lower intracellular ATP levels. In conclusion, intrinsic mitochondrial dysfunction observed in type 1 diabetes alters mitochondrial ATP and IFNgamma production; the latter is correlated with ROS generation. These changes impact T cell bioenergetics and function. PMID- 28883440 TI - Mechanism and DNA-based detection of field-evolved resistance to transgenic Bt corn in fall armyworm (Spodoptera frugiperda). AB - Evolution of resistance threatens sustainability of transgenic crops producing insecticidal proteins from the bacterium Bacillus thuringiensis (Bt). The fall armyworm (Spodoptera frugiperda) is a devastating pest of corn in the Western Hemisphere initially controlled by transgenic Bt corn producing the Cry1Fa insecticidal protein (event TC1507). However field-evolved resistance to TC1507 was observed in Puerto Rico in 2007 and has subsequently been reported in a number of locations in North and South America. Early studies on Puerto Rico fall armyworm populations found that the resistance phenotype was associated with reduced expression of alkaline phosphatase. However, in this work we show that field-evolved resistance to Cry1Fa Bt corn in Puerto Rico is closely linked to a mutation in an ATP Binding Cassette subfamily C2 (ABCC2) gene that functions as a Cry1Fa receptor in susceptible insects. Furthermore, we report a DNA-based genotyping test used to demonstrate the presence of the resistant (SfABCC2mut) allele in Puerto Rico populations in 2007, coincident with the first reports of damage to TC1507 corn. These DNA-based field screening data provide strong evidence that resistance to TC1507 in fall armyworm maps to the SfABCC2 gene and provides a useful molecular marker for detecting the SfABCC2mut allele in resistant fall armyworm. PMID- 28883441 TI - Spatio-Temporal Patterns of the International Merger and Acquisition Network. AB - This paper analyses the world web of mergers and acquisitions (M&As) using a complex network approach. We use data of M&As to build a temporal sequence of binary and weighted-directed networks for the period 1995-2010 and 224 countries (nodes) connected according to their M&As flows (links). We study different geographical and temporal aspects of the international M&A network (IMAN), building sequences of filtered sub-networks whose links belong to specific intervals of distance or time. Given that M&As and trade are complementary ways of reaching foreign markets, we perform our analysis using statistics employed for the study of the international trade network (ITN), highlighting the similarities and differences between the ITN and the IMAN. In contrast to the ITN, the IMAN is a low density network characterized by a persistent giant component with many external nodes and low reciprocity. Clustering patterns are very heterogeneous and dynamic. High-income economies are the main acquirers and are characterized by high connectivity, implying that most countries are targets of a few acquirers. Like in the ITN, geographical distance strongly impacts the structure of the IMAN: link-weights and node degrees have a non-linear relation with distance, and an assortative pattern is present at short distances. PMID- 28883442 TI - Interdisciplinary, Comprehensive Oral and Ocular Evaluation of Patients with Primary Sjogren's Syndrome. AB - A comprehensive evaluation of oral and ocular symptoms and findings in primary Sjogren's syndrome (pSS) patients may provide valuable information for management. Medical history was obtained from female pSS patients, and sex- and age-matched non-SS patients with sicca symptoms (non-SS sicca controls) as well as healthy subjects without sicca complaints (healthy controls). Oral (Summated Xerostomia Inventory, SXI) and ocular (McMonnies Dry Eye questionnaire, MDEIS, and Ocular Surface Disease Index, OSDI) subjective complaints were recorded. Objective findings including clinical oral dryness scores (CODS), unstimulated and stimulated saliva secretion rates (UWS/SWS), Schirmer I test, tear osmolarity, tear film break-up time (TFBUT), and ocular surface staining (OSS) were determined. The pSS and non-SS sicca controls were extensively troubled by subjective dryness, while the pSS group had higher CODS, significantly lower saliva and tear secretion, shorter TFBUT and higher OSS than both control groups. Furthermore, candida counts were significantly higher in the pSS patients. In the pSS group, subjective oral dryness significantly correlated with ocular dryness (MDEIS: r = 0.5, OSDI: r = 0.413) and SWS was significantly correlated with Schirmer I (r = 0.419). The findings imply that interdisciplinary subjective and objective evaluation of patients with xerostomia and xerophthalmia not only have implications for patient care, but also may guide clinicians in differentiating between pSS and non-SS sicca patients. PMID- 28883444 TI - The effect of a high frequency electromagnetic field in the microwave range on red blood cells. AB - The effect of red blood cells (RBC) exposed to an 18 GHz electromagnetic field (EMF) was studied. The results of this study demonstrated for the first time that exposure of RBCs to 18 GHz EMF has the capacity to induce nanospheres uptake in RBCs. The uptake of nanospheres (loading efficiency 96% and 46% for 23.5 and 46.3 nm nanospheres respectively), their presence and locality were confirmed using three independent techniques, namely scanning electron microscopy, confocal laser scanning microscopy and transmission electron microscopy. It appeared that 23.5 nm nanospheres were translocated through the membrane into the cytosol, while the 46.3 nm-nanospheres were mostly translocated through the phospholipid-cholesterol bilayer, with only some of these nanospheres passing the 2D cytoskeleton network. The nanospheres uptake increased by up to 12% with increasing temperature from 33 to 37 degrees C. The TEM analysis revealed that the nanospheres were engulfed by the cell membrane itself, and then translocated into the cytosol. It is believed that EMF-induced rotating water dipoles caused disturbance of the membrane, initiating its deformation and result in an enhanced degree of membrane trafficking via a quasi-exocytosis process. PMID- 28883443 TI - Planar polarized Rab35 functions as an oscillatory ratchet during cell intercalation in the Drosophila epithelium. AB - The coordination between membrane trafficking and actomyosin networks is essential to the regulation of cell and tissue shape. Here, we examine Rab protein distributions during Drosophila epithelial tissue remodeling and show that Rab35 is dynamically planar polarized. Rab35 compartments are enriched at contractile interfaces of intercalating cells and provide the first evidence of interfacial monopolarity. When Rab35 function is disrupted, apical area oscillations still occur and contractile steps are observed. However, contractions are followed by reversals and interfaces fail to shorten, demonstrating that Rab35 functions as a ratchet ensuring unidirectional movement. Although actomyosin forces have been thought to drive interface contraction, initiation of Rab35 compartments does not require Myosin II function. However, Rab35 compartments do not terminate and continue to grow into large elongated structures following actomyosin disruption. Finally, Rab35 represents a common contractile cell-shaping mechanism, as mesoderm invagination fails in Rab35 compromised embryos and Rab35 localizes to constricting surfaces.Various stages of tissue morphogenesis involve the contraction of epithelial surfaces. Here, the authors identify the Rab GTPase Rab35 as an essential component of this contractile process, which functions as a membrane ratchet to ensure unidirectional movement of intercalating cells. PMID- 28883445 TI - Plant litter dynamics in the forest-stream interface: precipitation is a major control across tropical biomes. AB - Riparian plant litter is a major energy source for forested streams across the world and its decomposition has repercussions on nutrient cycling, food webs and ecosystem functioning. However, we know little about plant litter dynamics in tropical streams, even though the tropics occupy 40% of the Earth's land surface. Here we investigated spatial and temporal (along a year cycle) patterns of litter inputs and storage in multiple streams of three tropical biomes in Brazil (Atlantic forest, Amazon forest and Cerrado savanna), predicting major differences among biomes in relation to temperature and precipitation regimes. Precipitation explained most of litter inputs and storage, which were generally higher in more humid biomes (litterfall: 384, 422 and 308 g m-2 y-1, storage: 55, 113 and 38 g m-2, on average in Atlantic forest, Amazon and Cerrado, respectively). Temporal dynamics varied across biomes in relation to precipitation and temperature, with uniform litter inputs but seasonal storage in Atlantic forest streams, seasonal inputs in Amazon and Cerrado streams, and aseasonal storage in Amazon streams. Our findings suggest that litter dynamics vary greatly within the tropics, but point to the major role of precipitation, which contrasts with the main influence of temperature in temperate areas. PMID- 28883447 TI - Software for improved field surveys of nesting marine turtles. AB - Field data are still recorded on paper in many worldwide beach surveys of nesting marine turtles. The data must be subsequently transferred into an electronic database, and this can introduce errors in the dataset. To minimize such errors, the "Turtles" software was developed and piloted to record field data by one software user accompanying one Tortuguero in Akumal beaches, Quintana Roo, Mexico, from June 1st to July 31st during the night patrols. Comparisons were made between exported data from the software with the paper forms entered into a database (henceforth traditional). Preliminary assessment indicated that the software user tended to record a greater amount of metrics (i.e., an average of 18.3 fields +/- 5.4 sd vs. 8.6 fields +/- 2.1 sd recorded by the traditional method). The traditional method introduce three types of "errors" into a dataset: missing values in relevant fields (40.1%), different answers for the same value (9.8%), and inconsistent data (0.9%). Only 5.8% of these (missing values) were found with the software methodology. Although only tested by a single user, the software may suggest increased efficacy and warrants further examination to accurately assess the merit of replacing traditional methods of data recording for beach monitoring programmes. PMID- 28883446 TI - Biomass burning in the Amazon region causes DNA damage and cell death in human lung cells. AB - Most of the studies on air pollution focus on emissions from fossil fuel burning in urban centers. However, approximately half of the world's population is exposed to air pollution caused by biomass burning emissions. In the Brazilian Amazon population, over 10 million people are directly exposed to high levels of pollutants resulting from deforestation and agricultural fires. This work is the first study to present an integrated view of the effects of inhalable particles present in emissions of biomass burning. Exposing human lung cells to particulate matter smaller than 10 um (PM10), significantly increased the level of reactive oxygen species (ROS), inflammatory cytokines, autophagy, and DNA damage. Continued PM10 exposure activated apoptosis and necrosis. Interestingly, retene, a polycyclic aromatic hydrocarbon present in PM10, is a potential compound for the effects of PM10, causing DNA damage and cell death. The PM10 concentrations observed during Amazon biomass burning were sufficient to induce severe adverse effects in human lung cells. Our study provides new data that will help elucidate the mechanism of PM10-mediated lung cancer development. In addition, the results of this study support the establishment of new guidelines for human health protection in regions strongly impacted by biomass burning. PMID- 28883448 TI - Effects of influent C/N ratios and treatment technologies on integral biogas upgrading and pollutants removal from synthetic domestic sewage. AB - Three different treatment technologies, namely mono-algae culture, algal bacterial culture, and algal-fungal culture, were applied to remove pollutants form synthetic domestic sewage and to remove CO2 from biogas in a photobioreactor. The effects of different initial influent C/N ratios on microalgal growth rates and pollutants removal efficiencies by the three microalgal cultures were investigated. The best biogas upgrading and synthetic domestic sewage pollutants removal effect was achieved in the algal-fungal system at the influent C/N ratio of 5:1. At the influent C/N ratio of 5:1, the algal fungal system achieved the highest mean chemical oxygen demand (COD) removal efficiency of 81.92% and total phosphorus (TP) removal efficiency of 81.52%, respectively, while the algal-bacterial system demonstrated the highest mean total nitrogen (TN) removal efficiency of 82.28%. The average CH4 concentration in upgraded biogas and the removal efficiencies of COD, TN, and TP were 93.25 +/- 3.84% (v/v), 80.23 +/- 3.92%, 75.85 +/- 6.61%, and 78.41 +/- 3.98%, respectively. These results will provide a reference for wastewater purification ad biogas upgrading with microalgae based technology. PMID- 28883450 TI - Virome analysis for identification of novel mammalian viruses in bats from Southeast China. AB - Bats have been shown as important mammal resevoirs to carry a variety of zoonotic pathogens. To analyze pathogenic species in bats from southeast coastal regions of China, we performed metagenomic sequencing technology for high throughput sequencing of six sentinels from southeast coastal area of China. We obtained 5,990,261 high quality reads from intestine and lung tissue of 235 bats, including 2,975,371 assembled sequences. 631,490 reads predicted overlapping sequences for the open reading frame (ORF), which accounts for 2.37% of all the sequences (15,012/631,490). Further, the acquired virus sequences were classified into 25 viral families, including 16 vertebrate viruses, four plant viruses and five insect viruses. All bat samples were screened by specific PCR and phylogenetic analysis. Using these techniques, we discovered many novel bat viruses and some bat viruses closely-related to known human/animal pathogens, including coronavirus, norovirus, adenovirus, bocavirus, astrovirus, and circovirus. In summary, this study extended our understanding of bats as the viral reservoirs. Additionally, it also provides a basis for furher studying the transmission of viruses from bats to humans. PMID- 28883451 TI - Magnetic states of nanostructures containing Ni2+ ions at the surface of SiO2 nanospheres. AB - Ultra-small magnetic particles containing Ni2+ ions were grown at the surface of SiO2 spheroidal nanoparticles (typical diameter: 50 nm) starting from NiCl2 solutions. Depending on preparation details, two samples characterized by magnetic sub-nanostructures or lamellar sub-nanoparticles at the SiO2 nanosphere surface were obtained. The decorated SiO2 nanospheres were submitted to physico chemical and magnetic characterization. In both samples, a magnetically blocked phase is observed at low temperature. Below 5 K, discontinuities in isothermal magnetization loops and magnetic relaxation effects suggest the onset of coherent quantum tunneling of nanoparticle magnetization (QTM). Relaxation effects give are described by a field- and temperature-dependent magnetic viscosity SV(H,T); the total spin number of magnetic units is estimated by fitting the isothermal SV(H) curve to a model for an assembly of particles with random anisotropy axes. The mean number of aligned spins involved in the low-temperature relaxation is 32 and 15 in the two considered samples. Phonon-assisted QTM plays an increasingly important role with raising temperature and the quantum regime gradually merges with the classical behavior. Above the blocking temperature the magnetic units behave as classical superparamagnetic particles. When the intra-particle ferromagnetic order disappears the Ni2+ ions respond individually to the magnetic field. PMID- 28883449 TI - Graphene Quantum Dot Solid Sheets: Strong blue-light-emitting & photocurrent producing band-gap-opened nanostructures. AB - Graphene has been studied intensively in opto-electronics, and its transport properties are well established. However, efforts to induce intrinsic optical properties are still in progress. Herein, we report the production of micron sized sheets by interconnecting graphene quantum dots (GQDs), which are termed 'GQD solid sheets', with intrinsic absorption and emission properties. Since a GQD solid sheet is an interconnected QD system, it possesses the optical properties of GQDs. Metal atoms that interconnect the GQDs in the bottom-up hydrothermal growth process, induce the semiconducting behaviour in the GQD solid sheets. X-ray absorption measurements and quantum chemical calculations provide clear evidence for the metal-mediated growth process. The as-grown graphene quantum dot solids undergo a Forster Resonance Energy Transfer (FRET) interaction with GQDs to exhibit an unconventional 36% photoluminescence (PL) quantum yield in the blue region at 440 nm. A high-magnitude photocurrent was also induced in graphene quantum dot solid sheets by the energy transfer process. PMID- 28883452 TI - Release and Degradation of Microencapsulated Spinosad and Emamectin Benzoate. AB - The dynamics of release and degradation of the microencapsulation formulation containing spinosad (SP) and emamectin benzoate (EM) were evaluated in the present study. SP and EM were microencapsulated using biodegradable poly-lactic acid (PLA) as the wall material. Their release from and degradation within the prepared SP and EM microspheres (SP-EM-microspheres) were studied. It was found that the encapsulation significantly prolonged the insecticide release. The release could be further extended if the external aqueous phase was pre-saturated with the insecticides and the microspheres were additionally coated with gelatin. On the other hand, increasing the water content of the emulsion or the hydrophilic polycaprolactone (PCL) content in the PLA/PCL mixture accelerated the release. Due to the photolysis and hydrolysis of SP and EM by sunlight, the toxicity of the non-encapsulated insecticides in water declined continuously from 0 through the 9th day (d), and dissipated in 13 d. In contrast, an aqueous suspension containing 5% SP-EM-microspheres maintained a mostly constant toxicity to Plutella xylostella for 17 d. The biodegradable SP-EM-microspheres showed significantly higher long-term toxicity to P. xylostella due to lower release, reduced photolysis and hydrolysis of the encapsulated insecticides, which were affected by the varied preparation conditions. PMID- 28883454 TI - Structural basis for functional selectivity and ligand recognition revealed by crystal structures of human secreted phospholipase A2 group IIE. AB - Secreted phospholipases A2s (sPLA2s) are involved in various pathological conditions such as rheumatoid arthritis and cardiovascular disease. Many inhibitors were developed and studied in clinical trials, but none have reached the market yet. This failure may be attributed to the lack of subtype selectivity for these inhibitors. Therefore, more structural information for subtype sPLA2 is needed to guide the selective inhibitor development. In this study, the crystal structure of human sPLA2 Group IIE (hGIIE), coupled with mutagenesis experiments, proved that the flexible second calcium binding site and residue Asn21 in hGIIE are essential to its enzymatic activity. Five inhibitor bound hGIIE complex structures revealed the key residues (Asn21 and Gly6) of hGIIE that are responsible for interacting with inhibitors, and illustrated the difference in the inhibitor binding pocket with other sPLA2s. This will facilitate the structure-based design of sPLA2's selective inhibitors. PMID- 28883455 TI - Sensory cue-combination in the context of newly learned categories. AB - A large body of prior research has evaluated how humans combine multiple sources of information pertaining to stimuli drawn from continuous dimensions, such as distance or size. These prior studies have repeatedly demonstrated that in these circumstances humans integrate cues in a near-optimal fashion, weighting cues according to their reliability. However, most of our interactions with sensory information are in the context of categories such as objects and phonemes, thereby requiring a solution to the cue combination problem by mapping sensory estimates from continuous dimensions onto task-relevant categories. Previous studies have examined cue combination with natural categories (e.g., phonemes), providing qualitative evidence that human observers utilize information about the distributional properties of task-relevant categories, in addition to sensory information, in such categorical cue combination tasks. In the present study, we created and taught human participants novel audiovisual categories, thus allowing us to quantitatively evaluate participants' integration of sensory and categorical information. Comparing participant behavior to the predictions of a statistically optimal observer that ideally combines all available sources of information, we provide the first evidence, to our knowledge, that human observers combine sensory and category information in a statistically optimal manner. PMID- 28883453 TI - beta-catenin, Twist and Snail: Transcriptional regulation of EMT in smokers and COPD, and relation to airflow obstruction. AB - COPD is characterised by poorly reversible airflow obstruction usually due to cigarette smoking. The transcription factor clusters of beta-catenin/Snail1/Twist has been implicated in the process of epithelial mesenchymal transition (EMT), an intermediate between smoking and airway fibrosis, and indeed lung cancer. We have investigated expression of these transcription factors and their "cellular localization" in bronchoscopic airway biopsies from patients with COPD, and in smoking and non-smoking controls. An immune-histochemical study compared cellular protein expression of beta-catenin, Snail1 and Twist, in these subject groups in 3 large airways compartment: epithelium (basal region), reticular basement membrane (Rbm) and underlying lamina propria (LP). beta-catenin and Snail1 expression was generally high in all subjects throughout the airway wall with marked cytoplasmic to nuclear shift in COPD (P < 0.01). Twist expression was generalised in the epithelium in normal but become more basal and nuclear with smoking (P < 0.05). In addition, beta-catenin and Snail1 expression, and to lesser extent of Twist, was related to airflow obstruction and to expression of a canonical EMT biomarker (S100A4). The beta-catenin-Snail1-Twist transcription factor cluster is up-regulated and nuclear translocated in smokers and COPD, and their expression is closely related to both EMT activity and airway obstruction. PMID- 28883456 TI - Knowledge diffusion of dynamical network in terms of interaction frequency. AB - In this paper, we present a knowledge diffusion (SKD) model for dynamic networks by taking into account the interaction frequency which always used to measure the social closeness. A set of agents, which are initially interconnected to form a random network, either exchange knowledge with their neighbors or move toward a new location through an edge-rewiring procedure. The activity of knowledge exchange between agents is determined by a knowledge transfer rule that the target node would preferentially select one neighbor node to transfer knowledge with probability p according to their interaction frequency instead of the knowledge distance, otherwise, the target node would build a new link with its second-order neighbor preferentially or select one node in the system randomly with probability 1 - p. The simulation results show that, comparing with the Null model defined by the random selection mechanism and the traditional knowledge diffusion (TKD) model driven by knowledge distance, the knowledge would spread more fast based on SKD driven by interaction frequency. In particular, the network structure of SKD would evolve as an assortative one, which is a fundamental feature of social networks. This work would be helpful for deeply understanding the coevolution of the knowledge diffusion and network structure. PMID- 28883457 TI - QTL mapping using an ultra-high-density SNP map reveals a major locus for grain yield in an elite rice restorer R998. AB - To dissect the genetic basis of yield formation in restorer line of hybrid rice, we conducted QTL analysis for 6 yield traits including panicles per plant (PPP), grains per panicle (GPP), grain yield per plant (GY), thousand-grain weight (TGW), above-ground biomass (AGB), and harvest index (HI) using SNP markers in a recombinant inbred lines (RILs) population derived from a cross between a tropical japonica inbred Francis and an elite indica restorer Guanghui 998 (R998). A total of 26 QTLs were detected using a high density genetic map consisting of 3016 bin markers. Nineteen out of the 26 QTL alleles from R998 had a beneficial effect on yield traits. Most of the QTLs were co-located with previously reported rice QTLs. qAGB6 and qHI9, controlling AGB and HI respectively, were detected as novel QTLs. Four QTLs for GY were repeatedly detected across two years, with all the beneficial alleles from R998. Notably, qGY8 explained over 20% of the yield variance in both years. Moreover, qGY8 together with qTGW8 and qHI8 formed a QTL cluster. Markers tightly linked with qGY8 were developed. Cloning of qGY8 will facilitate its further exploitation in high-yield breeding. PMID- 28883459 TI - Pedestrian collective motion in competitive room evacuation. AB - When a sizable number of people evacuate a room, if the door is not large enough, an accumulation of pedestrians in front of the exit may take place. This is the cause of emerging collective phenomena where the density is believed to be the key variable determining the pedestrian dynamics. Here, we show that when sustained contact among the individuals exists, density is not enough to describe the evacuation, and propose that at least another variable -such as the kinetic stress- is required. We recorded evacuation drills with different degrees of competitiveness where the individuals are allowed to moderately push each other in their way out. We obtain the density, velocity and kinetic stress fields over time, showing that competitiveness strongly affects them and evidencing patterns which have been never observed in previous (low pressure) evacuation experiments. For the highest competitiveness scenario, we detect the development of sudden collective motions. These movements are related to a notable increase of the kinetic stress and a reduction of the velocity towards the door, but do not depend on the density. PMID- 28883458 TI - Genetic correlations reveal the shared genetic architecture of transcription in human peripheral blood. AB - Transcript co-expression is regulated by a combination of shared genetic and environmental factors. Here, we estimate the proportion of co-expression that is due to shared genetic variance. To do so, we estimated the genetic correlations between each pairwise combination of 2469 transcripts that are highly heritable and expressed in whole blood in 1748 unrelated individuals of European ancestry. We identify 556 pairs with a significant genetic correlation of which 77% are located on different chromosomes, and report 934 expression quantitative trait loci, identified in an independent cohort, with significant effects on both transcripts in a genetically correlated pair. We show significant enrichment for transcription factor control and physical proximity through chromatin interactions as possible mechanisms of shared genetic control. Finally, we construct networks of interconnected transcripts and identify their underlying biological functions. Using genetic correlations to investigate transcriptional co-regulation provides valuable insight into the nature of the underlying genetic architecture of gene regulation.Covariance of gene expression pairs is due to a combination of shared genetic and environmental factors. Here the authors estimate the genetic correlation between highly heritable pairs and identify transcription factor control and chromatin interactions as possible mechanisms of correlation. PMID- 28883460 TI - Gender-based differences in host behavior and gut microbiota composition in response to high fat diet and stress in a mouse model. AB - Obesity is associated with a high prevalence of mood disorders such as anxiety and depression. Both stress and high fat diet can alter the gut microbiota and contribute to obesity. To examine the interrelationships between obesity, stress, gut microbiota and mood disorders, obesity was induced in mice using a high fat diet, and the mice were subsequently stressed using a chronic unpredictable mild stress protocol. During the experiment, the composition of the gut microbiota was analyzed by 16 S rRNA gene high-throughput sequencing, and anxiety-like behaviors were measured. The results revealed distinct gender differences in the impacts of obesity and stress on anxiety-like behaviors, activity levels, and composition of the gut microbiota. Male mice were more vulnerable to the anxiogenic effects of the high fat diet, and obese male mice showed decreased locomotion activity in response to stress whereas obese female mice did not. In females, stress caused the gut microbiota of lean mice to more closely resemble that of obese mice. Taken together, these results suggest the importance of considering gender as a biological variable in studies on the role of gut microbiota in obesity-related mood disorders. PMID- 28883461 TI - Stacking-fault strengthening of biomedical Co-Cr-Mo alloy via multipass thermomechanical processing. AB - The strengthening of metallic biomaterials, such as Co-Cr-Mo and titanium alloys, is of crucial importance to the improvement of the durability of orthopedic implants. In the present study, we successfully developed a face-centered cubic (fcc) Co-Cr-Mo alloy with an extremely high yield strength (1400 MPa) and good ductility (12%) by multipass hot-rolling, which is suitable for industrial production, and examined the relevant strengthening mechanisms. Using an X-ray diffraction line-profile analysis, we revealed that a substantial increase in the number of stacking faults (SFs) in the fcc gamma-matrix occurred at a greater height reduction (r), while physical modeling demonstrated that the contribution of the accumulated SFs (i.e., the reduction in SF spacing) with an increase in r successfully explains the entire strengthening behavior of the hot-rolled alloy. The present study sheds light on the importance of the SF strengthening mechanism, and will help to guide the design and manufacturing strategy for the high-strength Co-Cr-Mo alloys used in highly durable medical devices. PMID- 28883462 TI - Mapping a Type-specific Epitope by Monoclonal Antibody against VP3 Protein of Duck Hepatitis A Type 1 Virus. AB - Duck hepatitis A subtype 1 virus (DHAV-1) infection causes high mortality in ducklings, resulting in significant losses to duck industries. VP3 is a structural protein of DHAV-1. However, B-cell epitopes on VP3 have not been investigated. To stimulate VP3 antibody response, eukaryotic expression plasmid pCI-neo-VP3 was constructed and used as DNA immunogen to prepare mAbs. Western blot showed that 25.5 kDa VP3 could be detected by mAbs in duck embryo fibroblast (DEF) cells transfected with pCI-neo-VP3. Immunofluorescence assay showed that mAbs could specifically bind to DEF cells infected with DHAV-1. DAPI staining indicated that VP3 localizes to the cytoplasm and nucleus of DHAV-1 infected DEF. With neutralizing mAb 3B7, minimal epitope PSNI was mapped. Sequence alignment indicated that 205PSNI208 is highly conserved among DHAV-1, but different from those of DHAV-2 and DHAV-3. Epitope peptide reacted specifically with DHAV-1 positive duck sera by dot blotting, revealing PSNI is DHAV-1 type-specific epitope and the importance of these amino acids in antibody-epitope binding reactivity. These findings provided useful information for understanding the antigenicity of VP3 and might be valuable in the development of epitope-based vaccine or diagnostic kit for DHAV-1 infection and provide insights for understanding the pathogenesis of DHAV-1. PMID- 28883463 TI - Reovirus inhibits interferon production by sequestering IRF3 into viral factories. AB - Upon viral infection, an arms-race between the cellular intrinsic innate immune system and viral replication is established. To win this race, viruses have established multiple strategies to inhibit the cellular response. Mammalian reovirus (MRV) constitutes a great model to study pathogenesis and life cycle of dsRNA viruses. It replicates in the cytosol of infected cells by forming viral induced-replication compartments, or viral factories. Little is known about the strategy used by MRV to evade the cellular intrinsic immune system. In this study, we unraveled that MRV induces a replication-dependent global reduction in interferon-mediated antiviral immune response. We determined that although MRV leads to the activation and phosphorylation of interferon regulatory factor 3 (IRF3), the nuclear translocation of IRF3 was impaired in infected cells. Additionally, we showed that MRV does not degrade IRF3 but sequesters it in cytoplasmic viral factories. We demonstrate that the viral factory matrix protein MUNS is solely responsible for the sequestration of IRF3. This finding highlights novel mechanisms used by MRV to interfere with the intrinsic immune system and places the viral factories as not only a replication compartment but as an active strategy participating in immune evasion. PMID- 28883464 TI - Characterizing the virome of Ixodes ricinus ticks from northern Europe. AB - RNA viruses are abundant infectious agents and present in all domains of life. Arthropods, including ticks, are well known as vectors of many viruses of concern for human and animal health. Despite their obvious importance, the extent and structure of viral diversity in ticks is still poorly understood, particularly in Europe. Using a bulk RNA-sequencing approach that captures the complete transcriptome, we analysed the virome of the most common tick in Europe - Ixodes ricinus. In total, RNA sequencing was performed on six libraries consisting of 33 I. ricinus nymphs and adults sampled in Norway. Despite the small number of animals surveyed, our virus identification pipeline revealed nine diverse and novel viral species, phylogenetically positioned within four different viral groups - bunyaviruses, luteoviruses, mononegavirales and partitiviruses - and sometimes characterized by extensive genetic diversity including a potentially novel genus of bunyaviruses. This work sheds new light on the virus diversity in I. ricinus, expands our knowledge of potential host/vector-associations and tick transmitted viruses within several viral groups, and pushes the latitudinal limit where it is likely to find tick-associated viruses. Notably, our phylogenetic analysis revealed the presence of tick-specific virus clades that span multiple continents, highlighting the role of ticks as important virus reservoirs. PMID- 28883465 TI - The Oceanic Biological Pump: Rapid carbon transfer to depth at Continental Margins during Winter. AB - The oceanic biological pump is responsible for the important transfer of CO2-C as POC "Particulate Organic Carbon" to the deep sea. It plays a decisive role in the Earth's carbon cycle and significant effort is spent to quantify its strength. In this study we used synchronized daily time-series data of surface chlorophyll-a concentrations from the NASA's MODIS satellite in combination with hourly to daily observations from sea surface buoys and from an Internet Operated Vehicle (IOV) on the seafloor within Barkley Canyon (Northeast Pacific) to investigate the importance of winter processes in the export of fresh phytodetritus. The results indicate that phytoplankton pulses during winter can be as important in POC transfer to depth as the pulses associated with spring and summer blooms. Short winter phytoplankton pulses were observed to disappear from surface waters after low-pressure systems affected the area. Pulses of chlorophyll reached the IOV, at 870 m depth on the canyon seafloor, 12-72 hours later. These observed short pulses of biological carbon production regularly observed in the region from December to March have not been considered a significant component of the biological pump when compared with the denser summer productivity blooms. PMID- 28883466 TI - Multiscale cytometry and regulation of 3D cell cultures on a chip. AB - Three-dimensional cell culture is emerging as a more relevant alternative to the traditional two-dimensional format. Yet the ability to perform cytometry at the single cell level on intact three-dimensional spheroids or together with temporal regulation of the cell microenvironment remains limited. Here we describe a microfluidic platform to perform high-density three-dimensional culture, controlled stimulation, and observation in a single chip. The method extends the capabilities of droplet microfluidics for performing long-term culture of adherent cells. Using arrays of 500 spheroids per chip, in situ immunocytochemistry and image analysis provide multiscale cytometry that we demonstrate at the population scale, on 104 single spheroids, and over 105 single cells, correlating functionality with cellular location within the spheroids. Also, an individual spheroid can be extracted for further analysis or culturing. This will enable a shift towards quantitative studies on three-dimensional cultures, under dynamic conditions, with implications for stem cells, organs-on chips, or cancer research.3D cell culture is more relevant than the two dimensional format, but methods for parallel analysis and temporal regulation of the microenvironment are limited. Here the authors develop a droplet microfluidics system to perform long-term culture of 3D spheroids, enabling multiscale cytometry of individual cells within the spheroid. PMID- 28883467 TI - Tanycytes control the hormonal output of the hypothalamic-pituitary-thyroid axis. AB - The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating thyroid hormone levels in a narrow physiological range. As axons containing thyrotropin releasing hormone (TRH) terminate on hypothalamic tanycytes, these specialized glial cells have been suggested to influence the activity of the HPT axis, but their exact role remained enigmatic. Here, we demonstrate that stimulation of the TRH receptor 1 increases intracellular calcium in tanycytes of the median eminence via Galphaq/11 proteins. Activation of Galphaq/11 pathways increases the size of tanycyte endfeet that shield pituitary vessels and induces the activity of the TRH-degrading ectoenzyme. Both mechanisms may limit the TRH release to the pituitary. Indeed, blocking TRH signaling in tanycytes by deleting Galphaq/11 proteins in vivo enhances the response of the HPT axis to the chemogenetic activation of TRH neurons. In conclusion, we identify new TRH- and Galphaq/11 dependent mechanisms in the median eminence by which tanycytes control the activity of the HPT axis.The hypothalamic-pituitary-thyroid (HPT) axis regulates a wide range of physiological processes. Here the authors show that hypothalamic tanycytes play a role in the homeostatic regulation of the HPT axis; activation of TRH signaling in tanycytes elevates their intracellular Ca2+ via Galphaq/11 pathway, ultimately resulting in reduced TRH release into the pituitary vessels. PMID- 28883468 TI - Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages. AB - Macrophages (MPhis) with mutations in cystic fibrosis transmembrane conductance regulator (CFTR) have blunted induction of PI3K/AKT signaling in response to TLR4 activation, leading to hyperinflammation, a hallmark of cystic fibrosis (CF) disease. Here, we show that Ezrin links CFTR and TLR4 signaling, and is necessary for PI3K/AKT signaling induction in response to MPhi activation. Because PI3K/AKT signaling is critical for immune regulation, Ezrin-deficient MPhis are hyperinflammatory and have impaired Pseudomonas aeruginosa phagocytosis, phenocopying CF MPhis. Importantly, we show that activated CF MPhis have reduced protein levels and altered localization of the remaining Ezrin to filopodia that form during activation. In summary, we have described a direct link from CFTR to Ezrin to PI3K/AKT signaling that is disrupted in CF, and thus promotes hyper inflammation and weakens phagocytosis. PMID- 28883469 TI - Characteristics of newly diagnosed COPD patients treated with triple inhaled therapy by general practitioners: a real world Italian study. AB - : Factors predicting prescriptions of triple therapy were investigated in a large group of general practitioners in Italy. In the population treated by identified general practitioners, a cohort of newly diagnosed chronic obstructive pulmonary disease patients was extracted from IMS Health Longitudinal Database during the period 2010-2013. From the diagnosis, 1-year follow-up was evaluated. Thirty-two thousand forty-six newly diagnosed chronic obstructive pulmonary disease patients were evaluated (57.7% male, mean age 67 years). During 2 years prior to diagnosis less than 13% of patients were requested with a pulmonology evaluation and less than 5% with a spirometry; 65.1% cases were prescribed with a respiratory drug, which in 9.6% of cases was inhaled corticosteroid/long-acting beta2-agonist fixed dose combination. Two thousand and twenty eight patients (6.3% of the newly diagnosed chronic obstructive pulmonary disease patients) were treated with triple therapy during the first year of follow-up, whose 858 (42.3%) starting immediately, and 762 (37.6%) following an initial treatment with inhaled corticosteroid/long-acting beta2-agonist fixed-dose combination. Being older, being requested with pulmonologist evaluation or spirometry, being prescribed with a inhaled corticosteroid/long-acting beta2-agonist fixed-dose combination at diagnosis resulted independent predictors of triple therapy use. CHRONIC LUNG DISEASE: ENSURING CORRECT PRESCRIPTIONS FOR EARLY-STAGE DISEASE: An improved education program for doctors promoting correct use of medication for chronic lung disease is needed in Italy. Current guidelines state that inhaled corticosteroids (ICSs) should be reserved for patients with severe chronic obstructive pulmonary disease (COPD), but it appears that doctors do not always follow this advice. Fabiano Di Marco, at San Paolo Hospital-Universita degli Studi di Milano, and co-workers analyzed data from 32,046 COPD patients newly diagnosed by family doctors in Italy between 2010 and 2013. When the researchers followed up on patients after 1 year, 2028 (6.3%) of newly-diagnosed patients were being treated with triple inhaled therapy incorporating ICSs-42% of these patients had started triple therapy immediately upon diagnosis. Being an older male and having been prescribed with a ICS/LABA FDC at diagnosis were strong predictors of triple therapy use within 1 year from the diagnosis. PMID- 28883470 TI - Cytoglobin Promotes Cardiac Progenitor Cell Survival against Oxidative Stress via the Upregulation of the NFkappaB/iNOS Signal Pathway and Nitric Oxide Production. AB - Human cardiac stem/progenitor cells (hCPCs) may serve in regenerative medicine to repair the infarcted heart. However, this approach is severely limited by the poor survival of donor cells. Recent studies suggest that the mammalian globin cytoglobin (CYGB) regulates nitric oxide (NO) metabolism and cell death. In the present study, we found that CYGB is expressed in hCPCs. Through molecular approaches aimed at increasing or decreasing CYGB expression in hCPCs, we found that CYGB functions as a pro-survival factor in response to oxidative stress. This was associated with the upregulation of primary antioxidant systems such as peroxiredoxins-1, heme oxygenase-1, and anti-apoptotic factors, including BCL2, BCL-XL, and MCL1. Most significantly, we established that CYGB increased the expression of NFkB-dependent genes including iNOS, and that iNOS-dependent NO production was required for a feedforward loop that maintains CYGB expression. Our study delineates for the first time a role for a globin in regulating hCPC survival and establishes mechanistic insights in the function of CYGB. It provides a rationale for the exploration of the CYGB pathway as a molecular target that can be used to enhance the effectiveness of cardiac stem/progenitor cell therapy for ischemic heart disease. PMID- 28883471 TI - Potential Systematic Interception Errors are Avoided When Tracking the Target with One's Eyes. AB - Directing our gaze towards a moving target has two known advantages for judging its trajectory: the spatial resolution with which the target is seen is maximized, and signals related to the eyes' movements are combined with retinal cues to better judge the target's motion. We here explore whether tracking a target with one's eyes also prevents factors that are known to give rise to systematic errors in judging retinal speeds from resulting in systematic errors in interception. Subjects intercepted white or patterned disks that moved from left to right across a large screen at various constant velocities while either visually tracking the target or fixating the position at which they were required to intercept the target. We biased retinal motion perception by moving the pattern within the patterned targets. This manipulation led to large systematic errors in interception when subjects were fixating, but not when they were tracking the target. The reduction in the errors did not depend on how smoothly the eyes were tracking the target shortly before intercepting it. We propose that tracking targets with one's eyes when one wants to intercept them makes one less susceptible to biases in judging their motion. PMID- 28883472 TI - The Relationship between Hematological Indices and Autoimmune Rheumatic Diseases (ARDs), a Meta-Analysis. AB - This meta-analysis was undertaken to investigate the relationship between hematological indices and autoimmune rheumatic diseases (ARDs). PubMed, Embase, and Web of Science were searchedfor studies of ARDs and hematological indices. Standardized mean difference (SMD) was calculated with confidence interval (CI) of 95%. 18 studies were included in our meta-analysis. Compared to the healthy control group, neutrophil-lymphocyte ratio (NLR) was increased in patients with ankylosing spongdylitis(AS), Behcet's disease(BD), andrheumatoid arthritis(RA)(SMD = 0.33; 95% CI: 0.19 to 0.47; SMD = 1.90; 95% CI: 0.13 to 3.67; SMD = 0.75; 95% CI: 0.23 to 1.28). Platelet-lymphocyte ratio (PLR) was found increased in RA and SLE (SMD = 33.91; 95% CI: 20.50 to 47.32; SMD = 59.11; 95% CI: 4.46 to 113.76). Mean platelet volume (MPV)was irrelevant to BD and SLE by comparing with the healthy control group respectively. (SMD = 0.24; 95% CI: -0.49 to 0.97; SMD = -0.15; 95% CI: -1.77 to 1.48). Red cell distribution width (RDW) was not related to AS (SMD = 0.59, 95% CI: -0.37, 1.55). Our findings indicated that NLR had a strong association with AS, BD, and RA. PLR was also related to RA and SLE. NLR and PLR could be recommended as inexpensive diagnostic biomarkers for ARDs. PMID- 28883473 TI - Identification of Aspergillus fumigatus UDP-Galactopyranose Mutase Inhibitors. AB - Aspergillus fumigatus is an opportunistic human pathogen responsible for deadly, invasive infections in immunocompromised patients. The A. fumigatus cell wall is a complex network of polysaccharides among them galactofuran, which is absent in humans. UDP-galactopyranose mutase (UGM) catalyzes the conversion of UDP galactofuranose (UDP-Galf) to UDP-galactopyranose (UDP-Galp) and is an important virulence factor. UGM is a flavin-dependent enzyme that requires the reduced flavin for activity; flavin reduction is achieved by reaction with NADPH. The aim of this work was to discover inhibitors of UGM by targeting the NADPH binding site using an ADP-TAMRA probe in a high-throughput screening assay. The flavonoids (2S)-hesperetin and (2S)-naringenin were validated as competitive inhibitors of UGM against NADPH with Ki values of 6 uM and 74 uM, respectively. To gain insight into the active chemical substituents involved in the inhibition of UGM, several derivatives of these inhibitors were studied. The results show that the hydroxyl groups of (2S)-hesperetin are important for inhibition, in particular the phenyl-chroman moiety. Congo red susceptibility assay and growth temperature effects showed that these compounds affected cell wall biosynthesis in A. fumigatus. This work is the first report of inhibition studies on UGM from eukaryotic human pathogens. PMID- 28883475 TI - The Mobility Enhancement of Indium Gallium Zinc Oxide Transistors via Low temperature Crystallization using a Tantalum Catalytic Layer. AB - High-mobility indium gallium zinc oxide (IGZO) thin-film transistors (TFTs) are achieved through low-temperature crystallization enabled via a reaction with a transition metal catalytic layer. For conventional amorphous IGZO TFTs, the active layer crystallizes at thermal annealing temperatures of 600 degrees C or higher, which is not suitable for displays using a glass substrate. The crystallization temperature is reduced when in contact with a Ta layer, where partial crystallization at the IGZO back-channel occurs with annealing at 300 degrees C, while complete crystallization of the active layer occurs at 400 degrees C. The field-effect mobility is significantly boosted to 54.0 cm2/V.s for the IGZO device with a metal-induced polycrystalline channel formed at 300 degrees C compared to 18.1 cm2/V.s for an amorphous IGZO TFT without a catalytic layer. This work proposes a facile and effective route to enhance device performance by crystallizing the IGZO layer with standard annealing temperatures, without the introduction of expensive laser irradiation processes. PMID- 28883474 TI - Plasma exosomal miR-223 expression regulates inflammatory responses during cardiac surgery with cardiopulmonary bypass. AB - Cardiopulmonary bypass (CPB) induces inflammatory responses, and effective endogenous homeostasis is important for preventing systemic inflammation. We assessed whether plasma exosomal microRNAs in patients undergoing cardiac surgery with CPB are involved in the regulation of inflammatory responses. Plasma samples were isolated from CPB patients (n = 21) at 5 specified time points: pre-surgery, pre-CPB and 2 hours (h), 4 h and 24 h after CPB began. Plasma TNF-alpha expression was increased after CPB began compared to that in the pre-surgery samples. Plasma IL-8 and IL-6 expression peaked at 4 h after CPB began but was downregulated at 24 h. The number of plasma exosomes collected at 2 h (55.1 +/- 8.3%), 4 h (63.8 +/- 10.1%) and 24 h (83.5 +/- 3.72%) after CPB began was significantly increased compared to that in the pre-CPB samples (42.8 +/- 0.11%). These exosomes had a predominantly parental cellular origin from RBCs and platelets. Additionally, the plasma exosomal miR-223 levels were significantly increased after CPB began compared to those in the pre-CPB samples. Further, exosomal miR-223 from plasma collected after CPB began downregulated IL-6 and NLRP3 expression in the monocytes. Here, we present the novel findings that increased plasma exosomal miR-223 expression during cardiac surgery with CPB might play homeostatic roles in downregulating inflammatory responses through intercellular communication. PMID- 28883476 TI - Measurement of gut permeability using fluorescent tracer agent technology. AB - The healthy gut restricts macromolecular and bacterial movement across tight junctions, while increased intestinal permeability accompanies many intestinal disorders. Dual sugar absorption tests, which measure intestinal permeability in humans, present challenges. Therefore, we asked if enterally administered fluorescent tracers could ascertain mucosal integrity, because transcutaneous measurement of differentially absorbed molecules could enable specimen-free evaluation of permeability. We induced small bowel injury in rats using high- (15 mg/kg), intermediate- (10 mg/kg), and low- (5 mg/kg) dose indomethacin. Then, we compared urinary ratios of enterally administered fluorescent tracers MB-402 and MB-301 to urinary ratios of sugar tracers lactulose and rhamnose. We also tested the ability of transcutaneous sensors to measure the ratios of absorbed fluorophores. Urinary fluorophore and sugar ratios reflect gut injury in an indomethacin dose dependent manner. The fluorophores generated smooth curvilinear ratio trajectories with wide dynamic ranges. The more chaotic sugar ratios had narrower dynamic ranges. Fluorophore ratios measured through the skin distinguished indomethacin-challenged from same day control rats. Enterally administered fluorophores can identify intestinal injury in a rat model. Fluorophore ratios are measureable through the skin, obviating drawbacks of dual sugar absorption tests. Pending validation, this technology should be considered for human use. PMID- 28883477 TI - The Strong Cell-based Hydrogen Peroxide Generation Triggered by Cold Atmospheric Plasma. AB - Hydrogen peroxide (H2O2) is an important signaling molecule in cancer cells. However, the significant secretion of H2O2 by cancer cells have been rarely observed. Cold atmospheric plasma (CAP) is a near room temperature ionized gas composed of neutral particles, charged particles, reactive species, and electrons. Here, we first demonstrated that breast cancer cells and pancreatic adenocarcinoma cells generated micromolar level H2O2 during just 1 min of direct CAP treatment on these cells. The cell-based H2O2 generation is affected by the medium volume, the cell confluence, as well as the discharge voltage. The application of cold atmospheric plasma (CAP) in cancer treatment has been intensively investigated over the past decade. Several cellular responses to CAP treatment have been observed including the consumption of the CAP-originated reactive species, the rise of intracellular reactive oxygen species, the damage on DNA and mitochondria, as well as the activation of apoptotic events. This is a new previously unknown cellular response to CAP, which provides a new prospective to understand the interaction between CAP and cells in vitro and in vivo. The short-lived reactive species in CAP may activate cells in vivo to generate long lived reactive species such as H2O2, which may trigger immune attack on tumorous tissues via the H2O2-mediated lymphocyte activation. PMID- 28883478 TI - Dissection of iron signaling and iron accumulation by overexpression of subgroup Ib bHLH039 protein. AB - Iron is an essential growth determinant for plants, and plants acquire this micronutrient in amounts they need in their environment. Plants can increase iron uptake in response to a regulatory transcription factor cascade. Arabidopsis thaliana serves as model plant to identify and characterize iron regulation genes. Here, we show that overexpression of subgroup Ib bHLH transcription factor bHLH039 (39Ox) caused constitutive iron acquisition responses, which resulted in enhanced iron contents in leaves and seeds. Transcriptome analysis demonstrated that 39Ox plants displayed simultaneously gene expression patterns characteristic of iron deficiency and iron stress signaling. Thereby, we could dissect iron deficiency response regulation. The transcription factor FIT, which is required to regulate iron uptake, was essential for the 39Ox phenotype. We provide evidence that subgroup Ib transcription factors are involved in FIT transcriptional regulation. Our findings pose interesting questions to the feedback control of iron homeostasis. PMID- 28883479 TI - Refractive index engineering through swift heavy ion irradiation of LiNbO3 crystal towards improved light guidance. AB - Swift heavy ion irradiation has been widely used to modify refractive indices of optical materials for waveguide fabrication. In this work, we propose refractive index engineering by swift heavy ion (Ar) irradiation via electronic energy deposition to construct waveguides of diverse geometries in LiNbO3 crystal. The feasibility to modulate the refractive index of LiNbO3 crystal at variable depths through electronic energy depositions of argon ions at different energies has been experimentally explored. The surface and cladding-like optical waveguides with thicknesses of ~13, ~36 and ~23 MUm have been produced by using swift Ar ion irradiation at single energy of ~120, ~240, and double energy of (120 + 240) MeV, respectively. The fabricated waveguides are capable of effective waveguiding in single and multiple modes at 1064 nm, which enables efficient guided-wave second harmonic generation at room temperature. This work paves the way to produce waveguides with diverse geometries in dielectric crystals through electronic damage of multiple swift heavy ion irradiation. PMID- 28883480 TI - Genome-wide identification and co-expression network analysis provide insights into the roles of auxin response factor gene family in chickpea. AB - Auxin response factors (ARFs) are the transcription factors that regulate auxin responses in various aspects of plant growth and development. Although genome wide analysis of ARF gene family has been done in some species, no information is available regarding ARF genes in chickpea. In this study, we identified 28 ARF genes (CaARF) in the chickpea genome. Phylogenetic analysis revealed that CaARFs can be divided into four different groups. Duplication analysis revealed that 50% of CaARF genes arose from duplication events. We analyzed expression pattern of CaARFs in various developmental stages. CaARF16.3, CaARF17.1 and CaARF17.2 showed highest expression at initial stages of flower bud development, while CaARF6.2 had higher expression at later stages of flower development. Further, CaARF4.2, CaARF9.2, CaARF16.2 and CaARF7.1 exhibited differential expression under different abiotic stress conditions, suggesting their role in abiotic stress responses. Co-expression network analysis among CaARF, CaIAA and CaGH3 genes enabled us to recognize components involved in the regulatory network associated with CaARFs. Further, we identified microRNAs that target CaARFs and TAS3 locus that trigger production of trans-acting siRNAs targeting CaARFs. The analyses presented here provide comprehensive information on ARF family members and will help in elucidating their exact function in chickpea. PMID- 28883481 TI - Early X chromosome inactivation during human preimplantation development revealed by single-cell RNA-sequencing. AB - In female mammals, one X chromosome is transcriptionally inactivated (XCI), leading to dosage compensation between sexes, fundamental for embryo viability. A previous study using single-cell RNA-sequencing (scRNA-seq) data proposed that female human preimplantation embryos achieve dosage compensation by downregulating both Xs, a phenomenon named dampening of X expression. Using a novel pipeline on those data, we identified a decrease in the proportion of biallelically expressed X-linked genes during development, consistent with XCI. Moreover, we show that while the expression sum of biallelically expressed X linked genes decreases with embryonic development, their median expression remains constant, rejecting the hypothesis of X dampening. In addition, analyses of a different dataset of scRNA-seq suggest the appearance of X-linked monoallelic expression by the late blastocyst stage in females, another hallmark of initiation of XCI. Finally, we addressed the issue of dosage compensation between the single active X and autosomes in males and females for the first time during human preimplantation development, showing emergence of X to autosome dosage compensation by the upregulation of the active X chromosome in both male and female embryonic stem cells. Our results show compelling evidence of an early process of X chromosome inactivation during human preimplantation development. PMID- 28883482 TI - Low body surface area predicts hepatotoxicity of nintedanib in patients with idiopathic pulmonary fibrosis. AB - After the commercialization of nintedanib in Japan, a high incidence of hepatotoxicity resulting in treatment interruption was noted in idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib in our hospital. This study aimed to clarify the risk factors for hepatotoxicity of nintedanib. Sixty eight consecutive cases of IPF newly treated with nintedanib at a dose of 150 mg twice daily from September 2015 to September 2016 were enrolled: 46 patients (67.6%) exhibited aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) elevation and 16 patients (23.5%) also had a Common Terminology Criteria for Adverse Events (CTCAE) grade >=2. Body surface area (BSA) was significantly lower in the CTCAE grade >=2 group than in another group. A multivariate logistic regression analysis showed that the association between BSA and AST/ALT elevation with CTCAE grade >=2 was statistically significant. Eight of 10 patients who resumed nintedanib at a reduced dose of 100 mg twice daily after interruption due to hepatotoxicity did not again develop AST/ALT elevation. In conclusion, a low BSA was associated with hepatotoxicity of nintedanib at a dose of 150 mg twice daily. It would be a good option for patients with a small physique to start nintedanib at a dose of 100 mg twice daily and then increase if possible after confirming its safety. PMID- 28883484 TI - Astrocytes and oligodendrocytes in grey and white matter regions of the brain metabolize fatty acids. AB - The grey and white matter regions of the mammalian brain consist of both neurons and neuroglial cells. Among the neuroglia, the two macroglia oligodendrocytes and astrocytes are the most abundant cell types. While the major function of oligodendrocytes is the formation of the lipid-rich myelin structure, the heterogeneous group of astrocytes fulfils a multitude of important roles in cerebral development and homeostasis. Brain lipid homeostasis involves the synthesis of a specific cerebral lipidome by local lipid metabolism. In this study we have investigated the fatty acid uptake and lipid biosynthesis in grey and white matter regions of the murine brain. Key findings were: (i) white matter oligodendrocytes and astrocytes take up saturated and unsaturated fatty acids, (ii) different grey matter regions show varying lipid labelling intensities, (iii) the medial habenula, an epithalamic grey matter structure, and the oligodendrocytes and astrocytes therein are targeted by fatty acids, and (iv) in the medial habenula, the neutral lipid containing lipid droplets are found in cells facing the ventricle but undetectable in the habenular parenchyma. Our data indicate a role for oligodendrocytes and astrocytes in local lipid metabolism of white and grey matter regions in the brain. PMID- 28883483 TI - SERPINB2 is a novel TGFbeta-responsive lineage fate determinant of human bone marrow stromal cells. AB - TGF-beta1, a multifunctional regulator of cell growth and differentiation, is the most abundant bone matrix growth factor. During differentiation of human bone stromal cells (hBMSCs), which constitute bone marrow osteoblast (OS) and adipocyte (AD) progenitor cells, continuous TGF-beta1 (10 ng/ml) treatment enhanced OS differentiation as evidenced by increased mineralised matrix production. Conversely, pulsed TGF-beta1 administration during the commitment phase increased mature lipid-filled adipocyte numbers. Global gene expression analysis using DNA microarrays in hBMSCs treated with TGF-beta1 identified 1587 up- and 1716 down-regulated genes in OS-induced, TGF-beta1-treated compared to OS induced hBMSCs (2.0 fold change (FC), p < 0.05). Gene ontology (GO) analysis revealed enrichment in 'osteoblast differentiation' and 'skeletal system development-associated' genes and up-regulation of several genes involved in 'osteoblastic-differentiation related signalling pathways'. In AD-induced, TGF beta1-treated compared to AD-induced hBMSCs, we identified 323 up- and 369 down regulated genes (2.0 FC, p < 0.05) associated with 'fat cell differentiation', 'fatty acid derivative biosynthesis process', 'fatty acid derivative metabolic process', and 'inositol lipid-mediated'. Serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2) was down-regulated 3-fold in TGF-beta1-treated hBMSCs. siRNA-mediated SERPINB2 inhibition enhanced OS and AD differentiation. Thus, TGF-beta signalling is important for hBMSC OS and AD differentiation and SERPINB2 is a TGF-beta-responsive gene that plays a negative regulatory role in hBMSC differentiation. PMID- 28883485 TI - FLO5 gene controls flocculation phenotype and adhesive properties in a Saccharomyces cerevisiae sparkling wine strain. AB - Flocculation is an important feature for yeast survival in adverse conditions. The natural diversity of flocculating genes in Saccharomyces cerevisiae can also be exploited in several biotechnological applications. Flocculation is mainly regulated by the expression of genes belonging to the FLO family. These genes have a similar function, but their specific contribution to flocculation ability is still unclear. In this study, the distribution of FLO1, FLO5 and FLO8 genes in four S. cerevisiae wine strains was investigated. Subsequently, both FLO1 and FLO5 genes were separately deleted in a flocculent S. cerevisiae wine strain. After gene disruption, flocculation ability and agar adhesion were evaluated. FLO1 and FLO5 genes inheritance was also monitored. All strains presented different lengths for FLO1 and FLO5 genes. Results confirm that in S. cerevisiae strain F6789, the FLO5 gene drives flocculation and influences adhesive properties. Flocculation ability monitoring after a cross with a non-flocculent strain revealed that FLO5 is the gene responsible for flocculation development. PMID- 28883486 TI - Conditions for Eltonian Pyramids in Lotka-Volterra Food Chains. AB - In ecological communities consumers (excluding parasites and parasitoids) are in general larger and less numerous than their resource. This results in a well known observation known as 'Eltonian pyramids' or the 'pyramid of numbers', and metabolic arguments suggest that this pattern is independent of the number of trophic levels in a system. At the same time, Lotka-Volterra (LV) consumer resource models are a frequently used tool to study many questions in community ecology, but their capacity to produce Eltonian pyramids has not been formally analysed. Here, I address this knowledge gap by investigating if and when LV food chain models give rise to Eltonian pyramids. I show that Eltonian pyramids are difficult to reproduce without density-dependent mortality in the consumers, unless biologically plausible relationships between mortality rate and interaction strength are taken into account. PMID- 28883487 TI - Reconciling the opposing effects of warming on phytoplankton biomass in 188 large lakes. AB - Lake ecosystems are deeply integrated into local and regional economies through recreation, tourism, and as sources of food and drinking water. Shifts in lake phytoplankton biomass, which are mediated by climate warming will alter these benefits with potential cascading effects on human well-being. The metabolic theory of ecology suggests that warming reduces lake phytoplankton biomass as basal metabolic costs increase, but this hypothesis has not been tested at the global scale. We use satellite-based estimates of lake surface temperature (LST) and lake surface chlorophyll-a concentration (chl-a; as a proxy for phytoplankton biomass) in 188 of the world's largest lakes from 2002-2016 to test for interannual associations between chl-a and LST. In contrast to predictions from metabolic ecology, we found that LST and chl-a were positively correlated in 46% of lakes (p < 0.05). The associations between LST and chl-a depended on lake trophic state; warming tended to increase chl-a in phytoplankton-rich lakes and decrease chl-a in phytoplankton-poor lakes. We attribute the opposing responses of chl-a to LST to the effects of temperature on trophic interactions, and the availability of resources to phytoplankton. These patterns provide insights into how climate warming alters lake ecosystems on which millions of people depend for their livelihoods. PMID- 28883488 TI - Integrated Method to Attach DNA Handles and Functionally Select Proteins to Study Folding and Protein-Ligand Interactions with Optical Tweezers. AB - Optical tweezers has emerged as a powerful tool to study folding, ligand binding, and motor enzymes. The manipulation of proteins with optical tweezers requires attaching molecular handles to the protein of interest. Here, we describe a novel method that integrates the covalent attachment of DNA handles to target proteins with a selection step for functional and properly folded molecules. In addition, this method enables obtaining protein molecules in different liganded states and can be used with handles of different lengths. We apply this method to study the cAMP binding domain A (CBD-A) of Protein kinase A. We find that the functional selection step drastically improves the reproducibility and homogeneity of the single molecule data. In contrast, without a functional selection step, proteins often display misfolded conformations. cAMP binding stabilizes the CBD-A against a denaturing force, and increases the folded state lifetime. Data obtained with handles of 370 and 70 base pairs are indistinguishable, but at low forces short handles provide a higher spatial resolution. Altogether, this method is flexible, selects for properly folded molecules in different liganded states, and can be readily applicable to study protein folding or protein-ligand interactions with force spectroscopy that require molecular handles. PMID- 28883489 TI - Sliding friction of graphene/hexagonal -boron nitride heterojunctions: a route to robust superlubricity. AB - The origin of ultra-low friction exhibited by heterogeneous junctions of graphene and hexagonal boron nitride (h-BN) is revealed. For aligned interfaces, we identify a characteristic contact size, below which the junction behaves like its homogeneous counterparts with friction forces that grow linearly with the contact area. Superlubricity sets in due to the progressive appearance of Moire patterns resulting in a collective stick-slip motion of the elevated super-structure ridges that turns into smooth soliton-like gliding with increasing contact size. Incommensurability effects are enhanced in misaligned contacts, where the friction coefficients further drop by orders of magnitude. Our fully atomistic simulations show that the superlubric regime in graphene/h-BN heterostructures persists up to significantly higher loads compared to the well-studied twisted homogeneous graphene interface. This indicates the potential of achieving robust superlubricity in practical applications using two-dimensional layered materials heterojunctions. PMID- 28883490 TI - In vitro exposure of simulated meat-cooking fumes to assess adverse biological effects. AB - The heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is considered as a human carcinogenic or mutagenic compound that is produced from the co-condensation of creatinine and amino acids as meats cook at high temperatures. The cooking of meats at high temperatures produces fumes, and these fumes can be suspended as aerosols via the vapor-to-particle (or -droplet) process in a temperature gradient field. Size distributions of the aerosols included a significant portion of nano- and submicron-sized particles, and these can be directly deposited in the lungs and on skin by particle transport phenomena near cooking areas. In this study, for the first time, PhIP incorporated oleic acid (OA, simulating cooking oil) (PhIP@OA) particles, including individual particulate PhIP as simulated fumes from meat cooking, were constantly produced via collison atomization and subsequent drying processes. The aerosol particles were then dispersed in phosphate-buffered saline for cytotoxicity and senescence-associated beta-galactosidase assays, which were compared with dissolved PhIP in dimethyl sulfoxide. PhIP and PhIP@OA did not show significant cytotoxic effects on SHSY5Y, MRC5, and human dermal fibroblast cells compared with the dissolved PhIP but clearly induced premature senescence activities that may be caused by a limited release of PhIP molecules from the particulate PhIP. PMID- 28883491 TI - Lateral movements of a massive tail influence gecko locomotion: an integrative study comparing tail restriction and autotomy. AB - Tails are an intricate component of the locomotor system for many vertebrates. Leopard geckos (Eublepharis macularius) possess a large tail that is laterally undulated during steady locomotion. However, the tail is readily shed via autotomy, resulting in the loss of tail function, loss in body mass, and a cranial shift in the center of mass. To elucidate the function of tail undulations, we investigated changes in limb kinematics after manipulating the tail artificially by restricting tail undulations and naturally by removing the tail via autotomy. Restricting tail undulations resulted in kinematic adjustments similar to those that occur following tail autotomy, characterized by more flexed hind limb joints. These data suggest that effects of autotomy on locomotion may be linked to the loss of tail movements rather than the loss of mass or a shift in center of mass. We also provide empirical support for the link between lateral tail undulations and step length through the rotation of the pelvic girdle and retraction of the femur. Restriction and autotomy of the tail limits pelvic rotation, which reduces femur retraction and decreases step length. Our findings demonstrate a functional role for tail undulations in geckos, which likely applies to other terrestrial vertebrates. PMID- 28883492 TI - On the role of initial velocities in pair dispersion in a microfluidic chaotic flow. AB - Chaotic flows drive mixing and efficient transport in fluids, as well as the associated beautiful complex patterns familiar to us from our every day life experience. Generating such flows at small scales where viscosity takes over is highly challenging from both the theoretical and engineering perspectives. This can be overcome by introducing a minuscule amount of long flexible polymers, resulting in a chaotic flow dubbed 'elastic turbulence'. At the basis of the theoretical frameworks for its study lie the assumptions of a spatially smooth and random-in-time velocity field. Previous measurements of elastic turbulence have been limited to two-dimensions. Using a novel three-dimensional particle tracking method, we conduct a microfluidic experiment, allowing us to explore elastic turbulence from the perspective of particles moving with the flow. Our findings show that the smoothness assumption breaks already at scales smaller than a tenth of the system size. Moreover, we provide conclusive experimental evidence that 'ballistic' separation prevails in the dynamics of pairs of tracers over long times and distances, exhibiting a memory of the initial separation velocities. The ballistic dispersion is universal, yet it has been overlooked so far in the context of small scales chaotic flows.Elastic turbulence, a random-in time flow, can drive efficient mixing in microfluidics. Using a 3D particle tracking method, the authors show that the smoothness assumption breaks at scales far smaller than believed and the ballistic pair dispersion holds over much longer distances than expected. PMID- 28883494 TI - The Experimental Demonstration of High Efficiency Interaction-free Measurement for Quantum Counterfactual-like Communication. AB - We present an interaction-free measurement with quantum Zeno effect and a high efficiency eta = 74.6% +/- 0.15%. As a proof-of-principle demonstration, this measurement can be used to implement a quantum counterfactual-like communication protocol. Instead of a single photon state, we use a coherent light as the input source and show that the output agrees with the proposed quantum counterfactual communication protocol according to Salih et al. Although the counterfactuality is not achieved due to the presence of a few photons in the public channel, we show that the signal light is nearly absent in the public channel, which exhibits a proof-of-principle quantum counterfactual-like property of communication. PMID- 28883493 TI - Regulation of Akt-mTOR, ubiquitin-proteasome and autophagy-lysosome pathways in locomotor and respiratory muscles during experimental sepsis in mice. AB - Sepsis induced loss of muscle mass and function contributes to promote physical inactivity and disability in patients. In this experimental study, mice were sacrificed 1, 4, or 7 days after cecal ligation and puncture (CLP) or sham surgery. When compared with diaphragm, locomotor muscles were more prone to sepsis-induced muscle mass loss. This could be attributed to a greater activation of ubiquitin-proteasome system and an increased myostatin expression. Thus, this study strongly suggests that the contractile activity pattern of diaphragm muscle confers resistance to atrophy compared to the locomotor gastrocnemius muscle. These data also suggest that a strategy aimed at preventing the activation of catabolic pathways and preserving spontaneous activity would be of interest for the treatment of patients with sepsis-induced neuromyopathy. PMID- 28883495 TI - Spatially-resolved optical and structural properties of semi-polar [Formula: see text] Al x Ga1-x N with x up to 0.56. AB - Pushing the emission wavelength of efficient ultraviolet (UV) emitters further into the deep-UV requires material with high crystal quality, while also reducing the detrimental effects of built-in electric fields. Crack-free semi-polar [Formula: see text] Al x Ga1-x N epilayers with AlN contents up to x = 0.56 and high crystal quality were achieved using an overgrowth method employing GaN microrods on m-sapphire. Two dominant emission peaks were identified using cathodoluminescence hyperspectral imaging. The longer wavelength peak originates near and around chevron-shaped features, whose density is greatly increased for higher contents. The emission from the majority of the surface is dominated by the shorter wavelength peak, influenced by the presence of basal-plane stacking faults (BSFs). Due to the overgrowth technique BSFs are bunched up in parallel stripes where the lower wavelength peak is broadened and hence appears slightly redshifted compared with the higher quality regions in-between. Additionally, the density of threading dislocations in these region is one order of magnitude lower compared with areas affected by BSFs as ascertained by electron channelling contrast imaging. Overall, the luminescence properties of semi-polar AlGaN epilayers are strongly influenced by the overgrowth method, which shows that reducing the density of extended defects improves the optical performance of high AlN content AlGaN structures. PMID- 28883496 TI - Overexpression of Insig-2 inhibits atypical antipsychotic-induced adipogenic differentiation and lipid biosynthesis in adipose-derived stem cells. AB - Atypical antipsychotics (AAPs) are considered to possess superior efficacy for treating both the positive and negative symptoms of schizophrenia; however, AAP use often causes excessive weight gain and metabolic abnormalities. Recently, several reports have demonstrated that AAPs activate sterol regulatory element binding protein (SREBP). SREBP, SREBP cleavage-activating protein (SCAP) and insulin-induced gene (Insig) regulate downstream cholesterol and fatty acid biosynthesis. In this study, we explored the effects of clozapine, olanzapine and risperidone on SREBP signaling and downstream lipid biosynthesis genes in the early events of adipogenic differentiation in adipose-derived stem cells (ASCs). After the induction of adipogenic differentiation for 2 days, all AAPs, notably clozapine treatment for 3 and 7 days, enhanced the expression of SREBP-1 and its downstream lipid biosynthesis genes without dexamethasone and insulin supplementation. Simultaneously, protein level of SREBP-1 was significantly enhanced via inhibition of Insig-2 expression. By contrast, SREBP-1 activation was suppressed when Insig-2 expression was upregulated by transfection with Insig 2 plasmid DNA. In summary, our results indicate that AAP treatment, notably clozapine treatment, induces early-stage lipid biosynthesis in ASCs. Such abnormal lipogenesis can be reversed when Insig-2 expression was increased, suggesting that Insig/SCAP/SREBP signaling may be a therapeutic target for AAP induced weight gain and metabolic abnormalities. PMID- 28883497 TI - Spatiotemporal brain dynamics supporting the immediate automatization of inhibitory control by implementation intentions. AB - While cognitive interventions aiming at reinforcing intentional executive control of unwanted response showed only modest effects on impulse control disorders, the establishment of fast automatic, stimulus-driven inhibition of responses to specific events with implementation intention self-regulation strategies has proven to be an effective remediation approach. However, the neurocognitive mechanisms underlying implementation intentions remain largely unresolved. We addressed this question by comparing electrical neuroimaging analyses of event related potentials recorded during a Go/NoGo task between groups of healthy participants receiving either standard or implementation intentions instructions on the inhibition stimuli. Inhibition performance improvements with implementation intentions were associated with a Group by Stimulus interaction 200-250 ms post-stimulus onset driven by a selective decrease in response to the inhibition stimuli within the left superior temporal gyrus, the right precuneus and the right temporo-parietal junction. We further observed that the implementation intentions group showed already at the beginning of the task the pattern of task-related functional activity reached after practice in the group having received standard instructions. We interpret our results in terms of an immediate establishment of an automatic, bottom-up form of inhibitory control by implementation intentions, supported by stimulus-driven retrieval of verbally encoded stimulus-response mapping rules, which in turn triggered inhibitory processes. PMID- 28883498 TI - The mechanical and photoelastic properties of 3D printable stress-visualized materials. AB - Three-dimensional (3D) printing technology integrating frozen stress techniques has created a novel way to directly represent and characterize 3D interior discontinuities and the full-field stress induced by mining- or construction related disturbances of deeply buried rock masses. However, concerns have been raised about the similitude between the mechanical behaviours of the printed model and its prototype rock mass. Ensuring the mechanical properties of the printable materials are as close as possible to those of real rock mass is of critical significance. In this work, a transparent, light, photosensitive polymer material was investigated for applications in frozen stress tests. The chemical composition of the material was determined by integrating the results of infrared spectroscopy (IR spectroscopy), X-ray diffraction (XRD), pyrolysis, gas chromatography and mass spectrometry (PY-GC/MS). Measures to improve the mechanical properties of the printable material, including printing orientation, post-processing, and temperature control, were evaluated by comparing the treated material with its prototype rock. The optical stress sensitivity of the material, including stress-visualized properties and stress-frozen performance, was also tested. This study offers an understanding of how printable materials should be modified to better simulate real rock masses, in terms of not only their geological geometry but also their mechanical performance. PMID- 28883499 TI - A reminder before extinction strengthens episodic memory via reconsolidation but fails to disrupt generalized threat responses. AB - A reminder can temporarily renew flexibility of consolidated memories, referred to as reconsolidation. Pavlovian threat-conditioning studies suggest that a reminder can renew flexibility of threat responses but that episodic memories remain stable. In contrast, outside the threat-conditioning domain, studies testing memory for word lists or stories find that a reminder can renew flexibility of episodic memory. This discrepancy in findings leaves it unclear if episodic memories reconsolidate, or only Pavlovian responses. Here we unite the different approaches in the field and show that a reminder can retroactively strengthen episodic memory for Pavlovian threat-conditioned events, but that, in contrast to threat-conditioning studies with simple sensory stimuli, extinction after a reminder fails to prevent recovery of generalized threat responses. Our results indicate the episodic memories also reconsolidate, allowing strengthening of relevant memories. These findings also suggest that generalized threat responses and episodic memories are less susceptible to be modified by reminder interventions procedures. PMID- 28883500 TI - Quantitative imaging of anti-phase domains by polarity sensitive orientation mapping using electron backscatter diffraction. AB - Advanced structural characterisation techniques which are rapid to use, non destructive and structurally definitive on the nanoscale are in demand, especially for a detailed understanding of extended-defects and their influence on the properties of materials. We have applied the electron backscatter diffraction (EBSD) technique in a scanning electron microscope to non destructively characterise and quantify antiphase domains (APDs) in GaP thin films grown on different (001) Si substrates with different offcuts. We were able to image and quantify APDs by relating the asymmetrical intensity distributions observed in the EBSD patterns acquired experimentally and comparing the same with the dynamical electron diffraction simulations. Additionally mean angular error maps were also plotted using automated cross-correlation based approaches to image APDs. Samples grown on substrates with a 4 degrees offcut from the [110] do not show any APDs, whereas samples grown on the exactly oriented substrates contain APDs. The procedures described in our work can be adopted for characterising a wide range of other material systems possessing non centrosymmetric point groups. PMID- 28883501 TI - CAPS-1 requires its C2, PH, MHD1 and DCV domains for dense core vesicle exocytosis in mammalian CNS neurons. AB - CAPS (calcium-dependent activator protein for secretion) are multi-domain proteins involved in regulated exocytosis of synaptic vesicles (SVs) and dense core vesicles (DCVs). Here, we assessed the contribution of different CAPS-1 domains to its subcellular localization and DCV exocytosis by expressing CAPS-1 mutations in four functional domains in CAPS-1/-2 null mutant (CAPS DKO) mouse hippocampal neurons, which are severely impaired in DCV exocytosis. CAPS DKO neurons showed normal development and no defects in DCV biogenesis and their subcellular distribution. Truncation of the CAPS-1 C-terminus (CAPS Delta654 1355) impaired CAPS-1 synaptic enrichment. Mutations in the C2 (K428E or G476E) or pleckstrin homology (PH; R558D/K560E/K561E) domain did not. However, all mutants rescued DCV exocytosis in CAPS DKO neurons to only 20% of wild type CAPS 1 exocytosis capacity. To assess the relative importance of CAPS for both secretory pathways, we compared effect sizes of CAPS-1/-2 deficiency on SV and DCV exocytosis. Using the same (intense) stimulation, DCV exocytosis was impaired relatively strong (96% inhibition) compared to SV exocytosis (39%). Together, these data show that the CAPS-1 C-terminus regulates synaptic enrichment of CAPS 1. All CAPS-1 functional domains are required, and the C2 and PH domain together are not sufficient, for DCV exocytosis in mammalian CNS neurons. PMID- 28883502 TI - Activation of Endoplasmic Reticulum Stress in Granulosa Cells from Patients with Polycystic Ovary Syndrome Contributes to Ovarian Fibrosis. AB - Recent studies report the involvement of intra-ovarian factors, such as inflammation and oxidative stress, in the pathophysiology of polycystic ovary syndrome (PCOS), the most common endocrine disorder of reproductive age women. Endoplasmic reticulum (ER) stress is a local factor that affects various cellular events during a broad spectrum of physiological and pathological conditions. It may also be an important determinant of pro-fibrotic remodeling during tissue fibrosis. In the present study, we showed that ER stress was activated in granulosa cells of PCOS patients as well as in a well-established PCOS mouse model. Pharmacological inducers of ER stress, tunicamycin and thapsigargin, were found to increase the expression of pro-fibrotic growth factors, including transforming growth factor (TGF)-beta1, in human granulosa cells, and their expression also increased in granulosa cells of PCOS patients. By contrast, treatment of PCOS mice with an ER stress inhibitor, tauroursodeoxycholic acid or BGP-15, decreased interstitial fibrosis and collagen deposition in ovaries, accompanied by a reduction in TGF-beta1 expression in granulosa cells. These findings suggest that ER stress in granulosa cells of women with PCOS contributes to the induction of pro-fibrotic growth factors during ovarian fibrosis, and that ER stress may serve as a therapeutic target in PCOS. PMID- 28883503 TI - Differential impact of lipopolysaccharide defects caused by loss of RfaH in Yersinia pseudotuberculosis and Yersinia pestis. AB - RfaH enhances transcription of a select group of operons controlling bacterial surface features such as lipopolysaccharide (LPS). Previous studies have suggested that rfaH may be required for Yersinia pseudotuberculosis resistance to antimicrobial chemokines and survival during mouse infections. In order to further investigate the role of RfaH in LPS synthesis, resistance to host defense peptides, and virulence of Yersinia, we constructed DeltarfaH mutants of Y. pseudotuberculosis IP32953 and Y. pestis KIM6+. Loss of rfaH affected LPS synthesis in both species, resulting in a shorter core oligosaccharide. Susceptibility to polymyxin and the antimicrobial chemokine CCL28 was increased by loss of rfaH in Y. pseudotuberculosis but not in Y. pestis. Transcription of genes in the ddhD-wzz O-antigen gene cluster, but not core oligosaccharide genes, was reduced in DeltarfaH mutants. In addition, mutants with disruptions in specific ddhD-wzz O-antigen cluster genes produced LPS that was indistinguishable from the DeltarfaH mutant. This suggests that both Y. pseudotuberculosis and Y. pestis produce an oligosaccharide core with a single O-antigen unit attached in an RfaH-dependent fashion. Despite enhanced sensitivity to host defense peptides, the Y. pseudotuberculosis DeltarfaH strain was not attenuated in mice, suggesting that rfaH is not required for acute infection. PMID- 28883504 TI - Investigation of the polymerization mechanism of ferrocene doped C60 under high pressure and high temperature. AB - In situ high pressure and high temperature (HPHT) study has been carried out on C60/ferrocene (Fc) in order to detect the process of polymerization and reveal the polymerization mechanism. Pristine C60 was also studied under same conditions for comparison. In both cases, similar types of polymers can be observed after pressure and temperature release, but with different fractions, i.e. a larger amount of 2D polymers were formed in pure C60, while more branch-like polymers were synthesized in C60/Fc, although the most fraction of the polymers is still 1D chain-like polymer in both of the materials. The polymers formed in C60 can be detected both during the "up" run (pressure and temperature increase) and the "down" run (pressure and temperature decrease), while in C60/Fc, the polymers can only be synthesized in the "down" run. The differences between the two cases were attributed to the different initial lattice structures of the two materials and the confinement effect of the dopant. The polymerization mechanism on C60/Fc under HPHT was also revealed in this work. PMID- 28883505 TI - Channel Formation and Membrane Deformation via Sterol-Aided Polymorphism of Amphidinol 3. AB - Amphidinol 3 (AM3) is an anti-fungal polyene extracted from a marine dinoflagellate. Here, we examined the ion channel activity and membrane-embedded structure of AM3 using a lipid bilayer method and atomic force microscopy (AFM). AM3 exhibited large-conductance (~1 nS) and non-selective single-channel activity only when sterols were present in the membrane leaflet of the AM3-added side. The variable conductance suggests the formation of a multimeric barrel-stave pore. At high AM3 concentrations, giant-conductance "jumbo" channels (~40 nS) emerged. AFM revealed a thicker raft-like membrane phase with the appearance of a wrinkled surface, in which phase pores (diameter: ~10 nm) were observed. The flip-flop of ergosterol occurred only after the appearance of the jumbo channel, indicating that the jumbo channel induced a continuity between the outer and inner leaflets of the membrane: a feature characteristic of toroidal-like pores. Thus, AM3 forms different types of sterol-aided polymorphic channels in a concentration dependent manner. PMID- 28883506 TI - Deep-reef fish assemblages of the Great Barrier Reef shelf-break (Australia). AB - Tropical mesophotic and sub-mesophotic fish ecology is poorly understood despite increasing vulnerability of deeper fish assemblages. Worldwide there is greater fishing pressure on continental shelf-breaks and the effects of disturbances on deeper fish species have not yet been assessed. Difficult to access, deeper reefs host undocumented fish diversity and abundance. Baited Remote Underwater Video Stations (BRUVS) with lights were used to sample deeper habitats (54-260 m), in the Great Barrier Reef (GBR), Australia. Here we describe fish biodiversity, relative abundance and richness, assessing the prediction that depth would drive assemblage structure in the GBR. Distinct groups of fishes were found with depth whilst overall richness and abundance decreased steeply between 100 and 260 m. Commercially-valuable Lutjanidae species from Pristipomoides and Etelis genera, were absent from shallower depths. Few fish species overlapped between adjacent depth strata, indicating unique assemblages with depth. We also detected new location records and potential new species records. The high biodiversity of fish found in shelf-break environments is poorly appreciated and depth is a strong predictor of assemblage composition. This may pose a challenge for managers of commercial fisheries as distinct depth ranges of taxa may translate to more readily targeted habitats, and therefore, an inherent vulnerability to exploitation. PMID- 28883507 TI - Organotypic pancreatoids with native mesenchyme develop Insulin producing endocrine cells. AB - Replacement of lost beta cells in patients with diabetes has the potential to alleviate them of their disease, yet current protocols to make beta cells are inadequate for therapy. In vitro screens can reveal the signals necessary for endocrine maturation to improve beta cell production, however the complexities of in vivo development that lead to beta cell formation are lost in two-dimensional systems. Here, we create three-dimensional organotypic pancreatic cultures, named pancreatoids, composed of embryonic day 10.5 murine epithelial progenitors and native mesenchyme. These progenitors assemble in scaffold-free, floating conditions and, with the inclusion of native mesenchyme, develop into pancreatoids expressing markers of different pancreatic lineages including endocrine-like cells. Treatment of pancreatoids with (-)-Indolactam-V or phorbol 12-myristate 13-acetate, two protein kinase C activators, leads to altered morphology which otherwise would be overlooked in two-dimensional systems. Protein kinase C activation also led to fewer Insulin+ cells, decreased Ins1 and Ins2 mRNA levels, and increased Pdx1 and Hes1 mRNA levels with a high number of DBA+ cells. Thus, organotypic pancreatoids provide a useful tool for developmental studies, and can further be used for disease modeling, small molecules and genetic screens, or applied to human pluripotent stem cell differentiation for beta-like cell formation. PMID- 28883508 TI - Inter-subject Functional Correlation Reveal a Hierarchical Organization of Extrinsic and Intrinsic Systems in the Brain. AB - The brain is constantly monitoring and integrating both cues from the external world and signals generated intrinsically. These extrinsically and intrinsically driven neural processes are thought to engage anatomically distinct regions, which are thought to constitute the extrinsic and intrinsic systems of the brain. While the specialization of extrinsic and intrinsic system is evident in primary and secondary sensory cortices, a systematic mapping of the whole brain remains elusive. Here, we characterized the extrinsic and intrinsic functional activities in the brain during naturalistic movie-viewing. Using a novel inter-subject functional correlation (ISFC) analysis, we found that the strength of ISFC shifts along the hierarchical organization of the brain. Primary sensory cortices appear to have strong inter-subject functional correlation, consistent with their role in processing exogenous information, while heteromodal regions that attend to endogenous processes have low inter-subject functional correlation. Those brain systems with higher intrinsic tendency show greater inter-individual variability, likely reflecting the aspects of brain connectivity architecture unique to individuals. Our study presents a novel framework for dissecting extrinsically- and intrinsically-driven processes, as well as examining individual differences in brain function during naturalistic stimulation. PMID- 28883509 TI - The circadian clock in immune cells controls the magnitude of Leishmania parasite infection. AB - The intracellular parasite Leishmania uses neutrophils and macrophages as host cells upon infection. These immune cells harbour their own intrinsic circadian clocks, known to influence many aspects of their functions. Therefore, we tested whether the host circadian clocks regulate the magnitude of Leishmania major infection in mice. The extent of parasitic infection varied over 24 h in bone marrow-derived macrophages in vitro and in two different in vivo models, footpad and peritoneal cavity infection. In vivo this was paralleled by time of day dependent neutrophil and macrophage infiltration to the infection site and rhythmic chemokine expression. Thus, rhythmic parasitic infection observed in vivo was likely initiated by the circadian expression of chemoattractants and the subsequent rhythmic infiltration of neutrophils and macrophages. Importantly, all rhythms were abolished in clock-deficient macrophages and when mice lacking the circadian clock in immune cells were infected. Therefore we demonstrated a critical role for the circadian clocks in immune cells in modulating the magnitude of Leishmania infection. To our knowledge this is the first report showing that the circadian clock controls infection by protozoan parasites in mammals. Understanding the timed regulation of host-parasite interactions will allow developing better prophylactic and therapeutic strategies to fight off vector-borne diseases. PMID- 28883510 TI - Disseminated tuberculosis among hospitalised HIV patients in South Africa: a common condition that can be rapidly diagnosed using urine-based assays. AB - HIV-associated disseminated TB (tuberculosis) has been under-recognised and poorly characterised. Blood culture is the gold-standard diagnostic test, but is expensive, slow, and may under-diagnose TB dissemination. In a cohort of hospitalised HIV patients, we aimed to report the prevalence of TB-blood-culture positivity, performance of rapid diagnostics as diagnostic surrogates, and better characterise the clinical phenotype of disseminated TB. HIV-inpatients were systematically investigated using sputum, urine and blood testing. Overall, 132/410 (32.2%) patients had confirmed TB; 41/132 (31.1%) had a positive TB blood culture, of these 9/41 (22.0%) died within 90-days. In contrast to sputum diagnostics, urine Xpert and urine-lipoarabinomannan (LAM) combined identified 88% of TB blood-culture-positive patients, including 9/9 who died within 90-days. For confirmed-TB patients, half the variation in major clinical variables was captured on two principle components (PCs). Urine Xpert, urine LAM and TB-blood culture positive patients clustered similarly on these axes, distinctly from patients with localised disease. Total number of positive tests from urine Xpert, urine LAM and MTB-blood-culture correlated with PCs (p < 0.001 for both). PC1&PC2 independently predicted 90-day mortality (ORs 2.6, 95%CI = 1.3-6.4; and 2.4, 95%CI = 1.3-4.5, respectively). Rather than being a non-specific diagnosis, disseminated TB is a distinct, life-threatening condition, which can be diagnosed using rapid urine-based tests, and warrants specific interventional trials. PMID- 28883511 TI - Cytotoxic response against Epstein Barr virus coexists with diffuse large B-cell lymphoma tolerogenic microenvironment: clinical features and survival impact. AB - Epstein-Barr Virus (EBV) is present in neoplastic cells of 15% of Asian and Latin American diffuse large B-cell lymphoma (DLBCL) patients. Even though a tolerogenic microenvironment was recently described in DLBCL, little is known concerning immunomodulatory features induced by EBV. As suggested in Hodgkin lymphoma, EBV-specific cytotoxic T-cells are increased but showing immune exhaustion features. Hence, host immunity suppression may play a critical role in tumor progression. This study aimed to investigate, whether an association between tumor microenvironment features and EBV presence is taking place, and its clinical correlate. The incidence of EBV+DLBCL NOS was 12.6% in this cohort. Cytokine and chemokine transcripts expression and immunophenotype analysis showed that EBV infection was associated with increased gene expression of immunosuppressive cytokine (IL-10) together with increased CD8+ T-cells and granzyme B+ cytotoxic effector cells. However, this specific response coexists with a tolerogenic milieu, by PD-1 expression, in EBV+ and EBV-DLBCL cases. High PD-1+ cell counts, EBV presence and low CCL22 expression were associated with worse survival, supporting our hypothesis that EBV-specific response is mounted locally and its inhibition by, for example PD-1+ cells, may negatively affect outcome. The better understanding of the interplay between lymphoma cells and microenvironment in a viral framework could thereby facilitate the discovery of new targets for innovative anti-lymphoma treatment strategies. PMID- 28883512 TI - Leukaemia: Beyond the C. PMID- 28883513 TI - Prostate cancer: BET inhibitors - SPOP right there! PMID- 28883514 TI - Next generation highly resistant mirrors featuring all-silica layers. AB - A principal possibility to overcome fundamental (intrinsic) limit of pure optical materials laser light resistance is investigated by designing artificial materials with desired optical properties. We explore the suitability of high band-gap ultra-low refractive index material (n less than 1.38 at 550 nm) in the context of highly reflective coatings with enhanced optical resistance. The new generation all-silica (porous/nonporous) SiO2 thin film mirror with 99% reflectivity was prepared by glancing angle deposition (GLAD). Its damage performance was directly compared with state of the art hafnia/silica coating produced by Ion-Beam-Sputtering. Laser-Induced Damage Thresholds (LIDT) of both coatings were measured in nanosecond regime at 355 nm wavelength. Novel approach indicates the potential for coating to withstand laser fluence of at least 65 J/cm2 without reaching intrinsic threshold value. Reported concept can be expanded to virtually any design thus opening a new way of next generation thin film production well suited for high power laser applications. PMID- 28883515 TI - Factor Xa Mediates Calcium Flux in Endothelial Cells and is Potentiated by Igg From Patients With Lupus and/or Antiphospholipid Syndrome. AB - Factor (F) Xa reactive IgG isolated from patients with antiphospholipid syndrome (APS) display higher avidity binding to FXa with greater coagulant effects compared to systemic lupus erythematosus (SLE) non APS IgG. FXa signalling via activation of protease-activated receptors (PAR) leads to increased intracellular calcium (Ca2+). Therefore, we measured alterations in Ca2+ levels in human umbilical vein endothelial cells (HUVEC) following FXa-mediated PAR activation and investigated whether FXa reactive IgG from patients with APS or SLE/APS- alter these responses. We observed concentration-dependent induction of Ca2+ release by FXa that was potentiated by APS-IgG and SLE/APS- IgG compared to healthy control subjects' IgG, and FXa alone. APS-IgG and SLE/APS- IgG increased FXa mediated NFkappaB signalling and this effect was fully-retained in the affinity purified anti-FXa IgG sub-fraction. Antagonism of PAR-1 and PAR-2 reduced FXa-induced Ca2+ release. Treatment with a specific FXa inhibitor, hydroxychloroquine or fluvastatin significantly reduced FXa-induced and IgG potentiated Ca2+ release. In conclusion, PAR-1 and PAR-2 are involved in FXa mediated intracellular Ca2+ release in HUVEC and FXa reactive IgG from patients with APS and/or SLE potentiate this effect. Further work is required to explore the potential use of IgG FXa reactivity as a novel biomarker to stratify treatment with FXa inhibitors in these patients. PMID- 28883517 TI - Nab-Paclitaxel in combination with Cisplatin Versus Docetaxel Plus Cisplatin as First-Line Therapy in Non-small Cell Lung Cancer. AB - Albumin-bound paclitaxel (nab-PC) and docetaxel both produced favorable efficacy and safety as first-line therapy in advanced non-small cell lung cancer (NSCLC). However, the comparison between nab-PC and docetaxel remained unclear until now. This retrospective study aimed to compare the efficacy and safety of nab PC/cisplatin with docetaxel/cisplatin as first-line therapy in advanced NSCLC. 271 patients with advanced NSCLC, who received either nab-PC (55 patients) or docetaxel (216 patients) were reviewed from 2012 to 2016. The primary endpoint was objective overall response rate (ORR). The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety profiles. Nab-PC presented a significantly higher ORR than docetaxel (47.3% vs 31.9%; P = 0.033). The difference of ORR was more significantly remarkable in patients with squamous histology (58.3% vs 29.0%; P = 0.007). Additionally, the DCR of nab-PC was significantly higher than docetaxel. Patients in nab-PC group had a trend toward improved PFS and OS compared with patients in docetaxel group, but this didn't reach statistical significance. Grade >= 3 neutropenia was less in nab-PC group, while Grade >= 3 anemia and thrombocytopenia were less in docetaxel group. Nab-PC/cisplatin as first-line therapy, produced significantly higher efficacy and reduced neutropenia than docetaxel/cisplatin in advanced NSCLC. PMID- 28883516 TI - Effects of low-intensity pulsed electromagnetic fields on bone microarchitecture, mechanical strength and bone turnover in type 2 diabetic db/db mice. AB - Type 2 diabetic patients have impaired bone quality, leading to increased fracture risk. Substantial evidence demonstrates that pulsed electromagnetic fields (PEMF) could resist osteopenia/osteoporosis induced by estrogen deficiency and disuse. However, the effects of PEMF on osteopenia/osteoporosis associated with diabetes, especially for more prevalent type 2 diabetes, remain poorly understood. We herein investigated the skeletal effects and mechanisms of PEMF (15 Hz, 20 Gs) on leptin receptor-deficient db/db mice with typical type 2 diabetic symptoms. Our uCT results showed that 12-week PEMF exposure significantly improved both cancellous and cortical bone microarchitecture in db/db mice. Three-point bending and biomechanical indentation testing demonstrated that PEMF improved whole-bone structural properties and tissue-level material properties in db/db mice. PEMF significantly promoted bone formation in db/db mice evidenced by increased serum osteocalcin and bone mineral apposition rate, whereas PEMF exerted no observable alteration in bone resorption. Real-time PCR showed that PEMF upregulated tibial gene expression of osteoblastogenesis related of canonical Wnt/beta-catenin signaling but not osteoclastogenesis related RANKL-RANK signaling in db/db mice. Our findings demonstrate that PEMF improved bone quantity and quality with obvious anabolic activities in db/db mice, and imply that PEMF might become a clinically applicable treatment modality for improving bone quality in type 2 diabetic patients. PMID- 28883518 TI - New compounds identified through in silico approaches reduce the alpha-synuclein expression by inhibiting prolyl oligopeptidase in vitro. AB - Prolyl oligopeptidase (POP) is a serine protease that is responsible for the maturation and degradation of short neuropeptides and peptide hormones. The inhibition of POP has been demonstrated in the treatment of alpha synucleinopathies and several neurological conditions. Therefore, ligand-based and structure-based pharmacophore models were generated and validated in order to identify potent POP inhibitors. Pharmacophore-based and docking-based virtual screening of a drug-like database resulted in 20 compounds. The in vitro POP assays indicated that the top scoring compounds obtained from virtual screening, Hit 1 and Hit 2 inhibit POP activity at a wide range of concentrations from 0.1 to 10 uM. Moreover, treatment of the hit compounds significantly reduced the alpha-synuclein expression in SH-SY5Y human neuroblastoma cells, that is implicated in Parkinson's disease. Binding modes of Hit 1 and Hit 2 compounds were explored through molecular dynamics simulations. A detailed investigation of the binding interactions revealed that the hit compounds exhibited hydrogen bond interactions with important active site residues and greater electrostatic and hydrophobic interactions compared to those of the reference inhibitors. Finally, our findings indicated the potential of the identified compounds for the treatment of synucleinopathies and CNS related disorders. PMID- 28883520 TI - Penicilliumin B, a novel sesquiterpene methylcyclopentenedione from a deep sea derived Penicillium strain with renoprotective activities. AB - A novel sesquiterpene methylcyclopentenedione, penicilliumin B (1), was obtained from a deep sea-derived fungus Penicillium sp. F00120, together with three known sesquiterpene cyclohexenones (2-4). Penicilliumin B (1), presenting the first example with the sesquiterpene cyclopentenedione skeleton as natural products, was structurally determined by analysis of the NMR and MS spectroscopic data, while the absolute configurations were assigned by single-crystal X-ray experiments. The plausible biosynthetic pathway of the unusual cyclopentenone skeleton of 1 was proposed. Penicilliumin B (1), with low toxicity, was showed significant potential to inhibit the kidney fibrogenic action in vitro, by a mechanism dependent on disruption of oxidative stress, presenting a new type of promising renoprotective agent. PMID- 28883521 TI - Impact of maternal obesity on the incidence of pregnancy complications in France and Canada. AB - The aim of our study was to compare the impact of maternal obesity on the incidence of medical complications of pregnancy in France and Canada. We performed a prospective comparative cohort study using French data, retrieved from a prospective cohort of singleton deliveries, and Canadian data retrieved from QUARISMA, a cluster-randomized controlled trial conducted in Quebec, both between 2009 and 2011. Outcomes studied included, hypertensive disorders of pregnancy (HDP), venous thromboembolism, stillbirth, caesarean delivery and macrosomia. The impact of obesity across both cohorts was studied using univariate and multivariate logistic regression analyses, adjusting for relevant confounders. The French and Canadian databases included 26,973 and 22,046 deliveries respectively, with obesity rates of 9.1% and 16% respectively (p < 0.001). In both cohorts, obesity was significantly associated with an increased rate of HDP, cesarean delivery, and macrosomia. However, in both cohorts the relationship between increasing body mass index and the incidence of medical complication of pregnancy was the same, regardless the outcome studied. In conclusion, obesity is a risk factor for adverse maternal and fetal outcomes in both cohorts. Similar trends of increased risk were noted in both cohorts even though obesity is more prevalent in Canada. PMID- 28883519 TI - Monolithic Chip for High-throughput Blood Cell Depletion to Sort Rare Circulating Tumor Cells. AB - Circulating tumor cells (CTCs) are a treasure trove of information regarding the location, type and stage of cancer and are being pursued as both a diagnostic target and a means of guiding personalized treatment. Most isolation technologies utilize properties of the CTCs themselves such as surface antigens (e.g., epithelial cell adhesion molecule or EpCAM) or size to separate them from blood cell populations. We present an automated monolithic chip with 128 multiplexed deterministic lateral displacement devices containing ~1.5 million microfabricated features (12 um-50 um) used to first deplete red blood cells and platelets. The outputs from these devices are serially integrated with an inertial focusing system to line up all nucleated cells for multi-stage magnetophoresis to remove magnetically-labeled white blood cells. The monolithic CTC-iChip enables debulking of blood samples at 15-20 million cells per second while yielding an output of highly purified CTCs. We quantified the size and EpCAM expression of over 2,500 CTCs from 38 patient samples obtained from breast, prostate, lung cancers, and melanoma. The results show significant heterogeneity between and within single patients. Unbiased, rapid, and automated isolation of CTCs using monolithic CTC-iChip will enable the detailed measurement of their physicochemical and biological properties and their role in metastasis. PMID- 28883522 TI - Visualization of ligand-induced dopamine D2S and D2L receptor internalization by TIRF microscopy. AB - G protein-coupled receptors (GPCRs), including the dopamine receptors, represent a group of important pharmacological targets. Upon agonist binding, GPCRs frequently undergo internalization, a process that is known to attenuate functional responses upon prolonged exposure to agonists. In this study, internalization was visualized by means of total internal reflection fluorescence (TIRF) microscopy at a level of discrete single events near the plasma membrane with high spatial resolution. A novel method has been developed to determine the relative extent of internalized fluorescent receptor-ligand complexes by comparative fluorescence quantification in living CHO cells. The procedure entails treatment with the reducing agent sodium borohydride, which converts cyanine-based fluorescent ligands on the membrane surface to a long-lived reduced form. Because the highly polar reducing agent is not able to pass the cell membrane, the fluorescent receptor-ligand complexes located in internalized compartments remain fluorescent under TIRF illumination. We applied the method to investigate differences of the short (D2S) and the long (D2L) isoforms of dopamine D2 receptors in their ability to undergo agonist-induced internalization. PMID- 28883523 TI - Information seeking about tool properties in great apes. AB - Evidence suggests that great apes engage in metacognitive information seeking for food items. To support the claim that a domain-general cognitive process underlies ape metacognition one needs to show that selective information seeking extends to non-food items. In this study, chimpanzees (Pan troglodytes) and orangutans (Pongo abelii) either had to determine the location of a desired food item or a property of a non-food item (length of a tool). We manipulated whether subjects received prior information about the item's location or property. During the test, subjects had the opportunity to seek the respective information. Results show that apes engaged in more information seeking when they had no prior knowledge. Importantly, this selective pattern of information seeking applied to food as well as to tools. PMID- 28883524 TI - Flat building blocks for flat silicene. AB - Silicene is the silicon equivalent of graphene, which is composed of a honeycomb carbon structure with one atom thickness and has attractive characteristics of a perfect two-dimensional pi-conjugated sheet. However, unlike flat and highly stable graphene, silicene is relatively sticky and thus unstable due to its puckered or crinkled structure. Flatness is important for stability, and to obtain perfect pi-conjugation, electron-donating atoms and molecules should not interact with the pi electrons. The structural differences between silicene and graphene result from the differences in their building blocks, flat benzene and chair-form hexasilabenzene. It is crucial to design flat building blocks for silicene with no interactions between the electron donor and pi-orbitals. Here, we report the successful design of such building blocks with the aid of density functional theory calculations. Our fundamental concept is to attach substituents that have sp-hybrid orbitals and act as electron donors in a manner that it does not interact with the pi orbitals. The honeycomb silicon molecule with BeH at the edge designed according to our concept, clearly shows the same structural, charge distribution and molecular orbital characteristics as the corresponding carbon based molecule. PMID- 28883525 TI - Self-supporting sulfur cathodes enabled by two-dimensional carbon yolk-shell nanosheets for high-energy-density lithium-sulfur batteries. AB - How to exert the energy density advantage is a key link in the development of lithium-sulfur batteries. Therefore, the performance degradation of high-sulfur loading cathodes becomes an urgent problem to be solved at present. In addition, the volumetric capacities of high-sulfur-loading cathodes are still at a low level compared with their areal capacities. Aiming at these issues, two dimensional carbon yolk-shell nanosheet is developed herein to construct a novel self-supporting sulfur cathode. The cathode with high-sulfur loading of 5 mg cm-2 and sulfur content of 73 wt% not only delivers an excellent rate performance and cycling stability, but also provides a favorable balance between the areal (5.7 mAh cm-2) and volumetric (1330 mAh cm-3) capacities. Remarkably, an areal capacity of 11.4 mAh cm-2 can be further achieved by increasing the sulfur loading from 5 to 10 mg cm-2. This work provides a promising direction for high energy-density lithium-sulfur batteries.One of the challenges facing lithium sulfur batteries is to develop cathodes with high mass and high volume loading. Here the authors show that two-dimensional carbon yolk-shell nanosheets are promising sulfur host materials, enabling stable battery cells with high energy density. PMID- 28883526 TI - Synthesis, high-throughput screening and pharmacological characterization of beta lactam derivatives as TRPM8 antagonists. AB - The mammalian transient receptor potential melastatin channel 8 (TRPM8), highly expressed in trigeminal and dorsal root ganglia, mediates the cooling sensation and plays an important role in the cold hypersensitivity characteristic of some types of neuropathic pain, as well as in cancer. Consequently, the identification of selective and potent ligands for TRPM8 is of great interest. Here, a series of compounds, having a beta-lactam central scaffold, were prepared to explore the pharmacophore requirements for TRPM8 modulation. Structure-activity studies indicate that the minimal requirements for potent beta-lactam-based TRPM8 blockers are hydrophobic groups (benzyl preferentially or t Bu) on R1, R2, R3 and R5 and a short N-alkyl chain (<=3 carbons). The best compounds in the focused library (41 and 45) showed IC50 values of 46 nM and 83 nM, respectively, in electrophysiology assays. These compounds selectively blocked all modalities of TRPM8 activation, i.e. menthol, voltage, and temperature. Molecular modelling studies using a homology model of TRPM8 identified two putative binding sites, involving networks of hydrophobic interactions, and suggesting a negative allosteric modulation through the stabilization of the closed state. Thus, these beta-lactams provide a novel pharmacophore scaffold to evolve TRPM8 allosteric modulators to treat TRPM8 channel dysfunction. PMID- 28883527 TI - Quantifying the efficacy of first aid treatments for burn injuries using mathematical modelling and in vivo porcine experiments. AB - First aid treatment of burns reduces scarring and improves healing. We quantify the efficacy of first aid treatments using a mathematical model to describe data from a series of in vivo porcine experiments. We study burn injuries that are subject to various first aid treatments. The treatments vary in the temperature and duration. Calibrating the mathematical model to the experimental data provides estimates of the thermal diffusivity, the rate at which thermal energy is lost to the blood, and the heat transfer coefficient controlling the loss of thermal energy at the interface of the fat and muscle. A limitation of working with in vivo experiments is the difficulty of measuring variations in temperature across the tissue layers. This limitation motivates us to use a simple, single layer mathematical model. Using the solution of the calibrated mathematical model we visualise the temperature distribution across the thickness of the tissue. With this information we propose a novel measure of the potential for tissue damage. This measure quantifies two important factors: (i) the volume of tissue that rises above the threshold temperature associated with the accumulation of tissue damage; and (ii) the duration of time that the tissue remains above this threshold temperature. PMID- 28883528 TI - Knowledge, attitude, and practice about malaria: Socio-demographic implications for malaria control in rural Ghana. AB - Despite continuing international attention to malaria prevention, the disease remains a global public health problem. We investigated socio-demographic factors influencing knowledge, attitudes, and practices about malaria in rural Ghana. Our survey looked at 354 households. Mean knowledge score was higher among individuals with a history of volunteers having visited their households to educate them about malaria; families with 4-6 members; and males. Households with at least one under-five-aged child also had significantly higher knowledge scores. Households with at least one pregnant woman evinced a positive attitude towards malaria prevention. National malaria control strategies have achieved positive results in the fight against malaria. Nonetheless, multipronged community-based health strategies that integrate malaria programs and population growth control initiatives may be able to reach by 2030 the sustainable development goal of eliminating malaria. PMID- 28883529 TI - The formation of nanocrystalline ZrO2 nuclei in a Li2O-Al2O3-SiO2 glass - a combined XANES and TEM study. AB - The high economic importance of glass ceramics based on Li2O/Al2O3/SiO2 (LAS) is mainly due to their low coefficients of thermal expansion (CTE), which make these materials suitable candidates for a number of applications. The exact mechanism of the crystallization processes in LAS glasses is still not fully understood. The present work focuses on the formation and development of nanocrystalline ZrO2 within an LAS base composition which contains only ZrO2 as nucleating agent. Using a combination of transmission electron microscopy and X-ray absorption spectroscopy techniques, the temporal evolution of the ZrO2 nanocrystal formation is described. It is found that the formation of ZrO2 is initiated by liquid liquid phase separation droplets with high Zr content, which eventually evolve into the nanocrystalline ZrO2 precipitations. This process is accompanied by a gradual change of the coordination of the tetravalent Zr ions from sixfold in the glass to eightfold in the crystals. The diameters of the ZrO2 crystals stay well below 4 nm, even at late stages. The degree of crystallization at each step of the crystallization process is deduced, and from that, the Avrami coefficient n is determined to be n ~ 1, which describes a barrier-limited crystal growth process. PMID- 28883530 TI - Study on dose-dependent, frequency-dependent, and accumulative effects of 1.5 GHz and 2.856 GHz microwave on cognitive functions in Wistar rats. AB - Many studies have revealed the cognitive decline induced by microwave radiation. However, the systematic study on dose-dependent, frequency-dependent and accumulative effects of microwave exposure at different frequencies was lacking. Here, we studied the relationship between the effects and the power and frequency of microwave and analyzed the accumulative effects of two different frequency microwaves with the same average power density. After microwave radiation, declines in spatial learning and memory and fluctuations of brain electric activities were found in the 10 mW/cm2 single frequency exposure groups and accumulative exposure groups. Meanwhile, morphological evidences in hippocampus also supported the cognitive dysfunction. Moreover, the decrease of Nissl contents in neurons indicated protein-based metabolic disorders in neurons. By detecting the key functional proteins of cholinergic transmitter metabolism, cytokines, energy metabolism and oxidative stress in the hippocampus, we found that microwave could lead to multiple metabolic disorders. Our results showed that microwave-induced cognitive decline was largely determined by its power rather than frequency. Injury effects were also found in accumulative exposure groups. We particularly concerned about the safety dose, injury effects and accumulative effects of microwaves, which might be very valuable in the future. PMID- 28883532 TI - Patterns of Oxygen Pulse Curve in Response to Incremental Exercise in Patients with Chronic Obstructive Pulmonary Disease - An Observational Study. AB - In COPD, pulmonary hyperinflation causes decreased stroke volume thereby decreased oxygen pulse (O2P). While O2P flattening is related to myocardial ischemia in cardiac patients, O2P patterns have seldom been explored in COPD. The aims of the study were to investigate O2P-curve patterns and associated factors in COPD. Seventy-five patients with stable COPD were enrolled. The demographics, cardiac size, physiological measurements and stress EKG were compared among O2P curve pattern groups. An algorithm to identify O2P-curve patterns was developed in 28 patients. In the remaining 45 patients after excluding two with poor effort, this algorithm revealed 20 (44%) flattening, 16 (36%) increasing, and nine (20%) decreasing patterns. The flattening-type group had lower body mass, cardiac size, and diffusing capacity, and larger lung volumes (p = 0.05-<0.0001) compared to the increasing-type group. During exercise, the flattening-type group had a lower operable O2P and more hyperventilation and dyspnea (p = 0.02-<0.01). None had ST-T changes. Most differences were related to body mass and mildly to inspiratory fraction. The decreasing-type group performed higher effort than the increasing-type group (p < 0.05). In conclusion, O2P flattening was common and was associated with reduced body mass and pulmonary hyperinflation rather than with myocardial ischemia. The decreasing-type may be caused by motivation to exercise. PMID- 28883531 TI - Engineered proteins with sensing and activating modules for automated reprogramming of cellular functions. AB - Protein-based biosensors or activators have been engineered to visualize molecular signals or manipulate cellular functions. Here we integrate these two functionalities into one protein molecule, an integrated sensing and activating protein (iSNAP). A prototype that can detect tyrosine phosphorylation and immediately activate auto-inhibited Shp2 phosphatase, Shp2-iSNAP, is designed through modular assembly. When Shp2-iSNAP is fused to the SIRPalpha receptor which typically transduces anti-phagocytic signals from the 'don't eat me' CD47 ligand through negative Shp1 signaling, the engineered macrophages not only allow visualization of SIRPalpha phosphorylation upon CD47 engagement but also rewire the CD47-SIRPalpha axis into the positive Shp2 signaling, which enhances phagocytosis of opsonized tumor cells. A second SIRPalpha Syk-iSNAP with redesigned sensor and activator modules can likewise rewire the CD47-SIRPalpha axis to the pro-phagocytic Syk kinase activation. Thus, our approach can be extended to execute a broad range of sensing and automated reprogramming actions for directed therapeutics.Protein-based biosensors have been engineered to interrogate cellular signaling and manipulate function. Here the authors demonstrate iSNAP, a tool to detect tyrosine phosphorylation and activate desired protein enzymes allowing the control of phagocytosis in macrophages. PMID- 28883533 TI - Systems Identification and Characterization of Cell Wall Reassembly and Degradation Related Genes in Glycine max (L.) Merill, a Bioenergy Legume. AB - Soybean is a promising biomass resource for generation of second-generation biofuels. Despite the utility of soybean cellulosic biomass and post-processing residues in biofuel generation, there is no comprehensive information available on cell wall loosening and degradation related gene families. In order to achieve enhanced lignocellulosic biomass with softened cell walls and reduced recalcitrance, it is important to identify genes involved in cell wall polymer loosening and degrading. Comprehensive genome-wide analysis of gene families involved in cell wall modifications is an efficient stratagem to find new candidate genes for soybean breeding for expanding biofuel industry. We report the identification of 505 genes distributed among 12 gene families related to cell wall loosening and degradation. 1262 tandem duplication events contributed towards expansion and diversification of studied gene families. We identified 687 Simple Sequence Repeat markers and 5 miRNA families distributed on 316 and 10 genes, respectively. Publically available microarray datasets were used to explore expression potential of identified genes in soybean plant developmental stages, 68 anatomical parts, abiotic and biotic stresses. Co-expression networks revealed transcriptional coordination of different gene families involved in cell wall loosening and degradation process. PMID- 28883535 TI - Mechanisms of silver nanoparticle toxicity to the coastal marine diatom Chaetoceros curvisetus. AB - Inputs of silver nanoparticles (AgNPs) to marine waters continue to increase yet mechanisms of AgNPs toxicity to marine phytoplankton are still not well resolved. This study reports a series of toxicity experiments on a representative coastal marine diatom species Chaetoceros curvisetus using the reference AgNP, NM-300K. Exposure to AgNPs resulted in photosynthetic impairment and loss of diatom biomass in proportion to the supplied AgNP dose. The underlying mechanism of toxicity was explored via comparing biological responses in parallel experiments. Diatom responses to AgNP, free Ag(I) species, and dialysis bag-retained AgNP treatments showed marked similarity, pointing towards a dominant role of Ag(I) species uptake, rather than NPs themselves, in inducing the toxic response. In marked contrast to previous studies, addition of the organic complexing agent cysteine (Cys) alongside Ag only marginally moderated toxicity, implying AgCys- complexes were bioavailable to this diatom species. A preliminary field experiment with a natural phytoplankton community in the southeast Atlantic Ocean showed no significant toxic response at a NM-300 K concentration that resulted in ~40% biomass loss in the culture studies, suggesting a modulating effect of natural seawaters on Ag toxicity. PMID- 28883534 TI - Biological effects of dosing aerobic exercise and neuromuscular electrical stimulation in rats. AB - Aerobic exercise (AE) and non-aerobic neuromuscular electric stimulation (NMES) are common interventions used in physical therapy. We explored the dose dependency (low, medium, high) of these interventions on biochemical factors, such as brain derived neurotrophic growth factor (BDNF), vascular endothelial growth factor-A (VEGF-A), insulin-like growth factor-1 (IGF-1) and Klotho, in the blood and brain of normal rats, as well as a treadmill-based maximum capacity test (MCT). A medium dose of AE produced the most improvement in MCT with dose dependent changes in Klotho in the blood. A dose-dependent increase of BDNF was evident following completion of an NMES protocol, but there was no improvement in MCT performance. Gene expression in the hippocampus was increased after both AE and NMES, with IGF-1 being a signaling molecule that correlated with MCT performance in the AE conditions, but also highly correlated with VEGF-A and Klotho. Blood Klotho levels can serve as a biomarker of therapeutic dosing of AE, whereas IGF-1 is a key molecule coupled to gene expression of other molecules in the hippocampus. This approach provides a translatable paradigm to investigate the mode and mechanism of action of interventions employed in physical therapy that can improve our understanding of how these factors change under pathological conditions. PMID- 28883536 TI - Techniques and long-term effects of transjugular intrahepatic portosystemic shunt on liver cirrhosis-related thrombotic total occlusion of main portal vein. AB - Portal vein hypertension (PVH) in liver cirrhosis complicated with portal venous thrombosis (PVT) has been mainly treated with transjugular intrahepatic portosystemic shunt (TIPS). The clinical effects of TIPS have been confirmed, however, no large-scale studies have been focused on technical analyses and a long-term follow-up, especially on thrombotic total occlusion of main portal vein (MPV). To demonstrate critical techniques and clinical outcome of TIPS on liver cirrhosis-related thrombotic total occlusion of MPV, 98 patients diagnosed with liver cirrhosis related thrombotic total occlusion of MPV and treated with TIPS from January 2000 to January 2010 were retrospectively analyzed. Twenty-three (23.5%) patients had MPV (single site) thrombosis, 55 (56.1%) had multiple site thrombosis (MPV and other), 17 (17.3%) had cavernous transformation of portal vein, and 3 (3.1%) had post-transplant thrombosis. The successful rate of TIPS was 90.7%, without any procedure-related deaths or severe complications. Mean portal pressure was dropped from 33.08 +/- 1.38 mmHg preoperatively to 20.18 +/- 0.83 mmHg postoperatively (p < 0.001). Collectively, TIPS is safe and effective in treating liver cirrhosis-related thrombotic total occlusion of MPV. This complex procedure requires combination of indirect portography and percutaneous transhepatic portal techniques to increase the rate of success. PMID- 28883537 TI - Spontaneous approaches of divers by free-ranging orcas (Orcinus orca): age- and sex-differences in exploratory behaviours and visual laterality. AB - Running comparative studies of laterality in mammals is a way to deepen our understanding of the evolution of the brain hemisphere functions. Studies on vision highlighted a possible task-sharing between hemispheres depending on the characteristics of the observers, the nature of the observed stimulus and the context of the observation, a phenomenon that could go beyond the monitoring of conspecifics. Cetaceans are predators that adapted to an aquatic habitat and display a clear crossing of fibers to the side of the brain opposite the eye of origin. Here, we analysed the interactions between humans and cetaceans when free ranging orcas approach divers. Our study concentrated on the spontaneous exploratory behaviours of divers by orcas depending on their age and sex, and on the possible expression of a visual laterality. The results showed a significant preference for the use of the left eye but exclusively in adult females. Adult males had a more sustained attention than adult females, marked by a higher spatial proximity to divers, slower approaches and longer look durations. Adult females, probably more cautious, explored from the distance and more furtively. Our findings support a possible link between attentional/motivational states and visual laterality in mammals. PMID- 28883538 TI - Shorter sleep duration is associated with higher energy intake and an increase in BMI z-score in young children predisposed to overweight. AB - BACKGROUND: Inadequate sleep has been shown to be a contributor to obesity in both children and adults. Less evidence is available for toddlers and among those with higher obesity risk. The objective of this study was to examine the relationship between sleep patterns and body weight development in a group of young obesity-predisposed children, and to assess whether intakes of energy or macronutrients mediate this relationship. METHODS: Participants included 368 Danish children aged 2-6 years from the Healthy Start Study, a 1.3 year randomised controlled intervention trial. Sleep habits were measured using a 7 day sleep diary. Multivariate linear regression with adjustment for confounders was used to assess the association of sleep duration and sleep variability with 1.3 year changes (Delta) in body mass index (BMI) z-score from baseline to follow up. RESULTS: The average nighttime sleep duration was 10.7 h (range 8.8-12.5 h). After controlling for potential confounders, a significant inverse association between nighttime sleep duration and DeltaBMI z-score (beta=-0.090, P=0.046) was observed. This relationship was mediated by energy intake, with all macronutrients contributing to this mediation effect. No associations were found for sleep variability and DeltaBMI z-score but baseline intake of added sugars and sugary beverages were positively associated with sleep variability. CONCLUSION: Shorter sleep duration, mediated by energy intake in early in life, seems a risk factor for weight gain among young obesity-predisposed children. PMID- 28883539 TI - Role of adipose tissue in melanoma cancer microenvironment and progression. AB - BACKGROUND: An epidemiological association between excess weight and increased risk of cancer has been described in melanoma, for which the physiopathological mechanisms are still unknown. The study of tumor microenvironment and of the role of adipocytes in cancer development, progression and metastasis has recently received great interest. However, the role of peritumoral adipocytes has been characterized only in a few types of cancer, and in melanoma it still remains to be defined. METHODS: We investigated the interactions between adipocytes and melanoma cells using an in vitro co-culture system. We studied the morphological and functional properties of 3T3-L1 adipocytes before and after co-culture with A375 melanoma cells, in order to assess the role of adipocytes on melanoma migration. RESULTS: Morphological analysis showed that after 6 days of co-culture 3T3-L1 adipocytes were reduced in number and size. Moreover, we observed the appearance of dedifferentiated cells with a fibroblast-like phenotype that were not present in controls and that had lost the expression of some adipocyte specific genes, and increased the expression of collagen, metalloproteinases and genes typical of dedifferentiation processes. Through the Matrigel Invasion Test, as well the Scratch Test, it was possible to observe that co-culture with adipocytes induced in melanoma cells increased migratory capacity, as compared with controls. In particular, the increase in migration observed in co-culture was suppressed after adding the protein SFRP-5 in the medium, supporting the involvement of the Wnt5a pathway. The activation of this pathway was further characterized by immunofluorescence and western blot analysis, showing in melanocytes in co-culture the activation of beta-catenin and LEF-1, two transcription factors involved in migration processes, neo-angiogenesis and metastasis. CONCLUSIONS: These data allow us to hypothesize a dedifferentiation process of adipocytes toward fibroblast-like cells, which can promote migration of melanoma cells through activation of Wnt5a and the intracellular pathways of beta-catenin and LEF-1. PMID- 28883540 TI - BAT is independently affected by peripheral and central pathways. PMID- 28883541 TI - Prenatal risk factors influencing childhood BMI and overweight independent of birth weight and infancy BMI: a path analysis within the Danish National Birth Cohort. AB - BACKGROUND AND OBJECTIVES: Prenatal risk factors for childhood overweight may operate indirectly through development in body size in early life and/or directly independent hereof. We quantified the effects of maternal and paternal body mass index (BMI), maternal age, socioeconomic position (SEP), parity, gestational weight gain, maternal smoking during pregnancy, caesarean section, birth weight, and BMI at 5 and 12 months on BMI and overweight at 7 and 11 years. METHODS: Family triads with information on maternal, paternal and child BMI at ages 7 (n=29 374) and 11 years (n=18 044) were selected from the Danish National Birth Cohort. Information originated from maternal interviews and medical health examinations. Path analysis was used to estimate the direct and indirect effects of prenatal risk factors on childhood BMI z-scores (BMIz per unit score of the risk factor). Logistic regression was used to examine associations with overweight. RESULTS: The strongest direct effects on BMIz at age 7 were found for maternal and paternal BMI (0.19 BMIz and 0.14 BMIz per parental BMIz), low SEP (0.08 BMIz), maternal smoking (0.12 BMIz) and higher BMIz at 5 and 12 months (up to 0.19 BMIz per infant BMIz). For BMIz at age 11 with BMIz at age 7 included in the model, similar effects were found, but the direct effects of BMIz at age 5 and 12 months were mediated through BMI at age 7 (0.62 BMIz per BMIz). Same results were found for overweight. The sum of the direct effects can be translated to approximate absolute measures: 2.4 kg at 7 years, 5.7 kg at 11 years, in a child with average height and BMI. CONCLUSIONS: Parental BMI, low SEP and smoking during pregnancy have persisting, strong and direct effects on child BMI and overweight independent of birth weight and infancy BMI. PMID- 28883542 TI - Longitudinal micro-ultrasound assessment of the ob/ob mouse model: evaluation of cardiovascular, renal and hepatic parameters. AB - BACKGROUND/OBJECTIVES: Obesity is reaching epidemic proportions and is associated with increased risk factors for cardiovascular disease. Leptin-deficient mice (ob/ob) are widely employed to investigate obesity. Aim of this study was to provide a micro-ultrasound (MUUS) longitudinal evaluation of the ob/ob mouse model in terms of cardiovascular effects, consequences for renal microcirculation and liver fat accumulation. SUBJECTS/METHODS: Sixteen wild-type (wt) and eleven ob/ob male mice were studied at 8 (T0) and 25 (T1) weeks of age with a MUUS system (Vevo2100) and B-mode and Doppler images were acquired. Cardiac output (CO), ejection fraction (EF), stroke volume (SV), fractional shortening (FS) and E/A ratio were measured from cardiac images. Mean diameter (Dmabd, Dmcar), relative distension (relDabd and relDcar) and pulse wave velocity (PWVabd and PWVcar) were obtained for both abdominal aorta and common carotid. As regards renal microcirculation, renal resistivity and pulsatility index (RI and PI) were assessed. The ratio between grey levels related to liver and kidney (Steato Score) was used as index of hepatic steatosis. RESULTS: At T0, ob/ob mice showed reduced SV, EF, CO and relDabd values and increased LVmass, PWVabd, RI, PI and Steato-score measurements. The same comparison repeated at T1 highlighted similar results for SV, EF, CO, RI, PI and Steato-Score; furthermore, obese mice showed reduced Dmabd and Dmcar measurements in comparison with lean controls. The longitudinal analysis showed an increase in LVmass and Dmabd and a reduction of FS, EF, CO, relDabd and relDcar for wt animals, while no differences were found for the ob/ob group. CONCLUSIONS: ob/ob mice presented a premature cardiac dysfunction without a further age-related deterioration and a reduction in the abdominal aorta and carotid artery mean diameter in adult age. The proposed analysis can represent a valid approach for longitudinal studies aimed at testing new therapeutic strategies or for characterizing other mouse models. PMID- 28883543 TI - Pre-treatment microbial Prevotella-to-Bacteroides ratio, determines body fat loss success during a 6-month randomized controlled diet intervention. AB - On the basis of the abundance of specific bacterial genera, the human gut microbiota can be divided into two relatively stable groups that might have a role in personalized nutrition. We studied these simplified enterotypes as prognostic markers for successful body fat loss on two different diets. A total of 62 participants with increased waist circumference were randomly assigned to receive an ad libitum New Nordic Diet (NND) high in fiber/whole grain or an Average Danish Diet for 26 weeks. Participants were grouped into two discrete enterotypes by their relative abundance of Prevotella spp. divided by Bacteroides spp. (P/B ratio) obtained by quantitative PCR analysis. Modifications of dietary effects of pre-treatment P/B group were examined by linear mixed models. Among individuals with high P/B the NND resulted in a 3.15 kg (95% confidence interval (CI): 1.55; 4.76, P<0.001) larger body fat loss compared with ADD, whereas no differences was observed among individuals with low P/B (0.88 kg (95% CI: -0.61; 2.37, P=0.25)). Consequently, a 2.27 kg (95% CI: 0.09; 4.45, P=0.041) difference in responsiveness to the diets were found between the two groups. In summary, subjects with high P/B ratio appeared more susceptible to lose body fat on diets high in fiber and whole grain than subjects with a low P/B ratio. PMID- 28883544 TI - Global fibroblast activation throughout the left ventricle but localized fibrosis after myocardial infarction. AB - Fibroblast (Fb) differentiation and interstitial fibrosis contribute to cardiac remodeling and loss of function after myocardial infarction (MI). We investigated regional presence and regulation of fibrosis in a pig MI model. In vivo analysis of regional function and perfusion defined three regions: the scar, the myocardium adjacent to the scar (MIadjacent, reduced function, reduced perfusion reserve), and the remote myocardium (MIremote, minimal functional deficit, maintained perfusion). Interstitial and perivascular fibrosis, and increase of collagen type I, was only observed in the MIadjacent. Fb activated protein-alpha (FAP-alpha) was enriched in MIadjacent compared to MIremote. TGF-beta1, which triggers Fb differentiation, was upregulated in both MIadjacent and MIremote, whereas lysyl oxidase, a regulator of collagen cross-linking, and the proteoglycans decorin and biglycan were only increased in the MIadjacent. Fb isolated and cultured for 4 days had myoFb characteristics with little difference between MIremote and MIadjacent, although RNA sequencing revealed differences in gene expression profiles. Fbs from all regions maintained proliferative capacity, and induced contraction of 3-D collagen matrices but scar myoFb was more effective. These data suggest that after MI, signaling through TGF-beta1, possibly related to increased mechanical load, drives Fb activation throughout the left ventricle while regional signaling determines further maturation and extracellular matrix remodeling after MI. PMID- 28883545 TI - Copy number rather than epigenetic alterations are the major dictator of imprinted methylation in tumors. AB - It has been postulated that imprinting aberrations are common in tumors. To understand the role of imprinting in cancer, we have characterized copy-number and methylation in over 280 cancer cell lines and confirm our observations in primary tumors. Imprinted differentially methylated regions (DMRs) regulate parent-of-origin monoallelic expression of neighboring transcripts in cis. Unlike single-copy CpG islands that may be prone to hypermethylation, imprinted DMRs can either loose or gain methylation during tumorigenesis. Here, we show that methylation profiles at imprinted DMRs often not represent genuine epigenetic changes but simply the accumulation of underlying copy-number aberrations (CNAs), which is independent of the genome methylation state inferred from cancer susceptible loci. Our results reveal that CNAs also influence allelic expression as loci with copy-number neutral loss-of-heterozygosity or amplifications may be expressed from the appropriate parental chromosomes, which is indicative of maintained imprinting, although not observed as a single expression foci by RNA FISH.Altered genomic imprinting is frequently reported in cancer. Here, the authors analyze copy number and methylation in cancer cell lines and primary tumors to show that imprinted methylation profiles represent the accumulation of copy number alteration, rather than epigenetic alterations. PMID- 28883546 TI - API5 induces cisplatin resistance through FGFR signaling in human cancer cells. AB - Most tumors frequently undergo initial treatment with a chemotherapeutic agent but ultimately develop resistance, which limits the success of chemotherapies. As cisplatin exerts a high therapeutic effect in a variety of cancer types, it is often used in diverse strategies, such as neoadjuvant, adjuvant and combination chemotherapies. However, cisplatin resistance has often manifested regardless of cancer type, and it represents an unmet clinical need. Since we found that API5 expression was positively correlated with chemotherapy resistance in several specimens from patients with cervical cancer, we decided to investigate whether API5 is involved in the development of resistance after chemotherapy and to explore whether targeting API5 or its downstream effectors can reverse chemo resistance. For this purpose, cisplatin-resistant cells (CaSki P3 CR) were established using three rounds of in vivo selection with cisplatin in a xenografted mouse. In the CaSki P3 CR cells, we observed that API5 acted as a chemo-resistant factor by rendering cancer cells resistant to cisplatin-induced apoptosis. Mechanistic investigations revealed that API5 mediated chemo resistance by activating FGFR1 signaling, which led to Bim degradation. Importantly, FGFR1 inhibition using either an siRNA or a specific inhibitor disrupted cisplatin resistance in various types of API5high cancer cells in an in vitro cell culture system as well as in an in vivo xenograft model. Thus, our results demonstrated that API5 promotes chemo-resistance and that targeting either API5 or its downstream FGFR1 effectors can sensitize chemo-refractory cancers. PMID- 28883548 TI - A Novel Statistical Method to Diagnose, Quantify and Correct Batch Effects in Genomic Studies. AB - Genome projects now generate large-scale data often produced at various time points by different laboratories using multiple platforms. This increases the potential for batch effects. Currently there are several batch evaluation methods like principal component analysis (PCA; mostly based on visual inspection), and sometimes they fail to reveal all of the underlying batch effects. These methods can also lead to the risk of unintentionally correcting biologically interesting factors attributed to batch effects. Here we propose a novel statistical method, finding batch effect (findBATCH), to evaluate batch effect based on probabilistic principal component and covariates analysis (PPCCA). The same framework also provides a new approach to batch correction, correcting batch effect (correctBATCH), which we have shown to be a better approach to traditional PCA based correction. We demonstrate the utility of these methods using two different examples (breast and colorectal cancers) by merging gene expression data from different studies after diagnosing and correcting for batch effects and retaining the biological effects. These methods, along with conventional visual inspection based PCA, are available as a part of an R package exploring batch effect (exploBATCH; https://github.com/syspremed/exploBATCH ). PMID- 28883547 TI - Casein kinase 2 is a critical determinant of the balance of Th17 and Treg cell differentiation. AB - Th17 cells promote inflammatory reactions, whereas regulatory T (Treg) cells inhibit them. Thus, the Th17/Treg cell balance is critically important in inflammatory diseases. However, the molecular mechanisms underlying this balance are unclear. Here, we demonstrate that casein kinase 2 (CK2) is a critical determinant of the Th17/Treg cell balance. Both the inhibition of CK2 with a specific pharmacological inhibitor, CX-4945, and its small hairpin RNA (shRNA) mediated knockdown suppressed Th17 cell differentiation but reciprocally induced Treg cell differentiation in vitro. Moreover, CX-4945 ameliorated the symptoms of experimental autoimmune encephalomyelitis and reduced Th17 cell infiltration into the central nervous system. Mechanistically, CX-4945 inhibited the IL-6/STAT3 and Akt/mTOR signaling pathways. Thus, CK2 has a crucial role in regulating the Th17/Treg balance. PMID- 28883549 TI - In situ disordering of monoclinic titanium monoxide Ti5O5 studied by transmission electron microscope TEM. AB - The superlattice and domain structures exhibited by ordered titanium monoxide Ti5O5 are disrupted by low energy electron beam irradiation. The effect is attributed to the disordering of the oxygen and titanium sublattices. This disordering is caused by the displacement of both oxygen and titanium atoms by the incident electrons and results in a phase transformation of the monoclinic phase Ti5O5 into cubic B1 titanium monoxide. In order to determine the energies required for the displacement of titanium or oxygen atoms, i.e. threshold displacement energies, a systematic study of the disappearance of superstructure reflections with increasing electron energy and electron bombardment dose has been performed in situ in a transmission electron microscope (TEM). An incident electron energy threshold between 120 and 140 keV has been observed. This threshold can be ascribed to the displacements of titanium atoms with 4 as well as with 5 oxygen atoms as nearest neighbors. The displacement threshold energy of titanium atoms in Ti5O5 corresponding with the observed incident electron threshold energy lies between 6.0 and 7.5 eV. This surprisingly low value can be explained by the presence of either one or two vacant oxygen lattice sites in the nearest neighbors of all titanium atoms. PMID- 28883550 TI - Electrokinetically driven continuous-flow enrichment of colloidal particles by Joule heating induced temperature gradient focusing in a convergent-divergent microfluidic structure. AB - Enrichment of colloidal particles in continuous flow has not only numerous applications but also poses a great challenge in controlling physical forces that are required for achieving particle enrichment. Here, we for the first time experimentally demonstrate the electrokinetically-driven continuous-flow enrichment of colloidal particles with Joule heating induced temperature gradient focusing (TGF) in a microfluidic convergent-divergent structure. We consider four mechanisms of particle transport, i.e., advection due to electroosmosis, electrophoresis, dielectrophoresis and, and further clarify their roles in the particle enrichment. It is experimentally determined and numerically verified that the particle thermophoresis plays dominant roles in enrichment of all particle sizes considered in this study and the combined effect of electroosmosis induced advection and electrophoresis is mainly to transport particles to the zone of enrichment. Specifically, the enrichment of particles is achieved with combined DC and AC voltages rather than a sole DC or AC voltage. A numerical model is formulated with consideration of the abovementioned four mechanisms, and the model can rationalize the experimental observations. Particularly, our analysis of numerical and experimental results indicates that thermophoresis which is usually an overlooked mechanism of material transport is crucial for the successful electrokinetic enrichment of particles with Joule heating induced TGF. PMID- 28883551 TI - Shape-based separation of microalga Euglena gracilis using inertial microfluidics. AB - Euglena gracilis (E. gracilis) has been proposed as one of the most attractive microalgae species for biodiesel and biomass production, which exhibits a number of shapes, such as spherical, spindle-shaped, and elongated. Shape is an important biomarker for E. gracilis, serving as an indicator of biological clock status, photosynthetic and respiratory capacity, cell-cycle phase, and environmental condition. The ability to prepare E. gracilis of uniform shape at high purities has significant implications for various applications in biological research and industrial processes. Here, we adopt a label-free, high-throughput, and continuous technique utilizing inertial microfluidics to separate E. gracilis by a key shape parameter-cell aspect ratio (AR). The microfluidic device consists of a straight rectangular microchannel, a gradually expanding region, and five outlets with fluidic resistors, allowing for inertial focusing and ordering, enhancement of the differences in cell lateral positions, and accurate separation, respectively. By making use of the shape-activated differences in lateral inertial focusing dynamic equilibrium positions, E. gracilis with different ARs ranging from 1 to 7 are directed to different outlets. PMID- 28883552 TI - Preparing a personal development plan for all members of the dental team. AB - Personal development plans (PDPs) have been a requirement for NHS hospital staff, Foundation Training and Dental Core Training for some years; however, the General Dental Council (GDC) are changing continuing professional development (CPD) requirements in 2018 (enhanced CPD) making a PDP a requirement for all members of the dental team. A PDP consists of objectives for targeting CPD most relevant to your practice or intended practice to undertake over a defined period to maximise the improvement of your professional development. The aim of this article is to explain how to prepare a PDP ahead of the requirement to utilise its benefits in training and performance for the dental team. This article references a template for all members of the dental team to record their PDP. PMID- 28883553 TI - The use and understanding of dental notation systems in UK and Irish dental hospitals. AB - Aim To identify the types of dental notation systems used in dental hospitals, and their perceived advantages and disadvantages. In addition, to record the dental notation used in patient referral letters.Method A self-completed questionnaire survey asking about the use of dental notation systems was distributed to 16 dental hospitals in the UK and Ireland in the summer of 2016. In addition, dentist referrals to the Restorative Dentistry department of the University Dental Hospital of Manchester were sequentially assessed for the dental notation used.Results Twelve hospitals replied. In order of frequency, the notation systems in use were the Alphanumeric, the Palmer, and the Federation Dentaire Internationale system. No hospital used the Universal system. Perceived advantages and disadvantages of each of the different systems were volunteered. One hundred and twenty-four referral letters were assessed and 100 were identified where dental notation was used. The majority used Alphanumeric notation.Conclusion A variety of dental notation systems remain in use in dental hospitals. The move to electronic recording and communication of information regarding teeth is encouraging the use of the Alphanumeric system. General dental practitioners are predominantly using the Alphanumeric system as their notation of choice in referral letters to the Restorative Dentistry department in Manchester. PMID- 28883554 TI - Adaptive mutations of neuraminidase stalk truncation and deglycosylation confer enhanced pathogenicity of influenza A viruses. AB - It has been noticed that neuraminidase (NA) stalk truncation has arisen from evolutionary adaptation of avian influenza A viruses (IAVs) from wild aquatic birds to domestic poultry. We identified this molecular alteration after the adaptation of a 2009 pandemic H1N1 virus (pH1N1) in BALB/c mice. The mouse adapted pH1N1 lost its eight consecutive amino acids including one potential N linked glycosite from the NA stalk region. To explore the relationship of NA stalk truncation or deglycosylation with viral pathogenicity changes, we generated NA stalk mutant viruses on the pH1N1 backbone by reverse genetics. Intriguingly, either NA stalk truncation or deglycosylation changed pH1N1 into a lethal virus to mice by resulting in extensive pathologic transformation in the mouse lungs and systemic infection affecting beyond the respiratory organs in mice. The increased pathogenicity of these NA stalk mutants was also reproduced in ferrets. In further investigation using a human-infecting H7N9 avian IAV strain, NA stalk truncation or deglycosylation enhanced the replication property and pathogenicity of H7N9 NA stalk mutant viruses in the same mouse model. Taken together, our results suggest that NA stalk truncation or deglycosylation can be the pathogenic determinants of seasonal influenza viruses associated with the evolutionary adaptation of IAVs. PMID- 28883556 TI - Alternative sugars: Stevia. PMID- 28883555 TI - Associations between trunk muscle morphology, strength and function in older adults. AB - Skeletal muscle plays an important role in performing activities of daily living. While the importance of limb musculature in performing these tasks is well established, less research has focused on the muscles of the trunk. The purpose of the current study therefore, was to examine the associations between functional ability and trunk musculature in sixty-four community living males and females aged 60 years and older. Univariate and multivariate analyses of the a priori hypotheses were performed and reported with correlation coefficients and unstandardized beta coefficients (beta) respectively. The univariate analysis revealed significant correlations between trunk muscle size and functional ability (rectus abdominis: six-minute walk performance, chair stand test, sitting and rising test; lumbar multifidus: timed up and go) as well as trunk muscle strength and functional ability (trunk composite strength: six-minute walk performance, chair stand test, Berg balance performance, sitting and rising test). After controlling for covariates (age and BMI) in the multivariate analysis, higher composite trunk strength (beta = 0.34) and rectus abdominis size (beta = 0.33) were associated with better performance in the sitting and rising test. The importance of incorporating trunk muscle training into programs aimed at improving balance and mobility in older adults merits further exploration. PMID- 28883557 TI - Paediatric dentistry: Let's support each other. PMID- 28883558 TI - Nocturnal sleep architecture is altered by sleep bruxism. AB - Does sleep bruxism impair the night sleep architecture? PMID- 28883561 TI - Lips don't lie: Why there's more to a smile than just teeth. AB - An evaluation of the influence of teeth and the labial soft tissues on the perceived aesthetics of a smile. PMID- 28883564 TI - Lorna Jean Mary Knox. PMID- 28883565 TI - How can dentists help patients with diabetes? PMID- 28883567 TI - What is a profession? AB - Loss of autonomy should mean that dentistry may no longer be viewed as a profession. Relationships between medical professions, patients and politicians evolve as society disease patterns change. A new and more appropriately modern definition of what constitutes a profession may now be needed. PMID- 28883568 TI - NHS dentistry: Slow the troubling trend. PMID- 28883570 TI - Hypersensitivity - a touchy subject. AB - Clinical study to monitor dentinal hypersensitivity with episodic use of a desensitising dentifrice. PMID- 28883571 TI - BES meeting to focus on endodontic infections and systemic health. PMID- 28883574 TI - Dental education: Missing something vital? PMID- 28883576 TI - The antibiotic course has had its day. AB - A barrier to antibiotic conservation? PMID- 28883580 TI - Special feature: New regulations on X-ray use: likely implications for dental practices. PMID- 28883582 TI - Factors associated with use of general anaesthesia for dental procedures among British children. AB - Objectives To assess the demographic, socioeconomic, behavioural and clinical factors associated with use of dental general anaesthesia (DGA) among British children.Methods This study used data from 3053 children who participated in the 2013 Children's Dental Health Survey in England, Wales and Northern Ireland. Data were collected through parental questionnaires and clinical examinations. The crude and adjusted association of demographic (sex, age, ethnicity and country of residence), socioeconomic (socioeconomic classification and area deprivation), behavioural (age toothbrushing started, age when first went to the dentist, usual reason for dental visit and dental anxiety) and clinical factors (numbers of decayed and filled teeth) with DGA was assessed in logistic regression models.Results The lifetime prevalence of DGA use was 9.1%. Older children and those living in Wales, with higher levels of dental anxiety and more dental fillings, who visited the dentist only when in trouble, and who had parents in routine/manual occupations and parents who never worked have greater odds of reporting having ever used DGA.Conclusion This study shows that family socioeconomic background, usual reason for dental visit and country of residence were associated with DGA use among British children, over and above the effect of child age, dental anxiety and dental status. PMID- 28883584 TI - Social media and professionalism: a retrospective content analysis of Fitness to Practise cases heard by the GDC concerning social media complaints. AB - Introduction Since 2013, all General Dental Council (GDC) registrants' online activities have been regulated by the GDC's social media guidelines. Failure to comply with these guidelines results in a Fitness to Practise (FtP) complaint being investigated.Aims This study explores the prevalence of social media related FtP cases investigated by the GDC from 1 September 2013 to 21 June 2016.Method Documentary analysis of social media related FtP cases published on the GDC's website was undertaken. All cases that met the study's inclusion criteria were analysed using a quantitative content analysis framework.Findings It was found that 2.4% of FtP cases published on the GDC website during that period were related to breaches of the social media guidelines. All of the cases investigated were proven and upheld. Most of those named in the complaints were dental nurses and the most common type of complaint was inappropriate Facebook comments.Conclusions The low incidence rate should be interpreted with caution, being illustrative of the types of issues that might arise rather than the volume. The GDC will need to remain vigilant in this area and ensure that social media awareness training is an active part of CPD for all the dental team. PMID- 28883586 TI - What is digital about dentistry? PMID- 28883588 TI - Highly politicised opinions. PMID- 28883591 TI - Oral health: Caries risk category. PMID- 28883593 TI - New BDA Northern Ireland Director. PMID- 28883590 TI - Peri-implantitis and the prosthodontist. AB - Peri-implantitis has been described as progressive crestal bone loss around a dental implant. The condition is poorly understood, and is challenging to manage; it is commonly and widely attributed to issues with the implant, the implant surface, surgical technique and oral hygiene. The effect of prosthodontic stages of treatment on the postoperatively established state has not been adequately investigated. It is the authors' contention that the manner in which the implant is restored contributes significantly to prognosis and peri-implant disease experience, and that the role of prosthodontic aspects of treatment in the causation of peri-implantitis may be seriously underestimated. The prosthodontist has a clear role and responsibility in the avoidance of future peri-implant problems by ensuring that implants are restored in an entirely biologically and biomechanically sound manner. The number of implant treatments carried out year on-year is rising apace, with more and more implants being restored in general dental practice. With the rapid emergence of lower cost dental implant systems and a broadening range of generic restorative options and components for well established systems, there is an increasing need to consider and understand how the implant restorative process may have a negative impact upon the peri-implant tissues, and how this effect may be minimised and peri-implant health promoted and maintained by paying attention to detail throughout the entire process. PMID- 28883592 TI - Maternal smoking during pregnancy is associated with offspring hypodontia. AB - '...maternal smoking during pregnancy is a risk factor for having a child with hypodontia.' PMID- 28883594 TI - Conference report: 2nd Nazareth Conference on Dental Public Health. PMID- 28883595 TI - Chewing gum developed that detects peri-implant disease. PMID- 28883597 TI - 'Antibiotics advice is nothing new' says FGDP (UK). PMID- 28883598 TI - Comments regarding: Radia S, Sherriff M, McDonald F, Naini FB. Relationship between maxillary central incisor proportions and facial proportions. AB - '...the mean is a lonely place...' PMID- 28883599 TI - Plumbing the depths of barodontalgia. AB - Effect of a hyperbaric environment (diving conditions) on adhesive restorations: An in-vitro study. PMID- 28883600 TI - Tooth bleaching questions answered. AB - Tooth bleaching is an exciting treatment option for patients, which has many treatment options and considerations for the dentist. The purpose of this article is to answer questions in a Q&A fashion about different types of tooth bleaching and their applications to various clinical situations and patients' dental situations. PMID- 28883601 TI - How prepared are foundation dentists in England and Wales for independent general dental practice? AB - Introduction The Graduate Assessment of Preparedness for Practice (GAPP) questionnaire has been shown to be valid and reliable in assessing the preparedness of foundation dentists (FDs) for independent general dental practice (GDP). In this study it is used to establish preparedness at six weeks of dental foundation training (DFT) across England and Wales.Method GAPP questionnaires were sent to all FDs and ESs in England and Wales in mid-September 2012. Part 1 of the GAPP questionnaire collected the descriptive data of respondents. Part 2 comprised 34 'competence areas' designed to reflect the breadth of Preparing for Practice allowing respondents a 7-category Likert style response. Part 3 comprised open questions designed to allow respondents to expand on their views. Quantitative categorical data from Part 2 was analysed using IBM SPSS (version 20). Median scores were analysed and mean rank scores were generated in order to compare FD and ES responses. Part 2 results were cross-tabulated with the Part 1 descriptors and analysed using the Mann Whitney U and Kruskal Wallis H non parametric tests. Mean rank scores were considered to be statistically significant if P <=0.05. Part 3 data was analysed thematically using NVivo (version 10).Results FDs and ESs felt that FDs were generally well prepared for independent GDP, although FDs rated their preparedness significantly higher than ESs in all areas. FDs who graduated from 4-year courses felt significantly more prepared across most of the curriculum than those from 5-year courses, and graduates from outside the UK felt less prepared for GDP than those from a UK school.Conclusions FDs appear to be well prepared for independent GDP at six weeks of DFT. FDs rated their preparedness significantly higher than ESs across the curriculum. Coupled with the finding that the more experienced ESs felt their FDs were less well prepared, that may indicate FDs potentially overstate their level of preparedness. FDs who completed 4-year courses were generally more prepared across a range of curricular areas, some of which may reflect differences in the courses they completed, while others may relate to the individual being a graduate on entry to the course. Distribution of questionnaires through DFT schemes has resulted in a large number of respondents which may allow valuable generalisations to be made about the preparedness of graduates entering DFT in the UK. PMID- 28883603 TI - Dental radiography: Living in a bubble. PMID- 28883605 TI - Effect of a hyperbaric environment (diving conditions) on adhesive restorations: an in vitro study. AB - Objectives No recent study has addressed the effect of diving conditions (pressure increase) on adhesive restorations. We evaluated the impact of a simulated hyperbaric environment on microleakage of the dentine-composite resin interface. The ultimate aim was to propose recommendations for restorative dentistry for patients who are divers to limit barodontalgia (dental pain caused by pressure variations of the environment) and may lead to dangerous sequelae.Methods We bonded 20 dentine disks by using an adhesive system (Scothbond Universal) to ten intact composite cylinders and ten composite cylinders with porosity (Ceram X mono). For each group, the samples were divided into two subgroups, one submitted to a simulated hyperbaric environment and the other to an ambient environment. All samples were immersed in a silver nitrate solution to evaluate microleakage at the interface after analysis with a camera.Results Dye percolation for groups in the hyperbaric environment was greater than groups in ambient environment. For each subgroup, dye percolation was greater for samples with than without porosity.Conclusions High percolation percentages demonstrate that our simulated hyperbaric condition led to loss of sealing at the dentine-composite resin interface, especially with porous composites.Clinical significance Respect of the protocol and the quality of condensation for adhesive restorations are important in all clinical situations, especially for patients who are divers. A more interventionist approach must be adopted with these patients. PMID- 28883606 TI - Photothermal enhancement of chemotherapy in breast cancer by visible irradiation of Gold Nanoparticles. AB - Photothermal Therapy (PTT) impact in cancer therapy has been increasing due to the enhanced photothermal capabilities of a new generation of nanoscale photothermal agents. Among these nanoscale agents, gold nanoshells and nanorods have demonstrated optimal properties for translation of near infra-red radiation into heat at the site of interest. However, smaller spherical gold nanoparticles (AuNPs) are easier to produce, less toxic and show improved photoconversion capability that may profit from the irradiation in the visible via standard surgical green lasers. Here we show the efficient light-to-heat conversion of spherical 14 nm AuNPs irradiated in the visible region (at the surface plasmons resonance peak) and its application to selectively obliterate cancer cells. Using breast cancer as model, we show a synergistic interaction between heat (photoconversion at 530 nm) and cytotoxic action by doxorubicin with clear advantages to those of the individual therapy approaches. PMID- 28883607 TI - Isoniazid Killing of Mycobacterium smegmatis NADH Pyrophosphatase Mutant at Single-Cell Level using Microfluidics and Time-Lapse Microscopy. AB - We introduce single-cell analysis for isoniazid-treated Mycobacterium smegmatis mutant, msm1946-NADH pyrophosphatase, using microfluidics and automated time lapse microscopy. Mycobacterial NADH pyrophosphatase isoforms play an important role for the mechanism of isoniazid and ethionamide activation. Our single-cell analysis revealed important insights on isoniazid killing mechanism that was masked by traditional killing assays, raised significant questions related to viable but non-culturable subpopulation of cells, and existing methods that defines minimum inhibitory concentration of drugs. The major goal of this study was quantitatively analyze bacterial cell parameters to obtain high-resolution data for the time evolution of antibiotic killing at the single-cell level. The presented tools and methods could be applied to the closely related organisms to provide more detailed information for the design and employment of antibiotic treatments. PMID- 28883609 TI - Thermal activation energy of 3D vortex matter in NaFe1-x Co x As (x = 0.01, 0.03 and 0.07) single crystals. AB - We report on the thermally activated flux flow dependency on the doping dependent mixed state in NaFe1-x Co x As (x = 0.01, 0.03, and 0.07) crystals using the magnetoresistivity in the case of B//c-axis and B//ab-plane. It was found clearly that irrespective of the doping ratio, magnetoresistivity showed a distinct tail just above the T c,offset associated with the thermally activated flux flow (TAFF) in our crystals. Furthermore, in TAFF region the temperature dependence of the activation energy follows the relation [Formula: see text] with q = 1.5 in all studied crystals. The magnetic field dependence of the activation energy follows a power law of [Formula: see text] where the exponent alpha is changed from a low value to a high value at a crossover field of B = ~2 T, indicating the transition from collective to plastic pinning in the crystals. Finally, it is suggested that the 3D vortex phase is the dominant phase in the low temperature region as compared to the TAFF region in our series samples. PMID- 28883608 TI - GYY4137, a Hydrogen Sulfide Donor Modulates miR194-Dependent Collagen Realignment in Diabetic Kidney. AB - The relationship between hydrogen sulfide (H2S), microRNAs (miRs), matrix metalloproteinases (MMPs) and poly-ADP-ribose-polymerase-1 (PARP-1) in diabetic kidney remodeling remains mostly obscured. We aimed at investigating whether alteration of miR-194-dependent MMPs and PARP-1 causes renal fibrosis in diabetes kidney, and whether H2S ameliorates fibrosis. Wild type, diabetic Akita mice as well as mouse glomerular endothelial cells (MGECs) were used as experimental models, and GYY4137 as H2S donor. In diabetic mice, plasma H2S levels were decreased while ROS and expression of its modulator (ROMO1) were increased. In addition, alteration of MMPs-9, -13 and -14 expression, PARP-1, HIF1alpha, and increased collagen biosynthesis as well as collagen cross-linking protein, P4HA1 and PLOD2 were observed along with diminished vascular density in diabetic kidney. These changes were ameliorated by GYY4137. Further, downregulated miRNA 194 was normalized by GYY4137 in diabetic kidney. Similar results were obtained in in vitro condition. Interestingly, miR-194 mimic also diminished ROS production, and normalized ROMO1, MMPs-9, -13 and -14, and PARP-1 along with collagen biosynthesis and cross-linking protein in HG condition. We conclude that decrease H2S diminishes miR-194, induces collagen deposition and realignment leading to fibrosis and renovascular constriction in diabetes. GYY4137 mitigates renal fibrosis in diabetes through miR-194-dependent pathway. PMID- 28883610 TI - Analysis of Bioactive Amino Acids from Fish Hydrolysates with a New Bioinformatic Intelligent System Approach. AB - The current economics of the fish protein industry demand rapid, accurate and expressive prediction algorithms at every step of protein production especially with the challenge of global climate change. This help to predict and analyze functional and nutritional quality then consequently control food allergies in hyper allergic patients. As, it is quite expensive and time-consuming to know these concentrations by the lab experimental tests, especially to conduct large scale projects. Therefore, this paper introduced a new intelligent algorithm using adaptive neuro-fuzzy inference system based on whale optimization algorithm. This algorithm is used to predict the concentration levels of bioactive amino acids in fish protein hydrolysates at different times during the year. The whale optimization algorithm is used to determine the optimal parameters in adaptive neuro-fuzzy inference system. The results of proposed algorithm are compared with others and it is indicated the higher performance of the proposed algorithm. PMID- 28883611 TI - Genome-wide association study Identified multiple Genetic Loci on Chilling Resistance During Germination in Maize. AB - Maize (Zea mays, L.) cultivation has expanded greatly from tropical to temperate zones; however, its sensitivity to chilling often results in decreased germination rates, weak seedlings with reduced survival rates, and eventually lower yields. We conducted germination tests on the maize-282-diverse-panel (282 inbred lines) under normal (25 degrees C) and chilling (8 degrees C) conditions. Three raw measurements of germination were recorded under each condition: 1) germination rate, 2) days to 50% germination, and 3) germination index. Three relative traits were derived as indicators of cold-tolerance. By using the 2,271,584 single nucleotide polymorphisms (SNPs) on the panel from previous studies, and genome-wide association studies by using FarmCPU R package to identify 17 genetic loci associated with cold tolerance. Seven associated SNPs hit directly on candidate genes; four SNPs were in high linkage disequilibrium with candidate genes within 366 kb. In total, 18 candidate genes were identified, including 10 candidate genes supported by previous QTL studies and five genes supported by previous gene cloning studies in maize, rice, and Arabidopsis. Three new candidate genes revealed by two associated SNPs were supported by both QTL analyses and gene cloning studies. These candidate genes and associated SNPs provide valuable resources for future studies to develop cold-tolerant maize varieties. PMID- 28883612 TI - Human electronegative low-density lipoprotein modulates cardiac repolarization via LOX-1-mediated alteration of sarcolemmal ion channels. AB - Dyslipidemia is associated with greater risk of ventricular tachyarrhythmias in patients with cardiovascular diseases. We aimed to examine whether the most electronegative subfraction of low-density lipoprotein (LDL), L5, is correlated with QTc prolongation in patients with coronary artery disease (CAD) and investigate the effects of human L5 on the electrophysiological properties of cardiomyocytes in relation to the lectin-like oxidized LDL receptor (LOX-1). L5 was isolated from the plasma of 40 patients with angiography documented CAD and 13 patients with no CAD to correlate the QTc interval respectively. The mean concentration of L5 was higher and correlated with QTc in patients with CAD compared to controls. To examine the direct effect of L5 on QTc, mice were intravenously injected with L5 or L1. L5-injected wild-type but not LOX-1-/- mice showed longer QTc compared to L1-injected animals in vivo with corresponding longer action potential duration (APD) in cardiomyocytes incubated with L5 in vitro. The APD prolongation was mediated by an increase of L-type calcium current and a decrease of transient outward potassium current. We show that L5 was positively correlated with QTc prolongation in patients with ischemic heart disease. L5 can modulate cardiac repolarization via LOX-1-mediated alteration sarcolemmal ionic currents. PMID- 28883613 TI - Evidence that endogenous formaldehyde produces immunogenic and atherogenic adduct epitopes. AB - Endogenous formaldehyde is abundantly present in our bodies, at around 100 uM under normal conditions. While such high steady state levels of formaldehyde may be derived by enzymatic reactions including oxidative demethylation/deamination and myeloperoxidation, it is unclear whether endogenous formaldehyde can initiate and/or promote diseases in humans. Here, we show that fluorescent malondialdehyde formaldehyde (M2FA)-lysine adducts are immunogenic without adjuvants in mice. Natural antibody titers against M2FA are elevated in atherosclerosis-prone mice. Staining with an antibody against M2FA demonstrated that M2FA is present in plaque found on the aortic valve of ApoE -/- mice. To mimic inflammation during atherogenesis, human myeloperoxidase was incubated with glycine, H2O2, malondialdehyde, and a lysine analog in PBS at a physiological temperature, which resulted in M2FA generation. These results strongly suggest that the 1,4 dihydropyridine-type of lysine adducts observed in atherosclerosis lesions are likely produced by endogenous formaldehyde and malondialdehyde with lysine. These highly fluorescent M2FA adducts may play important roles in human inflammatory and degenerative diseases. PMID- 28883614 TI - An optical probe for detecting chondrocyte apoptosis in response to mechanical injury. AB - Cartilage injury induced by acute excessive contact stress is common and mostly affects young adult. Although early detection of cartilage injury may prevent serious and lifelong arthritic complications, early detection and treatment is not possible due to the lack of a reliable detection method. Since chondrocyte injury and subsequent cell death are the early signs of cartilage injury, it is likely that cartilage cell apoptosis can be used to predict the extent of injury. To test this hypothesis, a near infrared probe was fabricated to have high affinity to apoptotic cells. In vitro tests show that this apoptosis probe has low toxicity, high specificity, and high affinity to apoptotic cells. In addition, there is a positive relationship between apoptotic cell numbers and fluorescence intensities. Using a mouse xiphoid injury model, we found significant accumulation of the apoptosis probes at the injured xiphoid cartilage site. There was also a positive correlation between probe accumulation and the number of apoptotic chondrocytes within the injured xiphoid cartilage, which was confirmed by TUNEL assay. The results support that the apoptosis probes may serve as a powerful tool to monitor the extent of mechanical force-induced cartilage injury in vivo. PMID- 28883615 TI - Development of new experimental platform 'MARS'-Multiple Artificial-gravity Research System-to elucidate the impacts of micro/partial gravity on mice. AB - This Japan Aerospace Exploration Agency project focused on elucidating the impacts of partial gravity (partial g) and microgravity (MUg) on mice using newly developed mouse habitat cage units (HCU) that can be installed in the Centrifuge equipped Biological Experiment Facility in the International Space Station. In the first mission, 12 C57BL/6 J male mice were housed under MUg or artificial earth-gravity (1 g). Mouse activity was monitored daily via downlinked videos; MUg mice floated inside the HCU, whereas artificial 1 g mice were on their feet on the floor. After 35 days of habitation, all mice were returned to the Earth and processed. Significant decreases were evident in femur bone density and the soleus/gastrocnemius muscle weights of MUg mice, whereas artificial 1 g mice maintained the same bone density and muscle weight as mice in the ground control experiment, in which housing conditions in the flight experiment were replicated. These data indicate that these changes were particularly because of gravity. They also present the first evidence that the addition of gravity can prevent decreases in bone density and muscle mass, and that the new platform 'MARS' may provide novel insights on the molecular-mechanisms regulating biological processes controlled by partial g/MUg. PMID- 28883617 TI - Performance of cervical phIGFBP-1 test alone or combined with short cervical length to predict spontaneous preterm birth in symptomatic women. AB - We aimed to assess the accuracy of cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) test alone or in combination with cervical length (CL), to predict preterm birth (PTB) in symptomatic women. We performed a prospective cohort study from 2012 to 2015 including singleton pregnancies with symptoms of preterm labor, intact membranes and CL < 25 mm at 24-34 weeks of gestation. Studied outcome were spontaneous delivery within 7 and 14 days of testing and spontaneous PTB at <34 and <37 weeks of gestation. Among 180 women, 21 (11.7%) had a positive phIGFBP-1 test. Spontaneous PTB occurred within 7 days, 14 days of testing and before 34 weeks and 37 weeks in 7.8%, 10.6%, 12.9% and 28.8%, respectively. The phIGFBP-1 test had a low predictive performance for all studied outcomes varying for positive likelihood ratios (2.8 to 3.4) and negative likelihood ratios (0.8). Combining phIGFBP-1 and CL did not increase its predictive ability. After adjustment, positive phIGFBP-1 test was no more independently associated with a delivery within 7 days (p = 0.55), unlike CL < 15 mm (p = 0.04). In conclusion, phIGFBP-1 test alone or in combination with CL has a low predictive accuracy to predict PTB in symptomatic women. PMID- 28883616 TI - Association between Insomnia and Metabolic Syndrome in a Chinese Han Population: A Cross-sectional Study. AB - The association between insomnia and metabolic syndrome remains unclear, especially among different-aged groups. A cross-sectional study with 8017 participants was performed to identify whether insomnia was associated with metabolic syndrome or not. Demographic characteristics, lifestyles and other risk factors were collected using a predesigned, semi-structured, self-administered questionnaire, and physical examinations were conducted by certificated community physicians. Insomnia was not independently associated with metabolic syndrome across all subjects; however, the association between insomnia and metabolic syndrome was statistically significant in the male group (odds ratio (OR): 1.35, 95% confidence interval (CI): 1.02-1.77) and the middle-aged group (OR: 1.40, 95% CI: 1.09-1.79) but not in the female group, the young adult group or the older group. Analyses of the individual components of metabolic syndrome revealed that insomnia was independently associated with raised blood pressure (OR: 1.24, 95% CI: 1.05-1.43) and low high-density lipoprotein cholesterol (HDL-c) (OR: 1.16, 95% CI: 1.01-1.33). Insomnia was also independently associated with the severity of metabolic abnormalities (OR: 1.17, 95% CI: 1.03-1.32). This study demonstrates an independent association between insomnia and metabolic syndrome in males and middle-aged participants, which suggests that treatment for insomnia will contribute to the prevention of metabolic syndrome in males and the middle-aged population. PMID- 28883618 TI - CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway. AB - Cholangiocarcinoma is a devastating malignancy with fatal complications that exhibits low response and resistance to chemotherapy. Here, we evaluated the anticancer effects of CG200745, a novel histone deacetylase inhibitor, either alone or in combination with standard chemotherapy drugs in cholangiocarcinoma cells. CG200745 dose-dependently reduced the viability of cholangiocarcinoma cells in vitro and decreased tumour volume and weight in a xenograft model. Administering CG200745 along with other chemotherapeutic agents including gemcitabine, 5-fluorouracil (5-FU), cisplatin, oxaliplatin, or gemcitabine plus cisplatin further decreased cholangiocarcinoma cell viability, with a combination index < 1 that indicated synergistic action. CG200745 also enhanced the sensitivity of gemcitabine-resistant cells to gemcitabine and 5-FU, thereby decreasing cell viability and inducing apoptosis. This was accompanied by downregulation of YAP, TEAD4, TGF-beta2, SMAD3, NOTCH3, HES5, Axl, and Gas6 and upregulation of the miRNAs miR-22-3p, miR-22-5p, miR-194-5p, miR-194-3p, miR-194 5p, miR-210-3p, and miR-509-3p. The Ingenuity Pathway Analysis revealed that CG200745 mainly targets the Hippo signalling pathway by inducing miR-509-3p expression. Thus, CG200745 inhibits cholangiocarcinoma growth in vitro and in vivo, and acts synergistically when administered in combination with standard chemotherapeutic agents, enabling dose reduction. CG200745 is therefore expected to improve the outcome of cholangiocarcinoma patients who exhibit resistance to conventional therapies. PMID- 28883619 TI - Tertiary and quaternary structural basis of oxygen affinity in human hemoglobin as revealed by multiscale simulations. AB - Human hemoglobin (Hb) is a benchmark protein of structural biology that shaped our view of allosterism over 60 years ago, with the introduction of the MWC model based on Perutz structures of the oxy(R) and deoxy(T) states and the more recent Tertiary Two-State model that proposed the existence of individual subunit states -"r" and "t"-, whose structure is yet unknown. Cooperative oxygen binding is essential for Hb function, and despite decades of research there are still open questions related to how tertiary and quaternary changes regulate oxygen affinity. In the present work, we have determined the free energy profiles of oxygen migration and for HisE7 gate opening, with QM/MM calculations of the oxygen binding energy in order to address the influence of tertiary differences in the control of oxygen affinity. Our results show that in the alpha subunit the low to high affinity transition is achieved by a proximal effect that mostly affects oxygen dissociation and is the driving force of the allosteric transition, while in the beta subunit the affinity change results from a complex interplay of proximal and distal effects, including an increase in the HE7 gate opening, that as shown by free energy profiles promotes oxygen uptake. PMID- 28883620 TI - Antibody production by in vivo RNA transfection. AB - Monoclonal antibodies have a variety of applications in research and medicine. Here, we report development of a new method for production of monoclonal antibodies. Our method relies on in vivo RNA transfection rather than peptide vaccination. We took advantage of RNA transcripts complexed with DOTMA and DOPE lipids to transfect mice. Intravenous administration of our RNA vaccine to mice resulted in expression of the antigenic peptides by splenic dendritic cells and detection of the antigens in the serum. The RNA vaccine stimulated production of specific antibodies against the RNA-encoded peptides. We produced monoclonal antibodies against viral, bacterial, and human antigens. In addition, we showed that our RNA vaccine stimulated humoral immunity and rescued mice infected with influenza A virus. Our method could be used as an efficient tool to generate monoclonal antibodies and to stimulate humoral immunity for research and medical purposes. PMID- 28883621 TI - Assessing the potential for raw meat to influence human colonization with Staphylococcus aureus. AB - The role of household meat handling and consumption in the transfer of Staphylococcus aureus (S. aureus) from livestock to consumers is not well understood. Examining the similarity of S. aureus colonizing humans and S. aureus in meat from the stores in which those individuals shop can provide insight into the role of meat in human S. aureus colonization. S. aureus isolates were collected from individuals in rural and urban communities in Iowa (n = 3347) and contemporaneously from meat products in stores where participants report purchasing meat (n = 913). The staphylococcal protein A (spa) gene was sequenced for all isolates to determine a spa type. Morisita indices and Permutational Multivariate Analysis of Variance Using Distance Matrices (PERMANOVA) were used to determine the relationship between spa type composition among human samples and meat samples. spa type composition was significantly different between households and meat sampled from their associated grocery stores. spa types found in meat were not significantly different regardless of the store or county in which they were sampled. spa types in people also exhibit high similarity regardless of residential location in urban or rural counties. Such findings suggest meat is not an important source of S. aureus colonization in shoppers. PMID- 28883623 TI - MITF and BRN2 contribute to metastatic growth after dissemination of melanoma. AB - Melanoma tumors are highly heterogeneous, comprising of different cell types that vary in their potential for growth and invasion. Heterogeneous expression of the Microphthalmia-associated Transcription Factor (MITF) and the POU domain transcription factor BRN2 (POU3F2) has been found in malignant melanoma. Changing expression of these transcription factors as the disease progresses has been linked to the metastatic mechanism of phenotype switching. We therefore investigated the effects of MITF and BRN2 expression in melanoma growth and metastasis. Depletion of MITF resulted in a cell population that had a slowed cell cycle progression, was less invasive in vitro and had hindered tumor and metastasis forming ability in mouse xenograft studies. BRN2 depletion left a cell population with intact proliferation and invasion in vitro; however metastatic growth was significantly reduced in the mouse xenograft model. These results suggest that the proliferative population within melanoma tumors express MITF, and both MITF and BRN2 are important for metastatic growth in vivo. This finding highlights the importance of BRN2 and MITF expression in development of melanoma metastasis. PMID- 28883622 TI - SOCS2 Binds to and Regulates EphA2 through Multiple Mechanisms. AB - Suppressors of cytokine signaling (SOCS) proteins inhibit signaling by serving as substrate receptors for the Cullin5-RING E3 ubiquitin ligase (CRL5) and through a variety of CRL5-independent mechanisms. CRL5, SOCS2 and SOCS6 are implicated in suppressing transformation of epithelial cells. We identified cell proteins that interact with SOCS2 and SOCS6 using two parallel proteomics techniques: BioID and Flag affinity purification mass spectrometry. The receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) was identified as a SOCS2-interacting protein. SOCS2 EphA2 binding requires the SOCS2 SH2 domain and EphA2 activation loop autophosphorylation, which is stimulated by Ephrin A1 (EfnA1) or by phosphotyrosine phosphatase inhibition. Surprisingly, EfnA1-stimulated EphA2 SOCS2 binding is delayed until EphA2 has been internalized into endosomes. This suggests that SOCS2 binds to EphA2 in the context of endosomal membranes. We also found that SOCS2 overexpression decreases steady state levels of EphA2, consistent with increased EphA2 degradation. This effect is indirect: SOCS2 induces EfnA1 expression, and EfnA1 induces EphA2 down-regulation. Other RTKs have been reported to bind, and be regulated by, over-expressed SOCS proteins. Our data suggest that SOCS protein over-expression may regulate receptor tyrosine kinases through indirect and direct mechanisms. PMID- 28883624 TI - Intraoperative Fentanyl Consumption Does Not Impact Cancer Recurrence or Overall Survival after Curative Colorectal Cancer Resection. AB - Whether opioid use in cancer surgery would promote tumor dissemination in humans is inconclusive. We investigated the effect of intraoperative fentanyl dose on colorectal cancer (CRC) prognosis following resection in this retrospective study. A total of 1679 patients with stage I-III CRC undergoing tumor resection between January 2011 and December 2014 were evaluated through August 2016. Postoperative recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox regression models. Multivariable Cox regression analysis demonstrated no dose-response association between the amount of fentanyl dose and RFS (adjusted hazard ratio: 1.03, 95% CI: 0.89-1.19) or OS (adjusted hazard ratio: 0.84, 95% CI: 0.64-1.09). Patients were further classified into the high- and low-dose groups by the median of fentanyl dose (3.0 MUg.kg-1), and there was no significant difference in RFS or OS between groups, either (adjusted hazard ratio: 0.93, 95% CI: 0.74-1.17 for RFS; 0.79, 95% CI: 0.52-1.19 for OS). We concluded that intraoperative fentanyl consumption has no impact on recurrence free or overall survival in patients after curative CRC resection. PMID- 28883625 TI - Redundant Functions for Nap1 and Chz1 in H2A.Z Deposition. AB - H2A.Z is a histone H2A variant that contributes to transcriptional regulation, DNA damage response and limits heterochromatin spreading. In Saccharomyces cerevisiae, H2A.Z is deposited by the SWR-C complex, which relies on several histone chaperones including Nap1 and Chz1 to deliver H2A.Z-H2B dimers to SWR-C. However, the mechanisms by which Nap1 and Chz1 cooperate to bind H2A.Z and their contribution to H2A.Z deposition in chromatin is not well understood. Using structural modeling and molecular dynamics simulations, we identify a series of H2A.Z residues that form a chaperone-specific binding surface. Mutation of these residues revealed different surface requirements for Nap1 and Chz1 interaction with H2A.Z. Consistent with this result, we found that loss of Nap1 or Chz1 individually resulted in mild defects in H2A.Z deposition, but that deletion of both Nap1 and Chz1 resulted in a significant reduction of H2A.Z deposition at promoters and led to heterochromatin spreading. Together, our findings reveal unique H2A.Z surface dependences for Nap1 and Chz1 and a redundant role for these chaperones in H2A.Z deposition. PMID- 28883626 TI - Moral judgment modulation by disgust priming via altered fronto-temporal functional connectivity. AB - Moral judgments are not just the product of conscious reasoning, but also involve the integration of social and emotional information. Irrelevant disgust stimuli modulate moral judgments, with individual sensitivity determining the direction and size of effects across both hypothetical and incentive-compatible experimental designs. We investigated the neural circuitry underlying this modulation using fMRI in 19 individuals performing a moral judgment task with subliminal priming of disgust facial expressions. Our results indicate that individual changes in moral acceptability due to priming covaried with individual differences in activation within the dorsomedial prefrontal cortex (dmPFC). Further, whole-brain analyses identified changes in functional connectivity between the dmPFC and the temporal-parietal junction (TPJ). High sensitivity individuals showed enhanced functional connectivity between the TPJ and dmPFC, corresponding with deactivation in the dmPFC, and rating the moral dilemmas as more acceptable. Low sensitivity individuals showed the opposite pattern of results. Post-hoc, these findings replicated in the dorsal anterior cingulate cortex (daMCC), an adjacent region implicated in converting between objective and subjective valuation. This suggests a specific computational mechanism - that disgust stimuli modulate moral judgments by altering the integration of social information to determine the subjective valuation of the considered moral actions. PMID- 28883627 TI - Development of Fluorescent Probes that Target Serotonin 5-HT2B Receptors. AB - Some 5-HT2B fluorescent probes were obtained by tagging 1-(2,5-dimethoxy-4 iodophenyl)-propan-2-amine (DOI) with a subset of fluorescent amines. Some of the resulting fluorescent ligands showed excellent affinity and selectivity profiles at the 5-HT2B receptors (e.g. 12b), while retain the agonistic functional behaviour of the model ligand (DOI). The study highlighted the most salient features of the structure-activity relationship in this series and these were substantiated by a molecular modelling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human 5-HT2B receptor. One of the fluorescent ligands developed in this work, compound 12i, specifically labelled CHO-K1 cells expressing 5-HT2B receptors and not parental CHO-K1 cells in a concentration-dependent manner. 12i enables imaging and quantification of specific 5-HT2B receptor labelling in live cells by automated fluorescence microscopy as well as quantification by measurements of fluorescence intensity using a fluorescence plate reader. PMID- 28883629 TI - Reply to 'Pitfalls of using confocal-microscopy based automated quantification of synaptic complexes in honeybee mushroom bodies (response to Peng and Yang 2016)'. AB - In a comment on our Article "Sublethal Dosage of Imidacloprid Reduces the Microglomerular Density of Honey Bee Mushroom Bodies", Rossler et al. assert that our reported counts are overall lower than previously reported due to the use of automated quantification. We address these issues in this reply. PMID- 28883628 TI - Virulence of current German PEDV strains in suckling pigs and investigation of protective effects of maternally derived antibodies. AB - Porcine epidemic diarrhea (PED) has caused tremendous losses to the United States pig industry since 2013. From 2014, outbreaks were also reported from Central Europe. To characterize the Central European PEDV strains regarding their virulence in suckling piglets, and to assess the protective effect of maternally derived antibodies (MDA), four trial groups were randomly assigned, each consisting of two pregnant sows and their litter. To induce MDA in a subset of piglets, two sows received a cell culture-adapted PEDV strain, and another two sows were inoculated with field material from German PED outbreaks. Four sows stayed naive. Subsequently, all piglets were inoculated with the corresponding PEDV strains at an age of 3 to 6 days, and virus shedding, clinical signs and occurrence of specific antibodies were assessed. Piglets without MDA showed a morbidity of 100% and low lethality, while almost all MDA-positive piglets stayed clinically healthy and showed considerably lower virus shedding. Taken together, the Central European PEDV strains showed rather low virulence under experimental conditions, and pre-inoculation of sows led to a solid protection of their offspring. The latter is the prerequisite for a sow vaccination concept that could help to prevent PED induced losses in the piglet sector. PMID- 28883630 TI - A clinical investigation treating different types of fibroids identified by MRI T2WI imaging with ultrasound guided high intensity focused ultrasound. AB - Clinical data from 172 cases of uterine fibroids with different appearances on MRI-T2WI and accepted ultrasound guided high intensity focused ultrasound (USgHIFU) treatment were retrospectively analyzed. This study aimed to evaluate the clinical safety and efficacy of ablating different types of fibroids, classified by T2-weighted magnetic resonance imaging (MRI-T2WI). Based on MRI T2WI signal intensities, uterine fibroids were classified as three types: hypointensive (52 cases), isointensive (64 cases) and hyperintensive (56 cases). Evaluation parameters including treatment time, ablation efficiency, percentage non-perfused volume, fibroid reduction rate, adverse reactions, symptom severity scores (SSS) and re-intervention rate were assessed from 3 months to 1 year. The percentage non-perfused volume and ablation efficiency of hyperintensive uterine fibroids were lower than those of isointensive and hypointensive uterine fibroids. All fibroids shrunk and the SSS continued to reduce at 3 and 6 months after treatment respectively. At 12-month postoperative assessments, hypointensive fibroids continued to shrink, while the isointensive fibroids enlarged but remained smaller than pre-treatment. The incident rate of postoperative Society of Interventional Radiology B-class (SIRB-class) adverse events showed no significant differences. The re-interventional rate of hyperintensive fibroids was higher than in isointensive and hypointensive groups. USgHIFU ablation of all types of fibroids were safe and effective. PMID- 28883631 TI - Antihyperglycaemic and organic protective effects on pancreas, liver and kidney by polysaccharides from Hericium erinaceus SG-02 in streptozotocin-induced diabetic mice. AB - The present work was designed to investigate the antihyperglycaemic and protective effects of two Hericium erinaceus intracellular polysaccharide (HIPS) purified fractions (HIPS1 and HIPS2) from mycelia of H. erinaceus SG-02 on pancreas, liver and kidney in streptozotocin (STZ)-induced diabetic mice. The supplementation of HIPS1 and HIPS2 significantly decreased the blood glucose (GLU) levels; suppressed the abnormal elevations of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN) and creatinine (CRE) levels in serum; improved the antioxidant enzymatic (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)) activities; and attenuated the pathological damage to these organs. The HIPS1 showed superior effects in antihyperglycaemia and organic protection than HIPS2 possible owing to the abundant functional groups (-NH2, -COOH and S=O) in HIPS1, indicating that H. erinaceus SG-02 could be used as a functional food and natural drug for the prevention of diabetes and its complications. PMID- 28883632 TI - Extraction, separation and characterization of endotoxins in water samples using solid phase extraction and capillary electrophoresis-laser induced fluorescence. AB - This study focuses on one of the key environmental threats, endotoxins, also known as lipopolysaccharides (LPS). A capillary electrophoresis method in combination with laser induced fluorescence (LIF) detection was developed for the analysis of endotoxins from 16 different bacterial strains. LPSs were derivatized with the amino-reactive fluorescent dye, fluorescein isothiocyanate (FITC), separated by capillary zone electrophoresis (CZE) under the optimized conditions with the use of 50 mM sodium tetraborate buffer (pH 9.30), and detected by LIF detector. To improve the sensitivity of CZE-LIF detection for the determination of trace amounts of endotoxins and to remove possible interference materials in environmental samples, a solid phase extraction (SPE) pre-concentration technique was applied successfully. The SPE targeted at polysaccharide moieties of LPSs and showed LPS enrichment effects too. CE migration time could also reveal the O antigen chain lengths of LPSs. This CE method and SPE pretreatment showed linearity at 99.84%, and repeatabilities at 8.44% and 11.0% for endotoxins from E. Coli O55:B5 and E. Coli O26:B6. The limit of detection (LOD) could reach around 5 ng/mL at optimized condition. The method was applied successfully to the determination of LPS levels in tap water and wastewater, and demonstrated sensitive, reproducible and reliable results. PMID- 28883634 TI - Association of the resolvin precursor 17-HDHA, but not D- or E- series resolvins, with heat pain sensitivity and osteoarthritis pain in humans. AB - Resolvins are omega-3 fatty acid derived potent bioactive lipids that resolve inflammation and modulate transient receptor potential channels. Exogenous administration of the resolvin precursor 17-HDHA shows a strong analgesic effect in animal models of osteoarthritis and acute inflammatory pain, but has not been studied in humans. Our aim was to assess the role of 17-HDHA and resolvins in heat pain sensitivity and in osteoarthritis pain in humans. Resolvins D1, D2, D3, D5, E1 and 17-HDHA, were measured by liquid chromatography-mass spectrometry and tested for association with heat pain thresholds in 250 healthy volunteers who had undergone quantitative sensory testing. Resolvins D1, D2 and 17-HDHA were then tested in 62 individuals affected with knee osteoarthritis and 52 age matched controls and tested for association with knee pain. Circulating levels of docosahexaenoic acid (DHA) were also measured. Levels of 17-HDHA, but not those of the other 5 resolvins tested, were associated with increased heat pain thresholds (beta = 0.075; 95% CI 0.024, 0.126; p < 0.0046). 17-HDHA was associated with lower pain scores in OA patients (beta -0.41; 95% CI-0.69, -0.12; p < 0.005; adjusted for covariates) but not with radiographic osteoarthritis. The associations of 17-HDHA with heat pain sensitivity and osteoarthritis pain were independent of DHA levels. PMID- 28883633 TI - Pokemon GO and psychological distress, physical complaints, and work performance among adult workers: a retrospective cohort study. AB - The effects of Pokemon GO, a new mobile game application which utilizes augmented reality, on risky behavior and health have already been discussed in anecdotal evidence. However, there have been no studies about its effects on mental health. This study investigated the relationships between Pokemon GO and psychological distress from an existing workers' cohort in Japan. Online surveys were conducted to 3,915 full-time workers, at baseline (Nov 26, 2015-Feb 18, 2016) and at follow up (Dec 1-4, 2016), using a self-report questionnaire. Pokemon GO players were defined as participants who had played Pokemon GO for one month or longer. Psychological distress was measured using validated scales. Of the completers, 246 (9.7%) had continued to play Pokemon GO. They were significantly younger than non-players. From the results of the general linear modeling, improvement in psychological distress was significantly greater among Pokemon GO players than among non-players (p = 0.025). Cohen's d for the difference in psychological distress was -0.20 (95% CI, -0.33, -0.07). Pokemon GO may be effective for improving psychological distress among workers. Although its effect size is small, the game could have positive effects on the mental health of the adult working population. PMID- 28883636 TI - Precipitation in a warming world: Assessing projected hydro-climate changes in California and other Mediterranean climate regions. AB - In most Mediterranean climate (MedClim) regions around the world, global climate models (GCMs) consistently project drier futures. In California, however, projections of changes in annual precipitation are inconsistent. Analysis of daily precipitation in 30 GCMs reveals patterns in projected hydrometeorology over each of the five MedClm regions globally and helps disentangle their causes. MedClim regions, except California, are expected to dry via decreased frequency of winter precipitation. Frequencies of extreme precipitation, however, are projected to increase over the two MedClim regions of the Northern Hemisphere where projected warming is strongest. The increase in heavy and extreme precipitation is particularly robust over California, where it is only partially offset by projected decreases in low-medium intensity precipitation. Over the Mediterranean Basin, however, losses from decreasing frequency of low-medium intensity precipitation are projected to dominate gains from intensifying projected extreme precipitation. MedClim regions are projected to become more sub tropical, i.e. made dryer via pole-ward expanding subtropical subsidence. California's more nuanced hydrological future reflects a precarious balance between the expanding subtropical high from the south and the south-eastward extending Aleutian low from the north-west. These dynamical mechanisms and thermodynamic moistening of the warming atmosphere result in increased horizontal water vapor transport, bolstering extreme precipitation events. PMID- 28883635 TI - Tissue alkalosis in cold-ischemia time. AB - The control of pre-analytical-factors in human biospecimens collected for health research is currently required. Only two previous reports using post-mortem brain samples have tried to address the impact of cold-ischemia on tissue pH. Here we report pH variations according to time (third-order polynomial model) in mice for liver, kidney and lung samples. Tissue alkalosis in cold-ischemia time may be an underlying mechanism of gene expression changes. Therefore, tissue-pH regulation after organ removal may minimize biological stress in human tissue samples. PMID- 28883637 TI - Capture of organic iodides from nuclear waste by metal-organic framework-based molecular traps. AB - Effective capture of radioactive organic iodides from nuclear waste remains a significant challenge due to the drawbacks of current adsorbents such as low uptake capacity, high cost, and non-recyclability. We report here a general approach to overcome this challenge by creating radioactive organic iodide molecular traps through functionalization of metal-organic framework materials with tertiary amine-binding sites. The molecular trap exhibits a high CH3I saturation uptake capacity of 71 wt% at 150 degrees C, which is more than 340% higher than the industrial adsorbent Ag0@MOR under identical conditions. These functionalized metal-organic frameworks also serve as good adsorbents at low temperatures. Furthermore, the resulting adsorbent can be recycled multiple times without loss of capacity, making recyclability a reality. In combination with its chemical and thermal stability, high capture efficiency and low cost, the adsorbent demonstrates promise for industrial radioactive organic iodides capture from nuclear waste. The capture mechanism was investigated by experimental and theoretical methods.Capturing radioactive organic iodides from nuclear waste is important for safe nuclear energy usage, but remains a significant challenge. Here, Li and co-workers fabricate a stable metal-organic framework functionalized with tertiary amine groups that exhibits high capacities for radioactive organic iodides uptake. PMID- 28883638 TI - Mild traumatic brain injury induces memory deficits with alteration of gene expression profile. AB - Repeated mild traumatic brain injury (rmTBI), the most common type of traumatic brain injuries, can result in neurological dysfunction and cognitive deficits. However, the molecular mechanisms and the long-term consequence of rmTBI remain elusive. In this study, we developed a modified rmTBI mouse model and found that rmTBI-induced transient neurological deficits and persistent impairments of spatial memory function. Furthermore, rmTBI mice had long-lasting detrimental effect on cognitive function, exhibiting memory deficits even 12 weeks after rmTBI. Microarray analysis of whole genome gene expression showed that rmTBI significantly altered the expression level of 87 genes which are involved in apoptosis, stress response, metabolism, and synaptic plasticity. The results indicate the potential mechanism underlying rmTBI-induced acute neurological deficits and its chronic effect on memory impairments. This study suggests that long-term monitoring and interventions for rmTBI individuals are essential for memory function recovery and reducing the risk of developing neurodegenerative diseases. PMID- 28883639 TI - Hysteretic Dynamics of Multi-Stable Early Afterdepolarisations with Repolarisation Reserve Attenuation: A Potential Dynamical Mechanism for Cardiac Arrhythmias. AB - Some cardiovascular and non-cardiovascular drugs frequently cause excessive prolongation of the cardiac action potential (AP) and lead to the development of early afterdepolarisations (EADs), which trigger lethal ventricular arrhythmias. Combining computer simulations in APs with numerical calculations based on dynamical system theory, we investigated stability changes of APs observed in a paced human ventricular myocyte model by decreasing and/or increasing the rapid (I Kr) and slow (I Ks) components of delayed rectifying K+ current. Upon reducing I Kr, the APs without EADs (no-EAD response) showed gradual prolongation of AP duration (APD), and were annihilated without AP configuration changes due to the occurrence of saddle-node bifurcations. This annihilation caused a transition to an AP with EADs as a new stable steady state. Furthermore, reducing repolarisation currents (repolarisation reserve attenuation) evoked multi-stable states consisting of APs with different APDs, and caused multiple hysteretic dynamics. Depending on initial ion circumstances within ventricular myocytes, these multi-stable AP states might increase the local/global heterogeneity of AP repolarisations in the ventricle. Thus, the EAD-induced arrhythmias with repolarisation reserve attenuation might be attributed to the APD variability caused by multi-stability in cardiac AP dynamics. PMID- 28883640 TI - A somatotopic bidirectional hand prosthesis with transcutaneous electrical nerve stimulation based sensory feedback. AB - According to amputees, sensory feedback is amongst the most important features lacking from commercial prostheses. Although restoration of touch by means of implantable neural interfaces has been achieved, these approaches require surgical interventions, and their long-term usability still needs to be fully investigated. Here, we developed a non-invasive alternative which maintains some of the advantages of invasive approaches, such as a somatotopic sensory restitution scheme. We used transcutaneous electrical nerve stimulation (TENS) to induce referred sensations to the phantom hand of amputees. These sensations were characterized in four amputees over two weeks. Although the induced sensation was often paresthesia, the location corresponded to parts of the innervation regions of the median and ulnar nerves, and electroencephalographic (EEG) recordings confirmed the presence of appropriate responses in relevant cortical areas. Using these sensations as feedback during bidirectional prosthesis control, the patients were able to perform several functional tasks that would not be possible otherwise, such as applying one of three levels of force on an external sensor. Performance during these tasks was high, suggesting that this approach could be a viable alternative to the more invasive solutions, offering a trade-off between the quality of the sensation, and the invasiveness of the intervention. PMID- 28883641 TI - Calaxin establishes basal body orientation and coordinates movement of monocilia in sea urchin embryos. AB - Through their coordinated alignment and beating, motile cilia generate directional fluid flow and organismal movement. While the mechanisms used by multiciliated epithelial tissues to achieve this coordination have been widely studied, much less is known about regulation of monociliated tissues such as those found in the vertebrate node and swimming planktonic larvae. Here, we show that a calcium sensor protein associated with outer arm dynein, calaxin, is a critical regulator for the coordinated movements of monocilia. Knockdown of calaxin gene in sea urchin embryos results in uncoordinated ciliary beating and defective directional movement of the embryos, but no apparent abnormality in axoneme ultrastructure. Examination of the beating cycle of individual calaxin deficient cilia revealed a marked effect on the waveform and spatial range of ciliary bending. These findings indicate that calaxin-mediated regulation of ciliary beating is responsible for proper basal body orientation and ciliary alignment in fields of monociliated cells. PMID- 28883642 TI - Fungicidal activity of peptides encoded by immunoglobulin genes. AB - Evidence from previous works disclosed the antimicrobial, antiviral, anti-tumour and/or immunomodulatory activity exerted, through different mechanisms of action, by peptides expressed in the complementarity-determining regions or even in the constant region of antibodies, independently from their specificity and isotype. Presently, we report the selection, from available databases, of peptide sequences encoded by immunoglobulin genes for the evaluation of their potential biological activities. Synthetic peptides representing the translated products of J lambda and J heavy genes proved to act in vitro against pathogenic fungi, entering yeast cells and causing their death, and exerted a therapeutic effect in a Galleria mellonella model of infection by Candida albicans. No haemolytic, cytotoxic and genotoxic effects were observed on mammalian cells. These findings raise the hypothesis that antibodies could be the evolutionary result of the adaptive combination of gene products ancestrally devoted to innate antimicrobial immunity. PMID- 28883643 TI - Soil organic phosphorus transformations during 2000 years of paddy-rice and non paddy management in the Yangtze River Delta, China. AB - The contents and properties of soil organic phosphorus (Po) largely drive ecosystem productivity with increasing development of natural soil. We hypothesized that soil Po would initially increase with paddy management and then would persist under steady-state conditions. We analyzed soils from a 2000-year chronosequence of a rice-wheat rotation and an adjacent non-paddy 700-year chronosequence in Bay of Hangzhou (China) for their Po composition using solution 31P-NMR after NaOH-EDTA extraction. Land reclamation promoted Po accumulation in both paddy and non-paddy topsoils (depths <= 18 cm) until steady-state equilibria were reached within 200 years of land use. Greater Po concentrations were found, however, in the non-paddy subsoils than in those under paddy management. Apparently, the formation of a dense paddy plough pan hindered long-term Po accumulation in the paddy subsoil. The surface soils showed higher proportions of orthophosphate diesters under paddy than under non-paddy management, likely reflecting suppressed decomposition of crop residues despite elevated microbial P compounds stocks under anaerobic paddy-rice management. Intriguingly, the composition of Po was remarkably stable after 194-years of paddy management and 144-years of non-paddy management, suggesting novel steady-state equilibria of P dynamics had been reached in these man-made ecosystems after less than two centuries. PMID- 28883644 TI - Decreased hail size in China since 1980. AB - The response of hailstorm intensity to climate variability/change has become a topic of community interest recently. But the lack of persistent and homogenous observations makes it difficult to confidently describe its interannual variations. Hail size, as a common indicator of hailstorm intensity, displays distinct regional variability. Here, for the first time, we show robust evidence of a decrease in hail size using continuous and coherent hail size records from 2,254 manned stations in China since 1980. The stations were categorized based on their elevation: plateaus (above 2000 m), foothills (between 500 and 2000 m), and plains (below 500 m). Compared with 1980-1997, the hail size spectra from 1998 to 2015 all shifted toward smaller sizes significantly in plateaus, foothills, and plains. The proportion of overall hail events with maximum sizes of at least 5 and 20 mm significantly decreased since 1980. Meanwhile, the annual mean size of hail above 10 and 20 mm significantly decreased during the research period, especially after 1990. These changes in the hail size spectra may imply a weakened intensity of hailstorms in China in recent decades. PMID- 28883645 TI - Combining Biomarkers with EMR Data to Identify Patients in Different Phases of Sepsis. AB - Sepsis is a leading cause of death and is the most expensive condition to treat in U.S. hospitals. Despite targeted efforts to automate earlier detection of sepsis, current techniques rely exclusively on using either standard clinical data or novel biomarker measurements. In this study, we apply machine learning techniques to assess the predictive power of combining multiple biomarker measurements from a single blood sample with electronic medical record data (EMR) for the identification of patients in the early to peak phase of sepsis in a large community hospital setting. Combining biomarkers and EMR data achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 0.81, while EMR data alone achieved an AUC of 0.75. Furthermore, a single measurement of six biomarkers (IL-6, nCD64, IL-1ra, PCT, MCP1, and G-CSF) yielded the same predictive power as collecting an additional 16 hours of EMR data(AUC of 0.80), suggesting that the biomarkers may be useful for identifying these patients earlier. Ultimately, supervised learning using a subset of biomarker and EMR data as features may be capable of identifying patients in the early to peak phase of sepsis in a diverse population and may provide a tool for more timely identification and intervention. PMID- 28883646 TI - Heat conjugation of antibacterial agents from amino acids and plant oil. AB - Antimicrobial peptides are components of the innate immune systems in animals and plants as natural defense against pathogens. Critical issues like manufacturing costs have to be addressed before mass production of these peptides for agriculture or community sterilizations. Here, we report a cost-effective chemical synthesis method to produce antimicrobial cocktails, which was based on the heat conjugation of amino acids in the presence of phosphoric acid and plant oil at 150 degrees C. The conjugates showed potent biological activities against all tested bacteria including a multi-drug resistant Staphylococcus aureus strain Y5 and ampicillin resistant Pseudomonas aerugenosa ATCC9027 strain, demonstrating potential in agriculture, and prophylactic applications in hospital and community settings. PMID- 28883647 TI - Circulating miR-122 and miR-200a as biomarkers for fatal liver disease in ART treated, HIV-1-infected individuals. AB - Liver disease is one of the main contributors to the increased levels of morbidity and mortality seen in the HIV-1-infected, ART-treated population. Circulating miRNAs, particularly those located inside extracellular vesicles, are seen as promising biomarkers for a number of human disease conditions, including liver-related diseases. Here, we show that serum levels of miR-122 and miR-200a are greater in HIV/HCV co-infected individuals compared to HIV-1 mono-infected individuals. We also show that miR-122 and miR-200a are elevated in ART-treated, HIV-1-infected individuals prior to the development of fatal liver disease, suggesting that these miRNA may have some potential clinical utility as biomarkers. While this study is hypothesis generating, it shows clearly that both miR-122 and miR-200a are promising novel biomarkers for liver disease in the ART treated, HIV-1-infected population. PMID- 28883648 TI - The utility of mtDNA and rDNA for barcoding and phylogeny of plant-parasitic nematodes from Longidoridae (Nematoda, Enoplea). AB - The traditional identification of plant-parasitic nematode species by morphology and morphometric studies is very difficult because of high morphological variability that can lead to considerable overlap of many characteristics and their ambiguous interpretation. For this reason, it is essential to implement approaches to ensure accurate species identification. DNA barcoding aids in identification and advances species discovery. This study sought to unravel the use of the mitochondrial marker cytochrome c oxidase subunit 1 (coxI) as barcode for Longidoridae species identification, and as a phylogenetic marker. The results showed that mitochondrial and ribosomal markers could be used as barcoding markers, except for some species from the Xiphinema americanum group. The ITS1 region showed a promising role in barcoding for species identification because of the clear molecular variability among species. Some species presented important molecular variability in coxI. The analysis of the newly provided sequences and the sequences deposited in GenBank showed plausible misidentifications, and the use of voucher species and topotype specimens is a priority for this group of nematodes. The use of coxI and D2 and D3 expansion segments of the 28S rRNA gene did not clarify the phylogeny at the genus level. PMID- 28883649 TI - Dual role of carcinoembryonic antigen-related cell adhesion molecule 6 expression in predicting the overall survival of gastric cancer patients. AB - Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a member of the glycosylphosphatidylinositol-linked immunoglobulin superfamily that is implicated in many human cancers. Here, we aimed to investigate the role of CEACAM6 expression in predicting the overall survival (OS) in gastric cancer (GC). The impact of CEACAM6 on the survival of patients with GC (n = 876) was assessed using an online Kaplan-Meier plotter. Findings were validated using the OS data of patients (n = 160) recruited from Ruijin Hospital. We found that high CEACAM6 expression was associated with a better OS in early-stage or well differentiated GC, or who were treated without 5-fluorouracil (5-FU). Conversely, high CEACAM6 expression was associated with a poor OS in advanced-stage GC, poorly differentiated tumors, or who were treated with 5-FU. Furthermore, CEACAM6 may serve as a better marker for predicting OS in GC than CEA. In addition, CEACAM6 overexpression in GC cells increased apoptotic resistance to 5-FU. Moreover, CEACAM6 induced cluster of differentiation 4- and 8-positive lymphocytes were detected in early-stage GC. In conclusion, CEACAM6 plays a contradictory role in predicting the OS in GC. In early-stage GC, high CEACAM6 expression is associated with improved OS. However, in advanced-stage GC, high CEACAM6 expression is associated with a poor OS. PMID- 28883650 TI - A novel and stress adaptive alternative oxidase derived from alternative splicing of duplicated exon in oyster Crassostrea virginica. AB - Alternative oxidase (AOX) is a mitochondrial inner-membrane oxidase that accepts electrons directly from ubiquinol and reduces oxygen to water without involving cytochrome-linked electron transport chain. It is highly conserved in many non vertebrate taxa and may protect cells against hypoxia and oxidative stress. We identified two AOX mRNAs in eastern oyster Crassostrea virginica, CvAOXA and CvAOXB, which differ by 170 bp but encode AOXs of the same size. Sequence analyses indicate that CvAOX has 10 exons with a tandem duplication of exon 10, and 3' alternative splicing using either the first or second exon 10 produces the two variants CvAOXB or CvAOXA, respectively. The second exon 10 in CvAOXA is more conserved across taxa, while the first exon 10 in CvAOXB contains novel mutations surrounding key functional sites. Both variants are expressed in all organs with the expression of CvAOXA higher than that of CvAOXB under normal condition. Under stress by air exposure, CvAOXB showed significantly higher expression than CvAOXA and became the dominant variant. This is the first case of alternative splicing of duplicated exon in a mollusc that produces a novel variant adaptive to stress, highlighting genome's versatility in generating diversity and phenotypic plasticity. PMID- 28883651 TI - The role of transcriptional factor p63 in regulation of epithelial barrier and ciliogenesis of human nasal epithelial cells. AB - Disruption of nasal epithelial tight junctions (TJs) and ciliary dysfunction are found in patients with chronic rhinosinusitis (CRS) and nasal polyps (NPs), along with an increase of p63-positive basal cells and histone deacetylase (HDAC) activity. To investigate these mechanisms, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were transfected with siRNAs of TAp63 and DeltaNp63, treated with the NF-kB inhibitor curucumin and inhibitors of HDACs, and infected with respiratory syncytial virus (RSV). In TERT HNECs, knockdown of p63 by siRNAs of TAp63 and DeltaNp63, induced claudin-1 and 4 with Sp1 activity and enhanced barrier and fence functions. The knockdown of p63 enhanced the number of microvilli with the presence of cilia-like structures. Treatment with curcumin and inhibitors of HDACs, or infection with RSV prevented expression of p63 with an increase of claudin-4 and the number of microvilli. The knockdown or downregulation of p63 inhibited phospho-p38MAPK, and the p38MAPK inhibitor downregulated p63 and upregulated the barrier function. Thus, epithelial barrier and ciliogenesis of nasal epithelium are regulated in a p63 negative manner in normal and upper airway diseases. Understanding of the regulation of p63/p38 MAPK/NF-kappaB may be important in the therapy for airway allergy and its drug delivery system. PMID- 28883652 TI - Tracking the tumor invasion front using long-term fluidic tumoroid culture. AB - The analysis of invading leader cells at the tumor invasion front is of significant interest as these cells may possess a coordinated functional and molecular phenotype which can be targeted for therapy. However, such analyses are currently limited by available technologies. Here, we report a fluidic device for long-term three-dimensional tumoroid culture which recapitulated the tumor invasion front, allowing for both quantification of invasive potential and molecular characterization of invasive leader cells. Preliminary analysis of the invasion front indicated an association with cell proliferation and higher expression of growth differentiation factor 15 (GDF15). This device makes real time tracking of invading leader cell phenotypes possible and has potential for use with patient material for clinical risk stratification and personalized medicine. PMID- 28883653 TI - Excellent thermoelectric properties induced by different contact geometries in phenalenyl-based single-molecule devices. AB - We investigated the thermoelectric properties of phenalenyl-based molecular devices by using the non-equilibrium Green's function method combined with density function theory. The results show that the thermoelectric performance of molecular device can be significantly improved by different contact geometries. The ZT value of the device can reach 1.2 at room temperature, which is two orders of magnitude higher than that of graphene. Moreover, the change of the coupling between molecule and electrodes can also enhance the ZT value. The ZT value can be further optimized to 1.4 at 300 K and 5.9 at 100 K owing to the decrease of electronic thermal conductance and almost unchanged power factor. PMID- 28883654 TI - Target margin design for real-time lung tumor tracking stereotactic body radiation therapy using CyberKnife Xsight Lung Tracking System. AB - The objective of this study is to quantify the clinical accuracy of the Cyberknife Xsight Lung Tracking System (XLTS) in our center and calculate the PTV margin of XLTS treated lung tumors. Data from the treatment log files of 22 lung cancer patients treated with the CyberKnife XLTS were analyzed and the PTV margin was calculated. Segmentation, deformation, correlation, prediction and targeting errors were calculated from the log files of XLTS treatments. Two different methods were used to calculate anisotropic treatment margin. The relationships between tumor motion ranges and the correlation and prediction errors were also analyzed. Based on our estimation of a 4 mm global margin, 95% coverage in the S I direction and 100% coverage in the L-R and A-P directions were obtained. Strong correlations between tumor motion range and the standard deviation (SD) of correlation and prediction errors were also found. Tumor position motion caused by respiration can be compensated using the Xsight Lung Tracking System. We found total tracking errors to be less than 4 mm in all three directions. This result could provide a reference for the selection of PTV margin for treatment with the CyberKnife XLTS. PMID- 28883655 TI - Label-free characterization of ultra violet-radiation-induced changes in skin fibroblasts with Raman spectroscopy and quantitative phase microscopy. AB - Minimizing morbidities and mortalities associated with skin cancers requires sustained research with the goal of obtaining fresh insights into disease onset and progression under specific stimuli, particularly the influence of ultraviolet rays. In the present study, label-free profiling of skin fibroblasts exposed to time-bound ultra-violet radiation has been performed using quantitative phase imaging and Raman spectroscopy. Statistically significant differences in quantifiable biophysical parameters, such as matter density and cell dry mass, were observed with phase imaging. Accurate estimation of changes in the biochemical constituents, notably nucleic acids and proteins, was demonstrated through a combination of Raman spectroscopy and multivariate analysis of spectral patterns. Overall, the findings of this study demonstrate the promise of these non-perturbative optical modalities in accurately identifying cellular phenotypes and responses to external stimuli by combining molecular and biophysical information. PMID- 28883656 TI - The presence of acquired enamel pellicle changes acid-induced erosion from dissolution to a softening process. AB - Erosive wear undermines the structural properties of enamel resulting in irreversible enamel loss. A thin protein layer formed from natural saliva on tooth surfaces, acquired enamel pellicle (AEP), protects against erosive wear. The exact components in saliva responsible for such protection are not yet known. We prepared three solutions containing different components: proteins and ions [natural saliva (NS)], minerals with no proteins [artificial saliva (AS)] and neither proteins nor ions [deionised water (DW)]. To assess the protection of the three solutions against citric acid enamel erosion, enamel specimens were immersed in the corresponding solution for 24 h. All specimens were then exposed to five erosion cycles, each consisted of a further 30 min immersion in the same solution followed by 10-min erosion. Mean step height using a non-contacting profilometer, mean surface microhardness (SMH) using Knoop microhardness tester (final SMH), and roughness and 2D profiles using atomic force microscopy were measured after five cycles. The final SMH values were compared to the starting values (after 24 hr). NS group had significantly less tissue loss but greater SMH change (P < 0.0001) than AS and DW groups. Specimens in NS were softer and rougher (P < 0.001) but less eroded than specimens in AS and DW. PMID- 28883657 TI - Deamination-independent restriction of LINE-1 retrotransposition by APOBEC3H. AB - The APOBEC3 family of cytosine deaminase enzymes are able to restrict replication of retroelements, such as LINE-1. However, each of the seven APOBEC3 enzymes have been reported to act differentially to prevent LINE-1 retrotransposition and the mechanisms of APOBEC3-mediated LINE-1 inhibition has not been well understood. The prevailing view for many years was that APOBEC3-mediated LINE-1 inhibition was deamination-independent and relied on APOBEC3s blocking the LINE-1 reverse transcriptase DNA polymerization or transport of the LINE-1 RNA into the nucleus. However, recently it was shown that APOBEC3A can deaminate cytosine, to form uracil, on transiently exposed single-stranded LINE-1 cDNA and this leads to LINE 1 cDNA degradation. In this study, we confirmed that APOBEC3A is a potent deamination-dependent inhibitor of LINE-1 retrotransposition, but show that in contrast, A3H haplotype II and haplotype V restrict LINE-1 activity using a deamination-independent mechanism. Our study supports the model that different APOBEC3 proteins have evolved to inhibit LINE-1 retrotransposition through distinct mechanisms. PMID- 28883658 TI - Running reorganizes the circuitry of one-week-old adult-born hippocampal neurons. AB - Adult hippocampal neurogenesis is an important form of structural and functional plasticity in the mature mammalian brain. The existing consensus is that GABA regulates the initial integration of adult-born neurons, similar to neuronal development during embryogenesis. Surprisingly, virus-based anatomical tracing revealed that very young, one-week-old, new granule cells in male C57Bl/6 mice receive input not only from GABAergic interneurons, but also from multiple glutamatergic cell types, including mature dentate granule cells, area CA1-3 pyramidal cells and mossy cells. Consistently, patch-clamp recordings from retrovirally labeled new granule cells at 7-8 days post retroviral injection (dpi) show that these cells respond to NMDA application with tonic currents, and that both electrical and optogenetic stimulation can evoke NMDA-mediated synaptic responses. Furthermore, new dentate granule cell number, morphology and excitatory synaptic inputs at 7 dpi are modified by voluntary wheel running. Overall, glutamatergic and GABAergic innervation of newly born neurons in the adult hippocampus develops concurrently, and excitatory input is reorganized by exercise. PMID- 28883659 TI - Urine to highly porous heteroatom-doped carbons for supercapacitor: A value added journey for human waste. AB - Obtaining functionalized carbonaceous materials, with well-developed pores and doped heteroatoms, from waste precursors using environmentally friendly processes has always been of great interest. Herein, a simple template-free approach is devised to obtain porous and heteroatom-doped carbon, by using the most abundant human waste, "urine". Removal of inherent mineral salts from the urine carbon (URC) makes it to possess large quantity of pores. Synergetic effect of the heteroatom doping and surface properties of the URC is exploited by carrying out energy storage application for the first time. Suitable heteroatom content and porous structure can enhance the pseudo-capacitance and electric double layer capacitance, eventually generating superior capacitance from the URC. The optimal carbon electrode obtained particularly at 900 degrees C (URC-900) possesses high BET surface area (1040.5 m2g-1), good conductivity, and efficient heteroatom doping of N, S, and P, illustrating high specific capacitance of 166 Fg-1 at 0.5 Ag-1 for three-electrode system in inorganic electrolyte. Moreover, the URC-900 delivers outstanding cycling stability with only 1.7% capacitance decay over 5,000 cycles at 5 Ag-1. Present work suggests an economical approach based on easily available raw waste material, which can be utilized for large-scale production of new age multi-functional carbon nanomaterials for various energy applications. PMID- 28883660 TI - Chromatin remodeling system p300-HDAC2-Sin3A is involved in Arginine Starvation Induced HIF-1alpha Degradation at the ASS1 promoter for ASS1 Derepression. AB - Argininosuccinate synthetase 1 (ASS1) is the key enzyme that controls biosynthesis of arginine (Arg). ASS1 is silenced in many human malignancies therefore, these tumors require extracellular Arg for growth. The Arg-degrading recombinant protein, pegylated arginine deiminase (ADI-PEG20), has been in clinical trials for targeting Arg auxotrophic tumors by Arg starvation therapy. Resistance to Arg starvation is often developed through reactivation of ASS1 expression. We previously demonstrated that ASS1 silencing is controlled by HIF 1alpha and Arg starvation-reactivated ASS1 is associated with HIF-1alpha downregulation. However, mechanisms underlying ASS1 repression and HIF-1alpha turnover are not known. Here, we demonstrate that interplay of p300-HDAC2-Sin3A in the chromatin remodeling system is involved in HIF-1alpha degradation at the ASS1 promoter. The histone acetyltransferase p300 is normally associated with the ASS1 promoter to maintain acetylated H3K14ac and H3K27ac for ASS1 silencing. Arg starvation induces p300 dissociation, allowing histone HDAC2 and cofactor Sin3A to deacetylate these histones at the ASS1 promoter, thereby facilitating HIF 1alpha-proteasomal complex, driven by PHD2, to degrade HIF-1alpha in situ. Arg starvation induces PHD2 and HDAC2 interaction which is sensitive to antioxidants. This is the first report describing epigenetic regulation of chromosomal HIF 1alpha turnover in gene activation that bears important implication in cancer therapy. PMID- 28883661 TI - Visualizing Micro-anatomical Structures of the Posterior Cornea with Micro optical Coherence Tomography. AB - Diagnosis of corneal disease and challenges in corneal transplantation require comprehensive understanding of corneal anatomy, particularly that of the posterior cornea. Micro-optical coherence tomography (uOCT) is a potentially suitable tool to meet this need, owing to its ultrahigh isotropic spatial resolution, high image acquisition rate and depth priority scanning mode. In this study, we explored the ability of uOCT to visualize micro-anatomical structures of the posterior cornea ex vivo and in vivo using small and large animals. uOCT clearly delineated cornea layers and revealed micro-anatomical structures, including not only polygonal endothelial cells, stellate keratocytes, collagen fibres and corneal nerve fibres but also new structures such as the dome-shaped basolateral side of endothelial cells and lattice structures at the interface between endothelium and Descemet's membrane. Based on these observations, a short post-harvest longitudinal study was conducted on rat cornea to test the feasibility of using uOCT to monitor the quality of endothelial cells. This study successfully reveals a series of morphological features and pathological changes in the posterior cornea at the cellular level in situ and in real time with uOCT. These findings enrich knowledge of corneal anatomy and suggest that uOCT may be a promising imaging tool in corneal transplantation. PMID- 28883662 TI - Analyzing the Molecular Kinetics of Water Spreading on Hydrophobic Surfaces via Molecular Dynamics Simulation. AB - In this paper, we report molecular kinetic analyses of water spreading on hydrophobic surfaces via molecular dynamics simulation. The hydrophobic surfaces are composed of amorphous polytetrafluoroethylene (PTFE) with a static contact angle of ~112.4 degrees for water. On the basis of the molecular kinetic theory (MKT), the influences of both viscous damping and solid-liquid retarding were analyzed in evaluating contact line friction, which characterizes the frictional force on the contact line. The unit displacement length on PTFE was estimated to be ~0.621 nm and is ~4 times as long as the bond length of C-C backbone. The static friction coefficient was found to be ~[Formula: see text] Pa.s, which is on the same order of magnitude as the dynamic viscosity of water, and increases with the droplet size. A nondimensional number defined by the ratio of the standard deviation of wetting velocity to the characteristic wetting velocity was put forward to signify the strength of the inherent contact line fluctuation and unveil the mechanism of enhanced energy dissipation in nanoscale, whereas such effect would become insignificant in macroscale. Moreover, regarding a liquid droplet on hydrophobic or superhydrophobic surfaces, an approximate solution to the base radius development was derived by an asymptotic expansion approach. PMID- 28883664 TI - Patent watch: The evolving intellectual property landscape for pruritus therapies. PMID- 28883663 TI - An algorithm based on positive and negative links for community detection in signed networks. AB - Community detection problem in networks has received a great deal of attention during the past decade. Most of community detection algorithms took into account only positive links, but they are not suitable for signed networks. In our work, we propose an algorithm based on random walks for community detection in signed networks. Firstly, the local maximum degree node which has a larger degree compared with its neighbors is identified, and the initial communities are detected based on local maximum degree nodes. Then, we calculate a probability for the node to be attracted into a community by positive links based on random walks, as well as a probability for the node to be away from the community on the basis of negative links. If the former probability is larger than the latter, then it is added into a community; otherwise, the node could not be added into any current communities, and a new initial community may be identified. Finally, we use the community optimization method to merge similar communities. The proposed algorithm makes full use of both positive and negative links to enhance its performance. Experimental results on both synthetic and real-world signed networks demonstrate the effectiveness of the proposed algorithm. PMID- 28883665 TI - Spatiotemporal heterogeneity of core functional bacteria and their synergetic and competitive interactions in denitrifying sulfur conversion-assisted enhanced biological phosphorus removal. AB - Denitrifying sulfur conversion-assisted enhanced biological phosphorus removal (DS-EBPR) has recently been developed for simultaneously removing nitrogen and phosphorus from saline sewage with minimal sludge production. This novel process could potentially enable sustainable wastewater treatment. Yet, the core functional bacteria and their roles are unknown. Here, we used high-throughput 16S rRNA gene sequencing coupled with principal coordinates analysis and ANOVA with Tukey's test to unravel the spatiotemporal heterogeneity of functional bacteria and their synergetic and competitive interactions. We did not find any obvious spatial heterogeneity within the bacterial population in different size fractionated sludge samples, but the main functional bacteria varied significantly with operation time. Thauera was enriched (9.26~13.63%) as become the core functional genus in the DS-EBPR reactors and links denitrifying phosphorus removal to sulfide oxidation. The other two functional genera were sulfate-reducing Desulfobacter (4.31~12.85%) and nitrate-reducing and sulfide oxidizing Thiobacillus (4.79~9.92%). These bacteria cooperated in the DS-EBPR process: Desulfobacter reduced sulfate to sulfide for utilization by Thiobacillus, while Thauera and Thiobacillus competed for nitrate and sulfide as well as Thauera and Desulfobacter competed for acetate. This study is the first to unravel the interactions among core functional bacteria in DS-EBPR, thus improving our understanding of how this removal process works. PMID- 28883667 TI - NETWORK STRUCTURAL INFLUENCES ON THE ADOPTION OF EVIDENCE-BASED PREVENTION IN COMMUNITIES. AB - This study examined the impact of key variables in coalition communication networks, centralization and density, on the adoption of evidence-based substance abuse prevention. Data were drawn from a network survey and a corresponding community leader survey that measured leader attitudes and practices toward substance abuse prevention programs. Two types of coalition networks were measured: advice-seeking and discussion relations. For each community, we computed network-level measurements (n = 20), and then used multiple linear regression. Results showed that adoption outcomes were associated with a decrease in centralization for the advice network and an increase in centralization for the discussion network, controlling for density. This suggests that community coalitions might consider decreasing their network density in such a manner that distributes power and influence among a broader base of coalition members to seek advice about programs while simultaneously discussing these programs in a more concentrated group to facilitate decisions about which programs to adopt. PMID- 28883666 TI - A Statistical Framework to Evaluate Extreme Weather Definitions from A Health Perspective: A Demonstration Based on Extreme Heat Events. AB - A statistical framework for evaluating definitions of extreme weather phenomena can help weather agencies and health departments identify the definition(s) most applicable for alerts nd other preparedness operations related to extreme weather episodes. PMID- 28883668 TI - Daily physical activity of Brazilian carriers of arterial hypertension: a transversal analysis. AB - OBJECTIVE: To describe the profile of the practice of physical activity in the daily life of Brazilian adults with arterial hypertension and to analyze whether the practice performed complies with the recommendations of the World Health Organization. METHODS: Cross-sectional data were obtained from the Surveillance System of Risk Factors and Protection for Chronic Noncommunicable Diseases of 2014, involving 40,853 adults aged 18 years and over in all Brazilian capitals, interviewed by telephone survey. RESULTS: Walking, soccer and water aerobics were the main modalities of exercise and sport practiced. The weekly volume of effort led 35% of practitioners to reach the recommended goal of the World Health Organization. The low weekly frequency of activities stood out among hypertensives who did not reach the goal. CONCLUSION: Health services should clarify the need for regularity of physical activity for hypertensive individuals to benefit substantially. PMID- 28883670 TI - Medical Informatics as Academic and Scientific Discipline in Bosnia and Herzegovina - Twenty Five Years of Experiences from Faculty of Medicine, University of Sarajevo. PMID- 28883669 TI - Novel bioglasses for bone tissue repair and regeneration: Effect of glass design on sintering ability, ion release and biocompatibility. AB - Eight novel silicate, phosphate and borate glass compositions (coded as NCLx, where x = 1 to 8), containing different oxides (i.e. MgO, MnO2, Al2O3, CaF2, Fe2O3, ZnO, CuO, Cr2O3) were designed and evaluated alongside apatite wollastonite (used as comparison material), as potential biomaterials for bone tissue repair and regeneration. Glass frits of all the formulations were processed to have particle sizes under 53 MUm, with their morphology and dimensions subsequently investigated by scanning electron microscopy (SEM). In order to establish the nature of the raw glass powders, X-ray diffraction (XRD) analysis was also performed. The sintering ability of the novel materials was determined by using hot stage microscopy (HSM). Ionic release potential was assessed by inductively coupled plasma optical emission spectroscopy (ICP-OES). Finally, the cytotoxic effect of the novel glass powders was evaluated for different glass concentrations via a colorimetric assay, on which basis three formulations are considered promising biomaterials. PMID- 28883671 TI - A Three-Phase Decision Model of Computer-Aided Coding for the Iranian Classification of Health Interventions (IRCHI). AB - INTRODUCTION: Accurate coded data in the healthcare are critical. Computer Assisted Coding (CAC) is an effective tool to improve clinical coding in particular when a new classification will be developed and implemented. But determine the appropriate method for development need to consider the specifications of existing CAC systems, requirements for each type, our infrastructure and also, the classification scheme. AIM: The aim of the study was the development of a decision model for determining accurate code of each medical intervention in Iranian Classification of Health Interventions (IRCHI) that can be implemented as a suitable CAC system. METHODS: first, a sample of existing CAC systems was reviewed. Then feasibility of each one of CAC types was examined with regard to their prerequisites for their implementation. The next step, proper model was proposed according to the structure of the classification scheme and was implemented as an interactive system. RESULTS: There is a significant relationship between the level of assistance of a CAC system and integration of it with electronic medical documents. Implementation of fully automated CAC systems is impossible due to immature development of electronic medical record and problems in using language for medical documenting. So, a model was proposed to develop semi-automated CAC system based on hierarchical relationships between entities in the classification scheme and also the logic of decision making to specify the characters of code step by step through a web-based interactive user interface for CAC. It was composed of three phases to select Target, Action and Means respectively for an intervention. CONCLUSION: The proposed model was suitable the current status of clinical documentation and coding in Iran and also, the structure of new classification scheme. Our results show it was practical. However, the model needs to be evaluated in the next stage of the research. PMID- 28883672 TI - Comparison of Different Analgesic Techniques for Pain Relief During Extracorporeal Shock Wave Lithotripsy: a Double-blind, Randomized Clinical Trial. AB - BACKGROUND: Most patients experience some degree of pain during extracorporeal shock waves lithotripsy (ESWL). AIM: The aim of this study was to evaluate the effect of target-controlled infusion (TCI) of remifentanil or sufentanil and patient-controlled analgesia (PCA) with sufentanil or morphine for pain relief during ESWL. MATERIALS AND METHODS: In a double blind, randomized clinical trial, a total of 60 patients who were scheduled for elective ESWL, randomly assigned into four groups (A, B, C and D). Patients in group A and B received remifentanil and sufentanil with TCI, respectively. Also, patients in group C and D received sufentanil and morphine with PCA, respectively. All patients in four groups were assessed about the intensity of their pain with Visual Analogue Scale (VAS) in three phases; the discharge of the waves (phase A), during breaking the stones (phase B) and the end of the procedure (phase C). RESULTS: Patients in morphine PCA group experienced highest pain intensity in all stages, but patients in remifentanil TCI group experienced lowest pain intensity during lithotripsy. Remifentanil/TCI group experienced the lowest pain in B and C phases and the sufentanil/TCI group had the lowest pain only in the phase A. There was no significant difference in the occurrence of complications in all four groups. CONCLUSION: The current study demonstrates that efficacy of TCI pump in the reduction of pain during ESWL is superior to the PCA pump. Among the drugs that used in this study, remifentanil has more effective in pain management in the all phases during ESWL. We believe that using remifentanil/TCI should strongly be considered to clinicians in ESWL units. PMID- 28883673 TI - Impact of Gate 99mTc DTPA GFR, Serum Creatinine and Urea in Diagnosis of Patients with Chronic Kidney Failure. AB - AIM: The aim of this study was determination of validity of 99mTcDTPA estimation of GFR for early detection of chronic kidney failure. MATERIAL AND METHODS: There were 110 patients (54 males and 56 females) with kidney disease referred for evaluation of renal function at UCC of Kosovo. All patients were included in two groups. In the first group were included 30 patients confirmed with renal failure, whereas in the second group were included 80 patients with other renal disease. In study were included only patients with ready results of creatinine, urea and glucose in the blood serum. For estimation of GFR we have used the Gate GFR DTPA method. The statistical data processing was conducted using statistical methods such as arithmetic average, the student t-test, percentage or rate, sensitivity, specificity and accuracy of the test. RESULTS: The average age of all patients was 36 years old. The average age of female was 37 whereas of male 35. Patients with renal failure was significantly older than patients with other renal disease (p<0.005). Renal failure was found in 30 patients (27.27%). The concentration of urea and creatinine in blood serum of patients with renal failure were significantly higher than in patients with other renal disease (P< 0.00001). GFR in patients with renal failure were significantly lower than in patients with other renal disease, 51.75 ml/min (p<0.00001). Sensitivity of uremia and creatininemia for detection of renal failure were 83.33%, whereas sensitivity of 99mTcDTPA GFR was 100%. Specificity of uraemia and creatininemia were 63% whereas specificity of 99mTcDTPA GFR was 47.5%. Diagnostic accuracy of blood urea and creatinine in detecting of renal failure were 69%, whereas diagnostic accuracy of 99mTcDTPA GFR was 61.8%. CONCLUSION: Gate 99mTc DTPA scintigraphy in collaboration with biochemical tests are very sensitive methods for early detection of patients with chronic renal failure. PMID- 28883674 TI - Magnetic Resonance Imaging (MRI) and Visual Evoked Potentials (VEPs) of Occipital Region in Patients with Schizophrenia and Migraine Headache. AB - AIM: To examine the morphologic variations of occipital sulci patterns in patients with schizophrenia and migraine haeadache regarding gender and laterality as well as damage of visual pathway in patients with schizophrenia using magnetic resonance imagining (MRI) and visual evoked potentials (VEPs). METHODS: This study included 80 patients and brain scans and visual evoked potential responses recorded over the occipital cortex were performed to analyze the occipital region of both hemispheres. Average total volumes of both hemispheres and average values of amplitude of the healthy population for the comparasion were used. RESULTS: There was statistically significant difference between subjects considering gender (p=0.012). Parameters of parieto-occipital fissure (p=0.0314) showed statistically significant positive correlation with P100 amplitude (p=0.05), body of the calcarine sulcus (p=0.0213) had significant positive correlation with P100 amplitude (p=0.04), retro calcarine sulcus (p=0.0516) and P100 amplitude (p=0.03) showed statistically significant difference only of left hemisphere in male patients with schizophrenia with shallower depth of the sulcus and P100 amplitude reduction. CONCLUSION: Schizophrenia is associated with the volume changes of the occipital lobe. Comparative analysis of morphologic differences in the gray matter of occipital lobe using MRI and VEPs revealed changes especially of the left hemisphere (shallower depth of sulcus and P100 amplitude reduction) only among a group of male patients. PMID- 28883675 TI - Developing the Medication Reminder Mobile Application "Seeb". AB - INTRODUCTION: Today, the structure of comprehensive health care emphasizes self care more than therapy. Medication therapy is a strong instrument for therapy received through the health setting, especially in medication area. Error in medication administration has produced different problems and they cost billions of dollars every year. Regarding mobile phone extensions, we developed a local medication reminder mobile application called "Seeb" as a suitable solution for decreasing medication errors for Iranians. METHODS: We conducted a mixed methods study in three Phases: 1) Comparative study of existing mobile applications; 2) developed its object-oriented model; 3) Developed the initial version of "Seeb" that was approved for production. RESULTS: This application was designed for the appropriate medication administration including time and dosages through: recording patient and medication data; scheduling patients' medication; and reporting medication administration on progress. CONCLUSION: "Seeb" has been designed in compliance with Iranian health information technologists and pharmacists requirements. It is expected to reduce medication error and improve patient adherence to medical prescriptions. PMID- 28883676 TI - Exclusion of Non-English Speakers in Published Emergency Medicine Research - A Comparison of 2004 and 2014. AB - BACKGROUND: Non-English speakers (NES) as a proportion of the United States population have steadily increased in recent years. There remains substantial risk of excluding NES from research. OBJECTIVE: To assess whether the percentage of emergency medicine (EM) studies that exclude Non-English speakers from participation has changed with time. METHODS: In a structured fashion, the lead investigator analyzed all original research articles in Academic Emergency Medicine and Annals of Emergency Medicine retrospectively for 2004 and prospectively for 2014. An independent investigator conducted a blind review of a sample of articles to assess for interobserver agreement. Demographic data were analyzed using descriptive statistics. Chi-square, t-tests, and linear regression models were utilized; alpha set at 0.05. Cohen's kappa calculated to assess interrater reliability. RESULTS: We included a total of 236 original research articles. Overall, 11% excluded NES from research (10% AEM, 12% Annals). Cohen's kappa (nonweighted) was 0.73. Comparing all articles in 2004 vs. 2014, research excluded NES 6% vs. 16% of the time respectively (P=0.02). This was not statistically significant when comparing year to year for AEM (7.3% vs. 14.5%; P=0.12) and Annals (6.7% vs. 19%; P=0.06) separately. Factors affecting NES exclusion included type of study design (P<0.001), geographic area (P=0.009) and hospital type (P=0.035). Interestingly, 42% of articles failed to mention language as an exclusion or inclusion criteria. CONCLUSION: We found that the percentage of articles excluding NES from EM research increased between 2004 and 20014. Further, many investigators do not report whether NES are excluded/included in their studies. PMID- 28883677 TI - Comparison of Results of Measurement of Dimensions of the Placed Dental Implants on Cone Beam Computed Tomography with Dimensions of the Producers of the Implants. AB - INTRODUCTION: One of the most frequently used method for scanning patients with indication for dental implantation in dentistry is cone beam computed tomography. Implantation, CBCT imaging and implant programme are inevitable when planning a successful replacement of lost teeth. CBCT offers exact information about available bone and its density, adjacent tooth roots, the place of mandibular canal and maxillary sinus and adjacent anatomical structure. AIM: The goal of this study is to estimate accuracy of measurements on CBCT images ofpatients who have implants of different producers and determine if there is any statistically significant correlation between four test groups regardless of the alloy of which implants are made. MATERIAL AND METHODS: The study was a prospective-comparative, and included fifteen patients with hundred dental implants divided in four groups depending on the producer. RESULTS: Over dimensioning in the gained measurements of the whole sample on CBCT images in relation to dimensions of producers is between 0.1006mm and 0.368mm. Even though over dimensioning is measured in millimetres, it has to be taken into consideration in clinical practice when planning an implant placement, and we can recommend safety zone of 0.5mm. There have been no statistically significant differences in the gained results in over dimensioning of implants of different alloys for horizontal and vertical measurements on CBCT images of Astra Tech, Brendet titanium implants and Straumann titanium-zirconium implants. Based on the goals of the study there have been confirmed statistically significant correlations of great value (from 0.841 to 0.936) of high level of importance between manufactured value of dimensions and average dimensions values gained through CBCT imaging in four types of implants (four test groups). The total exactness of measurements on CBCT scan in this research is 96.66% for horizontal measuring and 96.92% for vertical measuring. Therefore, we can conclude that CBCT as radiological method has an unavoidable importance in planning and successful realisation of dental implant procedure. CONCLUSION: Cone Beam Computed Tomography provides exact measurements of dimensions of placed dental implant in relation to dimensions of the producers of the implant because the material from which dental implants have been made does not significantly affect the precision of the measurement. PMID- 28883678 TI - Mobile Clinical Decision Support System for Acid-base Balance Diagnosis and Treatment Recommendation. AB - INTRODUCTION: This paper presents mobile application implementing a decision support system for acid-base disorder diagnosis and treatment recommendation. MATERIAL AND METHODS: The application was developed using the official integrated development environment for the Android platform (to maximize availability and minimize investments in specialized hardware) called Android Studio. RESULTS: The application identifies disorder, based on the blood gas analysis, evaluates whether the disorder has been compensated, and based on additional input related to electrolyte imbalance, provides recommendations for treatment. CONCLUSION: The application is a tool in the hands of the user, which provides assistance during acid-base disorders treatment. The application will assist the physician in clinical practice and is focused on the treatment in intensive care. PMID- 28883679 TI - The Relationship Between Nephrolithiasis Risk with Body Fat Measured by Body Composition Analyzer in Obese People. AB - BACKGROUND: Nephrolithiasis (kidney stones) continues to be a major cause of morbidity and healthcare spending that visceral and subcutaneous adipose tissue may associate with kidney stone formation. This study aimed to investigate the relationship between nephrolithiasis with visceral fat scale in obese people in Western Iran for the first time. MATERIALS AND METHODS: In 2017, 103 participants with BMI>=30 kg/m2 were selected for the present study. The participants were divided into two groups, 52 as case group (having the kidney stone) and 58 as healthy control group (no kidney stone or history of the kidney stone or any other disease). The levels of body composition were checked by body composition analyzer (BoCA x1) based on Bio Impedance mechanism. RESULTS: Two groups were matched in terms of sex and BMI. There was a significant difference between two groups for the visceral fat to subcutaneous fat ratio (VSR) that accordingly, the mean VSR in the case group was higher than the control group. The difference for other variables between two groups was not significant. CONCLUSIONS: The results showed that visceral and subcutaneous fat and VSR were important risk factors for kidney stone formation (nephrolithiasis). Evaluating these fats in stone formers may facilitate a tailored metabolic evaluation and treatment plan. PMID- 28883680 TI - Health ATMs in Saudi Arabia: A Perspective. AB - BACKGROUND: Health ATMs are terminals which are connected to a centrally located database storing patients' electronic healthcare records (EHR). These machines are capable of collecting information in a far superior fashion than humans and are also able to rectify obsolete data in a manner that humans are generally not inclined to. OBJECTIVES: The main goal of this study is to assess the importance of adopting health ATMs in the Kingdom of Saudi Arabia (KSA), which can improve the confidence of patients, reward health self-management, and achieve positive health outcomes through their easy-to-use applications that are secure and accessible through various devices. METHODS: Strength, Weakness, Opportunity, and Threat (SWOT) analysis was used to assess the efficiency of adopting health ATMs in KSA and reveal the said characteristics. Three focus groups assembled in the cities of Riyadh, Jeddah and Dammam during the period 2013-2014. The groups consisted of individuals experienced in the function of health ATMs. RESULTS: It was found that the sector possessed a number of strengths that would help it in reaching the goals outlined therein, thereby achieving successful outcomes. CONCLUSIONS: Health ATMs could be a promising new advancement in the field of health if the project were to be planned and implemented correctly. Their benefits would consequently reach organizational and national levels. It is, therefore, crucial to educate the project managers about the benefits of learning from others as well as educating them about the needs and the requirements of the concerned organization. PMID- 28883681 TI - Occupational Disease Registries-Characteristics and Experiences. AB - INTRODUCTION: Due to growth of occupational diseases and also increase of public awareness about their consequences, attention to various aspects of diseases and improve occupational health and safety has found great importance. Therefore, there is the need for appropriate information management tools such as registries in order to recognitions of diseases patterns and then making decision about prevention, early detection and treatment of them. These registries have different characteristics in various countries according to their occupational health priorities. AIM: Aim of this study is evaluate dimensions of occupational diseases registries including objectives, data sources, responsible institutions, minimum data set, classification systems and process of registration in different countries. MATERIAL AND METHODS: In this study, the papers were searched using the MEDLINE (PubMed) Google scholar, Scopus, ProQuest and Google. The search was done based on keyword in English for all motor engines including "occupational disease", "work related disease", "surveillance", "reporting", "registration system" and "registry" combined with name of the countries including all subheadings. After categorizing search findings in tables, results were compared with each other. RESULTS: Important aspects of the registries studied in ten countries including Finland, France, United Kingdom, Australia, Czech Republic, Malaysia, United States, Singapore, Russia and Turkey. The results show that surveyed countries have statistical, treatment and prevention objectives. Data sources in almost the rest of registries were physicians and employers. The minimum data sets in most of them consist of information about patient, disease, occupation and employer. Some of countries have special occupational related classification systems for themselves and some of them apply international classification systems such as ICD-10. Finally, the process of registration system was different in countries. CONCLUSION: Because occupational diseases are often preventable, but not curable, it is necessary to all countries, to consider prevention and early detection of occupational diseases as the objectives of their registry systems. Also it is recommended that all countries reach an agreement about global characteristics of occupational disease registries. This enables country to compare their data at international levels. PMID- 28883683 TI - The Most Influential Scientist in the Development of Medical informatics (17): Eugene Garfield. PMID- 28883682 TI - Role of MRI in Diagnosis of Ruptured Intracranial Dermoid Cyst. AB - INTRODUCTION: Intracranial dermoid cystic tumors account for <1% of all intracranial masses. CASE REPORT: A 52-year-old male, having headaches, nausea and is presented with a history of 2 episodes of new onset seizures. On presentation, the patient had a normal physical exam, including a complete neurological and cranial nerve exam. METHODS: Precontrast MRI; TSE/T2Wsequence in axial/coronal planes; 3D - HI-resolution T1W sagittal; FLAIR/T2W axial; FLAIR/T2W, Flash/T2W oblique coronal plane, GRE/T2W axial. Post-contrast TSE/T1W sequence in axial, coronal and sagittal planes. Diffusion weighted and ADC mapping, postcontrast: TSE/T1W sequence in axial, coronal and sagittal planes. RESULTS: Subsequent MRI of the brain revealed an oval and lobulated 47x34x30mm (TRxAPxCC) non-enhancing T1-hyperintense mass in right cavernous sinus, with compression of surrounding mesial temporal lobe and right anterolateral aspect of mesencephalon. Findings are consistent with ruptured dermoid cyst, given the evacuated sebum content at its lower half. Sebum particles in millimetric sizes are seen within right Sylvian fissure, anterior horns of lateral ventricles and to a lesser extent within left Sylvian fissure, right parietal sulci, cerebral aqueduct, and basal cisterns. No restricted diffusion is seen, eliminating the possibility of epidermoid. A shunt catheter is evident traversing between right lateral ventricle and right parietal bone; besides, slit-like right lateral ventricle is noted (likely secondary to over-draining shunt catheter). CONCLUSION: Intracranial dermoid cysts are benign rare slow-growing tumors that upon rupture, however, widespread presence of T1 hyperintense droplets and leptomeningeal enhancement can be noted-making MRI the best imaging modality for diagnosis of this rare entity. PMID- 28883684 TI - Morphological study of the antennal sensilla in Gerromorpha (Insecta: Hemiptera: Heteroptera). AB - The external morphology and distribution of the antennal sensilla of 21 species from five families of semiaquatic bugs (Gerromorpha) were examined using scanning electron microscopy. Nine main types were distinguished based on their morphological structure: sensilla trichoidea, sensilla chaetica, sensilla leaflike, sensilla campaniformia, sensilla coeloconica, sensilla ampullacea, sensilla basiconica, sensilla placoidea and sensilla bell-mouthed. The specific morphological structure of one type of sensilla (bell-mouthed sensilla) was observed only in Aquarius paludum. Several subtypes of sensilla are described, differentiated by number, location and type of sensillum characteristic for each examined taxon. The present study provides new data about the morphology and distribution of the antennal sensilla in Gerromorpha. PMID- 28883685 TI - The forewing of the Aphis fabae (Scopoli 1763) (Hemiptera, Sternorrhyncha): a morphological and histological study. AB - Dorsal and ventral sides of the forewing of Aphis fabae (Scopoli 1763) (Sternorrhyncha, Hemiptera) were examined by scanning electron microscopy. Reinforcement elements on their surface as well as scale-like elements were described. Using histological methods, cross-sections of the material were done. They showed a two-layered membrane with a circular foramen inside. The course of veins and places of their bifurcation were followed. Common stem of radius (R), media (M), and cubitus anterior (CuA) veins were composed of separate tracheae, which ran separately at the beginning, then continued in a single tunnel, and finally disappeared. Nerves were not observed. Neither were tracheae visible on the further course of those veins. The presence of a devoid-of-trachea costal vein was confirmed. Under scanning electron microscope, convex reinforcements on dorsal side of the wing turned out to be more sclerotized parts of chitin, not giving a zigzag-like profile of the wing on sections. In this paper, we show for the first time a cross-section of a very delicate wing of an aphid representative. PMID- 28883686 TI - Principles of Experimental Design for Big Data Analysis. AB - Big Datasets are endemic, but are often notoriously difficult to analyse because of their size, heterogeneity and quality. The purpose of this paper is to open a discourse on the potential for modern decision theoretic optimal experimental design methods, which by their very nature have traditionally been applied prospectively, to improve the analysis of Big Data through retrospective designed sampling in order to answer particular questions of interest. By appealing to a range of examples, it is suggested that this perspective on Big Data modelling and analysis has the potential for wide generality and advantageous inferential and computational properties. We highlight current hurdles and open research questions surrounding efficient computational optimisation in using retrospective designs, and in part this paper is a call to the optimisation and experimental design communities to work together in the field of Big Data analysis. PMID- 28883687 TI - Experimental Porcine Toxoplasma gondii Infection as a Representative Model for Human Toxoplasmosis. AB - Porcine infections are currently not the state-of-the-art model to study human diseases. Nevertheless, the course of human and porcine toxoplasmosis is much more comparable than that of human and murine toxoplasmosis. For example, severity of infection, transplacental transmission, and interferon-gamma-induced antiparasitic effector mechanisms are similar in pigs and humans. In addition, the severe immunosuppression during acute infection described in mice does not occur in the experimentally infected ones. Thus, we hypothesise that porcine Toxoplasma gondii infection data are more representative for human toxoplasmosis. We therefore suggest that the animal model chosen must be critically evaluated for its assignability to human diseases. PMID- 28883689 TI - Lateral column lengthening for adolescent idiopathic pes planovalgus deformity - Systematic review. AB - : Pes planovalgus is the commonest foot deformity in children and presents with wide range of severity and symptoms. Surgery is mostly indicated for significant malalignment, resistant to non-surgical management. Lateral column lengthening is considered an appealing option as does not involve arthrodesis and allows for further growth and foot development. METHODS: We conducted a systematic review on lateral column lengthening for pes planovalgus deformity in line with PRISMA-P Checklist. We carried out detailed literature search on PubMed, Cochrane, EMBASE, CINAHL, Google Scholar and Bibliographies. We analysed selected studies for patient demographics, radiological, clinical outcome and complications. RESULTS: We identified seven studies with 103 patients involving 156 feet. The mean age was 13.3 years (Range 5.7-42) and mean follow up was 70.2 Months (Range 24.9 156). There was statistical significant improvement in Calcaneal pitch, Lateral Talo-metatarsal and AP Talo-navicular angles (p-value 0.001). The mean preoperative AOFAS Score (71 Feet) was 58.85 (Range 34-78) and mean postoperative AOFAS Score (91 Feet) was 92.25 (Range 73-100). Two studies (32 Feet) used author specified criteria has reported Good/Excellent result in 72% (23/32 feet) and Fair/Poor result in 18% (9/32) feet. Complications were reported in 17.5% (18/103) included nerve related, pseudo arthrosis, non-union and metal related complications. CONCLUSION: Surgical intervention with lateral column lengthening has good radiological and clinical outcome with high patient satisfaction and acceptable complications. The literature is mostly retrospective and there is need for prospective, multi-centre studies using patient centred validated outcome measure. PMID- 28883688 TI - A Controversial Medicolegal Issue: Timing the Onset of Perinatal Hypoxic-Ischemic Brain Injury. AB - Perinatal hypoxic-ischemic brain injury, as a result of chronic, subacute, and acute insults, represents the pathological consequence of fetal distress and birth or perinatal asphyxia, that is, "nonreassuring fetal status." Hypoxic ischemic injury (HII) is typically characterized by an early phase of damage, followed by a delayed inflammatory local response, in an apoptosis-necrosis continuum. In the early phase, the cytotoxic edema and eventual acute lysis take place; with reperfusion, additional damage should be assigned to excitotoxicity and oxidative stress. Finally, a later phase involves all the inflammatory activity and long-term neural tissue repairing and remodeling. In this model mechanism, loss of mitochondrial function is supposed to be the hallmark of secondary injury progression, and autophagy which is lysosome-mediated play a role in enhancing brain injury. Early-induced molecules driven by hypoxia, as chaperonins HSPs and ORP150, besides common markers for inflammatory responses, have predictive value in timing the onset of neonatal HII; on the other hand, clinical biomarkers for HII diagnosis, as CK-BB, LDH, S-100beta, and NSE, could be useful to predict outcomes. PMID- 28883690 TI - Direct-acting antiviral agents against hepatitis C virus and lipid metabolism. AB - Hepatitis C virus (HCV) infection induces steatosis and is accompanied by multiple metabolic alterations including hyperuricemia, reversible hypocholesterolemia and insulin resistance. Total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when a sustained virologic response (SVR) is achieved in patients with HCV. Steatosis is significantly more common in patients with HCV genotype 3 but interferon-free regimens are not always effective for treating HCV genotype 3 infections. HCV infection increases fatty acid synthase levels, resulting in the accumulation of fatty acids in hepatocytes. Of note, low density lipoprotein receptor, scavenger receptor class B type I and Niemann-Pick C1-like 1 proteins are candidate receptors that may be involved in HCV. They are also required for the uptake of cholesterol from the external environment of hepatocytes. Among HCV-infected patients with or without human immunodeficiency virus infection, changes in serum lipid profiles are observed during interferon free treatment and after the achievement of an SVR. It is evident that HCV affects cholesterol metabolism during interferon-free regimens. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes including hyperlipidemia. PMID- 28883692 TI - Fluctuation of zonulin levels in blood vs stability of antibodies. AB - AIM: To evaluate the measurement of zonulin level and antibodies of zonulin and other tight junction proteins in the blood of controls and celiac disease patients. METHODS: This study was conducted to assess the variability or stability of zonulin levels vs IgA and IgG antibodies against zonulin in blood samples from 18 controls at 0, 6, 24 and 30 h after blood draw. We also measured zonulin level as well as zonulin, occludin, vinculin, aquaporin 4 and glial fibrillary acidic protein antibodies in the sera of 30 patients with celiac disease and 30 controls using enzyme-linked immunosorbent assay methodology. RESULTS: The serum zonulin level in 6 out of 18 subjects was low or < 2.8 ng/mL and was very close to the detection limit of the assay. The other 12 subjects had zonulin levels of > 2.8 ng/mL and showed significant fluctuation from sample to sample. Comparatively, zonulin antibody measured in all samples was highly stable and reproducible from sample to sample. Celiac disease patients showed zonulin levels with a mean of 8.5 ng/mL compared to 3.7 ng/mL in controls (P < 0.0001). Elevation of zonulin level at 2SD above the mean was demonstrated in 37% of celiac disease patients, while antibodies against zonulin, occludin and other tight junction proteins was detected in up to 86% of patients with celiac disease. CONCLUSION: Due to its fluctuation, a single measurement of zonulin level is not recommended for assessment of intestinal barrier integrity. Measurement of IgG and IgA antibodies against zonulin, occludin, and other tight junction proteins is proposed for the evaluation of the loss of intestinal barrier integrity. PMID- 28883691 TI - Liquid biopsy in patients with hepatocellular carcinoma: Circulating tumor cells and cell-free nucleic acids. AB - Hepatocellular carcinoma (HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor. Therefore, to provide optimal treatment for each patient with HCC, more precise and effective biomarkers are urgently needed which could facilitate a more detailed individualized decision-making during HCC treatment, including the following; risk assessment, early cancer detection, prediction of treatment or prognostic outcome. In the blood of cancer patients, accumulating evidence about circulating tumor cells and cell-free nucleic acids has suggested their potent clinical utilities as novel biomarker. This concept, so-called "liquid biopsy" is widely known as an alternative approach to cancer tissue biopsy. This method might facilitate a more sensitive diagnosis and better decision-making by obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. In this article, we review recent developments based on the available literature on both circulating tumor cells and cell-free nucleic acids in cancer patients, especially focusing on Hepatocellular carcinoma. PMID- 28883693 TI - Effects of albumin/glutaraldehyde glue on healing of colonic anastomosis in rats. AB - AIM: To evaluate the effect of local surgical adhesive glue (albumin/glutaraldehyde-Bioglue) on the healing of colonic anastomoses in rats. METHODS: Forty Albino-Wistar male rats were randomly divided into two groups, with two subgroups of ten animals each. In the control group, an end-to-end colonic anastomosis was performed after segmental resection. In the Bioglue group, the anastomosis was protected with extraluminar application of adhesive glue containing albumin and glutaraldehyde. Half of the rats were sacrificed on the fourth and the rest on the eighth postoperative day. Anastomoses were resected and macroscopically examined. Bursting pressures were calculated and histological features were graded. Other parameters of healing, such as hydroxyproline and collagenase concentrations, were evaluated. The experimental data were summarized and computed from the results of a one-way ANOVA. Fisher's exact test was applied to compare percentages. RESULTS: Bursting pressures, adhesion formation, inflammatory cell infiltration, and collagen deposition were significantly higher on the fourth postoperative day in the albumin/glutaraldehyde group than in the control group. Furthermore, albumin/glutaraldehyde significantly increased adhesion formation, inflammatory cell infiltration, neoangiogenesis, and collagen deposition on the eighth postoperative day. There was no difference in fibroblast activity or hydroxyproline and collagenase concentrations. CONCLUSION: Albumin/glutaraldehyde, when applied on colonic anastomoses, promotes their healing in rats. Therefore, the application of protective local agents in colonic anastomoses leads to better outcomes. PMID- 28883694 TI - Cytoplasmic domain of tissue factor promotes liver fibrosis in mice. AB - AIM: To evaluate the role of tissue factor (TF) and protease activated receptor (PAR)-2 in liver fibrosis. METHODS: Using CCl4 administration for eight weeks, we induced hepatic fibrosis in wild-type C57BL/6 mice and in mice with deletion of the cytoplasmic signalling domain of TF (TFSCT/SCT), deletion of PAR-2 (PAR-2-/-) and combined deletion of TF signalling domain and PAR-2 (TFSCT/SCT/PAR-2-/-). Hepatic fibrosis area was assessed by quantitative imaging of picrosirius red staining. Hepatic collagen content was assessed by hydroxyproline levels. Hepatic stellate cells (alphaSMA positive) and hepatic macrophages (CD68 positive) were identified by immunohistochemistry. Hepatic gene expression was determined by PCR and liver TGFbeta1 content by ELISA. RESULTS: CCl4 treated mice with deletion of the PAR-2 gene (PAR-2-/-) and the cytoplasmic domain of TF (TFSCT/SCT) developed significantly less hepatic fibrosis, characterised by reduced liver fibrosis area and hydroxyproline content, compared to control wildtype mice treated with CCl4. The observed reduction in histological fibrosis was accompanied by a significant decrease in the hepatic content of TGFbeta, the prototypic fibrogenic cytokine, as well as fewer activated hepatic stellate cells and hepatic macrophages. Deletion of the TF cytoplasmic signalling domain reduced hepatic fibrosis to levels similar to those observed in mice lacking PAR-2 signalling but combined deletion provided no added protection against fibrosis indicating a lack of mutual modulating effects that have been observed in other contexts such as angiogenic responses. CONCLUSION: Tissue factor cytoplasmic domain is involved in TF-PAR-2 signalling initiating hepatic fibrosis and is a potential therapeutic target, as its deletion would not impact coagulation. PMID- 28883695 TI - Schistosoma japonicum attenuates dextran sodium sulfate-induced colitis in mice via reduction of endoplasmic reticulum stress. AB - AIM: To elucidate the impact of Schistosoma (S.) japonicum infection on inflammatory bowel disease by studying the effects of exposure to S. japonicum cercariae on dextran sodium sulfate (DSS)-induced colitis. METHODS: Infection was percutaneously established with 20 +/- 2 cercariae of S. japonicum, and colitis was induced by administration of 3% DSS at 4 wk post infection. Weight change, colon length, histological score (HS) and disease activity index (DAI) were evaluated. Inflammatory cytokines, such as IL-2, IL-10 and IFN-gamma, were tested by a cytometric bead array and real-time quantitative polymerase chain reaction (RT-PCR). Protein and mRNA levels of IRE1alpha, IRE1beta, GRP78, CHOP, P65, P P65, P-IkappaBalpha and IkappaBalpha in colon tissues were examined by Western blot and RT-PCR, respectively. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells, cleaved-caspase 3 expression and Bcl2/Bax were investigated to assess the apoptosis in colon tissues. RESULTS: Mice infected with S. japonicum cercariae were less susceptible to DSS. Mice infected with S. japonicum cercariae and treated with DSS showed decreased weight loss, longer colon, and lower HS and DAI compared with mice treated with DSS alone. A substantial decrease in Th1/Th2/Th17 response was observed after infection with S. japonicum. Endoplasmic reticulum (ER) stress and the nuclear factor-kappa B (NF-kappaB) pathway were reduced in mice infected with S. japonicum cercariae and treated with DSS, along with ameliorated celluar apoptosis, in contrast to mice treated with DSS alone. CONCLUSION: Exposure to S. japonicum attenuated inflammatory response in a DSS-induced colitis model. In addition to the Th1/Th2/Th17 pathway and NF-kappaB pathway, ER stress was shown to be involved in mitigating inflammation and decreasing apoptosis. Thus, ER stress is a new aspect in elucidating the relationship between helminth infection and inflammatory bowel disease (IBD), which may offer new therapeutic methods for IBD. PMID- 28883696 TI - Metabolomic profiling for identification of metabolites and relevant pathways for taurine in hepatic stellate cells. AB - AIM: To develop a reliable and simple method to identify important biological metabolites and relevant pathways for taurine in hepatic stellate cells (HSCs), in order to provide more data for taurine therapy. METHODS: All the biological samples were analyzed by using high-performance liquid chromatography-time electrospray ionization/quadrupole-time of flight mass spectrometry. Principal component analysis and partial least squares discriminant analysis were used to identify statistically different metabolites for taurine in HSCs, and metabolomic pathway analysis was used to do pathway analysis for taurine in HSCs. The chemical structure of the related metabolites and pathways was identified by comparing the m/z ratio and ion mode with the data obtained from free online databases. RESULTS: A total of 32 significant differential endogenous metabolites were identified, which may be related to the mechanism of action of taurine in HSCs. Among the seven relevant pathways identified, sphingolipid metabolism pathway, glutathione metabolism pathway and thiamine metabolism pathway were found to be the most important metabolic pathways for taurine in HSCs. CONCLUSION: This study showed that there were distinct changes in biological metabolites of taurine in HSCs and three differential metabolic pathways including sphingolipid pathway, glutathione pathway and thiamine metabolism pathway might be of key importance in mediating the mechanism of action of taurine in HSCs. PMID- 28883697 TI - Protective effects of Foeniculum vulgare root bark extract against carbon tetrachloride-induced hepatic fibrosis in mice. AB - AIM: To investigate the protective effects of Foeniculum vulgare root bark (FVRB), a traditional Uyghur medicine, against carbon tetrachloride (CCl4) induced hepatic fibrosis in mice. METHODS: Mice were randomly divided into eight groups (n = 20 each). Except for the normal control group, mice in the rest groups were intraperitoneally injected (i.p.) with 0.1% CCl4-olive oil mixture at 10 mL/kg twice a week to induce liver fibrosis. After 4 wk, mice were treated concurrently with the 70% ethanol extract of FVRB (88, 176, 352 and 704 mg/kg, respectively) daily by oral gavage for 4 wk to evaluate its protective effects. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), hexadecenoic acid (HA), laminin (LN), glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) in liver tissues were measured. Hematoxylin-eosin (H and E) staining and Masson trichrome (MT) staining were performed to assess histopathological changes in the liver. The expression of transforming growth factor beta1 (TGF-beta1), matrix metalloprotein 9 (MMP-9) and metallopeptidase inhibitor 1 (TIMP-1) was detected by immunohistochemical analysis. Additionally, TGF-beta1 and alpha-smooth muscle actin (alpha-SMA) protein expression was measured by Western blot. RESULTS: A significant reduction in serum levels of AST, ALT, TG, HA and LN was observed in the FVRB-treated groups, suggesting that FVRB displayed hepatoprotective effects. Also, the depletion of GSH, SOD, and MDA accumulation in liver tissues was suppressed by FVRB. The expression of TGF-beta1, MMP-9 and TIMP-1 determined by immunohistochemistry was markedly reduced in a dose-dependent manner by FVRB treatment. Furthermore, protective effects of FVRB against CCl4-induced liver injury were confirmed by histopathological studies. Protein expression of TGF beta1 and alpha-SMA detected by Western blot was decreased by FVRB treatment. CONCLUSION: Our results indicate that FVRB may be a promising agent against hepatic fibrosis and its possible mechanisms are inhibiting lipid peroxidation and reducing collagen formation in liver tissue of liver fibrosis mice. PMID- 28883698 TI - Hypothesized summative anal physiology score correlates but poorly predicts incontinence severity. AB - AIM: To explore the relationship between such a construct and an existing continence score. METHODS: A retrospective study of incontinent patients who underwent anal physiology (AP) was performed. AP results and Cleveland Clinic Continence Scores (CCCS) were extracted. An anal physiology score (APS) was developed using maximum resting pressures (MRP), anal canal length (ACL), internal and external sphincter defects and pudendal terminal motor latency. Univariate associations between each variable, APS and CCCS were assessed. Multiple regression analyses were performed. RESULTS: Of 508 (419 women) patients, 311 had both APS and CCCS measured. Average MRP was 51 mmHg (SD 23.2 mmHg) for men and 39 mmHg (19.2 mmHg) for women. Functional ACL was 1.7 cm for men and 0.7 cm for women. Univariate analyses demonstrated significant associations between CCCS and MRP (P = 0.0002), ACL (P = 0.0006) and pudendal neuropathy (P < 0.0001). The association between APS and CCCS was significant (P < 0.0001) but accounted for only 9.2% of the variability in CCCS. Multiple regression showed that the variables most useful in predicting CCCS were external sphincter defect, pudendal neuropathy and previous pelvic surgery, but only improving the scores predictive ability to 12.5%. CONCLUSION: This study shows that the ability of AP tests to predict continence scores improves when considered collectively, but that a constructed summation model before and after multiple regression is poor at predicting the variability in continence scores. PMID- 28883699 TI - Minor endoscopic sphincterotomy followed by large balloon dilation for large choledocholith treatment. AB - AIM: To evaluate early and late outcomes of endoscopic papillary large balloon dilation (EPLBD) with minor endoscopic sphincterotomy (mEST) for stone removal. METHODS: A total of 149 consecutive patients with difficult common bile duct (CBD) stones (diameter >= 10 mm or >= 3 stones) underwent conventional endoscopic sphincterotomy (EST) or mEST plus EPLBD from May 2012 to April 2016. Their demographic, laboratory and procedural data were collected, and pancreaticobiliary complications were recorded. RESULTS: Sixty-nine (94.5%) of the patients in the EPLBD + mEST group and 64 (84.2%) in the conventional EST group achieved stone clearance following the first session (P = 0.0421). The procedure time for EPLBD + mEST was shorter than for EST alone (42.1 +/- 13.6 min vs 47.3 +/- 11.8 min, P = 0.0128). The overall rate of early complications in the EPLBD + mEST group (11%) was lower than in the EST group (21.1%); however, the difference was not significant (P = 0.0938). The cumulative recurrence rate of cholangitis and CBD stones between the two groups was also similar. The procedure time was independently associated with post-endoscopic retrograde cholangiopancreatography pancreatitis (OR = 6.374, 95%CI: 1.193-22.624, P = 0.023), CBD stone diameter >= 16 mm (OR = 7.463, 95%CI: 2.705-21.246, P = 0.0452) and use of mechanical lithotripsy (OR = 9.913, 95%CI: 3.446-23.154, P = 0.0133) were independent risk factors for stone recurrence. CONCLUSION: EPLBD with mEST is more effective than EST alone for difficult CBD stone removal, with shorter procedure time and fewer early complications. PMID- 28883701 TI - Accuracy of endoscopic ultrasound-guided tissue acquisition in the evaluation of lymph nodes enlargement in the absence of on-site pathologist. AB - AIM: To evaluate factors that influence the diagnostic accuracy of endoscopic ultrasound (EUS)-guided tissue acquisition for lymph node enlargement in the absence of an on-site pathologist. METHODS: A retrospective analysis of patients who underwent EUS-guided tissue acquisition for the pathological diagnosis of lymph node enlargement between April 2012 and June 2015 is reported. Tissue acquisition was performed with both cytology and biopsy needles of different calibers. The variables evaluated were lymph node location and size, number of passes and type of needle used. Final diagnosis was based on surgical histopathology or, in non-operated cases, on EUS-guided tissue acquisition and imaging assessment with a minimum clinical follow-up of 6 mo. RESULTS: During the study period, 168 lymph nodes with a median size of 20.3 mm (range 12.5-27) were sampled from 152 patients. Ninety lymph nodes (53.6%) were located at mediastinum, and 105 (62.5%) were acquired with biopsy needles. The final diagnosis was benign/reactive origin in 87 cases (51.8%), malignant in 65 cases (38.7%), and lymphoma in 16 cases (9.5%). The sensitivity, specificity, positive predictive value and negative predictive value for the detection of malignancy were 74.1%, 100%, 100% and 80.6%, respectively. The overall accuracy was 87.5% (95%CI: 81.7-91.7). No variables were independently associated with a correct final diagnosis according to the multivariate analysis. CONCLUSION: EUS-guided tissue acquisition is a highly accurate technique for assessing lymph node enlargement. None of the variables evaluated were associated with diagnostic accuracy. PMID- 28883700 TI - Diagnostic value of FIB-4, aspartate aminotransferase-to-platelet ratio index and liver stiffness measurement in hepatitis B virus-infected patients with persistently normal alanine aminotransferase. AB - AIM: To assess the diagnostic value of FIB-4, aspartate aminotransferase-to platelet ratio index (APRI), and liver stiffness measurement (LSM) in patients with hepatitis B virus infection who have persistently normal alanine transaminase (PNALT). METHODS: We enrolled 245 patients with chronic hepatitis B: 95 in PNALT group, 86 in intermittently elevated alanine transaminase (PIALT1) group [alanine transaminase (ALT) within 1-2 * upper limit of normal value (ULN)], and 64 in PIALT2 group (ALT > 2 * ULN). All the patients received a percutaneous liver biopsy guided by ultrasonography. LSM, biochemical tests, and complete blood cell counts were performed. RESULTS: The pathological examination revealed moderate inflammatory necrosis ratios of 16.81% (16/95), 32.56% (28/86), and 45.31% (28/64), and moderate liver fibrosis of 24.2% (23/95), 33.72% (29/86), and 43.75% (28/64) in the PNALT, PIALT1, and PIALT2 groups, respectively. The degrees of inflammation and liver fibrosis were significantly higher in the PIALT groups than in the PNALT group (P < 0.05). No significant difference was found in the areas under the curve (AUCs) between APRI and FIB-4 in the PNALT group; however, significant differences were found between APRI and LSM, and between FIB 4 and LSM in the PNALT group (P < 0.05 for both). In the PIALT1 and PIALT2 groups, no significant difference (P > 0.05) was found in AUCs for all comparisons (P > 0.05 for all). In the overall patients, a significant difference in the AUCs was found only between LSM and APRI (P < 0.05). CONCLUSION: APRI and FIB-4 are not the ideal noninvasive hepatic fibrosis markers for PNALT patients. LSM is superior to APRI and FIB-4 in PNALT patients because of the influence of liver inflammation and necrosis. PMID- 28883702 TI - Doublecortin and CaM kinase-like-1 as an independent prognostic factor in patients with resected pancreatic carcinoma. AB - AIM: To elucidate the effect of expression of doublecortin and CaM kinase-like-1 (DCLK1) in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Tumor specimens were obtained from 136 patients with pancreatic cancer who had undergone resection without preoperative therapy between January 2000 and December 2013 at the Department of Surgical Oncology, Osaka City University. The resected specimens were analyzed for associations with clinicopathological data, including DCLK1 expression, epithelial mesenchymal transition (EMT) marker expression, and cancer stem cell (CSC) marker expression. Univariate and multivariate survival analyses were performed and we assessed the association between DCLK1 expression and clinicopathological factors, including the EMT marker and CSC marker. RESULTS: In total, 48.5% (66/136) of the pancreatic cancer samples were positive for DCLK1. Patients with DCLK1-positive tumors had significantly shorter survival times than those with DCLK1-negative tumors (median, 18.7 mo vs 49.5 mo, respectively; P < 0.0001). Positive DCLK1 expression correlated with histological grade (P = 0.0290), preoperative CA19-9 level (P = 0.0060), epithelial cell adhesion molecule (EpCAM) expression (P = 0.0235), and the triple-positive expression of CD44/CD24/EpCAM (P = 0.0139). On univariate survival analysis, five factors were significantly associated with worse overall survival: histological grade of G2 to G4 (P = 0.0091), high preoperative serum SPan-1 level (P = 0.0034), R1/2 (P < 0.0001), positive expression of DCLK1 (P < 0.0001) or CD44 (P = 0.0245). On multivariate survival analysis, R1/2 [odds ratio (OR) = 2.019, 95% confidence interval (CI): 1.380-2.933; P = 0.0004] and positive DCLK1 expression (OR = 1.848, 95%CI: 1.2854-2.661; P = 0.0009) were independent prognostic factors. CONCLUSION: DCLK1 expression was found to be an independent prognostic factor and it may play a crucial prognostic role by promoting acquisition of stemness. PMID- 28883703 TI - Study to determine guidelines for pediatric colonoscopy. AB - AIM: To investigated characteristics, diagnosis, bowel-cleansing preparation, sedation, and colonoscope length and diameter in Japanese pediatric patients receiving total colonoscopy. METHODS: The present study evaluated consecutive patients aged <= 15 years who had undergone their first colonoscopy in Kurume University between January 2007 and February 2015. Data were retrospectively analyzed. We identified 110 pediatric patients who had undergone colonoscopy that had reached the cecum, allowing the observation of the total colon. RESULTS: Hematochezia, abdominal pain, and diarrhea were the most common symptoms. For bowel-cleansing preparation, pediatric patients aged <= 12 years were treated with magnesium citrate, and patients aged 13-15 years were treated with polyethylene glycol 4000. For sedation, thiamylal with pentazocine, which has an analgesic effect, was used in patients aged <= 6 years, and midazolam with pentazocine was used in patients aged >= 7 years. Regarding the choice of endoscope, short and thin endoscopes were selected for younger patients, particularly patients aged <= 3 years. Positive diagnoses were made in 78 patients (70.9%). Inflammatory bowel disease (n = 49, 44.5%), including ulcerative colitis (n = 37, 33.6%) and Crohn's disease (n = 12, 10.9%), was the most common diagnosis. CONCLUSION: Colonoscopy offers a high diagnostic capability for pediatric patients with gastrointestinal symptoms. The selection of appropriate management the performance of colonoscopy is important in pediatric patients. PMID- 28883704 TI - Postoperative changes of manometry after restorative proctocolectomy in Korean ulcerative colitis patients. AB - AIM: To investigate the changes of postoperative anal sphincter function and bowel frequency in Korean patients with ulcerative colitis (UC). METHODS: A total of 127 patients with UC who underwent restorative proctocolectomy (RPC) during 20 years were retrospectively analyzed. The parameters of anal manometry and bowel frequency were compared according to the 6-mo intervals until 24 mo postoperatively. Manometry was used to measure the maximal squeezing pressure (MSP) and maximal resting pressure (MRP). RESULTS: MSP decreased after surgery until 6 mo (157 to 142 mmHg); thereafter, it improved and was recovered to and maintained at the preoperative value at 12 mo postoperatively (142-170 mmHg, P < 0.001). Although the decreased MRP (65 to 56 mmHg) improved after 18 mo (62 mmHg), it did not completely recover to the preoperative value. The decreased rectal capacity after surgery (90 to 82 mL) gradually increased up to 150 mL at 24 mo. Although bowel frequency showed significant gradual decreases at each interval, it was stabilized after 12 mo postoperatively (6.5 times/d). CONCLUSION: Postoperative changes of manometry and bowel frequency after restorative proctocolectomy in Korean patients with UC were not different from those in Western patients with UC. PMID- 28883705 TI - Threonine and tyrosine kinase may serve as a prognostic biomarker for gallbladder cancer. AB - AIM: To detect the expression of threonine and tyrosine kinase (TTK) in gallbladder cancer (GBC) specimens and analyze the associations between TTK expression and clinicopathological parameters and clinical prognosis. METHODS: A total of 68 patients with GBC who underwent surgical resection were enrolled in this study. The expression of TTK in GBC tissues was detected by immunohistochemistry. The assessment of TTK expression was conducted using the H scoring system. H-score was calculated by the multiplication of the overall staining intensity with the percentage of positive cells. The expression of TTK in the cytoplasm and nucleus was scored separately to achieve respective H-score values. The correlations between TTK expression and clinicopathological parameters and clinical prognosis were analyzed using Chi-square test, Kaplan Meier method and Cox regression. RESULTS: In both the nucleus and cytoplasm, the expression of TTK in tumor tissues was significantly lower than that in normal tissues (P < 0.001 and P = 0.026, respectively). Using the median H-score as the cutoff value, it was discovered that, GBC patients with higher levels of TTK expression in the nucleus, but not the cytoplasm, had favorable overall survival (P < 0.001), and it was still statistically meaningful in Cox regression analysis. Further investigation indicated that there were close negative correlations between TTK expression and tumor differentiation (P = 0.041), CA 19 9 levels (P = 0.016), T stage (P < 0.001), nodal involvement (P < 0.001), distant metastasis (P = 0.024) and TNM stage (P < 0.001). CONCLUSION: The expression of TTK in GBC is lower than that in normal tissues. Higher levels of TTK expression in GBC are concomitant with longer overall survival. TTK is a favorable prognostic biomarker for patients with GBC. PMID- 28883706 TI - Simple instruments facilitating achievement of transanal total mesorectal excision in male patients. AB - AIM: To assess the efficacy of a modified approach with transanal total mesorectal excision (taTME) using simple customized instruments in male patients with low rectal cancer. METHODS: A total of 115 male patients with low rectal cancer from December 2006 to August 2015 were retrospectively studied. All patients had a bulky tumor (tumor diameter >= 40 mm). Forty-one patients (group A) underwent a classical approach of transabdominal total mesorectal excision (TME) and transanal intersphincteric resection (ISR), and the other 74 patients (group B) underwent a modified approach with transabdominal TME, transanal ISR, and taTME. Some simple instruments including modified retractors and an anal dilator with a papilionaceous fixture were used to perform taTME. The operative time, quality of mesorectal excision, circumferential resection margin, local recurrence, and postoperative survival were evaluated. RESULTS: All 115 patients had successful sphincter preservation. The operative time in group B (240 min, range: 160-330 min) was significantly shorter than that in group A (280 min, range: 200-360 min; P = 0.000). Compared with group A, more complete distal mesorectum and total mesorectum were achieved in group B (100% vs 75.6%, P = 0.000; 90.5% vs 70.7%, P = 0.008, respectively). After 46.1 +/- 25.6 mo follow up, group B had a lower local recurrence rate and higher disease-free survival rate compared with group A, but these differences were not statistically significant (5.4% vs 14.6%, P = 0.093; 79.5% vs 65.1%, P = 0.130). CONCLUSION: Retrograde taTME with simple customized instruments can achieve high-quality TME, and it might be an effective and economical alternative for male patients with bulky tumors. PMID- 28883707 TI - Donor-derived infections among Chinese donation after cardiac death liver recipients. AB - AIM: To investigate blood cultures of deceased donors and report the confirmed transmission of bacterial infection from donors to liver recipients. METHODS: We retrospectively studied the results of blood cultures among our donation after cardiac death (DCD) donors and calculated the donor-derived bacterial infection rates among liver recipients. Study participants underwent liver transplantation between January 1, 2010 and February 1, 2017. The study involved a total of 67 recipients of liver grafts from 67 DCD donors. We extracted the data of donors' and patients' characteristics, culture results and clinical outcomes, especially the post-transplant complications in liver recipients, from electronic medical records. We analyzed the characteristics of the donors and the corresponding liver recipients with emphasis put on donor-derived infections. RESULTS: Head trauma was the most common origin of death among our 67 DCD donors (46.3%). Blood taken prior to the procurement operation was cultured for 53 of the donors, with 17 episodes of bloodstream infections developing from 13 donors. The predominant organism isolated from the blood of donors was Gram-positive bacteria (70.6%). Only three (4.5%) of 67 liver recipients developed confirmed donor-derived bacterial infections, with two isolates of multidrug-resistant Klebsiella pneumoniae and one isolate of multidrug-resistant Enterobacter aerogenes. The liver recipients with donor-derived infections showed relation to higher crude mortality and graft loss rates (33.3% each) within 3 mo post transplantation, as compared to those without donor-derived infections (9.4% and 4.7%, respectively). All three liver recipients received appropriate antimicrobial therapy. CONCLUSION: Liver recipients have high occurrence of donor-derived infections. The liver recipients with donor-derived multidrug-resistant Enterobacteriaceae infections can have good outcome if appropriate antimicrobial therapy is given. PMID- 28883708 TI - Rarity among benign gastric tumors: Plexiform fibromyxoma - Report of two cases. AB - Plexiform fibromyxoma is a very rare mesenchymal tumor of the stomach, found almost exclusively in the antrum/pylorus region. The most common presenting symptoms are anemia, hematemesis, nausea and unintentional weight loss, without sex or age predilection. We describe here two cases of plexiform fibromyxoma, involving a 16-year-old female and a 34-year-old male. Both patients underwent complete resection (R0) by distal gastrectomy and retrocolic gastrojejunostomy (according to Billroth 2); for both, the postoperative course was uneventful. Histology showed multiple intramural and subserosal nodules with characteristic plexiform growth, featuring bland spindle cells situated in an abundant myxoid stroma with low mitotic activity. Immunohistochemistry showed alpha-smooth muscle actin-positive spindle cells, focal positivity for CD10, and negative staining for KIT, DOG1, CD34, S100, beta-catenin, STAT-6 and anaplastic lymphoma kinase. One of the cases showed focal positivity for h-caldesmon and desmin. Upon follow up, no sign of disease was found. In the differential diagnosis of plexiform fibromyxoma, it is important to exclude the more common gastrointestinal stromal tumors as they have greater potential for aggressive behavior. Other lesions, like neuronal and vascular tumors, inflammatory fibroid polyps, abdominal desmoid type fibromatosis, solitary fibrous tumors and smooth muscle tumors, must also be excluded. PMID- 28883710 TI - Secure Skyline Queries on Cloud Platform. AB - Outsourcing data and computation to cloud server provides a cost-effective way to support large scale data storage and query processing. However, due to security and privacy concerns, sensitive data (e.g., medical records) need to be protected from the cloud server and other unauthorized users. One approach is to outsource encrypted data to the cloud server and have the cloud server perform query processing on the encrypted data only. It remains a challenging task to support various queries over encrypted data in a secure and efficient way such that the cloud server does not gain any knowledge about the data, query, and query result. In this paper, we study the problem of secure skyline queries over encrypted data. The skyline query is particularly important for multi-criteria decision making but also presents significant challenges due to its complex computations. We propose a fully secure skyline query protocol on data encrypted using semantically-secure encryption. As a key subroutine, we present a new secure dominance protocol, which can be also used as a building block for other queries. Finally, we provide both serial and parallelized implementations and empirically study the protocols in terms of efficiency and scalability under different parameter settings, verifying the feasibility of our proposed solutions. PMID- 28883709 TI - Tegafur-uracil-induced rapid development of advanced hepatic fibrosis. AB - Tegafur-uracil has been reported to have only minor adverse effects and is associated with liver injury in 1.79% of Japanese patients. The development of tegafur-uracil-induced hepatic fibrosis with portal hypertension is rare. Here, we report a case of a 74-year-old woman with rapidly developing tegafur-uracil induced hepatic fibrosis. The patient had no history of liver disease and had been treated with tegafur-uracil for 8 mo after breast cancer surgery. The patient was admitted to our hospital for abdominal distension and leg edema associated with liver dysfunction. Computed tomography imaging revealed massive ascites and splenomegaly, and a non-invasive assessment of liver fibrosis indicated advanced fibrosis. The histopathological findings revealed periportal fibrosis and bridging fibrosis with septation. The massive ascites resolved after discontinuing tegafur-uracil. These findings suggest that advanced hepatic fibrosis can develop from a relatively short-term administration of tegafur uracil and that non-invasive assessment is useful for predicting hepatic fibrosis. PMID- 28883711 TI - Quantifying Differential Privacy under Temporal Correlations. AB - Differential Privacy (DP) has received increasing attention as a rigorous privacy framework. Many existing studies employ traditional DP mechanisms (e.g., the Laplace mechanism) as primitives, which assume that the data are independent, or that adversaries do not have knowledge of the data correlations. However, continuous generated data in the real world tend to be temporally correlated, and such correlations can be acquired by adversaries. In this paper, we investigate the potential privacy loss of a traditional DP mechanism under temporal correlations in the context of continuous data release. First, we model the temporal correlations using Markov model and analyze the privacy leakage of a DP mechanism when adversaries have knowledge of such temporal correlations. Our analysis reveals that the privacy loss of a DP mechanism may accumulate and increase over time. We call it temporal privacy leakage. Second, to measure such privacy loss, we design an efficient algorithm for calculating it in polynomial time. Although the temporal privacy leakage may increase over time, we also show that its supremum may exist in some cases. Third, to bound the privacy loss, we propose mechanisms that convert any existing DP mechanism into one against temporal privacy leakage. Experiments with synthetic data confirm that our approach is efficient and effective. PMID- 28883712 TI - Integrated results from the COPERNICUS and GALILEO studies. AB - OBJECTIVES: To report on the efficacy and safety of intravitreal aflibercept in patients with macular edema secondary to central retinal vein occlusion (CRVO) in an integrated analysis of COPERNICUS and GALILEO. PATIENTS AND METHODS: Patients were randomized to receive intravitreal aflibercept 2 mg every 4 weeks or sham injections until week 24. From week 24 to week 52, all intravitreal aflibercept treated patients in both studies and sham-treated patients in COPERNICUS were eligible to receive intravitreal aflibercept based on prespecified criteria. In GALILEO, sham-treated patients continued to receive sham treatment through week 52. RESULTS: At week 24, mean gain in best-corrected visual acuity and mean reduction in central retinal thickness were greater for intravitreal aflibercept treated patients compared with sham, consistent with individual trial results. At week 52, after 6 months of intravitreal aflibercept as-needed treatment in COPERNICUS, patients originally randomized to sham group experienced visual and anatomic improvements but did not improve to the extent of those initially treated with intravitreal aflibercept, while the sham group in GALILEO did not improve over week 24 mean best-corrected visual acuity scores. Ocular serious adverse events occurred in <10% of patients. CONCLUSION: This analysis of integrated data from COPERNICUS and GALILEO confirmed that intravitreal aflibercept is an effective treatment for macular edema following CRVO. PMID- 28883713 TI - Patients' knowledge of heart failure and their perception of the disease. AB - PURPOSE: The aim of this study was to gain a deeper insight into patients' perception of chronic heart failure (CHF) symptoms by analyzing their compliance with nonpharmacological recommendations. PATIENTS AND METHODS: This was a prospective, single-center survey-based registry. Patients included in this study were hospitalized between December 2014 and January 2016 at the 1st Department of Cardiology, University Hospital of Lord's Transfiguration, Poznan University of Medical Sciences, and had been diagnosed with CHF at least 3 months prior to inclusion. Participants were divided according to New York Heart Association (NYHA) functional class into mild CHF (NYHA I and II) and severe CHF (NYHA III and IV), and according to age into young (<50 years), middle-aged (50-70 years) and old (>70 years). The survey included information about the patients' sex, age, education, length of the illness and 12 questions about their perception of CHF. This study included 201 patients. The mean age was 58+/-15 years. RESULTS: The younger the patients, the more often they thought that CHF is curable. The patients presenting with severe CHF tended to think that CHF is incurable significantly more often than those with mild CHF. Most of the patients considered loss of appetite, cough and vomiting the least alarming symptoms. Significantly more patients with severe CHF exercised less and reported reduced sexual activity more often in comparison to the mild CHF patients. Most of the young patients reported no changes to their sexual activity, body mass index (BMI) or exercise after diagnosis of CHF. Most of the old patients exercised less than before diagnosis of CHF. Significantly more middle-aged patients reduced their BMI, quit smoking and reported lower sexual activity after diagnosis of CHF in comparison to the other groups. CONCLUSION: Patients need to be better educated about the nature of CHF and the importance of lifestyle changes. PMID- 28883714 TI - Vascular aging and subclinical atherosclerosis: why such a "never ending" and challenging story in cardiology? AB - The true onset of atherosclerosis remains one of the biggest challenges for cardiologists. Is atheroma plaque development considered the earliest step of vascular aging? If so, when it starts? Before or after birth? If it starts before birth or early during childhood, it seems that Thomas Sydenham was right: "A man is as old as his arteries." Except disorganization of elastic fibers, less is known about the morphology of vascular aging and also about the molecular events influencing the age of arteries, arterial stiffness, and their role in the appearance of future complications. Cellular and molecular events responsible for the switch from physiologic to pathologic aging of human arteries are less known. Epigenetic, genetic, and environmental influences at the onset of early vascular aging (EVA) should specifically influence the process. This paper briefly reviews the controversial data regarding vascular aging with an emphasis on the less known facts about the morphology of EVA. PMID- 28883715 TI - Impact of age on extracorporeal membrane oxygenation survival of patients with cardiac failure. AB - PURPOSE: Extracorporeal membrane oxygenation (ECMO) is used to treat patients in critical condition with cardiogenic shock. However, few studies have examined the effect of old age in ECMO survival. This study analyzed the impact of age on ECMO survival of patients with cardiac failure, and analyzed predictive factors for survival according to age. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 95 patients who required veno-arterial (V-A) ECMO between May 2009 and May 2016 at a single center. Patients were classified into "age >=65" (n=48, 50.5%) and "age <65" (n=47, 49.5%) groups. RESULTS: The age >=65 group was significantly associated with increased mortality (HR: 1.715; 95% CI =1.038 2.831) at 90 days after ECMO initiation. These associations were attenuated and did not retain statistical significance after adjustment for comorbidities (HR: 1.485; 95% CI =0.844-2.614). To determine predictive factors of mortality, multivariate logistic analysis revealed that age >=65 (OR 5.750; 95% CI [1.508 21.920]; P=0.010), low pre-ECMO serum bicarbonate (OR 0.884; 95% CI [0.788 0.991]; P=0.035), and high pre-ECMO serum creatinine (OR 4.546; 95% CI [1.021 20.239]; P=0.047) were significantly associated with survival to 90 days. By analyzing two groups separately, high pre-ECMO serum potassium level (OR 3.552; 95% CI [1.023-12.331]; P=0.046) was the only independent predictor in patients aged <65 years while low Glasgow Coma Scale score (OR 0.698; 95% CI [0.478 1.019]; P=0.063) showed a considerable trend toward significance in patients aged >=65. CONCLUSION: Older age was not an independent risk factor for mortality at 90 days among V-A ECMO patients. In addition, our study provides understanding of the differences in predictive factors for ECMO survival according to age. Pre ECMO laboratory findings and mental status can assist clinicians in the prediction of a patient's prognosis. PMID- 28883716 TI - Spontaneous cervical artery dissection in patients aged over 70 years: two cases and systematic literature review. AB - OBJECTIVE: Spontaneous cervical artery dissection (CAD) is a cerebrovascular disease typically considered to affect the young population. Literature reports cases in the elderly only as incidental findings, making the diagnosis unlikely in older patients. Incidence and pathogeny in this specific population remain to be assessed. METHODS: We reviewed patients aged over 70 years admitted for spontaneous CAD in the Stroke Unit of the University Hospital of Nancy (northeastern France) over a period of 12 years as well as all reported cases in literature. RESULTS: During this period, only two patients aged over 70 years were diagnosed with internal carotid artery dissection in our center. The first patient was diagnosed with the typical radiological feature of long tapered stenosis due to mural hematoma. The second patient presented with the classic painful Horner syndrome. Literature review identified only two case reports and eight studies with an age range above 70 years. Headache was present in nearly all documented cases. Radiological features were the same as those usually described in younger patients. CONCLUSIONS: Even if spontaneous CAD in patients aged over 70 years would appear to be rare, it does occur with comparable clinical and radiological features as in the younger population. CAD is probably underdiagnosed in this population due to a higher prevalence of more common causes of stroke at this age. However, a simple investigation into headache or the Horner syndrome during the patient's diagnostic workup would lead to adapted exploration of cervical arteries and improve detection of CAD in the elderly. PMID- 28883717 TI - Assessing balance through the use of a low-cost head-mounted display in older adults: a pilot study. AB - INTRODUCTION: As the population ages, the prevention of falls is an increasingly important public health problem. Balance assessment forms an important component of fall-prevention programs for older adults. The recent development of cost effective and highly responsive virtual reality (VR) systems means new methods of balance assessment are feasible in a clinical setting. This proof-of-concept study made use of the submillimeter tracking built into modern VR head-mounted displays (VRHMDs) to assess balance through the use of visual-vestibular conflict. The objective of this study was to evaluate the validity, acceptability, and reliability of using a VRHMD to assess balance in older adults. MATERIALS AND METHODS: Validity was assessed by comparing measurements from the VRHMD to measurements of postural sway from a force plate. Acceptability was assessed through the use of the Simulator Sickness Questionnaire pre- and postexposure to assess possible side effects of the visual-vestibular conflict. Reliability was assessed by measuring correlations between repeated measurements 1 week apart. Variables of possible importance that were found to be reliable (r>=0.9) between tests separated by a week were then tested for differences compared to a control group. Assessment was performed as a cross-sectional single site community center-based study in 13 older adults (>=65 years old, 80.2+/-7.3 years old, 77% female, five at risk of falls, eight controls). The VR balance assessment consisted of four modules: a baseline module, a reaction module, a balance module, and a seated assessment. RESULTS: There was a significant difference in the rate at which participants with a risk of falls changed their tilt in the anteroposterior direction compared to the control group. Participants with a risk of falls changed their tilt in the anteroposterior direction at 0.7 degrees /second vs 0.4 degrees /second for those without a history of falls. No significant differences were found between pre/postassessment for oculomotor score or total Simulator Sickness Questionnaire score. Both the force plate and the head-mounted display balance-assessment system were able to detect differences between conditions meant to mask visual and proprioceptive information. CONCLUSION: This VRHMD is both affordable and portable, causes minimal simulator sickness, and produces repeatable results that can be used to assess balance in older adults. PMID- 28883718 TI - Contributions of COPD, asthma, and ten comorbid conditions to health care utilization and patient-centered outcomes among US adults with obstructive airway disease. AB - BACKGROUND: Among persons with obstructive airway disease, the relative contributions of chronic obstructive pulmonary disease (COPD), asthma, and common comorbid conditions to health care utilization and patient-centered outcomes (PCOs) have not been previously reported. METHODS: We followed a total of 3,486 persons aged >=40 years with COPD, asthma, or both at baseline, from the Medical Expenditure Panel Survey (MEPS) cohorts enrolled annually from 2008 through 2012 for 1 year. MEPS is a prospective observational study of US households recording self-reported COPD, asthma, and ten medical conditions: angina, arthritis, cancer, coronary heart disease, cognitive impairment, diabetes, hypertension, lung cancer, myocardial infarction, and stroke/transient ischemic attack. We studied the separate contributions of these conditions to health care utilization (all-cause and respiratory disease hospitalization, any emergency department [ED] visit, and six or more outpatient visits) and PCOs (seven or more days spent in bed due to illness, incident loss of mobility, and incident decline in self perceived health). RESULTS: COPD made the largest contributions to all-cause and respiratory disease hospitalization and ED visits, while arthritis made the largest contribution to outpatient health care. Arthritis and COPD, respectively, made the greatest contributions to the PCOs. CONCLUSION: COPD made the largest and second largest contributions to health care utilization and PCOs among US adults with obstructive airway disease. The twelve medical conditions collectively accounted for between 52% and 61% of the health care utilization outcomes and between 53% and 68% of the PCOs. Cognitive impairment, diabetes, hypertension, and stroke also made significant contributions. PMID- 28883719 TI - Incidence and risk factors of atrial fibrillation in Asian COPD patients. AB - OBJECTIVE: To investigate the incidence and risk factors of atrial fibrillation (AF) in Asian chronic obstructive pulmonary disease (COPD) patients. PATIENTS AND METHODS: We selected a study population older than 40 years with a COPD diagnosis and who had used at least one inhaled bronchodilator medication between 1998 and 2012. The date of the index COPD diagnosis was defined as the index date. We excluded patients with a history of AF, significant mitral valve disease, disorders of the thyroid gland, or ischemic heart disease before the index date. We followed all patients from the index date to the day of AF occurrence, the day of death, or the date of December 31, 2013. The baseline of comorbidities was identified before the index date. Comorbidities included hypertension, diabetes mellitus, end-stage renal disease, congenital heart failure, stroke, peripheral arterial occlusive disease, and malignancy. RESULTS: We included 6,208 COPD patients and 12,409 patients without COPD. The incidence of AF was higher in COPD patients than in those without COPD. The adjusted hazard ratio (HR) for AF among those with COPD was 2.23 with a 95% confidence interval (CI) of 1.98-2.51 compared to those without COPD. After multiple analyses, patients with hypertension (HR 1.43 [95% CI =1.26-1.62]) or heart failure (HR 2.36 [95% CI =1.81-3.08]) were found to have a significantly higher incidence of AF than those without these conditions. CONCLUSION: It is important for physicians to monitor, prevent, and provide early intervention for AF in COPD patients with hypertension or heart failure. PMID- 28883720 TI - Effect of a rehabilitation-based chronic disease management program targeting severe COPD exacerbations on readmission patterns. AB - BACKGROUND: Pulmonary rehabilitation (PR) is recommended after a severe COPD exacerbation, but its short- and long-term effects on health care utilization have not been fully established. AIMS: The aims of this study were to evaluate patient compliance with a chronic disease management (CDM) program incorporating home-based exercise training as the main component after a severe COPD exacerbation and to determine its effects on health care utilization in the following year. MATERIALS AND METHODS: COPD patients with a severe exacerbation were included in a case-cohort study at admission. An intervention group participated in a nurse-supervised CDM program during the 2 months after discharge, comprising of home-based PR with exercise components directly supervised by a physiotherapist, while the remaining patients followed usual care. RESULTS: Nineteen of the twenty-one participants (90.5%) were compliant with the CDM program and were compared with 29 usual-care patients. Compliance with the program was associated with statistically significant reductions in admissions due to respiratory disease in the following year (median [interquartile range]: 0 [0-1] vs 1 [0-2.5]; P=0.022) and in days of admission (0 [0-7] vs 7 [0-12]; P=0.034), and multiple linear regression analysis confirmed the protective effect of the CDM program (beta coefficient -0.785, P=0.014, and R2=0.219). CONCLUSION: A CDM program incorporating exercise training for COPD patients without limiting comorbidities after a severe exacerbation achieves high compliance and reduces admissions in the year following after the intervention. PMID- 28883721 TI - Determinants of each domain of the Short Physical Performance Battery in COPD. AB - BACKGROUND: The Short Physical Performance Battery (SPPB) is an assessment tool with good prognostic value in COPD. It includes the following: standing balance, 4 m gait speed test (4MGS), and the timed five-repetition sit-to-stand test (5STS). The specific differences in determinants between these three tasks have not been adequately characterized in COPD patients. We aimed to identify health related, functional, and psychological determinants of each SPPB test. METHODS: We conducted a cross-sectional analysis of 137 patients with stable COPD. Patients performed the SPPB, quadriceps muscle strength (QMS), exercise tolerance test (6-min walk test [6MWT]), and pulmonary function; and health-related and psychological factors, physical activity, the COPD assessment test (CAT), body mass index, age, and depression were assessed. RESULTS: Separate multivariable regression models predicting the 4MGS, 5STS, and balance test results described 31%, 39.1%, and 12.1% of the variance for each test, respectively. QMS was negatively associated with all three tests. The 6MWT was negatively associated with the 4MGS and 5STS. Depression and age were positively associated with 4MGS scores, whereas CAT and age were positively associated with 5STS scores. CONCLUSION: The three SPPB tests did not provide equivalent information regarding a COPD patient's status. The 5STS was associated with health status factors, while the 4MGS was associated with psychological factors. PMID- 28883722 TI - ACTIVATE: the effect of aclidinium/formoterol on hyperinflation, exercise capacity, and physical activity in patients with COPD. AB - The Phase IV, 8-week, randomized, double-blind, placebo-controlled ACTIVATE study (NCT02424344) evaluated the effect of aclidinium/formoterol (AB/FF) 400/12 MUg twice daily on lung hyperinflation, exercise capacity, and physical activity in patients with moderate-to-severe COPD. Patients received AB/FF (n=134) or placebo (n=133) (1:1) via the GenuairTM/Pressair(r) dry powder inhaler for 8 weeks. From Weeks 5 to 8, all patients participated in behavioral intervention (BI; daily messages providing step goals). The primary end point was trough functional residual capacity (FRC) at Week 4. Exercise endurance time and physical activity were assessed at Week 4 (pharmacotherapy only) and at Week 8 (8 weeks of pharmacotherapy plus 4 weeks of BI). Other end points included post-dose FRC, residual volume, and inspiratory capacity (IC) at rest and during exercise. After 4 weeks, trough FRC improved with AB/FF versus placebo but did not reach significance (125 mL; P=0.0690). However, post-dose FRC, residual volume, and IC at rest improved significantly with AB/FF at Week 4 versus placebo (all P<0.0001). AB/FF significantly improved exercise endurance time and IC at isotime versus placebo at Week 4 (P<0.01 and P<0.0001, respectively) and Week 8 (P<0.05 and P<0.0001, respectively). AB/FF achieved higher step counts (P<0.01) with fewer inactive patients (P<0.0001) at Week 4 versus placebo. Following BI, AB/FF maintained improvements in physical activity at Week 8 and nonsignificant improvements were observed with placebo. AB/FF 400/12 MUg demonstrated improvements in lung hyperinflation, exercise capacity, and physical activity versus placebo that were maintained following the addition of BI. A 4-week period of BI might be too short to augment the improvements of physical activity observed with AB/FF. PMID- 28883723 TI - Comparison of pulsed versus continuous oxygen delivery using realistic adult nasal airway replicas. AB - BACKGROUND: Portable oxygen concentrators (POCs) typically include pulse flow (PF) modes to conserve oxygen. The primary aims of this study were to develop a predictive in vitro model for inhaled oxygen delivery using a set of realistic airway replicas, and to compare PF for a commercial POC with steady flow (SF) from a compressed oxygen cylinder. METHODS: Experiments were carried out using a stationary compressed oxygen cylinder, a POC, and 15 adult nasal airway replicas based on airway geometries derived from medical images. Oxygen delivery via nasal cannula was tested at PF settings of 2.0 and 6.0, and SF rates of 2.0 and 6.0 L/min. A test lung simulated three breathing patterns representative of a chronic obstructive pulmonary disease patient at rest, during exercise, and while asleep. Volume-averaged fraction of inhaled oxygen (FiO2) was calculated by analyzing oxygen concentrations sampled at the exit of each replica and inhalation flow rates over time. POC pulse volumes were also measured using a commercial O2 conserver test system to attempt to predict FiO2 for PF. RESULTS: Relative volume averaged FiO2 using PF ranged from 68% to 94% of SF values, increasing with breathing frequency and tidal volume. Three of 15 replicas failed to trigger the POC when used with the sleep breathing pattern at the 2.0 setting, and four of 15 replicas failed to trigger at the 6.0 setting. FiO2 values estimated from POC pulse characteristics followed similar trends but were lower than those derived from airway replica experiments. CONCLUSION: For the POC tested, PF delivered similar, though consistently lower, volume-averaged FiO2 than SF rates equivalent to nominal PF settings. Assessment of PF oxygen delivery using POC pulse characteristics alone may be insufficient; testing using airway replicas is useful in identifying possible cases of failure and may provide a better assessment of FiO2. PMID- 28883724 TI - Nanomedicinal products: a survey on specific toxicity and side effects. AB - Due to their specific properties and pharmacokinetics, nanomedicinal products (NMPs) may present different toxicity and side effects compared to non nanoformulated, conventional medicines. To facilitate the safety assessment of NMPs, we aimed to gain insight into toxic effects specific for NMPs by systematically analyzing the available toxicity data on approved NMPs in the European Union. In addition, by comparing five sets of products with the same active pharmaceutical ingredient (API) in a conventional formulation versus a nanoformulation, we aimed to identify any side effects specific for the nano aspect of NMPs. The objective was to investigate whether specific toxicity could be related to certain structural types of NMPs and whether a nanoformulation of an API altered the nature of side effects of the product in humans compared to a conventional formulation. The survey of toxicity data did not reveal nanospecific toxicity that could be related to certain types of structures of NMPs, other than those reported previously in relation to accumulation of iron nanoparticles (NPs). However, given the limited data for some of the product groups or toxicological end points in the analysis, conclusions with regard to (a lack of) potential nanomedicine-specific effects need to be considered carefully. Results from the comparison of side effects of five sets of drugs (mainly liposomes and/or cytostatics) confirmed the induction of pseudo-allergic responses associated with specific NMPs in the literature, in addition to the side effects common to both nanoformulations and regular formulations, eg, with liposomal doxorubicin, and possibly liposomal daunorubicin. Based on the available data, immunotoxicological effects of certain NMPs cannot be excluded, and we conclude that this end point requires further attention. PMID- 28883726 TI - Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer. AB - Multidrug resistance (MDR) against chemotherapeutic agents has become one of the major obstacles to successful cancer therapy and MDR-associated proteins (MRPs) mediated drug efflux is the key factor for MDR. In this study, a redox-responsive polymer based on dextran (DEX) and indomethacin (IND), which could reduce MRPs mediated efflux of chemotherapeutics, was synthesized, and the obtained polymer could spontaneously form stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 50 nm and effectively encapsulate doxorubicin (DOX); the micelles contain a disulfide bridge (cystamine, SS) between IND and DEX (DEX-SS-IND). In vitro drug release results indicated that DEX-SS-IND/DOX micelles could maintain good stability in a stimulated normal physiological environment and promptly depolymerized and released DOX in a reducing environment. After incubating DEX-SS-IND/DOX micelles with drug-resistant tumor (MCF-7/ADR) cells, the intracellular accumulation and retention of DOX were significantly increased under the synergistic effects of redox-responsive delivery and the inhibitory effect of IND on MRPs. In vitro cytotoxicity showed that DEX-SS-IND/DOX micelles exhibited higher cytotoxicity against MCF-7/ADR cells. Moreover, DEX-SS-IND/DOX micelles showed significantly enhanced inhibition of tumor in BALB/c nude mice bearing MCF-7/ADR tumors and reduced systemic toxicity. Overall, the cumulative evidence indicates that DEX-SS IND/DOX micelles hold significant promise for overcoming MDR for cancer therapy. PMID- 28883725 TI - Gold nanoparticles enlighten the future of cancer theranostics. AB - Development of multifunctional nanomaterials, one of the most interesting and advanced research areas in the field of nanotechnology, is anticipated to revolutionize cancer diagnosis and treatment. Gold nanoparticles (AuNPs) are now being widely utilized in bio-imaging and phototherapy due to their tunable and highly sensitive optical and electronic properties (the surface plasmon resonance). As a new concept, termed "theranostics," multifunctional AuNPs may contain diagnostic and therapeutic functions that can be integrated into one system, thereby simultaneously facilitating diagnosis and therapy and monitoring therapeutic responses. In this review, the important properties of AuNPs relevant to diagnostic and phototherapeutic applications such as structure, shape, optics, and surface chemistry are described. Barriers for translational development of theranostic AuNPs and recent advances in the application of AuNPs for cancer diagnosis, photothermal, and photodynamic therapy are discussed. PMID- 28883728 TI - A charge-reversible nanocarrier using PEG-PLL (-g-Ce6, DMA)-PLA for photodynamic therapy. AB - A polyelectrolyte nanoparticle composed of PEG-PLL(-g-Ce6, DMA)-PLA was developed for nanomedicinal application in photodynamic therapy. These nanoparticles formed stable aggregates through the hydrophobic interaction of poly(lactic acid) and demonstrated pH-dependent behaviors such as surface charge conversion and enhanced cellular uptake at acidic pH, resulting in improved phototoxicity. In vivo animal imaging revealed that the prepared PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles effectively accumulated at the targeted tumor site through enhanced permeability and retention effects. Reversible surface charge for PEG-PLL (-g Ce6, DMA)-PLA nanoparticles allows the nanoparticles to escape the immune system and concentrate on the tumor tissue. Tumor growth in the nude mice treated with the nanoparticles decreased significantly and the hydrophobic interaction in the poly(lactic acid) block could allow the incorporation of multiple drugs. Therefore, the PEG-PLL(-g-Ce6, DMA)-PLA nanoparticles could have considerable potential as a nanomedicinal platform for photodynamic therapy. PMID- 28883727 TI - Vaccination with poly(D,L-lactide-co-glycolide) nanoparticles loaded with soluble Leishmania antigens and modified with a TNFalpha-mimicking peptide or monophosphoryl lipid A confers protection against experimental visceral leishmaniasis. AB - Visceral leishmaniasis (VL) persists as a major public health problem, and since the existing chemotherapy is far from satisfactory, development of an effective vaccine emerges as the most appropriate strategy for confronting VL. The development of an effective vaccine relies on the selection of the appropriate antigen and also the right adjuvant and/or delivery vehicle. In the present study, the protective efficacy of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs), which were surface-modified with a TNFalpha-mimicking eight amino-acid peptide (p8) and further functionalized by encapsulating soluble Leishmania infantum antigens (sLiAg) and monophosphoryl lipid A (MPLA), a TLR4 ligand, was evaluated against challenge with L. infantum parasites in BALB/c mice. Vaccination with these multifunctionalized PLGA nanoformulations conferred significant protection against parasite infection in vaccinated mice. In particular, vaccination with PLGA-sLiAg-MPLA or p8-PLGA-sLiAg NPs resulted in almost complete elimination of the parasite in the spleen for up to 4 months post challenge. Parasite burden reduction was accompanied by antigen-specific humoral and cellular immune responses. Specifically, injection with PLGA-sLiAg-MPLA raised exclusively anti-sLiAg IgG1 antibodies post-vaccination, while in p8-PLGA sLiAg-vaccinated mice, no antibody production was detected. However, 4 months post-challenge, in mice vaccinated with all the multifunctionalized NPs, antibody class switching towards IgG2a subtype was observed. The study of cellular immune responses revealed the increased proliferation capacity of spleen cells against sLiAg, consisting of IFNgamma-producing CD4+ and CD8+ T cells. Importantly, the activation of CD8+ T cells was exclusively attributed to vaccination with PLGA NPs surface-modified with the p8 peptide. Moreover, characterization of cytokine production in vaccinated-infected mice revealed that protection was accompanied by significant increase of IFNgamma and lower levels of IL-4 and IL-10 in protected mice when compared to control infected group. Conclusively, the above nanoformulations hold promise for future vaccination strategies against VL. PMID- 28883729 TI - Maternal exposure to nanosized titanium dioxide suppresses embryonic development in mice. AB - Although nanoscale titanium dioxide (nano-TiO2) has been extensively used in industrial food applications and daily products for pregnant women, infants, and children, its potential toxicity on fetal development has been rarely studied. The main objective of this investigation was to establish the effects of maternal exposure of nano-TiO2 on developing embryos. Female imprinting control region mice were orally administered nano-TiO2 from gestational day 0 to 17. Our findings showed that Ti concentrations in maternal serum, placenta, and fetus were increased in nano-TiO2-exposed mice when compared to controls, which resulted in reductions in the contents of calcium and zinc in maternal serum, placenta, and fetus, maternal weight gain, placental weight, fetal weight, number of live fetuses, and fetal crown-rump length as well as cauda length, and caused an increase in the number of both dead fetuses and resorptions. Furthermore, maternal nano-TiO2 exposure inhibited development of the fetal skeleton, suggesting a significant absence of cartilage, reduced or absent ossification, and an increase in the number of fetuses with dysplasia, including exencephaly, spina bifida, coiled tail, scoliosis, rib absence, and sternum absence. These findings indicated that nano-TiO2 can cross the blood-fetal barrier and placental barrier, thereby delaying the development of fetal mice and inducing skeletal malformation. These factors may be associated with reductions in both calcium and zinc in maternal serum and the fetus, and both the placenta and embryos may be major targets of developmental toxicity following maternal exposure to nano-TiO2 during the prenatal period. Therefore, the application of nano-TiO2 should be carried out with caution. PMID- 28883730 TI - Drug delivery approaches for breast cancer. AB - Breast cancer is one of the most common cancers affecting women worldwide. The controlled release of drugs to the precise site of the disease using a nanocarrier vehicle increases the therapeutic efficiency of the drugs. Nanotechnology-based approaches used to endorse clinical improvement from a disease also help to understand the interaction of malignant cells with their microenvironment. Receptor-based targeting is another approach for drug delivery which is undergoing clinical trials. Nanoparticles (NPs) delivery has been proven to promise high loading capacity, less toxicity, and stability of the drugs or biomolecules compared to traditional chemotherapeutic drugs. The goal of this review is to present the current problems of breast cancer therapy and discuss the NP-based targeting to overcome the hurdles of conventional drug therapy approach. PMID- 28883732 TI - Analyzing a single nucleotide polymorphism in schizophrenia: a meta-analysis approach. AB - BACKGROUND: Schizophrenia is a severe mental disorder affecting >21 million people worldwide. Some genetic studies reported that single nucleotide polymorphism (SNP) involving variant rs1344706 from the ZNF804A gene in human beings is associated with the risk of schizophrenia in several populations. Similar results tend to conflict with other reports in literature, indicating that no true significant association exists between rs1344706 and schizophrenia. We seek to determine the level of association of this SNP with schizophrenia in the Asian population using more recent genome-wide association study (GWAS) datasets. METHODS: Applying a computational approach with inclusion of more recent GWAS datasets, we conducted a meta-analysis to examine the level of association of SNP rs1344706 and the risk of schizophrenia disorder among the Asian population constituting Chinese, Indonesians, Japanese, Kazakhs and Singaporeans. For a total of 21 genetic studies, including a total of 28,842 cases and 35,630 controls, regression analysis, publication bias, Cochran's Q and I2 tests were performed. The DerSimonian and Laird random-effects model was used to assess the association of the genetic variant to schizophrenia. Leave-one-out sensitivity analysis was also conducted to determine the influence of each study on the final outcome of the association study. RESULTS: Our summarized analysis for Asian population revealed a pooled odds ratio of 1.06, 95% confidence interval of 1.01-1.11 and two-tailed P-value of 0.0228. Our test for heterogeneity showed the presence of large heterogeneity (I2=53.44%, P =0.00207) and Egger's regression test (P =0.8763) and Begg's test (P =0.8347), indicating no presence of publication bias among our selected studies. In our sensitivity analysis, 10 different studies comprising of ~50% of the entire study had an impact on our final results as each leave-one-out test became insignificant. Our result suggests that genetic variant rs1344706 might be associated with the development of schizophrenia in Asians. PMID- 28883733 TI - Fan the flame: trazodone-induced mania in a unipolar depressed patient with stable sertraline treatment. AB - Depressed patients often complain of sleep disturbance. Routine antidepressive strategies sometimes fail to deal with this intractable issue. Indeed, the supplementation of sleep promoting antidepressants (eg, trazodone, mirtazapine, and agomelatine) is prevalent in clinical practice. However, the combination of different antidepressants may increase the affective lability. Herein, we document a patient with unipolar depression who was compliant with sertraline treatment and who dramatically switched to mania after adding trazodone as a sleeping aid. This case extended our understanding of the potential manic switching risk when trazodone is used to promote sleep. PMID- 28883734 TI - Prognostic impact of blood pressure and heart rate at admission on in-hospital mortality after primary percutaneous intervention for acute myocardial infarction with ST-segment elevation in western Romania. AB - BACKGROUND: The purpose of this retrospective study was to evaluate the prognostic impact of systolic blood pressure (SBP) and heart rate (HR) on in hospital mortality in ST-segment elevation acute myocardial infarction (STEMI) patients, after primary percutaneous intervention (PCI). PATIENTS AND METHODS: The study included 294 patients admitted for STEMI. They were divided into five groups according to the SBP at admission: group I, <105 mmHg; group II, 105-125 mmHg; group III, 126-140 mmHg; group IV, 141-158 mmHg; and group V, >=159 mmHg. Increased HR was defined as >=80 beats per minute (bpm). In-hospital death was defined as all-cause death during admission and classified into cardiac and noncardiac death. RESULTS: Among the 294 patients admitted for STEMI, 218 (74%) were men. The mean age was 62+/-17 years. In-hospital mortality rate was 6% (n=18), with 11 (3.7%) deaths having cardiac causes. The highest mortality was registered in group I (n=9, 16%, P=0.018). Compared to the other groups, group I patients were older (P=0.033), more often smokers (P=0.026), and had a history of myocardial infarction (P=0.003), systemic hypertension (P=0.023), diabetes (P=0.041), or chronic kidney disease (P=0.0200). They more often had a HR >=80 bpm (P=0.028) and a Killip class 3 or 4 at admission (P=0.020). The peak creatine phosphokinase-MB level was significantly higher in this group (P=0.005), while the angiographic findings more often identified as culprit lesions were the right coronary artery (P=0.005), the left main trunk (P=0.040), or a multivessel coronary artery disease (P=0.044). Multivariate analysis showed that group I patients had a significantly higher risk for both all-cause death (P=0.006) and cardiac death (P=0.003). Patients with HR >=80 bpm also had higher mortality rates (P=0.0272 for general mortality and P=0.0280 for cardiac mortality). CONCLUSION: The present study suggests that SBP <105 mmHg and HR >=80 bpm at admission of STEMI patients are associated with a higher risk of in-hospital death, even after primary PCI. PMID- 28883731 TI - Antipsychotic-associated weight gain: management strategies and impact on treatment adherence. AB - Antipsychotic-induced weight gain is a major management problem for clinicians. It has been shown that weight gain and obesity lead to increased cardiovascular and cerebrovascular morbidity and mortality, reduced quality of life and poor drug compliance. This narrative review discusses the propensity of various antipsychotics to cause weight gain, the pharmacologic and nonpharmacologic interventions available to counteract this effect and its impact on adherence. Most antipsychotics cause weight gain. The risk appears to be highest with olanzapine and clozapine. Weight increases rapidly in the initial period after starting antipsychotics. Patients continue to gain weight in the long term. Children appear to be particularly vulnerable to antipsychotic-induced weight gain. Tailoring antipsychotics according to the needs of the individual and close monitoring of weight and other metabolic parameters are the best preventive strategies at the outset. Switching to an agent with lesser tendency to cause weight gain is an option, but carries the risk of relapse of the illness. Nonpharmacologic interventions of dietary counseling, exercise programs and cognitive and behavioral strategies appear to be equally effective in individual and group therapy formats. Both nonpharmacologic prevention and intervention strategies have shown modest effects on weight. Multiple compounds have been investigated as add-on medications to cause weight loss. Metformin has the best evidence in this respect. Burden of side effects needs to be considered when prescribing weight loss medications. There is no strong evidence to recommend routine prescription of add-on medication for weight reduction. Heterogeneity of study methodologies and other confounders such as lifestyle, genetic and illness factors make interpretation of data difficult. PMID- 28883735 TI - Hollow viscus injuries: predictors of outcome and role of diagnostic delay. AB - INTRODUCTION: Hollow viscus injuries (HVIs) are uncommon but potentially catastrophic conditions with high mortality and morbidity rates. The aim of this study was to analyze our 16-year experience with patients undergoing surgery for blunt or penetrating bowel trauma to identify prognostic factors with particular attention to the influence of diagnostic delay on outcome. METHODS: From our multicenter trauma registry, we selected 169 consecutive patients with an HVI, enrolled from 2000 to 2016. Preoperative, intraoperative, and postoperative data were analyzed to assess determinants of mortality, morbidity, and length of stay by univariate and multivariate analysis models. RESULTS: Overall mortality and morbidity rates were 15.9% and 36.1%, respectively. The mean length of hospital stay was 23+/-7 days. Morbidity was independently related to an increase of white blood cells (P=0.01), and to delay of treatment >6 hours (P=0.033), while Injury Severity Score (ISS) (P=0.01), presence of shock (P=0.01), and a low diastolic arterial pressure registered at emergency room admission (P=0.02) significantly affected postoperative mortality. CONCLUSION: There is evidence that patients with clinical signs of shock, low diastolic pressure at admission, and high ISS are at increased risk of postoperative mortality. Leukocytosis and delayed treatment (>6 hours) were independent predictors of postoperative morbidity. More effort should be made to increase the preoperative detection rate of HVI and reduce the delay of treatment. PMID- 28883736 TI - Omentum flap as a salvage procedure in deep sternal wound infection. AB - INTRODUCTION: Deep sternal wound infections (DSWIs) are rare but devastating complication after median sternotomy following cardiac surgery. Especially in the presence of artificial material or inadequate preliminary muscle flaps, the pedicled omentum flap is due to its immunological properties, the predetermined flap in salvage procedures. METHODS: We treated 14 patients suffering a mediastinitis and open thorax using a pedicled omentoplasty as a salvage procedure because of persisting DSWIs. Omentoplasty was performed in combination with a split skin graft and the wound was closed by a vacuum-assisted therapy for 7 days. The patients' sex and comorbid risk factors supporting DSWIs as well as the postoperative complications were recorded. RESULTS: Retrospective analysis of 14 patients (10 males and four females) after a follow-up time of 24 months was performed. The average age was 75 years (range: 67-83). Heart surgery took place electively in eight cases, in three cases urgently and three for emergency reasons. The preoperative Euro Score was 16 (range 3.51-42.58). We had no flap loss in any patients. The skin graft showed a full take in all patients. Two patients needed revision of an abdominal wound dehiscence after laparotomy and one patient developed hernia in the late outcome. DISCUSSION: The greater omentum flap has, over many years, become an ideal partner in the coverage and treatment of DSWIs. Especially due to its immunologic capacity and amorphous structure, it has the ability to fill up cavities and cover infected artificial material so residual infections can be controlled. PMID- 28883737 TI - Scabies masquerading as bullous pemphigoid: scabies surrepticius. AB - Scabies, a parasitic infestation caused by the mite Sarcoptes scabiei, is diagnosed by observing either the mite, its ova, or its excrement. The mite tracts, known as burrows and a characteristic presentation of the pruritic condition, are typically found on the web spaces between the fingers. Other cutaneous lesions include excoriated papules, pustules, and vesicles. However, atypical clinical variants of scabies, such as bullous, crusted, hidden, incognito, nodular, and scalp forms of the parasitic infestation, mimic the morphologic features of other non-parasitic dermatoses. A 76-year-old man presented with pruritic blisters and urticarial plaques that demonstrated not only pathology changes, but direct immunofluorescence also showed findings of bullous pemphigoid. His condition improved, but did not resolve, with topical corticosteroid cream for the management of the primary autoimmune blistering disorder. When other family members subsequently developed scabies, the correct diagnosis for his condition, bullous scabies, was established by demonstrating mites, ova, and scybala on a mineral oil preparation from a skin scraping of a newly appearing burrow. Bullous scabies can masquerade not only clinically, but also both pathologically and immunologically as bullous pemphigoid. Scabies serrupticius is introduced as a unifying term to designate all of the non-classic presentations of S. scabiei mite infestation. PMID- 28883738 TI - Checkpoint inhibitors for malignant melanoma: a systematic review and meta analysis. AB - BACKGROUND AND OBJECTIVES: Rates of malignant melanoma are continuing to increase, and until recently effective treatments were lacking. However, since 2011 three immunotherapeutic agents, known as checkpoint inhibitors, have been approved. This review aims to establish whether these three drugs - ipilimumab, nivolumab, and pembrolizumab - offer greater efficacy and tolerability compared to control interventions (placebo, immunotherapy, or chemotherapy) in patients with stage III or IV unresectable cutaneous melanoma. MATERIALS AND METHODS: A search on four major medical and scientific databases yielded 7,553 records, of which seven met the inclusion criteria, with a total study population of 3,628. Only prospective Phase II or III randomized controlled trials on checkpoint inhibitors for patients with unresectable cutaneous melanoma that reported data on survival (overall or progression-free), tumor response, or adverse events were included. Three meta-analyses were carried out. RESULTS: The hazard ratio for progression or death was 0.54 (95% confidence interval [CI]: 0.44-0.67), and the odds ratio for best overall response rate was 4.48 (95% CI: 2.77-7.24), both in favor of checkpoint inhibitors. However, control treatments were associated with an insignificantly lower rate of discontinuation of treatment due to adverse effects or treatment-related adverse events (odds ratio =1.63 [95% CI: 0.55 4.88]). CONCLUSION: This study finds that checkpoint inhibitors are more effective than control interventions, both in terms of survival and tumor response, and yet no less tolerable. PD1 therapies (nivolumab and pembrolizumab) appear to offer greater efficacy than CTLA4 therapy (ipilimumab). The combination of nivolumab and ipilimumab was, however, the most effective, but significantly less tolerable than monotherapy. The lack of published clinical data does, however, limit this study. Further research is needed in two areas in particular: 1) to determine the optimal use of checkpoint inhibitors, specifically in terms of combination therapy, and 2) to identify reliable biomarkers to predictive responders and guide treatment assignment. PMID- 28883739 TI - Hyperbilirubinemia in atazanavir-treated human immunodeficiency virus-infected patients: the impact of the UGT1A1*28 allele. PMID- 28883740 TI - A cross-sectional study of factors associated with the number of anatomical pain sites in an actual elderly general population: results from the PainS65+ cohort. AB - BACKGROUND: Several studies have illustrated that multisite pain is more frequent than single pain site, and it is associated with an array of negative consequences. However, there is limited knowledge available about the potential factors associated with multisite pain in the elderly general population. OBJECTIVE: This cross-sectional study examines whether the number of anatomical pain sites (APSs) is related to sociodemographic and health-related factors in older adults including oldest-old ages using a new method (APSs) to assess the location of pain on the body. MATERIALS AND METHODS: The sample came from the PainS65+ cohort, which included 6,611 older individuals (mean age = 76.0 years; standard deviation [SD] = 7.4) residing in southeastern Sweden. All the participants completed and returned a postal survey that measured sociodemographic data, total annual income, pain intensity and frequency, general well-being, and quality of life. The number of pain sites (NPS) was marked on a body manikin of 45 sections, and a total of 23 APSs were then calculated. Univariable and multivariable models of regression analysis were performed. RESULTS: Approximately 39% of the respondents had at least two painful sites. The results of the regression analysis showed an independent association between the APSs and the age group of 75-79 years, women, married, high pain intensity and frequency, and low well-being and quality of life, after adjustments for consumption of analgesics and comorbidities. The strongest association was observed for the higher frequency of pain. CONCLUSION: Our results suggest that APSs are highly prevalent with strong relationships with various sociodemographic and health-related factors and concur well with the notion that multisite pain is a potential indicator of increased pain severity and impaired quality of life in the elderly. Our comprehensive method of calculating the number of sites could be an essential part of the clinical presentation, assessment, and treatment of multisite pain. PMID- 28883741 TI - Treatment and prognostic factors for survival in newly diagnosed multiple myeloma patients with bortezomib and dexamethasone regimen: a single Chinese center retrospective study. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the efficacy and prognostic factors of bortezomib and dexamethasone (BD) chemotherapy regimen in the treatment of newly diagnosed multiple myeloma (MM) patients in our hospital. METHODS: A total of 47 newly diagnosed MM patients treated in our hospital from May 2010 to September 2016 were included in this study. All the enrolled patients received at least two cycles of BD chemotherapy regimen. RESULTS: The overall response rate after treatment was 68.5% with a complete response of 23.4%, very good partial response of 17.0%, partial response of 21.3% and minor response of 6.8%. The median time of overall survival (OS), progression-free survival (PFS) and time to progression (TTP) of the treated patients were 36.0, 19.0 and 18.0 months, respectively; the mean OS, PFS and TTP were 36.0, 19.3 and 18.8 months, respectively. Though some adverse events had occurred, none of the patients was discontinued from treatment. Level of albumin, beta2-microglobulin and cytogenetic abnormalities were prognostic factors for OS, and plasma cell percentage in bone marrow, beta2-microglobulin and cytogenetic abnormalities were prognostic factors for PFS as revealed by log-rank test of univariate analysis; no prognostic factors for OS and PFS were detected by COX regression of multivariate analysis. CONCLUSION: Our study demonstrated that BD regimen was effective and well tolerated in newly diagnosed MM patients, and prognostic factors for patients' survival include level of albumin, plasma cell percentage in bone marrow, beta2-microglobulin and cytogenetic abnormalities. PMID- 28883742 TI - Somatic symptom profiles in the general population: a latent class analysis in a Danish population-based health survey. AB - PURPOSE: The aim of this study was to identify and describe somatic symptom profiles in the general adult population in order to enable further epidemiological research within multiple somatic symptoms. METHODS: Information on 19 self-reported common somatic symptoms was achieved from a population-based questionnaire survey of 36,163 randomly selected adults in the Capital Region of Denmark (55.4% women). The participants stated whether they had been considerably bothered by each symptom within 14 days prior to answering the questionnaire. We used latent class analysis to identify the somatic symptom profiles. The profiles were further described by their association with age, sex, chronic disease, and self-perceived health. RESULTS: We identified 10 different somatic symptom profiles defined by number, type, and site of the symptoms. The majority of the population (74.0%) had a profile characterized by no considerable bothering symptoms, while a minor group of 3.9% had profiles defined by a high risk of multiple somatic symptoms. The remaining profiles were more likely to be characterized by a few specific symptoms. The profiles could further be described by their associations with age, sex, chronic disease, and self-perceived health. CONCLUSION: The identified somatic symptom profiles could be distinguished by number, type, and site of the symptoms. The profiles have the potential to be used in further epidemiological studies on risk factors and prognosis of somatic symptoms but should be confirmed in other population-based studies with specific focus on symptom burden. PMID- 28883743 TI - Medical decision making and risky choices: psychological and medicolegal consequences of HIV and HCV contamination of blood products. AB - AIMS: The overall goal of this article is to make a scientific comment about the psycho-social consequences of hemophilia patients affected by human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV) and to point out the related medicolegal issues. METHODS: This commentary takes into account some published evidences about the current scenario of hemophilia patients infected by HIV and/or HCV who received contaminated blood products in the late 1970s through 1985. RESULTS: Several psychological and medicolegal consequences are related with HIV and HCV contamination of blood products. A multidisciplinary approach is needed to treat all the difficulties experienced by these patients and to ensure good clinical decisions in medical practice. CONCLUSION: The literature on the psychosocial functioning of hemophilia patients with human HIV and HCV infection offers a number of implications, including medicolegal issues, that can be discussed for guaranteeing a good level of care and safeguard of this group of patients. PMID- 28883744 TI - Sexual autonomy and contraceptive use among women in Nigeria: findings from the Demographic and Health Survey data. AB - CONTEXT: The persistent low contraceptive use and high fertility in Nigeria despite improvements in educational achievements calls for an examination of the role of factors, which may moderate the use of modern contraception. This article explores the influence of sexual autonomy on the use of modern contraceptive methods among women and its relative importance compared with other, more traditional, indicators of women's autonomy such as education and occupation. DATA AND METHODS: Data from two Demographic and Health Surveys (DHS), 2008 and 2013, were used in this study. An index of sexual autonomy was constructed by combining related DHS variables, and its association with current use of modern contraception was examined at each time point as well as over time using multivariate regression analysis. RESULTS: The observed prevalence for use of modern contraception was 2.8 and 2.6 times higher among women who had high sexual autonomy in 2008 and 2013, respectively. The corresponding figures for women with secondary or higher education were 8.2 and 11.8 times higher, respectively, compared with women with no education. But after controlling for wealth index, religion, place of residence, autonomy and experience of intimate partner violence (IPV), the likelihood of use of modern contraception was lowered to about 2.5 (from 8.2) and 2.8 (from 11.8) times during 2008 and 2013, respectively, among women with secondary or higher education. The likelihood of use of modern contraception lowered only to 1.6 (from 2.8) and 1.8 (from 2.6) times among women with high sexual autonomy after controlling for other covariates, respectively, during the same period. CONCLUSION: Sexual autonomy seems to play an important role in women's use of modern contraceptive methods independent of education and a number of other factors related to women's status. Sexual autonomy needs to be simultaneously promoted alongside increasing educational opportunities to enhance women's ability to use modern contraception. PMID- 28883745 TI - Review of devices used in neuromuscular electrical stimulation for stroke rehabilitation. AB - Neuromuscular electrical stimulation (NMES), specifically functional electrical stimulation (FES) that compensates for voluntary motion, and therapeutic electrical stimulation (TES) aimed at muscle strengthening and recovery from paralysis are widely used in stroke rehabilitation. The electrical stimulation of muscle contraction should be synchronized with intended motion to restore paralysis. Therefore, NMES devices, which monitor electromyogram (EMG) or electroencephalogram (EEG) changes with motor intention and use them as a trigger, have been developed. Devices that modify the current intensity of NMES, based on EMG or EEG, have also been proposed. Given the diversity in devices and stimulation methods of NMES, the aim of the current review was to introduce some commercial FES and TES devices and application methods, which depend on the condition of the patient with stroke, including the degree of paralysis. PMID- 28883746 TI - Clinical impact of early diagnosis of autism on the prognosis and parent-child relationships. AB - Autism spectrum disorder (ASD) refers to a lifelong condition that usually appears in late infancy or early childhood, and is characterized by social and communication deficits that impede optimal functioning. Despite widespread research and greater public awareness, ASD has an unclear etiology and no known cure, making it difficult to acquire accurate and timely diagnoses. In addition, once an ASD diagnosis is made, parents find it challenging to navigate the healthcare system and determine which interventions are most effective and appropriate for their child. A growing body of evidence supports the value of early diagnosis and treatment with evidence-based interventions, which can significantly improve the quality of life of individuals with ASD as well as of their carers and families. Particularly noteworthy are early interventions that occur in natural surroundings and can be modified to address age-related goals throughout the lifespan. Therefore, the purpose of this review is to: 1) provide readers with a brief background related to ASD; 2) describe commonly used screening instruments and tools for early diagnosis; 3) describe early interventions that have empirical support; and 4) discuss how the parent-child and family relationships can be affected through this process. This information can provide professionals with information they can use to assist families who make critical and potentially life-changing decisions for children with ASD. PMID- 28883747 TI - Proton beam therapy in non-small cell lung cancer: state of the art. AB - This review summarizes the past and present status of proton beam therapy (PBT) for lung cancer. PBT has a unique characteristic called the Bragg peak that enables a reduction in the dose of normal tissue around the tumor, but is sensitive to the uncertainties of density changes. The heterogeneity in electron density for thoracic lesions, such as those in the lung and mediastinum, and tumor movement according to respiration necessitates respiratory management for PBT to be applied in lung cancer patients. There are two types of PBT - a passively scattered approach and a scanning approach. Typically, a passively scattered approach is more robust for respiratory movement and a scanning approach could result in a more conformal dose distribution even when the tumor shape is complex. Large tumors of centrally located lung cancer may be more suitably irradiated than with intensity-modulated radiotherapy (IMRT) or stereotactic body radiotherapy (SBRT). For a locally advanced lung cancer, PBT can spare the lung and heart more than photon IMRT. However, no randomized controlled trial has reported differences between PBT and IMRT or SBRT for early stage and locally advanced lung cancers. Therefore, a well-designed controlled trial is warranted. PMID- 28883748 TI - The predictive effect of medical illnesses for mental health care in adolescence: a register-based study. AB - BACKGROUND: Adolescence is a developmentally sensitive stage, during which a medical illness may have an effect on individual development, and vice versa. Chronic medical illnesses in adolescents have been associated with psychiatric symptoms. The aim of the present register-based pilot study was to assess whether, and to what extent, different medical diagnoses predict subsequent use of mental health services among adolescents. METHODS: The study material comprised data on visits to a pediatric clinic by 12- to 16-year-old adolescent patients over a period of 5 years. Altogether, 10,154 visits by 1,781 patients were identified. The associations of the medical diagnoses with a subsequent visit to the adolescent psychiatry clinic were analyzed using logistic regression. RESULTS: During the follow-up period, 299 patients (16.8%) visited or contacted the adolescent psychiatry clinic at least once. Of various diagnoses, the highest odds ratios (ORs) were observed for diabetes mellitus (OR=4.07, p<0.001) and neoplasms (OR=3.29, p=0.047). An association was found between adolescent psychiatry clinic visits and female gender. CONCLUSION: Medical symptoms and illnesses that require a referral to a pediatrician are a marked risk factor for later use of mental health services. The results call for screening for psychological distress among patients with somatic illnesses and prompt referrals to mental health services if required. PMID- 28883749 TI - Student-selected component in the medical curriculum: investigations and psychiatric referral for paracetamol overdose in an accident and emergency department. AB - BACKGROUND: A student-selected component (SSC) of the medical curriculum requires the student to be self-directed in locating and undertaking a placement in a clinical specialty of their choosing and completing a project. The clinical area for experience was an accident and emergency department, and our topic was a focused audit on the investigations and referral for paracetamol overdose. The purpose of this paper is twofold: to reflect on the education value to medical students of an SSC in a medical curriculum, and to highlight learning and understanding through completion of an audit. MATERIALS AND METHODS: An audit approach was applied. The aim of the project study was to investigate the level of compliance with best-practice guidelines for investigations and psychiatric referral in paracetamol overdose. RESULTS: A total of 40 cases meeting the inclusion criteria were randomly selected. The sample had a mean age of 27 years, of whom 70.5% were female, and the ingested dose of paracetamol ranged from 0.864 to 80 g. Paracetamol abuse may present as intentional and unintentional overdose. In our study, 85% of cases were identified as intentional overdose and 76% had a history of psychiatric illness. Generally, medical management was compliant with guidelines, with some minor irregularities. The international normalized ratio was the most underperformed test. CONCLUSION: Our choice of topic, paracetamol overdose, contributed to our understanding of the breadth of factors to be considered in the emergency medical management of a patient. In this regard, we had the benefit of understanding how the diagnostic and therapeutic factors, when applied in accordance with best-practice guidelines, work very effectively. The SSC impacted positively on our cognitive, personal, and professional development. In facilitating the student with choice, the SSC encouraged self-direction and proactivity. We gained experience in the discipline of research and acquired some skills in independent thinking and analysis. PMID- 28883750 TI - Effect of etoricoxib on experimental oxidative testicular ischemia-reperfusion damage in rats induced with torsion-detorsion. AB - Etoricoxib features antioxidant and anti-inflammatory properties concomitantly, suggesting that it may be beneficial in testicular ischemia reperfusion (I/R) damage. Our aim is to investigate the effects of etoricoxib on testicular I/R damage induced with torsion-detorsion (TD). The etoricoxib + torsion-detorsion (ETD) groups of animals were given etoricoxib in 50 and 100 mg/kg of body weight (ETD-50 and ETD-100), while the testes torsion-detorsion (TTD) and sham operation rat group (SOG) animals were given single oral doses of distilled water as a solvent. TTD, ETD-50 and ETD-100 groups were subjected to 720 degrees degrees torsion for four hours, and detorsion for four hours. The SOG group was not subjected to this procedure. Biochemical, gene expression and histopathological analyses were carried out on the testicular tissues. The levels of malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) were significantly higher, and the levels of total glutathione (tGSH) and glutathione reductase (GSHRd) were significantly lower in the TTD group, compared to the ETD-50, ETD-100 and SOG groups. Etoricoxib at a dose of 100 mg/kg better prevented I/R damage than the 50 mg/kg dose. Etoricoxib may be useful in clinical practice in the reduction of I/R damage on testes caused by torsion-detorsion. PMID- 28883751 TI - Resveratrol raises in vitro anticancer effects of paclitaxel in NSCLC cell line A549 through COX-2 expression. AB - The aim of this study was to determine the raising anticancer effects of resveratrol (Res) on paclitaxel (PA) in non-small cell lung cancer (NSCLC) cell line A549. The 10 ug/ml of Res had no effect on human fetal lung fibroblast MRC-5 cells or on A549 cancer cells and the 5 or 10 ug/ml of PA also had no effect on MRC-5 normal cells. PA-L (5 ug/ml) and PA-H (10 ug/ml) had the growth inhibitory effects in NSCLC cell line A549, and Res increased these growth inhibitory effects. By flow cytometry experiment, after Res (5 ug/ml)+PA-H (10 ug/ml) treatment, the A549 cells showed the most apoptosic cells compared to other group treatments, and after additional treatment with Res, the apoptosic cells of both two PA concentrations were raised. Res+PA could reduce the mRNA and protein expressions of COX-2, and Res+PA could reduce the COX-2 related genes of VEGF, MMP-1, MMP-2, MMP-9, NF-kappaB, Bcl-2, Bcl-xL, procollagen I, collagen I, collagen III and CTGF, TNF-alpha, IL-1beta, iNOS and raise the TIMP-1, TIMP-2, TIMP-3, IkappaB-alpha, p53, p21, caspase-3, caspase-8, caspase-9, Bax genes compared to the control cells and the PA treated cells. From these results, it can be suggested that Res could raise the anticancer effects of PA in A549 cells, thus Res might be used as a good sensitizing agent for PA. PMID- 28883752 TI - RhGLP-1 (7-36) protects diabetic rats against cerebral ischemia-reperfusion injury via up-regulating expression of Nrf2/HO-1 and increasing the activities of SOD. AB - The present study aimed to explore the neuroprotective effect and possible mechanisms of rhGLP-1 (7-36) against transient ischemia/reperfusion injuries induced by middle cerebral artery occlusion (MCAO) in type 2 diabetic rats. First, diabetic rats were established by a combination of a high-fat diet and low dose streptozotocin (STZ) (30 mg/kg, intraperitoneally). Second, they were subjected to MCAO for 2 h, then treated with rhGLP-1 (7-36) (10, 20, 40 ug/kg i.p.) at the same time of reperfusion. In the following 3 days, they were injected with rhGLP-1 (7-36) at the same dose and route for three times each day. After 72 h, hypoglycemic effects were assessed by blood glucose changes, and neuroprotective effects were evaluated by neurological deficits, infarct volume and histomorphology. Mechanisms were investigated by detecting the distribution and expression of the nuclear factor erythroid-derived factor 2 related factor 2 (Nrf2) in ischemic brain tissue, the levels of phospho-PI3 kinase (PI3K)/PI3K ratio and heme-oxygenase-1 (HO-l), as well as the activities of superoxide dismutase (SOD) and the contents of malondialdehyde (MDA). Our results showed that rhGLP-1 (7-36) significantly reduced blood glucose and infarction volume, alleviated neurological deficits, enhanced the density of surviving neurons and vascular proliferation. The nuclear positive cells ratio and expression of Nrf2, the levels of P-PI3K/PI3K ratio and HO-l increased, the activities of SOD increased and the contents of MDA decreased. The current results indicated the protective effect of rhGLP-1 (7-36) in diabetic rats following MCAO/R that may be concerned with reducing blood glucose, up-regulating expression of Nrf2/HO-1 and increasing the activities of SOD. PMID- 28883753 TI - Inhibition of anterior cingulate cortex excitatory neuronal activity induces conditioned place preference in a mouse model of chronic inflammatory pain. AB - The anterior cingulate cortex (ACC) is known for its role in perception of nociceptive signals and the associated emotional responses. Recent optogenetic studies, involving modulation of neuronal activity in the ACC, show that the ACC can modulate mechanical hyperalgesia. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC in a model of chronic inflammatory pain to assess their motivational effect in the conditioned place preference (CPP) test. Selective inhibition of pyramidal neurons induced preference during the CPP test, while activation of parvalbumin (PV)-specific neurons did not. Moreover, chemogenetic inhibition of the excitatory pyramidal neurons alleviated mechanical hyperalgesia, consistent with our previous result. Our results provide evidence for the analgesic effect of inhibition of ACC excitatory pyramidal neurons and a prospective treatment for chronic pain. PMID- 28883754 TI - The activation of alpha2-adrenergic receptor in the spinal cord lowers sepsis induced mortality. AB - The effect of clonidine administered intrathecally (i.t.) on the mortality and the blood glucose level induced by sepsis was examined in mice. To produce sepsis, the mixture of D-galactosamine (GaLN; 0.6 g/10 ml)/lipopolysaccharide (LPS; 27 ug/27 ul) was treated intraperitoneally (i.p.). The i.t. pretreatment with clonidine (5 ug/5 ul) increased the blood glucose level and attenuated mortality induced by sepsis in a dose-dependent manner. The i.t. post-treatment with clonidine up to 3 h caused an elevation of the blood glucose level and protected sepsis-induced mortality, whereas clonidine post-treated at 6, 9, or 12 h did not affect. The pre-treatment with oral D-glucose for 30 min prior to i.t. post-treatment (6 h) with clonidine did not rescue sepsis-induced mortality. In addition, i.t. pretreatment with pertussis toxin (PTX) reduced clonidine-induced protection against mortality and clonidine-induced hyperglycemia, suggesting that protective effect against sepsis-induced mortality seems to be mediated via activating PTX-sensitive G-proteins in the spinal cord. Moreover, pretreatment with clonidine attenuated the plasma tumor necrosis factor alpha (TNF-alpha) induced by sepsis. Clonidine administered i.t. or i.p. increased p-AMPKalpha1 and p-AMPKalpha2, but decreased p-Tyk2 and p-mTOR levels in both control and sepsis groups, suggesting that the up-regulations of p-AMPKalpha1 and p-AMPKalpha2, or down-regulations of p-mTOR and p-Tyk2 may play critical roles for the protective effect of clonidine against sepsis-induced mortality. PMID- 28883755 TI - Effect of glucose level on chemical hypoxia- and hydrogen peroxide-induced chemokine expression in human glioblastoma cell lines. AB - Glioblastoma multiforme (GBM) is the most common primary intracranial tumor in adults and has poor prognosis. The GBM-specific tumor microenvironment (TME) plays a crucial role in tumor progression, immune escape, local invasion, and metastasis of GBM. Here, we demonstrate that hypoxia, reactive oxygen species (ROS), and differential concentration of glucose influence the expression of cytokines and chemokines, such as IL-6, IL-8, and IP-10, in human glial cell lines. Treatment with cobalt chloride (CoCl2) and hydrogen peroxide (H2O2) significantly increased the expression levels of IL-6, IL-8, and IP-10 in a dose dependent manner in CRT-MG and U251-MG astroglioma cells, but not in microglia cells. However, we found strikingly different patterns of expression of cytokines and chemokines between H2O2-treated CRT-MG cells cultured in low- and high glucose medium. These results suggest that astroglioma and microglia cells exhibit distinct patterns of cytokine and chemokine expression in response to CoCl2 and H2O2 treatment, and different concentrations of glucose influence this expression under either hypoxic or oxidant-enriched conditions. PMID- 28883756 TI - Sodium butyrate has context-dependent actions on dipeptidyl peptidase-4 and other metabolic parameters. AB - Sodium butyrate (SB) has various metabolic actions. However, its effect on dipeptidyl peptidase 4 (DPP-4) needs to be studied further. We aimed to evaluate the metabolic actions of SB, considering its physiologically relevant concentration. We evaluated the effect of SB on regulation of DPP-4 and its other metabolic actions, both in vitro (HepG2 cells and mouse mesangial cells) and in vivo (high fat diet [HFD]-induced obese mice). Ten-week HFD-induced obese C57BL/6J mice were subjected to SB treatment by adding SB to HFD which was maintained for an additional 16 weeks. In HepG2 cells, SB suppressed DPP-4 activity and expression at sub-molar concentrations, whereas it increased DPP-4 activity at a concentration of 1,000 uM. In HFD-induced obese mice, SB decreased blood glucose, serum levels of insulin and IL-1beta, and DPP-4 activity, and suppressed the increase in body weight. On the contrary, various tissues including liver, kidney, and peripheral blood cells showed variable responses of DPP-4 to SB. Especially in the kidney, although DPP-4 activity was decreased by SB in HFD-induced obese mice, it caused an increase in mRNA expression of TNF alpha, IL-6, and IL-1beta. The pro-inflammatory actions of SB in the kidney of HFD-induced obese mice were recapitulated by cultured mesangial cell experiments, in which SB stimulated the secretion of several cytokines from cells. Our results showed that SB has differential actions according to its treatment dose and the type of cells and tissues. Thus, further studies are required to evaluate its therapeutic relevance in metabolic diseases including diabetes and obesity. PMID- 28883757 TI - Time-dependent proteomic and genomic alterations in Toll-like receptor-4 activated human chondrocytes: increased expression of lamin A/C and annexins. AB - Activation of Toll-like receptor-4 (TLR-4) in articular chondrocytes increases the catabolic compartment and leads to matrix degradation during the development of osteoarthritis. In this study, we determined the proteomic and genomic alterations in human chondrocytes during lipopolysaccharide (LPS)-induced inflammation to elucidate the underlying mechanisms and consequences of TLR-4 activation. Human chondrocytes were cultured with LPS for 12, 24, and 36 h to induce TLR-4 activation. The TLR-4-induced inflammatory response was confirmed by real-time PCR analysis of increased interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) expression levels. In TLR-4 activated chondrocytes, proteomic changes were determined by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-mass spectroscopy analysis, and genomic changes were determined by microarray and gene ontology analyses. Proteomics analysis identified 26 proteins with significantly altered expression levels; these proteins were related to the cytoskeleton and oxidative stress responses. Gene ontology analysis indicated that LPS treatment altered specific functional pathways including 'chemotaxis', 'hematopoietic organ development', 'positive regulation of cell proliferation', and 'regulation of cytokine biosynthetic process'. Nine of the 26 identified proteins displayed the same increased expression patterns in both proteomics and genomics analyses. Western blot analysis confirmed the LPS-induced increases in expression levels of lamin A/C and annexins 4/5/6. In conclusion, this study identified the time dependent genomic, proteomic, and functional pathway alterations that occur in chondrocytes during LPS-induced TLR-4 activation. These results provide valuable new insights into the underlying mechanisms that control the development and progression of osteoarthritis. PMID- 28883758 TI - Hydroquinone suppresses IFN-beta expression by targeting AKT/IRF3 pathway. AB - Previous studies have demonstrated the role of hydroquinone (HQ), a hydroxylated benzene metabolite, in modulating various immune responses; however, its role in macrophage-mediated inflammatory responses is not fully understood. In this study, the role of HQ in inflammatory responses and the underlying molecular mechanism were explored in macrophages. HQ down-regulated the expression of interferon (IFN)-beta mRNA in LPS-stimulated RAW264.7 cells without any cytotoxicity and suppressed interferon regulatory factor (IRF)-3-mediated luciferase activity induced by TIR-domain-containing adapter-inducing interferon beta (TRIF) and TANK-binding kinase 1 (TBK1). A mechanism study revealed that HQ inhibited IRF-3 phosphorylation induced by lipopolysaccharide (LPS), TRIF, and AKT by suppressing phosphorylation of AKT, an upstream kinase of the IRF-3 signaling pathway. IRF-3 phosphorylation is highly induced by wild-type AKT and poorly induced by an AKT mutant, AKT C310A, which is mutated at an inhibitory target site of HQ. We also showed that HQ inhibited IRF-3 phosphorylation by targeting all three AKT isoforms (AKT1, AKT2, and AKT3) in RAW264.7 cells and suppressed IRF-3-mediated luciferase activities induced by AKT in HEK293 cells. Taken together, these results strongly suggest that HQ inhibits the production of a type I IFN, IFN-beta, by targeting AKTs in the IRF-3 signaling pathway during macrophage-mediated inflammation. PMID- 28883759 TI - The advantage of topographic prominence-adopted filter for the detection of short latency spikes of retinal ganglion cells. AB - Electrical stimulation through retinal prosthesis elicits both short and long latency retinal ganglion cell (RGC) spikes. Because the short-latency RGC spike is usually obscured by electrical stimulus artifact, it is very important to isolate spike from stimulus artifact. Previously, we showed that topographic prominence (TP) discriminator based algorithm is valid and useful for artifact subtraction. In this study, we compared the performance of forward backward (FB) filter only vs. TP-adopted FB filter for artifact subtraction. From the extracted retinae of rd1 mice, we recorded RGC spikes with 8*8 multielectrode array (MEA). The recorded signals were classified into four groups by distances between the stimulation and recording electrodes on MEA (200-400, 400-600, 600-800, 800-1000 um). Fifty cathodic phase-1st biphasic current pulses (duration 500 us, intensity 5, 10, 20, 30, 40, 50, 60 uA) were applied at every 1 sec. We compared false positive error and false negative error in FB filter and TP-adopted FB filter. By implementing TP-adopted FB filter, short-latency spike can be detected better regarding sensitivity and specificity for detecting spikes regardless of the strength of stimulus and the distance between stimulus and recording electrodes. PMID- 28883760 TI - Retraction notice to: Myosin VI contributes to malignant proliferation of human glioma cells. AB - [This retracts the article on p. 139 in vol. 20, PMID: 26937209.]. PMID- 28883761 TI - Properties and applied use of the mosquitocidal bacterium, Bacillus sphaericus. AB - Strains of Bacillus sphaericus exhibit varying levels of virulence against mosquito larvae. The most potent strain, B. sphaericus 2362, which is the active ingredient in the commercial product VectoLex(r), together with another well known larvicide Bacillus thuringiensis subsp. israelensis, are used to control vector and nuisance mosquito larvae in many regions of the world. Although not all strains of B. sphaericus are mosquitocidal, lethal strains produce one or two combinations of three different types of toxins. These are (1) the binary toxin (Bin) composed of two proteins of 42 kDa (BinA) and 51 kDa (BinB), which are synthesized during sporulation and co-crystallize, (2) the soluble mosquitocidal toxins (Mtx1, Mtx2 and Mtx3) produced during vegetative growth, and (3) the two component crystal toxin (Cry48Aa1/Cry49Aa1). Non-mosquitocidal toxins are also produced by certain strains of B. sphaericus, for examples sphaericolysin, a novel insecticidal protein toxic to cockroaches. Larvicides based on B. sphaericus-based have the advantage of longer persistence in treated habitats compared to B. thuringiensis subsp. israelensis. However, resistance is a much greater threat, and has already emerged at significant levels in field populations in China and Thailand treated with B. sphaericus. This likely occurred because toxicity depends principally on Bin rather than various combinations of crystal (Cry) and cytolytic (Cyt) toxins present in B. thuringiensis subsp. israelensis. Here we review both the general characteristics of B. sphaericus, particularly as they relate to larvicidal isolates, and strategies or considerations for engineering more potent strains of this bacterium that contain built-in mechanisms that delay or overcome resistance to Bin in natural mosquito populations. PMID- 28883762 TI - Telephone-assisted CPR: A literature review. AB - INTRODUCTION: Despite numerous efforts, out-of-hospital cardiac arrest (OHCA) survival has not significantly increased in recent decades. The first telephone assisted cardiopulmonary resuscitation (T-CPR) studies were published in the 1980s, but only in the last decade has T-CPR been implemented in dispatch centers. T-CPR is still not available in all dispatch centers and no national or international T-CPR recommendations are available. METHODS: Studies from PubMed were identified and evaluated. Preliminary information from the European Dispatch Center Survey (EDiCeS) is also included. RESULTS: In all, 42 studies were included. T-CPR is implemented in 87.6 % of those dispatch centers which have joined the not-yet published EDiCeS. According to German Resuscitation Registry data, about 10 % of OHCA patients received T-CPR in 2014. Agonal breathing is the leading cause for nonrecognition of OHCA by the dispatcher. Sensitivity of OHCA recognition by the dispatcher is about 75 %, whereby 8-45 % of these patients were not in cardiac arrest. The time interval from call to first compression is 140-328 s. Instructing rescue breathing by telephone is time consuming, leads to extensive hands-off times, and often to ineffective ventilation; therefore, rescue breathing is not indicated in adults with primary cardiac arrest. Studies showed improved survival with standardized T-CPR implementation. CONCLUSION: T CPR is established in many dispatch centers. However, emergency call interrogation and T-CPR vary between dispatch centers and are often performed without evaluation. International recommendations with standardized quality control are necessary and may lead to improved survival. PMID- 28883763 TI - Cyberknife stereotactic radiosurgery and denosumab for giant cell tumour of the skull base: Case report. AB - Giant cell tumours (GCT) of the skull is a rare entity with only small number of cases reported in literature and optimal treatment is yet to be determined. These tumours have shown high recurrence rates after incomplete surgery, usually occurring during the first year. Even with new surgical techniques a complete resection in skull base tumours is not always possible without functional compromise. Therefore, adjuvant therapy is essential to enhance local control and quality of life. We report a rare case of a 34-year-old male with giant cell tumour (GCT) of the skull base involving the petrous bone, clivus and sphenoid body. The patient received Cyberknife stereotactic radiosurgery (CK SRS) and denosumab after surgery. This combined therapy allowed local control and tumour reduction with secondary neurological improvement during a 4-year follow up. PMID- 28883764 TI - Prognostic significance, diagnosis and treatment in patients with gastric cancer and positive peritoneal washings. A review of the literature. AB - Peritoneal dissemination is a common consequence of a relapse following a radical surgical treatment of gastric cancer. The development of the disease in the peritoneum depends not only on its stage, but also on free cancer cells exfoliated from the tumor mass or from involved lymph nodes, and which are capable of being implanted in the peritoneum. According to the latest TNM (7 edition; 2010) classification, patients with free cancer cells in the peritoneal washings qualify for stage IV of the disease. Patients in whom free cancer cells were found during the operation - have a recurrence of gastric cancer - mainly in the peritoneum, and the majority of them die within two years of the diagnosis. To properly assess the prognosis, it is vital to determine the stage of cancer by additionally assessing the washings for the presence of free cancer cells before taking a therapeutic decision. This also allows identifying those patients who require different medical procedures to obtain the best treatment results possible. Medical literature describes various methods of examining peritoneal washings aimed at detecting free cancer cells. The methods apply different cancer cell detection rates, sensitivity and specificity in prediction of a peritoneal relapse. Oncological Departments performing the evaluation of the washings employ non-standard methods of treatment in this group of patients and the results presented are promising. PMID- 28883765 TI - Software-based evaluation of a class solution for prostate IMRT planning. AB - AIM: To use plan analysis software to evaluate a class solution for prostate intensity modulated radiotherapy (IMRT) planning. BACKGROUND: Class solutions for radiotherapy planning are increasingly being considered for streamlining planning. Plan analysis software provides an objective approach to evaluating radiotherapy plans. MATERIALS AND METHODS: Three iterations of a class solution for prostate IMRT planning (T1, T2 and Tfinal) were compared to the clinical plan of 74 prostate patients using radiotherapy plan analysis software (Plan IQTM, Sun Nuclear Corporation). A set of institution-specific plan quality metrics (scores) were established, based on best practice guidelines. RESULTS: For CTV coverage, Tfinal was not significantly different to the clinical plan. With the exception of 95% PTV coverage, Tfinal metrics were significantly better than the clinical plan for PTV coverage. In the scoring analysis, mean dose, 95% and 107% isodose coverage scores were similar for all the templates and clinical plan. 100% coverage of the CTV clinical plan was similar to Tfinal but scored higher than T1 and T2. There were no significant differences between Tfinal and the clinical plan for the metrics and scores associated with organs at risk. The total plan score was similar for Tfinal and the clinical plan, although the scores for volume receiving total dose outside the PTV were higher for Tfinal than for the clinical plan (P < 0.0001). CONCLUSIONS: The radiotherapy plan analysis software was useful for evaluating a class solution for prostate IMRT planning and provided evidence that the class solution produced clinically acceptable plans for these patients. PMID- 28883766 TI - Intraoral stents in preventing adverse radiotherapeutic effects in lip cancer patients. AB - AIM: To fabricate and evaluate the efficacy of individualized intraoral stents to minimize the potential side effects of radiation on oral tissues in patients with early stages of lip cancer. BACKGROUND: Lower lip cancer is a common tumor found almost exclusively in middle-aged and elderly males. Surgery is the most common treatment of choice, although for less extensive lesions, exclusive radiotherapy may be preferred. Some studies have found that the use of intraoral stents in patients with intraoral cancer (e.g., of the tongue or floor of the mouth) obtained favorable results in preventing unnecessary radiation doses to adjacent normal tissue and reducing oral complications. However, studies investigating the efficacy of individualized intraoral stents in patients with lip cancer have not been reported in the literature. MATERIALS AND METHODS: Six patients with early stage lip cancer were eligible for curative radiotherapy and personalized intraoral stents. The stents were fabricated and all participants were evaluated for the occurrence of oral complications. RESULTS: The regions of the oral mucosa protected from radiation by intraoral stents showed no mucositis. One patient complained of mild oral dryness but without interference in habits. At follow-up, none of the patients had late xerostomia or signs of dental caries by radiation. CONCLUSIONS: The use of individualized intraoral stents was shown to be promising in reducing the adverse effects of radiation therapy in lip cancer patients. These findings highlight the importance of a multidisciplinary team during oncological therapy. PMID- 28883767 TI - The Knowledge, Attitudes and Practices of Nurses Toward Management of Hospital acquired Infections in the University Clinical Center of Kosovo. AB - BACKGROUND: Hospital Acquired Infections (HAIs) are called those infections that were not present at the time of patient' hospitalization in a hospital or other medical institutions and have been acquired after hospitalization. AIM: The aim of this paper was to investigate the level of knowledge, attitudes, and practices of nurses about preventing the spread and management of HAIs at University Clinical Center of Kosovo (UCCK). METHODS: The questionnaire was used as a tool for data collection in 6 clinics of UCCK during the November-December 2016. Out of 350 nurses, only 331 returned the questionnaire completed. Data were analyzed with descriptive and inferential statistics using Statistical Package-SPSS, version 22. RESULTS: The age of participants was 37.9 +/- 9.3 years by the mean. The general level of knowledge of nurses about the spread of HAIs was 90%, about the attitudes was 84.4% and about the nurses' practices was 76.2%. The work experience had a significant impact on the nurses' knowledge about management of HAIs OR = 2.18 (95% Cl 1.01-4.71), the attitudes of nurses OR = 3.99 (95% Cl 2.14 7.45) and the nurses' practices OR = 2.87 (95% Cl 1.65-4.99). The impact of the level of education in the knowledge OR = 0.22 (95% Cl 0.10-0.48) was significant (p <0.05), while its impact in the nurses' attitudes OR = 0.59 (95% Cl 0.32-1.09) and the nurses' practices OR = 0.8 (95% Cl 0.46-1.38) was not statistically significant (p>0.05). CONCLUSION: Nurses stated that they had the necessary competencies to practice safe patient care. However, there are necessary joint efforts of policymakers and managers of UCCK to implement intervention strategies in order to reduce HAIs. PMID- 28883768 TI - Comparison of Statistical Models of Predict the Factors Affecting the Length of Stay (LOS) in the Intensive Care Unit (ICU) of a Teaching Hospital. AB - INTRODUCTION: Modeling can be a useful tool to find out how the distributions of hospital length of stay (LOS) and the factors affecting the length of stay. The present study aims to determine factors affecting the length of stay and selecting suitable statistical models. MATERIAL AND METHOD: this is a cross - sectional study of 565 patients who were treated in the intensive care unit of Imam Khomeini hospital in Ahwaz. Preliminary data were collected retrospectively through the medical records of all patients admitted on intensive care units of Ahwaz Imam Khomeini Hospital in 2015. Statistical analysis and multivariate regression models were done using of SPSS 21 and STATA 7 software. RESULTS: Average length of stay in ICU was 8.16+/-0.75 days. The Mean and Median age of patients were 58.61+/-20 and 61 respectively, The Mean LOS for females (16.44+/ 9.37 days) was more than the men (11.5+/-5.35 days) (p<0.01). The maximum and minimum lengths of stay belonged to patients with endocrine disorders (14.7+/-3.1 days) and patients with gastrointestinal disorders (5.53+/-1.1 days) respectively (p<0.01). The goodness of fit for Gamma model showed that this model was more suitable and powerful than Log-normal model to predict the factors affecting the patient's length of stay in intensive care units of hospital. CONCLUSION: Gamma regression model was more robust to predict factors regarding the hospital length of stay. According to Gamma model the key factor in predicting the length of stay in ICU was the type of disease diagnosis. The result of statistical modeling can help managers and policy makers to estimate hospital resources and allocate them for different hospital services. PMID- 28883769 TI - Influence of Unemployment on Mental Health of the Working Age Population. AB - INTRODUCTION: Bosnia and Herzegovina has one of the highest unemployment rates in the Balkan region (43.2%), so unemployment is one of the most serious public concerns in our country. AIM: To analyze the influence of unemployment on mental health of the working age population who attend primary care center. MATERIAL AND METHODS: The study was carried out in the municipality of Bosanska Krupa, which has the highest unemployment rate in the Federation of Bosnia and Herzegovina (56%), and included 510 randomly selected working age patients (aged 23-65 years). We used the General Health Questionnaire-28 (GHQ-28) to evaluate mental health of the working age population. RESULTS: There were significantly more women than men (53.5% vs. 46.5%; p=0.02). The mean age of participants was 51.04+/-12.84 years. The experimental group included 318 (62.35%) unemployed working age participants: 160 (50.3%) had been unemployed for more than 5 years and had had no work experience, while 158 (49.7%) unemployed participants had had a previous work experience of more than five years. The control group included 192 (37.65%) employed working age participants. Unemployment had a significant influence on mental health of the working age population. The unemployed participants had a significantly poorer mental health compared to the employed (p=0.0003). A predictor of impaired mental health was a job loss. A significantly greater mental health impairment occured in the group of unemployed participants with previous work experience of more than five years compared to the unemployed participants who had had no work experience (p=0.001) and employed (p=0.000). CONCLUSION: Unemployment has a negative impact and leads to impaired mental health of the working age population in Bosnia and Herzegovina. A job loss has a predictive role. It indicates that social and health policies must be developed in order to improve well-being of the working age population. PMID- 28883770 TI - Frequency of Depression and its Correlation with Quality of Life of Patients with Oral Cavity Cancer. AB - INTRODUCTION: the effects of malignant tumors of oral cavity may be reflected through mental, physical, social and emotional well-being and quality of life of patients. Those suffering from malignancies show a large degree of psychological problems (fear, anxiety, depression, panic disorders, phobias) both at the time of diagnosis and during the treatment. AIM: to determine a level of depression in patients with oral cavity cancer and to link quality of life and level of depression of patients with oral cavity cancer. PATIENTS AND METHODS: The study was conducted at the Clinic of Maxillofacial Surgery of the Clinical Center University of Sarajevo (CCUS) in the period from July to late October 2015, through a survey of patients with verified oral cavity cancer, questionnaire related to socio-demographic characteristics of the patients, the University of Washington Quality of Life Questionnaire (UW-QOL), and the Beck Depression Inventory (BDI). RESULTS: Majority of patients from our study, specifically 50 (56%) of them, did not suffer from depression, 8 (9%) respondents suffered from mild depression, 14 (16%) respondents had moderate depression, whereas 17 (19%) of them had severe depression. CONCLUSION: quality of life and level of depression of patients with oral cavity cancer are in negative and almost linear correlation. The worse the evaluation results of one's physical or socio emotional health, the higher degree of depression. PMID- 28883771 TI - Behavioral Sexual Characteristics of Female Students in Bosnia and Herzegovina. AB - INTRODUCTION: Characteristics of sexual behaviour of female students, which will affect fertility in adulthood, represent one of the critical parameters of reproductive health. AIM: The aim of this study was assess characteristics of sexual behavior of female students in Bosnia and Herzegovina. MATERIALS AND METHODS: In a prospective study on a representative sample of 2,872 regular girls aged 19-24 years, an anonymous survey on the reproductive health of female students in Bosnia and Herzegovina from 2007 to 2009 was conducted. RESULTS: Of the total number (N = 2872) of surveyed female students, 49.44% were sexually active. Average sexarcha age was 18.14+/-1.83 years, and there was statistically significant earlier sexarcha in female students in Banja Luka vs. female students of the University of Sarajevo (p<0.001), as well as in female students in Mostar vs. female students of the University of Tuzla (p<0.001). Sexually active female students in 74,4 % cases had intercourses with only one partner, and 7,7 % of them had intercourses with three or more partners. Regarding the use of contraceptive methods, 69.4% female students were using contraception at first intercourse and 66.7% of them at last intercourse. 3.5% of sexually active students (N=50) had intentional abortion. Almost half (46.9%) of surveyed female students had regular pelvic exams; nearly two-third of those (63.4%) had gynecological exams in private institutions, and 36.6% of them in public health facilitie. Only one-third (35.8%) sexually active female students in BiH stated that Pap test was performed. CONCLUSION: Sexual behaviour of female students in BiH is less risky than in the immediate environment, but health care quality is poor. PMID- 28883772 TI - Comparison of Resilience and Psychological Wellbeing in Women with Irritable Bowel Syndrome and Normal Women. AB - INTRODUCTION: Resilience and Psychological Wellbeing are two important concepts in adaption of patients to chronic disease conditions. GOAL: To compare resilience and psychological wellbeing in women with irritable bowel syndrome and normal women. METHODS: This was an analytical-comparative study. The statistical population consisted of all patients with irritable bowel syndrome visiting Imam Ali Hospital in Zahedan. Of all patients, 50 female patients with irritable bowel syndrome and 50 normal women were randomly selected and matched. The research tools were resilience and psychological wellbeing scales. Collected data was assessed using multivariate analysis of variance (MANOVA). RESULTS: The results showed a difference between resilience and the components of positive relations with others, environmental mastery, purpose in life and acceptance in women with irritable bowel syndrome (IBS) and normal women (P < 0.05). CONCLUSION: more effective training programs can be designed and more efficient measures can be taken given the definite role of psychological factors (especially, resilience and psychological wellbeing) in incidence or exacerbation of physical disease symptoms in patients with irritable bowel syndrome. PMID- 28883773 TI - Emotional Profile of Women Victims of Domestic Violence. AB - INTRODUCTION: Research indicates that women victims of domestic violence show significant cognitive changes, emotional numbing, and avoidance of interpersonal relationships. AIM: The aim of this research was to analyze emotional profile of women victims of domestic violence, and to determine the relationship between dimensions of emotions and frequency of women exposure to domestic violence. METHODS: The research was conducted on the sample of 169 women, 111 were victims of domestic violence and 58 were women who did not experience domestic violence. Plutchik's Emotions Profile Index (EPI) was used for measuring of the emotion profile, and the Modified Inventory of Domestic Violence for measuring experiences of different types of violence. Basic socio-demographic data were also collected. RESULTS: Significant differences between women victims of domestic violence and women who did not experience domestic violence were found in a few dimensions of emotional profile. Women victims of domestic violence had higher results in the dimensions of deprivation/depression and aggression/destruction, while women who did not experience domestic violence had higher results in dimensions of reproduction and incorporation. Aggression was in significant negative correlation with reproduction, incorporation and self protection, whereas it was significant positive correlation with deprivation and opposition. There were significant and positive correlation between the dimensions of aggression and deprivation and frequency of all three forms of domestic violence and age of women. CONCLUSION: According to results obtained in this research, it can be concluded that women victims of domestic violence have significantly more intensive negative emotional dimensions in comparison to women who were not abused. Women victims of domestic violence with higher frequency of abuse describe themselves as more sad, apathetic, lonely, angry, quarrelsome and less sociable. Prominence of negative emotions, deprivation and aggression, can be factor of risk for mental health disorders and for re-victimisation of women victims of domestic violence. PMID- 28883774 TI - Palliative Care: a Cross Sectional Study Focused on Different Capacity Building Programmes Evaluated Through Self- Rated Knowledge and Efficiency in Family Medicine Tutors. AB - AIM: Educational possibilities in palliative care have been overseen in this part of Europe and therefore this important issue should be addressed to implement current treatment palliative care in Slovenia. This study was the first in Slovenia dealing with the self-rated knowledge and self-efficacy associated with educational programmes attended about palliative medicine at primary health care level. MATERIAL AND METHODS: Material for our work was general practitioner (GP) who work in education like tutors. A cross-sectional study was carried out from July to November 2015 with participation of them. For the purpose of the study (self-assessment of knowledge and efficacy), the validated questionnaire Palliative Kompetenztest (PKT) was applied with added some demographical data. 138 of the 250 invited GP answered the questionnaire. RESULTS: Knowledge was averagely assessed with 23.0 +/- 4.0 (out of 34) and self-efficacy achieved 38.5 +/- 8.6 out of 54 points. Physicians who attended "Step by step" educational model, rated their knowledge (26.2 +/- 3.4 (p < 0.001)) and self-efficacy higher (41.9 +/- 7.7 (p < 0.010)) in comparison with those who attended conferences and other palliative care related capacity building programmes. CONCLUSION: When taking into account self-assessed knowledge and efficacy in palliative care, it was shown the capacity-building program "Step by step" to be an effective model for GPs. However, self-perceived efficiency due to past experience was also shown to be associated with the efficiency score, therefore we should be restrained in favouring specific capacity building programme at this time. PMID- 28883775 TI - Seasonal and Monthly variation in stroke and its subtypes-10 Year Hospital-Based Study. AB - BACKGROUND AND OBJECTIVES: There is no evidence of long-term studies of seasonal variations in stroke in Iran. Hence, the aim of this study was to determine the seasonal and monthly variation of 28-day mortality in Isfahan, Iran. METHODS: From 2003 to 2013, In a Hospital-based retrospective study, 24186 cases with first-ever stroke were analyzed in Isfahan. Multinomial logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for seasonal and monthly 28-day mortality for stroke in general and three subtypes of stroke including intracranial hemorrhage (ICH), ischemic (IS) and subarachnoid hemorrhage (SAH). RESULTS: In this study, unadjusted and adjusted odds ratios of seasonal 28-day mortality of stroke was highest in the winter and lowest in the summer. Although, differences were not statistically significant. For total and IS stroke, the unadjusted 28-day mortality ratio (UMR) was significant in February (1.19, 95% CI 1.00 -1.42, P= 0.04) as compared to March. Whereas after adjusted, for total stroke, 28-day mortality was significantly lowest in May (0.746, 95% CI 0.575-0.97, p=0.029), June (0.777, 95% CI 0.60-0.99, p=0.49) and July (0.771, 95% CI 0.59-0.99 p=0.049) as compared to March. The AMR between months were not significant in SAH and IS. CONCLUSION: Our findings demonstrate clear obvious monthly variation of 28-day mortality of stroke and its subtypes in Isfahan but no seasonal variations were observed. PMID- 28883776 TI - Receptive Vocabulary and Cognition of Elderly People in Institutional Care. AB - INTRODUCTION: Basic cognitive functions such as: alertness, working memory, long term memory and perception, as well as higher levels of cognitive functions like: speech and language, decision-making and executive functions are affected by aging processes. Relations between the receptive vocabulary and cognitive functioning, and the manifestation of differences between populations of elderly people based on the primary disease is in the focus of this study. AIM: To examine receptive vocabulary and cognition of elderly people with: verified stroke, dementia, verified stroke and dementia, and without the manifested brain disease. MATERIAL AND METHODS: The sample consisted of 120 participants older than 65 years, living in an institution. A total of 26 variables was analyzed and classified into three groups: case history/anamnestic, receptive vocabulary assessment, and cognitive assessments. The interview with social workers, nurses and caregivers, as well as medical files were used to determine the anamnestic data. A Montreal Cognitive Assessment Scale (MoCA) was used for the assessment of cognition. In order to estimate the receptive vocabulary, Peabody Picture Vocabulary Test was used. RESULTS: Mean raw score of receptive vocabulary is 161.58 (+-21:58 points). The best results for cognitive assessment subjects achieved on subscales of orientation, naming, serial subtraction, and delayed recall. Discriminative analysis showed the significant difference in the development of receptive vocabulary and cognitive functioning in relation to the primary disease of elderly people. The biggest difference was between subjects without manifested brain disease (centroid = 1.900) and subjects with dementia (centroid = -1754). CONCLUSION: There is a significant difference between elderly with stroke; dementia; stroke and dementia, and elderly people without manifested disease of the brain in the domain of receptive vocabulary and cognitive functioning. Variables of serial subtraction, standardized test results of receptive vocabulary, delayed recall, abstraction, orientation and vigilance successfully discriminate studied groups. PMID- 28883777 TI - Importance of Early Detection of Potentially Malignant Lesions in the Prevention of Oral Cancer. AB - OBJECTIVE: The aim of this study was to assess the importance of early diagnosis of potentially malignant lesions in the prevention of oral cancer. MATERIAL AND METHODS: In order to achieve the set objectives, we selected our participant pool. Of the 340 patients who came to the initial examination at the Clinic for Oral Medicine and Periodontology, we selected 40 patients with potentially malignant oral lesions (PMOL) of both sexes and of different ages. After an extensive anamnesis and a clinical examination of all mucous membranes, we documented potentially malignant lesions, their localization, subjective and objective symptoms, duration of pathological lesion, and bad habits (smoking and alcohol). All lesions were colored with Toluidine blue, which indicates malignancy in 75% of cases. Patients who had a positive Toluidine blue staining test were sent to biopsy and pathohistological analysis. RESULTS: The most common potentially malignant lesions are Lichen reticularis (25%), Lichen erosivus (20%), and Leukoplakia (15%). The most common localization of lesions is the buccal mucosa bilaterally (26%), buccal mucosa unilaterally (10%), and the lower lip (10%). The staining test with Toluidine blue was positive at 23% PMOLs. In patients with positive Toluidine staining findings, biopsy and pathohistological analysis were performed, which showed that 20% of all lesions are carcinoma (CIS, Baseocellular Carcinoma, Squamocellular Carcinoma), while 14% are mucosal epithelial dysplasia. Statistical analysis confirmed the significance of positive staining of Toluidine blue and Leukoplakia (Spearman's coefficient = 0.427, p = 0.006, N = 40), and statistically significant positive association of Squamocellular Carcinoma and Toluidine blue staining (Spearman's coefficient = 0.619, p = 0.000, N = 40). CONCLUSION: Most oral cancers are caused by potentially malignant lesions, which is why a very detailed clinical examination with the visualization of pathological lesions is very important. Toluidine blue test can be an auxiliary tool for clinical diagnosis but does not replace the pathohistological finding. Biopsy and pathohistological findings are the gold standard in the diagnosis of oral cancers, as confirmed in our research. PMID- 28883778 TI - Examination of Risk Factors for the Development of Surgical Site Infections. AB - INTRODUCTION: Hospital-acquired infections (HAI) and surgical site infections (SSI) are a global public health problem. The aim of the study was to determine the incidence of SSIs at the Surgical Clinics of the University Clinical Centre Banja Luka and to identify risk factors for the development of SSIs. METHODS: In order to determine the frequency of SSIs through the incidence compared to the patients operated at the Surgical Clinics of the University Clinical Centre Banja Luka, we conducted a prospective cohort study which encompassed 11.216 operated patients, in the period from November 11th, 2014 to September 30th, 2015. In order to identify risk factors for the development of SSIs, a nested case-control study of risk factors for SSIs was conducted. The study group consisted of patients who were diagnosed with SSIs in the period of monitoring, while the control group was consisted of patients without SSIs who corresponded with the study group in age and sex. RESULTS: The highest values of incidence of SSIs were observed at the Department of Anesthesia and Intensive Care (2.65%), Department of Orthopaedic Surgery (2.48%) and the Department of Vascular Surgery (2.15%), and the lowest ones at the Department of Urology (0.59%). Among the cases of SSIs, deep infections of the surgical site were the most represented (82.7%). Multivariate logistic regression was used to identify the following independent risk factors: length of pore-operative stay in hospital (p=0.000; OR=1.062; 95% CI=1.037-1.087), reintervention (p=0.000; OR=22.409; 95% CI=6.361-79.071) and cotrticosteroids (p=0.023; OR=4.141; 95%CI=1.221-14.047). CONCLUSION: The incidence of SSIs at the Surgical Clinics of the University Clinical Centre Banja Luka is at the level of hospitals in developed countries. There are a number of risk factors for SSIs, which may be prevented. PMID- 28883779 TI - Users' Knowledge About Adverse Effects of Non-steroidal Anti-inflammatory Drugs in Tirana, Albania. AB - AIM: To assess the level of knowledge of the adult users of non-steroidal anti inflammatory drugs (NSAIDs) regarding their side effects and the socio demographic factors associated with the use of these drugs in the adult population of Albania. METHODS: This was a cross-sectional study including a representative sample of 199 individuals aged >=18 years (77% women; overall mean age: 30.3+/-10.0 years; overall response rate: 90%) who were users of NSAIDs recruited in ten different pharmacies in Tirana municipality during April-May 2015. A self-administered questionnaire contained basic socio-demographic information and questions about NSAIDs use, their types, participants' knowledge about NSAIDs side effects and their interaction with other drugs. RESULTS: In 56% of the cases, NSAIDs were taken by participants' own decisions, whereas in about 29% of the cases these drugs were prescribed by physicians. Acetaminophen, ketoprofen and ibuprofen were the most frequently used NSAIDs. Overall, 51% of participants thought NSAIDs could cause allergic reactions, whereas one third or fewer were aware of each of the following side effects: upper and lower gastrointestinal bleeding, hypertension, gastritis, kidney failure, myopathy, osteoporosis. About one third of participants were aware of NSAIDs-other drug interactions, whereas some of them were already taking contraindicated drugs. No significant differences were noticed regarding sex, age, educational level, employment status and marital status, with very few exceptions. CONCLUSION: Our findings indicate limited knowledge about NSAIDs side effects and their interaction with other drugs among the Albania adult population, which is a cause of concern. PMID- 28883780 TI - Intended Career Choice in Family Medicine in Slovenia: An Issue of Gender, Family Background or Empathic Attitudes in Final Year Medical Students? AB - BACKGROUND: Among a variety of complex factors affecting a decision to take family medicine as a future specialisation, this study focused on demographic characteristics and assessed empathic attitudes in final year medical students. METHODS: A convenience sampling method was employed in two consecutive academic years of final year medical students at the Faculty of Medicine in Ljubljana, Slovenia, in May 2014 and May 2015. A modified version of the 16-item Jefferson Scale of Empathy - Student Version (JSE-S) was administered to examine self reported empathic attitudes. An intended career in family medicine was reported using a five-point Likert scale. RESULTS: Of the 175 medical school seniors in study year 2013/14, there were 64 (36.6%) men and 111 (63.4%) women, while in the second group (study year 2014/5), there were 68 (40.5%) men and 100 (59.5%) women; 168 students in total. They were 24.9+/-1.6 (generation 2013/4) and 24.9+/ 1.7 (generation 2014/15) years old. Thirty-six percent of the students in the academic year 2013/14 intended to choose family medicine as a future career, and a similar proportion in academic year 2014/15 (31.7%). Gender (chi2=6.763, p=0.034) and empathic attitudes (c2=14.914; p=0.001) had a bivariate association with an intended career choice of family medicine in the 2014/15 generation. When logistic regression was applied to this group of students, an intended career choice in family medicine was associated with empathic attitudes (OR 1.102, 95% CI 1.040-1.167, p=0.001), being single (OR 3.659, 95% CI 1.150-11.628, p=0.028) and the father having only primary school education (OR 142.857 95% CI 1.868, p=0.025), but not with gender (OR 1.117, 95% CI 0.854-1.621, p=0.320). CONCLUSION: The level of students' father's education, and not living in an intimate partnership, increased the odds on senior medical students to choose family medicine, yet we expected higher JSE-S scores to be associated with interest in this speciality. To deepen our understanding, this study should be repeated to give us solid grounded insight into the determinants of career choice; associations with gender in particular need to be re-tested. PMID- 28883781 TI - Bosnian Franciscans and the Monasteries in Kresevo and Fojnica as Source of Scientific Bibliography. AB - All of these centuries-old records contain enormous treasures, and the modern medicine is increasingly searching for the sources of natural remedies. The Franciscans should be credited for carefully collecting the methods folk treatment and passed them on to future generations. In the words of Br. Marko Karamatic: "The fact that the Friars were engaged in healthcare, that they became the first graduate doctors in Bosnia and Herzegovina, that they wrote" herbal manuals " and other medical records, is the result of historical opportunities in these areas, and this activity became one of the most important tasks for the Franciscans. They performed their duties regardless of the circumstances. PMID- 28883782 TI - The Acceptability and Feasibility of Screening for Alcohol and Drug Misuse in a Hospital Emergency Department. AB - OBJECTIVES: Screening and brief intervention (SBI) is an evidence-based technique for reducing harmful consumption of alcohol and other drugs, which has been shown to be effective in Emergency Departments (EDs). The feasibility of SBI in the ED, however, remains contentious and no studies have been conducted on this topic in a New Zealand ED. MATERIALS AND METHODS: This study recruited 8 experienced ED nurses who attempted to provide SBI, using the ASSIST-Lite tool, to as many of their patients as possible over one calendar month. All nurses participated in a comprehensive 1-day training workshop on the administration and interpretation of the ASSIST-Lite and linked brief intervention. RESULTS: Only 46 (11.79%) of the 390 eligible patients were given the opportunity to participate over the data collection period. Analysis of the data showed there was a significant, negative correlation between the number of patients in the ED and the average number of screens that were performed by the nurses, and that the number of screens waned immediately after SBI training. Following the data collection period, the nurse participants were interviewed about their experience. These interviews revealed 3 main themes that contextualized the willingness to, but inherent difficulty of, administering the SBI within the ED environment. CONCLUSIONS: High patient-to nurse ratios in the ED currently preclude nurses from providing consistent SBI to all eligible patients; however, there are several practical considerations highlighted here that might help nurses increase the participation rate. PMID- 28883783 TI - Performing Arm-Based Network Meta-Analysis in R with the pcnetmeta Package. AB - Network meta-analysis is a powerful approach for synthesizing direct and indirect evidence about multiple treatment comparisons from a collection of independent studies. At present, the most widely used method in network meta-analysis is contrast-based, in which a baseline treatment needs to be specified in each study, and the analysis focuses on modeling relative treatment effects (typically log odds ratios). However, population-averaged treatment-specific parameters, such as absolute risks, cannot be estimated by this method without an external data source or a separate model for a reference treatment. Recently, an arm-based network meta-analysis method has been proposed, and the R package pcnetmeta provides user-friendly functions for its implementation. This package estimates both absolute and relative effects, and can handle binary, continuous, and count outcomes. PMID- 28883784 TI - Neuroscience of Compulsive Eating Behavior. AB - A systematic characterization of compulsivity in pathological forms of eating has been proposed in the context of three functional domains: (1) habitual overeating; (2) overeating to relieve a negative emotional state; and (3) overeating despite aversive consequences. In this review, we provide evidence supporting this hypothesis and we differentiate the nascent field of neurocircuits and neurochemical mediators of compulsive eating through their underlying neuropsychobiological processes. A better understanding of the neurobiological mechanisms that lead to compulsive eating behavior can improve behavioral and pharmacological intervention for disorders of pathological eating. PMID- 28883785 TI - Early Postnatal but Not Late Adult Neurogenesis Is Impaired in the Pitx3-Mutant Animal Model of Parkinson's Disease. AB - The generation of new neurons in the adult dentate gyrus has functional implications for hippocampal formation. Reduced hippocampal neurogenesis has been described in various animal models of hippocampal dysfunction such as dementia and depression, which are both common non-motor-symptoms of Parkinson's disease (PD). As dopamine plays an important role in regulating precursor cell proliferation, the loss of dopaminergic neurons in the substantia nigra (SN) in PD may be related to the reduced neurogenesis observed in the neurogenic regions of the adult brain: subventricular zone (SVZ) and dentate gyrus (DG). Here we examined adult hippocampal neurogenesis in the Pitx3-mutant mouse model of PD (aphakia mice), which phenotypically shows a selective embryonic degeneration of dopamine neurons within the SN and to a smaller extent in the ventral tegmental area (VTA). Proliferating cells were labeled with BrdU in aphakia mice and healthy controls from 3 to 42 weeks of age. Three weeks old mutant mice showed an 18% reduction of proliferating cells in the DG and of 26% in the SVZ. Not only proliferation but also the number of new neurons was impaired in young aphakia mice resulting in 33% less newborn cells 4 weeks after BrdU-labeling. Remarkably, however, the decline in the number of proliferating cells in the neurogenic regions vanished in older animals (8-42 weeks) indicating that aging masks the effect of dopamine depletion on adult neurogenesis. Region specific reduction in precursor cells proliferation correlated with the extent of dopaminergic degeneration in mesencephalic subregions (VTA and SN), which supports the theory of age- and region-dependent regulatory effects of dopaminergic projections. Physiological stimulation of adult neurogenesis by physical activity (wheel running) almost doubled the number of proliferating cells in the dentate gyrus of 8 weeks old aphakia mice to a number comparable to that of wild-type mice, abolishing the slight reduction of baseline neurogenesis at this age. The described age-dependent susceptibility of adult neurogenesis to PD-like dopaminergic degeneration and its responsiveness to physical activity might have implications for the understanding of the pathophysiology and treatment of non motor symptoms in PD. PMID- 28883786 TI - Arterial Pulsations cannot Drive Intramural Periarterial Drainage: Significance for Abeta Drainage. AB - Alzheimer's Disease (AD) is the most common form of dementia and to date there is no cure or efficient prophylaxis. The cognitive decline correlates with the accumulation of amyloid-beta (Abeta) in the walls of capillaries and arteries. Our group has demonstrated that interstitial fluid and Abeta are eliminated from the brain along the basement membranes of capillaries and arteries, the intramural periarterial drainage (IPAD) pathway. With advancing age and arteriosclerosis, the stiffness of arterial walls, this pathway fails in its function and Abeta accumulates in the walls of arteries. In this study we tested the hypothesis that arterial pulsations drive IPAD and that a valve mechanism ensures the net drainage in a direction opposite to that of the blood flow. This hypothesis was tested using a mathematical model of the drainage mechanism. We demonstrate firstly that arterial pulsations are not strong enough to produce drainage velocities comparable to experimental observations. Secondly, we demonstrate that a valve mechanism such as directional permeability of the IPAD pathway is necessary to achieve a net reverse flow. The mathematical simulation results are confirmed by assessing the pattern of IPAD in mice using pulse modulators, showing no significant alteration of IPAD. Our results indicate that forces other than the cardiac pulsations are responsible for efficient IPAD. PMID- 28883787 TI - Investigations into Hypoxia and Oxidative Stress at the Optic Nerve Head in a Rat Model of Glaucoma. AB - The vascular hypothesis of glaucoma proposes that retinal ganglion cell axons traversing the optic nerve head (ONH) undergo oxygen and nutrient insufficiency as a result of compromised local blood flow, ultimately leading to their degeneration. To date, evidence for the hypothesis is largely circumstantial. Herein, we made use of an induced rat model of glaucoma that features reproducible and widespread axonal transport disruption at the ONH following chronic elevation of intraocular pressure. If vascular insufficiency plays a role in the observed axonal transport failure, there should exist a physical signature at this time point. Using a range of immunohistochemical and molecular tools, we looked for cellular events indicative of vascular insufficiency, including the presence of hypoxia, upregulation of hypoxia-inducible, or antioxidant-response genes, alterations to antioxidant enzymes, increased formation of superoxide, and the presence of oxidative stress. Our data show that ocular hypertension caused selective hypoxia within the laminar ONH in 11/13 eyes graded as either medium or high for axonal transport disruption. Hypoxia was always present in areas featuring injured axons, and, the greater the abundance of axonal transport disruption, the greater the likelihood of a larger hypoxic region. Nevertheless, hypoxic regions were typically focal and were not necessarily evident in sections taken deeper within the same ONH, while disrupted axonal transport was frequently encountered without any discernible hypoxia. Ocular hypertension caused upregulation of heme oxygenase-1-an hypoxia-inducible and redox-sensitive enzyme in ONH astrocytes. The distribution and abundance of heme oxygenase-1 closely matched that of axonal transport disruption, and encompassed hypoxic regions and their immediate penumbra. Ocular hypertension also caused upregulations in the iron-regulating protein ceruloplasmin, the anaerobic glycolytic enzyme lactate dehydrogenase, and the transcription factors cFos and p-cJun. Moreover, ocular hypertension increased the generation of superoxide radicals in the retina and ONH, as well as upregulating the active subunit of the superoxide-generating enzyme NADPH oxidase, and invoking modest alterations to antioxidant-response enzymes. The results of this study provide further indirect support for the hypothesis that reduced blood flow to the ONH contributes to axonal injury in glaucoma. PMID- 28883788 TI - Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome. AB - Inability of mitochondria to generate energy leads to severe and often fatal myoencephalopathies. Among these, Leigh syndrome (LS) is one of the most common childhood mitochondrial diseases; it is characterized by hypotonia, failure to thrive, respiratory insufficiency and progressive mental and motor dysfunction, leading to early death. Basal ganglia nuclei, including the striatum, are affected in LS patients. However, neither the identity of the affected cell types in the striatum nor their contribution to the disease has been established. Here, we used a mouse model of LS lacking Ndufs4, a mitochondrial complex I subunit, to confirm that loss of complex I, but not complex II, alters respiration in the striatum. To assess the role of striatal dysfunction in the pathology, we selectively inactivated Ndufs4 in the striatal medium spiny neurons (MSNs), which account for over 95% of striatal neurons. Our results show that lack of Ndufs4 in MSNs causes a non-fatal progressive motor impairment without affecting the cognitive function of mice. Furthermore, no inflammatory responses or neuronal loss were observed up to 6 months of age. Hence, complex I deficiency in MSNs contributes to the motor deficits observed in LS, but not to the neural degeneration, suggesting that other neuronal populations drive the plethora of clinical signs in LS. PMID- 28883789 TI - Static and Dynamic Measures of Human Brain Connectivity Predict Complementary Aspects of Human Cognitive Performance. AB - In cognitive network neuroscience, the connectivity and community structure of the brain network is related to measures of cognitive performance, like attention and memory. Research in this emerging discipline has largely focused on two measures of connectivity-modularity and flexibility-which, for the most part, have been examined in isolation. The current project investigates the relationship between these two measures of connectivity and how they make separable contribution to predicting individual differences in performance on cognitive tasks. Using resting state fMRI data from 52 young adults, we show that flexibility and modularity are highly negatively correlated. We use a Brodmann parcellation of the fMRI data and a sliding window approach for calculation of the flexibility. We also demonstrate that flexibility and modularity make unique contributions to explain task performance, with a clear result showing that modularity, not flexibility, predicts performance for simple tasks and that flexibility plays a greater role in predicting performance on complex tasks that require cognitive control and executive functioning. The theory and results presented here allow for stronger links between measures of brain network connectivity and cognitive processes. PMID- 28883790 TI - Impedance Control for Robotic Rehabilitation: A Robust Markovian Approach. AB - The human-robot interaction has played an important role in rehabilitation robotics and impedance control has been used in the regulation of interaction forces between the robot actuator and human limbs. Series elastic actuators (SEAs) have been an efficient solution in the design of this kind of robotic application. Standard implementations of impedance control with SEAs require an internal force control loop for guaranteeing the desired impedance output. However, nonlinearities and uncertainties hamper such a guarantee of an accurate force level in this human-robot interaction. This paper addresses the dependence of the impedance control performance on the force control and proposes a control approach that improves the force control robustness. A unified model of the human robot system that considers the ankle impedance by a second-order dynamics subject to uncertainties in the stiffness, damping, and inertia parameters has been developed. Fixed, resistive, and passive operation modes of the robotics system were defined, where transition probabilities among the modes were modeled through a Markov chain. A robust regulator for Markovian jump linear systems was used in the design of the force control. Experimental results show the approach improves the impedance control performance. For comparison purposes, a standard [Formula: see text] force controller based on the fixed operation mode has also been designed. The Markovian control approach outperformed the [Formula: see text] control when all operation modes were taken into account. PMID- 28883791 TI - Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells. AB - Proteasome inhibition interfering with many cell signaling pathways has been extensively explored as a therapeutic strategy for cancers. Proteasome inhibitor YSY01A is a novel agent that has shown remarkable anti-tumor effects; however, its mechanisms of action are not fully understood. Here we report that YSY01A is capable of suppressing cancer cell survival by induction of apoptosis. Paradoxically, we find that YSY01A abrogates constitutive activation of STAT3 via proteasome-independent degradation of gp130 and JAK2, but not transcriptional regulation, in human A549 non-small cell lung cancer cells. The reduction in gp130 and JAK2 can be restored by co-treatment with 3-methyladenine, an early stage autophagy lysosome and type I/III PI3K inhibitor. YSY01A also effectively inhibits cancer cell migration and lung xenograft tumor growth with little adverse effect on animals. Thus, our findings suggest that YSY01A represents a promising candidate for further development of novel anticancer therapeutics targeting the proteasome. PMID- 28883792 TI - Antidiabetic Effect of Tibetan Medicine Tang-Kang-Fu-San in db/db Mice via Activation of PI3K/Akt and AMPK Pathways. AB - This study was to investigate the anti-diabetic effects and molecular mechanisms of Tang-Kang-Fu-San (TKFS), a traditional Tibetan medicine, in treating type 2 diabetes mellitus of spontaneous diabetic db/db mice. Firstly HPLC fingerprint analysis was performed to gain the features of the chemical compositions of TKFS. Next different doses of TKFS (0.5 g/kg, 1.0 g/kg, and 2.0 g/kg) were administrated via oral gavage to db/db mice and their controls for 4 weeks. TKFS significantly lowered hyperglycemia and ameliorated insulin resistance (IR) in db/db mice, indicated by results from multiple tests, including fasting blood glucose test, intraperitoneal insulin and glucose tolerance tests, fasting serum insulin levels and homeostasis model assessment of IR analysis as well as histology of pancreas islets. TKFS also decreased concentrations of serum triglyceride, total and low-density lipoprotein cholesterol, even though it did not change the mouse body weights. Results from western blot and immunohistochemistry analysis indicated that TKFS reversed the down-regulation of p-Akt and p-AMPK, and increased the translocation of Glucose transporter type 4 in skeletal muscles of db/db mice. In all, TKFS had promising benefits in maintaining the glucose homeostasis and reducing IR. The underlying molecular mechanisms are related to promote Akt and AMPK activation and Glucose transporter type 4 translocation in skeletal muscles. Our work showed that multicomponent Tibetan medicine TKFS acted synergistically on multiple molecular targets and signaling pathways to treat type 2 diabetes mellitus. PMID- 28883793 TI - A Multilevel Analysis of Real-World Variations in Oral Anticoagulation Initiation for Atrial Fibrillation in Valencia, a European Region. AB - Introduction: Beyond clinical trials, clinical practice guidelines, and administrative regulation, treatment decision-making can be influenced by individual and contextual factors. Our goal was to describe variations in the patterns of initiation of anticoagulation therapy in patients with atrial fibrillation by Health Areas (HA) in the region of Valencia in Spain and to quantify the influence of the HAs on variations in treatment choice. Methods: We conducted a population-based retrospective cohort study of all atrial fibrillation patients who started treatment with oral anticoagulants between November 2011 and February 2014 in each of the region's 24 HAs. We described patient and utilization characteristics per HA and initiation patterns over time, and we identified contextual and individual factors associated with differences in initiation patterns. Results: 21,879 patients initiated treatment with an oral anticoagulant in the 24 HAs. Initiation with direct oral anticoagulants (DOAC) in the first year was 14.6%. In November 2013 the ratio was 25.4%, with HA ratios ranging from 3.8 to 57.1%. DOAC-initiating patients had less comorbidity but were more likely to present episodes of previous ischemic stroke, hemorrhagic stroke, or TIA when compared with patients initiating with VKA treatment. Variability among HAs was statistically significant, with the majority of HAs ranking above or below the regional initiation average (ICC ~ 8%). Conclusion: There was high variability in the percentage of DOAC initiation and in the choice of DOAC among HAs. Interventions aimed to improve DOAC initiation decision-making and to reduce variations should take into account the Health Area component. PMID- 28883794 TI - A Meta-Analysis on Sex Differences in Resting-State Vagal Activity in Children and Adolescents. AB - Lower vagal activity is associated with psychopathology independent of age. Research suggests that alterations of vagal activity precede the development of psychopathology. The present review aimed to quantify sex differences in vagal activity in children and adolescents. Studies reporting on sex differences on measures of vagally-mediated heart rate variability derived from short-term recordings under resting conditions in boys and girls were included. Drawing on data from more than 5,000 children and adolescents, we provide evidence that healthy young girls display lower vagal activity and greater mean heart rate compared to boys, a finding that may have implications for risk associated with the development of internalizing psychopathology and somatic ill-health. PMID- 28883795 TI - Atrial Electrogram Fractionation Distribution before and after Pulmonary Vein Isolation in Human Persistent Atrial Fibrillation-A Retrospective Multivariate Statistical Analysis. AB - Purpose: Complex fractionated atrial electrograms (CFAE)-guided ablation after pulmonary vein isolation (PVI) has been used for persistent atrial fibrillation (persAF) therapy. This strategy has shown suboptimal outcomes due to, among other factors, undetected changes in the atrial tissue following PVI. In the present work, we investigate CFAE distribution before and after PVI in patients with persAF using a multivariate statistical model. Methods: 207 pairs of atrial electrograms (AEGs) were collected before and after PVI respectively, from corresponding LA regions in 18 persAF patients. Twelve attributes were measured from the AEGs, before and after PVI. Statistical models based on multivariate analysis of variance (MANOVA) and linear discriminant analysis (LDA) have been used to characterize the atrial regions and AEGs. Results: PVI significantly reduced CFAEs in the LA (70 vs. 40%; P < 0.0001). Four types of LA regions were identified, based on the AEGs characteristics: (i) fractionated before PVI that remained fractionated after PVI (31% of the collected points); (ii) fractionated that converted to normal (39%); (iii) normal prior to PVI that became fractionated (9%) and; (iv) normal that remained normal (21%). Individually, the attributes failed to distinguish these LA regions, but multivariate statistical models were effective in their discrimination (P < 0.0001). Conclusion: Our results have unveiled that there are LA regions resistant to PVI, while others are affected by it. Although, traditional methods were unable to identify these different regions, the proposed multivariate statistical model discriminated LA regions resistant to PVI from those affected by it without prior ablation information. PMID- 28883796 TI - Functions of NQO1 in Cellular Protection and CoQ10 Metabolism and its Potential Role as a Redox Sensitive Molecular Switch. AB - NQO1 is one of the two major quinone reductases in mammalian systems. It is highly inducible and plays multiple roles in cellular adaptation to stress. A prevalent polymorphic form of NQO1 results in an absence of NQO1 protein and activity so it is important to elucidate the specific cellular functions of NQO1. Established roles of NQO1 include its ability to prevent certain quinones from one electron redox cycling but its role in quinone detoxification is dependent on the redox stability of the hydroquinone generated by two-electron reduction. Other documented roles of NQO1 include its ability to function as a component of the plasma membrane redox system generating antioxidant forms of ubiquinone and vitamin E and at high levels, as a direct superoxide reductase. Emerging roles of NQO1 include its function as an efficient intracellular generator of NAD+ for enzymes including PARP and sirtuins which has gained particular attention with respect to metabolic syndrome. NQO1 interacts with a growing list of proteins, including intrinsically disordered proteins, protecting them from 20S proteasomal degradation. The interactions of NQO1 also extend to mRNA. Recent identification of NQO1 as a mRNA binding protein have been investigated in more detail using SERPIN1A1 (which encodes the serine protease inhibitor alpha-1-antitrypsin) as a target mRNA and indicate a role of NQO1 in control of translation of alpha-1 antitrypsin, an important modulator of COPD and obesity related metabolic syndrome. NQO1 undergoes structural changes and alterations in its ability to bind other proteins as a result of the cellular reduced/oxidized pyridine nucleotide ratio. This suggests NQO1 may act as a cellular redox switch potentially altering its interactions with other proteins and mRNA as a result of the prevailing redox environment. PMID- 28883797 TI - Genetic Bases of Bicuspid Aortic Valve: The Contribution of Traditional and High Throughput Sequencing Approaches on Research and Diagnosis. AB - Bicuspid aortic valve (BAV) is a common (0.5-2.0% of general population) congenital heart defect with increased prevalence of aortic dilatation and dissection. BAV has an autosomal dominant inheritance with reduced penetrance and variable expressivity. BAV has been described as an isolated trait or associated with syndromic conditions [e.g., Marfan Marfan syndrome or Loeys-Dietz syndrome (MFS, LDS)]. Identification of a syndromic condition in a BAV patient is clinically relevant to personalize aortic surgery indication. A 4-fold increase in BAV prevalence in a large cohort of unrelated MFS patients with respect to general population was reported, as well as in LDS patients (8-fold). It is also known that BAV is more frequent in patients with thoracic aortic aneurysm (TAA) related to mutations in ACTA2, FBN1, and TGFBR2 genes. Moreover, in 8 patients with BAV and thoracic aortic dilation, not fulfilling the clinical criteria for MFS, FBN1 mutations in 2/8 patients were identified suggesting that FBN1 or other genes involved in syndromic conditions correlated to aortopathy could be involved in BAV. Beyond loci associated to syndromic disorders, studies in humans and animal models evidenced/suggested the role of further genes in non-syndromic BAV. The transcriptional regulator NOTCH1 has been associated with the development and acceleration of calcium deposition. Genome wide marker-based linkage analysis demonstrated a linkage of BAV to loci on chromosomes 18, 5, and 13q. Recently, a role for GATA4/5 in aortic valve morphogenesis and endocardial cell differentiation has been reported. BAV has also been associated with a reduced UFD1L gene expression or involvement of a locus containing AXIN1/PDIA2. Much remains to be understood about the genetics of BAV. In the last years, high throughput sequencing technologies, allowing the analysis of large number of genes or entire exomes or genomes, progressively became available. The latter issue together with the development of "BigData" analysis methods improving their interpretation and integration with clinical data represents a promising opportunity to increase the disease knowledge and diagnosis in monogenic and multifactorial complex traits. This review summarized the main knowledge on the BAV genetic bases, the role of genetic diagnosis in BAV patient managements and the crucial challenges for the comprehension of genetics of BAV in research and diagnosis. PMID- 28883798 TI - Eye Development in Sepia officinalis Embryo: What the Uncommon Gene Expression Profiles Tell Us about Eye Evolution. AB - In metazoans, there is a remarkable diversity of photosensitive structures; their shapes, physiology, optical properties, and development are different. To approach the evolution of photosensitive structures and visual function, cephalopods are particularly interesting organisms due to their most highly centralized nervous system and their camerular eyes which constitute a convergence with those of vertebrates. The eye morphogenesis in numerous metazoans is controlled mainly by a conserved Retinal Determination Gene Network (RDGN) including pax, six, eya, and dac playing also key developmental roles in non-retinal structures and tissues of vertebrates and Drosophila. Here we have identified and explored the role of Sof-dac, Sof-six1/2, Sof-eya in eye morphogenesis, and nervous structures controlling the visual function in Sepia officinalis. We compare that with the already shown expressions in eye development of Sof-otx and Sof-pax genes. Rhodopsin is the pigment responsible for light sensitivity in metazoan, which correlate to correlate visual function and eye development. We studied Sof-rhodopsin expression during retina differentiation. By in situ hybridization, we show that (1) all of the RDGN genes, including Sof-pax6, are expressed in the eye area during the early developmental stages but they are not expressed in the retina, unlike Sof-otx, which could have a role in retina differentiation; (2) Sof-rhodopsin is expressed in the retina just before vision gets functional, from stage 23 to hatching. Our results evidence a role of Sof-six1/2, Sof-eya, and Sof-dac in eye development. However, the gene network involved in the retinal photoreceptor differentiation remains to be determined. Moreover, for the first time, Sof-rhodopsin expression is shown in the embryonic retina of cuttlefish suggesting the evolutionary conservation of the role of rhodopsin in visual phototransduction within metazoans. These findings are correlated with the physiological and behavioral observations suggesting that S. officinalis is able to react to light stimuli from stage 25 of organogenesis on, as soon as the first retinal pigments appear. PMID- 28883799 TI - REM Sleep and Endothermy: Potential Sites and Mechanism of a Reciprocal Interference. AB - Numerous data show a reciprocal interaction between REM sleep and thermoregulation. During REM sleep, the function of thermoregulation appears to be impaired; from the other hand, the tonic activation of thermogenesis, such as during cold exposure, suppresses REM sleep occurrence. Recently, both the central neural network controlling REM sleep and the central neural network controlling thermoregulation have been progressively unraveled. Thermoregulation was shown to be controlled by a central "core" circuit, responsible for the maintenance of body temperature, modulated by a set of accessory areas. REM sleep was suggested to be controlled by a group of hypothalamic neurons overlooking at the REM sleep generating circuits within the brainstem. The two networks overlap in a few areas, and in this review, we will suggest that in such overlap may reside the explanation of the reciprocal interaction between REM sleep and thermoregulation. Considering the peculiar modulation of thermoregulation by REM sleep the result of their coincidental evolution, REM sleep may therefore be seen as a period of transient heterothermy. PMID- 28883801 TI - Procrastinating Behavior in Computer-Based Learning Environments to Predict Performance: A Case Study in Moodle. AB - Introduction: Research about student performance has traditionally considered academic procrastination as a behavior that has negative effects on academic achievement. Although there is much evidence for this in class-based environments, there is a lack of research on Computer-Based Learning Environments (CBLEs). Therefore, the purpose of this study is to evaluate student behavior in a blended learning program and specifically procrastination behavior in relation to performance through Data Mining techniques. Materials and Methods: A sample of 140 undergraduate students participated in a blended learning experience implemented in a Moodle (Modular Object Oriented Developmental Learning Environment) Management System. Relevant interaction variables were selected for the study, taking into account student achievement and analyzing data by means of association rules, a mining technique. The association rules were arrived at and filtered through two selection criteria: 1, rules must have an accuracy over 0.8 and 2, they must be present in both sub-samples. Results: The findings of our study highlight the influence of time management in online learning environments, particularly on academic achievement, as there is an association between procrastination variables and student performance. Conclusion: Negative impact of procrastination in learning outcomes has been observed again but in virtual learning environments where practical implications, prevention of, and intervention in, are different from class-based learning. These aspects are discussed to help resolve student difficulties at various ages. PMID- 28883800 TI - Childhood Trauma and Minimization/Denial in People with and without a Severe Mental Disorder. AB - : Background: Childhood trauma has garnered extensive research concerning its role in the psychopathology of mental disorders, including psychosis. The Childhood Trauma Questionnaire (CTQ) utilizes a minimization/denial (MD) scale to denote potential under-reporters of trauma, yet MD scores are infrequently reported and validations of the scale are lacking in the literature. STUDY AIM: Elucidate differences in MD between patients with severe mental disorders to healthy individuals, and secondly, investigate if MD influences reports of childhood trauma between the groups. Methods: We included 621 patients with a DSM schizophrenia spectrum, bipolar spectrum diagnosis, or major depression disorder with psychotic features and 299 healthy controls as part of the NORMENT study in Oslo, Norway. History of childhood trauma was obtained using the CTQ. Clinical diagnoses were assessed using the Structured Clinical Interview for DSM Disorders. Results: A significantly greater proportion of healthy controls (42.8%) had a positive MD score compared to patients (26.7%). When controlling for MD, the patient group still exhibited elevated reports of childhood trauma compared to controls (Cohen's d = 1.27), concordant with reports of childhood trauma being more frequently reported in a population of severe mental disorders. Conclusion: Elevated MD in the healthy control group could suggest an enhanced self-serving bias, potentially attenuated in the psychiatric group. Clinicians and researchers would benefit from including the MD component of CTQ when assessing retrospective information on childhood trauma to rule out potential effect of MD. PMID- 28883802 TI - Absorption in Sport: A Cross-Validation Study. AB - Absorption has been identified as readiness for experiences of deep involvement in the task. Conceptually, absorption is a key psychological construct, incorporating experiential, cognitive, and motivational components. Although, no operationalization of the construct has been provided to facilitate research in this area, the purpose of this research was the development and examination of the psychometric properties of a sport-specific measure of absorption that evolved from the use of the modified Tellegen Absorption Scale (MODTAS; Jamieson, 2005) in mainstream psychology. The study aimed to provide evidence of the psychometric properties, reliability, and validity of the Measure of Absorption in Sport Contexts (MASCs). The psychometric examination included a calibration sample from Scotland and a cross-validation sample from Australia using a cross sectional design. The item pool was developed based on existing items from the modified Tellegen Absorption Scale (Jamieson, 2005). The MODTAS items were reworded and translated into a sport context. The Scottish sample consisted of 292 participants and the Australian sample of 314 participants. Congeneric model testing and confirmatory factor analysis for both samples and multi-group invariance testing across samples was used. In the cross-validation sample the MASC subscales showed acceptable internal consistency and construct reliability (>=0.70). Excellent fit indices were found for the final 18-item, six-factor measure in the cross-validation sample, [Formula: see text] = 197.486, p < 0.001; CFI = 0.957; TLI = 0.945; RMSEA = 0.045; SRMR = 0.044. Multi-group invariance testing revealed no differences in item meaning, except for two items. The MASC and the Dispositional Flow Scale-2 showed moderate-to-strong positive correlations in both samples, r = 0.38, p < 0.001 and r = 0.42, p < 0.001, supporting the external validity of the MASC. This article provides initial evidence in support of the psychometric properties, reliability, and validity of the sport-specific measure of absorption. The MASC provides rich research opportunities in sport psychology that can enhance the theoretical understanding between absorption and related constructs and facilitate future intervention studies. PMID- 28883805 TI - Applying Permutation Tests and Multivariate Modification Indices to Configurally Invariant Models That Need Respecification. AB - The assumption of equivalence between measurement-model configurations across groups is typically investigated by evaluating overall fit of the same model simultaneously to multiple samples. However, the null hypothesis (H0) of configural invariance is distinct from the H0 of overall model fit. Permutation tests of configural invariance yield nominal Type I error rates even when a model does not fit perfectly (Jorgensen et al., 2017, in press). When the configural model requires modification, lack of evidence against configural invariance implies that researchers should reconsider their model's structure simultaneously across all groups. Application of multivariate modification indices is therefore proposed to help decide which parameter(s) to free simultaneously in all groups, and I present Monte Carlo simulation results comparing their Type I error control to traditional 1-df modification indices. I use the Holzinger and Swineford (1939) data set to illustrate these methods. PMID- 28883803 TI - Basic Emotions in Human Neuroscience: Neuroimaging and Beyond. AB - The existence of so-called 'basic emotions' and their defining attributes represents a long lasting and yet unsettled issue in psychology. Recently, neuroimaging evidence, especially related to the advent of neuroimaging meta analytic methods, has revitalized this debate in the endeavor of systems and human neuroscience. The core theme focuses on the existence of unique neural bases that are specific and characteristic for each instance of basic emotion. Here we review this evidence, outlining contradictory findings, strengths and limits of different approaches. Constructionism dismisses the existence of dedicated neural structures for basic emotions, considering that the assumption of a one-to-one relationship between neural structures and their functions is central to basic emotion theories. While these critiques are useful to pinpoint current limitations of basic emotions theories, we argue that they do not always appear equally generative in fostering new testable accounts on how the brain relates to affective functions. We then consider evidence beyond PET and fMRI, including results concerning the relation between basic emotions and awareness and data from neuropsychology on patients with focal brain damage. Evidence from lesion studies are indeed particularly informative, as they are able to bring correlational evidence typical of neuroimaging studies to causation, thereby characterizing which brain structures are necessary for, rather than simply related to, basic emotion processing. These other studies shed light on attributes often ascribed to basic emotions, such as automaticity of perception, quick onset, and brief duration. Overall, we consider that evidence in favor of the neurobiological underpinnings of basic emotions outweighs dismissive approaches. In fact, the concept of basic emotions can still be fruitful, if updated to current neurobiological knowledge that overcomes traditional one-to one localization of functions in the brain. In particular, we propose that the structure-function relationship between brain and emotions is better described in terms of pluripotentiality, which refers to the fact that one neural structure can fulfill multiple functions, depending on the functional network and pattern of co-activations displayed at any given moment. PMID- 28883804 TI - The Influences of Emotion on Learning and Memory. AB - Emotion has a substantial influence on the cognitive processes in humans, including perception, attention, learning, memory, reasoning, and problem solving. Emotion has a particularly strong influence on attention, especially modulating the selectivity of attention as well as motivating action and behavior. This attentional and executive control is intimately linked to learning processes, as intrinsically limited attentional capacities are better focused on relevant information. Emotion also facilitates encoding and helps retrieval of information efficiently. However, the effects of emotion on learning and memory are not always univalent, as studies have reported that emotion either enhances or impairs learning and long-term memory (LTM) retention, depending on a range of factors. Recent neuroimaging findings have indicated that the amygdala and prefrontal cortex cooperate with the medial temporal lobe in an integrated manner that affords (i) the amygdala modulating memory consolidation; (ii) the prefrontal cortex mediating memory encoding and formation; and (iii) the hippocampus for successful learning and LTM retention. We also review the nested hierarchies of circular emotional control and cognitive regulation (bottom-up and top-down influences) within the brain to achieve optimal integration of emotional and cognitive processing. This review highlights a basic evolutionary approach to emotion to understand the effects of emotion on learning and memory and the functional roles played by various brain regions and their mutual interactions in relation to emotional processing. We also summarize the current state of knowledge on the impact of emotion on memory and map implications for educational settings. In addition to elucidating the memory-enhancing effects of emotion, neuroimaging findings extend our understanding of emotional influences on learning and memory processes; this knowledge may be useful for the design of effective educational curricula to provide a conducive learning environment for both traditional "live" learning in classrooms and "virtual" learning through online-based educational technologies. PMID- 28883807 TI - Comparing CAT12 and VBM8 for Detecting Brain Morphological Abnormalities in Temporal Lobe Epilepsy. AB - The identification of the brain morphological alterations that play important roles in neurodegenerative/neurological diseases will contribute to our understanding of the causes of these diseases. Various automated software programs are designed to provide an automatic framework to detect brain morphological changes in structural magnetic resonance imaging (MRI) data. A voxel-based morphometry (VBM) analysis can also be used for the detection of brain volumetric abnormalities. Here, we compared gray matter (GM) and white matter (WM) abnormality results obtained by a VBM analysis using the Computational Anatomy Toolbox (CAT12) via the current version of Statistical Parametric Mapping software (SPM12) with the results obtained by a VBM analysis using the VBM8 toolbox implemented in the older software SPM8, in adult temporal lobe epilepsy (TLE) patients with (n = 51) and without (n = 57) hippocampus sclerosis (HS), compared to healthy adult controls (n = 28). The VBM analysis using CAT12 showed that compared to the healthy controls, significant GM and WM reductions were located in ipsilateral mesial temporal lobes in the TLE-HS patients, and slight GM amygdala swelling was present in the right TLE-no patients (n = 27). In contrast, the VBM analysis via the VBM8 toolbox showed significant GM and WM reductions only in the left TLE-HS patients (n = 25) compared to the healthy controls. Our findings thus demonstrate that compared to VBM8, a VBM analysis using CAT12 provides a more accurate volumetric analysis of the brain regions in TLE. Our results further indicate that a VBM analysis using CAT12 is more robust and accurate against volumetric alterations than the VBM8 toolbox. PMID- 28883806 TI - Functional Neuroimaging in Traumatic Brain Injury: From Nodes to Networks. AB - Since the invention of functional magnetic resonance imaging (fMRI), thousands of studies in healthy and clinical samples have enlightened our understanding of the organization of cognition in the human brain and neuroplastic changes following brain disease and injury. Increasingly, studies involve analyses rooted in complex systems theory and analysis applied to clinical samples. Given the complexity in available approaches, concise descriptions of the theoretical motivation of network techniques and their relationship to traditional approaches and theory are necessary. To this end, this review concerns the use of fMRI to understand basic cognitive function and dysfunction in the human brain scaling from emphasis on basic units (or "nodes") in the brain to interactions within and between brain networks. First, major themes and theoretical issues in the scientific study of the injured brain are introduced to contextualize these analyses, particularly concerning functional "brain reorganization." Then, analytic approaches ranging from the voxel level to the systems level using graph theory and related approaches are reviewed as complementary approaches to examine neurocognitive processes following TBI. Next, some major findings relevant to functional reorganization hypotheses are discussed. Finally, major open issues in functional network analyses in neurotrauma are discussed in theoretical, analytic, and translational terms. PMID- 28883808 TI - Grass Carp Follisatin: Molecular Cloning, Functional Characterization, Dopamine D1 Regulation at Pituitary Level, and Implication in Growth Hormone Regulation. AB - Activin is involved in pituitary hormone regulation and its pituitary actions can be nullified by local production of its binding protein follistatin. In our recent study with grass carp, local release of growth hormone (GH) was shown to induce activin expression at pituitary level, which in turn could exert an intrapituitary feedback to inhibit GH synthesis and secretion. To further examine the activin/follistatin system in the carp pituitary, grass carp follistatin was cloned and confirmed to be single-copy gene widely expressed at tissue level. At the pituitary level, follistatin signals could be located in carp somatotrophs, gonadotrophs, and lactotrophs. Functional expression also revealed that carp follistatin was effective in neutralizing activin's action in stimulating target promoter with activin-responsive elements. In grass carp pituitary cells, follistatin co-treatment was found to revert activin inhibition on GH mRNA expression. Meanwhile, follistatin mRNA levels could be up-regulated by local production of activin but the opposite was true for dopaminergic activation with dopamine (DA) or its agonist apomorphine. Since GH stimulation by DA via pituitary D1 receptor is well-documented in fish models, the receptor specificity for follistatin regulation by DA was also investigated. Using a pharmacological approach, the inhibitory effect of DA on follistatin gene expression was confirmed to be mediated by pituitary D1 but not D2 receptor. Furthermore, activation of D1 receptor by the D1-specific agonist SKF77434 was also effective in blocking follistatin mRNA expression induced by activin and GH treatment both in carp pituitary cells as well as in carp somatotrophs enriched by density gradient centrifugation. These results, as a whole, suggest that activin can interact with dopaminergic input from the hypothalamus to regulate follistatin expression in carp pituitary, which may contribute to GH regulation by activin/follistatin system via autocrine/paracrine mechanisms. PMID- 28883809 TI - Recent Research Progress in China on Haemonchus contortus. AB - Haemonchus contortus is one of the most important parasites of ruminants with worldwide distribution that can bring huge economic losses to the breeding industry of cattle, sheep, and goats. In recent 20 years, studies on H. contortus in China mainly focused on the epidemiology, population genetics, anthelmintic resistance, structural and functional studies of important genes regulating the development of this parasite, interaction between parasite molecules and host cells and vaccine development against haemonchosis, and achieved good progress. However, there is no systematic review about the studies by Chinese researchers on H. contortus in China. The purpose of this review is to bring together the findings from the studies on H. contortus in China in order to obtain the knowledge gained from the recent studies in China and provide foundation for identifying future research directions to establish novel diagnostic methods, discover new drug targets and vaccine candidates for use in preventing and controlling H. contortus in China. PMID- 28883810 TI - From Farms to Markets: Gram-Negative Bacteria Resistant to Third-Generation Cephalosporins in Fruits and Vegetables in a Region of North Africa. AB - The role of food in human exposure to antimicrobial-resistant bacteria is a growing food safety issue. The contribution of fruits and vegetables eaten raw to this exposure is still unclear. The evaluation of contamination levels of fruits, vegetables and the agricultural environment by third-generation cephalosporin (3GC)-resistant Gram-negative bacteria was performed by analyzing 491 samples of fruits and vegetables collected from 5 markets and 7 farms in Bejaia area, north eastern Mediterranean coast of Algeria. Ninety soil samples and 45 irrigation water samples were also sampled in farms in order to assess them as potential inoculum sources. All samples were investigated at the same time on ceftazidime containing selective media for 3GC-resistant Gram-negative bacteria detection and on Hektoen media, for Salmonella spp. presence. The bacteria isolated (n = 30) from fruits and vegetables, soil and irrigation water collected in the farms were almost all non-fermenting bacterial species (Stenotrophomonas, Acinetobacter, Pseudomonas, Ochrobactrum) except one strain of Enterobacter cloacae and two strains of Citrobacter murliniae, isolated on one cucumber and two tomato samples in the same farm. Greater diversity in bacterial species and antimicrobial resistance profiles was observed at markets: Enterobacteriaceae (n = 41) were as strongly represented as non-fermenting bacteria (n = 37). Among Enterobacteriaceae, E. cloacae (n = 21), and Klebsiella pneumoniae (n = 13) were the most common isolates. Most of the K. pneumoniae isolates were extended spectrum beta-lactamase (ESBL) producers (n = 11). No Salmonella spp. was recovered in any sample. This study showed that fruits and vegetables including those which may be eaten up raw constitute a reservoir of 3GC-resistant Gram negative bacteria and multi-drug resistant-bacteria in general that can be transferred to humans through food. The general public should be informed of this hazard for health in order to encourage good domestic hygiene practices. In addition, further investigation is needed throughout the production chain to enrol professionals in actions to reduce this contamination. PMID- 28883811 TI - Culture Media and Individual Hosts Affect the Recovery of Culturable Bacterial Diversity from Amphibian Skin. AB - One current challenge in microbial ecology is elucidating the functional roles of the large diversity of free-living and host-associated bacteria identified by culture-independent molecular methods. Importantly, the characterization of this immense bacterial diversity will likely require merging data from culture independent approaches with work on bacterial isolates in culture. Amphibian skin bacterial communities have become a recent focus of work in host-associated microbial systems due to the potential role of these skin bacteria in host defense against the pathogenic fungus Batrachochytrium dendrobatidis (Bd), which is associated with global amphibian population declines and extinctions. As there is evidence that some skin bacteria may inhibit growth of Bd and prevent infection in some cases, there is interest in using these bacteria as probiotic therapy for conservation of at-risk amphibians. In this study, we used skin swabs from American toads (Anaxyrus americanus) to: (1) assess the diversity and community structure of culturable amphibian skin bacteria grown on high and low nutrient culture media, (2) determine which culture media recover the highest proportion of the total skin bacterial community of individual toads relative to culture-independent data, and (3) assess whether the plated communities from the distinct media types vary in their ability to inhibit Bd growth in in-vitro assays. Overall, we found that culture media with low nutrient concentrations facilitated the growth of more diverse bacterial taxa and grew distinct communities relative to media with higher nutrient concentrations. Use of low nutrient media also resulted in culturing proportionally more of the bacterial diversity on individual toads relative to the overall community defined using culture-independent methods. However, while there were differences in diversity among media types, the variation among individual hosts was greater than variation among media types, suggesting that swabbing more individuals in a population is the best way to maximize culture collections, regardless of media type. Lastly, the function of the plated communities against Bd did not vary across culture media type or between high and low nutrient media. These results inform current efforts for developing a probiotic-based approach for amphibian conservation and help to ensure that culture collections are capturing the majority of the important diversity in these systems. PMID- 28883812 TI - The Geographic Distribution of Saccharomyces cerevisiae Isolates within three Italian Neighboring Winemaking Regions Reveals Strong Differences in Yeast Abundance, Genetic Diversity and Industrial Strain Dissemination. AB - In recent years the interest for natural fermentations has been re-evaluated in terms of increasing the wine terroir and managing more sustainable winemaking practices. Therefore, the level of yeast genetic variability and the abundance of Saccharomyces cerevisiae native populations in vineyard are becoming more and more crucial at both ecological and technological level. Among the factors that can influence the strain diversity, the commercial starter release that accidentally occur in the environment around the winery, has to be considered. In this study we led a wide scale investigation of S. cerevisiae genetic diversity and population structure in the vineyards of three neighboring winemaking regions of Protected Appellation of Origin, in North-East of Italy. Combining mtDNA RFLP and microsatellite markers analyses we evaluated 634 grape samples collected over 3 years. We could detect major differences in the presence of S. cerevisiae yeasts, according to the winemaking region. The population structures revealed specificities of yeast microbiota at vineyard scale, with a relative Appellation of Origin area homogeneity, and transition zones suggesting a geographic differentiation. Surprisingly, we found a widespread industrial yeast dissemination that was very high in the areas where the native yeast abundance was low. Although geographical distance is a key element involved in strain distribution, the high presence of industrial strains in vineyard reduced the differences between populations. This finding indicates that industrial yeast diffusion it is a real emergency and their presence strongly interferes with the natural yeast microbiota. PMID- 28883814 TI - Virucidal Influence of Ionic Liquids on Phages P100 and MS2. AB - An increasing number of publications describe the potential of ionic liquids (ILs) as novel antimicrobials, antibacterial coatings and even as active pharmaceutical ingredients. Nevertheless, a major research area, notably their impact on viruses, has so far been neglected. Consequently the aim of this study was to examine the effects of ILs on the infectivity of viruses. A systematic analysis to investigate the effects of defined structural elements of ILs on virus activity was performed using 55 ILs. All structure activity relationships (SARs) were tested on the human norovirus surrogate phage MS2 and phage P100 representing non-enveloped DNA viruses. Results demonstrate that IL SAR conclusions, established for prokaryotes and eukaryotes, are not readily applicable to the examined phages. A virus-type-dependent IL influence was also apparent. Overall, four ILs, covering different structural elements, were found to reduce phage P100 infectivity by >=4 log10 units, indicating a virucidal effect, whereas the highest reduction for phage MS2 was about 3 log10 units. Results indicate that future applications of ILs as virucidal agents will require development of novel SARs and the obtained results serve as a good starting point for future studies. PMID- 28883813 TI - A Structural and Functional Elucidation of the Rumen Microbiome Influenced by Various Diets and Microenvironments. AB - The structure and function of the microbiome inhabiting the rumen are, amongst other factors, mainly shaped by the animal's feed intake. Describing the influence of different diets on the inherent community arrangement and associated metabolic activities of the most active ruminal fractions (bacteria and archaea) is of great interest for animal nutrition, biotechnology, and climatology. Samples were obtained from three fistulated Jersey cows rotationally fed with corn silage, grass silage or grass hay, each supplemented with a concentrate mixture. Samples were fractionated into ruminal fluid, particle-associated rumen liquid, and solid matter. DNA, proteins and metabolites were analyzed subsequently. DNA extracts were used for Illumina sequencing of the 16S rRNA gene and the metabolomes of rumen fluids were determined by 500 MHz-NMR spectroscopy. Tryptic peptides derived from protein extracts were measured by LC-ESI-MS/MS and spectra were processed by a two-step database search for quantitative metaproteome characterization. Data are available via ProteomeXchange with the identifier PXD006070. Protein- and DNA-based datasets revealed significant differences between sample fractions and diets and affirmed similar trends concerning shifts in phylogenetic composition. Ribosomal genes and proteins belonging to the phylum of Proteobacteria, particularly Succinivibrionaceae, exhibited a higher abundance in corn silage-based samples while fiber-degraders of the Lachnospiraceae family emerged in great quantities throughout the solid phase fractions. The analysis of 8163 quantified bacterial proteins revealed the presence of 166 carbohydrate active enzymes in varying abundance. Cellulosome affiliated proteins were less expressed in the grass silage, glycoside hydrolases appeared in slightest numbers in the corn silage. Most expressed glycoside hydrolases belonged to families 57 and 2. Enzymes analogous to ABC transporters for amino acids and monosaccharides were more abundant in the corn silage whereas oligosaccharide transporters showed a higher abundance in the fiber-rich diets. Proteins involved in carbon metabolism were detected in high numbers and identification of metabolites like short-chain fatty acids, methylamines and phenylpropionate by NMR enabled linkage between producers and products. This study forms a solid basis to retrieve deeper insight into the complex network of microbial adaptation in the rumen. PMID- 28883815 TI - Microbiota-Derived Extracellular Vesicles as New Systemic Regulators. PMID- 28883817 TI - Commentary: Nationwide Surveillance of Novel Oxazolidinone Resistance Gene optrA in Enterococcus Isolates in China from 2004 to 2014. PMID- 28883816 TI - Modulation of Zinc Homeostasis in Acanthamoeba castellanii as a Possible Antifungal Strategy against Cryptococcus gattii. AB - Cryptococcus gattii is a basidiomycetous yeast that can be found in the environment and is one of the agents of cryptococcosis, a life-threatening disease. During its life cycle, cryptococcal cells take hold inside environmental predators such as amoebae. Despite their evolutionary distance, macrophages and amoebae share conserved similar steps of phagocytosis and microbial killing. To evaluate whether amoebae also share other antifungal strategies developed by macrophages, we investigated nutritional immunity against cryptococcal cells. We focused on zinc homeostasis modulation in Acanthamoeba castellanii infected with C. gattii. The intracellular proliferation rate (IPR) in amoebae was determined using C. gattii R265 and mutants for the ZIP1 gene, which displays defects of growth in zinc-limiting conditions. We detected a reduced IPR in cells lacking the ZIP1 gene compared to wild-type strains, suggesting that amoebae produce a low zinc environment to engulfed cells. Furthermore, flow cytometry analysis employing the zinc probe Zinpyr-1 confirmed the reduced concentration of zinc in cryptococcal-infected amoebae. qRT-PCR analysis of zinc transporter-coding genes suggests that zinc export by members of the ZnT family would be involved in the reduced intracellular zinc concentration. These results indicate that amoebae may use nutritional immunity to reduce fungal cell proliferation by reducing zinc availability for the pathogen. PMID- 28883818 TI - Real-Time Assessment of Staphylococcus aureus Biofilm Disruption by Phage-Derived Proteins. AB - A current focus of research is the development of new tools for removing bacterial biofilms in industrial settings. Bacteriophage-encoded proteins, such as endolysins, virion-associated peptidoglycan hydrolases, and exopolysaccharide depolymerases, have been shown to be efficient against these structures. However, the current screening techniques for the identification of antibiofilm properties of phage-derived proteins have important shortcomings. The aim of this work was to use the rapid, reproducible and accurate technology "real-time cell analyzer" for screening and comparing the antibiofilm ability of four phage-derived compounds, three lytic proteins (LysH5, CHAP-SH3b, and HydH5-SH3b) and one exopolysaccharide depolymerase (Dpo7) against Staphylococcus aureus biofilms, which have been associated with recurrent contamination of food products. The data generated after biofilm treatment allowed for the calculation of different antibiofilm parameters: (1) the minimum biofilm eradicating concentration that removes 50% of the biofilm (ranging from 3.5 +/- 1.1 to 6.6 +/- 0.5 MUM), (2) the lowest concentration needed to observe an antibiofilm effect (~1.5 MUM for all the proteins), and (3) the specific antibiofilm activity and the percentage of biofilm removal that revealed LysH5 as the best antibiofilm compound. Overall, this technology might be used to quickly assess and compare by standardized parameters the disaggregating activity of phage antibiofilm proteins. PMID- 28883819 TI - Immunogenicity of DNA Vaccine against H5N1 Containing Extended Kappa B Site: In Vivo Study in Mice and Chickens. AB - Influenza is one of the most important illnesses in the modern world, causing great public health losses each year due to the lack of medication and broadly protective, long-lasting vaccines. The development of highly immunogenic and safe vaccines is currently one of the major problems encountered in efficient influenza prevention. DNA vaccines represent a novel and powerful alternative to the conventional vaccine approaches. To improve the efficacy of the DNA vaccine against influenza H5N1, we inserted three repeated kappa B (kappaB) motifs, separated by a 5-bp nucleotide spacer, upstream of the cytomegalovirus promoter and downstream of the SV40 late polyadenylation signal. The kappaB motif is a specific DNA element (10pb-long) recognized by one of the most important transcription factors NFkappaB. NFkappaB is present in almost all animal cell types and upon cell stimulation under a variety of pathogenic conditions. NFkappaB is released from IkappaB and translocates to the nucleus and binds to kappaB sites, thereby leading to enhanced transcription and expression of downstream genes. We tested the variants of DNA vaccine with kappaB sites flanking the antigen expression cassette and without such sites in two animal models: chickens (broilers and layers) and mice (BALB/c). In chickens, the variant with kappaB sites stimulated stronger humoral response against the target antigen. In mice, the differences in humoral response were less apparent. Instead, it was possible to spot several gene expression differences in the spleens isolated from mice immunized with both variants. The results of our study indicate that modification of the sequence outside of the sequence encoding the antigen might enhance the immune response to the target but understanding the mechanisms responsible for this process requires further analysis. PMID- 28883820 TI - Decidual Macrophage Functional Polarization during Abnormal Pregnancy due to Toxoplasma gondii: Role for LILRB4. AB - During gestation, Toxoplasma gondii infection produces a series of complications including stillbirths, abortions, and congenital malformations. The inhibitory receptor, LILRB4, which is mainly expressed by professional antigen-presenting cells (especially macrophages and dendritic cells) may play an important immune regulatory role at the maternal-fetal interface. To assess the role of LILRB4 during T. gondii infection, LILRB4-/- and T. gondii infected pregnant mouse models were established. Further, human primary-decidual macrophages were treated with anti-LILRB4 neutralizing antibody and then infected with T. gondii. These in vivo and in vitro models were used to explore the role of LILRB4 in T. gondii mediated abnormal pregnancy outcomes. The results showed that abnormal pregnancy outcomes were more prevalent in LILRB4-/- infected pregnant mice than in wild type infected pregnant mice. In subsequent experiments, expression levels of LILRB4, M1, and M2 membrane-functional molecules, arginine metabolic enzymes, and related cytokines were assessed in uninfected, infected, LILRB4-neutralized infected, and LILRB4-/- infected models. The results demonstrated T. gondii infection to downregulate LILRB4 on decidual macrophages, which strengthened M1 activation functions and weakened M2 tolerance functions by changing M1 and M2 membrane molecule expression, synthesis of arginine metabolic enzymes, and cytokine secretion profiles. These changes contributed to abnormal pregnancy outcomes. The results of this study provide not only a deeper understanding of the immune mechanisms operational during abnormal pregnancy, induced by T. gondii infection, but also identify potential avenues for therapeutic and preventive treatment of congenital toxoplasmosis. PMID- 28883821 TI - Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer. AB - Germline precursors and intermediates of broadly neutralizing antibodies (bNAbs) are essential to the understanding of humoral response to HIV-1 infection and B cell lineage vaccine design. Using a native-like gp140 trimer probe, we examined antibody libraries constructed from donor-17, the source of glycan-dependent PGT121-class bNAbs recognizing the N332 supersite on the HIV-1 envelope glycoprotein. To facilitate this analysis, a digital panning method was devised that combines biopanning of phage-displayed antibody libraries, 900 bp long-read next-generation sequencing, and heavy/light (H/L)-paired antibodyomics. In addition to single-chain variable fragments resembling the wild-type bNAbs, digital panning identified variants of PGT124 (a member of the PGT121 class) with a unique insertion in the heavy chain complementarity-determining region 1, as well as intermediates of PGT124 exhibiting notable affinity for the native-like trimer and broad HIV-1 neutralization. In a competition assay, these bNAb intermediates could effectively compete with mouse sera induced by a scaffolded BG505 gp140.681 trimer for the N332 supersite. Our study thus reveals previously unrecognized lineage complexity of the PGT121-class bNAbs and provides an array of library-derived bNAb intermediates for evaluation of immunogens containing the N332 supersite. Digital panning may prove to be a valuable tool in future studies of bNAb diversity and lineage development. PMID- 28883822 TI - The Role of the Chemokine System in Tissue Response to Prosthetic By-products Leading to Periprosthetic Osteolysis and Aseptic Loosening. AB - Millions of total joint replacements are performed annually worldwide, and the number is increasing every year. The overall proportion of patients achieving a successful outcome is about 80-90% in a 10-20-years time horizon postoperatively, periprosthetic osteolysis (PPOL) and aseptic loosening (AL) being the most frequent reasons for knee and hip implant failure and reoperations. The chemokine system (chemokine receptors and chemokines) is crucially involved in the inflammatory and osteolytic processes leading to PPOL/AL. Thus, the modulation of the interactions within the chemokine system may influence the extent of PPOL. Indeed, recent studies in murine models reported that (i) blocking the CCR2-CCL2 or CXCR2-CXCL2 axis or (ii) activation of the CXCR4-CXCL12 axis attenuate the osteolysis of artificial joints. Importantly, chemokines, inhibitory mutant chemokines, antagonists of chemokine receptors, or neutralizing antibodies to the chemokine system attached to or incorporated into the implant surface may influence the tissue responses and mitigate PPOL, thus increasing prosthesis longevity. This review summarizes the current state of the art of the knowledge of the chemokine system in human PPOL/AL. Furthermore, the potential for attenuating cell trafficking to the bone-implant interface and influencing tissue responses through modulation of the chemokine system is delineated. Additionally, the prospects of using immunoregenerative biomaterials (including chemokines) for the prevention of failed implants are discussed. Finally, this review highlights the need for a more sophisticated understanding of implant debris-induced changes in the chemokine system to mitigate this response effectively. PMID- 28883823 TI - Under the Microscope: Single-Domain Antibodies for Live-Cell Imaging and Super Resolution Microscopy. AB - Single-domain antibodies (sdAbs) have substantially expanded the possibilities of advanced cellular imaging such as live-cell or super-resolution microscopy to visualize cellular antigens and their dynamics. In addition to their unique properties including small size, high stability, and solubility in many environments, sdAbs can be efficiently functionalized according to the needs of the respective imaging approach. Genetically encoded intrabodies fused to fluorescent proteins (chromobodies) have become versatile tools to study dynamics of endogenous proteins in living cells. Additionally, sdAbs conjugated to organic dyes were shown to label cellular structures with high density and minimal fluorophore displacement making them highly attractive probes for super resolution microscopy. Here, we review recent advances of the chromobody technology to visualize localization and dynamics of cellular targets and the application of chromobody-based cell models for compound screening. Acknowledging the emerging importance of super-resolution microscopy in cell biology, we further discuss advantages and challenges of sdAbs for this technology. PMID- 28883825 TI - Seed Carotenoid and Tocochromanol Composition of Wild Fabaceae Species Is Shaped by Phylogeny and Ecological Factors. AB - Carotenoids distribution and function in seeds have been very scarcely studied, notwithstanding their pivotal roles in plants that include photosynthesis and phytohormone synthesis, pigmentation, membrane stabilization and antioxidant activity. Their relationship with tocochromanols, whose critical role in maintaining seed viability has already been evidenced, and with chlorophylls, whose retention in mature seed is thought to have negative effects on storability, remain also unexplored. Here, we aimed at elucidating seed carotenoids relationship with tocochromanols and chlorophylls with regard to phylogenetic and ecological traits and at understanding their changes during germination. The composition and distribution of carotenoids were investigated in seeds of a wide range of wild species across the Fabaceae (the second-most economically important family after the Poaceae). Photosynthetic pigments and tocochromanols were analyzed by HPLC in mature dry seeds of 50 species representative of 5 subfamilies within the Fabaceae (including taxa that represent all continents, biomes and life forms within the family) and at key timepoints during seedling establishment in three species representative of distinct clades. Total-carotenoids content positively correlated with tocopherols in the basal subfamilies Detarioideae, Cercidoideae, and Dialioideae, and with chlorophylls in the Papilionoideae. Papilionoideae lacked tocotrienols and had the highest total-carotenoids, chlorophyll and gamma-tocopherol contents. Interestingly, lutein epoxide was present in 72% of the species including several herbs from different subfamilies. Overall, species original from temperate biomes presented higher carotenoids and lower tocochromanols levels than those from tropical biomes. Also shrub species showed higher carotenoids content than herbs and trees. During germination, total content of photosynthetic pigments increased in parallel to changes in relative abundance of carotenoids: zeaxanthin and anteraxanthin decreased and beta-carotene augmented. Notably, the highest contents of nutritionally valuable carotenoids were found in Papilionoideae subfamily to which all pulses of socio-economic importance belong. The major differences in carotenoids and tocochromanols composition across the Fabaceae are apparently related to phylogeny in conjunction with ecological traits such as biome and growth form. PMID- 28883824 TI - Natural Killer (NK) Cell Education Differentially Influences HIV Antibody Dependent NK Cell Activation and Antibody-Dependent Cellular Cytotoxicity. AB - Immunotherapy using broadly neutralizing antibodies (bNAbs) endowed with Fc mediated effector functions has been shown to be critical for protecting or controlling viral replication in animal models. In human, the RV144 Thai trial was the first trial to demonstrate a significant protection against HIV infection following vaccination. Analysis of the correlates of immune protection in this trial identified an association between the presence of antibody-dependent cellular cytotoxicity (ADCC) mediated by immunoglobulin G (IgG) antibodies (Abs) to HIV envelope (Env) V1/V2 loop structures and protection from infection, provided IgA Abs with competing specificity were not present. Systems serology analyses implicated a broader range of Ab-dependent functions in protection from HIV infection, including but not limited to ADCC and Ab-dependent NK cell activation (ADNKA) for secretion of IFN-gamma and CCL4 and expression of the degranulation marker CD107a. The existence of such correlations in the absence of bNAbs in the RV144 trial suggest that NK cells could be instrumental in protecting against HIV infection by limiting viral spread through Fc-mediated functions such as ADCC and the production of antiviral cytokines/chemokines. Beside the engagement of FcgammaRIIIa or CD16 by the Fc portion of anti-Env IgG1 and IgG3 Abs, natural killer (NK) cells are also able to directly kill infected cells and produce cytokines/chemokines in an Ab-independent manner. Responsiveness of NK cells depends on the integration of activating and inhibitory signals through NK receptors, which is determined by a process during their development known as education. NK cell education requires the engagement of inhibitory NK receptors by their human leukocyte antigen ligands to establish tolerance to self while allowing NK cells to respond to self cells altered by virus infection, transformation, stress, and to allogeneic cells. Here, we review recent findings regarding the impact of inter-individual differences in NK cell education on Ab-dependent functions such as ADCC and ADNKA, including what is known about the HIV Env epitope specificity of ADCC competent Abs and the conformation of HIV Env on target cells used for ADCC assays. PMID- 28883826 TI - Efficient CRISPR/Cas9-Mediated Genome Editing Using a Chimeric Single-Guide RNA Molecule. AB - The CRISPR/Cas9 system has been applied in diverse eukaryotic organisms for targeted mutagenesis. However, targeted gene editing is inefficient and requires the simultaneous delivery of a DNA template for homology-directed repair (HDR). Here, we used CRISPR/Cas9 to generate targeted double-strand breaks and to deliver an RNA repair template for HDR in rice (Oryza sativa). We used chimeric single-guide RNA (cgRNA) molecules carrying both sequences for target site specificity (to generate the double-strand breaks) and repair template sequences (to direct HDR), flanked by regions of homology to the target. Gene editing was more efficient in rice protoplasts using repair templates complementary to the non-target DNA strand, rather than the target strand. We applied this cgRNA repair method to generate herbicide resistance in rice, which showed that this cgRNA repair method can be used for targeted gene editing in plants. Our findings will facilitate applications in functional genomics and targeted improvement of crop traits. PMID- 28883827 TI - Genetic and Quantitative Trait Locus Analysis of Cell Wall Components and Forage Digestibility in the Zheng58 * HD568 Maize RIL Population at Anthesis Stage. AB - The plant cell wall plays vital roles in various aspects of the plant life cycle. It provides a basic structure for cells and gives mechanical rigidity to the whole plant. Some complex cell wall components are involved in signal transduction during pathogenic infection and pest infestations. Moreover, the lignification level of cell walls strongly influences the digestibility of forage plants. To determine the genetic bases of cell wall components and digestibility, quantitative trait locus (QTL) analyses for six related traits were performed using a recombinant inbred line (RIL) population from a cross between Zheng58 and HD568. Eight QTL for in vitro neutral detergent fiber (NDF) digestibility were observed, out of which only two increasing alleles came from HD568. Three QTL out of ten with alleles increasing in vitro dry matter digestibility also originated from HD568. Five-ten QTL were detected for lignin, cellulose content, acid detergent fiber, and NDF content. Among these results, 29.8% (14/47) of QTL explained >10% of the phenotypic variation in the RIL population, whereas 70.2% (33/47) explained <=10%. These results revealed that in maize stalks, a few large effect QTL and a number of minor-effect QTL contributed to most of the genetic components involved in cell wall biosynthesis and digestibility. PMID- 28883828 TI - Simultaneous Extraction and Identification of Phenolic Compounds in Anoectochilus roxburghii Using Microwave-Assisted Extraction Combined with UPLC-Q-TOF-MS/MS and Their Antioxidant Activities. AB - This study used MAE and RSM to extract phenolic compounds from Anoectochilus roxburghii, and the optimum conditions defined by the model to give an optimum yield of 1.31%. The antioxidant activity in vitro showed when the concentration of phenolic compounds was reached 1 mg mL-1, the clearance rates were 82.58% for DPPH and 97.62% for ABTS+. In vivo antioxidant experiments used D-galactose to build oxidative damage in healthy Kunming mice. The result showed that the extractions of A. roxburghii can improve the antioxidant ability and the medium and low dose groups had better ability to scavenge free radicals. The UPLC-Q-TOF MS/MS was developed to identify 21 kinds of phenolic compounds by molecular mass, ms/ms fragmentation, as well as retention time. The result showed that the phenolic compounds of A. roxburghii had significant potential as a natural antioxidant to promote health and to reduce the risk of disease. PMID- 28883830 TI - Corrigendum to "Automated Feature Extraction in Brain Tumor by Magnetic Resonance Imaging Using Gaussian Mixture Models". AB - [This corrects the article DOI: 10.1155/2015/868031.]. PMID- 28883829 TI - Genomic Analysis of Terpene Synthase Family and Functional Characterization of Seven Sesquiterpene Synthases from Citrus sinensis. AB - Citrus aroma and flavor, chief traits of fruit quality, are derived from their high content in essential oils of most plant tissues, including leaves, stems, flowers, and fruits. Accumulated in secretory cavities, most components of these oils are volatile terpenes. They contribute to defense against herbivores and pathogens, and perhaps also protect tissues against abiotic stress. In spite of their importance, our understanding of the physiological, biochemical, and genetic regulation of citrus terpene volatiles is still limited. The availability of the sweet orange (Citrus sinensis L. Osbeck) genome sequence allowed us to characterize for the first time the terpene synthase (TPS) family in a citrus type. CsTPS is one of the largest angiosperm TPS families characterized so far, formed by 95 loci from which just 55 encode for putative functional TPSs. All TPS angiosperm families, TPS-a, TPS-b, TPS-c, TPS-e/f, and TPS-g were represented in the sweet orange genome, with 28, 18, 2, 2, and 5 putative full length genes each. Additionally, sweet orange beta-farnesene synthase, (Z)-beta-cubebene/alpha copaene synthase, two beta-caryophyllene synthases, and three multiproduct enzymes yielding beta-cadinene/alpha-copaene, beta-elemene, and beta cadinene/ledene/allo-aromandendrene as major products were identified, and functionally characterized via in vivo recombinant Escherichia coli assays. PMID- 28883831 TI - Helicobacter pylori Infection Is Associated with Type 2 Diabetes, Not Type 1 Diabetes: An Updated Meta-Analysis. AB - BACKGROUND: Extragastric manifestations of Helicobacter pylori (H. pylori) infection have been reported in many diseases. However, there are still controversies about whether H. pylori infection is associated with diabetes mellitus (DM). This study was aimed at answering the question. METHODS: A systematic search of the literature from January 1996 to January 2016 was conducted in PubMed, Embase databases, Cochrane Library, Google Scholar, Wanfang Data, China national knowledge database, and SinoMed. Published studies reporting H. pylori infection in both DM and non-DM individuals were recruited. RESULTS: 79 studies with 57,397 individuals were included in this meta-analysis. The prevalence of H. pylori infection in DM group (54.9%) was significantly higher than that (47.5%) in non-DM group (OR = 1.69, P < 0.001). The difference was significant in comparison between type 2 DM group and non-DM group (OR = 2.05), but not in that between type 1 DM group and non-DM group (OR = 1.23, 95% CI: 0.77 1.96, P = 0.38). CONCLUSION: Our meta-analysis suggested that there is significantly higher prevalence of H. pylori infection in DM patients as compared to non-DM individuals. And the difference is associated with type 2 DM but not type 1 DM. PMID- 28883832 TI - BMI Modulates the Effect of Thyroid Hormone on Lipid Profile in Euthyroid Adults. AB - The impacts of thyroid hormones (TH) on lipid profile in euthyroid adults have gained much attention. It is currently unknown whether BMI influences such interaction. In the present study, we investigate the role of BMI in modulating the association between TH and lipid parameters in 1372 euthyroid healthy adults. Our results show that thyroid parameters are differentially associated with lipid profile. FT3 is positively correlated with total cholesterol (beta = 0.176 +/- 0.046, P < 0.001) and LDL cholesterol levels (beta = 0.161 +/- 0.040, P < 0.001). FT4 is negatively correlated with TG (beta = -0.087 +/- 0.029, P < 0.01) while positively correlated with HDL cholesterol levels (beta = 0.013 +/- 0.005, P < 0.01). TSH is positively associated with TG (beta = 0.145 +/- 0.056, P < 0.05) and total cholesterol levels (beta = 0.094 +/- 0.030, P < 0.01). Importantly, BMI modulates the effect of TH on lipid profile: the interaction of FT4 and BMI and the interaction of FT3 and BMI reach statistical significance in predicting TG and HDL cholesterol levels, respectively. Stratified according to BMI levels, most associations between TH and lipid profile are significant only in normal weight group. In conclusion, in euthyroid adults, high normal FT3, TSH levels, and low normal FT4 levels are associated with unfavorable lipid profile. BMI mediates the effect of thyroid function on lipid profile in euthyroid adults. PMID- 28883833 TI - Preoperative Signs and Symptoms as Prognostic Markers in Nasal Septoplasty. AB - Identification of preoperative signs and symptoms that may predict the outcome of surgery is important, for both patient selection and the development of interventions for improving outcomes. The purpose of this study was to assess the value of some selected preoperative signs and symptoms for predicting outcomes of nasal septoplasty. Patients undergoing septoplasty with or without turbinoplasty responded to the Nasal Surgical Questionnaire (NSQ) preoperatively and six months postoperatively. The questionnaire contains visual analogue scales (VAS) for nasal obstruction during the day and at night. We compared preoperative and postoperative VAS scores in patients with unilateral versus bilateral septal deviation and patients with low versus high preoperative scores. Of 446 patients undergoing septoplasty from September 2014 to December 2015 who had responded to the preoperative NSQ, 286 (64.1%) also returned the postoperative version. There was greater improvement in obstruction in patients with preoperative unilateral compared to bilateral septal deviation (day scores, p = 0.04). The grade of deviation and the presence of concomitant bony conchal hypertrophy did not influence results. Patients with lower preoperative VAS scores obtained better end results than those with higher scores (p = 0.04). Type of septal deviation and preoperative VAS scores may aid in predicting outcome of nasal surgery. PMID- 28883834 TI - Ameloblastic Fibroodontoma: Uncommon Case Presentation in a 6-Year-Old Child with Review of the Literature. AB - Ameloblastic fibroodontoma is a benign mixed odontogenic neoplasm considered in patients with asymptomatic swelling and unerupted teeth that exhibit histologic features between ameloblastic fibroma and complex odontoma. Radiographically, this lesion appears as radiolucency admixed with focal radio opaque masses of irregular shapes and sizes. This lesion is confirmed by the presence of proliferating odontogenic epithelium, ectomesenchyme, and dental hard tissue formation on pathological analysis supplementing clinical and radiographic findings. As this tumour is less commonly seen in routine clinical practice, ameloblastic fibroodontoma with detailed orofacial features and periodic approach to its diagnosis is discussed. This paper reports a case of ameloblastic fibroodontoma of the mandible in a 6-year-old male patient with an uncommon case presentation and review of the literature. PMID- 28883836 TI - The Effect of Pyrroloquinoline Quinone on the Expression of WISP1 in Traumatic Brain Injury. AB - WISP1, as a member of the CCN4 protein family, has cell protective effects of promoting cell proliferation and inhibiting cell apoptosis. Although some studies have confirmed that WISP1 is concerned with colon cancer and lung cancer, there is little report about the influence of WISP1 in traumatic brain injury. Here, we found that the expression of WISP1 mRNA and protein decreased at 3 d and then increased at 5 d after traumatic brain injury (TBI). Meanwhile, immunofluorescence demonstrated that there was little colocation of WISP1 with GFAP, Iba1, and WISP1 colocalized with NeuN partly. WISP1 colocalized with LC3, but there was little of colocation about WISP1 with cleaved caspase-3. Subsequent study displayed that the expression of beta-catenin protein was identical to that of WISP1 after TBI. WISP1 was mainly located in cytoplasm of PC12 or SHSY5Y cells. Compared with the negative control group, WISP1 expression reduced obviously in SHSY5Y cells transfected with WISP1 si-RNA. CCK-8 assay showed that pyrroloquinoline quinone (PQQ) had little influence on viability of PC12 and SHSY5Y cells. These results suggested that WISP1 played a protective role after traumatic brain injury in rats, and this effect might be relative to autophagy caused by traumatic brain injury. PMID- 28883835 TI - An Overview of Lipid Droplets in Cancer and Cancer Stem Cells. AB - For decades, lipid droplets have been considered as the main cellular organelles involved in the fat storage, because of their lipid composition. However, in recent years, some new and totally unexpected roles have been discovered for them: (i) they are active sites for synthesis and storage of inflammatory mediators, and (ii) they are key players in cancer cells and tissues, especially in cancer stem cells. In this review, we summarize the main concepts related to the lipid droplet structure and function and their involvement in inflammatory and cancer processes. PMID- 28883837 TI - Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells. AB - Germline stem cells (GSCs) are adult stem cells that are responsible for the production of gametes and include spermatogonial stem cells (SSCs) and ovarian germline stem cells (OGSCs). GSCs are located in a specialized microenvironment in the gonads called the niche. Many recent studies have demonstrated that multiple signals in the niche jointly regulate the proliferation and differentiation of GSCs, which is of significance for reproductive function. Previous studies have demonstrated that the hedgehog (Hh) signaling pathway participates in the proliferation and differentiation of various stem cells, including GSCs in Drosophila and male mammals. Furthermore, the discovery of mammalian OGSCs challenged the traditional opinion that the number of primary follicles is fixed in postnatal mammals, which is of significance for the reproductive ability of female mammals and the treatment of diseases related to germ cells. Meanwhile, it still remains to be determined whether the Hh signaling pathway participates in the regulation of the behavior of OGSCs. Herein, we review the current research on the role of the Hh signaling pathway in mediating the behavior of GSCs. In addition, some suggestions for future research are proposed. PMID- 28883838 TI - Corrigendum to "Increasing Dose of Autologous Bone Marrow Mononuclear Cells Transplantation Is Related to Stroke Outcome: Results from a Pooled Analysis of Two Clinical Trials". AB - [This corrects the article DOI: 10.1155/2016/8657173.]. PMID- 28883840 TI - Modalities of ventricular pacing for cardiac resynchronization therapy in patients with heart failure: a meta-analysis and systematic review. AB - INTRODUCTION: This meta-analysis evaluated 14 studies which compared clinical and functional outcomes after different cardiac resynchronization therapy (CRT) modalities. MATERIAL AND METHODS: Relevant studies were selected from the Medline, PubMed, Cochrane, and Google Scholar databases until June 27th, 2016. We analyzed and compared the clinical outcomes (peak O2 consumption and LVEF) and functional outcomes (6-min walk distance and quality of life (SF-36)) of HF patients who received different CRT modalities with outcomes in patients who received conventional univentricular therapy. RESULTS: There was no significant difference in post-treatment 6-min walking distance between the biventricular (BiV) and left/right univentricular (LUV/RUV) groups (standardized difference in means = 0.049, 95% CI: -0.119 to 0.217, p = 0.566), or between the BiV and triventricular (TriV) groups (standardized difference in means = 0.035, 95% CI: 0.270 to 0.340, p = 0.822). Peak O2 consumption was comparable between BiV and LUV/RUV groups (standardized difference in means = 0.306, 95% CI: -0.002 to 0.614, p = 0.052). Patients in the TriV group had a significant improvement in LVEF compared to the BiV group (standardized difference in means = 0.647, 95% CI: 0.313 to 0.982, p < 0.001). CONCLUSIONS: TriV CRT is an attractive alternative to univentricular or BiV pacing for heart failure patients. It is necessary to conduct further large randomized trials to validate our present data. PMID- 28883842 TI - Diabetes as a risk factor of hospitalization in the surgical ward due to cancer in the elderly and middle-aged population. AB - INTRODUCTION: Diabetes can be considered as a risk factor of several types of malignancy. Surgery is one of the primary methods of cancer treatment. The objective of this study was to evaluate the association between diabetes and hospital admissions to the surgery unit due to malignancy among elderly and middle-aged people. MATERIAL AND METHODS: Data for analysis were taken from the medical records of 7,694 patients aged > 45, hospitalized in the General Surgery Ward in the Specialist District Hospital in Stalowa Wola in the Subcarpathian (Podkarpacie) Province, Poland, in the years 2010-2013. Among them malignancy was diagnosed in 652 patients and diabetes in 370 subjects. Ninety-three patients suffered from both diabetes and cancer. RESULTS: Diabetes was associated with significantly elevated risk of hospitalization due to malignancy compared with the non-diabetic population, odds ratio (OR) 4.051 (95% confidence interval: 3.154-5.203), p < 0.001. Among people with diabetes, elderly patients (> 65 years) had higher risk of hospital admission due to cancer compared with the middle-aged population, OR = 5.238 (2.873-9.550), p < 0.001. Also, urban residents had higher risk compared with rural inhabitants, OR = 2.272 (1.375 3.752), p = 0.002. CONCLUSIONS: Patients with diabetes, especially elderly and urban inhabitants, are at high risk of hospital admission due to malignancy. This indicates the need for oncological vigilance in such patients for early detection and treatment of cancers common in this population. PMID- 28883841 TI - Antiplatelet and anticoagulant therapy in elderly people with type 2 diabetes mellitus in Poland (based on the PolSenior Study). AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is an important and common cardiovascular risk factor. The purpose of the study was to evaluate the frequency of use of oral antiplatelet drugs (OAPs) and oral anticoagulant drugs (OACs) among the elderly with T2DM in Poland. MATERIAL AND METHODS: The study was based on the data collected in the Polish national PolSenior study. RESULTS: Among 4979 PolSenior participants aged 65 and over, 883 (17.8%) had previously diagnosed T2DM. Among them, 441 (49.9%) used at least one drug in pharmacological cardiovascular prevention, i.e. OAPs (mostly ASA) in 405 (45.9%) cases and OACs in 38 (4.3%). The use of these drugs significantly depended on the sex (p = 0.02) and personal income (p = 0.05). Age, place of residence and level of education did not affect the prevalence of pharmacological prevention. Previous stroke and myocardial infarction were mostly associated with OAPs, whereas a history of atrial fibrillation (AF) was related to OAC treatment. Among participants treated with OAPs, therapy was applied as secondary cardiovascular prevention in 211 (52.1%) subjects, and as primary prevention in 194 (47.9%) subjects. Among participants treated with OACs, 24 (64.9%) persons had a history of AF. Secondary cardiovascular pharmacological prevention should be considered in 45 untreated participants (12.5%), and primary cardiovascular pharmacological prevention (SCORE >= 10 and/or AF) in 154 participants (42.7%). CONCLUSIONS: Cardiovascular pharmacological prevention in the elderly with T2DM in Poland seems to be unsatisfactory. Educational programmes concerning current recommendations for pharmacological cardiovascular prevention should be developed among general practitioners. PMID- 28883843 TI - Plasma soluble CD36, carotid intima-media thickness and cognitive function in patients with type 2 diabetes. AB - INTRODUCTION: Diabetes and atherosclerosis are both risk factors of cognitive deficits. Scavenger receptor CD36 is associated with increasing risk of diabetes and atherosclerosis, and may play a role in cognitive deficits. The aim of this study is to determine the correlations of plasma soluble CD36 concentrations with carotid intima-media thickness (IMT) and cognitive function in patients with type 2 diabetes. MATERIAL AND METHODS: We determined the levels of soluble CD36 (sCD36), blood lipids, fasting blood glucose, glycosylated hemoglobin, carotid atherosclerosis as IMT, cognitive function by the Montreal Cognitive Assessment (MoCA) scoring system, and other clinical characteristics in 357 patients with type 2 diabetes. RESULTS: Diabetic patients with the lowest quartile of IMT (Q1) had lower sCD36 concentrations (ANOVA, ptrend < 0.05) and higher MoCA scores than upper ones (Q2-Q4) (ptrend < 0.05), and those with the highest quartile of sCD36(Q4) had higher FBG, LDL-C and carotid IMT than lower ones (Q1-Q3) (ptrend < 0.05 for all). Plasma log10(sCD36) was significantly correlated with carotid IMT (r = 0.202, p < 0.001) after adjustment for age, gender, and education level. Carotid IMT was significantly associated with MoCA scores (r = 0.284, p < 0.001) after adjustment for, age, gender, education level, duration of DM and hypertension. There were no correlations between sCD36 and MoCA scores (r = 0.038, p = 0.470). CONCLUSIONS: Our study shows that sCD36 is associated with carotid IMT, and carotid IMT is inversely correlated with cognitive function in type 2 diabetic patients. Nevertheless, no cross-sectional association between sCD36 and MoCA scores was detected in this study. PMID- 28883844 TI - Cardiovascular diseases, metabolic syndrome and health behaviours of postmenopausal women working in agriculture. AB - INTRODUCTION: The objective of the study was to examine the impact of occurrence of cardiovascular diseases (CVDs) and metabolic syndrome (MS) diagnoses on the frequency of health behaviours in postmenopausal women working in agriculture. MATERIAL AND METHODS: Eight hundred and ten postmenopausal women living in rural areas and working in agriculture, aged 46-70 and at least 12 months from the last menstrual period, were examined. Analysis of variance with multiple comparison tests was used to compare the Inventory of Health Behaviours among the women with and without CVDs and MS. RESULTS: The frequency of some health behaviours, mainly health practices, is higher in postmenopausal women working in agriculture with CVDs or MS than in those without CVDs or MS (p = 0.045). Women with such disorders more often limit their physical effort (p = 0.029), try to be less overworked (p < 0.001) and to take more rest (p = 0.027), more often limit consumption of animal fat and sugar (p = 0.024), more regularly visit physicians (p = 0.003) and more often take seriously recommendations concerning their health. However, an insufficient frequency of health behaviours was observed among both the healthy women and those with metabolic disorders and CVDs. One third of all the examined women had a high frequency of health behaviours, one third had an average frequency and one third had a low frequency; hence actions should be taken to improve the situation. CONCLUSIONS: Postmenopausal women working in agriculture more often perform beneficial health behaviours if they have MS and CVDs diagnosed in comparison to healthy women. PMID- 28883839 TI - Lipid lowering nutraceuticals in clinical practice: position paper from an International Lipid Expert Panel. PMID- 28883845 TI - The impact of hyperglycemia and hyperlipidemia on plasma P-selectin and platelet markers after ischemic stroke. AB - INTRODUCTION: Platelet activation plays a key role in the pathogenesis of ischemic cerebrovascular diseases. Thus, it is very important to identify novel pharmacological targets for platelet inhibition to improve ischemic stroke treatment. The aim of the study was to assess the relationship between metabolic disorders and platelet activity markers in patients with acute ischemic stroke. MATERIAL AND METHODS: Ninety-four patients with acute ischemic stroke were divided into four groups with: normolipidemia and normoglycemia (NL/NG), n = 25; normolipidemia and hyperglycemia (NL/HG), n = 21; hyperlipidemia and normoglycemia (HL/NG), n = 27; hyperlipidemia and hyperglycemia (NL/NG), n = 21. Twenty-one healthy subjects served as controls. We assessed the CD62P expression on resting and thrombin-activated blood platelets using the flow cytometer and anti-CD61 and anti-CD62P monoclonal antibodies. CD61-positive microparticles were defined as platelet-derived microparticles. The level of sP-selectin in serum was measured by the ELISA method. RESULTS: We observed a significant influence of hyperlipidemia and hyperglycemia on sP-selectin concentration. A strong correlation between higher sP-selectin concentration and enhanced LDL (p = 0.001), total cholesterol (p = 0.02), HbA1c level (p < 0.001) was noticed. The level of sP-selectin and PDMPs (p < 0.001) were significantly higher in all groups of stroke patients compared with the controls. CD62P expression on resting and thrombin activated platelets were significantly lower in groups of patients with stroke. CONCLUSIONS: Hyperlipidemia and hyperglycemia exert an equal stimulatory effect on tested platelet markers but with no synergistic action in stroke patients with both of the metabolic comorbidities. sP-selectin concentration in stroke patients best reflects the impact of hyperglycemia and hyperlipidemia on vascular lesions and platelet activation. PMID- 28883846 TI - Prior transient ischemic attacks may have a neuroprotective effect in patients with ischemic stroke. AB - INTRODUCTION: Although functional recovery and survival after ischemic infarction seem to improve in patients with prior transient ischemic attack (TIA), little is known about the role of characteristics of prior TIA in subsequent cerebral infarction. Thus, the objective of this study was to explore how the characteristics of prior TIA have a neuroprotective effect on patients with ischemic stroke. MATERIAL AND METHODS: A total of 221 patients admitted consecutively to a primary care center for first-ever ischemic stroke were divided into two groups on the basis of the presence or absence of prior TIAs. The initial NIHSS modified Rankin Scale was used to measure the severity and disability after the stroke. Subgroups were based on the TIA duration (< 10 min, 10 to 60 min, and > 60 min), TIA frequency (1 time, 2-3 times, more than 3 times), and the interval of stroke (< 1 week, 1-4 weeks, > 4 weeks). The severity of the neurologic picture on admission and functional disability after stroke were compared between patients with and without TIAs and subgroups as well. RESULTS: A total of 132 (59.73%) of the 221 patients had prior TIAs before stroke. Risk factors and the initial clinical picture did not differ between patients with or without TIAs. Patients with prior TIA had a more favorable outcome than those without TIA (59.09% vs. 43.82%), and a significant difference between the two groups was observed (chi2 = 4.976, p = 0.026). Furthermore, neurological outcome in patients with prior TIA lasting for 60 min, less than 3 times and shorter intervals within 4 weeks was significantly different from that in the non-TIA group (p < 0.05). CONCLUSIONS: Prior transient ischemic attacks may have a neuroprotective effect on the subsequent ischemic stroke, and this effect might be affected by the characteristics of TIAs. Patients with TIAs of low frequency, short duration and short interval are considered to have better neurological outcomes. PMID- 28883847 TI - Effects of aspiration pneumonia on the intensive care requirements and in hospital mortality of hospitalised patients with acute cerebrovascular disease. AB - INTRODUCTION: In this study, we aimed to evaluate the effects of the development of aspiration pneumonia (AP) on the intensive care unit (ICU) requirements and in hospital mortality of patients hospitalised in the neurology ward due to an acute cerebrovascular accident (CVA). MATERIAL AND METHODS: Five hundred and three patients hospitalised in the neurology ward following an acute CVA were retrospectively analysed. The patients were divided into two groups: those with AP (group 1) and those without AP (group 2). Demographic characteristics and physical and radiological findings, including the localisation, lateralisation and aetiology of the infarction, in addition to ICU requirements and mortality, were evaluated. RESULTS: Aspiration pneumonia was detected in 80 (15.9%) patients during the in-hospital stay. Transfer to the ICU for any reason was required in 37.5% of the patients in group 1 and 4.7% of those in group 2 (p < 0.001). In hospital mortality occurred in 7.5% and 1.4% of the patients in group 1 and group 2, respectively (p = 0.006). The incidence of AP was highest in patients with an infarction of the medial cerebral artery (MCA) (p < 0.001). The AP was associated with older age (p < 0.001), hypertension (p = 0.007), echocardiography findings (p = 0.032) and the modified Rankin Scale (mRS) score (p < 0.001). CONCLUSIONS: Our findings suggest that the requirement rate for transfer to the ICU and the mortality rate appear to be significantly higher in patients with a diagnosis of AP. Precautions should be taken, starting from the first day of hospitalisation, to decrease the incidence of AP in patients with acute CVA, focusing especially on older patients and those with a severe mRS score. PMID- 28883848 TI - Interleukin-6 signaling in patients with chronic heart failure treated with cardiac resynchronization therapy. AB - INTRODUCTION: Increased expression of interleukin-6 (IL-6) has been described in left ventricular dysfunction in the course of chronic heart failure. Cardiac resynchronization therapy (CRT) is a unique treatment method that may reverse the course of chronic heart failure (CHF) with reduced ejection fraction (HF-REF). We aimed to evaluate the IL-6 system, including soluble IL-6 receptor (sIL-6R) and soluble glycoprotein 130 (sgp130), in HF-REF patients, with particular emphasis on CRT effects. MATERIAL AND METHODS: The study enrolled 88 stable HF-REF patients (63.6 +/-11.1 years, 12 females, EF < 35%) and 35 comorbidity-matched controls (63.5 +/-9.8 years, 7 females). Forty-five HF-REF patients underwent CRT device implantation and were followed up after 6 months. Serum concentrations of IL-6, sIL-6R and sgp130 were determined using ELISA kits. RESULTS: The HF-REF patients had higher IL-6 (median: 2.6, IQR: 1.6-3.8 vs. 2.1, IQR: 1.4-3.1 pg/ml, p = 0.03) and lower sIL-6R concentrations compared to controls (median: 51, IQR: 36-64 vs. 53. IQR 44-76 ng/ml, p = 0.008). There was no significant difference between sgp130 concentrations. In the HF-REF group IL-6 correlated negatively with EF (r = -0.5, p = 0.001) and positively with BNP (r = 0.5, p = 0.008) and CRP concentrations (r = 0.4, p = 0.02). Patients who presented a positive response after CRT showed a smaller change of sIL-6R concentration compared to nonresponders (DeltasIL-6R: -0.2 +/-7.1 vs. 7 +/-14 ng/ml; p = 0.04). CONCLUSIONS: HF-REF patients present higher IL-6 and lower sIL-6R levels. IL-6 concentration reflects their clinical status. CRT-related improvement of patients' functional status is associated with a smaller change of sIL-6R concentration in time. PMID- 28883849 TI - Lipoprotein(a) is associated with left ventricular systolic dysfunction in a Chinese population of patients with hypertension and without coronary artery disease. AB - INTRODUCTION: Data on relationship between lipoprotein(a) (Lp(a)) and non ischemic heart dysfunction are limited. This study is aimed to assess the association between Lp(a) and left ventricular systolic dysfunction in a Chinese population of patients with hypertension and without coronary artery disease (CAD). MATERIAL AND METHODS: This cross-sectional study included 1611 patients with hypertension and without CAD in China. The factors associated with left ventricular ejection fraction (LVEF) were evaluated using univariate and multivariate analysis. RESULTS: A higher percentage of hypertensive patients with LVEF < 50% were men, and had lower plasma high-density lipoprotein cholesterol, but higher plasma Lp(a), serum creatinine, and hemoglobin levels than those with LVEF >= 50% using univariate analysis. When participants were classified as four groups according to Lp(a) quartiles, LVEF was decreased with increased Lp(a) levels. The prevalence of LVEF < 50% was increased with Lp(a) quartiles. Multiple linear regression analysis indicated that plasma Lp(a) levels, man, and serum creatinine levels were independently correlated with LVEF in hypertensive patients. Multiple logistic regression analysis indicated that plasma Lp(a) levels (OR = 5.566, 95% CI: 1.745-17.758, p = 0.004) or Lp(a) quartiles (quartile 4: OR = 3.234, 95% CI: 1.290-8.105, quartile 1 as reference, p = 0.012) was independently correlated with LVEF < 50% with adjustment for other potential confounders. Ordinal logistic regression analysis demonstrated that Lp(a) (OR = 5.760, 95% CI: 1.831-18.120, p = 0.003) was independently correlated with different LVEF categories (>= 50%, 35-49%, and < 35%) in hypertensive patients. CONCLUSIONS: Left ventricular ejection fraction is decreased with increased plasma Lp(a) levels. Lipoprotein(a) is independently correlated with left ventricular systolic dysfunction in patients with hypertension and without CAD. PMID- 28883850 TI - C-reactive protein levels predict systolic heart failure and outcome in patients with first ST-elevation myocardial infarction treated with coronary angioplasty. AB - INTRODUCTION: There is growing evidence that inflammation plays a pivotal role in the etiology and progression of atherosclerosis. High C-reactive protein (CRP) levels have been associated with high mortality in patients with acute myocardial infarction (AMI). Furthermore, in animal models CRP has been found to significantly increase infarct size. So there is growing evidence that CRP is not only a marker for cardiovascular disease but also might be pathogenic. The aim of our study was to test the hypothesis that peak CRP levels could predict heart failure (HF) in ST-elevation myocardial infarction (STEMI) patients. MATERIAL AND METHODS: Eighty-one consecutive patients with STEMI were prospectively enrolled in the study. C-reactive protein concentrations were measured on admission and after 6, 12, 24, 30, 48, 72 and 96 h. We assessed the association between the elevation of CRP, heart failure and cardiovascular mortality following the first 12 months after STEMI. RESULTS: C-reactive protein levels reached a peak after 48 h. Patients with STEMI and signs of HF showed significantly higher peak CRP levels. We found a positive correlation between maximum CK levels and peak CRP and a negative correlation between left ventricular ejection fraction (EF) and peak CRP. One year total mortality and HF mortality rates were found to be higher in patients with peak CRP > 47.5 mg/l than in those with CRP below that level (p < 0.001). CONCLUSIONS: Peak CRP levels in STEMI patients predict emergence of HF. Peak CRP is also a strong predictor of global and cardiovascular mortality during the following year after STEMI. PMID- 28883851 TI - Improvement of exercise tolerance in cardiopulmonary testing with sustained safety after regular training in outpatients with systolic heart failure (NYHA III) and an implantable cardioverter-defibrillator. Prospective 18-month randomized study. AB - INTRODUCTION: The aim of the study was to evaluate the impact of individual training on the level of physical capacity and echocardiographic parameters in patients with systolic heart failure (SHF), NYHA III and an implantable cardioverter-defibrillator (ICD). MATERIAL AND METHODS: The study included 84 patients with SHF, randomly assigned to one of two groups: with regular training (ICD-Ex) and a control group (ICD-control). The ICD-Ex group participated in a hospital rehabilitation program which after discharge was individually continued for 6 months in an outpatient setting. The ICD-control group participated in a training program during hospitalization, but after discharge did not perform any controlled activities. Prior to discharge, at 6 and 18 months cardiopulmonary exercise testing (CPX), standard echocardiographic examination and the 6-minute walk test (6-MWT) were performed in all patients. RESULTS: After 18 months in the ICD-Ex group most of the CPX parameters improved significantly (VO2 peak, ml/kg/min: 13.0 +/-4.1 vs. 15.9 +/-6.1, p < 0.0017; VCO2 peak, l/min: 1.14 +/ 0.34 vs. 1.58 +/-0.65, p < 0.0008; Watt: 74.5 +/-29.7 vs. 92.6 +/-39.1, p < 0.0006; METs 3.72 +/-1.81 vs. 4.35 +/-1.46, p < 0.0131). In the ICD-control group no significant improvement of any parameter was observed. Left ventricular systolic dimensions remained significantly lower at 18 months only in the ICD-Ex group (49.5 +/-11.0 vs. 43.4 +/-10.0, p < 0.011). Left ventricular ejection fraction in both groups significantly increased at 6 and 18 months compared to baseline (ICD-Ex: 25.07 +/-5.4 vs. 31.4 +/-9.2, p < 0.001, vs. 30.9 +/-8.9, p < 0.002, ICD-C: 25.1 +/-8.3 vs. 29.2 +/-7.7, p < 0.012 vs. 30.1 +/-9.1, p < 0.005). Distance of the 6-MWT was significantly improved after 6 and 18 months in the ICD Ex group and was overall longer than in the ICD-control group (491 +/-127 vs. 423 +/-114 m, p < 0.04). CONCLUSIONS: An individual, 6-month training program, properly controlled in patients with SHF and an implanted ICD, was safe and resulted in a significant improvement of exercise tolerance and capacity and echocardiographic parameters. PMID- 28883852 TI - A randomized clinical trial comparing hemodynamic responses to ketamine-propofol combination (ketofol) versus etomidate during anesthesia induction in patients with left ventricular dysfunction undergoing coronary artery bypass graft surgery. AB - INTRODUCTION: Anesthesia induction is often accompanied by a period of hemodynamic instability, which could be a significant problem in patients with compromised ventricular function. The aim of this study is to compare the hemodynamic responses to etomidate versus a combination of ketamine and propofol (ketofol) for anesthetic induction in patients with left ventricular dysfunction undergoing coronary artery bypass graft (CABG) surgery. MATERIAL AND METHODS: In a double-blind randomized clinical study, a total of 84 patients with ischemic left ventricular dysfunction (EF < 40%) were randomly assigned to two groups (A and B). Patients in group A received etomidate 0.2 mg/kg and a placebo (normal saline); group B received a combination of ketamine (1 mg/kg) and propofol (1.5 mg/kg) at the induction of anesthesia. Two minutes after induction, hemodynamic variables, including systolic, diastolic, mean arterial pressure (SAP, DAP, MAP) and heart rate (HR), were measured immediately before and after the laryngoscopy, and before intubation and post-intubation at 1, 2, and 3 min. RESULTS: The decrease in all hemodynamic parameters (SBP, DBP, MAP and HR) from induction time to laryngoscopy was greater in the ketofol group (group B) than in the etomidate group (group A) (p < 0.05). The ephedrine prescription rate due to hemodynamic changes was 24.4% (10 patients) and 5% (2 patients) in group B and group A, respectively (p = 0.03). CONCLUSIONS: We found that etomidate provides superior hemodynamic stability as compared to ketofol in patients with left ventricular dysfunction undergoing CABG surgery under general anesthesia. PMID- 28883853 TI - Cardiac surgery related cardio-renal syndrome assessed by conventional and novel biomarkers - under or overestimated diagnosis? AB - INTRODUCTION: Serum creatinine is a 'gold standard' criterion of recognizing and staging of acute kidney injury (AKI) despite it being a suboptimal, delayed indicator. The interpretation of increased values of biomarkers imposes great difficulty regarding cardiac surgery procedures performed with cardiopulmonary bypass and may lead to under- or overestimated diagnosis. The aim of this study was to evaluate the clinical utility of the sole serum creatinine or urine neutrophil gelatinase-associated lipocalin (NGAL) concentration used for identification of patients with AKI after cardiac surgery. MATERIAL AND METHODS: A prospective observational study was conducted on a group of 88 adult patients undergoing a coronary artery bypass grafting procedure. Serum creatinine was evaluated on the day of the operation, and 24 and 48 h post-operatively. Urinary NGAL concentration was measured: immediately after and one hour after cardiopulmonary bypass, and 24 h from the beginning of the operation. We assessed features of kidney injury and 30-day and 5-year mortality. RESULTS: Patients in the AKI group diagnosed with creatinine level and urine output criteria presented more advanced age (p = 0.01), higher body mass index (p = 0.01) and preoperative myocardial infarction (p = 0.02). Elevation of NGAL level was observed in 5 of 13 cases with AKI, based on creatinine criteria and 4 of 75 cases without AKI. Within 5 years after the surgical procedure the recurrence of renal failure was 36% in the AKI group (with perioperative NGAL elevation in 2 cases only). CONCLUSIONS: In the cardiac surgery patients the diagnosis of AKI based on sole serum creatinine or urine NGAL concentration confirmed transient kidney injury. However, the clinical implications of these findings are insufficient for prediction of clinical outcome. PMID- 28883854 TI - Predictive abilities of baseline measurements of fluid overload, assessed by bioimpedance spectroscopy and serum N-terminal pro-B-type natriuretic peptide, for mortality in hemodialysis patients. AB - INTRODUCTION: Fluid overload is one of the most important, yet modifiable, risk factors associated with worse outcomes in hemodialysis (HD) patients. However, its precise assessment in clinical practice is still under investigation. MATERIAL AND METHODS: This is an observational prospective study which included 285 stable patients with end-stage renal disease on standard thrice-weekly HD therapy. Overhydration was assessed by the combination of relative fluid overload (RFO), using bioimpedance spectroscopy, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). The outcome of interest was all-cause mortality. RESULTS: The median values for NT-proBNP and RFO were 4595 pg/ml and 6.9%, respectively. We divided the study population into four groups according to these median levels: group 1 - low NT-proBNP and low RFO; group 2 - high NT-proBNP and low RFO; group 3 - low NT-proBNP and high RFO; group 4 - high NT-proBNP and high RFO. During the follow-up (mean: 41.1, median: 48.7 months), 89 (31.2%) patients died. In the univariable Cox survival analysis only patients in group 4, and not those from group 2 or 3, had significantly higher HRs as compared to those in group 1 (HR = 1.5, 95% CI: 0.8-2.8, HR = 1.6, 95% CI: 0.8-2.9 and HR = 2.4, 95% CI: 1.3 4.2, for group 2, 3 and 4, respectively). Furthermore, these results were maintained in the multivariable Cox analysis. CONCLUSIONS: Including both bioimpedance and NT-proBNP monitoring in a more comprehensive fluid status assessment could improve the diagnosis of fluid overload with a final improvement in patients' outcome. PMID- 28883855 TI - Five gene variants in nonagenarians, centenarians and average individuals. AB - INTRODUCTION: Genetic factors contribute to the variation of human life span which is believed to be more profound after 85 years of age. The aim of the present study was to evaluate the frequency of 5 gene polymorphisms between nonagenarians, centenarians and average individuals. MATERIAL AND METHODS: Single nucleotide polymorphisms (SNPs) of telomerase reverse transcriptase (TERT; rs2736098), insulin-like growth factor-1 binding protein-3 (IGFBP3; A-202C, rs2857744), fork-head box O3A (FOXO3A; rs13217795 and rs2764264) factor and adiponectin (ADIPOQ; rs2241766) were evaluated in 405 individuals: n = 256 nonagenarians and centenarians (study group) and n = 149 average lifespan individuals (control group aged 18 - < 80 years). RESULTS: The frequency of women was significantly higher in the study group than the control group (64.5 vs. 49.7%, p = 0.004). Genotypic and allele frequencies did not differ between groups according to gender. However, in men, the frequency of TT genotype of FOXO3A; rs2764264 was higher in the study group than the control group (45.6 vs. 28.0%, p = 0.05). Overall, the frequency of the C allele of FOXO3A; rs2764264 was significantly lower in the study group than the control group (3.9 vs. 9.5%, respectively, p = 0.023). Furthermore, in the study group, the T allele was significantly more frequent in the nonagenarians (n = 239) than the centenarians (n = 17) in both FOXO3A; rs13217795 and rs2764264 (64.4 vs. 44.1%, p = 0.018 and 69.7 vs. 50.0%, p = 0.017, respectively). CONCLUSIONS: According to survival status, there is differentiation in the prevalence of both studied FOXO3A gene polymorphisms. The study group had half of the C alleles compared with the control group and centenarians less frequently had the T allele of both FOXO3A gene polymorphisms compared with nonagenarians. No difference was found between groups according to TERT, IGFBP3 and ADIPOQ gene polymorphisms. It seems that some polymorphisms may be significant in prolonging our lifespan. Nevertheless, confirmation in additional study populations is needed. PMID- 28883856 TI - Interleukin-21 gene polymorphism rs2221903 is associated with disease activity in patients with rheumatoid arthritis. AB - INTRODUCTION: Interleukin-21 (IL-21) is a cytokine which plays a significant role in the pathogenesis and disease activity of rheumatoid arthritis (RA). Genetic polymorphisms in the IL-21 gene may alter the synthesis of IL-21. The aim of this study was to examine IL-21 and IL-21R polymorphisms in patients with RA. MATERIAL AND METHODS: We examined 422 patients with RA and 338 healthy controls. Single nucleotide polymorphisms (SNPs) within the IL-21 (rs6822844 G>T, rs6840978 C>T, rs2221903 T>C) and IL-21R (rs2285452 G>A) genes were genotyped using TaqMan genotyping assays. RESULTS: There were no statistically significant differences in the distribution of studied genotypes and alleles between RA patients and the control group. To examine whether IL-21 polymorphisms affect disease activity in RA patients, we compared the distribution of IL-21 genotypes between patients with DAS28 <= 2.5 (patients with remission of disease symptoms) and patients with DAS28 > 2.5 (patients with active RA). Among patients with DAS28 > 2.5, increased prevalence of rs2221903 CT and CC genotypes was observed (OR = 1.54; 95% CI: 1.04 2.28; p = 0.035). CONCLUSIONS: The results of this study suggest that IL-21 and IL-21R gene polymorphisms are not risk loci for RA susceptibility, whereas the IL 21 rs2221903 polymorphism is associated with disease activity. PMID- 28883857 TI - Postmenopausal cognitive changes and androgen levels in the context of apolipoprotein E polymorphism. AB - INTRODUCTION: The focus of this study was to assess cognitive functions in relation to androgens and specifically testosterone and dehydroepiandrosterone in postmenopausal women as well as the correlation between cognitive functions and these two androgens according to polymorphism of the apolipoprotein E gene (APOE). MATERIAL AND METHODS: A group of 402 women was recruited to the study (minimum 2 years after the last menstruation, follicle-stimulating hormone (FSH) more than 30 U/ml and no dementia signs on Montreal Cognitive Assessment). The computerized battery of the Central Nervous System Vital Signs test was used to diagnose cognitive functions. APOE genotyping was performed by multiplex polymerase chain reaction (PCR). Testosterone (TTE) and dehydroepiandrosterone (DHEA) in the blood serum were assessed for further statistical correlations analysis. RESULTS: In the group of postmenopausal women, higher testosterone concentration was associated with lower scores for Neurocognition Index (NCI) (p = 0.028), memory (p = 0.008) and psychomotor speed (p < 0.001). Presence of at least one APOE epsilon4 allele potentiated testosterone's negative influence on cognitive functions (p < 0.05). Woman with a high normal level of DHEA scored significantly better in verbal (p = 0.027) and visual memory (p < 0.001) than other participants. APOE polymorphism did not modify the relationship between DHEA concentration and scores for cognitive functions. CONCLUSIONS: Hormonal balance variations after menopause may influence brain processes concerned with cognition, especially memory and psychomotor speed. The observed effects may be related to androgens' influence on higher cortical functions in the changed hormonal dynamics of the postmenopausal period. PMID- 28883858 TI - Association between low thyroid-stimulating hormone, posterior cortical atrophy and nitro-oxidative stress in elderly patients with cognitive dysfunction. AB - INTRODUCTION: Cortical atrophy is known to be a valuable sign of cognitive decline. The purpose of this study was to assess the association between low thyroid-stimulating hormone (TSH), posterior cortical atrophy (Koedam score - KS) and nitro-oxidative stress in elderly patients. MATERIAL AND METHODS: A study (SG) and a control group (CG), each subdivided by gender, were investigated. Subjects older than 59 years with low serum TSH level and with mild cognitive impairment were included in the SG. The CG was formed by subjects free of significant cortical atrophy and free or thyroid dysfunction. Demographic and clinical characteristics of the patients (Mini Mental State Examination, MMSE), Koedam score on cranial magnetic resonance imaging, and blood parameters (TSH, FT4, and nitric oxide - NOx) were assessed. RESULTS: Subjects in the study group had fewer years of education above the 8th grade compared with the control group (p < 0.0001). A significantly higher percentage of subjects in the study group had a Koedam score of 2 or 3 compared with controls, who had in the majority of cases a Koedam score of zero (p < 0.02). Significantly higher NOx levels were observed when study groups of both genders were compared with corresponding controls (p < 0.001). No significant differences were observed with regard to FT4 (p > 0.70). Nitric oxide was found to be significantly associated with TSH (p < 0.03) and KS (p < 0.002) when the whole study group was considered as well as when just the non-smoker study group was investigated. CONCLUSIONS: Our study revealed an association between subclinical thyroid hypofunction, nitro-oxidative stress, and posterior cortical atrophy as an early stage of global atrophy. PMID- 28883859 TI - Neuropsychiatric symptoms and faster progression of cognitive impairments as predictors of risk of conversion of mild cognitive impairment to dementia. AB - INTRODUCTION: The aim of this research, based on 7 years of observations, was to assess the relationship between the dynamics of changes in the realm of cognitive functions in the early stages of observations and the presence of neuropsychiatric symptoms as well as further progression of cognitive function impairments in people diagnosed with mild cognitive impairment (MCI). MATERIAL AND METHODS: One hundred and ninety three individuals were included in the study, all of whom referred themselves to the Mental Health Clinic and were diagnosed with MCI based on the criteria of the Working Group on MCI. It was assumed that these individuals would be subjected to systematic psychiatric and neuropsychological observation until they were diagnosed with dementia. This report concerns a completed 7-year period of these observations. Participants were assessed based on the following scales: MMSE, NPI and GDS. RESULTS: The obtained results indicate statistically significant differences between groups of subjects at the time of inclusion in the study, regarding the frequency of occurrence and severity of the following categories of impairments: thought impairments (p < 0.001), arousal/aggression (p < 0.001), depression/dysphoria (p < 0.001), disinhibition (p < 0.03), irritability/lability (p < 0.001), abnormal motor behaviors (p < 0.02), as well as sleep and night-time behavior disorders (p < 0.01) Moreover, individuals who developed dementia during observation exhibited greater progression in cognitive function impairment assessed with the MMSE scale in the first year of observation (p < 0.01). CONCLUSIONS: The accruing of cognitive function impairments and the presence of neuropsychiatric symptoms seem to be important risk factors for the development of dementia. PMID- 28883861 TI - Bioavailable testosterone is independently associated with Fatty Liver Index in postmenopausal women. AB - INTRODUCTION: Previous studies have examined the correlation between hyperandrogenemia and non-alcoholic fatty liver disease (NAFLD) in women and showed contradictory results. Therefore, we aimed to evaluate the relationship between testosterone level and Fatty Liver Index (FLI), as a surrogate marker for NAFLD, in a cohort of postmenopausal women. MATERIAL AND METHODS: A total of 150 postmenopausal women were included in this cross-sectional study. Anthropometric and biochemical parameters, as well as blood pressure, were obtained. Non alcoholic fatty liver disease is assessed by FLI, an algorithm based on body mass index, waist circumference, triglycerides and gamma-glutamyl transferase, as a simple and accurate predictor of hepatic steatosis. Women were divided into three groups (FLI < 30, n = 80; 30 <= FLI < 60, n = 44; FLI >= 60, n = 26). Homeostasis model assessment of insulin resistance (HOMA-IR) as a surrogate marker of insulin resistance was calculated. RESULTS: Multiple linear regression analysis revealed that the best model consisted of 4 parameters (e.g., bioavailable testosterone (beta = 0.288, p = 0.001), log HOMA-IR (beta = 0.227, p = 0.005), log high sensitivity C-reactive protein (beta = 0.322, p < 0.001), and retinol-binding protein 4 (beta = 0.226, p < 0.001)). Adjusted R2 for the best model was 0.550, which means that as much as 55.0% of variation in FLI could be explained with this model. CONCLUSIONS: Bioavailable testosterone is independently associated with FLI in postmenopausal women. PMID- 28883860 TI - Impact of beverage consumption, age, and site dependency on dual energy X-ray absorptiometry (DEXA) measurements in perimenopausal women: a prospective study. AB - INTRODUCTION: The aim of this study was to determine the best site for bone mineral density (BMD) measurements based on T-scores, age, and beverage consumption. MATERIAL AND METHODS: In this prospective study, 271 women stratified by age (average age: 61.9 years) underwent dual energy X-ray absorptiometry (DEXA) scanning of their lumbar spine, hips, and forearms. Osteoporosis was defined as a BMD of 2.5 standard deviations or more below the mean peak bone mass based on a reference population of adult women (translated as a T-score <= -2.5), as measured by DEXA. Participants were also evaluated regarding alcohol and caffeine consumption by a semiquantitative questionnaire. RESULTS: A significant discrepancy was observed in the classification of osteoporosis at different locations, with hip and forearm showing the best correlation (Pearson's r = 0.627, p < 0.001). In addition, for participants over 50 years of age, hip and forearm showed the best correlation. Significant correlations were also noted between forearm T-scores and caffeine consumed and, to a lesser extent, the level of alcohol consumption. In the group <= 50 years of age, lumbar spine and forearm T-scores were only associated with alcohol consumption. In the group over 50 years of age, hip and forearm T-scores were only associated with caffeine consumption. CONCLUSIONS: Bone mineral density measurements at the hip and forearm correlated with caffeine consumption in elderly Taiwanese women. This is an important finding since age and caffeine consumption are known risk factors for osteoporosis. PMID- 28883862 TI - Prevalence of chronic pain in the elderly Polish population - results of the PolSenior study. AB - INTRODUCTION: Pain is the most common complaint of elderly people. In Poland, no large studies on the prevalence of chronic pain in the elderly were conducted until recently. MATERIAL AND METHODS: The study was a part of the PolSenior project, a cross-sectional multidisciplinary study on ageing of the Polish population, and included a randomly selected group of 716 people aged 55-59 years, and 4979 people over 65 years. The survey was conducted through a standardized questionnaire. An evaluation of pain occurrence, location, intensity and coexistence of pains in relation to gender, age and use of health care was performed. RESULTS: Chronic pain affected 42.0% of respondents aged 65 years and over (48.6% of women and 35.8% of men) as compared to 35.2% of the pre-elderly. The most common pain locations were the lumbar region (51.6%) and knees (41.0%). The average number of pain sites was 3.1 +/-2.3. Average intensity of pain was 6.2 points on the VAS scale in people over 65 years and 6.0 points in the pre elderly (NS). Average pain intensity increased significantly from 5.7 points in patients reporting pain in one place to 7.2 points in those reporting six pain sites. Elderly respondents with pain compared to those without pain more frequently reported physician visits performed at least once a month (54.6% vs. 48.4%, p < 0.001). CONCLUSIONS: Polish elderly most frequently complained of low back and lower limb pain. In respondents reporting many sites of pain, an increase in the intensity of pain was observed. Elderly patients with chronic pain often use medical care. PMID- 28883863 TI - The evolution of natriuretic peptide augmentation in management of heart failure and the role of sacubitril/valsartan. AB - Heart failure (HF) is one of the leading causes of morbidity, mortality, and health care expenditures in the US and worldwide. For three decades, the pillars of treatment of HF with reduced ejection fraction (HFrEF) were medications that targeted the sympathetic nervous system (SNS) and the renin-angiotensin aldosterone system (RAAS). Prior attempts to augment the natriuretic peptide system (NPS) for the management of HF failed either due to lack of significant clinical benefit or due to the unacceptable side effect profile. This review article will discuss the NPS, the failure of early drugs which targeted the NPS as therapies for HF, and the sequence of events which led to the development of sacubitril plus valsartan (Entresto; LCZ696; Novartis). LCZ696 has been shown to be superior to the standard of care available for treatment of HFrEF in several substantial hard endpoints including heart failure hospitalizations, cardiovascular mortality, and all-cause mortality. PMID- 28883864 TI - The efficacy of hyperbaric oxygen in hemorrhagic stroke: experimental and clinical implications. AB - Hemorrhagic stroke, accounting for 10-30% of stroke cases, carries high rates of morbidity and mortality. This review presents the current knowledge on the efficacy of hyperbaric oxygen (HBO)-based modalities in the preclinical research on hemorrhagic stroke. Both preconditioning and post-treatment with HBO are considered as prospective therapeutic options. High efficacy of HBO therapy (HBOT) for brain hemorrhage has been noted. We found that moderate hyperbaric pressures appear optimal for therapeutic effect, while the therapeutic window of opportunity is short. HBO preconditioning offers more modest neuroprotective benefit as compared to HBO post-treatment for experimental intracerebral hemorrhage. We advocate for mandatory calculations of percent changes in the experimentally investigated indexes of HBO effectiveness and stress the need to design new clinical trials on HBO for hemorrhagic stroke. PMID- 28883866 TI - Race, sense of control over life, and short-term risk of mortality among older adults in the United States. AB - INTRODUCTION: Sense of control over life has been shown to have protective health effects in studies that have mostly enrolled White middle class individuals. It is unknown, however, whether populations differ in the protective health gain associated with sense of control over life. This study compared a nationally representative sample of Black and White older adults for protective effects of sense of control over life on short-term risk of all-cause mortality in the United States. MATERIAL AND METHODS: This longitudinal prospective study followed 1,493 White (n = 759) and Black (n = 734) older adults (age 66 or more) from 2001 to 2004. Race, demographics, socio-economics, sense of control over life, health behaviors, and self-rated health were measured at baseline in 2001. Outcome was all-cause mortality occurring between 2001 and 2004. Logistic regression models were used for data analysis. RESULTS: In the pooled sample, sense of control over life was protective against 3-year mortality risk above and beyond demographics, socio-economics, health behaviors, and self-rated health. We found a race by sense of control over life interaction, suggesting a stronger protective effect of control over life on mortality risk for Whites compared to Blacks. In race specific models, sense of control over life at baseline was predictive of mortality among Whites but not Blacks. CONCLUSIONS: In the United States, Black older adults do not gain a survival benefit associated with high levels of sense of control over life, as do their White counterparts. It is not clear why sense of control over life translates into survival for Whites but not for Blacks. PMID- 28883865 TI - Does genetic testing for ERalpha gene polymorphisms provide new possibilities of treatment for cognitive function disorders in postmenopausal women? AB - It is commonly considered that cognitive abilities decrease with age, especially with respect to processing and psychomotor speed. It is an interesting issue whether, apart from the ageing process, the undergoing of menopause itself deteriorates cognitive functions, compared to women at reproductive age. Hopes for improvement of cognitive functions were pinned on the use of menopausal hormone therapy. However, the results of studies concerning the effect of hormone replacement therapy on cognition proved to be contradictory. It seems that the essence of the problem is more complicated than only estrogen deficiency. It is suggested that estrogen receptor alpha (ERalpha) polymorphism may be responsible for the differences in the effect of estrogens on cognitive processes. The article presents current knowledge concerning the effect of estrogens on the central nervous system, especially the role of ERalpha polymorphism, with respect to foreseeing benefits from the use of exogenous estrogens for cognitive functions. At the present stage of research, ERalpha appears to be poorly specific; nevertheless, it may be an important instrument for the classification of peri- and post-menopausal patients in the group where therapy with the use of estrogens may bring about benefits in terms of prevention and treatment of cognitive disorders. It also seems necessary to conduct prophylactic, screening examination of cognitive functions in post-menopausal women, in order to identify those at risk of the development of dementia. PMID- 28883867 TI - Lifestyle measures for treating hypertension. PMID- 28883868 TI - The need to apply the best therapy in heart failure - the era after PARADIGM-HF. PMID- 28883869 TI - Ataxia in Childhood: Epidemiological, Clinical and Neuroradiologic Features, and the Risk of Recurrence. AB - OBJECTIVE: This study was conducted on the demographic data, clinical characteristics, electroencephalography, neuroradiological findings, and their impact on the recurrence of ataxia. MATERIALS & METHODS: A 3-yr retrospective review of 49 children with ataxia in Mofid Children Hospital, Tehran, Iran was conducted from Apr 2013 to Apr 2016. The demographic, clinical and paraclinical data were recorded in pre-prepared questionnaires. The patients were also classified in two groups of with or without recurrence and the results were compared. The diagnostic etiologies in our patients were classified as brain tumor, drug ingestion, encephalitis, post infectious immune-mediated disorders, pseudoataxia, trauma, congenital malformations of the central nervous system and hereditary ataxias. RESULTS: Forty-nine children with ataxia were enrolled. The mean age of the patients with a recurrence of ataxia was more than those without a recurrence. Neurodevelopmental delay in patients with recurrence was more frequent than those without a recurrence. Abnormal findings in the neuroimaging were seen more in the patients with recurrence than those without recurrence. The most common cause of ataxia in patients with recurrence was hereditary ataxia and in patients without recurrence was a viral post infectious disorder. CONCLUSION: After a mean follow-up period of 16.36 months (range: 2-37 months), 9 cases (18.4%) showed recurrence. Older age, abnormal neuroimaging, and neurodevelopmental delay should be considered as the risk factors of recurrence of ataxia in children. PMID- 28883870 TI - Assessment of the Relationship between Body Mass Index and Gross Motor Development in Children. AB - OBJECTIVE: Obesity is a growing epidemic and public health problem in children. The purpose of this study was to determine the effect of body mass index (BMI) on the gross motor development. MATERIALS & METHODS: In this cross-sectional study conducted in 2012-13 in Gorgan, northern Iran, the gross motor development of 90 children 3-5 yr old in three groups of lean, normal and obese/overweight were evaluated by the ages and stages questionnaires (ASQ) and Denver 2 scale. RESULTS: Totally, 90 children were enrolled and their developmental level was assessed with two ASQ and Denver II indices. The mean and standard deviation of the ASQ scores of the children was 53.11+/- 11.06 and based on Denver index, 9 children (10%) were at developmental delay status, 15 (16.7%) in the caution conditions, and 53 (58.9%) at normal developmental status. The developmental level was lower in obese/overweight group comparing with other groups according to both Denver and ASQ and there was a significant difference between obese/overweight group and normal group based in Denver and ASQ, respectively. There was no significant difference between underweight and normal and obese and underweight groups. CONCLUSION: Overweight and obesity could affect on the gross motor development. PMID- 28883871 TI - Drug-Induced Apnea in Children Admitted to Loghman Hakim Hospital, Tehran, Iran. AB - OBJECTIVE: Environmental hazards, including poisons, can cause irreparable effects and even fatal for children. Poisoning in children is common and serious, but often is preventable and treatable. This study aimed to evaluate the prevalence of drugs and chemical toxicity leading to apnea. In addition, we detected type of drug that induced apnea among children. MATERIALS & METHODS: In a retrospective cross-sectional study from Apr 2012 to Apr 2013, data of all hospitalized drug-induced Apnea in children were collected through hospital records. RESULTS: The most common cause of drug toxicity was methadone opium, baclofen and heroin (74%,13%,5%,2%). The mortality rate was 3.1%; all of them due to methadone poisoning. CONCLUSION: There was a high prevalence of Methadone poisoning and apnea in children. Methadone poisoning should be considered in apnea. PMID- 28883872 TI - Therapeutic Effects of Adrenocorticotropic Hormone ACTH in Children with Severely Intractable Seizure. AB - OBJECTIVE: Treatment of intractable seizures other than spasms is difficult and controversial. There are few studies on efficacy of adrenocorticotropic hormone (ACTH) in treatment of patients with intractable seizure. MATERIALS & METHODS: Twenty-five patients with intractable seizure other than spasm including 14 boys and 11 girls with median age of 58 months referred to university clinics of Pediatric Neurology in Isfahan, Iran, during 2014-2015 were prospectively investigated. ACTH was administrated according to our protocol. All cases were followed regularly and assessed for response to treatment and probable side effects, 3 wk after beginning of ACTH therapy and three months after the ACTH therapy. EEG finding were recorded before and three months after the end of ACTH therapy. Statistical analysis using Freidman test and Wilcoxon signed - rank test were performed in order to compare seizure frequency and EEG changes, respectively. RESULTS: Mean A significant reduction (>80%) in seizure frequency in 11 cases (44%) and moderate reduction (50%-80%) in 7 (28%) after 3 wk of ACTH therapy. Despite initial positive response, recurrence of seizure was observed in 7 out of 18 cases with favorable initial response within 3 months after ACTH therapy cessation. The comparison of EEG finding before and 3 months after ACTH therapy using Wilcoxon signed - rank test showed significant differences. CONCLUSION: ACTH therapy may be useful in treatment of children with intractable seizures who are resistant to usual antiepileptic drugs. However further studies should be performed to determine the long-term efficacy of ACTH in treatment of intractable seizure. PMID- 28883873 TI - Circadian Rhythm and the Seasonal Variation in Childhood Febrile Seizure. AB - OBJECTIVE: We aimed to assess the circadian rhythm and the seasonal variation in childhood febrile seizure (FS). MATERIALS & METHODS: This descriptive cross sectional study was conducted retrospectively on patients' records. Investigators assessed the records of patients with simple FS aged 6 to 60 months referred to Emergency Department of 17-Shahrivar Hospital, Rasht northern Iran during Jan 2010 to Jan 2013. Data were gathered by a checklist including age, sex, temperature, duration of seizure, seasonal, months, diurnal variation, and level of consciousness. RESULTS: Totally, 349 patients including 193 (55.3%) boys and 156 (44.7%) girls with the mean age of 22.85+/-18.34 months were enrolled in this study. The mean temperature of patients was 38.45+/-0.53 degrees C. The mean duration of seizure was 97.91+/-57 sec. Awake, drowsy and slept patients were noted in 170 (48.7%), 33(9.5%) and 146 (41.8%) cases, respectively. Most of the FS occurred in winter 118 (33.8%), afternoon 132 (37.8%) and in Jan 55 (15.8%). CONCLUSION: Body temperature adjusted by hypothalamus affecting by circadian rhythm. FS is the most common form of seizure in childhood occurred by multifactorial issues. Otherwise, the occurrence of seizure in patients with epilepsy may be affected by the circadian rhythm. Seizures happen more frequent at a specific time in 24 h during a day. PMID- 28883874 TI - Treatment of Cystic Craniopharyngioma with Intracystic Stereotactic Instillation of Phosphorus 32. AB - OBJECTIVE: Cystic craniopharyngiomas are considered the most common intracranial nonglial tumor in children with the tendency for cyst formations. The aim of this study was to evaluate the effect of intracystic phosphorus 32 (P32) therapies on controlling the growth of the cystic component of craniopharyngioma. MATERIALS & METHODS: This clinical study was conducted on 47 patients with cystic craniopharyngioma from March 1998 to June 2012 at Shohada Tajrish Hospital, Tehran, Iran. Patients were treated with stereotactic intracystic P32. The mean cyst volume was 23.5 ml, and the dose of radiation to the inner cyst wall was 250 Gy. RESULTS: The overall response rate was 78.1% and the mean survival was 113.1+/-11months. The survival rate at 1, 3, 5, and 10 years after p32 therapy was 91%, 77%, 73%, and 52%, respectively. There was no mortality related to the procedure and no visual or endocrinal deterioration. Visual improvement occurred in 88% of patients presented with recent deterioration due to the cyst enlargement. CONCLUSION: Intracystic p32 therapy was an effective and almost safe procedure for the treatment of cystic component of craniopharyngioma. PMID- 28883875 TI - Is Infantile Colic an Early Life Expression of Childhood Migraine? AB - OBJECTIVE: Migraine is the mosyndrome and infantile colic is a common cause of infantile cry. The pathogenesis of migraine and colic has not been well established and different factors may cause them. There is an association between infantile colic and the occurrence of childhood migraine. We aimed to assess whether infantile colic could be noted as an early life expression of childhood migraine or not. MATERIALS & METHODS: This retrospective case-control study was conducted on 5-15-year-old childrenin Rasht, Iran during 2015-2016. Forty-one cases were children with migraine with or without aura. Overall, 123 Control participants were children with the same age referred to the pediatric clinic for routine care. Data were gathered by a checklist including age, sex, birth weight, family history of migraine, the occurrence of colic and type of feeding during infancy. Data were reported by descriptive statistics and analyzed by Fisher exact test using SPSS ver. 19. RESULTS: Overall, 164 children with the mean age of 8.36+/- 2.53 yr were enrolled. Seventeen (41.46%) children with migraine vs. 44 (35.7%) children in control group had the positive history of infantile colic and Fisher exact test noted significant relation between migraine and colic. Thirty-three children with infantile colic (46.57%) had the positive family history of migraine, which was significantly higher than 27 children without colic (29.7%). There was a significant relation between infantile feeding and migraine. CONCLUSION: There is a probable relation between colic and migraine, therefore, migraine and colic as 2 pain syndromes may have a common pathophysiology and further investigations on this common pathophysiology is justified. PMID- 28883876 TI - Metabolic Screening in Children with Neurodevelopmental Delay, Seizure and/or Regression. AB - OBJECTIVE: Neurometabolic disorder is one of the important groups of diseases that prominently has presentation early infantile period. In this study, we evaluated the result of metabolic screening of the patient with seizure, developmental delay and/or regression in development, demographic disease clinical and radiological findings on admitted and outpatient visited children. MATERIALS & METHODS: Two-year retrospective review of 187 children with seizure, developmental delay and/or regression in the Mofid Children Hospital, Tehran, Iran was performed. The diagnosis was based on observation, findings of EEG and history of the patient, besides evaluation of patient milestones. The result of metabolic screening with Tandem mass spectrometry was evaluated using SPSS (ver.18.0) Statistical software. RESULTS: Totally, 187 children with seizure, regression and/or developmental delay were evaluated by metabolic screening with tandem mass spectrometry method. The results of laboratory examination had no relationship between positive results of metabolic screening and the mentioned disease. The relations between positive results of metabolic screening and seizure, regression and/or developmental delay were not statistically meaningful. CONCLUSION: Positive results of metabolic screening and seizure, regression and/or developmental delay were not statistically meaningful. PMID- 28883877 TI - Homocystinuria with Cerebral Venous Sinus Thrombosis: Excellent Recovery with Intravenous Recombinant Tissue Plasminogen Activator. AB - Hyperhomocysteinemia can cause cerebral venous thrombosis. Recombinant tissue plasminogen activator is one of the treatment options for cerebral venous thrombosis in selected cases. We present here a 7-year-old boy with homocysteinuria with stroke. MRI of brain showed cerebral venous sinus thrombosis. We successfully treated with intravenous recombinant tissue plasminogen activator. He recovered completely without any complications. Recombinant tissue plasminogen activator can be considered one of the treatment options in cerebral venous thrombosis in homocystinura. PMID- 28883878 TI - The Report of Three Rare Cases of the Niemann-pick Disease in Birjand, South Khorasan, Eastern Iran. AB - Niemann-Pick disease type C (NP-C) is a rare neurovisceral and irreversible disease leading to premature death and disabling neurological signs. This autosomal recessive disease with incidence rate of 1:120000 is caused by mutations in either the NPC1 or the NPC2 gene, which leads to accumulation of cholesterol in body tissues especially brain and progressive neurological symptoms. NP-C is characterized by nonspecific visceral, neurological and psychiatric manifestations in infants. The neurological involvement is typically proceeded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno-or hepatosplenomegaly in infancy or childhood). Early detection of NPC is important so that therapy with miglustat can delay onset of neurological symptoms and prolong survival. We describe here three infants from Birjand, South Khorasan, eastern Iran in 2016 with splenomegaly and different neurological signs that diagnosis was confirmed by genetic study. In all of them, NPC-509 was pathologically increased. They also had an unreported homozygous mutation (c.1415T>C, p.Leu472Pro) in exon 9 of the NPC1 gene. We found unreported homozygous mutation in NPC gene. Knowing this mutation is significant to our people. Genotype-phenotype correlations for this specific mutation needs to be further studied. PMID- 28883879 TI - Limb Girdle Muscular Dystrophy Type 2E Due to a Novel Large Deletion in SGCB Gene. AB - Autosomal recessive limb-girdle muscular dystrophies (LGMD type 2) are a group of clinically and genetically heterogeneous diseases with the main characteristics of weakness and wasting of the pelvic and shoulder girdle muscles. Among them are sarcoglycanopathies caused by mutations in at least four genes named SGCA, SGCB, SGCG and SGCD. Here we report a consanguineous Iranian family with two children affected with LGMD type 2E. Mutation analysis revealed a novel homozygous exon 2 deletion of SGCB gene in the patients with the parents being heterozygous for this deletion. This result presents a novel underlying genetic mechanism for LGMD type 2E. PMID- 28883880 TI - Semi Lobar Holoprosencephaly with Vertebral Segmentation Defects. AB - Holoprosencephaly is the most common embryonic brain defect. Foetuses who survive during intrauterine life are born with varying grades of brain and facial deformities. Extra craniofacial manifestations are common. Vertebral segmentation defects are rarely seen with holoprosencephaly, mainly in association with holoprosencephaly diencephalic hamartoblastoma (HDH) association. A female infant was born at term by normal delivery. Birth head circumference was below the 3rd percentile. Antenatal scan had showed microcephaly as the only abnormality. Physical examination revealed microcephaly, ocular hypotelorism, left ear skin tag and short neck. MRI of the brain showed semilobar holoprosencephaly. Neck radiograph revealed gross vertebral segmentation defect involving cervical and upper thoracic vertebrae. She had initial feeding difficulties. She showed severe global developmental delay and had underlying central diabetes insipidus. Vertebral segmentation defect is rare in holoprosencephaly. PMID- 28883881 TI - Zinc and Copper Metabolism and Risk of Autism: a reply to Sayehmiri et al. AB - OBJECTIVE: Sayehmiri et al. recently conducted a meta-analysis to explore the relationship between zinc and copper metabolism and autism spectrum disorders (ASD). Recent reports have elucidated a full behavioral profile of mice exposed to prenatal zinc deficiency and documented a phenotype similar to that found in autism spectrum disorders (ASD). These studies suggest that significant alterations in Zn metabolism may be an important nutritional component in the development of ASD. MATERIALS & METHODS: The idea that prenatal zinc deficiency may be to blame is cursorily challenged. Epidemiological studies show that high income countries with a low estimated prevalence of inadequate zinc intake report the highest prevalence of ASD. Consistent with other reports indicating a link between air pollution and ASD, it has recently been proposed that use of the herbicide, glyphosate, in agriculture may serve as an instrumental variable in predicting later neurodevelopmental impairment via emissions of the agricultural air pollutant, nitrous oxide (N2O). RESULTS: Work in anesthesiology has demonstrated the neurological effects from subanesthetic doses of N2O, including its inhibition of the alpha 7 nicotinic acetylcholine receptor (alpha7), a receptor coupled to both central nitric oxide (NO) metabolism and peripheral anti inflammation. CONCLUSION: This correspondence explores how the aforementioned nutritional phenotypes found by Sayehmiri et al. in their systematic review may be a compensatory mechanism to counter the effects (namely, alpha7 inhibition) of air pollutant exposures occurring during the most critical stages of fetal development. PMID- 28883882 TI - Effects of Combined Far-Infrared Radiation and Acupuncture at ST36 on Peripheral Blood Perfusion and Autonomic Activities. AB - Using four-channel photoplethysmography (PPG) for acquiring peripheral arterial waveforms, this study investigated vascular and autonomic impacts of combined acupuncture-far infrared radiation (FIR) in improving peripheral circulation. Twenty healthy young adults aged 25.5 +/- 4.6 were enrolled for 30-minute measurement. Each subject underwent four treatment strategies, including acupuncture at ST36 (Zusanli), pseudoacupuncture, FIR, and combined acupuncture FIR at different time points. Response was assessed at 5-minute intervals. Area under arterial waveform at baseline was defined as AreaBaseline, whereas AreaStim referred to area at each 5-minute substage during and after treatment. AreaStim/AreaBaseline was compared at different stages and among different strategies. Autonomic activity at different stages was assessed using low-to-high frequency power ratio (LHR). The results demonstrated increased perfusion for each therapeutic strategy from stage 1 to stage 2 (all p < 0.02). Elevated perfusion was noted for all treatment strategies at stage 3 compared to stage 1 except pseudoacupuncture. Increased LHR was noted only in subjects undergoing pseudoacupuncture at stage 3 compared to stage 1 (p = 0.045). Reduced LHR at stage 2 compared to stage 1 was found only in combined treatment group (p = 0.041). In conclusion, the results support clinical benefits of combined acupuncture-FIR treatment in enhancing peripheral perfusion and parasympathetic activity. PMID- 28883883 TI - Atractylodin Induces Myosin Light Chain Phosphorylation and Promotes Gastric Emptying through Ghrelin Receptor. AB - Atractylodin is one of the main constituents in the rhizomes of Atractylodes lancea Thunb., being capable of treating cancer cachexia-anorexia and age-related diseases as an agonist of growth hormone secretagogue receptor (GHSR). GHSR was herein expressed in human gastric smooth muscle cells (HGSMCs) and activated by ghrelin receptor agonist L-692,585. Like L-692,585, atractylodin also increased Ca2+ and enhanced the phosphorylation of myosin light chain (MLC) through GHSR in HGSMCs. In addition, atractylodin promoted gastric emptying and MLC phosphorylation in the gastric antrum of mice also through GHSR. Collectively, atractylodin can activate GHSR in gastric smooth muscle, as a potential target in clinical practice. PMID- 28883884 TI - iTRAQ-Based Quantitative Proteomics Analysis of the Protective Effect of Yinchenwuling Powder on Hyperlipidemic Rats. AB - Yinchenwuling powder (YCL) is an effective traditional Chinese medicine formula to modulate lipid levels. In this study, we established hyperlipidemic rat models and treated them with YCL. The serum concentrations of lipid, malondialdehyde (MDA), endothelin-1 (ET-1), and calcitonin gene-related peptide (CGRP) were measured. Adventitia-free vascular proteins between hyperlipidemic rats and YCL treated rats were identified using iTRAQ-based quantitative proteomics research approach. Proteins with 1.3-fold difference were analyzed through bioinformatics, and proteomic results were verified by Western blot. The results showed that the serum levels of TC, TG, LDL-C, ET-1, and MDA were significantly decreased, whereas the HDL-C and CGRP levels were significantly increased in the YCL-treated group. Proteomics technology identified 4,382 proteins, and 15 proteins were selected on the basis of their expression levels and bioinformatics. Of these proteins, 2 (Adipoq and Gsta1) were upregulated and 13 (C3, C4, C6, Cfh, Cfp, C8g, C8b, Lgals1, Fndc1, Fgb, Fgg, Kng1, and ApoH) were downregulated in the YCL treated rats. Their functions were related to immunity, inflammation, coagulation and hemostasis, oxidation and antioxidation, and lipid metabolism and transport. The validated results of ApoH were consistent with the proteomics results. This study enhanced our understanding on the therapeutic effects and mechanism of YCL on hyperlipidemia. PMID- 28883885 TI - Synergistic Antitumor Effects of Berbamine and Paclitaxel through ROS/Akt Pathway in Glioma Cells. AB - In our preliminary study, Berbamine (BA), one of the most commonly used traditional Chinese medicines, was effective in inducing the intracellular ROS levels. Since the regulation of cellular antioxidant capacity is crucial to the sensitivity of Ptx, it is feasible to propose that sensitizing cells to Ptx can be achieved through increasing the antioxidant capacity by codelivering BA. Cytotoxicity test demonstrates that either single or combinational treatment of BA and Ptx dose-dependently inhibits the proliferation of U-87 cells. Median effect analysis clearly proves the synergistic anticancer effect between BA and Ptx. Combinational treatment of both drugs induced more intracellular ROS generation than either of the drugs did. Cotreatment of NAC could partially reverse the ROS generation and ameliorate the cytotoxicity induced by BA plus Ptx. Moreover, sequential activation of ROS-dependent phosphor-Akt expression was dose-dependently inhibited by the combinational application of BA and Ptx, which was more significantly effective than the single treatment of either BA or Ptx. Additionally, the coadministration of BA and Ptx shows the strongest tumor delaying effect in a U87 xenograft model, demonstrating the synergism between two drugs. Therefore, BA is a promising adjuvant to traditional chemotherapy, especially in combination with Ptx, to treat malignant glioma. PMID- 28883886 TI - Differences in Complexion between Cold- and Heat-Prescription Groups in Sasang Medicine. AB - Sasang constitutional medicine (SCM) is a type of traditional Korean medicine (TKM) that classifies the human constitution into four types. The appearance of the complexion is one of the diagnostic factors of SCM but is rarely used in a quantitative and objective manner for diagnosis. In this study, an analysis using actual clinical data was conducted to assess the use of the complexion as a diagnostic element. A total of 528 Sasang medicine prescriptions from Korea Constitutional Multicenter Bank (KCMB) were classified into either a Cold prescription group or a Heat-prescription group, and the complexion differences of the patients were analyzed using the L*a*b* color space. After adjusting for age, BMI, and systolic blood pressure, significant differences were observed among the Cold- and Heat-prescription groups within each Sasang constitution. However, when the Sasang constitution was ignored, no significant difference was observed for either sex. This study quantitatively analyzed the complexion of patients, which is used as a diagnostic element in clinical practice. It is hoped that the results will contribute to objective medical treatments in the future, such as determining an appropriate herbal prescription based on the patient's complexion. PMID- 28883887 TI - Indices of immune function used by ecologists are mostly unaffected by repeated freeze-thaw cycles and methodological deviations. AB - BACKGROUND: Over the past couple of decades, measuring immunological parameters has become widespread in studies of ecology and evolution. A combination of different immunological indices is useful for quantifying different parts of the immune system and comprehensively assessing immune function. Running multiple immune assays usually requires samples to be repeatedly thawed and re-frozen. There is some evidence that repeated freezing and thawing can affect assay results, but this has never been comprehensively studied in some common ecological immunology assays. We tested the effect of multiple (1, 2, 3, 4, 5, 10) freeze-thaw cycles on the results of four commonly used immunological assays: haemolysis-haemagglutination titres, haptoglobin concentration, bacterial killing capacity and total immunoglobulins (IgY). We tested five different bird species from four different bird orders (Passeriformes, Columbiformes, Charadriiformes and Galliformes), and we included both captive and free-living individuals. In addition, we tested for haptoglobin concentrations and the haemolysis haemagglutination assay if re-analysing samples 1 year apart led to different results. For the haemolysis-haemagglutination assay we also tested two different sources of rabbit blood, and we compared untreated microtitre plates with plates that were "blocked" to prevent nonspecific interactions between the plate and assay reagents. RESULTS: Repeated freezing and thawing of plasma had no effect on lysis titres, haptoglobin concentrations, bacterial killing capacity, or total immunoglobulin levels. Agglutination titres were unaffected by up to five cycles but were lower after ten freeze-thaw cycles. For the haemolysis-haemagglutination assay and haptoglobin concentrations, re-analysing samples 1 year apart yielded highly correlated data. For the haemolysis-haemagglutination assay, the source of rabbit blood did not influence the results, and the untreated vs. blocked plates differed slightly overall, but at the individual level assay results were highly correlated. Using different rabbit blood sources or different types of microtitre plates yielded highly correlated data. CONCLUSIONS: Our data suggest that repeated freeze-thaw cycles do not impair assay results to the point of influencing ecological or evolutionary conclusions. Plasma samples can be safely stored in one tube and thawed repeatedly for different assays. Nevertheless, we recommend consistent treatment of samples in terms of freeze-thaw cycles or other laboratory treatments to minimize the potential for introducing a systematic bias. PMID- 28883888 TI - Spectroscopic evidence of a new energy scale for superconductivity in H3S. AB - The discovery of a superconducting phase in sulfur hydride under high pressure with a critical temperature above 200 K has provided fresh impetus to the search for superconductors at ever higher temperatures. Although this systems displays all the hallmarks of superconductivity, the mechanism through which it arises remains to be determined. Here we provide a first optical spectroscopy study of this superconductor. Experimental results for the optical reflectivity of H3S, under hydrostatic pressure of 150 GPa, for several temperatures and over the range 60 to 600 meV of photon energies, are compared with theoretical calculations based on Eliashberg theory. Two significant features stand out: some remarkably strong infrared active phonons at around 160 meV, and a band with a depressed reflectance in the superconducting state in the region from 450 meV to 600 meV. In this energy range H3S becomes more reflecting with increasing temperature, a change that is traced to superconductivity originating from the electron-phonon interaction. The shape, magnitude, and energy dependence of this band at 150 K agrees with our calculations. This provides strong evidence of a conventional mechanism. However, the unusually strong optical phonon suggests a contribution of electronic degrees of freedom. PMID- 28883889 TI - A review of factors affecting the transfer of sexual and reproductive health training into practice in low and lower-middle income country humanitarian settings. AB - BACKGROUND: A lack of access to sexual and reproductive health (SRH) care is the leading cause of morbidity and mortality among displaced women and girls of reproductive age. Efforts to address this public health emergency in humanitarian settings have included the widespread delivery of training programmes to address gaps in health worker capacity for SRH. There remains a lack of data on the factors which may affect the ability of health workers to apply SRH knowledge and skills gained through training programmes in humanitarian contexts. METHODS: We searched four electronic databases and ten key organizations' websites to locate literature on SRH training for humanitarian settings in low and lower-middle income countries. Papers were examined using content analysis to identify factors which contribute to health workers' capacity to transfer SRH knowledge, skills and attitudes learned in training into practice in humanitarian settings. RESULTS: Seven studies were included in this review. Six research papers focused on the response stage of humanitarian crises and five papers featured the disaster context of conflict. A range of SRH components were addressed including maternal, newborn health and sexual violence. The review identified factors, including appropriate resourcing, organisational support and confidence in health care workers that were found to facilitate the transfer of learning. The findings suggest the presence of factors that moderate the transfer of training at the individual, training, organisational, socio-cultural, political and health system levels. CONCLUSION: Supportive strategies are necessary to best assist trainees to apply newly acquired knowledge and skills in their work settings. These interventions must address factors that moderate the success of learning transfer. Findings from this review suggest that these are related to the individual trainee, the training program itself and the workplace as well as the broader environmental context. Organisations which provide SRH training for humanitarian emergencies should work to identify the system of moderating factors that affect training transfer in their setting and employ evidence-based strategies to ameliorate these. PMID- 28883890 TI - Facing the challenge of sustainable bioenergy production: Could halophytes be part of the solution? AB - Due to steadily growing population and economic transitions in the more populous countries, renewable sources of energy are needed more than ever. Plant biomass as a raw source of bioenergy and biofuel products may meet the demand for sustainable energy; however, such plants typically compete with food crops, which should not be wasted for producing energy and chemicals. Second-generation or advanced biofuels that are based on renewable and non-edible biomass resources are processed to produce cellulosic ethanol, which could be further used for producing energy, but also bio-based chemicals including higher alcohols, organic acids, and bulk chemicals. Halophytes do not compete with conventional crops for arable areas and freshwater resources, since they grow naturally in saline ecosystems, mostly in semi-arid and arid areas. Using halophytes for biofuel production may provide a mid-term economically feasible and environmentally sustainable solution to producing bioenergy, contributing, at the same time, to making saline areas - which have been considered unproductive for a long time - more valuable. This review emphasises on halophyte definition, global distribution, and environmental requirements. It also examines their enzymatic valorization, focusing on salt-tolerant enzymes from halophilic microbial species that may be deployed with greater advantage compared to their conventional mesophilic counterparts for faster degradation of halophyte biomass. PMID- 28883891 TI - The in vitro and ex vivo effect of Auranta 3001 in preventing Cryptosporidium hominis and Cryptosporidium parvum infection. AB - BACKGROUND: Cryptosporidium is a major cause of diarrhea worldwide in both humans and farm animals with no completely effective treatment available at present. In this study, we assessed the inhibitory effect of different concentrations of Auranta 3001 (0.1, 0.5 and 1%), a novel natural feed supplement, on C. hominis and C. parvum invasion of human ileocecal adenocarcinoma (HCT-8), bovine primary cells and C. parvum invasion of HCT-8, bovine primary cells and bovine intestinal biopsies. The effect of the feed supplement on the production of pro-inflammatory cytokines IL-8 and INF-gamma, the anti-inflammatory cytokine IL-10, the expression of CpSUB1 protease gene during infection was also assessed by quantitative PCR (q-PCR). Transepithelial electrical resistance (TEER) was employed to measure the integrity of tight junction dynamics of the culture models. RESULTS: Pre-treatment of intestinal cells or oocysts with the Auranta 3001 significantly reduced the invasiveness of C. hominis and C. parvum against HCT-8 and bovine primary cells in a dose dependent manner. The most pronounced reduction in the invasiveness of both parasites was observed when Auranta 3001 was present during infection. Levels of IL-8 were significantly reduced in both HCT-8 and bovine primary cells, while the levels of INF-gamma and IL-10 showed opposite trends in the two cell lines during infection in the presence of Auranta 3001. CpSUB1 gene protease expression, which mediates infection, was significantly reduced suggesting that this enzyme is a possible target of Auranta 3001. CONCLUSIONS: Although, C. hominis and C. parvum use different invasion mechanisms to infect cells, the novel feed additive can significantly attenuate the entry of Cryptosporidium in HCT-8 cells, primary bovine cells and bovine intestinal biopsies and thus provide an alternative method to control cryptosporidiosis. PMID- 28883892 TI - Impact of post-meal and one-time daily exercise in patient with type 2 diabetes mellitus: a randomized crossover study. AB - BACKGROUND: To evaluate the effectiveness of short-timed post-meal and one-time daily exercise on glycemic control in patients with T2DM. METHODS: Sixty-four T2DM patients were randomised into crossover design. Group A (n = 32) underwent post-meal exercise (moderate-intensity brisk walking covering 1500-1600 steps for 15 min, starting 15 min after each meal) from d1 to d60 followed by one-time daily exercise (45 min pre-breakfast brisk walking at stretch covering 4500-4800 steps) from d61 to d120, while it was vice versa for the group B (n = 32). The five-point blood glucose profile was performed on d1, d30, d60, d90 and d120, and HbA1c on d1, d60 and d120. Fitness wrist band was used for step-counting to ensure the intensity of exercise and compliance to exercise protocol. RESULTS: Group A patients showed a significant improvement in five point blood glucose profile and HbA1c after performing post-meal exercise (p < 0.001), which was mitigated after switchover to one-time daily exercise (p < 0.001). While, group B patients showed improvement in glucose profile and HbA1c (p < 0.001) after performing post-meal exercise, as compared to one-time daily exercise. Further, on pooled analysis (post-meal versus one-time daily exercise group) the beneficial effect of post-meal exercise on glucose profile and HbA1c was consistent as compared to one time daily exercise and the significance persisted on comparison between the two groups. No hypoglycemic events were noted between the groups during the study period. CONCLUSION: Post-meal exercise is more effective than routine one-time daily exercise for glycemic control in T2DM patients. PMID- 28883893 TI - The association between Alu hypomethylation and severity of type 2 diabetes mellitus. AB - BACKGROUND: Cellular senescence due to genomic instability is believed to be one of the mechanisms causing health problems in diabetes mellitus (DM). Low methylation levels of Alu elements or Alu hypomethylation, an epigenomic event causing genomic instability, were commonly found in aging people and patients with aging phenotypes, such as osteoporosis. RESULTS: We investigate Alu methylation levels of white blood cells of type 2 DM, pre-DM, and control. The DM group possess the lowest Alu methylation (P < 0.001, P < 0.0001 adjusted age). In the DM group, Alu hypomethylation is directly correlated with high fasting blood sugar, HbA1C, and blood pressure. CONCLUSION: Genome-wide hypomethylation may be one of the underlining mechanisms causing genomic instability in type 2 DM. Moreover, Alu methylation levels may be a useful biomarker for monitoring cellular senescence in type 2 DM patients. PMID- 28883894 TI - Epigenetic regulation of inflammation in localized aggressive periodontitis. AB - BACKGROUND: We have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals. However, mechanisms related to this phenotype are still not clear in the literature. The objective of this cross-sectional study is to examine the role of epigenetic regulation, specifically DNA methylation status of genes in the TLR pathway in this cohort. Peripheral blood was collected from 20 LAP patients and 20 healthy unrelated controls. Whole blood was stimulated with 1 MUl (100 ng/MUl) of purified Escherichia coli lipopolysaccharide (LPS) for 24 h and cyto/chemokines in the supernatants analyzed by Luminex multiplex assays. Genomic DNA extracted from buffy coats prepared from a second tube of whole blood was used for DNA methylation analysis by pyrosequencing of seven TLR signaling genes (FADD, MAP3K7, MYD88, IL6R, PPARA, IRAK1BP1, RIPK2). RESULTS: Significant differences in the methylation status were observed at specific CpG positions in LAP patients compared to healthy controls and interestingly also between severe and moderate LAP. Specifically, subjects with moderate LAP presented hypermethylation of both the upregulating (MAP3K7, MYD88, IL6R, and RIPK2) and downregulating (FADD, IRAK, and PPARA) genes, while severe LAP presented hypomethylation of these genes. Further analysis on CpG sites with significant differences in methylation status correlates with an increased pro-inflammatory cytokine profile for LAP patients. CONCLUSIONS: Our findings suggest that epigenetic modifications of genes in the TLR pathway may orchestrate the thresholds for balancing induction and prevention of tissue destruction during the course of disease, and thus differ significantly at different stages of the disease, where moderate LAP shows hypermethylation and severe LAP shows hypomethylation of several genes. TRIAL REGISTRATION: https://clinicaltrials.gov, NCT01330719. PMID- 28883895 TI - Alterations of sorbin and SH3 domain containing 3 (SORBS3) in human skeletal muscle following Roux-en-Y gastric bypass surgery. AB - BACKGROUND: Obesity is a disease that is caused by genetic and environmental factors. However, epigenetic mechanisms of obesity are less well known. DNA methylation provides a mechanism whereby environmental factors can influence gene transcription. The aim of our study was to investigate skeletal muscle DNA methylation of sorbin and SH3 domain containing 3 (SORBS3) with weight loss induced by Roux-en-Y gastric bypass (RYGB). RESULTS: Previously, we had shown increased methylation (5.0 to 24.4%) and decreased gene expression (fold change - 1.9) of SORBS3 with obesity (BMI > 30 kg/m2) compared to lean controls. In the present study, basal muscle biopsies were obtained from seven morbidly obese (BMI > 40 kg/m2) female subjects pre- and 3 months post-RYGB surgery, in combination with euglycemic-hyperinsulinemic clamps to assess insulin sensitivity. We identified 30 significantly altered promoter and untranslated region methylation sites in SORBS3 using reduced representation bisulfite sequencing (RRBS). Twenty nine of these sites were decreased (- 5.6 to - 24.2%) post-RYGB compared to pre RYGB. We confirmed the methylation in 2 (Chr.8:22,423,690 and Chr.8:22,423,702) of the 29 decreased SORBS3 sites using pyrosequencing. This decreased methylation was associated with an increase in SORBS3 gene expression (fold change + 1.7) post-surgery. In addition, we demonstrated that SORBS3 promoter methylation in vitro significantly alters reporter gene expression (P < 0.0001). Two of the SORBS3 methylation sites (Chr.8:22,423,111 and Chr.8:22,423,205) were strongly correlated with fasting plasma glucose levels (r = 0.9, P = 0.00009 and r = 0.8, P = 0.0010). Changes in SORBS3 gene expression post-surgery were correlated with obesity measures and fasting insulin levels (r = 0.5 to 0.8; P < 0.05). CONCLUSIONS: These results demonstrate that SORBS3 methylation and gene expression are altered in obesity and restored to normal levels through weight loss induced by RYGB surgery. PMID- 28883896 TI - Near-Wall Molecular Ordering of Dilute Ionic Liquids. AB - The interfacial behavior of ionic liquids promises tunable lubrication as well as playing an integral role in ion diffusion for electron transfer. Diluting the ionic liquids optimizes bulk parameters, such as electric conductivity, and one would expect dilution to disrupt the near-wall molecular ordering. We study this ordering in the ionic liquids [Emim]+[NTf2]-, [Emim]+[DCA]-, and [C4mpyr]+[NTf2] , diluted in the solvent dimethyl sulfoxide. We found a structural crossover from well-ordered ionic liquids to a well-ordered solvent with increasing dilution, but this occurs nonlinearly, with solvent molecules initially space-filling and solvating and later disrupting the ionic layers. This is of key importance for ionic liquids as optimized tunable nanolubricants. PMID- 28883897 TI - Mobility and Decay Dynamics of Charge Carriers in One-Dimensional Selenium van der Waals Solid. AB - Trigonal selenium is a semiconducting van der Waals solid that consists of helical atomic chains. We studied the mobility and decay dynamics of excess electrons and holes moving along the selenium chains. Excess charge carriers were generated by irradiation of powdered selenium with 3 MeV electron pulses. Their mobility and decay via trapping or recombination was studied by time-resolved microwave conductivity measurements as a function of temperature. The mobility of charge carriers along the Se chains is at least ca. 0.5 cm2.V-1.s-1 at room temperature. Charges decay predominantly by trapping at defects. The appreciable mobility, together with the potential for large-scale production of Se wires by liquid exfoliation, makes this material of great interest for use in nanoelectronics. PMID- 28883898 TI - Upregulation of PSMD10 caused by the JMJD2A histone demethylase. AB - PSMD10, also known as gankyrin, is associated with the proteasome and has been shown to be an oncoprotein in the liver. Here, we report that PSMD10 expression is stimulated by the histone demethylase JMJD2A/KDM4A and its interaction partner, the ETV1 transcription factor, in LNCaP prostate cancer cells. Global analysis of expression patterns revealed that PSMD10 mRNA levels are positively correlated with those of both JMJD2A and ETV1. In human prostate tumors, PSMD10 is highly overexpressed at the protein level and correlates with JMJD2A overexpression; further, PSMD10 expression is enhanced in the prostates of transgenic JMJD2A mice. Moreover, PSMD10 is particularly overexpressed in high Gleason score prostate tumors. Downregulation of PSMD10 in LNCaP prostate cancer cells impaired their growth, indicating that PSMD10 may exert a pro-oncogenic function in the prostate. Lastly, we observed that PSMD10 expression is correlated to YAP1, a component of the Hippo signaling pathway and whose gene promoter is regulated by JMJD2A, and that PSMD10 can cooperate with YAP1 in stimulating LNCaP cell growth. Altogether, these data indicate that PSMD10 is a novel downstream effector of JMJD2A and suggest that inhibition of the JMJD2A histone demethylase by small molecule drugs may be effective to curtail the oncogenic activity of PSMD10 in various PSMD10-overexpressing tumors. PMID- 28883899 TI - Caffeic Acid Phenethyl Ester Reduces Ischemia-Induced Kidney Mitochondrial Injury in Rats. AB - During partial nephrectomy, the avoidance of ischemic renal damage is extremely important as duration of renal artery clamping (i.e., ischemia) influences postoperative kidney function. Mitochondria (main producer of ATP in the cell) are very sensitive to ischemia and undergo damage during oxidative stress. Finding of a compound which diminishes ischemic injury to kidney is of great importance. Caffeic acid phenethyl ester (CAPE), biologically active compound of propolis, might be one of the promising therapeutic agents against ischemia caused damage. Despite wide range of biological activities of CAPE, detailed biochemical mechanisms of its action at the level of mitochondria during ischemia are poorly described and need to be investigated. We investigated if CAPE (22 mg/kg and 34 mg/kg, injected intraperitoneally) has protective effects against short (20 min) and longer time (40 min) rat kidney ischemia in an in vitro ischemia model. CAPE ameliorates in part ischemia-induced renal mitochondrial injury, improves oxidative phosphorylation with complex I-dependent substrate glutamate/malate, increases Ca2+ uptake by mitochondria, blocks ischemia-induced caspase-3 activation, and protects kidney cells from ischemia-induced necrosis. The protective effects on mitochondrial respiration rates were seen after shorter (20 min) time of ischemia whereas reduction of apotosis and necrosis and increase in Ca2+ uptake were revealed after both, shorter and longer time of ischemia. PMID- 28883900 TI - Corrigendum to "Paricalcitol Pretreatment Attenuates Renal Ischemia-Reperfusion Injury via Prostaglandin E2 Receptor EP4 Pathway". AB - [This corrects the article DOI: 10.1155/2017/5031926.]. PMID- 28883901 TI - Loss of Sigma-1 Receptor Chaperone Promotes Astrocytosis and Enhances the Nrf2 Antioxidant Defense. AB - Sigma-1 receptor (Sig-1R) functions as a chaperon that interacts with multiple proteins and lipids and is implicated in neurodegenerative and psychiatric diseases. Here, we used Sig-1R KO mice to examine brain expression profiles of astrocytes and ubiquitinated proteins, which are both hallmarks of central nervous system (CNS) pathologies. Our results showed that Sig-1R KO induces increased glial fibrillary acidic protein (GFAP) expression in primary neuron glia cultures and in the whole brain of fetus mice with concomitantly increased accumulations of ubiquitinated proteins. Astrogliosis was also observed in the neuron-glia culture. Upon proteasome or autophagy inhibitor treatments, the pronounced ubiquitinated proteins were further increased in Sig-1R KO neurons, indicating that the Sig-1R regulates both protein degradation and quality control systems. We found that Nrf2 (nuclear factor erythroid 2-related factor 2), which functions to overcome the stress condition, was enhanced in the Sig-1R KO systems especially when cells were under stressful conditions. Mutation or deficiency of Sig-1Rs has been observed in neurodegenerative models. Our study identifies the critical roles of Sig-1R in CNS homeostasis and supports the idea that functional complementation pathways are triggered in the Sig-1R KO pathology. PMID- 28883902 TI - SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice. AB - BACKGROUND: Diabetic cardiomyopathy (DCM) is a major threat for diabetic patients. Silent information regulator 1 (SIRT1) has a regulatory effect on mitochondrial dynamics, which is associated with DCM pathological changes. Our study aims to investigate whether resveratrol, a SRIT1 activator, could exert a protective effect against DCM. METHODS AND RESULTS: Cardiac-specific SIRT1 knockout (SIRT1KO) mice were generated using Cre-loxP system. SIRT1KO mice displayed symptoms of DCM, including cardiac hypertrophy and dysfunction, insulin resistance, and abnormal glucose metabolism. DCM and SIRT1KO hearts showed impaired mitochondrial biogenesis and function, while SIRT1 activation by resveratrol reversed this in DCM mice. High glucose caused increased apoptosis, impaired mitochondrial biogenesis, and function in cardiomyocytes, which was alleviated by resveratrol. SIRT1 deletion by both SIRT1KO and shRNA abolished the beneficial effects of resveratrol. Furthermore, the function of SIRT1 is mediated via the deacetylation effect on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), thus inducing increased expression of nuclear respiratory factor 1 (NRF-1), NRF-2, estrogen-related receptor-alpha (ERR-alpha), and mitochondrial transcription factor A (TFAM). CONCLUSIONS: Cardiac deletion of SIRT1 caused phenotypes resembling DCM. Activation of SIRT1 by resveratrol ameliorated cardiac injuries in DCM through PGC-1alpha-mediated mitochondrial regulation. Collectively, SIRT1 may serve as a potential therapeutic target for DCM. PMID- 28883903 TI - Dietary Polyphenols, Mediterranean Diet, Prediabetes, and Type 2 Diabetes: A Narrative Review of the Evidence. AB - Dietary polyphenols come mainly from plant-based foods including fruits, vegetables, whole grains, coffee, tea, and nuts. Polyphenols may influence glycemia and type 2 diabetes (T2D) through different mechanisms, such as promoting the uptake of glucose in tissues, and therefore improving insulin sensitivity. This review aims to summarize the evidence from clinical trials and observational prospective studies linking dietary polyphenols to prediabetes and T2D, with a focus on polyphenol-rich foods characteristic of the Mediterranean diet. We aimed to describe the metabolic biomarkers related to polyphenol intake and genotype-polyphenol interactions modulating the effects on T2D. Intakes of polyphenols, especially flavan-3-ols, and their food sources have demonstrated beneficial effects on insulin resistance and other cardiometabolic risk factors. Several prospective studies have shown inverse associations between polyphenol intake and T2D. The Mediterranean diet and its key components, olive oil, nuts, and red wine, have been inversely associated with insulin resistance and T2D. To some extent, these associations may be attributed to the high amount of polyphenols and bioactive compounds in typical foods conforming this traditional dietary pattern. Few studies have suggested that genetic predisposition can modulate the relationship between polyphenols and T2D risk. In conclusion, the intake of polyphenols may be beneficial for both insulin resistance and T2D risk. PMID- 28883904 TI - Centella asiatica Attenuates Mitochondrial Dysfunction and Oxidative Stress in Abeta-Exposed Hippocampal Neurons. AB - Centella asiatica has been used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) protects against the deleterious effects of amyloid-beta (Abeta) in neuroblastoma cells and attenuates Abeta-induced cognitive deficits in mice. Yet, the neuroprotective mechanism of CAW has yet to be thoroughly explored in neurons from these animals. This study investigates the effects of CAW on neuronal metabolism and oxidative stress in isolated Abeta-expressing neurons. Hippocampal neurons from amyloid precursor protein overexpressing Tg2576 mice and wild-type (WT) littermates were treated with CAW. In both genotypes, CAW increased the expression of antioxidant response genes which attenuated the Abeta-induced elevations in reactive oxygen species (ROS) and lipid peroxidation in Tg2576 neurons. CAW also improved mitochondrial function in both genotypes and increased the expression of electron transport chain enzymes and mitochondrial labeling, suggesting an increase in mitochondrial content. These data show that CAW protects against mitochondrial dysfunction and oxidative stress in Abeta-exposed hippocampal neurons which could contribute to the beneficial effects of the extract observed in vivo. Since CAW also improved mitochondrial function in the absence of Abeta, these results suggest a broader utility for other conditions where neuronal mitochondrial dysfunction occurs. PMID- 28883906 TI - Corrigendum to "Propofol Attenuates Small Intestinal Ischemia Reperfusion Injury through Inhibiting NADPH Oxidase Mediated Mast Cell Activation". AB - [This corrects the article DOI: 10.1155/2015/167014.]. PMID- 28883905 TI - Rosmarinic Acid Alleviates the Endothelial Dysfunction Induced by Hydrogen Peroxide in Rat Aortic Rings via Activation of AMPK. AB - Endothelial dysfunction is the key player in the development and progression of vascular events. Oxidative stress is involved in endothelial injury. Rosmarinic acid (RA) is a natural polyphenol with antioxidative, antiapoptotic, and anti inflammatory properties. The present study investigates the protective effect of RA on endothelial dysfunction induced by hydrogen peroxide (H2O2). Compared with endothelium-denuded aortic rings, the endothelium significantly alleviated the decrease of vasoconstrictive reactivity to PE and KCl induced by H2O2. H2O2 pretreatment significantly injured the vasodilative reactivity to ACh in endothelium-intact aortic rings in a concentration-dependent manner. RA individual pretreatment had no obvious effect on the vasoconstrictive reaction to PE and KCl, while its cotreatment obviously mitigated the endothelium-dependent relaxation impairments and the oxidative stress induced by H2O2. The RA cotreatment reversed the downregulation of AMPK and eNOS phosphorylation induced by H2O2 in HAEC cells. The pretreatment with the inhibitors of AMPK (compound C) and eNOS (L-NAME) wiped off RA's beneficial effects. All these results demonstrated that RA attenuated the endothelial dysfunction induced by oxidative stress by activating the AMPK/eNOS pathway. PMID- 28883908 TI - Increased Levels of Oxidative Stress Markers, Soluble CD40 Ligand, and Carotid Intima-Media Thickness Reflect Acceleration of Atherosclerosis in Male Patients with Ankylosing Spondylitis in Active Phase and without the Classical Cardiovascular Risk Factors. AB - OBJECTIVE: The primary aim of the study was to assess levels of oxidative stress markers, soluble CD40 ligand (sCD40L), serum pregnancy-associated plasma protein A (PAPP-A), and placental growth factor (PlGF) as well as carotid intima-media thickness (IMT) in patients with ankylosing spondylitis (AS) with active phase without concomitant classical cardiovascular risk factors. MATERIAL AND METHODS: The observational study involved 96 male subjects: 48 AS patients and 48 healthy ones, who did not differ significantly regarding age, BMI, comorbid disorders, and distribution of classical cardiovascular risk factors. In both groups, we estimated levels of oxidative stress markers, lipid profile, and inflammation parameters as well as sCD40L, serum PAPP-A, and PlGF. In addition, we estimated carotid IMT in each subject. RESULTS: The study showed that markers of oxidative stress, lipid profile, and inflammation, as well as sCD40L, PlGF, and IMT, were significantly higher in the AS group compared to the healthy group. CONCLUSION: Our results demonstrate that ankylosing spondylitis may be associated with increased risk for atherosclerosis. PMID- 28883907 TI - Cellular and Molecular Mechanisms of Diabetic Atherosclerosis: Herbal Medicines as a Potential Therapeutic Approach. AB - An increasing number of patients diagnosed with diabetes mellitus eventually develop severe coronary atherosclerosis disease. Both type 1 and type 2 diabetes mellitus increase the risk of cardiovascular disease associated with atherosclerosis. The cellular and molecular mechanisms affecting the incidence of diabetic atherosclerosis are still unclear, as are appropriate strategies for the prevention and treatment of diabetic atherosclerosis. In this review, we discuss progress in the study of herbs as potential therapeutic agents for diabetic atherosclerosis. PMID- 28883910 TI - Blood Interferon Signatures Putatively Link Lack of Protection Conferred by the RTS,S Recombinant Malaria Vaccine to an Antigen-specific IgE Response. AB - Malaria remains a major cause of mortality and morbidity worldwide. Progress has been made in recent years with the development of vaccines that could pave the way towards protection of hundreds of millions of exposed individuals. Here we used a modular repertoire approach to re-analyze a publically available microarray blood transcriptome dataset monitoring the response to malaria vaccination. We report the seminal identification of interferon signatures in the blood of subjects on days 1, 3 and 14 following administration of the third dose of the RTS,S recombinant malaria vaccine. These signatures at day 1 correlate with protection, and at days 3 and 14 to susceptibility to subsequent challenge of study subjects with live parasites. In addition we putatively link the decreased abundance of interferon-inducible transcripts observed at days 3 and 14 post-vaccination with the elicitation of an antigen specific IgE response in a subset of vaccine recipients that failed to be protected by the RTS,S vaccine. PMID- 28883909 TI - Computing Platforms for Big Biological Data Analytics: Perspectives and Challenges. AB - The last decade has witnessed an explosion in the amount of available biological sequence data, due to the rapid progress of high-throughput sequencing projects. However, the biological data amount is becoming so great that traditional data analysis platforms and methods can no longer meet the need to rapidly perform data analysis tasks in life sciences. As a result, both biologists and computer scientists are facing the challenge of gaining a profound insight into the deepest biological functions from big biological data. This in turn requires massive computational resources. Therefore, high performance computing (HPC) platforms are highly needed as well as efficient and scalable algorithms that can take advantage of these platforms. In this paper, we survey the state-of-the-art HPC platforms for big biological data analytics. We first list the characteristics of big biological data and popular computing platforms. Then we provide a taxonomy of different biological data analysis applications and a survey of the way they have been mapped onto various computing platforms. After that, we present a case study to compare the efficiency of different computing platforms for handling the classical biological sequence alignment problem. At last we discuss the open issues in big biological data analytics. PMID- 28883911 TI - Antibiotic resistance and biofilm formation among coagulase-negative staphylococci isolated from clinical samples at a tertiary care hospital of eastern Nepal. AB - BACKGROUND: Coagulase negative staphylococci were long regarded non-pathogenic as they are the commensals of human skin and mucosa but the recent changes in the medical practice and changes in underlying host populations, they are being considered significant pathogens associated with number of nosocomial infections. The objective of the study was to determine the species, antimicrobial susceptibility pattern, biofilm forming ability of the clinically significant CoNS isolates and to compare the different methods for the detection of biofilm formation. METHODS: A total of 52 clinically significant CoNS isolates obtained from different units during a year period were studied. Characterization was done using standard microbiological guidelines and antimicrobial susceptibility was done following CLSI guidelines. Biofilm formation was detected by using three methods i.e. tissue culture plate method, congo red agar method and tube adherence method. RESULTS: Among 52 isolates, S. epidermidis (52%) was the most common species which was followed by S. saprophyticus (18%) and S. haemolyticus (14%). Antimicrobial susceptibility pattern of CoNS documented resistance of 80% to ampicillin. Resistance to cefoxitin and ceftriaxone was observed in 58% of the isolates. Biofilm formation was observed in 65.38% of the isolates. The accuracy of Congo red agar and tube adherence method for the detection of biofilm formation was 82% and 76% respectively. CONCLUSION: CoNS isolates obtained from clinical samples should be processed routinely and antimicrobial susceptibility testing should be performed. Multidrug-resistant CoNS are prevalent. All the three methods i.e. tissue culture plate, Congo red agar and tube adherence method can be used in detecting biofilm formation. PMID- 28883912 TI - Infection control at an urban hospital in Manila, Philippines: a systems engineering assessment of barriers and facilitators. AB - BACKGROUND: Healthcare facilities in low- and middle-income countries, including the Philippines, face substantial challenges in achieving effective infection control. Early stages of interventions should include efforts to understand perceptions held by healthcare workers who participate in infection control programs. METHODS: We performed a qualitative study to examine facilitators and barriers to infection control at an 800-bed, private, tertiary hospital in Manila, Philippines. Semi-structured interviews were conducted with 22 nurses, physicians, and clinical pharmacists using a guide based on the Systems Engineering Initiative for Patient Safety (SEIPS). Major facilitators and barriers to infection control were reported for each SEIPS factor: person, organization, tasks, physical environment, and technology and tools. RESULTS: Primary facilitators included a robust, long-standing infection control committee, a dedicated infection control nursing staff, and innovative electronic hand hygiene surveillance technology. Barriers included suboptimal dissemination of hand hygiene compliance data, high nursing turnover, clinical time constraints, and resource limitations that restricted equipment purchasing. CONCLUSIONS: The identified facilitators and barriers may be used to prioritize possible opportunities for infection control interventions. A systems engineering approach is useful for conducting a comprehensive work system analysis, and maximizing resources to overcome known barriers to infection control in heavily resource-constrained settings. PMID- 28883913 TI - Glucosamine supplementation during late gestation alters placental development and increases litter size. AB - BACKGROUND: During late gestation the placental epithelial interface becomes highly folded, which involves changes in stromal hyaluronan. Hyaluronan is composed of glucoronate and N-acetyl-glucosamine. We hypothesized that supplementing gestating dams with glucosamine during this time would support placental folded-epithelial-bilayer development and increase litter size. In Exp. 1, gilts were unilaterally hysterectomized-ovariectomized (UHO). UHO gilts were mated and then supplemented daily with 10 g glucosamine (n = 16) or glucose (control, n = 17) from d 85 of gestation until slaughter (d 105). At slaughter, the number of live fetuses was recorded and each live fetus and its placenta was weighed. Uterine wall samples adjacent to the largest and smallest fetuses within each litter were processed for histology. In Exp. 2, pregnant sows in a commercial sow farm were supplemented with either 10 g glucosamine or glucose daily from d 85 of gestation to farrowing. Total piglets born and born alive were recorded for each litter. In Exp. 3, the same commercial farm and same protocol were used except that the dose of glucosamine and glucose was doubled to 20 g/d. RESULTS: In Exp. 1, the number of live fetuses tended to be greater in glucosamine-treated UHO gilts (P = 0.098). Placental morphometry indicated that the width of the folded bilayer was greater (P = 0.05) in glucosamine-treated gilts. In Exp. 2, litter size did not differ between glucosamine- and glucose treated sows. However in Exp. 3, the increased dose of glucosamine resulted in a significant treatment by parity interaction (P <= 0.01), in which total piglets born and born alive were greater in glucosamine treated sows of later parity (5 and 6). CONCLUSIONS: These results indicated that glucosamine supplementation increased the width of the folds of the placental bilayer and increased litter size in later parity, intact pregnant commercial sows. PMID- 28883914 TI - Effect of recombinant and native buffalo OVGP1 on sperm functions and in vitro embryo development: a comparative study. AB - BACKGROUND: An oviduct- specific glycoprotein, OVGP1, is synthesized and secreted by non-ciliated epithelial cells of the mammalian oviduct which provides an essential milieu for reproductive functions. The present study reports the effects of recombinant buffalo OVGP1 that lacks post-translational modifications, and native Buffalo OVGP1 isolated from oviductal tissue, on frozen- thawed sperm functions and in vitro embryo development. RESULTS: The proportion of viable sperms was greater (P < 0.05) in the recombinant OVGP1-treated group compared to the native OVGP1-treated group at 2 h, 3 h, and 4 h of incubation. The proportion of motile sperms at 3 h and 4 h of incubation; and membrane- intact sperms at 4 h was greater (P < 0.05) in the native OVGP1-treated group compared to the control and recombinant OVGP1-treated groups. The proportion of capacitated and acrosome- reacted sperms was greater (P < 0.05) in the native OVGP1-treated group compared to the recombinant OVGP1 group at 4 h. The rates of cleavage of embryos and their development to the blastocyst stage were greater (P < 0.05) in the presence of either native or recombinant OVGP1 in comparison to control at 10 MUg/mL concentration as compared to 5 or 20 MUg/mL. CONCLUSIONS: The study suggests that both native and recombinant OVGP1 impart a positive effect on various sperm features and in vitro embryo development. However, native OVGP1 was found to have a more pronounced effect in comparison to recombinant non-glycosylated OVGP1 on various sperm functions except viability. Hence, our current findings infer that glycosylation of OVGP1 might be essential in sustaining the sperm functions but not the in vitro embryo development. PMID- 28883915 TI - Evaluation of fatty acid metabolism and innate immunity interactions between commercial broiler, F1 layer * broiler cross and commercial layer strains selected for different growth potentials. AB - BACKGROUND: The broiler industry has undergone intense genetic selection over the past 50 yr. resulting in improvements for growth and feed efficiency, however, significant variation remains for performance and growth traits. Production improvements have been coupled with unfavourable metabolic consequences, including immunological trade-offs for growth, and excess fat deposition. To determine whether interactions between fatty acid (FA) metabolism and innate immunity may be associated with performance variations commonly seen within commercial broiler flocks, total carcass lipid %, carcass and blood FA composition, as well as genes involved with FA metabolism, immunity and cellular stress were investigated in male birds of a broiler strain, layer strain and F1 layer * broiler cross at d 14 post hatch. Heterophil: lymphocyte ratios, relative organ weights and bodyweight data were also compared. RESULTS: Broiler bodyweight (n = 12) was four times that of layers (n = 12) by d 14 and had significantly higher carcass fat percentage compared to the cross (n = 6; P = 0.002) and layers (P = 0.017) which were not significantly different from each other (P = 0.523). The carcass and whole blood FA analysis revealed differences in the FA composition between the three groups indicating altered FA metabolism, despite all being raised on the same diet. Genes associated with FA synthesis and beta oxidation were upregulated in the broilers compared to the layers indicating a net overall increase in FA metabolism, which may be driven by the larger relative liver size as a percentage of bodyweight in the broilers. Genes involved in innate immunity such as TLR2 and TLR4, as well as organelle stress indicators ERN1 and XBP1 were found to be non-significant, with the exception of high expression levels of XBP1 in layers compared to the cross and broilers. Additionally there was no difference in heterophil: lymphocytes between any of the birds. CONCLUSIONS: The results provide evidence that genetic selection may be associated with altered metabolic processes between broilers, layers and their F1 cross. Whilst there is no evidence of interactions between FA metabolism, innate immunity or cellular stress, further investigations at later time points as growth and fat deposition increase would provide useful information as to the effects of divergent selection on key metabolic and immunological processes. PMID- 28883916 TI - Circulating leptin and its muscle gene expression in Nellore cattle with divergent feed efficiency. AB - BACKGROUND: Leptin has a strong relation to important traits in animal production, such as carcass composition, feed intake, and reproduction. It is mainly produced by adipose cells and acts predominantly in the hypothalamus. In this study, circulating leptin and its gene expression in muscle were evaluated in two groups of young Nellore bulls with divergent feed efficiency. Individual dry matter intake (DMI) and average daily gain (ADG) of 98 Nellore bulls were evaluated in feedlot for 70 d to determinate the residual feed intake (RFI) and select 20 animals for the high feed efficient (LRFI) and 20 for the low feed efficient (HRFI) groups. Blood samples were collected on d 56 and at slaughter (80 d) to determine circulating plasma leptin. Samples of Longissimus dorsi were taken at slaughter for leptin gene expression levels. RESULTS: DMI and RFI were different between groups and LRFI animals showed less back fat and rump fat thickness, as well as less pelvic and kidney fat weight. Circulating leptin increased over time in all animals. Plasma leptin was greater in LRFI on 56 d and at slaughter (P = 0.0049). Gene expression of leptin were greater in LRFI animals (P = 0.0022) in accordance with the plasma levels. The animals of the LRFI group were leaner, ate less, and had more circulating leptin and its gene expression. CONCLUSION: These findings demonstrated that leptin plays its physiological role in young Nellore bulls, probably controlling food intake because feed efficient animals have more leptin and lower residual feed intake. PMID- 28883917 TI - Betaine affects muscle lipid metabolism via regulating the fatty acid uptake and oxidation in finishing pig. AB - BACKGROUND: Betaine affects fat metabolism in animals, but the specific mechanism is still not clear. The purpose of this study was to investigate possible mechanisms of betaine in altering lipid metabolism in muscle tissue in finishing pigs. METHODS: A total of 120 crossbred gilts (Landrace * Yorkshire * Duroc) with an average initial body weight of 70.1 kg were randomly allotted to three dietary treatments. The treatments included a corn-soybean meal basal diet supplemented with 0, 1250 or 2500 mg/kg betaine. The feeding experiment lasted 42 d. RESULTS: Betaine addition to the diet significantly increased the concentration of free fatty acids (FFA) in muscle (P < 0.05). Furthermore, the levels of serum cholesterol and high-density lipoprotein cholesterol were decreased (P < 0.05) and total cholesterol content was increased in muscle (P < 0.05) of betaine fed pigs. Experiments on genes involved in fatty acid transport showed that betaine increased expression of lipoprotein lipase(LPL), fatty acid translocase/cluster of differentiation (FAT/CD36), fatty acid binding protein (FABP3) and fatty acid transport protein (FATP1) (P < 0.05). The abundance of fatty acid transport protein and fatty acid binding protein were also increased by betaine (P < 0.05). As for the key factors involved in fatty acid oxidation, although betaine supplementation didn't affect the level of carnitine and malonyl-CoA, betaine increased mRNA and protein abundance of carnitine palmitransferase-1(CPT1) and phosphorylated-AMPK (P < 0.05). CONCLUSIONS: The results suggested that betaine may promoted muscle fatty acid uptake via up-regulating the genes related to fatty acid transporter including FAT/CD36, FATP1 and FABP3. On the other hand, betaine activated AMPK and up-regulated genes related to fatty acid oxidation including PPARalpha and CPT1. The underlying mechanism regulating fatty acid metabolism in pigs supplemented with betaine is associated with the up-regulation of genes involved in fatty acid transport and fatty acid oxidation. PMID- 28883919 TI - A case of Klinefelter syndrome with hypersexual desire. AB - : Klinefelter syndrome (KS) is a chromosomal disorder affecting males, with the typical karyotype of 47,XXY due to a supernumerary X chromosome, which causes progressive testicular failure resulting in androgen deficiency and infertility. Despite it being the most common sex chromosomal disorder, its diagnosis is easily missed. In addition to its classical clinical features of tall stature, gynaecomastia, small testes, and symptoms and signs of hypogonadism including infertility, KS is also often associated with neurocognitive, behavioural and psychiatric disorders. We present a 44-year-old man with KS who, despite having erectile dysfunction, paradoxically had increased libido. He used sildenafil to overcome his erectile dysfunction. Hypersexuality was manifested by very frequent masturbation, multiple sexual partners most of whom were casual, and a sexual offence conviction at the age of 17 years. Discussion focuses on the frequent failure of clinicians to diagnose KS, the neurocognitive, behavioural and psychiatric aspects of KS, this unusual presentation of hypersexuality in a man with KS, and the challenges of medical management of hypogonadism in a man with a history of a sexual offence. LEARNING POINTS: Klinefelter syndrome (KS) is common in men (about 1 in 600 males), but the diagnosis is very often missed.In addition to classic features of hypogonadism, patients with KS can often have associated neurocognitive, behavioural and/or psychiatric disorders.More awareness of the association between KS and difficulties related to verbal skills in boys could improve rates of early diagnosis and prevent longer-term psychosocial disability.Hypersexuality in the context of hypogonadism raises the possibility of sex steroid independent mechanistic pathways for libido.Testosterone replacement therapy in KS with hypersexuality should be undertaken with caution using a multidisciplinary team approach. PMID- 28883918 TI - Predicting intolerance of uncertainty in individuals with eating disorder symptoms. AB - BACKGROUND: Intolerance of Uncertainty (IU) is recognized for its contribution to various psychopathologies, in particular anxiety and depression. Studies highlight the relevance of IU for Eating Disorders (EDs) however, potential factors contributing to IU in EDs remain unstudied. METHODS: Three hundred and forty-nine women with ED symptoms and 214 individuals without ED symptoms were recruited and compared on levels of IU, insecure (anxious and avoidant) attachment styles, extraversion and openness. Secondly, the contribution of these factors to IU were tested. RESULTS: Compared to the non-ED group, the ED group scored higher on IU, insecure attachment, and lower on extraversion and openness. Regression analyses confirmed that higher insecure attachment, and lower extraversion predicted higher IU scores in the ED group, and that insecure attachment predicted higher IU scores in the non-ED group. CONCLUSIONS: Results confirm the relevance of IU to ED, and demonstrate that personality traits and insecure attachment styles contribute to IU in ED. Findings add to the growing literature on IU in ED and suggest that people with EDs may benefit from clinical interventions targeting IU. PMID- 28883920 TI - Exogenous T3 toxicosis following consumption of a contaminated weight loss supplement. AB - : A 42-year-old male presented with a one-week history of palpitations and sweating episodes. The only significant history was of longstanding idiopathic dilated cardiomyopathy. Initial ECG demonstrated a sinus tachycardia. Thyroid function testing, undertaken as part of the diagnostic workup, revealed an un measureable thyroid-stimulating hormone (TSH) and free thyroxine (T4). Upon questioning the patient reported classical thyrotoxic symptoms over the preceding weeks. Given the persistence of symptoms free tri-iodothyronine (T3) was measured and found to be markedly elevated at 48.9 pmol/L (normal range: 3.1-6.8 pmol/L). No goitre or nodular disease was palpable in the neck. Historically there had never been any amiodarone usage. Radionucleotide thyroid uptake imaging (123I) demonstrated significantly reduced tracer uptake in the thyroid. Upon further questioning the patient reported purchasing a weight loss product online from India which supposedly contained sibutramine. He provided one of the tablets and laboratory analysis confirmed the presence of T3 in the tablet. Full symptomatic resolution and normalised thyroid function ensued upon discontinuation of the supplement. LEARNING POINTS: Free tri-iodothyronine (T3) measurement may be useful in the presence of symptoms suggestive of thyrotoxicosis with discordant thyroid function tests.Thyroid uptake scanning can be a useful aid to differentiating exogenous hormone exposure from endogenous hyperthyroidism.Ingestion of thyroid hormone may be inadvertent in cases of exogenous thyrotoxicosis.Medicines and supplements sourced online for weight loss may contain thyroxine (T4) or T3 and should be considered as a cause of unexplained exogenous hyperthyroidism. PMID- 28883921 TI - British Thoracic Society Guideline for oxygen use in adults in healthcare and emergency settings. PMID- 28883922 TI - Assessment of patient-reported outcome measures in pleural interventions. AB - INTRODUCTION: There is a lack of data evaluating the clinical effect on symptoms of pleural intervention procedures. This has led to the development of patient reported outcome measures (PROMs) to define what constitutes patient benefit. The primary aim of this paper was to prospectively assess the effect of pleural procedures on PROMs and investigate the relationship between symptom change and clinical factors. METHODS: We prospectively collected data as part of routine clinical care from 158 patients with pleural effusion requiring interventions. Specific questionnaires included two patient-reported scores (a seven-point Likert scale and a 100 mm visual analogue scale (VAS) to assess symptoms). RESULTS: Excluding diagnostic aspiration, the majority of patients (108/126, 85.7%) experienced symptomatic benefit from fluid drainage (mean VAS improvement 42.6 mm, SD 24.7, 95% CI 37.9 to 47.3). There was a correlation between symptomatic benefit and volume of fluid removed post aspiration. A negative association was identified between the number of septations seen on ultrasound and improvement in dyspnoea VAS score in patients treated with intercostal chest drain. CONCLUSION: The results of our study highlight the effect of pleural interventions from a patient's perspective. The outcomes defined have the potential to form the basis of a clinical useful tool to appraise the effect, compare the efficiency and identify the importance of pleural interventions to the patients. PMID- 28883924 TI - Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown cause characterised by progressive fibrotic formation in lung tissue. We hypothesise that disrupted metabolic pathways in IPF contribute to disease pathogenesis. METHODS: Metabolomics of human IPF was performed using mass spectroscopy (IPF lung=8; donor lung=8). Gene expression of key metabolic enzymes was measured using microarrays. Of the 108 metabolites whose levels were found altered, 48 were significantly increased, whereas 60 were significantly decreased in IPF samples compared with normal controls. RESULTS: Specific metabolic pathways mediating the IPF remodelling were found with a downregulated sphingolipid metabolic pathway but an upregulated arginine pathway in IPF. In addition, disrupted glycolysis, mitochondrial beta-oxidation and tricarboxylic acid cycle, altered bile acid, haem and glutamate/aspartate metabolism were found in IPF samples compared with control. CONCLUSIONS: Our results show alterations in metabolic pathways for energy consumption during lung structural remodelling, which may contribute to IPF pathogenesis. We believe that this is the first report of simultaneously and systemically measuring changes of metabolites involving nine metabolic pathways in human severe IPF lungs. The measurement of the metabolites may serve in the future diagnosis and prognosis of IPF. PMID- 28883923 TI - Integrated care for resected early stage lung cancer: innovations and exploring patient needs. AB - There is no consensus as to the duration and nature of follow-up following surgical resection with curative intent of lung cancer. The integration of cancer follow-up into primary care is likely to be a key future area for quality and cost-effective cancer care. Evidence from other solid cancer types demonstrates that such follow-up has no adverse outcomes, similar health-related quality of life, high patient satisfaction rates at a lower cost to the healthcare system. Core elements for successful models of shared cancer care are required: clear roles and responsibilities, timely effective communication, guidance on follow-up protocols and common treatments and rapid routes to (re)access specialist care. There is thus a need for improved communication between hospital specialists and primary care. Unmet needs for patients with early stage lung cancer are likely to include psychological symptoms and carer stress; the importance of smoking cessation may frequently be overlooked or underappreciated in the current hospital-based follow-up system. There is therefore a need for quality randomised controlled trials of patients with resected early stage lung cancer to establish optimal protocols for primary care-based follow-up and to more adequately address patients' and carers' unmet psychosocial needs, including the crucial role of smoking cessation. PMID- 28883925 TI - Combining creative writing and narrative analysis to deliver new insights into the impact of pulmonary hypertension. AB - INTRODUCTION: Pulmonary hypertension is life limiting. Delays in diagnosis are common, and even after treatment has been initiated, pulmonary hypertension has marked effects on many aspects of social and physical function. We believed that a new approach to examining disease impact could be achieved through a combination of narrative research and creative writing. METHODS: Detailed unstructured narrative interviews with people with pulmonary hypertension were analysed thematically. Individual moments were also summarised and studied using creative writing, in which the interviewer created microstories from narrative and interview data. Stories were shared with their subjects, and with other patients, clinicians, researchers and the wider public. The study was carried out in hospital and in patients' homes. RESULTS: Narrative analysis generated a rich data set which highlighted profound effects of pulmonary hypertension on identity, and demonstrated how the disease results in very marked personal change with ongoing and unpredictable requirement for adaptation. The novel methodology of microstory development proved to be an effective tool to summarise, communicate and explore the consequences of pulmonary hypertension and the clinical challenges of caring for patients with this illness. CONCLUSIONS: A holistic approach to treatment of chronic respiratory diseases such as pulmonary hypertension requires and benefits from explicit exploration of the full impacts of the illness. Narrative analysis and the novel approach of targeted microstory development can form a valuable component of the repertoire of approaches to effectively comprehend chronic disease and can also facilitate patient-focused discussion and interventions. PMID- 28883926 TI - Clinical use of nintedanib in patients with idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a rare lung disease characterised by progressive loss of lung function, dyspnoea and cough. IPF has a variable clinical course but a poor prognosis. Nintedanib, a tyrosine kinase inhibitor, is one of two drugs approved for the treatment of IPF. In clinical trials, nintedanib slowed disease progression by reducing the rate of decline in forced vital capacity (FVC) in patients with IPF and mild or moderate lung function impairment. The effect of nintedanib was consistent across patient subgroups defined by baseline characteristics including FVC % predicted, diffusion capacity of the lung for carbon monoxide % predicted and the presence of emphysema. Recently, it has been shown that the rate of decline in FVC and the treatment effect of nintedanib are the same in patients with preserved lung volume (FVC >90% predicted) as in patients with greater impairment in FVC, supporting the value of early treatment of IPF. The adverse events most commonly associated with nintedanib, both in clinical trials and real-world clinical practice, are mild gastrointestinal events, particularly diarrhoea. Side effects are manageable in a majority of patients through symptomatic treatment, dose reductions and treatment interruptions, enabling most patients to stay on treatment in the long term. PMID- 28883928 TI - CPAP IMPACT: a protocol for a randomised trial of bubble continuous positive airway pressure versus standard care for high-risk children with severe pneumonia using adaptive design methods. AB - INTRODUCTION: Pneumonia is a leading cause of mortality among children in low resource settings. Mortality is greatest among children with high-risk conditions including HIV infection or exposure, severe malnutrition and/or severe hypoxaemia. WHO treatment recommendations include low-flow oxygen for children with severe pneumonia. Bubble continuous positive airway pressure (bCPAP) is a non-invasive support modality that provides positive end-expiratory pressure and oxygen. bCPAP is effective in the treatment of neonates in low-resource settings; its efficacy is unknown for high-risk children with severe pneumonia in low resource settings. METHODS AND ANALYSIS: CPAP IMPACT is a randomised clinical trial comparing bCPAP to low-flow oxygen in the treatment of severe pneumonia among high-risk children 1-59 months of age. High-risk children are stratified into two subgroups: (1) HIV infection or exposure and/or severe malnutrition; (2) severe hypoxaemia. The trial is being conducted in a Malawi district hospital and will enrol 900 participants. The primary outcome is in-hospital mortality rate of children treated with standard care as compared with bCPAP. ETHICS AND DISSEMINATION: CPAP IMPACT has approval from the Institutional Review Boards of all investigators. An urgent need exists to determine whether bCPAP decreases mortality among high-risk children with severe pneumonia to inform resource utilisation in low-resource settings. TRIAL REGISTRATION NUMBER: NCT02484183; Pre results. PMID- 28883927 TI - Listening panel agreement and characteristics of lung sounds digitally recorded from children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) case-control study. AB - INTRODUCTION: Paediatric lung sound recordings can be systematically assessed, but methodological feasibility and validity is unknown, especially from developing countries. We examined the performance of acoustically interpreting recorded paediatric lung sounds and compared sound characteristics between cases and controls. METHODS: Pneumonia Etiology Research for Child Health staff in six African and Asian sites recorded lung sounds with a digital stethoscope in cases and controls. Cases aged 1-59 months had WHO severe or very severe pneumonia; age matched community controls did not. A listening panel assigned examination results of normal, crackle, wheeze, crackle and wheeze or uninterpretable, with adjudication of discordant interpretations. Classifications were recategorised into any crackle, any wheeze or abnormal (any crackle or wheeze) and primary listener agreement (first two listeners) was analysed among interpretable examinations using the prevalence-adjusted, bias-adjusted kappa (PABAK). We examined predictors of disagreement with logistic regression and compared case and control lung sounds with descriptive statistics. RESULTS: Primary listeners considered 89.5% of 792 case and 92.4% of 301 control recordings interpretable. Among interpretable recordings, listeners agreed on the presence or absence of any abnormality in 74.9% (PABAK 0.50) of cases and 69.8% (PABAK 0.40) of controls, presence/absence of crackles in 70.6% (PABAK 0.41) of cases and 82.4% (PABAK 0.65) of controls and presence/absence of wheeze in 72.6% (PABAK 0.45) of cases and 73.8% (PABAK 0.48) of controls. Controls, tachypnoea, >3 uninterpretable chest positions, crying, upper airway noises and study site predicted listener disagreement. Among all interpretable examinations, 38.0% of cases and 84.9% of controls were normal (p<0.0001); wheezing was the most common sound (49.9%) in cases. CONCLUSIONS: Listening panel and case-control data suggests our methodology is feasible, likely valid and that small airway inflammation is common in WHO pneumonia. Digital auscultation may be an important future pneumonia diagnostic in developing countries. PMID- 28883929 TI - Frailty and patient-reported outcomes in subjects with chronic obstructive pulmonary disease: are they independent entities? AB - INTRODUCTION: There is a hypothesis that chronic obstructive pulmonary disease (COPD) is an accelerated ageing disease. Frailty is a geriatric syndrome characterised by physical, psychological and social vulnerability, thought to be a feature of ageing. The authors aimed to explore the relationship between frailty and physiological and patient-reported outcomes (PROs) in subjects with stable COPD. METHODS: We administered the Kihon Checklist that has been validated for frailty screening. We also assessed patient-reported measurements of health status and dyspnoea using the COPD Assessment Test (CAT), the St. George's Respiratory Questionnaire (SGRQ), the Hyland Scale, the Medical Outcomes Study 36 item short-form (SF-36), the Baseline Dyspnea Index (BDI) and the Dyspnea-12 (D 12). Pulmonary function was also measured. RESULTS: Of 79 consecutive COPD outpatients, 38 (48.1%), 24 (30.4%) and 17 (21.5%) patients were classified as robust, prefrail and frail, respectively. The total Kihon Checklist score was significantly weakly to moderately correlated with the CAT score (Spearman's rank correlation coefficient (Rs)=0.38, p<0.01), the SGRQ total score (Rs=0.65, p<0.01), the Hyland Scale score (Rs=-0.54, p<0.01), all subscale scores of the SF 36 (Rs=-0.64 to -0.31, p<0.01), the BDI score (Rs=-0.46, p<0.01) and the D-12 score (Rs=0.41, p<0.01). We found no or only weak correlations between the total Kihon Checklist score and lung function measurements. We found statistically significant between-group (robust, prefrail and frail) differences in most PRO scores. Using stepwise multiple regression analyses to identify the variables that predicted the total Kihon Checklist score, the SGRQ total score alone significantly explained 49.1% of the variance (p<0.01). DISCUSSION: Frailty was significantly correlated with PROs, especially health status, unlike lung function. Frailty should be assessed in addition to PROs separately from lung function as part of multidimensional analyses of COPD. PMID- 28883930 TI - Breathing-swallowing discoordination is associated with frequent exacerbations of COPD. AB - INTRODUCTION: Impaired coordination between breathing and swallowing (breathing swallowing discoordination) may be a significant risk factor for the exacerbation of chronic obstructive pulmonary disease (COPD). We examined breathing-swallowing discoordination in patients with COPD using a non-invasive and quantitative technique and determined its association with COPD exacerbation. METHODS: We recruited 65 stable outpatients with COPD who were enrolled in our prospective observational cohort study and did not manifest an apparent swallowing disorder. COPD exacerbation was monitored for 1 year before and 1 year after recruitment. Swallowing during inspiration (the I-SW pattern) and swallowing immediately followed by inspiration (the SW-I pattern) were identified. RESULTS: The mean frequency of the I-SW and/or SW-I patterns (I-SW/SW-I rate) was 21.5%+/-25.5%. During the 2-year observation period, 48 exacerbation incidents (25 patients) were identified. The I-SW/SW-I rate was significantly associated with the frequency of exacerbation. During the year following recruitment, patients with a higher I-SW/SW-I frequency using thicker test foods exhibited a significantly higher probability of future exacerbations (p=0.002, log-rank test). CONCLUSIONS: Breathing-swallowing discoordination is strongly associated with frequent exacerbations of COPD. Strategies that identify and improve breathing-swallowing coordination may be a new therapeutic treatment for patients with COPD. PMID- 28883931 TI - Rural to urban migration is associated with increased prevalence of childhood wheeze in a Latin-American city. AB - INTRODUCTION: The urbanisation process has been associated with increases in asthma prevalence in urban and rural areas of low-income and middle-income countries (LMICs). However, although rural to urban migration and migration between cities are considered important determinants of this process, few studies have evaluated the effects of internal migration on asthma in urban populations of LMICs. The present study evaluated the effects of internal migration on the prevalence of wheeze in an urban area of Latin America. METHODS: We did a cross sectional analysis of 2510 schoolchildren living in the city of Esmeraldas, Ecuador. Logistic regression was used to analyse associations between childhood wheeze and different aspects of migration among schoolchildren. RESULTS: 31% of schoolchildren were migrants. Rural to urban migrants had a higher prevalence of wheeze, (adj.OR=2.01,95% CI1.30 to 3.01, p=0.001) compared with non-migrants. Age of migration and time since migration were associated with wheeze only for rural to urban migrants but not for urban to urban migrants. Children who had migrated after 3 years of age had a greater risk of wheeze (OR 2.51, 95% CI 1.56 to 3.97, p=0.001) than non-migrants while migrants with less than 5 years living in the new residence had a higher prevalence of wheeze than non-migrants (<3 years: OR=2.34, 95% CI 1.26 to 4.33, p<0.007 and 3-5 years: OR=3.03, 95% CI 1.49 to 6.15, p<0.002). CONCLUSIONS: Our study provides evidence that rural to urban migration is associated with an increase in the prevalence of wheeze among schoolchildren living in a Latin-American city. Age of migration and time since migration were important determinants of wheeze only among migrants from rural areas. A better understanding of the social and environmental effects of internal migration could improve our understanding of the causes of the increase in asthma and differences in prevalence between urban and rural populations. PMID- 28883932 TI - Effect of vitamin D3 on the antimicrobial activity of human airway surface liquid: preliminary results of a randomised placebo-controlled double-blind trial. AB - INTRODUCTION: Vitamin D3 supplementation has been reported to prevent lung infections and increase the gene expression of antimicrobial peptides such as cathelicidin. We investigated the effect of vitamin D3 supplementation on the antimicrobial activity of airway surface liquid (ASL) in human subjects. Since smoking can increase the risk of respiratory infections, we also investigated the effect of smoking in the cathelicidin response to vitamin D3 in human airway epithelia in vitro. METHODS: This study is a subanalysis of single-centre community-based randomised placebo-controlled double-blind trial. Participants were randomised to receive 1000 international units per day of oral vitamin D3 or identical placebo for 90 days. Blood and ASL samples were collected preintervention and postintervention. 105 participants were originally enrolled, 86 completed the trial, and due to low protein concentration in the samples, 40 participants were finally analysed. Our primary outcome was ASL antimicrobial activity. We also considered secondary outcomes including changes in serum concentration of 25-hydroxyvitamin D3 (25(OH)D3), 1,25-hydroxyvitamin D3, calcium and parathyroid hormone (PTH). In addition, we studied the effect of cigarette smoke extract (CSE) exposure to primary human airway epithelial cell cultures on the gene expression of cathelicidin in response to vitamin D3 and expression of CYP27B1 (1-alpha hydroxylase), responsible for vitamin D3 activation. RESULTS: Vitamin D3 supplementation significantly increased both ASL antimicrobial activity and serum concentration of 25(OH)D3. In a subgroup analysis, we found that smokers did not increase their baseline antimicrobial activity in response to vitamin D3. Exposure to CSE on human airway epithelia decreased baseline CYP27B1 gene expression and cathelicidin response to 25(OH)D3. CONCLUSION: Vitamin D3 supplementation for 90 days increases ASL antimicrobial activity. Data from this preliminary study suggest that smoking may alter the ability of airway epithelia to activate vitamin D3 and increase the gene expression of cathelicidin antimicrobial peptide. TRIAL REGISTRATION NUMBER: NCT01967628; Post-results. PMID- 28883933 TI - Interventions for post-infectious irritable bowel syndrome: a systematic review of treatment efficacy. AB - BACKGROUND: Post-infectious irritable bowel syndrome (PI-IBS) due to traveler's diarrhea is the second most common illness seen in post-travel clinics, yet its optimal management remains unknown. We performed a systematic review to evaluate treatment efficacy in PI-IBS. METHODS: We searched Medline, EMBASE, LILACS, CINAHL, CAB abstracts, and the Cochrane Library to February 3, 2014 for intervention studies of the pharmacologic and non-pharmacologic management of PI IBS and examined the evidence according to a modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) scale. RESULTS: Of 336 records, 9 studies were included. Eight studies of pharmacologic interventions examined 5 agents (mesalazine or mesalamine, ondansetron, prednisolone, cholestyramine, and metronidazole). One study examined the non-pharmacologic intervention of different infant nutritional formulas following acute gastroenteritis. The quality of the evidence to date was low, with small sample size (fewer than 50 participants) and short duration of follow-up. Overall, the efficacy of pharmacological treatment ranged from no benefit (ondansetron and prednisolone) to moderately beneficial (cholestyramine and metronidazole). The evidence for mesalazine was equivocal: one study showed benefit, two others showed none. CONCLUSIONS: Heterogeneity in outcome measures and low strength of evidence preclude recommendations on the optimal management of PI-IBS by a specific agent. More comparative intervention research into PI-IBS treatment is needed for consistent best practice in PI-IBS management. Clinicians may elect to pursue therapeutic trials of mesalazine, cholestyramine, or metronidazole in individual patients, but should be aware that data supporting the efficacy of these agents is limited. PMID- 28883934 TI - A cross-sectional analysis of clinical presentations of and risk factors for enteric protozoan Infections in an Active Duty Population during Operation Iraqi Freedom. AB - BACKGROUND: Infectious travelers' diarrhea (TD) is a well-appreciated problem among service members serving abroad, particularly where infrastructure is limited due to ongoing combat operations, and efforts at sanitation and hygiene may not be considered an immediate priority. Bacterial and viral causes of travelers' diarrhea are well-described among deployed service members, however, gastrointestinal protozoan infections among deployed service members are less well documented. This study's purpose was to identify potential risk factors for, and clinical presentations of, enteric protozoan infections in an active duty military population deployed to combat operations in the Southwest Asia. METHODS: A cross-sectional study of enteric protozoan infections among US service members deployed in Al-Asad Air Base, Iraq in support of Operation Iraqi Freedom (OIF) was conducted in summer 2004. Subjects were obtained through a randomized sector sampling scheme, and through presentations for care at the air base medical facilities. All study participants provided a stool sample, either diarrhea or solid, upon study entry and completed a questionnaire documenting demographic information, clinical symptoms of any prior diarrheal episodes, and health risk behaviors. Basic diagnostic microscopy for protozoa was conducted to include acid fast and modified trichrome staining. RESULTS: Four hundred thirty-seven subjects were included in the analysis, and 75 (17.1 %) subjects were found to have enteric protozoan infections as identified by diagnostic stool microscopy. Blastocystis hominis (n = 36), Entamoeba coli (n = 25), Endolimax nana (n = 20), and Entamoeba histolytica (n = 5) were the predominant organisms isolated. Crude incidence of prior episodes of diarrhea was greater among subjects from whom enteric protozoa were isolated compared to those without (IRR 1.66, 95 % CI 1.47 1.87). Bivariate analysis of health risk and hygiene behaviors found increased odds for presence of Blastocystis hominis among those service members who reported off base ice (OR 3.61, 95 % CI 1.40-9.28) and raw vegetable consumption (OR 8.18, 95 % CI 1.40-47.5). CONCLUSIONS: This study suggests that US service members deployed to the early stages of OIF were at greater risk of acquiring enteric protozoa than previously understood. The noted prevalence of enteric protozoa among US service members in this study is higher than in prior reports, approaching prevalence expected in the general host nation population, suggesting that US service members operating at Al-Asad Air Base in early OIF were exposed to greater degrees of fecally contaminated food and water, and poor hygienic and sanitation practices. Consumption of food and water prepared by host nation parties in Southwest Asia may place US service members at risk for acquiring intestinal protozoa. PMID- 28883935 TI - Travel risk behaviors as a determinants of receiving pre-travel health consultation and prevention. AB - BACKGROUND: An estimated 30-60 % of travelers experience an illness while traveling. The incidence of travel-related illness can be reduced by preventive measures such as those provided by the Traveler Health Clinic (THC) in Kuwait. METHODS: The present study is an analytical comparative study between groups of travelers visiting the THC during the study period (May 2009 - December 2010) and an age- and gender-matched control group of non-visitors (800 people). Both groups completed a modified pre-departure questionnaire. RESULTS: Bivariate analysis revealed that Kuwaitis (68.2 %), those traveling for work (25.3 %) or leisure (59.5 %), those living in camps (20.4 %) or hotels (64.0 %), and those with knowledge of the THC from the media (28.1 %) or other sources (57.3 %), were more likely to be associated with a high frequency of visits to the THC (p < 0.001). Additionally, travelers heading to Africa (47 %) and South America (10 %) visited the THC more than did others (P < 0.05). Multivariate analysis revealed that nationality, followed by purpose of travel, duration of stay, and choice of travel destination are independent predictors of receiving pre-travel consultation from the THC. CONCLUSION: Nationality, purpose of travel, length of stay, and travel destination are predictors for receiving a pre-travel consultation from the THC. PMID- 28883936 TI - Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013. AB - BACKGROUND: Emerging antibiotic resistance amongst clinically significant bacteria is a public health issue of increasing significance worldwide, but it is relatively uncharacterized in Cambodia. In this study we performed standard bacterial cultures on samples from wounds at a Non-Governmental-Organization (NGO) Hospital in Phnom Penh, Cambodia. Testing was performed to elucidate pathogenic bacteria causing wound infections and the antibiotic resistance profiles of bacterial isolates. All testing was performed at the Naval Medical Research Unit, No.2 (NAMRU-2) main laboratory in Phnom Penh, Cambodia. METHODS: Between 2011-2013, a total of 251 specimens were collected from patients at the NGO hospital and analyzed for bacterial infection by standard bacterial cultures techniques. Specimens were all from wounds and anonymous. No specific clinical information accompanied the submitted specimens. Antibiotic susceptibility testing, and phenotypic testing for extended-spectrum beta-lactamase (ESBL) were performed and reported based on CLSI guidelines. Further genetic testing for CTX M, TEM and SHV ESBLs was accomplished using PCR. RESULTS: One-hundred and seventy six specimens were positive following bacterial culture (70 %). Staphlycoccus aureus was the most frequently isolated bacteria. Antibiotic drug resistance testing revealed that 52.5 % of Staphlycoccus aureus isolates were oxacillin resistant. For Escherichia coli isolates, 63.9 % were ciprofloxacin and levofloxacin resistant and 96 % were ESBL producers. Resistance to meropenem and imipenem was observed in one of three Acinetobacter spp isolates. CONCLUSIONS: This study is the first of its kind detailing the antibiotic resistance profiles of pathogenic bacteria causing wound infections at a single surgical hospital in Cambodia. The reported findings of this study demonstrate significant antibiotic resistance in bacteria from injured patients and should serve to guide treatment modalities in Cambodia. PMID- 28883937 TI - The local importance of global infectious diseases. PMID- 28883939 TI - Perceived risk of watery diarrhea and dysentery and intended compliance with chemoprophylaxis among a deployed military population. AB - BACKGROUND: Infectious diseases are a leading cause of morbidity among travelers to resource-limited regions and primary prevention is a cornerstone to risk reduction. Chemoprophylaxis has been successfully utilized for specific diseases. METHODS: We assessed self-reported compliance to daily chemoprophylaxis among deployed US military personnel. A 21 item self-completed questionnaire was completed by military personnel during mid-deployment. RESULTS: The perception of high disease risk was associated with an increased likelihood of compliance with daily chemoprophylaxis. However, 60 % of respondents stated they would not comply with a daily regimen. CONCLUSIONS: These data highlight the complexity of perceived risk and the difficulties with prophylactic interventions. PMID- 28883938 TI - The converging burdens of infectious and non-communicable diseases in rural-to urban migrant Sub-Saharan African populations: a focus on HIV/AIDS, tuberculosis and cardio-metabolic diseases. AB - Africa has the unenviable challenge of dealing with a double burden of disease: infectious diseases (IDs) such as HIV/AIDS and tuberculosis are high while non communicable diseases (NCDs) are rapidly rising in the region. Populations with increased susceptibility to both include migrants. This review highlights the susceptibility of rural-to-urban migrants in Sub-Saharan Africa to the IDs of HIV/AIDS and tuberculosis, and to NCDs, particularly cardiovascular diseases. The disruption that occurs with migration is often accompanied by unhealthy exposures and environments. These include partaking in risky sexual practices and a subsequent greater risk for HIV infection in migrants than the general populations which contributes to the spread of the disease. Migrants frequently work and live in conditions that are poorly ventilated and overcrowded with suboptimal sanitation which increases their risk for tuberculosis. Considering that migrants have an increased risk of acquiring both HIV/AIDS and tuberculosis, and in view of the interaction between these diseases, they are likely to be at high risk for co-infection. They are also likely to facilitate the geographical spread of these infections and serve as conduits of disease dissemination to rural areas. Changes in lifestyle behaviours that accompany migration and urbanisation are exemplified primarily by shifts in physical activity and dietary patterns which promote the development of obesity, diabetes, hypertension and cardiovascular diseases. Urban living and employment is generally less physically exerting than rural routines; when migrants relocate from their rural residence they adapt to their new environment by significantly reducing their physical activity levels. Also, nutritional patterns among migrants in urban centres change rapidly with a shift to diets higher in fat, sugar and salt. Consequently, increases in weight, blood pressure and glucose levels have been reported within a year of migration. Interactions between IDs and NCDs are common; considering that migrants have an increased susceptibility to IDs and demonstrate a rapid rise in their risk for NCDs, the concurrent prevalence of both is likely in this population. There is a need for a combined strategy to combat IDs and NCDs with screening and treatment programmes geared towards this high risk group. PMID- 28883940 TI - Correlating quantitative real-time PCR to rapid diagnostic test and RNA transcript expression in isolated gametocytemia and asexual parasitemia of Plasmodium falciparum malaria. AB - BACKGROUND: At present, only microscopic examination of stained thick and thin blood smears for malaria can differentiate clinically relevant asexual parasitemia from clinically irrelevant isolated gametocytemia. Microscopy is time consuming, labour intensive, and requires significant technical expertise to perform. Simple and rapid tests that can distinguish asexual from isolated sexual parasitemia are needed. METHODS: To determine if parasitemia and cycle threshold (CT) values on Plasmodium genus and P. falciparum-specific quantitative polymerase chain reaction (qPCR) assays correlate to positivity of rapid diagnostic test (RDT), and 18S rRNA gene copy number, we analyzed blood samples from Ontario patients with isolated P. falciparum gametocytemia or asexual stages. RNA transcripts were evaluated to determine whether there is correlation of expression to different life cycle stages of P. falciparum. RESULTS: 45 specimens containing isolated P. falciparum gametocytes, and 40 specimens containing isolated asexual stages by microscopy were identified and analyzed. By RDT, 40 of 45 (88.9 %) isolated gametocytemia specimens and 40 of 40 (100 %) asexual-stage specimens were positive for Plasmodium falciparum-specific histidine rich protein-2 (HRP-2). Fourteen of 45 (31.1 %) isolated gametocytemia specimens, and 36 of 40 (90 %) asexual-stage specimens were positive for Plasmodium genus aldolase T2 band. Positivity of the aldolase T2 band was associated with lower mean Plasmodium genus and P. falciparum-specific CT values, and to higher mean 18S rRNA gene copy by qPCR for both isolated gametocytemia and asexual-stage specimens. There was also a negative correlation of asexual parasitemia to both CT values, and positive correlation to 18S rRNA gene copy number. Analysis of asexual stage-specific erythrocyte binding antigen (eba-175) transcripts on 25 isolated gametocytemia and 20 asexual-stage specimens gave a positive predictive value of 62.5 % and negative predictive value of 100 % for asexual parasitemia. Thus, an absence of eba-175 transcripts excluded the presence of asexual (clinically relevant) parasitemia. CONCLUSIONS: Positivity of the aldolase T2 band of BinaxNow RDT correlated to higher parasite load in both isolated gametocytemia and asexual-stage specimens. Asexual stage-specific eba 175 RNA transcript expression provided reasonable negative predictive value for exclusion of asexual parasitemia in clinical samples, but was present in both isolated gametocytemia and asexual stage specimens. PMID- 28883941 TI - A cross-sectional household cluster serosurvey of hepatitis C virus antibodies in an urban slum of Cairo, Egypt in 2004. AB - BACKGROUND: Hepatitis C Virus (HCV) continues to be a burden to the Egyptian population and its economy. Despite all efforts, the prevalence of infection continues to be one of the highest in the world. The high national prevalence has been attributed to unintentional, nosocomial spread during an anti schistosomiasis campaign conducted in the 1970's, but that does not fully explain the persistent infection rates. Work is needed to further clarify risk associations. A serosurvey was performed in Manshiet Nasser, a slum in Cairo sometimes referred to as Mokattem Hills where a primary occupation is garbage collection and sorting, to characterize potential risk factors for infection. METHODS: Following a detailed mapping and census of the area, a cluster sampling was performed and demographic and risk behavior data and a blood sample were collected from subjects older than 6 months. Blood samples were tested using 4th generation anti-HCV EIA kit. RESULTS: The slum was estimated to house 45,000 residents. Blood samples were obtained from 2169 subjects. The age adjusted anti HCV seroprevalence was 9.1 %. Participants with HCV antibodies were more likely to be male, heads of households, subjects without formal education, and those with a lower standard of living. After adjustment of all prevalence ratios (aPR) for age, the following risk factors were significantly associated with higher risk of HCV infection: Garbage collection (aPR 1.5), history of blood transfusion (aPR 2.0), tattooing (aPR 1.4), history of schistosomiasis (aPR 1.5), and use of traditional latrines (aPR 2.0) or pits for sanitation (aPR 1.3). The results of the multivariate analysis indicated that age (p < 0.01), history of schistosomiasis (p < 0.05), garbage sorting (p = 0.05), blood transfusions (<0.001), and the use of traditional latrines for sanitation (p < 0.01) were significantly associated with infection. CONCLUSION: While HCV prevalence among those over 30 could be attributed to anti-schistosomiasis injections, the prevalence in younger age indicates ongoing transmission. Although specific behavioral risks were not identified, HCV infection appears to be an occupational hazard of garbage collection and sorting in this environment. Given the large reservoir of HCV infection in the population, further effort needs to be made to identify and mitigate new infections. PMID- 28883942 TI - Japanese encephalitis: a review of clinical guidelines and vaccine availability in Asia. AB - Travelers to Asia are at risk for acquiring Japanese Encephalitis (JEV), an arbovirus with high rates of morbidity and mortality. Recent advances in vaccination resulting in vaccines with low rates of side effects have strengthened the rationale to vaccinate more travelers to this region, as reflected in many updated national guidelines for prevention of disease in travelers. Vaccines however still require a complex pre-travel schedule and are costly, often leading to a requirement or desire for a vaccination option in the destination country. We explore current national guidelines for prevention of Japanese Encephalitis and seek to provide information on availability of JEV vaccines in various Asian countries. PMID- 28883943 TI - Phenomenological analysis of going home in Caribbean-American international travelers. AB - BACKGROUND: In travel health risk assessments visiting friends and relatives (VFR) travel status is often used as an indicator for high-risk travel behavior. VFR travelers have been associated with increased risk of travel-associated illnesses due to poor adherence to travel guidelines and lack of pre-travel health consultations. For travelers to dengue endemic regions, guidelines include compliance with mosquito avoidance practices (MAP). The goal of this study is to understand the meaning of travel experiences to the home country for immigrant and first generation American VFR travelers in the United States (US). METHODS: A phenomenology study was conducted on VFR travelers to identify social and physical environmental factors associated with travel health behaviors, and determine how 'going home' influences compliance with recommendations for dengue prevention. Purposive sampling identified participants for semi-structured interviews on travel behavior with iterative collection and analysis until data reached saturation. RESULTS: Interviews revealed five themes that defined the experience of going home: connectedness; control of the experience; two different experiences at home; seeing what home has to offer; and there is no place like home. Moreover, risk perception of health and disease risks in the travel destination influenced travel behavior and compliance with guidelines. CONCLUSIONS: VFR travel status does not fully capture the experience of international travel. Behavior was associated with the emergent concept of Cultural Embeddedness when traveling home and to new destinations. More research on improving terminology for travel health risk assessments is needed to improve prevention strategies in VFR travelers. PMID- 28883944 TI - Epidemiology of tunga penetrans infestation in selected areas in Kiharu constituency, Murang'a County, Kenya. AB - BACKGROUND: Tungiasis is a parasitic skin disease brought about by female Tunga penetrans when they burrow into the skin of their hosts. It is a disease that has largely been ignored. Epidemiology of tungiasis has not been widely studied in Kenya which could negatively affect effective intervention strategies. This study therefore sought to investigate epidemiology of tungiasis in selected areas in Kiharu constituency, Murang'a County in Kenya. METHODS: The study population comprised of public primary school pupils, the most vulnerable age group (n = 508) in Gaturi, Kimathi, Kahuhia and Mugoiri in Kiharu constituency. Public primary school pupils in the study area were randomly sampled. Through questionnaires and observations, data was collected. RESULTS: The overall prevalence of tungiasis in pupils in the study area was 19.1 %. In multinomial logistic regression analysis some factors were identified to be associated with tungiasis such as lack of regular use of closed foot ware (Adjusted odds ratio = 10.45; 95 % Confidence Interval; 1.49-73.23), living in earthen mud walled houses (aOR = 13.78; 95 % CI = 3.127-60.69), sharing living quarters with domestic animals (aOR = 3.1; 95 % CI = 0.003-.046) and learning in classrooms with dusty floors (aOR = 14.657; 95 % CI = 2.262-94.95). Treatment of tungiasis was found to be mainly through mechanical removal of embedded T. penetrans. CONCLUSION: This study shows that tungiasis in the selected study areas of Kiharu constituency is a disease of significant health concern. Factors associated with tungiasis were identified that should be the focus of sustainable and effective control measures. PMID- 28883945 TI - Norovirus: new developments and implications for travelers' diarrhea. AB - Noroviruses are the leading cause of acute gastroenteritis in the United States and are responsible for at least 50 % of acute gastroenteritis outbreaks occurring worldwide each year. In addition, noroviruses have caused outbreaks on cruise ships, in nursing homes and hospitals, and in deployed military personnel, but its role in the etiology of travelers' diarrhea is not well defined. The aim of this review is to describe the role of noroviruses in travelers' diarrhea in terms of epidemiology, current diagnostics, treatment and vaccine development efforts. Studies have shown prevalence rates of noroviruses in travelers' diarrhea cases ranging from 10-65 %. It is likely that norovirus prevalence rates are highly underestimated in travelers' diarrhea due to rapid onset, short duration of the illness, limited availability of laboratory facilities, and the fact that most clinical laboratories lack the diagnostic capability to detect noroviruses in stool. Further, additional studies are needed to accurately determine the true prevalence rates of norovirus as an etiologic agent of diarrhea among travelers to different regions around the world. With the rapid progress in the development of a norovirus vaccine, travelers could serve as an ideal population for future norovirus clinical trials. PMID- 28883946 TI - Malaria in the returning older traveler. AB - BACKGROUND: Increased co-morbidities and physiological changes mean older patients may be at higher risk of adverse outcomes from certain imported illnesses. One of the most commonly diagnosed imported infections in returning travelers is malaria. Increasing age is strongly and independently associated with increasing morbidity and mortality from malaria. Delayed diagnosis leads to higher risks of poor clinical outcomes in older patients presenting with malaria. The objective of this study was to quantify malaria presentations in older patients as a percentage of total malaria presentations, compare length of hospital stay (LOS) between the older and younger cohort, and to describe medical co-morbidities, length of time to diagnosis and factors contributing to delayed diagnosis and increased LOS in the older cohort. METHODS: A retrospective cohort study was undertaken in two university hospitals of all patients aged 65 years or older presenting with malaria from 2002-2012. A national hospital inpatient database was used to identify patients of all ages with a discharge diagnosis of malaria over this ten year period, and quantify LOS in those aged <65 and those aged 65 years or older. The case-notes for all of the older cohort were reviewed. RESULTS: There were a total of 203 cases, 12 of whom were aged >=65 years (5.9 %- total). Median time to diagnosis in this older group was two days (range 0-35), median LOS was eight days (range 1-77), compared to a median LOS of three days in those aged <65 years. All patients aged >=65 years presented with fever. Travel history was documented in only 6/12 charts, and 11/12 had two or more co-morbid illnesses. Six of the 12 patients were not diagnosed or treated within 48 h of presentation. CONCLUSIONS: This case series highlights the need for appropriate history-taking and timely diagnosis of the older traveler returning with fever, as delayed diagnosis and treatment can contribute to prolonged hospital stay and increased morbidity. With increasing numbers of older travelers, physicians must remain vigilant to the presence of imported illnesses, particularly malaria, in older patients with unexplained fever. PMID- 28883947 TI - Ecotourism as a source of infection with Schistosoma mansoni in Minas Gerais, Brazil. AB - BACKGROUND: In recent years, a new pattern of schistosomiasis transmission has been described which is related to recreational activities associated with rural or ecological tourism and migratory flows and accompanying changes in social dynamics in Brazil. The objective of this report is to describe two schistosomiasis outbreaks that occurred during the practice of rural tourism in Minas Gerais, Brazil, and review this pattern of transmission within the wider context of schistosomiasis control. FINDINGS: The first outbreak was characterized by its high infection rate, showing that 59 % of the exposed eco tourists became positive for infection with Schistosoma mansoni. In addition, all three disease transmitting species of intermediate host snails were found in the area. In the second outbreak, all members of one tourist family were infected and reported contact with water in a well-known tourist area. The malacological survey in the region revealed an infection rate with S. mansoni of 8.3 % among the collected snails. CONCLUSIONS: Infection of urban dwellers that report contact with contaminated water associated with ecotourism represents a new pattern of disease transmission and dissemination. The infection with the disease at these occasions finds its expression in outbreaks of acute schistosomiasis among internal tourists to rural areas. Therefore, epidemiological surveillance in endemic areas should be aware of this schistosomiasis transmission pattern, and a multidisciplinary approach, most of all sanitation and health education measures, is required in order increase the efficiency of control strategies. PMID- 28883948 TI - Antimicrobial resistance acquisition after international travel in U.S. travelers. AB - BACKGROUND: Prior studies have shown an increase in multidrug-resistant (MDR) E. coli colonization from two percent in U.S.-based to 11 % in deployed, healthy military personnel. It is unclear if colonization with MDR organisms occurs through deployment exposures or risks related to routine overseas travel. This study prospectively evaluates rates and risk factors associated with MDR gram negative bacterial and methicillin-resistant S. aureus (MRSA) colonization after international travel. METHODS: Participants traveled internationally for five or more days. Pre- and post-travel, colonizing bacteria from oropharyngeal, nares, groin, and peri-rectal (PR) areas were collected using BD CultureSwabTM MaxV(+). Identification and susceptibilities were done utilizing the BD PhoenixTM Automated Microbiology System. Non-MDR pre- and post-travel MDR bacteria within a subject were compared by pulsed-field gel electrophoresis (PFGE). A questionnaire solicited demographics and potential risk factors for MDR acquisition. RESULTS: Of 58 participants, 41 % were male and median age was 64 years. Pre- and post travel swabs were obtained a median of ten and seven days before and after travel, respectively. Itineraries included 18 participants traveling to the Caribbean and Central America, 17 to Asia, 16 to Africa, 5 to Europe, 4 to South and North America. Seventeen of 22 travelers used atovaquone/proguanil for malaria prophylaxis. The only MDR organism isolated was extended-spectrum beta lactamase (ESBL)-producing E. coli in five (9 %) participants post-travel (all PR and unrelated by PFGE). There were no statistically significant associations between exposure risks and new ESBL-producing E.coli colonization. Of 36 participants colonized with E. coli pre- and post-travel, new resistance was detected: TMP/SMX in 42 % of isolates (p < 0.01), tetracycline in 44 % (p < 0.01), and ampicillin-sulbactam in 33 % (p = 0.09). No participants were colonized with MRSA pre- or post-travel. CONCLUSION: Consistent with prior studies, new antimicrobial resistance was noted in colonizing E. coli after international travel. Nine percent of participants acquired new strains of ESBL producing E.coli without identified risks. PMID- 28883949 TI - Prevalence of active trachoma and associated risk factors among children in Gazegibela district of Wagehemra Zone, Amhara region, Ethiopia: community-based cross-sectional study. AB - BACKGROUND: Trachoma continues to be hyperendemic in many rural areas of Ethiopia. The aim of this study was to determine the prevalence and associated risk factors of active trachoma among children in Gazegibela district, Ethiopia. METHODS: A community-based cross-sectional study was conducted in April 2015 among children aged 1-9 years. Data were collected through an interview and eye examinations. Descriptive and logistic regression analyses were performed. RESULTS: Among 601 children, 315 (52.4 %) were positive for active trachoma. Of these cases, 49.1 % were trachomatous inflammation-follicular and 3.3 % were trachomatous inflammation-intense. Children from households using rivers and ponds as their source of drinking water were more likely to develop active trachoma compared to those from households using water from springs or hand-dug wells (aOR = 2.9, 95 % CI: 1.70-4.81). Children from farming households were more likely to develop active trachoma (AOR = 3.3, 95 % CI: 1.02-10.65), as were children from housholds that lacked a latrine (aOR = 12.9, 95 % CI: 5.96-28.29). Children who washed their face only once a day were more likely to have active trachoma compared to those who washed for two and more times a day (aOR = 2.6, 95 % CI: 1.43-4.72). CONCLUSION: There is a high prevalence of trachoma among children from Gazegibela district. Trachoma remains a public health challenge in this region, requiring intervention from the government and other stakeholders. PMID- 28883950 TI - Travellers returning ill from the tropics - a descriptive retrospective study. AB - International travel continues to increase in frequency. Health care providers need a wide understanding of the spectrum of travel related diseases and their management. This retrospective study analyses the demographic and clinical data of 360 travellers returning from the tropics presenting to an outpatient clinic at a tertiary hospital between 2003 - 2007. The aim of this study was to analyse the frequency of presenting symptoms and diseases in ill returning travellers and to correlate them to the areas visited and the duration and purpose of travel. The main symptoms during travel were diarrhoea (n = 200, 56 %) and fever (n = 124, 34 %). Travellers not visiting friends and relatives but with close contact to the local population were at more than two-fold increased risk of diarrhoea (Odds Ratio [OR] 2.5; 95 % confidence interval [CI] 1.1-6.0, p = 0.03) and fever (OR 2.4; 95 % CI 1.1-5.3; p = 0.02) compared to tourist travellers. Travellers visiting friends and relatives (VFR) were not at increased risk for diarrhoea (OR 0.6; 95 % CI 0.3-1.3; p = 0.17), or fever (OR 1.5; 95 % CI 0.7-3.4; p = 0.28). Thirty-two percent of all travellers (n = 115) were diagnosed with a specific pathogen. Malaria (6 %), giardiasis (6 %) and amebiasis (4 %) were the most frequently detected pathogens. The odds of malaria as a cause of the presenting illness was lower among travellers reporting pre-travel advice. Specific antimicrobial treatment was required in around one third of the patients. PMID- 28883951 TI - Incidence and risk factors for disease and non-battle injury aboard the hospital ship USNS COMFORT during a Humanitarian Assistance and Disaster Response Mission, Continuing Promise 2011. AB - BACKGROUND: Disease and non-battle injury (DNBI) are a leading cause of morbidity in deployments and can compromise operational mission performance. No study to date has examined DNBI incidence and impact aboard humanitarian aid/disaster response (HADR) mission ships. METHODS: From April to September 2011, US military and civilian personnel participated in Continuing Promise 2011, a HADR training mission aboard USNS COMFORT (T-AH 20). Health surveillance was conducted for the purpose of assessing DNBI trends and improving force health protection during the deployment through passive surveillance, collection of DNBI data among those seeking care at the ship's clinic, and actively through use of an anonymous weekly, self-report questionnaire. Categorical and total DNBI incidence rates were calculated per 100 person-weeks and incidence rate ratios (IRR) were calculated utilizing a negative binomial model to assess potential risk factors. RESULTS: The leading syndrome-specific cause of weekly visits to the ship's clinic was gastrointestinal (GI) followed by dermatologic and respiratory conditions (2.22, 1.97, and 1.46 cases per 100 person-weeks, respectively). The top three categorical DNBI were similarly represented by the questionnaire, with respiratory conditions having the highest reported rate followed by dermatologic and GI (11.79, 8.71, and 7.38 cases per 100 person-weeks, respectively). GI had the highest morbidity measures accounting for 61.9 % of lost work days and 27.3 % of reported moderate/severe impact to mission performance. Several factors were also associated with increased DNBI rates including personnel ages 26-36 (IRR = 1.23), officers (IRR = 1.23), days-off-ship (IRR = 1.09), and affiliation with nursing services (IRR = 1.48), naval mobile construction battalion (IRR = 3.17), and security (IRR = 1.71). CONCLUSIONS: DNBI can significantly impact mission performance on HADR missions, and establishing baseline rates and identifying risk factors can help improve force health protection in future HADR missions. PMID- 28883952 TI - Knowledge, attitudes, and practices regarding dengue infection among public sector healthcare providers in Machala, Ecuador. AB - BACKGROUND: Dengue fever is a rapidly emerging infection throughout the tropics and subtropics with extensive public health burden. Adequate training of healthcare providers is crucial to reducing infection incidence through patient education and collaboration with public health authorities. We examined how public sector healthcare providers in a dengue-endemic region of Ecuador view and manage dengue infections, with a focus on the 2009 World Health Organization (WHO) Dengue Guidelines. METHODS: A 37-item questionnaire of dengue knowledge, attitudes, and practices was developed and administered to dengue healthcare providers in Machala, Ecuador. Survey focus areas included: "Demographics," "Infection and Prevention of Dengue," "Dengue Diagnosis and the WHO Dengue Guide," "Laboratory Testing," "Treatment of Dengue," and "Opinions Regarding Dengue." RESULTS: A total of 76 healthcare providers participated in this study, of which 82 % were medical doctors and 14 % were nurses. Fifty-eight percent of healthcare professionals practiced in ambulatory clinics and 34 % worked in a hospital. Eighty-nine percent of respondents were familiar with the 2009 WHO Dengue Guidelines, and, within that group, 97 % reported that the WHO Dengue Guide was helpful in dengue diagnosis and clinical management. Knowledge gaps identified included Aedes aegypti mosquito feeding habits and dengue epidemiology. Individuals with greater dengue-related knowledge were more likely to consider dengue a major health problem. Only 22 % of respondents correctly reported that patients with comorbidities and dengue without warning signs require hospital admission, and 25 % of providers reported never admitting patients with dengue to the hospital. Twenty percent of providers reported rarely (<=25 % of cases) obtaining laboratory confirmation of dengue infection. Providers reported patient presumptive self-medication as an ongoing problem. Thirty-one percent of healthcare providers reported inadequate access to resources needed to diagnose and treat dengue. CONCLUSION: Participants demonstrated a high level of knowledge of dengue symptoms and treatment, but additional training regarding prevention, diagnosis, and admission criteria is needed. Interventions should not only focus on increasing knowledge, but also encourage review of the WHO Dengue Guidelines, avoidance of presumptive self medication, and recognition of dengue as a major health problem. This study provided an assessment tool that effectively captured healthcare providers' knowledge and identified critical gaps in practice. PMID- 28883953 TI - Health problems and health care seeking behavior among adult backpackers while traveling in Thailand. AB - BACKGROUND: Health problems among travelers in developing countries are not uncommon. Little is known about the occurrence of health problems and their impacts among backpackers in Thailand. The objective of this study was to assess the health problems and the health seeking behavior among adult backpackers who visited Thailand. METHODS: This was a cross-sectional questionnaire-based study. Data were collected from foreign adult backpackers in Khao San Road, Bangkok. They were asked about their demographic data, health problems (if any), and health-care seeking behavior if they became ill. RESULTS: During May to July 2015, 420 backpackers were enrolled in this study. Of these, 51.4 % were male with a median age of 26.4 years. Up to 66.9 % were of European origin, while 17.4 % were North American. Fifty-eight percent sought pre-travel consultation before traveling. In this study, 10.2 % (43/420) of the participants reported at least health problem during travel. Most of them (79.1 %) had single episode of illness. Of this, diarrhea was the most common health problem (30.4 %), followed by abdominal pain (14.3 %), skin problems (8.9 %), respiratory problems (8.9 %), accident-associated injury (7.1 %), and febrile illness (7.1 %). One third of backpackers with health problems spontaneously recovered without any treatment, while nearly a quarter treated themselves with standby medication, and one in five had to buy over the counter medication. Just over 9 % of backpackers with a health problem sought medical care at a hospital. Among travellers with health problems, 72.1 % reported that their health problems did not significantly impact to their trip, while 23.3 % had to delay or postpone their trip for at least 1 day, and 4.7 % had to cancel some trip and/or activity. Longer duration of stay was significantly related to higher occurrence of health problems while traveling. CONCLUSIONS: Approximately 10 % of adult backpackers experienced some health problems during their trip in Thailand. Although most of their health problems were mild, up to 22 % of backpackers with health problems need to seek medical care either in a clinic or in a hospital. PMID- 28883954 TI - The threat of antimalarial drug resistance. AB - The battle between man and malaria has continued for thousands of years. Antimalarial drugs are essential weapons to fight the disease, but their efficacy is threatened by drug resistance which continues to emerge creating a major obstacle to malaria control and jeopardizing renewed hopes for elimination. As 2016 is the first year under WHO Global Technical Strategy for Malaria 2016-2030, it is a good time to ponder the progress of both sides and plan for the future. PMID- 28883955 TI - Diarrheal disease and enteric infections in LMIC communities: how big is the problem? AB - Studies of enteric diseases have historically focused on observations of clinical diarrhea as a cause of mortality and morbidity. Emerging evidence suggests that diarrhea dramatically underestimates both exposure to enteropathogens and the long-term consequences arising from infection. High burden of pathogens in the gut, even in the absence of diarrhea, is common in infants in low and middle income countries. Continual challenge by pathogens, in conjunction with an inadequate diet stimulates an inflammatory disease that alters the structure of the gut, metabolic and immunological pathways and changes the microbiome. Both diarrhea and enteropathogen infection have been associated with reduced growth, reduced cognitive development, and reduced vaccine efficacy suggesting that the burden of diarrheal disease is dramatically underestimated. PMID- 28883957 TI - Knowledge, practices and perceptions of trachoma and its control among communities of Narok County, Kenya. AB - BACKGROUND: Trachoma is the leading infectious cause of blindness in the world. It is commonly found in cultural groups with poor hygiene. Trachoma control includes Surgery, Antibiotics, Facial cleanliness and Environmental Improvement (SAFE). Potentially blinding and active trachoma are monitored using trachomatous trichiasis (TT) in adults and trachoma inflammation-follicular (TF) in children aged 1-9 years respectively. A cross-sectional study to assess the knowledge, practices and perceptions of trachoma and its control was conducted in the endemic communities in Narok County. METHODS: Qualitative methods were used for data collection. Using purposive sampling, 12 focus group discussions (FGDs) with single sex adult and young men and women groups of homogenous characteristics, 12 key informant interviews with opinion leaders and 5 in-depth interviews (IDIs) with trichiasis patients and 6 with persons who have undergone trichiasis surgery were conducted. Data was audio recorded, transcribed, coded and analyzed manually by study themes; knowledge, practices and perceptions of trachoma transmission, infection signs, prevention and control. RESULTS: Majority of the community members had knowledge of trachoma and its transmission. The practices that contributed to transmission of infection included: failure to wash faces and bathe regularly, sharing of water basins and towels for face washing, traditional methods of trachoma treatment and dirty household environment. Due to socio cultural perceptions, toilets were unacceptable and use of bushes for human waste disposal was common. Poor perceptions on disease susceptibility, flies on children's faces, latrine ownership and usage and separation of human and animal dwellings also played a role in the transmission of trachoma. Fear of loss of sight during surgery was a deterrent to its uptake and a desire to be able to see and take care of domestic animals promoted surgery uptake. Majority of the community members were appreciative of Mass Drug Administration (MDA) though side effect such as vomiting and diarrhoea were reported. CONCLUSION: Poor practices and related socio-cultural perceptions are important risk factors in sustaining trachoma infection and transmission. Community members require health education for behavior change and awareness creation about surgery, MDA and its potential side effects for elimination of trachoma in Narok County, Kenya. TRIAL REGISTRATION: KEMRI SSC 2785. Registered 2 September 2014. PMID- 28883956 TI - Prevalence of Nasal colonization with Staphylococcus aureus in 4 cities in Peru. AB - BACKGROUND: Antimicrobial resistance (AMR) is a growing public health threat around the world and is not well characterized in the developing setting. Specifically, there is a lack of information regarding nasal colonization with S. aureus and methicillin-resistant Staphylococcus aureus (MRSA) in Latin America and Peru. METHODS: This is the report of the baseline findings of a prospective cohort study followed up over 1 year at four geographically and ecologically distinct Peruvian Air Force bases in order to determine S. aureus nasal colonization prevalence and risk factors. Additionally, all MRSA isolates underwent molecular analysis which included pulsed-field gel electrophoresis and determination of virulence and resistance genes. RESULTS: We enrolled 756 military personnel. Anterior nares colonization with Staphylococcus aureus was detected in 73 of 756 participants (9.7 %) and MRSA was detected in 2 of 756 (0.3 %). Colonization rates differed significantly (P = 0.02) between geographic enrollment sites: Talara-4.3 %, Iquitos-9.1 %, Arequipa-14.0 % and Lima-11.3 %. Risk factors for S. aureus colonization included being male and a reported history of respiratory disease. CONCLUSION: Overall, we found low prevalence of S. aureus and MRSA nasal colonization in this Peruvian military population. These findings contribute to the overall epidemiological understanding of S. aureus and MRSA in Latin America. The colonization rates which varied based on geographical location warrants further study. PMID- 28883958 TI - Hepatitis B vaccination for international travelers to Asia. AB - There is a wide range in prevalence of hepatitis B virus (HBV) infection and HBV immunization programs between different regions. Hepatitis B is a vaccine preventable disease yet is still endemic in the majority of countries in Asia. Despite the decreasing global prevalence of chronic HBV infection, there is still considerable risk of HBV infection among international travelers to high endemic areas. Numbers of international travelers are expected to increase year by year; thus immunization among this cohort is a crucial preventive measure. Among international travelers to Asia, HBV immunization should be recommended for those without previous HBV vaccination who plan to travel to countries with intermediate to high prevalence of HBV, and especially for those individuals at greater risk of HBV infection; including travelers engaging in casual sex, getting a tattoo or piercing, and those having dental surgery or other medical procedures. Longer duration of travel is also associated with a greater risk of HBV infection. Travelers from low HBV prevalence countries, especially those born before implementation of universal HBV vaccination, might benefit from HBV vaccination during long-term traveling to HBV intermediate to high endemic country. PMID- 28883959 TI - Update on non-vector transmission of dengue: relevant studies with Zika and other flaviviruses. AB - Human dengue virus infection without mosquito vector has been reported to occur as a result of mucocutaneous transmission, needlestick in patient care and laboratory accident, blood transfusion, bone marrow transplant, organ transplant, intrapartum and perinatal transmission, and breastfeeding. The emergence of Zika virus, another mosquito-borne flavivirus, has illustrated additional potential routes of non-vector transmission in humans. A recent study in another flavivirus, Japanese encephalitis virus, in pigs has also demonstrated non-vector transmission. We highlight some reports on dengue virus that have documented non vector transmission and that are relevant to the transmission of Zika virus and other flaviviruses. PMID- 28883960 TI - Prevalence of malaria and associated factors in Benna Tsemay district of pastoralist community, Southern Ethiopia. AB - BACKGROUND: Though the burden of malaria is declining, challenges in control continue globally, regionally and nationally as the transmission of malaria is dynamic and determinants differ by place and time, and across populations. The current level of knowledge on malaria prevalence and associated factors in specific communities, such as pastoralist communities of Ethiopia, is lacking. METHODS: A community based cross-sectional survey was conducted among pastoralist communities from December 2011 to January 2012. Background information and peripheral blood samples were collected from 461 randomly selected study participants. Multivariate regression analysis was done to explore the risk factors associated to malaria. RESULT: The prevalence of malaria among 461 examined study participants was 6.1 % (95 % CI = 4.2, 8.5). The infection rate with Plasmodium falciparum and Plasmodium vivax was 64.3 % (95 % CI = 45.5, 80.2) and 21.4 % (95 % CI = 19.8, 54.5), respectively, while mixed infection was 14.3 % (95 % CI = 4.7, 30.9). The infection rate was higher among lactating (22.2 %, 95 % CI =7.5, 45.3) and pregnant (17.6 %, 95 % CI = 4.7, 40.9) women compared with other community groups like infants (12 %). Mosquito net coverage of the study population was 90.1 % with an average of 1.8 per household. Traditional practices related to malaria prevention and treatment were not significantly associated with malaria infection (p > 0.05). Pregnancy (adjusted Odds Ratio [AOR]: 12.6, 95 % CI = 1.7, 94.7) and saving mosquito net for later use (AOR 9.6: 95 % CI = 2.2, 42.8) were independently associated with prevalent malaria infection. CONCLUSION: In spite of high coverage of mosquito nets, prevalence of malaria in this pastoralist community was high, affecting pregnant and lactating women at a higher rate. Pregnancy and saving mosquito nets for later use were identified as the associated risk factors. Health education on prevalence of malaria and knowledge on risk factors might be able to change the health behavior in this pastoralist community which consequently can decrease the malaria morbidity and mortality. TRIAL REGISTRATION: ISRCTN ISRCTN73824458, Registered 28 September 2014. PMID- 28883961 TI - Giardia lamblia infection increases risk of chronic gastrointestinal disorders. AB - BACKGROUND: Giardia lamblia is a common parasitic cause of infectious gastroenteritis in the United States and the world and may be linked to an increased risk of chronic gastrointestinal (GI) disorders. We sought to assess the risk of several chronic GI disorders following Giardia infection among active duty US military personnel. METHODS: This study was designed as a retrospective cohort study in which active duty military personnel with documented G. lamblia infection were assessed for the subsequent risk of developing a chronic GI disorder including irritable bowel syndrome (IBS), dyspepsia and gastroesophageal reflux disease (GERD). Post-giardia chronic GI disorder risk was compared to risk in uninfected personnel matched on several demographic characteristics and medical encounter information. Data were obtained from the Defense Medical Surveillance System and exposures (1998-2009) with outcomes identified based on documented medical encounters with specific medical billing codes. Modified Poisson regression was used to evaluate the relationship between G. lamblia infection and chronic GI disorders. RESULTS: A total of 80 Giardia cases were identified for an estimated incidence of 0.55 cases per 100,000 person-years. Cases were matched to 294 unexposed subjects. After adjusting for important covariates, there was an increased risk of IBS (relative risk: 2.1, p = 0.03) associated with antecedent Giardia infection. CONCLUSION: These data add to a growing body of literature and demonstrate an increased risk of IBS after infection with G. lamblia. PMID- 28883962 TI - Unrecognized human immunodeficiency virus infection and risk factors among elderly medical patients at the Korle Bu teaching hospital, Accra, Ghana. AB - BACKGROUND: The human immunodeficiency virus (HIV) infection usually infects persons in the reproductive age group (15-49 years), but elderly people are also susceptible. Many people in sub-Saharan Africa including Ghana believe that elderly people are not at risk for HIV. Despite numerous reports of the high prevalence of HIV infection among the elderly worldwide, there are no from Ghana. This work determined the sero-prevalence of HIV infection and risk factors for its transmission among 1,100 hospitalized elderly people at the Korle Bu Teaching Hospital (KBTH), Accra, Ghana. METHODS: Subjects voluntarily completed a risk factor questionnaire and provided a blood specimen for HIV testing. RESULTS: Of the study participants, 440 were male (mean age: 64 +/- 10.55 years), and 660 were female (mean age: 63 +/- 9.51 years). The overall HIV-1 sero-prevalence among the subjects was 4.18 % (n = 46). On multivariate analysis, there was no statistical significance between the socio-demographics or risk factors and the HIV status of the participants. CONCLUSION: The results suggest high prevalence of HIV-1 among hospitalized elderly people at KBTH, recommending the need to include the elderly in HIV/AIDS testing, prevention, and control programmes. TRIAL REGISTRATION: Trial registration number: MS-Et/M.9 - p4.10/2012-2013. Registered: 10th April, 2013. PMID- 28883963 TI - World Rabies Day - a decade of raising awareness. AB - World Rabies Day was set up in 2007 to raise global awareness about rabies, to provide information on how to prevent the disease in at-risk communities and support advocacy for increased efforts in rabies control. It is held annually on September 28th, with events, media outreach and other initiatives carried out by individuals, professionals, organisations and governments from the local to the international level. The Global Alliance for Rabies Control coordinates World Rabies Day, amplifying the campaign's reach through the provision of a central event platform and resources to support events across the world, the promotion of messages through key rabies stakeholders, and the implementation of specific activities to highlight particular issues. Over the last decade, more than 1,700 registered events have been held across the world and shared with others in the global rabies community. Events in canine rabies endemic countries, particularly in Africa and Asia, have increased over time. Beyond the individual events, World Rabies Day has gained the support of governments and international agencies that recognise its value in supporting existing rabies control initiatives and advocating for improvements. As the rabies landscape has changed, World Rabies Day remains a general day of awareness but has also become an integral part of national, regional and global rabies elimination strategies. The global adoption of 2030 as the goal for the elimination of rabies as a public health threat has led to even greater opportunities for World Rabies Day to make a sustainable impact on rabies, by bringing the attention of policy makers and donors to the ongoing situation and elimination efforts in rabies-endemic countries. PMID- 28883964 TI - Syphilis ascendant: a brief history and modern trends. AB - To provide a miniature review of recent literature surrounding a brief history of syphilis, to discuss the recently increasing incidence of syphilis, to discuss recent United State Preventative Service Task Force recommendations for syphilis screening, and to discuss congenital syphilis. The literature review was conducting using PubMed with the following search terms: syphilis, congenital syphilis, MSM and syphilis, prenatal syphilis, neurosyphilis, and other related terms. Treponema pallidum has been a constant, and unwanted, companion of humankind since antiquity. This sexually transmitted infection (STI) has the potential to affect virtually every rung of society-young and old, rich and poor, but it has a proclivity for the most vulnerable groups among us. Since record high rates of infection in the World War II era, tremendous progress has been made in effectively controlling the infection, and this has been largely mediated by the efficacy of penicillin on the causative spirochete. However, 2014 data from the Centers for Disease Control and Prevention demonstrated a sharp increase in the rate of new cases of syphilis, predominantly in men who have sex with men. Additionally, the numbers of newly diagnosed cases of congenital syphilis are on the rise as well. In effect, a burgeoning crisis has come to the doorstep of the medical community. We are faced with changing attitudes regarding sexual interactions. The authors believe that geolocation dating and sex applications for smart phones increase the availability of sexual encounters. Pre-exposure prophylaxis may be leading to more laissez-faire attitudes toward unprotected intercourse, and with increased opportunities for sexual encounters, co-infected states with other diseases may be altering the landscape of STIs. In 2016, in response to increasing rates of newly diagnosed syphilis, the United States Preventative Health Services Task Force reaffirmed the need for syphilis screening in at-risk populations. However, primary care physicians and advanced practice providers may not always be aware of which patients fall into that category. Due to the highly personal nature of discussing sexuality, sexual behavior may not be explored at all. Numerous challenges lie ahead of the infectious diseases, primary care, and public health communities in attempting to bend the curve of the ascendant rise in syphilis. To adequately combat this infection, sufficient funding will need to be provided to public health departments, adequate access to health care resources will be needed to allow for the necessary screening of patients, and primary care practitioners will need thoroughly engage with their patients to understand their sexual practices and to offer the necessary interventions. PMID- 28883966 TI - World Rabies Day campaign in the Philippines. AB - BACKGROUND: Rabies is a fatal disease, claiming the lives of around 59,000 people annually worldwide. It is considered a neglected and underreported disease leading to inadequate support from governments. Apart from dog vaccination and proper animal bite management, an integral part of a successful rabies control program is community education. The Philippine government conducts an extensive nationwide annual World Rabies Day (WRD) celebration as part of its community education. METHODS: Strong inter-sectoral collaboration at the national level is a key factor for the success of WRD, capitalizing on the partners' strengths to mobilize various sectors. Strategies include the National WRD Celebration and releasing national government memorandums. An invitation letter campaign was initiated, encouraging stakeholders to register their activities. Banners were given as an incentive for those who registered. Mass and social media were also utilized to promote WRD. RESULTS: Registered WRD events held in the Philippines rose from 10 events in 2012, to 37 events in 2013, to 66 events in 2014 and 76 events in 2015. The individual activities involved veterinary services and information, communication, and education (IEC) activities. Nine unique WRD IEC activities are highlighted in this paper. Promotion of WRD through social media was also utilized in recent years. More news items were published online than those printed in newspapers and aired on television. CONCLUSION: The campaign's success underlines the value of a national government-led program. The national rabies program sets the agenda for priority activities including the WRD campaign. Its capacity to allocate funds for the program also denotes stability which is beneficial for local program implementers. Different segments of society were tapped through various strategies. The campaign's flexibility allowed for a large range of activities and presented opportunities for expanding partnerships and integration with others interventions for its sustainability. With appropriate tools and government support, the extensive WRD campaign in the Philippines can be replicated in other countries. The strategies discussed prove that since different localities celebrate WRD in their own way, other countries can also organize activities adapted to their culture and contribute to the global campaign against rabies. PMID- 28883965 TI - Hepatic steatosis in HCV-infected persons in the direct-acting antiviral era. AB - Hepatitis C virus (HCV) infects 130-170 million people worldwide. Recently, direct-acting antivirals have been shown to eradicate HCV infection in 90-95 % of non-cirrhotic patients depending on genotype, treatment experience, and regimen used. Similar rates are achieved among compensated cirrhotics, although longer treatment duration and/or ribavirin may be required. HCV uses host lipid metabolism for its lifecycle and can cause hepatic steatosis and insulin resistance. Hepatic steatosis, defined as excessive triglyceride deposition in hepatocytes, affects approximately half of HCV-infected individuals. Genetic factors and co-morbidities can drive further steatosis, which in turn can instigate fibrosis and progression to cirrhosis and hepatocellular carcinoma. Polymorphisms in genes that modulate lipid deposition in hepatocytes such as patatin-like phospholipase domain-containing protein 3 (PNPLA3) and transmembrane six superfamily member 2 (TM6SF2) predispose people to steatosis. Metabolic syndrome, obesity, and insulin resistance are increasing worldwide and further contribute to hepatic steatosis, and alcohol has long been recognized as a cause of lipid deposition in the liver. HIV and antiretroviral drugs, but not HBV, may further drive hepatic steatosis. While many of these factors limit response to interferon-based regimens for treating HCV, responses to direct-acting antivirals appear not to be impaired. The effect of HCV eradication on hepatic steatosis and progression to fibrosis, cirrhosis, and hepatocellular carcinoma warrants further study in the era of direct-acting antivirals. PMID- 28883967 TI - Safety of antimalarial medications for use while scuba diving in malaria Endemic Regions. AB - BACKGROUND: Recreational diving occurs annually in areas of the world where malaria is endemic. The safety and efficacy of antimalarials for travelers in a hyperbaric environment is unknown. Of particular concern would be medications with adverse effects that could either mimic diving related illnesses such as barotrauma, decompression sickness (DCS) and gas toxicities, or increase the risk for such illnesses. METHODS: We conducted a review of PubMed and Cochrane databases to determine rates of neurologic adverse effects or other effects from antimalarials that may be a problem in the diving environment. RESULTS: One case report was found on diving and mefloquine. Multiple case reports and clinical trials were found describing neurologic adverse effects of the major chemoprophylactic medications atovaquone/proguanil, chloroquine, doxycycline, mefloquine, and primaquine. CONCLUSIONS: Of the available literature, atovaquone/proguanil and doxycycline are most likely the safest agents and should be preferred; atovaquone/proguanil is superior due to reduced rates of sunburn in the marine environment. Primaquine also appears to be safe, but has reduced efficacy against P. falciparum; mefloquine possesses the highest rate of neurologic side effects and therefore these agents should be limited to extreme cases of patients intolerant to other agents. Chloroquine appears unsafe in the hyperbaric environment and should be avoided. More studies are required to include database reviews of returned divers traveling to malaria endemic areas and randomized controlled trials in the hyperbaric environments. PMID- 28883968 TI - The role of pre-school teachers in the control of soil-transmitted helminthes in coastal region, Kenya. AB - BACKGROUND: Soil transmitted helminthes (STH) are significant health problems among school-age children. In Kenya's coastal region, the prevalence among pre school age children (PSAC) ranges from 27.8 to 66.7 %. Whereas some pre-schools are as far as 7 km from the nearest primary schools, the National School-Based Deworming Programme (NSBDP) requires the pre-school teachers to walk with the children to primary schools for deworming by trained primary school teachers. The long distances may contribute in making drug delivery ineffective and unsustainable. METHODS: To assess the pre-school teachers' knowledge, experiences and perceptions of STH and the NSBDP, a cross-sectional study using qualitative methods was conducted in four sub-counties of the Coast Region. Through purposive sampling, 41 pre-schools which are 2 or more kilometers away from a primary school were selected and in-depth interviews administered to the teachers. Separate in-depth interviews were administered to 34 community health extension workers, 40 opinion leaders and 38 primary school teachers all purposively selected to assess their perceptions of the role of pre-school teachers in the NSBDP. Data was audio recorded, transcribed, coded and analyzed manually by study themes. RESULTS: A third of the pre-school teachers were aware of signs of STHs and a half indicated that poor hygiene and sanitation practices are major causes. A majority of the pre-school teachers reported that health education and environmental sanitation are key control methods. Majority (39) had received information on NSBDP from various sources and all took part in community sensitization and in treating the pre-school children. A large majority of all study participants indicated that treating the children at pre-schools is ideal for increased coverage. Majority of the pre-school teachers perceived the NSBDP as important in improving the health status of the children. All study participants felt that the parents needed to be given adequate information on STHs and training the pre-school teachers to assist in community sensitization and drug administration would be useful. CONCLUSION: Pre-school teachers are a potential resource to the NSBDP that should be utilized to instill proper water and sanitation practices to the young children and assist in community sensitization. They should be empowered and allowed to administer treatment for STH control. County Governments, their current employers should find ways of engaging them in worm control efforts. TRIAL REGISTRATION: KEMRI SSC 2547, Registered 22 July 2013. PMID- 28883969 TI - Are you PEPped and PrEPped for travel? Risk mitigation of HIV infection for travelers. AB - The HIV pandemic persists globally and travelers are at risk for infection by the Human Immunodeficiency Virus (HIV). While HIV-focused guidelines delineate risk stratification and mitigation strategies for people in their home communities, travel issues are not addressed. In this review, direct and indirect evidence on HIV risk among travelers is explored. The burgeoning practice of employing pre exposure prophylaxis (PrEP) with anti-retroviral therapy in the non-travel setting is introduced, as well as the more established use of post-exposure prophylaxis (PEP). Challenges in applying these lessons to travelers are discussed, and a new guidelines process is scoped and recommended. PMID- 28883970 TI - The Pertussis resurgence: putting together the pieces of the puzzle. AB - Pertussis incidence is rising in almost every country where acellular pertussis (aP) vaccines have been introduced, and is occurring across all age groups from infancy to adulthood. The key question is why? While several known factors such as waning of immunity, detection bias due to more sensitive tests and higher awareness of the disease among practitioners, and evolutionary shifts among B. pertussis all likely contribute, collectively, these do not adequately explain the existing epidemiologic data, suggesting that additional factors also contribute. Key amongst these is recent data indicating that the immune responses induced by aP vaccines differ fundamentally from those induced by the whole cell pertussis (wP) vaccines, and do not lead to mucosal immunity. If so, it appears likely that differences in how the two categories of vaccines work, may be pivotal to our overall understanding of the pertussis resurgence. PMID- 28883972 TI - Molecular characterization and antibiotic resistance profiles of Salmonella isolated from fecal matter of domestic animals and animal products in Nairobi. AB - BACKGROUND: Salmonella has significant public health implications causing food borne and zoonotic diseases in humans. Treatment of infections due to Salmonella is becoming difficult due to emergence of drug resistant strains. There is therefore need to characterize the circulating non-typhoidal Salmonella (NTS) serovars in domestic animals and animal products in Kenya as well as determine their antibiotic resistance profiles. METHODS: A total of 740 fecal samples were collected from cows (n = 150), pigs (n = 182), chicken (n = 191) and chicken eggs (n = 217) from various markets and abattoirs in Nairobi. The prevalence of NTS serovars using culture techniques and biochemical tests, antimicrobial sensitivity testing using disc diffusion method of the commonly prescribed antibiotics and phylogenetic relationships using 16S rRNA were determined. RESULTS: The results showed that the overall prevalence of Salmonella was 3.8, 3.6, 5.9 and 2.6% for pigs, chicken, eggs and cows respectively. Two serovars were isolated S. Typhimurium (85%) and S. Enteritidis (15%) and these two serovars formed distinct clades on the phylogenetic tree. Forty percent of the isolates were resistant to one or more antibiotics. CONCLUSION: The isolation of Salmonella Typhimurium and Salmonella Enteritidis that are resistant to commonly used antibiotics from seemingly healthy animals and animal products poses a significant public health threat. This points to the need for regular surveillance to be carried out and the chain of transmission should be viewed to ascertain sources of contamination. PMID- 28883973 TI - Vectored immunoprophylaxis: an emerging adjunct to traditional vaccination. AB - The successful development of effective vaccines has been elusive for many of the world's most important infectious diseases. Additionally, much of the population, such as the aged or immunocompromised, are unable to mount an effective immunologic response for existing vaccines. Vectored Immunoprophylaxis (VIP) is a novel approach designed to address these challenges. Rather than utilizing an antigen to trigger a response from the host's immune system as is normally done with traditional vaccines, VIP genetically engineers the production of tailored antibodies from non-hematopoietic cells, bypassing the humoral immune system. Direct administration of genes encoding for neutralizing antibodies has proven to be effective in both preventing and treating several infectious diseases in animal models. While, a significant amount of work has focused on HIV, including an ongoing clinical trial, the approach has also been shown to be effective for malaria, dengue, hepatitis C, influenza, and more. In addition to presenting itself as a potentially efficient approach to solving long-standing vaccine challenges, the approach may be the best, if not only, method to vaccinate immunocompromised individuals. Many issues still need to be addressed, including which tissue(s) makes the most suitable platform, which vector(s) are most efficient at transducing the platform tissue used to secrete the antibodies, and what are the long-term effects of such a treatment. Here we provide a brief overview of this approach, and its potential application in treating some of the world's most intractable infectious diseases. PMID- 28883971 TI - Vaccination of HIV-infected pregnant women: implications for protection of their young infants. AB - BACKGROUND: The prevention of mother to child transmission of HIV has resulted in reduced burden of pediatric HIV-infection, but the prevalence of maternal HIV infection remains high in sub-Saharan African countries. HIV-exposed-uninfected infants have an increased risk of morbidity and mortality due to infectious diseases than HIV-unexposed infants, particularly during the first six months of life, which in part might be due to lower levels of pathogen-specific protective antibodies acquired transplacentally from their mothers. This could be mitigated by vaccinating pregnant women to boost antibody levels; although vaccine responses among HIV-infected pregnant women might differ compared to HIV uninfected women. We reviewed studies that compared natural and vaccine-induced antibody levels to different epitopes between HIV-infected and HIV-uninfected pregnant women. FINDINGS: Most studies reported lower baseline/pre-vaccination antibody levels in HIV-infected pregnant women, which may not be reversed by antiretroviral therapy during pregnancy. There were only few studies on vaccination of HIV-infected pregnant women, mainly on influenza virus and group B Streptococcus (GBS) vaccines. Immunogenicity studies on influenza vaccines indicated that HIV-infected pregnant women had lower vaccine induced hemagglutination inhibition antibody titers and a decreased likelihood of seroconversion compared to HIV-uninfected women; and while higher CD4+ T lymphocyte levels were associated with better immune responses to vaccination, HIV viral load was not associated with responses. Furthermore, infants born to influenza vaccinated HIV-infected pregnant women also had lower antibody levels and a lower proportion of HIV-exposed infants had titers above the putative correlate of protection compared to HIV-unexposed infants. The immunogenicity of a CRM197-conjugated trivalent GBS vaccine was also lower in HIV-infected pregnant women compared to HIV-uninfected women, irrespective of CD4+ T-lymphocyte counts. CONCLUSIONS: Poorer immunogenicity of vaccines reported in HIV-infected compared to HIV-uninfected pregnant women might compromise the potential benefits to their young infants. Alternate vaccination strategies, including vaccines with higher antigen concentration, adjuvanted vaccines or multiple doses schedules might be required in HIV-infected pregnant women to optimize antibody transferred to their fetuses. PMID- 28883974 TI - The salivary gland as a target for enhancing immunization response. AB - BACKGROUND: An organism's immune response to a vaccine is dependent on a number of factors, including the site of immunization. While muscle is the most common site for vaccine administration, other sites, including the salivary gland, are poised to confer stronger and broader immunoprotection. FINDINGS: Studies exploring the salivary gland as an immunization site have involved protein antigens, as well as live pathogens and DNA vaccines. While intraductal instillation of protein antigens into the salivary gland may result in a relatively transient increase in antibody production, DNA or attenuated pathogen vaccination appear to confer a lasting widespread mucosal immune response that includes robust salivary and enteric IgA, as well as high levels of circulating IgG. Furthermore, vaginal and lung antibodies are also seen. For enteric pathogens, a common class of pathogen encountered by travelers, this type of immune response provides for a level of redundant protection against foreign microbes with mucosal targets. CONCLUSION: The strength of immune response conferred by salivary gland vaccination is generally stronger than that seen in response to the same vaccine at a comparison site. For example, where other routes fail, immunization of the salivary gland has been shown to confer protection in lethal challenge models of infectious pathogens. A host of vaccines currently under development suffer from immunogenicity challenges, adding to the widespread interest and search for novel routes and adjuvants. With its capability to facilitate a strong and broad immune response, the salivary gland warrants consideration as an immunization site, especially for vaccines with immunogenicity challenges, as well as vaccines that would benefit from combined systemic and mucosal immunity. PMID- 28883975 TI - More harm than good? The questionable ethics of medical volunteering and international student placements. AB - It has been argued that much of international medical volunteering is done for the wrong reasons, in that local people serve as a means to meet volunteers' needs, or for the right reasons but ignorance and ill-preparedness harm the intended beneficiaries, often without volunteers' grasp of the damage caused. The literature on ethical concerns in medical volunteering has grown tremendously over the last years highlighting the need for appropriate guidelines. These same concerns, however, and an appreciation of the reasons why current aid paradigms are flawed, can serve as indicators on how to change existing practices to ensure a better outcome for those who are in need of help. Such paradigm change envisages medical assistance in the spirit of solidarity, social justice, equality, and collegial collaboration. PMID- 28883976 TI - Prospecting for an HIV vaccine. AB - Human immunodeficiency virus (HIV) sets several challenges for the development of a preventative HIV vaccine. Predictable, protective natural immunity against HIV does not occur and so unlike most other diseases for which vaccines exist, there are few guideposts from natural infection. Nonetheless, six vaccine efficacy trials have occurred. One in particular, the Thai trial called RV144, showed partial protective efficacy and potential ways ahead to a better vaccine approach. This coupled with other lessons from studies of acute infections as well as an increasingly complex knowledge of HIV-related vaccine immunology bring hope that a vaccine solution might be reached for this pervasive and deadly pandemic. PMID- 28883977 TI - Management of Plasmodium vivax risk and illness in travelers. AB - Malaria poses an exceptionally complex problem for providers of travel medicine services. Perceived high risk of exposure during travel typically prompts prescribing protective antimalarial drugs. Suppressive chemoprophylactic agents have dominated strategy for that practice for over 70 years. This broad class of therapeutic agents kills parasites after they emerge from the liver and attempt development in red blood cells. The dominance of suppressive chemoprophylaxis in travel medicine stems largely from the view of Plasmodium falciparum as the utmost threat to the patient - these drugs are poorly suited to preventing Plasmodium vivax and Plasmodium ovale due to inactivity against the latent liver stages of these species not produced by P. falciparum. Those hypnozoites awaken to cause multiple clinical attacks called relapses in the months following infection. Causal prophylactic agents kill parasites as they attempt development in hepatic cells. The only drug proven effective for causal prophylaxis against P. vivax is primaquine. That drug is not widely recommended for primary prophylaxis for travelers despite preventing both primary attacks of all the plasmodia and relapses of P. vivax. The long-held perception of P. vivax as causing a benign malaria in part explains the dominance of suppressive chemoprophylaxis strategies poorly suited to its prevention. Recent evidence from both travelers and patients hospitalized in endemic areas reveals P. vivax as a pernicious clinical threat capable of progression to severe disease syndromes associated with fatal outcomes. Effective prevention of clinical attacks of vivax malaria following exposure during travel requires primary causal prophylaxis or post-travel presumptive anti-relapse therapy following suppressive prophylaxis. PMID- 28883978 TI - Sanitation for all: the global opportunity to increase transgenerational health gains and better understand the link between NCDs and NTDs, a scoping review. AB - The global sanitation divide is narrowing. However, in many countries in Asia and Africa, the gap between rural and urban sanitation coverage is rather widening. Moreover, there is an increase in the burden of non-communicable diseases (NCDs), notwithstanding to the already high burden of neglected tropical diseases (NTDs). A scientific query is building on how the global 'sanitation for all' goal will address the dual burden of NTDs and NCDs, and help further understand the link between the two. This paper aims to discuss the link between i) sanitation and NTDs, and ii) sanitation and NCDs through a scoping review of the literature. PMID- 28883979 TI - Review: chronic and persistent diarrhea with a focus in the returning traveler. AB - BACKGROUND: Travelers' diarrhea is a common malady afflicting up to 50% of travelers after a 2-week travel period. An appreciable percentage of these cases will become persistent or chronic. We summarized the published literature reporting persistent/chronic diarrhea in travelers elucidating current understanding of disease incidence, etiology and regional variability. METHODS: We searched electronic databases (Medline, Embase, and Cochrane database of clinical trials) from 1990 to 2015 using the following terms: "chronic or persistent diarrh* and (returning) travel* or enteropathogen, GeoSentinel, and travel-associated infection. Included studies published in the English language on adult returning travelers (duration < 3-months) reporting denominator data. Point estimates and standard 95% confidence intervals were calculated for incidence using a random-effects model. Study incidence heterogeneity rates were assessed using x2 heterogeneity statistics, graphically represented with Forest plots. RESULTS: We identified 19 studies meeting the inclusion criteria (all published after 1999). 18 studies reported upon the incidence of persistent/chronic diarrhea as a syndromic diagnosis in returning travelers; one study reported adequate denominator data from which to assess pathogen specific etiology. Giardiasis comprise an appreicaible percentage of infectious mediated persistent/chronic diarrhea in returning travelers. The overall estimate of persistent/chronic diarrhea incidence was 6% (0.05-0.07) in 321,454, travelers; with significant heterogeniety observed across regions. The total number of regional travelers, and point estimates for incidence (95% CI) for Latin American, African, and Asian travelers were [15816 (0.09 [0.07-0.11]), 42290 (0.06 [0.05-0.07]), and 27433 (0.07 [0.06-0.09])] respectively. We identified lower published rates of chronic diarrhea from Sub-Saharan Africa relative to [North Africa, South Central Asia, and Central America]. Persistent/chronic diarrhea ranked fourth as a syndromic diagnosis in all regions. CONCLUSIONS: Persistent/Chronic diarrhea is a leading syndromic diagnosis in returning travelers across all regions. The 6% incidence [proportionate morbidity (PM) of 60] observed in over >300,000 global travelers is comparable to prior estimates. We identified lower published rates of chronic diarrhea from Sub-Saharan Africa relative to [North Africa, South Central Asia, and Central America]. Giardiasis comprises an appreciabile percentatge of travel-associated infectious mediated persistent/chronic diarrhea. There's a dearth of published data characterizing the incidence of specific enteropathogenic etiologies for persistent/chronic diarrhea in returning travelers. PMID- 28883980 TI - Guidelines for the prevention of travel-associated illness in older adults. AB - International travel to the developing world is becoming more common in elderly patients (defined here as individuals greater than 65 years old). When providing pre-travel counseling, providers must appreciate the changing physiology, comorbidities, immunity and pharmacokinetics associated with the aging process to prepare elderly patients for the stressors of international travel. These guidelines present an evidence-based approach to pre-travel counseling, immunization, and pharmacology concerns unique to elderly patients seeking care in a travel clinic setting. PMID- 28883981 TI - Immunization of mice with soluble lysate of interferon gamma expressing Plasmodium berghei ANKA induces high IFN-gamma production. AB - BACKGROUND: Efforts in search of lasting malaria vaccine have led to the development of transgenic rodent malaria parasites. As a result, wild type Plasmodium berghei ANKA (WTPbA) has recently been transformed to express mouse interferon gamma (mIFN-gamma). The immunomodulatory effect of this transgenic parasite on WTPbA infection has been demonstrated. However, the protective immune responses after repeated immunization with soluble lysate of this parasite has not been investigated. METHODS: Soluble lysate of transgenic PbA (TPbA) was prepared and concentration of IFN-gamma in lysate determined by ELISA. Four groups of 20 BALB/c mice each (two treatment groups and two control groups) were setup. Treatment Groups 1 and 2 were primed (at day 0) with lysate of TPbA containing 75 pg/ml IFN-gamma and live TPbA parasites respectively. Infection in Group 2 mice was cured with CoartemTM at 450 mg/kg for 3 days. At day 14 post priming, both groups were boosted twice at day 14 and day 28 with lysate of TPbA containing 75 pg/ml IFN-gamma and 35 pg/ml IFN-gamma respectively. Blood and spleen samples were collected at day 0, day 14, day 21 and day 28 for preparation of serum and cell cultures respectively. Serum IgG and cytokines (TNF-alpha and IFN-gamma) levels in culture supernatant were measred by ELISA.Survivorship and parasitemia were daily monitored for 21 days. Data were statistically analyzed using ANOVA student's t test. A p value of <0.05 was considered significant. RESULTS: At day 28 post-priming, IFN-gamma production in Group 1 was tenfold higher than in RBC control group (p = 0.070) There was significant difference in IFN-gamma production among the groups at day 28 (p < 0.0001). TNF-alpha production in Group 1 mice increased fourfold in Group 2 mice from day 14 to day 28 post-immunization (p = 0.0005). There was no significant effect on serum IgG production. Mice in treatment groups survived 5 to 4 days longer compared to non immunized group. CONCLUSION: The study has demonstrated that, repeated immunization with soluble lysate of TPbA induces Th 1 response leading to increased IFN-gamma and TNF-gamma production. PMID- 28883982 TI - Assessment of the agreement between the Framingham and DAD risk equations for estimating cardiovascular risk in adult Africans living with HIV infection: a cross-sectional study. AB - BACKGROUND: The Absolute cardiovascular disease (CVD) risk evaluation using multivariable CVD risk models is increasingly advocated in people with HIV, in whom existing models remain largely untested. We assessed the agreement between the general population derived Framingham CVD risk equation and the HIV-specific Data collection on Adverse effects of anti-HIV Drugs (DAD) CVD risk equation in HIV-infected adult Cameroonians. METHODS: This cross-sectional study involved 452 HIV infected adults recruited at the HIV day-care unit of the Yaounde Central Hospital, Cameroon. The 5-year projected CVD risk was estimated for each participant using the DAD and Framingham CVD risk equations. Agreement between estimates from these equations was assessed using the spearman correlation and Cohen's kappa coefficient. RESULTS: The mean age of participants (80% females) was 44.4 +/- 9.8 years. Most participants (88.5%) were on antiretroviral treatment with 93.3% of them receiving first-line regimen. The most frequent cardiovascular risk factors were abdominal obesity (43.1%) and dyslipidemia (33.8%). The median estimated 5-year CVD risk was 0.6% (25th-75th percentiles: 0.3-1.3) using the DAD equation and 0.7% (0.2-2.0) with the Framingham equation. The Spearman correlation between the two estimates was 0.93 (p < 0.001). The kappa statistic was 0.61 (95% confident interval: 0.54-0.67) for the agreement between the two equations in classifying participants across risk categories defined as low, moderate, high and very high. CONCLUSION: Most participants had a low-to-moderate estimated CVD risk, with acceptable level of agreement between the general and HIV-specific equations in ranking CVD risk. PMID- 28883983 TI - Antibiotic resistance in Campylobacter and other diarrheal pathogens isolated from US military personnel deployed to Thailand in 2002-2004: a case-control study. AB - BACKGROUND: Campylobacter continues to be an important cause of diarrheal disease worldwide and a leading cause in Southeast Asia. Studies of US soldiers and marines deployed to Thailand for a 2 to 3 week field exercise provide a unique population in which to study traveler's diarrhea. METHODS: A case-control study of 217 deployed military personnel was conducted from 2002 through 2004. Of these, 155 subjects who presented to a field medical unit with acute diarrhea were enrolled as cases. These subjects referred an additional 62 diarrhea-free colleagues who served as controls. Frequencies of isolation of Campylobacter spp. and other enteric pathogens were compared in cases and controls, and antibiotic resistance of isolates was described. RESULTS: Of the 155 subjects with diarrhea, Campylobacter spp. was the most commonly identified pathogen, found in 54 (35%) of the subjects, followed by non-typhoidal Salmonella species found in 36 (23%) subjects. Of the 57 separate C. jejuni and C. coli isolates from these individuals, 51 (89%) were resistant to ciprofloxacin by the disc diffusion method. Nearly one-third of the Campylobacter species were resistant to ampicillin and trimethoprim-sulfamethoxazole. Resistance to azithromycin remained low at 2% (n = 1). CONCLUSIONS: The significant morbidity and marked fluoroquinolone resistance associated with Campylobacter infections in Thailand are important considerations for clinicians providing counseling on appropriate antibacterial regimens for civilian and military travelers. PMID- 28883984 TI - The changing epidemiology of Japanese encephalitis and New data: the implications for New recommendations for Japanese encephalitis vaccine. AB - The epidemiology of Japanese Encephalitis and risk to the traveler has changed and continues to evolve. The spread of Japanese Encephalitis virus into new environments, changes in agricultural practice and animal vectors, climate change, peri-urban growth, changes in international travel to Asia, personal risk factors, mosquito vector free transmission, interactions with other flaviviruses and better information on infections without encephalitis and other factors make Japanese Encephalitis an underappreciated risk. There has also been a change in the incidence of Japanese Encephalitis cases that questions the current travel duration and geographic based recommendations. A safe, effective vaccine (Ixiaro) that may be administered in a short course regimen is now available in the United States without the risks of the previous vaccine. However, the vaccine is significantly underutilized. These changes in the epidemiology and new data on the risks of the Japanese Encephalitis virus require a review of the practice guidelines and expert recommendations that do not reflect the current state of knowledge. PMID- 28883985 TI - Local stakeholders' perceptions of community sensitization for school-based deworming programme in Kenya. AB - BACKGROUND: In Kenya, the National School-Based Deworming Programme (NSBDP) for soil-transmitted helminthes and schistosomiasis in prioritized areas has been going on since the year 2012. By the year 2013 over 6 million School Age Children (SAC) had been treated. A community sensitization supplement containing key messages and answers to frequently asked questions was developed as a guiding tool. Awareness creation methods used include county sensitization meetings, stakeholder forums, town criers and posters. To assess the local stakeholders' perceptions of community sensitization for programme implementation, a qualitative cross-sectional survey was conducted in four-sub-counties of coastal region. METHODS: In-depth interviews (IDIs) were administered to 40 purposively selected opinion leaders so as to explore their perceptions of awareness creation sources, adequacy of information given, length of period of awareness creation and period between which information is given and drugs are administered. Separate IDIs were administered to pre-school teachers (41), community health extension workers (34) and primary school teachers (38). To elicit more information, 20 focus group discussions (FGDs) categorized by gender and age were conducted among parents of school-age children. Data was audio recorded, transcribed, coded and analyzed manually by study themes. RESULTS: The most commonly reported source of information was school pupils. Due to low literacy levels, use of posters was regarded as ineffective and religious institutions, town criers and vernacular radio stations considered more effective. The information given during programme implementation was considered inadequate and use of complementary methods to reach all targeted children including the non enrolled, and relay adequate information reported as important. Use of school and chief's meetings with health personnel being present was mentioned as a useful method that would allow for interaction with participants indicating that they did not understand why adults were not being treated. Repeated awareness creation before deworming day to serve as a reminder and to reach those missing initial messages was also mentioned as important. Furthermore, the awareness creation period needed to be extended as 85% of the participants indicated that they learnt of deworming a day before it took place or after their children had received the drugs. CONCLUSION: Awareness creation is a key factor in the success of NSBDP implementation. For programme sustainability, preferences of local stakeholders need to be considered as control of worms can only be achieved through an integrated approach of deworming, health education and use of safe water and sanitation facilities which require collaboration with local stakeholders. PMID- 28883986 TI - Redox-active conducting polymers modulate Salmonella biofilm formation by controlling availability of electron acceptors. AB - Biofouling is a major problem caused by bacteria colonizing abiotic surfaces, such as medical devices. Biofilms are formed as the bacterial metabolism adapts to an attached growth state. We studied whether bacterial metabolism, hence biofilm formation, can be modulated in electrochemically active surfaces using the conducting conjugated polymer poly(3,4-ethylenedioxythiophene) (PEDOT). We fabricated composites of PEDOT doped with either heparin, dodecyl benzene sulfonate or chloride, and identified the fabrication parameters so that the electrochemical redox state is the main distinct factor influencing biofilm growth. PEDOT surfaces fitted into a custom-designed culturing device allowed for redox switching in Salmonella cultures, leading to oxidized or reduced electrodes. Similarly large biofilm growth was found on the oxidized anodes and on conventional polyester. In contrast, biofilm was significantly decreased (52 58%) on the reduced cathodes. Quantification of electrochromism in unswitched conducting polymer surfaces revealed a bacteria-driven electrochemical reduction of PEDOT. As a result, unswitched PEDOT acquired an analogous electrochemical state to the externally reduced cathode, explaining the similarly decreased biofilm growth on reduced cathodes and unswitched surfaces. Collectively, our findings reveal two opposing effects affecting biofilm formation. While the oxidized PEDOT anode constitutes a renewable electron sink that promotes biofilm growth, reduction of PEDOT by a power source or by bacteria largely suppresses biofilm formation. Modulating bacterial metabolism using the redox state of electroactive surfaces constitutes an unexplored method with applications spanning from antifouling coatings and microbial fuel cells to the study of the role of bacterial respiration during infection. PMID- 28883988 TI - The current state of genetic counseling and newborn screening: an interview with Megan Tucker. AB - Megan Tucker talks to Francesca Lake, Managing Editor: A certified genetic counselor for over 10 years, Megan is currently the director of the Indiana State University Genetic Counseling Graduate Program and the Genetic Counseling Clinic at Union Hospital (Terre Haute, IN, USA). She began her career split between the Center for Prenatal Diagnosis and the Medical Genetics and Neurodevelopmental Center at St Vincent Hospital (Indianapolis, IN, USA). During this time she was instrumental in both the development of the statewide Perinatal Loss Evaluation Program and a hospital protocol to ensure collection of cord blood to allow time to effectively genetically evaluate babies. Her current clinical focus is in cancer and psychiatric genetic counseling. PMID- 28883987 TI - Obesity and kidney disease: hidden consequences of the epidemic. AB - Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease and also for chronic kidney disease. A high BMI is one of the strongest risk factors for new-onset chronic kidney disease. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing chronic kidney disease in the long-term. The incidence of obesity related glomerulopathy has increased tenfold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that make preventive behaviors an affordable option. PMID- 28883989 TI - Osteoinductive effects of preoperative dexamethasone in human dental pulp stem cells primary culture. AB - AIM: The use of dexamethasone (DEX) in mesenchymal cell culture induces osteoblastic differentiation and, consequently, formation of mineralized tissues. Tissue engineering proposes the development of therapeutic strategies aimed at structural and functional regeneration of biological tissues. In this sense, cell characterization in vitro is critical to ensure the development of such techniques. Our objective was to evaluate the osteoinductive effect of DEX administered as a preoperative medication in primary cell culture of human dental pulp stem cell. METHODOLOGY: Cells from the third molar pulp were divided into two experimental groups, each with two preoperative medication protocols used in dental practice and differentiated by the intake of DEX in one of them. The assessment of proliferation, differentiation and viability through trypan blue, methylthiazol tetrazolium, and von Kossa and alizarin red assays, respectively, were held within fixed intervals: 7, 14, 21 and 28 days. CONCLUSION: This study has shown that DEX may influence in vitro human dental pulp stem cell behavior. PMID- 28883991 TI - What's next for genomics and prion diseases? PMID- 28883990 TI - The development of T cells from stem cells in mice and humans. AB - T cells develop from hematopoietic stem cells in the specialized microenvironment of the thymus. The main transcriptional players of T-cell differentiation such as Notch, Tcf-1, Gata3 and Bcl11b have been identified, but their role and regulation are not yet completely understood. In humans, functional experiments on T-cell development have traditionally been rather difficult to perform, but novel in vitro culture systems and in vivo xenograft models have allowed detailed studies on human T-cell development. Recent work has allowed the use of human severe combined immunodeficiency stem cells to unravel developmental checkpoints for human thymocyte development. PMID- 28883993 TI - Further insight into AE37 peptide vaccination in prostate cancer. PMID- 28883994 TI - Lipidomics of human umbilical cord serum: identification of unique sterol sulfates. AB - AIM: There are currently limited lipidomics data for human umbilical cord blood. Therefore, the lipidomes of cord sera from six newborns and sera from six nonpregnant females were compared. MATERIALS & METHODS: Sera lipidomics analyses were conducted using a high-resolution mass spectrometry analytical platform. RESULTS: Cord serum contained a diverse array of glycerophospholipids, albeit generally at lower concentrations than monitored in adult serum. The unexpected observations were that cord serum contained several neurosteroid sulfates and bile acid sulfates that were not detectable in adult serum. CONCLUSION: Our data are the first to demonstrate that cord serum contains bile acid sulfates that are synthesized early in the hydroxylase, neutral and acidic pathways of primary bile acid biosynthesis and support previous publications of cord blood perfluoralkyl toxins in newborns. PMID- 28883995 TI - Strategies to enhance graphic and results interpretation of a regression-based approach for method comparison studies. AB - To improve the effectiveness of a previous regression-based approach for the assessment of the agreement between different analytical methods, two modifications/integrations to the original scheme by means of log10 transformation of data and implementation of inherent combined imprecision are presented in this study. PMID- 28883992 TI - Integrating the glioblastoma microenvironment into engineered experimental models. AB - Glioblastoma (GBM) is the most lethal cancer originating in the brain. Its high mortality rate has been attributed to therapeutic resistance and rapid, diffuse invasion - both of which are strongly influenced by the unique microenvironment. Thus, there is a need to develop new models that mimic individual microenvironmental features and are able to provide clinically relevant data. Current understanding of the effects of the microenvironment on GBM progression, established experimental models of GBM and recent developments using bioengineered microenvironments as ex vivo experimental platforms that mimic the biochemical and physical properties of GBM tumors are discussed. PMID- 28883996 TI - Immunotherapy for penile cancer. PMID- 28883997 TI - Evaluation of T1/T2 ratios in a pilot study as a potential biomarker of biopsy: proven benign and malignant breast lesions in correlation with histopathological disease stage. AB - AIM: Early breast cancer detection is important for intervention and prognosis. Advances in treatment and outcome require diagnostic tools with highly positive predictive value. PURPOSE: To study the potential role of quantitative MRI (qMRI) using T1/T2 ratios to differentiate benign from malignant breast lesions. METHODS: A cross-sectional study of 69 women with 69 known or suspicious breast lesions were scanned with mixed-turbo spin echo pulse sequence. Patients were grouped according to histopathological assessment of disease stage: untreated malignant tumor, treated malignancy and benign disease. RESULTS & DISCUSSION: Elevated T1/T2 means were observed for biopsy-proven malignant lesions and for malignant lesions treated prior to qMRI with chemotherapy and/or radiation, as compared with benign lesions. The qMRI-obtained T1/T2 ratios correlated with histopathology. Analysis revealed correlation between elevated T1/T2 ratio and disease stage. This could provide valuable complementary information on tissue properties as an additional diagnostic tool. PMID- 28883998 TI - Endoplasmic reticulum stress and unfolded protein response in infection by intracellular parasites. AB - Perturbations of the physiological status of the endoplasmic reticulum (ER) trigger a specific response known as the ER stress response or unfolded protein response (UPR). In mammalian cells, the UPR is mediated by three ER transmembrane proteins (IRE1, PERK and ATF6) which activate three signaling cascades to restore ER homeostasis. In recent years, a cross-talk between UPR, inflammatory and microbial sensing pathways has been elucidated. Pathogen infection can lead to UPR activation; moreover, several pathogens subvert the UPR to promote their survival and replication. While the UPR in viral and bacterial infection has been characterized, little is known about the role of UPR in intracellular parasite infection. Here, we review recent findings on UPR induction/modulation by intracellular parasites in host cells. PMID- 28884000 TI - Catabolic and anabolic faces of insulin resistance and their disorders: a new insight into circadian control of metabolic disorders leading to diabetes. AB - Maintenance of glucose homeostasis during circadian behavioral cycles is critical. The processes controlling the switch between predominant lipolysis/fatty oxidation during fasting and predominant lipid storage/glucose oxidation following feeding are determined principally by insulin. Chronic elevated threshold of insulin resistance (IR) is a key pathological feature of obesity, Type 2 diabetes, sepsis and cancer cachexia; however, a temporal reduced threshold of IR is widely met in fasting/hibernation, pregnancy, antibacterial immunity, exercise and stress. Paradoxically, some of these cases are associated with catabolic metabolism, whereas others are related to anabolic pathways. This article considers the possible causes of circadian disorders in glucose and lipid metabolism that act as a driving force for obesity-promoted development of Type 2 diabetes. This is intended to provide improved insight into the pathogenesis of chronic circadian disorders that increase the risk of diabetes, and consider new targets for its metabolic and drug correction. PMID- 28883999 TI - Galactofuranose antigens, a target for diagnosis of fungal infections in humans. AB - The use of biomarkers for the detection of fungal infections is of interest to complement histopathological and culture methods. Since the production of antibodies in immunocompromised patients is scarce, detection of a specific antigen could be effective for early diagnosis. D-Galactofuranose (Galf) is the antigenic epitope in glycoconjugates of several pathogenic fungi. Since Galf is not biosynthesized by mammals, it is an attractive candidate for diagnosis of infection. A monoclonal antibody that recognizes Galf is commercialized for detection of aspergillosis. The linkage of Galf in the natural glycans and the chemical structures of the synthesized Galf-containing oligosaccharides are described in this paper. The oligosaccharides could be used for the synthesis of artificial carbohydrate-based antigens, not enough exploited for diagnosis. PMID- 28884002 TI - Biologically synthesized metal nanoparticles: recent advancement and future perspectives in cancer theranostics. PMID- 28884001 TI - 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid attenuates heptatocellular carcinoma in rats with NMR-based metabolic perturbations. AB - AIM: 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (M1) was synthesized and evaluated for in-vivo antiproliferative action in diethylnitrosamine-induced hepatocarcinogenic rats. MATERIALS & METHODS: The antiproliferative effect of M1 was assessed by various biochemical parameters, histopathology of liver and HPLC analysis. Proton nuclear magnetic resonance based serum metabolic study was implemented on rat sera to explore the effects of M1 on hepatocellular carcinoma-induced metabolic alterations. RESULTS: M1 showed protective action on liver and restored the arrangement of liver tissues in normal proportion. HPLC analysis displayed a good plasma drug concentration after its oral administration. Score plots of partial least squares discriminate analysis models exhibited that M1 therapy ameliorated hepatocellular carcinoma induced metabolic alterations which signified its antiproliferative potential. CONCLUSION: M1 manifested notable antiproliferative profile, and warrants further investigation for future anticancer therapy. PMID- 28884004 TI - Human epigenetics and microbiome: the potential for a revolution in both research areas by integrative studies. PMID- 28884003 TI - The transformation of the nuclear nanoarchitecture in human field carcinogenesis. AB - Morphological alterations of the nuclear texture are a hallmark of carcinogenesis. At later stages of disease, these changes are well characterized and detectable by light microscopy. Evidence suggests that similar albeit nanoscopic alterations develop at the predysplastic stages of carcinogenesis. Using the novel optical technique partial wave spectroscopic microscopy, we identified profound changes in the nanoscale chromatin topology in microscopically normal tissue as a common event in the field carcinogenesis of many cancers. In particular, higher-order chromatin structure at supranucleosomal length scales (20-200 nm) becomes exceedingly heterogeneous, a measure we quantify using the disorder strength (Ld ) of the spatial arrangement of chromatin density. Here, we review partial wave spectroscopic nanocytology clinical studies and the technology's promise as an early cancer screening technology. PMID- 28884005 TI - Gynecological cancers: an alternative approach to healing. AB - Grief and hope are two conflicting emotions that a patient recently diagnosed with cancer has to master. The real challenge for gynecologic oncologists is how to reach out. Conventional wisdom states that offering patients focus and belief when combating cancer in their lives allows them to embrace hope with greater confidence, which minimizes their grief. Three pictorial models are presented: '4 cusp approach' model used at the initial consultation; 'tapestry of bereavement or landscape of grief' model at the postsurgery consultation; and 'Venn-diagram' model at any time during patient management. We have applied these models in our practice and believe that they can act as a fulcrum for the patient, the family and healthcare team around which therapy should be centered. PMID- 28884006 TI - Engineering challenges in microphysiological systems. PMID- 28884007 TI - Combined-modality hypofractionated radiotherapy for elderly patients with glioblastoma: setting a new standard. PMID- 28884009 TI - Identifying relationships between unrelated pharmaceutical target proteins on the basis of shared active compounds. AB - AIM: Computational exploration of small-molecule-based relationships between target proteins from different families. MATERIALS & METHODS: Target annotations of drugs and other bioactive compounds were systematically analyzed on the basis of high-confidence activity data. RESULTS: A total of 286 novel chemical links were established between distantly related or unrelated target proteins. These relationships involved a total of 1859 bioactive compounds including 147 drugs and 141 targets. CONCLUSION: Computational analysis of large amounts of compounds and activity data has revealed unexpected relationships between diverse target proteins on the basis of compounds they share. These relationships are relevant for drug discovery efforts. Target pairs that we have identified and associated compound information are made freely available. PMID- 28884008 TI - Efficient method to create integration-free, virus-free, Myc and Lin28-free human induced pluripotent stem cells from adherent cells. AB - AIM: Nonviral induced pluripotent stem cell (IPSC) reprogramming is not efficient without the oncogenes, Myc and Lin28. We describe a robust Myc and Lin28-free IPSC reprogramming approach using reprogramming molecules. METHODS: IPSC colony formation was compared in the presence and absence of Myc and Lin28 by the mixture of reprogramming molecules and episomal vectors. RESULTS: While more colonies were observed in cultures transfected with the aforementioned oncogenes, the Myc and Lin28-free method achieved the same reprogramming efficiency as reports that used these oncogenes. Further, all colonies were fully reprogrammed based on expression of SSEA4, even in the absence of Myc and Lin28. CONCLUSION: This approach satisfies an important regulatory pathway for developing IPSC cell therapies with lower clinical risk. PMID- 28884010 TI - Mass spectrometry in medicine: a technology for the future? PMID- 28884011 TI - Adaptation to macrophage killing by Talaromyces marneffei. AB - Talaromyces (Penicillium) marneffei is an important opportunistic fungal pathogen. It causes disseminated infection in immunocompromised patients especially in Southeast Asian countries. The pathogenicity of T. marneffei depends on the ability of the fungus to survive the killing process and replicate inside the macrophage. Major stresses inside the phagosome of macrophages are heat, oxidative substances and nutrient deprivation. The coping strategies of this pathogen with these stresses are under investigation. This paper summarizes factors relating to the stress responses that contribute to the intracellular survival of T. marneffei. These include molecules in the MAP signal transduction cascade, heat shock proteins, antioxidant enzymes and enzymes responsible in nutrient retrieval. There is speculation that the ability of T. marneffei to withstand these defenses plays an important role in its pathogenicity. PMID- 28884012 TI - Performance of seven criteria to assess CA125 increments among ovarian cancer patients monitored during first-line chemotherapy and the post-therapy follow-up period. AB - AIM: To investigate seven CA125 criteria to monitor progressive ovarian cancer among patients with stage IC-IV disease. MATERIALS & METHODS: Four criteria were used to asses CA125 increments starting from concentrations >=35 U/ml and three criteria to asses increments starting from concentrations <35 U/ml. RESULTS: A total of 231 patients were allocated to CA125 monitoring. The performances of the CA125 criteria were similar with sensitivities of 30-55%, negative predictive values of 28-46%, positive predictive values of 90-100% and median lead times of 26-87 days. CONCLUSION: The criteria showed low sensitivity and inability to exclude progressive ovarian cancer. The study suggests that CA125 information cannot stand alone but should be considered used in conjunction with other investigative procedures. PMID- 28884014 TI - Expanding the investigation of meaningful effects in physiology research. PMID- 28884013 TI - Reconceptualizing cancer immunotherapy based on plant production systems. AB - Plants can be used as inexpensive and facile production platforms for vaccines and other biopharmaceuticals. More recently, plant-based biologics have expanded to include cancer immunotherapy agents. The following review describes the current state of the art for plant-derived strategies to prevent or reduce cancers. The review discusses avenues taken to prevent infection by oncogenic viruses, solid tumors and lymphomas. Strategies including cancer vaccines, monoclonal antibodies and virus nanoparticles are described, and examples are provided. The review ends with a discussion of the implications of plant-based cancer immunotherapy for developing countries. PMID- 28884015 TI - Point-of-care devices: the next frontier in personalized chemotherapy. PMID- 28884016 TI - Analytical validation of a 12-gene molecular test for the prediction of distant recurrence in breast cancer. AB - AIM: To validate the analytical performance of a 12-gene molecular assay that predicts distant recurrence for early-stage ER+/HER2- invasive breast cancer as run within a central reference laboratory. MATERIALS & METHODS: Formalin-fixed paraffin-embedded breast resections were evaluated by quantitative reverse transcription polymerase chain reaction for the expression of eight target genes, three housekeeper genes and one control gene to assess for DNA contamination. RESULTS: The assay results were highly correlated with a validated reference laboratory. The assay had a broad linear range for input RNA, with similar amplicon efficiencies for target and housekeeper genes. The assay test was highly reproducible, with comparable inter- and intrabatch precision to the reference laboratory. CONCLUSION: These studies demonstrate that the 12-gene molecular assay is highly robust and accurate. PMID- 28884017 TI - Development and validation of an impedance biosensor for point-of-care detection of vascular cell adhesion molecule-1 toward lupus diagnostics. AB - AIM: Systemic lupus erythematosus is an autoimmune disease that requires chronic monitoring. In this study, we demonstrate a proof-of-concept study of a highly attractive noninvasive strategy for monitoring systemic lupus erythematosus through biomarker quantification. RESULTS: This sensor technology requires 50 MUl of urine to detect and quantify vascular cell adhesion molecule-1 in 15 min. The sensor used nonfaradaic detection to demonstrate performance with and without detection antibody. Binding of immunoassay and target biomarkers were quantified with an impedance electrical immunoassay and correlated with an equivalent circuit. CONCLUSION: The novel sensor technology demonstrates detection in the range of 8 fg/ml to 800 pg/ml and comparative analysis with ELISA platforms was performed for 12 patient urine samples. PMID- 28884018 TI - PP2A-B' holoenzyme substrate recognition, regulation and role in cytokinesis. AB - Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase; it forms diverse heterotrimeric holoenzymes that counteract kinase actions. Using a peptidome that tiles the disordered regions of the human proteome, we identified proteins containing [LMFI]xx[ILV]xEx motifs that serve as interaction sites for B'-family PP2A regulatory subunits and holoenzymes. The B'-binding motifs have important roles in substrate recognition and in competitive inhibition of substrate binding. With more than 100 novel ligands identified, we confirmed that the recently identified LxxIxEx B'alpha-binding motifs serve as common binding sites for B' subunits with minor variations, and that S/T phosphorylation or D/E residues at positions 2, 7, 8 and 9 of the motifs reinforce interactions. Hundreds of proteins in the human proteome harbor intrinsic or phosphorylation responsive B'-interaction motifs, and localize at distinct cellular organelles, such as midbody, predicting kinase-facilitated recruitment of PP2A-B' holoenzymes for tight spatiotemporal control of phosphorylation at mitosis and cytokinesis. Moroever, Polo-like kinase 1-mediated phosphorylation of Cyk4/RACGAP1, a centralspindlin component at the midbody, facilitates binding of both RhoA guanine nucleotide exchange factor (epithelial cell transforming sequence 2 (Ect2)) and PP2A-B' that in turn dephosphorylates Cyk4 and disrupts Ect2 binding. This feedback signaling loop precisely controls RhoA activation and specifies a restricted region for cleavage furrow ingression. Our results provide a framework for further investigation of diverse signaling circuits formed by PP2A-B' holoenzymes in various cellular processes. PMID- 28884019 TI - Microtubule-binding protein FOR20 promotes microtubule depolymerization and cell migration. AB - Microtubules are highly dynamic filaments assembled from alphabeta-tubulin heterodimers and play important roles in many cellular processes, including cell division and migration. Microtubule dynamics is tightly regulated by microtubule associated proteins (MAPs) that function by binding to microtubules or free tubulin dimers. Here, we report that FOR20 (FOP-related protein of 20 kDa), a conserved protein critical for ciliogenesis and cell cycle progression, is a previously uncharacterized MAP that facilitates microtubule depolymerization and promotes cell migration. FOR20 not only directly binds to microtubules but also regulates microtubule dynamics in vitro by decreasing the microtubule growth rate and increasing the depolymerization rate and catastrophe frequency. In the in vitro microtubule dynamics assays, FOR20 appears to preferentially interact with free tubulin dimers over microtubules. Depletion of FOR20 inhibits microtubule depolymerization and promotes microtubule regrowth after the nocodazole treatment in HeLa cells. In addition, FOR20 knockdown significantly inhibits both individual and collective migration of mammalian cells. Taken together, these data suggest that FOR20 functions as a MAP to promote microtubule depolymerization and cell migration. PMID- 28884020 TI - Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer. AB - Next-generation sequencing using exome capture is a common approach used for analysis of familial cancer syndromes. Despite the development of robust computational algorithms, the accrued experience of analyzing exome data sets and published guidelines, the analytical process remains an ad hoc series of important decisions and interpretations that require significant oversight. Processes and tools used for sequence data generation have matured and are standardized to a significant degree. For the remainder of the analytical pipeline, however, the results can be highly dependent on the choices made and careful review of results. We used primary exome sequence data, generously provided by the corresponding author, from a family with highly penetrant familial non-medullary thyroid cancer reported to be caused by HABP2 rs7080536 to review the importance of several key steps in the application of exome sequencing for discovery of new familial cancer genes. Differences in allele frequencies across populations, probabilities of familial segregation, functional impact predictions, corroborating biological support, and inconsistent replication studies can play major roles in influencing interpretation of results. In the case of HABP2 rs7080536 and familial non-medullary thyroid cancer, these factors led to the conclusion of an association that most data and our re-analysis fail to support, although larger studies from diverse populations will be needed to definitively determine its role. PMID- 28884022 TI - Identification, Characterization, and Structure of Tm16 from Trichuris muris. AB - Trichuriasis is a disease of poverty for which excretory and secretory (ES) products that induce the protective immunity are being investigated as candidate vaccines antigens. In this study, ES products of T. muris and immune sera were produced. The immune sera recognized more than 20 proteins on a 2D-gel of ES products of T. muris adult worms. Tm16 was one of the proteins identified by mass spectrometry. Tm16 shares 57% sequence identity with Ov16, an immunodominant diagnostic antigen from Onchocerca volvulus. Recombinant Tm16 with a carboxyl terminal hexahistidine was produced using Pichia pastoris. Polyclonal antibodies against rTm16 were generated by one-prime and two-boost immunization of three female Balb/c mice with 25 MUg of recombinant Tm16 emulsified with ISA720 adjuvant. These polyclonal antibodies confirmed that Tm16 is localized to the ES products and the soluble fraction of the adult worm. Additionally, the high resolution crystal structure of Tm16 was solved by molecular replacement. Tm16 belongs to the phosphatidylethanolamine-binding-like protein (PEBP1) family and this is the first structure of a PEBP1 from a parasite. PMID- 28884023 TI - Clinical Features and Visual Acuity Outcomes in Culture-Positive Endogenous Fungal Endophthalmitis in Southern China. AB - PURPOSE: To report the causative organisms, management strategies, and visual outcomes of culture-proven endogenous fungal endophthalmitis in a case series from southern China. METHODS: We reviewed the microbiological and medical records of patients with culture-positive endogenous fungal endophthalmitis visiting the Zhongshan Ophthalmic Center, Guangzhou, China, between January 1, 2006, and March 31, 2016. RESULTS: The inclusion criteria were met in 32 eyes of 29 patients. Molds were a common causative organism in 15 patients (51.7%), while yeasts appeared in 14 patients (48.3%). Initial visual acuity (VA) at the level of finger counting or better was significantly related to a good visual outcome (P = 0.002). Molds as a causative agent were significantly associated with worse visual outcome than yeasts (P = 0.020). CONCLUSION: Molds were a common cause of culture-proven fungal endophthalmitis. Endogenous fungal endophthalmitis is generally associated with poor VA outcomes, especially if caused by molds and if the patient's initial VA is too low to permit finger counting. PMID- 28884021 TI - Genomic epidemiology of a national outbreak of post-surgical Mycobacterium abscessus wound infections in Brazil. AB - An epidemic of post-surgical wound infections, caused by a non-tuberculous mycobacterium, has been on-going in Brazil. It has been unclear whether one or multiple lineages are responsible and whether their wide geographical distribution across Brazil is due to spread from a single point source or is the result of human-mediated transmission. 188 isolates, collected from nine Brazilian states, were whole genome sequenced and analysed using phylogenetic and comparative genomic approaches. The isolates from Brazil formed a single clade, which was estimated to have emerged in 2003. We observed temporal and geographic structure within the lineage that enabled us to infer the movement of sub lineages across Brazil. The genome size of the Brazilian lineage was reduced relative to most strains in the three subspecies of Mycobacterium abscessus and contained a novel plasmid, pMAB02, in addition to the previously described pMAB01 plasmid. One lineage, which emerged just prior to the initial outbreak, is responsible for the epidemic of post-surgical wound infections in Brazil. Phylogenetic analysis indicates that multiple transmission events led to its spread. The presence of a novel plasmid and the reduced genome size suggest that the lineage has undergone adaptation to the surgical niche. PMID- 28884024 TI - Combined Phacoemulsification and Intravitreal Dexamethasone Implant (Ozurdex(r)) in Diabetic Patients with Coexisting Cataract and Diabetic Macular Edema. AB - PURPOSE: To investigate the effectiveness and safety of combined phacoemulsification and dexamethasone intravitreal implant in patients with cataract and diabetic macular edema. METHODS: In this two-center, retrospective, single-group study, the charts of 16 consecutive patients who underwent combined phacoemulsification and intravitreal dexamethasone implant were retrospectively reviewed. These 16 patients, 7 men and 9 women, were observed at least 3 months of follow-up. Primary outcome was the change of the central retinal thickness (CRT); secondary outcome was the change of best-corrected visual acuity (BCVA). Any ocular complications were recorded. RESULTS: Mean CRT decreased significantly from 486 +/- 152.4 MUm at baseline to 365.5 +/- 91 MUm at 30 days (p = .005), to 326 +/- 80 MUm at 60 days (p = .0004), and to 362 +/- 134 MUm at 90 days (p = .001). Mean BCVA was 20/105 (logMAR, 0.72 +/- 0.34) at baseline and improved significantly (p <= .007) at all postsurgery time points. One case of ocular hypertension was observed and successfully managed with topical therapy. No endophthalmitis or other ocular complications were observed. CONCLUSION: Intravitreal slow-release dexamethasone implant combined with cataract surgery may be an effective approach on morphologic and functional outcomes for patients with cataract and diabetic macular edema for at least three months after surgery. PMID- 28884025 TI - The Pattern of Retinal Nerve Fiber Layer and Macular Ganglion Cell-Inner Plexiform Layer Thickness Changes in Glaucoma. AB - BACKGROUND/AIMS: To investigate the patterns of retinal ganglion cell damage at different stages of glaucoma, using the circumpapillary retinal nerve fiber layer (RNFL) and macula ganglion cell-inner plexiform layer (GCIPL) thicknesses. METHODS: In 296 eyes of 296 glaucoma patients and 55 eyes of 55 healthy controls, the correlations of mean deviation (MD) with the superior and inferior quadrant RNFL/GCIPL thickness (defined as the average of three superior and inferior sectors, resp.) were analyzed. RESULTS: In early to moderate glaucoma, most of the RNFL/GCIPL thicknesses had significant positive correlations with the MD. In advanced glaucoma, the superior GCIPL thickness showed the highest correlation with MD (r = 0.495), followed by the superior RNFL (r = 0.452) (all; P < 0.05). The correlation coefficient of the inferior RNFL thickness with MD (r < 0.471) was significantly stronger in early to moderate glaucoma compared to that in advanced glaucoma (r = 0.192; P < 0.001). In contrast, the correlations of the superior GCIPL thickness with MD (r = 0.452) in advanced glaucoma was significantly stronger compared to that in early to moderate glaucoma (r = 0.159; P < 0.001). CONCLUSIONS: The most preserved region in advanced glaucoma appears to be the superior macular GCIPL, whereas the most vulnerable region for initial glaucoma is the inferior RNFL around the optic disc. PMID- 28884026 TI - Idiopathic Intracranial Hypertension: Prognostic Factors and Multidisciplinary Management. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) mostly affects young obese women and can lead to permanent visual impairment. However, prognostic factors and therapeutic strategy remain unclear. METHODS: We retrospectively collected data from all patients diagnosed and managed for IIH in our university center from January 2001 to December 2016. RESULTS: Seventy-nine patients were diagnosed with IIH. Bilateral transverse sinus stenosis (TSS) was found in 74% of the population. Visual outcome at 6 months was poor for 46% of patients, including all patients presenting weight gain of at least 5% since diagnosis (p < 0.001), whereas mean body mass index at diagnosis was not different between patients with poor versus good outcome (32.9 +/- 7.7 versus 34.6 +/- 9.4 kg.m-2). Other significant factors of poor prognosis were bilateral TSS (OR = 5.2; 95 CI: 1.24 24.9; p = 0.024). Thirteen patients with poor outcome after 6-month assessment underwent unilateral TSS stenting leading to visual improvement in 11 cases. CONCLUSION: Weight gain, rather than initial weight, emerged as the leading factor of poor visual outcome in patients with IIH, followed by presence of bilateral TSS. Consequently, first-line treatment must include dietary measures to control weight. Unilateral stenting appears to be a safe second-line treatment option for patients with bilateral TSS. PMID- 28884028 TI - Spontaneous Coronary Artery Dissection: A Rare Manifestation of Alport Syndrome. AB - Alport syndrome (AS) is a genetic disorder due to inheritance of genetic mutations which lead to production of abnormal type IV collagen. AS has been associated with renal, auditory, and ocular diseases due to the presence of abnormal alpha chains of type IV collagen in the glomerulus, cochlea, cornea, lens, and retina. The resulting disorder includes hereditary nephritis, corneal opacities, anterior lenticonus, fleck retinopathy, temporal retinal thinning, and sensorineural deafness. Aortic and aortic valve pathologies have been described as extrarenal manifestations of AS in multiple case reports. One case report described intramural hematoma of the coronary artery. We report the first case of true spontaneous coronary artery dissection (SCAD) with an intimal flap as a very rare manifestation of AS. The patient is a 36-year-old female with history of AS with chronic kidney disease, hypertension, and obesity who presented to the emergency room with acute onset of substernal chest pain radiating to her neck and arms. Troponin was elevated, and ECG showed transient 1 mm ST-segment elevation in the inferior leads. Subsequent coronary angiography revealed localized dissection of the left circumflex artery. Percutaneous coronary angioplasty was performed and her symptoms improved. This case illustrates that SCAD may be a manifestation of AS patients with chest pain. PMID- 28884027 TI - AAV-KLF7 Promotes Descending Propriospinal Neuron Axonal Plasticity after Spinal Cord Injury. AB - DPSN axons mediate and maintain a variety of normal spinal functions. Unsurprisingly, DPSN tracts have been shown to mediate functional recovery following SCI. KLF7 could contribute to CST axon plasticity after spinal cord injury. In the present study, we assessed whether KLF7 could effectively promote DPSN axon regeneration and synapse formation following SCI. An AAV-KLF7 construct was used to overexpress KLF7. In vitro, KLF7 and target proteins were successfully elevated and axonal outgrowth was enhanced. In vivo, young adult C57BL/6 mice received a T10 contusion followed by an AAV-KLF7 injection at the T7 9 levels above the lesion. Five weeks later, overexpression of KLF7 was expressed in DPSN. KLF7 and KLF7 target genes (NGF, TrkA, GAP43, and P0) were detectably increased in the injured spinal cord. Myelin sparring at the lesion site, DPSN axonal regeneration and synapse formation, muscle weight, motor endplate morphology, and functional parameters were all additionally improved by KLF7 treatment. Our findings suggest that KLF7 promotes DPSN axonal plasticity and the formation of synapses with motor neurons at the caudal spinal cord, leading to improved functional recovery and further supporting the potential of AAV-KLF7 as a therapeutic agent for spinal cord injury. PMID- 28884029 TI - A Step-by-Step Conservative Approach for CAD-CAM Laminate Veneers. AB - The use of CAD/CAM technology has allowed the fabrication of ceramic restorations efficiently and with predictable results. Lithium disilicate is a type of glass ceramic material that can be used for the elaboration of laminate veneers, being monolithic restorations which require characterization through a covering ceramic in order to achieve acceptable esthetic results. The next case report shows a predictable clinical protocol for the rehabilitation of the anterior teeth through the preparation of CAD/CAM veneers (e.max CAD, Ivoclar Vivadent, Liechtenstein) which have been characterized by a nanofluorapatite ceramic (e.max Ceram, Ivoclar Vivadent, Liechtenstein) through the layering technique. PMID- 28884030 TI - Insight into Natural History of Congenital Vitiligo: A Case Report of a 23-Year Old with Stable Congenital Vitiligo. AB - Vitiligo is a disorder of skin pigmentation. It affects approximately 1% of the world's population. Vitiligo occurs equally between the sexes with no racial predilections. The majority of cases are acquired and arise between the second and third decades of life. Acquired vitiligo has an unpredictable clinical course. Congenital vitiligo is rare with few reported cases. Due to the rarity of congenital vitiligo, little is known about the clinical course. For patients with acquired or congenital vitiligo, the psychosocial burden can have a profound impact on quality of life. The unknown course of congenital vitiligo can exacerbate the feelings of distress and embarrassment. We report of a case of congenital vitiligo that has been stable for 23 years. The patient had no associated autoimmune disease. The pathogenesis of congenital vitiligo is unknown. This case may be useful to assist clinicians caring for newborns with congenital vitiligo in reassuring parents. PMID- 28884031 TI - A Case of Lionfish Envenomation Presenting to an Inland Emergency Department. AB - Lionfish envenomation can cause erythema, edema, necrosis, and severe pain at the exposed site. Treatment often includes supportive wound care, pain management, and hot water immersion. We report a case of lionfish exposure presenting to an inland emergency department treated successfully with these measures. PMID- 28884032 TI - Neurological Manifestations of X-Linked Ichthyosis: Case Report and Review of the Literature. AB - A 5-year-old boy presented with mild autism and attention-deficit hyperactivity disorder (ADHD). Chromosomal microarray demonstrated a 1.7 Mb deletion at Xp22.31, which was consistent with X-linked ichthyosis (XLI). Further exam revealed dry, scaly skin on his abdomen and pretibial areas. Patients with mutations involving solely the STS gene or the recurrent ~2 Mb deletion may present with ADHD, whereas those with larger deletions including the NLGN4 gene can present with both ADHD and autism. However, our patient presented with mild autism in addition to ADHD despite having only the recurrent deletion without loss of NLGN4. Such neurological manifestations of XLI warrant attention as practical targets of clinical management. PMID- 28884033 TI - High-Grade B-Cell Neoplasm with Surface Light Chain Restriction and Tdt Coexpression Evolved in a MYC-Rearranged Diffuse Large B-Cell Lymphoma: A Dilemma in Classification. AB - According to World Health Organization (WHO) classification (2008), B-cell neoplasms are classified into precursor B-cell or a mature B-cell phenotype and this classification was also kept in the latest WHO revision (2016). We are reporting a male patient in his fifties, with tonsillar swelling diagnosed as diffuse large B-cell lymphoma (DLBCL), germinal center. He received 6 cycles of RCHOP and showed complete metabolic response. Two months later, he presented with severe CNS symptoms. Flow cytometry on bone marrow (BM) showed infiltration by CD10-positive Kappa-restricted B-cells with loss of CD20 and CD19, and downregulation of CD79b. Moreover, the malignant population showed Tdt expression. BM Cytogenetics revealed t(8;14)(q24;q32) within a complex karyotype. Retrospectively, MYC and Tdt immunostains performed on original diagnostic tissue and came negative for Tdt and positive for MYC. It has been rarely reported that mature B-cell neoplasms present with features of immaturity; however the significance of Tdt acquisition during disease course was not addressed before. What is unique in this case is that the emerging disease has acquired an immaturity marker while retaining some features of the original mature clone. No definitive WHO category would adopt high-grade neoplasms that exhibit significant overlapping features between mature and immature phenotypes. PMID- 28884034 TI - Snakebite Induced Thrombotic Microangiopathy Leading to Renal Cortical Necrosis. AB - Renal complications from snakebite result in high mortality and morbidity. Acute kidney injury (AKI) occurs in 5-30% of cases. Renal manifestation could include acute tubular necrosis, cortical necrosis, interstitial nephritis, glomerulonephritis, and vasculitis. We present a case of thrombotic microangiopathy (TMA) resulting in renal cortical necrosis. Renal biopsy showed fibrin thrombi in glomeruli and arterioles with cortical necrosis. Our patient progressed to end-stage renal disease. PMID- 28884035 TI - Cooccurrence of Chorea-Acanthocytosis and Mesial Temporal Sclerosis: A Possible Role of Caudate Nucleus. AB - Chorea-acanthocytosis (ChAc) is an orphan disease, caused by mutations on chromosome 9. Epileptic seizures of mesial temporal origin can be a predominant symptom. We report on a 29-year-old woman with ChAc and bilateral MTS. Previously, few patients with coexisting ChAc and MTS were reported. The underlying pathophysiology is unknown, and further studies are needed. PMID- 28884036 TI - Severe Hepatopulmonary Syndrome in a Child with Caroli Syndrome. AB - Hepatopulmonary Syndrome (HPS) is a potential complication of chronic liver disease and is more commonly seen in the adult population. Caroli Syndrome is a rare inherited disorder characterized by intrahepatic ductal dilation and liver fibrosis that leads to portal hypertension. In children with liver disease, HPS should be considered in the differential diagnosis of prolonged, otherwise unexplained, hypoxemia. The presence of HPS can improve patient priority on the liver transplantation wait list, despite their Pediatric End-Stage Liver Disease (PELD) score. We present a 6-year-old girl with Caroli Syndrome and End-Stage Renal Disease who presented with persistent hypoxemia. The goal of this report is to increase awareness of HPS in children. PMID- 28884038 TI - Differential Diagnosis of Parkinson Disease, Essential Tremor, and Enhanced Physiological Tremor with the Tremor Analysis of EMG. AB - We investigate the differential diagnostic value of tremor analysis of EMG on Parkinson's disease (PD), essential tremor (ET), and enhanced physiological tremor (EPT). Clinical data from 25 patients with PD, 20 patients with ET, and 20 patients with EPT were collected. The tremor frequency and muscle contraction pattern of the resting, posture, and 500 g and 1000 g overload were recorded. The frequency of PD tremor was 4-6 Hz, and the frequency of ET was also in this range; the frequency of EPT is 6-12 hz having some overlap with PD. The muscle contraction patterns of the ET and EPT group were mainly synchronous contraction, and the muscle contraction mode of the PD group was mainly alternating contraction. Having tremor latency from rest to postural position and having changes in tremor amplitude after mental concentration in PD might distinguish ET. Tremor analysis of EMG was able to distinguish PD from ET and EPT by varying the tremor frequency and muscle contraction pattern. It can also differentiate between PD and ET by the latency and concentration effect and ET and EPT by weight load effect. PMID- 28884037 TI - New Insights about Pulmonary Epithelioid Hemangioendothelioma: Review of the Literature and Two Case Reports. AB - Pulmonary epithelioid hemangioendothelioma (PEH) is a rare neoplasm of vascular origin. There are three different major imaging patterns identified in thoracic manifestation of epithelioid hemangioendothelioma: (1) multiple pulmonary nodules; (2) multiple pulmonary reticulonodular opacities; and (3) diffuse infiltrative pleural thickening. Radiographically, presence of bilateral multiple nodules is the most common pattern of presentation. The diagnosis is made on the basis of histopathological findings and confirmed by positive immunohistochemistry staining. Although the prognostic factors for PEH have not yet been well established, a better prognosis is usually associated with the multinodular pattern. We report two different imagological presentations of this rare disease, based on two institutional experiences, along with a review of the relevant literature. PMID- 28884039 TI - Nanotechnology-based combination therapy for overcoming multidrug-resistant cancer. AB - Multidrug resistance (MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse. Combination therapy is an effective strategy for overcoming MDR. However, the different pharmacokinetic (PK) profiles of combined drugs often undermine the combination effect in vivo, especially when greatly different physicochemical properties (e.g., those of macromolecules and small drugs) combine. To address this issue, nanotechnology-based codelivery techniques have been actively explored. They possess great advantages for tumor targeting, controlled drug release, and identical drug PK profiles. Thus, a powerful tool for combination therapy is provided, and the translation from in vitro to in vivo is facilitated. In this review, we present a summary of various combination strategies for overcoming MDR and the nanotechnology-based combination therapy. PMID- 28884040 TI - Recent progress on nanoparticle-based drug delivery systems for cancer therapy. AB - The development of cancer nanotherapeutics has attracted great interest in the recent decade. Cancer nanotherapeutics have overcome several limitations of conventional therapies, such as nonspecific biodistribution, poor water solubility, and limited bioavailability. Nanoparticles with tuned size and surface characteristics are the key components of nanotherapeutics, and are designed to passively or actively deliver anti-cancer drugs to tumor cells. We provide an overview of nanoparticle-based drug delivery methods and cancer therapies based on tumor-targeting delivery strategies that have been developed in recent years. PMID- 28884043 TI - Preclinical and clinical applications of specific molecular imaging for HER2 positive breast cancer. AB - Precision medicine and personalized therapy are receiving increased attention, and molecular-subtype classification has become crucial in planning therapeutic schedules in clinical practice for patients with breast cancer. Human epidermal growth factor receptor 2 (HER2) is associated with high-grade breast tumors, high rates of lymph-node involvement, high risk of recurrence, and high resistance to general chemotherapy. Analysis of HER2 expression is highly important for doctors to identify patients who can benefit from trastuzumab therapy and monitor the response and efficacy of treatment. In recent years, significant efforts have been devoted to achieving specific and noninvasive HER2-positive breast cancer imaging in vivo. In this work, we reviewed existing literature on HER2 imaging in the past decade and summarized the studies from different points of view, such as imaging modalities and HER2-specific probes. We aimed to improve the understanding on the translational process in molecular imaging for HER2 breast cancer. PMID- 28884044 TI - Survival after pulmonary metastasectomy in colorectal cancer patients: does a history of resected liver metastases worsen the prognosis? A literature review. AB - OBJECTIVE: : To assess the impact of past liver metastases on the survival duration of patients who are undergoing surgery for lung metastases. METHODS: : We conducted a review of literature published from 2007 to 2014. The studies were identified by searching PubMed, MEDLINE, and Embase and were supplemented by a manual search of the references listed by the retrieved studies. The following search terms were used: lung metastasectomy, pulmonary metastasectomy, lung metastases, and lung metastasis. We selected retrospective and prospective studies published from 2007 to 2014 on patients with lung metastases from colorectal cancer and were undergoing surgery with curative intent. We excluded reviews, studies that focused on surgical techniques, patients who were treated non-surgically, analyses of specific subgroups of patients, and those that did not report follow-up of the patients undergoing surgery. RESULTS: : We identified 28 papers that assessed survival after lung metastases, 21 of which were mostly retrospective studies that identified previous liver metastases to explore their impact on patient survival. In more than half of the papers analyzed (63.2%), patients with a history of resected liver metastases had a lower survival rate than those who did not have such a history, and the difference was statistically significant in eight of these studies. However, data were presented differently, and authors reported mean survival time, survival rates, or hazard ratios. CONCLUSIONS: : A history of liver metastases seems to be a negative prognostic factor, but the individual data need to undergo a meta-analysis. PMID- 28884041 TI - Natural and artificial small RNAs: a promising avenue of nucleic acid therapeutics for cancer. AB - Since the failure of traditional therapy, gene therapy using functional DNA sequence and small RNA/DNA molecules (oligonucleotide) has become a promising avenue for cancer treatment. The discovery of RNA molecules has impelled researchers to investigate small regulatory RNA from various natural and artificial sources and determine a cogent target for controlling tumor progression. Small regulatory RNAs are used for therapeutic silencing of oncogenes and aberrant DNA repair response genes. Despite their advantages, therapies based on small RNAs exhibit limitations in terms of stability of therapeutic drugs, precision-based delivery in tissues, precision-based intercellular and intracellular targeting, and tumor heterogeneity-based responses. In this study, we summarize the potential and drawbacks of small RNAs in nucleic acid therapeutics for cancer. PMID- 28884042 TI - Aberrant control of NF-kappaB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode. AB - The role of the transcription factor NF-kappaB in shaping the cancer microenvironment is becoming increasingly clear. Inflammation alters the activity of enzymes that modulate NF-kappaB function, and causes extensive changes in genomic chromatin that ultimately drastically alter cell-specific gene expression. NF-kappaB regulates the expression of cytokines and adhesion factors that control interactions among adjacent cells. As such, NF-kappaB fine tunes tissue cellular composition, as well as tissues' interactions with the immune system. Therefore, NF-kappaB changes the cell response to hormones and to contact with neighboring cells. Activating NF-kappaB confers transcriptional and phenotypic plasticity to a cell and thereby enables profound local changes in tissue function and composition. Research suggests that the regulation of NF kappaB target genes is specifically altered in cancer. Such alterations occur not only due to mutations of NF-kappaB regulatory proteins, but also because of changes in the activity of specific proteostatic modules and metabolic pathways. This article describes the molecular mode of NF-kappaB regulation with a few characteristic examples of target genes. PMID- 28884045 TI - BRAF mutation in colorectal carcinomas with signet ring cell component. AB - OBJECTIVE: : Signet ring cell carcinoma is a rare subtype of colorectal carcinoma (CRC) with an associated BRAFV600E mutation. We investigated frequencies of BRAF mutation in 28 CRCs containing variable signet ring cell component and their relation with clinicopathologic parameters. METHODS: : According to the presence of signet ring cell component, tumors were categorized into groups as follows: 0% 9%, 10%-24%, 25%-49%, and >50%. Genomic DNA was isolated and analyzed for BRAF V600E gene mutation by polymerase chain reaction-restriction fragment length polymorphism. Eleven of 28 cases (39.3%) showed BRAFV600E mutation, which was also confirmed by Sanger sequencing. To elucidate the importance of existence of signet ring cell component at the molecular level, we separated cases into two groups with cut-off levels of 10% and 50%, which pertain to percentages of signet ring cells. RESULTS: : Seven of 19 cases (36.8%) under the threshold of 50% and four of nine cases (44.4%) over this threshold value demonstrated BRAF mutation. Three of 7 cases (42.8%) featuring <10% signet ring cell component and eight out of 21 cases (38.1%) showing >10% were BRAF mutated. CONCLUSIONS: : BRAF mutation must be closely associated with the presence of malignant signet ring cells regardless of their percentages. PMID- 28884046 TI - Inhibition of IKK-NFkappaB pathway sensitizes lung cancer cell lines to radiation. AB - OBJECTIVE: : Cancer cell radioresistance is a stumbling block in radiation therapy. The activity in the nuclear factor kappa B (NFkappaB) pathway correlates with anti-apoptotic mechanisms and increased radioresistance. The IKK complex plays a major role in NFkappaB activation upon numerous signals. In this study, we examined the interaction between ionizing radiation (IR) and different members of the IKK-NFkappaB pathway, as well as upstream activators, RAF1, ERK, and AKT1. METHODS: : The effect of 4 Gy of IR on the expression of the RAF1-ERK-IKK NFkappaB pathway was examined in A549 and H1299 lung cancer cell lines using Western blot analysis and confocal microscopy. We examined changes in radiation sensitivity using gene silencing or pharmacological inhibitors of ERK and IKKbeta. RESULTS: : IKKalpha, IKKgamma, and IkappaBalpha increased upon exposure to IR, thereby affecting nuclear levels of NFkappaB (phospho-p65). ERK inhibition or siRNA-mediated down-regulation of RAF1 suppressed the post-irradiation survival of the examined lung cancer cell lines. A similar effect was detected on survival upon silencing IKKalpha/IKKgamma or inhibiting IKKbeta. CONCLUSIONS: : Exposure of lung cancer cells to IR results in NFkappaB activation via IKK. The genetic or pharmacological blockage of the RAF1-ERK-IKK-NFkappaB pathway sensitizes cells to therapeutic doses of radiation. Therefore, the IKK pathway is a promising target for therapeutic intervention in combination with radiotherapy. PMID- 28884047 TI - BsmI (rs1544410) and FokI (rs2228570) vitamin D receptor polymorphisms, smoking, and body mass index as risk factors of cutaneous malignant melanoma in northeast Italy. AB - OBJECTIVE: : To investigate whether vitamin D receptor gene (VDR) BsmI-rs1544410 and FokI-rs2228570 polymorphisms, smoking duration, and body mass index (BMI) are risk factors for cutaneous melanoma, especially metastatic melanoma. METHODS: : We studied 120 cutaneous melanoma cases [68 stage I and II non-metastatic melanoma (NMetM) patients, plus 52 Stage III and IV metastatic melanoma (MetM) patients], and 120 matching healthy controls from northeast Italy. VDR polymorphisms were measured by restriction fragment length polymorphism analysis. Absence or presence of BsmI and FokI restriction sites was denoted by " B" and " F" or by " b" and " f," respectively. RESULTS: : VDR-BsmI bb genotype was more frequent among MetM (32.7%) than among NMetM cases (13.2%), with odds ratio (OR)=3.18. Comparison of all melanoma patients vs healthy controls showed that the following biomarkers were at risk: >=20 years of smoking (OR=2.43); >=20 years of smoking combined with bb (OR=4.78), Bb+bb (OR=2.30), Ff (OR=3.04), and Ff+ff (OR=3.08); obesity (BMI>30 kg/m2) alone (OR=3.54); and obesity combined with Bb+bb (OR=3.52), Ff (OR=4.78), and Ff+ff (OR=6.56). Comparison of MetM vs NMetM patients revealed that the following biomarkers were at risk: >=20 years of smoking (OR=2.39), >=20 years of smoking combined with bb (OR=5.13), Bb+bb (OR=3.07), and Ff+ff (OR=2.66); and obesity combined with Bb+bb (OR=5.27), Ff (OR=6.28), and Ff+ff (OR=9.18). Triple combination of >=20 years of smoking, obesity, and Bb+bb yielded OR=9.65 for melanoma patients vs healthy controls and OR=12.2 for MetM vs. NMetM patients. CONCLUSIONS: : Risk factors for cutaneous MetM include two VDR polymorphisms combined with smoking duration and obesity. Results suggest gene-environment implications in melanoma susceptibility and severity. Future studies in larger cohorts and in subjects with different genetic background are warranted to extend our findings. PMID- 28884048 TI - Expression levels of beta-catenin and galectin-3 in meningioma and their effect on brain invasion and recurrence: a tissue microarray study. AB - OBJECTIVE: Meningiomas are neoplasms that arise from the meninges of the central nervous system (CNS). They constitute about 25.6% of CNS tumors diagnosed in Egypt. Some morphological variants of meningiomas display aggressive behavior, leading to brain-invasive growth pattern. Although meningiomas are usually treated by complete surgical excision, the risk of postoperative recurrence remains. Hence, additional biomarkers for predicting aggressive behavior must be discovered. This study aims to explore the clinical and biological relevance of the protein expression levels of beta-catenin and galectine-3 in meningioma and to understand the pathobiology of this neoplasm. METHODS: This retrospective study was carried out on 153 cases of meningioma by using tissue microarrays and immunohistochemistry for beta-catenin and galectine-3. RESULTS: High beta-catenin expression was significantly associated with transitional and meningiotheliomatous meningiomas, low tumor grade, low recurrence rate, and low incidence of brain invasion. Meanwhile, high galectin-3 expression was associated with brain invasion, recurrence, high tumor grade, and tumor type. Logistic regression analysis indicated that among all variables included in the model, beta-catenin and galactin-3 expression levels were significant predictors of tumor recurrence (P<0.001). CONCLUSIONS: Galectin-3 and beta-catenin are involved in meningioma recurrencebut not in brain invasion. These molecules could be important potential therapeutic targets and predictors for meningiomas. PMID- 28884049 TI - Potential predictive factors for pathologic complete response after the neoadjuvant treatment of rectal adenocarcinoma: a single center experience. AB - OBJECTIVE: : To assess the response rate of patients with rectal adenocarcinoma to neoadjuvant therapy and to identify the predictors of histological regression after neoadjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). METHODS: : This study recruited 64 patients. The patients had resectable cancer of the lower and the middle rectum (T3/T4 and/or N+) without distant metastasis and received neoadjuvant RT or CCRT followed by radical surgery with total mesorectal excision (TME) between January 2006 and December 2011. The patients were classified into non-response (NR), partial response (PR), and pathologic complete response (pCR) based on the Dworak tumor regression grading system. RESULTS: : The median age of patients was 57 years (ranging from 22 to 85). A total of 24 patients were treated with neoadjuvant CCRT, whereas 40 patients were treated with RT alone. Abdominoperineal resection (APR) was performed on 29 patients (45%). Anterior resection with TME was performed on 34 patients (53%). One patient had local resection. Histologically, 12 (19%), 24 (73%), and 28 (44%) patients exhibited pCR, PR, and NR, respectively. Univariate analysis revealed that the predictors of tumor regression were as follows: the absence of lymph node involvement from initial imaging (cN0) (P=0.021); normal initial carcinoembryonic antigen (CEA) level (P=0.01); hemoglobin level >=12 g/dl (P=0.009); CCRT (P=0.021); and tumor downstaging in imaging (P=0.001). Multivariate analysis showed that the main predictors of pCR were CT combined with neoadjuvant RT, cN0 stage, and tumor regression on imaging. CONCLUSIONS: : Identifying the predictors of pCR following neoadjuvant therapy aids the selection of responsive patients for non-aggressive surgical treatment and possible surveillance. PMID- 28884050 TI - Ready! Aim! Fire! targeting the right medical science journal. AB - OBJECTIVE: Inadvertently submitting a paper to a journal that is unlikely to publish it is a waste of resources and ultimately delays dissemination of one's research. A high proportion of manuscripts are rejected by their author's first choice journal. The aim of the present work was to review guidance provided within the literature for journal selection that might minimize the chance of manuscript rejection. We also consider papers that encompass more than one main medical science and describe the selection process that we used with a paper that was published in Cardiovascular Endocrinology. METHODS: A database search (Embase, PubMed and Medworm) was performed for all articles published in the scientific literature providing guidance on journal selection. Articles were identified that either had journal selection as their principal topic or included journal selection as part of a broader discussion of publishing. The relative performance of four free-to-use, web-based applications that claim to provide guidance on journal selection was compared. RESULTS: The searches identified 286 hits, of which 249 were in English. Of these papers, 16 discussed journal selection and a further 10 articles were identified from citations within the original 16 articles. Only one article described a comprehensive model for submission decision-making. Identification of appropriate candidate journals by various web-based applications was erratic, with the Jane database providing the most robust suggestions. CONCLUSION: Our work suggests that little attention has been focused in the scientific literature on the mechanisms that authors use to select a journal for their work. Nevertheless, scientists for the most part seem to have a good sense of where their papers are most likely to be accepted. Beyond ensuring that a manuscript fulfils all the target journal's requirements, the literature suggests that it is important to have an objective view of the scientific contribution or 'value' of your work. PMID- 28884051 TI - Anti-n-Methyl-d-Aspartate-Receptor (NMDAR) Encephalitis in Association with Ovarian Teratoma. AB - Anti-N-methyl-D-aspartate-Receptor (NMDAR) encephalitis is an autoimmune disorder with a multifaceted presentation that involves memory deficits, psychiatric symptoms, and autonomic instability. This case report describes the classic presentation of Anti-NMDAR encephalitis and highlights its association with ovarian teratomas. We present a 26 -year-old female who came in with new onset seizures and altered mentation who subsequently developed automatism. Electroencephalograms (EEG) showed left frontal spikes and right temporal delta activity. Magnetic resonance imaging (MRI) revealed right temporal hyper intensity. The diagnosis was established with positive anti-NMDAR antibodies in the cerebrospinal fluid (CSF). The patient was initially treated with steroids and valproic acid, however, her condition progressively worsened. A five-day course of intravenous immunoglobulins (IVIG) was started followed by rituximab. The clinical course was complicated with the patient developing neutropenic fever and cerebrospinal fluid cultures (CSF) growing methicillin-sensitive Staphylococcus aureus (MSSA). She underwent pelvic imaging which showed a right ovarian teratoma. Evidence suggests that removal of ovarian tumor leads to better clinical and mortality outcomes in patients with Anti-NMDAR encephalitis. It is important for the internist to consider paraneoplastic syndromes in patients with Anti-NMDAR encephalitis. PMID- 28884052 TI - Colovesical Fistula: An Unusual Complication of Cytomegalovirus Colitis. AB - Cytomegalovirus (CMV) is a double-stranded DNA virus that is associated with clinically significant disease in patients with advanced immunosuppression, particularly those with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). End-organ disease with CMV is classically associated with a CD4 cell count less than 50 cells/microliter. CMV colitis is the second most common manifestation of end-organ disease in this patient population. CMV-associated enteric fistula is a rare complication that has been described in only a few case reports in the literature. These cases describe gastrocolic, enterocutaneous, enterocolic, rectovaginal, and colocutaneous fistulae. However, colovesical fistula has not been described previously. Here, we report the first case of CMV-associated colovesical fistula in a patient with HIV infection and AIDS. PMID- 28884053 TI - Pes Anserinus Bursitis due to Tibial Spurs in Children. AB - Osteochondromas are the most common bone tumours. Although these tumors are relatively common in the long bones of children, the varied clinical and radiographic presentation of such neoplasms around the knee joint can cause diagnostic delays, especially when not associated with a palpable swelling. Proximal tibial osteochondromas can sometimes unusually present as spurs/ rose thorns leading to pes anserinus bursitis and vague knee pain. We describe the clinico-radiographic features of such proximal tibial metaphyseal osteochondromas giving rise to pes anserinus bursitis in three children, including bilaterally symmetrical osteochondroma in one of the cases, who were treated conservatively with good outcomes. PMID- 28884054 TI - The Role of Apixaban in the Treatment of Heparin-Induced Thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) can present as arterial and venous thrombosis in adults who are treated with heparin. We present a case of a patient who developed HIT when she was treated for deep venous thrombosis (DVT) and pulmonary embolism with heparin. During the treatment with heparin and while being transitioned to warfarin, she developed arterial thrombosis. A work-up for HIT was sent, and it was positive. She was started on the argatroban drip and her platelet counts stabilized. Since her platelet counts remained stable and were not increasing for three weeks, we decided to transition the patient to an oral anticoagulant. She was started on apixaban, a novel oral anticoagulant (NOAC), and her platelet counts remained stable. Therefore, through this case, we highlight the importance of platelet counts remaining stable when a patient with HIT is treated with apixaban. PMID- 28884056 TI - The effect of the electrical double layer on hydrodynamic lubrication: a non monotonic trend with increasing zeta potential. AB - In the present study, a modified Reynolds equation including the electrical double layer (EDL)-induced electroviscous effect of lubricant is established to investigate the effect of the EDL on the hydrodynamic lubrication of a 1D slider bearing. The theoretical model is based on the nonlinear Poisson-Boltzmann equation without the use of the Debye-Huckel approximation. Furthermore, the variation in the bulk electrical conductivity of the lubricant under the influence of the EDL is also considered during the theoretical analysis of hydrodynamic lubrication. The results show that the EDL can increase the hydrodynamic load capacity of the lubricant in a 1D slider bearing. More importantly, the hydrodynamic load capacity of the lubricant under the influence of the EDL shows a non-monotonic trend, changing from enhancement to attenuation with a gradual increase in the absolute value of the zeta potential. This non monotonic hydrodynamic lubrication is dependent on the non-monotonic electroviscous effect of the lubricant generated by the EDL, which is dominated by the non-monotonic electrical field strength and non-monotonic electrical body force on the lubricant. The subject of the paper is the theoretical modeling and the corresponding analysis. PMID- 28884055 TI - A biofunctionalizable ink platform composed of catechol-modified chitosan and reduced graphene oxide/platinum nanocomposite. AB - We present an ink platform for a printable polymer-graphene nanocomposite that is intended for the development of modular biosensors. The ink consists of catechol modified chitosan and reduced graphene oxide decorated with platinum nanoparticles (rGO-Pt). We modified the chitosan with catechol groups, in order to obtain adhesive properties and improve solubility. Dispersions of rGO-Pt in ethylene glycol were admixed with an aqueous solution of modified chitosan to yield an ink that is suitable for non-contact piezoelectric printing using a commercial microplotter (Sonoplot GIX Microplotter Desktop). As a proof of concept, printed patterns were biofunctionalized with DNA oligonucleotide probes for Streptococcus agalactiae (Group B streptococcus) using glutaraldehyde as a linker. Confocal microscopy revealed the successful hybridization of complementary polymerase chain reaction (PCR) products and low non-specific binding. Our results demonstrate that catechol-modified chitosan/rGO-Pt nanocomposites can be used as inks for piezoelectric printing and facilitate the attachment of biorecognition elements for biosensor applications. PMID- 28884057 TI - Fixation mechanisms of nanoparticles on substrates by electron beam irradiation. AB - For applications such as the fabrication of plasmonic waveguides we developed a patterning technique to fabricate an array of nanoparticles on a substrate using focused electron beams (Noriki, T.; Abe, S.;.Kajikawa, K.; Shimojo, M. Beilstein J. Nanotechnol.2015,6, 1010-1015). This technique consists of three steps: Firstly, nanoparticles are placed over the entire surface of a substrate. Secondly, the nanoparticles are fixed on the substrate by focused electron beam irradiation. The electron beam decomposes the organic molecules located around the particle into amorphous carbon. The amorphous carbon immobilizes the particle on the substrate. Finally, the unfixed nanoparticles are removed. However, in this original technique, the area in which the nanoparticles were fixed was wider than the electron-probe size of a few nanometers. To understand this widening mechanisms, the effects of accelerating voltage, particle size and substrate material are investigated by means of both experiments and simulation. It is demonstrated that the fixing area is greatly affected by the electrons back scattered by the substrate. The back-scattering leads to an increase in line width and thus reduces the resolution of this patterning technique. PMID- 28884058 TI - Nanostructures for sensors, electronics, energy and environment III. PMID- 28884059 TI - Parylene C as a versatile dielectric material for organic field-effect transistors. AB - An emerging new technology, organic electronics, is approaching the stage of large-scale industrial application. This is due to a remarkable progress in synthesis of a variety of organic semiconductors, allowing one to design and to fabricate, so far on a laboratory scale, different organic electronic devices of satisfactory performance. However, a complete technology requires upgrading of fabrication procedures of all elements of electronic devices and circuits, which not only comprise active layers, but also electrodes, dielectrics, insulators, substrates and protecting/encapsulating coatings. In this review, poly(chloro para-xylylene) known as Parylene C, which appears to become a versatile supporting material especially suitable for applications in flexible organic electronics, is presented. A synthesis and basic properties of Parylene C are described, followed by several examples of use of parylenes as substrates, dielectrics, insulators, or protecting materials in the construction of organic field-effect transistors. PMID- 28884060 TI - Low-temperature CO oxidation over Cu/Pt co-doped ZrO2 nanoparticles synthesized by solution combustion. AB - Zirconia (ZrO2) nanoparticles co-doped with Cu and Pt were applied as catalysts for carbon monoxide (CO) oxidation. These materials were prepared through solution combustion in order to obtain highly active and stable catalytic nanomaterials. This method allows Pt2+ and Cu2+ ions to dissolve into the ZrO2 lattice and thus creates oxygen vacancies due to lattice distortion and charge imbalance. High-resolution transmission electron microscopy (HRTEM) results showed Cu/Pt co-doped ZrO2 nanoparticles with a size of ca. 10 nm. X-ray diffraction (XRD) and Raman spectra confirmed cubic structure and larger oxygen vacancies. The nanoparticles showed excellent activity for CO oxidation. The temperature T50 (the temperature at which 50% of CO are converted) was lowered by 175 degrees C in comparison to bare ZrO2. Further, they exhibited very high stability for CO reaction (time-on-stream ~ 70 h). This is due to combined effect of smaller particle size, large oxygen vacancies, high specific surface area and better thermal stability of the Cu/Pt co-doped ZrO2 nanoparticles. The apparent activation energy for CO oxidation is found to be 45.6 kJ.mol-1. The CO conversion decreases with increase in gas hourly space velocity (GHSV) and initial CO concentration. PMID- 28884061 TI - Luminescent supramolecular hydrogels from a tripeptide and nitrogen-doped carbon nanodots. AB - The combination of different components such as carbon nanostructures and organic gelators into composite nanostructured hydrogels is attracting wide interest for a variety of applications, including sensing and biomaterials. In particular, both supramolecular hydrogels that are formed from unprotected D,L-tripeptides bearing the Phe-Phe motif and nitrogen-doped carbon nanodots (NCNDs) are promising materials for biological use. In this work, they were combined to obtain luminescent, supramolecular hydrogels at physiological conditions. The self-assembly of a tripeptide upon application of a pH trigger was studied in the presence of NCNDs to evaluate effects at the supramolecular level. Luminescent hydrogels were obtained whereby NCND addition allowed the rheological properties to be fine-tuned and led to an overall more homogeneous system composed of thinner fibrils with narrower diameter distribution. PMID- 28884062 TI - High-speed dynamic-mode atomic force microscopy imaging of polymers: an adaptive multiloop-mode approach. AB - Adaptive multiloop-mode (AMLM) imaging to substantially increase (over an order of magnitude) the speed of tapping-mode (TM) imaging is tested and evaluated through imaging three largely different heterogeneous polymer samples in experiments. It has been demonstrated that AMLM imaging, through the combination of a suite of advanced control techniques, is promising to achieve high-speed dynamic-mode atomic force microscopy imaging. The performance, usability, and robustness of the AMLM in various imaging applications, however, is yet to be assessed. In this work, three benchmark polymer samples, including a PS-LDPE sample, an SBS sample, and a Celgard sample, differing in feature size and stiffness of two orders of magnitude, are imaged using the AMLM technique at high speeds of 25 Hz and 20 Hz, respectively. The comparison of the images obtained to those obtained by using TM imaging at scan rates of 1 Hz and 2 Hz showed that the quality of the 25 Hz and 20 Hz AMLM imaging is at the same level of that of the 1 Hz TM imaging, while the tip-sample interaction force is substantially smaller than that of the 2 Hz TM imaging. PMID- 28884064 TI - Charge transfer from and to manganese phthalocyanine: bulk materials and interfaces. AB - Manganese phthalocyanine (MnPc) is a member of the family of transition-metal phthalocyanines, which combines interesting electronic behavior in the fields of organic and molecular electronics with local magnetic moments. MnPc is characterized by hybrid states between the Mn 3d orbitals and the pi orbitals of the ligand very close to the Fermi level. This causes particular physical properties, different from those of the other phthalocyanines, such as a rather small ionization potential, a small band gap and a large electron affinity. These can be exploited to prepare particular compounds and interfaces with appropriate partners, which are characterized by a charge transfer from or to MnPc. We summarize recent spectroscopic and theoretical results that have been achieved in this regard. PMID- 28884063 TI - Two-dimensional carbon-based nanocomposites for photocatalytic energy generation and environmental remediation applications. AB - In the pursuit towards the use of sunlight as a sustainable source for energy generation and environmental remediation, photocatalytic water splitting and photocatalytic pollutant degradation have recently gained significant importance. Research in this field is aimed at solving the global energy crisis and environmental issues in an ecologically-friendly way by using two of the most abundant natural resources, namely sunlight and water. Over the past few years, carbon-based nanocomposites, particularly graphene and graphitic carbon nitride, have attracted much attention as interesting materials in this field. Due to their unique chemical and physical properties, carbon-based nanocomposites have made a substantial contribution towards the generation of clean, renewable and viable forms of energy from light-based water splitting and pollutant removal. This review article provides a comprehensive overview of the recent research progress in the field of energy generation and environmental remediation using two-dimensional carbon-based nanocomposites. It begins with a brief introduction to the field, basic principles of photocatalytic water splitting for energy generation and environmental remediation, followed by the properties of carbon based nanocomposites. Then, the development of various graphene-based nanocomposites for the above-mentioned applications is presented, wherein graphene plays different roles, including electron acceptor/transporter, cocatalyst, photocatalyst and photosensitizer. Subsequently, the development of different graphitic carbon nitride-based nanocomposites as photocatalysts for energy and environmental applications is discussed in detail. This review concludes by highlighting the advantages and challenges involved in the use of two-dimensional carbon-based nanocomposites for photocatalysis. Finally, the future perspectives of research in this field are also briefly mentioned. PMID- 28884065 TI - Molecular characterizations of somatic hybrids developed between Pleurotus florida and Lentinus squarrosulus through inter-simple sequence repeat markers and sequencing of ribosomal RNA-ITS gene. AB - The 12 pfls somatic hybrids and 2 parents of Pleurotus florida and Lentinus squarrosulus were characterized by ISSR and sequencing of rRNA-ITS genes. Five ISSR primers were used and amplified a total of 54 reproducible fragments with 98.14% polymorphism among all the pfls hybrid populations and parental strains. UPGMA-based cluster exhibited a dendrogram with three major groups between the parents and pfls hybrids. Parent P. florida and L. squarrosulus showed different degrees of genetic distance with all the hybrid lines and they showed closeness to hybrid pfls 1m and pfls 1h, respectively. ITS1(F) and ITS4(R) amplified the rRNA-ITS gene with 611-867 bp sequence length. The nucleotide polymorphisms were found in the ITS1, ITS2 and 5.8S rRNA region with different number of bases. Based on rRNA-ITS sequence, UPGMA cluster exhibited three distinct groups between L. squarrosulus and pfls 1p, pfls 1m and pfls 1s, and pfls 1e and P. florida. PMID- 28884066 TI - Actinomycetes mediated synthesis of gold nanoparticles from the culture supernatant of Streptomyces griseoruber with special reference to catalytic activity. AB - Biogenic synthesis of nanoparticles has received a tremendous attention from the past few decades. The significant progress in the field of nanotechnology has resulted in a cost-effective and eco-friendly process for nanoparticle synthesis. In the present study, the extracellular synthesis of gold nanoparticles was carried out using culture supernatant of Streptomyces griseoruber, actinomycetes isolated from the soil. Bioreduction of gold nanoparticles was confirmed by UV visible spectrophotometer that showed the peak between 520 and 550 nm. The crystalline nature and mean size of the GNPs were confirmed using XRD. FTIR revealed the possible functional group that could be useful in immobilisation and stabilisation of GNPs. Size and distribution of the biosynthesized GNPs were analysed by HR-TEM that showed the formation of GNPs in the range of 5-50 nm. The synthesised GNPs showed good catalytic activity for the degradation of methylene blue. The study shows the rapid and eco-friendly synthesis of GNPs from Streptomyces griseoruber, and this is the first report on the catalytic activity of GNPs from actinomycetes so far. PMID- 28884067 TI - Optimization of thermostable organic solvent-tolerant lipase production by thermotolerant Rhizopus sp. using solid-state fermentation of palm kernel cake. AB - This study enhanced the production of thermostable organic solvent-tolerant (TS OST) lipase by locally isolated thermotolerant Rhizopus sp. strain using solid state fermentation (SSF) of palm kernel cake (PKC). The optimum conditions were achieved using a series of statistical approaches. The cultivation parameters, which include fermentation time, moisture content, temperature, pH, inoculum size, various carbon and nitrogen sources, as well as other supplements, were initially screened by the definitive screening design, and one-factor-at-a-time using PKC as the basal medium. Three significant factors (olive oil concentration, pH, and inoculum size) were further optimized using face-centred central composite design. The results indicated a successful and significant improvement of lipase activity by almost two-fold compared to the initial screening production. The findings showed that the optimal conditions were 2% (v/w) inoculum size, 2% (v/w) olive oil, 0.6% (w/w) peptone, 2% (v/w) ethanol, 70% moisture content at initial pH 10.0 and 45 degrees C within 72 h of fermentation. Process optimization resulted in maximum lipase activity of 58.63 U/gram dry solids (gds). The analysis of variance showed that the statistical model was significant (p value <0.0001) and reliable with a high value of R2 (0.98) and adjusted R2 (0.96). This indicates a better correlation between the actual and predicted responses of lipase production. By considering this study, the low-cost PKC through SSF appears to be promising in the utilization of agro industrial waste for TS-OST lipase production. This is because satisfactory enzyme activity could be attained that promises industrial applications. PMID- 28884068 TI - Different methodologies for sustainability of optimization techniques used in submerged and solid state fermentation. AB - Optimization techniques are considered as a part of nature's way of adjusting to the changes happening around it. There are different factors that establish the optimum working condition or the production of any value-added product. A model is accepted for a particular process after its sustainability has been verified on a statistical and analytical level. Optimization techniques can be divided into categories as statistical, nature inspired and artificial neural network each with its own benefits and usage in particular cases. A brief introduction about subcategories of different techniques that are available and their computational effectivity will be discussed. The main focus of the study revolves around the applicability of these techniques to any particular operation such as submerged fermentation (SmF) and solid state fermentation (SSF), their ability to produce secondary metabolites and the usefulness in the laboratory and industrial level. Primary studies to determine the enzyme activity of different microorganisms such as bacteria, fungi and yeast will also be discussed. l Asparaginase, the most commonly used drugs in the treatment of acute lymphoblastic leukemia (ALL) shall be considered as an example, a short discussion on models used in the production by the processes of SmF and SSF will be discussed to understand the optimization techniques that are being dealt. It is expected that this discussion would help in determining the proper technique that can be used in running any optimization process for different purposes, and would help in making these processes less time-consuming with better output. PMID- 28884069 TI - Cerebral Hemorrhage following Chiropractic Activator Treatment: Case Report and Review of Literature. PMID- 28884070 TI - Contemporary Issues in Exposure Assessment Using Biomonitoring. AB - In environmental epidemiology, use of biomonitoring (i.e., trace-level measurement of environmental chemicals or their metabolites in biospecimens) for exposure assessment has increased considerably in past decades. Although exposure biomarkers should reflect a person's exposure to the target chemicals (or their precursors) within a specific timeframe, timing, duration, and intensity of exposures are normally unknown and likely vary within the study period. Therefore, evaluating exposure beyond a single time point may require collecting more than one biospecimen. Of note, collection and sample processing procedures will impact integrity and usefulness of biospecimens. All of the above factors are fundamental to properly interpret biomonitoring data. We will discuss the relevance of the exposure assessment study protocol design to (a) ensure that biomonitoring specimens reflect the intended exposure, (b) consider the temporal variability of concentrations of the target biomarkers, and PMID- 28884071 TI - Increased risk of SSEs in bone-only metastatic breast cancer patients treated with zoledronic acid. AB - BACKGROUND: Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. METHODS: We retrospectively collected data on b MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. RESULTS: The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged >=60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002). CONCLUSIONS: Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA. PMID- 28884072 TI - Ochroconis gallopava bronchitis mimicking haemoptysis in a patient with bronchiectasis. AB - Ochroconis gallopava is an anamorphic mould characterized by slow growth rate and production of a maroon pigment, which has been isolated worldwide from soil, thermal springs, decaying vegetation, and chicken litter. It has been reported to cause localized, mostly pulmonary, and systemic infection in severely immunocompromised patients. We describe the case of a 76-year-old woman known for ulcerative colitis-related bronchiectasis treated with low dose oral steroids, who developed a fungal bronchitis with dark, bloody-like, sputum which was initially misinterpreted as haemoptysis. A filamentary mould grew on sputum culture, and was identified by DNA analysis as Ochroconis gallopava. We observed a significant clinical improvement after 6 weeks of itraconazole therapy. PMID- 28884074 TI - Exophthalmos associated to orbital zygomatic mucocele and complex maxillary malformation in a puppy. AB - A case of exophthalmos due to zygomatic mucocele in a puppy with ipsilateral segmental maxillary atrophy is reported. A 7-month-old, mixed breed, male dog suffered the sudden-onset of unilateral painful exophthalmos and a gradual swelling of the right temporal region. A compressing, right retrobulbar mass was observed by ultrasound. Computed tomography revealed a large multiloculated cyst like lesion of the right zygomatic gland projecting into the orbital space, thus displacing the eyeball. The ipsilateral molar part of the maxillary bone was underdeveloped, besides showing crowded, abnormal, multiple, unerupted maxillary molar teeth in the caudal maxillary region. Modified lateral orbitotomy and a selective caudal maxillary bone access were performed. The cyst-like lesion was removed and the zygomatic gland and the wall was collected for histology, which confirmed the mucocele. Clinical and imaging examinations six months after surgery showed neither recurrence of the mucocele nor ocular abnormalities. A possible common pathogenic mechanism involving these two conditions could be hypothesized. PMID- 28884073 TI - Connectome-based lesion-symptom mapping (CLSM): A novel approach to map neurological function. AB - Lesion-symptom mapping is a key tool in understanding the relationship between structure and function in neuroscience as it can provide objective evidence about which regions are crucial for a given process. Initial limitations with this approach were largely overcome by voxel-based lesion-symptom mapping (VLSM), a method introduced in the early 2000s, which allows for a whole-brain approach to study the association between damaged areas and behavioral impairment by applying an independent statistical test at every voxel. By doing so, this technique eliminated the need to predefine regions of interest or classify patients into groups based on arbitrary cutoff scores. VLSM has nonetheless its own limitations; chiefly, a bias towards recognizing cortical necrosis/gliosis but with poor sensitivity for detecting injury along long white matter tracts, thus ignoring cortical disconnection, which can per se lead to behavioral impairment. Here, we propose a complementary method that, instead, establishes a statistical relationship between the strength of connections between all brain regions of the brain (as defined by a standard brain atlas) and the array of behavioral performance seen in patients with brain injury: connectome-based lesion-symptom mapping (CLSM). Whole-brain CLSM therefore has the potential to identify key connections for behavior independently of a priori assumptions with applicability across a broad spectrum of neurological and psychiatric diseases. We propose that this approach can further our understanding of brain-structure relationships and is worth exploring in clinical and theoretical contexts. PMID- 28884075 TI - Laryngeal paralysis associated with a muscle pseudotumour in a young dog. AB - An 18-month-old male entire Bloodhound dog was presented with a six-week history of progressive inspiratory dyspnoea, stridor, dysphonia and exercise intolerance. CT scan performed elsewhere had revealed the presence of an unencapsulated nodular mass (3x1x5 cm) dorsal to the larynx and first tracheal rings. Laryngoscopy demonstrated the presence of bilateral laryngeal paralysis and distorted laryngeal architecture suggestive of extraluminal compression. Histopathology results of incisional biopsies from the mass were suggestive of a benign non-neoplastic muscular lesion. Surgery was performed to manage laryngeal paralysis and attempt mass excision. A second histopathology examination confirmed an inflammatory and dysplastic lesion suggestive of a pseudotumour. All clinical signs resolved after surgery and at the 13 months follow-up the dog remains asymptomatic. To the authors' knowledge, this is the first report of a case of laryngeal paralysis caused by a muscle pseudotumour in a young dog. PMID- 28884076 TI - Effects of storage temperature on the quantity and integrity of genomic DNA extracted from mice tissues: A comparison of recovery methods. AB - Efficient extraction of genomic DNA (gDNA) from biological materials found in harsh environments is the first step for successful forensic DNA profiling. This study aimed to evaluate two methods for DNA recovery from animal tissues (livers, muscles), focusing on the best storage temperature for DNA yield in term of quality, quantity, and integrity for use in several downstream molecular techniques. Six male Swiss albino mice were sacrificed, liver and muscle tissues (n=32) were then harvested and stored for one week in different temperatures, -20 degrees C, 4 degrees C, 25 degrees C and 40 degrees C. The conditioned animal tissues were used for DNA extraction by Chelex-100 method or NucleoSpinC Blood and Tissue kit. The extracted gDNA was visualized on 1.5% agarose gel electrophoresis to determine the quality of gDNA and analysed spectrophotometrically to determine the DNA concentration and the purity. Both methods, Chelex-100 and NucleoSpin Blood and Tissue kit found to be appropriate for yielding high quantity of gDNA, with the Chelex 100 method yielding a greater quantity (P < 0.045) than the kit. At -20 degrees C, 4 degrees C, and 25 degrees C temperatures, the concentration of DNA yield was numerically lower than at 40 degrees C. The NucleoSpinC Blood and Tissue kit produced a higher (P=0.031) purity product than the Chelex-100 method, particularly for muscle tissues. The Chelex-100 method is cheap, fast, effective, and is a crucial tool for yielding DNA from animal tissues (livers, muscles) exposed to harsh environment with little limitations. PMID- 28884077 TI - Environmentally toxicant exposures induced intragenerational transmission of liver abnormalities in mice. AB - Environmental toxicants such as chemicals, heavy metals, and pesticides have been shown to promote transgenerational inheritance of abnormal phenotypes and/or diseases to multiple subsequent generations following parental and/or ancestral exposures. This study was designed to examine the potential transgenerational action of the environmental toxicant trichloroethane (TCE) on transmission of liver abnormality, and to elucidate the molecular etiology of hepatocyte cell damage. A total of thirty two healthy immature female albino mice were randomly divided into three equal groups as follows: a sham group, which did not receive any treatment; a vehicle group, which received corn oil alone, and TCE treated group (3 weeks, 100 MUg/kg i.p., every 4th day). The F0 and F1 generation control and TCE populations were sacrificed at the age of four months, and various abnormalities histpathologically investigated. Cell death and oxidative stress indices were also measured. The present study provides experimental evidence for the inheritance of environmentally induced liver abnormalities in mice. The results of this study show that exposure to the TCE promoted adult onset liver abnormalities in F0 female mice as well as unexposed F1 generation offspring. It is the first study to report a transgenerational liver abnormalities in the F1 generation mice through maternal line prior to gestation. This finding was based on careful evaluation of liver histopathological abnormalities, apoptosis of hepatocytes, and measurements of oxidative stress biomarkers (lipid peroxidation, protein carbonylation, and nitric oxide) in control and TCE populations. There was an increase in liver histopathological abnormalities, cell death, and oxidative lipid damage in F0 and F1 hepatic tissues of TCE treated group. In conclusion, this study showed that the biological and health impacts of environmental toxicant TCE do not end in maternal adults, but are passed on to offspring generations. Hence, linking observed liver abnormality in the offspring to environmental exposure of their parental line. This study also illustrated that oxidative stress and apoptosis appear to be a molecular component of the hepatocyte cell injury. PMID- 28884078 TI - Effects of topical flurbiprofen sodium, diclofenac sodium, ketorolac tromethamine and benzalkonium chloride on corneal sensitivity in normal dogs. AB - To evaluate corneal sensitivity by using the Cochet-Bonnet(r) esthesiometer in normal canine eyes at different time points following instillation of three different topical non-steroidal anti-inflammatory drugs (flurbiprofen sodium 0.03%, diclofenac sodium 0.1% and ketorolac tromethamine 0.5%) and benzalkonium chloride 0.01%. Six healthy mixed breed dogs from the same litter were used in two different stages. First, one drop of flurbiprofen sodium 0.03% and diclofenac sodium 0.1% in each eye; second, one drop of ketorolac tromethamine 0.5% and benzalkonium chloride 0.01% in each eye. Baseline esthesiometry was obtained before eye drop application and every 15 minutes thereafter until a total of 105 minutes of evaluation time. A one-week interval was allowed between the two treatment phases. Statistical analysis was used to compare means according to time of evaluation and drug used. Diclofenac sodium 0.1% decreased corneal sensitivity at 75 and 90 minutes (P > 0.015) with possible interference on neuronal nociceptive activity and analgesic effect while ketorolac tromethamine 0.5% did not show any variation for esthesiometry means along the evaluation. Flurbiprofen sodium 0.03% resulted in increased esthesiometry values 30 minutes after instillation (P > 0.013), increasing corneal sensitivity and possibly producing a greater irritant corneal effect over its analgesic properties. Benzalkonium chloride 0.01% significantly increased corneal sensitivity at 15 minutes of evaluation (P > 0.001), most likely resulting from its irritating effect. Esthesiometry did not allow a definite conclusion over the analgesic effect of the NSAIDs tested; however it was effective in detecting fluctuations in corneal sensitivity. PMID- 28884079 TI - Podophyllotoxin: a novel potential natural anticancer agent. AB - OBJECTIVE: The aim of the present review is to give an overview about the role, biosynthesis, and characteristics of Podophyllotoxin (PTOX) as a potential antitumor agent with particular emphasis on key biosynthesis processes, function of related enzymes and characterization of genes encoding the enzymes. MATERIALS AND METHODS: Google scholar, PubMed and Scopus were searched for literatures which have studied identification, characterization, fermentation and therapeutic effects of PTOX and published in English language until end of 2016. RESULTS: PTOX is an important plant-derived natural product, has derivatives such as etoposide and teniposide, which have been used as therapies for cancers and venereal wart. PTOX structure is closely related to the aryltetralin lactone lignans that have antineoplastic and antiviral activities. Podophyllum emodi Wall. (syn. P. hexandrum) and Podophyllum peltatum L. (Berberidaceae) are the major sources of PTOX. It has been shown that ferulic acid and methylenedioxy substituted cinnamic acid are the enzymes involved in PTOX synthesis. PTOX prevents cell growth via polymerization of tubulin, leading to cell cycle arrest and suppression of the formation of the mitotic-spindles microtubules. CONCLUSION: Several investigations have been performed in biosynthesis of PTOX such as cultivation of these plants, though they were unsuccessful. Thus, it is important to find alternative sources to satisfy the pharmaceutical demand for PTOX. Moreover, further preclinical studies are warranted to explore the molecular mechanisms of these agents in treatment of cancer and their possible potential to overcome chemoresistance of tumor cells. PMID- 28884080 TI - Antibacterial, antioxidant and cell proliferative properties of Coccinia grandis fruits. AB - OBJECTIVE: Little knowledge is available on the antimicrobial and antioxidant properties of Coccina grandis fruits and no study has reported on its cell proliferative property. The aim of this study was to examine the antimicrobial, antioxidant and cell proliferative property of fruits of C. grandis. MATERIALS AND METHODS: Fruits of C. grandis were extracted using water; ethanol and acetone by cold and hot Soxhlet extraction. The antibacterial activities of the extracts were tested against Staphylococcusaureus,Enterococcusfaecalis,Escherichiacoli and Pseudomonasaeruginosa using the modified Kirby-Bauer diffusion method and compared against erythromycin. The antioxidant property was determined using Cayman's antioxidant assay; whereas cell proliferation/cytotoxic properties were evaluated using the Cell Titer 96 Aqueous One Solution Cell MTS assay with MDA-MB 321 breast cancer cells. Data were analyzed for correlation and differences using unpaired student's t-test and one-way ANOVA. A p value of <0.05 was considered statistically significant. RESULTS: Both cold and hot ethanol and acetone extracts of C. grandis fruits showed some degree of bacterial growth inhibition. Acetone extracts exhibited higher antibacterial activity. Both ethanol extracts showed antioxidant property when compared with standard Trolox. In contrary to cytotoxicity, all four extracts showed cell proliferation compared to controls at different concentrations. However, acetone extracts exhibited greater cell proliferation compared to ethanol extracts and cold extracts performed better than the hot extracts. CONCLUSION: C. grandis fruits exhibited some degree of antimicrobial, antioxidant and cell proliferative properties. Further investigation is warranted to isolate, confirm and characterize phytochemicals that are responsible for the medicinal properties observed. PMID- 28884081 TI - The Effect of ginger herbal spray on reducing xerostomia in patients with type II diabetes. AB - OBJECTIVE: The aim of the present study is to evaluate the effect of ginger herbal spray on reducing dry mouth in patients with Type II diabetes. MATERIALS AND METHODS: This clinical trial was conducted on 20 patients with Type II diabetes suffering from dry mouth. The control individual for each patient was the same patient himself/herself. Each patient filled out his/her questionnaire at three different times, (before treatment, after treatment with placebo, and after taking the drug). Furthermore, the Schirmer test was performed to measure the flow of saliva in the patients. The drug and the placebo were prepared as oral sprays containing herbal extracts of ginger. RESULTS: The mean amount of saliva after using the ginger plant spray increased significantly (p<0.001). The mean amount of saliva after treatment with medication was considerably different from the mean amount of saliva after treatment with the placebo (p<0.001). Our study included patients aged between 49 and 69 years old, (mean age 58.6 years old, and the standard deviation 5.3). The minimum and the maximum periods of type II diabetes were 2 and 21 years, the mean and the standard deviation of which were 8.8 and 5.8, respectively. CONCLUSION: With regard to the effectiveness of ginger herbal spray in rapidly increasing the patients' saliva and satisfaction as well as the acceptability of this type of medicine to treat dry mouths, ginger herbal spray could act as a new, cheap, and available treatment for diabetic patients with dry mouth. PMID- 28884082 TI - Effects of pomegranate seed oil on oxidant/antioxidant balance in heart and kidney homogenates and mitochondria of diabetic rats and high glucose-treated H9c2 cell line. AB - OBJECTIVE: Oxidative stress is a major cause of diabetes complications. The present study aimed to investigate the beneficial effects of Pomegranate Seed Oil (PSO) on diabetes-induced changes in oxidant/antioxidant balance of the kidney, heart and mitochondria from rats and H9c2 cell line. MATERIALS AND METHODS: In these in vivo and in vitro studies, male rats were divided into four groups (twelve each): group 1 served as control, group 2-4 received a single dose of streptozotocin (60 mg/kg, i.p), groups 3 and 4 received PSO (0.36 and 0.72 mg/kg/daily, gavage), respectively. After three weeks, six rats of each group and one week later the remaining animals were anaesthetized and the hearts and kidneys were removed and homogenized. Mitochondrial fractions were separated and enzyme activities were measured in each sample. H9c2 cells were pretreated with high levels of glucose (35 mM), and then, incubated with PSO. Finally, cell viability test, reactive oxygen species production and lipid peroxidation were evaluated. RESULTS: Significant reduction in enzymes activity (Superoxide dismutase, Glutathione S-transferase and Paraoxonase 1), compensatory elevation in Glutathione Reductase, Glutathione Peroxidase and Catalase activity followed by reduction after one week and significant elevation in Oxidative Stress Index (OSI) were observed in diabetic group. PSO treatment resulted in a significant increase in enzymes activity and decreased OSI values compared to diabetic group in both tissue and mitochondrial fractions. PSO remarkably decreased glucose induced toxicity, ROS level and lipid peroxidation in H9c2 cells. CONCLUSION: Results suggested that PSO has a protective effect against diabetes-induced alterations in oxidant/antioxidant balance in tissues, mitochondrial and H9c2 cell line. PMID- 28884083 TI - Hydro-alcoholic extract of Matricaria recutita exhibited dual anti-spasmodic effect via modulation of Ca2+ channels, NO and PKA2-kinase pathway in rabbit jejunum. AB - OBJECTIVE: Several studies have shown the antispasmodic activity of Matricariarecutita without detailing the underlying mechanism(s). The present study was designed to determine whether the antispasmodic mechanisms of M. recutita extract mediated via histaminergic/cholinergic receptors, Ca2+channels, activation of PKA2 and NO release in isolated rabbit jejunum. MATERIALS AND METHODS: The concentration- dependent (3 * 10-3-1.3 * 10-2 mg/ml) antispasmodic effect of the hydro-alcoholic extract of M. recutita flowers was studied in isolated rabbit jejunum. The isolated jejunum preparations were divided into seven groups, including the pharmacological probes that modulate cholinergic, histaminergic, and nitrergic receptors, as well as PKA2. RESULTS: M. recutita inhibited spontaneous smooth muscle contractility of the jejunum in a concentration-dependent manner (3 * 10-3-1.3 * 10-2 mg/ml) and reduced both K+- and Ca2+-induced contractions, which is similar to the effect of verapamil. The antispasmodic effect of M. recutita was inhibited by H89 (a PKA2 inhibitor). The myorelaxant effect of M. recutita increased in the presence of ACh/His and H89. CONCLUSION: M. recutita evoked antispasmodic and spasmolytic effects mediated through different signaling pathways. Our results have shown this dual inhibitory effect is mediated by blocking Ca2+ channels, activating His and ACh receptors, releasing NO, and activating PKA2. PMID- 28884084 TI - Crocin prevents acute angiotensin II-induced hypertension in anesthetized rats. AB - OBJECTIVE: Angiotensin II (Ang II), the main product of renin-angiotensin system (RAS) has a well-known role in cardiovascular regulation. Over-production of Ang II is one of the important underlying mechanisms of hypertension. In this study, the effect of crocin on cardiovascular responses in rats with acute hypertension induced by Ang II was evaluated. MATERIALS AND METHODS: Rats were divided into six groups (n = 6): 1) Control: rats that received saline, 2) Ang II: rats that received Ang II (300 ng/kg) infused in two min, 3) Losartan (Los) + Ang II : rats that received Los (10 mg/kg, i.v) before Ang II, and 4-6) Crocin (Cro) + Ang II groups: rats that received three doses of crocin (50, 100 and 200 mg/kg, slow i.v) 10 min before Ang II. Femoral artery and vein were cannulated for recording of cardiovascular parameters and injection of drugs, respectively. Systolic blood pressure (SBP), mean arterial blood pressure (MAP) and heart rate (HR) were continuously recorded by power lab system. After injection of reagents and extracts, maximum changes (?) of MAP, SBP and HR were recorded and compared with control group. RESULTS: Ang II (300 ng/kg) increased maximal changes in MAP, SBP and HR compared to control group (p<0.001) and Los significantly attenuated these effects of Ang II (p<0.001). Maximal changes of MAP, SBP and HR induced by Ang II, were significantly attenuated by pretreatment with all doses of crocin (50,100 and 200) (p<0.05 and p<0.001). Also, changes of MAP, SBP and HR in Crocin + Ang II groups were significantly different from Los + Ang II group (p<0.05 and p<0. 01). CONCLUSION: Based on the effects of crocin on acute Ang II-induced hypertension, it is hypothesized that the cardiovascular improving effects of crocin may be mediated via suppressing of RAS. PMID- 28884085 TI - Anti-anxiety and hypnotic effects of ethanolic and aqueous extracts of Lippia citriodora leaves and verbascoside in mice. AB - OBJECTIVES: The extract of Lippia citriodora and its main component, verbascoside, are known for their hypnotic effects in traditional medicine. In this study, the anxiolytic and hypnotic effects of L. citriodora leave extracts and verbascoside were evaluated in mice. MATERIALS AND METHODS: Animals were divided into 11 groups of six mice each. Group I received normal saline, Group II received Diazepam (2 mg/kg) as positive control, Groups III, IV and V received L. citriodora ethanolic extracts (50, 100 and 200 mg/kg, respectively), Groups VI, VII and VIII received L. citriodora aqueous extracts (50, 100 and 200 mg/kg, respectively) and Groups IX, X and XI received Verbascoside (25, 50 and 100 mg/kg, respectively). All agents were administrated intraperitoneally. To evaluate hypnotic activity, pentobarbital sleeping test, and for anxiolytic activity, elevated plus-maze (EPM), locomotor activity, open field and motor coordination (rotarod test) tests were used. To understand the role of GABAA receptor, flumazenil was also administered. RESULTS: The extracts and verbascoside increased the time spent and number of entries in the open arms of EPM. Moreover, these agents significantly increased the sleeping time induced by pentobarbital. In addition, the highest dose of extracts and verbascoside reduced time spent on the rod and total locomotion in the open field tests, respectively. Flumazenil inhibited the effects of extracts and verbascoside in EPM and hypnotic tests. CONCLUSION: These results suggested that ethanolic and aqueous extracts of L. citriodora and verbascoside exhibit anxiolytic, hypnotic and muscle relaxant effects especially at the highest doses and these effects are partially due to the interaction with GABAA receptor. PMID- 28884086 TI - Anti-nociceptive and anti-inflammatory effects of the methanolic extract of Opuntia humifusa stem. AB - OBJECTIVE: Opuntia humifusa (O. humifusa) Raf. has been used for the prevention and treatment of rheumatoid arthritis, inflammation, and cancer. Our study was designed to unveil the anti-nociceptive and anti-inflammatory effects of the methanolic extract of O. humifusa Raf stem (OHS). MATERIALS AND METHODS: The anti nociceptive effect was measured by hot plate, acetic acid-induced writhing, and tail flick assays in mice and rats. Moreover, the anti-inflammatory effect was measured by vascular permeability and carrageenan and serotonin-induced paw edema tests in rats. Furthermore, anti-inflammatory effect was also measured using macrophage-like LPS-induced RAW 264.7 cells. RESULTS: OHS extract inhibited acetic acid-induced writhing (p<0.0001), and delayed the reaction time of mice to the hot plate-induced thermal stimulation (p<0.0001) and tail flick tests (p<0.05). OHS extract attenuated the carrageenan and serotonin-induced paw edema in rats (p<0.001). Similarly, OHS extract significantly decreased Evans blue concentration in acetic acid induced vascular permeability test (p<0.0001), revealing its strong anti-inflammatory effect. Finally, among four different fractions of OHS extract, n-butanol fraction strongly decreased NO production (p<0.0001) and iNOS expression in LPS-induced RAW 264.7 cells. CONCLUSION: Our results suggest that the methanolic extract of O. humifusa stem can be used to develop a therapeutic or supportive drug and/or functional food against pain and inflammation related diseases. PMID- 28884087 TI - Curcumin attenuates harmful effects of arsenic on neural stem/progenitor cells. AB - OBJECTIVE: Arsenic, an environmental pollutant, decreases neuronal migration as well as cellular maturation and inhibits the proliferation of neural progenitor cells. Curcumin has been described as an antioxidant and neuroprotective agent with strong therapeutic potential in some neurological disorders. Human adipose derived stem cells (hADSCs), a source of multipotent stem cells, can self-renew and differentiate into neural cells. The aim of the present study was to investigate the preventive effect of curcumin against arsenic toxic effects on the viability, telomerase activity, and apoptosis of neural stem/progenitor cells (NSPCs) derived from hADSCs. MATERIALS AND METHODS: The characteristics of human adipose tissue were identified by immunocytochemistry for surface markers namely, CD105, CD73, and CD90. Using neurosphere assay, hADSCs were differentiated into neuronal cells. To characterize neural cells, expression of nestin, SOX2, MAP2, and GFAP were assessed by immunocytochemistry. Cytotoxicity and viability of NSPCs were evaluated by MTT assay. Reactive oxygen species (ROS) generated by arsenic exposure, were measured and caspase 3/7 activity and caspase-3 processing as well as the telomerase activity were determined. RESULTS: The isolated hADSCs positively expressed CD105, CD73, and CD90. Nestin, Sox2, GFAP, and MAP2 were expressed in the neurospheres derived from hADSCs. Curcumin/arsenic co-treatment significantly increased telomerase activity of NSPCs compared to arsenic group. Furthermore, curcumin significantly reduced arsenic-induced apoptosis (via inactivation of caspases) as well as arsenic-associated ROS generation. CONCLUSION: Our findings revealed that curcumin has the potential to prevent harmful effects of arsenic on neurogenesis. PMID- 28884089 TI - Splenic microRNA Expression Profiles and Integration Analyses Involved in Host Responses to Salmonella enteritidis Infection in Chickens. AB - To understand the role of miRNAs in regulating genes involved in the host response to Salmonella enteritidis (SE) infection, next generation sequencing was applied to explore the altered splenic expression of microRNAs (miRNAs) and deregulated genes in specific-pathogen-free chickens. Birds were either infected or not (controls, C) and those challenged with SE were evaluated 24 h later and separated into two groups on the basis of the severity of clinical symptoms and blood load of SE: resistant (R, SE challenged-slight clinical symptoms and <105 cfu / 10 MUL), and susceptible (S, SE challenged-severe clinical symptoms and >107 cfu/10 MUL). Thirty-two differentially expressed (DE) miRNAs were identified in spleen, including 16 miRNAs between S and C, 13 between R and C, and 13 between S and R. Through integration analysis of DE miRNAs and mRNA, a total of 273 miRNA-target genes were identified. Functional annotation analysis showed that Apoptosis and NOD-like receptor signaling pathway and adaptive immune response were significantly enriched (P < 0.05). Interestingly, apoptosis pathway was significantly enriched in S vs. C, while NOD-like receptor pathway was enriched in R vs. C (P < 0.05). Two miRNAs, gga-miR-101-3p and gga-miR-155, in the hub positions of the miRNA-mRNA regulatory network, were identified as candidates potentially associated with SE infection. These 2 miRNAs directly repressed luciferase reporter gene activity via binding to 3'-untranslated regions of immune-related genes IRF4 and LRRC59; over-expressed gga-miR-155 and interference gga-miR-101-3p in chicken HD11 macrophage cells significantly altered expression of their target genes and decreased the production of pro inflammatory cytokines. These findings facilitate better understanding of the mechanisms of host resistance and susceptibility to SE infection in chickens. PMID- 28884090 TI - Combination of Erythromycin and Curcumin Alleviates Staphylococcus aureus Induced Osteomyelitis in Rats. AB - Osteomyelitis is commonly caused by Staphylococcus aureus. Both erythromycin and curcumin can suppress S. aureus growth, but their roles in osteomyelitis are barely studied. We aim to explore the activities of erythromycin and curcumin against chronical osteomyelitis induced by methicillin-resistant S. aureus (MRSA). Chronicle implant-induced osteomyelitis was established by MRSA infection in male Wistar rats. Four weeks after bacterial inoculation, rats received no treatment, erythromycin monotherapy, curcumin monotherapy, or erythromycin plus curcumin twice daily for 2 weeks. Bacterial levels, bone infection status, inflammatory signals and side effects were evaluated. Rats tolerated all treatments well, with no death or side effects such as, diarrhea and weight loss. Two days after treatment completion, erythromycin monotherapy did not suppress bacterial growth and had no effect in bone infection, although it reduced serum pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL) 6. Curcumin monotherapy slightly suppressed bacterial growth, alleviated bone infection and reduced TNF-alpha and IL-6. Erythromycin and curcumin combined treatment markedly suppressed bacterial growth, substantially alleviated bone infection and reduced TNF-alpha and IL-6. Combination of erythromycin and curcumin lead a much stronger efficiency against MRSA induced osteomyelitis in rats than monotherapy. Our study suggests that erythromycin and curcumin could be a new combination for treating MRSA induced osteomyelitis. PMID- 28884092 TI - Objectivity in scientific publication. PMID- 28884088 TI - Oncolytic Viral Therapy for Mesothelioma. AB - The limited effectiveness of conventional therapy for malignant pleural mesothelioma demands innovative approaches to this difficult disease. Even with aggressive multimodality treatment of surgery, radiation, and/or chemotherapy, the median survival is only 1-2 years depending on stage and histology. Oncolytic viral therapy has emerged in the last several decades as a rapidly advancing field of immunotherapy studied in a wide spectrum of malignancies. Mesothelioma makes an ideal candidate for studying oncolysis given the frequently localized pattern of growth and pleural location providing access to direct intratumoral injection of virus. Therefore, despite being a relatively uncommon disease, the multitude of viral studies for mesothelioma can provide insight for applying such therapy to other malignancies. This article will begin with a review of the general principles of oncolytic therapy focusing on antitumor efficacy, tumor selectivity, and immune system activation. The second half of this review will detail results of preclinical models and human studies for oncolytic virotherapy in mesothelioma. PMID- 28884091 TI - Alterations of the Gut Microbiome in Hypertension. AB - Introduction: Human gut microbiota is believed to be directly or indirectly involved in cardiovascular diseases and hypertension. However, the identification and functional status of the hypertension-related gut microbe(s) have not yet been surveyed in a comprehensive manner. Methods: Here we characterized the gut microbiome in hypertension status by comparing fecal samples of 60 patients with primary hypertension and 60 gender-, age-, and body weight-matched healthy controls based on whole-metagenome shotgun sequencing. Results: Hypertension implicated a remarkable gut dysbiosis with significant reduction in within-sample diversity and shift in microbial composition. Metagenome-wide association study (MGWAS) revealed 53,953 microbial genes that differ in distribution between the patients and healthy controls (false discovery rate, 0.05) and can be grouped into 68 clusters representing bacterial species. Opportunistic pathogenic taxa, such as, Klebsiella spp., Streptococcus spp., and Parabacteroides merdae were frequently distributed in hypertensive gut microbiome, whereas the short-chain fatty acid producer, such as, Roseburia spp. and Faecalibacterium prausnitzii, were higher in controls. The number of hypertension-associated species also showed stronger correlation to the severity of disease. Functionally, the hypertensive gut microbiome exhibited higher membrane transport, lipopolysaccharide biosynthesis and steroid degradation, while in controls the metabolism of amino acid, cofactors and vitamins was found to be higher. We further provided the microbial markers for disease discrimination and achieved an area under the receiver operator characteristic curve (AUC) of 0.78, demonstrating the potential of gut microbiota in prediction of hypertension. Conclusion: These findings represent specific alterations in microbial diversity, genes, species and functions of the hypertensive gut microbiome. Further studies on the causality relationship between hypertension and gut microbiota will offer new prospects for treating and preventing the hypertension and its associated diseases. PMID- 28884093 TI - Hamstring injuries: update article. AB - Hamstring (HS) muscle injuries are the most common injury in sports. They are correlated to long rehabilitations and have a great tendency to recur. The HS consist of the long head of the biceps femoris, semitendinosus, and semimembranosus. The patient's clinical presentation depends on the characteristics of the lesion, which may vary from strain to avulsions of the proximal insertion. The most recognized risk factor is a previous injury. Magnetic resonance imaging is the method of choice for the injury diagnosis and classification. Many classification systems have been proposed; the current classifications aim to describe the injury and correlate it to the prognosis. The treatment is conservative, with the use of anti-inflammatory drugs in the acute phase followed by a muscle rehabilitation program. Proximal avulsions have shown better results with surgical repair. When the patient is pain free, shows recovery of strength and muscle flexibility, and can perform the sport's movements, he/she is able to return to play. Prevention programs based on eccentric strengthening of the muscles have been indicated both to prevent the initial injury as well as preventing recurrence. PMID- 28884094 TI - Is it safe to use local anesthesia with adrenaline in hand surgery? WALANT technique. AB - In the past it was taught that local anesthetic should not be used with adrenaline for procedures in the extremities. This dogma is transmitted from generation to generation. Its truth has not been questioned, nor the source of the doubt. In many situations the benefit of use was not understood, because it was often thought that it was not necessary to prolong the anesthetic effect, since the procedures were mostly of short duration. After the disclosure of studies of Canadian surgeons, came to understand that the benefits went beyond the time of anesthesia. The WALANT technique allows a surgical field without bleeding, possibility of information exchange with the patient during the procedure, reduction of waste material, reduction of costs, and improvement of safety. Thus, after passing through the initial phase of the doubts in the use of this technique, the authors verified its benefits and the patients' satisfaction in being able to immediately return home after the procedures. PMID- 28884095 TI - Hand and wrist surgery without suspending warfarin or oral antiplatelet - systematic review. AB - To assess, through a systematic literature review, whether or not it is necessary to suspend antithrombotic medications (warfarin, aspirin, and clopidogrel) to perform elective wrist and hand surgeries. The search for articles was performed using a combination of keywords in the databases available, without scientific design constraints, being selected series with five or more surgeries; the selected articles were analyzed regarding serious (need for surgical treatment) and mild complications (without surgery). Seven articles were retrieved and analyzed; 410 wrist and hand surgeries were performed in patients on warfarin or aspirin and clopidogrel, with three serious complications (0.7%) and 38 mild (9.2%); 2023 surgeries were performed in patients without use of antithrombotics, with zero serious and 18 (0.8%) minor complications. Patients using warfarin or oral antiplatelet (aspirin, clopidogrel, and aspirin associated with clopidogrel) need not suspend the medication to undergo wrist and hand surgery. PMID- 28884096 TI - Finite element analysis of the equivalent stress distribution in Schanz screws during the use of a femoral fracture distractor. AB - To evaluate the mechanical stress and elastic deformation exercised in the thread/shaft transition of Schanz screws in assemblies with different screw anchorage distances in the entrance to the bone cortex, through the distribution and location of tension in the samples. An analysis of 3D finite elements was performed to evaluate the distribution of the equivalent stress (triple stress state) in a Schanz screw fixed bicortically and orthogonally to a tubular bone, using two mounting patterns: (1) thread/shaft transition located 20 mm from the anchorage of the Schanz screws in the entrance to the bone cortex and (2) thread/shaft transition located 3 mm from the anchorage of the Schanz screws in entrance to the bone cortex. The simulations were performed maintaining the same direction of loading and the same distance from the force vector in relation to the center of the hypothetical bone. The load applied, its direction, and the distance to the center of the bone were constant during the simulations in order to maintain the moment of flexion equally constant. The present calculations demonstrated linear behavior during the experiment. It was found that the model with a distance of 20 mm between the Schanz screws anchorage in the entrance to the bone cortex and the thread/shaft transition reduces the risk of breakage or fatigue of the material during the application of constant static loads; in this model, the maximum forces observed were higher (350 MPa). The distance between the Schanz screws anchorage at the entrance to the bone cortex and the smooth thread/shaft transition of the screws used in a femoral distractor during acute distraction of a fracture must be farther from the entrance to the bone cortex, allowing greater degree of elastic deformation of the material, lower mechanical stress in the thread/shaft transition, and minimized breakage or fatigue. The suggested distance is 20 mm. PMID- 28884097 TI - Perilunate carpal dislocation. Clinical evaluation of patients operated with reduction and percutaneous fixation without capsular-ligament repair. AB - OBJECTIVE: To qualitatively assess surgeries performed in patients with perilunate dislocations without associated fractures, who were operated using the closed reduction and percutaneous fixation method. The follow-up time ranged from one to seven years. METHODS: 628 patient records with traumatic wrist injuries, operated by the same group of Hand Surgeons between 2008 and 2014 due to acute trauma were collected, with a mean follow-up of 3.2 years. Of these, 51 were cases of perilunate fracture-dislocations, and 38 were pure perilunate dislocations without associated fractures; of these, only 32 underwent percutaneous fixation without ligamentous repair, thus meeting the inclusion criteria. Of the nine patients with perilunate dislocations who were treated using the closed reduction and percutaneous fixation method, whose mean age was 38 years (range 26-49 years), the dominant side was the left in two-thirds of the cases, and the predominant trauma mechanism was direct trauma. RESULTS: This study is in agreement with the literature, showing that cases treated early present good results. CONCLUSION: 88% of patients who were treated by closed reduction and percutaneous fixation method maintained their daily activities and were assessed as excellent or good by the Clinical Scoring Chart. PMID- 28884098 TI - Are diaphyseal clavicular fractures still treated traditionally in a non-surgical way? AB - OBJECTIVE: To evaluate the decision of orthopedics surgeons regarding which cases they would indicate surgery or non-surgical treatment. METHODS: 20 images of radiographs with fracture in the middle third of the collar bone (AO/OTA 15-B) in anteroposterior view were analyzed, and divided into four groups: group 1 - fracture type AO/OTA 15-B1 without displacement; group 2 - fracture type AO/OTA 15-B1 with displacement; group 3 - fracture type AO/OTA 15-B2; group 4 - fracture type AO/OTA 15-B3. The evaluator was requested to indicate the choice of treatment, surgical or non-surgical. RESULTS: There was no strong correlation between the amount of surgical indications and the working experience or age of the medical evaluator. It was observed that the average of surgical indications in the total sample was 52%. When indications were studied in different areas of Brazil, there was no significant difference among them. No pattern for the Brazilian regions studied was observed in the case analysis. Even within a group (cases of the same complexity), no specific pattern of surgical indication was observed. CONCLUSION: No association between surgical indication and the length of professional experience was found. The Southern and Southeastern regions were those that most recommended surgeries in groups 2, 3, and 4. In no region the same level of surgical indication for cases of the same complexity rate was kept. PMID- 28884099 TI - Medial patellofemoral ligament and medial patellotibial ligament reconstruction in children: preliminary results. AB - OBJECTIVE: The aim of this study was to evaluate the reconstruction of the medial patellofemoral ligament associated with the medial patellotibial ligament in skeletally immature patients. METHOD: This is a case series study in patients with patellar instability with open physis. In total, seven patients were evaluated: four males and three females were operated using the proposed technique. Patients with open physis who had more than two episodes of recurring patellar dislocation were included. No patients underwent additional procedures. The distance from the anterior tibial tuberosity to the trochlea grove (TT-TG) was measured in all patients. On physical examination, the inverted J-sign, the apprehension sign, and the knee range of motion parameters were used in the pre- and post-operative period. In addition, the Kujala and Lysholm scores were applied before and 12 months after surgery. The results were analyzed with the Wilcoxon test. RESULTS: The mean age of the patients was 11.28 in both genders. Comparing the data of the pre- and post-operative period, the inverted J-sign was present in six patients (85.7%) vs. absent in one (14.3%). The apprehension sign was absent in cases in the postoperative period; the range of motion was 117.85 +/- 8.09 vs. 148.57 +/- 3.77. The Kujala score was 42.57 +/- 8.9 vs. 88.57 +/- 5.09 and the Lysholm scores were classified as excellent or good in 28.6% and 71.4%, respectively. CONCLUSION: The combined reconstruction of the medial patellofemoral ligament combined with the medial patellotibial ligament in skeletally immature patients with predisposing factors, presents satisfactory results without episodes of recurrence or residual subluxation; according to these preliminary results, it should be considered as a treatment option. PMID- 28884100 TI - Relationship between the critical shoulder angle and the development of rotator cuff lesions: a retrospective epidemiological study. AB - OBJECTIVE: To perform a retrospective epidemiological study of radiographs in order to evaluate the relationship between the anatomy of the scapula and the development of rotator cuff injuries (RCIs). METHODS: This study retrospectively evaluated the relation of the critical shoulder angle (CSA) and RCIs from January 2011 to November 2013; patients were examined in the Orthopedics and Traumatology Department of a university hospital. The CSA was measured by radiographic standardization of two groups: a control group of 34 asymptomatic shoulders and a study group of 44 shoulders with complete RCIs. RESULTS: The mean age in the control group was 59.97 years (45-84) and the mean age in the group with RCIs was 59.75 years (45-84). Regarding the CSA, the control group had a mean angle of 33.59 degrees (+/-3.37) and the group with RCIs had a mean angle of 39.75 degrees (+/-5.35; p < 0.007). CONCLUSION: There is an association between CSA and RCIs. PMID- 28884101 TI - What is the best fixation technique for the treatment of supracondylar humerus fractures in children? AB - OBJECTIVE: To define the best technique for the surgical treatment of supracondylar fracture of the humerus (SFH) in children, evaluating percutaneous pinning with side wires vs. cross-pinning. METHODS: Randomized controlled trials using the Medline, CAPES, and BIREME. The criteria for inclusion of articles criteria were: (1) randomized controlled trials (RCTs) comparing percutaneous wire fixation techniques, (2) SFH Gartland II B, III, and IV, and (3) children aged 1-14 years. The following were used as main variables: incidence of iatrogenic injury to the ulnar nerve and loss reduction. RESULTS: Eight studies were selected (521 patients) comparing surgical treatment with pinning in supracondylar fracture of the humerus in children Gartland II type B, III or IV. Iatrogenic injury to the ulnar nerve was greater with the cross-pinning technique, with RR 0.28 and p = 0.03, while the mini-open technique presented RR 0.14 and p = 0.2. A statistically significant greater loss of reduction in the lateral pinning was observed in FSU Gartland III and IV(p = 0.04). CONCLUSION: Based upon this meta-analysis of prospective randomized clinical trials, the following is recommended: (1) percutaneous pinning with lateral wires in supracondylar fractures of the humerus in children classified as Gartland II type B; (2) use of crossed wires for Gartland type III or IV, using the mini-open technique for the medial wire. PMID- 28884102 TI - Effects of preoperative walking ability and patient's surgical education on quality of life and functional outcomes after total knee arthroplasty. AB - OBJECTIVE: Prospectively analyze the effect of preoperative walking status and the patient's surgical education on functional outcomes and the three dimensions of quality of life (QoL) (pain, physical function, and mental health) after elective total knee arthroplasty (TKA). METHODS: A comparative analysis on the QoL and functional outcomes in patients who underwent total knee arthroplasty between January 2014 and June 2015. To compare effects of the patient's walking status and knowledge of the surgical procedure on QoL and functional outcomes following TKA by means of SF-36 questionnaire, CES D10, VAS, KSS, KSFS, WOMAC, as well as Friedmann and Wyman scores, 10MWT, and 30-second timed chair test, assessed before the operation and one, three, and six months after the operation. RESULTS: There were 168 knees in 154 patients: 46.75% men and 53.24% women. 52.38% of knees had grade-III OA and 40.47% of knees had grade-IV OA. Preoperatively, SF-36 PCS was 33.2 and MCS was 35.4. Mean KSS and KSFS in females was 37.3 (16.2) and 31.5 (13.8); in males it was 49.2 (18.4) and 42.5 (15.7), respectively. Mean WOMAC scores were 64.2 in females and 56.5 in males. Mean VAS and CES D10 scores were 8.8 and 8.2 in females, and 6.9 and 6.4 in males, respectively. Post operatively at the first, third, and sixth month, significant improvements in QoL and mean SF-36, CES D10, VAS, KSS, KSFS, WOMAC, and Friedmann and Wyman scores were observed, as well as in the 10MWT and 30 s timed chair test scores. Patients with better preoperative functional activity and satisfactory understanding of TKA presented a better functional performance and achieved a good quality life (p < 0.01). DISCUSSION: Surgeons educate TKA candidates regarding the surgical procedure, the nature of implants, and how the procedure would affect their lifestyle and what their expectations from TKA should be. These crucial considerations should boost their confidence, enhancing their involvement and cooperation in post-surgical rehabilitation, thereby improving their QoL, functional results, and post TKA experience. CONCLUSION: TKA candidates with good preoperative walking ability and understanding of knee arthroplasty have better QoL in early and late post-surgery periods. Patient's lifestyle and understanding significantly enhances the postoperative functional ability. PMID- 28884103 TI - Lateral patellar retinacular release: changes over the last ten years. AB - Lateral retinacular release is a useful resource in knee surgery that can be used for disorders of the extensor mechanism. For many years, it was indiscriminately used in the treatment of the various patellofemoral joint alterations, with conflicting functional results. This study aimed to analyze the changes that have occurred in the indications and clinical effectiveness of lateral retinacular release by reviewing the relevant literature of the past ten years, comparing it to the classic literature on the subject. It was found that less extensive releases decompress the lateral patellar facet, helping with pain control, while decreasing the risks of medial subluxation. Nowadays, there is clear evidence for its indication in the lateral patellar hypercompression syndrome associated with anterior knee pain, as long as there is no related instability; furthermore, it will normally play an adjuvant role in extensor mechanism alignment surgeries for cases of recurrent patellar instability. The initial results for symptomatic patellofemoral osteoarthritis are promising when lateral release is combined with cartilage debridement; in total knee replacement, it is more commonly used for the correction of valgus deformity in order to improve the components' congruency. Finally, distinguishing the different patellofemoral joint pathologies is seen as crucial in order to indicate this procedure. Further randomized control trials that compare surgical techniques with long-term results are still needed. PMID- 28884104 TI - Diffuse pigmented villonodular synovitis in knee joint: diagnosis and treatment. AB - Pigmented villonodular synovitis is a rare proliferative condition of the synovium. Although the condition can present in any joint, the knee is the most commonly affected site. Despite being a benign condition, pigmented villonodular synovitis is often aggressive, with marked extra-articular extension in some cases. Monoarticular involvement occurs in two forms: localized and diffuse. The latter is more common, with a high recurrence rate. There is no standard method of management of this lesion. Open surgery is a classical and effective method for treatment. Arthroscopic synovectomy, however, has gained popularity, and has several advantages over the open technique particularly in exclusively articular cases. The combined approach is suggested in cases with extra-articular involvement. Synovectomy through any approach may prevent secondary osteoarthritis and subsequent joint arthroplasty. Internal irradiation or external beam radiation as an adjuvant treatment to surgical synovectomy appears to decrease the rate of local recurrence in diffuse cases. The authors observed a great heterogeneity in reporting of functional results, and specific conclusions should not be drawn. Each patient should be managed in accordance with his/her particular condition. PMID- 28884105 TI - Analysis of postoperative monitoring of patients undergoing shoulder arthroscopy for anterior instability. AB - OBJECTIVE: Analyze the postoperative follow-up of patients undergoing shoulder arthroscopy for treatment of anterior instability and correlate with the prevalence of recurrence. METHODS: A six-question survey was applied by phone and mail to 65 patients, seeking information on the current result of the surgical procedure. All patients were treated arthroscopically for anterior shoulder instability, with at least 12 months of postoperative time. Patients with associated posterior labial lesions and revision surgeries were not included. RESULTS: At the time of the survey the patients had a median of 56 (IQR: 34.5 110.5) postoperative months. The mean sample age was 24.6 years (maximum = 47, minimum = 12; SD = 7.3). Complaint of pain in the shoulder was observed in 20 patients (30.7%). Dislocation recurrence was observed in 10 patients (15.3%). Forty-four patients (67.6%) considered their shoulder normal, which was more frequent in non-recurrence patients (p < 0.001). Forty-three patients (66.1%) returned to their previous level of sport and there was no difference between recurrence and non-recurrence patients (p = 0.456). It was found that the prevalence of recurrence was 5.6 (95% CI: 1.30-24.46) times higher in individuals who abandoned monitoring before six months postoperatively (p = 0.012). CONCLUSION: The abandonment of postoperative monitoring in the early stages, when the patients receive orientation for muscle strengthening, proprioceptive education, and dangerous movements to avoid, can increase the rates of recurrent shoulder dislocation in patients treated for anterior instability by arthroscopy. PMID- 28884106 TI - Understanding posterior meniscal roots lesions: from basic science to treatment. AB - The variability of symptoms and the fact that they are not easily recognized in imaging studies make the diagnosis and treatment of posterior meniscal roots lesions a challenging task to the orthopedist. In recent years, a more precise understanding of the anatomy and biomechanical impair of the knee joint in these cases has enabled great advances in therapeutic approaches. Well-documented studies have shown that the repair of these lesions presents superior functional and clinical improvement when compared with meniscectomy. However, the progression of degenerative joint changes in the long-term still exhibits conflicting results. PMID- 28884107 TI - Giant cell tumor locally advanced around the knee: treatment and literature review. AB - Giant cell tumor (GCT) is a benign bone tumor with aggressive characteristics. They are more prevalent in the third decade of life and demonstrate a preference for locating in the epiphyseal region of long bones. They have a high local recurrence rate, which depends on the type of treatment and initial tumor presentation. The risk of lung metastases is around 3%. Between October 2010 and August 2014, nine patients diagnosed with locally advanced GCT or with pathological fracture to the knee level underwent surgical treatment. The aim of this study was to evaluate the results of the treatment, particularly with regard to relapse, and to conduct a literature review. There was a predominance of males (77.7%). The most common location was the distal femur. Four patients (44%) developed local recurrence in the first year after surgery, three in distal femur and one in proximal tibia. Of the two patients with pathologic fracture at diagnosis, one of them presented recurrence after five months. The treatment of GCT is still a challenge. The authors believe that the best treatment method is wide resection and reconstruction of bone defects with non-conventional endoprostheses. Patients should be aware and well informed about the possible complications and functional losses that may occur as a result of the surgical treatment chosen and the need for further surgery in the medium and long term. PMID- 28884108 TI - Characteristics and clinical aspects of patients with spinal cord injury undergoing surgery. AB - OBJECTIVE: To identify the characteristics of patients with spinal cord injury (SCI) undergoing surgery. METHODS: Previously, 321 patients with SCI were selected. Clinical and socio-demographic variables were collected. RESULTS: A total of 211 patients were submitted to surgery. Fall and injuries in the upper cervical and lumbosacral regions were associated with conservative treatment. Patients with lesions in the lower cervical spine, worse neurological status, and unstable injuries were associated with surgery. Individuals undergoing surgery were associated with complications after treatment. The authors assessed whether age influenced the characteristics of patients submitted to surgery. Subjects with <60 years of age were associated with motorcycle accidents and the morphologies of injury were fracture-dislocation. Elderly individuals were associated to fall, SCI in the lower cervical spine and the morphology of injury was listhesis. Subsequently, the authors analyzed the gender characteristics in these patients. Women who suffered car accidents were associated to surgery. Women were associated with paraparesis and the morphologic diagnosis was fracture explosion, especially in the thoracolumbar transition and lumbosacral regions. Men who presented traumatic brain injury and thoracic trauma were related to surgery. These individuals had a worse neurological status and were associated to complications. Men and the cervical region were most affected, thereby, these subjects were analyzed separately (n = 92). The presence of complications increased the length of hospital stay. The simultaneous presence of morphological diagnosis, worst neurological status, tetraplegia, sensory, and motor alterations were associated with complications. Pneumonia and chest trauma were associated with mortality. CONCLUSION: These factors enable investments in prevention, rehabilitation, and treatment. PMID- 28884109 TI - Brachial plexus injury secondary to pseudoaneurysm of axillary artery after glenohumeral dislocation: case report. AB - Lesions of the axillary artery and consequent compression of the brachial plexus are extremely rare in patients with glenohumeral dislocation and may have greatly varying clinical manifestations. This joint is one of the most affected by dislocation in the human body, accounting for approximately 45% of cases. Less than 1% of patients with shoulder dislocation have vascular complications; however, when there is damage in the axillary artery, the incidence of associated brachial plexus injury is 27% to 44%. The authors report on a case of brachial plexus compression by an axillary artery pseudoaneurysm after a glenohumeral dislocation, aiming to highlight the existence of this association, in order to make an early diagnosis and avoid serious complications, such as neurologic injury. PMID- 28884110 TI - Malignant Triton tumor: a rare cause of sciatic pain and foot drop. AB - Malignant peripheral nerve sheath tumors (MPNST) are very rare and are frequently localized in the buttocks, thigh, arm, or paraspinal region; one variant is the malignant Triton tumor, with rhabdomyosarcomatous differentiation. The authors present a challenging differential diagnosis of a sciatic pain and foot drop in a woman with history of lumbar disk herniation, which was found to be caused by a Triton tumor of the sciatic nerve. She underwent surgical excision, followed by radiation and chemotherapy. Malignant Triton tumor cases have rarely been described and reported in the literature. The recommended treatment is radical excision followed by high-dose radiotherapy and chemotherapy. The prognosis, although poor, depends on the location, grade, and completeness of surgical margins. PMID- 28884111 TI - Rotator cuff repair in the Brazilian Unified Health System: Brazilian trends from 2003 to 2015. AB - OBJECTIVE: To assess the historical trend of rotator cuff repairs in Brazil between 2003 and 2015, using the database of the Brazilian Unified Health System's (Sistema Unico de Saude [SUS]) Department of Informatics (DataSUS). METHODS: Historical series using DataSUS. Surgeries performed between 2003 and 2015 were included and data relating to cuff tear repair were assessed, including decompression procedures were included. The numerator was the total number of rotator cuff repair and the denominator, the total population of the assessed locality. Population data were based on information from the Instituto Brasileiro de Geografia e Estatistica (IBGE). RESULTS: During the period, 50,207 surgeries were performed. The rate was presented as number of procedures per 100,000 inhabitants, and increased from 0.83 to 2.81, a growth of 238%. In 2015, the South region had the highest rate, 6.32, followed by the Southeast, 3.62, while the North had the lowest rate, 0.13. The growing trend can be observed in the Southeast, South, and Midwest, while the rate is stable in the North and Northeast. CONCLUSION: The rate of rotator cuff repairs in Brazil performed through the SUS increased from 0.83 to 2.81 between 2003 and 2015, representing a growth of 238%, but remains lower than that of developed countries. A trend of growth can be observed in the Southeast, South, and Midwest, while the rate is stable in the North and Northeast. PMID- 28884112 TI - Translation and validation of the new version of the Knee Society Score - The 2011 KS Score - into Brazilian Portuguese. AB - OBJECTIVE: Translation, cultural adaptation, and validation of the new version of the Knee Society Score - The 2011 KS Score - into Brazilian Portuguese and verification of its measurement properties, reproducibility, and validity. In 2012, the new version of the Knee Society Score was developed and validated. This scale comprises four separate subscales: (a) objective knee score (seven items: 100 points); (b) patient satisfaction score (five items: 40 points); (c) patient expectations score (three items: 15 points); and (d) functional activity score (19 items: 100 points). METHOD: A total of 90 patients aged 55-85 years were evaluated in a clinical cross-sectional study. The pre-operative translated version was applied to patients with TKA referral, and the post-operative translated version was applied to patients who underwent TKA. Each patient answered the same questionnaire twice and was evaluated by two experts in orthopedic knee surgery. Evaluations were performed pre-operatively and three, six, or 12 months post-operatively. The reliability of the questionnaire was evaluated using the intraclass correlation coefficient (ICC) between the two applications. Internal consistency was evaluated using Cronbach's alpha. RESULTS: The ICC found no difference between the means of the pre-operative, three-month, and six-month post-operative evaluations between sub-scale items. CONCLUSION: The Brazilian Portuguese version of The 2011 KS Score is a valid and reliable instrument for objective and subjective evaluation of the functionality of Brazilian patients who undergo TKA and revision TKA. PMID- 28884113 TI - In vitro Culture of Naive Human Bone Marrow Mesenchymal Stem Cells: A Stemness Based Approach. AB - Human bone marrow derived mesenchymal stem cells (BM-MSCs) resides in their niches in close proximity to hematopoietic stem cells (HSCs). These naive MSCs have tremendous potential in regenerative therapeutics, and may also be exploited by cancer and infectious disease agents. Hence, it is important to study the physiological and pathological roles of naive MSC. However, our knowledge of naive MSCs is limited by lack of appropriate isolation and in vitro culture methods. Established culture methods use serum rich media, and serial passaging for retrospective isolation of MSCs. These primed MSCs may not reflect the true physiological and pathological roles of naive MSCs (Figure 1). Therefore, there is a strong need for direct isolation and in vitro culture of naive MSCs to study their stemness (self-renewal and undifferentiated state) and developmental ontogeny. We have taken a niche-based approach on stemness to better maintain naive MSCs in vitro. In this approach, stemness is broadly divided as niche dependent (extrinsic), niche independent (intrinsic) and niche modulatory (altruistic or competitive). Using this approach, we were able to maintain naive CD271+/CD133+ BM-MSCs for 2 weeks. Furthermore, this in vitro culture system helped us to identify naive MSCs as a protective niche site for Mycobacterium tuberculosis, the causative organism of pulmonary tuberculosis. In this review, we discuss the in vitro culture of primed vs. naive human BM derived MSCs with a special focus on how a stemness based approach could facilitate the study of naive BM-MSCs. PMID- 28884114 TI - The Mediterranean Diet Reduces the Risk and Mortality of the Prostate Cancer: A Narrative Review. AB - Prostate cancer is the second most common cancer in the world among men, and is the fifth most common cause of cancer death among men. The aim of our review was to analyze observational and case-control studies to point out the effects of overweight and diets components on the cancer risk, particularly on risk of prostate cancer, and the effect of the Mediterranean diet (MD) on the reduction of risk and mortality of prostate cancer. It is known that incidence and progression of cancer is multifactorial. Cancer of the large bowel, breast, endometrium, and prostate are due also to a high body mass index and to high consumption of high carcinogenic dietary factors, as red and processed meat or saturated fats rich foods, and to a low consumption of vegetables and fruits. Previous meta-analysis suggested that high adherence to diet model based on the traditional MD pattern gives a significant protection from incidence and mortality of cancer of all types. The main component of the MD is olive oil, consumed in high amount by Mediterranean basin populations. In addition, phenolic compounds exert some strong chemo-preventive effects, which are due to several mechanisms, including both antioxidant effects and actions on cancer cell signaling and cell cycle progression and proliferation. The protective effect of the MD against the prostate cancer is also due to the high consumption of tomato sauce. Lycopene is the most relevant functional component in tomatoes; after activating by the cooking of tomato sauce, it exerts antioxidant properties by acting in the modulation of downregulation mechanisms of the inflammatory response. MD, therefore, represents a healthy dietary pattern in the context of a healthy lifestyle habits. In conclusion, our narrative review allows us to reaffirm how nutritional factors play an important role in cancer initiation and development, and how a healthy dietary pattern represented by MD and its components, especially olive oil, could exert a protective role by the development and progression of prostate cancer. PMID- 28884115 TI - Management of Peripheral and Truncal Venous Injuries. AB - Civilian injuries are increasing according to the World Health Organization, and this is attributed mainly to road traffic accidents and urban interpersonal violence. Vascular injuries are common in these scenarios and are associated with high morbidity and mortality rates. Associated peripheral venous trauma is less likely to lead to death and controversy remains whether ligation or repair should be the primary approach. Conversely, non-compressible truncal venous insult can be lethal due to exsanguination, thus a high index of suspicion is crucial. Operative management is demanding with fair results but recent endovascular adjuncts demonstrate promising results and seem to be the way forward for these serious conditions. PMID- 28884117 TI - The Role of miRNAs as Biomarkers for Pregnancy Outcomes: A Comprehensive Review. AB - Several studies showed that altered expression of the miRNA-ome in maternal circulation or in placental tissue may reflect not only gestational disorders, such as preeclampsia, spontaneous abortion, preterm birth, low birth weight, or macrosomia, but also prenatal exposure to environmental pollutants. Generally, the relationships between environmental exposure, changes in miRNA expression, and gestational disorders are explored separately, producing conflicting findings. However, validation of tissue-accessible biomarkers for the monitoring of adverse pregnancy outcomes needs a systematic methodological approach that takes also into account early-life environmental exposure. To achieve this goal, exposure to xenochemicals, endogenous agents, and diet should be assessed. This study has the aim to provide a comprehensive review on the role of miRNAs as potential biomarkers for adverse pregnancy outcomes and prenatal environmental exposure. PMID- 28884116 TI - The Role of Pontin and Reptin in Cellular Physiology and Cancer Etiology. AB - Pontin (RUVBL1, TIP49, TIP49a, Rvb1) and Reptin (RUVBL2, TIP48, TIP49b, Rvb2) are highly conserved ATPases of the AAA+ (ATPases Associated with various cellular Activities) superfamily and are involved in various cellular processes that are important for oncogenesis. First identified as being upregulated in hepatocellular carcinoma and colorectal cancer, their overexpression has since been shown in multiple cancer types such as breast, lung, gastric, esophageal, pancreatic, kidney, bladder as well as lymphatic, and leukemic cancers. However, their exact functions are still quite unknown as they interact with many molecular complexes with vastly different downstream effectors. Within the nucleus, Pontin and Reptin participate in the TIP60 and INO80 complexes important for chromatin remodeling. Although not transcription factors themselves, Pontin and Reptin modulate the transcriptional activities of bona fide proto-oncogenes such as MYC and beta-catenin. They associate with proteins involved in DNA damage repair such as PIKK complexes as well as with the core complex of Fanconi anemia pathway. They have also been shown to be important for cell cycle progression, being involved in assembly of telomerase, mitotic spindle, RNA polymerase II, and snoRNPs. When the two ATPases localize to the cytoplasm, they were reported to promote cancer cell invasion and metastasis. Due to their various roles in carcinogenesis, it is not surprising that Pontin and Reptin are proving to be important biomarkers for diagnosis and prognosis of various cancers. They are also current targets for the development of new therapeutic anticancer drugs. PMID- 28884119 TI - Genetic Association Study of KCNQ5 Polymorphisms with High Myopia. AB - Identification of genetic variations related to high myopia may advance our knowledge of the etiopathogenesis of refractive error. This study investigated the role of potassium channel gene (KCNQ5) polymorphisms in high myopia. We performed a case-control study of 1563 unrelated Han Chinese subjects (809 cases of high myopia and 754 emmetropic controls). Five tag single-nucleotide polymorphisms (SNPs) of KCNQ5 were genotyped, and association testing with high myopia was conducted using logistic regression analysis adjusted for sex and age to give Pasym values, and multiple comparisons were corrected by permutation test to give Pemp values. All five noncoding SNPs were associated with high myopia. The SNP rs7744813, previously shown to be associated with refractive error and myopia in two GWAS, showed an odds ratio of 0.75 (95% CI 0.63-0.90; Pemp = 0.0058) for the minor allele. The top SNP rs9342979 showed an odds ratio of 0.75 (95% CI 0.64-0.89; Pemp = 0.0045) for the minor allele. Both SNPs are located within enhancer histone marks and DNase-hypersensitive sites. Our data support the involvement of KCNQ5 gene polymorphisms in the genetic susceptibility to high myopia and further exploration of KCNQ5 as a risk factor for high myopia. PMID- 28884118 TI - The Role of Adenosine A2A Receptor, CYP450s, and PPARs in the Regulation of Vascular Tone. AB - Adenosine is an endogenous mediator involved in a myriad of physiologic functions, including vascular tone regulation. It is also implicated in some pathologic conditions. Four distinct receptor subtypes mediate the effects of adenosine, such as its role in the regulation of the vascular tone. Vascular tone regulation is a complex and continuous process which involves many mechanisms and mediators that are not fully disclosed. The vascular endothelium plays a pivotal role in regulating blood flow to and from all body organs. Also, the vascular endothelium is not merely a physical barrier; it is a complex tissue with numerous functions. Among adenosine receptors, A2A receptor subtype (A2AAR) stands out as the primary receptor responsible for the vasodilatory effects of adenosine. This review focuses on important effectors of the vascular endothelium, including adenosine, adenosine receptors, EETs (epoxyeicosatrienoic acids), HETEs (hydroxyeicosatetraenoic acids), PPARs (peroxisome proliferator activated receptors), and KATP channels. Given the impact of vascular tone regulation in cardiovascular physiology and pathophysiology, better understanding of the mechanisms affecting it could have a significant potential for developing therapeutic agents for cardiovascular diseases. PMID- 28884120 TI - Automated Classification of Lung Cancer Types from Cytological Images Using Deep Convolutional Neural Networks. AB - Lung cancer is a leading cause of death worldwide. Currently, in differential diagnosis of lung cancer, accurate classification of cancer types (adenocarcinoma, squamous cell carcinoma, and small cell carcinoma) is required. However, improving the accuracy and stability of diagnosis is challenging. In this study, we developed an automated classification scheme for lung cancers presented in microscopic images using a deep convolutional neural network (DCNN), which is a major deep learning technique. The DCNN used for classification consists of three convolutional layers, three pooling layers, and two fully connected layers. In evaluation experiments conducted, the DCNN was trained using our original database with a graphics processing unit. Microscopic images were first cropped and resampled to obtain images with resolution of 256 * 256 pixels and, to prevent overfitting, collected images were augmented via rotation, flipping, and filtering. The probabilities of three types of cancers were estimated using the developed scheme and its classification accuracy was evaluated using threefold cross validation. In the results obtained, approximately 71% of the images were classified correctly, which is on par with the accuracy of cytotechnologists and pathologists. Thus, the developed scheme is useful for classification of lung cancers from microscopic images. PMID- 28884121 TI - Contrast Microsphere Destruction by a Continuous Flow Ventricular Assist Device: An In Vitro Evaluation Using a Mock Circulation Loop. AB - OBJECTIVES: Transthoracic echocardiography (TTE) is fundamental in managing patients supported with ventricular assist devices (VAD). However imaging can be difficult in these patients. Contrast improves image quality but they are hydrodynamically fragile agents. The aim was to assess contrast concentration following passage through a VAD utilising a mock circulation loop (MCL). METHODS: Heartware continuous flow (CF) VAD was incorporated into a MCL. Definity(r) contrast was infused into the MCL with imaging before and after CF-VAD. 5 mm2 regions of interest were used to obtain signal intensity (decibels), as a surrogate of contrast concentration. RESULTS: Four pump speeds revealed significant reduction in contrast signal intensity after CF-VAD compared to before CF-VAD (all p < 0.0001). Combined pre- and postpump data at all speeds showed a 22.2% absolute reduction in contrast signal intensity across the CF-VAD (14.8 +/- 0.8 dB prepump versus 11.6 +/- 1.4 dB postpump; p < 0.0001). Mean signal intensity reduction at each speed showed an inverse relationship between speed and relative reduction in signal intensity. CONCLUSION: Contrast microsphere transit through a CF-VAD within a MCL resulted in significant reduction in signal intensity, consistent with destruction within the pump. This was evident at all CF-VAD pump speeds but relative signal drop was inversely proportional to pump speed. PMID- 28884122 TI - Advanced Oxidation Protein Products and Carbonylated Proteins as Biomarkers of Oxidative Stress in Selected Atherosclerosis-Mediated Diseases. AB - OBJECTIVES: The main question of this study was to evaluate the intensity of oxidative protein modification shown as advanced oxidation protein products (AOPP) and carbonylated proteins, expressed as protein carbonyl content (C=O) in abdominal aortic aneurysms (AAA), aortoiliac occlusive disease (AIOD), and chronic kidney disease (CKD). DESIGN AND METHODS: The study was carried out in a group of 35 AAA patients and 13 AIOD patients. However, CKD patients were divided into two groups: predialysis (PRE) included 50 patients or hemodialysis (HD) consisted of 34 patients. AOPP and C=O were measured using colorimetric assay kit, while C-reactive protein concentration was measured by high-sensitivity assay (hsCRP). RESULTS: The concentration of AOPP in both AAA and AIOD groups was higher than in PRE and HD groups according to descending order: AAA~AIOD > HD > PRE. The content of C=O was higher in the PRE group in comparison to AIOD and AAA according to the descending order: PRE~HD > AAA~AIOD. CONCLUSIONS: AAA, AIOD, and CKD-related atherosclerosis (PRE and HD) contribute to the changes in the formation of AOPP and C=O. They may promote modification of proteins in a different way, probably due to the various factors that influence oxidative stress here. PMID- 28884124 TI - Response to: Comment on "Detecting Key Genes Regulated by miRNAs in Dysfunctional Crosstalk Pathway of Myasthenia Gravis". PMID- 28884123 TI - Deviation of the Fecal Stream in Colonic Bowel Segments Results in Increased Numbers of Isolated Lymphoid Follicles in the Submucosal Compartment in a Novel Murine Model of Diversion Colitis. AB - INTRODUCTION: Diversion colitis is a significant health problem due to its high incidence in patients with diverting enterostomy. This mucosal inflammation presents characteristic histopathological features allowing for the differentiation of this entity from other inflammatory bowel diseases. The pathophysiology of this disease remains ill-defined, in part due to the lack of appropriate animal models. The present study was performed in order to develop and characterize a murine model of diversion colitis. METHODS: A diverting loop colostomy was performed in C57BL/6 mice either in the ascending colon or in the transverse colon. Animals were assessed for clinical and histopathological parameters during short-term and long-term survival. RESULTS: Animals with a colostomy in the transverse colon showed a good long-term survival and developed a mild colitis in the bypassed bowel closely resembling the human pathology on a histopathological level. CONCLUSION: This model is a promising tool to further elucidate the pathomechanism leading to impaired mucosal homeostasis in bypassed colonic segments. Moreover, the establishment of the model in the C57BL/6 background allows the combination of this colitis model with various transgenic mouse strains to investigate the effect of locally deregulated mucosal immunity on systemic immune homeostasis and to develop specific therapeutic strategies. PMID- 28884127 TI - Corrigendum to "Ciprofloxacin Controlled-Solid Lipid Nanoparticles: Characterization, In Vitro Release, and Antibacterial Activity Assessment". AB - [This corrects the article DOI: 10.1155/2017/2120734.]. PMID- 28884125 TI - Green Tea Extracts Epigallocatechin-3-gallate for Different Treatments. AB - Epigallocatechin-3-gallate (EGCG), a component extracted from green tea, has been proved to have multiple effects on human pathological and physiological processes, and its mechanisms are discrepant in cancer, vascularity, bone regeneration, and nervous system. Although there are multiple benefits associated with EGCG, more and more challenges are still needed to get through. For example, EGCG shows low bioactivity via oral administration. This review focuses on effects of EGCG, including anti-cancer, antioxidant, anti-inflammatory, anticollagenase, and antifibrosis effects, to express the potential of EGCG and necessity of further studies in this field. PMID- 28884126 TI - The Influence of Cigarette Smoke Exposure on the Copper Concentration in the Serum Depending on the Use of Menopausal Hormone Therapy. AB - This study evaluated the effect of menopausal hormone therapy (MHT) on serum concentration of copper in postmenopausal women depending on passive or active exposure to tobacco smoke or lack thereof. The study included healthy postmenopausal women aged 42-69 years, who used (n = 76) or did not use (n = 76) MHT. Salivary cotinine and serum copper concentrations were determined in all the study subjects. Salivary cotinine exceeded 14 ng/ml in 14 women from the MHT group (18.5%) and in 16 controls (21.1%). Up to 41 (27%) study subjects had serum copper above the upper normal limit (1.17 mg/l). No correlation was found between salivary cotinine and serum copper in women with cotinine concentrations <14 ng/ml, and these two parameters correlated weakly in subjects with cotinine >14 ng/ml. Salivary concentration of cotinine increased with serum copper level in the MHT group, but not in the controls; smokers using MHT presented with significantly higher serum copper than nonsmokers. These findings imply that MHT does not affect serum concentration of copper in women who are not exposed to tobacco smoke. However, MHT seems to contribute to unfavorable increase in serum copper in passive and active smokers. PMID- 28884128 TI - Erratum to "miR319, miR390, and miR393 Are Involved in Aluminum Response in Flax (Linum usitatissimum L.)". AB - [This corrects the article DOI: 10.1155/2017/4975146.]. PMID- 28884129 TI - Candidemia in the Neonatal Intensive Care Unit: A Retrospective, Observational Survey and Analysis of Literature Data. AB - We evaluated the epidemiology of Candida bloodstream infections in the neonatal intensive care unit (NICU) of an Italian university hospital during a 9-year period as a means of quantifying the burden of infection and identifying emerging trends. Clinical data were searched for in the microbiological laboratory database. For comparative purposes, we performed a review of NICU candidemia. Forty-one candidemia cases were reviewed (overall incidence, 3.0 per 100 admissions). Candida parapsilosis sensu stricto (58.5%) and C. albicans (34.1%) were the most common species recovered. A variable drift through years was observed; in 2015, 75% of the cases were caused by non-albicans species. The duration of NICU hospitalization of patients with non-albicans was significantly longer than in those with C. albicans (median days, 10 versus 12). Patients with non-albicans species were more likely to have parenteral nutrition than those with C. albicans (96.3% versus 71.4%). Candida albicans was the dominant species in Europe and America (median, 55% and 60%; resp.); non-albicans species predominate in Asia (75%). Significant geographic variation is evident among cases of candidemia in different parts of the world, recognizing the importance of epidemiological data to facilitate the treatment. PMID- 28884130 TI - Drinking Water Quality Status and Contamination in Pakistan. AB - Due to alarming increase in population and rapid industrialization, drinking water quality is being deteriorated day by day in Pakistan. This review sums up the outcomes of various research studies conducted for drinking water quality status of different areas of Pakistan by taking into account the physicochemical properties of drinking water as well as the presence of various pathogenic microorganisms. About 20% of the whole population of Pakistan has access to safe drinking water. The remaining 80% of population is forced to use unsafe drinking water due to the scarcity of safe and healthy drinking water sources. The primary source of contamination is sewerage (fecal) which is extensively discharged into drinking water system supplies. Secondary source of pollution is the disposal of toxic chemicals from industrial effluents, pesticides, and fertilizers from agriculture sources into the water bodies. Anthropogenic activities cause waterborne diseases that constitute about 80% of all diseases and are responsible for 33% of deaths. This review highlights the drinking water quality, contamination sources, sanitation situation, and effects of unsafe drinking water on humans. There is immediate need to take protective measures and treatment technologies to overcome unhygienic condition of drinking water supplies in different areas of Pakistan. PMID- 28884131 TI - MiR-219-5p Inhibits the Growth and Metastasis of Malignant Melanoma by Targeting BCL-2. AB - Malignant melanoma is a very dangerous tumor which is resistant to conventional therapy. MicroRNA exerts a vital function in promoting or inhibiting tumor development. The research has investigated the expression and function of miR-219 5p in melanoma. As a result, miR-219-5p expression was distinctly reduced in melanoma tissues and cell lines and was negatively correlated with Bcl-2 protein level in melanoma. Patients with low miR-219-5p level represented obviously a low overall survival in comparison with patients with high miR-219-5p level. The upregulation of miR-219-5p inhibited melanoma growth and metastasis and strengthened melanoma cells chemosensitivity by targeting Bcl-2. Therefore, the modulation of miR-219-5p expression may be a novel treatment strategy in melanoma. PMID- 28884133 TI - Bone Marrow Metastasis Is an Early Stage of Bone Metastasis in Breast Cancer Detected Clinically by F18-FDG-PET/CT Imaging. AB - OBJECTIVE: To determine the value of 18F-FDG PET/CT in detection of bone marrow (BM) metastasis in breast cancer which is considered an early stage of bone metastasis. PATIENTS AND METHODS: Retrospectively, breast cancer patients with bone metastasis were included. BM metastasis was considered if the lesion was PET positive/CT occult while bone metastasis was considered if the lesion was PET positive/ CT positive. BM metastases were observed sequentially on F18-FDG PET/CT. RESULTS: We included 35 patients. Eighteen patients (51%) had BM metastases in addition to other bone metastases. BM metastases comprised 24% of all lesions. Posttreatment scan was performed on 26/35 patients. Twenty-three percent of BM metastases had resolved completely without causing bone destruction after treatment. Sixty-five percent of BM metastases had converted into bone metastases after treatment. Twelve percent of BM metastases had persisted after treatment. CONCLUSION: This retrospective study showed clinically by 18F-FDG PET/CT imaging that BM metastasis is an early stage of bone metastasis in breast cancer. Interestingly, 18F-FDG-PET/CT showed that early eradication of individual BM metastasis by systemic treatment precluded development of bone metastasis. However, more research is needed to study the impact of an early diagnosis of BM metastases on treatment outcome. PMID- 28884132 TI - Renal Function Improvement by Telbivudine in Liver Transplant Recipients with Chronic Kidney Disease. AB - Chronic renal failure is a frequent complication in liver transplantation. Telbivudine, anti-hepatitis B virus (HBV) nucleoside, can improve renal function. It is interesting if using telbivudine for prophylaxis of HBV recurrence has additional value on renal function improvement. 120 liver transplant recipients with lamivudine prophylaxis for HBV recurrence were 1 : 1 randomized into lamivudine-continuous (n = 60) and telbivudine-replacement (n = 60) groups. Fifty eight patients in lamivudine-continuous group and 54 in telbivudine-replacement group completed the study. In telbivudine-replacement group, the estimated glomerular filtration rate (eGRF) was improved from 63.0 +/- 16.3 ml/min to 72.8 +/- 21.1 ml/min at 12 months after telbivudine administration (p = 0.003). Stratifying the patients according to renal function staging, the eGRF was improved from 74.7 +/- 6.9 ml/min to 84.2 +/- 16.6 ml/min (p = 0.002) in 32 stage II patients and from 48.2 +/- 7.3 ml/min to 59.7 +/- 11.8 ml/min in 20 stage III patients after 12 months of telbivudine administration (p < 0.001). Eleven (18.3%) patients with telbivudine developed polyneuritis during the trial and post hoc following-up. In conclusion, renal function was improved by telbivudine in liver transplant recipients with long-term chronic kidney disease. However, the high incidence of polyneuritis induced by telbivudine has to be closely monitored. This trial is registered with ClinicalTrials NCT02447705. PMID- 28884135 TI - Career Development Guidance and Mentorship during Anesthesia Residency Training: An Internet Survey. AB - BACKGROUND: We conducted a survey of Anesthesiology residency programs in the United States to identify current practice regarding mentorship and teaching of topics related to career development. METHODS: Program directors for all currently accredited Anesthesiology residency programs (N=129 as of April 2016) were contacted by e-mail and invited to complete a short internet survey. Two follow-up e-mails were sent at one-week intervals to those who had not yet responded. RESULTS: 59 program directors responded, yielding 53 complete responses, for an adjusted response rate of 41.1%. Program and practice management type (university versus other, hospital versus private) were not strongly associated with presence of a career development curriculum (CDC). In general, larger residency programs (30 or more residents) and university-based programs were more likely to provide lectures on specific CDC topics. Whether residency program directors agreed or disagreed with the premise that instruction should be provided on other topics besides anesthesia, was unrelated to the presence of CDC in their programs. CONCLUSIONS: The results of this survey demonstrate that the establishment of a mentorship program (even a rudimentary one) may be the first step in creating a CDC. Apart from having a CDC program already in place, the strongest predictor of CDC content was the size of the residency program. Though there are training programs that openly stated on our survey that they do not have a CDC in place, some of these programs still provided lectures on one or more of the topics surveyed. PMID- 28884134 TI - Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells. AB - During ischemia or inflammation of organs, intracellular pH can decrease if acid production exceeds buffering capacity. Thus, the microenvironment can expose parenchymal cells to a reduced extracellular pH which can alter pH-dependent intracellular functions. We have previously shown that while silencing caspase-8 in an in vivo ischemia reperfusion injury (IRI) model results in improved organ function and survival, removal of caspase-8 function in a donor organ can paradoxically result in enhanced receptor-interacting protein kinase 1/3- (RIPK1/3-) regulated necroptosis and accelerated graft loss following transplantation. In our current study, TRAIL- (TNF-related apoptosis-inducing ligand-) induced cell death in vitro at neutral pH and caspase-8 inhibition enhanced RIPK1-dependent necroptotic death were confirmed. In contrast, both caspase-8 inhibition and RIPK1 inhibition attenuated cell death at a cell pH of 6.7. Cell death was attenuated with mixed lineage kinase domain-like (MLKL) silencing, indicating that MLKL membrane rupture, a distinctive feature of necroptosis, occurs regardless of pH. In summary, there is a distinct regulatory control of apoptosis and necroptosis in endothelial cells at different intracellular pH. These results highlight the complexity of modulating cell death and therapeutic strategies that may need to consider different consequences on cell death dependent on the model. PMID- 28884136 TI - Neutrophils as Components of Mucosal Homeostasis. AB - Inflammatory responses in the intestinal mucosa inevitably result in the recruitment of neutrophils (polymorphonuclear leukocytes [PMNs]). Epithelial cells that line the mucosa play an integral role in the recruitment, maintenance, and clearance of PMNs at sites of inflammation. The consequences of such PMN epithelial interactions often determine tissue responses and, ultimately, organ function. For this reason, there is significant interest in understanding how PMNs function in the mucosa during inflammation. Recent studies have shown that PMNs play a more significant role in molding of the immune response than previously thought. Here, we review the recent literature regarding the contribution of PMNs to the development and resolution of inflammation, with an emphasis on the role of the tissue microenvironment and pathways for promoting epithelial restitution. These studies highlight the complex nature of inflammatory pathways and provide important insight into the difficulties of treating mucosal inflammation. PMID- 28884138 TI - Chronic Helicobacter cinaedi cellulitis diagnosed by microbial polymerase chain reaction. PMID- 28884140 TI - Treatment of cutaneous leiomyomas with 5% lidocaine patches in a patient with hereditary leiomyomatosis and renal cell cancer (Reed syndrome). PMID- 28884137 TI - Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication. AB - BACKGROUND & AIMS: The human hepatitis B virus (HBV) is a major cause of chronic hepatitis and hepatocellular carcinoma, but molecular mechanisms driving liver disease and carcinogenesis are largely unknown. We therefore studied cellular pathways altered by HBV infection. METHODS: We performed gene expression profiling of primary human hepatocytes infected with HBV and proved the results in HBV-replicating cell lines and human liver tissue using real-time polymerase chain reaction and Western blotting. Activation of signal transducer and activator of transcription (STAT3) was examined in HBV-replicating human hepatocytes, HBV-replicating mice, and liver tissue from HBV-infected individuals using Western blotting, STAT3-luciferase reporter assay, and immunohistochemistry. The consequences of STAT3 activation on HBV infection and cell survival were studied by chemical inhibition of STAT3 phosphorylation and small interfering RNA-mediated knockdown of STAT3. RESULTS: Gene expression profiling of HBV-infected primary human hepatocytes detected no interferon response, while genes encoding for acute phase and antiapoptotic proteins were up regulated. This gene regulation was confirmed in liver tissue samples of patients with chronic HBV infection and in HBV-related hepatocellular carcinoma. Pathway analysis revealed activation of STAT3 to be the major regulator. Interleukin-6 dependent and -independent activation of STAT3 was detected in HBV-replicating hepatocytes in cell culture and in vivo. Prevention of STAT3 activation by inhibition of Janus tyrosine kinases as well as small interfering RNA-mediated knockdown of STAT3-induced apoptosis and reduced HBV replication and gene expression. CONCLUSIONS: HBV activates STAT3 signaling in hepatocytes to foster its own replication but also to prevent apoptosis of infected cells. This very likely supports HBV-related carcinogenesis. PMID- 28884139 TI - Localized bullous pemphigoid in a melanoma patient with dual exposure to PD-1 checkpoint inhibition and radiation therapy. PMID- 28884141 TI - Apremilast for treatment of recalcitrant aphthous stomatitis. PMID- 28884142 TI - Corrigendum to "Low Body Mass Index Can Identify Majority of Osteoporotic Inflammatory Bowel Disease Patients Missed by Current Guidelines". AB - [This corrects the article DOI: 10.1100/2012/807438.]. PMID- 28884143 TI - Use of Genotype MTBDRplus Assay for Diagnosis of Multidrug-Resistant Tuberculosis in Nepal. AB - The main aims of this study were to study the patterns of mutations in rpoB, katG, and inhA genes in Mycobacterium tuberculosis strains isolated from patients from Nepal and to evaluate the performance of genotype MTBDRplus assay, taking conventional drug susceptibility testing as gold standard for diagnosis of MDR TB. A total of 69 Mycobacterium tuberculosis strains isolated from 73 smear positive sputum samples from patients suspected of suffering from multidrug resistant tuberculosis were used in our study. The drug susceptibility pattern of Mycobacterium tuberculosis isolated from these sputum specimens was determined by using genotype MTBDRplus assay taking conventional drug susceptibility testing as reference. The sensitivity and specificity of the genotype MTBDRplus assay for the detection of MDR-TB were found to be 88.7% and 100%, respectively. 88.7% of the rifampicin resistant isolates had mutations in rpoB gene. Similarly, 79.7% and 9.4% of isoniazid resistant isolates had mutations in katG and inhA genes, respectively. Genotype MTBDRplus assay was found to be very rapid and highly sensitive and specific method for diagnosis of MDR-TB and will be very helpful for early diagnosis of MDR-TB in high tuberculosis burden countries. PMID- 28884144 TI - Erratum: Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer. AB - [This corrects the article DOI: 10.1038/s41523-017-0015-9.]. PMID- 28884145 TI - Sensory experience shapes the integration of adult-born neurons into the olfactory bulb. AB - Olfaction is an ancient sensory modality which is heavily involved in viscerally important tasks like finding food and identifying mates. Olfactory processing involves interpreting stimuli from a non-continuous odor space, and translating them into an organized pattern of neuronal activity in the olfactory bulb. Additionally, olfactory processing is rapidly modulated by behavioral states and vice versa. This implies strong bidirectional neuromodulation between the olfactory bulb and other brain regions that include the cortex, hippocampus, and basal forebrain. Intriguingly, the olfactory bulb is one of the only brain regions where adult-born neurons are integrated into existing networks throughout life. The ongoing integration of adult-born neurons is known to be important for olfactory processing, odor discrimination, and odor learning. Furthermore, the survival and integration of the adult-born neurons is regulated by neuromodulatory signaling, sensory experience, and olfactory learning. Studies making use of new genetic markers to label and manipulate immature adult-born neurons reveal an increase in their population response to odors as they mature. Importantly, this reflects a period of developmental plasticity where adult-born neurons are especially sensitive to sensory experience and olfactory learning. In this review, we discuss the contribution of adult neurogenesis to olfactory bulb plasticity and information processing, with a focus on the developmental plasticity of adult born neurons, and how it is influenced by sensory experience and olfactory learning. Ultimately, recent studies raise important questions about behavioral-state-dependent effects on adult-born neurons, and the consequences of neuromodulation on the developmental plasticity of newborn neurons in the olfactory bulb. PMID- 28884146 TI - Optimizing Respiratory-Swallowing Coordination in Patients With Oropharyngeal Head and Neck Cancer. AB - Swallowing impairment (dysphagia) represents the highest functional morbidity in oropharyngeal (OP) head and neck (HNC) treated either with surgical approaches followed by radiation or with more recent organ preservation protocols, including combined chemotherapy and radiation. Despite the promising overall increasing survival rates, swallowing impairments remain chronic, are often resistant to traditional swallowing therapy, and have devastating consequences on health and well-being. The respiratory-swallow cross-system approach presented here extends beyond traditional swallowing interventions that commonly targets muscles and structures alone, and is instead, directed toward the re-establishment of optimal respiratory-swallowing coordination. Results from our work investigating a respiratory-swallow treatment (RST) paradigm is presented, including results from an RST clinical trial in HNC patients, primarily with OP cancers, with chronic and with intractable dysphagia post-cancer and post-traditional swallowing treatment. Future work will investigate the impact of RST on the degree and durability of clinical outcomes, including oral intake and quality of life, while also examining the potential added benefits of a home practice program that uses a commercially available and easy to use recording and analysis hardware and software. PMID- 28884147 TI - Use of a botulinum toxin A in dentistry and oral and maxillofacial surgery. AB - Botulinum toxin (BT) was the first toxin to be used in the history of human medicine. Among the eight known serotypes of this toxin, those currently used in medicine are types A and B. This review article mainly discusses BT type A (BTA) because it is usually used in dentistry including dental anesthesiology and oral and maxillofacial surgery. BTA has been used mainly in the treatment of temporomandibular joint disorder (TMD) and hypertrophy and hyperactivity of the masticatory muscles, along with being a therapeutic option to relieve pain and help in functional recovery from dental and oral and maxillofacial surgery. However, it is currently used broadly for cosmetic purposes such as reducing facial wrinkles and asymmetry. Although the therapeutic effect of BTA is temporary and relatively safe, it is essential to have knowledge about related anatomy, as well as the systemic and local adverse effects of medications that are applied to the face. PMID- 28884148 TI - Therapeutic potential of stellate ganglion block in orofacial pain: a mini review. AB - Orofacial pain is a common complaint of patients that causes distress and compromises the quality of life. It has many etiologies including trauma, interventional procedures, nerve injury, varicella-zoster (shingles), tumor, and vascular and idiopathic factors. It has been demonstrated that the sympathetic nervous system is usually involved in various orofacial pain disorders such as postherpetic neuralgia, complex regional pain syndromes, and atypical facial pain. The stellate sympathetic ganglion innervates the head, neck, and upper extremity. In this review article, the effect of stellate ganglion block and its mechanism of action in orofacial pain disorders are discussed. PMID- 28884149 TI - Smart syringe pumps for drug infusion during dental intravenous sedation. AB - Dentists often sedate patients in order to reduce their dental phobia and stress during dental treatment. Sedatives are administered through various routes such as oral, inhalation, and intravenous routes. Intravenous administration has the advantage of rapid onset of action, predictable duration of action, and easy titration. Typically, midazolam, propofol or dexmedetomidine are used as intravenous sedatives. Administration of these sedatives via infusion by using a syringe pump is more effective and successful than infusing them as a bolus. However, during intravenous infusion of sedatives or opioids using a syringe pump, fatal accidents may occur due to the clinician's carelessness. To prevent such risks, smart syringe pumps have been introduced clinically. They allow clinicians to perform effective sedation by using a computer to control the dose of the drug being infused. To ensure patient safety, various alarm features along with a drug library, which provides drug information and prevents excessive infusion by limiting the dose, have been added to smart pumps. In addition, programmed infusion systems and target-controlled infusion systems have also been developed to enable effective administration of sedatives. Patient-controlled infusion, which allows a patient to control his/her level of sedation through self-infusion, has also been developed. Safer and more successful sedation may be achieved by fully utilizing these new features of the smart pump. PMID- 28884150 TI - Remifentanil induces autophagy and prevents hydrogen peroxide-induced apoptosis in Cos-7 cells. AB - BACKGROUND: This study investigated the effect of remifentanil pretreatment on Cos-7 cells exposed to oxidative stress, and the influence of remifentanil on intracellular autophagy and apoptotic cell death. METHODS: Cells were divided into 4 groups: (1) Control: non-pretreated cells were incubated in normoxia (5% CO2, 21% O2, and 74% N2). (2) H2O2: non-pretreated cells were exposed to H2O2 for 24 h. (3) RPC+H2O2: cells pretreated with remifentanil were exposed to H2O2 for 24 h. (4) 3-MA+RPC+H2O2: cells pretreated with 3-Methyladenine (3-MA) and remifentanil were exposed to H2O2 for 24 h. We determined the cell viability of each group using an MTT assay. Hoechst staining and FACS analysis of Cos-7 cells were performed to observe the effect of remifentanil on apoptosis. Autophagy activation was determined by fluorescence microscopy, MDC staining, and AO staining. The expression of autophagy-related proteins was observed using western blotting. RESULTS: Remifentanil pretreatment increased the viability of Cos-7 cells exposed to oxidative stress. Hoechst staining and FACS analysis revealed that oxidative stress-dependent apoptosis was suppressed by the pretreatment. Additionally, fluorescence microscopy showed that remifentanil pretreatment led to autophagy-induction in Cos-7 cells, and the expression of autophagy-related proteins was increased in the RPC+H2O2 group. CONCLUSIONS: The study showed that remifentanil pretreatment stimulated autophagy and increased viability in an oxidative stress model of Cos-7 cells. Therefore, we suggest that apoptosis was activated upon oxidative stress, and remifentanil preconditioning increased the survival rate of the cells by activating autophagy. PMID- 28884151 TI - Effects of airway evaluation parameters on the laryngeal view grade in mandibular prognathism and retrognathism patients. AB - BACKGROUND: Failure to maintain a patent airway can result in brain damage or death. In patients with mandibular prognathism or retrognathism, intubation is generally thought to be difficult. We determined the degree of difficulty of airway management in patients with mandibular deformity using anatomic criteria to define and grade difficulty of endotracheal intubation with direct laryngoscopy. METHODS: Measurements were performed on 133 patients with prognathism and 33 with retrognathism scheduled for corrective esthetic surgery. A case study was performed on 89 patients with a normal mandible as the control group. In all patients, mouth opening distance (MOD), mandibular depth (MD), mandibular length (ML), mouth opening angle (MOA), neck extension angle (EXT), neck flexion angle (FLX), thyromental distance (TMD), inter-notch distance (IND), thyromental area (TMA), Mallampati grade, and Cormack and Lehane grade were measured. RESULTS: Cormack and Lehane grade I was observed in 84.2%, grade II in 15.0%, and grade III in 0.8% of mandibular prognathism cases; among retrognathism cases, 45.4% were grade I, 27.3% grade II, and 27.3% grade III; among controls, 65.2% were grade I, 26.9% were grade II, and 7.9% were grade III. MOD, MOA, ML, TMD, and TMA were greater in the prognathism group than in the control and retrognathism groups (P < 0.05). The measurements of ML were shorter in retrognathism than in the control and prognathism groups (P < 0.05). CONCLUSIONS: Laryngoscopic intubation was easier in patients with prognathism than in those with normal mandibles. However, in retrognathism, the laryngeal view grade was poor and the ML was an important factor. PMID- 28884152 TI - Body composition and hemodynamic changes in patients with special needs. AB - BACKGROUND: Some patients with special needs exhibit intellectual disability, including deficits in cognitive skills and decreased quality of life. The purpose of this study was to retrospectively compare changes in body composition and hemodynamics during general anesthesia in patients with and without special needs. METHODS: The backgrounds of patients who underwent oral maxillofacial surgery under general anesthesia were recorded from medical records. Intracellular water (ICW), extracellular water (ECW), stroke volume variation (SVV), and heart rate (HR) were recorded for 3 h after the start of anesthesia. Categorical data were compared using an unpaired t-test, and a P-value of less than 0.05 was regarded as significant. Numerical data were compared using the Bonferroni correction, and a P-value of less than 0.0125 was regarded as significant. RESULTS: A total of 21 patients were included in the study: 10 patients without special needs (non-S-group) and 11 patients with special needs (S-group). There were no significant differences in patients' backgrounds, except with regard to height (P = 0.03). In both groups, ICW and ECW were maintained, although they were lower in the S-group compared to the non-S-group. SVV was maintained in both groups, although it was higher in the S-group than the non-S group. HR was significantly lower in the S-group 1 h after induction of anesthesia (P < 0.003). CONCLUSIONS: Changes in hemodynamics due to body fluid imbalance should be monitored during general anesthesia, especially for patients with special needs. PMID- 28884153 TI - Prevalence of dental anxiety in 10-14 years old children and its implications. AB - BACKGROUND: The aim of this study was to provide insight on dental fear amongst schoolchildren and evaluate the association between caries experience and fear of dental procedures. METHODS: A sample size of 250 students (both sexes) of ages 10 14 years were enrolled in the study. Before dental examination, each participant was informed about the study and given the Children's Fear Survey Schedule - Dental Subscale (CFSS-DS) questionnaire. Children who scored greater than 38 were included in the 'with dental fear' group and those who scored less than 38 were assigned to the 'without dental fear' group. All oral check-ups were carried out on the school premises according to WHO criteria. RESULTS: There were 105 children (42%) who experienced dental fear. As CFSS-DS scores increased, scores on the Decayed, Missing and Filled Surfaces Index (DMFS) also increased. Scores were highest on "injections" followed by "dentist drill" and "feeling of choking". Children were significantly less anxious about items of dental treatment if they had experienced that particular form of treatment. Female participants were found to be more dentally anxious than the male participants. CONCLUSIONS: The data revealed dental fear in 10-14 years old children and showed that dental fear scores decreased with increase in age and experience. PMID- 28884154 TI - A survey of dental treatment under general anesthesia in a Korean university hospital pediatric dental clinic. AB - BACKGROUND: In South Korea, the number of cases of dental treatment for the disabled is gradually increasing, primarily at regional dental clinics for the disabled. This study investigated pediatric patients at a treatment clinic for the disabled within a university hospital who received dental treatment under general anesthesia. This data could assist those that provide dental treatment for the disabled and guide future treatment directions and new policies. METHODS: This study was a retrospective analysis of 263 cases in which patients received dental treatment under general anesthesia from January 2011 to May 2016. The variables examined were gender, age, reason for anesthesia, type of disability, time under anesthesia, duration of treatment, type of procedure, treatment details, and annual trends in the use of general anesthesia. RESULTS: Among pediatric patients with disabilities who received dental treatment under general anesthesia, the most prevalent age group was 5-8 years old (124 patients, 47.1%), and the primary reason for administering anesthesia was dental anxiety or phobia. The mean time under anesthesia was 132.7 +/- 77.6 min, and the mean duration of treatment was 101.9 +/- 71.2 min. The most common type of treatment was restoration, accounting for 158 of the 380 treatments performed. CONCLUSIONS: Due to increasing demand, the number of cases of dental treatment performed under general anesthesia is expected to continue increasing, and it can be a useful method of treatment in patients with dental anxiety or phobia. PMID- 28884155 TI - Dental anesthesia for patients with allergic reactions to lidocaine: two case reports. AB - Lidocaine, a local anesthetic commonly used in dental treatments, is capable of causing allergies or adverse effects similar to allergic reactions. However, the frequency of such occurrences in actual clinical settings is very rare, and even clinical tests on patients with known allergies to local anesthetics may often show negative results. When adverse effects, such as allergy to lidocaine, are involved, patients can be treated by testing other local anesthetics and choosing a local anesthetic without any adverse effects, or by performing dental treatment under general anesthesia in cases in which no local anesthetic without adverse effects is available. Along with a literature review, the authors of the present study report on two cases of patients who tested positive on allergy skin tests for lidocaine and bupivacaine and subsequently underwent successful dental treatments with either general anesthesia or a different local anesthetic. PMID- 28884156 TI - Dental treatment under general anesthesia in an intellectually disabled child with intellectually disabled parents. AB - Children with an intellectual disability often demonstrate lack of cooperation during dental treatment and require behavioral management. A child with mild intellectual disability can be managed adequately using restraints and medication. However, in cases of profound intellectual disability, dental treatment under general anesthesia is usually required. In cases where the patient is an intellectually disabled child who has intellectually disabled parents, it is difficult to evaluate the patient's preoperative condition and to obtain consent for treatment under general anesthesia. Furthermore, they are unable to respond to emergencies after treatment. Therefore, dental treatment should be performed under general anesthesia with hospitalization for children with an intellectual disability. This case presents the dental treatment of an intellectually disabled child, who has intellectually disabled parents, and who required general anesthesia and hospitalization. PMID- 28884157 TI - Use of ADMSTM during sedation for dental treatment of an intellectually disabled patient: a case report. AB - Dental treatment is often performed under general anesthesia or sedation when an intellectually disabled patient has a heightened fear of treatment or has difficulty cooperating. When it is impossible to control the patient due to the severity of intellectual disability, conscious sedation is not a viable option, and only deep sedation should be performed. Deep sedation is usually achieved by propofol infusion using the target controlled infusion (TCI) system, with deep sedation being achieved at a slightly lower concentration of propofol in disabled patients. In such cases, anesthesia depth monitoring using EEG, as with a Bispectral Index (BIS) monitor, can enable dental treatment under appropriate sedation depth. In the present case, we performed deep sedation for dental treatment on a 27-year-old female patient with mental retardation and severe dental phobia. During sedation, we used BIS and a newly developed Anesthetic Depth Monitor for Sedation (ADMSTM), in addition to electrocardiography, pulse oximetry, blood pressure monitoring, and capnometry for patient safety. Oxygen was administered via nasal prong to prevent hypoxemia during sedation. The BIS and ADMSTM values were maintained at approximately 70, and dental treatment was successfully performed in approximately 30 min.. PMID- 28884158 TI - A geo-coded inventory of anophelines in the Afrotropical Region south of the Sahara: 1898-2016. AB - Background: Understanding the distribution of anopheline vectors of malaria is an important prelude to the design of national malaria control and elimination programmes. A single, geo-coded continental inventory of anophelines using all available published and unpublished data has not been undertaken since the 1960s. Methods: We have searched African, European and World Health Organization archives to identify unpublished reports on anopheline surveys in 48 sub-Saharan Africa countries. This search was supplemented by identification of reports that formed part of post-graduate theses, conference abstracts, regional insecticide resistance databases and more traditional bibliographic searches of peer-reviewed literature. Finally, a check was made against two recent repositories of dominant malaria vector species locations ( circa 2,500). Each report was used to extract information on the survey dates, village locations (geo-coded to provide a longitude and latitude), sampling methods, species identification methods and all anopheline species found present during the survey. Survey records were collapsed to a single site over time. Results: The search strategy took years and resulted in 13,331 unique, geo-coded survey locations of anopheline vector occurrence between 1898 and 2016. A total of 12,204 (92%) sites reported the presence of 10 dominant vector species/sibling species; 4,473 (37%) of these sites were sampled since 2005. 4,442 (33%) sites reported at least one of 13 possible secondary vector species; 1,107 (25%) of these sites were sampled since 2005. Distributions of dominant and secondary vectors conform to previous descriptions of the ecological ranges of these vectors. Conclusion: We have assembled the largest ever geo-coded database of anophelines in Africa, representing a legacy dataset for future updating and identification of knowledge gaps at national levels. The geo-coded database is available on Harvard Dataverse as a reference source for African national malaria control programmes planning their future control and elimination strategies. PMID- 28884159 TI - A Reexamination of Thioredoxin Reductase from Thermoplasma acidophilum, a Thermoacidophilic Euryarchaeon, Identifies It as an NADH-Dependent Enzyme. AB - Flavin-containing Trx reductase (TrxR) of Thermoplasma acidophilum (Ta), a thermoacidophilic facultative anaerobic archaeon, lacks the structural features for the binding of 2'-phosphate of nicotinamide adenine dinucleotide phosphate (NADPH), and this feature has justified the observed lack of activity with NADPH; NADH has also been reported to be ineffective. Our recent phylogenetic analysis identified Ta-TrxR as closely related to the NADH-dependent enzymes of Thermotoga maritima and Desulfovibrio vulgaris, both being anaerobic bacteria. This observation instigated a reexamination of the activity of the enzyme, which showed that Ta-TrxR is NADH dependent; the apparent Km for NADH was 3.1 MUM, a physiologically relevant value. This finding is consistent with the observation that NADH:TrxR has thus far been found primarily in anaerobic bacteria and archaea. PMID- 28884160 TI - Micelle Maker: An Online Tool for Generating Equilibrated Micelles as Direct Input for Molecular Dynamics Simulations. AB - Micelles play an important role in both experimental and computational studies of the effect of lipid interactions on biological systems. The spherical geometry and the dynamical behavior of micelles makes generating micelle structures for use in molecular simulations challenging. An easy tool for generating simulation ready micelle models, covering a broad range of lipids, is highly desirable. Here, we present a new Web server, Micelle Maker, which can provide equilibrated micelle models as a direct input for subsequent molecular dynamics simulations from a broad range of lipids (currently 25 lipid types, including 24 glycolipids). The Web server, which is available at http://www.micellemaker.net, uses error checking routines to prevent clashes during the initial placement of the lipids and uses AMBER's GLYCAM library for generating minimized or equilibrated micelle models, but the resulting structures can be used as starting points for simulations with any force field or simulation package. Extensive validation simulations with an overall simulation time of 12 MUs using eight micelle models where assembly information is available show that all of the micelles remain very stable over the whole simulation time. Finally, we discuss the advantages of Micelle Maker relative to other approaches in the field. PMID- 28884161 TI - Conformational Dynamics Modulate Activation of the Ubiquitin Conjugating Enzyme Ube2g2. AB - The ubiquitin conjugating enzyme Ube2g2 together with its cognate E3 ligase gp78 catalyzes the synthesis of lysine-48 polyubiquitin chains constituting signals for the proteasomal degradation of misfolded proteins in the endoplasmic reticulum. Here, we employ NMR spectroscopy in combination with single-turnover diubiquitin formation assays to examine the role of the RING domain from gp78 in the catalytic activation of Ube2g2~Ub conjugates. We find that approximately 60% of the Ube2g2~Ub conjugates occupy a closed conformation in the absence of gp78 RING, with the population increasing to 82% upon gp78-RING binding. As expected, strong mutations in the hydrophobic patch residues of the ~Ub moiety result in Ube2g2~Ub populating only open states with corresponding loss of the ubiquitin conjugation activity. Less disruptive mutations introduced into the hydrophobic patch of the ~Ub moiety also destabilize the closed conformational state, yet the corresponding effect on the ubiquitin conjugation activity ranges from complete loss to an enhancement of the catalytic activity. These results present a picture in which Ube2g2's active site is in a state of continual dynamic flux with the organization of the active site into a catalytically viable conformation constituting the rate-limiting step for a single ubiquitin ligation event. Ube2g2's function as a highly specific K48-polyubiquitin chain elongator leads us to speculate that this may be a strategy by which Ube2g2 reduces the probability of nonproductive catalytic outcomes in the absence of available substrate. PMID- 28884162 TI - Modifier-Free Microfluidic Electrochemical Sensor for Heavy-Metal Detection. AB - Heavy-metal pollution poses severe threat to ecological systems and presents a great challenge for global sustainability. Portable point-of-care sensing platform for detection/monitoring of heavy-metal pollution in the environment is urgently demanded. Herein, a highly sensitive, robust, and low-cost microfluidic electrochemical carbon-based sensor (MUCS) for detection of trace heavy metals is presented. The miniaturized MUCS devices are based on a microfluidic paper channel combined with a novel three-dimensional layout with working and counter electrodes facing each other and analyte flowing along the microfluidic channel between these two electrodes. Pristine graphite foil free of any surface modifier is not only used as the electronically conductive pad but also directly employed as the working electrode for fabricating the MUCS. The resulting simple and portable device was applied in Cd2+ and Pb2+ detection using square-wave anodic stripping voltammetry. Detection limits down to 1.2 MUg/L for Cd2+ and 1.8 MUg/L for Pb2+ can be achieved over the MUCS. The MUCS devices are also found to be highly robust, and 10 repetitive measurements with a single MUCS device resulted to be highly reproducible. PMID- 28884163 TI - Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations. AB - Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl] benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank. As the docking poses obtained in the virtual screening pipeline did not align with the experimental cocrystal structures, we evaluated the predictions of their precise binding modes by performing molecular dynamics (MD) simulations. The MD simulations closely reproduced the experimentally observed protein-ligand cocrystal binding conformations and interactions for all compounds. These results suggest a computational workflow to generate experimental-quality protein-ligand binding models, overcoming limitations of docking results due to receptor flexibility and incomplete sampling, as a useful starting point for the structure-based lead optimization of novel BRD4(BD1) inhibitors. PMID- 28884164 TI - ecoAO: A Simple System for the Study of Human Aldehyde Oxidases Role in Drug Metabolism. AB - Although aldehyde oxidase (AO) is an important hepatic drug-metabolizing enzyme, it remains understudied and is consequently often overlooked in preclinical studies, an oversight that has resulted in the failure of multiple clinical trials. AO's preclusion to investigation stems from the following: (1) difficulties synthesizing metabolic standards due to the chemospecificity and regiospecificity of the enzyme and (2) significant inherent variability across existing in vitro systems including liver cytosol, S9 fractions, and primary hepatocytes, which lack specificity and generate discordant expression and activity profiles. Here, we describe a practical bacterial biotransformation system, ecoAO, addressing both issues simultaneously. ecoAO is a cell paste of MoCo-producing Escherichia coli strain TP1017 expressing human AO. It exhibits specific activity toward known substrates, zoniporide, 4-trans-(N,N dimethylamino)cinnamaldehyde, O6-benzylguanine, and zaleplon; it also has utility as a biocatalyst, yielding milligram quantities of synthetically challenging metabolite standards such as 2-oxo-zoniporide. Moreover, ecoAO enables routine determination of kcat and V/K, which are essential parameters for accurate in vivo clearance predictions. Furthermore, ecoAO has potential as a preclinical in vitro screening tool for AO activity, as demonstrated by its metabolism of 3 aminoquinoline, a previously uncharacterized substrate. ecoAO promises to provide easy access to metabolites with the potential to improve pharmacokinetic clearance predictions and guide drug development. PMID- 28884165 TI - Developmental Methylmercury Exposure Affects Swimming Behavior and Foraging Efficiency of Yellow Perch (Perca flavescens) Larvae. AB - Methylmercury (MeHg) is a pervasive and ubiquitous environmental neurotoxicant within aquatic ecosystems, known to alter behavior in fish and other vertebrates. This study sought to assess the behavioral effects of developmental MeHg exposure on larval yellow perch (Perca flavescens)-a nonmodel fish species native to the Great Lakes. Embryos were exposed to MeHg (0, 30, 100, 300, and 1000 nM) for 20 h and then reared to 25 days post fertilization (dpf) for analyses of spontaneous swimming, visual motor response (VMR), and foraging efficiency. MeHg exposures rendered total mercury (THg) body burdens of 0.02, 0.21, 0.95, 3.14, and 14.93 MUg/g (wet weight). Organisms exposed to 1000 nM exhibited high mortality; thus, they were excluded from downstream behavioral analyses. All MeHg exposures tested were associated with a reduction in spontaneous swimming at 17 and 25 dpf. Exposure to 30 and 100 nM MeHg caused altered locomotor output during the VMR assay at 21 dpf, whereas exposure to 100 nM MeHg was associated with decreased foraging efficiency at 25 dpf. For the sake of comparison, the second-lowest exposure tested here rendered a THg burden that represents the permissible level of consumable fish in the United States. Moreover, this dose is reported in roughly two-thirds of consumable fish species monitored in the United States, according to the Food and Drug Administration. Although the THg body burdens reported here were higher than expected in the environment, our study is the first to analyze the effects of MeHg exposure on fundamental survival behaviors of yellow perch larvae and advances in the exploration of the ecological relevance of behavioral end points. PMID- 28884166 TI - Crystal Structure of Thioesterase SgcE10 Supporting Common Polyene Intermediates in 9- and 10-Membered Enediyne Core Biosynthesis. AB - Enediynes are potent natural product anticancer antibiotics, and are classified as 9- or 10-membered according to the size of their enediyne core carbon skeleton. Both 9- and 10-membered enediyne cores are biosynthesized by the enediyne polyketide synthase (PKSE), thioesterase (TE), and PKSE-associated enzymes. Although the divergence between 9- and 10-membered enediyne core biosynthesis remains unclear, it has been observed that nascent polyketide intermediates, tethered to the acyl carrier protein (ACP) domain of PKSE, could be released by TE in the absence of the PKSE-associated enzymes. In this study, we determined the crystal structure of SgcE10, the TE that participates in the biosynthesis of the 9-membered enediyne C-1027. Structural comparison of SgcE10 with CalE7 and DynE7, two TEs that participate in the biosynthesis of the 10 membered enediynes calicheamicin and dynemicin, respectively, revealed that they share a common alpha/beta hot-dog fold. The amino acids involved in both substrate binding and catalysis are conserved among SgcE10, CalE7, and DynE7. The volume and the shape of the substrate-binding channel and active site in SgcE10, CalE7, and DynE7 confirm that TEs from both 9- and 10-membered enediyne biosynthetic machineries bind the linear form of similar ACP-tethered polyene intermediates. Taken together, these findings further support the proposal that the divergence between 9- and 10-membered enediyne core biosynthesis occurs beyond PKSE and TE catalysis. PMID- 28884168 TI - AUC-Maximized Deep Convolutional Neural Fields for Protein Sequence Labeling. AB - Deep Convolutional Neural Networks (DCNN) has shown excellent performance in a variety of machine learning tasks. This paper presents Deep Convolutional Neural Fields (DeepCNF), an integration of DCNN with Conditional Random Field (CRF), for sequence labeling with an imbalanced label distribution. The widely-used training methods, such as maximum-likelihood and maximum labelwise accuracy, do not work well on imbalanced data. To handle this, we present a new training algorithm called maximum-AUC for DeepCNF. That is, we train DeepCNF by directly maximizing the empirical Area Under the ROC Curve (AUC), which is an unbiased measurement for imbalanced data. To fulfill this, we formulate AUC in a pairwise ranking framework, approximate it by a polynomial function and then apply a gradient based procedure to optimize it. Our experimental results confirm that maximum-AUC greatly outperforms the other two training methods on 8-state secondary structure prediction and disorder prediction since their label distributions are highly imbalanced and also has similar performance as the other two training methods on solvent accessibility prediction, which has three equally-distributed labels. Furthermore, our experimental results show that our AUC-trained DeepCNF models greatly outperform existing popular predictors of these three tasks. The data and software related to this paper are available at https://github.com/realbigws/DeepCNF_AUC. PMID- 28884167 TI - Anxiolytic effects of buspirone and MTEP in the Porsolt Forced Swim Test. AB - Traditionally, a reduction in floating behavior or immobility in the Porsolt forced swim test (FST) is employed as a predictor of antidepressant efficacy. However, over the past several years, our studies of alcohol withdrawal-induced negative affect consistently indicate the coincidence of increased anxiety related behaviors on various behavioral tests with reduced immobility in the FST. Further, this behavioral profile correlates with increased mGlu5 protein expression within limbic brain regions. As the role for mGlu5 in anxiety is well established, we hypothesized that the reduced immobility exhibited by alcohol withdrawn mice when tested in the FST might reflect anxiety, possibly a hyper reactivity to the acute swim stressor. Herein, we evaluated whether or not the decreased FST immobility during alcohol withdrawal responds to systemic treatment with a behaviorally-effective dose of the prototypical anxiolytic, buspirone (5 mg/kg). We also determined the functional relevance of the withdrawal-induced increase in mGlu5 expression for FST behavior by comparing the effects of buspirone to a behaviorally effective dose of the mGlu5 negative allosteric modulator MTEP (3 mg/kg). Adult male C57BL/6J mice were subjected to a 14-day, multi-bottle, binge-drinking protocol that elicits hyper-anxiety and increases glutamate-related protein expression during early withdrawal. Control animals received only water. At 24hr withdrawal, animals from each drinking condition were subdivided into groups and treated with an IP injection of buspirone, MTEP, or vehicle, 30min prior to the FST. Drug effects on general locomotor activity were also assessed. As we reported previously, alcohol-withdrawn animals exhibited significantly reduced immobility in the FST compared to water controls. Both buspirone and MTEP significantly increased immobility in alcohol-withdrawn animals, with a modest increase also seen in water controls. No significant group differences were observed for locomotor activity, indicating that neither anxiolytic was sedating. These results provide predictive validity for increased swimming/reduced immobility in the FST as a model of anxiety and provide novel evidence in favor of mGlu5 inhibition as an effective therapeutic strategy for treating hyperanxiety during alcohol withdrawal. PMID- 28884169 TI - Cloud Engineering Principles and Technology Enablers for Medical Image Processing as-a-Service. AB - Traditional in-house, laboratory-based medical imaging studies use hierarchical data structures (e.g., NFS file stores) or databases (e.g., COINS, XNAT) for storage and retrieval. The resulting performance from these approaches is, however, impeded by standard network switches since they can saturate network bandwidth during transfer from storage to processing nodes for even moderate sized studies. To that end, a cloud-based "medical image processing-as-a-service" offers promise in utilizing the ecosystem of Apache Hadoop, which is a flexible framework providing distributed, scalable, fault tolerant storage and parallel computational modules, and HBase, which is a NoSQL database built atop Hadoop's distributed file system. Despite this promise, HBase's load distribution strategy of region split and merge is detrimental to the hierarchical organization of imaging data (e.g., project, subject, session, scan, slice). This paper makes two contributions to address these concerns by describing key cloud engineering principles and technology enhancements we made to the Apache Hadoop ecosystem for medical imaging applications. First, we propose a row-key design for HBase, which is a necessary step that is driven by the hierarchical organization of imaging data. Second, we propose a novel data allocation policy within HBase to strongly enforce collocation of hierarchically related imaging data. The proposed enhancements accelerate data processing by minimizing network usage and localizing processing to machines where the data already exist. Moreover, our approach is amenable to the traditional scan, subject, and project-level analysis procedures, and is compatible with standard command line/scriptable image processing software. Experimental results for an illustrative sample of imaging data reveals that our new HBase policy results in a three-fold time improvement in conversion of classic DICOM to NiFTI file formats when compared with the default HBase region split policy, and nearly a six-fold improvement over a commonly available network file system (NFS) approach even for relatively small file sets. Moreover, file access latency is lower than network attached storage. PMID- 28884170 TI - SERS-active metal-dielectric nanostructures integrated in microfluidic devices for label-free quantitative detection of miRNA. AB - In this work, SERS-based microfluidic PDMS chips integrating silver-coated porous silicon membranes were used for the detection and quantitation of microRNAs (miRNAs), which consist of short regulatory non-coding RNA sequences typically over- or under-expressed in connection with several diseases such as oncogenesis. In detail, metal-dielectric nanostructures which provide noticeable Raman enhancements were functionalized according to a biological protocol, adapted and optimized from an enzyme-linked immunosorbent assay (ELISA), for the detection of miR-222. Two sets of experiments based on different approaches were designed and performed, yielding a critical comparison. In the first one, the labelled target miRNA is revealed through hybridization to a complementary thiolated DNA probe, immobilized on the silver nanoparticles. In the second one, the probe is halved into shorter strands (half1 and half2) that interact with the complementary miRNA in two steps of hybridization. Such an approach, taking advantage of the Raman labelling of half2, provides a label-free analysis of the target. After suitable optimisation of the procedures, two calibration curves allowing quantitative measurements were obtained and compared on the basis of the SERS maps acquired on the samples loaded with several miRNA concentrations. The selectivity of the two step assay was confirmed by the detection of target miR-222 mixed with different synthetic oligos, simulating the hybridization interference coming from similar sequences in real biological samples. Finally, that protocol was applied to the analysis of miR-222 in cellular extracts using an optofluidic multichamber biosensor, confirming the potentialities of SERS-based microfluidics for early cancer diagnosis. PMID- 28884171 TI - Model-guided identification of novel gene amplification targets for improving succinate production in Escherichia coli NZN111. AB - Reconstruction and application of genome-scale metabolic models (GEMs) have facilitated metabolic engineering by providing a platform on which systematic computational analysis of metabolic networks can be performed. In this study, a GEM of Escherichia coli NZN111 was employed by the analysis of production and growth coupling (APGC) algorithm to identify genetic strategies for the overproduction of succinate. Through in silico simulation and reaction expression analysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), triosephosphate isomerase (TPI), and phosphoenolpyruvate carboxylase (PPC), encoded by gapA, pgk, tpiA, and ppc, respectively, were selected for experimental overexpression. The results showed that overexpressing any of these could improve both growth and succinate production. Specifically, overexpression of GAPDH or PGK showed a significant effect with up to 24% increase in succinate production. These results indicate that the APGC algorithm can be effectively used to guide genetic manipulation for strain design by identifying genome-wide gene amplification targets. PMID- 28884173 TI - Mediators of mutualistic microbe-microbe interactions. AB - The co-existence of different microbial species in one habitat is prerequisite for many ecosystem processes. To facilitate co-habitation of ecological niches, intricate mechanisms have evolved that regulate the growth and the behaviour of microbes. A crucial aspect for the establishment and maintenance of a microbial population is the communication among species. Whereas intraspecies communication processes have been widely studied, little is known about the molecular mechanisms underlying interspecies interactions. Through the advance of modern analytical and sequencing technologies, we are now beginning to gain deeper insights into these complex processes. A key feature of microbe-microbe interaction is the secretion of chemical mediators to influence either the microbial partner or co-occurring higher organisms to shape the specific microenvironment. Here we summarize recent advances in understanding the role of natural products as regulators of microbial interaction in various ecological niches. Special attention is paid to mutualistic relationships with relevance for ecology and agriculture as well as medicine. PMID- 28884172 TI - A 4-dimethylaminobenzoate-functionalized Ti6-oxo cluster with a narrow band gap and enhanced photoelectrochemical activity: a combined experimental and computational study. AB - Organic donor-pi-bridge-acceptor (D-pi-A) dyes with arylamines as an electron donor have been widely used as photosensitizers for dye-sensitized solar cells (DSSCs). However, titanium-oxo clusters (TOCs) functionalized with this kind of D pi-A structured dye-molecule have rarely been explored. In the present study, the 4-dimethylaminobenzoate-functionalized titanium-oxo cluster [Ti6(MU3 O)6(OiPr)6(DMABA)6].2C6H5CH3 (DMABA = 4-dimethylaminobenzoate) was synthesized and structurally characterized by single-crystal X-ray diffraction. For comparison, two other Ti6-oxo clusters, namely [Ti6(MU3-O)6(OiPr)6(AD)6] (AD = 1 adamantanecarboxylate) and [Ti6(MU3-O)2(MU2-O)(MU2-OiPr)4(OiPr)10(DMM)2] (DMM = dimethylmalonate), were also studied. The DMABA-functionalized cluster exhibits a remarkably reduced band gap of ~2.5 eV and much enhanced photocurrent response in comparison with the other two clusters. The electronic structures and electronic transitions of the clusters were studied by DFT and TDDFT calculations. The computational results suggest that the low-energy transitions of the DMABA functionalized cluster have a substantial charge-transfer character arising from the DMABA -> {Ti6} cluster core ligand-to-core charge transfer (LCCT), along with the DMABA-based intra-ligand charge transfer (ILCT). These low-energy charge transfer transitions provide efficient electron injection pathways for photon-to electron conversion. PMID- 28884174 TI - Probing RbBr solvation in freestanding sub-2 nm water clusters. AB - Concentration dependent solvation of RbBr in freestanding sub-2 nm water clusters was studied using core level photoelectron spectroscopy with synchrotron radiation. Spectral features recorded from dilute to saturated clusters indicate that either solvent shared or contact ion pairs are present in increasing amount when the concentration exceeds 2 mol kg-1. For comparison, spectra from anhydrous RbBr clusters are also presented. PMID- 28884175 TI - Protonation/reduction dynamics at the [4Fe-4S] cluster of the hydrogen-forming cofactor in [FeFe]-hydrogenases. AB - The [FeFe]-hydrogenases of bacteria and algae are the most efficient hydrogen conversion catalysts in nature. Their active-site cofactor (H-cluster) comprises a [4Fe-4S] cluster linked to a unique diiron site that binds three carbon monoxide (CO) and two cyanide (CN-) ligands. Understanding microbial hydrogen conversion requires elucidation of the interplay of proton and electron transfer events at the H-cluster. We performed real-time spectroscopy on [FeFe] hydrogenase protein films under controlled variation of atmospheric gas composition, sample pH, and reductant concentration. Attenuated total reflection Fourier-transform infrared spectroscopy was used to monitor shifts of the CO/CN- vibrational bands in response to redox and protonation changes. Three different [FeFe]-hydrogenases and several protein and cofactor variants were compared, including element and isotopic exchange studies. A protonated equivalent (HoxH) of the oxidized state (Hox) was found, which preferentially accumulated at acidic pH and under reducing conditions. We show that the one-electron reduced state Hred' represents an intrinsically protonated species. Interestingly, the formation of HoxH and Hred' was independent of the established proton pathway to the diiron site. Quantum chemical calculations of the respective CO/CN- infrared band patterns favored a cysteine ligand of the [4Fe-4S] cluster as the protonation site in HoxH and Hred'. We propose that proton-coupled electron transfer facilitates reduction of the [4Fe-4S] cluster and prevents premature formation of a hydride at the catalytic diiron site. Our findings imply that protonation events both at the [4Fe-4S] cluster and at the diiron site of the H cluster are important in the hydrogen conversion reaction of [FeFe]-hydrogenases. PMID- 28884176 TI - Morphometric characterization of fibrinogen's alphaC regions and their role in fibrin self-assembly and molecular organization. AB - The flexible C-terminal parts of fibrinogen's Aalpha chains named the alphaC regions have been shown to play a role in fibrin self-assembly, although many aspects of their structure and functions remain unknown. To examine the involvement of the alphaC regions in the early stages of fibrin formation, we used high-resolution atomic force microscopy to image fibrinogen and oligomeric fibrin. Plasma-purified full-length human fibrinogen or des-alphaC fibrinogen lacking most of the alphaC regions, untreated or treated with thrombin, was imaged. Up to 80% of the potentially existing alphaC regions were visualized and quantified; they were highly heterogeneous in their length and configurations. Conversion of fibrinogen to fibrin was accompanied by an increase in the incidence and length of the alphaC regions as well as transitions from more compact conformations, such as a globule on a string, to extended and more flexible offshoots. Concurrent dynamic turbidimetry, confocal microscopy, and scanning electron microscopy revealed that trimming of the alphaC regions slowed down fibrin formation, which correlated with longer protofibrils, thinner fibers, and a denser network. No structural distinctions, except for the incidence of the alphaC regions, were revealed in the laterally aggregated protofibrils made of the full-length or des-alphaC fibrinogens, suggesting a pure kinetic effect of the alphaC regions on the fibrin architecture. This work provides a structural molecular basis for the promoting role of the alphaC regions in the early stages of fibrin self-assembly and reveals this stage of fibrin formation as a potential therapeutic target to modulate the structure and mechanical properties of blood clots. PMID- 28884177 TI - Photocatalytic reduction of CO2 based on a CeO2 photocatalyst loaded with imidazole fabricated N-doped graphene and Cu(ii) as cocatalysts. AB - Cocatalysts are vital for improving photocatalytic activity. Incorporating nitrogen atoms on a graphene frame using an imidazole cycle resulted in a new N doped graphene (denoted as ING). Cerium(iv) oxide (CeO2) nanoparticles were dispersed on ING sheets, producing an ING/CeO2 hybrid material. The ING/CeO2 hybrid material was characterized using X-ray diffraction, transmission electron microscopy, Raman spectroscopy, ultraviolet-visible diffuse reflectance spectroscopy and surface photovoltage spectroscopy. Copper(ii) ions [Cu(ii)] were adsorbed on the ING/CeO2 hybrid material to directly form Cu(ii)/ING/CeO2, which could capture the photogenerated electrons to reduce carbon dioxide (CO2) to methanol (CH3OH) under incident light irradiation. The results showed that the yield from reducing CO2 to CH3OH during the photocatalytic process using Cu(ii)/ING/CeO2 as the photocatalyst approached 385.8 MUmol g-1 cat. h-1, whereas the yield was only 3.57 MUmol g-1 cat. h-1 using ING/CeO2 as the photocatalyst. This shows that the Cu(ii) ions play a vital role during photocatalytic reduction of CO2 by forming copper(i) ions [Cu(i)]. The percentage of ING in the ING/CeO2 hybrid material was investigated, and the results indicated that 3.6% of ING achieved an optimal yield of CH3OH during the photo-reduction process. The simultaneous roles of Cu(ii) ions and ING sheets demonstrate a synergistic strategy for improving the photocatalytic CO2 reduction. PMID- 28884178 TI - Screening of potential anti-adipogenic effects of phenolic compounds showing different chemical structure in 3T3-L1 preadipocytes. AB - This study was designed to analyze the anti-adipogenic effect of fifteen phenolic compounds from various chemical groups in 3T3-L1 pre-adipocytes. Cells were treated with 25 MUM, 10 MUM or 1 MUM of apigenin, luteolin, catechin, epicatechin, epigallocatechin, genistein, daizein, naringenin, hesperidin, quercetin, kaempferol, resveratrol, vanillic acid, piceatannol and pterostilbene for 8 days. At 25 MUM lipid accumulation was reduced by all the compounds, with the exception of catechin, epicatechin and epigallocatechin. At a dose of 10 MUM apigenin, luteolin, naringenin, hesperidin, quercetin and kaempferol induced significant reductions, and at 1 MUM only naringenin, hesperidin and quercetin were effective. The expression of c/ebpalpha was not. C/ebpbeta was significantly reduced by genistein and kaempferol, ppargamma by genistein and pterostilbene, srebp1c by luteolin, genistein, hesperidin, kaempferol, pterostilbene and vanillic acid, and lpl by kaempferol. In conclusion, the most effective phenolic compounds are naringenin, hesperidin and quercetin. Differences were found in terms of effects on the expression of genes involved in adipogenesis among the analyzed compounds. PMID- 28884179 TI - Morphology of a self-doped conducting oligomer for green energy applications. AB - A recently synthesized self-doped conducting oligomer, salt of bis[3,4 ethylenedioxythiophene]3thiophene butyric acid, ETE-S, is a novel promising material for green energy applications. Recently, it has been demonstrated that it can polymerize in vivo, in plant systems, leading to a formation of long-range conducting wires, charge storage and supercapacitive behaviour of living plants. Here we investigate the morphology of ETE-S combining the experimental characterisation using Grazing Incidence Wide Angle X-ray Scattering (GIWAXS) and atomistic molecular dynamics (MD) simulations. The GIWAXS measurements reveal a formation of small crystallites consisting of pi-pi stacked oligomers (with the staking distance 3.5 A) that are further organized in h00 lamellae. These experimental results are confirmed by MD calculations, where we calculated the X ray diffraction pattern and the radial distribution function for the distance between ETE-S chains. Our MD simulations also demonstrate the formation of the percolative paths for charge carriers that extend throughout the whole structure, despite the fact that the oligomers are short (6-9 rings) and crystallites are thin along the pi-pi stacking direction, consisting of only two or three pi-pi stacked oligomers. The existence of the percolative paths explains the previously observed high conductivity in in vivo polymerized ETE-S. We also explored the geometrical conformation of ETE-S oligomers and the bending of their aliphatic chains as a function of the oligomer lengths. PMID- 28884180 TI - Facile synthesis of photoluminescent inorganic-organic hybrid carbon dots codoped with B and N: towards an efficient lubrication additive. AB - A novel environmentally friendly bis-functional dicationic ionic liquid containing chelated orthoborate was synthesized and polycondensed with glutamic acid in order to synthesize inorganic-organic carbon dots (CD/IL) consisting of an ionic liquid moiety inserted in the carbon skeleton. The obtained CD/IL was found to be a new kind of nitrogen/boron-codoped nanomaterial, one with a mean particle diameter of 2.66 nm. CD/IL was verified to be a high-performance lubricant additive: in particular, the anti-wear and friction-reducing properties of poly(ethylene glycol) (PEG) were improved by 89.34% and 62.18%, respectively, when 1% CD/IL was added. Lubricants consisting of a mixture of CD/IL and PEG showed intense blue photo-fluorescence, and the corresponding photoluminescence (PL) intensity decreased considerably after carrying out a tribo-test. Moreover, CD/IL became transferred onto a rubbing steel interface during the tribo-test according to EDX and Raman analyses of a worn surface. CD/IL showed poor crystallinity, and interestingly, an intense G (~1600 cm-1) signature was detected on the steel surface after a high-load and long-duration tribo-test, which indicated that ordered carbon materials were generated on the interface, inhibiting the undesirable wear. PMID- 28884181 TI - Probing the solvation structure and dynamics in ionic liquids by time-resolved infrared spectroscopy of 4-(dimethylamino)benzonitrile. AB - In this work we demonstrate the use of the push-pull model system 4 (dimethylamino)benzonitrile (DMABN) as a convenient molecular probe to investigate the local solvation structure and dynamics by means of time-resolved infrared spectroscopy (TRIR). The photochemical features associated with this system provide several advantages due to the high charge separation between the ground and charge transfer states involving the characteristic nitrile bond, and an excited state lifetime that is long enough to observe the slow solvation dynamics in organic solvents and ionic liquids. The conversion from a locally excited state to an intramolecular charge transfer state (LE-ICT) in ionic liquids shows similar kinetic lifetimes in comparison to organic solvents. This similarity confirms that such conversion depends solely on the intramolecular reorganization of DMABN in the excited state, and not by the dynamics of solvation. In contrast, the relative shift of the nu(CN) vibration during the relaxation of the ICT state reveals two distinct lifetimes that are sensitive to the solvent environment. This study reveals a fast time component which is attributed to the dipolar relaxation of the solvent and a slower time component related to the rotation of the dimethylamino group of DMABN. PMID- 28884182 TI - Point defects in turbostratic stacked bilayer graphene. AB - The special properties of graphene can be largely influenced by point defects in the lattice. However, TEM studies of topological defects in few-layered graphene have rarely been reported. In this work, the two simplest forms of point defects monovacancy and divacancy in twisted bilayer graphene are characterized using aberration-corrected transmission electron microscopy (AC-TEM) at 80 kV. A convenient approach by using a negative mask in the fast Fourier transform (FFT) has been applied to separate the image signal of the two graphene layers. In the study combined with density functional theory (DFT) calculations and tight binding molecular dynamics simulations, the analysis of the defect structure and movement shows the stability and migration behavior of both defects. DFT calculations indicate that the migration of monovacancy in bilayer graphene needs to overcome a higher energy barrier. PMID- 28884183 TI - A comparison of the solvation structure and dynamics of the lithium ion in linear organic carbonates with different alkyl chain lengths. AB - The structure and dynamics of electrolytes composed of lithium hexafluorophosphate (LiPF6) in dimethyl carbonate, ethyl methyl carbonate, and diethyl carbonate were investigated using a combination of linear and two dimensional infrared spectroscopies. The solutions studied here have a LiPF6 concentration of X(LiPF6) = 0.09, which is typically found in commercial lithium ion batteries. This study focuses on comparing the differences in the solvation shell structure and dynamics produced by linear organic carbonates of different alkyl chain lengths. The IR experiments show that either linear carbonate forms a tetrahedral solvation shell (coordination number of 4) around the lithium ion irrespective of whether the solvation shell has anions in close proximity to the carbonates. Moreover, analysis of the absorption cross sections via FTIR and DFT computations reveals a distortion in the angle formed by Li+-O[double bond, length as m-dash]C which decreases from the expected 180 degrees when the alkyl chains of the carbonate are lengthened. In addition, our findings also reveal that, likely due to its asymmetric structure, ethyl methyl carbonate has a significantly more distorted tetrahedral lithium ion solvation shell than either of the other two investigated carbonates. IR photon echo studies further demonstrate that the motions of the solvation shell have a time scale of a few picoseconds for all three linear carbonates. Interestingly, a slowdown of the in place-motions of the first solvation shell is observed when the carbonate has a longer alkyl chain length irrespective of the symmetry. In addition, vibrational energy transfer with a time scale of tens of picoseconds is observed between strongly coupled modes arising from the solvation shell structure of the Li+ which corroborates the modeling of these solvation shells in terms of highly coupled vibrational states. Results of this study provide new insights into the molecular structure and dynamics of the lithium ion electrolyte components as a function of solvent structure. PMID- 28884184 TI - Branched polyethylenimine-functionalized carbon dots as sensitive and selective fluorescent probes for N-acetylcysteine via an off-on mechanism. AB - N-Acetylcysteine (NAC) plays an important role in optimizing the protective ability of cells as well as in the treatment of some chronic clinical conditions. Unfortunately, current methods for determining NAC based on fluorescence assay strategies remain poorly investigated. In this study, a new fluorescence method for highly sensitive and selective detection of NAC was developed. The detection method employed the fluorescence (FL) signal of branched polyethylenimine functionalized carbon dots (PEI-CDs) via an off-on mechanism. The detection system was based on the formation of cupric amine complexes by the reaction of Cu2+ ions with surface amino groups on PEI-CDs. The FL of PEI-CDs at 460.0 nm upon exciting at 360.0 nm was quenched as a result of electron transfer between the complexes and PEI-CDs. Upon addition of NAC to Cu2+-CD solution, electron transfer occurred from the mercapto group on NAC to Cu2+, leading to the formation of Cu+ species and the dissociation of cupric amine complexes. As a result, the FL signal of PEI-CDs was turned on since single excited electrons cannot be transferred from PEI-CDs to the cupric amine complexes. The detection limit of this method was 0.56 MUM, while the linear response ranged from 5.56 MUM to 277.8 MUM. PMID- 28884185 TI - Significant enhancement of the selectivity of propylene epoxidation for propylene oxide: a molecular oxygen mechanism. AB - As an attractive and environmentally friendly process for propylene oxide (PO) production, direct epoxidation of propylene (DEP) with molecular oxygen catalyzed by metal-based catalysts such as Ag and Cu has drawn much attention, but remains one of the biggest challenges in chemistry. In this work, the crucial competitive reactions of propylene alpha-H stripping (AHS) versus the oxametallacycle formation (OMMP formation) using adsorbed atomic oxygen (O*) or adsorbed molecular oxygen (O2*) as an oxidant are extensively compared on IB group metal surfaces (Cu, Ag and Au) with varied electronic and structural effects in order to explore the possibility to enhance the PO selectivity by virtue of first principles calculations. The determining factor for the PO selectivity is quantitatively revealed: it is found that with atomic O*, the AHS pathway was preferred, indicating the reason for low PO selectivity with current catalysts. By contrast, the undissociated molecular O2* species is found to prefer to electrophilically attack the C[double bond, length as m-dash]C double bond of propylene and form a special oxametallacycle intermediate (OOMMP) rather than nucleophilically abstracting the alpha-H. This OOMMP can readily cleave the O-O bond and transform into OMMP. These results demonstrate that the presence of undissociated O2* can efficiently promote the PO selectivity. Furthermore, the merit of such a molecular O2* mechanism can be rationalized by our quantitative barrier decomposition analyses, which reveal that the lower hydrogen affinity (DeltaEH) of the O2* species dominantly contributes to the limited AHS reaction, and boosts the OMMP selectivity. Therefore, DeltaEH can be applied as a selectivity descriptor. An efficient strategy to promote PO formation is presented. The insight obtained could pave the way for further development of catalysts for propylene epoxidation. PMID- 28884186 TI - Correction: An integrated anti-arrhythmic target network of compound Chinese medicine Wenxin Keli revealed by combined machine learning and molecular pathway analysis. AB - Correction for 'An integrated anti-arrhythmic target network of a Chinese medicine compound, Wenxin Keli, revealed by combined machine learning and molecular pathway analysis' by Taiyi Wang et al., Mol. BioSyst., 2017, 13, 1018 1030. PMID- 28884187 TI - Enantioselective recognition of an isomeric ligand by a biomolecule: mechanistic insights into static and dynamic enantiomeric behavior and structural flexibility. AB - Chirality is a ubiquitous basic attribute of nature, which inseparably relates to the life activity of living organisms. However, enantiomeric differences have still failed to arouse enough attention during the biological evaluation and practical application of chiral substances, and this poses a large threat to human health. In the current study, we explore the enantioselective biorecognition of a chiral compound by an asymmetric biomolecule, and then decipher the molecular basis of such a biological phenomenon on the static and, in particular, the dynamic scale. In light of the wet experiments, in silico docking results revealed that the orientation of the latter part of the optical isomer structures in the recognition domain can be greatly affected by the chiral carbon center in a model ligand molecule, and this event may induce large disparities between the static chiral bioreaction modes and noncovalent interactions (especially hydrogen bonding). Dynamic stereoselective biorecognition assays indicated that the conformational stability of the protein (S)-diclofop system is clearly greater than the protein-(R)-diclofop adduct; and moreover, the conformational alterations of the diclofop enantiomers in the dynamic process will directly influence the conformational flexibility of the key residues found in the biorecognition region. These points enable the changing trends of biopolymer structural flexibility and free energy to exhibit significant distinctions when proteins sterically recognize the (R)-/(S) stereoisomers. The outcomes of the energy decomposition further showed that the van der Waals' energy has roughly the same contribution to the chiral recognition biosystems, whereas the contribution of electrostatic energy to the protein-(R) diclofop complex is notably smaller than to the protein-(S)-diclofop bioconjugate. This proves that differences in the noncovalent bonds would have a serious impact on the stereoselective biorecognition between a biomacromolecule and chiral ligand. The present scenario is expected to attract more interest from both researchers and administrative agencies, since in a chiral environment, enantioselectivity exists in all of the biochemical processes of a chiral chemical, and this might finally elicit the disparate biological activities of (R)-/(S)-enantiomers. PMID- 28884188 TI - A convenient access to N-phosphonio-substituted NHC metal complexes [M = Ag(i), Rh(i), Pd(ii)]. AB - A series of NHC pre-ligands featuring a pendant phosphonium moiety attached to N' position through a propyl linker was readily obtained upon quaternization of N mesityl- and N-methyl-imidazole, or N-mesityl-imidazoline using (3-bromo-propyl) triphenylphosphonium bromide. Reactions of the resulting dicationic salts with [PdCl(allyl)]2 in the presence of K2CO3 afforded the anticipated NHC-ligated Pd(ii) metal complexes in high yields. Further treatment of the latter complexes with tBuOK induced a deprotonation of the carbon atom adjacent to the phosphonium moiety and the formation of the corresponding C,C-chelating NHC-phosphonium ylide Pd(ii) complexes. Investigation of an alternative synthetic route involving a silver transmetallation reaction incidentally allowed isolation and full characterization of an unusual dimeric tetranuclear NHC Ag(i) complex of general formula [(NHC~P+)2(Ag4Br6)2-]. PMID- 28884189 TI - An approach to spirooxindoles via palladium-catalyzed remote C-H activation and dual alkylation with CH2Br2. AB - A facile and efficient approach for the synthesis of spirooxindoles has been developed via the coupling of spirocyclic C,C-palladacycles with CH2Br2. The key spirocyclic palladacycles are generated catalytically via remote C-H activation. A range of spirooxindoles can be synthesized in good to excellent yields from readily available starting material. PMID- 28884191 TI - The Appearance and Diversification of Receptors for IgM During Vertebrate Evolution. AB - Three different receptors that interact with the constant domains of IgM have been identified: the polymeric immunoglobulin (Ig) receptor (PIGR), the dual receptor for IgA/IgM (FcalphauR) and the IgM receptor (FcuR). All of them are related in structure and located in the same chromosomal region in mammals. The functions of the PIGRs are to transport IgM and IgA into the intestinal lumen and to saliva and tears, whereas the FcalphauRs enhance uptake of immune complexes and antibody coated bacteria and viruses by B220+ B cells and phagocytes, as well as dampening the Ig response to thymus-independent antigens. The FcuRs have broad spectrum effects on B-cell development including effects on IgM homeostasis, B cell survival, humoral immune responses and also in autoantibody formation. The PIGR is the first of these receptors to appear during vertebrate evolution and is found in bony fish and all tetrapods but not in cartilaginous fish. The FcuR is present in all extant mammalian lineages and also in the Chinese and American alligators, suggesting its appearance with early reptiles. Currently the FcalphauR has only been found in mammals and is most likely the evolutionary youngest of the three receptors. In bony fish, the PIGR has either 2, 3, 4, 5 or 6 extracellular Ig-like domains, whereas in amphibians, reptiles and birds it has 4 domains, and 5 in all mammals. The increase in domain number from 4 to 5 in mammals has been proposed to enhance the interaction with IgA. Both the FcalphauRs and the FcuRs contain only one Ig domain; the domain that confers Ig binding. In both of these receptors this domain shows the highest degree of sequence similarity to domain 1 of the PIGR. All Ig domains of these three receptors are V type domains, indicating they all have the same origin although they have diversified extensively in function during vertebrate evolution by changing expression patterns and cytoplasmic signaling motifs. PMID- 28884192 TI - Erratum to: Of ions and messengers: an intricate link between potassium, glutamate, and cyclic di-AMP. AB - In the original publication, article title was incorrectly published as 'Perspective of ions and messengers: an intricate link between potassium, glutamate, and cyclic di-AMP'. The correct title should read as 'Of ions and messengers: an intricate link between potassium, glutamate, and cyclic di-AMP'. PMID- 28884193 TI - Neurotrophin Trk Receptors: New Targets for Cancer Therapy. AB - In the last few years, exciting reports have emerged regarding the role of the two types of neurotrophin receptors, p75NTR and Trks, not only in neurons, where they were discovered, but also in non-neural cells and, especially, in numerous cancers, including breast, lung, colon-rectum, pancreas, prostate, glioblastoma, neuroblastoma, myeloma, and lymphoid tumors. Traditionally, p75NTR, activated by all neurotrophins and their precursors, is an inhibitor. In various cancers, however, activated p75NTR induces variable effects, from inhibition to stimulation of cell proliferation, dependent on their direct or coordinate/indirect mechanism(s) of action. TrkA, TrkB, and TrkC, activated by distinct neurotrophins, are high affinity stimulatory receptors. In cancers, activation of Trks, especially of TrkB, are stimulators of cell proliferation, aggressiveness, and metastases. In rare cancers, these processes are due not to receptor activation but to fusion or mutation of the encoding genes. A considerable panel of anti-Trk drugs, developed recently, has been investigated both in vitro and in living mice for their effects on cancer cells. Many such drugs protect from cancers by preventing cell proliferation and inducing apoptosis. At present, these drugs are under control by trials, to promote introduction in human therapy. Moreover, anti-Trk drugs have been employed also in combination with classical chemotherapeutic drugs. So far, studies in mice have been positive. The chemotherapeutic/anti-receptor combinations exhibited in fact increased potency and down-regulation of resistance, with no increase of side effects. PMID- 28884194 TI - [Erratum to: Definition, classification, clinical diagnosis and prognosis of fibromyalgia syndrome : Updated guidelines 2017 and overview of systematic review articles]. PMID- 28884196 TI - ? PMID- 28884197 TI - ? PMID- 28884199 TI - Behavioral responses to visual overstimulation in the cockroach Periplaneta americana L. AB - In the visual systems of insects, different types of photoreceptors contribute to specialized visual channels that mediate distinct functions and behaviors. Large compound eyes of Periplaneta americana contain photoreceptors of two spectral classes, broadband green-sensitive photoreceptors and narrow-band UV-sensitive photoreceptors. Here, we investigated how visual stimulation by UV and green light affects locomotor, resting, and grooming behaviors in P. americana under conditions when light avoidance is not possible. We show that green but not UV light stimulates locomotor activity, inducing paradoxical positive masking. Duration of resting and grooming decreased with increasing light intensity, consistent with development of behavioral stress in response to visual overstimulation. A reaction of full immobility is described under UV light and at higher intensities of green light, with relative periods of immobility and grooming strongly negatively correlated. Low-intensity UV was more effective than low-intensity green light in suppressing grooming and inducing immobility. Our results suggest that locomotor activity in P. americana is mainly regulated by green-sensitive photoreceptors, and that dim UV light can trigger behavioral immobility, whereas both wavelengths induce stress-like reactions at high intensities. Considering the intrinsic UV sensitivity of green-sensitive photoreceptors, the contrasting behavioral responses indicate antagonistic interactions between UV and green visual channels. PMID- 28884198 TI - Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity. AB - AIMS/HYPOTHESIS: Tissue-resident macrophages sense the microenvironment and respond by producing signals that act locally to maintain a stable tissue state. It is now known that pancreatic islets contain their own unique resident macrophages, which have been shown to promote proliferation of the insulin secreting beta cell. However, it is unclear how beta cells communicate with islet resident macrophages. Here we hypothesised that islet macrophages sense changes in islet activity by detecting signals derived from beta cells. METHODS: To investigate how islet-resident macrophages respond to cues from the microenvironment, we generated mice expressing a genetically encoded Ca2+ indicator in myeloid cells. We produced living pancreatic slices from these mice and used them to monitor macrophage responses to stimulation of acinar, neural and endocrine cells. RESULTS: Islet-resident macrophages expressed functional purinergic receptors, making them exquisite sensors of interstitial ATP levels. Indeed, islet-resident macrophages responded selectively to ATP released locally from beta cells that were physiologically activated with high levels of glucose. Because ATP is co-released with insulin and is exclusively secreted by beta cells, the activation of purinergic receptors on resident macrophages facilitates their awareness of beta cell secretory activity. CONCLUSIONS/INTERPRETATION: Our results indicate that islet macrophages detect ATP as a proxy signal for the activation state of beta cells. Sensing beta cell activity may allow macrophages to adjust the secretion of factors to promote a stable islet composition and size. PMID- 28884200 TI - Spatial distribution of early red lesions is a risk factor for development of vision-threatening diabetic retinopathy. AB - AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by morphological lesions related to disturbances in retinal blood flow. It has previously been shown that the early development of retinal lesions temporal to the fovea may predict the development of treatment-requiring diabetic maculopathy. The aim of this study was to map accurately the area where lesions could predict progression to vision threatening retinopathy. METHODS: The predictive value of the location of the earliest red lesions representing haemorrhages and/or microaneurysms was studied by comparing their occurrence in a group of individuals later developing vision threatening diabetic retinopathy with that in a group matched with respect to diabetes type, age, sex and age of onset of diabetes mellitus who did not develop vision-threatening diabetic retinopathy during a similar observation period. RESULTS: The probability of progression to vision-threatening diabetic retinopathy was higher in a circular area temporal to the fovea, and the occurrence of the first lesions in this area was predictive of the development of vision-threatening diabetic retinopathy. The calculated peak value showed that the risk of progression was 39.5% higher than the average. There was no significant difference in the early distribution of lesions in participants later developing diabetic maculopathy or proliferative diabetic retinopathy. CONCLUSIONS/INTERPRETATION: The location of early red lesions in diabetic retinopathy is predictive of whether or not individuals will later develop vision threatening diabetic retinopathy. This evidence should be incorporated into risk models used to recommend control intervals in screening programmes for diabetic retinopathy. PMID- 28884201 TI - Pouch functional outcomes after restorative proctocolectomy with ileal-pouch reconstruction in patients with ulcerative colitis: Japanese multi-center nationwide cohort study. AB - BACKGROUND: Although several complications capable of causing pouch failure may develop after restorative proctocolectomy (RPC) for ulcerative colitis (UC), the incidences and causes are conflicting and vary according to country, race and institution. To avoid pouch failure, this study aimed to evaluate the rate of pouch failure and its risk factors in UC patients over the past decade via a nationwide cohort study. METHODS: We conducted a retrospective, observational, multicenter study that included 13 institutions in Japan. Patients who underwent RPC between January 2005 and December 2014 were included. The characteristics and backgrounds of the patients before and during surgery and their postoperative courses and complications were reviewed. RESULTS: A total of 2376 patients were evaluated over 6.7 +/- 3.5 years of follow-up. Twenty-seven non-functional pouches were observed, and the functional pouch rate was 98.9% after RPC. Anastomotic leakage (odds ratio, 9.1) was selected as a risk factor for a non functional pouch. The cumulative pouch failure rate was 4.2%/10 years. A change in diagnosis to Crohn's disease/indeterminate colitis (hazard ratio, 13.2) was identified as an independent risk factor for pouch failure. CONCLUSION: The significant risk factor for a non-functional pouch was anastomotic leakage. The optimal staged surgical procedure should be selected according to a patient's condition to avoid anastomotic failure during RPC. Changes in diagnosis after RPC confer a substantial risk of pouch failure. Additional cohort studies are needed to obtain an understanding of the long-standing clinical course of and proper treatment for pouch failure. PMID- 28884202 TI - Gcg CreERT2 knockin mice as a tool for genetic manipulation in pancreatic alpha cells. AB - AIMS/HYPOTHESIS: The Cre/loxP system, which enables tissue-specific manipulation of genes, is widely used in mice for diabetes research. Our aim was to develop a new Cre-driver mouse line for the specific and efficient manipulation of genes in pancreatic alpha cells. METHODS: A Gcg CreERT2 knockin mouse, which expresses a tamoxifen-inducible form of Cre from the endogenous preproglucagon (Gcg) gene locus, was generated by homologous recombination. The new Gcg CreERT2 mouse line was crossed to the Rosa26 tdTomato (R26 tdTomato ) Cre reporter mouse line in order to evaluate the tissue specificity, efficiency and tamoxifen dependency of Gcg CreERT2 -mediated recombination. Cell types of pancreatic islets were identified using immunohistochemistry. Biochemical and physiological data, including blood glucose levels, plasma glucagon and glucagon-like peptide (GLP)-1 levels, and pancreatic glucagon content, were collected and used to assess the overall effect of Gcg gene targeting on Gcg CreERT2/w heterozygous mice. RESULTS: Tamoxifen-treated Gcg CreERT2/w ;R26 tdTomato/w mice displayed Cre reporter activity, i.e. expression of tdTomato red fluorescent protein (RFP) in all known cells that produce proglucagon-derived peptides. In the adult pancreas, RFP was detected in 94-97% of alpha cells, whereas it was detected in a negligible (~ 0.2%) proportion of beta cells. While more than 98% of cells labelled with tamoxifen-induced RFP were glucagon-positive cells, 14-25% of pancreatic polypeptide (PP)-positive cells were also positive for RFP, indicating the presence of glucagon/PP bihormonal cell population. Tamoxifen-independent expression of RFP occurred in approximately 6% of alpha cells. In contrast to alpha cells and GLP-1-producing neurons, in which RFP expression persisted for at least 5 months after tamoxifen administration (presumably due to rare neogenesis in these cell types in adulthood), nearly half of RFP-positive intestinal L cells were replaced with RFP-negative L cells over the first 2 weeks after tamoxifen administration. Heterozygous Gcg CreERT2/w mice showed reduced Gcg mRNA levels in islets, but maintained normal levels of pancreatic and plasma glucagon. The mice did not exhibit any detectable baseline physiological abnormalities, at least in young adulthood. CONCLUSIONS/INTERPRETATION: The newly developed Gcg CreERT2 knockin mouse shows faithful expression of CreERT2 in pancreatic alpha cells, intestinal L cells and GLP-1-producing neurons. This mouse line will be particularly useful for manipulating genes in alpha cells, due to highly specific and efficient CreERT2-mediated recombination in this cell type in the pancreas. PMID- 28884203 TI - Left Ventricular Dilation: When Pediatric Meet Adult Guidelines. AB - Measuring and grading left ventricular (LV) size is essential for diagnostic, treatment, and prognostic purposes. Guidelines for quantifying LV size exist for pediatric and adult patients via M-mode measurements, but no data exist determining how well they agree with one another. The goal of this study was to determine the agreement between pediatric echocardiographic readers (PER), pediatric guidelines, and adult guidelines in assessing LV dilation. A retrospective review of all noncongenital echocardiograms from 9/2002 to 11/2015 that had a left ventricular end-diastolic diameter (LVEDD) >5.8 cm for males and >5.2 cm for females was performed. LV size was graded as normal (Z-score <= 2), mild (2 < Z-score <= 3), moderate (3 < Z-score <= 4), or severe (4 < Z-score) based on pediatric and adult guidelines. PER interpretation was also recorded. Agreement between LV size assessments was determined for these three interpretations. A total of 1489 echocardiograms met the inclusion criteria (654 males:835 females). Males were 19.0 +/- 6.9 years old and had a BSA of 1.9 +/- 0.3 m2, and LVEDD was 6.3 +/- 0.5 cm. Females were 18.7 +/- 8.3 years old and had a BSA of 1.8 +/- 0.3 m2, and LVEDD was 5.7 +/- 0.5 cm. There was a 63.91% agreement for males and an 81.8% agreement for females between PER and pediatric guidelines in assessing LV size. There was a 39.14% agreement for males and a 14.13% agreement for females between PER and adult guidelines in assessing LV size. There was a 41.44% agreement for males and a 14.49% agreement for females between adult and pediatric guidelines in assessing LV size. These agreement percentages did not change significantly when separating the population into greater than or less than 18 years of age cohorts. Pediatric echocardiographic readers were more consistent in following pediatric guidelines than adult guidelines in assessing LV size. The agreement for PER and pediatric guidelines was poor, especially for females, in relation to adult guidelines when assessing LV size. Further standardization and guidelines are needed for pediatric patients that are adult size. PMID- 28884204 TI - Exotic Earthworms Decrease Cd, Hg, and Pb Pools in Upland Forest Soils of Vermont and New Hampshire USA. AB - Exotic earthworms are present in the forests of northeastern USA, yet few studies have documented their effects on pollutant metals in soil. The objective of this study was to identify if Cd, Hg, and Pb strong-acid extractable concentrations and pools (bulk inventories) in forest soils decreased with the presence of exotic earthworms. We compared 'Low Earthworm Abundance' (LEA) sites (<=10 g m-2 earthworms, n = 13) and 'High Earthworm Abundance' (HEA) (>10 g m-2 earthworms, n = 17) sites at five watersheds across Vermont and New Hampshire. Organic horizon Cd, Hg, and Pb concentrations were lower at HEA than LEA sites. Organic horizon and total soil pools of Cd and Hg were negatively correlated with earthworm biomass. Soil profile Cd and Hg concentrations were lower at HEA than LEA sites. Our results suggest earthworms are decreasing accumulation of Cd, Hg, and Pb in forest soils, potentially via greater mobilization through organic matter disruption or bioaccumulation. PMID- 28884205 TI - Development of Brassica oleracea-nigra monosomic alien addition lines: genotypic, cytological and morphological analyses. AB - KEY MESSAGE: We report the development and characterization of Brassica oleracea nigra monosomic alien addition lines (MAALs) to dissect the Brassica B genome. Brassica nigra (2n = 16, BB) represents the diploid Brassica B genome which carries many useful genes and traits for breeding but received limited studies. To dissect the B genome from B. nigra, the triploid F1 hybrid (2n = 26, CCB) obtained previously from the cross B. oleracea var. alboglabra (2n = 18, CC) * B. nigra was used as the maternal parent and backcrossed successively to parental B. oleracea. The progenies in BC1 to BC3 generations were analyzed by the methods of FISH and SSR markers to screen the monosomic alien addition lines (MAALs) with each of eight different B-genome chromosomes added to C genome (2n = 19, CC + 1B1 8), and seven different MAALs were established, except for the one with chromosome B2 which existed in one triple addition. Most of these MAALs were distinguishable morphologically from each other, as they expressed the characters from B. nigra differently and at variable extents. The alien chromosome remained unpaired as a univalent in 86.24% pollen mother cells at diakinesis or metaphase I, and formed a trivalent with two C-genome chromosomes in 13.76% cells. Transmission frequency of all the added chromosomes was far higher through the ovules (averagely 14.40%) than the pollen (2.64%). The B1, B4 and B5 chromosomes were transmitted by female at much higher rates (22.38-30.00%) than the other four (B3, B6, B7, B8) (5.04-8.42%). The MAALs should be valuable for exploiting the genome structure and evolution of B. nigra. PMID- 28884206 TI - Neonatal congenital lung tumors - the importance of mid-second-trimester ultrasound as a diagnostic clue. AB - BACKGROUND: The differential diagnosis for primary lung masses in neonates includes a variety of developmental abnormalities; it also consists of the much rarer congenital primary lung tumors: cystic pleuropulmonary blastoma (cystic PPB), fetal lung interstitial tumor (FLIT), congenital peribronchial myofibroblastic tumor (CPMT), and congenital fibrosarcoma. Radiologic differentiation between malformations and tumors is often very challenging. OBJECTIVE: The objective was to establish distinctive features between developmental pulmonary abnormalities and primary lung tumors. MATERIALS AND METHODS: We conducted a retrospective study of 135 congenital lung lesions at a university mother and child center over a period of 10 years (2005-2015). During this time, we noted four tumors (two cystic PPBs and two FLITs) and 131 malformations. We recorded the following parameters: timing of conspicuity in utero (mid-second trimester, third trimester, or not seen prenatally), presence of symptoms at birth, prenatal and perinatal radiologic findings, and either histological diagnoses by pathology or follow-up imaging in non-operated cases. RESULTS: All lesions except the four tumors were detected during mid-second trimester ultrasound. In none of the tumors was any pulmonary abnormality found on the mid-second-trimester sonogram, contrary to the developmental pulmonary abnormalities. CONCLUSION: The timing of conspicuity in utero appears to be a key feature for the differentiation between malformations and tumors. Lesions that were not visible at the mid-second-trimester ultrasound should be considered as tumor. A cystic lung lesion in the context of a normal mid-second-trimester ultrasound is highly suggestive of a cystic PPB. Differentiating the types of solid congenital lung tumors based upon imaging features is not yet feasible. PMID- 28884207 TI - Kinematic Outcome Measures using Target-Reaching Arm Movement in Stroke. AB - This study aimed to quantitatively investigate upper extremity motor performance and disclose the abnormality of motor control induced by stroke. Ten patients and ten healthy subjects were instructed to perform target-reaching tasks at nine difficulty levels, and coordinates of the shoulder, elbow and tip of the index finger were recorded. Age-matched control performed significantly better than patients, as indicated by lower movement time (MT) and normalized jerk score (NJS) and higher peak velocity (V peak), percentage time to peak velocity (PTPV), fuzzy approximate entropy (fApEn) and relative joint angles correlation (RJAC); also, significant effects of difficulty on all parameters except RJAC and fApEn, were observed in two groups. There were significant correlations between PTPV and Fugl-Meyer assessment for upper extremity (FMA-UE) and between RJAC and FMA-UE at certain difficulty levels. The stroke-related differences could be explained by the increase in intrinsic neuromotor noise, and the difficulty-related differences may be related to extrinsic neuromotor noise. The increase in either noises could result in a degradation in motor control. The significant linear relationships between some kinematic parameters and the clinical score suggested that the kinematic parameters could be applied as quantitative outcome measures in the clinic in the future. PMID- 28884208 TI - Lacosamide treatment of childhood refractory focal epilepsy: the first reported side effect in paediatric patients. AB - PURPOSE: Lacosamide (LCM) is an effective antiepileptic drug (AED) approved for the treatment of focal epilepsy in both children and adults. The aim of this observational study was to review our centre's experience with LCM and to characterise its efficacy and tolerability as an adjunct therapy in children with refractory focal epilepsy. METHODS: We retrospectively reviewed the medical records of 12 paediatric patients who underwent treatment with LCM from January 2014 to December 2015. We recorded the treatment response at three time points: at 3 and 6 months after LCM therapy and at the final follow-up visit. Children showing seizure reduction >= 50% were considered responders. RESULTS: We included 12 patients (five boys), and their mean age was 13.8 years (range: 6.2-17.6 years) at the end of LCM treatment. The average length of follow-up after starting LCM was 23 months (11-37 months). Eight patients (66%) had > 50% reduction in seizures at the 3-month follow-up visit, and seven (58%) had > 50% reduction at the 6-month follow-up visit. Six patients (50%) maintained >= 50% reduction in seizures at the final follow-up visit. Two patients (16.6%) were seizure free at the 6-month and final follow-up visits. Common adverse side effects included dizziness, ataxia, nausea, and vomiting. Two patients developed status epilepticus (SE), one each at 3 and 11 days after the first LCM dose; they both discontinued treatment. CONCLUSIONS: Our study points to the efficacy of LCM in a small paediatric group. Furthermore, it was important to report status epilepticus after LCM administration in the paediatric population for the first time. PMID- 28884209 TI - Neural correlates of implicit knowledge about statistical regularities. AB - In this study, we examined the neural correlates of implicit knowledge about statistical regularities of temporal order and item chunks using functional magnetic resonance imaging (fMRI). In a familiarization scan, participants viewed a stream of scenes consisting of structured (i.e., three scenes were always presented in the same order) and random triplets. In the subsequent test scan, participants were required to detect a target scene. Test sequences included both forward order of scenes presented during the familiarization scan and backward order of scenes (i.e., reverse order of forward scenes). Behavioral results showed a learning effect of temporal order in the forward condition and scene chunks in the backward condition. fMRI data from the familiarization scan showed the difference of activations between the structured and random blocks in the left posterior cingulate cortex including the retrosplenial cortex. More important, in the test scan, we observed brain activities in the left parietal lobe when participants detected target scenes on temporal order information. In contrast, the left precuneus activated when participants detected target scenes based on scene chunks. Our findings help clarify the brain mechanisms of implicit knowledge about acquired regularities. PMID- 28884210 TI - Mortality in Swedish patients with Hirschsprung disease. AB - PURPOSE: Hirschsprung disease (HSCR) has previously been associated with increased mortality. The aim of this study was to assess mortality in patients with Hirschsprung disease in a population-based cohort. METHODS: This was a nationwide, population-based cohort study. The study exposure was HSCR and the study outcome was death. The cohort included all individuals with HSCR registered in the Swedish National Patient Register between 1964 and 2013 and ten age- and sex-matched controls per patient, randomly selected from the Population Register. Mortality and cause of death were assessed using the Swedish National Causes of Death Register. RESULTS: The cohort comprised 739 individuals with HSCR (565 male) and 7390 controls (5650 male). Median age of the cohort was 19 years (range 2-49). Twenty-two (3.0%) individuals with HSCR had died at median age 2.5 years (range 0-35) compared to 49 (0.7%) controls at median age 20 years (0-44), p < 0.001. Hazard ratio for death in HSCR patients compared to healthy controls was 4.77 (confidence interval (CI) 95% 2.87-7.91), and when adjusted for Down syndrome, the hazard ratio was 3.6 (CI 95% 2.04-6.37). CONCLUSIONS: The mortality rate in the HSCR cohort was 3%, which was higher than in controls also when data were adjusted for Down syndrome. PMID- 28884211 TI - The Changing Presentation of Paget's Disease of Bone in Australia, A High Prevalence Region. AB - Studies from several countries suggest that the incidence of Paget's disease of bone (PDB) and the severity of newly diagnosed cases are declining. The aim of this study was to examine secular changes in clinical presentation of PDB in Australia, which historically had the highest prevalence outside the United Kingdom. The participants were 293 patients (61% male) diagnosed between 1956 and 2013 with details recorded in the database of the Paget's Disease Research Group of Western Australia. The mean age at diagnosis was 62 years (range 28-90); 26% of participants had a family history of PDB and 11% had Sequestosome 1 (SQSTM1) mutations. After adjustment for covariates (SQSTM1 mutation status, family history, country of birth, smoking and dog exposure), there was a significant positive relationship between year of diagnosis and age at diagnosis (P < 0.001) and significant negative relationships between year of diagnosis and both pre treatment total plasma alkaline phosphatase activity (ALP) and number of involved bones (P < 0.001 for each). Patients with SQSTM1 mutations had more extensive disease (P < 0.001) and higher pre-treatment ALP (P = 0.013). In subgroup analyses, relationships between year of diagnosis and each of age at diagnosis, number of involved bones and ALP were similar in patients with sporadic or familial disease, and in patients with and without SQSTM1 mutations. We conclude that the severity of PDB in Western Australia has declined over recent decades. This is likely to reflect altered exposure to one or more environmental agents involved in pathogenesis. PMID- 28884212 TI - Routine Sildenafil Does Not Improve Clinical Outcomes After Fontan Operation. AB - Fontan operation can be complicated by persistent chest tube output (CTO) leading to prolonged hospital length of stay (LOS). Postoperative sildenafil administration has been shown to improve clinical outcomes in selected patients after Fontan. We initiated a practice change utilizing intravenous (IV) sildenafil in early postoperative period in all patients undergoing Fontan operation with aim to decrease LOS and CTO. Nineteen patients (February 2014-May 2016) received 0.35 mg/kg sildenafil IV (three doses) followed by enteral, 1 mg/kg every eight hours until hospital discharge. Clinical outcomes were compared to 84 pre-protocol controls. Vital signs were recorded after second sildenafil dose. Demographics were similar between groups. Sildenafil group had longer median LOS [9 (7, 11) vs. 13 (8, 25) days, p = 0.016]. CTO days were longer [6 (5, 8) vs. 8 (6, 13) days, p = 0.011]. Sildenafil group had longer mechanical ventilation [6.9 (3.5, 11.1) vs. 4 (2, 7) h, p = 0.045] and longer oxygen therapy [99 (52, 225) vs. 14.5 (14, 56) h, p = 0.001]. There was a trend towards more albumin 5% resuscitation in first 24 h [17 (1, 30) vs. 21 (10, 40) ml/kg, p = 0.069]. There was no difference in inotrope score at 24 h, maximum lactate, or fluid balance. Readmission rates were similar. There was no mortality. IV sildenafil was well tolerated, and no doses were held. Routine early administration of sildenafil after Fontan operation is not associated with an improvement in any measured clinical outcome, including postoperative CTO, LOS, colloid administration, or duration of mechanical ventilation. PMID- 28884213 TI - Reply to Radbruch et al.: 'interpreting signal-intensity ratios without visible T1 hyperintensities in clinical gadolinium retention studies'. PMID- 28884214 TI - [Opacification posterior to the intraocular lens - but no typical secondary cataract?] PMID- 28884215 TI - Effect of smoking cessation on quantitative computed tomography in smokers at risk in a lung cancer screening population. AB - OBJECTIVE: To longitudinally evaluate effects of smoking cessation on quantitative CT in a lung cancer screening cohort of heavy smokers over 4 years. METHODS: After 4 years, low-dose chest CT was available for 314 long-term ex smokers (ES), 404 continuous smokers (CS) and 39 recent quitters (RQ) who quitted smoking within 2 years after baseline CT. CT acquired at baseline and after 3 and 4 years was subjected to well-evaluated densitometry software, computing mean lung density (MLD) and 15th percentile of the lung density histogram (15TH). RESULTS: At baseline, active smokers showed significantly higher MLD and 15TH ( 822+/-35 and -936+/-25 HU, respectively) compared to ES (-831+/-31 and -947+/-22 HU, p<0.01-0.001). After 3 years, CS again had significantly higher MLD and 15TH (-801+/-29 and -896+/-23 HU) than ES (-808+/-27 and -906+/-20 HU, p<0.01-0.001) but also RQ (-813+/-20 and -909+/-15 HU, p<0.05-0.001). Quantitative CT parameters did not change significantly after 4 years. Importantly, smoking status independently predicted MLD at baseline and year 3 (p<0.001) in multivariate analysis. CONCLUSION: On quantitative CT, lung density is higher in active smokers than ex-smokers, and sustainably decreases after smoking cessation, reflecting smoking-induced inflammation. Interpretations of quantitative CT data within clinical trials should consider smoking status. KEY POINTS: * Lung density is higher in active smokers than ex-smokers. * Lung density sustainably decreases after smoking cessation. * Impact of smoking cessation on lung density is independent of potentially confounding factors. * Smoke-induced pulmonary inflammation and particle deposition influence lung density on CT. PMID- 28884216 TI - Standardized unfold mapping: a technique to permit left atrial regional data display and analysis. AB - PURPOSE: Left atrial arrhythmia substrate assessment can involve multiple imaging and electrical modalities, but visual analysis of data on 3D surfaces is time consuming and suffers from limited reproducibility. Unfold maps (e.g., the left ventricular bull's eye plot) allow 2D visualization, facilitate multimodal data representation, and provide a common reference space for inter-subject comparison. The aim of this work is to develop a method for automatic representation of multimodal information on a left atrial standardized unfold map (LA-SUM). METHODS: The LA-SUM technique was developed and validated using 18 electroanatomic mapping (EAM) LA geometries before being applied to ten cardiac magnetic resonance/EAM paired geometries. The LA-SUM was defined as an unfold template of an average LA mesh, and registration of clinical data to this mesh facilitated creation of new LA-SUMs by surface parameterization. RESULTS: The LA SUM represents 24 LA regions on a flattened surface. Intra-observer variability of LA-SUMs for both EAM and CMR datasets was minimal; root-mean square difference of 0.008 +/- 0.010 and 0.007 +/- 0.005 ms (local activation time maps), 0.068 +/- 0.063 gs (force-time integral maps), and 0.031 +/- 0.026 (CMR LGE signal intensity maps). Following validation, LA-SUMs were used for automatic quantification of post-ablation scar formation using CMR imaging, demonstrating a weak but significant relationship between ablation force-time integral and scar coverage (R 2 = 0.18, P < 0.0001). CONCLUSIONS: The proposed LA-SUM displays an integrated unfold map for multimodal information. The method is applicable to any LA surface, including those derived from imaging and EAM systems. The LA-SUM would facilitate standardization of future research studies involving segmental analysis of the LA. PMID- 28884217 TI - Critical genomic regulation mediated by Enhancer of Polycomb. AB - Enhancer of Polycomb (EPC) was first identified for its contributions to development in Drosophila and was soon-thereafter purified as a subunit of the NuA4/TIP60 acetyltransferase complex. Since then, EPC has often been left in the shadows as an essential, yet non-catalytic subunit of NuA4/TIP60; however, its deep conservation and disease association make clear that it warrants additional attention. In fact, recent studies in yeast demonstrated that its Enhancer of Polycomb, Epl1, was just as important for gene expression and acetylation as is the catalytic subunit of NuA4. Despite its conservation, studies of EPC have often remained siloed between organisms. Here, our goal is to provide a cohesive view of the current state of the EPC literature as it stands among the major model organisms in which it has been studied. EPC is involved in multiple processes, beginning with its cardinal role in regulating global and targeted histone acetylation. EPC also frequently serves as an important interaction partner in these basic cellular functions, as well as in multicellular development, such as in hematopoiesis and skeletal muscle differentiation, and in human disease. Taken together, a unifying theme from these studies highlights EPC as a critical genomic regulator. PMID- 28884219 TI - Cerebral air emboli complicating trans-bronchial needle aspiration using endo bronchial ultrasound. PMID- 28884218 TI - Use of Levosimendan in Postoperative Setting After Surgical Repair of Congenital Heart Disease in Children. AB - Low cardiac output is one of the most common complications after cardiac surgery. Levosimendan, a new inotrope agent, has been demonstrated in adult patient to be an effective treatment for this purpose when classical therapy is not effective. The aim of this study was to evaluate the effect of Levosimendan on cardiac output parameters in cardiac children with low cardiac output syndrome (LCOS.). We carried out a retrospective analysis on 62 children hospitalized in our pediatric intensive care unit (PICU) after cardiac surgery, which demonstrated LCOS not responding to classical catecholamine therapy and who received levosimendan as rescue therapy. LCOS parameters like diuresis, central venous oxygen saturation (SvO2), venous-to-arterial CO2 difference (?avCO2), and plasmatic lactate were compared before therapy and at 3, 6, 12, and 24 h after the beginning of the levosimendan infusion. We also analyzed the effect on the Vasoactive-inotropic score (VIS), adverse events, and mortality. After the beginning of levosimendan infusion, diuresis (1.1 vs. 3.5 ml/kg/h, p = 0.001) and SvO2 (59.5 vs. 63.3%, p = 0.026) increased significantly during the 24 h of infusion, and at the same time, plasmatic lactate (2.3 vs. 1.3 mmol/l, p < 0.001) decreased. ?avCO2 (10.8 vs. 9.4 mmHg, p = 0.21) and the VIS (44.5 vs. 22.5, p = 0.143) also decreased, but not significantly. No side effects were noted. The mortality in this patient group was 16%. Levosimendan is an effective treatment in children presenting LCOS after congenital heart surgery. Our study confirms the improvement of cardiac output already shown in other pediatric studies, with no undesirable side effects. PMID- 28884220 TI - Inflammatory response of disc cells against Propionibacterium acnes depends on the presence of lumbar Modic changes. AB - PURPOSE: Intervertebral disc with Propionibacterium acnes (P. acnes) is suggested to be an etiology of Modic type I changes in the adjacent bone marrow. However it is unknown if disc cells can respond to P. acnes and if bone marrow cells respond to bacterial and disc metabolites draining from infected discs. METHODS: Human disc cells (n = 10) were co-cultured with 10- and 100-fold excess of P. acnes over disc cells for 3 h and 24 h. Lipopolysaccharide was used as positive control. Expression of IL1, IL6, IL8, and CCL2 by disc cells was quantified by quantitative PCR. Lipase activity was measured in culture supernatants (n = 6). Human vertebral bone marrow mononuclear cells (BMNCs) (n = 2) were cultured in conditioned media from disc cell/P. acnes co-cultures and expression of IL1, IL6, IL8, and CCL2 was measured after 24 h. RESULTS: All disc cells responded to lipopolysaccharide but only 6/10 responded to P. acnes with increased cytokine expression. Cytokine increase was time- but not P. acnes concentration-dependent. Disc cell responsiveness was associated with the presence of lumbar Modic changes in the donor. Lipase activity was increased independent of disc cell responsiveness. BMNCs responded with inflammatory activity only when cultured in supernatants from responsive disc cell lines. CONCLUSION: Disc cell responsiveness to P. acnes associates with the presence of lumbar Modic changes. Furthermore, bone marrow cells had an inflammatory response to the cocktail of disc cytokines and P. acnes metabolites. These data indicate that low virulent P. acnes infection of the disc is a potential exacerbating factor to Modic changes. PMID- 28884221 TI - Evaluation of the Greek TranQol: a novel questionnaire for measuring quality of life in transfusion-dependent thalassemia patients. AB - The aim of our study was to evaluate the Greek version of the transfusion dependent quality of life (TranQol) questionnaire and report our experience of using this novel disease-specific quality of life (QoL) measure in patients with transfusion-dependent thalassemia (TDT). The TranQol and SF-36v2 questionnaires were administered to 94 adult TDT patients with a mean age of 32.1 years (SD = 7, range = 19-58), recruited from the Adult Thalassemia Unit of Hippokration General Hospital of Thessaloniki, Greece. The TranQol was evaluated in terms of construct validity, reliability, and responsiveness. There was a moderately strong correlation between the TranQol summary and both the SF-36v2 physical and mental component summaries (r = 0.4, p < 0.001 and r = 0.5, p < 0.001, respectively). There was also a moderately strong correlation between the physical health scale of TranQol and the relevant SF-36v2 scales, including physical functioning (r = 0.4, p < 0.001), role-physical (r = 0.6, p < 0.001), and bodily pain (r = 0.5, p < 0.001). TranQol also exhibited good internal consistency (Cronbach's alpha coefficient = 0.9) and excellent test-retest reliability (intra-class correlation coefficient = 0.9). The subgroup of patients that reported a better QoL 1 week after transfusion also demonstrated a significant improvement in their TranQol score. These are the first data regarding the administration of the Greek TranQol in a single thalassemia unit. The psychometric properties of the Greek TranQol confirmed it is a valid, reliable, and responsive to change questionnaire, which can be incorporated into future clinical trials. PMID- 28884223 TI - Optimism and the continued promise of maintenance chemotherapy. PMID- 28884222 TI - Diagnostic feasibility and safety of CT-guided core biopsy for lung nodules less than or equal to 8 mm: A single-institution experience. AB - OBJECTIVES: This retrospective study evaluated the diagnostic yield and safety of CT-guided core biopsy of pulmonary nodules <=8 mm. METHODS: We determined the diagnostic yield and safety profile of CT-guided lung biopsies for 125 pulmonary nodules <=8 mm. Pathological diagnoses were made by a combination of histopathological examination and imprint cytology. Results were compared with biopsy results for 134 pulmonary nodules >8 and <=10 mm. RESULTS: Final diagnoses were established in 94 nodules <=8 mm. The sensitivity, specificity and diagnostic accuracy of CT-guided core biopsy for nodules <=8 mm were 87.1 % (61/70 nodules), 100 % (24/24) and 90.4 % (85/94), respectively. Diagnostic failure rates were comparable for nodules <=8 mm and nodules >8 mm and <=10 mm (9/94, 9.6 % and 7/111, 6.3 %, respectively, P=0.385). The rate of tube thoracostomy for nodules <=8 mm was comparable to that for nodules >8 and <=10 mm (1.6 % vs. 0.7 %, P=0.611). Nodules <=6 mm had a higher non-diagnostic result rate of 15.4 % (6/39) than did nodules >8 and <=10 mm (3.7 %, 5/134, P=0.017). CONCLUSIONS: CT-guided pulmonary biopsy is feasible for lung nodules <=8 mm, especially those >6 mm, and has an acceptable diagnostic yield and safety profile. KEY POINTS: * CT-guided biopsy of lung nodules <=8 mm has high diagnostic accuracy. * Safety profiles are similar between nodules <=8 mm and 8 10 mm. * Nodules <=6 mm have higher rates of non-diagnostic results in biopsy. * Non-subpleural nodules and old age are risk factors for higher grade haemorrhage. * Biopsy is feasible for diagnosing nodules >6 and <=8 mm. PMID- 28884224 TI - Transfection of embryonated Muscovy duck eggs with a recombinant plasmid is suitable for rescue of infectious Muscovy duck parvovirus. AB - For members of the family Parvoviridae, rescue of infectious virus from recombinant plasmid is usually done in cultured cells. In this study, the whole genome of the pathogenic Muscovy duck parvovirus (MDPV) strain YY was cloned into the pBluescript II (SK) vector, generating recombinant plasmid pYY. With the aid of a transfection reagent, pYY plasmid was inoculated into 11-day-old embryonated Muscovy duck eggs via the chorioallantoic membrane route, resulting in the successful rescue of infectious virus and death of the embryos. The rescued virus exhibited pathogenicity in Muscovy ducklings similar to that of its parental strain, as evaluated based on the mortality rate. The results demonstrate that plasmid transfection in embryonated Muscovy duck eggs is a convenient and efficacious method for rescue of infectious MDPV in comparison to transfection of primary cells, which is somewhat time-consuming and laborious. PMID- 28884225 TI - Safety of endoscopic mucosal resection (EMR) of large non-pedunculated colorectal adenomas in the elderly. AB - BACKGROUND: Endoscopic mucosal resection (EMR) has been proven to be safe and effective for the treatment of colorectal adenomas. However, data are limited on the safety of this technique for large polyps and in elderly patients. Aims of our study were to examine the bleeding and perforation rates in patients with large non-pedunculated adenomas (>=20mm) and to evaluate the influence of size (>=40mm) and age (>=75 years) on the complication rates. METHODS: In this multicenter retrospective study, patients who underwent EMR of non-pedunculated adenomas >=20mm between January 2012 and March 2016 were included. The demographics of the patients, the use of antithrombotic drugs, size of the polyps, type of resection, pathology report, occurrence of post-polypectomy bleeding, and perforation- and recurrence rate were collected. RESULTS: In 343 patients, 412 adenomas were removed. Eighty patients (23.3%) were >=75 years of age, 138 polyps (33.5%) were >=40mm. Bleeding complications were observed in 28 cases (6.8%) and were found significantly more frequent in adenomas >=40mm, independent of the use of antithrombotic therapy. Five perforations (1.2%) were described, not related to the size of the polyp. There was no significant difference in complication rates between patients <75 years and patients >=75 years. Bleeding complications rates were significantly higher in patients receiving double antithrombotic therapy. CONCLUSION: EMR is safe in elderly patients. EMR of adenomas of >=40mm was associated with more bleeding complications. Future studies should address how the bleeding rates can be reduced in these patients, especially in those who use double antithrombotic treatment. PMID- 28884226 TI - The disengagement of visual attention in the gap paradigm across adolescence. AB - Attentional disengagement is important for successful interaction with our environment. The efficiency of attentional disengagement is commonly assessed using the gap paradigm. There is, however, a sharp contrast between the number of studies applying the gap paradigm to clinical populations and the knowledge about the underlying developmental trajectory of the gap effect. The aim of the present study was, therefore, to investigate attentional disengagement in a group of children aged 9-15. Besides the typically deployed gap and the overlap conditions, we also added a baseline condition in which the fixation point was removed at the moment that the target appeared. This allowed us to reveal the appropriate experimental conditions to unravel possible developmental differences. Correlational analyses showed that the size of the gap effect became smaller with increasing age, but only for the difference between the gap and the overlap conditions. This shows that there is a gradual increase in the capacity to disengage visual attention with increasing age, but that this effect only becomes apparent when the gap and the overlap conditions are compared. The gradual decrease of the gap effect with increasing age provides additional evidence that the attentional system becomes more efficient with increasing age and that this is a gradual process. PMID- 28884227 TI - Sleep quality in subjects suffering from chronic pain. AB - BACKGROUND: Sleeping problems are very common in patients with chronic pain. The aim of the study was to investigate the association between different dimensions of chronic pain and sleep quality in chronic pain patients. METHODS: In this cross-sectional interview-based questionnaire study, patients from 3 different pain treatment centers in Vienna aged 18-65 years, with pain lasting 3 months or longer were asked to participate. The association between the short-form McGill pain questionnaire (SF-MPQ) and sleep quality (sleep onset latency, interrupted sleep due to pain, sleep duration and recovering effect of sleep) was assessed. RESULTS: In this study 121 patients (male 32, female 89, mean age 49 +/- 9 years) could be analyzed. Of the patients 38.8% needed more than 30 min for falling asleep, 63.6% reported sleep fragmentation, 30.6% slept less than 5 h and 60.3% reported no recovering effect of sleep. The strongest associations between pain characteristics and sleep quality were found for pain intensity and affective pain aspects. Logistic regression analyses revealed that one point more in the total score of SF-MPQ increased the odds of needing more than 30 min for falling asleep, waking up more than 3 times due to pain, sleeping less than 5 h, and perceiving the sleep as non-recovering, by 6%. Adjusting for physical and psychological quality of life lowered the odds ratios and the association was no longer significant. CONCLUSION: The results underline the importance of paying attention to sleep quality in patients with chronic pain. The results also indicate that psychological factors might mediate the association between pain and sleep quality. PMID- 28884228 TI - Expression of ATF6 as a marker of pre-cancerous atypical change in ulcerative colitis-associated colorectal cancer: a potential role in the management of dysplasia. AB - BACKGROUND: Diagnosis of low-grade dysplasia (LGD) is important in the management of ulcerative colitis (UC), but it is often difficult to distinguish LGD from inflammatory regenerative epithelium. The unfolded protein response (UPR) is activated in inflammatory bowel disease and malignancies. We aimed to identify a UPR-related gene that is involved in the development of non-UC and UC-associated colorectal cancer (CRC), and to investigate whether the target gene is useful for the diagnosis of LGD. METHODS: Using our microarray gene expression database of 152 CRCs, we identified activating transcription factor 6 (ATF6) as a target gene. Immunohistochemistry (IHC) of ATF6 were analyzed in 137 surgically resected CRCs, 95 endoscopically resected adenomas and pTis cancers, and 136 samples from 51 UC patients (93 colitis without neoplasia, 31 dysplasia, and 12 UC-associated CRC). The diagnostic accuracy of ATF6 and p53 as markers of LGD was assessed. RESULTS: ATF6 expression was detectable in all CRCs but not in normal colonic mucosa, was elevated with increase in cellular atypia (adenoma with moderate atypia < severe atypia < pTis CRC, p < 0.001), and higher in dysplasia and CRC than in non-neoplastic colitis (p < 0.001). Notably, the difference between colitis and LGD was significant. Compared to p53-IHC, ATF6-IHC had better diagnostic accuracy for distinguishing LGD from background inflammatory mucosa (sensitivity 70.8 vs. 16.7%, specificity 78.5 vs.71.0%, respectively). CONCLUSIONS: ATF6 was expressed in lesions undergoing pre-cancerous atypical change in both non-UC and UC-associated CRC and may be used to distinguish LGD from inflammatory regenerative epithelium in UC patients. PMID- 28884229 TI - Time-to-event analysis of surgically treated posthemorrhagic hydrocephalus in preterm infants: a single-institution retrospective study. AB - PURPOSE: The purpose of this study is to report time points relevant to the neurosurgical management of posthemorrhagic hydrocephalus (PHH). METHODS: Data were collected retrospectively on 104 preterm infants with intraventricular hemorrhage (IVH) who received neurosurgical intervention for PHH at St. Louis Children's Hospital from 1994 to 2016. Kaplan-Meier curves were constructed for various endpoints. RESULTS: IVH grade on head ultrasound obtained through routine clinical care was II, III, and IV in 5 (4.8%), 33 (31.7%), and 66 (63.5%) of the patients, respectively. Neither IVH size nor location appeared to affect development of PHH. Days from birth to IVH, ventriculomegaly, temporizing neurosurgical procedure (TNP), and permanent neurosurgical intervention were 2.0 (95% CI 1.7-2.3), 3.0 (2.5-3.5), 24.0 (22.2-25.8), and 101.0 (90.4-111.6), respectively. Grades III and IV IVH did not differ in age at IVH diagnosis (Chi 2 (1 d.f.) = 1.32, p = 0.25), ventriculomegaly (Chi 2 = 0.73, p = 0.40), TNP (Chi 2 = 0.61, p = 0.43), or permanent intervention (Chi 2 = 2.48, p = 0.17). Ventricular reservoirs and ventriculosubgaleal shunts were used in 71 (68.3%) and 30 (28.8%), respectively. Eighty (76.9%) of the patients ultimately received a VPS. Five (4.8%) underwent a primary endoscopic third ventriculostomy (ETV), and two (1.9%) had ETV for a revision procedure. Four of the seven ETVs had choroid plexus cauterization. CONCLUSIONS: Although most infants who develop IVH and ventriculomegaly will do so within a few days of birth, at-risk infants should be observed for at least 4 weeks with serial head ultrasounds to monitor for PHH requiring surgery. PMID- 28884230 TI - Environmental impacts caused by cemeteries and crematoria, new funeral technologies, and preferences of the Northeastern and Southern Brazilian population as for the funeral process. AB - Cemeteries and crematoria are the main funeral ways used in the world nowadays. It is a little-studied segment in the present days, mainly as for the possible environmental impacts in the environment, such as those derived from dental amalgam, prostheses, and dioxins, among other. This article aimed to identify the environmental impacts caused by cemeteries and crematoria and to point out new trends in funeral processes such as freeze-drying and alkaline hydrolysis. The study is justified due to the large part of the Brazilian population that do not know the environmental impacts caused by cemeteries and crematoria, as well as to bring information about the new processes. For that, a research was carried out with 400 people. The main results show that among all the funeral processes, the new freeze-drying process was opted by 33% of the sample. We also identified that the main reasons for choosing the funeral process were less environmental impact (28%), no after-death expenses (grave payment) (16.1%), and the possibility of putting away or throwing away the remains wherever you want (14.9%). Finally, new funeral processes were well accepted by the Brazilian population-those who were interviewed-due to their benefits. PMID- 28884231 TI - Infant brachial neuritis following a viral prodrome: a case in a 6-month old child and review of the literature. AB - INTRODUCTION: Brachial neuritis, commonly known as Parsonage-Turner syndrome, affects two to three people per 100,000 and presents with pain and weakness of the arm and shoulder. Brachial neuritis is uncommon in infants. METHODS: Here, we present the case of a 6-month old female, who presented with right upper extremity weakness and paresis following a viral prodrome. We also present a summary of all reported cases of brachial neuritis in infants. RESULTS: This is the youngest case of brachial neuritis diagnosed at our institution. The child was treated with prednisolone and physical therapy. The patient is now 16 months old and her symptoms have significantly improved. CONCLUSIONS: Brachial neuritis should be considered in the differential when an infant presents with sudden onset of upper limb weakness, following a viral prodrome. Finally, a genetic workup is suggested for patients with recurring episodes. PMID- 28884232 TI - [18F]AV-1451 binding to neuromelanin in the substantia nigra in PD and PSP. AB - This study investigated binding of [18F]AV-1451 to neuromelanin in the substantia nigra of patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP). [18F]AV-1451 is a positron emission tomography radiotracer designed to bind pathological tau. A post-mortem study using [18F]AV-1451 discovered off target binding properties to neuromelanin in the substantia nigra. A subsequent clinical study reported a 30% decrease in [18F]AV-1451 binding in the midbrain of PD patients. A total of 12 patients and 10 healthy age-matched controls were recruited. An anatomical MRI and a 90-min PET scan, using [18F]AV-1451, were acquired from all participants. The standardized uptake value ratio (SUVR) from 60 to 90 min post-injection was calculated for the substantia nigra, using the cerebellar cortex as the reference region. The substantia nigra was delineated using automated region of interest software. An independent samples ANOVA and LSD post hoc testing were used to test for differences in [18F]AV-1451 SUVR between groups. Substantia nigra SUVR from 60 to 90 min was significantly greater in HC compared to both PSP and PD groups. Although the PD group had the lowest SUVR, there was no significant difference in substantia nigra uptake between PD and PSP. [18F]AV-1451 may be the first PET radiotracer capable of imaging neurodegeneration of the substantia nigra in parkinsonisms. Further testing must be done in PD and atypical parkinsonian disorders to support this off-target use of [18F]AV-1451. PMID- 28884233 TI - In Vivo Strain Analysis of Dilated Ascending Thoracic Aorta by ECG-Gated CT Angiographic Imaging. AB - Accurate assessment of aortic extensibility is a requisite first step for elucidating the pathophysiology of an ascending thoracic aortic aneurysm (ATAA). This study aimed to develop a framework for the in vivo evaluation of the full field distribution of the aortic wall strain by imaging analysis of electrocardiographic- (ECG) gated thoracic data of 34 patients with ATAA. Seven healthy controls (i.e., non-aneurysmal aorta) from patients who underwent ECG gated CT angiography for coronary artery diseases were included for comparison. To evaluate the systolic function, ECG-gated computed tomography (CT) angiography was used to generate patient-specific geometric meshes of the ascending aorta, and then to estimate both the displacement and strain fields using a mathematical algorithm. Results evidenced stiff behavior for the aneurysmal aorta compared with that of the healthy ascending aorta of the controls, with patients over 55 years of age displaying significantly lower extensibility. Moreover, the patient risk as quantified by the ratio of in vivo strain to the ruptured one increased significantly with increased systolic blood pressure, older age, and higher pressure-strain modulus. Statistical analysis also indicated that an increased pressure-strain modulus is a risk factor for ATAAs with bicuspid aortic valve, suggesting a different mechanism of failure in these patients. The approach here proposed for the in vivo evaluation of the aortic wall strain is simple and fast, with promising applicability in routine clinical imaging, and could be used to develop a rupture potential criterion on the basis of the aortic aneurysm extensibility. PMID- 28884234 TI - Impact of a Mental Health Based Primary Care Program on Quality of Physical Health Care. AB - We examine the impact of mental health based primary care on physical health treatment among community mental health center patients in New York State using propensity score adjusted difference in difference models. Outcomes are quality indicators related to outpatient medical visits, diabetes HbA1c monitoring, and metabolic monitoring of antipsychotic treatment. Results suggest the program improved metabolic monitoring for patients on antipsychotics in one of two waves, but did not impact other quality indicators. Ceiling effects may have limited program impacts. More structured clinical programs to may be required to achieve improvements in quality of physical health care for this population. PMID- 28884235 TI - A cross-sectional survey comparing a free treatment program for advanced schistosomiasis japonica to a general assistance program. AB - The prevalence and intensity of schistosomiasis has dropped dramatically in China due to an effective integrated control program. However, advanced schistosomiasis is becoming a key challenge on the road to elimination. The aims of this study were to compare the disease condition between advanced cases under the general assistance program (GAP) and free treatment program (FTP) and to determine whether the FTP should be popularized to provide an objective reference for policymakers in China's advanced schistosomiasis control program. One hundred and ninety-four patients with schistosomiasis japonica who were enrolled in the GAP or FTP participated in this study. Little significant difference was observed in the potential confounders, including general characteristics, comorbidities, and lifestyle, indicating a similar effect on the pathology of liver damage caused by schistosome infection. There was no apparent difference in the incidence of common clinical symptoms. Furthermore, no significant difference was observed in the ultrasound findings, implying that the GAP and FTP groups shared a similar degree of liver lesion. With the exception of the abnormal rates of aspartate aminotransferase (AST), alkaline phosphatase (ALP), and hyaluronic acid (HA), the other serological indicators were comparable between the groups. Overall, the FTP is not a better option for controlling advanced schistosomiasis in China. It is important to reveal the precise mechanism underlying the pathogenesis of advanced schistosomiasis so that specific approaches to treating and preventing the development of advanced schistosomiasis can be developed and schistosomiasis can be eliminated in China. PMID- 28884236 TI - Identification of a serotype-independent linear epitope of foot-and-mouth disease virus. AB - Foot-and-mouth disease (FMD), caused by foot-and-mouth disease virus (FMDV), is a highly contagious infectious disease that affects domestic and wild cloven-hoofed animals worldwide. VP2 is a structural protein of FMDV. In this study, an FMDV serotype-independent monoclonal antibody (MAb), 10B10, against the viral capsid protein VP2 was generated, and a series of GST fusion proteins expressing a truncated peptide of VP2 was subjected to Western blot analysis using MAb 10B10. Their results indicated that the peptide 8TLLEDRILT16 of VP2 is the minimal requirement of the epitope recognized by MAb 10B10. Importantly, this linear epitope was highly conserved among all seven serotypes of FMDV in a sequence alignment analysis. Subsequent alanine-scanning mutagenesis analysis revealed that the residues Thr8 and Asp12 of the epitope were crucial for MAb-10B10 binding. Furthermore, Western blot analysis also revealed that the MAb 10B10 directed epitope could be recognized by positive sera from FMDV-infected cattle. The discovery that MAb 10B10 recognizes a serotype-independent linear epitope of FMDV suggests potential applications for this MAb in the development of serotype independent tests for FMDV. PMID- 28884237 TI - Relationship between intracranial aneurysms and the severity of autosomal dominant polycystic kidney disease. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disease characterized by the progressive enlargement of innumerable renal cysts. Although the association of intracranial aneurysms (ICANs) with ADPKD is well known, the relationship between the ICAN and the disease severity including total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) is poorly understood. METHODS: We screened 265 patients with ADPKD (mean age, 48.8 years; range, 14.9-88.3 years) with MR angiography. The patients with a past history related to ICANs were excluded from the study. The incidence and characteristics of ICAN in patients with ADPKD were evaluated. TKV was measured by volumetric analyses of MR imaging. RESULTS: We detected 65 ICANs in 49 patients (37 women and 12 men, mean age, 52.7 years; range, 20.4-86 years). The incidence of ICANs was 18.5% and female patients had was higher incidence (23.1%) than male patients (11.4%) (p = 0.02). An age of those with ICANs was significantly higher than those without (p = 0.006), and the cumulative risk of diagnosis of ICANs increased with age. TKV was significantly larger in those with ICANs than those without (p = 0.001), but eGFR was not different between two groups (p = 0.07). By multivariate analyses, only TKV was significantly related to the development of ICANs (p = 0.02). CONCLUSIONS: The incidence of ICANs increased with age, was higher in females, and correlated with kidney enlargement in patients with ADPKD. Necessity of screening ICANs would be particularly high in elderly women with large kidneys. PMID- 28884238 TI - Medicolegal Sidebar: (Mis)Informed Consent in Medical Negligence Lawsuits. PMID- 28884240 TI - The serological markers of acute infection with hepatitis A, B, C, D, E and G viruses revisited. AB - Viral hepatitis is a liver infection caused by one of the six hepatitis viruses: hepatitis A, B, C, D, E, and G virus (HAV to HEV and HGV). These agents differ in their biological, immunological, pathological and epidemiological characteristics. They cause infections that, when symptomatic, lead to clinical manifestations and laboratory findings that are not specific to a particular virus, often making differential diagnosis difficult, especially when no knowledge is available regarding the patient's medical history or the epidemiological background. A number of acute-phase serological markers, such as anti-HAV, anti-HBc, anti-HDV and anti-HEV IgM antibodies, are able to provide a clear indication of an infection caused by HAV, HBV, HDV or HEV. Anti-HCV antibodies and HGV/RNA are used for the diagnosis of HCV and HGV infections. The importance of each of these markers will be reviewed, and different factors that can interfere with the diagnosis of acute infections caused by these viruses will be described. PMID- 28884239 TI - Nano-Composite Foam Sensor System in Football Helmets. AB - American football has both the highest rate of concussion incidences as well as the highest number of concussions of all contact sports due to both the number of athletes and nature of the sport. Recent research has linked concussions with long term health complications such as chronic traumatic encephalopathy and early onset Alzheimer's. Understanding the mechanical characteristics of concussive impacts is critical to help protect athletes from these debilitating diseases and is now possible using helmet-based sensor systems. To date, real time on-field measurement of head impacts has been almost exclusively measured by devices that rely on accelerometers or gyroscopes attached to the player's helmet, or embedded in a mouth guard. These systems monitor motion of the head or helmet, but do not directly measure impact energy. This paper evaluates the accuracy of a novel, multifunctional foam-based sensor that replaces a portion of the helmet foam to measure impact. All modified helmets were tested using a National Operating Committee Standards for Athletic Equipment-style drop tower with a total of 24 drop tests (4 locations with 6 impact energies). The impacts were evaluated using a headform, instrumented with a tri-axial accelerometer, mounted to a Hybrid III neck assembly. The resultant accelerations were evaluated for both the peak acceleration and the severity indices. These data were then compared to the voltage response from multiple Nano Composite Foam sensors located throughout the helmet. The foam sensor system proved to be accurate in measuring both the HIC and Gadd severity index, as well as peak acceleration while also providing additional details that were previously difficult to obtain, such as impact energy. PMID- 28884241 TI - Torsed appendix epididymis in an adult: misdiagnosis as tumor of tunica vaginalis on sonography. AB - We report the sonographic findings in a case of torsed appendix epididymis that occurred in an adult, which was misdiagnosed as a tunica vaginalis tumor such as cystic mesothelioma. Scrotal gray-scale sonography revealed an ovoid-shaped, heterogeneously hypoechoic mass with multiple tiny cystic foci and thick septa in the sac of the right tunica vaginalis, which abuts to the right epididymal head. Color Doppler sonography showed no blood flow within the mass. Pathological examination revealed torsion of the appendix epididymis. PMID- 28884242 TI - A comparative crossover study on the treatment of hemifacial spasm and blepharospasm: preseptal and pretarsal botulinum toxin injection techniques. AB - Hemifacial spasm (HFS) and benign essential blepharospasm (BEB) are chronic and disabling abnormal craniofacial movements that produce involuntary eyelid twitching and closure. The efficacy and safety of botulinum toxin type A (BoNT-A) injections have been accepted and widely used for the treatment of HFS and BEB. However, different injection sites may influence the effectiveness, doses, and side effects. The aim of this study is to compare the efficacy, patient satisfaction, and complications of low-dose BoNT-A injections between injection at the preseptal (PS) and the pretarsal (PT) portion of the orbicularis oculi muscle. A total of 40 patients, 31 patients with HFS and 9 patients with BEB, participated in this study. Each patient received both PS and PT BoNT-A injections in a crossover design study. Latency to response, duration of improvement, the Jankovic Rating Scale (JRS), self-response scale, patient satisfaction scale, and complications were compared. Low-dose injections of BoNT A at the PT portion produced a significantly higher response rate in terms of latency to response, duration of improvement, JRS, self-response scale, and patient satisfaction scale than the PS injections. Major side effects including ptosis and droopy eyelid were observed only after the PS injections. These findings confirmed that low-dose injections of BoNT-A at the PT portion provide more efficacy, patient satisfaction, and fewer complications than the PS injections for the treatment of involuntary eyelid twitching and closure in patients with HFS and BEB. PMID- 28884243 TI - Smoking Policy Change Within Permanent Supportive Housing. AB - Smoke-free policies effectively reduce secondhand smoke (SHS) exposure among non smokers, and reduce consumption, encourage quit attempts, and minimize relapse to smoking among smokers. Such policies are uncommon in permanent supportive housing (PSH) for formerly homeless individuals. In this study, we collaborated with a PSH provider in San Diego, California to assess a smoke-free policy that restricted indoor smoking. Between August and November 2015, residents completed a pre-policy questionnaire on attitudes toward smoke-free policies and exposure to secondhand smoke, and then 7-9 months after policy implementation residents were re-surveyed. At follow-up, there was a 59.7% reduction in indoor smoking. The proportion of residents who identified as current smokers reduced by 13% (95% CI: -38, 10.2). The proportion of residents who reported never smelling SHS indoors (apartment 24.2%, 95% CI: 4.2, 44.1; shared areas 17.2%, 95% CI: 1.7, 32.7); in outdoor areas next to the living unit (porches or patio 56.7%, 95% CI: 40.7, 72.8); and in other outdoor areas (parking lot 28.6%, 95% CI: 8.3, 48.9) was lower post-policy compared with pre-policy. Overall, resident support increased by 18.7%; however, the greatest increase in support occurred among current smokers (from 14.8 to 37.5%). Fewer current smokers reported that the policy would enable cessation at post-policy compared to pre-policy. Our findings demonstrate the feasibility of implementing smoke-free policies in PSH for formerly homeless adults. However, policy alone appears insufficient to trigger change in smoking behavior, highlighting the need for additional cessation resources to facilitate quitting. PMID- 28884244 TI - Lasers and intense pulsed light (IPL) association with cancerous lesions. AB - The development and use of light and lasers for medical and cosmetic procedures has increased exponentially over the past decade. This review article focuses on the incidence of reported cases of skin cancer post laser or IPL treatment. The existing evidence base of over 25 years of laser and IPL use to date has not raised any concerns regarding its long-term safety with only a few anecdotal cases of melanoma post treatment over two decades of use; therefore, there is no evidence to suggest that there is a credible cancer risk. Although laser and IPL technology has not been known to cause skin cancer, this does not mean that laser and IPL therapies are without long-term risks. Light therapies and lasers to treat existing lesions and CO2 laser resurfacing can be a preventative measure against BCC and SCC tumour formation by removing photo-damaged keratinocytes and encouraged re-epithelisation from stem cells located deeper in the epidermis. A review of the relevant literature has been performed to address the issue of long term IPL safety, focussing on DNA damage, oxidative stress induction and the impact of adverse events. PMID- 28884245 TI - Life satisfaction and inflammation in couples: an actor-partner analysis. AB - Life satisfaction has been linked to lower cardiovascular disease mortality. However, much less is known about the biological mechanisms linking life satisfaction to physical health. In addition, the dyadic context of life satisfaction has not been considered despite increasing evidence that partners influence each other in health-relevant ways. These questions were addressed with 94 married couples who completed measures of life satisfaction and had their blood drawn for determination of interleukin-6 (IL-6) and C-reactive protein (CRP). Actor-partner models showed that higher actor levels of life satisfaction predicted lower levels of IL-6 and CRP (p's < .05), whereas partner levels of life satisfaction did not predict any measure of inflammation. The actor results were not mediated by marital satisfaction or health behaviors. Finally, no actor * partner interactions were significant and these links were not moderated by marital satisfaction. These data highlight inflammation as a potentially important biological mechanism linking actor reports of life satisfaction to lower cardiovascular mortality. PMID- 28884246 TI - Impulsivity Dimensions and Risky Sex Behaviors in an At-Risk Young Adult Sample. AB - Impulsivity is a personality-based risk factor that has been well studied in relation to risky sexual behavior. Recent conceptualizations of impulsivity have proposed multidimensional facets comprised of premeditation, perseverance, sensation seeking, negative urgency, and positive urgency (UPPS-P model). Prior studies have found that these facets are associated with risky sexual behavior in adolescent and college student samples, but no prior studies have evaluated them in clinical samples. The current study examined how impulsivity-related traits related to two different risky sexual behaviors in a clinical sample of at-risk young adults who had both conduct disorder and substance use disorder symptoms as adolescents (n = 529). Lack of premeditation was also tested as a moderator of the relationship between facets of impulsivity and both risky sex outcomes. Results demonstrated that sensation seeking, negative urgency, and positive urgency were correlated with risky sex behaviors. Additionally, multiple regression analyses indicated that sensation seeking was uniquely associated with the number of sexual partners in the past 5 years, whereas positive urgency was uniquely associated with unprotected sex while under the influence. Finally, a significant interaction between lack of premeditation and negative urgency suggests that at-risk young adults with both high negative urgency and lack of premeditation were the likeliest to have the most sexual partners in the past 5 years. This study adds to the current understanding of the relationship between reward- and affect-driven facets of impulsivity and risky sexual behaviors and may lend utility to the development of interventions for at-risk populations. PMID- 28884247 TI - The potential forensic significance of convict archives from Van Diemen's Land, 1820-1877. PMID- 28884248 TI - Swipe Right: Dating Website and App Use Among Men Who Have Sex With Men. AB - This study explored the frequency of dating website and app usage among MSM to understand sub-group differences in use. Web-based survey data (N = 3105) were analyzed to assess the use of dating websites and apps. More than half (55.7%) of MSM in this sample were frequent users of dating websites and apps. Two-thirds (66.7%) of frequent users had casual partners only in the past 12 months and reported a high average number of casual sexual partners in the past 12 months (Mdn = 5.0) compared to never users (Mdn = 0.0; chi 2(2) = 734.94, adj. p < .001). The most frequently used dating website or app was Grindr, with 60.2% of the sample reporting some or frequent use. Adam4Adam (23.5%), Jack'd (18.9%) and Scruff (18.7%) were also frequently used. Dating websites and apps may be effective channels to reach a diverse group of MSM with HIV prevention messages. PMID- 28884249 TI - CDOCKER and lambda-dynamics for prospective prediction in D3R Grand Challenge 2. AB - The opportunity to prospectively predict ligand bound poses and free energies of binding to the Farnesoid X Receptor in the D3R Grand Challenge 2 provided a useful exercise to evaluate CHARMM based docking (CDOCKER) and [Formula: see text]-dynamics methodologies for use in "real-world" applications in computer aided drug design. In addition to measuring their current performance, several recent methodological developments have been analyzed retrospectively to highlight best procedural practices in future applications. For pose prediction with CDOCKER, when the protein structure used for rigid receptor docking was close to the crystallographic holo structure, reliable poses were obtained. Benzimidazoles, with a known holo receptor structure, were successfully docked with an average RMSD of 0.97 [Formula: see text]. Other non-benzimidazole ligands displayed less accuracy largely because the receptor structures we chose for docking were too different from the experimental holo structures. However, retrospective analysis has shown that when these ligands were re-docked into their holo structures, the average RMSD dropped to 1.18 [Formula: see text] for all ligands. When sulfonamides and spiros were docked with the apo structure, which agrees more with their holo structure than the structures we chose, five out of six ligands were correctly docked. These docking results emphasize the need for flexible receptor docking approaches. For [Formula: see text]-dynamics techniques, including multisite [Formula: see text]-dynamics (MS[Formula: see text]D), reasonable agreement with experiment was observed for the 33 ligands investigated; root mean square errors of 2.08 and 1.67 kcal/mol were obtained for free energy sets 1 and 2, respectively. Retrospectively, soft-core potentials, adaptive landscape flattening, and biasing potential replica exchange (BP-REX) algorithms were critical to model large substituent perturbations with sufficient precision and within restrictive timeframes, such as was required with participation in Grand Challenge 2. These developments, their associated benefits, and proposed procedures for their use in future applications are discussed. PMID- 28884250 TI - Memory Impairment in HIV-Infected Individuals with Early and Late Initiation of Regular Marijuana Use. AB - Marijuana use is disproportionately prevalent among HIV-infected individuals. The strongest neurocognitive effect of marijuana use is impairment in the domain of memory. Memory impairment is also high among HIV-infected persons. The present study examined 69 HIV-infected individuals who were stratified by age of regular marijuana initiation to investigate how marijuana use impacts neurocognitive functioning. A comprehensive battery assessed substance use and neurocognitive functioning. Findings indicated early onset marijuana users (regular use prior to age 18), compared to non-marijuana users and late onset marijuana users (regular use at age 18 or later), were over 8 times more likely to have learning impairment and nearly 4 times more likely to have memory impairment. A similar pattern of early onset marijuana users performing worse in learning emerged when examining domain deficit scores. The potential for early onset of regular marijuana use to exacerbate already high levels of memory impairment among HIV infected persons has important clinical implications, including increased potential for medication non-adherence and difficulty with independent living. PMID- 28884252 TI - MicroRNA-192 regulates hypertrophic scar fibrosis by targeting SIP1. AB - Hypertrophic scar (HS) is a fibro-proliferative disorder which is characterized by excessive deposition of collagen and accumulative activity of myofibroblasts. Increasing evidences have demonstrated miRNAs play a pivotal role in the pathogenesis of HS. MiR-192 is closely associated with renal fibrosis, but its effect on HS formation and skin fibrosis remains unknown. In the study, we presented that miR-192 was up-regulated in HS and HS derived fibroblasts (HSFs) compared to normal skin (NS) and NS derived fibroblasts (NSFs), accompanied by the reduction of smad interacting protein 1 (SIP1) expression and the increase of Col1, Col3 and alpha-SMA levels. Furthermore, we confirmed SIP1 was a direct target of miR-192 by using luciferase reporter assays. Meanwhile, the overexpression of miR-192 increased the levels of Col1, Col3 and alpha-SMA. The synthesis of collagen and more positive alpha-SMA staining were also observed in bleomycin-induced dermal fibrosis model of BALB/c mice treated with subcutaneous miR-192 mimics injection, whereas the inhibition of miR-192 decreased the expression of Col1, Col3 and alpha-SMA. Moreover, SIP1 siRNA could enhance the levels of Col1, Col3 and alpha-SMA, showing that the effect of knockdown SIP1 was similar to miR-192 mimics, and the phenomenon manifested miR-192 regulated HS fibrosis by targeting SIP1. Together, our results indicated that miR-192 was a critical factor of HS formation and facilitated skin fibrosis by targeting directly SIP1. PMID- 28884253 TI - Assessing transhumance corridors on high mountain environments by least cost path analysis: the case of yak herds in Gilgit-Baltistan, Pakistan. AB - Mountain environments in the world host highly specialized flora and fauna which are vulnerable because of land use and climate change. Transhumance and other land use traditional practices are present in most of the mountains of the world, and management tools able to cope with new socioeconomic settings and environmental changes are urgently needed. During past centuries, yak (Bos grunniens) herding in Northern Pakistan involved the migration of herds to high mountain international rangelands, but the recent establishment of international borders breaks the traditional transhumance paths, promoting several ecological problems. In this paper, we propose the use of least cost path (LCP) algorithm to identify the most efficient corridors of transhumance for yak herds on northern high altitudes of Pakistan. Specifically, LCP was implemented to identify the critical grazing areas and the connecting zones to be accounted in a new management plan for the yaks in the region. The LCP analysis showed that some grazing areas are connected with several paths, whereas other areas are connected to a lesser extent. The analyses identified a set of best minimum cost paths able to guarantee local connectivity. We also delineated several medium and low efficient paths that could play a crucial role for maintaining regional connectivity which is essential for reducing the isolation of herds and the consequent inbreeding problems. The analytical framework implemented in this study allowed to (1) provide valuable information concerning the movement of yak herds in Gilgit-Baltistan, (2) identify potential corridors that are able to promote herd movement between villages and high mountain rangelands, and (3) identify critical areas for the connectivity of yaks by ranking of the potential corridors according to their length and permeability. The analysis would be extended to other transhumant herds and high mountain areas that are facing sociopolitical transformations and environmental changes. PMID- 28884251 TI - The influence of hospital volume on long-term oncological outcome after rectal cancer surgery. AB - PURPOSE: The association between hospital volume and outcome in rectal cancer surgery is still subject of debate. The purpose of this study was to assess the impact of hospital volume on outcomes of rectal cancer surgery in the Netherlands in 2011. METHODS: In this collaborative research with a cross-sectional study design, patients who underwent rectal cancer resection in 71 Dutch hospitals in 2011 were included. Annual hospital volume was stratified as low (< 20), medium (20-50), and high (>= 50). RESULTS: Of 2095 patients, 258 patients (12.3%) were treated in 23 low-volume hospitals, 1329 (63.4%) in 40 medium-volume hospitals, and 508 (24.2%) in 8 high-volume hospitals. Median length of follow-up was 41 months. Clinical tumor stage, neoadjuvant therapy, extended resections, circumferential resection margin (CRM) positivity, and 30-day or in-hospital mortality did not differ significantly between volume groups. Significantly, more laparoscopic procedures were performed in low-volume hospitals, and more diverting stomas in high-volume hospitals. Three-year disease-free survival for low-, medium-, and high-volume hospitals was 75.0, 74.8, and 76.8% (p = 0.682). Corresponding 3-year overall survival rates were 75.9, 79.1, and 80.3% (p = 0.344). In multivariate analysis, hospital volume was not associated with long term risk of mortality. CONCLUSIONS: No significant impact of hospital volume on rectal cancer surgery outcome could be observed among 71 Dutch hospitals after implementation of a national audit, with the majority of patients being treated at medium-volume hospitals. PMID- 28884254 TI - Elderly-Onset and Adult-Onset Ulcerative Colitis Are More Similar than Previously Reported in a Nationwide Cohort. AB - BACKGROUND: Elderly-onset ulcerative colitis (EO-UC) is recognized as a distinct subpopulation of UC. To our knowledge, there have been no nationwide studies of EO-UC populations in the USA. AIMS: We aim to characterize differences in presentation at diagnosis and clinical course between EO-UC and adult-onset UC (AO-UC) patients in a national cohort. METHODS: Complete medical records of patients newly diagnosed with UC from October 2001 to October 2011 in the Veterans Affairs health system were obtained. Patients were followed until colectomy, death, or the end of the observation period on November 2015. EO-UC patients (age of diagnosis >=65 years) were compared to AO-UC patients (age of diagnosis <=40 years) with respect to demographic, severity, and therapeutic data. Statistical analysis was performed using JMP statistical software. RESULTS: We identified 836 newly diagnosed UC patients, of which 207 had EO-UC and 102 had AO-UC. The mean age of diagnosis was 72.4 years (EO-UC) and 32.9 years (AO-UC), with a mean 8-year follow-up period. The incidence of pancolitis at the time of diagnosis was similar between both groups (p = 0.67). There was no difference in steroid use (36.7 vs 45.1%, p = 0.1563), thiopurine use (19.3 vs 22.6%, p = 0.5081), and colectomy rates (6.3 vs 5.9%, p = 0.8911) between EO-UC and AO-UC populations. There was lower anti-TNF use in EO-UC patients compared to AO-UC patients (5.8 vs 14.7%, p = 0.0091). CONCLUSION: In this nationwide cohort, we found that the use of steroids, thiopurines, and colectomy was similar in both populations, while anti-TNF use was lower among the elderly. PMID- 28884256 TI - Geochemical distribution of major and trace elements in agricultural soils of Castilla-La Mancha (central Spain): finding criteria for baselines and delimiting regional anomalies. AB - Castilla-La Mancha (central Spain) is a region characterized by significant agricultural production aimed at high-quality food products such as wine and olive oil. The quality of agricultural products depends directly on the soil quality. Soil geochemistry, including dispersion maps and the recognition of baselines and anomalies of various origins, is the most important tool to assess soil quality. With this objective, 200 soil samples were taken from agricultural areas distributed among the different geological domains present in the region. Analysis of these samples included evaluation of edaphological parameters (reactivity, electrical conductivity, organic matter content) and the geochemistry of major and trace elements by X-ray fluorescence. The dataset obtained was statistically analyzed for major elements and, in the case of trace elements, was normalized with respect to Al and analyzed using the relative cumulative frequency (RCF) distribution method. Furthermore, the geographic distribution of analytical data was characterized and analyzed using the kriging technique, with a correspondence found between major and trace elements in the different geologic domains of the region as well as with the most important mining areas. The results show an influence of the clay fraction present in the soil, which acts as a repository for trace elements. On the basis of the results, of the possible elements related with clay that could be used for normalization, Al was selected as the most suitable, followed by Fe, Mn, and Ti. Reference values estimated using this methodology were lower than those estimated in previous studies. PMID- 28884255 TI - Using the chemical mass balance model to estimate VOC source contributions in newly built timber frame houses: a case study. AB - Basing on the material emission data obtained in a test chamber, chemical mass balance (CMB) was used to assess the source apportionment of volatile organic compound (VOC) concentrations in three newly built timber frame houses. CMB has been proven to be able to discriminate the source contributions for two contrasted environmental conditions (with and without ventilation). The shutdown of the ventilation system caused an increase in the VOC concentrations due to the increased contribution of indoor surface materials like the door material and furniture explaining together over 65% of total VOCs. While the increase in formaldehyde concentration is mainly due to furniture (contribution of 70%), the increase in alpha-pinene concentration is almost exclusively attributable to the emission of door material (up to 84%). The apportionment of VOC source contributions appears as highly dependent on the position of source materials in the building (surface materials or internal materials) and the ventilation conditions explaining that the concentrations of compounds after the shutdown of ventilation system do not increase in equivalent proportion. Knowledge of indoor sources and its contributions in real conditions may help in the selection of materials and in the improvement of construction operations to reduce the indoor air pollution. PMID- 28884257 TI - Crohn's Disease: Hard to Swallow! PMID- 28884258 TI - Do implicit attitudes toward physical activity and sedentary behavior prospectively predict objective physical activity among persons with obesity? AB - This study conducted among adults with obesity examined the associations between implicit attitudes toward physical activity and sedentary behavior, and physical activity behavior measured 4 months later. At baseline, 76 participants (M AGE = 56; M BMI = 39.1) completed a questionnaire assessing intentions toward physical activity and sedentary behavior and two computerized Single-Category Implicit Association Tests assessing implicit attitudes toward these two behaviors. At follow-up, physical activity was measured with accelerometers. Multiple regression analysis showed that implicit attitudes toward physical activity were positively and significantly associated with physical activity when participants' age, BMI, past physical activity and intentions were controlled for. Implicit attitudes toward sedentary behavior were not associated with physical activity. Adults with obesity who implicitly reported more favorable attitudes toward physical activity at baseline were more likely to present higher physical activity levels at follow-up. Implicit attitudes could be targeted in future research to enhance physical activity. PMID- 28884259 TI - Impact of mathematical pharmacology on practice and theory: four case studies. AB - Drug-discovery has become a complex discipline in which the amount of knowledge about human biology, physiology, and biochemistry have increased. In order to harness this complex body of knowledge mathematics can play a critical role, and has actually already been doing so. We demonstrate through four case studies, taken from previously published data and analyses, what we can gain from mathematical/analytical techniques when nonlinear concentration-time courses have to be transformed into their equilibrium concentration-response (target or complex) relationships and new structures of drug potency have to be deciphered; when pattern recognition needs to be carried out for an unconventional response time dataset; when what-if? predictions beyond the observational concentration time range need to be made; or when the behaviour of a semi-mechanistic model needs to be elucidated or challenged. These four examples are typical situations when standard approaches known to the general community of pharmacokineticists prove to be inadequate. PMID- 28884260 TI - Barriers and Facilitators of Responding to Problem Gambling: Perspectives from Australian Mental Health Services. AB - Despite high rates of comorbidity between problem gambling and mental health disorders, few studies have examined barriers or facilitators to the implementation of screening for problem gambling in mental health services. This exploratory qualitative study identified key themes associated with screening in mental health services. Semi-structured interviews were undertaken with 30 clinicians and managers from 11 mental health services in Victoria, Australia. Major themes and subthemes were identified using qualitative content analysis. Six themes emerged including competing priorities, importance of routine screening, access to appropriate screening tools, resources, patient responsiveness and workforce development. Barriers to screening included a focus on immediate risk as well as gambling being often considered as a longer-term concern. Clinicians perceived problem gambling as a relatively rare condition, but did acknowledge the need for brief screening. Facilitators to screening were changes to system processes, such as identification of an appropriate brief screening instrument, mandating its use as part of routine screening, as well as funded workforce development activities in the identification and management of problem gambling. PMID- 28884261 TI - The connection between exercise addiction and orthorexia nervosa in German fitness sports. AB - PURPOSE: The combination of physical activity and healthy eating habits has potentially positive effects on health. However, both practices can also lead to pathological behaviors such as exercise addiction (EA) and orthorexia nervosa (ON), thus generating negative effects. So far, studies analyzing the connection between these two phenomena cannot be found. The current paper is aiming to close this gap. METHODS: The sample (n = 1.008) consisted of 559 male and 449 female active members of three fitness studios, and was analyzed in a cross-sectional study design. The Exercise Addiction Inventory (EAI) was used to establish exercise addiction and the Dusseldorfer Orthorexie Skala (DOS) was used to evaluate orthorectic eating behavior. RESULTS: Out of the whole sample, 10.2% exhibit EA, while ON is prevalent in 3.4%. Twenty-three (2.3%) individuals suffer from both. There is a significant positive correlation between DOS and EAI (p < .001, r = .421). Female participants (p < .001, r = .452) show a higher correlation compared to male participants (p < .001, r = .418). CONCLUSION: The results suggest a positive correlation between ON and EA in the context of German fitness sports. Both seem to be serious phenomena and require further investigation. LEVEL OF EVIDENCE: Level V (cross-sectional descriptive study). PMID- 28884262 TI - Sleep correlates of substance use in community-dwelling Ethiopian adults. AB - PURPOSE: The relationship between sleep disturbances and substance use can have harmful effects. Evidence shows widespread use of substances, including khat, in the Ethiopian population. However, to the best of our knowledge, no study has investigated the sleep correlates of substance use in community-dwelling Ethiopian adults. MATERIALS AND METHODS: A cross-sectional study using simple random sampling was performed on community-dwelling adults (n = 371, age = 25.5 +/- 5.7 years, body mass index = 22.0 +/- 2.2 kg/m2) in Mizan-Aman, Ethiopia. Dichotomized sleep measures (sleep quality and sleep latency) assessed by the Pittsburgh Sleep Quality Index (PSQI) were used in association analysis using binary logistic regression with substance use (khat, smoking, and alcohol). RESULT: Sleep latency was associated with khat chewing (adjusted odds ratio (AOR) = 2.8, 95% confidence interval (CI) 1.7-4.4) and tobacco smoking (AOR = 2.1, 95% CI 1.4-3.0). Sleep quality was associated with khat chewing (AOR = 3.1, 95% CI 1.8-5.2), tobacco smoking (AOR = 1.7, 95% CI 1.2-2.5), and alcohol intake (AOR = 1.9, 95% CI 1.1-3.1). CONCLUSION: Sleep correlates of substance use were found in community-dwelling Ethiopians. These findings may aid in the development of targeted strategies to manage substance use-related sleep disturbances. PMID- 28884263 TI - Efficient propagation of archetype JC polyomavirus in COS-7 cells: evaluation of rearrangements within the NCCR structural organization after transfection. AB - John Cunningham virus (JCPyV) is an ubiquitous human pathogen that causes disease in immunocompromised patients. The JCPyV genome is composed of an early region and a late region, which are physically separated by the non-coding control region (NCCR). The DNA sequence of the NCCR distinguishes two forms of JCPyV, the designated archetype and the prototype, which resulted from a rearrangement of the archetype sequence. To date, the cell culture systems for propagating JCPyV archetype have been very limited in their availability and robustness. Prior to this study, it was demonstrated that JCPyV archetype DNA replicates in COS-7 simian kidney cells expressing SV40 TAg and COS-7 cells expressing HIV-1 Tat. Based on these observations, the present study was conducted to reproduce an in vitro model in COS-7 cells transfected with the JCPyV archetype strain in order to study JCPyV DNA replication and analyze NCCR rearrangements during the viral life cycle. The efficiency of JCPyV replication was evaluated by quantitative PCR (Q-PCR) and by hemagglutination (HA) assay after transfection. In parallel, sequence analysis of JCPyV NCCR was performed. JCPyV efficiently replicated in kidney-derived COS-7 cells, as demonstrated by a progressive increase in viral load and virion particle production after transfection. The archetypal structure of NCCR was maintained during the viral cycle, but two characteristic point mutations were detected 28 days after transfection. This model is a useful tool for analyzing NCCR rearrangements during in vitro replication in cells that are sites of viral persistence, such as tubular epithelial cells of the kidney. PMID- 28884264 TI - Ambulatory screening tool for sleep apnea: analyzing a single-lead electrocardiogram signal (ECG). AB - STUDY OBJECTIVE: The goal was to determine the utility and accuracy of automated analysis of single-lead electrocardiogram (ECG) data using two algorithms, cardiopulmonary coupling (CPC), and cyclic variation of heart rate (CVHR) to identify sleep apnea (SA). METHODS: The CPC-CVHR algorithms were applied to identify SA by analyzing ECG from diagnostic polysomnography (PSG) from 47 subjects. The studies were rescored according to updated AASM scoring rules, both manually by a certified technologist and using an FDA-approved automated scoring software, Somnolyzer (Philips Inc., Monroeville, PA). The CPC+CVHR output of Sleep Quality Index (SQI), Sleep Apnea Indicator (SAI), elevated low frequency coupling broadband (eLFCBB) and elevated low frequency coupling narrow-band (eLFCNB) were compared to the manual and automated scoring of apnea hypopnea index (AHI). RESULTS: A high degree of agreement was noted between the CPC-CVHR against both the manually rescored AHI and the computerized scored AHI to identify patients with moderate and severe sleep apnea (AHI > 15). The combined CPC+CVHR algorithms, when compared to the manually scored PSG output presents sensitivity 89%, specificity 79%, agreement 85%, PPV (positive predictive value) 0.86 and NPV (negative predictive value) 0.83, and substantial Kappa 0.70. Comparing the output of the automated scoring software to the manual scoring demonstrated sensitivity 93%, specificity 79%, agreement 87%, PPV 0.87, NPV 0.88, and substantial Kappa 0.74. CONCLUSION: The CPC+CVHR technology performed as accurately as the automated scoring software to identify patients with moderate to severe SA, demonstrating a clinically powerful tool that can be implemented in various clinical settings to identify patients at risk for SA. TRIAL REGISTRATION: NCT01234077. PMID- 28884265 TI - How is weight stigma related to children's health-related quality of life? A model comparison approach. AB - PURPOSE: Obesity is a highly stigmatizing condition for both adults and children, and both obesity and stigma experiences are negatively related with health related quality of life (HRQoL). However, the relations among these constructs have been modeled in different and sometimes inconsistent terms in past research, and have been the object of surprisingly few studies in pediatric populations. The present study addresses this gap by comparing, in a sample of preadolescent children, four competing models (i.e., additive, mediation, moderation, and moderated mediation models) accounting for the role of stigma experiences in the concurrent relation between body weight and HRQoL. METHODS: A community sample of 600 children aged 8-11 years completed the Perception of Teasing Scale to assess weight-based teasing experiences and the PedsQL 4.0 to assess HRQoL. Parent reported height and weight were used to calculate age- and gender-adjusted zBMI. Log-likelihood test, BIC difference, and Wald test were used for model comparisons. RESULTS: The mediation model outperformed both additive and moderation models and was found to be equally informative (but more parsimonious) as compared to the moderated mediation account. The same pattern of results was replicated for both global HRQoL and domain-specific quality of life domains (i.e., physical, emotional, social, and scholastic). CONCLUSIONS: The mediation model provided the best fitting and more parsimonious representation of the relations between body weight, stigma experiences, and HRQoL, meaning that an increased likelihood of experiencing weight-based teasing episodes, rather than excess weight per se, is associated with reduced quality of life in middle childhood. PMID- 28884266 TI - MicroRNA expression changes following synthesis of three full-sib Populus triploid populations with different heterozygosities. AB - KEY MESSAGE: Through high-throughput sequencing, we compared the relative expression levels of miRNA in three full-sib Populus triploid populations with that in their parents and one diploid hybrid population. We found similar numbers of miRNAs differentially expressed between the parents and the four progeny hybrid populations. In addition, unbalanced parental expression level dominance of miRNAs were found in the three allotriploid and interspecific hybrid populations, which may reprogram gene expression networks and contribute to the growth of Populus hybrids. These results indicated that hybridization has a great impact on the miRNA expression variation in the newly synthesized Populus triploid and diploid hybrid populations. However, we also found no significant differences in miRNA expression among one diploid and three triploid hybrid populations, hinting that miRNA abundances do not increase with the genome content. No dosage effect of miRNA expression could lead to dosage-dependent negative effects on target genes and their downstream pathway in polyploids. We speculate that polyploids may gain advantages from the slight decrease in miRNA regulation, suggesting an important molecular mechanism of polyploid advantage. Hybridization with three types of induced 2n gametes transmitted different parental heterozygosities has been proven as an efficient method for Populus triploid production. Several researches have shown that miRNA could be non additively expressed in allopolyploids. However, it is still unclear whether the non-additively expressed miRNAs result from the effect of hybridization or polyploidization, and whether a dose response to the additional genomic content exists for the expression of miRNA. Toward this end, through high-throughput sequencing, we compared the expression levels of miRNA in three full-sib Populus triploid populations with that in their parents and one interspecific hybrid population. We found similar numbers of miRNAs differentially expressed between the parents and the four progeny hybrid populations. Unbalanced parental expression level dominance of miRNAs were found in the three triploid and diploid hybrid populations, which may reprogram gene expression networks and affect the growth of Populus hybrids. These results indicated that hybridization has a great impact on the miRNA expression variation in the newly synthesized Populus triploid and diploid hybrid populations. However, we also found no significant differences in miRNA expression among the three triploid populations and the diploid hybrid population. No dosage effect of miRNA expression could lead to dosage-dependent negative effects on target genes and their downstream pathway in polyploids. We speculate that polyploids may gain advantages from the decrease in miRNA negative regulation, suggesting an important molecular mechanism of polyploid advantage. PMID- 28884267 TI - Diet and enteral nutrition in patients with chronic kidney disease not on dialysis: a review focusing on fat, fiber and protein intake. AB - The clinical data available on dietary requirements of patients with chronic kidney disease (CKD) not on dialysis are limited and largely inconclusive in terms of the renal, cardiovascular and nutritional outcomes achievable through dietary modifications. Restriction of protein intake during the early stages of CKD may in fact slow its progression, but at the same time this approach may also lead to protein-energy wasting, if energy intake is not adequate and properly monitored. Unfortunately, compliance to dietary recommendations is traditionally low in this patient population. A switch from saturated to mono- and polyunsaturated fats is generally recognized as advantageous for cardiac health; however, the benefits in term of renal function are largely unknown. Similarly, the association between dietary fiber intake and kidney disease is largely unknown. In fact, while there is evidence on the positive health effects of dietary fibers in the general population, nutritional guidelines for CKD lack formal recommendations concerning fiber intake. This paper reviews data and evidence from clinical trials and meta-analyses on renal and cardiovascular outcomes related to modifications in protein, fat and fiber intake. Suggestions for maintaining nutritional status through patient-oriented dietary patterns and enteral supplementation in CKD patients on conservative therapy are also presented. PMID- 28884268 TI - Can a Parenting Intervention to Prevent Early Conduct Problems Interrupt Girls' Risk for Intimate Partner Violence 10 Years Later? AB - This study tests whether a parenting intervention for families of preschoolers at risk for conduct problems can prevent later risk for intimate partner violence (IPV). Ninety-nine preschoolers at familial risk for conduct problems were randomly assigned to intervention or control conditions. Ten years later, 45 preschoolers and 43 of their siblings completed an assessment of their romantic relationships, including measures of physical and psychological IPV. The study focuses on the 54 females, including targets (n = 27) and siblings (n = 27) who participated in a 10-year follow-up (M age = 16.5, SD = 5.2, range = 10-28). Using an intent-to-treat (ITT) design, multivariate regressions suggest that females from families randomly assigned to intervention in early childhood scored lower than those in the control condition on perceptions of dating violence as normative, beliefs about IPV prevalence, exposure to IPV in their own peer group, and expected sanction behaviors for IPV perpetration and victimization. Findings suggest that early parenting intervention may reduce association of high-risk females with aggressive peers and partners in adolescence. PMID- 28884269 TI - CORR Insights(r): What is the Rate of Revision Discectomies After Primary Discectomy on a National Scale? PMID- 28884270 TI - River biofilm community changes related to pharmaceutical loads emitted by a wastewater treatment plant. AB - Wastewater treatment plants (WWTP) are the main sources of a broad spectrum of pharmaceuticals found in freshwater ecosystems. These pollutants raise environmental health concerns because of their highly bioactive nature and their chronic releases. Despite this, pharmaceuticals' effects on aquatic environments are poorly defined. Biofilms represent a major part of the microbial life in rivers and streams. They can drive key metabolic cycles and their organizations reflect exposures to changing chemical, physical, and biological constraints. This study estimated the concentrations, over a 3-year period, of ten pharmaceuticals and five nutrients in a river contaminated by a conventional WWTP fed by urban and hospital wastewaters. Variations in these concentrations were related to biofilm bacterial community dynamics. Rock biofilms had developed over defined periods and were harvested at four locations in the river from the up- and downstream WWTP discharge point. Pharmaceuticals were found in all locations in concentrations ranging from not being detected to 192 ng L-1. Despite the high dilution factor of the WWTP effluents by the receiving river, pharmaceuticals were found more concentrated downstream than upstream the WWTP. Shifts in bacterial community structures linked to the environmental emission of pharmaceuticals were superior to seasonal community changes. A community structure from a site located downstream but close to the WWTP was more strongly associated with high pharmaceutical loads and different from those of biofilm samples from the WWTP upstream or far downstream sites. These latter sites were more strongly associated with high nutrient contents. Low environmental concentrations of pharmaceuticals can thus be transferred from WWTP effluents to a connected stream and induce bacterial aquatic community changes over time. PMID- 28884271 TI - The effect of anaerobic digestion and storage on indicator microorganisms in swine and dairy manure. AB - The aim of this experimental study was to evaluate the influence of anaerobic digestion and storage on indicator microorganisms in swine and dairy excreta. Samples were collected every 90 days for 15 months at eight farms, four pig, and four dairy farms, four of them having a biogas plant. Moreover, to evaluate storage effects on samples, 20 l of manure and slurry taken at each farm (digested manure only in farms with a biogas plant) were stored in a controlled climatic chamber at 18 degrees C, for 6 months. The bacterial load and the chemical-physical characteristics of excreta were evaluated at each sampling time, stored slurry, and manure were sampled and analyzed every 2 months. A high variability of the concentration of bacteria in the different excreta types was observed during the experiment, mainly depending on the type and time of treatment. No sample revealed either the presence of Escherichia coli O157:H7 or of Salmonella, usually linked to the temporary rearing of infected animals in facilities. Anaerobic digestion and storage affected in a significant way the reduction of indicator bacteria like lactobacilli, coliforms, and streptococci. Anaerobic digestion lowered coliforms in pig slurry (- 2.80 log, P < 0.05), streptococci in dairy manure (- 2.44 log, P < 0.001) and in pig slurry (- 1.43 log, P < 0.05), and lactobacilli in pig slurry (- 3.03 log, P < 0.05). Storage lowered coliforms and the other indicators counts, in particular in fresh wastes, while clostridia did not show a reduction in concentration. PMID- 28884272 TI - Viewing Sexually Explicit Media and Its Association with Mental Health Among Gay and Bisexual Men Across the U.S. AB - Gay and bisexual men (GBM) have reported viewing significantly more sexually explicit media (SEM) than heterosexual men. There is evidence that viewing greater amounts of SEM may result in more negative body attitude and negative affect. However, no studies have examined these variables within the same model. A national sample of 1071 HIV-negative GBM in the U.S. participating in a larger study completed an online survey, which included measures of SEM consumption, male body attitudes, anxiety, and depression. Participants reported viewing 3 h of SEM per week, on average, and 96% of participants reported recently viewing at least some SEM. Greater consumption of SEM was directly related to more negative body attitude and both depressive and anxious symptomology. There was also a significant indirect effect of SEM consumption on depressive and anxious symptomology through body attitude. These findings highlight the relevance of both SEM on body image and negative affect along with the role body image plays in anxiety and depression outcomes for GBM. They also indicate a potential role for body image in explaining the co-occurrence of SEM consumption and negative affect. For interventions looking to alleviate negative affect for GBM, it may be important to address SEM consumption and body image as they are shown to be associated with both anxious and depressive symptomology. PMID- 28884273 TI - Validation of the Chinese (Mandarin) Version of the Oxford Knee Score in Patients with Knee Osteoarthritis. AB - BACKGROUND: With the increasing number of patients with knee osteoarthritis undergoing TKAs in China, there is a clear need for a valid, short, joint specific patient-reported outcome measure such as the Oxford Knee Score (OKS). QUESTIONS/PURPOSES: To test the translated and cross-culturally adapted Chinese (Mandarin) version of the Oxford Knee Score (OKS-CV) and its (1) reliability, (2) construct validity, (3) dimensionality, and (4) responsiveness. METHODS: Three native Chinese bilingual translators (a professional English translator, an experienced orthopaedic surgeon, an advanced-practice nursing specialist) translated the English-language OKS into Mandarin Chinese. A consensus panel created a synthesis of those efforts, which then was back-translated by two bilingual nonmedical, professional English-language translators. The OKS-CV was developed according to the guidelines of copyright holders. Between March 2013 and March 2015, 253 patients underwent TKAs. Among them, 114 Mandarin-speaking patients with knee osteoarthritis underwent primary unilateral TKA (age, 67 +/- 7 years; range, 55-84 years; female, 80%; preoperatively 54% had moderate to severe knee osteoarthritis), completed the preoperative questionnaires, and were followed up, with a mean postoperative followup of 2.7 years (SD, 0.5 years). Eligibility criteria were (1) patients with knee osteoarthritis who were scheduled to have a primary unilateral TKA, (2) patients who were fluent in Mandarin, and (3) consent to participate. The exclusion criteria were: (1) lack of understanding of Mandarin, and (2) inability to comprehend the questionnaires owing to cognitive impairment. To evaluate test-retest reliability, another group of 35 Mandarin-speaking outpatients with knee osteoarthritis (age, 61 +/- 10 years; range, 44-84 years; female, 77%) was recruited to complete the OKS-CV twice at a 1-week interval. Reliability was tested using Cronbach's alpha and intraclass correlation coefficient (ICC). Construct validity was evaluated using Spearman's rank correlation coefficient to quantify the correlations between the OKS-CV and the WOMAC, Short Form-8 Health Survey (SF-8TM), and EuroQol Group 5 Dimension Self-Report Questionnaire (EQ-5D). Exploratory factor analysis was performed to clarify dimensionality. The eigenvalue indicates the importance of each factor obtained from factor analysis. Responsiveness was determined by standardized response mean (SRM) and effect size (ES) from preoperative and postoperative scores of the OKS-CV. Floor and ceiling effects also were analyzed. RESULTS: The internal consistency (Cronbach's alpha = 0.89) and test-retest reliability (ICC = 0.93; 95% CI, 0.87-0.97) proved good. Convergent construct validity was supported by moderate to strong correlations between the OKS-CV and the WOMAC (r = -0.80, p < 0.001), the SF-8TM physical component summary (r = 0.65, p < 0.001), and the EQ-5D usual activities (r = -0.41, p < 0.001) and mobility (r = -0.35, p < 0.001). There also were correlations between the OKS-CV and the SF-8TM mental component summary (r = 0.58, p < 0.001) and the EQ-5D anxiety/depression (r = -0.35, p < 0.001). The factor analysis yielded three factors with eigenvalues greater than 1. Responsiveness was excellent (SRM = 1.52; ES = 1.52). No floor or ceiling effect was observed. CONCLUSIONS: The OKS CV showed good acceptability and psychometric properties for the intended population. Future studies are needed to evaluate the mental state of patients with knee osteoarthritis. CLINICAL RELEVANCE: The OKS-CV appears to be a reliable, valid, and responsive instrument for Chinese patients with knee osteoarthritis. Based on these results we believe the OKS-CV can be used as a valuable tool for the assessment of patient-reported outcomes in Chinese patients with knee osteoarthritis before and after TKA. PMID- 28884274 TI - Functional group influences on the reactive azo dye decolorization performance by electrochemical oxidation and electro-Fenton technologies. AB - Electrochemical water treatment technologies are highly promising to achieve complete decolorization of dyebath effluents, as demonstrated by several studies reported in the literature. However, these works are focused on the treatment of one model pollutant and generalize the performances of the processes which are not transposable since they depend on the pollutant treated. Thus, in the present study, we evaluate, for the first time, the influence of different functional groups that modify the dye structure on the electrochemical process decolorization performance. The textile azo dyes Reactive Orange 16, Reactive Violet 4, Reactive Red 228, and Reactive Black 5 have been selected because they present the same molecular basis structure with different functional groups. The results demonstrate that the functional groups that reduce the nucleophilicity of the pollutant hinder the electrophilic attack of electrogenerated hydroxyl radical. Thereby, the overall decolorization efficiency is consequently reduced as well as the decolorization rate. Moreover, the presence of an additional chromophore azo bond in the molecule enhances the recalcitrant character of the azo dyes as pollutants. The formation of a larger and more stable conjugated pi system increases the activation energy required for the electrophyilic attack of *OH, affecting the performance of electrochemical technologies on effluent decolorization. PMID- 28884276 TI - Pregnancy in Residency. PMID- 28884275 TI - Alloy Microstructure Dictates Corrosion Modes in THA Modular Junctions. AB - BACKGROUND: Adverse local tissue reactions (ALTRs) triggered by corrosion products from modular taper junctions are a known cause of premature THA failure. CoCrMo devices are of particular concern because cobalt ions and chromium orthophosphates were shown to be linked to ALTRs, even in metal-on-polyethylene THAs. The most common categories of CoCrMo alloy are cast and wrought alloy, which exhibit fundamental microstructural differences in terms of grain size and hard phases. The impact of implant alloy microstructure on the occurring modes of corrosion and subsequent metal ion release is not well understood. QUESTIONS/PURPOSES: The purpose of this study was to determine whether (1) the microstructure of cast CoCrMo alloy varies broadly between manufacturers and can dictate specific corrosion modes; and whether (2) the microstructure of wrought CoCrMo alloy is more consistent between manufacturers and has low implications on the alloy's corrosion behavior. METHODS: The alloy microstructure of four femoral stem and three femoral-head designs from four manufacturers was metallographically and electrochemically characterized. Three stem designs were made from cast alloy; all three head designs and one stem design were made from wrought alloy. Alloy samples were sectioned from retrieved components and then polished and etched to visualize grain structure and hard phases such as carbides (eg, M23C6) or intermetallic phases (eg, sigma phase). Potentiodynamic polarization (PDP) tests were conducted to determine the corrosion potential (Ecorr), corrosion current density (Icorr), and pitting potential (Epit) for each alloy. Four devices were tested within each group, and each measurement was repeated three times to ensure repeatable results. Differences in PDP metrics between manufacturers and between alloys with different hard phase contents were compared using one-way analysis of variance and independent-sample t-tests. Microstructural features such as twin boundaries and slip bands as well as corrosion damage features were viewed and qualitatively assessed in a scanning electron microscope. RESULTS: We found broad variability in implant alloy microstructure for both cast and wrought alloy between manufacturers, but also within the same implant design. In cast alloys, there was no difference in PDP metrics between manufacturers. However, coarse hard phases and clusters of hard phases (mainly intermetallic phases) were associated with severe phase boundary corrosion and pitting corrosion. Furthermore, cast alloys with hard phases had a lower Epit than those without (0.46 V, SD 0.042; 0.53 V, SD 0.03, respectively; p = 0.015). Wrought alloys exhibited either no hard phases or numerous carbides (M23C6). However, the corrosion behavior was mainly affected by lattice defects and banded structures indicative of segregations that appear to be introduced during bar stock manufacturing. Alloys with banding had a lower Ecorr (p = 0.008) and higher Icorr (p = 0.028) than alloys without banding (-0.76 V, SD 0.003; 0.73 V, SD 0.009; and 1.14 * 10-4 mA/cm2, SD 1.47 * 10-5; 5.2 * 10-5 mA/cm2, SD 2.57 * 10-5, respectively). Alloys with carbides had a slightly higher Ecorr (p = 0.046) than those without (-0.755 V, SD 0.005; -0.761 V, SD 0.004); however, alloys with carbides exhibited more severe corrosion damage as a result of phase boundary corrosion, hard phase detachment, and subsequent local crevice corrosion. CONCLUSIONS: The observed variability in CoCrMo alloy microstructure of both cast and wrought components in this study appears to be an important issue to address, perhaps through better standards, to minimize in vivo corrosion. The finding of the banded structures within wrought alloys is especially concerning because it unfavorably influences the corrosion behavior independent of the manufacturer. The findings suggest that a homogeneous alloy microstructure with a minimal hard phase fraction exhibits more favorable corrosion behavior within the in vivo environment of modular taper junctions, thus lowering metal ion release and subsequently the risk of ALTRs to corrosion products. Also, the question arises if hard phases fulfill a useful purpose in metal-on-polyethylene bearings, because they may come with a higher risk of phase boundary corrosion and pitting corrosion and the benefit they provide by adding strength is not needed (unlike in metal-on-metal bearings). CLINICAL RELEVANCE: Implant failure resulting from corrosion processes within modular junctions is a major concern in THA. Our results suggest that implant alloy microstructure is not sufficiently standardized and may also dictate specific corrosion modes and subsequent metal ion release. PMID- 28884277 TI - Global stability for epidemic models on multiplex networks. AB - In this work, we consider an epidemic model in a two-layer network in which the dynamics of susceptible-infected-susceptible process in the physical layer coexists with that of a cyclic process of unaware-aware-unaware in the virtual layer. For such multiplex network, we shall define the basic reproduction number [Formula: see text] in the virtual layer, which is similar to the basic reproduction number [Formula: see text] defined in the physical layer. We show analytically that if [Formula: see text] and [Formula: see text], then the disease and information free equilibrium is globally stable and if [Formula: see text] and [Formula: see text], then the disease free and information saturated equilibrium is globally stable for all initial conditions except at the origin. In the case of [Formula: see text], whether the disease dies out or not depends on the competition between how well the information is transmitted in the virtual layer and how contagious the disease is in the physical layer. In particular, it is numerically demonstrated that if the difference in [Formula: see text] and [Formula: see text] is greater than the product of [Formula: see text], the deviation of [Formula: see text] from 1 and the relative infection rate for an aware susceptible individual, then the disease dies out. Otherwise, the disease breaks out. PMID- 28884278 TI - HPV prevalence in vulvar cancer in Austria. AB - BACKGROUND: Even if vulvar cancer is not common, over one hundred women are affected in Austria per year. There is strong evidence that basaloid and warty variants are associated with types of human papillomavirus (HPV). METHODS: The aim of this study is to analyze the types of HPV in vulvar cancer in Austria. This cross-sectional period-prevalence international collaborative study on archival specimens was performed in cooperation with the Institut Catalan di Oncologia in Barcelona, Spain. A total of 177 consecutive samples of Austrian women were analyzed to detect the presence of various HPV types using the SPF10 PCR/DEIA/LiPA25 system. Furthermore, the expression of the tumor suppressor protein p16INK4a was analyzed by immunohistochemistry (CINtec histology kit, ROCHE). A tumor was considered HPV-driven if an overexpression of p16INK4a was detected. RESULTS: In all, 41 cases of vulvar cancer tested positive for HPV DNA (23%) and 32 (18%) were p16 positive. Patients with warty and basaloid squamous cell cancer were significantly younger than those with keratinizing squamous cell cancer (63.3 years vs. 71.0 years, p = 0.021). In addition, 77.4% of all cases suffering from warty or basaloid squamous cell cancer tested positive for HPV, compared to 9.5% of the keratinizing squamous cell cancer cases (p < 0.001). The most commonly detected HPV strain was type 16, followed by 31 and 33. CONCLUSION: Infection with HPV type 16 appears to be strongly correlated to the development of warty or basaloid squamous cell cancer. Vaccination against HPV can be expected to prevent this type of vulvar cancer. PMID- 28884279 TI - Primary HIV Infection: Clinical Presentation, Testing, and Treatment. AB - PURPOSE OF REVIEW: The purpose of this review was to provide current data on clinical presentation, diagnosis, and treatment of primary HIV infection (PHI). RECENT FINDINGS: In 65 to 95% of cases, PHI causes acute retroviral syndrome presenting with unspecific flu-like symptoms. Symptomatic PHI was associated with a faster clinical and immunological progression of HIV infection. Point-of-care tests remain less sensitive than fourth-generation immunoassays (IA) in PHI, especially after tenofovir-based prophylaxis use. Early antiretroviral treatment (ART) started during PHI prevents HIV transmission and decreases viral and immunological reservoir constitution. Recommended ART regimens in PHI are combinations of tenofovir and emtricitabine with either darunavir/ritonavir, or dolutegravir. Starting ART the earliest is highly recommended for clinical, virological, immunological, and public health benefits. Reducing HIV reservoir constitution in PHI may optimize potential opportunities for future functional cure. PMID- 28884280 TI - Clinical outcomes of everolimus in patients with advanced, nonfunctioning pancreatic neuroendocrine tumors: a multicenter study in Korea. AB - PURPOSE: Everolimus is a standard treatment option for advanced pancreatic neuroendocrine tumors (pNETs). This multicenter study evaluated the efficacy and safety of everolimus in low and intermediate grade advanced pNETs. METHODS: Tumors were graded according to the World Health Organization 2010 classification system. Patients with low or intermediate grade pNETs who received everolimus as first- or second-line chemotherapy between 2002 and 2014 were included. RESULTS: A total of 40 patients with metastatic or recurrent pNETs were included in this study. The median age was 54.5 years (range 19-83 years). Twelve patients (30%) experienced recurrence. There were 11 patients (27.5%) with low grade pNETs and 29 (72.5%) with intermediate. Everolimus was administered as first-line therapy in 30 patients (75%) and as second-line therapy in 10 patients (25%). The median progression-free survival (PFS) of patients with low and intermediate grade pNETs was significantly different (median not reached vs. 11 months, P = 0.015). On multivariate analysis, tumor grade (intermediate grade; HR 6.52, 95% CI 1.31 32.27, P = 0.022) was the only independent prognostic factor for PFS in pNETs. The most common adverse events were stomatitis, skin rash, and anemia. CONCLUSIONS: World Health Organization 2010 grade is the most important determinant for PFS in patients undergoing everolimus treatment for pNETs with an acceptable incidence of adverse events. PMID- 28884281 TI - Angiotensin Receptor Blockade by Inhibiting Glial Activation Promotes Hippocampal Neurogenesis Via Activation of Wnt/beta-Catenin Signaling in Hypertension. AB - Hypertension is one of the major risk factors for central nervous system (CNS) disorders like stroke and Alzheimer's disease (AD). On the other hand, CNS diseases like AD have been associated with gliosis and impaired neurogenesis. Further, renin angiotensin system (RAS) is intricately associated with hypertension; however, the accumulating evidences suggest that over-activity of RAS may perpetuate the brain inflammation related with AD. Therefore, in the present study, we examined the effect of hypertension and RAS on glial (astrocytes and microglia) activation and hippocampal neurogenesis in a rat model of chronic hypertension. We used Candesartan [angiotensin type 1 receptor (AT1R) blocker (ARB)] both at a low dose (0.1 mg/kg) and anti-hypertensive dose (2 mg/kg) to explore whether their effect on astrocyte and microglial activation, neuroinflammation, and neurogenesis is blood pressure (BP) dependent or independent. Our data revealed that hypertension induces robust microglial and astrocyte activation, neuroinflammation, and cripples hippocampal neurogenesis. Importantly, AT1R blockade by Candesartan, even at low dose (0.1 mg/kg), prevented astrocyte and microglial activation and neuroinflammation in the brain of hypertensive rats. Mechanistically, AT1R blockade prevented the activation of NADPH oxidase, reactive oxygen species (ROS) generation, suppression of MAP kinase and NFkB signaling. Importantly, we, for the first time to our knowledge, provided the evidence that AT1R blockade by activating Wnt/beta-catenin signaling, promotes neurogenesis during hypertensive state. We conclude that AT1R blockade prevents astrocyte and microglial activation and improves hippocampal neurogenesis in hypertensive state, independent of BP lowering action. PMID- 28884282 TI - Efficiency Analysis of Integrated Public Hospital Networks in Outpatient Internal Medicine. AB - Healthcare systems are evolving towards a complex network of interconnected services due to the increasing costs and the increasing expectations for high service levels. It is evidenced in the literature the importance of implementing management techniques and sophisticated methods to improve the efficiency of healthcare systems, especially in emerging economies. This paper proposes an integrated collaboration model between two public hospitals to reach the reduction of weighted average lead time in outpatient internal medicine department. A strategic framework based on value stream mapping and collaborative practices has been developed in real case study settled in Colombia. PMID- 28884284 TI - Body farms - characteristics and contributions. PMID- 28884283 TI - Clinical outcomes of early scheduled Fontan completion following Kawashima operation. AB - OBJECTIVES: This study reviewed late clinical features after Kawashima operation to confirm the impact of scheduled subsequent early Fontan completion. METHODS: Of the 17 consecutive patients who underwent the Kawashima operation between 1987 and 2010, 11 underwent the procedure as inter-stage palliation (scheduled Fontan group). Ten of these patients underwent subsequent early Fontan completion after a median interval of 0.6 years. The remaining 6 patients underwent the Kawashima operation initially as definitive surgery (non-scheduled group). Late Fontan completion was performed in 4 of these patients as salvage surgery to prevent progression of hypoxia after a median interval of 6.6 years. RESULTS: All patients completed follow-up; the mean follow-up period was 12 +/- 7 years (range 0.6-28.2). Cumulative survival at 10 years was 66% in the non-scheduled group and 79% in the scheduled group (p = 0.66). Pulmonary arteriovenous malformations developed after Kawashima operation in all 4 patients without antegrade pulmonary blood flow in the non-scheduled group but in only 2 of 11 patients in the scheduled group, both of which completely resolved after Fontan completion. In the scheduled Fontan group, 3 patients developed venovenous malformations between the Fontan pathway and the pulmonary veins or atrium after Fontan completion. CONCLUSIONS: Issues related to pulmonary arteriovenous malformations after Kawashima operation resolved with early scheduled Fontan completion. However, data on long-term outcomes are limited and the risk of death continues throughout early life. For unsuitable Fontan candidates, the Kawashima operation with antegrade pulmonary blood flow may provide definitive palliation. PMID- 28884285 TI - Immune TB Antibody Phage Display Library as a Tool To Study B Cell Immunity in TB Infections. AB - B cells and in particular antibodies has always played second fiddle to cellular immunity in regard to tuberculosis (TB). However, recent studies has helped position humoral immunity especially antibodies back into the foray in relation to TB immunity. Therefore, the ability to correlate the natural antibody responses of infected individuals toward TB antigens would help strengthen this concept. Phage display is an intriguing approach that can be utilized to study antibody-mediated responses against a particular infection via harvesting the B cell repertoire from infected individuals. The development of disease-specific antibody libraries or immune libraries is useful to better understand antibody mediated immune responses against specific disease antigens. This study describes the generation of an immune single-chain variable fragment (scFv) library derived from TB-infected individuals. The immune library with an estimated diversity of 109 independent clones was then applied for the identification of monoclonal antibodies against Mycobacterium tuberculosis alpha-crystalline as a model antigen. Biopanning of the library isolated three monoclonal antibodies with unique gene usage. This strengthens the role of antibodies in TB immunity in addition to the role played by cellular immunity. The developed library can be applied against other TB antigens and aid antibody-derived TB immunity studies in the future. PMID- 28884286 TI - Combination of Irinotecan, Oxaliplatin and 5-Fluorouracil as a Rechallenge Regimen for Heavily Pretreated Metastatic Colorectal Cancer Patients. AB - PURPOSE: Our objective was to evaluate the benefit of re-exposing patients with refractory metastatic colorectal cancer (mCRC) to a combination of oxaliplatin, irinotecan and 5-fluorouracil treatment. METHODS: We retrospectively analysed patients with mCRC who received a combination of oxaliplatin, irinotecan and fluorouracil as a rechallenge regimen after progressing on the same drugs. Both FOLFOXIRI and FOLFIRINOX were used. Toxicity was evaluated for each treatment cycle, and survival analysis was performed using the Kaplan-Meier method. RESULTS: A total of 21 patients who were treated between January 2011 and December 2013 were selected for this study. Most of the patients (95.2%) had an ECOG status of 0-1. The median age at diagnosis was 52.1 years (range 36-77 years), and 14 (66.6%) patients had wild-type KRAS. Thirteen patients received FOLFIRINOX, and eight received FOLFOXIRI. Most patients had previously received at least three regimens, with 80% receiving anti-VEGF and 66% anti-EGFR antibodies. The response rate was 38%, and 24% patients had stable disease. The median time to disease progression was 4.0 months (range 1.0-9.1 months), and the median overall survival duration was 8.6 months (range 6.3-11.5 months). Most patients required dose adjustment and treatment delays. One patient experienced grade 5 neutropenic sepsis. CONCLUSIONS: Both FOLFIRINOX and FOLFOXIRI are active and potentially feasible rechallenge treatment options for heavily pretreated patients with good performance status. With dose reduction and close monitoring for toxicity, the risk of serious adverse events can be minimised. PMID- 28884287 TI - Incidence of comprehensive hospitalization due to infection, cardiovascular disease, fractures, and malignancies in patients with rheumatoid arthritis. AB - To comprehensively analyze the overall incidence of hospitalization for comorbidities in patients with rheumatoid arthritis (RA). We prospectively analyzed overall hospitalizations for comorbidities using the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort. The incidence of hospitalized comorbidity was calculated. Risk factors for the most frequent hospitalized comorbidities were determined by multivariate logistic regression analysis. Among 5519 RA patients contributing 5336.5 person-years of observation, 435 incidences of hospitalized comorbidity [8.15/100 person-years; 95% confidence interval (CI) 7.40-8.95] were confirmed. The most frequent cause of hospitalized comorbidity was infection (1.52/100 person-years), primarily respiratory system infection (0.77/100 person-years), followed by malignancy (1.03/100 person-years), extra articular manifestations (0.78/100 person-years), bone fracture (0.77/100 person years), and acute coronary syndrome (0.22/100 person-years). Death occurred in 0.34/100 person-years (95% CI 0.20-0.53), and in 94.4% of cases the cause of death was the same as that of admission. The risk factors for the most frequent cause of hospitalization, hospitalized infection, were age [odds ratio (OR) 1.03; 95% CI 1.00-1.05], serum albumin level (OR 0.30; 95% CI 0.13-0.69), and corticosteroid use (prednisone > 5 mg/day; OR 3.66; 95% CI 1.81-7.35), but not methotrexate or biological agent use. The present study determined the overall burden of hospitalized comorbidities in patients with RA. These comprehensive data on hospitalized comorbidities may provide a basis for future improvements in the treatment of RA. PMID- 28884288 TI - Dyslipidemia incidence and the trend of lipid parameters changes in women with history of gestational diabetes: a 15-year follow-up study. AB - PURPOSE: Evidence shows that patients with gestational diabetes mellitus (GDM) may exhibit features of dyslipidemic phenotype later in life. We aimed to examine and compare dyslipidemia incidence rate and the trend of lipid changes over a 15 years follow-up between the women with the history of GDM and their healthy peers. METHODS: This longitudinal study included 289 patients with GDM and 1183 women without GDM, aged 20-50 years. Pooled logistic regression model was utilized to estimate odds ratio of dyslipidemia. The generalized estimating equation was used to evaluate the trend of lipid parameters changes over time. RESULTS: Person-time dyslipidemia incidence rate in women with previous GDM was 0.067 (CI: 0.038, 0.096) with a median progression time of 2.13 years and for those without GDM was 0.059 (CI: 0.046, 0.072) with the median time of 2.31 years ([Formula: see text] = 0.214). The generalized estimating equation (GEE) analysis revealed no significant difference in trend changes of lipid profiles between two groups. CONCLUSIONS: Lipid disorder after GDM might be more influenced by other variables (BMI, anthropometric features, and smoking/lifestyle habits) rather than by the GDM status alone. Lipid profile changes of GDM women do not become significantly worse than their non-GDM counterparts, as time progresses. PMID- 28884289 TI - Dispersals of the Siberian Y-chromosome haplogroup Q in Eurasia. AB - The human Y-chromosome has proven to be a powerful tool for tracing the paternal history of human populations and genealogical ancestors. The human Y-chromosome haplogroup Q is the most frequent haplogroup in the Americas. Previous studies have traced the origin of haplogroup Q to the region around Central Asia and Southern Siberia. Although the diversity of haplogroup Q in the Americas has been studied in detail, investigations on the diffusion of haplogroup Q in Eurasia and Africa are still limited. In this study, we collected 39 samples from China and Russia, investigated 432 samples from previous studies of haplogroup Q, and analyzed the single nucleotide polymorphism (SNP) subclades Q1a1a1-M120, Q1a2a1 L54, Q1a1b-M25, Q1a2-M346, Q1a2a1a2-L804, Q1a2b2-F1161, Q1b1a-M378, and Q1b1a1 L245. Through NETWORK and BATWING analyses, we found that the subclades of haplogroup Q continued to disperse from Central Asia and Southern Siberia during the past 10,000 years. Apart from its migration through the Beringia to the Americas, haplogroup Q also moved from Asia to the south and to the west during the Neolithic period, and subsequently to the whole of Eurasia and part of Africa. PMID- 28884290 TI - Attempt at standardization of bone quantitative ultrasound in Japan. AB - Dual X-ray absorptiometry (DXA) is used to diagnose osteoporosis. On the other hand, quantitative ultrasound (QUS) is widely used to assess bone density as part of medical screening as it is relatively inexpensive and easy to perform. Current QUS devices do not share precise ultrasound-related parameters, such as frequency, waveform, beam pattern, transient response, definition of propagation time, definition of degree of attenuation, and precise measurement site, resulting in different measurements across models. The Japan Osteoporosis Society established a QUS Standardization Committee in 2007 to investigate standardization of speed of sound (SOS) and broadband ultrasonic attenuation (BUA) measurements to resolve this issue. The committee came up with a formula to convert SOS and BUA values yielded by each model available in Japan. This has made it possible to convert QUS measurements from different models into standardized values, greatly improving the effectiveness of QUS measurements. PMID- 28884291 TI - Pre-treatment carcinoembryonic antigen and outcome of patients with rectal cancer receiving neo-adjuvant chemo-radiation and surgical resection: a systematic review and meta-analysis. AB - Neo-adjuvant chemo-radiation is the standard of care for patients with locally advanced rectal carcinoma. The aim of the present paper is to evaluate the relationship of the baseline serologic concentration of the carcinoembryonic antigen with the outcome. Data sources included MEDLINE and Web of Science databases. A systematic search of the databases by a predefined criterion has been conducted. Chemo-radiation followed by surgical resection of rectal tumors was the intervention of interest. From selected studies, the relationships between carcinoembryonic antigen and pathologic complete response, disease-free survival and overall survival were assessed. Carcinoembryonic antigen correlated significantly and inversely with the rate of pathologic complete responses (OR 2.00). Similar to this relationship, a low baseline carcinoembryonic antigen concentration was associated with a better disease-free survival (OR 1.88) and a better overall survival (OR 1.85). Heterogeneity of studies and publication bias were considerable in evaluating the relationship of baseline carcinoembryonic antigen and pathologic complete response. Baseline carcinoembryonic antigen should be regarded as a predictor of outcome of patients undergoing neo-adjuvant chemo-radiation. A calibration of the cutoff value from 5 to 3 ng/ml appears more appropriate to this patient population and should be evaluated in prospective trials. PMID- 28884293 TI - Human parainfluenza virus type 2 polymerase complex recognizes leader promoters of other species belonging to the genus Rubulavirus. AB - Leader sequence, located at the 3' terminus of paramyxovirus genomes, determines the degree of viral transcription and replication. The essential nucleotides in the leader sequence that influence viral propagation, however, have not been investigated in detail. In the present study, we show that polymerase complex of human parainfluenza virus type 2 (hPIV2) uses a luciferase-encoding hPIV2 mini genome possessing the leader sequence from other closely related viruses as a template. Furthermore, we demonstrate that although hPIV2 polymerase complex can recognize the leader sequence of hPIV4B, mumps virus (MuV) and PIV5 as well as Newcastle disease virus (NDV), it cannot recognize measles virus, hPIV1, Sendai virus (SeV) or hPIV3. We could obtain the chimeric hPIV2 possessing the leader sequence from hPIV4B, MuV and PIV5, but not from other species, including NDV and SeV. These results reveal that although hPIV2 polymerase complex can recognize the leader sequence from rubulaviruses to achieve efficient viral infection, this does not apply to viruses belonging to other genus. A comparison of leader sequence nucleotides among paramyxoviruses highlights the importance of the conservation in the first 13 nucleotides for infectious hPIV2 growth. PMID- 28884292 TI - The Advancement of Biomaterials in Regulating Stem Cell Fate. AB - Stem cells are well-known to have prominent roles in tissue engineering applications. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can differentiate into every cell type in the body while adult stem cells such as mesenchymal stem cells (MSCs) can be isolated from various sources. Nevertheless, an utmost limitation in harnessing stem cells for tissue engineering is the supply of cells. The advances in biomaterial technology allows the establishment of ex vivo expansion systems to overcome this bottleneck. The progress of various scaffold fabrication could direct stem cell fate decisions including cell proliferation and differentiation into specific lineages in vitro. Stem cell biology and biomaterial technology promote synergistic effect on stem cell-based regenerative therapies. Therefore, understanding the interaction of stem cell and biomaterials would allow the designation of new biomaterials for future clinical therapeutic applications for tissue regeneration. This review focuses mainly on the advances of natural and synthetic biomaterials in regulating stem cell fate decisions. We have also briefly discussed how biological and biophysical properties of biomaterials including wettability, chemical functionality, biodegradability and stiffness play their roles. PMID- 28884294 TI - A Concise Review of MicroRNA Exploring the Insights of MicroRNA Regulations in Bacterial, Viral and Metabolic Diseases. AB - MicroRNA (miRNA) is a small section of ribonucleic acid (RNA) that reduces the protein formation by making the pair of the complementary piece of mRNA. The genes of miRNA are present as transcriptional or polycistronic units in the chromosomes. The cellular multiplication, separation and existence like the multitude of genetic functions are affected by miRNA. Nearly 50% of identified miRNA are located in the residence in the intronic part of the genes. The mature miRNA is yielded in two steps. Drosha and RNA-induced silencing complex are the catalysts that play an important role in miRNA synthesis. The miRNA may function by just hindering the translation or complete vitiation of miRNA that occurs to control the genes. The microRNA antagonists and miRNA mimics are therapeutics approaches for the treatment of abnormalities. The upregulation and downregulation of miRNAs are linked to a number of diseases as miR-122 is associated with viral hepatitis, and some members of let-7 and other miRNAs are concerned with various diseases. Overexpressed miRNAs may function as both oncogenes and regulator of cellular processes. The miRNA functions can be altered by single-point mutations in miRNA target and epigenetic silencing of transcription units. There are numerous molecular targets for miRNA as degradation by nuclease and phosphodiesterase. Thus, miRNA has potential applications in disease diagnosis along with therapy, but the mechanisms involved in miRNA systems and its targeted delivery of miRNA are much more important to achieve its therapeutic applications. PMID- 28884295 TI - Dietary Patterns, Nutrition Knowledge, Lifestyle, and Health-Related Quality of Life: Associations with Anti-Hypertension Medication Adherence in a Sample of Australian Adults. AB - INTRODUCTION: Poor anti-hypertension medication (AHT) adherence can increase disease costs and adverse outcomes. Hypertensive individuals who have a better nutrition knowledge may lead a healthier lifestyle, have a better health-related quality of life (HRQoL) and greater confidence to change behaviour. On this basis, they may have better treatment adherence. AIM: To explore the association between the above-mentioned variables and AHT adherence in a group of Australian adults with high blood pressure (BP) in a cross-sectional clinical and community based study. METHODS: Adults with high BP (n = 270) completed a questionnaire including: food frequency questionnaire (FFQ), nutrition knowledge, HRQoL, self efficacy of diet and exercise, lifestyle and AHT adherence sections. Bivariate analysis and hierarchical logistic regression were used to explore the data. RESULTS: Three dietary patterns were identified from the FFQ, using factor and cluster analyses (Western, Snack and Alcohol, and Balanced). We observed that following a Western dietary pattern, having lower exercise self-efficacy and shorter sleep duration were more dominant in the poor AHT adherence individuals compared to their counterparts. A positive association was observed between self efficacy and sleep duration with AHT adherence. A Western dietary pattern was prevalent in high BP participants which slightly reduced the likelihood of good adherence. CONCLUSION: A healthier dietary pattern, better exercise self-efficacy and adequate sleep (more than six hours a night) may increase the likelihood of AHT adherence in individuals with high BP. Interventions focusing on improving these variables are required to confirm the findings of this study. PMID- 28884296 TI - An open-label, prospective, observational study of the efficacy of bisphosphonate therapy for painful osteoid osteoma. AB - OBJECTIVES: To assess the efficacy of bisphosphonate therapy on bone pain in patients with osteoid osteoma (OO) (main objective), and to describe bisphosphonate-induced changes in nidus mineralisation and regional bone-marrow oedema (BMO). METHODS: A prospective, observational study was conducted from 2011 to 2014. Patients with risk factors for complications of percutaneous or surgical ablation or recurrence after ablation, were offered once monthly intravenous bisphosphonate treatment until significant pain alleviation was achieved. RESULTS: We included 23 patients. The first two patients received pamidronate and the next 21 zoledronic acid (mean, 2.95 infusions per patient). Bisphosphonate therapy was successful in 19 patients (83%), whose mean pain visual analogue scale score decreased by 76.7%; this pain-relieving effect persisted in 17 patients (74%) with a mean follow-up time of 36 months. Computed tomography (CT) demonstrated a mean nidus density increase of 177.7% (p = 0.001). By magnetic resonance imaging (MRI), mean decreases were 38.4% for BMO surface area and 30.3% for signal intensity (p = 0.001 and p = 0.000, respectively). CONCLUSIONS: In 17/23 patients with painful OO managed conservatively with bisphosphonates, long term final success was achieved. Bisphosphonates may accelerate the spontaneous healing of OO. KEY POINTS: * 19/23 patients with OO managed with bisphosphonates experienced significant pain relief * Pain relief was sustained in 17/23 patients, mean follow-up of 36 months * CT demonstrated a significant increase in nidus mineralisation * MRI demonstrated a significant decrease in bone marrow oedema * Bisphosphonate therapy may accelerate the spontaneous healing of OO. PMID- 28884297 TI - The effect of different organic materials amendment on soil bacteria communities in barren sandy loam soil. AB - To effectively improve soil productivity and optimize organic fertilizer management while reducing environmental pollution and resource wasting in farmland system, the present study was conducted in Wuqiao Experiment Station of China Agricultural University, Hebei Province. Taking crop straw treatment as control, four kinds of organic materials including pig manure (PM), biogas residue (BR), biochar (BC) and crop straw (ST) were applied to soil at the same nitrogen (N) level. The soil bacteria community characteristics were explored using Illumina Miseq high-throughput sequencing technologies. The results were as follows: (1) Compared with ST, PM, BR and BC had no significant effect on Chao 1 and Shannon index. The dominant bacterial groups include Proteobacteria, Acidobacteria, Actinobacteria, Bacteroidetes, and Chloroflexi in sandy loam soil after the application of different organic materials. The abundance of Proteobacteria in BC treatment was significantly lower than that of ST (control) treatment (p < 0.05). On the contrary, compared to ST, the abundances of Acidobacteria increased by 65.0, 40.7, and 58.7% in the BC, BR, and PM treatments, respectively. (2) Compared to ST, the BC treatment significantly (p < 0.05) increased in soil organic carbon (SOC) and pH in the arable layer (0-20 cm) in the farmland (p < 0.05), and significantly increased the soil pH with a value of 0.26 level (p < 0.05). (3) Pearson correlation analysis results showed that the PCoA1 scores and soil pH were closely correlated (R 2 = 0.3738, p < 0.05). In addition, pairwise regression between PCoA1 scores and SOC (R 2 = 0.5008, p < 0.05), PCoA2 scores and SOC (R 2 = 0.4053, p < 0.05) were both closely correlated. In general, our results indicated that organic materials amendment shaped the bacterial community in sandy loam soil through changing the soil pH and SOC. PMID- 28884298 TI - Educational Interventions May Promote Better Blood Pressure Control in Russia. PMID- 28884299 TI - Can Inferior Vena Cava Measurement be an Alternative to Central Venous Pressure Measurement? PMID- 28884300 TI - What every radiologist should know about adnexal torsion. AB - Adnexal torsion is the fifth most common gynecologic surgical emergency, requiring clinician and radiologist awareness. It involves the rotation of the ovarian tissue on its vascular pedicle leading to stromal edema, hemorrhagic infarction, and necrosis of the adnexal structures with the subsequent sequelae. Expedient diagnosis poses a difficult challenge because the clinical presentation is variable and often misleading. Adnexal torsion can mimic malignancy as it can take a subacute, intermittent, or chronic course, and thereby can be complicated to diagnose. The torsion may occur in the normal ovary but is usually secondary to a preexisting adnexal mass. Early surgery is necessary to avoid irreversible adnexal damage and to preserve ovarian function especially in children and young women. Pelvic ultrasound forms the foundation of diagnostic evaluation due to its ability to directly and rapidly evaluate both ovarian anatomy and perfusion. Moreover, it is a noninvasive and accessible technique. However, the color Doppler appearance of the ovary should not be relied upon to rule out torsion because a torsed ovary or adnexa may still have preserved arterial flow due to the dual blood supply. MR and CT may be used as problem-solving tools needed after the ultrasound examination but should not be the first-line imaging modalities in this setting due to ionizing radiation and potential time delay in diagnosis. The goal of this article is to review the adnexal anatomy, to familiarize radiologists with the main imaging features, and to discuss the main mimickers and the most common pitfalls of adnexal torsion. Main points Adnexal torsion is an uncommon gynecological disorder caused by partial or complete rotation of the ovary and/or the Fallopian tube about the infundibulopelvic ligament. The ovaries receive a dual blood supply from the ovarian artery and uterine artery. The lack of pathognomonic symptoms and specific findings on physical examination makes this entity difficult to diagnose. Since the right adnexa are most commonly involved, symptoms may mimic acute appendicitis. Persistence of adnexal vascularization does not exclude torsion. In the pediatric age group, gray-scale ultrasound is the best modality of choice. Obtaining CT and/or MR images should not delay treatment in order to preserve ovarian viability. PMID- 28884301 TI - Clinical and pathologic predictors of central lymph node metastasis in papillary thyroid microcarcinoma: a retrospective cohort study. AB - OBJECTIVE: To identify the clinical and pathological predictors of central lymph node metastasis (CLNM) in patients with clinically lymph node-negative papillary thyroid microcarcinoma (PTMC). MATERIALS AND METHODS: Data pertaining to 541 clinically lymph node-negative PTMC patients who underwent thyroid surgery at the Shanghai General Hospital between January 2010 and December 2013 were retrospectively analyzed. According to histopathological evidence of central lymph node involvement, patients were divided into central lymph node metastasis (CLNM)-positive and CLNM-negative groups; risk factors for CLNM were identified statistically. RESULTS: LNM was found in 148 (27.4%) patients. Gender (P = 0.002), age (P < 0.001), tumor size (P < 0.001), multifocality (P < 0.001), and extrathyroidal extension (P < 0.001) were significantly different between CLNM positive and CLNM-negative groups. On multivariate analyses, male sex (odds ratio [OR] = 2.656), age <45 years (OR = 4.184), tumor size >0.575 cm (OR = 2.105), gross extrathyroidal extension (OR = 14.605) and multifocality (OR = 2.084) were independent risk factors for CLNM. Among patients who did not have any of these five risk factors, only 3.9% were found to have CLNM. CONCLUSIONS: A relatively high prevalence of CLNM was observed in patients with clinically lymph node negative PTMC. CLNM was associated with male sex, younger age, larger tumor size, extrathyroidal extension and multifocal PTMC. PMID- 28884302 TI - Monitoring vegetation cover in Chongqing between 2001 and 2010 using remote sensing data. AB - In this study, we applied asymmetric Gaussian function fitting to reconstruct a high-quality MODIS normalized difference vegetation index (NDVI) time series dataset. Following this, we retrieved vegetation cover data from the Chongqing area between 2001 and 2010 using this dataset, applying a dimidiate pixel method. We then used several analytical indices to analyze spatial and temporal changes and trends related to these changes. We determined that a reconstruction of the MODIS NDVI dataset using asymmetric Gaussian fitting in conjunction with a data quality weight coefficient improved data quality and created a foundation for accurate estimations of vegetation cover. We also determined that vegetation cover in the Chongqing area decreased gradually from east to west. During the 10 year study period, vegetation cover in the Chongqing area generally increased, changing from low to high coverage. This increase in vegetation cover was mainly the result of ecological protection policies and improving climate conditions. We also found that changes in vegetation cover were mainly the result of urban construction and afforestation initiatives, but vegetation cover improved overall. PMID- 28884303 TI - Efficacy and safety of clindamycin-based treatment for bone and joint infections: a cohort study. AB - Clindamycin has high bioavailability together with good diffusion in bone tissue and could represent an alternative antibiotic compound for the treatment of bone and joint infections (BJIs). However, data regarding the efficacy and safety of clindamycin for BJIs are limited. A monocentric cohort study based on our medical dashboard, which prospectively recorded 28 characteristics for all hospitalized patients since July 2005, was performed. BJIs were selected, and then, all mono microbial BJI managed with clindamycin-based therapy were included. Remission was defined as the absence of clinical and/or microbiological relapse after treatment. The duration of follow-up without relapse was determined retrospectively using computerized medical records. For 10 years, 196 BJIs, of which 80 (41%) were device-associated infections, were treated with clindamycin based therapy. The bacterial causative agent was Staphylococcus aureus in 130 cases (66%), coagulase-negative staphylococci in 29 cases (15%), streptococci in 31 cases (16%) and other bacteria in 6 cases (3%). When used in combination therapy, clindamycin was mainly paired with fluoroquinolones (31%) or rifampin (27%). The mean duration of clindamycin treatment was 7.4 +/- 3.2 weeks (range, 1 24). An AE was recorded for 9 (4.5%) patients. Remission was recorded for 111 (57%) patients, with a mean duration of clinical follow-up of 28 +/- 24 months. Treatment failure occurred in 22 (11%) patients, 50 patients (25%) were lost to follow-up, and 8 (4%) required long-term suppressive therapy. Among the assessable patients, clindamycin-based therapy was efficient in 111/133 cases (83%) and thus represents a reliable and safe alternative treatment option. PMID- 28884305 TI - Opportunities and challenges in conducting community-engaged dissemination/implementation research. PMID- 28884304 TI - Cell-cycle arrest biomarkers in urine to predict acute kidney injury in septic and non-septic critically ill patients. AB - PURPOSE: To analyse the usefulness of the composite index of the tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) as urinary biomarkers for the early prediction of AKI in septic and non septic patients. METHODS: This is a prospective, observational study including patients admitted to ICU from acute care departments and hospital length of stay <48 h. The main exclusion criteria were pre-existing eGFR <30 mL/min/1.73 m2 and hospitalisation 2 months prior to current admission. The [TIMP-2].[IGFBP7] index was analysed twice, within the first 12 h of ICU admission. RESULTS: The sample included 98 patients. AKI incidence during ICU stay was 50%. Sepsis was diagnosed in 40.8%. Baseline renal variables were comparable between subgroups except for a higher baseline eGFR in non-septic patients. Patients were stratified based on the presence of AKI and their highest level of [TIMP-2].[IGFBP7] within the first 12 h of stay. [TIMP-2].[IGFBP7] index values were dependent on the incidence of AKI but not of sepsis. [TIMP-2].[IGFBP7] values were significantly related to AKI severity according to AKIN criteria (p < 0.0001). The AUROC curve to predict AKI of the worst [TIMP-2].[IGFBP7] index value was 0.798 (sensitivity 73.5%, specificity 71.4%, p < 0.0001). Index values below 0.8 ruled out any need for renal replacement (NPV 100%), whereas an index >0.8 predicted a rate of AKI of 71% and AKIN >= 2 of 62.9%. CONCLUSIONS: In our study, urinary [TIMP-2].[IGFBP7] was an early predictor of AKI in ICU patients regardless of sepsis. Besides, index values <0.8(ng/mL)2/1000 ruled out the need for renal replacement. PMID- 28884306 TI - Probiotic Soy Milk Consumption and Renal Function Among Type 2 Diabetic Patients with Nephropathy: a Randomized Controlled Clinical Trial. AB - Diabetic nephropathy (DN) is one the most important complications of diabetes leading to end-stage renal disease. Dietary approaches have been considered to control of the kidney function deterioration among these patients. The aim of the present study was to determine the effects of fortified soy milk with Lactobacillus plantarum A7 on renal function biomarkers in type 2 DN patients. Forty-eight DN subjects were attended to this parallel randomized trial study. Participants were randomly assigned to consume a diet containing 200 mL/day probiotic soy milk in intervention group or soy milk in the control condition for 8 weeks. An inflammatory adipokine-Progranulin (PGRN), a cytokine receptor soluble tumor necrosis factor receptor 1 (sTNFR1), and serum levels of Neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (Cys-C) as the new renal function biomarkers were measured after 8 weeks of intervention according to the standard protocol. Our analysis showed that consumption of probiotic soy milk resulted in a significant reduction in the Cys-C and PGRN levels compared with the soy milk (P = 0.01) in the final adjusted model. In addition, after adjustment for age, weight, and energy intake, a marginally significant in the NGAL level was seen between two groups (P = 0.05). However, there was no significant differences on the sTNFR1concenteration between two groups (P = 0.06). Overall, intake of probiotic soy milk may have a beneficial effect on the renal function in patients with DN. PMID- 28884307 TI - The role of the transient receptor potential ankyrin type-1 (TRPA1) channel in migraine pain: evaluation in an animal model. AB - BACKGROUND: Clinical and experimental studies have pointed to the possible involvement of the transient receptor potential ankyrin type-1 (TRPA1) channels in migraine pain. In this study, we aimed to further investigate the role of these channels in an animal model of migraine using a novel TRPA1 antagonist, ADM_12, as a probe. METHODS: The effects of ADM_12 on nitroglycerin-induced hyperalgesia at the trigeminal level were investigated in male rats using the quantification of nocifensive behavior in the orofacial formalin test. The expression levels of the genes coding for c-Fos, TRPA1, calcitonin gene-related peptide (CGRP) and substance P (SP) in peripheral and central areas relevant for migraine pain were analyzed. CGRP and SP protein immunoreactivity was also evaluated in trigeminal nucleus caudalis (TNC). RESULTS: In rats bearing nitroglycerin-induced hyperalgesia, ADM_12 showed an anti-hyperalgesic effect in the second phase of the orofacial formalin test. This effect was associated to a significant inhibition of nitroglycerin-induced increase in c-Fos, TRPA1 and neuropeptides mRNA levels in medulla-pons area, in the cervical spinal cord and in the trigeminal ganglion. No differences between groups were seen as regards CGRP and SP protein expression in the TNC. CONCLUSIONS: These findings support a critical involvement of TRPA1 channels in the pathophysiology of migraine, and show their active role in counteracting hyperalgesia at the trigeminal level. PMID- 28884308 TI - Spa therapy adjunct to pharmacotherapy is beneficial in rheumatoid arthritis: a crossover randomized controlled trial. AB - This study aims to investigate whether 2-week spa therapy, as an adjunct to usual pharmacological therapy, has any beneficial effect in patients with rheumatoid arthritis (RA). In this single-blind crossover study, 50 patients were randomly assigned in a 1:1 manner to receive usual pharmacological therapy plus 2-week spa therapy or usual pharmacological therapy alone (period 1.6 months); after a 9 month washout, patients were crossed over to the opposite assignment (period 2.6 months). Spa therapy program included a daily saline balneotherapy session at 36 37 degrees C for 20 min except Sundays. The clinical outcomes were evaluated at baseline, after spa therapy (2 weeks) and 3 and 6 months after the spa therapy in both period and were pain (Visual Analogue Scale (VAS)), patient and physician global assessments (VAS), Health Assessment Questionnaire (HAQ), and Disease Activity Score (DAS28). Spa therapy was superior to control therapy in improving all the assessed clinical outcomes at the end of the spa therapy. This superiority persisted significantly in physician global assessment (p = 0.010) and with a trend in favor of spa group in patient global assessment (p = 0.058), function (p = 0.092), and disease activity (p = 0.098) at 3 months. Statistically significant improvements were found in spa therapy compared to control in disease activity (p = 0.006) and patient (p = 0.020) and physician global (p = 0.011) assessments, and a trend toward improvements in pain (p = 0.069) and swollen joints (p = 0.070) at 6 months. A 2-week spa therapy adjunct to usual pharmacological therapy provided beneficial clinical effects compared to usual pharmacological therapy alone, in RA patients treated with traditional disease modifying antirheumatic drugs. These beneficial effects may last for 6 months. PMID- 28884309 TI - Globulin-platelet model predicts significant fibrosis and cirrhosis in CHB patients with high HBV DNA and mildly elevated alanine transaminase levels. AB - The globulin-platelet model (GP) is a new noninvasive liver fibrosis model developed in chronic hepatitis B (CHB) patients. This study aimed to evaluate the diagnostic performance of GP model for liver fibrosis and cirrhosis in CHB patients with high HBV DNA and mildly elevated alanine transaminase (ALT) levels. We enrolled 316 CHB patients with HBV DNA >= 4 log 10 copies/mL and 40 IU/L < ALT <= 80 IU/L. The GP, aspartate transaminase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) were calculated. Using liver histology as a gold standard, the diagnostic performances of noninvasive fibrosis models were compared by the area under receiver operating characteristic curves (AUROCs). Of 316 patients, 146 (46.2%), 64 (20.3%) and 40 (12.7%) were classified as having significant fibrosis, severe fibrosis and cirrhosis, respectively. To predict significant fibrosis, the AUROC of GP was lower than APRI (0.64 vs 0.76, p < 0.001) and equivalent to FIB-4 (0.64 vs 0.66, p = 0.366). To predict severe fibrosis, the AUROC of GP was equivalent to APRI (0.82 vs 0.79, p = 0.409) and FIB-4 (0.82 vs 0.77, p = 0.224). To predict cirrhosis, the AUROC of GP was higher than APRI (0.91 vs 0.84, p = 0.033) and FIB-4 (0.91 vs 0.80, p = 0.004). GP is a more accurate noninvasive fibrosis model than APRI and FIB-4 to diagnose cirrhosis in CHB patients with high HBV DNA and mildly elevated ALT levels. The clinical application of GP model may reduce the need for liver biopsy in CHB patients. PMID- 28884311 TI - Improved Glycemic Control Achieved by Switching to Insulin Degludec in Insulin Treated Patients with Type 2 Diabetes in a Real-World Setting: a Non interventional, Retrospective Cohort Study. AB - INTRODUCTION: Retrospective cohort study evaluating the clinical effectiveness of insulin degludec (IDeg) in insulin-treated patients with type 2 diabetes switching from other insulins to IDeg in a real-world setting. METHODS: Data were drawn from the Maccabi Health Management Organization in Israel and included patients treated with IDeg between 1 September 2014 and 29 February 2016. Main inclusion criteria were age >=18 years, diagnosis of type 2 diabetes, and treated with insulin for at least 1 year prior to IDeg initiation. HbA1c, insulin dose, body weight, and body mass index were recorded before and 90 and 180 days post switch. RESULTS: Of 211 eligible patients, 57% were male, mean age +/- SD 62.2 +/ 12.1 years, and diabetes duration >10 years. Switching to IDeg decreased HbA1c from a mean 8.8 +/- 1.5% (73.0 +/- 16.4 mmol/mol) baseline by 0.58 +/- 1.0% (6.3 +/- 10.9 mmol/mol) (p < 0.001). Baseline HbA1c of >8.5% (69.0 mmol/mol) and daily insulin dose of >=50 U were associated with a greater reduction in HbA1c [1.0 +/- 1.1% (10.9 +/- 12.0 mmol/mol) and 1.2 +/- 1.1% (13.1 +/- 12.0 mmol/mol), respectively] compared with the total population. At 180 days post-switch, the mean daily basal insulin dose increased by 2 U compared with pre-switch. There was no significant change in body weight post-switch. CONCLUSIONS: In a real world setting, switching from another insulin to IDeg significantly improved glycemic control in patients with type 2 diabetes, without significant weight gain and with only a modest increase in insulin dose after IDeg initiation. FUNDING: Novo Nordisk. PMID- 28884310 TI - Radiation-induced acute dysphagia : Prospective observational study on 42 head and neck cancer patients. AB - PURPOSE: Acute toxicity in head and neck (H&N) cancer patients treated with definitive radiotherapy (RT) has a crucial role in compliance to treatments. The aim of this study was to correlate doses to swallowing-associated structures and acute dysphagia. METHODS: We prospectively analyzed 42 H&N cancer patients treated with RT. Dysphagia (grade >= 3) and indication for percutaneous endoscopic gastrostomy (PEG) insertion were classified as acute toxicity. Ten swallowing-related structures were considered for the dosimetric analysis. The correlation between clinical information and the dose absorbed by the contoured structures was analyzed. Multivariate logistic regression method using resampling methods (bootstrapping) was applied to select model order and parameters for normal tissue complication probability (NTCP) modelling. RESULTS: A strong multiple correlation between dosimetric parameters was found. A two-variable model was suggested as the optimal order by bootstrap method. The optimal model (Rs = 0.452, p < 0.001) includes V45 of the cervical esophagus (odds ratio [OR] = 1.016) and Dmean of the cricopharyngeal muscle (OR = 1.057). The model area under the curve was 0.82 (95% confidence interval 0.69-0.95). CONCLUSION: Our results suggested that the absorbed dose to the cricopharyngeal muscle and cervical esophagus might play a relevant role in the development of acute RT-related dysphagia. PMID- 28884312 TI - Kinematically aligned total knee arthroplasty limits high tibial forces, differences in tibial forces between compartments, and abnormal tibial contact kinematics during passive flexion. AB - PURPOSE: Following total knee arthroplasty (TKA), high tibial forces, large differences in tibial forces between the medial and lateral compartments, and anterior translation of the contact locations of the femoral component on the tibial component during passive flexion indicate abnormal knee function. Because the goal of kinematically aligned TKA is to restore native knee function without soft tissue release, the objectives were to determine how well kinematically aligned TKA limits high tibial forces, differences in tibial forces between compartments, and anterior translation of the contact locations of the femoral component on the tibial component during passive flexion. METHODS: Using cruciate retaining components, kinematically aligned TKA was performed on thirteen human cadaveric knee specimens with use of manual instruments without soft tissue release. The tibial forces and tibial contact locations were measured in both the medial and lateral compartments from 0 degrees to 120 degrees of passive flexion using a custom tibial force sensor. RESULTS: The average total tibial force (i.e. sum of medial + lateral) ranged from 5 to 116 N. The only significant average differences in tibial force between compartments occurred at 0 degrees of flexion (29 N, p = 0.0008). The contact locations in both compartments translated posteriorly in all thirteen kinematically aligned TKAs by an average of 14 mm (p < 0.0001) and 18 mm (p < 0.0001) in the medial and lateral compartments, respectively, from 0 degrees to 120 degrees of flexion. CONCLUSIONS: After kinematically aligned TKA, average total tibial forces due to the soft tissue restraints were limited to 116 N, average differences in tibial forces between compartments were limited to 29 N, and a net posterior translation of the tibial contact locations was observed in all kinematically aligned TKAs during passive flexion from 0 degrees to 120 degrees , which are similar to what has been measured previously in native knees. While confirmation in vivo is warranted, these findings give surgeons who perform kinematically aligned TKA confidence that the alignment method and surgical technique limit high tibial forces, differences in tibial forces between compartments, and anterior translation of the tibial contact locations during passive flexion. PMID- 28884313 TI - Endocan as an early biomarker of severity in patients with acute respiratory distress syndrome. AB - BACKGROUND: Plasma concentrations of endocan, a proteoglycan preferentially expressed in the pulmonary vasculature, may represent a biomarker of lung (dys)function. We sought to determine whether the measurement of plasma endocan levels early in the course of acute respiratory distress syndrome (ARDS) could help predict risk of death or of prolonged ventilation. METHODS: All patients present in the department of intensive care during a 150-day period were screened for ARDS (using the Berlin definition). Endocan concentrations were measured at the moment of ARDS diagnosis (T0) and the following morning (T1). We compared data from survivors and non-survivors and data from survivors with less than 10 days of ventilator support (good evolution) and those who died or needed more than 10 days of mechanical ventilation (poor evolution). Results are presented as numbers (percentages), mean +/- standard deviation or medians (percentile 25-75). RESULTS: Ninety-six consecutive patients were included [median APACHE II score of 21 (17-27) and SOFA score of 9 (6-12), PaO2/FiO2 ratio 155 (113-206)]; 64 (67%) had sepsis and 51 (53%) were receiving norepinephrine. Non-survivors were older (66 +/- 15 vs. 59 +/- 18 years, p = 0.045) and had higher APACHE II scores [27 (22-30) vs. 20 (15-24), p < 0.001] and blood lactate concentrations at study inclusion [2.1 (1.3-4.0) vs. 1.5 (0.9-2.6) mmol/L, p = 0.024] than survivors, but PaO2/FiO2 ratios [150 (116-207) vs. 158 (110-206), p = 0.95] were similar in the two groups. Endocan concentrations on the day after ARDS diagnosis were significantly higher in patients with poor evolution than in those with good evolution [12.0 (6.8-18.6) vs. 7.2 (5.4-12.5), p < 0.01]. CONCLUSION: Blood endocan concentrations early in the evolution of ARDS may be a useful marker of disease severity. PMID- 28884314 TI - Spectroscopic sampling of the left side of long-TE spin echoes: a free lunch? AB - OBJECTIVE: Use of spectroscopically-acquired spin echoes typically involves Fourier transformation of the right side of the echo while largely neglecting the left side. For sufficiently long echo times, the left side may have enough spectral resolution to offer some utility. Since the acquisition of this side is "free", we deemed it worthy of attention and investigated the spectral properties and information content of this data. MATERIALS AND METHODS: Theoretical expressions for left- and right-side spectra were derived assuming Lorentzian frequency distributions. For left-side spectra, three regimes were identified based upon the relative magnitudes of reversible and irreversible transverse relaxation rates, R 2' and R 2, respectively. Point-resolved spectroscopy (PRESS) data from muscle, fat deposit and bone marrow were acquired at 1.5 T to test aspects of the theoretical expressions. RESULTS: For muscle water or methylene marrow resonances, left-side signals were substantially or moderately larger than right-side signals but were similar in magnitude for muscle choline and creatine resonances. Left- versus right-side spectral-peak amplitude ratios depend sensitively on the relative values of R 2 and R 2' , which can be estimated given this ratio and a right-side linewidth measurement. CONCLUSION: Left-side spectra can be used to augment signal-to-noise and to estimate spectral R 2 and R 2' values under some circumstances. PMID- 28884315 TI - Is digital photography an accurate and precise method for measuring range of motion of the hip and knee? AB - BACKGROUND: Accurate measurements of knee and hip motion are required for management of musculoskeletal pathology. The purpose of this investigation was to compare three techniques for measuring motion at the hip and knee. The authors hypothesized that digital photography would be equivalent in accuracy and show higher precision compared to the other two techniques. METHODS: Using infrared motion capture analysis as the reference standard, hip flexion/abduction/internal rotation/external rotation and knee flexion/extension were measured using visual estimation, goniometry, and photography on 10 fresh frozen cadavers. These measurements were performed by three physical therapists and three orthopaedic surgeons. Accuracy was defined by the difference from the reference standard, while precision was defined by the proportion of measurements within either 5 degrees or 10 degrees . Analysis of variance (ANOVA), t-tests, and chi-squared tests were used. RESULTS: Although two statistically significant differences were found in measurement accuracy between the three techniques, neither of these differences met clinical significance (difference of 1.4 degrees for hip abduction and 1.7 degrees for the knee extension). Precision of measurements was significantly higher for digital photography than: (i) visual estimation for hip abduction and knee extension, and (ii) goniometry for knee extension only. CONCLUSIONS: There was no clinically significant difference in measurement accuracy between the three techniques for hip and knee motion. Digital photography only showed higher precision for two joint motions (hip abduction and knee extension). Overall digital photography shows equivalent accuracy and near equivalent precision to visual estimation and goniometry. PMID- 28884316 TI - Improving extracellular production of Serratia marcescens lytic polysaccharide monooxygenase CBP21 and Aeromonas veronii B565 chitinase Chi92 in Escherichia coli and their synergism. AB - Lytic polysaccharide monooxygenases (LPMOs) can oxidize recalcitrant polysaccharides and boost the conversion of the second most abundant polysaccharide chitin by chitinase. In this study, we aimed to achieve the efficient extracellular production of Serratia marcescens LPMO CBP21 and Aeromonas veronii B565 chitinase Chi92 by Escherichia coli. Twelve signal peptides reported with high secretion efficiency were screened to assess the extracellular production efficiency of CBP21 and Chi92, with glycine used as a medium supplement. The results showed that PelB was the most productive signal peptide for the extracellular production of CBP21 and Chi92 in E. coli. Furthermore, CBP21 facilitated the degradation of the three chitin substrates (colloidal chitin, beta-chitin, and alpha-chitin) by Chi92. This study will be valuable for the industrial production and application of the two enzymes for chitin degradation. PMID- 28884317 TI - Relationship of very low serum 25-hydroxyvitamin D3 levels with long-term survival in a large cohort of colorectal cancer patients from Germany. AB - To investigate the association of serum 25-hydroxyvitamin D (25(OH)D3) with survival in a large prospective cohort study of colorectal cancer (CRC) patients. The study population consisted of 2,910 patients diagnosed with CRC between 2003 and 2010 who participated in the DACHS study, a multicenter study from Germany with comprehensive long-term follow-up. 25(OH)D3 was determined in serum samples collected shortly after cancer diagnosis by High Performance Liquid Chromatography-Electro Spray Ionization-Mass Spectrometry. Analyses of survival outcomes were performed using Cox regression with comprehensive adjustment for relevant confounders. The majority (59%) of CRC patients were vitamin D deficient (serum 25(OH)D3 levels <30 nmol/L). During a median follow-up of 4.8 years, 787 deaths occurred, 573 of which were due to CRC. Compared to patients in the highest 25(OH)D3 quintile (>45.20 nmol/L), those in the lowest 25(OH)D3 quintile (<11.83 nmol/L) had a strongly increased mortality. Adjusted hazard ratios (95% Confidence Interval) were 1.78 (1.39-2.27), 1.65 (1.24-2.21), 1.32 (1.03-1.71) and 1.48 (1.18-1.85) for all-cause mortality, CRC-specific mortality, recurrence free and disease-free survival, respectively. Subgroup analyses did not show any significant effect modification across strata defined by sex, age, stage, body mass index, or the late entry. Dose-response analyses showed a strong inverse relationship between serum 25(OH)D3 levels and survival endpoints at 25(OH)D3 levels <30 nmol/L, and no association with mortality at higher 25(OH)D3 levels. Vitamin D deficiency is highly prevalent in CRC patients and a strong independent predictor of poor prognosis. The possibility of enhancing CRC prognosis by vitamin D supplementation, ideally combined with outdoor physical activity, should be evaluated by randomized controlled trials focusing on patients with vitamin D deficiency. PMID- 28884318 TI - Implications of fALS Mutations on Sod1 Function and Oligomerization in Cell Models. AB - Among the familial forms of amyotrophic lateral sclerosis (fALS), 20% are associated with the Cu,Zn-superoxide dismutase (Sod1). fALS is characterized by the accumulation of aggregated proteins and the increase in oxidative stress markers. Here, we used the non-invasive bimolecular fluorescence complementation (BiFC) assay in human H4 cells to investigate the kinetics of aggregation and subcellular localization of Sod1 mutants. We also studied the effect of the different Sod1 mutants to respond against oxidative stress by following the levels of reactive oxygen species (ROS) after treatment with hydrogen peroxide. Our results showed that only 30% of cells transfected with A4VSod1 showed no inclusions while for the other Sod1 mutants tested (L38V, G93A and G93C), this percentage was at least 70%. In addition, we found that 10% of cells transfected with A4VSod1 displayed more than five inclusions per cell and that A4V and G93A Sod1 formed inclusions more rapidly than L38V and G93C Sod1. Expression of WTSod1 significantly decreased the intracellular oxidation levels in comparison with expression of fALS Sod1 mutants, suggesting the mutations induce a functional impairment. All fALS mutations impaired nuclear localization of Sod1, which is important for maintaining genomic stability. Consistently, expression of WTSod1, but not of fALS Sod1 mutants, reduced DNA damage, as measured by the comet assay. Altogether, our study sheds light into the effects of fALS Sod1 mutations on inclusion formation, dynamics, and localization as well as on antioxidant response, opening novel avenues for investigating the role of fALS Sod1 mutations in pathogenesis. PMID- 28884319 TI - Benchmarking pre-spawning fitness, climate preferendum of some catfishes from river Ganga and its proposed utility in climate research. AB - The concept of threshold condition factor (Fulton), beyond which more than 50% of the female fish population may attain readiness for spawning coined as pre spawning fitness (K spawn50), has been proposed in the present article and has been estimated by applying the non-parametric Kaplan-Meier method for fitting survival function. A binary coding strategy of gonadal maturity stages was used to classify whether a female fish is "ready to spawn" or not. The proposed K spawn50 has been generated for female Mystus tengara (1.13-1.21 units), M. cavasius (0.846-0.945 units), and Eutropiichthys vacha (0.716-0.799 units). Information on the range of egg parameters (fecundity, egg weight, egg diameter) expected at the pre-spawning stage was also generated. Additional information on species-specific thermal and precipitation window (climate preferendum) within which K spawn50 is attained was also generated through the LOESS smoothing technique. Water temperatures between 31 and 36 degrees C (M. tengara), 30 and 32 degrees C (M. cavasius), and 29.5 and 31 degrees C (E. vacha) and monthly rainfall between 200 and 325 mm (M. tengara), > 250 mm (M. cavasius), and around 50 mm and between 350 and 850 mm (E. vacha) were found to be optimum for attainment of K spawn50. The importance of parameterization and benchmarking of K spawn50 in addition to other conventional reproductive biology parameters has been discussed in the present article. The purposes of the present study were fulfilled by generating baseline information and similar information may be generated for other species replicating the innovative methodology used in this study. PMID- 28884321 TI - Elevated rate of alcohol consumption in borderline personality disorder patients in daily life. AB - RATIONALE: Borderline personality disorder (BPD) is highly associated with alcohol use disorder, but little is known about how BPD individuals consume alcohol or the immediate effects of their consumption. There is therefore a need for research investigating drinking behavior in BPD. OBJECTIVES: The current study examined rate of alcohol consumption in BPD (N = 54) and community individuals (COM; N = 59) within ecologically valid drinking episodes. We hypothesized that rate of consumption would be elevated in BPD individuals. We further hypothesized that rate of consumption would be positively associated with subjective stimulation, but not sedation, and that stimulation would be associated with increased positive affect (PA) and reduced negative affect (NA). METHODS: Ambulatory assessment was used to assess rate of consumption, subjective alcohol response, and affect in the moment (N observations = 3444). Rate of consumption was defined as change in estimated blood alcohol concentration (eBAC) relative to drinking episode start. Multilevel modeling was used to test hypotheses. RESULTS: As hypothesized, BPD individuals demonstrated a faster increase in eBAC than COM individuals. Rate of consumption was associated with subjective stimulation, but not sedation, in both groups. Stimulation was associated with increased PA in both groups and reduced NA in the BPD group. CONCLUSIONS: BPD individuals consumed alcohol more rapidly than COM individuals. Faster consumption may serve as a means for BPD individuals to maximize the rewarding pharmacological effects of alcohol and to increase positive and reduce negative affect. PMID- 28884322 TI - Assessment of sleepiness, fatigue, and depression among Gulf Cooperation Council commercial airline pilots. AB - PURPOSE: No studies have assessed the prevalence of fatigue, depression, sleepiness, and the risk of obstructive sleep apnea (OSA) among commercial airlines pilots in the Gulf Cooperation Council (GCC). METHODS: This was a quantitative cross-sectional study conducted among pilots who were on active duty and had flown during the past 6 months for one of three commercial airline companies. We included participants with age between 20 and 65 years. Data were collected using a predesigned electronic questionnaire composed of questions related to demographic information in addition to the Fatigue Severity Scale (FSS), the Berlin Questionnaire, the Epworth Sleepiness Scale (ESS), and the Hospital Anxiety and Depression Scale (HADS). RESULTS: The study included 328 pilots with a mean age +/- standard deviation of 41.4 +/- 9.7 years. Overall, 224 (68.3%) pilots had an FSS score >= 36 indicating severe fatigue and 221 (67.4%) reported making mistakes in the cockpit because of fatigue. One hundred and twelve (34.1%) pilots had an ESS score >= 10 indicating excessive daytime sleepiness and 148 (45.1%) reported falling asleep at the controls at least once without previously agreeing with their colleagues. One hundred and thirteen (34.5%) pilots had an abnormal HADS depression score (>= 8), and 96 (29.3%) pilots were at high risk for OSA requiring further assessment. CONCLUSION: Fatigue, sleepiness, risk of OSA, and depression are prevalent among GCC commercial airline pilots. Regular assessment by aviation authorities is needed to detect and treat these medical problems. PMID- 28884320 TI - Direct-Acting Antivirals Decreased Tumor Recurrence After Initial Treatment of Hepatitis C Virus-Related Hepatocellular Carcinoma. AB - BACKGROUND: Suppressive activity of recurrence by interferon-free direct-acting antivirals (DAA) is not elucidated after curative treatment of hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 177 patients received DAA after curative manners of HCC: 89 patients underwent DAA therapy after initial HCC treatment, and the other 88 patients after repeated therapy of 2-10 times. Among a cohort of HCC patients with surgery and radiofrequency ablation, 89 patients were chosen adjusting age, gender, and Barcelona Clinic Liver Cancer (BCLC) staging with 89 patients with initial HCC therapy. RESULTS: HCC recurrence rates at the end of first and second year were 18.1 and 22.1% in patients with once of HCC therapy, 28.2 and 41.6% in those with 2-3 times of therapy, and 60.2 and 74.5% in those with 4 or more times of therapy, respectively (P < 0.0001). Recurrence rates were compared between 89 patients with DAA therapy after initial HCC therapy and 89 age-, gender-, and BCLC staging-matched patients without antiviral therapy after initial HCC therapy. HCC recurrence rates at first and second year were 18.1 and 25.0% in patients with DAA therapy and 21.8 and 46.5% in those without DAA therapy, respectively (P = 0.003). Multivariate analysis showed DAA therapy significantly decreased recurrence rate with a hazard ratio of 0.353 (confidence interval: 0.191-0.651) after adjustment with covariates of tumor multiplicity, alpha-fetoprotein value, and prothrombin time. CONCLUSIONS: DAA therapy significantly decreased recurrence rate when it was performed after initial HCC therapy. PMID- 28884323 TI - [Proctology for internists]. AB - In proctology patients can often be helped with very little effort. With knowledge of the most common disease symptoms the treating physician can in many cases correctly recognize the cause of the complaints and initiate the appropriate therapy or arrange referral to a proctological institution. This article aims to briefly and succinctly present the most common diseases in proctology (e.g. mariscae, hemorrhoids, anal fissures, perianal venous thrombosis, abscesses and fistulas, condyloma acuminatum and anal carcinoma) and to provide the treating internist, even outside of gastroenterology, assistance with the management of proctological symptoms. PMID- 28884324 TI - Natural and engineered polyhydroxyalkanoate (PHA) synthase: key enzyme in biopolyester production. AB - With the finite supply of petroleum and increasing concern with environmental issues associated with their harvest and processing, the development of more eco friendly, sustainable alternative biopolymers that can effectively fill the role of petro-polymers has become a major focus. Polyhydroxyalkanoate (PHA) can be naturally produced by many species of bacteria and the PHA synthase is believed to be key enzyme in this natural pathway. Natural PHA synthases are diverse and can affect the properties of the produced PHAs, such as monomer composition, molecular weights, and material properties. Moreover, recent studies have led to major advances in the searching of PHA synthases that display specific properties, as well as engineering efforts that offer more efficient PHA synthases, increased PHA compound production, or even novel biopolyesters which cannot be naturally produced. In this article, we review the updated information of natural PHA synthases and their engineering strategies for improved performance in polyester production. We also speculate future trends on the development of robust PHA synthases and their application in biopolyester production. PMID- 28884325 TI - The occurrence of toxic cyanobacterium Cylindrospermopsis raciborskii and its toxin cylindrospermopsin in the Huong River, Thua Thien Hue province, Vietnam. AB - This research reports the presence of species Cylindrospermopsis raciborskii and cylindrospermopsin (CYN) in the Huong River and the relationship between species with environmental factors to find a scientific basis for predicting the risk of pollution of the species and CYN in waters. Strains of C. raciborskii isolated from the river were also identified as potentially toxin-producing through the determination of the presence of toxins in the cultures by ELISA; the presence of the genes involved by PCR confirms the CYN-producing ability of species C. raciborskii from this water body. Our results have confirmed the presence of toxic cyanobacteria C. raciborskii in the Huong River. C. raciborskii from the Huong River are mostly solitary, straight trichomes. Analyses of all C. raciborskii strains from the Huong River by ELISA for cylindrospermopsin were positive. The contents of cylindrospermopsin (CYN) in each strain were different, ranging from 5.25 ng mg-1 wet weight in CR1DD to 70.83 ng mg-1 wet weight in CR1NY. PCR analysis confirmed that the genes involved in the production of this cyanotoxin were present in C. raciborskii. The relationship between densities and toxicity showed a correlation coefficient R of 0.88. This was a relatively high positive correlation index, indicating the close links between densities and toxins: toxin CYN concentrations increased when C. raciborskii densities increased. PMID- 28884326 TI - One question might be capable of replacing the Shoulder Pain and Disability Index (SPADI) when measuring disability: a prospective cohort study. AB - QUESTIONS: Is it possible to replace the Shoulder Pain and Disability Index (SPADI) with a single substitute question for people with shoulder pain, when measuring disability and how well does this substitute question perform as a predictor for recovery. DESIGN: A prospective cohort study. PARTICIPANTS: A total of 356 patients with shoulder pain in primary care. ANALYSES: Convergent, divergent, and "known" groups validity were assessed by using hypotheses testing. Responsiveness was assessed using the Receiver Operating Curve and hypothesis testing. In addition, we performed multivariate regression to assess if the substitute question showed similar properties as the SPADI and if it affected the model itself, using recovery as an outcome. RESULTS: The Spearman correlation coefficient between the total SPADI score and the substitute question was high, and moderate with the Shoulder Disability Questionnaire. The correlation between the substitute question and the EQ-5D-3L was low and the responsiveness was acceptable. The substitute question did not significantly contribute to both prognostic prediction models as opposed to the SPADI. Regardless all models showed poor to fair discrimination. CONCLUSION: The single question is a reasonable substitute for the SPADI and can be used as a screening instrument for shoulder disability in primary clinical practice. It has slightly poorer predictive power and should therefore not be used for prognosis. PMID- 28884327 TI - Introductory review: periostin-gene and protein structure. AB - Although many studies have described the role of periostin in various diseases, the function of the periostin protein structures derived from alternative splicing and proteinase cleavage at the C-terminal remain unknown. Further experiments revealing the protein structures that are highly related to diseases are essential to understand the function of periostin in depth, which would accelerate its clinical application by establishing new approaches for curing intractable diseases. Furthermore, this understanding would enhance our knowledge of novel functions of periostin related to stemness and response to mechanical stress. PMID- 28884329 TI - Perioperative Mortality Following Oesophagectomy and Pancreaticoduodenectomy in Australia. AB - INTRODUCTION: Oesophagectomy (OG) and pancreaticoduodenectomy (PD) remain associated with significant perioperative mortality rates (POMR). Improved outcomes in high-volume centres have led to these procedures being centralised in some countries. This retrospective, population-based cohort study was conducted to determine the Australian national, and state and territory based POMR associated with OG and PD, and assess trends over time. METHODS: Logistic regression analysis was performed using de-identified procedural data between 1 July 2005 and 30 June 2013 from the Australian Institute of Health and Welfare. Codes relating to OG and PD contained in the Australian Classification of Health Interventions were used to extract patient data. Mortality rates were risk adjusted for age, gender and urgency of admission. Temporal trends and differences between states/territories were investigated. RESULTS: The average Australian POMR throughout the study period was 3.5 and 3.0% for OG and PD, respectively. OG POMR showed no significant change over time (P = 0.30) or variation between states (P = 0.079). The annual POMR associated with PD, however, showed a significant decrease during the study period (P = 0.01) with variation in PD POMR outcomes evident amongst different regions (P = 0.0004). CONCLUSION: This study demonstrates a comparable Australian PD and OG POMR when correlated with international studies. National PD POMR improved throughout the study with consistent improvement across the states and territories. This study does, however, show variation in PD POMR between states and territories. Potential intra-state variation merits further investigation. PMID- 28884328 TI - The Glycine soja NAC transcription factor GsNAC019 mediates the regulation of plant alkaline tolerance and ABA sensitivity. AB - KEY MESSAGE: Overexpression of Gshdz4 or GsNAC019 enhanced alkaline tolerance in transgenic Arabidopsis. We proved that Gshdz4 up-regulated both GsNAC019 and GsRD29B but GsNAC019 may repress the GsRD29B expression under alkaline stress. Wild soybean (Glycine soja) has a high tolerance to environmental challenges. It is a model species for dissecting the molecular mechanisms of salt-alkaline stresses. Although many NAC transcription factors play important roles in response to multiple abiotic stresses, such as salt, osmotic and cold, their mode of action in alkaline stress resistance is largely unknown. In our study, we identified a G. soja NAC gene, GsNAC019, which is a homolog of the Arabidopsis AtNAC019 gene. GsNAC019 was highly up-regulated by 50 mM NaHCO3 treatment in the roots of wild soybean. Further investigation showed that a well-characterized transcription factor, Gshdz4 protein, bound the cis-acting element sequences (CAATA/TA), which are located in the promoter of the AtNAC019/GsNAC019 genes. Overexpression of Gshdz4 positively regulated AtNAC019 expression in transgenic Arabidopsis, implying that AtNAC019/GsNAC019 may be the target genes of Gshdz4. GsNAC019 was demonstrated to be a nuclear-localized protein in onion epidermal cells and possessed transactivation activity in yeast cells. Moreover, overexpression of GsNAC019 in Arabidopsis resulted in enhanced tolerance to alkaline stress at the seedling and mature stages, but reduced ABA sensitivity. The closest Arabidopsis homolog mutant plants of Gshdz4, GsNAC019 and GsRD29B containing athb40, atnac019 and atrd29b were sensitive to alkaline stress. Overexpression or the closest Arabidopsis homolog mutant plants of the GsNAC019 gene in Arabidopsis positively or negatively regulated the expression of stress related genes, such as AHA2, RD29A/B and KIN1. Moreover, this mutation could phenotypically promoted or compromised plant growth under alkaline stress, implying that GsNAC019 may contribute to alkaline stress tolerance via the ABA signal transduction pathway and regulate expression of the downstream stress related genes. PMID- 28884330 TI - Prospects in the use of aptamers for characterizing the structure and stability of bioactive proteins and peptides in food. AB - Food-derived bioactive proteins and peptides have gained acceptance among researchers, food manufacturers and consumers as health-enhancing functional food components that also serve as natural alternatives for disease prevention and/or management. Bioactivity in food proteins and peptides is determined by their conformations and binding characteristics, which in turn depend on their primary and secondary structures. To maintain their bioactivities, the molecular integrity of bioactive peptides must remain intact, and this warrants the study of peptide form and structure, ideally with robust, highly specific and sensitive techniques. Short single-stranded nucleic acids (i.e. aptamers) are known to have high affinity for cognate targets such as proteins and peptides. Aptamers can be produced cost-effectively and chemically derivatized to increase their stability and shelf life. Their improved binding characteristics and minimal modification of the target molecular signature suggests their suitability for real-time detection of conformational changes in both proteins and peptides. This review discusses the developmental progress of systematic evolution of ligands by exponential enrichment (SELEX), an iterative technology for generating cost effective aptamers with low dissociation constants (K d) for monitoring the form and structure of bioactive proteins and peptides. The review also presents case studies of this technique in monitoring the structural stability of bioactive peptide formulations to encourage applications in functional foods. The challenges and potential of aptamers in this research field are also discussed. Graphical abstract Advancing bioactive proteins and peptide functionality via aptameric ligands. PMID- 28884331 TI - Paratuberculosis in Latin America: a systematic review. AB - Latin America is the definition of the American group, where languages of Latin origin are spoken, including countries in South, Central, and North America. Paratuberculosis is a gastrointestinal contagious chronic disease that affects ruminants, whose etiological agent is the bacilli Mycobacterium avium subsp. paratuberculosis (MAP). Paratuberculosis is characterized by intermittent diarrhea, decreased milk production, dehydration, and progressive weight loss and is possibly involved in Crohn's disease, a human intestinal disease. MAP is resistant to environmental factors, pasteurization, and water disinfection, which coupled with the subclinical-clinical nature of the disease, and makes paratuberculosis a relevant socioeconomic and public health issue, justifying the descriptive review of research on the disease carried out in Latin American countries. A survey of articles, published until September 2016, on the Scopus database, PubMed, Agris, and Science Direct, about detection of the agent and the disease in Latin America, without restrictions to the date of the research was performed. The keywords were as follows: "paratuberculosis," "Mycobacterium avium subsp. paratuberculosis," "cattle," "milk," "wildlife," "goat," "ovine," "dairy," and the name of each country in English. Studies found from nine of the 20 Latin America countries, 31 related to Brazil, 17 to Argentina, 14 to Chile, eight to Colombia, six to Mexico, two to Peru, two to Venezuela, and one to Panama and to Bolivia, each. The agent was detected in cattle, goats, sheep, domesticated water buffalo, and wild animals. Microbiological culture, PCR, and ELISA were the frequent techniques. The small number of studies may result in overestimation or underestimation of the real scenario. PMID- 28884332 TI - Subchondral mesenchymal stem cells from osteoarthritic knees display high osteogenic differentiation capacity through microRNA-29a regulation of HDAC4. AB - : Subchondral bone deterioration and osteophyte formation attributable to excessive mineralization are prominent features of end-stage knee osteoarthritis (OA). The cellular events underlying subchondral integrity diminishment remained elusive. This study was undertaken to characterize subchondral mesenchymal stem cells (SMSCs) isolated from patients with end-stage knee OA who required total knee arthroplasty. The SMSCs expressed surface antigens CD29, CD44, CD73, CD90, CD105, and CD166 and lacked CD31, CD45, and MHCII expression. The cell cultures exhibited higher proliferation and greater osteogenesis and chondrogenesis potencies, whereas their population-doubling time and adipogenic lineage commitment were lower than those of bone marrow MSCs (BMMSCs). They also displayed higher expressions of embryonic stem cell marker OCT3/4 and osteogenic factors Wnt3a, beta-catenin, and microRNA-29a (miR-29a), concomitant with lower expressions of joint-deleterious factors HDAC4, TGF-beta1, IL-1beta, TNF-alpha, and MMP3, in comparison with those of BMMSCs. Knockdown of miR-29a lowered Wnt3a expression and osteogenic differentiation of the SMSCs through elevating HDAC4 translation, which directly regulated the 3'-untranslated region of HDAC4. Likewise, transgenic mice that overexpressed miR-29a in osteoblasts exhibited a high bone mass in the subchondral region. SMSCs in the transgenic mice showed a higher osteogenic differentiation and lower HDAC4 signaling than those in wild type mice. Taken together, high osteogenesis potency existed in the SMSCs in the osteoarthritic knee. The miR-29a modulation of HDAC4 and Wnt3a signaling was attributable to the increase in osteogenesis. This study shed an emerging light on the characteristics of SMSCs and highlighted the contribution of SMSCs in the exacerbation of subchondral integrity in end-stage knee OA. KEY MESSAGES: Subchondral MSCs (SMSCs) from OA knee expressed embryonic stem cell marker Oct3/4. The SMSCs showed high proliferation and osteogenic and chondrogenic potencies. miR-29a regulated osteogenesis of the SMSCs through modulation of HDAC4 and Wnt3a. A high osteogenic potency of the SMSCs existed in mice overexpressing miR-29a in bone. Aberrant osteogenesis in SMSCs provides a new insight to subchondral damage in OA. PMID- 28884333 TI - Supplement intervention associated with nutritional deficiencies in autism spectrum disorders: a systematic review. AB - PURPOSE: Nutritional supplements have been used for correction of deficiencies that may occur in patient with autism spectrum disorder (ASD) and to improve core symptoms. We aim to provide current best evidence about supplements for nutritional deficiencies and core symptoms in children with ASD and to evaluate the effectiveness and safety. METHODS: A systematic literature search of scientific databases was performed to retrieve relevant randomized controlled trials. Risk of bias was assessed for each study. RESULTS: 18 randomized controlled trials of five supplements were included. B6/Mg was not helpful for improving ASD symptoms (seven RCTs). Two RCTs of methyl B12 reported some improvement in ASD severity but the effects on the correction of deficiencies were inconclusive. Two RCTs of vitamin D3 both reported increased levels of mean 25(OH)D in serum but inconsistent results in behavioral outcomes. Omega-3 fatty acid supplementation did not affect ASD behaviors but may correct deficiencies (six RCTs). One RCT of folinic acid reported positive results in improving ASD symptoms measured by various behavioral scales. CONCLUSIONS: Current evidence for the use of supplements for correcting nutritional deficiencies in children with ASD and to improve the symptoms is little. More studies are needed. PMID- 28884334 TI - Periostin in kidney diseases. AB - Chronic kidney disease is an incurable to date pathology, with renal replacement therapy through dialysis or transplantation being the only available option for end-stage patients. A deeper understanding of the molecular mechanisms governing the progression of kidney diseases will permit the identification of unknown mediators and potential novel markers or targets of therapy which promise more efficient diagnostic and therapeutic applications. Over the last years, periostin was established by several studies as a novel key player in the progression of renal disease. Periostin is de novo expressed focally by the injured kidney cells during the development of renal disease. In diverse cohorts of renal disease patients, the expression levels of periostin in the kidney and urine were highly correlated with the stage of the pathology and the decline of renal function. Subsequent studies in animal models demonstrated that periostin is centrally involved in mediating renal inflammation and fibrosis, contributing to the deterioration of renal structure and function. Genetic or pharmaco-genetic inhibition of periostin in animal models of renal disease was efficient in arresting the progression of the pathology. This review will summarize the recent advances on periostin in the field of kidney diseases and will discuss its utility of as a novel target of therapy for chronic kidney disease. PMID- 28884335 TI - Association between objective signs and subjective symptoms of dry eye disease in patients with systemic sclerosis. AB - The aim of this study was to evaluate the association between clinical signs and symptoms of dry eye disease (DED) in patients with systemic sclerosis (SSc). This cross-sectional observational study included 19 SSc patients and 19 normal subjects with no ocular symptoms or ocular surface disorders. Clinical parameters included tear film break-up time (tBUT), Schirmer I, lissamine green (LG) dye, and tear film osmolarity tests, tear production, and tear secretion flow. For assessment of the dry eye symptoms, the Ocular Surface Disease Index (OSDI) questionnaire was administered to all patients. The following mean values were found in SSc patients: OSDI 33.6 +/- 19.86; osmolarity of the tear fluid 310.8 mOsmol/l +/- 14.47; tBUT time 5.158 +/- 2.328 s; Schirmer I test 5.395 mm/5 min; LG grading score 2.026 +/- 0.8893; collected tear fluid volume 6.397 +/- 2.761 ul. The calculated average tear velocity was 4.654 +/- 1.963 ul/min. A significant correlation was found between the OSDI as a subjective parameter and disease duration. Early recognition of dry eye symptoms, a possible extra intestinal manifestation of SSc, should be included in the check up of the disease to reduce ocular complications. The objective tear functional tests were strongly influenced by individual factors like age and disease duration. PMID- 28884336 TI - The effects of constraining vision and eye movements on whole-body coordination during standing turns. AB - Turning the body towards a new direction is normally achieved via a top-down synergy whereby gaze (eye direction in space) leads the upper body segments, which in turn lead the feet. These anticipatory eye movements are observable even in darkness and constraining the initial eye movements modifies the stereotyped top-down reorientation sequence. Our aim was to elucidate the relative contributions of vision and eye movements to whole-body coordination during large standing turns by observing the effects of separately removing visual information or suppressing eye movements throughout the turn. We predicted that constraining eye movements would modify the steering synergy, whereas removing vision would have little effect. We found that preventing eye movements modified both timing and spatial characteristics of axial segment and feet rotation. When gaze was fixed, gait initiation, but not axial segment rotation, was delayed in comparison to both full vision and no vision turns. When eye movements were prevented, the predictable relationship between the extent head rotation led the body and peak head angular velocity was abolished suggesting that anticipatory head movements normally subserve gaze behaviour. In addition, stepping frequency significantly reduced during the gaze fixation condition but not during the no-vision condition, suggesting that oculomotor control is linked to stepping behaviour. PMID- 28884338 TI - Reply to "a Rare Complication of Bariatric Surgery: Retrograde Intussusception". PMID- 28884340 TI - Assessing Effects of Preoperative Anemia on Adverse Outcomes After Coronary Surgery. PMID- 28884337 TI - The multifaceted role of periostin in priming the tumor microenvironments for tumor progression. AB - Tumor microenvironment consists of tumor cells, stromal cells, extracellular matrix and a plethora of soluble components. The complex array of interactions between tumor cells and their surrounding tumor microenvironments contribute to the determination of the fate of tumor cells during tumorigenesis and metastasis. Matricellular protein periostin is generally absent in most adult tissues but is highly expressed in tumor microenvironments. Current evidence reveals that periostin plays a critical role in establishing and remodeling tumor microenvironments such as the metastatic niche, cancer stem cell niche, perivascular niche, pre-metastatic niche, fibrotic microenvironment and bone marrow microenvironment. Here, we summarize the current knowledge of the multifaceted role of periostin in the tumor microenvironments. PMID- 28884339 TI - Altered expression of circadian clock genes in polyglandular autoimmune syndrome type III. AB - PURPOSE: Circadian timing system is a highly conserved, ubiquitous molecular "clock" which creates internal circadian rhythmicity. Dysregulation of clock genes expression is associated with various diseases including immune dysregulation. In this study we investigated the circadian pattern of Clock related genes in patients with polyglandular autoimmune syndrome type III (PAS type III). METHODS: Nineteen patients diagnosed with PAS type III and 12 healthy controls were enrolled. mRNA and protein expression of Clock-related genes (CLOCK, BMAL1, ROR and Per-1,-2,-3), as well as the GR-a and the GILZ genes were determined by real-time quantitative PCR and western blot analysis from blood samples drawn at 8 pm and 8am. Serum cortisol and TSH, as well as plasma ACTH, were measured by chemiluminescence. RESULTS: There were no statistical significant differences in the metabolic profile, cortisol, ACTH and TSH levels between patients and controls. Patients with PAS type III expressed higher transcript levels of CLOCK, BMAL1 and Per-1 in the evening than in the morning (p = 0.03, p = 0.029, p = 0.013, respectively), while the ratios (Rpm/am) of GR-a, CLOCK, BMAL1, and Per-3 mRNA levels were statistically different between patients and controls. Cortisol circadian variation (Fpm/am) was positively correlated with GILZ mRNA circadian pattern (Rpm/am) in the patient group and with the GR-a mRNA (Rpm/am) in the control group. CONCLUCIONS: Our findings suggest that there is an aberrant circadian rhythm of Clock-related genes in patients with PAS type III. The disruption of the expression of 4 circadian Clock-related genes could indicate a possible association with the pathogenesis of the disease. PMID- 28884341 TI - [Current strategies in the treatment of ventricular tachycardia by catheter ablation : A review]. AB - The treatment of ventricular tachycardia has recently undergone relevant changes as certain interventional treatment options, such as radiofrequency catheter ablation, have gained in importance. Numerous current publications have demonstrated the advantages of catheter ablation compared to conventional therapy with antiarrhythmic drugs in terms of effectiveness and morbidity. Improving the ablation technique and identifying those patient collectives who are most likely to benefit from ablation are still the objectives of current research. The treatment of ventricular tachycardia in the setting of different cardiac and non cardiac conditions can be challenging and requires understanding of the current procedures and the recommendations for catheter ablation of ventricular tachycardia. This review succinctly summarizes the current research in this evolving field of interventional cardiology. PMID- 28884342 TI - Pre-operative guided imagery in female pelvic medicine and reconstructive surgery: a randomized trial. AB - INTRODUCTION AND HYPOTHESIS: The purpose was to determine if pre-operative guided imagery (GIM) would help women to feel more prepared, less anxious, and have higher satisfaction scores 6 weeks after surgery compared with routine care. METHODS: Eligible women planning to undergo pelvic floor surgery were enrolled and randomized. The GIM group received an institution-specific CD that uses GIM to detail day of surgery (DOS) events and expectations. Participants were asked to listen to the CD once daily during the week before surgery. At three time points (surgical consent visit, DOS, and 6-weeks post-operatively), we measured anxiety using the State and Trait Anxiety Inventory for Adults (STADI), in addition to preparedness for surgery and overall satisfaction (ten-point Likert scales). Data were analyzed in SPSS 23 using two-tailed t tests. RESULTS: A total of 38 out of 44 (86%) enrolled participants completed the study (GIM: 18, control: 20). The GIM self-reported compliance rate was 72%, with an average use of 4.8 times (range = 3-8 times). Women in the GIM group reported a significant increase from baseline in preparedness for surgery on both DOS and 6 weeks post operatively (7.32 +/- 1.81 vs 9.11 +/- 1.13, p = 0.001) and (7.32 +/- 1.81 vs 9.22 +/- 0.81, p = 0.001) respectively; a change that was not seen in the control group. Satisfaction was high in both the GIM and the control group (9.55 +/- 0.85 and 9.05 +/- 1.70, p = 0.263). In all patients, anxiety increased from baseline to DOS and dropped at 6 weeks post-operatively, and was not significantly different in the two groups. CONCLUSIONS: Guided imagery improved patient preparedness for pelvic floor surgery with an overnight stay on their DOS and 6 weeks post-operatively. PMID- 28884343 TI - Prognostic impact of isolated right ventricular dysfunction in sepsis and septic shock: an 8-year historical cohort study. AB - BACKGROUND: Echocardiographic myocardial dysfunction is reported commonly in sepsis and septic shock, but there are limited data on sepsis-related right ventricular dysfunction. This study sought to evaluate the association of right ventricular dysfunction with clinical outcomes in patients with severe sepsis and septic shock. METHODS: Historical cohort study of adult patients admitted to all intensive care units at the Mayo Clinic from January 1, 2007 through December 31, 2014 for severe sepsis and septic shock, who had an echocardiogram performed within 72 h of admission. Patients with prior heart failure, cor-pulmonale, pulmonary hypertension and valvular disease were excluded. Right ventricular dysfunction was defined by the American Society of Echocardiography criteria. Outcomes included 1-year survival, in-hospital mortality and length of stay. RESULTS: Right ventricular dysfunction was present in 214 (55%) of 388 patients who met the inclusion criteria-isolated right ventricular dysfunction was seen in 100 (47%) and combined right and left ventricular dysfunction in 114 (53%). The baseline characteristics were similar between cohorts except for the higher mechanical ventilation use in patients with isolated right ventricular dysfunction. Echocardiographic findings demonstrated lower right ventricular and tricuspid valve velocities in patients with right ventricular dysfunction and lower left ventricular ejection fraction and increased mitral E/e' ratios in patients with combined right and left ventricular dysfunction. After adjustment for age, comorbidity, illness severity, septic shock and use of mechanical ventilation, isolated right ventricular dysfunction was independently associated with worse 1-year survival-hazard ratio 1.6 [95% confidence interval 1.2-2.1; p = 0.002) in patients with sepsis and septic shock. CONCLUSIONS: Isolated right ventricular dysfunction is seen commonly in sepsis and septic shock and is associated with worse long-term survival. PMID- 28884344 TI - Coats' disease: not such a smooth ride. PMID- 28884345 TI - Karyotype reshufflings of Festuca pratensis * Lolium perenne hybrids. AB - Many different processes have an impact on the shape of plant karyotype. Recently, cytogenetic examination of Lolium species has revealed the occurrence of spontaneous fragile sites (FSs) associated with 35S rDNA regions. The FSs are defined as the chromosomal regions that are sensitive to forming gaps or breaks on chromosomes. The shape of karyotype can also be determined by interstitial telomeric sequences (ITSs), what was recognized for the first time in this paper in chromosomes of Festuca pratensis * Lolium perenne hybrids. Both FSs and ITSs can contribute to genome instabilities and chromosome rearrangements. To evaluate whether these cytogenetic phenomena have an impact on karyotype reshuffling observed in Festuca * Lolium hybrids, we examined F1 F. pratensis * L. perenne plants and generated F2-F9 progeny by fluorescent in situ hybridization (FISH) using rDNA sequences, telomere and centromere probes, as well as by genomic in situ hybridization (GISH). Analyses using a combination of FISH and GISH revealed that intergenomic rearrangements did not correspond to FSs but overlapped with ITSs for several analyzed genotypes. It suggests that internal telomeric repeats can affect the shape of F. pratensis * L. perenne karyotypes. However, other factors that are involved in rearrangements and have a more crucial impact could exist, but they are still unknown. PMID- 28884346 TI - Quality of randomized controlled trials published in the International Urogynecology Journal 2007-2016. AB - INTRODUCTION AND HYPOTHESIS: Randomized controlled trials (RCTs) provide the best quality clinical evidence. The aim of this study was to assess the quality of RCTs published by the International Urogynecology Journal (IUJ) in 2007-2016. METHODS: RCTs in original articles were extracted from PubMed and IUJ homepage. Change in RCT quality over time was assessed with Jadad and van Tulder scales and Cochrane Collaboration's risk of bias tool (CCRBT). Jadad scores of 3-5 or van Tulder scores of >5 indicated high-quality RCTs. The effect on RCT quality of including funding source and institutional review board (IRB) approval statements and describing the intervention was assessed. In addition, changes in RCT topics over time were assessed. RESULTS: Annual RCT frequencies did not change significantly (6.7-15.7%): 36.1% and 25.7% described blinding and allocation concealment, respectively. Both tended to increase between 2013 and 2016, particularly 2013 and 2014. Funding statement inclusion (39.1% overall) and intervention description (78.2% overall) tended to increase steadily. IRB statement inclusion (60.4% overall) increased significantly (p < 0.01). Jadad scores and van Tulder rose significantly until 2014 (p < 0.01). Frequencies of high-quality RCTs tended to rise. CCRBT indicated that RCTs with a low risk of bias tended to increase until 2014. However, from 2015, Jadad scores, van Tulder, and CCRBT the low risk tended to decreased. RCTs with funding and IRB approval statements had higher Jadad and van Tulder scores than unfunded RCTs (p < 0.01 and p < 0.01, respectively). Intervention description did not associate with better quality. CONCLUSIONS: RCT quality improved over time, but a dip in quality was observed in 2015-2016 because of decreased blinding and allocation concealment. PMID- 28884347 TI - Effects of levosimendan for perioperative cardiovascular dysfunction in patients receiving cardiac surgery: a meta-analysis with trial sequential analysis. PMID- 28884348 TI - Extravesical robotic ureteral reimplantation for ureterovaginal fistula. AB - INTRODUCTION: We present a video describing the technical considerations for performing an extravesical robotic ureteral reimplantation. METHODS: A 55-year old woman presented with urinary incontinence secondary to a ureterovaginal fistula after robotic-assisted hysterectomy. After failure of more conservative measures, she proceeded to a robotic ureteral reimplantation. Following port placement, the ureter is identified at the level of the iliac vessels and dissected circumferentially. The ureter is dissected free to the level of the ureterovaginal fistula, transected, and the distal remnant ligated. The ureter is spatulated, a cystotomy created, and a running anastomosis with mucosa-to-mucosa apposition performed over a stent. Care is taken to ensure it is tension free. The integrity of the anastomosis is tested with retrograde filling of the bladder. Postoperatively, a drainage catheter is left to allow for adequate healing. Follow-up imaging is performed to ensure a patent anastomosis. RESULTS: The patient had an uncomplicated postoperative course. A cystogram showed adequate healing at 10 days, and the stent was removed at 6 weeks. A follow-up renal ultrasound 6 weeks later showed no hydronephrosis. CONCLUSIONS: Extravesical robotic ureteral reimplantation is a useful technique for managing ureterovaginal fistula; here we highlight pertinent technical considerations. PMID- 28884349 TI - Functional and morphological recovery of solitary kidneys after drainage. Double J stent placement vs emergency ureteroscopy: which one is reasonable? AB - The purpose of the study was to evaluate the functional and morphological recovery of solitary kidneys following the relief of obstruction by two different approaches. Data of 65 adult patients with acute renal failure in obstructed solitary kidney were evaluated. Depending on the type of emergent decompression procedure while 34 patients were treated with a double J stent placement only 31 patients underwent ureteroscopic lithotripsy with double J stent placement. Following these procedures, in addition to the amount of excreted urine during the first 24 h, changes in the serum creatinine levels and the degree of hydronephrosis were noted and evaluated during the first week of follow-up after intervention. Evaluation of the urine output values during the first 24-h period revealed a statistically significant difference in favour of ureteroscopic lithotripsy. Serum creatinine levels in terms of the mean change in serum creatinine values and also percentage of the changes revealed no statistically significant change between two groups. Comparative evaluation of the change in the degree of hydronephrosis between baseline and post-procedural seventh day values revealed a statistically significant decrease in favour of ureteroscopic lithotripsy. Lastly, there was a statistically insignificant but meaningful difference with respect to the percent of change in the degree of hydronephrosis between two group of cases. Although temporary decompression of the obstructed solitary kidney by placing a double J stent may relieve the obstruction to a certain extent; emergent ureteroscopic lithotripsy could be applied as a reasonable alternative where adequate experience and technical availability are present. PMID- 28884350 TI - Simple and effective: transvaginal vesico-vaginal fistula repair with a modified Latzko technique. AB - INTRODUCTION AND HYPOTHESIS: The incidence of vesico-vaginal fistulas after hysterectomies for benign indications in developed countries is less than one percent. The objective of this video is to demonstrate an easy-to-follow, step-by step approach to repairing a small, uncomplicated vesico-vaginal fistula transvaginally using a modified Latzko technique. METHODS: In this video, we present a case of a 46-year-old woman who developed a simple, uncomplicated vesico-vaginal fistula after a total abdominal hysterectomy. To correct her fistula, we used a modified Latzko technique, which is a transvaginal approach to vesico-vaginal fistula repair that involves mobilizing the vaginal mucosa around the fistula and then closing the pubo-vesical fascia and vaginal mucosa in layers. RESULTS: The patient had successful surgical correction of her vesico vaginal fistula without recurrence of the fistula. CONCLUSIONS: For small, uncomplicated vesico-vaginal fistulas, a transvaginal approach has an equivalent success rate to that of other approaches with less invasiveness and faster recovery times. Therefore, it is reasonable to use a modified Latzko technique to help restore the quality of life to women affected by small, uncomplicated vesico vaginal fistulas. PMID- 28884351 TI - Tube Thoracostomy Complications: More to Learn: Reply. PMID- 28884352 TI - Risk Factors for Knee Injury in Golf: A Systematic Review. AB - BACKGROUND: Golf is commonly considered a low-impact sport that carries little risk of injury to the knee and is generally allowed following total knee arthroplasty (TKA). Kinematic and kinetic studies of the golf swing have reported results relevant to the knee, but consensus as to the loads experienced during a swing and how the biomechanics of an individual's technique may expose the knee to risk of injury is lacking. OBJECTIVES: Our objective was to establish (1) the prevalence of knee injury resulting from participation in golf and (2) the risk factors for knee injury from a biomechanical perspective, based on an improved understanding of the internal loading conditions and kinematics that occur in the knee from the time of addressing the ball to the end of the follow-through. METHODS: A systematic literature search was conducted to determine the injury rate, kinematic patterns, loading, and muscle activity of the knee during golf. RESULTS: A knee injury prevalence of 3-18% was established among both professional and amateur players, with no clear dependence on skill level or sex; however, older players appear at greater risk of injury. Studies reporting kinematics indicate that the lead knee is exposed to a complex series of motions involving rapid extension and large magnitudes of tibial internal rotation, conditions that may pose risks to the structures of a natural knee or TKA. To date, the loads experienced by the lead knee during a golf swing have been reported inconsistently in the literature. Compressive loads ranging from 100 to 440% bodyweight have been calculated and measured using methods including inverse dynamics analysis and instrumented knee implants. Additionally, the magnitude of loading appears to be independent of the club used. CONCLUSIONS: This review is the first to highlight the lack of consensus regarding knee loading during the golf swing and the associated risks of injury. Results from the literature suggest the lead knee is subject to a higher magnitude of stress and more demanding motions than the trail knee. Therefore, recommendations regarding return to golf following knee injury or surgical intervention should carefully consider the laterality of the injury. PMID- 28884353 TI - A prospective longitudinal investigation of the (dis)continuity of mental health difficulties between mid- to late-childhood and the predictive role of familial factors. AB - Understanding individual variation in the continuity of youth mental health difficulties is critical for identifying the factors that promote recovery or chronicity. This study establishes the proportion of children showing psychopathology at 9 years, whose pathology had either remitted or persisted at 13. It describes the socio-demographic and clinical profiles of these groups, and examines the factors in 9-year-olds' familial environments that predict longitudinal remission vs. persistence of psychopathology. The study utilised data from a prospective longitudinal study of 8568 Irish children. Child psychopathology was assessed using the Strengths and Difficulties Questionnaire (SDQ). Analysis established the rates of continuity of SDQ classifications between 9 and 13 years. Analysis also investigated the familial factors that predicted the remission vs. persistence of psychopathological symptoms, controlling for socio-demographic and child factors. Average SDQ scores improved between the ages of 9 and 13, F(1, 7292) = 276.52, p < 0.001, [Formula: see text] = 0.04. Of children classified Abnormal aged 9, 41.1% remained so classified at 13, 21.4% were reclassified Borderline, and 37.6% Normal. Demographic and child risk factors for persistence of pathology were maleness (beta = -1.00, p = 0.001, CI = 0.20-0.67), one-carer households (beta = -0.71, p = 0.04, CI = 0.25-0.97), poor physical health (beta = -0.64, p = 0.03, CI = 0.30-0.92), and low cognitive ability (beta = 0.61, p = 0.002, CI = 1.26-2.70). Controlling for these factors, the only familial variable at 9 years that predicted subsequent pathological persistence was caregiver depression (beta = -0.07, p = 0.03, CI = 0.87-0.99). The analysis highlights substantial rates of psychopathological discontinuity in a community sample and identifies the children most at risk of chronic mental health problems. These results will inform the targeting of early interventions and distribution of clinical resources. PMID- 28884354 TI - Synthetic biology for manufacturing chemicals: constraints drive the use of non conventional microbial platforms. AB - Genetically modified microbes have had much industrial success producing protein based products (such as antibodies and enzymes). However, engineering microbial workhorses for biomanufacturing of commodity compounds remains challenging. First, microbes cannot afford burdens with both overexpression of multiple enzymes and metabolite drainage for product synthesis. Second, synthetic circuits and introduced heterologous pathways are not yet as "robust and reliable" as native pathways due to hosts' innate regulations, especially under suboptimal fermentation conditions. Third, engineered enzymes may lack channeling capabilities for cascade-like transport of metabolites to overcome diffusion barriers or to avoid intermediate toxicity in the cytoplasmic environment. Fourth, moving engineered hosts from laboratory to industry is unreliable because genetic mutations and non-genetic cell-to-cell variations impair the large-scale fermentation outcomes. Therefore, synthetic biology strains often have unsatisfactory industrial performance (titer/yield/productivity). To overcome these problems, many different species are being explored for their metabolic strengths that can be leveraged to synthesize specific compounds. Here, we provide examples of non-conventional and genetically amenable species for industrial manufacturing, including the following: Corynebacterium glutamicum for its TCA cycle-derived biosynthesis, Yarrowia lipolytica for its biosynthesis of fatty acids and carotenoids, cyanobacteria for photosynthetic production from its sugar phosphate pathways, and Rhodococcus for its ability to biotransform recalcitrant feedstock. Finally, we discuss emerging technologies (e.g., genome to-phenome mapping, single cell methods, and knowledge engineering) that may facilitate the development of novel cell factories. PMID- 28884355 TI - Influenza-associated thrombotic microangiopathies. AB - Thrombotic microangiopathy (TMA) refers to phenotypically similar disorders, including hemolytic uremic syndromes (HUS) and thrombotic thrombocytopenic purpura (TTP). This review explores the role of the influenza virus as trigger of HUS or TTP. We conducted a literature survey in PubMed and Google Scholar using HUS, TTP, TMA, and influenza as keywords, and extracted and analyzed reported epidemiological and clinical data. We identified 25 cases of influenza-associated TMA. Five additional cases were linked to influenza vaccination and analyzed separately. Influenza A was found in 83%, 10 out of 25 during the 2009 A(H1N1) pandemic. Two patients had bona fide TTP with ADAMTS13 activity <10%. Median age was 15 years (range 0.5-68 years), two thirds were male. Oligoanuria was documented in 81% and neurological involvement in 40% of patients. Serum C3 was reduced in 5 out of 14 patients (36%); Coombs test was negative in 7 out of 7 and elevated fibrin/fibrinogen degradation products were documented in 6 out of 8 patients. Pathogenic complement gene mutations were found in 7 out of 8 patients tested (C3, MCP, or MCP combined with CFB or clusterin). Twenty out of 24 patients recovered completely, but 3 died (12%). Ten of the surviving patients underwent plasma exchange (PLEX) therapy, 5 plasma infusions. Influenza-mediated HUS or TTP is rare. A sizable proportion of tested patients demonstrated mutations associated with alternative pathway of complement dysregulation that was uncovered by this infection. Further research is warranted targeting the roles of viral neuraminidase, enhanced virus-induced complement activation and/or ADAMTS13 antibodies, and rational treatment approaches. PMID- 28884357 TI - Estimation of HbA1c in hospitalized patients with bronchial asthma. PMID- 28884356 TI - Diagnostic value of MRI-based 3D texture analysis for tissue characterisation and discrimination of low-grade chondrosarcoma from enchondroma: a pilot study. AB - OBJECTIVES: To explore the diagnostic value of MRI-based 3D texture analysis to identify texture features that can be used for discrimination of low-grade chondrosarcoma from enchondroma. METHODS: Eleven patients with low-grade chondrosarcoma and 11 patients with enchondroma were retrospectively evaluated. Texture analysis was performed using mint Lesion: Kurtosis, entropy, skewness, mean of positive pixels (MPP) and uniformity of positive pixel distribution (UPP) were obtained in four MRI sequences and correlated with histopathology. The Mann Whitney U-test and receiver operating characteristic (ROC) analysis were performed to identify most discriminative texture features. Sensitivity, specificity, accuracy and optimal cut-off values were calculated. RESULTS: Significant differences were found in four of 20 texture parameters with regard to the different MRI sequences (p<0.01). The area under the ROC curve values to discriminate chondrosarcoma from enchondroma were 0.876 and 0.826 for kurtosis and skewness in contrast-enhanced T1 (ceT1w), respectively; in non-contrast T1, values were 0.851 and 0.822 for entropy and UPP, respectively. The highest discriminatory power had kurtosis in ceT1w with a cut-off >=3.15 to identify low grade chondrosarcoma (82 % sensitivity, 91 % specificity, accuracy 86 %). CONCLUSION: MRI-based 3D texture analysis might be able to discriminate low-grade chondrosarcoma from enchondroma by a variety of texture parameters. KEY POINTS: * MRI texture analysis may assist in differentiating low-grade chondrosarcoma from enchondroma. * Kurtosis in the contrast-enhanced T1w has the highest power of discrimination. * Tools provide insight into tumour characterisation as a non invasive imaging biomarker. PMID- 28884358 TI - Effective enhancement of resistance to Phytophthora infestans by overexpression of miR172a and b in Solanum lycopersicum. AB - MAIN CONCLUSION: Overexpression of miR172a and b in tomato ( Solanum lycopersicum ) Zaofen No. 2 increased resistance to Phytophthora infestans infection by suppressing of an AP2/ERF transcription factor. The miR172 family has been shown to participate in the growth phase transition, flowering time control, abiotic and biotic stresses by regulating the expression of a small group of AP2/ERF transcription factors. In this study, the precursors of miR172a and b were cloned from tomato, Solanum pimpinellifolium L3708. We used the degradome sequencing to determine the cleavage site of miR172 to a member of the AP2/ERF transcription factor family (Solyc11g072600.1.1). qRT-PCR results showed that the expression of AP2/ERF was negatively correlated with the expression of miR172 in S. pimpinellifolium L3708 infected with Phytophthora infestans. Overexpression of miR172a and b in S. lycopersicum Zaofen No. 2 conferred greater resistance to P. infestans infection, as evidenced by decreased disease index, lesion sizes, and P. infestans abundance. The SOD and POD play important roles in scavenging late massive ROS in plant-pathogen interaction. Malonaldehyde (MDA) is widely recognized as an indicator of lipid peroxidation. Membrane damage in plants can be estimated by measuring leakage of electrolytes, which is evaluated by determining relative electrolyte leakage (REL). Less H2O2 and O2-, higher activities of POD and SOD, less MDA content and REL, and higher chlorophyll content and photosynthetic rate were also shown in transgenic plants after inoculation with P. infestans. Our results constitute the first step towards further investigations into the biological function and molecular mechanism of miR172-mediated silencing of AP2/ERF transcription factors in S. lycopersicum-P. infestans interaction and provide a candidate gene for breeding to enhance biotic stress-resistance in S. lycopersicum. PMID- 28884359 TI - Development of a shear stress-free microfluidic gradient generator capable of quantitatively analyzing single-cell morphology. AB - Microfluidics, the science of engineering fluid streams at the micrometer scale, offers unique tools for creating and controlling gradients of soluble compounds. Gradient generation can be used to recreate complex physiological microenvironments, but is also useful for screening purposes. For example, in a single experiment, adherent cells can be exposed to a range of concentrations of the compound of interest, enabling high-content analysis of cell behaviour and enhancing throughput. In this study, we present the development of a microfluidic screening platform where, by means of diffusion, gradients of soluble compounds can be generated and sustained. This platform enables the culture of adherent cells under shear stress-free conditions, and their exposure to a soluble compound in a concentration gradient-wise manner. The platform consists of five serial cell culture chambers, all coupled to two lateral fluid supply channels that are used for gradient generation through a source-sink mechanism. Furthermore, an additional inlet and outlet are used for cell seeding inside the chambers. Finite element modeling was used for the optimization of the design of the platform and for validation of the dynamics of gradient generation. Then, as a proof-of-concept, human osteosarcoma MG-63 cells were cultured inside the platform and exposed to a gradient of Cytochalasin D, an actin polymerization inhibitor. This set-up allowed us to analyze cell morphological changes over time, including cell area and eccentricity measurements, as a function of Cytochalasin D concentration by using fluorescence image-based cytometry. PMID- 28884360 TI - Calcium and zinc decrease intracellular iron by decreasing transport during iron repletion in an in vitro model. AB - PURPOSE: Iron is an essential micronutrient that participates in a number of vital reactions and its absorption may be altered by various nutritional factors such as other micronutrients. Our hypothesis is that iron absorption is decreased because of the interactions with zinc and calcium. We evaluated the interaction between calcium and zinc on iron uptake and transport, intracellular Fe and Zn levels and mRNA expression of DMT1, ferroportin, Zip4 and ZnT1 in an in vitro model. METHODS: Caco-2 cells were cultivated with 1 mM Ca; 10 or 30 uM Zn and/or 10, 20 or 30 uM Fe for 24 h. RESULTS: Intracellular Fe decreased in cells incubated with 30 uM Zn or with the mix Ca/10 uM Zn/Fe. Zn mostly increased under Ca, Zn and Fe treatment. DMT1 mRNA expression decreased when intracellular Fe increased. Ferroportin expression displayed no change in cells cultured with different Fe concentrations. The mix of Ca, Zn and Fe increased DMT1 and ferroportin expression mainly under high Zn concentration. Zip4 expression was mostly augmented by Ca and Fe; however, ZnT1 showed no change in all conditions studied. Fe uptake was higher in all the conditions studied compared to control cells; however, Fe transport increased only in cells incubated with Fe alone. In all the other conditions, Fe transport was lower than that in control cells. CONCLUSIONS: The present findings suggest that Ca and Zn interfere with iron metabolism. This interference is through an increase in ferroportin activity, which results in a diminished net iron absorption. PMID- 28884362 TI - Erratum to: Applications of the BLEND Software to Crystallographic Data from Membrane Proteins. PMID- 28884361 TI - Importance of glomerular filtration rate change as surrogate endpoint for the future incidence of end-stage renal disease in general Japanese population: community-based cohort study. AB - BACKGROUND: Because of the necessity for extended period and large costs until the event occurs, surrogate endpoints are indispensable for implementation of clinical studies to improve chronic kidney disease (CKD) patients' prognosis. METHODS: Subjects with serum creatinine level for a baseline period over 1-3 years were enrolled (n = 69,238) in this community-based prospective cohort study in Okinawa, Japan, and followed up for 15 years. The endpoint was end-stage renal disease (ESRD). The percent of estimated glomerular filtration rate (%eGFR) change was calculated on the basis of the baseline period. RESULTS: Subjects had a mean +/- SD age, 55.59 +/- 14.69 years; eGFR, 80.15 +/- 21.15 ml/min/1.73 m2. Among the subjects recruited, 15.81% had a low eGFR (<60 ml/min/1.73 m2) and 36.1/100,000 person years developed ESRD. Cox proportional hazards models adjusted for baseline characteristics showed that the risk of ESRD tended to be high with high rates of decrease in %eGFR changes over 2 or 3 years in the high- and low-eGFR groups. The specificities and positive predictive values for ESRD based on a cutoff value of %eGFR change of less than -30% over 2 or 3 years were high in the high- and low-eGFR groups. CONCLUSIONS: %eGFR change tends to be associated with the risk of ESRD. %eGFR change of less than -30% over 2 or 3 years can be a candidate surrogate endpoint for ESRD in the general Japanese population. PMID- 28884363 TI - Surgical considerations when reporting MRI studies of soft tissue sarcoma of the limbs. AB - Soft tissue sarcomas (STS) are rare tumours that require prompt diagnosis and treatment at a specialist centre. Magnetic resonance imaging (MRI) has become the modality of choice for identification, characterisation, biopsy planning and staging of soft tissue masses. MRI enables both the operating surgeon and patient to be optimally prepared prior to surgery for the likelihood of margin-negative resection and to anticipate possible sacrifice of adjacent structures and consequent loss of function. The aim of this review is to aid the radiologist in performing and reporting MRI studies of soft tissue sarcomas, with particular reference to the requirements of the surgical oncologist. PMID- 28884364 TI - A new chemical complex can rapidly concentrate lentivirus and significantly enhance gene transduction. AB - In this study, we developed a new purification method using chondroitin sulfate C (CSC) and protamine sulfate (PS) to concentrate lentivirus. To evaluate the efficiency of this new method, we compared it with several previously described purification protocols, including virus concentrated by ultracentrifugation (Ultra), precipitated by polyethylene glycol (PEG), and sedimented by CSC combined with polybrene (PB). After using the different methods to purify and concentrate equivalent amounts of lentivirus supernatant, the virus pellets precipitated by the different methods were resuspended using the equivalent volumes of DMEM. Subsequently, 10 MUl of each lentivirus stock carrying EGFP gene was used to transduce two types of cells, human embryonic kidney 293T (HEK293T) cells and mouse mesenchymal stem cells (mMSC). It was obvious that HEK293T and mMSC appeared much intensiver green fluorescence through virus transduction from PS method than from other methods. To quantitate the transduction efficiency of the viruses, we examined virus titer in the cells after transduction using a real time PCR-based analysis. Accordingly, we verified that PS precipitation could generate virus with a higher titer (4.39 * 108 IU/ml) than PB (2.43 * 108 IU/ml), Ultra (1.16 * 108 IU/ml), and PEG (0.56 * 108 IU/ml) in HEK293T cells. As for HEK293T cells in mMSC, the PS method also generated virus with a higher titer (4.66 * 108 IU/ml) than the Ultra method (2.36 * 108 IU/ml), and a much higher titer than those of the other chemical-based precipitation methods using PB (4.82 * 106 IU/ml) and PEG (8.98 * 104 IU/ml). Furthermore, the HEK293T cells and mMSC transduced by PS(1X)-virus appeared to have higher cell growth ratios, respectively, than the HEK293T cells and mMSC transduced by lentivirus using the other methods. We conclude that our new method for purifying lentivirus is cost effective, time-saving, and highly efficient, and that lentivirus purification by this means could possibly be used to transduce a variety of cells, including stem cells. PMID- 28884365 TI - Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies. AB - Tumors are highly heterogeneous tissues where malignant cells are surrounded by and interact with a complex tumor microenvironment (TME), notably composed of a wide variety of immune cells, as well as vessels and fibroblasts. As the dialectical influence between tumor cells and their TME is known to be clinically crucial, we need tools that allow us to study the cellular composition of the microenvironment. In this focused research review, we report MCP-counter, a methodology based on transcriptomic markers that assesses the proportion of several immune and stromal cell populations in the TME from transcriptomic data, and we highlight how it can provide a way to decipher the complex mechanisms at play in tumors. In several malignancies, MCP-counter scores have been used to show various prognostic impacts of the TME, which we also show to be linked with the mutational burden of tumors. We also compared established molecular classifications of colorectal cancer and clear-cell renal cell carcinoma with the output of MCP-counter, and show that molecular subgroups have different TME profiles, and that these profiles are consistent within a given subgroup. Finally, we provide insights as to how knowing the TME composition may shape patient care in the near future. PMID- 28884366 TI - Weather conditions: a neglected factor in human salivary cortisol research? AB - There is ample evidence that environmental stressors such as extreme weather conditions affect animal behavior and that this process is in part mediated through the elevated activity of the hypothalamic pituitary adrenal axis which results in an increase in cortisol secretion. This relationship has not been extensively researched in humans, and weather conditions have not been analyzed as a potential confounder in human studies of stress. Consequently, the goal of this paper was to assess the relationship between salivary cortisol and weather conditions in the course of everyday life and to test a possible moderating effect of two weather-related variables, the climate region and timing of exposure to outdoors conditions. The sample consisted of 903 secondary school students aged 18 to 21 years from Mediterranean and Continental regions. Cortisol from saliva was sampled in naturalistic settings at three time points over the course of a single day. We found that weather conditions are related to salivary cortisol concentration and that this relationship may be moderated by both the specific climate and the anticipation of immediate exposure to outdoors conditions. Unpleasant weather conditions are predictive for the level of salivary cortisol, but only among individuals who anticipate being exposed to it in the immediate future (e.g., in students attending school in the morning shift). We also demonstrated that isolated weather conditions or their patterns may be relevant in one climate area (e.g., Continental) while less relevant in the other (e.g., Mediterranean). Results of this study draw attention to the importance of controlling weather conditions in human salivary cortisol research. PMID- 28884367 TI - Pelvic floor muscle activity during impact activities in continent and incontinent women: a systematic review. AB - INTRODUCTION AND HYPOTHESIS: Investigating the activity of the pelvic floor muscles (PFMs) in women during impact activities such as jumping, running or coughing may elucidate different aspects of PFM activation and therefore clarify the pathophysiology of stress urinary incontinence (SUI). A systematic review (PROSPERO 2016:CRD42016035624) was conducted to summarize current evidence on PFM activity during impact activities in both continent and incontinent women. METHODS: PubMed, EMBASE, Cochrane, and SPORTDiscus databases were systematically searched for studies published up to December 2016. The PICO approach (patient, intervention, comparison, outcome) was used to construct the search queries. Original studies were included that investigated PFM activity during impact activities if they included terms related to muscle activity and measurement methods, test positions, activities performed and continence status. Two reviewers screened titles and abstracts independently to ascertain if the included studies fulfilled the inclusion criteria, and extracted data on outcome parameters. RESULTS: The search revealed 28 studies that fulfilled the inclusion criteria, of which 26 were cross-sectional studies. They used different electromyography measurement methods, test activities, test positions, and comparisons with other structures. Ten studies compared continent and incontinent women. The timing of PFM activity in relation to the activity of other trunk muscles seems to be a crucial factor in maintaining continence. Women with SUI have delayed PFM activity. CONCLUSIONS: The findings of this systematic review suggest that impact activities causing involuntary and reflex PFM activity should be the subject of further study. This may help guide clinical studies to improve our understanding of how the PFMs react during impact activities and to determine best practices that can be included in rehabilitation programmes. PMID- 28884368 TI - Anatomical and Optical Properties of Atrial Tissue: Search for a Suitable Animal Model. AB - The purpose of this study was to evaluate structural and optical properties of atrial tissue from common animal models and to compare it with human atria. We aimed to do this in a format that will be useful for development of better ablation tools and/or new means for visualizing atrial lesions. Human atrial tissue from clinically relevant age group was compared and contrasted with atrial tissue of large animal models commonly available for research purposes. These included pigs, sheep, dogs and cows. The presented data include area measurements of smooth atrial surface available for ablation and estimates of thickness of collagen and muscle for five different species. We also described methods to quantify presence of collagen and overall thickness of atrial wall. Provided information enables placement of atrial lesions to locations with clinically relevant atrial wall thickness and macroscopic structure ultimately helping investigators to develop better ablation and imaging tools. It also highlights the impact of collagen thickness on optical measurements and lesion visualization. PMID- 28884369 TI - Carbon Nanotube Fiber Ionization Mass Spectrometry: A Fundamental Study of a Multi-Walled Carbon Nanotube Functionalized Corona Discharge Pin for Polycyclic Aromatic Hydrocarbons Analysis. AB - Mass spectrometry continues to tackle many complicated tasks, and ongoing research seeks to simplify its instrumentation as well as sampling. The desorption electrospray ionization (DESI) source was the first ambient ionization source to function without extensive gas requirements and chromatography. Electrospray techniques generally have low efficiency for ionization of nonpolar analytes and some researchers have resorted to methods such as direct analysis in real time (DART) or desorption atmospheric pressure chemical ionization (DAPCI) for their analysis. In this work, a carbon nanotube fiber ionization (nanoCFI) source was developed and was found to be capable of solid phase microextraction (SPME) of nonpolar analytes as well as ionization and sampling similar to that of direct probe atmospheric pressure chemical ionization (DP-APCI). Conductivity and adsorption were maintained by utilizing a corona pin functionalized with a multi walled carbon nanotube (MWCNT) thread. Quantitative work with the nanoCFI source with a designed corona discharge pin insert demonstrated linearity up to 0.97 (R2) of three target PAHs with phenanthrene internal standard. Graphical Abstract ?. PMID- 28884370 TI - Diagnosis of gastrogastric fistula on computed tomography: a quantitative approach. AB - OBJECTIVE: To determine if the attenuation of contrast material in the excluded stomach compared with the gastric pouch is helpful in diagnosing gastrogastric (GG) fistula. MATERIALS AND METHODS: In a retrospective study, 13 CT scans in 12 patients (age 43.2 +/- 9.2, 10 females) who had undergone Roux-en-Y gastric bypass and who had oral contrast in both the gastric pouch and excluded stomach were qualitatively and quantitatively evaluated for GG fistula by two radiologists, using upper GI series (UGI) as the gold standard. Quantitative analysis was performed by computing the relative attenuation (RA) ratio (HU in excluded stomach/HU in gastric pouch). Statistical analysis was performed to determine if the RA ratio values correlated with the UGI findings of GG fistula. RESULTS: 46.2% (6/13) of UGI studies demonstrated a GG fistula. Statistical analysis demonstrated a significant difference in RA ratio (P < 0.05) between the fistula group (1.12 +/- 0.29) and the reflux group (0.56 +/- 0.19). A receiver operating characteristic analysis identified an RA ratio of 0.8 that maximized sensitivity (100%), at the expense of specificity (78.6%), for diagnosing GG fistula. In contrast, the initial qualitative evaluation for GG fistula yielded a lower sensitivity (45.8%) and a higher specificity (89.2%). After taking RA ratios into account, radiologists' final conclusions achieved higher sensitivity (58.3%) and specificity (100%). CONCLUSION: The relative attenuation ratio of oral contrast in the excluded stomach versus the gastric pouch can be a reliable tool in differentiating GG fistula from oral contrast reflux up the biliopancreatic limb on CT. PMID- 28884372 TI - Anthropogenic Activities Induce Depletion in Microbial Communities at Urban Sites of the River Ganges. AB - The Ganges is the largest river of India, worshiped by Hindus with a belief that bathing in the river causes the remission of sins and is considered very pure. It is heavily polluted by the unrestricted human usage including ritual practices, urbanization, and industrialization. Such perturbations may subsequently influence the bacterial community composition and ecosystem functioning. Here, we applied targeted amplicon sequencing to determine the impact of spatial variation on the microbial community assemblage of the Ganga River. The river bacterial community demonstrates taxonomic variability across the sites with accumulation of Firmicutes (20.9%) Verrucomicrobia (6.09%), Actinobacteria (4.51%), and Synergistetes (1.16%), at rural site while Proteobacteria (49.4%) and Bacteroidetes (12.7%) predominate at urban sites. Furthermore, sites under study establish the unique taxonomic signature which could represent the impact of spatial variation on the microbial community assemblage. PMID- 28884371 TI - EGFR T790M mutation testing of non-small cell lung cancer tissue and blood samples artificially spiked with circulating cell-free tumor DNA: results of a round robin trial. AB - The European Commision (EC) recently approved osimertinib for the treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) harboring EGFR T790M mutations. Besides tissue-based testing, blood samples containing cell-free circulating tumor DNA (ctDNA) can be used to interrogate T790M status. Herein, we describe the conditions and results of a round robin trial (RRT) for T790M mutation testing in NSCLC tissue specimens and peripheral blood samples spiked with cell line DNA mimicking tumor-derived ctDNA. The underlying objectives of this two-staged external quality assessment (EQA) approach were (a) to evaluate the accuracy of T790M mutations testing across multiple centers and (b) to investigate if a liquid biopsy-based testing for T790M mutations in spiked blood samples is feasible in routine diagnostic. Based on a successfully completed internal phase I RRT, an open RRT for EGFR T790M mutation testing in tumor tissue and blood samples was initiated. In total, 48 pathology centers participated in the EQA. Of these, 47 (97.9%) centers submitted their analyses within the pre-defined time frame and 44 (tissue), respectively, 40 (plasma) successfully passed the test. The overall success rates in the RRT phase II were 91.7% (tissue) and 83.3% (blood), respectively. Thirty-eight out of 48 participants (79.2%) successfully passed both parts of the RRT. The RRT for blood-based EGFR testing initiated in Germany is, to the best of our knowledge, the first of his kind in Europe. In summary, our results demonstrate that blood based genotyping for EGFR resistance mutations can be successfully integrated in routine molecular diagnostics complementing the array of molecular methods already available at pathology centers in Germany. PMID- 28884373 TI - Prevalence of and factors associated with renal dysfunction in rheumatoid arthritis patients: a cross-sectional study in community hospitals. AB - This study was designed to determine the prevalence of renal dysfunction in rheumatoid arthritis (RA) patients and to identify factors associated with this complication. Between October 2014 and May 2015, we consecutively recruited RA patients at rheumatology sections of community hospitals in Japan. Each patient's absolute and body surface area (BSA)-indexed estimated glomerular filtration rate (eGFR) values were measured twice over a 3-month interval. Renal dysfunction was defined as absolute eGFR or BSA-indexed eGFR < 60. Albuminuria and hematuria were also recorded. Associations between renal dysfunction and possible risk factors were examined by multivariate logistic regression analyses. A total of 1908 outpatients with RA were included in this study. The prevalence of renal dysfunction based on absolute eGFR and BSA-indexed eGFR was 33.8 and 18.6%, respectively. Albuminuria was observed in 8.1% of this patient cohort, and the prevalence of hematuria was 7.5%. Advanced age (odds ratio [OR] 7.24, p < 0.001), female sex (OR 3.12, p < 0.001), hypertension (OR 2.22, p < 0.001), and obesity (OR 0.59, p < 0.001) were independently associated with the risk of absolute eGFR based renal dysfunction. Advanced age (OR 5.19, p < 0.001) and hypertension (OR 3.05, p < 0.001) also had associations with BSA-indexed eGFR-based renal dysfunction. RA duration, stages, severity, and cumulative steroid dose were considered significant risk factors in univariate analyses, but their associations were less potent after adjustment for other covariates. Renal dysfunction is relatively common in RA patients and is mainly associated with advanced age and hypertension but not with RA-related factors. PMID- 28884374 TI - "Eyeball test" of thermographic patterns for predicting a successful lateral infraclavicular block. AB - PURPOSE: Increased distal skin temperature can be used to predict the success of lateral infraclavicular (LIC) block. We hypothesized that an "eyeball test" of specific infrared thermographic patterns after LIC block could be used to determine block success. METHODS: In this observational study, five observers trained in four distinct thermographic patterns independently evaluated thermographic images of the hands of 40 patients at baseline and at one-minute intervals for 30 min after a LIC block. Sensitivity, specificity, and predictive values of a positive and a negative test were estimated to evaluate the validity of specific thermographic patterns for predicting a successful block. Sensory and motor block of the musculocutaneous, radial, ulnar, and median nerves defined block success. Fleiss' kappa statistics of multiple interobserver agreements were used to evaluate reliability. RESULTS: As a diagnostic test, the defined specific thermographic patterns of the hand predicted a successful block with increasing accuracy over the 30-min observation period. Block success was predicted with a sensitivity of 92.4% (95% confidence interval [CI], 86.8 to 96.2) and with a specificity of 84.0% (95% CI, 70.3 to 92.4) at min 30. The Fleiss' kappa for the five observers was 0.87 (95% CI, 0.77 to 0.96). CONCLUSION: We conclude that visual evaluation by an eyeball test of specific thermographic patterns of the blocked hands may be useful as a valid and reliable diagnostic test for predicting a successful LIC block. PMID- 28884375 TI - Patterns of Alcohol Intake of Pregnant and Lactating Women in Rural Western Australia. AB - Objectives Monitoring surveys and research outline a paucity of alcohol consumption data for women in the period of lactation, particularly in rural areas of developed countries. Identifying the drinking profile of ante- and postnatal women in this population will aid in the effective dissemination of public health interventions. This paper will present the first alcohol consumption data of pregnant and breastfeeding women living in rural Western Australia (WA). Methods A prospective cohort of 489 mothers and their infants were recruited between April 2010 and November 2011. All women regardless of their infant feeding method were followed up at 4, 10, 16, 26, 32, 40 and 52 weeks postpartum. Data were analysed to ascertain the prevalence and patterns of alcohol consumption during pregnancy and lactation. Results Approximately 20% of women consumed alcohol during pregnancy, with a predominance of women from older age groups and smokers. At 4, 6 and 12 months postpartum; 45.9%, 47.0% and 51.9% of breastfeeding mothers were consuming alcohol respectively. Conclusions for Practice There remains a considerable proportion of women who continue to drink during pregnancy. Although proven successful, public health campaigns now need to target women who are older and who smoke. Women are continuing to consume alcohol during the period of lactation, with the majority doing so at low levels. PMID- 28884376 TI - Environmental risk assessment of lead-zinc mining: a case study of Adudu metallogenic province, middle Benue Trough, Nigeria. AB - Assessment of the impacts of lead-zinc mining in Adudu-Imon metallogenic province was carried out. Reconnaissance and detailed field studies were done. Lithologies, stream sediments, farmland soils, mine tailings, artificial pond water, stream water, well water, and borehole water were collected and subjected to atomic absorption spectrometry (AAS) and X-ray fluorescence (XRF) analyses. Geochemical maps were generated using ArcGIS 10.1. Significant contamination with cadmium (Cd), iron (Fe), and lead (Pb) was recorded in the collected water samples. Virtually all collected soil samples were observed to be highly contaminated when compared with the European Union environmental policy standard. The discharge of mining effluents through farmlands to the Bakebu stream, which drains the area, further exposes the dwellers of this environment to the accumulation of potentially harmful metals (PHMs) in their bodies through the consumption of food crops, aquatic animals, and domestic uses of the water collected from the stream channels. The study revealed non-conformity of past mining operations in the Adudu-Imon province to existing mining laws in Nigeria. Inhabitants of this region should stop farming in the vicinity of the mines, fishing from the Bakebu stream channels should be discouraged, and domestic use of the water should be condemned, even as concerned government agencies put necessary mercenaries in place to ensure conformity of miners to standard mining regulations in Nigeria. PMID- 28884377 TI - IDH mutation status trumps the Pignatti risk score as a prognostic marker in low grade gliomas. AB - Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS). Mean age of patients was 45 years; 71% were classified as low-risk by the Pignatti system. IDH mutations were detected in 62%, p53 mutations in 17%, the 1p/19q codeletion in 46%, and MGMT methylation in 40% of patients. Survival analyses were performed in the 49 patients without contrast enhancement. In the univariate analysis, IDH mutations, the 1p/19q codeletion, and the combination of IDH mutations with the 1p/19q codeletion were associated with both longer PFS (P = 0.006, P = 0.037, and P = 0.003, respectively) and longer OS (P < 0.001, P = 0.02, and P < 0.001, respectively). The multivariate analysis identified absence of IDH mutations as a factor for greater risk of progression [hazard ratio (HR) = 3.1; P = 0.007]and death (HR = 6.4; P < 0.001). We suggest that IDH mutations may be more effective than the Pignatti score in discriminating low- and high-risk patients with LGG. PMID- 28884378 TI - Efficacy of topical tofacitinib in promoting hair growth in non-scarring alopecia: possible mechanism via VEGF induction. AB - Tofacitinib is a Janus kinase 3 (JAK3) inhibitor that promotes hair growth; however, the efficacy and mechanism of this effect are not yet understood. This study aimed to evaluate the efficacy and mechanism of topical tofacitinib on hair growth in mice. Eight-week-old male C57BL/6 mice were divided equally into four groups and treated topically with tofacitinib, minoxidil, or vehicle once daily for 21 days. Weekly photographs were taken to determine the area and rate of hair growth, and tissue samples were collected for histopathological evaluation. mRNA and protein expression of anagen-maintaining growth factors, including vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), were determined via RT-PCR and ELISA, respectively. Tofacitinib-treated mice exhibited more hair regrowth than either minoxidil-treated or control mice did between day 7 and 21 (P < 0.05). Topical tofacitinib also promoted more rapid hair growth rate than topical minoxidil or control did (P < 0.001). Histopathology showed a distinct increase in the number of hair follicles, mostly in the anagen phase, in the tofacitinib-treated group. Hair follicles in the minoxidil- and vehicle treated groups were more often classified as catagen and anagen. VEGF mRNA and protein expression in the tofacitinib-treated group was significantly greater than those in the other groups (P < 0.05). IGF-1 mRNA expression was not upregulated in tofacitinib-treated mice. Topical tofacitinib is effective in promoting hair growth, and the possible mechanism involves increased VEGF levels and lowered inflammation. This study will help develop a new therapeutic option for non-scarring alopecia. PMID- 28884380 TI - Role of calmodulin and calcineurin in regulating flagellar motility and wave polarity in Leishmania. AB - We have previously reported the involvement of cyclic AMP in regulating flagellar waveforms in Leishmania. Here, we investigated the roles of calcium, calmodulin, and calcineurin in flagellar motility regulation in L. donovani. Using high-speed videomicroscopy, we show that calcium-independent calmodulin and calcineurin activity is necessary for motility in Leishmania. Inhibition of calmodulin and calcineurin induced ciliary beats interrupting flagellar beating in both live (in vivo) and ATP-reactivated (in vitro) parasites. Our results indicate that signaling mediated by calmodulin and calcineurin operates antagonistically to cAMP signaling in regulating the waveforms of Leishmania flagellum. These two pathways are possibly involved in maintaining the balance between the two waveforms, essential for responding to environmental cues, survival, and infectivity. PMID- 28884379 TI - Genetic interaction of purinergic P2X7 receptor and ER-alpha polymorphisms in susceptibility to osteoporosis in Chinese postmenopausal women. AB - Osteoporosis (OP) is an increasing public health problem worldwide. Genetic factors are considered to be major contributors to the pathogenesis of OP. The aim of this study was to investigate the association of the purinergic P2X7 receptor (P2X7R) and estrogen receptor-alpha (ER-alpha) genes with OP risk, and the effect of the possible interaction between the two genes on predisposition to OP in Chinese postmenopausal women. A total of 596 subjects, including 350 OP patients and 246 controls, were recruited in this case-control study. Five functional single-nucleotide polymorphisms (SNPs) in the P2X7R gene (rs2393799, rs7958311, rs1718119, rs2230911, rs3751143) and two ER-alpha PvuII and XbaI polymorphisms were genotyped and analyzed. Single-gene variant analysis showed that the carriers of the CC genotype of P2X7R rs3751143 revealed an increased OP risk. Haplotype rs1718119G-rs2230911G-rs3751143C also appeared to be a significant 'risk' haplotype with OP. For the ER-alpha gene, no evidence of significant association of PvuII or XbaI polymorphism with OP risk was found. Moreover, there was a significant gene-gene interaction between P2X7R rs3751143 and ER-alpha PvuII; the cross-validation consistency was 10/10 and the testing accuracy was 0.5818 (P = 0.0107). A 1.67-fold-increased risk for OP was detected in individuals carrying the genotypes of AC or CC of rs3751143 and Pp or PP of PvuII compared to subjects with AA of rs3751143 and pp of PvuII. Our findings suggest an important association of the P2X7R rs3751143CC genotype and the rs1718119G-rs2230911G-rs3751143C haplotype with an increased OP risk. Also, the P2X7R rs3751143 and ER-alpha PvuII two-locus interaction confers a significantly high susceptibility to OP in Chinese postmenopausal women. PMID- 28884381 TI - Development of a Computer-Aided Differential Diagnosis System to Distinguish Between Usual Interstitial Pneumonia and Non-specific Interstitial Pneumonia Using Texture- and Shape-Based Hierarchical Classifiers on HRCT Images. AB - A computer-aided differential diagnosis (CADD) system that distinguishes between usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) using high-resolution computed tomography (HRCT) images was developed, and its results compared against the decision of a radiologist. Six local interstitial lung disease patterns in the images were determined, and 900 typical regions of interest were marked by an experienced radiologist. A support vector machine classifier was used to train and label the regions of interest of the lung parenchyma based on the texture and shape characteristics. Based on the regional classifications of the entire lung using HRCT, the distributions and extents of the six regional patterns were characterized through their CADD features. The disease division index of every area fraction combination and the asymmetric index between the left and right lungs were also evaluated. A second SVM classifier was employed to classify the UIP and NSIP, and features were selected through sequential-forward floating feature selection. For the evaluation, 54 HRCT images of UIP (n = 26) and NSIP (n = 28) patients clinically diagnosed by a pulmonologist were included and evaluated. The classification accuracy was measured based on a fivefold cross-validation with 20 repetitions using random shuffling. For comparison, thoracic radiologists assessed each case using HRCT images without clinical information or diagnosis. The accuracies of the radiologists' decisions were 75 and 87%. The accuracies of the CADD system using different features ranged from 70 to 81%. Finally, the accuracy of the proposed CADD system after sequential-forward feature selection was 91%. PMID- 28884382 TI - Therapy-free interval has prognostic value in patients with recurrent cervical cancer treated with chemotherapy following definitive concurrent chemoradiotherapy. AB - PURPOSE: Patients with cervical cancer recurrence after concurrent chemoradiotherapy (CCRT) who are not candidates for surgical resection or salvage radiotherapy have a dismal prognosis. The predictive factors for the effects of chemotherapy and prognostic factors in these patients were analyzed. METHODS: We collected data for patients with recurrent cervical cancer who were primarily treated with CCRT between 2000 and 2013. Among them, 57 patients treated with only systemic chemotherapy were analyzed for the overall survival (OS), the overall response rate (ORR), and prognostic factors. RESULTS: The median age was 47 years. Inside the irradiated field recurrence occurred in 24, outside in 20 and both in 13 patients. Time to recurrence after the CCRT (i.e., therapy-free interval; TFI) were <6 months in 11, 6-12 months in 15, >=12 months in 23 patients, and persistent disease in 8 patients. The median OS was 18 months and ORR was 15.7%. Those with a longer TFI showed a tendency for better ORR (p = 0.051) and those receiving a taxane-containing regimen showed significantly higher ORR (p = 0.0232). Multivariate analysis revealed a significant correlation between the median OS and TFI (HR = 4.688, 95% CI = 2.178-11.10, p < 0.0001) and chemotherapy response (HR = 20.08, 95% CI = 3.936-368.4, p < 0.0001). Furthermore, even in patients with stable disease, the median OS increased corresponding to the length of the TFI (p < 0.0001). CONCLUSIONS: TFI has predictive value for response to chemotherapy and prognosis of patients with recurrent cervical cancer after definitive CCRT. PMID- 28884383 TI - Phosphorus and nitrogen co-limitation of forest ground vegetation under elevated anthropogenic nitrogen deposition. AB - Plant growth in northern forest ecosystems is considered to be primarily nitrogen limited. Nitrogen deposition is predicted to change this towards co limitation/limitation by other nutrients (e.g., phosphorus), although evidence of such stoichiometric effects is scarce. We utilized two forest fertilization experiments in southern Sweden to analyze single and combined effects of nitrogen and phosphorus on the productivity, composition, and diversity of the ground vegetation. Our results indicate that the productivity of forest ground vegetation in southern Sweden is co-limited by nitrogen and phosphorus. Additionally, the combined effect of nitrogen and phosphorus on the productivity was larger than when applied solely. No effects on species richness of any of these two nutrients were observed when applied separately, while applied in combination, they increased species richness and changed species composition, mainly by promoting more mesotrophic species. All these effects, however, occurred only for the vascular plants and not for bryophytes. The tree layer in a forest has a profound impact on the productivity and diversity of the ground vegetation by competing for both light and nutrients. This was confirmed in our study where a combination of nitrogen and high tree basal area reduced cover of the ground vegetation compared to all the other treatments where basal area was lower after stand thinning. During the past decades, nitrogen deposition may have further increased this competition from the trees for phosphorus and gradually reduced ground vegetation diversity. Phosphorus limitation induced by nitrogen deposition may, thus, contribute to ongoing changes in forest ground vegetation. PMID- 28884384 TI - Study of ChiR function in Serratia marcescens and its application for improving 2,3-butanediol from crystal chitin. AB - Microbial utilization of chitin, a potential renewable biomass feedstock, is being pursued as a means of developing novel consolidated bioprocessing for the production of chemicals. Serratia marcescens is a gram-negative bacterium that is known for its chitinolytic capability and as a native 2,3-butanediol producer. In S. marcescens, ChiR has been suggested to be a positive regulator of chitinase production. In this study, we aim to understand the effect of ChiR in regulating nine chitinase-related genes in S. marcescens Db11 and demonstrate manipulation of chiR as a useful and efficient genetic target to enhance chitin utilization. First, a chiR overexpression (chiROE) strain and a chiR deletion (DeltachiR) strain were generated and characterized in terms of cellular growth, chitinase activity, and total secreted protein. Compared to the wild-type Db11 strain, the S. marcescens chiROE strain showed an increase in chitinase activity (2.14- to 6.31-fold increase). Increased transcriptional expression of chitinase-related genes was measured using real-time PCR, showing 2.12- to 10.93-fold increases. The S. marcescens DeltachiR strain showed decreases in chitinase activity (4.5- to 25-fold decrease), confirming ChiR's role as a positive regulator of chitinase expression. Finally, chiR overexpression was investigated as a means of increasing biochemical production (2,3-butanediol) from crystal chitin. The chiROE strain produced 1.13 +/- 0.08 g/L 2,3-butanediol from 2% crystal chitin, a 2.83-fold improvement from the wild-type strain, indicating ChiR is an important and useful genetic engineering target for enhancing chitin utilization in S. marcescens. PMID- 28884385 TI - Low frequency of polyps in colonic regions with diverticulosis. AB - PURPOSE: Conflicting evidence exists regarding any association between diverticulosis and adenomatous polyps. We evaluated the prevalence of polyps and cancer in colonic regions containing diverticula. METHODS: Six hundred consecutive colonoscopy reports from a single endoscopist were reviewed to determine prevalence and location of diverticulosis and polyps. Additionally, pathology reports of 88 colon cancer resection specimens were reviewed for the presence of diverticulosis, and compared with expected prevalence of diverticulosis in that colonic region based on the collected colonoscopy data. RESULTS: Overall, rates of detected polyps were comparable between patients with and without diverticulosis. However, analyzing the data by colonic segment containing diverticulosis, the prevalence of adenomatous polyps was reduced in regions of diverticulosis compared to the same colonic segment unaffected by diverticulosis (7 vs. 17% for rectosigmoid (p = 0.005); 5 vs. 18% for descending (p < 0.0001); and 17 vs. 27% for ascending colon (p = 0.0495)). Among colon cancer resection specimens, the prevalence of diverticulosis was significantly reduced in the rectosigmoid and ascending colon, compared with expected rates of diverticulosis in those regions. (13 vs. 42% in rectosigmoid (p = 0.0006); 3 vs. 17% in ascending colon (p = 0.043)). CONCLUSION: Despite similar overall frequency of polyps in patients with and without diverticulosis, polyps were significantly less likely in the colonic segment affected by diverticulosis. Additionally, the frequency of diverticulosis in areas of cancer in the rectosigmoid and ascending colon was significantly lower than expected compared with the expected frequency of diverticulosis for those colonic regions. These observations suggest a true negative association between colonic neoplasia and diverticulosis. PMID- 28884386 TI - Association between cardiac autonomic control and cognitive performance among patients post stroke and age-matched healthy controls-an exploratory pilot study. AB - Associations between autonomic nervous system health and cognitive performance have been described in different populations. Autonomic disturbances are a common phenomenon in patients post stroke. Little is known about the relationship between post stroke disturbances of the autonomic nervous system and the commonly occurring disturbances of cognitive functions revealed by victims of stroke. To assess the association between heart rate variability (HRV) and cognitive performance among patients post ischemic stroke and healthy age-matched controls, 13 patients post first-ever ischemic stroke aged 40-80 years and 15 age-matched healthy controls were evaluated. HRV was monitored during sustained handgrip, while breathing at a rate of six breaths per minute, while performing the serial 3 subtraction task sitting at rest, and while cycling. Patients post stroke had greater error rate in the serial-3 subtraction task, and lower HRV (both at rest and during task performance) relative to healthy controls (at rest 26 ms [10-53] vs. 43 ms [29-88]). The HRV of stroke patients showed less sensitivity to changes in testing conditions, and also failed to show the correlation with cognitive performance exhibited by the healthy subjects. Stroke patients experience autonomic nervous system dysfunction in parallel to their motor and cognitive impairments. Too often only the latter receive appropriate treatment consideration in the rehabilitation setting. The current results, and earlier research, point to the importance of focusing clinical attention to the status of the autonomic nervous system, as amelioration of its functioning is likely to enhance motor and cognitive functioning as well. PMID- 28884387 TI - Genome-wide DNA methylation patterns in coronary heart disease. AB - BACKGROUND: To better understand the molecular mechanisms of atherosclerosis, we conducted a comparative analysis of DNA methylation patterns in right coronary arteries in the area of advanced atherosclerotic plaques (CAP), great saphenous vein (GSV), and internal mammary artery (IMA) of patients affected by coronary heart disease. METHODS: DNA methylation data (accession number E-GEOD-62867) were divided into three paired groups: CAP vs. IMA, CAP vs. GSV, and IMA vs. GSV. Differentially methylated genes (DMGs) were extracted to analyze the changes in the DMGs in the three different tissues. The gplots package was used for the clustering and heatmap analysis of DMGs. Subsequently, DMG-related pathways were identified using DAVID (Database for Annotation, Visualization and Integrated Discovery) and transcription factors (TFs) were predicted. RESULTS: Based on the filtering criterion of p < 0.05, and a mean beta value difference of >=0.2, there were 252, 373, and 259 DMGs, respectively, in the CAP vs. IMA, CAP vs. GSV, and IMA vs. GSV groups. Interestingly, the S100A10 gene was hypomethylated in CAP compared with IMA and GSV. Clustering and heatmap analyses suggested that DMGs were segregated into two distinct clusters. Hypermethylated genes in CAP as compared with GSV were only involved in the pathway of fat digestion and absorption, while hypomethylated genes in CAP compared with GSV mainly participated in immune response-associated pathways (cytokine-cytokine receptor interaction, MAPK signaling pathway). CONCLUSION: The DNA methylation differences in vascular tissues of patients with coronary artery disease may provide new insights into the mechanisms underlying the development of atherosclerosis. The functions identified here-cytokine-cytokine receptor interaction, MAPK signaling pathway, DMG (S100A10), and TF (NF-kB)-may serve as potential targets in the treatment of atherosclerosis. PMID- 28884388 TI - Circulating C3 and glucose metabolism abnormalities in patients with OSAHS. AB - PURPOSE: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a common breathing disorder during sleep characterized by multiple disease roots, including disorders of complement and glycometabolism. And the main purpose of the present study is to make clear the effect of complement C3 on glucose metabolism abnormalities in patients with OSAHS. METHODS: This was a cross-sectional study. Two hundred six patients, mean age 44.58 +/- 11.84 years and 26 female patients (26/206), had been suspected with OSAHS and underwent overnight polysomnography. The assessment of complement levels included complement 3 (C3), complement 4 (C4), and serum total complement (TC). The measured indicators of glucose metabolism were fasting blood glucose (FPG), fasting insulin (FINS), and 75 g oral glucose tolerance test-derived glucose. A multivariate linear regression was used to determine relevant factors with 2-h postprandial blood glucose (2hPG) and C3. RESULTS: The patients were classified according to apnea-hypopnea index (AHI) into four groups: simple snore (n = 21), mild OSAHS (n = 43), moderate OSAHS (n = 35), and severe OSAHS (n = 107). The level of C3 in the severe OSAHS was higher than other groups (simple snore: 1.16 +/- 0.18 g/L VS 1.00 +/- 0.18 g/L, p < 0.001; mild OSAHS: 1.16 +/- 0.18 g/L VS 1.04 +/- 0.17 g/L, p < 0.001; moderate OSAHS: 1.16 +/- 0.18 g/L VS 1.06 +/- 0.14 g/L, p = 0.003) and no-severe OSAHS group (1.16 +/- 0.18 g/L VS 1.04 +/- 0.16 g/L, p < 0.001). And C3 was associated with AHI, average pulse oxygen saturation (A-spo2), homeostasis model assessment insulin resistance (HOMA-IR), 2hPG, age, sleep stage (I + II)/TST, and sleep stage (III)/TST, respectively. HOMA-IR was correlated to AHI after adjustment with age and BMI. OSAHS was an independent risk of C3 regardless of obesity and sleep parameters (p = 0.002). After adjustment with neck circumference (NC), BMI, AHI, sleep stage (I + II)/TST, and sleep stage (III)/TST,C3 level was associated with 2hPG (p < 0.001). CONCLUSIONS: A high level in C3 is correlated with the occurrence of OSAHS and C3 alterations in OSAHS patients seem to contribute to disorders of glucose metabolism. And targeting OSAHS to improve glucose metabolism and immune function could be useful. PMID- 28884390 TI - Patients treated for acute VTE during periods of treatment-related thrombocytopenia have high rates of recurrent thrombosis and transfusion-related adverse outcomes. AB - Venous thromboembolism (VTE) is a common complication of hematologic malignancies. Prolonged periods of thrombocytopenia are experienced universally by patients undergoing treatment for these diseases, yet data to guide management of anticoagulation in this setting are lacking. To obtain data on the management and outcomes of VTE in patients with thrombocytopenia related to the treatment of hematologic malignancies. This was an observational cohort study of patients experiencing VTE during periods of treatment-related thrombocytopenia over a 5 year period at the Fred Hutchinson Cancer Research Center. Medical records were reviewed for diagnostic, treatment and outcomes data, including bleeding events (categorized by WHO criteria) and progression or recurrence of VTE. Eighty-two patients meeting inclusion criteria were identified. Forty-eight percent were male and the median age was 55. Sixty-seven patients received anticoagulation, 88% of these were managed with transfusion support for a platelet goal of 50 * 109/L. Thirty-one patients experienced bleeding events, 22 of which were grade 2 and nine of which were grade 3/4. The median platelet count at the time of bleeding event was 54 * 109/L. Seven patients experienced progression of thrombosis and/or recurrence. Eleven patients experienced transfusion reactions and 30 experienced volume overload requiring diuretics or dialysis. While bleeding events were not uncommon, the majority of events were non-major/non clinically relevant. Most bleeding events occurred while the platelet count was within the 'goal' range of >=50 * 109/L, and many patients experienced transfusion related adverse events. Prospective studies are urgently needed to identify the optimal transfusion strategy for these patients. PMID- 28884389 TI - Microbial communities in pesticide-contaminated soils in Kyrgyzstan and bioremediation possibilities. AB - In Kyrgyzstan, many former storehouses and dump sites for obsolete pesticides exist. In 2009/2010, an inventory and assessment of these sites including risks of environmental hazard has been conducted by FAO and the World Bank. Monitoring revealed high concentration of pesticides listed as persistent organic pollutants (POPs). The purpose of this research was to study the microbial structural complexes of the pesticide-contaminated soils in these dumping zones, and to search for and select microorganism's destructors with cytochrome P450 genes for pesticide degradation. Culture-dependent and culture-independent approaches were used to determine the taxonomic composition of these bacterial communities. The universal primer set for the 16S ribosomal RNA (rRNA) gene and the specific primer set P450R were used to amplify the cytochrome P450 hydroxylase gene. In soils from Suzak A and B and soils from Balykchy dumping sites, the bacteria from the Actinobacteria phylum (Micrococcus genus) were dominant. These bacteria made up 32-47% of the indigenous local microflora; bacteria species from the Pseudomonas genus (Gammaproteobacteria phylum) made up 23% in Suzak, 12% in Balykchy soils. Bacillus species from the Firmicutes phylum were found only in Suzak soils. The 16S rRNA analyses and the specific primer set P450R have revealed bacteria with cytochrome genes which are directly involved in the degradation process of organic carbon compounds. Experiments were carried out to help select active degraders from the bacterial populations isolated and used to degrade Aldrin in laboratory. Active bacterial strains from the Pseudomonas fluorescens and Bacillus polymyxa population were selected which demonstrated high rates of degradation activity on Aldrin. PMID- 28884391 TI - Prognostic Significance of Surgical Margin Size After Neoadjuvant FOLFOX and/or FOLFIRI for Colorectal Liver Metastases. AB - PURPOSE: Optimal margin size when resecting colorectal liver metastases (CRLM) remains unclear, particularly in the setting of perioperative chemotherapy. We evaluated the prognostic significance of margin size in patients who received neoadjuvant FOLFOX and/or FOLFIRI prior to resection of CRLM. METHODS: Clinicopathologic factors were collected for patients who underwent curative liver resections for CRLM between 4/2004-1/2016 and received neoadjuvant oxaliplatin and/or irinotecan and 5-FU (FOLFOX, FOLFIRI). Margins were categorized as < 1, >= 1-< 5, >= 5-< 10, or >= 10 mm and evaluated for association with overall survival (OS) and disease-free survival (DFS) by Cox multiple regression analysis. Margin status was classified as positive (< 1 mm) or negative (>= 1 mm) and similarly evaluated. RESULTS: Of 227 patients, the median age was 58 years and most had synchronous (80%) lesions. The majority had colon cancers (75%). Margin sizes were 13% < 1 mm, 27% >= 1-< 5 mm, 23% >= 5-< 10 mm, 36% >= 10 mm. Most (63%) received chemotherapy post-liver resection. Five year OS and DFS were 54% (95% CI 46-62%) and 22% (95% CI 16-28%), respectively. Positive margins significantly increased the risk of death without post-liver resection chemotherapy (HR = 3.32, p = 0.0077), but not with post-liver resection chemotherapy (HR = 1.00, p = 0.99). Negative margin sizes of >= 1-< 5, >= 5-< 10, and >= 10 mm were not significant predictors of OS (p > 0.05). CONCLUSION: Patients undergoing liver resection for CRLM should receive post-resection chemotherapy if negative margins (>= 1 mm) cannot be achieved. For patients receiving FOLFOX and/or FOLFIRI chemotherapy, wider margins did not improve OS. PMID- 28884392 TI - Socioeconomic status and breast cancer treatment. AB - PURPOSE: Evidence suggests substantial disparities in breast cancer survival by socioeconomic status (SES). We examine the extent to which receipt of newer, less invasive, or more effective treatments-a plausible source of disparities in survival-varies by SES among elderly women with early-stage breast cancer. METHODS: Multivariate regression analyses applied to 11,368 women (age 66-90 years) identified from SEER-Medicare as having invasive breast cancer diagnosed in 2006-2009. Socioeconomic status was defined based on Medicaid enrollment and level of poverty of the census tract of residence. All analyses controlled for demographic, clinical health status, spatial, and healthcare system characteristics. RESULTS: Poor and near-poor women were less likely than high SES women to receive sentinel lymph node biopsy and radiation after breast-conserving surgery (BCS). Poor women were also less likely than near-poor or high SES women to receive any axillary surgery and adjuvant chemotherapy. There were no significant differences in use of aromatase inhibitors (AI) between poor and high SES women. However, near-poor women who initiated hormonal therapy were more likely to rely exclusively on tamoxifen, and less likely to use the more expensive but more effective AI when compared to both poor and high SES women. CONCLUSIONS: Our results indicate that SES disparities in the receipt of treatments for incident breast cancer are both pervasive and substantial. These disparities remained despite women's geographic area of residence and extent of disease, suggesting important gaps in access to effective breast cancer care. PMID- 28884393 TI - Effects of long exposure to spent potliner on seeds, root tips, and meristematic cells of Allium cepa L. AB - Spent potliner (SPL) is a solid waste generated in the aluminum mining and processing industry. It is sometimes dumped into the environment and leach in contact with water, thereupon affecting living beings, which are likely to be exposed to the waste for long periods. Considering this, we aimed to evaluate the effects of extended exposure to SPL through bioassays using Allium cepa as plant model system. Seeds of A. cepa were either directly exposed to SPL (continuous exposure) or first germinated in water and then exposed to SPL (discontinuous exposure). The germination rate was determined from 24 to 192 h of exposure. The maximum effects of SPL on germination were observed after 96 h in both exposure approaches. For the parameter root elongation, the discontinuous treatment was more efficient in demonstrating differences among the applied SPL concentrations (60% of reduction). Microscopic analysis was carried out in root tip cells discontinuously exposed to SPL for 96 h. A mitodepressive effect was observed (above 50%), as well as increased rate of chromosome abnormalities (up to 100 fold) and induction of cell death. The consequences of exposure to SPL for longer periods are discussed. PMID- 28884394 TI - A decrease in the number and incidence of osteoporotic hip fractures among elderly individuals in Niigata, Japan, from 2010 to 2015. AB - We investigated the incidence of hip fracture in patients aged >=50 years in 2015 in Niigata Prefecture, Japan. We also determined the long-term trend in hip fracture incidence from 1985 to 2015. In 2015, 3214 hip fractures occurred in Niigata Prefecture. The crude incidence rate of hip fracture was 282.7 per 100,000 persons per year (122.9 in men and 416.4 in women). The incidence of hip fracture decreased from 2010 to 2015 in all age groups except in men aged 65-69 years and women aged 60-64 years. The percentage of patients who took anti osteoporotic medication before their hip fractures increased from 10.2% in 2010 to 14.9% in 2015. The age-specific incidence in women tended to increase until 2010, but significantly decreased from 2010 to 2015 (p < 0.001). Similarly, the incidence in men decreased from 2010 to 2015 but was not significantly different from that in 1994 (p = 0.633); this incidence had been increasing since 1999. In conclusion, a generally increasing trend was observed in the incidence of hip fractures for 30 years in both men and women in Niigata Prefecture; however, it turned into a descending trend beginning in 2010. PMID- 28884395 TI - Cellular cholesterol is required for porcine nidovirus infection. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine epidemic diarrhea virus (PEDV) are porcine nidoviruses that are considered emerging and re emerging viral pathogens of pigs that pose a significant economic threat to the global pork industry. Although cholesterol is known to affect the replication of a broad range of viruses in vitro, its significance and role in porcine nidovirus infection remains to be elucidated. Therefore, the present study was conducted to determine whether cellular or/and viral cholesterol levels play a role in porcine nidovirus infection. Our results showed that depletion of cellular cholesterol by treating cells with methyl-beta-cyclodextrin (MbetaCD) dose-dependently suppressed the replication of both nidoviruses. Conversely, cholesterol depletion from the viral envelope had no inhibitory effect on porcine nidovirus production. The addition of exogenous cholesterol to MbetaCD-treated cells moderately restored the infectivity of porcine nidoviruses, indicating that the presence of cholesterol in the target cell membrane is critical for viral replication. The antiviral activity of MbetaCD on porcine nidovirus infection was found to be predominantly exerted when used as a treatment pre-infection or prior to the viral entry process. Furthermore, pharmacological sequestration of cellular cholesterol efficiently blocked both virus attachment and internalization and, accordingly, markedly affected subsequent post-entry steps of the replication cycle, including viral RNA and protein biosynthesis and progeny virus production. Taken together, our data indicate that cell membrane cholesterol is required for porcine nidovirus entry into cells, and pharmacological drugs that hamper cholesterol-dependent virus entry may have antiviral potential against porcine nidoviruses. PMID- 28884396 TI - Ginsenoside Re Protects Trimethyltin-Induced Neurotoxicity via Activation of IL-6 Mediated Phosphoinositol 3-Kinase/Akt Signaling in Mice. AB - Ginseng (Panax ginseng), an herbal medicine, has been used to prevent neurodegenerative disorders. Ginsenosides (e.g., Re, Rb1, or Rg1) were obtained from Korean mountain cultivated ginseng. The anticonvulsant activity of ginsenoside Re (20 mg/kg/day * 3) against trimethyltin (TMT) insult was the most pronounced out of ginsenosides (e.g., Re, Rb1, and Rg1). Re itself did not significantly alter tumor necrosis factor-alpha (TNF-alpha), interferon-Upsilon (IFN-Upsilon), and interleukin-1beta (IL-1beta) expression, however, it significantly increases the interleukin-6 (IL-6) expression. In addition, Re attenuated the TMT-induced decreases in IL-6 protein level. Therefore, IL-6 knockout (-/-) mice were employed to investigate whether Re requires IL-6 dependent neuroprotective activity against TMT toxicity. Re significantly attenuated TMT-induced lipid peroxidation, protein peroxidation, and reactive oxygen species in the hippocampus. Re-mediated antioxidant effects were more pronounced in IL-6 (-/-) mice than in WT mice. Consistently, TMT-induced increase in c-Fos-immunoreactivity (c-Fos-IR), TUNEL-positive cells, and nuclear chromatin clumping in the dentate gyrus of the hippocampus were significantly attenuated by Re. Furthermore, Re attenuated TMT-induced proapoptotic changes. Protective potentials by Re were comparable to those by recombinant IL-6 protein (rIL-6) against TMT-insult in IL-6 (-/-) mice. Moreover, treatment with a phosphoinositol 3-kinase (PI3K) inhibitor, LY294002 (1.6 ug, i.c.v) counteracted the protective potential mediated by Re or rIL-6 against TMT insult. The results suggest that ginsenoside Re requires IL-6-dependent PI3K/Akt signaling for its protective potential against TMT-induced neurotoxicity. PMID- 28884398 TI - Developmental exposure of decabromodiphenyl ether impairs subventricular zone neurogenesis and morphology of granule cells in mouse olfactory bulb. AB - Polybrominated diphenyl ethers (PBDEs) are additive flame retardants widely used in various products (e.g., textiles, consumer electronics, and plastics). Strong evidence indicates that PBDEs are developmental neurotoxicants that can cause neurodevelopmental disabilities and cognitive defects. Currently, decabromodiphenyl ether (BDE 209) is the only PBDE permitted for production in most countries. This study investigated the impact of BDE 209 on postnatal neurogenesis in the subventricular zone (SVZ) of ICR mice. For this purpose, pregnant ICR mice were orally administrated a daily dose of 0, 20 or 100 mg/kg BDE 209 from gestation day 6 to postnatal day 16. Bromodeoxyuridine (BrdU) incorporation and in vivo postnatal electroporation were performed to label the newly generated cells in the SVZ. On PND 16, a reduction of type-B stem cells was found in the 100 mg/kg group. BDE 209 also decreased the number of newborn cells and Calretinin+ interneurons in granule cell layer at the dose of 100 mg/kg. In addition, we observed impaired neuronal migration and dendritic development of newborn olfactory granule cells in both 20 and 100 mg/kg groups. In conclusion, developmental exposure to BDE 209 produces adverse effects on SVZ neurogenesis and dendritic growth of mouse offspring. These findings suggest a potential risk of BDE 209 in human neurodevelopment. PMID- 28884397 TI - BRCA1 gene: function and deficiency. AB - The BRCA1 protein, a hereditary breast and ovarian cancer-causing gene product, is known as a multifunctional protein that performs various functions in cells. It is well known, along with BRCA 2, to cause hereditary breast and ovarian cancer, but here we will specifically focus on BRCA1. We introduce the mechanism and the latest report on homologous recombination repair, replication, involvement in checkpoint regulation, transcription, chromatin remodeling, and cytoplasmic function (centrosome regulation, apoptosis, selective autophagy), and consider the possibility of carcinogenesis from inhibition of the intracellular functions in each. We also consider the possibility of drug development based on each function. Finally, we will explain, from data obtained through basic research, that an appropriate regimen is important for raising the response rate for poly (ADP)-ribose polymerase inhibitors, in the case of low susceptibility, iatrogenic toxicity, tolerance, etc. PMID- 28884399 TI - Bias and Correction in RNA-seq Data for Marine Species. AB - RNA-seq is a recently developed approach widely used for transcriptome profiling in biological analyses that use next-generation sequencing technologies. Accurate estimation of gene expression levels is critical for answering biological questions. Here, we show that the commonly used measure of gene expression levels, fragments per kilobase of transcript per million mapped reads (FPKM), is biased in transcript length, GC content, and dinucleotide frequencies in the RNA seq analysis of marine species. We used a generalized linear model to correct the observed biases of FPKM. We used RNA-seq data sets from eight species obtained by different sequencing methods to evaluate the correction methods. Our work contributes to the understanding of potential technical artifacts in RNA-seq experiments for marine species, and presents a means by which more accurate gene expression measures can be obtained. PMID- 28884400 TI - Nutrition and Aging: a Practicing Oncologist's Perspective. AB - Malnutrition is common in patients with cancer and is associated with a variety of negative outcomes. These can include reduced treatment tolerance and worsened cancer prognosis. Various aspects of aging, including sensory, physical, or psychosocial changes, place older patients at a particularly high risk for malnutrition, and these geriatric factors must be identified early and addressed. Despite the lack of available evidence on the optimal nutritional interventions for older adults with cancer, the oncologist must be prepared to address the common nutritional concerns that arise in both advanced cancer and survivorship settings. While BMI, weight loss, and serum albumin are commonly used as surrogates of malnutrition, the use of a comprehensive screening tool may promote early identification of disrupted eating patterns and allow for prompt intervention. New digital technologies have also demonstrated promise to improve nutritional assessment capabilities. Use of conventional nutritional support in conjunction with novel nutraceutical and anti-cachexia approaches may enhance the effectiveness of interventions and improve our ability to reverse malnutrition associated alterations in body composition. Future geriatric-focused nutrition research will be crucial in helping guide our patients and effectively addressing their dietary and lifestyle concerns. PMID- 28884401 TI - 4D flow image quality with blood pool contrast: a comparison of gadofosveset trisodium and ferumoxytol. AB - To evaluate the effect of MRI blood pool contrast agent on 4D flow image quality and ventricular volume measurements. Adult patients referred for clinical cardiac MRI (n = 22) were imaged with 4D flow. Patients with renal failure (n = 10) received ferumoxytol, and the remainder (n = 12) received gadofosveset trisodium. Image quality was assessed with (1) signal-to-noise ratio (SNR); (2) contrast-to noise ratio (CNR); and (3) 5-point Likert scale based on endocardial border definition (1 = none; 2 = partial but unable to visualize; 3 = able to roughly estimate; 4 = visible for most of the cardiac cycle; 5 = excellent definition). A subset (n = 15) had short axis steady-state free precession (SSFP) cine imaging allowing for comparison of standard volumetric measurement technique with 4D flow derived volumetric measurements. 4D flow studies using ferumoxytol demonstrated a higher median Likert score of 5 (IQR, 5-5) versus 3 (IQR, 2-3). Median cavity SNR and CNR were higher for ferumoxytol compared to gadofosveset trisodium [65 (IQR, 50-74) versus 22 (IQR, 14-28), p < 0.001; and 40 (IQR, 32-49) versus 4 (IQR, 3 10), p < 0.001]. Good correlation (p < 0.001) was seen between SSFP and 4D flow measured ventricular volumes (ESV and EDV) with ferumoxytol (r = 0.998, mean difference = 1.2 mL, LOA = - 7.7-10.1 mL) and gadofosveset trisodium (r = 0.942, mean difference = - 2.7 mL, LOA = - 35.7-27.1 mL). Ferumoxytol used off-label as an MRI blood pool contrast agent offers an attractive alternative to gadofosveset trisodium in patients with renal failure, with excellent 4D flow image quality and good correlation of volumetric measurements compared to the CMR reference (SSFP). PMID- 28884402 TI - Obstructive Sleep Apnea Increases the Risk of Cardiopulmonary Adverse Events Associated with Ambulatory Colonoscopy Independent of Body Mass Index. AB - BACKGROUND: The relationship between body mass index (BMI) and cardiopulmonary adverse events (CAEs) for ambulatory colonoscopy is unclear. AIM: To assess the association of BMI and CAEs associated with ambulatory colonoscopy. METHODS: This is a retrospective cohort analysis of 418 patients who underwent outpatient colonoscopy at the Durham Veterans Affairs Medical Center categorized as normal/overweight (BMI < 30), obese (BMI 30-34), or morbidly obese (BMI >= 35). Adjusted logistic regression analyses were performed. RESULTS: At least one CAE occurred in 46.4% of patients (220 events, 72.7% were hypoxia). The rate of CAEs (BMI < 30: 43.8%, BMI 30-34: 48.0%, BMI >= 35: 50.6%, p = 0.53) and rate of hypoxia (BMI < 30: 34.8%, BMI 30-34: 40.9%, BMI >= 35: 43.2%, p = 0.32) were numerically higher for obese and morbidly obese patients, but not statistically significant. Obese (OR 1.10, 95% CI 0.70-1.73) and morbidly obese (OR 1.07, 95% CI 0.61-1.85) patients did not have an increased risk of CAEs after adjusting for age, ASA class, obstructive sleep apnea (OSA), and type of sedation. OSA was independently associated with an increased risk of CAEs (OR 1.71, 95% CI 1.09 2.74, p = 0.02) after adjusting for BMI, age, ASA class, and type of sedation. CONCLUSION: OSA confers a higher risk of CAEs independent of BMI and sedation type. Consideration of undiagnosed OSA is recommended for appropriate pre procedure risk stratification. While not statistically significant in this study, there may be clinically significant increased risks of CAEs and hypoxia for patient with BMI > 30 that require further evaluation with larger studies. PMID- 28884403 TI - Resonance Raman studies on the flavohemoglobin of the protist Giardia intestinalis: evidence of a type I/II-peroxidase-like heme environment and roles of the active site distal residues. AB - Flavohemoglobins are microbial enzymes that counter nitrosative stress, but the details of their underlying enzymatic activities and structure-function relationships are not completely understood. These enzymes have been identified in Gram-negative bacteria, certain fungi, and the parasitic protist Giardia intestinalis (gFlHb) which, despite lacking the ability to make heme, encodes several hemeproteins. To gain knowledge about the biophysical properties of the active site of gFlHb, we used resonance Raman spectroscopy to probe the wild-type protein and variants at globin domain positions E11, E7, and B10 on the distal, ligand-binding side of the heme. The heme of gFlHb has a peroxidase-like environment resembling that of the well-characterized E. coli flavohemoglobin HMP. We provide evidence that gFlHb has two Fe-His stretching modes, a feature that also occurs in type I/II-peroxidases in which a proximal histidine with strong imidazolate character and a nearby carboxylic acid residue can exist as a tautomeric pair depending on the position of a shared proton. Characterization of the distal variants Tyr30Phe, Gln54Leu, and Leu59Ala shows that TyrB10 and GlnE7 but not LeuE11 are implicated in stabilisation of bound exogenous ligands such as CO and O2. Our work revealed that several biophysical properties of the heme active site of gFlHb are highly conserved compared to HMP and suggest that they are conserved across the flavohemoglobin family. PMID- 28884404 TI - Palatability of nine fodders species used by guinea pigs (Cavia porcellus). AB - Nine fodders commonly offered to the guinea pigs by the breeders in Lubumbashi (Democratic Republic of Congo) were compared for chemical composition and for both daily dry matter intake and palatability indices by using 13 three-month-old guinea pigs. Four different plant families were provided to each guinea pig, and each animal was exposed to all the experimental diets studied for 8 consecutive days. The fodder species were three grasses: Trypsacum laxum, Panicum maximum, and Pennisetum purpureum; three trees or bushes Moringa oleifera, Leucaena leucocephala, and Bauhinia variegata; and three flowering plants Bidens oligoflora, Bidens pilosa, and Commelina diffusa. Dry matter content varied from 14 to 44/100 g FM, and CP from 13 to 28/100 g DM. B. variegata and P. purpureum showed the lowest CP value and L. leucocephala the highest. The grasses and the Commelina had higher levels of hemicelluloses than the tree fodders, especially P. maximum (45/100 g DM). High levels of K were found in the grasses and Bidens, and high Ca in the tree fodders and Bidens. The guinea pigs preferred, in a descending order, P. purpureum (0.79), B. pilosa (0.78), C. diffusa (0.78), T. laxum (0.77), P. maximum (0.76), B. oligoflora (0.75), M. oleifera (0.45), L. leucocephala (0.37), and B. variegata (0.33). The DMI and the palatability index were strongly correlated to the ash (r = 0.82; p ? 0.05) and the potassium (r = 0.88; p ? 0.05) contents in fodders. PMID- 28884405 TI - Ethnicity and Language Proficiency Differences in the Provision of and Intention to Use Prenatal Screening for Down's Syndrome and Congenital Anomalies. A Prospective, Non-selected, Register-Based Study in the Netherlands. AB - Objective We aimed to conduct an analysis of the associations between the information provision procedure of prenatal screening for Down's syndrome and congenital anomalies and the intention to participate in prenatal screening (PS) of ethnicity groups and Dutch language proficiency groups. Design Using a prospective web-based registration form, we asked counselors (midwives, general practitioners, nurses and gynecologists) to report whether and how they offered information about PS to pregnant women. Duration The study was conducted from 2008 to 2010. Participants We collected data on the characteristics of the women who received an information offer about PS from counselors. Measurements Measures included socio-demographic and language proficiency level (LPL) characteristics, key elements of the provision procedure of PS, and intentional participation in PS. Findings The dataset represents 37% of the total population in the study area. Women with a non-native Dutch background and/or insufficient Dutch LPL received fewer information offers about PS, faced a reduced chance of receiving counseling, and showed lower intentional participation rates for PS. Key Conclusions Women with a non-native Dutch background and/or with an insufficient LPL are underserved in the Dutch PS program. These findings present evidence indicating that the fundamental principle of the Dutch Population Screening Act, namely, equal access to PS for all pregnant women, is not being realized. Implications for Practice Therefore, the study findings are important for national and international healthcare, policy makers and governmental professionals to allow ethnic and LPL-related differences in the provision and intentional uptake of PS. PMID- 28884406 TI - Similarities and Differences in Barriers and Opportunities Affecting Climate Change Adaptation Action in Four North American Landscapes. AB - Climate change presents a complex set of challenges for natural resource managers across North America. Despite recognition that climate change poses serious threats to species, ecosystems, and human communities, implementation of adaptation measures is not yet happening on a broad scale. Among different regions, a range of climate change trajectories, varying political contexts, and diverse social and ecological systems generate a myriad of factors that can affect progress on climate change adaptation implementation. In order to understand the general versus site-specific nature of barriers and opportunities influencing implementation, we surveyed and interviewed practitioners, decision makers, and scientists involved in natural resource management in four different North American regions, northern Ontario (Canada), the Adirondack State Park (US), Arctic Alaska (US), and the Transboundary Rocky Mountains (US and Canada). Common barriers among regions related to a lack of political support and financial resources, as well as challenges related to translating complex and interacting effects of climate change into management actions. Opportunities shared among regions related to collaboration, funding, and the presence of strong leadership. These commonalities indicate the importance of cross-site learning about ways to leverage opportunities and address adaptation barriers; however, regional variations also suggest that adaptation efforts will need to be tailored to fit specific ecological, political, social and economic contexts. Comparative findings on the similarities and differences in barriers and opportunities, as well as rankings of barriers and opportunities by region, offers important contextual insights into how to further refine efforts to advance adaptation actions in those regions. PMID- 28884407 TI - Can Preoperative Frailty Accurately Predict Morbidity and Mortality Following Liver Surgery? PMID- 28884408 TI - Religion and health in Europe: cultures, countries, context. AB - Much of the research on the relationships between religious participation and health comes from the United States. Studies in other geographic regions or cultural contexts is more sparse. Evidence presented by Ahrenfelt et al., and that from other research studies, is reviewed concerning the associations between religion and health within Europe and world-wide. The evidence within Europe suggests protective associations between various forms of religious participation and lower depression, lower mortality, and better self-rated health. Methodological challenges in such research are reviewed, and discussion is given as to whether a person-culture-fit explanation suffices to account for the existing data and to what other mechanisms might be operative. PMID- 28884409 TI - Chronic exposure to rapamycin and episodic serum starvation modulate ageing of human fibroblasts in vitro. AB - Mild stress-induced activation of stress response (SR) pathways, such as autophagy, heat shock response, oxidative SR, DNA damage response, and inflammatory response, can be potentially health beneficial. Using the model system of cellular ageing and replicative senescence in vitro, we have studied the ageing modulatory effects of the two conditions, rapamycin and serum starvation. Chronic exposure to 0.1, 1 and 10 nM rapamycin positively modulated the survival, growth, morphology, telomere length, DNA methylation levels, 8-oxo dG level in DNA, N6-methyl-adenosine level in RNA, and ethanol stress tolerance of serially passaged normal human skin fibroblasts. Furthermore, episodic (once a week) serum starvation of human skin fibroblasts extended their replicative lifespan by about 22%, along with the maintenance of early passage youthful morphology even in late passage cultures. Although the results of this study may be considered preliminary, it can be inferred that intermittent and episodic induction of SR, rather than chronic up-regulation of SR, is more effective and applicable in the practice of hormesis for healthy ageing and longevity. PMID- 28884410 TI - AN-7, a butyric acid prodrug, sensitizes cutaneous T-cell lymphoma cell lines to doxorubicin via inhibition of DNA double strand breaks repair. AB - We previously found that the novel histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) had greater selectivity against cutaneous T-cell lymphoma (CTCL) than SAHA. AN-7 synergizes with doxorubicin (Dox), an anthracycline antibiotic that induces DNA breaks. This study aimed to elucidate the mechanism underlying the effect of AN-7 on Dox-induced double strand DNA breaks (DSBs) in CTCL, MyLa and Hut78 cell lines. The following markers/assays were employed: comet assay; western blot of gammaH2AX and p-KAP1; immunofluorescence of gammaH2AX nuclear foci; Western blot of repair protein; quantification of DSBs-repair through homologous recombination. DSB induction by Dox was evidenced by an increase in DSB markers, and DSBs-repair, by their subsequent decrease. The addition of AN-7 slightly increased Dox induction of DSBs in MyLa cells with no effect in Hut78 cells. AN-7 inhibited the repair of Dox-induced DSBs, with a more robust effect in Hut78. Treatment with AN-7 followed by Dox reduced the expression of DSB-repair proteins, with direct interference of AN-7 with the homologous recombination repair. AN-7 sensitizes CTCL cell lines to Dox, and when combined with Dox, sustains unrepaired DSBs by suppressing repair protein expression. Our data provide a mechanistic rationale for combining AN-7 with Dox or other DSB inducers as a therapeutic modality in CTCL. PMID- 28884411 TI - Role of calcitonin gene-related peptide in energy metabolism. AB - PURPOSE: Calcitonin gene-related peptide (CGRP) is a neuropeptide produced by alternative tissue-specific splicing of the primary transcript of the CALC genes. CGRP is widely distributed in the central and peripheral nervous system, as well as in several organs and tissues. The presence of CGRP in the liver and brown and white adipose tissue suggests an effect of this neuropeptide on regulation of energy homeostasis. METHODS: In this review, we summarize the current knowledge of the effect of CGRP on the control of energy metabolism, primarily focusing on food intake, thermoregulation and lipid metabolism in adipose tissue, liver and muscle. RESULTS: CGRP induces anorexia, stimulating anorexigenic neuropeptide and/or inhibiting orexigenic neuropeptide expression, through cAMP/PKA pathway activation. CGRP also induces energy expenditure, increasing the skin temperature and brown adipose tissue thermogenesis. It has been also suggested that information related to peripheral lipid stores may be conveyed to the brain via CGRP-sensory innervation from adipose tissue. More recently, it was demonstrated that mice lacking alphaCGRP are protected from obesity induced by high-fat diet and that CGRP regulates the content of lipid in liver, muscle and adipose tissue. CONCLUSIONS: It is unclear the receptor responsible by CGRP effects, as well as whether this neuropeptide acts directly or indirectly in liver, muscle and adipose tissue. PMID- 28884413 TI - Knockdown of long non-coding RNA prostate cancer-associated ncRNA transcript 1 inhibits multidrug resistance and c-Myc-dependent aggressiveness in colorectal cancer Caco-2 and HT-29 cells. AB - The long non-coding RNA (lncRNA) prostate cancer-associated ncRNA transcript 1 (PCAT-1) has been shown to promote prostate cancer cell proliferation through c Myc and is associated with the poor prognosis of CRC patients. In the current study, it was hypothesized that the effect of PCAT-1 on the aggressiveness of CRC cells was dependent on the function of c-Myc. Human CRC cell lines Caco-2 and HT 29 were transfected with specific PCAT-1 shRNAs, and cell migration, invasiveness, and resistance to 5-fluorouracil were measured. To elucidate the role of c-Myc in PCAT-1 function, c-Myc was overexpressed in PCAT-1-silenced CRC cells and the effect of c-Myc overexpression on the aggressiveness of PCAT-1 silenced cells was detected. The results showed that knockdown of PCAT-1 in CRC cells suppressed cell motility and invasiveness, and sensitized the cells to 5 fluorouracil, as evidenced by the reduced viability and induced apoptosis in PCAT 1-silenced cells compared to the parental cells in response to 5-fluorouracil treatment. The expression of c-Myc in PCAT-1-silenced CRC cells was down regulated, and forced expression of c-Myc partially restored the invasiveness in PCAT-1-silenced cells. In summary, the findings outlined in the current study suggest that PCAT-1 regulates the invasiveness and drug resistance in CRC cells and that PCAT-1 may promote CRC cell invasion by modulating the expression of c Myc. PMID- 28884412 TI - Mesenchymal Stem Cells (MSCs) Therapy for Recovery of Fertility: a Systematic Review. AB - In recent years, the mesenchymal stem cells (MSCs) have provided the new opportunities to treat different disorders including infertility. Different studies have suggested that the MSCs have ability to differentiate into germ-like cells under specific induction conditions as well as transplantation to gonadal tissues. The aim of this systematic review was to evaluate the results obtained from different studies on MSCs therapy for promoting fertility. This search was done in PubMed and Science Direct databases using key words MSCs, infertility, therapy, germ cell, azoospermia, ovarian failure and mesenchymal stem cell. Among the more than 11,400 papers, 53 studies were considered eligible for more evaluations. The obtained results indicated that the most studies were performed on MSCs derived from bone marrow and umbilical cord as compared with the other types of MSCs. Different evaluations on animal models as well as in vitro studies supported from their role in the recovery of spermatogenesis and folliculogenesis. Although the data obtained from this systematic review are promising, but the further studies need to assess the efficiency and safety of transplantation of these cells in fertility recovery. PMID- 28884414 TI - Effect of programmed intermittent epidural boluses and continuous epidural infusion on labor analgesia and obstetric outcomes: a randomized controlled trial. AB - PURPOSE: Continuous epidural infusion and programmed intermittent epidural boluses are analgesic techniques routinely used for pain relief in laboring women. We aimed to assess both techniques and compare them with respect to labor analgesia and obstetric outcomes. METHODS: After Institutional Review Board approval, 132 laboring women aged between 18 and 45 years were randomized to epidural analgesia of 10 mL of a mixture of 0.1% bupivacaine plus 2 ug/mL of fentanyl either by programmed intermittent boluses or continuous infusion (66 per group). Primary outcome was quality of analgesia. Secondary outcomes were duration of labor, total drug dose used, maternal satisfaction, sensory level, motor block level, presence of unilateral motor block, hemodynamics, side effects, mode of delivery, and newborn outcome. RESULTS: Patients in the programmed intermittent epidural boluses group received statistically less drug dose than those with continuous epidural infusion (24.9 vs 34.4 mL bupivacaine; P = 0.01). There was no difference between groups regarding pain control, characteristics of block, hemodynamics, side effects, and Apgar scores. CONCLUSIONS: Our study evidenced a lower anesthetic consumption in the programmed intermittent boluses group with similar labor analgesic control, and obstetric and newborn outcomes in both groups. PMID- 28884417 TI - Neratinib: First Global Approval. AB - Neratinib (NerlynxTM) is an oral, irreversible inhibitor of the human epidermal growth factor receptors HER1 (EGFR), HER2 and HER4. The drug originally arose from research by Wyeth (now Pfizer) and is now being developed by Puma Biotechnology primarily for the treatment of HER2-positive (HER+) breast cancer. Neratinib is approved in the USA for the extended adjuvant treatment of patients with HER2+ early-stage breast cancer who have been previously treated with a trastuzumab-based adjuvant regimen, and is in the preregistration phase for this indication in the EU. Neratinib, as monotherapy and/or combination therapy, is also in phase 3 development for metastatic breast cancer and in phase 1/2 development for advanced breast cancer and other solid tumours, including non small cell lung cancer, colorectal cancer and glioblastoma. This article summarizes the milestones in the development of neratinib leading to this first approval for breast cancer. PMID- 28884416 TI - Repeated Stress Exaggerates Lipopolysaccharide-Induced Inflammatory Response in the Rat Spleen. AB - Spleen is an immune organ innervated with sympathetic nerves which together with adrenomedullary system control splenic immune functions. However, the mechanism by which prior stress exposure modulates the immune response induced by immunogenic challenge is not sufficiently clarified. Thus, the aim of this study was to investigate the effect of a single (2 h) and repeated (2 h daily for 7 days) immobilization stress (IMO) on the innate immune response in the spleen induced by lipopolysaccharide (LPS, 100 ug/kg). LPS elevated splenic levels of norepinephrine and epinephrine, while prior IMO prevented this response. LPS did not alter de novo production of catecholamines, however, prior IMO attenuated phenylethanolamine N-methyltransferase gene expression. Particularly repeated IMO exacerbated LPS-induced down-regulation of alpha1B- and beta1-adrenergic receptors (ARs), while enhanced alpha2A- and beta2-AR mRNAs. Elevated expression of inflammatory mediators (iNOS2, IL-1beta, IL-6, TNF-alpha, IL-10) was observed following LPS and repeated IMO again potentiated this effect. These changes were associated with enhanced Ly6C gene expression, a monocyte marker, and elevated MCP-1, GM-CSF, and CXCL1 mRNAs suggesting an increased recruitment of monocytes and neutrophils into the spleen. Additionally, we observed increased Bax/Bcl-1 mRNA ratio together with reduced B cell numbers in rats exposed to repeated IMO and treated with LPS but not in acutely stressed rats. Altogether, these data indicate that repeated stress via changes in CA levels and specific alpha- and beta-AR subtypes exaggerates the inflammatory response likely by recruiting peripheral monocytes and neutrophils to the spleen, resulting in the induction of apoptosis within this tissue, particularly in B cells. These changes may alter the splenic immune functions with potentially pathological consequences. PMID- 28884418 TI - Altruism and Religion: A New Paradigm for Organ Donation. AB - Activity of NGO's supporting living donor kidney donations can affect the shortage of kidneys. Matnat Chaim is a Jewish orthodox organization active in Israel since 2009. This is a voluntary organization with aims to shorten and eliminate the waiting list for kidneys. Since the beginning of its activity, it has said to play a key role in 379 kidney transplantations. In 2015, out of 174 live donor kidney transplantations that took place in Israel, Matnat Chaim had a key role in 88 of them (50.6%). We found some ethical issues concerning the organization's activity. The donor can restrict his or her donation to specific characteristics of recipient which can result in organs transplanted in a homogeneous group of the population. Another issue is the question of whether nudging people to kidney donation takes place and whether it is valid to do so. We found that Matnat Chaim does a great deal for promotion and intermediation of kidney donations in Israel. This form of promotion can be implemented by other organizations and countries. PMID- 28884415 TI - Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement. AB - INTRODUCTION: With the goal of generate uniform criteria among centers dealing with pituitary tumors and to enhance patient care, the Pituitary Society decided to generate criteria for developing Pituitary Tumors Centers of Excellence (PTCOE). METHODS: To develop that task, a group of ten experts served as a Task Force and through two years of iterative work an initial draft was elaborated. This draft was discussed, modified and finally approved by the Board of Directors of the Pituitary Society. Such document was presented and debated at a specific session of the Congress of the Pituitary Society, Orlando 2017, and suggestions were incorporated. Finally the document was distributed to a large group of global experts that introduced further modifications with final endorsement. RESULTS: After five years of iterative work a document with the ideal criteria for a PTCOE is presented. CONCLUSIONS: Acknowledging that very few centers in the world, if any, likely fulfill the requirements here presented, the document may be a tool to guide improvements of care delivery to patients with pituitary disorders. All these criteria must be accommodated to the regulations and organization of Health of a given country. PMID- 28884419 TI - Identification of HSP70 gene in Corythucha ciliata and its expression profiles under laboratory and field thermal conditions. AB - Previous laboratory studies have demonstrated that insects can tolerate high temperatures by expressing inducible heat shock proteins (HSPs). This HSP-based tolerance, however, has seldom been studied under field conditions. Here, we cloned the HSP70 gene of Corythucha ciliata (Cchsp70), an invasive insect species with substantial thermal tolerance in subtropical China. We also compared the relative mRNA expression levels of Cchsp70 in response to controlled temperature treatments (2 h at 33-43 degrees C at 2 degrees C intervals in the laboratory) and to natural increases in temperature (08:00-14:00 at 2-h intervals, 29.7-37.2 degrees C) on a hot summer day in the field. The complete cDNA of Cchsp70 is 2256 bp long and has a 1917 bp open reading frame that encodes a protein (CcHSP70) with 639 amino acids. The expression levels of Cchsp70 significantly increased in response to high temperatures in both laboratory and field. At similar temperatures, however, the expression levels were much higher in the field than in the laboratory. These results suggest that CcHSP70 contributes to the thermal tolerance of C. ciliata and that factors in addition to thermal stress may induce Cchsp70 expression in the field. PMID- 28884420 TI - Relation between biophysical properties of nanostructures and their toxicity on zebrafish. AB - In recent years, the use of commercial nanoparticles in different industry and health fields has increased exponentially. However, the uncontrolled application of nanoparticles might present a potential risk to the environment and health. Toxicity of these nanoparticles is usually evaluated by a fast screening assay in zebrafish (Danio rerio). The use of this vertebrate animal model has grown due to its small size, great adaptability, high fertilization rate and fast external development of transparent embryos. In this review, we describe the toxicity of different micro- and nanoparticles (carbon nanotubes, dendrimers, emulsions, liposomes, metal nanoparticles, and solid lipid nanoparticles) associated to their biophysical properties using this model. The main biophysical properties studied are size, charge and surface potential due to their impact on the environment and health effects. The review also discusses the correlation of the effects of the different nanoparticles on zebrafish. Special focus is made on morphological abnormalities, altered development and abnormal behavior. The last part of the review debates changes that should be made in future directions in order to improve the use of the zebrafish model to assess nanotoxicity. PMID- 28884421 TI - Assessing responsiveness over time of the PROMIS(r) pediatric symptom and function measures in cancer, nephrotic syndrome, and sickle cell disease. AB - PURPOSE: Previous studies provided evidence for the validity of the PROMIS Pediatric measures in cross-sectional studies. This study evaluated the ability of the PROMIS Pediatric measures to detect change over time in children and adolescents with cancer, nephrotic syndrome (NS), or sickle cell disease (SCD). METHODS: Participants (8-17 years) completed measures of fatigue, pain interference, anger, anxiety, depressive symptoms, mobility, upper extremity, and peer relationships at three or four time points (T1-T4). Between T1 and T2, children with cancer received chemotherapy and children with SCD experienced a pain exacerbation. Children with NS were first assessed during active disease (T2), with T3 and T4 conducted at disease remission. For the primary analysis of responsiveness, we expected better scores at T3 (recovery) compared to T2 (event) for all diseases. T1 and T4 are also expected to have better scores than T2. Linear mixed models were used and adjusted for time, gender, age, race/ethnicity, education, comorbid conditions, and disease. RESULTS: Enrolled were 96 children with cancer, 121 children with SCD, and 127 children with NS. Fatigue, pain interference, mobility, and upper extremity scores worsened from T1 (baseline) to T2 (event) (p < 0.01), and significantly improved from T2 to T3 and T4 (p < 0.01). Similarly, anxiety and depressive symptoms significantly improved from T2 to T3 and T4 (p < 0.01). CONCLUSIONS: This study provides evidence for the responsiveness of seven PROMIS Pediatric measures to clinical disease state in three chronic illnesses. The findings support use of PROMIS Pediatric measures in clinical research. PMID- 28884422 TI - Less strict intervention thresholds for the FRAX and TBS-adjusted FRAX predict clinical fractures in osteopenic postmenopausal women with no prior fractures. AB - Little is known about the clinical relevance of treating post-menopausal women with no prior history of fragility fracture and bone mineral densities (BMD) within the osteopenic range. In recent years, in addition to BMD and FRAX fracture probability assessments, a surrogate measure of bone micro-architecture quality, called the trabecular bone score (TBS), has been proven to predict future fragility fractures independently of both BMD and the FRAX. In this retrospective analysis of a follow-up study, we compared three risk assessment instruments-the FRAX, the TBS, and a TBS-adjusted FRAX score-in their ability, to predict future fragility fractures over a minimum of five years of follow-up among post-menopausal osteopenic women with no prior fragility fractures. We also sought to determine if more- versus less-stringent criteria were better when stratifying patients into higher-risk patients warranting osteoporosis-targeted intervention versus lower-risk patients in whom intervention would usually be deemed unnecessary. Over a mean 5.2 years follow-up, 18 clinical fragility fractures were documented among 127 women in the age 50 years and older (mean age = 66.1). On multivariate analysis utilizing regression models and Kaplan-Meier curve analysis, less-stringent criteria for the FRAX and TBS-adjusted FRAX were capable of predicting future fractures (with sensitivity/specificity of 83/31; 39/77 and 78/50% for TBS, FRAX and TBS-adjusted FRAX, respectively), while more stringent criteria were incapable of doing so (with sensitivity/specificity of 56/60; 39/77 and 39/74 for TBS, FRAX and TBS-adjusted FRAX, respectively). Neither TBS threshold alone was a significant predictor of future fracture in our study. However, hazard ratio analysis revealed slight superiority of the TBS adjusted FRAX over the FRAX alone (HR = 3.09 vs. 2.79). Adjusting the FRAX tool by incorporating the TBS may be useful to optimize the detection of post menopausal osteopenic women with no prior fractures who warrant osteoporosis targeted therapy. PMID- 28884423 TI - Electronic Cigarette Use in US Adults at Risk for or with COPD: Analysis from Two Observational Cohorts. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) are battery-operated nicotine delivery devices used by some smokers as a cessation tool as well as by never smokers. OBJECTIVE: To determine the usage of e-cigarettes in older adults at risk for or with chronic obstructive pulmonary disease (COPD). DESIGN: Prospective cohorts. PARTICIPANTS: COPDGene (N = 3536) and SPIROMICS (N = 1060) subjects who were current or former smokers aged 45-80. MAIN MEASURES: Participants were surveyed to determine whether e-cigarette use was associated with longitudinal changes in COPD progression or smoking habits. KEY RESULTS: From 2010 to 2016, participants who had ever used e-cigarettes steadily increased to 12-16%, but from 2014 to 2016 current use was stable at ~5%. E-cigarette use in African-Americans (AA) and whites was similar; however, AA were 1.8-2.9 times as likely to use menthol-flavored e-cigarettes. Current e-cigarette and conventional cigarette users had higher nicotine dependence and consumed more nicotine than those who smoked only conventional cigarettes. E-cigarette users had a heavier conventional cigarette smoking history and worse respiratory health, were less likely to reduce or quit conventional cigarette smoking, had higher nicotine dependence, and were more likely to report chronic bronchitis and exacerbations. Ever e-cigarette users had more rapid decline in lung function, but this trend did not persist after adjustment for persistent conventional cigarette smoking. CONCLUSIONS: E-cigarette use, which is common in adults with or at risk for COPD, was associated with worse pulmonary-related health outcomes, but not with cessation of smoking conventional cigarettes. Although this was an observational study, we find no evidence supporting the use of e-cigarettes as a harm reduction strategy among current smokers with or at risk for COPD. PMID- 28884424 TI - Immunobiology of spinal cord injuries and potential therapeutic approaches. AB - The incidence of spinal cord injuries (SCI) is high every year. As the spinal cord is the highway that allows for the brain to control the rest of the body, spinal cord injuries greatly impact the quality of life of the patients. The SCI include the primary response consisting of the initial accident-induced damage and the secondary response that is characterized by damage due to inflammation and biological responses. Astrocytes are the first to act at the site of the injury, forming a glial scar and attracting immune cells. The immune system plays a role in cleaning out the debris caused by the injury, as well as preventing neurons to grow and heal. The secondary injury caused by the inflammatory response is the major target to combat SCI. This article critically reviews the key players in the inflammatory SCI response and potential therapies, specifically targeting astrocytes, neutrophils, and macrophages. These cells are both beneficial and detrimental following SCI, depending on the released molecules and the types of cells infiltrated to the site of injury. Indeed, depending on the subtype of macrophages, M1 or M2, beneficial or detrimental response could be incited. Therapeutic strategies to regulate and manipulate the immune cells via increasing or decreasing their recruitment to the site of injury could be developed together with upregulating and downregulating the release of certain chemicals from the infiltrated cells. PMID- 28884425 TI - Can a Neurosteroid Ameliorate Fragile X-Associated Tremor/Ataxia Syndrome? PMID- 28884426 TI - Thyroid autoimmune antibodies in patients with papillary thyroid carcinoma: a double-edged sword? AB - PURPOSE: The relationship between thyroid autoimmunity and thyroid cancer remains controversial. The objective of this study is to comprehensively analyze the association between thyroid autoimmune antibodies and disease statuses of papillary thyroid carcinoma (PTC). METHODS: Patients were divided into different groups according to their final diagnoses after radioiodine therapy as well as their serum anti-thyroglobulin antibody (TgAb) and anti-thyroidperoxidase antibody (TPOAb) titers. Clinicopathologic characteristics were then compared between groups. RESULTS: In all, 1126 PTC patients met the inclusion criteria. When compared with thyroid autoimmune antibody negative group, patients in positive group were young female predominant. After age and gender adjusted, patients in thyroid autoimmune antibody positive group had much more cervical metastatic node count and this effect was limited to the central compartment but not to the lateral compartment. Antibody positivity rate was much lower in patients with distant metastasis and multivariable logistic regression analysis showed positive status of antibody was a protective factor of distant metastasis of PTC with an OR value of 0.403 (95% CI 0.216-0.622, p < 0.001). Additionally, subgroup analysis demonstrated single TgAb positivity and combined positivity of TgAb and TPOAb were shown to be related to less distant metastatic disease. CONCLUSIONS: Positive thyroid auto-antibody status could be a risk factor of more metastatic cervical lymph nodes while a protective factor of distant metastatic disease in PTC patients. The association between thyroid autoimmunity and thyroid cancer can be patient and antibody specific. A systemic immunosupression status may exist in PTC patients with distant metastasis. PMID- 28884427 TI - Effect of oleuropein on cognitive deficits and changes in hippocampal brain derived neurotrophic factor and cytokine expression in a rat model of post traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a condition that develops after an individual has experienced a major trauma. This psychopathological response to traumatic stressors induces learning and memory deficits in rats. Oleuropein (OLE), a major compound in olive leaves, has been reported to possess several pharmacological properties, including anti-cancer, anti-diabetic, anti atherosclerotic and neuroprotective activities. However, the cognitive effects of OLE and its mechanism of action have remained unclear in PTSD. In this study, we examined whether OLE improved spatial cognitive impairment induced in rats following single prolonged stress (SPS), an animal model of PTSD. Male rats were treated intraperitoneally (i.p.) with vehicle or various doses of OLE for 14 consecutive days after the SPS procedure. The SPS procedure resulted in cognitive impairment in the object recognition task and the Morris water maze test, which was reversed by OLE (100 mg/kg, i.p). Additionally, as assessed by immunohistochemistry and reverse transcription-polymerase chain reaction analysis, the administration of OLE significantly alleviated memory-associated decreases in the levels of brain-derived neurotrophic factor and cAMP response element-binding protein and mRNA in the hippocampus. Together, these findings suggest that OLE attenuated SPS-induced cognitive impairment significantly by inhibiting the expression of pro-inflammatory mediators in the rat brain. Thus, OLE reversed several behavioral impairments triggered by the traumatic stress of SPS and might be a potential useful therapeutic intervention for PTSD. PMID- 28884428 TI - In vitro and in vivo anti-proliferative evaluation of bis(4'-(4-tolyl)-2,2':6',2" terpyridine)copper(II) complex against Ehrlich ascites carcinoma tumors. AB - The bis(4'-(4-tolyl)-2,2':6',2"-terpyridine)copper(II) complex [Cu(ttpy)2]Cl2 was synthesized and authenticated by single crystal analysis, which shows distorted octahedral geometry around copper(II) ion. The crystal packing is stabilized by C H...pi inter and intramolecular interactions. The complex was found to be lipophilic as determined by shake-flask method. In vitro cytotoxicity of the complex was tested against Ehrlich ascites carcinoma (EAC) and L6 myotube cell lines. The complex exhibit potent cytotoxicity with respect to the commercially available anticancer drug cisplatin. Hoechst 33258, AO/EB and PI (flow cytometry) staining methods suggest that the complex can induce apoptosis in EAC cells. Cell cycle analyses also support the induced apoptosis. Cellular uptake studies revealed that the complex can go into the cytoplasm and accumulate in the cell nuclei. The complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway by activating caspase 3 and caspase 7 and regulates the Bcl 2 family proteins. In vivo study of the complex was validated against the animal tumor growth (EAC) cell in Swiss albino mice. The bis(4'-(4-tolyl)-2,2':6',2" terpyridine)copper(II) complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway and significantly reduced the body weight and solid tumor volume in Swiss albino mice. PMID- 28884429 TI - Effects of hypergravity on gene levels in anti-gravity muscle and bone through the vestibular system in mice. AB - We recently reported that hypergravity with 3 g for 4 weeks affects muscle and bone through the vestibular system in mice. The purpose of this study was to investigate the effects of hypergravity with 2 g, which had no influence on circulating glucocorticoid level, on the gene levels in muscle and bone, as well as the roles of the vestibular system in those changes using vestibular lesioned (VL) mice. Hypergravity for 2 and 8 weeks or VL exerted little effects on the mRNA levels of muscle differentiation factors and myokines in the soleus muscle. Although hypergravity for 2 weeks significantly elevated alkaline phosphatase (ALP) and type I collagen mRNA levels in the tibia, VL significantly attenuated the levels of ALP mRNA enhanced by hypergravity. In conclusion, the present study suggests that a 2-g load for 2 weeks enhances osteoblast differentiation partly through the vestibular system in mice. PMID- 28884430 TI - Investigation of the accumulation of ash, heavy metals, and polycyclic aromatic hydrocarbons to assess the stability of lysis-cryptic growth sludge reduction in sequencing batch reactor. AB - The accumulation of ash, heavy metals, and polycyclic aromatic hydrocarbons (collectively called potential accumulating substances, PAS) was evaluated to ascertain the stability of lysis-cryptic growth sludge reduction process (LSRP) for municipal sludge treatment. One sequencing batch reactor (SBR) incorporated with homogenization was run to test the LSRP and another SBR as a control. The continuous monitoring results for 2 months showed that the ash and heavy metals slightly increased, and the polycyclic aromatic hydrocarbons decreased by 18.0%, indicating that there may be negligible accumulations during the LSRP. Their accumulations met pattern I, as demonstrated by statistical analysis, proving no PAS accumulation for LSRP. This was further confirmed by sludge activity and system performance. Moreover, the mechanism for no PAS accumulation was discussed. It was concluded that the LSRP was stable with no worries about PAS accumulation under the operational conditions. PMID- 28884432 TI - Plasma enterolactone and risk of prostate cancer in middle-aged Swedish men. AB - PURPOSE: Enterolactone (ENL) is formed in the human gut after consumption of lignans, has estrogenic properties, and has been associated with risk of prostate cancer. We examined the association between plasma ENL levels and prostate cancer in a nested case-control study within the population-based Malmo Diet and Cancer cohort. We also examined the association between plasma ENL and dietary and lifestyle factors. METHODS: The study population consisted of 1010 cases occurring during a mean follow-up of 14.6 years, and 1817 controls matched on age and study entry date. We used national registers (95%) and hospital records (5%) to ascertain cases. Diet was estimated by a modified diet history method. Plasma ENL concentrations were determined by a time-resolved fluoroimmunoassay. Odds ratios were calculated by unconditional logistic regression. RESULTS: There were no significant associations between plasma ENL and incidence of all prostate cancer (odds ratio 0.99 [95% confidence interval 0.77-1.280] for the highest ENL quintile versus lowest, p for trend 0.66). However, in certain subgroups of men, including men with abdominal obesity (p for interaction = 0.012), we observed associations between high ENL levels and lower odds of high-risk prostate cancer. Plasma ENL was positively associated with consumption of high-fibre bread, fruit, tea, and coffee; with age, and with height, while it was negatively associated with smoking and waist circumference; however, although significant, all associations were rather weak (r <= |0.14|). CONCLUSION: ENL concentration was not consistently associated with lower prostate cancer risk, although it was weakly associated with a healthy lifestyle. PMID- 28884433 TI - Oviposition inhibitor in umbelliferous medicinal plants for the common yellow swallowtail (Papilio machaon). AB - Umbelliferous medicinal plants, such as Angelica acutiloba Kitagawa and Angelica dahurica Bentham et Hooker filius ex Franchet et Savatier, account for a large percentage of crude drug consumption in Japan. The most serious problem in the cultivation of umbelliferous medicinal plants is the feeding damage caused by the common yellow swallowtail (Papilio machaon hippocrates C. & R. Felder, 1864). When we compared the numbers of eggs laid by P. machaon on six umbelliferous medicinal plants, the eggs on A. acutiloba, A. dahurica, and Glehnia littoralis Fr. Schmidt ex Miquel were the most numerous, those on Saposhnikovia divaricata Schischkin and Cnidium officinale Makino were rare, and Bupleurum falcatum Linne was not oviposited at all. To identify oviposition inhibitors for P. machaon in B. falcatum, S. divaricata, and C. officinale, the volatile chemical constituents of these umbelliferous medicinal plants were compared with GC-MS. We carried out multivariate analysis of gas chromatographic data and concluded that germacrene D, alpha-humulene, and trans-caryophyllene play important roles in protecting plants from oviposition by P. machaon. Their oviposition repellent activity was confirmed by the fact that the number of eggs laid on the leaves around a repellent device containing a mixture of germacrene D, alpha-humulene, and trans caryophyllene was reduced by 40% compared to a control. PMID- 28884434 TI - Clinical Predictors of Malignancy in Patients with Pheochromocytoma and Paraganglioma. AB - BACKGROUND AND PURPOSE: Factors associated with malignancy in patients with pheochromocytoma (adrenal tumors, Pheo) and paraganglioma (extra-adrenal, PGL) are not well-defined and all patients require lifelong surveillance. The primary aim of our study was to determine genetic and clinical variables associated with malignancy in patients with Pheo/PGL. METHODS: Single institution retrospective review was performed of all patients who underwent surgery (1/95-1/15) for Pheo/PGL. Malignancy was defined as histology-confirmed distant metastasis, lymph nodal involvement, or tumor bed recurrence. RESULTS: A total of 157 Pheo/PGL patients (44 malignant, 113 benign) with mean follow-up of 87 months were included. Compared with patients with benign Pheo/PGL, patients with malignant Pheo/PGL were younger (median 42 vs 50 years, p = 0.014), had larger tumors (median 6.5 vs 4 cm, p < 0.001) and had PGL (63.6 vs 4.4%, p < 0.001). Genetic testing was performed in 60 patients and was positive in 38 (63%). Although positive genetic results were equally likely in malignant vs benign Pheo/PGL (76 vs 54%, p = 0.1), all 11 patients with germline SDHB mutations had malignant disease. In multivariable analysis, younger age, larger tumor size, and PGL were associated with malignancy (p < 0.05). Pheo patients with negative genetic testing and negative family history who developed metachronous metastases all had primary tumors >=4 cm in size. CONCLUSIONS: Patients who are young, have larger tumors, positive genetic testing (especially SDHB) or have PGL require long-term follow-up. Patients with negative genetic testing or family history and Pheo <4 cm have a lower risk of malignancy, and de-escalated long-term surveillance may be appropriate follow-up. PMID- 28884431 TI - Angiotensin II AT2 Receptors Contribute to Regulate the Sympathoadrenal and Hormonal Reaction to Stress Stimuli. AB - Angiotensin II, through AT1 receptor stimulation, mediates multiple cardiovascular, metabolic, and behavioral functions including the response to stressors. Conversely, the function of Angiotensin II AT2 receptors has not been totally clarified. In adult rodents, AT2 receptor distribution is very limited but it is particularly high in the adrenal medulla. Recent results strongly indicate that AT2 receptors contribute to the regulation of the response to stress stimuli. This occurs in association with AT1 receptors, both receptor types reciprocally influencing their expression and therefore their function. AT2 receptors appear to influence the response to many types of stressors and in all components of the hypothalamic-pituitary-adrenal axis. The molecular mechanisms involved in AT2 receptor activation, the complex interactions with AT1 receptors, and additional factors participating in the control of AT2 receptor regulation and activity in response to stressors are only partially understood. Further research is necessary to close this knowledge gap and to clarify whether AT2 receptor activation may carry the potential of a major translational advance. PMID- 28884435 TI - Aggression by Children Exposed to IPV: Exploring the Role of Child Depressive Symptoms, Trauma-Related Symptoms, & Warmth in Family Relationships. AB - Multi-informant reports of aggression by siblings in families with and without a history of IPV were compared. Associations between aggressive behavior and child depressive and trauma-related symptoms, as well as maternal and sibling warmth were also explored. Mothers, observers and the siblings themselves reported on aggressive behaviour. Mothers reported on child trauma-related symptoms while children provided self-report on depressive symptoms and mother-child and sibling warmth. The frequency of observed aggression did not differ across groups on average, although more sibling dyads exposed to IPV engaged in aggression than those not exposed. Child reports of sibling aggression did not differ across groups but mothers reported significantly less aggressive behavior by children exposed to IPV than those not exposed. Regression results indicated that depressive and trauma-related symptoms were significant risk factors for aggression, while the role of mother-child and sibling warmth was more complex. Results were discussed within a developmental psychopathology framework. PMID- 28884437 TI - Extrapolation of a Brivaracetam Exposure-Response Model from Adults to Children with Focal Seizures. AB - INTRODUCTION: Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration-effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A). METHODS: The existing adult PK/PD model for brivaracetam was applied to a combined adult-pediatric dataset of levetiracetam. This model was then used to predict the effective oral twice-daily dose of brivaracetam in children aged >=4 to <16 years as adjunctive treatment for focal (partial onset) seizures. The existing model described daily seizure counts using a negative binomial distribution, taking previous-day seizure frequencies into account, and using a mixture model to separate 'placebo-like' and 'responder' subpopulations. The model was adapted to describe aggregated monthly seizure counts for adult patients in the levetiracetam studies: daily seizure counts were only available for children in the levetiracetam studies. RESULTS: The levetiracetam PK/PD model successfully described both the adult and pediatric data using the same drug effect parameters, and using a model structure similar to the existing adult brivaracetam PK/PD model. CONCLUSION: Simulation with the adult brivaracetam PK/PD model in combination with an existing pediatric brivaracetam population PK model allowed characterization of the dose-response curve, suggesting maximum response at brivaracetam 4 mg/kg/day dosing (capped at 200 mg/day, the maximum adult dose) in children aged >=4 years. PMID- 28884438 TI - Development of a standard reference material containing 22 chlorinated hydrocarbon gases at 1 MUmol/mol in nitrogen. AB - A gas standard mixture containing 22 chlorinated hydrocarbons in high purity nitrogen was prepared using a two-step weighing method and a gasifying apparatus developed in-house. The concentration of each component was determined using a gas chromatograph with flame ionization detection (GC/FID). Linear regression analysis of every component was performed using the gas standard mixture with concentrations ranging from 1 to 10 MUmol/mol, showing the complete gasification of volatile organic compound (VOCs) species in a selected cylinder. Repeatability was also examined to ensure the reliability of the preparation method. In addition, no significant difference was observed between domestic treated and imported treated cylinders, which were conducive to reduction of the cost of raw materials. Moreover, the results of stability testing at different pressures and long-term stability tests indicated that the gas standard at 1 MUmol/mol level with relative expanded uncertainties of 5% was stable above 2 MPa for a minimum of 12 months. Finally, a quantity comparison was conducted between the gas standard and a commercial gas standard from Scott Specialty Gases (now Air Liquide America Specialty Gases). The excellent agreement of every species suggested the favorable accuracy of our gas standard. Therefore, this reference material can be applied to routine observation of VOCs and for other purposes. PMID- 28884436 TI - Effects of VEGF levels on anti-VEGF therapy for patients with idiopathic choroidal neovascularization. AB - The objective of this study is to investigate the levels of vascular endothelial growth factor (VEGF) and other cytokines in aqueous humor of patients with idiopathic choroidal neovascularization (CNV) and their effects together with central retinal thickness (CRT) on the response to intravitreal injection of anti VEGF antibody ranibizumab. This clinical study recruited 32 eyes from 32 patients with CNV under or besides fovea. VEGF, interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1 levels were detected in aqueous humor (0.1 ml) sampled during intravitreal injection. Aqueous humor controls were from nine cataract patients without any systemic disorders. The VEGF levels in aqueous humor were negatively related (r = -0.373, p = 0.035) to CRT, which was positively related (r = 0.743, p < 0.001) to the number of injections. The VEGF levels before treatment and during the third injection in four patients with three or more injections were 13.42 +/- 8.50 and 5.75 +/- 3.68 (p = 0.055), respectively. The average best corrected visual acuity (BCVA) before and 12 months after treatment were 57.03 +/- 16.15 and 75.16 +/- 11.78 (p < 0.001), and the average CRT before and 12 months after treatment were 352.09 +/- 84.15 and 251.13 +/- 63.96 (p < 0.001), respectively. The visual improvement was negatively related (r = -0.815, p < 0.001) to the visual baseline, and the vision 12 months after treatment was positively related (r = 0.581, p < 0.001) to that before treatment. No severe ocular or systemic complication appeared during treatment and follow-ups for all the patients. Intravitreal injection of anti-VEGF antibody ranibizumab is safe and effective for the treatment of idiopathic CNV through decreasing CRT. The patients with larger CRT baseline need more injections of ranibizumab. PMID- 28884439 TI - Neurotrophins and neuroinflammation in fetuses exposed to maternal depression and anxiety disorders during pregnancy: a comparative study on cord blood. AB - In recent years, there have been changes in the approach to maternal psychiatric disorders and their effects on the fetus, with the focus redirected to the search for biological markers. Neurotrophic factors and inflammatory processes have received particular attention in the past few years. According to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the study sample (n = 136) consisted of three groups: mothers with major depressive disorder (MDD group, n = 25), mothers with anxiety disorder (AD group, n = 18), and mothers without any psychiatric disorders (not diagnosed (ND) group, n = 93). During the delivery/cesarean section, a blood sample was obtained from the umbilical cord. Serum concentrations of BDNF, NT-3, FGF2, TNF-alpha, and neopterin were determined by enzyme-linked immunosorbent assay (ELISA), according to the manufacturer's procedure. Clinical and biochemical characteristics were assessed. We did not find a significant difference among the three study groups with regard to BDNF, NT-3, and TNF-alpha levels. The ANOVA test indicated statistically significant differences in FGF2 levels and neopterin between the study groups. The newborns of mothers with AD had significantly higher FGF2 levels and significantly higher neopterin levels when compared with those of mothers with MDD and healthy mothers. The present study sheds light on the effects of higher FGF2 and neopterin levels in fetuses exposed to AD. Our results should be replicated through further prospective studies with a larger sample size. PMID- 28884440 TI - Disappearance of multiple hyperechoic liver nodules in sporadic porphyria cutanea tarda after treatment with ledipasvir/sofosbuvir for hepatitis C. AB - Ultrasonography in a 60-year-old man with chronic hepatitis C (CHC) demonstrated multiple hyperechoic nodules. Radiological investigations did not reveal any signs of malignancy. However, magnetic resonance chemical shift imaging showed multiple focal fatty changes in the liver. Urinary levels of uroporphyrin and coproporphyrin were elevated, and we made a diagnosis of porphyria cutanea tarda. Direct-acting antivirals, ledipasvir/sofosbuvir, were initiated for CHC, which led to sustained viral response, resolution of the liver nodules, and normalization of urinary porphyrin. Hepatitis C virus infection can cause porphyria cutanea tarda with multiple hyperechoic liver nodules, which might be cured by direct-acting antivirals. PMID- 28884441 TI - Inhibition of retroviral Gag assembly by non-silencing miRNAs promotes autophagic viral degradation. AB - We recently reported an unconventional mechanism by which miRNAs inhibit HIV-1 viral production. This occurs when miRNAs bind nonspecifically to the viral structural protein Gag, interfering with viral RNA-mediated Gag assembly at the plasma membrane. Consequently, misassembled viral complexes are redirected into the endocytic pathway where they are delivered to lysosomes for degradation. In this study, we demonstrate that autophagy is a critical mediator of the viral degradation pathway and that this pathway is not HIV-1 specific. Misassembled viral complexes were found to colocalize extensively with LC3 and p62 in late endosomes/lysosomes, demonstrating a convergence of autophagy with functional degradative compartments. Knocking down autophagosome formation machineries reduced this convergence, while treatment with autophagy-inducer rapamycin enhanced the convergence. Furthermore, similar autophagy-dependent nonspecific miRNA inhibition of murine leukemia virus (MLV) assembly was shown. Overall, these results reveal autophagy as a crucial regulator of the retroviral degradation pathway in host cells initiated by nonspecific miRNA-Gag interactions. These findings could have significant implications for understanding how cells may regulate retroviral complex assembly by miRNA expression and autophagy, and raise the possibility that similar regulations can occur in other biological contexts. PMID- 28884442 TI - Whitening and anti-wrinkle activities of ferulic acid isolated from Tetragonia tetragonioides in B16F10 melanoma and CCD-986sk fibroblast cells. AB - Ferulic acid isolated from Tetragonia tetragonioides was tested for its whitening effect on the B16F10 mouse melanoma cell line and its anti-wrinkle activity on the CCD-986sk human dermal fibroblast cell line. Ferulic acid, one of the primary phenolic compounds that can be isolated from T. tetragonioides, has been reported to show potential as a functional food, for its whitening effect and anti-wrinkle activity. To measure its whitening and anti-wrinkle activities, cells were treated with ferulic acid isolated from T. tetragonioides at concentrations between 5 and 20 MUM. Ferulic acid showed no cytotoxicity at concentrations up to 20 MUM. Ferulic acid inhibited melanin synthesis, tyrosinase expression, and microphthalmia transcription factor expression in B16F10 cells stimulated with alpha-melanocyte stimulating hormone. Ferulic acid induced procollagen synthesis, hyaluronic acid synthesis, tissue inhibitor of metalloproteinase synthesis, and inhibited matrix metalloproteinase (MMP)-1 and MMP-9 expression in CCD-986sk cells stimulated with UV-B. On the basis of these results, we conclude that ferulic acid isolated from T. tetragonioides shows potential for use as a functional food, with whitening and anti-wrinkle activities. PMID- 28884443 TI - Megakaryoblastic transformation of therapy-related myeloid neoplasms with concomitant MYC amplification on double minute chromosomes. PMID- 28884444 TI - The CCAAT box in the proximal SERCA2 gene promoter regulates basal and stress induced transcription in cardiomyocytes. AB - The cardiac sarco/endoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) is vital for the correct handling of calcium concentration in cardiomyocytes. Recent studies showed that the induction of endoplasmic reticulum (ER) stress (ERS) with the SERCA2 inhibitor Thapsigargin (Tg) increases the mRNA and protein levels of SERCA2a. The SERCA2 gene promoter contains an ERS response element (ERSE) at position -78 bp that is conserved among species and might transcriptionally regulate SERCA2 gene expression. However, its involvement in SERCA2 basal and calcium-mediated transcriptional activation has not been elucidated. In this work, we show that in cellular cultures of neonatal rat ventricular myocytes, the treatment with Tg or the calcium ionophore A23187 increases the SERCA2a mRNA and protein abundance, as well as the transcriptional activity of two chimeric human SERCA2 gene constructs, containing -254 and -2579 bp of 5'-regulatory region cloned in the pGL3-basic vector and transiently transfected in cultured cardiomyocytes. We found that the ERSE present in the SERCA2 proximal promoter contains a CCAAT box that is involved in basal and ERS-mediated hSERCA2 transcriptional activation. The EMSA results showed that the CCAAT box present in the ERSE recruits the NF-Y transcription factor. Additionally, by ChIP assays, we confirmed in vivo binding of NF-Y and C/EBPbeta transcription factors to the SERCA2 gene proximal promoter. PMID- 28884445 TI - Antiviral activity of quercetin-3-beta-O-D-glucoside against Zika virus infection. AB - Q3G is a natural derivative of quercetin and is already widely used in various foods and drinks. Our results clearly demonstrated that Q3G exerts antiviral activity against ZIKV in both tissue culture and knockout mice, and that post exposure in vivo treatment with Q3G could have a beneficial effect. In the future, Q3G should be tested in human cell lines (such as Huh-7, HeLa, or K048, a fetal brain neural stem cell line) to provide further data supporting its potential efficacy in humans; in addition, live viral loads or viremia should be tested in treated animals to supplement the survival results observed in this study. Although the treatment regimens will need to be further optimized (i.e., dosage, frequency of treatment, and administration routes), our results support the results of Q3G efficacy studies in nonhuman primates against ZIKV infection. Further studies will also be needed to investigate the mechanism of Q3G antiviral action, in order to obtain valuable insights into the design of novel targets for antiviral therapeutics in the future. PMID- 28884447 TI - Guidelines in review: Comparison of ESC and ACC/AHA guidelines for the diagnosis and management of patients with stable coronary artery disease. AB - In 2012, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) Task Force on Practice Guidelines jointly with the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons produced a set of recommendations intended to assist physicians in the diagnosis and management of patients with stable ischemic heart disease. Two years later, a focused update on the 2012 guidelines was published. A year before this update, The Task Force on the management of stable coronary artery disease (CAD) of the European Society of Cardiology (ESC) issued a guideline on the management of stable CAD. This document brings together European and American recommendations that include the use of stress testing and non-invasive imaging for the diagnosis and management of patients with known or suspected stable CAD. PMID- 28884446 TI - Analysis of Homeostatic Mechanisms in Biochemical Networks. AB - Cell metabolism is an extremely complicated dynamical system that maintains important cellular functions despite large changes in inputs. This "homeostasis" does not mean that the dynamical system is rigid and fixed. Typically, large changes in external variables cause large changes in some internal variables so that, through various regulatory mechanisms, certain other internal variables (concentrations or velocities) remain approximately constant over a finite range of inputs. Outside that range, the mechanisms cease to function and concentrations change rapidly with changes in inputs. In this paper we analyze four different common biochemical homeostatic mechanisms: feedforward excitation, feedback inhibition, kinetic homeostasis, and parallel inhibition. We show that all four mechanisms can occur in a single biological network, using folate and methionine metabolism as an example. Golubitsky and Stewart have proposed a method to find homeostatic nodes in networks. We show that their method works for two of these mechanisms but not the other two. We discuss the many interesting mathematical and biological questions that emerge from this analysis, and we explain why understanding homeostatic control is crucial for precision medicine. PMID- 28884448 TI - Conference report: the 5th Asia Pacific Protein Association Conference joint meeting with the 12th International Symposium of the Protein Society of Thailand. PMID- 28884449 TI - Insulin Resistance and Hunger in Childhood Obesity: A Patient and Physician's Perspective. AB - This article is co-authored by the mother of a child with obesity and insulin resistance, who gives her perspective. It is also co-authored by the treating Obesity Medicine clinician and an investigator in obesity clinical research (both certified in Obesity Medicine), who give their perspectives. The discussion focuses upon the potential clinical use of metformin in managing young patients with obesity and insulin resistance. The article integrates what is scientifically known about the mechanisms of actions of metformin and how these mechanisms are reflected in the clinical response of young patients. PMID- 28884450 TI - Illness Representations of Pertussis and Predictors of Child Vaccination Among Mothers in a Strict Vaccination Exemption State. AB - Background Vaccine preventable diseases are making a comeback in the US. However, research is lacking on illness representations of vaccine preventable diseases and their application in improving childhood immunization. Objective We utilized the common sense model of self-regulation to examine illness representations of pertussis and their associations with child's receipt of any vaccine, up-to-date vaccination status, and mothers' intentions to follow the recommended vaccination schedule in the future. Methods We developed vaccine worry and vaccine hassles scales to assess mothers' worries and hassles for child vaccination, and used an open ended question to assess mother's illness representations of pertussis. We surveyed mothers with children <3 years old (N = 160) in the Appalachian state of West Virginia, which only allows medical vaccine exemptions. Results Some children (5.0%) had received no vaccination, 15.0% were not up-to-date with the recommended vaccination schedule, and 13.8% mothers reported no intention to follow the recommended schedule in future (future intention). Illness representations included identity (17.8%), timeline (61.8%), consequences (58.6%), cause (35.0%), and cure/control (56.7%). Higher vaccine worry was associated with child receiving no vaccine. Not using daycare, higher vaccine worry, and difficulty breathing (identity) were associated with child not being up-to-date. Higher vaccine worry, cough (identity), and belief that vaccines are ineffective (cure/control) were associated with no future intention. Conclusions Vaccination interventions need to address mothers' worry regarding vaccine safety. 'Common Sense' beliefs regarding vaccines need to be reconciled with scientific data about vaccine safety and effectiveness, even among those with high socio-economic status in a strict vaccination state. PMID- 28884452 TI - Microsurgical Reconstruction Following Oncologic Resection in Pediatric Patients: A 15-Year Experience. AB - BACKGROUND: Free tissue transfer in the pediatric population is a challenging endeavor, even for experienced microsurgeons. Some surgeons argue these cases can be limited by vessel size and spasticity and should be undertaken only when absolutely necessary. We present a 15-year experience examining outcomes of free tissue transfer in pediatric oncologic patients. METHODS: All free flaps performed at a single institution in pediatric patients (age range 3-17) between January 2000 and December 2014 were reviewed. RESULTS: Overall, 102 patients (mean age 12.1 +/- 4.0 years) were identified who underwent 109 free flaps. The most common flaps were the fibula free flap (46%) and the anterolateral thigh free flap (27%). 81 cases (74%) had malignant disease with 70 cases (64%) involving the head and neck region. 21 cases (19%) had preoperative radiation and 58 cases (53%) had preoperative chemotherapy. 5 cases had total flap loss (4.6%) and 17 cases (15.6%) had immediate post-operative complications, with wound infection (4.6%) being most common. 17 cases (15.6%) had long-term complications with delayed or non-union (4.6%) being most common. Survival rate was 91.7% at 1 year and 78.9% at 5 years. CONCLUSIONS: Free tissue transfer is a reliable and appropriate choice in pediatric patients requiring soft tissue or bony reconstruction. Even in pediatric oncologic patients with preoperative chemotherapy or radiation, flap survival and outcomes are comparable to the adult population. Pediatric free tissue transfer should not be avoided but instead considered the gold standard for patients with complex defects, just as it is in the adult population. PMID- 28884453 TI - Gastric cancer associated with refractory cytomegalovirus gastritis. AB - Cytomegalovirus (CMV) sometimes causes gastritis, especially in immunocompromised patients, but whether CMV gastritis promotes the development of gastric cancer is unknown. Here, we report a case of gastric cancer that developed in the presence of CMV gastritis, which had been present for at least 4 years and was refractory to treatment. An 80-year-old woman had noted epigastric discomfort and appetite loss. Esophagogastroduodenoscopy revealed a shallow geographical ulcer extending from the upper body to the pylorus. Histological findings of the biopsy and serology were suggestive of CMV gastritis. Serum anti-Helicobacter pylori antibody test was positive, suggesting co-infection with CMV and H. pylori. Her gastritis was unimproved with repeated antiviral therapy and eradication of H. pylori. Thirty months later, wide-spread gastric cancer had developed. We suggest the possibility that the addition of chronic inflammation of CMV infection to H. pylori-induced gastritis facilitated the development of gastric cancer. PMID- 28884454 TI - Prevalence of patient-reported gastrointestinal symptoms and agreement with clinician toxicity assessments in radiation therapy for anal cancer. AB - PURPOSE: Gastrointestinal (GI) symptoms pose a significant burden to patients receiving chemoradiation therapy (CRT) for anal cancer; however, the impact of symptoms from the patient perspective has not been quantified. This retrospective study examined and compared patient and clinician reports of acute GI toxicity during CRT. MATERIALS AND METHODS: Patients treated with definitive RT using intensity-modulated radiation therapy for anal cancer between 9/09 and 11/12 were reviewed. Median RT dose was 56 Gy (range 45-56), and 76 patients (97%) received concurrent 5-fluorouracil-based chemotherapy. During RT, patients completed the 7 item Bowel Problem Scale (BPS) weekly. Clinicians assessed toxicity separately using CTCAE v. 3.0. Scores of BPS >= 3 and CTCAE >= 1 were considered to be clinically meaningful. Agreement of the two assessments was evaluated by Cohen's kappa coefficient. RESULTS: Seventy-eight patients completed at least one BPS and had a corresponding clinician assessment. Patients reporting scores of >=3 was highest at week 5 (n = 68) for diarrhea (44.1%), proctitis (57.4%), and mucus (48.4%), while urgency (47.6%), tenesmus (31.7%), and cramping (27%) were highest at week 4 (n = 63). Baseline bleeding scores (26.7%; score >=3) improved during treatment (13.4% at week 5). "Poor" agreement was observed between patient- and clinician-reported proctitis (Cohen's k = 0.11; n = 58); however, there was "good" agreement for diarrhea (Cohen's k = 0.68; n = 58). CONCLUSIONS: Acute GI toxicity during definitive CRT for anal cancer was most significant during weeks 4-5, while rectal bleeding improved during treatment. Discrepancies in patient- and clinician-reported symptoms demonstrate the potential for patient-reported outcomes to be useful tools for anal cancer clinical assessments. PMID- 28884455 TI - Mild electrokinetic treatment of cadmium-polluted manure for improved applicability in greenhouse soil. AB - Applications of cadmium (Cd) and salinity-containing manures contribute to Cd pollution and salinization in greenhouse soils. In this study, chicken manure polluted with Cd (5.6 mg/kg) was mildly electrokinetically treated (0.25 V/cm) for 48 h with intermittent replacement of catholyte with 20 mM acetic acid solution to remove Cd and salinity for application without need of post-treatment in greenhouse soil. The electrokinetic treatment created pH conditions mainly ranging from 5.0 to 8.0 within the manure for minimizing re-precipitation of desorbed Cd and evaporative loss of ammonium. However, without manure pre acidification, electrokinetic treatment resulted in negligible removal of total Cd but 61.7% of increase in the small fraction of exchangeable Cd, due to poor desorption but enhanced formation of exchangeable Cd. In contrast, manure pre acidification with 20 mM acetic acid favored Cd desorption, leading to electrokinetic removal of exchangeable, carbonate-bound, and total Cd by 32.2%, 34.5%, and 14.5%, respectively. Mild electrokinetic treatment of manure with and without pre-acidification resulted in similar removal of salinity (72.3% and 68.0%), similar pH condition (7.2 and 7.4), and basically same evaporative loss of ammonium (14.6% and 14.2%). Overall, the mild electrokinetic treatment considerably lowered the risk of Cd and the salinity from the pre-acidified manure for improved applicability in greenhouse soil, and more studies are needed to enhance the performance of electrokinetic Cd removal from manure. PMID- 28884456 TI - Erratum to: Repeat Rifaximin for Irritable Bowel Syndrome: No Clinically Significant Changes in Stool Microbial Antibiotic Sensitivity. PMID- 28884457 TI - [The development of clinical practice algorithms for the appropriate use of psychotropic drugs in older persons with high risk of falls]. AB - Psychotropic drugs (hypno-sedatives, antidepressants and antipsychotics) are commonly used in the older population. On the long term, psychotropic drug use in older persons is associated with several negative functional outcomes such as an increased risk of falls. Gradual withdrawal of psychotropic drugs in older persons is feasible and leads to a significant reduction of falls. Both withdrawal of psychotropic drugs as well as the initiation of appropriate treatment with psychotropic drugs requires knowledge, consultation and cooperation between disciplines and a mentality change among healthcare professionals. In order to inform and support healthcare professionals, the Centre of Expertise for Fall and Fracture Prevention Flanders developed three clinical practice algorithms for the appropriate use of psychotropic drugs in older persons with high risk of falls and a fact sheet with background information. PMID- 28884458 TI - Erratum to: The cardiothoracic ratio and all-cause and cardiovascular disease mortality in patients undergoing maintenance hemodialysis: results of the MBD-5D study. PMID- 28884459 TI - The Study on the Correlation Between Six Kinds of Mineral Elements and Diabetes. AB - The study aimed to explore the relationship of six kinds of mineral elements and diabetes among adults in northeast China. A cross-sectional survey was conducted in Jilin Province, northeast China. A total of 366 males and 204 females aged 18 ~ 77 years from Jingyu town, Dongliao town, and Changling town were included using a multistage stratified random cluster sampling design. Data was obtained from face to face interview, physical examination, and laboratory measurement. We defined the normal people (3.9 ~ 6.0 mmol/L), impaired fasting glucose (IFG) individuals (6.1 ~ 6.9 mmol/L), and diabetes mellitus (DM) (> 7.0 mmol/L) according to the WHO diagnostic criteria. Kruskal-Wallis test, Spearman rank correlation, as well as binary logistic regression were used to analyze influencing factors. lg(Cu/Zn)was correlated with DM (OR 8.390; 95% CI of OR 1.272-55.347). The specific mineral elements such as Zn, Ca, as well as Cu/Zn ratio may be the potential risk factors for diabetes. So, the supplement or reduction of these elements is supposed to be told to IFG to prevent or delay the occurrence of diabetes or DM to avoid its complication. PMID- 28884461 TI - Erratum to: Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial. PMID- 28884460 TI - Potassium Channels: A Potential Therapeutic Target for Parkinson's Disease. AB - The pathogenesis of the second major neurodegenerative disorder, Parkinson's disease (PD), is closely associated with the dysfunction of potassium (K+) channels. Therefore, PD is also considered to be an ion channel disease or neuronal channelopathy. Mounting evidence has shown that K+ channels play crucial roles in the regulations of neurotransmitter release, neuronal excitability, and cell volume. Inhibition of K+ channels enhances the spontaneous firing frequency of nigral dopamine (DA) neurons, induces a transition from tonic firing to burst discharge, and promotes the release of DA in the striatum. Recently, three K+ channels have been identified to protect DA neurons and to improve the motor and non-motor symptoms in PD animal models: small conductance (SK) channels, A-type K+ channels, and KV7/KCNQ channels. In this review, we summarize the physiological and pharmacological effects of the three K+ channels. We also describe in detail the laboratory investigations regarding K+ channels as a potential therapeutic target for PD. PMID- 28884462 TI - Benchmarking adult CT-dose levels to regional and national references using a dose-tracking software: a multicentre experience. AB - OBJECTIVES: To benchmark CT-dose data for standard adult CT studies to regional and national reference levels using a dose-tracking system. METHODS: Data from five CT systems from three hospitals were collected over a 1- to 2.5-year period (2012-2014), using the same type of dose management system. Inclusion criteria were adult patients and standard CT-head, CT-abdomen-pelvis, CT-thorax, CT-lumbar spine, CT-pulmonary embolism, CT-cervical spine and CT-thorax-abdomen studies, with one helical scan. Volumetric CT-dose index (CTDIvol), dose length product (DLP) and scan length from 31,709 scans were analysed statistically. RESULTS: After dose optimisation CTDIvol and DLP values were below the national diagnostic reference levels (DRLs) for all CT studies and for all systems investigated. Mostly no significant differences were found between CTDIvol and DLP levels (p values >= 0.01) of CT studies performed on different scanners within the same hospital. Significant dose differences (p values < 0.01) were instead observed among hospitals for comparable CT studies. Dose level range and scan length differences for similar CT studies were revealed. CONCLUSIONS: Dose-tracking systems help to reduce CT-dose levels below national DRLs. However, dose and protocol data comparison between and within hospitals has the potential to further reduce variability in dose data of standard adult CT studies. KEY POINTS: * Retrospective three-centre study on dose levels of standard adult CT procedures. * Dose-tracking systems help hospitals to stay below national dose reference levels. * Dose-tracking systems help to align CT dose levels between scanners within hospitals. * Benchmarking shows CT dose level variability for similar examinations in different hospitals. * Differences in dose level range/scan length for similar CT studies are revealed. PMID- 28884463 TI - Response to the comment: Is observed upper airway obstruction patterns during drug-induced sedation endoscopy dose-dependent? PMID- 28884464 TI - Tribute to Volker Schumpelick, Editor-in-Chief Emeritus of Hernia. PMID- 28884465 TI - Coordinating medical education and health care systems: the power of the social accountability approach. AB - CONTEXT: As the purpose of medical education is to produce graduates able to most effectively address people's health concerns, there is general agreement that coordination with the health care system is essential. For too long, coordination has been dealt with in a subjective manner with only few landmarks to ensure objective and measurable achievements. Over the last 30 years, since the Edinburgh Declaration on medical education, progress has been made, namely with the concept of social accountability. METHODS: The social accountability approach provides a way to plan, deliver and assess medical education with the explicit aim to contribute to effective, equitable and sustainable health system development. It is based on a system-wide scope exploring issues from identification of people's and society's health needs to verification of the effects of medical education in meeting those needs. A wide international consultation among medical education leaders led to the adoption of the Global Consensus on Social Accountability of Medical Schools. EXPERIENCES: Benchmarks of social accountability are in the process of being conceived and tested, enabling medical schools to steer medical education in a more purposeful way in relation to determinants of health. A sample of schools using the social accountability approach claims to have had a positive influence on health care system performance and people's health status. CONCLUSION: Improved coordination of medical education and other key stakeholders in the health system is an important challenge for medical schools as well as for countries confronted with an urgent need for optimal use of their health workforce. There is growing interest worldwide in defining policies and strategies and supporting experiences in this regard. PMID- 28884466 TI - Celebrating the quality of our referees. PMID- 28884467 TI - Cre-expressing neurons in visual cortex of Ntsr1-Cre GN220 mice are corticothalamic and are depolarized by acetylcholine. AB - The Ntsr1-Cre GN220 mouse expresses Cre-recombinase in corticothalamic (CT) neurons in neocortical layer 6. It is not known if the other major types of pyramidal neurons in this layer also express this enzyme. By electrophysiological recordings in slices and histological analysis of the uptake of retrogradely transported beads we show that Cre-positive neurons are CT and not corticocortical or corticoclaustral types. Furthermore, we show that Ntsr1-Cre positive cells are immuno-positive for the nuclear transcription factor Forkhead box protein P2 (FoxP2). We conclude that Cre-expression is limited to a specific type of pyramidal neuron: CT. However, it appears as not all CT neurons are Cre expressing; there are indications that the penetrance of the gene is about 90%. We demonstrate the utility of assigning a specific identity to individual neurons by determining that the CT neurons are potently modulated by acetylcholine acting on both nicotinic and muscarinic acetylcholine receptors. These results corroborate the suggested function of these neurons in regulating the gain of thalamocortical transfer of sensory information depending on attentional demand and state of arousal. PMID- 28884468 TI - When I say ... healing. PMID- 28884469 TI - Cancer of the esophagus and asbestos exposure. AB - BACKGROUND: Our study aimed at analyzing incidence and mortality from esophageal cancer within a cohort of workers with previous occupational asbestos exposure (ARDCo Program). METHODS: A 10-year follow-up study was conducted in the 14 515 male subjects included in this program between October 2003 and December 2005. Follow-up began when exposure stopped. Asbestos exposure was analyzed by industrial hygienists using data from a standardized questionnaire. The Cox model was used, with age as the time axis variable adjusted for smoking, time since first exposure (TSFE) and cumulative exposure index (CEI) of exposure to asbestos. RESULTS: We reported a significant dose-response relationship between CEI of exposure to asbestos and esophageal cancer, in both incidence (hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.00-1.58), and mortality (HR 1.40, [95%CI 1.12-1.75]). CONCLUSIONS: This large-scale study suggests the existence of a relationship between asbestos exposure and cancer of the esophagus. PMID- 28884470 TI - Breast conserving therapy and mastectomy revisited: Breast cancer-specific survival and the influence of prognostic factors in 129,692 patients. AB - This large population-based study compared breast-conserving surgery with radiation therapy (BCT) with mastectomy on (long-term) breast cancer-specific (BCSS) and overall survival (OS), and investigated the influence of several prognostic factors. Patients with primary T1-2N0-2M0 breast cancer, diagnosed between 1999 and 2012, were selected from the Netherlands Cancer Registry. We investigated the 1999-2005 (long-term outcome) and the 2006-2012 cohort (contemporary adjuvant systemic therapy). Cause of death was derived from the Statistics Netherlands (CBS). Multivariable analyses, per time cohort, were performed in T1-2N0-2, and separately in T1-2N0-1 and T1-2N2 stages. The T1-2N0-1 stages were further stratified for age, hormonal receptor and HER2 status, adjuvant systemic therapy and comorbidity. In total, 129,692 patients were included. In the 1999-2005 cohort, better BCSS and OS for BCT than mastectomy was seen in all subgroups, except in patients < 40 years with T1-2N0-1 stage. In the 2006-2012 cohort, superior BCSS and OS were found for T1-2N0-1, but not for T1 2N2. Subgroup analyses for T1-2N0-1 showed superior BCSS and OS for BCT in patients >50 years, not treated with chemotherapy and with comorbidity. Both treatments led to similar BCSS in patients <50 years, without comorbidity and those treated with chemotherapy. Although confounding by severity and residual confounding cannot be excluded, this study showed better long-term BCSS for BCT than mastectomy. Even with more contemporary diagnostics and therapies we identified several subgroups that may benefit from BCT. Our results support the hypothesis that BCT might be preferred in most breast cancer patients when both treatments are suitable. PMID- 28884472 TI - A crustacean lobula plate: Morphology, connections, and retinotopic organization. AB - The lobula plate is part of the lobula complex, the third optic neuropil, in the optic lobes of insects. It has been extensively studied in dipterous insects, where its role in processing flow-field motion information used for controlling optomotor responses was discovered early. Recently, a lobula plate was also found in malacostracan crustaceans. Here, we provide the first detailed description of the neuroarchitecture, the input and output connections and the retinotopic organization of the lobula plate in a crustacean, the crab Neohelice granulata using a variety of histological methods that include silver reduced staining and mass staining with dextran-conjugated dyes. The lobula plate of this crab is a small elongated neuropil. It receives separated retinotopic inputs from columnar neurons of the medulla and the lobula. In the anteroposterior plane, the neuropil possesses four layers defined by the arborizations of such columnar inputs. Medulla projecting neurons arborize mainly in two of these layers, one on each side, while input neurons arriving from the lobula branch only in one. The neuropil contains at least two classes of tangential elements, one connecting with the lateral protocerebrum and the other that exits the optic lobes toward the supraesophageal ganglion. The number of layers in the crab's lobula plate, the retinotopic connections received from the medulla and from the lobula, and the presence of large tangential neurons exiting the neuropil, reflect the general structure of the insect lobula plate and, hence, provide support to the notion of an evolutionary conserved function for this neuropil. PMID- 28884473 TI - Pharmacotherapy for smoking cessation: effects by subgroup defined by genetically informed biomarkers. AB - BACKGROUND: Smoking cessation therapies are not effective for all smokers, and researchers are interested in identifying those subgroups of individuals (e.g. based on genotype) who respond best to specific treatments. OBJECTIVES: To assess whether quit rates vary by genetically informed biomarkers within pharmacotherapy treatment arms and as compared with placebo. To assess the effects of pharmacotherapies for smoking cessation in subgroups of smokers defined by genotype for identified genome-wide significant polymorphisms. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group specialised register, clinical trial registries, and genetics databases for trials of pharmacotherapies for smoking cessation from inception until 16 August 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that recruited adult smokers and reported pharmacogenomic analyses from trials of smoking cessation pharmacotherapies versus controls. Eligible trials included those with data on a priori genome-wide significant (P < 5 * 10-8) single-nucleotide polymorphisms (SNPs), replicated non-SNPs, and/or the nicotine metabolite ratio (NMR), hereafter collectively described as biomarkers. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary outcome was smoking abstinence at six months after treatment. The secondary outcome was abstinence at end of treatment (EOT). We conducted two types of meta-analyses- one in which we assessed smoking cessation of active treatment versus placebo within genotype groups, and another in which we compared smoking cessation across genotype groups within treatment arms. We carried out analyses separately in non Hispanic whites (NHWs) and non-Hispanic blacks (NHBs). We assessed heterogeneity between genotype groups using T2, I2, and Cochrane Q statistics. MAIN RESULTS: Analyses included 18 trials including 9017 participants, of whom 6924 were NHW and 2093 NHB participants. Data were available for the following biomarkers: nine SNPs (rs1051730 (CHRNA3); rs16969968, rs588765, and rs2036527 (CHRNA5); rs3733829 and rs7937 (in EGLN2, near CYP2A6); rs1329650 and rs1028936 (LOC100188947); and rs215605 (PDE1C)), two variable number tandem repeats (VNTRs; DRD4 and SLC6A4), and the NMR. Included data produced a total of 40 active versus placebo comparisons, 16 active versus active comparisons, and 64 between-genotype comparisons within treatment arms.For those meta-analyses showing statistically significant heterogeneity between genotype groups, we found the quality of evidence (GRADE) to be generally moderate. We downgraded quality most often because of imprecision or risk of bias due to potential selection bias in genotyping trial participants. Comparisons of relative treatment effects by genotypeFor six-month abstinence, we found statistically significant heterogeneity between genotypes (rs16969968) for nicotine replacement therapy (NRT) versus placebo at six months for NHB participants (P = 0.03; n = 2 trials), but not for other biomarkers or treatment comparisons. Six-month abstinence was increased in the active NRT group as compared to placebo among participants with a GG genotype (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.07 to 2.03), but not in the combined group of participants with a GA or AA genotype (RR 0.43, 95% CI 0.15 to 1.26; ratio of risk ratios (RRR) GG vs GA or AA of 3.51, 95% CI 1.19 to 10.3). Comparisons of treatment effects between genotype groups within pharmacotherapy randomisation armsFor those receiving active NRT, treatment was more effective in achieving six-month abstinence among individuals with a slow NMR than among those with a normal NMR among NHW and NHB combined participants (normal NMR vs slow NMR: RR 0.54, 95% CI 0.37 to 0.78; n = 2 trials). We found no such differences in treatment effects between genotypes at six months for any of the other biomarkers among individuals who received pharmacotherapy or placebo. AUTHORS' CONCLUSIONS: We did not identify widespread differential treatment effects of pharmacotherapy based on genotype. Some genotype groups within certain ethnic groups may benefit more from NRT or may benefit less from the combination of bupropion with NRT. The reader should interpret these results with caution because none of the statistically significant meta-analyses included more than two trials per genotype comparison, many confidence intervals were wide, and the quality of this evidence (GRADE) was generally moderate. Although we found evidence of superior NRT efficacy for NMR slow versus normal metabolisers, because of the lack of heterogeneity between NMR groups, we cannot conclude that NRT is more effective for slow metabolisers. Access to additional data from multiple trials is needed, particularly for comparisons of different pharmacotherapies. PMID- 28884471 TI - The complexity of empathy during medical school training: evidence for positive changes. AB - CONTEXT: Empathy is an essential aspect of clinical care, associated with improved patient satisfaction, increased adherence to treatment, and fewer malpractice complaints. Previous studies suggest that empathy declines during medical training. However, past research relied on a single narrowly operationalised, self-report measure of empathy. As empathy is a complex socio emotional construct, it is critical to assess changes across its distinct components using multiple measures in order to better understand how it is influenced by medical training. METHODS: In a longitudinal study, medical students completed a series of self-report and behavioural measures twice per year during the first 3 years of their study (2012-2015). These included the previously used Jefferson Scale of Physician Empathy (JSPE), designed to assess empathy in the clinical context, the Questionnaire of Cognitive and Affective Empathy (QCAE), designed to assess overall empathy and its main components, and behavioural measures of sensitivity to others' pain and understanding of others' emotions, both of which are important aspects of empathy. The employment of multiple measures allowed for a more complete assessment of medical students' empathy and related processes. RESULTS: In reflection of findings in previous work, students' empathy assessed by the JSPE decreased over training. However, on the QCAE, aspects of students' empathy, specifically overall cognitive empathy and its subcomponent perspective taking, and the emotion contagion subcomponent of affective empathy improved, whereas the remaining subcomponents remained stable. During medical school, students also exhibited comparable growth in their understanding of others' emotions and increased sensitivity to others' pain. CONCLUSIONS: Changes in empathy during medical school cannot be simply characterised as representing an overall decline. Indeed, aspects of empathy thought to be valuable in positive physician-patient interactions improve during training. Overall, this study points to the importance of assessing the distinct components of empathy using multiple forms of measurement in order to better understand the mechanisms involved in empathy changes in medical practice. PMID- 28884474 TI - Recognition by natural killer cells of N6-isopentenyladenosine-treated human glioma cell lines. AB - Cancer cell stress induced by cytotoxic agents promotes antitumor immune response. Here, we observed that N6-isopentenyladenosine (iPA), an isoprenoid modified adenosine with a well established anticancer activity, was able to induce a significant upregulation of cell surface expression of natural killer (NK) cell activating receptor NK Group 2 member D (NKG2D) ligands on glioma cells in vitro and xenografted in vivo. Specifically suboptimal doses of iPA (0.1 and 1 uM) control the selective upregulation of UL16-binding protein 2 on p53wt expressing U343MG and that of MICA/B on p53mut-expressing U251MG cells. This event made the glioblastoma cells a potent target for NK cell-mediated recognition through a NKG2D restricted mechanism. p53 siRNA-mediated knock-down and pharmacological inhibition (pifithrin-alpha), profoundly prevented the iPA action in restoring the immunogenicity of U343MG cells through a mechanism that is dependent upon p53 status of malignancy. Furthermore, accordingly to the preferential recognition of senescent cells by NK cells, we found that iPA treatment was critical for glioma cells entry in premature senescence through the induction of S and G2/M phase arrest. Collectively, our results indicate that behind the well established cytotoxic and antiangiogenic effects, iPA can also display an immune-mediated antitumor activity. The indirect engagement of the innate immune system and its additional activity in primary derived patient's glioma cell model (GBM17 and GBM37), fully increase its translational relevance and led to the exploitation of the isoprenoid pathway for a valid therapeutic intervention in antiglioma research. PMID- 28884476 TI - Probiotics for preventing urinary tract infection in people with neuropathic bladder. AB - BACKGROUND: Neuropathic or neurogenic bladder describes a process of dysfunctional voiding as the result of injury in the brain, spinal cord or nerves innervating the bladder. People with neuropathic bladder, such as from spinal cord injury (SCI), are at significant risk of morbidity from urinary tract infections (UTI). Effective methods to prevent UTI in people with SCI have been sought for many years. Probiotics (micro-organisms that exert beneficial health effects in the host) have been recommended for bacterial interference of the urological tract to reduce colonisation by uropathogen and to manage the dual problems of infection and antibiotic resistance. OBJECTIVES: This review looked at the benefits and harms of probiotics in preventing symptomatic UTI in people with neuropathic bladder compared with placebo, no therapy, or non-antibiotic prophylaxis (cranberry juice, methenamine hippurate, topical oestrogen). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 10 March 2017 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), quasi-RCTs and cross-over RCTs looking at the use of probiotics for the prophylaxis of UTI in people with neuropathic bladders was considered for inclusion. Men, women and children of all ages with neuropathic bladders from neurological injury such as suprapontine, supra sacral and sacral aetiologies was included. All bladder management types, including reflex voiding, time voiding, indwelling and intermittent catheterization were eligible for this review.Studies comparing probiotics to placebo, no treatment or other non-antibiotic prophylaxis was included. Studies comparing probiotics with antibiotics or in combination with antibiotics were excluded. DATA COLLECTION AND ANALYSIS: Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) or standardised mean difference (SMD) and 95% CI were planned for continuous outcomes. MAIN RESULTS: This review includes a total of three studies (one cross-over and two parallel RCTs) which involved 110 participants. All three studies looked at intravesical instillation of a low virulent Escherichia coli (E. coli) strain in reducing the risk of symptomatic UTI in participants with neuropathic bladder, predominantly from SCI. Two studies used the E. coli 83972 strain and one study used the E. coli HU2117 strain.We did not find any RCTs involving other probiotics or other routes of administration for preventing UTI in people with neuropathic bladder.There was consistency in definition of symptomatic UTI in all three studies. Symptoms that all studies considered were relevant to diagnose UTI were adequately defined. All three studies defined microbiological diagnosis of symptomatic UTI.Asymptomatic bacteriuria was not considered an outcome measure in any of the included studies; however it was defined in two studies to establish successful inoculation.It is uncertain if the risk of symptomatic UTI is reduced with bladder inoculation using E. coli because the certainty of the evidence is very low (3 studies, 110 participants: RR 0.32, 95% CI 0.08 to 1.19; I2 = 82%).Two studies reported adverse events. One study reported one episode of autonomic dysreflexia. One study reported three symptomatic UTI occurring in two patients, and two studies mentioned the absence of septicaemia and pyelonephritis. Intravesical instillation was reported as "generally safe". One study reported high attrition rates in participants due to the need to adhere to strict instillation protocols.The overall quality of the studies was poor. All three studies had high risk of attrition bias due to failure of an intention-to-treat analysis which undermines the randomisation process and weakened the results of the studies. All three studies also had high risk of reporting bias. AUTHORS' CONCLUSIONS: In this review, there were no studies identified addressing oral probiotics in preventing UTI in people with neuropathic bladder. It is uncertain if the risk of symptomatic UTI is reduced in people with neuropathic bladders via intravesical instillation of non-pathogenic E. coli as data were derived from small studies with high risk of bias.Although very minimal levels of harm was reported with this procedure, due to variable success rates, the need for strict adherence to instillation protocols together with high attrition rates in these studies, it is doubtful bladder instillation will be a widely accepted intervention in its current form.It is recommended that further appropriately powered RCTs with more robust methodological reporting be carried out. PMID- 28884475 TI - Chronic exposure of interleukin-13 suppress the induction of matrix metalloproteinase-1 by tumour necrosis factor alpha in normal and scleroderma dermal fibroblasts through protein kinase B/Akt. AB - Peripheral blood mononuclear cells taken from patients with scleroderma express increased levels of interleukin (IL)-13. Moreover, the expression of matrix metalloproteinase-1 (MMP-1) from involved scleroderma skin fibroblasts is refractory to stimulation by tumour necrosis factor (TNF)-alpha. To elucidate the mechanism(s) involved, we examined the effect of IL-13 on TNF-alpha-induced MMP-1 expression in normal and scleroderma human dermal fibroblast lines and studied the involvement of serine/threonine kinase B/protein kinase B (Akt) in this response. Dermal fibroblast lines were stimulated with TNF-alpha in the presence of varying concentrations of IL-13. Total Akt and pAkt were quantitated using Western blot analyses. Fibroblasts were treated with or without Akt inhibitor VIII in the presence of IL-13 followed by TNF-alpha stimulation. MMP-1 expression was analysed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using analysis of variance (anova) or Student's t-test. Upon TNF-alpha stimulation, normal dermal fibroblasts secrete more MMP-1 than systemic sclerosis (SSc) fibroblasts. This increase in MMP-1 is lost when fibroblasts are co-incubated with IL-13 and TNF alpha. IL-13 induced a significant increase in levels of pAkt in dermal fibroblasts, while Akt inhibitor VIII reversed the suppressive effects of IL-13 on the response of cultured fibroblasts to TNF-alpha, increasing their expression of MMP-1. We show that IL-13 suppresses MMP-1 in TNF-alpha-stimulated normal and scleroderma dermal fibroblast. Akt inhibitor VIII is able to reverse the suppressive effect of IL-13 on MMP-1 expression and protein synthesis. Our data suggest that IL-13 regulates MMP-1 expression in response to TNF-alpha through an Akt-mediated pathway and may play a role in fibrotic diseases such as scleroderma. PMID- 28884478 TI - Medical students as teachers: hands-on quality improvement education. PMID- 28884477 TI - Fragile X granules are a family of axonal ribonucleoprotein particles with circuit-dependent protein composition and mRNA cargos. AB - Local axonal protein synthesis plays a crucial role in the formation and function of neuronal circuits. Understanding the role of this mechanism in specific circuits requires identifying the protein composition and mRNA cargos of the ribonucleoprotein particles (RNPs) that form the substrate for axonal translation. FXGs (Fragile X granules) are axonal RNPs present in a stereotyped subset of mature axons in the intact brain that contain one or more of the Fragile X related (FXR) proteins (FMRP, FXR2P, and FXR1P) along with mRNA and ribosomes. Here we performed a systematic survey of the FXR protein composition and mRNA association of FXGs in the brain. We have identified four FXG types that can be categorized based on their FXR protein complement. All FXGs contain FXR2P, with FMRP and/or FXR1P present in circuit-selective subsets. Individual neuronal cell types predominantly express a single FXG type, with FMRP-containing FXGs the most prevalent in forebrain neurons. All FXG types associate with ribosomes and mRNA, but the specific mRNA cargos are a function of FXG type, brain region and neuron class. Transcripts for beta-catenin and its regulator APC associate with a subset of forebrain FXGs. Moreover, both these transcripts can colocalize within individual FXGs, suggesting that the axonal translation of functionally related proteins may be coordinately regulated with high spatiotemporal resolution. Cell type-dependent expression of specific RNP types with distinct mRNA cargos, such as FXGs, presents a potential mechanism for regulating local translation and its output in a circuit-dependent manner. PMID- 28884479 TI - Transcriptional repression of Aurora-A gene by wild-type p53 through directly binding to its promoter with histone deacetylase 1 and mSin3a. AB - In this study, we firstly showed that p53 transcriptionally represses Aurora-A gene expression through directly binding to its promoter. DNA affinity precipitation assay and chromatin immunoprecipitation assay indicated that p53 physically bound to the Aurora-A promoter. Moreover, the in vitro and in vivo assays showed that p53 directly bound to the Aurora-A promoter together with histone deacetylase 1 (HDAC1) and mSin3a as corepressors. Furthermore, we identified that the nucleotides -360 to -354 (CCTGCCC), upstream of the Aurora-A transcriptional start site, was responsible for the p53-mediated repression. Mutation within this site disrupted its interaction with p53, mSin3a and HDAC1, as well as attenuated the repressive effect of p53 on Aurora-A promoter activity. Treatment with trichostatin A (TSA), a HDAC1 inhibitor, disrupted the interaction of p53-HDAC1-mSin3a complex with the nucleotides -365~-345 region, and enhanced the Aurora-A promoter activity and gene expression. Additionally, knockdown of p53 or mSin3a also drastically blocked the formation of p53-HDAC1-mSin3a repressive complex onto this promoter region and elevated the Aurora-A promoter activity and gene expression. Moreover, the p53-HDAC1-mSin3a repressive complex also involved in the inhibition of Aurora-A gene expression upon cisplatin treatment. Finally, the clinical investigation showed that Aurora-A and p53 exhibited an inverse correlation in both the expression level and prognostic status, and the low p53/high Aurora-A showed the poorest prognosis of NSCLC patients. Our findings showed novel regulatory mechanisms of p53 in regulating Aurora-A gene expression in NSCLC cells. PMID- 28884480 TI - Blood monocytes sample MelanA/MART1 antigen for long-lasting cross-presentation to CD8+ T cells after differentiation into dendritic cells. AB - Human blood monocytes are very potent to take up antigens. Like macrophages in tissue, they efficiently degrade exogenous protein and are less efficient than dendritic cells (DCs) at cross-presenting antigens to CD8+ T cells. Although it is generally accepted that DCs take up tissue antigens and then migrate to lymph nodes to prime T cells, the mechanisms of presentation of antigens taken up by monocytes are poorly documented so far. In the present work, we show that monocytes loaded in vitro with MelanA long peptides retain the capacity to stimulate antigen-specific CD8+ T cell clones after 5 days of differentiation into monocytes-derived dendritic cells (MoDCs). Tagged-long peptides can be visualized in electron-dense endocytic compartments distinct from lysosomes, suggesting that antigens can be protected from degradation for extended periods of time. To address the pathophysiological relevance of these findings, we screened blood monocytes from 18 metastatic melanoma patients and found that CD14+ monocytes from two patients effectively activate a MelanA-specific CD8 T cell clone after in vitro differentiation into MoDCs. This in vivo sampling of tumor antigen by circulating monocytes might alter the tumor-specific immune response and should be taken into account for cancer immunotherapy. PMID- 28884481 TI - Estrogen receptor beta selective agonist ameliorates liver cirrhosis in rats by inhibiting the activation and proliferation of hepatic stellate cells. AB - BACKGROUND AND AIM: The aim of this study is to explore the roles of estrogen receptor (ER) subtypes and corresponding agonists/antagonists on the development of cirrhosis and activation and proliferation of hepatic stellate cells (HSCs). METHODS: Carbon tetrachloride (CCl4 )-induced cirrhotic ovariectomized rats were administered non-selective ER agonist (beta-estradiol, E2), ER selective agonists (ERalpha agonist, propylpyrazoletriol; ERbeta agonist, diarylpropionitrile [DPN]; and G-protein-coupled ER [GPER] agonist, G1), or E2 + ER selective antagonists (ERalpha antagonist, MPP; ERbeta antagonist, PHTPP; and GPER antagonist, G15) for 12 weeks. The expression of the three ER subtypes in livers and HSCs and the effects of the drugs on hepatic fibrosis, isolated HSCs, and uteri were evaluated. RESULTS: Selective ER agonists/antagonists had various effects on CCl4 -induced cirrhosis. The cirrhotic rats in the CCl4 + E2, CCl4 + DPN, CCl4 + E2 + MPP, and CCl4 + E2 + G15 groups presented reduced fibrosis scores, compared with those in the CCl4 group. The cirrhotic rats in the E2 + PHTPP group presented increased fibrosis scores that similar to those in the CCl4 group. The ovariectomized rats had enlarged uteri with increased uterus indexes after E2 administration; however, the proliferative effects of E2 were partially blocked by MPP or G15, but not PHTPP. In the in vitro study, DPN attenuated the transformation of quiescent HSCs to activated phenotype, suppressed collagen I, and alpha-smooth muscle actin expression. DPN also suppressed platelet-derived growth factor-induced proliferation in cultured HSCs, which was reversed by PHTPP. CONCLUSIONS: The antifibrogenic effects of estrogen were mediated by ERbeta but not ERalpha or GPER. The ERbeta selective agonist exerted a fibrosuppressive effect by inhibiting the activation and proliferation of HSCs, but did not induce uterine hyperplasia. PMID- 28884483 TI - Training medical students how to extract, assess and communicate evidence from an article. PMID- 28884482 TI - Histological characterization of umbilical cord in alpaca (Vicugna pacos). AB - The histomorphometric features of umbilical cord constituents in seven foetuses of alpaca (Vicugna pacos) from Cerro de Pasco, Department, Peru, were determined. Sections of 2-5 cm of umbilical cord were fixed in 10% neutral buffered formalin and processed for light microscopy. Standard histological slides stained with haematoxylin and eosin, Masson's trichrome and Van Gieson's trichrome were obtained. Histologically, common features of umbilical artery and vein were observed as well as mucous connective tissue, some cell features that compound this tissue constituted by cells presented features of myofibroblasts. Among most important findings that were observed, the lumen of umbilical vein was obliterated into star-shaped form with the thinner umbilical artery wall; the smooth muscles and fibroblast were comparatively more in number in umbilical artery than that of umbilical vein, and the tunica media was larger in dimension than the tunica adventitia in umbilical vein. Conclusively, this histological study features an observation of the umbilical cord of alpaca foetuses and shows the similarity between them and those of other mammal species, including dromedaries and South American camelids. PMID- 28884484 TI - Identification of telocytes in the porcine heart. AB - Recently, a new interstitial cell type called telocyte has been identified. Telocytes are found in many organs including the heart, where they are especially well described. However, their presence in the porcine heart has not yet been proven. The pig is a valuable animal model in research because of its resemblance with man, making it interesting to determine whether telocytes can be found in pigs as well. The focus of this study is the identification and ultrastructural description of telocytes in the heart tissue of pig. Using transmission electron microscopy, telocytes were found in both left and right atrium and ventricle, usually close to cardiomyocytes and/or blood vessels. Their most important characteristic is the long cytoplasmic processes called telopodes, which have a moniliform aspect, measure tens of MUm and usually have a thickness below 0.2 MUm. This unique morphological feature enables telocytes to be recognized from other interstitial cells such as fibroblasts. Additional observations include the ability to release extracellular vesicles and to make contacts with other structures such as endothelial cells, suggesting a role in intercellular communication. PMID- 28884485 TI - Clustal Omega for making accurate alignments of many protein sequences. AB - Clustal Omega is a widely used package for carrying out multiple sequence alignment. Here, we describe some recent additions to the package and benchmark some alternative ways of making alignments. These benchmarks are based on protein structure comparisons or predictions and include a recently described method based on secondary structure prediction. In general, Clustal Omega is fast enough to make very large alignments and the accuracy of protein alignments is high when compared to alternative packages. The package is freely available as executables or source code from www.clustal.org or can be run on-line from a variety of sites, especially the EBI www.ebi.ac.uk. PMID- 28884486 TI - Are sound abatement measures necessary in the cytology reading room? A study of auditory distraction. AB - OBJECTIVE: Listening to music and other auditory material during microscopy work is common practice among cytologists. While many cytologists would claim several benefits of such activity, research in other fields suggests that it might adversely affect diagnostic performance. Using a cross-modal distraction paradigm, the aim of the present study was to investigate the effect of auditory stimulation on the visual interpretation of cell images. METHODS: Following initial training, 34 participants undertook cell interpretation tests under four auditory conditions (liked music, disliked music, speech and silence) in a counterbalanced repeated-measures study. Error rate, area under the receiver operating characteristic curve, criterion and response time were measured for each condition. RESULTS: There was no significant effect of auditory stimulation on the accuracy or speed with which cell images were interpreted, mirroring the results of a previous visual distraction study. CONCLUSION: To the extent that the experiment reflects clinical practice, listening to music or other forms of auditory material whilst undertaking microscopy duties is unlikely to be a source of distraction in the cytopathology reading room. From a cognitive perspective, the results are consistent with the notion that high focal-task engagement may have blocked any attentional capture the sound may otherwise have produced. PMID- 28884487 TI - Radiofrequency ablation in patients with large cervical heterotopic gastric mucosa and globus sensation: Closing the treatment gap. AB - BACKGROUND AND AIM: Symptomatic cervical heterotopic gastric mucosa, also known as cervical inlet patch (CIP), may present in various shapes and causes laryngopharyngeal reflux (LPR). Unfortunately, argon plasma coagulation, standard treatment of small symptomatic CIP, is limited in large CIP mainly because of concerns of stricture formation. Therefore, we aimed to investigate radiofrequency ablation (RFA), a novel minimally invasive ablation method, in the treatment of CIP focusing on large symptomatic patches. METHODS: Consecutive patients with macroscopic and histological evidence of large (>=20 mm diameter) heterotopic gastric mucosa were included in this prospective trial. Primary outcome was complete macroscopic and histological eradication rate of CIP. Secondary outcome measures were symptom improvement, quality of life, severity of LPR and adverse events. RESULTS: Ten patients (females, n = 5) underwent RFA of symptomatic CIP. Complete histological and macroscopic eradication of CIP was observed in 80% (females, n = 4) of individuals after two ablations. Globus sensations significantly improved from median visual analog scale score 8 (5-9) at baseline to 1.5 (1-7) after first ablation and 1 (1-2) after final evaluation (P < 0.001). Mental health scores significantly increased from 41.4 (+/- 8.5) to 54.4 (+/- 4.4) after RFA (P = 0.007). LPR improved significantly (P = 0.005) with absence of strictures after a mean follow up of 1.9 (+/- 0.5) years. CONCLUSIONS: This is the first study on RFA focusing on therapy of large symptomatic heterotopic gastric mucosa. Hereby, we demonstrate that this new technique can be successfully implemented in patients where treatment was limited so far (NCT03023280). PMID- 28884488 TI - Uniqueness of Entamoeba sulfur metabolism: sulfolipid metabolism that plays pleiotropic roles in the parasitic life cycle. AB - Sulfur metabolism is ubiquitous and terminally synthesizes various biomolecules that are crucial for organisms, such as sulfur-containing amino acids and co factors, sulfolipids and sulfated saccharides. Entamoeba histolytica, a protozoan parasite responsible for amoebiasis, possesses the unique sulfur metabolism features of atypical localization and its terminal product being limited to sulfolipids. Here, we present an overall scheme of E. histolytica sulfur metabolism by relating all sulfotransferases and sulfatases to their substrates and products. Furthermore, a novel sulfur metabolite, fatty alcohol disulfates, was identified and shown to play an important role in trophozoite proliferation. Cholesteryl sulfate, another synthesized sulfolipid, was previously demonstrated to play an important role in encystation, a differentiation process from proliferative trophozoite to dormant cyst. Entamoeba survives by alternating between these two distinct forms; therefore, Entamoeba sulfur metabolism contributes to the parasitic life cycle via its terminal products. Interestingly, this unique feature of sulfur metabolism is not conserved in the nonparasitic close relative of Entamoeba, Mastigamoeba, because lateral gene transfer-mediated acquisition of sulfatases and sulfotransferases, critical enzymes conferring this feature, has only occurred in the Entamoeba lineage. Hence, our findings suggest that sulfolipid metabolism has a causal relationship with parasitism. PMID- 28884489 TI - Voltage and wear debris from Ti-6Al-4V interact to affect cell viability during in-vitro fretting corrosion. AB - Fretting corrosion (or mechanically assisted corrosion, MAC) is a major corrosion mechanism in modular orthopedic implants. There is a complex interplay between fretting corrosion and the surrounding biological environment that includes particle generation and electrochemical potential excursions and currents. The goal of this work is to directly investigate the effects of fretting on cells in vitro. Using an in vitro fretting device, MC3T3 preosteoblasts were cultured onto Ti-6Al-4V disks adjacent to the fretting site. Under fretting corrosion conditions, cell viability dramatically decreased to 0.5% with the voltage drop reaching -1 V (vs. Ag/AgCl). Under the same fretting corrosion conditions, but potentiostatically holding the Ti-6Al-4V sample surface potential to -300 mV or 50 mV (vs. Ag/AgCl), the cell viability increases to 70% and 38%, respectively. The results indicate that both cathodic potential excursions and wear debris play significant roles in affecting cell viability. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 160-167, 2018. PMID- 28884490 TI - Manganese Dioxide Nanozymes as Responsive Cytoprotective Shells for Individual Living Cell Encapsulation. AB - A powerful individual living cell encapsulation strategy for long-term cytoprotection and manipulation is reported. It uses manganese dioxide (MnO2 ) nanozymes as intelligent shells. As expected, yeast cells can be directly coated with continuous MnO2 shells via bio-friendly Mn-based mineralization. Significantly, the durable nanozyme shells not only can enhance the cellular tolerance against severe physical stressors including dehydration and lytic enzyme, but also enable the survival of cells upon contact with high levels of toxic chemicals for prolonged periods. More importantly, these encased cells after shell removal via a facile biomolecule stimulus can fully resume growth and functions. This strategy is applicable to a broad range of living cells. PMID- 28884491 TI - Pd-PEPPSI-IPent-SiO2 : A Supported Catalyst for Challenging Negishi Coupling Reactions in Flow. AB - A silica-supported precatalyst, Pd-PEPPSI-IPent-SiO2 , has been prepared and evaluated for its proficiency in the Negishi cross-coupling of hindered and electronically deactivated coupling partners. The precatalyst Pd-PEPPSI-IPent loaded onto packed bed columns shows high catalytic activity for the room temperature coupling of deactivated/hindered biaryl partners. Also for the first time, the flowed Csp3 -Csp2 coupling of secondary alkylzinc reagents to (hetero)aromatics has been achieved with high selectivity with Pd-PEPPSI-IPent SiO2 . These couplings required residence times as short as 3 minutes to effect completion of these challenging transformations with excellent selectivity for the nonrearranged product. PMID- 28884492 TI - Patterned semiconductor structures modulate neuronal outgrowth: Implication for the development of a neurobionic interface. AB - Auditory implants stimulate the neurons by broad electrical fields, which leads to a low number of spectral channels. A reduction in the distance between the electrode and the neuronal structures might lead to better electrical transduction. The use of microstructured semiconductors offers a large number of contacts, which could attract neurons and stimulate them individually. To investigate the interaction between neurons and semiconductors, differentiated neuronal precursor cells were cultured on silicon wafers. Different structures were added on the wafers by electron beam lithography, and deep reactive ion etching in different depths (2 and 7 um). Grooved surfaces guided the neurons and resulted in straight oriented axons, but neuronal outgrowth was impaired by the 7 um grooves. Within the 7 um structures, the neuronal cell body was totally encased and the nuclei were deformed from a round to an elliptical shape. On both square and cylindrical structures neuronal bridging could be detected in different forms, either between the tops of the structures or between the bottom and the top. Furthermore, neuronal bridges were established on the lateral part of the structures, and change in direction of neuronal growth was induced by the structure. Finally, it could be shown that neuronal growth cones were particularly attracted by the top of the cylinders, which might allow for the stimulation of neurons via this structure. In conclusion, study results indicate that structured semiconductors can modulate neuronal growth and its direction, offering a novel method for the development of new implants with improved neuronal stimulation. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 65-72, 2018. PMID- 28884493 TI - Endoscopic submucosal dissection in the West: Current status and future directions. AB - Endoscopic submucosal dissection (ESD) was first conceptually described almost 30 years ago in Japan and is now widely practiced throughout East Asia. ESD expands the boundaries of endoscopic resection (ER) by allowing en bloc resection of large early neoplastic lesions within the gastrointestinal tract (GIT). This offers advantages over other ER techniques by facilitating definitive histological staging and curative treatment of early cancer in selected cases. Indeed, the experience of ESD in Eastern countries is significant, and excellent outcomes from high-volume centers are reported. The potential benefits of ESD are recognized by Western endoscopists, but its adoption has been limited. A number of factors contribute to this, including epidemiological differences in GIT neoplasia between Western and Eastern populations and limitations in training opportunities. In this review, we discuss the role of ESD, its current status and the future in Western endoscopic practice. PMID- 28884494 TI - Multilayered pore-closed PLGA microsphere delivering OGP and BMP-2 in sequential release patterns for the facilitation of BMSCs osteogenic differentiation. AB - Bone tissue regeneration may be more effectively administrated by controlled release of multiple biofactors, given that bone healing comprises a cascade of biological events controlled by numerous cytokines and growth factors (GFs). Here, we propose a novel microcarrier with the capability to sequentially deliver dual biofactors for better controlling the bone regeneration process. First, osteogenic growth peptide (OGP) was incorporated in porous poly(lactic-co glycolic) acid (PLGA) microspheres by a simple solution dipping method and subsequent pore-closing treatment. Then, a multilayered polyelectrolyte coating ((HA-CS)2 -Hep-BMP-2-Hep-(CS-HA)2 ) was prepared on the surface of such OGP loaded pore-closed PLGA microspheres by layer-by-layer assembly. Results showed that the OGP release was minimal (<17.1%) in the first 15 days but accelerated remarkably thereafter, while at least 60.3% of the bone morphogenetic protein-2 (BMP-2) load was released in the first 15 days and only very slow release was observed subsequently. Further in vitro cell experiments showed that the dual biomolecule-loaded microspheres elicited more cells with extremely elongated cellular morphology, much higher alkaline phosphatase level and upregulated expression of osteocalcin. Such a dual loading of OGP and BMP-2 had a more positive impact on bone marrow mesenchymal stem cells proliferation and osteogenic differentiation compared with either OGP or BMP-2 alone, suggesting potential synergistic benefit of the sequential release of multiple peptide-based biofactors in a coordinated manner. Overall, this dual delivery system may provide a therapeutic strategy sequentially targeting multiple events (or mechanisms) during bone healing, which is believed to benefit the regenerative repair of bone defects. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 95-105, 2018. PMID- 28884495 TI - Asymmetrical size and functionality of the pampas deer (Ozotoceros bezoarticus) testes: Right testis is bigger but left testis is more efficient in spermatogenesis. AB - Information about gonadal asymmetries in ruminants is very scarce. In this work, we performed three complementary studies to compare characteristics of both testes: (i) weight and size of offspring and adult dead males; (ii) the tissue:fluid relationship determined by ultrasound scanning; and (iii) the spermatogenic status using fine needle aspiration cytology. The right testis was heavier than the left one in both offspring and adult animals and had greater width and volume in adult males than the left one. The ultrasound pixel intensity was similar in both testes. The right testis tended to have more spermatogonia (p = .06) and had a greater percentage of early spermatids (p = .004) than the left testis. On the other hand, the left testis had a greater percentage of spermatozoa (p = .05). The left testis had a greater spermatozoa/spermatogonia ratio (p = .02) and tended to have more spermatozoa/Sertoli cells ratio (p = .07). The spermatogenic index tended to be greater in the left than in the right testis (p = .06). Overall, we concluded that the right testis of pampas deer males is bigger but according to the cytology, it seems to be less spermatogenically effective than the left one, but these differences are not explained by different tissue:fluid ratio in each testis. Although differences were greater in adults than in offspring, asymmetry was observed even in just born offspring. PMID- 28884496 TI - Potential Role of Curcumin Against Biofilm-Producing Organisms on the Skin: A Review. AB - Turmeric root (Curcuma longa) is predominantly used as a spice, but has also long been known to possess antimicrobial, analgesic, antiinflammatory, and anticancer properties. One predominant group of active compounds in turmeric are curcuminoids, namely bright yellow-pigmented curcumin. While modern science has yet to fully investigate the therapeutic claims of turmeric and its derivatives, results have proven promising in decreasing pain and inflammation in arthritis, improving insulin sensitivity in diabetes, and even curing a variety of infections. The purpose of this review is to discuss the potential for curcumin as an agent against microbial infections, with a special focus on the skin and in the development of bacterial biofilms. Curcumin has demonstrated bactericidal efficacy against a variety of infections when administered with antibiotics in several clinical studies, with consistent antimicrobial activity demonstrated in vitro, as well as in urinary tract infections, gingival infections, and chronic wound infections. Hypothesized mechanisms of action include curcumin's ability to perturb bacterial membranes, disturb protofillament assembly, and even impair bacterial virulence factors. Further investigation is needed to fully understand which organisms are most susceptible to the effects of curcumin and how curcumin can be implemented in dermatology to treat skin conditions such as chronic wounds and acne vulgaris. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28884497 TI - Risk stratification of Asian patients with heart failure and reduced ejection fraction: the effectiveness of the Echo Heart Failure Score. PMID- 28884498 TI - Aldo-keto reductase and alcohol dehydrogenase contribute to benznidazole natural resistance in Trypanosoma cruzi. AB - The improvement of Chagas disease treatment is focused not only on the development of new drugs but also in understanding mechanisms of action and resistance to drugs conventionally used. Thus, some strategies aim to detect specific changes in proteins between sensitive and resistant parasites and to evaluate the role played in these processes by functional genomics. In this work, we used a natural Trypanosoma cruzi population resistant to benznidazole, which has clones with different susceptibilities to this drug without alterations in the NTR I gene. Using 2DE-gel electrophoresis, the aldo-keto reductase and the alcohol dehydrogenase proteins were found up regulated in the natural resistant clone and therefore their possible role in the resistance to benznidazole and glyoxal was investigated. Both genes were overexpressed in a drug sensitive T. cruzi clone and the biological changes in response to these compounds were evaluated. The results showed that the overexpression of these proteins enhances resistance to benznidazole and glyoxal in T. cruzi. Moreover, a decrease in mitochondrial and cell membrane damage was observed, accompanied by a drop in the intracellular concentration of reactive oxygen species after treatment. Our results suggest that these proteins are involved in the mechanism of action of benznidazole. PMID- 28884499 TI - Peroral endoscopic myotomy in achalasia and large epiphrenic diverticulum. AB - Symptomatic epiphrenic diverticula are mostly treated surgically with laparoscopic diverticulectomy, myotomy and anterior fundoplication. However, in case the patient does not agree with surgical therapy or is contraindicated, there are limited ways of alternative treatment. We present a case report of a 72 year-old female patient with severe dysphagia, regurgitation, paroxysmal cough, weight loss and malnutrition who was diagnosed with achalasia and large epiphrenic diverticulum. She did not give consent to the proposed surgical treatment. Alternatively, peroral endoscopic myotomy (POEM) was carried out. In one-year follow up, we observed complete symptom resolution, significant weight gain, improvement of nutritional status and no complications. We suggest that POEM could serve as an effective and safe alternative treatment for patients with achalasia and esophageal epiphrenic diverticula. PMID- 28884500 TI - Under-diagnosed chronic kidney disease in Jordanian adults: prevalence and correlates. AB - BACKGROUND: Jordan has no relevant database or registry by which chronic kidney disease (CKD) would be early identified. The purpose of the present study is to uncover the prevalence of CKD in a national sample of Jordanian patients at high risk and examine the association of CKD with demographic and clinical factors. METHODS: This is a cross-sectional, correlational study that involved 540 outpatients at high risk for CKD. Demographic and clinical data were obtained in the period from September 2013 to March 2014. Prevalence of CKD was defined based on the National Kidney Foundation Kidney Disease Outcomes Quality Initiative Classification of CKD using estimated glomerular filtration rate. Associations of CKD and demographic and clinical factors were examined using bivariate analysis. RESULTS: The majority of the sample were females (64%), their mean age (+/-SD) was 55.0 +/- 12.5 years, their mean eGFR (+/-SD) was 116.0 +/- 47.5. One third of patients had eGFR of 23.5%, 5.4%, 0.7% and 0.7% which corresponds with mild, moderate, severe and very severe reduction in eGFR, respectively. Ageing, being male, unemployment, packs/years of smoking, co-morbidities [hypertension (HTN), diabetes mellitus (DM) and cardiovascular disease] and low high density lipoprotein (HDL) correlated positively with development of CKD. CONCLUSION: This study demonstrates a high rate of under-diagnosed CKD among Jordanians. Several demographic and clinical factors are linked with the development of CKD. Policymakers and healthcare providers need to establish an evidence-based practice project to prevent and screen for CKD in Jordan. PMID- 28884501 TI - Procalcitonin, erythrocyte sedimentation rate and C-reactive protein in acute pulmonary exacerbations of cystic fibrosis. AB - INTRODUCTION: Acute pulmonary exacerbations of cystic fibrosis (APECF) are a leading cause of morbidity and mortality among patients with cystic fibrosis (CF). APECF require frequent administration of antibiotics and subsequently lead to development of resistant organisms. OBJECTIVES: The aim of this study was to identify inflammatory markers that may be help identify need for antibiotics and exacerbation as well as predict risk of exacerbations. METHODS: A total of 17 patients were enrolled, and baseline erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and procalcitonin levels were obtained in addition to obtaining these levels during admissions for APECF. RESULTS: A total of 28 APECF were recorded. ESR and CRP significantly increased during exacerbation (P < .01 for both). Procalcitonin did not increase during exacerbations. Baseline elevations in ESR and CRP increased risk of an exacerbation (RR = 2.3 and 4.5, respectively). CONCLUSIONS: ESR and CRP are useful markers for CF exacerbations, as levels rise with exacerbations. Baseline elevations in ESR and CRP were noted to show an increased risk for CF exacerbations. Procalcitonin, in contrast, is not a useful inflammatory marker. PMID- 28884502 TI - Fabrication of tough poly(ethylene glycol)/collagen double network hydrogels for tissue engineering. AB - In this study, a series of poly(ethylene glycol)/collagen (PEG/Col) double network (DN) hydrogel is fabricated from PEG and Col. Results of the compressive strength test indicate that the strength and toughness of these DN hydrogels are significantly enhanced. The fracture strength of PEG/Col DN hydrogels increases by 9- to 12-fold compared with that of PEG single network (SN) hydrogel, and by 36- to 48-fold compared with that of Col SN hydrogel. Taking advantage of both PEG and Col building blocks, the PEG/Col DN hydrogels possess a strengthened skeleton. Moreover, the water-storage capability and favorable biocompatibility of Col are effectively maintained. Given that the DN hydrogels can provide the appropriate environment for the adhesion, growth, and proliferation of MC3T3-E1 cells, PEG/Col DN hydrogels have potential as a load-bearing tissue repair material. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 192 200, 2018. PMID- 28884503 TI - Efficient secretion of three fungal laccases from Saccharomyces cerevisiae and their potential for decolorization of textile industry effluent-A comparative study. AB - Laccases are enzymes with a broad range of biotechnological applications and have, for example, the ability to oxidize many xenobiotics including synthetic dyes. In order to obtain an efficient laccase for the decolorization of dyes which spoil wastewater from the textile industry, genes encoding three various laccase enzymes were expressed in Saccharomyces cerevisiae. The expression of laccases from ascomycete Myceliophthora thermophila (MtL), and two basidiomycetes Trametes versicolor (TvL) and Trametes trogii (TtL) was optimized via selection of plasmids, promoters, media composition, and cultivation conditions. For the first time, the activity of the three secreted laccases was directly compared with the use of various substrates, including different dyes and a wastewater sample. A strong constitutive ADH1 promoter, minimal growth medium, optimized combination of copper and organic nitrogen source, and low cultivation temperature were shown to significantly increase the yields and relative activities of secreted laccases. Heterologous expression of three fungal laccases was successfully achieved in S. cerevisiae being the highest for MtL and the lowest for TvL. MtL, and particularly TtL, showed the decolorization capacity. This is the first report which compared decolorization of synthetic dyes and wastewater by several recombinant laccases and suggested MtL and TtL to be applicable in the ecofriendly enzymatic treatment of colored industry effluent. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:69-80, 2018. PMID- 28884506 TI - Evaluation of a series of silk fibroin protein-based nonwoven mats for use as an anti-adhesion patch for wound management in robotic surgery. AB - A novel anti-adhesion nonwoven mat mainly composed of silk fibroin protein (SFP) was fabricated via the single-spinneret electrospinning technique. A series of SFP-based electrospun nonwoven mats containing additives of different synthetic polymer ratios, such as pure SFP, SFP/poly(vinyl alcohol) (PVA), SFP/polyethylene glycol (PEG), and SFP/polyethylene oxide (PEO) were produced and compared. All membranes were porous and had diameters of 324.02 +/- 113.7, 308.86 +/- 74.02, 366.22 +/- 115.81, and 341.82 +/- 119.42 nm, respectively. The average pore size for each membrane was 1.132 +/- 0.99, 0.811 +/- 0.424, 0.975 +/- 0.741, and 0.784 +/- 0.497 MUm2 . No nonwoven mats showed significant cytotoxicity toward fibroblast cells based on the results of MTT assays. Surprisingly, for all groups of SFP-based nonwoven mats, nitrate formation was reduced by up to 94.55 +/- 14.50%, 92.16 +/- 19.38%, 91.28 +/- 28.375%, and 92.00 +/- 12.64% in lipopolysaccharide-induced RAW 264.7 macrophages model. Tissue anti-adhesion potential was evaluated in an in vitro fibroblast cell adhesion model and in vivo wounded mice model. In vitro, the mean cell anti-adhesion percentage of fibroblast cells changed over time in the following order: PVA/SFP > SFP > PEG/SFP~PEO/SFP. In vivo, SFP and PVA/SFP-treated groups both showed superior collagen regeneration and wound closure. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 221-230, 2018. PMID- 28884505 TI - Alternative Oils Tested as Feedstocks for Enzymatic FAMEs Synthesis: Toward a More Sustainable Process. AB - Previously isolated and characterized Pseudomonas lipases were immobilized in a low-cost MP-1000 support by a re-loading procedure that allowed a high activity per weight of support. Immobilized LipA, LipC, and LipCmut lipases, and commercial Novozym(r) 435 were tested for fatty acid methyl ester (FAMEs) synthesis using conventional and alternative feedstocks. Triolein and degummed soybean oils were used as model substrates, whereas waste cooking oil and M. circinelloides oil were assayed as alternative, low cost feedstocks, whose free fatty acid (FFA), and acylglyceride profile was characterized. The reaction conditions for FAMEs synthesis were initially established using degummed soybean oil, setting up the best water and methanol concentrations for optimum conversion. These conditions were further applied to the alternative feedstocks and the four lipases. The results revealed that Pseudomonas lipases were unable to use the FFAs, displaying a moderate FAMEs synthesis, whereas a 44% FAMEs production was obtained when M. circinelloides oil was used as a substrate in the reaction catalysed by Novozym(r) 435, used under the conditions established for degummed soybean oil. However, when Novozym(r) 435 was tested under previously described optimal conditions for this lipase, promising values of 85 and 76% FAMEs synthesis were obtained for waste cooking oil and M. circinelloides oil, respectively, which might result in promising, nonfood, alternative feedstocks for enzymatic biodiesel production. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1209-1217, 2017. PMID- 28884507 TI - Extracellular matrix derived from periodontal ligament cells maintains their stemness and enhances redifferentiation via the wnt pathway. AB - Large numbers of viable cells cannot be obtained from periodontal ligament tissues of patients with periodontitis. Therefore, it is imperative to establish an ex vivo environment that can support cell proliferation and delay senescence. Here, we have successfully reconstructed a native extracellular matrix (ECM), derived from early-passage human periodontal ligament cells (PDLCs) using the NH4 OH/Triton X-100 protocol. The ECM was investigated by scanning electron microscopy and immunostaining for specific ECM proteins (collagen I and fibronectin). Late-passage ECM-expanded PDLCs exhibited a much higher proliferation index and lower levels of reactive oxygen species (ROS), confirmed by the increased expression of pluripotent markers and enhanced osteogenic capacity. Interestingly, the Wnt pathway was suppressed during the ECM expansion mediated increase in pluripotency, but was activated in an osteogenic differentiation environment, as confirmed by treatment with the XAV-939 beta catenin inhibitor or the SP600125 c-Jun N-terminal kinase (JNK) inhibitor. Cell sheets formed by ECM-expanded PDLCs exhibited an enhanced periodontal tissue regeneration capacity compared to those formed on tissue culture polystyrene (TCP) surfaces in vivo. Taken together, the cell-free ECM provides a tissue specific cell niche for the ex vivo expansion of PDLCs while retaining stemness and osteogenic potential, partially via the Wnt pathway. This represents a promising matrix for future applications in periodontal tissue regeneration therapy. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 272 284, 2018. PMID- 28884504 TI - The where, what, and when of membrane protein degradation in neurons. AB - Membrane protein turnover and degradation are required for the function and health of all cells. Neurons may live for the entire lifetime of an organism and are highly polarized cells with spatially segregated axonal and dendritic compartments. Both longevity and morphological complexity represent challenges for regulated membrane protein degradation. To investigate how neurons cope with these challenges, an increasing number of recent studies investigated local, cargo-specific protein sorting, and degradation at axon terminals and in dendritic processes. In this review, we explore the current answers to the ensuing questions of where, what, and when membrane proteins are degraded in neurons. (c) 2017 The Authors Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 283-297, 2018. PMID- 28884508 TI - The unique calcium chelation property of poly(vinyl phosphonic acid-co-acrylic acid) and effects on osteogenesis in vitro. AB - There is a clear clinical need for a bioactive bone graft substitute. Poly(vinyl phosphonic acid-co-acrylic acid) (PVPA-co-AA) has been identified as a promising candidate for bone regeneration but there is little evidence to show its direct osteogenic effect on progenitor or mature cells. In this study mature osteoblast like cells (SaOS-2) and human bone marrow-derived mesenchymal stem cells (hBM MSCs) were cultured with PVPA-co-AA polymers with different VPA:AA ratio and at different concentrations in vitro. We are the first to report the direct osteogenic effect of PVPA-co-AA polymer on bone cells and, more importantly, this effect was dependent on VPA:AA ratio and concentration. Under the optimized conditions, PVPA-co-AA polymer not only has an osteoconductive effect, enhancing SaOS-2 cell mineralization, but also has an osteoinductive effect to promote hBM MSCs' osteogenic differentiation. Notably, the same PVPA-co-AA polymer at different concentrations could lead to differential osteogenic effects on both SaOS-2 and hBM-MSCs in vitro. This study furthers knowledge of the PVPA-co-AA polymer in osteogenic studies, which is critical when utilizing the PVPA-co-AA polymer for the design of novel bioactive polymeric tissue engineering scaffolds for future clinical applications. (c) 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 168-179, 2018. PMID- 28884509 TI - Evaluation of osteogenic inductivity of a novel BMP2-mimicking peptide P28 and P28-containing bone composite. AB - We developed a novel BMP2-mimicking peptide P28, which possesses two distinct special structural elements-seven repetitive aspartic acids and phosphorylated serine designed to promote affinity to hydroxyapatite as well as nucleation of apatite crystallization and mineralization. In this work, we systematically studied the osteogenic inductivity of P28 in vitro and in vivo in comparison with BMP2. We confirmed its effects on proliferation, recruitment, and osteogenic differentiation of MC3T3-E1 cells in vitro. Furthermore, we loaded P28 into a biomimetic bone composite nanohydroxyapatite/collagen/poly(l-lactide) (nHAC/PLA) and evaluated its ability to promote bone regeneration in vivo using a rabbit femoral condyle defect model. The micro-CT reconstruction and quantification analysis and the histological analysis indicated that P28/nHAC/PLA bone composite was capable of repairing bone defects. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 210-220, 2018. PMID- 28884510 TI - Cryoconcentration of flavonoid extract for enhanced biophotovoltaics and pH sensitive thin films. AB - Flavonoids are important value added products for dye sensitized solar cells biosensors, functional foods, medicinal supplements, nanomaterial synthesis, and other applications. Brassica oleracea contains high levels of anthocyanins in leaf sap vacuoles, and there are many viable extraction techniques that vary in terms of simplicity, environmental impact, cost, and extract photochemical/electrochemical properties. The efficiency of value added biotechnologies from flavonoid is a function of anthocyanin activity/concentration and molecule stability (i.e., ability to retain molecular resonance under a wide range of conditions). In this paper, we show that block cryoconcentration and partial thawing of anthocyanin from B. oleracea is a green, facile, and highly efficient technique that does not require any special equipment or protocols for producing enhanced value added products. Cryoconcentration increased anthocyanin activity and total phenol content approximately 10 times compared with common extraction techniques. Cryoconcentrated extract had enhanced electrochemical properties (higher oxidation potential), improved chroma, and higher UV absorbance than extract produced with other methods for a pH range of 2-12, with minimal effect on the diffusion coefficient of the extract. As a proof of concept for energy harvesting and sensor applications, dye sensitized solar cells and pH-sensitive thin films were prepared and tested. These devices were comparable with other recently published biotechnologies in terms of efficacy, but did not require expensive/environmentally detrimental extraction or concentration methods. This low cost, biorenewable, and simple method can be used for development of a variety of value added products. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:206-217, 2018. PMID- 28884511 TI - Effects of pH, conductivity, host cell protein, and DNA size distribution on DNA clearance in anion exchange chromatography media. AB - Flowthrough anion exchange chromatography is commonly used as a polishing step in downstream processing of monoclonal antibodies and other therapeutic proteins to remove process-related impurities and contaminants such as host cell DNA, host cell proteins, endotoxin, and viruses. DNA with a wide range of molecular weight distributions derived from Chinese Hamster Ovary cells was used to advance the understanding of DNA binding behavior in selected anion exchange media using the resin (Toyopearl SuperQ-650M) and membranes (Mustang(r) Q and Sartobind(r) Q) through DNA spiking studies. The impacts of the process parameters pH (6-8), conductivity (2-15 mS/cm), and the potential binding competition between host cell proteins and host cell DNA were studied. Studies were conducted at the least and most favorable experimental conditions for DNA binding based on the anticipated electrostatic interactions between the host cell DNA and the resin ligand. The resin showed 50% higher DNA binding capacity compared to the membrane media. Spiking host cell proteins in the load material showed no impact on the DNA clearance capability of the anion exchange media. DNA size distributions were characterized based on a "size exclusion qPCR assay." Results showed preferential binding of larger DNA fragments (>409 base pairs). (c) 2017 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 34:141-149, 2018. PMID- 28884512 TI - Bone-healing capacity of conditioned medium derived from three-dimensionally cultivated human mesenchymal stem cells and electrical stimulation on collagen sponge. AB - Continuing from our previous study, we hypothesized that combining electrical stimulation (ES) and three-dimensional (3D) culture would be a useful strategy to obtain more bioactive factors in conditioned medium (CM) derived from human mesenchymal stem cells (hMSC). Our aim in this study was to investigate the bone healing capacity of CM derived from hMSC after 4 days of culture on a collagen sponge-exposed (CM-ES) or unexposed (CM-control; CM-CON) to ES in comparison with that of hMSC implantation. A cytokine assay of both CMs revealed the presence of cytokines, growth factors, and trophic factors. In vitro evaluation of both CMs showed increased cell growth and alkaline phosphatase activity of the hMSC, with little difference between CMs. We investigated the bone-healing effect using two bone disease models: bone defect and inflammatory bone loss. The calvaria defect was implanted with whole CM or 3D-precultured hMSC unexposed to ES. Microcomputed tomography analysis after 4 weeks indicated a twofold greater bone volume in the CM-CON and CM-ES groups than in the hMSC and vehicle groups, though we found no difference between the CM groups. However, CM-ES enhanced the bone healing of interleukin-1-induced bone loss to a level comparable with hMSC, whereas CM-CON did not. These results show that 3D-cultured CM had a greater or similar capacity for bone healing as treatment using hMSC transplantation, and CM-ES was especially effective against inflammatory bone loss. Thus, 3D-cultured CM with or without ES presents an encouraging alternative to MSC-based bone healing. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 311-320, 2018. PMID- 28884513 TI - TGF-beta1 attenuated branching morphogenesis of embryonic murine submandibular gland through Smad3 activation. AB - Transforming growth factor-beta1 (TGF-beta1) plays several crucial regulatory roles in multiple physiological and pathological processes. The aim of this work was to investigate the role of TGF-beta1 in branching morphogenesis of salivary gland. We harvested and cultured submandibular salivary glands (SMGs) from murine embryos, which were then treated with exogenous TGF-beta1, or its neutralized antibody, Smad3 inhibitor, or Smad3 small interfering RNA (siRNA). Our results suggested that TGF-beta1 attenuated branching morphogenesis of embryonic murine SMG via Smad3 activation, thus playing a negative regulatory role in salivary gland development. PMID- 28884514 TI - Estrogenic regulation of skeletal muscle proteome: a study of premenopausal women and postmenopausal MZ cotwins discordant for hormonal therapy. AB - Female middle age is characterized by a decline in skeletal muscle mass and performance, predisposing women to sarcopenia, functional limitations, and metabolic dysfunction as they age. Menopausal loss of ovarian function leading to low circulating level of 17beta-estradiol has been suggested as a contributing factor to aging-related muscle deterioration. However, the underlying molecular mechanisms remain largely unknown and thus far androgens have been considered as a major anabolic hormone for skeletal muscle. We utilized muscle samples from 24 pre- and postmenopausal women to establish proteome-wide profiles, associated with the difference in age (30-34 years old vs. 54-62 years old), menopausal status (premenopausal vs. postmenopausal), and use of hormone replacement therapy (HRT; user vs. nonuser). None of the premenopausal women used hormonal medication while the postmenopausal women were monozygotic (MZ) cotwin pairs of whom the other sister was current HRT user or the other had never used HRT. Label-free proteomic analyses resulted in the quantification of 797 muscle proteins of which 145 proteins were for the first time associated with female aging using proteomics. Furthermore, we identified 17beta-estradiol as a potential upstream regulator of the observed differences in muscle energy pathways. These findings pinpoint the underlying molecular mechanisms of the metabolic dysfunction accruing upon menopause, thus having implications for understanding the complex functional interactions between female reproductive hormones and health. PMID- 28884515 TI - Controlled Hydrothermal Crystallization of Anhydrous Ln2 (OH)4 SO4 (Ln=Eu-Lu, Y) as a New Family of Layered Rare Earth Metal Hydroxides. AB - Anhydrous hydroxide sulfates Ln2 (OH)4 SO4 (Ln=Eu-Lu, Y) were hydrothermally synthesized as a new family of layered rare earth metal hydroxides (LRHs). They crystallize in the monoclinic system (space group C2/m) with structures built up by alternate stacking of interlayer SO42- and the two-dimensional host layer composed of tricapped [LnO9 ] trigonal prisms along the a axis. In distinct contrast to the recently discovered hydrated LRHs Ln2 (OH)4 SO4 ?2 H2 O, which only exist for Ln=La-Dy, the host layers of the anhydrous phase are linked together by sharing edges instead of an O node of the SO42- tetrahedron. Rietveld refinement showed that the cell dimension tends to decrease for smaller Ln3+ , while the axis angle (beta=98.78-100.31 degrees ) behaves oppositely. Comparative thermogravimetric/differential thermal analysis in air revealed that the dehydroxylation and desulfurization temperatures become gradually higher and lower, respectively, for smaller Ln3+ , and thus the temperature range of Ln2 O2 SO4 existence is narrowed. The newly discovered Ln2 (OH)4 SO4 , together with their hydrated counterparts, allow for the first time green synthesis of Ln2 O2 SO4 with water as the only exhaust for the full spectrum of lanthanides. Calcining Ln2 (OH)4 SO4 in H2 yielded phase-pure Ln2 O2 S for Eu and Gd and a mixture of Ln2 O2 S and Ln2 O3 for the other Ln. The effects of the lanthanide contraction were clearly revealed, and photoluminescence was found for the anhydrous LRHs of Eu and Tb. PMID- 28884516 TI - Removing vessel constriction on the embryonic heart results in changes in valve gene expression, morphology, and hemodynamics. AB - BACKGROUND: The formation of healthy heart valves throughout embryonic development is dependent on both genetic and epigenetic factors. Hemodynamic stimuli are important epigenetic regulators of valvulogenesis, but the resultant molecular pathways that control valve development are poorly understood. Here we describe how the heart and valves recover from the removal of a partial constriction (banding) of the OFT/ventricle junction (OVJ) that temporarily alters blood flow velocity through the embryonic chicken heart (HH stage 16/17). Recovery is described in terms of 24- and 48-hr gene expression, morphology, and OVJ hemodynamics. RESULTS: Collectively, these studies show that after 24 hr of recovery, important epithelial-mesenchymal transformation (EMT) genes TGFbetaRIII and Cadherin 11 (CDH11) transcript levels normalize return to control levels, in contrast to Periostin and TGFbeta,3 which remain altered. In addition, after 48 hr of recovery, TGFbeta3 and CDH11 transcript levels remain normalized, whereas TGFbetaRIII and Periostin are down-regulated. Analyses of OFT cushion volumes in the hearts show significant changes, as does the ratio of cushion to cell volume at 24 hr post band removal (PBR). Morphologically, the hearts show visible alteration following band removal when compared to their control age-matched counterparts. CONCLUSIONS: Although some aspects of the genetic/cellular profiles affected by altered hemodynamics seem to be reversed, not all gene expression and cardiac growth normalize following 48 hr of band removal. Developmental Dynamics 247:531-541, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28884517 TI - Biocompatibility assessment of titanium dioxide nanoparticles in mice fetoplacental unit. AB - As the applications of titanium dioxide nanomaterials (nTiO2 ) are growing with an ever-increasing speed, the hazardous risks of this material have become a major concern. Several recent studies have reported that nTiO2 can cross the placental barrier in pregnant mice and cause neurotoxicity in their offspring. However, the influence of these nanoparticles on the fetoplacental unit during the pregnancy is yet to be studied. The present study reports on the effects of nTiO2 on the anatomical structure of fetal brain and liver in a pregnant mice model. Moreover, changes in the size and weight of the fetus and placenta are investigated as markers of fetal growth. Lastly, the toxicity of nTiO2 in primary brain and liver is quantified. Animals treated with nTiO2 showed a disrupted anatomical structure of the fetal brain and liver. Furthermore, the fetus and placental unit in the mice treated with these nanoparticles were smaller compared to untreated controls. Toxicity analyses revealed that nTiO2 was toxic to the brain and liver cells and the mechanism of cell death was mostly necrosis. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 580-589, 2018. PMID- 28884518 TI - Pectoral nerves and serratus plane block for persistent post surgical pain after video-assisted thoracic surgery. PMID- 28884519 TI - Gelatin methacrylate scaffold for bone tissue engineering: The influence of polymer concentration. AB - Gelatin methacrylate (GelMA) is an inexpensive, photocrosslinkable, cell responsive hydrogel which has drawn attention for a wide range of tissue engineering applications. The potential of GelMA scaffolds was demonstrated to be tunable for different tissue engineering (TE) applications through modifying the polymer concentration, methacrylation degree, or UV light intensity. Despite the promising results of GelMA hydrogels in tissue engineering, the influence of polymer concentration for bone tissue engineering (BTE) scaffolds was not established yet. Thus, in this study, we have demonstrated the effect of polymer concentration in GelMA scaffolds on osteogenic differentiation. We prepared GelMA scaffolds with 5 and 10% polymer concentrations and characterized the scaffolds in terms of porosity, pore size, swelling characteristics, and mechanical properties. Subsequent to the scaffolds characterization, the scaffolds were seeded with bone marrow derived rat mesenchymal stem cells and cultured in osteogenic media to evaluate the possible osteogenic differentiation effect exerted by the polymer concentration. After 7, 14, 21, and 28 days, DNA content, calcium deposition, and alkaline phosphatase (ALP) activity of scaffolds were evaluated quantitatively by colorimetric bioassays. Furthermore, the distribution of the calcium deposition within the scaffolds was attained qualitatively and quantitatively by microcomputer tomography (uCT). Our data suggest that GelMA hydrogels prepared with 5% polymer concentration has promoted homogeneous extracellular matrix calcification and it is a great candidate for BTE applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 201-209, 2018. PMID- 28884520 TI - Relative pressure estimation from velocity measurements in blood flows: State-of the-art and new approaches. AB - The relative pressure difference across stenotic blood vessels serves as an important clinical index for the diagnosis of many cardiovascular diseases. While the clinical gold standard for relative pressure difference measurements is invasive catheterization, Phase-Contrast Magnetic Resonance Imaging has emerged as a promising tool for enabling a noninvasive quantification, by linking highly spatially resolved velocity measurements with relative pressures via the incompressible Navier-Stokes equations. In this work, we provide a review and analysis of current methods for relative pressure estimation and propose 3 additional techniques. Methods are compared using synthetic data from numerical examples, and sensitivity to subsampling and noise was explored. Through our analysis, we verify that the newly proposed approaches are more robust with respect to spatial subsampling and less sensitive to noise and therefore provide improved means for estimating relative pressure differences noninvasively. PMID- 28884521 TI - A Single-Framework Synthetic Antibody Library Containing a Combination of Canonical and Variable Complementarity-Determining Regions. AB - Synthetic antibody libraries have been used to generate antibodies with favorable biophysical and pharmacological properties. Here, we describe the design, construction, and validation of a phage-displayed antigen-binding fragment (Fab) library built on a modified trastuzumab framework with four fixed and two diversified complementarity-determining regions (CDRs). CDRs L1, L2, H1, and H2 were fixed to preserve the most commonly observed "canonical" CDR conformation preferred by the modified trastuzumab Fab framework. The library diversity was engineered within CDRs L3 and H3 by use of custom-designed trinucleotide phosphoramidite mixes and biased towards human antibody CDR sequences. The library contained ~7.6 billion unique Fabs, and >95 % of the library correctly encoded both diversified CDR sequences. We used this library to conduct selections against the human epidermal growth factor receptor-3 extracellular domain (HER3-ECD) and compared the CDR diversity of the naive library and the anti-HER3 selection pool by use of next-generation sequencing. The most commonly observed CDR combination isolated, named Her3-3, was overexpressed and purified in Fab and immunoglobulin G (IgG) formats. Fab HER3-3 bound to HER3-ECD with a KD value of 2.14 nm and recognized cell-surface HER3. Although HER3-3 IgG bound to cell-surface HER3, it did not inhibit the proliferation of HER3-positive cells. Near-infrared imaging showed that Fab HER3-3 selectively accumulated in a murine HER3-postive xenograft, thus providing a lead for the development of HER3 imaging probes. PMID- 28884522 TI - Development of a high-throughput microscale cell disruption platform for Pichia pastoris in rapid bioprocess design. AB - The time and cost benefits of miniaturized fermentation platforms can only be gained by employing complementary techniques facilitating high-throughput at small sample volumes. Microbial cell disruption is a major bottleneck in experimental throughput and is often restricted to large processing volumes. Moreover, for rigid yeast species, such as Pichia pastoris, no effective high throughput disruption methods exist. The development of an automated, miniaturized, high-throughput, noncontact, scalable platform based on adaptive focused acoustics (AFA) to disrupt P. pastoris and recover intracellular heterologous protein is described. Augmented modes of AFA were established by investigating vessel designs and a novel enzymatic pretreatment step. Three different modes of AFA were studied and compared to the performance high-pressure homogenization. For each of these modes of cell disruption, response models were developed to account for five different performance criteria. Using multiple responses not only demonstrated that different operating parameters are required for different response optima, with highest product purity requiring suboptimal values for other criteria, but also allowed for AFA-based methods to mimic large scale homogenization processes. These results demonstrate that AFA-mediated cell disruption can be used for a wide range of applications including buffer development, strain selection, fermentation process development, and whole bioprocess integration. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:130-140, 2018. PMID- 28884523 TI - Response of umbilical cord mesenchymal stromal cells to varying titanium topographical signals. AB - A wide variety of titanium implant modifications have been developed to improve tissue- or cell-material interactions including bone bonding, implant failure, and contact osteogenesis. Osteogenesis can be stimulated by mechanobiological signals such as topography though translation of in vivo reactions to in vitro bioactivity and stem cell culture data, and vice versa, is challenging. We hypothesized that a systematic in vitro approach comparing clinically well accepted implant surface topographical modifications could shed light on potential cell biological mechanisms provoked by submicron-, micron- or macrostructured surfaces. In this study, we investigated the response of umbilical cord derived mesenchymal stromal cells (UC-MSCs) to anodized, particle blasted, and plasma sprayed highly porous Plasmapore surfaces, which is known to promote bony ingrowth in vivo. After 21 days, UC-MSCs undergo a morphological shift from a 2D to 3D behavior on micro- or macrostructures visualized by actin vinculin fluorescence and are able to fill the porous surfaces completely. Cell viability after 7 days was significantly decreased on the micro- and macrostructured surfaces particle blasted and Plasmapore, compared to polished controls. The analysis of osteogenic differentiation under noninduced conditions revealed a significantly elevated ALP activity on Plasmapore, indicating a beneficial effect of this macrostructured surface toward osteogenic differentiation supported by late elevated gene expression of osteopontin evaluated by qPCR. Mineralization as well as in vitro bioactivity was pronounced on anodized surfaces. Our findings point to synergistic implant modification strategies allowing early contact osteogenesis and bone ingrowth for future implant designs. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 180-191, 2018. PMID- 28884525 TI - [Research strategies in standard decoction of medicinal slices]. AB - This paper discusses the research situation of the standard decoction of medicinal slices at home and abroad. Combined with the experimental data, the author proposes that the standard decoction of medicinal slices is made of single herb using standard process which should be guided by the theory of traditional Chinese medicine, based on clinical practice and referred to modern extraction method with a standard process. And the author also proposes the principles of establishing the specification of process parameters and quality standards and established the basis of drug efficacy material and biological reference. As a standard material and standard system, the standard decoction of medicinal slices can provide standards for clinical medication, standardize the use of the new type of medicinal slices especially for dispensing granules, which were widely used in clinical. It can ensure the accuracy of drugs and consistency of dose, and to solve current supervision difficulties. Moreover the study of standard decoction of medicinal slices will provide the research on dispensing granules, traditional Chinese medicine prescription standard decoction and couplet medicines standard decoction a useful reference. PMID- 28884524 TI - HIV transmission and retention in care among HIV-exposed children enrolled in Malawi's prevention of mother-to-child transmission programme. AB - INTRODUCTION: In Malawi, HIV-infected pregnant and breastfeeding women are offered lifelong antiretroviral therapy (ART) regardless of CD4 count or clinical stage (Option B+). Their HIV-exposed children are enrolled in the national prevention of mother-to-child transmission (PMTCT) programme, but many are lost to follow-up. We estimated the cumulative incidence of vertical HIV transmission, taking loss to follow-up into account. METHODS: We abstracted data from HIV exposed children enrolled into care between September 2011 and June 2014 from patient records at 21 health facilities in central and southern Malawi. We used competing risk models to estimate the probability of loss to follow-up, death, ART initiation and discharge, and used pooled logistic regression and inverse probability of censoring weighting to estimate the vertical HIV transmission risk. RESULTS: A total of 11,285 children were included; 9285 (82%) were born to women who initiated ART during pregnancy. At age 30 months, an estimated 57.9% (95% CI 56.6-59.2) of children were lost to follow-up, 0.8% (0.6-1.0) had died, 2.6% (2.3-3.0) initiated ART, 36.5% (35.2-37.9) were discharged HIV-negative and 2.2% (1.5-2.8) continued follow-up. We estimated that 5.3% (95% CI 4.7-5.9) of the children who enrolled were HIV-infected by the age of 30 months, but only about half of these children (2.6%; 95% CI 2.3-2.9) were diagnosed. CONCLUSIONS: Confirmed mother-to-child transmission rates were low, but due to poor retention only about half of HIV-infected children were diagnosed. Tracing of children lost to follow-up and HIV testing in outpatient clinics should be scaled up to ensure that all HIV-positive children have access to early ART. PMID- 28884526 TI - [Study on balance of process of alcohol precipitation of ganmaoling granules]. AB - Ganmaoling granule is the first brand of domestic cold medicine sales, but its preparation method and process control parameters are relatively rough. Therefore it is urgent to upgrade the technologies of large varieties of traditional Chinese medicine (TCM). This paper focused on the balance between the remove of impurity and the retention of linarin during the process of alcohol precipitation of Ganmaoling granules. The effects of four factors on the process were investigated via single factor experiments. The results showed that the precipitating period, the initial ethanol concentration and the final ethanol concentration had a great effect on retention of linarin while the initial density of the extract has not. Similarly, the initial ethanol concentration, the final ethanol concentration and the initial extract density have a great effect on the yield of dry extract while the time of alcohol precipitation has not. The parameters of alcohol precipitation of Ganmaoling granules were optimized as 16 h of precipitating period, 95% ethanol as the initial reagent, 70% of the final ethanol concentration, and 1.10 of the initial extract density. PMID- 28884527 TI - [Modeling of thermal degradation of linarin during concentration process]. AB - Ganmaoling granule, with annual sale of over one billion yuan, is the first brand of domestic cold medicine sales. As the only traditonal Chinese medicine(TCM) quality control indicator of Ganmaoling granule, linarin is thermally unstable. Its content will be changed significantly during the production process, which would then affect the quality of the finished product. In this paper, the law of degradation of linarin was investigated. The experimental results showed that degradation reaction of linarin belongs to the first reaction characteristics. The effective methods to reduce the loss of linarin would be realized fortunately by strictly controlling the heating temperature or shortening the heating time. PMID- 28884528 TI - [On-line monitoring of extraction of coldrine by near-infrared spectrum]. AB - Extraction of the four Chinese herbals is the beginning step of the production process of coldrine granules and influences on drug quality significantly. In this paper, the on-line near infrared spectrum was collected during the extraction process of coldrine and then pre-processed by the first derivative. Partial least square regression (PLSR) model was developed for the quantity indicators of linarin, chlorogenic acid and solid content, according to results of both HPLC and weight-loss as reference methods. The correlation coefficient, root mean square error of cross-validation (RMSECV), root mean square error of calibration (RMSEC) and root mean square error of prediction (RMSEP) were used to optimize model parameters and confirm their performance. Correlation coefficients of three quality control indicator models reached more than 0.95.Values of RMSEC of linarin, chloroenic acid and solid content were 0.010 4, 0.009 34 and 0.055 5, respectively. And the values of RMSEP were 0.009 47, 0.142 and 0.008 42, respectively. The models, built on-line analyze data, revealed that the correlation coefficients of predicted values and measured values were greater than 0.97 and values of RSEP of linarin, chloroenic acid and solid content were 8.14%, 8.17% and 9.86%, respectively. The results showed that the NIR method could achieve the on-line detection and real-time monitoring of multi-indexes during the extraction process of coldrine. The technology could be used for drug quality control in the process of practical production, reducing the batch differences and ensuring pharmaceutical quality stability. In addition, it could provide real-time production data for subsequent product quality backtracking. PMID- 28884529 TI - [Study on main pharmacodynamics and underlying mechanisms of 999 Ganmaoling]. AB - To observe synergistic effects of 999 Ganmaoling (GML) and its Chinese/Western materia medica (CMM and WMM) on pharmacodynamic action and to study underlying mechanisms, their anti-inflammatory, antipyretic effects were compared by assaying the increased capillary permeability induced by glacial acetic acid in mice, ear swelling induced by Xylene in mice, non-specific pleurisy induced by carrageenan in rats, and yeast induced fever in rats. Crystal violet (CV) and microbial activity (XTT) assay were used to evaluate the inhibition of GML and its CMM and WMM on KPN biofilm formation, and scanning electron microscopy (SEM) was applied for observing KPN biofilm morphology changes. The results showed that compared with control group, GML could reduce exudation amount of Evans-Blue and the degree of Ear swelling significantly, and CMM and WMM have no significant effects. The concentration of TNF-alpha and IL-1beta of rat pleural effusion in GML, CMM and WMM group decreased significantly. The concentration of TNF-alpha, IL-1beta and IL-8 in GML group, TNF-alpha, IL-8 in WMM group and IL-8 in CMM in rats serum decreased significantly. The body temperature in rats decreased significantly in GML and WMM group after 4-8 h of administration. CMM group showed no significant difference in rat body temperature compare with control. Compared with control group, GML (55-13.75 g*L-1) could inhibit KPN biofilm formation and reduce number of viable cells in the KPN biofilm. CMM (45-22.5 g*L 1) and WMM (10 g*L-1) could also inhibit KPN biofilm formation and reduce number of viable cells (P<0.01). Result of SEM also showed that GML (55 g*L-1) and its CMM (45 g*L-1) and WMM (10 g*L-1) could interfere the bacterial arrangement of KPN biofilm and extracellular matrix. GML and its CMM & WMM could inhibit the formation of KPN biofilm, CMM & WMM in GML showed synergism and complementation in inhibit KPN biofilm. Results showed that GML had obvious anti-inflammatory and antipyretic effects and could destruct KPN mature biofilm. WMM and CMM showed obvious synergistic effect against inflammation and inhibition of KPN biofilm formation and reduction of number of viable cells but no same effects against fever. PMID- 28884530 TI - [Study on toxicity of 999 Ganmaoling grain and influence of diet on hepatic toxicity]. AB - This paper was aimed to compare the acute toxicity of 999 Ganmaoling grain and its different ingredients, and investigate the influence of routine diet on the hepatic toxicity induced by Ganmaoling in mice, so as to provide experimental basis for the clinical safety evaluation. Mice were given a single dose of Ganmaoling grain or its different ingredients respectively by gavage, and then observed for 14 days. LD50 values of Ganmaoling grain or its chemical ingredient and the maximal tolerated dose of its herb ingredient were determined. Mice were divided into starvation and diet group, a single dose of Ganmaoling grain was administered by gavage. LD50 values were estimated after 14 day observation. Mice were divided into starvation and diet group. At the same time,control group was set up for each. A single dose of Ganmaoling grain was given. Serum biochemical indexes were detected, liver weight index was calculated and liver tissue morphological change was observed after 6 h. LD50 values were 4.42, 0.64 g*kg-1 for Ganmaoling grain group and chemical ingredient group, respectively. The maximal tolerated dose of the herb ingredient group was close to 24.24 g*kg-1. The toxic symptom was basically similar in the Ganmaoling grain and the chemical ingredient group. The body weight and food intake were decreased to a certain extent in both groups. There were pathological changes of liver and heart tissue in some of the surviving animals. The animals in the Ganmaoling grain group exhibited a lighter toxicity and recovered faster than that in the chemical ingredient group. LD50 values of Ganmaoling grain were 2.56, 6.93 g*kg-1 for starvation and diet group respectively. TD50 values were 1.29, 6.31 g*kg-1 for starvation and diet group respectively. The toxicity of 999 Ganmaoling was less, which may be related to the reduction of toxicity after the combination of herb and chemical ingredients. Compared with starvation group, the values of LD50 and TD50 of diet group was significantly increased, and toxicity was decreased. From the point of view of safety, it is safer to use Ganmaoling in the absence of hunger or after meal. The above tests provide experimental basis for the clinical safety use of Ganmaoling. PMID- 28884531 TI - [Studies on chemical constituents of Valeriana plants and their biological activities]. AB - The recent progresses on chemical components and pharmacological activities of the genus Valerianawere summarized.Besides-essential oil, the chemical composition of Valerianais mainly focused on monoterpenoids,sesquiterpenoids,lignans, flavonoids, alkaloids, etc. Iridoids are the main chemical components ofmonoterpenoids. There are two types ofiridoidson the basis of the cyclopentane open or not. The Valerianahas been drawmuch attention for their significant sedation,spasmolysis,antidepression,antitumor, against adenosine A1 receptors and cytotoxicityactivity,and had certain function for cardiovascular disease treatment. Given to the fact of the lack of systematic review and summary of studies on the Valeriana, we summarized and analyze the study literatures on the pharmacological activity of Valerianain recent years, and providedsome basisfor further study. PMID- 28884532 TI - [Screening of different AFLP fragments between near-isogenic lines of male sterile and fertile Salvia miltiorrhiza and their comparison analysis]. AB - There is distinctive advantage of using male sterile lines to breed new cultivar and produce hybrids, when compared with general breeding method on yield and quality. In our previous work, near-isogenic lines (NILs) of male sterile and fertile Salvia miltiorrhiza have been obtained through continuous hybridization in many years. In this investigation, 378 primer combination were screened by using AFLP and BSA technique, in which 26 markers amplified from seven primers were found to tightly link to male sterile gene. Based on these markers, two linkage genetic maps were constructed. A 2 027,2 028 bp fragment was amplifed from NILs of fertile and sterile S. miltiorrhiza, respectively, using genome walking technique and previous E11/M4-208 marker as template. Four base mutations were found in intron when comparing both fragments. Among all different markers between NILs of male sterile and fertile S. miltiorrhiza, four was found to have 100% identities to chromosome 1, 3 and 5 of Arabidopsis, namely, E01/M09-418, E05/M13-308, E05/M04-750 and E01/M01-204. The E01/M09-418 marker was very close to male sterile gene of S. miltiorrhiza with distance of 2.1 cM, which also had 100% identities to male sterile gene MS2 in Arabidopsis. Both were distributed in chromosome 3 of Arabidopsis. The 2 028 bp fragment also had 100% identities to MS2 gene. Another E05/M04-750 marker that had 100% identities to chromosome 5 of Arabidopsis was found to have high identities to POP085-M05 gene of poplars and low affinity calcium antiporter CAX2 of Arabidopsis with very low E-value. The constructed genetic map and differential fragments with potential functions found in this study provide a solid foundation to lock male sterile genes in S. miltiorrhiza genome and to discover their functions. PMID- 28884533 TI - [Transcriptome-based gene mining and bioinformatics analysis of p-hydroxybenzoate geranyltransferase genes in Arnebia euchroma]. AB - The p-hydroxybenzoate geranyltransferases(PGT) play an important role in the biosynthesis pathways of shikonin derivatives. Six PGTs were obtained from transcriptome datebase of Arnebia euchroma by using bioinformatics methods and the proteins'physiochemical properties they encoded were predicted. The result of protein domain prediction showed all of the six protein sequences contained the conserved domain of Ubia prenyltransferase family and possessed the motif NDxxDxxxD for prenyldiphosphate binding and a GX(K/Y)STAL sequence for putative aromatic ring binding. The phylogenetic tree showed that PGT and p hydroxybenzoate polyprenyltransferase(PPT) belonged to two different clades. The results of gene expression analyses showed that the expression levels in the red shikonin-proficient line and the overground part of A. euchroma that could produce shikonin derivatives was much higher than the white shikonin-deficient line and the underground part, which suggested a positive correlation between the expression levels of PGT genes and shikonin production. This study aims to lay a foudation for further understanding of the function and enzymatic properties of PGT and provide a basis for the biosynthesis pathways and metabolic regulation of shikonin derivatives. PMID- 28884534 TI - [Study on quality evaluation of sequence and SSR information in transcriptome of Astragalus membranacus]. AB - In this study, 454/Roche GS FLX sequencing technology was used to obtain the data of the Astragalus membranaceus. Four hundred and fifty-four Sequencing System Software was applied to carry out the transcription of the group from scratch. Using MISA tools, 9 893 unigenes were selected for the sequence of the genome of A. membranaceus, and the information of SSR locus was analyzed. According to the result, the average length of reads was 413 bp, about 86% of the reads was involved in the splicing, the length of the N50 was 1 205 bp, the number of unigenes was measured by the whole transcript. 1 729 SSR loci in the A. membranaceus transcriptome were searched, the occurrence frequency of SSR was 9.24%, the frequency of SSR in the whole transcriptome was 13.42%, the average length of SSR was 7.97 kb. One hundred and twenty-seven kinds of core repeat sequences were found, the dominant type was TG/AC type of dinucleotide, it appeared to account for 4.25% of the total SSR locus. The results of the sequence of the transcription of the A. membranaceus transcriptome revealed the overall expression, and a large number of unigenessequence was obtained, and the SSR locus in the genome of the A. membranaceus is high, and the type is diverse, and the polymorphism of the gene is high. PMID- 28884535 TI - [Study of deltamethrin detection method and its residual dynamics in Loincerae Japonicae Flos]. AB - This paper reports the residual dynamics of deltamethrin and detection method in Loincerae Japonicae Flos to provide scientific basis for safe and appropriate use of deltamethrin. A field experiment was conducted in Fengqiu, Henan Province China. The field plots were sprayed with deltamethrin at the recommended dose and a high dose, respectively, and a control was set up, totally being 3 treatments with 3 replications. The flowers were picked at 2 hours, 1, 2, 3, 4, 5, 7, 9, 11, 13 and 15 days after pesticide application and then dried. The residue of deltamethrin was determined by gas chromatography method with electron capture detector for the above samples. Results showed that recoveries of deltamethrin ranged from 76.4% to 86.9%,and the relative standard deviation was below 11%,Linearity was observed over a range of 5-500 MUg*L -1 with correlation coefficient was 0. 999 2. The established method meets the requirements of pesticide residue analytical methods. The degradation of deltamethrin followed the first order dynamics. The residue dynamic equation of the high dose and recommended dose deltamethrin were C=5.992 2e-0.338t and C=1.536 9e-0.31t respectively, and the half-life of deltamethrin in Loincerae Japonicae Flos was 2.09-2.24 days, which indicates that deltamethrin is an easily degradable pesticide. It is concluded that deltamethrin should be used in aphids occurring period and the safety interval was more than 7 days to ensure the safety of Loincerae Japonicae Flos consuming. PMID- 28884536 TI - [Study on seed quality test and quality standard of Lonicera macranthoides]. AB - Referring to the rules for agricultural seed testing (GB/T 3543-1995) issued by China, the test of sampling, purity, thousand seed weight, moisture, viability, relative conductivity and germination rate had been studied for seed quality test methods of Lonicera macranthoides. The seed quality from 38 different collection areas was measured to establish quality classification standard by K-means clustering. The results showed that at least 7.5 g seeds should be sampled, and passed 20-mesh sieve for purity analysis.The 500-seed method used to measure thousand seed weight. The moisture was determined by crushed seeds dried in high temperature (130+/-2) C for 3 h.The viability determined by 25 C 0.1% TTC stained 5h in dark. 1.0 g seeds soaked in 50 ml ultra pure water in 25 C for 12 hours to determine the relative conductivity. The seed by 4 Cstratification for 80 days were cultured on paper at 15 C. Quality of the seeds from different areas was divided into three grades. The primary seed quality classification standard was established.The I grade and II grade were recommend use in production. PMID- 28884538 TI - [Introduction trial of medicine mulberry (Morus nigra) in Chongqing]. AB - Medicine mulberry (Morus nigra) mainly distributed in southern areas of Xinjiang Uighur Autonomous Region and introduced by grafting, is a unique Morus species, whose plant number is little. As a traditional herbal medicine, medicine mulberry with high levels of secondary metabolites has important values of scientific research and utilization. In order to solve the introduction problems for medicine mulberry, we have established its rapid propagation system through tissue culture since 2011. The shoots of medicine mulberry through tissue culture were transplanted into the field to carry out an introduction experiment. Here, we firstly reported that the growth status and pest and disease occurrence of medicine mulberry in the field of Chongqing and found that the medicine mulberry through tissue culture had well-developed root system, it showed better growth than medicine mulberry by grafting technique, and Pseudodendrothrips moil was a major pest of medicine mulberry. The introduction technique for medicine mulberry established successfully in this study could lay the foundation for large-scale cultivation and high efficiency utilization of medicine mulberry. PMID- 28884537 TI - [Morphological and cytohistological observations of seed germination and protocorm development of Bletilla striata]. AB - In order to investigate the mechanism of growth for Bletilla striata, which could be applied for rapid propagation, morphological and cytohistological of seed germination and protocorm development in vitro culture were observed using paraffin section techniques. In this study, we have found that the development of B. striata goes through four stages: embryo, protocorm, rhizome and pseudobulb. The end away from embryo suspensor is able to differentiate green buds after the seed of B. striata swelling, growing point. At the same time, the other end of embryo grows many white villous roots, with the green bud differentiating into cotyledon, the embryo breaking through seed coat and being protocorm. The shoot apical meristem of protocorm consists of tunica, corpus and leaf primordium, whose developmental flowing tunica-corpus theory. After more vascular bundle appeared from the leaf primordium, B. striata grows into the stage of rhizome. While in the stage of rhizome, the root primordium of tissue culture seedlings are differentia initially that derived from rhizome vascular bundle, belonging to internal origin. Subsequently, the pseudobulb forms by the inner meristem growing into mature parenchymatous tissue and the rhizome enlargement gradually. PMID- 28884539 TI - [Lignans from cultivated Gynura nepalensis]. AB - Taking application of some isolation and purification technologies, including solvent extraction, rude solvent isolation, column chromatographies on silica gel and Sephadex LH-20 , and preparative HPLC , 4 compounds were obtained from Gynura nepalensis cultivated in a suburban area of Beijing. Their structures were identified by spectroscopic methods in conjunction with comparison of the NMR data with literature values as 7S,8R-9'-O-ethyl-dehydrodiconiferyl-9-acetate (1), 9'-O-ethyl-dehydrodiconiferyl alcohol (2), dehydrodiconiferyl-9,9'-diacetate(3), and (+)-medioresinol(4), respectively. 1 is a new 2,3-dihydrobenzofuran-8,3' neolignane type compound, and 2-4 were isolated from G.nepalensis for the first time. The complete assignment of the 1H- and 13C-NMR spectroscopic data of the four compounds recorded in DMSO-d6 was achieved. PMID- 28884540 TI - [Rapid analysis of compounds in leaves of Chinese seabuckthorn and Tibetan seabuckthorn by UPLC/Q-TOF-MS]. AB - The study is aimed to analyze the chemical components in leaves of Chinese seabuckthorn and Tibetan seabuckthorn qualitatively and compare the differences between them by using ultra performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS).The chromatographic separation of the components was achieved ona Waters ACQUITY UPLC-T3 column (2.1 mm*100 mm, 1.7 MUm)using gradient mobile phase consisting of acetonitrile (A) and aqueous solution (B). The identification of the separated compounds was performed on atandem mass spectrometry (MS/MS)by fragmentation patterns under the negative electrospray ionization. The parameters of ion source were as follows:capillary voltage, 2 000 V; Cone voltage, 40 V. The ion source temperature, 100 C; collision gas argon; sheath gas flow rate, 900 L*h-1; sheath gas temperature, 450 C. Through the analysis of mass spectrometry data and with the help of literature data, a total of 35 compounds were detected and most of them were flavonoids. Among these compounds, 29 were common components for the two species, two components were unique to Chinese seabuckthorn and 4 were characteristic components of Tibetan seabuckthorn. The results indicated that the compositions of the two kinds of seabuckthorn leaves were quite similar. It is also demonstrated that UPLC/Q-TOF-MS method could be applied to rapidly and effectively analyze and speculate the compounds in leaves of Chinese seabuckthorn and Tibetan seabuckthorn. PMID- 28884541 TI - [Determination of five effective components in medicinal material of Tripterygium by UPLC-ESI-MS/MS]. AB - This paper is aimed to develop a method for the determination of five effective components in medicinal material of Tripterygium using ultra performance liquid chromalography coupled with electrospray ionization tandem mass spectrometry(UPLC ESI-MS/MS), which then was used to study their contents in raw materials from different areas and different sources.The separation was performed on a Waters ACQUITY UPLC-CSH-C18S column(2.1 mm*100 mm,1.7 MUm), usingacetonitrile-0.2% ammonium form ateaqueous solutionas mobile phase. The target components were detected in multiple-reaction monitoring(MRM) mode by mass spectrometry with electrospray ionization (ESI) source operated in positive ionization mode. The quantitative results showed that good linearity was achieved in their respective linear ranges and fine determination coefficient (r > 0.997 8),and the overall recoveries ranged from 96.72%-103.2% with the RSD ranging from 1.0%-2.4%.The method is sensitive and accurate, and suitable for the effective components quantification in medicinal material of Tripterygium; contents of five effective components from different sources vary significantly, so the quality and safety of medicinal material of Tripterygium needs to be improved. It is very important to control the quality with multi-index for clinic safety. PMID- 28884542 TI - [Simultaneous determination of thirteen components in Polygoni Multifori Caulis by UPLC-MS/MS]. AB - A comprehensive analytical method based on UPLC-MS/MS was developed for the simultaneous determination of thirteen components including three stilbenes (stilbeneglucoside, polydatin, resveratrol), four anthraquinones (emodin, physcion, emodin-8-beta-D-glucopyranoside, aloe-emodin), five flavonoids (epicatechin, rutin, hyperoside, astragalin,quercetin) and one phenolic acid (gallic acid) in Polygoni Multifori Caulis.The separation was carried out on a Waters BEH C18 column(2.1 mm*100 mm,1.7 MUm)with gradient elution of acetonitrile water (0.1% acetic acid) at a flow rate of 0.25 mL*min-1, and column temperature was 35 C. The target compounds were analyzed by multiple reaction monitoring (MRM) mode. TOPSIS analysis ware performed to evaluate the samples from different areas and commercial herbs according to the contents of thirteen components. The correlation coefficients of all the calibration curves were higher than 0.991 5. The average recoveries ranged from 95.24% to 102.3%, and the relative standard deviations were less than 5%. The result of TOPSIS analysis showed that the comprehensive quality of Polygoni Multifori Caulis sample from Guangzhou was better. The developed method with good repeatability and accuracy was suitable for the simultaneous determination of multiple functional substances, which provided a new basis for the comprehensive assessment and overall control of the quality of Polygoni Multifori Caulis. PMID- 28884543 TI - [Simultaneous determination of four coumaroylspermidine constituents in Carthamus tinctorius by HPLC-DAD]. AB - The HPLC-DAD method was established to simultaneously determine the contents of four coumaroylspermidine[ N1, N5, N10-(Z)-tri-p-coumaroylspermidine (1), N1, N5 (Z)-N10-(E)-tri-p-coumaroylspermidine (2), N1(E)-N5-(Z)-N10-(E)-tri-p coumaroylspermidine (3), and N1, N5, N10-(E)-tri-p-coumaroyl-spermidine (4) ] in Carthamus tinctorius. The method was performed on an Eclipse XDB-C18 column (4.6 mm*250 mm, 5 MUm) eluted with 47% methanol in an isocratic program. The flow rate was 1 mL*min-1; the injection volume was 10 MUL, and the column temperature was 30 C. The detective wavelength was 270, 280, 290, and 300 nm, respectively. Four coumaroylspermidine constituents showed a good linearity in the range of 0.002 1 0.041 6 (r=0.999 5), 0.002 6-0.051 2 (r=0.999 7), 0.002 7-0.054 0 (r=0.999 8) g*L 1, and 0.005 0-0.100 4 (r=0.999 8) g*L-1, respectively. The average recoveries of these four coumaroylspermidine constituents were in the range of 98.61%-100.9% (RSD 2.3%-3.0%). In conclusion, the method is simple, rapid, and sensitive, which could be used as a quantitative determination method for the four coumaroylspermidine components in C.tinctorius. PMID- 28884544 TI - [Development of FTIR fingerprint for identification of armand clematis stem (Chuanmutong) and related herbs]. AB - Armand clematis stem (Clematidis Armandii Caulis, Chuanmutong) is a widely used Chinese herb to disinhibit urine and relieve stranguria. It is difficult to be identified owing to its various macroscopic feature and unknown characteristic compounds. Thus, total of 24 Chuanmutong samples and 7 related herbs including four manshurian aristolochia stem (Aristolochiae Manshuriensis Caulis, Guanmutong) and three akebia stem (Akebiae Caulis, Mutong) samples were collected and analyzed in the range of 4 000 - 400 cm-1 by Fourier Transform Infrared (FTIR) and two-dimensional infrared correlation spectroscopy (2D-FTIR) techniques. The FTIR spectra of 24 Chuanmutong samples are consistent in the spectrum profiles, position and intensity of characteristic peaks. 20 of the 24 Chuanmutong samples were randomly selected as calibration samples to calculate and simulate mean spectrum. This mean spectrum is named as FTIR fingerprint of Chuanmutong with characteristic peaks at 3 412, 2 932, 1 739, 1 639, 1 509, 1 456, 1 426, 1 376, 1 332, 1 261, 1 159, 1 035, 897 ,609 cm-1. Meanwhile, the limited level (Mean-3sigma=0.992 6) to identify true or false Chuanmutong by correlation coefficient of FTIR spectra was calculated based on the 20 Chuanmutong calibration samples. Then, the rest 4 Chuanmutong, 4 Guanmutong and 3 Mutong samples were used as validation samples to evaluate the identification efficacy. The result shows that the FTIR spectra of 4 Chuanmutong validation samples were similar to the fingerprint. Their correlation coefficients of FTIR spectra were over the limited level and accepted as Chuanmutong. However, the spectra of Guanmutong and Mutong were significantly different from Chuanmutong fingerprint. The correlation coefficients of Guanmutong (0.902 1-0.940 4, n=4) and Mutong (0.954 9-0.978 9, n=3) FTIR spectra were less than the limited level and rejected from Chuanmutong. Furthermore, the number, position and intensity of auto-peaks on the 2D-FTIR were drastically different among the three herbs. It is concluded that the developed FTIR fingerprinting can be rapidly and accurately identify Chuanmutong and differentiate from related herbs. PMID- 28884545 TI - [Repair effect of Qinbai Qingfei concentrated pellets to AEC-II of rats infected by Mycoplasmal pneumonia]. AB - To discuss the repair mechanism of Qinbai Qingfei concentrated pellets to AEC-II of rats infected by mycoplasma through the observation of the changes and distribution of TGF-beta and SP-A in lungs, totally 60 Wistar rats that weighing 80-100 g were collected, with male and female in half. The rats were divided into six groups randomly, with 10 rats each group, namely blank group, model group, positive group and Qinbai Qingfei concentrated pellets high, middle and low dose groups. Rats were infected through nasal intubation drip of MP. After 10 days of administration, serum and bronchoalveolar lavage fluid (BALF) were collected to detect the concentration of surface activity related protein A (SP-A) by ELISA, left pulmonary tissues of rats were collected to observe the expression and distribution of transforming growth factor-beta (TGF-beta) and SP-A by immunohistochemistry, and right pulmonary tissues were taken to detect TGF-beta and SP-A mRNA expression level by real-time quantitative PCR (RT-PCR). Qinbai Qingfei concentrated pellets can reduce the expression of TGF-beta and increase the expression of SP-A in the lung tissues of rats infected by mycoplasma. Specifically, TGF-beta was mainly distributed among the lung interstitium, while SPAs were mainly distributed in AEC-II and parts of alveolar macrophage. The level of SP-A was reduced in serum and increased in BALF in rats in Qinbai Qingfei concentrated pellets groups. It was proved that Qinbai Qingfei concentrated pellets can restore the normal morphology and function of the lung by reducing the content of TGF-beta to inhibit epithelial-mesenchymal transition (EMT) of alveolar type II epithelial cells and increasing the expression of SP-A. Qinbai Qingfei concentrated pellets have the repairing ability to capillary vessel damage caused by MP in lung tissues of rats. PMID- 28884546 TI - [Inhibitory effects of vina-ginsenoside R7 on activation of rat C6 astrocytes induced by LPS and TNF-alpha combination]. AB - To investigate the inhibitory effect and mechanism of vina-ginsenoside R7 (R7) on the activation of rat C6 astrocytes cells induced by LPS/TNF-alpha, cells in logarithmic growth phase were cultured in DMEM medium without FBS for 24 h. After dissociated using 0.25% EDTA-trypsin, the cells were seeded into respective plates at the density of 1.5*106 cells per mL and cultured overnight. The cells were divided into the following groups: control group (no treatment), model group (treated with LPS 1 MUg*mL-1 and TNF-alpha 10 MUg*L-1 treated for 24 h), R7 groups (pre-treated with 6.25, 12.5, 25, 50, and 75 MUmol*L-1 R7, 4 MUmol*L-1 L NMMA for 2 h and then stimulated with LPS 1 mg*L-1 and TNF-alpha 10 MUg*L-1 for 24 h). Cell viability was analyzed by CCK-8 kit. Secretion of nitric oxide (NO) in the medium was measured by Greiss method. Concentrations of interleukin-6 (IL 6) and tumor necrosis factor (TNF-alpha) were assayed by ELISA kits. Gene expressions of inflammatory factors were examined by quantitative-PCR analysis. Activation of NF-kappaB was detected by dual luciferase reporter gene assay kit. The results showed that R7 could significantly inhibit the secretion of NO from C6 cells in a dose-effect manner, with an IC50 of 34 MUmol*L-1. And it could reduce cell proliferation induced by LPS/TNF-alpha stimulation. Furthermore, R7 at 50 MUmol*L-1 significantly down-regulated gene expressions of iNOS (P<0.001), TNF-alpha (P<0.001), IL-1beta(P<0.05), and COX-2 (P<0.001), but could not change gene expression of IL-6. However, R7 reduced the secretion of TNF-alpha (P<0.001) and IL-6 (P<0.001). Further studies disclosed that, different concentrations of R7 (25, 50, 100 MUmol*L-1) could significantly inhibit the transcription activity of NF-kappaB(P<0.05, P<0.01, and P<0.001). In conclusion, R7 could inhibit inflammatory responses in C6 cells induced by LPS/TNF-alpha probably by inhibiting the transcription activity of NF-kappaB, which indicates its possible therapeutic effect in neurological diseases related to neuroinflammation. PMID- 28884547 TI - [Effects of aqueous extract of Cassiae Semen on activity hepatic microsomal CYP450 isozymes in rats]. AB - To study the effect of aqueous extract of Cassiae Semen on the activity, mRNA and protein expressions of cytochrome P450(CYP450) system in rat liver microsomes, microsomes of rat liver were prepared after the oral administration with aqueous extract of Cassiae Semen for 14 days. The enzyme activity was quantified by Cocktail method. Meanwhile, the mRNA and protein expressions of CYP1A2, CYP2B1, CYP2C11, CYP2D2, CYP2E1 and CYP3A1 in the livers were detected by RT-PCR and Western blot. The result of this experiment was that aqueous extract of Cassiae Semen obviously induced the enzyme activities of CYP1A2, CYP2B1, CYP2C11, CYP2D2, CYP2E1 and CYP3A1. Low dose of aqueous extract of Cassiae Semen significantly reduced the activity of CYP2D2, but the activity of CYP2D2 was significantly induced by middle dose and high dose of aqueous extract of Cassiae Semen. These subtypes were increased in a dose-dependent manner except for CYP3A1. The mRNA levels of CYP1A2, CYP2C11, CYP2D2 and CYP2E1 were also induced in rats treated with aqueous extract of Cassiae Semen, but with no significant effect in CYP2B1 and CYP3A1 mRNA expressions. The protein levels of CYP2C11 and CYP2E1 were also induced in rats treated with aqueous extract of Cassiae Semen, but with no significant difference. Since the enzyme activity, mRNA and protein expressions of CYP450, particularly CYP2C11and2E1subtypes, were induced or inhibited by aqueous extract of Cassiae Semen to varing degrees, suggesting the potential drug drug interactions should be concerned. PMID- 28884548 TI - [Nuclear magnetic resonance-based metabonomics for sedative and hypnotic effect of Banxia Houpo decoction]. AB - Insomnia was a common disease, which might be correlated with gamma-aminobutyric acid A (GABAA) receptor mechanism, cytokine regulatory mechanism, excitatory amino acid mechanism and hydroxytryptamine (5-HT) receptor mechanism, but the correlations between these independent mechanisms and pathological characterization were still unclear. To further explore the effect of Banxia Houpo decoction on known or unknown biological pathways during treatment of insomnia, the metabonomics method based on 1H-NMR was developed for detecting the significant changes in metabolomics after the administration with Banxia Houpo decoction in pentobarbital sodium-induced rat sleeping experiment. Serum and urine samples were analyzed by 1H-NMR. Principal component analysis (PCA) was carried out for endogenous small molecule metabolites in urine and serum. H-NMR spectroscopies and relevant metabolites were found and identified by Simca-p 17.0 (Umet-rics, Umea, Sweden) and Chenomx NMR Suite 7.1 (Chenomx, Inc., Edmonton, Alberta, Canada) software. The result suggests that Banxia Houpo decoction group and indiplon group had significant differences. The load diagram showed the biggest variation metabolites and intergroup significant differences among 10 metabolic substances. According to the experiment, Banxia Houpo decoction group and indiplon group can prolonge the sleeping time of pentobarbital sodium-induced sprague-dawley rats, with a synergistic effect. The significant changes of these biomarkers indicated that the Banxia Houpo decoction could aid sleep by adjusting the content of glutamine, creatine phosphate, 2-oxoglutarate, and reducing the activity of brain nerves. PMID- 28884549 TI - [Comparison of essential oil from Mentha haplocalyx and menthol used as penetration enhancers]. AB - The aim of this paper was to investigate and compare the penetration-enhancing characteristics of menthol and essential oil from Mentha haplocalyx(M.haplocalyx oil) on the transdermal absorption of the complex traditional Chinese medicine(TCM) components. A series of TCM components were selected as model drugs based on their lipophilicity (logP value), namely osthole(OT, logP=3.85), tetramethylpyrazine(TMP, logP=2.34), ferulic acid(FA, logP=1.26), puerarin(PR, logP=-0.35) and geniposide(GP, logP=-1.01), in order to simply and characterize the TCM complex components system. Transdermal experiment in vitro was employed to investigate and compare the penetration-enhancing characteristics of menthol and M.haplocalyx oil on the transdermal absorption of these model drugs. Meanwhile, Fourier transform infrared spectroscopy(FTIR) was used to further compare the effect of menthol and M. haplocalyx oil on the molecular structure of stratum corneum(SC). The results showed that both of menthol and M.haplocalyx oil at proper concentration could promote the transdermal absorption of the selected model drugs. After application of menthol, the drug logP values gradually tended to have negative linear relationship with the logarithm of penetration enhancement ratio(ER); while after application of M.haplocalyx oil, the logP values tended to have parabolic relationship with the logarithm of ER. However, both menthol and M.haplocalyx oil exhibited higher efficiency for the drugs with relative low lgP value(ie hydrophilic drugs), with similar penetration-enhancing characteristics between these two. Infrared spectroscopy results showed that menthol and M.haplocalyx oil could affect the skin barrier functions mainly via stratum corneum lipids, with similar effect intensity, and this was consistent with the results of transdermal experiment in vitro. Thus, Menthol had similar penetration-enhancing characteristics with M.haplocalyx oil, and had same effect on the SC molecular structure. Therefore, as transdermal penetration enhancer, the menthol with single composition could be considered to replace M.haplocalyx oil with complex compositions. PMID- 28884550 TI - [Metabonomics on toxicity reduction of Glycyrrhizae Radix et Rhizoma for Aconiti Lateralis Radix Preparata in Sini Tang]. AB - To analyze the endogenous metabolite changes in rat plasma after intervention by Sini Tang and Sini Tang without Glycyrrhizae Radix et Rhizoma based on GC-MS metabonomics technology, and study the toxicity reduction effect of Glycyrrhizae Radix et Rhizoma in Sini Tang on Aconiti Lateralis Radix Preparata. Eighteen SD rats were randomly divided into normal group, Sini Tang group and Sini Tang without Glycyrrhizae Radix et Rhizoma group on average. The rats in Sini Tang group and Sini Tang without Glycyrrhizae Radix et Rhizoma group were treated respectively with physic liquor by intragastric administration at the dose of 0.02 mL*g -1 (equivalent to 0.8 g*mL -1 crude drugs) once a day for 7 days. The rats in normal group were given with equal volume of saline solution. The plasma samples were collected from each rat 0.5 h after the last administration for GC MS detection. The data was used for multivariate statistical analysis to obtain 14 potential metabolic markers(13 of them were identified). Then their relative content and metabolic pathways were analyzed. Compared with Sini Tang without Glycyrrhizae Radix et Rhizoma group, seven metabolic markers of were reduced in Sini Tang group. Analysis on physiological functions of these potential metabolic markers showed that the Glycyrrhizae Radix et Rhizoma in Sini Tang could reduce the toxicity of Aconiti Lateralis Radix Preparata by adjusting the glycolysis, lipid metabolism, citrate cycle and some amino acids metabolism. PMID- 28884551 TI - [Pharmacokinetics of bullatine A in Aconitum brachypodum total alkaloids gel in transdermal delivery]. AB - In this study, the changes of bullatine A in plasma and skin of mice with time in microemulsion gel and ordinary gel of Aconitum brachypodum total alkaloids were compared through UPLC-MS/MS, and their pharmacokinetic parameters were also compared and analyzed, to investigate the feasibility of microemulsion agent in the transdermal drug delivery. UPLC-MS/MS method for simultaneous determination of bullatine A in plasma and skin had high sensitivity and was in line with the pharmacokinetic study requirements for transdermal drug delivery. The main pharmacokinetic parameters for microemulsion gel in the plasma were as follows: Cmax=(37.62+/-14.31) MUg*L-1, Tmax=(3.40+/-1.34) h, AUC0-infinity=(1 027.7+/-260) MUg*L-1*h-1, MRT=(34.80+/-12.31) h, MRTlast=(10.68+/-0.57) h, t1/2=(23.11+/-9.20) h; main pharmacokinetic parameters for ordinary gel in the blood: Cmax=(52.23+/ 15.90) MUg*L-1, Tmax=(4.00+/-0.00) h, AUC0-infinity=(728.60+/-280.80) MUg*L-1*h 1, MRT=(20.69+/-3.98) h, MRTlast=(9.34+/-0.42) h, t1/2=(14.69+/-3.15) h. The results showed that the microemulsion gel had more stable transdermal absorption, longer duration of action and higher bioavailability than ordinary gel, indicating that the microemulsion gel had a good and stable transdermal effect. There was no significant difference in bioavailability of bullatine A in skin between microemulsion gel and ordinary gel. PMID- 28884552 TI - [Effect of puerarin in Longmaining formula on pharmacokinetics-pharmacodynamics correlation in rats with myocardial ischemia]. AB - To study the pharmacokinetics of puerarin in compound Longmaining(FFLMN) in normal rats and myocardial ischemia rats, and investigate its correlation with anti-myocardial ischemia effect of FFLMN. Models of myocardial ischemia rats were produced by subcutaneous injection of isoproterenol(ISO), then FFLMN extract solution was administered by gavage. Orbital sinus blood sampling was collected at different time points after gavage. HPLC-UV method was applied to determine the concentration of puerarin in plasma, and compare the difference in pharmacokinetics between normal rats and model rats after application of same dose of FFLMN. Meanwhile, microplate reader was used to determine IL-6 and SOD activities in plasma of different time points, and draw dose-effect curve. The results indicated that the pharmacokinetics of puerarin conformed to the two compartment model in both normal group and myocardial ischemia model group. In the comparison of main pharmacokinetic parameters between two groups: AUC0 infinity=(11.451+/-3.228) mg*h*L-1,AUC0-t=(14.047+/-3.765) mg*h*L-1, Cmax=(5.623+/-1.40) mg*L-1 in normal group; AUC0-infinity=(68.849+/-50.396 9) mg*h*L-1, AUC0-t= (58.312+/-45.802) mg*h*L-1,Cmax=(18.456+/-7.517) mg*L-1 in treatment group. The SOD level was significantly increased and IL-6 concentration was significantly decreased in plasma, indicating that as compared with the normal group, puerarin in FFLMN had a higher plasma concentration, slower elimination rate and higher bioavailability. Therefore, puerarin concentration in plasma has correlation with the anti-myocardial ischemia effect of FFLMN, which could increase SOD level and inhibit the release of IL-6. PMID- 28884553 TI - [Effect of rat intestinal flora in vitro on metabolites of acteoside]. AB - Acteoside was used for anaerobic incubation with rat intestinal flora in vitro. HPLC was used to detect the changes of acteoside at different incubation time points and HPLC-Q-TOF-MS was used to identify the metabolites of acteoside. The results showed that acteoside could be metabolized by rat intestinal flora in vitro and the metabolites were 3,4-dihydroxyphenyl acid, caffeic acid and 3-(3' hydroxyphenyl) propionic acid. PMID- 28884555 TI - [Clinical characteristics and drug combination analysis in patients with inflammatory bowel disease based on real world HIS data of 14 758 cases]. AB - To analyze the characteristics and clinical medicine for inflammatory bowel disease based on the diagnostic information and medical advice information in hospital information system of 20 3A hospitals. Frequency analysis and correlation analysis results showed that the most common complications for inflammatory bowel disease included hypertension (2 058 cases, 13.94%), chronic superficial gastritis (1 611 cases, 10.92%), bowel benign tumor (1 351 cases, 9.51%), coronary heart disease (1 346 cases, 9.15%), chronic gastritis (1 044 cases, 7.07%), stomachache (1 030 cases, 6.98%), chronic antrum gastritis (988 cases, 6.69%), type 2 diabetes mellitus (956 cases, 6.48%), upper respiratory infection (816 cases, 5.53%) and gastrointestinal bleeding (784 cases, 5.31%). The most-frequently-used drug combination was montmorillonite powder-berberine hydrochloride tablets (35.56%), followed by glycyrrhiza compound-ambroxol (29.8%), Yunnan Baiyao-hemocoagulase (28.8%), and berberine hydrochloride tablets aspirin (27.91%). The study indicated that the complications of inflammatory bowel disease had their own features, so we should attach importance to the treatment of these complications. Meanwhile, Chinese medicine accounted for a high proportion in the drug combinations for inflammatory bowel disease, thus importance shall be attached to integrative Chinese and western medicine to achieve ideal treatment effect. PMID- 28884554 TI - [Percutaneous permeability of rhein at shenque acupoint in vitro]. AB - To study rhein's permeative properties of acupoint and non-acupoint and different species' transdermal administration in vitro. Cumulative permeation amount and steady-state infiltration rate were taken as evaluative indexes to assess the permeability difference. The Valia-Chien diffusion cell method was used to conduct the permeability test, with fresh acupoint and non-acupoint skin of rat, rabbit and swine in vitro as permeation barriers, and blank 20% EtOH saline as absorption liquid. HPLC was used to determine the rhein. The absorption difference was observed by confocal laser scanning microscopy. The 24-hour cumulative permeation amount through acupoint skin in rats was (102.63+/-9.60) MUg*cm-2, the steady-state infiltration rate was 4.307 MUg*cm-2*h-1, both were higher than that through non-acupoint skin. The thickness of acupoint skin in rat was thinner than that in rabbit and swine. The cumulative permeation amount and steady-state infiltration rate of rhein in acupoint of rat were signally higher than those in rabbit and swine. The absorption difference can be clearly observed through an accumulation of fluorescence. In conclusion, species and acupoint all affect the permeability of rhein in vitro. The permeation amount and rate of rhein on Shenque acupoint were better than that on non-acupoint skin, which could verify that treatment through Shenque acupoint is superior to that through non acupoint. The preliminary mechanism may be the drug delivery through Shenque acupoint as a channel and carrier, which is a visual verification the specificity and superiority of clinical application through Shenque acupoint in treating diseases. PMID- 28884556 TI - [Discussion of price forecasting of Notoginseng Radix et Rhizoma based on ARIMA model]. AB - Based on the analysis of price fluctuations on Notoginseng Radix et Rhizoma, this paper takes advantage of the price data of Notoginseng Radix et Rhizoma which specification is 120 from January 2004 to August 2015, using autoregressive integrated moving average model [ARIMA (p, d, q)] forecasting the price of Notoginseng Radix et Rhizoma from September 2015 to August 2016. In the process of determining the form of model, the stability test used to determine the model of p, and the autocorrelation function and particles autocorrelation functions to identify the p and q of model. According to test the model, the forecast minimum error model was identified. In this paper, ARIMA (2,1,3) model was used to predict next year's price of Notoginseng Radix et Rhizoma, for providing information for Notoginseng Radix et Rhizoma growers, pharmaceutical companies. PMID- 28884557 TI - Factors predicting outcome of surgical treatment of spontaneous spinal hematomas: a retrospective cohort study in four tertiary reference centers. AB - BACKGROUND AND OBJECTIVES: Spontaneous spinal extradural hematoma (SSEH) is a rare but disabling disorder. Most of the previous assumptions regarding the factors that contribute to poor neurological recovery from SSEH are based on small case samples or conditions with similar clinical presentations but different physiopathologies. Our goal was to find the most relevant prognostic factors for neurological recovery in patients suffering SSEH treated with surgical evacuation. MATERIAL AND METHODS: From a retrospective database of 29 surgical patients with SSEH, several clinical and radiological variables were recorded. These variables were compared between patients with good and poor neurological recovery, considering good as an improvement by at least one point in the ASIA scale. RESULTS: Among the patients included, morbidity and mortality rate was 6.9 and 3.4%, respectively, with a mean follow up of 7.1 months. Neurological full recovery was experienced by 33% of the patients included, and 86% of individuals had an improvement in their neurological condition at last follow-up. Lesser intramedullary lesions were significantly associated with greater chances of improvement in ASIA scale at discharge and at follow up. Surgical decompression within the first 24 hours of onset of symptoms were correlated with better neurological outcomes at follow up. CONCLUSIONS: MRI is a powerful tool to predict the neurological outcome in SSEH patients, and it should be considered as an another resource to better know the patients with greater chances of having neurological recovery, especially in cases where the neurological examination is not reliable at the initial exam. PMID- 28884558 TI - Spinal angiolipoma: observations upon three cases. PMID- 28884559 TI - Artificial neural network predicts hemorrhagic contusions following decompressive craniotomy in traumatic brain injury. AB - OBJECTIVE: This study aimed to explore relevant factors of hemorrhagic contusions following decompressive craniotomy (DC) in traumatic brain injury (TBI), and create an artificial neural network (ANN) prediction model of the risk factors of hemorrhagic contusions. METHODS: This study analyzed 425 patients with TBI who underwent DC in the Neurosurgery Department of Shaoxing People's Hospital between 2009 and 2014. Patients were divided into two groups according to the first postoperative CT scans: hemorrhage group and non-hemorrhage group. Gender, age, preoperative situations (Initial Rotterdam CT score, GCS score, pupillary response, laboratory data and preoperative hematoma), the time gap between trauma and DC, postoperative CT scans, and Glasgow Outcome Scale (GOS) scores were recorded. ANN was used to predict hematoma. Correlation analysis was used to state the relationship between increased hemorrhage volumes and GOS scores. RESULTS: The ANN prediction model was established. This model included 11 parameters: initial Rotterdam CT score, GCS score, C-reactive protein, age, the time gap between trauma and DC, pupillary response, platelet count, bone-flap size, glucose level, hernia magnitude and preoperative hematoma volume. The overall predictive accuracy of the model was 73.0%. CONCLUSION: Initial Rotterdam CT scores and GCS scores may predict the risk of expansion contusions following DC. The ANN prediction model has a high accuracy to forecast hemorrhage. PMID- 28884560 TI - Retroperitoneal hematoma after minimally invasive lumbar discectomy: is the percutaneous endoscopic approach really safe? PMID- 28884561 TI - Tanycytic ependymoma of the brain stem, presentations of rare cystic disease variants and review of literature. AB - INTRODUCTION: The aim of this paper was to systematically review the evidence linking Propionibacterium acnes (P. acnes) with the develop Tanycytic ependymoma (tcE) is a rare variant of ependymoma and management guidelines for patients with this disease are not established. EVIDENCE ACQUISITION: We performed a systematic search on Pubmed complimented by hand-searching citation lists to identify patients with pathologically confirmed tcE. Signs and symptoms, radiological and specific pathological findings as well as reported treatment modalities and outcomes were recorded and analyzed. EVIDENCE SYNTHESIS: Fifty-one studies involving a total of 77 patients were identified and included in this review. Most cases of tcEs occurred in the spinal cord (50.6%), followed by lesions located in upper intracranial sites (36.4%) and only a few at the cervicomedullary junction (3.9%). Female to male ratio was calculated as about 1:1.5, with a mean age at diagnosis of approximately 36.1+/-18 years. Complete resection of the tumor without further additional therapy was the treatment of choice in most cases (63.6%), radiotherapy was considered in 10 cases (13.0%). In 18 reported cases of tcE (23.4%), the treatment was not documented. Defined follow-up periods for patients with tcE were only documented in 44 cases (57.1%), the mean follow-up was 22.3 months. 36 cases (46.8%) had no recurrence of tumor after treatment (26 months mean follow-up). CONCLUSIONS: This comprehensive review on tcEs supports surgery as the initial treatment modality of choice. Radiotherapy can be considered when total gross resection cannot be achieved and allows for prolonged progression-free survival. Given the benign nature of this subtype of ependymoma, aggressive treatment such as chemotherapy is usually not indicated. PMID- 28884562 TI - OMPSQ-Short Score and determinants of chronic pain: cross-sectional results from a middle-aged birth cohort. AB - BACKGROUND: The Orebro Musculoskeletal Pain Screening Questionnaire (OMPSQ) was developed to identify patients at risk of developing work disability due to pain. So far, neither the OMPSQ or its short version (OMSPQ-short) have been tested in population-based samples. AIM: We examined the associations between several well known determinants for chronic pain and OMPSQ-Short Score. DESIGN: Cross sectional study. SETTING: All measurements and tests were made at the University of Oulu. POPULATION: Subjects belonging to the Northern Finland Birth Cohort 1966 answered a questionnaire at the age of 46 years (N.=5637). METHODS: The questionnaire included the OMPSQ-short as well as questions about smoking, education, location, number of pain sites, and physical activity. In addition, body weight and height were measured in order to calculate the Body Mass Index. RESULTS: In multivariate logistic regression analysis, reporting 4-5 pain sites (females OR 3.4; males 3.0), >=6 pain sites (females OR 12.4; males 7.4) and current smoking (females 1.8; males 2.6) were associated with being classified into the OMPSQ high risk group. In females, also obesity (OR 1.6) and less than 9 years of education (2.7) were associated with higher OMPSQ Score. The frequency of physical activity was not associated with the OMPSQ Score. CONCLUSIONS: High number of pain sites and smoking among both genders, and obesity and low education level among females is associated with higher OMPSQ scores. Therefore, the OMPSQ-short may be a working instrument for also screening the general population. CLINICAL REHABILITATION IMPACT: Results of this study may improve the detection of patients at high risk of developing work disability due to pain. PMID- 28884563 TI - Expressions and significance of HIF-1alpha and AQP-3 in intervertebral disc degeneration tissues of cervical spondylotic myelopathy. PMID- 28884565 TI - How should we manage patients with functional dyspepsia in clinical practice? PMID- 28884564 TI - Pattern of food intolerance in patients with gastro-esophageal reflux symptoms. AB - BACKGROUND: Many food items have been involved in gastro-esophageal reflux disease pathogenesis and dietary modification has been proposed as first-line treatment. Test-based exclusion diets have shown to significantly reduce reflux symptoms. We aimed to assess the patterns of food intolerance in a series of patients with typical gastro-esophageal reflux symptoms (GERS). METHODS: We retrospectively evaluated all patients with typical reflux symptoms, attending the Centre Study Association on Food Intolerance and Nutrition of Ferrara from January 2010 to October 2015, who resulted positive to at least one food item at the Leucocytotoxic Test. The presence and severity of typical GERS (heartburn and/or acid regurgitation) were assessed using the Gastro-esophageal Reflux Disease Impact Scale (GIS) questionnaire. Only individuals with a GIS Score of at least 5 points were included. RESULTS: Almost all patients (91.1%) were intolerant to at least 5 food items. The most frequent food intolerance (more than 33% of patients) were found for milk (55.4%), lettuce (46.4%), coffee (43.7%), brewer's yeast (42.9%), pork (42.9%), tuna (37.5%), rice (35.7%), sole (34.8%), asparagus (34.8%) and eggs (33.9%). Nine different clusters of food intolerance were detected. CONCLUSIONS: Patients with typical gastro-esophageal reflux symptoms seem to have intolerance to multiple food items, some of which (lettuce, brewer's yeast, tuna, rice, sole and asparagus) have not yet been associated to gastro-esophageal reflux disease. PMID- 28884566 TI - Effects on cognitive function of propofol medium and long chain lipid emulsion in patients with hepatic encephalopathy. AB - BACKGROUND: Our study aimed to investigate the effects of propofol medium and long chain lipid emulsion on cognitive function of the patients with hepatic encephalopathy undergoing hemofiltration treatment. METHODS: A total of 87 patients diagnosed with hepatic encephalopathy from January 2014 to January 2016 were continuously selected, and randomly (using random number method) divided into an observation group (45 cases) and a control group (42 cases). All patients were treated with persistent hemofiltration; the patients in control group were not given any sedative measures, while the patients in observation group were given a propofol medium-long chain lipid emulsion injection with a dose determined by each individual's degree of restlessness and tolerance to hemofiltration (intravenous injection was performed with the first dose of 100 mg, and then patients are subjected to micro-infusion pump with a dose of 0.5~4 mg/kg/h, sedation lasted for 24 h). The indicators of treatment outcome and cognitive function changes of these two groups were compared. RESULTS: Our results showed that the blood ammonia, beta-endorphin and total bilirubin levels all decreased after treatment, and those of observation group decreased more significantly, (P<0.05). At the same time levels of alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) of both of the two groups were lower than those before treatment, in addition, the levels of ALT and GGT in patients of observation group decreased more significantly than those of the patients in control group, (P<0.05). Finally, we found that Mini-Mental State Examination (MMSE) scores at two different time points (immediately after treatment and two weeks after treatment) of both two groups increased and the scores of the observation group were even higher than those of the control group, (P<0.05). CONCLUSIONS: Based on our results we found that propofol medium-long chain lipid emulsion can significantly improve the curative effect of hemofiltration on patients with hepatic encephalopathy, and can also improve their cognitive function. We recommend the use of this propofol emulsion when considering hemofiltration treatment in this group of patients. PMID- 28884568 TI - Computational Study of Low Interlayer Friction in Tin+1Cn (n = 1, 2, and 3) MXene. AB - The friction of adjacent Tin+1Cn (n = 1, 2, and 3) MXene layers is investigated using density functional theory (DFT) calculations and classical molecular dynamics simulations with ReaxFF potentials. The calculations reveal the sliding pathways in all three MXene systems with low energy barriers. The friction coefficients for interlayer sliding are evaluated using static calculations. Both DFT and ReaxFF methods predict friction coefficients between 0.24 and 0.27 for normal loads less than 1.2 GPa. The effect of titanium (Ti) vacancies in sublayers and terminal oxygen (O) vacancies at surfaces on the interlayer friction is further investigated using the ReaxFF potential. These defects are found to increase the friction coefficients by increasing surface roughness and creating additional attractive forces between adjacent layers. However, these defective MXenes still maintain friction coefficients below 0.31. We also consider functionalized Ti3C2 MXene terminated with -OH and -OCH3 and find that compared to the -O-terminated surface both groups further reduce the interlayer friction coefficient to 0.10-0.14. PMID- 28884567 TI - High peak PaO2 values associated with adverse outcome in patients treated with noninvasive ventilation for acute cardiogenic pulmonary edema and pneumonia. AB - BACKGROUND: Noninvasive ventilation (NIV) has a sigificant impact on mortality in acute respiratory failure (ARF). Predictive parameters for mortality are of high interest. METHODS: We retrospectively analyzed 3759 blood gas analysis and clinical parameters of 475 patients presenting with ARF based on acute cardiogenic pulmonary edema and/or pneumonia. The influence of peak arterial oxygen partial pressure levels (PaO2) with respect to its predictive value for in hopital and long-term mortality was investigated. RESULTS: Overall intra-hospital mortality was 24%. Peak PaO2 levels in kPa were significantly higher in non survivors (20.01+/-10.11) compared to survivors (15.65+/-6.79, P<0.001). A univariate Cox proportional-hazards analysis for long-term mortality revealed associations with maximum PaO2 levels (overall cohort: HR= 1.02; 95% CI: 1.007 1.03; P=0.003; CPE: HR= 1.02; 95% CI: 0.99-1.04, P=0.05, pneumonia: HR= 1.02; 95% CI: 1-1.4, P=0.02). A PaO2 cut-off value of 13 kiloPascal (kPa) was calculated by means of Youden Index and remained true even after correction for APACHE 2 Score (HR= 1.50; 95% CI: 1.00-2.25; P=0.05) and for PaCO2 (HR= 1.63; 95% CI: 1.14-2.33; P=0.01). CONCLUSIONS: Peak PaO2 levels were associated with worse in-hopital and long-term mortality in patients treated with NIV due to ARF. These findings may indicate that application of high oxygen may be detrimental in such patients. PMID- 28884569 TI - Endogenous MicroRNA-Triggered and Real-Time Monitored Drug Release via Cascaded Energy Transfer Payloads. AB - It is a great challenge to design a drug delivery system with a controlled manner, especially one triggered by an exclusive endogenous disease marker and with an easily tracked release process. Herein, we developed a drug delivery platform of carbon dots which were connected to a stem-loop molecular beacon loaded with doxorubicin and polyethylene glycol modified folic acid. Such a platform enables one to release drugs on demand under the stimuli of endogenous microRNA-21, and turn on the fluorescence of carbon dots and doxorubicin, which allows one to monitor the drug release process. The intracellular experiment indicated that folic acid could mediate endocytosis of the nanocarrier, and the overexpressed endogenous microRNA-21 served as a unique key to unlock the drug nanocarrier by competitive hybridization with the molecular beacon, which finally resulted in fluorescence recovery and realized a chemotherapeutic effect within human breast cancer cells. The nanocarrier may have potential application in personalized treatment of different cancer subtypes in which the corresponding miRNAs are overexpressed. PMID- 28884571 TI - Clickable Multifunctional Dumbbell Particles for in Situ Multiplex Single-Cell Cytokine Detection. AB - We report a novel strategy for fabrication of multifunctional dumbbell particles (DPs) through click chemistry for monitoring single-cell cytokine releasing. Two different types of DPs were prepared on a large scale through covalent bioorthogonal reaction between methyltetrazine and trans-cyclooctene on a microchip under a magnetic field. After collection of the DPs, the two sides of each particle were further functionalized with different antibodies for cell capturing and cytokine detection, respectively. These DPs labeled with different fluorescent dyes have been used for multiplex detection and analysis of cytokines secreted by single live cells. Our results show that this new type of DPs are promising for applications in cell sorting, bioimaging, single-cell analysis, and biomedical diagnostics. PMID- 28884570 TI - Electrochromic Asymmetric Supercapacitor Windows Enable Direct Determination of Energy Status by the Naked Eye. AB - Because of the popularity of smart electronics, multifunctional energy storage devices, especially electrochromic supercapacitors (SCs), have attracted tremendous research interest. Herein, a solid-state electrochromic asymmetric SC (ASC) window is designed and fabricated by introducing WO3 and polyaniline as the negative and positive electrodes, respectively. The two complementary materials contribute to the outstanding electrochemical and electrochromic performances of the fabricated device. With an operating voltage window of 1.4 V and an areal capacitance of 28.3 mF cm-2, the electrochromic devices show a high energy density of 7.7 * 10-3 mW h cm-2. Meanwhile, they exhibit an obvious and reversible color transition between light green (uncharged state) and dark blue (charged state), with an optical transmittance change between 55 and 12% at a wavelength of 633 nm. Hence, the energy storage level of the ASC is directly related to its color and can be determined by the naked eye, which means it can be incorporated with other energy cells to visual display their energy status. Particularly, a self-powered and color-indicated system is achieved by combining the smart windows with commercial solar cell panels. We believe that the novel electrochromic ASC windows will have great potential application for both smart electronics and smart buildings. PMID- 28884572 TI - Nanobody-Based Apolipoprotein E Immunosensor for Point-of-Care Testing. AB - Alzheimer's disease (AD) biomarkers can reflect the neurochemical indicators used to estimate the risk in clinical nephrology. Apolipoprotein E (ApoE) is an early biomarker for AD in clinical diagnosis. In this research, through bactrian camel immunization, lymphocyte isolation, RNA extraction, and library construction, ApoE-specific Nbs with high affinity were successfully separated from an immune phage display nanobody library. Herein, a colorimetric immunosensor was developed for the point-of-care testing of ApoE by layer-by-layer nanoassembly techniques and novel nanobodies (Nbs). Using highly oriented Nbs as the capture and detection antibodies, an on-site immunosensor was developed by detecting the mean gray value of fade color due to the glutaraldehyde@3-aminopropyltrimethoxysilane oxidation by H2O2. The detection limit of AopE is 0.42 pg/mL, and the clinical analysis achieves a good performance. The novel easily operated immunosensor may have potential application in the clinical diagnosis and real-time monitoring for AD. PMID- 28884573 TI - Cornlike Ordered Mesoporous Silicon Particles Modified by Nitrogen-Doped Carbon Layer for the Application of Li-Ion Battery. AB - The cornlike ordered mesoporous silicon (OM-Si) particles modified by the nitrogen-doped carbon layer (OM-Si@NC) are successfully fabricated and used as the anode of lithium-ion battery (LIBs). The influences of the N-doped carbon layer on the structure and electrochemical properties of the OM-Si@NC composite are detailedly investigated by transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectrum, X-ray photoelectron spectroscopy (XPS), and charge/discharge tests. The results reveal that the amorphous N-doped carbon layer can offer the abundant conductive pathways for fast lithium ion transportation and electron transfer, which not only leads to a high specific capacity under high ampere density but also serves as a structural barrier maintaining the whole integrity and settling the mechanical breaking due to the huge volume changes of Si host. Therefore, the as-synthesized OM-Si@NC composite exhibits a high original discharge capacity of 2548 mA h g-1 under 0.2 A g-1 as well as a large reversible capacity of 1336 mA h g-1 under 1 A g-1 after 200 circles. The OM-Si@NC composite prepared by a relatively simple and feasible synthesis method shows excellent electrochemical performances and turns out to be promising for the application of high power LIBs. PMID- 28884574 TI - Polypyrrole Films with Micro/Nanosphere Shapes for Electrodes of High-Performance Supercapacitors. AB - We demonstrate a simple and efficient one-step procedure for synthesizing a solid state polypyrrole (PPy) thin film for supercapacitor applications using alternating current impedance spectroscopy. By controlling the frequency and amplitude we were able to create unique PPy nano/microstructures with a particular morphology of the loop. Our PPy micro/nanosphere shows extremely high capacitance of 568 F/g, which is close to the theoretical value of 620 F/g and 20 100% higher than that of other reported PPy electrodes. Most of all, this material presents high capacitance and significantly improved electrochemical stability without pulverization of its structure, demonstrating 77% retention of the capacitance value even after 10 000 charge/discharge cycles. These results are a consequence of the larger surface area and adequate porosity generated due to the balance between the nano/micro PPy loops. This created porous structure also allows the favored penetration of electrolyte and high ion mobility within the polymer and prevents the mechanical failure of the physical structure during volume variation associated with the insertion/deinsertion of ions upon cycling. PMID- 28884575 TI - Novel Au Catalysis Strategy for the Synthesis of Au@Pt Core-Shell Nanoelectrocatalyst with Self-Controlled Quasi-Monolayer Pt Skin. AB - Design of catalytically active Pt-based catalysts with minimizing the usage of Pt is a major issue in fuel cells. Herein, for the first time, we have developed a Au catalytic reduction strategy to synthesize a Au@Pt core-shell electrocatalyst with a quasi-monolayer Pt skin spontaneously formed from the gold surface catalysis. In the presence of presynthesized gold nanocrystals (used as the catalyst and Au seeds) and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer (used as reductant), under the Au surface catalysis, platinum ions can be reduced and deposited on the gold nanocrystals to form a Pt skin surface with a quasi-monatomic thickness. In the present strategy, Pt ions can be reduced only under the catalysis of gold surface and thus when the surface of Au NPs is covered by a monatomic Pt layer, the reduction reaction of Pt ions will be spontaneously turned off. Therefore, the significant advantage of this synthesis strategy is that the formation of quasi-monolayer Pt skin surface can be self controlled and is completely free of controlling the dosage of platinum ions and the size distribution of Au cores. The synthesized Au@Pt core@shell structure exhibited enhanced electrocatalytic activities for oxygen reduction reaction and methanol oxidation reaction, which are 6.87 and 10.17 times greater than those of Pt/C catalyst, respectively. The present study provides a new strategy for obtaining high-performance bimetallic/multimetallic electrocatalysts with high utilization of precious metals. PMID- 28884576 TI - Facile Pyrolyzed N-Doped Binder Network for Stable Si Anodes. AB - Although nanoengineering provides improved stability of Si-based nanostructures, a facile and efficacious method to directly use raw Si practices is still absent. Herein, we report a pyrolyzed N-doped binder network to improve the cycling stability of raw Si particles. Such an N-doped binder network is formed at a conformal pyrolysis condition of the electrode binder using polyacrylonitrile and provides a tight encapsulation of the Si particles with significantly improved cycling stability. In contrast to the single Si particles that pulverize and lose the total capacity at the 20th cycle, the discharge capacity could be retained ~1700 mA h g-1 at the 100th cycle for the Si particles imbedded in the pyrolyzed N-doped binder network. Our results demonstrate that such a facile remedy could significantly improve the cycling stability of raw Si particles for high-energy density lithium-ion batteries. PMID- 28884577 TI - Uranium Release from Acidic Weathered Hanford Sediments: Single-Pass Flow-Through and Column Experiments. AB - The reaction of acidic radioactive waste with sediments can induce mineral transformation reactions that, in turn, control contaminant fate. Here, sediment weathering by synthetic uranium-containing acid solutions was investigated using bench-scale experiments to simulate waste disposal conditions at Hanford's cribs (Hanford, WA). During acid weathering, the presence of phosphate exerted a strong influence over uranium mineralogy and a rapidly precipitated, crystalline uranium phosphate phase (meta-ankoleite [K(UO2)(PO4).3H2O]) was identified using spectroscopic and diffraction-based techniques. In phosphate-free system, uranium oxyhydroxide minerals such as K-compreignacite [K2(UO2)6O4(OH)6.7H2O] were formed. Single-pass flow-through (SPFT) and column leaching experiments using synthetic Hanford pore water showed that uranium precipitated as meta-ankoleite during acid weathering was strongly retained in the sediments, with an average release rate of 2.67 * 10-12 mol g-1 s-1. In the absence of phosphate, uranium release was controlled by dissolution of uranium oxyhydroxide (compreignacite type) mineral with a release rate of 1.05-2.42 * 10-10 mol g-1 s-1. The uranium mineralogy and release rates determined for both systems in this study support the development of accurate U-release models for the prediction of contaminant transport. These results suggest that phosphate minerals may be a good candidate for uranium remediation approaches at contaminated sites. PMID- 28884578 TI - Enhanced Anti-Infective Efficacy of ZnO Nanoreservoirs through a Combination of Intrinsic Anti-Biofilm Activity and Reinforced Innate Defense. AB - The increasing prevalence of implant-associated infections (IAIs) imposes a heavy burden on patients and medical providers. Bacterial biofilms are recalcitrant to antiseptic drugs and local immune defense and can attenuate host proinflammatory response to interfere with bacterial clearance. Zinc oxide nanoparticles (ZnO NPs) play a dual role in antibacterial and immunomodulatory activities but compromise the cytocompatibility because of their intracellular uptake. Here, ZnO NPs were immobilized on titanium to form homogeneous nanofilms (from discontinuous to continuous) through magnetron sputtering, and the possible antimicrobial activity and immunomodulatory effect of nano-ZnO films were investigated. Nano-ZnO films were found to prohibit sessile bacteria more than planktonic bacteria in vitro, and the antibacterial effect occurred in a dose dependent manner. Using a novel mouse soft tissue IAI model, the in vivo results revealed that nano-ZnO films possessed outstanding antimicrobial efficacy, which could not be ascribed solely to the intrinsic anti-infective activity of nano-ZnO films observed in vitro. Macrophages and polymorphonuclear leukocytes (PMNs), two important factors in innate immune response, were cocultured with nano-ZnO and bacteria/lipopolysaccharide in vitro, and the nano-ZnO films could enhance the antimicrobial efficacy of macrophages and PMNs through promoting phagocytosis and secretion of inflammatory cytokines. This study provides insights into the anti infective activity and mechanism of ZnO and consolidates the theoretical basis for future clinical applications of ZnO. PMID- 28884579 TI - Facile Processing of Free-Standing Polyaniline/SWCNT Film as an Integrated Electrode for Flexible Supercapacitor Application. AB - Flexible supercapacitors (SCs) with compact configuration are ideal energy storage devices for portable electronics, owing to their original advantages (e.g., fast charging/discharging). To effectively reduce the volume of SCs, an integrated electrode of free-standing polyaniline (PANI)/single-wall carbon nanotube (SWCNT) film with high performance has been developed via a facile solution deposition method, which can be employed as current collector and active material in the meantime. Thanks to the strong pi-pi interactions between PANI and CNTs, an efficient conductive network with ordered PANI molecular chains is formed in this hybrid film electrode, which is beneficial for the ion diffusion process and fast redox reaction resulting in a high capacitance of 446 F g-1 and outstanding cycling stability, achieving 98% retention over 13 000 cycles. Predictably, solid-state SCs constructed by this free-standing PANI/SWCNT film electrode exhibited remarkable mechanical stability and flexibility in a compact configuration, let alone its excellent capacitive performance (218 F g-1). Moreover, the highest energy density of flexible solid-state SC reached 19.45 Wh kg-1 at a power density of 320.5 W kg-1, further indicating a good potential as an energy storage device. This work would inspire other simple process techniques for high-performance flexible SCs, catering to the demand of portable electronic devices. PMID- 28884580 TI - Enhancing Performance and Uniformity of Perovskite Solar Cells via a Solution Processed C70 Interlayer for Interface Engineering. AB - Although some kinds of semiconductor metal oxides (SMOs) have been applied as electron selective layers (ESLs) for planar perovskite solar cells (PSCs), electron transfer is still limited by low electron mobility and defect film formation of SMO ESLs fabricated via low-temperature solution process. Herein, the C70 interlayer between TiO2 and (HC(NH2)2PbI3)x(CH3NH3PbCl3)1-x is prepared by spin-coating and low-temperature annealing for planar n-i-p PSCs. The resultant TiO2/C70 ESL shows good surface morphology, efficient electron extraction, and facilitation of high-quality perovskite film formation, which can be attributed to the suitable nanosize and the superior electronic property of C70 molecules. In comparison with pristine TiO2-based PSCs, the efficiency and hysteresis index are, respectively, enhanced 28% and reduced 76% by adding the C70 interlayer between TiO2 and perovskite on the basis of statistical data of more than 50 cells. With the main advantages of low-temperature process and optimized interface, the champion efficiency of PSCs on flexible substrates could exceed 12% in contrast with the above 18% on rigid substrate. PMID- 28884581 TI - Rationalization of Anomalous Pseudocontact Shifts and Their Solvent Dependence in a Series of C3-Symmetric Lanthanide Complexes. AB - Bleaney's long-standing theory of magnetic anisotropy has been employed with some success for many decades to explain paramagnetic NMR pseudocontact shifts, and has been the subject of many subsequent approximations. Here, we present a detailed experimental and theoretical investigation accounting for the anomalous solvent dependence of NMR shifts for a series of lanthanide(III) complexes, namely [LnL1] (Ln = Eu, Tb, Dy, Ho, Er, Tm, and Yb; L1: 1,4,7-tris[(6 carboxypyridin-2-yl)methyl]-1,4,7-triazacyclononane), taking into account the effect of subtle ligand flexibility on the electronic structure. We show that the anisotropy of the room temperature magnetic susceptibility tensor, which in turn affects the sign and magnitude of the pseudocontact chemical shift, is extremely sensitive to minimal structural changes in the first coordination sphere of L1. We show that DFT structural optimizations do not give accurate structural models, as assessed by the experimental chemical shifts, and thus we determine a magnetostructural correlation and employ this to evaluate the accurate solution structure for each [LnL1]. This approach allows us to explain the counterintuitive pseudocontact shift behavior, as well as a striking solvent dependence. These results have important consequences for the analysis and design of novel magnetic resonance shift and optical emission probes that are sensitive to the local solution environment and polarity. PMID- 28884582 TI - Complex Dynamical Networks Constructed with Fully Controllable Nonlinear Nanomechanical Oscillators. AB - Control of the global parameters of complex networks has been explored experimentally in a variety of contexts. Yet, the more difficult prospect of realizing arbitrary network architectures, especially analog physical networks that provide dynamical control of individual nodes and edges, has remained elusive. Given the vast hierarchy of time scales involved, it also proves challenging to measure a complex network's full internal dynamics. These span from the fastest nodal dynamics to very slow epochs over which emergent global phenomena, including network synchronization and the manifestation of exotic steady states, eventually emerge. Here, we demonstrate an experimental system that satisfies these requirements. It is based upon modular, fully controllable, nonlinear radio frequency nanomechanical oscillators, designed to form the nodes of complex dynamical networks with edges of arbitrary topology. The dynamics of these oscillators and their surrounding network are analog and continuous-valued and can be fully interrogated in real time. They comprise a piezoelectric nanomechanical membrane resonator, which serves as the frequency-determining element within an electrical feedback circuit. This embodiment permits network interconnections entirely within the electrical domain and provides unprecedented node and edge control over a vast region of parameter space. Continuous measurement of the instantaneous amplitudes and phases of every constituent oscillator node are enabled, yielding full and detailed network data without reliance upon statistical quantities. We demonstrate the operation of this platform through the real-time capture of the dynamics of a three-node ring network as it evolves from the uncoupled state to full synchronization. PMID- 28884583 TI - Herpes Esophagitis With Concomitant Eosinophilic Esophagitis in a Child: A Case Report. PMID- 28884585 TI - Analysis of the cost-effectiveness of carbetocin for the prevention of hemorrhage following cesarean delivery in Ecuador. AB - AIM: To compare the cost of carbetocin with that of oxytocin for the prevention and management of hemorrhage following cesarean delivery in Ecuador. MATERIALS & METHODS: We developed a decision tree based cost-effectiveness model to compare carbetocin with oxytocin in the prevention of hemorrhage following cesarean delivery in Ecuador. Our model was run from a third party payer perspective and was validated by local experts in the field. The efficacy of the interventions was determined based on a systematic review of the literature. Direct costs were calculated based on current National Health Service price lists and retail price. Since the period covered by the analysis was 1 year, costs and health effects were not discounted. RESULTS: The difference in costs between the interventions was US$16.26, with a difference in effectiveness of 0.0067 disability adjusted life years averted. The incremental cost-effectiveness ratio for carbetocin compared with oxytocin for prevention of hemorrhage following cesarean delivery was US$2432.89 per disability adjusted life year averted. CONCLUSION: Carbetocin is as efficacious and safe as oxytocin for primary prevention of hemorrhage in cesarean delivery in Ecuador. It is highly cost effective for reducing the need for additional uterotonic drugs in both emergency and elective cesarean delivery. PMID- 28884584 TI - A fruitful decade for fungal polyketides from 2007 to 2016: antimicrobial activity, chemotaxonomy and chemodiversity. AB - The last three decades have shown that the fungi can be 'biofactories' of novel, bioactive secondary metabolites that produce numerous natural products with novel skeletons and biological activities. Particularly in the last 10 years, large numbers of antimicrobial fungal secondary metabolites have been discovered. This review provides an overview of key, defining developments of the last 10 years regarding the discovery of antimicrobial activity, chemotaxonomy and chemodiversity of fungal polyketides. PMID- 28884586 TI - Worsening Necrotic Skin Infection: What Lurks Below. PMID- 28884588 TI - Nutritional Assessment of Snacks and Beverages in Southeastern Virginia Daycare Centers. AB - This study sought to determine the nutritional quality of snacks and beverages provided at licensed daycare centers of variable sizes in Southeastern Virginia. This cross-sectional study employed self-report surveys about snack offerings administered at each daycare site that agreed to participate. In addition, researchers completed an observation survey on the day of visit to observe and document the food and beverages actually served at snack time. Although many daycare directors reported serving fresh fruit and vegetables for snacks, there was a poor correlation on the offering of these healthy snacks between researchers and directors ( P < .05). Researchers observed salty, caloric dense foods for snack time more frequently than fresh fruits and vegetables. These findings demonstrate the importance of improving and perhaps regulating the quality and diversity of snacks and beverages offered in childcare, as dietary amendments may prevent the development of childhood obesity. PMID- 28884587 TI - Anticancer activity of metal nanoparticles and their peptide conjugates against human colon adenorectal carcinoma cells. AB - In the present study, nanoparticles of gold, iron oxide and zinc oxide (ZnO) were studied for cytotoxicity in the colorectal cancer cell HT 29. The metallic nanoparticles in the range of <50 and <100 nm were screened for anticancer activity by MTT assay. The nanoparticles were tested at concentrations ranging from 0.5 to 50 ug/ml. Zinc oxide exhibited significant anti-cancer activity in comparison to other nanoparticles. It had an IC50 value of 17.12 ug/ml. The mechanism of action was studied by fluorescence microscopy with acridine orange, propidium iodide and DAPI staining techniques. The ROS production of ZnO nanoparticles was determined by DCFH-DA. The ZnO nanoparticles were conjugated with novel hydrophobic peptides and evaluated for anticancer activity. It was observed that the nanoparticles peptide complex showed better cytotoxicity than either peptide or nanoparticle alone. Thus, the ZnO nanoparticles tested in our study has anticancer activity against colon cancer cells. It can also be conjugated with peptides and used for targeting cancer cells with higher efficacy. PMID- 28884589 TI - Is there a role for modified probiotics as beneficial microbes: a systematic review of the literature. AB - Our objective was to conduct a systematic review and meta-analysis for the use of modified (heat-killed or sonicated) probiotics for the efficacy and safety to prevent and treat various diseases. Recent clinical research has focused on living strains of probiotics, but use in high-risk patients and potential adverse reactions including bacteremia has focused interest on alternatives to the use of live probiotics. We searched MEDLINE/PubMed, Embase, Cochrane Central Register of Controlled Trials, CINAHL, Alt Health Watch, Web of Science, Scopus, PubMed, from inception to February 14, 2017 for randomised controlled trials involving modified probiotic strains. The primary outcome was efficacy to prevent or treat disease and the secondary outcome was incidence of adverse events. A total of 40 trials were included (n=3,913): 14 trials (15 arms with modified probiotics and 20 control arms) for the prevention of diseases and 26 trials (29 arms with modified probiotics and 32 control arms) for treatment of various diseases. Modified microbes were compared to either placebo (44%), or the same living probiotic strain (39%) or to only standard therapies (17%). Modified microbes were not significantly more or less effective than the living probiotic in 86% of the preventive trials and 69% of the treatment trials. Modified probiotic strains were significantly more effective in 15% of the treatment trials. Incidence rates of adverse events were similar for modified and living probiotics and other control groups, but many trials did not collect adequate safety data. Although several types of modified probiotics showed significant efficacy over living strains of probiotics, firm conclusions could not be reached due to the limited number of trials using the same type of modified microbe (strain, daily dose and duration) for a specific disease indication. Further research may illuminate other strains of modified probiotics that may have potential as clinical biotherapeutics. PMID- 28884590 TI - Galacto-oligosaccharides ameliorate dysbiotic Bifidobacteriaceae decline in Japanese patients with type 2 diabetes. AB - Gut microbiota affects the host's metabolism, and it is suggested that there are differences in gut microbiota composition between patients with type 2 diabetes and healthy individuals. Additionally, dysbiosis may increase the concentration of lipopolysaccharides (LPS), causing metabolic endotoxemia, which induces impaired glucose tolerance. Several studies have reported relationships between metabolic diseases and the gut microbiota; and prebiotics, such as oligosaccharides, are commonly consumed to regulate gut microbiotas in healthy individuals. Galacto-oligosaccharides (GOS) are a major prebiotic, which specifically increase Bifidobacteriaceae abundance. Recent studies have reported that Bifidobacteriaceae improved metabolic endotoxemia or impaired glucose tolerance. However, there are few studies reporting the effects of GOS on patients with type 2 diabetes. In the current study, we compared clinical parameters, faecal gut microbiota, their associated metabolic products and their components such as LPS, and LPS-binding protein (LBP) produced by the host, between patients with diabetes and healthy controls. We then assessed the effects of GOS on glycaemic control, and gut microbiotas and metabolites in patients with type 2 diabetes in a double-blind controlled manner. LBP levels were significantly higher in patients with diabetes than those of healthy subjects, which was consistent with previous reports. The abundance of Bifidobacteriaceae and the diversity of intestinal microbiota were significantly lower in patients with diabetes than in healthy subjects. Interestingly, Bifidobacteriaceae was markedly restored in patients with diabetes after consumption of GOS, whereas LBP and glucose tolerance did not improve during this short-term trial period. In the present study, we demonstrated that GOS can ameliorate dysbiosis in patients with diabetes, and continuous intake of GOS may be a promising method for managing type 2 diabetes. PMID- 28884591 TI - Monitoring of Recommended Metabolic Laboratory Parameters Among Medicaid Recipients on Second-Generation Antipsychotics in Federally Qualified Health Centers. AB - BACKGROUND: In 2004, a consensus statement outlining recommended metabolic monitoring for patients prescribed second-generation antipsychotics (SGAs) was published. More than a decade later, suboptimal adherence rates to these recommendations continue to be reported, which could lead to long-term and costly complications. OBJECTIVES: To define the prevalence of appropriately monitored Medicaid patients receiving care at federally qualified health centers (FQHCs) prescribed SGAs. METHODS: This was a retrospective study examining electronic health record and Medicaid claims data to assess the rates of glucose and lipid monitoring for patients prescribed SGAs from January 2014 to August 2016 in a FQHC. Prescription and laboratory claims for patients receiving care at 4 FQHCs were reviewed. Descriptive statistics were used to evaluate the primary outcome. RESULTS: A total of 235 patients were included in the analysis. Patients initiated on SGA therapy (n = 92) had baseline glucose and lipid monitoring rates of 50% and 23%, respectively. The 3-month monitoring rates were 37% for glucose and 26% for lipids, whereas annual rates were 71% and 40%, respectively. Patients continuing SGA therapy (n = 143) had annual glucose and lipid monitoring rates of 67% and 44%. CONCLUSIONS: Medicaid patients at FQHCs initially prescribed SGAs have low baseline and 3-month metabolic monitoring, whereas annual monitoring was comparable to previously published studies. Adults receiving chronic care at a FQHC were more likely to receive glucose monitoring. Those with type 2 diabetes mellitus and/or hyperlipidemia were more likely to receive glucose and lipid monitoring. PMID- 28884592 TI - Peripheral nerve intersectional repair by bi-directional induction and systematic remodelling: biodegradable conduit tubulization from basic research to clinical application. AB - In terms of the clinical effect of peripheral nerve injury repair, the biological degradable conduit 2 mm small gap tubulization is far better than the traditional epineurial or perineurium neurorrhaphy. The assumption of the bi-directional induction between the central system and the terminal effector during peripheral nerve regeneration is purposed and proved in clinical by our group. The surgical approach of transferring a portion of or the whole contralateral C7 nerve to repair a part of or the whole ipsilateral brachial plexus injury is clinically promoted, in which the most important idea and practice is to use the cone conduit designed by the group to repair thick nerves with fine nerves. Some of the patients suffering from cerebral palsy or cerebral haemorrhage and those who got cerebral infarction yet have not reached recovery after 3-6 months could regain some functions of the ipsilateral upper limb and improve the life quality by transfer of a portion of or the whole contralateral C7 nerve and connection by cone conduit. PMID- 28884593 TI - Effect of Sequential Sectioning of Ligaments on Syndesmotic Instability in the Coronal Plane Evaluated Arthroscopically. AB - BACKGROUND: Arthroscopic evaluation of the syndesmosis allows direct visualization of syndesmotic instability. The purpose of this study was to determine the minimum degree of ligamentous injury necessary to destabilize the syndesmosis in the coronal plane when assessed arthroscopically and pinpoint where such instability should be measured within the incisura. METHODS: Fourteen cadaveric specimens were divided into 2 groups and arthroscopically assessed first with the syndesmosis intact and then following serial differential ligamentous transection. Group 1 (n = 7): anterior-inferior tibiofibular (AITFL), interosseous (IOL), posterior-inferior tibiofibular (PITFL), and deltoid (DL) ligament. Group 2 (n = 7): PITFL-IOL-AITFL-DL. At each step, a standard 100-N lateral hook test was applied and tibiofibular coronal plane diastasis measured arthroscopically at both the anterior and posterior third of the incisura. These measurements were in turn compared with those of the stressed intact ligamentous state. RESULTS: There was no significant syndesmotic instability measured at either the anterior or posterior margin of the incisura after transection of a singular ligament (AITFL or PITFL) or after the IOL was additionally transected. Diastasis at the posterior margin was significantly increased when all syndesmotic ligaments were sectioned (group 1: P = .018; group 2: P = .008), but this was not noted along the anterior margin. Diastasis at the anterior margin reached significance only with complete transection of syndesmosis and DL (group 1: P < .001; group 2: P = .044). CONCLUSION: Under arthroscopic evaluation, the syndesmosis becomes unstable in the coronal plane only when all syndesmotic ligaments are transected, which should preferentially be measured at the posterior margin of the incisura. Anteriorly, diastasis becomes apparent only with addition of DL disruption, although this added finding may aid in diagnosis of occult deltoid injury. CLINICAL RELEVANCE: AITFL, IOL, and PITFL need to be injured to produce coronal plane syndesmotic instability. Arthroscopic assessment of such instability should occur along the posterior margin of the incisura. When they exist, similar findings anteriorly suggest concomitant deltoid injury. PMID- 28884594 TI - Predicting Failure of Nonoperative Treatment for Insertional Achilles Tendinosis. AB - : Nonoperative treatment for midportion Achilles tendinosis is well defined by the literature. Multiple modalities are described for the management of insertional Achilles pathology, but no consensus exists regarding efficacy. Surgical intervention for insertional Achilles tendinosis (IAT) is successful greater than 80% of the time. Our objective was to risk stratify patients who would fail nonsurgical management of IAT and thus benefit progressing to surgery. We reviewed the records of 664 patients with IAT. The cohort was 53% male and 80% obese. Mean age was 53.7 years (standard deviation 14.7 years). Average duration of symptoms was 10.4 months (standard deviation 28 months). Of the parameters collected, 4 were found to correlate with failing nonoperative treatment: visual analog scale, limited ankle range of motion, previous corticosteroid injection, and presence of Achilles tendon enthesophyte. We found that as the number of risk factors increased so did the chance of failing nonoperative treatment. With all 4 parameters, chance of failing conservative treatment was only 55%. Thus, nonoperative management should be exhausted until surgery is the only remaining option. However, the presence of one of the aforementioned risk factors can aid a surgeon in the decision to pursue surgery in the appropriate clinical scenario. LEVELS OF EVIDENCE: Level IV: Retrospective Case series. PMID- 28884595 TI - Risk of osteoporosis in thyroid cancer patients using levothyroxine: a population based study. AB - BACKGROUND: The outcomes of thyroid cancer patients using levothyroxine are largely undetermined. METHODS: The study population consisted of 9398 patients newly diagnosed with thyroid cancer; their data was retrieved from a subset of the National Health Insurance Research Database of Taiwan during the period of 1999-2011. In this nationwide retrospective cohort study, we compared the risk of osteoporosis among thyroid cancer patients with levothyroxine use, those without levothyroxine use, and propensity-score-matched non-thyroid controls. We also investigated the duration-response and dose-response relationships between levothyroxine use and the risk of osteoporosis. The competing risk was also analyzed. RESULTS: The mean duration of follow-up was 6.63 years for patients without thyroid cancer, 5.45 years for thyroid cancer patients without levothyroxine use, and 6.46 years for thyroid cancer patients with levothyroxine use. The incidence of osteoporosis was higher in the thyroid cancer cohort than in the non-thyroid-cancer cohort (8.69 vs. 6.60 per 1000 person-years, respectively), with an adjusted hazard ratio of 1.39 (95% confidence interval [CI] = 1.22-1.58). Thyroid cancer patients with levothyroxine use exhibited a significantly higher risk of osteoporosis than non-thyroid-cancer patients, while thyroid cancer patients not using levothyroxine did not have significant higher risks than non-thyroid-cancer patients. Compared with patients without thyroid cancer, the risk of osteoporosis increased from 1.53 (95% CI = 0.91-2.57) in patients receiving a cumulative dose of <=265 mg levothyroxine, to 3.62 in those receiving a cumulative dose of >395 mg levothyroxine (95% CI = 2.16-6.06). CONCLUSION: Our population-based cohort study showed that thyroid cancer patients receiving levothyroxine have a higher risk of osteoporosis. PMID- 28884596 TI - 3D-map modelling for the melting points prediction of intumescent flame-retardant coatings. AB - The applicability of 3D map modelling for melting point prediction was studied. The melting points in the ammonium polyphosphate-pentaerythritol-melamine chemical system of intumescent flame-retardant coatings over a wide range of concentrations were collected. The ternary diagram (triangle) of the melting points was plotted and an approximated 3D map was built for the range 205-345 degrees C. The present work contains the thermal data for the observed ternary system and provides a new graphic system for making predictions for intumescent flame-retardant coatings. The applicability of the calculated 3D map for obtaining experimental samples of fire-retardant paints with a low melting point for thin steel constructions was shown. PMID- 28884597 TI - A Piecewise Local Partial Least Squares (PLS) Method for the Quantitative Analysis of Plutonium Nitrate Solutions. AB - We have developed a piecewise local (PL) partial least squares (PLS) analysis method for total plutonium measurements by absorption spectroscopy in nitric acid based nuclear material processing streams. Instead of using a single PLS model that covers all expected solution conditions, the method selects one of several local models based on an assessment of solution absorbance, acidity, and Pu oxidation state distribution. The local models match the global model for accuracy against the calibration set, but were observed in several instances to be more robust to variations associated with measurements in the process. The improvements are attributed to the relative parsimony of the local models. Not all of the sources of spectral variation are uniformly present at each part of the calibration range. Thus, the global model is locally overfitting and susceptible to increased variance when presented with new samples. A second set of models quantifies the relative concentrations of Pu(III), (IV), and (VI). Standards containing a mixture of these species were not at equilibrium due to a disproportionation reaction. Therefore, a separate principal component analysis is used to estimate of the concentrations of the individual oxidation states in these standards in the absence of independent confirmatory analysis. The PL analysis approach is generalizable to other systems where the analysis of chemically complicated systems can be aided by rational division of the overall range of solution conditions into simpler sub-regions. PMID- 28884598 TI - Skin targeting of curcumin solid lipid nanoparticles-engrossed topical gel for the treatment of pigmentation and irritant contact dermatitis. AB - Irritant contact dermatitis (ICD) and hyperpigmentation are the problems associated with skin. Topical curcumin (CUR) although effective in hyperpigmentation and ICD, is a challenging molecule due to low-solubility. Encapsulation of CUR into solid lipid nanoparticles (SLNs) makes it amenable to topical dosing as their small size promotes its penetration into the skin. CUR SLNs were prepared using Precirol ATO5 and Tween-80 by probe ultrasonication method. Further, CUR-SLNs were incorporated into Carbopol gel and investigated for ex-vivo skin permeation, skin deposition and skin irritation studies. The potential of CUR-SLN gel was checked against hyperpigmentation through the inhibition of tyrosinase enzyme. It was further evaluated for possible effects on ICD using BALB/c mice. The optimized CUR-SLN showed the particle size of 51 nm and 93% EE. Ex vivo permeation of CUR-SLN gel exhibited controlled drug release up to 24 h, similarly in vitro drug deposition studies showed potential for skin targeting. In vitro tyrosinase inhibition assay indicates that the formulated gel has potential in skin depigmentation. The gel also confirmed proficient suppression of ear swelling and reduction in skin water content in the BALB/c mouse. Thus, the CUR-SLN gel would be a safe and effective alternative to conventional vehicles for treatment of ICD and pigmentation. PMID- 28884599 TI - A Simplified Approach Using Rate of Change Arrows to Adjust Insulin With Real Time Continuous Glucose Monitoring. PMID- 28884600 TI - Dapagliflozin/Saxagliptin Fixed-Dose Tablets: A New Sodium-Glucose Cotransporter 2 and Dipeptidyl Peptidase 4 Combination for the Treatment of Type 2 Diabetes. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of the fixed-dose combination (FDC) product, QTERN (dapagliflozin/saxagliptin) tablets. DATA SOURCES: Searches of MEDLINE (1946 to July 1, 2017) were conducted using the keywords QTERN, saxagliptin, and dapagliflozin. Additional data were obtained from the prescribing information, the product dossier, and Clinicaltrials.gov . STUDY SELECTION AND DATA EXTRACTION: All English language articles related to pharmacology, pharmacokinetics, efficacy, or safety of the combination therapy in human subjects were reviewed. DATA SYNTHESIS: The pharmacokinetics of saxagliptin and dapagliflozin were not affected significantly when administered as an FDC product. Saxagliptin may suppress the increased secretion of glucagon associated with dapagliflozin. The combination dapagliflozin/saxagliptin has been studied as add-on therapy to metformin in patients with uncontrolled type 2 diabetes mellitus (T2DM). The difference in hemoglobin A1C (A1C) between saxagliptin + dapagliflozin + metformin (triple therapy) and saxagliptin + metformin was -0.59 (95% CI = -0.81 to -0.37, P < 0.0001), and the difference between triple therapy and dapagliflozin + metformin was -0.27 (95% CI = -0.48 to -0.05, P = 0.0166). The combination was well tolerated when added to metformin. CONCLUSION: QTERN (dapagliflozin/saxagliptin) tablets are a reasonable option for patients with T2DM not controlled on metformin, but cost, insurance coverage, and a lackluster reduction in A1C will likely limit its use until more data regarding its effects on complications of diabetes and cardiovascular outcomes become available. PMID- 28884601 TI - Systematic review of AAC intervention research for adolescents and adults with autism spectrum disorder. AB - Much of augmentative and alternative communication (AAC) research for individuals with autism spectrum disorder has focused on young children. Given that the lives, communication, strengths, and needs of adolescents and adults with autism spectrum disorder are quite different from those of young children, the purpose of the current study was to consolidate current AAC intervention research findings specific to these individuals. A systematic review was conducted to identify and evaluate relevant research. Results indicate that AAC intervention benefits adolescents and adults with autism spectrum disorder. However, more research is urgently needed. Future research focused on supporting communicative functions other than requesting (e.g., social closeness, information transfer) while participating in contexts important to the lives of adolescents and adults may be particularly valuable. PMID- 28884602 TI - Enhancement of anticancer activity by silibinin and paclitaxel combination on the ovarian cancer. AB - BACKGROUND: Ovarian carcinoma is the most lethal cancer among all gynaecological malignancies. One of the most chemotherapy drugs used for ovarian cancer is paclitaxel which induces apoptosis. Paclitaxel has been used for many years. Similar to the most cancers this responds to chemotherapy initially but in a long run, drug resistance happens which fails the treatment procedure. Combination of chemotherapy drugs has been suggested to deal with this issue. Silibinin, a plant extraction, has been used from ancient time in traditional medicine and identified to have powerful antioxidant activity. AIM: The aim of this study was to examine the effect of paclitaxel and silibinin combination on SKOV-3 cancer cell line. MATERIALS AND METHODS: The human epithelial ovarian cancer cell line, SKOV-3, was cultured and treated with paclitaxel, silibinin and paclitaxel plus silibinin for 48 hours. MTT assay was carried out to determine cell viability. For apoptotic process, we used real-time PCR to study P53 and P21 genes expression after drug treatment and network analysis was performed using Pathway Studio web tool (Elsevier). RESULTS: Cell growth was inhibited considerably (p < .05) by combination of paclitaxel and silibinin after 48 hours of treatment. Also silibinin and paclitaxel combination induced apoptosis in SKOV-3 cells. Expression analysis by real-time PCR showed the significant up-regulation of two tumour suppressor genes, P53 and P21 in response to combination of silibinin and paclitaxel. In addition, computational network analysis demonstrated the crosstalk between paclitaxel, silibinin and ovarian cancer. CONCLUSIONS: Our results showed that combination of chemotherapy drugs of silibinin and paclitaxel can be more efficient in treatment of ovarian cancer cells. PMID- 28884604 TI - Novel treatment options for the management of heterozygous familial hypercholesterolemia. AB - INTRODUCTION: Even though statins represent the mainstay of treatment of heterozygous familial hypercholesterolemia (FH), their low-density lipoprotein cholesterol (LDL-C) lowering efficacy is finite and most patients with FH will not achieve LDL-C targets with statin monotherapy. Addition of ezetimibe with or without bile acid sequestrants will also not lead to treatment goals in many of these patients, particularly in those with established cardiovascular disease. In this selected subgroup of the FH population, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors provide substantial reductions in LDL-C levels, reduce cardiovascular morbidity and appear to be safe. Mipomersen, an antisense single-strand oligonucleotide that inhibits the production of apoB by binding to the mRNA that encodes the synthesis of apoB, and lomitapide, an inhibitor of microsomal triglyceride transfer protein, also reduce LDL-C levels but are currently indicated only for the management of homozygous FH. Areas covered: In the present review, the role of PCSK9 inhibitors, mipomersen and lomitapide in the management of FH is briefly discussed. Other LDL-C-lowering agents under evaluation include inclisiran, a small interference RNA molecule that induces long-term inhibition of PSCK9 synthesis, anacetrapib, a cholesterol ester transfer protein inhibitor, ETC-1002 (bempedoic acid), an inhibitor of adenosine triphosphate citrate lyase, and gemcabene, which reduces hepatic apolipoprotein C III mRNA. The safety and efficacy of these agents are also reviewed. Expert Commentary: Even though several novel treatment options for heterozygous FH are under development, it remains to be shown whether these treatments will also reduce cardiovascular morbidity in these high-risk patients. PMID- 28884603 TI - Folic Acid in Pregnancy and Childhood Asthma: A US Cohort. AB - Prenatal folic acid exposure has been linked to higher risk of childhood asthma in countries that do not fortify the food supply with folic acid. This study seeks to examine this association in the United States, where the food supply is generally fortified with folic acid. Participants were 1279 mother-child pairs from Project Viva, an ongoing prospective birth cohort, with folic acid intake in pregnancy assessed through validated food frequency questionnaires. The primary outcome was physician-diagnosed asthma at mid-childhood. In an unadjusted logistic regression model, higher folic acid intake was associated with lower odds of asthma in mid-childhood (odds ratio [OR] 0.48; 95% CI 0.31-0.76). However, in the adjusted analysis this association was attenuated (adjusted OR [aOR] 0.80; 95% CI 0.49-1.33). Our results suggest that in the United States, where there is generalized folic acid fortification of food, maternal folic acid intake during pregnancy is not associated with asthma development in offspring. PMID- 28884605 TI - Nanomedicines: a theranostic approach for hepatocellular carcinoma. AB - The liver is an imperative organ of tremendous importance concerned with maintenance of metabolic functions and detoxification of exogenous and endogenous challenges like xenobiotics, viral infections and chronic alcoholism. Liver diseases particularly hepatitis B virus infections, liver cirrhosis and hepatocellular carcinoma continue to pose a significant health challenge worldwide due to the lack of therapeutic management options besides liver resection and transplantation. Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer mortality worldwide. HCC has a high mortality rate because of poor diagnosis. The majority of patients with liver cancer die within one year as a result of poor patient compliance. HCC is clinically treated by chemotherapy besides surgery. However, most anticancer drugs have high toxicity and low specificity, leading to systemic toxicity and severe side effects. To limit the severe side effects of cancer chemotherapy on normal tissues, tumor targeting drug delivery systems need to be explored, which provides the impetus to develop targeted therapies for achieving higher efficacy with minimal side effects. The nanostructures used as good drug carriers, possess advantages of good solubility including high drug encapsulation efficiency, high cellular uptake, further desirable pharmacokinetics and can preferentially accumulate at the tumor site through the enhanced permeability and retention (EPR) effect with the goal of minimizing toxic effects on healthy tissues while maintaining antitumor efficacy. PMID- 28884606 TI - Stigma Resistance in Stable Schizophrenia: The Relative Contributions of Stereotype Endorsement, Self-Reflection, Self-Esteem, and Coping Styles. AB - OBJECTIVE: Stigma resistance (SR) has recently emerged as a prominent aspect of research on recovery from schizophrenia, partly because studies have suggested that the development of stigma-resisting beliefs may help individuals lead a fulfilling life and recover from their mental illness. The present study assessed the relationship between personal SR ability and prediction variables such as self-stigma, self-esteem, self-reflection, coping styles, and psychotic symptomatology. METHOD: We performed an exploratory cross-sectional study of 170 community-dwelling patients with schizophrenia. Self-stigma, self-esteem, self reflection, coping skills, and SR were assessed through self-report. Psychotic symptom severity was rated by the interviewers. Factors showing significant association in univariate analyses were included in a stepwise backward regression model. RESULTS: Stepwise regressions revealed that acceptance of stereotypes of mental illness, self-esteem, self-reflection, and only 2 adaptive coping strategies (positive reinterpretation and religious coping) were significant predictors of SR. The prediction model accounted for 27.1% of the variance in the SR subscale score in our sample. CONCLUSIONS: Greater reflective capacity, greater self-esteem, greater preferences for positive reinterpretation and religious coping, and fewer endorsements of the stereotypes of mental illness may be key factors that relate to higher levels of SR. These factors are potentially modifiable in tailored interventions, and such modification may produce considerable improvements in the SR of the investigated population. This study has implications for psychosocial rehabilitation and emerging views of recovery from mental illness. PMID- 28884607 TI - Assessing the Relationship between Disordered Gamblers with Psychosis and Increased Gambling Severity: The Mediating Role of Impulsivity. AB - OBJECTIVE: Recent research suggests that disordered gambling and psychosis co occur at higher rates than expected in the general population. Gamblers with psychosis also report greater psychological distress and increased gambling severity. However, the mechanism by which psychosis leads to greater gambling symptomology remains unknown. The objective of the present research was to test whether impulsivity mediated the relationship between comorbid psychosis and gambling severity. METHOD: The sample consisted of 394 disordered gamblers voluntarily seeking treatment at a large university hospital in Sao Paulo, Brazil. A semistructured clinical interview (Mini-International Neuropsychiatric Interview) was used to diagnosis the presence of psychosis by registered psychiatrists. Severity of gambling symptoms was assessed using the Gambling Symptom Assessment Scale, and the Barratt Impulsiveness Scale-11 provided a measure of impulsivity. RESULTS: Of the sample, 7.2% met diagnostic criteria for psychosis. Individuals with a dual diagnosis of psychosis did not report greater gambling severity. Conversely, dual diagnoses of psychosis were associated with greater levels of impulsivity. Higher levels of impulsivity were also associated with greater gambling severity. Importantly, support for our hypothesised mediation model was found such that impulsivity mediated the association between disordered gambling and psychosis and gambling severity. CONCLUSION: Impulsivity appears to be a transdiagnostic process that may be targeted in treatment among disordered gamblers with a dual diagnosis of psychosis to reduce problematic gambling behaviours. PMID- 28884608 TI - Analysis of Risk Factors of Stroke and Venous Thromboembolism in Females With Oral Contraceptives Use. AB - Thrombotic diathesis has been a well-known complication of oral contraceptive use for more than 50 years. This is true not only for venous thrombosis but also for an arterial one. The etiology is usually multifactorial and depends on several additional risk factors. We analyzed the prevalence of inherited and acquired thrombophilia in a cohort of 770 females who had a thrombotic event in association with oral contraceptive use (700 women with venous thromboembolism [VTE], 70 with stroke). Moreover, we tried to identify additional risk factors. Inherited thrombophilia was found in 44.5% with higher frequency in the cohort with VTE (42%) than in females with stroke (24%). The most frequent finding was factor V Leiden. Cigarette smoking was significantly more frequent in the group with stroke (50% vs 25%). The prevalence of cigarette smoking in the group with VTE did not exceed the frequency in general population. Women on oral contraceptive pills have higher risk of venous as well as arterial thrombosis. The risk of venous thrombosis is increased in females with inherited thrombophilia, whereas those with some additional acquired risk factors (especially smoking) may be predisposed to arterial thrombosis. However, the absolute risk of thrombosis in healthy women is low, far less than the risk of unintended pregnancy. Moreover, the risk may be reduced by keeping some rules before the prescription of the pills, healthy life style, and a proper choice of contraception. PMID- 28884609 TI - Impact of Classical Risk Factors for Arterial or Venous Thrombosis in Patients With Antiphospholipid Syndrome. AB - There are classical risk factors associated with arterial thrombosis (AT) or venous thromboembolic disease (VTD). However, less is known about these risk factors and AT or VTD episodes in patients with antiphospholipid syndrome (APS). Our aim was to elucidate whether APS-related thrombotic episodes are associated with the same risk factors as the non-APS population. We gathered demographics, medical history, complications, and causes of death associated with the risk factors for AT or VTD in patients with APS. We analyzed 677 thrombotic events in 386 patients. Type 2 diabetes mellitus and grade 3 obesity were associated with VTD instead of AT. There were no significant differences between the groups for almost all laboratory tests analyzed, although lupus anticoagulant was significantly higher in the VTD group. We suggest that thrombosis in APS is due to the APS itself and that the risks factors for AT or VTD do not have a main role. Our findings may have an ethnical background. Therefore, it may be difficult to elaborate predictive thrombotic clinical scores applicable to patients with different ethnical background. PMID- 28884610 TI - Performance of Current Thromboembolism Risk Assessment Tools in Patients With Gastric Cancer and Validity After First Treatment. AB - Patients with gastric cancer (GC) are at higher risk of thromboembolism when compared to other solid tumors. We aim to determine the predictive performance of current venous thromboembolism (VTE) predictive tools and their variability and validity after first treatment. Single institution cohort of GC-treated patients (2010*15). We abstracted predictive tools, validated for VTE prediction in patient with cancer; including the Khorana Score (KRS), platelet to lymphocyte ratio (PLR), and neutrophil to lymphocyte ratio (NLR). The primary outcome was CAT prediction. We included 112 patients who were predominantly men (66%), 58 (51 64)-year-olds, with adenocarcinoma (84%) and advanced disease (59%). The median follow-up was 21.3 months (9.5-42.6). The VTE occurrence was 12%. The median time from diagnosis to VTE occurrence was 59 days (36-258). In our cohort, performance status (PS; hazard ratio [HR], 8.02; 95% confidence interval [CI], 2.37-27.14; P < .01) was an independent predictor of VTE whereas KRS (univariate HR, 2.3; 95% CI, 0.7-7.4; P = .17), PLR (univariate HR, 0.8; 95% CI, 0.2-3.1; P = .8), and NLR (univariate HR, 0.8; 95% CI, 0.3-2.5; P = .8) at baseline were not associated with VTE risk. The posttreatment KRS was an independent predictor of VTE (HR, 3.69; 95% CI, 1.17-11.65; P = .25) along with PS (HR, 7.58; 95% CI, 2.27-25.33; P = .01). Posttreatment KRS appears as a valid tool to identify patients with GC at high risk of VTE after first cancer treatment. PMID- 28884611 TI - An Evaluation of the Activated Partial Thromboplastin Time Waveform. AB - The activated partial thromboplastin time (APTT) waveform includes several parameters that are related to various underlying diseases. The APTT waveform was examined in various diseases. Regarding the pattern of APTT waveform, a biphasic pattern of the first or second derivative curve (DC) was observed in patients with hemophilia and patients positive for antiphospholipid (aPL) antibodies or coagulation factor VIII (FVIII) inhibitors. The time of the first and second DC and fibrin formation at 1/2 height were prolonged in patients with hemophilia, patients with inhibitors, patients positive for aPL, patients treated with anti Xa agents, and patients with disseminated intravascular coagulation (DIC). These values all tended to decrease in pregnant women (at 28-36 weeks' gestation). The height of the second derivative peak 1 was significantly lower in patients with hemophilia, patients with FVIII inhibitors, patients positive for aPL, patients treated with anti-Xa agents, and patients with DIC; these values tended to be significantly higher in pregnant women. The height of the first DC was significantly lower in patients who were positive for FVIII inhibitors and was significantly higher in patients treated with anti-Xa agents and pregnant women. The height of the first and second DC was useful for the analysis of hemophilia, FVIII inhibitor, and aPL. PMID- 28884612 TI - Conjugation with 20 kDa dextran decreases the autoxidation rate of bovine hemoglobin. AB - Haemoglobin-based oxygen carrier (HBOC) is highly susceptible to autoxidation that renders a series of tissue and cellular toxicities. HBOC is prepared by chemical modification of haemoglobin (Hb), which typically increases the autoxidation rate of Hb. Thus, it is necessary to decrease the autoxidation of HBOC. In the present study, two dextran-bHb conjugates (dex20-bHb and dex40-bHb) were prepared by conjugation with 20 kDa or 40 kDa dextrans, where the thiol group of Cys-93(beta) was reversibly protected. The autoxidation rate of bHb was decreased by conjugation with 20 kDa dextran and maintained by conjugation with 40 kDa dextran. In order to understand the low autoxidation rate of dex20-bHb, the effects of aldehyde modification and dextran on the autoxidation rate of dex20-bHb were investigated. The high oxygen affinity, high tetramer stability and dextran itself were found to decrease the autoxidation rate of dex20-bHb. The conjugated dextran had a predominant effect on decreasing the autoxidation rate of bHb, which was particularly promising for the potential development of safe HBOCs. Conjugation with dextran is of general significance to decrease the oxidation process of the heme-containing proteins, such as Hb and myoglobin. PMID- 28884613 TI - Frequency of Adverse Event Monitoring in Ambulatory Patients on Amiodarone or Dofetilide. AB - BACKGROUND: Published studies state that adherence to regular laboratory assessments for anti-arrhythmic drugs is as low as 20%. Monitoring adherence is important as other studies have shown that up to 93% of patients on amiodarone experience an adverse drug event leading to a potentially lethal event. OBJECTIVE: To determine whether patients prescribed amiodarone or dofetilide are being monitored according to package labeling and guideline recommendations for adverse events. METHODS: Patients prescribed amiodarone or dofetilide from a 2 year period were eligible for inclusion. Patients with ventricular arrhythmias, prescribed more than 1 anti-arrhythmic agent, or received anti-arrhythmic monitoring outside the health-care system were excluded. Adherence to monitoring parameters was assessed according to labeled recommendations and published guidelines. The primary objective was to determine the frequency of baseline and follow-up monitoring recommendations for patients receiving amiodarone or dofetilide. The secondary objective was to determine rates of adverse drug events. RESULTS: One hundred patients were evaluated (amiodarone n = 50, dofetilide n = 50). Average rates of baseline and follow-up amiodarone monitoring parameters were 55% and 57%, respectively. Average rates of baseline and follow up dofetilide monitoring were 99.6% and 85%, respectively. There was a statistically significant difference in abnormally elevated thyroid-stimulating hormone levels (8%-30%, P <= .005) after patients were prescribed amiodarone. Twelve percent of patients taking dofetilide had an increase in QTc interval by >15%. CONCLUSIONS: Amiodarone adverse event monitoring was lower than dofetilide in this cohort. Improving the monitoring of these agents may decrease morbidity risk in this population. PMID- 28884614 TI - Characteristics of Inmates Who Misuse Prescription Medication. AB - Substance use disorders are common among incarcerated individuals, and prescribed medications have been reported as abused, diverted, or otherwise misused in correctional settings. We conducted a retrospective chart review of electronic medical records and reports on institutional charges for misuse of authorized medication by inmates in the New Jersey Department of Corrections between 2003 and 2013. The most frequently cited medications for misuse were gabapentin, diphenhydramine, clonidine, and ibuprofen. When compared with the entire current inmate population, subjects were more likely to have any history of a substance use disorder, to be in treatment for a mental illness, to have any diagnosis of antisocial personality disorder, to have any history of malingering, and to be prescribed a greater number of medicines. Prescribers in correctional settings should be aware that medications not traditionally prescribed by a psychiatrist may also be misused, and caution should be taken to manage this risk. PMID- 28884615 TI - Resveratrol-loaded nanoparticles conjugated with kidney injury molecule-1 as a drug delivery system for potential use in chronic kidney disease. AB - AIM: We used resveratrol (Res)-loaded nanoparticles (Res NPs) as a novel method for improving the pharmacokinetic properties of Res and analyzed the effect of Res NPs in chronic kidney disease (CKD). MATERIALS & METHODS: We coupled anti kidney injury molecule-1 antibodies to Res NPs and analyzed safety and efficacy. RESULTS: Res NPs had low toxicity and induced autophagy. Res NPs inhibited the NLRP3 inflammasome and IL-1beta secretion. Higher NLRP3 expression levels were observed in peripheral blood monocytic cells of CKD patients than healthy individuals. Treatment with kidney injury molecule-1-Res NPs significantly reduced creatinine and protected against tubulointerstitial injury in a murine model of CKD. CONCLUSION: Res NPs through NLRP3 inflammasome attenuation and autophagy induction may be as a strategy to prevent CKD. PMID- 28884616 TI - Effect of walking in footwear with varying heel sole differentials on shank and foot segment kinematics. AB - BACKGROUND: When walking in footwear with a positive "heel sole differential", the sagittal kinematics of the base of the footwear appear to mimic normal barefoot foot kinematics, creating an "effective foot," yet sagittal shank, thigh, and trunk kinematics appear to remain unchanged. These observations have not been quantified. OBJECTIVES: To quantify these observations by assessing the effect of different heel sole differentials on sagittal shank and foot segment kinematics of able-bodied walking. STUDY DESIGN: Cross-sectional study. METHODS: Gait data from 10 nondisabled females were collected while they walked with no heel (mean heel sole differential = 0 (standard deviation = 0) mm), mid-heel (mean heel sole differential = 37 (standard deviation = 10) mm), and high-heel shoes (mean heel sole differential = 71 (standard deviation = 17) mm) to calculate the shank-to-vertical angle and foot-to-horizontal angle. RESULTS: There were no significant differences between shoe conditions in stride lengths ( p = 0.056) or shank kinematics between 0% and 50% gait cycle ( p = 0.079). There were significant differences in foot kinematics ( p = 0.000), with foot segment angle increasing with increasing heel sole differential. CONCLUSION: The ankle joint and actual foot segment adapt their kinematics to maintain consistent shank kinematics. The finding that heel sole differential and foot segment angle can be varied without influencing shank segment kinematics has implications for orthotic and prosthetic practice. Clinical relevance Heel sole differentials of footwear can be varied without implications for shank kinematics, which is relevant for both orthotics and prosthetics. Assessments and interventions with varying heel sole differential footwear may be helpful in patients with short calf muscle or restricted ankle motion who may walk more normally if an appropriate heel sole differential were provided. PMID- 28884617 TI - Strengths and Gaps in Physicians' Risk Communication: A Scenario Study of the Influence of Numeracy on Cancer Screening Communication. AB - OBJECTIVE: Many patients have low numeracy, which impedes their understanding of important information about health (e.g., benefits and harms of screening). We investigated whether physicians adapt their risk communication to accommodate the needs of patients with low numeracy, and how physicians' own numeracy influences their understanding and communication of screening statistics. METHODS: UK family physicians ( N = 151) read a description of a patient seeking advice on cancer screening. We manipulated the level of numeracy of the patient (low v. high v. unspecified) and measured physicians' risk communication, recommendation to the patient, understanding of screening statistics, and numeracy. RESULTS: Consistent with best practices, family physicians generally preferred to use visual aids rather than numbers when communicating information to a patient with low (v. high) numeracy. A substantial proportion of physicians (44%) offered high quality (i.e., complete and meaningful) risk communication to the patient. This was more often the case for physicians with higher (v. lower) numeracy who were more likely to mention mortality rates, OR=1.43 [1.10, 1.86], and harms from overdiagnosis, OR=1.44 [1.05, 1.98]. Physicians with higher numeracy were also more likely to understand that increased detection or survival rates do not demonstrate screening effectiveness, OR=1.61 [1.26, 2.06]. CONCLUSIONS: Most physicians know how to appropriately tailor risk communication for patients with low numeracy (i.e., with visual aids). However, physicians who themselves have low numeracy are likely to misunderstand the risks and unintentionally mislead patients by communicating incomplete information. High-quality risk communication and shared decision making can depend critically on factors that improve the risk literacy of physicians. PMID- 28884619 TI - Correction to: Arheiam, et al., Arab dentists' refusal to treat HIV positive patients: a survey of recently graduated dentists from three Arab dental schools. PMID- 28884618 TI - Predictors of Change in Quality of Life in Patients With End-Stage Disease During Hospitalization. AB - BACKGROUND: Currently, there are no studies aimed at evaluating the quality of life (QoL) of patients with end-stage disease during hospitalization and the factors that influence it. AIM: The aim of the research was to identify predictors of change in the QoL of patients hospitalized due to advanced stage of disease. METHODS: The sample consisted of 140 patients with end-stage disease who were hospitalized on this account. For evaluation of QoL, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was used. The Hospital Anxiety and Depression Scale and Karnofsky Performance Status questionnaires were used for the assessment of mental and functional status. For the evaluation of predictors of negative change in QoL, a logistic regression analysis was used. RESULTS: During hospitalization, there was a significant deterioration in the scores given for all domains of the functional QLQ-C30 scale, but not the symptomatic scale. Predictors of change in overall QoL detected were marital status, improved functional status, and depression detected on admission to hospital. Gender and age were found to be protective factors against deterioration in overall QoL. CONCLUSION: Sociodemographic characteristics and mental and functional status may be associated with change in QoL of patients with end-stage disease during hospitalization. PMID- 28884620 TI - Nusinersen for the treatment of spinal muscular atrophy. AB - INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive degenerative neuromuscular disorder characterized by loss of spinal motor neurons leading to muscle weakness. This review article focuses on a novel antisense oligonucleotide treatment, first ever approved for SMA (nusinersen, SpinrazaTM) and describes the exciting journey from early ASO clinical trials to regulatory approval of the first ever known effective treatment for SMA. Areas covered: This article reviews the results of the published open label nusinersen studies in infants and children, and briefly covers the preliminary findings of the recently completed but as yet unpublished nusinersen-sham controlled trials, as well as the presymptomatic nusinersen trial known as Nurture. Clinical use of nusinersen is also reviewed. Expert commentary: Collectively, the studies show improvement in motor function across SMA of all types, including SMA type 3. Best motor response was observed with early treatment; presymptomatic treatment prevented disease manifestations. Nusinersen was found to be safe and well tolerated across all age groups studied. Nusinersen has irrevocably altered the natural history of SMA and allowed for the first time children to transition between SMA types. Nusinersen should be considered as standard of care for the treatment of SMA of all types. PMID- 28884621 TI - Corrigendum. PMID- 28884623 TI - Association Between Weather Variables, Airborne Inoculum Concentration, and Raspberry Fruit Rot Caused by Botrytis cinerea. AB - Botrytis fruit rot (BFR), one of the most important diseases of raspberry (Rubus spp.), is controlled primarily with fungicides. Despite the use of fungicides, crop losses due to BFR are high in most years. The aim of this study was to investigate the association between airborne inoculum, weather variables, and BFR in order to improve the management of the disease as well as harvest and storage decisions. Crop losses, measured as the percentage of diseased berries during the harvest period, were monitored in unsprayed field plots at four sites in three successive years, together with meteorological data and the number of conidia in the air. Based on windowpane analysis, there was no evidence of correlation between crop losses and temperature, vapor pressure deficit, wind, solar radiation, or probability of infection. There were significant correlations between crop losses and airborne inoculum and between crop losses and humidity related variables, and the best window length was identified as 7 days. Using 7 day average airborne inoculum concentration combined with 7-day average relative humidity for periods ending 6 to 8 days before bloom, it was possible to accurately predict crop losses (R2 of 0.86 to 0.89). These models could be used to assist with managing BFR, timing harvests, and optimizing storage duration in raspberry crops. PMID- 28884622 TI - Ex Vivo and In Vivo Noninvasive Imaging of Epidermal Growth Factor Receptor Inhibition on Colon Tumorigenesis Using Activatable Near-Infrared Fluorescent Probes. AB - BACKGROUND: Near-infrared fluorescence (NIRF) imaging combined with enzyme activatable NIRF probes has yielded promising results in cancer detection. OBJECTIVE: To test whether 3-dimensional (3-D) noninvasive in vivo NIRF imaging can detect effects of epidermal growth factor receptor (EGFR) inhibitor on both polypoid and flat tumor load in azoxymethane (AOM)-induced colon tumors or tumors in ApcMin/+ mice. METHODS: The AOM-injected KK-HIJ mice received EGFR inhibitor diet or chow diet. These and ApcMin/+ mice were given cathepsin-activatable probes (ProSense 680) before imaging. In vivo imaging was performed using quantitative tomographic NIRF imaging. Ex vivo imaging and histologic examination were performed. Dual imaging by micro computed tomography (CT) and 3D NIRF imaging was used to verify tumor location. RESULTS: Tumor load reduction by EGFR inhibition was detected ex vivo using cathepsin B probes. In vivo imaging revealed intense activation of probes only in large tumors. Dual imaging with microCT and 3D NIRF imaging improved tumor detection in vivo. CONCLUSIONS: The 3 D NIRF imaging with ProSense 680 can detect and quantify drug effects on colon tumors ex vivo. The NIRF imaging with ProSense 680 probe has limitations as a valid nonendoscopic method for intestinal tumor detection. Combing with other imaging modalities will improve the specificity and sensitivity of intestinal tumor detection in vivo. PMID- 28884624 TI - Identification of Weather Conditions Associated with the Occurrence, Severity, and Incidence of Black Seed Disease of Strawberry Caused by Mycosphaerella fragariae. AB - Black seed disease (BSD) of strawberry is a sporadic disease caused by Mycosphaerella fragariae. Because little is known about potential crop losses or the weather conditions conducive to disease development, fungicides are generally not applied or are applied based on a preset schedule. Data collected from 2000 to 2011 representing 50 farm-years (total of 186 strawberry fields) were used to determine potential crop losses and to study the influence of weather on disease occurrence and development. First, logistic regression was used to model the relationship between occurrence of BSD and weather variables. Second, linear and nonlinear regressions were used to model the number of black seed per berry (severity) and the percentage of diseased berries (incidence). Of the 186 fields monitored, 78 showed black seed symptoms, and the number of black seed per berry ranged from 1 to 10, whereas the percentage of diseased berries ranged from 3 to 32%. The most influential weather variable was total rainfall (in millimeters) in May, with a threshold of 103 mm of rain (absence of BSD < 103 mm < presence of BSD). Similarly, nonlinear models with the total rainfall in May accurately predicted both disease severity and incidence (r = 0.94 and 0.97, respectively). Considering that management actions such as fungicide application are not needed every year in every field, these models could be used to identify fields that are at risk of BSD. PMID- 28884626 TI - In silico and empirical approaches toward understanding the structural adaptation of the alkaline-stable lipase KV1 from Acinetobacter haemolyticus. AB - Interests in Acinetobacter haemolyticus lipases are showing an increasing trend concomitant with growth of the enzyme industry and the widening search for novel enzymes and applications. Here, we present a structural model that reveals the key catalytic residues of lipase KV1 from A. haemolyticus. Homology modeling of the lipase structure was based on the structure of a carboxylesterase from the archaeon Archaeoglobus fulgidus as the template, which has a sequence that is 58% identical to that of lipase KV1. The lipase KV1 model is comprised of a single compact domain consisting of seven parallel and one anti-parallel beta-strand surrounded by nine alpha-helices. Three structurally conserved active-site residues, Ser165, Asp259, and His289, and a tunnel through which substrates access the binding site were identified. Docking of the substrates tributyrin and palmitic acid into the pH 8 modeled lipase KV1 active sites revealed an aromatic platform responsible for the substrate recognition and preference toward tributyrin. The resulting binding modes from the docking simulation correlated well with the experimentally determined hydrolysis pattern, for which pH 8 and tributyrin being the optimum pH and preferred substrate. The results reported herein provide useful insights into future structure-based tailoring of lipase KV1 to modulate its catalytic activity. PMID- 28884627 TI - Apoptosis-mediated neurotoxicity and altered gene expression induced by silver nanoparticles. AB - Although not fully recognized, the neurotoxic effects of silver nanoparticles (Ag NPs) are thought to occur through induction of oxidative stress and apoptosis. To investigate the exact underlying molecular mechanism, we aimed to explore the apoptotic effects of intraperitoneal injection of Ag-NPs and investigated the possible attributed changes in the mRNA expression of Bcl-2 and Bax genes in the rat hippocampus. Two in vivo sets of experiments, one to demonstrate apoptosis and the other to assess gene expression, were conducted on male Wistar rats. In each set, the first group, acting as control, received saline and the other three groups received Ag-NP at doses of 100, 200, and 400 ppm for five successive days. Ten days after the last injection, hippocampal tissue of the first set of rats was assessed for apoptosis using terminal deoxynucleotidyl transferase-mediated deoxy uridine triphosphate nick-end labeling staining. In the second set of experiments, mRNA expression of Bcl-2 and Bax genes was evaluated using real-time polymerase chain reaction. Ag-NP treatment was shown to induce apoptosis in a dose-dependent manner. Furthermore, Ag-NP reduced mRNA level of Bcl-2 in the rat hippocampal cells at all investigated doses compared to the control group ( p < 0.001). The mRNA level of Bax, on the other hand, was increased in these cells. The increase was significant compared to the control group at the doses of 200 ppm ( p < 0.05) and 400 ppm ( p < 0.001). Our results show that Ag-NPs reduce Bcl 2 and increase Bax genes expression, resulting in increased Bax/Bcl-2 ratios in rat hippocampal cells. This altered gene expression induces cell apoptosis and contributes to the neurotoxicity of Ag-NPs. PMID- 28884628 TI - The effect of tannic acid on bone mechanical and geometric properties, bone density, and trabecular histomorphometry as well as the morphology of articular and growth cartilages in rats co-exposed to cadmium and lead is dose dependent. AB - Cadmium (Cd) and lead (Pb) are toxic elements that accumulate to the largest extent in bones. Rats were used to investigate whether tannic acid (TA; 0.5%, 1.0%, 1.5%. 2.0%, or 2.5%) would have a protective effect on the structure and properties of bones in the case of exposure to Cd and Pb (diet: 7 mg Cd/kg and 50 mg Pb/kg) for 6 weeks. The effects of administration of TA in Cd- and Pb-poisoned rats on bone characteristics and the morphology of articular and growth cartilages were determined. All the rats administered Cd and Pb had an enhanced Cd and Pb concentration in blood plasma and bone and reduced bone Ca content irrespective of the TA administration. Cd and Pb alone reduced the mechanical endurance and histomorphometric parameters of trabecular bone and the thickness of the growth plate and articular cartilage. Tannic acid improved cancellous bone parameters in the rat exposed to Cd and Pb. A diet rich in TA improved articular cartilage constituents in heavy metal-poisoned rats. These results suggest that alimentary TA supplementation can counteract in a dose-dependent manner some of the destructive changes evoked by Cd and Pb possibly by reducing the exposure. PMID- 28884629 TI - Maternal Lifestyle Impairs Embryonic Growth: The Rotterdam Periconception Cohort. AB - Previously, embryonic growth has been assumed to be uniform, but in recent years, it has become more clear that genetic and environmental factors may influence the intrauterine environment and therefore embryonic growth trajectories as well as pregnancy course and outcome. The objective of this study was to investigate associations between modifiable maternal nutrition and lifestyle factors during the periconception period and embryonic growth. We established a prospective cohort including 342 women less than 13 weeks pregnant. At enrollment, women filled out a questionnaire regarding demographic and medical data and a validated food frequency questionnaire. Participants received multiple 3-dimensional ultrasound examinations up until the 12th week of pregnancy, and crown-rump length (CRL) and embryonic volume (EV) were measured offline using V-Scope Virtual Reality software (version 1.0.0) in a Barco I-Space. Associations between maternal periconception vegetable and fruit intake, folic acid supplement use, smoking, and alcohol consumption and embryonic growth measurements were assessed by linear mixed models adjusted for potential confounders. No or postconception initiation of folic acid supplement use was significantly associated with a 0.76 mm (-7.8%) and 1.63 mm (-3.7%) smaller CRL and a 0.01 cm3 (-19.5%) and 0.86 cm3 ( 12.2%) smaller EV at 7+0 and 11+0 weeks of gestation, respectively. Smoking, alcohol consumption, and inadequate fruit and vegetable intake showed weaker associations with embryonic growth parameters. These results emphasize the influence of periconceptional maternal folic acid supplement use on embryonic growth. Results regarding maternal nutrition and lifestyle factors also suggest an association with embryonic growth, but this has to be confirmed in a larger study. PMID- 28884630 TI - Fetal and Placental DNA Stimulation of TLR9: A Mechanism Possibly Contributing to the Pro-inflammatory Events During Parturition. AB - INTRODUCTION: While there is evidence for a relationship between cell-free fetal DNA (cffDNA) and parturition, questions remain regarding whether cffDNA could trigger a pro-inflammatory response on the pathway to parturition. We hypothesized that placental and/or fetal DNA stimulates toll-like receptor 9 (TLR9) leading to secretion of pro-inflammatory cytokines by macrophage cells. METHODS: Four in vitro DNA stimulation studies were performed using RAW 264.7 mouse peritoneal macrophage cells incubated in media containing the following DNA particles: an oligodeoxynucleotide (ODN2395), intact genomic DNA (from mouse placentas, fetuses and adult liver), mouse DNA complexed with DOTAP (a cationic liposome forming compound), and telomere-depleted mouse DNA. Interleukin 6 (IL6) secretion was measured in the media by enzyme-linked immunosorbent assay; and the cell pellet was homogenized for protein content (picograms IL6/mg protein). RESULTS: Robust IL6 secretion was observed in response to ODN2395 (a CpG-rich TLR9 agonist), mouse DNA-DOTAP complexes, and telomere-depleted mouse DNA in concentrations of 5 to 15 MUg/mL. In contrast, ODN A151 (containing telomere sequence motifs), intact genomic mouse DNA, and restriction enzyme-digested DNA had no effect on IL6 secretion. The IL6 response was significantly inhibited by chloroquine (10 MUg/mL), thereby confirming the important role for TLR9 in the response by macrophage cells. CONCLUSIONS: DNA derived from mouse placentas and fetuses, and depleted of telomeric sequences, stimulates a robust pro inflammatory response by macrophage cells, thereby supporting the hypothesis that cffDNA is able to stimulate an innate immune response that could trigger the onset of parturition. These findings are of clinical importance, as we search for effective treatment/prevention of preterm parturition. PMID- 28884631 TI - Takotsubo cardiomyopathy associated with Paragonimiasis westermani. AB - An 11-year-old boy collapsed during morning assembly at his junior high school. The automated external defibrillator detected ventricular fibrillation and provided shock delivery. He was successfully resuscitated and reverted to sinus rhythm. Electrocardiography showed ST-T elevation in the precordial leads. Echocardiography and angiography demonstrated akinesia of the apex and mid-wall of the left ventricle with preserved contraction of the basal segments, which suggested Takotsubo cardiomyopathy. The patient and his family had often eaten uncooked crab, and his father had a past history of infection with Paragonimiasis westermani. The patient had had a persistent cough and chest pain for several weeks. Chest radiograph showed cystic cavities in the left upper lung. Microbiological examination of the sputum demonstrated an egg of P. westermani and immunological assay showed a raised antibody titre to P. westermani. On the12th day of admission, he developed seizures, and magnetic resonance imaging demonstrated cerebral involvement. After the administration of praziquantel for 3 days, the clinical manifestations improved immediately, and echocardiography normalised within 3 weeks. The patient was discharged on the 32nd day + and follow-up was normal. Takotsubo cardiomyopathy following a potentially fatal arrhythmia is a rare cardiac complication associated with pulmonary and central nervous system infection by P. westermani. PMID- 28884632 TI - A comprehensive analysis of the computed tautomer fractions of the imidazole ring of histidines in Loligo vulgaris. AB - A recently introduced electrostatic-based method to determine the pKa values of ionizable residues and fractions of ionized and tautomeric forms of histidine (His) and acid residues in proteins, at a given fixed pH, is applied here to the analysis of a His-rich protein, namely Loligo vulgaris (pdb id 1E1A), a 314 residue all-beta protein. The average tautomeric fractions for the imidazole ring of each of the six histidines in the sequence were computed using an approach that includes, but is not limited to, molecular dynamic simulations coupled with calculations of the ionization states for all 94 ionizable residues of protein 1E1A in water at pH 6.5 and 300 K. The electrostatic-calculated tautomeric fractions of the imidazole ring of His were compared with predictions obtained from an existent NMR-based methodology. Our results indicate that: (i) the averaged electrostatic-based tautomeric predictions for the imidazole ring of all histidines of Loligo vulgaris are dominated by the Nepsilon2-H rather than the Ndelta1-H form, although such preferences from the NMR-based methodology are not so well defined; (ii) the computed average absolute difference between the electrostatic- and the NMR-based tautomeric predictions among all six histidines vary among 0% to 17%; (iii) for the His showing the largest fraction of the neutral form (81%), the absolute difference between the NMR- and electrostatic based computed tautomeric predictions is only 3%; and (iv) the tautomeric predictions for the imidazole ring of His computed with the NMR-based methodology are stable within a certain, well-defined, range of variations of a tautomer related parameter. PMID- 28884633 TI - Oxidative removal of aromatic amino acids by manganese dioxide: kinetic modeling and effect of co-solutes. AB - The degradation of aromatic amino acids, including L-tryptophan, L-tyrosine, and L-phenylalanine, by delta-MnO2 was investigated. L-tryptophan and L-tyrosine underwent rapid oxidative degradation in the delta-MnO2 suspension solution. In contrast, L-phenylalanine was not oxidized by delta-MnO2. The degradation of L tryptophan was faster than that of L-tyrosine. The oxidation rates of amino acids increased with increasing concentration of delta-MnO2. The increase of concentrations of substrates and pH disfavored the degradation. The kinetics modeling showed that the reaction orders of amino acids, MnO2, and H+ were 0.67, 1.24, 0.72 and 0.32, 1.20, 1.05 for L-tryptophan and L-tyrosine, respectively. The coexistence of metal ions markedly inhibited the degradation in the order of Al3+ > Mn2+ > Zn2+ > Ca2+ > Mg2+. The inhibition effect of metal ions was related to the stability constant and hydration radius of metal ions. The addition of fulvic acid to the reaction solutions did not affect the degradation of substrate. This finding suggests that delta-MnO2 selectively oxidize aromatic amino acids and it can be used as an efficient oxidant for the removal of certain aromatic acid pollutants. PMID- 28884634 TI - The context and quality of evidence used by tobacco interests to oppose ANVISA's 2012 regulations in Brazil. AB - Evidence is an important resource for policy makers. Alongside its practical utility, evidence is a persuasive strategic and rhetorical tool. This study scrutinises the information used by tobacco interests in opposition to Brazil's National Health Surveillance Agency's (ANVISA) 2012 regulations. We analysed one prominent document widely cited in the policy discourse, produced by Fundacao Getulio Vargas (FGV) in 2010 when ANVISA initiated public consultations. The FGV document formed the basis of opposition to the regulations. We conducted four levels of analysis of the FGV document: (1) identifying the main arguments, (2) linking the arguments with evidence, (3) analysing the quality of evidence and (4) a contextual analysis, examining how evidence was interpreted and represented. Three of five arguments were supported by information produced by an external source. Sixty eight percent of evidence sources were supported by the tobacco industry and only 31% were peer-reviewed. Information was often misrepresented in the arguments. Tobacco interests continue to draw from sources they claim are scientific to legitimise their opposition to tobacco regulation. The information from these sources are often misrepresented, used to distract from the health objectives of policy and receive direct or indirect support from the tobacco industry. PMID- 28884635 TI - Psoriasis in solid organ transplant patients: best practice recommendations from The Medical Board of the National Psoriasis Foundation. AB - BACKGROUND: Treatment of solid organ transplant patients who have psoriasis can be a therapeutic challenge. Biologic and systemic drugs used to treat psoriasis can result in an increase in infections or malignancies. OBJECTIVE: We sought to develop a treatment algorithm for organ transplant recipients (OTR) diagnosed with psoriasis vulgaris. METHODS: A systematic literature search for psoriasis treatment in organ transplant patients was performed using MEDLINE and GOOGLE. RESULTS: In mild-to-moderate disease, topical therapy should be a first-line treatment. In moderate-to-severe disease, first-line treatment is acitretin with narrow band ultraviolet light (NBUVB), NBUVB, or acitretin. Second-line treatment is increasing the current antirejection drug dose. Other systemic or biologic therapies should be reserved for more severe or refractory cases. CONCLUSION: No systematic clinical studies have been done to explore psoriasis treatments among affected solid organ transplant patients who have psoriasis, and only a few case reports are available. The algorithm for best practices was developed based on these reports and on the clinical experience and judgment of the Medical Board of the National Psoriasis Foundation. There remains a need for further research on the management of psoriasis in the organ transplant patient population. PMID- 28884636 TI - Acceptability of the POWERPLAY Program: A Workplace Health Promotion Intervention for Men. AB - The workplace health promotion program, POWERPLAY, was developed, implemented, and comprehensively evaluated among men working in four male-dominated worksites in northern British Columbia, Canada. The purpose of this study was to explore the POWERPLAY program's acceptability and gather recommendations for program refinement. The mixed-method study included end-of-program survey data collected from 103 male POWERPLAY program participants, interviews with workplace leads, and field notes recorded during program implementation. Data analyses involved descriptive statistics for quantitative data and inductive analysis of open-ended questions and qualitative data. Among participants, 70 (69%) reported being satisfied with the program, 51 (51%) perceived the program to be tailored for northern men, 56 (62%) believed the handouts provided useful information, and 75 (74%) would recommend this program to other men. The findings also highlight program implementation experiences with respect to employee engagement, feedback, and recommendations for future delivery. The POWERPLAY program provides an acceptable approach for health promotion that can serve as a model for advancing men's health in other contexts. PMID- 28884639 TI - A Call for Gender-Inclusive Global Health Strategies. AB - The WHO's "Global Strategy for Women's, Children's, and Adolescents' Health 2016 2030" (GS-WCAH 2016-2030) is a comprehensive plan developed to improve the lives of women, children, and adolescents. Due to the success in the creation, ratification, and advocacy of the GS-WCAH 2016-2030, the clear health outcome disparities between males and females, and the general absence of male health from existing policies and sponsored programs, it is time now to develop a global strategy specifically drafted to improve the lives of men and boys. The following commentary provides three points for why a male-oriented program, like the GS WCAH 2016-2030, should be created: (a) health outcomes disparities, (b) economic impact of poor male health, and (c) fathers' role in promoting the health of women, children, and adolescents. Implications for how male health can be incorporated into future projects and priorities are provided, as well as advocacy for overall gender-inclusivity in regard to global public health efforts. PMID- 28884637 TI - Men's Mental Health Promotion Interventions: A Scoping Review. AB - There is an increasing need for mental health promotion strategies that effectively engage men. Although researchers have examined the effectiveness of diverse mental wellness interventions in male-dominated industries, and reviewed suicide prevention, early intervention, and health promotion interventions for boys and men, few have focused on sex-specific program effects. The purpose of this review was to (a) extend the previous reviews to examine the effectiveness of mental health promotion programs in males, and (b) evaluate the integration of gender-specific influences in the content and delivery of men's mental health promotion programs. A search of MEDLINE, CINAHL, PsycINFO, and EMBASE databases for articles published between January 2006 and December 2016 was conducted. Findings from the 25 included studies indicated that a variety of strategies offered within (9 studies) and outside (16 studies) the workplace show promise for promoting men's mental health. Although stress was a common area of focus (14 studies), the majority of studies targeted multiple outcomes, including some indicators of positive well-being such as self-efficacy, resilience, self-esteem, work performance, and happiness/quality of life. The majority of programs were offered to both men and women, and six studies explicitly integrated gender related influences in male-specific programs in ways that recognized men's interests and preferences. PMID- 28884638 TI - Low-Intensity Extracorporeal Shockwave Therapy Can Improve Erectile Function in Patients Who Failed to Respond to Phosphodiesterase Type 5 Inhibitors. AB - Managing patients with erectile dysfunction (ED) who failed to respond to phosphodiesterase type 5 inhibitors (PDE5is) is a challenging task. Recently, low intensity extracorporeal shockwave therapy (LI-ESWT) was reported to improve ED by enhancing perfusion of the penis. The current study was performed to evaluate whether combined treatment with LI-ESWT and PDE5is can restore erectile function in patients who failed to respond to PDE5is alone. This was an open-label single arm prospective study. ED patients with an erection hardness score (EHS) ?2 under a maximal dosage of PDE5is were enrolled. Sociodemographic information and detailed medical history were recorded. LI-ESWT treatment consisted of 3,000 shockwaves once weekly for 12 weeks. All patients continued their regular PDE5is use. The EHS and the 5-item version of the International Index of Erectile Function (IIEF-5) were used to evaluate the change in erectile function 1 and 3 months after LI-ESWT. A total of 52 patients were enrolled. After LI-ESWT treatment, 35 of the 52 patients (67.3%) could achieve an erection hard enough for intercourse (EHS ? 3) under PDE5is use at the 1-month follow-up. Initial severity of ED was the only significant predictor of a successful response (EHS1: 35.7% vs. EHS2: 78.9%, p = .005). Thirty-three of the 35 (94.3%) subjects who responded to LI-ESWT could still maintain their erectile function at the 3-month follow-up. LI-ESWT can serve as a salvage therapy for ED patients who failed to respond to PDE5is. Initial severity of ED was an important predictor of a successful response. PMID- 28884640 TI - Advocacy and Legislative Engagement: Every School Nurse's Responsibility. AB - It is a professional responsibility of school nurses to be engaged with their elected officials and the legislative process. Legislative contact can be an intimidating process, but nurses and the public in general can be prepared through their elected official's website and professional association resources. Background information and voting history from legislative sessions along with current bills can guide the conversation leading to a productive encounter for all participants. PMID- 28884641 TI - Paint Your Definition of School Nursing. PMID- 28884642 TI - The ABCs of Burn Care for School-Age Children. AB - Burn injuries are among the most painful injuries any child can endure. This article explains common sources of burn injuries in student populations, diagnosis and classification of burn injuries, initial burn management, and how to determine when a child needs to be evaluated by a physician. PMID- 28884643 TI - The Role of the Designated State Data Champion. AB - Step Up & Be Counted! (Step Up!) is a joint project of the National Association of School Nurses (NASN) and the National Association of State School Nurse Consultants (NASSNC). The goal of the initiative is to develop a National School Nurse Standardized Data Set that will be used by nurses across the country to uniformly collect data the same way. The data will be used to determine the health of children and youth, the care that is delivered in schools, and the impact of school nurses on academic success and well-being. This article focuses on the role of the Designated State Data Champion in the initiative. PMID- 28884644 TI - The role of language in expressing the life sciences in a polarized age. AB - This Perspective is based on the keynote plenary lecture delivered at the Annual Conference of the Association for Politics and the Life Sciences (APLS), held on October 23, 2015, at the University of Wisconsin-Madison. PMID- 28884645 TI - The "chicken-and-egg" development of political opinionsThe roles of genes, social status, ideology, and information. AB - Twin studies have revealed political ideology to be partially heritable. Neurological research has shown that ideological differences are reflected in brain structure and response, suggesting a direct genotype-phenotype link. Social and informational environments, however, also demonstrably affect brain structure and response. This leads to a "chicken-and-egg" question: do genes produce brains with ideological predispositions, causing the preferential absorption of consonant information and thereby forming an ideology, or do social and informational environments do most of the heavy lifting, with genetic evidence the spurious artifact of outdated methodology? Or are both inextricably intertwined contributors? This article investigates the relative contributions of genetic and environmental factors to ideological development using a role-play experiment investigating the development of opinions on a novel political issue. The results support the view that the process is bidirectional, suggesting that, like most traits, political ideology is produced by the complex interplay of genetic and (social/informational) environmental influences. PMID- 28884650 TI - Communities ready for takeoffIntegrating social assets for biofuel site-selection modeling. AB - Although much of the social science literature supports the importance of community assets for success in many policy areas, these assets are often overlooked when selecting communities for new infrastructure facilities. Extensive collaboration is crucial for the success of environmental and economic projects, yet it often is not adequately addressed when making siting decisions for new projects. This article develops a social asset framework that includes social, creative, and human capital to inform site-selection decisions. This framework is applied to the Northwest Advanced Renewables Alliance project to assess community suitability for biofuel-related developments. This framework is the first to take all necessary community assets into account, providing insight into successful site selection beyond current models. The framework not only serves as a model for future biorefinery projects but also guides tasks that depend on informed location selection for success. PMID- 28884651 TI - Nonverbal contention and contempt in U.K. parliamentary oversight hearings on fiscal and monetary policy. AB - In parliamentary committee oversight hearings on fiscal policy, monetary policy, and financial stability, where verbal deliberation is the focus, nonverbal communication may be crucial in the acceptance or rejection of arguments proffered by policymakers. Systematic qualitative coding of these hearings in the 2010-15 U.K. Parliament finds the following: (1) facial expressions, particularly in the form of anger and contempt, are more prevalent in fiscal policy hearings, where backbench parliamentarians hold frontbench parliamentarians to account, than in monetary policy or financial stability hearings, where the witnesses being held to account are unelected policy experts; (2) comparing committees across chambers, hearings in the House of Lords committee yield more reassuring facial expressions relative to hearings in the House of Commons committee, suggesting a more relaxed and less adversarial context in the former; and (3) central bank witnesses appearing before both the Lords and Commons committees tend toward expressions of appeasement, suggesting a willingness to defer to Parliament. PMID- 28884652 TI - The incidence of pregnancy-related stroke: A systematic review and meta-analysis. AB - Background Stroke risk is increased during pregnancy, but estimates of pregnancy related stroke incidence vary widely. Aims A systematic review and meta-analysis was conducted to assess the incidence of stroke during pregnancy and the puerperium. Ovid Medline, EMBASE, and ISI Web of Science were searched for studies published between 1990 and January 2017 reporting stroke incidence during pregnancy and postpartum, from defined pregnancy populations. Pooled analyses were conducted using a random effects approach and expressed as an incidence rate per 100,000 pregnancies, with 95% confidence intervals. Subgroup analyses of stroke type and timing were conducted. Summary of review Eleven studies met inclusion criteria. Variation in estimated rates was noted based on geography and study methodology. The pooled crude rate of pregnancy-related stroke was 30.0 per 100,000 pregnancies (95% confidence interval 18.8-47.9). The pooled crude rates from nonhemorrhagic stroke (arterial and cerebral venous sinus thrombosis) were 19.9 (95% confidence interval 10.7-36.9) and from hemorrhage 12.2 (95% confidence interval 6.4-23.2) per 100,000 pregnancies. For studies separately reporting cerebral venous sinus thrombosis, the rates were roughly equal between ischemic stroke (12.2, 95% confidence interval 6.7-22.2), cerebral venous sinus thrombosis (9.1, 95% confidence interval 4.3-18.9), and hemorrhage (12.2, 95% confidence interval 6.4-23.2). The crude stroke rate for antenatal/perinatal stroke was 18.3 (95% confidence interval 11.9-28.2), and for postpartum stroke was 14.7 (95% confidence interval 8.3-26.1). Conclusions Stroke affects 30.0 per 100,000 pregnancies, with ischemia, cerebral venous sinus thrombosis, and hemorrhage causing roughly equal numbers and with highest risk peripartum and postpartum. Organized approaches to the management of this high-risk population, informed by existing evidence from stroke and obstetrical care are needed. PMID- 28884653 TI - Smartphone electrographic monitoring for atrial fibrillation in acute ischemic stroke and transient ischemic attack. AB - Rationale Paroxysmal atrial fibrillation is a common and preventable cause of devastating strokes. However, currently available monitoring methods, including Holter monitoring, cardiac telemetry and event loop recorders, have drawbacks that restrict their application in the general stroke population. AliveCorTM heart monitor, a novel device that embeds miniaturized electrocardiography (ECG) in a smartphone case coupled with an application to record and diagnose the ECG, has recently been shown to provide an accurate and sensitive single lead ECG diagnosis of atrial fibrillation. This device could be used by nurses to record a 30-s ECG instead of manual pulse taking and automatically provide a diagnosis of atrial fibrillation. Aims To compare the proportion of patients with paroxysmal atrial fibrillation detected by AliveCorTM ECG monitoring with current standard practice. Sample size 296 Patients. Design Consecutive ischemic stroke and transient ischemic attack patients presenting to participating stroke units without known atrial fibrillation will undergo intermittent AliveCorTM ECG monitoring administered by nursing staff at the same frequency as the vital observations of pulse and blood pressure until discharge, in addition to the standard testing paradigm of each participating stroke unit to detect paroxysmal atrial fibrillation. Study outcome Proportion of patients with paroxysmal atrial fibrillation detected by AliveCorTM ECG monitoring compared to 12-lead ECG, 24-h Holter monitoring and cardiac telemetry. Discussion Use of AliveCorTM heart monitor as part of routine stroke unit nursing observation has the potential to be an inexpensive non-invasive method to increase paroxysmal atrial fibrillation detection, leading to improvement in stroke secondary prevention. PMID- 28884654 TI - Controlled clinical trials of cell therapy in stroke: Meta-analysis at six months after treatment. AB - Background Cell therapy is promising in experimental studies and has been assessed only in a few studies on humans. Aims To evaluate the effect of cell therapy in humans. Methods We included clinical trials with a control group that reported safety and efficacy six months following treatment. Quality was evaluated and clinical scales data were extracted. Quantitative analysis was based on the standardized means difference (SMD). Among 28 trials published from 1995 to 2016, nine studies (194 patients; 191 controls) were eligible. Publication biases were assessed with the funnel plot and pre-specified explanatory variables were tested with a group analysis and a meta-regression. Results The overall quality was moderate. Cell therapy had a positive effect on the outcome (SMD: 0.57, 95% CI: 0.22-0.92; p = 0.002). The sensitivity analysis showed an upper level of effect size of 0.81 (95% CI: 0.34-1.27; p = 0.001) and a lower level of 0.455 (95% CI: 0.04-0.87; p = 0.03). None of the pre-specified explanatory variable was significantly correlated to outcome: age, ratio infarction/hemorrhage, delay from stroke to treatment, route of administration, cell type, randomization, and blinded outcome assessment. The significant heterogeneity (p = 0.03) was not explained by publication biases (p = 0.09) and was more likely due to methodological and quality differences between the trials. Conclusions This result suggests that cell therapy is beneficial in stroke and is expected to help in the designing of stem cells controlled clinical trials (CCT) in large populations. PMID- 28884655 TI - Screening for the presence of lipophilic marine biotoxins in shellfish samples using the neuro-2a bioassay. AB - The neuro-2a bioassay is considered as one of the most promising cell-based in vitro bioassays for the broad screening of seafood products for the presence of marine biotoxins. The neuro-2a assay has been shown to detect a wide array of toxins like paralytic shellfish poisons (PSPs), ciguatoxins, and also lipophilic marine biotoxins (LMBs). However, the neuro-2a assay is rarely used for routine testing of samples due to matrix effects that, for example, lead to false positives when testing for LMBs. As a result there are only limited data on validation and evaluation of its performance on real samples. In the present study, the standard extraction procedure for LMBs was adjusted by introducing an additional clean-up step with n-hexane. Recovery losses due to this extra step were less than 10%. This wash step was a crucial addition in order to eliminate false-positive outcomes due to matrix effects. Next, the applicability of this assay was assessed by testing a broad range of shellfish samples contaminated with various LMBs, including diarrhetic shellfish toxins/poisons (DSPs). For comparison, the samples were also analysed by LC-MS/MS. Standards of all regulated LMBs were tested, including analogues of some of these toxins. The neuro-2a cells showed good sensitivity towards all compounds. Extracts of 87 samples, both blank and contaminated with various toxins, were tested. The neuro 2a outcomes were in line with those of LC-MS/MS analysis and support the applicability of this assay for the screening of samples for LMBs. However, for use in a daily routine setting, the test might be further improved and we discuss several recommended modifications which should be considered before a full validation is carried out. PMID- 28884656 TI - Preface: Studies on Understanding and Anti-Tumor Agents of Reproductive Cancer Cells. PMID- 28884657 TI - The prevalence and progression of mild cognitive impairment among clinic and community populations: a systematic review and meta-analysis. AB - BACKGROUND: It has been reported that up to 42% of the population aged over 60 are affected by mild cognitive impairment (MCI) worldwide. This study aims to investigate the prevalence and progression of MCI through a meta-analysis. METHODS: We searched Embase and PubMed for relevant literature. Stable disease rate (SR), reversion rate (RR), dementia rate (DR), and Alzheimer's disease rate (AR) were used to evaluate the progression of MCI. The prevalence and progression rates were both obtained by reported percentile and indirect data analysis. Additionally, we carried out sensitivity analysis of each index by excluding some studies due to influence analysis with the most publication bias. RESULTS: Effect size (ES) was used to present adjusted overall prevalence (16%) and progression rates including SR (45%), RR (15%), DR (34%), and AR (28%) of MCI. Compared with clinic-based outcomes, MCI prevalence, SR, and RR are significantly higher in community, while DR and AR are lower. Despite significant heterogeneity found among the studies, no publication bias was observed. CONCLUSIONS: Age and gender were observed to be associated with MCI, in which age was considered as an impact factor for DR. The strong heterogeneity may result from variations in study design and baselines. Standardized MCI criteria were suggested to systematically evaluate MCI in the future. PMID- 28884658 TI - Sphingobacterium corticis sp. nov., isolated from bark of Populus * euramericana. AB - A Gram-stain negative, aerobic, non-motile bacterial strain, 23D10-4-9T, was isolated from symptomatic canker bark tissue of Populus * euramericana. The isolate grew between 4 and 35 degrees C, with optimal growth occurring at 25 degrees C. The species was positive for catalase and negative for oxidase activity. Nitrate was not reduced to nitrite. It showed activities toward beta galactosidase and beta-glucosidase. Citrate was not utilized. Acid was produced from d-glucose. The major fatty acids were iso-C15 : 0, C16 : 1omega7c and iso C17 : 0 3-OH. The main polar lipid profiles of the novel isolate included phosphatidylethanolamine, phospholipids and seven unknown lipids. The predominant menaquinone of the novel isolate was MK-7. The DNA G+C content was 40.6 mol%. 16S rRNA gene data revealed that the novel isolate shares the greatest sequence similarity with Sphingobacterium populi 7Y-4T (96.1 %). Based on phenotypic and genotypic characteristics, the isolate represents a novel species within the genus Sphingobacterium, for which the name Sphingobacteriumcorticis sp. nov. is proposed. The type strain is 23D10-4-9T (=CFCC 12640T=KCTC 42248T). PMID- 28884659 TI - Winogradskyella maritima sp. nov., isolated from seawater. AB - A novel bacterium, designated HME9613T, was isolated from seawater of the Yellow Sea in the Republic of Korea. Cells of strain HME9613T were Gram-stain-negative, aerobic, motile by gliding and rod-shaped. Strain HME9613T grew optimally at 25 degrees C, at pH 7 and in the presence of 3 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain HME9613T formed a lineage within the genus Winogradskyella of the family Flavobacteriaceae, and showed highest sequence similarity to Winogardskyella exilis 022-2-26T (95.9 %). The 16S rRNA gene sequence similarity between strain HME9613T and other Winogradskyella species ranged from 93.7 to 95.9 %. The major fatty acids were iso-C15 : 1 G, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and iso-C15 : 0. The polar lipid profile consisted of phosphatidylethanolamine, two unidentified aminolipids and two unidentified lipids. The predominant respiratory quinone was menaquinone-6 (MK-6). The DNA G+C content of the strain HME9613T was 38.4 mol%. On the basis of phenotypic, chemotaxonomic, phylogenetic and genotypic data, strain HME9613T represents a novel species within the genus Winogradskyella, for which the name Winogradskyella maritima sp. nov. is proposed. The type strain is HME9613T (=KCTC 42189T=CECT 8979T). PMID- 28884660 TI - Parasphingopyxis algicola sp. nov., isolated from a marine red alga Asparagopsis taxiformis and emended description of the genus Parasphingopyxis Uchida et al. 2012. AB - An aerobic, Gram-stain-negative, yellow-pigmented bacterium, designated strain ATAX6-5T, was isolated from a marine red alga, Asparagopsistaxiformis, in South Korea. Cells were non-motile rods showing catalase- and oxidase-positive reactions. Growth of strain ATAX6-5T was observed at 5-35 degrees C (optimum, 30 degrees C), at pH 6.0-9.5 (optimum, pH 7.0) and in the presence of 0-6.0 % (w/v) NaCl (optimum, 2 %). Ubiquinone-10 was detected as the sole isoprenoid quinone and C18 : 1omega7c, C16 : 0 and C17 : 1omega6c were identified as the major cellular fatty acids. Diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, phosphatidylcholine, an unknown phospholipid and four unknown glycolipids were detected as polar lipids. The G+C content of the genomic DNA was 60.4 mol%. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain ATAX6-5T formed a tight phylogenic lineage with Parasphingopyxis lamellibrachiae JAMH 0132T with a 100 % bootstrap value. Strain ATAX6-5T was most closely related to P. lamellibrachiae JAMH 0132T with a 96.9 % 16S rRNA gene sequence similarity. Based on phenotypic, chemotaxonomic and molecular features, strain ATAX6-5T clearly represents a novel species of the genus Parasphingopyxis, for which the name Parasphingopyxis algicola sp. nov. is proposed. The type strain is ATAX6-5T (=KACC 18993T=JCM 31719T). An emended description of the genus Parasphingopyxis is also proposed. PMID- 28884661 TI - Reclassification of Sphingopyxis contaminans as Sphingorhabdus contaminans comb. nov. and emended description of the genus Sphingorhabdus. AB - With the description of the genus Sphingorhabdus, the taxonomic position of Sphingopyxis contaminans was re-evaluated based on analyses of 16S rRNA gene sequences and phenotypic and chemotaxonomic characteristics. The results revealed that Sphingopyxis contaminans is clearly a member of the genus Sphingorhabdus and we proposed that Sphingopyxis contaminans(Subhash Y, Sasikala C, Ramana CV. Int J Syst Evol Microbiol 2014;64:2238-2243) should be reclassified as Sphingorhabduscontaminans comb. nov. An emended description of the genus Sphingorhabdus is also provided. PMID- 28884662 TI - Streptomyces cerasinus sp. nov., isolated from soil in Thailand. AB - A novel actinomycete, strain SR3-134T, belonging to the genus Streptomyces, was isolated from soil collected from the Sakaerat Environmental Research Station, Thailand Institute of Scientific and Technological Research, Nakhon Ratchasima Province, Thailand. The taxonomic position of the strain was characterized by using a polyphasic approach. ll-Diaminopimelic acid, glucose, mannose and ribose were detected in its whole-cell hydrolysates. The N-acyl type of muramic acid was acetyl. The menaquinones were MK-9(H8), MK-9(H6), MK-9(H4) and MK-9(H2). The predominant cellular fatty acids were anteiso-C15 : 0, iso-C16 : 0, C16 : 0, iso C15 : 0, anteiso-C17 : 0 and iso-C14 : 0. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannoside. blast analysis of the almost-complete 16S rRNA gene showed 98.7 % sequence similarities to Streptomyces lanatus JCM 4588T and Streptomyces psammoticus JCM 4434T. The DNA G+C content was 71.4 mol%. Strain SR3-134T showed low DNA-DNA relatedness (12.9+/-4.0-44.1+/-1.0 %) to S. lanatus JCM 4588T and S. psammoticus JCM 4434T. The new strain could also be distinguished from its closely related strains by differences in their phenotypic characteristics. The results of taxonomic analysis suggested that strain SR3-134T represented a novel species of the genus Streptomyces for which the name Streptomyces cerasinus sp. nov. is proposed. The type strain is SR3-134T (=TISTR 2494T=KCTC 39910T). PMID- 28884663 TI - Proposal of 'Candidatus Frankia californiensis', the uncultured symbiont in nitrogen-fixing root nodules of a phylogenetically broad group of hosts endemic to western North America. AB - The genus Frankia comprises a group of nitrogen-fixing actinobacteria that form root-nodule symbioses with perennial dicotyledonous plants in the nitrogen-fixing clade. These bacteria have been characterized phylogenetically and grouped into four clusters (clusters 1-4). Cluster 2 contains mostly uncultured strains that induce nodules on species of the genera Datisca (Datiscaceae), Coriaria (Coriariaceae), Ceanothus (Rhamnaceae) and several genera in the family Rosaceae (Cercocarpus, Chamaebatia, Dryas, Purshia), all of which except members of the genus Coriaria are present within the California Floristic Province (CFP) or neighbouring areas of western North America. Those strains occurring in western North America are genetically very closely related to one another, and genetically distinct from strains characterized from other locales. We hereby propose to create a 'Candidatus Frankia californiensis' species for those cluster 2 strains of the genus Frankia with both high genetic similarity and a geographical distribution in or near the CFP. PMID- 28884664 TI - Early nasopharyngeal microbial signature associated with severe influenza in children: a retrospective pilot study. AB - A few studies have highlighted the importance of the respiratory microbiome in modulating the frequency and outcome of viral respiratory infections. However, there are insufficient data on the use of microbial signatures as prognostic biomarkers to predict respiratory disease outcomes. In this study, we aimed to evaluate whether specific bacterial community compositions in the nasopharynx of children at the time of hospitalization are associated with different influenza clinical outcomes. We utilized retrospective nasopharyngeal (NP) samples (n=36) collected at the time of hospital arrival from children who were infected with influenza virus and had been symptomatic for less than 2 days. Based on their clinical course, children were classified into two groups: patients with mild influenza, and patients with severe respiratory or neurological complications. We implemented custom 16S rRNA gene sequencing, metagenomic sequencing and computational analysis workflows to classify the bacteria present in NP specimens at the species level. We found that increased bacterial diversity in the nasopharynx of children was strongly associated with influenza severity. In addition, patients with severe influenza had decreased relative abundance of Staphylococcus aureus and increased abundance of Prevotella (including P. melaninogenica), Streptobacillus, Porphyromonas, Granulicatella (including G. elegans), Veillonella (including V. dispar), Fusobacterium and Haemophilus in their nasopharynx. This pilot study provides proof-of-concept data for the use of microbial signatures as prognostic biomarkers of influenza outcomes. Further large prospective cohort studies are needed to refine and validate the performance of such microbial signatures in clinical settings. PMID- 28884665 TI - Prototheca blaschkeae subsp. brasiliensis subsp. nov., isolated from cow milk. AB - A strain of an achlorophyllic alga, named PR24T, was isolated from cow milk samples from the state of Minas Gerais, Brazil. Based on 18S rDNA, 28S rRNA, D1/D2 region of the LSU rDNA and SSU rRNA gene sequence similarities, this strain was found to be a member of the genus Prototheca and closely related to Protothecablaschkeae SAG2064T. However, the novel strain could easily be distinguished from recognized Prototheca species by internal transcribed spacer, species-specific PCR, single-strand conformation polymorphism-PCR analysis and phenotypic characteristics. The inability to grow in Sabouraud broth at pH 4.0 and the different cellular fatty acid composition clearly distinguished PR24T from the reference strain of P. blaschkeae. The combination of genotypic and phenotypic data indicates that strain PR24T represents a subspecies of P. blaschkeae, for which the name Prototheca blaschkeae subsp. brasiliensis subsp. nov. is proposed. The respective type strain is PR24T (=DSM 103592T=IHEM 26958T). PMID- 28884666 TI - ICTV Virus Taxonomy Profile: Picornaviridae. AB - The family Picornaviridae comprises small non-enveloped viruses with RNA genomes of 6.7 to 10.1 kb, and contains >30 genera and >75 species. Most of the known picornaviruses infect mammals and birds, but some have also been detected in reptiles, amphibians and fish. Many picornaviruses are important human and veterinary pathogens and may cause diseases of the central nervous system, heart, liver, skin, gastrointestinal tract or upper respiratory tract. Most picornaviruses are transmitted by the faecal-oral or respiratory routes. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Picornaviridae, which is available at www.ictv.global/report/picornaviridae. PMID- 28884667 TI - Influenza virus replication in macrophages: balancing protection and pathogenesis. AB - Macrophages are essential for protection against influenza A virus infection, but are also implicated in the morbidity and mortality associated with severe influenza disease, particularly during infection with highly pathogenic avian influenza (HPAI) H5N1 virus. While influenza virus infection of macrophages was once thought to be abortive, it is now clear that certain virus strains can replicate productively in macrophages. This may have important consequences for the antiviral functions of macrophages, the course of disease and the outcome of infection for the host. In this article, we review findings related to influenza virus replication in macrophages and the impact of productive replication on macrophage antiviral functions. A clear understanding of the interactions between influenza viruses and macrophages may lead to new antiviral therapies to relieve the burden of severe disease associated with influenza viruses. PMID- 28884668 TI - Borrelia lanei sp. nov. extends the diversity of Borrelia species in California. AB - The diversity of Borrelia species discovered in California appears to be particularly high. A divergent group of Borrelia strains collected from Ixodes ticks in California was described by Postic and co-workers and designated 'genomospecies 2' (Postic D, Garnier M, Baranton G. Int J Med Microbiol 2007;297:263-271; Postic D, Ras NM, Lane RS, Hendson M, Baranton G. J Clin Microbiol 1998;36:3497-3504). We performed multilocus sequence analysis (MLSA) using eight housekeeping loci (clpA, clpX, nifS, pepX, pyrG, recG, rplB and uvrA) on 12 strains of this Borreliagenospecies to confirm that these strains form a distinct group within the Borreliaburgdorferi s. l. complex (Margos G, Hojgaard A, Lane RS, Cornet M, Fingerle V et al.Ticks Tick Borne Dis 2010;1:151-158). Phylogenetic and genetic distance analyses based on sequences of the MLSA housekeeping genes corroborated the distinctness of this group; genetic distances to all other members of the B. burgdorferi s.l. complex were 96 % or lower. We propose the name Borrelia lanei sp. nov. for this genospecies in honor of Professor Robert S. Lane, University of California Berkeley, for his contributions to Borrelia and tick research. The type strain for Borrelia lanei sp. nov., strain CA28-91T, has been deposited to two culture collections (=DSM 17992T=CIP 109135T). PMID- 28884669 TI - Acinetobacter guangdongensis Feng et al. 2014 is a junior heterotypic synonym of Acinetobacter indicus Malhotra et al. 2012. AB - A draft whole-genome sequence was obtained for Acinetobacter guangdongensis strain KCTC 42012T and compared against those of the type strains of all Acinetobacter species with validly published names. High similarity was found to Acinetobacter indicus CCM 7832T (average nucleotide identity based on blast and digital DNA-DNA hybridization values of 96.3 and 70.4 %, respectively). In addition, the metabolic, physiological and chemotaxonomic features of KCTC 42012T were shown to be congruent with those of A. indicus. We conclude that Acinetobacter guangdongensisFeng et al. 2014 is a later heterotypic synonym of Acinetobacter indicus Malhotra et al. 2012. PMID- 28884670 TI - Basic Processes in Salmonella-Host Interactions: Within-Host Evolution and the Transmission of the Virulent Genotype. AB - Transmission and virulence are central aspects of pathogen evolution. However, in many cases their interconnection has proven difficult to assess by experimentation. Here we discuss recent advances from a mouse model for Salmonella diarrhea. Mouse models mimic the enhanced susceptibility of antibiotic treated individuals to nontyphoidal salmonellosis. In streptomycin-pretreated mice, Salmonella enterica subspecies 1 serovar Typhimurium efficiently colonizes the gut lumen and elicits pronounced enteropathy. In the host's gut, S. Typhimurium forms two subpopulations that cooperate to elicit disease and optimize transmission. The disease-causing subpopulation expresses a set of dedicated virulence factors (the type 3 secretion system 1 [TTSS-1]) that drive gut tissue invasion. The virulence factor expression is "costly" by retarding the growth rate and exposing the pathogen to innate immune defenses within the gut tissue. These costs are compensated by the gut inflammation (a "public good") that is induced by the invading subpopulation. The inflamed gut lumen fuels S. Typhimurium growth, in particular that of the TTSS-1 "off" subpopulation. The latter grows up to very high densities and promotes transmission. Thus, both phenotypes cooperate to elicit disease and ensure transmission. This system has provided an experimental framework for studying within-host evolution of pathogen virulence, how cooperative virulence is stabilized, and how environmental changes (e.g., antibiotic therapy) affect the transmission of the virulent genotype. PMID- 28884671 TI - Detection of fungal pathogens by a new broad range real-time PCR assay targeting the fungal ITS2 region. AB - PURPOSE: The rise in the incidence of fungal infections and the expanding spectrum of fungal pathogens make early and broad detection of fungal pathogens essential. In the present study, a panfungal real-time PCR assay for the broad range detection of fungal DNA (Fungi assay) in a wide variety of clinical specimens was developed. METHODOLOGY: Our in-house, HybProbe real-time PCR assay targets the ITS2 region of fungal DNA. The applicability was evaluated by testing 105 clinical samples from 98 patients with suspected fungal infection. Samples included tissue biopsies, paraffin embedded tissues, aspirates, EDTA anticoagulated blood, cerebrospinal fluids and bronchoalveolar lavages. RESULTS: Fungal pathogens were identified by the Fungi assay in 47 samples. In all of these cases, conventional methods and clinical data were also indicative for a fungal infection. Five samples were interpreted false negative. blast analyses of the amplicons derived from 11 samples revealed the presence of environmental fungal species while other tests and clinical data did not suggest a fungal infection. This fact might indicate contaminated samples. The remaining 42 samples were negative by the Fungi assay as well as the conventional methods and were therefore regarded as true negatives. Thus, sensitivity was 90.4 % and specificity 79.2 %. CONCLUSION: The Fungi assay improved the targeted diagnosis of fungal infections allowing pathogen identification in samples that were histologically positive but culture negative. For reliable diagnosis, results have to be interpreted in context with conventional methods and clinical data. PMID- 28884672 TI - Geofilum rhodophaeum sp. nov., isolated from coastal sediment. AB - A novel Gram-stain-negative, facultatively anaerobic, filamentous and rose-brown pigmented bacterium, designated strain HF401T, was isolated from marine sediment off the coast of Weihai, China. The isolate grew at temperatures between 4 and 45 degrees C (optimal growth at 33 degrees C), at pH 6.5-8.5 (optimal growth at pH 7.5) and with 0.5-6.0 % (w/v) NaCl (optimal growth at 3.0 %). The predominant menaquinone was menaquinone 7 (MK-7). The G+C content of the genomic DNA was 50.8 mol% (from high-performance liquid chromatography). The major fatty acids were iso-C15 : 0, C16:0, anteiso-C15 : 0 and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2OH). The major polar lipids were phosphatidylethanolamine, phospholipid and an unidentified lipid. Phylogenetic analysis of 16S rRNA gene sequences indicated that strain HF401T formed a distinct branch with Geofilum rubicundum JCM 15548T in the family Marinilabiliaceae. The most closely related strains of strain HF401T were Natronoflexuspectinivorans AP1T (96.2 % 16S rRNA gene sequence similarity), G. rubicundum JCM 15548T (96.2 %) and Alkalitaleasaponilacus SC/BZ-SP2T (96.0 %). Average nucleotide identity (ANI) values between strain HF401T and G. rubicundum JCM 15548T showed a relatedness of 71.3 % (ANIb) and 86.0 % (ANIm). The percentage of conserved proteins (POCP) value between strain HF401T and G. rubicundum JCM 15548T was 61.2 %. Based on polyphasic analysis, especially the phylogenetic relationships and the higher POCP value, strain HF401T is considered to represent a novel species in the genus Geofilum, for which the name Geofilum rhodophaeum sp. nov. is proposed. The type strain of Geofilum rhodophaeum is HF401T (KCTC 42595T=MCCC 1H00119T). PMID- 28884673 TI - Reclassification of Halothiobacillus hydrothermalis and Halothiobacillus halophilus to Guyparkeria gen. nov. in the Thioalkalibacteraceae fam. nov., with emended descriptions of the genus Halothiobacillus and family Halothiobacillaceae. AB - The genus Halothiobacillus contains four species of obligate autotrophs with validly published names, of which Halothiobacillus halophilus and Halothiobacillus hydrothermalis are very distant from the type species - on the basis of the 16S rRNA gene, they have 90.7 % and 90.9 % identity to that of the type species, Halothiobacillus neapolitanus. As these values fall below the Yarza cut-off for the rank of genus, and these two species also show no clear affiliation to the closely related genus Thioalkalibacter, a polyphasic study was undertaken to determine if they represent a separate genus. Unlike Halothiobacillus spp. sensu stricto, H. halophilus and H. hydrothermalis are halophilic (rather than halotolerant) and moderately alkaliphilic (rather than neutrophilic) and additionally do not produce tetrathionate as a detectable intermediate of thiosulfate metabolism, indicating some significant metabolic differences. On the basis of these data and of functional gene examination, it is proposed that they be circumscribed as a new genus Guyparkeria gen.nov, for which the type species is Guyparkeria halophila gen. nov., comb. nov. Additionally, Thioalkalibacter and Guyparkeria gen. nov. fall distant from the Halothiobacillaceae so the Thioalkalibacteraceae fam. nov. is proposed, for which Thioalkalibacter is the type genus. Emended descriptions of Halothiobacillus, Halothiobacillus neapolitanus and the Halothiobacillaceae are provided. PMID- 28884674 TI - Thalassotaleaprofundi sp. nov. isolated from a deep-sea seamount. AB - The Gram-stain-negative, rod-shaped, strictly aerobic, motile bacterial strain, designated YM155T, was isolated from a seamount near the Yap Trench in the tropical western Pacific. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain YM155T was related to the genus Thalassotalea and had highest 16S rRNA gene sequence similarities with the type strains of Thalassotalea piscium T202T (97.2 %) and Thalassotalea agariperforans M-M1T (97.2 %). The predominant cellular fatty acids were C17 : 1omega8c, summed feature 3 (composed of iso-C15 : 0 2-OH and/or C16 : 1omega7c) and iso-C16 : 0. Ubiquinone 8 (Q-8) was the respiratory quinone. The polar lipid profile contained phosphatidylglycerol, phosphatidylethanolamine, two unidentified phospholipids and one unidentified lipid. The genomic DNA G+C content of strain YM155T was 36.1 mol%. On the basis of the evidence presented in this study, strain YM155T represents a novel species of the genus Thalassotalea, for which we propose the name Thalassotalea profundi sp. nov. (type strain YM155T=KACC 18563T=CGMCC 1.15922T). PMID- 28884675 TI - Sphingomonas frigidaeris sp. nov., isolated from an air conditioning system. AB - A strictly aerobic Gram-stain-negative bacterium, designated strain KER25-10T, was isolated from a laboratory air conditioning system in South Korea. Cells were yellow-pigmented, non-motile rods showing catalase- and oxidase-positive reactions. The strain grew at pH 4.0-9.0 (optimum, pH 6.0-7.0) and 10-40 degrees C (optimum, 30 degrees C) and in the presence of 0-3 % (w/v) NaCl (optimum, 0 %). The G+C content of the genomic DNA was 65.1 mol%. Strain KER25-10T contained ubiquinone-10 (Q-10) as the predominant isoprenoid quinone and C16 : 0, C17 : 1omega6c, summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c) and summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c) as the major fatty acids. The major polar lipids were sphingoglycolipid, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine. Only spermidine was detected as the polyamine. Phylogenetic analysis based on 16S rRNA sequences indicated that strain KER25-10T formed a distinct phylogenetic lineage within the genus Sphingomonas of the family Sphingomonadaceae and the strain was most closely related to Sphingomonas kyeonggiense THG-DT81T with a 96.8 % 16S rRNA gene sequence similarity. On the basis of phenotypic, chemotaxonomic and molecular features, strain KER25-10T clearly represents a novel species of the genus Sphingomonas, for which the name Sphingomonas frigidaeris sp. nov. is proposed. The type strain is KER25-10T (=KACC 19285T=JCM 32053T). PMID- 28884676 TI - The MtrAB two-component system controls antibiotic production in Streptomyces coelicolor A3(2). AB - MtrAB is a highly conserved two-component system implicated in the regulation of cell division in the Actinobacteria. It coordinates DNA replication with cell division in the unicellular Mycobacterium tuberculosis and links antibiotic production to sporulation in the filamentous Streptomyces venezuelae. Chloramphenicol biosynthesis is directly regulated by MtrA in S. venezuelae and deletion of mtrB constitutively activates MtrA and results in constitutive over production of chloramphenicol. Here we report that in Streptomyces coelicolor, MtrA binds to sites upstream of developmental genes and the genes encoding ActII 1, ActII-4 and RedZ, which are cluster-situated regulators of the antibiotics actinorhodin (Act) and undecylprodigiosin (Red). Consistent with this, deletion of mtrB switches on the production of Act, Red and streptorubin B, a product of the Red pathway. Thus, we propose that MtrA is a key regulator that links antibiotic production to development and can be used to upregulate antibiotic production in distantly related streptomycetes. PMID- 28884677 TI - Spathaspora boniae sp. nov., a D-xylose-fermenting species in the Candida albicans/Lodderomyces clade. AB - Two yeast isolates producing asci-containing elongate ascospores with curved ends typical of the genus Spathaspora were isolated from rotting wood samples collected in an Atlantic rainforest ecosystem in Brazil. Phylogenetic analysis of the LSU rRNA gene D1/D2 domain sequences demonstrated that the strains represent a new species and placed it next to Candida blackwellae, in a clade that also contains Candida albicans and Candida dubliniensis. Other sequences of the ribosomal gene cluster supported same placementin the same clade, and a phylogenomic analysis placed this new species in an early emerging position relative to the larger C. albicans/Lodderomyces clade. One interpretation is that the genus Spathaspora is, in fact, paraphyletic. In conformity with this view, we propose the novel species Spathaspora boniae sp. nov. to accommodate the isolates. The type strain of Spathaspora boniae sp. nov. is UFMG-CM-Y306T (=CBS 13262T). The MycoBank number is MB 821297. A detailed analysis of xylose metabolism was conducted for the new species. PMID- 28884678 TI - Oryzihumus soli sp. nov., isolated from soil and emended description of the genus Oryzihumus. AB - A novel strain designated Aerobe-19T was isolated from a soil sample collected from a lawn located in Seoul National University in Korea. The cells were Gram stain-positive, aerobic, and coccus-shaped. Colonies were circular with entire edges, convex, opaque and pale yellow. The strain grew at 15-30 C (optimum, 30 C), pH 5.0-7.0 (optimum, 6.0) and in the presence of 0-0.5 % (w/v) NaCl. Phylogenetically, the strain was found to be closely related to members of the genus Oryzihumus and showed 16S rRNA gene sequence similarities of 96.4 and 96.3 % with Oryzihumus leptocrescens NRRL B-24347T and Oryzihumus terrae KACC 16543T, respectively. The major cellular fatty acids were anteiso-C17 : 0, iso-C15 : 0, anteiso-C15 : 0 and iso-C16 : 0. The predominant menaquinone was MK-8 (H4). The polar lipids profile revealed the presence of diphosphatidylglycerol, glycolipids, unknown amino-glycophospholipid, unknown phospholipid and unknown lipids. The peptidoglycan type was A1gamma. The DNA G+C content of this stain was 73.9 mol%. On the basis of data presented, strain Aerobe-19T is considered to represent a novel species of the genus Oryzihumus, for which the name Oryzihumus soli sp. nov. is proposed. The type strain is Aerobe-19T (=KACC 18485T =KCTC 39705T=NBRC 111450T). PMID- 28884679 TI - The integration of a macrophage-adapted live vaccine strain of equine infectious anaemia virus (EIAV) in the horse genome. AB - Integration is an important feature of retroviruses and retrovirus-based therapeutic transfection vectors. The non-primate lentivirus equine infectious anaemia virus (EIAV) primarily targets macrophages/monocytes in vivo. Investigation of the integration features of EIAVDLV121 strains, which are adapted to donkey monocyte-derived macrophages (MDMs), is of great interest. In this study, we analysed the integration features of EIAVDLV121 in equine MDMs during in vitro infection. Our previously published integration sites (IS) for EIAVFDDV13 in fetal equine dermal (FED) cells were also analysed in parallel as references. Sequencing of the host genomic regions flanking the viral IS showed that reference sequence (RefSeq) genes were preferentially targeted for integration by EIAVDLV121. Introns, AT-rich regions, long interspersed nuclear elements (LINEs) and DNA transposons were also predominantly biased toward viral insertion, which is consistent with EIAVFDDV13 integration into the horse genome in FED cells. In addition, the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, specifically gag junctions for EIAVDLV121 and tight junctions for EIAVFDDV13, are regulators of metabolic function, which is consistent with the common bioprocesses, specifically cell cycle and chromosome/DNA organization, identified by gene ontology (GO) analysis. Our results demonstrate that EIAV integration occurs in regions that harbour structural and topological features of local chromatin in both macrophages and fibroblasts. Our data on EIAV will facilitate further understanding of lentivirus infection and the development of safer and more effective gene therapy vectors. PMID- 28884680 TI - Thigmo Responses: The Fungal Sense of Touch. AB - The growth and development of most fungi take place on a two-dimensional surface or within a three-dimensional matrix. The fungal sense of touch is therefore critical for fungi in the interpretation of their environment and often signals the switch to a new developmental state. Contact sensing, or thigmo-based responses, include thigmo differentiation, such as the induction of invasion structures by plant pathogens in response to topography; thigmonasty, where contact with a motile prey rapidly triggers its capture; and thigmotropism, where the direction of hyphal growth is guided by physical features in the environment. Like plants and some bacteria, fungi grow as walled cells. Despite the well demonstrated importance of thigmo responses in numerous stages of fungal growth and development, it is not known how fungal cells sense contact through the relatively rigid structure of the cell wall. However, while sensing mechanisms at the molecular level are not entirely understood, the downstream signaling pathways that are activated by contact sensing are being elucidated. In the majority of cases, the response to contact is complemented by chemical cues and both are required, either sequentially or simultaneously, to elicit normal developmental responses. The importance of a sense of touch in the lifestyles and development of diverse fungi is highlighted in this review, and the candidate molecular mechanisms that may be involved in fungal contact sensing are discussed. PMID- 28884681 TI - Resource depletion through primate stone technology. AB - Tool use has allowed humans to become one of the most successful species. However, tool-assisted foraging has also pushed many of our prey species to extinction or endangerment, a technology-driven process thought to be uniquely human. Here, we demonstrate that tool-assisted foraging on shellfish by long tailed macaques (Macaca fascicularis) in Khao Sam Roi Yot National Park, Thailand, reduces prey size and prey abundance, with more pronounced effects where the macaque population size is larger. We compared availability, sizes and maturation stages of shellfish between two adjacent islands inhabited by different-sized macaque populations and demonstrate potential effects on the prey reproductive biology. We provide evidence that once technological macaques reach a large enough group size, they enter a feedback loop - driving shellfish prey size down with attendant changes in the tool sizes used by the monkeys. If this pattern continues, prey populations could be reduced to a point where tool assisted foraging is no longer beneficial to the macaques, which in return may lessen or extinguish the remarkable foraging technology employed by these primates. PMID- 28884682 TI - MicroCT-based phenomics in the zebrafish skeleton reveals virtues of deep phenotyping in a distributed organ system. AB - Phenomics, which ideally involves in-depth phenotyping at the whole-organism scale, may enhance our functional understanding of genetic variation. Here, we demonstrate methods to profile hundreds of phenotypic measures comprised of morphological and densitometric traits at a large number of sites within the axial skeleton of adult zebrafish. We show the potential for vertebral patterns to confer heightened sensitivity, with similar specificity, in discriminating mutant populations compared to analyzing individual vertebrae in isolation. We identify phenotypes associated with human brittle bone disease and thyroid stimulating hormone receptor hyperactivity. Finally, we develop allometric models and show their potential to aid in the discrimination of mutant phenotypes masked by alterations in growth. Our studies demonstrate virtues of deep phenotyping in a spatially distributed organ system. Analyzing phenotypic patterns may increase productivity in genetic screens, and facilitate the study of genetic variants associated with smaller effect sizes, such as those that underlie complex diseases. PMID- 28884683 TI - Characterisation of the biflavonoid hinokiflavone as a pre-mRNA splicing modulator that inhibits SENP. AB - We have identified the plant biflavonoid hinokiflavone as an inhibitor of splicing in vitro and modulator of alternative splicing in cells. Chemical synthesis confirms hinokiflavone is the active molecule. Hinokiflavone inhibits splicing in vitro by blocking spliceosome assembly, preventing formation of the B complex. Cells treated with hinokiflavone show altered subnuclear organization specifically of splicing factors required for A complex formation, which relocalize together with SUMO1 and SUMO2 into enlarged nuclear speckles containing polyadenylated RNA. Hinokiflavone increases protein SUMOylation levels, both in in vitro splicing reactions and in cells. Hinokiflavone also inhibited a purified, E. coli expressed SUMO protease, SENP1, in vitro, indicating the increase in SUMOylated proteins results primarily from inhibition of de-SUMOylation. Using a quantitative proteomics assay we identified many SUMO2 sites whose levels increased in cells following hinokiflavone treatment, with the major targets including six proteins that are components of the U2 snRNP and required for A complex formation. PMID- 28884684 TI - Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells. AB - Genetic analysis has revealed that the dual specificity protein kinase DYRK1A has multiple roles in the development of the central nervous system. Increased DYRK1A gene dosage, such as occurs in Down syndrome, is known to affect neural progenitor cell differentiation, while haploinsufficiency of DYRK1A is associated with severe microcephaly. Using a set of known and newly synthesized DYRK1A inhibitors, along with CRISPR-mediated gene activation and shRNA knockdown of DYRK1A, we show here that chemical inhibition or genetic knockdown of DYRK1A interferes with neural specification of human pluripotent stem cells, a process equating to the earliest stage of human brain development. Specifically, DYRK1A inhibition insulates the self-renewing subpopulation of human pluripotent stem cells from powerful signals that drive neural induction. Our results suggest a novel mechanism for the disruptive effects of the absence or haploinsufficiency of DYRK1A on early mammalian development, and reveal a requirement for DYRK1A in the acquisition of competence for differentiation in human pluripotent stem cells. PMID- 28884686 TI - Turning taboos into action. PMID- 28884685 TI - Standardized mean differences cause funnel plot distortion in publication bias assessments. AB - Meta-analyses are increasingly used for synthesis of evidence from biomedical research, and often include an assessment of publication bias based on visual or analytical detection of asymmetry in funnel plots. We studied the influence of different normalisation approaches, sample size and intervention effects on funnel plot asymmetry, using empirical datasets and illustrative simulations. We found that funnel plots of the Standardized Mean Difference (SMD) plotted against the standard error (SE) are susceptible to distortion, leading to overestimation of the existence and extent of publication bias. Distortion was more severe when the primary studies had a small sample size and when an intervention effect was present. We show that using the Normalised Mean Difference measure as effect size (when possible), or plotting the SMD against a sample size-based precision estimate, are more reliable alternatives. We conclude that funnel plots using the SMD in combination with the SE are unsuitable for publication bias assessments and can lead to false-positive results. PMID- 28884687 TI - Questions on asparaginase-associated pancreatitis. PMID- 28884688 TI - Liquorice: a treatment for all sorts? PMID- 28884689 TI - While We Still Have Time. PMID- 28884690 TI - "Death is an adventure": the power of terminal diagnosis. PMID- 28884691 TI - Correction to Lancet Oncol 2017; 18: 1182-91. PMID- 28884692 TI - Why is survival after pembrolizumab affected by previous radiotherapy? PMID- 28884693 TI - Why is survival after pembrolizumab affected by previous radiotherapy? - Authors' reply. PMID- 28884694 TI - Fasting conditions in clinical oncology trials and drug labelling. PMID- 28884695 TI - Fasting conditions in clinical oncology trials and drug labelling - Authors' reply. PMID- 28884696 TI - Primary medical therapy for BRAFV600E-mutant melanoma brain metastases-is this good enough? PMID- 28884698 TI - Correction to Lancet Oncol 2017; 18: 1274-84. PMID- 28884697 TI - Primary medical therapy for BRAFV600E-mutant melanoma brain metastases-is this good enough? - Authors' reply. PMID- 28884699 TI - Correction to Lancet Oncol 2017; 18: 917-28. PMID- 28884700 TI - Correction to Lancet Oncol 2017; 18: 1040-48. PMID- 28884701 TI - Palliative care in Africa: a scoping review from 2005-16. AB - Since the last comprehensive review on the development of national palliative care in Africa was undertaken 12 years ago, in 2005, we did a scoping review of peer-reviewed, published articles on palliative care development between 2005-16 for each African country. The scoping review was conducted by assessing the medical literature and including local expert recommendations of suggested articles. We did a basic quality assessment of the articles using the journals' impact factor, journal quartile, and the number of citations as suitable metrics for quality consideration. Articles published in English, Spanish, Portuguese, and French that mentioned at least one dimension of WHO's palliative care public health strategy (implementation of services, education, policies, or medicine availability) and vitality (activity by professionals or advocates) were included. Of the 518 articles found, 49 met the inclusion criteria. Information on 26 (48%) of 54 African countries was found. Most services were concentrated in Kenya, South Africa, and Uganda, and 14 (26%) countries showed an increase in services during this timeframe. Stand-alone palliative care policies exist in Malawi, Mozambique, Rwanda, Swaziland, Tanzania, and Zimbabwe. Postgraduate diplomas in palliative care are available in Kenya, South Africa, Uganda, and Tanzania. Restricted access to opioids, prescriber restriction laws, and a low prevalence of morphine use remain common barriers to adequate palliative care provision. Although information on palliative care is unevenly distributed, the available information showed an increased development of palliative care services in a subset of African countries. Despite this growth, however, there is still minimal to no identified palliative care development in most African countries. PMID- 28884702 TI - Radiotherapy for the treatment of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma is an aggressive disease that continues to be associated with poor outcomes. Although, traditionally this disease is considered to be resistant to radiotherapy, more recent evidence suggests that radiotherapy can produce positive outcomes. Over the past 15 years, the development of new, highly conformal radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), has enabled investigators to optimise the delivery of high-dose radiotherapy to the whole of the hemithorax. Prospective single-arm trials have shown that the median survival of patients who have completed high-dose hemithoracic radiotherapy after extrapleural pneumonectomy could reach 23.9-39.4 months independent of the chemotherapeutic response, suggesting that IMRT could potentially have an intrinsic benefit to this subset of patients. These observations have led to a change in practice, with the introduction of adjuvant pleural IMRT after pleurectomy-decortication and the development of induction accelerated hemithoracic IMRT followed by extrapleural pneumonectomy. This Review focuses on recent observations on the role of radiotherapy in the treatment of malignant pleural mesothelioma, with particular emphasis on the results of clinical trials that evaluate the role of high-dose hemithoracic radiotherapy. PMID- 28884703 TI - Definition and recommendations for advance care planning: an international consensus supported by the European Association for Palliative Care. AB - Advance care planning (ACP) is increasingly implemented in oncology and beyond, but a definition of ACP and recommendations concerning its use are lacking. We used a formal Delphi consensus process to help develop a definition of ACP and provide recommendations for its application. Of the 109 experts (82 from Europe, 16 from North America, and 11 from Australia) who rated the ACP definitions and its 41 recommendations, agreement for each definition or recommendation was between 68-100%. ACP was defined as the ability to enable individuals to define goals and preferences for future medical treatment and care, to discuss these goals and preferences with family and health-care providers, and to record and review these preferences if appropriate. Recommendations included the adaptation of ACP based on the readiness of the individual; targeting ACP content as the individual's health condition worsens; and, using trained non-physician facilitators to support the ACP process. We present a list of outcome measures to enable the pooling and comparison of results of ACP studies. We believe that our recommendations can provide guidance for clinical practice, ACP policy, and research. PMID- 28884704 TI - Hypoglossal paresis caused by a solitary breast cancer metasasis at the basal skull. PMID- 28884705 TI - Cryptochrome-1 Gene Expression is a Reliable Prognostic Indicator in Egyptian Patients with Chronic Lymphocytic Leukemia: A Prospective Cohort Study AB - Objective: Traditional prognostic factors have proved insufficient to account for heterogeneity in the clinical behavior of chronic lymphocytic leukemia (CLL). Cryptochrome-1 (CRY-1) is a circadian clock gene essential in maintaining the circadian rhythm and regulating cell proliferation. We evaluated CRY-1 gene expression in CLL and addressed its putative role as a prognostic indicator for the clinical course of CLL. Materials and Methods: A total of 100 CLL patients at diagnosis were studied for CRY-1 gene expression by real-time reverse transcription polymerase chain reaction and were followed for assessment of time to first treatment (TFT). Results: CRY-1 was expressed in 94% of the CLL patients at diagnosis. The median CRY-1 relative gene expression level (0.006) stratified patients into high and low expression groups. Forty of 100 (40%) CLL patients showed high CRY-1, 54/100 (54%) showed low CRY-1, and 6/100 (6%) had undetectable CRY-1 gene expression. High CRY-1 gene expression was concordant with CD38+, Zap 70+, and double CD38+Zap-70+ expression; unfavorable/intermediate cytogenetics; unmutated immunoglobulin heavy-chain variable-region gene; and diffuse marrow infiltration. The high CRY-1 gene expression patient group exhibited shorter TFT than the patients with low CRY-1 gene expression. A Cox proportional hazard regression model identified CRY-1 gene expression to be independently predictive for TFT. Conclusion: CRY-1 is differentially expressed among CLL patients, stratifying them into low-risk and high-risk groups. CRY-1 gene expression could constitute a reliable prognostic indicator for CLL progression, complementing the role of standard well-established prognostic factors. CRY-1 gene expression could be employed as a prognostic indicator for disease progression during the initial prognostic work-up and follow-up for CLL patients. PMID- 28884707 TI - Review of medical radiography and tomography with proton beams. AB - The use of hadron beams, especially proton beams, in cancer radiotherapy has expanded rapidly in the past two decades. To fully realize the advantages of hadron therapy over traditional x-ray and gamma-ray therapy requires accurate positioning of the Bragg peak throughout the tumor being treated. A half century ago, suggestions had already been made to use protons themselves to develop images of tumors and surrounding tissue, to be used for treatment planning. The recent global expansion of hadron therapy, coupled with modern advances in computation and particle detection, has led several collaborations around the world to develop prototype detector systems and associated reconstruction codes for proton computed tomography (pCT), as well as more simple proton radiography, with the ultimate intent to use such systems in clinical treatment planning and verification. Recent imaging results of phantoms in hospital proton beams are encouraging, but many technical and programmatic challenges remain to be overcome before pCT scanners will be introduced into clinics. This review introduces hadron therapy and the perceived advantages of pCT and proton radiography for treatment planning, reviews its historical development, and discusses the physics related to proton imaging, the associated experimental and computation issues, the technologies used to attack the problem, contemporary efforts in detector and computational development, and the current status and outlook. PMID- 28884708 TI - Dual-echo ASL based assessment of motor networks: a feasibility study. AB - OBJECTIVE: Dual-echo arterial spin labeling (DE-ASL) technique has been recently proposed for the simultaneous acquisition of ASL and blood-oxygenation-level dependent (BOLD)-functional magnetic resonance imaging (fMRI) data. The assessment of this technique in detecting functional connectivity at rest or during motor and motor imagery tasks is still unexplored both per-se and in comparison with conventional methods. The purpose is to quantify the sensitivity of the DE-ASL sequence with respect to the conventional fMRI sequence (cvBOLD) in detecting brain activations, and to assess and compare the relevance of node features in decoding the network structure. APPROACH: Thirteen volunteers were scanned acquiring a pseudo-continuous DE-ASL sequence from which the concomitant BOLD (ccBOLD) simultaneously to the ASL can be extracted. The approach consists of two steps: (i) model-based analyses for assessing brain activations at individual and group levels, followed by statistical analysis for comparing the activation elicited by the three sequences under two conditions (motor and motor imagery), respectively; (ii) brain connectivity graph-theoretical analysis for assessing and comparing the network models properties. MAIN RESULTS: Our results suggest that cvBOLD and ccBOLD have comparable sensitivity in detecting the regions involved in the active task, whereas ASL offers a higher degree of co localization with smaller activation volumes. The connectivity results and the comparative analysis of node features across sequences revealed that there are no strong changes between rest and tasks and that the differences between the sequences are limited to few connections. SIGNIFICANCE: Considering the comparable sensitivity of the ccBOLD and cvBOLD sequences in detecting activated brain regions, the results demonstrate that DE-ASL can be successfully applied in functional studies allowing to obtain both ASL and BOLD information within a single sequence. Further, DE-ASL is a powerful technique for research and clinical applications allowing to perform quantitative comparisons as well as to characterize functional connectivity. PMID- 28884709 TI - Hydrothermal Synthesis of SnQ (Q=Te, Se, S) and Their Thermoelectric Properties. AB - Lead-free IV-VI semiconductors SnQ (Q=Te, Se, S) are deemed as promising thermoelectric materials. In this work, we designed a hydrothermal route to selectively synthesize single phase SnTe, SnSe and SnS nanopowders. For all three samples, the phase structure were characterized by X-ray diffraction, SnTe particles with octahedron structure and SnSe/SnS particles with plate-like shape were observed by field emission scanning electron microscopy and transmission electron microscopy, the formation mechanism was discussed in detail. Then, SnTe, SnSe and SnS nanopowders were densified by spark plasma sintering for investigating thermoelectric properties. It was noticed that SnSe and SnS exhibited remarkably anisotropy in both electrical and thermal properties attributed to the layered crystal structure. The highest ZT values 0.79 at 873 K, 0.21 at 773 K, and 0.13 at 773 K were achieved for SnTe, SnSe and SnS bulk samples, respectively. PMID- 28884706 TI - Biological Features of Bone Marrow Mesenchymal Stromal Cells in Childhood Acute Lymphoblastic Leukemia. AB - OBJECTIVE: Mesenchymal stromal cells (MSCs) have a supportive role in hematopoiesis and as components of the bone marrow (BM) microenvironment may present alterations during acute lymphoblastic leukemia (ALL) and be affected by chemotherapeutic agents. We examined the biological and functional characteristics of MSCs in ALL diagnosis and treatment and their effect on MSC qualitative properties. MATERIALS AND METHODS: Immunophenotypic characterization, evaluation of clonogenicity, and proliferative capacity were measured. Apoptotic features, cell-cycle analysis, and stromal cell-derived factor 1alpha and angiopoietin-1 levels in MSC supernatant at diagnosis and in different phases of treatment were assessed. Chemotherapy was administered according to the Berlin Frankfurt-Munster-2000 protocol. BM samples from children with solid tumors without BM involvement were used as the control group. RESULTS: The morphology, the immunophenotypic profile, and the apoptotic characteristics of the MSCs were not affected by leukemia. The secretion of factors involved in the trafficking of hematopoietic cells in the BM seems to be upregulated at diagnosis in comparison to the treatment phases. MSCs are influenced by the disease in terms of their functional characteristics such as clonogenicity and proliferation rate. These effects cease as soon as treatment is initiated. Chemotherapy does not seem to exert any effect on any of the MSC features examined. CONCLUSION: MSCs from children with ALL are affected by their interaction with the leukemic environment, but this phenomenon ceases upon treatment initiation, while no effect is observed by chemotherapy itself. PMID- 28884710 TI - Atmospheric pulsed laser deposition and thermal annealing of plasmonic silver nanoparticle films. AB - A new method for pulsed laser deposition of plasmonic silver nanoparticle (NP) films in flowing gas at atmospheric pressure is described. The ablation was done using an excimer laser at 248 nm. Fast optical imaging shows that the ablation plume is captured by the flowing gas, and is expected to form a NP aerosol, which is carried 5-20 mm to the substrate. The dependence of the deposition rate on laser fluence, gas flow velocity, and target-substrate distance was investigated using electron microscopy and absorption spectroscopy of the deposited films. The NP films were annealed in argon and hydrogen at 400 degrees C, and in air for temperatures in the range 200 degrees C-900 degrees C, leading to strong enhancement, and narrowing of the surface plasmon resonance. The films were used for surface enhanced Raman spectroscopy of a 10-5 molar solution of Rhodamine 6G; films annealed in air at 400 degrees C were five times more sensitive than the as-deposited films. PMID- 28884711 TI - [Clinical polymorphism of amyotrophic lateral sclerosis]. AB - AIM: To clarify clinical polymorphism of amyotrophic lateral sclerosis (ALS). MATERIAL AND METHODS: The study was based on records of a hospital personalized register. Ninety-four patients, aged from 25 to 81 years, diagnosed with ALS according to El Escorial criteria were included. Electromyography and, if necessary, transcranial magnetic stimulation and magnetic-resonance tomography were used to confirm the diagnosis. Disease progression was assessed with the ARSFRS. Age at disease onset, progression rate and duration of survival of patients, rare symptoms of ALS ('extramotor'), time for palliative care (gastrostomy, non-invasive and invasive lung ventilation) and provision of the care to the patient, family history were recorded in a specially designed questionnaire. RESULTS: Most of the patients had sporadic ALS, only two familial cases were identified. Spinal onset ALS was found in 66.0% of the patients, bulbar onset in 29.8%, diffuse onset (spinal and bulbar motor neurons were affected simultaneously) in 4.2%. Moderate ALS progression was observed in 42.6% of the patients, mean time till death was 3.0+/-1.2 years. A slow progression was found in patients with cervical, low back and bulbar onset. A rapid and even 'momentary' type of progression was in diffuse and breast onset. An extremely slow progression with the long-term hospital treatment and survival >5 years was found in 9.7%. Rare ALS symptoms were represented by specific cognitive and psychological impairments, a type of frontal/temporal dysfunction, but only 5 (5.3%) patients were diagnosed with ALS-dementia. Signs of pathological muscle fatigue (myasthenic syndrome) were identified in 18 (19.1%), extrapyramidal disorders in 5 (5.3%), coordination disorders in 4 (4.3%), pain in 12 (12.8%), sensory symptoms in 5 (5.3%) of the patients. CONCLUSION: ALS is a multisystemic neurodegeneration disease though the progressive motor neuron death determines the fatal outcome. PMID- 28884712 TI - [Clinical and neurovisualization characteristics of apathetic depression]. AB - AIM: To study apathetic depression first diagnosed at late age and identify its relation to cognitive and social dysfunction as well as to morphological and functional changes in the brain. MATERIAL AND METHODS: Thirty-two patients at the age above 60 years with newly diagnosed depressive episode and 15 healthy age matched volunteers were included in the study. All patients were divided into two groups by the score on the Apathy scale (AS): >14 - depression with apathy (n=21), <14 - depression without apathy (n=11). Patients were examined using psychometric methods (HAMD, GDS, AS, SHAPS, SF-36, MoCA-test), neuroimaging (MRI scanner with a magnetic field strength of 1.5 Tesla - EXCEL ART Vantage Atlas-X, Toshiba, Japan) and statistical data analysis. RESULTS AND CONCLUSION: Apathy component in clinical depression reflects a tendency towards the increase in depression severity and cognitive deterioration that results in the substantial lowering of quality of life and correlates with cerebrovascular changes, decrease in gray and white matter volume and mean cortical thickness of large hemispheres. PMID- 28884713 TI - [Mental disorders in patients with breast cancer: a differentiated approach to the study of nozogeny]. AB - AIM: To study mental disorders in patients with breast cancer (BC) at different stages of the disease taking into account premorbid characteristics and psychosomatic correlations in their development. MATERIAL AND METHODS: The study included 82 patients with histologically confirmed BC. The first group consisted of 30 patients (mean age 49.7+/-11.1 years) with the first established diagnosis of BC and mental disorders caused by somatic disease (ICD-10 F40-F48, stress related neurotic and somatoform disorders). The second group included 52 patients (mean age 56.8+/-6.7 years) with illness duration and follow-up >=3 years (17 years in some cases) with signs of personality disorder (PD) according to ICD-10 F62. Clinical/pschopathological, follow-up and statistical methods were used. RESULTS AND CONCLUSION: Mental disorders are represented by two nosologic categories: nosogenic reactions and pathological personality. Manifestation of a nozogeny reaction is closely correlated with premorbid personality characteristics. Anxious - depressive nozogenic reaction (n=17) is strongly correlated with the anxious type of personality accentuation and weakly correlated with personality characteristics of the affective (bipolar) range. Anxious-nozogenic dissociative response (n=9) was characteristic of hysterical and expansive schizotypal PD with a significant direct correlation with constitutional hyperthymia. Anxiety - hypomanic nozogeny response (n=4) was observed in schizotypal PD correlated with symptoms of persistent hyperthymia. Five types of PD are formed in the follow-up period: hypochondriacal dysthymia, 'paranoia struggle', 'aberrant hypochondria', hypomanic endoform response with the phenomenon of post-traumatic growth and 'new life'. PMID- 28884714 TI - [Therapeutic monitoring and prediction of the efficacy of neurotrophic treatment in patients with amnestic type of mild cognitive impairment]. AB - AIM: To perform therapeutic monitoring and prediction of the neurotrophic therapy efficacy in patients with amnestic type of mild cognitive impairment (aMCI) in a model of course cerebrolysin therapy. MATERIAL AND METHODS: The study involved a group of 19 elderly patients who met the diagnostic criteria of aMCI. All patients received a course of neurotrophic therapy consisting of 20 intravenous infusions of cerebrolysin (30 ml of cerebrolysin in 100 ml of isotonic sodium chloride solution). To assess the therapy efficacy, psychometric scales (CGI, MMSE, MoCA-test, MDRS, FAB, Clock Drawing Test, BNT, Word Recall test, delayed reproduction of 10 words, naming digits in a direct and reverse order) were used at 0, 4, 10 and 26 weeks of the study. Antibodies to p75 neurotrophin receptor (NTR) were measured by ELISA in blood serum of 19 patients before cerebrolysin therapy and after 10 and 26 weeks of treatment. RESULTS AND CONCLUSION: The study showed that aMCI patients had an increased level of antibodies against P75NTR that was significantly decreased after 5.5 month of cerebrolysin treatment. Therefore, it can be a potential biomarker of long-term therapeutic effect of cerebrolysin treatment in aMCI patients. The modified fragment 155-164 of P75 NTR determined in the serum of patients can be an effective indicator for monitoring and predicting the efficacy of long-term neurotrophic therapy. PMID- 28884715 TI - [Multicenter observational program for evaluation of the effectiveness of the recognan (citicoline) in the correction of cognitive impairment in patients with chronic cerebrovascular pathology]. AB - AIM: To study the efficacy and safety of recognan (citicoline) in the treatment of cognitive and depressive disorders in chronic cerebrovascular pathology (chronic brain ischemia) developed in patients with arterial hypertension and/or atherosclerosis. MATERIAL AND METHODS: Seven hundred and thirty-six patients with cerebrovascular pathology, cognitive impairment and mild dementia were examined. The sample included 279 (37.9%) men and 457 (62.1%) women aged from 35 to 80 years (mean age 64.5+/-8.7 years). The drug recognan ('Gerofarm', Russia) was administered in the dose of 1000 mg daily during 30 days. Recovery of cognitive functions was assessed with MSSE, correction of visual/spatial coordination with CDT, depression severity with MGDS. RESULTS: The improvement of cognitive function, memory and visual/spatial coordination, decrease in depression severity were observed during the treatment. CONCLUSION: Recognan reduced cognitive dysfunction and disturbances of visual/spatial coordinationas well as had a positive effect on the emotional sphere decreasing the level of depression. PMID- 28884716 TI - [Efficacy of different doses of botox in treatment of chronic migraine]. AB - AIM: To compare the efficacy of botox used in doses of 155 U and 195 U for preventive treatment of chronic migraine (CM). MATERIAL AND METHODS: Thirty-nine women with CM were stratified into two groups according to the dose of botox. The duration of the study was 9 month, patient's state was assessed before treatment and after repeated injections (every 3 month). RESULTS AND CONCLUSION: With regard to the frequency of migraine attacks, the 1st and 2nd injections of botox were equally effective. After the 3rd injection, the frequency was significantly lower in group 2 (195 U). After 2nd and 3rd injections, an effect on patient's adaptation assessed with the MIDAS and patient's satisfaction with treatment were higher. The results suggest the dose-dependent efficacy of repeated injections of botox. The dose of 195 U can be recommended in preventive treatment of CM as more effective. PMID- 28884717 TI - [Clinical and emotional/behavioral characteristics of acute and chronic low-back pain]. AB - AIM: To analyze clinical and emotional/behavioral characteristics of acute and chronic low-back pain that significantly affect quality-of-life. MATERIAL AND METHODS: Fifty-three patients with pain syndromes were examined using the painDETECT questionnaire, the Visual Analog Scale for Pain, The McGill Pain Questionnaire and laboratory and instrumental methods of neurological assessment. RESULTS AND CONCLUSION: A 'picture of the patient with acute and chronic pain' was built, a group of patients with neuropathic component of pain was described. The size of herniated discs was not correlated with VAS assessments and the neuropathic component had a mild effect on pain intensity. The significant correlation was found between the severity of pain and coping strategies for pain. The results indicate the importance of effective and safety pain stopping, in particular at the acute stage, to prevent pain chronification. A drug of choice in case of intensive pain and marked nociceptive component are highly effective and safe nonsteroidal anti-inflammatory drugs, in particular etoricoxib (Arcoxia), a selective COX-2 inhibitor. PMID- 28884718 TI - [Dynamics of indicators of the functional state of the central nervous system in Navy operators treated with cytoflavin after a long working cycle]. AB - AIM: To evaluate the efficacy of cytoflavin in the correction of functional state and working ability of Navy operators after a long working cycle. MATERIAL AND METHODS: Results of the examination of 25 Navy operators, aged from 27 to 42 years, were analyzed at baseline and after treatment with cytoflavin. The Rusalov questionnaire for Individuality Formal Dynamic Properties and EEG were used to evaluate the state of participants. RESULTS AND CONCLUSION: The results demonstrate the ability of cytoflavin to exert the positive effect on the energetic component of the functional state of Navy operators after a long working cycle, increasing the psychomotor activity and optimizing the spontaneous electrical activity of the brain. The activation of energetic potential, physical activity and emotional reactions by cytoflavin is correlated with the growth of the central nervous system reserves in Navy operators treated after a long working cycle. PMID- 28884719 TI - [Vestibular migraine: diagnostic difficulties and treatment optimization]. AB - AIM: The study aimed at showing actual information about vestibular migraine and presenting different features of vestibular migraine for prevention of diagnostic mistakes and choosing an effective treatment. MATERIAL AND METHODS: Fifty patients with vestibular migraine were diagnosed according to the International Classification of Headache Disorders 3rd edition and examined in a neurological department. RESULTS: Problems with outpatient diagnosis and treatment were found. Many patients were not diagnosed correctly and, therefore, did not receive effective management of vestibular migraine. All clinical features, information of disease history and different objective signs were important for differential diagnosis with other types of dizziness. Management according to guidelines for migraine treatment and recent research of vestibular migraine showed its efficiency for patients. CONCLUSION: Spreading of actual information about vestibular migraine is important due to its underdiagnosis. Knowledge of clinical features is helpful for diagnosis and differential diagnosis. Treatment approaches according to guidelines and last research should be used. PMID- 28884720 TI - [Etiopathogenetic factors of peripheral neuropathic pain in rheumatoid arthritis]. AB - AIM: To determine a neuropathic component of pain and define its causes in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: One hundred and eighty-three patients with confirmed RA, mean age 46,5+/-11,7 years, RA duration from 3 month to 30 years, were studied. Rheumatology, neurological, using the DN4 questionnaire, examinations and stimulation electromyography were used. Results and sonclusion. Signs of neuropathic pain (NP) assessed with the DN4 were identified in 73 (43%) patients with RA. These patients were older, had longer RA duration as well as higher clinical stage of disease and reduced functional abilities. There were no correlation between NP and disease activity. Peripheral nervous system (PNS) lesions were seen in 96% patients with NP: sensory motor neuropathy (55%), tunnel syndrome (14%), mononeuropathy (19%) and their combinations (4%), cervical myelopathy (4%). PNS lesions is the main etiopathogenetic factor of peripheral NP in RA. This finding opens new perspectives for complex treatment, including group B vitamins, of chronic pain in RA. PMID- 28884721 TI - [A search of target regions for association studies between DNA methylation and cognitive impairment in schizophrenia]. AB - AIM: To develop a strategy for the search for candidate genes and targets for epigenetic studies of cognitive impairments in patients with schizophrenia. MATERIAL AND METHODS: A search for literature on epigenetics of schizophrenia and cognitive functions was performed. Single nucleotide polymorphisms (SNPs) that can create or abolish a site for DNA methylation or transcription factor sites were determined using a custom script. RESULTS AND CONCLUSION: Eight candidate genes, including BDNF, COMT, RELN, SNRPN, PSMA4, FAM63B, IL-1RAP, MAD1L1, as well as 750 targets in CpG islands in the linkage regions identified in GWAS of schizophrenia and 406 targets in SNV located within transcription factor binding sites were selected. PMID- 28884722 TI - [Severe carotid stenosis: cerebral autoregulation in the ipsilateral region]. AB - AIM: To study cerebral autoregulation (CA) in region of the stenotic carotid artery. MATERIAL AND METHODS: The study involved 35 patients with critical stenosis of the carotid arteries, including 24 patients were asymptomatic and 11 patients with symptomatic course. Blood flow velocity in middle cerebral arteries was monitored using Multi Dop X (DWL, Germany) with simultaneous noninvasive systemic blood pressure registration (CNAP, Austria). CA was assessed by calculating the phase shift (PS) between spontaneous oscillations of blood flow velocity and blood pressure within the range of systemic Mayer waves (80-120 mHz). RESULTS: In 18 patients, the CA indicators were in the normal range (PS 1.2+/-0.3 rad). Seventeen patients, including asymptomatic as well as symptomatic types, had impaired CA (PS 0.2+/-0.2 rad and 0.3+/-0.2 rad, respectively). Reconstructive surgery, irrespective of clinical manifestations, led to the significant increase in PS (p<0.001) in the early postoperative period (0.9+/-0.5 and 0.9+/-0.3 rad, respectively). CONCLUSION: A significant variability in the cerebrovascular reserve capacity in symptomatic and asymptomatic types of carotid artery stenosis was found. CA can be used in determining the indications for surgical treatment and evaluation of its effectiveness in patients with stenosis of carotid arteries. PMID- 28884723 TI - [First cases of Pompe's disease in Kazakhstan]. AB - The article presents the clinical observations of two newly diagnosed patients with Pompe disease in the Republic of Kazakhstan, confirmed by genetic research. PMID- 28884724 TI - ['Primary', 'basic' and 'secondary' symptoms of schizophrenia in the concept of E. Bleuler]. AB - Two first works of swiss psychiatrist E. Bleuler that revise the symptomatology of Kraepelinian dementia praecox leaning on some findings of the psychoanalysis of S. Freud, C. Jung, F. Riklin, K. Abraham and on the P. Janet's concept of psychasthenia are analyzed. The early concept of primary (testifying the direct organic lesion) and secondary (of psychogenic origin) symptoms of schizophrenia formulated by E. Bleuler is compared with his following concept of 'basic' and 'accessory' symptoms of schizophrenia. The concept of primary and secondary symptoms of schizophrenia was created firstly as a ground for the prognosis of the disease, and the concept of basic and accessory symptoms for the confident diagnosis of the disease. E. Bleuler's concept accentuated the diagnosis of schizophrenia on the psychopathological and pathopsychological state of the patient, in contrast to E. Kraepelin's concept of dementia praecox based on the course and outcome, made possible the expansion of schizophrenia boundaries at the expense of different psychotic and nonpsychotic disorders that other authors attributed to the forms of 'degenerative madness', neuroses and psychopathies. PMID- 28884725 TI - [Ethical aspects of teaching of nervous diseases]. AB - Ethical aspects of training of physicians are considered. The author highlights the importance of teaching the basic disciplines during the training of the neurologist. An analysis of most frequent mistakes that arise in practical activity as a consequence of overestimation of paraclinical methods of investigation, underestimation of a role of treatment that the patient receives due to other indications is presented. The formation of life attitude of the physician is the extremely important component of teaching process. One should not forget the lessons of history shown examples of physicians that gave their lives to save patients. Also, there are examples of physicians who had violated the fundamental humanitarian principles. PMID- 28884726 TI - [Polyneuropathies in intestinal diseases]. AB - Different aspects of polyneuropathies (PN) developed due to the deficit of group B vitamins in intestinal diseases are considered. Neurological disturbances related to intestinal diseases are caused by malabsorption that leads to the deficit of some compounds extremely important for normal cell metabolism, pathological changes of mucous coat of the stomach and intestine and higher sensitivity to the plant protein gluten. Vitamin B12 deficit can lead to a number of neurological disturbances; patients with pernicious anemia most often develop myelopathy and PN. An increase in serum vitamin B1 concentration is identified in 30-80% of patients with alcoholism. However, vitamin B1 deficit is seen also in ulcer disease, chronic gastritis, acute pancreatitis, esophageal metastatic lesions as well as in primary tumors of the stomach and intestine. Demyelinating as well as axonal PN may develop in patients with enteropathy. Gluten intolerance is the most often cause of PN in pathological changes in the intestine Possibilities of clinical and paraclinical diagnosis of these disorders are analyzed. PMID- 28884727 TI - [Disturbance of oligodendrocyte differentiation in schizophrenia in relation to main hypothesis of the disease]. AB - Increasing evidence coming from neuroimaging, molecular genetic and post-mortem studies have implicated oligodendrocyte abnormalities and compromised myelin integrity in schizophrenia. Activity-dependent myelination in adult brain is considered to be an important mechanism of neural circuit's plasticity due to the presence of a large population of oligodendrocyte progenitor cells (OPC) in the adult CNS. Growing evidence for impairment of oligodendrocyte differentiation has been reported in the brain of schizophrenia subjects. OPC are very vulnerable inflammation, oxidative stress, and elevated glutamate levels leading to excitotoxicity. The mechanisms of prolonged suppression of oligodendrocyte differentiation caused by prenatal maternal infection or preterm birth are discussed in view of increased risk of schizophrenia, neurodevelopmental and inflammation hypotheses of the disease. The data that some neuroleptics stimulate OPC differentiation and ameliorate myelin alterations support the notion that impairment in the differentiation of OPCs contributes to oligodendrocyte abnormalities and to the pathophysiology of schizophrenia. PMID- 28884728 TI - [Psychiatry of the future: multidimensionality of the problems of modern psychiatry and development of classification systems]. AB - The success and achievements in the area of neurosciences due to the development of neuroimaging, neurochemical and genome studies provide tasks for psychiatry determined by the necessity to develop new classifications of mental diseases, primarily ICD-11, specify clinical diagnostic criteria and rethink the essence of some mental disorders. In spite of the multiple direction of scientific opinions on the discussed issues, the development of modern psychiatry is characterized by intensive search of biological background of psychiatric disorders and elaboration of effective approaches to the diagnosis and treatment of mental diseases, including medical rehabilitation of patients. PMID- 28884729 TI - [Mental disorders in Hodgkin's Lymphoma]. AB - This literature review differentially describes mental disorders in patients with Hodgkin's lymphoma (HL) with an emphasis on psychotic disorders, affective states and adjustment disorders. Psychotic disorders observed in patients with HL include affective, delusional conditions, delirium. There are different psychogenic states among the adjustment disorders. Attention is drawn to the frequency of anxious, depressive or mixed states. Conversion disorders and behavioral disorders that lead to non-compliance in patients with HL are described as well. In nosologic aspect, mental disorders in HL are classified as somatogenic and adjustement disorders. PMID- 28884730 TI - [Pharmacological effects and clinical application of pantogam and pantogam active]. AB - Clinical studies and experience in the use of pantogam (hopanthenic acid) and pantogam active (rac-gopantenic/D-, L-gopantenic acid) showed their efficacy and safety in patients with various pathologies. Pantogam has a unique spectrum of pharmacological effects (nootropic, anticonvulsant, mild activating) in the absence of addiction, hyperstimulation or withdrawal syndrome. Pantogam active, having also an additional anxiolytic effect, is characterized by bimodal activity, improves not only cognitive functions, but also emotional state in patients in psychiatric, neurological and cardiological practice with such diseases and conditions as anxiety/anxiety-depressive disorders, chronic brain ischemia, ischemic heart disease, chronic heart failure, arterial hypertension, epilepsy, craniocerebral trauma, schizophrenia as well as cognitive impairment in the structure of neurological and psychogenic deficiencies. PMID- 28884731 TI - [Optimization of the algorithm for the detection and the differential non pharmacological correction of the risk factors and the preclinical stages of atherosclerosis at the level of the health resort-based primary care]. AB - This article presents the results of a comparative prospective study of 276 subjects at the age between 40 and 65 years presenting with risk factors (RF) of atherosclerosis and its preclinical stages (APC). All of them were reckoned to be at a moderate risk of developing APC based on the results of evaluation with the use of the SCORE scale which implied the necessity of their differential non pharmacological treatment during a two-year period with the application of a variety of preventive therapeutic strategies. The patients were allocated to three different (initially comparable) groups. The main group (group 1) was comprised of 98 subjects who received the optimized combined treatment including climatotherapy, dietary therapy, psychotherapy, hydrotherapy, physiotherapy, and hypoxytherapy; in addition, they were involved in the program of therapeutic physical exercises and in the educational program. The group of comparison (group 2) consisted of 88 subjects who were advised to withstand pernicious habits, to keep to the prescribed diet, and intensify the physical activity. The subjects included in the control group 3 were given no preventive treatment whatsoever. The optimized system for the early diagnostics and identification of the risk factors and/or ACD was employed for examining the members of group 1. By the end of the study, risk factors of atherosclerosis and APC were documented in 86.2% and 76.6% of the patients of group 1, respectively. The number of disability days averaged 7.2 per person versus 16.3 and 22.6 in comparison and control groups, respectively. There were no newly diagnosed cases of cardiovascular diseases (CVD) over the study period among the patients of group 1, in contrast to 11.4% and 25.6% such cases in groups 2 and 3, respectively. The results of this study give evidence that the optimized strategy of non-pharmacological correction of the risk factors and the preclinical stages of atherosclerosis at the level of the health resort-based primary care has advantages over the standard therapy because it makes it possible to reduce the frequency of development of new cases of cardiovascular diseases and to decrease the disability rate. It is concluded that the proposed approach enhances the effectiveness of primary prophylaxis of cardiovascular diseases associated with atherosclerosis and relieves the burden of this pathology. It can therefore be recommended for the more extensive application at the level of the health resort-based primary care settings. PMID- 28884732 TI - [The rehabilitative treatment of the patients presenting with chronic obstructive pulmonary disease including the application of the manual handling methods]. AB - AIM: The objective of the present study was to identify the peculiar features and advantages of different methods for the mechanical impact on the thoracic tissues of the patients presenting with chronic obstructive pulmonary disease (COPD) and to develop specific indications for their clinical applications. MATERIAL AND METHODS: This randomized prospective comparative study included 137 patients with COPD. In accordance with the currently accepted classification (GOLD, 2013), all the patients had COPD of medium severity. The smoldering inflammatory process was diagnosed in 75 (54.7%) patients, grade I and II respiratory insufficiency in 80 (58.4%) and 57 (41.6%) patients, respectively. The external respiration function was evaluated by means of pneumotachometry techniques during the forced expiratory maneuver and by spirometry. The pulmonary hemodynamics and myocardial contractility of the right ventricle were studied with the use of rheopulmonography and central hemodynamics by tetrapolar thoracic rheography. The routine inflammatory and immune tests were employed. RESULTS: Investigations of the systemic circulation have demonstrated the prevalence of its hyperkinetic type (54,0%) over the hypokinetic and eukinetic ones (23,3% and 22,7% respectively). All the patients were divided into three group identical in terms of clinical and functional characteristics. The patients comprising group 1 (n=46) were prescribed the rehabilitative treatment in the form of classical chest massage, those of group 2 (n=47) were treated by means of intense massage of asymmetric chest zones, and the patients included in group 3 (n=44) underwent manual therapy. It was shown that intense massage produced the most pronounced beneficial effect. Classical massage also resulted in the reduction of the inflammatory manifestations but its effectiveness was significantly lower than that of the intense treatment (r<0,05-0,02). Manual therapy failed to cause any appreciable changes in the character and severity of the inflammatory process (r>0,5). CONCLUSION: The intense massage of asymmetric chest zones proved to provide the most efficient tool for the anti-inflammatory treatment of the patients presenting with chronic obstructive pulmonary disease in comparison with other known methods for the mechanical impact on the thoracic tissues. However, the application of this technique is limited in the patients with the hypokinetic type of systemic circulation and pulmonary hypertension. The most important advantage of chest massage by the conventional method is the possibility of its application for the treatment of the patients suffering from severe forms of COPD associated with pulmonary and systemic cardiohemodynamic disturbances with alveolar hypoxia. Manual therapy can be recommended in the first place to the patients with COPD in remission and the accompanying functional blockade of the vertebral segments. PMID- 28884733 TI - [The application of impulse magnetic therapy for the treatment of the patients presenting with lymphedema of the lower extremities]. AB - AIM: The principal objective of the present work was to evaluate the influence of impulse magnetic therapy on the state of the microcirculatory system in the patients presenting with lymphedema of the lower extremities. MATERIAL AND METHODS: The study included 59 patients with stage of 1 and 2 lymphedema who were divided into two groups. Those comprising the first group had impulse magnetic therapy applied to their lower extremities while the patients making up the second group served as controls. All the patients were examined with the use of the laser Doppler flowmetry (LDF) that revealed the initially present pathological changes in the microcirculatory system of their lower extremities. RESULTS: The study has demonstrated that the application of impulse magnetic therapy produced a positive effect on all the constituent components of the microcirculatory blood stream of the patients suffering from lymphedema of the lower extremities. Specifically, the initially increased arteriolar tonus was decreased, the blood flow in the capillary vessels was improved, and congestive phenomena in the venular segments of the microcirculation blood stream were markedly reduced. The results of the LDF examination in the control group gave no evidence of significant changes in the patients' microcirculatory system. The results of the LDF examination of the patients of the control group suggested the absence of any appreciable changes in the microcirculatory system. CONCLUSION: The present study has demonstrated the advisability of the application of impulse magnetic therapy for the treatment of the patients presenting with lymphedema of the lower extremities as a minimally invasive technique for the evaluation of the condition of the microcirculatory system and the objective assessment of the effectiveness of the outcomes of physiotherapy in the patients with vascular pathology. PMID- 28884734 TI - [The meteopathic reactions as reflected in the indicators of electropuncture diagnostics. A pilot study]. AB - The present article was designed to report the results of the electropuncture diagnostics (EPD) with the use of the 'Prognoz' electropunctural device obtained during the examination of 12 patients who experienced meteopathic reactions (MPR) during magnetic storms. The most frequently detected changes were deviations affecting the acupuncture channels (AC) of the heart, pericardium and triple energizer. The latter underwent the most pronounced deviation from the 'balanced condition'. In 2 cases out of the three (66,6%), its hypofunction was documented The pericardium channel was characterized by extreme asymmetry of its left and right branches. To a lesser extent, a similar asymmetry was apparent in the acupuncture channels of the heart. The present pilot study revealed the noticeable changed in the functional state of two AC (pericardium and triple energizer) in people suffering from meteopathic reactions. It is concluded that the further studies involving a larger population of the weather-dependent subjects is likely to identify other sensitive acupuncture channels; the analysis of their functional condition may be instrumental in determining the typical MPR profiles based on the results of the evaluation of the effectiveness of electropunctural diagnostics. The newly detected patterns may be useful for the development of the personalized approach to the prediction, prevention, and relief of the meteopathic reactions. PMID- 28884735 TI - [The spa and health resort-based treatment of metabolic syndrome with the application of the therapeutic courses of different duration: the evaluation according long-term results]. AB - AIM: The objective of the present study was to estimate the effectiveness of the new therapeutic modalities for the spa and health resort-based treatment of metabolic syndrome based on the results of the long-term follow-up observations. MATERIAL AND METHODS: A total of 100 patients presenting with metabolic syndrome were recruited for the participation in the study. All of them underwent a shortened course of mineral water intake in the combination with the use of the herbal medicinal products. RESULTS: The results of the study give evidence of the more favorable changes in the clinical and instrumental characteristics of the patients with metabolic syndrome treated with the use of the proposed approach in comparison the patients treated by the conventional methods. Moreover, the beneficial effects of the proposed approach persisted during a longer period. The basal treatment given to our patients was supplemented by dietary therapy, therapeutic physical exercise, narzan baths, intake of mineral water having a temperature of 35-37 degrees S in conjunction with sulphate mineral water (narzan) cooled to 13-15 degrees S, and a phytococktail. CONCLUSION: The results of the long-term observations confirmed the enhanced effectiveness of the spa and health resort-based treatment of metabolic syndrome including the therapeutic courses with the intake of cooled narzan mineral water in the combination with phytococktails. This therapeutic modality increased the duration of the favorable changes of various parameters that characterize metabolic syndrome. Specifically, they persisted during 5-6 months after the application of the standard methods, were still apparent within 6-7 months after the two-week course of the treatment with cold narzan and phytococktails, and during 8-9 months when the duration of the treatment course was extended up to 3 weeks. PMID- 28884736 TI - [The application of low-frequency ultrasound for the comprehensive treatment and rehabilitation of the patients presenting with chronic endometritis]. AB - The incidence of chronic endometritis remains rather high despite considerable progress in reproductive medicine including the advent of the new methods for assisted reproduction; the pregnancy rate after the treatment of this condition is still unacceptably low. It implies the necessity of the careful preparation of endometrium for the implantation of the embryo especially in women with a history of unsuccessful outcomes of the IVF treatment. It calls for the development of the efficient therapeutic modalities for the management of chronic endometritis and restoration of the normal reproductive function; their introduction into the therapeutic algorithm remains equally relevant. The characteristic features of chronic endometritis include blood circulatory disorders in the vessels of the uterus and in the pelvic vascular basin, changes of local immunity in the endometrium concomitant with the activation of cellular and humoral responses of inflammation in the form of enhanced leukocyte infiltration and increased production of cytokines. The long duration of such a process results in the development of fibrosis that, in its turn, leads to chronic tissue hypoxia, potentiation of inflammation, and disruption of decidualization that hampers successful implantation. The article shows the possibility of using low-intensity ultrasound for the treatment and rehabilitation of the patients presenting with chronic endometritis. The data concerning the primary biophysical processes developing in the tissues under the influence of ultrasound are discussed. The therapeutic effects and their underlying mechanisms and described. The physiotherapeutic treatment considerably improved vascular hemodynamics in the pelvic basin and produced trophotropic, defibrosing, and anti-inflammatory effects. The clinical data giving evidence of the high effectiveness of the application of intrauterine ultrasound cavitation provide a basis for the recommendation to include this physical factor in the existing algorithms for the pre-gravid preparation of the women presenting with disorders of the reproductive function and chronic endometritis. PMID- 28884737 TI - [The application of the acupuncture techniques for the combined treatment of neurotic tics in the children]. AB - : At present, the frequency of neurosis in the children is growing under the influence of the increasingly intensive stressful factors. The neurotic ticks are one of the manifestations of neurosis in the children characterized by involuntary movements; they are often accompanied by hyperactivity, deficit of attention, fatigue, and headaches. AIM: The objective of the present study was to evaluate the effectiveness of acupuncture used for the treatment of neurotic tics in the children. MATERIAL AND METHODS: The study was carried out at the basis of the department of children's rehabilitation of the Moscow city polyclinic #39. All the children were counselled by a neurologist, psychologist, and acupuncturist. An electroencephalogram was obtained from each patient and a questionnaire study involving the patients' parents was conducted. The patients were treated with the application of reflexotherapy and were given recommendations of a psychologist. A total of 30 children at the age from 6 to 12 years were available for the examination. The participants of the study were allocated to two groups depending on the strategy of the outpatient care. Group 1 was comprised of the patients (n=17) who were given 3 courses of reflexotherapy in addition to pharmacotherapy and psychologist's recommendations. The patients included in group 2 served as controls (n=13) and received only medications and psychotherapy without acupuncture. The effectiveness of the treatment was evaluated based on the dynamics of the patients' complaints. RESULTS AND DISCUSSION: The resullts of the study give evidence of the higher effectiveness of the treatment of the children suffering from neurotic ticks with the application of acupuncture therapy compared with the conventional approach. A few courses of reflexotherapy provided in the combination with pharmacotherapy and the compliance with the recommendations of a psychologist resulted in the more efficient elimination of the neurotic tics together with the associated hyperactivity, deficit of attention, fatigue, and headaches than the use of medication therapy and psychotherapy without acupuncture. PMID- 28884738 TI - [The influence of physical loads on the functional parameters of the eyes in the children and adolescents regularly engaged in sports activities]. AB - : Myopia (short-sightedness) is the most common refractive disorder throughout the world prone to progression which is caused, inter alia, by violation of the working regime and resting conditions in the combination with the enhanced physical and psychological stresses. AIM: The objective of the present study was to evaluate the influence of the strenuous physical exercises on the visual analyzer in the children and adolescents regularly engaged in sports activities. MATERIAL AND METHODS: A total of 600 children and adolescents at the age from 8 to 17 years were recruited for the participation in the study. They were allocated to two groups of 300 subjects each. The first group was comprised of the children regularly involved in sport activities ('athletes') while the second group included the children and adolescents not involved in the sports activities on a regular basis ('schoolchildren'). The groups were additionally divided into two subgroups that consisted of 150 members each. One subgroup within each group was composed of the persons with emmetropic refraction ('healthy') while the other included the children presenting with mild or moderately severe myopia. The parameters of visual acuity, the length of the anterior-posterior segment of the eye, and indices of regional hemodynamics of the eye were evaluated in all the participants of the study. RESULTS: Twelve months after the initiation of the study, the members of the first group ('athletes') were found to exhibit a slight decrease in visual acuity with and without ts correction and without correction as well as a statistically significant decrease of refraction by 0.14+/-0.18 dptr on the average (p=0.009). In the members of the second group not engaged in sports activities on a regular bases ('schoolchildren#), the decrease in visual acuity without correction and parameters of refraction averaged 0.06+/-0.19 dptr (p=0.004) and 0.35+/-0.61 dptr (p<0.001), respectively. Deterioration of short sightedness amongst the children of the first group ('athletes') was documented in 3 cases (2.0%) compared with 11 (7.3%) in the second group ('schoolchildren'). Among the healthy adolescents, myopia was diagnosed 12 months after the beginning of the observations in 9 cases (6%) in the first group ('athletes') and in 15 (10%) cases in the second group ('schoolchildren'). CONCLUSION: The results of the present study give evidence that physical training on a regular basis facilitates the reduction of the risk of developing myopia; moreover, it helps to stabilize the visual acuity without correction and reduce the rate of progression of the myopic process in the adolescents having mild and moderate myopia. PMID- 28884739 TI - [The influence of the main components of the ultraphonophoresis phytocomplex method on the release of the biologically active substances (an experimental study)]. AB - The present study was designed to investigate kinetics of flavonoidrelease from the working compositions containing a phytocomplex. The basic parameters of this processes during phonophoresis were determined in the model in vitro experiments. The study has demonstrated the dependence of the flavonoid release rate on their initial concentration in the working compositions and the influence of dimethylsulfoxide (as well as the main and auxiliary agents of the working composition) on the release of biologically active substances. The technological methods designed for the enhancement of the effectiveness of the phytocomplex phonophoresis technique are proposed. PMID- 28884740 TI - [The specific features of the psycho-emotional status and the application of psychotherapy for the rehabilitative treatment of the patients presenting with rheumatoid arthritis]. AB - The relevance of the problem of rheumatoid arthritis arises from the influence of such factors as its prevalence rate, unpredictability, tendency towards the transition to the chronic form, severe pain syndrome, high levels of disability, and long-term loss of working ability, as well as the accompanying psycho emotional disorders. The present reviews article was designed to analyze the premorbid personality characteristics, the specifics features of mental health, and the response to the disease in the patients presenting with rheumatoid arthritis. Special emphasis is placed on the discusses of the relationship between the intensity of the pain syndrome and psycho-emotional disorders. The factors responsible for the development of the depressive states associated with rheumatoid arthritis are distinguished; they are shown to be related to both pathogenesis and the clinical symptoms of the underlying pathology as well as the general course of the disease and the specific features of the patients' psychological condition. The most extensively applied psychodiagnostics techniques are described, and the commonest psychotherapeutic approaches to the combined therapy and rehabilitation of the patients presenting with rheumatoid arthritis are overviewed. PMID- 28884741 TI - [The nephroprotective potential of peloid therapy used for the rehabilitation of the patients presenting with chronic pyelonephritis]. AB - This review article presents the data on the mechanism of action of peloid therapy from the perspective of its defibrosing effect, the structure and functions of the extracellular matrix under the normal and pathological conditions. In addition, role of this treatment modality in the progression of tubulointerstitial fibrosis which determines the severity and prognosis of chronic pyelonephritis is considered. The researchers are currently carry out the extensive studies aimed at the search of the methods for the primary and secondary prevention of chronic pyelonephritis. A wide range of pharmacotherapeutic modalities are currently used for this purpose. Moreover the development of long-acting anti-relapse medications is currently underway along with the further improvement of high-tech reconstructive surgical methods for the intervention on the organs of the urinary system. At the same time, the nephroprotective potential of the natural physical factors, such as therapeutic muds, e.g. peloids, remains poorly explored even though their well apparent thermophysical properties, unique organic and mineral composition, and saturation with biologically active compounds are well known long ago. The systemic response to peloid therapy manifests itself as the changes in the metabolism of the intercellular matrix and collagen of the connective tissue associated with the alterations in the process of fibrogenesis and the development of tubulointerstitial disorders. The direct and indirect influence of peloids on the connective tissue is possible. The indirect effects are attributable to the peloid impact on the antioxidant status, immunity, hormonal regulation, and metabolic processes. These findings suggest the necessity of the relevant experimental and clinical studies for the evaluation of the influence of peloid therapy on the structure and metabolism of the connective tissue in the kidneys including dynamics of the markers of inflammation, proliferation and fibrogenesis, and the hormonal status of the patients suffering from chronic pyelonephritis based on the application of the modern technologies in accordance with the requirements of evidence-based medicine. PMID- 28884742 TI - IPA1: a direct target of SL signaling. AB - The plant hormone strigolactone (SL) is important for many processes in plants, but its molecular mode of action has been difficult to elucidate. A new discovery has identified the SPL transcription factor, IPA1, as a crucial component directly involved in SL signaling. PMID- 28884743 TI - Three-dimensional analysis of the physiological foramen geometry of maxillary and mandibular molars by means of micro-CT. AB - The aim of this study was to investigate the physiological foramen diameter, shape and distance between physiological and anatomical apex of maxillary and mandibular first and second molars. Accurate knowledge of the physiological foramina morphology; thus, inherent mechanical shaping technical hindrances, is decisive when taking the corresponding root canal final preparation decision. The morphological dimensions of a total of 1727 physiological foramina were investigated by means of micro-computed tomography. Mean narrow and wide (to a high number, oval) diameters of the physiological foramen were 0.24, 0.22 and 0.33 mm and 0.33, 0.31 and 0.42 mm in mesiobuccal (MB), distobuccal (DB) and palatal (P) roots in maxillary first molars; 0.24, 0.22 and 0.33 mm and 0.41, 0.33 and 0.44 in MB, DB, and P roots in maxillary second molars. Mandibular first molars showed mean narrow and wide diameters of 0.24 and 0.30 mm and of 0.39 and 0.46 mm in mesial (M) and distal (D) roots; second mandibular molars showed 0.25 and 0.31 mm and 0.47 mm in M and D roots. The mean distance between the physiological foramina and anatomical apex was 0.82, 0.81 and 1.02 mm and 0.54, 0.43 and 0.63 mm in MB, DB and P roots of the maxillary first and second molars, respectively. A mean distance of 0.95 mm (M) and 1.05 mm (D) in the first and 0.78 mm (M) and 0.81 mm (D) in the second mandibular molars was observed. Based on the results obtained, assumable recommendations for final preparation size of the physiological foramen were calculated. However, when taking into consideration, the resulting standard deviations of marginal errors must be cautiously considered when taking a final decision in clinical endodontic treatment. PMID- 28884744 TI - Pulmonary large cell neuroendocrine carcinoma with adenocarcinoma-like features: napsin A expression and genomic alterations. AB - Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive malignancy, which was recently found to comprise three major genomic subsets: small cell carcinoma-like, non-small cell carcinoma (predominantly adenocarcinoma)-like, and carcinoid-like. To further characterize adenocarcinoma like subset, here we analyzed the expression of exocrine marker napsin A, along with TTF-1, in a large series of LCNECs (n=112), and performed detailed clinicopathologic and genomic analysis of napsin A-positive cases. For comparison, we analyzed napsin A expression in other lung neuroendocrine neoplasms (177 carcinoids, 37 small cell carcinomas) and 60 lung adenocarcinomas. We found that napsin A was expressed in 15% of LCNEC (17/112), whereas all carcinoids and small cell carcinomas were consistently negative. Napsin A reactivity in LCNEC was focal in 12/17 cases, and weak or moderate in intensity in all cases, which was significantly lower in the extent and intensity than seen in adenocarcinomas (P<0.0001). The combination of TTF-1-diffuse/napsin A-negative or focal was typical of LCNEC but was rare in adenocarcinoma, and could thus serve as a helpful diagnostic clue. The diagnosis of napsin A-positive LCNECs was confirmed by classic morphology, diffuse labeling for at least one neuroendocrine marker, most consistently synaptophysin, and the lack of distinct adenocarcinoma component. Genomic analysis of 14 napsin A-positive LCNECs revealed the presence of mutations typical of lung adenocarcinoma (KRAS and/or STK11) in 11 cases. In conclusion, LCNECs are unique among lung neuroendocrine neoplasms in that some of these tumors exhibit low-level expression of exocrine marker napsin A, and harbor genomic alterations typical of adenocarcinoma. Despite the apparent close biological relationship, designation of adeno-like LCNEC as a separate entity from adenocarcinoma is supported by their distinctive morphology, typically diffuse expression of neuroendocrine marker(s) and aggressive behavior. Further studies are warranted to assess the clinical utility and optimal method of identifying adenocarcinoma-like and other subsets of LCNEC in routine practice. PMID- 28884745 TI - Clinicopathologic and genetic characteristics of young patients with pleural diffuse malignant mesothelioma. AB - Pleural diffuse malignant mesothelioma typically presents during the seventh decade of life and has poor prognosis. Recent epidemiologic studies have shown differences between young and older mesothelioma patients, but the biology of pleural mesothelioma in young patients is poorly understood. We studied the clinicopathologic and genetic characteristics in pleural mesothelioma patients aged 35 years and younger. Thirty-six consecutive pleural mesothelioma patients aged 35 years and younger were compared with 48 older patients. We examined demographic and clinical characteristics, histologic type, growth patterns, mitotic index, and nuclear grade on hematoxylin and eosin-stained slides, BAP1 protein expression by immunohistochemistry, and CDKN2A and NF2 deletions by fluorescence in situ hybridization. Clinicopathologic and cytogenetic results were compared between young and older groups, and correlated with overall survival. Young patients were more frequently women, reported less asbestos exposure, and had a greater frequency of prior therapeutic radiation and family history of breast cancer than older patients (P<0.05 each). There were no histologic differences between young and older patients (all P>0.05). CDKN2A deletion was less prevalent in young patients (P=0.01), loss of BAP1 protein expression less frequent in young patients (P=0.06), and NF2 deletion rates similar between groups (P>0.05 each). Median overall survival was 40 vs 26 months (P=0.10) in young and older patients, respectively, and 47 vs 31 months (P=0.04) when comparing patients with epithelioid histology only. High mitotic index and non-epithelioid histology were the only characteristics associated with a poor overall survival in young patients. Young patients with pleural mesothelioma have an equal sex distribution and are more likely to have a history of mantle radiation, family history of breast cancer, and lower rates of CDKN2A deletion than older patients. Our results suggest that pleural mesothelioma in young patients has distinctive clinical and genetic characteristics, despite some similarities to pleural mesothelioma in older patients. PMID- 28884746 TI - Inflammatory leiomyosarcoma is a distinct tumor characterized by near haploidization, few somatic mutations, and a primitive myogenic gene expression signature. AB - Inflammatory leiomyosarcoma is a soft-tissue tumor resembling conventional leiomyosarcoma, but with a prominent intrinsic inflammatory component. Previous studies have suggested that inflammatory leiomyosarcoma differs genetically from leiomyosarcoma, but in-depth analyses are lacking. Here we provide a comprehensive picture of the genome and transcriptome of inflammatory leiomyosarcoma by combining cytogenetic, single-nucleotide polymorphism array, mRNA-sequencing, and whole-exome sequencing data. The results show that inflammatory leiomyosarcoma has a specific genetic profile characterized by near haploidization with or without subsequent whole-genome doubling. Consistently, both parental copies of chromosomes 5 and 22 are preserved. Apart from recurrent mutation of the NF1 gene, additional somatic events that could serve as driver mutations were not found at either the nucleotide or the genome level. Furthermore, no fusion transcripts were identified. Global gene expression profiling revealed particularly prominent differential expression of genes, including ITGA7, MYF5, MYF6, MYOD1, MYOG, and PAX7, involved in muscle development and function, providing strong argument for grouping inflammatory leiomyosarcoma with myogenic sarcomas, rather than with myofibroblastic lesions. Combined with previously published data, there are now 10 cases of inflammatory leiomyosarcoma with confirmed near-haploid genotype. These patients differ from leiomyosarcoma patients in being younger (median 41 years), showing a male predominance (9:1), and few relapses (1 of 8 informative patients). Thus, the clinical, morphological, and genetic data provide compelling support for inflammatory leiomyosarcoma being a distinct subtype of myogenic tumors. PMID- 28884747 TI - Adverse prognostic value of PD-L1 expression in primary resected pulmonary squamous cell carcinomas and paired mediastinal lymph node metastases. AB - Immunohistochemical assessment of programmed cell death (PD)-ligand 1 (PD-L1) expression in lung cancer in the context of therapeutically targeting the PD1/PD L1 axis is still controversially discussed. This includes the comparability of antibody clones, prognostic value, and discrepancies between primary tumors and metastases. We assessed tumoral PD-L1 expression using clones E1L3N and SP142 in 372 primary resected pulmonary squamous cell carcinomas, including 40 paired N2 lymph node metastases, in relation with clinico-pathological parameters. PD-L1 expression was negative (<1%) in 163/372 (44%, E1L3N) or 231/370 patients (62%, SP142). Positivity of 1-<50% was observed in 135 (36%, E1L3N) or 92 patients (25%, SP142) and >=50% in 74 (20%, E1L3N) or 47 patients (13%, SP142). PD-L1 staining correlated significantly between both antibodies (r=0.781; P<0.001). Scores correlated significantly between full-slide sections (N=40) and tissue microarrays, and between primaries and N2 metastases (P<0.001 all). CD8+ tumor infiltrating lymphocyte counts positively correlated with PD-L1 expression (P<0.001). PD-L1 >=50% showed the best prognostic discrimination using the split sample validation method. It was associated with shorter disease-specific survival in the observation group (E1L3N: P=0.035, SP142: P=0.002) and validation group (E1L3N: P=0.024, SP142: P=0.101) and shorter time to recurrence (observation group: E1L3N: P=0.056, SP142: P<0.001; validation group: E1L3N: P=0.036, SP142: P=0.247). Multivariate analysis showed that PD-L1 expression >=50% determined by clone E1L3N was an independent prognostic factor in the observation group regarding disease-specific survival (HR=2.768; 95% CI=1.149 6.666; P=0.023) and time to recurrence (HR=2.164; 95% CI=1.056-4.436; P=0.035) and in the validation group (disease-specific survival: HR=1.978; 95% CI=0.928 4.214; P=0.077 and time to recurrence: HR=1.571; 95% CI=0.838-2.944; P=0.159). High PD-L1 expression was associated with adverse prognosis in pulmonary squamous cell carcinoma. Clone E1L3N was more sensitive than SP142 and superior regarding prognostication. PD-L1 expression correlated significantly between primary tumor and N2 metastases, rendering mediastinal lymph node metastases adequate for immunohistochemical assessment. PMID- 28884748 TI - A FISH assay efficiently screens for BRAF gene rearrangements in pancreatic acinar-type neoplasms. AB - Approximately 1-2% of pancreatic neoplasms are acinar cell carcinomas. Recently, BRAF gene rearrangements were identified in over 20% of acinar-type neoplasms, which included both pure acinar cell carcinomas and mixed carcinomas with acinar differentiation, using next-generation sequencing-based platforms, providing a potential therapeutic target for patients with these neoplasms. Thus, it is clinically important to develop a rapid, cost- and material-efficient assay to screen for BRAF gene fusions in pancreatic acinar-type neoplasms. We developed a dual color, break-apart FISH assay to detect BRAF gene rearrangements in these neoplasms and evaluated its performance in comparison to next-generation sequencing-based studies. A blinded BRAF rearrangement FISH investigation was performed on 31 acinar-type neoplasms that had been studied previously by next generation sequencing-based analysis as well as on 18 additional acinar-type neoplasms that were accrued over the past 2 years. In total, BRAF fusions were identified in 12/49 (24%) acinar-type neoplasms by FISH. BRAF fusion partners were uncovered by using targeted next-generation sequencing studies in 11 FISH positive cases that had sufficient material for next-generation sequencing studies. SND1 was the most frequent fusion partner involved in BRAF-fusion acinar type neoplasms (50%), followed by HERPUD1 (18%). No BRAF fusions were identified by next-generation sequencing in any of the FISH-negative cases investigated. FISH analysis showed that BRAF rearrangements were diffusely present across tumor rich areas in BRAF-fusion acinar-type neoplasms, which is consistent with an oncogenic driver alteration pattern. Thus, we demonstrated that, in comparison to targeted next-generation sequencing-based technologies, the FISH assay is highly sensitive and specific as well as time- and cost-efficient in the detection of BRAF fusions in acinar-type neoplasms. The FISH assay can be easily implemented in diagnostic settings to identify acinar-type neoplasms patients potentially suitable for targeted therapy to inhibit MAPK pathway activity. PMID- 28884749 TI - Comprehensive clinical and molecular analyses of neuroendocrine carcinomas of the breast. AB - Neuroendocrine breast carcinomas represent a rare subtype of breast cancer. Their definition, prevalence, and prognosis remain controversial in the literature. The 2012 WHO classification of breast cancer categorizes neuroendocrine carcinomas into three morphologically distinct subtypes: well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. We aimed to gain insight into the clinical, morphologic, phenotypic, and molecular features of 47 neuroendocrine breast carcinomas. Targeted next-generation sequencing by an AmpliSeq 22 cancer gene hotspot panel and the Prosigna assay were performed on 42/47 and 35/47 cases, respectively. Average age at diagnosis was 69 years. All tumors were estrogen receptor-positive and the large majority expressed progesterone receptor (89%), GATA3 (98%), FOXA1 (96%), and CK8/18 (98%). There was an almost equal distribution of luminal A (52%) and B (48%) carcinomas. Almost half of the cohort (49%) displayed a high risk of recurrence score with the Prosigna test. Patients with a neuroendocrine carcinoma had a shorter disease-free survival compared with those affected by carcinomas of no special type matched for age, size, grade, and estrogen receptor status. No significant differences were observed in terms of overall survival. Stratification of neuroendocrine carcinomas using the 2012 WHO criteria did not reveal statistically significant differences among the distinct categories (well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation), in terms of either progression-free or overall survival. Our targeted sequencing analysis found three cases (7%) harboring a PIK3CA mutation, and in three other cases (7%) TP53 mutations were detected. This study showed that neuroendocrine breast carcinoma is a distinct subtype of luminal carcinoma with a low rate of PIK3CA mutations and with an aggressive clinical behavior. An accurate identification of neuroendocrine differentiation may be useful to better tailor patient adjuvant therapy within luminal carcinomas. PMID- 28884750 TI - Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations. AB - Chronic pain is the greatest source of disability globally and claims related to chronic pain feature in many insurance and medico-legal cases. Brain imaging (for example, functional MRI, PET, EEG and magnetoencephalography) is widely considered to have potential for diagnosis, prognostication, and prediction of treatment outcome in patients with chronic pain. In this Consensus Statement, a presidential task force of the International Association for the Study of Pain examines the capabilities of brain imaging in the diagnosis of chronic pain, and the ethical and legal implications of its use in this way. The task force emphasizes that the use of brain imaging in this context is in a discovery phase, but has the potential to increase our understanding of the neural underpinnings of chronic pain, inform the development of therapeutic agents, and predict treatment outcomes for use in personalized pain management. The task force proposes standards of evidence that must be satisfied before any brain imaging measure can be considered suitable for clinical or legal purposes. The admissibility of such evidence in legal cases also strongly depends on laws that vary between jurisdictions. For these reasons, the task force concludes that the use of brain imaging findings to support or dispute a claim of chronic pain - effectively as a pain lie detector - is not warranted, but that imaging should be used to further our understanding of the mechanisms underlying pain. PMID- 28884751 TI - Tuberculous meningitis. AB - Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens for TBM are based on those used to treat pulmonary tuberculosis, which probably results in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood-brain barrier penetrance. The role of adjunctive anti-inflammatory, host-directed therapies - including corticosteroids, aspirin and thalidomide - has not been extensively explored. To address this deficit, two expert meetings were held in 2009 and 2015 to share findings and define research priorities. This Review summarizes historical and current research into TBM and identifies important gaps in our knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential modulation; vascular and hypoxia-mediated tissue injury; the role of intensified antibiotic treatment; and the importance of rapid and accurate diagnostics and supportive care in TBM. PMID- 28884752 TI - Alzheimer disease: Revising the risk of Alzheimer disease in women. PMID- 28884753 TI - Cladribine - an old newcomer for pulsed immune reconstitution in MS. AB - The EMA has approved cladribine tablets for the treatment of multiple sclerosis. The drug is not new, and the journey to its approval has been a long one, but the old concepts that cladribine therapy are based on provide a new option for the possibility of drug-free remission. PMID- 28884754 TI - Bifidobacteria exert species-specific effects on constipation in BALB/c mice. AB - Constipation is one of the most common gastrointestinal complaints worldwide. The aim of this study was to determine whether edible bifidobacteria (Bifidobacterium longum, B. infantis, B. animalis, B. bifidum, B. adolescentis or B. breve) exhibit interspecies differences in alleviating constipation induced by loperamide in BALB/c mice and to analyse the main reasons for the interspecies differences. BALB/c mice were given bifidobacteria by gavage once per day for 8 days. The primary outcome measures, which included related constipation indicators, and the secondary outcome measures, which included changes in the concentration of short-chain fatty acids in faeces and changes in the faecal flora, were used to evaluate the therapeutic effects of the edible bifidobacteria on constipation. The findings show that the six species of Bifidobacterium differed in their ability to relieve constipation. B. longum, B. infantis and B. bifidum were the most effective in relieving constipation, B. adolescentis and B. breve were partially effective and B. animalis was not effective. Furthermore, edible Bifidobacterium treated constipation by increasing the abundance of Lactobacillus and decreasing the abundance of Alistipes, Odoribacter and Clostridium. Higher concentrations of short-chain fatty acids were found in the faecal samples from the edible Bifidobacterium treatment groups. Meanwhile, an increased concentration of acetic acid could alleviate constipation. In conclusion, edible bifidobacteria exhibit interspecies differences in the alleviation of constipation. Meanwhile, bifidobacteria improved constipation symptoms by increasing the concentration of acetic acid and the relative abundance of Lactobacillus and reducing the content of Alistipes, Odoribacter and Clostridium. PMID- 28884757 TI - An in-tether chiral center modulates the proapoptotic activity of the KLA peptide. AB - The helical peptide KLA (KLAKLAKKLAKLAK) is a well-known inducer of cellular apoptosis, acting to disrupt the mitochondrial membrane. However, its weak cellular uptake impedes development of any further applications. Here, we have utilized a novel in-tether chiral center induced helicity strategy (CIH) to develop a potent apoptosis inducer based on this KLA sequence. Notably, for the two resulting epimers of the CIH-KLA peptide, the CIH-KLA-(R) epimer exhibited superior cellular uptakes and special mitochondrial targeting when compared with its S counterpart. This work provides a promising and versatile method to modify the KLA peptide and a proof-of-concept application for the CIH strategy in modifying bioactive peptides. PMID- 28884758 TI - Prebiotic synthesis of 2-deoxy-d-ribose from interstellar building blocks promoted by amino esters or amino nitriles. AB - Understanding the prebiotic genesis of 2-deoxy-d-ribose, which forms the backbone of DNA, is of crucial importance to unravelling the origins of life, yet remains open to debate. Here we demonstrate that 20 mol% of proteinogenic amino esters promote the selective formation of 2-deoxy-d-ribose over 2-deoxy-d-threopentose in combined yields of >=4%. We also demonstrate the first aldol reaction promoted by prebiotically-relevant proteinogenic amino nitriles (20 mol%) for the enantioselective synthesis of d-glyceraldehyde with 6% ee, and its subsequent conversion into 2-deoxy-d-ribose in yields of >= 5%. Finally, we explore the combination of these two steps in a one-pot process using 20 mol% of an amino ester or amino nitrile promoter. It is hence demonstrated that three interstellar starting materials, when mixed together with an appropriate promoter, can directly lead to the formation of a mixture of higher carbohydrates, including 2 deoxy-d-ribose. PMID- 28884760 TI - Chemical systems out of equilibrium. PMID- 28884761 TI - Equilibrium between inactive ready Ni-SIr and active Ni-SIa states of [NiFe] hydrogenase studied by utilizing Ni-SIr-to-Ni-SIa photoactivation. AB - Previously, the Ni-SIr state of [NiFe] hydrogenase was found to convert to the Ni SIa state by light irradiation. Herein, large activation energies and a large kinetic isotope effect were obtained for the reconversion of the Ni-SIa state to the Ni-SIr state after the Ni-SIr-to-Ni-SIa photoactivation, suggesting that the Ni-SIa state reacts with H2O and leaves a bridging hydroxo ligand for the Ni-SIr state. PMID- 28884762 TI - Proteins at air-water and oil-water interfaces in an all-atom model. AB - We study the behavior of five proteins at the air-water and oil-water interfaces by all-atom molecular dynamics. The proteins are found to get distorted when pinned to the interface. This behavior is consistent with the phenomenological way of introducing the interfaces in a coarse-grained model through a force that depends on the hydropathy indices of the residues. Proteins couple to the oil water interface stronger than to the air-water one. They diffuse slower at the oil-water interface but do not depin from it, whereas depinning events are observed at the other interface. The reduction of the disulfide bonds slows the diffusion down. PMID- 28884763 TI - On the role of topology in regulating transcriptional cascades. AB - We study the impact of topology on the response of a transcriptional cascade with certain circuit topologies to a constant and time-varying input signal. We systematically analyze the response of the output to activating and repressing cascades. We identify two types of responses for a linear cascade, namely the "Decaying mode", where the input signal becomes exceedingly weaker as it propagates, and the "Bistable mode", where the input signal can either be amplified or die out in the pathway. We examine how the transition occurs from one mode to the other as we add coherent and/or incoherent feed-forward loops in an otherwise linear cascade. We find that pathways with at least one incoherent feedforward loop can perform adaptive responses with the quality of response varying among different topologies. Furthermore, we study the origin of a (non)monotonic input-output profile for various circuit topologies over a wide range of parameter space. For a time-varying input signal, we identify some circuit topologies that are more prone to noise propagation than others that are more reliable in blocking out high-amplitude fluctuations. We discuss the effect of cell to cell variation in protein expression on the output of a linear cascade and compare the robustness of activating and repressing cascades to noise propagations. In the end, we apply our model to study an example of a transcription cascade that guides the development of Bacillus subtilis spores and discuss an example from a metabolic pathway where a transition from the decaying to bistable mode can occur by changing the topology of interactions in the pathway. PMID- 28884764 TI - The reversal of the spontaneous exchange bias effect and zero-field-cooling magnetization in La1.5Sr0.5Co1-xFexMnO6: the effect of Fe doping. AB - The crystal structure, electronic structure and magnetic properties were systematically studied in a series of Fe-doped La1.5Sr0.5CoMnO6 double perovskites. The X-ray diffraction patterns of the samples are all refined with a rhombohedral (R3[combining macron]c) structure. The parameters a and c continuously increase with increasing Fe doping concentration x. X-ray photoelectron spectroscopy (XPS) spectra of the Mn, Co, and Fe 2p core levels, consistent with the soft X-ray absorption spectroscopy (XAS) spectra of Mn, Co, and Fe L2,3 edges, indicate that their valence states are Mn3+ and Mn4+, Co2+ and Co3+, and Fe3+, respectively. However, relative to samples with x <= 0.1, there is an abrupt change of photon energy in the Co- and Fe-2p XAS spectra for x >= 0.2, implying the spin state transition is from high to low. In addition, this is further confirmed by a comparison between the calculated effective spin moment from the paramagnetic data and the theoretical value. Interestingly, we demonstrate the reversal of both zero-field-cooling magnetization and the sign switching of the spontaneous exchange bias (SEB) with the doping concentration from magnetic measurements. The magnetization reverses from positive to negative with the temperature decreasing across the compensation temperature at the critical concentration x = 0.2. Meanwhile, the exchange bias field of the SEB reverses from large negative values to positive ones. Our findings allow us to propose that the spin state transition caused by inhomogeneity is considered to play an important role in the reversal of the magnetization and the SEB effect. PMID- 28884765 TI - Enhancement in thermoelectric performance of SiGe nanoalloys dispersed with SiC nanoparticles. AB - SiGe is one of the most widely used thermoelectric materials for radioisotope thermoelectric generator applications for harnessing waste-heat at high temperatures. In the present study, we report a simple experimental strategy for enhancing the thermoelectric and mechanical properties of n-type SiGe nanoalloys by dispersing SiC nanoparticles in a SiGe nanoalloy matrix. This strategy yielded a high value of figure-of-merit (ZT) of ~1.7 at 900 degrees C in the SiGe/SiC nanocomposite, which is nearly twice that reported for its pristine bulk counterpart and ~15% higher than that of pristine SiGe nanoalloys. This significant enhancement in the ZT primarily originates from a reduction in the lattice thermal conductivity, owing to a high density of nano-scale interfaces, lattice-scale modulations and mass fluctuations, which lead to extensive scattering of heat-carrying phonons. The dispersion of SiC nanoparticles also significantly enhances the mechanical properties of the resulting SiGe/SiC nanocomposite, including fracture toughness and hardness. The enhancement in the thermoelectric and mechanical properties of the SiGe/SiC nanocomposites has been correlated with their microstructural features, elucidated employing X-ray diffraction, and scanning and transmission electron microscopy. PMID- 28884766 TI - Anion binding by p-aminoazobenzene-derived aromatic amides: spectroscopic and electrochemical studies. AB - The synthesis and complexing properties of p-aminoazobenzene-derived mono-, bis-, and trisamides were described. Ligands 3 and 4 bind anions, including fluorides, chlorides, bromides, acetates, benzoates, dihydrogen phosphates, hydrogen sulfates, and p-toluenesulfonates, in chloroform forming 1 : 1 complexes. The highest value of stability constant was evaluated for the 4-F- complex (log K = 5.63 +/- 0.21). On the basis of 1H NMR, and FTIR spectroscopy, the possible nature of the ligand-anion interactions was proposed. The E ? Z isomerization process of tripodal amide 4 in chloroform was studied. The effect of anions on Z to E thermal back isomerization was investigated. PMID- 28884767 TI - Tuning hexagonal NaYbF4 nanocrystals down to sub-10 nm for enhanced photon upconversion. AB - Enhancing upconversion emission is critical for small-sized lanthanide doped upconversion nanocrystals. A promising way is increasing the doping concentration of excitation energy absorbers, the Yb3+ sensitizer. However, it is still a challenge to obtain small-sized hexagonal NaLnF4 (Ln: lanthanide) upconversion nanocrystals with a high Yb3+ concentration due to the fast growth of NaYbF4 crystals, which hinders their applications particularly in biology. We here demonstrate a highly repeatable and controllable method for tuning the size of hexagonal NaYbF4 nanocrystals, down to ~7 nm, without the assistance of additional impurity doping. By monitoring the reaction process, we found that ultrasmall hexagonal NaYbF4 nanocrystals were formed through an in situ transformation of their cubic counterparts. We observed an enhanced upconversion emission of NaYbF4:Tm nanocrystals when compared to that of NaYbF4:Y/Tm nanocrystals with less Yb3+ doping. After coating a thin layer of a NaYF4 shell on NaYbF4:Tm nanocrystals, a ~100 times upconversion emission enhancement with over 800 times stronger emission in the ultraviolet and blue ranges was observed. This versatile method, together with the strong upconversion emission of the as prepared ultrasmall nanocrystals, should facilitate the future applications of upconversion nanocrystals. PMID- 28884768 TI - The composition of potentially bioactive triterpenoid glycosides in red raspberry is influenced by tissue, extraction procedure and genotype. AB - The beneficial effects of consumption of berry fruits on a range of chronic diseases has been attributed (at least in part) to the presence of unique phytochemicals. Recently, we identified novel ursolic acid-based triterpenoid glycosides (TTPNs) in raspberry fruit and demonstrated their survival in human ileal fluids after feeding which confirmed their colon-availability in vivo. In this paper, in vitro digestion studies demonstrated that certain TTPNs were stable under gastrointestinal conditions and confirmed that these components may have been responsible for bioactivity noted in previous studies. Sequential extractions of raspberry puree, isolated seeds and unseeded puree showed that certain TTPN components (e.g. peak T1 m/z 679, and T2 m/z 1358) had different extractabilities in water/solvent mixes and were differentially associated with the seeds. Purified seed TTPNs (mainly T1 and T2) were shown to be anti-genotoxic in HT29 and CCD841 cell based in vitro colonocyte models. Further work confirmed that the seeds contained a wider range of TTPN-like components which were also differentially extractable in water/solvent mixes. This differential extractability could influence the TTPN composition and potential bioactivity of the extracts. There was considerable variation in total content of TTPNs (~3 fold) and TTPN composition across 13 Rubus genotypes. Thus, TTPNs are likely to be present in raspberry juices and common extracts used for bioactivity studies and substantial variation exists in both content and composition due to genetics, tissue source or extraction conditions, which may all affect observed bioactivity. PMID- 28884769 TI - An experimental and computational framework for engineering multifunctional nanoparticles: designing selective anticancer therapies. AB - A key challenge in the treatment of cancer with nanomedicine is to engineer and select nanoparticle formulations that lead to the desired selectivity between tumorigenic and non-tumorigenic cells. To this aim, novel designed nanomaterials, deep biochemical understanding of the mechanisms of interaction between nanomaterials and cells, and computational models are emerging as very useful tools to guide the design of efficient and selective nanotherapies. This works shows, using a combination of detailed experimental approaches and simulations, that the specific targeting of cancer cells in comparison to non-tumorigenic cells can be achieved through the custom design of multivalent nanoparticles. A theoretical model that provides simple yet quantitative predictions to tune the nanoparticles targeting and cytotoxic properties by their degree of functionalization is developed. As a case study, a system that included a targeting agent and a drug and is amenable to controlled experimental manipulation and theoretical analysis is used. This study shows how at defined functionalization levels multivalent nanoparticles can selectively kill tumor cells, while barely affecting non-tumorigenic cells. This work opens a way to the rational design of multifunctionalized nanoparticles with defined targeting and cytotoxic properties for practical applications. PMID- 28884770 TI - Theoretical modeling of voltage effects and the chemical mechanism in surface enhanced Raman scattering. AB - Theoretical approaches can provide insight into the mechanisms and magnitudes of electromagnetic and chemical effects in surface-enhanced Raman scattering (SERS), properties that are not readily available experimentally. Here, we model the SERS spectra of two geometries of the prototypical Ag20-pyridine cluster using a semiempirical INDO/SCI approach that allows a straightforward decomposition of the enhancement factors at each wavelength into electromagnetic and chemical terms, with proper treatment of resonant charge-transfer contributions to the enhancement. The method also enables us to determine the dependence of the enhancement on the electrochemical potential. We show that the electromagnetic enhancements for the Ag20 cluster are <10 far from resonance but can increase to 102 to 103 on resonance with plasmon excitation in the cluster. The decomposition also shows that for the systems studied here, the chemical enhancements are primarily due to resonance with excited states with significant charge-transfer character. This term is typically <10 but can be >102 at electrochemical potentials where the charge-transfer excited states are resonant with the incoming light, leading to total enhancements of >104. PMID- 28884771 TI - Iron-catalyzed intermolecular cycloaddition of diazo surrogates with hexahydro 1,3,5-triazines. AB - We report here an unprecedented iron-catalyzed cycloaddition reaction of diazo surrogates with hexahydro-1,3,5-triazines, providing five-membered heterocycles in moderate to high yields under mild reaction conditions. This cycloaddition features C-N and C-C bond formation using a cheap iron catalyst. Importantly, different to our former report on a gold-catalyzed system, both donor/donor and donor/acceptor diazo substrates are tolerated in this iron-catalyzed protocol. PMID- 28884772 TI - AFM combined to ATR-FTIR reveals Candida cell wall changes under caspofungin treatment. AB - Fungal pathogens from Candida genus are responsible for severe life-threatening infections and the antifungal arsenal is still limited. Caspofungin, an antifungal drug used for human therapy, acts as a blocking agent of the cell wall synthesis by inhibiting the beta-1,3-glucan-synthase encoded by FKS genes. Despite its efficiency, the number of genetic mutants that are resistant to caspofungin is increasing. An important challenge to improve antifungal therapy is to understand cellular phenomenon that are associated with drug resistance. Here we used atomic force microscopy (AFM) combined to Fourier transform infrared spectroscopy in attenuated total reflection mode (ATR-FTIR) to decipher the effect of low and high drug concentration on the morphology, mechanics and cell wall composition of two Candida strains, one susceptible and one resistant to caspofungin. Our results confirm that caspofungin induces a dramatic cell wall remodelling via activation of stress responses, even at high drug concentration. Additionally, we highlighted unexpected changes related to drug resistance, suggesting that caspofungin resistance associated with FKS gene mutations comes from a combination of effects: (i) an overall remodelling of yeast cell wall composition; and (ii) cell wall stiffening through chitin synthesis. This work demonstrates that AFM combined to ATR-FTIR is a valuable approach to understand at the molecular scale the biological mechanisms associated with drug resistance. PMID- 28884774 TI - High-energy asymmetric supercapacitors based on free-standing hierarchical Co-Mo S nanosheets with enhanced cycling stability. AB - Layered transition metal sulfides (TMS) are emerging as advanced materials for energy storage and conversion applications. In this work, we report a facile and cost-effective anion exchange technique to fabricate a layered, multifaceted, free standing, ultra-thin ternary cobalt molybdenum sulfide nanosheet (Co-Mo-S NS) architecture grown on a 3D porous Ni foam substrate. The unique Co-Mo layered double hydroxides are first synthesized as precursors and consequently transformed into ultra-thin Co-Mo-S NS. When employed as an electrode for supercapacitors, the Co-Mo-S NS delivered an ultra-high specific capacitance of 2343 F g-1 at a current density of 1 mA cm-2 with tremendous rate capability and extraordinary cycling performance (96.6% capacitance retention after 20 000 cycles). Furthermore, assembled Co-Mo-S/nitrogen doped graphene nanosheets (NGNS) in an asymmetric supercapacitor (ASC) device delivered an excellent energy density of 89.6 Wh kg-1, an amazing power density of 20.07 kW kg-1, and superior cycling performance (86.8% capacitance retention after 50 000 cycles). Such exceptional electrochemical performance of Co-Mo-S NS is ascribed to the good electrical contact with the 3D Ni foam, ultra-high contact area with the electrolyte, and enhanced architectural softening during the charging/discharging process. It is expected that the fabricated, unique, ultra-thin Co-Mo-S NS have great potential for future energy storage devices. PMID- 28884775 TI - Modeling of active swimmer suspensions and their interactions with the environment. AB - In this article, we review mathematical models used to study the behaviour of suspensions of micro-swimmers and the accompanying biophysical phenomena, with specific focus on stimulus response. The methods discussed encompass a range of interactions exhibited by the micro-swimmers; including passive hydrodynamic (gyrotaxis) and gravitational (gravitaxis) effects, and active responses to chemical cues (chemotaxis) and light intensities (phototaxis). We introduce the simplest models first, and then build towards more sophisticated recent developments, in the process, identifying the limitations of the former and the new results obtained by the latter. We comment on the accuracy/validity of the models adopted, based on the agreement between theoretical results and experimental observations. We conclude by identifying some of the open problems and associated challenges faced by researchers in the realm of active suspensions. PMID- 28884776 TI - Ruthenium catalyzed beta-C(sp3)-H functionalization on the 'privileged' piperazine nucleus. AB - beta-C(sp3)-H functionalization on the 'privileged' piperazine nucleus has been disclosed using ruthenium catalysis. The ruthenium catalyzed synthesis of a variety of piperazine fused indoles from ortho-piperazinyl (hetero)aryl aldehydes is presented. This transformation takes place via the dehydrogenation of piperazine followed by an intramolecular nucleophilic addition of the transient enamine moiety onto the carbonyl group and aromatization cascade. PMID- 28884777 TI - Ru atom-modified covalent triazine framework as a robust electrocatalyst for selective alcohol oxidation in aqueous electrolytes. AB - This work demonstrates that a single Ru atom-modified covalent triazine framework (Ru-CTF) has selectivity for the electrooxidation of benzyl alcohol in water over the oxygen evolution reaction. Additionally, Ru-CTF displayed higher stability than an immobilized Ru-organometallic complex due to the covalently cross-linked structure of CTF. PMID- 28884778 TI - A bodipy based hydroxylamine sensor. AB - With this research, we have developed a bodipy based system as the first "turn on" fluorescence system for the detection hydroxylamine. PMID- 28884779 TI - Electrochemical ion transfer mediated by a lipophilic Os(ii)/Os(iii) dinonyl bipyridyl probe incorporated in thin film membranes. AB - A new lipophilic dinonyl bipyridyl Os(ii)/Os(iii) complex successfully mediates ion transfer processes across voltammetric thin membranes. An added lipophilic cation-exchanger may impose voltammetric anion or cation transfer waves of Gaussian shape that are reversible and repeatable. The peak potential is found to shift with the ion concentration in agreement with the Nernst equation. The addition of tridodecylmethylammonium nitrate to the polymeric film dramatically reduces the peak separation from 240 mV to 65 mV, and the peak width to a near theoretical value of 85 mV, which agrees with a surface confined process. It is suggested that the cationic additive serves as a phase transfer catalyst. PMID- 28884780 TI - Synthesis of a water-soluble 2,6-helic[6]arene derivative and its strong binding abilities towards quaternary phosphonium salts: an acid/base controlled switchable complexation process. AB - A water-soluble 2,6-helic[6]arene derivative was conveniently synthesized, and it showed strong binding abilities towards quaternary phosphonium salts in aqueous solution. Moreover, an acid/base controlled switchable complexation process was also described. PMID- 28884781 TI - Novel routes to electromagnetic enhancement and its characterisation in surface- and tip-enhanced Raman scattering. AB - Quantitative understanding of the electromagnetic component in enhanced Raman spectroscopy is often difficult to achieve on account of the complex substrate structures utilised. We therefore turn to two structurally simple systems amenable to detailed modelling. The first is tip-enhanced Raman scattering under electron scanning tunnelling microscopy control (STM-TERS) where, appealing to understanding developed in the context of photon emission from STM, it is argued that the localised surface plasmon modes driving the Raman enhancement exist in the visible and near-infrared regime only by virtue of significant modification to the optical properties of the tip and sample metals (gold here). This is due to the strong dc field-induced (~109 V m-1) non-linear corrections to the dielectric function of gold via the third order susceptibility term in the polarisation. Also, sub-5 nm spatial resolution is shown in the modelling. Secondly, we suggest a novel deployment of hybrid plasmonic waveguide modes in surface enhanced Raman scattering (HPWG-SERS). This delivers strong confinement of electromagnetic energy in a ~10 nm oxide 'gap' between a high-index dielectric material of nanoscale width (a GaAs nanorod and a 100 nm Si slab are considered here) and a metal, yielding a monotonic variation in the Raman enhancement factor as a function of wavelength with no long-wavelength cut-off, both features that contrast with STM-TERS. PMID- 28884782 TI - Electrochemical control of strong coupling states between localized surface plasmons and molecule excitons for Raman enhancement. AB - The intensity of Raman scattering from dye molecules strongly coupled with localized surface plasmons of metal nanostructures was controlled by the electrochemical potential. Through in situ electrochemical extinction and surface enhanced Raman scattering measurements, it is found that the redox state of the molecules affects the coupling strength, leading to the change in the intensity of the Raman scattering. Analysis of the Raman spectrum provides information on the molecules in strong coupling states showing effective enhancement of Raman scattering. PMID- 28884783 TI - Ex vivo model unravelling cell distribution effect in hydrogels for cartilage repair. AB - The implantation of chondrocyte-laden hydrogels is a promising cartilage repair strategy. Chondrocytes can be spatially positioned in hydrogels and thus in defects, while current clinical cell therapies introduce chondrocytes in the defect depth. The main aim of this study was to evaluate the effect of spatial chondrocyte distribution on the reparative process. To reduce animal experiments, an ex vivo osteochondral plug model was used and evaluated. The role of the delivered and endogenous cells in the repair process was investigated. Full thickness cartilage defects were created in equine osteochondral plugs. Defects were filled with (A) chondrocytes at the bottom of the defect, covered with a cell-free hydrogel, (B) chondrocytes homogeneously encapsulated in a hydrogel, and (C, D) combinations of A and B with different cell densities. Plugs were cultured for up to 57 days, after which the cartilage and repair tissues were characterized and compared to baseline samples. Additionally, at day 21, the origin of cells in the repair tissue was evaluated. Best outcomes were obtained with conditions C and D, which resulted in well-integrated cartilage-like tissue that completely filled the defect, regardless of the initial cell density. A critical role of the spatial chondrocyte distribution in the repair process was observed. Moreover, the osteochondral plugs stimulated cartilage formation in the hydrogels when cultured in the defects. The resulting repair tissue originated from the delivered cells. These findings confirm the potential of the osteochondral plug model for the optimization of the composition of cartilage implants and for studying repair mechanisms. PMID- 28884784 TI - The Association Between the Use of Zolpidem and the Risk of Alzheimer's Disease Among Older People. AB - OBJECTIVES: To evaluate the association between zolpidem use and the risk of Alzheimer's disease among older people. DESIGN: A retrospective cohort study using data from 2001 to 2011 from the National Health Insurance Research Database. SETTING: Taiwan. PARTICIPANTS: A total of 6,922 patients aged 65 years or older enrolled from January 2002 to December 2004 (the enrollment period). INTERVENTION (EXPOSURE): Zolpidem users were identified as patients who used zolpidem during the enrollment period. The index date was the date of the first zolpidem prescription. Dosage of zolpidem use was defined using cumulative defined daily dose (cDDD) based on the cumulative dosage that patients took within one year after the index date (grouped as: less than 28, 28-90, 91-180, and more than 180 cDDD). MEASUREMENTS: The occurrence of Alzheimer's disease was defined as the time period from the end of one year after the index date to the date of the Alzheimer's disease diagnosis. The propensity score was used to adjust the measured confounders of Alzheimer's disease. Cox proportional hazards models were used to evaluate the association between zolpidem use and the incidence of Alzheimer's disease. RESULTS: Zolpidem users with a high cumulative dose (>180 cDDD) in the first year after initiation had a significantly greater risk of Alzheimer's disease than non-zolpidem users (HR = 2.97, 95% CI = 1.61 5.49) and low cumulative dose (<28 cDDD) users (HR = 4.18, 95% CI = 1.77-9.86). CONCLUSION: We found the use of a high cumulative dose of zolpidem was associated with an increased risk of Alzheimer's disease among older people living in Taiwan. It is advised to use caution when considering long-term use of zolpidem in older patients. PMID- 28884786 TI - Muscle Ultrasound As a Link to Muscle Quality and Frailty in the Clinic. PMID- 28884785 TI - Certolizumab pegol (CDP870) for rheumatoid arthritis in adults. AB - BACKGROUND: Tumour necrosis factor (TNF)-alpha inhibitors are beneficial for the treatment of rheumatoid arthritis (RA) for reducing the risk of joint damage, improving physical function and improving the quality of life. This review is an update of the 2014 Cochrane Review of the treatment of RA with certolizumab pegol. OBJECTIVES: To assess the clinical benefits and harms of certolizumab pegol (CZP) in people with RA who have not responded well to conventional disease modifying anti-rheumatic drugs (DMARDs). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL: Cochrane Library 2016, Issue 9), MEDLINE, Embase, Web of Knowledge, reference lists of articles, clinicaltrials.gov and ICTRP of WHO. The searches were updated from 2014 (date of the last search for the previous version) to 26 September 2016. SELECTION CRITERIA: Randomised controlled trials that compared certolizumab pegol with any other agent, including placebo or methotrexate (MTX), in adults with active RA, regardless of current or prior treatment with conventional disease-modifying anti rheumatic drugs (DMARDs), such as MTX. DATA COLLECTION AND ANALYSIS: Two review authors independently checked search results, extracted data and assessed trial quality. We resolved disagreements by discussion or referral to a third review author. MAIN RESULTS: We included 14 trials in this update, three more than previously. Twelve trials (5422 participants) included measures of benefit. We pooled 11 of them, two more than previously. Thirteen trials included information on harms, (5273 participants). The duration of follow-up varied from 12 to 52 weeks and the range of doses of certolizumab pegol varied from 50 to 400 mg given subcutaneously. In Phase III trials, the comparator was placebo plus MTX in seven trials and placebo in five. In the two Phase II trials the comparator was only placebo.The approved dose of certolizumab pegol, 200 mg every other week, produced clinically important improvements at 24 weeks for the following outcomes:- American College of Rheumatology (ACR) 50% improvement (pain, function and other symptoms of RA): 25% absolute improvement (95% confidence interval (CI) 20% to 33%); number need to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 5); risk ratio (RR) 3.80 (95% CI 2.42 to 5.95), 1445 participants, 5 studies.- The Health Assessment Questionnaire (HAQ): -12% absolute improvement (95% CI -9% to -14%); NNTB of 8 (95% CI 7 to 11); mean difference (MD) - 0.35 (95% CI -0.43 to -0.26; 1268 participants, 4 studies) (scale 0 to 3; lower scores mean better function).- Proportion of participants achieving remission (Disease Activity Score (DAS) < 2.6) absolute improvement 10% (95% CI 8% to 16%); NNTB of 8 (95% CI 6 to 12); risk ratio (RR) 2.94 (95% CI 1.64 to 5.28), 2420 participants, six studies.- Radiological changes: erosion score (ES) absolute improvement -0.29% (95% CI -0.42% to -0.17%); NNTB of 6 (95% CI 4 to 10); MD 0.67 (95% CI -0.96 to -0.38); 714 participants, two studies (scale 0 to 230), but not a clinically important difference.-Serious adverse events (SAEs) were statistically but not clinically significantly more frequent for certolizumab pegol (200 mg every other week) with an absolute rate difference of 3% (95% CI 1% to 4%); number needed to treat for an additional harmful outcome (NNTH) of 33 (95% CI 25 to 100); Peto odds ratio (OR) 1.47 (95% CI 1.13 to 1.91); 3927 participants, nine studies.There was a clinically significant increase in all withdrawals in the placebo groups (for all doses and at all follow-ups) with an absolute rate difference of -29% (95% CI -16% to -42%), NNTH of 3 (95% CI 2 to 6), RR 0.47 (95% CI 0.39 to 0.56); and there was a clinically significant increase in withdrawals due to adverse events in the certolizumab groups (for all doses and at all follow-ups) with an absolute rate difference of 2% (95% CI 0% to 3%); NNTH of 58 (95% CI 28 to 329); Peto OR 1.45 (95% CI 1.09 to 1.94) 5236 participants Twelve studies.We judged the quality of evidence to be high for ACR50, DAS remission, SAEs and withdrawals due to adverse events, and moderate for HAQ and radiological changes, due to concerns about attrition bias. For all withdrawals we judged the quality of evidence to be moderate, due to inconsistency. AUTHORS' CONCLUSIONS: The results and conclusions did not change from the previous review. There is a moderate to high certainty of evidence from randomised controlled trials that certolizumab pegol, alone or combined with methotrexate, is beneficial in the treatment of RA for improved ACR50 and health related quality of life, an increased chance of remission of RA, and reduced joint damage as seen on x-ray. Fewer people stopped taking their treatment, but most of these who did stopped due to serious adverse events. Adverse events were more frequent with active treatment. We found a clinically but not statistically significant risk of serious adverse events. PMID- 28884787 TI - Ultrasonic Echo Intensity as a New Noninvasive In Vivo Biomarker of Frailty. AB - OBJECTIVES: To investigate whether muscle quality based on echo intensity (EI) is associated with muscle strength (MS) and correlates with risk of frailty in elderly outpatients. DESIGN: Cross-sectional, experimental study. SETTING: Outpatient clinic. PARTICIPANTS: Individuals aged 20 to 90 (N = 112). Individuals aged 20 to 59 participated as controls. Those aged 60 and older participated in the experimental group and were subdivided into robust, prefrail, and frail according to the Fried frailty criteria. MEASUREMENTS: EI, muscle thickness (MT), and subcutaneous fat thickness (SFT) of the anterior compartment of the thigh were measured using ultrasound images. MS was quantified using a hand dynamometer. Participants responded to a questionnaire asking about demographic and physical characteristics, frailty criteria, and quality of life. RESULTS: There was a significant negative correlation between EI and MS (Women: correlation coefficient (r) = -.522, P < .001; Men: r = -.355, P < .001). A similar trend was found for MT but not SFT. Statistically significant differences were also found between EI values, MT, MS, and quality of life and the different stages of frailty (P < .01). CONCLUSIONS: Higher levels of EI were associated with lower levels of strength and greater frailty. These results, although needing to be replicated in larger and more-diverse populations, suggest that EI obtained using ultrasound images might be used as noninvasive imaging biomarker of frailty in elderly adults and opens the possibility of accurately testing interventions performed to prevent it. PMID- 28884788 TI - Triple cancers concurrently detected in a case of antitranscriptional intermediary factor-1gamma antibody-positive dermatomyositis. PMID- 28884791 TI - How does mutation affect the distribution of phenotypes? AB - The potential for mutational processes to influence patterns of neutral or adaptive phenotypic evolution is not well understood. If mutations are directionally biased, shifting trait means in a particular direction, or if mutation generates more variance in some directions of multivariate trait space than others, mutation itself might be a source of bias in phenotypic evolution. Here, we use mutagenesis to investigate the affect of mutation on trait mean and (co)variances in zebrafish, Danio rerio. Mutation altered the relationship between age and both prolonged swimming speed and body shape. These observations suggest that mutational effects on ontogeny or aging have the potential to generate variance across the phenome. Mutations had a far greater effect in males than females, although whether this is a reflection of sex-specific ontogeny or aging remains to be determined. In males, mutations generated positive covariance between swimming speed, size, and body shape suggesting the potential for mutation to affect the evolutionary covariation of these traits. Overall, our observations suggest that mutation does not generate equal variance in all directions of phenotypic space or in each sex, and that pervasive variation in ontogeny or aging within a cohort could affect the variation available to evolution. PMID- 28884789 TI - Imputation of Gait Speed for Noncompleters in the 400-Meter Walk: Application to the Lifestyle Interventions for Elders Study. AB - When a 400-m walk test with time constraint (in 15 minutes) is administered, analysis of the associated 400-m gait speed can be challenging because some older adults are unable to complete the distance in time (noncompleters). A simplistic imputation method is to calculate the observed speeds of the noncompleters as the partially completed distance divided by the corresponding amount of elapsed time as an estimate of gait speed over the full 400-m distance. This common practice has not been validated to the best of our knowledge. We propose a Bayesian multiple imputation (MI) method to impute the unobserved 400-m gait speed for noncompleters. Briefly, MI is performed under the assumption that the unobserved 400-m gait speed of noncompleters is left-censored from a normal distribution. We illustrate the application of the Bayesian MI method using longitudinal data collected from the Lifestyle Interventions for Elders (LIFE) study. A simulation study was performed to assess the bias in estimation of the mean 400-m gait speed using both methods. The results indicate that the simplistic imputation method tends to overestimate the population mean, whereas the Bayesian MI method yields minimal bias as the sample size increases. PMID- 28884790 TI - Fitness change in relation to mutation number in spontaneous mutation accumulation lines of Chlamydomonas reinhardtii. AB - Although all genetic variation ultimately stems from mutations, their properties are difficult to study directly. Here, we used multiple mutation accumulation (MA) lines derived from five genetic backgrounds of the green algae Chlamydomonas reinhardtii that have been previously subjected to whole genome sequencing to investigate the relationship between the number of spontaneous mutations and change in fitness from a nonevolved ancestor. MA lines were on average less fit than their ancestors and we detected a significantly negative correlation between the change in fitness and the total number of accumulated mutations in the genome. Likewise, the number of mutations located within coding regions significantly and negatively impacted MA line fitness. We used the fitness data to parameterize a maximum likelihood model to estimate discrete categories of mutational effects, and found that models containing one to two mutational effect categories (one neutral and one deleterious category) fitted the data best. However, the best-fitting mutational effects models were highly dependent on the genetic background of the ancestral strain. PMID- 28884792 TI - Profiling of Single-Cell Transcriptomes. AB - Complex biological systems are composed of multiple cell types whose transcriptional activity can vary due to differences in cell state, environmental stimulation, or intrinsic programs. Conventional bulk analysis methods capture the average transcriptional programs of the cell population, thus missing the unique cellular signature of each single cell. In recent years, the development of single-cell RNA-sequencing (scRNA-seq) technologies has provided a powerful approach to dissect the cellular heterogeneity of complex biological systems. However, such approaches require specialized equipment or are costly. In this article, we describe an improved Smart-seq2-based method to profile the transcriptome of hundreds of single cells simultaneously, without utilizing commercial kits or requiring any specialized single-cell capture/library preparation tools. Moreover, we introduce the Automated Single-cell Analysis Pipeline (ASAP), which allows researchers without strong computational expertise to explore scRNA-seq data using a wide range of commonly used algorithms and sophisticated visualization tools. (c) 2017 by John Wiley & Sons, Inc. PMID- 28884793 TI - Using Vascular Landmarks to Orient 3D Optical Coherence Tomography Images of the Mouse Eye. AB - Comparing 3D structural information obtained by optical coherence tomography (OCT) requires accurate alignment of images acquired from individual subjects. Despite the widespread use of OCT to image the anterior and posterior mouse eye, few approaches to align the resulting image data have been described, in part due to a lack of well-characterized landmarks that are suitable for alignment. Here, we provide an OCT acquisition and analysis protocol that incorporates the use of the long posterior ciliary arteries as landmarks. In mammals, these two large choroidal vessels lie in a plane approximately parallel to the horizon. Our OCT imaging approach resolves these vessels in the mouse eye and suggests that their location is reproducible. The protocol may be useful for preparing 3D OCT data to compare experimental cohorts of mice and for standardizing results from independent research laboratories. (c) 2017 by John Wiley & Sons, Inc. PMID- 28884794 TI - Pathology Evaluation of Developmental Phenotypes in Neonatal and Juvenile Mice. AB - Necropsy (or autopsy) is the post mortem dissection of an animal to examine and collect organs and tissues in order to understand the effects and causes of disease. The systematic harvesting of samples at necropsy is an essential step in defining the reason for an unexpected death and in characterizing the features (i.e., phenotype) of a newly discovered condition. Phenotypic evaluation of young (neonatal and juvenile) mice emphasizes morphologic (macroscopic and microscopic) techniques and biochemical (clinical chemistry, hematologic, and molecular) analyses. This paper describes the most common procedures utilized to gather phenotypic data from neonatal and juvenile mice, with advanced alternatives for preparing special specimens (e.g., blood smears, electron microscopic samples). These techniques are applicable to young mice of all strains and are effective regardless of the fundamental cause, including genetically engineered or spontaneous mutations and exposure to pathogens or xenobiotic agents (i.e., foreign chemicals). (c) 2017 by John Wiley & Sons, Inc. PMID- 28884795 TI - Assortment and the analysis of natural selection on social traits. AB - A central problem in evolutionary biology is to determine whether and how social interactions contribute to natural selection. A key method for phenotypic data is social selection analysis, in which fitness effects from social partners contribute to selection only when there is a correlation between the traits of individuals and their social partners (nonrandom phenotypic assortment). However, there are inconsistencies in the use of social selection that center around the measurement of phenotypic assortment. Here, we use data analysis and simulations to resolve these inconsistencies, showing that: (i) not all measures of assortment are suitable for social selection analysis; and (ii) the interpretation of assortment, and how to detect nonrandom assortment, will depend on the scale at which it is measured. We discuss links to kin selection theory and provide a practical guide for the social selection approach. PMID- 28884796 TI - The evolution of between-species reproductive interference capability under different within-species mating regimes. AB - Sexual selection sometimes favors male traits that benefit their bearers, but harm their mates. The harmful effects of male traits may also extend to females of other species via heterospecific mating interactions. This could affect the coexistence of closely related species during secondary contact. We examined the evolution of the interspecific interfering capability of a beetle (Callosobruchus chinensis) with a congener (C. maculatus) using C. chinensis males reared under conditions of monogamy and polygamy for 17 generations. After experimental evolution, C. chinensis males reared under polygamous conditions imposed greater impacts on offspring production by C. maculatus females than did C. chinensis males reared under monogamous conditions. However, the mechanism by which differential mating regimes altered the effect of C. chinensis males on C. maculatus females was unclear, because we did not find evidence for the expected genital evolution in C. chinensis, despite their body size divergence. Our findings suggest that traits that originally evolved through sexual selection in two allopatric species could influence the coexistence of these species or the likelihood of reinforcement during secondary contact. PMID- 28884797 TI - SAPHO syndrome associated with hidradenitis suppurativa and pyoderma gangrenosum successfully treated with adalimumab and methotrexate: a case report and review of the literature. AB - SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a rare inflammatory condition describing the combination of skin, bone, and joint manifestations that has a heterogeneous presentation. We report a case of severe SAPHO syndrome in association with hidradenitis suppurativa and pyoderma gangrenosum in a 27-year-old male. The patient had an initial migratory arthritis affecting the knees, ankles, metacarpophalangeal joints, proximal interphalangeal joints, wrists, shoulder, and lower back, which progressed to a persistent arthritis and swelling at the sternum, shoulders, wrists, hands, feet, and lower back. Radiographic changes were consistent with the diagnosis of SAPHO syndrome. Serum proinflammatory cytokine levels were significantly elevated and improved substantially after 3 months of therapy. Rationale for therapy in this patient was the observation that tumor necrosis alpha antagonists have been successfully used in SAPHO syndrome, and since arthropathy was so prominent in our patient, we elected to use adalimumab combined with methotrexate. PMID- 28884798 TI - Neonatal skin care: what should we do? A four-week follow-up randomized controlled trial at Zagazig University Hospitals. AB - INTRODUCTION: Taking care of newborn skin is necessary to avoid skin infections. The normal daily exposure to external factors affects the skin negatively. Skin hygiene and proper skin cleansing as well as protection of the infant skin barrier are essential to maintain barrier function and overall infant health. AIM: The aim of this work is to assess the neonatal skin care effectiveness in promotion of normal skin development and protection of the optimal skin function by avoiding the different neonatal skin disorders which cause skin infection. CONCLUSION: In conclusion, proper care and good hygiene of the normal mature neonatal skin are essential to maintain skin barrier function and overall health. This is achieved by optimizing epidermal barrier integrity that includes: bathing and using emollient; preventing and managing infections and skin injury; minimizing transepidermal water loss (TEWL); minimizing heat loss and percutaneous absorption of toxins. Baby bath products as well as baby wipes are safe to use and do not appear to affect an infant's skin barrier integrity. It is therefore sensible to use cleansers that have been specially designed for baby's skin, which are pH neutral and very mild to avoid irritant dermatitis and allergic dermatitis. PMID- 28884799 TI - Teriflunomide-induced psoriasiform changes of fingernails: a new example of paradoxical side effect? PMID- 28884800 TI - A photoconverter gel-assisted blue light therapy for the treatment of rosacea. PMID- 28884801 TI - Neurobiology of developmental coordination disorder: time to raise our game. PMID- 28884802 TI - A female Viking warrior confirmed by genomics. AB - OBJECTIVES: The objective of this study has been to confirm the sex and the affinity of an individual buried in a well-furnished warrior grave (Bj 581) in the Viking Age town of Birka, Sweden. Previously, based on the material and historical records, the male sex has been associated with the gender of the warrior and such was the case with Bj 581. An earlier osteological classification of the individual as female was considered controversial in a historical and archaeological context. A genomic confirmation of the biological sex of the individual was considered necessary to solve the issue. MATERIALS AND METHODS: Genome-wide sequence data was generated in order to confirm the biological sex, to support skeletal integrity, and to investigate the genetic relationship of the individual to ancient individuals as well as modern-day groups. Additionally, a strontium isotope analysis was conducted to highlight the mobility of the individual. RESULTS: The genomic results revealed the lack of a Y-chromosome and thus a female biological sex, and the mtDNA analyses support a single-individual origin of sampled elements. The genetic affinity is close to present-day North Europeans, and within Sweden to the southern and south-central region. Nevertheless, the Sr values are not conclusive as to whether she was of local or nonlocal origin. DISCUSSION: The identification of a female Viking warrior provides a unique insight into the Viking society, social constructions, and exceptions to the norm in the Viking time-period. The results call for caution against generalizations regarding social orders in past societies. PMID- 28884803 TI - Long-Term Research in Ecology and Evolution (LTREE): 2015 survey data. AB - To systematically assess views on contributions and future activities for long term research in ecology and evolution (LTREE), we conducted and here provide data responses and associated metadata for a survey of ecological and evolutionary scientists. The survey objectives were to: (1) Identify and prioritize research questions that are important to address through long-term, ecological field experiments; and (2) understand the role that these experiments might play in generating and applying ecological and evolutionary knowledge. The survey was developed adhering to the standards of the American Association for Public Opinion Research. It was administered online using Qualtrics Survey Software. Survey creation was a multi-step process, with questions and format developed and then revised with, for example, input from an external advisory committee comprising senior and junior ecological and evolutionary researchers. The final questionnaire was released to ~100 colleagues to ensure functionality and then fielded 2 d later (January 7th , 2015). Two professional societies distributed it to their membership, including the Ecological Society of America, and it was posted to three list serves. The questionnaire was available through February 8th 2015 and completed by 1,179 respondents. The distribution approach targeted practicing ecologists and evolutionary biologists in the U.S. Quantitative (both ordinal and categorical) closed-ended questions used a predefined set of response categories, facilitating direct comparison across all respondents. Qualitative, open-ended questions, provided respondents the opportunity to develop their own answers. We employed quantitative questions to score views on the extent to which long-term experimental research has contributed to understanding in ecology and evolutionary biology; its role compared to other approaches (e.g., short-term experiments); justifications for and caveats to long-term experiments; and the relative importance of incentives for conducting long-term research. Qualitative questions were used to assess community views on the most important topics and questions for long-term research to address, and primary incentives and challenges to realizing this work. Finally, demographic data were collected to determine if views were conditional on such things as years of experience and field of expertise. The final questionnaire and all responses are provided for unrestricted use. PMID- 28884804 TI - Frequent and parallel habitat transitions as driver of unbounded radiations in the Cape flora. AB - The enormous species richness in the Cape Floristic Region (CFR) of Southern Africa is the result of numerous radiations, but the temporal progression and possible mechanisms of these radiations are still poorly understood. Here, we explore the macroevolutionary dynamics of the Restionaceae, which include 340 species that are found in all vegetation types in the Cape flora and are ecologically dominant in fynbos. Using an almost complete (i.e., 98%) species level time calibrated phylogeny and models of diversification dynamics, we show that species diversification is constant through the Cenozoic, with no evidence of an acceleration with the onset of the modern winter-wet climate, or a recent density-dependent slowdown. Contrary to expectation, species inhabiting the oldest (montane) and most extensive (drylands) habitats did not undergo higher diversification rates than species in the younger (lowlands) and more restricted (wetland) habitats. We show that the rate of habitat transitions is more closely related to the speciation rate than to time, and that more than a quarter of all speciation events are associated with habitat transitions. This suggests that the unbounded Restionaceae diversification resulted from numerous, parallel, habitat shifts, rather than persistence in a habitat stimulating speciation. We speculate that this could be one of the mechanisms resulting in the hyperdiverse Cape flora. PMID- 28884806 TI - Neurophysiological mechanisms and functional impact of mirror movements in children with unilateral spastic cerebral palsy. AB - : Children with unilateral spastic cerebral palsy (CP) often have mirror movements, i.e. involuntary imitations of unilateral voluntary movements of the contralateral upper extremity. The pathophysiology of mirror movements has been investigated in small and heterogeneous cohorts in the literature. Specific pathophysiology of mirror movements and their impact on upper extremity function require systematic investigation in larger and homogeneous cohorts of children with unilateral spastic CP. Here we review two possible neurophysiological mechanisms underlying mirror movements in children with CP and those with typical development: (1) an ipsilateral corticospinal tract projecting from the contralesional motor cortex (M1) to both upper extremities; (2) insufficient interhemispheric inhibition between the two M1s. We also discuss clinical implications of mirror movements in children with unilateral CP and suggest that a thorough examination of the relationship between the pathophysiology and clinical manifestations of mirror movements is warranted. We suggest two premises: (1) the presence of mirror movements is indicative of an ipsilateral corticospinal tract reorganization; and (2) the corticospinal tract organization may affect patients' responses to certain treatment. If these premises are supported through future research, mirror movements should be clinically evaluated for patient selection to maximize benefits of therapy, hence promoting individualized medicine in this population. WHAT THIS PAPER ADDS: Mirror movements may be indicative of the underlying corticospinal tract reorganization in children with unilateral spastic cerebral palsy (CP). Future research will benefit from systematic investigations of the relationship between mirror movements and its pathophysiology. Mirror movements may be a potential biomarker for individualized medicine in children with unilateral spastic CP. PMID- 28884805 TI - Evaluation of the relation between lipid coat, transepidermal water loss, and skin pH. AB - OBJECTIVE: The epidermis is an epidermal barrier which accumulates lipid substances and participates in skin moisturizing. An evaluation of the epidermal barrier efficiency can be made, among others, by the measurement of the following values: the lipid coat, the transepidermal water loss (TEWL) index, and pH. MATERIALS: The study involved 50 Caucasian, healthy women aged 19-35 years (mean 20.56). METHODS: Measurements were made using Courage & Khazaka Multi Probe Adapter MPA 580: Tewameter TM 300, pH-Meter PH 905, Sebumeter SM 815. The areas of measurements included forehead, nose, left cheek, right cheek, chin, and thigh. RESULTS: In the T-zone, the lipid coat was in the range between 0 and 270 MUg/cm2 (mean 128 MUg/cm2 ), TEWL between 1 and 55 g/m2 /h (mean 11.1 g/m2 /h), and pH 4.0-5.6 (mean 5.39). Lower values of the lipid coat up to 100 MUg/cm2 were accompanied by TEWL greater than 30 g/m2 /h and less acidic pH of 5.6-9.0. In the U-zone the range of lipid coat was up to 200 MUg/cm2 (mean 65.2 MUg/cm2 ), the skin pH remained 4.0-5.6 (mean 5.47), and TEWL was in the range between 1 and 20 g/m2 /h (mean 8.7 g/m2 /h). Lower values of the lipid coat up to 100 MUg/cm2 were accompanied by TEWL between 1 and 20 g/m2 /h and less acidic pH of 5.6-9.0. High values of the lipid coat between 180 and 200 MUg/cm2 were connected with TEWL of 1-15 g/m2 /h. On the skin of the thigh, we observed a very thin lipid coat - 35 MUg/cm2 (mean 5.6 MUg/cm2 ), pH (mean 5.37), and TEWL (mean 8.5 g/m2 /h) were considered by us to be within regular limits. CONCLUSIONS: In the T-zone, a thinner lipid coat resulted in relatively high TEWL and pH levels changing toward alkaline. In the U-zone, thinner lipid coat was accompanied by lower TEWL and pH changing toward alkaline. We also observed that lower values of lipid coat up to 100 MUg/cm2 were associated with higher pH values ranging toward the basic character pH 5.6-9.0). PMID- 28884807 TI - Co-creation by the ABIM Geriatric Medicine Board and the AGS - Helping Move Geriatrics Forward. AB - The American board of internal medicine (ABIM) establishes standards for physicians. The American geriatrics society (AGS) is a not-for-profit membership organization of nearly 6,000 health professionals devoted to improving the health, independence, and quality of life of all older people. Beginning in 2013, ABIM redesigned its governance structure, including the role of the specialty boards. Specialty boards are charged with responsibilities for oversight in four main areas: (1) the assessments used in initial certification and maintenance of certification (MOC); (2) medical knowledge self-assessment and practice assessment in the specialty; (3) building relationships with relevant professional societies and other organizational stakeholders; and (4) issues related to training requirements for initial certification eligibility within the specialty. The aim of this paper is to inform the geriatrics community regarding the function of geriatric medicine board (GMB) of the ABIM, and to invite the geriatrics community to fully engage with and leverage the GMB as a partner to: (1) develop better certification examinations and processes, identifying better knowledge and practice assessments, and in establishing appropriate training and MOC requirements for geriatric medicine; (2) leverage ABIM assets to conduct applied research to guide the field in the areas of training and certification and workforce development in geriatric medicine; (3) make MOC relevant for practicing geriatricians. Active engagement of the geriatrics community with ABIM and the GMB will ensure that certification in geriatric medicine provides the greatest possible value and meaning to physicians, patients, and the public. PMID- 28884808 TI - Fraction magnitude understanding and its unique role in predicting general mathematics achievement at two early stages of fraction instruction. AB - BACKGROUND: Prior studies on fraction magnitude understanding focused mainly on students with relatively sufficient formal instruction on fractions whose fraction magnitude understanding is relatively mature. AIM: This study fills a research gap by investigating fraction magnitude understanding in the early stages of fraction instruction. It extends previous findings to children with limited and primary formal fraction instruction. SAMPLE(S): Thirty-five fourth graders with limited fraction instruction and forty fourth graders with primary fraction instruction were recruited from a Chinese primary school. METHODS: Children's fraction magnitude understanding was assessed with a fraction number line estimation task. Approximate number system (ANS) acuity was assessed with a dot discrimination task. Whole number knowledge was assessed with a whole number line estimation task. General reading and mathematics achievements were collected concurrently and 1 year later. RESULTS: In children with limited fraction instruction, fraction representation was linear and fraction magnitude understanding was concurrently related to both ANS and whole number knowledge. In children with primary fraction instruction, fraction magnitude understanding appeared to (marginally) significantly predict general mathematics achievement 1 year later. CONCLUSIONS: Fraction magnitude understanding emerged early during formal instruction of fractions. ANS and whole number knowledge were related to fraction magnitude understanding when children first began to learn about fractions in school. The predictive value of fraction magnitude understanding is likely constrained by its sophistication level. PMID- 28884809 TI - The relationship between motor skills and psychosocial factors in young children: A test of the elaborated environmental stress hypothesis. AB - BACKGROUND: The elaborated environmental stress hypothesis (EESH) provides a framework that describes how motor skills may indirectly cause internalizing problems through various mediating psychosocial factors. While there is evidence to support this framework, little is known about how the proposed relationships may vary across different stages of development. AIMS: This study aimed to investigate whether peer problems and perceived self-competence mediated the relationship between motor skills and internalizing problems in pre-primary children, and at 18-month follow up. SAMPLE: A community sample of 197 pre primary school children (M = 5.40 years, SD = 0.30 years; 102 males, 95 females) participated at Time 1, with 107 completing the Time 2 follow-up. METHODS: Standardized instruments were used to measure motor skills and verbal IQ. Perceived self-competence was measured using a self-report measure. Participant peer problems and internalizing problems were measured using teacher report. Age, gender, and verbal IQ were included as covariates. RESULTS: Mediation analysis using PROCESS showed that the relationship between motor skills and internalizing problems was mediated by peer problems at Time 1. At Time 2, the relationship was mediated by peer problems and perceived physical competence. CONCLUSIONS: The current results indicate the EESH may function differently across different periods of development. The transition from pre-primary to Grade 1 represents a time of important cognitive and psychosocial development, which has implications for how the relationship between motor skills and internalizing problems can be understood. These findings highlight potential age-appropriate targets for psychomotor interventions aiming to improve the emotional well-being of young children. PMID- 28884810 TI - Comparison between the Valsalva maneuver and intraoperative traction measurements in pelvic organ prolapse assessment. AB - OBJECTIVE: To compare the assessment of pelvic organ prolapse (POP) between the Pelvic Organ Prolapse Quantification (POP-Q) system with Valsalva maneuver and intraoperative measurement with mechanical traction. METHODS: A prospective observational study included 100 women with POP attending a tertiary urogynecology clinic in the UK and undergoing vaginal prolapse surgical procedures between October 2011 and October 2014. The women were examined in the clinic using POP-Q with the Valsalva maneuver and in the operating theater under general anesthesia with mechanical traction. The two sets of measurements were compared. RESULTS: All POP-Q measurements obtained with traction demonstrated significantly higher descent as compared with those measured by Valsalva maneuver (mean differences: Aa 0.64 cm; Ap 1.32 cm; Ba 0.96 cm; Bp 1.34 cm; C 3.57 cm; D 3.40 cm; all P<0.001). The perineal body and total vaginal lengths did not differ significantly. CONCLUSION: Measurements of six POP-Q points obtained with traction showed a higher grade of POP than those assessed with Valsalva maneuver. On this basis, surgeons might decide on the extent of surgical procedure after examination under anesthesia; however, preoperative patient counselling would be essential to obtain consent for this approach. The clinical significance of the findings requires further evaluation. PMID- 28884812 TI - Cross-cultural similarities and differences in motives to forgive: A comparison between and within cultures. AB - Recently, researchers have begun to explore people's motives to forgive those who have offended them. Using a recall method, we examined whether such motives (relationship-, offender- or self-focused) differ between and within cultures that are more collectivistic (Moluccan Islands in Indonesia) or more individualistic (the Netherlands) and whether this depends on people's relationship with the offender. More specifically, we examined the idea that other-focused motives should be more important in cultures that are more collectivistic and that self-focused motives should prevail in more individualistic cultures. We found that Moluccan participants indeed endorsed relationship- and offender-focused motives more than Dutch participants. Moluccan and Dutch participants did not, however, differ in the extent to which they endorsed self-focused motives. Furthermore, Dutch participants were more likely to endorse relationship motives (especially in close relations) than self-focused motives. For Moluccan participants, relationship-, offender- and self-focused motives were equally important and also did not depend on how close they were with the offender. Differences between the samples could not be explained by the extent to which people defined themselves as more independent or interdependent. The implications of these findings for future research on forgiveness motives are discussed. PMID- 28884811 TI - Repeated cervical length measurements for the verification of short cervical length. AB - OBJECTIVE: To determine if the verification of short cervical length with a repeated measurement improved the identification of patients with short cervical length at increased risk of preterm delivery. METHODS: The present secondary analysis analyzed prospective cohort study data from patients with singleton pregnancies without a history of preterm delivery who presented for obstetric care in the Netherlands and delivered between November 18, 2009, and January 1, 2013. Cervical length was measured during standard anomaly scan and a second measurement was performed if the cervical length was 30 mm of shorter. Logistic regression and Cox proportional hazards modeling were used to evaluate associations between cervical length measurements and spontaneous preterm delivery before 37 weeks of pregnancy. RESULTS: Cervical length measurements from 12 358 patients were included; 221 (1.8%) had an initial cervical length measurement of 30 mm or shorter. A second cervical length measurement was performed for 167 (75.6%) patients; no differences were identified in the odds of spontaneous preterm delivery when evaluated using the first, second, or a mean of both measurements, regardless of whether cervical length was analyzed as a continuous or dichotomous variable. CONCLUSION: Among patients with singleton pregnancies, verification of short cervical length did not improve the identification of short cervical length. PMID- 28884813 TI - Adult-onset brain tumors and neurodegeneration: Are polyphenols protective? AB - Aging is a primary risk factor for both neurodegenerative disorders (NDs) and tumors such as adult-onset brain tumors. Since NDs and tumors are severe, disabling, progressive and often incurable conditions, they represent a pressing problem in terms of human suffering and economic costs to the healthcare systems. The current challenge for physicians and researchers is to develop new therapeutic strategies in both areas to improve the patients' quality of life. In addition to genetics and environmental stressors, the increase in cellular oxidative stress as one of the potential common etiologies has been reported for both disorders. Recently, the scientific community has focused on the beneficial effects of dietary antioxidant classes, known as nutraceuticals, such as carotenoids, vitamins, and polyphenols. Among these compounds, polyphenols are considered to be one of the most bioactive agents in neurodegeneration and tumor prevention. Despite the beneficial activity of polyphenols, their poor bioavailability and inefficient delivery systems are the main factors limiting their use in medicine and functional food. The development of polymeric nanoparticle-based delivery systems able to encapsulate and preserve polyphenolic compounds may represent a promising tool to enhance their stability, solubility, and cell membrane permeation. In the present review we provide an overview of the main polyphenolic compounds used for ND and brain tumor prevention and treatment that explores their mechanisms of action, recent clinical findings and principal factors limiting their application in medicine. PMID- 28884814 TI - Insights into the genetic structure of the rabbitfish Chimaera monstrosa (Holocephali) across the Atlantic-Mediterranean transition zone. AB - A comparison of the genetic structure of Chimaera monstrosa populations from the Atlantic Ocean and the Mediterranean Sea was carried out using mitochondrial DNA analysis. Results indicate high and significant pairwise PhiST values with no shared haplotypes between the two areas. Furthermore, migration rate estimates suggested absence of gene flow between the two basins. These findings, coupled with the species vertical distribution, suggest that the shallow depth of the Strait of Gibraltar may act as a barrier limiting the dispersal capabilities of these populations, which likely became separated at the end of the middle Pleistocene. PMID- 28884815 TI - The effect of expressive writing on the error-related negativity among individuals with chronic worry. AB - The error-related negativity (ERN), an ERP elicited immediately after errors, is enlarged among individuals with anxiety. The relationship between anxiety and enlarged ERN has spurred interest in understanding potential therapeutic benefits of decreasing its amplitude within anxious individuals. The current study used a tailored intervention-expressive writing-in an attempt to reduce the ERN among a sample of individuals with chronic worry. Consistent with hypotheses, the ERN was reduced in the expressive writing group compared to an unrelated writing control group. Findings provide experimental support that the ERN can be reduced among anxious individuals with tailored interventions. Expressive writing may serve to "offload" worries from working memory, therefore relieving the distracting effects of worry on cognition as reflected in a decreased ERN. PMID- 28884816 TI - Exploiting off-targeting in guide-RNAs for CRISPR systems for simultaneous editing of multiple genes. AB - Bioinformatics tools to design guide-RNAs (gRNAs) in Clustered Regularly Interspaced Short Palindromic Repeats systems mostly focused on minimizing off targeting to enhance efficacy of genome editing. However, there are circumstances in which off-targeting might be desirable to target multiple genes simultaneously with a single gRNA. We termed these gRNAs as promiscuous gRNAs. Here, we present a computational workflow to identify promiscuous gRNAs that putatively bind to the region of interest for a defined list of genes in a genome. We experimentally validated two promiscuous gRNA for gene deletion, one targeting FAA1 and FAA4 and one targeting PLB1 and PLB2, thus demonstrating that multiplexed genome editing through design of promiscuous gRNA can be performed in a time and cost-effective manner. PMID- 28884817 TI - Association Between CYP2C19*17 Alleles and pH Probe Testing Outcomes in Children With Symptomatic Gastroesophageal Reflux. AB - Esophageal pH monitoring remains a primary diagnostic tool for detecting gastroesophageal reflux disease (GERD). GERD that is refractory to proton pump inhibitor (PPI) medications may be related to CYP2C19 variants. Current PPI dosing practices in children do not take into account CYP2C19 allelic variants, which may lead to underdosing and subsequently to a misperception of PPI therapy failure. We hypothesized that pH probe acid exposure outcomes associate with CYP2C19*17 alleles among children with clinical concern for GERD. We identified a retrospective cohort of 74 children (age range 0.71-17.1 years, mean 8.5, SD 4.6) with stored endoscopic tissue samples and who had also undergone esophageal pH testing while on PPI therapy. These individuals were genotyped for common CYP2C19 alleles and were dichotomized to either CYP2C19*17 allelic carriers without corresponding loss of function alleles as cases vs controls. Associations between pH probe acid exposure outcomes and CYP2C19*17 alleles were investigated. Compared to controls, children who carry CYP2C19*17 alleles without corresponding loss-of-function alleles demonstrated statistically significant longer times with pH < 4 (76.46 vs 33.47 minutes, P = .03); and higher percent of time with pH < 4.0 (5.71 vs 2.67 minutes, P = .04). These findings remained statistically significant using multiple-regression modeling with test duration, PPI dose, and race as confounding variables. PPI therapy in children with *17 alleles may be better optimized with CYP2C19 genotype-guided dosing prior to pH probe testing. PMID- 28884818 TI - The Effect of Medicaid on Dental Care of Poor Adults: Evidence from the Oregon Health Insurance Experiment. AB - OBJECTIVE: To evaluate the effect of Medicaid coverage on dental care outcomes, a major health concern for low-income populations. DATA SOURCES: Primary and secondary data on health care use and outcomes for participants in Oregon's 2008 Medicaid lottery. STUDY DESIGN: We used the lottery's random selection to gauge the causal effects of Medicaid on dental care needs, medication, and emergency department visits for dental care. DATA COLLECTION: Data were collected for lottery participants over 2 years, including mail surveys (N = 23,777) and in person questionnaires (N = 12,229). Emergency department (ED) records were matched to lottery participants in Portland (N = 24,646). PRINCIPAL FINDINGS: Medicaid coverage significantly reduced the share of respondents who reported needing dental care (-9.8 percentage points, p < .001) or having unmet dental care needs (-13.5 percentage points, p < 0.001). Medicaid doubled the share visiting the ED for dental care (+2.6 percentage points, p = .003) and the use of anti-infective medications often prescribed for dental care, but it had no detectable effect on uncovered dental care or out-of-pocket spending. CONCLUSIONS: Expansion of Medicaid covering emergency dental care substantially reduced unmet need for dental care, increasing ED dental visits and medication use, while not changing patient use of uncovered dental services. PMID- 28884819 TI - A three-dimensional statistical model for imaged microstructures of porous polymer films. AB - A thresholded Gaussian random field model is developed for the microstructure of porous materials. Defining the random field as a solution to stochastic partial differential equation allows for flexible modelling of nonstationarities in the material and facilitates computationally efficient methods for simulation and model fitting. A Markov Chain Monte Carlo algorithm is developed and used to fit the model to three-dimensional confocal laser scanning microscopy images. The methods are applied to study a porous ethylcellulose/hydroxypropylcellulose polymer blend that is used as a coating to control drug release from pharmaceutical tablets. The aim is to investigate how mass transport through the material depends on the microstructure. We derive a number of goodness-of-fit measures based on numerically calculated diffusion through the material. These are used in combination with measures that characterize the geometry of the pore structure to assess model fit. The model is found to fit stationary parts of the material well. PMID- 28884820 TI - Endoluminal weight loss and metabolic therapies: current and future techniques. AB - Obesity is a public health epidemic associated with a number of comorbidities, most notably type 2 diabetes and hypertension, as well as elevated all-cause mortality. The treatment for obesity and its associated comorbidities has most recently expanded into the field of bariatric endoscopy. This field bridges a gap between lifestyle counseling with or without pharmaceutical treatment and the most effective treatment of obesity, bariatric surgery. Because of its minimally invasive nature, bariatric endoscopic therapy has the potential to appeal to the large sector of the obese population that resists surgery, as well as those early in the onset of obesity. To date, five endoscopic devices have been approved by the U.S. Food and Drug Administration for the treatment of obesity, and many more are in development, undergoing clinical trials, or being used around the world. Here, we present the current state of the field, highlight recent developments, and describe the clinical outcomes of these minimally invasive procedures in terms of weight loss, improvement in metabolic profile, and reduction in comorbidities. PMID- 28884821 TI - Associations between intratumoral and peritumoral M2 macrophage counts and cervical squamous cell carcinoma invasion patterns. AB - OBJECTIVE: To study the correlation between M2 tumor-associated macrophages (TAMs) and invasion patterns in cervical squamous cell carcinoma (SCC) tissues. METHODS: In the present observational study, two commercial SCC tissue microarrays were evaluated by immunohistochemical analysis between January 1, 2016, and December 31, 2016. CD163-positive cells in a cervical SCC tissue microarray were identified. Tissue samples were stratified into groups based on a pushing border pattern (PBP), a diffuse infiltration pattern (DIP), or non tumorous tissues included as a control group; M2 TAM numbers and distributions were compared. RESULTS: The microarrays included 109 cervical SCC samples and 45 non-tumorous control samples. The mean number of intratumoral M2 TAMs in cervical SCC tissue samples (35.8 +/- 28.3) was significantly higher than the number of intraepithelial M2 TAMs in non-tumorous cervical samples (1.2 +/- 3.6) (P<0.001); similarly, the number of peritumoral M2 TAMs in cervical SCC (44.7 +/- 29.4) was higher than in non-tumorous cervical tissues (10.4 +/- 9.2) (P<0.001). The numbers of intratumoral (P=0.046) and peritumoral (P=0.002) M2 TAMs were higher among the DIP group compared with the PBP group. CONCLUSION: A close relationship was identified between M2 TAMs and invasion patterns in cervical SCC. Further, M2 TAM infiltration was more pronounced in DIP compared with PBP SCC tissue samples. PMID- 28884822 TI - RNA binding protein Musashi-2 regulates PIWIL1 and TBX1 in mouse spermatogenesis. AB - RNA-binding proteins (RBP) are important facilitators of post-transcriptional gene regulation. We have previously established that nuclear overexpression of the RBP Musashi-2 (MSI2) during male germ cell maturation is detrimental to sperm cell development and fertility. Herein we determine the genes and pathways impacted by the upregulation of Msi2. Microarray analysis and qPCR confirmed differential gene expression in factors fundamental to the cell cycle, cellular proliferation, and cell death. Similarly, comparative protein expression analysis via iTRAQ, immunoblot, and immunolocalization, identified differential expression and localization of important regulators of transcription, translation, RNA processing, and spermatogenesis. Specifically, the testis-expressed transcription factor, Tbx1, and the piRNA regulator of gamete development, Piwil1, were both found to be targeted for translational repression by MSI2. This study provides key evidence to support a fundamental role for MSI2 in post-transcriptional regulation during male gamete development. PMID- 28884824 TI - Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects. AB - Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects. PMID- 28884823 TI - Evaluation of the natural history of patients who aspirate. AB - OBJECTIVES/HYPOTHESIS: The natural clinical progression of aspiration to eventual pulmonary compromise is not well understood. We hypothesized that dietary modification recommendations, Penetration-Aspiration Scale (PAS) score, and dysphagia etiology would be associated with changes in time to first pulmonary event and overall survival for patients with documented aspiration on radiologic testing. This study identified a cohort of patients with detectable unsensed penetration or aspiration on videofluoroscopic swallowing study (VFSS), and followed this cohort over time for development of pulmonary events and death. We then evaluated the association of aspiration severity and dietary modification recommendations on incidence of these endpoints. STUDY DESIGN: Retrospective chart review. METHODS: A total of 2,616 VFSS exam reports were reviewed from our institution performed between January 1, 2009 and December 31, 2010. Aspiration or unsensed penetration (PAS of 5 or greater) was detected in 564 (21.5%) of these patients, who were then included in the study cohort. Medical records were reviewed retrospectively for development of pulmonary events (pneumonia, pneumonitis, or other life-threatening pulmonary illness) and all-cause mortality for up to 54 months after initial VFSS. Univariate Kaplan-Meier analysis and multivariate Cox regression were performed for time to first pulmonary event and survival predicted by recommended diet, PAS score, and dysphagia etiology. RESULTS: Dysphagia etiology was highly associated with increased development of pulmonary events for some patients, especially those with generalized nonspecific dysphagia due to deconditioning or frailty (hazard ratio [HZ] vs. stroke 2.95, 95% confidence interval [CI]: 1.53-5.69, P = .001) and esophageal dysphagia (HZ: 2.66, 95% CI: 1.17-6.02, P = .019). Dysphagia etiology was also associated with increased mortality for patients with generalized nonspecific dysphagia due to deconditioning or frailty (HZ: 3.32, 95% CI: 2.0-5.52, P < .001), postsurgical patients (HZ: 1.73, 95% CI: 1.05-2.86, P = .032), and chronic neurologic disease (HZ: 1.87, 95% CI: 1.12-3.13, P = .017). Dietary modification recommendations at the time of VFSS (prohibition of oral intake or modification of food consistency) had no significant impact on time to first pulmonary event (P = .37) or survival (P = .17), whereas PAS score was associated with decreased time to first pulmonary event on univariate but not multivariate analysis (HZ for 1-point increase: 1.6, 95% CI: 0.99-1.36, P = .067). Kaplan-Meier estimate of overall 3 year mortality for this patient cohort was 39%. CONCLUSIONS: Etiology of dysphagia is associated with a higher mortality rate and development of pulmonary events in patients with unsensed penetration or aspiration on VFSS, especially for those patients with generalized deconditioning and frailty or esophageal dysphagia. Severity of aspiration as defined by PAS was not associated with altered overall survival. Recommendations for dietary modification to a nothing by mouth status or modified food consistency had no statistically significant association with development of pulmonary events or survival in patients with detectable unsensed penetration or aspiration on VFSS compared to full-diet recommendation. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:S1-S10, 2017. PMID- 28884825 TI - Parental versus non-parental-directed donation: an 11-year experience of infectious disease testing at a pediatric tertiary care blood donor center. AB - BACKGROUND: Directed donation is associated with a higher prevalence of donations that are positive for infectious disease markers; however, little is known about the positive rates among parental-directed, non-parental-directed, and allogeneic donations. STUDY DESIGN AND METHODS: We reviewed blood-collection records from January 1997 through December 2008, including infectious disease results, among parental, non-parental, and community donations. Infectious disease rates were compared by Mann-Whitney U test. RESULTS: In total, 1532 parental, 4910 non parental, and 17,423 community donations were examined. Among parental donors, the median rate of positive infectious disease testing was 8.66% (interquartile range (IQR), 4.49%) for first-time donors and 1.26% (IQR, 5.86%) for repeat donors; among non-parental donors, the rate was 1.09% (IQR, 0.98%) for first-time donors and 0% (IQR, 0.83%) for repeat donors; and, among community donors, the rate was 2.95% (IQR, 1.50%) for first-time donors and 0.45% (IQR, 0.82%) for repeat donors. The mean rate of positive infectious disease testing for first time parental donors was significantly higher (7.63%), whereas all repeat donors had similar rates. However, the rate of positive infectious disease testing among first-time non-parental donors was significantly lower than that in the other groups, especially for the period from 2001 through 2008. CONCLUSION: First-time non-parental and community donors had significantly higher infectious disease risk than the respective repeat donors. First-time parental donors had the highest rates of positive infectious disease testing. We suggest that first-time parental blood donation should be discouraged. Repeat community donors or first time non-parental donors provide a safer alternative. These findings can foster better patient education, donor selection, and possibly a reduced risk of infectious disease. PMID- 28884826 TI - An experimental test of the physiological consequences of avian malaria infection. AB - Chronic, low-intensity parasite infections can reduce host fitness through negative impacts on reproduction and survival, even if they produce few overt symptoms. As a result, these parasites can influence the evolution of host morphology, behaviour and physiology. The physiological consequences of chronic infection can provide insight into the processes underlying parasite-driven natural selection. Here, we evaluate the physiological consequences of natural, low-intensity infection in an avian host-parasite system: adult male red-winged blackbirds (Agelaius phoeniceus) infected with haemosporidian parasites. Chronic haemosporidian infection has previously been shown to reduce both reproductive success and survival in several avian species. We used antimalarial medications to experimentally reduce haemosporidian parasitaemia (the proportion of blood cells infected with haemosporidian parasites) and measured the effect of treatment on body condition, haematology, immune function, physiological stress and oxidative state. Treatment with an antimalarial medication reduced parasitaemia for the most prevalent haemosporidian parasites from the genus Plasmodium. Treatment also increased haemoglobin and haematocrit, and decreased red blood cell production rates. We detected no effect of treatment on body condition, immune metrics, plasma corticosterone concentrations, total antioxidant capacity or reactive oxygen metabolites. Our results suggest that the damage and replacement of red blood cells during infection could be important costs of chronic haemosporidian infection. Strong links between parasitaemia and the physiological consequences of infection indicate that even for relatively low intensity infections, measuring parasitaemia rather than only presence/absence could be important when evaluating the role of infection in influencing hosts' behaviour, physiology or fitness. PMID- 28884827 TI - Linking social and spatial networks to viral community phylogenetics reveals subtype-specific transmission dynamics in African lions. AB - Heterogeneity within pathogen species can have important consequences for how pathogens transmit across landscapes; however, discerning different transmission routes is challenging. Here, we apply both phylodynamic and phylogenetic community ecology techniques to examine the consequences of pathogen heterogeneity on transmission by assessing subtype-specific transmission pathways in a social carnivore. We use comprehensive social and spatial network data to examine transmission pathways for three subtypes of feline immunodeficiency virus (FIVPle ) in African lions (Panthera leo) at multiple scales in the Serengeti National Park, Tanzania. We used FIVPle molecular data to examine the role of social organization and lion density in shaping transmission pathways and tested to what extent vertical (i.e., father- and/or mother-offspring relationships) or horizontal (between unrelated individuals) transmission underpinned these patterns for each subtype. Using the same data, we constructed subtype-specific FIVPle co-occurrence networks and assessed what combination of social networks, spatial networks or co-infection best structured the FIVPle network. While social organization (i.e., pride) was an important component of FIVPle transmission pathways at all scales, we find that FIVPle subtypes exhibited different transmission pathways at within- and between-pride scales. A combination of social and spatial networks, coupled with consideration of subtype co-infection, was likely to be important for FIVPle transmission for the two major subtypes, but the relative contribution of each factor was strongly subtype-specific. Our study provides evidence that pathogen heterogeneity is important in understanding pathogen transmission, which could have consequences for how endemic pathogens are managed. Furthermore, we demonstrate that community phylogenetic ecology coupled with phylodynamic techniques can reveal insights into the differential evolutionary pressures acting on virus subtypes, which can manifest into landscape-level effects. PMID- 28884828 TI - Neutrophil extracellular traps in acrolein promoted hepatic ischemia reperfusion injury: Therapeutic potential of NOX2 and p38MAPK inhibitors. AB - Neutrophil is a significant contributor to ischemia reperfusion (IR) induced liver tissue damage. However, the exact role of neutrophils in IR induced innate immune activation and liver damage is not quite clear. Our study sheds light on the role of chronic oxidative stress end products in worsening the IR inflammatory process by neutrophil recruitment and activation following liver surgery. We employed specific inhibitors for molecular targets-NOX2 (NADPH oxidase 2) and P38 MAPK (Mitogen activated protein kinase) signal to counteract neutrophil activation and neutrophil extracellular trap (NET) release induced liver damage in IR injury. We found that acrolein initiated neutrophil chemotaxis and induced NET release both in vitro and in vivo. Acrolein exposure caused NET induced nuclear and mitochondrial damage in HepG2 cells as well as aggravated the IR injury in rat liver. Pretreatment with F-apocynin and naringin, efficiently suppressed acrolein induced NET release in vitro. Notably, it suppressed the expression of inflammatory cytokines, P38MAPK-ERK activation, and apoptotic signals in rat liver exposed to acrolein and subjected to IR. Moreover, this combination effectively attenuated acrolein induced NET release and hepatic IR injury. In the current study we have shown that the acrolein accumulation in liver due to chronic stress, is responsible for neutrophil recruitment and its activation leading to NET induced liver damage during surgery. Our study shows that therapeutic targeting of NOX2 and P38MAPK signaling in patients with chronic hepatic disorders would improve post operative hepatic function and survival. PMID- 28884829 TI - Preventive dental care among Medicaid-enrolled senior adults: from community to nursing facility residence. AB - OBJECTIVE: The primary objective of this study was to determine whether the utilization rate of preventive oral health care services while senior adults were community-dwelling differed from the rate after those same senior adults were admitted to nursing facilities. A secondary objective was to evaluate other significant predictors of receipt of preventive oral health procedures after nursing facility entry. METHODS: Iowa Medicaid claims from 2007-2014 were accessed for adults who were 68+ years upon entry to a nursing facility and continuously enrolled in Medicaid for at least three years before and at least two years after admission (n = 874). Univariate, bivariate and multivariable analyses were conducted. RESULTS: During the five years that subjects were followed, 52.8% never received a dental exam and 75.9% never received a dental hygiene procedure. More Medicaid-enrolled senior adults received >=1 preventive dental procedure in the two years while residing in a nursing facility compared to the three years before entry. In multivariable analyses, the strongest predictor of preventive oral health care utilization after entry was the receipt of preventive oral health services before entry (p < 0.01). CONCLUSIONS: The strongest predictor of receipt of dental procedures in the two years after nursing facility entry was the receipt of dental procedures in the three years before entry while community-dwelling. This underscores the importance of the senior adult establishing a source of dental care while community-dwelling. PMID- 28884830 TI - The inhibitory effect in Fraxinellone on oxidative stress-induced senescence correlates with AMP-activated protein kinase-dependent autophagy restoration. AB - As a natural metabolite of limonoids from Dictamnus dasycarpus, fraxinellone has been reported to be neuroprotective and anti-inflammatory. However, its influence on cellular metabolism remains largely unknown. In the present study, we investigated the effect of fraxinellone on cellular senescence-induced by oxidative stress and the potential mechanism. We found that fraxinellone administration caused growth arrest and certainly repressed the activity of senescence associated beta-galactosidase as well as the expression of senescence associated-genes. Interestingly, this effect of fraxinellone is closely correlated with the restoration of impaired autophagy and the activation of AMPK. Notably, fraxinellone reacts in an AMPK-dependent but mTORC1-independent manner. Together, our study demonstrates for the first time that fraxinellone has the effect on senescence inhibition and AMPK activation, and supports the notion that autophagic mechanism is important for aging prevention. These findings expanded the list of natural compounds and will be potentially utilized for aging decay and/or AMPK activation. PMID- 28884831 TI - Addressing Antiretroviral Therapy-Associated Drug-Drug Interactions in Patients Requiring Treatment for Opportunistic Infections in Low-Income and Resource Limited Settings. AB - An increasing number of human immunodeficiency virus (HIV)-infected patients are achieving virologic suppression on antiretroviral therapy (ART) limiting the use of primary and secondary antimicrobial prophylaxis. However, in low-income and resource-limited settings, half of those infected with HIV are unaware of their diagnosis, and fewer than 50% of patients on ART achieve virologic suppression. Management of comorbidities and opportunistic infections among patients on ART may lead to inevitable drug-drug interactions (DDIs) and even toxicities. Elderly patients, individuals with multiple comorbidities, those receiving complex ART, and patients living in low-income settings experience higher rates of DDIs. Management of these cytochrome P450-mediated, nonmediated, and drug transport system DDIs is critical in HIV-infected patients, particularly those in resource limited settings with few options for ART. This article critically analyzes and provides recommendations to manage significant DDIs and drug toxicities in HIV infected patients receiving ART. PMID- 28884832 TI - Psychometric evaluation of the Caregiver Preparedness Scale in caregivers of adults with heart failure. AB - Well-prepared informal caregivers play an important role in heart failure (HF) care, so an instrument to evaluate their preparedness to care is important. To date, HF caregiver preparedness has been rarely investigated quantitatively. The Caregiver Preparedness Scale (CPS) has been used in other chronic condition populations, but its psychometric characteristics have never been tested in HF caregivers. The purpose of this study was to test the validity and reliability of the 8-item CPS in HF caregivers. In a convenience sample of 317 HF caregivers (72.4% female, mean age 54), we tested the CPS' factorial structure with confirmatory factor analysis (CFA) and its concurrent validity with the Caregiver Contribution to Self-Care of HF Index (CC-SCHFI), and the Hospital Anxiety and Depression Scale (HADS). We also tested CPS' reliability with composite reliability indicators, Cronbach's alpha, factor score determinacy coefficient, and intraclass correlation coefficient (ICC). The CFA for a one-factor model resulted in supportive fit indices (e.g., comparative fit index .97). Significant correlations (p < .05) of the CPS with both the CC-SCHFI and the HADS supported concurrent validity. The composite reliability index, Cronbach's alpha, factor score determinacy coefficient, and ICC were .89, .91, .96, .91, respectively, supporting reliability. Our study provides evidence that the CPS is a valid and reliable instrument to measure HF caregiver preparedness, enabling clinicians, and researchers to target specific interventions to HF caregivers. PMID- 28884834 TI - Transplantation of hypoxic preconditioned neural stem cells benefits functional recovery via enhancing neurotrophic secretion after spinal cord injury in rats. AB - Spinal cord injury (SCI) is a debilitating, costly, and common pathological condition that affects the function of central nervous system (CNS). To date, there are few promising therapeutic strategies available for SCI. To look for a suitable therapeutic strategy, we have developed a sublethal hypoxic preconditioning procedure using Fluorescence-activated cell sorting (FACS) analysis, LDH releasing, and cell viability assays in vitro. Meanwhile, we have examined the benefits of neural stem cells (NSCs) transplantation prior to hypoxic preconditioning on functional recovery and potential mechanism via MRI screening, H&E, and Nissl staining, immunofluorescence staining and Elisa assays. Our data showed that transplantation of hypoxic prconditioned NSCs could enhance neuronal survival, especially 5-TH+ and ChAT+ neurons, in the injured spinal cord to reinforce functional benefits. The hypoxia exposure upregulated HIF-1alpha, neurotrophic and growth factors including neurotrophin-3 (NT-3), glial cell derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) in vitro and in vivo. Furthermore, functional recovery, including locomotor and hypersensitivities to mechanical and thermal stimulation assessed via behavioral and sensory tests, improved significantly in rats with engraftment of NSCs after hypoxia exposure from day 14 post-SCI, compared with the control and N-NSCs groups. In short, the approach employed in this study could result in functional recovery via upregulating neurotrophic and growth factors, which implies that hypoxic preconditioning strategy could serve as an effective and feasible strategy for cell-based therapy in the treatment of SCI in rats. PMID- 28884833 TI - Circulatory Flow Restoration Versus Cardiopulmonary Resuscitation: New Therapeutic Approach in Sudden Cardiac Arrest. AB - Sudden cardiac arrest (SCA) remains a major problem for health authorities worldwide. Insufficiencies of current cardiopulmonary resuscitation (CPR) are most probably related to an inappropriate concept and applied methods that still concentrate on heartbeat as priority, instead of blood circulation to maintain organs' perfusions. The aim of this works is to propose a new therapeutic approach for SCA in a more effective and secure manner compared with current CPR methods. It correlates to a non-invasive circulatory flow restoration (CFR) device composed of a multilayered thoracic and infradiaphragmatic compartments that will be pulsated alternatively and in fixed frequencies using a low-pressure pneumatic generator. Proof-of-concept studies with different prototypes and methods of SCA, showed restoration of hemodynamics (BP >= 100 mm Hg) and increased urine output after 20 min of cardiac arrest in pediatric dogs and piglets. In summary, a CFR device can induce shear stress-mediated endothelial function to restore microcirculation and cellular metabolism. This represents a cost-effective method, predisposes to return of spontaneous circulation in case of SCA, adaptable for all age groups, in public and hospital environments. PMID- 28884835 TI - Non-invasive electromyographic estimation of motor unit number in the external anal sphincter of the rat. AB - AIMS: The external anal sphincter (EAS) is essential for maintaining fecal continence. Neurological disorders or traumatic injuries to muscle and nervous systems could lead to EAS denervation. Currently, there are no techniques available to document global innervation changes in the EAS in vivo. The aim of this study was to develop a novel approach to non-invasively estimate the number of functioning motor units (MUs) in the EAS and validate with immunofluorescent techniques in rats. METHODS: Intra-rectal surface electromyography (EMG) signals of the EAS, induced by a series of intra-vaginally delivered pudendal nerve stimulations with different intensities, were recorded. Variation in EMG responses at different intensities was used to estimate the value of a single motor unit potential (SMUP) in order to perform the proposed EAS motor unit number estimation (MUNE) approach. The EAS MUNE was tested in 12 female Sprague Dawley rats, and validated by comparing against the EAS myofiber counting results achieved by performing immunostaining of acetylcholine receptors in 7 of the 12 rats. RESULTS: The mean MU number was 35 +/- 9, with an averaged SMUP size of 52.49 +/- 20.39 MUV. The mean number of successfully identified myofibers was 652.7 +/- 130.6 myofiber/EAS. Significance of linear regression between the immunofluorescent results and the MUNE was confirmed (P < 0.01). CONCLUSIONS: Our study represents the first effort to non-invasively assess the innervation of the EAS in vivo using the rat as a pre-clinical model. This approach can potentially enable future clinical applications for advanced diagnosis and treatment of neurogenic EAS disorders. PMID- 28884836 TI - A Probabilistic Approach to Assess External Doses to the Public Considering Spatial Variability of Radioactive Contamination and Interpopulation Differences in Behavior Pattern. AB - Dose assessment is an important issue from the viewpoints of protecting people from radiation exposure and managing postaccident situations adequately. However, the radiation doses received by people cannot be determined with complete accuracy because of the uncertainties and the variability associated with any process of defining individual characteristics and in the dose assessment process itself. In this study, a dose assessment model was developed based on measurements and surveys of individual doses and relevant contributors (i.e., ambient dose rates and behavior patterns) in Fukushima City for four population groups: Fukushima City Office staff, Senior Citizens' Club, Contractors' Association, and Agricultural Cooperative. In addition, probabilistic assessments were performed for these population groups by considering the spatial variability of contamination and interpopulation differences resulting from behavior patterns. As a result of comparison with the actual measurements, the assessment results for participants from the Fukushima City Office agreed with the measured values, thereby validating the model and the approach. Although the assessment results obtained for the Senior Citizens' Club and the Agricultural Cooperative differ partly from the measured values, by addressing further considerations in terms of dose reduction effects due to decontamination and the impact of additional exposure sources in agricultural fields, these results can be improved. By contrast, the measurements obtained for the participants from the Contractors' Association were not reproduced well in the present study. To assess the doses to this group, further investigations of association members' work activities and the related dose reduction effects are needed. PMID- 28884837 TI - Cognitive-behavioral therapy for eating disorders in primary care settings: Does it work, and does a greater dose make it more effective? AB - OBJECTIVE: This study aimed to determine whether cognitive-behavioral therapy (CBT) for eating disorders can be effective in a routine, primary care clinical setting, and to assess dose response. METHOD: The participants were 47 patients who commenced treatment with a publicly-funded primary care eating disorder service. They attended 7-33 sessions of individual CBT (mean = 17), using an evidence-based approach. Routine measures were collected pre- and post-therapy. RESULTS: Three-quarters of the patients completed treatment. Using intention to treat analysis (multiple imputation), the patients showed substantial improvements in eating attitudes, bulimic behaviors, and depression. However, there was no association between the level of improvement and the length of therapy past the 8th to 12th session. DISCUSSION: The level of effectiveness shown here is comparable to that previously demonstrated by more specialist services in secondary and tertiary care. The nonlinear association between number of sessions and recovery highlights the importance of early change, across the eating disorders. PMID- 28884839 TI - Effects of Glut1 gene silencing on proliferation, differentiation, and apoptosis of colorectal cancer cells by targeting the TGF-beta/PI3K-AKT-mTOR signaling pathway. AB - This study aims to investigate the effects of glucose transport l (Glut1) gene on proliferation, differentiation, and apoptosis of colorectal cancer (CRC) cells by regulating the TGF-beta/PI3K-AKT-mTOR signaling pathway. Immunohistochemistry was conducted to detect the positive Glut1 expression. Normal human CRC epithelial cells (CCD-18Co) and CRC cell line HCT116 were grouped into the control, blank, negative control (NC), and shGlut1-1 groups. RT-qPCR and Western blotting were performed to detect the expressions of Glut1, TGF-beta1, PI3K, AKT, PTEN, mTOR, Bcl-2, and Bax. Protein expression of phosphorylated-PI3K (p-PI3K), p-S473-AKT, p S389-S6K1, p-T70-4EBP1, Cleaved caspase-3 and Cleaved-PARP were detected. MTT assay, flow cytometry, and colony formation assay were performed in order to detect cell viability, cell cycle, and apoptosis, respectively. The positive expression rate of Glut1 in CRC tissues was 75% +/- 8%, while in the adjacent normal tissues it was 0%. In comparison to adjacent normal tissues, CRC tissues had increased Glut1, TGF-beta1, PI3K, AKT, mTOR, and Bcl-2 expressions, and p PI3K, p-S473-AKT, p-S389-S6K1, and p-T70-4EBP1 expressions; and decreased PTEN, Bax, Cleaved caspase-3, and Cleaved-PARP expressions. In comparison with the blank and NC groups, cells in the shGlut1-1 group showed decreased Glut1, TGF beta1, PI3K, AKT, mTOR, and Bcl-2 expressions, and p-PI3K, p-S473-AKT, p-S389 S6K1, and p-T70-4EBP1 expressions; and increased PTEN, Bax, Cleaved caspase-3, and Cleaved-PARP expressions, along with more arrested cells in C0/C1 phase than in S phase and slower cell growth. These results suggested that silencing the Glut1 gene inhibited proliferation and promoted apoptosis of CRC cells by inactivating TGF-beta/PI3K-AKT-mTOR signaling pathway. PMID- 28884838 TI - Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome. AB - BACKGROUND: Abdominal pain in irritable bowel syndrome (IBS) remains challenging to treat effectively. Researchers have attempted to elucidate visceral nociceptive processes in order to guide treatment development. Transient receptor potential (TRP) channels have been implied in the generation (TRPV1, TRPV4, TRPA1) and inhibition (TRPM8) of visceral pain signals. Pathological changes in their functioning have been demonstrated in inflammatory conditions, and appear to be present in IBS as well. AIM: To provide a comprehensive review of the current literature on TRP channels involved in visceral nociception. In particular, we emphasise the clinical implications of these nociceptors in the treatment of IBS. METHODS: Evidence to support this review was obtained from an electronic database search via PubMed using the search terms "visceral nociception," "visceral hypersensitivity," "irritable bowel syndrome" and "transient receptor potential channels." After screening the abstracts the articles deemed relevant were cross-referenced for additional manuscripts. RESULTS: Recent studies have resulted in significant advances in our understanding of TRP channel mediated visceral nociception. The diversity of TRP channel sensitization pathways is increasingly recognised. Endogenous TRP agonists, including poly-unsaturated fatty acid metabolites and hydrogen sulphide, have been implied in augmented visceral pain generation in IBS. New potential targets for treatment development have been identified (TRPA1 and TRPV4,) and alternative means of affecting TRP channel signalling (partial antagonists, downstream targeting and RNA-based therapy) are currently being explored. CONCLUSIONS: The improved understanding of mechanisms involved in visceral nociception provides a solid basis for the development of new treatment strategies for abdominal pain in IBS. PMID- 28884840 TI - Hydroxycarbamide in children with sickle cell anaemia after first-dose vs. chronic therapy: pharmacokinetics and predictive models for drug exposure. AB - AIMS: The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew ) vs. those receiving chronic therapy (HCchronic ), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements. METHODS: Utilizing data from two prospective, multicenter trials of hydroxycarbamide (Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia; NCT01506544 and Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease), plasma drug concentration vs. time profiles were evaluated with a model independent approach in the HCnew and HCchronic groups. Various predictive scenarios were analysed to evaluate whether systemic exposure with hydroxycarbamide could be accurately predicted. RESULTS: Absorption of hydroxycarbamide was rapid, variable and dose independent. Dose-normalized peak plasma concentrations and drug exposure (AUC) were higher, and weight-normalized apparent oral clearance was lower in the HCnew group. We assessed a PK-guided dosing strategy along with other predictive scenarios and found that inclusion of plasma samples only slightly improved the accuracy of AUC predictions when compared to a population-based method. CONCLUSIONS: Children naive to hydroxycarbamide exhibit a different PK profile compared to children receiving chronic therapy. Accuracy of population-based dosing is sufficient to target AUCs in individual patients. Further clearance/bioavailability studies are needed to address the factors responsible for variability in the disposition of hydroxycarbamide. PMID- 28884841 TI - Sclerostin antibody enhances bone formation in a rat model of distraction osteogenesis. AB - Neutralizing monoclonal sclerostin antibodies are effective in promoting bone formation at a systemic level and in orthopedic scenarios including closed fracture repair. In this study we examined the effects of sclerostin antibody (Scl-Ab) treatment on regenerate volume, density, and strength in a rat model of distraction osteogenesis. Surgical osteotomy was performed on 179 Sprague Dawley rats. After 1 week, rats underwent distraction for 2 weeks, followed by 6 weeks for consolidation. Two treatment groups received biweekly subcutaneous Scl-AbIII (a rodent form of Scl-Ab; 25 mg/kg), either from the start of distraction onward or restricted to the consolidation phase. These groups were compared to controls receiving saline. Measurement modalities included longitudinal DXA, ex vivo QCT, and microCT, tissue histology, and biomechanical four-point bending tests. Bone volume was increased in both Scl-Ab treatments regimens by the end of consolidation (+26-38%, p < 0.05), as assessed by microCT. This was associated with increased mineral apposition. Importantly, Scl-Ab led to increased strength in united bones, and this reached statistical significance in animals receiving Scl-Ab during consolidation only (+177%, p < 0.01, maximum load to failure). These data demonstrate that Scl-Ab treatment increases bone formation, leading to regenerates with higher bone volume and improved strength. Our data also suggest that the optimal effects of Scl-Ab treatment are achieved in the latter stages of distraction osteogenesis. These findings support further investigation into the potential clinical application of sclerostin antibody to augment bone distraction, such as limb lengthening, particularly in the prevention of refracture. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1106-1113, 2018. PMID- 28884842 TI - Distribution of Mycobacterium tuberculosis in Korea in the preceding decade. AB - BACKGROUND: Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (MTB); it is transmitted among people through air. The aim of this study was to assess the prevalence of TB and its clinical trends by collecting and analyzing data on specimens in Korea. METHODS: All clinical specimens referred to the Dankook University Hospital Laboratory in Cheonan, Korea, from September 2005 to June 2016 were tested to isolate MTB using solid and liquid cultures, acid-fast bacilli (AFB) smears, and polymerase chain reactions (PCR). RESULTS: In total, 146 150 specimens were collected; the mean TB positivity rate was 7.8%. The highest positivity rate was observed among patients 30-39 years of age (12.6%), followed by those 20-29 years of age (12.2%). The mean positivity rate was highest in 2010 and lowest in 2016 (10.7% and 6.7%, respectively). When comparing 2015-2011, we saw a decrease in the number of TB positive patients of 3.4%; this represented an annual decrease in 0.9%. CONCLUSION: Our data revealed a trend for a decrease in TB prevalence over time. Moreover, TB positivity rates were highest among the younger age groups in our study. Therefore, rapid diagnosis and treatment of TB in younger individuals are crucial. PMID- 28884843 TI - Simple Light-Triggered Fluorescent Labeling of Silica Nanoparticles for Cellular Imaging Applications. AB - A simple and mild light-triggered fluorescent labeling approach, based on the photolysis and reactive carbene insertion of diazirine, to rapidly generate fluorescent nanoparticles is reported. Proof of concept studies demonstrated that the non-fluorescent SiNPs could be covalently labeled by diazirine-conjugated fluorescein (dFITC) upon photo irradiation (lambda=365 nm) to afford fluorescent SiNPs with good fluorescent stability and low cytotoxicity. In vitro cellular imaging results indicated that the internalization of SiNPs into living cells could be readily visualized based on fluorescein-labeled SiNPs (F-SiNPs) in real time. We believe that the light-triggered labeling approach may offer a valuable method for surface modification of nanomaterials to achieve new functions. PMID- 28884844 TI - An open-label clinical trial assessing the efficacy and safety of Bend Skincare Anti-Aging Formula on minimal erythema dose in skin. AB - BACKGROUND/PURPOSE: Sunburn and other health risks associated with excess sun exposure place huge economic burdens on societies, and create discomfort and disease within susceptible individuals. Oral supplements that reduce sunburn may be advantageous. This study evaluated the safety and efficacy of Bend Skincare Anti-Aging Formula to ameliorate sunburn induced with a solar simulator. METHODS: Subjects (n = 28) with Fitzpatrick skin phototypes I, II, or III took 4 capsules daily of the supplement providing 1400 mg of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), 120 mg of gamma-linolenic acid (GLA), 5 mg of lutein, 2.5 mg of zeaxanthin, and 1000 IU of vitamin D3 for 8 weeks. Skin on each subject's back was exposed to a progressive sequence of timed ultraviolet (UV) radiation exposure doses at baseline, and after 4- and 8-week treatment to determine their minimal erythema dose (MED). Results were compared before and after treatment using 3 paired t tests and subsequently 3 linear mixed models. RESULTS: Treatment significantly improved tolerance to UV exposure as evidenced by increased MED at 4 and 8 weeks compared with baseline (P < .001). This protection increased with prolonged use of Bend Skincare Anti-Aging Formula as demonstrated by progressively increased MED between baseline and 4 weeks, and again between 4 and 8 weeks (P < .001). Nearly 86% of patients responded to treatment within 4 weeks and 100% of patients responded by the end of the study, resulting in a 39% mean increase in MED at 4 weeks, and an 84% mean increase in MED at 8 weeks compared with baseline. Treatment was well tolerated with no product associated adverse events (AE) and only a few mild and expected side effects. CONCLUSION: Bend Skincare Anti-Aging Formula safely and effectively provides significant skin photoprotection that increases with continued use. PMID- 28884845 TI - Selective Stabilization of the Spin States of a Magnetically Anisotropic Dysprosium Ion Induced by Photo-Excitation of the Associated Cyclic pi-Conjugated System. AB - The presence of a new electronic interaction, which couples a 4 f-electronic system with a total angular momentum J and a photoexcited cyclic pi-conjugated system with an orbital angular momentum L, in the bis(phthalocyaninato)dysprosium single-molecule magnet ([DyPc2 ]- ) is reported. Two pi-pi* excited states in the visible spectral region of the [DyPc2 ]- complex, which are denoted here as QL and QH , showed significantly different temperature and field dependences of the magnetic circular dichroism (MCD) A-term intensity. This phenomenon not only indicates the presence of a "J-L" interaction, but also that the interaction generates two different preferred orientations of the J-L pair, either parallel (for the QH band) or antiparallel (for the QL band), depending on the excitation energy. We have constructed a theoretical model that reproduces the temperature and field dependences, and quantitatively evaluated the J-L interaction. PMID- 28884846 TI - The responsibility of gynecologists and obstetricians in providing safe abortion services within the limits of the law. AB - Approximately 47 000 women die each year worldwide as a result of the complications of unsafe abortion, almost exclusively in low- and middle-income countries with restrictive abortion laws. In these countries, very few women who comply with the conditions imposed by the law can access safe abortion services in the public health system. The main obstacle is the unwillingness of gynecologists and obstetricians to provide abortion services by claiming conscientious objection, which is often used to hide their fear of the stigma associated with abortion. This happens because many colleagues are unaware that without access to legal services these women will resort to an unsafe abortion and its consequences. This violates the statement from FIGO's Committee for the Ethical Aspects of Human Reproduction and Women's Health, which asserts that: "The primary conscientious duty of obstetrician-gynecologists is at all times to treat, or provide benefit and prevent harm, to the patients for whose care they are responsible. Any conscientious objection to treating a patient is secondary to this primary duty." PMID- 28884847 TI - How does the exosite of rhomboid protease affect substrate processing and inhibition? AB - Rhomboid proteases constitute a family of intramembrane serine proteases ubiquitous in all forms of life. They differ in many aspects from their soluble counterparts. We applied molecular dynamics (MD) computational approach to address several challenging issues regarding their catalytic mechanism: How does the exosite of GlpG rhomboid protease control the kinetics efficiency of substrate hydrolysis? What is the mechanism of inhibition by the non-competitive peptidyl aldehyde inhibitors bound to the GlpG rhomboid active site (AS)? What is the underlying mechanism that explains the hypothesis that GlpG rhomboid protease is not adopted for the hydrolysis of short peptides that do not contain a transmembrane domain (TMD)? Two fundamental features of rhomboid catalysis, the enzyme recognition and discrimination of substrates by TMD interactions in the exosite, and the concerted mechanism of non-covalent pre-catalytic complex to covalent tetrahedral complex (TC) conversion, provide answers to these mechanistic questions. PMID- 28884848 TI - Perfluoroalkyltricyanoborate and Perfluoroalkylcyanofluoroborate Anions: Building Blocks for Low-Viscosity Ionic Liquids. AB - The potassium perfluoroalkyltricyanoborates K[Cn F2 n+1 B(CN)3 ] [n=1 (1 d), 2 (2 d)] and the potassium mono(perfluoroalkyl)cyanofluoroborates K[Cn F2 n+1 BF(CN)2 ] [n=1 (1 c), 2 (2 c)] and [Cn F2 n+1 BF2 (CN)]- [n=1 (1 b), 2 (2 b), 3 (3 b), 4 (4 b)] are accessible with perfect selectivities on multi-gram scales starting from K[Cn F2 n+1 BF3 ] and Me3 SiCN. The K+ salts are starting materials for the preparation of salts with organic cations, for example, [EMIm]+ (EMIm=1-ethyl-3 methylimidazolium). These [EMIm]+ salts are hydrophobic room-temperature ionic liquids (RTILs) that are thermally, chemically and electrochemically very robust, offering electrochemical windows up to 5.8 V. The RTILs described herein, exhibit very low viscosities with a minimum of 14.0 mPa s at 20 degrees C for [EMIm]1 c, low melting points down to -57 degrees C for [EMIm]2 b and extraordinary high conductivities up to 17.6 mS cm-1 at 20 degrees C for [EMIm]1 c. The combination of these properties makes these ILs promising materials for electrochemical devices as exemplified by the application of selected RTILs as component of electrolytes in dye-sensitised solar cells (DSSCs, Gratzel cells). The efficiency of the DSSCs was found to increase with a decreasing viscosity of the neat ionic liquid. In addition to the spectroscopic characterisation, single crystals of the potassium salts of the anions 1 b-d, 2 d, 3 b and 4 c as well as of [nBu4 N]2 c have been studied by X-ray diffraction. PMID- 28884849 TI - Anger parameters in parolees undergoing psychoeducation: Temporal stability, social desirability bias, and comparison with non-offenders. AB - BACKGROUND: Anger is commonly measured as if it were a single, simple construct. This may be particularly unhelpful if the main purpose of a measure is to determine change and responsiveness to interventions. AIMS: Our primary aim was to assess five anger parameters in parolees - frequency, duration, intensity, latency, and threshold - and to test for effects of psychoeducation and social desirability bias on parolees' scores. Average anger scores for the offender sample were compared with those in a non-offender sample. METHODS: The offender sample was drawn from male parolees in San Antonio. Age-matched volunteers recruited at public libraries were engaged for baseline comparisons. The Anger Parameters Scale and the Marlow-Crowne Scale were used to assess anger and social desirability, respectively. Parole officers delivered a psychoeducation course to parolees over 12 weeks, and anger and social desirability measures were taken before and afterwards. RESULTS: At baseline, parolees were angry more often, stayed angry longer, and reached higher levels of anger than the non-offenders, confirming their eligibility for the programme. Mean anger scores were not significantly different after psychoeducation than before it. Parolees' reported anger was significantly and negatively correlated with social desirability scores. CONCLUSIONS: Only three of the five anger parameters were prominent among these offenders: frequency, duration, and intensity of their outbursts. Psychoeducation did not produce improvement, possibly because it was instructional rather than therapeutic, but also because group means may mask useful individual differences. Concurrent assessment of social desirability is likely to assist in interpretation of anger measures. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28884850 TI - Regioregular Phthalocyanines Substituted with Bulky Donors at Non-Peripheral Positions. AB - Three regioregular phthalocyanines (1-3) were synthesized selectively by the cyclic tetramerization of phthalonitriles bearing a bulky diarylamine substituent at the next position of nitrile. The steric repulsion at the tetramerization of bulky phthalonitriles allowed for the selective formation of regioregular phthalocyanines as confirmed by NMR and single crystal X-ray structural analyses. The absorption spectrum of 1 substituted with di(4-tert-butylphenyl)amine groups at the non-peripheral positions showed a non-split Q-band at 764 nm, which was redshifted by 83 nm compared with that of metal free phthalocyanine (H2 Pc). The TD-DFT calculation and electrochemical studies prove that the substitution of diarylamine groups at the alpha-positions effectively destabilizes the HOMO energy level, which causes a large redshift of the Q-band. Moreover, 1 can generate a one-electron oxidation species through chemical oxidation. The Q-band position of 2 bearing 4,4'-dimetoxyphenylamine units was further shifted by 10 nm compared with that of 1. In addition, 3 having carbazole units showed a small redshift of the Q-band relative to H2 Pc. The hole-mobility of 2 in thin film was determined to be 1.1*10-5 cm V-1 s-1 by using a space charge limited current method. A perovskite solar cell employing 2 as a hole-transporting layer gave an efficiency of 5.1 % under standard global 100 Wcm-2 AM 1.5 G illumination. PMID- 28884851 TI - "Bottom-up" in situ proteomic differentiation of human and non-human haemoglobins for forensic purposes by matrix-assisted laser desorption/ionization time-of flight tandem mass spectrometry. AB - RATIONALE: The detection and identification of human blood on crime-related items are of particular relevance to many investigations because shed blood can provide evidence of violent contact between individuals. However, for any detection and identification technique, specificity is a critical performance characteristic to assess; that is, whether the technique has the capability to differentiate between human blood (which usually is of relevance to a criminal investigation) and non-human blood (which usually would not be associated with a crime but may be detected incidentally). METHODS: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) approaches using "top-down" (detection of intact proteins) and "bottom-up" (detection of tryptic peptide markers) were used to detect and identify haemoglobin in blood from humans and from a range of Australian native mammals; the technique could be carried out directly on blood stains without the need to extract proteins (i.e., in situ measurement). Imaging of haemoglobin was achieved in bloodied fingermarks, including those that had been enhanced using two "industry standard" fingermark enhancement processes. RESULTS: Differentiation of intact haemoglobin proteins in human and non-human blood using "top-down" MALDI-TOF-MS was difficult. However, in situ "bottom-up" approaches using tandem mass spectrometry (MS/MS) and de novo sequencing of tryptic digest peptides allowed unambiguous differentiation. Imaging mass spectrometry of human haemoglobin, even when it was mixed with animal blood, was achieved in bloodied fingermarks that had been enhanced using two common processes (staining with Amido Black or dusted with magnetic powder) and "lifted" using adhesive tape. CONCLUSIONS: The MALDI-TOF-MS-based in situ "bottom-up" proteomic methodology described here shows great promise for the detection of human blood and even imaging of blood in bloodied fingermarks. The approach is sensitive, can differentiate between human blood and that from many animals (including several Australian native animals), and can be implemented after traditional crime scene fingermark enhancement techniques have been carried out. PMID- 28884853 TI - Continuous Intravenous Acetaminophen for Analgesia: First, Back to the Drawing Table? PMID- 28884852 TI - Crystal structure of a marine glycoside hydrolase family 99-related protein lacking catalytic machinery. AB - Algal polysaccharides of diverse structures are one of the most abundant carbon resources for heterotrophic, marine bacteria with coevolved digestive enzymes. A putative sulfo-mannan polysaccharide utilization locus, which is conserved in marine flavobacteria, contains an unusual GH99-like protein that lacks the conserved catalytic residues of glycoside hydrolase family 99. Using X-ray crystallography, we structurally characterized this protein from the marine flavobacterium Ochrovirga pacifica to help elucidate its molecular function. The structure reveals the absence of potential catalytic residues for polysaccharide hydrolysis, which-together with additional structural features-suggests this protein may be noncatalytic and involved in carbohydrate binding. PMID- 28884855 TI - Overexpression of miR-216b: Prognostic and predictive value in acute myeloid leukemia. AB - Accumulating studies have shown that miR-216b acted as a tumor suppressor and was down-regulated in solid tumors. However, little studies revealed the role or clinical implication of miR-216b in blood cancers. Herein, we reported miR-216b expression and its clinical significance in patients with acute myeloid leukemia (AML). In the current study, we analyzed bone marrow (BM) miR-216b expression in 115 de novo AML patients examined by real-time quantitative PCR. Notably, BM miR 216b expression was significantly up-regulated in AML patients, and could serve as a potential biomarker distinguishing AML from controls. No significant correlations of BM miR-216 expression were found with sex, age, white blood cells, hemoglobin, platelets, BM blasts, French-American-British classifications, and karyotypes. Significantly, patients with high miR-216b expression tended to have a lower frequency of FLT3-ITD mutation and higher incidence of U2AF1 and IDH1/2 mutations. Moreover, complete remission (CR) rate and overall survival were negatively affected by BM miR-216b overexpression among cytogenetically normal AML (CN-AML). Cox regression analyses showed that high BM miR-216b expression may act as an independent risk factor in CN-AML patients. Among the follow-up patients, BM miR-216b level in CR phase was markedly lower than in diagnosis time, and was returned in relapse phase. Collectively, our findings indicated that miR-216b overexpression was a frequent event in de novo AML, and independently conferred a poor prognosis in CN-AML. Moreover, miR-216b expression was a valuable biomarker correlated with disease recurrence in AML. PMID- 28884857 TI - Amerindian ancestry and extended longevity in Nicoya, Costa Rica. AB - OBJECTIVES: The aim of this study was to address the hypothesis that Amerindian ancestry is associated with extended longevity in the admixed population of Nicoya, Costa Rica. The Nicoya Peninsula of Costa Rica has been considered a "longevity island," particularly for males. METHODS: We estimated Amerindian ancestry using 464 ancestral informative markers in 20 old Nicoyans aged >=99 years, and 20 younger Nicoyans (60-65 years). We used logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) of the association of Amerindian ancestry and longevity. RESULTS: Older Nicoyans had higher Amerindian ancestry compared to younger Nicoyans (43.3% vs 36.0%, P = .04). Each 10% increase of Amerindian ancestry was associated with more than twice the odds of being long-lived (OR = 2.32, 95% CI = 1.03-5.25). CONCLUSIONS AND IMPLICATIONS: To our knowledge, this is the first time that ancestry is implicated as a likely determinant of extended longevity. Amerindian-specific alleles may protect against early mortality. The identification of these protective alleles should be the focus of future studies. PMID- 28884858 TI - Unassisted return of spontaneous circulation after ventricular fibrillation. PMID- 28884859 TI - Network meta-analysis. PMID- 28884856 TI - Significance of measurement of serum trough level and anti-drug antibody of adalimumab as personalised pharmacokinetics in patients with Crohn's disease: a subanalysis of the DIAMOND trial. AB - BACKGROUND: Significance of monitoring adalimumab trough levels and anti adalimumab antibodies (AAA) for disease outcome in Crohn's disease (CD) patients remained unclear. AIM: To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. METHODS: We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide (TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. RESULTS: There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 +/- 3.3 MUg/mL vs 5.4 +/- 4.3 MUg/mL: P <.001). Adalimumab trough level of 5.0 MUg/mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 (P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6TGN level of >222.5 p mol/8 *108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. CONCLUSION: Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. (UMIN Registration No. 000005146). PMID- 28884860 TI - Pharmacological treatment of oro-facial pain - health technology assessment including a systematic review with network meta-analysis. AB - This health technology assessment evaluated the efficacy of pharmacological treatment in patients with oro-facial pain. Randomised controlled trials were included if they reported pharmacological treatment in patients >=18 years with chronic (>=3 months) oro-facial pain. Patients were divided into subgroups: TMD muscle [temporomandibular disorders (TMD) mainly associated with myalgia]; TMD joint (TMD mainly associated with temporomandibular joint pain); and burning mouth syndrome (BMS). The primary outcome was pain intensity reduction after pharmacological treatment. The scientific quality of the evidence was rated according to GRADE. An electronic search in PubMed, Cochrane Library, and EMBASE from database inception to 1 March 2017 combined with a handsearch identified 1552 articles. After screening of abstracts, 178 articles were reviewed in full text and 57 studies met the inclusion criteria. After risk of bias assessment, 41 articles remained: 15 studies on 790 patients classified as TMD-joint, nine on 375 patients classified as TMD-muscle and 17 on 868 patients with BMS. Of these, eight studies on TMD-muscle, and five on BMS were included in separate network meta-analysis. The narrative synthesis suggests that NSAIDs as well as corticosteroid and hyaluronate injections are effective treatments for TMD-joint pain. The network meta-analysis showed that clonazepam and capsaicin reduced pain intensity in BMS, and the muscle relaxant cyclobenzaprine, for the TMD-muscle group. In conclusion, based on a limited number of studies, evidence provided with network meta-analysis showed that clonazepam and capsaicin are effective in treatment of BMS and that the muscle relaxant cyclobenzaprine has a positive treatment effect for TMD-muscle pain. PMID- 28884862 TI - A Pathogenic Mechanism Potentially Operative in Multiple Progressive Diseases and Its Therapeutic Implications. AB - A variety of peptide signaling moieties that we have termed intracrines can act in the interiors of their cells of synthesis or of target cells after internalization. These intracrine factors are known to be upregulated in such disorders as diabetic nephropathy, systolic heart failure, and age-related macular degeneration. Indeed, a similar set of intracrines is upregulated in each of these disorders, suggesting a commonality of mechanism. In addition, several chronic neurodegenerative disorders such as Alzheimer disease and Parkinson disease involve intercellular trafficking of intracellular disease-causing proteins. These disorders can be considered intracrine-like. Here the mechanistic and therapeutic implications of these observations, and of the relevant modes of intracrine action, are discussed, including the possibility that similar therapeutic approaches could be effective in multiple progressive disorders and the implications of these observations for intracrine pharmacology in general. PMID- 28884861 TI - Use of iDXA spine scans to evaluate total and visceral abdominal fat. AB - OBJECTIVES: Abdominal fat may be a better predictor than body mass index (BMI) for risk of metabolically-related diseases, such as diabetes, cardiovascular disease, and some cancers. We sought to validate the percent fat reported on dual energy X-ray absorptiometry (DXA) regional spine scans (spine fat fraction, SFF) against abdominal fat obtained from total body scans using the iDXA machine (General Electric, Madison, WI), as previously done on the Prodigy model. METHODS: Total body scans and regional spine scans were completed on the same day (N = 50). In alignment with the Prodigy-based study, the following regions of interest (ROI) were assessed from total body scans and compared to the SFF from regional spine scans: total abdominal fat at (1) lumbar vertebrae L2-L4 and (2) L2-Iliac Crest (L2-IC); (3) total trunk fat; and (4) visceral fat in the android region. Separate linear regression models were used to predict each total body scan ROI from SFF; models were validated by bootstrapping. RESULTS: The sample was 84% female, a mean age of 38.5 +/- 17.4 years, and mean BMI of 23.0 +/- 3.8 kg/m2 . The SFF, adjusted for BMI, predicted L2-L4 and L2-IC total abdominal fat (%; Adj. R2 : 0.90) and total trunk fat (%; Adj. R2 : 0.88) well; visceral fat (%) adjusted R2 was 0.83. Linear regression models adjusted for additional participant characteristics resulted in similar adjusted R2 values. CONCLUSIONS: This replication of the strong correlation between SFF and abdominal fat measures on the iDXA in a new population confirms the previous Prodigy model findings and improves generalizability. PMID- 28884863 TI - Phosphopeptide enrichment with cross-linked Os(II)(dmebpy)2 Cl-derivatized acrylamide and vinylimidazole copolymer. AB - RATIONALE: Reversible phosphorylation of proteins catalyzed by kinases and phosphatases plays a key regulatory role in intracellular biological processes. Protein phosphorylation profiling is still a challenge due to its low stoichiometry, diversity of phosphorylated protein forms, and dynamic nature of phosphorylation states. Mass spectrometry (MS) has been widely used for the characterization of protein phosphorylation, due to its high sensitivity and MS/MS sequencing capability. However, the low abundance and ionization efficiency of phosphorylated peptides and interference from their non-phosphorylated counterparts and other peptides in the enzymatic digests of proteins complicate the localization of phosphorylation sites in liquid chromatography (LC)/MS analysis. So the enrichment of phosphopeptides from the digests is often required before LC/MS. Immobilized metal affinity chromatography (IMAC) and metal oxide affinity chromatography (MOAC) are the two most commonly used enrichment techniques for phosphopeptides prior to MS analysis. METHODS: Cross-linked Os(II)(4,4'-dimethyl-2,2'-bipyridine)2 Cl-derivatized acrylamide and vinylimidazole copolymer were applied for the enrichment of phosphopeptides. RESULTS: Under neutral loading buffer conditions phosphopeptides bind on the Os polymer without nonspecific binding of acidic peptides. Differential binding of monophosphorylated and multiply phosphorylated peptides can be achieved under different concentrations of imidazole. Sequential elution of bound phosphopeptides can be obtained with elution buffers of different pH values below 3. The loading buffers with imidazole can be aqueous or 7/3 H2 O/ACN. Once phosphopeptides bind onto the Os-polymer, washing with water, 0.1% acetic acid (pH ~ 3) or 1/1 H2 O/ACN 0.05% acetic acid (pH ~3) does not elute phosphopeptides. The Os-polymer does not show bias of binding and elution toward phosphopeptide standards with singly, doubly and triply phosphorylated sites. CONCLUSIONS: Cross-linked Os(II)(dimethylbipyridine)2 Cl-derivatized poly(acrylamide)-poly(vinylimidazole) copolymer is proven to be a new efficient IMAC resin for phosphopeptide enrichment and shows some unique properties for differential binding and sequential elution of phosphopeptides. It could become a better alternative to traditional IMAC and TiO2 for phosphopeptide enrichment. PMID- 28884864 TI - A systematic literature search to identify performance measure outcomes used in clinical studies of racehorses. AB - BACKGROUND: Racing performance is often used as a measurable outcome variable in research studies investigating clinical diagnoses or interventions. However, the use of many different performance measures largely precludes conduct of meaningful comparative studies and, to date, those being used have not been collated. OBJECTIVES: To systematically review the veterinary scientific literature for the use of racing performance as a measurable outcome variable in clinical studies of racehorses, collate and identify those most popular, and identify their advantages and disadvantages. STUDY DESIGN: Systematic literature search. METHODS: The search criteria "((racing AND performance) AND (horses OR equidae))" were adapted for both MEDLINE and CAB Abstracts databases. Data were collected in standardised recording forms for binary, categorical and quantitative measures, and the use of performance indices. RESULTS: In total, 217 studies that described racing performance were identified, contributing 117 different performance measures. No one performance measure was used in all studies, despite 90.3% using more than one variable. Data regarding race starts and earnings were used most commonly, with 88.0% and 54.4% of studies including at least one measure of starts and earnings, respectively. Seventeen variables were used 10 times or more, with the top five comprising: 'return to racing', 'number of starts', 'days to first start', 'earnings per period of time' and 'earnings per start'. MAIN LIMITATIONS: The search strategies may not have identified all relevant papers, introducing bias to the review. CONCLUSIONS: Performance indices have been developed to improve assessment of interventions; however, they are not widely adopted in the scientific literature. Use of the two most commonly identified measures, whether the horse returned to racing and number of starts over a defined period of time, would best facilitate future systematic reviews and meta-analyses in advance of the development of a gold standard measure of race performance outcome. PMID- 28884866 TI - Perceived stigma and social support in treatment for pharmaceutical opioid dependence. AB - INTRODUCTION AND AIMS: The dramatic increase in pharmaceutical opioid (PO) use in high-income countries is a growing public health concern. Stigma and social support are important as they may influence treatment uptake and outcomes, yet few studies exist regarding perceived stigma and social support among people with PO dependence. The aims of the study are to: (i) compare characteristics of those with PO dependence from iatrogenic and non-iatrogenic causes; (ii) document perceived stigma and its correlates in people in treatment for PO dependence; and (iii) examine correlates of social support in people in treatment for PO dependence. DESIGN AND METHODS: This prospective cohort study included (n = 108) PO-dependent people referred from treatment services. Telephone interviews were conducted at baseline, 3, 12 and 24 months. Multivariate linear regression was used to examine correlations. RESULTS: Mean age was 41 (SD = 10.5). Half (n = 56, 52%) were female. Two in five met the criteria for iatrogenic dependence (n = 41, 38%), with iatrogenic dependence associated with chronic pain, and no history of injection or heroin use. One quarter of study subjects reported past month unsanctioned opioid use (n = 25, 23%). Being married/de facto or female was associated with higher levels of perceived stigma. Unsanctioned opioid use, iatrogenic dependence and mental health conditions were associated with lower social support. DISCUSSION AND CONCLUSIONS: Stigma affects all people in treatment. Those who are married/de facto and female may benefit from interventions to address stigma. The association of low social support with poorer mental health and ongoing substance use indicate that treatment could focus more on this area. PMID- 28884867 TI - Uncovering allostery and regulation in SAMHD1 through molecular dynamics simulations. PMID- 28884865 TI - Physical training improves visceral adipose tissue health by remodelling extracellular matrix in rats with estrogen absence: a gene expression analysis. AB - Adipose tissue development is associated with modifications involving extracellular matrix remodelling, and metalloproteinases play a significant role in this process. Reduced circulating sexual hormones cause impacts on the size, morphology and functions of the adipose tissue, increasing susceptibility to diseases. This study investigated whether exercise training may be an alternative strategy to combat the effects promoted by estrogen decay through modulation in gene expression patterns in the extracellular matrix (ECM) of visceral adipose tissue of ovariectomized rats. Nulliparous rats (n = 40) were randomly distributed into four groups (n = 10/group): sham sedentary (Sh-S), sham resistance training (Sh-Rt), ovariectomized sedentary (Ovx-S) and ovariectomized resistance training (Ovx-Rt). The Sh-S animals did not have any type of training. The body mass and food intake, ECM gene expression, gelatinase MMP-2 activity and adipocyte area were measured. A lack of estrogen promoted an increase in body mass, food intake and the visceral, parametrial and subcutaneous adipocyte areas. The ovariectomy upregulated the expression of MMP-2, MMP-9, TGF-beta, CTGF, VEGF A and MMP-2 activity. On the other hand, resistance training decreased the body mass, food intake and the adipocyte area of the three fat depots analysed; upregulated TIMP-1, VEGF-A and MMP-2 gene expression; downregulated MMP-9, TGF beta and CTGF gene expression; and decreased the MMP-2 activity. We speculate that resistance training on a vertical ladder could play an important role in maintaining and remodelling ECM by modulation in the ECM gene expression and MMP 2 activity, avoiding its destabilization which is impaired by the lack of estrogen. PMID- 28884868 TI - A novel multielectrode combined mapping and ablation basket catheter: A future player in the atrial fibrillation ablation space? PMID- 28884869 TI - The future of the international drug control system and national drug prohibitions. AB - A major impediment to any nation abandoning the policy of drug prohibition has been the fact that international drug treaties to which the majority of United Nations (UN) member states are signatory prohibit the non-medical use of amphetamines, cannabis, cocaine and heroin. The future of these treaties is now uncertain because of decisions by Uruguay, eight US states and Canada to legalize cannabis use. This paper: (1) provides a brief account of the international drug control treaties; (2) outlines the major criticisms of the treaties; (3) analyses critically proposals for treaty reform; and (4) provides a personal view on policies that nation states could adopt to minimize the harms from the use of cannabis, party drugs and hallucinogens, opioids, stimulants and new psychoactive substances. It is argued that: a major risk of cannabis legalization in the United States is promotion of heavy use and increased harm by a weakly regulated industry; some cautious national experiments with the regulation of party drugs and hallucinogens would be informative; a strong case remains for prohibiting the nonmedical use of opioids while mitigating the adverse effects that this policy has on opioid-dependent people; stimulant legalization will probably increase problem use but prohibition is difficult to enforce, highlighting the urgency of finding better ways to reduce demand for these drugs and respond to problem users; and that it is unclear what the best approach is to reducing possible harms that may arise from the use of new psychoactive substances. PMID- 28884870 TI - Phosphorylated SNAP25 in the CA1 regulates morphine-associated contextual memory retrieval via increasing GluN2B-NMDAR surface localization. AB - Although our previous studies have demonstrated both protein kinase C (PKC) and GluN2B-containing N-methyl-d-aspartate receptor (GluN2B-NMDAR) play crucial roles in morphine-associated learning and memory, the relationship between them remains unexplored. In this study, we validated the enhanced PKC and membrane GluN2B protein expression in the hippocampal CA1 after morphine conditioned place preference (CPP) expression in rats. Interestingly, we also found that phosphorylation of SNAP25 at Ser187 (pSer187-SNAP25), a PKC-activated target, was significantly increased following morphine CPP expression. Blocking the pSer187 SNAP25 by intra-CA1 injection of an interfering peptide impaired morphine CPP expression and accompanied by the reduced ratio of GluN2B membrane/total in the CA1. In addition, intra-CA1 blockade of pSer187-SNAP25 did not affect natural learning and memory process as evidenced by intact sucrose-induced CPP expression and normal locomotor activity in rats. Therefore, our results reveal that enhanced pSer187-SNAP25 by PKC recruits GluN2B-NMDAR to the membrane surface in the hippocampal CA1 and mediates context-induced addiction memory retrieval. Our findings in this study fill in the missing link and provide better understanding of the molecular mechanisms involved in morphine-associated contextual memory retrieval. PMID- 28884871 TI - LncRNA-ATB: An indispensable cancer-related long noncoding RNA. AB - OBJECTIVES: Long non-coding RNAs (lncRNAs) are a group of non-protein-coding RNAs that are greater than 200 nucleotides in length. Increasing evidence indicates that lncRNAs, which may serve as either oncogenes or tumour suppressor genes, play a vital role in the pathophysiology of human diseases, especially in tumourigenesis and progression. Deregulation of lncRNAs impacts different cellular processes, such as proliferation, dedifferentiation, migration, invasion and anti-apoptosis. The aim of this review was to explore the molecular mechanism and clinical significance of long non-coding RNA-activated by transforming growth factor beta (lncRNA-ATB) in various types of cancers. MATERIALS AND METHODS: In this review, we summarize and analyze current studies concerning the biological functions and mechanisms of lncRNA-ATB in tumour development. The related studies were obtained through a systematic search of Pubmed, Web of Science, Embase and Cochrane Library. RESULTS: Long non-coding RNAs-ATB is a novel cancer-related lncRNA that was recently found to exhibit aberrant expression in a variety of malignancies, including hepatocellular carcinoma, colorectal cancer, gastric cancer, and lung cancer. Dysregulation of lncRNA-ATB has been shown to contribute to proliferation, migration and invasion of cancer cells. Long non-coding RNAs ATB promotes tumourigenesis and progression mainly through competitively binding miRNAs to induce epithelial-mesenchymal transition (EMT). CONCLUSIONS: Long non coding RNAs-ATB likely represents a feasible cancer biomarker or therapeutic target. PMID- 28884873 TI - Impact of premature activation of the right ventricle with programmed stimulation in Brugada syndrome. AB - BACKGROUND: In Brugada syndrome (BrS), it has been reported that delayed activation in the RV is related to the development of type-1 ECG, which is more critical than type-2. On the other hand, the coexistence of complete right bundle branch block (CRBBB), which also causes delayed activation in the RV, sometimes makes typical BrS ECG misleading. We hypothesized that premature stimulation of the RV can unmask the influence of delayed activation in the RV and convert the morphology of ECG in BrS patients. METHODS AND RESULTS: In 35 BrS patients with type-1 ECG including 8 patients with concomitant CRBBB and 6 control subjects with CRBBB, progressively premature single stimulations were delivered from the RV apex on electrophysiological study. Then we evaluated QRS morphology of fusion beats created by single premature stimulation in each patient. In 29 (83%) of 35 of the BrS patients, conversion from type-1 to type-2 ECG was observed during the process of single premature stimulation. Additionally, in all 8 BrS patients with concomitant CRBBB, type-1 or type-2 BrS ECG was revealed by premature stimulation with relief of CRBBB. These findings were not observed in any of the control subjects with CRBBB. CONCLUSION: Single premature stimulation of the RV converts ECG from type-1 to type-2 in most BrS cases and unmasks type-1 ECG in all BrS cases with CRBBB. Our results could suggest that type-1 ECG is associated with delayed activation of the RV compared with type-2 ECG. PMID- 28884872 TI - The tip of the muscle is a dominant location of ventricular ectopy originating from papillary muscles in the left ventricle. AB - INTRODUCTION: Frequent ventricular premature complexes (VPCs) may cause symptoms and/or lead to deterioration of LV systolic function. Although frequent VPCs may be abolished by catheter ablation, it may be challenging in case of their origin from the LV papillary muscles (PMs). Our collaborative study aimed to analyze in detail the site of origin and the outcome of ablation. METHODS: Consecutive 34 patients (males: 68%; aged 62 +/- 12 years; LV ejection fraction: 50 +/- 9%) undergoing catheter ablation of VPCs originating from PMs were included. All procedures were guided by intracardiac echocardiography. RESULTS: The size and shape of PMs were highly variable. The length of anterolateral and posteromedial PM was 23 +/- 4 mm and 28 +/- 7 mm, respectively. In about one-third of patients, the PM was formed by two distinctly separate heads. The ectopic foci were located on anterolateral, posteromedial or both PM in 35%, 56% and 9% of cases, respectively. Their location was found within the distal, mid, or proximal (basal) third of PM in the 67%, 19%, and 14%, respectively. A total of 86% of PM foci were acutely abolished and long-term success was achieved in 65% of patients. Absence of VPCs of other morphologies and a high burden of ectopic activity before ablation were associated with favorable clinical outcome. CONCLUSION: VPCs originate predominantly from the distal portion of the PM. This knowledge may facilitate the mapping in patients with infrequent ectopic beats. Intracardiac echocardiography is of crucial importance for navigation of the ablation catheter and for assessment of its stability at PM target sites. PMID- 28884874 TI - Cerebral dopaminergic and glutamatergic transmission relate to different subjective responses of acute alcohol intake: an in vivo multimodal imaging study. AB - Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [18 F]fallypride and [18 F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [18 F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P < 0.05, corrected for multiple comparisons). Dopamine release in the ACC and orbitofrontal and ventromedial PFCs were correlated with subjective 'liking' and 'wanting' effects (P < 0.05). In contrast, baseline mGluR5 availability was positively correlated with the 'high' effect of alcohol in dorsolateral, ventrolateral and ventromedial PFCs and in the medial temporal lobe, thalamus and caudate nucleus (P < 0.05). Although neither proton-magnetic resonance spectroscopy glutamate nor glutamine levels were affected by alcohol, baseline ACC glutamate levels were negatively associated with the alcohol 'liking' effect (P < 0.003). These data reveal new mechanistic understanding and differential neurobiological underpinnings of the effects of acute alcohol consumption on human behavior. Specifically, prefrontal dopamine release may encode alcohol 'liking' and 'wanting' effects in specific areas underlying value processing and motivation, whereas mGluR5 availability in distinct prefrontal-temporal-subcortical regions is more related to the alcohol 'high' effect. PMID- 28884875 TI - Successful collection of peripheral blood stem cells upon VIDE chemomobilization in sarcoma patients. AB - OBJECTIVES: In patients with Ewing sarcoma and some distinct subgroups of soft tissue sarcoma (STS), a quantitatively sufficient autologous peripheral blood stem cell (PBSC) collection for stem cell support might facilitate treatment continuation, dose-intensification, and high-dose chemotherapy. Here, we provide a detailed evaluation of PBSC collection upon vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) chemomobilization. METHODS: Mobilization and collection parameters of 42 sarcoma patients (Ewing sarcoma n = 35, other STS n = 7) were analyzed retrospectively. Data were evaluated with regard to the number of previous VIDE therapy cycles. RESULTS: All patients reached the collection goal of >=2.0 * 106 CD34+ cells/kg body weight (bw) upon VIDE/G-CSF mobilization, in the majority of cases with one single leukapheresis (LP) session (n = 29, 69%). No significant differences were identified with regard to mobilization and collection variables or the number of previous induction VIDE therapy cycles. However, upon 5 cycles of VIDE, we found the highest relative proportion of patients who required two or three LP sessions. CONCLUSIONS: Our data demonstrate the feasibility of successful PBSC collection upon VIDE chemomobilization even after up to five cycles of induction therapy, while at the same time the increasing risk of bone marrow exhaustion with every consecutive cycle is outlined. PMID- 28884877 TI - Self-administered acupressure for insomnia disorder: a pilot randomized controlled trial. AB - Self-administered acupressure has potential as a low-cost alternative treatment for insomnia. To evaluate the short-term effects of self-administered acupressure for alleviating insomnia, a pilot randomized controlled trial was conducted. Thirty-one subjects (mean age: 53.2 years; 77.4% female) with insomnia disorder were recruited from a community. The participants were randomized to receive two lessons on either self-administered acupressure or sleep hygiene education. The subjects in the self-administered acupressure group (n = 15) were taught to practise self-administered acupressure daily for 4 weeks. The subjects in the comparison group (n = 16) were advised to follow sleep hygiene education. The primary outcome was the Insomnia Severity Index (ISI). Other measures included a sleep diary, Hospital Anxiety and Depression Scale and Short-form Six-Dimension. The subjects in the self-administered acupressure group had a significantly lower ISI score than the subjects in the sleep hygiene education group at week 8 (effect size = 0.56, P = 0.03). However, this observed group difference did not reach a statistically significant level after Bonferroni correction. With regard to the secondary outcomes, moderate between-group effect sizes were observed in sleep onset latency and wake after sleep onset based on the sleep diary, although the differences were not significant. The adherence to self-administered acupressure practice was satisfactory, with 92.3% of the subjects who completed the lessons still practising acupressure at week 8. In conclusion, self administered acupressure taught in a short training course may be a feasible approach to improve insomnia. Further fully powered confirmatory trials are warranted. PMID- 28884876 TI - Intranasal insulin treatment restores cognitive deficits and insulin signaling impairment induced by repeated methamphetamine exposure. AB - Long-term use of methamphetamine (MA) causes a broad range of cognitive deficits. Recently, it has been reported insulin signaling and mitochondrial biogenesis are involved in cognitive processes. This study aimed to examine whether MA induces cognitive deficits concomitant with insulin signaling impairment and mitochondrial dysfunctions and also intranasal (IN) insulin treatment can reverse cognitive deficits caused by MA. Rats were repeatedly treated with increasing doses of MA (1-10 mg/kg) twice a day for 10 days, and their cognitive functions were assessed using Y-maze, novel object recognition and passive avoidance tasks. The expression of components involved in insulin signaling (IR/IRS2/PI3K/Akt/GSK3beta) and mitochondrial biogenesis (PGC-1alpha, NRF1, and TFAM) was measured in the hippocampus. Therapeutic effects of IN insulin delivery (0.5- IU/day, for 7 days after MA discontinuation) were also investigated in MA treated animals. Our results showed that repeated MA exposure induced cognitive deficits, and led to insulin signaling impairment and mitochondrial dysfunction. Interestingly, IN insulin treatment reduced MA-induced cognitive impairments possibly through activating insulin signaling, particularly PI3K/Akt/GSK3beta pathway, and mitochondrial biogenesis. Thus, insulin and insulin signaling pathway can be considered as useful targets for the treatment of abnormalities associated with MA abuse. PMID- 28884878 TI - Fragmentation patterns of chromophore-tagged peptides in visible laser induced dissociation. AB - RATIONALE: Tandem mass spectrometry (MS/MS) is the pivotal tool for protein structural characterization and quantification. Identification relies on the fragmentation step of tryptic peptides in bottom-up strategy. Specificity of fragmentation can be obtained using laser-induced dissociation (LID) in the visible range, after tagging of the targeted peptides with an adequate chromophore. Backbone fragmentation is required to obtain specific fragments and confident identification. We present herein a study of fragmentation patterns of chromophore-tagged peptides in LID, showing the potential of LID methodology to provide the maximum number of fragments for further identification and quantification. METHODS: A total of 401 cysteine-containing tryptic peptides originating from the human proteome were derivatizated on the thiol group of cysteine with a Dabcyl maleimide chromophore, which has a high photo-absorption cross section at 473 nm. The derivatized peptides were then analyzed by LID at 473 nm on a Q Exactive instrument. RESULTS: LID spectra present a characteristic fragment at m/z 252.112 for all precursors. This product ion arises from the internal dissociation of the Dabcyl chromophore. Several peptide-backbone fragment ions are also detected. Results show the quasi absence of fragmentation at the cysteine site. This indicates that part of the energy must be redistributed across the entire system despite excitation initially localized at the chromophore. Indeed, the fragmentation mainly occurs at 3 to 5 amino acids from the derivatized cysteine residue. CONCLUSIONS: LID of derivatized cysteine containing peptides displays the initial fragmentation of the chromophore. As energy is redistributed all along the peptide sequence, fragmentation of the peptide backbone is also observed. Thus, LID of chromophore-tagged peptides produces adequate fragment ions, allowing both good sequence coverage for a greater confidence of identification, and a large choice of transitions for specific quantification. PMID- 28884879 TI - Analysis of hepatitis B surface antigen (HBsAg) using high-sensitivity HBsAg assays in hepatitis B virus carriers in whom HBsAg seroclearance was confirmed by conventional assays. AB - AIM: We investigated the utility of high-sensitivity hepatitis B surface antigen (HBsAg) assays compared with conventional HBsAg assays. METHODS: Using serum samples from 114 hepatitis B virus (HBV) carriers in whom HBsAg seroclearance was confirmed by conventional HBsAg assays (cut-off value, 0.05 IU/mL), the amount of HBsAg was re-examined by high-sensitivity HBsAg assays (cut-off value, 0.005 IU/mL). Cases negative for HBsAg in both assays were defined as consistent cases, and cases positive for HBsAg in the high-sensitivity HBsAg assay only were defined as discrepant cases. RESULTS: There were 55 (48.2%) discrepant cases, and the range of HBsAg titers determined by high-sensitivity HBsAg assays was 0.005 0.056 IU/mL. Multivariate analysis showed that the presence of nucleos(t)ide analog therapy, liver cirrhosis, and negative anti-HBs contributed to the discrepancies between the two assays. Cumulative anti-HBs positivity rates among discrepant cases were 12.7%, 17.2%, 38.8%, and 43.9% at baseline, 1 year, 3 years, and 5 years, respectively, whereas the corresponding rates among consistent cases were 50.8%, 56.0%, 61.7%, and 68.0%, respectively. Hepatitis B virus DNA negativity rates were 56.4% and 81.4% at baseline, 51.3% and 83.3% at 1 year, and 36.8% and 95.7% at 3 years, among discrepant and consistent cases, respectively. Hepatitis B surface antigen reversion was observed only in discrepant cases. CONCLUSIONS: Re-examination by high-sensitivity HBsAg assays revealed that HBsAg was positive in approximately 50% of cases. Cumulative anti HBs seroconversion rates and HBV-DNA seroclearance rates were lower in these cases, suggesting a population at risk for HBsAg reversion. PMID- 28884880 TI - A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies. AB - Mutations in GLI3, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue patterning. Here, we report a novel missense variant in the fifth zinc finger domain of GLI3 (c.1826G>A; p.(Cys609Tyr)) initially identified in a proband with preaxial polydactyly type IV, developmental delay, sensorineural hearing loss, skeletal, and genitourinary anomalies. Additional family members exhibited various digital anomalies such as preaxial polydactyly, syndactyly, and postaxial polydactyly either in isolation or combined. Functional studies of Cys609Tyr GLI3 in cultured cells showed abnormal GLI3 processing leading to decreased GLI3 repressor production, increased basal transcriptional activity, and submaximal GLI reporter activity with Hedgehog pathway activation, thus demonstrating an intriguing molecular mechanism for this GLI3-related phenotype. Given the complexity of GLI3 post-translational processing and opposing biological functions as a transcriptional activator and repressor, our findings highlight the importance of performing functional studies of presumed GLI3 variants. This family also demonstrates how GLI3 variants are variably expressed. PMID- 28884881 TI - Effects of a Randomized Weight Loss Intervention Trial in Obese Adolescents on Tibia and Radius Bone Geometry and Volumetric Density. AB - Obese adolescents have increased fracture risk, but effects of alterations in adiposity on bone accrual and strength in obese adolescents are not understood. We evaluated 12-month changes in trabecular and cortical volumetric bone mineral density (vBMD) and cortical geometry in obese adolescents undergoing a randomized weight management program, and investigated the effect of body composition changes on bone outcomes. Peripheral quantitative computed tomography (pQCT) of the radius and tibia, and whole-body dual-energy X-ray absorptiometry (DXA) scans were obtained at baseline, 6 months, and 12 months in 91 obese adolescents randomized to standard care versus behavioral intervention for weight loss. Longitudinal models assessed effects of body composition changes on bone outcomes, adjusted for age, bone length, and African-American ancestry, and stratified by sex. Secondary analyses included adjustment for physical activity, maturation, vitamin D, and inflammatory biomarkers. Baseline body mass index (BMI) was similar between intervention groups. Twelve-month change in BMI in the standard care group was 1.0 kg/m2 versus -0.4 kg/m2 in the behavioral intervention group (p < 0.01). Intervention groups were similar in bone outcomes, so they were combined for subsequent analyses. For the tibia, BMI change was not associated with change in vBMD or structure. Greater baseline lean body mass index (LBMI) associated with higher cortical vBMD in males, trabecular vBMD in females, and polar section modulus (pZ) and periosteal circumference (Peri-C) in both sexes. In females, change in LBMI positively associated with gains in pZ and Peri-C. Baseline visceral adipose tissue (VFAT) was inversely associated with pZ in males and cortical vBMD in females. Change in VFAT did not affect bone outcomes. For the radius, BMI and LBMI changes positively associated with pZ in males. Thus, in obese adolescents, weight loss intervention with modest changes in BMI was not detrimental to radius or tibia bone strength, and changes in lean, but not adiposity, measures were beneficial to bone development. (c) 2017 American Society for Bone and Mineral Research. PMID- 28884882 TI - A retro-prospective effectiveness study on 3448 implant operations at one referral clinic: A multifactorial analysis. Part II: Clinical factors associated to peri-implantitis surgery and late implant failures. AB - BACKGROUND: Little knowledge is available on implant treatment in large effectiveness studies in routine practice. PURPOSE: To report retro-prospective data on prevalence of peri-implantitis surgery and late implant failures in a large number of routine patients at 1 referral clinic. MATERIALS AND METHODS: Altogether 9582 implants with an anodized surface (Nobel Biocare AB) were consecutively placed between 2003 and 2011 and followed-up to end of 2015. All peri-implantitis operations and late implant failures were consecutively identified. A logistic multivariate data analysis was performed to identify association between the complications and different clinical factors. Furthermore, data on prevalence on risk for inflammation and bone loss at implants ("peri-implantitis") and surgery related to peri-implantitis was collected for another reference group of about 10 000 implant patients during 3 consecutive years (2013-2015). RESULTS: Cumulative survival rates for implant operations without peri-implantitis surgery or implant failures were calculated to 96.4% (95% CI: 97.3-95.4) and 95.0% (95% CI: 96.0-94.1) after 10 years, respectively. Risk for "peri-implantitis surgery" showed a significant association (P < .05) to number of placed implants (hazard ratio [HR] 1.40; 95% CI: 1.24-1.59). Three factors showed significant association to risk for "late implant failures," where "treatment in lower jaw" had the highest risk; HR 2.03. "Overall implant failures" were associated to 4 significant factors where "surgeon" (HR 2.50) showed highest impact on risk. "Numbers of implants" and "bone resorption" at surgery were the 2 significant factors that were consistent for all the time periods of failures during follow-up (early/late/total). On an average 7.4% of examined patients in the reference group were denoted with highest risk group ("peri-implantitis") of which on an average 12.7% of these patients had surgery related to peri-implantitis. CONCLUSIONS: "The dentist" involved in the surgical and prosthetic rehabilitation of the implant patients, "number of implants" and degree of "bone resorption" seem to have most impact on overall implant complications and failures in the present patient group. PMID- 28884883 TI - Diagnostic imaging using positron emission tomography for gynecological malignancy. AB - Imaging has played a pivotal role in the management of gynecological malignancy. Positron emission tomography (PET), particularly 18 F-fluorodeoxyglucose (18 F FDG) PET to reflect cellular glycolytic metabolism, is being increasingly used and has proven superior to conventional imaging including ultrasonography, computed tomography (CT), and magnetic resonance imaging. Studies of and evidence for the utility of 18 F-FDG PET/CT for the detection of local or metastatic disease, treatment planning, response assessment, restaging of recurrent disease, and prognostic assessment are growing. We review the latest evidence for and limitations of 18 F-FDG PET/CT in the diagnosis of gynecological malignancy. Moreover, we also describe the benefits of and evidence for other tracers. PMID- 28884884 TI - A randomized double-blind placebo-controlled crossover-style trial of buspirone in functional dysphagia and ineffective esophageal motility. AB - BACKGROUND: Studies suggest that Ineffective Esophageal Motility (IEM) is the manometric correlate of Functional Dysphagia (FD). Currently, there is no accepted therapy for either condition. Buspirone is a serotonin modulating medication and has been shown to augment esophageal peristaltic amplitude in healthy volunteers. We aimed to determine if buspirone improves manometric parameters and symptoms in patients with overlapping IEM/FD. METHODS: We performed a prospective, double-blind, placebo-controlled, crossover-style trial of 10 patients with IEM/FD. The study consisted of two 2-week treatment arms with a 2-week washout period. Outcomes measured at baseline, end of week 2, and week 6 include high resolution esophageal manometry (HREM), the Mayo Dysphagia Questionnaire-14 (MDQ-14), and the GERD-HRQL. RESULTS: The mean age of our 10 patients was 53 +/- 9 years and 70% were female. After treatment with buspirone, 30% of patients had normalization of IEM on manometry; however, there was 30% normalization in the placebo group as well. Comparing buspirone to placebo, there was no statistically significant difference in the HREM parameters measured. There was also no statistically significant difference in symptom outcomes for buspirone compared to placebo. Of note, patients had a statistically significant decrease in the total GERD-HRQL total score when treated with placebo compared to baseline levels. DISCUSSION: Despite previous data demonstrating improved esophageal motility in healthy volunteers, our study shows no difference in terms of HREM parameters or symptom scores in IEM/FD patients treated with buspirone compared to placebo. Further research is necessary to identify novel agents for this condition. PMID- 28884885 TI - Effect of different light-dark schedules on estrous cycle in mice, and implications for mitigating the adverse impact of night work. AB - Approximately 20% of workers in developed countries are involved in night work. Nevertheless, many studies have strongly suggested that night-work-induced chronic circadian misalignment increases the risk of a diverse range of health problems. Although a relation between night work and irregular menstrual cycles has been indicated epidemiologically, a direct causal link remains elusive. Here, we report that repetitive reversal of light-dark (LD) cycles triggers irregular estrous cycles in mice. The findings showed that the estrous cycle remained irregular for more than four weeks after the mice were returned to regular LD cycles. Importantly, the magnitude of the negative impact of reversed LD cycles on the estrous cycle, or more specifically the decreased number of normal estrous cycles during the observation period, was dependent on the difference in the frequency of LD reversal. Presently, no clear solution to prevent night-work mediated menstrual abnormalities is available, and reducing night work in modern society is difficult. Our findings indicate that optimizing work schedules could significantly prevent menstrual problems without reducing total night-work time. PMID- 28884886 TI - One-Step Multigram-Scale Biomimetic Synthesis of Psiguadial B. AB - A gram-scale synthesis of psiguadial B, a purported inhibitor of human hepatoma cell growth, has been achieved in one step by a biomimetic three-component coupling of caryophyllene, benzaldehyde, and diformylphloroglucinol. This cascade reaction is catalyzed by N,N'-dimethylethylenediamine, and proceeds at ambient temperature to generate four stereocenters, two rings, one C-O bond, and three C C bonds. Combined computational and experimental investigations suggest the biosynthesis of the natural product is non-enzyme mediated, and is the result of a Michael addition between caryophyllene and a reactive ortho-quinone methide, followed by two sequential intramolecular cationic cyclization events. PMID- 28884888 TI - FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability? AB - The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FOXP1 (NM_032682.5:c.975-2A>C and NM_032682.5:c.1574G>A) and additional features. One had a lung disease resembling neuroendocrine cell hyperplasia of infancy (NEHI), and the second had a skeletal disorder with undertubulation of the long bones and relapsing-remitting fevers associated with flushing and edema. Although attribution of these traits to mutation of FOXP1 requires ascertainment of additional patients, we hypothesize that the variable expression of these additional features might arise by means of stochastic developmental variation. PMID- 28884889 TI - Novel homozygous missense mutation in NT5C2 underlying hereditary spastic paraplegia SPG45. AB - SPG45 is a rare form of autosomal recessive spastic paraplegia associated with mental retardation. Detailed phenotyping and mutation analysis was undertaken in three individuals with SPG45 from a consanguineous family of Arab Muslim origin. Using whole-exome sequencing, we identified a novel homozygous missense mutation in NT5C2 (c.1379T>C; p.Leu460Pro). Our data expand the molecular basis of SPG45, adding the first missense mutation to the current database of nonsense, frameshift, and splice site mutations. NT5C2 mutations seem to have a broad clinical spectrum and should be sought in patients manifesting either as uncomplicated or complicated HSP. PMID- 28884887 TI - Impaired antioxidant enzyme functions with increased lipid peroxidation in epithelial ovarian cancer. AB - We aimed to identify the possible role of oxidant-antioxidant status in epithelial ovarian cancer (EOC) by measuring (a) antioxidant enzyme (AOE) activities [total superoxide dismutase (SODtotal ), manganese-SOD (Mn-SOD), copper,zinc-SOD (Cu,Zn-SOD), catalase (CAT) and glutathione peroxidase (GPx1)], (b) Mn-SOD protein expression, (c) lipid peroxidation markers [malondialdehyde (MDA), 8-epi-prostaglandin-F2alpha (8-epi-PGF2alpha)] and by evaluating the possible correlations between tumor biomarkers, reproductive hormone levels and all measured parameters, comprehensively. The data obtained from the patients with EOC (M, n = 26) evaluated according to the histopathological/clinical characteristics of tumors and compared with data of healthy controls [Ctissue (C1) and Cblood/urine (C2), n = 30, respectively). Significantly, low activities of tumor SODtotal (52%), Mn-SOD (42%), Cu,Zn-SOD (55%); high activities of tumor and erythrocyte CAT (66%, 33% respectively) and tumor GPx1 (60%); high levels of tumor Mn-SOD protein expression; tumor MDA (193%) and urinary 8-epi-PGF2alpha (179%) were observed in serous EOC tumors (M1, n = 18) compared with controls (P < 0.05). However, higher levels of tumor MDA, Mn-SOD protein expression and urinary 8-epi-PGF2alpha were observed along with lower tumor CAT activity in poorly differentiated or undifferentiated (grade 3, G 3) versus well or moderately well differentiated (grade 1-2, G 1-2) serous EOC tumors. Obtained data indicate the presence of a severe redox imbalance in EOC and draw attention to the criticial role of AOEs in the pathogenesis of the disease. (c) 2017 IUBMB Life, 69(10):802-813, 2017. PMID- 28884890 TI - Research into action? The Eastside Illicit Drinkers Group for Education's (EIDGE) experiences as a community-based group in Vancouver, Canada. AB - The Eastside Illicit Drinkers Group for Education has been supportive of research dedicated to establishing the effectiveness of Managed Alcohol Programs since its inception. Dedicated funding for MAPs in Vancouver, British Columbia is contingent on the research demonstrating that alcohol-related harms are reduced while participating in a Managed Alcohol Program. The Eastside Illicit Drinkers Group for Education understands the need for evidence-based research but we are critical of how much research is needed before sustainable funding can be established for these innovative programs. PMID- 28884892 TI - Basic research, chronobiology, ontogeny and clinical sleep medicine. PMID- 28884891 TI - Investigation of suitability of ventrogluteal site for intramuscular injections in children aged 36 months and under. AB - PURPOSE: This study was performed to determine suitability of ventrogluteal (VG) site for intramuscular (IM) injections in children aged 36 months and under. DESIGN AND METHODS: The present study was designed as a prospective descriptive study and performed between 2016 January and June. The study included a total of 120 children aged 36 months and under that met the study criteria. The subcutaneous tissue thickness and muscle thickness of anterolateral, deltoid, and VG sites were measured and assessed by ultrasound. RESULT: A strong and powerful correlation was identified between the measurements of subcutaneous tissue and muscle thicknesses in the injection site by the age groups. The thickness of subcutaneous tissue was deltoid < anterolateral < VG by age groups. The muscle thickness of anterolateral and VG sites was significantly higher than that of deltoid site. PRACTICE IMPLICATIONS: This study established that skin thickness of VG site was suitable for IM injection in children aged 36 months and under. PMID- 28884893 TI - Chimerism for 20q11.2 microdeletion of GDF5 explains discordant phenotypes in monochorionic-diamniotic twins. AB - Microdeletions of 20q11.2 are rare but have been associated with characteristic clinical findings. A 1.6 Mb minimal critical region has been identified that includes three OMIM genes: GDF5, EPB41L1, and SAMHD. Here we describe a male monozygotic, monochorionic-diamniotic twin pair with discordant phenotypes, one with multiple findings that overlap with those reported in 20q11.2 deletions, and the other unaffected. Microarray analysis revealed mosaicism for a 363 Kb deletion encompassing GDF5 in the peripheral blood of both twins, which was confirmed by FISH. Subsequent FISH on buccal cells identified the deletion only in the affected twin. The blood FISH findings were interpreted as representing chimerism resulting from anastomosis and the blood exchange between the twins in utero. The implications of this finding are discussed, as is the contribution of GDF5 to the associated clinical findings of 20q11.2 deletions. PMID- 28884895 TI - The case for government-run liquor stores in the Australian Northern Territory: Looking outside the box in regulating the supply of alcohol. PMID- 28884894 TI - CDP-choline circumvents mercury-induced mitochondrial damage and renal dysfunction. AB - Heavy metal ions are known to produce harmful alterations on kidney function. Specifically, the accumulation of Hg2+ in kidney tissue may induce renal failure. In this work, the protective effect of CDP-choline against the deleterious effects induced by Hg2+ on renal function was studied. CDP-choline administered ip at a dose of 125 mg/kg body weight prevented the damage induced by Hg2+ administration at a dose of 3 mg/kg body weight. The findings indicate that CDP choline guards mitochondria against Hg2+ -toxicity by preserving their ability to retain matrix content, such as accumulated Ca2+ . This nucleotide also protected mitochondria from Hg2+ -induced loss of the transmembrane electric gradient and from the generation of hydrogen peroxide and membrane TBARS. In addition, CDP choline avoided the oxidative damage of mtDNA and inhibited the release of the interleukins IL-1 and IL6, recognized as markers of acute inflammatory reaction. After the administration of Hg2+ and CDP, CDP-choline maintained nearly normal levels of renal function and creatinine clearance, as well as blood urea nitrogen (BUN) and serum creatinine. PMID- 28884896 TI - The contribution of alcohol use and other lifestyle factors to socioeconomic differences in all-cause mortality in a Swedish cohort. AB - INTRODUCTION AND AIMS: A relationship between socioeconomic position (SEP) and mortality has been found in high-income countries. One possible explanation is socioeconomic differentials in health behaviours. The aim was to investigate to what degree the association between SEP and all-cause mortality is explained by differences in alcohol use and other lifestyle factors. DESIGN AND METHODS: The study was based on data from a large public health survey from Stockholm County in 2002, with 5 year follow-up for all-cause mortality. Proportional hazard models estimated the effect of education, occupational class and income on all cause mortality, before and after adjusting for alcohol use (both separate and combined effects of levels and patterns of drinking), smoking, physical activity and body mass index. RESULTS: The prevalence of lifestyle factors showed a marked social gradient. All three SEP indicators showed higher mortality for the most disadvantaged SEP group than in the least disadvantaged group. Adjusting for a combined measure of alcohol use attenuated the SEP differences in mortality by a fifth, whereas adjusting for volume of consumption resulted in considerably smaller attenuations. Adjusting for smoking resulted in attenuations of 6-18%. In the fully adjusted model, physical activity and body mass index did not account for the socioeconomic differences in mortality beyond that of alcohol and smoking.? DISCUSSION AND CONCLUSIONS: Irrespective of whether SEP is defined by education, occupational class or income, the unequal distribution of hazardous alcohol use and smoking contributes to a notable proportion of the socioeconomic differences in mortality in Sweden. [Syden L, Landberg J. The contribution of alcohol use and other lifestyle factors to socioeconomic differences in all-cause mortality in a Swedish cohort. Drug Alcohol Rev 2016;00:000-000]. PMID- 28884897 TI - Shedding Light on Alopecia Areata in Pediatrics: A Retrospective Analysis of Comorbidities in Children in the National Alopecia Areata Registry. AB - Alopecia areata (AA) is a common autoimmune disease and it is challenging to predict which patients will have severe disease. The purpose of this retrospective study was to identify comorbidities in children enrolled in the National Alopecia Areata Registry. Atopic dermatitis was more common in patients with severe AA than in those with mild disease. The most common autoimmune comorbidities were vitiligo, psoriasis, thyroid disease, and juvenile idiopathic arthritis. PMID- 28884898 TI - Response Letter to "Contact Dermatitis Associated with Alopecia and Hyperpigmentation". PMID- 28884899 TI - Yellow-Orange Penile Papules. PMID- 28884900 TI - Verrucous Penile Plaque in an 11-Year-Old Boy. PMID- 28884901 TI - Contact Dermatitis Associated with Alopecia and Hyperpigmentation. PMID- 28884902 TI - The Role of Elimination Diets in Atopic Dermatitis-A Comprehensive Review. AB - BACKGROUND/OBJECTIVES: Diet is a common concern for individuals with atopic dermatitis (AD) and their families. Studies regarding the effect of dietary interventions on AD exist, but many are limited by small size and poor design. Conflicting results present a challenge to clinicians seeking to counsel patients. The aim of the current review is to examine the published literature and generate helpful conclusions for clinicians faced with dietary questions in AD. METHODS: A PubMed search was performed focusing on dietary interventions for AD in children and adults through July 2016. The search was limited to the English language and included studies that evaluated one or more forms of dietary modification for the treatment of AD. Studies of supplementation, such as with vitamins, minerals, or probiotics, were not included, nor were studies on prevention of the development of AD. A total of 43 articles met the inclusion criteria and were included in the final analysis. RESULTS: Trials varied in type, duration, and the AD patient populations studied. Overall, there is some level I evidence to support specific exclusion diets in preselected patients but insufficient evidence for strict elimination diets (diets that are typically limited to six to eight foods). Data supporting other interventions are mixed and based on small, poorly designed studies. CONCLUSIONS: A comprehensive literature review reveals some promising results and several areas in need of further study. More evidence is needed to form a strong foundation for recommendations regarding the utility and role of elimination diets in AD management, but current evidence suggests that strict diet management is not effective in the treatment AD in the vast majority of patients. PMID- 28884903 TI - Long-Term Follow-Up of Lymphatic Malformations in Children Treated with Sildenafil. AB - BACKGROUND/OBJECTIVES: Lymphatic malformations (LMs) are challenging to treat. Reports on the benefits of sildenafil for LM management have been mixed. This study evaluated long-term clinical outcomes of pediatric LM patients after sildenafil treatment. METHODS: A retrospective chart review was performed on pediatric LM patients treated with sildenafil in the past 5 years. Patients were also contacted to complete a survey of comprehensive questions about their LM after sildenafil and subsequent interventions. RESULTS: Of 12 patients identified, 10 (83.3%) participated in the follow-up survey. The average age was 8 years (range 4-16 yrs), median treatment duration was 9 months, and the average time of follow-up after sildenafil was 4 years; one patient is still taking sildenafil. Ten patients surveyed (83.3%) reported positive therapeutic response, with improvement in the size and compressibility of their LM during posttreatment clinical visits. Six received additional interventions (four sirolimus, one sclerotherapy, one surgery) after sildenafil was discontinued, with all but one reporting a positive response to subsequent interventions. Minor side effects at the time of sildenafil treatment included mild flushing, dizziness, and transient nausea, but no adverse effects were reported at the long-term follow-up. CONCLUSION: This is the first report of long-term follow-up of pediatric LM patients treated with sildenafil. Our findings suggest that sildenafil is beneficial for the symptomatic treatment of LMs. Additional analysis on the role of sildenafil as adjuvant therapy is necessary to optimize the use of this medication in the management of complex LMs. PMID- 28884904 TI - Patient Perspectives: What is perioral dermatitis? PMID- 28884906 TI - Pediatric Dermatology Photoquiz: A 14-Year-Old Boy with Abrupt-Onset Hair Changes. PMID- 28884905 TI - Macrodystrophia Lipomatosa. AB - Macrodystrophia lipomatosa is an exceedingly rare overgrowth of mesenchymal and fibroadipose tissue manifesting as a form of gigantism affecting one or more digits on the distal upper or lower extremities. We present a 25-year-old man who presented with overgrowth of the right hand associated with occasional pain, numbness, and limited function who was found to have macrodystrophia lipomatosa with fibrolipomatous hamartoma of the median nerve. Reports of this condition are limited in the dermatology literature, and early recognition can lead to better outcomes. PMID- 28884907 TI - Crusted Plaques, Cicatricial Alopecia, Whitish Plaques in the Oral Cavity, and Dystrophic Nails in a Child. PMID- 28884909 TI - Atypical Spitz Tumors are Biohistologically Categorizable as Melanocytic Tumors of Uncertain Malignant Potential. PMID- 28884908 TI - Analysis of Dermatologic Consultations in a Neonatal Intensive Care Unit Over a 7 Year Period: Retrospective Review of 60 Cases. AB - BACKGROUND/OBJECTIVES: The need for dermatology consultations for neonatal intensive care unit (NICU) patients is increasing, but no study has systemically examined the skin diseases of patients in NICUs. The aim of this study was to analyze dermatology consultations in the NICU of a tertiary medical center in Korea and determine the effect of the dermatology consultation on the clinical course and management of the patients after the consultation. METHODS: The medical records of patients undergoing dermatologic consultation during their stay in a NICU between March 2009 and February 2016 were reviewed retrospectively. RESULTS: Sixty patients were enrolled in this study; the male-to female ratio was 1:1.1, and mean age at the time of consultation was 3.7 weeks. Mean gestational age was 33.7 weeks, and 35 of the subjects (58.3%) were preterm neonates. Mean birth weight was 2.14 kg (range 550-4,200 g). The most-common disease category was birthmarks and neoplasms (20.0%), followed by eczematous dermatoses (18.3%), skin appendageal disease (16.7%), and infectious disease (13.3%). CONCLUSION: This study identified the dermatologic problems of neonates in a NICU and can raise dermatologists' awareness of the types of patients they may encounter in a NICU. PMID- 28884910 TI - Successful Use of Cyclosporin A for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Three Children. AB - BACKGROUND/OBJECTIVES: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are medical emergencies. Mainstays of treatment include removal of the offending agent, supportive care, and wound care. The use of immunosuppressive agents such as corticosteroids and intravenous immunoglobulin (IVIg) is controversial. Some case reports and small studies report the successful use of cyclosporin A (CsA) for SJS/TEN in halting disease progression, fostering reepithelialization, and reducing mortality. OBJECTIVE: To report on the efficacy of cyclosporine A in the treatment of SJS/TEN in three pediatric patients. METHODS: We describe three pediatric patients seen at a tertiary care hospital in Boston, Massachusetts, diagnosed with SJS/TEN confirmed by skin biopsy who were successfully treated with CsA with improvements seen in time to cessation of disease progression or new lesion formation, reepithelialization, and duration of hospital stay. RESULTS: The average time cessation of disease progression or new lesion formation after CsA administration was 2.2 days (range 1.5-3 days) and average time to remission or reepithelialization was 13 days (range 10-15 days). The average length of hospital stay was 11.7 days (range 4-19 days). CONCLUSIONS: We describe three pediatric patients treated successfully with CsA and provide evidence for the use of cyclosporine in children with SJS/TEN. These results further support previous observations that CsA use for SJS/TEN produces consistently favorable outcomes. The results in this case series are limited by their observational nature. Additional trials are needed to evaluate the safety and efficacy of CsA use in children. PMID- 28884911 TI - Final Diagnosis of 112 Girls Presenting With Genital Mucocutaneous Symptoms and Signs: The Mayo Clinic Experience. AB - Pediatric genital mucocutaneous diseases are rare. A retrospective review was performed of children presenting with symptomatology of genital dermatoses to a hospital-based dermatology service. This study highlights that the range of genital diseases in children is not as broad as in adults. The diagnosis of genital mucocutaneous disease in children is usually genital lichen sclerosus, but other diagnoses should be considered. PMID- 28884912 TI - Sudden-Onset Reddish-Brown Macules on the Palms and Soles of Two Children. PMID- 28884913 TI - A Girl with Gray Hair and Pyogenic Infections. PMID- 28884914 TI - White Eyelashes and Red Eyes in a 7-Year-Old Boy. PMID- 28884915 TI - Severe Mucha-Habermann-Like Ulceronecrotic Skin Disease in T-Cell Acute Lymphoblastic Leukemia Responsive to Basiliximab and Stem Cell Transplant. AB - A 5-year-old girl with T-cell acute lymphoblastic leukemia (T-ALL) developed a progressive eruption of crusted papules and ulcerative plaques involving 80% of her body surface area with histopathology consistent with febrile ulceronecrotic Mucha-Habermann disease (FUMHD), although multiple specimens also contained clonal leukemic cells. Her skin disease was refractory to many classic treatments for FUMHD, including methotrexate, and became so severe that concern about superinfection prevented intensification of chemotherapy for her malignancy. The addition of basiliximab promoted gradual improvement of the skin, allowing for chemotherapy intensification and subsequent bone marrow transplantation, after which the eruption resolved completely. This report describes a severe case of FUMHD-like eruption associated with clonal leukemic cells that improved with basiliximab, suggesting anti-CD25 therapy as a novel treatment for ulceronecrotic skin disease in the setting of high interleukin-2 levels. PMID- 28884916 TI - Post-Chikungunya Rheumatic Disease in a 13-Year-Old Boy. AB - Chikungunya is a mosquito-borne viral infection that causes an acute febrile illness and can result in acute or chronic musculoskeletal disease. A 13-year-old boy presented with post-Chikungunya rheumatic disease featuring connective tissue disease signs including digital ulcerations, cuticular dystrophy, dilated capillary loops, and digital tapering. PMID- 28884917 TI - Molluscum Contagiosum: Review and Update on Management. AB - Molluscum contagiosum (MC) is an infectious dermatosis that commonly presents in children and immunocompromised individuals. Although lesions usually resolve spontaneously after several months, they can be symptomatic and cause psychosocial distress. We review the evidence underlying treatment methods available for MC lesions, including potassium hydroxide, salicylic acid, hydrogen peroxide, retinoids, cantharidin, cryotherapy, curettage, and pulsed dye laser to aid practicing dermatologists in therapy selection. PMID- 28884918 TI - Adams-Oliver Syndrome Type 2 in Association with Compound Heterozygous DOCK6 Mutations. AB - Adams-Oliver syndrome (AOS) is a multiple congenital anomaly syndrome characterized by aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLDs). We present a case of type 2 autosomal recessive AOS associated with heterozygous mutations in the dedicator of cytokinesis 6 (DOCK6) gene, with characteristic findings of ACC, TTLD, intracerebral periventricular calcifications, and polymicrogyria. PMID- 28884919 TI - Granulomatosis with Polyangiitis Presenting with Pyoderma Gangrenosum-Like Ulceration and Negative Cytoplasmic Antineutrophilic Cytoplasmic Antibodies in a Child. AB - Granulomatosis with polyangiitis (GPA), a vasculitis that most commonly affects small to medium-size vessels of the respiratory tract and kidneys, may also present with a wide array of skin findings. We present the case of a 12-year-old boy with pyoderma gangrenosum-like ulcerations on his lower extremity as the initial manifestation of GPA despite negative cytoplasmic antineutrophilic cytoplasmic antibodies (c-ANCAs). Although GPA is strongly associated with c ANCA, c-ANCA may be negative on presentation. Thus clinical and pathologic clues must be relied upon when serologic confirmation is negative. PMID- 28884920 TI - Firm Erythematous Nodules in a Hospitalized Infant. PMID- 28884921 TI - Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1. AB - Mutations in GLE1 underlie Lethal Congenital Contracture syndrome (LCCS) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD). Both LCCS and LAAHD are characterized by reduced fetal movements, congenital contractures, and a severe form of motor neuron disease that results in fetal death or death in the perinatal period, respectively. We identified bi-allelic mutations in GLE1 in two unrelated individuals with motor delays, feeding difficulties, and respiratory insufficiency who survived beyond the perinatal period. Each affected child had missense variants predicted to result in amino acid substitutions near the C terminus of GLE1 that are predicted to disrupt protein-protein interaction or GLE1 protein targeting. We hypothesize that mutations that preserve function of the coiled-coil domain of GLE1 cause LAAHD whereas mutations that abolish the function of the coiled-coil domain cause LCCS. The phenotype of LAAHD is now expanded to include multiple individuals surviving into childhood suggesting that LAAHD is a misnomer and should be re-named Arthrogryposis with Anterior Horn Cell Disease (AAHD). PMID- 28884922 TI - Congenital heart defects in molecularly proven Kabuki syndrome patients. AB - The prevalence of congenital heart defects (CHD) in Kabuki syndrome ranges from 28% to 80%. Between January 2012 and December 2015, 28 patients had a molecularly proven diagnosis of Kabuki syndrome. Pathogenic variants in KMT2D (MLL2) were detected in 27 patients, and in KDM6A gene in one. CHD was diagnosed in 19/27 (70%) patients with KMT2D (MLL2) variant, while the single patient with KDM6A change had a normal heart. The anatomic types among patients with CHD included aortic coarctation (4/19 = 21%) alone or associated with an additional CHD, bicuspid aortic valve (4/19 = 21%) alone or associated with an additional CHD, perimembranous subaortic ventricular septal defect (3/19 = 16%), atrial septal defect ostium secundum type (3/19 = 16%), conotruncal heart defects (3/19 = 16%). Additional CHDs diagnosed in single patients included aortic dilatation with mitral anomaly and hypoplastic left heart syndrome. We also reviewed CHDs in patients with a molecular diagnosis of Kabuki syndrome reported in the literature. In conclusion, a CHD is detected in 70% of patients with KMT2D (MLL2) pathogenic variants, most commonly left-sided obstructive lesions, including multiple left-sided obstructions similar to those observed in the spectrum of the Shone complex, and septal defects. Clinical management of Kabuki syndrome should include echocardiogram at the time of diagnosis, with particular attention to left-sided obstructive lesions and mitral anomalies, and annual monitoring for aortic arch dilatation. PMID- 28884923 TI - Low-voltage areas detected by high-density electroanatomical mapping predict recurrence after ablation for paroxysmal atrial fibrillation. AB - INTRODUCTION: We aimed to evaluate the extent of atrial fibrosis in paroxysmal atrial fibrillation (AF) and the correlation with ablation outcomes after pulmonary vein antral isolation (PVAlphaI) using a mapping system with high resolution and high-spatial sampling. METHODS AND RESULTS: We prospectively enrolled 80 consecutive patients (45 males, median age 60.26 years) with symptomatic paroxysmal AF who were scheduled for PVAI. Prior to PVAI, high density bipolar voltage mapping (median number of 2,485 points) was carried out during sinus rhythm in all patients. Criteria for an adequate left atrium (LA) shell were > 2,000 points. Each acquired point was classified according to the peak-to-peak bipolar voltage electrogram based on two criteria (criterion A: healthy > 0.8 mV, border zone: 0.4-0.8 mV and scarred: < 0.4 mV, criterion Beta: healthy: > 0.5 mV, border zone: 0.25-0.5 mV and scarred: < 0.25 mV). The extent of low-voltage area < 0.4 mV significantly predicted atrial tachyarrhythmia recurrence after the blanking period (P = 0.002). In univariate analysis, the presence of LA voltage areas < 0.4 mV more than 10% of the total surface area was the only significant predictor of arrhythmia recurrence. The analysis based on window B cutoff values failed to demonstrate any predictors of arrhythmia recurrence. CONCLUSION: These data demonstrate that the existence of LA voltage areas < 0.4 mV more than 10% of the total LA surface area predicts arrhythmia recurrence following PVAI for paroxysmal AF. PMID- 28884924 TI - Two novel mutations in XYLT2 cause spondyloocular syndrome. AB - We report on two new patients with spondyloocular syndrome. Both patients harbor novel homozygous mutations in the XYLT2 gene. The patients present severe generalized osteoporosis, multiple fractures, short stature, cataract, and mild hearing impairment. XYLT2 mutations have been identified in spondyloocular syndrome, however only five mutations have been reported previously. These two patients with novel mutations extend the phenotypic and genotypic spectrum of spondyloocular syndrome. PMID- 28884926 TI - An investigation of the beam damage effect on in situ liquid secondary ion mass spectrometry analysis. AB - RATIONALE: During in situ liquid secondary ion mass spectrometry (SIMS) analysis, the primary ion beam is normally scanned on a very small area to collect signals with high ion doses (1014 to 1016 ions/cm2 ). As a result, beam damage may become a concern when compared with the static limit of SIMS analysis, in which the dose is normally less than 1012 ions/cm2 . Therefore, a comparison of ion yields in in situ liquid SIMS analysis versus traditional static SIMS analysis of corresponding dry samples is of great interest. METHODS: In this study, a dipalmitoylphosphatidylcholine (DPPC) liposome solution was used as a model system. Both liquid sample and dry sample were examined. Secondary ion yields using three primary ion species (Bi+ , Bi3+ and Bi3++ ) with various beam currents were investigated. RESULTS: Usable ion yields for both positive and negative characteristic signals (including molecular ions and characteristic fragment ions) were achievable based on optimized experimental conditions for in situ liquid SIMS analysis. The ion yield of the key DPPC molecular ion was comparable to that of traditional static SIMS, and unexpected low fragmentation was observed. The flexible structure of the liquid plays an important role for these observations. CONCLUSIONS: Therefore, beam damage may not be a concern in in situ liquid SIMS analysis if proper experimental conditions are used. PMID- 28884925 TI - Widespread transcriptional alternations in oligodendrocytes in the adult mouse brain following chronic stress. AB - Emerging evidence shows that oligodendrogenesis and myelination are highly responsive to behavioral experience, including physical activity and social experience. This form of myelin plasticity is being increasingly appreciated and examined in the prefrontal cortex (PFC), a critical brain region involved in complex emotional and cognitive behavior. However, it remains unclear whether myelination in other brain regions is affected by behavioral experience. Here we report that exposure to 4 weeks of chronic variable stress induced anxiety- and depressive-like behavior in male adult mice. In concert with these behavioral responses, transcriptional analysis of PFC, and nucleus accumbens (NAc)-a brain region critical for reward response-revealed downregulation of transcripts encoding for myelin genes and oligodendrocyte-specific genes. In contrast, upregulation of myelin-related transcripts was observed in the corpus callosum (CC), whereas the amygdala (AMG) did not show significant changes. Shorter exposure to the same stressors induced behavioral changes to a less extent and was followed by a stress habituation period. However, reduced myelin and oligodendrocyte-specific gene transcripts were detected as early as one week following stress exposure in the PFC and NAc. These data indicate that oligodendrocyte and their progenitors in multiple brain regions are responsive to stressful experiences and show distinctive and region-specific patterns of gene expression. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 152-162, 2018. PMID- 28884927 TI - Peeling skin syndrome associated with novel variant in FLG2 gene. AB - Peeling skin syndrome is a rare genodermatosis characterized by variably pruritic superficial generalized peeling of the skin with several genes involved until now little is known about the association between FLG2 and peeling skin syndrome. We describe multiple family members from a consanguineous Saudi family with peeling skin syndrome. Next Generation Sequencing identifies a cosegregating novel variant in FLG2 c.632C>G (p.Ser211*) as a likely etiology in this family. Here, we reported on the clinical manifestation of homozygous loss of function variant in FLG2 as a disease-causing gene for peeling skin syndrome and expand the dermatology findings. PMID- 28884928 TI - Expression of receptor tyrosine kinase targets PDGFR-beta, VEGFR2 and KIT in canine transitional cell carcinoma. AB - Transitional cell carcinoma (TCC) is the most common neoplasia of the canine urinary tract. It tends to be locally invasive and has a moderate metastatic rate. Receptor tyrosine kinases (RTKs) play an important role in promoting cell growth, differentiation and regulation of cell function. RTK inhibitor toceranib phosphate has been used anecdotally to treat TCC. The goal of this study was to evaluate archived normal urinary bladder, TCC and cystitis bladder samples for expression of toceranib phosphate targets: VEGFR2, PDGFR-beta and stem cell factor receptor (KIT). A significant number of TCC samples expressed PDGFR-beta compared with cystitis and normal bladder samples (P<.0001). While all the tumour samples stained positively for VEGFR2, there was no significant difference between tumour, cystitis and normal bladder samples in intensity scores or staining distribution. Minimal positive staining for KIT was noted in the tumour samples. Based on this proof of target study, further investigation is warranted to determine clinical response of TCC to toceranib phosphate. PMID- 28884929 TI - Identification of lactic acid bacteria in the feces of dairy cows fed whole crop maize silage to assess the survival of silage bacteria in the gut. AB - In order to assess the survival of lactic acid bacteria (LAB) in whole crop maize silage in the gut of dairy cows, one representative silage sample and three different feces samples were collected from dairy cows on three dairy farms in Hua Bei, China and three dairy farms in Kyushu, Japan. The composition of the bacterial community was examined by denaturing gradient gel electrophoresis and quantitative polymerase chain reaction. Lactobacillus acetotolerans was detected in all bunker-made maize silage samples, regardless of the dairy farm or sampling region from which they were sourced. A total of eight LAB species were detected in the maize silage samples, of which three (L. acetotolerans, L. pontis and L. casei) appeared to survive digestion. The populations of L. acetotolerans in silage and feces were 106-7 and 103-4 copies/g, respectively, indicating that, even for the LAB species showing potential survival in the gut, competition in this niche may be harsh and the population may substantially decrease during the digestion process. It may be difficult for silage LAB to survive in the gut of silage-fed dairy cows, because marked decrease in population can take place during the digestion process, even for surviving species. PMID- 28884930 TI - Retreatment with sofosbuvir/ledipasvir with or without lead-in interferon-beta injections in patients infected with genotype 1b hepatitis C virus after unsuccessful daclatasvir/asunaprevir therapy. AB - AIM: To improve the therapeutic efficacy of sofosbuvir/ledipasvir (SOF/LDV) for the retreatment of patients after daclatasvir/asunaprevir (DCV/ASV), a customized therapy with or without lead-in interferon (IFN)-beta injections was formulated according to the types of resistance-associated substitutions (RAS) in the non structural protein (NS)5A region of genotype 1b hepatitis C virus (HCV). METHODS: Thirty-three patients failing prior DCV/ASV received SOF/LDV for 12 weeks. Patients with HCV carrying unfavorable NS5A-RAS and/or those previously treated with simeprevir were given lead-in IFN-beta injections twice a day for 2 weeks; sequential changes in the NS5A-RAS during the injection period were evaluated using deep sequencing. RESULTS: Lead-in injections were not undertaken in 27 patients; a sustained viral response (SVR) was achieved in 26 patients, while viral relapse occurred in 1 patient with HCV carrying NS5A-L28M/R30H/Y93H mutations. Among the 6 patients receiving lead-in injections, viral relapse occurred in 2 patients who had an unfavorable IFN-lambda3-related gene single nucleotide polymorphism allele; both patients had been previously treated with simeprevir, and HCV carrying NS5A-L31V/Y93H mutations had emerged after DCV/ASV. Deep sequencing revealed no changes in the NS5A-RAS profiles during the lead-in injection period in either patient. In contrast, in a patient with a favorable allele who was infected with similar unfavorable HCV strains, NS5A-L31/Y93 wild type strains appeared during the injection period, enabling an SVR. CONCLUSION: Using customized therapies based on the NS5A-RAS profiles, a high SVR rate was obtained after SOF/LDV in patients failing prior DCV/ASV. Lead-in IFN-beta injections did not improve the efficacy in patients with HCV carrying unfavorable NS5A-RAS except in those with a favorable IFN-lambda3-related gene allele. PMID- 28884931 TI - Percutaneous ventricular assist devices for catheter ablation of ventricular tachycardia in structural heart disease: "A Conditio Sine Qua Non"? PMID- 28884932 TI - The relationship between depression and chronotype: A longitudinal assessment during childhood and adolescence. AB - BACKGROUND/OBJECTIVE: During adolescence, chronotype shifts toward "eveningness." "Eveningness" is related to negative physical and mental health outcomes. Little is known about what influences the shift in chronotype beyond pubertal status. The current study examined the influence of earlier depression predicting later individual differences in adolescent chronotype, accounting for pubertal status, and the prospective prediction of later increases in depression from earlier chronotype. METHODS: Youth (age M = 12.06, SD = 2.35; 56.5% girls) from the community completed repeated assessments of depression, including both self reports (14 assessments) and diagnostic interviews (eight assessments), over a 48 month period. At the 36-month timepoint, participants completed chronotype and pubertal development measures. Regression and ANOVA analyses examined: (1) the influence of earlier depression levels (baseline to 36 months) upon chronotype, and (2) chronotype (at 36 months) upon later depression (48 months). RESULTS: Youth with higher earlier depression symptoms (beta = -0.347, P < .001) and history of depression diagnosis (beta = -0.13, P = .045) showed a greater eveningness preference controlling for pubertal status, age, and gender. Further, depression diagnosis history interacted with pubertal status to predict chronotype: (F(1,243) = 4.171, P = .045) such that the influence of depression on chronotype was greatest among postpubertal youth (t = 3.271, P = .002). Chronotype (greater eveningness preference) predicted prospective increases in depression symptoms (beta = -0.16, P = .03) and onset of depressive episode (b = 0.085, OR = 0.92, P = .03) 1 year later. CONCLUSION: Depression, experienced earlier in life, predicts greater preference for eveningness, especially among postpubertal youth. In turn, later depression is predicted by evening preference. These findings suggest the reciprocal interplay between mood and biological rhythms, especially depression and chronotype, during adolescence. PMID- 28884933 TI - Prediction of nearest neighbor effects on backbone torsion angles and NMR scalar coupling constants in disordered proteins. AB - Using fine-tuned hydrogen bonding criteria, a library of coiled peptide fragments has been generated from a large set of high-resolution protein X-ray structures. This library is shown to be an improved representation of phi/psi torsion angles seen in intrinsically disordered proteins (IDPs). The phi/psi torsion angle distribution of the library, on average, provides good agreement with experimentally observed chemical shifts and 3 JHN-Halpha coupling constants for a set of five disordered proteins. Inspection of the coil library confirms that nearest-neighbor effects significantly impact the phi/psi distribution of residues in the coil state. Importantly, 3 JHN-Halpha coupling constants derived from the nearest-neighbor modulated backbone phi distribution in the coil library show improved agreement to experimental values, thereby providing a better way to predict 3 JHN-Halpha coupling constants for IDPs, and for identifying locations that deviate from fully random behavior. PMID- 28884934 TI - Extracellular vesicle-mediated MFG-E8 localization in the extracellular matrix is required for its integrin-dependent function in mouse mammary epithelial cells. AB - Milk fat globule-EGF factor 8 (MFG-E8) is a divalent-binding secretory protein possessing an Arg-Gly-Asp (RGD) motif and a phosphatidylserine (PS)-binding motif. This protein has been shown to be involved in mammary gland development and morphogenesis. Integrin-binding activity is necessary for these MFG-E8 dependent cell processes. Although the target cells and molecules of MFG-E8 in the cellular microenvironment are important to understand its physiological function, its localization is largely unclear. Here, we found that mouse MFG-E8 localized to the basal lamina of the mammary gland during involution. In a model system of mammary COMMA-1D cells, exogenously and endogenously expressed MFG-E8 was deposited in the extracellular matrix (ECM) with membranous particles dependently on the PS-binding motifs in the discoidin domains that were essential for association ability to extracellular vesicles (EVs). These data showed the basal MFG-E8 localization mechanism in which EVs served as a scaffold. Such an immobilized MFG-E8 associating with cell substrata but not soluble one in the culture media promoted integrin-dependent suppression of beta-casein expression. These results suggest that MFG-E8 requires EVs to transduce cellular signals from the basolateral side of the adhesion cells by accumulating in ECM. PMID- 28884935 TI - Identification of Nursing Diagnosis-Outcome-Intervention Linkages for Inpatients in the Obstetrics Department Nursing Unit in South Korea. AB - PURPOSE: To identify the NANDA-I-NOC-NIC (NNN) linkages for inpatients of the obstetrics nursing unit using electronic nursing records. METHODS: In this retrospective, descriptive survey, the electronic nursing records for 220 adult patients aged >=18 years who were discharged after obstetrics nursing unit were analyzed. FINDINGS: The 7 most frequent nursing diagnoses were found to be associated with 9 nursing outcomes and 26 nursing interventions. CONCLUSIONS: Herein, the list of nursing diagnoses was observed to comprise the safety/protection domain, the list of nursing outcomes the physiological health domain, and the list of nursing interventions the physiological: complex domain. IMPLICATIONS FOR NURSING PRACTICE: This result can contribute to improving the nursing quality and will help continuing education and documentation system refinement. PMID- 28884936 TI - Dietary cation and anion difference: Effects on milk production and body fluid distribution in lactating dairy goats under tropical conditions. AB - This study aimed to determine the effect of dietary cation and anion difference (DCAD) on milk production and body fluid distribution in lactating dairy goats. Ten dairy goats were selected and divided into two groups, five animals each. Animals received either control DCAD (control, 22.81 mEq/100 g dry matter (DM)) or high DCAD (DCAD, 39.08 mEq/100 g DM). The results indicated that rectal temperature (Tr), respiration rate, milk yield and compositions did not differ between groups. But the percentage change of Tr from the DCAD group was lower than the control group between 09.00 and 13.00 hours. DM intake tended to increase in the DCAD group. Dairy goats in the DCAD group drank more water, but urinary excretion and plasma antidiuretic hormone concentration remained unchanged. Apparent water balance was higher from the DCAD group over 24 h. There was no effect of DCAD on plasma and blood volumes, but tended to increase in extracellular fluid and thereby increased total body water. The present results indicate that animals supplemented with high DCAD increase their total body water and apparent water balance. These results have contributed to the process of adaptation for evaporative cooling and would be useful in slowing down the elevation in Tr. PMID- 28884937 TI - Review: A Japanese population-based meta-analysis of vonoprazan versus PPI for Helicobacter pylori eradication therapy: Is superiority an illusion? AB - BACKGROUND: Vonoprazan (VPZ) is a novel acid suppressant that has been used in Helicobacter pylori (H. pylori) eradication therapies in recent years. However, the efficacy and safety of VPZ vs proton-pump inhibitor (PPI) in H. pylori eradication therapies remain controversial. OBJECTIVE: To perform a meta-analysis in order to assess the efficacy and safety of VPZ vs PPI for H. pylori eradication. MATERIALS AND METHODS: The PubMed, EMBASE, and Cochrane Library databases were searched up to July 10, 2017, for relevant randomized controlled trials (RCTs) and nonrandomized clinical studies (NRCTs). The pooled eradication rate (ER) and pooled occurrence rates of adverse events were used to compare the efficacy and safety of VPZ - and PPI-containing regimens. RESULT: A total of 14 studies with 14 636 patients were included in this meta-analysis. The results showed that the pooled ER of VPZ -containing regimens was much higher than that of PPI-containing regimens when used as first-line therapies. This difference was significant for both intention-to-treat (85.1% vs 68.0%, P < .00001) and per protocol analyses (89.0% vs 74.2%, P < .00001). Moreover, subgroup analysis indicated significant superiority of VPZ in both patients with clarithromycin resistant strains (81.5% vs 40.9%, P < .00001) and those with clarithromycin susceptible strains (94.9% vs 89.6%, P = .006). However, VPZ did not show superiority to PPI as part of a second-line triple therapy based on both intention-to-treat (83.4% vs 82.0%, P = .79) and per-protocol analyses (89.3% vs 90.1%, P = .06). Finally, RCT subgroup analysis showed the safety of VPZ containing regimens to be better than PPI-containing regimens (26.4% vs 33.3%, P = .008), whereas there was no significant difference in this regard for the NRCT subgroup analysis (5.7% vs 4.7%, P = .08). CONCLUSIONS: The efficacy of VPZ is superior to PPI in first-line H. pylori triple eradication therapies but not in second-line therapies. The safety of VPZ -containing regimens appears to be equal or even superior to that of PPI. However, most reports included in this study had low levels of evidence. Hence, adequate and high-quality RCTs will be needed to support our results. PMID- 28884938 TI - The Nursing Diagnosis Disturbed Thought Processes: An Integrative Review. AB - PURPOSE: To analyze and synthetize the existing scientific literature in relation to the nursing diagnosis disturbed thought processes (DTPs) (00130). METHODS: An integrative review was developed, identifying relevant papers through a search of international and Spanish databases and the examination of key manuals. FINDINGS: Theoretical papers propose modifications for the nursing diagnosis DTPs. Most of the research papers offer data about its frequency in different clinical settings. CONCLUSIONS: There exists an interest in the nursing diagnosis DTPs. However, the available evidence is not very extensive and further work is necessary in order to refine this nursing diagnosis. IMPLICATIONS FOR NURSING PRACTICE: The re-inclusion of DTPs in the NANDA-I classification will specially contribute to increment its utility in mental healthcare. PMID- 28884939 TI - An Extensive Family of Heterometallic Titanium(IV)-Metal(III) Rings with Structure Control through Templates. AB - A family of heterometallic [Cat][Tix MO(x+1 )(O2 Ct Bu)2x+2 ] rings is reported where Cat=a secondary or tertiary alkyl ammonium ion, x=7, 8 or 9, and M=FeIII , GaIII , CrIII , InIII and AlIII . The structures are regular polygons with eight, nine or ten vertices with each edge bridged by an oxide and two pivalates. The size of the ring formed is controlled by the alkylammonium cation present. In each case a homometallic by-product is found [Cat][Tix O(x+1 )(O2 Ct Bu)2x-1 ]. PMID- 28884940 TI - Variable phenotypic expression in a large Noonan syndrome family segregating a novel SOS1 mutation. AB - Noonan syndrome (NS) is an autosomal dominant multisystem condition with a variable phenotype. The most characteristic features are short stature, congenital heart defects, and recognizable facial features. Mutations in SOS1 are found in 10-20% of patients with NS. Different genotype-phenotype studies mention correlations between SOS1 mutations and some features, such as ectodermal abnormalities and specific facial features. We present a large NS family with a novel pathogenic mutation; SOS1 c.3134C>G, p.Pro1045Arg. Ten family members with NS are included with genetically confirmed mutation and clinical evaluation. The phenotype shows a broad spectrum from only few suggestive features for NS in the older generation to typical features in the youngest generation. We report on a novel pathogenic mutation in the SOS1 gene and a large clinical spectrum in a NS family with ten genetically confirmed affected individuals. PMID- 28884942 TI - Structural properties of bioactive peptides with alpha-glucosidase inhibitory activity. AB - Bioactive peptides are emerging as promising class of drugs that could serve as alpha-glucosidase inhibitors for the treatment of type 2 diabetes. This article identifies structural and physicochemical requirements for the design of therapeutically relevant alpha-glucosidase inhibitory peptides. So far, a total of 43 fully sequenced alpha-glucosidase inhibitory peptides have been reported and 13 of them had IC50 values several folds lower than acarbose. Analysis of the peptides indicates that the most potent peptides are tri- to hexapeptides with amino acids containing a hydroxyl or basic side chain at the N-terminal. The presence of proline within the chain and alanine or methionine at the C-terminal appears to be relevant for high activity. Hydrophobicity and isoelectric points are less important variables for alpha-glucosidase inhibition whilst a net charge of 0 or +1 was predicted for the highly active peptides. In silico simulated gastrointestinal digestion revealed that the high and moderately active peptides, including the most potent peptide (STYV), were gastrointestinally unstable, except SQSPA. Molecular docking of SQSPA, STYV, and STY (digestion fragment of STYV) with alpha-glucosidase suggested that their hydrogen bonding interactions and binding energies were comparable with acarbose. The identified criteria will facilitate the design of new peptide-derived alpha-glucosidase inhibitors. PMID- 28884941 TI - Characterization of the novel HLA-DQB1*05:155 allele by sequencing-based typing. AB - HLA-DQB1*05:155 differs from HLA-DQB1*05:01:01 by one nucleotide substitution at position 474 (G>C). PMID- 28884943 TI - Xenotransplantation of human intestine into mouse abdomen or subcutaneous tissue: Novel platforms for the study of the human enteric nervous system. AB - BACKGROUND: Current efforts to develop stem cell therapy as a novel treatment for neurointestinal diseases are limited by the unavailability of a model system to study cell transplantation in the human intestine. We propose that xenograft models support enteric nervous system (ENS) development in the fetal human intestine when transplanted into mice subcutaneously or intra-abdominally. METHODS: Fetal human small and large intestine were grafted onto the small intestinal mesentery and into the subcutaneous tissue of immunodeficient mice for up to 4 months. Intestinal cytoarchitecture and ENS development were studied using immunohistochemistry. KEY RESULTS: In both abdominal and subcutaneous grafts, the intestine developed normally with formation of mature epithelial and mesenchymal layers. The ENS was patterned in two ganglionated plexuses containing enteric neurons and glia, including cholinergic and nitrergic neuronal subtypes. c-Kit-immunoreactive interstitial cells of Cajal were present in the gut wall. CONCLUSIONS & INFERENCES: Abdominal xenografts represent a novel model that supports the growth and development of fetal human intestine. This in vivo approach will be a useful method to study maturation of the ENS, the pathophysiology of neurointestinal diseases, and the long-term survival and functional differentiation of neuronal stem cells for the treatment of enteric neuropathies. PMID- 28884944 TI - Characterization of the novel HLA-A*02:07:10 allele by sequencing-based typing. AB - HLA-A*02:07:10 differs from HLA-A*02:07:01 by one nucleotide substitution at position 117. PMID- 28884945 TI - Enzymatic Cascade Catalysis for the Synthesis of Multiblock and Ultrahigh Molecular-Weight Polymers with Oxygen Tolerance. AB - Synthesis of well-defined multiblock and ultrahigh-molecular-weight (UHMW) polymers has been a perceived challenge for reversible-deactivation radical polymerization (RDRP). An even more formidable task is to synthesize these extreme polymers in the presence of oxygen. A novel methodology involving enzymatic cascade catalysis is developed for the unprecedented synthesis of multiblock polymers in open vessels with direct exposure to air and UHMW polymers in closed vessels without prior degassing. The success of this methodology relies on the extraordinary deoxygenation capability of pyranose oxidase (P2Ox) and the mild yet efficient radical generation by horseradish peroxidase (HRP). The facile and green synthesis of multiblock and UHMW polymers using biorenewable enzymes under environmentally benign and scalable conditions provides a new pathway for developing advanced polymer materials. PMID- 28884946 TI - Risk factors for postoperative infection in Chinese lung cancer patients: A meta analysis. AB - OBJECTIVE: The objective of this study was to identify risk factors for postoperative infection in Chinese lung cancer patients. METHODS: A comprehensive search was performed in PubMed, EMbase, CNKI, and WanFang Data databases to identify studies investigating risk factors for postoperative infection in Chinese lung cancer patients. Meta-analysis was performed by using Revman 5.2 software. RESULTS: A total of 12 studies were included. The results of meta analysis showed that old age, male gender, diabetes, cigarette smoking, squamous cell carcinoma, pulmonary diseases, longer of mechanical ventilation, and longer time of surgery procedure were associated with increased risk of postoperative infection. In addition, prophylactic antibiotic was associated with decreased risk of postoperative infection. CONCLUSION: The current meta-analysis suggests that the old age, male gender, diabetes mellitus, cigarette smoking, squamous cell carcinoma, pulmonary diseases, longer of mechanical ventilation, and longer of surgery time are risk factors for postoperative infection in Chinese lung cancer patients. Due to the limited quality and quantity of included studies, more high-quality studies are needed to verify the above results. PMID- 28884947 TI - Confirmation of an ARID2 defect in SWI/SNF-related intellectual disability. AB - We present a 4-year-old girl with delayed neuromotor development, short stature of prenatal onset, and specific behavioral and craniofacial features harboring an intragenic deletion in the ARID2 gene. The phenotype confirmed the major features of the recently described ARID2-related intellectual disability syndrome. However, our patient showed overlapping features with Nicolaides-Baraitser syndrome and Coffin-Siris syndrome, providing further arguments to reclassify these disorders as "SWI/SNF-related intellectual disability syndromes." PMID- 28884948 TI - Exploring research cultures through internationalization at home for doctoral students in Hong Kong and Sweden. AB - Cultural skills are fundamental to developing global academic scholars. Internationalization at home can facilitate the acquisition of these skills without students having to go abroad. However, research on the effect of internationalization of higher education is scarce, despite apparent benefits to incorporating cultural sensitivity in research. Further, little is known about the role information and communication technology plays. In this pilot study, we describe the experience of doctoral students with an internationalization-at-home program, and its impact on developing an understanding about different research cultures. Eight doctoral nursing students from Sweden and Hong Kong participated in five webinars as "critical friends". The study followed a descriptive, qualitative design. The results demonstrated that students observed cultural differences in others' research training programs. However, while cultural differences reinforced friendship among local peers, they challenged engagement with critical friends. Challenges led to the perception of one another not as critical friends but as "distant" friends. We discuss the possible reasons for these outcomes, and emphasize a need to nurture connectivity and common goals. This would prepare students to identify, translate, and recognize cultural differences to help develop knowledge of diverse research cultures. PMID- 28884949 TI - Estimated glucose disposal rate predicts mortality in adults with type 1 diabetes. AB - AIMS: This study aimed to investigate the association between insulin resistance as determined by the estimated glucose disposal rate (eGDR), and survival in adults with type 1 diabetes (T1D) in Sweden. MATERIAL AND METHODS: Using the Swedish National Diabetes Register, indviduals with T1D were included from January 1, 2005 to December 31, 2012. Outcomes were retrieved from National healthcare registers. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the associations between eGDR (mg/kg/min) categorized into <4, 4 to 5.99, 6 to 7.99, and >=8 (reference) and outcomes. Relative survival methods were used to compare survival to a matched Swedish reference population. RESULTS: Among 17 050 included individuals with T1D, 10.5%, 20.2%, 20.5% and 48.9% had an eGDR of <4, 4 to 5.99, 6 to 7.99, and >=8, respectively. Individuals with an eGDR <8 were older and had more comorbidities. During a median follow-up of 7.1 years, there were 946 (6%) deaths; 264 (15%), 367 (11%), 195 (6%) and 120 (1%) deaths occurred in individuals with an eGDR of <4, 4 to 5.99, 6 to 7.99 and >=8, respectively. After adjustment for a wealth of different covariates including diabetes duration, age, sex and renal function, individuals with an eGDR <4, 4 to 5.99, and 6 to 7.99 had an increased risk of death compared to those with an eGDR >=8 (adjusted HRs, 95% CIs, P values: 2.78, 2.04 to 3.77, <.001; 1.92, 1.49 to 2.46, <.001; 1.73, 1.34 to 2.21, <.001). Survival in individuals with an eGDR >=8 was equal to a matched general population. CONCLUSIONS: There is a strong association between eGDR and all-cause mortality, as well as cardiovascular mortality, in individuals with T1D. Our findings may guide preventive measures by improving risk assessment in individuals with T1D. PMID- 28884950 TI - Abnormal gray matter volume and impulsivity in young adults with Internet gaming disorder. AB - Reduced executive control is one of the central components of model on the development and maintenance of Internet gaming disorder (IGD). Among the various executive control problems, high impulsivity has consistently been associated with IGD. We performed voxel-based morphometric analysis with diffeomorphic anatomical registration by using an exponentiated Lie algebra algorithm (DARTEL) to investigate the relationship of gray matter abnormalities to impulsivity in IGD. Thirty-one young male adults whose excessive Internet gaming began in early adolescence, and 30 age-matched male healthy controls were examined. IGD subjects showed smaller gray matter volume (GMV) in brain regions implicated in executive control, such as the anterior cingulate cortex and the supplementary motor area. The GMVs in the anterior cingulate cortex and the supplementary motor area were negatively correlated with self-reporting scales of impulsiveness. IGD subjects also exhibited smaller GMV in lateral prefrontal and parietal cortices comprising the left ventrolateral prefrontal cortex and the left inferior parietal lobule when compared with healthy controls. The GMVs in the left ventrolateral prefrontal cortex were negatively correlated with lifetime usage of Internet gaming. These findings suggest that gray matter abnormalities in areas related to executive control may contribute to high impulsivity of young adults with IGD. Furthermore, alterations in the prefrontal cortex were related with long-term excessive Internet gaming during adolescence. PMID- 28884951 TI - Evaluation of chemical stability of polymers of XIENCE everolimus-eluting coronary stents in vivo by pyrolysis-gas chromatography/mass spectrometry. AB - The polymers poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and poly(n-butyl methacrylate) (PBMA) are employed in manufacturing the XIENCE family of coronary stents. PBMA serves as a primer and adheres to both the stent and the drug coating. PVDF-HFP is employed in the drug matrix layer to hold the drug everolimus on the stent and control its release. Chemical stability of the polymers of XIENCE stents in the in-vivo environment was evaluated by pyrolysis gas chromatography with mass spectrometry (Py-GC/MS) detection. For this evaluation, XIENCE stents explanted from porcine coronary arteries and from human coronary artery specimens at autopsy after 2-4 and 5-7 years of implantation, respectively, were compared to freshly manufactured XIENCE stents (controls). The comparison of pyrograms of explanted stent samples and controls showed identical fragmentation fingerprints of polymers, indicating that PVDF-HFP and PBMA maintained their chemical integrity after multiple years of XIENCE coronary stent implantation. The findings of the present study demonstrate the chemical stability of PVDF-HFP and PBMA polymers of the XIENCE family of coronary stents in the in-vivo environment, and constitute a further proof of the suitability of PVDF-HFP as a drug carrier for the drug eluting stent applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1721 1729, 2018. PMID- 28884953 TI - A retro-prospective effectiveness study on 3448 implant operations at one referral clinic: A multifactorial analysis. Part I: Clinical factors associated to early implant failures. AB - BACKGROUND: Limited numbers of large effectiveness studies on routine dental implant treatment are available in the literature. PURPOSE: To report retro prospective data on prevalence of early implant failures in a large number of routine patients/operations at 1 referral clinic. MATERIALS AND METHODS: A total of 2848 patients were consecutively provided with 9582 implants with an anodized surface (Nobel Biocare AB) during 3448 implant operations between 2003 and 2011. All patients were invited to a follow-up program and early implant failures up to first annual examination were consecutively identified. A logistic multivariate data analysis was performed to identify possible factors with an association to early implant failures. RESULTS: A total of 43, 73, and 81 implant operations were denoted as early failures depending on when cut-off time was defined, using: abutment connection, prosthesis placement, or at first year of follow-up, respectively. Five factors showed significant association to "early implant failures," where the highest risk for a failure was associated to "surgeon" (hazard ratio [HR] 5.13), followed by "not prosthetic treatment at the referral clinic" (HR 2.71). When all 5 significant factors were present, the risk for an early failure after an operation was 7.0%, and the risk decreased to 0.1% when none/lowest risk factors were present. CONCLUSIONS: The role of the surgeons/dentists involved in the rehabilitation of the implant patients and numbers of placed implants (degree of tooth loss) showed the strongest associations to early implant failures in the present clinic. Also increased bone resorption was associated to increased risk for implant failure. PMID- 28884952 TI - Soluble Dietary Fiber Reduces Trimethylamine Metabolism via Gut Microbiota and Co Regulates Host AMPK Pathways. AB - SCOPE: Evidence from animal experiments and clinical medicine suggests that high dietary fiber intake, followed by gut microbiota-mediated fermentation, decreases trimethylamine (TMA) metabolism, the mechanism of which, however, remains unclear. The objective of this analysis was to evaluate, using mice fed with red meat, the effects of soluble dietary fiber (SDF) intervention on TMA metabolism. METHODS AND RESULTS: Low- or high-dose soluble dietary fiber (SDF) from natural wheat bran (LN and HN, low- and high-dose natural SDF), fermented wheat bran (LF and HF, low- and high-dose fermented SDF), and steam-exploded wheat bran (LE and HE, low- and high-dose exploded SDF groups) were used to examine whether SDF interventions in mice fed with red meat can alter TMA and trimethylamine N-oxide (TMAO) metabolism by gut microbial communities in a diet-specific manner. Results demonstrated that SDF-diets could reduce TMA and trimethylamine N-oxide (TMAO) metabolism by 40.6 and 62.6%, respectively. DF feeding, particularly fermented SDF, reshaped gut microbial ecology and promoted the growth of certain beneficial microflora species. SDF-diet decreased energy intake, weight gain, intestinal pH values, and serum lipid and cholesterol levels. SDF-diet also enhanced the production of short chain fatty acids with activation of the intestinal epithelial adenosine monophosphate-activated protein kinase (AMPK). CONCLUSION: These findings suggest a central mechanism via which SDF-diet may control TMA metabolism by gut microflora and co-regulate the AMPK pathways of the host. PMID- 28884954 TI - Native Desorption Electrospray Ionization Liberates Soluble and Membrane Protein Complexes from Surfaces. AB - Mass spectrometry (MS) applications for intact protein complexes typically require electrospray (ES) ionization and have not been achieved via direct desorption from surfaces. Desorption ES ionization (DESI) MS has however transformed the study of tissue surfaces through release and characterisation of small molecules. Motivated by the desire to screen for ligand binding to intact protein complexes we report the development of a native DESI platform. By establishing conditions that preserve non-covalent interactions we exploit the surface to capture a rapid turnover enzyme-substrate complex and to optimise detergents for membrane protein study. We demonstrate binding of lipids and drugs to membrane proteins deposited on surfaces and selectivity from a mix of related agonists for specific binding to a GPCR. Overall therefore we introduce this native DESI platform with the potential for high-throughput ligand screening of some of the most challenging drug targets including GPCRs. PMID- 28884956 TI - Osteoblast cell membrane chromatography coupled with liquid chromatography and time-of-flight mass spectrometry for screening specific active components from traditional Chinese medicines. AB - A method using osteoblast membrane chromatography coupled with liquid chromatography and time-of-flight mass spectrometry was developed to recognize and identify the specific active components from traditional Chinese medicines. Primary rat osteoblasts were used for the preparation of the stationary phase in the cell chromatography method. Retention components from the cell chromatography were collected and analyzed by liquid chromatography with time-of-flight mass spectrometry. This method was applied in screening active components from extracts of four traditional Chinese medicines. In total, 24 potentially active components with different structures were retained by osteoblast cell chromatography. There were five phenolic glucosides and one triterpenoid saponin from Curculigo orchioides Gaertn, two organic acids and ten flavonoids from Epimedium sagittatum Maxim, one phthalide compound and one organic acid from Angelica sinensis Diels, and two flavonoids and two saponins from Anemarrhena asphodeloides Bunge. Among those, four components (icariin, curculigoside, ferulaic acid, and timosaponin BII) were used for in vitro pharmacodynamics validation. They significantly increased the osteoblast proliferation, alkaline phosphatase activity, levels of bone gla protein and collagen type 1, and promoted mineralized nodule formation. The developed method was an effective screening method for finding active components from complex medicines that act on bone diseases. PMID- 28884955 TI - HLA-B*40:302, a novel allele identified by sequence-based typing in a Korean individual. AB - B*40:302 differs from B*40:02:01:01 by a single nonsynonymous nucleotide substitution at codon 81 (CCG->CTG). PMID- 28884957 TI - Long-term sequelae of hippocampal lesions in patients with transient global amnesia: A multiparametric MRI study. AB - BACKGROUND: MRI signal diffusion-weighted imaging (DWI) hyperintensity in the hippocampus in patients with transient global amnesia (TGA) are resolved within several days after the onset of TGA. PURPOSE: To use multiparametric MRI to unravel the sequelae of TGA. STUDY TYPE: A prospective longitudinal study. POPULATION: Eight TGA patients. FIELD STRENGTH/SEQUENCE: A 3.0T Siemens Tim Trio MRI scanner with T1 -weighted MPRAGE, diffusion-weighted echo planar imaging, and multiecho gradient-recalled echo sequences. ASSESSMENT: Brain MRI scanned within 72 hours, 2 weeks, and 3 months after onset of TGA, respectively. T1 image hippocampus was first segmented into 12 subregions using FreeSurfer and registered to DWI to locate DWI lesion. Then a T1 image with segmented hippocampus was registered to its corresponding apparent diffusion coefficient (ADC) map, fractional anisotropy (FA) map, and quantitative susceptibility map, respectively. Finally, the volume, water diffusion and anisotropy, and magnetic susceptibility of DWI lesion were analyzed. STATISTICAL TESTS: A paired samples t test was performed to detect measurement differences between three tests. Pearson correlation was used to assess the correlations between all measurements. RESULTS: Hyperintensity was detected in the head, body, and caudate of CA1 and hippocampal tail. No significant changes existed in CA1/unit volume across the three timepoint measurements (all, P > 0.480). In Test 1, ratio ADC (DWI lesion / adjacent healthy, rADC) and ratio FA (rFA) decreased below, while ratio susceptibility increased above 1.0. In Test 2, all the episodes normalized around 1.0. In Test 3, rADC remained normalization, but rFA decreased and ratio susceptibility increased again. In Test 1 and Test 3 (vs. Test 2), decreased FA values were accompanied with lower axial diffusivity and/or higher radial diffusivity (all, P < 0.001). Moreover, rFA significantly correlated with ratio susceptibility in Test 3 (r = -0.665, P = 0.039). DATA CONCLUSION: Microstructural sequelae in hippocampus were demonstrated, which indicates that ischemic lesions may be associated with TGA. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1350-1358. PMID- 28884959 TI - Turkish Society of Physiological Sciences 43rd National Physiology Congress, 07 - 10 September 2017, Pamukkale University, Congress Center, Denizli (Turkey). PMID- 28884958 TI - Serum lactate in liver resection with intermittent Pringle maneuver: the "square root- shape. AB - BACKGROUND: Serum lactate (sLac) concentration during liver resection with intermittent hepatic hilum clamping (i.e. Pringle maneuver, PM) was retrospectively investigated. METHODS: A total of 133 patients who underwent liver resection were enrolled. We analyzed the sLac peri-operatively. Correlations were searched between the PM and lactatemia and its variations (i.e. lactate clearance, cLac) and other factors which it might be related to. Lactatemia in triplicate intraoperatively was recorded, just after the awakening, and 1 and 2 h later. The cLac between two consecutive measurements [(sLac1 - sLac2 )/sLac1 ] was computed. RESULTS: A reliable dependence of sLac was found from the cumulative PM. More than 76 min of cumulative Pringle Time (cPT) exposed patients to a worse cLac at the end of the resection phase (P < 0.0001). We found cPT >76 min, global operation time >365 min and bleeding >225 ml to be predictors of hyperlactatemia (sLac >4 mmol/L). Normal liver resulted as a risk factor for hyperlactatemia and steatosis was not (P = 0.030 vs. P = 0.325). Finally, cLac showed a "square-root- shape, just like the mathematical operation sign. CONCLUSIONS: Lactatemia during liver resection depends on the duration of PM, bleeding and the duration of the operation. Normal liver may expose the patient to the risk of hyperlactatemia. PMID- 28884960 TI - Genotypic-phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from Turkey. AB - Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder (LSD) characterized by a chronic, progressive course with multiorgan involvement. In our study, clinical, biochemical, molecular findings, and response to enzyme replacement therapy (ERT) for at least 6 months were evaluated in 20 patients with MPS VI. Treatment effects on clinical findings such as liver and spleen sizes, cardiac and respiratory parameters, visual and auditory changes, joints' range of motions, endurance tests and changes in urinary glycosaminoglycan excretions, before and after ERT were analyzed. ERT caused increased physical endurance and decreased urinary dermatan sulfate/chondroitin sulfate ratios. Changes in growth parameters, cardiac, respiratory, visual, auditory findings, and joint mobility were not significant. All patients and parents reported out an increased quality of life, which were not correlated with clinical results. The most prevalent mutation was p.L321P, accounting for 58.8% of the mutant alleles and two novel mutations (p.G79E and p.E390 K) were found. ERT was a safe but expensive treatment for MPS VI, with mild benefits in severely affected patients. Early treatment with ERT is mandatory before many organs and systems are involved. PMID- 28884961 TI - Bartonellosis in Chronic Kidney Disease: An Unrecognized and Unsuspected Diagnosis. AB - Systemic cat scratch disease or bartonellosis is a clinical entity caused by Bartonella henselae, which manifests with necrotizing granulomas in visceral organs. The cat flea, Ctenocephalides felis, is the vector responsible for horizontal transmission of the disease from cat to cat, and its bite can also infect humans. In immunocompromised patients including chronic kidney disease and renal transplant recipients, it can cause persistent and disseminated cat scratch disease. The aim of this paper is to perform a systematic review of the studies that have addressed the diagnostic methods of cat scratch disease in chronic kidney disease and renal transplant recipients. This review was searched via electronic PubMed and Google scholar databases. Few qualitative full-text original articles in chronic kidney disease and kidney transplant were extracted. At this paper, 19 articles identified including six articles in chronic kidney disease and 13 articles in renal transplant recipients. Of these six identified case reports in chronic kidney disease, serology via immunofluorescence antibody test was led to diagnosis of cat scratch disease in five patients and a one patient showed nonreactive serologic test. Polymerase chain reaction usage to detect deoxyribonucleic acid in tissue biopsy and bone marrow biopsy was led to diagnosis. Cat scratch disease diagnosis in 13 renal transplant recipients was attained more by combining serology and polymerase chain reaction to detect deoxyribonucleic acid in tissue specimens. These selected studies demonstrate that serology and polymerase chain reaction via deoxyribonucleic acid extraction of tissue specimens yield the best outcome in diagnostic field of bartonellosis. PMID- 28884963 TI - Identification of HLA-B*58:01:21, a novel allele in a Korean individual. AB - B*58:01:21 has a single nucleotide change, c.264A>G (ACA->ACG at codon 88) compared with B*58:01:01:01. PMID- 28884964 TI - Anion-pi Catalysis of Diels-Alder Reactions. AB - Among concerted cycloadditions, the Diels-Alder reaction is the grand old classic, which is usually achieved with acid catalysis. In this report, hydroxypyrones, oxa-, and thiazolones are explored because they provide access to anionic dienes. Their [4+2] cycloaddition with cyclic and acyclic dienophiles, such as maleimides and fumarates, affords bicyclic products with four new stereogenic centers. Bifunctional anion-pi catalysts composed of amine bases next to the pi surface of naphthalenediimides (NDIs) are shown to selectively stabilize the "open", fully accessible anionic exo transition state on the pi acidic aromatic surface. Our results also include reactivities that are hard to access with conventional organocatalysts, such as the exo-specific and highly enantioselective Diels-Alder reaction of thiazolones and maleimides with complete suppression of the otherwise dominant Michael addition. With increasing pi acidity of the anion-pi catalysts, the rates, chemo-, diastereo-, and enantioselectivities increase consistently. PMID- 28884962 TI - Delphi consensus on bile duct injuries during laparoscopic cholecystectomy: an evolutionary cul-de-sac or the birth pangs of a new technical framework? AB - Bile duct injury (BDI) during laparoscopic cholecystectomy remains a serious iatrogenic surgical complication. BDI most often occurs as a result of misidentification of the anatomy; however, clinical evidence on its precise mechanism and surgeons' perceptions is scarce. Surgeons from Japan, Korea, Taiwan, and the USA, etc. (n = 614) participated in a questionnaire regarding their BDI experience and near-misses; and perceptions on landmarks, intraoperative findings, and surgical techniques. Respondents voted for a Delphi process and graded each item on a five-point scale. The consensus was built when >=80% of overall responses were 4 or 5. Response rates for the first- and second round Delphi were 60.6% and 74.9%, respectively. Misidentification of local anatomy accounted for 76.2% of BDI. Final consensus was reached on: (1) Effective retraction of the gallbladder, (2) Always obtaining critical view of safety, and (3) Avoiding excessive use of electrocautery/clipping as vital procedures; and (4) Calot's triangle area and (5) Critical view of safety as important landmarks. For (6) Impacted gallstone and (7) Severe fibrosis/scarring in Calot's triangle, bail-out procedures may be indicated. A consensus was reached among expert surgeons on relevant landmarks and intraoperative findings and appropriate surgical techniques to avoid BDI. PMID- 28884965 TI - Favorable effects of hydroxychloroquine on serum low density lipid in patients with systemic lupus erythematosus: A systematic review and meta-analysis. AB - AIMS: Hydroxychloroquine (HCQ) has shown to have significant immunomodulatory effects in the treatment of systemic lupus erythematosus (SLE). Current studies show favorable effects of HCQ on traditional cardiac risk factors in patients with SLE. This review examined the effects of HCQ on serum low-density lipoprotein (LDL) level in patients with SLE. METHODS: A systematic search of seven major literature search databases from their inception until 3 April, 2017 identified nine studies. Random-effects pooled mean difference with corresponding 95% confidence intervals (CI) were estimated. Heterogeneity was measured by I2 . Publication bias was assessed by visual inspection of funnel plots. Sensitivity analysis examined whether HCQ effect on serum total cholesterol level was similar to the main analysis. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the overall quality of evidence. RESULTS: Pooled study participants were 559 patients from eight observation studies (two before-after studies; six case-control studies) examining the effects of HCQ on serum LDL. Pooled study participants' characteristics were as follows: mean age 45.719, female 95.262%, and prednisone use 58.366%. HCQ reduced mean LDL levels by 24.397 mg/dL (95% CI 8.921-39.872; P = 0.002). The number of studies identifying statin use was too few to perform meta-regression analysis of statin use. Heterogeneity was extensive (I2 = 94.739%). Symmetrical funnel plot visualized no evidence of publication bias. CONCLUSION: HCQ was associated with serum LDL level reduction by mean 24.397 mg/dL in patients with SLE. Future prospective studies are need to fully characterize the treatment effect. PMID- 28884966 TI - Enhancement of the luminescence properties of Sr3 (PO4 )2 :Dy3+ ,Li+ white-light emitting phosphors by charge compensator Li+ co-doping. AB - Sr3 (PO4 )2 :Dy3+ ,Li+ phosphors were prepared using a simple high temperature solid method for luminescence enhancement. The structures of the as-prepared samples agreed well with the standard phase of Sr3 (PO4 )2 , even when Dy3+ and Li+ were introduced. Under ultraviolet excitation at 350 nm, the Sr3 (PO4 )2 :Dy3+ sample exhibited two emission peaks at 483 nm and 580 nm, which were due to the 4 F9/2 -> 6 H15/2 and 4 F9/2 -> 6 H13/2 transitions of Dy3+ ions, respectively. A white light was fabricated using these two emissions from the Sr3 (PO4 )2 :Dy3+ phosphors. The luminescence properties of Sr3 (PO4 )2 :Dy3+ ,Li+ phosphors, including emission intensity and decay time, were improved remarkably with the addition of Li+ as the charge compensator, which would promote their application in near-ultraviolet excited white-light-emitting diodes. PMID- 28884967 TI - Sexual Expression of Nursing Home Residents: Systematic Review of the Literature. AB - PURPOSE: Living longer, baby boomers will need specialized care offered by nursing homes to manage chronic conditions. This review explores the knowledge, attitudes, and experiences towards older people's sexuality and sexual expression in nursing homes-an important area of research to meet the needs of this emerging population. DESIGN: A primary search of the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PubMed databases and secondary inclusion of cited references covering the period January 2000 to November 2016 identified 12 relevant studies. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the screening process, data were extracted, summarized, and compared, and risk of bias was assessed focusing on ethical considerations, sample size and sampling methods, validity and reliability of data collection instruments, participation, cooperation, and response rate. FINDINGS: Overall, sexual expression in older adults is recognized as a basic need that should be supported. Positive attitudes towards sexuality in nursing homes were correlated with a higher level of knowledge about older adults' sexuality. In addition, positive predictors of attitudes towards sexuality in nursing homes were found to be: age, level of education, and years of experience. Barriers to addressing sexuality in the elderly are the lack of privacy and staff discomfort, which together represent common causes for loneliness and lack of intimacy in nursing homes. CONCLUSIONS: Nursing research and practice need to shift their focus towards individual needs of nursing home residents to accommodate their values and expectations. CLINICAL RELEVANCE: Care providers must include a thorough assessment of sexual health of older adults living in nursing homes in routine practice, and include sexual health in the treatment plan. PMID- 28884968 TI - Boys have not caught up, family influences still continue: Influences on executive functioning and behavioral self-regulation in elementary students in Germany. AB - The development of self-regulation is influenced by various child-level and family-level characteristics. Previous research focusing on the preschool period reported a female advantage in self-regulation and negative effects of various adverse features of the family environment on self-regulation. The present study aimed to investigate growth in self-regulation (i.e., executive functioning and behavioral self-regulation) over 1 school year during early elementary school and to explore the influences of child sex, the level of home chaos, and family educational resources on self-regulation. Participants were 263 German children (51% girls; mean age 8.59 years, SD = 0.56 years). Data were collected during the fall and spring of the school year. A computer-based standardized test battery was used to assess executive functioning. Caregiver ratings assessed children's behavioral self-regulation and information on the family's home environment (chaotic home environment and educational resources). Results suggest growth in elementary school children's executive functioning over the course of the school year. However, there were no significant changes in children's behavioral self regulation between the beginning and the end of Grade 3. Sex differences in inhibitory control/cognitive flexibility and behavioral self-regulation were found, suggesting an advantage for girls. Educational resources in the family but not chaotic family environment were significantly related to self-regulation at both time-points. Children from families with more educational resources scored higher on self-regulation measures compared to their counterparts from less advantaged families. We did not find evidence for child-level or family-level characteristics predicting self-regulation growth over time. Findings add to the evidence of a gender gap in self-regulation skills, but suggest that it might not further widen towards the end of elementary school age. Adequate self-regulation skills should be fostered in both girls and boys. Results also add to the importance of supporting self-regulation development in children from disadvantaged family backgrounds early in life. PMID- 28884969 TI - Evaluation of Bioequivalence Between the New Procaterol Hydrochloride Hydrate Dry Powder Inhaler and the Approved Dry Powder Inhaler in Patients With Asthma in a Randomized, Double-Blind, Double-Dummy, Crossover Comparison Study: A Phase 3 Study. AB - Procaterol hydrochloride hydrate (procaterol) is a beta2 -adrenergic receptor agonist that induces a strong bronchodilatory effect. The procaterol dry powder inhaler (DPI) has been frequently used in patients with bronchial asthma or chronic obstructive pulmonary disease. We evaluated the bioequivalence and safety between the new procaterol DPI (new DPI) and the approved procaterol DPI (approved DPI). This study was a randomized, double-blind, double-dummy, crossover comparison to evaluate the pharmacodynamic equivalence of the new DPI and the approved DPI in patients with bronchial asthma. Primary efficacy variables were area under the concentration-time curve (AUC) forced expiratory volume in the first second (FEV1 )/h and maximum FEV1 during the 480-minute measurement period. Patients were divided into 2 groups, New-DPI-First (n = 8) and Approved-DPI-First (n = 8), according to the investigational medical product that was administered first. Patients inhaled 20 MUg of procaterol in each period. FEV1 was measured by a spirometer at predose and at 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after each investigational medical product administration. Equivalence was evaluated by confirming that the 2-sided 90%CIs for the difference between the new and the approved DPI in means of AUC (FEV1 )/h and maximum FEV1 were within the acceptance criteria of -0.15 to 0.15 L. The difference in means of AUC (FEV1 )/h and maximum FEV1 was 0.041 L and 0.033 L, respectively, and the 90%CI was 0.004 to 0.078 L and -0.008 to 0.074 L, respectively. These CIs were both within the acceptance criteria. The new DPI was assessed as being bioequivalent to the approved DPI. PMID- 28884970 TI - A Dithiol Compound Binds to the Zinc Finger Protein TRAF6 and Suppresses Its Ubiquitination. AB - Despite various inhibitors targeting the zinc center(s) of enzymes, drugs that target zinc fingers have not been examined in detail. We previously developed a dithiol compound named SN-1 that has an inhibitory effect on the function of zinc finger transcription factors, but its mechanism of action has not yet been elucidated. To establish a general principle for new drugs, the details of the action of SN-1 against a zinc finger protein were examined. As a zinc-finger containing protein, we focused on TRAF6, which is related to cancer and inflammation. Binding of SN-1 to TRAF6 and its effect on TRAF6 ubiquitination were examined in vitro, and the binding mode was calculated by computational methodology. Furthermore, ubiquitination of TRAF6 and downstream signaling was examined by cell-based experiments. The results show that SN-1 binds to TRAF6, inhibiting its auto-ubiquitination and downstream NF-kappaB signaling. Docking studies indicate that SN-1 binds directly to the first zinc finger of TRAF6. This binding disrupts the neighboring structure, that is, the RING finger domain, to suppress the ubiquitin ligase activity of TRAF6. Taken together, this study provides a platform for developing new small molecules that target zinc finger proteins. PMID- 28884972 TI - In Situ Fabrication of Inorganic/Organic Hybrid Based on Cu/Co-ZIF and Cu2 O. AB - We successfully fabricate a well-defined inorganic/organic hybrid Cu2 O@Cu/Co-ZIF (ZIF=zeolitic imidazolate frameworks) by use of growth of dual-metal Cu/Co-ZIF on the obtained Cu2 O hollow spheres. The key point of the strategy is coupling the in situ self-sacrificing template. Cu2 O and the coordination of metal ions (Cu+ and Co2+ ) with 2-methylimidazole. This new hybrid was characterized by powder X ray diffraction, (scanning) transmission electron microscopy, energy-dispersive spectroscopy mapping, in situ FT-IR spectroscopy, UV/Vis diffuse reflection spectroscopy, N2 sorption measurements, and electron spin resonance. It was evidenced that Cu/Co-ZIF nanocrystals have been assembled to continuous shells surrounding the Cu2 O cores as well as in the voids between layers and inner pores. Cu2 O@Cu/Co-ZIF exhibits visible light responsiveness and holds potential as narrow band gap semiconductor and visible photocatalyst. PMID- 28884971 TI - Testing the face shape hypothesis in twins discordant for nonsyndromic orofacial clefting. AB - Nonsyndromic orofacial clefts (OFCs) are complex traits characterized by multifactorial inheritance and wide phenotypic variability. Numerous studies have shown subtle differences in the faces of unaffected relatives from cleft families compared to controls, the implication being that such outward differences are an incomplete expression reflecting an underlying genetic predisposition. Twins discordant for OFCs provide a unique opportunity to further test this idea, as the unaffected co-twin shares on average 50% (for dizygotic twins) and 100% (for monozygotic twins) of the genetic risk factors as the affected twin. We used 3D surface imaging and spatially-dense morphometry to compare facial shape in a sample of 44 unaffected co-twins and age- and sex-matched unaffected controls (n = 241). Unaffected co-twins showed statistically significant differences in the midface, lateral upper face, and forehead regions, compared to controls. Furthermore, co-twins were characterized by a distinct pattern of midfacial retrusion, broader upper faces, and greater protrusion of the mandible and brow ridges. This same general facial pattern was shown in both unaffected monozygotic and dizygotic co-twin subsets. These results provide additional support that altered facial shape is a phenotypic marker for OFC susceptibility. PMID- 28884974 TI - 42nd FEBS Congress, From Molecules to Cells and Back, Jerusalem, Israel, September 10-14, 2017. PMID- 28884973 TI - A novel multiplex polymerase chain reaction assay for detection of both HLA A*31:01/HLA-B*15:02 alleles, which confer susceptibility to carbamazepine-induced severe cutaneous adverse reactions. AB - HLA-A*31:01 and HLA-B*15:02 have been widely reported to confer genetic susceptibility to carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCARs). Accordingly, the screening for these alleles has been highly recommended to prevent SCAR prior to introducing CBZ therapy. Although a number of methods are available for screening of HLA-A*31:01 or HLA-B*15:02 alleles separately, developing an assay that can detect both these alleles would be more clinically practical, cost-effective and less time-consuming. Therefore, in this study, a multiplex polymerase chain reaction (PCR) using TaqMan Probe was designed and validated to be able to detect HLA-A*31:01 and HLA-B*15:02. In comparison with Luminex-SSO/SBT/SSB, the multiplex PCR assay for detection of HLA-A*31:01 and HLA B*15:02 had a perfect agreement in the validation group of 125 samples. The method was able to detect the target genes at the DNA concentration of 0.037 ng/MUL. The unit cost of this assay is less than $5 USD with total time of 110 minutes. PMID- 28884975 TI - Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: Strides to date. AB - Although an increasing number of clinical trials have been developed for cognition in Down syndrome, there has been limited success to date in identifying effective interventions. This review describes the progression from pre-clinical studies with mouse models to human clinical trials research using pharmacological interventions to improve cognition and adaptive functioning in Down syndrome. We also provide considerations for investigators when conducting human clinical trials and describe strategies for the pharmaceutical industry to advance the field in drug discovery for Down syndrome. Future research focusing on earlier pharmaceutical interventions, development of appropriate outcome measures, and greater collaboration between industry, academia, advocacy, and regulatory groups will be important for addressing limitations from prior studies and developing potential effective interventions for cognition in Down syndrome. PMID- 28884976 TI - Prenatal alcohol exposure enhances the susceptibility to NMDA-induced generalized tonic-clonic seizures in developing rats. AB - AIMS: Prenatal alcohol exposure (PAE) is associated with a higher likelihood of developing generalized tonic-clonic seizures (GTCS) in infants and children. However, experimental studies of PAE-related seizures have yielded conflicting results. Here, we investigated the effect of acute PAE on N-methyl-D-aspartate (NMDA)-induced seizures in developing rats. METHODS: Pregnant Sprague Dawley rats were given an oral dose of either ethanol (5 g/kg body weight) or vehicle on embryonic day 18. The offspring were tested for susceptibility to NMDA-induced seizures on postnatal day 7 (P7), 21 (P21), 35 (P35), and 42 (P42). Specifically, the prevalence and latency of NMDA-induced continuous wild running-like behaviors (CWR), flexion seizures (FS), wild running seizures (WRS), GTCS, and tonic seizures (TS) were recorded and analyzed. RESULTS: N-methyl-D-aspartate-induced seizures consisted of CWR, FS, GTCS, and TS in P21 rats. Thus, GTCS were consistently observed during development. PAE significantly increases the prevalence of GTCS in female and male P7-P21 rats and P7-P35 rats, respectively, but not in older rats. PAE also increases the prevalence of TS in male, but not female P21-P35 rats. CONCLUSIONS: The PAE animal model of GTCS may provide a new opportunity to investigate the mechanisms that underlie neuronal hyperexcitability in developing animals prenatally-exposed to alcohol. PMID- 28884977 TI - Organoid technology for brain and therapeutics research. AB - Brain is one of the most complex organs in human. The current brain research is mainly based on the animal models and traditional cell culture. However, the inherent species differences between humans and animals as well as the gap between organ level and cell level make it difficult to study human brain development and associated disorders through traditional technologies. Recently, the brain organoids derived from pluripotent stem cells have been reported to recapitulate many key features of human brain in vivo, for example recapitulating the zone of putative outer radial glia cells. Brain organoids offer a new platform for scientists to study brain development, neurological diseases, drug discovery and personalized medicine, regenerative medicine, and so on. Here, we discuss the progress, applications, advantages, limitations, and prospects of brain organoid technology in neurosciences and related therapeutics. PMID- 28884978 TI - Response to Letter to the Editor: Can MR spectroscopy and muscle biopsy findings be correlated in MELAS and CPEO? PMID- 28884979 TI - Effects of Antiepileptic Drugs on the Carotid Artery Intima-Media Thickness in Epileptic Patients. AB - BACKGROUND AND PURPOSE: It has been reported that taking antiepileptic drugs (AEDs) may increase the risk of atherosclerosis. We performed a meta-analysis to evaluate the carotid artery intima-media thickness (CA-IMT) as a surrogate factor for atherosclerosis in epileptic patients. METHODS: We searched NCBI (PubMed), ISI Web of Knowledge, EMBASE, and the Cochrane Library databases for studies of the association between AEDs and CA-IMT in epileptic patients. A random-effects meta-analysis was used to pool results across studies. RESULTS: Fifteen studies involving 1,775 epileptic patients were included in the analysis. The overall CA IMT was significantly larger among users of AEDs [mean difference (MD)=0.09 mm, 95% confidence interval (CI)=0.06-0.12 mm). When stratified by age, the MD was similar in adult patients (MD=0.09 mm, 95% CI=0.06-0.13 mm), but no significant difference was observed in children (MD=0.03 mm, 95% CI=0.00-0.07 mm). Regarding specific AEDs, monotherapy with carbamazepine (CBZ) or valproic acid (VPA) was associated with a larger CA-IMT, while phenytoin monotherapy was not and the result for lamotrigine was inconclusive. CONCLUSIONS: This study suggests that using AEDs is associated with the CA-IMT in patients with epilepsy, particularly for adult patients. In particular, CBZ and VPA may be related to a significant increase in CA-IMT. PMID- 28884980 TI - Perioperative Stroke, In-Hospital Mortality, and Postoperative Morbidity Following Transcatheter Aortic Valve Implantation: A Nationwide Study. AB - BACKGROUND AND PURPOSE: Perioperative stroke is a significant complication of transcatheter aortic valve implantation (TAVI). This study aimed to quantify perioperative stroke as an independent risk factor for in-hospital mortality and postoperative morbidity in patients receiving TAVI. METHODS: A retrospective cohort study was conducted using the National Inpatient Sample. Patients undergoing TAVI during 2012 and 2013 were identified using diagnostic codes of International Classification of Diseases, ninth revision. Univariate and multivariate analyses were performed using patient demographics and comorbidities to identify predictors of mortality and morbidity, defined by a length of stay of >14 days and/or discharge to a place other than home. RESULTS: Data were obtained from 7,556 patients undergoing TAVI during 2012 and 2013. The incidence rates of mortality and morbidity were 4.57 and 71.12%, respectively. Perioperative stroke was an independent risk factor for mortality [odds ratio (OR)=3.182, 95% confidence interval (CI)=1.530-6.618, p=0.002], as were infection (OR=17.899, 95% CI=9.876-32.440, p<0.001) and pericardial tamponade (OR=7.272, 95% CI=2.874 18.402, p<0.001). Stroke also predicted morbidity (OR=5.223, 95% CI=2.005-13.608, p=0.001), which was also associated with age, being female, being Asian, moderate and high Van Walraven scores (VWR), and infection. CONCLUSIONS: In conclusion, perioperative stroke was found to be independently associated with in-hospital mortality and postoperative morbidity, as are age and high VWR. Our findings support the use of further preoperative, intraoperative, and postoperative management strategies during TAVI. PMID- 28884981 TI - Ultrastructural Changes in Skeletal Muscle of Infants with Mitochondrial Respiratory Chain Complex I Defects. AB - BACKGROUND AND PURPOSE: The pathogenesis of mitochondrial disease (MD) involves the disruption of cellular energy metabolism, which results from defects in the mitochondrial respiratory chain complex (MRC). We investigated whether infants with MRC I defects showed ultrastructural changes in skeletal muscle. METHODS: Twelve infants were enrolled in this study. They were initially evaluated for unexplained neurodegenerative symptoms, myopathies, or other progressive multiorgan involvement, and underwent muscle biopsies when MD was suspected. Muscle tissue samples were subjected to biochemical enzyme assays and observation by transmission electron microscopy. We compared and analyzed the ultrastructure of skeletal muscle tissues obtained from patients with and without MRC I defects. RESULTS: Biochemical enzyme assays confirmed the presence of MRC I defects in 7 of the 12 patients. Larger mitochondria, lipid droplets, and fused structures between the outer mitochondrial membrane and lipid droplets were observed in the skeletal muscles of patients with MRC I defects. CONCLUSIONS: Mitochondrial functional defects in MRC I disrupt certain activities related to adenosine triphosphate synthesis that produce changes in the skeletal muscle. The ultrastructural changes observed in the infants in this study might serve as unique markers for the detection of MD. PMID- 28884982 TI - Comparison of Somatic and Sudomotor Nerve Fibers in Type 2 Diabetes Mellitus. AB - BACKGROUND AND PURPOSE: The objective of this study was to find a sensitive method for the early detection of diabetic polyneuropathy (DPN) and determine the relationship between the functions of somatic and autonomic small nerve fibers in DPN. METHODS: Patients with type 2 diabetes mellitus and DPN based on clinical symptoms, signs, intraepidermal nerve fiber density (IENFD), and findings in the quantitative sudomotor axon reflex test (QSART) were enrolled retrospectively. Neurological examinations and nerve conduction studies were performed on all patients. Heart-rate variability during deep breathing (DB ratio) and the Valsalva maneuver (Valsalva ratio) were used to quantify the cardiovagal function. Patients were divided into two groups: 1) normal nerve conduction, defined as small-fiber neuropathy (SFN) and 2) abnormal nerve conduction, defined as mixed-fiber neuropathy. RESULTS: In total, 82 patients were enrolled (age: 60.7+/-10.7 years, mean+/-SD). A decreased IENFD was the most frequent abnormality across all of the patients, followed by abnormalities of the QSART and cardiovagal function. A decreased IENFD was more sensitive than the QSART, DB ratio, and Valsalva ratio for detecting diabetic SFN. The DB ratio was significantly correlated with the duration of diabetes mellitus and clinical symptoms and signs. There was no correlation between the IENFD and the findings of the QSART for the distal leg. CONCLUSIONS: Measuring the IENFD was a more sensitive method than the QSART for the early detection of DPN. The degree of involvement of the somatic small nerve fibers and sudomotor nerve fibers was independent in DPN. PMID- 28884983 TI - Unusual Neurological Presentation of Nevoid Basal Cell Carcinoma Syndrome (Gorlin Goltz Syndrome). PMID- 28884984 TI - Tafamidis for a Transplant Patient with Transthyretin Amyloid Polyneuropathy. PMID- 28884985 TI - Staged endovascular repair of critical limb ischemia in high risk patients: the procedural and clinical outcomes. AB - BACKGROUND: The aim of this paper was to retrospectively evaluate the procedural and clinical outcomes after staged angioplasty in high-risk, chronic, critical limb ischemia (CLI) patients. METHODS: Between 2013 and 2015, 29 patients (29 limbs) (mean age 77 years) were treated by staged revascularization procedures in 1) the iliac artery-DFA alone or with the femoropopliteal artery followed by 2) the femoropopliteal artery and a below-the-knee artery. All patients had long segment iliofemoral artery and below-the-knee artery (TASCII D) occlusions with abnormal serum myoglobin and ischemic lesions. Clinical outcome was assessed at 1, 3, 6, and 12 months. Clinical treatment efficacy was defined as patient survival with resolved CLI without major amputations after the last revascularization procedure. RESULTS: Angioplasty was performed in all limbs with a technical success rate of 100%. All the patients received 2 stage endovascular interventions. The interval time between the two stages was 19.56+/-6.56 days. In the second stage, the peroneal artery (PA) in 11 patients, the anterior tibial artery (ATA) in 7 patients, both the PA and ATA in 6 patients, and the posterior tibial artery (PTA) in 6 patients were recanalized. Rest pain and lesions were resolved in all patients after the second-stage revascularization. An upward shift of limb status and EQ-5D scores after the first or second revascularization indicated a significant change. No major amputations occurred, although minor amputations were required in 5 patients within 3 months after the second endovascular revascularization. The primary patency was 82.76%. Repeat TLR was necessary for 5 patients after endovascular BTK revascularization. Clinical treatment efficacy was 71% at 12 months; the cumulative rate of repeat target limb revascularization was 45.6%. CONCLUSIONS: Staged endovascular treatment in high-risk CLI patients can effectively relieve rest pain and symptoms of necrosis, which greatly improves the survival and quality of life of patients less suited for conventional repair. PMID- 28884986 TI - Corticosteroids in management of anaphylaxis; a systematic review of evidence. AB - Summary: As anaphylaxis is a medical emergency, there are no randomized controlled clinical trials on its emergency management. Therefore, current guidelines are mostly based on data from observational studies, animal and laboratory studies. Although epinephrine is the mainstay of recommended treatment, corticosteroids are also frequently used. This review evaluates the evidence on the use of corticosteroids in emergency management of anaphylaxis from published human and animal or laboratories studies. Thirty original research papers were found with 22 human studies and eight animal or laboratory studies. The average rate of corticosteroid use in emergency treatment was 67.99% (range 48% to 100%). Corticosteroids appear to reduce the length of hospital stay, but did not reduce revisits to the emergency department. There was no consensus on whether corticosteroids reduce biphasic anaphylactic reactions. None of the human studies had sufficient data to compare the response to treatment in different treatment groups (i.e. corticosteroids, epinephrine, antihistamines). Animal studies demonstrated that corticosteroids act through multiple mechanisms. These modulate gene expression, with effects becoming evident 4 to 24 hours after administration. A much quicker response has been detected within 5 to 30 minutes, through blockade of signal activation of glucocorticoid receptors independent of their genomic effects. Therefore, we conclude that there is no compelling evidence to support or oppose the use of corticosteroid in emergency treatment of anaphylaxis. However, based on the available data, it appears to be beneficial and there was no evidence of adverse outcomes related to the use of corticosteroids in emergency treatment of anaphylaxis. PMID- 28884987 TI - The link between chronic spontaneous urticaria and metabolic syndrome. AB - Summary: Metabolic syndrome (MS) is a cluster of risk factors for cardiovascular disease and is considered a chronic low-level systemic inflammatory condition. Recent preliminary findings have shown an increased prevalence of MS among patients with chronic urticaria (CU) as compared to controls, with a particularly higher prevalence detected in patients with uncontrolled CU. Chronic spontaneous urticaria (CSU) appears to share some pathomechanisms with MS, including a pro inflammatory state, increased oxidative stress, alterations in adipokine profile and activation of the coagulation system. Further studies are needed to assess the association of MS and its components with CU/CSU and to obtain more precise information regarding epidemiological aspects, clinical significance and implications. The aim of this review is to present the most relevant literature data on the link between CU/CSU and MS. PMID- 28884988 TI - Assessment of allergen-specific IgE by immunoblotting method in atopic dermatitis. AB - Summary: Background and Objectives. Stimulating the immune system by exposure to various allergens to produce specific IgE has a significant role in the pathogenesis of atopic dermatitis. Identifying disease-causing allergens, prevention of exposure to those allergens, and immunotherapy will play an important role in the treatment of Atopic Disease. The purpose of this study was to determine the common allergens of northwest of Iran in patients with atopic dermatitis that are resistant to treatment. Materials and methods. In this descriptive-analytical study, serum levels of total IgE and frequency of specific IgE were measured by Immunoblotting against 20 common allergens in 150 cases of patients with atopic dermatitis, attending to dermatology and asthma and allergy clinics from 2010 to 2011. The control group consisted of individuals who had been clinically healthy. Results. In the 90% of patients that were included in this study, total IgE levels were higher than in healthy people with mean serum levels of total IgE 227.51 +/- 103 IU/ml. 136 patients (90.6%) had specific IgE for at least one allergen. The frequency of positive allergens among the patients who were included in this study were 53.34%, 26.8%, and 19.56% respectively in plants and fungus allergens group, animal allergens group and food allergens group. After avoiding of the allergens (which they had been sensitized to), 60% of patients were cured with immune therapy, and total IgE serum levels in the control group were not increased. Conclusion. Identifying the abundant allergens such as cultivated rye, Timothy grass, house dust mite, birch, cat, horse, potato, dog, egg white, cow milk, in order to advise patients to avoid them or to do immunotherapy and desensitization, is useful in this area. PMID- 28884989 TI - Hydroxychloroquine in the treatment of anti-histamine refractory chronic spontaneous urticaria, randomized single-blinded placebo-controlled trial and an open label comparison study. AB - Summary: Background. The management of anti-histamine refractory chronic spontaneous urticaria (CSU) has poorly defined therapeutic options. Some patients with CSU respond poorly to a fourfold increase in dosage of H1-anti-histamines treatment. Aim. The objective of this study was to determine the effect of an adjunct treatment of hydroxychloroquine (HCQ) on remission rate and reduction of urticarial symptoms. Methods. Sixty subjects with anti-histamine refractory CSU were randomly assigned to 400 mg of HCQ daily or placebo for 12 weeks in a single blind placebo controlled trial. In a second follow up trial, non-remission subjects were offered open-label HCQ in the placebo group or a leukotriene receptor antagonist (LTRA) in the HCQ group for 12 weeks. All subjects took 4 H1 anti-histamines tablets throughout the study. The endpoints measured were the urticarial symptom score (USS) and dermatology life quality index (DLQI). Results. Forty-eight patients (24 HCQ, 24 placebos) completed the randomized trial medication. Five of 24 on HCQ treatment but none on placebo had a remission at 12 weeks (P = 0.01). There was a low proportion of therapeutic failures occurred with 12-week HCQ treatment (n = 5) compared with placebo (n = 14, P = 0.001). After 12 weeks, USS and DLQI significantly improved in HCQ group over the placebo group. Forty non-remission subjects completed an open-label HCQ (n = 22) or LTRA (n = 18) comparison study. The remission rates on HCQ and LTRA were 22.72% and 5.55% at 12 weeks. However, no significant difference between the two groups in the therapeutic responses was observed. The mean USS on HCQ significantly decreased compared to the LTRA group, but there was no significant difference in DLQI. The adverse events reported were minimal and there were no subjects who discontinued the trial. Conclusions. This study suggests that HCQ is clinically effective as an adjunct treatment for CSU. PMID- 28884990 TI - Evaluation of asthma control in the pharmacy: an Italian cross-sectional study. AB - Summary: Background. In Western countries a large proportion of asthmatic patients remain uncontrolled, despite the availability of effective drugs. An involvement of pharmacies / pharmacists in asthma management has been suggested in guidelines, since this could provide a relevant support. Objective. The present cross-sectional study aimed at assessing the level of asthma control, by using ACT questionnaire, in the community pharmacies in the County of Verona, North East of Italy. Methods. A call for participation was sent by Verona Pharmacists' Association to all the pharmacies located in the Verona municipality. Patients with a medical prescription and an asthma exemption code were recruited in pharmacies. They were asked to fill the ACT questionnaire and to answer some additional questions on asthma treatment, smoke habits and comorbidities. Results. Thirty-seven community pharmacies recruited 239 patients. According to the ACT score, more than 50% of patients had a controlled asthma but 20% of them were totally uncontrolled and 12% were using oral steroid. Only 2.9% of patients had received an asthma action plan. Asthma was intermittent in 17.6% of patients, mild persistent in 13.8%, moderate persistent in 63.1% and severe in 5.4%. Discordance was observed between the self-perceived asthma control and objective parameters, when available. Of note, in the severe asthma group, most patients had an ACT > 20. Conclusion. This is the first Italian pharmacy-based study on asthma control. A better asthma control was recorded in this study in comparison with other trials, but about 50% of patients were insufficiently controlled. The community pharmacies can play a relevant role in the preliminary assessment of asthma control by using easy and not time consuming tools, such as ACT. PMID- 28884991 TI - Acute cardiac disease in a patient with hyper-IgE syndrome. AB - Summary: We describe the case of a 24-year-old male with hyper-IgE syndrome (HIES) which was diagnosed at 4 years of age and died from a very rare cardiac complication. He had typical clinical and laboratory manifestations of HIES, including total serum IgE as high as > 100,000 IU/mL. Stem cell transplantation was not available. During the 20-year follow-up, he suffered numerous various infections of the skin and deep organs, partial lung resection, as well as multiple bone fractures. At age 24, he developed acute decompensated heart failure associated with elevated serum troponin I and brain natriuretic protein. Two-dimensional echocardiogram revealed global hypokinesis of the left ventricle with estimated ejection fraction 20-25%, and catheterization revealed ectasia of multiple coronary arteries. Endomyocardial biopsy showed lymphocytic myocarditis, focal necrosis, mild fibrosis, and myxoid degeneration, but cultures were negative. The patient improved on corticosteroid therapy and was discharged on heart failure therapy and external defibrillator. Six weeks later, he developed supraventricular tachycardia and persistent global hypokinesis and was treated with amiodarone. A trial of intravenous immunoglobulin was initiated and was repeated as outpatient every four weeks for four times. However, his cardiac function did not improve and he developed severe hypotension and pulseless electrical activity arrest. Resuscitation was unsuccessful. To the best of our knowledge, this is the first reported case of HIES complicated with lymphocytic myocarditis. Both immunologists and cardiologists need to be aware of such a complication and practice caution in using immunosuppressants when the patient's immune status is markedly compromised. PMID- 28884992 TI - New therapeutic approach by sirolimus for enteropathy treatment in patients with LRBA deficiency. AB - Summary: Purpose. To report the successful use of sirolimus for management of enteropathy in four patients with LPS-responsive beige-like anchor protein (LRBA) deficiency. Methods. Case series. Results. sirolimus therapy led to a complete improvement of symptoms including decrease in frequency and severity of diarrhea, as well as patients' weight gain. No signs of abdominal cramps and anorexia were also detected during the follow up period after treatment. Conclusions. sirolimus with its potential efficacy and immunomodulatory properties may be recommended for the treatment of severe enteropathy refractory to conventional therapy in patients with LRBA deficiency. PMID- 28884994 TI - The International Health Regulations (IHR) - 10 years of global public health security. PMID- 28884993 TI - Cholera, 2016. PMID- 28884995 TI - The opioid epidemic: What can surgeons do about it? PMID- 28884996 TI - CoC Chair Dr. Shulman works to improve quality of cancer care. PMID- 28884997 TI - Latin America Indicator Research Coalition examines prehospital care using a trauma systems applicationof LCoGS indicator 1. PMID- 28884998 TI - Profiles in surgical research: Julie A. Freischlag, MD, FACS, FRCSEd(Hon). PMID- 28884999 TI - Near-Infrared Trigged Stimulus-Responsive Photonic Crystals with Hierarchical Structures. AB - Stimuli-responsive photonic crystals (PCs) trigged by light would provide a novel intuitive and quantitative method for noninvasive detection. Inspired by the flame-detecting aptitude of fire beetles and the hierarchical photonic structures of butterfly wings, we herein developed near-infrared stimuli-responsive PCs through coupling photothermal Fe3O4 nanoparticles with thermoresponsive poly(N isopropylacrylamide) (PNIPAM), with hierarchical photonic structured butterfly wing scales as the template. The nanoparticles within 10 s transferred near infrared radiation into heat that triggered the phase transition of PNIPAM; this almost immediately posed an anticipated effect on the PNIPAM refractive index and resulted in a composite spectrum change of ~26 nm, leading to the direct visual readout. It is noteworthy that the whole process is durable and stable mainly owing to the chemical bonding formed between PNIPAM and the biotemplate. We envision that this biologically inspired approach could be utilized in a broad range of applications and would have a great impact on various monitoring processes and medical sensing. PMID- 28885000 TI - A Multiplatform Approach for the Discovery of Novel Drug-Induced Kidney Injury Biomarkers. AB - Drug-induced kidney injury (DIKI) is a common toxicity observed in pharmaceutical development. We demonstrated the use of label-free liquid chromatography-mass spectrometry (LC-MS) and multiplex liquid chromatography-single reaction monitoring (LC-SRM) as practical extensions of standard immunoassay based safety biomarker assessments for identification of new toxicity marker candidates and for improved mechanistic understanding. Two different anticancer drugs, doxorubicin (DOX) and cisplatin (cis-diamminedichloridoplatinum, CDDP), were chosen as the toxicants due to their different modes of nephrotoxicity. Analyses of urine samples from toxicant treated and untreated rats were compared to identify biochemical analytes that changed in response to toxicant exposure. A discovery (label-free LC-MS) and targeted proteomics (multiplex LC-SRM) approach was used in combination with well established immunoassay experiments for the identification of a panel of urinary protein markers related to drug induced nephrotoxicity in rats. The initial generation of an expanded set of markers was accomplished using the label-free LC-MS discovery screen and ELISA based analysis of six nephrotoxicity biomarker proteins. Diagnostic performance of the expanded analyte set was statistically compared to conventional nephrotoxicity biomarkers. False discovery rate (FDR) analysis revealed 18 and 28 proteins from the CDDP and DOX groups, respectively, exhibiting significant differences between the vehicle and treated groups. Multiplex SRM assays were constructed to more precisely quantify candidate markers selected from the discovery screen and immunoassay experiments. To evaluate the sensitivity and specificity for each of the candidate biomarkers, histopathology severity scores were used as a benchmark for renal injury followed by receiver-operating characteristic (ROC) curve analysis on selected biomarkers. Further examination of the best performing analytes revealed relevant biological significance after consideration of anatomical localization and functional roles. In summary, the inclusion of mass spectrometry together with conventional ELISA based assays resulted in the identification of an expanded set of biomarkers with a realistic potential for providing additional beneficial information in mechanistic investigations of drug induced kidney injury and with similar responsiveness to conventionally applied indicators of renal injury. PMID- 28885001 TI - Two Are Better than One: Halloysite Nanotubes-Supported Surface Imprinted Nanoparticles Using Synergy of Metal Chelating and Low pKa Boronic Acid Monomers for Highly Specific Luteolin Binding under Neutral Condition. AB - Surface-imprinted nanoparticles with double recognition (DM-MIPs) are fabricated onto halloysite nanotubes (HNTs) for highly specific separation of natural flavone luteolin (LTL) under neutral condition. Specifically, a two-step strategy via consecutive surface-initiated atom transfer radical polymerization (SI-ATRP) is employed to introduce inherent recognition of molecular imprinting and reversible covalent affinity of boronic acid ligands and immobilized Zn2+ into DM MIPs. First, Zn2+-immobilized poly(vinyl imidazole) (PVLD) shell based on the HNTs via the first SI-ATRP is prepared to capture LTL by metal chelating. Then HNTs-supported surface imprinted nanoparticles are prepared using low pKa boronic acid monomer 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AMC-FPBA) via the second SI-ATRP. Taking advantage of low apparent pKa of AMC-FPBA and large high-affinity binding site density, DM-MIPs possess a promising binding with cis-diol-containing LTL under neutral condition. In static adsorption, DM MIPs show large LTL loading amount (83.42 mg g-1), fast capture kinetics, remarkable selectivity, and excellent recyclability at pH = 7.0. More importantly, by reducing the pH to 4.0, the loaded TLL can be simply released. As a proof of this concept, a commercially available LTL with 85% purity can be easily enriched and further purified, and the product exhibits the similar antibacterial performance with standard substance. PMID- 28885002 TI - A New Nucleoside Antibiotic Chokes Bacterial RNA Polymerase. PMID- 28885003 TI - Differential Enzymatic 16O/18O Labeling for the Detection of Cross-Linked Nucleic Acid-Protein Heteroconjugates. AB - Cross-linking of nucleic acids to proteins in combination with mass spectrometry permits the precise identification of interacting residues between nucleic acid protein complexes. However, the mass spectrometric identification and characterization of cross-linked nucleic acid-protein heteroconjugates within a complex sample is challenging. Here we establish a novel enzymatic differential 16O/18O-labeling approach, which uniquely labels heteroconjugates. We have developed an automated data analysis workflow based on OpenMS for the identification of differentially isotopically labeled heteroconjugates against a complex background. We validated our method using synthetic model DNA oligonucleotide-peptide heteroconjugates, which were subjected to the labeling reaction and analyzed by high-resolution FTICR mass spectrometry. PMID- 28885004 TI - Gold-Catalyzed Solid-Phase Synthesis of 3,4-Dihydropyrazin-2(1H)-ones: Relevant Pharmacophores and Peptide Backbone Constraints. AB - Here, we report the efficient solid-phase synthesis of N-propargyl peptides using Fmoc-amino acids and propargyl alcohol as key building blocks. Gold-catalyzed nucleophilic addition to the triple bond induced C-N bond formation, which triggered intramolecular cyclization, yielding 1,3,4-trisubstituted-5-methyl-3,4 dihydropyrazin-2(1H)-ones. Conformations of acyclic and constrained peptides were compared using a two-step conformer distribution analysis at the molecular mechanics level and density functional theory. The results indicated that the incorporation of heterocyclic molecular scaffold into a short peptide sequence adopted extended conformation of peptide chain. The amide bond adjacent to the constraint did not show significant preference for either cis or trans isomerism. Prepared model compounds demonstrate a proof of concept for gold-catalyzed polymer-supported synthesis of variously substituted 3,4-dihydropyrazin-2(1H) ones for applications in drug discovery and peptide backbone constraints. PMID- 28885005 TI - MOF-Mediated Destruction of Cancer Using the Cell's Own Hydrogen Peroxide. AB - A novel reduced iron metal-organic framework nanoparticle with cytotoxicity specific to cancer cells is presented. This nanoparticle was prepared via a hydrothermal method, reduced using hydroquinone, and finally conjugated with folic acid (namely, rMOF-FA). The synthesized nanoparticle shows the controlled release of iron in an acidic ex-vivo environment. Iron present on the rMOF-FA and released into solution can react with high levels of hydrogen peroxide found specifically in cancer cells to increase the hydroxyl radical concentration. The hydroxyl radicals oxidize proteins, lipids, and/or DNA within the biological system to decrease cell viability. In vitro experiments demonstrate that this novel nanoparticle is cytotoxic to cancer cells (HeLa) through generation of OH* inside the cells. At low concentrations of rMOF-FA, the cancer cell viability decreases dramatically, with no obvious reduction of normal cell (NIH-3T3) viability. The calculated half-maximum inhibitory concentration value (IC50) was 43 MUg/mL for HeLa cells, which was significantly higher than 105 MUg/mL for NIH 3T3. This work thus demonstrates a new type of agent for controlled hydroxyl radical generation using the Fenton reaction to kill the tumor cells. PMID- 28885006 TI - Preparation of Ice-Templated MOF-Polymer Composite Monoliths and Their Application for Wastewater Treatment with High Capacity and Easy Recycling. AB - An ice-templating process was used to fabricate polymer/MOF monoliths, specifically chitosan/UiO-66, as adsorbents for water treatment. The ice templated macropores enhanced mass transport, while the monoliths could be easily recovered from solution. This was demonstrated by the adsorption of methylchlorophenoxypropionic acid (MCPP, a herbicide compound) from dilute aqueous solution. To enhance the stability, the freeze-dried monoliths were treated with NaOH solution, solvent exchanged, and dried. The treated chitosan/UiO-66 monolith achieved an adsorption capacity of 34.33 mg g-1 (a maximum theoretic value of 334 mg g-1 by the Langmuir model), closer to the capacity (36.00 mg g-1) of the freshly prepared UiO-66 nanoparticles and much higher than that of the NaOH-washed UiO-66 nanoparticles (18.55 mg g-1), by performing the tests in 60 ppm MCPP solution. The composite monolith could be easily picked up using tweezers and used for recycling tests. Over 80% of the adsorption capacity was retained after three more cycles. The powder X-ray diffraction and N2 sorption studies suggested the crystalline structure of UiO-66 was destroyed during NaOH washing procedure. This, however, provides the potential to improve the adsorption capacity by developing methods to fabricate true polymer/MOF composites. PMID- 28885008 TI - Metallic Transition Metal Selenide Holey Nanosheets for Efficient Oxygen Evolution Electrocatalysis. AB - Catalysts for oxygen evolution reaction (OER) are pivotal to the scalable storage of sustainable energy by means of converting water to oxygen and hydrogen fuel. Designing efficient electrocatalysis combining the features of excellent electrical conductivity, abundant active surface, and structural stability remains a critical challenge. Here, we report the rational design and controlled synthesis of metallic transition metal selenide NiCo2Se4-based holey nanosheets as a highly efficient and robust OER electrocatalyst. Benefiting from synergistic effects of metallic nature, heteroatom doping, and holey nanoarchitecture, NiCo2Se4 holey nanosheets exhibit greatly enhanced kinetics and improved cycling stability for OER. When further employed as an alkaline electrolyzer, the NiCo2Se4 holey nanosheet electrocatalyst enables a high-performing overall water splitting with a low applied external potential of 1.68 V at 10 mA cm-2. This work not only represents a promising strategy to design the efficient and robust OER catalysts but also provides fundamental insights into the structure-property performance relationship of transition metal selenide-based electrocatalytic materials. PMID- 28885007 TI - Stereoselective Differences between the Reinforcing and Motivational Effects of Cathinone-Derived 4-Methylmethcathinone (Mephedrone) In Self-Administering Rats. AB - Mephedrone (4-methylmethcathinone (4-MMC)) (MEPH) is a new psychoactive substance (NPS) of the synthetic cathinone class. MEPH has a chiral center and exists as two enantiomers (R-,S-MEPH), yet stereospecific effects of MEPH have not been extensively investigated in preclinical assays. Because significant behavioral and neurochemical differences can exist between enantiomers, probing effects of stereochemistry on biological activity enables separation of adverse and therapeutic effects. Our prior work showed that R-MEPH, relative to S-MEPH, produced greater locomotor activation, place preference, and facilitation of brain reward thresholds in rodents. The present study sought to determine if MEPH enantiomers display stereospecific reward and reinforcement in rat self administration assays. In Experiment 1, rats were trained to self-administer racemic MEPH (0.50 mg/kg/inf), and dose substitution effects of R-MEPH (0.50 mg/kg/inf) and S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) were examined. In Experiment 2, separate rats were trained to self-administer R-MEPH (0.25, 0.50, 2.00 mg/kg/inf) or S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) and were thereafter evaluated under progressive-ratio access conditions. Within this cohort, 50 kHz ultrasonic vocalizations (USVs) were recorded to measure potential differences in subjective positive affect associated with MEPH enantiomer self-administration. We identified enantiomer- and dose-dependent effects on infusions earned during self administration following acquisition of racemic MEPH, with greatest infusions under low-effort, fixed-ratio 1 access conditions from low-dose S-MEPH self administration. When taxed with progressive-ratio access conditions, rats trained to self-administer R-MEPH showed higher break points than those of rats trained to self-administer S-MEPH. Additionally, R-MEPH elicited greatest rates of 50 kHz USVs compared to S-MEPH. Taken together, these data suggest that the R-enantiomer of MEPH is primarily responsible for the rewarding, reinforcing, and motivational properties of racemic MEPH, which increases our understanding of stereospecific preferences pertaining to MEPH abuse. PMID- 28885009 TI - A Combined Variable-Temperature Neutron Diffraction and Thermogravimetric Analysis Study on a Promising Oxygen Electrode, SrCo0.9Nb0.1O3-delta, for Reversible Solid Oxide Fuel Cells. AB - The present study investigates the temperature-structure-stoichiometry relationship of a promising oxygen electrode SrCo0.9Nb0.1O3-delta over a temperature (T) range from room temperature (RT) to 900 degrees C. The techniques employed are variable-temperature neutron diffraction (VTND) and thermogravimetric analysis (TGA). At T < 75 degrees C, VTND reveals a tetragonal (P4/mmm) structure with a G-type magnetic ordering. Above 75 degrees C, the nucleus structure remains the same, while the magnetic ordering disappears. A phase transition from tetragonal (P4/mmm) to cubic (Pm3m) is observed at 412 degrees C, where the two Co sites and three O sites in the P4/mmm phase converge to one equivalent site, respectively. The phase transition temperature coincides with the peak temperature of oxygen uptake obtained by TGA. It is also observed that the Nb dopant has no preferred Co site to occupy. The oxygen vacancies are mostly located at the O3 site surrounding the Co2 site in the P4/mmm structure. The intermediate-spin state of Co3+ at the Co2 site is responsible for the observed distortions of CoO6 octahedra, i.e., elongation of Co2O6 octahedra and shortening of Co1O6 octahedra along the c-axis, which is a phenomenon known as Jahn-Teller distortion. At high temperatures, large thermal displacement factor for O2- is observed with high concentration of oxygen vacancies, providing a structural environment favorable to high O2- conductivity in Nb-doped SrCoO3 based oxygen electrode materials. PMID- 28885010 TI - Synthesis, Structure and Reactivity of a Borylene Cation [(NHSi)2B(CO)]+ Stabilized by Three Neutral Ligands. AB - A borylene cation stabilized by bis(silylene) and carbon monoxide was prepared and structurally characterized via the reaction of bis(silylene)-stabilized bromoborylene with W(CO)6. This is the first example of a borylene cation coordinated by three neutral ligands, which can be viewed as a cationic form of a long-sought Lewis base-stabilized zerovalent boron compound. This cation can cleave dihydrogen. PMID- 28885011 TI - Atmospheric Transport and Deposition of Bromoanisoles Along a Temperate to Arctic Gradient. AB - Bromoanisoles (BAs) arise from O-methylation of bromophenols, produced by marine algae and invertebrates. BAs undergo sea-air exchange and are transported over the oceans. Here we report 2,4-DiBA and 2,4,6-TriBA in air and deposition on the Swedish west coast (Rao) and the interior of arctic Finland (Pallas). Results are discussed in perspective with previous measurements in the northern Baltic region in 2011-2013. BAs in air decreased from south to north in the order Rao > northern Baltic > Pallas. Geometric mean concentrations at Pallas increased significantly (p < 0.05) between 2002 and 2015 for 2,4-DiBA but not for 2,4,6 TriBA. The logarithm of BA partial pressures correlated significantly to reciprocal air temperature at the coastal station Rao and over the Baltic, but only weakly (2,4-DiBA) or not significantly (2,4,6-TriBA) at inland Pallas. Deposition fluxes of BAs were similar at both sites despite lower air concentrations at Pallas, due to greater precipitation scavenging at lower temperatures. Proportions of the two BAs in air and deposition were related to Henry's law partitioning and source regions. Precipitation concentrations were 10 40% of those in surface water of Bothnian Bay, northern Baltic Sea. BAs deposited in the bay catchment likely enter rivers and provide an unexpected source to northern estuaries. BAs may be precursors to higher molecular weight compounds identified by others in Swedish inland lakes. PMID- 28885012 TI - The Impact of the Major Baltic Inflow of December 2014 on the Mercury Species Distribution in the Baltic Sea. AB - The Baltic Sea is a marginal sea characterized by stagnation periods of several years. Oxygen consumption in its deep waters leads to the buildup of sulfide from sulfate reduction. Some of the microorganisms responsible for these processes also transform reactive ionic mercury to neurotoxic methylmercury. Episodic inflows of oxygenated saline water from the North Sea temporally re-establish oxic life in deep waters of the Baltic Sea. Thus, this sea is an especially important region to better understand mercury species distributions in connection with variable redox conditions. Mercury species were measured on three Baltic Sea campaigns, during the preinflow, ongoing inflow, and subsiding inflow of water, respectively, to the central basin. The inflowing water caused the removal of total mercury by 600 nmol m-2 and of methylmercury by 214 nmol m-2 in the Gotland Deep, probably via attachment of the mercury compounds to sinking particles. It appears likely that the consequences of the oxygenation of Baltic Sea deep waters, which are the coprecipitation of mercury species and the resettlement of the oxic deep waters, could lead to the enhanced transfer of accumulated mercury and methylmercury to the planktonic food chain and finally to fish. PMID- 28885013 TI - Facile Bulk Synthesis of pi-Cubic SnS. AB - The cubic modification of binary tin sulfide (SnS) has gained significant interest as an earth-abundant, low-toxicity solar absorber material with a band gap close to the optimal value for the conversion of sunlight. We herein report a simple synthesis for the metastable material, which will allow more elaborate characterization methods to be used on this material, and present a full powder refinement of the material along with some preliminary results on the optical and thermal stability properties. PMID- 28885014 TI - Synthesis and Evaluation of Dolastatin 10 Analogues Containing Heteroatoms on the Amino Acid Side Chains. AB - Synthetic analogues of the natural occurring dolastatin 10 are of great interest in cancer due to their potent in vitro activity and their uses as payloads in antibody drug conjugates (ADCs). Modification of the dolastatin 10 core scaffold has mainly focused on modifications of the P1, N-terminus, and P5, C-terminus, with minimal attention to the P2 subunit. In this paper we discuss the introduction of heteroatoms to the P2 side chain, which results in potent activity in vitro. The most active compounds contained azides in the P2 unit and required a phenylalanine-derived P5 subunit. PMID- 28885016 TI - Characterization of the Key Aroma Compounds in Five Varieties of Mandarins by Gas Chromatography-Olfactometry, Odor Activity Values, Aroma Recombination, and Omission Analysis. AB - In this study, volatile compounds of five varieties of mandarin juices [Tankan, Miyagawa, Mashui (MS), Skiranui, and Ponkan (PG)] were investigated by gas chromatography-olfactometry (GC-O) and gas chromatography-mass spectrometry (GC MS). A total of 47 volatile compounds were identified by GC-MS. Partial least squares regression was used to process the mean scores from sensory evaluation by panelists of volatile compounds and samples. The sample PG was associated with "fruity", "floral", and "sweet" notes, while MS was correlated with "green" and "peely" notes. In addition, 36 aroma-active compounds, including esters, alcohols, aldehydes, ketones, and monoterpenes, were detected by GC-O. According to the quantitative results, 29 aroma compounds were important, which indicated that their odor activity values (OAVs) were >=1. On the basis of the GC-O results and OAVs of these volatile compounds, 22 odor-active compounds were mixed to simulate successfully the overall aroma of PG mandarin juice. Furthermore, omission experiments confirmed that nonanal, hexanal, linalool, and (R)-(+) limonene were the key odorants for the overall aroma of PG juice sample and that beta-ionone, decanal, gamma-terpinene, and methyl butyrate were also important odor-active compounds. PMID- 28885015 TI - A Small Molecule Causes a Population Shift in the Conformational Landscape of an Intrinsically Disordered Protein. AB - Intrinsically disordered proteins (IDPs) have roles in myriad biological processes and numerous human diseases. However, kinetic and amplitude information regarding their ground-state conformational fluctuations has remained elusive. We demonstrate using nuclear magnetic resonance (NMR)-based relaxation dispersion that the D2 domain of p27Kip1, a prototypical IDP, samples multiple discrete, rapidly exchanging conformational states. By combining NMR with mutagenesis and small-angle X-ray scattering (SAXS), we show that these states involve aromatic residue clustering through long-range hydrophobic interactions. Theoretical studies have proposed that small molecules bind promiscuously to IDPs, causing expansion of their conformational landscapes. However, on the basis of previous NMR-based screening results, we show here that compound binding only shifts the populations of states that existed within the ground state of apo p27-D2 without changing the barriers between states. Our results provide atomic resolution insight into how a small molecule binds an IDP and emphasize the need to examine motions on the low microsecond time scale when probing these types of interactions. PMID- 28885017 TI - Parameterization of Acyclic Diaminocarbene Ligands Applied to a Gold(I)-Catalyzed Enantioselective Tandem Rearrangement/Cyclization. AB - Computed descriptors for acyclic diaminocarbene ligands are developed in the context of a gold catalyzed enantioselective tandem [3,3]-sigmatropic rearrangement-[2+2]-cyclization. Surrogate structures enable the rapid identification of parameters that reveal mechanistic characteristics. The observed selectivity trends are validated in a robust multivariate analysis facilitating the development of a highly enantioselective process. PMID- 28885018 TI - Molecular Mechanisms of Perfluorooctanoate-Induced Hepatocyte Apoptosis in Mice Using Proteomic Techniques. AB - The stability of perfluorooctanoate (PFOA) coupled with its wide use cause serious concerns regarding its potential risk to human health. The molecular mechanisms of PFOA-induced hepatotoxicity relevant to human health was investigated using both in vivo (mouse model) and in vitro (human hepatocyte cells, HL-7702) techniques. Both male and female Balb/c mice were administered PFOA at 0.05, 0.5, or 2.5 mg/kg-d for 28-d, with serum PFOA concentrations after exposure being found at environmentally relevant levels. Liver samples were examined for histology and proteomic change using iTRAQ and Western Blotting, showing dose-dependent hepatocyte apoptosis and peroxisome proliferation. At high doses, genotoxicity resulting from ROS hypergeneration was due to suppression of Complex I subunits in the electron transport chain and activation of PPARalpha in both genders. However, at 0.05 mg/kg-d, Complex I suppression occurred only in females, making them more sensitive to PFOA-induced apoptosis. In vitro assays using HL-7702 cells confirmed that apoptosis was also induced through a similar mechanism. The dose/gender-dependent toxicity mechanisms help to explain some epidemiological phenomena, i.e., liver cancer is not often associated with PFOA exposure in professional workers. Our results demonstrated that a proteomic approach is a robust tool to explore molecular mechanisms of toxic chemicals at environmentally relevant levels. PMID- 28885019 TI - Sulfonium as a Surrogate for Ammonium: A New alpha7 Nicotinic Acetylcholine Receptor Partial Agonist with Desensitizing Activity. AB - Weak partial agonists that promote a desensitized state of the alpha7 nicotinic acetylcholine receptor (nAChR) have been associated with anti-inflammatory effects. Exemplar compounds feature a tertiary or quaternary ammonium group. We report the synthesis, structure, and electrophysiological evaluation of 1-ethyl-4 phenylthiomorpholin-1-ium triflate, a weak partial agonist with a sulfonium isostere of the ammonium pharmacophore. These results offer new insights in understanding nAChR-ligand interactions and provide a new chemical space to target the alpha7 nAChR. PMID- 28885021 TI - Ruthenium Phosphine-Pyridone Catalyzed Cross-Coupling of Alcohols To form alpha Alkylated Ketones. AB - An efficient and green route to access diverse functionalized ketones via dehydrogenative-dehydrative cross-coupling of primary and secondary alcohols is demonstrated. Selective and tunable formation of ketones or alcohols is catalyzed by a recently developed proton responsive ruthenium phosphine-pyridone complex. Light alcohols such as ethanol could be used as alkylating agents in this methodology. Moreover, selective tandem double alkylation of isopropanol is achieved by sequential addition of different alcohols. PMID- 28885020 TI - Facile Aqueous Route to Nitrogen-Doped Mesoporous Carbons. AB - An aqueous-based approach for the scalable synthesis of nitrogen-doped porous carbons with high specific surface area (SSA) and high nitrogen content is presented. Low molecular weight polyacrylonitrile (PAN) is solubilized in water in the presence of ZnCl2 that also acts as a volatile porogen during PAN pyrolysis to form mesoporous structures with significantly increased SSA. By templating with commercial SiO2 nanoparticles, nanocellulose fillers or filter paper, nanocarbons with SSA = 1776, 1366, and 1501 m2/g, respectively and 10 wt % N content were prepared. The materials formed by this benign process showed excellent catalytic activity in oxygen reduction reaction via the four-electron mechanism. PMID- 28885022 TI - Effect of Storage on Lactase-Treated beta-Casein and beta-Lactoglobulin with Respect to Bitter Peptide Formation and Subsequent in Vitro Digestibility. AB - Using active lactose to hydrolyze lactose during storage is a common process to produce lactose-hydrolyzed (LH) milk. Proteolysis induced by residual proteases in commercial lactase was studied in a system using purified beta-casein or beta lactoglobulin during a 60-day storage period at 22 or 38 degrees C. The proteolysis of beta-casein by residual proteases occurred more extensively than that of beta-lactoglobulin. Peptidomic analysis by LC-ESI-MS/MS revealed that Ile, Leu, Tyr, and Phe residues near the C-terminus of beta-casein were the main sites of cleavage by the residual proteases, generating assumed bitter peptides. In the subsequent in vitro digestion study, proteolysis during storage was shown to greatly affect the subsequent digestibility of beta-casein, leading to an elevated degree of hydrolysis and the formation of new digested peptides. This study highlights the potential influence of residual proteases in commercial lactase on the storage quality and digestibility of LH milk containing active lactase. PMID- 28885023 TI - Crystalline Structure and Vacancy Ordering across a Surface Phase Transition in Sn/Cu(001). AB - We report a surface X-ray diffraction study of the crystalline structure changes and critical behavior across the (3?2 * ?2)R45 degrees -> (?2 * ?2)R45 degrees surface phase transition at 360 K for 0.5 monolayers of Sn on Cu(100). The phase transition is of the order-disorder type and is due to the disordering of the Cu atomic vacancies present in the low temperature phase. Two different atomic sites for Sn atoms, characterized by two different heights, are maintained across the surface phase transition. PMID- 28885024 TI - Construction of Sierpinski Triangles up to the Fifth Order. AB - Self-similar fractal structures are of fundamental importance in science, mathematics, and aesthetics. A series of molecular defect-free Sierpinski triangle fractals have been constructed on surfaces recently. However, the highest order of the fractals is only 4 because of the limitation of kinetic growth. Here complete fifth-order Sierpinski triangles with a lateral length of 0.05 MUm were successfully prepared in ultrahigh vacuum by a combination of templating and coassembly methods. Fe atoms, 4,4"-dicyano-1,1':3',1"-terphenyl, and 1,3-bis(4-pyridyl)benzene molecules were used to build fractals on the reconstructed Au(100)-(hex) surface. The new strategy may be applied to construct various Sierpinski triangles of higher orders. PMID- 28885025 TI - Systematic Search for Chemical Reactions in Gas Phase Contributing to Methanol Formation in Interstellar Space. AB - A massive search for chemical routes leading to methanol formation in gas phase has been conducted using computational chemistry, at the CBS-QB3 level of theory. The calculations were performed at five different temperatures (100, 80, 50, 20, and 10 K) and at three pressures (0.1, 0.01, and 0.001 atm) for each temperature. The search was focused on identifying reactions with the necessary features to be viable in the interstellar medium (ISM). A searching strategy was applied to that purpose, which allowed to reduce an initial set of 678 possible reactions to a subset of 11 chemical routes that are recommended, for the first time, as potential candidates for contributing to methanol formation in the gas phase of the ISM. They are all barrier-less, and thus they are expected to take place at collision rates. Hopefully, including these reactions in the currently available models, for the gas-phase methanol formation in the ISM, would help improving the predicted fractional abundance of this molecule in dark clouds. Further investigations, especially those dealing with grain chemistry and electronic excited states, would be crucial to get a complete picture of the methanol formation in the ISM. PMID- 28885026 TI - Interaction of the Lipopeptide Biosurfactant Lichenysin with Phosphatidylcholine Model Membranes. AB - Lichenysins produced by Bacillus licheniformis are anionic lipopeptide biosurfactants with cytotoxic, antimicrobial, and hemolytic activities that possess enormous potential for chemical and biological applications. Through the use of physical techniques such as differential scanning calorimetry, small- and wide-angle X-ray diffraction, and Fourier-transform infrared spectroscopy as well as molecular dynamics simulations, we report on the interaction of Lichenysin with synthetic phosphatidylcholines differing in hydrocarbon chain length. Lichenysin alters the thermotropic phase behavior of phosphatidylcholines, displaying fluid-phase immiscibility and showing a preferential partitioning into fluid domains. The interlamellar repeat distance of dipalmitoylphosphatidylcholine (DPPC) is modified, affecting both the phospholipid palisade and the lipid/water interface, which also experiences a strong dehydration. Molecular dynamics confirms that Lichenysin is capable of interacting both with the hydrophobic portion of DPPC and with the polar headgroup region, which is of particular relevance to explain much of its properties. The results presented here help to establish a molecular basis for the Lichenysin-induced perturbation of model and biological membranes previously described in the literature. PMID- 28885027 TI - alpha-Cyclodextrin: How Effectively Can Its Hydrophobic Cavity Be Hydrated? AB - Cyclodextrins (CDs) are among the most widely used native host systems with ability to form inclusion complexes with various molecular objects. This ability is so strong that the "hydrophobic" CD cavity never remains empty, even in the guest-free state it is filled with water molecules. However, no consensus has been reached concerning both the total number of hydrating water molecules and their preferred binding location in the CDs. Several outstanding questions regarding the CD hydration still wait to be answered: (1) Which spots of the CD cavity ("hot spots") have the highest affinity for the guest water molecules? (2) How stable are water clusters inside the cavity? (3) Which mode of water binding, sequential or bulk, is thermodynamically more favored? (4) What is the upper limit of the number of water molecules bound inside the host cavity? (5) What factors do control the CD hydration process? Here, using alphaCD as a typical representative of the cyclodextrin family, we endeavor to answer these questions by combining experimental measurements (differential scanning calorimetry and thermogravimetry) with theoretical (DFT) calculations. Enthalpies of the alphaCD hydrate formation are evaluated and the role of different factors, such as the number and mode of binding (sequential vs bulk) of water molecules, type of hydrogen bonds established (water-water vs water-alphaCD), and the dielectric properties of the medium, on the complexation process is assessed. The results obtained shed light on the intimate mechanism of water binding to alphaCD and disclose the key factors governing the process. PMID- 28885028 TI - Numerical Calculation Method of Apparent Contact Angles on Heterogeneous Double Roughness Surfaces. AB - Double-roughness surfaces can be used to mimic lotus surfaces. The apparent contact angles (ACAs) of droplets on these surfaces were first calculated by Herminghaus. Then Patankar utilized the pillar model to improve the Herminghaus approach and put forward the formulas for ACAs calculation of the homogeneous double-roughness surfaces where the dual-scale structures and the bases were the same wettable materials. In this paper, we propose a numerical calculation method of ACAs on the heterogeneous double-roughness surfaces where the dual-scale structures and the bases are made of different wettable materials. This numerical calculation method has successfully enhanced the Herminghaus approach. It is promising to become a novel design approach of heterogeneous superhydrophobic surfaces, which are frequently applied in technical fields of self-cleaning, anti icing, antifogging, and enhancing condensation heat transfer. PMID- 28885029 TI - Polymer Nanosheets from Supramolecular Assemblies of Conjugated Linoleic Acid High Surface Area Adsorbents from Renewable Materials. AB - We present a strategy for robustly cross-linking self-assembled lamellar mesophases made from plant-derived materials to generate polymer nanosheets decorated with a high density of functional groups. We formulate a supramoleclar complex by hydrogen-bonding conjugated linoleic acid moieties to a structure directing tribasic aromatic core. The resulting constructs self-assemble into a thermotropic lamellar mesophase. Photo-cross-linking the mesophase with the aid of an acrylate cross-linker yields a polymeric material with high-fidelity retention of the lamellar mesophase structure. Transmission electron microscopy images demonstrate the preservation of the large area, highly ordered layered nanostructures in the polymer. Subsequent extraction of the tribasic core and neutralization of the carboxyl groups by NaOH result in exfoliation of polymer nanosheets with a uniform thickness of ~3 nm. The nanosheets have a large specific area of ~800 m2/g, are decorated by negatively charged carboxylate groups at a density of 4 nm-2, and exhibit the ability to readily adsorb positively charged colloidal particles. The strategy as presented combines supramolecular self-assembly with the use of renewable or sustainably derived materials in a scalable manner. The resulting nanosheets have potential for use as adsorbents and, with further development, rheology modifiers. PMID- 28885031 TI - Enantioselective Synthesis of beta-Fluoro-beta-aryl-alpha-aminopentenamides by Organocatalytic [2,3]-Sigmatropic Rearrangement. AB - The tetramisole-promoted catalytic enantioselective [2,3]-sigmatropic rearrangement of quaternary ammonium salts bearing a (Z)-3-fluoro-3-arylprop-2 ene group generates, after addition of benzylamine, a range of beta-fluoro-beta aryl-alpha-aminopentenamides containing a stereogenic tertiary fluorine substituent. Cyclic and acyclic nitrogen substituents as well as various aromatic substituents are tolerated, giving the beta-fluoro-beta-aryl-alpha aminopentenamide products in up to 76% yield, 96:4 dr, and 98:2 er. PMID- 28885030 TI - Platelet Adhesion and Activation on Chiral Surfaces: The Influence of Protein Adsorption. AB - Adsorbed proteins and their conformational change on blood-contacting biomaterials will determine their final hemocompatibility. It has frequently been reported that surface chirality of biomaterials may highly influence their protein adsorption behavior. Here, lysine and tartaric acid with different chirality were immobilized onto TiO2 films respectively, and the influence of surface chirality on protein adsorption, platelet adhesion, and activation was also investigated. It showed that the l- and d-molecule grafted samples had almost the same grafting density, surface topography, chemical components, and hydrophilicity in this study. However, biological behaviors such as protein adsorption, platelet adhesion, and activation were quite different. The d-lysine grafted surface had a greater ability to inhibit both bovine serum albumin and fibrinogen adsorption, along with less degeneration of fibrinogen compared to the l-lysine anchored surface. However, the d-tartaric acid grafted surface adsorbed more protein but with less denatured fibrinogen compared to the l-tartaric acid grafted one. Further studies showed that the secondary structural change of the adsorbed albumin and fibrinogen on all surfaces with deduction of the alpha-helix content and increase of disordered structure, while the changing degree was apparently varied. As a result, the d-lysine immobilized surface absorbed less platelets and red blood cells and achieved slightly increased platelet activation. For tartaric acid anchored surfaces, a larger number of platelets adhered to the D-surface but were less activated compared to the L-surface. In conclusion, the surface chirality significantly influenced the adsorption and conformational change of blood plasma protein, which in turn influenced both platelet adhesion and activation. PMID- 28885033 TI - Adsorption of DNA Fragments at Aqueous Graphite and Au(111) via Integration of Experiment and Simulation. AB - We combine single molecule force spectroscopy measurements with all-atom metadynamics simulations to investigate the cross-materials binding strength trends of DNA fragments adsorbed at the aqueous graphite C(0001) and Au(111) interfaces. Our simulations predict this adsorption at the level of the nucleobase, nucleoside, and nucleotide. We find that despite challenges in making clear, careful connections between the experimental and simulation data, reasonable consistency between the binding trends between the two approaches and two substrates was evident. On C(0001), our simulations predict a binding trend of dG > dA ~ dT > dC, which broadly aligns with the experimental trend. On Au(111), the simulation-based binding strength trends reveal stronger adsorption for the purines relative to the pyrimadines, with dG ~ dA > dT ~ dC. Moreover, our simulations provide structural insights into the origins of the similarities and differences in adsorption of the nucleic acid fragments at the two interfaces. In particular, our simulation data offer an explanation for the differences observed in the relative binding trend between adenosine and guanine on the two substrates. PMID- 28885032 TI - Effective Surface Passivation of InP Nanowires by Atomic-Layer-Deposited Al2O3 with POx Interlayer. AB - III/V semiconductor nanostructures have significant potential in device applications, but effective surface passivation is critical due to their large surface-to-volume ratio. For InP such passivation has proven particularly difficult, with substantial depassivation generally observed following dielectric deposition on InP surfaces. We present a novel approach based on passivation with a phosphorus-rich interfacial oxide deposited using a low-temperature process, which is critical to avoid P-desorption. For this purpose we have chosen a POx layer deposited in a plasma-assisted atomic layer deposition (ALD) system at room temperature. Since POx is known to be hygroscopic and therefore unstable in atmosphere, we encapsulate this layer with a thin ALD Al2O3 capping layer to form a POx/Al2O3 stack. This passivation scheme is capable of improving the photoluminescence (PL) efficiency of our state-of-the-art wurtzite (WZ) InP nanowires by a factor of ~20 at low excitation. If we apply the rate equation analysis advocated by some authors, we derive a PL internal quantum efficiency (IQE) of 75% for our passivated wires at high excitation. Our results indicate that it is more reliable to calculate the IQE as the ratio of the integrated PL intensity at room temperature to that at 10 K. By this means we derive an IQE of 27% for the passivated wires at high excitation (>10 kW cm-2), which constitutes an unprecedented level of performance for undoped InP nanowires. This conclusion is supported by time-resolved PL decay lifetimes, which are also shown to be significantly higher than previously reported for similar wires. The passivation scheme displays excellent long-term stability (>7 months) and is additionally shown to substantially improve the thermal stability of InP surfaces (>300 degrees C), significantly expanding the temperature window for device processing. Such effective surface passivation is a key enabling technology for InP nanowire devices such as nanolasers and solar cells. PMID- 28885034 TI - Treatment outcomes of Class II malocclusion cases treated with miniscrew-anchored Forsus Fatigue Resistant Device: A randomized controlled trial. AB - OBJECTIVE: To evaluate the skeletal, dental, and soft tissue effects of the Forsus Fatigue Resistant Device (FRD) used with miniscrew anchorage and compare them with those of the conventional Forsus FRD. MATERIALS AND METHODS: This study was carried out on 38 patients. These patients were randomly allocated into three groups. The 14 patients in group 1 (aged 12.76 +/- 1.0 years) were treated with the FRD appliance. In group 2, the 15 patients (aged 12.52 +/- 1.12 years) received treatment with FRD using miniscrew anchorage, and the 9 patients in group 3 (aged 12.82 +/- 0.9 years) received no treatment as a control group. Linear and angular measurements were made on lateral cephalograms before and immediately after Forsus treatment. Data were analyzed statistically using paired t-, ANOVA, and Tukey tests. RESULTS: Class I molar relationship and overjet correction were achieved in both treatment groups. Although mandibular growth was statistically nonsignificant, there was a significant headgear effect on the maxilla. Mandibular incisor proclination, maxillary incisor retroclination, and distalization of maxillary molars were significant in both treatment groups. However, no significant differences were found between the treatment groups. CONCLUSIONS: Class II correction was mainly dentoalveolar in both treatment groups. Use of miniscrews with Forsus did not enhance mandibular forward growth nor prevent labial tipping of the mandibular incisors. PMID- 28885035 TI - Can rapid maxillary expansion cause auditory improvement in children and adolescents with hearing loss? A systematic review. AB - OBJECTIVE: To evaluate whether the use of palatal expansion techniques can influence hearing loss in children and adolescents with previous hearing impairment. MATERIALS AND METHODS: Electronic searches in PubMed, Scopus, Web of Science, The Cochrane Library, Lilacs, OpenGrey, and Google Scholar were performed with a controlled vocabulary and free-text terms relating to palatal expansion and hearing loss. No language or time restrictions were imposed. Clinical trials that focused on human patients treated with rapid or semirapid maxillary expansion in children and teenagers with hearing loss were included. Data extraction was undertaken by two authors, with conflict resolution by a third author. Risk of bias assessment and data extraction were performed on the selected studies. RESULTS: Seventy-four citations were retrieved by the search. Initially, 12 studies were selected according to the eligibility criteria, but three studies were excluded because of the presence of adults, absence of hearing level evaluation, and oversampling, resulting in nine studies. The mean improvement in hearing levels varied from 2 to 19 dB among the studies. The risk of bias varied from low to moderate risk. CONCLUSIONS: The evidence indicated that there was a hearing improvement after maxillary expansion in patients with hearing loss in the evaluated studies, although more controlled and randomized studies are necessary to investigate this issue further. PMID- 28885037 TI - Will Biosimilar Insulins Be Cheaper? PMID- 28885036 TI - Postnatal diet remodels hepatic DNA methylation in metabolic pathways established by a maternal high-fat diet. AB - AIM: We investigate how postweaning diet may modify the epigenetic landscape to meet metabolic demands later in life. METHODS: Sprague-Dawley rats were exposed to a high-fat (HF) diet during gestation and lactation. At weaning, male offspring were placed either on an HF diet (HF/HF) or a control diet (HF/C). Methylation-dependent immunoprecipitation sequencing and methylation-sensitive restriction enzyme sequencing were used to quantify hepatic DNA methylation. RESULTS: Out of the 3966 identified differentially methylated regions, 37% were mapped to gene bodies while 6% fell within promoter or downstream regions. Differentially methylated genes were clustered in the type II diabetes mellitus and the adipocytokine signaling pathways. CONCLUSION: Our results indicate that compared with a lifelong HF diet, offspring exposed to a new postweaning control diet are able to remodel the hepatic epigenome, emphasizing the dynamic nature of the methylome even after early life. PMID- 28885038 TI - Assessing the relative importance of correlates of loneliness in later life. Gaining insight using recursive partitioning. AB - OBJECTIVES: Improving the design and targeting of interventions is important for alleviating loneliness among older adults. This requires identifying which correlates are the most important predictors of loneliness. This study demonstrates the use of recursive partitioning in exploring the characteristics and assessing the relative importance of correlates of loneliness in older adults. METHOD: Using exploratory regression trees and random forests, we examined combinations and the relative importance of 42 correlates in relation to loneliness at age 68 among 2453 participants from the birth cohort study the MRC National Survey of Health and Development. RESULTS: Positive mental well-being, personal mastery, identifying the spouse as the closest confidant, being extrovert and informal social contact were the most important correlates of lower loneliness levels. Participation in organised groups and demographic correlates were poor identifiers of loneliness. The regression tree suggested that loneliness was not raised among those with poor mental wellbeing if they identified their partner as closest confidante and had frequent social contact. CONCLUSION: Recursive partitioning can identify which combinations of experiences and circumstances characterise high-risk groups. Poor mental wellbeing and sparse social contact emerged as especially important and classical demographic factors as insufficient in identifying high loneliness levels among older adults. PMID- 28885039 TI - Primary health care decision making in pre-dialysis chronic kidney disease. AB - OBJECTIVES: This qualitative descriptive study explored the primary health care decisions of a group of 12 Australians in Stages 3B to 5 with chronic kidney disease in the preservation of kidney health. METHODS: Questioning within the qualitative interviews focused on gaining an understanding of the participants' perceptions of their kidney health and the decisions made as a consequence of their interaction within the Australian primary health care system. RESULTS: Participants were dependent on their General Practitioner to recognise their symptoms, make the correct diagnosis and authorise the correct referral for specialist nephrology care. Three pathways in this process were identified: 'easy'; 'difficult' and 'protracted'. Clinician failure to correctly attribute symptoms to chronic kidney disease influenced the 'difficult' pathway, while failure to adequately communicate kidney health status influenced the 'protracted' pathway. Use of the language of 'recovery', 'stability' and 'protection' held meaning to the participants in gaining an understanding of their kidney health. DISCUSSION: Identifying pathways to diagnosis and referral can raise awareness of the challenges kidney health consumers face in their participation within the primary health care arena. Using consumer meaningful language improves the capacity of these consumers to engage in their own primary health care agenda. PMID- 28885040 TI - Validation of Next-Generation Sequencer for 24-Chromosome Aneuploidy Screening in Human Embryos. AB - BACKGROUND: Next-Generation Sequencing (NGS) is the latest approach for preimplantation genetic diagnoses (PGD). AIM: The purpose of this study was to standardize and validate an NGS method for comprehensive chromosome screening and to investigate its applicability to PGD. METHODS: Embryo biopsy, whole-genome amplification, array comparative genomic hybridization (aCGH), and semiconductor sequencing were employed. RESULTS: A total of 204 whole-genome-amplified products were tested with an NGS-based protocol, from which 100 samples were used for standardization and to evaluate the quality of the results produced by this new technique. The remaining 104 samples tested by NGS were previously analyzed by using the aCGH protocol to determine the sensitivity and specificity of this new technique. In total, 4896 chromosomes were assessed, out of which 196 carried a copy number imbalance. NGS sensitivity and specificity for calling aneuploidy was 100%. CONCLUSION: This is the first study reporting preclinical validation and accuracy assessment of the Ion Torrent Personal Genome Machine (PGM) NGS-based comprehensive chromosome screening method using blastomeres and blastocysts. The NGS proved to be a robust methodology and is ready for clinical application in reproductive medicine, with the major advantage of low cost and enhanced precision when compared with other technologies used for comprehensive chromosome screening. PMID- 28885041 TI - Developmental Origins of Rumination in Middle Childhood: The Roles of Early Temperament and Positive Parenting. AB - Rumination, a thinking style characterized by a repetitive inward focus on negative cognitions, has been linked to internalizing disorders, particularly depression. Moreover, research suggests that rumination may be a cognitive vulnerability that predisposes individuals to psychopathology. Surprisingly little is known, however, about the etiology and development of rumination. The present study examined the role of specific components of child temperamental negative emotionality (sadness, fear, anger) and effortful control (inhibition), as well as parenting behaviors during early childhood on the development of rumination in middle childhood. Early childhood (age 3) temperament and parenting behaviors were assessed observationally and rumination was self-reported in middle childhood (age 9) in a large community sample (N = 425; 47.1% female). Two significant interactions emerged. First, temperamental anger interacted with inhibitory control (IC) such that high anger and low IC predicted higher levels of rumination, whereas low anger and low IC predicted lower levels of rumination. Second, IC interacted with parenting such that children with low IC and positive parenting had lower levels of rumination. In contrast, children with high IC reported similar levels of rumination regardless of parenting quality. Overall, these findings highlight the interplay of early IC with temperamental anger and positive parenting in the development of ruminative tendencies in middle childhood. PMID- 28885042 TI - Searching for Life on Mars Before It Is Too Late. AB - Decades of robotic exploration have confirmed that in the distant past, Mars was warmer and wetter and its surface was habitable. However, none of the spacecraft missions to Mars have included among their scientific objectives the exploration of Special Regions, those places on the planet that could be inhabited by extant martian life or where terrestrial microorganisms might replicate. A major reason for this is because of Planetary Protection constraints, which are implemented to protect Mars from terrestrial biological contamination. At the same time, plans are being drafted to send humans to Mars during the 2030 decade, both from international space agencies and the private sector. We argue here that these two parallel strategies for the exploration of Mars (i.e., delaying any efforts for the biological reconnaissance of Mars during the next two or three decades and then directly sending human missions to the planet) demand reconsideration because once an astronaut sets foot on Mars, Planetary Protection policies as we conceive them today will no longer be valid as human arrival will inevitably increase the introduction of terrestrial and organic contaminants and that could jeopardize the identification of indigenous martian life. In this study, we advocate for reassessment over the relationships between robotic searches, paying increased attention to proactive astrobiological investigation and sampling of areas more likely to host indigenous life, and fundamentally doing this in advance of manned missions. Key Words: Contamination-Earth Mars-Planetary Protection-Search for life (biosignatures). Astrobiology 17, 962-970. PMID- 28885043 TI - Negotiating the Edge: The Rationalization of Sexual Risk Taking Among Western Male Sex Tourists to Thailand. AB - Every year thousands of Western men travel to Thailand as sex tourists to participate in paid-for sex. Although many of these men will use condoms to protect themselves against sexually transmitted infections (STIs), others will not, despite the risks. By applying Steven Lyng's (1990) concept of edgework to data collected from 14 face-to-face interviews with male sex tourists in Pattaya, Thailand, and 1,237 online discussion board posts, this article explores the ways in which these men understood and sought to rationalize the sexual risks they took. We argue that notions of likelihood of infection and significance of consequence underpin these behaviors, and we identify the existence of understandings of sexual risk that reject mainstream safer-sex messages and frame condomless sex as a broadly safe activity for heterosexual men. The article concludes by summarizing the difficulties inherent in driving behavior change among this group of men, for whom sexual risks appear to be easily rationalized away as either inconsequential or irrelevant. PMID- 28885044 TI - Rapid biosynthesis of Bauhinia variegata flower extract-mediated silver nanoparticles: an effective antioxidant scavenger and alpha-amylase inhibitor. AB - Silver nanoparticles (AgNPs) were biosynthesized using Bauhinia variegata flower extract (BVFE). The BVF-AgNPs was found to be spherical shaped with the size of 5 15 nm. The phytoconstituents analysis and FTIR spectrum indicated that bioactive compounds like, phenols, flavonoids, benzophenones, nitro compounds, aromatics and aliphatic amines from BVFE might absorb on the surface of BVF-AgNPs. The synthesized BVF-AgNPs showed potent antioxidant property and alpha-amylase enzyme activity inhibition. The IC50 value of BVF-AgNPs was found to be 4.64 and 16.6 ug/ml for DPPH and ferric reducing power assay, respectively. The IC50 value of BVF-AgNPs for alpha-amylase inhibition was found to be 38 ug/ml. The Ki value of BVF-AgNPs for alpha-amylase inhibitory effect was found to be 21 ug/ml with the non-competitive mode of inhibition. These results suggest that BVF-AgNPs might be an effective nano-drug to treat diabetic conditions. PMID- 28885045 TI - Duret hemorrhage complicating a sinking skin flap syndrome. AB - Duret hemorrhage has always been reported during an episode of increased intracranial pressure with transtentorial herniation. We reported a Duret hemorrhage occurring during an episode of intracranial hypotension resulted in sinking skin flap syndrome which was responsible for acute paradoxal descending transtentorial herniation and Duret hemorrhage, 10 days after large hemicraniectomy which could indicate early cranioplasty. PMID- 28885047 TI - Dating Infidelity in Turkish Couples: The Role of Attitudes and Intentions. AB - Studies on dating infidelity have mostly been carried out in individualistic, Western cultures and have tended to investigate either attitudes or intentions toward infidelity in isolation from each other. The current study therefore investigated dating infidelity in a more collectivist, predominantly Muslim culture. Informed by the theory of planned behavior, it tested intentions as a potential mechanism that might account for the association between attitudes toward infidelity and reported infidelity. In doing so, the role of gender and infidelity history was also investigated in regard to attitudes and intentions toward infidelity. A sample of 420 college students (292 women) completed the Turkish versions of the Attitudes Towards Infidelity Scale and the Intentions Towards Infidelity Scale. A 2 (gender) * 2 (infidelity history: yes, no) multivariate analysis of variance (MANOVA) revealed main effects but no interaction effect. Men compared to women and cheaters compared to noncheaters reported more favorable attitudes and intentions toward infidelity. Moreover, intentions toward infidelity fully and partly mediated the association between attitudes toward infidelity and infidelity for women and men, respectively. Findings are interpreted in light of dating infidelity research, with a focus on universal and culturally specific aspects. Recommendations are made for future research. PMID- 28885046 TI - Cerebellar Contributions to Language in Typical and Atypical Development: A Review. AB - In this review, we present the growing literature suggesting, from a variety of angles, that the cerebellum contributes to higher-order cognitive functions, rather than simply sensorimotor functions, and more specifically to language and its development. The cerebellum's association with language function is determined by the specific cortico-cerebellar connectivity to the right cerebellum from the left cortical hemisphere. The findings we review suggest that the cerebellum plays an important role as part of a broader language network, and also implies that the cerebellum may be a potential new therapeutic target to treat speech and language deficits, especially during development. PMID- 28885048 TI - Correction to: Semerci SY et al., Urgent surgical management of congenital intracranial hemangiopericytoma in a preterm neonate. PMID- 28885049 TI - Effect of Plant Antimicrobial Agents Containing Marinades on Storage Stability and Microbiological Quality of Broiler Chicken Cuts Packed with Modified Atmosphere Packaging. AB - The food industry, including the meat industry, is currently looking for natural preservatives to prevent the growth of harmful microbes in foods. The potential of plant-derived antimicrobial extracts to increase the shelf life and to delay the microbiological spoilage of marinated broiler chicken cuts in modified atmosphere packages during cold storage was investigated in this study. We evaluated the impact of aqueous ethanolic extracts of Finnish sea buckthorn berries and lingonberries and supercritical CO2-extracted herbal extracts from an antimicrobial blend and oregano leaves on the shelf life of broiler meat. The commercial antimicrobial blend extract and the oregano extract inhibited the growth of lactic acid bacteria (LAB) and Brochothrix thermosphacta in the marinated samples. The antimicrobial blend extract also reduced the growth of psychrotrophic aerobic bacteria, whereas the sea buckthorn and lingonberry extracts did not. Only minor antimicrobial activity against Enterobacteriaceae by all the extracts was observed. Plate count analysis, denaturing gradient gel electrophoresis, and quantitative real-time PCR indicated that LAB, which are the major spoilage group in marinated modified atmosphere-packaged poultry products, were not significantly affected by the berry extracts studied. During this shelf life study, LAB isolates of Lactobacillus and Leuconostoc were identified in the marinated samples. Antimicrobial blends and oregano leaf extracts can act as antimicrobial agents in marinade blends, although tailoring of the dose is needed because of their strong taste. Further studies for exploiting synergistic effects of plant extracts could contribute to the development of potential and more effective antimicrobial blends. Studies are needed in meat matrices and in product applications to demonstrate the efficacy of these compounds. PMID- 28885050 TI - Effects of Nitrite and Erythorbate on Clostridium perfringens Growth during Extended Cooling of Cured Ham. AB - To control the growth of Clostridium perfringens in cured meat products, the meat and poultry industries commonly follow stabilization parameters outlined in Appendix B, "Compliance Guidelines for Cooling Heat-Treated Meat and Poultry Products (Stabilization)" ( U.S. Department of Agriculture, Food Safety and Inspection Service [USDA-FSIS], 1999 ) to achieve cooling (54.4 to 4.4 degrees C) within 15 h after cooking. In this study, extended cooling times and their impact on C. perfringens growth were examined. Phase 1 experiments consisted of cured ham with 200 mg/kg ingoing sodium nitrite and 547 mg/kg sodium erythorbate following five bilinear cooling profiles: a control (following Appendix B guidelines: stage A cooling [54.4 to 26.7 degrees C] for 5 h, stage B cooling [26.7 to 4.4 degrees C] for 10 h), extended stage A cooling for 7.5 or 10 h, and extended stage B cooling for 12.5 or 15 h. A positive growth control with 0 mg/kg nitrite added (uncured) was also included. No growth was observed in any treatment samples except the uncured control (4.31-log increase within 5 h; stage A). Phase 2 and 3 experiments were designed to investigate the effects of various nitrite and erythorbate concentrations and followed a 10-h stage A and 15-h stage B bilinear cooling profile. Phase 2 examined the effects of nitrite concentrations of 0, 50, 75, 100, 150, and 200 mg/kg at a constant concentration of erythorbate (547 mg/kg). Results revealed changes in C. perfringens populations for each treatment of 6.75, 3.59, 2.43, -0.38, -0.48, and -0.50 log CFU/g, respectively. Phase 3 examined the effects of various nitrite and erythorbate concentrations at 100 mg/kg nitrite with 0 mg/kg erythorbate, 100 with 250, 100 with 375, 100 with 547, 150 with 250, and 200 with 250, respectively. The changes in C. perfringens populations for each treatment were 4.99, 2.87, 2.50, 1.47, 0.89, and -0.60 log CFU/g, respectively. Variability in C. perfringens growth for the 100 mg/kg nitrite with 547 mg/kg erythorbate treatment was observed between phases 2 and 3 and may have been due to variations in treatment pH and NaCl concentrations. This study revealed the importance of nitrite and erythorbate for preventing growth of C. perfringens during a much longer (25 h) cooling period than currently specified in the USDA-FSIS Appendix B. PMID- 28885051 TI - Degradation of Histamine by Lactobacillus plantarum Isolated from Miso Products. AB - Histamine is a toxic chemical and is the causative agent of food poisoning. This foodborne toxin may be degraded by the oxidative deamination activity of certain microorganisms. In this study, we isolated four histamine-degrading Lactobacillus plantarum bacteria from miso products. Among them, L. plantarum D-103 exhibited 100% degradation of histamine in de Man Rogosa Sharpe (MRS) broth containing 50 ppm of histamine after 24 h of incubation at 30 degrees C. The optimal growth, histamine oxidase, and histamine-degrading activity of L. plantarum D-103 were observed in histamine MRS broth at pH 7.0, 3% NaCl, and 30 degrees C. It also exhibited tolerance to broad ranges of pH (4 to 10) and salt concentrations (0 to 12%) in histamine MRS broth. Therefore, the histamine-degrading L. plantarum D 103 might be used as an additive culture to prevent histamine accumulation in miso products during fermentation. PMID- 28885052 TI - Migraine and vascular disease biomarkers: A population-based case-control study. AB - Background The underpinnings of the migraine-stroke association remain uncertain, but endothelial activation is a potential mechanism. We evaluated the association of migraine and vascular disease biomarkers in a community-based population. Methods Participants (300 women, 117 men) were recruited as a part of the Dutch CAMERA 1 (Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis) study. Participants were aged 30-60 (mean 48) years, 155 migraine had with aura (MA), 128 migraine without aura (MO), and 134 were controls with no severe headaches. Plasma concentrations of fibrinogen, Factor II, D-dimer, high sensitivity C-reactive protein (hs-CRP), and von Willebrand factor antigen were compared between groups, also stratifying by sex. Results Fibrinogen and hs-CRP were elevated in migraineurs compared to controls. In logistic regression analyses, MO and MA had increased likelihood of elevated fibrinogen, and MA had increased likelihood of elevated Factor II and hs-CRP. Fibrinogen and Factor II were associated with MA in women but not men. In the migraine subgroup, the total number of years of aura, but not headache, predicted elevated hs-CRP, and the average number of aura, but not headache, attacks predicted all biomarkers but Factor II. Conclusions Elevated vascular biomarkers were associated with migraine, particularly MA, as well as with years of aura and number of aura attacks. PMID- 28885053 TI - Board Walk - September 2017. PMID- 28885055 TI - The Evolution of Tree Diversity / L'evolution de la diversite chez les arbres. PMID- 28885054 TI - A Multicenter Randomized Controlled Trial of Zephyr Endobronchial Valve Treatment in Heterogeneous Emphysema (TRANSFORM). AB - RATIONALE: Single-center randomized controlled trials of the Zephyr endobronchial valve (EBV) treatment have demonstrated benefit in severe heterogeneous emphysema. This is the first multicenter study evaluating this treatment approach. OBJECTIVES: To evaluate the efficacy and safety of Zephyr EBVs in patients with heterogeneous emphysema and absence of collateral ventilation. METHODS: This was a prospective, multicenter 2:1 randomized controlled trial of EBVs plus standard of care or standard of care alone (SoC). Primary outcome at 3 months post-procedure was the percentage of subjects with FEV1 improvement from baseline of 12% or greater. Changes in FEV1, residual volume, 6-minute-walk distance, St. George's Respiratory Questionnaire score, and modified Medical Research Council score were assessed at 3 and 6 months, and target lobe volume reduction on chest computed tomography at 3 months. MEASUREMENTS AND MAIN RESULTS: Ninety seven subjects were randomized to EBV (n = 65) or SoC (n = 32). At 3 months, 55.4% of EBV and 6.5% of SoC subjects had an FEV1 improvement of 12% or more (P < 0.001). Improvements were maintained at 6 months: EBV 56.3% versus SoC 3.2% (P < 0.001), with a mean +/- SD change in FEV1 at 6 months of 20.7 +/- 29.6% and -8.6 +/- 13.0%, respectively. A total of 89.8% of EBV subjects had target lobe volume reduction greater than or equal to 350 ml, mean 1.09 +/- 0.62 L (P < 0.001). Between-group differences for changes at 6 months were statistically and clinically significant: DeltaEBV-SoC for residual volume, -700 ml; 6-minute-walk distance, +78.7 m; St. George's Respiratory Questionnaire score, -6.5 points; modified Medical Research Council dyspnea score, -0.6 points; and BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, -1.8 points (all P < 0.05). Pneumothorax was the most common adverse event, occurring in 19 of 65 (29.2%) of EBV subjects. CONCLUSIONS: EBV treatment in hyperinflated patients with heterogeneous emphysema without collateral ventilation resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance, and quality of life, with an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT02022683). PMID- 28885056 TI - The Evolution of Tree Diversity: Proceedings of the 2016 IUFRO Genomics and Forest Tree Genetics Conference, Phylogenetics and Genomic Evolution Session, Arcachon, France. PMID- 28885057 TI - Plasticity in older adults' theory of mind performance: the impact of motivation. AB - OBJECTIVE: Recently, motivation has been found to attenuate the age-related decline in Theory of Mind (ToM) performance (i.e. faux pas recognition). However, whether or not this effect could be generalized to other ToM tasks is still unknown. In the present study, we investigated whether and how motivation could enhance older adults' performance and reduce age differences in ToM tasks (Faux Pas vs. Animation task) that differ in familiarity. METHOD: Following a previous paradigm, 171 Chinese adults (87 younger adults and 84 older adults) were recruited, and we experimentally manipulated the level of perceived closeness between participants and the experimenter before administering the ToM tasks in order to enhance participants' motivation. RESULTS: Results showed that, for the Faux Pas task, we replicated previous findings such that older adults under the enhanced motivation conditions performed equally well as younger adults. Conversely, for the Animation task, younger adults outperformed older adults, regardless of motivation. DISCUSSION: These results indicate that motivation can enhance older adults' performance in ToM tasks, however, this beneficial effect cannot be generalized across ToM tasks. PMID- 28885058 TI - Ustekinumab use in Crohn's disease: a Canadian tertiary care centre experience. AB - OBJECTIVES: Real world data regarding clinical response to ustekinumab in Crohn's disease is lacking. We report our experience of ustekinumab use using a novel subcutaneous (SC) induction strategy and aim to identify predictors of response. MATERIALS AND METHODS: A retrospective, observational study of compassionate ustekinumab use in Crohn's disease was conducted with the use of a standard or high dose SC induction protocol. Symptomatic response was assessed after 3 months (short-term), and if remaining on therapy, within 3-12 months (medium-term) and at least 12 months (long-term). Endoscopic or radiologic response was assessed when available. Survival analysis of time to failure (cessation of ustekinumab) and multivariate logistic regression to identify predictors of response were performed. RESULTS: Seventy-nine patients commenced ustekinumab, with six patients lost to follow-up and five asymptomatic at baseline. Symptomatic response was assessed in 68 patients; 56% (38) of patients had a short-term symptomatic response. Type of preceding anti-TNF response was the only significant predictor of short-term response, with primary non-response being a strong predictor. In the medium-term, symptomatic response occurred in 72% (30/42) of patients and endoscopic or radiologic response was achieved in 72% (26/36) of patients assessed. The median time to failure was 22 months. Maintenance dose escalation to 90 mg every 4 weeks was successful in three of 16 patients. CONCLUSIONS: Fifty-six percent of patients had short-term symptomatic response, with a history of primary non-response to prior anti-TNF therapy being a predictor of response. Dose escalation had only modest benefit. PMID- 28885059 TI - Viral deubiquitinases: role in evasion of anti-viral innate immunity. AB - Host anti-viral innate-immune signalling pathways are regulated by a variety of post-translation modifications including ubiquitination, which is critical to regulate various signalling pathways for synthesis of anti-viral molecules. A homeostasis of host immune responses, induced due to viral infection and further ubiquitination, is maintained by the action of deubiquitinases (DUB). Infecting viruses utilize the process of deubiquitination for tricking host immune system wherein viral DUBs compete with host DUBs for inhibition of innate-immune anti viral signalling pathways, which instead of maintaining an immune homeostasis bring about virus-mediated pathogenesis. This suggests that viruses co-evolve with their hosts to acquire similar machinery for tricking immune surveillance and establishing infection. PMID- 28885060 TI - Tracking the southern river terrapin (Batagur affinis) through environmental DNA: prospects and challenges. AB - Environmental DNA detection has emerged as a powerful tool to monitor aquatic species without the need for capture or visual identification and is particularly useful for rare or elusive species. Our objective was to develop an eDNA approach for detecting the southern river terrapin (Batagur affinis) in Malaysia. We designed species-specific primers for a fragment of B. affinis mtDNA and evaluated their effectiveness in silico, in vitro and in situ. The primers amplified 110 bp of the cytochrome b mtDNA sequence of B. affinis from aquarium water samples housing nine juvenile B. affinis. We also successfully detected B. affinis eDNA from river samples taken from a site where turtles were known to be in the vicinity. Prospects and challenges of using an eDNA approach to help determine the distribution of B. affinis, essential information for an effective conservation plan, are discussed. PMID- 28885061 TI - Psychometric evaluation of the Rheumatoid Arthritis Symptom Questionnaire (RASQ) in an observational study. AB - OBJECTIVE: To describe the psychometric performance of the scores produced by the Rheumatoid Arthritis Symptom Questionnaire (RASQ), a new patient-reported outcome (PRO) questionnaire developed to assess the signs and symptoms of rheumatoid arthritis (RA). METHODS: Adult subjects with clinically confirmed RA completed a set of questionnaires (including the RASQ) at an initial study visit (Day 1), and then completed the RASQ and the Patient Global Impression of Change (PGI-C) on their own on Day 8. Demographic and health data were summarized using descriptive statistics, and psychometric analyses were conducted, including: acceptability, item and scale distribution, reliability (internal consistency and test-re-test reliability), and construct-related validity (convergent validity and known groups methods). RESULTS: In total, 200 subjects (females = 61.5%; white = 72.0%; and age [mean] = 60.7 years) with RA were recruited across the US and included in the analysis. There were no missing data recorded for the RASQ, and scores were well distributed for both timepoints. The RASQ Total Symptom Score surpassed the threshold (alpha >= 0.70) for internal consistency at Day 1 (alpha = 0.967) and test-re-test score reliability (intra-class correlation coefficient [ICC] > 0.70) (ICC = 0.960). Convergent validity analyses demonstrated that the RASQ items and Total Symptom Score had high correlations (convergent validity) with other PRO questionnaires. Known-groups methods demonstrated that the RASQ (Total Symptom Score and all single items) can differentiate between clinically distinct groups. CONCLUSIONS: The RASQ is capable of producing psychometrically sound scores when administered to adults with RA. PMID- 28885062 TI - Out-of-hospital cardiac arrest: always coronary angiography? AB - INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) remains one of the principle challenges in the setting of critical care medicine and emergency cardiology. Areas covered: Long-term survival rates even after successful resuscitation are variable but increasing in the recent years; due to the improvement of base and advanced cardiac life support techniques an increasing number of resuscitated patients are admitted to the hospital. Recent data suggested that patients surviving to hospital discharge after OHCA presented long-term outcome similar to patients with ST-elevation myocardial infarction. However, limited and incompletely clear data are available in the literature about the selection and risk stratification of patients to be subjected to coronary angiography, particularly in patients who have unfavorable clinical features in whom procedures may be futile and may affect public reporting of morality. Recently the ESC and AHA addressed appropriate treatments for ST-elevation myocardial infarction (STEMI) patients with out-of-hospital cardiac arrest. Expert commentary: Immediate coronary intervention in the setting of OHCA appears to be associated with better survival to discharge; the documentation of an occluded coronary artery in medium 25% of patients without signs of STEMI at ECG helps to explain why early angiography can improve outcomes. In the treatment of OHCA we can find some ethical issues; for example a combination of comorbidities with advanced age and prolonged ischemia indicated by severe lactic acidosis may signify a high enough chance of multiorgan failure or anoxic brain injury and where the benefit of coronary reperfusion therapy appears minimal. PMID- 28885063 TI - Treatment-free interval as a metric of patient experience and a health outcome of value for advanced multiple myeloma: the case for the histone deacetylase inhibitor panobinostat, a next-generation novel agent. AB - BACKGROUND: Patients with relapsed or relapsed/refractory multiple myeloma (RRMM) face poor treatment options by the time third-line therapy is required, despite advances in overall survival in recent years. Treatment free interval (TFI) and opportunities to maintain quality of life (QoL) have been cited as additional measures of efficacy that can be utilized in personalized treatment decisions. METHODS: The clinical health outcomes data from PANORAMA-1, the pivotal phase-3 trial comparing panobinostat-bortezomib-dexamethasone (PAN-BTZ-DEX) with placebo (PBO)-BTZ-DEX in RRMM patients treated with 1 to 3 prior regimens, retrospectively assessed TFI as a health outcome measure and metric of patient treatment experience relevant to the RRMM population. RESULTS: PAN-BTZ-DEX shows promise for prolonged TFI (mean TFI, 7.49 months; 95% CI, 6.02 to 8.71) compared to PBO-BTZ-DEX (mean TFI, 3.86 months; 95% CI, 3.08 to 4.60) for heavily pre treated advanced RRMM patients), due to the short duration of therapy and extended progression free-survival. Further, QoL during the TFI was similar to baseline. CONCLUSIONS: PAN-BTZ-DEX provides a treatment regimen with prolonged TFI benefits previously not available for RRMM patients. TFI has not been traditionally measured in clinical trials, but should be assessed in prospective data collection given its value to payers, providers, and patients. PMID- 28885064 TI - Araniella cucurbitina: the first molecular evidence of a Palearctic species of genus Araniella inhabiting India. AB - The present study represents first genetic record of single spider species Araniella cucurbitina, genus Araniella from Uttarakhand, India. There are 12 identified species under Araniella genus and they are distributed in Palearctic region. Here, we used known N = 47 (2 from present study and 45 from GenBank) cytochrome oxidase 1 (CO1) sequences of A. cucurbitina representing seven different geographical groups, additionally 23 sequences of eight Araniella species were used for phylogenetic relationship. The CO1 (561 bp) sequences of A. cucurbitina consisted of n = 14 haplotypes, where haplotype 14 (Hap 14) represents Indian species, while all 13 haplotypes (Hap1-13) shared between six A. cucurbitina groups. The overall 'h' and 'pi' diversities among seven groups of A. cucurbitina were 0.85291 and 0.00888, respectively, while overall evolutionary divergence was 0.04. The Indian Hap 14, showed minimum sequence divergence (0.02) from Italy and Czech Republic haplotypes (Hap 6), it means it is the closest group compared to others. Evolutionary divergence among eight species of Araniella ranges from 0.003 to 0.114. The maximum likelihood (ML) topology based on 14 haplotypes of A. cucurbitina was divided into two major clades and further two subclades. Furthermore, ML topology between eight species of Araniella was divided into three major clades, where A. cucurbitina and A. proxima clustered together in clade 'A', while six others were present together in clade 'B' and 'C'. This study helps to identify the Indian species from the rest of Araniella species and other cucurbitina population across the world. This study further needs to be on a large scale to know the exact status distribution and molecular phylogeography of this single species of genus Araniella from India. PMID- 28885065 TI - Recovery and serious mental illness: a review of current clinical and research paradigms and future directions. AB - INTRODUCTION: Recovery from serious mental illness has historically not been considered a likely or even possible outcome. However, a range of evidence suggests the courses of SMI are heterogeneous with recovery being the most likely outcome. One barrier to studying recovery in SMI is that recovery has been operationalized in divergent and seemingly incompatible ways: as an objective outcome versus a subjective process. Areas covered: This paper offers a review of recovery as a subjective process and recovery as an objective outcome; contrasts methodologies utilized by each approach to assess recovery; reports rates and correlates of recovery; and explores the relationship between objective and subjective forms of recovery. Expert commentary: There are two commonalities of approaching recovery as a subjective process and an objective outcome: (i) the need to make meaning out of one's experiences to engage in either type of recovery and (ii) there exist many threats to engaging in meaning making that may impact the likelihood of moving toward recovery. We offer four clinical implications that stem from these two commonalities within a divided approach to the concept of recovery from SMI. PMID- 28885066 TI - Nanoparticle size-specific actin rearrangement and barrier dysfunction of endothelial cells. AB - In this work, we evaluated the impact of gold nanoparticles on endothelial cell behavior and function beyond the influence on cell viability. Five types of gold nanoparticles were studied: 5 nm and 20 nm bare gold nanoparticles, 5 nm and 20 nm gold nanoparticles with biocompatible polyethylene glycol (PEG) coating and 60 nm bare gold nanoparticles. We found that all tested gold nanoparticles did not affect cell viability significantly and reduced the reactive oxygen species (ROS) level in endothelial cells. Only 20 nm bare gold nanoparticles caused an over 50% increase in endothelial barrier permeability and slow recovery of barrier function was observed after the gold nanoparticles were removed. This impairment in endothelial barrier function was caused by unbalanced forces between intracellular tensions and paracellular forces, actin microfilament rearrangement, which occurred through a Rho/ROCK kinase-dependent pathway and broke the force balance between intracellular tensions and paracellular forces. The size-specific effect of gold nanoparticles on endothelial cells may have important implications regarding the behavior of nanoparticles in the biological system and provide valuable guidance in nanomaterial design and biomedical applications. PMID- 28885067 TI - Differential gene expression in primary fibroblasts induced by proton and cobalt 60 beam irradiation. AB - INTRODUCTION: Proton beam therapy delivers a more conformal dose distribution than conventional radiotherapy, thus improving normal tissue sparring. Increasing linear energy transfer (LET) along the proton track increases the relative biological effectiveness (RBE) near the distal edge of the Spread-out Bragg peak (SOBP). The severity of normal tissue side effects following photon beam radiotherapy vary considerably between patients. AIM: The dual study aim was to identify gene expression patterns specific to radiation type and proton beam position, and to assess whether individual radiation sensitivity influences gene expression levels in fibroblast cultures irradiated in vitro. METHODS: The study includes 30 primary fibroblast cell cultures from patients previously classified as either radiosensitive or radioresistant. Cells were irradiated at three different positions in the proton beam profile: entrance, mid-SOBP and at the SOBP distal edge. Dose was delivered in three fractions * 3.5 Gy(RBE) (RBE 1.1). Cobalt-60 (Co-60) irradiation was used as reference. Real-time qPCR was performed to determine gene expression levels for 17 genes associated with inflammation response, fibrosis and angiogenesis. RESULTS: Differences in median gene expression levels were observed for multiple genes such as IL6, IL8 and CXCL12. Median IL6 expression was 30%, 24% and 47% lower in entrance, mid-SOBP and SOBP distal edge groups than in Co-60 irradiated cells. No genes were found to be oppositely regulated by different radiation qualities. Radiosensitive patient samples had the strongest regulation of gene expression; irrespective of radiation type. CONCLUSIONS: Our findings indicate that the increased LET at the SOBP distal edge position did not generally lead to increased transcriptive response in primary fibroblast cultures. Inflammatory factors were generally less extensively upregulated by proton irradiation compared with Co-60 photon irradiation. These effects may possibly influence the development of normal tissue damage in patients treated with proton beam therapy. PMID- 28885068 TI - The phylogenetic relationships and molecular systematics of scincid lizards of the genus Heremites (Sauria, Scincidae) in the Middle East based on mtDNA sequences. AB - The taxonomic status of species included in the genus Heremites in Iran and Iraq is uncertain. Three of these species have been assigned to the genus based on morphology: Heremites auratus transcaucasica, H. vittatus, and H. septemtaeniatus. We examined the phylogenetic relationships and taxonomic status of the Iranian and Iraqi species of Heremites by performing phylogenetic analyses using mitochondrial DNA sequences (cytochrome b and 16S rRNA). Phylogenetic relationships and estimated genetic distances indicated that the Heremites populations of the area (Iran and Iraq) form five distinct clades. Three of these clades are found only in Iran, specifically in: (1) Fars and Hormozgan provinces; (2) Northeastern Khuzestan; and (3) Khorasan and Isfahan provinces. The fourth clade (H. septemtaeniatus) is found in west and Mahshahr in Iran as well as in eastern and northern parts of Iraq. The fifth clade, Heremites vittatus, is found in Iran and Iraq. We also confirm the absence of H. auratus in Iran and Iraq. It also indicated that H. vittatus is sister taxon to the other groups that our analyses estimate the divergence of this clade in the Middle Miocene (15.9 Mya). The clade containing the Fars-Hormozgan and Khuzestan populations diverged at the end of the Miocene (8.5 Mya). The Isfahan and Khorasan populations separated at the Pliocene (4.2 Mya) from the western Iranian group, the group in Mahshahr, Iran and the groups in northern and eastern Iraq. PMID- 28885069 TI - JQ1 reduces Epstein-Barr virus-associated lymphoproliferative disease in mice without sustained oncogene repression. PMID- 28885070 TI - The Nepean Belief Scale: preliminary reliability and validity in obsessive compulsive disorder. AB - OBJECTIVES: To examine the psychometric characteristics of the Nepean Belief Scale (NBS), a short clinician-administered scale that assesses the characteristics and intensity of beliefs in obsessive-compulsive disorder (OCD). METHODS: The NBS was administered by two clinicians to 27 subjects with OCD as part of a larger study that included a comprehensive assessment using the Yale Brown Obsessive Compulsive Symptom Scale (Y-BOCS), the Overvalued Ideas Scale (OVIS) and the Symptom Checklist 90-Revised (SCL-90R). Test-retest reliability of the NBS was assessed by administering the scale 5 days after initial administration. RESULTS: The 5-item NBS proved easy to use with an assessment time of less than 5 min. Its interrater reliability revealed 99.5% concordance, while the kappa for test-retest reliability was 0.98 (95% CI = 0.95-1.00). Cronbach alpha coefficient for internal consistency was 0.87. The NBS was found to have excellent convergent and discriminant validity. CONCLUSIONS: Preliminary results suggest that the NBS could be a useful shorter alternative to the currently more widely used instruments for assessing beliefs such as the OVIS and the Brown Assessment of Belief Scale. The NBS has clear instructions and definitions, excellent interrater reliability and convergent validity, and it more accurately measures belief-related insight. PMID- 28885071 TI - Genetic effects of released swimming crab (Portunus trituberculatus) on wild populations inferred from mitochondrial control region sequences. AB - Along the coast of Shandong Province in China, an extensive hatchery-release programme has been conducted for more than 10 years. However, no information has been reported concerning the long-term effects on the wild population resulting from the release of large numbers of juveniles in Portunus trituberculatus. In this study, sequence variation of swimming crab P. trituberculatus based on the mitochondrial control region was investigated for 946 swimming crabs at the releasing sites from 2012 to 2014. The result showed that the wild P. trituberculatus was characterized by high genetic diversity indices, and not significantly different from the previous study. Low FST values were estimated among the groups of different years and different sites, which suggested no genetic differentiation found in the wild population after the stock enhancement programme. Hence, the long-term extensive hatchery release programme has not affected the genetic structure of wild P. trituberculatus populations along the coast of Shandong Province. PMID- 28885073 TI - Corrigendum to: Fall-related healthcare use and costs in neurogenic orthostatic hypotension with Parkinson's disease. PMID- 28885072 TI - Programming characteristics of cochlear implants in children: effects of aetiology and age at implantation. AB - OBJECTIVE: We investigated effects of aetiology and age at implantation on changes in threshold (T) levels, comfortable (C) levels and dynamic range (DR) for cochlear implants (CIs) in children over the first five years of life. DESIGN: Information was collected at 6 months post-activation of CIs, and at 3 and 5 years of age. STUDY SAMPLE: One hundred and sixty-one children participating in the Longitudinal Outcomes of Children with Hearing Impairment (LOCHI) study. RESULTS: Children with neural and structural cochlear lesions had higher T-levels and C-levels as compared to those without these conditions. Parameter settings varied from manufacturer's defaults more often in the former than in the latter group. Investigation of the effect of age at implantation for children without neural and structural cochlear lesions showed that those implanted at <=12 months of age had higher T-levels and narrower DR at 6 months post-activation, as compared to the later-implanted group. For both early- and later-implanted groups, the C-levels at 6 months post-activation were lower than those at age 3 and 5 years. There were no significant differences in T-levels, C levels, or DR between age 3 and 5 years. CONCLUSIONS: Aetiology and age at implantation had significant effects on T-levels and C-levels. PMID- 28885074 TI - Clinical risks of St John's Wort (Hypericum perforatum) co-administration. AB - INTRODUCTION: St. John's wort (SJW) is a common medicinal herb used for the treatment of mild to moderate depression. Hyperforin, one of the chief components of SJW, plays an important role in the induction of cytochrome P450 enzymes (CYP) and P-glycoprotein transporter (P-gp), and therefore, affects the pharmacokinetics of various drugs. There are several clinical studies demonstrating the interaction of SJW with the metabolism of conventional drugs which may cause life-threatening events. Areas covered: This review focuses on human studies that have evaluated pharmacokinetic alterations of conventional drugs in concomitant use with different SJW preparations. Expert opinion: SJW preparations have demonstrated clinically important interactions with several classes of conventional drugs such as immunosuppressants, anticancer agents, cardiovascular drugs, oral contraceptives, and lipid lowering agents that caused life-threatening events in several cases. The patient information label on the SJW products should provide enough information regarding the possible risk of interaction. Hyperforin seems to be the major ingredient responsible for CYP and P-gp inducing activity of SJW; thus, hyperforin-free products may be future candidates to decrease SJW's drug interactions. PMID- 28885075 TI - CompNanoTox2015: novel perspectives from a European conference on computational nanotoxicology on predictive nanotoxicology. AB - A first European Conference on Computational Nanotoxicology, CompNanoTox, was held in November 2015 in Benahavis, Spain with the objectives to disseminate and integrate results from the European modeling and database projects (NanoPUZZLES, ModENPTox, PreNanoTox, MembraneNanoPart, MODERN, eNanoMapper and EU COST TD1204 MODENA) as well as to create synergies within the European NanoSafety Cluster. This conference was supported by the COST Action TD1204 MODENA on developing computational methods for toxicological risk assessment of engineered nanoparticles and provided a unique opportunity for cross fertilization among complementary disciplines. The efforts to develop and validate computational models crucially depend on high quality experimental data and relevant assays which will be the basis to identify relevant descriptors. The ambitious overarching goal of this conference was to promote predictive nanotoxicology, which can only be achieved by a close collaboration between the computational scientists (e.g. database experts, modeling experts for structure, (eco) toxicological effects, performance and interaction of nanomaterials) and experimentalists from different areas (in particular toxicologists, biologists, chemists and material scientists, among others). The main outcome and new perspectives of this conference are summarized here. PMID- 28885076 TI - Late mucosal ulcers in dose-escalated adaptive dose-painting treatments for head and-neck cancer. AB - BACKGROUND: To identify predictive factors for the development of late grade 4 mucosal ulcers in adaptive dose-escalated treatments for head-and-neck cancer. MATERIAL AND METHODS: Patient data of four dose-escalated three-phase adaptive dose-painting by numbers (DPBN) clinical trials were analyzed in this study. Correlations between the development of late grade 4 ulcers and factors related with the treatment, disease characteristics and the patient were investigated. Dosimetrical thresholds were searched among the highest doses received by 1.75 cm3 (D1.75cc) of the primary gross tumor volume (GTVT) and the corresponding normalized isoeffective dose (NID21.75cc, with a reference dose of 2Gy/fraction and alpha/beta of 3 Gy). RESULTS: From 39 studied patients, nine developed late grade 4 mucosal ulcers. The continuation to either smoke or drink alcohol after therapy was the factor that showed a strong (eight out of nine patients) association with the occurrence of grade 4 ulcers. Six of the patients who continued to smoke or/and drink had D1.75cc and NID21.75cc above 84 Gy and 95.5 Gy, respectively. Seven of the patients with grade 4 had the dose levels above these thresholds, but even if the D1.75cc threshold was significant in the prediction of late grade 4 ulcers, it could not be considered as the only contributing factor. CONCLUSIONS: The search for patterns provided strong reasons to apply a dosimetrical threshold for the peak-dose volume of 1.75 cm3 as a preventive measure for late grade 4 mucosal ulcers. Also, patients that continue to smoke or drink alcohol after therapy have increased risk to develop late mucosal ulcers. PMID- 28885077 TI - Innate immunity may play a role in growth and relapse of chordoid meningioma. AB - Chordoid meningioma (CM) is a rare subtype of meningioma, which represents only 0.5% of all meningiomas. It is classified as Grade II according to the World Health Organization classification because of its tendency to relapse. Pathological and clinical characteristics have been studied in order to forecast the future evolution of the lesions. However, information about infiltration of macrophagic elements and mast cells is very scarce. The authors analyzed the immunohistochemical patterns of three cases and a relapse of CM, in order to verify whether infiltrating macrophages are in a polarized state and what would be the proportion between such elements and mastocytes. Results suggest that macrophages in CMs are mainly in a non-polarized or M2 state and their abundance might be associated with a major potential of relapse; additionally, there is an inverse correlation between the number of mast cells and macrophages. Further studies are requested in order to confirm these intriguing data. PMID- 28885078 TI - The law of unintended consequences: current design challenges in inferior vena cava filters. AB - INTRODUCTION: Venous thromboembolic disease (VTD) encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) is a commonly encountered condition with potentially fatal sequelae. When unable to be adequately anticoagulated, patients require a mechanical means to prevent PE. This review discusses the history of inferior vena cava interruption and the development of inferior vena cava filters (IVCF). Areas covered: Milestone innovations in the mechanical treatment of VTD, their successes and shortcomings are discussed. The unforeseen complications that have occurred with implantation of IVCF have a profound impact on the present utilization of retrievable filters. Particular attention is dedicated to the evidence for safe and effective use of IVCF and the challenges presented to further improvement of these technologies. Expert commentary: While evidence suggests that IVCF are effective in preventing PE, the recent 'de volution' from permanent to retrievable design has unleashed an epidemic device related complications. Retrievable filter design is reliant on a 'Goldilocks' premise: make the device stable (so it doesn't migrate), but not too stable (so you can still retrieve it). Efforts must be aimed at optimizing utilization using decision support tools, meticulous follow up after deployment, and conversion from retrievable to permanent devices if the patient requires lifelong mechanical prophylaxis. PMID- 28885079 TI - A review of renal disease in children with HIV infection. AB - Human immunodeficiency virus (HIV) infection continues to be a leading cause of morbidity and mortality. HIV-infected individuals are now surviving for a relatively longer period and this is because of easy accessibility to antiretroviral therapy these days. As a result, chronic disease-related complications are now being recognized more often. Kidney disease in HIV-infected children can vary from glomerular to tubular-interstitial involvement. We searched the database to identify various kidney diseases seen in HIV-infected children. We describe the epidemiology, pathogenesis, pathology, clinical and laboratory manifestations, management and outcome of commonly seen kidney disease in HIV-infected children. We also provide a brief overview of toxicity of antiretroviral drugs seen in HIV-infected children. Kidney involvement in HIV infected children may arise because of HIV infection per se, opportunistic infections, immune mediated injury and drug toxicity. HIV-associated nephropathy is perhaps the most common and most severe form of kidney disease. Proteinuria may be a cost-effective screening test in the long-term management of HIV infected children, however, there are no definite recommendations for the same. Other important renal diseases are HIV immune complex kidney disease, thrombotic microangiopathy, interstitial nephritis and vasculitis. PMID- 28885080 TI - Survival of localized NSCLC patients without active treatment or treated with SBRT. AB - BACKGROUND: Little information on the natural history of patients with localized NSCLC is available since many of the studies covering the subject lack information on pathological confirmation, staging procedures and comorbidity. No randomized studies have compared SBRT with no treatment for patients with localized NSCLC. The purpose of this study was to evaluate whether SBRT has influence on overall survival for patients with localized NSCLC and investigate the effect of baseline ventilatory lung function on overall survival. MATERIAL AND METHODS: From 2007 to 2013, 136 patients treated with SBRT at Odense University Hospital were prospectively recorded. The thoracic SBRT consisted of three fractions of 15-22 Gy delivered in 9 days. For comparison, a national group of 73 untreated patients in the same time period was extracted from the Danish Lung Cancer Registry. All patients had histologically/cytologically proven NSCLC T1-2N0M0 with a tumour diameter <=5 cm. RESULTS: The 5-year relative survival was 44% versus 7% for the SBRT and untreated groups, respectively. In a propensity score matched comparison the median overall survival was 47 months versus 11 months for the SBRT and untreated groups, respectively (p < .05). On multivariate analysis, SBRT was significantly associated with improved prognosis while ECOG performance status 2+ and tumour diameter >=3 cm significantly predicted poorer prognosis. Severe to very severe reduction of forced expiratory volume in one second (FEV1) did not predict poorer survival for the SBRT treated patients with localized NSCLC. CONCLUSIONS: SBRT offers more favourable survival than no treatment for patients with localized NSCLC. Performance status of 0-1, tumour diameter less than 3 cm and SBRT predicted improved survival. SBRT should not be withheld for patients with localized NSCLC based on poor ventilatory lung function. PMID- 28885081 TI - The Denominator: Evolving the Electronic Medical Record To Discover Who Needs Palliative Care. PMID- 28885082 TI - Human Papillomavirus Testing by Veterans Administration Women's Health Providers: Are They Adhering to Guidelines? AB - BACKGROUND: Evidence-based guidelines have been created by professional societies, including the United States Preventive Services Task Force (USPSTF) and American Society for Colposcopy and Cervical Pathology (ASCCP), for use of human papillomavirus (HPV) cotesting in cervical cancer screening. We investigated whether Veterans Health Administration (VA) providers at one VA medical center follow these guidelines. MATERIALS AND METHODS: Retrospective chart review of women aged 21-65 who had an HPV test ordered with pap testing in fiscal year 2014 at one Veterans Administration (VA) medical center to evaluate concordance of HPV ordering with screening (USPSTF) and management (ASCCP) guidelines. We collected data on patient characteristics and gynecologic history and documented the reason, if given, for HPV testing. RESULTS: Of the 210 eligible HPV tests evaluated, 142 tests (68%) were determined to be guideline discordant. Of the 142 guideline-discordant tests, 90 had no documented reason for HPV testing in the chart. Site of care was not significant. CONCLUSIONS: This study demonstrates potential overuse of HPV testing among women's health providers at one VA medical center. This may indicate that VA providers lack an understanding of HPV cotesting guidelines. Further studies are needed to characterize VA provider adherence to HPV testing guidelines nationally. Implementation of educational interventions and decision aids may improve VA providers' adherence to guidelines. PMID- 28885083 TI - Risk factors for progressive neuromuscular scoliosis requiring posterior spinal fusion after selective dorsal rhizotomy. AB - OBJECTIVE Selective dorsal rhizotomy (SDR) via limited laminectomy is an effective treatment of lower-extremity spasticity in the pediatric population. Children with spasticity are also at risk for neuromuscular scoliosis; however, specific risk factors for progressive spinal deformity requiring posterior spinal fusion (PSF) after SDR are unknown. The authors' goal was to identify potential risk factors. METHODS The authors performed a retrospective cohort study of patients who underwent SDR via limited laminectomy between 2003 and 2014 and who had at least 1 year of follow-up. They analyzed demographic, clinical, and radiographic variables to elucidate risk factors for progressive neuromuscular scoliosis. The primary outcome was need for PSF. RESULTS One hundred thirty-four patients underwent SDR and had at least 12 months of follow-up (mean 65 months); 48 patients (36%) had detailed pre- and postoperative radiographic data available. The mean age at surgery was 10 years (SD 5.1 years). Eighty-four patients (63%) were ambulatory before SDR, 109 (82%) underwent a single-level laminectomy, and a mean of 53% of the dorsal rootlets from L-1 to S-1 were sectioned. Fifteen patients (11.2%) subsequently required PSF for progressive deformity. Nonambulatory status (p < 0.001) and a preoperative Cobb angle > 30 degrees (p = 0.003) were significantly associated with PSF on univariate analysis, but no statistically significant correlation was found with any clinical or radiographic variable and PSF after SDR on multivariate regression analysis. CONCLUSIONS Patients with preoperative nonambulatory status and Cobb angle > 30 degrees may be at risk for progressive spinal deformity requiring PSF after SDR. These are well-known risk factors for progressive deformity in children with spasticity in general. Although our analysis suggests SDR via limited laminectomy may not significantly accelerate the development of neuromuscular scoliosis, further case-control studies are critical to elucidate the impact of SDR on spinal deformity. PMID- 28885084 TI - Influence of gray level discretization on radiomic feature stability for different CT scanners, tube currents and slice thicknesses: a comprehensive phantom study. AB - BACKGROUND: Radiomic analyses of CT images provide prognostic information that can potentially be used for personalized treatment. However, heterogeneity of acquisition- and reconstruction protocols influences robustness of radiomic analyses. The aim of this study was to investigate the influence of different CT scanners, slice thicknesses, exposures and gray-level discretization on radiomic feature values and their stability. MATERIAL AND METHODS: A texture phantom with ten different inserts was scanned on nine different CT-scanners with varying tube currents. Scans were reconstructed with 1.5 mm or 3 mm slice thickness. Image pre processing comprised gray-level discretization in ten different bin widths ranging from 5 to 50 HU and different resampling methods (i.e., linear, cubic and nearest neighbor interpolation to 1 * 1 * 3 mm3 voxels) were investigated. Subsequently, 114 textural radiomic features were extracted from a 2.1 cm3 sphere in the center of each insert. The influence of slice thickness, exposure and bin width on feature values was investigated. Feature stability was assessed by calculating the concordance correlation coefficient (CCC) in a test-retest setting and for different combinations of scanners, tube currents and slice thicknesses. RESULTS: Bin width influenced feature values, but this only had a marginal effect on the total number of stable features (CCC > 0.85) when comparing different scanners, slice thicknesses or exposures. Most radiomic features were affected by slice thickness, but this effect could be reduced by resampling the CT-images before feature extraction. Statistics feature 'energy' was the most dependent on slice thickness. No clear correlation between feature values and exposures was observed. CONCLUSIONS: CT-scanner, slice thickness and bin width affected radiomic feature values, whereas no effect of exposure was observed. Optimization of gray-level discretization to potentially improve prognostic value can be performed without compromising feature stability. Resampling images prior to feature extraction decreases the variability of radiomic features. PMID- 28885085 TI - Targeting the central projection of the dural trigeminovascular system for migraine prophylaxis. AB - Migraine abortives likely target both peripheral-dural and central trigeminovascular mechanisms in mediating their therapeutic effects. However, in preclinical assays, many migraine preventives have little success at inhibiting similar trigeminovascular-mediated peripheral changes within the dural microenvironment. In addition, their effects on central trigeminovascular neuronal responses are largely unknown. Using a validated preclinical model of acute dural-intracranial (migraine-like) head pain, using Sprague Dawley rats, we tested whether migraine preventives suppress ongoing firing of central trigeminocervical neurons, and evoked responses to cranial neurovascular activation. Flunarizine, sodium valproate, propranolol, and amitriptyline, all dose-dependently inhibited ongoing spontaneous firing of dural trigeminovascular neurons, and differentially affected neuronal responses to intracranial-dural and extracranial-cutaneous somatosensory stimulation. Lamotrigine, only effective in the treatment of migraine aura, did not affect responses. These data provide a mechanistic rationale for the clinical effects of migraine preventives in the treatment of migraine, via the modulation of dural-responsive central trigeminovascular neurons. Also, given their limited effect on peripheral dural vasdilatory responses, these data also suggest that migraine preventives specifically target central, rather than peripheral, components of trigeminal neurovascular mechanisms involved in migraine pathophysiology, to mediate their preventive action. Finally, these data further validate this preclinical model of central trigeminovascular activation to screen migraine preventives. PMID- 28885087 TI - Encephalocele development from a congenital meningocele: case report. AB - A fetal MRI study obtained at 21 weeks' gestation revealed a suboccipital meningocele without hydrocephalus. One day after term birth, MRI demonstrated an acquired cerebellar encephalocele, and MRI obtained 5 months later showed progressive enlargement of the encephalocele, still without obvious hydrocephalus. The patient underwent an operation in which an external ventricular drain was placed, the grossly normal cerebellum was reduced into the posterior fossa without resection, and the dural defect was closed. The drain was weaned out over 5 days, and no ventriculoperitoneal shunt was placed. Postoperative MR images revealed normal cerebellum and no hydrocephalus. The patient is developmentally normal. Meningocele and encephalocele are embryologically distinct. An acquired encephalocele could develop from hydrocephalus (which was not present in this case), or secondary to the lower resistance to expansion into the dural defect of the meningocele relative to the resistance to expansion of the fetal skull. The cerebellar tissue was normal in this case, and was thus preserved. The developmental prognosis is excellent. To the authors' knowledge, this is the first reported case of this occurrence. It is important to differentiate between congenital and acquired encephalocele etiologies, because resection of the cerebellar tissue in an acquired encephalocele (as is routinely done in cases of congenital encephalocele) would be expected to result in neurological deficits. PMID- 28885086 TI - Enlarging pediatric ectopic Rathke's cleft cyst in the prepontine cistern: case report. AB - Rathke's cleft cyst is a cystic disease that occurs in the sella turcica or, occasionally, in the suprasellar area. An ectopic Rathke's cleft cyst is extremely rare, and its nature is less well understood. The authors report the case of a 14-year-old girl who presented with a growing cystic lesion in the prepontine cistern, immediately behind the dorsum sellae. Preoperative imaging and intraoperative investigation showed part of the cyst wall continuing into the dorsum sellae, to the pituitary gland. The cisternal portion of the cyst wall was totally resected via a right subtemporal approach. Histopathological examination of the cyst wall showed a monolayer of ciliated cells, identical to those of Rathke's cleft cyst. To the best of the authors' knowledge, this represents the first pediatric case of Rathke's cleft cyst occurring in the prepontine cistern. PMID- 28885088 TI - Progression of trunk imbalance in adolescent idiopathic scoliosis with a thoracolumbar/lumbar curve: is it predictable at the initial visit? AB - OBJECTIVE Progression of trunk imbalance is an important finding during follow-up of patients with adolescent idiopathic scoliosis (AIS). Nevertheless, no factors that predict progression of trunk imbalance have been identified. The purpose of this study was to identify parameters that predict progression of trunk imbalance in cases of AIS with a structural thoracolumbar/lumbar (TL/L) curve. METHODS This study included 105 patients with AIS and a structural TL/L curve who were followed up at an outpatient clinic. Patients with trunk imbalance (trunk shift >= 20 mm) at the initial visit were excluded. All patients were followed up for more than 2 years. Patients were divided into the following groups according to progression of trunk imbalance: 1) Group P, trunk shift >= 20 mm at the final visit and degree of progression >= 10 mm; and 2) Group NP, trunk shift < 20 mm at the final visit or degree of progression < 10 mm. Radiological parameters included Cobb angle, upper end vertebrae and lower end vertebrae (LEV), LEV tilt, disc wedge angle between LEV and LEV+1, trunk shift, apical vertebral translation, and apical vertebral rotation (AVR). Each parameter was compared between groups. Radiological parameters were assessed at every visit using whole spine standing anteroposterior radiographs. RESULTS Among the 105 patients examined, 13 showed trunk imbalance with progression >= 10 mm at the final visit (Group P). Multivariate logistic regression analysis identified a lower Risser grade (p = 0.002) and a greater initial AVR (p = 0.020) as predictors of progressive trunk imbalance. A change in LEV tilt during follow-up was associated with trunk imbalance (p = 0.001). CONCLUSIONS Risser grade and AVR measured at the initial visit may predict progression of trunk imbalance. Surgeons should consider the risk of progressive trunk imbalance if patients show skeletal immaturity and a greater AVR at the initial visit. PMID- 28885089 TI - Non-Suicidal Self-Injury Elevates Suicide Risk among United States Military Personnel with Lifetime Attempted Suicide. AB - Military psychiatric inpatients with and without a lifetime history of non suicidal self-injury (NSSI), combined with a history of at least one suicide attempt, were compared on suicide ideation severity, number of suicide attempts, and Interpersonal-Psychological Theory of Suicide variables. Data were derived from baseline assessments performed in a psychotherapy randomized controlled trial. Lifetime history of NSSI and lifetime number of suicide attempts were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS; Posner et al., 2011 ). Individuals with versus without a combined lifetime history of attempted suicide and NSSI showed significant elevations on thwarted belongingness and acquired capability for suicide. No significant between-group differences were found on perceived burdensomeness, frequency, duration, and controllability of suicide ideation, or number of lifetime suicide attempts. A history of NSSI, above and beyond attempted suicide, appears to increase service members' social alienation and acquired capability for suicide. PMID- 28885090 TI - Difference in target definition using three different methods to include respiratory motion in radiotherapy of lung cancer. AB - INTRODUCTION: Minimizing the planning target volume (PTV) while ensuring sufficient target coverage during the entire respiratory cycle is essential for free-breathing radiotherapy of lung cancer. Different methods are used to incorporate the respiratory motion into the PTV. MATERIAL AND METHODS: Fifteen patients were analyzed. Respiration can be included in the target delineation process creating a respiratory GTV, denoted iGTV. Alternatively, the respiratory amplitude (A) can be measured based on the 4D-CT and A can be incorporated in the margin expansion. The GTV expanded by A yielded GTV + resp, which was compared to iGTV in terms of overlap. Three methods for PTV generation were compared. PTVdel (delineated iGTV expanded to CTV plus PTV margin), PTVsigma (GTV expanded to CTV and A was included as a random uncertainty in the CTV to PTV margin) and PTV? (GTV expanded to CTV, succeeded by CTV linear expansion by A to CTV + resp, which was finally expanded to PTV?). RESULTS: Deformation of tumor and lymph nodes during respiration resulted in volume changes between the respiratory phases. The overlap between iGTV and GTV + resp showed that on average 7% of iGTV was outside the GTV + resp implying that GTV + resp did not capture the tumor during the full deformable respiration cycle. A comparison of the PTV volumes showed that PTVsigma was smallest and PTVSigma largest for all patients. PTVsigma was in mean 14% (31 cm3) smaller than PTVdel, while PTVdel was 7% (20 cm3) smaller than PTVSigma. CONCLUSIONS: PTVsigma yields the smallest volumes but does not ensure coverage of tumor during the full respiratory motion due to tumor deformation. Incorporating the respiratory motion in the delineation (PTVdel) takes into account the entire respiratory cycle including deformation, but at the cost, however, of larger treatment volumes. PTVSigma should not be used, since it incorporates the disadvantages of both PTVdel and PTVsigma. PMID- 28885091 TI - No Occultation in the International Association for Hospice and Palliative Care Position Statement on Palliative Care and Assisted Suicide. PMID- 28885092 TI - Infant Discovery Learning and Lower Extremity Coordination: Influence of Prematurity. AB - AIMS: Preterm infants at increased risk for neurodevelopmental disabilities, including cerebral palsy, demonstrate reduced selective leg joint coordination. Full-term infants demonstrate more selective hip-knee coordination when specific leg actions are reinforced using an overhead infant mobile. The purpose of this pilot study was to determine the ability of preterm infants to: (1) perform and learn through discovery, the contingency between leg action and mobile activation, and (2) demonstrate more selective hip-knee coordination when leg actions are reinforced with mobile activation. METHODS: At both 3 and 4-months corrected age, ten infants born very preterm and with very low birth weight participated in 2 sessions of mobile reinforcement on consecutive days. RESULTS: The preterm group at 4-months, but not 3-months, learned the contingency between leg action and mobile activation. Preterm infants at 4-months were separated into those that learned (n = 6) and did not learn (n = 4) the contingency. As a group, preterm infants at 4-months who learned the contingency, did not demonstrate more selective hip-knee coordination when interacting with the mobile on Day 2 as compared to spontaneous kicking on Day 1. CONCLUSIONS: Preterm infants, as compared to full-term infants, may have difficulty producing more selective hip knee coordination during task-specific leg action. PMID- 28885093 TI - Heart rate recovery time in metabolically healthy and metabolically unhealthy obese children. AB - BACKGROUND: Autonomic dysfunction is an emerging non-traditional cardiovascular risk factor that correlates with obesity, components of metabolic syndrome, as well as cardiorespiratory fitness. As a simple and validated index of autonomic balance, heart rate recovery (HRR) has been reported as a useful biomarker for predicting cardiovascular morbidity and mortality. OBJECTIVES: The aim of this study was to compare HRR in metabolically healthy vs. metabolically unhealthy obese children. METHODS: A total of 56 obese children of whom 31 had metabolic syndrome were examined. All the participants underwent the multistage submaximal cycle ergometer test and HRR was determined one minute after the test. RESULTS: The HRR was significantly lower (18.9 +/- 3.7) in a group of metabolically unhealthy obese children compared to metabolically healthy obese children (24 +/- 4.1) p < 0.001. Logistic regression analysis showed that reduction in HRR was also influenced by higher BMI. CONCLUSION: Our findings implicate the presence of the autonomic dysfunction as reflected by impaired heart rate recovery (HRR) in obese children with metabolic syndrome. PMID- 28885094 TI - Frontal and occipital horn ratio is associated with multifocal intraparenchymal hemorrhages in neonatal shunted hydrocephalus. AB - OBJECTIVE Placement of a cerebrospinal fluid diversion device (i.e., shunt) is a routine pediatric neurosurgical procedure, often performed in the first weeks of life for treatment of congenital hydrocephalus. In the postoperative period, shunt placement may be complicated by subdural, catheter tract, parenchymal, and intraventricular hemorrhages. The authors observed a subset of infants and neonates who developed multifocal intraparenchymal hemorrhages (MIPH) following shunt placement and sought to determine any predisposing perioperative variables. METHODS A retrospective review of the electronic medical record at a tertiary care children's hospital was performed for the period 1998-2015. Inclusion criteria consisted of shunt placement, age < 30 days, and available pre- and postoperative brain imaging. The following data were collected and analyzed for each case: ventricular size ratios, laboratory values, clinical presentation, shunt and valve type, and operative timing and approach. RESULTS A total of 121 neonates met the inclusion criteria for the study, and 11 patients (9.1%) had MIPH following shunt placement. The preoperative frontal and occipital horn ratio (FOR) was significantly higher in the patients with MIPH than in those without (0.65 vs 0.57, p < 0.001). The change in FOR (?FOR) after shunt placement was significantly greater in the MIPH group (0.14 vs 0.08, p = 0.04). Among neonates who developed MIPH, aqueductal stenosis was the most common etiology (45%). The type of shunt valve was associated with incidence of MIPH (p < 0.001). Preoperative clinical parameters, including head circumference, bulging fontanelle, and coagulopathy, were not significantly associated with development of MIPH. CONCLUSIONS MIPH represents an underrecognized complication of neonatal shunted hydrocephalus. Markers of severity of ventriculomegaly (FOR) and ventricular response to CSF diversion (?FOR) were significantly associated with occurrence of MIPH. Choice of shunt and etiology of hydrocephalus were also significantly associated with MIPH. After adjusting for corrected age, etiology of hydrocephalus, and shunt setting, the authors found that ?FOR after shunting was still associated with MIPH. A prospective study of MIPH prevention strategies and assessment of possible implications for patient outcomes is needed. PMID- 28885095 TI - Spatial rectal dose/volume metrics predict patient-reported gastro-intestinal symptoms after radiotherapy for prostate cancer. AB - BACKGROUND: Gastro-intestinal (GI) toxicity after radiotherapy (RT) for prostate cancer reduces patient's quality of life. In this study, we explored associations between spatial rectal dose/volume metrics and patient-reported GI symptoms after RT for localized prostate cancer, and compared these with those of dose surface/volume histogram (DSH/DVH) metrics. MATERIAL AND METHODS: Dose distributions and six GI symptoms (defecation urgency/emptying difficulties/fecal leakage, >=Grade 2, median follow-up: 3.6 y) were extracted for 200 patients treated with image-guided RT in 2005-2007. Three hundred and nine metrics assessed from 2D rectal dose maps or DSHs/DVHs were subject to 50-times iterated five-fold cross-validated univariate and multivariate logistic regression analysis (UVA, MVA). Performance of the most frequently selected MVA models was evaluated by the area under the receiving-operating characteristics curve (AUC). RESULTS: The AUC increased for dose-map compared to DSH/DVH-based models (mean SD: 0.64 +/- 0.03 vs. 0.61 +/- 0.01), and significant relations were found for six versus four symptoms. Defecation urgency and faecal leakage were explained by high doses at the central/upper and central areas, respectively; while emptying difficulties were explained by longitudinal extensions of intermediate doses. CONCLUSIONS: Predictability of patient-reported GI toxicity increased using spatial metrics compared to DSH/DVH metrics. Novel associations were particularly identified for emptying difficulties using both approaches in which intermediate doses were emphasized. PMID- 28885096 TI - Infant hydrocephalus in sub-Saharan Africa: the reality on the Tanzanian side of the lake. AB - OBJECTIVE Infant hydrocephalus is estimated to affect more than 100,000 new infants each year in sub-Saharan Africa (SSA). Bugando Medical Centre (BMC), a government-funded and patient cost-shared referral center, serves over 13 million people in the Lake and Western regions of Tanzania. The goals of this study were to characterize the infant population affected by hydrocephalus who presented to BMC and were treated with a ventriculoperitoneal shunt (VPS) to determine the rate of early complications associated with this surgical procedure and to assess its potential risk factors. METHODS Data were prospectively collected from all patients less than 1 year of age who, over a period of 7 months, were diagnosed with hydrocephalus and admitted to BMC for insertion of a primary VPS. Demographic data, maternal history, preoperative studies, surgical procedure, and surgical complications developing by the time of the first follow-up visit were analyzed. Risk factors associated with the surgical complications were determined. RESULTS During the 7-month study period, 125 infants eligible for the study were included in the analysis. Overall, 75% were younger than 6 months of age, and 56% were males. Only 7% of mothers had a gestational ultrasound, 98% did not receive preconception folic acid, and 25% delivered their child at home. In most patients with hydrocephalus the etiology was uncertain (56%), and other patients had postinfectious (22.4%) or myelomeningocele-associated (16%) hydrocephalus. Patients' mean head circumference on admission was 51.4 +/- 6.3 cm. Their median age at shunt surgery was 137 days, and 22.4% of the patients were operated on without having undergone radiological assessment. The majority of shunts were placed in a right parietooccipital location. Thirteen patients had undergone a previous intraventricular endoscopic procedure. Overall, at least one surgical complication was found in 33.6% of patients up to the first follow-up assessment (median follow-up time of 70 days); shunt infection was the most common complication. The postoperative mortality rate was 9%. The risk factors associated with early surgical complications were tumor-related etiology, larger head circumference, and postoperative hospital stays of greater duration. CONCLUSIONS In a region of the continent where most infant hydrocephalus cases had an uncertain etiology, most patients presented to the hospital in a late stage, with no prenatal diagnosis and with large head circumferences. Standard preoperative investigations were not uniformly performed, and the surgical complications, led by VPS infection, were disturbingly high. Younger patient age, previous endoscopic procedure, surgeon involved, and cranial location of the VPS had no statistical relation to the surgical complications. This study shows that the positive results previously reported by SSA mission hospitals, subspecialized in pediatric neurosurgery, are still not generalizable to every hospital in East Africa. To improve maternal and neonatal care in the Lake region of Tanzania, the development of a fluxogram to determine hydrocephalus etiology, a strict perioperative protocol for VPS insertion, and an increase in the number of endoscopic procedures are recommended to BMC. PMID- 28885097 TI - Predictors of a high defibrillation threshold test during routine ICD implantation. AB - BACKGROUND: There is growing evidence that routine defibrillation threshold (DFT) testing during implantable cardioverter defibrillator (ICD) implantation is not necessary. However a small group of patients might be at risk if no DFT testing is performed. METHODS: Patients with a new pectoral ICD implantation in our hospital between 2006 and 2014 were included in a retrospective registry. A clinical high DFT was defined as a safety margin <10 J of the maximal device output. Logistic regression for prediction of high DFT was performed using patient characteristics, clinical, echocardiographic and device-related parameters. RESULTS: DFT testing was performed in 788/864 (91.2%) procedures. In 76 (8.8%) patients no DFT testing was performed mainly due to atrial fibrillation, intra-cardiac thrombus, hemodynamic instability or logistical reasons. A high DFT was present in 44 (5.6%) patients. A QRS duration >=150 ms, a low left ventricular ejection fraction (LVEF <=25%), a severely dilated left ventricle >=60 mm and right sided pre-pectoral implantations were univariate predictors of a high DFT. Independent predictors of a high DFT were a LVEF <=25% (HR 2.195, 95%CI 1.085-4.443) and right sided pre-pectoral implantations (HR 3.135, 95% CI 1.186-8.287). CONCLUSIONS: A high DFT is still present in about 5% of patients and is more frequent in patients with a severely dilated left ventricle, a very low LVEF, right sided pre-pectoral implantation and wider QRS duration. It might be clinically important to continue DFT testing in these high risk patients. PMID- 28885098 TI - Rosuvastatin inhibits high glucose-stimulated upregulation of VCAM-1 via the MAPK signalling pathway in endothelial cells. AB - OBJECTIVE: The aim of this study is to investigate the molecular mechanisms and effect of rosuvastatin on adhesion molecule induction in human endothelial cells under high-glucose conditions (HG). METHODS AND RESULTS: The effects of rosuvastatin on vascular cell adhesion molecule (VCAM)-1 production and pERK phosphorylation were measured in HG-induced human umbilical vein endothelial cells (HUVECs) with inhibitors targeting the mitogen-activated protein kinase (MAPK) signal pathway. HG increased levels of VCAM-1. Treatment with rosuvastatin inhibited VCAM-1 expression in a concentration- and time-dependent manner. In addition, we investigated the effects of rosuvastatin on the extracellular signal regulated kinase (ERK) 1/2 signal pathway. Rosuvastatin completely inhibited HG induced phosphorylation of ERK. ERK/MAPK inhibitors completely prevented the VCAM 1 inhibition effect of rosuvastatin under HG condition. CONCLUSIONS: This study demonstrated that rosuvastatin suppresses HG-induced VCAM-1 production via the MAPK signalling pathway, playing a role in the suppression of atherosclerosis. PMID- 28885099 TI - Experimental design-based isotope-dilution SPME-GC/MS method development for the analysis of smoke flavouring products. AB - For the implementation of Regulation (EC) No 2065/2003 related to smoke flavourings used or intended for use in or on foods a method based on solid-phase micro extraction (SPME) GC/MS was developed for the characterisation of liquid smoke products. A statistically based experimental design (DoE) was used for method optimisation. The best general conditions to quantitatively analyse the liquid smoke compounds were obtained with a polydimethylsiloxane/divinylbenzene (PDMS/DVB) fibre, 60 degrees C extraction temperature, 30 min extraction time, 250 degrees C desorption temperature, 180 s desorption time, 15 s agitation time, and 250 rpm agitation speed. Under the optimised conditions, 119 wood pyrolysis products including furan/pyran derivatives, phenols, guaiacol, syringol, benzenediol, and their derivatives, cyclic ketones, and several other heterocyclic compounds were identified. The proposed method was repeatable (RSD% <5) and the calibration functions were linear for all compounds under study. Nine isotopically labelled internal standards were used for improving quantification of analytes by compensating matrix effects that might affect headspace equilibrium and extractability of compounds. The optimised isotope dilution SPME GC/MS based analytical method proved to be fit for purpose, allowing the rapid identification and quantification of volatile compounds in liquid smoke flavourings. PMID- 28885100 TI - Recent Suicide Attempts Across Multiple Social Identities Among Gay and Bisexual Men: An Intersectionality Analysis. AB - This study draws from intersectionality to describe variations in recent suicide attempts (RSA) among gay and bisexual men (GBM) across sociodemographics. Using survey data, logistic regression modeling explored RSA in two analytical stages: (1) the individual effects of each sociodemographic were measured; (2) two-way interaction terms between sociodemographics were tested and added to the models created in stage A. In stage A, only education and income achieved significance. In stage B, the study found that (a) education and income interacted significantly such that the odds of RSA increased for those with a lower income and a lower education; (b) sexual orientation and partnership status interacted, resulting in decreased odds among bisexual men in heterosexual partnerships; and (c) income and education interacted with geography; the effects of these variables were significant only among urban men. These findings suggest that GBM are at unequal risk of RSA according to intersecting sociodemographics. PMID- 28885101 TI - Association between the maximal distance of atrial septal protrusion and cryptogenic stroke. AB - Background and purpose Previous studies have suggested that atrial septal aneurysm is a potential risk factor for cerebral embolism. However, the association between the level of atrial septal protrusion and cerebral embolism is still unclear. The purpose of the present study was to assess the association between the maximal distance of atrial septal protrusion and cryptogenic stroke. Methods A total of 588 consecutive acute ischemic stroke patients (70 +/- 11 (mean +/- SD) years, 401 men) who underwent transesophageal echocardiography were enrolled. The maximal distance of atrial septal protrusion into the right or left atrium was measured. Atrial septal aneurysm was diagnosed when the maximal distance of atrial septal protrusion was >10 mm. Cryptogenic stroke was defined as non-lacunar ischemic stroke without >50% proximal artery stenosis or occlusion, cardioembolic sources, >=4 mm atherosclerotic plaques in the aortic arch, or carotid or vertebral artery dissection. Results The rate of cryptogenic stroke increased with the increasing maximal distance of atrial septal protrusion. The maximal distance of atrial septal protrusion (multivariate adjusted odds ratio (OR) per 1 mm, 1.14; 95% confidence interval (CI), 1.04-1.24; P = 0.003) and atrial septal aneurysm (multivariate-adjusted OR, 4.32; 95% CI, 1.22-20.39; P = 0.022) was independently associated with cryptogenic stroke. Conclusions The maximal distance of atrial septal protrusion was independently associated with cryptogenic stroke. PMID- 28885102 TI - Home programs for upper extremity recovery post-stroke: a survey of occupational therapy practitioners. AB - BACKGROUND: Upper extremity hemiparesis is an impairment post-stroke that impacts quality of life. Home programs are an intervention strategy used by many occupational therapists to support continued motor recovery post-stroke, yet little is known about how these programs are designed and implemented. OBJECTIVES: The purpose of this study was to describe how occupational therapy practitioners approach this task and specifically what strategies they use to support adherence and what types of technology are most commonly used. METHODS: An on-line survey methodology was used. Participants were recruited through multiple sources including state associations and occupational therapy educational program directors. RESULTS: A total of 73 occupational therapy practitioners submitted complete surveys. It was found that majority of occupational therapy practitioners in the sample (n = 53) reported creating home programs focused on upper extremity motor recovery more than 80% of the time. Range of motion and strengthening were reported as being in the top three most commonly used interventions by more than half the sample, however incorporating clients' goals and interests were reported most often as strategies to create meaning in the home program. Respondents also reported limited incorporation of technology and strategies to support adherence. Personal motivation was reported by occupational therapy practitioners to be a key moderator of adherence to a home program. CONCLUSIONS: Occupational therapy practitioners often provide home programs for individuals post-stroke focusing on upper extremity function. Future research that aims to understand stakeholders' perspectives on home programs and determine effective strategies for ensuring adherence is needed. PMID- 28885103 TI - LGBQ-Specific Elderly Housing as a "Sparkling Sanctuary": Boundary Work on LGBQ Identity and Community in Relationship to Potential LGBQ-Specific Elderly Housing in Sweden. AB - This study explored how boundaries in relationship to community and identity were created and negotiated among lesbian, gay, bisexual, and queer (LGBQ) people within the framework of picturing LGBQ-specific elderly housing as a housing alternative in older age, by applying focus group methodology. "An island as a sparkling sanctuary" was identified as a metaphor for how symbolic resources defining the LGBQ community can be manifested in LGBQ-specific qualities of elderly housing. The boundary work underlying this manifestation included elaborations on the dilemma between exclusiveness and normality. The findings illustrate further how symbolic resources and collective identities were developed through dialectic interplay between internal and external definitions. Further, the findings show how boundary work generated shared feelings of similarity and group membership. The associated symbolic and social resources not only served to deal with difficult situations but also to manifest LGBQ identity and sense of community as a "gold medal." PMID- 28885104 TI - Not Threat, But Threatening: Potential Causes and Consequences of Gay Innumeracy. AB - Existing literature on numeracy suggests that people are likely to perceive outgroups as larger if the group is perceived as threatening. However, some studies also suggest that numeracy is a function of wishful thinking or even a lack of political knowledge. We engage the literature on numeracy of the gay and lesbian population by employing data from 1977 and 2013 surveys of American adults. We examine the factors that are associated with estimating the gay population. Next we explore how innumeracy may shape attitudes about homosexuality and gay rights. Our findings suggest that estimates of the gay population are partly a function of knowledge, and perhaps wishful thinking, but not threat. However, our analysis also reveals that higher estimates of the gay population are associated with less support for gay civil rights in the current era and were not a factor in the past. PMID- 28885105 TI - Canadian Stroke Congress Abstracts 2017; Calgary, Alberta September 9-11, 2017. PMID- 28885107 TI - 2017 Canadian Stroke Congress Abstracts. PMID- 28885109 TI - Late Breaking Abstracts. PMID- 28885108 TI - Other Additional Abstracts. PMID- 28885110 TI - Corrigenda. PMID- 28885111 TI - Effects of different montages of transcranial direct current stimulation on the risk of falls and lower limb function after stroke. AB - BACKGROUND: Stroke is associated with high rates of falling and severe impairment of lower limb in patients who survive. OBJECTIVE: The aim of this study was to analyze the effectiveness of different montages of transcranial direct current stimulation (tDCS) on reducing falls and on lower limb function after acute stroke. METHODS: Sixty participants with acute stroke were randomly allocated into four groups with different electrode's setups: anodal, cathodal, bilateral and sham tDCS. Each patient received 10 stimulation sessions (five consecutive days for two weeks). Four Square Step Test, Occurrence of Falling Index, Overall Stability Index, Falls Efficacy Scale - International, Berg Balance Scale, Six minute walk test and Sit to Stand Test were measured at baseline, post-treatment, and at one- and three-month follow-up. RESULTS: At baseline, no differences between the groups in terms of clinical and demographic characteristics were found. However, after treatment and during follow up, all the groups that received active stimulation showed greater reduction in the risk of falls and improved performance of the lower limb's motor skills when compared to the sham group. No significant differences were found between the three types of active montages in relation to the risk of falling. In relation to lower limb function, bilateral stimulation provided a higher improvement when compared to anodal and cathodal tDCS. CONCLUSIONS: This is the first trial with different setups of tDCS on acute stroke patients. tDCS presents as an effective treatment strategy in reducing the risk of falls and improving lower limb function after a stroke. ClinicalTrials.gov (NCT 02422173). PMID- 28885112 TI - Management of failing bioprosthesis in elderly patients who have undergone transcatheter aortic valve replacement. AB - INTRODUCTION: Transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of symptomatic aortic stenosis. The number of TAVR procedures is expected to increase exponentially in the next decade. Therefore, patients will inevitably present with signs and symptoms attributable to TAVR bioprosthesis failure many years after an acutely successful procedure. Their management will become increasing important moving forward. Areas covered: The aim of this article is to review the causes of bioprosthesis failure and outline optimal management strategies in elderly patients. The principal causes outlined are valve degeneration, endocarditis, thrombosis, migration and compression. Expert commentary: A key question for TAVR moving forward is its efficacy with regards to long-term durability. The 5-year durability of TAVR prosthesis is excellent but comprehensive longer-term follow-up is awaited. Other mechanisms of failure include: TAVR endocarditis, diagnosis can be challenging and it is essential to have high clinical suspicion; TAVR migration, a rare complication that can be treated with second TAVR prosthesis; TAVR thrombosis, either subclinical identified on computed tomography or obstructive symptomatic thrombosis identified on echocardiogram, both types are effectively treated by formal anticoagulation; TAVR compression, a phenomenon observed in post-mortem examination following cardiopulmonary resuscitation, treatment options include balloon post-dilatation and second TAVR prosthesis implantation. PMID- 28885113 TI - A 3D printed surgical analogue to reduce donor tooth trauma during autotransplantation. AB - Surgical trauma and prolonged extra-alveolar exposure of the donor tooth's root sheath are both complicating factors during tooth autotransplantation surgery. This case report describes a 12-year-old female patient who underwent surgical transplantation of a maxillary second premolar to a central incisor site. A three dimensional printed analogue of the donor tooth was fabricated from a cone beam (CBCT) scan of the tooth in order to minimise the extra-oral (exposure) time and frequency of trial insertions of the donor tooth into the recipient socket. The laboratory and clinical aspects of this novel technique are described. PMID- 28885114 TI - Clinical predictors of tissue necrosis following rattlesnake envenomation. AB - BACKGROUND: Rattlesnake envenomation (RSE) causes edema, hemotoxicity and tissue necrosis. Necrosis may result in permanent disability. OBJECTIVE: To study patient-related factors associated with tissue necrosis after Crotalus envenomation. METHODS: Prospective cohort study of patients admitted to the Medical Toxicology service with diagnosis of RSE between April 2011 and November 2014. Inclusion criteria were age >=18 years and upper extremity (UE) envenomation site. Primary outcome was tissue necrosis, including dermonecrosis, manifesting as bullae. Secondary outcome was amputation. RESULTS: 77 subjects, age 18 to 88 years, met inclusion criteria. Rattlesnake species was unknown in most cases. All received Fab antivenom. 62 (82%) had a digital envenomation. 31 (40.3%) had necrosis. Necrotic area ranged from 0.1 cm2 to 14 cm2. Procedural interventions, (superficial debridement, dermotomy, surgical exploration, and operative debridement of devitalized tissue) occurred in 25 (32.5%). Five (6.5%) underwent dermotomy and 6 (7.8%) operative debridement. No amputations were performed. Patients with cyanosis on presentation had increased risk of developing necrosis (11/12; RR 2.98 95% CI 1.99-4.46). Ecchymosis on presentation was also associated with increased risk of necrosis (24/32; RR 4.04 95% CI 2.08 7.86). Patients with social or regular ethanol use were more likely to develop necrosis than those without (28/53; RR 4.23 95% CI 1.42-12.6). Regular cocaine use was associated with increased risk of operative debridement (4/6; RR 9.13 95% CI 2.33-35.8). A nonsignificant risk of operative debridement occurred with tobacco use (RR 1.14 95%CI 0.99-1.31 p = 0.09). Time to antivenom did not correlate with risk of necrosis. CONCLUSION: UE RSE patients who presented with cyanosis, ecchymosis or history of ethanol use were at increased risk of developing necrosis. Cocaine use was associated with increased risk of operative debridement. PMID- 28885115 TI - A 9-Week Jaques-Dalcroze Eurhythmics Intervention Improves Single and Dual-Task Gait Speed in Community-Dwelling Older People. AB - BACKGROUND: Falls are a major public health concern among older adults, and most occur while walking, especially under dualtask conditions. Jaques-Dalcroze eurhythmics (JDE) is a music-based movement training program that emphasizes multitask coordinated movement. A previous 6-mo JDE study in older people demonstrated improved gait and balance; however, the effects of short-term JDE interventions on fall risk-related outcomes are largely unknown. We conducted a preliminary investigation on whether a 9-week JDE intervention improved gait and stability in a community-dwelling older cohort, hypothesizing that improvements would occur in all outcome measures. METHODS: Nine participants (78.9 +/- 12.3 y) completed the supervised JDE intervention (once/week for 60 min). Gait speed was determined by the 6-m timed walk test (6MTW); dual-task gait speed was determined by another 6MTW while counting backward from 50 aloud; and coordinated stability was assessed using a Swaymeter-like device. RESULTS: Gait speed (0.92 +/- 0.11 vs 1.04 +/- 0.12 m/sec, P = .04) and dual-task gait speed (0.77 +/- 0.09 vs 0.92 +/- 0.11 m/sec, P = .0005) significantly improved. CONCLUSIONS: This novel intervention is an effective short-term physical activity option for those that plan physical activity or fall-risk reduction programs for the older people. PMID- 28885116 TI - Intrinsic subtype characterization of local recurrences and new contralateral primary tumors in patients with low risk breast cancer. Influence of age and primary surgery. PMID- 28885117 TI - The interperiosteodural concept applied to the jugular foramen and its compartmentalization. AB - OBJECTIVE The dura mater is made of 2 layers: the endosteal layer (outer layer), which is firmly attached to the bone, and the meningeal layer (inner layer), which directly covers the brain and spinal cord. These 2 dural layers join together in most parts of the skull base and cranial convexity, and separate into the orbital and perisellar compartments or into the spinal epidural space to form the extradural neural axis compartment (EDNAC). The EDNAC contains fat and/or venous blood. The aim of this dissection study was to anatomically verify the concept of the EDNAC by focusing on the dural layers surrounding the jugular foramen area. METHODS The authors injected 10 cadaveric heads (20 jugular foramina) with colored latex and fixed them in formalin. The brainstem and cerebellum of 7 specimens were cautiously removed to allow a superior approach to the jugular foramen. Special attention was paid to the meningeal architecture of the jugular foramen, the petrosal inferior sinus and its venous confluence with the sigmoid sinus, and the glossopharyngeal, vagus, and accessory nerves. The 3 remaining heads were bleached with a 20% hydrogen peroxide solution. This procedure produced softening of the bone without modifying the fixed soft tissues, thus permitting coronal and axial dissections. RESULTS The EDNAC of the jugular foramen was limited by the endosteal and meningeal layers and contained venous blood. These 2 dural layers joined together at the level of the petrous and occipital bones and separated at the inferior petrosal sinus and the sigmoid sinus, and around the lower cranial nerves, to form the EDNAC. Study of the dural sheaths allowed the authors to describe an original compartmentalization of the jugular foramen in 3 parts: 2 neural compartments-glossopharyngeal and vagal-and the interperiosteodural compartment. CONCLUSIONS In this dissection study, the existence of the EDNAC concept in the jugular foramen was demonstrated, leading to the proposal of a novel 3-part compartmentalization, challenging the classical 2-part compartmentalization, of the jugular foramen. PMID- 28885118 TI - Stereotactic radiosurgery for Spetzler-Martin Grade IV and V arteriovenous malformations: an international multicenter study. AB - OBJECTIVE Due to the complexity of Spetzler-Martin (SM) Grade IV-V arteriovenous malformations (AVMs), the management of these lesions remains controversial. The aims of this multicenter, retrospective cohort study were to evaluate the outcomes after single-session stereotactic radiosurgery (SRS) for SM Grade IV-V AVMs and determine predictive factors. METHODS The authors retrospectively pooled data from 233 patients (mean age 33 years) with SM Grade IV (94.4%) or V AVMs (5.6%) treated with single-session SRS at 8 participating centers in the International Gamma Knife Research Foundation. Pre-SRS embolization was performed in 71 AVMs (30.5%). The mean nidus volume, SRS margin dose, and follow-up duration were 9.7 cm3, 17.3 Gy, and 84.5 months, respectively. Statistical analyses were performed to identify factors associated with post-SRS outcomes. RESULTS At a mean follow-up interval of 84.5 months, favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RIC) and was achieved in 26.2% of patients. The actuarial obliteration rates at 3, 7, 10, and 12 years were 15%, 34%, 37%, and 42%, respectively. The annual post-SRS hemorrhage rate was 3.0%. Symptomatic and permanent RIC occurred in 10.7% and 4% of the patients, respectively. Only larger AVM diameter (p = 0.04) was found to be an independent predictor of unfavorable outcome in the multivariate logistic regression analysis. The rate of favorable outcome was significantly lower for unruptured SM Grade IV-V AVMs compared with ruptured ones (p = 0.042). Prior embolization was a negative independent predictor of AVM obliteration (p = 0.024) and radiologically evident RIC (p = 0.05) in the respective multivariate analyses. CONCLUSIONS In this multi-institutional study, single-session SRS had limited efficacy in the management of SM Grade IV-V AVMs. Favorable outcome was only achieved in a minority of unruptured SM Grade IV-V AVMs, which supports less frequent utilization of SRS for the management of these lesions. A volume-staged SRS approach for large AVMs represents an alternative approach for high-grade AVMs, but it requires further investigation. PMID- 28885119 TI - Volume of distribution and clearance of peptide-based nanofiber after convection enhanced delivery. AB - OBJECTIVE Drug clearance may be a limiting factor in the clinical application of convection-enhanced delivery (CED). Peptide-based nanofibers (NFPs) have a high aspect ratio, and NFPs loaded with drugs could potentially maintain effective drug concentrations for an extended period sufficient for cancer therapy. The objective of this study was to assess the volume of distribution (Vd) and clearance of variable lengths of NFPs when administered using CED. METHODS NFPs composed of multiple methoxypolyethylene glycol (mPEG)-conjugated constructs (mPEG2000-KLDLKLDLKLDL-K( FITC)-CONH2, for which FITC is fluorescein isothiocyanate) were assembled in an aqueous buffer. The NFPs were approximately 5 nm in width and were formulated into different lengths: 100 nm (NFP-100), 400 nm (NFP-400), and 1000 nm (NFP-1000). The NFP surface was covalently conjugated with multiple Cy5.5 fluorophores as the optical reporters to track the post-CED distribution. Forty-two 6- to 8-week-old Ntv-a;p53fl/fl mice underwent CED to the striatum. Animals were killed immediately, 24 hours or 72 hours after CED. The brains were extracted and sectioned for assessing NFP Vd to volume of infusion (Vi) ratio, and clearance using fluorescence microscopy. RESULTS CED of NFPs was well tolerated by all the animals. The average Vd/Vi ratios for NFP-100, NFP-400, NFP-1000, and unconjugated positive control (free Cy5.5) were 1.87, 2.47, 1.07, and 3.0, respectively, which were statistically different (p = 0.003). The percentages remaining of the original infusion volume at 24 hours for NFP-100, 400, and -1000 were 40%, 90%, and 74%, respectively. The percentages remaining at 72 hours for NFP-100, -400, and -1000 were 15%, 30%, and 46%, respectively. Unconjugated Cy5.5 was not detected at 24 or 72 hours after CED. CONCLUSIONS CED of NFPs is feasible with Vd/Vi ratios and clearance rates comparable to other nanocarriers. Of the 3 NFPs, NFP-400 appears to provide the best distribution and slowest clearance after 24 hours. NFP provides a dynamic theranostic platform, with the potential to deliver clinically efficacious drug payload to brain tumor after CED. PMID- 28885120 TI - Threshold of the extent of resection for WHO Grade III gliomas: retrospective volumetric analysis of 122 cases using intraoperative MRI. AB - OBJECTIVE WHO Grade III gliomas are relatively rare and treated with multiple modalities such as surgery, chemotherapy, and radiotherapy. The impact of the extent of resection (EOR) on improving survival in patients with this tumor type is unclear. Moreover, because of the heterogeneous radiological appearance of Grade III gliomas, the MRI sequence that best correlates with tumor volume is unknown. In the present retrospective study, the authors evaluated the prognostic significance of EOR. METHODS Clinical and radiological data from 122 patients with newly diagnosed WHO Grade III gliomas who had undergone intraoperative MRI guided resection at a single institution between March 2000 and December 2011 were analyzed retrospectively. Patients were divided into 2 groups by histological subtype: 81 patients had anaplastic astrocytoma (AA) or anaplastic oligoastrocytoma (AOA), and 41 patients had anaplastic oligodendroglioma (AO). EOR was calculated using pre- and postoperative T2-weighted and contrast-enhanced T1-weighted MR images. Univariate and multivariate analyses were performed to evaluate the prognostic significance of EOR on overall survival (OS). RESULTS The 5-, 8-, and 10-year OS rates for all patients were 74.28%, 70.59%, and 65.88%, respectively. The 5- and 8-year OS rates for patients with AA and AOA were 72.2% and 67.2%, respectively, and the 10-year OS rate was 62.0%. On the other hand, the 5- and 8-year OS rates for patients with AO were 79.0% and 79.0%; the 10-year OS rate is not yet available. The median pre- and postoperative T2-weighted high signal intensity volumes were 56.1 cm3 (range 1.3-268 cm3) and 5.9 cm3 (range 0 180 cm3), respectively. The median EOR of T2-weighted high-signal intensity lesions (T2-EOR) and contrast-enhanced T1-weighted lesions were 88.8% (range 0.3% 100%) and 100% (range 34.0%-100%), respectively. A significant survival advantage was associated with resection of 53% or more of the preoperative T2-weighted high signal intensity volume in patients with AA and AOA, but not in patients with AO. Univariate analysis showed that preoperative Karnofsky Performance Scale score (p = 0.0019), isocitrate dehydrogenase 1 ( IDH1) mutation (p = 0.0008), and T2-EOR (p = 0.0208) were significant prognostic factors for survival in patients with AA and AOA. Multivariate analysis demonstrated that T2-EOR (HR 3.28; 95% CI 1.22 8.81; p = 0.0192) and IDH1 mutation (HR 3.90; 95% CI 1.53-10.75; p = 0.0044) were predictive of survival in patients with AA and AOA. CONCLUSIONS T2-EOR was one of the most important prognostic factors for patients with AA and AOA. A significant survival advantage was associated with resection of 53% or more of the preoperative T2-weighted high-signal intensity volume in patients with AA and AOA. PMID- 28885121 TI - Epilepsy, headache, and abdominal pain after shunt surgery for idiopathic normal pressure hydrocephalus: the INPH-CRasH study. AB - OBJECTIVE Adverse events related to shunt surgery are common and might have a negative effect on outcome in patients with idiopathic normal pressure hydrocephalus (INPH). The authors' objectives were to establish the frequencies of epilepsy, headache, and abdominal pain and determine their impact on patient quality of life (QOL), in long-term follow-up after shunt surgery for INPH. METHODS One hundred seventy-six shunt-treated patients with INPH (mean age 74 years) and 368 age- and sex-matched controls from the population were included. The mean follow-up time after surgery was 21 months (range 6-45 months). Each participant answered a questionnaire regarding present frequency and severity of headache and abdominal pain. Confirmed diagnoses of epilepsy and all prescriptions for antiepileptic drugs (AEDs) before and after shunt surgery for INPH were gathered from national registries. Equivalent presurgical and postsurgical time periods were constructed for the controls based on the date of surgery (the division date for controls is referred to as virtual surgery). All registry data covered a mean period of 6 years (range 3-8 years) before surgery/virtual surgery and 4 years (range 2-6 years) after surgery/virtual surgery. Provoked epileptic seizures were excluded. Patient QOL was assessed with the EuroQoL 5-dimension 5-level instrument. RESULTS Epilepsy was more common in shunt-treated patients with INPH than in controls (4.5% vs 1.1%, respectively; p = 0.023), as was treatment with AEDs (14.8% vs 7.3%, respectively; p = 0.010). No difference was found between the populations before surgery/virtual surgery (epilepsy, 2.3% [INPH] vs 1.1% [control], p = 0.280; AED treatment, 8.5% [INPH] vs 5.4% [control], p = 0.235). New-onset epilepsy and new AED treatment after surgery/virtual surgery were more common in INPH (epilepsy, 2.3% [INPH] vs 0.0% [control], p = 0.011; AED, 8.5% [INPH] vs 3.3% [control], p = 0.015). At follow up, more patients with INPH than controls experienced headache several times per month or more often (36.1% vs 11.6%, respectively; p < 0.001). Patients with INPH and unilateral headache had more right-sided headaches than controls (p = 0.038). Postural headache was experienced by 16% (n = 27 of 169) of the patients with INPH. Twenty percent (n = 35) of the patients with INPH had persistent abdominal pain. Headache was not correlated to lower QOL. The study was underpowered to draw conclusions regarding QOL in patients with INPH who had epilepsy and abdominal pain, but the finding of no net difference in mean QOL indicates that no correlation between them existed. CONCLUSIONS Epilepsy, headache, and abdominal pain are common in long-term follow-up in patients after shunt surgery for INPH and are more common among patients with INPH than in the general population. All adverse events, including mild and moderate ones, should be considered during postoperative follow-ups and in the development of new methods for shunt placement. PMID- 28885122 TI - Clinicopathological variables of sporadic schwannomas of peripheral nerve in 291 patients and expression of biologically relevant markers. AB - OBJECTIVE While sporadic peripheral schwannomas (SPSs) are generally well treated with surgery, their biology is not well understood. Consequently, treatment options are limited. The aim of this study was to provide a comprehensive description of SPS. The authors describe clinicopathological features and treatment outcomes of patients harboring these tumors, and they assess expression of biomarkers using a clinically annotated tissue microarray. Together, these data give new insight into the biology and management of SPS. METHODS Patients presenting with a primary SPS between 1993 and 2011 (n = 291) were selected from an institutional registry to construct a clinical database. All patients underwent follow-up, and short- and long-term outcomes were assessed. Expression of relevant biomarkers was assessed using a new tissue microarray (n = 121). RESULTS SPSs were generally large (mean 5.5 cm) and frequently painful at presentation (55%). Most patients were treated with surgery (80%), the majority of whom experienced complete resolution (52%) or improvement (18%) of their symptoms. Tumors that were completely resected (85%) did not recur. Some patients experienced short-term (16%) and long-term (4%) complications postoperatively. Schwannomas expressed higher levels of platelet-derived growth factor receptor beta (2.1) than malignant peripheral nerve sheath tumors (MPNSTs) (1.5, p = 0.004) and neurofibromas (1.33, p = 0.007). Expression of human epidermal growth factor receptor-2 was greater in SPSs (0.91) than in MPNSTs (0.33, p = 0.002) and neurofibromas (0.33, p = 0.026). Epidermal growth factor receptor was expressed in far fewer SPS cells (10%) than in MPNSTs (58%, p < 0.0001) or neurofibromas (37%, p = 0.007). SPSs more frequently expressed cytoplasmic survivin (66% of tumor cells) than normal nerve (46% of cells), but SPS expressed nuclear survivin in fewer tumor cells than in MPNSTs (24% and 50%, respectively; p = 0.018). CONCLUSIONS Complete resection is curative for SPS. Left untreated, however, these tumors can cause significant morbidity, and not all patients are candidates for resection. SPSs express a pattern of biomarkers consistent with the dysregulation of the tumor suppressor merlin observed in neurofibromatosis Type 2 associated schwannomas, suggesting a shared etiology. This SPS pattern is distinct from that of other tumors of the peripheral nerve sheath. PMID- 28885123 TI - Thirty-Day Inpatient Readmissions for Asian American and Pacific Islander Subgroups Compared With Whites. AB - Asian and Pacific Islander (API) 30-day potentially preventable readmissions (PPRs) are understudied. Hawaii Health Information Corporation data from 2007 2012 statewide adult hospitalizations ( N = 495,910) were used to compare API subgroup and White PPRs. Eight percent of hospitalizations were PPRs. Seventy-two percent of other Pacific Islanders, 60% of Native Hawaiians, and 52% of Whites with a PPR were 18 to 64 years, compared with 22% of Chinese and 21% of Japanese. In multivariable models including payer, hospital, discharge year, residence location, and comorbidity, PPR disparities existed for some API subpopulations 65+ years, including Native Hawaiian men (odds ratio [OR] = 1.14; 95% confidence interval [CI] = 1.04-1.24), Filipino men (OR = 1.19; 95% CI = 1.04-1.38), and other Pacific Islander men (OR = 1.30; 95% CI = 1.19-1.43) and women (OR = 1.23; 95% CI = 1.02-1.51) compared with Whites, while many API groups 18 to 64 years had significantly lower PPR odds. Distinct PPR characteristics across API subpopulations and age groups can inform policy and practice. Further research should determine why elderly API have higher PPR rates, while nonelderly rates are lower. PMID- 28885124 TI - Thoracic spinal cord impingement by an arachnoid web at the level of a hemivertebra: case report. AB - Congenital scoliosis due to a hemivertebra requires surgical stabilization prior to skeletal maturity if rapidly progressive curve growth occurs. Here the authors present the unique case of a man who, at the age of 12 years, had undergone Harrington rod placement for stabilization of progressive congenital scoliosis due to a T-11 hemivertebra and then, at the age of 53 years, presented with acutely progressive myelopathy due to spinal cord compression from an arachnoid web at T-11 despite a solid fusion mass at the prior surgical site. The patient underwent a posterior midline approach for resection of the T-11 pedicle at the level of the hemivertebra, intradural spinal cord detethering with resection of the arachnoid web at T-11, and T2-L2 instrumented fusion with deformity correction, leading to subsequent resolution of his acute myelopathic symptoms. In conclusion, arachnoid web formation superimposed on preexisting tension on the thoracic spinal cord from congenital scoliosis due to a T-11 hemivertebra caused acute myelopathy in an adult with a previously solid fusion mass from childhood. The resolution of acute myelopathy and halting of further progression occurred with pedicle resection, arachnoid web fenestration, and spinal deformity correction. PMID- 28885125 TI - Risk factor analysis of kyphotic malalignment after cervical intramedullary tumor resection in adults. AB - OBJECTIVE A number of studies have reported that surgery for cervical intramedullary tumors via the posterior approach can result in postoperative sagittal malalignment of the cervical spine; however, the risk factors remain unclear. The purpose of this study was to investigate the changes in cervical spinal alignment after surgery for cervical intramedullary tumors in adults and to elucidate the risk factors for cervical spinal sagittal misalignment. METHODS Data for the period from April 2001 to December 2011 for all adults who had undergone surgery for cervical intramedullary spinal cord tumors at a single institution were retrospectively analyzed to determine the postoperative changes in cervical spine alignment. Patients younger than 20 years of age and those who required postoperative radiotherapy were excluded from the study. Patients were divided into 2 groups according to tumor location: upper tumor (U) group, in which the central region of the tumor was above the C-5 level; and lower tumor (L) group, in which the central region of the tumor was at or below the C-5 level. Changes in alignment of the cervical spine were measured on plain lateral radiographs. Data on atrophy of the deep extensor muscles (DEMs), tumor location, detachment of the DEMs from the C-2 spinous process, the C2-7 angle before surgery, patient age at surgery, tumor histology, patient sex, tumor size, and number of laminae affected were reviewed for each patient, and the correlation of each of these factors with cervical spinal malalignment was evaluated using statistical analysis. RESULTS The 54 adults eligible for analysis had a mean age of 49.1 years. Ependymoma was the most common cervical intramedullary tumor (63.0%) in this series. In the tumor location U group, the kyphotic angle of the C2-7 spinal segments increased after surgery (-5.8 degrees +/- 2.8 degrees ). In contrast, in the L group, the C2-7 lordotic angle increased after surgery (6.4 degrees +/- 2.6 degrees ). In the univariate analysis, atrophy of the DEMs, detachment of the DEMs from the C-2 spinous process, and an upper cervical location of the tumor were identified as factors significantly correlated with the development of cervical spinal kyphosis after surgery. Multiple linear regression analysis revealed the following as risk factors for kyphotic change of the cervical spine after surgery: 1) atrophy of the DEMs after surgery (beta = 0.54, p < 0.01), and 2) detachment of the DEMs from the C-2 spinous process (beta = -0.37, p < 0.01). CONCLUSIONS Atrophy of the DEMs after surgery and detachment of the DEMs from the C-2 spinous process are directly related to the risk of cervical spinal kyphosis after surgery for cervical intramedullary tumors in adults. Therefore, preservation of the DEMs, especially those attached to the C-2 spinous process, is important for the prevention of kyphotic malalignment of the cervical spine after surgery for intramedullary tumors. PMID- 28885126 TI - Utility and costs of radiologist interpretation of perioperative imaging in patients with traumatic single-level thoracolumbar fractures. AB - OBJECTIVE The cost of spine management is rising. As diagnostic imaging accounts for approximately 10% of total patient care spending, there is interest in determining if economies could be made with regard to the routine consultation of radiology for image interpretation. In the context of spine trauma, both the spine surgeon and the radiologist interpret perioperative imaging. Authors of the present study investigated the impact of radiologist interpretation of perioperative imaging from patients with traumatic single-level thoracolumbar fractures given that spine surgeons are expected to be comfortable interpreting pathologies of the musculoskeletal system. METHODS The authors conducted a retrospective review of all patients presenting with a single-level thoracolumbar fracture treated at the McGill University Health Centre in the period from January 2003 to December 2010. The time between image capture and radiologist interpretation as well as the number of extraskeletal and/or incidental findings was extracted from the radiology reports on all perioperative images including radiographic, fluoroscopic, and CT images. The cost of interpretation was obtained from the provincial health insurance entity of Quebec. RESULTS Eighty two patients met the study inclusion criteria. Radiologists took a median of 1 day (IQR 0-5.5 days) to interpret preoperative radiographs. Intraoperative fluoroscopic images and postoperative radiographs were read by the radiologist a median of 19 days (IQR 4-56.75 days) and 34 days (IQR 1-137.5 days) after capture, respectively (p < 0.05). Preoperative radiologist dictations reported extraskeletal and/or incidental findings for 8.1% of radiographs; there were no intraoperative or postoperative extraskeletal findings beyond those previously reported on the preoperative radiographs. Radiologists took a median of 1 day (IQR 0-1 day) to read both preoperative and postoperative CT scans; extraskeletal and/or incidental findings were present in 46.2% of preoperative reports and 4.5% of postoperative reports. There were no intraoperative or postoperative radiological findings that provoked reoperation. A total of 66 intraoperative fluoroscopy images and 225 postoperative radiographs were read for a cost of $1399.20 and $1867.50 (Canadian dollars), respectively, for radiologist interpretation. This cost amounted to 40.3% of all perioperative image interpretation spending. CONCLUSIONS In the management of single-level thoracolumbar fractures, radiologists add information to the diagnostic picture when interpreting preoperative radiographs and perioperative CT scans; however, the interpretation of intraoperative fluoroscopic images and postoperative radiographs comes with significant delay, does not add additional information, and represents an area of potential cost and professional-resource reduction. PMID- 28885127 TI - Timing and risks of chemoprophylaxis after spinal surgery: a single-center experience with 6869 consecutive patients. AB - OBJECTIVE Venous thromboembolism (VTE) after spinal surgery is a major cause of morbidity, but chemoprophylactic anticoagulation can prevent it. However, there is variability in the timing and use of chemoprophylactic anticoagulation after spine surgery, particularly given surgeons' concerns for spinal epidural hematomas. The goal of this study was to provide insight into the safety, efficacy, and timing of anticoagulation therapy after spinal surgery. METHODS The authors retrospectively examined records from 6869 consecutive spinal surgeries performed in their departments at Northwestern University. Data on patient demographics, surgery, hospital course, timing of chemoprophylaxis, and complications, including deep venous thrombosis (DVT), pulmonary embolism (PE), and spinal epidural hematomas requiring evacuation, were collected. Data from the patients who received chemoprophylaxis (n = 1904) were compared with those of patients who did not (n = 4965). The timing of chemoprophylaxis, the rate of VTEs, and the incidence of spinal epidural hematomas were analyzed. RESULTS The chemoprophylaxis group had more risk factors, including greater age (59.70 vs 51.86 years, respectively; p < 0.001), longer surgery (278.59 vs 145.66 minutes, respectively; p < 0.001), higher estimated blood loss (995 vs 448 ml, respectively; p < 0.001), more comorbid diagnoses (2.69 vs 1.89, respectively; p < 0.001), history of VTE (5.8% vs 2.1%, respectively; p < 0.001), and a higher number were undergoing fusion surgery (46.1% vs 24.7%, respectively; p < 0.001). The prevalence of VTE was higher in the chemoprophylaxis group (3.62% vs 2.03%, respectively; p < 0.001). The median time to VTE occurrence was shorter in the nonchemoprophylaxis group (3.6 vs 6.8 days, respectively; p = 0.0003, log-rank test; hazard ratio 0.685 [0.505-0.926]), and the peak prevalence of VTE occurred in the first 3 postoperative days in the nonchemoprophylaxis group. The average time of initiation of chemoprophylaxis was 1.46 days after surgery. The rates of epidural hematoma were 0.20% (n = 4) in the chemoprophylaxis group and 0.18% (n = 9) in the nonchemoprophylaxis group (p = 0.622). CONCLUSIONS The risks of spinal epidural hematoma among patients who receive chemoprophylaxis and those who do not are low and equivalent. Administering anticoagulation therapy from 1 day before to 3 days after surgery is safe for patients at high risk for VTE. PMID- 28885128 TI - Sagittal alignment and complications following lumbar 3-column osteotomy: does the level of resection matter? AB - OBJECTIVE Three-column osteotomy (3CO) is a demanding technique that is performed to correct sagittal spinal malalignment. However, the impact of the 3CO level on pelvic or truncal sagittal correction remains unclear. In this study, the authors assessed the impact of 3CO level and postoperative apex of lumbar lordosis on sagittal alignment correction, complications, and revisions. METHODS In this retrospective study of a multicenter spinal deformity database, radiographic data were analyzed at baseline and at 1- and 2-year follow-up to quantify spinopelvic alignment, apex of lordosis, and resection angle. The impact of 3CO level and apex level of lumbar lordosis on the sagittal correction was assessed. Logistic regression analyses were performed, controlling for cofounders, to investigate the effects of 3CO level and apex level on intraoperative and postoperative complications as well as on the need for subsequent revision surgery. RESULTS A total of 468 patients were included (mean age 60.8 years, mean body mass index 28.1 kg/m2); 70% of patients were female. The average 3CO resection angle was 25.1 degrees and did not significantly differ with regard to 3CO level. There were no significant correlations between the 3CO level and amount of sagittal vertical axis or pelvic tilt correction. The postoperative apex level significantly correlated with greater correction of pelvic tilt (2 degrees per more caudal level, R = -0.2, p = 0.006). Lower-level 3CO significantly correlated with revisions for pseudarthrosis (OR = 3.88, p = 0.001) and postoperative motor deficits (OR = 2.02, p = 0.026). CONCLUSIONS In this study, a more caudal lumbar 3CO level did not lead to greater sagittal vertical axis correction. The postoperative apex of lumbar lordosis significantly impacted pelvic tilt. 3CO levels that were more caudal were associated with more postoperative motor deficits and revisions. PMID- 28885129 TI - Relationship between vertebral artery blood flow in different head positions and vertigo. AB - OBJECTIVE: To identify the vertebral artery blood flow in different head positions in patients with positional vertigo with no specific diagnosis. METHODS: Patients with history of vestibular symptoms associated with changes in head position were enrolled into the study. Healthy volunteers were evaluated as control group. Doppler ultrasonography examination of the cervical segment of the vertebral arteries was performed under three different head positions: (i) supine position, (ii) head hyperextended and rotated to the right side and (iii) head hyperextended and rotated to the left side. RESULTS: In the study group, right and left vertebral artery blood flow was significantly lower in the ipsilateral hyperextended position compared to standard supine position (respectively p = .014; p = .001), but did not differ significantly when compared between the standard supine and contralateral hyperextended positions (respectively = .959; p = .669). In the control group, left and right vertebral artery blood flow did not differ significantly when the head was hyperextended to the right or left sides compared to standard supine position (p > .05). CONCLUSIONS: Our data demonstrated that the etiology of vestibular complaints in patients with undiagnosed positional vertigo might be related to impairment in vertebral artery blood flow according to head positions. PMID- 28885130 TI - A comparison of relative proton stopping power measurements across patient size using dual- and single-energy CT. AB - PURPOSE: To evaluate the accuracy and precision across phantom size of a dual energy computed tomography (DECT) technique used to calculate relative proton stopping power (SPR) in tissue-simulating materials and a silicone implant relative to conventional single-energy CT (SECT). MATERIAL AND METHODS: A 32 cm lateral diameter (CIRS model 062M, Norfolk, Virginia) electron density phantom containing inserts which simulated the chemical composition of eight tissues in a solid-water background was scanned using SECT and DECT. A liquid water insert was included to confirm CT number accuracy. All materials were also placed in four water tanks, ranging from 15 to 45 cm in lateral width and scanned using DECT and SECT. A silicone breast implant was scanned in the same water phantoms. SPR values were calculated based on commercial software (syngo CT Dual Energy, Siemens Healthcare GmbH) and compared to reference values derived from proton beam measurements. Accuracy and precision were quantified across phantom size using percent error and standard deviation. Graphical and regression analysis were used to determine whether SECT or DECT was superior in estimating SPR across phantom size. RESULTS: Both DECT and SECT SPR data resulted in good agreement with the reference values. Percent error was +/-3% for both DECT and SECT in all materials except lung and dense bone. The coefficient of variation (CV) across materials and phantom sizes was 1.12% for SECT and 0.96% for DECT. Material specific regression and graphical analysis did not reveal size dependence for either technique but did show reduced systematic bias with DECT for dense bone and liver. Mean percent error in SPR for the implant was reduced from 11.46% for SECT to 0.49% for DECT. CONCLUSIONS: We demonstrate the superior ability of DECT to mitigate systematic bias in bones and liver and estimate SPR in a silicone breast implant. PMID- 28885131 TI - Applying a Treatment Effects Model to Investigate Public Amenity Effect on Physical Activity of the Elderly. AB - The increasing elderly population puts significant health, economic, and social burdens on society. Physical activity is one of the most cost-effective ways to maintain the health of the elderly. This study adopts a treatment effects model to investigate the causal relationship between environment attributes and physical activity among the elderly, while taking endogeneity into account. The data were collected from 274 participants by face-to-face interviews in Taichung, Taiwan. Performing physical activity regularly in parks is the most important measure of the amount of physical activity by the elderly. Providing sufficient and accessible parks in metropolitan residential neighborhoods could be one of the most cost-effective ways to promote physical activity for the elderly living in midsize Asian cities. PMID- 28885132 TI - No long-term risk of wrist osteoarthritis due to subchondral haematomas in distal radial fractures. AB - OBJECTIVE: The objective of this study of distal radius fractures was to determine if a subchondral haematoma in an unfractured compartment predicts secondary osteoarthritis. METHODS: In 1995-1997, 41 patients, 22 women, a median age of 41 years (20-57 years) with a displaced distal radius fracture underwent diagnostic wrist arthroscopy in addition to the fracture treatment. In 12 patients (7/12 women), subchondral haematomas were identified in a joint compartment not involved in the fracture. RESULTS: At 13-15 years, 37 patients were still alive. Twenty-eight patients attended the follow-up and 8/28 had had a subchondral haematoma within an uninjured compartment at the time of arthroscopy. The range of motion at 13-15 years was impaired in the injured wrist, but unrelated to the presence of a subchondral haematoma. The mean grip strength in patients with subchondral haematoma was 80% of the contralateral, compared to 78% in patients without. No correlation was found between the presence of a subchondral haematoma at arthroscopy and the development of radiographic osteoarthritis in the long term. CONCLUSION: The presence of a subchondral hematoma in an uninjured compartment at the time of fracture did not alter the long-term clinical or radiographic outcome after a distal radius fracture. PMID- 28885133 TI - The addition of duraplasty to posterior fossa decompression in the surgical treatment of pediatric Chiari malformation Type I: a systematic review and meta analysis of surgical and performance outcomes. AB - OBJECTIVE Surgery is the definitive treatment of Chiari malformation Type I (CM I). It involves posterior fossa decompression, which can be performed along with C-1 laminectomy, reconstructive duraplasty, or tonsil shrinkage. The aim of this study was to provide an updated systematic review and meta-analysis of the latest available evidence regarding posterior fossa decompression only (PFDO) versus posterior fossa decompression with duraplasty (PFDD) in the treatment of CM-I in children. METHODS A literature search was performed in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for article identification, screening, eligibility, and inclusion. Relevant articles were identified from 6 electronic databases from their inception to April 2016. These articles were screened against established criteria for inclusion into this study. RESULTS From 12 relevant studies identified, 1492 pediatric patients treated via PFDD were compared with 1963 pediatric patients treated by PFDO for CM-I. PFDD was associated with greater overall clinical improvement (p = 0.009), along with longer length of stay (p < 0.0001) and more postoperative complications (p = 0.0001) compared with PFDO. No difference was observed between PFDD and PFDO in terms of revision surgery incidence (p = 0.13), estimated blood loss (p = 0.14), syrinx improvement (p = 0.09), or scoliosis improvement (p = 0.95). CONCLUSIONS It appears that the addition of duraplasty to posterior decompression in the definitive treatment of CM-I in children may alter surgical and performance outcomes. In particular, parameters of overall clinical improvement, length of stay, and postoperative complication may differ between children undergoing PFDD and those undergoing PFDO. Current evidence in the literature is of low to very low quality that, as of yet, has not been able to completely control for inherent selection bias both in study design and surgeon preference. Future, large prospective registries and randomized controlled trials are warranted to validate the findings of this study. PMID- 28885134 TI - Gay Seouls: Expanding Religious Spaces for Non-Heterosexuals in South Korea. AB - What Protestant congregations offer spaces for worship and dialogue among persons with different sexual orientations? The academic literature finds or assumes that non-heterosexuals are stigmatized or invisible in theologically conservative congregations and are welcomed in progressive, affirming congregations. This article develops an alternative claim that some conservative or evangelical congregations offer attractive spaces for non-heterosexuals to worship and dialogue. We illustrate with an exploratory study of four congregations in South Korea-two theologically progressive, two evangelical-whose pastors welcomed everybody regardless of sexual orientation or gender identity. The "inclusive evangelical" congregations retained conservative theology on sexuality (sexual relations only within heterosexual marriage) but offered more empathic dialogue with non-heterosexuals than did most evangelical congregations; they also provided more resources, conventional religious culture, and ties to traditional affective networks than the affirming-progressive congregations. Inclusive evangelical congregations offer an institutional venue for non-heterosexual Christians in Korea to potentially reconcile three central values: conservative Christianity, traditional (Confucian) affective networks, and expressive individualism. PMID- 28885135 TI - Percutaneous closure of aorta-right atrial tunnel in a newborn. AB - A tunnel between the aorta and right atrium in a newborn was occluded with 5*6 Amplatzer Duct Occluder II-Additional Size. Our case is different because of enlarged right atrium and atypical location of tunnel orifice. PMID- 28885136 TI - Contacts of healthcare workers, patients and visitors in general wards in Singapore. AB - To characterize contacts in general wards, a prospective survey of healthcare workers (HCWs), patients and visitors was conducted using self-reported diary, direct observation and telephone interviews. Nurses, doctors and assorted HCWs reported a median of 14, 18 and 15 contact persons over one work shift, respectively. Within 1 h, we observed 3.5 episodes with 25.6 min of cumulative contact time for nurses, 2.9 episodes and 22.1 min for doctors and 5.0 episodes with 44.3 min for assorted-HCWs. In interactions with patients, nurses had multiple brief episodes of contact; doctors had fewer episodes and less cumulative contact time; assorted-HCWs had fewer contact episodes of longer durations (than for nurses and doctors). Assortative mixing occurred amongst HCWs: those of the same HCW type were the next most frequent class of contact after patients. Over 24-h, patients contacted 14 persons with 23 episodes and 314.5 min of contact time. Patient-to-patient contact episodes were rare, but a maximum of five were documented from one patient participant. 22.9% of visitors reported contact with patients other than the one they visited. Our study revealed differences in the characteristics of contacts among different HCW types and potential transmission routes from patients to others within the ward environment. PMID- 28885137 TI - Effects of reducing processed culinary ingredients and ultra-processed foods in the Brazilian diet: a cardiovascular modelling study. AB - OBJECTIVE: To estimate the impact of reducing saturated fat, trans-fat, salt and added sugar from processed culinary ingredients and ultra-processed foods in the Brazilian diet on preventing cardiovascular deaths by 2030. DESIGN: A modelling study. SETTING: Data were obtained from the Brazilian Household Budget Survey 2008/2009. All food items purchased were categorized into food groups according to the NOVA classification. We estimated the energy and nutrient profile of foods then used the IMPACT Food Policy model to estimate the reduction in deaths from CVD up to 2030 in three scenarios. In Scenario A, we assumed that the intakes of saturated fat, trans-fat, salt and added sugar from ultra-processed foods and processed culinary ingredients were reduced by a quarter. In Scenario B, we assumed a reduction of 50 % of the same nutrients in ultra-processed foods and processed culinary ingredients. In Scenario C, we reduced the same nutrients in ultra-processed foods by 75 % and in processed culinary ingredients by 50 %. RESULTS: Approximately 390 400 CVD deaths might be expected in 2030 if current mortality patterns persist. Under Scenarios A, B and C, CVD mortality can be reduced by 5.5, 11.0 and 29.0 %, respectively. The main impact is on stroke with a reduction of approximately 6.0, 12.6 and 32.0 %, respectively. CONCLUSIONS: Substantial potential exists for reducing the CVD burden through overall improvements of the Brazilian diet. This might require reducing the penetration of ultra-processed foods by means of regulatory policies, as well as improving the access to and promotion of fresh and minimally processed foods. PMID- 28885138 TI - Characterization of five unclassified orthobunyaviruses (Bunyaviridae) from Africa and the Americas. AB - The Bunyaviridae family is made up of a diverse range of viruses, some of which cause disease and are a cause for concern in human and veterinary health. Here, we report the genomic and antigenic characterization of five previously uncharacterized bunyaviruses. Based on their ultrastructure, antigenic relationships and phylogenomic relationships, the five viruses are classified as members of the Orthobunyavirus genus. Three are viruses in the California encephalitis virus serogroup and are related to Trivittatus virus; the two others are most similar to the Mermet virus in the Simbu serogroup, and to the Tataguine virus, which is not currently assigned to a serogroup. Each of these five viruses was pathogenic to newborn mice, indicating their potential to cause illness in humans and other animals. PMID- 28885139 TI - Prevalence of fosfomycin resistance and plasmid-mediated fosfomycin-modifying enzymes among carbapenem-resistant Enterobacteriaceae in Zhejiang, China. AB - Two hundred and thirty-three nonduplicated clinical isolates of carbapenem resistant Enterobacteriaceae were collected from four hospitals in Zhejiang, China. 45.1 % (105/233) strains were resistant to fosfomycin, among which plasmid mediated fosfomycin-modifying enzymes fosA, fosA2, fosA3 and fosA5 were positive, and the other fos genes were negative. 80 % (12/15) Enterobacter cloacae isolates were positive for fosA. 100 % (73/73) Klebsiella pneumoniae isolates were positive for fosA5. A conjugation experiment indicated that fosfomycin resistance could be transferred to an Escherichia coli recipient strain successfully. Fosfomycin still exhibits partial activity in carbapenem-resistant Enterobacteriaceae, especially carbapenem-resistant Escherichia coli. To our knowledge, plasmid-mediated fosfomycin-modifying enzymes account for the dominance in the carbapenem-resistant Enterobacteriaceae. Therefore, we need to pay attention to the plasmid-mediated fosfomycin-modifying enzymes fosA and fosA5 in Enterobacter cloacae and K. pneumoniae to prevent clonal dissemination in China. PMID- 28885140 TI - Xenogenic rolling-circle replication of a synthetic beak and feather disease virus genomic clone in 293TT mammalian cells and Nicotiana benthamiana. AB - The preparation of infectious beak and feather disease circovirus virions (BFDV) has until now relied on the extraction of virus from whole tissue of deceased or euthanized parrots known to be infected with the virus. Extraction from diseased tissue is necessary, as the virus has yet to be grown in vitro using tissue cultured cells from any source. While infectious DNA clones have been synthesized for porcine and duck circoviruses, and both replicate in host cells and result in active viral infection in animals, this has not been shown for BFDV. The aim of this study was to prepare an infectious BFDV genomic clone that could be used as challenge material in birds for vaccine testing. A putatively infectious BFDV genomic clone was designed and tested in mammalian cell culture, and in the plant Nicotiana benthamiana in the presence of plant-specific ssDNA geminivirus replication components. Replication was assessed using rolling-circle amplification, qPCR, replication-deficient clones and rescue plasmids. We showed that a synthetic partially dimeric BFDV genomic clone self-replicated when transfected into 293TT mammalian cells, and was also replicated in N. benthamiana in the presence of geminivirus replication elements. This is the first report of a BFDV genome replicating in any cell system, and the first report of a circovirus replicating with the aid of a geminivirus in a plant. Both of these developments could open up possibilities for making reagents and vaccines for BFDV, testing vaccine efficacy and investigating viral replication using rationally designed artificial genomes. PMID- 28885142 TI - Sonic Hedgehog switches on Wnt/planar cell polarity signaling in commissural axon growth cones by reducing levels of Shisa2. AB - Commissural axons switch on responsiveness to Wnt attraction during midline crossing and turn anteriorly only after exiting the floor plate. We report here that Sonic Hedgehog (Shh)-Smoothened signaling downregulates Shisa2, which inhibits the glycosylation and cell surface presentation of Frizzled3 in rodent commissural axon growth cones. Constitutive Shisa2 expression causes randomized turning of post-crossing commissural axons along the anterior-posterior (A-P) axis. Loss of Shisa2 led to precocious anterior turning of commissural axons before or during midline crossing. Post-crossing commissural axon turning is completely randomized along the A-P axis when Wntless, which is essential for Wnt secretion, is conditionally knocked out in the floor plate. This regulatory link between Shh and planar cell polarity (PCP) signaling may also occur in other developmental processes. PMID- 28885141 TI - Automated long-term recording and analysis of neural activity in behaving animals. AB - Addressing how neural circuits underlie behavior is routinely done by measuring electrical activity from single neurons in experimental sessions. While such recordings yield snapshots of neural dynamics during specified tasks, they are ill-suited for tracking single-unit activity over longer timescales relevant for most developmental and learning processes, or for capturing neural dynamics across different behavioral states. Here we describe an automated platform for continuous long-term recordings of neural activity and behavior in freely moving rodents. An unsupervised algorithm identifies and tracks the activity of single units over weeks of recording, dramatically simplifying the analysis of large datasets. Months-long recordings from motor cortex and striatum made and analyzed with our system revealed remarkable stability in basic neuronal properties, such as firing rates and inter-spike interval distributions. Interneuronal correlations and the representation of different movements and behaviors were similarly stable. This establishes the feasibility of high-throughput long-term extracellular recordings in behaving animals. PMID- 28885144 TI - Trajectory Predictor by Using Recurrent Neural Networks in Visual Tracking. AB - Motion models have been proved to be a crucial part in the visual tracking process. In recent trackers, particle filter and sliding windows-based motion models have been widely used. Treating motion models as a sequence prediction problem, we can estimate the motion of objects using their trajectories. Moreover, it is possible to transfer the learned knowledge from annotated trajectories to new objects. Inspired by recent advance in deep learning for visual feature extraction and sequence prediction, we propose a trajectory predictor to learn prior knowledge from annotated trajectories and transfer it to predict the motion of target objects. In this predictor, convolutional neural networks extract the visual features of target objects. Long short-term memory model leverages the annotated trajectory priors as well as sequential visual information, which includes the tracked features and center locations of the target object, to predict the motion. Furthermore, to extend this method to videos in which it is difficult to obtain annotated trajectories, a dynamic weighted motion model that combines the proposed trajectory predictor with a random sampler is proposed. To evaluate the transfer performance of the proposed trajectory predictor, we annotated a real-world vehicle dataset. Experiment results on both this real-world vehicle dataset and an online tracker benchmark dataset indicate that the proposed method outperforms several state-of-the-art trackers. PMID- 28885145 TI - Reinforcement Learning for Constrained Energy Trading Games With Incomplete Information. AB - This paper considers the problem of designing adaptive learning algorithms to seek the Nash equilibrium (NE) of the constrained energy trading game among individually strategic players with incomplete information. In this game, each player uses the learning automaton scheme to generate the action probability distribution based on his/her private information for maximizing his own averaged utility. It is shown that if one of admissible mixed-strategies converges to the NE with probability one, then the averaged utility and trading quantity almost surely converge to their expected ones, respectively. For the given discontinuous pricing function, the utility function has already been proved to be upper semicontinuous and payoff secure which guarantee the existence of the mixed strategy NE. By the strict diagonal concavity of the regularized Lagrange function, the uniqueness of NE is also guaranteed. Finally, an adaptive learning algorithm is provided to generate the strategy probability distribution for seeking the mixed-strategy NE. PMID- 28885143 TI - Promiscuous bacteria have staying power. AB - Being able to take up DNA from their environment might allow pneumococcal bacteria to colonize the human nose and throat for longer periods of time. PMID- 28885146 TI - Adaptive Neural Network Control of a Flapping Wing Micro Aerial Vehicle With Disturbance Observer. AB - The research of this paper works out the attitude and position control of the flapping wing micro aerial vehicle (FWMAV). Neural network control with full state and output feedback are designed to deal with uncertainties in this complex nonlinear FWMAV dynamic system and enhance the system robustness. Meanwhile, we design disturbance observers which are exerted into the FWMAV system via feedforward loops to counteract the bad influence of disturbances. Then, a Lyapunov function is proposed to prove the closed-loop system stability and the semi-global uniform ultimate boundedness of all state variables. Finally, a series of simulation results indicate that proposed controllers can track desired trajectories well via selecting appropriate control gains. And the designed controllers possess potential applications in FWMAVs. PMID- 28885148 TI - Ultra-Wideband Millimeter-Wave Dielectric Characteristics of Freshly Excised Normal and Malignant Human Skin Tissues. AB - Millimeter waves have recently gained attention for the evaluation of skin lesions and the detection of skin tumors. Such evaluations heavily rely on the dielectric contrasts existing between normal and malignant skin tissues at millimeter-wave frequencies. However, current studies on the dielectric properties of normal and diseased skin tissues at these frequencies are limited and inconsistent. In this study, a comprehensive dielectric spectroscopy study is conducted for the first time to characterize the ultra-wideband dielectric properties of freshly excised normal and malignant skin tissues obtained from skin cancer patients having undergone Mohs micrographic surgeries at Hackensack University Medical Center. Measurements are conducted using a precision slim-form open-ended coaxial probe in conjunction with a millimeter-wave vector network analyzer over the frequency range of 0.5-50 GHz. A one-pole Cole-Cole model is fitted to the complex permittivity dataset of each sample. Statistically considerable contrasts are observed between the dielectric properties of malignant and normal skin tissues over the ultra-wideband millimeter-wave frequency range considered. PMID- 28885147 TI - Quantitative Susceptibility Mapping (QSM) Algorithms: Mathematical Rationale and Computational Implementations. AB - Quantitative susceptibility mapping (QSM) solves the magnetic field-to magnetization (tissue susceptibility) inverse problem under conditions of noisy and incomplete field data acquired using magnetic resonance imaging. Therefore, sophisticated algorithms are necessary to treat the ill-posed nature of the problem and are reviewed here. The forward problem is typically presented as an integral form, where the field is the convolution of the dipole kernel and tissue susceptibility distribution. This integral form can be equivalently written as a partial differential equation (PDE). Algorithmic challenges are to reduce streaking and shadow artifacts characterized by the fundamental solution of the PDE. Bayesian maximum a posteriori estimation can be employed to solve the inverse problem, where morphological and relevant biomedical knowledge (specific to the imaging situation) are used as priors. As the cost functions in Bayesian QSM framework are typically convex, solutions can be robustly computed using a gradient-based optimization algorithm. Moreover, one can not only accelerate Bayesian QSM, but also increase its effectiveness at reducing shadows using prior knowledge based preconditioners. Improving the efficiency of QSM is under active development, and a rigorous analysis of preconditioning needs to be carried out for further investigation.Quantitative susceptibility mapping (QSM) solves the magnetic field-to-magnetization (tissue susceptibility) inverse problem under conditions of noisy and incomplete field data acquired using magnetic resonance imaging. Therefore, sophisticated algorithms are necessary to treat the ill-posed nature of the problem and are reviewed here. The forward problem is typically presented as an integral form, where the field is the convolution of the dipole kernel and tissue susceptibility distribution. This integral form can be equivalently written as a partial differential equation (PDE). Algorithmic challenges are to reduce streaking and shadow artifacts characterized by the fundamental solution of the PDE. Bayesian maximum a posteriori estimation can be employed to solve the inverse problem, where morphological and relevant biomedical knowledge (specific to the imaging situation) are used as priors. As the cost functions in Bayesian QSM framework are typically convex, solutions can be robustly computed using a gradient-based optimization algorithm. Moreover, one can not only accelerate Bayesian QSM, but also increase its effectiveness at reducing shadows using prior knowledge based preconditioners. Improving the efficiency of QSM is under active development, and a rigorous analysis of preconditioning needs to be carried out for further investigation. PMID- 28885150 TI - Fixed Points of Belief Propagation-An Analysis via Polynomial Homotopy Continuation. AB - Belief propagation (BP) is an iterative method to perform approximate inference on arbitrary graphical models. Whether BP converges and if the solution is a unique fixed point depends on both the structure and the parametrization of the model. To understand this dependence it is interesting to find all fixed points. In this work, we formulate a set of polynomial equations, the solutions of which correspond to BP fixed points. To solve such a nonlinear system we present the numerical polynomial-homotopy-continuation (NPHC) method. Experiments on binary Ising models and on error-correcting codes show how our method is capable of obtaining all BP fixed points. On Ising models with fixed parameters we show how the structure influences both the number of fixed points and the convergence properties. We further asses the accuracy of the marginals and weighted combinations thereof. Weighting marginals with their respective partition function increases the accuracy in all experiments. Contrary to the conjecture that uniqueness of BP fixed points implies convergence, we find graphs for which BP fails to converge, even though a unique fixed point exists. Moreover, we show that this fixed point gives a good approximation, and the NPHC method is able to obtain this fixed point. PMID- 28885149 TI - Learning from Narrated Instruction Videos. AB - Automatic assistants could guide a person or a robot in performing new tasks, such as changing a car tire or repotting a plant. Creating such assistants, however, is non-trivial and requires understanding of visual and verbal content of a video. Towards this goal, we here address the problem of automatically learning the main steps of a task from a set of narrated instruction videos. We develop a new unsupervised learning approach that takes advantage of the complementary nature of the input video and the associated narration. The method sequentially clusters textual and visual representations of a task, where the two clustering problems are linked by joint constraints to obtain a single coherent sequence of steps in both modalities. To evaluate our method, we collect and annotate a new challenging dataset of real-world instruction videos from the Internet. The dataset contains videos for five different tasks with complex interactions between people and objects, captured in a variety of indoor and outdoor settings. We experimentally demonstrate that the proposed method can automatically discover, learn and localize the main steps of a task in input videos. PMID- 28885151 TI - Sharable and Individual Multi-View Metric Learning. AB - This paper presents a sharable and individual multi-view metric learning (MvML) approach for visual recognition. Unlike conventional metric leaning methods which learn a distance metric on either a single type of feature representation or a concatenated representation of multiple types of features, the proposed MvML jointly learns an optimal combination of multiple distance metrics on multi-view representations, where not only it learns an individual distance metric for each view to retain its specific property but also a shared representation for different views in a unified latent subspace to preserve the common properties. The objective function of the MvML is formulated in the large margin learning framework via pairwise constraints, under which the distance of each similar pair is smaller than that of each dissimilar pair by a margin. Moreover, to exploit the nonlinear structure of data points, we extend MvML to a sharable and individual multi-view deep metric learning (MvDML) method by utilizing the neural network architecture to seek multiple nonlinear transformations. Experimental results on face verification, kinship verification, and person re-identification show the effectiveness of the proposed sharable and individual multi-view metric learning methods. PMID- 28885152 TI - Multimodal Breast Parenchymal Patterns Correlation Using a Patient-Specific Biomechanical Model. AB - In this paper, we aim to produce a realistic 2-D projection of the breast parenchymal distribution from a 3-D breast magnetic resonance image (MRI). To evaluate the accuracy of our simulation, we compare our results with the local breast density (i.e., density map) obtained from the complementary full-field digital mammogram. To achieve this goal, we have developed a fully automatic framework, which registers MRI volumes to X-ray mammograms using a subject specific biomechanical model of the breast. The optimization step modifies the position, orientation, and elastic parameters of the breast model to perform the alignment between the images. When the model reaches an optimal solution, the MRI glandular tissue is projected and compared with the one obtained from the corresponding mammograms. To reduce the loss of information during the ray casting, we introduce a new approach that avoids resampling the MRI volume. In the results, we focus our efforts on evaluating the agreement of the distributions of glandular tissue, the degree of structural similarity, and the correlation between the real and synthetic density maps. Our approach obtained a high-structural agreement regardless the glandularity of the breast, whilst the similarity of the glandular tissue distributions and correlation between both images increase in denser breasts. Furthermore, the synthetic images show continuity with respect to large structures in the density maps. PMID- 28885153 TI - Thee-Dimensional Single-Track-Location Shear Wave Elasticity Imaging. AB - Conventional multiple-track-location shear wave elasticity imaging (MTL-SWEI) is a powerful tool for noninvasively estimating tissue elasticity. The resolution and noise levels of MTL-SWEI systems, however, are limited by ultrasound speckle. Single-track-location SWEI (STL-SWEI) is a novel variant which fixes the position of the tracking beam and modulates the push location to effectively cancel out the effects of speckle-induced bias. We present here a 3-D STL-SWEI system, which provides full suppression of lateral and elevation speckle bias for high resolution volumetric elasticity imaging, and requires no spatial smoothing to make accurate measurements of shear wave speed. We demonstrate and analyze the system's performance in homogeneous and layered elasticity phantoms. PMID- 28885154 TI - Sequence Synopsis: Optimize Visual Summary of Temporal Event Data. AB - Event sequences analysis plays an important role in many application domains such as customer behavior analysis, electronic health record analysis and vehicle fault diagnosis. Real-world event sequence data is often noisy and complex with high event cardinality, making it a challenging task to construct concise yet comprehensive overviews for such data. In this paper, we propose a novel visualization technique based on the minimum description length (MDL) principle to construct a coarse-level overview of event sequence data while balancing the information loss in it. The method addresses a fundamental trade-off in visualization design: reducing visual clutter vs. increasing the information content in a visualization. The method enables simultaneous sequence clustering and pattern extraction and is highly tolerant to noises such as missing or additional events in the data. Based on this approach we propose a visual analytics framework with multiple levels-of-detail to facilitate interactive data exploration. We demonstrate the usability and effectiveness of our approach through case studies with two real-world datasets. One dataset showcases a new application domain for event sequence visualization, i.e., fault development path analysis in vehicles for predictive maintenance. We also discuss the strengths and limitations of the proposed method based on user feedback. PMID- 28885156 TI - The VSPA Foot: A Quasi-Passive Ankle-Foot Prosthesis With Continuously Variable Stiffness. AB - Most commercially available prosthetic feet do not exhibit a biomimetic torque angle relationship, and are unable to modulate their mechanics to assist with other mobility tasks, such as stairs and ramps. In this paper, we present a quasi passive ankle-foot prosthesis with a customizable torque-angle curve and an ability to quickly modulate ankle stiffness between tasks. The customizable torque-angle curve is obtained with a cam-based transmission and a fiberglass leaf spring. To achieve variable stiffness, the leaf spring's support conditions can be actively modulated by a small motor, shifting the torque-angle curve to be more or less stiff. We introduce the design, characterize the available torque angle curves, and present kinematics from a transtibial amputee subject performing level-ground walking, stair ascent/descent, and ramp ascent/descent. The subject exhibited a more normative range of motion on stairs and ramps at lower stiffness levels, and preferred different stiffness levels for each task. Paired with an appropriate intent recognition system, our novel ankle prosthesis could improve gait biomechanics during walking and many other mobility tasks. PMID- 28885155 TI - A Nonlinear Dynamics-Based Estimator for Functional Electrical Stimulation: Preliminary Results From Lower-Leg Extension Experiments. AB - Miniature inertial measurement units (IMUs) are wearable sensors that measure limb segment or joint angles during dynamic movements. However, IMUs are generally prone to drift, external magnetic interference, and measurement noise. This paper presents a new class of nonlinear state estimation technique called state-dependent coefficient (SDC) estimation to accurately predict joint angles from IMU measurements. The SDC estimation method uses limb dynamics, instead of limb kinematics, to estimate the limb state. Importantly, the nonlinear limb dynamic model is formulated into state-dependent matrices that facilitate the estimator design without performing a Jacobian linearization. The estimation method is experimentally demonstrated to predict knee joint angle measurements during functional electrical stimulation of the quadriceps muscle. The nonlinear knee musculoskeletal model was identified through a series of experiments. The SDC estimator was then compared with an extended kalman filter (EKF), which uses a Jacobian linearization and a rotation matrix method, which uses a kinematic model instead of the dynamic model. Each estimator's performance was evaluated against the true value of the joint angle, which was measured through a rotary encoder. The experimental results showed that the SDC estimator, the rotation matrix method, and EKF had root mean square errors of 2.70 degrees , 2.86 degrees , and 4.42 degrees , respectively. Our preliminary experimental results show the new estimator's advantage over the EKF method but a slight advantage over the rotation matrix method. However, the information from the dynamic model allows the SDC method to use only one IMU to measure the knee angle compared with the rotation matrix method that uses two IMUs to estimate the angle. PMID- 28885157 TI - Conformational Space Sampling Method Using Multi-Subpopulation Differential Evolution for De novo Protein Structure Prediction. AB - Protein structure prediction can be considered as a multimodal optimization problem for sampling the protein conformational space associated with an extremely complex energy landscape. To address this problem, a conformational space sampling method using multi-subpopulation differential evolution, MDE, is proposed. MDE first devotes to generate given numbers of concerned modal under the ultrafast shape recognition-based modal identification protocol, which regards each individual as one modal at beginning. Then, differential evolution is used for keeping the preserved modal survival in the evolution process. Meanwhile, a local descent direction used to sample along with is constructed based on the abstract convex underestimate technique for modal enhancement, which could enhance the ability of sampling in the region with lower energy. Through the sampling process of evolution, several certain clusters contain a series of conformations in proportion to the energy score will be obtained. Representative conformations in the generated clusters can be directly picked out as decoy conformations for further refinement with no extra clustering operation needs. A total of 20 target proteins are tested, in which ten target proteins are tested for comparison with Rosetta and three evolutionary algorithms, and ten easy/hard target proteins in CASP 11 are tested for further verifying the effectiveness of MDE. Test results show strong sampling ability that MDE holds, and near-native conformations can be effectively obtained. PMID- 28885158 TI - Reduction of Qualitative Models of Biological Networks for Transient Dynamics Analysis. AB - Qualitative models of dynamics of signalling pathways and gene regulatory networks allow for the capturing of temporal properties of biological networks while requiring few parameters. However, these discrete models typically suffer from the so-called state space explosion problem which makes the formal assessment of their potential behaviors very challenging. In this paper, we describe a method to reduce a qualitative model for enhancing the tractability of analysis of transient reachability properties. The reduction does not change the dimension of the model, but instead limits its degree of freedom, therefore reducing the set of states and transitions to consider. We rely on a transition centered specification of qualitative models by the mean of automata networks. Our framework encompasses the usual asynchronous Boolean and multi-valued network, as well as 1-bounded Petri nets. Applied to different large-scale biological networks from the litterature, we show that the reduction can lead to a drastic improvement for the scalability of verification methods. PMID- 28885159 TI - Identification of protein complexes by using a spatial and temporal active protein interaction network. AB - The rapid development of proteomics and high-throughput technologies has produced a large amount of Protein-Protein Interaction (PPI) data, which makes it possible for considering dynamic properties of protein interaction networks (PINs) instead of static properties. Identification of protein complexes from dynamic PINs becomes a vital scientific problem for understanding cellular life in the post genome era. Up to now, a plenty of models or methods have been proposed for the construction of dynamic PINs to identify protein complexes. However, most of the constructed dynamic PINs just focus on the temporal dynamic information and thus overlook the spatial dynamic information of the complex biological systems.To address the limitation of the existing dynamic PIN analysis approaches, in this paper, we propose a new model-based scheme for the construction of the Spatial and Temporal Active Protein Interaction Network (ST-APIN) by integrating time course gene expression data and subcellular location information. To evaluate the efficiency of ST-APIN, the commonly used classical clustering algorithm MCL is adopted to identify protein complexes from ST-APIN and the other three dynamic PINs, NF-APIN, DPIN, TC-PIN. The experimental results show that, the performance of MCL on ST-APIN outperforms those on the other three dynamic PINs in terms of matching with known complexes, sensitivity, specificity and f-measure. Furthermore, we evaluate the identified protein complexes by GO (Gene Ontology) function enrichment analysis. The validation shows that the identified protein complexes from ST-APIN are more biologically significant. This study provides a general paradigm for constructing the ST-APINs, which is essential for further understanding of molecular systems and the biomedical mechanism of complex diseases. PMID- 28885160 TI - A Differential Electrochemical Readout ASIC With Heterogeneous Integration of Bio Nano Sensors for Amperometric Sensing. AB - A monolithic biosensing platform is presented for miniaturized amperometric electrochemical sensing in CMOS. The system consists of a fully integrated current readout circuit for differential current measurement as well as on-die sensors developed by growing platinum nanostructures (Pt-nanoS) on top of electrodes implemented with the top metal layer. The circuit is based on the switch-capacitor technique and includes pseudodifferential integrators for concurrent sampling of the differential sensor currents. The circuit further includes a differential to single converter and a programmable gain amplifier prior to an ADC. The system is fabricated in [Formula: see text] technology and measures current within [Formula: see text] with minimum input-referred noise of [Formula: see text] and consumes [Formula: see text] from a [Formula: see text] supply. Differential sensing for nanostructured sensors is proposed to build highly sensitive and offset-free sensors for metabolite detection. This is successfully tested for bio-nano-sensors for the measurement of glucose in submilli molar concentrations with the proposed readout IC. The on-die electrodes are nanostructured and cyclic voltammetry run successfully through the readout IC to demonstrate detection of [Formula: see text]. PMID- 28885161 TI - Virtual and Augmented Reality Systems for Renal Interventions: A Systematic Review. AB - PURPOSE: Many virtual and augmented reality systems have been proposed to support renal interventions. This paper reviews such systems employed in the treatment of renal cell carcinoma and renal stones. METHODS: A systematic literature search was performed. Inclusion criteria were virtual and augmented reality systems for radical or partial nephrectomy and renal stone treatment, excluding systems solely developed or evaluated for training purposes. RESULTS: In total, 52 research papers were identified and analyzed. Most of the identified literature (87%) deals with systems for renal cell carcinoma treatment. About 44% of the systems have already been employed in clinical practice, but only 20% in studies with ten or more patients. Main challenges remaining for future research include the consideration of organ movement and deformation, human factor issues, and the conduction of large clinical studies. CONCLUSION: Augmented and virtual reality systems have the potential to improve safety and outcomes of renal interventions. In the last ten years, many technical advances have led to more sophisticated systems, which are already applied in clinical practice. Further research is required to cope with current limitations of virtual and augmented reality assistance in clinical environments. PMID- 28885162 TI - Adaptive Approximation-Based Regulation Control for a Class of Uncertain Nonlinear Systems Without Feedback Linearizability. AB - In this paper, for a general class of uncertain nonlinear (cascade) systems, including unknown dynamics, which are not feedback linearizable and cannot be solved by existing approaches, an innovative adaptive approximation-based regulation control (AARC) scheme is developed. Within the framework of adding a power integrator (API), by deriving adaptive laws for output weights and prediction error compensation pertaining to single-hidden-layer feedforward network (SLFN) from the Lyapunov synthesis, a series of SLFN-based approximators are explicitly constructed to exactly dominate completely unknown dynamics. By the virtue of significant advancements on the API technique, an adaptive API methodology is eventually established in combination with SLFN-based adaptive approximators, and it contributes to a recursive mechanism for the AARC scheme. As a consequence, the output regulation error can asymptotically converge to the origin, and all other signals of the closed-loop system are uniformly ultimately bounded. Simulation studies and comprehensive comparisons with backstepping- and API-based approaches demonstrate that the proposed AARC scheme achieves remarkable performance and superiority in dealing with unknown dynamics. PMID- 28885163 TI - Closeness-Centrality-Based Synchronization Criteria for Complex Dynamical Networks With Interval Time-Varying Coupling Delays. AB - This paper investigates synchronization in complex dynamical networks (CDNs) with interval time-varying delays. The CDNs are representative of systems composed of a large number of interconnected dynamical units, and for the purpose of the mathematical analysis, the leading work is to model them as graphs whose nodes represent the dynamical units. At this time, we take note of the importance of each node in networks. One way, in this paper, is that the closeness-centrality mentioned in the field of social science is grafted onto the CDNs. By constructing a suitable Lyapunov-Krasovskii functional, and utilizing some mathematical techniques, the sufficient and closeness-centrality-based conditions for synchronization stability of the networks are established in terms of linear matrix inequalities. Ultimately, the use of the closeness-centrality can be weighted with regard to not only the interconnection relation among the nodes, which was utilized in the existing works but also more information about nodes. Here, the centrality will be added as the concerned information. Moreover, to avoid the computational burden causing the nonconvex term including the square of the time-varying delay, how to deal with it is applied by estimating it to the convex term including time-varying delay. Finally, two illustrative examples are given to show the advantage of the closeness-centrality in point of the robustness on time-delay. PMID- 28885164 TI - A Diversity-Enhanced Resource Allocation Strategy for Decomposition-Based Multiobjective Evolutionary Algorithm. AB - The multiobjective evolutionary algorithm (MOEA) based on decomposition transforms a multiobjective optimization problem into a set of aggregated subproblems and then optimizes them collaboratively. Since these subproblems usually have different degrees of difficulty, resource allocation (RA) strategies have been reported to enhance performance, attempting to dynamically assign proper amounts of computational resources for the solution of each of these subproblems. However, existing schemes for decomposition-based MOEAs fully rely on the relative improvement of the aggregated functions to do this. This paper proposes a diversity-enhanced RA strategy for this kind of MOEA, depending on both relative improvement on aggregated function value and solution density around each subproblem to assign computational resources. Thus, one subproblem surrounded with fewer solutions in its neighboring area and more relative improvement on the aggregated function value will be allocated a higher probability for evolution. Our experimental results show the advantages of our proposed strategy over two popular RA strategies available for decomposition based MOEAs, on tackling a set of complicated benchmark problems. PMID- 28885165 TI - Synchronization Control for a Class of Discrete-Time Dynamical Networks With Packet Dropouts: A Coding-Decoding-Based Approach. AB - The synchronization control problem is investigated for a class of discrete-time dynamical networks with packet dropouts via a coding-decoding-based approach. The data is transmitted through digital communication channels and only the sequence of finite coded signals is sent to the controller. A series of mutually independent Bernoulli distributed random variables is utilized to model the packet dropout phenomenon occurring in the transmissions of coded signals. The purpose of the addressed synchronization control problem is to design a suitable coding-decoding procedure for each node, based on which an efficient decoder based control protocol is developed to guarantee that the closed-loop network achieves the desired synchronization performance. By applying a modified uniform quantization approach and the Kronecker product technique, criteria for ensuring the detectability of the dynamical network are established by means of the size of the coding alphabet, the coding period and the probability information of packet dropouts. Subsequently, by resorting to the input-to-state stability theory, the desired controller parameter is obtained in terms of the solutions to a certain set of inequality constraints which can be solved effectively via available software packages. Finally, two simulation examples are provided to demonstrate the effectiveness of the obtained results. PMID- 28885166 TI - Robust Fusion of Color and Depth Data for RGB-D Target Tracking Using Adaptive Range-Invariant Depth Models and Spatio-Temporal Consistency Constraints. AB - This paper presents a novel robust method for single target tracking in RGB-D images, and also contributes a substantial new benchmark dataset for evaluating RGB-D trackers. While a target object's color distribution is reasonably motion invariant, this is not true for the target's depth distribution, which continually varies as the target moves relative to the camera. It is therefore nontrivial to design target models which can fully exploit (potentially very rich) depth information for target tracking. For this reason, much of the previous RGB-D literature relies on color information for tracking, while exploiting depth information only for occlusion reasoning. In contrast, we propose an adaptive range-invariant target depth model, and show how both depth and color information can be fully and adaptively fused during the search for the target in each new RGB-D image. We introduce a new, hierarchical, two-layered target model (comprising local and global models) which uses spatio-temporal consistency constraints to achieve stable and robust on-the-fly target relearning. In the global layer, multiple features, derived from both color and depth data, are adaptively fused to find a candidate target region. In ambiguous frames, where one or more features disagree, this global candidate region is further decomposed into smaller local candidate regions for matching to local layer models of small target parts. We also note that conventional use of depth data, for occlusion reasoning, can easily trigger false occlusion detections when the target moves rapidly toward the camera. To overcome this problem, we show how combining target information with contextual information enables the target's depth constraint to be relaxed. Our adaptively relaxed depth constraints can robustly accommodate large and rapid target motion in the depth direction, while still enabling the use of depth data for highly accurate reasoning about occlusions. For evaluation, we introduce a new RGB-D benchmark dataset with per frame annotated attributes and extensive bias analysis. Our tracker is evaluated using two different state-of-the-art methodologies, VOT and object tracking benchmark, and in both cases it significantly outperforms four other state-of-the art RGB-D trackers from the literature. PMID- 28885167 TI - Event-Triggered Distributed Control of Nonlinear Interconnected Systems Using Online Reinforcement Learning With Exploration. AB - In this paper, a distributed control scheme for an interconnected system composed of uncertain input affine nonlinear subsystems with event triggered state feedback is presented by using a novel hybrid learning scheme-based approximate dynamic programming with online exploration. First, an approximate solution to the Hamilton-Jacobi-Bellman equation is generated with event sampled neural network (NN) approximation and subsequently, a near optimal control policy for each subsystem is derived. Artificial NNs are utilized as function approximators to develop a suite of identifiers and learn the dynamics of each subsystem. The NN weight tuning rules for the identifier and event-triggering condition are derived using Lyapunov stability theory. Taking into account, the effects of NN approximation of system dynamics and boot-strapping, a novel NN weight update is presented to approximate the optimal value function. Finally, a novel strategy to incorporate exploration in online control framework, using identifiers, is introduced to reduce the overall cost at the expense of additional computations during the initial online learning phase. System states and the NN weight estimation errors are regulated and local uniformly ultimately bounded results are achieved. The analytical results are substantiated using simulation studies. PMID- 28885168 TI - Generalized Multi-View Embedding for Visual Recognition and Cross-Modal Retrieval. AB - In this paper, the problem of multi-view embedding from different visual cues and modalities is considered. We propose a unified solution for subspace learning methods using the Rayleigh quotient, which is extensible for multiple views, supervised learning, and nonlinear embeddings. Numerous methods including canonical correlation analysis, partial least square regression, and linear discriminant analysis are studied using specific intrinsic and penalty graphs within the same framework. Nonlinear extensions based on kernels and (deep) neural networks are derived, achieving better performance than the linear ones. Moreover, a novel multi-view modular discriminant analysis is proposed by taking the view difference into consideration. We demonstrate the effectiveness of the proposed multi-view embedding methods on visual object recognition and cross modal image retrieval, and obtain superior results in both applications compared to related methods. PMID- 28885169 TI - Connectivity-Preserving Approach for Distributed Adaptive Synchronized Tracking of Networked Uncertain Nonholonomic Mobile Robots. AB - This paper addresses a distributed connectivity-preserving synchronized tracking problem of multiple uncertain nonholonomic mobile robots with limited communication ranges. The information of the time-varying leader robot is assumed to be accessible to only a small fraction of follower robots. The main contribution of this paper is to introduce a new distributed nonlinear error surface for dealing with both the synchronized tracking and the preservation of the initial connectivity patterns among nonholonomic robots. Based on this nonlinear error surface, the recursive design methodology is presented to construct the approximation-based local adaptive tracking scheme at the robot dynamic level. Furthermore, a technical lemma is established to analyze the stability and the connectivity preservation of the total closed-loop control system in the Lyapunov sense. An example is provided to illustrate the effectiveness of the proposed methodology. PMID- 28885170 TI - Event-Triggered Control for the Disturbance Decoupling Problem of Boolean Control Networks. AB - This paper investigates the disturbance decoupling problem (DDP) of Boolean control networks (BCNs) by event-triggered control. Using the semi-tensor product of matrices, algebraic forms of BCNs can be achieved, based on which, event triggered controllers are designed to solve the DDP of BCNs. In addition, the DDP of Boolean partial control networks is also derived by event-triggered control. Finally, two illustrative examples demonstrate the effectiveness of proposed methods. PMID- 28885171 TI - Gestational Age and Outcomes in Critical Congenital Heart Disease. AB - BACKGROUND AND OBJECTIVES: It is unknown how gestational age (GA) impacts neonatal morbidities in infants with critical congenital heart disease (CCHD). We aim to quantify GA-specific mortality and neonatal morbidity in infants with CCHD. METHODS: Cohort study using a database linking birth certificate, infant hospital discharge, readmission, and death records, including infants 22 to 42 weeks' GA without chromosomal anomalies (2005-2012, 2 988 925 live births). The International Classification of Diseases, Ninth Revision diagnostic and procedure codes were used to define CCHD and neonatal morbidities (intraventricular hemorrhage, retinopathy, periventricular leukomalacia, chronic lung disease, necrotizing enterocolitis). Adjusted absolute risk differences (ARDs) with 95% confidence intervals (CIs) were calculated. RESULTS: We identified 6903 out of 2 968 566 (0.23%) infants with CCHD. The incidence of CCHD was highest at 29 to 31 weeks' GA (0.9%) and lowest at 39 to 42 weeks (0.2%). Combined neonatal morbidity or mortality in infants with and without CCHD was 82.8% and 57.9% at <29 weeks and declined to 10.9% and 0.1% at 39 to 42 weeks' GA. In infants with CCHD, being born at 34 to 36 weeks was associated with a higher risk of death or morbidity than being born at 37 to 38 weeks (adjusted ARD 9.1%, 95% CI 5.5% to 12.7%), and being born at 37 to 38 weeks was associated with a higher risk of death or morbidity than 39 to 42 weeks (adjusted ARD 3.2%, 95% CI 1.6% to 4.9%). CONCLUSIONS: Infants born with CCHD are at high risk of neonatal morbidity. Morbidity remains increased across all GA groups in comparison with infants born at 39 to 42 weeks. This substantial risk of neonatal morbidity is important to consider when caring for this patient population. PMID- 28885172 TI - Status and Prospects of Next Generation Sequencing Technologies in Crop Plants. AB - The history of DNA sequencing dates back to 1970s. During this period the two first generation nucleotide sequencing techniques were developed. Subsequently the Sanger's dideoxy method of sequencing gained popularity over Maxam and Gilbert's chemical method of sequencing. However, in the last decade, we have observed revolutionary changes in DNA sequencing technologies leading to the emergence of next-generation sequencing (NGS) techniques. NGS technologies have enhanced the throughput and speed of sequencing combined with bringing down the overall cost of the process over a time. The major applications of NGS technologies being genome sequencing and resequencing, transcriptomics, metagenomics in relation to plant-microbe interactions, exon and genome capturing, development of molecular markers and evolutionary studies. In this review, we present a broader picture of evolution of NGS tools, its various applications in crop plants, and future prospects of the technology for crop improvement. PMID- 28885173 TI - Next-Generation Sequencing Promoted the Release of Reference Genomes and Discovered Genome Evolution in Cereal Crops. AB - In recent decades, next-generation sequencing (NGS) was developed and brought biology into a new era. Rice, maize, wheat, sorghum and barley are the most important cereal crops and feed most of the world's population. Great progress in the study of cereal genomes has been made with the help of NGS. Reference genome sequence assembly and re-sequencing have grown exponentially. Thus, evolution and comparative genomics are renewed, including origin verification, evolution tracking and so on. In this review, we briefly record the development of sequencing technology, the comparison of next-generation sequencing methods and platforms and summarize the bioinformatics tools used for NGS data analysis. We describe how NGS accelerates reference genome assembly and new evolutionary findings. We finally discuss how to discover more valuable resources and improve cereal breeding in the future. PMID- 28885174 TI - Advanced Applications of Next-Generation Sequencing Technologies to Orchid Biology. AB - Next-generation sequencing technologies are revolutionizing biology by permitting, transcriptome sequencing, whole-genome sequencing and resequencing, and genome-wide single nucleotide polymorphism profiling. Orchid research has benefited from this breakthrough, and a few orchid genomes are now available; new biological questions can be approached and new breeding strategies can be designed. The first part of this review describes the unique features of orchid biology. The second part provides an overview of the current next-generation sequencing platforms, many of which are already used in plant laboratories. The third part summarizes the state of orchid transcriptome and genome sequencing and illustrates current achievements. The genetic sequences currently obtained will not only provide a broad scope for the study of orchid biology, but also serves as a starting point for uncovering the mystery of orchid evolution. PMID- 28885175 TI - Bioinformatics Resources for Plant Genomics: Opportunities and Bottlenecks in The -omics Era. AB - The sudden exponential increase of biological data concerning genome structure and functionalities, also fostered by the advent of Next Generation Sequencing (NGS) technologies, while expanding the opportunity to highlight still uncovered molecular aspects, challenges bioinformatics in several repects. Data management, processing, updating, dissemination and integration are the major areas of concern. The rapid increase in various omics technologies causes two major issues, which may even appear contrasting: the dissemination of poorly curated datasets, still in the form of raw collections or preliminary draft results, and the fast updating of information that, as a consequence, affects the establishment of stable reliable resources. These issues are mainly caused by the lower rate of bioinformatics in extracting added value information from the large amount of data, when compared to the faster technologies involved in data production. This review describes main bioinformatics resources for plants genomics to underline the heterogeneity of the available collections, coherent with the multifaceted complexity of plant sciences. It aims to provide an in depth report highlighting bottlenecks that may significantly affect a fluent progress in the field and attempts to suggest possible solutions to the various issues. PMID- 28885176 TI - Applications of Bioinformatics to Plant Biotechnology. AB - Bioinformatics encompasses many tools and techniques that today are essential for all areas of research in the biological sciences. New databases with a wealth of information about genomes, proteins, metabolites, and metabolic pathways appear almost daily. Particularly, for scientists who carry out research in plant biology, the amount of information has multiplied exponentially due to the large number of databases available for many individual plant species. In this sense, bioinformatics together with next generation sequencing and 'omics' approaches, can provide tools for plant breeding and the genetic engineering of plants. In addition, these technologies enable a better understanding of the processes and mechanisms that can lead to plants with increased tolerance to different abiotic stress conditions and resistance to pathogen attack, as well as the development of crop varieties with improved nutritional quality of seeds and fruits. PMID- 28885177 TI - Quantitative Genetics of Disease Resistance in Wheat. AB - Wheat (Triticum aestivum L.) is one of the top three global food security crops. Fusarium head blight is one of the major constraints in sustainable wheat production and resistance to the disease is polygenic. This review provides an overview of recent efforts in mapping these genes/loci with the objective to aid marker-assisted selection breeding. PMID- 28885178 TI - A Rice Genetic Improvement Boom by Next Generation Sequencing. AB - Rice (Oryza sativa L.) is a staple food crop for people worldwide, and a key goal has been to increase its grain yield. An increasing population that relies on a decreasing level of farmland has rendered the traditional method for the isolation and use of genetic loci in rice breeding unsatisfactory. Recently, the rapid development in next generation sequencing (NGS) has boosted the number of genome sequences for hundreds to thousands of rice varieties. A MutMap strategy and bulk segregation analysis (BSA) has been developed to directly identify candidate genes based on NGS. The genome-wide association analysis (GWAS) has become a commonly used approach toward identifying the genetic loci and candidate genes for several traits that are closely associated with grain yield. The Multi parent Advanced Generation Inter-Cross population (MAGIC) is introduced here to discuss potential applications for mapping QTLs for rice varietal development. These strategies broaden the capacity of functional gene identification and its application as a complementary method to insert mutants that comprise T-DNA and transposons. High-throughput SNP analysis platforms, such as the SNP array, provide novel strategies for genomic-assisted selections (GAS) for rice genetic improvements. Moreover, accurate genome sequence information enables genome editing for the utilization of key recessive genes that control important agronomic traits. This review summarizes how NGS accelerates rice genetic improvements through the identification and utilization of key functional genes that regulate agronomic traits. PMID- 28885179 TI - Dual RNA-Sequencing to Elucidate the Plant-Pathogen Duel. AB - RNA-sequencing technology has been widely adopted to investigate host responses during infection with pathogens. Dual RNA-sequencing (RNA-seq) allows the simultaneous capture of pathogen specific transcripts during infection, providing a more complete view of the interaction. In this review, we focus on the design of dual RNA-seq experiments and the application of downstream data analysis to gain biological insight into both sides of the interaction. Recent literature in this area demonstrates the power of the dual RNA-seq approach and shows that it is not limited to model systems where genomic resources are available. A reduction in sequencing cost and single cell transcriptomics coupled with protein and metabolite level dual approaches are set to enhance our understanding of plant-pathogen interactions. Sequencing costs continue to decrease and single cell transcriptomics is becoming more feasible. In combination with proteomics and metabolomics studies, these technological advances are likely to contribute to our understanding of the temporal and spatial aspects of dynamic plant pathogen interactions. PMID- 28885180 TI - Next-Generation Sequencing Sheds New Light on Small RNAs in Plant Reproductive Development. AB - Reproductive development is a key step of the plant life cycles and indicates the start of a new life cycle. The reproductive organs including flower, fruit and seed, have diverse and complex structures, which is a syndrome in the evolution of angiosperms. The development of plant reproductive organs depends on the correct spatial and temporal expression of numerous genes acting in concert to form regulatory networks. Small non-coding RNAs (sRNAs) play a key role in the reproductive development through different modes of sequence-specific interaction with their targets. The sRNAs guide transcriptional and post-transcriptional regulation to intensively integrate into the complex process. Next generation sequencing techniques (NGS) has greatly extended scientist's capabilities to identified and quantify sRNAs by supplying a massive of sequences. In turn this has led to a greater understanding of the many complex roles and interactions that sRNAs are involved with during reproductive development. In this review, we provide an overview of the biogenesis and classification of plant sRNAs, and summarize the recent progress in the understanding of plant sRNA in the flower, and fruit/seed development. Also, we discuss NGS approaches to profile global sRNA expression, as well as the application of sRNA-seq/degradome-seq approaches to identify novel sRNAs and verify their targets related to the above development processes. PMID- 28885181 TI - ChIP-Seq: A Powerful Tool for Studying Protein-DNA Interactions in Plants. AB - DNA-binding proteins, including transcription factors, epigenetic and chromatin modifiers, control gene expressions in plants. To pinpoint the binding sits of DNA-binding proteins in genome is crucial for decoding gene regulatory networks. Chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-Seq) is a widely used approach to identify the DNA regions bound by a specific protein in vivo. The information generated from ChIP-Seq has tremendously advanced our understanding on the mechanism of transcription factors, cofactors and histone modifications in regulating gene expression. In this review, we reviewed the recent research advance of ChIP-Seq in plants, including description of the ChIP-Seq workflow and its various applications in plants, and in addition, provided perspective of the potential advances of ChIP Seq. PMID- 28885182 TI - Cataloging Plant Genome Structural Variations. AB - Structural variation (SV) is a type of genetic variation identified through the comparison of genome structures which often have direct and significant associations with phenotypic variations. Building on the next generation sequencing (NGS) technologies, research on plant structural variations are gaining momentum and have revolutionized our view on the functional impact of the 'hidden' diversity that were largely understudied before. Herein, we first describe the current state of plant genomic SV research based on NGS and in particular focus on the biological insights gained from the large-scale identification of various types of plant SVs. Specific examples are chosen to demonstrate the genetic basis for phenotype diversity in model plant and major agricultural crops. Additionally, development of new genomic mapping technologies, including optical mapping and long read sequencing, as well as improved computational algorithms associated with these technologies have helped to pinpoint the exact nature and location of genomic SVs with much better resolution and precision. Future direction of plant research on SVs should focus on the population level to build a comprehensive catalog of SVs, leading to full assessment of their impact on biological diversity. PMID- 28885183 TI - From Microscopy to Genomic Approach in Soil Biodiversity Assessment. AB - Soil biota represents a major component of the earth's biodiversity and for over 200 years, the microscopy approach was the only way to explore it. In the last decade, the DNA-based technique has been adopted in soil ecology. Due to the rapid development of cutting-edge technology, the field is transitioning from barcoding individuals to metabarcoding communities. With the advent of next generation sequencing and a rapid decline in sequencing cost, it has become feasible to assess soil biodiversity at species level. This review article summarizes current approaches in soil biodiversity research along with their advantages and disadvantages. PMID- 28885184 TI - Balsam-pear-like rutile/anatase core/shell titania nanorod arrays for photoelectrochemical water splitting. AB - In this work, a solution combustion followed by dissolution in hydrogen peroxide is adopted to achieve a precursor for decorating anatase TiO2 nanosheets along single-crystalline rutile TiO2 nanorods, which achieves balsam-pear-like core/shell nanorod arrays with enhanced photoelectrochemical water splitting. The photocurrent of the rutile/anatase nanorods is about 1.4 times and 20.7 times that of the rutile nanorods and the anatase nanosheets at 0.8 V vs SCE, respectively. The enhanced photoelectrochemical performance is attributed to the novel nanoarchitecture, which can simultaneously offer high surface area, enhanced light-harvesting, rutile/anatase junction for charge carrier separation and conductive pathway for charge carrier collection. The photoanode design can also give hints to other functional materials. PMID- 28885185 TI - Nanoscale x-ray investigation of magnetic metallofullerene peapods. AB - Endohedral lanthanide ions packed inside carbon nanotubes (CNTs) in a one dimensional assembly have been studied with a combination of high resolution transmission electron microscopy (HRTEM), scanning transmission x-ray microscopy (STXM), and x-ray magnetic circular dichroism (XMCD). By correlating HRTEM and STXM images we show that structures down to 30 nm are resolved with chemical contrast and record x-ray absorption spectra from endohedral lanthanide ions embedded in individual nanoscale CNT bundles. XMCD measurements of an Er3N@C80 bulk sample and a macroscopic assembly of filled CNTs indicate that the magnetic properties of the endohedral Er3+ ions are unchanged when encapsulated in CNTs. This study demonstrates the feasibility of local magnetic x-ray characterisation of low concentrations of lanthanide ions embedded in molecular nanostructures. PMID- 28885186 TI - High-speed true random number generation based on paired memristors for security electronics. AB - True random number generator (TRNG) is a critical component in hardware security that is increasingly important in the era of mobile computing and internet of things. Here we demonstrate a TRNG using intrinsic variation of memristors as a natural source of entropy that is otherwise undesirable in most applications. The random bits were produced by cyclically switching a pair of tantalum oxide based memristors and comparing their resistance values in the off state, taking advantage of the more pronounced resistance variation compared with that in the on state. Using an alternating read scheme in the designed TRNG circuit, the unbiasedness of the random numbers was significantly improved, and the bitstream passed standard randomness tests. The Pt/TaO x /Ta memristors fabricated in this work have fast programming/erasing speeds of ~30 ns, suggesting a high random number throughput. The approach proposed here thus holds great promise for physically-implemented random number generation. PMID- 28885187 TI - A review on mechanical considerations for chronically-implanted neural probes. AB - This review intends to present a comprehensive analysis of the mechanical considerations for chronically-implanted neural probes. Failure of neural electrical recordings or stimulation over time has shown to arise from foreign body reaction and device material stability. It seems that devices that match most closely with the mechanical properties of the brain would be more likely to reduce the mechanical stress at the probe/tissue interface, thus improving body acceptance. The use of low Young's modulus polymers instead of hard substrates is one way to enhance this mechanical mimetism, though compliance can be achieved through a variety of means. The reduction of probe width and thickness in comparison to a designated length, the use of soft hydrogel coatings and the release in device tethering to the skull, can also improve device compliance. Paradoxically, the more compliant the device, the more likely it will fail during the insertion process in the brain. Strategies have multiplied this past decade to offer partial or temporary stiffness to the device to overcome this buckling effect. A detailed description of the probe insertion mechanisms is provided to analyze potential sources of implantation failure and the need for a mechanically enhancing structure. This leads us to present an overview of the strategies that have been put in place over the last ten years to overcome buckling issues. Particularly, great emphasis is put on bioresorbable polymers and their assessment for neural applications. Finally, a discussion is provided on some of the key features for the design of mechanically-reliable, polymer-based next generation of chronic neuroprosthetic devices. PMID- 28885188 TI - Ab initio phonon thermal transport in monolayer InSe, GaSe, GaS, and alloys. AB - We compare vibrational properties and phonon thermal conductivities (kappa) of monolayer InSe, GaSe, and GaS systems using density functional theory and Peierls Boltzmann transport methods. In going from InSe to GaSe to GaS, system mass decreases giving both increasing acoustic phonon velocities and decreasing scattering of these heat-carrying modes with optic phonons, ultimately giving kappaInSe < kappaGaSe < kappaGaS. This behavior is demonstrated by correlating the scattering phase space limited by fundamental conservation conditions with mode scattering rates and phonon dispersions for each material. We also show that, unlike flat monolayer systems such as graphene, in InSe, GaSe and GaS thermal transport is governed by in-plane vibrations. Alloying of InSe, GaSe, and GaS systems provides an effective method for modulating their kappa through intrinsic vibrational modifications and phonon scattering from mass disorder giving reductions ~ 2-3.5 times. This disorder also suppresses phonon mean free paths in the alloy systems compared to those in their crystalline counterparts. This work provides fundamental insights of lattice thermal transport from basic vibrational properties for an interesting set of two dimensional materials. PMID- 28885189 TI - Addendum: Measurement of charged particle yields from PMMA irradiated by a 220 MeV/u 12C beam. AB - In this paper we report the re-analysis of the data published in (Piersanti et al. 2014) documenting the charged secondary particles production induced by the interaction of a 220 MeV/u 12C ion beam impinging on a polymethyl methacrylate (PMMA) target, measured in 2012 at the GSI facility in Darmstadt (Germany). This re-analysis takes into account the inhomogeneous light response of the LYSO crystal in the experimental setup measured in a subsequent experiment (2014) performed in the Heidelberg Ion- Beam Therapy Center. A better description of the detector and re-calculation of the geometrical efficiencies have been implemented as well, based on an improved approach that accounts also for the energy dependence of the emission spectrum. The new analysis has small effect on the total secondary charged flux, but has an impact on the production yield and emission velocity distributions of the different particle species (protons, deuterons and tritons) at different angles with respect to the beam direction (60 degrees and 90 degrees ). All these observables indeed depend on the particle identification algorithms and hence on the LYSO detector energy response. The results of the data re-analysis presented here are intended to supersede and replace the results published in (Piersanti et al. 2014). PMID- 28885190 TI - Film dosimetry using a smart device camera: a feasibility study for point dose measurements. AB - In this work, a methodology for using a smartphone camera, in conjunction with a light-tight box operating in reflective transmission mode, is investigated as a proof of concept for use as a film dosimetry system. An imaging system was designed to allow the camera of a smartphone to be used as a pseudo densitometer. Ten pieces of Gafchromic EBT3 film were irradiated to doses up to 16.89 Gy and used to evaluate the effects of reproducibility and orientation, as well as the ability to create an accurate dose response curve for the smartphone based dosimetry system, using all three colour channels. Results were compared to a flatbed scanner system. Overall uncertainty was found to be best for the red channel with an uncertainty of 2.4% identified for film irradiated to 2.5 Gy and digitised using the smartphone system. This proof of concept exercise showed that although uncertainties still exceed a flatbed scanner system, the smartphone system may be useful for providing point dose measurements in situations where conventional flatbed scanners (or other dosimetry systems) are unavailable or unaffordable. PMID- 28885191 TI - Radiation dose and risk in children undergoing cardiac interventions performed using flat detector angiography systems. AB - The purpose of the study was to measure radiation doses and estimate risk from various beam projections in children undergoing cardiac interventions. The dose area product (DAP) was measured for eleven patent ductus arteriosus device closures (PDA), four atrial septal defect device closures (ASD), and three balloon pulmonary valvuloplasty (BPV) interventions performed using a flat detector system. The total mean DAPs for PDA, ASD and BPV were 1.9 Gycm2, 9.8 Gycm2 and 6.2 Gycm2 respectively. The fluoroscopic kerma dose rates increased by 10%, 33% and 92% when changing the projection from posterior-anterior to lateral projection for PDA interventions among infants, <5 yrs and >5 yrs respectively. The effective dose (ED) and organ doses were estimated from DAP using Monte Carlo software. Lungs received the highest organ dose of 7.4 mGy (PDA), 20.7 mGy (ASD) and 17.3 mGy (BPV) compared to other organs. The mean EDs from PDA, ASD and BPV were 2.5 mSv, 6.1 mSv and 4.9 mSv respectively. PDA intervention performed in infants had a radiation risk 66% higher than children aged between 3-10 years. Their lifetime attributable risk as per BEIR VII for cancer incidence was 1 in 907 males and 1 in 1047 females. PMID- 28885192 TI - Confinement sensitivity in quantum dot singlet-triplet relaxation. AB - Spin-orbit mediated phonon relaxation in a two-dimensional quantum dot is investigated using different confining potentials. Elliptical harmonic oscillator and cylindrical well results are compared to each other in the case of a two electron GaAs quantum dot subjected to a tilted magnetic field. The lowest energy set of two-body singlet and triplet states are calculated including spin-orbit and magnetic effects. These are used to calculate the phonon induced transition rate from the excited triplet to the ground state singlet for magnetic fields up to where the states cross. The roll of the cubic Dresselhaus effect, which is found to be much more important than previously assumed, and the positioning of 'spin hot-spots' are discussed and relaxation rates for a few different systems are exhibited. PMID- 28885193 TI - Time crystals: a review. AB - Time crystals are time-periodic self-organized structures postulated by Frank Wilczek in 2012. While the original concept was strongly criticized, it stimulated at the same time an intensive research leading to propositions and experimental verifications of discrete (or Floquet) time crystals-the structures that appear in the time domain due to spontaneous breaking of discrete time translation symmetry. The struggle to observe discrete time crystals is reviewed here together with propositions that generalize this concept introducing condensed matter like physics in the time domain. We shall also revisit the original Wilczek's idea and review strategies aimed at spontaneous breaking of continuous time translation symmetry. PMID- 28885194 TI - Evidence for thermal activation in the glassy dynamics of insulating granular aluminum conductance. AB - Insulating granular aluminum is one of the proto-typical disordered insulators whose low temperature electrical conductance exhibits ubiquitous non-equilibrium phenomena. These include slow responses to temperature or gate voltage changes, characteristic field effect anomalies and ageing phenomena typical of a glass. In this system the influence of temperature on the glassy dynamics has remained elusive. A similar situation was met in insulating indium oxide and it was concluded that in high carrier density Anderson insulators, electronic slow relaxations essentially proceed via activationless processes. In this work we experimentally demonstrate that thermal effects do play a role and that the slow dynamics in granular aluminum is subject to thermal activation. We show how its signatures can be revealed and activation energy distributions can be extracted, providing a promising grasp on the nature of the microscopic mechanism at work in glassy Anderson insulators. We explain why some of the experimental protocols previously used in the literature fail to reveal thermal activation in these systems. Our results and analyses call for a reassessment of the emblematic case of indium oxide, and question the existence of purely activationless dynamics in any of the systems studied so far. PMID- 28885195 TI - SERRS and absorption spectra of pyridine on Au m Ag n (m + n = 6) bimetallic nanoclusters: substrate composition and applied electric field effects. AB - Surface-enhanced Raman scattering (SERS) and absorption spectra of the pyridine molecule adsorbed on Au m Ag n (m + n = 6) bimetallic clusters are theoretically investigated by time-dependent density functional theory. The contributions of static chemical enhancement to the ground-state system are analyzed, and the static Raman intensity of Py-Au m Ag n complexes are enhanced by an order of 10. A method of visualization on charge transfer is used to distinguish the contributions of charge-transfer enhancement and electromagnetic enhancement. The intensity of surface-enhanced resonance Raman scattering (SERRS) spectroscopy of Py-Au m Ag n is strongly enhanced by an order of 103-105, compared to the static Raman intensity of pyridine. The influence of the static external electric field on SERS is investigated by calculating the optical properties of the Py-Au3Ag3 complex. The intensity of SERRS spectra and normal Raman spectra can be significantly enhanced by the positive electric fields, and the intensities of specific Raman vibrational modes could be selectively enhanced or weakened by tuning the direction and strength of the static electric field applied on Py Au3Ag3. PMID- 28885196 TI - Propagation of registration uncertainty during multi-fraction cervical cancer brachytherapy. AB - Multi-fraction cervical cancer brachytherapy is a form of image-guided radiotherapy that heavily relies on 3D imaging during treatment planning, delivery, and quality control. In this context, deformable image registration can increase the accuracy of dosimetric evaluations, provided that one can account for the uncertainties associated with the registration process. To enable such capability, we propose a mathematical framework that first estimates the registration uncertainty and subsequently propagates the effects of the computed uncertainties from the registration stage through to the visualizations, organ segmentations, and dosimetric evaluations. To ensure the practicality of our proposed framework in real world image-guided radiotherapy contexts, we implemented our technique via a computationally efficient and generalizable algorithm that is compatible with existing deformable image registration software. In our clinical context of fractionated cervical cancer brachytherapy, we perform a retrospective analysis on 37 patients and present evidence that our proposed methodology for computing and propagating registration uncertainties may be beneficial during therapy planning and quality control. Specifically, we quantify and visualize the influence of registration uncertainty on dosimetric analysis during the computation of the total accumulated radiation dose on the bladder wall. We further show how registration uncertainty may be leveraged into enhanced visualizations that depict the quality of the registration and highlight potential deviations from the treatment plan prior to the delivery of radiation treatment. Finally, we show that we can improve the transfer of delineated volumetric organ segmentation labels from one fraction to the next by encoding the computed registration uncertainties into the segmentation labels. PMID- 28885197 TI - Cardiac frequency and cutaneous microcirculation during and after exercising in the view of physical condition. AB - INTRODUCTION: In the field of cardiovascular diseases an ergometer test is a common diagnostical method in which a change in microcirculation can be reached. In this paper cardiac frequency and cutaneous microcirculation during and after exercising will be compared with each other. MATERIALS AND METHODS: The cutaneous microcirculation of 6 healthy volunteers (2 females, 4 males) is measured. As an instrument the PeriFlux 5000 combined with a Laser-Doppler-Flow(LDF)-Probe (Perimed Instruments) is used. The cardiac frequency (CF) is measured by the POLAR T31 sensor and as an ergometer the ERGO-FIT (r) 457 is used. RESULTS: The mean initial LDF (97,7+/-57,3 PU) decreases at the beginning (64,5+/-21,7 PU), increases during theexercise, reaches its maximum (247,8+/-82,1 PU) after the end of the exercise and drops to lower values (256,4+/-69,5 PU)after a few minutes. Contrasting to the LDF the mean initial CF (86+/-22/min) increases at the beginning (97+/-9/min),furthermore during the whole exercise (103+/-9/min) and then falls after having finished the exercise (96+/-3/min).Furthermore, during regeneration, one can see the CF decreasing towards its initial value, while LDF reaches its maximum. CONCLUSION: In further studies, realized with volunteers with well-known levels of physical condition, a directconnection between cutaneous microcirculation and physical condition might be found. PMID- 28885198 TI - Engineering of cell-laden gelatin-based microgels for cell delivery and immobilization in regenerative therapies. AB - Cell-based therapies often face the challenge of low cell retention and viability upon transplantation. Hence, biomaterials, which can immobilize transplanted cells, while at the same time support cell viability, are essential for successful clinical application. Noteworthy, biomaterials in the micrometer range such as microcapsules or microspheres have the advantage of a minimally invasive introduction into tissue.Hence, we established an approach to generate gelatin based cell carriers in the form of microspherical hydrogels. Fibroblasts were microencapsulated in glycidylmethacrylate (GMA)-functionalized gelatin by photopolymerization. While the degree of GMA-functionalization was kept constant, the hydrogel cross-linking density was adjusted by varying the time of irradiation or the average gelatin-chain length.Stable microspheres were synthesized from 10 wt% GMA-gelatin solutions for all irradiation periods tested (0.5 -2 min). Evaluation of cell viability revealed that microgels with the same weight content of biopolymer but with decreased cross-linking densities and thus decreased storage and E modulus, resulted in best cell support. Noteworthy, encapsulated cells partially migrated out of the microspheres and attached to the spherical surface.10 wt% GMA-gelatin-based hydrogels with E moduli comparable to the native cellular niche proved to be a promising biomaterial suitable for the production of cell-laden microspheres and shall be evaluated further for biomedical application. PMID- 28885199 TI - Adipogenic differentiation of human adipose derived mesenchymal stem cells in 3D architectured gelatin based hydrogels (ArcGel). AB - Polymeric matrices mimicking multiple functions of the ECM are expected to enable a material induced regeneration of tissues. Here, we investigated the adipogenic differentiation of human adipose derived mesenchymal stem cells (hADSCs) in a 3D architectured gelatin based hydrogel (ArcGel) prepared from gelatin and L-lysine diisocyanate ethyl ester (LDI) in an one-step process, in which the formation of an open porous morphology and the chemical network formation were integrated. The ArcGel was designed to support adipose tissue regeneration with its 3D porous structure, high cell biocompatibility, and mechanical properties compatible with human subcutaneous adipose tissue. The ArcGel could support initial cell adhesion and survival of hADSCs. Under static culture condition, the cells could migrate into the inner part of the scaffold with a depth of 840+/-120 MUm after 4 days, and distributed in the whole scaffold (2 mm in thickness) within 14 days. The cells proliferated in the scaffold and the fold increase of cell number after 7 days of culture was 2.55+/-0.08. The apoptotic rate of hADSCs in the scaffold was similar to that of cells maintained on tissue culture plates. When cultured in adipogenic induction medium, the hADSCs in the scaffold differentiated into adipocytes with a high efficiency (93+/-1%). Conclusively, this gelatin based 3D scaffold presented high cell compatibility for hADSC cultivation and differentiation, which could serve as a potential implant material in clinical applications for adipose tissue reparation and regeneration. PMID- 28885200 TI - Divisive influence of interleukin-1 receptor antagonist polymorphisms in melanoma patients. AB - OBJECTIVE: The interleukin-1 receptor antagonist (IL-1RA) contributes to tumor survival and progression in multiple cancer entities. IL-1RA polymorphisms influence IL-1RA expression patterns and function. A known polymorphism was correlated with clinical outcomes in melanoma patients with particularly aggressive disease. METHODS: DNA of 343 controls and 97 melanoma patients with poor prognostic indicators (time from diagnosis to death, nodal status, metastasis) was analyzed for a variable number of tandem repeat polymorphisms (VNTR) of the IL-1RA gene. Five alleles containing two (allele 2), three (allele 4), four (allele 1), five (allele 3) or six (allele 5) 86-bp repeats were targeted via PCR amplification. RESULTS: Genotype 1/2 is less common in the melanoma patient group vs. the control (28.8% vs. 39.6%; p = 0.06). Significant was the stage of the melanoma in order to predict the survivability (p = 0.008). The 1/1 and 1/2 genotype appeared to have lower hazards ratios than the 2/2 genotype (p > 0.05). CONCLUSIONS: Compared to the general population, the distribution of alleles coding for IL-1RA is different in melanoma patients. This alteration and the potential impact on tumor protein function and systemic inflammatory response may warrant further investigation. PMID- 28885201 TI - The mechanisms of late scaffold thrombosis. AB - Coronary scaffolds have been recently developed to address the long-term limitations of metallic drug eluting stents. Concerns have however been expressed on the safety of these devices, with evidence of both early and late scaffold thrombosis. While early thrombosis has been associated with incomplete scaffold expansion, leading to flow disturbances, blood recirculation, and platelet activation, the pathophysiology of late events remains less understood. Recent cases series have shown that malapposition and scaffold dismantling might play a role in this phenomenon, an observation that further confirms the importance of an accurate implantation. Further, the role of dual antiplatelet therapy, and whether prolonging it may reduce event rates, remains to be elucidated. As well, the role of inflammatory phenomena has been proposed but never demonstrated. This brief review summarizes the current evidence on these phenomena. PMID- 28885202 TI - Reference range and variability of Laser-Doppler-Fluxmetry. AB - The Laser Doppler technique (Laser-Doppler-Fluxmetry, LDF), a noninvasive method to estimate skin blood flow (LDF), is frequently used in research and clinical routine [1]. Here, the measurements were carried out with a new Laser Doppler system, the DOP-system, which allows to measure frequency spectra in four different frequency windows according to the velocities in venules (low velocity), capillaries (low to medium velocities), and in arteries (with high and very high velocities). However, the diagnostic reliability or the effectiveness of the LDF has not yet been evaluated sufficiently, which is indispensable, where medical diagnostics and therapy controls are concerned. For a valid interpretation of LDF values of individual patients, the knowledge of the reference range and the variability of the measured parameters is required.In four successive studies the reference range (62 apparently healthy subjects), the circadian variability (8 subjects), the variability from day-to-day (6 subjects) and over one year with monthly measurements (6 subjects) were evaluated.With the knowledge of the reference range, microcirculatory disorders can now be diagnosed using the DOP method. Following a standard measurement procedure there was no dependence of the measured data on the day or season of measurement. PMID- 28885203 TI - Vascular malformations of upper and lower extremity - from radiological interventional therapy to surgical soft tissue reconstruction - an interdisciplinary treatment. AB - This article presents our experience in managing peripheral vascular malformations of upper and lower extremities over a 4-year period in a series of 46 patients of the Department of Plastic Surgery treated in the Interdisciplinary Center of Vascular Anomalies (ICVA) at the University of Regensburg. The patients presented vascular malformations of upper and lower extremity and were selected from our prospective vascular anomalies file archive from 2012 to 2016. During this period in the ICVA at University of Regensburg were performed more than 1400 radiological interventional treatments in patients with vascular malformations.The purpose of this retrospective study was to review combined embolotherapy, sclerotherapy (embolo/sclerotherapy), and surgical procedures (surgical excision and soft tissue reconstruction) to manage vascular malformations. Treatments were principally induced to reduce pain, daily physical limitations, social discomfort and recover tegument continuity after ulceration.The 46 patients were first examined with noninvasive radiological procedures. After diagnosis was posed, embolo/sclerotherapy, surgical procedures and clinically as well as radiological follow-ups were coordinated and established by the multidisciplinary team. All vascular malformations were categorized according to the classification approved at the April 2014 General Assembly of International Society for the Study of Vascular Anomalies (ISSVA) in Melbourne, Australia. Arteriovenous malformations (AVMs) were further classified following the Cho-Do and Schobinger classification.Embolo/sclerotherapy shows to be the most appropriate procedure in vascular malformations treatment. Nevertheless was found that in case of complications or lack of improvement as well as to improve functional or aesthetical results, a following partial or complete surgical excision and immediate soft tissue reconstruction seems to be the gold-standard treatment. In addition, the precise clinical and radiological diagnosis as well as an intensive postoperative patient care have a significant positive influence on the clinical outcome and patient satisfaction while decreasing morbidity and recurrence during early and late follow-up.Vascular malformations require a multidisciplinary approach and individual treatment after complex excision and indispensable reconstruction. PMID- 28885204 TI - Quantitative evaluation of real-time maximum liver capacity (LiMAx) and time intensity curve (TIC) analysis in CEUS-based microperfusion. AB - PURPOSE: To compare the diagnostic performance of real-time maximum liver capacity (LiMAx) with dynamic contrast-enhanced ultrasound (CEUS)-based liver microcirculation. MATERIALS AND METHODS: 23 patients underwent liver function capacity (LiMAx) test and consecutive or previous CEUS examinations. A bolus injection of 1.4 ml sulfur hexafluoride microbubbles was administered for CEUS measurements (1-6 MHz) and quantitative perfusion analysis (TIC) was performed with an integrated perfusion software using stored cine-loops. Two perfusion parameters, time to peak (TtoP) and area under the curve (Area), were evaluated in liver parenchyma and portal vein using TIC analysis.To compare quantification parameters, patients were classified in patients representing a healthy population (LiMAx value >315 MUg/kg/h) and those representing patients with liver disease (LiMAx value <315 MUg/kg/h). RESULTS: Comparing perfusion parameters derived from portal vein measurements, TtoP and Area were higher in patients with normal liver function TtoP: 25.0+/-8.4 s, Area: 1483+/-920 a.u. compared to patients with impaired liver function TtoP: 22.4+/-14.0 s; Area 1351+/-1212 a.u. This difference however was not statistically significant (p = 0.52, p = 0.48).In parameters derived from measurements in liver parenchyma TtoP was higher (38.5+/ 11.3 s) and Area was lower (999+/-632 a.u.) in patients with normal liver function compared to patients with impaired liver function (TtoP; 30.6+/-11.0 s, p = 0.156; Area: 1202+/-719 a.u.) (p = 0.16, p = 0.56).In a simple linear regression model, none of the perfusion parameters measured in portal vein (TtoP portal, Area portal) and liver parenchyma (TtoP liver, Area liver) correlated significantly with respective LiMAx values (p = 0.194-0.950). CONCLUSION: Within the framework of this study, CEUS-based perfusion parameters were not able to assess severity of liver disease, assessed with LiMAx- test. PMID- 28885205 TI - Reduced microperfusion due to portal vein thrombosis: Impact on the outcome of percutaneous thermal tumor ablation. AB - PURPOSE: To determine the influence of pre-interventionally existing portal vein thrombosis on the ablation success of percutaneous tumor ablation of HCC. MATERIALS AND METHODS: 15 patients with HCC and pre-existing portal vein thrombosis underwent thermal tumor ablation. We retrospectively analyzed the pre- and post-interventionally performed CT and MRI scans in terms of technical success as well as the complication rate. The portal vein thrombosis was classified into segmental, lobar and central thrombus. RESULTS: In 13/15 cases (87%) complete ablation with no evidence of residual tumor tissue was seen 6 weeks after the procedure in contrast-enhanced MRI scans and contrast-enhanced ultrasound (CEUS). No major and 2 minor complications were observed after the ablation procedure. CONCLUSION: Reduced perfusion due to pre-interventionally existing portal vein thrombosis has no significant impact on the ablation success or the complication rate. PMID- 28885206 TI - Ultrasound elastography in diagnosis and follow-up for patients with chronic recurrent parotitis. AB - PURPOSE: Chronic recurrent parotitis (CRP) is a non-obstructive disease with episodes characterized by painful swelling of the parotid gland. It presents in both a juvenile and an adult form, with no clear information on its actual origin. Diagnosis is based on patient medical history and ultrasound examination but is frequently not correctly identified. Acoustic Radiation Force Impulse Imaging (ARFI) is a novel ultrasound elastography technology that has recently been implemented in the diagnostic work-up of patients with malignancies. This study aimed to answer whether ARFI can reasonably be employed in the initial examination and follow-up during therapy in patients with CRP. MATERIAL AND METHODS: Mechanical tissue properties of the salivary glands were analyzed by ARFI in 37 parotid glands of patients with CRP. RESULTS: Having integrated ARFI into our diagnostic protocol for CRP, affected parotid glands were found to exhibit lower tissue elasticity compared to both healthy contralateral glands in the same individuals as well as those of healthy individuals. Most importantly, this method enabled us to quantitatively assess the patient benefit of therapy regarding the recovery of the glands' diseased parenchyma. CONCLUSIONS: ARFI provides a quick, easy, and reliable diagnostic tool for the assessment of disease severity and progression in patients with CRP that can be seamlessly implemented into preexisting ultrasound protocols. PMID- 28885207 TI - Effect of irreversible electroporation of prostate cancer on microcirculation: Imaging findings in contrast-enhanced T1-weighted 3D MRI. AB - OBJECTIVES: Irreversible electroporation (IRE) is a novel focal ablation technique applicable for treatment of prostate cancer (PCa). We aim to evaluate imaging findings of T1-weighted contrast-enhanced MRI after percutaneous IRE of low-risk PCa. METHODS: A total of 13 male patients underwent IRE of focal low risk PCa and were included in this analysis. Prostate IRE was conducted using 2-4 electrodes being placed under CT-fluoroscopy guidance. Dynamic contrast-enhanced 3D isotropic fat-saturated T1-weighted MRI (DCE-MRI) was performed 24-72 hours before and 24-72 hours after ablation. RESULTS: Ablated prostate was either homogeneously (8/13 [62%]) or heterogeneously (5/13 [38%]) hypo attenuating. Peripheral contrast enhancement manifesting as a hyper attenuating margin was observed during the arterial (60 sec) (3/13 [23%]) and venous (240 sec) (10/13 [77%]) phase. The ablation defect showed a sharp (8/13 [62%]) or blurry (5/13 [38%]) margin. CONCLUSIONS: The results show a venous peripheral rim enhancement in most of the cases, indicating reactive hyperaemia. The heterogeneous appearance of the defect zone in some cases may be secondary to sustained vascularization. PMID- 28885208 TI - The diagnostic value of contrast-enhanced ultrasound (CEUS) as a new technique for imaging of vascular complications in renal transplants compared to standard imaging modalities. AB - BACKGROUND: Vascular complications in renal transplant patients are a well-known issue in post transplant patient care. If malfunctioning of the renal transplant is suspected to be caused by vascular complications an early diagnosis and therapy is required to maintain the renal transplant. Computed tomography (CT), digital substraction angiography (DSA) and radioisotope renography are the gold standard imaging modalities to diagnose vascular complications. OBJECTIVE: To analyse the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) in comparison to the standard imaging modalities CT, DSA and radioisotope renography in the diagnosis of vascular complications in renal transplant patients. METHODS: A total of 33 renal transplant recipients with elevated kidney function parameters with initial diagnostic imaging between 2006 and 2017 were included in the study. The imaging studies and clinical data were analysed retrospectively. The diagnostic accuracy of CEUS was compared to CT, DSA and renal scintigraphy respectively which are classified as gold standard for diagnosis of vascular complications in renal transplant patients. Out of 23 patients 15 patients showed vascular complications in CT, DSA or radioisotope renography and in 15 out of 15 patients CEUS detected the vascular complication. RESULTS: CEUS showed a sensitivity of 100%, a specificity of 66.7%, a positive predictive value (PPV) of 71.4%, and a negative predictive value (NPV) of 100%. CONCLUSIONS: CEUS is a non nephrotoxic and safe method for the initial imaging of vascular complications in renal transplant recipients. Compared to the gold standard imaging modalities CT, DSA and radioisotope renography CEUS shows a high sensitivity and NPV in detecting vascular complications. In cases with suspected stenosis of the transplant renal artery additional DSA might be needed. PMID- 28885209 TI - Investigation of the acute plantar fasciitis with contrast-enhanced ultrasound and shear wave elastography - first results. AB - BACKGROUND: The plantar fasciitis is a common disease with a high prevalence in public and a frequent cause of heel pain. OBJECTIVE: In our pilot study, we wanted to characterise the feasibility of shear-wave elastography and contrast enhanced ultrasound (CEUS) in the assessment of the plantar fasciitis. METHODS: 23 cases of painful heels were examined by B-Mode ultrasound, Power Doppler (PD), shear wave elastography and contrast-enhanced ultrasound before anti-inflammatory radiation. Time-intensity-curves were analysed by the integrated software. The results for area-under-the-curve (AUC), peak, time-to-peak (TTP) and mean-transit time (MTT) were compared between the plantar fascia and the surrounding tissue. RESULTS: All cases showed thickening of the plantar fascia, in most cases with interstitial oedema (87.0%). Shear wave elastography showed inhomogeneous stiffness of the plantar fascia. 83.3% of cases showed a visible hyperperfusion in CEUS at the proximal plantar fascia in comparison to the surrounding tissue. This hyperperfusion could also be found in 75.0% of cases with no signs of vascularisation in PD. AUC (p = 0.0005) and peak (p = 0.037) were significantely higher in the plantar fascia than in the surrounding tissue. CONCLUSION: CEUS and shear wave elastography are new diagnostic tools in the assessment of plantar fasciitis and can provide quantitative parameters for monitoring therapy. PMID- 28885210 TI - Does Virtual Touch IQ elastography help to improve the preoperative diagnosis of parotid tumors: A prospective trial. AB - BACKGROUND: It is difficult to assess tumors of the parotid gland preoperatively. However, it is essential for the surgeon to know which kind of tumor is present. Ultrasound is the method of choice, but there is still no reliable differential diagnostic tool for determining whether a tumor is malignant or benign. OBJECTIVE: The aim of our study was to examine the value of Virtual Touch imaging quantification (VTIQ) elastograpy in distinguishing between malignant and benign tumors as well as in identifying the most common benign tumor types. METHODS: The parenchyma of 100 parotid glands and 12 lymph nodes of healthy volunteers and 50 tumors of the parotid gland were analyzed via ultrasound, color Doppler ultrasound, and VTIQ, and the results were then compared with histopathology. RESULTS: In comparison with benign tumors, in malignant tumors the tumor border was diffuse, the perfusion higher, and the VTIQ quality much lower. Share wave velocity of the user-defined region of interest was more frequently higher than 6.8 m/s in malignant tumors in comparison to benign tumors. CONCLUSIONS: VTIQ in combination with ultrasound examination provides additional information for distinguishing between benign and malignant tumors and shows promise for integration into preexisting ultrasound protocols. PMID- 28885211 TI - Postoperative control of functional muscle flaps for facial palsy reconstruction: Ultrasound guided tissue monitoring using contrast enhanced ultrasound (CEUS) and ultrasound elastography. AB - BACKGROUND AND OBJECTIVES: Facial paralysis causes excruciating impairments including facial asymmetry, limited eye closure, oral incontinence and social dysfunction. Modern plastic surgical reconstructions render favorable results with well-perfused dynamic muscle flaps. Post-operative tissue monitoring is a critical determinant for success. Contrast-enhanced Ultrasound (CEUS) and elastography have proven superior properties to evaluate tissue perfusion in various organs. We evaluated their role for functional muscle flaps positioned at the sub-skin level in facial palsy patients. METHODS: From 2016-2017 five patients received muscle flap reconstructions. Flaps included four free transplants and one pedicled transfer. Postoperatively tissue vitality and blood flow were assessed with CEUS. One experienced examiner using linear probes (6-9, 6-15 MHz) and bolus injections of Sulphur-hexafluoride microbubbles evaluated tissue perfusion. Using the time intensity curve- (TIC)-analysis measurements were recorded for TTP (time to peak) and AUC (Area under curve). Tissue elasticity was assessed with ultrasound elastography. RESULTS: All flaps were successful and showed no major complications. TTP-values in flap tissue showed slightly decreased values of 35.12+/-33.99 s and 25.04+/-10.86 s compared to surrounding tissue with 19.88+/-6.94 s. AUC-analysis however revealed higher values of 292.25+/-169.52 RU and 274.51+/-115.88 RU than surrounding tissue with 150.90+/-40.21 RU. Elastography demonstrated predominantly elastic flap tissue whereas surrounding tissue confirmed a slightly harder tissue quality. CEUS in combination with elastography verified tissue vitality and blood flow in a safe and reproducible manner. CONCLUSIONS: Post-operative perfusion monitoring in muscle flaps positioned at a sub-skin level may be performed superiorly by CEUS and elastography in a quick, reproducible and minimally-invasive fashion. PMID- 28885212 TI - Comparison of computed tomography (CT) and contrast-enhanced ultrasound (CEUS) for the quantitative evaluation of an ablation defect following radiofrequency ablation of malignant liver lesions. AB - OBJECTIVE: To compare contrast-enhanced computed tomography (CT) and contrast enhanced ultrasound (CEUS) for the quantitative evaluation of an ablation defect following radiofrequency ablation of malignant liver lesions in a prospective study. MATERIALS AND METHODS: 22 radiofrequency ablations of malignant liver tumors were performed. The ablation defects were then measured and evaluated by two independent examiners via contrast-enhanced computed tomography (CT) and contrast-enhanced ultrasound (CEUS) using a 1-5 MHz multifrequency convex ultrasound transducer (LOGIQ E9, GE) with respect to the short-axis diameter, the long-axis diameter, and the area. RESULTS: Quantitative evaluation of ablation defects is possible with both contrast-enhanced CT and CEUS. The average long axis diameter was 47.1 mm (+/-11.08;+/-23,5%) on CEUS and 56.48 mm (+/-14.14;+/ 25,0%) on CT; the short-axis diameter was 39.72 mm (+/-11.14;+/-28,05%) on CEUS and 40.27 mm (+/-10.50;+/-26,07%) on CT; the area was 1439.82 mm2 (+/-678.57;+/ 47,13%) on CEUS and 2392.68 mm2 (1147.67;+/-48,0%) on CT. On average, ablation defects are assessed to be larger on CT than on CEUS. A significant correlation between the modalities could not be achieved for all measurement axes. CONCLUSION: CEUS can be used for the postinterventional detection and evaluation of ablation defects. However, these are always assessed to be larger on contrast enhanced CT than CEUS. PMID- 28885213 TI - Presentation of a variation of the chorioallantoic membrane set up as a potential model for individual therapy for squamous cell carcinoma of the oropharynx. AB - The chorioallantoic membrane of fertilized chicken eggs in an early phase of breeding presents an approved test situation for the growth and treatment of human cancer cells.These models work due to the inoculation of cells into the membrane that stays within the egg shell during the time of investigation. In this study a modification of this model is presented. Samples of native tumors, rather than cell lines, are transplanted into the membrane and the body of the egg is taken out of the shell and placed in a plastic bowl. These modifications lead to an enhanced accessibility to the chorioallantoic membrane and the surrounding vessels thus facilitating intra venous access and application of pharmaceuticals and a focused radiotherapy. With the current modifications the embryo was kept alive and additionally, the vascularized tumor environment was preserved. PMID- 28885214 TI - Breast sensitivity after mastectomy and autologous reconstruction. AB - BACKGROUND: Breast Carcinoma is the most common malign tumor disease in women. 20 30% of these tumors have to be treated by removing all of the breast tissue. After that kind of therapeutic procedure, most of the women are severely traumatized and ask for reconstruction. The goldstandard of breast reconstruction is the free perforator flap from the lower abdomen (DIEAP-flap), which can provide body-own tissue and natural shape for the reconstructed breast.Many studies evaluate the shape of the reconstructed breast but neglect the skin sensitivity. Claim of this study was to compare this important part of reconstruction on two different techniques of mastectomy. OBJECTIVE: In this retrospective study we evaluated which technique of mastectomy and breast reconstruction with DIEAP-Flap offers the highest outcome for sensibility of the reconstructed breast. Skin sparing mastectomy was compared with conventional mastectomy and the results of skin sensitivity were measured. METHODS: Ten patients underwent breast reconstruction with free abdominal perforator flap between 2011 and 2015 after conventional mastectomy (CM) and were compared with ten patients, who had a skin sparing mastectomy (SSM) with immediate reconstruction by DIEAP-flap during the same time interval. These two groups were matched by age, height, weight and the time between reconstruction and examination. The sensitivity of the skin was measured by Semmes-Weinstein Filaments in the strength beginning from 0,07 g till 300 g for deep sensation. The logarithmic profile of these measurements had been transferred into a continuous data system beginning from 1 point, which stands for no sensation, till 7 points for pressure threshold of 0,07 g. RESULTS: Patients who underwent DIEAP-reconstruction after skin sparing mastectomy showed a higher sensation at all regions of the new breast in comparison to reconstruction after conventional mastectomy, beginning from the nipple to the areola and the breast skin. The results in the CM-group were 1.0 points at the mamilla, 1.33 pts. at the areola and 1.78 pts. at the breast skin. In the SSM-group, the findings were 3 pts. at the mamilla, 3.25 pts. at the areola and 5.25 pts. at the breast skin. CONCLUSION: The skin sparing mastectomy combined with immediate reconstruction by DIEAP-flap provides an excellent therapeutic option for patients, who are suitable for this technique, which takes into account not only the form but also the sensitivity of the breast. PMID- 28885215 TI - Hyperspectral imaging as a novel diagnostic tool in microcirculation of wounds. AB - : Monitoring of perfusion is a cornerstone in surgery, phlebology and basic science to proof wound healing by interventions. In chronic wound management it is of utmost importance to realize and parametrize wound bed perfusion to verify actual, and plan further treatment by noninvasive diagnostics. Up to now monitoring is based on visual inspection of wounds as conventionally practiced over more than decades. The main problems of visual inspection are the lack of standardization and comparability because of interindividual variations. Therefore technical performance with contact free probes based on standardized perfusion measuring is strongly needed. Hyperspectral imaging (HSI) was investigated to overcome manual and visual wound inspection in monitoring of wound healing. HSI works noninvasive, and imaging of relevant perfusion parameters is possible without the need of contrast enhancing drugs. METHODS: HSI technology uses imaging spectroscopic analysis in visual and near infrared spectrum to get information on imaged tissue in less than 10 s. Tissue is radiated by broad spectrum light and the following parameters are calculated from remitted spectra: the grade of oxygenation and the volume proportion of hemoglobin (in superficial and also deeper (8 mm) tissues. The calculated data comprise the "Tissue hemoglobin oxygen saturation" (StO2) as percental oxygenation index to assess superficial perfusion (VIS-spectrum), the "Near infrared perfusion" (NIR) to assess deeper perfusion (near infrared spectrum) and the "Tissue hemoglobin index" (THI) to measure the percental volume of hemoglobin of surface perfusion (VIS-spectrum). The measurements of these parameters are calculated as false color-coded perfusion results on screen.We investigated different kind of wounds (combustion, infection, ulcer wounds, wounds in immune disorders, trauma wounds) determining superficial and deeper oxygen saturation, hemoglobin distribution and water content using hyperspectral imaging with TIVITATM Tissue system. RESULTS: Hyperspectral Imaging allowed easy real time determination and visualization of hemodynamically relevant parameters- superficial and deeper oxygen saturation, total hemoglobin and tissue water content. In the patient with scleroderma, acral lesions with decreased perfusion correlated well with necrotic skin aspects.HSI clearly revealed macroscopic conspicuous suture wounds after Dupuytren surgery, infected soft tissue wounds with strong inflammatory hyperemia, edema in burn injuries, spatial geometry of abscess formation and chronic ulcer wounds. All measurements influenced further surveillance decisions. Hyperspectral imaging seems suitable for routine diagnostics and monitoring of skin and soft tissue lesions like acute and chronic wounds. It allows surveillance of postoperative suture wounds and burn wounds. Special indications may be transplant surveillance and monitoring of therapeutical interventions. PMID- 28885216 TI - Microcirculation measurements: Barriers for use in clinical routine. AB - BACKGROUND: In patients with shock, inflammation and sepsis alterations in microcirculation are common problems. Although the pathophysiologic consequences are well understood, measurements of microcirculation have not entered clinical routine so far. OBJECTIVE: To characterize the requirements for clinical microcirculation measurement techniques and the barriers for implementation into routine practice. METHODS: Clinical review of reliability, reproducibility, validity, availability and usefulness of clinically available measurement techniques to be used in patients with sepsis or cardiac surgery with cardiopulmonary bypass. RESULTS: Few methods such as video microscopy are readily available at the bedside, but are hampered by the high variability of measurements and the lack of reliable automated software analysis. The correlation of microcirculation impairment measured by in-vivo microscopy with fatal outcomes has been established, but no recommendations have been given which parameters should be targeted to improve outcomes. Measurement of regional brain tissue oxygenation has been recommended for cardiac surgery, but does not specifically target microcirculation. CONCLUSIONS: International guidelines for the management of sepsis or cardiac anesthesia do not recommend specific goals targeting the microcirculation directly, but global hemodynamics. The reason for this may be attributed to the lack of methods that fulfill the requirements necessary to be clinically acceptable. Once the validity, i.e. any improvement in patient's outcomes attributable to microcirculation measurements, can be established, clinical measurement of microcirculation could become part of routine treatment of patients with sepsis, inflammation and shock. Until then, more clinical studies targeting microcirculation are urgently needed. PMID- 28885217 TI - Continuing medical education and pharmaceutical industry involvement: An evaluation of policies adopted by Canadian professional medical associations. AB - BACKGROUND: Professional medical associations (PMAs) play a crucial role in providing accredited continuing medical education (CME) to physicians. Funding from the pharmaceutical industry may lead to biases in CME. OBJECTIVE: This study examines publicly available policies on CME, adopted by Canadian PMAs as of December 2015. METHODS: Policies were evaluated using an original scoring tool comprising 21 items, two questions about PMAs' general and CME funding from industry, and three enforcement measures. RESULTS: We assessed 236 policies adopted by Canadian PMAs (range, 0 to 32). Medical associations received summative scores that ranged from 0% to 49.2% of the total possible points (maximum score = 63). Twenty-seven associations received an overall score of 0%. The highest mean scores were achieved in the areas of industry involvement in planning CME activities (mean: 1.1/3), presence of a review process for topics of CME activities (mean: 1.1/3), content review for balanced information (mean: 1.1/3), and responsibility of distribution of funds (mean: 1.0/3). The lowest mean scores were achieved in the areas of awards (mean: 0.0/3), industry personnel, representatives, and employees (mean: 0.1/3), distribution of industry funded educational materials at CME activities (mean: 0.1/3), and distinction between marketing and educational materials (mean: 0.1/3). CONCLUSION: These results suggest that Canadian PMAs' publicly available policies on industry involvement in CME are generally weak or non-existent; therefore, the accredited CME that is provided to Canadian physicians may be viewed as open to bias. We encourage all Canadian medical associations to strengthen their policies to avoid the potential for industry influence in CME. PMID- 28885218 TI - Off-label use of medicines: The need for good practice guidelines. AB - BACKGROUND: 'Off-label use' is the term used for the prescription and dispensing of a medicinal product for any indication, patient group, route of administration, dosage or treatment regimen other than that listed in the Summary of Product Characteristics. OBJECTIVE: In this article the authors present a brief overview of current practices of off-label use in Europe and the applicable European law and jurisprudence. They then go on to present a set of guidelines for best practice in off-label use which underlines the need for guidance on prescription to be firmly rooted in the need to ensure patient safety above all other concerns. METHODS: The article was written from desk research and expert engagement, including a presentation and Q&A in the European Parliament. RESULTS: This article intends to demonstrate that off-label use entails increased risks for patients, especially when it is not underpinned by rigorous clinical studies or the reporting routes for use are not well defined. CONCLUSIONS: Europe is seeing a growing trend the promotion of off-label prescription of medicinal products for reasons other than pure medical need, including motives such as cost containment. This poses a numer of questions for the ethical and legal framework for medicine prescription and dispensing in Europe. PMID- 28885219 TI - Recognition of possible risk factors for clinically significant drug-drug interactions among Indian people living with HIV receiving highly active antiretroviral therapy and concomitant medications. AB - BACKGROUND: Greatest challenges for clinician is to recognize risk factors for clinically significant drug interactions (CSDIs). There is a lack of awareness about CSDIs among healthcare professionals in India. OBJECTIVE: To recognize all possible risk factors for drug-drug interactions (DDIs) and to identify clinically significant drug interactions (CSDIs), the prevalence, pattern of occurrence of DDIs in People Living with HIV (PLW-HIV) receiving highly active antiretroviral therapy (HAART) and concomitant medications. METHODS: A retrospective medical record review was carried out by clinical pharmacist with ethics committee approval. Case files of HIV patients receiving HAART with concomitant medications were analyzed for CSDIs using University of Liverpool drug interaction database and CSDIs were classified based on red flag indication (RFI) or contraindicated drug-drug interaction (XDDIs) and orange flag indication (OFI) or DDIs that needs close monitoring. Patients with DDIs (cases) and patients without DDIs (controls) were compared with Chi-square tests. P value <0.05 was considered as statistically significant. RESULTS: A total of 240 HIV patients' cases were screened. Out of which 267 DDIs were reported in 107 patients. Prevalence of DDIs was higher in male 71 (66.4%) compared to female 36 (33.6%). On zero-inflated poisson regression analysis, factors of polypharmacy, opportunistic infections, comorbid condition like Ischemic heart disease, respiratory tract infections, and psychiatric disorder were found to be predictors of high risk factors for DDIs to HAART. Fourteen XDDIs with RFI and two hundred fifty three DDIs with OFI were reported. XDDIs were atazanavir with fluconazole 4 (28.6%), ritonavir with fluconazole 4 (28.6%), nevirapine with rifampicin 2 (14.4%), ritonavir with quetiapine, atazanavir with pantoprazole. Pharmacokinetic DDIs were highest 238 (89.1%). Sixteen DDIs were reported in a single patient. The majority 97 (90.6%) patients had developed <=5 DDIs, 8 (7.5%) developed six to eleven DDIs. The highest DDIs were reported with efavirenz 49 (18.4%) and zidovudine 44 (16.5%) based HAART regimen. CONCLUSION: In India, with the increasing access to HAART usage, Clinician must focus to pay attention to recognize possible risk factors for CSDIs associated with HAART regimen and strictly to avoid "Red Flag Indication combinations" while prescribing so as to prevent CSDIs. PMID- 28885220 TI - Antidepressants and suicide among young women in Sweden 1999-2013. AB - OBJECTIVE: To establish whether the young women (15-24 year old) who committed suicide in Sweden (1999-2013) received antidepressant treatment or not, and to what extent, prior to and/or at the time of suicide. To investigate the belief that increased prescription of antidepressants would drastically reduce the number of suicides. METHODS: An analysis of data from the Swedish Prescribed Drug Register, the Causes of Death Register, with registers cross checked, and from the National Board of Forensic Medicine. RESULTS: This analysis shows a covariance between increased prescription of antidepressants and an increasing trend in the number of suicides among young women. In the period 1999-2003 antidepressants were found in toxicological analyses done in 23% of the young women who committed suicide, and in 39% of cases for 2009-2013. CONCLUSION: An increasingly larger proportion of young women who later committed suicide, had in the last few years been treated with antidepressants, prior to and at the time of the suicide. The previous assumptions that treatment with antidepressants would lead to a drastic reduction in suicide rates, are incorrect for the population of young women. On the contrary, it was found that an increasing tendency of completed suicides follow the increased prescription of antidepressants. PMID- 28885221 TI - The establishment of the Drug Naming Committee to restrict look-alike medication names in Iran: A qualitative study. AB - BACKGROUND: Medication errors is a prominent issue on the health policy agenda due to its significant human and financial costs; confusing drug names are one of the most common causes of them. This issue necessitates the adoption of a mechanism to restrict such a confusion before approving drug names. OBJECTIVE: Following the establishment of a committee and developed relevant criteria as mechanisms to address the issue of drug names similarity Iran, there were problems in this process. This study explores the process of adopting this mechanism. METHODS: This qualitative study was conducted using date gathered through documents, observation and 31 semi-structured interviews. Ethical approval was achieved from the Research Ethics Committee in TUMS. Confidentiality was ensured at all the interviews. The interviews were recorded verbatim, transcribed and coded, using the MAXQDA ver.12 software. Data were analyzed utilizing the Health Policy Triangle Framework. RESULTS: High rate of medication errors and warning from the WHO about drug names in Iran pushed the issue of drug proprietary names to the FDO agenda. A National Drugs Naming Committee was established and relevant criteria were developed by the Food and Drug Organization (FDO). This committee was dissolved for four years; the function was delegated to the General Office of Trademarks Registry. However, the committee was reestablished and resumed functioning. Finings mainly indicated a higher rate of medication errors during dissolving the committee. CONCLUSION: Health policy makers have a public responsibility for making a decision and the consequences. Regarding the process of naming drugs, it is important for policy makers to consider two issues: patient safety and trademarks rights. However, the Iran FDO adopted an approach to address these issues, a more multifaceted, integrated approach to initial naming of drugs is suggested. The committee' function is seen to hold the most promise. However the function is partially complete to ensure patient safety. Given the change experienced by altering relevant organizational authorities in the FDO, the sustainability of the committee cannot hope to be guaranteed. Yet, the need for such a guarantee is particularly important. PMID- 28885222 TI - Opinions of Maltese doctors and pharmacists on medication errors. AB - BACKGROUND: Pharmacovigilance directive 2010/84/EU focused attention on medication errors and encouraged regulators to identify causing and contributing factors. OBJECTIVES: (1) To study opinions of doctors/pharmacists on factors bearing a causal link to MEs as well as ways to minimise MEs (2) to test whether differences in opinion exist between subgroups of doctors and pharmacists working in community, hospital or office settings. METHODS: Different questionnaires were circulated to doctors and pharmacists. Respondents were subdivided according to their primary practice. RESULTS: 320 responses were received (204 doctors/116 pharmacists). Differences in opinion reaching statistical significance were observed on distractions from staff, overwork and fatigue, availability of technical resources and having more than 1 doctor on duty. For pharmacists', differences on issues of generic medicine availability and interruptions were found. CONCLUSION: Distractions and interruptions while executing tasks was flagged as an area requiring attention. Issues of overwork and fatigue affect especially doctors in hospital the majority of which are of the opinion that regulatory control on patient numbers could minimize errors. Increasing technical resources and keeping knowledge up-to-date, addressing overwork and high patient workloads have been identified as important areas when looking to reduce MEs. PMID- 28885223 TI - Prescription audit of NSAIDs and gastroprotective strategy in elderly in primary care. AB - BACKGROUND: The use of non-steroidal anti-inflammatory drug (NSAIDs) is deemed a major risk factor for peptic ulcer disease in elderly population that requires concomitant therapy with gastroprotective agents (GPAs). OBJECTIVE: This study evaluated the rational prescribing of NSAIDs and GPAs, and extent of adherence to the guideline recommendations in primary care. METHODS: Nationwide audit of prescriptions issued to elderly patients (>=65 years) with hypertension or diabetic hypertension in primary care. RESULTS: Among 2090 elderly, 45.9% were on low-dose aspirin, and 13.5% on other NSAIDs. Diclofenac-XR was the most frequently prescribed NSAIDs to three-quarter patients whereas naproxen, the safest NSAID for patients with high cardiovascular (CV) risk, was rarely prescribed. Among those on NSAID, 82.9% were on a scheduled dosing regimen; of these 78.8% received long-term NSAID therapy (3.9+/-0.9 months). The prescription rate of GPAs was low: 29.2% for aspirin and 33.3% for other NSAIDs. A quarter of the patients on histamine type-2 receptor antagonists received ranitidine at subtherapeutic single-dose for gastroprotection. Approximately half of the patients on proton pump inhibitors (PPIs) were prescribed supra-therapeutic double-dose regimen: omeprazole and esomeprazole accounted for 63.2% of overall prescribed PPIs. CONCLUSIONS: The rational choice of NSAIDs and physicians' adherence to gastroprotective measures was suboptimal in primary care. The choice of NSAIDs and gastroprotective strategy in elderly be guided by the CV and gastrointestinal adverse events likelihood due to the NSAIDs and risk profile of patients for such adverse events. PMID- 28885224 TI - Impaired reproduction after exposure to ADHD drugs: Systematic review of animal studies. AB - BACKGROUND: Few studies have reported on long-term harms caused by ADHD drugs but they are known to impair growth. OBJECTIVE: To assess whether ADHD drugs impair reproduction in mammals. METHODS: Systematic review of reproduction in studies of animals treated with ADHD drugs. DATA SOURCES: PubMed, Biosis and EMBASE. RESULTS: We included 17 studies. The studies were generally of poor quality or poorly reported. Two studies reported the use of one of three advised randomisation methods. Fifteen studies used placebo which suggested blinding. On clonidine, the ability to produce offspring was reduced for male rats, which approached two females each. In one study, 10 treated rats produced no offspring while all four controls did. In another study, 10 treated rats impregnated nine females while 10 controls impregnated 16. On methylphenidate, vaginal opening was delayed in two studies (in one, the mean difference was 4.0 days, 95% CI 2.5 to 5.6, and number of estrous cycles was halved; in the other, the minimum delay was 6 days), while in two other studies no difference occurred. Generally, the impairments improved after a drug-free period and were less pronounced when treatment started later in life. CONCLUSION: ADHD drugs impair the reproduction in animals. PMID- 28885225 TI - Rey-Osterrieth Complex Figure - copy and immediate recall (3 minutes): Normative data for Spanish-speaking pediatric populations. AB - OBJECTIVE: To generate normative data for the Rey-Osterrieth Complex Figure (ROCF) in Spanish-speaking pediatric populations. METHOD: The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the ROCF as part of a larger neuropsychological battery. The ROCF copy and immediate recall (3 minutes) scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models showed main effect for age on copy and immediate recall scores, such that scores increased linearly as a function of age. Age2 affected ROCF copy score for all countries, except Puerto Rico; and ROCF immediate recall scores for all countries, except Chile, Guatemala, Honduras, Paraguay, and Puerto Rico. Models indicated that children whose parent(s) had a MLPE >12 years obtained higher scores compared to children whose parent(s) had a MLPE<=12 years for Chile, Puerto Rico, and Spain in the ROCF copy, and Paraguay and Spain for the ROCF immediate recall. Sex affected ROCF copy and immediate recall score for Chile and Puerto Rico with girls scoring higher than boys. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate approach to interpret the ROCF Test in pediatric populations. PMID- 28885227 TI - Be Sweet to Babies During Painful Procedures: A Pilot Evaluation of a Parent Targeted Video. AB - BACKGROUND: Breastfeeding (BF), skin-to-skin care (SSC), and sucrose effectively reduce babies' pain during newborn blood work, but these strategies are infrequently used. Our team developed a parent-targeted video intervention showing the effectiveness of the 3 pain management strategies. PURPOSE: To evaluate neonatal intensive care unit (NICU) parents' (1) baseline knowledge and previous use of BF, SSC, and sucrose for procedural pain management; (2) intention to advocate/use BF, SSC, or sucrose for their infants' future blood work after viewing the video; (3) intention to recommend the video to other parents; and (4) perceptions of the video and identify areas for improvement. METHODS: Cross-sectional survey of parents in an NICU. RESULTS: Fifty parents were enrolled: 33 mothers and 17 fathers. More than two-thirds (68%) of parents had prior knowledge of analgesic effects of sucrose; knowledge of SSC and BF as pain-reduction strategies was lower: 44% and 34%, respectively. Eighty-six percent of parents felt the video was the right length; 7 (14%) felt the video was too long. After viewing the video, 96% of parents intended to advocate for BF, SSC, or sucrose for pain management and 88% parents would recommend the video to other parents. IMPLICATIONS FOR PRACTICE: The video is acceptable to parents, is feasible to deliver to parents in an NICU, and has potential to increase parents' intent to advocate for pain management strategies for their infants. IMPLICATIONS FOR RESEARCH: Future studies are required to evaluate the effectiveness of this parent-targeted intervention on increasing actual use of pain management in clinical practice. PMID- 28885228 TI - Genetic and Transcriptomic Bases of Intestinal Epithelial Barrier Dysfunction in Inflammatory Bowel Disease. AB - BACKGROUND: Intestinal barrier defects are common in patients with inflammatory bowel disease (IBD). To identify which components could underlie these changes, we performed an in-depth analysis of epithelial barrier genes in IBD. METHODS: A set of 128 intestinal barrier genes was selected. Polygenic risk scores were generated based on selected barrier gene variants that were associated with Crohn's disease (CD) or ulcerative colitis (UC) in our study. Gene expression was analyzed using microarray and quantitative reverse transcription polymerase chain reaction. Influence of barrier gene variants on expression was studied by cis expression quantitative trait loci mapping and comparing patients with low- and high-risk scores. RESULTS: Barrier risk scores were significantly higher in patients with IBD than controls. At single-gene level, the associated barrier single-nucleotide polymorphisms were most significantly enriched in PTGER4 for CD and HNF4A for UC. As a group, the regulating proteins were most enriched for CD and UC. Expression analysis showed that many epithelial barrier genes were significantly dysregulated in active CD and UC, with overrepresentation of mucus layer genes. In uninflamed CD ileum and IBD colon, most barrier gene levels restored to normal, except for MUC1 and MUC4 that remained persistently increased compared with controls. Expression levels did not depend on cis-regulatory variants nor combined genetic risk. CONCLUSIONS: We found genetic and transcriptomic dysregulations of key epithelial barrier genes and components in IBD. Of these, we believe that mucus genes, in particular MUC1 and MUC4, play an essential role in the pathogenesis of IBD and could represent interesting targets for treatment. PMID- 28885229 TI - Impact of Diagnostic Delay and Associated Factors on Clinical Outcomes in a U.S. Inflammatory Bowel Disease Cohort. AB - BACKGROUND: The impact of diagnostic delay in inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), on disease course remains uncertain. This study examines factors that may influence time to diagnosis and disease outcomes in a U.S. patient cohort. METHODS: We retrospectively collected data on patient characteristics, time to diagnosis, disease phenotype, and complications in 177 patients with inflammatory bowel disease (110 CD and 67 UC) diagnosed at our institution from 2008 to 2015. Factors potentially affecting time to diagnosis were analyzed. Association between disease complications (perianal disease, intestinal strictures, surgery, fistula, abscess, and perforation) and time to diagnosis was tested by multivariable analysis. RESULTS: The median time to diagnosis was longer for patients with CD compared with patients with UC (median 9.5 versus 3.1 months; P < 0.001). The median time from symptom onset to initial physician visit was similar for patients with CD and patients with UC (1 month). However, the median time from symptom onset to specialist evaluation was longer for patients with CD compared with patients with UC: 7 months (interquartile range: 3-23) versus 3 months (interquartile range: 1-8), respectively (P < 0.001). In CD, ileal disease and hematochezia were positively and negatively correlated, respectively, with longer time to diagnosis (P < 0.05). Compared with patients with time to diagnosis <=4 months, patients with time >26 months had increased overall complications (odds ratio, 8.22; P = 0.007) and intestinal strictures (odds ratio, 8.96; P = 0.012) at time of diagnosis. Such correlation persisted at follow-up. CONCLUSIONS: Time to diagnosis was long in CD. Physician-related delay in diagnosing CD was associated with increased overall complications and intestinal strictures (See Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B646). PMID- 28885230 TI - Novel Artificial Restriction Fragment Length Polymorphism Methods for Genotyping Immunity-related GTPase M Promoter Polymorphisms. PMID- 28885231 TI - Effectiveness of Shortwave Diathermy for Subacromial Impingement Syndrome and Value of Night Pain for Patient Selection: A Double-Blinded, Randomized, Placebo Controlled Trial. AB - OBJECTIVE: The aim of this study was to investigate the effectiveness of short wave diathermy (SWD) in patients with subacromial impingement syndrome. DESIGN: In this double-blinded, randomized, placebo-controlled trial, 57 patients (aged 35-65 yrs) were classified into night pain positive (NP[+]) (n = 28) and night pain negative (NP[-]) (n = 29) groups. Both groups were randomly assigned to SWD (NP[+], n = 14; NP[-], n = 14) and sham (NP[+], n = 15; NP[-], n = 14) subgroups. Visual analog scale, Constant-Murley Scale (CS), and Shoulder Disability Questionnaire (SDQ) scores were used for evaluation. RESULTS: There was only a significant difference in pain with activity at 1-mo (mean difference [MD], 1.65; 95% confidence interval, -3.01 to -0.28]) and 2-mo evaluations (MD, -2.1; 95% confidence interval, -3.51 to -0.69) between SWD versus sham groups. In the NP(+) SWD group, the CS pain score was significantly higher than in the NP(+) sham group at all evaluations after treatment. At 1 mo, the NP(-) SWD group showed significantly better pain, strength, total CS, and SDQ scores than the NP( ) sham group. At 2 mos, the pain, range of motion, strength, and total CS and SDQ scores were better in the NP(-) SWD group than in the NP(-) sham group (P < 0.05). CONCLUSIONS: Short wave diathermy is more effective in subacromial impingement syndrome without NP. PMID- 28885232 TI - Comparison of Proliferation Markers Ki67 and Phosphohistone-H3 (pHH3) in Breast Ductal Carcinoma In Situ. AB - Proliferative index is a prognostic feature of invasive ductal carcinoma of the breast, and has more recently emerged as a predictor of ductal carcinoma in situ (DCIS) local recurrence and progression when used in combination with other predictive markers. Ki67 is the most commonly used immunohistochemical marker of proliferative index. However, high interobserver and interlaboratory variability has been reported, in part due to differences in staining methodologies, positivity thresholds, and approaches to quantification. Phosphohistone-H3 (pHH3) is a marker of mitotic activity that has emerged as a more reliable indicator of proliferation in other neoplasms. Quantification of proliferative index was compared in 48 cases of DCIS using Ki67 and pHH3 immunohistochemistry. A strong linear relationship between Ki67 and pHH3 quantification was observed (P<0.0001, R=0.75). Interobserver concordance was modestly higher for pHH3 than Ki67 proliferative indices. However, positive pHH3 staining was more dichotomous (either negative or uniformly positive) and specific for mitotic activity, and interpretation of pHH3 proliferative indices was significantly faster than that of Ki67. The strong correlation between pHH3 and Ki67 supports the use of this marker as a measure of proliferative activity in DCIS. PMID- 28885233 TI - Diagnostic Value of PCT and CRP for Detecting Serious Bacterial Infections in Patients With Fever of Unknown Origin: A Systematic Review and Meta-analysis. AB - BACKGROUND: It is vital to recognize the cause of an infection to enable earlier treatment. Studies have shown that procalcitonin (PCT) and C-reactive protein (CRP) have very high sensitivity and specificity for diagnosing serious bacterial infections (SBIs), with PCT performing better than CRP. METHODS: Multiple databases were searched for relevant studies, and full-text articles involving diagnosis with PCT and CRP were reviewed. All meta-analyses were conducted with Review Manager 5.0. Sensitivity and bias analyses were performed to evaluate the quality of articles. In addition, a funnel plot and Egger test were used to assess possible publication bias. RESULT: A total of 17 articles met the criteria for inclusion. The concentrations of both PCT and CRP were higher in the SBI group than in the nonbacterial infection group. Sensitivity for differentiating bacterial infections from nonbacterial infections was higher for PCT compared with CRP, whereas there was no significant difference in specificity. The area under the summary receiver operating characteristic curve for PCT was larger than that for CRP. CONCLUSION: Both PCT and CRP are useful markers and should be used to evaluate SBIs with fever of unknown origin. PMID- 28885235 TI - Corticosteroids Therapy for Paraneoplastic Nephrotic Syndrome. PMID- 28885234 TI - Assessing the Relationship Between the Electrically Evoked Compound Action Potential and Speech Recognition Abilities in Bilateral Cochlear Implant Recipients. AB - OBJECTIVES: The primary objective of the present study was to examine the relationship between suprathreshold electrically evoked compound action potential (ECAP) measures and speech recognition abilities in bilateral cochlear implant listeners. We tested the hypothesis that the magnitude of ear differences in ECAP measures within a subject (right-left) could predict the difference in speech recognition performance abilities between that subject's ears (right-left). DESIGN: To better control for across-subject variables that contribute to speech understanding, the present study used a within-subject design. Subjects were 10 bilaterally implanted adult cochlear implant recipients. We measured ECAP amplitudes and slopes of the amplitude growth function in both ears for each subject. We examined how each of these measures changed when increasing the interphase gap of the biphasic pulses. Previous animal studies have shown correlations between these ECAP measures and auditory nerve survival. Speech recognition measures included speech reception thresholds for sentences in background noise, as well as phoneme discrimination in quiet and in noise. RESULTS: Results showed that the between-ear difference (right-left) of one specific ECAP measure (increase in amplitude growth function slope as the interphase gap increased from 7 to 30 us) was significantly related to the between-ear difference (right-left) in speech recognition. Frequency-specific response patterns for ECAP data and consonant transmission cues support the hypothesis that this particular ECAP measure may represent localized functional acuity. CONCLUSIONS: The results add to a growing body of literature suggesting that when using a well-controlled research design, there is evidence that underlying neural function is related to postoperative performance with a cochlear implant. PMID- 28885236 TI - Effectiveness of the conductive educational approach added to conventional physiotherapy in the improvement of gait parameters of poststroke patients: randomized-controlled pilot study. AB - Our objective was to assess the benefits of the conductive education (CE) approach added to conventional physiotherapy in gait functions of poststroke, hemiparetic patients. A randomized-controlled trial was designed in a rehabilitation clinic. Late and chronic poststroke patients with gait disturbances (n=17, median age: 55 years, range: 41-72 years) were enrolled in the study. All patients received conventional physiotherapy. However, patients of only one group took part in therapy on the basis of the CE approach. The gait parameters, semiobjective outcome measures, functional independence measure, and International Classification of Functioning, Disability and Health domains were collected. The effectiveness of the CE approach was underlined by those outcome measures that were only significant (P<=0.05) in the conductive group: functional independence measure motor subscale; maintaining body position and walking long distances; and muscle strength in some muscle groups. The results suggest that CE could have an additive effect on gait improvement of stroke patients. PMID- 28885237 TI - Exploring the Perceived Value of a Personalized Informatics Tool to Anticipate and Mitigate Patient Risk. AB - Health care systems are implementing a myriad of strategies to improve patient outcomes and reduce both adverse events and unplanned readmissions. These approaches include interventions related to people, processes, and technology. This article describes the development of a technology-based model in the form of an actionable risk profile, which was used by one inpatient surgical unit (people) during a daily care team briefing (process). The risk profile was evaluated for its perceived value to the care team as a method of organizing care and anticipating patients' needs. Preliminary findings of the proof of concept are presented along with recommendations for practice and research. PMID- 28885238 TI - Improving the Implementation of Lung Cancer Screening Guidelines at an Academic Primary Care Practice. AB - Expert groups recommend annual chest computed tomography for lung cancer screening (LCS) in high-risk patients. Lung cancer screening in primary care is a complex process that includes identification of the at-risk population, comorbidity assessment, and shared decision making. We identified three key processes required for high-quality screening implementation in our academic primary care practice: (1) systematic collection of lifetime cumulative smoking history to identify potentially eligible patients; (2) visit-based clinical reminders and order sets embedded in the electronic health record (EHR); and (3) tools to facilitate shared decision making and appropriate test ordering. We applied quality improvement techniques to address gaps in these processes. Over 12 months, we developed and implemented a nurse protocol for collecting complete smoking history and entering that data into discrete EHR fields. We obtained histories on over 50% of the clinic's more than 2,300 known current and former smokers, aged 55-80 years. We then built and pilot tested an automated visit based reminder (VBR) system, driven by the discrete smoking history data. The VBR included an order set and template for documentation of shared decision making. Physicians interacted with the VBR in approximately 30% of opportunities for use. Further work is needed to better understand how to systematically provide appropriate LCS in primary care environments. PMID- 28885239 TI - Opioid Use in Children and Adolescents After Anterior Cruciate Ligament Repair. AB - Opioid overdose is a leading cause of death from unintentional injury in the United States. When more opioids are prescribed than needed, leftover opioids may be misused if not properly disposed. The purpose of this study is to describe the opioid use of subjects (aged 13-21 years) after an anterior cruciate ligament (ACL) repair. After obtaining IRB approval, we obtained consent from 100 subjects (over an 8-month period) undergoing ACL reconstructions performed by five sports medicine surgeons. The mean age of enrolled subjects was 16 years, most were female (60%) and white (72%). While in the hospital, many subjects received the following: a regional anesthetic technique through a single shot femoral nerve block (50%); ketorolac (89%); and acetaminophen (84%). One week after surgery, we interviewed subjects to determine the amount of opioid used (36%) as compared to the amount prescribed. PMID- 28885240 TI - Advancing Value-Based Population Health Management Through Payer-Provider Partnerships: Improving Outcomes for Children With Complex Conditions. AB - Population health management (PHM) approaches to improve cost and quality remain limited. To address this gap, stakeholders within an integrated delivery and financing system in Western Pennsylvania designed, implemented, and tested a value-based care model for children with medically complex conditions that could be scaled across the broader pediatric population. The model included: (1) a multilevel, interdisciplinary infrastructure; (2) actionable analytics reports to guide continuous quality improvement; (3) alternative provider payments; (4) consumer-directed spending accounts; and (5) shared savings with practices. Four practices caring for 215 children (0.40 Spearman rho) with (Equation is included in full-text article.)O2peak. The follow-up analyses demonstrated a significant correlation between changes in (Equation is included in full-text article.)O2peak and changes in PF, RP, VT, and MH. Changes in (Equation is included in full-text article.)O2 peak explained 4% of the changes in the PF and VT scores. CONCLUSION: The correlations between exercise capacity and HRQOL were weak and varied considerably among patients. The ECR program improved both exercise capacity and HRQOL, but it was not necessarily the same patients who improved both parameters. Therefore, it is recommended to use separate objective measures and patient-reported outcomes when evaluating the effect of ECR. PMID- 28885282 TI - The Importance of Community in Online RN-BSN Courses. PMID- 28885283 TI - Report of the 2017 Omaha System International Conference: A Vision for the Future. PMID- 28885284 TI - Modeling Flow Sheet Data to Support Secondary Use. PMID- 28885286 TI - Predicting Perioperative Complications in Adult Spinal Deformity Surgery Using a Simple Sliding Scale. AB - STUDY DESIGN: A retrospective database study. OBJECTIVE: The aim of this study was to develop and validate a sliding scale for predicting perioperative complications associated with adult spinal deformity (ASD) surgery. SUMMARY OF BACKGROUND DATA: ASD surgery can have high perioperative complication rates, which is associated with increased morbidity and mortality. METHODS: Data on consecutive ASD patients undergoing posterior corrective surgery over a 6-year interval were collected from a prospective database. The patients' preoperative general condition, surgical status, and perioperative complications occurring within 30 days of surgery were analyzed and independent predictors were determined using multivariable logistic regression analysis. We made the sliding scale using cut-off values from receiver operating curve analysis and validated the performance of this model. RESULTS: Three hundred four patients were included with a mean age of 62.9 years. One hundred eight patients (35.5%) were affected by at least one perioperative complication with a total of 195 perioperative complications, including neurological (12.8%), excessive blood loss (11.2%), delirium (11.2%), and infection (3.6%). Total independent predictors were age [odds ratio (OR): 1.042], operation time (OPT) (OR: 2.015), and estimated blood loss (EBL) (OR: 4.885) with cut-off values of approximately 70 years, 6 hours, and 2000 mL, respectively. Fusion of >=10 segments (OR: 2.262), three-column osteotomy (OR: 1.860), current use of antihypertensive (OR: 2.595) and anticoagulant (OR: 7.013), and body mass index (OR: 1.160) were risk factors for neurological complications, infection, and deep vein thrombosis/pulmonary thrombosis. Our proposed sliding scale had a sensitivity of 91%, specificity of 58.1%, and the incidence of perioperative complication in the validation dataset was smaller than that without this scale (P <= 0.05). CONCLUSION: Patients' age, current medication, and degenerative pathology might be independent preoperative as well as operative predictors. An age and comorbidities based sliding scale with classifications of OPT and EBL may be useful for risk prediction in ASD surgery. LEVEL OF EVIDENCE: 3. PMID- 28885287 TI - Whether Orthotic Management and Exercise are Equally Effective to the Patients With Adolescent Idiopathic Scoliosis in Mainland China?: A Randomized Controlled Trial Study. AB - STUDY DESIGN: A prospective randomized controlled trial. OBJECTIVE: The aim of this study was to investigate the effectiveness of orthotic management versus exercise on spinal curvature, body symmetry, and quality of life. SUMMARY OF BACKGROUND DATA: A number of well-designed studies comparing conservative treatment of adolescent idiopathic scoliosis (AIS) have been conducted and the evidence becomes stronger. However, there is a lack of the information on the effectiveness of orthotic management versus exercise. METHODS: The inclusion criteria recommended by the Scoliosis Research Society (SRS) and the international Society on Scoliosis Orthopedic and Rehabilitation Treatment (SOSORT) were used during enrollment. Eligible patients were randomly assigned to either bracing group or exercise group. Patients in the bracing group were prescribed with a rigid thoracolumbosacral orthosis and requested to wear 23 h/day, while patients in the exercise group were treated with the protocol of the Scientific Exercise Approach to Scoliosis. Data regarding angle of trunk inclination, Cobb angle, shoulder balance, body image, and quality of life (QoL) were collected every 6 months. RESULTS: Twenty-four patients in the bracing group and 29 patients in the exercise group participated in this study. For the intergroup comparison, the bracing group showed better results about the correction of spinal curvature (Cobb angle at the first 12 months of intervention, P = 0.039), scores concerning QoL, especially function (P < 0.001), mental health (P < 0.001), and total score (P < 0.001), were higher than that of the exercise group. The results of body symmetry evaluation did not differ significantly between the two groups. For the intragroup comparison, parameters of spinal curvature (baseline vs. 12-month, P < 0.03 in the exercise group and P < 0.001 in the bracing group), QoL (baseline vs. 12-month, P < 0.001), and TAPS (baseline vs. 12-month, P < 0.033) significantly improved over the studied period. Shoulder balance (baseline vs. 12-month, P < 0.005) showed significant improvement only in the bracing group. CONCLUSION: Both interventions of bracing and exercise showed significant treatment effectiveness on the patients with AIS. Bracing was superior to capture corrections in parameters of spinal curvature and body symmetry, while the QoL, especially in aspect of the functional and psychological status, was significantly better in the exercise group. LEVEL OF EVIDENCE: 1. PMID- 28885289 TI - Mesenchymal Stem Cell Levels of Human Spinal Tissues. AB - STUDY DESIGN: Systematic review. OBJECTIVE: The aim of this study was to investigate, quantify, compare, and compile the various mesenchymal stem cell (MSC) tissue sources within human spinal tissues to act as a compendium for clinical and research application. SUMMARY OF BACKGROUND DATA: Recent years have seen a dramatic increase in academic and clinical understanding of human MSCs. Previously limited to cells isolated from bone marrow, the past decade has illicited the characterization and isolation of human MSCs from adipose, bone marrow, synovium, muscle, periosteum, peripheral blood, umbilical cord, placenta, and numerous other tissues. As researchers explore practical applications of cells in these tissues, the absolute levels of MSCs in specific spinal tissue will be critical to guide future research. METHODS: The PubMED, MEDLINE, EMBASE, and Cochrane databases were searched for articles relating to the harvest, characterization, isolation, and quantification of human MSCs from spinal tissues. Selected articles were examined for relevant data, categorized according to type of spinal tissue, and when possible, standardized to facilitate comparisons between sites. RESULTS: Human MSC levels varied widely between spinal tissues. Yields for intervertebral disc demonstrated roughly 5% of viable cells to be positive for MSC surface markers. Cartilage endplate cells yielded 18,500 to 61,875 cells/0.8 mm thick sample of cartilage end plate. Ligamentum flavum yielded 250,000 to 500,000 cells/g of tissue. Annulus fibrosus fluorescence activated cell sorting treatment found 29% of cells positive for MSC marker Stro 1. Nucleus pulposus yielded mean tissue samples of 40,584 to 234,137 MSCs per gram of tissue. CONCLUSION: Numerous tissues within and surrounding the spine represent a consistent and reliable source for the harvest and isolation of human MSCs. Among the tissues of the spine, the annulus fibrosus and ligamentum flavum each offer considerable levels of MSCs, and may prove comparable to that of bone marrow. LEVEL OF EVIDENCE: 5. PMID- 28885288 TI - Early Effects of Medicare's Bundled Payment for Care Improvement Program for Lumbar Fusion. AB - STUDY DESIGN: Retrospective analysis of Medicare claims linked to hospital participation in the Center for Medicare and Medicaid Innovation's episode-based Bundled Payment for Care Improvement (BPCI) program for lumbar fusion. OBJECTIVE: To describe the early effects of BPCI participation for lumbar fusion on 90-day reimbursement, procedure volume, reoperation, and readmission. SUMMARY OF BACKGROUND DATA: Initiated on January 1, 2013, BPCI's voluntary bundle payment program provides a predetermined payment for services related to a Diagnosis Related Group-defined "triggering event" over a defined time period. As an alternative to fee-for-service, these reforms shift the financial risk of care on to hospitals. METHODS: We identified fee-for-service beneficiaries over age 65 undergoing a lumbar fusion in 2012 or 2013, corresponding to the years before and after BPCI initiation. Hospitals were grouped based on program participation status as nonparticipants, preparatory, or risk-bearing. Generalized estimating equation models adjusting for patient age, sex, race, comorbidity, and hospital size were used to compare changes in episode costs, procedure volume, and safety indicators based on hospital BPCI participation. RESULTS: We included 89,605 beneficiaries undergoing lumbar fusion, including 36% seen by a preparatory hospital and 7% from a risk-bearing hospital. The mean age of the cohort was 73.4 years, with 59% women, 92% White, and 22% with a Charlson Comorbidity Index of 2 or more. Participant hospitals had greater procedure volume, bed size, and total discharges. Relative to nonparticipants, risk-bearing hospitals had a slightly increased fusion procedure volume from 2012 to 2013 (3.4% increase vs. 1.6% decrease, P = 0.119), did not reduce 90-day episode of care costs (0.4% decrease vs. 2.9% decrease, P = 0.044), increased 90-day readmission rate (+2.7% vs. 10.7%, P = 0.043), and increased repeat surgery rates (+30.6% vs. +7.1% points, P = 0.043). CONCLUSION: These early, unintended trends suggest an imperative for continued monitoring of BPCI in lumbar fusion. LEVEL OF EVIDENCE: 3. PMID- 28885290 TI - Spinal Gout Without Spinal Symptom in a Junior School Student: A Case Report. AB - STUDY DESIGN: Case report. OBJECTIVE: We report a case of a 16-year-old boy with intermittent and migratory polyarthralgia, who made a diagnostic dilemma. SUMMARY OF BACKGROUND DATA: Spinal involvement without spinal symptom in gout seems to be rare. However, the relationship of spinal gout to symptoms is poorly understood. METHODS: Description of the case report. RESULTS: Laboratory findings cannot explain his symptoms; however, a computed tomography of the pelvis revealed the presence of space-occupying lesion involving the left side of spine at L5-S1 level, and the later biopsy revealed that was a urate crystal, which help us make the diagnosis of spinal gout. CONCLUSION: Gout can be a cunning disease which has various manifestations, and spinal involvement can be asymptomatic. LEVEL OF EVIDENCE: 5. PMID- 28885291 TI - How Common Is the Ponticulus Posticus?: A Computed Tomography Based Analysis of 2917 Patients. AB - STUDY DESIGN: A computed tomography (CT) study of the morphology of the C1 vertebra. OBJECTIVE: Is to determine the prevalence of ponticulus posticus (PP) by analyzing CT scans performed on a large, diverse population in the northeast United States. This study also proposes a CT-based classification system both to aid in unifying the description of PP, and to aid in future research. SUMMARY OF BACKGROUND DATA: The prevalence of PP varies from 5% to 68% in published studies. There may be geographic variation in the prevalence of PP. Our objective was to establish the prevalence of PP in the general population, and to develop a comprehensive classification system to describe PP. METHODS: We evaluated cervical spine CT scans performed on patients in the emergency room of a level I trauma center over a 1-year period (January 1, 2014-December 31, 2014). The CT images were evaluated for the presence of a PP, and if present the following demographic data were collected: age, sex, race/ethnicity, and body mass index (BMI). We propose a novel classification system to standardize the description of PP identified on CT scan. RESULTS: Two thousand, nine hundred and seventeen cervical spine CT scans were reviewed in this study. The prevalence of PP was 22.5%. Men had a higher prevalence of PP than women (53.5% male vs. 46.5% female P <= 0.01). When compared with the overall population, African-Americans were more likely to have a PP (P <= 0.01), while Caucasian patients were less likely (P <= 0.01). The novel classification consisted of a two letter designation for each patient, with the first letter denoting the right sided arch and the second letter the left sided arch. Each side of the arch described as an A, B, or C type. The A type had no presence of a PP, B type had in incomplete PP, and C type had a complete PP. The most common type of a PP was CC encompassing 25% of the patients. The presence of a PP was more common in the left sided arch than the right side (B and C type Left 89.2% vs. B and C type Right 84.7%, P = 0.02). CONCLUSION: We found a 22.5% prevalence of PP in 2917 patients undergoing a cervical spine CT. This is the largest study to evaluating the prevalence of PP. LEVEL OF EVIDENCE: 4. PMID- 28885292 TI - Incidence and Risk Factors of Anterior Arch Fracture of the Atlas Following C1 Laminectomy Without Fusion. AB - STUDY DESIGN: A retrospective multicenter study. OBJECTIVE: To identify the incidence of anterior arch fracture (AAF) of the atlas following C1 (first cervical vertebra) laminectomy without fusion, and its risk factors. SUMMARY OF BACKGROUND DATA: C1 laminectomy without fusion is a widely accepted surgical procedure performed to decompress the spinal cord that is compromised at the C1/C2 level, but without instability. Several case series have reported spontaneous AAF following this procedure. However, the incidence of post laminectomy AAF and its risk factors have not been studied. METHODS: This retrospective study included patients who underwent C1 laminectomy without fusion in any of the four participating institutions between April 2002 and March 2016. The incidence of AAF following C1 laminectomy was determined, and the included patients were grouped into those who developed AAF (AAF group) and those who did not (non-AAF group). Patient demographics and radiographic parameters including subaxial cervical balance on x-ray (C2-7 sagittal vertical axis, C2-7 lordosis, C2-7 coronal cobb angle, and T1-slope), and morphology of the atlas on computed tomography (CT) scan were compared with the AAF and non-AAF groups. RESULTS: Seventy patients who underwent C1 laminectomy without fusion were included in the study. The incidence of AAF was 14.2% (10/70). Multivariate analysis revealed that a large inferior facet angle (IFA, defined as the coronal inclination angle of the C1/2 facet as measured on CT) and the presence of subaxial ankylosis (bony ankylosis below C2 on CT) were independent risk factors for AAF. There were no significant differences in the subaxial cervical balance as measured on x-ray between the AAF and non-AAF groups (P > 0.05). CONCLUSION: The incidence of AAF after C1 laminectomy without fusion is not uncommon. Preoperative assessment using CT may identify patients at high risk of AAF. LEVEL OF EVIDENCE: 4. PMID- 28885293 TI - Surgeon Reimbursement Relative to Hospital Payments for Spinal Fusion: Trends From 10-year Medicare Analysis. AB - STUDY DESIGN: Retrospective, economic analysis. OBJECTIVE: The aim of this study was to analyze the trend in hospital charge and payment adjusted to corresponding surgeon charge and payment for cervical and lumbar fusions in a Medicare sample population from 2005 to 2014. SUMMARY OF BACKGROUND DATA: Previous studies have reported trends and variation in hospital charges and payments for spinal fusion, but none have incorporated surgeon data in analysis. Knowledge of the fiscal relationship between hospitals and surgeons over time will be important for stakeholders as we move toward bundled payments. METHODS: A 5% Medicare sample was used to capture hospital and surgeon charges and payments related to cervical and lumbar fusion for degenerative disease between 2005 and 2014. We defined hospital charge multiplier (CM) as the ratio of hospital/surgeon charge. Similarly, the hospital/surgeon payment ratio was defined as hospital payment multiplier (PM). The year-wise and regional trend in patient profile, length of stay, discharge disposition, CM, and PM were studied for all fusion approaches separately. RESULTS: A total of 40,965 patients, stratified as 15,854 cervical and 25,111 lumbar fusions, were included. The hospital had successively higher charges and payments relative to the surgeon from 2005 to 2014 for all fusions with an inverse relation to hospital length of stay. Increasing complexity of fusion such as for anterior-posterior cervical fusion had higher hospital reimbursements per dollar earned by the surgeon. There was regional variation in how much the hospital charged and received per surgeon dollar. CONCLUSION: Hospital charge and payment relative to surgeon had an increasing trend despite a decreasing length of stay for all fusions. Although the hospital can receive higher payments for higher-risk patients, this risk is not reflected proportionally in surgeon payments. The shift toward value-based care with shared responsibility for outcomes and cost will likely rely on better aligning incentives between hospital and providers. LEVEL OF EVIDENCE: 3. PMID- 28885294 TI - Point-of-View: Risk Factors for Surgical Site Infection After Posterior Lumbar Spinal Surgery. PMID- 28885295 TI - Morphometric Analysis of Rat Spinal Cord Angioarchitecture by Phase Contrast Radiography: From 2D to 3D Visualization. AB - STUDY DESIGN: An advanced imaging of vasculature with synchrotron radiation X-ray in a rat model. OBJECTIVE: To develop the potential for quantitative assessment of vessel network from two-dimensional (2D) to 3D visualization by synchrotron radiation X-ray phase contrast tomography (XPCT) in rat spinal cord model. SUMMARY OF BACKGROUND DATA: Investigation of microvasculature contributes to the understanding of pathological development of spinal cord injury. A few of X-ray imaging is available to visualize vascular architecture without usage of angiography or invasive casting preparation. METHODS: A rat spinal cord injury model was produced by modified Allen method. Histomorphometric detection was simultaneously analyzed by both histology and XPCT from 2D to 3D visualization. The parameters including tissue lesion area, microvessel density, vessel diameter, and frequency distribution of vessel diameter were evaluated. RESULTS: XPCT rendered the microvessels as small as capillary scale with a pixel size of 3.7 MUm. It presented a high linear concordance for characterizing the 2D vascular morphometry compared with the histological staining (r = 0.8438). In the presence of spinal cord injury model, 3D construction quantified the significant angioarchitectural deficiency in the injury epicenter of cord lesion (P<0.01). CONCLUSION: XPCT has a great potential to detect the smallest vascular network with pixel size up to micron dimension. It is inferred that the loss of abundant microvessels (<=40 MUm) is responsible for local ischemia and neural dysfunction. XPCT holds a promise for morphometric analysis from 2D to 3D imaging in experimental model of neurovascular disorders. LEVEL OF EVIDENCE: N/A. PMID- 28885296 TI - Prospective, Randomized, Double-Blind, Placebo-Controlled Clinical Trial Assessing the Effects of Applying a Force to C5 by a Mechanically Assisted Instrument on Referred Pain to the Shoulder. AB - STUDY DESIGN: Randomized, prospective, double-blind, placebo-controlled clinical trial. OBJECTIVE: To determine the effects of applying a force to C5 of the spine by a mechanically assisted instrument (MAI) in patients with referred shoulder pain. SUMMARY OF BACKGROUND DATA: Manipulating C5 of the spine is a chiropractic treatment for referred shoulder pain; there are no clinical trials evaluating its efficacy. Outcome measures were patient ranked questionnaires and independent examiner findings. One hundred and twenty-five patients were diagnosed with referred shoulder pain of cervical origin; 65 patients were in the treatment cohort and 60 patients in the placebo cohort. METHODS: This was a prospective, randomized, double-blind, placebo-controlled trial assessing the effects of applying a force to C5 by a MAI to patients with referred shoulder pain. The treatment cohort had the MAI set at the maximum setting to transmit a force into the spine; the placebo cohort had the MAI turned off. Primary outcome measures were frequency and severity of extreme shoulder pain obtained via a patient reported questionnaire; secondary outcome measures were patient ranked pain and functional outcomes as well as examiner assessed range of motion and strength. Assessment procedures were completed at 24 weeks posttreatment and data were analyzed with intent-to-treat protocol. RESULTS: There was a reduction in the frequency but not severity of extreme shoulder pain in the treatment cohort, average ranking reducing from weekly to monthly (P < 0.05). Patients treated with the MAI had 10 N (P = 0.04) better internal rotation strength after 6 months posttreatment. No differences with any other outcome measures between the two cohorts at the 24-week study period. CONCLUSION: The major effect of applying a MAI to the level of C5 of the spine in referred shoulder pain is improved shoulder strength for internal rotation in this randomized double-blinded clinical trial. LEVEL OF EVIDENCE: 2. PMID- 28885297 TI - Spinal Surgeons' Opinions on Pre- and Postoperative Rehabilitation in Patients Undergoing Lumbar Spinal Fusion Surgery: A Survey-Based Study in the Netherlands and Sweden. AB - STUDY DESIGN: A cross-sectional survey in the Netherlands and Sweden. OBJECTIVE: To investigate Dutch and Swedish spinal surgeons' opinions on spinal fusion pre- and postoperative rehabilitation. SUMMARY OF BACKGROUND DATA: Lumbar spinal fusion surgery is increasingly provided in patients with chronic low back pain. No guidelines however exist for pre- and postoperative rehabilitation and it is unknown what opinions spinal surgeons currently have about pre- and postoperative rehabilitation. METHODS: A survey was circulated to Dutch and Swedish spinal surgeons. Reminders were sent after 4 and 8/9 weeks. Data of completed questionnaires of orthopedic- and neurosurgeons currently performing lumbar spinal fusion were included for analysis. Analysis comprised a range of descriptive summaries (numerical, graphical, and tabular). RESULTS: Surveys of 34 Dutch and 48 Swedish surgeons were analyzed. Surgeons provided preoperative information on postoperative mobilization. Spinal fusion techniques varied, but technique did not influence postoperative treatment. Swedish surgeons recommended slightly faster mobilization than Dutch (direct vs. 1-day postoperative), and more activities the first day (sitting, standing, walking). Stair climbing was the most reported discharge criterion; however, time point to start varied. More Swedish surgeons referred to postoperative physiotherapy than Dutch (88% vs. 44%). Time-point to start home activities varied from 1 week to more than 6 months. Pain increase was allowed for less than 24 hours (The Netherlands 81%, Sweden 92%). CONCLUSION: Findings reflect variability in lumbar spinal fusion rehabilitation in two European countries, especially in postoperative phase. The study proposes many new research topics and acts as starting point for future research valuable for the spinal community. LEVEL OF EVIDENCE: 3. PMID- 28885298 TI - Increasing Body Mass Index is Associated With Worse Perioperative Outcomes and Higher Costs in Adult Spinal Deformity Surgery. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To investigate associations of obesity with outcomes and costs of adult spinal deformity (ASD) surgery. SUMMARY OF BACKGROUND DATA: Increasing body mass index (BMI) is a risk factor for complications after nondeformity spine surgery, but its effect on ASD surgery is unknown. METHODS: We reviewed records of 244 ASD patients who underwent spinal arthrodesis of >=5 levels from 2010 to 2014 and categorized them by World Health Organization BMI groups: BMI < 30, nonobese (64%); BMI = 30-34.99, class-I obese (21%); and BMI >= 35, class-II/III obese (15%). We used multivariate logistical regression to determine odds of transfusion, inpatient complications, prolonged intensive care unit (ICU) stay (>2 days), prolonged total length of hospital stay (LOS) (>1 week), and high episode-of-care costs (>$80,000). RESULTS: Preoperative characteristics were similar among groups, except sex, preoperative hemoglobin concentration, and performance/type of osteotomy (all, P = 0.01). On univariate analysis, the groups differed in rates of prolonged ICU stay (P < 0.001), prolonged total LOS (P = 0.016), and high episode-of-care costs (P = 0.013). Inpatient complication rates were similar among groups (P = 0.218). On multivariate analysis, compared with nonobese patients, class I obese patients had greater odds of prolonged ICU stay (odds ratio [OR] = 2.24, 95% confidence interval [CI]: 1.06, 4.71). Class II/III obese patients also had greater odds of prolonged total LOS (OR = 2.21, 95% CI: 1.03, 4.71), and high episode-of-care costs (OR = 2.91, 95% CI: 1.31, 6.50). CONCLUSION: In ASD surgery, BMI >=35 is associated with significantly worse perioperative outcomes and higher costs compared with those of nonobese patients. LEVEL OF EVIDENCE: 3. PMID- 28885299 TI - Correlates of Stigma Severity Among Persons Seeking Opioid Detoxification. AB - INTRODUCTION: Among people with opioid use disorder (OUD), stigma is a known barrier to accessing treatment and has negative impacts on physical and mental health. The purpose of this study was to understand the factors associated with self-stigma and perceived stigma severity among people with OUD entering an inpatient detoxification program. METHODS: Between December 2015 and August 2016, consecutive persons seeking inpatient opioid detoxification were asked to complete a survey that included sociodemographic, drug use, treatment variables, an 8-item General Self-Stigma scale, and a 3-item Treatment Stigma scale. Correlates of stigma severity were estimated using ordinary least squares regression. RESULTS: The 407 participants had an average age of 32.4 (+/-8.79) years, with 72.2% male and 84.5% non-Hispanic White. Two-thirds had ever received medication-assisted treatment for OUD and 323 (79.4%) had ever been admitted to a detoxification program. Adjusted mean General Self-Stigma scores were positively and significantly associated with recent injection drug use (b = 0.262, P = 0.032), and having previously entered detoxification programs (b = 0.330, P = 0.016). Adjusted mean Treatment Stigma scores were positively and significantly associated with years of education (b = 0.142, P = 0.002), having ever been prescribed naltrexone (b = 0.277, P = 0.025) and having previously entered detoxification programs (b = 0.389, P = 0.007). CONCLUSION: People with OUD presenting for inpatient detoxification struggle with experiences of self and perceived stigma. Strikingly, people with previous detoxification program admission had higher levels of stigma on both scales. Our findings suggest an opportunity for targeted intervention in this group. PMID- 28885300 TI - Use of Smoking Cessation Methods Among Patients Receiving Office-based Buprenorphine Maintenance Treatment. AB - OBJECTIVES: Provision of smoking-cessation treatment is limited in office-based buprenorphine maintenance treatment (BMT) settings. This study describes smoking and smoking-cessation behaviors among patients receiving office-based BMT. METHODS: Cross-sectional study of patients receiving office-based BMT at a community health center in the Bronx, NY. We interviewed patients assessing sociodemographic, and substance use and tobacco use characteristics, including methods used for smoking cessation. We reported simple frequencies and explored associations of BMT characteristics with smoking behaviors. RESULTS: Of 68 patients, 87.7% were current cigarette smokers, 7.9% were former smokers, and 4.4% had never smoked. Of lifetime smokers, 83.1% reported at least 1 prior quit attempt, and 78.5% had used medication (75.4% used nicotine replacement therapy, 29.2% varenicline, and 9.2% bupropion). Ten patients (15.4%) reported using electronic cigarettes to try to quit smoking. Stopping "cold turkey" (40.0%) and gradually decreasing the number of cigarettes smoked (32.3%) were nonpharmacological methods of quitting tried most often. Use of behavioral support, including stop-smoking programs and counseling, was low. Higher dose and longer duration of BMT was associated with greater smoking frequency. CONCLUSIONS: Patients receiving BMT have a high prevalence of cigarette smoking, though most have tried to quit, and have prior experience with pharmacotherapy for smoking cessation. Efforts to optimize smoking-cessation treatments among BMT patients are needed. PMID- 28885301 TI - Perceptions of Neighborhood Mediate the Relationship Between PTSD Symptoms and Coping in a Neighborhood-Matched Substance-Using Sample. AB - OBJECTIVES: People with substance use problems living in neighborhoods with high levels of disorder are disproportionately likely to experience trauma and develop PTSD symptoms. We sought to evaluate the relationships between objective neighborhood disorder, perceptions of neighborhood, and the use of maladaptive coping behaviors among both non-substance-using and substance-using participants with and without PTSD symptoms. METHODS: Participants (255 non-drug users [NDUs], 168 marijuana and/or alcohol users [MAUs], and 273 opioid and/or stimulant users) completed the Addiction Severity Index, PTSD Checklist-Civilian Version, The COPE Inventory, and the Perceived Neighborhood Scale. The Neighborhood Inventory for Environmental Typology (NIfETy) was used to objectively assess neighborhood disorder at participants' home addresses. Regression modeling was used to assess within-group predictors of PTSD and test for mediation in the relationships between PTSD, perceptions of neighborhood, and coping behaviors. RESULTS: In NDUs, lower sense of community partially mediated the relationship between PTSD symptoms and using mental disengagement to cope. In MAUs, higher levels of perceived crime partially mediated the individual relationships between PTSD symptoms and using mental disengagement, focusing on and venting emotions, and using substances to cope. Opioid and/or stimulant users with PTSD symptoms reported using higher levels of mental disengagement, focusing on and venting emotions, and substances to cope and perceived a higher degree of crime; no mediation was inferred. CONCLUSION: Perceptions of community and crime may be more predictive of PTSD symptoms than objectively measured neighborhood disorder. These perceptions partially mediate the relationship between maladaptive coping behaviors and PTSD symptoms. PMID- 28885302 TI - Postinfection Irritable Bowel Syndrome: The Links Between Gastroenteritis, Inflammation, the Microbiome, and Functional Disease. AB - Postinfection irritable bowel syndrome (PI-IBS) is a diarrheal disease that develops after infectious gastroenteritis (IGE). Profound alterations in the microbiota accompany IGE yet only 10% of IGE patients progress to PI-IBS. This review explores research linking IGE severity, psychological comorbidity, PI-IBS, and the microbiome in various patient populations. Selective pressures caused by inflammation and increased gastrointestinal motility during gastroenteritis can alter intestinal bacterial phyla including Bacteroidetes, Firmicutes, and Proteobacteria. More specifically, classes such as Bacteroides and Clostridia are differentially abundant in many PI-IBS patients. Altered microbiota may perpetuate a cycle of enteric and systemic inflammation, potently activating neural afferent signaling in the enteric nervous system and causing pain and diarrhea in PI-IBS patients. Altered production of microbial metabolites, for example short chain fatty acids, may have enteric and systemic effects on the host. Longitudinal sampling to characterize changes in the microbiota's genetic, metabolic, and transcriptional activities over time from IGE to PI-IBS may enable improved diagnosis and classification of PI-IBS cases into subtypes, allowing for targeted antibiotic, probiotic, and prebiotic treatments. PI-IBS is a heterogenous and largely organic disease marked by specific alterations in functions of the microbiota and is an important model for studying microbial influences on intestinal, neurological, and psychological host functions. PMID- 28885303 TI - Validation of Probe-based Confocal Laser Endomicroscopy (pCLE) Criteria for Diagnosing Colon Polyp Histology. AB - BACKGROUND: Validated probe-based confocal endomicroscopy (pCLE) criteria for distinguishing hyperplastic polyps (HPs) and tubular adenomas (TA) have not yet been developed. AIM: To develop pCLE criteria for distinguishing HP from TA and evaluate its performance characteristics among experts. METHODS: pCLE criteria for colon polyp histology were developed and tested in 2 phases prospectively. Phase I: 8 preliminary criteria were developed and tested internally. Criteria achieving an accuracy of >75% (epithelial surface: regular vs. irregular; goblet cells: increased vs. decreased; gland axis: horizontal vs. vertical; gland shape: slit/stellate vs. villiform; image scale: gray vs. dark) were evaluated in Phase II of study wherein external assessors evaluated these criteria in a separate set of pCLE videos. Accuracy and interobserver agreement (95% confidence intervals) were determined for colon histology prediction. RESULTS: Phase I (criteria development/internal testing): 8 criteria were assessed by 4 pCLE experts using 28 videos (14 HP/14 TA). Five of 8 pCLE criteria met selection for phase II (accuracy >75%). Phase II (external validation): 36 pCLE colon polyp videos (HP 16/TA 20) were evaluated by 8 external assessors. Overall accuracy in diagnosis of colon polyp histology was 84.9% (95% confidence interval, 81.7-87.7). Of predictions made with high confidence (75%), histology was predicted with an accuracy of 91%, sensitivity 83%, specificity 100%, negative predictive value 87% and positive predictive value 98%. Interobserver agreement was substantial (kappa=0.73). CONCLUSIONS: We demonstrate the development and validation of pCLE criteria for prediction of colon polyp histology. Using these criteria, overall accuracy in differentiating TA from HP was high with substantial interobserver agreement. PMID- 28885304 TI - Bowel Preparations Administered the Morning of Colonoscopy Provide Similar Efficacy to a Split Dose Regimen: A Meta Analysis. AB - BACKGROUND: Comparative efficacy of same-day bowel preparations for colonoscopy remains unclear. AIMS: A meta-analysis of randomized controlled trials comparing the efficacy of same-day versus split dose bowel preparations for colonoscopy. METHODS: A systematic search was conducted in MEDLINE, clinicaltrials.gov, Cochrane Registry, EMBASE, SCOPUS, Web of Science and CINAHL. Studies were gathered using keywords: "morning preparation", "morning bowel preparation", "same day bowel preparation", and "colonoscopy." Pooled estimates of bowel preparation quality were analyzed among studies with categorical and continuous outcomes according to relative risk (RR) or mean difference (MD). A random effects model was chosen a priori for all analyses. RESULTS: A total of 1216 studies were retrieved with 15 trials meeting inclusion criteria. The categorical outcome of high quality bowel preparation for any same-day bowel preparation versus any split preparation was no different with a RR 0.95 [0.90;1.00] (P=0.62). Adenoma detection rate (ADR) was not different between groups, RR 0.97 [0.79;1.20] (P=0.81). Willingness to repeat and tolerability did not differ (RR 1.14 [0.96,1.36] (P=0.14) and RR 1.00 [0.96;1.04] (P=0.98), respectively. Adverse events were similar except for bloating, which was less frequent among the same day preparation group, RR 0.68 [0.40;0.94] (P=0.02). CONCLUSION: No clinically significant differences were noted among recipients of same day or split dose regimens. Adenoma detection rate, willingness to repeat and tolerability were similar, but bloating and interference with sleep favored the same-day preparations. Given lack of clinical differences, patient preference should dictate timing of colonoscopy preparation. PMID- 28885305 TI - Successful Esophageal Dilation of Eosinophilic Esophagitis (EoE) Patients With a Previous Postdilation Complication: Start Low and Go Slow. AB - INTRODUCTION: Esophageal dilation is an effective and safe treatment option for fibrostenotic eosinophilic esophagitis (EoE). Despite the safety, adverse events occur, yet there is scarce literature on the best treatment postcomplications. METHODS: Patients with diagnosis of EoE (>=15 eosinophils per high-power field) from 2011 to 2015 treated at our center were included. Thirty patients with fibrostenotic disease had records available regarding serial dilation therapy. Eight patients previously experienced complications by outside providers. Groups were created based on history of complication before our dilation versus a group without. Mean difference and odds ratio with 95% confidence interval (CI) were calculated. RESULTS: There were 8 complications, 7 occurred during dilation and 1 during passage of the endoscope. Esophageal diameter at initial dilation was lower in patients with prior complications 9.0+/-1.51 versus 11.73+/-2.98 mm (95% CI: -4.44, -1.02; P=0.003). However, end-esophageal diameter was similar across both groups 15.8+/-1.8 versus 16.1+/-2.0 mm. Total number of dilation sessions: 4.0+/-1.8 versus 2.32+/-1.0 (95% CI: 0.17, 3.19; P=0.03), as well as sessions to reach 17 mm diameter 3.8+/-1.0 versus 2.3+/-1.0 (95% CI: -0.08, 2.89; P=0.04), were higher in the patients with complications. The length of time in months to reach an esophageal diameter of 17 mm was longer in patients with complications, but the difference was not statistically significant 3.50+/-0.6 versus 2.3+/-2.3 months (P=0.09). CONCLUSIONS: Esophageal dilation is a safe and effective modality to treat severe fibrostenotic EoE in patients with prior history of complications. The keys to success are: (1) start with lower diameter bougies and (2) dilate slowly over a longer time course to reach targeted diameter and symptom resolution. PMID- 28885306 TI - Community, population health, and health care organizations. PMID- 28885307 TI - The treatment of paraprotein-related kidney disease. AB - PURPOSE OF REVIEW: Myeloma kidney and amyloid light-chain (AL) amyloidosis remain the principal kidney complications of paraproteins. In this review, we update readers to many of the recent advances which have occurred in the care and outcomes for patients with these presentations. RECENT FINDINGS: Myeloma kidney has historically caused a severe acute kidney injury with very poor outcomes. The combination of new diagnostic techniques, enabling a rapid diagnosis and novel chemotherapy agents has transformed these poor outcomes for the better. Two multicentre randomized controlled trials have recently evaluated if the removal of free light chains by high cut-off haemodialysis improves renal outcomes beyond effective chemotherapy alone. Although we await the full articles of these studies to be published, abstracts suggested the studies will have contradictory primary results. In the field of AL amyloidosis, there are now novel criteria for the risk stratification of kidney outcomes which can be used in combination with markers of early kidney response to provide clinicians with powerful tools to guide patient discussions. SUMMARY: Across both AL amyloidosis and myeloma kidney patient outcomes continue to improve. Principally this improvement has been driven by the continuing development of novel chemotherapy agents in this field. PMID- 28885308 TI - Military Decorative Pin Dermatitis: Prevention for Nickel Allergy Among Service Members. PMID- 28885309 TI - Effectiveness of European Regulation on Euxyl K400 Sensitization in Northeastern Italy From 1996 to 2012 and Occupation. PMID- 28885310 TI - Contact Allergy to Hydroperoxides of Linalool and D-Limonene in a US Population. AB - BACKGROUND: Linalool and D-limonene are common fragrance ingredients that readily oxidize on exposure to air. The resulting hydroperoxides of linalool and D limonene have been shown to have high frequencies of positive patch test reactions in several European and international studies. OBJECTIVE: The aim of the study was to investigate the prevalence of contact allergy to the hydroperoxides of linalool and D-limonene in a US population. METHODS: In this retrospective study, 103 patients with suspected fragrance allergy were patch tested to linalool 10% petrolatum (pet), hydroperoxides of linalool 1% pet, D limonene 10% pet, and/or the hydroperoxides of D-limonene 0.3% pet between July 9, 2014, and October 25, 2016. CONCLUSIONS: In this study, the frequency of positive patch test reactions to the hydroperoxides of linalool is 20% (19/96), and the frequency of positive reactions to the hydroperoxides of D-limonene is 8% (7/90). These high frequencies suggest that patch testing to the hydroperoxides of linalool and limonene should be performed in all patients with suspected fragrance allergy. PMID- 28885311 TI - Allergenic Ingredients in Hand Wet Wipes. PMID- 28885312 TI - Angioedema, Stomatitis, and Urticaria Caused by Contact Allergy to Invisalign. PMID- 28885313 TI - Benzalkonium Chloride: An Irritant and Sensitizer. AB - BACKGROUND: Benzalkonium chloride (BAK) is a known irritant, and potentially cross-reacting quaternary ammonium compounds are commonly used as preservatives in personal care products. OBJECTIVE: The aim of the study was to review positive reactions to BAK in 615 patients patch tested for suspected allergic contact dermatitis. METHODS: A retrospective chart review was performed in 615 patients patch tested from June 2015 to October 2016. All patients were tested to a Modified American Contact Dermatitis Society core series of 70 allergens including BAK (0.1% aqueous). Initial readings were performed at 48 hours with final readings performed between 72 and 168 hours. Results were graded as + (weak: papules and erythema), ++ (strong: papules and edema or vesicles), or +++ (extreme: coalescing vesicles, spreading or bullous reactions). RESULTS: A total of 141 men (23%) and 475 women (77%) were tested (mean age, 49 years). Four hundred thirty-two (70%) were atopic. Of 615 patients, 198 (32%) tested positive to BAK, and 64 (10%) had ++ or +++ reactions at their final reading. On average, BAK-positive patients were using at least 1 product containing BAK or possible cross-reactors. CONCLUSIONS: Widespread exposure to irritants in dermatitis patients can predispose to sensitization. Products containing BAK or potential cross-reactors should be used carefully in patients with compromised skin barriers. PMID- 28885314 TI - Treatment of Multiple-Resistant and/or Recurrent Cutaneous Warts With Squaric Acid Dibutylester: A Randomized, Double-blind, Vehicle-controlled Clinical Trial. AB - BACKGROUND: Contact immunotherapy with squaric acid dibutylester (SADBE) for cutaneous warts has been reported to be effective, although no controlled studies are available so far. OBJECTIVE: The aim of this study was to evaluate the efficacy of SADBE on cutaneous warts by a randomized, double-blind, vehicle controlled, clinical trial. METHODS: Thirty-six patients were randomly assigned to SADBE (18 cases) or vehicle (18 cases) group. At 8 weeks, subjects were clinically evaluated for number/size reduction rate and for Investigator Global Assessment. Those who showed improvement extended therapy up to 40 weeks, whereas those who showed unresponsiveness were either switched to SADBE application for up to 48 weeks (if in the vehicle group) or withdrawn from the study (if under SADBE). RESULTS: At 8 weeks, a significant reduction in wart number (P = 0.020) and size (P = 0.010) in the SADBE group, with clearing rates of 41.2% versus 12.5% in the SADBE and vehicle groups, respectively, was observed. Nine remaining SADBE responders who underwent treatment extension up to 40 weeks achieved clearing versus 2 patients of the vehicle group who remained unresponsive. Clearing was obtained in 81.8% of patients who underwent previous ineffective vehicle treatment and had been switched to SADBE. CONCLUSIONS: Squaric acid dibutylester is an effective therapeutic option and is significantly more effective than vehicle. PMID- 28885315 TI - Tuberous Breast: Past, Present, and Future: Personal Classification, Treatment, and Surgical Outcomes. AB - BACKGROUND: Tuberous breast (TB) is a rare congenital deformity, which may appear in different clinical forms representing various degrees of a single pathological entity. The worst cases are characterized by severe hypoplasia. Following a detailed analysis of the available relevant literature and a significant number of treated cases, in this article, the authors propose a new classification, with the aim of summarizing and simplifying a more intuitive categorization of the malformation, considering all the clinical aspects and including all types of TBs, even the minor ones, thus allowing a more immediate diagnosis and surgical planning. METHODS: Between September 2006 and December 2015, 78 patients with TBs underwent surgical procedures to correct the deformity. The patients' mean age was 18.6 years, ranging between 17 and 26 years. There being 11 monolateral deformities, the treated TBs amounted to 145. A periareolar approach, adipo glandular flaps, and dual plane breast implant placements were performed. Postoperative follow-up include photos collected 12 months after operation. The authors present a personal classification including all the forms of the deformity, plus the minor forms based on the following 2 principal categories: hypoplastic and normoplastic TBs, taking into account all the clinical aspects of the malformation including the morphology and the consistency of the breast. CONCLUSIONS: Preoperative identification of the type of the deformity is essential to obtain satisfactory results and a complete and intuitive classification including all the possible variants of the deformity, even the minor forms, and fundamental in diagnosing and resolving the problem. In this article, the authors propose a personal classification and surgical procedure to resolve the malformation. PMID- 28885316 TI - Evaluation of Single Tooth Loss to Maxillary Sinus and Surrounding Bone Anatomy With Cone-Beam Computed Tomography: A Multicenter Study. AB - BACKGROUND: Posterior maxillary tooth loss may complicate the implant treatment due to the alterations in alveolar anatomy and maxillary sinus pneumatization. This study aimed to comprehensively examine the anatomical structure of this region from cone-beam computed tomography (CBCT) images. MATERIALS AND METHODS: The posterior maxilla regions with single tooth loss were analyzed by dividing the variables into 3 subgroups from images of 597 patients chosen from 1160 CBCTs. Variables associated with sinus membrane (SM), sinus dimensions, ostium, septa, sinus neighborhood, alveolar bone height (ABH) and width (RW), posterior superior alveolar artery (PSAA), and adjacent roots were evaluated. RESULTS: The majority of the patients demonstrated 0 to 5 mm membrane thickness. Irregular SM thickening was lower for female patients. While females showed higher number of narrow sinus, males had higher RW than females. Sinus augmentation classification showed negative correlation with ABH, root-tip sinus floor and edentulous site classification. Posterior septa height was correlated with number of septa and ABH. PSAA diameter and location were also correlated between each other. CONCLUSION: The present results define formation of a sinus space with 11 mm coronal and 16 mm apical width after single tooth loss. A flat or semispherical thickening around 4 mm is usual in most cases with 51% possibility of anterior septum existence. A ridge anatomy, around 7.5 mm ABH and 7.2 to 9.3 RW from coronal to apical, complements this anatomy. Further studies are needed to clarify the reasons behind the SM and crestal anatomy variations between genders. PMID- 28885317 TI - Ridge Preservation After Maxillary Third Molar Extraction Using 30% Porosity PLGA/HA/beta-TCP Scaffolds With and Without Simvastatin: A Pilot Randomized Controlled Clinical Trial. AB - OBJECTIVE: To evaluate clinically and radiographically, in humans, the healing of maxillary third molars postextraction sockets after application of different ridge preservation techniques 3 months after tooth extraction. MATERIALS AND METHODS: Twenty-six sockets (13 patients) were randomly assigned to 4 treatment modalities: deproteinized bovine bone mineral with 10% collagen (DBBM-C), poly(D,L-lactide-co-glycolide) with hydroxyapatite/beta-TCP scaffold (PLGA/HA), PLGA/HA/beta-TCP with 2.0% simvastatin scaffold (PLGA/HA/S), and spontaneous healing (control). Clinical complications were assessed, and cone-beam computed tomographies were taken in 5 patients 3 months after surgeries. For statistical purposes, the Fisher exact test was used (P < 0.05). RESULTS: After 3 months, 6 of 9 grafts from the PLGA/HA group were lost (P < 0.05). PLGA/HA/S' loss was only 2 of 8 (P > 0.05), but no loss was observed in the DBBM-C group. Pain was present in 3 of 8 sites that lost the graft (37.5%) (P > 0.05) and infection in 1 of 8 (12.5%) (P > 0.05), with these only occurring in the PLGA/HA group. CONCLUSIONS: Poly (D, L-lactide-co-glycolide) with hydroxyapatite/beta-TCP (PLGA/HA/beta-TCP) scaffolds, with and without simvastatin, failed to obtain the initial expected results and presented more complications. Scaffolds with simvastatin showed to be superior, with less clinical complications than scaffolds without simvastatin. PMID- 28885318 TI - Gamma prime (gamma') fibrinogen and carotid intima-media thickness: the Atherosclerosis Risk in Communities study. AB - : We assessed if gamma' fibrinogen, an isoform of fibrinogen, is independently associated with subclinical atherosclerosis beyond total fibrinogen in black and white men and women participating in the Atherosclerosis Risk in Communities study. Fasting gamma' fibrinogen was measured in 6847 Atherosclerosis Risk in Communities participants, ages 51-70 years, in 1993-1995. Carotid intima-media far wall thickness (CIMT) was measured by B-mode ultrasonography at the common, internal and bifurcation carotids. The association of gamma' fibrinogen tertiles with overall and segment-specific mean CIMT was assessed with linear regression, controlling for fibrinogen as well as cardiovascular risk factors, including high sensitivity C-reactive protein and D-dimer. gamma' Fibrinogen values ranged from 8.0 to 80.3 mg/dl and were positively related to age, female sex, black race, smoking, BMI, lipids and SBP. Crude gamma' fibrinogen was directly associated with all CIMT measures except for the internal carotid, but explained less than 1% of the variance in the associations. Adjustment for total fibrinogen eliminated these associations, and total fibrinogen remained an independent predictor of CIMT without explaining additional variance. Adjustment for potential confounding variables did not alter the observed associations, which did not differ by race or sex. In these cross-sectional data, gamma' fibrinogen was not independently associated with CIMT when controlling for total fibrinogen. gamma' Fibrinogen and total fibrinogen together explained a very small proportion of the variance in CIMT, regardless of the carotid site. If gamma' fibrinogen adds to total fibrinogen's ability to predict subclinical atherosclerosis, it may be in younger populations. PMID- 28885320 TI - An Examination of the Perceived Importance and Skills Related to Policies and Policy Making Among State Public Health Injury Prevention Staff. AB - OBJECTIVE: The purpose of this research is to use the Public Health Workforce Interests and Needs Survey to assess in greater detail state injury prevention staff perceptions of policy development and related skills and their awareness and perception of "Health in All Policies" (HiAP). DESIGN: The Public Health Workforce Interests and Needs Survey gauged public health practitioners' perspectives on workplace environment, job satisfaction, national trends, and training needs, and gathered demographics on the workforce. This study utilizes data from the state health agency frame only, focusing solely on those permanently employed, central office staff in injury prevention. Respondents were sampled from 5 paired Health and Human Services regions. SETTING/PARTICIPANTS: Approximately 25 000 invitations were sent to central office employees. The response rate was 46% (n = 10 246). The analysis in this article includes only injury prevention employees with programmatic roles, excluding clerical and custodial staff, providing us with a total of 97 respondents. When weighted, this resulted in a weighted population size of 365 injury prevention workers. MAIN OUTCOME MEASURES: The main outcome measures include demographics, responses to understanding of and skill levels related to policy development, and perceptions of HiAP public health trend. RESULTS: State injury prevention workers reported lower policy-making skill but had an overall appreciation of the importance of policies. In general, state injury prevention workers heard of HiAP, thought there should be more emphasis on it, but did not think that HiAP would have an impact on their day-to-day work. CONCLUSIONS/IMPLICATIONS FOR POLICY AND PRACTICE: Efforts are needed for all state injury prevention workers to become better skilled in policy development, implementation, and evaluation in order to become stronger injury prevention advocates and role models. PMID- 28885321 TI - Bone fracture risk in patients with rheumatoid arthritis: A meta-analysis. AB - BACKGROUND: Patients with rheumatoid arthritis (RA) are predisposed to osteoporotic fracture. The present study aims to determine the association between rheumatoid arthritis (RA) and bone fracture risk, and in relation to gender and site-specific fractures. METHODS: Studies related to bone fracture in patients with RA were searched from databases including PubMed, EMBASE, and OVID from inception through April 2016. The quality of the studies was evaluated using the Newcastle-Ottawa Scale. Meta-analysis was performed with Stata13.1 software. The results were reported based on risk ratio (RR) and 95% confidence interval (95% CI) using a random effects model. RESULTS: The meta-analysis of 13 studies showed a significant higher risk of bone fracture in patients with RA than in patients without RA (RR = 2.25, 95% CI [1.76-2.87]). Subgroup analyses showed that both female and male patients with RA had increased risk of fracture when compared with female and male patients without RA (female: RR = 1.99, 95% CI [1.58-2.50]; male: RR = 1.87, 95% CI [1.48-2.37]). Another subgroup analysis of site-specific fracture also showed that RA is positively correlated with the incidence of vertebral fracture (RR = 2.93, 95% CI [2.25-3.83]) or hip fracture (RR = 2.41, 95% CI [1.83-3.17]). CONCLUSION: RA is a risk factor for bone fracture in both men and women, with comparable risks of fractures at the vertebral and hip. PMID- 28885319 TI - Getting the Word Out: New Approaches for Disseminating Public Health Science. AB - The gap between discovery of public health knowledge and application in practice settings and policy development is due in part to ineffective dissemination. This article describes (1) lessons related to dissemination from related disciplines (eg, communication, agriculture, social marketing, political science), (2) current practices among researchers, (3) key audience characteristics, (4) available tools for dissemination, and (5) measures of impact. Dissemination efforts need to take into account the message, source, audience, and channel. Practitioners and policy makers can be more effectively reached via news media, social media, issue or policy briefs, one-on-one meetings, and workshops and seminars. Numerous "upstream" and "midstream" indicators of impact include changes in public perception or awareness, greater use of evidence-based interventions, and changes in policy. By employing ideas outlined in this article, scientific discoveries are more likely to be applied in public health agencies and policy-making bodies. PMID- 28885322 TI - Is serum high-mobility group box 1 (HMGB-1) level correlated with liver fibrosis in chronic hepatitis B? AB - BACKGROUND: High-mobility group box 1 (HMGB1), identified as an alarmin molecule, was shown to have a role in virus-triggered liver injury. We aimed to evaluate the association between serum levels of HMGB1 and liver fibrosis. METHOD: This cross-sectional case-control study included 189 chronic hepatitis B (CHB) patients and 51 healthy controls. All patients underwent liver biopsy and modified Knodell scoring system used to determine the fibrosis level in CHB patients. Serum HMGB1 levels were determined with enzyme-linked immunosorbent assay (ELISA). RESULTS: Mean serum HMGB1 levels of patients (58.1 +/- 54.7) were found to be higher than those of the control group (7.1 +/- 4.3) (P = .001). HMGB1 levels of patients with advanced-stage fibrosis (stage 4 and 5) were detected to be higher than those of patients with early-stage fibrosis (stage 1 3). However, this difference was not statistically significant (P > .05). Albumin levels of fibrosis 3 and 4 patients were lower than fibrosis 1 and 2 patients. ALT, HBV DNA, and AFP levels of fibrosis 5 patients were significantly higher than fibrosis 1 and 2 patients, and their platelet and albumin levels are lower than fibrosis 1 and 2 patients (P < .001). In a logistic regression model, fibrosis levels were correlated with ALT values and inversely correlated with albumin levels. CONCLUSION: In this study, we demonstrated that serum HMGB1 levels increase in the early course of liver injury and this increase is not correlated with severity of the liver damage. PMID- 28885323 TI - PIK3CG single nucleotide polymorphisms are associated with poor responsiveness to clopidogrel and increased risk of ischemia in patients with coronary heart disease. AB - BACKGROUND: This study explores the associations between PIK3CG single nucleotide polymorphisms (SNPs, rs1129293 and rs17398575) and patient responsiveness to clopidogrel to evaluate the risks of ischemia in patients with coronary heart disease (CHD). METHODS: The study consisted of 513 CHD patients who received clopidogrel as part of antiplatelet therapy, after percutaneous coronary intervention. According to the patient responsiveness to clopidogrel, the subjects were assigned to either clopidogrel-resistant (CR) or clopidogrel sensitive (CS) groups. CR group was determined by patients' platelet aggregation rate of >=70% and poor responsiveness to clopidogrel, and CS group by patients' platelet aggregation rates of <70% and good responsiveness to clopidogrel. Polymerase chain reaction using TaqMan probe was employed to detect PIK3CG polymorphism. Haplotype and linkage disequilibrium analyses were performed. Prognosis analysis was performed using the Kaplan-Meier curve. RESULTS: Significant difference was found in genotype and rs1129293 and rs17398575 allele frequency between the CR and CS groups. Haplotype analysis indicated that the frequency of TG allele was higher in the CR group compared with the CS group, and the frequency of CA allele was lower in the CR group compared with the CS group. Patients with rs1129293 CT + TT genotype and T allele, rs1129293 AG + GG genotype and G allele exhibited an increased CR risk. Logistic regression analysis determined hypertension history as an independent risk factor for CR. The Kaplan Meier curve suggests that distribution curve of cumulative probability nonischemic events was different between patients with rs1129293 and rs17398575 alleles. Stable CHD patients with TT genotype of rs1129293 allele and GG genotype of rs17398575 allele showed poorer prognosis compared to those with other genotypes and patients with acute coronary syndromes. CONCLUSION: A positive correlation may exist between PIK3CG SNPs (rs1129293 and rs17398575) and patients with poor responsiveness to clopidogrel. These findings show that this factor may contribute to an increased risk of ischemia in patients suffering from CHD. PMID- 28885324 TI - The application of high-field magnetic resonance perfusion imaging in the diagnosis of pancreatic cancer. AB - Pancreatic cancer is the fourth leading cause of cancer death in the world. It is a disease of insidious progression and high lethality. The present study was to investigate the diagnostic value of high-filed magnetic resonance (MR) perfusion imaging in pancreatic cancer. Thirty-three patients with suspected pancreatic cancer were recruited in our study and underwent routine MR imaging. When compared with para-tumoral and normal tissue, the pancreatic lesions showed significant lower slope, peak enhancement (PE), and signal enhancement ratio (SER) as well as higher time to peak (TTP). Para-tumoral tissue was found to have significantly lower slope and PE, slightly higher TTP than normal tissue. MR perfusion imaging displays hemodynamic alterations in both pancreatic cancer and surrounding pancreatic tissue, and provides indirect assessment of tumor vascularity. In conclusion, high field MR perfusion imaging has important clinical significance in early diagnosis of pancreatic cancer. PMID- 28885325 TI - Combination therapy of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea and their association with a decreased risk of cardiovascular disease in type 2 diabetes mellitus patients. AB - BACKGROUND: Clinical trials assessing the combination therapy of metformin plus dipeptidyl peptidase-4 inhibitors versus metformin plus Sulfonylureas on risk of cardiovascular disease, cardiovascular mortality and/or all-cause mortality in type 2 diabetes have shown conflicting results. We therefore evaluated the combination therapy on the risk of cardiovascular disease, cardiovascular mortality and/or all-cause mortality in type 2 diabetes. METHODS: A systematic search of Medline/PubMed (from 2000 to September 2015), EMBASE (from 2000 to September 2015), and Web of Knowledge (from 2000 to September 2015) for research articles published in English was carried out to examine how combination therapy affects the risk of CVD mortality and/or all-cause mortality in T2DM patients. In addition, the risks of cardiovascular events, CVD mortality, and/or all-cause mortality as well as the adjusted relative risk (RR) or equivalent (hazard ratio or odds ratio) and the corresponding variance or equivalent are reported. RESULTS: The accumulative RRs (95% confidence intervals) for T2DM patients treated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea were 0.71 (0.56-0.90) for nonfatal cardiovascular events, 1.001 (0.85-1.18) for fatal cardiovascular events, 0.58 (0.41-0.82) for CVD mortality, and 0.72 (0.59-0.87) for all-cause mortality. CONCLUSIONS: The combination therapy of metformin plus DPP-4 inhibitor significantly decreased the RR of nonfatal cardiovascular events, CVD mortality, and all-cause mortality, compared with the combination therapy of metformin plus sulfonylurea. However, the number fatal cardiovascular events (e.g., heart failure) was not significantly different between the 2 groups. PMID- 28885326 TI - Melanoma in situ of penis: a very rare entity: A case report and review of the literature. AB - RATIONALE: Melanoma in situ of the penis is very rare and there are no clear guidelines for its surgical treatment. PATIENT CONCERNS: The authors describe the case of a 69-year-old man who presented with an asymptomatic brown macula on his glans penis and foreskin that appeared about 8 years earlier, enlarged in the last few months. DIAGNOSES: A diagnostic biopsy showed the characteristics of a melanoma in situ. INTERVENTIONS: The authors decided to excise the lesion keeping a healthy margin of 1 cm all over around except close to the urethral meatus, where it was impossible, and where only 5 mm of free margin was excised. A full thickness mucosal graft from oral cavity was performed to repair the defect. OUTCOMES: No recurrence or metastasis occurred during 50 months after the operation. LESSONS: Considering that at the sixth clinical follow-up the patient was alive and disease free at 50 months after surgery, the chosen treatment has proved successful. PMID- 28885327 TI - Risk factors for pain after Frey's procedure in chronic pancreatitis. AB - Pancreatic pain is the most frequent symptom of chronic pancreatitis (CP) and is difficult to treat. This retrospective study aimed to determine the risk factors for pain in CP.From January 2009 and March 2014, 75 consecutive patients with CP who underwent Frey's procedure were reviewed for this study. According to Izbicki pain scores, these patients were divided into 2 groups: (1) pain (Izbicki pain score of >10 after a decrease of >50%) and (2) pain-free (Izbicki pain score of <=10). Demographic data, medical history, postoperative variables, and follow-up evaluations of the patients were documented.The postoperative pain score (11.8) was significantly lower than the preoperative score (51.8) after a median follow up of 4.2 years. Alcoholism (odds ratio [OR] 7.767, P = .002) and preoperative analgesic medication use (OR 4.113, P = .030) were independent risk factors for pain.Frey's procedure is an effective operation for pain relief in patients with CP. Alcoholism and preoperative analgesic medication use were 2 factors for failure to achieve complete pain relief. PMID- 28885328 TI - Use of thiazolidinediones and risk of hip fracture in old people in a case control study in Taiwan. AB - Little research is available on the association between use of thiazolidinediones and hip fracture in old people in Taiwan. We conducted a population-based case control study to examine this issue.Using the database of the Taiwan National Health Insurance Program, we identified 603 type 2 diabetic subjects 65 years or older in age with newly diagnosed hip fracture in 2000 to 2013 as cases. We randomly selected 603 type 2 diabetic subjects 65 years or older without hip fracture as the controls. Both cases and controls were matched with sex, age, comorbidities, and index year of diagnosing hip fracture. Current use of thiazolidinediones was defined as subjects whose last remaining one tablet of thiazolidinediones was noted <=30 days before the date of diagnosing hip fracture. Never use of thiazolidinediones was defined as subjects who never had a prescription of thiazolidinediones. The odds ratio (OR) and 95% confidence interval (CI) for hip fracture associated with thiazolidinediones use was estimated by the multivariable unconditional logistic regression analysis.After adjustment for covariables, the multivariable logistic regression analysis revealed that the adjusted OR of hip fracture was 1.64 for subjects with current use of thiazolidinediones (95% CI 1.01, 2.67), when compared with subjects with never use of thiazolidinediones.Our findings suggest that current use of thiazolidinediones is associated with a 64% higher risk of hip fracture in type 2 diabetic old people in Taiwan. Clinicians should consider the possibility of thiazolidinediones-associated hip fracture among type 2 diabetic old people currently using thiazolidinediones. PMID- 28885329 TI - Simultaneous endoscopic submucosal dissection for multiple early gastric cancers in a low volume center. AB - The aim of the study is to evaluate the safety and efficacy of simultaneous endoscopic submucosal dissection (ESD) for multiple early gastric cancers.A total of 70 solitary early gastric cancers from 70 patients and 20 multiple early gastric cancers from 10 patients were included in this retrospective study. The curative resection rate, en bloc resection rate, procedure-related complications, and local recurrence were compared between the 2 groups.There was no statistical difference in the rate of complete resection, en bloc resection, and curative resection between the 2 groups (P > .05). No significant difference was found with respect to the occurrence of postoperative bleeding (P > .05). Procedure time was significantly longer in the simultaneous group than that in the single group (87.6 +/- 25.1 min vs 54.6 +/- 22.0 min, P = .004). The overall incidence of synchronous early gastric cancer was 7.5%.Simultaneous ESD for multiple early gastric cancers is a safe and feasible choice in low-volume hospital. The entire stomach should be examined meticulously during and after ESD. Larger randomized studies are needed to validate our results. PMID- 28885330 TI - Fractional curve progression with maintenance of fusion mass in congenital scoliosis: An 18-year follow-up of a case report. AB - RATIONALE: The management of congenital scoliosis concentrates on early diagnosis and proper surgical treatment before the development of severe deformities. Decision making regarding the appropriate fusion levels, proper surgical treatment, and reduction amount of kyphoscoliosis is very important but difficult in the treatment of congenital scoliosis, especially in young children. PATIENT CONCERNS: We report an 11-year follow-up of revision surgery for fractional curve progression after combined anterior and posterior fusion without hemivertebra resection using pedicle screw fixation (PSF) in congenital kyphoscoliosis at age 4 years (a total 18-year follow-up). A T12 hemivertebra was documented in a 4 year-old girl and was treated by combined anterior and posterior fusion in two stages with PSF. The fusion mass was maintained but the distal compensatory curve progressed during the follow-up period. The patient underwent a posterior vertebral column resection (PVCR) with extended posterior fusion at the age of 11, 7 years after initial surgery. OUTCOMES: Eleven years after the revision surgery with PVCR, the patient showed satisfactory results and her spine was well balanced. LESSONS: The cause of revision surgery for the curve progression may include inappropriate fusion level, incomplete hemivertebra resection, or failure of anterior and posterior fusion. Especially, inappropriate fusion level may result in deterioration of the compensatory curve even without progression of the fusion mass. CONCLUSION: Appropriate selection of fusion levels, complete resection of hemivertebra, and satisfactory reduction of scoliosis and kyphosis are important factors for deformity correction and prevention of progression of both main and compensatory curves (adding-on of structural curve or progression of compensatory curve) as well as reducing the influence of adjacent vertebral growth using as short a fusion as possible. PMID- 28885331 TI - Population-based cohort study investigating the correlation of diabetes mellitus with pleural empyema in adults in Taiwan. AB - We assessed the association between diabetes mellitus and the risk of pleural empyema in Taiwan.A population-based retrospective cohort study was conducted using the database of the Taiwan National Health Insurance Program. There were 28,802 subjects aged 20 to 84 years who were newly diagnosed with diabetes mellitus from 2000 to 2010 as the diabetes group and 114,916 randomly selected subjects without diabetes mellitus as the non-diabetes group. The diabetes group and the non-diabetes group were matched by sex, age, comorbidities, and the year of index date. The incidence of pleural empyema at the end of 2011 was estimated. A multivariable Cox proportional hazards regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) for pleural empyema associated with diabetes mellitus.The overall incidence of pleural empyema was 1.65-fold higher in the diabetes group than that in the non-diabetes group (1.58 vs 0.96 per 10,000 person-years, 95% CI 1.57-1.72). After adjusting for confounders, a multivariable Cox proportional hazards regression model revealed that the adjusted HR of pleural empyema was 1.71 in subjects with diabetes mellitus (95% CI 1.16-2.51), compared with those without diabetes mellitus. In further analysis, even in the absence of any comorbidity, the adjusted HR was 1.99 for subjects with diabetes mellitus alone (95% CI 1.18-3.38).Diabetic patients confer a 1.71-fold increased hazard of developing pleural empyema. Even in the absence of any comorbidity, the risk remains existent. PMID- 28885332 TI - Comparisons of front plate, percutaneous sacroiliac screws, and sacroiliac anterior papilionaceous plate in fixation of unstable pelvic fractures. AB - BACKGROUND: This observational study was aimed at comparing the clinical efficacy of sacroiliac anterior plate fixation (SAPF), sacroiliac anterior papilionaceous plate (SAPP), and percutaneous sacroiliac screw internal fixation (PSCIF) introduced for patients with unstable pelvic fracture. METHODS: Seventy-eight patients with unstable pelvic fracture (Tile type B or C) were recruited. Twenty six patients underwent SAPF, 26 underwent SAPP, and 26 underwent PSCIF. Matta scores were calculated to evaluate the reduction of pelvic fractures, and Majeed scores were applied for the assessment of functional recoveries after surgery. Other perioperative clinical indicators were also recorded, including operation time, bleeding status, length of incision, ambulation time, fracture healing time, and incision infection. RESULTS: Total operation time of PSCIF was remarkably shorter than that of SAPF and SAPP (P < .05), and the bleeding volume of SAPF and SAPP group was almost 26~29 times as high as that of PSCIF group (P < .05). Besides, SAPP resulted in significant blood loss compared with SAPF (P < .05), while SAPF resulted in significantly larger operative incision length than SAPP and PSCIF (P < .05). Moreover, patients' stay time was prolonged in both SAPF and SAPP groups than in the PSCIF group (P < .05). Patients who received PSCIF exhibited significantly higher Matta and Majeed scores than those who received SAPF (all P < .05). Finally, SAPP was associated with fewer complications than SAPF, and complications were barely observed in the PSCIF group. CONCLUSION: PSCIF may be more appropriate for patients with unstable pelvic fractures in comparison with SAPP and SAPF. Besides, SAPP is likely to be more efficacious than SAPF especially for Tile C patients. PMID- 28885333 TI - Rapidly decreasing level of prostate-specific antigen during initial androgen deprivation therapy is a risk factor for early progression to castration resistant prostate cancer: A retrospective study. AB - To build a practical model for predicting the progression to castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT).In all, 185 patients with prostate cancer who had received ADT as the primary therapy at our institution, from 2003 to 2014, were retrospectively enrolled. The following clinical variables were included in the analysis: age, clinical tumor, node, metastasis stage, Gleason score, risk groups of prostate cancer, prostate specific antigen (PSA) at the initiation of ADT, PSA nadir after ADT, velocity of PSA decline, and the time to PSA nadir. Cox proportional-hazards regression models were calculated to estimate effects of these variables on the time of progression to CRPC.On univariate and multivariate analyses, the presence of distant metastasis before ADT (hazard ratio [HR] 6.030, 95% confidence interval (CI) 3.229-11.263, P = .001), higher PSA nadir (HR 1.185, 95% CI 1.080-1.301, P = .001), a velocity of PSA decline >11 ng/mL per month (HR 2.124, 95% CI 1.195 3.750, P = .001), and a time to PSA nadir <=9 months (HR 0.276, 95% CI 0.162 0.469, P = .004) were significantly associated with an increased risk of progression to CRPC.Patients with a rapidly decreasing PSA level in the initial phase of ADT are more likely to progress to CRPC. Our findings provide a practical approach to screen patients during ADT for early identification of those likely to progress to CRPC, allowing treatment to be modified to improve outcomes. PMID- 28885334 TI - Potential association between elevated serum human epididymis protein 4 and renal fibrosis: A systemic review and meta-analysis. AB - BACKGROUND: Human epididymis protein 4 (HE4), a matrix metalloprotease 2 (MMP2), and a matrix metalloprotease 9 (MMP9) inhibitor, promotes renal fibrosis by inhibiting the degradation of type I collagen. However, the predictive value of HE4 for renal fibrosis remains controversial, even though it has been identified as one of the most upregulated genes in cultured fibrosis-associated myofibroblasts. This systematic review and meta-analysis was conducted to investigate the potential association between circulating HE4 and renal fibrosis. METHODS: Original and review articles published until January 2017 that analyzed the performance of serum HE4 in renal fibrosis were systematically searched for in PubMed (1966-2017.1), Cochrane Library, Web of Science, EMBASE (1980-2017.1), China National Knowledge Infrastructure, Wanfang Database, and VIP (Weipu Database). The meta-analysis was performed using RevMan 5.3 version. Pertinent studies were reviewed and the standardized mean difference (SMD) with 95% confidence interval was extracted. A total of 5 studies reporting 460 participants were included in the final analysis. Subgroup and sensitivity analyses were performed to explore the potential sources of between-study heterogeneity. RESULTS: The results demonstrated that elevated serum HE4 favored the diagnosis of renal fibrosis across all trials (SMD = 1.41; 95% confidence interval, 0.82-2.01; P < .001). The bubble graph indicated statistically robust result. The pooled SMD was similar after removing any single study for sensitivity analysis. CONCLUSION: The present study suggests a positive association between circulating HE4 and renal fibrosis. Further studies are needed to investigate the effects of interventions on HE4, and the value of HE4 as a biomarker. PMID- 28885335 TI - Rescue patient from tracheal obstruction by dislocated bronchial stent during tracheostomy surgery with readily available tools: A case report. AB - RATIONALE: Airway stenting is a well-established method that relieves symptoms and maintains airway patency in patients with airway obstruction. Serious complications caused by airway stents such as stent dislocation and airway obstruction during surgery are life-threatening. PATIENT CONCERNS: An 80-year-old man was treated with bronchial stent for left bronchus obstruction caused by metastatic esophageal cancer. During tracheostomy surgery, he suffered from acute tracheal obstruction caused by dislocated bronchial stent. DIAGNOSES: Esophageal cancer, left bronchus obstruction, respiratory failure, tracheal obstruction. INTERVENTIONS: Threading a 5.0-sized endotracheal tube combined with an Eschmann tracheal tube introducer to prop up the collapsed stent. OUTCOMES: The bronchial stent was re-expanded and threaded into right main bronchus and ventilation restored. LESSONS: Patient with airway stent undergoing surgery with airway involved should be performed under the support of a backup physician and equipment that are capable of handling potentially life-threatening complications of airway stent. If not, in the emergent situation of tracheal obstruction due to tracheal/bronchial stent, protruding through the stent with a suitable, small sized endotracheal tube with Eschmann tracheal tube introducer may be an alternative skill for saving life weighted with possible complications. PMID- 28885336 TI - The synergistic effect of inflammation and metabolic syndrome on intraocular pressure: A cross-sectional study. AB - Intraocular pressure is associated with metabolic syndrome. C-reactive protein (CRP) is associated with cardiovascular disease, irrespective of the presence of metabolic syndrome. In this study, we examined the synergistic effect of CRP and metabolic syndrome on intraocular pressure.A total of 1041 subjects were included for data analyses in this cross-sectional study. Intraocular pressure was measured using a noncontact tonometer, and serum CRP levels were measured using a commercially available kit.The intraocular pressure was significantly higher in the subjects with metabolic syndrome than in those without (14.1 +/- 3.0 vs 13.4 +/- 3.0 mm Hg, P = .002). Furthermore, intraocular pressures significantly increased according to CRP tertiles (13.1 +/- 3.0, 13.7 +/- 3.0, and 13.8 +/- 3.0 mm Hg from the lowest to highest tertile of CRP, respectively; P = .002). The highest intraocular pressure was observed in subjects with metabolic syndrome in the highest CRP tertile (P value for trend < .001). Multivariate linear regression analysis revealed that the influence of CRP was independent of metabolic syndrome and that high CRP levels were significantly associated with high intraocular pressure (95% confidence interval: 0.080-1.297, P = .027).In conclusion, systemic inflammation, reflected by serum CRP levels, is associated with high intraocular pressure in subjects with and without metabolic syndrome. PMID- 28885337 TI - B-cell lymphocyte kinase polymorphisms rs13277113, rs2736340, and rs4840568 and risk of autoimmune diseases: A meta-analysis. AB - BACKGROUND: B-cell lymphocyte kinase (BLK) is an inhibitor of B cells that has an important influence on several autoimmune diseases, but there is a lack of comprehensive analysis of its association with autoimmune diseases. Hence, it is meaningful to conduct a comprehensive analysis. METHODS: A systematic literature search was performed on the PubMed, ScienceDirect, and Web of Science databases up to June 30, 2016. The data were extracted and quality-assessed before conducting the meta-analysis. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were assessed with the STATA version 12.0 software. Subgroup and sensitivity analysis were conducted to explore potential sources of heterogeneity. RESULTS: Altogether, 33 studies with 68,874 cases and 90,684 controls, 24 studies with 31,095 cases and 39,077 controls for rs13277113, 21 studies with 26,388 cases and 40,635 controls for rs2736340, and 4 studies with 11,391 cases and 10,972 controls for rs4840568 were included in this meta analysis. The results revealed that the BLK rs13277113 and rs2736340 polymorphisms increased the risk of autoimmune diseases in the total analysis (A vs G: OR = 1.33, 95% CI = 1.27-1.39, P < .01; T vs C: OR = 1.34, 95% CI = 1.27 1.41, P < .01), and rs4840568 was positively associated with systemic lupus erythematosus (SLE) (A vs G: OR = 1.32, 95% CI = 1.22-1.43, P = .01). CONCLUSION: This meta-analysis shows that the BLK (rs13277113, rs2736340, rs4840568) polymorphisms may be a risk factor for developing autoimmune diseases, especially for Asian populations and SLE. PMID- 28885338 TI - Association between MDM2 SNP309, p53 Arg72Pro, and hepatocellular carcinoma risk: A MOOSE-compliant meta-analysis. AB - Epidemiological studies have determined the associations between polymorphisms on the promoter of MDM2 (SNP309) and the codon 72 on exon 4 of p53 (p53 Arg72Pro) and the risk of hepatocellular carcinoma (HCC); however, the results were not always consistent. The aim of the present meta-analysis was to evaluate the overall associations between these 2 variants and HCC risk.The MEDLINE, Web of science, EMBASE, Cochrane Library, and CNKI databases were searched for eligibility studies and the data were synthesized under the fixed- or random effects model. Heterogeneity among the studies was evaluated with the Cochrane test Q and I statistic.For MDM2 SNP309, the pooled odds ratio (OR) from 15 independent studies with a total of 4038 cases and 5491 controls suggested a significant association for the variant with HCC risk [allele model, G vs T: pooled OR = 1.48, 95% confidence interval (95% CI) = 1.26-1.73; pooled OR = 1.53, 95% CI = 1.26-1.81, for G/T vs T/T; pooled OR = 2.04, 95% CI = 1.54-2.71 for G/G vs T/T]. For p53 Arg72Pro, a total of 21 studies with 7285 cases and 9710 controls suggested that the variant was also associated with HCC risk under common genetic model (allele Pro vs Arg, pooled OR = 1.13, 95% CI = 1.02-1.25; Pro/Pro vs Arg/Arg, pooled OR = 1.32, 95% CI =1.06-1.64). No publication bias was found for all the meta-analysis as suggested by the Begg funnel plot and Egger tests.These results suggested that variants MDM2 SNP309 and p53 Arg72Pro are susceptibility factors for HCC; however, more studies are warranted to validate the results. PMID- 28885339 TI - Role of chemotherapy and thrombolysis in treatment of choriocarcinoma accompanied with pulmonary embolism: A case report with literature review. AB - RATIONALE: Choriocarcinoma accompanied with pulmonary embolism (PE) is rare and difficult to diagnose and treat. There are about 25 cases reported in literature, which presented variable clinical characteristics and prognosis. PATIENT CONCERNS: We reported a case of choriocarcinoma presenting PE as the first manifestation in a 26-year-old Chinese female. DIAGNOSES: Four months before her admission to our hospital, she presented to a local hospital with respiratory manifestations, and was first diagnosed as bronchitis and treated with antibiotics without improvement, and subsequently suspected of having pulmonary tuberculosis and receive anti-tuberculosis therapy, with no response. Upon admission to our hospital, spiral computed tomography-pulmonary angiography revealed complete occlusion of right pulmonary artery, leading to PE. She received thrombolysis and anticoagulant therapy, without improvement. Further interrogation of the patient revealed a history of irregular vaginal bleeding and multiple pregnancies and abortions. Following the laboratory report of a significantly elevated level of serum beta-human chorionic gonadotropin (beta HCG) combined with other clinical and laboratory findings, a diagnosis of choriocarcinoma accompanied with PE was established based on the criteria formulated by the International Federation of Gynecology and Obstetrics and guideline of European Society for Medical Oncology. INTERVENTIONS: With 1 cycle of chemotherapy with etoposide-methotrexateactinomycin D-cyclophosphamide vincristine (EMA-CO), her dyspnea and other symptoms improved, with a significant decrease in the serum beta-HCG level and pulmonary artery pressure. OUTCOMES: Unfortunately, she showed bone marrow inhibition, could not continue further chemotherapy, and finally died after discharging. We reviewed 25 similar cases in the literature, and found that all 17 cases receiving chemotherapy showed complete recovery while 6 of 8 cases without chemotherapy died during hospitalization. LESSONS: This case report illustrates the challenges in diagnosis of choriocarcinoma presenting with respiratory manifestations, and highlights the importance of early diagnosis and timely appropriate chemotherapy in management of this disease. PMID- 28885340 TI - A case report of lung adenocarcinoma with polyserous effusions as the onset symptom. AB - RATIONALE: Coexistence of lung adenocarcinoma and polyserous effusions is quite rare. This complexity of etiology adds difficulty to the diagnosis and is likely to cause misdiagnosis and maldiagnosis. PATIENT CONCERNS: A 43-year-old woman was admitted with symptoms of dry cough, chest suffocation, polyserous effusions, and generalized edema. Only a small number of heterocysts were detected in the ascites, and malignant cells were detected in the pleural and pericardial effusions. After cytology tests of pericardial, pleural effusions, and ascites, puncture biopsy of the left lung lesion was performed with CT guidance, and immunohistochemical tests were performed. DIAGNOSES: The diagnosis of lung adenocarcinoma was histopathologically confirmed by puncture biopsy with CT guidance of the left lower lung lesion. INTERVENTIONS: Combined treatments(pemetrexed/cisplatin) was administered after the left lung lesion immunohistochemistry. OUTCOMES: The patient has survived more than 1 year after pemetrexed/cisplatin combination chemotherapy. LESSONS: Coexistence of lung adenocarcinoma and polyserous effusions is quite rare. Close attention should be paid whenever a patient with coexistence of ascites, pleural effusion, and pericardial effusion. More diverse methods could be helpful to identify the diagnosis and avoid misdiagnosis. Patients with advanced lung adenocarcinoma need individualized therapy, including pemetrexed/cisplatin combination chemotherapy. PMID- 28885341 TI - Differences in platelet-related parameters among patients with audiographically distinct sudden sensorineural hearing loss: A retrospective study. AB - We explored possible relationships between sudden sensorineural hearing loss (SSNHL) in patients differing in terms of audiographic data and the levels of vascular markers in routine blood data.We included 37 patients with low-frequency SSNHL (LF-SSNHL), 28 with high-frequency SSNHL (HF-SSNHL), 32 with all-frequency SSNHL (AF-SSNHL), 32 with total-deafness SSNHL (TD-SSNHL), and 31 age- and sex matched healthy controls. Peripheral venous blood samples were collected, and routine blood parameters including platelet and lymphocyte count, mean platelet volume (MPV), and platelet-to-lymphocyte ratio (PLR) were measured. Each group was divided into recovery subgroup and unrecovery subgroup in accordance with hearing level after 1 month therapy, then compared the difference of platelet and lymphocyte count, MPV, and PLR between the 2 subgroups.No significant difference was observed between platelet count of all SSNHL patients and control group (all P > .05). MPV of AF-SSNHL and TD-SSNHL, PLR of all SSNHL patients were significantly higher than those of control group (all P < .05), while lymphocyte count of all audiographically distinct SSNHL patients was significantly lower than that of control group (all P < .05). However, the difference of platelet count, lymphocyte count, MPV, and PLR among audiographically distinct SSNHL patients was not significant (all P > .05). In HF-SSNHL patients, lymphocyte count of unrecovery subgroup was significantly lower, while MPV and PLR of the unrecovery subgroup were significantly higher than those of recovery subgroup (all P < .05). In AF-SSNHL patients, MPV of the unrecovery group was significantly higher than that of recovery subgroup (P < .05).Lymphocyte count, MPV, and PLR may be relative to SSSNHL, but they could not be used to distinct SSNHL audiographically. Lower lymphocyte, higher MPV, and PLR may be indicative for the prognosis of HF-SSNHL patients; higher MPV may be related to bad treatment outcome of AF-SSNHL patients. PMID- 28885342 TI - Clinical features of idiopathic restrictive cardiomyopathy: A retrospective multicenter cohort study over 2 decades. AB - Idiopathic restrictive cardiomyopathy (RCMP) has not been fully understood because this disease is difficult to diagnose. The present study aimed to assess the clinical profile and outcome of idiopathic RCMP from a multicenter cohort.This investigation is a retrospective study of consecutive patients with idiopathic RCMP at 10 centers in Korea between 1990 and 2010. We evaluated the clinical characteristics of the patients and prognostic factors associated with mortality using multivariate Cox proportional hazards regression analyses.The study included 53 patients (26 men, 49.1%). During a median follow-up of 1.7 years, 17 patients (32.1%) died and 5 patients (9.4%) received a heart transplant. The 5-year survival rate of the overall patients was 64.4% +/- 7.8%. In multivariable analyses, the predictors of mortality were tricuspid regurgitation (TR) >= moderate (hazard ratio [HR] 32.55, P < .001) and left ventricular end-diastolic diameter (LVEDD) (HR 0.85, P < .001).Idiopathic RCMP showed unfavorable prognosis. Advanced TR and lower LVEDD are independent adverse predictors of mortality in patients with idiopathic RCMP. PMID- 28885343 TI - Risk factors and the surgery affection of respiratory complication and its mortality after acute traumatic cervical spinal cord injury. AB - The aim of this study is to estimate the risk factors of both respiratory complication (RC) and mortality after acute traumatic cervical spinal cord injury (TCSCI). Between July 2005 and July 2015, in 181 patients (142 males and 39 females; mean age 41.0 years) with acute TCSCI, we compared the difference and odds ratio in RC group (n = 73) with that of non-RC group (n = 108), and also death group (n = 15) and survival group (n = 166). We collected injury-related information after half a year of injury, which is as follows: the causes of injury, time of surgery, ICU (intensive care unit) days, ventilator days, ASIA (American Spinal Injury Association) classification, neurological injury, CIPS (Clinical Pulmonary Infection Score), and BMI (body mass index). Besides these, we gathered the general information such as age, gender, smoking history, and use of steroids. The study compared perioperative parameters; surgery-related and instrumentation- and graft-related complication rates; clinical parameters; patient satisfaction; and radiologic parameters. Variations like gender (odds ratio [OR] = 1.269, 95% confidence interval [CI] [0.609-2.646]), smoking history (OR = 2.902, 95% CI [1.564-5.385]), AIS grade (grade A) (OR = 6.439, 95% CI [3.334-12.434]), neurological level (C1-C4) (OR = 2.714, 95% CI [1.458-5.066]), and steroid use (OR = 2.983, 95% CI [1.276-6.969]) have a facilitated effect on RC. When we estimated surgery-related affection, only the time of surgery and anterior approach compared with posterior has significant difference in RC (P < .05). Between death and survival group, the aspect of age, non-surgical, CPIS, AIS grade, and BMI have statistically significant difference. Survival analysis reveals significant difference in aforementioned groups. In patients suffering from acute TCSCI, those who are old, have long smoking history, complete spinal cord injury, C1-C4, high CPIS, and fat have high incidence of RC and mortality. PMID- 28885344 TI - Surgical treatment for lumbar hyperlordosis after resection of a spinal lipoma associated with spina bifida: A case report. AB - RATIONALE: A hyperlordosis deformity of the lumbar spine is relatively rare, and surgical treatment has not been comprehensively addressed. In this case report, we describe the clinical presentation, surgical treatment, and medium-term follow up of a patient presenting with a progressive lumbar hyperlordosis deformity after resection of a spinal lipoma associated with spina bifida. PATIENT CONCERNS: The patient was a 20-year-old woman presenting with a progressive hyperlordosis deformity of the lumbar spine associated with significant back pain (visual analog pain score of 89/100 mm), but with no neurological symptoms. DIAGNOSES: The lumbar lordosis (LL), measured on standing lateral view radiographs, was 114 degrees , with a sagittal vertical axis (SVA) of -100 mm. The patient had undergone excision of a lipoma, associated with spina bifida of the lumbar spine, at 7 months of age.She was first evaluated at our hospital at 18 years of age for progressive spinal deformity and lumbago. INTERVENTIONS: An in situ fusion, from T5 to S1, using pedicle screws with bone graft obtained from the iliac crest, was performed. OUTCOMES: Postoperatively, the LL decreased to 93 degrees , and the SVA decreased to -50 mm. The decision to not correct the hyperlordosis deformity fully was intentional. Seven years and 1 month postsurgery, the patient had no limitations in standing and walking and reported a pain score of 8/100 mm; there was no evidence of a loss of correction. LESSONS: Lumbar hyperlordosis after resection of a spinal lipoma associated with spina bifida is rare. Posterior fixation provided an effective treatment in this case. As the lumbar hyperlordosis deformity is often high, correction can be difficult. In this case, although the correction and fusion were performed in situ, there was no progression of either the deformity or the lumbago. Early detection remains an essential component of effective treatment, allowing correction when the spinal deformity is easily reversible. PMID- 28885345 TI - Long-term effectiveness of the Diabetes Conversation Map Program: A prepost education intervention study among type 2 diabetic patients in Taiwan. AB - Health education is compulsory for patients with chronic and life-threatening disease, especially for those with diabetes mellitus (DM). This study aimed to examine the long-term effectiveness of the Diabetes Conversation Map Program (DCMP) among DM patients in Taiwan.A quasi-experimental research design using convenience sampling and nonrandom group assignment was applied to recruit 95 type 2 diabetic subjects from a hospital in Taiwan. In addition to routine care, the experiment group (n = 49) received 7 sessions of DCMP that delivered over 2 months, while the control group (n = 46) received only routine care during the same period. We conducted structured questionnaire survey and reviewed medical record at 3 time points (before DCMP, 3 days after DCMP, and 3 months after DCMP completion) to collect the effectiveness data. The effectiveness was determined using the generalized estimating equation model.We found that improvements in the body mass index, blood glucose, glycated hemoglobin, self-monitoring of blood glucose, and diabetic health literacy in the DCMP group compared with controls (all P values <.05), with no significant changes in depressive symptoms. The positive effects were further maintained for 3 months after DCMP.The findings may serve as a reference for helping healthcare professionals provide appropriate interventions to improve adaptation processes and clinical outcomes for DM patients. PMID- 28885346 TI - A case-control study of the association between self-reported occupational and recreational physical activity and lung cancer. AB - This case-control study with a Fujian population investigated whether self reported occupational and recreational physical activity may be associated with lung cancer.The population comprised 1622 patients with newly diagnosed primary lung cancer and 1622 age- and gender-matched healthy controls.High-intensity occupational physical activity was associated with significantly higher risk of lung cancer (OR = 1.354, 95% CI: 1.068-1.717), especially nonsmall cell lung carcinoma (OR = 1.384, 95% CI: 1.087-1.762). Moderate or low intensity recreational physical activity was associated with reduced risk of lung cancer. The protective effect of recreational physical activity was observed in current or former smokers, but not never-smokers, and in subjects with normal or high BMI, but not low BMI, as well as people without a history of chronic lung disease. The frequency of recreational physical activity was associated with a linear reduction in the risk of lung cancer (P < .001), and also specifically nonsmall cell lung cancer (P < .001).Occupational and recreational physical activity was associated with different effects on the risk of lung cancer in a Fujian population. While recreational physical activity was associated with decreased risk of lung cancer, occupational physical activity was associated with increased risk of lung cancer. PMID- 28885347 TI - Metastases to the thyroid gland: A report of 32 cases in PUMCH. AB - RATIONALE: Metastases of nonthyroid malignancies to the thyroid gland are rare, and only sporadic cases have been reported in literature. We present our experience in treating patients with metastases to the thyroid gland at Peking Union Medical College Hospital. PATIENT CONCERNS: The clinical data of 32 patients who presented with secondary thyroid tumors were retrospectively analyzed. INTERVENTIONS: Eleven patients (34.5%) had thyroidectomy.Two patients (6.25%) had tracheostomies to alleviate compression caused by enlarged thyroid tumors. OUTCOMES: The most common primary lesion was in the lungs (14/32), followed by the kidney (5/32) and gastrointestinal system (5/32). The interval from the diagnosis of the primary tumor to thyroid metastasis varied from 0 month to 16 years. Ten patients (31.3%) are still alive, and the longest follow-up survival time was 7 years. LESSONS: Thyroid metastases are rare, and the lung was the most common primary site of origin. It seems that thyroidectomy has not been considered in cases with a high clinical stage of the neoplastic process such as lung cancer. PMID- 28885348 TI - Effect of transcutaneous electrical nerve stimulation therapy for the treatment of primary dysmenorrheal. AB - BACKGROUND: This study aimed to investigate the effect and safety of transcutaneous electrical nerve stimulation (TENS) therapy for relieving pain in women with primary dysmenorrhea (PD). METHODS: In this study, 134 participants with PD were randomly divided into the intervention group and the sham group, with 67 participants in each group. Participants in the intervention group received TENS, whereas those in the sham group received sham TENS. The primary outcome was measured by the Numeric Rating Scale (NRS). The secondary outcomes were measured by the duration of relief from dysmenorrheal pain, number of ibuprofen tablets taken, and the World Health Organization quality of life (WHOQOL)-BREF score, as well as the adverse events. RESULTS: A total of 122 participants completed the study. Compared to sham TENS, TENS showed a greater effect in pain relief with regard to the NRS (P < .01), duration of relief from dysmenorrheal pain (P < .01), and number of ibuprofen tablets taken (P < .01). However, no significant differences in the quality of life, measured by the WHOQOL-BREF score, were found between 2 groups. The adverse event profiles were also similar between 2 groups. CONCLUSION: TENS was efficacious and safe in relieving pain in participants with PD. PMID- 28885349 TI - Endoscopic submucosal dissection for large colorectal epithelial neoplasms: A single center experience in north China. AB - Colorectal endoscopic submucosal dissection (ESD) is a technically difficult procedure with a higher risk of complications, especially for large colorectal epithelial neoplasms. This study aimed to report our experience and clinical outcomes, and to estimate the factors associated with incomplete resection and complications.One hundred forty one colorectal epithelial neoplasms in 130 consecutive patients treated by ESD at the endoscopy center of Tianjin Medical University General Hospital from January 2013 to January 2016 were included. Factors associated with the incomplete resection and perforation were evaluated.The mean colorectal epithelial neoplasm size was 26.5 +/- 9.5 (15.0 60.0) mm, the mean procedure time of colorectal ESD was 76.1 +/- 48.7 (36.5 195.0) minutes. The en bloc resection rate, the en bloc R0 resection rate, and the curative resection rate, were 93.6% (132/141), 91.5% (129/141), and 88.7% (125/141), respectively. Perforation during colorectal ESD occurred in 7 patients (4.9%), postoperative bleeding occurred in 4 patients (2.8%). There was no recurrence occurred in all patients during follow periods of 13.2 +/- 8.6 (6.0 36.0) month. Submucosal fibrosis was the only independent factor related to both incomplete resection (odds ratio [OR] 12.425; 95% confidence interval [CI] 2.501 61.734; P = .002) and perforation (OR 10.646; 95%CI 1.188-95.421; P = .035) of colorectal ESD.Colorectal ESD is a safe and effective technique for en bloc resection of large colorectal epithelial neoplasms. Submucosal fibrosis was independently related to incomplete resection and perforation. PMID- 28885350 TI - Usefulness of three-dimensional spherical index to assess different types of left ventricular remodeling: A meta-analysis. AB - BACKGROUND: Left ventricular (LV) remodeling after myocardial injury, volume or pressure overload is characterized by a change in LV shape from an ellipse to more of a sphere. The usefulness of 3-dimensional (3D) sphericity index (SpI) for accurate evaluation of LV remodeling remains uncertain despite extensive research. METHODS: We searched Pubmed, Embase, Web of Science, and Cochrane databases to identify relevant studies from January 1, 1990 to August 1, 2016. The quality of each study was evaluated using the Newcastle-Ottawa Scale. Meta regression and sensitivity and subgroup analyses based on patterns of LV remodeling were performed. RESULTS: Thirteen studies with a total of 1064 patients were included in this meta-analysis. There was evidence of obvious heterogeneity (I = 82.4%; P < .001), which was mainly accounted for by the pattern of remodeling according to meta-regression. The result of subgroup meta analyses suggested that SpI in patients with eccentric remodeling was significantly higher compared with control group (95% confidence interval [CI], 0.78-1.10). No statistic difference was found in LV SpI between healthy controls and patients with concentric hypertrophy (95% CI, -0.89 to 0.16) or myocardial injury (95% CI, -0.13 to 0.41). CONCLUSION: 3D SpI can be widely used to assess LV remodeling in patients with eccentric remodeling, but has limitations in predicting concentric hypertrophy and regional or chronic myocardial injury. PMID- 28885351 TI - A Mal De Meleda patient with severe flexion contractures of hands and feet: A case report in West China. AB - RATIONALE: Palmoplantar keratoderma (PPK) is a genetically heterogeneous group of skin diseases, which is characterized by erythema and hyperkeratosis. Mal de Meleda (MDM) is a rare type of PPK with an estimated prevalence in the general population of 1 in 100,000. PATIENT CONCERNS: In this study, we report a MDM patient with severe lesion in skin and flexion contractures of fingers and toes. DIAGNOSES: MDM was diagnosed based on clinical manifestations and gene test. INTERVENTIONS: This patient was treated with oral acitretin and topical tazarotene. OUTCOMES: Physical examinations indicated that the hyperkeratosis was in remission, but the erythema was expanding to her elbows progressively. Due to the adverse events (e.g., dry eyes and lips), the patient stopped taking the oral drug. LESSONS: MDM is a rare subtype of PPK, which is inherited in an autosomal recessive pattern and has characteristics that skin lesions on hands and feet appear soon after birth and develop progressively. MDM can lead to severe flexion contractures in some cases. The reliable method for the diagnosis of MDM is gene test. PMID- 28885352 TI - Successful 5-azacytidine treatment of myeloid sarcoma and leukemia cutis associated with myelodysplastic syndrome: A case report and literature review. AB - RATIONALE: Myeloid sarcoma (MS) and leukemia cutis (LC) are extramedullary tumors comprising myeloid blasts. They can occur de novo or concurrently with hematological disorders, usually acute myeloid leukemia (AML). AML chemotherapy is generally the initial therapy for MS and LC, and hematopoietic stem cell transplantation (HSCT) can be considered as additional therapy. However, treatment for older patients who are unable to continue intensive chemotherapy is not currently standardized. PATIENT CONCERNS: A 71-year-old Japanese woman was diagnosed with multiple MSs associated with myelodysplastic syndrome (MDS), using bone marrow aspiration and lymph node biopsy. DIAGNOSES: Additionally, LC was diagnosed by skin biopsy. Extramedullary MS and LC lesions were formed by massive infiltration of myeloblastic cells. INTERVENTIONS: Twenty courses of 5 azacytidine (5-Aza) were administrated as maintenance therapy after induction therapy with daunorubicin and cytarabine. OUTCOMES: Myeloblasts decreased in the bone marrow and the LC disappeared after induction therapy. The MSs completely disappeared, except for the palatine tonsil lesion, after 5-Aza maintenance therapy. 5-Aza treatment provided long-term partial response for more than 21 months. LESSONS: 5-Aza was well tolerated and may be a good option for the treatment of MS and LC associated with MDS, especially in older patients who cannot receive HSCT. PMID- 28885354 TI - Acute versus subacute community-acquired meningitis: Analysis of 611 patients. AB - Community-acquired meningitis can be classified into acute and subacute presentations by the duration of illness of <= or >5 days, respectively. There are currently no studies comparing the clinical features, management decisions, etiologies, and outcomes between acute and subacute presentations.It is a retrospective study of adults with community-acquired meningitis hospitalized in Houston, TX between January 2005 and January 2010. An adverse clinical outcome was defined as a Glasgow Outcome Scale score of <=4.A total of 611 patients were identified, of which 458 (75%) were acute and 153 subacute (25%). The most common etiologies were unknown in 418 (68.4%), viral in 94 (15.4%), bacterial in 47 (7.7%), fungal in 42 patients (6.9%), and other noninfectious etiologies in 6 (1%). Patients with subacute meningitis were more likely to be immunosuppressed or have comorbidities, had fungal etiologies, and had higher rates of hypoglycorrachia and abnormal neurological findings (P <.05). Patients with an acute presentation were more likely to be treated empirically with intravenous antibiotics and had higher cerebrospinal fluid pleocytosis and serum white blood cell counts (P <.05). On logistic regression, age >65 years and abnormal neurological findings were predictive of an adverse clinical outcome in both acute and subacute meningitis, whereas fever was also a significant prognostic factor in acute meningitis. (P <.05).Acute and subacute meningitis differ in regards to clinical presentations, etiologies, laboratory findings, and management decisions, but did not differ in rates of adverse clinical outcomes. Future studies including thoroughly investigated patients with new diagnostic molecular methods may show different results and outcomes. PMID- 28885353 TI - Association of congenital anomalies with fracture of spine, trunk, and upper and lower limbs among young people: A population-based matched cohort study in Taiwan. AB - According to the Traditional Chinese Medicine (TCM) theory, congenital anomalies are caused by kidney malfunctions, which decreased the bone quality, and may eventually result in bone fractures. This retrospective cohort study investigated the relationship between congenital anomalies and fracture of spine, trunk, and upper and lower limbs in young people. We utilized data from the National Health Insurance Research Database of Taiwan. This study included patients with congenital anomalies (International Classification of Diseases/ICD-9 code: 740 759) and a comparison group of patients without congenital anomalies. Cases evaluated were fracture of spine and trunk (ICD-9 codes: 805-809), fracture of upper limbs (ICD-9 codes: 810-819), and fracture of lower limbs (ICD-9 codes: 820 829). Our study shows that in comparison to the control group, patients with congenital anomalies are 1.11 times more likely to develop fractures. This is the first documented research study that supports the TCM theory that "the Kidney governs the bones, and healthy bones give the body stabilization and prevent fracture." PMID- 28885355 TI - Secondary hypertrophic osteoarthropathy caused by non-pleural or pulmonary tumors. AB - Hypertrophic osteoarthropathy (HOA) is a rare paraneoplastic syndrome characterized by digital clubbing, periosteal reaction, polyarthralgia, arthritis, and synovitis. Herein, we report a case series of patients with secondary HOA caused by non-pleural or pulmonary tumors.The radiologic databases of 2 tertiary university hospitals were retrospectively screened for secondary HOA patients. In addition, a systemic review of the published case reports. Only HOA cases with non-pleural or pulmonary malignancies were involved into the study. HOA in primary pleural or pulmonary malignant or benign disorders, as well in inflammatory diseases were excluded. In all cases, plain radiography was performed and clinical signs were documented.In our databases, 6 patients with secondary HOA were identified. In addition, the systemic review yielded 24 eligible patients. The most prevalent primary tumors were nasopharyngeal carcinoma and esophageal cancer in 6 patients (20%), respectively. In 17 patients, (56.7%) HOA was associated with lung metastases, and in 10 patients (33.3%), no lung metastases were detected. In 14 patients (46.7%), HOA was symptomatically before a tumor diagnosis was made. Plain radiography displayed typically features with periostal enlargement in every case.This study is the first report about secondary HOA caused by non-pleural or pulmonary tumors. Various primary tumors were identified, including several rare tumors such as sarcomas. HOA is a rare disorder with typically radiologically findings, which is not only associated with lung cancer or pleural mesothelioma and can even occur in tumor patients without lung metastasis. PMID- 28885356 TI - Correlations between lumbar neuromuscular function and pain, lumbar disability in patients with nonspecific low back pain: A cross-sectional study. AB - This study aims to examine the correlations between lumbar neuromuscular function and pain, lumbar disability in patients with nonspecific low back pain (NSLBP).Ninety patients, with ages 18 to 37 years old, with NSLBP were recruited in this study. The lumbar neuromuscular function was tested by the CON-TREX multijoint isokinetic test and training machine. This study uses the visual analog scale (VAS) and Roland-Morris Disability Questionnaire (RMDQ) to evaluate the pain and the dysfunction index of patients who have low back pain, respectively.Pearson correlation coefficient is used to evaluate the correlation between lumbar neuromuscular function and the VAS and RMDQ scores. VAS and RMDQ scores have correlations with the proprioception in the flexion of the lumbar vertebra flexion; the peak torque of both flexion and extension muscle groups; and average power and endurance at different angular velocities. The decrease of lumbar muscle strength, endurance, and lumbar proprioception of the lumbar vertebra leads to an increase in pain intensity and lumbar disability.This study suggests that patients with chronic low back pain require targeted training in muscle strength, endurance, and lumbar proprioception, providing a theoretical basis for prevention and treatment of chronic NSLBP patients. PMID- 28885357 TI - Comparative effectiveness of azithromycin for treating scrub typhus: A PRISMA compliant systematic review and meta-analysis. AB - BACKGROUND: Scrub typhus is a zoonotic disease that remains an important health threat in endemic areas. Appropriate anti-rickettsial treatment ensures a successful recovery. Doxycycline is a recommended drug, but it is contraindicated in pregnant women and young children. Azithromycin is a safer alternative drug, but its effectiveness remains largely unclear. Herein, we conducted a systematic review and meta-analysis to determine the effectiveness of azithromycin. METHODS: Studies that investigated azithromycin in treating scrub typhus were systematically identified from electronic databases up to December 2016. Information regarding study population, disease severity, treatment protocols, and responses was extracted and analyzed. RESULTS: In this review, 5 studies were included, which comprised a total of 427 patients. When comparing the treatment failure rate, we observed a favorable outcome in patients treated with azithromycin (risk ratio [RR] 0.83, 95% confidence interval [CI] 0.23-2.98). However, patients in the azithromycin group had longer time to defervescence (mean difference 4.38 hours, 95% CI -2.51 to 11.27) and higher rate of fever for more than 48 hours (RR 1.31, 95% CI 0.81-2.12). Moreover, patients treated with azithromycin had less adverse effects (RR 0.8, 95% CI 0.42-1.52). CONCLUSIONS: Azithromycin is as effective as other anti-rickettsial drugs with higher treatment success rates, lower frequency of adverse effects, and longer time to defervescence (GRADE 2B). Therefore, it is reasonable to use azithromycin as the first-line treatment against scrub typhus. Further studies are warranted to elucidate the effectiveness of azithromycin in specific patient groups, at high dose and influence of drug resistance. PMID- 28885359 TI - Sustained dysfunctional information processing in patients with Internet gaming disorder: 6-month follow-up ERP study. AB - Internet gaming disorder (IGD), defined as an inability to control Internet-based game play, leads to serious impairment in psychological and social functioning, but few studies have identified the neurophysiological characteristics of patients with IGD. The aim of this study was to determine neurophysiological markers of P300 components associated with changes in symptoms after outpatient management with pharmacotherapy in patients with IGD. The present prospective longitudinal study included 18 patients with IGD and 29 healthy controls. The patients with IGD completed a 6-month outpatient management program including selective serotonin reuptake inhibitor-based pharmacotherapy. Event-related potentials (ERPs) were acquired during the auditory oddball task. ERPs of the patients with IGD were recorded before and after treatment. Between-group differences and the pre-to-post treatment differences in P300 components were investigated using repeated-measures analysis of variance. The primary treatment outcome was a change in score on Young Internet Addiction Test between before and after treatment. At baseline assessments, the IGD group showed significantly reduced P300 amplitudes and delayed latencies at the midline centro-parietal site compared with those in the healthy controls. No significant changes in the P300 indices were observed between pre and post-treatment in the patients with IGD after 6 months of treatment, even though the patients with IGD exhibited significant improvements in their IGD symptoms. Furthermore, no significant difference in ERPs was observed between responders and nonresponders to a 6-month treatment in patients with IGD. These results suggest that reduced P300 amplitudes and delayed latencies are candidate endophenotypes in the pathophysiology of IGD. PMID- 28885358 TI - Comorbidity of post-traumatic stress disorder and anxiety in flood survivors: Prevalence and shared risk factors. AB - Post-traumatic stress disorder (PTSD) and anxiety are both prevalent in trauma related populations. However, comorbidity of these 2 psychiatric disorders has not been investigated in flood survivors. This study aimed to estimate the extent to which PTSD and anxiety co-occur in flood survivors, and identify shared risk factors for PTSD only and comorbidity of PTSD and anxiety.Individuals who experienced Dongting Lake flood in 1998 were enrolled in this study using stratified and systematic random sampling method. Information on social support, personality traits, PTSD, and anxiety was collected using self-report questionnaires. The intensity of exposure to the flood was measured by some questions. Logistic regression analyses were used to identify factors associated with PTSD only and comorbidity of PTSD and anxiety.In all, 325 participants were enrolled in this study. The prevalence of PTSD, anxiety, and comorbidity of PTSD and anxiety among survivors of the 1998 Dongting Lake flood at 17-year follow-up was 9.54%, 9.23%, and 6.15%, respectively. Furthermore, 64.52% of those with PTSD had anxiety and 66.67% of those with anxiety had PTSD. Loss of relative, injury of body, damage of house, and emotional instability were shared risk factors for PTSD only and comorbidity of PTSD and anxiety, in comparison with neither PTSD nor anxiety.Post-traumatic stress disorder only and comorbidity of PTSD and anxiety are prevalent in flood survivors, and are both related to the intensity of exposure to the flood and personality traits, indicating that integrated intervention strategies of PTSD and anxiety for flood survivors are needed. PMID- 28885360 TI - The prognostic value and potential drug target of phosphatase and tensin homolog in breast cancer patients: A meta-analysis. AB - BACKGROUND: The prognostic significance of phosphatase and tensin homolog (PTEN) in patients with breast cancer (BC) remains controversial. The aims of our meta analysis are to evaluate its association with clinicopathological characteristics and prognostic value in patients with breast cancer. METHODS: PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure (CNKI) were systematically searched up to December 2016. The meta-analysis was performed using hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (CI) as effect measures. A fixed or random effect model was used depending on the heterogeneity analysis. Statistical analysis was performed using Review manager software version 5.3. RESULTS: Seventeen studies including 4343 patients with breast cancer were analyzed. The meta-analysis indicated that breast cancers with PTEN loss were significantly associated with the tumor size >=2 cm group (ORFEM = 1.68, 95%CIFEM [1.34, 2.10]), negative expression of estrogen receptor (ORREM = 1.95, 95%CIREM [1.09, 3.49]), negative expression of progesterone receptor (ORFEM = 1.72, 95%CIFEM [1.43, 2.08]), the advanced stage (ORREM = 1.94, 95%CIREM [1.35, 2.80]), positive axillary lymph node metastasis (ORREM = 1.80, 95%CIREM [1.30, 2.50]), and the local recurrence (ORFEM = 1.70, 95%CIFEM [1.26, 2.28]). None of other clinicopathological parameters such as the HER2 status and distant metastasis were associated with PTEN loss. The decreased PTEN expression was significantly correlated with the overall survival (OS) of patients (HRREM = 1.83, 95%CIREM [1.32, 2.53]) and the disease-free survival (DFS) of patients (HRREM = 2.43, 95%CIREM [1.31, 4.53]). CONCLUSION: Our meta-analysis demonstrates that PTEN loss is of particular importance for predicting breast cancer aggressiveness and poor prognosis. PTEN is a potential drug target for the development of individualized treatment in BC patients. PMID- 28885361 TI - Angioimmunoblastic T-cell lymphoma and hypereosinophilic syndrome with FIP1L1/PDGFRA fusion gene effectively treated with imatinib: A case report. AB - RATIONALE: Hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and organ damage. Some cases of HES are caused by the FIP1L1/PDGFRA fusion gene and respond to imatinib. FIP1L1/PDGFRA-positive HES occasionally evolves into chronic eosinophilic leukemia or into another form of myeloproliferative neoplasm; however, the development of a malignant lymphoma is very rare. We present a rare case of angioimmunoblastic T-cell lymphoma (AITL) and HES with the FIP1L1/PDGFRA gene rearrangement. PATIENT CONCERNS: A man in his 30s presented to our hospital with fever, hypereosinophilia, widespread lymphadenopathy, and splenomegaly. Laboratory tests showed hypereosinophilia, increased soluble interleukin-2 receptor, and increased vitamin B12. Positron emission tomography with F fluorodeoxyglucose (FDG) showed positive FDG uptake in multiple enlarged lymph nodes throughout the body and the red bone marrow. A bone marrow biopsy showed hypereosinophilia without dysplasia and an increased number of blasts. The FIP1L1/PDGFRA fusion gene was positive upon fluorescence in situ hybridization (FISH) analysis of the peripheral blood. Furthermore, biopsy of a lymph node from the neck revealed restiform hyperplasia of capillary vessels, with small lymphoma cells arranged around the capillaries. Lymphoma cells were positive for CD3, CD4, and CD10, and negative for CD20. Lymphoma cells were also positive for the FIP1L1/PDGFRA fusion gene by FISH analysis. DIAGNOSES: From these findings, the patient was diagnosed with HES and AITL with FIP1L1/PDGFRA. INTERVENTIONS: After the diagnosis, corticosteroid was administered but was ineffective. Imatinib was then administered. OUTCOMES: Imatinib was very effective for treating HES and AITL, and complete remission was achieved in both. LESSONS: This report presents the first case in which the FIP1L1/PDGFRA fusion gene was positive both in peripheral blood and lymph nodes, implying the possibility that the tumor cells acquired the FIP1L1/PDGFRA fusion gene in the early stage of hematopoietic progenitor cell developments. Imatinib was very effective in treating both HES and lymphoma, suggesting that the FIP1L1/PDGFRA fusion gene plays a key role in the pathogenesis of both HES and lymphoma. PMID- 28885362 TI - The protective efficacy and safety of bandage contact lenses in children aged 5 to 11 after frontalis muscle flap suspension for congenital blepharoptosis: A single-center randomized controlled trial. AB - BACKGROUND: Postoperative complications, lagophthalmos and exposure keratopathy sometimes occur after surgery for congenital blepharoptosis. Bandage contact lenses (BCL) can help prevent some ocular surface disorders. The study aims to evaluate the efficacy and safety of BCL for protection of the ocular surface in children aged 5 to 11 years after frontalis muscle flap suspension for congenital blepharoptosis. METHODS: We conducted a prospective randomized clinical study of 30 eyes of 30 patients with congenital blepharoptosis consecutively enrolled at the Ophthalmology Ward of the Children's Hospital of Chongqing Medical University, China from September 1, 2016, to February 30, 2017. After frontalis muscle flap suspension surgery, patients were randomly assigned to undergo BCL application (BCL group, 15 eyes) or no BCL application (control group, 15 eyes). All patients were treated with bramycin 0.3% and polyvinyl alcohol drops after surgery. The primary outcomes were dry eye assessed by tear film break time (TFBUT), fluoresce in corneal staining (FCS) on slit-lamp on days 1, 3, and 15 postoperatively, and lower tear meniscus height (LTMH) on optical coherence tomography on days 1 and 15 postoperatively. Secondary outcomes were pairwise correlation of TFBUT, FCS and LTMH. RESULTS: In the BCL group, abnormal TFBUT and FCS were only found in 2 patients (13.33%) on postoperative day 15. In the control group, the incidence of dry eye assessed by TFBUT was 67.00% (10/15 eyes) on day 1, 73.33% (11/15 eyes) on day 3, and 53.33% (8/15 eyes) on day 15 (P < .001). LTMH were significantly higher in the BCL group than the control group postoperatively (P < .001). Significant positive correlations were found between LTMH and TFBUT pre-operation and on days 1 and 15 post-operation. For LTMH and FCSS (R = -0.815, P < .001), and TFBUT and FCS (R = -0.837, P < .001), the Pearson coefficient was negative on postoperative day 1, but not correlated on day 15. CONCLUSIONS: Silicone hydrogel BCL were safe and efficacious for protective use in children after frontalis muscle flap suspension for congenital blepharoptosis. PMID- 28885363 TI - Prevalence, risk factors, and prognosis of orthostatic hypotension in diabetic patients: A systematic review and meta-analysis. AB - BACKGROUND: Orthostatic hypotension (OH) is a major clinical sign of cardiovascular autonomic dysfunction in diabetic patients. Our aim was to quantitatively evaluate the prevalence and risk factors of OH in patients with diabetes mellitus (DM) and assess its prognosis. METHODS: A comprehensive search of the PubMed, Embase, China National Knowledge Infrastructure, VIP Chinese Journal, Wanfang, and SINOMED databases was conducted for related published work up to September 25, 2016, and manually searched eligible studies from the references in accordance with the inclusion criteria. RESULTS: We included 21 studies in the analysis, with a total sample size of 13,772. The pooled prevalence of OH in DM was 24% (95% confidence interval [CI]: 19-28%). Potential risk factors, that is, glycosylated hemoglobin A (HbA1c) (odds ratio [OR], 1.13, 95% CI, 1.07-1.20), hypertension (OR, 1.02, 95% CI, 1.01-1.02), and diabetic nephropathy (OR, 2.37, 95% CI, 1.76-3.19), were significantly associated with OH in DM. In addition, the prognosis of OH in DM was associated with higher risk of total mortality and cardiovascular events. CONCLUSION: The pooled prevalence of OH in DM appears high. HbA1c, hypertension, and diabetic nephropathy are risk factors for OH in DM. OH indicates poor prognosis in diabetic patients. Attention should be focused on diabetic patients with the stated risk factors to prevent OH. PMID- 28885364 TI - Comparison of laparoscopic-assisted radical vaginal hysterectomy and abdominal radical hysterectomy in patients with early stage cervical cancer: A retrospective study. AB - BACKGROUND: The aim of this study was to compare the safety and survival outcomes of early stage cervical cancer patients treated by laparoscopically assisted radical vaginal hysterectomy (LARVH) versus abdominal radical hysterectomy (ARH). METHODS: Since March 2008 to July 2012, the patients with early stage cervical cancer undergoing LARVH or ARH in Beijing hospital have been entered into this study. Statistical analysis used Statistical Product and Service Solutions (SPSS) and significance was defined as P < .05. RESULT: Forty-two patients were included in LARVH group and 35 patients in ARH group. Both groups were similar with respect to age, body mass index (BMI), histological diagnosis, and stage. There were no differences in operative time, vaginal length, and postoperative complications, but blood loss, rate of transfusion, length of catheterized, and length of hospital stay were significantly less in LARVH. Number of lymph node retrieved was less than ARH. No differences were seen regarding recurrence rate, length of disease free survival, overall survival, and mortality rate after a median follow up of 58.5 and 48.5 months. CONCLUSION: LARVH is a suitable alternative to ARH for early-stage cervical cancer, which shows less blood loss, shorter catheterized and hospital stay, and similar survival outcomes. PMID- 28885365 TI - Therapeutic efficacy of neuromuscular electrical stimulation and electromyographic biofeedback on Alzheimer's disease patients with dysphagia. AB - To study the therapeutic effect of neuromuscular electrical stimulation and electromyographic biofeedback (EMG-biofeedback) therapy in improving swallowing function of Alzheimer's disease patients with dysphagia.A series of 103 Alzheimer's disease patients with dysphagia were divided into 2 groups, among which the control group (n = 50) received swallowing function training and the treatment group (n = 53) received neuromuscular electrical stimulation plus EMG biofeedback therapy. The mini-mental state scale score was performed in all patients along the treatment period. Twelve weeks after the treatment, the swallowing function was assessed by the water swallow test. The nutritional status was evaluated by Mini Nutritional Assessment (MNA) as well as the levels of hemoglobin and serum albumin. The frequency and course of aspiration pneumonia were also recorded.No significant difference on mini-mental state scale score was noted between 2 groups. More improvement of swallowing function, better nutritional status, and less frequency and shorter course of aspiration pneumonia were presented in treatment group when compared with the control group.Neuromuscular electrical stimulation and EMG-biofeedback treatment can improve swallowing function in patients with Alzheimer's disease and significantly reduce the incidence of adverse outcomes. Thus, they should be promoted in clinical practice. PMID- 28885366 TI - Acute vanishing bile duct syndrome after therapy with cephalosporin, metronidazole, and clotrimazole: A case report. AB - RATIONALE: Vanishing bile duct syndrome (VBDS) consists of a series of diseases characterized by the loss of >50% bile duct in portal areas. Many factors are associated with VBDS including infections, neoplasms, and drugs. Antibiotic is one of the most frequently reported causes of VBDS. PATIENT CONCERNS: A 29-year old female was admitted because of liver injury for over 3 months. Tests for viruses that can cause hepatitis and autoantibodies were all negative. She was prescribed with antibiotics approximately a week before liver injury while there was no history of alcohol consumption. DIAGNOSES: Liver biopsy demonstrated a loss of intrahepatic bile duct in most of the portal tracts. INTERVENTIONS: This patient was treated with ursodeoxycholic acid, polyene phosphatidylcholine, and bicyclol. Most importantly, the treatments in our hospital were proved by the ethics committee of Department of Infectious Disease, Anhui Provincial Hospital. OUTCOMES: The symptoms were improved. She is still under treatment. LESSONS: VBDS is rare but can be severe. A liver biopsy offers an important evidence for the diagnosis of VBDS, especially for those with a history of susceptible drugs taking. PMID- 28885367 TI - Compulsive skin-picking behavior after deep brain stimulation in a patient with refractory obsessive-compulsive disorder: A case report. AB - RATIONAL: The therapeutic effect of deep brain stimulation (DBS) for refractory obsessive-compulsive disorder (OCD) has been studied, but complications after this treatment have rarely been noted. PATIENT CONCERNS: A 28-year-old man with treatment-resistant OCD received bilateral ventral capsule/ventral striatum stimulation for 12 months. DIAGNOSIS: Compulsive skin-picking behavior and infection were noted following 12-month DBS treatment. INTERVENTION: We removed the implanted right-side pulse generator. OUTCOMES: The local inflammation and skin-picking behavior gradually improved. The stimulator device was re-implanted 4 months later. LESSONS: We suggest that patients with the OC spectrum should be evaluated for skin-picking behaviors during presurgical and postsurgical follow up to reduce the infection and device removal rates. PMID- 28885368 TI - Successful management of octreotide-insensitive thyrotropin-secreting pituitary adenoma with bromocriptine and surgery: A case report and literature review. AB - RATIONALE: Case reports concerning the value of dopamine agonists in the treatment of patients with thyrotropin-secreting pituitary adenoma (TSHoma) are limited. Herein, we present a rare case of octreotide-insensitive TSHoma responding to bromocriptine therapy. PATIENT CONCERNS: A 45-year-old Chinese man was admitted to Peking Union Medical College Hospital with marked clinical manifestations of hyperthyroidism. DIAGNOSES: Thyroid function tests demonstrated elevated concentrations of free thyroid hormones in the presence of normal thyrotropin. Magnetic resonance imaging findings showed a pituitary microadenoma on the right side of the sellar region. Based on characteristic endocrine results and neuroimaging findings, the patient was diagnosed with TSHoma. INTERVENTIONS: Most patients with TSHomas are significantly responsive to somatostatin analog treatment. However, our patient was orally administered with bromocriptine to normalize thyroid function as assessed by suppression tests conducted prior to surgery. A transsphenoidal surgery was performed by an experienced neurosurgeon for tumor removal. OUTCOMES: The pituitary lesion was totally resected. Following the operation, the results of thyroid function tests were immediately within reference limits. During the follow-up, there was no residual or recurrent tumor. LESSONS: Attention should be paid to the role of dopamine agonists such as bromocriptine and cabergoline as adjuvant therapy for TSHomas that are insensitive to traditional medical treatment by somatostatin analogs. PMID- 28885369 TI - Influencing factors of glycemic variability in hospitalized type 2 diabetes patients with insulin therapy: A Strobe-compliant article. AB - Previous studies have shown that glucose fluctuation is closely related to oxidative stress and diabetic complications. However, only few studies have evaluated the influencing factors of glycemic variability (GV) in type 2 diabetes (T2D) patients so far.This was a cross-sectional study design. A total of 366 cases of hospitalized patients with T2D using insulin therapy, whom received continuous glucose monitoring from January 2014 to December 2016, were enrolled for this study. The evaluation variables of GV included standard deviation of blood glucose, coefficient of variation (CV%), mean amplitude of glycemic excursion, and absolute means of daily differences.In 366 T2D patients with insulin therapy, 148 were used multiple daily injections (MDI) insulin regimen; 144 were on premixed insulin injection; and 74 were treated with continuous subcutaneous insulin injection. Compared with MDI insulin regimen, patients on premixed insulin injection have less insulin dose per day, lower mean blood glucose, and better glycated hemoglobin (HbA1c) (all P <.05). Generalized linear model showed that family history of diabetes, duration of diabetes, higher HbA1c, and higher level of aspartate aminotransferase and high-density lipoprotein cholesterol were positively associated with GV parameters. Otherwise, serum levels of C-peptide, premixed insulin injection, history of cardiovascular disease, and serum concentration of uric acid were inversely associated with GV parameters.Dysfunction of pancreatic beta-cell and better insulin sensitivity were independent contributors to the fluctuation of blood glucose. Moreover, premixed insulin therapy may obtain better glucose control and lower within-day and day-to-day glucose variability for Chinese T2D patients with insulin therapy. PMID- 28885370 TI - Usefulness of titanium mesh cage for posterior C1-C2 fixation in patients with atlantoaxial instability. AB - The aim of this study was to investigate the usefulness of titanium mesh cage as an interlaminar spacer combined with nitinol shape memory loop fixation in patients with atlantoaxial instability.From April 2009 to March 2017, among the patients with atlantoaxial instability, a total of 30 patients were treated by nitinol shape memory loop fixation combined with titanium mesh cage as a spacer. We retrospectively reviewed 30 enrolled patients. Successful fusion was determined as improvement of symptoms and radiologic findings of bone fusion. We also reviewed surgical complications, instrumentation failure, bony fusion rate, and posterior atlantodental interval (PADI).After surgery, the symptoms of all patients significantly improved. Successful fusion was documented throughout the follow-up period. Evidence of solid bridging bone was found, and no instability was seen on flexion-extension radiographs and callus formation on 3D cervical spine computed tomography (CT) 6 months postoperatively in all cases. No surgical complications were observed. No cases of instrumentation failure were observed. The mean PADI also improved significantly to 22.45 +/- 1.11 mm 6 months postoperatively compared with the preoperative value of 18.37 +/- 1.16 mm (P < .05).We obtained a good fusion rate by using titanium mesh cage spacer with nitinol shape memory alloy loop in patients with atlantoaxial instability. This technique can help surgeons in avoiding vertebral artery injury and reducing bleeding and operation time. Therefore, we suggest that titanium mesh cage spacer combined with nitinol shape memory alloy loop can be a good substitute of autograft for C1-C2 fusion in treating atlantoaxial instabilities. PMID- 28885371 TI - Clinical and diagnostic features of angiosarcoma with pulmonary metastases: A retrospective observational study. AB - Angiosarcoma with pulmonary metastasis is a rare, fatal disease that often presents with multiple pulmonary nodules and diffuse alveolar hemorrhage. We herein review the detailed clinical characteristics of pulmonary metastatic angiosarcoma and determine a reasonable diagnostic strategy.The medical records of 11 patients with pulmonary angiosarcoma were reviewed.The mean age of the patients was 45.7 years (range, 30-71 years). All patients were male. The most common symptom was hemoptysis (8/11). Common initial misdiagnoses were tuberculosis (5/11), vasculitis (2/11), nontuberculous infectious disease (1/11), and constrictive pericarditis (1/11). Chest computed tomography (CT) of patients with hemoptysis showed bilateral, randomly distributed, variably shaped, and differently sized nodules, as well as ground-glass opacities (GGO) (8/11). The right heart was the most common primary tumor site (8/11), but the sensitivity of echocardiography was limited; CT angiography and cardiac magnetic resonance imaging (MRI) revealed more atrial masses. CT-guided needle biopsy was difficult to perform in most patients because of the small size of the nodules. The diagnosis was made by surgical biopsy of either the lung (3/9) or heart (6/9). The median overall survival of patients who underwent lung biopsy and those who underwent cardiac/pericardiac biopsy was 4.1 and 1.4 months, respectively (P = .098). The median overall survival of the 9 available patients was 5.0 months (95% confidence interval, 0.500-8.544).Angiosarcoma with pulmonary metastases should be considered in patients with hemoptysis and concurrent GGO and nodules on their chest CT scan. Careful cardiologic monitoring is necessary for these patients, even without any cardiac symptoms or signs, and enhanced cardiac MRI is the first recommendation. Surgical biopsy is reliable for histological diagnosis, but the safety of the lung biopsy should be carefully assessed. When primary cardiac tumors are identified, heart biopsy should be preferentially considered. PMID- 28885372 TI - Light therapy for multiple sclerosis-associated fatigue: Study protocol for a randomized controlled trial. AB - BACKGROUND: Fatigue is the most commonly reported symptom among multiple sclerosis (MS) patients, more than a quarter of whom consider fatigue to be their most disabling symptom. However, there are few effective treatment options for fatigue. We aim to investigate whether supplemental exposure to bright white light will reduce MS-associated fatigue. METHODS: Eligible participants will have clinically confirmed multiple sclerosis based on the revised McDonald criteria (2010) and a score >=36 on the Fatigue Severity Scale (FSS). Participants will be randomized 1:1 to bright white light (10,000 lux; active condition) or dim red light (<300 lux; control condition) self-administered for 1 hour twice daily. The study will include a 2-week baseline period, a 4-week treatment period, and a 4 week washout period. Participants will record their sleep duration, exercise, caffeine, and medication intake daily. Participants will record their fatigue using the Visual Analogue Fatigue Scale (VAFS) 4 times every third day, providing snapshots of their fatigue level at different times of day. Participants will self-report their fatigue severity using FSS on 3 separate visits: at baseline (week 0), following completion of the treatment phase (week 6), and at study completion (week 10). The primary outcome will be the change in the average FSS score after light therapy. We will perform an intention-to-treat analysis, comparing the active and control groups to assess the postintervention difference in fatigue levels reported on FSS. Secondary outcome measures include change in global VAFS scores during the light therapy and self-reported quality of life in the Multiple Sclerosis Quality of Life-54. DISCUSSION: We present a study design and rationale for randomizing a nonpharmacological intervention for MS-associated fatigue, using bright light therapy. The study limitations relate to the logistical issues of a self-administered intervention requiring frequent participant self-report in a relapsing condition. Ultimately, light therapy for the treatment of MS-associated fatigue may provide a low-cost, noninvasive, self administered treatment for one of the most prevalent and burdensome symptoms experienced by people with MS. PMID- 28885373 TI - Age-adjusted Charlson comorbidity score is associated with the risk of empyema in patients with COPD. AB - Patients with chronic obstructive pulmonary disease (COPD) have a higher risk of pneumonia than the general population due to their impaired lung defense. They also have a higher risk of empyema and more comorbidities than patients without COPD. This study aimed to evaluate the risk of empyema in patients with COPD after adjusting for age and comorbidities using the age-adjusted Charlson comorbidity index (ACCI).Data were retrieved from the National Health Insurance Research Database. COPD patients were defined as inpatients aged >40 years with an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code for COPD. In total, 558,660 COPD patients were enrolled and separated into 3 groups by ACCI score to represent the severity of comorbidity (<=2, 3-5, and >5). Other comorbidities assessed included autoimmune diseases, gastroesophageal reflux disease, dyslipidemia, chest wall injury, and thoracostomy.Of the 558,660 patients, 36,556 (6.54%) had low ACCI scores (<=2), 208,292 (37.28%) had moderate ACCI scores (3-5), and 313,812 (56.17%) had high ACCI scores (>5). The mean ages of the low, moderate, and high groups were 50.66, 70.62, and 78.05 years, respectively. The hazard ratio (HRs) for empyema were 1.26 (95% confidence interval (CI) = 1.13-1.40) in the moderate ACCI group and 1.55 (95% CI = 1.39-1.72) in the high ACCI group compared with the low ACCI group. The overall incidence of empyema in COPD patients was 2.57 per 1000 person years.This is the first study to use ACCI scores to analyze the risk of empyema in patients with COPD. Patients with high ACCI scores were older and had more complicated comorbidities, resulting in a higher risk of empyema and poor prognosis. The subgroup analysis indicated that COPD patients with comorbid autoimmune disease, gastroesophageal reflux disease, chest wall injury, or history of thoracostomy did not have a higher risk of empyema than patients without these comorbidities.Empyema is an important issue in patients with COPD and is associated with significant morbidity and mortality. Awareness of the risk factors for empyema, close monitoring, and early intervention may improve patient outcomes and decrease mortality. PMID- 28885374 TI - Predictive factors to diagnosis undifferentiated early gastric cancer after endoscopic submucosal dissection. AB - It is difficult to predict precisely whether the lesion corresponds to endoscopic resection indication. Furthermore, discrepancy may occur between endoscopic forceps biopsy (EFB) and finally resected specimen, which may be diagnosed as undifferentiated cancer and additional surgery may be required. Our study aimed to evaluate predictive factors to diagnose undifferentiated cancer after endoscopic submucosal dissection (ESD).Among the 532 patients diagnosed by ESD between January 2009 and December 2015, 557 early gastric cancer (EGC) cases were studied. Factors predicting diagnosis of undifferentiated cancer and clinical outcomes of the lesions were retrospectively analyzed.Among the 557 cases with EGC, 535 (96.1%) were diagnosed as differentiated cancer and 22 (3.9%) as the undifferentiated type with ESD. Tumor size was larger (mean size 20.67 vs 13.59 mm, P < .001) and age was lower (60.24 vs 64.50 years, P < .001) in the group with undifferentiated cancer. En bloc resection rate was similar (95.5% vs 95.9%, P = .886), but the complete resection rate was lower (72.7% vs 92.4%, P < .001) in the group with undifferentiated cancer. On multivariate analysis, tumor size >=10 mm (OR = 11.340, P = .032), age <55 years (OR = 5.972, P = .004), surface redness (OR = 11.562, P = .024), and whitish discoloration (OR = 35.368, P < .001) were predominantly associated with undifferentiated cancer.Young age (<55 years), large tumor size (>=10 mm), surface redness, and whitish discoloration are predictors of undifferentiated cancer, and lesions with these features detected need to be treated cautiously. PMID- 28885375 TI - Tenofovir alafenamide nephrotoxicity in an HIV-positive patient: A case report. AB - RATIONALE: Tenofovir alafenamide (TAF) is novel prodrug of Tenofovir, a nucleotide reverse transcriptase inhibitor. TAF is less nephrotoxic than its predecessor prodrug, tenofovir disoproxil fumarate (TDF). Tenofovir causes mitochondrial dysfunction and tubular injury when there is elevated accumulation in proximal tubule cells. TAF's unique pharmacokinetic profile enables provision of lower required doses for antiviral efficacy. Lower concentrations reach renal tubules minimizing intracellular accumulation and mitochondrial damage. TAF has not been associated with the histologic markers of tenofovir-associated nephrotoxicity that are seen with TDF, such as dysmorphic mitochondria in proximal tubule cells. Here, we report a patient with dysmorphic mitochondria on kidney biopsy after initiating therapy with TAF. LESSONS: This case suggests that at risk individuals may experience tubular mitochondrial injury from lower concentrations of tenofovir with TAF. PMID- 28885376 TI - Clinicopathological features of diabetic and nondiabetic renal diseases in type 2 diabetic patients with nephrotic-range proteinuria. AB - Heavy proteinuria with or without features of nephrotic syndrome is associated with many primary and systemic diseases. For diabetic patients, distinguishing nondiabetic renal disease (NDRD) from diabetic nephropathy (DN) is important in choosing treatment modalities and determining renal prognosis. However, clinical relevance of heavy proteinuria is inconsistent with clinical DN assessments. This study investigated the clinicopathological features and renal outcomes of DN and NDRD in type 2 diabetic patients with nephrotic-range proteinuria.We enrolled 220 cases of type 2 diabetic patients who underwent renal biopsy. They were grouped according to the presence of nephritic-range proteinuria and pathological features. Baseline characteristics, laboratory findings, types of pathological diagnosis, and renal outcomes were analyzed in patients with heavy proteinuria.Upon kidney biopsy, 129 patients (58.6%) showed nephritic-range proteinuria. Patients with heavy proteinuria (an average urine protein-to creatinine ratio of 10,008 +/- 7307 mg/gCr) showed lower serum albumin levels and higher total cholesterol levels, but did not show any difference in age, duration of diabetes, renal function, or the presence of retinopathy compared with those with mild-to-moderate proteinuria (an average urine protein-to-creatinine ratio of 1581 +/- 979 mg/gCr). Renal biopsy revealed that the prevalence of NDRD was 37.2% in patients with heavy proteinuria, which was significantly lower than that in patients with mild-to-moderate proteinuria (63.7%). The most common pathological types of NDRD were membranous nephropathy (41.7%), IgA nephropathy (14.6%), and minimal change disease (10.4%). NDRD patients showed lower prevalence of diabetic retinopathy and better kidney function irrespective of proteinuria. Immunosuppressive treatment was administered more frequently in patients with heavy proteinuria (56.3%) compared with patients with mild-to moderate proteinuria (20%) because of the pathological differences according to the amount of proteinuria. Renal outcomes were significantly worse in patients with DN than in patients with NDRD.DN patients with heavy proteinuria exhibited different prevalence of NDRD and worse prognosis. Renal biopsy in type 2 diabetic patients should be more extensively considered to accurately diagnose NDRD, guide further management, and predict renal outcomes, especially in patients with nephrotic-range proteinuria. PMID- 28885377 TI - Clinical Pearls in Venovenous Extracorporeal Life Support for Adult Respiratory Failure. AB - Extracorporeal life support (ECLS) has been widely utilized to treat neonatal respiratory failure for two decades. However, its uptake in the case of adult respiratory failure has been slow because of a paucity of quality evidence and a sluggish tempo of ECLS-related technological advances. In recent years, interest in ECLS has been piqued after encouraging results were reported from its use during the 2009 H1N1 influenza pandemic. In a world constantly under threat from another influenza epidemic or deadly novel respiratory infection, e.g., the severe acute respiratory syndrome (SARS) virus, the Middle East respiratory syndrome coronavirus (MERS-CoV), the role of venovenous (VV) ECLS as a treatment modality for acute respiratory distress syndrome (ARDS) cannot be overemphasized. In hopes of standardizing practice, the Extracorporeal Life Support Organization (ELSO) has published books and guidelines on ECLS. However, high-level evidence to guide clinical decisions is still expediently needed in this field. Relying on the available literature and our experience in the recent South Korean MERS-CoV outbreak, we hope to highlight key physiologic and clinical points in VV ECLS for adult respiratory failure in this review. PMID- 28885378 TI - Radial Force: An Underestimated Parameter in Oversizing Transcatheter Aortic Valve Replacement Prostheses: In Vitro Analysis with Five Commercialized Valves. AB - The goal is to inform in depth on transcatheter aortic valve replacement (TAVR) prosthesis mechanical behavior, depending on frame type, design, and size, and how it crucially impacts the oversizing issue in clinical use, and ultimately the procedure outcome. Transcatheter aortic valve replacement is an established therapy for high-risk patients suffering from aortic stenosis, and the indication for TAVR is progressively expanding to intermediate-risk patients. Choosing the optimal oversizing degree is crucial to safely anchor the TAVR valve-which involves limiting the risks for embolism, aortic regurgitation, conductance disturbance, or annulus rupture-and to increase the valve prosthesis performance. The radial force (RF) profiles of five TAVR prostheses were measured in vitro: the CoreValve 23 and 26 (Medtronic, Minneapolis, MN), the Acurate neo S (Symetis, Ecublens, Vaud, Switzerland), and the SAPIEN XT 23 and 26 (Edwards Lifesciences, Irvine, CA). Measurements were run with the RX Machine equipment (Machine Solutions Inc., Flagstaff, AZ), which is used in ISO standard tests for intravascular stents. Test protocols were adapted for TAVR prostheses. With the prostheses RF profiles' results, mechanical behavior differences could be described and discussed in terms of oversizing strategy and clinical impact for all five valves. Besides, crossing the prostheses' RF profiles with their recommended size windows made the assessment of borderline size cases possible and helped analyze the risks when accurate measurement of patient aortic annulus proves difficult. The prostheses' RF profiles bring new support in clinical decision-making for valve type and size in patients. PMID- 28885379 TI - Risk Stratification of Patients With Current Generation Continuous-Flow Left Ventricular Assist Devices Being Bridged to Heart Transplantation. AB - Patients bridged to transplant (BTT) with continuous-flow left ventricular assist devices (CF-LVADs) have increased in the past decade. Decision support tools for these patients are limited. We developed a risk score to estimate prognosis and guide decision-making. We included heart transplant recipients bridged with CF LVADs from the United Network for Organ Sharing (UNOS) database and divided them into development (2,522 patients) and validation cohorts (1,681 patients). Univariate and multivariate Cox proportional hazards models were performed. Variables that independently predicted outcomes (age, African American race, recipient body mass index [BMI], intravenous [IV] antibiotic use, pretransplant dialysis, and total bilirubin) were assigned weight using linear transformation, and risk scores were derived. Patients were grouped by predicted posttransplant mortality: low risk (<= 38 points), medium risk (38-41 points), and high risk (>= 42 points). We performed Cox proportional hazards analysis on wait-listed CF-LVAD patients who were not transplanted. Score significantly discriminated survival among the groups in the development cohort (6.7, 12.9, 20.7; p = 0.001), validation cohort (6.4, 10.1, 13.6; p < 0.001), and ambulatory cohort (6.4, 11.5, 17.2; p < 0.001). We derived a left ventricular assist device (LVAD) BTT risk score that effectively identifies CF-LVAD patients who are at higher risk for worse outcomes after heart transplant. This score may help physicians weigh the risks of transplantation in patients with CF-LVAD. PMID- 28885380 TI - Use of Durable Continuous-Flow Ventricular Assist Devices in Patients on Immunosuppression. AB - Durable ventricular assist device (VAD) therapy remains an important treatment for end-stage heart failure. Despite advancements in device design, postimplant infectious complications continue to plague this population. In this study, we aim to evaluate the use of durable VAD therapy in patients on active immunosuppression. All patients undergoing durable, continuous-flow VAD placement on active immunosuppression at our center from 2004 to 2012 were included in the analysis (group immunosuppressed [IS]; n = 13). Demographic data, comorbidities, device details, immunosuppression details including indication, postimplant infections, and outcomes were collected and compared with patients without immunosuppression (group non-IS; n = 259). Mean age in the IS group was 56.3 +/- 12.4 years, and 12 patients (92.3%) were male. Twelve patients (92.3%) were implanted as a bridge to transplant. Incidence of any postimplant infection and device-related infection was 1.15 infections/patient * year and 0.38 infections/patient * year, respectively. Survival to discharge was 84.6% and 93.1% (p = 0.25), and 1 year survival was 75.0% and 83.1% (p = 0.47) in the IS and non-IS group, respectively. Mean duration of support was 384 +/- 466 days, and mean follow-up was 2.1 +/- 1.5 years. Active immunosuppression may lead to a modest increase in postimplant infection rate in durable VAD patients than in non IS patients undergoing the same treatment; however, late on-device survival is not affected. Immunosuppression should not be considered an absolute contraindication to device implant. PMID- 28885381 TI - Characteristics of Medical Adverse Events/Near Misses Associated With Laparoscopic/Thoracoscopic Surgery: A Retrospective Study Based on the Japanese National Database of Medical Adverse Events. AB - OBJECTIVES: The aim of this study was to clarify the characteristics of adverse events/near misses during laparoscopic/thoracoscopic surgery. METHODS: Using relevant key words for minimally invasive surgeries, 540 records were identified in the database of the Japan Council for Quality Health Care. After data review and the classification of adverse events, 746 events associated with laparoscopic (laparo group) and/or thoracoscopic (thoraco group) surgery were identified. We calculated the frequency of each event, compared the frequency regarding recurrent events, and evaluated the types of event that had resulted in deaths between the 2 groups. RESULTS: There were 582 events in the laparo group, 159 in the thoraco group, and 5 in those undergoing combined surgery. Overall, injury of other organs (11.4%, 85/746), retention of a foreign body (9.1%, 68/746), breakage/failure of medical equipment or devices (6.2%, 46/746), massive bleeding (5.9%, 44/746), misperception of anatomy (5.6%, 42/746), and vascular injury (4.8%, 36/746) were frequently reported. There were marked differences in the frequency of injury of other organs (laparo group: 13.4%, 78/582; thoraco group: 4.4%, 7/159), massive bleeding (laparo group: 3.4%, 20/582; thoraco group: 14.5%, 23/159), and vascular injury (laparo group: 2.6%, 15/582; thoraco group: 12.6%, 20/159) between the 2 groups. Among the 56 patient-death reports, 132 adverse events were identified. In the thoraco group, bleeding events were frequently observed, whereas in the laparo group, various categories of events were noted. CONCLUSIONS: We observed recurrent incidents and differences in the frequency between the 2 groups. Surgeons should keep in mind these characteristics. Retention of a foreign body and the breakage/malfunctioning of instruments might be reduced by the introduction of specialized checklists.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 28885382 TI - The Ideal Hospital Discharge Summary: A Survey of U.S. Physicians. AB - BACKGROUND: Hospital discharge summaries enable communication between inpatient and outpatient physicians. Despite existing guidelines for discharge summaries, they are frequently suboptimal. OBJECTIVE: The aim of this study was to assess physicians' perspectives about discharge summaries and the differences between summaries' authors (hospitalists) and readers (primary care physicians [PCPs]). METHODS: A national survey of 1600 U.S. physicians was undertaken. Primary measures included physicians' preferences in discharge summary standardization, content, format, and audience. RESULTS: A total of 815 physicians responded (response rate = 51%). Eighty-nine percent agreed that discharge summaries "should have a standardized format." Most agreed that summaries should "document everything that was done, found, and recommended in the hospital" (64%) yet "only include details that are highly pertinent to the hospitalization" (66%). Although 74% perceived patients as an important audience of discharge summaries, only 43% agreed that summaries "should be written in language that patients...can easily understand," and 68% agreed that it "should be written solely for provider-to provider communication." Compared with hospitalists, PCPs preferred comprehensive summaries (68% versus 59%, P = 0.002). More PCPs agreed that separate summaries should be created for patients and for provider-to-provider communication than hospitalists (60% versus 47%, P < 0.001). Compared with PCPs, more hospitalists believe that "hospitalists are too busy to prepare a high-quality discharge summary" (44% versus 23%, P < 0.001) and "PCPs have insufficient time to read an entire discharge summary" (60% versus 38%, P < 0.001). CONCLUSIONS: Physicians believe that discharge summaries should have a standardized format but do not agree on how comprehensive or in what format they should be. Efforts are necessary to build consensus toward the ideal discharge summary. PMID- 28885383 TI - Application of a Modified Pedicled Adipofascial Lateral Arm Flap in the Prevention and Treatment of Radial Nerve Injuries. AB - The fasciocutaneous lateral arm flap is a workhorse flap in upper extremity reconstruction. However, its adipofascial variant is not widely used. The technique can be used in various clinical scenarios. The adipofascial flap can be transposed to circumferentially wrap the radial nerve with a pliable, vascularized fat and fascial envelope, mimicking the natural fatty environment of peripheral nerves. This technique has the advantage of providing a scar tissue barrier, a barrier to hardware irritation and a milieu for vascular regeneration of the nerve. Suggested applications include nerve coverage in the setting of posterior humerus plating to prevent adhesions; anticipation of bone grafting in the setting of an open fractures with bone loss, infection, or with the use of the Masquelet technique; in revision total elbow arthroplasty or endoprosthetic humerus replacement; and in the setting of neurolysis, repair or nerve grafting. The technique is straightforward and does not require microvascular expertise. PMID- 28885384 TI - A New Stem Guide and a Tuberosity Anchoring "Lasso" System for Shoulder Hemiarthroplasty in the Treatment of Complex Proximal Humerus Fractures. AB - Hemiarthroplasty implantation for proximal humerus fracture is challenging. In case of young demanding patients with functional rotator cuff, humeral head replacement is an option if open reduction internal fixation is not a viable solution. The criteria for success in terms of clinical outcomes and longevity are anatomic healing of the tuberosities and stem positioning (restoring correct height, version, and axis). The purpose of this article is to describe a technique including a new stem guide and a tuberosity anchor "lasso" system for the implantation of hemiarthroplasty in complex proximal humerus fractures. A standard delto-pectoral approach is performed. After humeral head removal and tuberosity mobilization and debridement, a stem-positioning system guarantees correct height and version of the humeral stem, established after anatomic reduction of the greater tuberosity. A centering device is added on the humeral stem to prevent any varus or valgus. Fixation of the tuberosities is achieved with 6 nonabsorbable sutures fixed on a polyester "lasso" anchoring system circling the humerus, respecting the direction of rotator cuff tendons and adding double circumferential tightening. After reduction of the implant, stability, and passive range of motion are assessed intraoperatively and fluoroscopic control of the prosthesis is performed. The patient is maintained in a sling in neutral rotation and passive motion is started after 4 weeks; active motion is allowed after 2 months. We believe this surgical technique could help limit complications and prevent revision of the humeral stem in case of further conversion to reverse shoulder arthroplasty. PMID- 28885385 TI - Blood pressure variability in individuals with and without (pre)diabetes: The Maastricht Study. AB - OBJECTIVE: The mechanisms associating (pre)diabetes and cardiovascular disease (CVD) are incompletely understood. We hypothesize that greater blood pressure variability (BPV) may underlie this association, due to its association with (incident) CVD. Therefore, we investigated the association between (pre)diabetes and very short-term to mid-term BPV, that is within-visit, 24-h and 7-day BPV. METHODS: Cross-sectional data from The Maastricht Study [normal glucose metabolism (NGM), n = 1924; prediabetes, n = 511; type 2 diabetes mellitus (T2DM), n = 975; 51% men, aged 60 +/- 8 years]. We determined SD for within-visit BPV (n = 3244), average real variability for 24-h BPV (n = 2699) day (0900-2100 h) and night (0100-0600 h) separately, and SD for 7-day BPV (n = 2259). Differences in BPV as compared with NGM were assessed by multiple linear regressions with adjustment for potential confounders. RESULTS: In T2DM, the average systolic/diastolic values of within-visit, 24-h and 7-day BPV were 4.8/2.6, 10.5/7.3 and 10.4/6.5 mmHg, respectively, and in prediabetes 4.9/2.6, 10.3/7.0 and 9.4/5.9 mmHg, respectively. T2DM was associated with greater nocturnal systolic BPV [0.42 mmHg (95% confidence interval: 0.05-0.80)], and greater 7-day systolic [0.76 mmHg (0.32-1.19)] and diastolic BPV [0.65 mmHg (0.29 1.01)], whereas prediabetes was associated with greater within-visit systolic BPV only [0.35 mmHg (0.06-0.65)], as compared with NGM. CONCLUSION: Both T2DM and prediabetes are associated with slightly greater very short-term to mid-term BPV, which may, according to previous literature, explain a small part of the increased CVD risk seen in (pre)diabetes. Nevertheless, these findings do not detract from the fact that very short-term to mid-term BPV is substantial and important in individuals with and without (pre)diabetes. PMID- 28885386 TI - A Delta Neutrophil Index for the Prediction of Contrast-Induced Nephropathy in Patients With St-Elevation Myocardial Infarction Followed By Percutaneous Coronary Intervention. AB - PURPOSE: We assessed the usefulness of the delta neutrophil index (DNI), reflecting immature granulocytes, to stratify risk for developing contrast induced nephropathy (CIN) in patients with ST-elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) in a clinical setting. METHODS: This study retrospectively analyzed prospective data of eligible adult patients admitted to the emergency department (ED) with STEMI followed by PCI. We determined DNI at multiple time points and analyzed the development of CIN and in-hospital mortality according to CIN incidence. RESULTS: Overall, 564 patients with STEMI followed by PCI were included. Of these, 58 patients (10.3%) had CIN. Areas under the curve for predictability of CIN using the DNI within 2 h after PCI (I) and 24 h on ED admission (24) among patients with CIN were 0.775 (P < 0.001) and 0.751 (P < 0.001), respectively. Multivariable logistic regression demonstrated that increased DNI values at time I (odds ratio [OR], 1.632; 95% confidence interval [CI], 1.357-1.964; P < 0.001) and time 24 (OR, 1.503; 95% CI, 1.272-1.777; P < 0.001) were strong independent factors for predicting CIN among patients with STEMI who underwent PCI. Increasing predictability of CIN was closely associated with DNI more than 1.8% on ED admission (OR, 12.494; 95% CI, 6.540-23.87; P < 0.001) and more than 1.9% at time 24 (OR, 10.45; 95% CI, 5.769-18.928; P < 0.001). CONCLUSION: The DNI is easily obtained as part of the complete blood count measurement without requiring additional cost or time. High DNI independently predicts the development of CIN in patients with acute STEMI followed by PCI. PMID- 28885388 TI - Differences in Physical Capacity Between Junior and Senior Australian Footballers. AB - Kelly, SJ, Watsford, ML, Austin, DJ, Spurrs, RW, Pine, MJ, and Rennie, MJ. Differences in physical capacity between junior and senior Australian footballers. J Strength Cond Res 31(11): 3059-3066, 2017-The purpose of this study was to profile and compare anthropometric and physical capacities within elite junior and senior Australian football (AF) players of various chronological ages and stages of athletic development. Seventy-nine players, including junior and senior AF players from one professional club, were profiled using 11 assessments. Junior players were divided into 2 groups based on chronological age (under 16 and 18 years) and senior players according to years since drafted to a professional AF team (1-2 years, 3-7 years, and 8+ years). Parametric data were assessed using a 1-way analysis of variance (ANOVA), whereas nonparametric data were assessed using a Kruskal-Wallis ANOVA. The magnitude difference between players was measured using the Hopkins' effect size (ES). Significant differences were evident between under-16 players and all senior player groups for anthropometric (p = 0.001-0.019/ES = 1.25-2.13), absolute strength (p = 0.001 0.01/ES = 1.82-4.46), and relative strength (p = 0.001-0.027/ES = 0.84-3.55). The under-18 players displayed significantly lower absolute strength (p = 0.001 0.012/ES = 1.82-3.79) and relative strength (p = 0.001-0.027/ES = 0.85-4.00) compared with the 3-7 and 8+ players. Significant differences were evident between the under-16 players and senior player groups for explosive jumping and throwing tests (p = 0.001-0.017/ES = 1.03-2.99). Minimal differences were evident between all player groups for running assessments; however, the under-16 players were significantly slower compared with the 8+ players for the 3-km time trial (p < 0.02/ES = 1.31), whereas both junior player groups covered significantly less distance during the Yo-Yo IR2 (p < 0.02/ES = 1.19 and 1.60). Results of this study display a significant deficit in strength between junior and senior AF players. PMID- 28885387 TI - Evidence for Persistent Immune Suppression in Patients Who Develop Chronic Critical Illness After Sepsis. AB - BACKGROUND: Many sepsis survivors develop chronic critical illness (CCI) and are assumed to be immunosuppressed, but there is limited clinical evidence to support this. We sought to determine whether the incidence of secondary infections and immunosuppressive biomarker profiles of patients with CCI differ from those with rapid recovery (RAP) after sepsis. METHODS: This prospective observational study evaluated 88 critically ill patients with sepsis and 20 healthy controls. Cohorts were defined based on clinical trajectory (early death, RAP, or CCI), whereas immunosuppression was clinically determined by the presence of a postsepsis secondary infection. Serial blood samples were collected for absolute lymphocyte counts (ALCs), monocytic human leukocyte antigen-DR (mHLA-DR) expression, and plasma-soluble programmed death-ligand 1 (sPD-L1) concentrations. RESULTS: Of the 88 patients with sepsis, 3 (3%) died within 14 days of sepsis onset, 50 (57%) experienced RAP, and 35 (40%) developed CCI. Compared with RAP patients, CCI patients exhibited a higher incidence and overall number of infections adjusted for hospital length of stay. ALC and mHLA-DR levels were dramatically reduced at the time of sepsis diagnosis when compared with healthy controls, whereas sPD-L1 concentrations were significantly elevated. There were no differences between RAP and CCI patients in ALC, sPD-L1, or mHLA-DR at the time of diagnosis or within 24 h after sepsis diagnosis. However, in contrast to the RAP group, CCI patients failed to exhibit any trend toward restoration of normal values of ALC, HLA-DR, and sPD-L1. CONCLUSIONS: Septic patients demonstrate clinical and biological evidence to suggest they are immunosuppressed at the time of sepsis diagnosis. Those who develop CCI have a greater incidence of secondary infections and persistently aberrant markers of impaired host immunity, although measurements at the time of sepsis onset did not distinguish between subjects with RAP and CCI. PMID- 28885389 TI - Load-Velocity Relationship in Variations of the Half-Squat Exercise: Influence of Execution Technique. AB - Perez-Castilla, A, Garcia-Ramos, A, Padial, P, Morales-Artacho, AJ, and Feriche, B. Load-velocity relationship in variations of the half-squat exercise: influence of execution technique. J Strength Cond Res XX(X): 000-000, 2017-Previous studies have revealed that the velocity of the bar can be used to determine the intensity of different resistance training exercises. However, the load-velocity relationship seems to be exercise dependent. This study aimed to compare the load velocity relationship obtained from 2 variations of the half-squat exercise (traditional vs. ballistic) using 2 execution techniques (eccentric-concentric vs. concentric-only). Twenty men performed a submaximal progressive loading test in 4 half-squat exercises: eccentric-concentric traditional-squat, concentric only traditional-squat, countermovement jump (i.e., ballistic squat using the eccentric-concentric technique), and squat jump (i.e., ballistic squat using the concentric-only technique). Individual linear regressions were used to estimate the 1 repetition maximum (1RM) for each half-squat exercise. Thereafter, another linear regression was applied to establish the relationship between the relative load (%RM) and mean propulsive velocity (MPV). For all exercises, a strong relationship was observed between %RM and MPV: eccentric-concentric traditional squat (R = 0.949), concentric-only traditional-squat (R = 0.920), countermovement jump (R = 0.957), and squat jump (R = 0.879). The velocities associated with each %RM were higher for the ballistic variation and the eccentric-concentric technique than for the traditional variation and concentric-only technique, respectively. Differences in velocity among the half-squat exercises decreased with the increment in the relative load. These results demonstrate that the MPV can be used to predict exercise intensity in the 4 half-squat exercises. However, independent regressions are required for each half-squat exercise because the load-velocity relationship proved to be task specific. PMID- 28885390 TI - Epidemiology of Admissions From the Emergency Department Among Febrile Infants Younger Than 90 Days in the United States, 2002 to 2012. AB - BACKGROUND AND OBJECTIVES: Febrile infants younger than 90 days are often subjected to invasive diagnostic evaluation and hospitalization to monitor for serious bacterial infection (SBI) despite recent changes in SBI risk and advances in diagnostics. Nationwide provider practices, over time, are unknown for this group. Our objective was to determine the likelihood of admission and associated complications of care for such infants, particularly those at lowest risk for SBI. METHODS: This is a retrospective cohort study including multisite emergency department (ED) visits using administrative data from the Pediatric Emergency Care Applied Research Network Core Data Project. We examined uncomplicated febrile infants younger than 90 days seen in the ED from 2002 to 2012 who did not have an explicit infectious diagnosis, critical illness, or chronic condition. RESULTS: We identified 38,224 infants, among whom, 11,600 (31%) were admitted. We observed a 3% increase in ED admission every year during the study period (P < 0.05). Age less than 30 days and black race were independent predictors of admission (P < 0.01). We identified 227 complications of care in the ED. Among those with a specified cause, 49% were attributed to antibiotic use or procedures related to the diagnosis and empiric treatment of suspected infection. CONCLUSIONS: Despite the decreasing risk of SBI and diagnostic advances during the study period, the odds of hospital admission increased for febrile infants at low risk for sepsis. We also provide first data on therapeutic and diagnostic test-related adverse events in this setting. These data provide further justification for a consensus guideline on management of such infants. PMID- 28885391 TI - Abusive Injuries Are Worse Than Vehicular Injuries: Should We Refocus Prevention? AB - OBJECTIVES: The objective of this study was to compare the injury severity and outcome of motor vehicle and nonaccidental traumatic injuries and examine trends in mortality rates over time. METHODS: We reviewed data from 2005 to 2013 from a level 1 pediatric trauma center including demographics, injury severity, and outcomes. Primary outcomes of interest were mortality rates and hospital length of stay. RESULTS: Injury severity scores were significantly worse for nonaccidental traumas (NATs) (P < 0.001) compared with motor vehicle collisions and motor pedestrian collisions. Nonaccidental traumas were also found to have significantly longer length of stay and higher fatality rates (P < 0.001). Significant differences were also found for the types of injuries sustained for head, extremity, trunk, and other injuries (P < 0.001), and for internal injuries (P < 0.01. Admission rates also dropped for both motor vehicle collisions and motor pedestrian collisions across the 9-year period (P < 0.001) but remained stable for NATs. CONCLUSION: In this study population, more severe injuries, higher mortality rates, and longer hospital stays were observed in pediatric NAT compared with those sustained through vehicular means. Furthermore, we observed statistically significant declines in motor vehicle-related injuries compared with NAT. PMID- 28885392 TI - The Effect of External Thermomechanical Stimulation and Distraction on Reducing Pain Experienced by Children During Blood Drawing. AB - This study aimed to investigate the sole and combined effects of external thermomechanical stimulation and distraction in pain relief of children during blood drawing.This is a randomized clinical trial. The sample consisted of 218 children aged 6 to 12 years who were randomly assigned to 4 groups: group 1 received no intervention, group 2 received external thermomechanical stimulation using Buzzy, group 3 received distraction via DistrACTION Cards, and group 4 received a combination of both external thermomechanical stimulation and distraction. Preprocedural anxiety was assessed through parents' and observers' observations using the Children's Anxiety and Pain Scale. Children's pain levels were assessed by themselves, observers, and parents, as reported using the Faces Pain Scale-Revised. Preprocedural anxiety did not differ significantly (P > 0.05). When the 3 study groups were compared with the control group, all 3 groups had significantly lower pain levels than the control group (P < 0.001). The lowest pain level was measured in the combined condition (Buzzy and DistrACTION Cards). The mean score of the device group was lower than the distraction group. PMID- 28885393 TI - The association between red cell distribution width, erythropoietin levels, and coronary artery disease. AB - BACKGROUND: Red cell distribution width (RDW) is a cardiac marker for risk stratification and prognostic evaluation of coronary artery disease (CAD); however, the underlying mechanism remains unclear. Erythropoietin (EPO), a crucial factor affecting erythropoiesis, has been reported to be a protective molecule regulating the process of myocardial ischemia and relevant damage. No study has as yet reported the relationship between RDW and endogenous EPO in CAD patients. This cross-sectional study aimed to establish the association between endogenous EPO levels and increases in RDW in CAD patients. PATIENTS AND METHODS: Two hundred participants who underwent coronary arteriography were recruited from July 2015 to October 2015. The participants were divided into CAD and non-CAD groups on the basis of angiography diagnosis. Demographic data were obtained through personal interviews and general clinical methods. RESULTS: RDW and EPO levels in the CAD group were higher than those in the non-CAD group. The correlation between RDW and EPO levels was statistically significant among CAD patients (r=0.411, P<0.001). The increases in EPO and RDW were related to the prevalence of CAD. The levels of RDW were correlated to endogenous EPO levels in CAD patients. CONCLUSION: Increased EPO and RDW might be risk factors for CAD. Endogenous EPO levels are associated with increases in RDW in CAD patients. PMID- 28885394 TI - Pleiotrophin levels are associated with improved coronary collateral circulation. AB - OBJECTIVES: Elucidation of the underlying mechanisms of angiogenesis and arteriogenesis in coronary collateral formation is necessary for new therapies. Pleiotrophin is a secreted multifunctional cytokine and associated with the formation of functional cardiovascular neovascularization in a series of experimental animal models. We aimed to evaluate the serum levels of pleiotrophin in patients with chronic total coronary artery occlusion and poor or good collateral development. METHODS: We included 88 consecutive patients (mean age of the entire population: 63.7+/-12.1 years, 68 male patients) with stable angina pectoris who underwent coronary angiography and had chronic total occlusion in at least one major coronary artery. Collateral grading was performed according to the Rentrop classification. After grading, patients were divided into poor collateral circulation (Rentrop grade 0 and 1) and good collateral circulation (Rentrop grades 2 and 3) groups. Serum pleiotrophin levels were measured using a commercial human ELISA kit. RESULTS: Fifty-eight patients had good and 30 patients had poor coronary collaterals. The good collateral group had higher serum pleiotrophin levels than the poor collateral group (690.1+/-187.9 vs. 415.3+/-165.9 ng/ml, P<0.001). Pleiotrophin levels were higher with higher Rentrop grade (P<0.001). In multivariate analysis, increased pleiotrophin was associated independently with good collateral development (odds ratio: 1.007; confidence interval: 1.003-1.012; P=0.002). CONCLUSION: This study showed that increased serum pleiotrophin levels are associated with better developed coronary collateral circulation. Further studies are needed to better understand the relationship. PMID- 28885395 TI - Recurrent myocardial infarction in an aneurysmal coronary artery managed with stent grafts. PMID- 28885396 TI - A prospective multicenter cohort study of cutaneous melanoma: clinical staging and potential associations with HIF-1alpha and VEGF expressions. AB - Melanoma is a highly prevalent cancer that is associated with substantial mortality. Although clinical staging procedures can serve as relatively robust prognostic indicators, we aimed to determine whether assessments of the abundance of hypoxia inducible factor-1alpha (HIF-1alpha) or vascular endothelial growth factor (VEGF) in postexcisional melanoma tumor tissues may enable more accurate determination of tumor aggressiveness. We carried out a multicenter prospective study, in which we systematically evaluated 376 consecutive patients diagnosed with melanoma, and performed histochemical assessments for both HIF-1alpha and VEGF immunoreactivity in the tumor biopsies. Multivariate analyses showed that higher HIF-1alpha expression, but not high VEGF, were associated significantly and independently with increased tumor aggressiveness as derived from several well-established aggressiveness criteria. A limitation of this study was that this was a descriptive prospective study lacking a post-hoc verification arm. Thus, the presence of increased numbers of positively labeled HIF-1alpha cells in melanoma tumors may potentially serve as an indicator of tumor phenotype and prognosis, and accordingly guide therapy. PMID- 28885397 TI - Accuracy of Endometrial Sampling in Endometrial Carcinoma: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To assess the agreement between preoperative endometrial sampling and final diagnosis for tumor grade and subtype in patients with endometrial carcinoma. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane library were searched from inception to January 1, 2017, for studies that compared tumor grade and histologic subtype in preoperative endometrial samples and hysterectomy specimens. METHODS OF STUDY SELECTION: In eligible studies, the index test included office endometrial biopsy, hysteroscopic biopsy, or dilatation and curettage; the reference standard was hysterectomy. Outcome measures included tumor grade, histologic subtype, or both. TABULATION, INTEGRATION, AND RESULTS: Two independent reviewers assessed the eligibility of the studies. Risk of bias was assessed (Quality Assessment of Diagnostic Accuracy Studies). A total of 45 studies (12,459 patients) met the inclusion criteria. The pooled agreement rate on tumor grade was 0.67 (95% CI 0.60-0.75) and Cohen's kappa was 0.45 (95% CI 0.34-0.55). Agreement between hysteroscopic biopsy and final diagnosis was higher (0.89, 95% CI 0.80-0.98) than for dilatation and curettage (0.70, 95% CI 0.60-0.79; P=.02); however, it was not significantly higher than for office endometrial biopsy (0.73, 95% CI 0.60-0.86; P=.08). The lowest agreement rate was found for grade 2 carcinomas (0.61, 95% CI 0.53-0.69). Downgrading was found in 25% and upgrading was found in 21% of the endometrial samples. Agreement on histologic subtypes was 0.95 (95% CI 0.94-0.97) and 0.81 (95% CI 0.69-0.92) for preoperative endometrioid and nonendometrioid carcinomas, respectively. CONCLUSION: Overall there is only moderate agreement on tumor grade between preoperative endometrial sampling and final diagnosis with the lowest agreement for grade 2 carcinomas. PMID- 28885398 TI - Trends in Seeing an Obstetrician-Gynecologist Compared With a General Physician Among U.S. Women, 2000-2015. AB - OBJECTIVE: To assess trends in the percentage of U.S. women who visit an obstetrician-gynecologist (ob-gyn) and the percentage who visit a general physician (general practitioner, family medicine, and internist). METHODS: We used data from the 2000-2015 National Health Interview Surveys, cross-sectional nationally representative surveys, to identify the percentage of U.S. women who have visited an ob-gyn and the percentage who have visited a general physician during the preceding 12 months. Unadjusted percentages, and percentages adjusted for sociodemographic and health factors, were entered into joinpoint regressions to assess unadjusted and adjusted trends over time. RESULTS: The adjusted percentage of U.S. women who saw a general physician during the preceding 12 months did not significantly change from 2000 to 2015, ranging from 70.1% in 2007 to 74.2% in 2003 (P>.05 for trend). However, although the adjusted percentage that saw an ob-gyn in the preceding 12 months did not change from 2000 to 2003 or 2007-2011 (P>.05), it declined from 45.0% to 41.2% between 2003 and 2007 and from 41.8% to 38.4% between 2011 and 2015 (P<.001 for trends). The adjusted percentage that saw both an ob-gyn and a general physician was 32.4% in 2000, reaching as high as 35.2% in 2003, but then declined to 29.8% in 2015 (P<.001 for trend). Unadjusted results were similar. CONCLUSION: The percentage of women who visit an ob-gyn has declined since 2000. To assure high-quality and coordinated care, physicians should identify whether women see both health care provider types or only one to help assure that all recommended services are being offered. PMID- 28885399 TI - Clinical Risk Factors Associated With Peripartum Maternal Bacteremia. AB - OBJECTIVE: To evaluate risk factors associated with maternal bacteremia in febrile peripartum women. METHODS: We performed a case-control study of women with fevers occurring between 7 days before and up to 42 days after delivery of viable neonates at two academic hospitals. Women with positive blood cultures were matched with the next two febrile women meeting inclusion criteria with negative blood cultures in the microbiology data without other matching parameters. We compared maternal and neonatal characteristics and outcomes between women in the case group and those in the control group with univariate analysis. We then used logistic regression to examine the association between clinical characteristics and maternal bacteremia. RESULTS: After excluding blood cultures positive only for contaminants, we compared 115 women in the case group with 285 in the control group. Bacteremic women were more likely to experience their initial fever during labor (40.9% compared with 22.8%, P<.01) and more likely to have fever at or above 102 degrees F (62.6% compared with 31.6%, P<.01). These associations persisted in the adjusted analysis: multiparity (adjusted odds ratio [OR] 1.75, 95% CI 1.07-2.87), initial fever during labor (adjusted OR 2.82, 95% CI 1.70-4.70), and fever at or above 102 degrees F (adjusted OR 3.83, 95% CI 2.37-6.19). In an analysis restricted to neonates whose mothers had initial fevers before or in the immediate 24 hours after delivery, neonates born to women in the case group had higher rates of bacteremia compared with those born to women in the control group (9.0% compared with 1.3%, P<.01). Eight of the nine bacteremic neonates born to bacteremic mothers (89%) grew the same organism as his or her mother in blood culture. CONCLUSION: Maternal bacteremia is associated with multiparity, initial fever during labor, and fever at or above 102 degrees F; however, 37.5% of cases of bacteremia occurred in women with maximum fevers below this threshold. Obstetricians should maintain a heightened suspicion for an infectious source of fever in women with these clinical characteristics. PMID- 28885400 TI - Internal Validation of the Sepsis in Obstetrics Score to Identify Risk of Morbidity From Sepsis in Pregnancy. AB - OBJECTIVE: To prospectively validate the Sepsis in Obstetrics Score, a pregnancy specific sepsis scoring system, to identify risk for intensive care unit (ICU) admission for sepsis in pregnancy. METHODS: This is a prospective validation study of the Sepsis in Obstetrics Score. The primary outcome was admission to the ICU for sepsis. Secondary outcomes included admission to a telemetry unit and time to administration of antibiotic therapy. We evaluated test characteristics of a predetermined score of 6 or greater. RESULTS: Between March 2012 and May 2015, 1,250 pregnant or postpartum women presented to the emergency department and met systemic inflammatory response syndrome criteria. Of those, 425 (34%) had a clinical suspicion or diagnosis of an infection, 14 of whom (3.3%) were admitted to the ICU. The Sepsis in Obstetrics Score had an area under the curve of 0.85 (95% CI 0.76-0.95) for prediction of ICU admission for sepsis. This is within the prespecified 15% margin of the area under the curve of 0.97 found in the derivation cohort. A score of 6 or greater had a sensitivity of 64%, specificity of 88%, positive predictive value of 15%, and negative predictive value of 98.6%. Women with a score 6 or greater were more likely to be admitted to the ICU (15% compared with 1.4%, P<.01), admitted to a telemetry unit (37.3% compared with 7.2%, P<.01), and have antibiotic therapy initiated (90% compared with 72.9%, P<.01), initiated more quickly (3.2 compared with 3.7 hours, P=.03), although not within 1 hour (5.6 compared with 3.4%, P=.44). CONCLUSION: The Sepsis in Obstetrics Score is a validated pregnancy-specific score to identify risk of ICU admission for sepsis with the threshold score of 6 having a negative predictive value of 98.6%. Adherence to antibiotic administration guidelines is poor. PMID- 28885401 TI - Inpatient Postpartum Long-Acting Reversible Contraception: Care That Promotes Reproductive Justice. AB - Inpatient insertion of long-acting reversible contraceptives (LARC) (intrauterine devices and implants) is increasingly offered to women immediately after childbirth. Enthusiasm for this approach stems from robust safety, effectiveness, and cost-effectiveness data and responsiveness to women's needs and preferences. Although clinical evidence for immediate postpartum LARC is well-established, the ethical implications of enhancing access to this care have not been fully considered. Contraceptive policies and practices often embody a tension between fostering liberal availability and potentially coercive promotion of some methods. Historical contraceptive policies and contemporary disparities in LARC use point to the need to consider whether health policies and health care practices support all women's reproductive wishes. Immediate postpartum LARC services need to be designed and implemented with the goal of ensuring autonomy and equity in postpartum contraceptive care. To this end, these services should include strategic plans to promote universal availability, prevent coercion, and enable device removal. PMID- 28885402 TI - Tranexamic Acid for the Management of Obstetric Hemorrhage. AB - Obstetric hemorrhage remains the most common cause of maternal mortality worldwide. It is believed that increased fibrinolytic activity, secondary to release and activation of endothelial tissue plasminogen activator, is involved in its pathogenesis. Tranexamic acid (TXA), an antifibrinolytic agent, has been shown to be beneficial in trauma patients if used within 3 hours of injury. A recent large randomized controlled trial showed that TXA given to hemorrhaging women within 3 hours after delivery was associated with decreased risk of death resulting from bleeding with no increase in thromboembolic complications. Limited evidence suggests that prophylactic TXA reduces blood loss at the time of delivery and decreases transfusion rates in the obstetric population. Tranexamic acid appears to be a safe and effective option in the treatment of obstetric hemorrhage. In addition, the limited available evidence supports the need for a well-designed adequately powered clinical trial to test its benefit as a prophylactic agent. PMID- 28885403 TI - Postpartum Management After Obstetric Anal Sphincter Injuries. AB - A 26-year-old woman, gravida 1 para 1, experiences a severe perineal laceration that extends through the rectal mucosa after a vaginal delivery. She asks you, "What can be done to optimize my recovery?" PMID- 28885404 TI - What Is New in Obstetrics and Gynecology Simulation?: Best Articles From the Past Year. AB - This month we focus on obstetrics and gynecology simulation. Dr. Burda discusses four recent publications, which are concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 28885405 TI - Human Papillomavirus Vaccine: More Good News. PMID- 28885406 TI - Trends in Obstetrician-Gynecologist Visits. PMID- 28885407 TI - Value-Based Medical Education in Obstetrics and Gynecology: A Paradigm Shift. PMID- 28885408 TI - Connect the Dots-October 2017. PMID- 28885409 TI - A Plea for MERSQI: The Medical Education Research Study Quality Instrument. AB - OBJECTIVE: To describe the quality of educational scholarship presented at a large national conference of obstetrics and gynecology educators. METHODS: We reviewed Council on Resident Education in Obstetrics and Gynecology-Association of Professors of Gynecology and Obstetrics annual meeting abstracts from 2015 and 2016, published as supplements to Obstetrics & Gynecology. For this uncontrolled observational study, abstracts were reviewed and scored using the Medical Education Research Study Quality Instrument (MERSQI). Comparisons between types of submissions (oral presentations or posters), origin of the report (academic or community), setting (undergraduate, graduate, postgraduate), and focus of the study (tool development or evaluation) were made. Abstracts from award-winning presentations and full manuscripts were compared with the remaining abstracts. One- and two-tailed Student t tests with a two-sample unequal variance (heteroscedastic) test were performed with a significance threshold of P<=.05. RESULTS: One hundred eighty-six abstracts and articles were available, with 101 posters and 77 oral presentations that could be scored in all six of the MERSQI domains. The average MERSQI score was 9.05 (+/-1.90) with scores ranging from 5 to 13.5 (median 9). Abstracts from full-text articles scored more than 1 point higher than other abstracts (10.2 compared with 9.0, P<.001, Cohen's d=0.72). Statistically significant smaller magnitude differences were found comparing tool development with evaluation, academic with community studies, and for award with nonaward winners. No differences were found comparing oral and poster presentations. CONCLUSION: The quality of educational scholarship presented at a national meeting of obstetrics and gynecology educators falls within the published range for other specialties. The MERSQI scoring system is a useful method for tracking and benchmarking the quality of medical education scholarship in obstetrics and gynecology. PMID- 28885410 TI - Distressing Sexual Function at Midlife: Unmet Needs, Practical Diagnoses, and Available Treatments. AB - Female sexual dysfunction (FSD) is characterized as chronic sexual symptoms that manifest with personal distress in the domains of desire, arousal, orgasm, and pain. Extensive epidemiologic evidence estimates that almost 50% of perimenopausal and postmenopausal women experience FSD. Screening for FSD is not readily conducted and patient-physician discussion of sexuality is limited by the lack of physician training on the topic and by the patient-held belief that sexual issues are not medical in nature. The purpose of this commentary is to provide clinicians with a framework to approach the discussion of FSD, to clinically identify FSD through patient symptoms and physical signs, and to manage FSD in perimenopausal and postmenopausal patients with the available U.S. Food and Drug Administration-approved and off-label treatments. Particular attention will be paid to FSD with common midlife onset including vulvovaginal atrophy, vulvodynia, and hypoactive sexual desire disorder. Although evaluating FSD can be a challenge, triaging symptoms by addressing pain before desire and arousal will improve patient outcomes and greatly simplify FSD management. PMID- 28885411 TI - Improvement in Outcomes of Major Obstetric Hemorrhage Through Systematic Change. AB - OBJECTIVE: To report the outcomes over 14 years of sustained systematic institutional focus on the care of women with major obstetric hemorrhage, defined as estimated blood loss greater than 1,500 mL. METHODS: A retrospective cohort study of women with major obstetric hemorrhage at our hospital from 2000 to 2014 compares baseline conditions (age, multiparity, prior cesarean delivery, morbidly adherent placenta), morbidity (lowest mean temperature, lowest mean pH, coagulopathy, hysterectomy), and mortality among three time periods (period 1=January 2000 to December 2001, period 2=January 2002 to August 2005, period 3=September 2005 to December 2014). We also describe the systematic changes that helped to sustain our improved outcomes. RESULTS: During the three time periods, there were 5,811, 12,912, and 38,971 births; the rate of major obstetric hemorrhage increased over these periods: 2.1, 3.8 and 5.3 cases per 1,000 births, respectively. Two deaths from hemorrhage occurred in period 1 and none thereafter. Among women who experienced massive hemorrhage, morbidity significantly improved in each successive period: median lowest pH increased from 7.23 to 7.34 to 7.35 (periods 2 and 3 significantly higher than period 1), median lowest maternal temperature ( degrees C) improved, 35.2 to 36.1 to 36.4 (all difference significant), and the rate of coagulopathy decreased, 58.3% to 28.6% to 13.2% (period 3 significantly lower than periods 1 and 2) (all P values <.001). Peripartum hysterectomies were more frequent and more frequently planned over time rather than urgent in each successive period: 0 of 6 to 6 of 18 (33%) to 31 of 64 (48.4%) (P=.044). During period 3, we reorganized the obstetric rapid response team, instituted a massive transfusion protocol and use of uterine balloon tamponade, and promoted a culture of safety in two ways-through more intensive education regarding hemorrhage and escalation (encouraging all staff to contact senior leaders). CONCLUSION: A sustained level of patient safety is achievable when treating major obstetric hemorrhage, as shown by a progressive decrease in morbidity despite increasing rates of hemorrhage. PMID- 28885412 TI - Outcomes Associated With a Five-Point Surgical Site Infection Prevention Bundle in Women Undergoing Surgery for Ovarian Cancer. AB - OBJECTIVE: To identify risk factors for surgical site infection and to define rates associated with cytoreductive surgery before and after implementation of an infection prevention bundle. METHODS: We conducted a prospective quality improvement study. Patients who underwent ovarian, fallopian tube, or peritoneal cancer cytoreductive surgery at an academic tertiary care center from April 2014 to April 2016 were prospectively enrolled. Patient demographics, surgical variables, and surgical site infection rates were compared with a historical cohort after introduction of a 5-point infection prevention bundle, including: 1) preoperative and intraoperative skin preparation with 4% chlorhexidine and intraoperative vaginal preparation with 4% chlorhexidine; 2) preoperative use of oral antibiotics and mechanical bowel preparation; 3) appropriate timing of intraoperative antibiotics; 4) adoption of enhanced sterile surgical techniques for colon procedures and incisional closure; and 5) perioperative incision management. RESULTS: During the study period, 219 women underwent surgery: 91 prebundle and 128 treated in the postbundle period. Stage, body mass index, proportion of patients undergoing colon or upper abdominal surgery, and estimated blood loss were not different between the cohorts. Overall, the surgical site infection rate prebundle was 18 (20%); this was reduced to four (3%) postbundle (odds ratio [OR] 0.13, 95% CI 0.037-0.53; P<.001). Patients who underwent a colon resection prebundle had an infection rate of 14 (33%) compared with three (7%) in the postbundle group (OR 0.14, 95% CI 0.037-0.53; P<.001). Additionally, rates of surgical site infection-related hospital readmission were also lower in the postbundle (4/128 [3%]) compared with the prebundle group (12/91 [13%]; P=.005). CONCLUSION: Infection is common after ovarian cancer cytoreductive surgery. Implementation of a 5-point surgical site infection prevention bundle in women undergoing ovarian cancer operations was associated with dramatically decreased infection rates and lower hospital readmission rates. PMID- 28885413 TI - Change in Human Papillomavirus Prevalence Among U.S. Women Aged 18-59 Years, 2009 2014. AB - OBJECTIVE: To examine changes in prevalence of vaginal human papillomavirus (HPV) between 2009-2010 and 2013-2014 among both vaccinated and unvaccinated U.S. women. METHODS: We evaluated HPV prevalence among women 18-59 years old using cross-sectional survey data from three different cycles of the National Health and Nutrition Examination Survey. Data were stratified into four age groups (18 26, 27-34, 35-44, and 45-49 years) to examine trends over time among women of different ages in the postvaccine era. Multivariable analyses, which controlled for descriptive variables, were used to examine the prevalence of quadrivalent vaccine-type HPV by vaccination status. RESULTS: We observed a significant decrease in the prevalence of vaccine-type HPV among women 18-59 years of age from 2009-2010 to 2013-2014. This decline was only significant in those 18-26 years old when the sample was stratified into the four age groups. Among vaccinated 18-26 year olds, HPV prevalence remained low from 2009-2010 (3.9%) to 2013-2014 (2.0%; prevalence ratio 0.51, 95% CI 0.18-1.46). Unvaccinated women 18 26 years old also demonstrated a significant decrease over time from 19.5% in 2009-2010 to 9.7% in 2013-2014 (prevalence ratio 0.44, 95% CI 0.22-0.91). Prevalence did not significantly change among unvaccinated women 26 years old or older. CONCLUSIONS: The decline in HPV infections among unvaccinated 18- to 26 year-old women suggests that young women in the United States are beginning to benefit from herd immunity resulting from the introduction of the HPV vaccine. PMID- 28885414 TI - Urinary Symptoms and Their Associations With Urinary Tract Infections in Urogynecologic Patients. AB - OBJECTIVE: To assess urinary symptoms associated with urinary tract infection (UTI) in a urogynecologic population of women. METHODS: In this cohort study, we enrolled 150 urogynecologic patients who completed the validated UTI Symptom Assessment questionnaire and contributed transurethral catheterized urine samples. The primary measure (UTI diagnosis) was defined in three ways. Self report (a nonculture-based UTI diagnosis) was defined by a yes or no response to the query "Do you think you have a UTI?" Two culture-based UTI diagnoses also were analyzed: standard urine culture (10 colony-forming units [CFU]/mL or greater) and enhanced quantitative urine culture (10 CFU/mL or greater) of any uropathogen. Statistical analyses were performed on patient demographics and urinary symptom prevalence among patient groups. RESULTS: Although the presence of the urinary symptoms of frequency and urgency (respectively) differ somewhat between UTI-positive and UTI-negative women (self-report [P=.005 and P<.001], standard urine culture [P=.038 and P=.044], or enhanced quantitative urine culture [P=.059 and P=.098]), the presence of dysuria (pain or burning) during urination was significantly more prevalent in UTI-positive women for all UTI definitions (self-report P<.001, standard urine culture P<.001, and enhanced quantitative urine culture P=.010). Furthermore, women reporting dysuria had higher severity and bother scores for all other urinary symptoms assessed by the UTI Symptom Assessment questionnaire compared with women not reporting dysuria (frequency P=.001, urgency P=.006, dysuria P<.001). CONCLUSION: Our findings show that, in women seeking urogynecologic care, the presence of frequency and urgency of urination does not confirm a culture-based UTI diagnosis. Instead, clinicians can more readily detect UTI using the presence of dysuria, which more effectively discriminates UTI-positive and UTI-negative individuals, regardless of the culture-based method used to diagnose UTI. PMID- 28885415 TI - Interactive Pelvic Anatomy Model: A Tool for Teaching Basic Pelvic Anatomy. AB - BACKGROUND: A knowledge deficit of pelvic anatomy has been noted in obstetrics and gynecology residents. In this article, we introduce an innovative anatomic model that uses readily accessible and reusable materials to simulate and teach anatomic relationships in the female pelvis. INSTRUMENT: Our anatomic model is a reusable and cost-effective modification of an existing pelvic model. We used felt fabric pieces with hook-and-loop fasteners to simulate the pelvic floor, perineum, and surrounding musculature as they attach to corresponding sites on a standard bony pelvis. Our design incorporates the relationship of the ureter and major blood vessels in the pelvis by using yarn and ribbon. By allowing the student to build the anatomy of the pelvis piece by piece, the model provides the student a hands-on illustration of anatomic relationships in three dimensions. EXPERIENCE: At our institution, both learners and faculty have positively evaluated our model. We have used it to teach residents and fourth-year medical students surgically relevant anatomy. It is currently being evaluated as an addition to standard anatomy lectures in medical student clerkships. CONCLUSION: Our model introduces an innovative design that uses inexpensive and reusable materials. Residents, faculty, and student learners at our institution have positively received the model. PMID- 28885416 TI - Reducing False-Positive Pregnancy Test Results in Patients With Cancer. AB - OBJECTIVE: To assess whether the use of a laboratory test specific for intact human chorionic gonadotropin (hCG) would reduce the number of false-positive pregnancy test results. METHODS: From October 21, 2014, to January 20, 2015, and April 1, 2015, to June 2, 2015, all serum samples sent for pregnancy screening at a large cancer center with a value of 5 milli-international units/mL or greater total beta-hCG were frozen and stored and then retested using intact hCG reagent. We compared the accuracy of total beta-hCG and intact hCG results for the diagnosis of clinically confirmed pregnancy. A negative test was defined as 14 milli-international units/mL or less, our current institutional cutoff. We also assessed a cutoff of less than 5 milli-international units/mL, a historical cutoff to rule out pregnancy. RESULTS: We performed intact hCG testing on 64 patient samples, of which 34 had originally resulted positive when tested for total beta-hCG. These included 21 cases of clinically confirmed pregnancy and 13 false-positive cases. No women were pregnant when their intact hCG concentration was 14 milli-international units/mL or less, and all pregnancies were detected at and above this concentration. Intact hCG reduced the number of false-positive pregnancy test results from 13 to 1, a 92% reduction (95% CI 64-99%), corresponding to a reduction in the false-positive rate from 38% (95% CI 22-56%) to 3% (95% CI 1-15%). CONCLUSION: The use of intact hCG reagent in patients with cancer reduces the rate of false-positive pregnancy test results without increasing the rate of false-negative test results. PMID- 28885417 TI - Association of Nonsteroidal Antiinflammatory Drugs and Postpartum Hypertension in Women With Preeclampsia With Severe Features. AB - OBJECTIVE: To estimate whether nonsteroidal antiinflammatory drugs (NSAIDs) are associated with persistent postpartum hypertension in a cohort of women with preeclampsia and severe features. METHODS: We conducted a retrospective cohort study at a single, tertiary center from January 2013 to December 2015. All women diagnosed with severe preeclampsia who remained hypertensive for greater than 24 hours after delivery were included. The primary outcome was the rate of persistent postpartum hypertension, defined as systolic blood pressure 150 mm Hg or greater or diastolic 100 mm Hg or greater (or both), on two occasions, at least 4 hours apart. Secondary outcomes included severe maternal morbidity: pulmonary edema, renal dysfunction, stroke, eclampsia, and intensive care unit admission. Additional outcomes included length of postpartum hospital stay, receipt of narcotics, and hospital readmission. Multivariable logistic regression was performed to adjust for confounders. Adjusted odds ratios (ORs) are reported for applicable study outcomes. RESULTS: Of the 399 women with severe preeclampsia, 324 (81%) remained hypertensive 24 hours after delivery. Two hundred forty-three (75%) received NSAIDs (either ibuprofen or ketorolac) and 81 (25%) did not. After multivariable logistic regression, the likelihood of reaching a blood pressure of 150 mm Hg systolic or 100 mm Hg diastolic (or both), on two occasions, at least 4 hours apart, was similar between those who received NSAIDs compared with those who did not (70% compared with 73%; adjusted OR 1.1, 95% CI 0.6-2.0). Similarly, puerperal occurrence of pulmonary edema (3% compared with 10%; OR 4.4, 95% CI 1.5-13.1), renal dysfunction (5% compared with 8%; OR 1.7, 95% CI 0.6-4.8), eclampsia (1% compared with 0%; P=.34), or intensive care unit admission (3% compared with 8%; OR 2.4, 95% CI 0.8-7.1) was similar between the groups. There were no differences in the rate of narcotic use (89% compared with 75%; adjusted OR 0.6 95% CI 0.18-1.70). CONCLUSION: In this cohort of women with preeclampsia and severe features before delivery, NSAIDs were not associated with increased rates of persistent postpartum hypertension. PMID- 28885419 TI - Competency-Based Objectives in Global Underserved Women's Health for Medical Trainees. AB - The Association of Professors of Gynecology and Obstetrics Committee on Global Health developed an inclusive definition of global women's health and competency based objectives that reflected work internationally, as well as with U.S. vulnerable and underserved populations, such as refugee and immigrant populations or those who would otherwise have compromised access to health care. The knowledge, skill, and attitude-based competencies required to fulfill each learning objective were mapped to the Accreditation Council for Graduate Medical Education Outcomes Project's educational domains and the Consortium of Universities for Global Health competency domains. The proposed global women's health definition and competency-based learning objective framework is a first step in ensuring quality standards for educating trainees to address global women's health needs. By proposing these objectives, we hope to guide future program development and spark a broader conversation that will improve health for vulnerable women and shape educational, ethical, and equitable global health experiences for medical trainees. PMID- 28885418 TI - Autoimmune Progesterone Dermatitis Presenting as Stevens-Johnson Syndrome. AB - BACKGROUND: Autoimmune progesterone dermatitis is an uncommon disease presenting with cyclical skin eruptions corresponding with the menstrual cycle luteal phase. Because symptoms are precipitated by rising progesterone levels, treatment relies on hormone suppression. CASE: A 22-year-old nulligravid woman presented with symptoms mistaken for Stevens-Johnson syndrome. A cyclic recurrence of her symptoms was noted, and the diagnosis of autoimmune progesterone dermatitis was made by an intradermal progesterone challenge. After 48 months, she remained refractory to medical management and definitive surgical treatment with bilateral oophorectomy was performed. CONCLUSION: Autoimmune progesterone dermatitis is a challenging diagnosis owing to its rarity and variety of clinical presentations. Treatment centers on suppression of endogenous progesterone and avoidance of exogenous triggers. When these modalities fail, surgical management must be undertaken. PMID- 28885420 TI - A Missed Opportunity for U.S. Perinatal Human Immunodeficiency Virus Elimination: Pre-exposure Prophylaxis During Pregnancy. AB - OBJECTIVE: To estimate the proportion of women at increased risk of sexual human immunodeficiency virus (HIV) acquisition during pregnancy in a high HIV incidence urban setting to identify those who may be eligible for pre-exposure prophylaxis. METHODS: We conducted a retrospective cohort study of women who received prenatal care at a large academic center in 2012. Univariable analyses and multiple logistic regression models were built to identify correlates for pre-exposure prophylaxis eligibility. RESULTS: Among 1,637 pregnant women, mean age was 27.6 years (SD 6.3), 59.7% were African American, and 56.0% were single. Based on the Centers for Disease Control and Prevention's guidelines, more than 10% of women were at increased risk for HIV acquisition during pregnancy and eligible for pre exposure prophylaxis. Younger [adjusted odds ratio (OR) 0.9/1-year increase, 95% CI 0.8-0.9], single (adjusted OR 2.4, 95% CI 1.2-4.8), African American women (adjusted OR 3.3, 95% CI 1.6-6.7) with higher parity (adjusted OR 1.3/one-child increase, 95% CI 1.1-1.5), and who smoked regularly during pregnancy (adjusted OR 1.8, 95% CI 1.0-3.0) had greater odds of being eligible for pre-exposure prophylaxis at any time during pregnancy. CONCLUSIONS: Pregnancy is a vulnerable period during which some heterosexual women in urban settings have a high risk for HIV acquisition and stand to benefit from pre-exposure prophylaxis. PMID- 28885421 TI - Evidence-Based Bundles and Cesarean Delivery Surgical Site Infections: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To estimate the association of implementation of evidence-based bundles with surgical site infection rates after cesarean delivery. DATA SOURCES: We searched MEDLINE through PubMed, EMBASE, Scopus, the Cochrane Database of Systematic Reviews, Google Scholar, and ClinicalTrials.gov. METHODS OF STUDY SELECTION: We searched electronic databases for randomized controlled trials and observational studies comparing evidence-based infection prevention bundles for cesarean delivery, defined as implementation of three or more processes proven to prevent surgical site infection such as chlorhexidine skin preparation, antibiotic prophylaxis, and hair clipping, with usual care. The primary outcome was overall surgical site infection, defined using Centers for Disease Control and Prevention's National Healthcare Safety Network criteria. Secondary outcomes were superficial or deep surgical site infection and endometritis. Quality of studies and heterogeneity were assessed using validated measures. Pooled relative risks (RRs) with 95% CIs were calculated using random-effects models. Numbers needed to treat were estimated for outcomes with significant reduction. TABULATIONS, INTEGRATION, AND RESULTS: We found no randomized controlled trials. Fourteen preintervention and postintervention studies met inclusion criteria. Eight were full-text articles, and six were published abstracts. Quality of most of the primary studies was adequate with regard to the intervention, but modest in terms of implementation. The rate of surgical site infection was significantly lower after implementing an evidence-based bundle (14 studies: pooled rates 6.2% baseline compared with 2.0% intervention, pooled RR 0.33, 95% CI 0.25-0.43, number needed to treat=24). Evidence-based bundles were also associated with a lower rate of superficial or deep surgical site infection (six studies: pooled rate 5.9% baseline compared with 1.1% intervention, pooled RR 0.19, 95% CI 0.12 0.32, number needed to treat=21). The rate of endometritis was low at baseline and not significantly different after intervention (six studies: pooled rate 1.3% baseline compared with 0.9% intervention, pooled RR 0.57, 95% CI 0.31-1.06). CONCLUSION: Evidence-based bundles are associated with a significant reduction in surgical site infection after cesarean delivery. PMID- 28885422 TI - Sitting With Fatima: How Longitudinal Learning Inspired My Passion for Obstetrics and Gynecology. PMID- 28885423 TI - Early Second-Trimester Fetal Growth Restriction and Adverse Perinatal Outcomes. AB - OBJECTIVE: To estimate the risk of adverse perinatal outcomes among women with isolated fetal growth restriction from 17 to 22 weeks of gestation. METHODS: This was a retrospective cohort study of all singleton, nonanomalous pregnancies undergoing ultrasonography to assess fetal anatomy between 17 and 22 weeks of gestation at a single center from 2010 to 2014. After excluding patients with fetal structural malformations, chromosomal abnormalities, or identified infectious etiologies, we compared perinatal outcomes between pregnancies with and without fetal growth restriction, defined as estimated fetal weight less than the 10th percentile for gestational age. Our primary outcome was small for gestational age (SGA) at birth, defined as birth weight less than the 10th percentile. Secondary outcomes included preterm delivery at less than 37 and less than 28 weeks of gestation, preeclampsia, abruption, stillbirth, neonatal death, neonatal intensive care unit admission, intraventricular hemorrhage, need for respiratory support, and necrotizing enterocolitis. RESULTS: Of 12,783 eligible patients, 355 (2.8%) had early second-trimester fetal growth restriction. Risk factors for growth restriction were African American race and tobacco use. Early second-trimester growth restriction was associated with a more than fivefold increase in risk of SGA at birth (36.9% compared with 9.1%, adjusted odds ratio [OR] 5.5, 95% CI 4.3-7.0), stillbirth (2.5% compared with 0.4%, OR 6.2, 95% CI 2.7-12.8), and neonatal death (1.4% compared with 0.3%, OR 5.2, 95% CI 1.6-13.5). Rates of indicated preterm birth at less than 37 weeks of gestation (7.3% compared with 3.3%, OR 2.3, 95% CI 1.5-3.5) and less than 28 weeks of gestation (2.5% compared with 0.2%, OR 10.8, 95% CI 4.5-23.4), neonatal need for respiratory support (16.9% compared with 7.8%, adjusted OR 1.6, 95% CI 1.1-2.2), and necrotizing enterocolitis (1.4% compared with 0.2%, OR 7.7, 95% CI 2.3-20.9) were also significantly higher for those with growth restriction. Rates of preeclampsia, abruption, and other neonatal outcomes were not significantly different. CONCLUSION: Although fetal growth restriction in the early second trimester occurred in less than 3% of our cohort and most of those with isolated growth restriction did not have adverse outcomes, it is a strong risk factor for SGA, stillbirth, neonatal death, and indicated preterm birth. PMID- 28885424 TI - Creating Flexible and Sustainable Work Models for Academic Obstetrician Gynecologists Engaged in Global Health Work. AB - OBJECTIVE: To describe various work models for obstetrics and gynecology global health faculty affiliated with academic medical centers and to identify barriers and opportunities for pursuing global health work. METHODS: A mixed-methods study was conducted in 2016 among obstetrics and gynecology faculty and leaders from seven academic medical institutions in Boston, Massachusetts. Global health faculty members were invited to complete an online survey about their work models and to participate in semistructured interviews about barriers and facilitators of these models. Department chairs and residency directors were asked to participate in interviews. RESULTS: The survey response rate among faculty was 65.6% (21/32), of which 76.2% (16/21) completed an interview. Five department leaders (45.5% [5/11]) participated in an interview. Faculty described a range of work models with varied time and compensation, but only one third reported contracted time for global health work. The most common barriers to global health work were financial constraints, time limitations, lack of mentorship, need for specialized training, and maintenance of clinical skills. Career satisfaction, creating value for the obstetrics and gynecology department, and work model flexibility were the most important facilitators of sustainable global health careers. CONCLUSION: The study identified challenges and opportunities to creating flexible and sustainable work models for academic obstetrics and gynecology clinicians engaged in global health work. Additional research and innovation are needed to identify work models that allow for sustainable careers in global women's health. There are opportunities to create professional standards and models for academic global health work in the obstetrics and gynecology specialty. PMID- 28885426 TI - The Evolution of and Evidence for Opportunistic Salpingectomy. AB - In the absence of significant benefit from either novel therapeutics or screening, the focus of decreasing ovarian cancer incidence and mortality has shifted toward primary prevention. Histopathologic data have demonstrated that up to 70% of ovarian cancers may actually arise from the fallopian tube. This has led to the increased adoption of opportunistic salpingectomy as a tool for ovarian cancer prevention. In turn, the potential surgical risks and ovarian cancer prevention of this emerging practice have generated multiple studies. In this comprehensive review, we address the origins of ovarian cancer, the historical context and recent trends of tubal surgery, the existing population based data on ovarian cancer risk reduction, and provide a detailed review of the evidence on surgical risks of salpingectomy. To date, the safety and ovarian cancer risk reduction evidence sheds a positive light on opportunistic salpingectomy. Although research on this subject has grown substantially in recent years, there remains a paucity of large, prospective studies that examine clinical outcomes. PMID- 28885425 TI - Reducing Pain During Intrauterine Device Insertion: A Randomized Controlled Trial in Adolescents and Young Women. AB - OBJECTIVE: To estimate the effect of a 1% lidocaine paracervical nerve block on pain during intrauterine device (IUD) insertion compared with a sham block in adolescents and young women. METHODS: We conducted a multisite, single-blind, sham-controlled randomized trial in adolescents and young women having a 13.5-mg levonorgestrel IUD inserted. Enrollment occurred at three family planning clinics in Philadelphia, Pennsylvania. Eligible adolescents and young women were aged 14 22 years, nulliparous, not currently or recently pregnant, and English-speaking. Participants were randomized using computer-generated allocation in block sizes of four to receive a 10-mL 1% lidocaine paracervical block or a sham block (1 cm depression of the vaginal epithelium at paracervical block sites with a wooden cotton-tipped applicator). Only patients were blinded. The primary outcome was pain after IUD insertion measured with a 100-mm visual analog scale. Using a two sided t test and assuming a 20-mm difference in visual analog scale scores, a SD of 28 mm, an alpha of 0.05, and 90% power, a sample of 43 participants per group was estimated. RESULTS: Between March 2015 and July 2016, 95 participants enrolled (47 lidocaine block group; 48 sham block group). All were included in the analysis. Forty-four percent were white, 36% black, 65% privately insured, and 79% previously used contraception. The median visual analog scale score after IUD insertion was 30.0 (95% CI 20.0-58.0) in the lidocaine block group and 71.5 (95% CI 66.0-82.0) in the sham block (P<.001). CONCLUSION: A 10-mL 1% lidocaine paracervical nerve block reduces pain during IUD insertion in adolescents and young women compared with a sham block with pressure on the vaginal epithelium. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02352714. PMID- 28885427 TI - Safety of Medical Abortion Provided Through Telemedicine Compared With In Person. AB - OBJECTIVE: To compare the proportion of medical abortions with a clinically significant adverse event among telemedicine and in-person patients at a clinic system in Iowa during the first 7 years of the service. METHODS: We conducted a retrospective cohort study. We analyzed data on clinically significant adverse events (hospital admission, surgery, blood transfusion, emergency department treatment, and death) for all medical abortions performed by telemedicine or in person at a clinic system in Iowa between July 1, 2008, and June 30, 2015. Data on adverse events came from required reporting forms submitted to the mifepristone distributor. We calculated the prevalence of adverse events and 95% CIs comparing telemedicine with in-person patients. The analysis was designed as a noninferiority study. Assuming the prevalence of adverse events to be 0.3%, telemedicine provision was considered to be inferior to in-person provision if the prevalence were 0.6% or higher. The required sample size was 6,984 in each group (one-sided alpha=0.025, power 90%). To explore whether patients with adverse events presented to emergency departments and were not reported, we conducted a survey of the 119 emergency departments in Iowa, asking whether they had treated a woman with an adverse event in the prior year. RESULTS: During the study period, 8,765 telemedicine and 10,405 in-person medical abortions were performed. Forty-nine clinically significant adverse events were reported (no deaths or surgery; 0.18% of telemedicine patients with any adverse event [95% CI 0.11-0.29%] and 0.32% of in-person patients [95% CI 0.23-0.45%]). The difference in adverse event prevalence was 0.13% (95% CI -0.01% to 0.28%, P=.07). Forty-two emergency departments responded to the survey (35% response rate); none reported treating a woman with an adverse event after medical abortion. CONCLUSION: Adverse events are rare with medical abortion, and telemedicine provision is noninferior to in-person provision with regard to clinically significant adverse events. PMID- 28885428 TI - A Brief Prenatal Intervention of Behavioral Change to Reduce the Risk of Maternal Cytomegalovirus: A Randomized Controlled Trial. AB - OBJECTIVE: To estimate the effects of a brief prenatal behavioral intervention on risk behaviors for maternal cytomegalovirus (CMV) infection. METHODS: Women were screened with CMV serology during prenatal care before 20 weeks of gestation and followed for at least 10 weeks. Women without serologic evidence of primary CMV infection were approached. Participants were apprised of serostatus and then randomized 2:1 to either a brief behavioral intervention during their prenatal care visit or to standard care (a brochure). The 7- to 10-minute in-office intervention included a video and hygiene education using motivational interviewing. Participants were then given a reminder calendar to take home and weekly text message reminders. The primary outcome was change in behavioral compliance score on a scale of 0-100. Secondary outcomes included process evaluation and domains of behavior change. A sample size of 180 participants was planned to compare the behavioral compliance score change of at least 15% between intervention and control groups with 80% power and 2.5% two-sided alpha. RESULTS: From April 2013 to October 2014, 197 women were randomized. One hundred eighty seven (96%) had outcome data available. Mean gestational age at screening and randomization was 9 4/7 and 13 6/7 weeks of gestation, respectively. Primary outcome assessment occurred at a mean of 28 4/7 weeks of gestation. Baseline behavioral compliance scores increased modestly in the intervention group (mean: 7-point increase from 80.7 to 87.7, 95% CI 2.4-5.9) compared with the comparison group (mean: 4-point increase from 79.7 to 84.1, 95% CI 5.9-8.4; mean difference in change score: 3.0, 95% CI, 0.8-5.2; P=.007). Those in the intervention group reported change in risk perception related to perceived severity and susceptibility, self-efficacy, and perceived norms (P<.05 for all). CONCLUSION: A brief behavioral intervention delivered in the prenatal care setting was modestly effective at changing behaviors related to CMV infection risk. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01819519. PMID- 28885429 TI - Long-Acting Reversible Contraception Initiation With a 2- to 3-Week Compared With a 6-Week Postpartum Visit. AB - OBJECTIVE: To evaluate whether a department policy changing the scheduling of the postpartum visit from 6 weeks to 2-3 weeks after delivery is associated with higher long-acting reversible contraception initiation at the postpartum visit. METHODS: We conducted a quasiexperimental before-after study to evaluate long acting reversible contraception initiation, specifically an intrauterine device or contraceptive implant, at the postpartum visit between women scheduled for follow-up at 6 weeks (before policy change) and 2-3 weeks after delivery (after policy change). Secondary outcomes included postpartum visit completion, overall contraception initiation at the postpartum visit, overall contraceptive use at 6 months after delivery, and repeat pregnancies by 6 months postpartum. We obtained delivery and postpartum information using the electronic medical record and contacted participants 3 and 6 months after delivery to assess contraception use and repeat pregnancies. RESULTS: We enrolled 586 participants between December 2014 and November 2015, of whom 512 women (256 in each cohort) continued to meet eligibility criteria after delivery. Long-acting reversible contraception initiation rates at the postpartum visit were lower in the 2- to 3-week (16.5%, 95% CI 12.2-21.8) compared with the 6-week group (31.1%, 95% CI 25.2-37.7, P<.01), primarily as a result of patient and health care provider preferences for delaying intrauterine device insertion to a later visit. More women completed a scheduled 2- to 3-week postpartum visit (90.2%, 95% CI 86.0-93.3) compared with a 6-week visit (81.6%, 95% CI 76.4-85.9, P<.01). Deferral of any contraception initiation was higher in the 2- to 3-week group (27.3%, 95% CI 21.9-33.4) compared with the 6-week group (15.8%, 95% CI 11.5-21.4, P<.01), but there were no differences in overall contraceptive use patterns at 6 months postpartum. No intrauterine device perforations or expulsions were observed in women who underwent insertion at 2-3 weeks postpartum. Five pregnancies were reported in each cohort by 6 months after delivery. CONCLUSION: Scheduling a visit at 2-3 weeks after delivery was not associated with increased long-acting reversible contraception initiation at this visit despite higher postpartum visit attendance. PMID- 28885430 TI - Aggressive Angiomyxoma of the Vulva and Bladder. AB - BACKGROUND: Aggressive angiomyxoma is a rare, locally infiltrative tumor, frequently occurring in female patients. Although wide local excision is considered standard therapy, radical surgery may be needed. CASE: A 49-year-old woman presented with an aggressive angiomyxoma involving the vulva and bladder. Given the hormone receptor status and size of the tumor, the patient was initially treated with fulvestrant and goserelin acetate in an attempt to reduce the size of the mass. She was followed up at 1- to 3-month intervals; after 6 months of treatment, owing to increasing size of the mass and worsening symptoms, the decision was made to proceed with radical surgery. CONCLUSION: Although a less radical surgical approach is preferred, radical surgery is possible for treatment of aggressive angiomyxoma when needed. PMID- 28885431 TI - Geographic Comparison of Women in Academic Obstetrics and Gynecology Department Based Leadership Roles. AB - OBJECTIVE: To describe and compare geographic representation of women in obstetrics and gynecology department-based leadership roles across American Congress of Obstetricians and Gynecologists (ACOG) districts and U.S. Census Bureau regions while accounting for the proportion of women practicing in each area. METHODS: We conducted a cross-sectional observational study. To more meaningfully quantify representation of women as leaders in ACOG districts and U.S. Census Bureau regions, we calculated representation ratios-the proportion of department-based leaders who were women divided by the proportion of obstetrician gynecologists who were women. A ratio of 1.0 indicates proportionate representation and less than 1.0 indicates underrepresentation. We calculated 95% CIs to compare representation of women in leadership roles across geographic areas. The gender of major department-based leaders (chair, vice chair, division director) and educational leaders (fellowship, residency, associate residency, medical student clerkship director) was determined from websites. RESULTS: The proportion of department chairs who were women was highest in the West and lowest in the South Census Bureau regions. Representation ratios for women in major department-based leadership roles demonstrated underrepresentation relative to the practicing base nationally and in all four regions. Although women were underrepresented in major department-based leadership throughout the country, there was significantly higher women's representation in major department-based leadership roles in the West (ratio 0.82, 95% CI 0.68-0.99) compared with the Northeast (ratio 0.50, 95% CI 0.42-0.59) and the South (ratio 0.45, 95% CI 0.36 0.57). Similarly, in the division director role, the West (ratio 0.85, 95% CI 0.68-1.1) had significantly higher representation of women compared with the Northeast (ratio 0.50, 95% CI 0.40-0.62). Nationally, women were underrepresented as fellowship directors, proportionately represented as residency program directors, and overrepresented as medical student clerkship directors. CONCLUSION: Representation ratios of women in major department-based leadership roles, which account for the proportion of women practicing in each geographic area, suggest that women were more likely to advance to the department-based leadership roles of chair, vice chair, or division director in the western United States. PMID- 28885432 TI - Throw Out a Lifeline, Someone Is Drifting Away: It Takes a Village to Combat Burnout. AB - The increasing prevalence of professional burnout threatens not only the individual but the community of caregivers and, therefore, our patients. There is a growing body of individual actions that can be taken to reduce or reverse the effect of burnout. However, no amount of individual resolve will be sufficient if we do not create a climate conducive to mutual assistance and support. PMID- 28885433 TI - Put away your microscopes: the ependymoma molecular era has begun. AB - PURPOSE OF REVIEW: To synthesize, integrate, and comment on recent research developments to our understanding of the molecular basis of ependymoma (EPN), and to place this in context with current treatment and research efforts. RECENT FINDINGS: Our recent understanding of the histologically defined molecular entity EPN has rapidly advanced through genomic, transcriptomic, and epigenomic profiling studies. SUMMARY: These advancements lay the groundwork for development of future EPN biomarkers, models, and therapeutics. Our review discusses these discoveries and their impact on our clinical understanding of this disease. Lastly, we offer insight into clinical and research areas requiring further validation, and open questions remaining in the field. PMID- 28885435 TI - Treatment of Metastatic Eyelid Carcinoma. AB - PURPOSE: The aim of this study was to report management and outcomes in patients affected by eyelids carcinomas involving regional lymph nodes. METHODS: We have retrospectively analyzed the data of patients affected by eyelids carcinoma with nodal involvement. The clinical records of 10 patients with malignant eyelid carcinoma and regional nodal metastasis treated between September 2011 and March 2015 have been analyzed. RESULTS: The study included 5 women and 5 men (median age 54,5 years; range 37-80 years). The most common tumor was the squamous cell carcinoma (4 cases) followed by sebaceous carcinoma (2 cases): 1 case of epidermoid carcinoma, 1 case of malignant melanoma, 1 case of Merkel carcinoma, and 1 case of basal cell carcinoma. All patients were treated by surgical resection; in 2 cases, orbital exenteration was required. The treatment of regional nodal metastasis consisted of parotidectomy and radical neck dissection followed by radiation therapy. None of the patients developed local recurrence. Three patients died: one, affected by Merkel cell carcinoma, died after 2 months because of metastatic dissemination to the lung; another one, affected by epidermoid carcinoma involving the orbit, died because of liver metastasis; the third one, affected by malignant melanoma, died because of other causes. The follow-up time ranged from 9 to 36 months (median 19.3 months). CONCLUSIONS: Patients affected by advanced malignant eyelid carcinoma need to be strictly controlled because metastasis can develop at least 5 years after surgical treatment. Therapy may include a combination of local surgery, neck dissection, and radiation. PMID- 28885436 TI - Intracranial Foreign Body in a Patient With Paranoid Schizophrenia. AB - Self-inflicted penetrating head injuries in patients with paranoid schizophrenia are an infrequent phenomenon. The authors report on a psychiatric patient who presented with epistaxis. Computed tomography showed a nail passing from the nasal cavity into the frontal lobe. Given the proximity to large intracranial vessels, a craniotomy was performed and the nail was retracted. The patient later reported having hammered the nail into the nasal cavity with the intention to "kill the voice in my head." Despite use of the latest imaging modalities, metal artifacts may have limited the assessment of vascular involvement. Surgical decision-making preventing secondary damage is crucial in them. PMID- 28885437 TI - Cellular Angiofibroma of the Nasopharynx. AB - Angiofibroma is a common tumor of the nasopharynx region but cellular type is extremely rare in head and neck. A 13-year-old boy presented with frequent epistaxis and nasal obstruction persisting for 6 months. According to the clinical symptoms and imaging studies juvenile angiofibroma was suspected. Following angiographic embolization total excision of the lesion by midfacial degloving approach was performed. Histological examination revealed that the tumor consisted of staghorn blood vessels and irregular fibrous stroma. Stellate fibroblasts with small pyknotic to large vesicular nuclei were seen in a highly cellular stroma. These findings identified cellular angiofibroma mimicking juvenile angiofibroma. This article is about a very rare patient of cellular angiofibroma of nasopharynx. PMID- 28885438 TI - A Volumetric and Craniometric Analysis of Cranial Base Differences in Unicoronal Craniosynostosis. AB - BACKGROUND: The authors hypothesized that patients with unicoronal craniosynostosis (UCS) have deviation of the vault, cranial base, and face resulting in significant differences in skull base morphology and segmental cranial vault volume relative to nonaffected controls. METHODS: Unicoronal craniosynostosis patients were collected from the authors' IRB-approved, prospective, craniofacial registry; controls were from a trauma registry. Mimics software was used to compare those with UCS to controls for a series of standardized craniometric angles and distances. A segmented volumetric analysis of anterior, middle, and posterior cranial fossae was performed, as well. RESULTS: The study included 18 patients with UCS and 19 controls. Nearly all angles measured were statistically different in UCS versus controls. Overall cranial vault volume did not differ between UCS and controls (P = 0.250). Three volumetric ratios comparing the synostosed side to the contralateral were significantly less than controls: anterior (0.44 +/- 0.03 versus 0.5 +/- 0.01, P < 0.001), middle (0.45 +/- 0.02 versus 0.5 +/- 0.02, P < 0.001), posterior (0.46 +/- 0.02 versus 0.50 +/- 0.02, P < 0.001). The ratio of total middle volume to total cranial volume was larger in UCS patients versus controls, but the posterior ratio was smaller: anterior (0.13 +/- 0.02 versus 0.12 +/- 0.02, P = 0.545), middle (0.50 +/- 0.05 versus 0.42 +/- 0.04, P = 0.001), posterior (0.37 +/- 0.05 versus 0.45 +/- 0.03, P = 0.001). CONCLUSIONS: This study provides quantitative evidence of the degree of angulation and torsion of the cranial base in UCS and its profound effect on volumetric differences in the cranial vault, with significant restriction on the synostosed side and compensatory expansion on the nonsynostosed side. Future work will focus on the effects of volumetric differences on cerebral architecture and postoperative volumetric changes. PMID- 28885439 TI - Multiple Recurrent Fibromatosis With Cranial Fasciitis Characteristics in a Pediatric Patient. AB - Cranial fasciitis is a rare, rapidly growing, but benign fibroblastic tumor of the skull that generally presents in childhood. Local resection or curettage of the affected bone is generally curative and the tumor is thought not to recur. Cranial fasciitis is distinguished by positive cytoplasmic and nuclear beta catenin staining. Fibromatosis is a clonal myofibroblastic nonmalignant proliferation that generally demonstrates positive nuclear beta-catenin staining. In this report, the authors present a patient with fibromatosis with cranial fasciitis characteristics in a 2.5-month-old boy who has had 7 recurrences (total 8 resections) of this fibroblastic neoplasm over 6 years of follow-up. PMID- 28885440 TI - Is Orbital Floor Reconstruction With Titanium Mesh Safe? AB - To reconstruct the orbital floor defects there are a lot of reconstruction materials, the surgeon must choose one of them. The authors share their experience with 10 patients suffering from orbital trauma causing orbital floor fracture; those fractures were reconstructed using titanium mesh. No complications were encountered postoperatively apart from 1 patient with ectropion. Titanium mesh is a perfect material for the reconstruction of the orbital fractures, eliminating the need for autogenous bone graft. PMID- 28885441 TI - Evaluation of the Post Orthognathic Surgery Satisfaction: a Comparative Cross Sectional Study of Patients Class II and III. AB - The aim of this study was to analyze the degree of postoperative satisfaction regarding facial and dental esthetics, masticatory and respiratory function, and psychosocial factors in patients with dentofacial deformity Class II compared with Class III. The patients were divided into 2 groups with 50 patients in Group 1 (Class II) and 30 patients in Group 2 (Class III). Assessing the degree of postoperative satisfaction, the authors did not observe a significant difference between the groups in terms of improvements in the aesthetic and functional aspects and the psychological impact of the treatment. It can be concluded that regardless of the type of dentofacial changes, the treatment well indicated and conducted, results in significant positive effects on patients lives, both aesthetically and in the function, and psychosocial great benefit. PMID- 28885443 TI - Temporal Deformity Objectively Measured Before and After Surgery for Metopic Synostosis: Retrusion Rather than Hollowing. AB - The temporal contour deformity typical of metopic synostosis is often referred to as temporal hollowing, but has not been quantitatively defined. This deformity is present before surgery and remains to a varying extent at long-term follow-up. The present study aimed to objectively evaluate the degree of this contour deformity in metopic synostosis before and after surgical correction.All children surgically treated for metopic synostosis at Sahlgrenska University Hospital between 2002 and 2014 (n = 120) with appropriate computed tomography scans (n = 160) performed preoperatively and/or at follow-up at 3 years of age were included. Depending on age, 1 of 2 surgical techniques was used. Children presenting before the age of 6 months were treated with frontal remodeling in combination with a spring (S group), whereas children older than 6 months were treated with a bone transplant (BT group). The bony temporal deformity was measured with a semiautomatic MATLAB program and patients were compared to sex- and age-matched controls.The deformity was significantly reduced in both groups (P < 0.001). In the S group, it was reduced from a mean +/- standard deviation of 3.6 +/- 1.9% to 1.0 +/- 1.2% and in the BT group, it was reduced from 3.3% +/- 1.4% to 1.1% +/- 0.8%.The contour deformity in metopic synostosis is present both before and after surgery and should therefore be termed temporal retrusion (TR). This assessment method enables objective comparison of TR before and after surgical correction and is a potential tool to evaluate TR in metopic synostosis. PMID- 28885444 TI - Surgical Treatment of Nonsyndromic Craniosynostosis. AB - Studies on the treatment of nonsyndromic craniosynostosis demonstrate decreasing morbidity and mortality; however, complication rates still range from 5% to 14%. Here, the authors present their last 10 years' experience treatment of nonsyndromic single suture craniosynostosis. A retrospective review was performed on patients who underwent open surgical treatment of nonsyndromic craniosynostosis over 10 years. Patient characteristics and clinical outcomes were reviewed. Radiological analysis of intracranial volumes was performed using Amira software. The authors' technique for treatment of sagittal synostosis was the Foreshortening and Lateral Expansion of the Cranium Activated by Gravity (FLAG) procedure. The authors identified 106 patients with a median age of 0.8 years. Sagittal synostosis was most common (n = 65, 61%). Seventeen percent underwent distraction of the cranial vault; the remainder underwent traditional remodeling procedures. The average operative time was 131 minutes, blood loss was 296 mL (30 mL/kg), and intraoperative transfusion was 332 mL (34 mL/kg). There were 2 postoperative complications. Six patients required an additional major operation years later, most commonly for increased intracranial pressure. The authors separately analyzed 50 patients with sagittal synostosis treated with the FLAG procedure. There were no postoperative complications, and only 4 patients required reoperation. The average operative time for the FLAG procedure was 97.3 minutes. Intracranial volume increased by 191.45 mL (28.3-427.5 mL) with 28% average relative cranial vault expansion (4.5%-93.2%). Surgical correction of craniosynostosis using the FLAG technique is safe and effective with minimal morbidity and long standing results. Treatment should involve a structured approach, which minimizes operative times and decreases complication rates. PMID- 28885446 TI - Implementing a Health System-wide Patient Blood Management Program with a Clinical Community Approach. AB - BACKGROUND: Patient blood management programs are gaining popularity as quality improvement and patient safety initiatives, but methods for implementing such programs across multihospital health systems are not well understood. Having recently incorporated a patient blood management program across our health system using a clinical community approach, we describe our methods and results. METHODS: We formed the Johns Hopkins Health System blood management clinical community to reduce transfusion overuse across five hospitals. This physician led, multidisciplinary, collaborative, quality-improvement team (the clinical community) worked to implement best practices for patient blood management, which we describe in detail. Changes in blood utilization and blood acquisition costs were compared for the pre- and post-patient blood management time periods. RESULTS: Across the health system, multiunit erythrocyte transfusion orders decreased from 39.7 to 20.2% (by 49%; P < 0.0001). The percentage of patients transfused decreased for erythrocytes from 11.3 to 10.4%, for plasma from 2.9 to 2.2%, and for platelets from 3.1 to 2.7%, (P < 0.0001 for all three). The number of units transfused per 1,000 patients decreased for erythrocytes from 455 to 365 (by 19.8%; P < 0.0001), for plasma from 175 to 107 (by 38.9%; P = 0.0002), and for platelets from 167 to 141 (by 15.6%; P = 0.04). Blood acquisition cost savings were $2,120,273/yr, an approximate 400% return on investment for our patient blood management efforts. CONCLUSIONS: Implementing a health system-wide patient blood management program by using a clinical community approach substantially reduced blood utilization and blood acquisition costs. PMID- 28885447 TI - Promoting Safety, Quality, and Value through Patient Blood Management. PMID- 28885448 TI - Scientists Must Shape Our Future as They Have Shaped Our Past: Perspective of the Former US EPA Administrator. PMID- 28885449 TI - Pandemic Influenza A H1N1 Vaccination and Subsequent Risk of Type 1 Diabetes in Norway. PMID- 28885450 TI - Automated Evaluation of Choroidal Thickness and Minimum Rim Width Thickness in Nonarteritic Anterior Ischemic Optic Neuropathy. AB - BACKGROUND: The aim of this study was to evaluate and compare peripapillary choroidal thickness (pCT) and macular choroidal thickness (CT), Bruch membrane opening-minimum rim width (BMO-MRW), retinal nerve fiber layer (RNFL) thickness, and optic disc area among nonarteritic anterior ischemic optic neuropathy (NAION) eyes, the contralateral unaffected eyes, and healthy control eyes. METHODS: Twenty-six patients diagnosed with NAION (29 affected and 21 unaffected eyes) and 29 healthy matched control individuals (29 eyes) were analyzed by swept-source optical coherence tomography. All participants underwent scanning by Spectralis optical coherence tomography to analyze BMO-MRW, RNFL thickness, and optic disc area. RESULTS: Mean pCT in the NAION eyes, unaffected fellow eyes, and the control group was 130.5 +/- 72.1 MUm, 149.6 +/- 75.7 MUm, and 103.7 +/- 36.7 MUm, respectively (analysis of variance [ANOVA], P = 0.04). Mean macular CT in the NAION eyes, unaffected fellow eyes, and the control group was 226.1 +/- 79.8 MUm, 244.6 +/- 81.4 MUm, and 189.9 +/- 56.4 MUm, respectively (ANOVA, P = 0.03). Mean and all sectorial RNFL and BMO-MRW thickness values were significantly thinner in the NAION eyes vs the unaffected fellow and control eyes (P <= 0.00). The unaffected fellow eyes in NAION patients showed a significantly thicker average and sectorial BMO-MRW values than control eyes (P <= 0.02) except for the nasal sector (P = 0.09). Mean optic disc area derived from BMO analysis was not significantly different among groups (ANOVA, P = 0.86). CONCLUSIONS: The fellow unaffected eyes in patients with NAION showed significantly thicker mean peripapillary and macular choroidal and BMO-MRW thicknesses than disease-free control eyes. No differences in the mean optic disc area were found. Both a thick peripapillary choroid and a thick neuroretinal rim might contribute to the development of NAION or possibly be a secondary phenomenon. PMID- 28885451 TI - Visual Structure and Function in Collision Sport Athletes. AB - BACKGROUND: Vision-based measures have been shown to be useful markers in multiple sclerosis (MS), Alzheimer and Parkinson disease. Therefore, these testing paradigms may have applications to populations explaining repetitive head trauma that has been associated with long-term neurodegenerative sequelae. We investigated retinal structure and visual function in professional collision sport athletes compared to age- and race-matched control participants. METHODS: In this cross-sectional study, participants underwent spectral-domain optical coherence tomography (OCT) measurements of peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC = ganglion cell + inner plexiform layers) thickness. High-contrast visual acuity (100% level), low contrast letter acuity (LCLA) (1.25% and 2.5% levels), and King-Devick Test of rapid number naming performance were administered. Vision-specific quality of life (QOL) measures were assessed. RESULTS: Among 46 collision sport athletes (boxing, n = 14; football, n = 29; ice hockey, n = 3) and 104 control participants, average RNFL thickness was a significant predictor of athlete vs control status with athletes demonstrating 4.8-MUm of thinning compared to controls (P = 0.01, generalized estimating equation [GEE] models accounting for age and within-subject, intereye correlations). Athlete vs control status was not a predictor of RNFL thickness for the subgroup of football players in this cohort (P = 0.60). Binocular (P = 0.001) and monocular (P = 0.02) LCLA at 2.5% contrast and vision-specific QOL (P = 0.04) were significant predictors of athlete vs control status (GEE models accounting for age and within-subject, intereye correlations). Rapid number naming performance times were not significantly different between the control and athlete groups. CONCLUSIONS: This study showed that retinal axonal and neuronal loss is present among collision sport athletes, with most notable differences seen in boxers. These findings are accompanied by reductions in visual function and QOL, similar to patterns observed in multiple sclerosis, Alzheimer and Parkinson diseases. Vision-based changes associated with head trauma exposure that have the potential to be detected in vivo represent a unique opportunity for further study to determine if these changes in collision sport athletes are predictive of future neurodegeneration. PMID- 28885452 TI - MicroRNA-mediated downregulation of potassium-chloride-cotransporter and vesicular gamma-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis-induced visceral pain in rats. AB - Loss of GABAergic inhibition in pain pathways has been considered to be a key component in the development of chronic pain. In the present study, we intended to examine whether miR-92b-mediated posttranscriptional dysregulation of spinal potassium chloride cotransporter (KCC2) and vesicular gamma-aminobutyric acid transporter (VGAT) plays a major role in the development and maintenance of long term visceral hyperalgesia in neonatal zymosan-treated rats. Neonatal cystitis was induced by transurethral zymosan administration from postnatal (P) days 14 to 16 (protocol 1). Two other zymosan protocols were also used: adult rechallenge on P57 to 59 following neonatal P14 to 16 exposures (protocol 2), and adult zymosan exposures on P57 to 59 (protocol 3). Both neonatal and adult bladder inflammation protocols demonstrated an increase in spinal miR-92b-3p expression and subsequent decrease in KCC2 and VGAT expression in spinal dorsal horn neurons. In situ hybridization demonstrated a significant upregulation of miR-92b-3p in the spinal dorsal horn neurons of neonatal cystitis rats compared with saline-treated controls. In dual in situ hybridization and immunohistochemistry studies, we further demonstrated coexpression of miR-92b-3p with targets KCC2 and VGAT in spinal dorsal horn neurons, emphasizing a possible regulatory role both at pre- and post-synaptic levels. Intrathecal administration of lentiviral pLSyn-miR-92b 3p sponge (miR-92b-3p inhibitor) upregulated KCC2 and VGAT expression in spinal dorsal horn neurons. In behavioral studies, intrathecal administration of lentiviral miR-92b-3p sponge attenuated an increase in visceromotor responses and referred viscerosomatic hypersensitivity following the induction of cystitis. These findings indicate that miR-92b-3p-mediated posttranscriptional regulation of spinal GABAergic system plays an important role in sensory pathophysiology of zymosan-induced cystitis. PMID- 28885453 TI - Peripheral afferents and spinal inhibitory system in dynamic and static mechanical allodynia. PMID- 28885455 TI - Spousal criticism and hostility in response to pain: what is the alternative? PMID- 28885454 TI - Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. AB - Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a noneuphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine whether CBD is anti nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. Osteoarthritis was induced in male Wistar rats (150-175 g) by intra-articular injection of sodium monoiodoacetate (MIA; 3 mg). On day 14 (end-stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology, whereas pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 after MIA. Joint nerve myelination was calculated by G ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100 300 MUg) were assessed. In end-stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (P < 0.0001; n = 8). Acute, transient joint inflammation was reduced by local CBD treatment (P < 0.0001; n = 6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (P < 0.0001; n = 8), and was also found to be neuroprotective (P < 0.05; n = 6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain. PMID- 28885457 TI - Cannabis constituent synergy in a mouse neuropathic pain model. AB - Cannabis and its psychoactive constituent Delta9-tetrahydrocannabinol (THC) have efficacy against neuropathic pain, however, this is hampered by their side effects. It has been suggested that co-administration with another major constituent cannabidiol (CBD) might enhance the analgesic actions of THC and minimise its deleterious side effects. We examined the basis for this phytocannabinoid interaction in a mouse chronic constriction injury (CCI) model of neuropathic pain. Acute systemic administration of THC dose-dependently reduced CCI-induced mechanical and cold allodynia, but also produced motor incoordination, catalepsy, and sedation. Cannabidiol produced a lesser dose dependent reduction in allodynia, but did not produce the cannabinoid side effects. When co-administered in a fixed ratio, THC and CBD produced a biphasic dose-dependent reduction in allodynia. At low doses, the THC:CBD combination displayed a 200-fold increase in anti-allodynic potency, but had lower efficacy compared with that predicted for an additive drug interaction. By contrast, high THC:CBD doses had lower potency, but greater anti-allodynic efficacy compared with that predicted for an additive interaction. Only the high dose THC:CBD anti allodynia was associated with cannabinoid side effects and these were similar to those of THC alone. Unlike THC, the low dose THC:CBD anti-allodynia was not cannabinoid receptor mediated. These findings demonstrate that CBD synergistically enhances the pain-relieving actions of THC in an animal neuropathic pain model, but has little impact on the THC-induced side effects. This suggests that low dose THC:CBD combination treatment has potential in the treatment of neuropathic pain. PMID- 28885458 TI - Compassionate Nitric Oxide Adjuvant Treatment of Persistent Mycobacterium Infection in Cystic Fibrosis Patients. AB - BACKGROUND: Mycobacterium abscessus is one of the most antibiotic-resistant pathogens in cystic fibrosis (CF) patients. Nitric oxide (NO) has broad-spectrum antimicrobial activity. Clinical studies indicated that it is safe and tolerable when given as 160 ppm intermittent inhalations. METHODS: A prospective compassionate adjunctive inhaled NO therapy in 2 CF patients with persistent Mycobacterium abscessus infection. RESULTS: No adverse events were reported. Both subjects showed significant reduction in quantitative polymerase chain reaction results for Mycobacterium abscessus load in sputum during treatment; estimated colony forming unit decreased from 7000 to 550 and from 3000 to 0 for patient 1 and patient 2, respectively. CONCLUSIONS: Intermittent inhalations with 160 ppm NO are well tolerated, safe and result in significant reduction of Mycobacterium abscessus load. It may constitute an adjuvant therapeutic approach for CF patients with Mycobacterium abscessus lung disease. Further studies are needed to define dosing, duration and long-term clinical outcome. PMID- 28885456 TI - Tumor necrosis factor alpha secreted from oral squamous cell carcinoma contributes to cancer pain and associated inflammation. AB - Patients with oral cancer report severe pain during function. Inflammation plays a role in the oral cancer microenvironment; however, the role of immune cells and associated secretion of inflammatory mediators in oral cancer pain has not been well defined. In this study, we used 2 oral cancer mouse models: a cell line supernatant injection model and the 4-nitroquinoline-1-oxide (4NQO) chemical carcinogenesis model. We used the 2 models to study changes in immune cell infiltrate and orofacial nociception associated with oral squamous cell carcinoma (oSCC). Oral cancer cell line supernatant inoculation and 4NQO-induced oSCC resulted in functional allodynia and neuronal sensitization of trigeminal tongue afferent neurons. Although the infiltration of immune cells is a prominent component of both oral cancer models, our use of immune-deficient mice demonstrated that oral cancer-induced nociception was not dependent on the inflammatory component. Furthermore, the inflammatory cytokine, tumor necrosis factor alpha (TNFalpha), was identified in high concentration in oral cancer cell line supernatant and in the tongue tissue of 4NQO-treated mice with oSCC. Inhibition of TNFalpha signaling abolished oral cancer cell line supernatant evoked functional allodynia and disrupted T-cell infiltration. With these data, we identified TNFalpha as a prominent mediator in oral cancer-induced nociception and inflammation, highlighting the need for further investigation in neural immune communication in cancer pain. PMID- 28885459 TI - Association Between Mode of Delivery and Risk of Infection in Early Childhood: A Cohort Study. AB - BACKGROUND: Infections are the leading cause of morbidity and mortality in children. Caesarean section as a potential risk factor for infection has recently gained interest. Delivery by caesarean section has increased greatly, with nonmedical reasons playing an increasing role. We aimed to analyze the association between mode of delivery and hospitalizations because of infection and symptoms of infection at home in early childhood. METHODS: A cohort study, based on the Odense Child Cohort, following infants from gestation until a mean age of 3.5 years. Data on hospitalization because of infections were collected from the Danish National Patient Registry. Data on symptoms of infection at home were collected via a text message-based questionnaire. RESULTS: A total of 1921 children were born by vaginal delivery, 283 by elective caesarean section and 227 by acute caesarean section. An adjusted regression model showed an incidence rate ratio for hospitalizations because of infection in children born by elective caesarean section compared with children born by vaginal delivery of 1.45 (95% confidence interval: 1.16-1.80; P = 0.001). The analyses on symptoms of infection at home found no associations between any symptom of infection and mode of delivery. Symptom-specific subanalyses showed contrasting results. CONCLUSIONS: Mode of delivery showed a strong association to hospitalization because of infectious disease during early childhood. Overall, no association was present between rate of symptoms of infection at home and mode of delivery. PMID- 28885460 TI - Potential Diarrheal Pathogens Common Also in Healthy Children in Angola. AB - BACKGROUND: Globally, diarrhea kills almost 1500 children daily. In diagnostics, molecular methods are replacing traditional assays. We aimed to investigate enteropathogens in children with and without diarrhea in Luanda, the capital of Angola. METHODS: One hundred and ninety-four stool samples from 98 children with acute diarrhea and 96 children without diarrhea were investigated for 17 enteropathogens with multiplex real-time polymerase chain reaction. RESULTS: The median age of children was 10.5 months. Enteropathogens, bacteria, viruses and parasites were detected in 91%, 78%, 50% and 25%, respectively. A positive finding was significantly (P = 0.003) more common in diarrhea when testing for all pathogens combined, for bacteria alone and for viruses alone. More than one pathogen was found more frequently in diarrhea than in non-diarrhea stool samples, in 87% and in 59% (P < 0.0001), respectively. The median number (interquartile range) of pathogens detected was 3 (2) versus 1.5 (2; P < 0.0001), respectively. When age was taken into account, diarrhea was found to be associated with enterotoxigenic and enteroaggregative Escherichia coli, Shigella, Campylobacter, rotavirus, sapovirus and Cryptosporidium. CONCLUSIONS: Multiplex polymerase chain reaction detected enteropathogens in almost all stool samples of children in Luanda, albeit this occurred more often in diarrhea. Children with diarrhea showed more mixed infections than children without diarrhea. PMID- 28885461 TI - Vaccinations and Malaria Chemoprophylaxis of Adolescents Traveling From Greece to International Destinations: A Nine-Year Prospective Study. AB - BACKGROUND: There are few publications focusing on vaccination and malaria chemoprophylaxis in adolescent travelers. We assessed pretravel vaccinations and malaria chemoprophylaxis of adolescents 12-18 years old traveling from Greece to international destinations. METHODS: We prospectively studied 239 adolescents 12 18 years old during 2008-2016. A standard questionnaire was used to collect data. RESULTS: Adolescents sought pretravel services at a mean of 24.1 days before departure. Their main destinations were sub-Saharan Africa (79 adolescents; 33.1%), Latin America (56; 23.5%) and North America (26; 10.9%). Almost half (46.1%) of them planned to stay abroad for at least 3 months. Sixteen (7.4%) adolescents planned to visit friends and relatives. The yellow fever vaccine and the typhoid vaccine were the most frequently administered vaccines (74.1% and 20.5%, respectively), while the hepatitis A vaccine and the tetanus-diphtheria vaccine accounted for most routine vaccinations (18% and 14.2%, respectively). The rabies and the typhoid fever vaccines were administered inadequately to adolescents traveling to endemic areas. Malaria chemoprophylaxis should have been prescribed in many cases traveling to sub-Saharan Africa and the Indian subcontinent. CONCLUSIONS: Only a small number of adolescents from Greece traveling abroad seek pretravel counseling. We found significant gaps in typhoid fever and rabies vaccinations of adolescents traveling to endemic areas. We also found gaps in prescription of malaria chemoprophylaxis for those traveling to high-risk areas. There is a need to develop communication strategies to access adolescent travelers and improve appropriate vaccination and use of malaria chemoprophylaxis. PMID- 28885463 TI - Author Response: Implementation of an Early Mobility Pathway in Neurointensive Care Unit Patients With Ventriculostomies. PMID- 28885462 TI - Early Mobilization of Patients With External Ventricular Devices. PMID- 28885464 TI - Through the Resolution of Conflict. PMID- 28885465 TI - Interprovider Communication Using a Scheduled Provider Alert-Response Communication System in 3 Inpatient Neurology Units. PMID- 28885467 TI - Perceived Cognitive Deficits in a Sample of Persons Living With Multiple Sclerosis. PMID- 28885466 TI - Perceived Cognitive Deficits in a Sample of Persons Living With Multiple Sclerosis. AB - PURPOSE: The aims of this study were to describe the nature and diversity of perceived cognitive deficits using the Perceived Deficits Questionnaire (PDQ), to assess the reliability of the PDQ, and to explore self-reported predictors of PDQ scores in a large community-based sample of persons with multiple sclerosis (MS). MATERIALS AND METHODS: Persons with MS enrolled in a randomized controlled trial provided demographic data and completed the PDQ along with measures of cognitive and memory strategies, cognitive abilities, self-efficacy, and depressive symptoms and neuropsychological tests. RESULTS: Most of the 183 participants were non-Hispanic white women, approximately 49 years old, and diagnosed with MS 12.5 years prior. The most frequent cognitive complaints regarded trouble remembering telephone numbers, mind drifting, and forgetting why one came into a room. The PDQ scores were significantly related to self-rated cognitive abilities, depressive symptoms, self-efficacy, and use of cognitive strategies, but not to scores on neuropsychological performance tests. When controlling for other variables, self-rated cognitive abilities was the strongest, significant predictor of perceived cognitive deficits. CONCLUSION: Persons with MS most frequently experience deficits related to short-term memory and attention. The PDQ total is a reliable measure of perceived cognitive deficits in persons with MS, is feasible for use by nurses in clinical settings-can be administered in approximately 5 minutes, and is easily scored. PMID- 28885468 TI - Trauma registry in Spain. Comment to "Trauma systems around the world: A systematic overview". PMID- 28885469 TI - Bigger is better: Comparison of alternative devices for tension hemopneumothorax and pulseless electrical activity in a Yorkshire swine model. AB - BACKGROUND: Tension pneumothorax is a cause of potentially preventable death in prehospital and battlefield settings and 14-gauge angiocatheter (14G AC) decompression remains the current treatment standard, despite its high incidence of failure. Traumatic pneumothorax is often associated with hemothorax, but 14G AC has no proven efficacy for associated hemothorax. We sought to compare the 14G AC to three alternative devices for treatment of tension hemopneumothorax (t H/PTX) in a positive-pressure ventilation swine model. METHODS: Our tension model was modified to incorporate a persistent air leak and pleural blood. Tension physiology was achieved with escalating carbon dioxide insufflation via transdiaphragmatic trocar, and 10% estimated blood volume was instilled into each chest. Intervention was randomized between 14G AC, 10-gauge angiocatheter (10G AC), modified Veress-type needle (mVN), and 3-mm laparoscopic trocar (LT). After recovery, serial tension-induced pulseless electrical activity (PEA) events were induced and decompressed. Success of rescue, time to rescue, and physiologic data were recorded. RESULTS: One hundred ninety-five t-H/PTX and 88 PEA events were conducted in 25 swine. Laparoscopic trocar and 10G AC were more successful and had faster median time to rescue for t-H/PTX compared with 14G AC, whereas mVN performed comparably. Following PEA, 14G AC and mVN succeeded at rescue only 50% and 57% of the time, whereas 10G AC and LT had 100% success at return of spontaneous circulation. Time to successful return of circulation following PEA did not differ between devices; however, there was a noticeable difference in the rate of meaningful hemodynamic recovery following PEA favoring LT and 10G AC. There were no significant injuries noted. CONCLUSIONS: While mVN performed comparably to 14G AC, both have unacceptable failure rates. Ten-gauge AC and LT performed superiorly in both t-H/PTX and PEA. We believe there is now ample evidence supporting replacement of the 14G AC with 10G AC in current treatment recommendations. PMID- 28885471 TI - Partners in Research: Together We'll Make a Difference. PMID- 28885470 TI - Poor microcirculatory flow dynamics are associated with endothelial cell damage and glycocalyx shedding after traumatic hemorrhagic shock. AB - BACKGROUND: Endothelial cell damage and glycocalyx shedding after trauma can increase the risk of inflammation, coagulopathy, vascular permeability, and death. Bedside sublingual video-microscopy may detect worse flow and perfusion associated with this endotheliopathy. We compared markers of endotheliopathy with physical flow dynamics after traumatic hemorrhagic shock. METHODS: Sublingual incident dark field video-microscopy was performed at three time points after injury (<10 hours, 10-30 hours, and 30-50 hours). Values for microcirculatory flow index (MFI), Point Of carE Microcirculation assessment (POEM) score, proportion of perfused vessels (PPV), microcirculatory heterogeneity index (MHI), perfused vessel density (PVD), and total vessel density (TVD) were obtained. ELISAs were performed to measure concentrations of thrombomodulin and syndecan-1 as biomarkers of endothelial cell damage and glycocalyx shedding respectively. Flow parameters were dichotomized to above and below average, and biomarkers compared between groups; below average MFI, POEM, PPV, PVD, and TVD, and above average MHI were considered poor microcirculatory flow dynamics. RESULTS: A total of 155 sublingual video-microscopy clips corresponding to 39 time points from 17 trauma patients were analyzed. Median age was 35 (IQR 25-52); 16/17 were men. Within 10 hours of injury, syndecan-1 concentrations were significantly higher compared to 17 age- and sex-matched healthy controls (30 [IQR 20-44] ng/mL) for worse TVD (78 [IQR 63-417] ng/mL), PVD (156 [IQR 63-590] ng/mL), PPV (249 [IQR 64 578] ng/mL), MFI (249 [IQR 64-578] ng/mL), MHI (45 [IQR] 38-68) ng/mL), and POEM scores (108 [IQR 44-462] ng/mL) (all p < 0.01). Thrombomodulin was also raised within 10 hours of injury when compared to healthy controls (2.9 [IQR 2.2-3.4] ng/mL) for worse PPV (4.1 [IQR 3.4-6.2] ng/mL) and MFI (4.1 [IQR 3.4-6.2] ng/mL) (both p < 0.05). CONCLUSIONS: Endothelial cell damage and glycocalyx shedding are associated with worse flow, density, and heterogeneity within microvessels after traumatic hemorrhagic shock. The clinical utility of these biomarkers and flow parameters at the bedside are yet to be elucidated. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 28885472 TI - What Problems Are You Trying to Solve? PMID- 28885473 TI - INS 2017 Infusion Nursing Grand Rounds. PMID- 28885474 TI - INS 2017 ePoster Presentations. PMID- 28885475 TI - Project HANDS: A Bundled Approach to Increase Short Peripheral Catheter Dwell Time. AB - Increasing short peripheral catheter (SPC) dwell time is becoming common practice. A number of variables lead to unscheduled restarts and significant complications with SPCs. Preventing complications is important to patient outcomes as dwell time increases. This quality improvement project compared the use of a manufactured securement device versus tape and transparent occlusive dressing while instituting a standardized insertion and care bundle with a 96 hour dwell time. Major findings included no statistically significant difference in restart rates in SPCs secured with a device compared with those secured with tape and transparent occlusive dressing (P = .06). These results differ from other published studies and may be due to the traditional nature of the hospital's infusion team and patients' average length of stay. PMID- 28885476 TI - Determining the Risk of Sepsis Using Nurse-Compounded Elastomeric Pumps for Continuous Infusion in Outpatient Parenteral Antibiotic Therapy. AB - Limited availability of compounded antibiotics used for continuous infusion outpatient parenteral antibiotic therapy (OPAT) can delay or interrupt an OPAT course. To solve this problem, OPAT nurses at a hospital in Australia have been compounding elastomeric pumps for immediate use. The incidence of sepsis in 5014 patients before and after the introduction of nurse compounding was compared. There were no cases of laboratory-confirmed bloodstream infection among the nurse compounded group compared with 2 cases (0.045/1000 catheter days) among the control group without nurse compounding (P = .16). No compounding medication errors occurred in more than 180 patient years of follow-up among the nurse compounding group. Nurse compounding can be a safe and convenient alternative when immediate access to preloaded elastomeric pumps is required. PMID- 28885477 TI - Understanding the Patient Experience of Peripherally Inserted Central Catheter Related Deep Vein Thrombosis Using Interpretive Phenomenology. AB - The purpose of this interpretive phenomenological study was to determine what it means to patients to live with a peripherally inserted central catheter (PICC) related deep vein thrombosis and to describe the influence of the experience on the individual's quality of life. The sample included 11 adult patients from an acute care setting who developed a PICC-related symptomatic thrombus between November 2014 and March 2016, using purposive sampling. Three distinct themes emerged from the data in this study: a loss of trust in health care providers, additional burdens to existing problems, and a yearning for understanding. PMID- 28885478 TI - Use of Electronic Tablets for Patient Education on Flushing Peripherally Inserted Central Catheters. AB - The purpose of this study was to examine the efficacy of using an electronic tablet to provide patient education for flushing peripherally inserted central catheters (PICCs) as a way to reduce the incidence of occlusion. Eleven patients, newly diagnosed with cancer, participated in a pilot study that used a video on PICC flushing and remote coaching using FaceTime (Apple, Cupertino, CA) to teach patients how to maintain their PICCs in their homes. At the end of the 6-week intervention, no adverse outcomes (occlusions or infections) were noted among the patients who participated in the study. PMID- 28885479 TI - High-Dose Subcutaneous Immunoglobulin in Patients With Multifocal Motor Neuropathy: A Nursing Perspective. AB - Multifocal motor neuropathy (MMN), an immune neuromuscular condition causing progressive weakness, usually responds to immune-mediated treatments, including intravenous immunoglobulin (IVIG). Fifteen patients with MMN receiving IVIG were enrolled in an open-label, single-center trial and switched to 20% subcutaneous immunoglobulin (SCIG) using a smooth transition protocol (ie, changing the therapy without interruption or impact on the intended outcome of the therapy). Patients received individualized training and support based on motivation and ability to learn, follow directions, and maintain compliance. Although some patients required assistance during the training phase, most managed self infusion and reported satisfaction in managing therapy autonomously. Educating patients with neuropathies to self-infuse high-dose SCIG at home and with flexibility in dosing schedules was successfully demonstrated in this patient group. PMID- 28885480 TI - Is Thrombus With Subcutaneous Edema Detected by Ultrasonography Related to Short Peripheral Catheter Failure? A Prospective Observational Study. AB - Short peripheral catheter (SPC) failure is an important clinical problem. The purpose of this study was to clarify the relationship between SPC failure and etiologies such as thrombus, subcutaneous edema, and catheter dislodgment using ultrasonography and to explore the risk factors associated with the etiologies. Two hundred catheters that were in use for infusion, excluding chemotherapy, were observed. Risk factors were examined by logistic regression analysis. Sixty catheters were removed as the result of SPC failure. Frequency of thrombus with subcutaneous edema in SPC failure cases was significantly greater than in those cases where therapy was completed without complications (P < .01). Multivariate analysis demonstrated that 2 or more insertion attempts were significantly associated with thrombus with subcutaneous edema. Results suggest that subsurface skin assessment for catheterization could prevent SPC failure. PMID- 28885481 TI - Comparison of an Electromagnetic Middle Ear Implant and Hearing Aid Word Recognition Performance to Word Recognition Performance Obtained Under Earphones. AB - OBJECTIVE: To report the results of patients with the Maxum middle ear implant (MEI) and compare word recognition scores (WRS) and speech perception gap (SP Gap) of Maxum versus optimally fit hearing aids (HA). STUDY DESIGN: Case series with chart review. SETTING: Single, private otology clinic. PATIENTS: Eleven ears, in nine adult patients (two women; average age 62.7 yr). INTERVENTIONS: Twelve consecutive ears with moderate to severe sensorineural hearing loss (SNHL) underwent implantation of the Maxum system. One patient was not included due to inadequate preoperative testing. MAIN OUTCOME MEASURES: Primary outcome measures included word recognition score (WRS) and SP Gap (maximum word understanding [PB max] - WRSaided) improvement compared with HAs. RESULTS: The average Maxum WRS was 64.7% (range, 28-94%), a 41.6% improvement (range, 10-66%) over HAs (p < 0.001). The average Maxum SP Gap was 6.6% (range, -8 to 24%), a 41.6% improvement (range, 10-66%) over HAs (p < 0.001). CONCLUSION: These data demonstrate that the Maxum provides superior WRS than HAs for patients with significant aided SP Gaps. There is a significant, very strong correlation between Maxum WRS and PB max (r = 0.85, p = 0.001). This implies that PB max may reasonably predict WRS outcomes with Maxum before implantation, and the SP Gap can reasonably predict the degree of additional potential benefit with Maxum. In advising patients who may be candidates for both a CI and MEI, PB max and SP Gap measurements will provide useful predictive information to help clinicians counsel patients on their choice of hearing technology. LEVEL OF EVIDENCE: 4. PMID- 28885482 TI - Comparison of Localized and Systemic Otitis Media With ANCA-Associated Vasculitis. AB - OBJECTIVE: To investigate differences in immune activity based on the presence of multiple organ involvement in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and whether hearing outcomes are different between patients with AAV localized to the ear and patients with systemic AAV. STUDY DESIGN: Retrospective case review. SETTING: University hospital. PATIENTS: Twenty patients with otitis media with AAV (OMAAV) who met the criteria proposed by the OMAAV study group in Japan. MAIN OUTCOME MEASURE(S): Serum levels of C reactive protein, ANCA titer, soluble interleukin-2 receptor levels, and hearing outcome. RESULTS: Thirteen patients had disease involvement of organs other than the ear (systemic OMAAV group); involvement was localized to the ear in seven patients (localized OMAAV group). Serum levels of C-reactive protein, ANCA titer, and soluble interleukin-2 receptor were not significantly different between the groups. Hearing levels at diagnosis and in remission were significantly worse in the localized OMAAV group compared with the systemic OMAAV group. Hearing gain was not significantly different between groups. CONCLUSION: It is suggested that immune activity in patients with AAV localized to the ear is equivalent to activity in patients with systemic AAV. Therefore, we may need treatment for OMAAV equal in intensity to that for systemic AAV. As the hearing level at diagnosis was worse in patients with AAV localized to the ear than in patients with systemic AAV, earlier diagnosis may be needed to improve hearing outcome. PMID- 28885483 TI - Assessing Readability and Reliability of Online Patient Information Regarding Vestibular Schwannoma. AB - HYPOTHESIS: The aim of this study is to objectively assess the quality and readability of websites related to vestibular schwannomas. BACKGROUND: Patients are increasingly seeking information on confirmed or suspected diagnoses through the Internet. Clinicians are often concerned regarding the accuracy, quality, and readability of web-based sites. METHODS: Online information relating to vestibular schwannoma was searched using the three most popular search engines. The terms "acoustic neuroma" and "vestibular schwannoma" were used. The top 50 results from each site were assessed for readability using the Flesch-Kincaid Grade Level, Flesch Reading Ease Score, and the Gunning-Fog Index. Quality of website information was scored using the DISCERN tool. RESULTS: Of 300 search results analyzed, 58 separate appropriate websites were identified. The mean readability score using Flesch-Kincaid Grade Level was 10.27 (95% confidence interval [CI] 9.84-10.70). The mean Flesch Reading Ease Score was 48.75 (95% CI 46.57-50.92). The Gunning-Fog Index was 13.40 (95% CI 12.92-13.89). These scores equate to someone finishing secondary school/first year university student. DISCERN scores were highly variable but consistently demonstrated great variability in quality of information. CONCLUSION: Online patient information on vestibular schwannoma is highly variable in quality. Although there are a wide range of different websites easily available to patients on their condition and its treatment options, the information is written at a difficult level which may exceed the understanding level of many patients as it is written at a higher than average level of expected reading ability. PMID- 28885484 TI - Comparative evaluation of the white matter fiber integrity in patients with prelingual and postlingual deafness. AB - The aim of this study was to perform a comparative investigation of white matter integrity in patients with prelingual and postlingual deafness; we carried out a tract-based statistical analysis of diffusion tensor anisotropy in eight and ten adults with prelingual and postlingual deafness, respectively. Patients with deafness showed significant decreases in diffusion anisotropy at the right internal capsule, the right thalamus, and the splenium of the corpus callosum as well as within the bilateral superior temporal gyrus (including Heschl gyrus) and right temporal white matter. Furthermore, relative to patients with postlingual deafness, those with prelingual deafness showed lower anisotropy in the right superior temporal gyrus, bilateral temporal white matter, and the genu and anterior body of the corpus callosum. We believe that, in patients with deafness, reception of early auditory stimuli before language acquisition might be more critical to white matter maturation and brain reorganization than the nature of auditory stimuli itself or the duration of disuse. These findings provide the theoretical background for early auditory rehabilitation. PMID- 28885485 TI - Alterations in endocytic protein expression with increasing age in the transgenic APP695 V717I London mouse model of amyloid pathology: implications for Alzheimer's disease. AB - A major risk factor for the development of Alzheimer's disease (AD) is increasing age, but the reason behind this association has not been identified. It is thought that the changes in endocytosis seen in AD patients are causal for this condition. Thus, we hypothesized that the increased risk of developing AD associated with ageing may be because of changes in endocytosis. We investigated using Western blotting whether the expression of endocytic proteins involved in clathrin-mediated and clathrin-independent endocytosis are altered by increasing age in a mouse model of amyloid pathology. We used mice transgenic for human amyloid precursor protein containing the V717I London mutation. We compared the London mutation mice with age-matched wild-type (WT) controls at three ages, 3, 9 and 18 months, representing different stages in the development of pathology in this model. Having verified that the London mutation mice overexpressed amyloid precursor protein and beta-amyloid, we found that the expression of the smallest isoform of PICALM, a key protein involved in the regulation of clathrin-coated pit formation, was significantly increased in WT mice, but decreased in the London mutation mice with age. PICALM levels in WT 18-month mice and clathrin levels in WT 9-month mice were significantly higher than those in the London mutation mice of the same ages. The expression of caveolin-1, involved in clathrin-independent endocytosis, was significantly increased with age in all mice. Our results suggest that endocytic processes could be altered by the ageing process and such changes could partly explain the association between ageing and AD. PMID- 28885486 TI - Bacopa monnieri extract enhances learning-dependent hippocampal long-term synaptic potentiation. AB - Bacopa monnieri has been used in Ayurvedic medicine as a memory enhancer for a long time; however, its direct effect on synaptic plasticity has not been investigated. To the best of our knowledge, this study is the first to report the effect of B. monnieri on long-term synaptic potentiation in acute hippocampal slices. Adult male Wistar rats were orally administered either sterile water or the ethanolic extract of B. monnieri for 60 days. The extracellular recording was performed to measure the field excitatory postsynaptic potential in the acute hippocampal slices of these rats. Our results showed that B. monnieri extract significantly increased long-term potentiation magnitude compared with the control group, whereas there was no change in basal synaptic transmission. The data support the beneficial mnemonic effect of B. monnieri, and suggest that this effect might be because of the increase of learning-associated synaptic machinery, resulting in the long-term potentiation enhancement and strengthening of hippocampal synapses, which plays a critical role in learning and memory formation. PMID- 28885487 TI - Luminance information decoding on the basis of local field potential signals of pigeon optic tectum neurons. AB - Important aspects of brain information processing can be understood by examining decoding of visual stimuli from neuronal response signals. In this research, the luminance information is decoded from the local field potential signal in the optic tectum region of the pigeon. We designed a luminance visual stimulus model with transient flicker characteristics, recorded multichannel local field potential (LFP) signals using a microelectrode array, extracted LFP Fourier transform energy and phase features, constructed a multivariate linear inverse filter luminance information decoding algorithm, and evaluated decoding effects using a cross-correlation method. We found that LFP signal phase decoding of luminance information yielded better effects than amplitude decoding of luminance information. In the case of optimal frequency band, channels, delay time, and other parameters, the results of phase and amplitude codecoding could reach 0.94+/-0.02. Comparing the differences between neuronal spike decoding and LFP decoding, we found that LFP signal phase and amplitude codecoding resulted in luminance closer to that of the actual stimulus and required fewer decoding electrode channels. PMID- 28885488 TI - Complement (C1q) Binding De Novo Donor-Specific Antibodies and Cardiac-Allograft Vasculopathy in Pediatric Heart Transplant Recipients. AB - BACKGROUND: We hypothesized C1q binding de novo donor-specific antibody (DSA) after heart transplant (HT) is a higher risk for development of coronary artery vasculopathy (CAV) in children. METHODS: A retrospective analysis of 127 pediatric HT recipients transplanted between January 2005 and December 2014 was used to determine complement (C1q)-binding de novo DSA on the outcomes of HT and the ability of the C1q assay to predict CAV development. RESULTS: Of 127 patients, 59 (46.4%) developed de novo DSA, 37 of those had C1q+ DSA. There was no difference in baseline characteristics except patients who developed C1q+ DSA more often received a donor heart from a female compared with C1q- DSA group (P = 0.034). The DSA median fluorescent intensity (MFI) value of 7000 or greater had 80% sensitivity and 80% specificity (C statistics 0.89, P <0.05) for predicting positive C1q binding. Multivariate analyses identified C1q binding DSA as an independent risk for CAV with a hazard ratio (HR) of 3.25 (95% confidence interval [CI], 1.33-7.93; P = 0.0095). In multivariable Cox proportional hazard models, the covariates associated with graft loss included: C1q+ DSA (HR, 3.2; 95% CI, 1.34-7.86; P < 0.009), pre-HT renal insufficiency (HR, 11.3; 95% CI, 3.71 34.29; P < 0.0001), and pre-HT ventilator support (HR, 3.3; 95% CI, 1.39-7.81; P = 0.007). CONCLUSIONS: The DSA strength in MFI correlates with positive C1q binding activity and hence functional capabilities of DSA. Close monitoring of DSA strength in MFI and function (C1q assay) may be useful for identifying pediatric HT recipient at risk for development of CAV. PMID- 28885490 TI - The Authors' Reply. PMID- 28885489 TI - Frailty and Postkidney Transplant Health-Related Quality of Life. AB - BACKGROUND: Health-related quality of life (HRQOL) reflects a patient's disease burden, treatment effectiveness, and health status and is summarized by physical, mental, and kidney disease-specific scales among end-stage renal disease patients. Although on average HRQOL improves postkidney transplant (KT), the degree of change depends on the ability of the patient to withstand the stressor of dialysis versus the ability to tolerate the intense physiologic changes of KT. Frail KT recipients may be extra vulnerable to either of these stressors, thus affecting change in HRQOL after KT. METHODS: We ascertained frailty, as well as physical, mental, and kidney disease-specific HRQOL in a multicenter prospective cohort of 443 KT recipients (May 2014 to May 2017) using Kidney Disease Quality of Life Instrument Short Form. We quantified the short-term (3 months) rate of post-KT HRQOL change by frailty status using adjusted mixed-effects linear regression models. RESULTS: Mean HRQOL scores at KT were 43.3 (SD, 9.6) for physical, 52.8 (SD, 8.9) for mental, and 72.6 (SD, 12.8) for kidney disease specific HRQOL; frail recipients had worse physical (P < 0.001) and kidney disease-specific HRQOL (P = 0.001), but similar mental HRQOL (P = 0.43). Frail recipients experienced significantly greater rates of improvement in physical HRQOL (frail, 1.35 points/month; 95% confidence interval [CI], 0.65-2.05; nonfrail, 0.34 points/month; 95% CI, -0.17-0.85; P = 0.02) and kidney disease specific HRQOL (frail, 3.75 points/month; 95% CI, 2.89-4.60; nonfrail, 2.41 points/month; 95% CI, 1.78-3.04; P = 0.01), but no difference in mental HRQOL (frail, 0.54 points/month; 95% CI, -0.17-1.25; nonfrail, 0.46 points/month; 95% CI, -0.06-0.98; P = 0.85) post-KT. CONCLUSIONS: Despite decreased physiologic reserve, frail recipients experience improvement in post-KT physical and kidney disease-specific HRQOL better than nonfrail recipients. PMID- 28885492 TI - Cardiac Risk Score-Halfway There. PMID- 28885491 TI - Pancreas Transplantation With Grafts From Donors Deceased After Circulatory Death: 5 Years Single-Center Experience. AB - BACKGROUND: Donation after circulatory death (DCD) pancreas transplantation has been shown to be an additional way to deal with donor organ shortages. The results of 5-year DCD pancreas transplantation are presented. METHODS: A retrospective, single-center analysis (2011-2015) was performed to compare the results of donation after brain death (DBD) to DCD pancreas transplantation. RESULTS: During the study period, 104 pancreas transplantations (83 from DBD and 21 from DCD) were performed. Median Pancreas Donor Risk Index (PDRI) was 1.47, (DBD, 1.61 vs DCD, 1.35; P = 0.144). Without the factor DCD, PDRI from DCD donors was significantly lower (DBD, 1.61 vs DCD, 0.97; P < 0.001). Donor age was the only donor-related risk factor associated with pancreas graft survival (Hazard ratio, 1.06; P = 0.037). Postoperative bleeding and kidney delayed graft function occurred more frequently in recipients from DCD (P = 0.006). However, DCD pancreata had a lower incidence of thrombosis. Kidney and pancreas graft survival were equally good in both groups. CONCLUSIONS: Pancreas transplantation from DCD donors yields comparable results to DBD donors when PDRI of DCD is relatively low. Most DCD donors are younger donors with trauma as cause of death. These DCD pancreas grafts may be a better option to cope with increasing organ shortages than exploring the limits with older (and higher PDRI) DBD donors. PMID- 28885493 TI - Systematic Review and Meta-Analysis of Posttransplant Hepatic Artery and Biliary Complications in Patients Treated With Transarterial Chemoembolization Before Liver Transplantation. AB - BACKGROUND: Hepatic artery complications are feared complications after liver transplantation and may compromise the biliary tract, graft, and patient survival. The objective of this systematic review and meta-analysis was to compare risk of hepatic artery and biliary complications after liver transplantation in patients who underwent neoadjuvant transarterial chemoembolization (TACE) versus no TACE. METHODS: Comprehensive searches were performed in Embase, MEDLINE OvidSP, Web of Science, Google Scholar, and Cochrane databases to identify studies concerning hepatocellular cancer patients undergoing preliver transplantation TACE. Quality assessment of studies was done by the validated checklist of Downs and Black. Meta-analyses were performed to evaluate the incidence of all hepatic artery complications, hepatic artery thrombosis, and biliary tract complications, using binary random-effect models. RESULTS: Fourteen retrospective studies, representing 1122 TACE patients, met the inclusion criteria. Postoperative hepatic artery complications consisted of hepatic artery thrombosis, stenosis, and (pseudo)-aneurysms. Preliver transplantation TACE was significantly associated with occurrence of posttransplant hepatic artery complications (odds ratio, 1.57; 95% confidence interval, 1.09-2.26; P = 0.02). No significant association between neoadjuvant TACE and hepatic artery thrombosis alone or biliary tract complications was found. CONCLUSIONS: Patients treated with TACE before liver transplantation may be at increased risk for development of hepatic artery complications after liver transplantation. PMID- 28885495 TI - Isoglycyrrhizinate Magnesium Enhances Hepatoprotective Effect of FK506 on Ischemia-Reperfusion Injury Through HMGB1 Inhibition in a Rat Model of Liver Transplantation. AB - BACKGROUND: Ischemia-reperfusion injury after liver transplantation (LT) impairs graft function and affects prognosis of recipients. Isoglycyrrhizinate magnesium (Iso) is a hepatoprotective drug usually used after liver injury. In this study, we intended to explore whether Iso alone have protective effect after ischemia reperfusion injury in a rat model of liver transplantation. We also aimed to study whether Iso could enhance the hepatoprotective effect of FK506 (tacrolimus) and underlying mechanism. METHODS: Rats after LT were treated with different concentration of FK506 with or without, Iso or lower-dose FK506 plus Iso. Alanine transaminase, aspartate transaminase, and albumin level were measured after 48 hours, 72 hours, and 7 days. A cell ischemic/reperfusion model was established to further study the mechanism of hepatoprotective effect of FK506 and Iso. RESULTS: Iso treatment alone had no effect on liver grafts after LT, but lower-dose FK506 + Iso was better for maintenance of liver function than lower-dose FK506 alone at 48 hours, 72 hours, and 7 days after LT. In terms of mechanism, FK506 induced autophagy which resulted in significantly reduced apoptosis and maintained proliferative potential. However, autophagy induced by FK506 also lead to high mobility group box (HMGB) 1 release from nuclei, resulting in hepatocyte injury through triggering of p38 phosphorylation and chemokine release. Iso effectively inhibited the release of HMGB1 and downstream inflammatory cytokines. CONCLUSIONS: Iso could inhibit release of HMGB1 by FK506 and enhance the hepatoprotective effect of FK506 in rat LT. Combining Iso with FK506 would be promising for the patients after LT. PMID- 28885496 TI - beta Cell Replacement Therapy: The Next 10 Years. AB - beta cell replacement with either pancreas or islet transplantation has progressed immensely over the last decades with current 1- and 5-year insulin independence rates of approximately 85% and 50%, respectively. Recent advances are largely attributed to improvements in immunosuppressive regimen, donor selection, and surgical technique. However, both strategies are compromised by a scarce donor source. Xenotransplantation offers a potential solution by providing a theoretically unlimited supply of islets, but clinical application has been limited by concerns for a potent immune response against xenogeneic tissue. beta cell clusters derived from embryonic or induced pluripotent stem cells represent another promising unlimited source of insulin producing cells, but clinical application is pending further advances in the function of the beta cell like clusters. Exciting developments and rapid progress in all areas of beta cell replacement prompted a lively debate by members of the young investigator committee of the International Pancreas and Islet Transplant Association at the 15th International Pancreas and Islet Transplant Association Congress in Melbourne and at the 26th international congress of The Transplant Society in Hong Kong. This international group of young investigators debated which modality of beta cell replacement would predominate the landscape in 10 years, and their arguments are summarized here. PMID- 28885494 TI - Prevalence and Predictors of Patient-Reported Long-term Mental and Physical Health After Donation in the Adult-to-Adult Living-Donor Liver Transplantation Cohort Study. AB - BACKGROUND: Prospective and longitudinal studies have examined liver donors' medical outcomes beyond the first 1 to 2 years postdonation. There is no analogous longitudinal evidence on long-term psychosocial outcomes, including patient-reported clinically significant mental health problems and perceptions of physical well-being. We examined prevalence, descriptive characteristics, and predictors of diagnosable mental health conditions and self-reported physical health problems, including fatigue and pain, in the long-term years after liver donation. METHODS: Donors from 9 centers who initially completed telephone interviews at 3 to 10 years postdonation (mean, 5.8 years; SD, 1.9) were reinterviewed annually for 2 years using validated measures. Outcomes were examined descriptively. Repeated-measures regression analyses evaluated potential predictors and correlates of outcomes. RESULTS: Of 517 donors initially interviewed (66% of those eligible), 424 (82%) were reassessed at least once. Prevalence rates of major depression and clinically significant pain were similar to general population norms; average fatigue levels were better than norms. All prevalence rates showed little temporal change. Anxiety and alcohol use disorder rates exceeded normative rates at 1 or more assessments. Longer postdonation hospitalization, female sex, higher body mass index, concerns about donation related health effects, and burdensome donation-related financial costs were associated with increased risk for most outcomes (P's < 0.05). Men were at higher risk for alcohol use disorder (P < 0.001). CONCLUSIONS: Anxiety and alcohol use disorders were more common than would be expected; they may warrant increased research attention and clinical surveillance. Surveillance for long-term problems in the areas assessed may be optimized by targeting donors at higher risk based on identified predictors and correlates. PMID- 28885498 TI - Patient and Kidney Allograft Survival in Recipients With End-Stage Renal Disease From Amyloidosis. AB - BACKGROUND: Outcomes after kidney transplantation for patients with amyloidosis associated end-stage renal disease (ESRD) have not been well characterized. METHODS: We performed a retrospective propensity score matched cohort study with Cox proportional hazards modeling using data from the United Network of Organ Sharing including patients transplanted from 1987 to 2015 (N = 310 629). RESULTS: Amyloidosis patients (N = 576) had higher rates of death (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.28-1.95) and graft loss (HR, 1.49; 95% CI, 1.19-1.87) compared with nonamyloidosis patients. The results were similar when the cohort was restricted to patients transplanted on or after 2001 (HR, 1.72; 95% CI, 1.31-2.26 for death; HR, 1.77; 95% CI, 1.35-2.33 for graft loss). However, there was no significant difference in risk of death or graft loss when amyloidosis patients were compared with those with diabetes-associated ESRD (mortality: HR, 0.99; 95% CI, 0.84-1.17; allograft loss: HR, 1.00; 95% CI, 0.84 1.20), or when compared with elderly patients (age, >65 years at the time of transplant) (mortality: HR, 0.99; 95% CI, 0.81-1.21; graft loss: HR, 1.02; 95% CI, 0.82-1.26). CONCLUSIONS: For patients with amyloidosis-associated ESRD deemed suitable for transplantation, patient and graft survivals are diminished compared to kidney transplant recipients overall, but are comparable to other high-risk subgroups. PMID- 28885500 TI - Endocrine Surgery: A Hopkins Legacy. AB - : The field of Endocrine Surgery is linked to extraordinary contributions made by Hopkins leaders in surgery including William Stewart Halsted, Harvey Cushing, and John L Cameron. Halsted's contributions to the anatomic basis of thyroid and parathyroid surgery were based on his experimental and clinical work performed at Johns Hopkins Hospital. Halsted's disciple, Harvey Cushing, created the field of modern neurosurgery and recognized the disease and syndrome that are immortalized with his name. The Halstedian principles promulgated and transmitted by John L Cameron to subsequent generations of endocrine surgeons at Hopkins have transformed the field of Endocrine Surgery with the stamp of Johns Hopkins Hospital. PMID- 28885497 TI - Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection. AB - BACKGROUND: Little is known about how new-generation adenosine triphosphate competitive mechanistic target of rapamycin (mTOR) kinase inhibitors affect immunity and allograft rejection. METHODS: mTOR complex (C) 1 and 2 signaling in dendritic cells and T cells was analyzed by Western blotting, whereas immune cell populations in normal and heart allograft recipient mice were analyzed by flow cytometry. Alloreactive T cell proliferation was quantified in mixed leukocyte reaction; intracellular cytokine production and serum antidonor IgG levels were determined by flow analysis and immunofluorescence staining used to detect IgG in allografts. RESULTS: The novel target of rapamycin kinase inhibitor AZD2014 impaired dendritic cell differentiation and T cell proliferation in vitro and depressed immune cells and allospecific T cell responses in vivo. A 9-day course of AZD2014 (10 mg/kg, intraperitoneally, twice daily) or rapamycin (RAPA) (1 mg/kg, intraperitoneally, daily) prolonged median heart allograft survival time significantly (25 days for AZD2014, 100 days for RAPA, 9.5 days for control). Like RAPA, AZD2014 suppressed graft mononuclear cell infiltration, increased regulatory T cell to effector memory T cell ratios and reduced T follicular helper and B cells 7 days posttransplant. By 21 days (10 days after drug withdrawal), however, T follicular helper and B cells and donor-specific IgG1 and IgG2c antibody titers were significantly lower in RAPA-treated compared with AZD2014-treated mice. Elevated regulatory T cell to effector memory T cell ratios were maintained after RAPA, but not AZD2014 withdrawal. CONCLUSIONS: Immunomodulatory effects of AZD2014, unlike those of RAPA, were not sustained after drug withdrawal, possibly reflecting distinct pharmacokinetics or/and inhibitory effects of AZD2014 on mTORC2. PMID- 28885499 TI - A Concentric Neighborhood Solution to Disparity in Liver Access That Contains Current UNOS Districts. AB - BACKGROUND: Policymakers are deliberating reforms to reduce geographic disparity in liver allocation. Public comments and the United Network for Organ Sharing Liver and Intestinal Committee have expressed interest in refining the neighborhoods approach. Share 35 and Share 15 policies affect geographic disparity. METHODS: We construct concentric neighborhoods superimposing the current 11 regions. Using concepts from concentric circles, we construct neighborhoods for each donor service area (DSA) that consider all DSAs within 400, 500, or 600 miles as neighbors. We consider limiting each neighborhood to 10 DSAs and use no metrics for liver supplies and demands. We change Model for End Stage Liver Disease (MELD) thresholds for the Share 15 policy to 18 or 20 and apply 3- and 5-point MELD proximity boosts to enhance local priority, control travel distances, and reduce disparity. We conduct simulations comparing current allocation with the neighborhoods and sharing policies. RESULTS: Concentric neighborhoods structures provide an array of solutions where simulation results indicate that they reduce geographic disparity, annual mortalities, and the airplane travel distances by varying degrees. Tuning of the parameters and policy combinations can lead to beneficial improvements with acceptable transplant volume loss and reductions in geographic disparity and travel distance. Particularly, the 10-DSA, 500-mile neighborhood solution with Share 35, Share 15, and 0-point MELD boost achieves such while limiting transplant volume losses to below 10%. CONCLUSIONS: The current 11 districts can be adapted systematically by adding neighboring DSAs to improve geographic disparity, mortality, and airplane travel distance. Modifications to Share 35 and Share 15 policies result in further improvements. The solutions may be refined further for implementation. PMID- 28885501 TI - Outcomes of Abdominal Surgery in Patients With Mechanical Ventricular Assist Devices: A Multi-Institutional Study. AB - OBJECTIVE: The aim of this study was to examine the outcomes of elective and emergent abdominal operations performed in end-stage heart failure patients supported with ventricular assist devices (VADs). SUMMARY OF BACKGROUND DATA: With the growing volume of end-stage heart failure patients receiving VADs, an increasing number of these patients require surgery for noncardiac pathology. There is a paucity of studies on the safety of abdominal operations in this population. METHODS: We performed a retrospective chart review across 3 hospitals of patients with VADs who underwent abdominal surgeries between 2003 and 2015. We used Chi-square, Fisher exact, and Mann-Whitney U tests for comparison of elective and emergent cases. RESULTS: Fifty-seven patients underwent 63 operations, of which 23 operations were elective, 24 were emergent, and 16 were emergently performed in the same admission as VAD placement and analyzed separately. Patients undergoing elective versus emergent procedures had similar comorbidities (Charlson score 2.9 vs 3.0). 43% versus 32% of patients had VADs as a destination therapy. Although perioperative anticoagulation approach was variable, holding warfarin and starting heparin/enoxaparin/bivalirudin bridge was most common (65% vs 54%). Although 2-fold higher in the emergent group (50 vs 100 mL, P = 0.06), median estimated blood loss was low. Postoperative bleeding requiring transfusion was not very common (13% vs 8%), whereas rate of ischemic cerebrovascular accident (4% each) and venous thromboembolism was low (0% vs 13%, P = 0.23). Thirty-day mortality rate was 4% versus 17%, P = 0.19. CONCLUSION: VAD patients have an acceptable risk profile for abdominal surgery. PMID- 28885502 TI - Outcomes of Endovascular Repair for Abdominal Aortic Aneurysms: A Nationwide Survey in Japan. AB - OBJECTIVE: To analyze data on patients treated with a bifurcated stent graft for abdominal aortic aneurysm (AAA). BACKGROUND: The Japan Committee for Stentgraft Management (JACSM) was established in 2007 to manage the safety of endovascular aortic aneurysm repair (EVAR) in Japan. The JACSM registry includes detailed anatomical and clinical data of all patients who undergo stent graft insertion in Japan. METHODS: Among 51,380 patients treated with bifurcated stent graft for AAA, we identified 38,008 eligible patients (excluding those with rupture or insufficient data). The analyzed factors included age, sex, comorbidities, AAA pathology and etiology, aneurysm and neck diameters, 7 anti-instructions for use (IFU) factors, and endoleaks at hospital discharge. The endpoints were death, adverse events, sac dilatation (>=5 mm), and reintervention. RESULTS: The rates of intraoperative and in-hospital mortality were 0.08% and 1.07%, respectively. Infectious aneurysm and pseudo-aneurysm were associated with overall survival and reintervention. Older age, large aneurysm diameter, and all types of persistent endoleaks were strong predictors of adverse events, sac dilatation, and reintervention. Comorbid cerebrovascular disease, renal dysfunction, and respiratory disorders were also risk factors. In total, 47.6% of patients violated the IFU; among the anti-IFU factors assessed, poor access and severe neck calcification were strong risk factors for mortality, reintervention, and adverse events. The sac dilatation rate at 5 years was 23.3%. CONCLUSIONS: Although the analysis included EVAR with poor anatomy, the perioperative mortality rate was acceptable compared with that in previous large population studies. PMID- 28885503 TI - Commentary of "Why do General Surgeons Decide to Retire?" PMID- 28885505 TI - Current Surgical Therapy: John Cameron's Contribution to Surgical Education and Training via Textbook. PMID- 28885504 TI - Life-long Lessons Learned From John Cameron in 7 Words. PMID- 28885506 TI - The Theory and Practice of Pancreatic Surgery in France. AB - OBJECTIVE: Measure the caseload of pancreatectomies that influences their short term outcome, at a national level, and assess the applicability of a centralization policy. BACKGROUND: There is agreement that pancreatectomies should be centralized. However, previous studies have failed to accurately define a "high-volume" center. METHODS: French healthcare databases were screened to identify all adult patients who had elective pancreatectomies between 2007 and 2012. The patients' age, comorbidities, indication, and extent of surgery, and also the hospital administrative-type and location were retrieved. The annual caseload of pancreatectomy was calculated for each hospital facility. The primary endpoint was 90-day mortality. Spline modeling was used to identify the different annual-caseload that influenced mortality. Logistic regressions were performed to assess if their influence was independent of confounders, and the accuracy of the model calculated. RESULTS: Overall, 22,366 patients underwent a pancreatectomy and the mortality was 8.1%. Two cut-offs were identified (25 and 65 per year): compared with centers performing >65 resections per year, the adjusted OR of mortality was 1.865 (1.529-2.276) in centers performing <=25 resections per year and 1.234 (1.031-1.478) in those performing 26 to 65 resections per year. The average number of facilities performing <=25, 26 to 65, and >65 pancreatectomies per year was 456, 20, and 9, respectively. The percentage of patients operated in these facilities was 56.6%, 19.9%, and 23.3%, respectively.For pancreaticoduodenectomies (12,670 patients; mortality 9.2%), there were 2 cut offs (16 and 40 pancreaticoduodenectomies per year), and both were independent predictors of mortality (adjusted OR of 1.979 and 1.333). For distal pancreatectomies (7085 patients; 6.2% mortality), there were 2 cut-offs (13 and 25 distal pancreatectomies per year), but neither was an independent predictor of outcome (area under the receiver-operating characteristic curve of the model = 0.778). CONCLUSIONS: Centralization of pancreatic surgery is theoretically justified, but currently unrealizable. As the incidence of pancreatic cancer increases, there is an urgent need to improve the training of surgeons and develop both intermediate and high-volume centers. PMID- 28885507 TI - Appropriate Surgical Care: Who Decides?: The I. Ridgeway Trimble Lecture. PMID- 28885509 TI - Modeling Surgical Technical Skill Using Expert Assessment for Automated Computer Rating. AB - OBJECTIVE: Computer vision was used to predict expert performance ratings from surgeon hand motions for tying and suturing tasks. SUMMARY BACKGROUND DATA: Existing methods, including the objective structured assessment of technical skills (OSATS), have proven reliable, but do not readily discriminate at the task level. Computer vision may be used for evaluating distinct task performance throughout an operation. METHODS: Open surgeries was videoed and surgeon hands were tracked without using sensors or markers. An expert panel of 3 attending surgeons rated tying and suturing video clips on continuous scales from 0 to 10 along 3 task measures adapted from the broader OSATS: motion economy, fluidity of motion, and tissue handling. Empirical models were developed to predict the expert consensus ratings based on the hand kinematic data records. RESULTS: The predicted versus panel ratings for suturing had slopes from 0.73 to 1, and intercepts from 0.36 to 1.54 (Average R = 0.81). Predicted versus panel ratings for tying had slopes from 0.39 to 0.88, and intercepts from 0.79 to 4.36 (Average R = 0.57). The mean square error among predicted and expert ratings was consistently less than the mean squared difference among individual expert ratings and the eventual consensus ratings. CONCLUSIONS: The computer algorithm consistently predicted the panel ratings of individual tasks, and were more objective and reliable than individual assessment by surgical experts. PMID- 28885508 TI - Defining Benchmarks in Liver Transplantation: A Multicenter Outcome Analysis Determining Best Achievable Results. AB - : : This multicentric study of 17 high-volume centers presents 12 benchmark values for liver transplantation. Those values, mostly targeting markers of morbidity, were gathered from 2024 "low risk" cases, and may serve as reference to assess outcome of single or any groups of patients. OBJECTIVE: To propose benchmark outcome values in liver transplantation, serving as reference for assessing individual patients or any other patient groups. BACKGROUND: Best achievable results in liver transplantation, that is, benchmarks, are unknown. Consequently, outcome comparisons within or across centers over time remain speculative. METHODS: Out of 7492 liver transplantation performed in 17 international centers from 3 continents, we identified 2024 low risk adult cases with a laboratory model for end-stage liver disease score <=20 points, a balance of risk score <=9, and receiving a primary graft by donation after brain death. We chose clinically relevant endpoints covering intra- and postoperative course, with a focus on complications graded by severity including the complication comprehensive index (CCI). Respective benchmarks were derived from the median value in each center, and the 75 percentile was considered the benchmark cutoff. RESULTS: Benchmark cases represented 8% to 49% of cases per center. One-year patient-survival was 91.6% with 3.5% retransplantations. Eighty-two percent of patients developed at least 1 complication during 1-year follow-up. Biliary complications occurred in one-fifth of the patients up to 6 months after surgery. Benchmark cutoffs were <=4 days for ICU stay, <=18 days for hospital stay, <=59% for patients with severe complications (>= Grade III) and <=42.1 for 1-year CCI. Comparisons with the next higher risk group (model for end stage liver disease 21 30) disclosed an increase in morbidity but within benchmark cutoffs for most, but not all indicators, while in patients receiving a second graft from 1 center (n = 50) outcome values were all outside of benchmark values. CONCLUSIONS: Despite excellent 1-year survival, morbidity in benchmark cases remains high with half of patients developing severe complications during 1-year follow-up. Benchmark cutoffs targeting morbidity parameters offer a valid tool to assess higher risk groups. PMID- 28885510 TI - Pylorus Resection Does Not Reduce Delayed Gastric Emptying After Partial Pancreatoduodenectomy: A Blinded Randomized Controlled Trial (PROPP Study, DRKS00004191). AB - OBJECTIVES: The aim of this study was to investigate the effect of pylorus resection on postoperative delayed gastric emptying (DGE) after partial pancreatoduodenectomy (PD). BACKGROUND: PD is the standard treatment for tumors of the pancreatic head. Preservation of the pylorus has been widely accepted as standard procedure. DGE is a common complication causing impaired oral intake, prolonged hospital stay, and postponed further treatment. Recently, pylorus resection has been shown to reduce DGE. METHODS: Patients undergoing PD for any indication at the University of Heidelberg were randomized to either PD with pylorus preservation (PP) or PD with pylorus resection and complete stomach preservation (PR). The primary endpoint was DGE within 30 days according to the International Study Group of Pancreatic Surgery definition. RESULTS: Ninety-five patients were randomized to PP and 93 patients to PR. There were no baseline imbalances between the groups. Overall, 53 of 188 patients (28.2%) developed a DGE (grade: A 15.5%; B 8.8%; C 3.3%). In the PP group 24 of 95 patients (25.3%) and in the PR group 29 of 93 patients (31.2%) developed DGE (odds ratio 1.534, 95% confidence interval 0.788 to 2.987; P = 0.208). Higher BMI, indigestion, and intraabdominal major complications were significant risk factors for DGE. CONCLUSIONS: In this randomized controlled trial, pylorus resection during PD did not reduce the incidence or severity of DGE. The development of DGE seems to be multifactorial rather than attributable to pyloric dysfunction alone. Pylorus preservation should therefore remain the standard of care in PD. TRIAL REGISTRATION: German Clinical Trials Register DRKS00004191. PMID- 28885511 TI - Response: "Intraoperative Fluid Resuscitation: Importance of Individualized Treatment". PMID- 28885512 TI - Diagnosis and Treatment of Intestinal Melanoma Metastases in the Era of Effective Systemic Treatment: Retraction. PMID- 28885513 TI - Measuring Postoperative Complications: On the Right Path but Far Away From the Destination: Retraction. PMID- 28885514 TI - Helping Those Who Are Brought Into a Closer Connection With You. PMID- 28885515 TI - Ethics in Practice: From Moral Distress to Moral Resilience. PMID- 28885516 TI - Treating Acute Pain in the Opiate-Dependent Patient. AB - Opioid drugs, including prescription as well as heroin, have come to the national spotlight due to the unprecedented rate of overdose and addiction. The Centers for Disease Control and Prevention (CDC) has termed this problem as an "epidemic" that has reached record numbers of deaths in 2014. Approximately half of these deaths are the result from prescribed opioids. Also on the rise are the numbers of individuals who are diagnosed with chronic pain and are treated with opioids, methadone and buprenorphine. Individuals currently taking opioids for chronic pain confound the treatment of acute pain after traumatic injury. Goals of treatment include effective pain relief, prevention of opioid withdrawal, and managing the associated behavioral and psychological factors with drug addiction and dependence. The CDC has put forth guidelines on how to treat chronic pain but has yet to provide recommendations on how to treat acute pain in this unique population. The purpose of this literature review is to provide resources to treat pain, given a tolerant opioid-dependent patient. PMID- 28885518 TI - Dissemination of a Child Passenger Safety Program Through Trauma Center-Community Partnerships. PMID- 28885517 TI - Dissemination of a Child Passenger Safety Program Through Trauma Center-Community Partnerships. AB - Improper child passenger restraint use contributes to higher pediatric motor vehicle collision morbidity and mortality among cultural minority populations. Child passenger safety education improves caregiver knowledge of restraint use, but effective interventions require culturally specific programming. The purpose of this study was to evaluate the effectiveness of a child passenger safety education program culturally adapted through a pediatric trauma center's community partnerships. A nonexperimental observational cohort study using program evaluation data for the child passenger safety education programs during a 24-month period. Paired pretest/posttest self-reported survey responses measured changes in caregiver knowledge and self-efficacy of restraint use. Data were analyzed by class location and by caregiver language using a paired t test and Wilcoxon's signed ranks test. A total of 1,795 paired survey responses were collected in English, Spanish, or Russian. An increase in mean knowledge scores occurred overall, with a difference in mean of 0.565 (SE = 0.022, 95% CI [0.521, 0.607]). Stratification by class site and by language reflected significant increases in median scores, but findings were variable by study group. Pretest median scores for self-efficacy of restraint use were high for all groups, but the increases in posttest medians were also significant across groups (p <= .001). Caregiver knowledge and self-efficacy for child passenger restraint use increased after participation in the community classes. The pediatric trauma center's community partnerships facilitated uptake and adaption of the child passenger safety education programs and increased the injury prevention outreach to minority communities. PMID- 28885519 TI - Preparing Global Trauma Nurses for Leadership Roles in Global Trauma Systems. AB - Trauma leads to 5.7 million annual deaths globally, accounting for 25%-33% of global unintentional deaths and 90% of the global trauma burden in low- and middle-income countries. The Lancet Commission on Global Surgery and the World Health Organization assert that emergent and essential surgical capacity building and trauma system improvement are essential to address the global burden of trauma. In response, the Rutgers Global Surgery program, the School of Nursing and Medicine, and the Robert Wood Johnson University Hospital faculty collaborated in the first Interprofessional Models in Global Injury Care and Education Symposium in June 2016. This 2-week symposium combined lectures, high fidelity simulation, small group workshops, site visits to Level I trauma centers, and a 1-day training course from the Panamerican Trauma Society. The aim was to introduce global trauma nurses to trauma leadership and trauma system development. After completing the symposium, 10 nurses from China, Colombia, Kenya, Puerto Rico, and Uruguay were surveyed. Overall, 88.8% of participants reported high levels of satisfaction with the program and 100% stated being very satisfied with trauma lectures. Symposia, such as that developed and offered by Rutgers University, prepare nurses to address trauma within system-based care and facilitate trauma nursing leadership in their respective countries. PMID- 28885520 TI - Caring for Trauma Patients With Coexisting Heart Failure. AB - The coexisting conditions of traumatic injury coupled with a comorbid condition such as heart failure create a complex scenario for the trauma nurse to manage. Initial care of the trauma patient includes following the Advanced Trauma Life Support guidelines and managing the airway, breathing, and circulation (ABC) of the patient. Once the airway is secure and breathing is managed, the team addresses circulation. At this point in the patient's care, the team typically does not know which, if any, comorbid conditions exist. Managing circulation for a hypotensive or hypoperfused patient will most likely include 1-2 L of crystalloid solution being given intravenously. Although most patients can tolerate this fluid volume challenge, excess volume can be difficult for a patient with heart failure. This article describes the monitoring and management techniques that are recommended for patients presenting with trauma and the comorbid condition of heart failure. PMID- 28885521 TI - Caring for Trauma Patients With Coexisting Heart Failure. PMID- 28885523 TI - Debrief in Emergency Departments to Improve Compassion Fatigue and Promote Resiliency. PMID- 28885522 TI - Debrief in Emergency Departments to Improve Compassion Fatigue and Promote Resiliency. AB - The purpose of this case study was to describe compassion fatigue using one nurse's experience as an example and to present the process of Personal Reflective Debrief as an intervention to prevent compassion fatigue in emergency department (ED) nurses. Debriefing after adverse outcomes using a structured model has been used in health care as a nonthreatening and relatively low-cost way to discuss unanticipated outcomes, identify opportunities for improvement, and heal as a group. There are many methods of debrief tailored to specific timing around events, specific populations of health care workers, and amount of time for debriefing. Debrief with personal and group reflection will help develop insights that nurses may need to understand their own emotions and experiences, as well as to develop knowledge that can be used in subsequent situations. Regular engagement in a proactive scheduled Personal Reflective Debrief has been identified as a method of promoting resiliency in an environment where the realities of emergency nursing make compassion fatigue an imminent concern. Nurses working in the ED normally experience some level of stress because of high acuity patients and high patient volume; yet, repeated exposure puts them at risk for developing compassion fatigue. The Personal Reflective Debrief is one way emergency nurses can alleviate some of this caring-related stress and thereby become more resilient. Increasing nurses' resilience to workplace stress can counter compassion fatigue. The key is to provide planned, proactive resources to positively improve resiliency. PMID- 28885524 TI - Iliac Vascular Injury in the Absence of a Pelvic Fracture. AB - This case study presents a rare iliac vascular injury in the absence of a pelvic fracture. A 36-year-old man sustained a blunt injury after being stuck by a motor vehicle. The only positive computed tomographic finding was in the pelvis that showed a 4 * 2-cm left retroperitoneal soft-tissue collection, appearing to encompass the left common and left external iliac veins. A pelvic venogram was obtained on Day 2 revealing a focal injury to the left external iliac vein with 60% narrowing. The patient was treated with clopidogrel and acetylsalicylic acid and discharged from the hospital to his home 3 days later. A follow-up pelvic venogram in 6 weeks later showed complete healing of previously visualized left external iliac venous injury without any residual stenosis. PMID- 28885526 TI - Editorial. PMID- 28885527 TI - Interview With Eugene A. Woods, FACHE, President and CEO, Carolinas HealthCare System, Charlotte, North Carolina. PMID- 28885525 TI - Variables to Predict Mortality in Hip Fractures in Patients Over 65 Years of Age: A Study on the Role of Anticoagulation as a Risk Factor. AB - The objective of this research was to study the possible relationship between the consumption of dicoumarinic agents (understanding the consumption of acenocoumarol as regulated and monitored anticoagulation) and the mortality rate in people older than 65 years undergoing a hip fracture (HF) intervention. It was a retrospective, observational and descriptive study. Nine hundred fifty-seven patients were included who underwent an intervention for HF between the years 2012 and 2014 in a third-level hospital. Patients took acenocoumarol (16.1%), which compared with nonanticoagulated patients took longer in receiving intervention, they remained hospitalized for more days, and they presented greater mortality within the first year after the intervention. Likewise, those who presented greater risk according to the classification system used by the American Society of Anesthesiologists (ASA) to estimate the risk of anesthesia for the different states of the patients who were anticoagulated also suffered greater mortality. The next factors increased the mortality in the first year: advanced age, delayed surgery, male sex, need for transfusion, high international normalized ratio, consumption of acenocoumarol, and a high ASA risk. We concluded the consumption of acenocoumarol increased the risk of mortality within the first year after surgery in 1.3 of possible cases. Other risk factors that also independently increased the risk of mortality included advanced age, male sex, delayed surgery, the need for transfusions, and surgical risk (for high levels in the ASA classification). PMID- 28885528 TI - Every Moment Matters: Cultivating a Culture of C.A.R.E. PMID- 28885529 TI - The Three-Legged Stool: Why Safety, Quality, and Equity Depend on Each Other. PMID- 28885530 TI - Emotional Intelligence and Burnout in Academic Radiation Oncology Chairs. AB - EXECUTIVE SUMMARY: The importance of emotional intelligence (EI) in physicians has attracted attention as researchers begin to focus on the relationship of EI to retention, promotion, and productivity among academic physicians. However, to date, no formal evaluation of EI has been conducted among current department chairs. The objectives of this study were to assess the EI of current chairs of academic radiation oncology departments and to correlate EI with a self-reported assessment of burnout.The authors invited 95 chairs of academic radiation oncology departments to participate in a survey, approved by an institutional review board, consisting of the Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF) and the abbreviated Maslach Burnout Inventory (a-MBI). TEIQue-SF scores were evaluated for correlation with respondents' demographics and self reported burnout scores on the a-MBI. Sixty chairs responded to the survey, for a response rate of 63.2%. The median (interquartile range) TEIQue-SF for the responding cohort was 172 (155-182) out of a maximum possible score of 210. The a MBI emotional exhaustion and depersonalization subscores were low, with median (interquartile range) scores of 4 (2.25-6.75) and 1 (0-2.75) out of maximum possible scores of 18 and 30, respectively. Higher TEIQue-SF global scores were weakly correlated with decreased burnout. The study results show that academic radiation oncology chairs had a high EI and low rates of self-reported burnout. EI may be of increasing importance with respect to recruitment and retention of academic medical leaders. PMID- 28885531 TI - Practitioner Application: Emotional Intelligence and Burnout in Academic Radiation Oncology Chairs. PMID- 28885532 TI - Governance Practices in an Era of Healthcare Transformation: Achieving a Successful Turnaround. AB - EXECUTIVE SUMMARY: This article illustrates the successful application of principles established by the American Hospital Association (AHA) to foster hospital transformations (). We examined a small community hospital's successful transition from one emergency care center (ECC) physician group to another and the methods by which significant improvements in outcomes were achieved. The foundation of this transformation included a generative governance style at the board level, a shared governance model at the employee level, a renewed sense of employee and physician engagement, and a sense of individual accountability. Outcomes included improved communication, a more unified vision throughout the ECC (which led to improved efficiency and accountability among staff), improved metrics, and a positive impact on the community's perception of care. Press Ganey scores and ECC operational metrics demonstrated significant increases in patient satisfaction and decreases in wait times for seven operational metrics. These data serve as a proxy for the transformation's success. Structured interviews revealed an increase in employee satisfaction associated with the transition. The positive outcomes demonstrate the importance of the AHA-articulated governance principles. The AHA recommendations for a superior value-based care model closely align with the methods illustrated through Bristol Hospital's successful transformation. Other institutions can apply the lessons from this case study to drive positive change and improve patient care. PMID- 28885533 TI - Practitioner Application: A Method for a Successful Turnaround: Using Governance Practices in an Era of Healthcare Transformation. PMID- 28885534 TI - An Organizational Model for Excellence in Healthcare Delivery: Evidence From Winners of the Baldrige Quality Award. AB - EXECUTIVE SUMMARY: Winners of the Baldrige National Quality Award in healthcare have documented top quartile clinical outcomes and patient satisfaction across a variety of American communities and a full spectrum of care. Their results also show high levels of satisfaction among physicians, nurses, and other workers, as well as effective financial performance. The managerial methods they use collectively, the Baldrige model-are consistent with organizational theory literature and are found across all winners. The winners have sustained excellence after winning and expanded it by acquisition of other healthcare organizations.The model differs substantially from traditional management approaches in healthcare delivery. It is a comprehensive program that emphasizes a shared focus on excellence, systematically responsive management, evidence based medicine, multidimensional measures and negotiated goals, improvement of work processes, thorough training, and extensive rewards. The model could be expanded on a much larger scale. Doing so successfully would substantially improve the quality and cost of healthcare, as well as the satisfaction and commitment of care providers and other staff. The opportunity deserves further study and trial by large healthcare delivery systems, insurers, and consulting companies. PMID- 28885535 TI - Practitioner Application: An Organizational Model for Excellence in Healthcare Delivery: Evidence From Winners of the Baldrige Quality Award. PMID- 28885536 TI - Moving Upstream in U.S. Hospital Care Toward Investments in Population Health. AB - EXECUTIVE SUMMARY: The root causes for most health outcomes are often collectively referred to as the social determinants of health. Hospitals and health systems now must decide how much to "move upstream," or invest in programs that directly affect the social determinants of health. Moving upstream in healthcare delivery requires an acceptance of responsibility for the health of populations. We examine responses of 950 nonfederal, general hospitals in the United States to the 2015 American Hospital Association Population Health Survey to identify characteristics that distinguish those hospitals that are most aligned with population health and most engaged in addressing social determinants of health. Those "upstream" hospitals are significantly more likely to be large, not-for-profit, metropolitan, teaching-affiliated, and members of systems. Internally, the more upstream hospitals are more likely to organize their population health activities with strong executive-level involvement, full-time equivalent support, and coordination at the system level.The characteristics differentiating hospitals strongly involved in population health and upstream activity are not unlike those characteristics associated with diffusion of many innovations in hospitals. These hospitals may be the early adopters in a diffusion process that will eventually include most hospitals or, at least, most not-for-profit hospitals. Alternatively, the population health and social determinants movements could be transient or could be limited to a small portion of hospitals such as those identified here, with distinctive patient populations, missions, and resources. PMID- 28885537 TI - Practitioner Application: Moving Upstream in U.S. Hospital Care Toward Investments in Population Health. PMID- 28885538 TI - Clinical relevance of 18F-FDG PET/CT lower-limb imaging in patients with malignant cutaneous melanoma. AB - OBJECTIVE: The aim of this study was to assess the clinical relevance of imaging the lower limbs when using 2-(F)-fluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography with computed tomography (PET/CT) for malignant cutaneous melanoma in patients without previously known or suspected primary or metastatic melanoma lesions in the lower limbs. PATIENTS AND METHODS: We retrospectively assessed 880 consecutive F-FDG PET/CT scans performed for adult patients in a context of suspected melanoma spanning a period of 5 years. All scans were correlated with the associated patient records (clinical history, physical examinations, and pathology reports), as well as follow-up imaging examinations, up until at least 6 months after the end of the study. RESULTS: Among the 461 whole-body scans included for analysis, 109 reported unusual activity in the lower limbs, but with at most 21 scans showing lower-limb lesions attributed to melanoma on follow-up. No scan showed melanoma lesions exclusively in the lower limbs, and in no case did imaging the lower limbs upstage a patient. Imaging the lower limbs changed the actual clinical management of the melanoma for only one patient, with precautionary local radiation therapy administered following the detection of an asymptomatic distal femur bone metastasis in an otherwise plurimetastatic patient headed for palliative care. CONCLUSION: Our study, the largest of its kind, confirms that, when using F-FDG PET/CT for staging, restaging, or surveillance of malignant cutaneous melanoma in patients without previously known or suspected lower-limb melanoma lesions, imaging the lower extremities offers little additional clinically relevant information and stopping the scan at the proximal thighs has essentially no clinical impact. PMID- 28885539 TI - A comparison of 18F-FDG PET/MR with PET/CT in pulmonary tuberculosis. AB - PURPOSE: PET/computed tomography (CT) has been shown to detect lesions in patients with pulmonary tuberculosis (PTB) and may be useful for assessing PTB disease in clinical research studies. However, radiation dose is of concern for clinical research in individuals with an underlying curable disease. This study aimed to determine whether PET/MR is equivalent to PET/CT in PTB. MATERIALS AND METHODS: Ten patients with microbiologically confirmed PTB were recruited. Patients received 129.0+/-4.1 MBq of fluorine-18-fluorodeoxyglucose. Five of the 10 patients underwent a PET/MR scan, followed by PET/CT. The remaining five were first imaged on the PET/CT, followed by the PET/MRI. PET acquisition began at 66.7+/-14.4 min (mean+/-SD) after injection when performing PET/MR first (PET/CT: 117.2+/-5.6 min) and 92.4+/-7.6 min when patients were imaged on PET/MR second (PET/CT: 61.1+/-3.9 min). PET data were reconstructed iteratively with Ordinary Poisson Ordered-Subset Expectation-Maximization and reconstruction parameters were matched across the two scanners. A visual lesion detection task and a standardized uptake value (SUV) analysis were carried out. The CT Hounsfield unit values of PTB lesions were also compared with MR-based attenuation correction mu map tissue classes. RESULTS: A total of 108 PTB lesions were detected on PET/MR and 112 on PET/CT. SUV analysis was carried out on 50 of these lesions that were observed with both modalities. Mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) were significantly lower on PET/MR (SUVmean: 2.6+/-1.4; SUVmax: 4.3+/-2.5) than PET/CT (SUVmean: 3.5+/-1.5; SUVmax: 5.3+/-2.4). CONCLUSION: PET/MR visual performance was shown to be comparable to PET/CT in terms of the number of PTB lesions detected. SUVs were significantly lower on PET/MR. Dixon-based attenuation correction underestimates the linear attenuation coefficient of PTB lesions, resulting in lower SUVs compared with PET/CT. However, the use of PET/MR to measure the response of lung lesions to assess response to treatment in research studies is unlikely to be affected by these differences in quantification. PMID- 28885540 TI - Stress-only myocardial perfusion scintigraphy: a prospective study on the accuracy and observer agreement with quantitative coronary angiography as the gold standard. AB - OBJECTIVE: Patients with normal stress perfusion have an excellent prognosis. Prospective studies on the diagnostic accuracy of stress-only scans with contemporary, independent examinations as gold standards are lacking. PATIENTS AND METHODS: A total of 109 patients with typical angina and no previous coronary artery disease underwent a 2-day stress (exercise)/rest, gated, and attenuation corrected (AC), 99m-technetium-sestamibi perfusion study, followed by invasive coronary angiography. The stress datasets were evaluated twice by four physicians with two different training levels (expert and novice): familiar and unfamiliar with AC. The two experts also made a consensus reading of the integrated stress rest datasets. The consensus reading and quantitative data from the invasive coronary angiography were applied as reference methods. RESULTS: The sensitivity/specificity were 0.92-1.00/0.73-0.90 (reference: expert consensus reading), 0.93-0.96/0.63-0.82 (reference: >=1 stenosis>70%), and 0.75-0.88/0.70 0.88 (reference: >=1 stenosis>50%). The four readers showed a high and fairly equal sensitivity independent of their familiarity with AC. The expert familiar with AC had the highest specificity independent of the reference method. The intraobserver and interobserver agreements on the stress-only readings were good (readers without AC experience) to excellent (readers with AC experience). CONCLUSION: AC stress-only images yielded a high sensitivity independent of the training level and experience with AC of the nuclear physician, whereas the specificity correlated positively with both. Interobserver and intraobserver agreements tended to be the best for physicians with AC experience. PMID- 28885541 TI - Identification of optimal mask size parameter for noise filtering in 99mTc methylene diphosphonate bone scintigraphy images. AB - Tc-methylene diphosphonate (Tc-MDP) bone scintigraphy images have limited number of counts per pixel. A noise filtering method based on local statistics of the image produces better results than a linear filter. However, the mask size has a significant effect on image quality. In this study, we have identified the optimal mask size that yields a good smooth bone scan image. Forty four bone scan images were processed using mask sizes 3, 5, 7, 9, 11, 13, and 15 pixels. The input and processed images were reviewed in two steps. In the first step, the images were inspected and the mask sizes that produced images with significant loss of clinical details in comparison with the input image were excluded. In the second step, the image quality of the 40 sets of images (each set had input image, and its corresponding three processed images with 3, 5, and 7-pixel masks) was assessed by two nuclear medicine physicians. They selected one good smooth image from each set of images. The image quality was also assessed quantitatively with a line profile. Fisher's exact test was used to find statistically significant differences in image quality processed with 5 and 7-pixel mask at a 5% cut-off. A statistically significant difference was found between the image quality processed with 5 and 7-pixel mask at P=0.00528. The identified optimal mask size to produce a good smooth image was found to be 7 pixels. The best mask size for the John-Sen Lee filter was found to be 7*7 pixels, which yielded Tc methylene diphosphonate bone scan images with the highest acceptable smoothness. PMID- 28885542 TI - Correlation of the apparent diffusion coefficient and the standardized uptake value in neoplastic lesions: a meta-analysis. AB - OBJECTIVE: Diffusion-weighted imaging and fluorine-18-fluorodeoxyglucose PET are increasingly being recognized as feasible oncological techniques. The apparent diffusion coefficient (ADC) measured by diffusion-weighted imaging and the standardized uptake value (SUV) from fluorine-18-fluorodeoxyglucose PET have similar clinical applications. The aim of this study was to assess the correlation between these two parameters in various cancers. MATERIALS AND METHODS: Several major databases were searched for eligible studies. The correlation coefficient (rho) values were pooled in a random-effects model. Begg's test was used to analyze the existence of publication bias and the sources of heterogeneity were explored in subgroup analyses on the basis of study design, diagnostic method, scanning modality, and tumor type. RESULTS: Thirty-five articles were accepted. The pooled rho value of all of the accepted studies was 0.30 (95% confidence interval: -0.33 to -0.27), and notable heterogeneity was present (I=69.4%, P<0.001), which indicated a relatively weak negative correlation. The pooled rho values were -0.26, -0.33, -0.32, and -0.33 for the SUVmax/ADCmean, SUVmax/ADCmin, SUVmean/ADCmean, and SUVmean/ADCmin relationships, respectively. The study design and diagnostic method were potential sources of heterogeneity. Lung cancer showed a stronger correlation (rho=-0.42) than head and neck cancer (rho=-0.27), cervical cancer (rho=-0.21), and breast cancer (rho= 0.23). A Begg's test indicated no significant publication bias among the accepted studies (P>0.05). CONCLUSION: The two functional parameters of ADC and SUV showed a very weak inverse correlation, which may contribute toward a sophisticated characterization of tumor biology. However, the findings require further validation with trials with large samples and different tumor types. PMID- 28885543 TI - 3D Printed, Microgroove Pattern-Driven Generation of Oriented Ligamentous Architectures. AB - Specific orientations of regenerated ligaments are crucially required for mechanoresponsive properties and various biomechanical adaptations, which are the key interplay to support mineralized tissues. Although various 2D platforms or 3D printing systems can guide cellular activities or aligned organizations, it remains a challenge to develop ligament-guided, 3D architectures with the angular controllability for parallel, oblique or perpendicular orientations of cells required for biomechanical support of organs. Here, we show the use of scaffold design by additive manufacturing for specific topographies or angulated microgroove patterns to control cell orientations such as parallel (0 degrees ), oblique (45 degrees ) and perpendicular (90 degrees ) angulations. These results demonstrate that ligament cells displayed highly predictable and controllable orientations along microgroove patterns on 3D biopolymeric scaffolds. Our findings demonstrate that 3D printed topographical approaches can regulate spatiotemporal cell organizations that offer strong potential for adaptation to complex tissue defects to regenerate ligament-bone complexes. PMID- 28885544 TI - Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral. AB - Influenza viruses are respiratory pathogens that are responsible for annual influenza epidemics and sporadic influenza pandemics. Oseltamivir (Tamiflu(r)) is currently the only FDA-approved oral drug that is available for the prevention and treatment of influenza virus infection. However, its narrow therapeutic window, coupled with the increasing incidence of drug resistance, calls for the next generation of influenza antivirals. In this study, we discovered hesperadin, an aurora B kinase inhibitor, as a broad-spectrum influenza antiviral through forward chemical genomics screening. Hesperadin inhibits multiple human clinical isolates of influenza A and B viruses with single to submicromolar efficacy, including oseltamivir-resistant strains. Mechanistic studies revealed that hesperadin inhibits the early stage of viral replication by delaying the nuclear entry of viral ribonucleoprotein complex, thereby inhibiting viral RNA transcription and translation as well as viral protein synthesis. Moreover, a combination of hesperadin with oseltamivir shows synergistic antiviral activity, therefore hesperadin can be used either alone to treat infections by oseltamivir resistant influenza viruses or used in combination with oseltamivir to delay resistance evolution among oseltamivir-sensitive strains. In summary, the discovery of hesperadin as a broad-spectrum influenza antiviral offers an alternative to combat future influenza epidemics and pandemics. PMID- 28885546 TI - An Energy Efficient Technique Using Electric Active Shielding for Capacitive Coupling Intra-Body Communication. AB - Capacitive coupling intra-body communication (CC-IBC) has become one of the candidates for healthcare sensor networks due to its positive prevailing features of energy efficiency, transmission rate and security. Under the CC-IBC scheme, some of the electric field emitted from signal (SIG) electrode of the transmitter will couple directly to the ground (GND) electrode, acting equivalently as an internal impedance of the signal source and inducing considerable energy losses. However, none of the previous works have fully studied the problem. In this paper, the underlying theory of such energy loss is investigated and quantitatively evaluated using conventional parameters. Accordingly, a method of electric active shielding is proposed to reduce the displacement current across the SIG-GND electrodes, leading to less power loss. In addition, the variation of such loss in regard to frequency range and positions on human body was also considered. The theory was validated by finite element method simulation and experimental measurement. The prototype result shows that the receiving power has been improved by approximate 5.5 dBm while the total power consumption is maximally 9 mW less using the proposed technique, providing an energy efficient option in physical layer for wearable and implantable healthcare sensor networks. PMID- 28885545 TI - TRIM44 Is a Poor Prognostic Factor for Breast Cancer Patients as a Modulator of NF-kappaB Signaling. AB - Many of the tripartite motif (TRIM) proteins function as E3 ubiquitin ligases and are assumed to be involved in various events, including oncogenesis. In regard to tripartite motif-containing 44 (TRIM44), which is an atypical TRIM family protein lacking the RING finger domain, its pathophysiological significance in breast cancer remains unknown. We performed an immunohistochemical study of TRIM44 protein in clinical breast cancer tissues from 129 patients. The pathophysiological role of TRIM44 in breast cancer was assessed by modulating TRIM44 expression in MCF-7 and MDA-MB-231 breast cancer cells. TRIM44 strong immunoreactivity was significantly associated with nuclear grade (p = 0.033), distant disease-free survival (p = 0.031) and overall survival (p = 0.027). Multivariate analysis revealed that the TRIM44 status was an independent prognostic factor for distant disease-free survival (p = 0.005) and overall survival (p = 0.002) of patients. siRNA-mediated TRIM44 knockdown significantly decreased the proliferation of MCF-7 and MDA-MB-231 cells and inhibited the migration of MDA-MB-231 cells. Microarray analysis and qRT-PCR showed that TRIM44 knockdown upregulated CDK19 and downregulated MMP1 in MDA-MB-231 cells. Notably, TRIM44 knockdown impaired nuclear factor-kappa B (NF-kappaB)-mediated transcriptional activity stimulated by tumor necrosis factor alpha (TNFalpha). Moreover, TRIM44 knockdown substantially attenuated the TNFalpha-dependent phosphorylation of the p65 subunit of NF-kappaB and IkappaBalpha in both MCF-7 and MDA-MB-231 cells. TRIM44 would play a role in the progression of breast cancer by promoting cell proliferation and migration, as well as by enhancing NF kappaB signaling. PMID- 28885547 TI - A Stereo Dual-Channel Dynamic Programming Algorithm for UAV Image Stitching. AB - Dislocation is one of the major challenges in unmanned aerial vehicle (UAV) image stitching. In this paper, we propose a new algorithm for seamlessly stitching UAV images based on a dynamic programming approach. Our solution consists of two steps: Firstly, an image matching algorithm is used to correct the images so that they are in the same coordinate system. Secondly, a new dynamic programming algorithm is developed based on the concept of a stereo dual-channel energy accumulation. A new energy aggregation and traversal strategy is adopted in our solution, which can find a more optimal seam line for image stitching. Our algorithm overcomes the theoretical limitation of the classical Duplaquet algorithm. Experiments show that the algorithm can effectively solve the dislocation problem in UAV image stitching, especially for the cases in dense urban areas. Our solution is also direction-independent, which has better adaptability and robustness for stitching images. PMID- 28885548 TI - Novel Insights into the Adipokinome of Obese and Obese/Diabetic Mouse Models. AB - The group of adipokines comprises hundreds of biological active proteins and peptides released from adipose tissue. Alterations of those complex protein signatures are suggested to play a crucial role in the pathophysiology of multifactorial, metabolic diseases. We hypothesized that also the pathophysiology of type-2-diabetes is linked to the dysregulation of the adipocyte secretome. To test this, we investigated mouse models with monogenic defects in leptin signaling which are susceptible to adipositas (C57BL/6 Cg-Lepob (obob)) or adipositas with diabetes (C57BL/KS Cg-Leprdb (dbdb)) according to their genetic background. At the age of 17 weeks, visceral fat was obtained and primary murine adipocytes were isolated to harvest secretomes. Quantitative proteome analyses (LC-ESI-MS/MS) identified more than 800 potential secreted proteins. The secretome patterns revealed significant differences connected to the pathophysiology of obese mice. Pathway analyses indicated that these differences focus on exosome modelling, but failed to provide more precise specifications. To investigate the relationship of secretome data to insulin sensitivity, we examined the content of diabetogenic lipids, i.e., diacylglycerols (DAGs), identified as key players in lipid-induced insulin resistance. In contrast to obob mice, fat tissue of dbdb mice showed elevated DAG content, especially of DAG species with saturated fatty acid C16:0 and C18:0, while unsaturated fatty acid C16:1 were only changed in obob. Furthermore, DAG signatures of the models specifically correlate to secreted regulated adipokines indicating specific pathways. In conclusion, our data further support the concept that the fat tissue is an endocrine organ that releases bioactive factors corresponding to adipose tissue health status. PMID- 28885550 TI - Methods for Real-Time Prediction of the Mode of Travel Using Smartphone-Based GPS and Accelerometer Data. AB - We propose and compare combinations of several methods for classifying transportation activity data from smartphone GPS and accelerometer sensors. We have two main objectives. First, we aim to classify our data as accurately as possible. Second, we aim to reduce the dimensionality of the data as much as possible in order to reduce the computational burden of the classification. We combine dimension reduction and classification algorithms and compare them with a metric that balances accuracy and dimensionality. In doing so, we develop a classification algorithm that accurately classifies five different modes of transportation (i.e., walking, biking, car, bus and rail) while being computationally simple enough to run on a typical smartphone. Further, we use data that required no behavioral changes from the smartphone users to collect. Our best classification model uses the random forest algorithm to achieve 96.8% accuracy. PMID- 28885549 TI - MDG-1, a Potential Regulator of PPARalpha and PPARgamma, Ameliorates Dyslipidemia in Mice. AB - Hyperlipidemia is a serious epidemic disease caused by lipid metabolism disorder, which is harmful to human health. MDG-1, a beta-d-fructan polysaccharide extracted from Ophiopogon japonicus, has been shown to improve abnormal blood lipid levels and alleviate diabetes. However, the underlying mechanism on hyperlipidemia is largely unknown. In this study, male C57BL/6 mice were randomly separated into three groups, respectively: low-fat diet (Con), high-fat diet (HFD), and high-fat diet plus 50/00 MDG-1 (HFD + MDG-1). Body weight was measured and the serum lipid levels were analyzed. Using gene microarray, various core pathways, together with levels of gene expression within hepatocytes, were analyzed. RT-PCR was used to confirm the identity of the differentially expressed genes. MDG-1 could prevent obesity in HFD-induced mice and improve abnormal serum lipids. Besides, MDG-1 could regulate hyperlipidemia symptoms, specifically, and decrease fasting blood glucose, improve glucose tolerance, and ameliorate insulin resistance. According to results from gene microarray, most of the identified pathways were involved in the digestion and absorption of fat, biosynthesis, and catabolism of fatty acids as well as the secretion and biological synthesis of bile acids. Furthermore, MDG-1 may act upon peroxisome proliferator-activated receptors (PPAR) alpha and gamma, activating PPARalpha whilst inhibiting PPARgamma, thus having a potent hypolipidemic effect. PMID- 28885551 TI - Design and Validation of a 150 MHz HFFQCM Sensor for Bio-Sensing Applications. AB - Acoustic wave resonators have become suitable devices for a broad range of sensing applications due to their sensitivity, low cost, and integration capability, which are all factors that meet the requirements for the resonators to be used as sensing elements for portable point of care (PoC) platforms. In this work, the design, characterization, and validation of a 150 MHz high fundamental frequency quartz crystal microbalance (HFF-QCM) sensor for bio sensing applications are introduced. Finite element method (FEM) simulations of the proposed design are in good agreement with the electrical characterization of the manufactured resonators. The sensor is also validated for bio-sensing applications. For this purpose, a specific sensor cell was designed and manufactured that addresses the critical requirements associated with this type of sensor and application. Due to the small sensing area and the sensor's fragility, these requirements include a low-volume flow chamber in the nanoliter range, and a system approach that provides the appropriate pressure control for assuring liquid confinement while maintaining the integrity of the sensor with a good base line stability and easy sensor replacement. The sensor characteristics make it suitable for consideration as the elemental part of a sensor matrix in a multichannel platform for point of care applications. PMID- 28885553 TI - Deviation of Chinese Adults' Diet from the Chinese Food Pagoda 2016 and Its Association with Adiposity. AB - Changing diet in China contributes to a raising prevalence of overweight and obesity. This study aimed to evaluate the dietary status of Chinese adults (20-59 years old) using the China Food Pagoda (CFP) proposed in the Chinese Dietary Guidelines 2016 (CDG), and investigate the association between adiposity and deviation of real diet from CFP using an ordered logistic regression. Results showed that the consumption of fruits, eggs, meat, and poultry increased significantly during 2004-2011, while the consumption of cereal, potatoes, and beans dropped down significantly during the same period (all p < 0.05). Meanwhile, great disparity was detected between real consumption and recommended intake in CFP. In particular, a deficient intake was found for milk and milk products, eggs, and fruit, while over-consumption was observed for cereal, potatoes and beans, meat and poultry, legumes and nuts, oil, and salt. In addition, over-consumption of cereal, legumes and nuts, and salt, as well as under-consumption of vegetables, and meat and poultry, were associated with a higher risk of having high body mass index (BMI), while lower consumption of cereal, potatoes and beans, eggs, and higher consumption of vegetables contributed to low hazard of overweight/obesity (all p < 0.05). The huge disparity between real consumption and the CFP calls for specific health education campaigns. PMID- 28885552 TI - Structure of Pigment Metabolic Pathways and Their Contributions to White Tepal Color Formation of Chinese Narcissus tazetta var. chinensis cv Jinzhanyintai. AB - Chinese narcissus (Narcissus tazetta var. chinensis) is one of the ten traditional flowers in China and a famous bulb flower in the world flower market. However, only white color tepals are formed in mature flowers of the cultivated varieties, which constrains their applicable occasions. Unfortunately, for lack of genome information of narcissus species, the explanation of tepal color formation of Chinese narcissus is still not clear. Concerning no genome information, the application of transcriptome profile to dissect biological phenomena in plants was reported to be effective. As known, pigments are metabolites of related metabolic pathways, which dominantly decide flower color. In this study, transcriptome profile and pigment metabolite analysis methods were used in the most widely cultivated Chinese narcissus "Jinzhanyintai" to discover the structure of pigment metabolic pathways and their contributions to white tepal color formation during flower development and pigmentation processes. By using comparative KEGG pathway enrichment analysis, three pathways related to flavonoid, carotenoid and chlorophyll pigment metabolism showed significant variations. The structure of flavonoids metabolic pathway was depicted, but, due to the lack of F3'5'H gene; the decreased expression of C4H, CHS and ANS genes; and the high expression of FLS gene, the effect of this pathway to synthesize functional anthocyanins in tepals was weak. Similarly, the expression of DXS, MCT and PSY genes in carotenoids synthesis sub-pathway was decreased, while CCD1/CCD4 genes in carotenoids degradation sub-pathway was increased; therefore, the effect of carotenoids metabolic pathway to synthesize adequate color pigments in tepals is restricted. Interestingly, genes in chlorophyll synthesis sub-pathway displayed uniform down-regulated expression, while genes in heme formation and chlorophyll breakdown sub-pathways displayed up-regulated expression, which also indicates negative regulation of chlorophyll formation. Further, content change trends of various color metabolites detected by HPLC in tepals are consistent with the additive gene expression patterns in each pathway. Therefore, all three pathways exhibit negative control of color pigments synthesis in tepals, finally resulting in the formation of white tepals. Interestingly, the content of chlorophyll was more than 10-fold higher than flavonoids and carotenoids metabolites, which indicates that chlorophyll metabolic pathway may play the major role in deciding tepal color formation of Chinese narcissus. PMID- 28885555 TI - A UWB/Improved PDR Integration Algorithm Applied to Dynamic Indoor Positioning for Pedestrians. AB - Inertial sensors are widely used in various applications, such as human motion monitoring and pedestrian positioning. However, inertial sensors cannot accurately define the process of human movement, a limitation that causes data drift in the process of human body positioning, thus seriously affecting positioning accuracy and stability. The traditional pedestrian dead-reckoning algorithm, which is based on a single inertial measurement unit, can suppress the data drift, but fails to accurately calculate the number of walking steps and heading value, thus it cannot meet the application requirements. This study proposes an indoor dynamic positioning method with an error self-correcting function based on the symmetrical characteristics of human motion to obtain the definition basis of human motion process quickly and to solve the abovementioned problems. On the basis of this proposed method, an ultra-wide band (UWB) method is introduced. An unscented Kalman filter is applied to fuse inertial sensors and UWB data, inertial positioning is applied to compensation for the defects of susceptibility to UWB signal obstacles, and UWB positioning is used to overcome the error accumulation of inertial positioning. The above method can improve both the positioning accuracy and the response of the positioning results. Finally, this study designs an indoor positioning test system to test the static and dynamic performances of the proposed indoor positioning method. Results show that the positioning system both has high accuracy and good real-time performance. PMID- 28885554 TI - Advances in Genomic Profiling and Analysis of 3D Chromatin Structure and Interaction. AB - Recent sequence-based profiling technologies such as high-throughput sequencing to detect fragment nucleotide sequence (Hi-C) and chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) have revolutionized the field of three dimensional (3D) chromatin architecture. It is now recognized that human genome functions as folded 3D chromatin units and looping paradigm is the basic principle of gene regulation. To better interpret the 3D data dramatically accumulating in past five years and to gain deep biological insights, huge efforts have been made in developing novel quantitative analysis methods. However, the full understanding of genome regulation requires thorough knowledge in both genomic technologies and their related data analyses. We summarize the recent advances in genomic technologies in identifying the 3D chromatin structure and interaction, and illustrate the quantitative analysis methods to infer functional domains and chromatin interactions, and further elucidate the emerging single-cell Hi-C technique and its computational analysis, and finally discuss the future directions such as advances of 3D chromatin techniques in diseases. PMID- 28885556 TI - Combining Multi-Source Remotely Sensed Data and a Process-Based Model for Forest Aboveground Biomass Updating. AB - Monitoring and understanding the spatio-temporal variations of forest aboveground biomass (AGB) is a key basis to quantitatively assess the carbon sequestration capacity of a forest ecosystem. To map and update forest AGB in the Greater Khingan Mountains (GKM) of China, this work proposes a physical-based approach. Based on the baseline forest AGB from Landsat Enhanced Thematic Mapper Plus (ETM+) images in 2008, we dynamically updated the annual forest AGB from 2009 to 2012 by adding the annual AGB increment (ABI) obtained from the simulated daily and annual net primary productivity (NPP) using the Boreal Ecosystem Productivity Simulator (BEPS) model. The 2012 result was validated by both field- and aerial laser scanning (ALS)-based AGBs. The predicted forest AGB for 2012 estimated from the process-based model can explain 31% (n = 35, p < 0.05, RMSE = 2.20 kg/m2) and 85% (n = 100, p < 0.01, RMSE = 1.71 kg/m2) of variation in field- and ALS-based forest AGBs, respectively. However, due to the saturation of optical remote sensing-based spectral signals and contribution of understory vegetation, the BEPS-based AGB tended to underestimate/overestimate the AGB for dense/sparse forests. Generally, our results showed that the remotely sensed forest AGB estimates could serve as the initial carbon pool to parameterize the process based model for NPP simulation, and the combination of the baseline forest AGB and BEPS model could effectively update the spatiotemporal distribution of forest AGB. PMID- 28885557 TI - Evaluation of a Pilot Implementation to Integrate Alcohol-Related Care within Primary Care. AB - Alcohol use is a major cause of disability and death worldwide. To improve prevention and treatment addressing unhealthy alcohol use, experts recommend that alcohol-related care be integrated into primary care (PC). However, few healthcare systems do so. To address this gap, implementation researchers and clinical leaders at Kaiser Permanente Washington partnered to design a high quality Program of Sustained Patient-centered Alcohol-related Care (SPARC). Here, we describe the SPARC pilot implementation, evaluate its effectiveness within three large pilot sites, and describe the qualitative findings on barriers and facilitators. Across the three sites (N = 74,225 PC patients), alcohol screening increased from 8.9% of patients pre-implementation to 62% post-implementation (p < 0.0001), with a corresponding increase in assessment for alcohol use disorders (AUD) from 1.2 to 75 patients per 10,000 seen (p < 0.0001). Increases were sustained over a year later, with screening at 84.5% and an assessment rate of 81 patients per 10,000 seen across all sites. In addition, there was a 50% increase in the number of new AUD diagnoses (p = 0.0002), and a non-statistically significant 54% increase in treatment within 14 days of new diagnoses (p = 0.083). The pilot informed an ongoing stepped-wedge trial in the remaining 22 PC sites. PMID- 28885558 TI - The Relationship between Survival Sex and Borderline Personality Disorder Symptoms in a High Risk Female Population. AB - Engaging in survival sex and mental illness are overrepresented within homeless populations. This article assesses the relationship between symptoms of borderline personality disorder (BPD) and engaging in survival sex among homeless women. One hundred and fifty-eight homeless women completed surveys on self reported BPD symptomology and sexual history. Bivariate and multivariate analyses conducted in this study provided insights into the association of experiencing BPD symptoms and engaging in survival sex. Results indicate that some symptoms of BPD are robustly correlated with engaging in survival sex among homeless adult women. Implications for service agencies and others working with at-risk female populations are discussed. PMID- 28885559 TI - A Critical Review on Health Promoting Benefits of Edible Mushrooms through Gut Microbiota. AB - Mushrooms have long been used for medicinal and food purposes for over a thousand years, but a complete elucidation of the health-promoting properties of mushrooms through regulating gut microbiota has not yet been fully exploited. Mushrooms comprise a vast, and yet largely untapped, source of powerful new pharmaceutical substances. Mushrooms have been used in health care for treating simple and common diseases, like skin diseases and pandemic diseases like AIDS. This review is aimed at accumulating the health-promoting benefits of edible mushrooms through gut microbiota. Mushrooms are proven to possess anti-allergic, anti cholesterol, anti-tumor, and anti-cancer properties. Mushrooms are rich in carbohydrates, like chitin, hemicellulose, beta and alpha-glucans, mannans, xylans, and galactans, which make them the right choice for prebiotics. Mushrooms act as a prebiotics to stimulate the growth of gut microbiota, conferring health benefits to the host. In the present review, we have summarized the beneficial activities of various mushrooms on gut microbiota via the inhibition of exogenous pathogens and, thus, improving the host health. PMID- 28885560 TI - A Novel Energy-Efficient Approach for Human Activity Recognition. AB - In this paper, we propose a novel energy-efficient approach for mobile activity recognition system (ARS) to detect human activities. The proposed energy efficient ARS, using low sampling rates, can achieve high recognition accuracy and low energy consumption. A novel classifier that integrates hierarchical support vector machine and context-based classification (HSVMCC) is presented to achieve a high accuracy of activity recognition when the sampling rate is less than the activity frequency, i.e., the Nyquist sampling theorem is not satisfied. We tested the proposed energy-efficient approach with the data collected from 20 volunteers (14 males and six females) and the average recognition accuracy of around 96.0% was achieved. Results show that using a low sampling rate of 1Hz can save 17.3% and 59.6% of energy compared with the sampling rates of 5 Hz and 50 Hz. The proposed low sampling rate approach can greatly reduce the power consumption while maintaining high activity recognition accuracy. The composition of power consumption in online ARS is also investigated in this paper. PMID- 28885561 TI - Acute and Late Toxicities of Concurrent Chemoradiotherapy for Locally-Advanced Non-Small Cell Lung Cancer. AB - For patients with unresectable locally-advanced non-small cell lung cancer (LA NSCLC), concurrent chemoradiotherapy improves overall survival as compared to sequential chemotherapy and radiation therapy, but is associated with higher rates of toxicities. Acute, clinically significant esophagitis or pneumonitis can occur in one in five patients. The risks of esophagitis and pneumonitis can impact the decision to deliver concurrent therapy and limit the total dose of radiation therapy that is delivered. Hematologic toxicities and emesis are common toxicities from systemic therapies for LA-NSCLC and can result in delaying chemotherapy dosing or chemotherapy dose reductions. Late treatment morbidities, including pulmonary fibrosis and cardiac toxicities, can also significantly impact quality of life and potentially even survival. Recent advances in radiation therapy treatment delivery, better knowledge of normal tissue radiotherapy tolerances and more widespread and improved uses of supportive care and medical management of systemic therapy toxicities have improved the therapeutic ratio and reduced the rates of chemoradiotherapy-induced toxicities. This review details the acute and late toxicities associated with definitive chemoradiotherapy for LA-NSCLC and discusses toxicity management and strategies to mitigate the risks of treatment-related toxicities. PMID- 28885562 TI - Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells. AB - Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non-transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours. PMID- 28885564 TI - Relationship between the Nutritional Status of Vitamin A per Trimester of Pregnancy with Maternal Anthropometry and Anemia after Roux-en-Y Gastric Bypass. AB - The aim of this study was to compare the nutritional status of vitamin A per trimester of pregnancy, as well as to assess its influence on pre-pregnancy BMI, total gestational weight gain (TGWG) and presence of anemia in women who had previously undergone Roux-en-Y gastric bypass (RYGB). An analytical, longitudinal and retrospective study comprising 30 pregnant women who had previously undergone RYGB was undertaken. In all trimesters of pregnancy, the serum concentrations of retinol, beta-carotene, stages of vitamin A deficiency (VAD), night blindness (NB), anemia and anthropometric variables were assessed. VAD in pregnancy affected 90% of women, 86.7% developed NB and 82.8% had mild VAD. TGWG above/below the recommended range was related to the low serum concentrations of beta-carotene (p = 0.045) in the second trimester and women with TGWG above the recommended range showed 100% of inadequacy of this nutrient in the third trimester. Among the pregnant women with anemia, 90.9% had VAD and 86.4% had NB. This study highlights the importance of monitoring the nutritional status of vitamin A in prenatal care, due to its relationship with TGWG and the high percentage of VAD and NB found since the beginning of pregnancy. It also reaffirms the use of the cut-off <1.05 MUmol/L for determining VAD. PMID- 28885565 TI - Tracking Dietary Patterns over 20 Years from Childhood through Adolescence into Young Adulthood: The Saskatchewan Pediatric Bone Mineral Accrual Study. AB - Dietary patterns established during adolescence might play a role in adulthood disease. We examined the stability of dietary patterns (DPs) from childhood through adolescence and into young adulthood (from age 8 to 34 years). Data from 130 participants (53 females) of Saskatchewan Pediatric Bone Mineral Accrual Study (aged 8-15 years, at baseline) were included. Multiple 24-h recalls were collected annually from 1991 to 1997, 2002 to 2005, and 2010 and 2011. Using principal component analysis, "Vegetarian-style", "Western-like", "High-fat, high protein", "Mixed", and "Snack" DPs were derived at baseline. Applied DP scores for all annual measurements were calculated using factor loading of baseline DPs and energy-adjusted food group intakes. We analyzed data using generalized estimating equations. The tracking coefficient represents correlation between baseline dietary pattern scores and all other follow-up dietary pattern scores. We found a moderate tracking for the "Vegetarian-style" (beta = 0.44, p < 0.001) and "High-fat, high-protein" (beta = 0.39, p < 0.001) DPs in females and "Vegetarian-style" DP (beta = 0.30, p < 0.001) in males. The remaining DPs showed poor-to-fair tracking in both sexes. No tracking for "Western-like" DP in females was observed. Assessing overall change in DP scores from childhood to young adulthood showed an increasing trend in adherence to "Vegetarian-style" DP and decreasing trend in adherence to "High-fat, high-protein" DP by age in both sexes (p < 0.001), while "Western-like" and "Mixed" DP scores increased only in males (p < 0.001). These findings suggest that healthy dietary habits established during childhood and adolescence moderately continue into adulthood. PMID- 28885563 TI - The Effect of Sepsis on the Erythrocyte. AB - Sepsis induces a wide range of effects on the red blood cell (RBC). Some of the effects including altered metabolism and decreased 2,3-bisphosphoglycerate are preventable with appropriate treatment, whereas others, including decreased erythrocyte deformability and redistribution of membrane phospholipids, appear to be permanent, and factors in RBC clearance. Here, we review the effects of sepsis on the erythrocyte, including changes in RBC volume, metabolism and hemoglobin's affinity for oxygen, morphology, RBC deformability (an early indicator of sepsis), antioxidant status, intracellular Ca2+ homeostasis, membrane proteins, membrane phospholipid redistribution, clearance and RBC O2-dependent adenosine triphosphate efflux (an RBC hypoxia signaling mechanism involved in microvascular autoregulation). We also consider the causes of these effects by host mediated oxidant stress and bacterial virulence factors. Additionally, we consider the altered erythrocyte microenvironment due to sepsis induced microvascular dysregulation and speculate on the possible effects of RBC autoxidation. In future, a better understanding of the mechanisms involved in sepsis induced erythrocyte pathophysiology and clearance may guide improved sepsis treatments. Evidence that small molecule antioxidants protect the erythrocyte from loss of deformability, and more importantly improve septic patient outcome suggest further research in this area is warranted. While not generally considered a critical factor in sepsis, erythrocytes (and especially a smaller subpopulation) appear to be highly susceptible to sepsis induced injury, provide an early warning signal of sepsis and are a factor in the microvascular dysfunction that has been associated with organ dysfunction. PMID- 28885566 TI - Effects of Cinnamon Consumption on Glycemic Indicators, Advanced Glycation End Products, and Antioxidant Status in Type 2 Diabetic Patients. AB - The aim of the current study was to determine the effect of a daily intake of three grams of cinnamon over eight weeks on glycemic indicators, advanced glycation end products, and antioxidant status in patients with type 2 diabetes. In a double-blind, randomized, placebo controlled clinical trial study, 44 patients with type 2 diabetes, aged 57 +/- 8 years, were randomly assigned to take either a three g/day cinnamon supplement (n = 22) or a placebo (n = 22) for eight weeks. We measured the fasting blood glucose, insulin, hemoglobinbA1c, homeostasis model assessment for insulin resistance (HOMA-IR), carboxymethyl lysine, total antioxidant capacity, and malondialdehyde levels at the beginning and the end of the study. Thirty-nine patients (20 in the intervention group and 19 in the control group) completed the study. After an eight-week intervention, changes in the level of fasting blood glucose, insulin, hemoglobinbA1c, HOMA-IR, carboxymethyl lysine, total antioxidant capacity, and malondialdehyde were not significant in either group, nor were any significant differences between groups observed in these glycemic and inflammatory indicators at the end of the intervention. Our study revealed that cinnamon supplementation had no significant effects on glycemic and inflammatory indicators in patients with type 2 diabetes. PMID- 28885568 TI - Emotion-Based Cognition in Mice Is Differentially Influenced by Dose and Chemical Form of Dietary Docosahexaenoic Acid. AB - Docosahexaenoic acid (DHA) is a major constituent, and primary omega-3 fatty acid, in the brain. Evidence suggests that DHA consumption may promote cognitive functioning and prevent cognitive decline, and these effects may be particularly relevant in the context of fear or stress. However, the potency and efficacy of dietary DHA may depend on the form of DHA (e.g., phospholipid; PL vs. triglyceride; TG). In this study, we compared in mice the effects of consuming PL and TG forms of DHA on associative, avoidance (fear) based learning and memory. Diets consisted of either no DHA or 1%, 2%, and 4% PL- or TG-DHA. After 4 weeks on the test diets (n = 12/group), we used the 3-day passive avoidance (PA) and elevated plus maze (EPM) to examine fear and fear-associated learning and memory. We found a significant (p < 0.05) diet by time interaction in the PA and EPM. Compared to the control and the 1% TG-DHA group, mice consuming the diet supplemented with 1% PL-DHA displayed a significantly greater latency by test day 2 in the 3-day PA. No differences in latency between any of the groups were observed during trials 1 and 3. Mice consuming the 2% PL-DHA diet spent significantly more time frequenting the open arms during the first minute, but not the last 4 min, of the test. Compared to all other groups, mice fed the 4% TG DHA diet had increased spleen, liver, and visceral fat weight. Consumption of the lower dose PL-DHA may confer enhanced efficacy, particularly on fear-based learning behavior. PMID- 28885567 TI - Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy-Mitochondria, Calcium Dynamics and Reactive Oxygen Species. AB - Acquired epilepsies can arise as a consequence of brain injury and result in unprovoked seizures that emerge after a latent period of epileptogenesis. These epilepsies pose a major challenge to clinicians as they are present in the majority of patients seen in a common outpatient epilepsy clinic and are prone to pharmacoresistance, highlighting an unmet need for new treatment strategies. Metabolic and homeostatic changes are closely linked to seizures and epilepsy, although, surprisingly, no potential treatment targets to date have been translated into clinical practice. We summarize here the current knowledge about metabolic and homeostatic changes in seizures and acquired epilepsy, maintaining a particular focus on mitochondria, calcium dynamics, reactive oxygen species and key regulators of cellular metabolism such as the Nrf2 pathway. Finally, we highlight research gaps that will need to be addressed in the future which may help to translate these findings into clinical practice. PMID- 28885569 TI - Re-Assembly and Analysis of an Ancient Variola Virus Genome. AB - We report a major improvement to the assembly of published short read sequencing data from an ancient variola virus (VARV) genome by the removal of contig-capping sequencing tags and manual searches for gap-spanning reads. The new assembly, together with camelpox and taterapox genomes, permitted new dates to be calculated for the last common ancestor of all VARV genomes. The analysis of recently sequenced VARV-like cowpox virus genomes showed that single nucleotide polymorphisms (SNPs) and amino acid changes in the vaccinia virus (VACV)-Cop-O1L ortholog, predicted to be associated with VARV host specificity and virulence, were introduced into the lineage before the divergence of these viruses. A comparison of the ancient and modern VARV genome sequences also revealed a measurable drift towards adenine + thymine (A + T) richness. PMID- 28885570 TI - Litchi chinensis as a Functional Food and a Source of Antitumor Compounds: An Overview and a Description of Biochemical Pathways. AB - Litchi is a tasty fruit that is commercially grown for food consumption and nutritional benefits in various parts of the world. Due to its biological activities, the fruit is becoming increasingly known and deserves attention not only for its edible part, the pulp, but also for its peel and seed that contain beneficial substances with antioxidant, cancer preventive, antimicrobial, and anti-inflammatory functions. Although literature demonstrates the biological activity of Litchi components in reducing tumor cell viability in in vitro or in vivo models, data about the biochemical mechanisms responsible for these effects are quite fragmentary. This review specifically describes, in a comprehensive analysis, the antitumor properties of the different parts of Litchi and highlights the main biochemical mechanisms involved. PMID- 28885572 TI - Special Issue: Asymmetric Synthesis 2017. AB - The use of asymmetric synthetic methodologies plays a crucial role, nowadays, in the preparation of bioactive or other interesting compounds [...]. PMID- 28885571 TI - Prevalence, Causes and Social Factors of Visual Impairment among Chinese Adults: Based on a National Survey. AB - Visual impairment has become a global challenge, especially for developing countries. This study aims to estimate the prevalence, causes and social factors of visual impairment among Chinese adults. Data were from a nationally representative population-based cross-sectional study. The study population were 1,909,199 non-institutionalized adults aged 18 years and older in mainland China. In the survey, low vision and blindness were checked by ophthalmologists according to the WHO best-corrected visual acuity (BCVA) criteria. Population weighted numbers and prevalence of low vision and blindness with 95% confidence intervals (CIs) were estimated where appropriate. Multivariable logistic regression analysis was used to identify the social factors of visual impairment. The weighted prevalence of visual impairment was 17.17 (95% CI, 16.84-17.50) per 1000 Chinese adults aged 18 years and older. Cataract (57.35%), disorders of choroid and retina (9.80%), and disorders of cornea (6.49%) contributed more than 70 percent to the visual impairment in Chinese adults. Older age groups, young or middle-aged male adults, female elders, illiterate, rural dwellers, non-eastern residents, singles, unemployment, and from family with lower income were associated with visual impairment. More efforts are warranted to enhance treatment and rehabilitation among people with eye disorders to prevent visual impairment. PMID- 28885573 TI - Study of Gravity Effects on Titanium Laser Welding in the Vertical Position. AB - To obtain satisfactory welds in positional laser beam welding, it is necessary to know how process parameters will influence the quality of welds in different welding positions. In this study, the titanium alloy Ti6Al4V sheets were laser welded in two vertical welding positions (vertical up and vertical down), and the appearance, porosity, strength, and ductility of the laser joints were evaluated. Results show that undercuts of the vertical up welds were greater than that of vertical down welds, while the porosity contents were much higher in vertical down welds than that in vertical up welds. When welding with a higher heat input, the vertical up welding position resulted in poor weld profiles (undercuts and burn-through holes), whereas the vertical down welding position led to excessive porosity contents in welds. Both severe undercut and excessive porosity were detrimental to the tensile properties of the welds. Weld appearance was improved and porosity contents were reduced by using a lower heat input, achieving better weld quality. Therefore, it is suggested that process parameter settings with relatively high laser powers and welding speeds, which can result in lower heat inputs, are used when laser welding the Ti6Al4V titanium alloys vertically. PMID- 28885575 TI - Effect of Multi-Pass Friction Stir Processing on Mechanical Properties for AA2024/Al2O3 Nanocomposites. AB - In the present work, an aluminum metal matrix reinforced with (Al2O3) nanoparticles was fabricated as a surface composite sheet using friction stir processing (FSP). The effects of processing parameters on mechanical properties, hardness, and microstructure grain were investigated. The results revealed that multi-pass FSP causes a homogeneous distribution and good dispersion of Al2O3 in the metal matrix, and consequently an increase in the hardness of the matrix composites. A finer grain is observed in the microstructure examination in specimens subjected to second and third passes of FSP. The improvement in the grain refinement is 80% compared to base metal. The processing parameters, particularly rotational tool speed and pass number in FSP, have a major effect on strength properties and surface hardness. The ultimate tensile strength (UTS) and the average hardness are improved by 25% and 46%, respectively, due to presence of reinforcement Al2O3 nanoparticles. PMID- 28885574 TI - Release of VEGF from Dental Implant Improves Osteogenetic Process: Preliminary In Vitro Tests. AB - INTRODUCTION: During osseointegration process, the presence of an inflammatory event could negatively influence the proper osteogenetic ability of the implant surface. In order to reduce this possibility, an implementation of angiogenetic event through the release of Vascular Endothelial Growth Factor (VEGF) can be a tool as co-factor for osteoblastic differentiation. In this paper, novel dental implant surfaces enriched with VEGF have been tested. MATERIAL AND METHODS: The ability of VEGF-enriched titanium implants to improve the osteogenetic properties of Mesenchymal stem cells (MSC), also in the presence of an inflammatory environment, have been in vitro tested. Molecular biology, morphological analyses, and biochemical tests have been performed in order to confirm biological properties of these surfaces. RESULTS: Our results confirm that the presence of VEGF onto the implant surface is able not only to protect the cells from in vitro aging and from Reactive Oxygen Species (ROS) damage, but it also improves their osteogenic and endothelial differentiation, even in the presence of inflammatory cytokines. CONCLUSION: This study establishes a biologically powerful novel tool that could enhance bone repair in dental implant integration. PMID- 28885576 TI - Porcine Bone Scaffolds Adsorb Growth Factors Secreted by MSCs and Improve Bone Tissue Repair. AB - An ideal tissue-engineered bone graft should have both excellent pro-osteogenesis and pro-angiogenesis properties to rapidly realize the bone regeneration in vivo. To meet this goal, in this work a porcine bone scaffold was successfully used as a Trojan horse to store growth factors produced by mesenchymal stem cells (MSCs). This new scaffold showed a time-dependent release of bioactive growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), in vitro. The biological effect of the growth factors-adsorbed scaffold on the in vitro commitment of MSCs into osteogenic and endothelial cell phenotypes has been evaluated. In addition, we have investigated the activity of growth factor-impregnated granules in the repair of critical-size defects in rat calvaria by means of histological, immunohistochemical, and molecular biology analyses. Based on the results of our work bone tissue formation and markers for bone and vascularization were significantly increased by the growth factor enriched bone granules after implantation. This suggests that the controlled release of active growth factors from porcine bone granules can enhance and promote bone regeneration. PMID- 28885577 TI - Self-Assembled Gold Nano-Ripple Formation by Gas Cluster Ion Beam Bombardment. AB - In this study, we used a 30 keV argon cluster ion beam bombardment to investigate the dynamic processes during nano-ripple formation on gold surfaces. Atomic force microscope analysis shows that the gold surface has maximum roughness at an incident angle of 60 degrees from the surface normal; moreover, at this angle, and for an applied fluence of 3 * 1016 clusters/cm2, the aspect ratio of the nano ripple pattern is in the range of ~50%. Rutherford backscattering spectrometry analysis reveals a formation of a surface gradient due to prolonged gas cluster ion bombardment, although the surface roughness remains consistent throughout the bombarded surface area. As a result, significant mass redistribution is triggered by gas cluster ion beam bombardment at room temperature. Where mass redistribution is responsible for nano-ripple formation, the surface erosion process refines the formed nano-ripple structures. PMID- 28885579 TI - Room Temperature Tunable Multiferroic Properties in Sol-Gel-Derived Nanocrystalline Sr(Ti1-xFex)O3-delta Thin Films. AB - Sr(Ti1-xFex)O3-delta (0 <= x <= 0.2) thin films were grown on Si(100) substrates with LaNiO3 buffer-layer by a sol-gel process. Influence of Fe substitution concentration on the structural, ferroelectric, and magnetic properties, as well as the leakage current behaviors of the Sr(Ti1-xFex)O3-delta thin films, were investigated by using the X-ray diffractometer (XRD), atomic force microscopy (AFM), the ferroelectric test system, and the vibrating sample magnetometer (VSM). After substituting a small amount of Ti ion with Fe, highly enhanced ferroelectric properties were obtained successfully in SrTi0.9Ti0.1O3-delta thin films, with a double remanent polarization (2Pr) of 1.56, 1.95, and 9.14 MUC.cm 2, respectively, for the samples were annealed in air, oxygen, and nitrogen atmospheres. The leakage current densities of the Fe-doped SrTiO3 thin films are about 10-6-10-5 A.cm-2 at an applied electric field of 100 kV.cm-1, and the conduction mechanism of the thin film capacitors with various Fe concentrations has been analyzed. The ferromagnetic properties of the Sr(Ti1-xFex)O3-delta thin films have been investigated, which can be correlated to the mixed valence ions and the effects of the grain boundary. The present results revealed the multiferroic nature of the Sr(Ti1-xFex)O3-delta thin films. The effect of the annealing environment on the room temperature magnetic and ferroelectric properties of Sr(Ti0.9Fe0.1)O3-delta thin films were also discussed in detail. PMID- 28885578 TI - Weight Management Interventions in Women with and without PCOS: A Systematic Review. AB - Polycystic ovary syndrome (PCOS) is a common endocrinopathy among women associated with reproductive, metabolic and psychological features. While weight management is recommended as first-line treatment, it is unclear if women with PCOS achieve similar benefits as women without PCOS. This systematic review thus aimed to compare the efficacy of weight management interventions in women with and without PCOS. Databases were searched until May 2017. The primary outcome was weight and anthropometric, reproductive, metabolic and psychological measures were secondary outcomes. Of 3264 articles identified, 14 studies involving n = 933 (n = 9 high and n = 5 moderate risk of bias) met the inclusion criteria. No statistically significant differences in weight or weight loss following the intervention were found between women with and without PCOS in five studies, with the remaining studies not comparing the difference in weight or weight loss between these groups. Secondary outcomes did not differ significantly between the two groups. This review identified that there is a paucity of high quality research in this area and that more rigorous research is needed. PMID- 28885580 TI - Wound Healing Potential of Chlorogenic Acid and Myricetin-3-O-beta-Rhamnoside Isolated from Parrotia persica. AB - Wound healing is a complex physiological process that is controlled by a well orchestrated cascade of interdependent biochemical and cellular events, which has spurred the development of therapeutics that simultaneously target these active cellular constituents. We assessed the potential of Parrotia persica (Hamamelidaceae) in wound repair by analyzing the regenerative effects of its two main phenolic compounds, myricetin-3-O-beta-rhamnoside and chlorogenic acid. To accomplish this, we performed phytochemical profiling and characterized the chemical structure of pure compounds isolated from P. persica, followed by an analysis of the biological effects of myricetin-3-O-beta-rhamnoside and chlorogenic acid on three cell types, including keratinocytes, fibroblasts, and endothelial cells. Myricetin-3-O-beta-rhamnoside and chlorogenic acid exhibited complementary pro-healing properties. The percentage of keratinocyte wound closure as measured by a scratch assay was four fold faster in the presence of 10 ug/mL chlorogenic acid, as compared to the negative control. On the other hand, myricetin-3-O-beta-rhamnoside at 10 ug/mL was more effective in promoting fibroblast migration, demonstrating a two-fold higher rate of closure compared to the negative control group. Both compounds enhanced the capillary-like tube formation of endothelial cells in an in vitro angiogenesis assay. Our results altogether delineate the potential to synergistically accelerate the fibroblastic and remodelling phases of wound repair by administering appropriate amounts of myricetin-3-O-beta-rhamnoside and chlorogenic acid. PMID- 28885582 TI - Effect of Vertical Shoot-Positioned, Scott-Henry, Geneva Double-Curtain, Arch Cane, and Parral Training Systems on the Volatile Composition of Albarino Wines. AB - Viticultural practices influence both grape and wine quality. The influence of training systems on volatile composition was investigated for Albarino wine from Rias Baixas AOC in Northwest Spain. The odoriferous contribution of the compounds to the wine aroma was also studied. Volatile compounds belonging to ten groups (alcohols, C6-compounds, ethyl esters, acetates, terpenols, C13-norisoprenoids, volatile phenols, volatile fatty acids, lactones and carbonyl compounds) were determined in Albarino wines from different training systems, Vertical Shoot Positioned (VSP), Scott-Henry (SH), Geneva Double-Curtain (GDC), Arch-Cane (AC), and Parral (P) during 2010 and 2011 vintages. Wines from GDC showed the highest total volatile composition with the highest concentrations of alcohols, ethyl esters, fatty acids, and lactones families. However, the highest levels of terpenes and C13-norisoprenoids were quantified in the SH system. A fruitier aroma was observed in Albarino wines from GDC when odor activity values were calculated. PMID- 28885581 TI - Work-Related Noise Exposure in a Cohort of Patients with Chronic Tinnitus: Analysis of Demographic and Audiological Characteristics. AB - Work-related noise exposure is one of the major factors contributing to the development of adult-onset hearing loss and tinnitus. The aim of this study was to analyze, in patients with chronic tinnitus and long-term occupational noise exposure, (A) characteristics of hearing loss, tinnitus, comorbidities, demographic characteristics and a history of work-related noise exposure and (B) differences among individuals employed in occupations with high and low risk of developing work-related noise-induced hearing loss (NIHL). One hundred thirty six patients with chronic tinnitus and at least a 10 year-long working history were divided into two groups based on the risk of their profession to induce NIHL. Individuals employed in jobs at high risk for NIHL were mostly males and exhibited a poorer hearing threshold, more evident in the left ear. Tinnitus was mostly bilateral; the next largest presentation was left-sided; patients described their tinnitus as buzzing or high-pitched. Correlation between age, length of tinnitus and worse hearing was found. Patients with a higher degree of hearing impairment were mostly males and were more likely to have a family history of hearing loss and at least one cardiovascular comorbidity. Our study shows some differences in individuals with tinnitus and a history of a profession associated with increased exposure to NIHL compared to those without such a history. PMID- 28885583 TI - Migration and Accumulation of Octachlorodipropyl Ether in Soil-Tea Systems in Young and Old Tea Gardens. AB - The migration and accumulation of octachlorodipropyl ether (OCDPE) in soil-tea systems were investigated using a gas chromatography-electron capture detector (GC-ECD) method in young and old tea gardens. When the residual concentration of OCDPE was 100 g a.i. hm-2 in soils, the peak concentrations of OCDPE in fresh leaves of young and old tea plants were 0.365 mg/kg and 0.144 mg/kg, taking 45 days and 55 days, respectively. Equations for the accumulation curves of OCDPE in fresh leaves of young and old tea plants were Ct = 0.0227e0.0566t (R2 = 0.9154) and Ct = 0.0298e-0.0306t (R2 = 0.7156), and were Ct = 3.8435e0.055t (R2 = 0.9698) and Ct = 1.5627e-0.048t (R2 = 0.9634) for dissipation curves, with a half-life of 14.4 days and 12.6 days, respectively. These results have practical guiding significance for controlling tea food safety. PMID- 28885584 TI - Morphological Evaluation of Tumor-Infiltrating Lymphocytes (TILs) to Investigate Invasive Breast Cancer Immunogenicity, Reveal Lymphocytic Networks and Help Relapse Prediction: A Retrospective Study. AB - Tumor-infiltrating lymphocytes (TILs) in breast cancer are a key representative of the tumor immune microenvironment and have been shown to provide prognostic and predictive biomarkers. The extent of lymphocytic infiltration in tumor tissues can be assessed by evaluating hematoxylin and eosin (H&E)-stained tumor sections. We investigated tissue microarrays of 31 invasive breast cancer patients, looking at quantity and topological distribution of CD3+, CD8+, CD20+, Ki67+, FoxP3+ TILs and CD3+/FoxP3+, CD8+/FoxP3+ cell ratios. We separately evaluated TILs at the invasive edge and at the center of the tumor, to find any clinical implications of tumor heterogeneity. No statistically significant difference was found in quantity and distribution of both TIL subsets and TIL ratios, by comparing patients who suffered from a local or distant recurrence of the tumor (relapse group: 13 patients) with patients not showing cancer relapse (non-relapse group: 18 patients). In the whole sample, we observed three main statistically significant positive correlations: (1) between CD3+ and CD8+ T cells; (2) between FoxP3+ and Ki67+ lymphocyte infiltration; (3) between CD3+/FoxP3+ cell ratio (C3FR) and CD8+/FoxP3+ cell ratio (C8FR). Tumor heterogeneity and stronger positive TIL associations were found in the non relapse group, where both CD3-CD8 and FoxP3-Ki67 inter-correlations were found to be significant at the center of the tumor, while the correlation between C3FR and C8FR was significant at the invasive edge. No correlations between TIL subsets were detected in the relapse group. Our findings suggest the existence of stronger inter-subtype lymphocytic networks in invasive breast cancer not showing recurrence. Further evaluations of clinical and topological correlations between and within TIL subsets are needed, in addition to the assessment of TIL quantification and distribution, in order to follow up on whether morphological evaluation of TILs might reveal the underlying lymphocytic functional connectivity and help relapse prediction. PMID- 28885585 TI - Hair Regenerative Mechanisms of Red Ginseng Oil and Its Major Components in the Testosterone-Induced Delay of Anagen Entry in C57BL/6 Mice. AB - Hair loss (alopecia) is a universal problem for numerous people in the world. The present study was conducted to investigate the effects of red ginseng oil (RGO) and its major components on hair re-growth using testosterone (TES)-induced delay of anagen entry in C57BL/6 mice and their mechanisms of action. Seven-week-old C57BL/6 mice were daily treated with TES for 1 h prior to topical application of 10% RGO, 1% linoleic acid (LA), 1% beta-sitosterol (SITOS), or 1% bicyclo(10.1.0)tridec-1-ene (BICYCLO) once a day for 28 days. Hair regenerative capacity was significantly restored by treatment of RGO and its major compounds in the TES-treated mice. Histological analysis showed that RGO along with LA and SITOS but not BICYCLO promoted hair growth through early inducing anagen phase that was delayed by TES in mice. Treatment of mice with RGO, LA, or SITOS up regulated Wnt/beta-catenin and Shh/Gli pathways-mediated expression of genes such as beta-catenin, Lef-1, Sonic hedgehog, Smoothened, Gli-1, Cyclin D1, and Cyclin E in the TES-treated mice. In addition, RGO and its major components reduced the protein level of TGF-beta but enhanced the expression of anti-apoptotic protein Bcl-2. These results suggest that RGO is a potent novel therapeutic natural product for treatment of androgenic alopecia possibly through hair re-growth activity of its major components such as LA and SITOS. PMID- 28885586 TI - Senna singueana: Antioxidant, Hepatoprotective, Antiapoptotic Properties and Phytochemical Profiling of a Methanol Bark Extract. AB - Natural products are considered as an important source for the discovery of new drugs to treat aging-related degenerative diseases and liver injury. The present study profiled the chemical constituents of a methanol extract from Senna singueana bark using HPLC-PDA-ESI-MS/MS and 36 secondary metabolites were identified. Proanthocyanidins dominated the extract. Monomers, dimers, trimers of (epi)catechin, (epi)gallocatechin, (epi)guibourtinidol, (ent)cassiaflavan, and (epi)afzelechin represented the major constituents. The extract demonstrated notable antioxidant activities in vitro: In DPPH (EC50 of 20.8 ug/mL), FRAP (18.16 mM FeSO4/mg extract) assays, and total phenolic content amounted 474 mg gallic acid equivalent (GAE)/g extract determined with the Folin-Ciocalteu method. Also, in an in vivo model, the extract increased the survival rate of Caenorhabditis elegans worms pretreated with the pro-oxidant juglone from 43 to 64%, decreased intracellular ROS inside the wild-type nematodes by 47.90%, and induced nuclear translocation of the transcription factor DAF-16 in the transgenic strain TJ356. Additionally, the extract showed a remarkable hepatoprotective activity against d-galactosamine (d-GalN) induced hepatic injury in rats. It significantly reduced elevated AST (aspartate aminotransferase), and total bilirubin. Moreover, the extract induced a strong cytoplasmic Bcl-2 expression indicating suppression of apoptosis. In conclusion, the bark extract of S. sengueana represents an interesting candidate for further research in antioxidants and liver protection. PMID- 28885587 TI - Anti-HIV Activities and Mechanism of 12-O-Tricosanoylphorbol-20-acetate, a Novel Phorbol Ester from Ostodes katharinae. AB - APOBEC3G is a member of the human cytidine deaminase family that restricts Vif deficient viruses by being packaged with progeny virions and inducing the G to A mutation during the synthesis of HIV-1 viral DNA when the progeny virus infects new cells. HIV-1 Vif protein resists the activity of A3G by mediating A3G degradation. Phorbol esters are plant-derived organic compounds belonging to the tigliane family of diterpenes and could activate the PKC pathway. In this study, we identified an inhibitor 12-O-tricosanoylphorbol-20-acetate (hop-8), a novel ester of phorbol which was isolated from Ostodes katharinae of the family Euphorbiaceae, that inhibited the replication of wild-type HIV-1 and HIV-2 strains and drug-resistant strains broadly both in C8166 cells and PBMCs with low cytotoxicity and the EC50 values ranged from 0.106 MUM to 7.987 MUM. One of the main mechanisms of hop-8 is to stimulate A3G expressing in HIV-1 producing cells and upregulate the A3G level in progeny virions, which results in reducing the infectivity of the progeny virus. This novel mechanism of hop-8 inhibition of HIV replication might represents a promising approach for developing new therapeutics for HIV infection. PMID- 28885588 TI - Human Erythrocyte Acetylcholinesterase in Health and Disease. AB - The biochemical properties of erythrocyte or human red blood cell (RBC) membrane acetylcholinesterase (AChE) and its applications on laboratory class and on research are reviewed. Evidence of the biochemical and the pathophysiological properties like the association between the RBC AChE enzyme activity and the clinical and biophysical parameters implicated in several diseases are overviewed, and the achievement of RBC AChE as a biomarker and as a prognostic factor are presented. Beyond its function as an enzyme, a special focus is highlighted in this review for a new function of the RBC AChE, namely a component of the signal transduction pathway of nitric oxide. PMID- 28885589 TI - The Small Glutathione Peroxidase Mimic 5P May Represent a New Strategy for the Treatment of Liver Cancer. AB - Glutathione peroxidase (GPx) is an antioxidant protein containing selenium. Owing to the limitations of native GPx, considerable efforts have been made to develop GPx mimics. Here, a short 5-mer peptides (5P) was synthesized and characterized using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Enzyme coupled assays were used to evaluate GPx activity. The cell viability and apoptosis of H22 cells were tested, and mice bearing H22 cell derived tumors were used to determine the effects of 5P on tumor inhibition. In comparison with other enzyme models, 5P provided a suitable substrate with proper catalytic site positions, resulting in enhanced catalytic activity. In our mouse model, 5P showed excellent inhibition of tumor growth and improved immunity. In summary, our findings demonstrated the design and synthesis of the small 5P molecule, which inhibited tumor growth and improved immunity. Notably, 5P could inhibit tumor growth without affecting normal growth. Based on these advantages, the novel mimic may have several clinical applications. PMID- 28885590 TI - Ethnopharmacology and Therapeutic Value of Bridelia micrantha (Hochst.) Baill. in Tropical Africa: A Comprehensive Review. AB - Bridelia micrantha is traditionally used in tropical Africa to treat a wide range of human and animal diseases. The aim of this study was to summarise the research that has been done on the ethnomedicinal uses, phytochemistry and pharmacological properties of B. micrantha so as to understand its importance and potential value in primary healthcare systems. The literature search for information on ethnomedicinal uses and pharmacological activities of B. micrantha was undertaken using databases such as Web of Science, Scopus, Google Scholar, Science Direct, BioMed Central (BMC), PubMed and Springerlink. Other relevant literature sources included books, book chapters, websites, theses, conference papers and other scientific publications. This study showed that B. micrantha is used as herbal medicine in just over half (57.3%) of the countries in tropical Africa where it is indigenous. A total of 54 ethnomedicinal uses of B. micrantha have been recorded with a high degree of consensus on burns, wounds, conjunctivitis, painful eyes, constipation, gastric ulcers, cough, headache, rheumatism, painful joints, dysentery, ethnoveterinary medicine, malaria, sexually transmitted infections, stomach ache, tape worms and diarrhoea. Different plant parts, aqueous and organic extracts exhibited anthelmintic, antimicrobial, anticonvulsant and sedative, antidiabetic, antidiarrhoeal, antinociceptive, antioxidant, antiplasmodial, antischistosomal, hepatoprotective, insecticidal and beta-lactamase inhibitory activities. PMID- 28885591 TI - Polymeric Nanocomposite Membranes for Next Generation Pervaporation Process: Strategies, Challenges and Future Prospects. AB - Pervaporation (PV) has been considered as one of the most active and promising areas in membrane technologies in separating close boiling or azeotropic liquid mixtures, heat sensitive biomaterials, water or organics from its mixtures that are indispensable constituents for various important chemical and bio separations. In the PV process, the membrane plays the most pivotal role and is of paramount importance in governing the overall efficiency. This article evaluates and collaborates the current research towards the development of next generation nanomaterials (NMs) and embedded polymeric membranes with regard to its synthesis, fabrication and application strategies, challenges and future prospects. PMID- 28885592 TI - A Tailored Ontology Supporting Sensor Implementation for the Maintenance of Industrial Machines. AB - The longtime productivity of an industrial machine is improved by condition-based maintenance strategies. To do this, the integration of sensors and other cyber physical devices is necessary in order to capture and analyze a machine's condition through its lifespan. Thus, choosing the best sensor is a critical step to ensure the efficiency of the maintenance process. Indeed, considering the variety of sensors, and their features and performance, a formal classification of a sensor's domain knowledge is crucial. This classification facilitates the search for and reuse of solutions during the design of a new maintenance service. Following a Knowledge Management methodology, the paper proposes and develops a new sensor ontology that structures the domain knowledge, covering both theoretical and experimental sensor attributes. An industrial case study is conducted to validate the proposed ontology and to demonstrate its utility as a guideline to ease the search of suitable sensors. Based on the ontology, the final solution will be implemented in a shared repository connected to legacy CAD (computer-aided design) systems. The selection of the best sensor is, firstly, obtained by the matching of application requirements and sensor specifications (that are proposed by this sensor repository). Then, it is refined from the experimentation results. The achieved solution is recorded in the sensor repository for future reuse. As a result, the time and cost of the design process of new condition-based maintenance services is reduced. PMID- 28885593 TI - Effect of Iron Oxide Nanoparticles and Amoxicillin on Bacterial Growth in the Presence of Dissolved Organic Carbon. AB - The impact of emerging contaminants in the presence of active pharmaceutical pollutants plays an important role in the persistence and activity of environmental bacteria. This manuscript focuses on the impact of amoxicillin functionalized iron oxide nanoparticles on bacterial growth, in the presence of dissolved organic carbon (humic acid). The impact of these emerging contaminants individually and collectively on the growth profiles of model gram positive and negative bacteria was tracked for 24 h. Results indicate exposure to subinhibitory concentrations of amoxicillin bound iron oxide nanoparticles, in the presence of humic acid, increase bacterial growth in Pseudomonas aeruginosa and Staphylococcus aureus. Accelerated bacterial growth was associated with an increase in iron ions, which have been shown to influence upregulation of cellular metabolism. Though iron oxide nanoparticles are often regarded as benign, this work demonstrates the distinguishable impact of amoxicillin bound iron oxide nanoparticles in the presence of dissolved organic carbon. The results indicate differential impacts of combined contaminants on bacterial growth, having potential implications for environmental and human health. PMID- 28885595 TI - Thermal Flow Sensors for Harsh Environments. AB - Flow sensing in hostile environments is of increasing interest for applications in the automotive, aerospace, and chemical and resource industries. There are thermal and non-thermal approaches for high-temperature flow measurement. Compared to their non-thermal counterparts, thermal flow sensors have recently attracted a great deal of interest due to the ease of fabrication, lack of moving parts and higher sensitivity. In recent years, various thermal flow sensors have been developed to operate at temperatures above 500 degrees C. Microelectronic technologies such as silicon-on-insulator (SOI), and complementary metal-oxide semiconductor (CMOS) have been used to make thermal flow sensors. Thermal sensors with various heating and sensing materials such as metals, semiconductors, polymers and ceramics can be selected according to the targeted working temperature. The performance of these thermal flow sensors is evaluated based on parameters such as thermal response time, flow sensitivity. The data from thermal flow sensors reviewed in this paper indicate that the sensing principle is suitable for the operation under harsh environments. Finally, the paper discusses the packaging of the sensor, which is the most important aspect of any high temperature sensing application. Other than the conventional wire-bonding, various novel packaging techniques have been developed for high-temperature application. PMID- 28885594 TI - Exploring the Relationship between Housing and Health for Refugees and Asylum Seekers in South Australia: A Qualitative Study. AB - Housing is an important social determinant of health; however, little is known about the impact of housing experiences on health and wellbeing for people from refugee and asylum-seeking backgrounds. In this paper, we outline a qualitative component of a study in South Australia examining these links. Specifically, interviews were conducted with 50 refugees and asylum seekers who were purposively sampled according to gender, continent and visa status, from a broader survey. Interviews were analysed thematically. The results indicated that housing was of central importance to health and wellbeing and impacted on health through a range of pathways including affordability, the suitability of housing in relation to physical aspects such as condition and layout, and social aspects such as safety and belonging and issues around security of tenure. Asylum seekers in particular reported that living in housing in poor condition negatively affected their health. Our research reinforces the importance of housing for both the physical and mental health for asylum seekers and refugees living in resettlement countries. Improving housing quality, affordability and tenure security all have the potential to lead to more positive health outcomes. PMID- 28885596 TI - Research on High Layer Thickness Fabricated of 316L by Selective Laser Melting. AB - Selective laser melting (SLM) is a potential additive manufacturing (AM) technology. However, the application of SLM was confined due to low efficiency. To improve efficiency, SLM fabrication with a high layer thickness and fine powder was systematically researched, and the void areas and hollow powders can be reduced by using fine powder. Single-track experiments were used to narrow down process parameter windows. Multi-layer fabrication relative density can be reached 99.99% at the exposure time-point distance-hatch space of 120 MUs-40 MUm 240 MUm. Also, the building rate can be up to 12 mm3/s, which is about 3-10 times higher than the previous studies. Three typical defects were found by studying deeply, including the un-melted defect between the molten pools, the micro-pore defect within the molten pool, and the irregular distribution of the splashing phenomenon. Moreover, the microstructure is mostly equiaxed crystals and a small amount of columnar crystals. The averages of ultimate tensile strength, yield strength, and elongation are 625 MPa, 525 MPa, and 39.9%, respectively. As exposure time increased from 80 MUs to 200 MUs, the grain size is gradually grown up from 0.98 MUm to 2.23 MUm, the grain aspect ratio is close to 1, and the tensile properties are shown as a downward trend. The tensile properties of high layer thickness fabricated are not significantly different than those with a coarse-powder layer thickness of low in previous research. PMID- 28885598 TI - Report from the 1st MYCOKEY International Conference Global Mycotoxin Reduction in the Food and Feed Chain Held in Ghent, Belgium, 11-14 September 2017. AB - This conference is organized within the framework of the H2020-Research and Innovation Action-Societal Challenge 2-"Food security, sustainable agriculture and forestry, marine, maritime and inland water research and the bioeconomy challenge"-GA 678781 MycoKey "Integrated and innovative key actions for mycotoxin management in the food and feed chain" [...]. PMID- 28885597 TI - Hypoxia Is a Critical Parameter for Chondrogenic Differentiation of Human Umbilical Cord Blood Mesenchymal Stem Cells in Type I/III Collagen Sponges. AB - Umbilical cord blood (UCB) is an attractive alternative to bone marrow for isolation of mesenchymal stem cells (MSCs) to treat articular cartilage defects. Here, we set out to determine the growth factors (bone morphogenetic protein 2 (BMP-2) and transforming growth factor-beta (TGF-beta1)) and oxygen tension effects during chondrogenesis of human UCB-MSCs for cartilage engineering. Chondrogenic differentiation was induced using 3D cultures in type I/III collagen sponges with chondrogenic factors in normoxia (21% O2) or hypoxia (<5% O2) for 7, 14 and 21 days. Our results show that UCB-MSCs can be committed to chondrogenesis in the presence of BMP-2+TGF-beta1. Normoxia induced the highest levels of chondrocyte-specific markers. However, hypoxia exerted more benefit by decreasing collagen X and matrix metalloproteinase-13 (MMP13) expression, two chondrocyte hypertrophy markers. However, a better chondrogenesis was obtained by switching oxygen conditions, with seven days in normoxia followed by 14 days in hypoxia, since these conditions avoid hypertrophy of hUCB-MSC-derived chondrocytes while maintaining the expression of chondrocyte-specific markers observed in normoxia. Our study demonstrates that oxygen tension is a key factor for chondrogenesis and suggests that UBC-MSCs 3D-culture should begin in normoxia to obtain a more efficient chondrocyte differentiation before placing them in hypoxia for chondrocyte phenotype stabilization. UCB-MSCs are therefore a reliable source for cartilage engineering. PMID- 28885599 TI - Family Social Environment and Parenting Predictors of Alcohol Use among Adolescents in Lithuania. AB - The role of the family as the social environment in shaping adolescent lifestyle has recently received substantial attention. This study was focused on investigating the association between familial and parenting predictors and alcohol use in school-aged children. Adolescents aged 13- and 15-year from a representative sample (N = 3715) of schools in Lithuania were surveyed during the spring of 2014. The methodology of the cross-national Health Behaviour in School aged Children (HBSC) study was applied. HBSC international questionnaires were completed in the classroom anonymously for obtaining information about drinking of alcoholic beverages and family characteristics-family's affluence and structure, style of communication in the family, parenting style, parental monitoring, family time together, etc. Univariate and multivariate logistic regression analysis was applied for assessment of the association between familial variables and weekly alcohol use. Analysis has demonstrated that adolescents from non-intact families tended to show significantly higher risk of being weekly drinkers (OR = 1.69; 95% CI: 1.30-2.19). The following parenting factors were associated with weekly use of alcohol: father's and mother's low monitoring, father's authoritarian-repressive and mother's permissive-neglectful parenting style. Frequent family time together and frequent electronic media communication with parents showed an inverse negative effect than was predicted. The study suggests that alcohol misuse among adolescents could be associated with a non-intact family structure as well as with complex family and parenting determinants which should be investigated more thoroughly by further studies. PMID- 28885601 TI - Attitudes towards Human Papilloma Virus Vaccination in the Latin American Andean Region. AB - This commentary explores the distribution of human papilloma virus (HPV) and HPV related diseases, and factors affecting attitudes towards HPV, HPV-related diseases, and HPV vaccination in the Latin American Andean region. Lack of knowledge of HPV, known negative attitudes or incorrect assumptions about HPV, HPV-related diseases, and HPV vaccination provide a basis upon which to develop targeted HPV awareness and preventive health media campaigns. For maximal effect, media campaigns should use the internet, radio, and television to address health care providers, parents, and students. Additional programming can be developed for clinics to use in-house with their clients. Ministries of Education, Finance, and Health all have roles to play to increase national HPV, HPV-related diseases, and HPV vaccination awareness. PMID- 28885600 TI - A Cross-Sectional Study of Dietary and Genetic Predictors of Blood Folate Levels in Healthy Young Adults. AB - Since 1998, the U.S. has mandated folic acid (FA) fortification of certain grain products to reduce the risk of neural tube defects. Folate intake and red blood cell (RBC) folate concentrations increased substantially post-intervention, although recent studies raise concerns about the level of ongoing benefit. This study investigated blood folate level determinants in healthy young adults, including intake of naturally occurring food folate, synthetic FA, and the interaction of naturally occurring food folate with a common missense variant in the FOLH1 gene thought to affect absorption. Participants (n = 265) completed the Diet History Questionnaire II, RBC folate testing, and were genotyped for the 484T>C FOLH1 variant. Men reported significantly greater intake of all folate sources except for supplemental FA, but RBC folate levels did not significantly differ by sex. Synthetic FA was a stronger predictor of RBC folate than naturally occurring food folate. In the largest racial group, synthetic FA and the interaction of FOLH1 genotype with naturally occurring food folate significantly predicted RBC folate, with the overall model accounting for 13.8% of the variance in RBC folate levels. Blood folate levels rely on a complex interaction of natural and synthetic folate intake as well as FOLH1 genotype. PMID- 28885602 TI - Network Location-Aware Service Recommendation with Random Walk in Cyber-Physical Systems. AB - Cyber-physical systems (CPS) have received much attention from both academia and industry. An increasing number of functions in CPS are provided in the way of services, which gives rise to an urgent task, that is, how to recommend the suitable services in a huge number of available services in CPS. In traditional service recommendation, collaborative filtering (CF) has been studied in academia, and used in industry. However, there exist several defects that limit the application of CF-based methods in CPS. One is that under the case of high data sparsity, CF-based methods are likely to generate inaccurate prediction results. In this paper, we discover that mining the potential similarity relations among users or services in CPS is really helpful to improve the prediction accuracy. Besides, most of traditional CF-based methods are only capable of using the service invocation records, but ignore the context information, such as network location, which is a typical context in CPS. In this paper, we propose a novel service recommendation method for CPS, which utilizes network location as context information and contains three prediction models using random walking. We conduct sufficient experiments on two real-world datasets, and the results demonstrate the effectiveness of our proposed methods and verify that the network location is indeed useful in QoS prediction. PMID- 28885603 TI - Functional Characterization of Selected Universal Stress Protein from Salvia miltiorrhiza (SmUSP) in Escherichia coli. AB - The multigene universal stress protein (USP) family is evolutionarily conserved. Members play indispensable roles in plant tolerance to abiotic stresses. Although relatively well-characterized in model plants, such as Arabidopsis thaliana and Oryzasativa, this family has not been investigated in Salvia miltiorrhiza, an important herbal plant for which yields can be limited by various abiotic stresses. Here, we identified 32 USP family members in the S. miltiorrhiza genome, and used phylogenetic analysis to sort these SmUSPs into four groups. Groups A and B belong to the ATP-binding class whereas Groups C and D are in the non-ATP-binding class. Motif analysis and multiple sequence alignment hinted that members of group A and B were able to bind ATP. Our qRT-PCR data from different tissues/organs and under salt and heat stresses provided an overall expression pattern for those genes. Three SmUSPs (SmUSP1, SmUSP8, and SmUSP27) were cloned from S. miltiorrhiza and functionally characterized in Escherichiacoli. Compared with the control cells, those that expressed SmUSPs exhibited enhanced tolerance to salt, heat, and a combination of the two. This suggested that the protein has a protective role in cells when exposed to single-stress and multiple-stress conditions. Our findings provide valuable information that helps improve our understanding of the evolutionary and functional conservation and diversity associated with the USP gene family in S. miltiorrhiza. PMID- 28885604 TI - Overprescribing of antibiotics by UK ophthalmologists. PMID- 28885605 TI - Searching for the best blood-derived eye drops. PMID- 28885607 TI - Same-site surgical revision of failed trabeculectomy blebs with mitomycin C augmentation: long-term follow-up. AB - PurposeTo determine the long-term outcomes of same-site revision of failed filtering blebs with mitomycin C application.Patients and methodsNoncomparative retrospective case series of 45 eyes of 39 patients. Main outcome measures were surgical success (<=21, <=18, and <=16 mm Hg reduction in intraocular pressure (IOP)). Other outcome measures included best-corrected visual acuity (VA), visual field loss, number of glaucoma medications, need for further interventions, time from surgery to recommencement of medications or interventions, and complications.ResultsMean follow-up was 126+/-59.6 months (range 16-227 months). The overall success proportion at last follow-up was 96% for IOP <=21 mm Hg (criterion 1), 91% for IOP <=18 mm Hg (criterion 2), and 84% for IOP <=16 mm Hg (criterion 3). Absolute success at last follow-up was 64%, 38%, and 33% for criteria 1, 2, and 3, respectively. Mean baseline IOP was reduced from 24.2+/-5.5 to 12.4+/-5.5 mm Hg at last follow-up. Ten eyes (22%) had early and 3 (7%) eyes had late complications. None of these complications resulted in visual loss or surgery failure. Nine eyes (20%) required further glaucoma surgery. Nine eyes (20%) required further glaucoma laser.ConclusionsSame-site, augmented, bleb revision is a safe and effective technique to control IOP and prevent further visual loss in patients with failed trabeculectomies. PMID- 28885606 TI - An overview of the clinical applications of optical coherence tomography angiography. AB - Optical coherence tomography angiography (OCTA) has emerged as a novel, non invasive imaging modality that allows the detailed study of flow within the vascular structures of the eye. Compared to conventional dye angiography, OCTA can produce more detailed, higher resolution images of the vasculature without the added risk of dye injection. In our review, we discuss the advantages and disadvantages of this new technology in comparison to conventional dye angiography. We provide an overview of the current OCTA technology available, compare the various commercial OCTA machines technical specifications and discuss some future software improvements. An approach to the interpretation of OCTA images by correlating images to other multimodal imaging with attention to identifying potential artefacts will be outlined and may be useful to ophthalmologists, particularly those who are currently still unfamiliar with this new technology. This review is based on a search of peer-reviewed published papers relevant to OCTA according to our current knowledge, up to January 2017, available on the PubMed database. Currently, many of the published studies have focused on OCTA imaging of the retina, in particular, the use of OCTA in the diagnosis and management of common retinal diseases such as age-related macular degeneration and retinal vascular diseases. In addition, we describe clinical applications for OCTA imaging in inflammatory diseases, optic nerve diseases and anterior segment diseases. This review is based on both the current literature and the clinical experience of our individual authors, with an emphasis on the clinical applications of this imaging technology. PMID- 28885608 TI - A novel use of ultrasound biomicroscopy. PMID- 28885609 TI - Vitreous cavity length in keratoconus: implications for keratoplasty. AB - PurposeTo compare axial length (AL) with vitreous cavity length (VCL) in patients with keratoconus and to ascertain whether graft size can be tailored to reduce myopic refractive error in patients with keratoconus undergoing penetrating keratoplasty (PK).Patients and methodsThe AL and VCL were measured prospectively in patients with keratoconus not undergoing PK (Group 1) and in normal phakic, emmetropic individuals (Group 2). A retrospective analysis of these measurements in patients with keratoconus who had undergone PK (Group 3) was also performed. The postoperative spherical equivalent (SE) was then correlated to size of donor buttons.ResultsKeratoconus patients tended to have a longer mean VCL than emmetropic normal individuals. The mean VCL of these patients (Group 1) was 16.49 mm+/-SD 1.13 compared to the mean VCL of 15.94 mm+/-SD 0.56 in normals (Group 2, P<0.0001). Patients with keratoconus who had an undersized graft showed reduced myopic refractive error compared to those with same size or oversized grafts.ConclusionVCL measurement is more accurate than AL measurement in deciding upon graft-host size disparity for corneal graft in patients with keratoconus. In patients with increased VCL, undersizing the donor button helps in reducing postoperative myopia. We recommend VCL measurement as part of the routine workup in all keratoconus patients undergoing corneal transplants. PMID- 28885610 TI - In silico and preclinical drug screening identifies dasatinib as a targeted therapy for T-ALL. PMID- 28885611 TI - Secondary acute lymphoblastic leukemia is a distinct clinical entity with prognostic significance. AB - The effect of prior malignancy on the risk of developing, and prognosis of, acute lymphoblastic leukemia (ALL) is unknown. This observational study utilized the California Cancer Registry to estimate the risk of developing ALL after a prior malignancy using standardized incidence ratios (SIRs, 95% confidence intervals). ALL occurring after a malignancy with an SIR>1 (increased-risk (IR) malignancies) was considered secondary ALL (s-ALL). Adjusted hazard ratios (aHRs, 95% confidence intervals) compared the effect of s-ALL with de novo ALL on overall survival. A total of 14 481 patients with ALL were identified (1988-2012) and 382 (3%) had a known prior malignancy. Any prior malignancy predisposed patients to developing ALL: SIR 1.62 (1.45-1.79). Hematologic malignancies (SIR 5.57, 4.38 6.98) and IR-solid tumors (SIR 2.11, 1.73-2.54) increased the risk of developing ALL. s-ALL increased the risk of death compared with de novo ALL (aHR 1.38 (1.16 1.63)) and this effect was more pronounced among younger patients (age<40 years: aHR 4.80 (3.15-7.30); age?40 years: aHR 1.40 (1.16-1.69)) (interaction P<0.001). This population-based study demonstrates that s-ALL is a distinct entity that occurs after specific malignancies and carries a poor prognosis compared with de novo ALL, particularly among patients <40 years of age. PMID- 28885613 TI - MicroRNA-155 regulates casein kinase 1 gamma 2: a potential pathogenetic role in chronic lymphocytic leukemia. PMID- 28885612 TI - Understanding CD30 biology and therapeutic targeting: a historical perspective providing insight into future directions. AB - CD30 is a member of the tumor necrosis factor receptor superfamily. It is characteristically expressed in certain hematopoietic malignancies, including anaplastic large cell lymphoma and Hodgkin lymphoma, among others. The variable expression of CD30 on both normal and malignant lymphoid cells has focused research efforts on understanding the pathogenesis of CD30 upregulation, its contribution to lymphomagenesis through anti-apoptotic mechanisms, and its effect on cell survival. Given the restriction of CD30 to certain tumor types, the logical extension of this has been to attempt to exploit it as a therapeutic target. The efficacy of naked anti-CD30 antibodies in practice was, however, modest. Moreover, combinations with bacterial toxins and radioimmunoconjugates have also had limited success. The development of the antibody-drug compound brentuximab vedotin (BV), however, has rejuvenated interest in CD30 as a tumor target. Phase I and II clinical trials in Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T cell lymphoma, and even CD30-expressing B-cell lymphomas, have shown the compound is well tolerated, but more importantly, able to deliver meaningful disease control even in patients with multiply relapsed or refractory disease. FDA approval has been granted for its use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. A recent phase III trial of BV in cutaneous T-cell lymphoma has confirmed its superiority to standard of care therapies. In this manuscript, we explore the history of CD30 as a tumor marker and as a therapeutic target, both in the laboratory and in the clinic, with a view to understanding future avenues for further study. PMID- 28885614 TI - Crystal structure of E. coli apolipoprotein N-acyl transferase. AB - In Gram-negative bacteria, lipid modification of proteins is catalysed in a three step pathway. Apolipoprotein N-acyl transferase (Lnt) catalyses the third step in this pathway, whereby it transfers an acyl chain from a phospholipid to the amine group of the N-terminal cysteine residue of the apolipoprotein. Here, we report the 2.6-A crystal structure of Escherichia coli Lnt. This enzyme contains an exo membrane nitrilase domain fused to a transmembrane (TM) domain. The TM domain of Lnt contains eight TM helices which form a membrane-embedded cavity with a lateral opening and a periplasmic exit. The nitrilase domain is located on the periplasmic side of the membrane, with its catalytic cavity connected to the periplasmic exit of the TM domain. An amphipathic lid loop from the nitrilase domain interacts with the periplasmic lipid leaflet, forming an interfacial entrance from the lipid bilayer to the catalytic centre for both the lipid donor and acceptor substrates. PMID- 28885615 TI - Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation. AB - Inflammation has emerged to be a critical mechanism responsible for neural damage and neurodegenerative diseases. Microglia, the resident innate immune cells in retina, are implicated as principal components of the immunological insult to retinal neural cells. The involvement of microglia in retinal inflammation is complex and here we propose for the first time that necroptosis in microglia triggers neuroinflammation and exacerbates retinal neural damage and degeneration. We found microglia experienced receptor-interacting protein kinase 1 (RIP1)- and RIP3-dependent necroptosis not only in the retinal degenerative rd1 mice, but also in the acute retinal neural injury mice. The necroptotic microglia released various pro-inflammatory cytokines and chemokines, such as tumor necrosis factor-alpha and chemokine (C-C motif) ligand 2, which orchestrated the retinal inflammation. Importantly, necroptosis blockade using necrostatin-1 could suppress microglia-mediated inflammation, rescue retinal degeneration or prevent neural injury in vivo. Meanwhile, cultured microglia underwent RIP1/3-mediated necroptosis and the necroptotic microglia produced large amounts of pro inflammatory cytokines in response to lipopolysaccharide or oxidative stress in vitro. Mechanically, TLR4 deficiency ameliorated microglia necroptosis with decreased expression levels of machinery molecules RIP1 and RIP3, and suppressed retinal inflammation, suggesting that TLR4 signaling was required in microglia necroptosis-mediated inflammation. Thus, we proposed that microglia experienced necroptosis through TLR4 activation, promoting an inflammatory response that serves to exacerbate considerable neural damage and degeneration. Necroptosis blockade therefore emerged as a novel therapeutic strategy for tempering microglia-mediated neuroinflammation and ameliorating neural injury and neurodegenerative diseases. PMID- 28885618 TI - Loss of BIM augments resistance of ATM-deficient thymocytes to DNA damage-induced apoptosis but does not accelerate lymphoma development. PMID- 28885616 TI - MyD88 is an essential component of retinoic acid-induced differentiation in human pluripotent embryonal carcinoma cells. AB - We have previously reported that myeloid differentiation primary response gene 88 (MyD88) is downregulated during all-trans retinoic acid (RA)-induced differentiation of pluripotent NTera2 human embryonal carcinoma cells (hECCs), whereas its maintained expression is associated with RA differentiation resistance in nullipotent 2102Ep hECCs. MyD88 is the main adapter for toll-like receptor (TLR) signalling, where it determines the secretion of chemokines and cytokines in response to pathogens. In this study, we report that loss of MyD88 is essential for RA-facilitated differentiation of hECCs. Functional analysis using a specific MyD88 peptide inhibitor (PepInh) demonstrated that high MyD88 expression in the self-renewal state inhibits the expression of a specific set of HOX genes. In NTera2 cells, MyD88 is downregulated during RA-induced differentiation, a mechanism that could be broadly replicated by MyD88 PepInh treatment of 2102Ep cells. Notably, MyD88 inhibition transitioned 2102Ep cells into a stable, self-renewing state that appears to be primed for differentiation upon addition of RA. At a molecular level, MyD88 inhibition combined with RA treatment upregulated HOX, RA signalling and TLR signalling genes. These events permit differentiation through a standard downregulation of Oct4-Sox2-Nanog mechanism. In line with its role in regulating secretion of specific proteins, conditioned media experiments demonstrated that differentiated (MyD88 low) NTera2 cell media was sufficient to differentiate NTera2 cells. Protein array analysis indicated that this was owing to secretion of factors known to regulate angiogenesis, neurogenesis and all three branches of TGF-beta Superfamily signalling. Collectively, these data offer new insights into RA controlled differentiation of pluripotent cells, with notable parallels to the ground state model of embryonic stem cell self-renewal. These data may provide insights to facilitate improved differentiation protocols for regenerative medicine and differentiation-therapies in cancer treatment. PMID- 28885617 TI - Post-translational regulation of p53 function through 20S proteasome-mediated cleavage. AB - The tumor suppressor p53 is a transcription factor that regulates the expression of a range of target genes in response to cellular stress. Adding to the complexity of understanding its cellular function is that in addition to the full length protein, several p53 isoforms are produced in humans, harboring diverse expression patterns and functionalities. One isoform, Delta40p53, which lacks the first transactivation domain including the binding region for the negative regulator MDM2, was shown to be a product of alternative translation initiation. Here we report the discovery of an alternative cellular mechanism for Delta40p53 formation. We show that the 20S proteasome specifically cleaves the full-length protein (FLp53) to generate the Delta40p53 isoform. Moreover, we demonstrate that a dimer of FLp53 interacts with a Delta40p53 dimer, creating a functional hetero tetramer. Consequently, the co-expression of both isoforms attenuates the transcriptional activity of FLp53 in a dominant negative manner. Finally, we demonstrate that following oxidative stress, at the time when the 20S proteasome becomes the major degradation machinery and FLp53 is activated, the formation of Delta40p53 is enhanced, creating a negative feedback loop that balances FLp53 activation. Overall, our results suggest that Delta40p53 can be generated by a 20S proteasome-mediated post-translational mechanism so as to control p53 function. More generally, the discovery of a specific cleavage function for the 20S proteasome may represent a more general cellular regulatory mechanism to produce proteins with distinct functional properties. PMID- 28885619 TI - Powering stem cell decisions with ubiquitin. PMID- 28885620 TI - Oxidative stress-induced S100B accumulation converts myoblasts into brown adipocytes via an NF-kappaB/YY1/miR-133 axis and NF-kappaB/YY1/BMP-7 axis. AB - Muscles of sarcopenic people show hypotrophic myofibers and infiltration with adipose and, at later stages, fibrotic tissue. The origin of infiltrating adipocytes resides in fibro-adipogenic precursors and nonmyogenic mesenchymal progenitor cells, and in satellite cells, the adult stem cells of skeletal muscles. Myoblasts and brown adipocytes share a common Myf5+ progenitor cell: the cell fate depends on levels of bone morphogenetic protein 7 (BMP-7), a TGF-beta family member. S100B, a Ca2+-binding protein of the EF-hand type, is expressed at relatively high levels in myoblasts from sarcopenic humans and exerts anti myogenic effects via NF-kappaB-dependent inhibition of MyoD, a myogenic transcription factor acting upstream of the essential myogenic factor, myogenin. Adipogenesis requires high levels of ROS, and myoblasts of sarcopenic subjects show elevated ROS levels. Here we show that: (1) ROS overproduction in myoblasts results in upregulation of S100B levels via NF-kappaB activation; and (2) ROS/NF kappaB-induced accumulation of S100B causes myoblast transition into brown adipocytes. S100B activates an NF-kappaB/Ying Yang 1 axis that negatively regulates the promyogenic and anti-adipogenic miR-133 with resultant accumulation of the brown adipogenic transcription regulator, PRDM-16. S100B also upregulates BMP-7 via NF-kappaB/Ying Yang 1 with resultant BMP-7 autocrine activity. Interestingly, myoblasts from sarcopenic humans show features of brown adipocytes. We also show that S100B levels and NF-kappaB activity are elevated in brown adipocytes obtained by culturing myoblasts in adipocyte differentiation medium and that S100B knockdown or NF-kappaB inhibition in myoblast-derived brown adipocytes reconverts them into fusion-competent myoblasts. At last, interstitial cells and, unexpectedly, a subpopulation of myofibers in muscles of geriatric but not young mice co-express S100B and the brown adipocyte marker, uncoupling protein-1. These results suggest that S100B is an important intracellular molecular signal regulating Myf5+ progenitor cell differentiation into fusion competent myoblasts or brown adipocytes depending on its levels. PMID- 28885621 TI - Primary hyperparathyroidism. AB - In this Review, we describe the pathogenesis, diagnosis and management of primary hyperparathyroidism (PHPT), with a focus on recent advances in the field. PHPT is a common endocrine disorder that is characterized by hypercalcaemia and elevated or inappropriately normal serum levels of parathyroid hormone. Most often, the presentation of PHPT is asymptomatic in regions of the world where serum levels of calcium are routinely measured. In addition to mild hypercalcaemia, PHPT can manifest with osteoporosis and hypercalciuria as well as with vertebral fractures and nephrolithiasis, both of which can be asymptomatic. Other clinical forms of PHPT, such as classical disease and normocalcaemic PHPT, are less common. Parathyroidectomy, the only curative treatment for PHPT, is recommended in patients with symptoms and those with asymptomatic disease who are at risk of progression or have subclinical evidence of end-organ sequelae. Parathyroidectomy results in an increase in BMD and a reduction in nephrolithiasis. Various medical therapies can increase BMD or reduce serum levels of calcium, but no single drug can do both. More data are needed regarding the neuropsychological manifestations of PHPT and the pathogenetic mechanisms leading to sporadic PHPT, as well as on risk factors for complications of the disorder. Future work that advances our knowledge in these areas will improve the management of the disorder. PMID- 28885624 TI - Bone diseases: New hope for old bones. PMID- 28885623 TI - Chronic endocrine consequences of traumatic brain injury - what is the evidence? AB - Traumatic brain injury (TBI) is a major public health problem with potentially debilitating consequences for the individual. Hypopituitarism after TBI has received increasing attention over the past decade; development of the condition as a consequence of TBI was previously hardly mentioned in textbooks on the subject. Hypopituitarism has been reported in more than 25% of patients with TBI and is now thought to be one of the most important causes of treatable morbidity in TBI survivors. However, most clinicians dealing with neuroendocrine diseases and TBI generally do not see such a high incidence of hypopituitarism. This disproportion is not clearly explained, but recent data indicate that diagnostic testing, which is designed for high-risk populations and not for a cohort of patients with, for example, de novo isolated growth hormone deficiency (the predominant finding in TBI), might have overestimated the true risk and disease burden of hypopituitarism. In this Opinion article, we discuss current recommendations for post-traumatic hypopituitarism in light of recent evidence. PMID- 28885625 TI - Obesity: Role for creatine metabolism in energy expenditure. PMID- 28885622 TI - Adult-onset autoimmune diabetes: current knowledge and implications for management. AB - Adult-onset autoimmune diabetes is a heterogeneous disease that is characterized by a reduced genetic load, a less intensive autoimmune process and a mild metabolic decompensation at onset compared with young-onset type 1 diabetes mellitus (T1DM). The majority of patients with adult-onset autoimmune diabetes do not require insulin treatment for at least 6 months after diagnosis. Such patients are defined as having latent autoimmune diabetes in adults (LADA), which is distinct from classic adult-onset T1DM. The extensive heterogeneity of adult onset autoimmune diabetes is apparent beyond the distinction between classic adult-onset T1DM and LADA. LADA is characterized by genetic, phenotypic and humoral heterogeneity, encompassing different degrees of insulin resistance and autoimmunity; this heterogeneity is probably a result of different pathological mechanisms, which have implications for treatment. The existence of heterogeneous phenotypes in LADA makes it difficult to establish an a priori treatment algorithm, and therefore, a personalized medicine approach is required. In this Review, we discuss the current understanding and gaps in knowledge regarding the pathophysiology and clinical features of adult-onset autoimmune diabetes and highlight the similarities and differences with classic T1DM and type 2 diabetes mellitus. PMID- 28885628 TI - Fluctuation tension and shape transition of vesicles: renormalisation calculations and Monte Carlo simulations. AB - It has been known for long that the fluctuation surface tension of membranes r, computed from the height fluctuation spectrum, is not equal to the bare surface tension sigma, which is introduced in the theory either as a Lagrange multiplier to conserve the total membrane area or as an external constraint. In this work we relate these two surface tensions both analytically and numerically. They are also compared to the Laplace tension gamma, and the mechanical frame tension tau. Using the Helfrich model and one-loop renormalisation calculations, we obtain, in addition to the effective bending modulus kappaeff, a new expression for the effective surface tension sigmaeff = sigma - epsilonkBT/(2ap) where kBT is the thermal energy, ap the projected cut-off area, and epsilon = 3 or 1 according to the allowed configurations that keep either the projected area or the total area constant. Moreover we show that the crumpling transition for an infinite planar membrane occurs for sigmaeff = 0, and also that it coincides with vanishing Laplace and frame tensions. Using extensive Monte Carlo (MC) simulations, triangulated membranes of vesicles made of N = 100-2500 vertices are simulated within the Helfrich theory. As compared to alternative numerical models, no local constraint is applied and the shape is only controlled by the constant volume, the spontaneous curvature and sigma. It is shown that the numerical fluctuation surface tension r is equal to sigmaeff both with radial MC moves (epsilon = 3) and with corrected MC moves locally normal to the fluctuating membrane (epsilon = 1). For finite vesicles of typical size R, two different regimes are defined: a tension regime for [small sigma, Greek, circumflex]eff = sigmaeffR2/kappaeff > 0 and a bending one for -1 < [small sigma, Greek, circumflex]eff < 0. A shape transition from a quasi-spherical shape imposed by the large surface energy, to more deformed shapes only controlled by the bending energy, is observed numerically at [small sigma, Greek, circumflex]eff ? 0. We propose that the buckling transition, observed for planar supported membranes in the literature, occurs for [small sigma, Greek, circumflex]eff ? -1, the associated negative frame tension playing the role of a compressive force. Hence, a precise control of the value of sigmaeff in simulations cannot but enhance our understanding of shape transitions of vesicles and cells. PMID- 28885629 TI - Urea-glass preparation of titanium niobium nitrides and subsequent oxidation to photoactive titanium niobium oxynitrides. AB - Titanium niobium oxynitrides (TiNbON) are an attractive category of potential photocatalysts, but strategies for preparing them remain limited. We adapt the wet chemical "urea glass" method for pure transition metal nitrides to single phase mixed-metal titanium niobium nitrides for a range of niobium mole fractions. We then oxidize the nitrides by heating in air to prepare titanium niobium oxynitride that absorbs visible light of lambda<= 550 nm. The materials are characterized by powder X-ray diffraction, scanning electron microscopy, and diffuse reflectance UV-vis spectroscopy. Their photochemical activity as a function of Nb fraction is benchmarked with methylene blue photomineralization promoted by full-spectrum AM 1.5G solar irradiation with and without a lambda>= 400 nm cut-on filter. First-order Langmuir-Hinshelwood rate constants for photomineralization reveal a composition with ~8% Nb to have superior reactivity. Full compositional analysis by Kjeldahl chemical nitrogen determination and energy-dispersive X-ray spectroscopy yields a chemical formula of Ti0.92Nb0.08O1.97N0.03. Finally, electron paramagnetic resonance spectroscopy correlates a localized Nb4+ defect with increased photochemical reaction rate. PMID- 28885626 TI - Evidence for a primate origin of zoonotic Helicobacter suis colonizing domesticated pigs. AB - Helicobacter suis is the second most prevalent Helicobacter species in the stomach of humans suffering from gastric disease. This bacterium mainly inhabits the stomach of domesticated pigs, in which it causes gastric disease, but it appears to be absent in wild boars. Interestingly, it also colonizes the stomach of asymptomatic rhesus and cynomolgus monkeys. The origin of modern human-, pig- or non-human primate-associated H. suis strains in these respective host populations was hitherto unknown. Here we show that H. suis in pigs possibly originates from non-human primates. Our data suggest that a host jump from macaques to pigs happened between 100 000 and 15 000 years ago and that pig domestication has had a significant impact on the spread of H. suis in the pig population, from where this pathogen occasionally infects humans. Thus, in contrast to our expectations, H. suis appears to have evolved in its main host in a completely different way than its close relative Helicobacter pylori in humans. PMID- 28885627 TI - Ecological and genomic profiling of anaerobic methane-oxidizing archaea in a deep granitic environment. AB - Recent single-gene-based surveys of deep continental aquifers demonstrated the widespread occurrence of archaea related to Candidatus Methanoperedens nitroreducens (ANME-2d) known to mediate anaerobic oxidation of methane (AOM). However, it is unclear whether ANME-2d mediates AOM in the deep continental biosphere. In this study, we found the dominance of ANME-2d in groundwater enriched in sulfate and methane from a 300-m deep underground borehole in granitic rock. A near-complete genome of one representative species of the ANME 2d obtained from the underground borehole has most of functional genes required for AOM and assimilatory sulfate reduction. The genome of the subsurface ANME-2d is different from those of other members of ANME-2d by lacking functional genes encoding nitrate and nitrite reductases and multiheme cytochromes. In addition, the subsurface ANME-2d genome contains a membrane-bound NiFe hydrogenase gene putatively involved in respiratory H2 oxidation, which is different from those of other methanotrophic archaea. Short-term incubation of microbial cells collected from the granitic groundwater with 13C-labeled methane also demonstrates that AOM is linked to microbial sulfate reduction. Given the prominence of granitic continental crust and sulfate and methane in terrestrial subsurface fluids, we conclude that AOM may be widespread in the deep continental biosphere. PMID- 28885630 TI - From direct to indirect lithium targets: a comprehensive review of omics data. AB - Metal ions are critical to a wide range of biological processes. Among them, lithium (Li) has been recognised for its benefit as a treatment for bipolar disorder (BD). However, we are yet to grasp the extent of its role in biological processes, despite its molecular targets having been extensively studied. Here we review a wide range of transcriptomic, proteomic and metabolomic studies in order to obtain a full picture of Li effects at various levels. Multifarious patterns of Li-regulated genes, proteins and metabolites are identified. Some of these patterns are explained as the outcomes of individual Li targets. For instance, Li inhibition of GSK-3 has a wide range of effects: axis development in embryos; cell and tissue differentiation, in particular neurogenesis and osteogenesis; or control of apoptosis. This results in neuroprotection and an attenuation of cognitive deficits. Lithium plays an important role in mitochondrial function, which it improves via its role in phospholipid metabolism and inositol depletion. This is also seen in metabolomics, where its role in the mitochondrial respiratory chain influences energy production and oxidative stress. Lithium also affects the proteins involved in the processing of APP, thus highlighting a possible involvement in Alzheimer's disease. Finally, Li also impacts lipid homeostasis, with studies showing that environmental exposure can impact lipid transport and prostaglandin synthesis. It is seldom possible to establish a causal relationship between Li targets at the molecular level and the resulting effects at the system level. For example, Li effects on adenylate cyclase regulation are not easily linked to any omic pattern despite the importance of the adenylate pathway. Nevertheless, refining our knowledge on the cellular functions of individual Li targets would improve our understanding and interpretation of omics data. This review demonstrates that Li is key to a wide range of processes at all levels, from neuroprotection to oxidative stress and energy production. A corollary of this work is the need for an increased awareness of environmental issues related to Li industrial wastes, in particular considering the widespread use of this metal in our modern society. PMID- 28885631 TI - Surface fouling as a mechanism for chemotaxis in isotropic catalytic swimmers. AB - We present microscopic models for surface fouling of an isotropic spherical catalytic microswimmer at and away from equilibrium and show how a foulant gradient can induce chemotactic behavior. Our simulations establish that the presence of foulant manifests itself in two ways: as a braking effect on propulsive particle motion, and as a drift term which probes the foulant concentration gradient. Our results suggest that, while foulant gradients are unlikely to be directly useful for chemotactically directed particles, they nevertheless exert a non-negligible influence on particle motion under a wide range of conditions. PMID- 28885632 TI - The theory of surface-enhanced Raman scattering on semiconductor nanoparticles; toward the optimization of SERS sensors. AB - We present an expression for the lowest order nonzero contribution to the surface enhanced Raman spectrum obtained from a system of a molecule adsorbed on a semiconductor nanoparticle. Herzberg-Teller vibronic coupling of the zero-order Born-Oppenheimer states results in an expression which may be regarded as an extension of the Albrecht A-, B-, and C-terms to SERS substrates. We show that the SERS enhancement is caused by combinations of several types of resonances in the combined system, namely, surface, exciton, charge-transfer, and molecular resonances. These resonances are coupled by terms in the numerator, which provide selection rules that enable various tests of the theory and predict the relative intensities of the Raman lines. Furthermore, by considering interactions of the various contributions to the SERS enhancement, we are able to develop ways to optimize the enhancement factor by tailoring the semiconductor nanostructure, thereby adjusting the locations of the various contributing resonances. This provides a procedure by which molecular sensors can be constructed and optimized. We provide several experimental examples on substrates such as monolayer MoS2 and GaN nanorods. PMID- 28885633 TI - Colloidal nanoparticle size control: experimental and kinetic modeling investigation of the ligand-metal binding role in controlling the nucleation and growth kinetics. AB - Despite the major advancements in colloidal metal nanoparticles synthesis, a quantitative mechanistic treatment of the ligand's role in controlling their size remains elusive. We report a methodology that combines in situ small angle X-ray scattering (SAXS) and kinetic modeling to quantitatively capture the role of ligand-metal binding (with the metal precursor and the nanoparticle surface) in controlling the synthesis kinetics. We demonstrate that accurate extraction of the kinetic rate constants requires using both, the size and number of particles obtained from in situ SAXS to decouple the contributions of particle nucleation and growth to the total metal reduction. Using Pd acetate and trioctylphosphine in different solvents, our results reveal that the binding of ligands with both the metal precursor and nanoparticle surface play a key role in controlling the rates of nucleation and growth and consequently the final size. We show that the solvent can affect the metal-ligand binding and consequently ligand coverage on the nanoparticles surface which has a strong effect on the growth rate and final size (1.4 nm in toluene and 4.3 nm in pyridine). The proposed kinetic model quantitatively predicts the effects of varying the metal concentration and ligand/metal ratio on nanoparticle size for our work and literature reports. More importantly, we demonstrate that the final size is exclusively determined by the nucleation and growth kinetics at early times and not how they change with time. Specifically, the nanoparticle size in this work and many literature reports can be predicted using a single, model independent kinetic descriptor, (growth-to nucleation rate ratio)1/3, despite the different metals and synthetic conditions. The proposed model and kinetic descriptor could serve as powerful tools for the design of colloidal nanoparticles with specific sizes. PMID- 28885634 TI - Pd-P nanoparticles supported on PxOy-incorporated carbon nanotubes for enhanced methanol oxidation in an alkaline medium. AB - Phosphorous oxide (PxOy)-incorporated carbon nanotubes (PCNTs) and nitric acid treated carbon nanotubes (OCNTs) are first synthesized, then phosphorous modified palladium nanoparticles (Pd-P NPs) supported on PCNTs (Pd-P/PCNTs) and OCNTs (Pd P/OCNTs) are synthesized and employed as electrocatalysts in a methanol oxidation reaction. Pd-P/PCNTs show enhanced electrocatalytic activity and stability in comparison to Pd-P/OCNTs. Combining surface analysis and electrochemical performance, PxOy incorporated into CNTs could create anchoring sites for Pd ions and P precursors, which could facilitate the synthesis of Pd-P NPs in an aqueous solution containing Pd ions and sodium hypophosphite serving as a reducing agent and a P source. The electronic modification of embedded Pd-P NPs on PxOy incorporated CNTs accounts for the enhanced electrochemical performance of Pd P/PCNTs. PMID- 28885635 TI - Regenerative nanobots based on magnetic layered double hydroxide for azo dye removal and degradation. AB - A highly regenerative multifunctional nanobot system, using Fe3O4@SiO2@MgFe-LDH nanoparticles, is developed for efficient removal of waterborne azo dyes and pharmaceuticals. Efficient capture of pollutants, powerful Fenton degradation, and superior materials regeneration lead to a simple and cost-effective wastewater remediation solution. PMID- 28885636 TI - Further expanding versatility of surface-enhanced Raman spectroscopy: from non traditional SERS-active to SERS-inactive substrates and single shell-isolated nanoparticle. AB - After surface-enhanced Raman spectroscopy (SERS) was initiated over four decades ago, its practical application seems to be far behind the fundamental research that has made tremendous progress. SERS as a highly sensitive technique has not been widely adopted by the materials science and surface science communities or in the market of analytical instruments. In this discussion, we first classify the previous approaches along this direction over the past four decades and divide them into three strategies. Based on our recent theoretical and experimental approaches, we discuss in more detail the third strategy related to shell-isolated nanostructures. It can significantly expand the SERS study on nontraditional SERS-active (i.e. weakly SERS-active) materials (e.g. Pt, Ni, Fe, etc.) and even SERS-inactive materials (e.g. Si and Al2O3). We then focus on a single shell-isolated nanoparticle and how to controllably locate the strong electromagnetic field just at the probe surface of various materials. The use of side illumination at a high incident angle and/or nanocubes can further enhance the Raman signal by one to two orders of magnitude, which could be helpful for quantitative studies for surface science, heterogeneous catalysis, and soft matter science. PMID- 28885637 TI - "Is There An App For That?" Orthopaedic Patient Preferences For A Smartphone Application. AB - BACKGROUND: Patients are seeking out medical information on the Internet and utilizing smartphone health applications ("apps"). Smartphone use has exponentially increased among orthopaedic surgeons and patients. Despite this increase, patients are rarely directed to specific apps by physicians. No study exists querying patient preferences for a patient-centered, orthopaedic smartphone application. OBJECTIVES: The purpose of this study is to 1) determine Internet use patterns amongst orthopaedic patients; 2) ascertain access to and use of smartphones; and 3) elucidate what features orthopaedic patients find most important in a smartphone application. METHODS: We surveyed patients in an orthopaedic practice in an urban academic center to assess demographics, access to and patterns of Internet and Smartphone use, and preferences for features in a smartphone app. RESULTS: A total of 310 surveys were completed. Eighty percent of patients reported Internet access, and 62% used the Internet for health information. Seventy-seven percent owned smartphones, 45% used them for health information, and 28% owned health apps. Only 11% were referred to an app by a physician. The highest ranked features were appointment reminders, ability to view test results, communication with physicians, and discharge instructions. General orthopaedic information and pictures or videos explaining surgery were the 2 lowest ranked features. Seventy-one percent of patients felt an app with some of the described features would improve their healthcare experiences, and 40% would pay for the app. CONCLUSIONS: The smartphone is an under-utilized tool to enhance patient-physician communication, increase satisfaction, and improve quality of care. Patients were enthusiastic about app features that are often included in patient health portals, but ranked orthopaedic educational features lowest. Further study is required to elucidate how best to use orthopaedic apps as physician-directed educational opportunities to promote patient satisfaction and quality of care. PMID- 28885638 TI - Speech Recognition and Cognitive Skills in Bimodal Cochlear Implant Users. AB - Purpose: To examine the relation between speech recognition and cognitive skills in bimodal cochlear implant (CI) and hearing aid users. Method: Seventeen bimodal CI users (28-74 years) were recruited to the study. Speech recognition tests were carried out in quiet and in noise. The cognitive tests employed included the Reading Span Test and the Trail Making Test (Daneman & Carpenter, 1980; Reitan, 1958, 1992), measuring working memory capacity and processing speed and executive functioning, respectively. Data were analyzed using paired-sample t tests, Pearson correlations, and partial correlations controlling for age. Results: The results indicate that performance on some cognitive tests predicts speech recognition and that bimodal listening generates a significant improvement in speech in quiet compared to unilateral CI listening. However, the current results also suggest that bimodal listening requires different cognitive skills than does unimodal CI listening. This is likely to relate to the relative difficulty of having to integrate 2 different signals and then map the integrated signal to representations stored in the long-term memory. Conclusions: Even though participants obtained speech recognition benefit from bimodal listening, the results suggest that processing bimodal stimuli involves different cognitive skills than does unimodal conditions in quiet. Thus, clinically, it is important to consider this when assessing treatment outcomes. PMID- 28885639 TI - Targeting Immune Checkpoints in Cancer Therapy. PMID- 28885640 TI - Inner Speech's Relationship With Overt Speech in Poststroke Aphasia. AB - Purpose: Relatively preserved inner speech alongside poor overt speech has been documented in some persons with aphasia (PWA), but the relationship of overt speech with inner speech is still largely unclear, as few studies have directly investigated these factors. The present study investigates the relationship of relatively preserved inner speech in aphasia with selected measures of language and cognition. Method: Thirty-eight persons with chronic aphasia (27 men, 11 women; average age 64.53 +/- 13.29 years, time since stroke 8-111 months) were classified as having relatively preserved inner and overt speech (n = 21), relatively preserved inner speech with poor overt speech (n = 8), or not classified due to insufficient measurements of inner and/or overt speech (n = 9). Inner speech scores (by group) were correlated with selected measures of language and cognition from the Comprehensive Aphasia Test (Swinburn, Porter, & Al, 2004). Results: The group with poor overt speech showed a significant relationship of inner speech with overt naming (r = .95, p < .01) and with mean length of utterance produced during a written picture description (r = .96, p < .01). Correlations between inner speech and language and cognition factors were not significant for the group with relatively good overt speech. Conclusions: As in previous research, we show that relatively preserved inner speech is found alongside otherwise severe production deficits in PWA. PWA with poor overt speech may rely more on preserved inner speech for overt picture naming (perhaps due to shared resources with verbal working memory) and for written picture description (perhaps due to reliance on inner speech due to perceived task difficulty). Assessments of inner speech may be useful as a standard component of aphasia screening, and therapy focused on improving and using inner speech may prove clinically worthwhile. Supplemental Materials: https://doi.org/10.23641/asha.5303542. PMID- 28885641 TI - FDA's Innovative Plan to Address the Enormous Toll of Smoking. PMID- 28885642 TI - Going With the Flow: The Promise and Challenge of Liquid Biopsies. PMID- 28885643 TI - Current practice of BHS members in the treatment of osteonecrosis of the femoral head in adults. AB - INTRODUCTION: The management of osteonecrosis (ON) of the femoral head remains controversial. It is unclear the extent to which non-arthroplasty procedures are used and there has been no previous report of the trends in operative management of ON in the UK. Our objective is to report current trends in management of ON of the femoral head amongst specialist hip surgeons in the UK. METHODS: A single stage internet-based survey was e-mailed to 352 eligible members of the British Hip Society (BHS). This consisted of 10 question stems including 16 hypothetical clinical scenarios with imaging. RESULTS: 115 active Consultant members of the BHS completed the survey. For symptomatic pre-collapse ON we found core decompression (CD) was the most common operative intervention and for post collapse ON we found that total hip arthroplasty (THA) was the most common operative intervention. We found no difference in the rate of operative intervention between 24 and 48-year-old patients at any stage of ON but joint preserving procedures were more often selected for the younger patient and arthroplasty for the older patient. Surgeons were more likely to offer arthroplasty to a 48-year-old patient at an earlier stage of disease. CONCLUSIONS: Our respondents would offer different operative interventions dependent on stage of ON and patient age. Core decompression (CD) and arthroplasty were common but variation in treatment options offered suggests a lack of consensus amongst UK hip surgeons. We suggest that further research such as a prospective RCT is needed to gain consensus on management of this condition. PMID- 28885644 TI - Detection of total hip arthroplasties at airport security checkpoints - how do updated security measures affect patients? AB - INTRODUCTION: There have been historical reports on the experiences of patients with total hip arthroplasty (THA) passing through standard metal detectors at airports. The purpose of this study was to analyse those who had recently passed through airport security and the incidence of: (i) triggering of the alarm; (ii) extra security searches; and (iii) perceived inconvenience. METHODS: A questionnaire was given to 125 patients with a THA during a follow-up appointment. Those who had passed through airport security after January 2014 met inclusion criteria. A survey was administered that addressed the number of encounters with airport security, frequency of metal detector activation, additional screening procedures utilised, whether security officials required prosthesis documentation, and perceived inconvenience. RESULTS: 51 patients met inclusion criteria. 10 patients (20%) reported triggered security scanners. 4 of the 10 patients stated they had surgical hardware elsewhere in the body. 13 of the 51 patients (25%) believed that having their THA increased the inconvenience of traveling. This is different from the historical cohort with standard metal detectors which patients reported a greater incidence of alarm triggering (n = 120 of 143; p = 0.0001) and perceived inconvenience (n = 99 of 143; p = 0.0001). DISCUSSIONS: The percentage of patients who have THA triggering security alarms has decreased. Furthermore, the number of patients who feel that their prosthesis caused traveling inconvenience has decreased. We feel that this decrease in alarms triggered and improved perceptions about inconvenience are related to the increased usage of new technology. PMID- 28885645 TI - Update of NICE guidance for hip fractures in adults. PMID- 28885646 TI - Relationship between clinical results of total hip replacement and postoperative activities including weeding and snow shovelling. AB - INTRODUCTION: Weeding or snow shovelling is indispensable for life in farm villages of northern countries. Clarifying the relationships between the degrees of these activities after total hip replacement (THR) and the clinical results of THR may enable us to predict the results of THR for high-level activity patients. The relationships between work activities after THR and the results were investigated. METHODS: The subjects were 95 post-THR patients, who consulted 6 hospitals in August 2012. First, the Japanese Orthopaedic Association Hip-Disease Evaluation Questionnaire (JHEQ) and a questionnaire on postoperative activity were administered. Then, the Japanese Orthopaedic Association hip score (JOA score) was evaluated. RESULTS: The subjects' average age was 68 years. The average period after surgery was 4 years and 5 months. Weeding and snow shovelling were performed after THR in 44.2% and 40.0% of cases, respectively. The rate of farming after surgery (25.6%) was greater than that of swimming (21.1%). Both the JOA score and JHEQ were higher in those who played sports after THR than in those who did not (p = 0.003, p = 0.0046). The JOA score of those who performed work activities after THR was higher than that of those who did not (p = 0.0295). CONCLUSIONS: Nearly half of patients performed weeding or snow shovelling after THR, and about 1/4 of the patients engaged in farming after THR. The clinical results in cases doing sports and work activities after THR were better than those of cases not doing such activities. Therefore, these activities may be positively recommended. PMID- 28885648 TI - Improving registration accuracy during total hip arthroplasty: a cadaver study of a new, 3-D mini-optical navigation system. AB - INTRODUCTION: Maintaining accuracy of component placement is an important step in ensuring the long-term stability of components during total hip arthroplasty (THA). Computer-assisted navigation has improved accuracy but errors associated with the registration process are known to impact the accuracy of final measurements. The purpose of this cadaver study was to determine the registration error associated with a novel mini-navigation system. METHODS: 3 board-certified orthopaedic surgeons performed 4 THA procedures each via the posterolateral approach on 6 cadavers (12 hips) using the mini-navigation tool. Pre- and post operative radiographs and post-operative computed tomography (CT) images were obtained. Image analysis was performed by 2 radiologists not involved in the surgical procedures. During registration, surgeons aligned the alignment rod with the anterior pelvic plane (APP) to provide a reference plane for comparison with traditional navigation. Cup position from the device was compared with measurements gathered from post-op imaging. RESULTS: The mean difference between CT and device measurements for inclination was -1.7 degrees (standard deviation [SD] 4.9 degrees ), while the mean absolute difference was 4.2 degrees (SD 3.2 degrees ). The mean difference between anteversion angles calculated from CT scans and from the device was -3.5 degrees (SD 4.5 degrees ), with an absolute difference of 4.0 degrees (SD 4.0 degrees ). 100% (12/12) of inclination measurements and 92% (11/12) of anteversion measurements fell within both the clinical and statistical limits of agreement when analyzed via the Bland-Altman technique. CONCLUSIONS: This study demonstrates that the registration error associated with this new mini-navigation system compares favourably with the known registration error associated with traditional navigation systems. PMID- 28885647 TI - 10-year results of the Birmingham Hip Resurfacing: a non-designer case series. AB - INTRODUCTION: Recent controversies surrounding metal-on-metal (MoM) hip resurfacing has led to a substantial decline in its use. Despite this, there is good evidence to support the use of specific implants in select patients. PATIENTS AND METHODS: A retrospective analysis of Birmingham Hip Resurfacing (BHR) patients with a minimum of 10 years follow-up was performed. Functional scoring was performed with the Oxford Hip Score (OHS) and failure was defined as revision for any cause. 111 patients underwent 121 BHR procedures. All patients had a minimum follow-up of 10 years. 70 patients (63%) were male. Mean patient age at surgery was 52.5 years (male 53.9 years, female 48.8 years). RESULTS: Overall survival at 10 years was 91% (97% male, 80% female). There was a statistically significant improvement in OHS postoperatively which remains at 10 year follow-up (p = <0.05). There was no significant difference in scores between the male and female groups. Revisions were most often in patients with smaller component sizes but this was not found to be statistically significant. CONCLUSIONS: Our results reflect that of the wider literature in that good outcomes can be obtained with this implant in a select group of patients and results are comparable to that of conventional hip arthroplasty in patients of a similar age. PMID- 28885649 TI - L5 radiculopathy secondary to migration of a revision stemmed acetabular cup. AB - INTRODUCTION: Stemmed acetabular components are used in patients undergoing revision total hip arthroplasty in cases with major acetabular defects or pelvic discontinuity. Conflicting results relating to the survival of the component, and complication rates are reported in the literature. We present a case of L5 radiculopathy secondary to proximal migration of this device. CASE DESCRIPTION: A 79-year-old man was admitted to our department in 2012 with increasing pain and paresthesias, initially diagnosed as left L5 radiculopathy. In 2002, he had undergone revision surgery due to aseptic loosening of the acetabular component with a stemmed acetabular cup. Radiological findings were severe osteolysis around the acetabular cup with proximal migration. MRI showed osteolysis involving the left L5/S1 facet joint and evidence of soft tissue in the left foramina encasing the L5 radicular nerve. Nerve conduction and electromyography studies revealed chronic L5 radiculopathy. DISCUSSIONS: This case report illustrates the importance of considering acetabular loosening in a patient presenting with radicular symptoms. If a stemmed acetabular cup is chosen for an acetabular reconstruction, careful surgical technique should be employed in order to achieve durable fixation. If the patient has pelvic discontinuity, other options of reconstruction have showed better outcomes in the literature. PMID- 28885650 TI - The posterior acetabular wall (PAW): an aid to acetabular orientation at primary THA. AB - INTRODUCTION: Incorrect acetabular component positioning during total hip arthroplasty (THA) may lead to dislocation, impingement, wear and revision. Surgeons commonly use the transverse acetabular ligament (TAL) as a landmark for acetabular component orientation. The posterior acetabular wall (PAW) is a structure easily viewed on plain radiography and its position can help guide acetabular component position. In this study, we examine the efficacy of preoperative radiographs in predicting cup position relative to the PAW. METHODS: Prospective data was recorded on radiographic findings of the posterior wall (prominent, normal, deficient) on a consecutive series of 200 primary THAs utilising a standardised posterior approach. The final cup position relative to the wall was recorded (prominent, flush, deep). Cup inclination and version were then assessed by postoperative radiography and any instances of dislocation recorded. RESULTS: There were 117 females and 83 males with a mean age of 66.5 years. 154 were recorded as having a normal PAW on radiographs, 152 had the cup positioned in line with the TAL and flush to the PAW. 29 had a deficient PAW and 27 of these had a cup positioned prominently with 17 having a prominent PAW and of these 16 a deep cup position. Postoperative radiographs showed a mean cup version of 20.8 degrees and inclination of 44.7 degrees using this method. There were 21 outliers (10.5%) with no dislocations at a minimum 12-month follow up. CONCLUSIONS: The TAL is a continuation of the posterior labrum. As such, the posterior wall is a useful adjunct to and surrogate landmark for the TAL. It has the added advantage that it is visible on radiographs and so aids surgical planning with respect to cup positioning. PMID- 28885651 TI - The practice pattern of anticoagulation prophylaxis for patients undergoing total hip replacement in a major orthopaedic centre; a retrospective review. AB - METHODS: In a major centre for orthopaedic surgery, we retrospectively analysed 1,469 patients who underwent elective hip replacement since 2010. All patients but 2 received anticoagulation postoperatively and rivaroxaban was the preferred choice for anticoagulation. RESULTS: The incidence of all adverse events in those who received rivaroxaban was 1.7%. Only 0.3% had a minor upper gastrointestinal bleed and 1.3% developed a minor wound bleeding or haematoma. The occurrence of symptomatic venous thromboembolism (VTE) was 0.2% of all patients. CONCLUSIONS: In this analysis, the incidence of adverse events was lower than the previously 4 published national figures. PMID- 28885652 TI - Vascularised and modified lower-leg rotationplasty for the treatment of severe infection and bone loss of the proximal femur: a case report. AB - CASE DESCRIPTION: We report a reconstructive case in a paraplegic patient, who suffers from a severe proximal femur infection. Aiming at the preservation of the capacity to remain in a seated position to operate a wheelchair, lower leg rotationplasty was considered suitable for reconstruction. Due to severe infection and subclinical femoral artery stenosis, rotationplasty was supercharged by the inferior epigastric artery. Furthermore, extensor tendons of the foot were attached to the acetabulum to facilitate stability of the neo-hip joint. RESULTS: Follow-up examination 1 year after surgery revealed no complications and a satisfied patient. CONCLUSIONS: Especially in paraplegic patients, lower leg rotationplasty is a possible treatment option for severe femoral infection. Supercharging provides well-vascularised tissue to the former infection site and improves wound healing. PMID- 28885653 TI - Reply to Comments on: Novel use of infrared thermal imaging to predict arteriovenous fistula patency and maturation. PMID- 28885654 TI - What is the best setting for receiving dialysis vascular access repair and maintenance services? AB - INTRODUCTION: Advances in dialysis vascular access (DVA) management have changed where beneficiaries receive this care. The effectiveness, safety, quality, and economy of different care settings have been questioned. This study compares patient outcomes of receiving DVA services in the freestanding office-based center (FOC) to those of the hospital outpatient department (HOPD). It also examines whether outcomes differ for a centrally managed system of FOCs (CMFOC) compared to all other FOCs (AOFOC). METHODS: Retrospective cohort study of clinically and demographically similar patients within Medicare claims available through United States Renal Data System (USRDS) (2010-2013) who received at least 80% of DVA services in an FOC (n = 80,831) or HOPD (n = 133,965). Separately, FOC population is divided into CMFOC (n = 20,802) and AOFOC (n = 80,267). Propensity matching was used to control for clinical, demographic, and functional characteristics across populations. RESULTS: FOC patients experienced significantly better outcomes, including lower annual mortality (14.6% vs. 17.2%, p<0.001) and DVA-related infections (0.16 vs. 0.20, p<0.001), fewer hospitalizations (1.65 vs. 1.91, p<0.001), and lower total per-member-per-month (PMPM) payments ($5042 vs. $5361, p<0.001) than HOPD patients. CMFOC patients had lower annual mortality (12.5% vs. 13.8%, p<0.001), PMPM payments (DVA services) ($1486 vs. $1533, p<0.001) and hospitalizations ($1752 vs. $1816, p<0.001) than AOFOC patients. CONCLUSIONS: Where nephrologists send patients for DVA services can impact patient clinical and economic outcomes. This research confirmed that patients who received DVA care in the FOC had better outcomes than those treated in the HOPD. The organizational culture and clinical oversight of the CMFOC may result in more favorable outcomes than receiving care in AOFOC. PMID- 28885655 TI - Comments on: Novel use of infrared thermal imaging to predict arteriovenous fistula patency and maturation. PMID- 28885656 TI - Bladder cancer to patients younger than 30 years: a retrospective study and review of the literature. AB - OBJECTIVES: The aim of this report was to study the specific characteristics of bladder cancer in patients younger than 30 years. MATERIALS AND METHODS: Five patients with a mean age of 24 +/- 2.83 years were included in the study. All patients had painless macroscopic hematuria as the first symptom. Three patients had pTa as a first diagnosis, one had pT1 and one pT2. All the patients had smoking as a risk factor and at least one additional possible risk factor. RESULTS: One patient with pTa had an aggressive course and after multiple recurrences was diagnosed with pT2 and refused to be submitted to radical cystectomy and died from the disease even though he received a multimodality treatment. The other two patients with the pTa diagnosis had no recurrence after the first TUR-BT and the patient with the pT1 diagnosis after one recurrence with a pTa histology is free of recurrence for the last 2 years. The patient diagnosed with pT2 was submitted to a radical cystectomy and an s-pouch diversion with a preservation of the genital system in order to have the ability of a future motherhood with the acceptance of course risks. CONCLUSIONS: Young patients with bladder cancer is a difficult group of patients and show more reluctance to comply to the necessary strict follow-up of the repeated urinary cytology examinations, cystoscopies and CT pyelographies. Herein, we report a retrospective study of five patients younger than 30 years with bladder cancer. PMID- 28885657 TI - Is hypogonadism the cause of penile self-amputation in a patient with prior testes self-mutilation? AB - INTRODUCTION: This paper presents a rare event of genital self-mutilation and few cases are reported in the literature. CASE DESCRIPTION: We report on a patient who performed partial self-penectomy 18 months after bilateral testicular amputation, as a form of self-mutilation. CONCLUSIONS: The main hypotheses to explain the recurrence of self-mutilation would be hypogonadism. PMID- 28885658 TI - Circulating tumor DNA is effective for detection of KRAS mutation in colorectal cancer: a meta-analysis. AB - BACKGROUND:: Circulating tumor DNA (ctDNA) offers a novel and minimally invasive approach to the detection of the KRAS oncogene mutation in colorectal cancer. This study was conducted to compare the prognostic value of ctDNA with that of the current gold standard tumor tissue analysis. METHODS:: A systematic literature review was conducted to identify relevant articles published from inception to December 27, 2016; the PubMed, Web of Science, Embase, Wanfang and China National Knowledge Infrastructure databases were searched. Pooled specificity, sensitivity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio (DOR) estimates and areas under summary receiver operating characteristic (AUSROC) curves were calculated. We also performed subgroup and sensitivity analyses. RESULTS:: Twenty-three studies with 1,715 colorectal cancer patients were included. The overall sensitivity and specificity were 0.75 (95% confidence interval [CI], 0.66-0.82) and 0.98 (CI, 0.95-0.99), respectively. The positive likelihood ratio was 31.8 (95% CI, 14.8-68.3), and the negative likelihood ratio was 0.26 (95% CI, 0.19-0.36). In addition, the AUSROC and DOR were 0.96 (95% CI, 0.93-0.97) and 123 (95% CI, 52-291), respectively. Substantial heterogeneity was observed across studies (I2 = 95%, 95% CI, 91-99). None of the subgroups investigated, including those defined by blood sample type, study region, TNM stage, detection site and detection method, could indicate the source of the observed heterogeneity. The results of the sensitivity analysis indicated that the results of our meta-analysis were stable. CONCLUSIONS:: Circulating tumor DNA may serve as a viable alternative to tissue analysis for the detection of KRAS mutations in colorectal cancer. PMID- 28885659 TI - The role of serum neuron-specific enolase in patients with prostate cancer: a systematic review of the recent literature. AB - In this systematic review, we evaluated the value of serum concentrations of neuron-specific enolase (NSE) in patients with prostate cancer (PCa) in order to clarify the possible role of NSE in the diagnosis, management, treatment and monitoring of PCa. A comprehensive search of the recent literature was conducted to find relevant data on the role of NSE in PCa. Two hundred and eighty-two records were revealed, and 19 articles including 1,772 patients with PCa (either confirmed or suspected) were selected. After reviewing the articles, the major result was that elevated serum NSE appears to correlate with prognosis in advanced PCa, particularly in patients with progressive and metastatic castration resistant PCa. Based on the existing literature, the role of serum NSE in PCa patients should be further evaluated. PMID- 28885660 TI - Cortactin and phosphorylated cortactin tyr421 and tyr466 expression in supraglottic laryngeal carcinomas and lymph node metastases. AB - BACKGROUND: The most important adverse prognostic factor for laryngeal squamous cell carcinoma (LSCC) is the presence of cervical lymph node metastases. The supraglottic area of the larynx is richly supplied with lymphatics, and 25%-75% of supraglottic carcinomas metastasize in neck lymph nodes. Cortactin is a multidomain protein related to actin cytoskeleton regulation, podosome and lamellipodia formation, integrin signaling, axon guidance and extracellular matrix degradation. Cortactin is involved in metastasis formation because of its role in cell mobility. The present study focused mainly on the role of cortactin and phosphorylated cortactin (residues tyr421 and tyr466) expression and subcellular localization in primary supraglottic LSCCs and their cervical lymph node metastases. METHODS: The immunohistochemical expression of cortactin, p-Y466 cortactin and p-Y421-cortactin was assessed in 38 primary supraglottic LSCCs and 10 lymph node metastases. The statistical approach included bootstrapping analysis. RESULTS: Despite a significantly higher expression of cortactin in carcinoma cells than in adjacent normal laryngeal mucosa, no associations emerged between prognosis and the expression of cortactin or its isoforms in supraglottic LSCC. Statistical analysis found cortactin expression higher in less differentiated LSCCs (p = 0.03). A significant direct correlation was found between cortactin and p-Y466-cortactin levels (p = 0.031), and between p-Y466 cortactin and p-Y421-cortactin levels (p = 0.001). CONCLUSIONS: Cortactin expression in carcinoma cells and its known involvement in the EGFR pathway suggest a role for this protein as a target for LSCC therapy. Further prospective studies are needed to investigate the potential of cortactin, p-Y466-cortactin and p-Y421-cortactin expression as markers of response to treatment (particularly EGFR-directed agents) in LSCC. PMID- 28885661 TI - EGFR as a clinical marker in glioblastomas and other gliomas. AB - Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein and a member of the tyrosine kinase superfamily receptor. Gliomas are tumors originating from glial cells, which show a range of aggressiveness depending on grade and stage. Many EGFR gene alterations have been identified in gliomas, especially glioblastomas, including amplifications, deletions and single nucleotide polymorphisms (SNPs). Glioblastomas are discussed as a separate entity due to their high correlation with EGFR mutants and the reported association of the latter with survival and response to treatment in this glioma subgroup. This review is a comprehensive report of EGFR gene alterations and their relations with several clinical factors in glioblastomas and other gliomas. It covers all EGFR gene alterations including point mutations, SNPs, methylations, copy number variations and amplifications, assessed with regard to different clinical variables, including response to therapy and survival. This review also discusses the current prognostic status of EGFR in glioblastomas and other gliomas, and highlights gaps in previous studies. This serves as an update for the medical community about the role of EGFR gene alterations in gliomas and specifically glioblastomas, as a means for targeted treatment and prognosis. PMID- 28885662 TI - Differential diagnosis of alterations in arterial flow and tissue oxygenation on venoarterial extracorporeal membrane oxygenation. AB - BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) may be life-saving in several clinical situations, but it is also one of the most invasive therapeutic procedures, with significant potential for life-threatening complications. Pulse pressure waves are typically very small or even absent at the onset of ECMO therapy, and will reappear with the improvement of cardiac function. A low pulse pressure may indicate low cardiac output due to heart failure during sustained ECMO support. A sudden loss of pulse pressure during ECMO therapy, however, may reveal complications like pericardial tamponade, hemothorax or pneumothorax. Near infrared spectroscopy (NIRS) has been shown to be useful in detecting cerebral and lower limb ischemic events during ECMO therapy and could furthermore improve differential diagnosis in the event pulsatility of the arterial pressure trace is lost. METHODS: We are reporting on 3 different complications of ECMO and their impact on arterial pulse pressure, arterial oxygen tension and regional tissue oxygenation measured by NIRS. RESULTS: Pericardial hematoma, overinflation of the lung, and tension pneumothorax may impede cardiac output during VA-ECMO and cause a loss of pulse pressure. Monitoring of regional tissue oxygenation using NIRS, in addition to arterial and mixed venous oxygen tension, may allow early recognition and treatment of ECMO complications. CONCLUSIONS: Together with the appearance of a flat, non pulsatile arterial pressure trace as well as a reduction in mixed venous oxygen saturation the improvement of upper body rSO2 measured by NIRS enables timely recognition of complications that interfere with natural cardiac output during VA-ECMO. PMID- 28885663 TI - Removal of bile acids by extracorporeal therapies: an in vitro study. AB - INTRODUCTION: Bile acids (BAs) accumulating in the circulation in patients with liver failure are considered to be responsible for pruritus, which strongly impairs quality of life of the affected patients. The aim of this study was the in vitro characterization of different BAs regarding their removability with high flux dialysis as well as with different adsorbents, and the evaluation of their binding to plasma proteins. METHODS: Dialysis experiments were conducted in pediatric circuits with human plasma. For the adsorption studies, batch tests using 10% adsorbent in spiked human plasma were carried out. The binding of BAs to plasma compounds was determined by centrifugation of spiked plasma through spin columns. Sieving coefficients were determined using an albumin filter and a high-flux dialyzer. RESULTS: With high-flux dialysis, only hydrophilic BAs such as glycocholic and taurocholic acid could be removed efficiently, while all tested BAs were removed by adsorption. CONCLUSIONS: In conclusion, the hydrophilicity of BAs plays a major role in their removability using extracorporeal approaches. Adsorption-based systems offer particular advantages for the removal of hydrophobic BAs. PMID- 28885664 TI - Postoperative acute kidney injury in living donor liver transplantation recipients. AB - PURPOSE: There are many risk factors for postoperative acute kidney injury in liver transplantation. The aim of this study is to investigate the risk factors for postoperative acute kidney injury in living donor liver transplantation recipients. METHODS: 220 living donor liver transplantation recipients were retrospectively evaluated in the study. According to the Kidney Disease Improving Global Outcomes Guidelines, acute kidney injury in postoperative day 7 was investigated for all patients. The patient's demographic data, preoperative and intraoperative parameters, and outcomes were recorded. RESULTS: Acute kidney injury was found in 27 (12.3%) recipients. In recipients with acute kidney injury, female population, model for end-stage liver disease score, norepinephrine requirement, duration of mean arterial pressure less than 60 mmHg, the usage of gelatin and erythrocyte suspension and blood loss were significantly higher than recipients with nonacute kidney injury (for all p<0.05). In multivariate analyses, the likelihood of acute kidney injury on postoperative day 7 were increased 2.8-fold (1.1-7.0), 2.7-fold (1.02-7.3), 3.4-fold (1.2-9.9) and 5.1-fold (1.7-15.0) by postoperative day 7, serum tacrolimus level >=10.2 ng dL 1, intraoperative blood loss >=14.5 mL kg-1, the usage of gelatin >5 mL kg-1 and duration of MAP less than 60 mmHg >=5.5 minutes respectively (for all p<0.05). CONCLUSIONS: In living donor liver transplantation recipients, serum tacrolimus levels, intraoperative blood loss, hypotension period and the usage of gelatin may be risk factors for acute kidney injury in the early postoperative period. PMID- 28885665 TI - Comparison of 2 plating techniques for lateral clavicle fractures, using a new standardized biomechanical testing setup. AB - BACKGROUND: Conservative treatment of lateral clavicle fractures (Neer type II) often ends with unsatisfactory results for patients. Operative treatment is thus gaining acceptance. A retrospective study found success using a double plate technique for these injuries. For the current study, a standardized testing setup was developed to compare the mechanical properties of single versus double plate technique for lateral clavicle fractures. METHODS: Six synthetic bones were tested for each technique. Neer type IIB fractures were created using computer aided design (CAD). Fatigue testing was carried out with a cantilever bending test. Parameters measured were cycles undergone, failure load and stiffness at the point of failure. RESULTS: The standardized testing setup was able to provide reproducible failures. The double plate technique lasted about 16,000 more cycles and withstood an additional 22.4 N on average. CONCLUSIONS: The new modified standardized testing setup produced reproducible fixation failures for both clavicle fracture fixation techniques. The double plate technique seems to be mechanically superior to the single plate technique. PMID- 28885666 TI - Double acid etching treatment of dental implants for enhanced biological properties. AB - BACKGROUND: The topographical features on the surface of dental implants have been considered as a critical parameter for enhancing the osseointegration of implants. In this work, we proposed a surface obtained by a combination of shot blasting and double acid etching. The double acid etching was hypothesized to increase the submicron topography and hence further stimulate the biological properties of the titanium implant. METHODS: The topographical features (surface roughness and real surface area), wettability and surface chemical composition were analyzed. RESULTS: The results showed that the proposed method produced a dual roughness, mainly composed of randomly distributed peaks and valleys with a superimposed nanoroughness, and hence with an increased specific surface area. Despite the fact that the proposed method does not introduce significant chemical changes, this treatment combination slightly increased the amount of titanium available on the surface, reducing potential surface contaminants. Furthermore, the surface showed increased contact angle values demonstrating an enhanced hydrophobicity on the surface. The biological behavior of the implants was then assessed by culturing osteoblast-like cells on the surface, showing enhanced osteoblast adhesion, proliferation and differentiation on the novel surface. CONCLUSIONS: Based on these results, the described surface with dual roughness obtained by double acid etching may be a novel route to obtain key features on the surface to enhance the osseointegration of the implant. Our approach is a simple method to obtain a dual roughness that mimics the bone structure modified by osteoclasts and increases surface area, which enhances osseointegration of dental implants. PMID- 28885667 TI - Variations in retinal nerve fiber layer measurements on optical coherence tomography after implantation of trifocal intraocular lens. AB - PURPOSE: To establish the changes produced after implantation of a trifocal intraocular lens (IOL) on retinal nerve fiber layer measurements performed with Fourier-domain optical coherence tomography (OCT). METHODS: This prospective study included 100 eyes of 50 patients with bilateral cataract in surgical range, no other associated ocular involvement, refractive errors between +5 and -5 spherical diopters, and less than 1.5 D of corneal astigmatism. The eyes were operated by phacoemulsification with implantation of 2 different trifocal IOLs (FineVision and AT LISA tri 839MP) in randomized equal groups. Cirrus OCT and Spectralis OCT were performed before surgery and 3 months later. Both analyzed the thickness of the nerve fiber layer and thickness divided by quadrants (6 in case of Spectralis and 4 in case of Cirrus HD). RESULTS: The mean age of patients was 67.5 +/- 5.8 years. The global nerve fiber layer thickness measured with Spectralis OCT was 96.77 MUm before surgery and 99.55 MUm after. With Cirrus OCT, the global thickness was 85.29 MUm before surgery and 89.77 MUm after. Statistically significant differences in global thickness measurements between preimplantation and postimplantation of the IOL were found with both OCT in the 2 groups. Statistically significant differences were also found in temporal and superior quadrants. CONCLUSIONS: The implantation of a diffractive trifocal IOL alters the results of the optic nerve fiber layer on Fourier-domain OCT in these patients, which should be taken into account in the posterior study of these patients. PMID- 28885668 TI - The role of intraoperative optical coherence tomography in pediatric hyphema: a case report. AB - PURPOSE: Intraoperative optical coherence tomography (iOCT) is a valuable tool during vitreoretinal surgery, helping the decision-making process. It is particularly useful in pediatric cases to evaluate the macular anatomy intraoperatively, avoiding further potentially dangerous surgery in children. The aim of this report is to describe the role of integrated iOCT in the management of traumatic hyphema in a pediatric patient. CASE REPORT: A 5-year-old girl was referred to our department with a history of recent domestic trauma in her right eye. Massive bleeding in the anterior chamber without visualization of the posterior segment was evident. Surgery was planned for the next day under general anesthesia. A 25-G irrigation cannula and 25-G vitrectome were inserted at the limbus into the anterior chamber for removal of the anterior chamber clot. Careful inspection of the posterior pole and retinal periphery to exclude pathologic findings was carried out. A real-time OCT integrated system was used to assess the macular anatomy and the corneal state. The postoperative course was uneventful and full visual recovery was achieved. CONCLUSIONS: The objective confirmation of macular integrity by means of iOCT after anterior chamber clearing had great prognostic value, excluding the need for surgical revision with a second general anesthesia in this young patient. PMID- 28885669 TI - Long-term intraocular pressure after combined trabeculotomy-trabeculectomy in glaucoma associated with Sturge-Weber syndrome. AB - PURPOSE: Vision loss in Sturge-Weber syndrome (SWS), a rare congenital disorder, is primarily due to glaucoma. METHODS: We reviewed the data of all consecutive SWS-associated glaucoma cases in patients who had undergone combined trabeculotomy-trabeculectomy (CTT) at a tertiary glaucoma facility between January 1993 and December 2015. We analyzed the preoperative and postoperative intraocular pressure (IOP), corneal clarity, visual acuity, success rate, need for repeat surgery, and number of topical antiglaucoma medications needed at last follow-up. RESULTS: Twenty-six eyes of 20 patients with SWS (surgical age 0.7-96 months; mean 18.64 +/- 29.74 months) had undergone primary CTT. The mean preoperative IOP was 32.76 +/- 7.86 mm Hg (range 22-54 mm Hg) with medication (mean 3.11 +/- 1.17; range 1-5). At the last follow-up (61-288 months); mean SD 134.73 +/- 67.77 months), two eyes had IOP <6 mm Hg. Twenty-four eyes analyzed had an IOP of 13.63 +/- 6.11 (mean +/- SD; range 9-41) mm Hg. All these had an IOP <15 mm Hg at last follow-up except one, which had an IOP of 41 mm Hg. There was a mean reduction of 54.62% +/- 31.33% in IOP from baseline. The antiglaucoma medication score at last follow-up visit was 0-3. No eye achieved predefined complete success or modified complete success. A total of 41.7% (10/24) of eyes attained both qualified and modified qualified success. Eleven eyes needed repeat surgeries. No intraoperative complications were noted. Visual acuity was below 6/60 in four eyes. CONCLUSIONS: Combined trabeculotomy-trabeculectomy showed promising results as a treatment for SWS-associated glaucoma in children. Long term visual and surgical outcomes are encouraging. PMID- 28885670 TI - Novel ABCA4 mutation leads to loss of a conserved C-terminal motif: implications for predicting pathogenicity based on genetic testing. AB - PURPOSE: Mutations in the ABCA4 gene result in a broad spectrum of severe retinal degeneration, including Stargardt macular dystrophy, fundus flavimaculatus, autosomal recessive retinitis pigmentosa, and cone-rod dystrophy. In addition to the detection of well-characterized mutations, genetic testing frequently yields novel variants of unknown significance. The purpose of this report is to describe an approach to aid in the assessment of genetic variants of unknown significance. CASE REPORT: We report an 11-year-old girl with Stargardt disease harboring novel compound heterozygous deletions of ABCA4 (c.850_857delATTCAAGA and c.6184_6187delGTCT). The pathogenicity of these variants was otherwise unknown. Both deletions introduce premature stop codons and are localized within the open reading frame of ABCA4. The c.850_857delATTCAAGA occurs early in the gene and leads to a significantly truncated protein of only 317 amino acids. The c.6184_6187delGTCT, is localized to the 3' terminus of the ORF and results in removal of the last 161 out of 2,273 amino acids of ABCA4, including the VFVNFA motif, which has been shown to be critical in ABCA4 protein function. Homology based protein modeling of ABCA4 harboring this deletion suggests significant alterations in the protein structure and function. CONCLUSIONS: Our analyses allowed us to classify novel variants in ABCA4 as being clearly loss-of-function mutations, and thus pathogenic variants. In cases of variants of unknown significance, appraising the protein structure-function consequences of genetic mutations using in silico tools may help to predict the clinical importance of variants of uncertain pathogenicity. PMID- 28885671 TI - The effect of strabismus surgery on choroidal thickness. AB - PURPOSE: To determine the effects of strabismus surgery on choroidal thickness. METHODS: This was a prospective randomized study. The measurements of subfoveal and macular choroidal thickness of patients who underwent strabismus surgery were obtained by enhanced depth imaging optic coherence tomography. The patients were grouped as patients who had 1 horizontal muscle surgery (group 1), 1 oblique muscle surgery (group 2), 2 horizontal muscle surgeries (group 3), or 1 horizontal and 1 oblique muscle surgery (group 4). Choroidal thickness of the patients was measured preoperatively and on the postoperative first day, second week, first month, and third month. Choroidal thickness was measured at subfoveal area (S) and at the nasal (N1, N2) and temporal (T1, T2) fovea with 500-MUm intervals. RESULTS: The average age of the 37 patients was 15.59 +/- 13.84 years. In preoperative and postoperative first day comparison, a decrease in choroidal thickness was found in all areas in group 1. In group 2, a significant decrease was found in N2, N1, and S values. In group 3, a significant decrease was found in N2, N1, and T2 values. In group 4, a significant decrease was found in N1 value. The second week comparison of all groups showed significant postoperative decrease in choroidal thickness in all areas. On the postoperative first month, a significant decrease in choroidal thickness was found only in the subfoveal area of group 1 and the N1 area of group 2. At the postoperative third month, there was no change in any group. CONCLUSIONS: Strabismus surgery causes a decrease in choroidal thickness in the early postoperative period. PMID- 28885672 TI - A comparative study of the visual outcomes between a new trifocal and an extended depth of focus intraocular lens. AB - PURPOSE: To evaluate and compare the visual outcomes and ocular optical performance of the PanOptix trifocal intraocular lens (IOL) and Symfony extended range of vision IOL. METHODS: Sixty-eight eyes of 34 patients were divided into 2 groups: 20 patients with the PanOptix IOL and 14 patients with the Symfony IOL. Binocular uncorrected distance visual acuity, best-corrected distance visual acuity (BCDVA), distance-corrected intermediate visual acuity (DCIVA) at 80 and 60 cm, and distance-corrected near visual acuity (DCNVA) at 40 cm were evaluated. Additionally, preferred reading distance with best-corrected distance and visual acuity at that distance, binocular defocus curves, mesopic and photopic contrast sensitivity, photic phenomena, and monocular total higher order aberrations (HOAs) were also measured. RESULTS: The visual outcomes for PanOptix and Symfony IOL groups, respectively, were as follows: BCDVA: -0.03 +/- 0.03 and -0.02 +/- 0.03 logMAR; DCIVA at 80 cm: 0.06 +/- 0.06 and 0.06 +/- 0.04 logMAR; DCIVA at 60 cm: 0.06 +/- 0.10 and 0.05 +/- 0.04 logMAR; DCNVA: 0.04 +/- 0.06 and 0.20 +/- 0.07 logMAR (p<0.001). Similar preferred reading distances were found for both groups (37.0 +/- 4.6 and 38.9 +/- 5.7 cm, respectively). The visual acuities at those distances were 0.09 +/- 0.08 and 0.19 +/- 0.08 logMAR (p<0.001), respectively. The defocus curves showed significantly better outcomes for the PanOptix IOL from -2.0 to -4.0 D (p<0.001). No significant differences were found for contrast sensitivity, halometry, or HOAs between the groups. CONCLUSIONS: The PanOptix and Symfony IOLs showed comparable visual performance at distance and intermediate. However, the PanOptix IOL provided better near and preferred reading distance VAs and showed a more continuous range of vision than the Symfony IOL. PMID- 28885673 TI - Reproducibility and normal values of static pupil diameters. AB - PURPOSE: To provide additional information on normal values of static pupil diameter measurements for binocular infrared pupillometry with PupilX, a commercial pupillometer, and assess the reproducibility of this device's measurements. METHODS: The pupil diameters from 91 study participants with normal eyes with an average age of 39.7 years (SD 16.4 years) were measured with PupilX under scotopic (0 lx), mesopic (1 lx), and photopic (16 lx) illumination. To assess the repeatability of the device, each measurement was repeated 5 times. RESULTS: The mean pupil diameters were 6.5 mm (SD 1.3 mm), 5.5 mm (SD 1.2 mm), and 4.03 mm (SD 0.9 mm) under scotopic, mesopic, and photopic illumination. Left and right eyes showed no difference in mean pupil diameters. The mean unsigned anisocoria was 0.26 mm (SD 0.32 mm) under scotopic, 0.26 mm (SD 0.27 mm) under mesopic, and 0.19 mm (SD 0.19 mm) under photopic illumination. The decrease in pupil diameter with age was largest for scotopic (~0.057 mm/y) and smallest for photopic illumination (~0.025 mm/y). The repeatability of the pupillometer was better than 0.2 mm. CONCLUSIONS: This study provides reference values for age- and light-related pupil diameters measured with the PupilX digital pupillometer in normal subjects. PMID- 28885674 TI - The outcome of transscleral cyclophotocoagulation for the management of acute angle closure. AB - PURPOSE: To investigate the outcome of transscleral cyclophotocoagulation (TCP) in the treatment of acute angle closure (AAC) refractory to medical treatment. METHODS: This is a retrospective interventional case series. The inclusion criteria include patients diagnosed with AAC who had TCP. Pre-TCP and post-TCP intraocular pressure (IOP), visual acuity, and AAC treatment were analyzed. The complications and the results of subsequent treatments including lens extraction if performed were also assessed. RESULTS: Thirteen eyes (13 patients) met the study criteria. The median time to TCP from presentation was 5 days (range 3-30 days). The mean presenting IOP was 56 +/- 6 mm Hg (range 48-70 mm Hg) and the medically treated mean IOP before TCP was 40 +/- 5 mm Hg (range 34-52 mm Hg). All patients (100%) responded to TCP. The mean post-TCP IOP at day 1 and months 1, 3, 6, 12, and 24 were 19, 23, 19, 19, 18, and 17 mm Hg. There was 1 case of hyphema post-TCP. Lens extraction +/- goniosynechialysis was performed in 10 patients (77%) from 1 month post-TCP onwards. The mean IOP prior to lens extraction was 26 mm Hg (range 19-32 mm Hg). The mean IOP 3 months after lens extraction was 15 mm Hg (range 8-19 mm Hg). The mean number of topical IOP-lowering medications 12 months post-TCP was 1.1. CONCLUSIONS: Transscleral cyclophotocoagulation is effective and safe in reducing IOP in patients with AAC refractory to medical and laser peripheral iridotomy treatments. We advocate that TCP should be considered early in the management of AAC refractory to medical treatment to avoid irreversible optic neuropathy. PMID- 28885675 TI - Up-regulated HMGB1 in the pleural effusion of non-small cell lung cancer (NSCLC) patients reduces the chemosensitivity of NSCLC cells. AB - BACKGROUND:: Pleural effusion is one of the complications of human non-small cell lung cancer (NSCLC). High mobility group box-1 protein (HMGB1) correlates highly with invasion and metastasis in multiple tumors. The aim of this study was to explore the clinical value of HMGB1 in NSCLC patients, and to investigate the role of HMGB1 in the development of pleural effusion. In addition, we also investigated the regulatory role of HMGB1 in the sensitivity of NSCLC cells to cisplatin. METHODS:: 46 NSCLC malignant pleural effusion (MPE) and 31 benign pleural effusion samples were quantitatively analyzed with Enzyme-Linked Immunosorbent Assay (ELISA) for cytokines, such as IL-1beta, IL-6, IL-8 and HMGB1. The HMGB1 expression in NSCLC tissues was examined with RT-qPCR and western blotting methods. Then the influence by HMGB1 on the chemosensitivity of lung cancer A549 cells was examined with MTT assay and colony forming assay for the A549 cells post the treatment with cisplatin or (and) HMGB1. RESULTS:: The results demonstrated that HMGB1 was up-regulated in the pleural effusion of NSCLC patients, along with the up-regulated levels of proinflammatory cytokines such as IL-6 and IL-8. And the up-regulation of HMGB1 was confirmed at both the mRNA and protein levels in the NSCLC tissues. Recombinant HMGB1 reduced the sensitivity of A549 cells to cisplatin in vitro. CONCLUSIONS:: In conclusion, HMGB1 was up regulated in the pleural effusion and tumor tissues of NSCLC patients. HMGB1 reduced the sensitivity of NSCLC A549 cells to cisplatin in vitro. PMID- 28885676 TI - Cooperation between in-hospital psychological support and pastoral care providers: obstacles and opportunities for a modern approach. AB - The meaning that patients with cancer attribute to life influences their expectations and their attitudes to the disease and its treatment. Over the centuries, religion has commonly been the answer encoded by the social setting when it came to matters of life and death. The present article analyzes the historical grounds for forms of cooperation between the scientific disciplines that focus on mental health and the approach of religion, centered on the Italian situation. Such cooperation was hard to imagine in the past, but the situation has changed considerably and cooperation is not only possible but extremely desirable. Acknowledgment of their spiritual needs helps patients to battle with their disease. The care of patients should include catering for their spiritual needs by ensuring the constant presence of a chaplain on hospital wards. PMID- 28885677 TI - Significance of stroma in biology of oral squamous cell carcinoma. AB - The worldwide annual incidence of oral squamous cell carcinoma (OSCC) is over 300,000 cases with a mortality rate of 48%. This cancer type accounts for 90% of all oral cancers, with the highest incidence in men over 50 years of age. A significantly increased risk of developing OSCC exists among smokers and people who consume alcohol daily. OSCC is an aggressive cancer that metastasizes rapidly. Despite the development of new therapies in the treatment of OSCC, no significant increase in 5-year survival has been recorded in the past decades. The latest research suggests focus should be put on examining tumor stroma activation within OSCC, as the stroma may contain cells that can produce signal molecules and a microenvironment crucial for the development of metastases. The aim of this review is to provide an insight into the factors that activate OSCC stroma and hence faciliate neoplastic progression. It is based on the currently available data on the role and interaction between metalloproteinases, cytokines, growth factors, hypoxia factor and extracellular adhesion proteins in the stroma of OSCC and neoplastic cells. Their interplay is additionally presented using the Systems Biology Graphical Notation in order to sublimate the collected knowledge and enable the more efficient recognition of possible new biomarkers in the diagnostics and follow-up of OSCC or in finding new therapeutic targets. PMID- 28885678 TI - Understanding urinary toxicity after radiotherapy for prostate cancer: first steps forward. AB - One of the most relevant achievements of Professor Gianni Bonadonna was the implementation of the methodology of controlled clinical trials in medical oncology. It is valid for all cancer types, oncological disciplines and clinical endpoints, both survival and toxicity. This narrative review reports on the status of the current knowledge of the radiation-induced urinary syndrome after external-beam radiotherapy for prostate cancer. In recent years, the syndrome has been the object of large-scale prospective observational trials specifically devoted to investigating the association of patient and treatment features with acute/late urinary toxicity. The first results of these trials allow initial attempts at predictive modeling, which can serve as a basis for the optimization of patient selection and treatment planning. PMID- 28885679 TI - PMA2020: Rapid Turn-Around Survey Data to Monitor Family Planning Service and Practice in Ten Countries. PMID- 28885680 TI - ERRATUM. PMID- 28885681 TI - Announcing a New Journal Section: Data Papers. PMID- 28885683 TI - Microwave heating modelling of a green smoothie: Effects on glucoraphanin, sulforaphane and S-methyl cysteine sulfoxide changes during storage. AB - BACKGROUND: The heating of a green smoothie during an innovative semi-continuous microwave treatment (MW; 9 kW for 15 s) was modelled. Thermal and dielectric properties of the samples were previously determined. Furthermore, the heating effect on the main chemopreventive compounds of the smoothie and during its subsequent storage up to 30 days at 5 or 15 degrees C were studied. Such results were compared to conventional pasteurisation (CP; 90 degrees C for 45 s) while unheated fresh blended samples were used as the control. RESULTS: A procedure was developed to predict the temperature distribution in samples inside the MW oven with the help of numerical tools. MW-treated samples showed the highest sulforaphane formation after 20 days, regardless of the storage temperature, while its content was two-fold reduced in CP samples. Storage of the smoothie at 5 degrees C is crucial for maximising the levels of the bioactive compound S methyl cysteine sulfoxide. CONCLUSION: The proposed MW treatment can be used by the food industry to obtain an excellent homogeneous heating of a green smoothie product retaining high levels of bioactive compounds during subsequent retail/domestic storage up to 1 month at 5 degrees C. (c) 2017 Society of Chemical Industry. PMID- 28885682 TI - Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. AB - BACKGROUND AND PURPOSE: The mesolimbic dopamine system originating in the ventral tegmental area (VTA) is involved in the development of depression, and firing patterns of VTA dopaminergic neurons are key determinants in this process. Here, we describe a crucial role for the M-type Kv 7.4 channels in modulating excitability of VTA dopaminergic neurons and in the development of depressive behaviour in mice. EXPERIMENTAL APPROACH: We used Kv 7.4 channel knockout mice and a social defeat model of depression in combination with electrophysiological techniques (patch clamp recording and in vivo single-unit recordings), immunohistochemistry, single-cell PCR and behavioural analyses (social interaction time and glucose preference tests) to investigate VTA circuits involved in the development of depression-like behaviour. KEY RESULTS: Among the Kv 7 channels, Kv 7.4 channels are selectively expressed in dopaminergic neurons of the VTA. Using a newly identified selective Kv 7.4 channel activator, fasudil, and Kv 7.4 channel knockout mice, we demonstrate that these channels are a dominant modulator of excitability of VTA dopaminergic neurons, in vitro and in vivo. Down-regulation of Kv 7.4 channels could be a causal factor of the altered excitability of VTA dopaminergic neurons and depression-like behaviour. The selective Kv 7.4 channel activator, fasudil, strongly alleviated depression-like behaviour in the social defeat mouse model of depression. CONCLUSION AND IMPLICATIONS: Because expression of Kv 7.4 channels in the CNS is limited, selectively targeting this M channel subunit is likely to produce less on-target side effects than non-selective M channel modulators. Thus, Kv 7.4 channels may offer alternative targets in treatment of depression. PMID- 28885684 TI - Personality traits of nurses and organizational climate in relation to the use of coercion in psychiatric wards. AB - PURPOSE: The aim of this study was to analyze the personality traits of nurses and the organizational climate in psychiatric wards affecting the frequency of the use of coercion. DESIGN AND METHODS: The study applied a descriptive, longitudinal design based on a 1-year prospective observation. FINDINGS: The best predictor for the initiation of coercion by nursing personnel was a low score on the Creative Personality Factor Scale in Adjective Check List and the low score in the area of Leadership in Kolb's Organizing Climate Questionnaire (KOQC). The best predictor for decisions to use coercion was the low score in the area Requirements in the KOQC, whereas the best predictors for the participation in coercion were a high value for Leadership area and a low value for Requirements area in KOQC. PRACTICE IMPLICATIONS: The nursing personnel should be given frequent practical and theoretical training regarding the use of coercion. PMID- 28885685 TI - Gut microbiota-derived endotoxin enhanced the incidence of cardia bifida during cardiogenesis. AB - Cytotoxicity and inflammation-associated toxic responses could be induced by bacterial lipopolysaccharides (LPS) in vitro and in vivo, respectively. However, the mechanism involved in LPS-induced cardiac malformation in prenatal fetus is still unknown. In this study, we demonstrated that LPS was induced in gut microbiota imbalance mice, and next, LPS exposure during gastrulation in the chick embryo increased the incidence of cardia bifida. Gene transfection and tissue transplantation trajectory indicated that LPS exposure restricted the cell migration of cardiac progenitors to primary heart field in gastrula chick embryos. In vitro explant allograft of GFP-labeled anterior primitive streak demonstrated that LPS treatments could inhibit cell migration. A similar observation was also obtained from the cell migration assay of scratch wounds using primary culture of cardiomyocytes or H9c2 cells. In the embryos exposed to LPS, expressions of Nkx2.5 and GATA5 were disturbed. These genes are associated with cardiomyocyte differentiation when heart tube fusion occurs. Furthermore, pHIS3, C-caspase3 immunohistological staining indicated that cell proliferation decreased, cell apoptosis increased in the heart tube of chick embryo. Meanwhile, in vivo, pHIS3 immunohistological staining and Hochest/PI staining also draw the similar conclusions. The LPS exposure also caused the production of excess ROS, which might damage the cardiac precursor cells of developing embryos. At last, we showed that LPS-induced cardia bifida could be partially rescued through the addition of antioxidants. Together, these results reveal that excess ROS generation is involved in the LPS-induced defects in heart tube during chick embryo development. PMID- 28885686 TI - Refining the predictors of outcome in patients with resectable esophageal cancer. PMID- 28885687 TI - Peptide supplementation to nutrient-adequate diets enhanced internal egg quality during storage in hens at peak production. AB - BACKGROUND: There is paucity of information on the use of dietary peptides in laying hens and its effects on egg production and quality. In the current study, peptide from enzymatic hydrolysis of soybean protein was incorporated into laying hens' diets to investigate its effect on egg production and internal egg quality. RESULTS: There were no treatment effects on egg production (average hen day production was 96%) during the experiment. Final body weight of the hens increased quadratically (P < 0.05) in response to peptide supplementation. There were no significant effects of peptide supplementation on internal egg quality of the fresh eggs. Peptide supplementation tended to increase yolk colour (P < 0.10) in eggs collected at 4 weeks of the study and stored at room temperature for 14 days. For the eggs collected at 8 weeks of the experiment and stored at room temperature for 14 days, peptide supplementation linearly increased (P < 0.05) albumen height, Haugh unit and yolk index but linearly decreased (P < 0.01) yolk width. CONCLUSION: Peptide supplementation to laying hens at peak production, receiving diets meeting their nutrient requirement, did not improve hen production but positively helped to maintain hens' body weight and egg quality during storage. (c) 2017 Society of Chemical Industry. PMID- 28885688 TI - Changes in physiological and some nutritional, nutraceuticals, chemical-physical, microbiological and sensory quality of minimally processed cactus pears cvs 'Bianca', 'Gialla' and 'Rossa' stored under passive modified atmosphere. AB - BACKGROUND: The objective of this study was to compare the overall quality changes of minimally processed cactus pears cvs 'Bianca', Gialla' and 'Rossa' stored at 4 degrees C for 10 days. Periodically in-package CO2 , O2 and C2 H4 were determined and fruit were assessed for overall quality changes (pH, acidity, sugars, phenolics, betacyanins and betaxanthines, antioxidant capacity, colour, firmness, microbiological population and sensory attributes). In a preliminary study three different polymeric films were tested to select the most suitable to design a package with a short lag time to achieve steady-state conditions. RESULTS: Results showed marked differences between measured in-package CO2 and O2 values and those calculated based on respiration of peeled fruit and film permeance to CO2 and O2 provided by manufactures. The sensory evaluation of packed fruit indicated in film BBT-Bolphane, which created a steady-state in package partial pressure for CO2 of 4.3-4.8 kPa and for O2 of 4.8-5.5 kPa, as the best film. Results of in-package gas composition with the three cultivars were similar to those achieved in cv. 'Gialla' with the preliminary test. All measured qualitative parameters changed slightly over the storage period for all cultivars and followed the same trend, despite significant differences existing among cultivars. CONCLUSION: This study clearly showed a similar physiological behavior of minimally processed 'Bianca', 'Gialla' and 'Rossa' cactus pears. Storage conditions optimal for one cultivar fit well for the others; thus mixing fruit of different cultivars in a package designed for one specific cultivar does not lead to relevant deviation from expected results. (c) 2017 Society of Chemical Industry. PMID- 28885689 TI - Systematic-analysis of mRNA expression profiles in skeletal muscle of patients with type II diabetes: The glucocorticoid was central in pathogenesis. AB - Since the past 30 years, the prevalence of diabetes has more than doubled, making it an urgent challenge globally. We carried out systematic analysis with the public data of mRNA expression profiles in skeletal muscle to study the pathogenesis, since insulin resistance in the skeletal muscle is an early feature. We utilized three GEO datasets, containing total 60 cases and 63 normal samples. After the background removal, R package QC was utilized to finish the preprocessing of datasets. We obtained a dataset containing 2481 genes and 123 samples after the preprocessing. Quantitative quality control measures were calculated to represent the quality of these datasets. MetaDE package provides functions for conducting different systematic analysis methods for differential expression analysis. The GO term enrichment was carried out using PANTHER. Protein-protein interactions, drug-gene interactions, and genetic association of the identified differentially expressed genes were analyzed using STRING v10.0 online tool, DGIdb, and the Genetic Association Database, respectively. The datasets had good performances on IQC and EQC, which suggested that the datasets had good internal and external quality. Totally 96 differentially expressed genes were detected using 0.01 as cutoff of AW. The enriched GO terms were mainly associated with the response to glucocorticoid. There were seven genes involving in the gluconeogenesis were differentially expressed, which might be the potential treatment target for this disease. The closely connected networks and potential targets of existed drugs suggested that some of the drugs might be applied to the treatment of diabetes as well. PMID- 28885690 TI - Global analysis of gene expression profiles in the submandibular salivary gland of klotho knockout mice. AB - Salivary dysfunction commonly occurs in many older adults and is considered a physiological phenomenon. However, the genetic changes in salivary glands during aging have not been characterized. The present study analyzed the gene expression profile in salivary glands from accelerated aging klotho deficient mice (klotho-/ , 4 weeks old). Microarray analysis showed that 195 genes were differentially expressed (z-score > 2 in two independent arrays) in klotho null mice compared to wild-type mice. Importantly, alpha2-Na+ /K+ -ATPase (Atp1a2), Ca2+ -ATPase (Atp2a1), epidermal growth factor (EGF), and nerve growth factor (NGF), which have been suggested to be regulators of submandibular salivary gland function, were significantly decreased. When a network was constructed from the differentially expressed genes, proliferator-activated receptor-gamma (PPAR gamma), which regulates energy homeostasis and insulin sensitivity, was located at the core of the network. In addition, the expression of genes proposed to regulate various PPAR gamma-related cellular pathways, such as Klk1b26, Egfbp2, Cox8b, Gpx3, Fabp3, EGF, and NGFbeta, was altered in the submandibular salivary glands of klotho-/- mice. Our results may provide clues for the identification of novel genes involved in salivary gland dysfunction. Further characterization of these differentially expressed genes will be useful in elucidating the genetic basis of aging-related changes in the submandibular salivary gland. PMID- 28885691 TI - Fibroblast growth factor 2 induces proliferation and distribution of G2 /M phase of bovine endometrial cells involving activation of PI3K/AKT and MAPK cell signaling and prevention of effects of ER stress. AB - Fibroblast growth factor 2 (FGF2) is abundantly expressed in conceptuses and endometria during pregnancy in diverse animal models including domestic animals. However, its intracellular mechanism of action has not been reported for bovine endometrial cells. Therefore, the aim of this study was to identify functional roles of FGF2 in bovine endometrial (BEND) cell line which has served as a good model system for investigating regulation of signal transduction following treatment with interferon-tau (IFNT) in vitro. Results of present study demonstrated that administration of FGF2 to BEND cells increased their proliferation and regulated the cell cycle through DNA replication by an increase of PCNA and Cyclin D1. FGF2 also increased phosphorylation of AKT, P70S6K, S6, ERK1/2, JNK, and P38 in BEND cells in a dose-dependent manner, and expression of each of those transcription factors was inhibited by their respective pharmacological inhibitor including Wormannin, U0126, and SP600125. In addition, the increase in proliferation of BEND cells and activation of the protein kinases in response to FGF2 was suppressed by BGJ398, a FGFR inhibitor. Furthermore, proliferation of BEND cells was inhibited by tunicamycin, but treatment of BEND cells with FGF2 restored proliferation of BEND cells. Consistent with this result, the stimulated unfolded protein response (UPR) regulatory proteins induced by tunicamycin were down-regulated by FGF2. Results of this study suggest that FGF2 promotes proliferation of BEND cells and likely enhances uterine capacity and maintenance of pregnancy by activating cell signaling via the PI3K and MAPK pathways and by restoring ER stress through the FGFR. PMID- 28885692 TI - Control of basal jasmonate signalling and defence through modulation of intracellular cation flux capacity. AB - Unknown mechanisms tightly regulate the basal activity of the wound-inducible defence mediator jasmonate (JA) in undamaged tissues. However, the Arabidopsis fatty acid oxygenation upregulated2 (fou2) mutant in vacuolar two-pore channel 1 (TPC1D454N ) displays high JA pathway activity in undamaged leaves. This mutant was used to explore mechanisms controlling basal JA pathway regulation. fou2 was re-mutated to generate novel 'ouf' suppressor mutants. Patch-clamping was used to examine TPC1 cation channel characteristics in the ouf suppressor mutants and in fou2. Calcium (Ca2+ ) imaging was used to study the effects fou2 on cytosolic Ca2+ concentrations. Six intragenic ouf suppressors with near wild-type (WT) JA pathway activity were recovered and one mutant, ouf8, affected the channel pore. At low luminal calcium concentrations, ouf8 had little detectable effect on fou2. However, increased vacuolar Ca2+ concentrations caused channel occlusion, selectively blocking K+ fluxes towards the cytoplasm. Cytosolic Ca2+ concentrations in unwounded fou2 were found to be lower than in the unwounded WT, but they increased in a similar manner in both genotypes following wounding. Basal JA pathway activity can be controlled solely by manipulating endomembrane cation flux capacities. We suggest that changes in endomembrane potential affect JA pathway activity. PMID- 28885693 TI - Epidemiological and molecular analysis of hepatitis B virus infection in manicurists in Central Brazil. AB - The aim of this study was to investigate the serological and molecular prevalence of hepatitis B virus (HBV) infection in 514 manicurists/pedicurists and identify the risk factors related with this infection. Samples were tested for HBV serological markers, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) by enzyme-linked immunosorbent assay (ELISA). Anti-HBc-positive samples were tested to investigate occult hepatitis B by PCR. HBsAg-positive samples were genotyped and the viral loads of HBV-DNA positive samples were quantified. The overall HBV prevalence was 5.6% (29/514) and of HBsAg was 0.4% (2/514). One case of occult hepatitis B was found. The genotypes A1 and F2 were identified in two HBsAg-positive samples. Low level of education, not being born in the State of Mato Grosso do Sul and working in the central region of the city were associated with the HBV infection. No single manicurist/pedicurist was infected by HCV or HIV. These findings suggest that despite the exposure to blood contact, this occupation was not associated to an increased risk of acquiring HBV, HCV, and HIV infections. PMID- 28885694 TI - Influence of preoperative septic peritonitis and anastomotic technique on the dehiscence of enterectomy sites in dogs: A retrospective review of 210 anastomoses. AB - OBJECTIVE: To determine the influence of preoperative septic peritonitis (PSP) and stapled versus hand-sewn anastomoses on the dehiscence of intestinal resection and anastomosis (IRA). We hypothesized that the incidence of IRA dehiscence would be greater (1) when performed with PSP and (2) for hand-sewn anastomoses. STUDY DESIGN: Retrospective. ANIMAL POPULATIONS: Client-owned dogs at Michigan State University Veterinary Teaching Hospital. METHODS: Records of dogs surviving 72 hours after IRAs between 2003 and 2013 were reviewed for age, gender, neuter status, weight, presence of PSP, preoperative albumin, IRA indication and location, anastomotic technique, suture type, postoperative dehiscence and timing, duration of hospitalization, last follow-up, and other complications. Univariate logistic regression and chi-square analysis were used to screen prognostic factors; factors with P < .3 were included in a multivariate analysis. RESULTS: Two hundred and ten IRAs in 198 dogs fulfilled the inclusion criteria. Dehiscence was diagnosed in 11.4% cases, 6.6% without PSP, and 21.1% with PSP (P = .01). Indication for IRA did not influence the risk of dehiscence. No association was detected between anastomotic technique and IRA dehiscence in dogs without PSP (stapled 4.2%, hand-sewn 8.1%); however, stapled anastomoses were less likely to dehisce in dogs with PSP (stapled 9.7%, hand-sewn 28.9%). Risk factors for dehiscence included PSP (P = .005) and hand-sewn technique (P = .02). CONCLUSION: Our results confirmed that PSP is a risk factor for dehiscence of IRA and suggest that patients with PSP may be a unique surgical population, in which stapling may be preferred over hand-sewn anastomoses after enterectomies. PMID- 28885695 TI - Evaluation of Grenache, Graciano and Tempranillo grape stilbene content after field applications of elicitors and nitrogen compounds. AB - BACKGROUND: Stilbenes have a significant biological activity and are one of the most important non-flavonoid contributors to grape and wine health-related properties. The accumulation of this class of compounds could be favored by viticultural practices such as the application of biostimulants. However, stilbene concentration also depends on several factors, including, for example, grape variety. Therefore, the aim of this work was to study the influence of foliar treatments carried out with elicitors (methyl jasmonate (MeJ) and a commercial foliar spray (YD)) and nitrogen compounds (phenylalanine and urea) on the grape stilbene composition of three varieties: Grenache, Graciano and Tempranillo. An ultra-high-pressure liquid chromatographic methodology was validated for stilbene determination. RESULTS: Results showed that, despite the huge influence of the grape variety, YD significantly improved stilbene composition in Grenache and Graciano, while MeJ increased the stilbene content in Graciano and Tempranillo. As for the nitrogen treatments, phenylalanine significantly increased the stilbene concentration in Graciano, while urea treatment increased it in Tempranillo. However, the application of elicitors had a greater effect than the nitrogen compounds. CONCLUSION: Overall, the foliar application of the elicitors could be a suitable practice for increasing the amount of stilbenes in grape and, therefore, its nutraceutical properties. (c) 2017 Society of Chemical Industry. PMID- 28885696 TI - Survivorship care planning in skin cancer: An unbiased statistical approach to identifying patterns of care-plan use. AB - BACKGROUND: Nearly 1 in 5 Americans will develop skin cancer, and as a result, survivors of skin cancer compose one of the largest groups of cancer survivors. Survivorship care plans (SCPs) are an important tool for improving patient outcomes and provide critical information to both survivors and health care professionals. Recent efforts have been made to expand SCP utilization; however, which patients currently receive SCPs is poorly understood. METHODS: This study used 596 individuals with a diagnosis of melanoma (n = 391) or nonmelanoma skin cancer (n = 205) who had used an Internet-based SCP tool from May 2010 to December 2016 to model the patient and provider characteristics that determine SCP utilization. RESULTS: Survivors were predominantly white (95.3%) and female (56.5%). Survivors who received a treatment summary were more likely to also receive an SCP. University and nonuniversity cancer centers used SCPs at a higher rate than other care settings. Survivors whose care was managed by a team rather than just an individual physician were also more likely to receive an SCP. Survivors older than 70 years at diagnosis were almost twice as likely to receive a plan as survivors who were diagnosed at a younger age. CONCLUSIONS: With a convenience sample of skin cancer survivors, it is possible to model factors that predict the receipt of SCPs. Important variables include the diagnosis age, treatment setting, physician type, and treatment-summary utilization. A closer examination of these variables identified several disparities in care-plan use and, therefore, opportunities to improve the distribution of SCPs. Further validation in additional cohorts of survivors is necessary to confirm these conclusions. Cancer 2018;124:183-91. (c) 2017 American Cancer Society. PMID- 28885697 TI - Second-look arthroscopic findings after CORA-based leveling osteotomy. AB - OBJECTIVE: To describe the arthroscopic appearance of intra-articular structures mid-term (9 months) and long-term (>12 months) after CORA-based leveling osteotomy (CBLO). STUDY DESIGN: Case series. ANIMALS: Dogs (n = 41) with second look arthroscopy of the stifle after CBLO for treatment of a cranial cruciate ligament (CCL) deficiency. Both stifles were re-evaluated (stifles n = 42) in 1 dog. METHODS: Medical records of dogs that had second-look arthroscopy after CBLO were reviewed. Arthroscopic images of the femoral condyles were independently reviewed. The surgical report documented the integrity of menisci and articular cartilage of the tibial plateaus. RESULTS: The population included 7 stifles with stable partial CCL tears, 35 stifles with complete CCL tears (n = 28), or incompetent partial CCL tears (n = 7). Median time to second look arthroscopy was 16 months (9-24 months) for stable partial tears. The CCL remained intact in 6 stifles. The Outerbridge score of the articular cartilage of the femoral condyles was as 0 (6) or 1 (1). The articular cartilage of the tibial plateaus appeared normal in all stifles. Median time to second look arthroscopy of stifles with complete tears was 12 months (range, 9-34 months). The caudal cruciate ligament was normal or mildly fibrillated. The appearance of the articular cartilage of the femoral condyles was scored as 0 or near normal (grade 1-2) in all dogs. The articular cartilage of the tibial plateaus appeared normal, except in 1 dog with grade 4 lesion. CONCLUSION: CBLO results in minimal to no change in articular cartilage in at a median time of 14 months after surgery. Postoperative clinical lameness is often attributed to late onset meniscal pathology. PMID- 28885698 TI - Autoimmune antibodies to collagen XIII in myasthenia gravis patients. AB - INTRODUCTION: Evaluation of the nerve fascicular structure can be useful in diagnosing nerve damage, but it is a very challenging task with 3T MRI because of limited resolution. In this pilot study, we present the feasibility of high resolution 7T MRI for examining the nerve fascicular structure. METHODS: A 3 dimensional (3D) gradient-spoiled sequence was used for imaging peripheral nerves in extremities. Images acquired with different in-plane resolutions (0.42 * 0.42 mm vs. 0.12 * 0.12 mm), and different main field strengths (7T vs. 3T) were compared. RESULTS: The individual nerve fascicles were identified at 0.12 * 0.12 mm resolution in both field strengths but not at 0.42 * 0.42 mm resolution. The fascicular structure was more sharply depicted in 7T images than in 3T images. DISCUSSION: High-resolution 3D imaging with 7T MRI demonstrated feasibility for imaging nerve fascicular structures. Muscle Nerve 57: 506-510, 2018. PMID- 28885701 TI - "My Esteemed Colleague, I Must Respectfully Disagree...". PMID- 28885699 TI - Alteration of microRNA profiles by a novel inhibitor of human La protein in HBV transformed human hepatoma cells. AB - A pyrazolopyridine HBSC11 was previously identified as a novel inhibitor of human La protein with anti-hepatitis B virus (HBV) activity. However, the underlying mechanism(s) of HBV inhibition by HBSC11 remains unclear. This study aimed to examine the regulation of microRNA (miRNA) by HBSC11 in HBV-transformed human hepatoma HepG2.2.15 cells using microarray and quantitative real-time PCR. Target genes of the differentially expressed miRNAs were predicted and subjected to bioinformatics analysis. Results showed that HBSC11 significantly upregulated the expression of miR-3912-5p, miR-6793-5p, and miR-7159-5p in HepG2.2.15 cells. Target genes of the three miRNAs were mainly involved in the regulation of nucleic acid-templated transcription, negative regulation of gene expression, nucleic acid binding transcription factor activity and regulation of phosphorylation. In addition, target genes were enriched in certain regulatory pathways related to HBV infection and HBV-associated disease progression, such as the transforming growth factor (TGF)-beta, Wnt, and p53 signaling. Our study demonstrates the involvement of miR-3912-5p, miR-6793-5p, and miR-7159-5p and the potential modulation of specific pathways (TGF-beta, Wnt, and p53 signaling) in HBSC11-mediated inhibition of HBV replication. This study provides insight into the molecular mechanism of the action of HBSC11 against HBV infection and will support the development of antiviral drugs targeting La protein. PMID- 28885702 TI - On the Modeling of Inactivation of Listeria innocua in Milk by High Pressure Processing. PMID- 28885700 TI - Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials. AB - BACKGROUND: Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies. METHODS: The first early phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation (approximately two-thirds of patients underwent >=1 hematopoietic stem cell transplantation); 13.2% of patients received dinutuximab. RESULTS: From the time of the patient's first early-phase trial enrollment (383 patients), the 1-year and 4-year PFS rates ( +/- standard error) were 21% +/- 2% and 6% +/- 1%, respectively, whereas the 1-year and 4-year OS rates were 57% +/- 3% and 20% +/- 2%, respectively. The median TTP was 58 days (interquartile range, 31-183 days [350 patients]); the median follow-up was 25.3 months (33 patients were found to be without disease recurrence/progression). The median time from diagnosis to first disease recurrence/progression was 18.7 months (range, 1.4-64.8 months) (176 patients). MYCN amplification and 11q loss of heterozygosity were prognostic of worse PFS and OS (P = .003 and P<.0001, respectively, and P = .02 and P = .03, respectively) after early-phase trial enrollment. CONCLUSIONS: This recent COG cohort of patients with recurrent/refractory neuroblastoma is inclusive and representative. To the authors' knowledge, the current study is the first meta-analysis of PFS, TTP, and OS within the context of modern therapy. These results will inform the design of future phase 2 studies by providing a) historical context during the search for more effective agents; and, b) factors prognostic of PFS and OS after disease recurrence to stratify randomization. Cancer 2017;123:4914-23. (c) 2017 American Cancer Society. PMID- 28885703 TI - Combined Effect of Polyphenol-Chitosan Coating and Irradiation on the Microbial and Sensory Quality of Carp Fillets. AB - Irradiation can extend the shelf-life of fish, but it may cause unacceptable change on quality. Since rose polyphenols have high antioxidant and antibacterial activities, this study evaluated the combined effect of polyphenol-chitosan coatings and irradiation (3 kGy) on the microbial and sensory qualities of carp fillets during storage at 4 degrees C. A dose of 3 kGy irradiation reduced the initial total viable counts (TVC) and psychrophiles, and increased the initial b* and thiobarbituric acid reactive substance (TBARS) values. During storage, TBARS, TVC and psychrophiles of nonirradiated samples increased faster and were higher than those irradiated. Regardless of irradiation treatment, samples coated with chitosan containing rose polyphenols had lower TBARS, pH and bacteria than that in no coating or chitosan coating batches. Carp treated with combined treatment could preserve an acceptable sensory quality at the end of storage. The result indicated that polyphenol-chitosan coating combined with irradiation can maintain fish quality by preventing bacterial growth, oxidation, and changes in color and sensory acceptability. PMID- 28885704 TI - Response Letter to the Editor: "On the Modeling of Inactivation of Listeria Innocua in Milk by High Pressure Processing". PMID- 28885706 TI - Halloysite Nanocapsules Containing Thyme Essential Oil: Preparation, Characterization, and Application in Packaging Materials. AB - Halloysite nanotubes (HNTs), which are natural nanomaterials, have a hollow tubular structure with about 15 nm inner and 50 nm outer diameters. Because of their tubular shape, HNTs loaded with various materials have been investigated as functional nanocapsules. In this study, thyme essential oil (TO) was encapsulated successfully in HNTs using vacuum pulling methods, followed by end-capping or a layer-by-layer surface coating process for complete encapsulation. Nanocapsules loaded with TO were mixed with flexographic ink and coated on a paper for applications as food packaging materials. Scanning electron microscopy and transmission electron microscopy were used to characterize the morphology of the nanocapsules and to confirm the TO loading of the nanocapsules. Fourier transform infrared spectroscopy and thermogravimetric analyses analysis were used to complement the structural information. In addition, the controlled release of TO from the nanocapsules showed sustained release properties over a period of many days. The results reveal that the release properties of TO in these nanocapsules could be controlled by surface modifications such as end-capping and/or surface coating of bare nanocapsules. The packaging paper with TO-loaded HNT capsules was effective in eliminating against Escherichia coli during the first 5 d and showed strong antibacterial activity for about 10 d. PMID- 28885707 TI - Physical function metric over measure: An illustration with the Patient-Reported Outcomes Measurement Information System (PROMIS) and the Functional Assessment of Cancer Therapy (FACT). AB - BACKGROUND: Measuring patient-reported outcomes (PROs) is becoming an integral component of quality improvement initiatives, clinical care, and research studies in cancer, including comparative effectiveness research. However, the number of PROs limits comparability across studies. Herein, the authors attempted to link the Functional Assessment of Cancer Therapy-General Physical Well-Being (FACT-G PWB) subscale with the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) calibrated item bank. The also sought to augment a subset of the conceptually most similar FACT-G PWB items with PROMIS PF items to improve the linking. METHODS: Baseline data from 5506 participants in the Measuring Your Health (MY-Health) study were used to identify the optimal items for linking FACT-G PWB with PROMIS PF. A mixed methods approach identified the optimal items for creating the 5-item FACT/PROMIS-PF5 scale. Both the linked and augmented relationships were cross-validated using the follow-up MY-Health data. RESULTS: A 5-item FACT-G PWB item subset was found to be optimal for linking with PROMIS PF. In addition, a 2-item subset, including only items that were conceptually very similar to the PROMIS item bank content, were augmented with 3 PROMIS PF items. This new FACT/PROMIS-PF5 provided superior score recovery. CONCLUSIONS: The PROMIS PF metric allows for the evaluation of the extent to which similar questionnaires can be linked and therefore expressed on the same metric. These results allow for the aggregation of existing data and provide an optimal measure for future studies wishing to use the FACT yet also report on the PROMIS PF metric. Cancer 2018;124:153-60. (c) 2017 American Cancer Society. PMID- 28885708 TI - Biosynthesis of Silver Nanoparticles from Persimmon Byproducts and Incorporation in Biodegradable Sodium Alginate Thin Film. AB - : Fruit industrial wastes such as persimmon seed, peel, and calyx were used to synthesize silver nanoparticles (AgNPs) and their antioxidant activities were compared with byproduct powders having different granularities. The AgNPs were incorporated in sodium alginate thin films and transparency and mechanical properties of the films was analyzed. Persimmon byproduct AgNPs were characterized by ultraviolet-visible spectroscopy, dynamic light scattering, X ray diffraction, energy-dispersive x-ray spectroscopy, and scanning electron microscopy. The byproduct AgNPs displayed higher antioxidant activities than powders of different granularities (P < 0.05). Fabrication of alginate thin films incorporating byproduct AgNPs resulted in improved transparency (P < 0.05). The incorporation of persimmon byproduct AgNPs with excellent antioxidant activities into sodium alginate thin films did not diminish the mechanical properties of the thin films. Therefore, fruit industrial waste such as persimmon byproducts could be used to derive AgNPs and could be incorporated into biodegradable alginate thin films, with numerous applications including food packaging. PRACTICAL APPLICATION: Fruit industrial wastes such as persimmon seed, peel, and calyx were used to synthesize silver nanoparticles (AgNPs) which were incorporated in sodium alginate thin films. This study evaluated the antioxidant activities and mechanical properties of the films that could be useful in the manufacture of food packaging using biodegradable films. PMID- 28885709 TI - Prenylation of viral proteins by enzymes of the host: Virus-driven rationale for therapy with statins and FT/GGT1 inhibitors. AB - Intracellular bacteria were recently shown to employ eukaryotic prenylation system for modifying activity and ensuring proper intracellular localization of their own proteins. Following the same logic, the proteins of viruses may also serve as prenylation substrates. Using extensively validated high-confidence prenylation predictions by PrePS with a cut-off for experimentally confirmed farnesylation of hepatitis delta virus antigen, we compiled in silico evidence for several new prenylation candidates, including IRL9 (CMV) and few other proteins encoded by Herpesviridae, Nef (HIV-1), E1A (human adenovirus 1), NS5A (HCV), PB2 (influenza), HN (human parainfluenza virus 3), L83L (African swine fever), MC155R (molluscum contagiosum virus), other Poxviridae proteins, and some bacteriophages of human associated bacteria. If confirmed experimentally, these findings may aid in dissection of molecular functions of uncharacterized viral proteins and provide a novel rationale for statin and FT/GGT1-based inhibition of viral infections. Prenylation of bacteriophage proteins may aid in moderation of microbial infections. PMID- 28885710 TI - Isoflavones from green vegetable soya beans and their antimicrobial and antioxidant activities. AB - BACKGROUND: Green vegetable soya beans, known as Maodou in China, are supplied as vegetable-type fruits of the soybean plant. Previous study indicated that green vegetable soya beans exhibited antioxidative and anti-inflammatory activities. However, the material basis and pharmacological activities of green soybean plant were not unravelled clearly. In this study, we investigated the chemical ingredients and their pharmacological activities. RESULTS: Investigation of the chemical ingredients indicated that two new isoflavones, 2'-hydroxyerythrin A (1), and daidzein-7-O-beta-d-{6"-[(E)-but-2-enoyl]}glycoside (2), together with seven known ones - 7,4'-dihydroxy-6-methoxyisoflavone (3), daidzein (4), daidzin (5), genistein (6), formononetin (7), ononin (8), and isoerythrinin A (9) - were obtained. The structures of compounds 1-9 were elucidated on the basis of spectroscopic and chemical analysis. We evaluated the antimicrobial efficacies and free-radical scavenging potential of the isolated compounds (1-9). Compounds 1 and 9 exhibited the most pronounced efficacy against the tested bacterial strains with IC50 values ranging from 10.6 to 22.6 MUg mL-1 . The isolated compounds showed moderate radical scavenging properties with compound 6 being the most active, followed by compounds 3, 1 and 4. CONCLUSIONS: This study indicated that the isoflavones from soya beans could be considered as potential antioxidants or antimicrobials in the food, cosmetics and pharmaceutical industries. (c) 2017 Society of Chemical Industry. PMID- 28885711 TI - Hepatitis B among immigrants from Myanmar: Genotypes and their clinical relevance. AB - Hepatitis B virus (HBV) from 76 adult immigrants in Australia from Myanmar was characterized to determine the prevalence of different HBV genotypes and subgenotypes. A mutational analysis was then performed to determine the presence of clinically significant mutations and correlate them to clinical outcomes. Initial genotyping revealed 68 patients with genotype C (89.5%) and eight patients with genotype B (10.5%). Phylogenetic analysis revealed the large majority of the genotype C infections were of subgenotype C1 (67/68). Sequencing of the HBV polymerase gene (and overlapping surface gene) revealed no mutations associated with antiviral resistance. HBV surface gene mutations were detected in 10 patients with subgenotype C1. HBV BCP/PC sequencing was obtained for 71/76 (93%) patients. BCP and/or PC mutations were identified in 57/71 (80%) of PCR positive patients. Treatment had been commenced for 15/76 (18%) patients, a further 26 untreated patients were in a stage of disease where HBV treatment would be considered standard of care. It was identified that genotype C1 is the predominant sub-genotype in this population. Genotype C is known to be associated with increased risk of development of HCC. This highlights the need for screening for HCC given the potential for the development of liver cancer. It was also identified that people with HBV were potentially not receiving optimal therapy in a timely fashion. PMID- 28885714 TI - Monoclonal gammopathy of undetermined significance as viewed by haematology healthcare professionals. AB - OBJECTIVES: To investigate the words and descriptions used by haematology healthcare professionals (HCPs) to describe monoclonal gammopathy of undetermined significance (MGUS) to their patients. METHODS: A cross-sectional survey of haematology HCPs attending an annual haematology conference was undertaken. Content analysis was applied to the returned qualitative responses. RESULTS: In total, 55 people, many of whom were doctors (n = 32; 58.2%), responded. The majority of respondents reported using simple terminology such as "abnormal protein" to describe MGUS to their patients. Some reported using analogies that the patient was more likely to be familiar with, such as comparing a paraprotein to the finding of a mole or lump. Education level, age and cognitive ability were cited as important factors in deciding how and whether information was relayed to patients. Many respondents supported frequent follow-up and the transfer of low risk MGUS patients to primary care. However, several highlighted a lack of awareness and understanding of MGUS outside of haematology, particularly within primary care. Only 41.8% of respondents reported providing all of their patients with an information leaflet. CONCLUSIONS: With an ageing population, it is important to consider management strategies for MGUS patients. Our findings will assist those in making these arrangements. PMID- 28885715 TI - Genome evolution is driven by gene expression-generated biophysical constraints through RNA-directed genetic variation: A hypothesis. AB - The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the biogenesis of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti-parasite genome defence systems, and implies that gene expression-related biophysical constraints represent a driving force of genome evolution. PMID- 28885712 TI - Pathological complete response in patients with esophageal cancer after the trimodality approach: The association with baseline variables and survival-The University of Texas MD Anderson Cancer Center experience. AB - BACKGROUND: Reports are limited regarding clinical and pretreatment features that might predict a pathological complete response (pathCR) after treatment in patients with esophageal cancer (EC). This might allow patient selection for different strategies. This study examines the association of a pathCR with pretreatment variables, overall survival (OS), recurrence-free survival (RFS), and patterns of recurrence in a large cohort from a single institution. METHODS: The baseline clinical features of 911 consecutive patients with EC who were treated with trimodality therapy from January 2000 to November 2013 were analyzed. A pathCR was defined as a surgical specimen with no residual carcinoma (primary or nodes). Logistic regressions were used to identify independent baseline features associated with a pathCR. We applied log-rank testing and Cox models to determine the association between a pathCR and the time-to-event outcomes (OS and RFS). RESULTS: Of 911 patients, 218 (23.9%) achieved a pathCR. The pathCR rate was 23.1% for adenocarcinoma and 32.2% for squamous cell carcinoma. A lower pathCR rate was observed for 1) older patients (>60 years), 2) patients with poorly differentiated tumors, 3) patients with signet ring cells (SRCs), and 4) patients with a higher T stage. Patients with a pathCR had longer OS and RFS than those without a pathCR (P = .0021 and P = .0011, respectively). Recurrences occurred more in non-pathCR patients. Distant metastases were the most common type of recurrence. PathCR patients developed brain metastases at a marginally higher rate than non-pathCR patients (P = .051). CONCLUSIONS: In this large cohort study, a pathCR is confirmed to be associated with better OS and RFS. The presence of a poorly differentiated tumor or SRCs reduces the likelihood of a pathCR. Future research should focus on molecular classifiers. Cancer 2017;123:4106-4113. (c) 2017 American Cancer Society. PMID- 28885716 TI - MicroRNAs are potential objective and early biomarkers for acute rejection of transplanted limbs in a rat model. AB - BACKGROUND: Limb transplantation is considered to be a treatment option for amputees. Visual skin inspection and histological assessment are used to assess rejection, but these techniques are largely subjective. Using a rat model, we examined the potential of several microRNAs (miRNAs) to be used as objective and minimally invasive biomarkers of acute rejection of transplanted limbs. METHODS: Three Brown Norway rats and 15 Lewis rats were assigned to 2 groups. In the allograft group, 3 Brown Norway rats were used as the donors and 6 Lewis rats as the recipients. In the syngeneic (control) group, 9 Lewis rats were used as the donors and recipients. The hind limbs of the donors were orthotopically transplanted to the recipients. Plasma samples were obtained from all recipients before surgery and on posttransplantation days 3, 7, 10, and 14. All recipients were euthanized on day 14, and skin tissues were harvested for histological assessment. RESULTS: On posttransplantation days 10 and 14, the plasma expression of miRNA-146a, miRNA-155, and miRNA-182 was significantly upregulated in the allograft group compared with the syngeneic control group. Of these 3 miRNAs, miRNA-182 had the highest sensitivity and specificity; however the cutoff point for miRNA-182 was close to the baseline and miRNA-155 was considered to be most suitable for identifying rejection. Most skin samples in the allograft group were classified as exhibiting grade III rejection on day 14. CONCLUSIONS: Some miRNAs are upregulated during acute rejection of transplanted limbs. These miRNAs are potential biomarkers for the objective, early, minimally invasive diagnosis of rejection. PMID- 28885717 TI - Effects of cyclin D1 gene silencing on cell proliferation, cell cycle, and apoptosis of hepatocellular carcinoma cells. AB - This study aims to investigate the effects of Cyclin D1 silencing on cell cycle, cell proliferation, and apoptosis of hepatocellular carcinoma cells (HCC). Cells were divided into the blank group, negative control group (HCC cells transfected with control shRNA), Cyclin D1 shRNA group (HCC cells transfected with Cyclin D1 shRNA), and the normal group (human normal liver L-02 cells). Expressions of Cyclin D1, Caspase-3, Bcl-2, and C-myc were detected by RT-qPCR and Western blotting. Cell proliferation was detected by Cell Counting Kit-8. Cell cycle and apoptosis were detected by flow cytometry. Tumor xenograft in nude mice was performed to detect in vivo tumorigenesis. HCC tissues and HCC cells exhibited elevated expression levels of Cyclin D1. Cyclin D1 expression levels was found to be correlated with tumor size and tumor staging. Compared with the normal group, the blank group showed enhanced cell proliferation, a reduction in the amount of cells in G0/G1 phase, increased number cells in S and G2/M phase, reduced apoptosis, elevated expressions of Cyclin D1, Bcl-2, and C-myc, decreased Caspase 3 activity and significant tumorigenicity. In comparison with the blank group, the Cyclin D1 shRNA group revealed weakened cell proliferation, reduced cells in S and G2/M phase, increased cells in G0/G1 phase, increased Annexin V positive cell ratio, decreased expression of Cyclin D1, Bcl-2, and C-myc, elevated Caspase 3 activity and inhibited tumorigenicity. In conclusion, Cyclin D1 gene silencing suppresses cell proliferation and inhibits cell apoptosis, which may be a new target approach in the treatment and management for HCC. PMID- 28885718 TI - Transvaginal Ultrasound-Guided Core Needle Biopsy of Pelvic Masses. AB - OBJECTIVES: This study assessed the efficacy and safety of transvaginal ultrasound (US)-guided core needle biopsy (CNB) for obtaining adequate pelvic mass samples for histologic analysis and evaluated factors that may affect biopsy success. METHODS: Two hundred cases underwent transvaginal US-guided CNBs for primary inoperable tumors, suspicion of metastases to the ovaries or peritoneum, recurrence, or other solid lesions in the pelvis. Biopsy samples were obtained from the pelvic cavity (67.0%), vaginal cuff or vaginal wall (17.5%), or peritoneal cake (15.5%). The potential influences of the biopsy site (pelvic cavity, vaginal cuff or vaginal wall, or peritoneal cake), vascularization, ascites, tumor size, and tumor type (inoperable, metastases, recurrence, or solid pelvic tumor) on the success of transvaginal US-guided CNB were evaluated by a univariate analysis. RESULTS: Adequate samples were obtained in 192 of 200 biopsies (96.0%), of which 190 yielded successful diagnoses (95.0%). The biopsy site had a significant effect on biopsy adequacy, as there was a significantly lower probability of obtaining satisfactory specimens for histologic verification from the peritoneal cake compared to pelvic tumors and the vaginal cuff or vaginal wall (P < .01). Adequacy was also affected by tumor size (P < .05) but not by vascularization, ascites, or tumor type. No complications occurred during the biopsy procedures. CONCLUSIONS: Transvaginal US-guided CNB is a safe and effective alternative to more invasive methods for evaluating pelvic lesions, such as laparoscopy and laparotomy. PMID- 28885719 TI - Post-transplant consolidation plus lenalidomide maintenance vs lenalidomide maintenance alone in multiple myeloma: A systematic review. AB - BACKGROUND: In newly diagnosed multiple myeloma (NDMM), autologous stem cell transplantation (ASCT) remains the standard approach for transplant-eligible patients. To control the inevitable relapse, post-transplant consolidation/maintenance strategies are commonly used. However, the benefit of post-transplant consolidation is still uncertain METHOD: We conducted a systematic review of phase II/III studies to compare the efficacy of post-ASCT consolidation plus lenalidomide maintenance (CON+LEN) vs lenalidomide maintenance alone (LEN alone) in NDMM. A meta-analysis using fixed and random effects models was performed. RESULTS: Fourteen studies were included with 2275 participants with NDMM treated with ASCT and lenalidomide maintenance. Two groups were identified: CON+LEN group (n = 1102) and LEN alone group (n = 1173). There was no statistically significant difference in the complete response rate between the two groups [RR = 1.1; 95% CI: 0.83-1.44; P = .490]. Interestingly, we found that very good partial response or better rate is around 1.5-fold significantly higher in the CON+LEN group compared to LEN alone group [RR: 1.46; 95% CI: 1.25-1.70; P < .0001]. However, there was no significant difference between the two groups regarding PFS [RR: 1.0; 95% CI: 0.92-1.08, P = .929] and OS [RR: 0.9; 95% CI: 0.92-1.01; P = .148] at 3-4 years follow-up. The risk of secondary primary malignancy (SPM) was also similar between the two groups (RR: 1.2; 95% CI: 0.84 1.92; P = .2). Data on adverse events were limited. CONCLUSION: Our data suggest that, in NDMM patients treated with upfront ASCT, post-transplant consolidation may improve depth of response, but does not add to OS or PFS, compared to lenalidomide maintenance alone. However, data in this context are still immature. PMID- 28885720 TI - Stathmin/Op18 depletion induces genomic instability and leads to premature senescence in human normal fibroblasts. AB - Stathmin/oncoprotein18 regulates microtubule dynamics and participates in mitotic entry and exit. We isolated stathmin as a physically interacting partner of KIFC1, a minus-end-directed kinesin functioning in bipolar spindle formation and maintenance. We found that stathmin depletion leads to multipolar spindle formation in IMR-90 normal human fibroblasts. Stathmin-depleted IMR-90 cells showed early mitotic delay but managed to undergo chromosome segregation by forming multiple poles or pseudo-bipoles. Consistent with these observations, lagging chromosomes, and micronuclei were elevated in stathmin-depleted IMR-90 cells, demonstrating that stathmin is essential for maintaining genomic stability during mitosis in human cells. Genomic instability induced by stathmin depletion led to premature senescence without any indication of cell death in normal IMR-90 cells. Double knock-down of both stathmin and p53 also did not induce cell death in IMR-90 cells, while the stathmin knock-down triggered apoptosis in p53 proficient human lung adenocarcinoma cells. Our results suggest that stathmin is essential in bipolar spindle formation to maintain genomic stability during mitosis, and the depletion of stathmin prevents the initiation of chromosome instability by inducing senescence in human normal fibroblasts. PMID- 28885721 TI - Targeting intracellular Staphylococcus aureus to lower recurrence of orthopaedic infection. AB - Staphylococcus aureus is often found in orthopaedic infections and may be protected from commonly prescribed antibiotics by forming biofilms or growing intracellularly within osteoblasts. To investigate the effect of non-antibiotic compounds in conjunction with antibiotics to clear intracellular and biofilm forming S. aureus causing osteomyelitis. SAOS-2 osteoblast-like cell lines were infected with S. aureus BB1279. Antibiotics (vancomycin, VAN; and dicloxacillin, DICLOX), bacterial efflux pump inhibitors (piperine, PIP; carbonyl cyanide m chlorophenyl hydrazone, CCCP), and bone morphogenetic protein (BMP-2) were evaluated individually and in combination to kill intracellular bacteria. We present direct evidence that after gentamicin killed extracellular planktonic bacteria and antibiotics had been stopped, seeding from the infected osteoblasts grew as biofilms. VAN was ineffective in treating the intracellular bacteria even at 10* MIC; however in presence of PIP or CCCP the intracellular S. aureus was significantly reduced. Bacterial efflux pump inhibitors (PIP and CCCP) were effective in enhancing permeability of antibiotics within the osteoblasts and facilitated killing of intracellular S. aureus. Confocal laser scanning microscopy (CLSM) showed increased uptake of propidium iodide within osteoblasts in presence of PIP and CCCP. BMP-2 had no effect on growth of S. aureus either alone or in combination with antibiotics. Combined application of antibiotics and natural agents could help in the treatment of osteoblast infected intracellular bacteria and biofilms associated with osteomyelitis. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1086-1092, 2018. PMID- 28885722 TI - Astrocytic signaling supports hippocampal-prefrontal theta synchronization and cognitive function. AB - Astrocytes interact with neurons at the cellular level through modulation of synaptic formation, maturation, and function, but the impact of such interaction into behavior remains unclear. Here, we studied the dominant negative SNARE (dnSNARE) mouse model to dissect the role of astrocyte-derived signaling in corticolimbic circuits, with implications for cognitive processing. We found that the blockade of gliotransmitter release in astrocytes triggers a critical desynchronization of neural theta oscillations between dorsal hippocampus and prefrontal cortex. Moreover, we found a strong cognitive impairment in tasks depending on this network. Importantly, the supplementation with d-serine completely restores hippocampal-prefrontal theta synchronization and rescues the spatial memory and long-term memory of dnSNARE mice. We provide here novel evidence of long distance network modulation by astrocytes, with direct implications to cognitive function. PMID- 28885723 TI - Biofilm formation of beta-hemolytic group G Streptococcus dysgalactiae subspecies equisimilis isolates and its association with emm polymorphism. AB - Biofilm formation has been well known as a determinant of bacterial virulence. Group G Streptococcus dysgalactiae subspecies equisimilis (SDSE), a relevant pathogen with increasing medical importance, was evaluated for the biofilm forming potential. Microtiter plate assay was used to assess the most feasible medium for group G SDSE to form a biofilm. Among 246 SDSE isolates examined, 46.7%, 43.5%, 33.3%, and 26.4% of isolates showed moderate or strong biofilm forming abilities using tryptic soy broth (TSB), brain heart infusion broth (BHI), Todd-Hewitt broth (THB), and C medium with 30 mM glucose (CMG), respectively. The addition of glucose significantly increased the biofilm-forming ability of group G SDSE. FCT (fibronectin-collagen-T-antigen) typing of SDSE was first undertaken and 11 FCT types were found. Positive associations of stG10.0 or negative associations of stG245.0, stG840.0, and stG6.1 with biofilm-forming ability of SDSE were, respectively, found. This was the first investigation demonstrating biofilm-forming potential in clinical group G SDSE isolates; also, some significant associations of biofilm-forming ability with certain emm types were presented. PMID- 28885725 TI - Supporting spirituality in the care of older people living with dementia: a hermeneutic phenomenological inquiry into nurses' experiences. AB - BACKGROUND: Spirituality is defined as a search for answers to existential questions about the meaning of life and the individual's relationship with the sacred or transcendent. This relationship may or may not involve affiliation with a specific religion. Studies on spirituality have focused on palliative care, and there are limited studies into the spirituality in the care of older people with dementia. AIM: To describe the experiences of nurses supporting spirituality in the care of older people living with dementia. METHOD: This study, informed by Heideggerian hermeneutic phenomenology, was conducted in 2014/15. Data were collected by interviewing a purposive sample of 17 nurses. RESULTS: Supporting the spirituality of older people with dementia was seen as understanding their spirituality within a framework of person-centeredness and individuality. The participants came to understand the spiritual needs of older people with dementia through both verbal and nonverbal expression and by learning about older people's individual spiritual backgrounds. Meeting spiritual needs meant approaching the person with dementia as a valuable human as well as paying attention, to and supporting, his/her personal philosophy of life within nursing care. CONCLUSION: Learning and developing an understanding of the spiritual needs of older people with dementia is challenging. The nurses offered person-centred, spiritual care, to people with dementia from a variety of perspectives, which is important in the provision of comprehensive care. There is a need to find usable tools to help nurses to learn and understand the individual spiritual needs of older people with dementia and to explore how these older adults experience having their spirituality supported within their nursing care. PMID- 28885724 TI - First progress report on the Japan Endoscopy Database project. AB - BACKGROUND AND AIM: The Japan Endoscopy Database (JED) Project was started to develop the world's largest endoscopic database, capture the actual performance of endoscopic practice, and standardize the terminology and fundamental items needed for a clinical and research registry. This paper presents a progress report on the first phase of this project undertaken at eight endoscopic centers in Japan. METHODS: The list of data items to be collected was drafted by the MSED J (Minimal Standard Endoscopic Database) subcommittee. These items were aggregated offline by integrating data from two endoscopic filing systems between July 2015 and December 2015. The study population included all patients who underwent esophagogastroduodenoscopy or colonoscopy at all eight centers, patients who underwent enteroscopy at five of the eight centers, and patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) at four of the eight centers. RESULTS: Data collected in this phase included 61 070 endoscopic procedures, of which 40 475 were esophagogastroduodenoscopies, 215 were enteroscopies, 19 204 were colonoscopies, and 1176 were ERCPs. Frequencies of complications were 0.68% for esophagogastroduodenoscopy, 0% for enteroscopy, 0.43% for colonoscopy, and 13.34% for ERCP. In addition, we obtained various data including Helicobacter pylori infection status, past history of endoscopy in patients who underwent enteroscopy or colonoscopy, and degree of difficulty of ERCP, although the frequencies of reporting were sometimes low, with some items <20%. CONCLUSION: Results of the first phase suggest that the JED project can provide vast quantities of useful data about endoscopic procedures. PMID- 28885726 TI - Achieving interfragmentary compression without special drilling technique or screw design. AB - : Traditional fracture fixation teaching suggests that fully threaded screws do not provide interfragmentary compression unless placed through a glide hole. Based on this assumption, pelvic surgeons typically use fully threaded screws in the treatment of comminuted transforaminal sacral fractures to limit iatrogenic neuroforaminal stenosis. Clinical experience with fully threaded screws suggests that interfragmentary compression actually does occur. We hypothesized that the use of a fully threaded screw does not produce any interfragmentary compression and that there is no difference in insertional torque between partially threaded and fully threaded screws. To test this hypothesis, fully and partially threaded 7.0 millimeter (mm) cannulated screws were placed across two synthetic bone blocks fabricated to simulate normal and osteoporotic bone. We compared two groups of normal and osteoporotic blocks for compression achieved and maximal insertional torque generated with fully threaded and partially threaded screw insertion. A micro computed tomography (CT) scan of the composite blocks was obtained to investigate for structural changes created during screw insertion. For both groups, compression was achieved with fully threaded screws and the maximal insertional torque was higher using fully threaded screws. Micro CT analysis demonstrated local bone damage with structural disruption in the near segment of the fully threaded screw path in comparison to the partially threaded. CLINICAL SIGNIFICANCE: this study demonstrates that compression is generated using fully threaded screws without using a predrilled glide hole. The insertional torque required to generate compression with fully threaded screws is increased but is clinically applicable. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1099-1105, 2018. PMID- 28885727 TI - Does benefit justify research with children? AB - The inclusion of children in research gives rise to a difficult ethical question: What justifies children's research participation and exposure to research risks when they cannot provide informed consent? This question arises out of the tension between the moral requirement to obtain a subject's informed consent for research participation, on the one hand, and the limited capacity of most children to provide informed consent, on the other. Most agree that children's participation in clinical research can be justified. But the ethical justification for exposing children to research risks in the absence of consent remains unclear. One prevalent group of arguments aims to justify children's risk exposure by appealing to the concept of benefit. I call these 'benefit arguments'. Prominent versions of this argument defend the idea that broadening our understanding of the notion of benefit to include non-medical benefits (such as the benefit of a moral education) helps to justify children's research participation. I argue that existing benefit arguments are not persuasive and raise problems with the strategy of appealing to broader notions of benefit to justify children's exposure to research risk. PMID- 28885728 TI - Liquid Quinones for Solvent-Free Redox Flow Batteries. AB - Liquid benzoquinone and naphthoquinone having diethylene glycol monomethyl ether groups are designed and synthesized as redox active materials that dissolve supporting electrolytes. The Li-ion batteries based on the liquid quinones using LiBF4 /PC show good performance in terms of voltage, capacity, energy efficiency, and cyclability in both static and flow modes. A battery is constructed without using intentionally added organic solvent, and its high energy density (264 W h L 1 ) demonstrates the potential of solvent-free organic redox flow batteries using liquid active materials. PMID- 28885729 TI - Leptin induces matrix metalloproteinase 7 expression to promote ovarian cancer cell invasion by activating ERK and JNK pathways. AB - Leptin, an adipokine secreted by adipose tissue, induces cell invasion and metastasis. MMP7 is a member of the matrix metalloproteinase family that plays an important role in cell invasion. Here we evaluate the possible role and underlying mechanism of MMP7 in the leptin-mediated cell invasion in ovarian cancer cell lines. All experiments were carried out in cultured SKOV3, OVCAR3, and CaoV-3 ovarian cell lines. MMP7 expression was determined using the Western blot following treatment to various concentrations of leptin for defined time intervals. The activation of ERK, JNK, and P38 MAP kinases were determined using Western blotting. Wound healing and BD matrigel invasion assays were used to measure cell migration and invasion. The siRNA approach and pharmacological inhibitors of ERK and JNK pathway were used to confirm the receptor-dependent effect of leptin and a role for ERK and JNK pathway. Zymography assay was employed to determine MMP2 and MMP9 activation. Results show that leptin induces ERK1/2 and JNK1/2 activation and subsequently promotes MMP7 expression in SKOV3 (4.8 +/- 0.14 fold of control, P < 0.01) and OVCAR3 (3.1 +/- 0.19 fold of control, P < 0.01) ovarian cancer cell lines. These effects was reversed by knockdown of OB-Rb and/or pre-incubation with PD98059 (ERK1/2 inhibitor), SP600125 (JNK1/2 inhibitor). Gelatin zymography showed that MMP7 gene silencing attenuated leptin-induced MMP9 activation in SKOV3 cell line. Taken together, our results suggest new evidences for a modulatory effect of leptin in regulation of ovarian cancer cell invasion by stimulating MMP7 expression via ERK and JNK pathways. PMID- 28885730 TI - Low angiomotin-p130 with concomitant high Yes-associated protein 1 expression is associated with adverse prognosis of advanced gastric cancer. AB - Angiomotin (AMOT) promotes angiogenesis and plays a role in neovascularization during tumorigenesis. Recently, the AMOT isoform, AMOT-p130, was shown to exert a regulatory effect on Yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway. The specific roles of AMOT-p130 and YAP1 in advanced gastric cancer (AGC) are yet to be established. In this study, a total of 166 patients with AGC were enrolled, and AMOT-p130 and YAP1 levels were analyzed by immunohistochemistry using tissue microarrays. Low AMOT-p130 together with high YAP1 expression (n = 30, 18.1%) was associated with high T stage (p = 0.042), high TNM stage (p = 0.025), and venous invasion (p = 0.048). A Kaplan-Meier survival analysis with log-rank test revealed a significant correlation with decreased AMOT-p130 coupled with high nuclear YAP1 expression with shorter overall survival (p = 0.0045) and disease-free survival (p = 0.0028). Furthermore, multivariate analyses showed that the low AMOT-p130/high YAP1 expression profile was an independent prognostic factor for disease-free survival (p = 0.008, HR = 1.874, CI, 1.177-2.986) and overall survival (p = 0.012, HR = 1.903, CI, 1.152-3.143). Our findings collectively demonstrate that low AMOT-p130 combined with high YAP1 expression is correlated with an unfavorable AGC prognosis. PMID- 28885731 TI - A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with desmoplasia in mice. AB - : The anticancer efficacy of TNF-related apoptosis-inducing ligand (TRAIL)-based therapy is limited because of systemic toxicity, poor bioavailability, and development of TRAIL resistance. We developed a tumor-targeted LCPP (lipid/calcium/phosphate/protamine) nanoparticle (NP) to deliver TRAIL plasmid DNA (pDNA) into hepatocellular carcinoma (HCC) cells in a mouse model of HCC. TRAIL pDNA was encapsulated in a pH stimuli-responsive calcium phosphate (CaP) core, and protamine was added to facilitate nuclear delivery of pDNA. In addition, intracellular release of Ca2+ from the CaP core overcame TRAIL resistance by calcium influx-dependent DR5 up-regulation. TRAIL expression also attenuated fibrosis in liver tissues surrounding HCCs by reverting activated hepatic stellate cells (HSCs) to a quiescent state or by directly inducing apoptosis in activated HSCs. CONCLUSION: TRAIL pDNA delivered by HCC-targeted LCPP NPs in combination with conventional sorafenib treatment attenuated HCC progression as well as liver fibrosis. Overall, our study presents an effective TRAIL-based cancer therapy that could be developed for clinical applications. (Hepatology 2018;67:899-913). PMID- 28885732 TI - A role of human beta defensin-1 in predicting prostatic adenocarcinoma in cases of false-negative biopsy. AB - The purpose of this study was to clarify the role of human beta defensin-1 (hBD 1) in predicting PAC in morphologically normal prostate glands. In total, 25 patients with a negative initial biopsy for PAC and diagnosed as PAC positive in subsequent biopsies performed within 1 year of the initial biopsy were included. As a control group, 22 patients negative for PAC in at least three consecutive histologic examinations were selected. Expression of hBD-1 was analyzed separately via immunohistochemistry in paired cores of non-neoplastic gland and PAC in the false-negative group and control group. Loss of hBD-1 expression was observed in 95.6% and 90.0% PAC cases with Gleason Patterns 3 and 4 in repeat biopsies, respectively. hBD-1 loss of basal cells in 40 (85.1%) previous non neoplastic biopsy cores in the false-negative group was observed, in contrast to preserved basal cell expression of hBD-1 in 64 (72.7%) biopsy cores in the control group (p = 0.001). Multivariate logistic regression analysis showed that hBD-1 basal cell loss (>=20% of prostatic glands in total cores) is an independent factor for predicting PAC (odds ratio: 4.739, confidence interval: 1.093-20.554, p = 0.038). hBD-1 loss of basal cells is a useful indicator to identify extremely high-risk patients with initially negative biopsy. PMID- 28885733 TI - Attachment styles, pain intensity and emotional variables in women with fibromyalgia. AB - This study aims to explore the relations between attachment styles and pain intensity and certain emotional variables (anxiety, depression and alexithymia) in a sample of fibromyalgia patients, in comparison with healthy women. Data were collected from 146 women with fibromyalgia and 122 healthy women. The variables studied were attachment style, pain intensity, anxiety, depression and alexithymia dimensions. Patients with fibromyalgia showed lower percentages of secure attachment style (69.9% vs. 86%) whilst showing higher avoidant attachment (19.8% vs. 7.4%), as well as increased numbers of anxious-ambivalent attachment (10.3% vs. 6.6%) than healthy women (X2 = 9.915, p = .007). Also, fibromyalgia patients showed significantly higher scores in two of the insecure attachment factors (p < .000; p = .020) and lower scores on the secure attachment factor (p = .008) in comparison with healthy women. Higher scores of alexithymia were found in women showing anxious-ambivalent and avoidant attachment styles in comparison with those showing a secure attachment style, regardless of the group they belonged to. In fibromyalgia patients, higher anxiety (p = .005) was found among the women with anxious-ambivalent attachment styles (Mean = 15.15; SD = 1.15) in comparison with those with secure attachment style (Mean = 11.18; SD = .45). No relation was found between attachment style and pain intensity. Avoidant attachment seems to carry out a contradictory role and warrants further research. The results found seem to highlight the need for the Attachment-Diathesis Model of Chronic Pain to include attachment styles as a predictor of the emotional experience of pain in fibromyalgia patients. PMID- 28885735 TI - The seating mechanics of head-neck modular tapers in vitro: Load-displacement measurements, moisture, and rate effects. AB - The mechanically assisted crevice corrosion performance of head-neck modular tapers is a significant concern in orthopedic biomaterials. Fretting crevice corrosion processes in modular tapers are thought to be influenced by a wide array of factors including seating mechanics of the junction, hence there is a need for in vitro test methods that can assess their performance. This study presented a test method to directly measure the load-displacement seating mechanics of modular tapers and used this method to compare the seating mechanics for different tapers, moisture, seating loads and seating rates. Seating mechanics were explored whereby the instantaneous load-displacement behavior of the head seating onto the neck is captured and used to define the mechanics of seating. Two distinct taper design/material combinations were assembled wet or dry using axially applied loads (500, 1,000, 2,000, and 4,000 N) at two loading rates of 100 and 104 N/s (n = 5 for each condition) using a servohydraulic test frame. The results showed that pull-off strength scaled with seating load and ranged between 43% and 68% of seating load depending on sample and wetness. Tapers seated wet had higher pull-off strengths (2,200 +/- 300 N) than those seated dry (1,800 +/- 200 N, p < 0.05). Seating mechanics (load-displacement plots) varied due to sample type and due to wetness with differences in seating energy, seating stiffness, and seating displacement. These results show the detailed mechanics of seating during assembly and provide significant insight into the complex interplay of factors associated with even "ideal" seating (axial, quasistatic) loading. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1164-1172, 2018. PMID- 28885734 TI - Chronic myelomonocytic leukemia masquerading as cutaneous indeterminate dendritic cell tumor: Expanding the spectrum of skin lesions in chronic myelomonocytic leukemia. AB - Chronic myelomonocytic leukemia (CMML) is a hematopoietic stem cell neoplasm exhibiting both myelodysplastic and myeloproliferative features. Cutaneous involvement by CMML is critical to recognize as it typically is a harbinger of disease progression and an increased incidence of transformation to acute myeloid leukemia. Cutaneous lesions of CMML exhibit heterogeneous histopathologic features that can be challenging to recognize as CMML. We describe a 67-year-old man with a 3-year history of CMML who had been managed on single-agent azacitidine with stable disease before developing splenomegaly and acute onset skin lesions. Examination of these skin lesions revealed a dense infiltrate of histiocytic cells morphologically resembling Langerhans type cells (lacking frank histopathologic atypia), and with the immunophenotype of an indeterminate cell histiocytosis (S100+ CD1a+ and langerin-). Given the history of CMML, next generation sequencing studies were performed on the skin biopsy. These revealed a KRAS (p.G12R) mutation identical to that seen in the CMML 3 years prior, establishing a clonal relationship between the 2 processes. This case expands the spectrum for and underscores the protean nature of cutaneous involvement by CMML and underscores the importance of heightened vigilance when evaluating skin lesions of CMML patients. PMID- 28885736 TI - Prevalence and prognostic impact of anemia and iron deficiency in patients hospitalized in an internal medicine ward: The PRO-IRON study. AB - OBJECTIVES: To assess prevalence, predictive factors, and prognostic impact on in hospital mortality of anemia, iron deficiency anemia (IDA), iron deficiency with or without anemia (ID), and iron deficiency without anemia (IDWA) in patients admitted to an internal medicine ward. METHODS: This 1-year prospective study collected data on demographics, medical history, and blood tests in 771 consecutive patients on admission. RESULTS: Most patients were >=65 years old (80%) and had hypertension (63%), moderate chronic kidney disease (CKD) (43%), and heart failure (41%). Prevalence of anemia, IDA, ID, and IDWA was 67%, 41%, 58%, and 18%, respectively. Anemia was independently associated with age >=65 years (OR 1.76, 95% CI 1.15-2.70), active cancer (OR 2.44, 95% CI 1.42-4.39), and moderate CKD (OR 1.65, 95% CI 1.12-2.43). ID was independently associated with female gender (OR 2.29, 95% CI 1.64-3.22), heart failure (OR 1.65, 95% CI 1.16 2.37), and moderate CKD (OR 2.95, 95% CI 2.04-4.30). Incidence of in-hospital mortality was 21% and independently associated with anemia (RR 1.82, 95% CI 1.21 2.74). CONCLUSIONS: Anemia and iron deficiency were highly prevalent in internal medicine patients. As anemia negatively impacts on in-hospital mortality, awareness should be raised for effective diagnosis and management of these comorbidities in hospitalized patients. PMID- 28885737 TI - Vascular Pattern Analysis on Microvascular Sonography for Differentiation of Pleomorphic Adenomas and Warthin Tumors of Salivary Glands. AB - OBJECTIVES: Pleomorphic adenomas and Warthin tumors are the most common salivary gland tumors. It is important to differentiate between them because at least a partial parotidectomy is necessary for pleomorphic adenomas, whereas enucleation is sufficient for Warthin tumors. This study aimed to evaluate the usefulness of vascular pattern analysis using microvascular sonography to differentiate between the tumors. METHODS: Sixty-two patients with pathologically proven pleomorphic adenomas (n = 38) and Warthin tumors (n = 24) were included. For all tumors, grayscale, power Doppler, and microvascular sonographic examinations were performed. Differences in vascular patterns (vascular distribution and internal vascularity) on power Doppler and microvascular sonography as well as grayscale sonographic features (size, shape, border, echogenicity, heterogeneity, and cystic change) between pleomorphic adenomas and Warthin tumors were evaluated. A comparison of diagnostic performances of grayscale sonography with power Doppler sonography and grayscale sonography with microvascular sonography was performed. The level of interobserver agreement between 2 reviewers in diagnosing tumors was evaluated. RESULTS: No grayscale sonographic features showed a significant difference between the tumors. Vascular distributions and internal vascularity on power Doppler sonography (P = .01 and .002) and microvascular sonography (both P < .001) were all significantly different. The diagnostic accuracy of grayscale sonography with microvascular sonography (79.0%) was higher than that of grayscale sonography with power Doppler sonography (72.6%). This difference was significant according to the McNemar test (P = .004). Interobserver agreement was excellent in diagnosing tumors on both grayscale sonography with power Doppler sonography (kappa = 0.83) and grayscale sonography with microvascular sonography (kappa = 0.94). CONCLUSIONS: Vascular pattern analysis using microvascular sonography with other sonographic features is helpful for differentiating between pleomorphic adenomas and Warthin tumors. PMID- 28885738 TI - Wearable Large-Scale Perovskite Solar-Power Source via Nanocellular Scaffold. AB - Dramatic advances in perovskite solar cells (PSCs) and the blossoming of wearable electronics have triggered tremendous demands for flexible solar-power sources. However, the fracturing of functional crystalline films and transmittance wastage from flexible substrates are critical challenges to approaching the high performance PSCs with flexural endurance. In this work, a nanocellular scaffold is introduced to architect a mechanics buffer layer and optics resonant cavity. The nanocellular scaffold releases mechanical stresses during flexural experiences and significantly improves the crystalline quality of the perovskite films. The nanocellular optics resonant cavity optimizes light harvesting and charge transportation of devices. More importantly, these flexible PSCs, which demonstrate excellent performance and mechanical stability, are practically fabricated in modules as a wearable solar-power source. A power conversion efficiency of 12.32% for a flexible large-scale device (polyethylene terephthalate substrate, indium tin oxide-free, 1.01 cm2 ) is achieved. This ingenious flexible structure will enable a new approach for development of wearable electronics. PMID- 28885739 TI - Role of Acid in Tailoring Prussian Blue as Cathode for High-Performance Sodium Ion Battery. AB - Prussian blue (PB) with concave centers is synthesized successfully through a hydrothermal method with the assistance of acid. In this study, the role of the acid is investigated systematically by adjusting the reaction temperature and time, using different kinds and amounts of acid, and changing the amount of PVP surfactant added. It is found that the acid can not only trigger the chemical reaction to form cubic PB, but also act as an etching reagent to tailor the morphology. The as-obtained cubic PB with concave centers demonstrates a superior cycle stability and rate performance, which can achieve a capacity of 107 mA h g 1 at 0.2 A g-1 . The corresponding capacity retention is 74 % after 500 cycles relative to the second cycle. Even at a current density of 5 A g-1 , the specific capacity remains at 82 mA h g-1 . Furthermore, the full cell, using PB as the cathode and hard carbon as the anode, exhibits a high capacity of 70 mA h g-1 at 0.1 A g-1 , and can power an LED light successfully. This work provides new insights into the role of acid in tailoring the morphology of PB, and opens a new avenue toward the design of unique structures to improve sodium storage. PMID- 28885740 TI - Preferential encoding of movement amplitude and speed in the primary motor cortex and cerebellum. AB - Voluntary movements require control of multiple kinematic parameters, a task carried out by a distributed brain architecture. However, it remains unclear whether regions along the motor system encode single, or rather a mixture of, kinematic parameters during action execution. Here, rapid event-related functional magnetic resonance imaging was used to differentiate brain activity along the motor system during the encoding of movement amplitude, duration, and speed. We present cumulative evidence supporting preferential encoding of kinematic parameters along the motor system, based on blood-oxygenation-level dependent signal recorded in a well-controlled single-joint wrist-flexion task. Whereas activity in the left primary motor cortex (M1) showed preferential encoding of movement amplitude, the anterior lobe of the right cerebellum (primarily lobule V) showed preferential encoding of movement speed. Conversely, activity in the left supplementary motor area (SMA), basal ganglia (putamen), and anterior intraparietal sulcus was not preferentially modulated by any specific parameter. We found no preference in peak activation for duration encoding in any of the tested regions. Electromyographic data was mainly modulated by movement amplitude, restricting the distinction between amplitude and muscle force encoding. Together, these results suggest that during single-joint movements, distinct kinematic parameters are controlled by largely distinct brain-regions that work together to produce and control precise movements. Hum Brain Mapp 38:5970-5986, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28885741 TI - Fused 1,2,3-Thiaselenazoles Synthesized from 1,2,3-Dithiazoles through Selective Chalcogen Exchange. AB - A new approach to the synthesis of fused 1,2,3-thiaselenazoles-rare five-membered heterocycles that contain two different chalcogens-from the corresponding 1,2,3 dithiazoles and SeO2 was accomplished by selective exchange of S and Se atoms. The fused carbo- and heterocyclic units were indene, naphthalenone, cyclohexadienone, cyclopentadiene, benzoannulene, and benzoxazine. The molecular structures of two of the thiaselenadiazole products and one of the dithiazole precursors were confirmed by single-crystal X-ray diffraction. The reaction is highly solvent selective; it only takes place in solvents that contain a C=O group (e.g., DMF or tetramethylurea). According to DFT calculations, the reaction is thermodynamically favorable. Based on the DFT calculations and 77 Se NMR spectroscopy, two tentative mechanisms that feature isomeric transition states and intermediates are suggested for the reaction via ring-opening addition of SeO2 to the S-X dithiazole bond (X=N or S). The DFT-calculated first adiabatic electron affinities of the compounds were chalcogen independent and positive in all cases, which assumes formation of thermodynamically stable radical anions (RAs). These calculated RAs featured either normal or abnormal elongation of the S1-X2 (X=S or Se) bond relative to their neutral precursors and possessed pi* or sigma* SOMOs, respectively. PMID- 28885743 TI - alpha- and beta-[Bmim][BiCl4 (2,2'-bpy)]: Two Polymorphic Bismuth-Containing Ionic Liquids with Crystallization-Induced Phosphorescence. AB - This work reports the syntheses, structures, and luminescence properties of two supramolecular polymorphic compounds composed of a hybrid bismuth(III) chloride anion and an imidazolium cation, namely alpha- (1) and beta- (2) [Bmim][BiCl4 (2,2'-bpy)] (Bmim=1-butyl-3-methyl imidazolium; 2,2'-bpy=2,2'-bipyridine). They are the first two examples of Bi3+ -containing ionic liquids (ILs). Their different packing modes may be ascribed to the rotational flexibility of the butyl group on the [Bmim]+ cation. A comparative study of the weak intermolecular interactions present in the two polymorphs has been performed by Hirshfeld surface and two-dimensional fingerprint analyses. Investigations of the luminescence properties revealed that crystallization induced greenish-yellow phosphorescence with quantum yields of 26.07 % for 1 and 36.59 % for 2, which are among the highest hitherto reported for hybrid halobismuthate compounds. The difference in phosphorescence may be attributed to the different weak interactions in 1 and 2, especially pi-pi contacts. This work opens the way to further research on new types of polymorphism-dependent luminescent materials based on a combination of rotationally isomeric IL cations with organic decorated bismuth(III) chloride anions. PMID- 28885742 TI - Adaptive bulk motion exclusion for improved robustness of abdominal magnetic resonance imaging. AB - Non-Cartesian magnetic resonance imaging (MRI) sequences have shown great promise for abdominal examination during free breathing, but break down in the presence of bulk patient motion (i.e. voluntary or involuntary patient movement resulting in translation, rotation or elastic deformations of the body). This work describes a data-consistency-driven image stabilization technique that detects and excludes bulk movements during data acquisition. Bulk motion is identified from changes in the signal intensity distribution across different elements of a multi-channel receive coil array. A short free induction decay signal is acquired after excitation and used as a measure to determine alterations in the load distribution. The technique has been implemented on a clinical MR scanner and evaluated in the abdomen. Six volunteers were scanned and two radiologists scored the reconstructions. To show the applicability to other body areas, additional neck and knee images were acquired. Data corrupted by bulk motion were successfully detected and excluded from image reconstruction. An overall increase in image sharpness and reduction of streaking and shine-through artifacts were seen in the volunteer study, as well as in the neck and knee scans. The proposed technique enables automatic real-time detection and exclusion of bulk motion during MR examinations without user interaction. It may help to improve the reliability of pediatric MRI examinations without the use of sedation. PMID- 28885745 TI - Intravoxel incoherent motion MRI as a means to measure in vivo perfusion: A review of the evidence. AB - The idea that in vivo intravoxel incoherent motion magnetic resonance signal is influenced by blood motion in the microvasculature is exciting, because it suggests that local and quantitative perfusion information can be obtained in a simple and elegant way from a few diffusion-weighted images, without contrast injection. When the method was proposed in the late 1980s some doubts appeared as to its feasibility, and, probably because the signal to noise and image quality at the time was not sufficient, no obvious experimental evidence could be produced to alleviate them. Helped by the tremendous improvements seen in the last three decades in MR hardware, pulse design, and post-processing capabilities, an increasing number of encouraging reports on the value of intravoxel incoherent motion perfusion imaging have emerged. The aim of this article is to review the current published evidence on the feasibility of in vivo perfusion imaging with intravoxel incoherent motion MRI. PMID- 28885746 TI - Pseudo-extravasation rate constant of dynamic susceptibility contrast-MRI determined from pharmacokinetic first principles. AB - Dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) is widely used to obtain informative perfusion imaging biomarkers, such as the relative cerebral blood volume (rCBV). The related post-processing software packages for DSC-MRI are available from major MRI instrument manufacturers and third-party vendors. One unique aspect of DSC-MRI with low-molecular-weight gadolinium (Gd) based contrast reagent (CR) is that CR molecules leak into the interstitium space and therefore confound the DSC signal detected. Several approaches to correct this leakage effect have been proposed throughout the years. Amongst the most popular is the Boxerman-Schmainda-Weisskoff (BSW) K2 leakage correction approach, in which the K2 pseudo-first-order rate constant quantifies the leakage. In this work, we propose a new method for the BSW leakage correction approach. Based on the pharmacokinetic interpretation of the data, the commonly adopted R2 * expression accounting for contributions from both intravascular and extravasating CR components is transformed using a method mathematically similar to Gjedde Patlak linearization. Then, the leakage rate constant (KL ) can be determined as the slope of the linear portion of a plot of the transformed data. Using the DSC data of high-molecular-weight (~750 kDa), iron-based, intravascular Ferumoxytol (FeO), the pharmacokinetic interpretation of the new paradigm is empirically validated. The primary objective of this work is to empirically demonstrate that a linear portion often exists in the graph of the transformed data. This linear portion provides a clear definition of the Gd CR pseudo-leakage rate constant, which equals the slope derived from the linear segment. A secondary objective is to demonstrate that transformed points from the initial transient period during the CR wash-in often deviate from the linear trend of the linearized graph. The inclusion of these points will have a negative impact on the accuracy of the leakage rate constant, and even make it time dependent. PMID- 28885747 TI - Palladium-Catalyzed 2,2,2-Trifluoroethoxylation of Aromatic and Heteroaromatic Chlorides Utilizing Borate Salt and the Synthesis of a Trifluoro Analogue of Sildenafil. AB - A simple and convenient method was developed for the introduction of a 2,2,2 trifluoroethoxy group to various aromatic and heteroaromatic systems. The novel process utilizes aromatic chlorides as substrates, and tetrakis(2,2,2 trifluoroethoxy) borate salt as an inexpensive and readily available fluoroalkoxy source in a palladium-catalyzed cross-coupling reaction. The power of the developed methodology was demonstrated in the synthesis of a fluorous derivative of Sildenafil. PMID- 28885749 TI - Paediatric food-induced anaphylaxis hospital presentations in New Zealand. AB - AIM: Globally, rates of paediatric food-induced anaphylaxis (FIA) are increasing. Little data is available regarding the epidemiology of FIA among New Zealand (NZ) children. This study investigated the incidence of paediatric (0-14 years) FIA hospital presentations in NZ over a 10-year period. METHODS: Ministry of Health public hospital discharge data from 2006 to 2015 were analysed using FIA-related International Classification of Diseases codes (T78.0 - anaphylactic shock due to adverse food reaction and T78.2 - anaphylactic shock unspecified and free text qualifier) to identify acute hospital presentations. RESULTS: The overall annualised FIA hospital presentation rate was 16.2 per 100 000 children. Subgroup analysis indicated a significantly higher rate in males (19.1/100 000) than in females (13.1/100 000), and among children aged less than 2 years of age (50.5/100 000) compared with older children. Rates among Asian and Pacific children were higher than Maori and NZ European children. In 67.7% of cases, a single specific allergen was suggested by the information provided; among these cases, nuts (48%), specifically peanuts (26%), were the most commonly reported allergen, followed by cow's milk (21%). Time trend analysis showed a 2.8-fold increase in the overall annualised rate for the 10-year period. CONCLUSION: These findings are consistent with other international studies indicating increasing rates of FIA in children. These data will provide information for a review of NZ paediatric allergy services to ensure current international standards with regard to the equitable delivery of timely, appropriate and accessible care are being met. Reasons for differences by gender, age and ethnicity require further investigation. PMID- 28885748 TI - Extensive study on physicochemical properties of polychlorinated biphenyls in a commercial ion trap mass spectrometer, relevance in analytical and environmental chemistry. AB - Polychlorinated biphenyls (PCBs) exist as 209 congeners, consisting of biphenyl molecules, where the number and substitution positions of halogen atoms are known to affect industrial uses, environmental transport mechanisms, distribution, fate, and toxicity. The complexity of the problem requires accurate physicochemical studies of an increasing number of congeners in order to understand the environmental and biological processes at play. This work presents a systematic study on the thermodynamic and kinetic properties of PCBs by quadrupole ion trap mass spectrometry. A clear relationship between structure and behavior of PCBs in mass spectrometry experiments has been observed. Overall data demonstrate that di-ortho congeners show lower thermodynamic stability and higher fragmentation rate than non/mono-ortho. Congeners follow different fragmentation mechanisms according to the number of chlorine atoms in ortho position of the biphenyl system. Experimental kinetic curves of mono/non-ortho and di-ortho congeners show a strong similarity with classical first-order kinetics curves; in particular, di-ortho congeners follow a first-order consecutive reaction, while mono/non-ortho follow a first-order parallel reaction. For each studied congener, the kinetic constant of reaction (fragmentation) has been determined. Data support environmental levels and biochemical transformations described in literature. The general picture of the PCB behavior inside a quadrupole ion trap provides the basis for the development of reliable and cost-effective analytical methods to the determination of ultra-low level trace of PCB congeners. PMID- 28885750 TI - Ultrathin Anionic Tungstophosphite Molecular Wire with Tunable Hydrophilicity and Catalytic Activity for Selective Epoxidation in Organic Media. AB - The extended 1D tungstophosphite molecular wire is obtained by connection of polyoxometalates. Self-assembly of a triangular PIII O3 unit with tungstate produces a hexagonal [HPIII W6 O21 ]2- building block, which then connects linearly to form the molecular wire. The surface property of the molecular wire is tuned to hydrophobic using organoammonium cations, and the surface-modified material disperses easily in organic media. The multifunctional material, which possesses nanostructure, hydrophobicity, and redox properties simultaneously, is suitable for olefin epoxidation in organic solvent. PMID- 28885751 TI - High Oxidation State Molybdenum N-Heterocyclic Carbene Alkylidyne Complexes: Synthesis, Mechanistic Studies, and Reactivity. AB - The first synthetic protocol to high oxidation state molybdenum(VI) N heterocyclic carbene (NHC) alkylidyne complexes (NHC=1,3-diisopropylimidazol-2 ylidene, 1,3-dimethyl-4,5-R2 -imidazol-2-ylidene, R2 =H, Cl, CN) is reported. Steric limitations of the NHCs and the benzylidyne are described. All novel complexes were characterized by single crystal X-ray diffraction and solution NMR techniques. It was shown that all complexes presented here show activity in the self-metathesis of 1-phenyl-1-propyne at room temperature. To identify mechanistic differences, an experimental sequence to detect dissociation of ligands was developed. Results reveal dissociation of less electron-donating NHCs in course of the reaction. Mechanistic and reactivity differences were attributed to electronic and steric effects through Tolman's electronic parameter and the percentage of buried volume. Furthermore, Mo-1 containing the 1,3 dimethylimidazol-2-ylidene ligand showed good activity in self-metathesis reactions of p-substituted 1-phenyl-1-propynes with electron-donating moieties at room temperature. PMID- 28885752 TI - Dual-echo ASL contributes to decrypting the link between functional connectivity and cerebral blow flow. AB - Arterial spin labeling (ASL) MRI with a dual-echo readout module (DE-ASL) enables noninvasive simultaneous acquisition of cerebral blood flow (CBF)-weighted images and blood oxygenation level dependent (BOLD) contrast. Up to date, resting-state functional connectivity (FC) studies based on CBF fluctuations have been very limited, while the BOLD is still the method most frequently used. The purposes of this technical report were (i) to assess the potentiality of the DE-ASL sequence for the quantification of resting-state FC and brain organization, with respect to the conventional BOLD (cvBOLD) and (ii) to investigate the relationship between a series of complex network measures and the CBF information. Thirteen volunteers were scanned on a 3 T scanner acquiring a pseudocontinuous multislice DE-ASL sequence, from which the concomitant BOLD (ccBOLD) simultaneously to the ASL can be extracted. In the proposed comparison, the brain FC and graph theoretical analysis were used for quantifying the connectivity strength between pairs of regions and for assessing the network model properties in all the sequences. The main finding was that the ccBOLD part of the DE-ASL sequence provided highly comparable connectivity results compared to cvBOLD. As expected, because of its different nature, ASL sequence showed different patterns of brain connectivity and graph indices compared to BOLD sequences. To conclude, the resting-state FC can be reliably detected using DE-ASL, simultaneously to CBF quantifications, whereas a single fMRI experiment precludes the quantitative measurement of BOLD signal changes. Hum Brain Mapp 38:5831-5844, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28885753 TI - Study of gas-phase reactions of NO2+ with aromatic compounds using proton transfer reaction time-of-flight mass spectrometry. AB - The study of ion chemistry involving the NO2+ is currently the focus of considerable fundamental interest and is relevant in diverse fields ranging from mechanistic organic chemistry to atmospheric chemistry. A very intense source of NO2+ was generated by injecting the products from the dielectric barrier discharge of a nitrogen and oxygen mixture upstream into the drift tube of a proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS) apparatus with H3 O+ as the reagent ion. The NO2+ intensity is controllable and related to the dielectric barrier discharge operation conditions and ratio of oxygen to nitrogen. The purity of NO2+ can reach more than 99% after optimization. Using NO2+ as the chemical reagent ion, the gas-phase reactions of NO2+ with 11 aromatic compounds were studied by PTR-TOF-MS. The reaction rate coefficients for these reactions were measured, and the product ions and their formation mechanisms were analyzed. All the samples reacted with NO2+ rapidly with reaction rate coefficients being close to the corresponding capture ones. In addition to electron transfer producing [M]+ , oxygen ion transfer forming [MO]+ , and 3-body association forming [M.NO2 ]+ , a new product ion [M-C]+ was also formed owing to the loss of C?O from [MO]+ .This work not only developed a new chemical reagent ion NO2+ based on PTR-MS but also provided significant interesting fundamental data on reactions involving aromatic compounds, which will probably broaden the applications of PTR-MS to measure these compounds in the atmosphere in real time. PMID- 28885754 TI - Deficits in voluntary pursuit and inhibition of risk taking in sensation seeking. AB - Sensation seeking has been associated with substance use and other risk-taking behaviors. The present functional magnetic resonance imaging (fMRI) study investigated the neural correlates underlying risk taking in sensation seeking. Twenty-eight high sensation seekers (HSS; 14 female and 14 male young adults) and 28 low sensation seekers (LSS; 14 female and 14 male young adults) performed an interactive, sequential gambling task that allowed for voluntary pursuit or inhibition of risk taking. Behaviorally, HSS versus LSS exhibited a stronger tendency toward risk taking. Comparison of the groups revealed that when taking risks, HSS relative to LSS exhibited reduced fMRI responses in brain areas involved in risk processing, such as the dorsomedial prefrontal cortex and the thalamus. Importantly, during the voluntary inhibition of risk taking, HSS relative to LSS showed greater fMRI responses in brain areas implicated in cognitive control (the bilateral anterior cingulate cortex) and negative emotion (the right anterior insula). These findings suggest that risk taking in sensation seeking may be driven by both a hypoactive neural system in the voluntary pursuit of risk taking and a hyperactive neural system in the voluntary inhibition of risk taking, thus providing implications for future prevention programs targeting sensation-seeking behaviors. Hum Brain Mapp 38:6019-6028, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28885755 TI - Effects of an individualised nutritional education and support programme on dietary habits, nutritional knowledge and nutritional status of older adults living alone. AB - AIMS AND OBJECTIVES: The effects of an individualised nutritional education and support programme on dietary habits, nutritional knowledge and nutritional status of 71 older adults living alone were examined. BACKGROUND: Although a regular dietary meal plan is recommended for improving nutritional status of older adults living alone, little research is done in this field in Korea. DESIGN: A pre- and post-test controlled quasi-experimental design was used at public health centres. METHODS: The intervention group participated in an intensive nutritional education and support programme once a week for 8 weeks with dietary menus provided by home visiting nurses/dieticians; control group received usual care. Dietary habits and nutritional knowledge were assessed using structured questionnaires; nutritional intake status was analysed using Computer Aided Nutritional Analysis Program 5.0. RESULTS: The mean age of participants was 77.6 years, and 81.7% of the participants were women. At 8 weeks, there were significant interactions of group by time for dietary habits, nutritional knowledge and selected nutritional status of protein, iron and vitamins of B2 and C. Changes over time in the mean score of dietary habits and nutritional knowledge were significantly improved in the intervention group compared to the control group. The percentages of normal nutrition intake of protein, iron and vitamins A and C in the intervention group were significantly higher than the control group at 8 weeks. CONCLUSIONS: Nutritional education and support programme positively impacted dietary habits, nutritional knowledge and selected nutritional status in older adults living alone, and we highlight the need for community-based nutritional education and counselling programmes. RELEVANCE TO CLINICAL PRACTICE: Older adults living alone in a community have relatively poor nutritional status and thus require tailored nutritional intervention according to objective nutritional analysis. It is necessary to link visiting nurses with dieticians in the community to manage effective nutritional programme continuously. PMID- 28885756 TI - Synthesis of Functionalized Quinolines through a Reaction of Amides and Alkynes Promoted by Triflic Anhydride/Pyridine. AB - A concise, novel and flexible metal-free single step to synthesize functionalized quinolines is reported. Triflic anhydride-mediated (Tf2 O) activation of amides is discussed in the presence of pyridine to offer strong electrophiles, thereby showcasing excellent productivity, high regio- and chemoselectivity, and widely tolerable substrates. This approach provides a straightforward and efficient way to construct azaheterocycle structures. PMID- 28885757 TI - Frequency-specific neuromodulation of local and distant connectivity in aging and episodic memory function. AB - A growing literature has focused on the brain's ability to augment processing in local regions by recruiting distant communities of neurons in response to neural decline or insult. In particular, both younger and older adult populations recruit bilateral prefrontal cortex (PFC) as a means of compensating for increasing neural effort to maintain successful cognitive function. However, it remains unclear how local changes in neural activity affect the recruitment of this adaptive mechanism. To address this problem, we combined graph theoretical measures from functional MRI with diffusion weighted imaging and repetitive transcranial magnetic stimulation (rTMS) to resolve a central hypothesis: how do aged brains flexibly adapt to local changes in cortical activity? Specifically, we applied neuromodulation to increase or decrease local activity in a cortical region supporting successful memory encoding (left dorsolateral PFC or DLPFC) using 5 or 1 Hz rTMS, respectively. We then assessed a region's local within module degree, or the distributed between-module degree (BMD) between distant cortical communities. We predicted that (1) local stimulation-related deficits may be counteracted by boosting BMD between bilateral PFC, and that this effect should be (2) positively correlated with structural connectivity. Both predictions were confirmed; 5 Hz rTMS increased local success-related activity and local increases in PFC connectivity, while 1 Hz rTMS decreases local activity and triggered a more distributed pattern of bilateral PFC connectivity to compensate for this local inhibitory effect. These results provide an integrated, causal explanation for the network interactions associated with successful memory encoding in older adults. Hum Brain Mapp 38:5987-6004, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28885758 TI - Bronsted Base-Mediated Regio- and Stereoselective trans-Silaboration of Propargylamides: Access to 1,2-Vinylborasilanes. AB - A facile method for the preparation of beta-boryl-alpha-silyl aryl acrylamides using phenyllithium, dimethylphenylsilylpinacolborane, and propargylamides is reported. A key feature of this transition metal-free reaction is the Bronsted base deprotonation of aryl secondary propargylamide to produce a Lewis base that activates the B-Si bond, which is followed by a sequential intramolecular alpha silylation-trans-beta-borylation. The reaction proceeds in complete regio- and stereoselectivity. A wide variety of N- and aryl-substituted propargylamides afford trans-1,2-vinylborasilanes in high yield. The vicinal borasilane products undergo a variety of subsequent chemoselective transformations. PMID- 28885759 TI - Host-Guest Complexes of Cyclodextrins and Nanodiamonds as a Strong Non-Covalent Binding Motif for Self-Assembled Nanomaterials. AB - We report the inclusion of carboxy- and amine-substituted molecular nanodiamonds (NDs) adamantane, diamantane, and triamantane by beta-cyclodextrin and gamma cyclodextrin (beta-CD and gamma-CD), which have particularly well-suited hydrophobicity and symmetry for an optimal fit of the host and guest molecules. We studied the host-guest interactions in detail and generally observed 1:1 association of the NDs with the larger gamma-CD cavity, but observed 1:2 association for the largest ND in the series (triamantane) with beta-CD. We found higher binding affinities for carboxy-substituted NDs than for amine-substituted NDs. Additionally, cyclodextrin vesicles (CDVs) were decorated with d-mannose by using adamantane, diamantane, and triamantane as non-covalent anchors, and the resulting vesicles were compared with the lectin concanavalin A in agglutination experiments. Agglutination was directly correlated to the host-guest association: adamantane showed lower agglutination than di- or triamantane with beta-CDV and almost no agglutination with gamma-CDV, whereas high agglutination was observed for di- and triamantane with gamma-CDV. PMID- 28885760 TI - Extending Long-lived Charge Separation Between Donor and Acceptor Blocks in Novel Copolymer Architectures Featuring a Sensitizer Core. AB - A bifunctional RuII photosensitizer unit was decorated with one n- and one p-type polymer chain to form precisely controlled hierarchical copolymer-type architectures for light-induced charge separation. The applied modular chemistry on-the-complex strategy benefits from separately prepared building blocks and their orthogonal linkage in the two final assembly steps. Upon visible light absorption, electron transfer is initiated between the conjugated poly(3,6 carbazole) chain and the styrenic poly(naphthalene diimide) segments. Steady state and time-resolved spectroscopy show complete charge separation within a few nanoseconds (>95 % efficiency) persisting several tens of microseconds. The recombination is significantly reduced in comparison to low-molecular model systems or to non-conjugated congeners, reflecting the higher charge mobility in conjugated polymers. In summary, the modularity of the presented approach is expected to serve as a versatile platform to tailor the interface between the charge transport domains in a systematic fashion. PMID- 28885761 TI - X-ray Structure Analysis of N-Containing Nucleophilic Compounds by the Crystalline Sponge Method. AB - Crystalline sponges (CS) used under a set of standard conditions have often failed to give viable N-containing nucleophilic compounds. Despite the high affinity of these nucleophiles to the binding sites of the CS, N-containing compounds considerably harm the coordination framework of the CS during the guest soaking step. Herein, it is disclosed that these compounds are efficiently absorbed into the CS, without harming the host, under mild conditions (<4 degrees C, <2 MUg) that normally do not work for common organic guests. Moreover, the use of ZnCl2 as the metal component of CS significantly improved the tolerance and robustness of the host framework toward N-containing compounds. Out of 22 drug (or drug-like) N-containing compounds chosen from the WHO model list of essential medicines, we succeeded in analyzing 17 analytes with the modified protocols and/or by using the ZnCl2 -noded CS. This demonstrates that the CS method is now a practical tool for drug-discovery research in pharmaceutical industries. PMID- 28885762 TI - Transition-Metal-Free Ring-Opening Silylation of Indoles and Benzofurans with (Diphenyl-tert-butylsilyl)lithium. AB - A practical method is presented for ring opening various indoles and benzofurans with concomitant stereoselective silylation using readily generated (diphenyl tert-butylsilyl)lithium to afford ortho-beta-silylvinylanilines or -phenols. Dearomatization of the heteroarene core proceeds in the absence of any transition metal catalyst through addition of a silyl anion and a subsequent stereoselective beta-elimination. DFT calculations provide insight into the mechanism. Functionalizing C-X bond cleavage of heteroarenes is rare and generally requires transition-metal catalysts. PMID- 28885763 TI - The Maastricht Frailty Screening Tool for Hospitalised Patients (MFST-HP) to Identify Non-Frail Patients. AB - BACKGROUND: The Maastricht frailty screening tool for hospitalised patients (MFST HP) is a frailty screening tool that is fully integrated in the nursing assessment at admission. This study aims to determine the predictive value of the MFST-HP for the health outcomes length of hospital stay, discharge destination, readmission and mortality. METHODS: Data of 2691 hospitalised patients (70+), admitted between 01-01-2013 and 31-12-2013, were included in the study. The predictive value of the MFST-HP was analysed by means of receiver operating characteristics curves. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for different MFST-HP cut-off scores were examined. RESULTS: Mean age of the population was 78.9 years (SD 6.4) and their average length of stay was 10.2 days (SD 9.7). Nearly 75.0% of the patients were discharged to their home and around. Approximately 25% of the patients were readmitted within 120 days. Mortality rates were 4.3% and 9.5% (within 30 or 120 days postdischarge, respectively). The area under the curve was moderate and varied from 0.50 to 0.69 for the different outcomes. As a result of high values on negative predictive value (between 73.5% and 96.7%) the MFST-HP is able to rule out a large proportion of non-frail patients. In this study 84% of the patients had a MFST-HP score of >= 6, suggested as most favourable cut off. CONCLUSIONS: The MFST-HP seems to operate more strongly as a non-frailty indicator than as a frailty indicator and may in this respect help professionals to decide upon subsequent care. The MFST-HP is able to rule out 84% of the non frail population in this study. The remaining 16% need to be assessed by means of a comprehensive geriatric assessment or rapid geriatric assessment, to gain more insight in the level of vulnerability in the frail-group. PMID- 28885764 TI - Porphyrin Derivatives Inhibit the Interaction between Receptor Activator of NF kappaB and Its Ligand. AB - Receptor activator of NF-kappaB (RANK), a member of the TNF-receptor superfamily, plays an important role in bone resorption and stimulates immune and epithelial cell activation. Denosumab, a human monoclonal antibody that blocks the RANK ligand (RANKL), is approved for the treatment of osteoporosis and bone metastasis. However, a small molecule that inhibits the RANK-RANKL interaction would be beneficial to decrease cost and to facilitate treatments with orally available therapeutic agents. Herein we report the discovery of the first nonpeptidic inhibitors of RANK-RANKL interactions. In screening a chemical library by competitive ELISA, the porphyrin verteporfin was identified as a hit. Derivatives were screened, and the chlorin-macrocycle-containing pheophorbide A and purpurin 18 were found to bind recombinant RANKL, to inhibit RANK-RANKL interactions in the ELISA, and to suppress the RANKL-dependent activation of model cells and the differentiation of RANK-expressing precursors into osteoclasts. This discovery of a family of small molecules that inhibit RANK activation presents an initial basis for further development of nonpeptidic therapeutic agents targeting the interaction between RANK and RANKL. PMID- 28885765 TI - Reducing hospital-acquired pressure ulcers using bundle methodology in pediatric and neonatal patients receiving extracorporeal membrane oxygenation therapy: An integrative review and call to action. AB - PURPOSE: This review focuses on identifying (1) evidence of the effectiveness of care bundle methodology to reduce hospital-acquired pressure ulcers (HAPUs) in pediatric and neonatal patients receiving extracorporeal membrane oxygenation (ECMO) therapy and (2) barriers to implementing HAPU care bundles in this at-risk population. DESIGN AND METHODS: An integrative review was conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A search of the scientific literature was performed. Studies included were published between January 2011 and February 2016. A total of seven articles met inclusion criteria. Data were extracted from each published article and analyzed to identify common themes, specifically bundle methodology and barriers to implementing HAPU bundles, in this population. RESULTS: There is limited research on effectiveness of care bundle methodology in reducing HAPUs in children, and no research specific to its effectiveness in pediatric or neonatal ECMO patients. No research was identified studying barriers to implementation of HAPU care bundles in this population. PRACTICE IMPLICATIONS: Nurses are well poised to test innovative strategies to prevent HAPUs. Nurses should consider implementing and testing bundle methodology to reduce HAPU in this at-risk population, and conduct research to identify any barriers to implementing this strategy. There is literature to support the use of nurses as unit-based skin care champions to facilitate teamwork and reliable use of the bundle, both critical components to the success of bundle methodology. PMID- 28885766 TI - Computer-assisted cytologic diagnosis in pancreatic FNA: An application of neural networks to image analysis. AB - BACKGROUND: Fine-needle aspiration (FNA) biopsy is an accurate method for the diagnosis of solid pancreatic masses. However, a significant number of cases still pose a diagnostic challenge. The authors have attempted to design a computer model to aid in the diagnosis of these biopsies. METHODS: Images were captured of cell clusters on ThinPrep slides from 75 pancreatic FNA cases (20 malignant, 24 benign, and 31 atypical). A K-means clustering algorithm was used to segment the cell clusters into separable regions of interest before extracting features similar to those used for cytomorphologic assessment. A multilayer perceptron neural network (MNN) was trained and then tested for its ability to distinguish benign from malignant cases. RESULTS: A total of 277 images of cell clusters were obtained. K-means clustering identified 68,301 possible regions of interest overall. Features such as contour, perimeter, and area were found to be significantly different between malignant and benign images (P <.05). The MNN was 100% accurate for benign and malignant categories. The model's predictions from the atypical data set were 77% accurate. CONCLUSIONS: The results of the current study demonstrate that computer models can be used successfully to distinguish benign from malignant pancreatic cytology. The fact that the model can categorize atypical cases into benign or malignant with 77% accuracy highlights the great potential of this technology. Although further study is warranted to validate its clinical applications in pancreatic and perhaps other areas of cytology as well, the potential for improved patient outcomes using MNN for image analysis in pathology is significant. Cancer Cytopathol 2017;125:926-33. (c) 2017 American Cancer Society. PMID- 28885767 TI - Creating Oxidase-Peroxidase Fusion Enzymes as a Toolbox for Cascade Reactions. AB - A set of bifunctional oxidase-peroxidases has been prepared by fusing four distinct oxidases to a peroxidase. Although such fusion enzymes have not been observed in nature, they could be expressed and purified in good yields. Characterization revealed that the artificial enzymes retained the capability to bind the two required cofactors and were catalytically active as oxidase and peroxidase. Peroxidase fusions of alditol oxidase and chitooligosaccharide oxidase could be used for the selective detection of xylitol and cellobiose with a detection limit in the low-micromolar range. The peroxidase fusions of eugenol oxidase and 5-hydroxymethylfurfural oxidase could be used for dioxygen-driven, one-pot, two-step cascade reactions to convert vanillyl alcohol into divanillin and eugenol into lignin oligomers. The designed oxidase-peroxidase fusions represent attractive biocatalysts that allow efficient biocatalytic cascade oxidations that only require molecular oxygen as an oxidant. PMID- 28885768 TI - Characterization of the novel HLA-DRB1*13:241 allele by sequencing-based typing. AB - HLA-DRB1*13:241 differs from HLA-DRB1*13:02:01 by one nucleotide substitution at position 335. PMID- 28885769 TI - Water Splitting via Decoupled Photocatalytic Water Oxidation and Electrochemical Proton Reduction Mediated by Electron-Coupled-Proton Buffer. AB - Water splitting mediated by electron-coupled-proton buffer (ECPB) provides an efficient way to avoid gas mixing by separating oxygen evolution from hydrogen evolution in space and time. Though electrochemical and photoelectrochemcial water oxidation have been incorporated in such a two-step water splitting system, alternative ways to reduce the cost and energy input for decoupling two half reactions are desired. Herein, we show the feasibility of photocatalytic oxygen evolution in a powder system with BiVO4 as a photocatalyst and polyoxometalate H3 PMo12 O40 as an electron and proton acceptor. The resulting reaction mixture was allowed to be directly used for the subsequent hydrogen evolution with the reduced H3 PMo12 O40 as electron and proton donors. Our system exhibits excellent stability in repeated oxygen and hydrogen evolution, which brings considerable convenience to decoupled water splitting. PMID- 28885770 TI - Room-temperature Synthesis of Amorphous Molybdenum Oxide Nanodots with Tunable Localized Surface Plasmon Resonances. AB - Two-dimensional (2D) semiconductors have recently emerged as a remarkable class of plasmonic alternative to conventional noble metals. However, tuning of their plasmonic resonances towards different wavelengths in the visible-light region with physical or chemical methods still remains challenging. In this work, we design a simple room-temperature chemical reaction route to synthesize amorphous molybdenum oxide (MoO3-x ) nanodots that exhibit strong localized surface plasmon resonances (LSPR) in the visible and near-infrared region. Moreover, tunable plasmon resonances can be achieved in a wide range with the changing surrounding solvent, and accordingly the photoelectrocatalytic activity can be optimized with the varying LSPR peaks. This work boosts the light-matter interaction at the nanoscale and could enable photodetectors, sensors, and photovoltaic devices in the future. PMID- 28885771 TI - Impact of donor age in donation after circulatory death liver transplantation: Is the cutoff "60" still of relevance? AB - Advanced donor age has been identified as a risk factor when combined with donor warm ischemia time (WIT), eg, in donation after circulatory death (DCD). In several countries, DCD livers older than 60 years are not considered suitable due to concerns related to poor graft function and development of ischemic cholangiopathy. In this study, we evaluate outcomes after DCD liver transplantation using grafts from donors older than 60 years. We analyzed outcomes after DCD liver transplantation (n = 315), comparing donors > 60 years (n = 93) and donors <= 60 years (n = 222) from our center between 2005 and 2015. End points included graft function and complications and patient and graft survival. Multivariate risk analysis was performed to define further key factors that predicted inferior outcome. Donor age at the cutoff 60 years failed to stratify patient and graft survival. The rate of vascular, biliary, and overall complications was comparably low in both cohorts, and the median comprehensive complication index was 42.7 points, independent from the donor age. Second, donor body mass index (BMI) above a threshold of 25 kg/m2 significantly impacted on graft and patient survival at any donor age, whereas donor WIT and cold ischemia times were not predictive for graft loss. In conclusion, older DCD donors can be successfully used for liver transplantation with good longterm outcomes when further risk factors are limited. Additional risk is transmitted by an increased donor BMI regardless of donor age. Liver Transplantation 24 352-362 2018 AASLD. PMID- 28885773 TI - Far-UV-Excited Luminescence of Nitrogen-Vacancy Centers: Evidence for Diamonds in Space. AB - The nitrogen-vacancy (NV) centers in diamond are among the most thoroughly investigated defects in solid-state matter; however, our understanding of their properties upon far-UV excitation of the host matrix is limited. This knowledge is crucial for the identification of NV as the carrier of extended red emission (ERE) bands detected in a wide range of astrophysical environments. Herein, we report a study on the photoluminescence spectra of NV-containing nanodiamonds excited with synchrotron radiation over the wavelength range of 125-350 nm. We observed, for the first time, an emission at 520-850 nm with a quantum yield greater than 20 %. Our results share multiple similarities with the ERE phenomena, suggesting that nanodiamonds are a common component of dust in space. PMID- 28885772 TI - Overt hepatic encephalopathy impairs learning on the EncephalApp stroop which is reversible after liver transplantation. AB - After an initial exposure, patients can develop test-taking/learning strategies called the "test sophistication effect." Patients with cirrhosis with prior overt hepatic encephalopathy (OHE) could have persistent learning impairments. The aim was to define learning/test sophistication on EncephalApp (downloadable application) in OHE patients compared with patients without prior overt hepatic encephalopathy (no-OHE) patients and controls cross-sectionally and longitudinally. The EncephalApp Stroop App consists of 2 sections: the easier "Off" run assesses psychomotor speed while the difficult "On" run assesses cognitive flexibility. For the cross-sectional analysis, outpatients with cirrhosis with/without controlled OHE and healthy controls underwent EncephalApp testing, which requires 5 Off and 5 On runs. We studied the difference in time required between completing trial 1 compared with trial 5 (delta 1-5) in both the On and Off runs in controls, all patients with cirrhosis, and between prior OHE/no-OHE patients with cirrhosis. For the longitudinal analyses, 2 groups of patients with cirrhosis were studied; 1 was administered the EncephalApp >= 2 weeks apart, and the second was administered before and 6 months after liver transplantation. The study included 89 controls and 230 patients with cirrhosis (85 prior OHE; Model for End-Stage Liver Disease, 11) with similar age (64 versus 61 years; P = 0.92). Patients with cirrhosis had impaired EncephalApp total times and impaired learning on the On runs compared with controls. OHE patients had worse EncephalApp times and learning with the On runs compared with no-OHE patients, which persisted in the longitudinal cohort. No differences in learning were seen in the Off runs. After transplant, there was restoration of learning capability with the On runs in the OHE patients. In conclusion, cognitive flexibility tested by the EncephalApp On runs improves over time in healthy controls and no-OHE but not prior OHE. Psychomotor speed remains similar over time. The learning impairment manifested by patients with cirrhosis with OHE is restored after transplant. Liver Transplantation 23 1396-1403 2017 AASLD. PMID- 28885774 TI - Small-for-size grafts increase recurrence of hepatocellular carcinoma in liver transplantation beyond milan criteria. AB - Living donor liver transplantation (LDLT) has been reported to have high rates of hepatocellular carcinoma (HCC) recurrence compared with deceased donor liver transplantation (DDLT). This has been assumed to be due to the frequent use of small-for-size grafts (SFSGs) in LDLT rather than DDLT, but the relationship between graft size and prognosis remains controversial. This study aimed to clarify the effect of SFSGs on the oncologic outcomes of patients with HCC who underwent LDLT. Between January 2005 and December 2015, 597 consecutive patients underwent LDLT. Among these patients, those with HCC who underwent LDLT were randomly matched at a 1:3 ratio (graft-to-recipient body weight ratio [GRWR] < 0.8%:GRWR > 0.8%) according to propensity score. HCC recurrence and patient survival were analyzed using the Kaplan-Meier method and log-rank test. In addition, stratified subgroup analysis based on the Milan criteria was performed. SFSG was defined as a GRWR < 0.8%. Using propensity score matching, 82 patients with GRWR < 0.8% and 246 patients with GRWR >= 0.8% were selected. For patients with HCC within the Milan criteria, no significant difference of HCC recurrence (P = 0.82) and patient survival (P = 0.95) was found based on GRWR. However, for patients with HCC beyond the Milan criteria, 1-, 3-, and 5-year recurrence-free survival rates were 52.4%, 49.3%, and 49.3%, respectively, for patients with GRWR < 0.8%, and 76.5%, 68.3%, and 64.3%, respectively, for patients with GRWR >= 0.8% (P = 0.049). The former group exhibited poor patient survival rates (P = 0.047). In conclusion, for patients with HCC within the Milan criteria, no significant difference in oncologic outcomes was found based on liver graft size. However, among the patients with HCC beyond the Milan criteria, SFSG recipients showed poor oncologic outcomes. Because extended criteria are frequently used in LDLT for HCC, a recipient's prognosis can be improved if a liver graft of appropriate size is carefully selected during donor selection. Liver Transplantation 24 35-43 2018 AASLD. PMID- 28885775 TI - In vitro metabolism of the synthetic cannabinoids CUMYL-PINACA, 5F-CUMYL-PINACA, CUMYL-4CN-BINACA, 5F-CUMYL-P7AICA and CUMYL-4CN-B7AICA. AB - Synthetic cannabinoid consumption trends underlie fast changes and provide several challenges to clinical and forensic toxicologists. Due to their extensive metabolism, parent compounds are hardly detectable in urine. Therefore, knowledge of the metabolism of synthetic cannabinoids is essential to allow their detection in biological matrices. The aim of the present study was the elucidation of the metabolism of CUMYL-PINACA, 5F-CUMYL-PINACA, CUMYL-4CN-BINACA, 5F-CUMYL-P7AICA, and CUMYL-4CN-B7AICA with a focus on the analytical and interpretational differentiation of the compounds. Microsomal assay mixtures containing co substrates, 10 MUg/mL substrate and 1 mg/mL pooled human liver microsomes were incubated for 1 hour at 37 degrees C. Investigation of the metabolites was performed on a Thermo Fischer Ultimate 3000 UHPLC system coupled to a Sciex 6600 QTOF System. Hydroxylation was observed to be a major biotransformation step for all 5 cumyl-derivatives, followed by dihydroxylation. For CUMYL-PINACA, a major metabolic pathway was hydroxylation at the pentyl moiety, followed by a second hydroxylation at that pentyl moiety or oxidation to ketone. A major metabolic pathway for the compounds containing a nitrile function was nitrile hydrolysis followed by carboxylation and further hydroxylation. For the fluorinated compounds, oxidative defluorination and carboxylation were abundant metabolic steps. Some of the metabolic transformations lead to structurally identical metabolites, which should not be used as marker for the intake of a particular parent compound. In addition, several constitutional isomers containing either an indazole or azaindole core structure were detected, which should be differentiated by retention time rather than by their mass spectra alone. PMID- 28885776 TI - Monitoring of transferrin isoforms in biological samples by capillary electrophoresis. AB - Work dealing with the monitoring of transferrin isoforms in human serum and other body fluids by capillary electrophoresis is reviewed. It comprises capillary zone electrophoresis and capillary isoelectric focusing efforts that led to the exploration and use of assays for the determination of carbohydrate-deficient transferrin as a marker for excessive alcohol intake, genetic variants of transferrin, congenital disorders of glycosylation and beta-2-transferrin, which is a marker for cerebrospinal fluid leakage. This paper provides insight into the development, specifications, strengths, weaknesses, and routine use of the currently known capillary electrophoresis based assays suitable to detect transferrin isoforms in body fluids. The achievements reached so far indicate that capillary zone electrophoresis is an attractive technology to monitor the molecular forms of transferrin in biological specimens as the assays do not require an elaborate sample pretreatment and thus can be fully automated for high throughput analyses on multicapillary instruments. Assays based on capillary isoelectric focusing are less attractive. They require immunoextraction of transferrin from the biological matrix and mobilization after focusing if instrumentation with a whole-column imaging detector is not available. Interactions of the carrier ampholytes with the iron of transferrin may prevent iron saturation and thus provide more complicated isoform patterns. PMID- 28885777 TI - Field-Effect Biosensors for On-Site Detection: Recent Advances and Promising Targets. AB - There is an explosive interest in the immediate and cost-effective analysis of field-collected biological samples, as many advanced biodetection tools are highly sensitive, yet immobile. On-site biosensors are portable and convenient sensors that provide detection results at the point of care. They are designed to secure precision in highly ionic and heterogeneous solutions with minimal hardware. Among various methods that are capable of such analysis, field-effect biosensors are promising candidates due to their unique sensitivity, manufacturing scalability, and integrability with computational circuitry. Recent developments in nanotechnological surface modification show promising results in sensing from blood, serum, and urine. This report gives a particular emphasis on the on-site efficacy of recently published field-effect biosensors, specifically, detection limits in physiological solutions, response times, and scalability. The survey of the properties and existing detection methods of four promising biotargets, exosomes, bacteria, viruses, and metabolites, aims at providing a roadmap for future field-effect and other on-site biosensors. PMID- 28885779 TI - The global challenge to improve the sexual and reproductive health of women affected by FGM/C. PMID- 28885778 TI - Histopathologic follow-up and HPV test results with HSIL Papanicolaou test results in China's largest academic women's hospital. AB - BACKGROUND: Cervical cancer screening in China is largely limited to occasional opportunistic screening in urban centers. The current study reports histopathologic follow-up and human papillomavirus (HPV) results in women with high-grade squamous intraepithelial lesion (HSIL) Papanicolaou (Pap) tests reported at the largest academic women's hospital in China and compares these findings with those of published Western studies among frequently screened women. METHODS: A retrospective cohort study documented HSIL Pap tests, patient age, HPV results, and histopathologic follow-up from 2011 through 2015 in the Obstetrics and Gynecology Hospital of Fudan University (OGHFU) in Shanghai, China. Of 886,122 Pap test results, 4269 (0.48%) reported HSIL. Histopathologic follow-up was available for 2351 cases and HPV results were available for 2092 cases. RESULTS: HSIL reporting rates increased with patient age from 0.16% at age <30 years to 0.58% at ages 30 to 49 years and 0.75% at age >=50 years. HSIL rates were found to be significantly higher for women tested using liquid-based cytology (0.52%-0.55%) compared with conventional Pap tests (0.19%). Among 2351 cases with histopathologic follow-up, cervical intraepithelial neoplasia of type 2/3 was diagnosed in 74.1% of cases and squamous cell carcinoma in 14.2% of cases. Squamous cell carcinoma was diagnosed in 22.8% of patients aged >=50 years who underwent biopsy. HPV-positive HSIL rates using 3 different HPV tests ranged from 88.1% to 93.9%. CONCLUSIONS: At OGHFU, the finding of an increase in HSIL cytology rates with increasing patient age contrasted with a finding of decreasing HSIL rates with increasing age previously reported in regularly screened cotested patients in the United States. The increasing HSIL rates with older age and high rates of cervical cancer diagnoses noted at OGHFU appear to be best explained by the absence of consistent intraepithelial lesion ablation achievable with frequent screening and treatment. Cancer Cytopathol 2017;125:947 53. (c) 2017 American Cancer Society. PMID- 28885780 TI - Vacancy-Rich Monolayer BiO2-x as a Highly Efficient UV, Visible, and Near Infrared Responsive Photocatalyst. AB - Vacancy-rich layered materials with good electron-transfer property are of great interest. Herein, a full-spectrum responsive vacancy-rich monolayer BiO2-x has been synthesized. The increased density of states at the conduction band (CB) minimum in the monolayer BiO2-x is responsible for the enhanced photon response and photo-absorption, which were confirmed by UV/Vis-NIR diffuse reflectance spectra (DRS) and photocurrent measurements. Compared to bulk BiO2-x , monolayer BiO2-x has exhibited enhanced photocatalytic performance for rhodamine B and phenol removal under UV, visible, and near-infrared light (NIR) irradiation, which can be attributed to the vacancy VBi-O ''' as confirmed by the positron annihilation spectra. The presence of VBi-O ''' defects in monolayer BiO2-x promoted the separation of electrons and holes. This finding provides an atomic level understanding for developing highly efficient UV, visible, and NIR light responsive photocatalysts. PMID- 28885781 TI - Thermosensitive Hydrogel Containing Doxycycline Exerts Inhibitory Effects on Abdominal Aortic Aneurysm Induced By Pancreatic Elastase in Mice. AB - Doxycycline (DOX) is reported to exert therapeutic effects against abdominal aortic aneurysm (AAA), a severe degenerative disease. In this study, a DOX hydrogel formulation of DOX/PECTgel is studied, and its phase transition behavior and in vitro release profiles are explored. In addition, the anti-AAA effects and bioavailability of DOX/PECTgel are evaluated in an elastase induced AAA mouse model. The results show that the phase transition temperature of 30% poly(e caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) solution is above 34 degrees C. In vitro release profiles of DOX/PECTgel indicate a fast release of DOX at the first two days, followed by a slow and sustained release for 14 d. In vivo single-dose single subcutaneous injection of DOX/PECTgel containing 8.4 or 4.2 mg mL-1 DOX presents comparatively preventive effects on AAA, compared to intraperitoneal injections of DOX alone at a dose of 15 mg kg-1 for seven injections, while DOX bioavailability of the DOX/PECTgel treated groups is 1.39 times or 1.19 times of the DOX alone treated group, respectively. PMID- 28885782 TI - Evaluation of Pulse-Width of Spinal Nerve Stimulation in a Rat Model of Bladder Micturition Reflex. AB - OBJECTIVES: The spinal nerve stimulation (SNS) evoked motor threshold (Tmot ) response across different pulse-widths (PWs) was first explored and a subset of selected stimulation PWs were further assessed with respect to bladder reflex contraction (BRC). MATERIALS AND METHODS: In anesthetized female rats, wire electrodes were placed under each of the L6 spinal nerves to produce bilateral SNS. The relationship of Tmot response with PW was analyzed using a monoexponential nonlinear regression. A cannula was placed into the bladder via the urethra to ensure an isovolumetric bladder. Saline infusion induced BRC. RESULTS: The chronaxie of the Tmot -PW curve was 0.04 ms. The stimulation charges/energies (current * PW) associated with shorter PWs of 0.02, 0.03, and 0.06 ms were significantly lower than those with longer PW (e.g., >0.15 ms). SNS (Tmot , 10 Hz) at selected PWs from 0.03 to 0.21 ms inhibited the frequency of BRCs. There were no significantly different attenuations among tested PWs. SNS of PWs of 0.03, 0.06, and 0.09 ms decreased bladder contraction frequency from 103 +/- 3%, 100 +/- 4%, and 103 +/- 4% of controls, to 52 +/- 16% (n = 8, p = 0.02, paired t-test), 56 +/- 15% (n = 11, p = 0.02) and 40 +/- 19% (n = 10, p = 0.01), respectively. CONCLUSIONS: Effective PWs to produce bladder inhibitory effects in the rat appear much shorter than 0.21 ms typically used with sacral neuromodulation in practice. Potential battery savings manifested by shorter PW while maintaining equivalent efficacy would provide more efficient therapy delivery and increased longevity of the stimulator. PMID- 28885783 TI - Uterine balloon tamponade for the management of postpartum haemorrhage: a challenge and an opportunity for better evidence. PMID- 28885784 TI - Changes in Tonsil B Cell Phenotypes and EBV Receptor Expression in Children Under 5-Years-Old. AB - BACKGROUND: Palatine tonsils are principally B cell organs that are the initial line of defense against many oral pathogens, as well as the site of infection for others. While the size of palatine tonsils changes greatly in the first five years of life, the cellular changes during this period are not well studied. Epstein Barr virus (EBV) is a common orally transmitted virus that infects tonsillar B cells. Naive B cells are thought to be the target of primary infection with EBV in vivo, suggesting that they are targeted by the virus. EBV enters B cells through CD21, but studies of older children and adults have not shown differences in surface CD21 between naive B cells and other tonsil B cell populations. METHODS: In this study, we used an 11-color flow cytometry panel to detail the changes in B cell subpopulations in human tonsils over the first five years of life from 33 healthy US children. RESULTS: We provide reference ranges for tonsil B cell subpopulations over this age range. We show that the frequency of naive tonsil B cells decreases over the early years of life, and that naive B cells expressed higher surface levels of CD21 relative to other tonsil B cell populations. CONCLUSIONS: We show that young children have a higher frequency of naive tonsil B cells, and importantly that these cells express increased surface EBV receptor, suggesting that young children have a larger pool of cells that can be infected by the virus. (c) 2017 International Clinical Cytometry Society. PMID- 28885786 TI - 3D Miniaturization of Human Organs for Drug Discovery. AB - "Engineered human organs" hold promises for predicting the effectiveness and accuracy of drug responses while reducing cost, time, and failure rates in clinical trials. Multiorgan human models utilize many aspects of currently available technologies including self-organized spherical 3D human organoids, microfabricated 3D human organ chips, and 3D bioprinted human organ constructs to mimic key structural and functional properties of human organs. They enable precise control of multicellular activities, extracellular matrix (ECM) compositions, spatial distributions of cells, architectural organizations of ECM, and environmental cues. Thus, engineered human organs can provide the microstructures and biological functions of target organs and advantageously substitute multiscaled drug-testing platforms including the current in vitro molecular assays, cell platforms, and in vivo models. This review provides an overview of advanced innovative designs based on the three main technologies used for organ construction leading to single and multiorgan systems useable for drug development. Current technological challenges and future perspectives are also discussed. PMID- 28885785 TI - Homogeneous Water Oxidation by Half-Sandwich Iridium(III) N-Heterocyclic Carbene Complexes with Pendant Hydroxy and Amino Groups. AB - Herein, we report three IrIII Cp* complexes with hydroxy- or amino-functionalized N-heterocyclic carbene (NHC) ligands that catalyze efficient water oxidation induced by addition of ceric ammonium nitrate (CAN). The pendant hydroxy or amino groups are very important for activity, and the complexes with heteroatom functionalized NHC ligands show up to 15 times higher rates of oxygen evolution in CAN-induced water oxidation than a reference IrIII Cp* complex without heteroatom functionalization. The formation of molecular high-valent Ir intermediates that are presumably involved in the rate-determining step for water oxidation is established by UV/Vis spectroscopy and ESI-MS under turnover conditions. The hydroxy groups on the NHC ligands, as well as chloride ligands on the iridium center are proposed to structurally stabilize the high-valent species, and thereby improve the catalytic activity. The IrIII complex with a hydroxy-functionalized NHC shows the highest catalytic activity with a TON of 2500 obtained in 3 h and with >90 % yield relative to the amount of oxidant used. PMID- 28885787 TI - An Inexpensive, Point-of-Care Urine Test for Bladder Cancer in Patients Undergoing Hematuria Evaluation. AB - Although hematuria (blood in urine) is the most common symptom of bladder cancer, 70-98% of hematuria cases are benign. These hematuria patients unnecessarily undergo costly, invasive, and expensive evaluation for bladder cancer. Therefore, there remains a need for noninvasive office-based tests that can rapidly and reliably rule out bladder cancer in patients undergoing hematuria evaluation. Herein, a clinical assay for matrix metalloproteinases ("Ammps") is presented, which generates a visual signal based on the collagenase activity (in urine of patients) on the Ammps substrates. Ammps substrates are generated by crosslinking gelatin with Fe(II) chelated alginate nanoparticles, which precipitate in urine samples. The cleavage of gelatin-conjugated alginate (Fe(II)) nanoparticles by collagenases generates free-floating alginate (Fe(II)) nanoparticles that participate in Fenton's reaction to generate a visual signal. In a pilot study of 88 patients, Ammps had 100% sensitivity, 85% specificity, and a negative predictive value (NPV) of 100% for diagnosing bladder cancer. This high NPV can be useful in ruling out bladder cancer in patients referred for hematuria evaluation. PMID- 28885788 TI - 2016 ACS Governors Survey: Issues affecting surgical practice. PMID- 28885789 TI - Postoperative data reporting for global services. PMID- 28885790 TI - Coding for dialysis circuit interventions. PMID- 28885791 TI - RS3 -the Montana Rural Surgery Support System-is a model forsurgical care in rural CAHs. PMID- 28885792 TI - Training and networking opportunities for medical studentsat the ACS Clinical Congress. PMID- 28885794 TI - Politics and the president's gallbladder. PMID- 28885793 TI - Gastrectomy for cancer: What are the benefits of a minimally invasive approach? PMID- 28885795 TI - National Doctors' Day initiative highlights gratitude for mentors. PMID- 28885796 TI - Joint Commission releases data on challenging requirementsfor OBS practices. PMID- 28885797 TI - Using the NCDB to explore trends in cancer. PMID- 28885798 TI - J. Marion Sims, MD: A controversial legacy. PMID- 28885799 TI - Response from the author. PMID- 28885800 TI - Looking forward. PMID- 28885802 TI - Amusement park injuries are not amusing. PMID- 28885803 TI - Looking forward. PMID- 28885804 TI - Out of unspeakable tragedy comes progress in bleeding control. PMID- 28885805 TI - Bleeding control training: An opportunity for local volunteerism, community engagement, and peer education. PMID- 28885806 TI - New adult trauma center on Chicago's South Side will treat violence as a disease. PMID- 28885807 TI - Implementing World Health Assembly Resolution 68.15: National surgical, obstetric, and anesthesia strategic plan development--the Zambian experience. PMID- 28885808 TI - Domestic volunteerism: Dr. Freiwald brings surgical care to uninsured patients in San Diego. PMID- 28885809 TI - 2016 ACS Governors Survey: MACRA: Are surgeons ready? PMID- 28885810 TI - ACS CRP Dissemination and Implementation Committee issues call for participants in pilot project. AB - According to HHS, dissemination and implementation research is designed "to bridge the gap between public health, clinical research, andeveryday practice by building a knowledge base about how health information, interventions, and new clinical practices andpolicies are transmitted and translated for public health and health care service use in specific settings". PMID- 28885811 TI - New resources available for your personal and professional development. PMID- 28885812 TI - Time-outs and their role in improving safety and quality in surgery. PMID- 28885813 TI - Asleep at the wheel: Obstructive sleep apnea. AB - Left untreated, OSA can lead to hypertension, stroke, congestive heart failure, and atrial fibrillation and s associated with type 2diabetes and depression.... OSA strikes people of any age, including infants, and is most commonly seen in overweight or obese menolder than 40 years of age. PMID- 28885814 TI - In memoriam: Thomas E. Starzl, MD, PhD, FACS, organ transplantation pioneer. PMID- 28885815 TI - CQGS releases preliminary standards for quality surgical care for older adults. PMID- 28885816 TI - New ACS surgical practice guidelines now include patient education. PMID- 28885817 TI - High Specific Power Dual-Metal-Ion Rechargeable Microbatteries Based on LiMn2O4 and Zinc for Miniaturized Applications. AB - Miniaturized rechargeable batteries with high specific power are required for substitution of the large sized primary batteries currently prevalent in integrated systems since important implications in dimensions and power are expected in future miniaturized applications. Commercially available secondary microbatteries are based on lithium metal which suffers from several well-known safety and manufacturing issues and low specific power when compared to (super) capacitors. A high specific power and novel dual-metal-ion microbattery based on LiMn2O4, zinc, and an aqueous electrolyte is presented in this work. Specific power densities similar to the ones exhibited by typical electrochemical supercapacitors (3400 W kg-1) while maintaining specific energies in the range of typical Li-ion batteries are measured (~100 Wh kg-1). Excellent stability with very limited degradation (99.94% capacity retention per cycle) after 300 cycles is also presented. All of these features, together with the intrinsically safe nature of the technology, allow anticipation of this alternative micro power source to have high impact, particularly in the high demand field of newly miniaturized applications. PMID- 28885818 TI - Molecular Fin Effect from Heterogeneous Self-Assembled Monolayer Enhances Thermal Conductance across Hard-Soft Interfaces. AB - Thermal transport across hard-soft interfaces is critical to many modern applications, such as composite materials, thermal management in microelectronics, solar-thermal phase transition, and nanoparticle-assisted hyperthermia therapeutics. In this study, we use equilibrium molecular dynamics (EMD) simulations combined with the Green-Kubo method to study how molecularly heterogeneous structures of the self-assembled monolayer (SAM) affect the thermal transport across the interfaces between the SAM-functionalized gold and organic liquids (hexylamine, propylamine and hexane). We focus on a practically synthesizable heterogeneous SAM featuring alternating short and long molecular chains. Such a structure is found to improve the thermal conductance across the hard-soft interface by 46-68% compared to a homogeneous nonpolar SAM. Through a series of further simulations and analyses, it is found that the root reason for this enhancement is the penetration of the liquid molecules into the spaces between the long SAM molecule chains, which increase the effective contact area. Such an effect is similar to the fins used in macroscopic heat exchanger. This "molecular fin" structure from the heterogeneous SAM studied in this work provides a new general route for enhancing thermal transport across hard-soft material interfaces. PMID- 28885819 TI - Exchange Bias in the [CoO/Co/Pd]10 Antidot Large Area Arrays. AB - Magnetic nanostructures revealing exchange bias effect have gained a lot of interest in recent years due to their possible applications in modern devices with various functionalities. In this paper, we present our studies on patterned [CoO/Co/Pd]10 multilayer where ferromagnetic material is in a form of clusters, instead of being a continuous layer. The system was patterned using nanosphere lithography technique which resulted in creation of an assembly of well-ordered antidots or islands over a large substrate area. We found that the overall hysteresis loop of the films consists of hard and soft components. The hard component hysteresis loop exhibits a large exchange bias field up to -11 kOe. The patterning process causes a slight increase of the exchange field as the antidot radius rises. We also found that the material on edges of the structures gives rise to a soft unbiased magnetization component. PMID- 28885821 TI - Isotopic Characterization of Mercury Downstream of Historic Industrial Contamination in the South River, Virginia. AB - Historic point source mercury (Hg) contamination from industrial processes on the South River (Waynesboro, Virginia) ended decades ago, but elevated Hg concentrations persist in the river system. In an effort to better understand Hg sources, mobility, and transport in the South River, we analyzed total Hg (THg) concentrations and Hg stable isotope compositions of streambed sediments, stream bank soils, suspended particles, and filtered surface waters. Samples were collected along a longitudinal transect of the South River, starting upstream of the historic Hg contamination point-source and extending downstream to the confluence with the South Fork Shenandoah River. Analysis of the THg concentration and Hg isotopic composition of these environmental samples indicates that the regional background Hg source is isotopically distinct in both Delta199Hg and delta202Hg from Hg derived from the original source of contamination, allowing the tracing of contamination-sourced Hg throughout the study reach. Three distinct end-members are required to explain the Hg isotopic and concentration variation observed in the South River. A consistent negative offset in delta202Hg values (~0.280/00) was observed between Hg in the suspended particulate and dissolved phases, and this fractionation provides insight into the processes governing partitioning and transport of Hg in this contaminated river system. PMID- 28885822 TI - Three-Dimensional Cell Culture and Drug Testing in a Microfluidic Sidewall Attached Droplet Array. AB - Three-dimensional (3D) cell culture provides an effective way over conventional two-dimensional (2D) monolayer culture to more closely imitate the complex cellular organization, heterogeneity, and interactions as well as tissue microenvironments in vivo. Here we present a novel droplet-based 3D cell culture method by using droplet array attached on the sidewall of a PDMS piece. Such an arrangement not only avoids cells from adhering on the chip surface for achieving 3D cell culture in nanoliter-scale droplets, but also facilitates performing multiple operations to cells in droplets, including cell suspension droplet generation, drug treatment, and cell staining with a capillary-based liquid handling system, as well as in situ observation and direct scanning with a confocal laser scanning microscope. We optimized the system by studying the effects of various conditions to cell culture including droplet volume, cell density and fabrication methods of the PDMS pieces. We have applied this system in the 3D culture of HepG2 cells and the stimulation testing of an anticancer drug, doxorubicin, to 3D cell spheroids. PMID- 28885820 TI - Strategies for Editing Virulent Staphylococcal Phages Using CRISPR-Cas10. AB - Staphylococci are prevalent skin-dwelling bacteria that are also leading causes of antibiotic-resistant infections. Viruses that infect and lyse these organisms (virulent staphylococcal phages) can be used as alternatives to conventional antibiotics and represent promising tools to eliminate or manipulate specific species in the microbiome. However, since over half their genes have unknown functions, virulent staphylococcal phages carry inherent risk to cause unknown downstream side effects. Further, their swift and destructive reproductive cycle make them intractable by current genetic engineering techniques. CRISPR-Cas10 is an elaborate prokaryotic immune system that employs small RNAs and a multisubunit protein complex to detect and destroy phages and other foreign nucleic acids. Some staphylococci naturally possess CRISPR-Cas10 systems, thus providing an attractive tool already installed in the host chromosome to harness for phage genome engineering. However, the efficiency of CRISPR-Cas10 immunity against virulent staphylococcal phages and corresponding utility as a tool to facilitate their genome editing has not been explored. Here, we show that the CRISPR-Cas10 system native to Staphylococcus epidermidis exhibits robust immunity against diverse virulent staphylococcal phages. On the basis of this activity, a general two-step approach was developed to edit these phages that relies upon homologous recombination machinery encoded in the host. Variations of this approach to edit toxic phage genes and access phages that infect CRISPR-less staphylococci are also presented. This versatile set of genetic tools enables the systematic study of phage genes of unknown functions and the design of genetically defined phage based antimicrobials that can eliminate or manipulate specific Staphylococcus species. PMID- 28885823 TI - Carboxylated Fullerene at the Oil/Water Interface. AB - The self-assembly of carboxylated fullerene with poly(styrene-b-2-vinylpyridine) (PS-b-P2VP) with different molecular weights, poly-2-vinylpyridine, and amine terminated polystyrene, at the interface between toluene and water was investigated. For all values of the pH, the functionalized fullerene interacted with the polymers at the water/toluene interface, forming a nanoparticle network, reducing the interfacial tension. At pH values of 4.84 and 7.8, robust, elastic films were formed at the interface, such that hollow tubules could be formed in situ when an aqueous solution of the functionalized fullerene was jetted into a toluene solution of PS-b-P2VP at a pH of 4.84. With variation of the pH, the mechanical properties of the fullerene/polymer assemblies can be varied by tuning the strength of the interactions between the functionalized fullerenes and the PS b-P2VP. PMID- 28885824 TI - Structural Design of Two Fluorine-Beryllium Borates BaMBe2(BO3)2F2 (M = Mg, Ca) Containing Flexible Two-Dimensional [Be3B3O6F3]infinity Single Layers without Structural Instability Problems. AB - Molecular structural design is a compelling strategy to develop new compounds and optimize the crystal structure by atomic-scale manipulation. Herein, two fluorine beryllium borates, BaMgBe2(BO3)2F2 and BaCaBe2(BO3)2F2, have been rationally designed to overcome the structural instability problems of Sr2Be2B2O7 (SBBO). When relatively large Ba atoms were introduced, the [Be6B6O15]infinity double layers of SBBO were successfully broken, generating flexible [Be3B3O6F3]infinity single layers. Also, the strategy adopted in this work has many implications in understanding the structural chemistry and designing novel optical functional materials in a beryllium borate system. PMID- 28885826 TI - Applications of Flow Microreactors in Electrosynthetic Processes. AB - The fundamental advantages and potential benefits of flow microreactor technology include extremely large surface-to-volume ratios, precise control over temperature and residence time, extremely fast molecular diffusion, and increased safety during reactive processes. These advantages and benefits can be applied to a wide range of electrosynthetic techniques, and so the integration of flow microreactors with electrosynthesis has received significant research interest from both academia and industry. This review presents an up-to-date overview of electrosynthetic processes in continuous-flow microreactors. In addition, the advantages of continuous-flow electrochemistry are discussed, along with a thorough comparison of microreactor-based processes and conventional batch reaction systems. PMID- 28885825 TI - Nanoparticle Biokinetics in Mice and Nonhuman Primates. AB - Despite the preponderance of iron oxide nanoparticles (NPs) designed for theranostic applications, widespread clinical translation of these NPs lags behind. A better understanding of how NP pharmacokinetics vary between small and large animal models is needed to rapidly customize NPs for optimal performance in humans. Here we use noninvasive magnetic resonance imaging (MRI) to track iron oxide NPs through a large number of organ systems in vivo to investigate NP biokinetics in both mice and nonhuman primates. We demonstrate that pharmacokinetics are similar between mice and macaques in the blood, liver, spleen, and muscle, but differ in the kidneys, brain, and bone marrow. Our study also demonstrates that full-body MRI is practical, rapid, and cost-effective for tracking NPs noninvasively with high spatiotemporal resolution. Our techniques using a nonhuman primate model may provide a platform for testing a range of NP formulations. PMID- 28885827 TI - Attachment Site Cysteine Thiol pKa Is a Key Driver for Site-Dependent Stability of THIOMAB Antibody-Drug Conjugates. AB - The incorporation of cysteines into antibodies by mutagenesis allows for the direct conjugation of small molecules to specific sites on the antibody via disulfide bonds. The stability of the disulfide bond linkage between the small molecule and the antibody is highly dependent on the location of the engineered cysteine in either the heavy chain (HC) or the light chain (LC) of the antibody. Here, we explore the basis for this site-dependent stability. We evaluated the in vivo efficacy and pharmacokinetics of five different cysteine mutants of trastuzumab conjugated to a pyrrolobenzodiazepine (PBD) via disulfide bonds. A significant correlation was observed between disulfide stability and efficacy for the conjugates. We hypothesized that the observed site-dependent stability of the disulfide-linked conjugates could be due to differences in the attachment site cysteine thiol pKa. We measured the cysteine thiol pKa using isothermal titration calorimetry (ITC) and found that the variants with the highest thiol pKa (LC K149C and HC A140C) were found to yield the conjugates with the greatest in vivo stability. Guided by homology modeling, we identified several mutations adjacent to LC K149C that reduced the cysteine thiol pKa and, thus, decreased the in vivo stability of the disulfide-linked PBD conjugated to LC K149C. We also present results suggesting that the high thiol pKa of LC K149C is responsible for the sustained circulation stability of LC K149C TDCs utilizing a maleimide-based linker. Taken together, our results provide evidence that the site-dependent stability of cys-engineered antibody-drug conjugates may be explained by interactions between the engineered cysteine and the local protein environment that serves to modulate the side-chain thiol pKa. The influence of cysteine thiol pKa on stability and efficacy offers a new parameter for the optimization of ADCs that utilize cysteine engineering. PMID- 28885828 TI - Multidrug Resistance Protein 4 (MRP4/ABCC4) Protects Cells from the Toxic Effects of Halobenzoquinones. AB - Halobenzoquinones (HBQs) are frequently detected disinfection byproducts (DBPs) in treated water. Recent studies have demonstrated that HBQs are highly cytotoxic and capable of inducing the generation of reactive oxygen species (ROS) and depleting cellular glutathione (GSH). Multidrug resistance proteins (MRPs/ABCCs) are known to play a critical role in the elimination of numerous drugs, carcinogens, toxicants, and their conjugated metabolites. In general, little is known about the roles of transporters in DBP toxicity. Here, we hypothesize that MRPs may play roles in the detoxication of HBQs. To test this hypothesis, we used human embryonic kidney 293 (HEK293) cells stably expressing MRPs (MRP1, 3, 4, and 5) and HEK293 cells with empty vector (HEK-V) to examine the comparative cytotoxicity of four HBQs: 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), 2,6-dibromo 1,4-benzoquinone (2,6-DBBQ), 2,6-dichloro-3-methyl-1,4-benzoquinone (DCMBQ), and 2,3,6-trichloro-1,4-benzoquinone (TriCBQ). The cytotoxicity (IC50) of the four HBQs in HEK-MRP1, -MRP3, -MRP4, and -MRP5 cells and the control HEK-V cells clearly showed that MRP4 had the most significant effect on reducing the toxicity of the four HBQs. To further support MRP4-mediated detoxication of HBQs, we examined the HBQ-induced ROS levels in HEK-MRP4 and HEK-V cells. ROS levels were significantly reduced in HEK-MRP4 cells compared with HEK-V cells after HBQ treatment. Furthermore, it was found that MRP4-mediated detoxication of the HBQs was GSH dependent, as the cytotoxicity of the HBQs was increased in GSH-depleted HEK-MRP4 cells in comparison to HEK-MRP4 cells. The GSH-dependent protection of cells from HBQs supports the possibility of HBQ-GSH conjugate efflux by MRP4. This study demonstrates a role for MRP4 in cellular protection against HBQ DBP induced toxicity and oxidative stress. PMID- 28885829 TI - Membrane-Active Amphipathic Peptide WRL3 with in Vitro Antibiofilm Capability and in Vivo Efficacy in Treating Methicillin-Resistant Staphylococcus aureus Burn Wound Infections. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has become increasingly prevalent in hospitals, clinics, and the community. MRSA can cause significant and even lethal infections, especially in skin burn wounds. The currently available topical agents have largely failed to eliminate MRSA infections due to resistance. Therefore, there is an urgent need for new and effective approaches for treating MRSA. Here, we show that a novel engineered amphipathic peptide, WRL3 (WLRAFRRLVRRLARGLRR-NH2), exhibits potent antimicrobial activity against MRSA, even in the presence of various salts or serum. The cell selectivity of WRL3 was demonstrated by its ability to specifically eliminate MRSA cells over host cells in a coculture model. Additionally, WRL3 showed a synergistic effect against MRSA when combined with ceftriaxone and effectively inhibited sessile biofilm bacteria growth leading to a reduction in biomass. Fluorescent measurements and microscopic observations of live bacterial cells and artificial membranes revealed that WRL3 exerted its bactericidal activity possibly by destroying the bacterial membrane. In vivo studies indicate that WRL3 is able to control proliferation of MRSA in wound tissue and reduce bioburden and provides a more favorable environment for wound healing. Collectively, our data suggest that WRL3 has enormous potential as a novel antimicrobial agent for the treatment of clinical MRSA infections of skin burn wounds. PMID- 28885830 TI - Oligoprolines as Molecular Entities for Controlling Distance in Biological and Material Sciences. AB - Nature utilizes large biomolecules to fulfill tasks that require spatially well defined arrangements at the molecular level such as electron transfer, ligand receptor interactions, or catalysis. The creation of synthetic molecules that enable precise control over spacing and functionalization provides opportunities across diverse disciplines. Key requirements of functionalizable oligomeric scaffolds include the specific control of their molecular properties where the correct balance of flexibility and rigidity must be maintained in addition to the prerequisite of defined length. These molecules must ideally be equally applicable in aqueous and organic environments, they must be easy to synthesize in a controlled stepwise fashion, and they must be easily modified with a palette of chemical appendages having diverse functionalities. Oligoproline, a peptidic polymer comprised of repeating units of the amino acid proline, is an ideal platform to meet such challenges. Oligoproline derives its characteristic rigidity and well-defined secondary structure from the innate features of proline. It is the only naturally occurring amino acid that has its side-chain cyclized to its alpha-amino group, generating often-populated trans and cis conformers around the tertiary amide bonds formed in proline oligomers. Oligoprolines are widely applied to define distance on the molecular level as they are capable of serving as both a "molecular ruler" with a defined length and as a "molecular scaffold" with precisely located and predictably oriented substitutions along the polymeric backbone. Our investigations focus on the use of oligoproline as a molecular scaffold. Toward this end, we have investigated the role of solvent upon helical structure of oligoproline, and the effect that substituents on the pyrrolidine ring and the oligomer termini have on the stability of the helix. We have also further explored the molecular characteristics of oligoproline through spectroscopic and crystallographic methods. All of these structural insights laid the basis for implementation of oligoproline in materials science and chemical biology. Within this Account, we highlight the value of oligoprolines for applications in distinctly different research areas. Toward materials chemistry, we have utilized oligoprolines for the size-controlled generation of noble metal nanoparticles, and to probe the role of spatial preorganization of pi-systems for molecular self-assembly. Within the biological realm, we have applied oligoprolines to probe the role of distance on G-protein coupled receptor-mediated ligand uptake by cancerous cells and to investigate the effects of charge preorganization on the efficacy of cationic cell-penetrating peptides. PMID- 28885832 TI - Flattened Calixarene-like Cyclic BODIPY Array: A New Photosynthetic Antenna Model. AB - A cyclic BODIPY array, characterized by a rigid flattened calixarene-like conformation, acts as a photosynthetic antenna mimic. The system in question, triBODIPY, is a better antenna than the corresponding BF2-free ligand. On the basis of absorption spectral studies and supporting calculations, it is concluded that exciton coupling between the BODIPY subunits occurs readily. TriBODIPY supports a complex with Li+@C60 that bring an antenna-like light absorber into close proximity to an electronic acceptor without the need for linking spacers. As inferred from X-ray diffraction analyses of complexes between triBODIPY and C60, it is inferred that the fullerene complexes are stabilized via convex concave donor-acceptor interactions. Steady state absorption/fluorescence, time correlated single photon counting, and transient absorption measurements have allowed a complete characterization of the complexes in both the ground and excited states, including the host-guest recognition features, fluorescence quenching effects, and charge separation/recombination dynamics. PMID- 28885831 TI - Hybrid Surface Patterns Mimicking the Design of the Adhesive Toe Pad of Tree Frog. AB - Biological materials achieve directional reinforcement with oriented assemblies of anisotropic building blocks. One such example is the nanocomposite structure of keratinized epithelium on the toe pad of tree frogs, in which hexagonal arrays of (soft) epithelial cells are crossed by densely packed and oriented (hard) keratin nanofibrils. Here, a method is established to fabricate arrays of tree frog-inspired composite micropatterns composed of polydimethylsiloxane (PDMS) micropillars embedded with polystyrene (PS) nanopillars. Adhesive and frictional studies of these synthetic materials reveal a benefit of the hierarchical and anisotropic design for both adhesion and friction, in particular, at high matrix fiber interfacial strengths. The presence of PS nanopillars alters the stress distribution at the contact interface of micropillars and therefore enhances the adhesion and friction of the composite micropattern. The results suggest a design principle for bioinspired structural adhesives, especially for wet environments. PMID- 28885833 TI - The Face of a Molecule. AB - Recent technological advances in mass spectrometry and NMR spectroscopy have enabled new approaches for the rapid and insightful profiling of natural product mixtures. MALDI-MS with the provision of biosynthetic heavy-isotope-labeled precursors can be a powerful method by which to interrogate a natural product metabolome and to gain insight into its unique constituents; this is illustrated herein by the detection, isolation, and characterization of cryptomaldamide. MS/MS-based Molecular Networks, facilitated by the Global Natural Products Social (GNPS) platform, is rapidly changing the way in which we dereplicate known natural products in mixtures, find new analogues in desired structure classes, and identify fundamentally new chemical entities. This method can be linked to genomic information to assist in genome-driven natural products discovery and is illustrated here with the characterization of the columbamides. Similarly, algorithmic interpretation of NMR data is facilitating the automatic identification or classification of new natural products. We developed such a tool named the Small Molecule Accurate Recognition Technology (SMART), which employs a convolutional neural network to classify HSQC spectra of organic molecules using pattern recognition principles. The discovery and rapid classification of several new peptides from a marine cyanobacterium as members of the viequeamide class provides an example of its utility in natural products research. These three illustrations represent different methods by which to look at the external features of a chemical substance and derive valuable insights into its identity or, as described herein, the "face of a molecule". PMID- 28885834 TI - Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors. AB - Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis, and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM). It could effectively induce cell apoptosis and autophagy and ultimately led to cell death. Importantly, compound 35 showed excellent in vivo antitumor efficacy in the HCT116 xenograft model. This proof-of-concept study demonstrates the feasibility of discovering an inhibitor targeting cancer metabolism and epigenetics and provides an efficient strategy for multitarget antitumor drug discovery. PMID- 28885835 TI - New Class of Anion-Accelerated Amino-Cope Rearrangements as Gateway to Diverse Chiral Structures. AB - We report useful new lithium-assisted asymmetric anion-accelerated amino-Cope rearrangement cascades. A strategic nitrogen atom chiral auxiliary serves three critical roles, by (1) enabling in situ assembly of the chiral 3-amino-1,5-diene precursor, (2) facilitating the rearrangement via a lithium enolate chelate, and (3) imparting its influence on consecutive inter- or intramolecular C-C or C-X bond-forming events via resulting chiral enamide intermediates or imine products. The mechanism of the amino-Cope rearrangement was explored with density functional theory. A stepwise dissociation-recombination mechanism was found to be favored. The stereochemistry of the chiral auxiliary determines the stereochemistry of the Cope product by influencing the orientation of the lithium dienolate and sulfinylimine fragments in the recombination step. These robust asymmetric anion-accelerated amino-Cope enabled cascades open the door for rapid and predictable assembly of complex chiral acyclic and cyclic nitrogen-containing motifs in one pot. PMID- 28885836 TI - Lipid Peroxidation and Cyclooxygenase Enzyme Inhibitory Compounds from Prangos haussknechtii. AB - Purification of extracts from Prangos haussknechtii Bioss afforded prenylated coumarins 1 and 2, monoterpenoid 3, amino acid derivative 4, and seven known compounds. Spectroscopic methods permitted establishment of the structures and relative configuration of these compounds. The pure isolates were tested for antioxidant and anti-inflammatory activities using lipid peroxidation (LPO), 3 (4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and cyclooxygenase (COX-1 and -2) enzyme inhibitory assays. Compounds 1-4 inhibited LPO with IC50 values between 43 and 114 MUM and reduced MTT to formazan blue between 48 and 128 MUM. In anti-inflammatory assays using cyclooxygenase enzymes, COX-1 and -2, these compounds showed inhibition, with IC50 values ranging from 34 to 56 MUM. PMID- 28885837 TI - Selective Derivatization of a Hexaphosphane from Functionalization of White Phosphorus. AB - The reaction of LGa (L = Dipp(4-(Dipp-imino)pent-2-en-2-yl)amide; Dipp: 2,6 diisopropylphenyl) and white phosphorus was revisited. A plethora of unprecedented polyphosphanes in addition to the known monoinserted product LGaP4 (1) are observed. An optimized synthesis of the hitherto unknown hexaphosphane (LGa)2P6 (3) is presented, and its subsequent selective derivatization with Bronsted acids, MeOTf, Ph2ECl (E = P, As), and NaOCP provides access to a wealth of functionalized hexa- and heptaphosphanes. PMID- 28885838 TI - Diastereoselective Ritter-like Reaction on Cyclic Trifluoromethylated N,O-Acetals Derived from l-Tartaric Acid. AB - Despite the presence of the highly electron-withdrawing fluorinated substituent, cyclic alpha-trifluoromethylated N-acyliminium ions were successfully generated from fluorinated O-acetyl-N,O-acetal l-tartaric acid derivatives. The addition of nitriles on these intermediates occurred with high to excellent syn diastereoselectivity and led, in most cases, to oxazolines and amides as single diastereomers. The diastereoselectivity of the addition and the nature of the reaction product depend on the substituents on the hydroxyl groups of the tartaric acid scaffold. This methodology gave access to enantiopure, highly functionalized 5-(trifluoromethyl)pyrrolidin-2-one derivatives, bearing the fluorinated substituent on a tetrasubstituted carbon. PMID- 28885839 TI - CO2 Stimuli-Responsive, Injectable Block Copolymer Hydrogels Cross-Linked by Discrete Organoplatinum(II) Metallacycles via Stepwise Post-Assembly Polymerization. AB - Supramolecular polymeric gels cross-linked by well-defined, discrete metal organic macrocycles (MOMs) or metal-organic cages have become a prevailing topic within the field of supramolecular self-assembly. However, the realization of supramolecular polymeric hydrogels cross-linked by discrete organometallic architectures with good biocompatibility is still a great challenge. Herein, we present the successful preparation of CO2 stimuli-responsive, injectable block copolymer hydrogels cross-linked by discrete organoplatinum(II) metallacycles. Through the combination of coordination-driven self-assembly and stepwise post assembly polymerization, star block copolymers (SBCPs) containing well-defined hexagonal metallacycles as cores were successfully prepared, which featured CO2 stimuli-responsive properties including CO2-triggered morphology transition and CO2-induced thermoresponsive behavior. Interestingly, the resultant SBCPs were capable of forming supramolecular hydrogels with MOMs as junctions near physiological temperature, which allowed the realization of a reversible gel-to sol transformation through the removal and addition of CO2. More importantly, the resultant supramolecular hydrogels presented good cytocompatibility in vitro. Therefore, this study provides a new strategy for the construction of new "smart" supramolecular hydrogels with promising applications as biological materials. PMID- 28885840 TI - Chemical Synthesis of (RP)- and (SP)-[16O,17O,18O]Phosphoenol Pyruvate. AB - Enzymes and chirality are intimately associated. For their mechanisms to be studied, chiral substrates are needed as probes. Here, we report a concise synthesis of (RP)- and (SP)-[16O,17O,18O]phosphoenol pyruvate starting from enantiomerically pure (R)-2-chloro-1-phenylethanol, which was transformed into 18O-labeled 3-methyl-1-phenylbutane-1,3-diol. The diol was reacted with tris(dimethylamino)phosphane and consecutively with H217O to yield a mixture of cyclic H-phosphonates labeled with 17O and 18O. They were silylated and subjected to a Perkow reaction with ethyl 3-chloropyruvate. Two protected [16O,17O,18O]phosphoenol pyruvates were formed and finally globally deprotected. Their configuration was reassessed by a known enzymatic test in combination with conversion of the formed d-glucose-6-phosphate into mixtures of labeled methyl d glucose-4,6-phosphates, which were analyzed by 31P NMR spectroscopy. The enzymatic test supported the configuration assigned to labeled stereogenic phosphorus atoms on the basis of synthesis. PMID- 28885841 TI - Tuning Product Selectivity for Aqueous CO2 Reduction with a Mn(bipyridine)-pyrene Catalyst Immobilized on a Carbon Nanotube Electrode. AB - The development of high-performance electrocatalytic systems for the controlled reduction of CO2 to value-added chemicals is a key goal in emerging renewable energy technologies. The lack of selective and scalable catalysts in aqueous solution currently hampers the implementation of such a process. Here, the assembly of a [MnBr(2,2'-bipyridine)(CO)3] complex anchored to a carbon nanotube electrode via a pyrene unit is reported. Immobilization of the molecular catalyst allows electrocatalytic reduction of CO2 under fully aqueous conditions with a catalytic onset overpotential of eta = 360 mV, and controlled potential electrolysis generated more than 1000 turnovers at eta = 550 mV. The product selectivity can be tuned by alteration of the catalyst loading on the nanotube surface. CO was observed as the main product at high catalyst loadings, whereas formate was the dominant CO2 reduction product at low catalyst loadings. Using UV vis and surface-sensitive IR spectroelectrochemical techniques, two different intermediates were identified as responsible for the change in selectivity of the heterogenized Mn catalyst. The formation of a dimeric Mn0 species at higher surface loading was shown to preferentially lead to CO formation, whereas at lower surface loading the electrochemical generation of a monomeric Mn-hydride is suggested to greatly enhance the production of formate. These results emphasize the advantages of integrating molecular catalysts onto electrode surfaces for enhancing catalytic activity while allowing excellent control and a deeper understanding of the catalytic mechanisms. PMID- 28885842 TI - Catalytic Activity Control via Crossover between Two Different Microstructures. AB - Metal nanocatalysts hold great promise for a wide range of heterogeneous catalytic reactions, while the optimization strategy of catalytic activity is largely restricted by particle size or shape control. Here, we demonstrate that a reversible microstructural control through the crossover between multiply twinned nanoparticle (MTP) and single crystal (SC) can be readily achieved by solvent post-treatment on gold nanoparticles (AuNPs). Polar solvents (e.g., water, methanol) direct the transformation from MTP to SC accompanied by the disappearance of twinning and stacking faults. A reverse transformation from SC to MTP is achieved in nonpolar solvent (e.g., toluene) mixed with thiol ligands. The transformation between two different microstructures is directly observed by in situ TEM and leads to a drastic modulation of catalytic activity toward the gas-phase selective oxidation of alcohols. On the basis of the combined experimental and theoretical investigations of alcohol chemisorption on these nanocatalysts, we propose that the exposure of {211}-like microfacets associated with twin boundaries and stack faults accounts for the strong chemisorption of alcohol molecules on MTP AuNPs and thus the exceptionally high catalytic activity. PMID- 28885843 TI - Theoretical Kinetics Analysis for H Atom Addition to 1,3-Butadiene and Related Reactions on the C4H7 Potential Energy Surface. AB - The oxidation chemistry of the simplest conjugated hydrocarbon, 1,3-butadiene, can provide a first step in understanding the role of polyunsaturated hydrocarbons in combustion and, in particular, an understanding of their contribution toward soot formation. On the basis of our previous work on propene and the butene isomers (1-, 2-, and isobutene), it was found that the reaction kinetics of H-atom addition to the C?C double bond plays a significant role in fuel consumption kinetics and influences the predictions of high-temperature ignition delay times, product species concentrations, and flame speed measurements. In this study, the rate constants and thermodynamic properties for H-atom addition to 1,3-butadiene and related reactions on the C4H7 potential energy surface have been calculated using two different series of quantum chemical methods and two different kinetic codes. Excellent agreement is obtained between the two different kinetics codes. The calculated results including zero point energies, single-point energies, rate constants, barrier heights, and thermochemistry are systematically compared among the two quantum chemical methods. 1-Methylallyl (C4H71-3) and 3-buten-1-yl (C4H71-4) radicals and C2H4 + C2H3 are found to be the most important channels and reactivity-promoting products, respectively. We calculated that terminal addition is dominant (>80%) compared to internal H-atom addition at all temperatures in the range 298-2000 K. However, this dominance decreases with increasing temperature. The calculated rate constants for the bimolecular reaction C4H6 + H -> products and C2H4 + C2H3 > products are in excellent agreement with both experimental and theoretical results from the literature. For selected C4 species, the calculated thermochemical values are also in good agreement with literature data. In addition, the rate constants for H atom abstraction by H atoms have also been calculated, and it is found that abstraction from the central carbon atoms is the dominant channel (>70%) at temperatures in the range of 298-2000 K. Finally, by incorporating our calculated rate constants for both H atom addition and abstraction into our recently developed 1,3-butadiene model, we show that laminar flame speed predictions are significantly improved, emphasizing the value of this study. PMID- 28885844 TI - Synthesis and C-H Functionalization Chemistry of Thiazole-Semicoronenediimides (TsCDIs) and -Coronenediimides (TCDIs). AB - Coronenediimide (CDI) derivatives have a planar structure, a reasonably high electron affinity, and a rigid and extended delocalized pi-system. Therefore, this core and variants thereof may be promising building blocks for the synthesis of electron transport materials. Herein, we have synthesized thiazole semicoronenediimides (TsCDIs) and -coronenediimides (TCDIs) by a two-step process from a perylenediimide (PDI) precursor. Conditions for C-H arylation and heteroarylation of the thiazole moiety of this core were developed and were successfully used for the synthesis of dimer, triad, and polymeric materials. The optical and electrochemical properties of these materials and their monomers were examined as a function of side-chain modification and pi-extension. With their broad optical absorption and low reduction potentials, these materials could be candidates as organic semiconductors for applications in OFETs and as nonfullerene acceptors. PMID- 28885845 TI - Near-Infrared Photoswitching of Azobenzenes under Physiological Conditions. AB - Biological tissue exhibits an absorbance minimum in the near-infrared between 700 and 900 nm that permits deep penetration of light. Molecules that undergo photoisomerization in this bio-optical window are highly desirable as core structures for the development of photopharmaceuticals and as components of chemical-biological tools. We report the systematic design, synthesis, and testing of an azobenzene derivative tailored to undergo single-photon photoswitching with near-infrared light under physiological conditions. A fused dioxane ring and a methoxy substituent were used to place oxygen atoms in all four ortho positions, as well as two meta positions, relative to the azobenzene N?N double bond. This substitution pattern, together with a para pyrrolidine group, raises the pKa of the molecule so that it is protonated at physiological pH and absorbs at wavelengths >700 nm. This azobenzene derivative, termed DOM azo, is stable for months in neutral aqueous solutions, undergoes trans-to-cis photoswitching with 720 nm light, and thermally reverts to the stable trans isomer with a half-life near 1 s. PMID- 28885846 TI - Tip-Induced Switch of Germanene Atomic Structure. AB - A new germanene crystallographic structure is investigated by scanning tunnelling microscopy and density functional theory calculations. We found that germanene can crystallize in two stable but different structures when grown on Al(111) at the same temperature. These structures are evidenced in scanning tunnelling images by a honeycomb contrast and by a hexagonal contrast. These contrasts are relevant of a Ge network with one (hexagonal) or two (honeycomb) Ge atoms per unit cell shifted upward with respect to the other Ge atoms. These structures appear alternatively and can be turned on and off by a tip-induced process. PMID- 28885848 TI - Structure and Interfacial Tension of a Hard-Rod Fluid in Planar Confinement. AB - The structural properties and interfacial tension of a fluid of rodlike hard spherocylinder particles in contact with hard structureless flat walls are studied by means of Monte Carlo simulation. The calculated surface tension between the rod fluid and the substrate is characterized by a nonmonotonic trend as a function of the bulk concentration (density) over the range of isotropic bulk concentrations. As suggested by earlier theoretical studies, a surface ordering scenario is confirmed by our simulations: the local orientational order close to the wall changes from uniaxial to biaxial nematic when the bulk concentration reaches about 85% of the value at the onset of the isotropic nematic phase transition. The surface ordering coincides with a wetting transition whereby the hard wall is wetted by a nematic film. Accurate values of the fluid-solid surface tension, the adsorption, and the average particle-wall contact distance are reported (over a broad range of densities into the dense nematic region for the first time), which can serve as a useful benchmark for future theoretical and experimental studies on confined rod fluids. The simulation data are supplemented with predictions from second-virial density functional theory, which are in good qualitative agreement with the simulation results. PMID- 28885847 TI - Regulation of Reduced Folate Carrier (RFC) by Vitamin D Receptor at the Blood Brain Barrier. AB - Folates are essential for brain development and function. Folate transport in mammalian tissues is mediated by three major folate transport systems, i.e., reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor alpha (FRalpha), known to be regulated by ligand-activated nuclear receptors, such as vitamin D receptor (VDR). Folate uptake at the choroid plexus, which requires the actions of both FRalpha and PCFT, is critical to cerebral folate delivery. Inactivating FRalpha or PCFT mutations cause severe cerebral folate deficiency resulting in early childhood neurodegeneration. The objective of this study was to investigate the role of RFC in folate uptake at the level of the blood-brain barrier (BBB) and its potential regulation by VDR. We detected robust expression of RFC in different in vitro BBB model systems, particularly in immortalized cultures of human cerebral microvascular endothelial cells (hCMEC/D3) and isolated mouse brain capillaries. [3H]-methotrexate uptake by hCMEC/D3 cells at pH 7.4 was inhibited by PT523 and pemetrexed, antifolates with high affinity for RFC. We also showed that activation of VDR through calcitriol (1,25-dihydroxyvitamin D3) exposure up-regulates RFC mRNA and protein expression as well as function in hCMEC/D3 cells and isolated mouse brain capillaries. We further demonstrated that RFC expression could be down-regulated by VDR-targeting siRNA, further confirming the role of VDR in the direct regulation of this folate transporter. Together, these data suggest that augmenting RFC functional expression could constitute a novel strategy for enhancing brain folate delivery for the treatment of neurometabolic disorders caused by loss of FRalpha or PCFT function. PMID- 28885849 TI - Design of Two-Dimensional Graphene-like Dirac Materials beta12-XBeB5 (X = H, F, Cl) from Non-graphene-like beta12-Borophene. AB - Two-dimensional (2D) Dirac materials and boron sheets have attracted intensive interest recently. However, 2D Dirac materials remain rare and difficult to be realized experimentally, and 2D boron sheets generally have high dynamical instability. Stimulated by the experimental observation of Dirac cones in nongraphene-like beta12 boron sheets and based on the understanding of boron sheet electronic organization, we theoretically design new 2D Dirac materials beta12-XBeB5 (X = H, F, Cl) with high stability. We confirm beta12-HBeB5 as the global energy minimum among its 2D allotropes based on global structure search methods, a strong indication of its experimental feasibility. Our designed beta12 HBeB5 has not only a high Fermi velocity, but also a Dirac state very robust against extraordinary large tensile strains, an advantage for flexible electronics applications. Our work opens a new avenue to designing feasible 2D Dirac materials and stabilizing borophene sheets. PMID- 28885850 TI - Fast Surface Diffusion and Crystallization of Amorphous Griseofulvin. AB - Among molecular glasses, griseofulvin (GSF) is one of the fastest crystallizing. To understand this property, we have measured the surface diffusion in GSF using the method of surface grating decay. Surface diffusion in amorphous GSF is extremely fast, outpacing bulk diffusion by a factor of 108 at the glass transition temperature Tg (361 K). Among all molecular glasses studied (13 in all), GSF has the second fastest surface diffusion (to o-terphenyl) when compared at Tg. The GSF result fits the overall trend for molecular glasses without intermolecular hydrogen bonds, where surface diffusion systematically slows down with increasing molecular size. This result is particularly noteworthy because GSF has many hydrogen-bond acceptors but no donors, indicating that, so long as they do not participate in hydrogen bonding, the polar functional groups have a similar effect on surface diffusion as the nonpolar hydrocarbon groups. In contrast, the formation of intermolecular hydrogen bonds strongly inhibits surface diffusion. The surface crystal growth rate of amorphous GSF is nearly proportional to its surface diffusion coefficient, as noted for other systems, supporting the view that surface crystal growth is controlled by surface diffusion. In addition, the fast surface diffusion of GSF glasses explains the fast crystal growth along fracture surfaces and suggests a basis to understand fast crystal growth in the bulk through continuous creation of microcracks. PMID- 28885851 TI - Pyridine-Directed Asymmetric Hydrogenation of 1,1-Diarylalkenes. AB - Highly enantioselective pyridine-directed rhodium-catalyzed asymmetric hydrogenation of challenging 1,1-diarylalkenes is achieved by using [Rh(NBD)DuanPhos]BF4 as a precatalyst. Various types of 2-pyridine substituted 1,1-diarylalkenes could be hydrogenated with good to excellent enantioselectivities, which provide an efficient route to the synthesis of pharmaceutically and biologically active compounds containing a 2-pyridyl ethane unit. PMID- 28885852 TI - Thermodynamic Anomalies in Stretched Water. AB - Via molecular dynamics simulations of the TIP4P/2005 water model, we study liquid water's anomalous behavior at large negative pressure produced through isochoric cooling. We find that isochores without a pressure minimum can display "reentrant" behavior whereby a system that cavitates upon cooling can then rehomogenize upon further cooling. This behavior is a consequence of the underlying density maximum along the spinodal, but its actual manifestation in simulations is strongly influenced by finite size effects. These observations suggest that water under strong hydrophilic confinement may display richer phase behavior than hitherto assumed. This also suggests that propensity toward cavitation does not always correlate with greater tension, contrary to the prevailing assumption for interpreting water stretching experiments. We also show that a maximum spinodal density in water results in a locus of maximum compressibility and a minimum speed of sound that are independent from any influence of a liquid-liquid critical point (LLCP). However, we demonstrate that structural signatures of a Widom line, which likely emanates from an LLCP at elevated pressure, extend to large negative pressure, but such signatures are only observed upon sampling water's underlying potential energy landscape, rather than the thermalized metastable liquid. PMID- 28885853 TI - Suppression of the Coffee-Ring Effect and Evaporation-Driven Disorder to Order Transition in Colloidal Droplets. AB - The formation of a ring-like deposit at the periphery of a drying colloidal droplet is a vexing problem in many applications. We show a complete suppression of such deposits when a droplet of aqueous colloidal suspension, deposited on a glass substrate coated with a thin layer of silicone oil, is evaporated. This coating prevents the periphery of the aqueous droplet from getting pinned to the substrate and helps in suppressing the ring formation. It also decreases the surface area of the droplet, thereby decreasing the evaporation rate. These two factors together, driving the colloidal particles slowly to the center of the droplet, contribute to form an ordered crystallite at the end of the evaporation process. Brownian dynamics simulations performed to study ordering in the aggregate show that the spherical colloidal particles form face-centered cubic structures. Experiments and simulations show that slow rates of droplet evaporation and smaller-sized colloidal particles further lead to high-quality ordered colloidal crystallites. PMID- 28885854 TI - Phenoxazine: A Privileged Scaffold for Radical-Trapping Antioxidants. AB - Diphenylamines are widely used to protect petroleum-derived products from autoxidation. Their efficacy as radical-trapping antioxidants (RTAs) relies on a balance of fast H-atom transfer kinetics and stability to one-electron oxidation by peroxidic species. Both H-atom transfer and one-electron oxidation are enhanced by substitution with electron-donating substituents, such as the S-atom in phenothiazines, another important class of RTA. Herein we report the results of our investigations of the RTA activity of the structurally related, but essentially ignored, phenoxazines. We find that the H-atom transfer reactivity of substituted phenoxazines follows an excellent Evans-Polanyi correlation spanning kinh = 4.5 * 106 M-1 s-1 and N-H BDE = 77.4 kcal mol-1 for 3-CN,7-NO2-phenoxazine to kinh = 6.6 * 108 M-1 s-1 and N-H BDE = 71.8 kcal mol-1 for 3,7-(OMe)2 phenoxazine (37 degrees C). The reactivity of the latter compound is the greatest of any RTA ever reported and is likely to represent a reaction without an enthalpic barrier since log A for this reaction is likely ~8.5. The very high reactivity of most of the phenoxazines studied required the determination of their kinetic parameters by inhibited autoxidations in the presence of a very strong H-bonding cosolvent (DMSO), which slowed the observed rates by up to 2 orders of magnitude by dynamically reducing the equilibrium concentration of (free) phenoxazine as an H-atom donor. Despite their remarkably high reactivity toward peroxyl radicals, the phenoxazines were found to be comparatively stable to one-electron oxidation relative to diphenylamines and phenothiazines (E degrees ranging from 0.59 to 1.38 V vs NHE). Thus, phenoxazines with comparable oxidative stability to commonly used diphenylamine and phenothiazine RTAs had significantly greater reactivity (by up to 2 orders of magnitude). Computations suggest that this remarkable balance in H-atom transfer kinetics and stability to one-electron oxidation results from the ability of the bridging oxygen atom in phenoxazine to serve as both a pi-electron donor to stabilize the aminyl radical and sigma-electron acceptor to destabilize the aminyl radical cation. Perhaps most excitingly, phenoxazines have "non-classical" RTA activity, where they trap >2 peroxyl radicals each, at ambient temperatures. PMID- 28885855 TI - (Z)-Selective Hydrosilylation of Terminal Alkynes with HSiMe(OSiMe3)2 Catalyzed by a Ruthenium Complex Containing an N-Heterocyclic Carbene. AB - The N-heterocyclic-carbene-ligated ruthenium complex [RuHCl(CO)(H2IMes)(PCy3)] exhibits high catalytic activity for the (Z)-selective hydrosilylation of various terminal alkynes with 1,1,1,3,5,5,5-heptamethyltrisiloxane (HSiMe(OSiMe3)2). The stereoretentive derivatization of the (Z)-alkenylsiloxanes allows the synthesis of biologically active compounds, e.g. potent antitumor agents and inhibitors for induced-NO synthase. PMID- 28885856 TI - Spirometrically Confirmed Chronic Obstructive Pulmonary Disease Worsens Long-Term Prognosis after Percutaneous Coronary Intervention. PMID- 28885857 TI - Exaggerated Increase in Pulmonary Artery Pressure during Exercise in Adults Born Preterm. PMID- 28885858 TI - The Latino Integrative Medical Group Visit as a Model for Pain Reduction in Underserved Spanish Speakers. AB - OBJECTIVES: Chronic pain is a common problem in the United States, one for which there is a dearth of effective treatments. Nonpharmacological options are a promising alternative, especially for Spanish-speaking Latinos. This pilot study would like to assess the feasibility of an adapted Integrative Medical Group Visit (IMGV) curriculum for a Spanish-speaking Latino chronic pain population. DESIGN AND INTERVENTION: We translated and adapted the curriculum of the IMGV for a Spanish-speaking Latino chronic pain population. We then tested the feasibility of using this model with two pilot groups (N = 19) using a pre-postdesign. SUBJECTS: This intervention was targeted for underserved Spanish-speaking Latino patients with chronic pain. SETTINGS/LOCATION: This study took place at a safety net academic teaching hospital, the Boston Medical Center, and at a community health center located in a majority Latino neighborhood, the East Boston Neighborhood Health Clinic. OUTCOME MEASURES: We used the validated Spanish translations of the Patient-Reported Outcomes Measurement Information System (PROMIS-29) (short version), Personal Health Questionnaire (PHQ-8), and Perceived Stress Scale (PSS-10). We also gathered qualitative information through focus groups and in-depth interviews. RESULTS: Using PROMIS measures, there was a statistically significant reduction in pain interference (p = 0.01), fatigue (p = 0.01), and depression (p = 0.01). Qualitative data also indicated the participants felt they benefited from the visits and having care in Spanish was unique. CONCLUSIONS: This model offers a promising nonpharmacological option for Spanish-speaking patients with chronic pain and could offer an alternative for addressing disparities for this population. PMID- 28885859 TI - Interventions Designed to Promote Exclusive Breastfeeding in High-Income Countries: A Systematic Review Update. AB - BACKGROUND: Worldwide, women seldom reach the recommended target of exclusive breastfeeding up to 6 months postpartum. The aim of the current study was to update a previously published review that presented a conceptual and methodological synthesis of interventions designed to promote exclusive breastfeeding up to 6 months in high-income countries. MATERIALS AND METHODS: A systematic search of leading databases was conducted for scholarly, peer reviewed, randomized controlled trials published from June 2013 to December 2016. Twelve new articles were identified as relevant; all were published in English and assessed exclusive breastfeeding with a follow-up period extending beyond 4 months postpartum. Articles were analyzed for overall quality of evidence in regard to duration of exclusive breastfeeding, using the Grading and Recommendations Assessment, Development, and Evaluation approach. RESULTS: A significant increase in the duration of exclusive breastfeeding was found in 4 of the 12 studies. All four successful interventions had long-duration postpartum programs, implemented by telephone, text message, or through a website. Some of the successful interventions also included prenatal education or in-hospital breastfeeding support. CONCLUSIONS: Results from this review update correspond closely with previous findings, in that all of the successful interventions had lengthy postnatal support or an education component. More studies assessed intervention fidelity than in the previous review; however, there was little discussion of maternal body-mass index. While a pattern of successful interventions is beginning to emerge, further research is needed to provide a robust evidence base to inform future interventions, particularly with overweight and obese women. PMID- 28885860 TI - Anti lingo 1 (opicinumab) a new monoclonal antibody tested in relapsing remitting multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). The modern treatment era for MS witnessed a growing pool of drugs now available for use in clinical practice. These therapies work at different levels, however there is a lack of treatments acting on the neurodegenerative component or improving mechanism of repair. Areas covered: The latest knowledge about the pathophysiological changes occurring in MS have translated into novel treatments at different stages of development. Drugs for MS work mainly through modulating the inflammatory factors of the disease, but enhancing remyelination may be more successful in reducing long-term disability. Anti-LINGO-1 (opicinumab) is the first investigational product that achieved phase I trial with the aim of remyelination and axonal protection and/or repair in MS. Expert commentary: Over the past decade considerable strength has been applied to find more reliable strategies to improve myelin repair. The anti-LINGO 1 trial showed that the drug is safe and tolerable. A future phase II trial will provide more insights regarding the compound. The greatest challenge for myelin repair therapies will be how to monitor their efficacy. Eventually research will need to focus on consistent tools to assess the grade of remyelination in vivo. PMID- 28885861 TI - Deuterated drugs; updates and obviousness analysis. AB - INTRODUCTION: The pharmacokinetics and/or toxicity of many known drugs can be modified by selective deuteration, an area of significant commercial interest and scientific and regulatory progress. Areas covered: This review firstly discusses recent developments in deuterated drugs including the FDA approval of deutetrabenazine. Secondly, it discusses 35 U.S.C. S103 'obviousness' as it relates to recent patent prosecution, and also to Inter Partes Review (IPR). IPR is a new post-award review of patentability under S102 or S103, two IPR petitions upon deuterated drugs have been instituted and included S103 arguments. Finally, an extended analysis of S103 obviousness based upon the practices of major pharmaceutical companies is provided, that supports rather late priority dates, while S102 is also discussed. Expert opinion: The total value of transactions involving deuterated drugs is close to $5 billion. While the importance of S103 'obviousness' rejections remains in patent applications under current prosecution, IPR of issued patents is developing and will affect likely affect S103 interpretations in this area. However, patents are still issuing with later priority dates, and further litigation will likely occur. PMID- 28885862 TI - Volume and Tissue Composition Changes Measured with Dual-Energy X-Ray Absorptiometry in Melanoma-Related Limb Lymphedema. AB - : Abstracts Background: The aim of this cross-sectional study was to investigate the volume, fat mass, and lean mass in both upper and lower limbs measured with dual-energy X-ray absorptiometry (DXA) in melanoma patients with melanoma-related limb lymphedema. METHODS AND RESULTS: Four hundred thirty-one patients who had undergone surgical treatment with wide local excision and unilateral axillary or inguinal sentinel lymph node biopsy and/or complete lymph node dissection participated in a survey, and they underwent clinical examination and measurements of their upper or lower limbs with DXA. Limb lymphedema was diagnosed on the basis of history and characteristic physical findings on the clinical examination. The inter-limb differences in volume, fat mass, and lean mass measured with DXA were categorized as none/mild, moderate, or severe according to reference values (taking handedness into account for the upper limbs). Of the 431 patients, 109 (25%) had clinical melanoma-related limb lymphedema corresponding to 23 (10%) who had undergone axillary nodal surgery and 86 (45%) who had undergone inguinal nodal surgery. The majority of patients developed lymphedema within the first year (90%) after surgery, and the majority of lymphedemas were categorized as mild. The increase in the volume of limbs with lymphedema was primarily due to an increase in fat mass. CONCLUSION: There is a high prevalence of melanoma-related limb lymphedema. The increase in volume in the limb with lymphedema is primarily due to an increase in fat mass. This increase in fat mass in limbs with lymphedema is important for the understanding of the pathophysiology and may be important in the treatment of lymphedema. PMID- 28885863 TI - Long Noncoding RNA Bladder Cancer Associated Transcript 1 Promotes the Proliferation, Migration, and Invasion of Nonsmall Cell Lung Cancer Through Sponging miR-144. AB - Nonsmall cell lung cancer (NSCLC) is a type of malignant tumor, accounting for 80% of all lung cancer morbidity. Long noncoding RNA (lncRNA) BLACAT1 (bladder cancer associated transcript 1), also known as linc-UBC1, has been tested to be an oncogenic lncRNA in other cancers. However, the role of BLACAT1 in NSCLC is still unknown. In clinical study, BLACAT1 expression was significantly upregulated in 48 cases of NSCLC tissues compared with adjacent normal tissues, especially in pathological TNM III samples. In NSCLC cells, BLACAT1 expression was also upregulated. Both in vivo and in vitro, BLACAT1 silencing transfected with si-BLACAT1 could suppress proliferation, migration, and invasion, and induce G0/G1 phase arrest. Bioinformatics methods and luciferase reporter assay revealed the close link within miR-144 and BLACAT1 3'-untranslated region (UTR). Furthermore, combining experiments of miR-144 and BLACAT1 indicated that miR-144 could reverse the function of BLACAT1 on NSCLC cells' phenotype. Overall, this study reveals the overexpression of BLACAT1 in NSCLC tissue and cells, and discovers the oncogenic role of BLACAT1 in NSCLC genesis through sponging miR 144, providing a potential biomarker for early detection and prognosis prediction of NSCLC. PMID- 28885864 TI - Examining Trauma and Readiness to Change among Women in a Community Re-Entry Program. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) and co-occurring substance use disorders (SUDs) are common among women who are incarcerated. OBJECTIVE: The purpose of this study was to examine the relationship between trauma and readiness to change substance use behaviors. METHODS: This study used data from 103 participants enrolled in a residential re-entry program for women with SUDs and trauma history. Women reporting clinically elevated Trauma Symptom Inventory (TSI) subscale scores were compared to those without elevated scores on the University of Rhode Island Change Assessment (URICA) readiness to change instrument. Primary analyses included t-tests and ANCOVA to control for age and ethnicity. RESULTS: In general, women with clinically elevated trauma scores also reported greater readiness to change. The analyses revealed significant differences on the URICA Readiness to Change scores between women who had elevated Defensive Avoidance and Impaired Self-Reference according to the TSI. Results approached significance for women who had elevated TSI subscale scores for Sexual Concerns and Dissociation. CONCLUSIONS: These results point to a need to further understand links between trauma and readiness to change, particularly, the role of posttraumatic growth and psychological distress. This study has implications for social workers and clinicians delivering evidence-based treatment. Women who had high trauma symptoms were more willing to address change. Findings also suggest a need to tailor interventions to include motivational components that are also trauma-informed. PMID- 28885865 TI - Changes in Insurance Coverage and Stage at Diagnosis Among Nonelderly Patients With Cancer After the Affordable Care Act. AB - Purpose To examine change in the percent uninsured and early-stage diagnosis among nonelderly patients with newly diagnosed cancer after the Affordable Care Act (ACA). Patients and Methods By using the National Cancer Data Base, we estimated absolute change (APC) and relative change in percent uninsured among patients with newly diagnosed cancer age 18 to 64 years between 2011 to the third quarter of 2013 (pre-ACA implementation) and the second to fourth quarter of 2014 (post-ACA) in Medicaid expansion and nonexpansion states by family income level. We also examined demographics-adjusted difference in differences in APC between Medicaid expansion and nonexpansion states. We similarly examined changes in insurance and early-stage diagnosis for the 15 leading cancers in men and women (top 17 cancers total). Results Between the pre-ACA and post-ACA periods, percent uninsured among patients with newly diagnosed cancer decreased in all income categories in both Medicaid expansion and nonexpansion states. However, the decrease was largest in low-income patients who resided in expansion states (9.6% to 3.6%; APC, -6.0%; 95% CI, -6.5% to -5.5%) versus their counterparts who resided in nonexpansion states (14.7% to 13.3%; APC, -1.4%; 95% CI, -2.0% to 0.7%), with an adjusted difference in differences of -3.3 (95% CI, -4.0 to -2.5). By cancer type, the largest decrease in percent uninsured occurred in patients with smoking- or infection-related cancers. A small but statistically significant shift was found toward early-stage diagnosis for colorectal, lung, female breast, and pancreatic cancer and melanoma in patients who resided in expansion states. Conclusion Percent uninsured among nonelderly patients with newly diagnosed cancer declined substantially after the ACA, especially among low-income people who resided in Medicaid expansion states. A trend toward early-stage diagnosis for select cancers in expansion states also was found. These results reinforce the importance of policies directed at providing affordable coverage to low income, vulnerable populations. PMID- 28885866 TI - Caspase inhibitors: a review of recently patented compounds (2013-2015). AB - INTRODUCTION: Although many caspase inhibitors have been patented, caspase inhibitors have not entered the market due to their toxicity and poor pharmacokinetic profile. Areas covered: In this article, we review patents (2013 2015) for peptide and non-peptide caspase inhibitors and their compositions. Expert opinion: Noteworthy patents include a peptidic caspase-2 inhibitor for nasal administration and a peptidomimetic caspase-6 inhibitor that can be administered via several routes for the treatment of neurodegenerative diseases. Furthermore, caspase-1 inhibitors for contact dermatitis and inflammation, cardiovascular diseases, and liver diseases and a caspase-3 inhibitor for cerebral stroke have been patented. Of particular interest is the novel use of tyrosine kinase inhibitors (sunitinib and its derivatives) for the prevention and treatment of age-related ocular diseases via inhibition of the caspase-3, dual leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) pathways. However, for effective clinical application of caspase inhibitors, novel peptidic and nonpeptidic caspase inhibitors with lower toxicity and improved efficacy should be developed via structural modifications, and further animal studies and preclinical and clinical trials are needed. In addition, the poor pharmacokinetic properties of classic caspase inhibitors may be improved by using advanced drug delivery systems that employ liposomes, polymers, and nanoparticles through effective administration routes. PMID- 28885867 TI - Clinical characteristics of recessive retinal degeneration due to mutations in the CDHR1 gene and a review of the literature. AB - BACKGROUND: The clinical phenotype of patients presenting with autosomal recessive CDHR1-related retinopathy has not been well described. MATERIALS AND METHODS: This is a retrospective case series of patients presenting to a single institution. Clinical data, including age, visual acuity, dilated fundus exam, fundus photos, fundus autofluorescence (FAF), optical coherence tomography, full field electroretinograms (ERGs), and results of genetic testing, were collected. RESULTS: Four patients were identified to have biallelic mutations in the CDHR1 gene. All four patients were found to have at least one c.783G>A (p.Pro261 = ) mutation. A novel splice site mutation, c.152-2A>G, was identified in two patients. Patients became symptomatic between the fourth and sixth decades of life. Three patients presented initially with nyctalopia and peripheral visual field constriction, and one patient presented with simultaneous onset of photophobia and nyctalopia. The fundus appearance was characterized by macular atrophy with or without peripheral retinal pigment epithelium changes and arteriolar attenuation. FAF showed a hyperautofluorescent ring surrounding a central area of speckled hypoautofluorescence. Full-field electroretinography was available on three patients and showed decreased cone-and-rod responses. CONCLUSIONS: CDHR1-related retinal dystrophy should be considered in adult patients with a retinal dystrophy who present with symptoms of cone-and-rod dysfunction and macular atrophy on ophthalmoscopic examination. PMID- 28885868 TI - Evaluating the MoA/human relevance framework for F-344 rat liver epithelioid granulomas with mineral oil hydrocarbons. AB - Toxicology feeding studies of mineral oil hydrocarbons (MOHs), within the carbon number range C22-C28, results in species-specific epithelioid granulomas in the liver of F-344 rats but not in other rat strains, or species. While MOH has been detected, and some pathological effects have been shown to occur in other organs/tissues of F-344 rats and other rat strains/species, it is generally accepted that the effect of toxicological concern is species-specific inflammatory liver granuloma. As oil retention and other MOH-related nontoxic pathological changes in the liver are observed in humans, some have hypothesized that the potential for oil accumulation over a lifetime, through dietary sources, may predispose humans to similar liver effects as observed in F-344 rats. To address this concern, a mode of action/human relevance framework (MoA/HRF) analysis for MOH-induced epithelioid granuloma in the F-344 rat model was developed. The key events for the development of liver epithelioid granulomas were identified as increased MOH intestinal absorption, preferential tissue retention and ultimately formation of necrotic granulomas encased by infiltrating inflammatory lymphocytes. The hypothesized MoA was evaluated using the modified Bradford Hill considerations for causality and was considered to be established in the F-344 rodent model. However, key strain/species differences in the rate of intestinal absorption, tissue retention of MOH and inflammatory response to MOH in the liver were identified. Overall, the F-344 rat MoA was not considered to be relevant to humans, consistent with data showing no evidence for the formation of epithelioid granulomas with humans even in cases of massive ingestion of MOHs. PMID- 28885869 TI - Improving Student Engagement in Veterinary Business Studies. AB - Improving Student Engagement in Veterinary Business StudiesIn a densely packed veterinary curriculum, students may find it particularly challenging to engage in the less overtly clinical subjects, yet pressure from industry and an increasingly competitive employment market necessitate improved veterinary student education in business and management skills. We describe a curriculum intervention (formative reflective assignment) that optimizes workplace learning opportunities and aims to provide better student scaffolding for their in-context business learning. Students were asked to analyze a business practice they experienced during a period of extra-mural studies (external work placement). Following return to the college, they were then instructed to discuss their findings in their study group, and produce a group reflection on their learning. To better understand student engagement in this area, we analyzed individual and group components of the assignment. Thematic analysis revealed evidence of various depths of student engagement, and provided indications of the behaviors they used when engaging at different levels. Interactive and social practices (discussing business strategies with veterinary employees and student peers) appeared to facilitate student engagement, assist the perception of relevance of these skills, and encourage integration with other curriculum elements such as communication skills and clinical problem solving. PMID- 28885870 TI - A Natural Experiment on the Effect of Time Given for Quizzes on Veterinary Student Performance in a Required Principles of Anesthesia Course. AB - Assessments can cause significant distress in veterinary students and are listed as some of the greatest causes of academic stress. The purpose of this natural experiment was to determine if there is a relationship between amount of time given to complete quizzes and the students' score on the quiz. The Principles of Anesthesia course is required of all students. Quizzes are administered at the start of a class period and spaced throughout the course to cover 2-4 lectures per quiz. Once the allotted time has passed (3-6 minutes), students are notified they have 2 minutes to return the quiz to the instructor. To complete the quiz, students had 3 minutes in 2012 and 2013, 4 minutes in 2014, 5 minutes in 2015, and 6 minutes in 2016. The average quiz score was significantly lower with 3 minutes than with 4 or 6 minutes. Students in the bottom quartile scored significantly higher with 4, 5, or 6 minutes than with 3 minutes. Students in the upper quartile scored significantly higher with 4 minutes than with 3 minutes and with 4 minutes than with 5 minutes. The time provided for students to complete a free-response quiz was not associated with student performance once a certain minimum time (4 minutes) was provided. Providing students an appropriate, but not excessive, amount of time to complete assessments will allow for appropriately applied assessments and preserve time dedicated to instruction. PMID- 28885871 TI - Using the Virtual World of Second Life in Veterinary Medicine: Student and Faculty Perceptions. AB - Virtual worlds are emerging technologies that can enhance student learning by encouraging active participation through simulation in immersive environments. At Ross University School of Veterinary Medicine (RUSVM), the virtual world of Second Life was piloted as an educational platform for first-semester students to practice clinical reasoning in a simulated veterinary clinical setting. Under the supervision of one facilitator, four groups of nine students met three times to process a clinical case using Second Life. In addition, three groups of four clinical faculty observed one Second Life meeting. Questionnaires using a 4-point Likert scale (1=strongly disagree to 4=strongly agree) and open-ended questions were used to assess student and clinical faculty perceptions of the Second Life platform. Perception scores of students (M=2.7, SD=0.7) and clinical faculty (M=2.7, SD=0.5) indicate that Second Life provides authentic and realistic learning experiences. In fact, students (M=3.4, SD=0.6) and clinical faculty (M=2.9, SD=1.0) indicate that Second Life should be offered to future students. Moreover, content analyses of open-ended responses from students and faculty support the use of Second Life based on reported advantages indicating that Second Life offers a novel and effective instructional method. Ultimately, results indicate that students and clinical faculty had positive educational experiences using Second Life, suggesting the need for further investigation into its application within the curriculum. PMID- 28885872 TI - Teaching Tip: Simulated Tumors as an Aid to Teaching Principles of Surgical Oncology. AB - Tumors of the skin and subcutaneous tissues are an important cause of morbidity and mortality in small animals. In many cases, surgical excision is an essential component of successful therapy and it should be performed in a specific way based on the type and grade of the tumor. Students require adequate training to develop both clinical decision-making skills and technical surgical skills, which we believe contribute to optimal clinical results. We have developed an inexpensive and simple technique that aims to replicate a naturally occurring subcutaneous tumor and allows trainees to plan and perform three common surgical procedures: incisional biopsy, marginal excision, and wide surgical excision. Artificial tumors were created by subcutaneous injection of a heated, oil-based solution that adhered to surrounding tissue as it solidified. Simulated masses were successfully created in all specimens. Many students performed the exercises with technical proficiency; however, some technical errors were identified and provided an opportunity to discuss the challenges of and solutions to several of these situations. This exercise may be a valuable addition to the veterinary curriculum, aiding student development of both technical skills and knowledge in the field of surgical oncology. PMID- 28885873 TI - Bovine Reproductive Palpation Training: Does the Cow Make a Difference? AB - Gaining experience and dexterity for trans-rectal cattle palpation requires substantial training. Simulation allows students to perform palpation without risks and to obtain feedback, but many believe live cattle palpation is essential. Limited research exists on the proper training method for live animal trans-rectal palpation. This study compared student improvement in laboratory palpation skills when assigned to the same cows versus choosing a cow at random. The hypothesis for the study was that students assigned the same cow, as compared to students choosing a cow at random, would be more accurate at palpation, would learn what structures are present on the ovaries and what size the reproductive tract measures, and would be able to follow the cyclicity of the cow. Cervical diameter, uterine tone, diameter of left and right uterine horns, and ovarian structures were recorded over time. Responses were compared to laboratory instructors' responses and Z-tests for proportions were used to test the differences in percentage correct at each time point for each palpation exercise. Overall the experiment showed that assigning students to certain cows will not improve their trans-rectal palpation training. However, asking students to identify specific landmarks with quantitative measurements did allow for more productive laboratory time and engaged students. The results of the present study also suggest that if there is limited time available for palpation instruction, choosing cows with behavior allowing easy handling is important to the educational process. PMID- 28885874 TI - Impact of Virtual Patients as Optional Learning Material in Veterinary Biochemistry Education. AB - Biochemistry and physiology teachers from veterinary faculties in Hannover, Budapest, and Lublin prepared innovative, computer-based, integrative clinical case scenarios as optional learning materials for teaching and learning in basic sciences. These learning materials were designed to enhance attention and increase interest and intrinsic motivation for learning, thus strengthening autonomous, active, and self-directed learning. We investigated learning progress and success by administering a pre-test before exposure to the virtual patients (vetVIP) cases, offered vetVIP cases alongside regular biochemistry courses, and then administered a complementary post-test. We analyzed improvement in cohort performance and level of confidence in rating questions. Results of the performance in biochemistry examinations in 2014, 2015, and 2016 were correlated with the use of and performance in vetVIP cases throughout biochemistry courses in Hannover. Surveys of students reflected that interactive cases helped them understand the relevance of basic sciences in veterinary education. Differences between identical pre- and post-tests revealed knowledge improvement (correct answers: +28% in Hannover, +9% in Lublin) and enhanced confidence in decision making ("I don't know" answers: -20% in Hannover, -7.5% in Lublin). High case usage and voluntary participation (use of vetVIP cases in Hannover and Lublin >70%, Budapest <1%; response rates in pre-test 72% and post-test 48%) indicated a good increase in motivation for the subject of biochemistry. Despite increased motivation, there was only a weak correlation between performance in final exams and performance in the vetVIP cases. Case-based e-learning could be extended and generated cases should be shared across veterinary faculties. PMID- 28885875 TI - Post-Traumatic Growth and Resilience in Adolescent and Young Adult Cancer Patients: An Overview. AB - The aim of this study was to provide an overview of the literature on post traumatic growth (PTG) and resilience among adolescent and young adult (AYA) cancer patients. A literature search in Embase, PsychInfo, PubMed, Web of Science, Cochrane Library, and Cinahl was carried out. Thirteen articles met the pre-defined inclusion criteria. Qualitative interview studies showed that AYA cancer patients report PTG and resilience: PTG is described by AYA cancer patients in terms of benefit finding, including changing view of life and feeling stronger and more confident, whereas resilience is described as a balance of several factors, including stress and coping, goals, optimism, finding meaning, connection, and belonging. Quantitative studies showed that sociodemographic and clinical characteristics were not associated with PTG. Enduring stress was negatively, and social support positively, associated with PTG. Symptom distress and defensive coping were negatively and adaptive cognitive coping was positively associated with resilience. Both PTG and resilience were positively associated with satisfaction with life and health-related quality of life (HRQoL). Resilience was found to be a mediator in the relationship between symptom distress and HRQoL. Two interventions aiming to promote resilience, a stress management and a therapeutic music video-intervention, were not successful in significantly increasing overall resilience. Most AYA cancer patients report at least some PTG or resilience. Correlates of PTG and resilience, including symptom distress, stress, coping, social support, and physical activity, provide further insight to improve the effectiveness of interventions aimed at promoting these positive outcomes and potentially buffer negative outcomes. PMID- 28885876 TI - Subcutaneous Draining of Lower Extremity Edema in a Patient With Advanced Cancer Relieves Scrotal Swelling and Improves Mobility. PMID- 28885877 TI - In Response to "Why Burnout Is So Hard to Fix". PMID- 28885878 TI - Reply to S. Prince. PMID- 28885879 TI - Infusion Room-Based Transition to Practice Model for Teaching Cancer Systemic Therapy Management. AB - PURPOSE: Oncology training requirements mandate that fellows demonstrate competence in delivery of cancer therapeutics, understand clinical indications for treatment, and manage toxicities by completion of training. An academic training environment may hinder fellows' engagement in prescribing, monitoring, and adjusting cancer therapy; thus, trainees may complete their fellowship with limited experience in developing such critical skills. To provide hands-on experience in cancer systemic therapy management, we created a novel infusion room-based rotation in the final year of training; here we report the structure, logistics, and evaluation of this innovative program. METHODS: In 2004, The University of Florida Hematology Oncology Fellowship Program created an outpatient infusion room rotation called Transition to Practice (TTP). We surveyed 20 graduates of the program to assess the ability of the rotation to teach skills necessary for systemic therapy management and identify which fellowship rotations had an impact on their readiness to practice independently. RESULTS: Nineteen graduates completed the survey. TTP was rated highest for promoting independence in making decisions related to therapy and adjustment to the treatment plan. It was less valuable in teaching the financial aspects of cancer therapy encounters. The Veterans Affairs Medical Center continuity clinic and the TTP rotation were highly regarded for preparing graduates to practice oncology independently. CONCLUSION: We consider the TTP model an effective learning environment for oncology trainees to develop the essential skill set for managing cancer systemic therapy on the basis of this single-institution analysis of recent graduates. This model could be applied to training other oncology professionals, such as advanced practice providers, who are new to the field. PMID- 28885880 TI - Bilateral Adrenalectomy for Metastatic Esophageal Adenocarcinoma: A Case Report. PMID- 28885883 TI - ? PMID- 28885882 TI - ? PMID- 28885884 TI - [The internet-based anorexia nervosa-register for adolescent patients in Germany]. PMID- 28885885 TI - ? PMID- 28885886 TI - ? PMID- 28885887 TI - ? PMID- 28885888 TI - Crossmodal processing of emotions in alcohol-dependence and Korsakoff syndrome. AB - INTRODUCTION: Decoding emotional information from faces and voices is crucial for efficient interpersonal communication. Emotional decoding deficits have been found in alcohol-dependence (ALC), particularly in crossmodal situations (with simultaneous stimulations from different modalities), but are still underexplored in Korsakoff syndrome (KS). The aim of this study is to determine whether the continuity hypothesis, postulating a gradual worsening of cognitive and brain impairments from ALC to KS, is valid for emotional crossmodal processing. METHODS: Sixteen KS, 17 ALC and 19 matched healthy controls (CP) had to detect the emotion (anger or happiness) displayed by auditory, visual or crossmodal auditory-visual stimuli. Crossmodal stimuli were either emotionally congruent (leading to a facilitation effect, i.e. enhanced performance for crossmodal condition compared to unimodal ones) or incongruent (leading to an interference effect, i.e. decreased performance for crossmodal condition due to discordant information across modalities). Reaction times and accuracy were recorded. RESULTS: Crossmodal integration for congruent information was dampened only in ALC, while both ALC and KS demonstrated, compared to CP, decreased performance for decoding emotional facial expressions in the incongruent condition. CONCLUSIONS: The crossmodal integration appears impaired in ALC but preserved in KS. Both alcohol-related disorders present an increased interference effect. These results show the interest of more ecological designs, using crossmodal stimuli, to explore emotional decoding in alcohol-related disorders. They also suggest that the continuum hypothesis cannot be generalised to emotional decoding abilities. PMID- 28885889 TI - A Genetic Variant of ASCT2 Hampers In Vitro RNA Splicing and Correlates with Human Longevity. AB - Given the role of amino acid regulation for physiological and pathological cell proliferation, we investigated whether the variability of solute carrier family 1, member 5 (SLC1A5, namely ASCT2), encoding for ASCT2 protein, a major glutamine transporter, is related to longevity. A total of 607 differently aged unrelated individuals, 351 very old subjects (>=85 years, range 85-106 years, mean age 93.82 +/- 4.44 years) and 256 younger controls (<85 years, range 64-84 years, mean age 73.60 +/- 5.70 years) were analyzed. Single-nucleotide polymorphisms (SNPs) were selected by a tagging SNP approach prioritizing those most likely to be of functional relevance. Genotyping was carried out using iPLEX Gold Genotyping Assay (Sequenom MassARRAY), and a logistic regression analysis was used to examine the associations between genotypes and the longevity phenotype. Age-associated variants were predicted to be involved in the alteration of an exonic splicing enhancer (ESE) site by Human Splicing Finder (HSF) v.3. Minigene constructs containing the alleles associated with longevity allowed the assessment of the functional effects of the polymorphisms. Two polymorphisms were found associated with human longevity (rs3027958 and rs1644343). Indeed, the major alleles of both SNPs positively influence the probability to become long lived. In vitro assays suggested that the minor allele of rs3027958 alters an ESE site, thus inducing intron retention. We provide evidence about the functional role of intronic variants of the ASCT2 gene in hampering the splicing process, and the effect of these variants on survival, confirming the crucial role played by this amino acid transporter in modulating longevity. PMID- 28885890 TI - Qualitative Radiogenomics: Association between Oncotype DX Test Recurrence Score and BI-RADS Mammographic and Breast MR Imaging Features. AB - Purpose To evaluate the association between Breast Imaging Reporting and Data System (BI-RADS) mammographic and magnetic resonance (MR) imaging features and breast cancer recurrence risk in patients with estrogen receptor-positive breast cancer who underwent the Oncotype DX assay. Materials and Methods In this institutional review board-approved and HIPAA-compliant protocol, 408 patients diagnosed with invasive breast cancer between 2004 and 2013 who underwent the Oncotype DX assay were identified. Mammographic and MR imaging features were retrospectively collected according to the BI-RADS lexicon. Linear regression assessed the association between imaging features and Oncotype DX test recurrence score (ODxRS), and post hoc pairwise comparisons assessed ODxRS means by using imaging features. Results Mammographic breast density was inversely associated with ODxRS (P <= .05). Average ODxRS for density category A was 24.4 and that for density category D was 16.5 (P < .02). Both indistinct mass margins and fine linear branching calcifications at mammography were significantly associated with higher ODxRS (P < .01 and P < .03, respectively). Masses with indistinct margins had an average ODxRS of 31.3, which significantly differed from the ODxRS of 18.5 for all other mass margins (P < .01). The average ODxRS for fine linear branching calcifications was 29.6, whereas the ODxRS for all other suspicious calcification morphologies was 19.4 (P < .03). Average ODxRS was significantly higher for irregular mass margins at MR imaging compared with spiculated mass margins (24.0 vs 17.6; P < .02). The presence of nonmass enhancement at MR imaging was associated with lower ODxRS than was its absence (16.4 vs 19.9; P < .05). Conclusion The BI-RADS features of mammographic breast density, calcification morphology, mass margins at mammography and MR imaging, and nonmass enhancement at MR imaging have the potential to serve as imaging biomarkers of breast cancer recurrence risk. Further prospective studies involving larger patient cohorts are needed to validate these preliminary findings. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28885891 TI - Signal Enhancement of the Dentate Nucleus at Unenhanced MR Imaging after Very High Cumulative Doses of the Macrocyclic Gadolinium-based Contrast Agent Gadobutrol: An Observational Study. AB - Purpose To test for measurable visual enhancement of the dentate nucleus (DN) on unenhanced T1-weighted magnetic resonance (MR) images in a cohort of patients with a primary brain tumor who had not received linear gadolinium-based contrast agents (GBCAs) but had received many injections of macrocyclic GBCAs. Materials and Methods Seventeen patients with high-grade gliomas who had received 10-44 administrations of the macrocyclic GBCA gadobutrol (0.1 mmol/kg of body weight) were retrospectively included in this regional ethics committee-approved study. Two neuroradiologists inspected T1-weighted MR images with optimized window settings to visualize small differences in contrast at the baseline and at the last examination for the presence of visual DN signal enhancement. Signal intensity (SI) in the DN was normalized to the SI of the pons, and a one-sample t test was used to test for differences between baseline normalized SI (nSI) in the DN (nSIDN) and the average change in nSIDN of all postbaseline MR imaging sessions (DeltanSIDNavg) or the change in nSIDN from baseline to the last MR imaging session (DeltanSIDN). Linear and quadratic correlation analyses were used to examine the association between the number of macrocyclic GBCA administrations and DeltanSIDN or DeltanSIDNavg. Results The mean +/- standard deviation number of macrocyclic GBCA administrations was 22.2 +/- 10.6 administered throughout 706 days +/- 454. Visually appreciable signal enhancement was observed in two patients who had received 37 and 44 macrocyclic GBCA injections. Mean DeltanSIDN was greater than zero (0.03 +/- 0.05; P = .016), and there was a significant linear association between the number of macrocyclic GBCA injections and DeltanSIDN (r = 0.69, P = .002) and DeltanSIDNavg (r = 0.77, P < .001). Conclusion A small but statistically significant dose-dependent T1-weighted signal enhancement was observed in the DN after multiple macrocyclic GBCA injections. Visually appreciable enhancement in the DN was observed on contrast optimized images in two patients who had received 37 and 44 standard doses of macrocyclic GBCAs. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28885881 TI - Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. AB - BACKGROUND: Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy. METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12 month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. RESULTS: Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. CONCLUSIONS: Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .). PMID- 28885892 TI - Bridging the Gap in Implementation Science: Evaluating a Capacity-Building Program in Data Management, Analysis, Utilization, and Dissemination in Low- and Middle-Income Countries. AB - Building capacity in implementation science within health programs is dependent on training in theory and practice of epidemiology, statistics, and research in addition to high self-efficacy toward application of training. This article describes a training program providing technical assistance to more than 300 health facilities in Kenya and Tanzania, its evaluation results, and its ability to improve participants' knowledge, competencies, and self-efficacy on data management, analysis, and dissemination among health care professionals. Two months prior to the training, participants (n = 98) were emailed a pre-course survey including 19 questions using a Likert-type response for planning the content of the workshop. Six to 12 weeks after the training, a post-course survey was emailed to all participants. Five different trainings were conducted indicating 5 participant cohorts. The questions posed involved course satisfaction, course impact on knowledge and skills, and self-efficacy in data analysis and utilization. Post-course survey results revealed that the participants had confidence in data analysis, which was significantly different from the pre-test results (0.05 alpha). Qualitative commentary complemented the findings of the impact of the workshop. Four manuscripts and 13 abstracts have been submitted post training. Results suggest that a short-term training program can achieve immediate gains in data and research self-efficacy among health care professionals. Although increasing self-efficacy is a necessary first step in developing skills, educators should engage in continuing education for sustainable dissemination practices. There is an urgent need to determine the current infrastructure to promote scientific dissemination. This will assist countries to produce better evidence to support their programs, policies, and overall health programs. PMID- 28885894 TI - Comparison of Self-Identified Minor-Attracted Persons Who Have and Have Not Successfully Refrained From Sexual Activity With Children. AB - The present study compares community-based minor-attracted persons (MAPs) with and without histories of sexual activity with children. MAP actors (N = 342) were significantly older than non-actors (N = 223), with longer duration of pedophilic attraction, more antisocial traits, greater attraction to boys, greater difficulty controlling their attraction, and more positive attitudes toward adult child sexual activity. Additionally, more MAP actors reported prior mental health treatment, nonsexual offenses, and childhood sexual and nonsexual abuse. Over a third of the whole sample reported chronic suicidal ideation. These findings support the existence of MAPs who successfully refrain from sexually engaging with children, identifying multiple protective and risk factors. PMID- 28885893 TI - Does Patient-Centered Medical Home Recognition Relate to Accountable Care Organization Participation? AB - As of April 2015, less than 10% of Medicare Shared Savings Program Accountable Care Organizations (MSSP ACOs) included Rural Health Clinics (RHCs). In order to understand why RHCs are not participating in this ACO model in greater numbers, this study examined the influence of several factors on ACO participation. Data for this study were collected via a survey distributed during the summers of 2012, 2013, and 2014 to all RHCs in 9 states. This study had a cross-sectional design using survey research. The unit of analysis was the RHC; the total sample size was 178. This study found that those respondents who reported knowing very little about ACOs had the lowest "willingness to join an ACO" score and that the passage of time increased RHC willingness to join an ACO. Also, patient-centered medical home (PCMH) recognition was the most influential factor related to an RHC's adopting the ACO model. If ACO model adoption is to increase in rural areas, this study suggests that strategies would need to include methods for (1) targeting RHCs that have PCMH recognition; (2) increasing PCMH recognition in rural areas; and (3) increasing RHC knowledge about what an ACO is, how the model works, and why this model may benefit RHCs and other rural primary care providers. PMID- 28885896 TI - A Systematic Review of Electronic Mindfulness-Based Therapeutic Interventions for Weight, Weight-Related Behaviors, and Psychological Stress. AB - INTRODUCTION: Recent research indicates that mindfulness-based interventions are effective for stress, maladaptive weight-related behaviors, and weight loss. Little is presently known about their applicability and effectiveness when delivered electronically, including through Web-based and mobile device media. The primary aims of this review were to identify what types of electronic mindfulness-based interventions have been undertaken for stress, maladaptive weight-related behaviors, and weight loss, and to assess their overall effectiveness. METHODS: A systematic search of PubMed (MEDLINE), Embase, CINAHL, and Web of Science databases was undertaken in June 2016. RESULTS: A total of 21 studies were identified that met inclusion criteria and were selected in the final review. Of these, 19 were mindfulness-based interventions for stress reduction. Two were Web-based mindful eating/intuitive eating interventions for weight. Only one electronic mindfulness-based study was identified that targeted both stress and maladaptive weight-related behaviors. Most electronic interventions were effective for stress reduction N = 14/19 (74%). There were insufficient electronic mindfulness-based interventions for weight to determine if they were effective or not. Additionally, no mobile mindfulness-based intervention was identified for weight or weight-related behaviors. CONCLUSION: Electronic mindfulness-based interventions through diverse media appear to be effective for stress reduction. More studies are needed that target weight and weight-related behaviors as well as studies that target both stress and weight. More randomized controlled trials (RCTs) that assess mobile mindfulness-based apps are needed as we only identified four app trials for stress. Mobile mindfulness-based interventions for weight and weight-related behaviors are a future area of research novelty. PMID- 28885895 TI - Meta-Analysis of Comparative Trials Evaluating a Prophylactic Single-Use Negative Pressure Wound Therapy System for the Prevention of Surgical Site Complications. AB - BACKGROUND: We report the first meta-analysis on the impact of prophylactic use of a specific design of negative pressure wound therapy (NPWT) device on surgical site complications. METHODS: Articles were identified in which the specific single-use NPWT device (PICO?, Smith & Nephew) was compared with standard care for surgical site infection (SSI), dehiscence, or length of stay (LOS). Risk ratio (RR) +/-95% confidence interval (CI) (SSI; dehiscence) or mean difference in LOS +/-95% CI was calculated using RevMan v5.3. RESULTS: There were 1863 patients (2202 incisions) represented by 16 articles. Among 10 randomized studies, there was a significant reduction in SSI rate of 51% from 9.7% to 4.8% with NPWT intervention (RR 0.49 [95% CI 0.34-0.69] p < 0.0001). There were six observational studies assessing reduction in SSI rate of 67% from 22.5% to 7.4% with NPWT (RR 0. 32 [95% CI 0.18-0.55] p < 0.0001). Combining all 16 studies, there was a significant reduction in SSI of 58% from 12.5% to 5.2% with NPWT (RR 0.43 [95% CI 0.32-0.57] p < 0.0001). Similar effects were seen irrespective of the kind of surgery (orthopedic, abdominal, colorectal, or cesarean section), although the numbers needed to treat (NNT) were lower in operations with higher frequencies of complications. There was a significant reduction in dehiscence from 17.4% to 12.8% with NPWT (RR 0.71 [95% CI 0.54-0.92] p < 0.01). The mean reduction in hospital LOS by NPWT was also significant (-0.47 days [95% CI -0.71 to -0.23] p < 0.0001). CONCLUSIONS: The significant reduction in SSI, wound dehiscence, and LOS on the basis of pooled data from 16 studies shows a benefit of the PICO single-use NPWT system compared with standard care in closed surgical incisions. PMID- 28885897 TI - Personal Pornography Viewing and Sexual Satisfaction: A Quadratic Analysis. AB - Personal pornography viewing has been associated with lower sexual satisfaction in both experimental and observational research. The language used to hypothesize this relationship typically suggests that it is frequent viewing, rather than infrequent or only occasional viewing, that is responsible for any adverse effects. When the nature of the relationship between a predictor and a criterion depends on the levels of the predictor, a curvilinear relationship is indicated. Nevertheless, studies have assumed linearity in their analytical approach. Curvilinear relationships will go undetected unless they are specifically tested. This article presents results from a survey of approximately 1,500 U.S. adults. Quadratic analyses indicated a curvilinear relationship between personal pornography viewing and sexual satisfaction in the form of a predominately negative, concave downward curve. The nature of the curvilinearity did not differ as a function of participants' gender, relationship status, or religiosity. But the negative acceleration was slightly more pronounced for men than for women, for people not in a relationship than for people in a relationship, and for religious people than for nonreligious people. For all groups, negative simple slopes were present when viewing reached once a month or more. These results are correlational only. However, if an effects perspective were adopted, it would suggest that consuming pornography less than once a month has little or no impact on satisfaction, that reductions in satisfaction tend to initiate once viewing reaches once a month, and that additional increases in the frequency of viewing lead to disproportionately larger decrements in satisfaction. PMID- 28885898 TI - Antibiotic Prescribing Practices for Prevention of Surgical Site Infections in Australia: Increased Uptake of National Guidelines after Surveillance and Reporting and Impact on Infection Rates. AB - BACKGROUND: Antimicrobial prophylaxis is the single most effective intervention to reduce risk of surgical site infections (SSIs); however, prescribing practices should be aligned with accepted and recommended surgical antibiotic prophylaxis (SAP) regimens to be effective. As part of a comprehensive surveillance network, SAP data are collated and analyzed for compliance with recommendations. Results are reported to hospitals for quality improvement purposes. In this study, statewide results were analyzed to ascertain changes over time and whether improved compliance was associated with a reduction in risk for SSI. METHODS: A standardized tool for monitoring SAP and SSIs was used in Victorian healthcare facilities. For the current study, data submitted for the period 2003-2015 were analyzed. Compliance with national recommendations (Australian Therapeutic Guidelines-Antibiotic) was used as the reference standard for antibiotic selection, timing, and duration Results: A total of 144,075 surgical procedures were surveyed during the study period. During this period, the proportion of patients receiving antibiotic agents according to national guidelines increased. Across all surgical groups, the odds ratio (OR) for appropriate SAP choice increased by 13%/year. Greatest improvement was seen for colorectal procedures (19%/year), with the smallest change observed for cholecystectomy and cardiac operations (9%/year). The OR for receiving an antibiotic agent at the recommended time increased by 12%/year and the odds of the antibiotic agent being discontinued within 24 hours by 27%/year. Non-compliance with a recommended SAP agent and timing was associated with an increased risk of SSI across all procedure groups (OR 1.33, 95% confidence interval 1.24-1.43). CONCLUSION: Sustained improvements in prescribing practices for SAP have been demonstrated through a comprehensive surveillance and reporting system. Non-compliance with SAP guidelines is associated with an increased risk for SSI. Quality improvement programs must focus on uptake and implementation of evidence-based guidelines. PMID- 28885899 TI - Watson, the game is a foot...or a palm. PMID- 28885900 TI - Renal denervation: Are we on the right path? PMID- 28885901 TI - Bedside manners: How to deal with delirium. PMID- 28885902 TI - Measuring both serum amylase and lipase for acute pancreatitis lowers quality and raises cost. PMID- 28885903 TI - A minimally invasive treatment for early GI cancers. AB - Endoscopic submucosal dissection (ESD) allows curative resection of early malignant gastrointestinal (GI) lesions, potentially avoiding open surgery. Unfortunately, awareness of this technique is low, and many patients undergo surgery without consideration of ESD. This article reviews the indications for ESD and its advantages and limitations, and guides internists in their approach to patients with early GI cancer. PMID- 28885904 TI - Reproductive planning for women after solid-organ transplant. AB - Women who receive transplants require contraception counseling because of the teratogenicity of immunosuppressant medications and the risks posed by pregnancy after transplant. Fortunately, pregnancy can succeed with careful planning and monitoring. PMID- 28885905 TI - Postoperative delirium in a 64-year-old woman. PMID- 28885906 TI - Another complication of cirrhosis. PMID- 28885907 TI - Antibiotic stewardship: Why we must, how we can. AB - Improving our antibiotic use is critical to the safety of our patients and the future of medicine. This can improve patient outcomes, save money, reduce resistance, and help prevent negative consequences such as Clostridium difficile infection. The US Centers for Disease Control and Prevention (CDC) is undertaking a nationwide effort to appropriately improve antibiotic use in inpatient and outpatient settings. PMID- 28885908 TI - Heartburn or heart attack? A mimic of MI. PMID- 28885909 TI - Palmar erythema as a sign of cancer. PMID- 28885910 TI - Metastatic pulmonary calcification and end-stage renal disease. PMID- 28885911 TI - Renal denervation: What happened, and why? AB - Despite promising results in initial trials, renal denervation failed to achieve its efficacy end points as a treatment for resistant hypertension in the SYMPLICITY HTN-3 trial, the largest trial of this treatment to date (N Engl J Med 2014; 370:1393-1401). Is renal denervation dead, or will future trials and newer technology revive it? PMID- 28885912 TI - To the Editor: Anticoagulation for atrial fibrillation. PMID- 28885913 TI - In Reply: Anticoagulation for atrial fibrillation. PMID- 28885914 TI - To the Editor: Cardiac mass: Tumor or thrombus? PMID- 28885915 TI - Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug. AB - PURPOSE: Liposomes have been studied as a colloidal carrier in drug delivery systems, especially for oral administration. However, their low structural integrity in the gut is still a major shortcoming. Membrane disruptive effects of physiological bile salts in the small intestine result in premature drug release prior to intestinal absorption. Thus, we analyzed the stabilizing effect of sodium deoxycholate when incorporated into nano-sized liposomes. METHOD: Cefotaxime-loaded liposomes were prepared with different sodium deoxycholate concentrations (3.75- 30 mM) by rotary film evaporation followed by nano-size reduction. The physical integrity of liposomes was evaluated by monitoring cefotaxime leakage, particle sizes in different simulated physiological media. The oral bioavailability and pharmacokinetics of cefotaxime was assessed in rats (n = 6 per group) after single dose of drug-encapsulated in liposomes containing bile salt, drug in conventional liposomes, and cefotaxime solution (oral and intravenous). RESULTS: Simulated gastric fluid with low pH showed less effect on the stability of liposomes in comparison to media containing physiological bile salts. Liposomes containing 15 mM sodium deoxycholate were most stable in size and retained the majority of encapsulated cefotaxime even in fed state of simulated intestinal fluid being the most destructive media. Pharmacokinetics data showed an increase in Cmax and AUC0-inf in the following order: cefotaxime solution < conventional liposomes < liposomes made with bile salts. The total oral bioavailability of cefotaxime in liposomes containing bile salt was found to be 5-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. CONCLUSION: Incorporation of bile salts, initially used as membrane permeation enhancer, also acted as a stabilizer against physiological bile salts. The nano-sized liposomes containing sodium deoxycholate were able to reduce the leakage of encapsulated cefotaxime in the gut due to the improved vesicle stability and to enhance the oral bioavailability of acid-labile drugs up to 5-fold. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28885916 TI - Calcitriol Reverses Induced Expression of Efflux Proteins and Potentiates Cytotoxic Activity of Gemcitabine in Capan-2 Pancreatic Cancer Cells. AB - PURPOSE: Efflux and influx proteins play a major role in chemo-resistance by affecting the net cellular uptake of anti-cancer drugs. Hence, alteration of the efflux and influx protein expression may result in variations of chemotherapeutics uptake and consequently cell death rate. The present study investigated the effects of pre-treatment of capan-2 pancreatic cancer cells with calcitriol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or silibinin on the induction of three major efflux proteins and the main gemcitabine influx protein. The influence of the pre-treatments on the net cellular uptake of gemcitabine, total ATPase activity, and cell death rate were also evaluated. METHODS: Capan-2 pancreatic cancer cells were pre-treated for 24 h with calcitriol, BHT, BHA, or silibinin, followed by gemcitabine treatment. The concentration of gemcitabine was quantified using ultra-performance liquid chromatography (UPLC). Real-time polymerase chain reaction (RT-PCR) was utilized in order to investigate the expression of the mRNAs. The expression of the proteins was assessed using western blotting. Measurement of the ATPase activity was conducted utilizing a colorimetric method and viability of the cells was determined using a luminescent cell viability assay. RESULTS: Protein expression studies showed that BHT, silibinin, and BHA increased expression of the efflux proteins and decreased the overall uptake of gemcitabine, whereas calcitriol significantly inhibited expression of the efflux proteins and increased gemcitabine uptake. Expression of specific mRNAs correlated reasonably well with the levels of corresponding proteins. Additionally, the expression of efflux proteins and ATPase activity were well correlated, signifying that the induced efflux proteins are functionally active. Moreover, pre-treatment with calcitriol resulted in a significant increase in cell death with gemcitabine treatment, whereas, BHA significantly reduced the cell death rate. On the other hand, pre treatment with BHT and silibinin had no significant effect on the cell death rate. CONCLUSIONS: Pre-treatment of the pancreatic cancer cells with calcitriol significantly increased gemcitabine cellular uptake and consequently decreased cell viability after treatment with gemcitabine, whereas BHA significantly reduced gemcitabine uptake and decreased cell death rate, which were at least partially attributed to the alteration of expression of efflux and influx proteins. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28885918 TI - Travelers' Diarrhea: An Update on the Incidence, Etiology, and Risk in Military Deployments and Similar Travel Populations. AB - Travelers' diarrhea (TD) has historically been a common illness among visitors to developing nations. Although recent studies indicate decreasing incidence of TD among short-term travelers, a systematic review of illness among long-term travelers, including deployed military personnel, has not been conducted in more than 10 years. We conducted a literature search of studies published between 2005 and 2015 that evaluated TD in populations of deployed military personnel or similar long-term travelers (travel >=1 month) to developing nations. Our literature search identified 28 studies for inclusion. We found that the incidence of TD remained high (10% clinical incidence, 30% self-reported incidence), with variability depending on region of travel and similar rates in both military and civilian long-term travelers. Bacteria (Escherichia coli, Campylobacter, Shigella, and Salmonella species) were the most commonly identified enteropathogens. Fifty percent of affected individuals experienced lost ability to work and 5% required hospitalization. This systematic review demonstrates that among deployed military personnel and long-term travelers, TD remains a prevalent disease that can significantly impact individual readiness for duty. These data demonstrate that to maintain operational readiness among deployed personnel, a focus on vigilance for disease and early treatment of cases is vital. PMID- 28885917 TI - Preface: Guidelines for the Treatment of Travelers' Diarrhea in Deployed Military Personnel. AB - Diarrheal disease frequently affects military personnel deployed to developing countries, resulting in decreased job performance and potential negative impacts on military operational readiness. Travelers' diarrhea is a self-limiting illness; however, antibiotic treatment (with and without use of adjunct loperamide therapy) has been shown to significantly reduce clinical presentation of symptoms and duration of illness. Nonetheless, the choice of first-line antibiotics must be carefully considered as increasing resistance of enteric pathogens in endemic regions has rendered many first-line antibiotics ineffective (e.g., Campylobacter spp. are resistant to fluoroquinolones in Southeast Asia). Presently, there are no standardized recommendations for the treatment of travelers' diarrhea among deployed military personnel. Therefore, an expert panel was convened to develop evidence-based, consensus-driven guidelines that address key clinical issues related to self-treatment, antibiotic treatment for acute watery diarrhea and febrile diarrhea/dysentery, and diagnostics. These guidelines "Management of Acute Diarrheal Illness during Deployment" are published in this supplement along with articles reviewing the evidence-based data that supported their development. PMID- 28885919 TI - Diagnostics in a Forward Deployed Setting. AB - Current diagnostic methods for enteric pathogens include conventional/traditional microbiology, microscopy, enzyme immunoassay, automated identification platforms, and molecular methods. The choice of diagnostic test in the forward deployed military setting often depends on turnaround time, potential etiologic agents, costs, and laboratory capabilities. The military operational environment presents many challenges that impact the practicality and performance of even robust diagnostic platforms. With recent developments in diagnostic platforms and availability of high-performance multiplex molecular methods to pair with traditional culture and antibiotic susceptibility tests, there are more opportunities to gather information on the etiologic causes and clinical impacts of traveler's diarrhea, both in civilians and in deployed military populations. Nevertheless, further assessment of new test methods is warranted to determine field applicability in forward deployed military settings. PMID- 28885920 TI - Antibiotic Therapy for Acute Watery Diarrhea and Dysentery. AB - Diarrheal disease affects a large proportion of military personnel deployed to developing countries, resulting in decreased job performance and operational readiness. Travelers' diarrhea is self-limiting and generally resolves within 5 days; however, antibiotic treatment significantly reduces symptom severity and duration of illness. Presently, azithromycin is the preferred first-line antibiotic for the treatment of acute watery diarrhea (single dose 500 mg), as well as for febrile diarrhea and dysentery (single dose 1,000 mg). Levofloxacin and ciprofloxacin are also options for acute watery diarrhea (single dose 500 mg and 750 mg, respectively) and febrile diarrhea/dysentery in areas with high rates of Shigella (500 mg once for 3 days [once daily with levofloxacin and twice daily with ciprofloxacin]), but are becoming less effective because of increasing fluoroquinolone resistance, particularly among Campylobacter spp. Another alternate for acute watery diarrhea is rifaximin (200 mg 3 times per day for 3 days); however, it should not be used with invasive illness. Use of loperamide in combination with antibiotic treatment is also beneficial as it has been shown to further reduce gastrointestinal symptoms and duration of illness. Because of regional differences in the predominance of pathogens and resistance levels, choice of antibiotic should take travel destination into consideration. PMID- 28885921 TI - Acquisition of Multidrug-Resistant Gram-Negative Organisms During Travel. AB - The rate of multidrug resistance has continued to increase worldwide, presenting clinicians with further challenges related to patient care. In this article, we review information related to the acquisition of multidrug-resistant (MDR) Gram negative organisms among travelers, including deployed personnel, as well as the potential impact on wound microbiology and travelers' diarrhea. Travel to Asia, experiencing travelers' diarrhea, and use of antibiotics, whereas abroad have been associated with an increased risk of acquiring MDR Enterobacteriaceae colonization. Acquisition of new pathogens (MDR and non-MDR) through travel may result in microbiome changes (both gastrointestinal and nongastrointestinal), which may lead to alterations in the gastrointestinal flora and antimicrobial resistance. Although the long-term impact of MDR Enterobacteriaceae is unknown, host colonization changes may occur, which could lead to infectious outcomes. In particular, a well-recognized complication is urinary tract infections (UTIs), whereas MDR wound infections, pneumonia, and travelers' diarrhea are also potential outcomes relevant to military health. PMID- 28885924 TI - Research on Health Effects of Low-Level Ionizing Radiation Exposure: Opportunities for the Armed Forces Radiobiology Research Institute. PMID- 28885923 TI - Implementation and Evaluation of Deployment Health Guidelines on Acute Diarrhea Management: A Medical Call to Arms. PMID- 28885925 TI - Military Global Health Engagement and Low-Dose Ionizing Radiation. PMID- 28885922 TI - Management of Acute Diarrheal Illness During Deployment: A Deployment Health Guideline and Expert Panel Report. AB - BACKGROUND: Acute diarrheal illness during deployment causes significant morbidity and loss of duty days. Effective and timely treatment is needed to reduce individual, unit, and health system performance impacts. METHODS: This critical appraisal of the literature, as part of the development of expert consensus guidelines, asked several key questions related to self-care and healthcare-seeking behavior, antibiotics for self-treatment of travelers' diarrhea, what antibiotics/regimens should be considered for treatment of acute watery diarrhea and febrile diarrhea and/or dysentery, and when and what laboratory diagnostics should be used to support management of deployment-related travelers' diarrhea. Studies of acute diarrhea management in military and other travelers were assessed for relevance and quality. On the basis of this critical appraisal, guideline recommendations were developed and graded by the Expert Panel using good standards in clinical guideline development methodology. RESULTS: New definitions for defining the severity of diarrhea during deployment were established. A total of 13 graded recommendations on the topics of prophylaxis, therapy and diagnosis, and follow-up were developed. In addition, four non-graded consensus-based statements were adopted. CONCLUSIONS: Successful management of acute diarrheal illness during deployment requires action at the provider, population, and commander levels. Strong evidence supports that single dose antimicrobial therapy is effective in most cases of moderate to severe acute diarrheal illness during deployment. Further studies are needed to address gaps in available knowledge regarding optimal therapies for treatment, prevention, and laboratory testing of acute diarrheal illness. PMID- 28885926 TI - Operation Babylift: Delivering a Nameless Cargo to Freedom, Part II. PMID- 28885927 TI - Woman in War. PMID- 28885928 TI - PTSD and Risk of Suicide. PMID- 28885929 TI - The Relationship Between Emerging Adult Alcohol Consumption and Military Enlistment. AB - BACKGROUND: The use and abuse of alcohol among active duty personnel is well documented in the research literature. Over the last decade rates of heavy and excessive drinking within the military have increased significantly, coinciding with both Operation Enduring Freedom and Operation Iraqi Freedom. The heavy use of alcohol by military personnel can be attributed to multiple factors such as the psychosocial and environmental stressors of military life and is frequently linked to mental health issues, the transient nature of the armed forces, the number and length of deployments, and exposure to life-threatening situations in combat environments. However, it is also likely rates of heavy alcohol use in the military are influenced by the possibility that individuals who already drink heavily choose to enlist in the armed services. The purpose of the present study was to test the association between drinking in emerging adulthood and military enlistment in a nationally representative sample of participants. METHODS: Using data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we tested the relationship between alcohol consumption in emerging adulthood and military enlistment in a sample of young adults ages 24 to 32 (n = 12,288). Results were stratified for men and women. FINDINGS: Results of the multivariate logistic regression models stratified by gender indicated male participants who reported consuming alcohol in the past year were more likely to join the military relative to nondrinkers after controlling for respondent age, race, and education. There were no significant associations between alcohol consumption and military enlistment for women. DISCUSSION: These findings demonstrate limited support for a relationship between alcohol consumption and military service. For men who drink, choosing military service may be influenced by the culture of drinking within the armed services. However, given the limited support found in the present study for a link between drinking in emerging adulthood and military service, the current high use of alcohol among active duty personnel is likely influenced by socialization processes within the military as well as from the stress of increased deployments to life-threatening combat situations. These results have important implications for informing policy and prevention programs within the armed services to improve both the short-term and long-term success of military service members. PMID- 28885930 TI - Therapeutic Lifestyle Changes: Impact on Weight, Quality of Life, and Psychiatric Symptoms in Veterans With Mental Illness. AB - INTRODUCTION: Veterans with mental illness tend to have shorter life spans and suboptimal physical health because of a variety of factors. These factors include poor nutrition, being overweight, and smoking cigarettes. Nonphysical contributors that may affect quality of life are the stigma associated with mental illness, social difficulties, and spiritual crises. Current mental health treatment focuses primarily on the delivery of medication and evidence-based psychotherapies, which may not affect all the above areas of a Veteran's life as they focus primarily on improving psychological symptoms. Clinicians may find greater success using integrative, comprehensive, multifaceted programs to treat these problems spanning the biological, psychological, social, and spiritual domains. These pilot studies test an adjunctive, holistic, behavioral approach to treat mental illness. This pilot work explores the hypotheses that engagement in a greater number of therapeutic lifestyle changes (TLCs) leads to improvement in quality of life, reduction of psychiatric symptoms, and weight loss. MATERIALS AND METHODS: Institutional Review Boards for human subjects at the Veterans Affairs (VA) Greater Los Angeles and Long Beach Healthcare Systems approved pilot study activities at their sites. Pilot Study 1 was a prospective survey study of Veterans with mental illness, who gained weight on an atypical antipsychotic medication regimen, participating in a weight management study. At each session of the 1-year study, researchers asked a convenience sample of 55 Veterans in the treatment arm whether they engaged in each of the eight TLCs: exercise, nutrition/diet, stress management and relaxation, time in nature, relationships, service to others, religious or spiritual involvement, and recreation. Pilot Study 2 applied the TLC behavioral intervention and examined 19 Veterans with mental illness, who attended four classes about TLCs, received individual counseling over 9 weeks, and maintained journals to track TLC practice. Besides weekly journals, researchers also collected prospective data on quality of life, psychiatric symptoms, vitals, and anthropometric measurements. In both studies, investigators tested for main effects of the total number of TLCs practiced and study week using mixed-effects linear models with independent intercepts by participant. RESULTS: In Study 1, engagement in more TLC behaviors was significantly associated with higher ratings of quality of life, as well as greater weight loss for each additional type of TLC practiced. In Study 2, TLC practice increased significantly over 9 weeks, and was significantly associated with improvements in quality of life and diastolic blood pressure. CONCLUSION: Counseling Veterans to practice TLCs provides a holistic adjunct to current treatments for mental illness. TLCs may confer multiple benefits upon Veterans with mental illness, enhancing quality of life and well-being along with weight management efforts. As these were pilot studies, the samples sizes were relatively small and a control group was lacking. Our findings may have broader implications supporting a holistic approach in both primary and mental health care settings. Future research will expand this work to address its weaknesses and examine the cost differential between this holistic approach and traditional mental health treatment. PMID- 28885931 TI - Impact of Engagement in Exercise on Sleep Quality Among Veterans With Posttraumatic Stress Disorder Symptoms. AB - BACKGROUND: Exercise has beneficial effects for physical health outcomes and has also been shown to reduce the severity of psychological health symptoms. Recent studies have shown a potentially positive impact of exercise on posttraumatic stress disorder (PTSD). Prominent among those with PTSD, sleep disturbance and nightmares are among the top three PTSD symptoms commonly reported by treatment seeking Veterans. Regular physical exercise has been consistently associated with better sleep. This study utilized a longitudinal design to explore the relationship between exercise and sleep among Veterans with PTSD symptoms at baseline and one-year follow-up. MATERIALS AND METHODS: Veterans (n = 76) who served in support of Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn were recruited for this study. Correlations were assessed between PTSD symptoms, sleep, and engagement in exercise at each time point (baseline, one year follow-up). Regression analyses were conducted to examine the relationship between engagement in exercise at baseline and PTSD symptoms at one-year follow up, as well as sleep quality at one-year follow-up. Regression models controlled for demographic variables (age and gender), alcohol use, baseline PTSD symptoms, and baseline sleep quality. RESULTS: Multiple regression analyses demonstrated that engagement in exercise at baseline was significantly associated with better sleep quality at one-year follow-up while controlling for age, gender, alcohol use, baseline PTSD symptoms, and baseline sleep quality (beta = -0.128, p < 0.05). Multiple regression analyses examining the relationship between engagement in exercise at baseline and PTSD symptoms at one-year follow-up (controlling for age, gender, alcohol use, baseline PTSD symptoms, and baseline sleep quality) did not yield statistically significant results (beta = 0.053, p = 0.57). CONCLUSION: Results from the present study found that engagement in exercise at baseline was associated with better sleep quality at one-year follow-up. These findings were consistent with the current literature suggesting exercise can have a positive impact on sleep quality. Furthermore, our findings suggest that exercise could be considered as an adjunctive intervention for individuals with PTSD-particularly for those patients whose difficulties with sleep are predominant. Given that exercise is highly accessible and is embedded in the military culture, future research should examine the way in which exercise can be leveraged in PTSD treatment, specifically in ameliorating sleep difficulties. Exercise may also reap demonstrable public health benefits in multiple psychological and physical domains and reduce the psychiatric and medical morbidity and mortality associated with PTSD. PMID- 28885932 TI - Screening for Complicated Grief in a Military Mental Health Clinic. AB - INTRODUCTION: Bereavement is one of the most common and stressful life experiences one can endure. Typical grief reactions follow a course of recovery in which individuals come to terms with the loss and resume functioning within weeks to months. However, for some, grief remains indefinitely distressing. Complicated Grief (CG) refers to significant chronic impairment that stems from bereavement. Military service members experience myriad factors that likely increase their risk for developing CG. Such factors include unique bonds between service members, exposure to constant and extreme levels of stress, multiple losses, separation from family and loved ones, witnessing/learning about sudden violent and traumatic deaths, and handling human remains. The aim of this project was to explore the practicality and efficiency of screening for CG within a busy military mental health clinic, and also explore relationships between contextual variables related to a death that might be associated with screening positive for CG. MATERIALS AND METHODS: As part of a clinical needs assessment, patients from a single mental health clinic at Naval Medical Center San Diego completed a brief grief survey that asked if they experienced a death of a person close to them, collected metrics related to losses they have experienced and included validated screeners for CG (The Brief Grief Questionnaire [BGQ] and the Inventory for Complicated Grief [ICG]). No data concerning gender, age, marital status, socioeconomic status, diagnosis, or purpose of visit (i.e., initial or follow-up visit) were collected. Institutional review board approval was obtained. RESULTS: In our sample of service members presenting to an adult outpatient military mental health clinic, 43.5% reported having experienced a loss that still impacts them. Of that group, 61.7% screened positive on the BGQ, 59.2% screened positive on the ICG using a cutoff of 25, and 46.1% screened positive on the ICG using the cutoff of 30. These findings suggest that military service members seeking mental health treatment who endorsed experiencing a loss are at high risk for experiencing persisting, impairing grief. Additionally, patients who either lost a fellow service member and/or experienced loss while on deployment reported significantly higher scores on the BGQ or ICG than if they did not report those factors. Furthermore, correlations between total number of losses and ICG scores suggest that service members who experienced multiple losses may be more susceptible to CG symptoms. CONCLUSION: The findings from this preliminary investigation suggest that many service members receiving care in military mental health care are experiencing grief-related symptoms and distress, and a brief screen for grief can help capture many of those with grief related impairment. Research shows that CG needs to be directly targeted to treat its symptoms and associated impairment. We recommend that military mental health clinics consider adding some type of grief screener to their standard intake as well as making providers aware of the importance of monitoring potential grief reactions in their patients. PMID- 28885933 TI - A Qualitative Study of Participation in Cardiac Rehabilitation Programs in an Integrated Health Care System. AB - INTRODUCTION: Despite strong incentives to use cardiac rehabilitation (CR), patient participation is low in the Veterans Health Administration (VHA). This is paradoxical given that VHA is an integrated health care system that offers a range of CR programs which should logically reduce barriers to access to CR participation. The purpose of this study was to better understand the contextual factors that influence patient participation in CR and how patients consider factors together when making decisions about CR participation. MATERIALS AND METHODS: Using a qualitative study design we examined patient and provider perceptions of CR across six VHA medical centers with high- and low-enrollment rates between December 2014 and October 2015. We conducted semistructured interviews with CR eligible patients who had both enrolled and not enrolled in CR (n = 16), cardiology providers who could refer patients to CR and CR staff who provided CR services (n = 15). Data were analyzed using grounded thematic techniques. RESULTS: We identified program and patient-specific factors related to CR participation. The four program factors were: program responsiveness to patient needs, CR schedule, specialized CR program equipment, and the CR program social environment. Program factors were primarily discussed by individuals associated with sites that had high CR enrollment rates. The patient-specific factor that promoted participation was patient perceptions of CR benefits. Disincentives to participation included competing conditions or obligations, logistical/cost challenges, convenience, and fear of exercise. CR participation entailed a complex process in which patients balanced factors that reinforced patient perceptions that CR was beneficial against factors that acted as disincentives to participation. CONCLUSIONS: CR participation was influenced by both program and patient factors. Patients weighed factors that fostered perceptions that CR was beneficial against factors that served as disincentives to CR participation when considering CR participation. High-enrollment sites may be better at countering disincentives to participate and/or improve patient perceptions of CR. Actionable ways to improve CR participation include encouraging providers to strongly and frequently endorse CR, educating patients about the importance and benefits of CR, emphasizing how exercises are individualized, supervised and monitored, educating patients about how CR is safe and effective, how CR offers peer support, and structuring CR programs to be responsive to patient needs in terms of duration, frequency, schedule, and location. PMID- 28885934 TI - Medical Encounters During a Joint Canadian/U.S. Exercise in the High Arctic (Exercise Arctic Ram). AB - The Arctic Ram Exercise was conducted in February 2016, near Resolute Bay on Cornwallis Island in Nunavut, Canada, to demonstrate the ability of the Canadian Armed Forces (CAF) to rapidly deploy to the arctic as an immediate response team. This report describes medical problems experienced by the 187 CAF and 28 U.S. forces involved in the exercise. Sixty-six airborne soldiers performed tactical static line jumps and linked up with soldiers on the ground for the exercise. Medical events were recorded by medics on the drop zone and by medical personnel at the Unit Medical Station in Resolute Bay. Average temperature during the exercise was -21 degrees C and wind chill was -44 degrees C. Two U.S. soldiers were injured in association with the jump and an additional 62 patients presented at the clinic during the exercise for an overall medical event incidence of 30%. The incidence of frostbite was 17%. At the end of the exercise, a physician actively examined CAF soldiers in one unit (n = 126) and found that 21% had experienced frostbite. The incidence of frostbite was high in this exercise compared to past cold-weather military operations, likely related to the very low temperatures and wind chills. PMID- 28885935 TI - Automated Bone Age Analysis with Lossy Image Files. AB - BACKGROUND: In our U.S. Department of Defense hospital system, pediatric endocrinology and radiology resources to evaluate bone age radiographs are limited. Our tertiary care center provides expert specialty support to remotely stationed beneficiaries at more than 30 Department of Defense medical facilities using a well-established, asynchronous, Health Insurance Portability and Accountability Act compliant system that allows for physician-to-physician teleconsultation. Up to 14% of these teleconsultations are for endocrinology assessment, many of which include bone age analysis. We sought to evaluate the feasibility of using an automated bone age analysis program using the file format most commonly provided to us, lossy JPEG image files saved at lower quality, to improve access to our consultation services. METHODS: All patients seen in the Tripler Army Medical Center pediatric endocrinology clinic, who were being evaluated for poor growth during the 2-month study period and who had a bone age film performed at Tripler Army Medical Center during that time, were eligible to have their deidentified bone age films analyzed. We imported lossy JPEG bone age image files from our hospital web viewer to BoneXpert, version 2.1, using a fully automated, custom built system that reconstructed each file's true resolution and then packaged the original image into a Digital Imaging and Communications in Medicine header. The original JPEG files were saved at 70% quality. Bone age readings were compared between our pediatric endocrinologists (ENDO), pediatric radiologists (RADS), and BoneXpert (BONE). Additionally, adult height prediction from ENDO and BONE were compared. FINDINGS: 35 bone age images were evaluated over a 2-month period. Most patients were being evaluated for idiopathic short stature or growth hormone deficiency. Analysis of variance showed no significant differences in mean bone age readings between the 3 groups (mean bone age reading = 9.0, 9.1, and 9.1 years for ENDO, RADS, and BONE, respectively, p = 0.827). Mean (SD) differences between physician and software bone age readings were -0.09 (0.89) years (ENDO) and -0.03 (1.01) years (RADS). Mean difference for adult height predictions was only -0.2 cm (p = 0.806). DISCUSSION: Automated analysis of lossy JPEG files of bone age images using the BoneXpert software appears to be feasible and accurate. Larger studies are needed to validate these results. PMID- 28885936 TI - Vancomycin vs. Vancomycin/Piperacillin-Tazobactam-Associated Acute Kidney Injury in Noncritically Ill Patients at a Tertiary Care Military Treatment Facility. AB - BACKGROUND: Broad-spectrum antibiotics are often used as initial empiric therapy in patients at risk for infections by multidrug-resistant organisms. Emerging literature and anecdotal reports within Tripler Army Medical Center indicate an increased incidence of vancomycin-associated acute kidney injury when used in combination with piperacillin-tazobactam. This is a retrospective, single-center study comparing the incidence of acute kidney injury in noncritically ill patients receiving either vancomycin or vancomycin in combination with piperacillin-tazobactam in a 206-bed tertiary care military training facility. METHODS: Data were collected from electronic medical records between May 2012 and October 2014 and evaluated via multivariable logistic regression models. Patients included for analysis were 17 years of age and older, were admitted to medical/surgical wards, and received vancomycin or vancomycin in combination with piperacillin-tazobactam for at least 48 hours. A vancomycin trough level, baseline serum creatinine level, and at least two follow-up serum creatinine levels were required for inclusion. Patients were excluded if they were pregnant, admitted to an intensive care unit while on antimicrobial therapy, or their baseline serum creatinine was equal to or greater than 1.5 mg/dL. RESULTS: Of 1,133 patients evaluated retrospectively, 455 were included for analysis. Of 202 patients, 49 (24%) taking vancomycin in combination with piperacillin-tazobactam developed acute kidney injury in contrast to 28 of the 253 patients (11%) given vancomycin without piperacillin-tazobactam (unadjusted odds ratio 2.57 [95% confidence interval (CI) 1.55-4.28], p < 0.001). Dual therapy remained significant after adjusting for age, sex, body mass index, concomitant nephrotoxic agents, and preexisting comorbid status as evaluated by Charlson comorbidity index (adjusted odds ratio 2.14 [95% CI 1.26-3.6], p = 0.005). Contrast administration (p < 0.001), fluoroquinolone administration (p < 0.001), and Charlson Comorbidity Index > 6 (p = 0.008) were also found to be independent risk factors for acute kidney injury. CONCLUSION: Significant increased incidence of nephrotoxicity was noted with vancomycin and piperacillin-tazobactam as compared to vancomycin within Tripler Army Medical Center. This finding influenced our institution's decision to add ceftaroline as a formulary agent in the treatment of skin and soft-tissue infections and further supported the need for rapid de-escalation of antibiotics within our military training facility. PMID- 28885937 TI - Utility of the Nanosphere Verigene in the Identification of Bacteremia Isolates From the Burn Intensive Care Unit. AB - INTRODUCTION: The Nanosphere Verigene Blood Culture Nucleic Acid Tests allow pathogen and antimicrobial resistance marker identification within 2.5 hours of a positive blood culture. This study assessed the sensitivity of the Verigene among Burn Intensive Care Unit (BICU) isolates and acceleration to targeted antibiotic therapy. METHODS: Bacterial identifications from BICU patients with positive blood cultures over 8 months were compared using 2 different platforms, the Verigene Gram-positive and Gram-negative blood culture tests vs. the bioMerieux Vitek2 automated system. Turnaround times were compared, and Verigene sensitivity for identification and resistance marker detection was calculated. Antimicrobial stewardship was assessed by comparing date/time for empiric and targeted therapy to the Verigene result time. RESULTS: Forty-four isolates (29 target and 15 nontarget) from 17 patients were included. The Verigene correctly identified 15 of 17 Gram-negative (sensitivity 88.2%; 95% confidence interval [CI] [87.9, 88.9]) and 8 of 12 Gram-positive target organisms (sensitivity 66.7%; 95% CI [66.3, 67.5]). None of the nontarget isolates were identified. There were no discordant identifications. Resistance marker identification by the Verigene was 100% concordant with confirmatory testing. For 11 isolates with complete laboratory and clinical data, the median time between Verigene and final culture results was 59.3 hours (37.3, 102.2) and from Verigene results to targeted therapy was 62.2 hours (43.6, 66.2). DISCUSSION: Reasons for lower sensitivity than previously reported are unclear and, on the basis of this limited retrospective review, further study in the BICU population is needed. The Verigene appears useful for antimicrobial stewardship by accelerating the identification of blood isolates. PMID- 28885938 TI - Hidden Hearing Injury: The Emerging Science and Military Relevance of Cochlear Synaptopathy. AB - INTRODUCTION: The phenomenon recently described as "hidden hearing loss" was the subject of a meeting co-hosted by the Department of Defense Hearing Center of Excellence and MIT Lincoln Laboratory to consider the potential relevance of noise-related synaptopathic injury to military settings and performance, service related injury scenarios, and military medical priorities. Participants included approximately 50 researchers and subject matter experts from academic, federal, and military laboratories. Here we present a synthesis of discussion topics and concerns, as well as specific research objectives identified to develop militarily relevant knowledge. MATERIALS AND METHODS: We consider findings from studies to date that have demonstrated cochlear synaptopathy and neurodegenerative processes apparently linked to noise exposure in animal models. We explore the potential relevance of these findings to the prediction and prevention of military hearing injuries, and to comorbid injuries in the neurological domain. RESULTS: Noise-induced cochlear synaptopathic injury is not detected by conventional audiometric assessment of threshold sensitivity. Animal studies suggest there may be a generous window of opportunity for intervention to mitigate or prevent cochlear neurodegenerative processes, e.g., by administration of neurotrophins or antioxidants. However, it is not yet known if the mechanisms that underlie "hidden hearing loss" also occur in human beings or, if so, how to identify them early, and how and when to intervene. CONCLUSION: Neurological injuries resulting from noise exposures via the auditory system have potentially significant implications for military Service Member performance, long-term Veteran health, and noise exposure standards. Mediated via auditory pathways, such injuries have possible relationship to clinical impairments including speech perception, and may be a largely overlooked contributor to cognitive symptoms associated with other military service-related injuries such as blast exposure and brain trauma. The potential health and performance consequences of noise induced cochlear synaptopathic injury are easily overlooked, especially if it is assumed that hearing threshold sensitivity loss is the major concern. There should be a renewed impetus to further characterize and model synaptopathic mechanisms of auditory injury; study its potential impact on human auditory function, cognition, and performance metrics of military relevance; and develop solutions for auditory protection (including noise dosimetry) and treatment if appropriate following noise or blast exposure in military scenarios. We identify specific problems, solution objectives, and research objectives. Recommended research calls for a multidisciplinary approach to address cochlear nerve synaptopathy, central (brain) dysfunction, noise exposure measurement and metrics, and clinical assessment. PMID- 28885939 TI - Outcomes From U.S. Military-Supported Overseas Training Rotations in Tropical Medicine and Global Health, 2006-2015. AB - BACKGROUND: Since 2006, the Division of Tropical Public Health at the Uniformed Services University (USU) has sponsored the Tropical Medicine Training Program (TMTP). Despite practice guidelines stating that global health education should include the collection and evaluation of data on the impact of the training experiences, no quantitative evaluation of program outcomes had previously occurred. The objective of this report was to evaluate TMTP outcomes to guide program improvement. METHODS: We developed an anonymous, web-based survey to assess program outcomes as part of routine program evaluation. The survey addressed four main areas of potential TMTP impact: (1) career engagement, (2) military service contributions, (3) scholarly activity, and (4) acquisition of knowledge and skills. In February 2016, we sent the survey electronically to 222 program participants between Fiscal Years 2006 and 2015 who had e-mails available in DoD administrative systems. FINDINGS: Ninety-eight (44%) of these responded to the survey. TMTP demonstrated impact in several areas. Increased knowledge and skills were reported by 81% of trainees, and 70% reported increased interest in serving at military overseas medical research laboratories. Subsequent career engagement by trainees included seven assignments to overseas research laboratories, 71 military deployments, and 193 short-term military missions. The ability to achieve many of the desired outcomes was associated with time elapsed since completion of formal medical education, including 24% who were still enrolled in graduate medical education. DISCUSSION/IMPACT/RECOMMENDATIONS: The TMTP has improved the U.S. military's ability to perform surveillance for emerging tropical and infectious diseases and has contributed to force health protection and readiness. Although many of the outcomes, such as service in the overseas research laboratories and military deployments, are dependent on military service requirements, these results remain perhaps the most relevant ways that the TMTP meets global health requirements of the US military and the nation. Additional outcomes from this training are expected to accrue as these participants complete their medical postgraduate training programs. PMID- 28885940 TI - Collaborative Systems Biology Projects for the Military Medical Community. AB - INTRODUCTION: This pilot study was conducted to examine, for the first time, the ongoing systems biology research and development projects within the laboratories and centers of the U.S. Army Medical Research and Materiel Command (USAMRMC). The analysis has provided an understanding of the breadth of systems biology activities, resources, and collaborations across all USAMRMC subordinate laboratories. METHODS: The Systems Biology Collaboration Center at USAMRMC issued a survey regarding systems biology research projects to the eight U.S.-based USAMRMC laboratories and centers in August 2016. This survey included a data call worksheet to gather self-identified project and programmatic information. The general topics focused on the investigators and their projects, on the project's research areas, on omics and other large data types being collected and stored, on the analytical or computational tools being used, and on identifying intramural (i.e., USAMRMC) and extramural collaborations. RESULTS: Among seven of the eight laboratories, 62 unique systems biology studies were funded and active during the final quarter of fiscal year 2016. Of 29 preselected medical Research Task Areas, 20 were associated with these studies, some of which were applicable to two or more Research Task Areas. Overall, studies were categorized among six general types of objectives: biological mechanisms of disease, risk of/susceptibility to injury or disease, innate mechanisms of healing, diagnostic and prognostic biomarkers, and host/patient responses to vaccines, and therapeutic strategies including host responses to therapies. We identified eight types of omics studies and four types of study subjects. Studies were categorized on a scale of increasing complexity from single study subject/single omics technology studies (23/62) to studies integrating results across two study subject types and two or more omics technologies (13/62). Investigators at seven USAMRMC laboratories had collaborations with systems biology experts from 18 extramural organizations and three other USAMRMC laboratories. Collaborators from six USAMRMC laboratories and 58 extramural organizations were identified who provided additional research expertise to these systems biology studies. CONCLUSIONS: At the end of fiscal year 2016, USAMRMC laboratories self-reported 66 systems biology/computational biology studies (62 of which were unique) with 25 intramural and 81 extramural collaborators. Nearly two-thirds were led by or in collaboration with the U.S. Army Telemedicine and Advanced Technology Research Center/Department of Defense Biotechnology High-Performance Computing Software Applications Institute and U.S. Army Center for Environmental Health Research. The most common study objective addressed biological mechanisms of disease. The most common types of Research Task Areas addressed infectious diseases (viral and bacterial) and chemical agents (environmental toxicant exposures, and traditional and emerging chemical threats). More than 40% of the studies (27/62) involved collaborations between the reporting USAMRMC laboratory and one other organization. Nearly half of the studies (30/62) involved collaborations between the reporting USAMRMC laboratory and at least two other organizations. These survey results indicate that USAMRMC laboratories are compliant with data-centric policy and guidance documents whose goals are to prevent redundancy and promote collaborations by sharing data and leveraging capabilities. These results also serve as a foundation to make recommendations for future systems biology research efforts. PMID- 28885941 TI - The Impact of Vaccine Refusal on Physician Office Visits During the Subsequent 12 Months. AB - We hypothesized that families who are nonadherent to the routine vaccination schedule (RVS) present less frequently for physician visits. We conducted a retrospective chart review to compare the number of visits made over the subsequent 12-month period by families that refused the RVS versus those who were adherent. Subjects were aged 0 to 4 years, enrolled to Keller Army Hospital, and had a diagnosis indicating the RVS was refused. Age-matched controls, who were adherent to the RVS, were randomly chosen for each case. Subjects made significantly more total visits than CASES: 7 (interquartile range [IQR] = 1-20) versus 6 (IQR = 2-17), p = 0.0049. When each visit type was compared independently, there was no significant difference in the number of acute (p = 0.494) or emergency department (p = 0.077) visits between groups. However, subjects who refused to follow the RVS made significantly fewer routine care visits during the 1-year follow-up period compared to those that adhered to the RVS (p < 0.001). PMID- 28885942 TI - Motivations for Weight Loss Among Active Duty Military Personnel. AB - INTRODUCTION: Rates of overweight and obesity among Active Duty Military Personnel remain high despite fitness test requirements, negative consequences of fitness test failure, and emphasis on weight and appearance standards. Specific motivating factors for weight loss influence weight loss program interest and often differ by gender, race, ethnicity, or age. This study investigates the weight loss motivations endorsed by a diverse population of Active Duty Military Personnel initiating a behavioral weight loss study, to inform the development of future recruitment efforts and program development. MATERIALS AND METHODS: Active Duty Military Personnel (n = 248) completed a 16-item questionnaire of weight loss motivations before initiating a behavioral weight loss study. We evaluated endorsement patterns by demographic characteristics (body mass index [BMI], gender, race, ethnicity, age, and military rank). Data collection for this study was approved by the Institutional Review Board of Wilford Hall Ambulatory Surgical Center and acknowledged by the Institutional Review Board of the University of Tennessee Health Science Center. RESULTS: Results indicated that improved physical health, improved fitness, improved quality of life, and to live long were endorsed as "very important" motivations by at least three-fourths of the sample. "To pass the fitness test" was endorsed less frequently as a "very important" motivation, by 69% of the sample. A greater proportion of women as compared to men endorsed being very motivated by improving mood/well-being, quality of life, physical mobility, job performance, appearance, and sex life, as well as fitting into clothes. Participants categorized in the "Other" racial group and African Americans more frequently endorsed motivations to improve fitness and physical strength when compared to Caucasians. Moreover, participants in the "Other" race category were significantly more likely to rate their ability to physically defend themselves, improve physical mobility, and improve interactions with friends as motivators. Participants who identified as Hispanic endorsed significantly higher frequency of being motivated to improve their ability to physically defend themselves, interactions with friends, physical mobility, and sex life compared to those who identified as non-Hispanic. A significantly lower percentage of officers of lower rank (i.e., O1-3) endorsed being motivated to improve their quality of life. Improving confidence was a significant motivator for younger and lower ranking enlisted personnel (i.e., E1 4). Younger participants were also significantly more likely to want to improve their ability to physically defend themselves. CONCLUSION: We conclude that overweight and obese Military Personnel are motivated by various reasons to engage in weight loss, including their military physical fitness test. Findings may assist the development of recruitment efforts or motivationally focused intervention materials for weight loss interventions tailored for the diverse population of Active Duty Military Personnel. PMID- 28885943 TI - Systematic Review of Live Tissue Versus Simulation Education for Prehospital Trauma Providers. AB - BACKGROUND: Advanced simulation capabilities have provided medical educators novel approaches for learners. Simulation has successfully replaced many aspects of medical education that previously used animal live-tissue training (LTT) for physician education. However, prehospital trauma providers, such as combat medics, currently used LTT to prepare for patient care. This use of LTT has sparked a debate about the optimal educational modality for this unique learner population. At this time, there is no clear evidence-based recommendation available to recommend either LTT or simulation as a superior modality. METHODS: The authors performed a systematic review of observational studies and randomized control trials (RCTs) to examine the use of LTT versus simulation in the trauma education of prehospital providers. The authors judged studies for inclusion and data abstraction independently and in duplicate, while also assessing quality and risk of bias. Since the literature demonstrated a heterogeneous background, no meta-analysis was performed. RESULTS: 12 studies met inclusion criteria: seven RCTs, four prospective cohorts, one cross-sectional study. Two of seven RCTs were presented as abstracts only. Ten of 12 studies were performed in a military setting, whereas two occurred in a civilian setting. Four studies used swine, two used goats, one used swine and goats, one used canines, and four did not specify the animal type. The authors used the Cochrane Collaboration tool to assess RCTs and found a considerable risk of bias. They used the Newcastle-Ottawa score to assess prospective cohorts (mean score of 5.75 +/- 0.5, range 1-9), and the cross sectional study (score 4, range 1-9). CONCLUSION: The existing literature provides limited, low-to-moderate quality outcome data. Evidence does not exist at this time to recommend either LTT or simulation as a superior educational modality for prehospital trauma care providers. PMID- 28885944 TI - The Value of Live Tissue Training for Combat Casualty Care: A Survey of Canadian Combat Medics With Battlefield Experience in Afghanistan. AB - INTRODUCTION: The optimum method for training military personnel for combat casualty care is unknown. In particular, there is debate regarding the incremental benefit of live animal tissue training (LTT) over inanimate human patient simulators (HPSs). Although both LTT and HPS are currently used for predeployment training, the efficacy of these models has not been established. MATERIALS AND METHODS: Canadian Armed Forces combat medics, deployed to Afghanistan between 2006 and 2011, were surveyed retrospectively regarding their experience with combat casualty care and predeployment training. HPSs were used to prepare these combat medics for early rotations. In later years, personnel received a combination of training modalities including HPS and LTT, using anaesthetized porcine models in accordance with appropriate animal care standards. Among those deployed on multiple rotations, there was a cohort who was prepared for deployment using only HPS training, and who later were prepared using mixed-modality training, which included LTT. We asked these medics to compare their predeployment training using HPS only versus their mixed-modality training in how each training package prepared them for battlefield trauma care. RESULTS: Thirty-eight individuals responded, with 20 respondents deployed on multiple rotations. Respondents performed life-saving skills during 89% of the rotations. Self-perceived competence and preparedness were notably higher after incorporation of LTT than after HPS alone. Of 17 respondents deployed on both early and late rotations, the majority felt the latter training was more worthwhile. In addition, almost all individuals felt that LTT should be added to HPS training. Narrative comments described multiple benefits of adding LTT to other types of training. CONCLUSIONS: Among many experienced Canadian Armed Forces personnel, LTT is considered essential predeployment preparation. Individuals who experienced only HPS training before active duty on their first combat deployment reported feeling more competent on subsequent combat deployments after the addition of live tissue models. IMPACT: There has been a movement away from the use of LTT in preparing combat medics for deployment. This article suggests that we should reconsider any decision to completely exclude Live Tissue Training as part of our training plan for combat medics. RECOMMENDATIONS: Military medical organizations should consider judiciously incorporating LTT with human patient simulation training to prepare combat medics for treating battlefield trauma. PMID- 28885945 TI - Effect of Novel Continuing Medical Education Curriculum on Attitudes and Understanding of Primary Care Medicine for the Naval Surface Provider. AB - INTRODUCTION: Naval Surface Forces provide care in austere environments with unique facility, personnel, and material limitations that can put the patient at risk without proper consideration of these circumstances. Tailored shipboard education currently exists but is greatly dependent on the time, preferences, expertise, and ability of a single teaching officer, allowing for significant variability in the level of training. MATERIALS AND METHODS: One hundred and twenty-two individuals were trained in 19 topics presented over 12 months through the Naval Surface Forces Pacific Command Medical Readiness Division to all surface providers on Naval Base San Diego. Participants completed pre- and post course assessments for each training session based on the objectives of the lesson, as well as reassessments and subjective course critiques every 3 months. RESULTS: Fifteen of 19 courses showed more than 20% improvement, with a range of improvement from 21 to 67%, and an average of 30% (95% confidence interval: 26.1 33.8, p < 0.001). Short-term follow-up showed higher-than-baseline scores at 6-, 9-, and 12-month follow-up; these were significantly higher than nonattendees (p = 0.003, 0.05, 0.004, respectively). Students who reported being either very confident or very confident and comfortable with teaching the content increased from 40.6% before the course to 60.8% after the course. Pre- (p = 0.02) and post- (p = 0.01) course level of confidence was directly correlated to students' assessment of the courses' applicability, with increasing level of confidence correlating to a perceived increase in applicability of the material. CONCLUSION: This study demonstrates improvement in Naval surface provider knowledge and attitudes in a variety of subject areas after implementation of a novel curriculum tailored specifically to address the unique considerations for practice at sea. Material was beneficial to all trainees despite significant differences in training background. Confidence gained as a result of the course was directly correlated to perceived relevance of the material, but not to educational background. Future work could investigate the use of curriculum in deployed providers and incorporation into current training of the OPNAVINST 6400.1c, Appendix A. PMID- 28885946 TI - The Association Between Service Members' Participation in Humanitarian Aid and Disaster Relief and Mental Health Symptoms and Treatments. AB - INTRODUCTION: There is a scarcity of research establishing a relationship between mental illness and the U.S. military service members who participate in the field of military humanitarian assistance/disaster relief (HA/DR). One of the few studies in this area showed that participation in military HA/DR was not associated with depressive symptoms, however, the study was limited by sample size. This study examined (1) the relationship between participation in military HA/DR and mental health symptoms and military stress and (2) the relationship between HA/DR and mental health treatment and therapy. MATERIALS AND METHODS: Data from the 2011 Health Related Behaviors Survey was used. The analytic sample consisted of U.S. military service members who participated in HA/DR (the Haiti earthquake and Deepwater Horizon oil spill in the Gulf) (n = 573) compared to those who participated in non-HA/DR deployments from 2007 to 2011 (n = 986). Multivariate models were used to examine the relationship between the independent variables and dependent variables while controlling for a set of variables that may confound the relationship between the two. RESULTS: The logistic regression model found that participating in HA/DR deployments decreased the likelihood of service members reporting post-traumatic stress disorder (PTSD) symptoms by 3% (p < 0.1) and depressive symptoms by 1% (p < 0.05). Furthermore, participation decreased the likelihood of having a prescription for antidepressants during and/or 3 months after deployment by 1% (p < 0.05). Additional results showed that junior enlisted and senior enlisted members were more likely to report symptoms of PTSD than senior officers (p < 0.05). Marines were more likely to seek treatment and therapy for depression than U.S. Coastguard members (p < 0.1). CONCLUSION: Results showed that participation in HA/DR was associated with significant reductions in PTSD symptoms, depressive symptoms, and the use of antidepressants by service members. Further research needs to understand the mechanism of these associations for better planning and implementation of HA/DR and delivery of care to service members who participate in these missions. PMID- 28885947 TI - Family Functioning Differences Across the Deployment Cycle in British Army Families: The Perceptions of Wives and Children. AB - INTRODUCTION: Military deployment can have an adverse effect on a soldier's family, though little research has looked at these effects in a British sample. We investigated wives' of U.K.-serving soldiers perceptions of marital and family functioning, across three stages of the deployment cycle: currently deployed, postdeployment and predeployed, plus a nonmilitary comparison group. Uniquely, young (aged 3.5-11 years) children's perceptions of their family were also investigated, using the parent-child alliance (PCA) coding scheme of drawings of the family. MATERIALS AND METHODS: Two hundred and twenty British military families of regular service personnel from the British Army's Royal Armoured Corps, were sent survey packs distributed with a monthly welfare office newsletter. Wives were asked to complete a series of self-report items, and the youngest child in the family between the ages of 3.5 and 11 years was asked to draw a picture of their family. Complete data were available for 78 military families, and an additional 34 nonmilitary families were recruited via opportunity sampling. RESULTS: Results indicated wives of currently deployed and recently returned personnel were less satisfied with their family and its communication, and children's pictures indicated higher levels of dysfunctional parent-child alliance, whereas predeployed families responded similarly to nonmilitary families. Marital satisfaction was similar across all groups except predeployed families who were significantly more satisfied. Nonmilitary and predeployed families showed balanced family functioning, and currently and recently deployed families demonstrated poor family functioning. In comparison to nonmilitary families, predeployed families showed a large "spike" in the rigidity subscale of the Family Adaptability and Cohesion Evaluation Scale IV. CONCLUSION: Wives' perceptions of family functioning, but not marital satisfaction, differed between the deployment groups. The results from the coded children's drawings correlated with the self-report measures from the wife/mother, indicating that children's drawings could be a useful approach when working with younger children in this area. It is tentatively suggested that the differences across deployment stage on family functioning could be mediated not only by communication difficulties between deployed personnel and their families, but also by its effect on the children in the family. Larger-scale longitudinal research is needed to investigate this further. PMID- 28885948 TI - Evaluating the Military Medical Evacuation Chain: Need for Expeditious Evacuation Out of Theater? AB - BACKGROUND: An important factor within the military medical logistical chain is the capability of expeditious evacuation from point of injury, through a Medical Treatment Facility, to the country of residence where highest level of care can be provided. Although many factors can relate to patient outcome, the evaluation of the medical evacuation chain related to long-term patient outcome can be important for investigating possibilities for performance improvement in this domain. This article aims to provide a means to evaluate the quality of care of the medical evacuation chain. METHODS: Repatriated service members from the Afghan theater between 2004 and 2014 were invited to participate in a survey concerning functional outcome and quality of life using Lower Extremity Functional Scale, Short Form health survey 36, and EuroQol-6D questionnaires. Possible associations between these outcomes were analyzed in respect to duration of medical evacuation from point of injury to arrival in the Dutch military hospital. The duration was dichotomized into within and after 72 hours. Ordinal regression was used to analyze a possible association with duration as a continuous variable. FINDINGS: Sixty percent (28/47) of battle casualties arrived in The Netherlands within 72 hours. For the nonbattle injury cohort this was 30% (7/23). Of those who became ill, 18% (5/28) was evacuated in 72 hours. No significant independent associations between interval duration and measured outcomes were found. CONCLUSION: Repatriated battle casualties had lower outcome scores compared to the disease nonbattle injured service members. Significant differences in functional outcome and quality of life with respect to evacuation duration were not found. Specialized tactical evacuation and en route care capability during strategic evacuation contributed to relative high standards of care. Combined with our results, this could implicate that delivery of the right care to the right patient at the right time is a justifiable paradigm. The main focus of the medical support organization is to offer the highest level of care per echelon as soon as possible in conjunction with facilitating maximum social support through expeditious evacuation out of theater. Further research using semistructured interviews among the direct circle around battle casualties, including caregivers, is needed to provide insight into these complex matters. PMID- 28885949 TI - Assessing Military Community Support: Relations Among Perceived Military Community Support, Child Psychosocial Adjustment, and Parent Psychosocial Adjustment. AB - INTRODUCTION: The emotional, cognitive, and behavioral health of the nearly two million children of military service members in the United States is important as these children play an integral role in the operational readiness of the armed forces. For example, when a service member's child experiences psychosocial difficulties, these difficulties often impact the service member's personal well being and ability to focus at work, impairing the service member's ability to focus on the mission. Although military service members and their families (e.g., children and spouses) face many of the same stressors as their civilian counterparts, they also experience additional stressors related to being a military family, including frequent relocation, unpredictable schedule changes, short- and long-term family separation, and threats to service members' safety. Psychosocial functioning and resilience to stress may be influenced by a variety of factors. One important factor that influences parent and child functioning is community support. Community support may be especially important for military families because of the increased significance of social support during stress such as deployment and geographic relocation. Research is promising regarding the protective effects of community support in civilian populations. However, there is a comparable dearth in the literature regarding military families and no validated measures designed specifically to assess the construct of community support in military families. We therefore aimed to develop and examine a new measure, the Community Assessment of Military Perceived Support (CAMPS) and examine its potential relationship with the psychosocial functioning of military parents and their children. MATERIALS AND METHODS: The CAMPS was developed and initially tested with both quantitative and qualitative methods. The CAMPS was then used to examine the relationships among perceived community support and child/parent psychosocial symptoms. This cross-sectional correlational study was conducted in a sample of military parents with children between the ages of 2 and 18 years of age who completed an online, anonymous survey. RESULTS: One hundred and fifty-seven military parents completed the CAMPS. Internal consistency was excellent (alpha = 0.94). More community support as measured by the CAMPS was associated with fewer child and parent psychosocial symptoms (p < 0.01) and the relationship between perceived military community support and child well-being was mediated by parent well-being (95% confidence interval [-0.19, -0.04]). Together, parent psychosocial functioning and perceived military community support explained 24% of the variance in child psychosocial functioning. CONCLUSION: The CAMPS is an internally consistent measure that appears to be associated with military parent and child psychosocial functioning. Given the importance of military community support, the CAMPS may have potential as a tool for outcome research and program evaluation. Future research is required to validate the CAMPS in a larger, more diverse military sample. Moreover, longitudinal studies are needed to determine the directionality of the relationship between community military support and psychosocial functioning. PMID- 28885950 TI - Family Characteristics Associated With Child Maltreatment Across the Deployment Cycle of U.S. Army Soldiers. AB - OBJECTIVE: Soldier deployment can create a stressful environment for U.S. Army families with young children. Prior research has identified elevated rates of child maltreatment in the 6 months immediately following a soldier's return home from deployment. In this study, we longitudinally examine how other child- and family-level characteristics influence the relationship of deployment to risk for maltreatment of dependent children of U.S. Army soldiers. METHODS: We conducted a person-time analysis of substantiated reports and medical diagnoses of maltreatment among the 73,404 children of 56,087 U.S. Army soldiers with a single deployment between 2001 and 2007. Cox proportional hazard models estimated hazard rates of maltreatment across deployment periods and simultaneously considered main effects for other child- and family-level characteristics across periods. RESULTS: In adjusted models, maltreatment hazard was highest in the 6 months following deployment (hazard ratio [HR] = 1.63, p < 0.001). Children born prematurely or with early special needs independently had an increased risk for maltreatment across all periods (HR = 2.02, p < 0.001), as well as those children whose soldier-parent had been previously diagnosed with a mental illness (HR = 1.68, p < 0.001). In models testing for effect modification, during the 6 months before deployment, children of female soldiers (HR = 2.22, p = 0.006) as well as children of soldiers with a mental health diagnosis (HR = 2.78, p = 0.001) were more likely to experience maltreatment, exceeding the risk at all other periods. CONCLUSIONS: Infants and children are at increased risk for maltreatment in the 6 months following a parent's deployment, even after accounting for other known family- and child-level risk factors. However, the risk does not appear to be the same for all soldiers and their families in relation to deployment, particularly for female soldiers and those who had previously diagnosed mental health issues, for whom the risk appears most elevated before deployment. Accounting for the unique needs of high-risk families at different stages of a soldier's deployment cycle may allow the U.S. Army to better direct resources that prevent and address child maltreatment. PMID- 28885951 TI - Providers' Perspectives on Barriers and Facilitators to Connecting Women Veterans to Alcohol-Related Care From Primary Care. AB - BACKGROUND: Unhealthy drinking is relatively common among women U.S. military Veterans. Primary care is often the setting where patients first come into contact with the health care system, and providers in this setting play a critical role in connecting unhealthy drinkers to appropriate care. Little is known about primary care providers' perspectives on factors that affect whether women Veterans presenting to primary care with unhealthy drinking connect to alcohol-related care. Understanding factors that affect whether patients connect to alcohol-related care may improve providers' ability to support women Veterans with unhealthy drinking get needed care. METHODS: This qualitative study used semi-structured interviews with 14 providers from two Veterans Administration Women's Health primary care clinics, including nurses, nurse practitioners, physicians' assistants, and physicians, and colocated mental health providers. The interviews were transcribed, and themes pertaining to providers' perspectives on barriers and facilitators to connecting women Veterans' with unhealthy drinking to alcohol-related care were identified through template analysis. FINDINGS: Primary care providers perceived numerous provider- and clinic-level factors as relevant to their ability to connect women Veterans to alcohol-related care. Barriers providers described were insufficient care resources, provider prioritization of alcohol-related care, insufficient knowledge of care options or the referral process among providers, time constraints during routine clinical visits, and the referral process for alcohol-related care. They also described resources available in primary care, primary care provider behaviors, and initiatives at the Veterans Administration as helpful. DISCUSSION: Although primary care providers are gatekeepers to specialty treatment services, ongoing education, and colocated mental health staff could help reduce barriers to these services, ultimately improving health outcomes for women Veterans and others with unhealthy drinking. PMID- 28885952 TI - Military Sexual Trauma in Female Veterans is Associated With Chronic Pain Conditions. AB - INTRODUCTION: Little is known about the impact of MST on chronic pain conditions among female Veterans. The primary objective of this study was to compare the prevalence of chronic pain conditions among U.S. female veterans with a history of military sexual trauma (MST) to those without a history of MST. We anticipated that female Veterans with a history of MST would have higher associations with chronic pain conditions than the female Veterans without a history of MST. MATERIALS AND METHODS: This was a large-scale, retrospective study using the Veterans' Health Administration Corporate Data Warehouse with institutional approval (15-H175). International Classification of Diseases, 9th Revision codes from the outpatient visits, outpatient problem lists, and inpatient discharge diagnoses were used to identify chronic pain diagnoses. Baseline demographic data including date of birth, self-identified race/ethnicity, and body mass index were obtained. Significant findings in the univariate analysis were then placed into a multivariable logistic regression model to adjust the effect of each predictor for the presence of others. Significance was set at p < 0.01 because of multiple comparisons made. RESULTS: For the entire cohort (516,950 women), 28.9% (149,540) were diagnosed with headaches, 18.3% (94,393) with chronic pelvic pain, 14.4% (74,216) with chronic back pain, 10.5% (54,302) with nonspecific joint pain, 9% (48,509) with fibromyalgia, 6.2% (32,037) with generalized abdominal pain, 4.2% (21,911) with irritable bowel syndrome, and 3.2% (16,309) with dyspareunia. Most women had more than one chronic pain diagnosis. At baseline, women with a history of MST were younger (63.3 +/- 15.9 vs. 67.4 +/- 17.9 years p < 0.001), heavier (29.5+/- 6.2 vs. 28.8 +/- 6.1 kg/m2 p < 0.001), smokers (49.3 vs. 38.8% p < 0.001), and more likely to be non-Hispanic white (56.3 vs. 52.3% p < 0.001) than women without a history of MST. Women with a history of MST had more pain diagnoses than those without the history of MST (all p < 0.001). The adjusted odds ratio of women with history of MST presenting with any pain condition compared to a women without a history of MST was 1.26 (95% confidence interval 1.24-1.28). In the multivariable model there remained an association between MST and chronic pain conditions including irritable bowel syndrome, chronic pelvic pain, back pain, chronic joint pain, fibromyalgia, dyspareunia, chronic abdominal pain, and headaches after adjusting for baseline differences in age, body mass index, smoking, and ethnicity. Importantly, drug abuse, and overdose were also associated with MST. CONCLUSION: A history of MST is associated with chronic pain diagnoses. Weaknesses of this study are those applicable to analyses of any retrospective database study. Specifically, the data are limited by the accuracy of physician coding and reporting. The strength of this study is that it represents a comprehensive, retrospective evaluation of potential sources for chronic pain within the female veteran population. In summary, we found that female veteran survivors of MST face an increased burden of chronic pain, including a broad range of pain conditions independent of the psychological effects of MST. PMID- 28885953 TI - Expanding the Understanding of Risk Behavior Associated With Homelessness Among Veterans. AB - INTRODUCTION: To advance large-scale efforts to end veteran homelessness, an understanding of factors that contribute to housing insecurity is necessary. Common risk behaviors (e.g., substance use and risky sexual practices) are associated with lengthier experiences of homelessness among the general homeless population, but less understood among homeless veterans. Additionally, whether emerging risk behaviors among veterans (e.g., sensation seeking and aggression) are associated with lengthy homeless experiences is unknown. MATERIALS AND METHODS: Data were drawn from a sample of Los Angeles County veterans surveyed using a mixed nonprobability sampling strategy, which included recruiting veterans via national and local veterans service organizations, college organizations, and social media campaigns. Measures aligning with factors of sensation seeking (reckless driving, gambling, suicidal ideation); substance use (alcohol misuse, tobacco use, driving while intoxicated); risky sexual practices (risking getting a sexually transmitted disease); and aggression (looking to start a fight) were tested in multivariate, multinomial logistic regression analyses to determine their association with varying lengths of homelessness in the past year (less than 1 month, 2-6 months, 6 months to 1 year). RESULTS: Risking getting a sexually transmitted disease, gambling, suicidal ideation, alcohol misuse, tobacco use, driving while intoxicated, and looking to start a fight were associated with 6 or more months of homelessness. Several indicators of risk were associated with brief periods of homelessness, including gambling and looking to start a fight. Although a clear exposure-response effect was not detected with risk behaviors, results suggested there may be some wavering of engagement in risk behaviors over time. CONCLUSION: Findings suggest sensation seeking and aggression risk behaviors should be included in risk assessments and prevention efforts along with substance use and risky sexual practices to reduce veterans' risk of becoming homeless and reducing risk of chronic homelessness. Further research is needed to understand the trajectory of these risk behaviors and the mechanisms that underlie the association between these risk behaviors and homelessness for veterans. PMID- 28885954 TI - Medical Evaluation Board for Mental Health Condition: U.S. Army Officer Medical Evaluation Board Data by Branch and Component. AB - OBJECTIVE: A retrospective review of Medical Evaluation Board (MEB) data to determine the effect of career field or Army component on the relative risk for mental health (MH) related MEBs among Army Officers, may identify specific populations for enhanced screening before accession, or groups that may require targeted preventive resources during their careers. METHOD: 4 years' of data available on Army Officers from the Department of the Army's Electronic Disability Evaluation System database, contained specific information on the officers' physical profiles, career fields, and service component. This information was compared with a dataset provided by the Defense Manpower Data Center (DMDC), reporting documented force strength by career field and service component for the corresponding years, allowing for calculation and comparison of MEB and MH-MEB rates between Army components and between career fields. RESULTS: Significant differences in MEB and MH-MEB rates were found between Army components, but database gaps make this assessment uncertain. When comparing MEB and MH-MEB rates between career fields (regardless of service component), 9 career fields had statistically significant higher risk rates of MEB and/or MH MEB, whereas 13 career fields showed significantly lower rates of MEB and/or MH MEB. CONCLUSION: Frequency of Army Officer MEBs and/or MH-MEBs were variable and career field dependent; the underlying causes of these variations warrant further research. The use of the Electronic Disability Evaluation System database for the Integrated Disability Evaluation System process is a rich source of data for in depth analysis, but the program itself and the procedures for its use need to be improved to obtain more complete information. PMID- 28885955 TI - Comparison of Clinical Features in a Population of Basic Military Trainees Versus the General Department of Defense Beneficiary Population Presenting With Influenza. AB - INTRODUCTION: Upper respiratory tract infection (URI) is a well-documented cause of morbidity, extra expense, and lost training time among basic military trainees (BMTs). The goal of this study was to characterize the clinical presentation of influenza in the BMT population and to better understand how this presentation differs from that of the general Department of Defense (DoD) beneficiary population (non-BMTs). MATERIALS AND METHODS: Clinical and demographic data were collected in a prospective study that enrolled DoD beneficiaries presenting to medical treatment facilities in San Antonio, Texas, with URI symptoms between January 2005 and March 2011. Vital signs and symptom duration were collected at the time of enrollment along with basic demographic information. RESULTS: Among 4,448 participants enrolled, 466 (10.5%) tested positive for influenza: 198 of 3,103 BMTs (6.4%) vs. 268 of 1,345 non-BMTs (20%) (p < 0.01); 412 of 466 had complete data for nine symptom-related variables. BMTs were more likely to be Caucasian males and younger than non-BMTs. BMTs had a higher temperature at the time of presentation (101.5 degrees F vs. 100.5 degrees F, p < 0.01). BMTs presented less frequently than non-BMTs with chills (79.7% vs. 94.4%, p < 0.01), malaise (62.1% vs. 87.0%, p < 0.01), nausea (30.2% vs. 43.0%, p < 0.01), and vomiting (12.1% vs. 21.7%, p = 0.01). Multiple logistic regression analysis showed that BMTs were less likely to have the four symptoms compared to non-BMTs even after controlling for gender and age (chills: odds ratio [OR] = 0.3, 95% confidence interval [CI] = 0.1-0.6, p < 0.01; malaise: OR = 0.5, 95% CI = 0.3 0.8, p < 0.01; nausea: OR = 0.5, 95% CI = 0.3-0.8, p < 0.01; vomiting: OR = 0.4, 95% CI = 0.2-0.8, p < 0.01). Although there was no difference in the frequency of subjective fever between the two groups, reported duration of fever was significantly shorter in BMTs than non-BMTs: median of 1 day (range 0-10) vs. 2 days (range 0-8) (p < 0.01). BMTs presented with a composite symptom index mean of 6.2 (standard deviation = 1.4) symptoms, whereas non-BMTs presented with a mean of 6.9 (standard deviation = 1.3) symptoms (p < 0.01). CONCLUSIONS: The pretest probability of a BMT presenting with URI symptoms having influenza is significantly lower than that for the general DoD beneficiary population. BMTs with influenza presented sooner, with higher fever, and with fewer overall symptoms than the general DoD beneficiary population. These differences are likely attributable to early reporting and response bias and less likely attributed to age. Military efforts to identify BMTs with suspected influenza infection early and to refer them for treatment promptly are efficacious. PMID- 28885956 TI - Combat Casualties and Severe Shock: Risk Factors for Death at Role 3 Military Facilities. AB - BACKGROUND: Although significant research has been conducted on combat casualties receiving blood products, there is limited data for the subpopulation presenting in shock. The purpose of this study was to evaluate combat casualties arriving to a role 3 facility with an initial systolic blood pressure (SBP) <= 90 in order to identify clinical characteristics and associations between presentation, transfusion therapy, and mortality outcomes. METHODS: The Department of Defense Trauma Registry was queried from 2001 to 2010 for trauma-related casualties who arrived at a role 3 combat surgical facility with a SBP <= 90. Transfers from role 2 facilities were excluded. Data captured included demographics, admission vital signs, laboratory values, blood products, and mortality. Relationships between admission physiology, blood product utilization, and mortality were developed. Independent associations between variables were determined by logistic regression analysis. RESULTS: 1,703 patients were identified who met our inclusion criteria and composite mortality was 23%. Mortality in those receiving a balanced transfusion ratio was 18% versus 27% (p < 0.0001). Hypotensive casualties who survived were significantly more likely to have a higher presenting Glasgow Coma Score (GCS), temperature, SBP, shock index, and pH. In addition, this group was also more likely to have a lower international normalized ratio, pCO2, and base deficit (p < 0.001). Age, heart rate, and pulse pressure were not significantly different between groups. Independent predictors of mortality included Injury Severity Score, presentation GCS, and initial pH value (p < 0.0001). In contrast, independent predictors of survival included those with above-knee amputation and a balanced transfusion (p < 0.0001). CONCLUSIONS: Combat casualties hypotensive on arrival to surgical facilities have a significant expected mortality. Those receiving balanced transfusions demonstrated improved survival. Of the five independent risk factors, pH, GCS, and the presence of above-knee amputation are typically available during initial evaluation. These factors may be helpful in determining resource allocation and mortality risk, especially in triage or mass casualty settings. PMID- 28885957 TI - Blunt Scrotal Trauma in Soldiers-Epidemiology and Outcome. AB - INTRODUCTION: Blunt scrotal trauma (BST) is common among soldiers but its incidence and outcome are unknown. The purpose of this study was to estimate the incidence, clinical findings, and outcome of BST in soldiers referred to a primary care field physician. MATERIALS AND METHODS: The medical records of soldiers in their military services who sustained BST and were evaluated by primary care field doctors over a 10-year period were reviewed. Anamnestic data, physical findings, primary care physician decisions, hospitalization, and surgery rates as well as final outcomes were analyzed. RESULTS: The medical records of 382,036 soldiers were reviewed and 668 cases (0.175%) of BST were identified. All patients complained of scrotal pain and 10% of dysuria. The most common physical findings included: scrotal tenderness (71.7%), scrotal edema (16.2%), and scrotal hematoma (4.8%). In 11.8% of the visits microhematuria was found in urine dip stick. A total of 243 patients (36.4%) were referred to emergency department, but only 9 (3.7%) were hospitalized. Of these, 3 patients underwent surgical exploration due to suspected testicular rupture in ultrasonography. Finally, testicular rupture was found only in 1 patient. This testis was sutured. In another patient testicular torsion was found and orchiectomy done. 168 patients (25.1%) developed prolonged scrotal pain lasting for more than 2 weeks after the trauma. CONCLUSIONS: Blunt testicular trauma is not an uncommon phenomenon among soldiers. Surgical intervention is rarely needed and in 99.6% of cases seen by general practitioners supportive management is suffice. The phenomenon of prolonged post-traumatic testicular pain, developing in a quarter of the patients after BST pain deserves more research. PMID- 28885958 TI - Repeat Hospitalizations Predict Mortality in Patients With Heart Failure. AB - INTRODUCTION: Heart failure (HF) affects more than 5.1 million Americans and is projected to increase. Understanding the relationship between hospitalization and mortality can help to guide clinical management. The aim of the study is to evaluate the impact of repeat HF hospitalizations on all-cause mortality and to determine risk variables related to patient mortality. MATERIALS AND METHODS: Using administrative data from the Military Health System, a cohort of patients with an index admission for HF between 2007 and 2011 was identified. HF hospitalizations were defined as any hospital claim with an International Classification of Diseases, Ninth Revision diagnosis of 428.xx in the primary diagnosis field over the 7-year study period (2007-2013). Patients were subsequently categorized based on total number of HF hospitalizations. A multivariate Cox regression model, adjusting for age, sex, and comorbidities, was used to estimate hazard ratios. Kaplan-Meier survival curves were constructed based on the frequency of HF hospitalizations. RESULTS: Of the 51,286 patients admitted for HF, 54.7% were male with a mean (SD) age of 76.3 (10.8) years, and 29,714 died during 135,211 person-years of follow-up. Mean survival time was 2.6, 1.8, 1.5, and 1.3 years after the first, second, third, and fourth hospitalization, respectively. The mortality rate of patients at 30 days and 1 year postindex HF hospitalization was 7.4% and 27.3%, respectively. A history of dementia and chronic kidney disease without dialysis decreased overall survival. CONCLUSIONS: Repeat HF hospitalizations remain a strong predictor of mortality for existing patients with HF. As a result, clinicians and patients can individualize the optimal treatment strategy and resources on the basis of the suspected prognosis. PMID- 28885959 TI - Statins and Musculoskeletal Conditions in U.S. Air Force Active Duty Service Members. AB - BACKGROUND: This study examined the association of statin use and musculoskeletal conditions in statin users and nonusers within the population of U.S. Air Force active duty Service members in the military health care system. METHODS: The study was a retrospective cohort analysis of Service members between 2004 and 2014 as identified from personnel data having physical fitness and cardiac risk data available and who were free of musculoskeletal diagnoses for 6 months before the study period. Based on pharmacy data, participants were divided into two groups: statin users (received a statin for at least 90 days) and nonusers (never received a statin throughout the study period). Using participants' baseline characteristics, a propensity score was generated and used to match statin users to nonusers in a 1:3 ratio. Conditional logistic regression was used to determine the odds ratio (OR) for a musculoskeletal injury. FINDINGS: A total of 123,138 participants met study criteria (592 statin users and 122,546 nonusers). Of these, 516 statin users were propensity score matched to 1,548 nonusers. Among matched pairs, statin users had a higher OR (OR: 1.369; 95% confidence interval [CI]: 1.166-1.606) for musculoskeletal conditions. This association was driven by a higher frequency of back problems in statin users relative to nonusers. The number needed to be exposed for one additional person to be harmed was 20.104 (95% CI: 10.326-232.711). DISCUSSION: Statin use was associated with an increased likelihood of musculoskeletal conditions in the population of U.S. Air Force active duty Service members. Further investigations should evaluate the contribution of duty-related physical requirements as well as the duration of musculoskeletal condition-associated duty limitations. PMID- 28885960 TI - International Classification of Disease Coding of Exertional Heat Illness in U.S. Army Soldiers. AB - INTRODUCTION: The severity of exertional heat illnesses (EHI) ranges from relatively minor heat exhaustion to potentially life-threatening heat stroke. Epidemiological surveillance of the types of and trends in EHI incidence depends on application of the appropriate International Classification of Disease, 9th Revision (ICD-9) diagnostic code. However, data examining whether the appropriate EHI ICD-9 code is selected are lacking. The purpose of this study was to determine whether the appropriate ICD-9 code is selected in a cohort of EHI casualties. MATERIALS AND METHODS: Chart reviews of 290 EHI casualties that occurred in U.S. Army soldiers from 2009 to 2012 were conducted. The ICD-9 diagnostic code was extracted, as were the initial and peak values for aspartate transaminase, alanine transaminase, creatine kinase, and creatinine. Diagnostic criteria for heat injury and heat stroke include evidence of organ and/or tissue damage; 2 out of 3 of the following must have been met to be considered heat injury (ICD-9 code 992.8) or heat stroke (ICD-9 code 992.0): aspartate transaminase/ alanine transaminase fold increase >3, creatine kinase fold increase >5, and/or creatinine >=1.5mg/dL. Contingency tables were constructed from which sensitivity, specificity, and positive and negative predictive value were calculated. RESULTS: The 290 cases in this cohort represent ~29% of all EHI at Fort Benning and ~6% of all EHI Army-wide during the study period. There were 80 cases that met the laboratory diagnostic criteria for heat injury/stroke, however of those, 28 cases were diagnosed as an EHI other than heat injury/stroke (sensitivity = 0.65). 210 cases did not meet the laboratory diagnostic criteria, but 66 of those were incorrectly diagnosed as heat injury or heat stroke (specificity = 0.69). Positive and negative predictive values were 0.44 and 0.84, respectively. In total, the incorrect ICD-9 code was applied to 94 of 290 total cases. CONCLUSIONS: Our data suggest that caution is warranted when examining epidemiological surveillance data on EHI severity, as there was disagreement between the laboratory data and the selected ICD-9 code in ~1/3 of all cases in this cohort. Of note is the lack of an ICD-9 or -10 code for heat injury; we recommend coding for heat exhaustion as the primary diagnosis and additional codes to capture the accompanying muscle, tissue, and/or organ damage. PMID- 28885961 TI - Effectiveness of Ice-Sheet Cooling Following Exertional Hyperthermia. AB - BACKGROUND: The procedure of wrapping a heat casualty in ice-water soaked bed sheets to reduce core temperature has received little investigation, despite the practice and recommendation for its use in some military settings. Thus, the purpose of this study was to investigate the cooling efficacy of ice-sheet cooling (ISC) following exertional hyperthermia. METHODS: 13 (11 males, 2 females) participants (age = 23 +/- 3 years, height = 176.5 +/- 10.3 cm, mass = 78.6 +/- 15.3 kg, body fat = 19.6 +/- 8.6%, and body surface area = 1.95 +/- 0.22 m2) volunteered to complete 2 randomized, crossover design trials on an outdoor recreation field (34.4 +/- 1.4 degrees C, 54.4 +/- 4.1% relative humidity). Each trial consisted of exercise (self-paced 400-m warm-up, 1,609-m run, and 100-m sprints) followed by 15 minutes of either lying supine in the shade with no treatment (control [CON]) or being treated with ice-water soaked sheets wrapped around their body (ISC). Physiological (rectal temperature [Tre], heart rate, mean-weighted skin temperature) and perceptual measures (thermal sensation, rating of perceived exertion) were assessed after each exercise protocol, every 3 minutes during treatment, and every 5 minutes during recovery. FINDINGS: By design, there were no differences during exercise between ISC and CON for Tre (p = 0.16), skin temperature (p = 0.52), heart rate (p = 0.62), thermal sensation (p = 0.89), or rating of perceived exertion (p = 0.99). There were greater decreases in Tre at 3 (ISC 0.33 +/- 0.26 degrees C vs. CON 0.03 +/- 0.30 degrees C, p = 0.01) and 6 minutes (ISC 0.47 +/- 0.27 degrees C vs. CON 0.30 +/- 0.19 degrees C, p = 0.05) of treatment; however, the overall rate of cooling was not different between trials (CON 0.05 +/- 0.02 degrees C/min vs. ISC 0.06 +/- 0.02 degrees C/min, p = 0.72). Skin temperature (Tsk) was significantly reduced from 3 minutes (ISC 34.4 +/- 1.7 degrees C vs. CON 36.6 +/- 0.5 degrees C, p = 0.007) through 15 minutes (ISC 32.4 +/- 1.5 vs. CON 36.1 +/- 0.4 degrees C, p < 0.001) of treatment. There was a trend for lower heart rate with ISC (p = 0.051). Thermal sensation was reduced from 3 minutes of treatment (ISC 3.5 +/- 0.9 vs. CON 4.5 +/ 0.6, p = 0.002) through 15 minutes (ISC 2.8 +/- 1.0 vs. CON 3.9 +/- 0.4, p = 0.005). DISCUSSION: ISC does not provide effective reduction in Tre following exertional hyperthermia compared to no treatment. However, perceptual benefits may warrant the use of ISC in settings where rapid reductions in core temperature are not a concern (i.e., recovery from exercise). Thus, clinicians should continue to utilize validated techniques (i.e., cold-water immersion) for the treatment of exertional heat illnesses. PMID- 28885962 TI - Cold Acclimation Does Not Alter Physiological or Perceptual Responses During Subsequent Exercise in the Heat. AB - INTRODUCTION: Warfighters often train and conduct operations in cold environments. Specifically, military trainees and divers that are repeatedly exposed to cold water may experience inadvertent cold acclimatization, which results in body heat retention. These same warfighters can quickly switch between environments (cold to hot or hot to cold) given the nature of their work. This may present a risk of early onset of hyperthermia when cold-acclimatized warfighters are subsequently exposed to physiological insults that increase body temperature, such as exercise and heat stress. However, there is currently no evidence that suggests this is the case. The purpose of this work, therefore, is to determine what impact, if any, repeated immersion in cold water has on subsequent exercise in the heat. MATERIALS AND METHODS: Twelve healthy subjects (values in mean +/- SD: age, 25.6 +/- 5.2 years; height, 174.0 +/- 8.9 cm; weight, 75.6 +/- 13.1 kg) voluntarily provided written informed consent in accordance with the San Diego State University Institutional Review Board. They first completed 120 minutes of moderate treadmill walking in 40 degrees C and 40% relative humidity. During this trial, subjects' physiological and perceptual responses were recorded. Twenty-four hours later, subjects began a cold acclimation protocol, which consisted of seven, 90-minute immersions in cold water (10 degrees C, water level to chest). Each immersion was also separated by 24 hours. Subjects then repeated a subsequent trial of exercise in the heat 24 hours after the final immersion of the cold acclimation protocol. RESULTS: Results from cold acclimation revealed no change in core temperature, a decrease in skin temperature, and attenuated shivering and lactate responses, which supports a successful insulative-hypothermic cold acclimation response. This type of cold acclimation response primarily results in heat retention with associated energy conservation. Findings for heat trials (pre-cold acclimation and post-cold acclimation) revealed no differences between trials for all measurements, suggesting that cold acclimation did not influence physiological or perceptual responses during exercise in the heat. CONCLUSION: Our findings indicate that military divers or trainees that are frequently exposed to cold water, and hence have the ability to experience cold acclimatization, will likely not be at greater risk of increased thermal strain when subsequently exposed to physical activity in hot environments. In this study, no physiological or perceptual differences were observed between trials before and after cold acclimation, suggesting that cold acclimation does not present a greater hyperthermia risk during subsequent exercise in the heat. PMID- 28885963 TI - Three-Year Analysis of Value and Utilization After Development of an Ultrasound Based Orthopedic Injection Clinic. AB - INTRODUCTION: Sonography is an effective method of diagnosing and treating musculoskeletal conditions, and the use of ultrasound has been shown to improve the accuracy, safety, and efficacy of both therapeutic and diagnostic injections. In 2012, we established an injection clinic at our institution to address our growing need for diagnostic and therapeutic injections. METHODS: We performed an analysis of value and utilization following the development of an orthopedic injection clinic. This included an evaluation of the cost of materials, equipment, and training required to develop and run the clinic, and an analysis of the services rendered and relative value units (RVUs) generated over 3 fiscal years (FYs). RESULTS: The cost to develop the clinic was $42,498.30. The cost to run the clinic thereafter was $16.90 to $21.60 per injection. By the end of FY 2012, 60% of providers performed at least 1 injection under ultrasound guidance. Every successive year thereafter, 100% of providers were using ultrasound guidance. In FY 2012, we performed 738 injections, 5.4% used ultrasound guidance and generated a total of 1,786.36 RVUs. In FY 2013, we performed 1,814 injections, 17.6% used ultrasound guidance, and generated a total of 7,224.5 RVUs. In FY 2014, we performed 2,821 injections, 25.2% used ultrasound guidance, and generated 13,786.82 RVUs. RVUs generated solely from ultrasound guided injections were 463.2 (2012), 3,694 (2013), 8,221.8 (2014). Injection accuracy was at least 98%. Average time until injection was 0 days. CONCLUSION: The cost to start an injection clinic is modest, with the potential for large annual growth and early return on investment, and can generate significant revenue by recapturing RVUs that would otherwise be lost to outside referrals. Furthermore, it helps to increase clinic throughput, maximize services rendered during a single patient visit improving the overall quality of their encounter, expands the clinical practice of our midlevel providers, offloads clinical time for surgical providers, and can help expedite clinical decision making. PMID- 28885964 TI - Cervical Joint Position Sense in Hypobaric Conditions: A Randomized Double-Blind Controlled Trial. AB - : Well-adapted motor actions require intact and well-integrated information from all of the sensory systems, specifically the visual, vestibular, and somatosensory systems, including proprioception. Proprioception is involved in the sensorimotor control by providing the central nervous system with an updated body schema of the biomechanical and spatial properties of the body parts. With regard to the cervical spine, proprioceptive information from joint and muscle mechanoreceptors is integrated with vestibular and visual feedback to control head position, head orientation, and whole body posture. Postural control is highly complex and proprioception from joints is an important contributor to the system. Altitude has been used as a paradigm to study the mechanisms of postural control. Determining the mechanisms of postural control that are affected by moderate altitude is important as unpressurized aircrafts routinely operate at altitudes where hypoxia may be a concern. Deficits in motor performance arise when the reliance on proprioceptive feedback is abolished either experimentally or because of a disorder. As pilots require good neck motor control to counteract the weight of their head gear and proprioceptive information plays an important role in this process, the aim of this study was to determine if hypoxia at moderate altitudes would impair proprioception measured by joint position sense of the cervical spine in healthy subjects. METHODS: Thirty-six healthy subjects (Neck Disability Index < 5) volunteered to participate. Neck position sense was evaluated using a three-dimensional motion analyzer. To create the environment, a hypobaric chamber was used to simulate artificial moderate altitude. Head repositioning error was measured by asking the subject to perform a head-to neutral task after submaximal flexion-extension and right/left rotation movements, and a head-to-target task, in which the subjects had to return to a 30 degrees right and left rotation position. FINDINGS: Exposure to artificial acute moderate altitude of 7,000 feet had no significant effects on cervical joint position sense measured by head repositioning accuracy in healthy subjects. Discussion/impact/recommendations: Postural control mechanisms are very sensitive to acute mild hypoxia and have been recently investigated. Acute hypobaric hypoxia at moderate and high altitudes has a negative effect on postural control. However, which part of the postural system is affected has not yet been determined and proprioception has been little investigated. The results from this study highlighted that in healthy subjects with good cervical spine proprioception at baseline, artificial hypoxia induced by the simulation of moderate altitude does not increase head repositioning error. Further studies should investigate cervical joint position sense in real aircraft, at different altitudes and in a group of experienced helicopter pilots, to evaluate the impact of moderate altitude on cervical joint position sense in a different population. Conducting the same experiments in a population of pilots and in real flight conditions should be considered, since various factors such as the level of proprioception, head posture, type of movement, head load, muscle fatigue, flight altitude, and the length of flight time might influence the kinesthetic sensitivity. PMID- 28885965 TI - Olecranon Bursitis in a Military Population: Epidemiology and Evidence for Prolonged Morbidity in Combat Recruits. AB - INTRODUCTION: Olecranon bursitis (OB) is a benign but disturbing condition that may adversely affect a military recruit's combat preparedness. This study was designed to assess incidence, risk factors, and associated medical burden of OB in the Israel Defense Forces. MATERIALS AND METHODS: This is a retrospective study drawing on medical records of all Israel Defense Forces soldiers diagnosed as having OB between 2005 and 2015. OB was classified as septic and noninfectious. Crude incidence rates and duty-specific incidence rates were calculated. Medical burden was defined by the number of physician visits, referrals to orthopedic specialist consultations, duration of symptoms, and duration of pharmaceutical treatment. Demographic and occupational information (age, sex, height, weight, socioeconomic status, country of origin, type of military service, time of presentation to medical services) was used to identify risk factors for septic bursitis and longer duration of symptoms. Statistical analysis was performed in R statistical software. Risk factors were evaluated using the Chi-square test for categorical variables and Pearson correlation coefficients were used for continuous variables. The study was approved by the Israeli Defense Force IRB. RESULTS: A total of 2,692 soldiers were diagnosed with OB during the study period. The crude annual incidence rate of OB was 29/100,000 person-years (PY). Combat duty had an incidence of 97/100,000 PY, and noncombat duties had an incidence of 12/10,000 PY (p < 0.001). Female incidence (8.4/100,000 PY) was similar to male incidence (11/100,000 PY) in administrative duties (p = 0.54). More cases were diagnosed during summer and autumn than in other seasons (p = 0.016). Septic bursitis constituted 24% of all cases, was more frequent in combat soldiers (32%), and on average presented earlier in service than noninfectious OB (13 vs. 17 weeks since recruitment). The mean duration of symptoms was estimated at 17.58 weeks, with a mean of 1.75 physician visits per soldier. About 19% received a specialist referral. Origin from the former USSR was associated with a higher duration of symptoms (p = 0.012). CONCLUSION: Type of military service was the principal risk factor for OB, as indicated by a higher incidence of the disorder among combat compared to noncombat units, possibly the result of field training without protective gear and repetitive trauma to elbows. The greater number of diagnoses of OB during summer and autumn, when training is more intensive, support that explanation. Sex did not affect incidence of OB in administrative units. The medical burden appears to be relatively low, since most of the soldiers had only one physician visit. OB is highly prevalent in military compared to civilian populations. Outdoor training involving crawling is a probable explanation for the much higher rates among combat units and increased number of diagnoses during warm summer and autumn months. Prevention by use of protective gear seems to be the most promising intervention. PMID- 28885966 TI - The Effect of Anthropomorphic Test Device Lower Leg Surrogate Selection on Impact Mitigating System Evaluation in Low- and High-Rate Loading Conditions. AB - INTRODUCTION: The lower legs are at risk of substantial injury during events such as frontal automotive crashes and antivehicular mine blasts. Loading to occupants can be assessed using an instrumented anthropomorphic test device (ATD), whose measurements can be compared to established injury criteria. NATO's AEP-55 STANAG 4569 recognizes two surrogates for lower leg injury assessments from impacts with intruding floor pans resulting from underbelly blast loads; (1) the rigid Hybrid III instrumented lower leg, and; (2) the compliant MILitary Lower eXtremity (MIL LX). The established injury criterion for the Hybrid III leg specifies a maximum lower tibia compressive load of 5.4 kN, whereas the MIL-LX limit is 2.6 kN measured at the upper tibia for similar injury severity levels. The difference in compliance between the two legs could affect the evaluation of protection levels, resulting in an over- or under-estimation of the force attenuation of energy attenuating (EA) floor mats. MATERIALS AND METHODS: The responses of the two lower leg surrogates were evaluated at impact velocities up to 12 m/s, representing floor intrusions during antivehicle mine blasts. An air cannon was used to accelerate a rigid or padded floor plate into the sole of the surrogate lower legs, loading them axially, in order to assess the protective capability of commercial EA floor mats. The peak load from the lower and upper load cells in the Hybrid III and MIL-LX legs were compared to identify at what point their respective injury criteria would be exceeded in both the padded and unpadded conditions. RESULTS: Comparisons of the surrogate legs' responses resulted in different evaluations of risk, with the Hybrid III leg exceeding its limit at an impact speed of 6.0 m/s, and the MIL-LX exceeding its limit at 5.5 m/s (for tests including an EA product). Furthermore, the inclusion of an EA mat had a greater relative protective effect on the Hybrid III than the MIL-LX leg, with padding reducing the force to 17 to 34% of the unpadded condition for the Hybrid III, versus 67 to 89% of the unpadded condition for the MIL-LX. The load reduction was found to be velocity dependent for both surrogates. CONCLUSION: These results indicate that the two surrogates are not equivalent in their assessment of protective capability. Therefore, the selection of ATD leg for testing of EA mats (and other protective devices) will influence the evaluation of these systems, and more robust metrics are required to identify which is the most appropriate surrogate for evaluating injury to the lower limb. PMID- 28885967 TI - Outcomes of Medializing Tibial Tubercle Osteotomy With Medial Reefing and Vastus Medialis Obliquus Advancement Coupled With Lateral Retinacular Z-Lengthening for Recurrent Patellar Instability. AB - PURPOSE: Patella-femoral dislocations, although rare, can result in functionally limiting symptoms and limited return to prior activity levels. The purpose of this study is to report outcomes of a three-in-one patellar realignment surgery for treatment of recurrent patellar instability in a young, active duty military population. METHODS: We conducted a retrospective chart review of all patients who underwent our senior author's three-in-one patellar realignment surgery for recurrent patellar instability in the setting of underlying anatomic malalignment. Our primary outcome measure was the rate of recurrent instability. Secondary outcome measures included rate of return to full unrestricted active duty military service and the functional outcome scores. RESULTS: A total of 13 patients with an average follow-up of 16 months were included in this study. During the follow-up period, there were no reported instability events (either dislocation or subluxation). Three (23%) patients were separated secondary to issues with their operative knee and two additional patients were no longer on active duty at time of final follow-up. Six patients had paired (pre- and postoperative) Single Assessment Numerical Evaluation scores which showed a statistically significant improvement (p < 0.05) between the median pre- and postoperative Single Assessment Numerical Evaluation scores of 45 and 85, respectively. CONCLUSION: Our study demonstrates that the described patellar realignment procedure is effective at substantially reducing and possibly eliminating the symptoms of recurrent instability and allows a modest return to unrestricted active duty. PMID- 28885968 TI - Diagnosing Chronic Obstructive Pulmonary Disease Among Afghanistan and Iraq Veterans: Veterans Affair's Concordance With Clinical Guidelines for Spirometry Administration. AB - BACKGROUND: Early diagnosis and treatment of chronic obstructive pulmonary disease (COPD) can slow disease progression. The Department of Veterans Affairs (VA)/Department of Defense Clinical Practice Guidelines (CPG), established to improve patient outcomes, recommend the use of spirometry in the COPD diagnostic process. The aims of this study were to assess VA health care providers' performance related to CPG-recommended spirometry administration in the evaluation of newly diagnosed COPD among veterans, determine the patient characteristics that may influence the adherence rate, and compare VA concordance rates to those of other health plans. METHODS: Administrative health care data related to Operations Enduring Freedom/Iraqi Freedom/New Dawn (OEF/OIF/OND) veterans was used to identify newly diagnosed COPD cases and the proportion of cases receiving spirometry. Cases were defined as veterans who had their first medical encounter with a coded diagnosis of COPD >= 6 months after their initial VA health care evaluation. The relationship between prediagnostic and comorbid conditions and the administration of CPG-concordant spirometry was examined using regression analyses. FINDINGS: Among the 923,646 OEF/OIF/OND veterans receiving VA health care between January 2002 and December 2014, 32,076 (3%) had a coded diagnosis of COPD. Among those, 22,156 (69%) were identified as newly diagnosed COPD cases; only 6,827 (31%) had CPG-concordant spirometry. Concordant spirometry was more likely to occur in veterans aged >=40. A pre-existing tobacco use disorder marginally changed the concordance rate. DISCUSSION: VA provider adherence to CPG-concordant spirometry would decrease the prevalence of false positive COPD cases and lead to more targeted disease treatment. Future research should focus on such cases by assessing the association between COPD diagnosis and bronchodilator responsiveness. PMID- 28885969 TI - The Use of the Abdominal Aortic and Junctional Tourniquet During Cardiopulmonary Resuscitation Following Traumatic Cardiac Arrest in Swine. AB - BACKGROUND: Standard cardiopulmonary resuscitation (CPR) is ineffective in treating traumatic cardiac arrest (TCA) following hemorrhagic shock despite fluid resuscitation. CPR adjuncts, including abdominal compressions and external counter pressure, have shown some success in laboratory settings. The Abdominal Aortic and Junctional Tourniquet (AAJT) is a device that occludes both venous and arterial blood at the level of the aortic bifurcation and likely increases thoracic pressure when applied to the abdomen. We developed a swine model of controlled hemorrhage to induce a state of TCA to test the ability of the AAJT to improve the efficacy of CPR. METHODS: Twelve splenectomized, Yorkshire, male swine (70-90 kg) were randomized into two groups: presence or absence of AAJT placement. Controlled hemorrhage was performed at a rate of 2 mL/kg/min until systolic blood pressure reached below 10 mm Hg (defined as cardiac arrest). Following 3 minutes of arrest, the animals underwent CPR using a mechanical compression device along with either the presence or absence of the AAJT. Concurrently, 5 units of whole blood (2,500 mL) were delivered through the jugular vein at 500 mL/min. Efficacy of CPR was assessed by analyzing rates of return of spontaneous circulation (ROSC) and survival. Blood pressure, carotid blood flow, and other hemodynamic values were also compared. FINDINGS: No significant differences between groups were observed before treatments. The controlled hemorrhage resulted in an average loss of 2,654 +/- 323 g of blood over 18.2 +/- 3.9 minutes. All animals that had a ROSC survived to the end of the 1-hour observation period. Animals with AAJT survived 83% (5/6) compared to 17% (1/6) of animals without AAJT. Finally, blood pressure, carotid flow, mean pulmonary artery pressure, and end tidal carbon dioxide were all significantly different between groups at the end of the first 10-minute compression period. DISCUSSION/IMPACT/RECOMMENDATIONS: These results suggest that the AAJT could allow for increased CPR efficacy in cases of TCA when used in conjunction with rapid, massive blood transfusions. PMID- 28885970 TI - Essential Medications for Patients With Suspected or Confirmed Ebola Virus Disease in Resource-Limited Environments. AB - BACKGROUND: In 2014, the U.S. Public Health Service (USPHS) Commissioned Corps deployed to Monrovia, Liberia, to operate a 25-bed Ebola treatment unit (ETU) constructed by the U.S. Military. The ETU was named the Monrovia Medical Unit (MMU) and was constructed from an U.S. Air Force Expeditionary Medical Support (EMEDS) unit with modifications on the basis of consultation from Medecins Sans Frontieres, the World Health Organization, and expert panels from the U.S. Department of Defense and Department of Health and Human Services. From November 12, 2014, to April 30, 2015, 42 patients (18 confirmed Ebola virus disease [EVD] and 24 suspected EVD) from nine countries were treated by USPHS providers at the MMU. The medications used in the MMU were primarily procured from the EMEDS 25 bed pharmacy cache. However, specific formulary additions were made for treatment of EVD. METHODS: Using the MMU pharmacy dispensing data, we compared and contrasted the medications used in the MMU with recommendations in published EVD treatment guidelines for austere settings. FINDINGS: After comparing and contrasting the MMU pharmacy dispensing data with publications with EVD medication recommendations applicable to resource-limited settings, 101 medications were included in the USPHS Essential Medications for the Management of EVD List (EML) for an austere, isolated clinical environment. DISCUSSION/IMPACT/RECOMMENDATIONS: Because Ebola outbreaks often occur in remote areas, proactive planning, improved preparedness, and optimal patient care for EVD are needed, especially in the context of austere environments with a scarcity of resources. We developed the EML to assist in the planning for future Ebola outbreaks in a remote clinical environment and to provide a list of medications that have been used in an ETU. The EML is a comprehensive medication list that builds on the existing publications with EVD treatment recommendations applicable to supply-constrained clinical environments. As well, it is a resource for the provision of medications when evaluating donations, procurement, and may help inform estimates for product inventory requirements for an ETU. We hope the EML will improve readiness and enhance the capabilities of local and regional international responders. PMID- 28885971 TI - Fatal and Non-Fatal Electrocution Injuries at U.S. Marine Corps Forward Medical Facilities During Operation Enduring Freedom and Operation Iraqi Freedom. AB - INTRODUCTION: Death from electrocution is rare and generally an accidental occurrence. In contrast to civilian patterns of electrocution injury, the military work environment suffers from a greater percentage of fatal high-voltage electrocutions. This study compared U.S. and international electrocution case fatality rates to rates among deployed military personnel presenting for care at expeditionary medical care facilities. We also sought to identify potential risk factors for fatal electrocution injury among deployed military personnel. MATERIALS AND METHODS: A retrospective analysis was performed on electrocution injuries presenting to U.S. Marine Corps forward deployed medical facilities in Iraq and Afghanistan between January 2004 and December 2012. Descriptive statistics were used to describe the study population and compare fatal and nonfatal electrocutions. Fatality rates were reported in cases per 1,000,000 people per year. RESULTS: A total of 38 patients were identified; all were males with a mean (SD) age of 25.3 (5.3) years. Most electrocutions occurred on base (68%), whereas a smaller number (21%) occurred while conducting operations outside of the base. A majority of fatal cases (80%) occurred while outside of base on foot or vehicle mounted patrol. The rate of fatal electrocutions among U.S. Marine Corps personnel during this period was 37 per 1,000,000 people per year, 7-fold higher than the international electrocution fatality rate of 5.4 per 1,000,000 people per year and nearly three-fold above the U.S. utility and construction worker's fatality rate of 14 per 1,000,000 people per year. CONCLUSIONS: Electrocution injuries occurring during foot or vehicle mounted patrols seem to account for findings of higher case fatality rates among deployed military personnel than those found in international or high risk civilian occupational settings. Basic life support training for medical and nonmedical military personnel is critical to optimizing care delivered at the scene of these injuries. PMID- 28885972 TI - Use of Rifapentine and Isoniazid Directly Observed Therapy for the Treatment of Latent Tuberculosis Infection in a Military Clinic. AB - BACKGROUND: There are 8.6 million cases of active tuberculosis (TB) worldwide, and an estimated one-third of the world population has latent tuberculosis infection (LTBI). In the United States, up to 80% of active cases may be caused by untreated reactivated latent infection. A case of TB can spread rapidly impacting the readiness of a unit. To prevent the development of TB, it is critical that active duty service members with LTBI complete treatment. The use of isoniazid (INH) and rifapentine (RPT) as a directly observed therapy (DOT) treatment option was recommended by the Centers for Disease Control and Prevention in late 2011. Since then, there have been limited studies on the use of this treatment regimen in a civilian clinic setting and to our knowledge no studies within a military setting. METHODS: This study compares the completion rate of LTBI treatment in 2 military public health clinics, using a retrospective chart review of 179 subjects who attempted treatment with INH/RPT DOT and 186 with the non-INH/RPT non-DOT regimen. FINDINGS: When compared to other LTBI regimens completed or attempted in this period, completion rates were higher in INH/RPT DOT regimens. The INH/RPT DOT treatment regimen allowed enough flexibility with completion between 11 and 16 weeks for active duty service members to increase completion to 94.6%, compared to 73% in the non-INH/RPT regimen. RECOMMENDATIONS: This project demonstrated the feasibility of INH/RPT DOT treatment within the military population resulting in a higher completion rate than the non-INH/RPT non-DOT regimen. The use of the INH/RPT DOT regimen should be considered for use in all military or similar populations. PMID- 28885973 TI - Hemorrhagic Stroke in a Young Healthy Male Following Use of Pre-Workout Supplement Animal Rage XL. AB - So-called "pre-workout" supplements are substances marketed as natural dietary supplements with claims of helping athletes achieve more focused and intense workouts. The use of such products remains popular among American youth as a whole, but is especially high among active duty service members. Supplements are minimally regulated by the Food and Drug Administration (FDA), and unlike pharmaceuticals, supplements are often brought to market without any testing to show neither efficacy nor safety. Several case reports have documented serious adverse events and raise the question of whether supplement use was a causative factor. Reported events occurring after use of pre-workout supplements include, among others, ischemic stroke, hemorrhagic stroke, myocardial infarction, hepatitis, and death. Here, we present the case of a healthy 25-year-old active duty male who experienced a bilateral cerebellar hemorrhagic stroke occurring shortly after taking a supplement named Animal Rage XL. Hemorrhagic stroke occurring in a healthy 25-year-old male with no risk factors is exceedingly rare. This is the first known case of stroke temporally associated with this particular supplement, which is currently available for purchase at military exchanges. Additionally, several of the active ingredients in this supplement have been shown to cause hypertension, tachycardia, and vasospasm. All of these effects could increase the likelihood and severity of a hemorrhagic stroke. The investigated ingredients in this abstract include beta-phenethylamine, creatine monophosphate, and caffeine. PMID- 28885974 TI - Melanoma in an Active Duty Marine. AB - Given that the majority of active duty service members are young and healthy, potentially malignant diagnoses such as skin cancer may be overlooked. Although melanoma accounts for only approximately 1% of skin cancers, it causes the greatest majority of skin cancer deaths. We present the case of a 27-year-old active duty Marine who presented with a hyperpigmented macule at his lateral neck that was a malignant melanoma in situ. This article reviews risk factors for the development of melanoma, offers guidelines for primary care providers, reviews resources for providers in a deployed or austere environment, offers recommendations for prevention and early diagnosis, and discusses follow up. PMID- 28885976 TI - Quantitative Microbial Risk Assessment for Spray Irrigation of Dairy Manure Based on an Empirical Fate and Transport Model. AB - BACKGROUND: Spray irrigation for land-applying livestock manure is increasing in the United States as farms become larger and economies of scale make manure irrigation affordable. Human health risks from exposure to zoonotic pathogens aerosolized during manure irrigation are not well understood. OBJECTIVES: We aimed to a) estimate human health risks due to aerosolized zoonotic pathogens downwind of spray-irrigated dairy manure; and b) determine which factors (e.g., distance, weather conditions) have the greatest influence on risk estimates. METHODS: We sampled downwind air concentrations of manure-borne fecal indicators and zoonotic pathogens during 21 full-scale dairy manure irrigation events at three farms. We fit these data to hierarchical empirical models and used model outputs in a quantitative microbial risk assessment (QMRA) to estimate risk [probability of acute gastrointestinal illness (AGI)] for individuals exposed to spray-irrigated dairy manure containing Campylobacter jejuni, enterohemorrhagic Escherichia coli (EHEC), or Salmonella spp. RESULTS: Median risk estimates from Monte Carlo simulations ranged from 10-5 to 10-2 and decreased with distance from the source. Risk estimates for Salmonella or EHEC-related AGI were most sensitive to the assumed level of pathogen prevalence in dairy manure, while risk estimates for C. jejuni were not sensitive to any single variable. Airborne microbe concentrations were negatively associated with distance and positively associated with wind speed, both of which were retained in models as a significant predictor more often than relative humidity, solar irradiation, or temperature. CONCLUSIONS: Our model-based estimates suggest that reducing pathogen prevalence and concentration in source manure would reduce the risk of AGI from exposure to manure irrigation, and that increasing the distance from irrigated manure (i.e., setbacks) and limiting irrigation to times of low wind speed may also reduce risk. https://doi.org/10.1289/EHP283. PMID- 28885975 TI - Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates. AB - Wnt5a-Ror signaling constitutes a developmental pathway crucial for embryonic tissue morphogenesis, reproduction and adult tissue regeneration, yet the molecular mechanisms by which the Wnt5a-Ror pathway mediates these processes are largely unknown. Using a proteomic screen, we identify the kinesin superfamily protein Kif26b as a downstream target of the Wnt5a-Ror pathway. Wnt5a-Ror, through a process independent of the canonical Wnt/beta-catenin-dependent pathway, regulates the cellular stability of Kif26b by inducing its degradation via the ubiquitin-proteasome system. Through this mechanism, Kif26b modulates the migratory behavior of cultured mesenchymal cells in a Wnt5a-dependent manner. Genetic perturbation of Kif26b function in vivo caused embryonic axis malformations and depletion of primordial germ cells in the developing gonad, two phenotypes characteristic of disrupted Wnt5a-Ror signaling. These findings indicate that Kif26b links Wnt5a-Ror signaling to the control of morphogenetic cell and tissue behaviors in vertebrates and reveal a new role for regulated proteolysis in noncanonical Wnt5a-Ror signal transduction. PMID- 28885977 TI - Estimated Effects of Future Atmospheric CO2 Concentrations on Protein Intake and the Risk of Protein Deficiency by Country and Region. AB - BACKGROUND: Crops grown under elevated atmospheric CO2 concentrations (eCO2) contain less protein. Crops particularly affected include rice and wheat, which are primary sources of dietary protein for many countries. OBJECTIVES: We aimed to estimate global and country-specific risks of protein deficiency attributable to anthropogenic CO2 emissions by 2050. METHODS: To model per capita protein intake in countries around the world under eCO2, we first established the effect size of eCO2 on the protein concentration of edible portions of crops by performing a meta-analysis of published literature. We then estimated per-country protein intake under current and anticipated future eCO2 using global food balance sheets (FBS). We modeled protein intake distributions within countries using Gini coefficients, and we estimated those at risk of deficiency from estimated average protein requirements (EAR) weighted by population age structure. RESULTS: Under eCO2, rice, wheat, barley, and potato protein contents decreased by 7.6%, 7.8%, 14.1%, and 6.4%, respectively. Consequently, 18 countries may lose >5% of their dietary protein, including India (5.3%). By 2050, assuming today's diets and levels of income inequality, an additional 1.6% or 148.4 million of the world's population may be placed at risk of protein deficiency because of eCO2. In India, an additional 53 million people may become at risk. CONCLUSIONS: Anthropogenic CO2 emissions threaten the adequacy of protein intake worldwide. Elevated atmospheric CO2 may widen the disparity in protein intake within countries, with plant-based diets being the most vulnerable. https://doi.org/10.1289/EHP41. PMID- 28885978 TI - In Vitro Evaluation of Mitochondrial Function and Estrogen Signaling in Cell Lines Exposed to the Antiseptic Cetylpyridinium Chloride. AB - BACKGROUND: Quaternary ammonium salts (QUATS), such as cetylpyridinium chloride (CPC) and benzalkonium chloride (BAK), are frequently used in antiseptic formulations, including toothpastes, mouthwashes, lozenges, throat and nasal sprays, and as biocides. Although in a recent ruling, the U.S. Food and Drug Administration (FDA) banned CPC from certain products and requested more data on BAK's efficacy and safety profile, QUATS, in general, and CPC and BAK, in particular, continue to be used in personal health care, food, and pharmaceutical and cleaning industries. OBJECTIVES: We aimed to assess CPC's effects on mitochondrial toxicity and endocrine disruption in vitro. METHOD: Mitochondrial O2 consumption and adenosine triphosphate (ATP) synthesis rates of osteosarcoma cybrid cells were measured before and after CPC and BAK treatment. Antiestrogenic effects of the compounds were measured by a luciferase-based assay using recombinant human breast carcinoma cells (VM7Luc4E2, ERalpha-positive). RESULTS: CPC inhibited both mitochondrial O2 consumption [half maximal inhibitory concentration (IC50): 3.8MUM] and ATP synthesis (IC50: 0.9MUM), and additional findings supported inhibition of mitochondrial complex 1 as the underlying mechanism for these effects. In addition, CPC showed concentration-dependent antiestrogenic activity half maximal effective concentration [(EC50): 4.5MUM)]. BAK, another antimicrobial QUATS that is structurally similar to CPC, and the pesticide rotenone, a known complex 1 inhibitor, also showed mitochondrial inhibitory and antiestrogenic effects. In all three cases, there was overlap of the antiestrogenic activity with the mitochondrial inhibitory activity. CONCLUSIONS: Mitochondrial inhibition in vitro occurred at a CPC concentration that may be relevant to human exposures. The antiestrogenic activity of CPC, BAK, rotenone, and triclosan may be related to their mitochondrial inhibitory activity. Our findings support the need for additional research on the mitochondrial inhibitory and antiestrogenic effects of QUATS, including CPC and BAK. https://doi.org/10.1289/EHP1404. PMID- 28885980 TI - Domain topology of human Rasal. AB - Rasal is a modular multi-domain protein of the GTPase-activating protein 1 (GAP1) family; its four known members, GAP1m, Rasal, GAP1IP4BP and Capri, have a Ras GTPase-activating domain (RasGAP). This domain supports the intrinsically slow GTPase activity of Ras by actively participating in the catalytic reaction. In the case of Rasal, GAP1IP4BP and Capri, their remaining domains are responsible for converting the RasGAP domains into dual Ras- and Rap-GAPs, via an incompletely understood mechanism. Although Rap proteins are small GTPase homologues of Ras, their catalytic residues are distinct, which reinforces the importance of determining the structure of full-length GAP1 family proteins. To date, these proteins have not been crystallized, and their size is not adequate for nuclear magnetic resonance (NMR) or for high-resolution cryo-electron microscopy (cryoEM). Here we present the low resolution structure of full-length Rasal, obtained by negative staining electron microscopy, which allows us to propose a model of its domain topology. These results help to understand the role of the different domains in controlling the dual GAP activity of GAP1 family proteins. PMID- 28885981 TI - From surnames to linguistic and genetic diversity: five centuries of internal migrations in Spain. AB - In a previous study concerning 33,753 single Spanish surnames (considered as tokens) occurring 51,419,788 times we have shown that the present-day geography of contemporary surname variability in Spain still corresponds to the political geography of the country at the end of the Middle Ages. Here we reprocess the same database, by clustering surnames with Self-Organizing Maps (SOMs) according to their geographic distribution, to identify the monophyletic surnames showing a geo-historical origin in one of the 47 provinces of continental Spain. They are 25,714, and they occur 12,348,109 times, meaning that about 75% of the Spanish population bears a surname that had a polyphyletic origin. From monophyletic surnames we compute migration matrices accounting for the internal migrations that took place since five centuries ago, when Spanish surnames started to be patrilineally inherited. The mono/ polyphyletic classification we obtain fits ancient census data and is compatible with published molecular diversity of the Y chromosomes associated to selected Spanish surnames. Monophyletic surnames indicate that i) the provinces exhibiting a higher percentage of autochthonous surnames are also ii) those from which emigration corresponds to a local isolation-by-distance model of diffusion and iii) those that attracted a lower number of immigrants. These are also the provinces where languages other than Castilian are spoken. We suggest that demographic stability explains linguistic resilience, as people prefer to move to areas in which the linguistic variety is more similar to their own. So far the reciprocal influence of migration and language has been investigated at local scales, here we outline how to investigate it at national scales and for time-depths of centuries. PMID- 28885979 TI - Adaptation to Climate Change: A Comparative Analysis of Modeling Methods for Heat Related Mortality. AB - BACKGROUND: Multiple methods are employed for modeling adaptation when projecting the impact of climate change on heat-related mortality. The sensitivity of impacts to each is unknown because they have never been systematically compared. In addition, little is known about the relative sensitivity of impacts to "adaptation uncertainty" (i.e., the inclusion/exclusion of adaptation modeling) relative to using multiple climate models and emissions scenarios. OBJECTIVES: This study had three aims: a) Compare the range in projected impacts that arises from using different adaptation modeling methods; b) compare the range in impacts that arises from adaptation uncertainty with ranges from using multiple climate models and emissions scenarios; c) recommend modeling method(s) to use in future impact assessments. METHODS: We estimated impacts for 2070-2099 for 14 European cities, applying six different methods for modeling adaptation; we also estimated impacts with five climate models run under two emissions scenarios to explore the relative effects of climate modeling and emissions uncertainty. RESULTS: The range of the difference (percent) in impacts between including and excluding adaptation, irrespective of climate modeling and emissions uncertainty, can be as low as 28% with one method and up to 103% with another (mean across 14 cities). In 13 of 14 cities, the ranges in projected impacts due to adaptation uncertainty are larger than those associated with climate modeling and emissions uncertainty. CONCLUSIONS: Researchers should carefully consider how to model adaptation because it is a source of uncertainty that can be greater than the uncertainty in emissions and climate modeling. We recommend absolute threshold shifts and reductions in slope. https://doi.org/10.1289/EHP634. PMID- 28885982 TI - Anthropologists, Italians and "human races". PMID- 28885983 TI - Pure wurtzite GaP nanowires grown on zincblende GaP substrates by selective area vapor liquid solid epitaxy. AB - We report on the growth of single phase wurtzite (WZ) GaP nanowires (NWs) on GaP (111) B substrates by metal organic molecular beam epitaxy following the selective area vapor-liquid-solid (SA-VLS) approach. During the SA-VLS process, precursors are supplied directly to the NW sidewalls, and the short diffusion length of gallium (or its precursors) does not significantly limit axial growth. Transmission electron microscopy (TEM) images reveal that no stacking faults are present along a 600 nm long NW. The lattice constants of the pure WZ GaP obtained from the TEM images agree with values determined previously by x-ray diffraction from non-pure NW ensembles. PMID- 28885984 TI - Investigation of the in-plane and out-of-plane electrical properties of metallic nanoparticles in dielectric matrix thin films elaborated by atomic layer deposition. AB - Pt nanoparticles in a Al2O3 dielectric matrix thin films are elaborated by means of atomic layer deposition. These nanostructured thin films are integrated in vertical and planar test structures in order to assess both their in-plane and out-of-plane electrical properties. A shadow edge evaporation process is used to develop planar devices with electrode separation distances in the range of 30nm. Both vertical and planar test structures show a Poole-Frenkel conduction mechanism. Low trap energy levels (<0.1eV) are identified for the two test structures which indicates that the Pt islands themselves are not acting as traps in the PF mechanism. Furthermore, a more than three order of magnitude current density difference is observed between the two geometries. This electrical anisotropy is attributed to a large electron mobility difference in the in-plane and out-of-plane directions which can be related to different trap distributions in both directions. PMID- 28885985 TI - Synergetic effect of Sn addition and oxygen-deficient atmosphere to design active hematite photoelectrodes for light-induced water splitting. AB - This work describes a microwave-assisted hydrothermal conditions method to design pure and Sn-hematite photoelectrodes at different synthesis time with additional thermal treatment under air and N2 atmosphere. The hematite photoelectrode designed under N2 atmosphere and Sn deposited on its surface, which is represented by material synthesized at 4 hours exhibit the highest performance. Hence, the Sn-addition followed by high annealing temperature conducted at oxygen deficient atmosphere seems to create of oxygen vacancies and have prevented the dopant segregation to form SnO2 phase at the hematite crystal reducing its energy and suppressing the grain growth. The increased number of donor density provided by the oxygen vacancies (confirmed by X-ray photoelectron data) and a possible reduction in the grain boundary energy or hematite crystal interface might favor the charge separation and increase the electron transfer through the hematite into the back contact (FTO substrate). As consequence, the light-induced water oxidation reaction efficiency of Sn-hematite photoelectrode was significantly increased in comparison with pure ones, even though the vertical rod morphology was not preserved. This finding provides a novel insight on the intentional Sn addition revealing that the dopant segregation at the hematite crystal surface (or at the grain boundaries) could be the more relevant factor for developing active hematite photoelectrodes by increasing the electron mobility than the columnar morphology control. PMID- 28885986 TI - Estimation of baroreflex sensitivity by the bivariate phase rectified signal averaging method: a comparison with the phenylephrine method. AB - OBJECTIVES: A novel technique to assess spontaneous baroreflex sensitivity (BRS) by bivariate phase-rectified signal averaging (PRSA-BRS) has been recently proposed and its independent prognostic power demonstrated. This method, however, has never been compared with the phenyleprine test (Phe-BRS), commonly regarded as the reference method in clinical and research applications. APPROACH: In 192 heart failure (HF) and 41 post-myocardial infarction (post-MI) patients we compared PRSA-BRS with Phe-BRS, assessing both association and agreement. MAIN RESULTS: Phe-BRS and PRSA-BRS were (mean +/- SD) 4.8 +/- 5.0 (range: 3.8,25.0) and 1.2 +/- 1.5 (-2.1,6.9) ms mmHg-1 in HF (p < 0.0001), and 5.0 +/- 3.8 (-1.2,12.5) and 0.8 +/- 1.7 (-2.0,6.9) ms mmHg-1 in post-MI patients (p = 0.001). Moderate association was observed (r = 0.53, p < 0.0001 and r = 0.43, p = 0.004 in HF and post-MI, respectively). The vast majority (86% in HF and 90% in post-MI) of PRSA-BRS measurements were smaller than corresponding Phe-BRS values. The difference between PRSA-BRS and Phe-BRS was strongly dependent on the magnitude of BRS, with a trend towards more negative differences as BRS increased. Negative PRSA-BRS values were observed in 15% of HF and in 37% of post-MI patients, whereas negative Phe-BRS values were observed in 8% of HF and 5% of post-MI patients. SIGNIFICANCE: Although the association with Phe-BRS suggests that PRSA-BRS contains relevant information about cardiac autonomic control and reflects the strength of the baroreceptor-heart rate reflex, the marked disagreement between the two measurements indicates that PRSA-BRS measurements cannot be taken as estimates of BRS. Many factors may account for the observed lack of agreement: the different physiological conditions under which Phe-BRS and PRSA-BRS are measured, the inclusion of non-baroreflex mediated components of RR-intervals in PRSA-BRS and some computational aspects related to the normalization of PRSA-BRS values. PMID- 28885987 TI - Theoretical and experimental comparison of lag-based and time-based exponential moving average models of QT hysteresis. AB - OBJECTIVE: In the electrocardiogram, adaptation of the QT interval to variations in heart rate is not instantaneous. Quantification of this hysteresis phenomenon relies on mathematical models describing the relation between the RR and QT time series. These models reproduce hysteresis through an effective RR interval computed as a linear combination of the history of past RR intervals. This filter depends on a time constant parameter that may be used as a biomarker. APPROACH: The most common hysteresis model is based on an autoregressive filter with an impulse response that decreases exponentially with the beat number (lag-based model). Recognizing that the QT time series is unevenly spaced, we propose two exponential moving average filters (time-based models) to define the effective RR interval: one with an impulse response that decreases exponentially with time in seconds, and one with a step response that relaxes exponentially with time in seconds. These two filters are neither linear nor time-invariant. Recurrence formulas are derived to enable efficient implementation. MAIN RESULTS: Application to clinical signals recorded during tilt table test, exercise and 24 h Holter demonstrates that the three models perform similarly in terms of goodness-of-fit. When comparing the hysteresis time constant in two conditions with different heart rates, however, the time-based models are shown to reduce the bias on the hysteresis time constant caused by heart rate acceleration and deceleration. SIGNIFICANCE: Time-based models should be considered when intergroup differences in both heart rate and QT hysteresis are expected. PMID- 28885988 TI - Dapsone-induced severe cutaneous adverse drug reactions are strongly linked with HLA-B*13: 01 allele in the Thai population. AB - OBJECTIVES: A previous publication in Chinese leprosy patients showed that the HLA-B*13:01 allele is a strong genetic marker for dapsone-induced drug hypersensitivity reactions, however there are no data describing whether HLA B*13:01 is a valid marker for prediction of dapsone-induced drug hypersensitivity reactions in other ethnicities or nonleprosy patients. The aim of this study is to investigate whether there is an association between HLA genotypes and dapsone induced severe cutaneous adverse reactions (SCARs) in Thai nonleprosy patients. PATIENTS AND METHODS: HLA-B genotypes of 15 patients with dapsone-induced SCARs (11 drug reaction with eosinophilia and systemic symptoms, 4 Stevens-Johnson syndrome/toxic epidermal necrolysis), 29 control patients, and 986 subjects from the general Thai population were determined by the reverse PCR sequence-specific oligonucleotides probe. RESULTS: The HLA-B*13:01 allele was significantly associated with dapsone-induced SCARs compared with dapsone-tolerant controls (odds ratio: 54.00, 95% confidence interval: 7.96-366.16, P=0.0001) and the general population (odds ratio: 26.11, 95% confidence interval: 7.27-93.75, P=0.0001). In addition, HLA-B*13:01 associated with dapsone-induced SJS-TEN (OR: 40.50, 95% confidence interval: 2.78-591.01, P=0.0070) and DRESS (OR: 60.75, 95% confidence interval: 7.44-496.18, P=0.0001). CONCLUSION: This study demonstrated an association between HLA-B*13:01 and dapsone-induced SCARs including Stevens Johnson syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms in nonleprosy patients. Moreover, these results suggest that the HLA-B*13:01 allele may be a useful genetic marker for prediction of dapsone-induced SCARs in Thai and Han-Chinese populations. PMID- 28885989 TI - The role of health information technology in advancing care management and coordination in accountable care organizations. AB - BACKGROUND: To be successful, accountable care organizations (ACOs) must effectively manage patient care. Health information technology (HIT) can support care delivery by providing various degrees of coordination. Few studies have examined the role of HIT functionalities or the role of different levels of coordination enabled by HIT on care management processes. PURPOSES: We examine HIT functionalities in ACOs, categorized by the level of coordination they enable in terms of information and work flow, to determine which specific HIT functionalities and levels of coordination are most strongly associated with care management processes. METHODOLOGY/APPROACH: Retrospective cross-sectional analysis was done using 2012 data from the National Survey of Accountable Care Organizations. HIT functionalities are categorized into coordination levels: information capture, the lowest level, which coordinates through standardization; information provision, which supports unidirectional activities; and information exchange, which reflects the highest level of coordination allowing for bidirectional exchange. The Care Management Process index (CMP index) includes 13 questions about the extent to which care is planned, monitored, and supported by providers and patients. Multiple regressions adjusting for organizational and ACO contractual factors are used to assess relationships between HIT functionalities and the CMP index. FINDINGS: HIT functionality coordinating the most complex interdependences (information exchange) was associated with a 0.41 standard deviation change in the CMP index (beta = .41, p < .001), but the associations for information capture (beta = -.01, p = .97) and information provision (beta = .15, p = .48) functionalities were not significant. IMPLICATIONS: The current study has shed some light on the relationship between HIT and care management processes by specifying the coordination roles that HIT may play and, in particular, the importance of information exchange functionalities. Although these represent early findings, further research can help policy makers and clinical leaders understand how to prioritize HIT development given resource constraints. PMID- 28885990 TI - Financial performance, employee well-being, and client well-being in for-profit and not-for-profit nursing homes: A systematic review. AB - BACKGROUND: Expanding the opportunities for for-profit nursing home care is a central theme in the debate on the sustainable organization of the growing nursing home sector in Western countries. PURPOSES: We conducted a systematic review of the literature over the last 10 years in order to determine the broad impact of nursing home ownership in the United States. Our review has two main goals: (a) to find out which topics have been studied with regard to financial performance, employee well-being, and client well-being in relation to nursing home ownership and (b) to assess the conclusions related to these topics. The review results in two propositions on the interactions between financial performance, employee well-being, and client well-being as they relate to nursing home ownership. METHODOLOGY/APPROACH: Five search strategies plus inclusion and quality assessment criteria were applied to identify and select eligible studies. As a result, 50 studies were included in the review. Relevant findings were categorized as related to financial performance (profit margins, efficiency), employee well-being (staffing levels, turnover rates, job satisfaction, job benefits), or client well-being (care quality, hospitalization rates, lawsuits/complaints) and then analyzed based on common characteristics. FINDINGS: For-profit nursing homes tend to have better financial performance, but worse results with regard to employee well-being and client well-being, compared to not for-profit sector homes. We argue that the better financial performance of for profit nursing homes seems to be associated with worse employee and client well being. PRACTICAL IMPLICATIONS: For policy makers considering the expansion of the for-profit sector in the nursing home industry, our findings suggest the need for a broad perspective, simultaneously weighing the potential benefits and drawbacks for the organization, its employees, and its clients. PMID- 28885991 TI - Chronic Diarrhea and Metabolic Acidosis Associated With Topiramate Use. PMID- 28885993 TI - Effect of E-OJ-01 on Cardiac Conditioning in Young Exercising Adults: A Randomized Controlled Trial: Erratum. PMID- 28885992 TI - Ursodiol-Associated Paroxysmal Atrial Fibrillation. PMID- 28885994 TI - Continuing Education for Nursing Contact Hours and CRNI(r) Recertification Units. PMID- 28885996 TI - Predesigned labels to prevent medication errors in hospitalized patients: a quasi experimental design study. AB - INTRODUCTION: Our institution implemented the use of pre-designed labeling of intravenous drugs and fluids, administration routes and infusion pumps of to prevent medication errors. OBJECTIVE: To evaluate the effectiveness of predesigned labeling in reducing medication errors in the preparation and administration stages of prescribed medication in patients hospitalized with invasive lines, and to characterize medication errors. METHODS: This is a pre/post intervention study. Pre-intervention group: invasively administered dose from July 1st to December 31st, 2014, using traditional labeling (adhesive paper handwritten note). Post-intervention group: dose administered from January 1st to June 30th, 2015, using predesigned labeling (labeling with preset data-adhesive labels, color- grouped by drugs, labels with colors for invasive lines). Outcome: medication errors in hospitalized patients, as measured with notification form and record electronics. Tabulation/analysis Stata-10, with descriptive statistics, hypotheses testing, estimating risk with 95% confidence. RESULTS: In the pre-intervention group, 5,819 doses of drugs were administered invasively in 634 patients. Error rate of 1.4 x 1,000 administrations. The post-intervention group of 1088 doses comprised 8,585 patients with similar routes of administration. The error rate was 0.3 x 1,000 (p = 0.034). Patients receiving medication through an invasive route who did not use predesigned labeling had 4.6 times more risk of medication error than those who had used predesigned labels (95% CI: 1.25 to 25.4). The adult critically ill patient unit had the highest proportion of medication errors. The most frequent error was wrong dose administration. 41.2% produced harm to the patient. CONCLUSIONS: The use of predesigned labeling in invasive lines reduces errors in medication in the last two phases: preparation and administration. PMID- 28885995 TI - Glucagon-Like Peptide-1 (GLP-1) Treatment Ameliorates Cognitive Impairment by Attenuating Arc Expression in Type 2 Diabetic Rats. AB - BACKGROUND Glucagon-like peptide-1 (GLP-1) has been reported to exert some beneficial effects on the central nervous system (CNS). However, the effect of GLP-1 on cognitive impairment associated with type 2 diabetes is not well known. This study investigated the effect of GLP-1 on ameliorating memory deficits in type 2 diabetic rats. MATERIAL AND METHODS Type 2 diabetic rats were induced by a high-sugar, high-fat diet, followed by streptozotocin (STZ) injection and then tested in the Morris Water Maze (MWM) 1 week after the induction of diabetes. The mRNA expression of Arc, APP, BACE1, and PS1 were determined by real-time quantitative PCR, and the Arc protein was analyzed by immunoblotting and immunohistochemistry. RESULTS Type 2 diabetic rats exhibited a significant decline in learning and memory in the MWM tests, but GLP-1 treatment was able to protect this decline and significantly improved learning ability and memory. The mRNA expression assays showed that GLP-1 treatment markedly reduced Arc, APP, BACE1, and PS1 expressions, which were elevated in the diabetic rats. Immunoblotting and immunohistochemistry results also confirmed that Arc protein increased in the hippocampus of diabetic rats, but was reduced after GLP-1 treatment. CONCLUSIONS Our findings suggest that GLP-1 treatment improves learning and memory deficits in type 2 diabetic rats, and this effect is likely through the reduction of Arc expression in the hippocampus. PMID- 28885997 TI - Susac syndrome: the first case report in Peru. AB - Susac Syndrome is a rare entity, characterized by a triad of subacute encephalopathy, retinal artery occlusion and sensorineural hearing loss. It is more common in women and the age of onset fluctuates between 9-58 years of age. The pathogenesis is presented as microangiopathic changes at the cerebral, retinal and cochlear levels associated with an autoimmune mechanism. We present the case of a 31-year-old woman who started with a diffuse headache, puerile behavior, bradylalia and somnolence. As the disease progressed, she had auditory deficit and arterial obstruction of the right temporal retinal branch in retinal fluorescein angiography. Brain magnetic resonance showed rounded hyperintense lesions in the corpus callosum, periventricular region and cerebellum. This is the first reported case of Susac Syndrome in Peru, presented with the classic triad, which is an infrequent presentation. However, cases that show incomplete forms should be evaluated in a timely manner to initiate timely treatment and avoid irreversible consequences. PMID- 28885998 TI - Mortality trend of gallbladder cancer in Araucania Region, Chile, 2004-2014. AB - BACKGROUND: Chile has the highest mortality rate for gallbladder cancer in the Andean region. The areas most affected by this cancer are found in southern Chile. OBJECTIVE: To describe the mortality rate trends for gallbladder cancer in the Araucania region between 2004 and 2014. METHODS: Ecological observational descriptive study. The cases were identified by the codes ICD-10: C-23. The population at risk was obtained from the projections of the National Institute of Statistics of Chile. The mortality rate was modeled using the Poisson regression method, including age, time, and interaction between the two variables. The annual percentage change (APC) was used as a summary measure. RESULTS: In 2014, the Araucania region had a standardized mortality rate of 10.36 per 100,000 inhabitants, while in the country it was 6.13 per 100,000. At the country level, the temporal evolution of mortality due to gallbladder cancer presented an annual percentage change of 9.1% (incidence rate ratio = 0.91 p-value <0.05), while in Araucania the decrease was 7 % (incidence rate ratio = 0.93 p-value= 0.16), which is not statistically significant. The mortality rate was 2.68 times higher in women than in Araucania men (p-value <0.05), a result similar to that of the country. At the national level, the trend according to age group shows a decrease for all groups, being the one of greater magnitude in those people from 45 to 54 years with an annual percent change of -5.36%, these results are not observed in the Araucania. CONCLUSIONS: Mortality from gallbladder cancer shows a decreasing trend in the period studied for the whole country; however, this is not so for the Araucania region, which maintains a higher mortality rate than that of the country. PMID- 28886000 TI - Inflammatory illness: Why the next wave of antidepressants may target the immune system. PMID- 28885999 TI - Weight change in older adults and mortality: the Multiethnic Cohort Study. AB - OBJECTIVE: To investigate the association between weight change in older adults and mortality in a multiethnic population. METHODS: We performed a prospective analysis using data on weight change between the baseline (1993-1996) and the 10 year follow-up (2003-2007) surveys in relation to subsequent mortality among 63 040 participants in the Multiethnic Cohort Study in Hawaii and California. The participants were African American, Native Hawaiian, Japanese American, Latino and white, aged 45-75 years at baseline, and did not report heart disease or cancer at either survey. RESULTS: During an average of 7.3 years of follow-up after the 10-year survey, 6623 deaths were identified. Compared with individuals whose weight remained stable (+/-2.5 kg), those who lost weight and those with the highest weight gain (>10 kg) were at increased risk of all-cause mortality, with the risks greater for the weight loss (hazard ratios (HR): 2.86; 95% confidence interval (95% CI): 2.62-3.11 for >10 kg) than the weight-gain group (HR: 1.25; 95% CI: 1.11-1.41 for >10 kg), thus resulting in a reverse J-shaped curve. Japanese Americans and Latinos had stronger associations of weight loss >10 kg with mortality than did African Americans, Native Hawaiians and whites. The increase in risk with weight gain >10 kg was greater for older (?55 years at baseline) than younger individuals, whereas the increase in mortality associated with weight loss was greater for the normal weight (<25 kg m-2 at baseline) participants and never smokers, compared with overweight/obese persons and current smokers, respectively. CONCLUSIONS: Our findings confirm the association between weight change and a higher mortality in a healthy, multiethnic population, with higher risks for weight loss than weight gain. On the basis of these observations, public health recommendation should focus on the prevention of weight loss, as well as weight stability within the non-obese range, for middle-aged and older adults. PMID- 28886001 TI - SPOP tips the balance of BETs in cancer. PMID- 28886002 TI - Sex-specific disease-associated modules for depression. PMID- 28886004 TI - Uncovering cancer: How enlisting T cells can boost the power of immunotherapy. PMID- 28886003 TI - Functional precision cancer medicine-moving beyond pure genomics. AB - The essential job of precision medicine is to match the right drugs to the right patients. In cancer, precision medicine has been nearly synonymous with genomics. However, sobering recent studies have generally shown that most patients with cancer who receive genomic testing do not benefit from a genomic precision medicine strategy. Although some call the entire project of precision cancer medicine into question, I suggest instead that the tools employed must be broadened. Instead of relying exclusively on big data measurements of initial conditions, we should also acquire highly actionable functional information by perturbing-for example, with cancer therapies-viable primary tumor cells from patients with cancer. PMID- 28886005 TI - Correction: Breaking through: How researchers are gaining entry into barricaded bacteria. PMID- 28886006 TI - The enteric virome in hematopoietic stem cell transplantation: ready for its close-up. PMID- 28886008 TI - Children first. PMID- 28886009 TI - Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. AB - Functional failure of tau contributes to age-dependent, iron-mediated neurotoxicity, and as iron accumulates in ischemic stroke tissue, we hypothesized that tau failure may exaggerate ischemia-reperfusion-related toxicity. Indeed, unilateral, transient middle cerebral artery occlusion (MCAO) suppressed hemispheric tau and increased iron levels in young (3-month-old) mice and rats. Wild-type mice were protected by iron-targeted interventions: ceruloplasmin and amyloid precursor protein ectodomain, as well as ferroptosis inhibitors. At this age, tau-knockout mice did not express elevated brain iron and were protected against hemispheric reperfusion injury following MCAO, indicating that tau suppression may prevent ferroptosis. However, the accelerated age-dependent brain iron accumulation that occurs in tau-knockout mice at 12 months of age negated the protective benefit of tau suppression against MCAO-induced focal cerebral ischemia-reperfusion injury. The protective benefit of tau knockout was revived in older mice by iron-targeting interventions. These findings introduce tau-iron interaction as a pleiotropic modulator of ferroptosis and ischemic stroke outcome. PMID- 28886010 TI - Mobility can promote the evolution of cooperation via emergent self-assortment dynamics. AB - The evolution of costly cooperation, where cooperators pay a personal cost to benefit others, requires that cooperators interact more frequently with other cooperators. This condition, called positive assortment, is known to occur in spatially-structured viscous populations, where individuals typically have low mobility and limited dispersal. However many social organisms across taxa, from cells and bacteria, to birds, fish and ungulates, are mobile, and live in populations with considerable inter-group mixing. In the absence of information regarding others' traits or conditional strategies, such mixing may inhibit assortment and limit the potential for cooperation to evolve. Here we employ spatially-explicit individual-based evolutionary simulations to incorporate costs and benefits of two coevolving costly traits: cooperative and local cohesive tendencies. We demonstrate that, despite possessing no information about others' traits or payoffs, mobility (via self-propulsion or environmental forcing) facilitates assortment of cooperators via a dynamically evolving difference in the cohesive tendencies of cooperators and defectors. We show analytically that this assortment can also be viewed in a multilevel selection framework, where selection for cooperation among emergent groups can overcome selection against cooperators within the groups. As a result of these dynamics, we find an oscillatory pattern of cooperation and defection that maintains cooperation even in the absence of well known mechanisms such as kin interactions, reciprocity, local dispersal or conditional strategies that require information on others' strategies or payoffs. Our results offer insights into differential adhesion based mechanisms for positive assortment and reveal the possibility of cooperative aggregations in dynamic fission-fusion populations. PMID- 28886011 TI - Correction: Correction: AKT Inhibitors Promote Cell Death in Cervical Cancer through Disruption of mTOR Signaling and Glucose Uptake. AB - [This corrects the article DOI: 10.1371/journal.pone.0107846.]. PMID- 28886007 TI - Microglia emerge as central players in brain disease. AB - There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS. PMID- 28886012 TI - The adiponectin receptor AdipoR2 and its Caenorhabditis elegans homolog PAQR-2 prevent membrane rigidification by exogenous saturated fatty acids. AB - Dietary fatty acids can be incorporated directly into phospholipids. This poses a specific challenge to cellular membranes since their composition, hence properties, could greatly vary with different diets. That vast variations in diets are tolerated therefore implies the existence of regulatory mechanisms that monitor and regulate membrane compositions. Here we show that the adiponectin receptor AdipoR2, and its C. elegans homolog PAQR-2, are essential to counter the membrane rigidifying effects of exogenously provided saturated fatty acids. In particular, we use dietary supplements or mutated E. coli as food, together with direct measurements of membrane fluidity and composition, to show that diets containing a high ratio of saturated to monounsaturated fatty acids cause membrane rigidity and lethality in the paqr-2 mutant. We also show that mammalian cells in which AdipoR2 has been knocked-down by siRNA are unable to prevent the membrane-rigidifying effects of palmitic acid. We conclude that the PAQR-2 and AdipoR2 proteins share an evolutionarily conserved function that maintains membrane fluidity in the presence of exogenous saturated fatty acids. PMID- 28886013 TI - Secondary bacterial infections and antibiotic resistance among tungiasis patients in Western, Kenya. AB - Tungiasis or jigger infestation is a parasitic disease caused by the female sand flea Tunga penetrans. Secondary infection of the lesions caused by this flea is common in endemic communities. This study sought to shed light on the bacterial pathogens causing secondary infections in tungiasis lesions and their susceptibility profiles to commonly prescribed antibiotics. Participants were recruited with the help of Community Health Workers. Swabs were taken from lesions which showed signs of secondary infection. Identification of suspected bacteria colonies was done by colony morphology, Gram staining, and biochemical tests. The Kirby Bauer disc diffusion test was used to determine the drug susceptibility profiles. Out of 37 participants, from whom swabs were collected, specimen were positive in 29 and 8 had no growth. From these, 10 different strains of bacteria were isolated. Two were Gram positive bacteria and they were, Staphylococcus epidermidis (38.3%) and Staphylococcus aureus (21.3%). Eight were Gram negative namely Enterobacter cloacae (8.5%), Proteus species (8.5%), Klebsiellla species (6.4%), Aeromonas sobria (4.3%), Citrobacter species (4.3%), Proteus mirabillis(4.3%), Enterobacter amnigenus (2.1%) and Klebsiella pneumoniae (2.1%). The methicillin resistant S. aureus (MRSA) isolated were also resistant to clindamycin, kanamycin, erythromycin, nalidixic acid, trimethorprim sulfamethoxazole and tetracycline. All the Gram negative and Gram positive bacteria isolates were sensitive to gentamicin and norfloxacin drugs. Results from this study confirms the presence of resistant bacteria in tungiasis lesions hence highlighting the significance of secondary infection of the lesions in endemic communties. This therefore suggests that antimicrobial susceptibility testing may be considered to guide in identification of appropriate antibiotics and treatment therapy among tungiasis patients. PMID- 28886015 TI - Freezing during tapping tasks in patients with advanced Parkinson's disease and freezing of gait. AB - INTRODUCTION: Parkinson's disease patients with freezing of gait also experience sudden motor blocks (freezing) during other repetitive motor tasks. We assessed the proportion of patients with advanced PD and freezing of gait who also displayed segmental "freezing" in tapping tasks. METHODS: Fifteen Parkinson's disease patients with freezing of gait were assessed. Freezing of gait was evaluated using a standardized gait trajectory with the usual triggers. Patients performed repetitive tapping movements (as described in the MDS-UPDRS task) with the hands or the feet in the presence or absence of a metronome set to 4 Hz. Movements were recorded with a video motion system. The primary endpoint was the occurrence of segmental freezing in these tapping tasks. The secondary endpoints were (i) the relationship between segmental episodic phenomena and FoG severity, and (ii) the reliability of the measurements. RESULTS: For the upper limbs, freezing was observed more frequently with a metronome (21% of trials) than without a metronome (5%). For the lower limbs, the incidence of freezing was higher than for the upper limbs, and was again observed more frequently in the presence of an auditory cue (47%) than in its absence (14%). CONCLUSION: Although freezing of the lower limbs was easily assessed during an MDS-UPDRS task with a metronome, it was not correlated with the severity of freezing of gait (as evaluated during a standardized gait trajectory). Only this latter was a reliable measurement in patients with advanced Parkinson's disease. PMID- 28886014 TI - Downregulation of autophagy is associated with severe ischemia-reperfusion induced acute kidney injury in overexpressing C-reactive protein mice. AB - C-reactive protein (CRP), was recently reported to be closely associated with poor renal function in patients with acute kidney injury (AKI), but whether CRP is pathogenic or a mere biomarker in AKI remains largely unclear. Impaired autophagy is known to exacerbate renal ischemia-reperfusion injury (IRI). We examined whether the pathogenic role of CRP in AKI is associated with reduction of autophagy. We mated transgenic rabbit CRP over-expressing mice (Tg-CRP) with two autophagy reporter mouse lines, Tg-GFP-LC3 mice (LC3) and Tg-RFP-GFP-LC3 mice (RG-LC3) respectively to generate Tg-CRP-GFP-LC3 mice (PLC3) and Tg-CRP-RFP-GFP LC3 mice (PRG-LC3). AKI was induced by IRI. Compared with LC3 mice, PLC3 mice developed more severe kidney damage after IRI. Renal tubules were isolated from LC3 mice at baseline for primary culture. OKP cells were transiently transfected with GFP-LC3 plasmid. CRP addition exacerbated lactate dehydrogenase release from both cell types. Immunoblots showed lower LC-3 II/I ratios and higher levels of p62, markers of reduced autophagy flux, in the kidneys of PLC3 mice compared to LC3 mice after IRI, and in primary cultured renal tubules and OKP cells treated with CRP and H2O2 compared to H2O2 alone. Immunohistochemistry showed much fewer LC-3 punctae, and electron microscopy showed fewer autophagosomes in kidneys of PLC3 mice compared to LC3 mice after IRI. Similarly, CRP addition reduced GFP-LC3 punctae induced by H2O2 in primary cultured proximal tubules and in GFP-LC3 plasmid transfected OKP cells. Rapamycin, an autophagy inducer, rescued impaired autophagy and reduced renal injury in vivo. In summary, it was suggested that CRP be more than mere biomarker in AKI, and render the kidney more susceptible to ischemic/oxidative injury, which is associated with down-regulating autophagy flux. PMID- 28886016 TI - Twelve-month contraceptive continuation among women initiating short- and long acting reversible contraceptives in North Kivu, Democratic Republic of the Congo. AB - CONTEXT: Despite the inclusion of sexual and reproductive health (SRH) services in the minimum standards of health care in humanitarian settings, access to SRH services, and especially to contraception, is often compromised in war. Very little is known about continuation and switching of contraceptive methods in these settings. An evaluation of a contraceptive services program in North Kivu, Democratic Republic of the Congo (DRC) was conducted to measure 12-month contraceptive continuation by type of contraceptive method (short-acting or long acting). METHODS: A stratified systematic sample of women who initiated a contraceptive method 12-18 months prior to data collection was selected retrospectively from facility registers. A total of 548 women was interviewed about their contraceptive use: 304 who began a short-acting method (pills, injectables) and 244 who began a long-acting method (intra-uterine devices, implants). Key characteristics of short-acting method versus long-acting method acceptors were compared using chi-square statistics for categorical data and t tests for continuous data. Unadjusted and adjusted Cox proportional hazard ratios were estimated to assess factors associated with discontinuation. RESULTS: At 12 months, 81.6% women reported using their baseline contraceptive method continuously, with more long-acting than short-acting contraceptive acceptors (86.1% versus 78.0%, p = .02) continuing contraceptive use. Use of a short-acting method (Hazard ratio (HR) 1.74 [95%CI 1.13-2.67]) and desiring a child within two years (HR 2.58 [95%CI 1.45-4.54]) were associated with discontinuation within the first 12 months of use. The vast majority (88.3%) of women reported no prior contraceptive use. CONCLUSION: This is the first study of contraceptive continuation in a humanitarian setting. The high percentages of women continuing contraceptive use found here demonstrates that women will choose to initiate and continue use of their desired contraceptive method, even in a difficult, unstable and low contraceptive prevalence setting like North Kivu. PMID- 28886017 TI - B-cell phenotype and IgD-CD27- memory B cells are affected by TNF-inhibitors and tocilizumab treatment in rheumatoid arthritis. AB - BACKGROUND: The use of TNF-inhibitors and/or the IL-6 receptor antagonist, tocilizumab, in rheumatoid arthritis (RA) have pleiotropic effects that also involve circulating B-cells. The main goal of this study was to assess the effect of TNF-inhibitors and tocilizumab on B-cell phenotype and gene expression in RA. METHODS: Blood samples were collected from untreated early RA (ERA) patients, established RA patients under methotrexate treatment, established RA patients before and after treatment with TNF-inhibitors and tocilizumab, and healthy donors. B-cell subpopulations were characterized by flow cytometry and B-cell gene expression was analyzed by real-time PCR on isolated B-cells. Serum levels of BAFF, CXCL13 and sCD23 were determined by ELISA. RESULTS: The frequency of total CD19+ B cells in circulation was similar between controls and all RA groups, irrespective of treatment, but double negative (DN) IgD-CD27- memory B cells were significantly increased in ERA and established RA when compared to controls. Treatment with TNF-inhibitors and tocilizumab restored the frequency of IgD-CD27- B-cells to normal levels, but did not affect other B cell subpopulations. TACI, CD95, CD5, HLA-DR and TLR9 expression on B-cells significantly increased after treatment with either TNF-inhibitors and/ or tocilizumab, but no significant changes were observed in BAFF-R, BCMA, CD69, CD86, CXCR5, CD23, CD38 and IgM expression on B-cells when comparing baseline with post-treatment follow-ups. Alterations in B-cell gene expression of BAFF-R, TACI, TLR9, FcgammaRIIB, BCL-2, BLIMP-1 and beta2M were found in ERA and established RA patients, but no significant differences were observed after TNF inhibitors and tocilizumab treatment when comparing baseline and follow-ups. Serum levels of CXCL13, sCD23 and BAFF were not significantly affected by treatment with TNF-inhibitors and tocilizumab. CONCLUSIONS: In RA patients, the use of TNF-inhibitors and/ or tocilizumab treatment affects B-cell phenotype and IgD-CD27- memory B cells in circulation, but not B-cell gene expression levels. PMID- 28886019 TI - Testing students' e-learning via Facebook through Bayesian structural equation modeling. AB - Learning is an intentional activity, with several factors affecting students' intention to use new learning technology. Researchers have investigated technology acceptance in different contexts by developing various theories/models and testing them by a number of means. Although most theories/models developed have been examined through regression or structural equation modeling, Bayesian analysis offers more accurate data analysis results. To address this gap, the unified theory of acceptance and technology use in the context of e-learning via Facebook are re-examined in this study using Bayesian analysis. The data (S1 Data) were collected from 170 students enrolled in a business statistics course at University of Malaya, Malaysia, and tested with the maximum likelihood and Bayesian approaches. The difference between the two methods' results indicates that performance expectancy and hedonic motivation are the strongest factors influencing the intention to use e-learning via Facebook. The Bayesian estimation model exhibited better data fit than the maximum likelihood estimator model. The results of the Bayesian and maximum likelihood estimator approaches are compared and the reasons for the result discrepancy are deliberated. PMID- 28886018 TI - Minimal important change and other measurement properties of the Oxford Elbow Score and the Quick Disabilities of the Arm, Shoulder, and Hand in patients with a simple elbow dislocation; validation study alongside the multicenter FuncSiE trial. AB - STUDY DESIGN: Validation study using data from a multicenter, randomized, clinical trial (RCT). OBJECTIVES: To evaluate the reliability, validity, responsiveness, and minimal important change (MIC) of the Dutch version of the Oxford Elbow Score (OES) and the Quick Disabilities of the Arm, Shoulder, and Hand (Quick-DASH) in patients with a simple elbow dislocation. BACKGROUND: Patient-reported outcome measures are increasingly important for assessing outcome following elbow injuries, both in daily practice and in clinical research. However measurement properties of the OES and Quick-DASH in these patients are not fully known. METHODS: OES and Quick-DASH were completed four times until one year after trauma. Mayo Elbow Performance Index, pain (VAS), Short Form-36, and EuroQol-5D were completed for comparison. Data of a multicenter RCT (n = 100) were used. Internal consistency was determined using Cronbach's alpha. Construct and longitudinal validity were assessed by determining hypothesized strength of correlation between scores or changes in scores, respectively, of (sub)scales. Finally, floor and ceiling effects, MIC, and smallest detectable change (SDC) were determined. RESULTS: OES and Quick-DASH demonstrated adequate internal consistency (Cronbach alpha, 0.882 and 0.886, respectively). Construct validity and longitudinal validity of both scales were supported by >75% correctly hypothesized correlations. MIC and SDC were 8.2 and 12.0 point for OES, respectively. For Quick-DASH, these values were 11.7 and 25.0, respectively. CONCLUSIONS: OES and Quick-DASH are reliable, valid, and responsive instruments for evaluating elbow-related quality of life. The anchor based MIC was 8.2 points for OES and 11.7 for Quick-DASH. PMID- 28886020 TI - Low plasma cortisol and fecal cortisol metabolite measures as indicators of compromised welfare in domestic horses (Equus caballus). AB - The hypothalamic-pituitary-adrenal (HPA) axis response to chronic stress is far from straight forward, particularly with regards to animal welfare. There are reports of no effect as well as both decreases and increases in cortisol after chronic stressors. Therefore, the first aim of the present study was to determine how measures of compromised welfare, such as chronic pain and haematological anomalies, related to cortisol levels in domestic horses (Equus caballus). Domestic horses are an informative model to investigate the impact of chronic stress (due to environment, pain, work, housing conditions...) on the HPA axis. The second aim was to determine whether levels of fecal cortisol metabolites (FCM) may be used as an indicator of welfare measures. The present study used fifty-nine horses (44 geldings and 15 mares), from three riding centres in Brittany, France. The primary findings show that horses whose welfare was clearly compromised (as indicated by an unusual ears backward position, presence of vertebral problems or haematological anomalies, e.g. anaemia) also had lower levels of both FCM and plasma cortisol. This work extends our previous findings showing that withdrawn postures, indicators of depressive-like behavior in horses, are associated with lower plasma cortisol levels. We also found that evening plasma cortisol levels positively correlated with FCM levels in horses. Future research aims to determine the extent to which factors of influence on welfare, such as living conditions (e.g. single stalls versus group housing in pasture or paddocks), early life factors, and human interaction, act as mediators of cortisol levels in horses. PMID- 28886021 TI - Complete genome sequences of two strains of Treponema pallidum subsp. pertenue from Ghana, Africa: Identical genome sequences in samples isolated more than 7 years apart. AB - BACKGROUND: Treponema pallidum subsp. pertenue (TPE) is the causative agent of yaws, a multi-stage disease, endemic in tropical regions of Africa, Asia, Oceania, and South America. To date, four TPE strains have been completely sequenced including three TPE strains of human origin (Samoa D, CDC-2, and Gauthier) and one TPE strain (Fribourg-Blanc) isolated from a baboon. All TPE strains are highly similar to T. pallidum subsp. pallidum (TPA) strains. The mutation rate in syphilis and related treponemes has not been experimentally determined yet. METHODOLOGY/PRINCIPAL FINDINGS: Complete genomes of two TPE strains, CDC 2575 and Ghana-051, that infected patients in Ghana and were isolated in 1980 and 1988, respectively, were sequenced and analyzed. Both strains had identical consensus genome nucleotide sequences raising the question whether TPE CDC 2575 and Ghana-051 represent two different strains. Several lines of evidence support the fact that both strains represent independent samples including regions showing intrastrain heterogeneity (13 and 5 intrastrain heterogeneous sites in TPE Ghana-051 and TPE CDC 2575, respectively). Four of these heterogeneous sites were found in both genomes but the frequency of alternative alleles differed. The identical consensus genome sequences were used to estimate the upper limit of the yaws treponeme evolution rate, which was 4.1 x 10-10 nucleotide changes per site per generation. CONCLUSIONS/SIGNIFICANCE: The estimated upper limit for the mutation rate of TPE was slightly lower than the mutation rate of E. coli, which was determined during a long-term experiment. Given the known diversity between TPA and TPE genomes and the assumption that both TPA and TPE have a similar mutation rate, the most recent common ancestor of syphilis and yaws treponemes appears to be more than ten thousand years old and likely even older. PMID- 28886022 TI - FtsEX-mediated regulation of the final stages of cell division reveals morphogenetic plasticity in Caulobacter crescentus. AB - During its life cycle, Caulobacter crescentus undergoes a series of coordinated shape changes, including generation of a polar stalk and reshaping of the cell envelope to produce new daughter cells through the process of cytokinesis. The mechanisms by which these morphogenetic processes are coordinated in time and space remain largely unknown. Here we demonstrate that the conserved division complex FtsEX controls both the early and late stages of cytokinesis in C. crescentus, namely initiation of constriction and final cell separation. DeltaftsE cells display a striking phenotype: cells are chained, with skinny connections between cell bodies resulting from defects in inner membrane fusion and cell separation. Surprisingly, the thin connections in DeltaftsE cells share morphological and molecular features with C. crescentus stalks. Our data uncover unanticipated morphogenetic plasticity in C. crescentus, with loss of FtsE causing a stalk-like program to take over at failed division sites. PMID- 28886023 TI - Geographic patterns and environmental factors associated with human yellow fever presence in the Americas. AB - BACKGROUND: In the Americas, yellow fever virus transmission is a latent threat due to the proximity between urban and wild environments. Although yellow fever has nearly vanished from North and Central America, there are still 13 countries in the Americas considered endemic by the World Health Organization. Human cases usually occur as a result of the exposure to sylvatic yellow fever in tropical forested environments; but urban outbreaks reported during the last decade demonstrate that the risk in this environment still exists. The objective of this study was to identify spatial patterns and the relationship between key geographic and environmental factors with the distribution of yellow fever human cases in the Americas. METHODOLOGY/PRINCIPAL FINDINGS: An ecological study was carried out to analyze yellow fever human cases reported to the Pan American Health Organization from 2000 to 2014, aggregated by second administrative level subdivisions (counties). Presence of yellow fever by county was used as the outcome variable and eight geo-environmental factors were used as independent variables. Spatial analysis was performed to identify and examine natural settings per county. Subsequently, a multivariable logistic regression model was built. During the study period, 1,164 cases were reported in eight out of the 13 endemic countries. Nearly 83.8% of these cases were concentrated in three countries: Peru (37.4%), Brazil (28.1%) and Colombia (18.4%); and distributed in 57 states/provinces, specifically in 286 counties (3.4% of total counties). Yellow fever presence was significantly associated with altitude, rain, diversity of non-human primate hosts and temperature. A positive spatial autocorrelation revealed a clustered geographic pattern in 138/286 yellow fever positive counties (48.3%). CONCLUSIONS/SIGNIFICANCE: A clustered geographic pattern of yellow fever was identified mostly along the Andes eastern foothills. This risk map could support health policies in endemic countries. Geo-environmental factors associated with presence of yellow fever could help predict and adjust the limits of other risk areas of epidemiological concern. PMID- 28886024 TI - Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: A randomized, double-blind, placebo controlled study. AB - CONTEXT: Low testosterone (T) levels are often found in obese men with impaired glucose tolerance (IGT) and overt type 2 diabetes (T2DM); however, the mechanisms underlying this condition and its correct therapy are still under debate. OBJECTIVE: To evaluate the effectiveness of clomiphene citrate (CC) in increasing endogenous T levels in obese men with low serum T and with IGT or T2DM treated with metformin (MET). DESIGN: Cross-over, randomized, double-blind, placebo controlled study. METHODS: 24 obese men, aged 47.3 +/-. 6.3 (range 35-55 years), with low T level (<=3 ng/mL) and naive diagnosis of IGT or T2DM were included. Subjects were randomized to CC 25 mg/day or placebo (Plac) with MET 2 g/day for 3 months. After a 6-week wash-out period, subjects were moved to the alternative arm for additional 3 months. Clinical evaluation and blood exams performed prior to and at the end of treatment. RESULTS: Of 24 randomized, 21 were evaluable, classified as IGT (n = 11) or T2DM (n = 10). Compared to baseline levels, T levels increased significantly after 3 months of CC treatment (3.03+/-0.80 to 5.99+/-1.67 ng/mL P<0.001) but not after the Plac treatment (2.87+/-0.78 to 3.09+/-0.84 ng/mL P<0.001 between the treatments). T changes were similar in IGT and T2DM subjects. Gonadotropins as well raised significantly after CC treatment (LH 3.83+/-1.45 to 8.53+/-6.40 mU/mL; FSH 4.84+/-1.67 to 10.15+/-5.08 mU/mL P<0.001 respectively), whereas no changes for LH (3.51+/-1.59 to 3.63+/-1.39 mU/mL) but a smooth increased for FSH (4.61+/-2.49 to 5.39+/-2.65 mU/mL; P = 0.004) were shown after Plac treatment (LH P = 0.001 and FSH P = 0.002 between treatments). Furthermore, fasting glucose (106.8+/-23.2 to 101.1+/-25.7 mg/dL; P = 0.004), insulin (19.3+/-12.1 to 15.6+/-10.1 MUU/mL; P = 0.010) and HOMA-IR (4.94+/-2.89 to 3.69+/-2.12; P = 0.001) decreased significantly during the CC treatment period, whereas no significant changes were observed in any of these parameters in the Plac treatment. CONCLUSIONS: A low dose of CC therapy was able to significantly increase serum T levels in all participants with mild modifications of clinical and metabolic parameters. TRIAL REGISTRATION: EudraCT 2011-000439-10. PMID- 28886025 TI - Robust phase-retrieval-based X-ray tomography for morphological assessment of early hepatic echinococcosis infection in rats. AB - Propagation-based phase-contrast computed micro-tomography (PPCT) dominates the non-destructive, three-dimensional inner-structure measurement in synchrotron based biomedical research due to its simple experimental setup. To quantitatively visualize tiny density variations in soft tissues and organs closely related to early pathological morphology, an experimental study of synchrotron-based X-ray PPCT combined with generalized phase and attenuation duality (PAD) phase retrieval was implemented with the hepatic echinococcosis (HE) infection rat model at different stages. We quantitatively analyzed and evaluated the different pathological characterizations of hepatic echinococcosis during the development of this disease via our PAD-based PPCT and especially provided evidence that hepatic alveolar echinococcosis invades the liver tissue and spreads through blood flow systems with abundant blood supply in the early stage. Additionally, the infiltration of tiny vesicles in HE lesions can be clearly observed by our PAD-PPCT technique due to the striking contrast-to-noise ratio (CNR) and mass density resolution, which cannot be found by the medical imaging techniques, such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound, in hospitals. The results demonstrated that our PAD-PPCT technique has a great potential for indicating the subtle structural information of pathological changes in soft biomedical specimens, especially helpful for the research of early micro-morphology of diseases. PMID- 28886027 TI - Evolutionary analysis and interaction prediction for protein-protein interaction network in geometric space. AB - Prediction of protein-protein interaction (PPI) remains a central task in systems biology. With more PPIs identified, forming PPI networks, it has become feasible and also imperative to study PPIs at the network level, such as evolutionary analysis of the networks, for better understanding of PPI networks and for more accurate prediction of pairwise PPIs by leveraging the information gained at the network level. In this work we developed a novel method that enables us to incorporate evolutionary information into geometric space to improve PPI prediction, which in turn can be used to select and evaluate various evolutionary models. The method is tested with cross-validation using human PPI network and yeast PPI network data. The results show that the accuracy of PPI prediction measured by ROC score is increased by up to 14.6%, as compared to a baseline without using evolutionary information. The results also indicate that our modified evolutionary model DANEOsf-combining a gene duplication/neofunctionalization model and scale-free model-has a better fitness and prediction efficacy for these two PPI networks. The improved PPI prediction performance may suggest that our DANEOsf evolutionary model can uncover the underlying evolutionary mechanism for these two PPI networks better than other tested models. Consequently, of particular importance is that our method offers an effective way to select evolutionary models that best capture the underlying evolutionary mechanisms, evaluating the fitness of evolutionary models from the perspective of PPI prediction on real PPI networks. PMID- 28886026 TI - Population FBA predicts metabolic phenotypes in yeast. AB - Using protein counts sampled from single cell proteomics distributions to constrain fluxes through a genome-scale model of metabolism, Population flux balance analysis (Population FBA) successfully described metabolic heterogeneity in a population of independent Escherichia coli cells growing in a defined medium. We extend the methodology to account for correlations in protein expression arising from the co-regulation of genes and apply it to study the growth of independent Saccharomyces cerevisiae cells in two different growth media. We find the partitioning of flux between fermentation and respiration predicted by our model agrees with recent 13C fluxomics experiments, and that our model largely recovers the Crabtree effect (the experimentally known bias among certain yeast species toward fermentation with the production of ethanol even in the presence of oxygen), while FBA without proteomics constraints predicts respirative metabolism almost exclusively. The comparisons to the 13C study showed improvement upon inclusion of the correlations and motivated a technique to systematically identify inconsistent kinetic parameters in the literature. The minor secretion fluxes for glycerol and acetate are underestimated by our method, which indicate a need for further refinements to the metabolic model. For yeast cells grown in synthetic defined (SD) medium, the calculated broad distribution of growth rates matches experimental observations from single cell studies, and we characterize several metabolic phenotypes within our modeled populations that make use of diverse pathways. Fast growing yeast cells are predicted to perform significant amount of respiration, use serine-glycine cycle and produce ethanol in mitochondria as opposed to slow growing cells. We use a genetic algorithm to determine the proteomics constraints necessary to reproduce the growth rate distributions seen experimentally. We find that a core set of 51 constraints are essential but that additional constraints are still necessary to recover the observed growth rate distribution in SD medium. PMID- 28886028 TI - Traits underlying community consequences of plant intra-specific diversity. AB - A plant's performance and interactions with other trophic levels are recorgnized to be contingent upon plant diversity and underlying associational dynamics, but far less is known about the plant traits driving such phenomena. We manipulated diversity in plant traits using pairs of plant and a substitutive design to elucidate the mechanisms underlying diversity effects operating at a fine spatial scale. Specifically, we measured the effects of diversity in sex (sexual monocultures vs. male and female genotypes together) and growth rate (growth rate monocultures vs. fast- and slow-growing genotypes together) on growth of the shrub Baccharis salicifolia and on above- and belowground consumers associated with this plant. We compared effects on associate abundance (# associates per plant) vs. density (# associates per kg plant biomass) to elucidate the mechanisms underlying diversity effects; effects on abundance but not density suggest diversity effects are mediated by resource abundance (i.e. plant biomass) alone, whereas effects on density suggest diversity effects are mediated by plant based heterogeneity or quality. Sexual diversity increased root growth but reduced the density (but not abundance) of the dietary generalist aphid Aphis gossypii and its associated aphid-tending ants, suggesting sex mixtures were of lower quality to this herbivore (e.g. via reduced plant quality), and that this effect indirectly influenced ants. Sexual diversity had no effect on the abundance or density of parasitoids attacking A. gossypii, the dietary specialist aphid Uroleucon macolai, or mycorrhizae. In contrast, growth rate diversity did not influence plant growth or any associates except for the dietary specialist aphid U. macolai, which increased in both abundance and density at high diversity, suggesting growth rate mixtures were of higher quality to this herbivore. These results highlight that plant associational and diversity effects on consumers are contingent upon the source of plant trait variation, and that the nature of such dynamics may vary both within and among trophic levels. PMID- 28886029 TI - Establishing baseline biodiversity data prior to hydroelectric dam construction to monitoring impacts to bats in the Brazilian Amazon. AB - The modification of Amazonian rivers by the construction of megaprojects of hydroelectric dams has widely increased over the last decade. Robust monitoring programs have been rarely conducted prior to the establishment of dams to measure to what extent the fauna, and its associated habitats may be affected by upcoming impacts. Using bats as models, we performed analyses throughout the area under the influence of the Santo Antonio hydroelectric dam, Southwestern Brazilian Amazonia before its construction to estimate how the fauna and its associated habitats would be affected by the upcoming impacts. We surveyed bats in 49 plots distributed along the areas going to be inundated by the dam and those remaining dry. As predictors for the species distribution, we tested the variables of vegetation structure and topography. Species composition largely differed between the dry plots and the plots located in areas that will be flooded, and this was strongly associated with the variables of forest basal area and elevation. Vegetation-related variables also had strong influence on the guilds distribution. The flooding of lower elevations areas is expected to negatively affect the species number and abundance of frugivorous species. In contrast, it is likely that animalivores will be less vulnerable to dam-induced flooding, since they were abundant in the areas not expect to be inundated. We urge for the implementation of studies to predict impacts caused by large hydroelectric dams, including tests of the influence of the local conditions that shape diversity to avoid massive losses of the biota, and to build preventive monitoring and management actions. PMID- 28886030 TI - Analysis of the whole transcriptome from gingivo-buccal squamous cell carcinoma reveals deregulated immune landscape and suggests targets for immunotherapy. AB - BACKGROUND: Gingivo-buccal squamous cell carcinoma (GBSCC) is one of the most common oral cavity cancers in India with less than 50% patients surviving past 5 years. Here, we report a whole transcriptome profile on a batch of GBSCC tumours with diverse tobacco usage habits. The study provides an entire landscape of altered expression with an emphasis on searching for targets with therapeutic potential. METHODS: Whole transcriptomes of 12 GBSCC tumours and adjacent normal tissues were sequenced and analysed to explore differential expression of genes. Expression changes were further compared with those in TCGA head and neck cohort (n = 263) data base and validated in an independent set of 10GBSCC samples. RESULTS: Differentially expressed genes (n = 2176) were used to cluster the patients based on their tobacco habits, resulting in 3 subgroups. Immune response was observed to be significantly aberrant, along with cell adhesion and lipid metabolism processes. Different modes of immune evasion were seen across 12 tumours with up-regulation or consistent expression of CD47, unlike other immune evasion genes such as PDL1, FUT4, CTLA4 and BTLA which were downregulated in a few samples. Variation in infiltrating immune cell signatures across tumours also indicates heterogeneity in immune evasion strategies. A few actionable genes such as ITGA4, TGFB1 and PTGS1/COX1 were over expressed in most samples. CONCLUSION: This study found expression deregulation of key immune evasion genes, such as CD47 and PDL1, and reasserts their potential as effective immunotherapeutic targets for GBSCC, which requires further clinical studies. Present findings reiterate the idea of using transcriptome profiling to guide precision therapeutic strategies. PMID- 28886031 TI - Can the tardigrade Hypsibius dujardini survive in the absence of the geomagnetic field? AB - Earth's geomagnetic field has undergone critical changes in the past. Studies on the influence of the magnetic field on Earth's organisms are crucial for the understanding of evolution of life on Earth and astrobiological considerations. Numerous studies conducted both on plants and animals confirmed the significant influence of the geomagnetic field on the metabolism of living organisms. Water bears (Tardigrada), which are a mong the most resistant animals due to their cryptobiotic abilities, show significant resistance to a number of environmental stressors, but the influence of the geomagnetic field on their fitness has not been addressed before. In our studies, we used eutardigrade Hypsibius dujardini to analyse whether isolation from the geomagnetic field had an effect on mortality. We found that Hypsibius dujardini specimens demonstrated relatively high mortality during anhydrobiosis, also in control groups exposed to the normal geomagnetic field. Moreover, similar mortality was observed in anhydrobiotic specimens isolated from the geomagnetic field. However, a significant difference was noted between tardigrade survival and the moment of their isolation from the geomagnetic field. In particular, tardigrade mortality substantially increased in absence of a magnetic field during the process of entering anhydrobiosis and returning to active life. Our results suggest that these processes rely on complex metabolic processes that are critically influenced by the geomagnetic field. PMID- 28886032 TI - Emergence phenology, uncertainty, and the evolution of migratory behavior in Anax junius (Odonata: Aeshnidae). AB - Mass migrations by Odonata, although less studied than those of Monarch butterflies and plague locusts, have provoked comment and study for many years. Relatively recently, increasing interest in dragonflies, supported by new technologies, has resulted in more detailed knowledge of the species involved, behavioral mechanisms, and geographic extent. In this paper we examine, in four independent but complementary studies, how larval habitat and emergence phenology interact with climate to shape the evolution of migratory strategy in Anax junius, a common species throughout much of the eastern United States and southern Canada. In brief, we argue that fish predation on larvae, coupled with the need for ample emergent vegetation for oviposition and adult eclosion, dictates that larval development and survival is optimal in ponds that are neither permanent nor extremely ephemeral. Coupled with annual variation in regional weather and winters in much of their range too cold for adult survival, conditions facing newly emerged A. junius may unpredictably favor either local reproduction or long-distance movement to more favorable areas. Both temperature and hydroperiod tend to favor local reproduction early in the adult activity period and migration later, so late emerging adults are more likely to migrate. No single pond is always predictably suitable or unsuitable, however, so ovipositing females also may spread the risk to their offspring by ovipositing at multiple sites that, for migrants, may be distributed over very long distances. PMID- 28886033 TI - Population structure of sea-type and lake-type sockeye salmon and kokanee in the Fraser River and Columbia River drainages. AB - Population structure of three ecotypes of Oncorhynchus nerka (sea-type Sockeye Salmon, lake-type Sockeye Salmon, and Kokanee) in the Fraser River and Columbia River drainages was examined with microsatellite variation, with the main focus as to whether Kokanee population structure within the Fraser River drainage suggested either a monophyletic or polyphyletic origin of the ecotype within the drainage. Variation at 14 microsatellite loci was surveyed for sea-type and lake type Sockeye Salmon and Kokanee sampled from 121 populations in the two river drainages. An index of genetic differentiation, FST, over all populations and loci was 0.087, with individual locus values ranging from 0.031 to 0.172. Standardized to an ecotype sample size of 275 individuals, the least genetically diverse ecotype was sea-type Sockeye Salmon with 203 alleles, whereas Kokanee displayed the greatest number of alleles (260 alleles), with lake-type Sockeye Salmon intermediate (241 alleles). Kokanee populations from the Columbia River drainage (Okanagan Lake, Kootenay Lake), the South Thompson River (a major Fraser River tributary) drainage populations, and the mid-Fraser River populations all clustered together in a neighbor-joining analysis, indicative of a monophyletic origin of the Kokanee ecotype in these regions, likely reflecting the origin of salmon radiating from a refuge after the last glaciation period. However, upstream of the mid-Fraser River populations, there were closer relationships between the lake-type Sockeye Salmon ecotype and the Kokanee ecotype, indicative of the Kokanee ecotype evolving independently from the lake-type Sockeye Salmon ecotype in parallel radiation. Kokanee population structure within the entire Fraser River drainage suggested a polyphyletic origin of the ecotype within the drainage. Studies employing geographically restricted population sampling may not outline accurately the phylogenetic history of salmonid ecotypes. PMID- 28886034 TI - Determinants of maternal near miss among women in public hospital maternity wards in Northern Ethiopia: A facility based case-control study. AB - BACKGROUND: In Ethiopia, 20,000 women die each year from complications related to pregnancy, childbirth and post-partum. For every woman that dies, 20 more experience injury, infection, disease, or disability. "Maternal near miss" (MNM), defined by the World Health Organization (WHO) as a woman who nearly dies, but survives a complication during pregnancy, childbirth or within 42 days of a termination, is a proxy indicator of maternal mortality and quality of obstetric care. In Ethiopia, few studies have examined MNM. This study aims to identify determinants of MNM among a small population of women in Tigray, Ethiopia. METHODS: Unmatched case-control study was conducted in hospitals in Tigray Region, Northern Ethiopia, from January 30-March 30, 2016. The sample included 103 cases and 205 controls recruited from among women seeking obstetric care at six (6) public hospitals. Clients with life-threatening obstetric complications, including hemorrhage, hypertensive diseases of pregnancy, dystocia, infection, and anemia or clinical signs of severe anemia (in women without hemorrhage) were taken as cases and those with normal obstetric outcomes were controls. Cases were selected based on proportion to size allocation while systematic sampling was employed for controls. Binary and multiple variable logistic regression ("odds ratio") analyses were calculated at 95% CI. RESULTS: Roughly 90% of cases and controls were married and 25% experienced their first pregnancy before the age of 16 years. About two-thirds of controls and 45.6% of cases had gestational ages between 37-41 weeks. Among cases, severe obstetric hemorrhage (44.7%), hypertensive disorders (38.8%), dystocia (17.5%), sepsis (9.7%) and severe anemia (2.9%) were leading causes of MNM. Histories of chronic maternal medical problems like hypertension, diabetes were reported in 55.3% of cases and 33.2% of controls. Women with no formal education [AOR = 3.2;95%CI:1.24, 8.12], being less than 16 years of age at first pregnancy [AOR = 2.5;95%CI:1.12,5.63], induced labor[AOR = 3.0; 95%CI:1.44, 6.17], history of cesarean section[AOR = 4.6; 95% CI: 1.98, 7.61] or chronic medical disorder[AOR = 3.5;95%CI:1.78, 6.93], and women who traveled more than 60 minutes before reaching their final place of care[AOR = 2.8;95% CI: 1.19,6.35] had higher odds of experiencing MNM. CONCLUSIONS: Macro-developments like increasing road and health facility access as well as expanding education will all help reduce MNM. Work should be continued to educate women and providers about common predictors of MNM like history of C section and chronic illness as well as teenage pregnancy. These efforts should be carried out at the facility, community, and individual levels. Targeted follow-up with women with history of chronic disease and C-section could also help reduce MNM. PMID- 28886035 TI - Temporal causal inference with stochastic audiovisual sequences. AB - Integration of sensory information across multiple senses is most likely to occur when signals are spatiotemporally coupled. Yet, recent research on audiovisual rate discrimination indicates that random sequences of light flashes and auditory clicks are integrated optimally regardless of temporal correlation. This may be due to 1) temporal averaging rendering temporal cues less effective; 2) difficulty extracting causal-inference cues from rapidly presented stimuli; or 3) task demands prompting integration without concern for the spatiotemporal relationship between the signals. We conducted a rate-discrimination task (Exp 1), using slower, more random sequences than previous studies, and a separate causal-judgement task (Exp 2). Unisensory and multisensory rate-discrimination thresholds were measured in Exp 1 to assess the effects of temporal correlation and spatial congruence on integration. The performance of most subjects was indistinguishable from optimal for spatiotemporally coupled stimuli, and generally sub-optimal in other conditions, suggesting observers used a multisensory mechanism that is sensitive to both temporal and spatial causal inference cues. In Exp 2, subjects reported whether temporally uncorrelated (but spatially co-located) sequences were perceived as sharing a common source. A unified percept was affected by click-flash pattern similarity and the maximum temporal offset between individual clicks and flashes, but not on the proportion of synchronous click-flash pairs. A simulation analysis revealed that the stimulus-generation algorithms of previous studies is likely responsible for the observed integration of temporally independent sequences. By combining results from Exps 1 and 2, we found better rate-discrimination performance for sequences that are more likely to be integrated than those that are not. Our results support the principle that multisensory stimuli are optimally integrated when spatiotemporally coupled, and provide insight into the temporal features used for coupling in causal inference. PMID- 28886036 TI - Potential role of sirtuin 1 in Muller glial cells in mice choroidal neovascularization. AB - This study investigated the potential role of sirtuin 1 in Muller glial cells in choroidal neovascularization. In the in vitro study, primary Muller glial cells were cultured and treated with resveratrol, a sirtuin 1 activator. Glial fibrillary acidic protein expression and angiogenesis-related gene expression were examined using quantitative polymerase chain reaction and phagocytosis, as a marker of Muller glial cell function; in addition, a latex bead assay was used to analyze cell function. For the in vivo study, choroidal neovascularization was induced in C57BL/6 mice via laser photocoagulation, and resveratrol was administered intravitreally. Eyecup whole mounts were created to measure choroidal neovascularization volumes on day 7. Immunohistochemical analysis with anti-glial fibrillary acidic protein antibody was used to detect Muller glial cell activation in eyes with choroidal neovascularization on day 1, 3, 5, and 7 after laser surgery. Resveratrol significantly promoted glial fibrillary acidic protein, anti-angiogenic factor, pigment epithelium-derived factor, and thrombospondin-1 expression in the cells as well as the phagocytic activities. Treatment of the choroidal neovascularization model with resveratrol resulted in early activation of Muller glial cells near choroidal neovascularization sites. Resveratrol-activated cells but not the controls migrated to the top of choroidal neovascularization sites and into the lesions from day 3. Resveratrol reduced the choroidal neovascularization size relative to controls. In conclusion, sirtuin 1 activation in Muller glial cells suppressed the development of choroidal neovascularization, and therefore, might be a therapeutic option. PMID- 28886037 TI - Growing season carries stronger contributions to albedo dynamics on the Tibetan plateau. AB - The Tibetan Plateau has experienced higher-than-global-average climate warming in recent decades, resulting in many significant changes in ecosystem structure and function. Among them is albedo, which bridges the causes and consequences of land surface processes and climate. The plateau is covered by snow/ice and vegetation in the non-growing season (nGS) and growing season (GS), respectively. Based on the MODIS products, we investigated snow/ice cover and vegetation greenness in relation to the spatiotemporal changes of albedo on the Tibetan Plateau from 2000 through 2013. A synchronous relationship was found between the change in GSNDVI and GSalbedo over time and across the Tibetan landscapes. We found that the annual average albedo had a decreasing trend, but that the albedo had slightly increased during the nGS and decreased during the GS. Across the landscapes, the nGSalbedo fluctuated in a synchronous pattern with snow/ice cover. Temporally, monthly snow/ice coverage also had a high correspondence with albedo, except in April and October. We detected clear dependencies of albedo on elevation. With the rise in altitude, the nGSalbedo decreased below 4000 m, but increased for elevations of 4500-5500 m. Above 5500 m, the nGSalbedo decreased, which was in accordance with the decreased amount of snow/ice coverage and the increased soil moisture on the plateau. More importantly, the decreasing albedo in the most recent decade appeared to be caused primarily by lowered growing season albedo. PMID- 28886039 TI - Infection prevention and control practice for Crimean-Congo hemorrhagic fever-A multi-center cross-sectional survey in Eurasia. AB - BACKGROUND: Crimean Congo Hemorrhagic Fever (CCHF) is a life threatening acute viral infection that presents significant risk of nosocomial transmission to healthcare workers. AIM: Evaluation of CCHF infection prevention and control (IP&C) practices in healthcare facilities that routinely manage CCHF cases in Eurasia. METHODS: A cross-sectional CCHF IP&C survey was designed and distributed to CCHF centers in 10 endemic Eurasian countries in 2016. RESULTS: Twenty-three responses were received from centers in Turkey, Pakistan, Russia, Georgia, Kosovo, Bulgaria, Oman, Iran, India and Kazakhstan. All units had dedicated isolation rooms for CCHF, with cohorting of confirmed cases in 15/23 centers and cohorting of suspect and confirmed cases in 9/23 centers. There was adequate personal protective equipment (PPE) in 22/23 facilities, with 21/23 facilities reporting routine use of PPE for CCHF patients. Adequate staffing levels to provide care reported in 14/23 locations. All centers reported having a high risk CCHFV nosocomial exposure in last five years, with 5 centers reporting more than 5 exposures. Education was provided annually in most centers (13/23), with additional training requested in PPE use (11/23), PPE donning/doffing (12/23), environmental disinfection (12/23) and waste management (14/23). CONCLUSIONS: Staff and patient safety must be improved and healthcare associated CCHF exposure and transmission eliminated. Improvements are recommended in isolation capacity in healthcare facilities, use of PPE and maintenance of adequate staffing levels. We recommend further audit of IP&C practice at individual units in endemic areas, as part of national quality assurance programs. PMID- 28886038 TI - Diagnoses, infections and injuries in Northern Syrian children during the civil war: A cross-sectional study. AB - BACKGROUND: The civil war in Syria including the deliberate targeting of healthcare services resulted in a complex humanitarian emergency, seriously affecting children's health. The objectives of this study are to document diagnoses and disease categories in Northern Syrian children after four years of conflict, and to document infectious diseases and injuries in this vulnerable population. METHODS: In a prospective cross-sectional observational sample study conducted in May 2015, healthcare workers registered demographics, comorbidities, and diagnoses (categorised according to the International Classification of Diseases version 10) in children visited at home and in internally displaced persons camps in four Syrian governorates. RESULTS: Of 1080 filled-out records, 1002 were included. Children originated from Aleppo (41%), Idleb (36%), Hamah (15%) and Lattakia (8%). Median age was 6 years (0-15; IQR 3-11), 61% were boys, 40% were younger than 5 years old. Children suffered from respiratory (29%), neurological (19%), digestive (17%), eye (5%) and skin (5%) diseases. Clinical malnutrition was seen in 4%, accidental injury in 3%, intentional injury in 1%, and mental disorders in 2%. Overall, 64% had features of infectious diseases (OR 0.635; CI 0.605-0.665). Most common comorbidities were chronic respiratory diseases (14, malnutrition (5%), acute flaccid paralysis (5%), and epilepsy (4%). Logistic regression analysis indicated that the risk for children to have communicable diseases was higher in Aleppo than in Idleb (OR 1.7; CI 1.2-2.3), Hamah (OR 4.9; CI 3.3-7.5), or Lattakia (OR 5.5; CI 3.3-9.3). Children in Aleppo and Lattakia were more at risk to be injured than in Idleb (OR 5.6; CI 2.1-14.3), or in Hamah (OR 5.9; CI 1.4-25.6), but more often from intentional violence in Lattakia. Mental problems were more prominent in Hamah. CONCLUSIONS: Four years far in the conflict, 64% of the studied children in four Northern Syrian governorates suffer from infections, mostly from respiratory, neurological and digestive origin, while 4% was injured or victim of intentional aggression. Substandard living conditions and the lack of paediatric healthcare put Syrian children at risk for serious infections, epidemics and morbidity, and ask for urgent international humanitarian relief efforts. PMID- 28886040 TI - Residual volume/total lung capacity ratio confers limited additive significance to lung clearance index for assessment of adults with bronchiectasis. AB - BACKGROUND: Mosaicism and hyperinflation are common pathophysiologic features of bronchiectasis. The magnitude of ventilation heterogeneity might have been affected by the degree of hyperinflation. Some studies have evaluated the discriminative performance of lung clearance index (LCI) in bronchiectasis patients, but the additive diagnostic value of hyperinflation metrics to LCI is unknown. OBJECTIVE: To compare LCI and the ratio of residual volume to total lung capacity (RV/TLC), along with the LCI normalized with RV/TLC, in terms of discriminative performance, correlation and concordance with clinical variables in adults with bronchiectasis. METHODS: Measurement items included chest high resolution computed tomography, multiple-breath nitrogen washout test, spirometry, and sputum culture. We analyzed bronchodilator responses by stratifying LCI and RV/TLC according to their median levels (LCIHigh/RV/TLCHigh, LCILow/RV/TLCHigh, LCIHigh/RV/TLCLow, and LCILow/RV/TLCLow). RESULTS: Data from 127 adults with clinically stable bronchiectasis were analyzed. LCI had greater diagnostic value than RV/TLC in discriminating moderate-to-severe from mild bronchiectasis, had greater concordance in reflecting clinical characteristics (including the number of bronchiectatic lobes, radiological severity score, and the presence of cystic bronchiectasis). Normalization of LCI with RV/TLC did not contribute to greater discriminative performance or concordance with clinical variables. The LCI, before and after normalization with RV/TLC, correlated statistically with age, sex, HRCT score, Pseudomonas aeruginosa colonization, cystic bronchiectasis, and ventilation heterogeneity (all P<0.05). Different bronchodilator responses were not significant among the four subgroups of bronchiectasis patients, including those with discordant LCI and RV/TLC levels. CONCLUSION: LCI is superior to RV/TLC for bronchiectasis assessment. Normalization with RV/TLC is not required. Stratification of LCI and RV/TLC is not associated with significantly different bronchodilator responses. PMID- 28886041 TI - Lower limb arterial calcification (LLAC) scores in patients with symptomatic peripheral arterial disease are associated with increased cardiac mortality and morbidity. AB - AIMS: The association of coronary arterial calcification with cardiovascular morbidity and mortality is well-recognized. Lower limb arterial calcification (LLAC) is common in PAD but its impact on subsequent health is poorly described. We aimed to determine the association between a LLAC score and subsequent cardiovascular events in patients with symptomatic peripheral arterial disease (PAD). METHODS: LLAC scoring, and the established Bollinger score, were derived from a database of unenhanced CT scans, from patients presenting with symptomatic PAD. We determined the association between these scores outcomes. The primary outcome was combined cardiac mortality and morbidity (CM/M) with a secondary outcome of all-cause mortality. RESULTS: 220 patients (66% male; median age 69 years) were included with follow-up for a median 46 [IQR 31-64] months. Median total LLAC scores were higher in those patients suffering a primary outcome (6831 vs. 1652; p = 0.012). Diabetes mellitus (p = 0.039), ischaemic heart disease (p = 0.028), chronic kidney disease (p = 0.026) and all-cause mortality (p = 0.012) were more common in patients in the highest quartile of LLAC scores. The area under the curve of the receiver operator curve for the LLAC score was greater (0.929: 95% CI [0.884-0.974]) than for the Bollinger score (0.824: 95% CI [0.758 0.890]) for the primary outcome. A LLAC score >= 4400 had the best diagnostic accuracy to determine the outcome measure. CONCLUSION: This is the largest study to investigate links between lower limb arterial calcification and cardiovascular events in symptomatic PAD. We describe a straightforward, reproducible, CT derived measure of calcification-the LLAC score. PMID- 28886042 TI - Domestication reduces alternative splicing expression variations in sorghum. AB - Domestication is known to strongly reduce genomic diversity through population bottlenecks. The resulting loss of polymorphism has been thoroughly documented in numerous cultivated species. Here we investigate the impact of domestication on the diversity of alternative transcript expressions using RNAseq data obtained on cultivated and wild sorghum accessions (ten accessions for each pool). In that aim, we focus on genes expressing two isoforms in sorghum and estimate the ratio between expression levels of those isoforms in each accession. Noticeably, for a given gene, one isoform can either be overexpressed or underexpressed in some wild accessions, whereas in the cultivated accessions, the balance between the two isoforms of the same gene appears to be much more homogenous. Indeed, we observe in sorghum significantly more variation in isoform expression balance among wild accessions than among domesticated accessions. The possibility exists that the loss of nucleotide diversity due to domestication could affect regulatory elements, controlling transcription or degradation of these isoforms. Impact on the isoform expression balance is discussed. As far as we know, this is the first time that the impact of domestication on transcript isoform balance has been studied at the genomic scale. This could pave the way towards the identification of key domestication genes with finely tuned isoform expressions in domesticated accessions while being highly variable in their wild relatives. PMID- 28886043 TI - Haplotype dependent association of rs7927894 (11q13.5) with atopic dermatitis and chronic allergic rhinitis: A study in ECAP cohort. AB - The T allele of rs7927894 (at 11q13.5) was associated with atopic dermatitis and other allergic diseases. Our purpose was to replicate the association with allergic phenotypes and explore the role of rs7927894 in predisposing to persistent allergic rhinitis and atopic asthma. We also wanted to explore if other SNPs at 11q13.5 contributed to effect of rs7927894. We studied patients with atopic dermatitis (N = 270), atopic asthma (N = 486), persistent allergic rhinitis (N = 589) and controls matched for age, sex and region (N = 540, N = 372 and N = 1178, respectively). We found that rs7927894 T was associated with atopic dermatitis (OR = 1.39, CI: 1.12-1.73, P = 0.003) and independently with persistent allergic rhinitis (OR = 1.24, CI:1.07-1.43, P = 0.0043, Pcorrected = 0.013) but not atopic asthma. Analysis of additional tagging SNPs (rs7930763, rs2513517, rs7125552) showed that effect of rs7927894 T was limited to haplotypes encoding G at rs7125552. In conclusion, rs7927894 T is associated not only with atopic dermatitis but also persistent allergic rhinitis. Since these effects are haplotype dependent rs7927894 alone does not account for the association between 11q13.5 and atopic dermatitis/persistent allergic rhinitis. PMID- 28886044 TI - Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin. AB - BACKGROUND: Approximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults. AIM: To investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight. METHOD: EFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records. RESULTS: Thirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85-19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55-13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level). CONCLUSION: Genetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV infected children. PMID- 28886045 TI - Maternal treatment with short-chain fatty acids modulates the intestinal microbiota and immunity and ameliorates type 1 diabetes in the offspring. AB - We recently hypothesized that the intestinal microbiota and the innate immune system play key roles in the mechanism of Kilham Rat Virus-induced type 1 diabetes in the LEW1.WR1 rat. We used this animal model to test the hypothesis that maternal therapy with short-chain fatty acids can modulate the intestinal microbiota and reverse virus-induced proinflammatory responses and type 1 diabetes in rat offspring. We observed that administration of short-chain fatty acids to rat breeders via drinking water prior to pregnancy and further treatment of the offspring with short-chain fatty acids after weaning led to disease amelioration. In contrast, rats that were administered short-chain fatty acids beginning at weaning were not protected from type 1 diabetes. Short-chain fatty acid therapy exerted a profound effect on the intestinal microbiome in the offspring reflected by a reduction and an increase in the abundances of Firmicutes and Bacteroidetes taxa, respectively, on day 5 post-infection, and reversed virus-induced alterations in certain bacterial taxa. Principal component analysis and permutation multivariate analysis of variance tests further revealed that short-chain fatty acids induce a distinct intestinal microbiota compared with uninfected animals or rats that receive the virus only. Short-chain fatty acids downregulated Kilham Rat Virus-induced proinflammatory responses in the intestine. Finally, short-chain fatty acids altered the B and T cell compartments in Peyer's patches. These data demonstrate that short-chain fatty acids can reshape the intestinal microbiota and prevent virus-induced islet autoimmunity and may therefore represent a useful therapeutic strategy for disease prevention. PMID- 28886046 TI - Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study. AB - Stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders. Chronic water avoidance stress (WAS) in rodents is a model with high construct and face validity to bladder hypersensitive syndromes, such as interstitial cystitis/bladder pain syndrome (IC/BPS), characterized by urinary frequency and bladder hyperalgesia and heightened stress responsiveness. Given the overlap of the brain circuits involved in stress, anxiety, and micturition, we evaluated the effects chronic stress has on bladder function, as well as its effects on regional brain activation during bladder filling. Female Wistar-Kyoto rats were exposed to WAS (10 days) or sham paradigms. One day thereafter, cystometrograms were obtained during titrated bladder dilation, with visceromotor responses (VMR) recorded simultaneously. Cerebral perfusion was assessed during passive bladder distension (20-cmH2O) following intravenous administration of [14C]-iodoantipyrine. Regional cerebral blood flow was quantified by autoradiography and analyzed in 3 dimensionally reconstructed brains with statistical parametric mapping. WAS animals compared to controls demonstrated a decreased pressure threshold and visceromotor threshold triggering the voiding phase. At 20-cmH2O, VMR was significantly greater in WAS animals compared to controls. WAS animals showed greater activation in cortical regions of the central micturition circuit, including the posterior cingulate, anterior retrosplenial, somatosensory, posterior insula, orbital, and anterior secondary ("supplementary") motor cortices, as well as in the thalamus, anterior hypothalamus, parabrachial and Barrington nuclei, and striatum. Seed analysis showed increased functional connectivity of WAS compared to control animals of the posterior cingulate cortex to the pontine parabrachial nucleus; of the Barrington nucleus to the anterior dorsal midline and ventrobasilar thalamus and somatosensory and retrosplenial cortices; and of the posterior insula to anterior secondary motor cortex. Our findings show a visceral hypersensitivity during bladder filling in WAS animals, as well as increased engagement of portions of the micturition circuit responsive to urgency, viscerosensory perception and its relay to motor regions coordinating imminent bladder contraction. Results are consistent with recent findings in patients with interstitial cystitis, suggesting that WAS may serve as an animal model to elucidate the mechanisms leading to viscerosensitive brain phenotypes in humans with IC/BPS. PMID- 28886047 TI - Optimal waist circumference threshold for diagnosing metabolic syndrome in African people living with HIV infection. AB - BACKGROUND: The applicability of the internationally advocated cut-off points of waist circumference (WC) derived from Caucasians to diagnose metabolic syndrome (MS) in HIV-infected Africans is unknown. This study aimed to determine the optimal WC cutoffs for MS diagnosis in HIV-infected people receiving care at public healthcare facilities in the Western Cape Province in South Africa. METHODS: Data from 748 randomly selected participants (591 women), with a median age of 38 years, were analysed. The Youden's index and the top-left-point approaches were used to determine the optimal cutoffs of WC for predicting >=2 non-adipose MS components. RESULTS: The two approaches generated the same WC cut off point in women, 92 cm (sensitivity 64%, specificity 64%) but different cut off points in men: 87 cm (sensitivity 48%, specificity 85%) based on the Younden's index and 83 cm (sensitivity 59%, specificity 74%) by the top-left point method. The advocated thresholds of 94 cm in men had low sensitivity (30%) but high specificity (92%) whereas 80 cm in women showed low specificity (32%) but high sensitivity (85%) for diagnosing MS in this sample. Most African specific cut-off points performed well, with 90 cm providing acceptable performance in both men (sensitivity 43%, specificity 88%) and women (sensitivity 66%, specificity 59%). CONCLUSIONS: This study underlines the sub-optimal performance of internationally recommended WC thresholds for MS diagnosis in HIV infected Africans, and supports the need to revisit the guidelines on WC criterion in African population across the board. A single threshold of 90 cm for both genders would be a practical suggestion. PMID- 28886048 TI - A single-source photon source model of a linear accelerator for Monte Carlo dose calculation. AB - PURPOSE: To introduce a new method of deriving a virtual source model (VSM) of a linear accelerator photon beam from a phase space file (PSF) for Monte Carlo (MC) dose calculation. MATERIALS AND METHODS: A PSF of a 6 MV photon beam was generated by simulating the interactions of primary electrons with the relevant geometries of a Synergy linear accelerator (Elekta AB, Stockholm, Sweden) and recording the particles that reach a plane 16 cm downstream the electron source. Probability distribution functions (PDFs) for particle positions and energies were derived from the analysis of the PSF. These PDFs were implemented in the VSM using inverse transform sampling. To model particle directions, the phase space plane was divided into a regular square grid. Each element of the grid corresponds to an area of 1 mm2 in the phase space plane. The average direction cosines, Pearson correlation coefficient (PCC) between photon energies and their direction cosines, as well as the PCC between the direction cosines were calculated for each grid element. Weighted polynomial surfaces were then fitted to these 2D data. The weights are used to correct for heteroscedasticity across the phase space bins. The directions of the particles created by the VSM were calculated from these fitted functions. The VSM was validated against the PSF by comparing the doses calculated by the two methods for different square field sizes. The comparisons were performed with profile and gamma analyses. RESULTS: The doses calculated with the PSF and VSM agree to within 3% /1 mm (>95% pixel pass rate) for the evaluated fields. CONCLUSION: A new method of deriving a virtual photon source model of a linear accelerator from a PSF file for MC dose calculation was developed. Validation results show that the doses calculated with the VSM and the PSF agree to within 3% /1 mm. PMID- 28886049 TI - Can public health reconcile profits and pandemics? An analysis of attitudes to commercial sector engagement in health policy and research. AB - BACKGROUND: Public health's terms of engagement with unhealthy commodity industries (alcohol, tobacco and ultra-processed food and drinks) have become increasingly contested in policy and research. We sought to identify approaches that could attract consensus support within and across policy domains. METHODS: Using snowball sampling, we undertook an online survey of 335 health researchers, advocates and policymakers, in 40 countries, assessing responses to stated principles, claims and recommendations for engaging with unhealthy commodity industries in relation to key policy and research initiatives. RESULTS: Most respondents identified a fundamental conflict between industry interests and public health objectives for all three industries, with agreement greatest in relation to tobacco and weakest for food. This pattern was replicated across diverse questions regarding potential forms of engagement, including in rejecting voluntarism and partnership approaches to health policy. While awareness of tobacco industry tactics to influence policy and research was higher than for alcohol and food, most respondents rejected the view that the influence of the latter was less significant for public health. Proposals that health and research organisations should divest their funds attracted less support with respect to food, while restricting publication of industry-funded research in academic journals was the issue that most divided opinion. Respondents reported most difficulty in answering questions about the food industry. CONCLUSIONS: The strong consensus around restricting interactions with the tobacco industry supports increased implementation of the WHO Framework Convention on Tobacco Control's conflict of interest provisions. There is strong support for the extension of such practices to the alcohol industry, challenging current norms. More mixed responses indicate a need for greater clarity in defining the food industry, and for research analyzing links, similarities and differences across different types of unhealthy commodity producers. Partnership approaches to addressing non-communicable diseases seem incapable of attracting widespread support across public health, challenging practice in many contexts. PMID- 28886050 TI - Establishing contemporary trends in hepatitis B sero-epidemiology in an Indigenous population. AB - BACKGROUND: Indigenous populations globally are disproportionately affected by chronic hepatitis B virus (HBV) infection however contemporary sero-prevalence data are often absent. In the Indigenous population of the Northern Territory (NT) of Australia the unique C4 sub-genotype of HBV universally circulates. There are no studies of the sero-prevalence, nor the impact of the vaccination program (which has a serotype mismatch compared to C4), at a population-wide level. METHODS: We examined all available HBV serology results obtained from the three main laboratories serving NT residents between 1991 and 2011. Data were linked with a NT government database to determine Indigenous status and the most recent test results for each individual were extracted as a cross-sectional database including 88,112 unique individuals. The primary aim was to obtain a contemporary estimate of HBsAg positivity for the NT by Indigenous status. RESULTS: Based on all tests from 2007-2011 (35,633 individuals), hepatitis B surface antigen (HBsAg) positivity was 3.40% (95%CI 3.19-3.61), being higher in Indigenous (6.08%[5.65%-6.53%]) than non-Indigenous (1.56%[1.38%-1.76%]) Australians, p<0.0001. Birth cohort analysis showed HBsAg positivity fell over time for Indigenous people, with this decrease commencing prior to universal infant vaccination (which commenced in 1990), with an ongoing but slower rate of decline since 1990, (0.23% decrease per year versus 0.17%). CONCLUSIONS: HBsAg positivity is high in the NT, particularly in the Indigenous population. HBsAg positivity has fallen over time but a substantial part of this decrease is due to factors other than the universal vaccination program. PMID- 28886051 TI - The mre11 A470 alleles influence the hereditability and the segregation of telosomes in Saccharomyces cerevisiae. AB - Telomeres, the nucleoprotein complexes at the termini of linear chromosomes, are essential for the processes of end replication, end protection, and chromatin segregation. The Mre11 complex is involved in multiple cellular roles in DNA repair and structure in the regulation and function of telomere size homeostasis. In this study, we characterize yeast telomere chromatin structure, phenotypic heritability, and chromatin segregation in both wild-type [MRE11] and A470 motif alleles. MRE11 strains confer a telomere size of 300 base pairs of G+T irregular simple sequence repeats. This DNA and a portion of subtelomeric DNA is embedded in a telosome: a MNase-resistant non-nucleosomal particle. Chromatin immunoprecipitation shows a three to four-fold lower occupancy of Mre11A470T proteins than wild-type proteins in telosomes. Telosomes containing the Mre11A470T protein confer a greater resistance to MNase digestion than wild-type telosomes. The integration of a wild-type MRE11 allele into an ectopic locus in the genome of an mre11A470T mutant and the introduction of an mre11A470T allele at an ectopic site in a wild-type strain lead to unexpectedly differing results. In each case, the replicated sister chromatids inherit telosomes containing only the protein encoded by the genomic mre11 locus, even in the presence of protein encoded by the opposing ectopic allele. We hypothesize that the telosome segregates by a conservative mechanism. These data support a mechanism for the linkage between sister chromatid replication and maintenance of either identical mutant or identical wild-type telosomes after replication of sister chromatids. These data suggest the presence of an active mechanism for chromatin segregation in yeast. PMID- 28886052 TI - Comparison of clinical features and 3-month treatment response among three different choroidal thickness groups in polypoidal choroidal vasculopathy. AB - Eyes with polypoidal choroidal vasculopathy (PCV) were recently reported to have various choroidal thickness, and choroidal thickness might be associated with visual outcome in the treatment of many retinal disorders. The range of subfoveal choroidal thickness (SFCT), clinical features, and 3-month treatment response among three groups having different range of SFCT were investigated in PCV eyes. In 78 treatment-naive eyes with PCV, SFCT was measured using optical coherence tomography. Eyes were classified into thin, medium, and thick groups, using mean and one standard deviation of SFCT. Clinical features and imaging findings were compared among the three groups. Some eyes were treated with three consecutive monthly injection of anti-vascular endothelial growth factor (VEGF) as an initial treatment. They were also classified into three thickness groups, and the short term post-treatment improvement in visual acuity and central retinal thickness were compared among groups. The mean SFCT was 271.9 +/- 135.6 MUm. Twelve, 53, and 13 eyes were classified into thin (<136.3 MUm), medium (136.3-407.5 MUm), and thick (>407.5 MUm) groups, respectively. The thin group showed older age, lower visual acuity, and a higher prevalence of fundus tessellation than the other two groups (P <0.05). In multiple linear regression analyses, baseline BCVA was correlated with baseline SFCT. Forty-six eyes completed three consecutive anti VEGF treatments. The thin group showed no visual improvement after treatment (P = 0.141), unlike the other two groups showing visual improvement (P<0.05). Eyes with PCV have a broad range of SFCT, and PCV eyes with a thin choroid manifest worse visual function than eyes with a medium or thick choroid. PMID- 28886053 TI - Response of Korean pine's functional traits to geography and climate. AB - This study analyzed the characteristics of Korean pine (Pinus koraiensis) functional trait responses to geographic and climatic factors in the eastern region of Northeast China (41 degrees -48 degrees N) and the linear relationships among Korean pine functional traits, to explore this species' adaptability and ecological regulation strategies under different environmental conditions. Korean pine samples were collected from eight sites located at different latitudes, and the following factors were determined for each site: geographic factors-latitude, longitude, and altitude; temperature factors-mean annual temperature (MAT), growth season mean temperature (GST), and mean temperature of the coldest month (MTCM); and moisture factors-annual precipitation (AP), growth season precipitation (GSP), and potential evapotranspiration (PET). The Korean pine functional traits examined were specific leaf area (SLA), leaf thickness (LT), leaf dry matter content (LDMC), specific root length (SRL), leaf nitrogen content (LNC), leaf phosphorus content (LPC), root nitrogen content (RNC), and root phosphorus content (RPC). The results showed that Korean pine functional traits were significantly correlated to latitude, altitude, GST, MTCM, AP, GSP, and PET. Among the Korean pine functional traits, SLA showed significant linear relationships with LT, LDMC, LNC, LPC, and RPC, and LT showed significant linear relationships with LDMC, SRL, LNC, LPC, RNC, and RPC; the linear relationships between LNC, LPC, RNC, and RPC were also significant. In conclusion, Korean pine functional trait responses to latitude resulted in its adaptation to geographic and climatic factors. The main limiting factors were precipitation and evapotranspiration, followed by altitude, latitude, GST, and MTCM. The impacts of longitude and MAT were not obvious. Changes in precipitation and temperature were most responsible for the close correlation among Korean pine functional traits, reflecting its adaption to habitat variation. PMID- 28886054 TI - How much would each researcher receive if competitive government research funding were distributed equally among researchers? AB - Scientists are increasingly dissatisfied with funding systems that rely on peer assessment and, accordingly, have suggested several proposals for reform. One of these proposals is to distribute available funds equally among all qualified researchers, with no interference from peer review. Despite its numerous benefits, such egalitarian sharing faces the objection, among others, that it would lead to an unacceptable dilution of resources. The aim of the present paper is to assess this particular objection. We estimate (for the Netherlands, the U.S. and the U.K.) how much researchers would receive were they to get an equal share of the government budgets that are currently allocated through competitive peer assessment. For the Netherlands, we furthermore estimate what researchers would receive were we to differentiate between researchers working in low-cost, intermediate-cost and high-cost disciplines. Given these estimates, we then determine what researchers could afford in terms of PhD students, Postdocs, travel and equipment. According to our results, researchers could, on average, maintain current PhD student and Postdoc employment levels, and still have at their disposal a moderate (the U.K.) to considerable (the Netherlands, U.S.) budget for travel and equipment. This suggests that the worry that egalitarian sharing leads to unacceptable dilution of resources is unjustified. Indeed, our results strongly suggest that there is room for far more egalitarian distribution of funds than happens in the highly competitive funding schemes so prevalent today. PMID- 28886055 TI - Comparative analysis of the oral mucosae from rodents and non-rodents: Application to the nonclinical evaluation of sublingual immunotherapy products. AB - BACKGROUND: A comparative characterization of the oral mucosa in various animals is needed to identify the best animal model(s) for nonclinical evaluation of sublingual immunotherapy products. With this aim, we studied the histological characteristics and immune cell infiltrates of oral mucosae from common animal species. METHODS: Three oral regions (i.e. ventral surface of the tongue, mouth floor and cheek) obtained from eight animal species, including rodents (i.e. mice, rats, hamsters, guinea pigs) and non-rodents (i.e. rabbits, dogs, minipigs and monkeys) were characterized by histology and immunohistology in comparison with a human tongue. RESULTS: Rodents exhibit a thin keratinized epithelium with low epithelial extensions, whereas non-rodents, most particularly minipigs and monkeys, display a non-keratinized epithelium with larger rete ridges, similarly to humans. Glycogen-rich cells in the superficial epithelial layers are observed in samples from both minipigs, monkeys and humans. Comparable immune subpopulations detected in the 3 oral regions from rodent and non-rodent species include MHC-II+ antigen presenting cells, mostly CD163+ macrophages, located in the lamina propria (LP) and muscle tissue in the vicinity of resident CD3+CD4+ T cells. Limited numbers of mast cells are also detected in the LP and muscle tissue from all species. CONCLUSION: The oral mucosae of minipigs and monkeys are closest to that of humans, and the immune networks are quite similar between all rodents and non-rodents. Taking into account the ethical and logistical difficulties of performing research in the latter species, rodents and especially mice, should preferentially be used for pharmacodynamics/efficacy studies. Our data also support the use of minipigs to perform biodistribution and safety studies of sublingual immunotherapy products. PMID- 28886056 TI - Development and feasibility of Inlife: A pilot study of an online social support intervention for informal caregivers of people with dementia. AB - BACKGROUND: Informal caregivers of individuals with dementia have an increased risk to face social isolation due to progression of the disease. Online social media interventions might offer a new opportunity to increase access to social support and enhance positive interactions and openness in dementia care networks. OBJECTIVE: This explorative pilot study describes (1) the development of an online social support intervention Inlife, and (2) the evaluation of the feasibility of this intervention and the measurements to assess its effectiveness. METHODS: The Medical Research Council (MRC) framework guided the development of the online social support intervention. This is a stepwise approach that integrates potential users' views with the development and validation of the program content. The program was developed by combining (1) individual caregiver interviews (n = 10), (2) focus group sessions with experts and web designers (n = 6), and (3) individual think-aloud tests (n = 2). Subsequently, a pilot study with informal caregivers was conducted (n = 25) to examine the program's feasibility and preliminary effectiveness. Online self report measures were completed at baseline and at four follow-up time points. RESULTS: In total, 23 participants completed the newly developed Inlife intervention. Despite the high number of low-active users (17/23, 73%), Inlife had a good feasibility score of 7.1 (range: 1-10). The Calendar and Timeline were used most frequently and contributed to better care coordination and positive interactions. CONCLUSIONS: Although the Inlife platform received a sufficient feasibility rating, the uptake was not optimal. Therefore, the Inlife platform was adapted to limit the number of low-active users and improve user friendliness. Recommendations for additional treatment adherence were provided. The development according to the MRC framework and the sufficient feasibility rating of Inlife formed the basis for a future effectiveness study. PMID- 28886057 TI - Principal component-based weighted indices and a framework to evaluate indices: Results from the Medical Expenditure Panel Survey 1996 to 2011. AB - Producing indices composed of multiple input variables has been embedded in some data processing and analytical methods. We aim to test the feasibility of creating data-driven indices by aggregating input variables according to principal component analysis (PCA) loadings. To validate the significance of both the theory-based and data-driven indices, we propose principles to review innovative indices. We generated weighted indices with the variables obtained in the first years of the two-year panels in the Medical Expenditure Panel Survey initiated between 1996 and 2011. Variables were weighted according to PCA loadings and summed. The statistical significance and residual deviance of each index to predict mortality in the second years was extracted from the results of discrete-time survival analyses. There were 237,832 surviving the first years of panels, represented 4.5 billion civilians in the United States, of which 0.62% (95% CI = 0.58% to 0.66%) died in the second years of the panels. Of all 134,689 weighted indices, there were 40,803 significantly predicting mortality in the second years with or without the adjustment of age, sex and races. The significant indices in the both models could at most lead to 10,200 years of academic tenure for individual researchers publishing four indices per year or 618.2 years of publishing for journals with annual volume of 66 articles. In conclusion, if aggregating information based on PCA loadings, there can be a large number of significant innovative indices composing input variables of various predictive powers. To justify the large quantities of innovative indices, we propose a reporting and review framework for novel indices based on the objectives to create indices, variable weighting, related outcomes and database characteristics. The indices selected by this framework could lead to a new genre of publications focusing on meaningful aggregation of information. PMID- 28886058 TI - Sparse trees and shrubs confers a high biodiversity to pastures: Case study on spiders from Transylvania. AB - The integration of food production and biodiversity conservation represents a key challenge for sustainability. Several studies suggest that even small structural elements in the landscape can make a substantial contribution to the overall biodiversity value of the agricultural landscapes. Pastures can have high biodiversity potential. However, their intensive and monofunctional use typically erodes its natural capital, including biodiversity. Here we address the ecological value of fine scale structural elements represented by sparsely scattered trees and shrubs for the spider communities in a moderately intensively grazed pasture in Transylvania, Eastern Europe. The pasture was grazed with sheep, cattle and buffalo (ca 1 Livestock Unit ha-1) and no chemical fertilizers were applied. Sampling sites covered the open pasture as well as the existing fine-scale heterogeneity created by scattered trees and shrub. 40 sampling locations each being represented by three 1 m2 quadrats were situated in a stratified design while assuring spatial independency of sampling locations. We identified 140 species of spiders, out of which 18 were red listed and four were new for the Romanian fauna. Spider species assemblages of open pasture, scattered trees, trees and shrubs and the forest edge were statistically distinct. Our study shows that sparsely scattered mature woody vegetation and shrubs substantially increases the ecological value of managed pastures. The structural complexity provided by scattered trees and shrubs makes possible the co occurrence of high spider diversity with a moderately high intensity grazing possible in this wood-pasture. Our results are in line with recent empirical research showing that sparse trees and shrubs increases the biodiversity potential of pastures managed for commodity production. PMID- 28886059 TI - Optimisation of a machine learning algorithm in human locomotion using principal component and discriminant function analyses. AB - Assessment methods in human locomotion often involve the description of normalised graphical profiles and/or the extraction of discrete variables. Whilst useful, these approaches may not represent the full complexity of gait data. Multivariate statistical methods, such as Principal Component Analysis (PCA) and Discriminant Function Analysis (DFA), have been adopted since they have the potential to overcome these data handling issues. The aim of the current study was to develop and optimise a specific machine learning algorithm for processing human locomotion data. Twenty participants ran at a self-selected speed across a 15m runway in barefoot and shod conditions. Ground reaction forces (BW) and kinematics were measured at 1000 Hz and 100 Hz, respectively from which joint angles ( degrees ), joint moments (N.m.kg-1) and joint powers (W.kg-1) for the hip, knee and ankle joints were calculated in all three anatomical planes. Using PCA and DFA, power spectra of the kinematic and kinetic variables were used as a training database for the development of a machine learning algorithm. All possible combinations of 10 out of 20 participants were explored to find the iteration of individuals that would optimise the machine learning algorithm. The results showed that the algorithm was able to successfully predict whether a participant ran shod or barefoot in 93.5% of cases. To the authors' knowledge, this is the first study to optimise the development of a machine learning algorithm. PMID- 28886060 TI - Benzene exposure is associated with cardiovascular disease risk. AB - Benzene is a ubiquitous, volatile pollutant present at high concentrations in toxins (e.g. tobacco smoke) known to increase cardiovascular disease (CVD) risk. Despite its prevalence, the cardiovascular effects of benzene have rarely been studied. Hence, we examined whether exposure to benzene is associated with increased CVD risk. The effects of benzene exposure in mice were assessed by direct inhalation, while the effects of benzene exposure in humans was assessed in 210 individuals with mild to high CVD risk by measuring urinary levels of the benzene metabolite trans,trans-muconic acid (t,t-MA). Generalized linear models were used to assess the association between benzene exposure and CVD risk. Mice inhaling volatile benzene had significantly reduced levels of circulating angiogenic cells (Flk-1+/Sca-1+) as well as an increased levels of plasma low density lipoprotein (LDL) compared with control mice breathing filtered air. In the human cohort, urinary levels of t,t-MA were inversely associated several populations of circulating angiogenic cells (CD31+/34+/45+, CD31+/34+/45+/AC133-, CD34+/45+/AC133+). Although t,t-MA was not associated with plasma markers of inflammation or thrombosis, t,t-MA levels were higher in smokers and in individuals with dyslipidemia. In smokers, t,t-MA levels were positively associated with urinary metabolites of nicotine (cotinine) and acrolein (3 hydroxymercapturic acid). Levels of t,t-MA were also associated with CVD risk as assessed using the Framingham Risk Score and this association was independent of smoking. Thus, benzene exposure is associated with increased CVD risk and deficits in circulating angiogenic cells in both smokers and non-smokers. PMID- 28886062 TI - Energy reserves mobilization: Strategies of three decapod species. AB - In food deprivation assays, several different responses have been observed in crustaceans. However, studying energy reserves utilization among more than one species during the same starvation period has not yet been performed, particularly to discern whether the responses are due to intrinsic and/or environmental factors. We hypothesize that decapod species with similar feeding habits have the same strategies in the use of energetic reserves during starvation, even though they inhabit different environments. The aim of this study was to compare the energy reserves mobilization of three decapods species (Cherax quadricarinatus, Palaemon argentinus and Munida gregaria) with similar feeding habits, exposed to similar food deprivation conditions. The crayfish, shrimp and squat-lobster were experimentally kept at continuous feeding or continuous starvation throughout 15 days. Every 3rd day, the midgut gland index (MGI), and the glycogen, lipid and protein contents were measured in the midgut gland (MG) and pleon muscle. Palaemon argentinus mobilized more reserves during starvation, followed by C. quadricarinatus, and the last M. gregaria. The starved shrimps presented low MGI, whereas MG showed a reduction in glycogen (from day 6 to 15), lipid (from day 3 to 15), and protein levels (at day 9 and 15) while in their muscle, lipid reserves decreased at days 3 and 6. In C. quadricarinatus, the most affected parameters in the MG were MGI, glycogen (from day 6 to 15), and lipids (at day 12 and 15). In the MG of M. gregaria only the glycogen was reduced during fasting from 3 to 15 days. Even though the three studied species have similar feeding habitats, we found that their energetic profile utilization is different and it could be explained by the habitat, life span, temperature, organ/tissue, and metabolism of the species. Our results may be useful to understand the several different responses of crustaceans during starvation. PMID- 28886061 TI - Biophysical analysis of the effect of chemical modification by 4-oxononenal on the structure, stability, and function of binding immunoglobulin protein (BiP). AB - Binding immunoglobulin protein (BiP) is a molecular chaperone important for the folding of numerous proteins, which include millions of immunoglobulins in human body. It also plays a key role in the unfolded protein response (UPR) in the endoplasmic reticulum. Free radical generation is a common phenomenon that occurs in cells under healthy as well as under stress conditions such as ageing, inflammation, alcohol consumption, and smoking. These free radicals attack the cell membranes and generate highly reactive lipid peroxidation products such as 4 oxononenal (4-ONE). BiP is a key protein that is modified by 4-ONE. In this study, we probed how such chemical modification affects the biophysical properties of BiP. Upon modification, BiP shows significant tertiary structural changes with no changes in its secondary structure. The protein loses its thermodynamic stability, particularly, that of the nucleotide binding domain (NBD) where ATP binds. In terms of function, the modified BiP completely loses its ATPase activity with decreased ATP binding affinity. However, modified BiP retains its immunoglobulin binding function and its chaperone activity of suppressing non-specific protein aggregation. These results indicate that 4-ONE modification can significantly affect the structure-function of key proteins such as BiP involved in cellular pathways, and provide a molecular basis for how chemical modifications can result in the failure of quality control mechanisms inside the cell. PMID- 28886063 TI - Movement evaluation of front crawl swimming: Technical skill versus aesthetic quality. AB - The study aim was to compare expert with non-expert swimmers' rating of the aesthetic and technical qualities of front crawl in video-taped recordings of swimmers with low, middle, and high level proficiency. The results suggest that: i) observers' experience affects their judgment: only the expert observers correctly rated the swimmers' proficiency level; ii) evaluation of movement (technical and aesthetic scores) is correlated with the level of skill as expressed in the kinematics of the observed action (swimming speed, stroke frequency, and stroke length); iii) expert and non-expert observers use different strategies to rate the aesthetic and technical qualities of movement: equating the technical skill with the aesthetic quality is a general rule non-expert observers follow in the evaluation of human movement. PMID- 28886064 TI - SEXCMD: Development and validation of sex marker sequences for whole-exome/genome and RNA sequencing. AB - Over the last decade, a large number of nucleotide sequences have been generated by next-generation sequencing technologies and deposited to public databases. However, most of these datasets do not specify the sex of individuals sampled because researchers typically ignore or hide this information. Male and female genomes in many species have distinctive sex chromosomes, XX/XY and ZW/ZZ, and expression levels of many sex-related genes differ between the sexes. Herein, we describe how to develop sex marker sequences from syntenic regions of sex chromosomes and use them to quickly identify the sex of individuals being analyzed. Array-based technologies routinely use either known sex markers or the B-allele frequency of X or Z chromosomes to deduce the sex of an individual. The same strategy has been used with whole-exome/genome sequence data; however, all reads must be aligned onto a reference genome to determine the B-allele frequency of the X or Z chromosomes. SEXCMD is a pipeline that can extract sex marker sequences from reference sex chromosomes and rapidly identify the sex of individuals from whole-exome/genome and RNA sequencing after training with a known dataset through a simple machine learning approach. The pipeline counts total numbers of hits from sex-specific marker sequences and identifies the sex of the individuals sampled based on the fact that XX/ZZ samples do not have Y or W chromosome hits. We have successfully validated our pipeline with mammalian (Homo sapiens; XY) and avian (Gallus gallus; ZW) genomes. Typical calculation time when applying SEXCMD to human whole-exome or RNA sequencing datasets is a few minutes, and analyzing human whole-genome datasets takes about 10 minutes. Another important application of SEXCMD is as a quality control measure to avoid mixing samples before bioinformatics analysis. SEXCMD comprises simple Python and R scripts and is freely available at https://github.com/lovemun/SEXCMD. PMID- 28886065 TI - Hepatitis C virus mediated chronic inflammation and tumorigenesis in the humanised immune system and liver mouse model. AB - Hepatitis C is a liver disease caused by infection of the Hepatitis C virus (HCV). Many individuals infected by the virus are unable to resolve the viral infection and develop chronic hepatitis, which can lead to formation of liver cirrhosis and cancer. To understand better how initial HCV infections progress to chronic liver diseases, we characterised the long term pathogenic effects of HCV infections with the use of a humanised mouse model (HIL mice) we have previously established. Although HCV RNA could be detected in infected mice up to 9 weeks post infection, HCV infected mice developed increased incidences of liver fibrosis, granulomatous inflammation and tumour formation in the form of hepatocellular adenomas or hepatocellular carcinomas by 28 weeks post infection compared to uninfected mice. We also demonstrated that chronic liver inflammation in HCV infected mice was mediated by the human immune system, particularly by monocytes/macrophages and T cells which exhibited exhaustion phenotypes. In conclusion, HIL mice can recapitulate some of the clinical symptoms such as chronic inflammation, immune cell exhaustion and tumorigenesis seen in HCV patients. Our findings also suggest that persistence of HCV-associated liver disease appear to require initial infections of HCV and immune responses but not long term HCV viraemia. PMID- 28886066 TI - Colonic cytomegalovirus detection by mucosal PCR and antiviral therapy in ulcerative colitis. AB - BACKGROUND: We aimed to identify the risk factors associated with colonic cytomegalovirus (CMV) infection in ulcerative colitis (UC) and to compare the clinical course between antiviral therapy-treated and -untreated groups in mucosal CMV-polymerase chain reaction (PCR) -positive cases. METHODS: We retrospectively selected 46 UC patients (>15 years old) in active phase who underwent colonoscopy with biopsy and were analyzed for CMV infection by mucosal PCR between October 2011 and December 2015 at our institution. Colonic CMV in inflamed mucosa was detected using quantitative real-time PCR. The clinical course was evaluated, including need for drug therapy/surgery or drug therapy intensification. In addition, we evaluated the clinical course between CMV-DNA- cases and CMV-DNA+ cases with low viral load. RESULTS: At baseline, CMV-DNA+ patients were significantly older, had higher endoscopic scores, and required higher corticosteroid doses during the past 4 weeks than CMV-DNA- patients (p< 0.05). No significant differences were observed in disease duration, disease distribution, laboratory data, or use of other medication between CMV-DNA+ and CMV-DNA- patients. In the anti-CMV-treated group with a median (range) DNA load of 16,000 (9,000-36,400), 3patients achieved remission without additional UC therapy, 2 required additional UC therapy, and 1 required colectomy despite azathioprine and infliximab therapy. In the CMV-untreated group with a median (range) DNA load of 919 (157-5,480), all patients achieved remission with UC therapy alone. No significant difference was observed in the clinical course between CMV-DNA- cases and CMV-DNA+ cases with low viral loads. CONCLUSIONS: Aging, endoscopic UC activity, and corticosteroid dose predispose to colonic CMV infection, as determined by mucosal PCR, in UC. UC treatment without anti-CMV therapy may be warranted, particularly in patients with low-load CMV-DNA. Anti CMV therapy alone does not always achieve clinical response in UC even in cases with high-load PCR. PMID- 28886067 TI - A wireless soil moisture sensor powered by solar energy. AB - In a variety of agricultural activities, such as irrigation scheduling and nutrient management, soil water content is regarded as an essential parameter. Either power supply or long-distance cable is hardly available within field scale. For the necessity of monitoring soil water dynamics at field scale, this study presents a wireless soil moisture sensor based on the impedance transform of the frequency domain. The sensor system is powered by solar energy, and the data can be instantly transmitted by wireless communication. The sensor electrodes are embedded into the bottom of a supporting rod so that the sensor can measure soil water contents at different depths. An optimal design with time executing sequence is considered to reduce the energy consumption. The experimental results showed that the sensor is a promising tool for monitoring moisture in large-scale farmland using solar power and wireless communication. PMID- 28886068 TI - Analysis of simple sequence repeat (SSR) structure and sequence within Epichloe endophyte genomes reveals impacts on gene structure and insights into ancestral hybridization events. AB - Epichloe grass endophytes comprise a group of filamentous fungi of both sexual and asexual species. Known for the beneficial characteristics they endow upon their grass hosts, the identification of these endophyte species has been of great interest agronomically and scientifically. The use of simple sequence repeat loci and the variation in repeat elements has been used to rapidly identify endophyte species and strains, however, little is known of how the structure of repeat elements changes between species and strains, and where these repeat elements are located in the fungal genome. We report on an in-depth analysis of the structure and genomic location of the simple sequence repeat locus B10, commonly used for Epichloe endophyte species identification. The B10 repeat was found to be located within an exon of a putative bZIP transcription factor, suggesting possible impacts on polypeptide sequence and thus protein function. Analysis of this repeat in the asexual endophyte hybrid Epichloe uncinata revealed that the structure of B10 alleles reflects the ancestral species that hybridized to give rise to this species. Understanding the structure and sequence of these simple sequence repeats provides a useful set of tools for readily distinguishing strains and for gaining insights into the ancestral species that have undergone hybridization events. PMID- 28886069 TI - Osmotic behaviour of human mesenchymal stem cells: Implications for cryopreservation. AB - Aimed at providing a contribution to the optimization of cryopreservation processes, the present work focuses on the osmotic behavior of human mesenchymal stem cells (hMSCs). Once isolated from the umbilical cord blood (UCB) of three different donors, hMSCs were characterized in terms of size distribution and their osmotic properties suitably evaluated through the exposure to hypertonic and isotonic aqueous solutions at three different temperatures. More specifically, inactive cell volume and cell permeability to water and di-methyl sulfoxide (DMSO) were measured, being cell size determined using impedance measurements under both equilibrium and dynamic conditions. Experimental findings indicate that positive cell volume excursions are limited by the apparent increase of inactive volume, which occurs during both the shrink-swell process following DMSO addition and the subsequent restoration of isotonic conditions in the presence of hypertonic solutions of impermeant or permeant solutes. Based on this evidence, hMSCs must be regarded as imperfect osmometers, and their osmotic behavior described within a scenario no longer compatible with the simple two parameter model usually utilized in the literature. In this respect, the activation of mechano-sensitive ion-channels seemingly represents a reasonable hypothesis for rationalizing the observed osmotic behavior of hMSCs from UCB. PMID- 28886070 TI - MicroRNA miR-301a is a novel cardiac regulator of Cofilin-2. AB - Calsarcin-1 deficient mice develop dilated cardiomyopathy (DCM) phenotype in pure C57BL/6 genetic background (Cs1-ko) despite severe contractile dysfunction and robust activation of fetal gene program. Here we performed a microRNA microarray to identify the molecular causes of this cardiac phenotype that revealed the dysregulation of several microRNAs including miR-301a, which was highly downregulated in Cs1-ko mice compared to the wild-type littermates. Cofilin-2 (Cfl2) was identified as one of the potential targets of miR-301a using prediction databases, which we validated by luciferase assay and mutation of predicted binding sites. Furthermore, expression of miR-301a contrastingly regulated Cfl2 expression levels in neonatal rat ventricular cardiomyocytes (NRVCM). Along these lines, Cfl2 was significantly upregulated in Cs1-ko mice, indicating the physiological association between miR-301a and Cfl2 in vivo. Mechanistically, we found that Cfl2 activated serum response factor response element (SRF-RE) driven luciferase activity in neonatal rat cardiomyocytes and in C2C12 cells. Similarly, knockdown of miR301a activated, whereas, its overexpression inhibited the SRF-RE driven luciferase activity, further strengthening physiological interaction between miR-301a and Cfl2. Interestingly, the expression of SRF and its target genes was strikingly increased in Cs1-ko suggesting a possible in vivo correlation between expression levels of Cfl2/miR 301a and SRF activation, which needs to be independently validated. In summary, our data demonstrates that miR-301a regulates Cofilin-2 in vitro in NRVCM, and in vivo in Cs1-ko mice. Our findings provide an additional and important layer of Cfl2 regulation, which we believe has an extended role in cardiac signal transduction and dilated cardiomyopathy presumably due to the reported involvement of Cfl2 in these mechanisms. PMID- 28886071 TI - Dynamics of the aortic annulus in 4D CT angiography for transcatheter aortic valve implantation patients. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a well-established treatment for patients with severe aortic valve stenosis. This procedure requires pre-operative planning by assessment of aortic dimensions on CT Angiography (CTA). It is well-known that the aortic root dimensions vary over the heart cycle. However, sizing is commonly performed at either mid-systole or end diastole only, which has resulted in an inadequate understanding of its full dynamic behavior. STUDY GOAL: We studied the variation in annulus measurements during the cardiac cycle and determined if this variation is dependent on the amount of calcification at the annulus. METHODS: We measured and compared aortic root annular dimensions and calcium volume in CTA acquisitions at 10 cardiac cycle phases in 51 aortic stenosis patients. Sub-group analysis was performed based on the volume of calcium by splitting the population into mildly and severely calcified valves subgroups. RESULTS: For most annulus measurements, the largest differences were found between 10% and 70 to 80% cardiac cycle phases. Mean difference (+/-standard deviation) in annular minimum diameter, maximum diameter, area, and aspect ratio between mid-systole and end-diastole phases were 1.0 +/- 0.29 mm (p = 0.065), 0.30 +/- 0.24 mm (p = 0.7), 24.1 +/- 7.6 mm2 (p < 0.001), and 0.041 +/- 0.012 (p = 0.039) respectively. Calcium volume measurements varied strongly during the cardiac cycle. The dynamic annulus area was behaving differently between mildly and severely calcified subgroups (p = 0.02). Furthermore, patients with severe aortic calcification were associated with larger annulus diameters. CONCLUSION: There is a significant variation of annulus area and calcium volume measurement during the cardiac cycle. In our measurements, only the dynamic variation of the annulus area is dependent on the severity of the aortic calcification. For TAVI candidates, the annulus area is significantly larger in mid-systole compared to end-diastole. PMID- 28886072 TI - Stakeholder perspectives for optimization of tuberculosis contact investigation in a high-burden setting. AB - INTRODUCTION: Optimal tuberculosis contact investigation impacts TB prevention, timely case finding and linkage to care, however data on routine implementation in high burden contexts is limited. MATERIALS AND METHODS: In a multi-method qualitative study based on individual interviews with TB patients, facility observations and focus group discussions with health workers (HWs) in 13 public health facilities, and key informant interviews with governmental and non governmental experts, we describe TB contact investigation in the context of an urban setting in Kenya and identify opportunities for optimization. RESULTS: Invitation of TB patients to bring close contacts by HWs was key for all patient decisions that led to contact screening in addition to patients' understanding of TB transmission and desire to avoid contacts suffering from TB. Sub-optimal HW enquiry of TB patients and contacts presenting at the facility were missed opportunities which stemmed from lack of standardized operational procedures, documentation tools and HW training. Stakeholders proposed provision of fast tracked and holistic health packages for contacts seeking TB screening, and sustainable government led funding for the requisite infrastructure and workforce. CONCLUSION: TB contact invitation by HWs leading to contact screening occurs in this context. Stakeholder perspectives inform the design of an operational framework for optimized delivery. PMID- 28886073 TI - Outcomes of patients with altered level of consciousness and abnormal electroencephalogram: A retrospective cohort study. AB - INTRODUCTION: Nonconvulsive seizures (NCS) are frequent in hospitalized patients and may further aggravate injury in the already damaged brain, potentially worsening outcomes in encephalopathic patients. Therefore, both early seizure recognition and treatment have been advocated to prevent further neurological damage. OBJECTIVE: Evaluate the main EEG patterns seen in patients with impaired consciousness and address the effect of treatment with antiepileptic drugs (AEDs), continuous intravenous anesthetic drugs (IVADs), or the combination of both, on outcomes. METHODS: This was a single center retrospective cohort study conducted in a private, tertiary care hospital. Consecutive adult patients with altered consciousness submitted to a routine EEG between January 2008 and February 2011 were included in this study. Based on EEG pattern, patients were assigned to one of three groups: Group Interictal Patterns (IP; EEG showing only interictal epileptiform discharges or triphasic waves), Group Rhythmic and Periodic Patterns (RPP; at least one EEG with rhythmic or periodic patterns), and Group Ictal (Ictal; at least one EEG showing ictal pattern). Groups were compared in terms of administered antiepileptic treatment and frequency of unfavorable outcomes (modified Rankin scale >=3 and in-hospital mortality). RESULTS: Two hundred and six patients (475 EEGs) were included in this analysis. Interictal pattern was observed in 35.4% (73/206) of patients, RPP in 53.4% (110/206) and ictal in 11.2% (23/206) of patients. Treatment with AEDs, IVADs or a combination of both was administered in half of the patients. While all Ictal group patients received treatment (AEDs or IVADs), only 24/73 (32.9%) IP group patients and 55/108 (50.9%) RPP group patients were treated (p<0.001). Hospital length of stay (LOS) and frequency of unfavorable outcomes did not differ among the groups. In hospital mortality was higher in IVADs treated RPP patients compared to AEDs treated RPP patients [11/19 (57.9%) vs. 11/36 (30.6%) patients, respectively, p = 0.049]. Hospital LOS, in-hospital mortality and frequency of unfavorable outcomes did not differ between Ictal patients treated exclusively with AEDs or IVADs. CONCLUSION: In patients with acute altered consciousness and abnormal routine EEG, antiepileptic treatment did not improve outcomes regardless of the presence of periodic, rhythmic or ictal EEG patterns. PMID- 28886074 TI - Unique transcriptomic response to sepsis is observed among patients of different age groups. AB - Sepsis is a major cause of morbidity and mortality, especially at the extremes of age. To understand the human age-specific transcriptomic response to sepsis, a multi-cohort, pooled analysis was conducted on adults, children, infants, and neonates with and without sepsis. Nine public whole-blood gene expression datasets (636 patients) were employed. Age impacted the transcriptomic host response to sepsis. Gene expression from septic neonates and adults was more dissimilar whereas infants and children were more similar. Neonates showed reductions in inflammatory recognition and signaling pathways compared to all other age groups. Likewise, adults demonstrated decreased pathogen sensing, inflammation, and myeloid cell function, as compared to children. This may help to explain the increased incidence of sepsis-related organ failure and death in adults. The number of dysregulated genes in septic patients was proportional to age and significantly differed among septic adults, children, infants, and neonates. Overall, children manifested a greater transcriptomic intensity to sepsis as compared to the other age groups. The transcriptomic magnitude for adults and neonates was dramatically reduced as compared to children and infants. These findings suggest that the transcriptomic response to sepsis is age dependent, and diagnostic and therapeutic efforts to identify and treat sepsis will have to consider age as an important variable. PMID- 28886075 TI - Incorporating abundance information and guiding variable selection for climate based ensemble forecasting of species' distributional shifts. AB - Ecological niche models (ENMs) have increasingly been used to estimate the potential effects of climate change on species' distributions worldwide. Recently, predictions of species abundance have also been obtained with such models, though knowledge about the climatic variables affecting species abundance is often lacking. To address this, we used a well-studied guild (temperate North American quail) and the Maxent modeling algorithm to compare model performance of three variable selection approaches: correlation/variable contribution (CVC), biological (i.e., variables known to affect species abundance), and random. We then applied the best approach to forecast potential distributions, under future climatic conditions, and analyze future potential distributions in light of available abundance data and presence-only occurrence data. To estimate species' distributional shifts we generated ensemble forecasts using four global circulation models, four representative concentration pathways, and two time periods (2050 and 2070). Furthermore, we present distributional shifts where 75%, 90%, and 100% of our ensemble models agreed. The CVC variable selection approach outperformed our biological approach for four of the six species. Model projections indicated species-specific effects of climate change on future distributions of temperate North American quail. The Gambel's quail (Callipepla gambelii) was the only species predicted to gain area in climatic suitability across all three scenarios of ensemble model agreement. Conversely, the scaled quail (Callipepla squamata) was the only species predicted to lose area in climatic suitability across all three scenarios of ensemble model agreement. Our models projected future loss of areas for the northern bobwhite (Colinus virginianus) and scaled quail in portions of their distributions which are currently areas of high abundance. Climatic variables that influence local abundance may not always scale up to influence species' distributions. Special attention should be given to selecting variables for ENMs, and tests of model performance should be used to validate the choice of variables. PMID- 28886076 TI - Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans. AB - INTRODUCTION: Toll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity in vitro. Low tumor TLR9 expression has been associated with poor survival in Caucasian patients with triple negative breast cancer (TNBC). African American (AA) patients with TNBC have worse prognosis than Caucasians but whether this is due to differences in tumor biology remains controversial. We studied the prognostic significance of tumor Toll like receptor-9 (TLR9) protein expression among African American (AA) triple negative breast cancer (TNBC) patients. Germline TLR9 variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk. METHODS: TLR9 expression was studied with immunohistochemistry in archival tumors. Exome Variant Server and The Cancer Genome Atlas were used to determine the genetic variation in the general EA and AA populations, and AA breast cancer cases. Minor allele frequencies (MAFs) were compared between EAs (n = 4300), AAs (n = 2203), and/or AA breast cancer cases (n = 131). RESULTS: Thirty-two TLR9 variants had a statistically significant MAF difference between general EAs and AAs. Twenty-one of them affect a CpG site. Rs352140, a variant previously associated with protection from breast cancer, is more common in EAs than AAs (p = 2.20E-16). EAs had more synonymous alleles, while AAs had more rare coding alleles. Similar analyses comparing AA breast cancer cases with AA controls did not reveal any variant class differences; however, three previously unreported TLR9 variants were associated with late onset breast cancer. Although not statistically significant, rs352140 was observed less frequently in AA cases compared to controls. Tumor TLR9 protein expression was not associated with prognosis. CONCLUSIONS: Tumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in TLR9 variant MAFs between EAs and AAs. They may affect TLR9 expression and function. Rs352140, which may protect from breast cancer, is 1.6 X more common among EAs. These findings call for a detailed analysis of the contribution of TLR9 to breast cancer pathophysiology and health disparities. PMID- 28886077 TI - Exploration of ethno-medicinal knowledge among rural communities of Pearl Valley; Rawalakot, District Poonch Azad Jammu and Kashmir. AB - BACKGROUND: Medicinal plants are the basic source of health care in the Pearl Valley District Poonch, Azad Jammu, and Kashmir. The basic aim of present study was to record information about the use of plants in herbal preparation and quantification of recorded data. MATERIALS AND METHODS: The research was conducted with the null hypothesis that there was no differential distribution of knowledge among the communities between genders and among different age groups in the study area and across cultural medicinal uses of the plants are similar. To check these hypotheses information about medicinal plants was collected from 46 laypeople and 18 herbalists by using an open ended and semistructured questionnaire. Different ethnobotanical indices were calculated in order to quantify the knowledge on the medicinal plants reported in the study. RESULTS: Our study recorded 136 species of medicinal plants belonging to 45 families with Asteraceae (14 species) as the dominant family of the area. Decoction (26 species), juice and powder (24 species each) were most common methods of preparation. Spearman's correlation analysis showed that age and gender had the significant effect on both numbers of mentioned species and different uses. A number of known medicinal plants and the number of different uses (H: 38.51; p < 0.001) differ significantly as indicated by Kruskal-Wallis tests. These results showed that the knowledge about the plant varies among different age groups, which were the first hypothesis of the present study. The highest use values (UVs) were reported for Berberis lyceum and Ajuga bracteosa (1.13 each) followed by Abies pindrow (1.03). Highest informant consensus factor (ICF) values were recorded for digestive system diseases (ICF = 0.90) and muscular and skeletal system diseases (ICF = 0.89). The value of Jaccarad index ranged from 6.11 to 32.97 with an average value of 19.84, percentage of similarity was highest between study area and Pir Lasura National Park (34.62%). CONCLUSION: High similarity might be due to the fact that the communities living in these areas have same sociocultural values and have more opportunities to exchange their traditional knowledge. The present study provides practical evidence about the use of medicinal plants among the inhabitants of the Pearl Valley. PMID- 28886078 TI - MicroRNA-223 and microRNA-21 in peripheral blood B cells associated with progression of primary biliary cholangitis patients. AB - Recently, there is ample evidence suggesting the important role of microRNAs (miRNAs) in autoimmune diseases via modulating B cells function. Primary biliary cholangitis (PBC) is a progressive immune-mediated liver disease with unclear pathogenic mechanism. Whether the miRNA in peripheral B cells of PBC involve the mechanisms of pathology and progression is not known. The present study explores miRNA deregulation in peripheral B-cell of PBC from stage I to IV and healthy controls. Peripheral B cells were obtained from 72 PBC patients (stage I, n = 17; stage II, n = 23; stage III, n = 16; stage IV, n = 16) and 15 healthy controls. Initially, in a discovery study, miRNA array analysis was performed, subsequently, in a validation study, quantitative PCR was used to investigate miRNA expression profile in B cells of PBS patients compared to healthy controls. Based on bioinformatics analysis, we identified the potential biological processes and significant signaling pathways affected by these microRNAs, and generated the microRNA-gene network. The discovery study identified 558 miRNAs differentially expressed in B cells of PBC patients compared to controls. Interestingly, among all differentially expressed miRNAs, hsa-miR-223-3p and hsa miR-21-5p were the only miRNAs that showed consistent and significant down regulation from stage I to stage III of PBC. Bioinformatics showed that potential target genes of both miRNAs involved in migration, cell differentiation, apoptosis, and signal transduction pathways. In conclusion, our results suggest that the expression profiles of miRNA in peripheral B cells of PBC patients are closely associated with the disease progression, especially the down-regulation of hsa-miR-223-3p and hsa-miR-21-5p. Taken together, our study offers novel perspectives on the role of miRNAs in PBC pathogenesis. PMID- 28886079 TI - Associations between lower-limb muscle activation and knee flexion in post-stroke individuals: A study on the stance-to-swing phases of gait. AB - Reduced knee flexion is a leading feature of post-stroke gait, but the causes have not been well understood. The purpose of this study was to investigate the relationship between the knee flexion and the lower-limb muscle activation within the stance-to-swing phases of gait cycle in the post-stroke hemiplegic patients. Ten stroke patients and 10 age- and gender-matched healthy subjects participated in the experiment. The lower-limb kinematic signals and the surface electromyography (sEMG) signals of the left and right rectus femoris (RF), biceps femoris (BF) and lateral gastrocnemius (GS) were recorded during walking. The angle range (AR) of knee flexion, the root mean square (RMS) and the mean frequency (MNF) of sEMG signals were calculated from the terminal stance (TSt) to the initial swing (ISw) phases of gait cycle. Stroke patients showed lower bilateral AR of knee flexion and lower RMS of GS on the paretic side, but higher MNF of RF on the non-paretic side compared with the controls. Within the stroke patients, significant differences were found between their paretic and non paretic limbs in the AR of knee flexion, as well as in the RMS and MNF of GS (p < 0.05). Regression analysis showed that the RMS of BF, MNF of BF and MNF of GS explained 82.1% of variations in AR of knee flexion on paretic side (r2 = 0.821). But the RMS and MNF of all the muscles (including the RF, GS and BF) could explain 65.6% of AR of knee flexion variations on the non-paretic side (r2 = 0.656), and 45.2% of variations for the healthy subjects (r2 = 0.452). The reduced knee flexion during gait was associated with altered magnitude and frequency of muscle contractions and with simplified muscle synergy in the post stroke hemiplegic patients. Identifying the muscles that are responsible for knee stiffness may facilitate improvement of rehabilitation strategy for post-stroke gait. PMID- 28886080 TI - Stalk formation of Brevundimonas and how it compares to Caulobacter crescentus. AB - The Caulobacter crescentus cell extension known as a stalk represents an unusual bacterial morphology. C. crescentus produces stalks under multiple nutrient conditions, but the length of the stalk is increased in response to phosphate starvation. However, the exact function of the stalk is not known, nor is it known how much stalk biogenesis or function is conserved with other stalked bacteria. Work presented here shows that many organisms in the Caulobacter genus and the next closest genus (Brevundimonas) generally do not synthesize stalks in the relatively-rich PYE growth medium, suggesting that the synthesis of a stalk under nutrient-rich conditions by C. crescentus may be the exception instead of the norm among its phylogenetic group. Brevundimonas subvibrioides can be induced to synthesize stalks by genetically mimicking phosphate starvation conditions, indicating stalk synthesis in this organism may be performed on an as-need basis. This mutation, however, does not appear to increase the incidence of holdfast synthesis. While B. subvibrioides stalks appear to be synthesized with the same polarity with respect to holdfast as C. crescentus stalks, evidence is presented that suggests B. subvibrioides may disassemble stalks when they are no longer needed. Many homologs of C. crescentus genes encoding stalk-associated proteins are absent in the B. subvibrioides genome, and B. subvibrioides PstA-GFP as well as C. crescentus StpX-GFP are able to enter the B. subvibrioides stalk compartment, calling into question the level of compartmentalization of the B. subvibrioides stalk. In summary, this work begins to address how much the C. crescentus model for this unusual morphological adaptation can be extended to related organisms. PMID- 28886081 TI - Orexin A affects HepG2 human hepatocellular carcinoma cells glucose metabolism via HIF-1alpha-dependent and -independent mechanism. AB - Orexins are hypothalamic neuropeptides that regulate feeding, reward, wakefulness and energy homeostasis. The present study sought to characterize the involvement of orexin A in glucose metabolism in HepG2 human hepatocellular carcinoma cells, and investigated the role of hypoxia-inducible factor-1alpha (HIF-1alpha) in the response. HepG2 cells were exposed to different concentrations of orexin A (10-9 to 10-7 M) in vitro, without or with the orexin receptor 1 (OX1R) inhibitor (SB334867), HIF-1alpha inhibitor (YC-1) or a combination of both inhibitors. Subsequently, OX1R, HIF-1alpha expression and localization, glucose uptake, glucose transporter 1 (GLUT1) expression and ATP content were measured. We further investigated the intracellular fate of glucose by measuring the gene expression of pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase (LDHA) and pyruvate dehydrogenase B (PDHB), as well as metabolite levels including lactate generation and mitochondrial pyruvate dehydrogenase (PDH) activity. The activity of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was also assessed. Our results showed that the expression of OX1R was predominantly located in the nucleus in HepG2 cells. Orexin A oxygen-independently promoted the mRNA and protein expression of HIF 1alpha as well as its nuclear accumulation in HepG2 cells and the elevated HIF 1alpha protein was associated, at least partly, with the activation of the PI3K/Akt/mTOR pathway. Orexin A stimulated GLUT1 expression, glucose uptake as well as ATP generation in HepG2 cells via OX1R acting through the HIF-1alpha pathway. Moreover, orexin A inhibited LDHA, PDK1 expression and lactate production, stimulated PDHB expression and PDH enzyme activity independent of HIF 1alpha. Our results indicated that orexin signaling facilitated the glucose flux into mitochondrial oxidative metabolism rather than glycolysis in HepG2 cells. These findings provide new insight into the regulation of glucose metabolism by orexin A in hepatocellular carcinoma cells. PMID- 28886082 TI - Haloperidol induces pharmacoepigenetic response by modulating miRNA expression, global DNA methylation and expression profiles of methylation maintenance genes and genes involved in neurotransmission in neuronal cells. AB - INTRODUCTION: Haloperidol has been extensively used in various psychiatric conditions. It has also been reported to induce severe side effects. We aimed to evaluate whether haloperidol can influence host methylome, and if so what are the possible mechanisms for it in neuronal cells. Impact on host methylome and miRNAs can have wide spread alterations in gene expression, which might possibly help in understanding how haloperidol may impact treatment response or induce side effects. METHODS: SK-N-SH, a neuroblasoma cell line was treated with haloperidol at 10MUm concentration for 24 hours and global DNA methylation was evaluated. Methylation at global level is maintained by methylation maintenance machinery and certain miRNAs. Therefore, the expression of methylation maintenance genes and their putative miRNA expression profiles were assessed. These global methylation alterations could result in gene expression changes. Therefore genes expressions for neurotransmitter receptors, regulators, ion channels and transporters were determined. Subsequently, we were also keen to identify a strong candidate miRNA based on biological and in-silico approach which can reflect on the pharmacoepigenetic trait of haloperidol and can also target the altered neuroscience panel of genes used in the study. RESULTS: Haloperidol induced increase in global DNA methylation which was found to be associated with corresponding increase in expression of various epigenetic modifiers that include DNMT1, DNMT3A, DNMT3B and MBD2. The expression of miR-29b that is known to putatively regulate the global methylation by modulating the expression of epigenetic modifiers was observed to be down regulated by haloperidol. In addition to miR-29b, miR-22 was also found to be downregulated by haloperidol treatment. Both these miRNA are known to putatively target several genes associated with various epigenetic modifiers, pharmacogenes and neurotransmission. Interestingly some of these putative target genes involved in neurotransmission were observed to be upregulated while CHRM2 gene expression was down regulated. CONCLUSIONS: Haloperidol can influence methylation traits thereby inducing a pharmacoepigenomic response, which seems to be regulated by DNMTs and their putative miRNA expression. Increased methylation seems to influence CHRM2 gene expression while microRNA could influence neurotransmission, pharmacogene expression and methylation events. Altered expression of various therapeutically relevant genes and miRNA expression, could account for their role in therapeutic response or side effects. PMID- 28886083 TI - Nurse-led telephone-based follow-up of secondary prevention after acute coronary syndrome: One-year results from the randomized controlled NAILED-ACS trial. AB - BACKGROUND: Secondary prevention after acute coronary syndrome (ACS) could reduce morbidity and mortality, but guideline targets are seldom reached. We hypothesized that nurse-led telephone-based intervention would increase adherence. METHODS: The NAILED ACS trial is a prospective, controlled, randomized trial. Patients admitted for ACS at Ostersund hospital, Sweden, were randomized to usual follow-up by a general practitioner or a nurse-led intervention. The intervention comprised telephone follow-up after 1 month and then yearly with lifestyle counselling and titration of medications until reaching target values for LDL-C (<2.5 mmol/L) and blood pressure (BP; <140/90 mmHg) or set targets were deemed unachievable. This is a 12-month exploratory analysis of the intervention. RESULTS: A total of 768 patients (396 intervention, 372 control) completed the 12 month follow-up. After titration at the 1-month follow-up, mean LDL-C was 0.38 mmol/L (95% CI 0.28 to 0.48, p<0.05), mean systolic BP 7 mmHg (95% CI 4.5 to 9.2, p<0.05), and mean diastolic BP 4 mmHg (95% CI 2.4 to 4.1, p<0.05) lower in the intervention group. Target values for LDL-C and systolic BP were met by 94.1% and 91.9% of intervention patients and 68.4% and 65.6% of controls (p<0.05). At 12 months, mean LDL was 0.3 mmol/L (95% CI 0.1 to 0.4, p <0.05), systolic BP 1.5 mmHg (95% CI -1.0 to 4.1, p = 0.24), and mean diastolic BP 2.1 mmHg (95% CI 0.6 to 3.6, p <0.05) lower in the intervention group. Target values for LDL-C and systolic BP were met in 77.7% and 68.9% of intervention patients and 63.2% and 63.7% of controls (p<0.05 and p = 0.125). CONCLUSION: Nurse-led telephone-based secondary prevention was significantly more efficient at improving LDL-C and diastolic BP levels than usual care. The effect of the intervention declined between 1 and 12 months. Further evaluation of the persistence to the intervention is needed. PMID- 28886084 TI - An in vitro simulation method for the tribological assessment of complete natural hip joints. AB - The use of hip joint simulators to evaluate the tribological performance of total hip replacements is widely reported in the literature, however, in vitro simulation studies investigating the tribology of the natural hip joint are limited with heterogeneous methodologies reported. An in vitro simulation system for the complete natural hip joint, enabling the acetabulum and femoral head to be positioned with different orientations whilst maintaining the correct joint centre of rotation, was successfully developed for this study. The efficacy of the simulation system was assessed by testing complete, matched natural porcine hip joints and porcine hip hemiarthroplasty joints in a pendulum friction simulator. The results showed evidence of biphasic lubrication, with a non-linear increase in friction being observed in both groups. Lower overall mean friction factor values in the complete natural joint group that increased at a lower rate over time, suggest that the exudation of fluid and transition to solid phase lubrication occurred more slowly in the complete natural hip joint compared to the hip hemiarthroplasty joint. It is envisaged that this methodology will be used to investigate morphological risk factors for developing hip osteoarthritis, as well as the effectiveness of early interventional treatments for degenerative hip disease. PMID- 28886085 TI - Meibomian gland features in a Norwegian cohort of patients with primary Sjogren's syndrome. AB - PURPOSE: To assess the tear film and meibomian gland (MG) features in a Norwegian cohort of patients with primary Sjogren's syndrome (pSS) and in age- and gender matched control subjects. METHODS: Thirty-four female patients with pSS (age 52.9+/-11.9 years) and 32 female control subjects (age 49.0+/-11.5 years) were recruited. After completion of Ocular Surface Disease Index (OSDI) questionnaire and McMonnies Dry Eye Questionaire, participants underwent measurements of tear osmolarity, tear break-up time (TBUT), ocular surface and corneal staining, Schirmer I test, corneal sensitivity, MG expressibility evaluations, and lid margin morphology examination using slitlamp microscopy. Non-contact infrared meibography images were assessed by computer-assisted analysis. The MG loss, calculated as (tarsal area-MG area)/tarsal area, was evaluated in both upper (UL) and lower lids (LL). RESULTS: Compared to the control group, pSS patients demonstrated higher MG loss in both UL (33.8+/-13.2% vs. 24.4+/-8.5%, p< 0.01) and LL (52.5+/-15.7% vs. 43.0+/-9.6%, p<0.05), as well as higher lid abnormality score (0.8+/-0.8 vs. 0.2+/-0.6, p< 0.01). Furthermore, pSS patients showed higher OSDI and McMonnies questionnaire scores, elevated osmolarity, shorter TBUT, shorter blink interval, less wetting in Schirmer I test, more ocular surface staining and more corneal staining. MG loss in UL correlated negatively with TBUT (r = -0.386, p = 0.029) in the pSS group, whereas MG loss in LL correlated negatively with TBUT (r = -0.380, p = 0.035) in the control group. CONCLUSIONS: Significantly elevated dry eye symptoms and signs were found in the pSS group compared with the control group, which might be attributed to both decreased aqueous tear production and increased tear evaporation. PMID- 28886087 TI - Hong Kong Hospital Authority resource efficiency evaluation: Via a novel DEA Malmquist model and Tobit regression model. AB - The Hospital Authority (HA) is a statutory body managing all the public hospitals and institutes in Hong Kong (HK). In recent decades, Hong Kong Hospital Authority (HKHA) has been making efforts to improve the healthcare services, but there still exist some problems like unfair resource allocation and poor management, as reported by the Hong Kong medical legislative committee. One critical consequence of these problems is low healthcare efficiency of hospitals, leading to low satisfaction among patients. Moreover, HKHA also suffers from the conflict between limited resource and growing demand. An effective evaluation of HA is important for resource planning and healthcare decision making. In this paper, we propose a two-phase method to evaluate HA efficiency for reducing healthcare expenditure and improving healthcare service. Specifically, in Phase I, we measure the HKHA efficiency changes from 2000 to 2013 by applying a novel DEA Malmquist index with undesirable factors. In Phase II, we further explore the impact of some exogenous factors (e.g., population density) on HKHA efficiency by Tobit regression model. Empirical results show that there are significant differences between the efficiencies of different hospitals and clusters. In particular, it is found that the public hospital serving in a richer district has a relatively lower efficiency. To a certain extent, this reflects the socioeconomic reality in HK that people with better economic condition prefers receiving higher quality service from the private hospitals. PMID- 28886086 TI - Xenon for tunnelling analysis of the efflux pump component OprN. AB - Tripartite efflux pumps are among the main actors responsible for antibiotics resistance in Gram-negative bacteria. In the last two decades, structural studies gave crucial information about the assembly interfaces and the mechanistic motions. Thus rigidifying the assembly seems to be an interesting way to hamper the drug efflux. In this context, xenon is a suitable probe for checking whether small ligands could act as conformational lockers by targeting hydrophobic cavities. Here we focus on OprN, the outer membrane channel of the MexEF efflux pump from Pseudomonas aeruginosa. After exposing OprN crystals to xenon gas pressure, 14 binding sites were observed using X-ray crystallography. These binding sites were unambiguously characterized in hydrophobic cavities of OprN. The major site is observed in the sensitive iris-like region gating the channel at the periplasmic side, built by the three key-residues Leu 405, Asp 109, and Arg 412. This arrangement defines along the tunnel axis a strong hydrophobic/polar gradient able to enhance the passive efflux mechanism of OprN. The other xenon atoms reveal strategic hydrophobic regions of the channel scaffold to target, with the aim to freeze the dynamic movements responsible of the open/close conformational equilibrium in OprN. PMID- 28886088 TI - An empirical research on relationships between subjective judgement, technology acceptance tendency and knowledge transfer. AB - The purpose of this study was to explore the relationships among employees' usage intention pertaining to mobile information devices, focusing on subjective judgement, technology acceptance tendency, information sharing behavior and information transfer. A research model was established to verify several hypotheses. The research model based on integrated concepts of knowledge management and technology acceptance modeling. Participants were employees of enterprises in Taiwan, selected by combining snowball and convenience sampling. Data obtained from 779 e-surveys. Multiple-regression analysis was employed for hypothesis verification. The results indicate that perceived ease-of-use of mobile devices was affected by computer self-efficacy and computer playfulness directly; meanwhile, perceived ease-of-use directly affects perceived usefulness. In addition, perceived ease-of-use and perceived usefulness can predict information-sharing behavior in a positive manner, and impact knowledge transfer as well. Based on the research findings, it suggested that enterprises should utilize mobile information devices to create more contact with customers and enrich their service network. In addition, it is recommended that managers use mobile devices to transmit key information to their staff and that they use these devices for problem-solving and decision-making. Further, the staff's skills pertaining to the operation of mobile information devices and to fully implement their features are reinforced in order to inspire the users' knowledge transfer. Enhancing the playfulness of the interface is also important. In general, it is useful to promote knowledge transfer behavior within an organization by motivating members to share information and ideas via mobile information devices. In addition, a well-designed interface can facilitate employees' use of these devices. PMID- 28886089 TI - Drug exposure in register-based research-An expert-opinion based evaluation of methods. AB - BACKGROUND: In register-based pharmacoepidemiological studies, construction of drug exposure periods from drug purchases is a major methodological challenge. Various methods have been applied but their validity is rarely evaluated. Our objective was to conduct an expert-opinion based evaluation of the correctness of drug use periods produced by different methods. METHODS: Drug use periods were calculated with three fixed methods: time windows, assumption of one Defined Daily Dose (DDD) per day and one tablet per day, and with PRE2DUP that is based on modelling of individual drug purchasing behavior. Expert-opinion based evaluation was conducted with 200 randomly selected purchase histories of warfarin, bisoprolol, simvastatin, risperidone and mirtazapine in the MEDALZ-2005 cohort (28,093 persons with Alzheimer's disease). Two experts reviewed purchase histories and judged which methods had joined correct purchases and gave correct duration for each of 1000 drug exposure periods. RESULTS: The evaluated correctness of drug use periods was 70-94% for PRE2DUP, and depending on grace periods and time window lengths 0-73% for tablet methods, 0-41% for DDD methods and 0-11% for time window methods. The highest rate of evaluated correct solutions for each method class were observed for 1 tablet per day with 180 days grace period (TAB_1_180, 43-73%), and 1 DDD per day with 180 days grace period (1 41%). Time window methods produced at maximum only 11% correct solutions. The best performing fixed method TAB_1_180 reached highest correctness for simvastatin 73% (95% CI 65-81%) whereas 89% (95% CI 84-94%) of PRE2DUP periods were judged as correct. CONCLUSIONS: This study shows inaccuracy of fixed methods and the urgent need for new data-driven methods. In the expert-opinion based evaluation, the lowest error rates were observed with data-driven method PRE2DUP. PMID- 28886090 TI - Relation of accommodative microfluctuation with dry eye symptoms in short tear break-up time dry eye. AB - PURPOSE: To investigate accommodative microfluctuations (AMFs) and visual function in short tear break-up time (BUT)-type dry eye (DE) and non-DE subjects. METHODS: This prospective comparative study included 48 volunteers with DE symptoms (mean age 34.8 +/- 5.5 years, age range 25-42 years) and 73 without DE symptoms (mean age 30.6 +/- 4.7 years, age range 25-42 years). The eyes were divided into two groups: (1) DE group with DE symptoms and BUT <= 5 s and (2) non DE group without DE symptoms and BUT > 5 s. We excluded eyes with Schirmer score <= 5 mm and positive keratoconjunctival epithelial damage. Tear evaluation, AMF, and functional visual acuity (VA) examinations were performed. AMF parameters included total high-frequency component (HFC), HFC with low accommodation for the task of staring into the distance (HFC1), and HFC with high accommodation for deskwork (HFC2). Functional VA parameters included starting VA, functional VA, visual maintenance ratio, and blink frequency. RESULTS: A total of 33 and 34 eyes were categorized in the DE and non-DE groups, respectively. Mean blink frequency and HFC1 values were significantly higher in the DE group than they were in the non-DE group. CONCLUSIONS: DEs with symptoms showed abnormal AMF and visual function, which may be associated with DE symptoms. PMID- 28886091 TI - A study of the structural properties of sites modified by the O-linked 6-N acetylglucosamine transferase. AB - Protein O-GlcNAcylation (O-GlcNAc) is an essential post-translational modification (PTM) in higher eukaryotes. The O-linked beta-N-acetylglucosamine transferase (OGT), targets specific Serines and Threonines (S/T) in intracellular proteins. However, unlike phosphorylation, fewer than 25% of known O-GlcNAc sites match a clear sequence pattern. Accordingly, the three-dimensional structures of O-GlcNAc sites were characterised to investigate the role of structure in molecular recognition. From 1,584 O-GlcNAc sites in 620 proteins, 143 were mapped to protein structures determined by X-ray crystallography. The modified S/T were 1.7 times more likely to be annotated in the REM465 field which defines missing residues in a protein structure, while 7 O-GlcNAc sites were solvent inaccessible and unlikely to be targeted by OGT. 132 sites with complete backbone atoms clustered into 10 groups, but these were indistinguishable from clusters from unmodified S/T. This suggests there is no prevalent three-dimensional motif for OGT recognition. Predicted features from the 620 proteins were compared to unmodified S/T in O-GlcNAcylated proteins and globular proteins. The Jpred4 predicted secondary structure shows that modified S/T were more likely to be coils. 5/6 methods to predict intrinsic disorder indicated O-GlcNAcylated S/T to be significantly more disordered than unmodified S/T. Although the analysis did not find a pattern in the site three-dimensional structure, it revealed the residues around the modification site are likely to be disordered and suggests a potential role of secondary structure elements in OGT site recognition. PMID- 28886092 TI - Prediction of long-term outcomes of HIV-infected patients developing non-AIDS events using a multistate approach. AB - OBJETIVES: Outcomes of people living with HIV (PLWH) developing non-AIDS events (NAEs) remain poorly defined. We aimed to classify NAEs according to severity, and to describe clinical outcomes and prognostic factors after NAE occurrence using data from CoRIS, a large Spanish HIV cohort from 2004 to 2013. DESIGN: Prospective multicenter cohort study. METHODS: Using a multistate approach we estimated 3 transition probabilities: from alive and NAE-free to alive and NAE experienced ("NAE development"); from alive and NAE-experienced to death ("Death after NAE"); and from alive and NAE-free to death ("Death without NAE"). We analyzed the effect of different covariates, including demographic, immunologic and virologic data, on death or NAE development, based on estimates of hazard ratios (HR). We focused on the transition "Death after NAE". RESULTS: 8,789 PLWH were followed-up until death, cohort censoring or loss to follow-up. 792 first incident NAEs occurred in 9.01% PLWH (incidence rate 28.76; 95% confidence interval [CI], 26.80-30.84, per 1000 patient-years). 112 (14.14%) NAE-experienced PLWH and 240 (2.73%) NAE-free PLWH died. Adjusted HR for the transition "Death after NAE" was 12.1 (95%CI, 4.90-29.89). There was a graded increase in the adjusted HRs for mortality according to NAE severity category: HR (95%CI), 4.02 (2.45-6.57) for intermediate-severity; and 9.85 (5.45-17.81) for serious NAEs compared to low-severity NAEs. Male sex (HR 2.04; 95% CI, 1.11-3.84), age>50 years (1.78, 1.08-2.94), hepatitis C-coinfection (2.52, 1.38-4.61), lower CD4 cell count at cohort entry (HR 2.49; 95%CI 1.20-5.14 for CD4 cell count below 200 and HR 2.16; 95%CI 1.01-4.66 for CD4 cell count between 200-350, both compared to CD4 cell count higher than 500) and concomitant CD4<200 cells/mL (2.22, 1.42 3.44) were associated with death after NAE. CD4 count and HIV-1 RNA at engagement, previous AIDS and hepatitis C-coinfection predicted mortality in NAE free persons. CONCLUSION: NAEs, including low-severity events, increase prominently the risk for mortality in PLWH. Prognostic factors differ between NAE experienced and NAE-free persons. These findings should be taken into account in the clinical management of PLWH developing NAEs and may permit more targeted prevention efforts. PMID- 28886094 TI - Investigating the multivariate nature of NHL player performance with structural equation modeling. AB - Hockey is a complex and multifaceted game, yet many of the statistical tools used to evaluate performance are univariate. To garner a better understanding of hockey's multifaceted nature, two structural equation models (SEMs) assessing the interrelations between offense, defense, and possession were built from three seasons of NHL data. Overall, it was found that the concepts of offense, defense, and possession are best understood via a small constellation of measured variables, and that offense mediates the relationship between possession and defense such that higher levels of offense leads to poorer defensive performance. These findings are discussed within the context of ranking player performance. PMID- 28886093 TI - Comparison of risk classification between EndoPredict and MammaPrint in ER positive/HER2-negative primary invasive breast cancer. AB - PURPOSE: To compare the concordance in risk classification between the EndoPredict and the MammaPrint scores obtained for the same cancer samples on 40 estrogen-receptor positive/HER2-negative breast carcinomas. METHODS: Formalin fixed, paraffin-embedded invasive breast carcinoma tissues that were previously analyzed with MammaPrint as part of routine care of the patients, and were classified as high-risk (20 patients) and low-risk (20 patients), were selected to be analyzed by the EndoPredict assay, a second generation gene expression test that combines expression of 8 genes (EP score) with two clinicopathological variables (tumor size and nodal status, EPclin score). RESULTS: The EP score classified 15 patients as low-risk and 25 patients as high-risk. EPclin re classified 5 of the 25 EP high-risk patients into low-risk, resulting in a total of 20 high-risk and 20 low-risk tumors. EP score and MammaPrint score were significantly correlated (p = 0.008). Twelve of 20 samples classified as low-risk by MammaPrint were also low-risk by EP score (60%). 17 of 20 MammaPrint high-risk tumors were also high-risk by EP score. The overall concordance between EP score and MammaPrint was 72.5% (kappa = 0.45, (95% CI, 0.182 to 0.718)). EPclin score also correlated with MammaPrint results (p = 0.004). Discrepancies between both tests occurred in 10 cases: 5 MammaPrint low-risk patients were classified as EPclin high-risk and 5 high-risk MammaPrint were classified as low-risk by EPclin and overall concordance of 75% (kappa = 0.5, (95% CI, 0.232 to 0.768)). CONCLUSIONS: This pilot study demonstrates a limited concordance between MammaPrint and EndoPredict. Differences in results could be explained by the inclusion of different gene sets in each platform, the use of different methodology, and the inclusion of clinicopathological parameters, such as tumor size and nodal status, in the EndoPredict test. PMID- 28886096 TI - Success of a weight loss plan for overweight dogs: The results of an international weight loss study. AB - INTRODUCTION: Obesity is a global concern in dogs with an increasing prevalence, and effective weight loss solutions are required that work in different geographical regions. The main objective was to conduct an international, multi centre, weight loss trial to determine the efficacy of a dietary weight loss intervention in obese pet dogs. METHODS: A 3-month prospective observational cohort study of weight loss in 926 overweight dogs was conducted at 340 veterinary practices in 27 countries. Commercially available dry or wet weight loss diets were used, with the initial energy allocation being 250-335 kJ/kg target body weight0.75/day (60-80 kcal/kg target body weight0.75/day) depending on sex and neuter status. The primary outcome measure was percentage weight loss; the main secondary outcomes were changes in activity, quality of life, and food seeking behaviour, which were subjectively determined from owner descriptions. RESULTS: At baseline, median (range) age was 74 (12 to 193) months and median body condition score was 8 (range 7-9). 896 of the 926 dogs (97%) lost weight, with mean weight loss being 11.4 +/-5.84%. Sexually intact dogs lost more weight than neutered dogs (P = 0.001), whilst female dogs lost more weight than male dogs (P = 0.007), with the difference being more pronounced in North and South American dogs (median [Q1, Q3]: female: 11.5% [8.5%, 14.5%]; male: 9.1% [6.3%, 12.1%], P = 0.053) compared with those from Europe (female: 12.3% [8.9%, 14.9%]; male: 10.9% [8.6%, 15.4%]). Finally, subjective scores for activity (P<0.001) and quality of life (P<0.001) increased sequentially, whilst scores for food-seeking behaviour decreased sequentially (P<0.001) during the study. CONCLUSION: This is the largest international multi-centre weight loss study conducted to date in obese dogs. Most dogs lost a clinically significant amount of weight, although there were notable differences between dogs of different sex, neuter status and in different geographical locations. PMID- 28886095 TI - Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia. AB - We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/ mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Behavioral changes in the HET mice were accompanied by reduced thickness of the dorsomedial prefrontal cortex. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood. Moreover, the brains of Slc1a1+/- mice displayed elevated levels of oxidized glutathione, a trend for increased oxidative DNA damage, and significantly increased levels of cytokines. This latter finding was further supported by SLC1A1 knockdown and overexpression studies in differentiated human neuroblastoma cells, which led to decreased or increased cytokine expression, respectively. Taken together, our results suggest that partial loss of the Slc1a1 gene in mice causes haploinsufficiency associated with behavioral, histological and biochemical changes that reflect an altered redox state and may promote the expression of behavioral features and inflammatory states consistent with those observed in schizophrenia. PMID- 28886097 TI - Population genetics, community of parasites, and resistance to rodenticides in an urban brown rat (Rattus norvegicus) population. AB - Brown rats are one of the most widespread urban species worldwide. Despite the nuisances they induce and their potential role as a zoonotic reservoir, knowledge on urban rat populations remains scarce. The main purpose of this study was to characterize an urban brown rat population from Chanteraines park (Hauts-de Seine, France), with regards to haematology, population genetics, immunogenic diversity, resistance to anticoagulant rodenticides, and community of parasites. Haematological parameters were measured. Population genetics was investigated using 13 unlinked microsatellite loci. Immunogenic diversity was assessed for Mhc Drb. Frequency of the Y139F mutation (conferring resistance to rodenticides) and two linked microsatellites were studied, concurrently with the presence of anticoagulant residues in the liver. Combination of microscopy and molecular methods were used to investigate the occurrence of 25 parasites. Statistical approaches were used to explore multiple parasite relationships and model parasite occurrence. Eighty-six rats were caught. The first haematological data for a wild urban R. norvegicus population was reported. Genetic results suggested high genetic diversity and connectivity between Chanteraines rats and surrounding population(s). We found a high prevalence (55.8%) of the mutation Y139F and presence of rodenticide residues in 47.7% of the sampled individuals. The parasite species richness was high (16). Seven potential zoonotic pathogens were identified, together with a surprisingly high diversity of Leptospira species (4). Chanteraines rat population is not closed, allowing gene flow and making eradication programs challenging, particularly because rodenticide resistance is highly prevalent. Parasitological results showed that co-infection is more a rule than an exception. Furthermore, the presence of several potential zoonotic pathogens, of which four Leptospira species, in this urban rat population raised its role in the maintenance and spread of these pathogens. Our findings should stimulate future discussions about the development of a long-term rat-control management program in Chanteraines urban park. PMID- 28886098 TI - Molecular and biochemical responses of hypoxia exposure in Atlantic croaker collected from hypoxic regions in the northern Gulf of Mexico. AB - A major impact of global climate change has been the marked increase worldwide in the incidence of coastal hypoxia (dissolved oxygen, DO<2.0 mg l-1). However, the extent of hypoxia exposure to motile animals such as fish collected from hypoxic waters as well as their molecular and physiological responses to environmental hypoxia exposure are largely unknown. A suite of potential hypoxia exposure biomarkers was evaluated in Atlantic croaker collected from hypoxic and normoxic regions in the northern Gulf of Mexico (nGOM), and in croaker after laboratory exposure to hypoxia (DO: 1.7 mg l-1). Expression of hypoxia-inducible factor alpha, hif-alpha; neuronal nitric oxide synthase, nNOS; and insulin-like growth factor binding protein, igfbp mRNAs and protein carbonyl (PC, an oxidative stress indicator) content were elevated several-fold in brain and liver tissues of croaker collected from nGOM hypoxic sites. All of these molecular and biochemical biomarkers were also upregulated ~3-10-fold in croaker brain and liver tissues within 1-2 days of hypoxia exposure in controlled laboratory experiments. These results suggest that hif-alphas, nNOS and igfbp-1 transcripts and PC contents are useful biomarkers of environmental hypoxia exposure and some of its physiological effects, making them important components for improved assessments of long-term impacts of environmental hypoxia on fish populations. PMID- 28886099 TI - Serial QuantiFERON-TB Gold testing in patients with psoriasis treated with ustekinumab. AB - BACKGROUND: There is increasing concern about the risk of latent tuberculosis infection (LTBI) reactivation during the use of biologics for psoriasis. Although ustekinumab had been documented with low risk of tuberculosis, the long-term follow-up of LTBI as determined by QuantiFERON-TB Gold (QFT-G) testing in patients treated with ustekinumab is limited. OBJECTIVES: This study aims to use serial QFT-G testing as a screening method for detecting LTBI in patients with psoriasis from an intermediate tuberculosis burden country. METHODS: This retrospective review investigated 134 psoriatic patients in whom ustekinumab was prescribed for at least one year between 2010 and 2016 in National Taiwan University Hospital. All patients underwent annular QFT-G testing during ustekinumab therapy. RESULTS: Among the 134 enrolled patients, baseline LTBI rate was 13.4% (18/134). Indeterminate QFT-G result was noted in 5.2% (7/134) of patients and 71.4% (5/7) of them turn to be QFT-G negative during the next testing. 81.3% (109/134) of patients had a negative QFT-G at baseline and the seroconversion rate was 7.3% (8/109) in the serial QFT-G. All the patients in the conversion group were referred to a pulmonologist for evaluation and 81.5% (22/27) of them underwent chemoprophylactic therapy while on ustekinumab. No active TB infection was noted during further follow-up with or without chemoprophylaxis. CONCLUSIONS: This study revealed that psoriatic patients receiving long-term ustekinumab therapy had a low QFT-G conversion rate (7.3%). The clinical significance of QFT-G conversion remains controversial and needs larger scale trials to investigate. PMID- 28886100 TI - Biomechanical evaluation of tibial bone adaptation after revision total knee arthroplasty: A comparison of different implant systems. AB - The best methods to manage tibial bone defects following total knee arthroplasty remain under debate. Different fixation systems exist to help surgeons reconstruct knee osseous bone loss (such as tantalum cones, cement, modular metal augments, autografts, allografts and porous metaphyseal sleeves) However, the effects of the various solutions on the long-term outcome remain unknown. In the present work, a bone remodeling mathematical model was used to predict bone remodeling after total knee arthroplasty (TKA) revision. Five different types of prostheses were analyzed: one with a straight stem; two with offset stems, with and without supplements; and two with sleeves, with and without stems. Alterations in tibia bone density distribution and implant Von Mises stresses were quantified. In all cases, the bone density decreased in the proximal epiphysis and medullary channels, and an increase in bone density was predicted in the diaphysis and around stem tips. The highest bone resorption was predicted for the offset prosthesis without the supplement, and the highest bone formation was computed for the straight stem. The highest Von Mises stress was obtained for the straight tibial stem, and the lowest was observed for the stemless metaphyseal sleeves prosthesis. The computational model predicted different behaviors among the five systems. We were able to demonstrate the importance of choosing an adequate revision system and that in silico models may help surgeons choose patient-specific treatments. PMID- 28886101 TI - High prevalence of gastric intestinal metaplasia detected by confocal laser endomicroscopy in Zambian adults. AB - BACKGROUND: Confocal laser endomicroscopy (CLE) may increase the detection of gastric premalignant lesions, and facilitate targeted biopsies for histology. The study aim was to analyse premalignant lesions in Zambian adults using CLE. METHODS: Using CLE and histology we analysed the antral mucosa for gastric premalignant lesions in asymptomatic adults living with HIV and in HIV seronegative adults. Fasting gastric pH and the presence of Helicobacter pylori (H. pylori) were also evaluated. RESULTS: We enrolled 84 HIV seropositive participants (median age 43 years; 55 (65%) female), of whom 32 (38%) were anti retroviral therapy (ART)-naive. Also enrolled were 22 HIV seronegative controls (median age 39 years, 12 (55%) females). Hypochlorhydria was found in 48 (57%) HIV positive and 8 (38%) HIV negative controls (P = 0.14). Detection of gastric intestinal metaplasia (GIM) was higher (P = 0.007) using CLE (49, 54%) than histology (9, 9%) and, using CLE, GIM was similar between HIV positive (41, 60%) and negative groups (8, 36%; P = 0.08). Gastric luminal fluorescein leakage was significantly associated with the presence of GIM [OR 8.2; 95% CI 2.5-31, P<0.001]. CONCLUSION: CLE is useful for the detection of GIM, and luminal fluorescein leakage may represent a novel CLE marker for GIM. GIM is common in Zambian adults, and is highly prevalent irrespective of HIV infection or use of ART. PMID- 28886102 TI - Three-dimensional friction measurement during hip simulation. AB - OBJECTIVES: Wear of total hip replacements has been the focus of many studies. However, frictional effects, such as high loading on intramodular connections or the interface to the bone, as well as friction associated squeaking have recently increased interest about the amount of friction that is generated during daily activities. The aim of this study was thus to establish and validate a three dimensional friction setup under standardized conditions. MATERIALS AND METHODS: A standard hip simulator was modified to allow for high precision measurements of small frictional effects in the hip during three-dimensional hip articulation. The setup was verified by an ideal hydrostatic bearing and validated with a static-load physical pendulum and an extension-flexion rotation with a dynamic load profile. Additionally, a pendulum model was proposed for screening measurement of frictional effects based on the damping behavior of the angular oscillation without the need for any force/moment transducer. Finally, three dimensional friction measurements have been realized for ceramic-on-polyethylene bearings of three different sizes (28, 36 and 40 mm). RESULTS: A precision of less than 0.2 Nm during three-dimensional friction measurements was reported, while increased frictional torque (resultant as well as taper torque) was measured for larger head diameters. These effects have been confirmed by simple pendulum tests and the theoretical model. A comparison with current literature about friction measurements is presented. CONCLUSIONS: This investigation of friction is able to provide more information about a field that has been dominated by the reduction of wear. It should be considered in future pre clinical testing protocols given by international organizations of standardization. PMID- 28886103 TI - Epigenetic regulation of human SOX3 gene expression during early phases of neural differentiation of NT2/D1 cells. AB - Sox3/SOX3 is one of the earliest neural markers in vertebrates. Together with the Sox1/SOX1 and Sox2/SOX2 genes it is implicated in the regulation of stem cell identity. In the present study, we performed the first analysis of epigenetic mechanisms (DNA methylation and histone marks) involved in the regulation of the human SOX3 gene expression during RA-induced neural differentiation of NT2/D1 cells. We show that the promoter of the human SOX3 gene is extremely hypomethylated both in undifferentiated NT2/D1 cells and during the early phases of RA-induced neural differentiation. By employing chromatin immunoprecipitation, we analyze several histone modifications across different regions of the SOX3 gene and their dynamics following initiation of differentiation. In the same timeframe we investigate profiles of selected histone marks on the promoters of human SOX1 and SOX2 genes. We demonstrate differences in histone signatures of SOX1, SOX2 and SOX3 genes. Considering the importance of SOXB1 genes in the process of neural differentiation, the present study contributes to a better understanding of epigenetic mechanisms implicated in the regulation of pluripotency maintenance and commitment towards the neural lineage. PMID- 28886104 TI - Availability, diversification and versatility explain human selection of introduced plants in Ecuadorian traditional medicine. AB - Globally, a majority of people use plants as a primary source of healthcare and introduced plants are increasingly discussed as medicine. Protecting this resource for human health depends upon understanding which plants are used and how use patterns will change over time. The increasing use of introduced plants in local pharmacopoeia has been explained by their greater abundance or accessibility (availability hypothesis), their ability to cure medical conditions that are not treated by native plants (diversification hypothesis), or as a result of the introduced plants' having many different simultaneous roles (versatility hypothesis). In order to describe the role of introduced plants in Ecuador, and to test these three hypotheses, we asked if introduced plants are over-represented in the Ecuadorian pharmacopoeia, and if their use as medicine is best explained by the introduced plants' greater availability, different therapeutic applications, or greater number of use categories. Drawing on 44,585 plant-use entries, and the checklist of >17,000 species found in Ecuador, we used multi-model inference to test if more introduced plants are used as medicines in Ecuador than expected by chance, and examine the support for each of the three hypotheses above. We find nuanced support for all hypotheses. More introduced plants are utilized than would be expected by chance, which can be explained by geographic distribution, their strong association with cultivation, diversification (except with regard to introduced diseases), and therapeutic versatility, but not versatility of use categories. Introduced plants make a disproportionately high contribution to plant medicine in Ecuador. The strong association of cultivation with introduced medicinal plant use highlights the importance of the maintenance of human-mediated environments such as homegardens and agroforests for the provisioning of healthcare services. PMID- 28886105 TI - First complete female mitochondrial genome in four bivalve species genus Donax and their phylogenetic relationships within the Veneroida order. AB - BACKGROUND: Four species of the genus Donax (D. semistriatus, D. trunculus, D. variegatus and D. vittatus) are common on Iberian Peninsula coasts. Nevertheless, despite their economic importance and overexploitation, scarce genetic resources are available. In this work, we newly determined the complete mitochondrial genomes of these four representatives of the family Donacidae, with the aim of contributing to unveil phylogenetic relationships within the Veneroida order, and of developing genetic markers being useful in wedge clam identification and authentication, and aquaculture stock management. PRINCIPAL FINDINGS: The complete female mitochondrial genomes of the four species vary in size from 17,044 to 17,365 bp, and encode 13 protein-coding genes (including the atp8 gene), 2 rRNAs and 22 tRNAs, all located on the same strand. A long non-coding region was identified in each of the four Donax species between cob and cox2 genes, presumably corresponding to the Control Region. The Bayesian and Maximum Likelihood phylogenetic analysis of the Veneroida order indicate that all four species of Donax form a single clade as a sister group of other bivalves within the Tellinoidea superfamily. However, although Tellinoidea is actually monophyletic, none of its families are monophyletic. CONCLUSIONS: Sequencing of complete mitochondrial genomes provides highly valuable information to establish the phylogenetic relationships within the Veneroida order. Furthermore, we provide here significant genetic resources for further research and conservation of this commercially important fishing resource. PMID- 28886106 TI - Hepatocellular carcinoma in elderly: Clinical characteristics, treatments and outcomes compared with younger adults. AB - The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. The present study aims to evaluate the role of age on treatments and outcome of HCC patients. 1530 patients firstly diagnosed with HCC were retrospectively included and classified as older (>=65 years, n = 318, 21%) and younger patients (<65 years, n = 1212, 79%). The two groups were compared with clinical characteristics, tumor burden, Barcelona Clinics Liver Cancer (BCLC) stage, treatments and long-term prognosis. Elderly patients were more HCV infected, had more diabetes, poorer performance status, and were less aggressively treated. The proportion of HCC within BCLC stage 0-A, B or C was similar between the two groups, but elderly patients were more presented with BCLC stage D. The overall survival of older patients was poorer compared to younger patients before and after propensity score matching. However, elderly patients were less often effectively treated with surgery and loco-regional therapies across different BCLC stages. After stratified by BCLC stages or treatments, older patients showed comparable long-term outcome to younger patients. Performance status, BCLC stages and effective treatments, rather than age, was independent factors determining prognosis in the whole cohort and only elderly patients by multivariate analysis. In conclusion, older could have comparable survival to younger patients within the same tumor stage or after similar treatments. Thus, equally active treatments should be encouraged to elderly patients. PMID- 28886107 TI - Self-rated health in Senegal: A comparison between urban and rural areas. AB - INTRODUCTION: Although the relationship between mortality and self-rated health has been demonstrated in sub-Saharan Africa, information in this area is rudimentary. In Senegal, no study has been undertaken comparing self-rated health between urban and rural areas. The objective of this study is therefore to compare self-rated health and its main predictors in Dakar and in a rural isolated area, Tessekere municipality, taking into account socio-demographic and economic factors, social relations, as well as measures of physical and mental health. MATERIAL AND METHODS: This study was carried out in 2015 on a population sample of 1000 individuals living in Dakar and 500 individuals living in the municipality of Tessekere, constructed using the quota method. Self-rated health, health variables, psychosocial, sociodemographic and economic characteristics were collected during face-to-face interviews. Statistical analyses used were Chi square tests and binary logistic regressions. RESULTS: Results show that self rated health in Senegalese urban area (Dakar) is better than in rural area (Tessekere), but the determinants of self-rated health partly differ between these two environments. Age and gender play a fundamental role in self-rated health as much in Dakar as in Tessekere but diabetes and social support play a role in self-rated health only in urban environment, whereas economic well-being is associated to self-rated health only in rural area. CONCLUSION: The analyses carried out in these two environments show that despite the existence of common determinants (age, gender, stress), the determinants for formulating an answer to the question of self-rated health differ. People's social and cultural environments thus play a fundamental role in the process of rating one's health and, in the short and long term, in the mortality rate. PMID- 28886108 TI - The potential role of genetic assimilation during maize domestication. AB - Domestication research has largely focused on identification of morphological and genetic differences between extant populations of crops and their wild relatives. Little attention has been paid to the potential effects of environment despite substantial known changes in climate from the time of domestication to modern day. In recent research, the exposure of teosinte (i.e., wild maize) to environments similar to the time of domestication, resulted in a plastic induction of domesticated phenotypes in teosinte. These results suggest that early agriculturalists may have selected for genetic mechanisms that cemented domestication phenotypes initially induced by a plastic response of teosinte to environment, a process known as genetic assimilation. To better understand this phenomenon and the potential role of environment in maize domestication, we examined differential gene expression in maize (Zea mays ssp. mays) and teosinte (Zea mays ssp. parviglumis) between past and present conditions. We identified a gene set of over 2000 loci showing a change in expression across environmental conditions in teosinte and invariance in maize. In fact, overall we observed both greater plasticity in gene expression and more substantial changes in co expressionnal networks in teosinte across environments when compared to maize. While these results suggest genetic assimilation played at least some role in domestication, genes showing expression patterns consistent with assimilation are not significantly enriched for previously identified domestication candidates, indicating assimilation did not have a genome-wide effect. PMID- 28886109 TI - Radon-induced lung cancer deaths may be overestimated due to failure to account for confounding by exposure to diesel engine exhaust in BEIR VI miner studies. AB - BACKGROUND: EPA reported that radon is the second leading cause of lung cancer in the United States, killing 21,100 people per year. EPA relies on the BEIR VI models, based on an evaluation of radon exposure and lung cancer risk in studies of miners. But these models did not account for co-exposure to diesel exhaust, a known human carcinogen recently classified by IARC. It is probable then that a portion of the lung cancer deaths in the miner cohorts are originally attributable to the exposure to diesel rather than radon. OBJECTIVE: To re evaluate EPA's radon attributable lung cancer estimates accounting for diesel exposure information in the miner cohorts. METHODS: We used estimates of historical diesel concentrations, combined with diesel exposure-response functions, to estimate the risks of lung cancer attributable to diesel engine exhaust (DEE) exposure in the miner studies. We re-calculated the fatal lung cancer risk attributable to radon after accounting for risk from diesel and re estimated the number of U.S. deaths associated with radon in the U.S. using EPA's methodology. RESULTS: Considering the probable confounding with DEE exposure and using the same estimate of baseline mortality from 1989-91 that the EPA currently uses in their calculations, we estimate that radon-induced lung cancer deaths per year are 15,600 (95% CI: 14,300, 17,000)- 19,300 (95% CI: 18,800, 20,000) in the U.S. population, a reduction of 9%-26%. The death estimates would be 12,900 15,900 using 2014 baseline vital statistics. CONCLUSIONS: We recommend further research on re-evaluating the health effects of exposure to radon that accounts for new information on diesel exhaust carcinogenicity in BEIR VI models, up-to date vital statistics and new epidemiological evidence from residential studies. PMID- 28886110 TI - Quality improvement of surface triangular mesh using a modified Laplacian smoothing approach avoiding intersection. AB - We present a systematic procedure to improve the qualities of triangular molecular surface meshes and at the same time preserve the manifoldness. The procedure utilizes an algorithm to remove redundant points having three or four valences and another algorithm to smooth the mesh using a modified version of Laplacian method without causing intersecting triangles. This approach can be effectively applied to any manifold surface meshes with arbitrary complex geometry. In this paper, the tested meshes are biomolecular surface meshes exhibiting typically highly irregular geometry. The results show that the qualities of the surface meshes are greatly improved and the manifoldness of the surface meshes are preserved. Compared with the original meshes, these improved molecular surface meshes can be directly applied to boundary element simulations and generation of body-fitted volume meshes using Tetgen. The procedure has been incorporated into our triangular molecular surface mesh generator, TMSmesh 2.0. It can be also used as a standalone program and works together with any other surface triangular mesh generator to obtain qualified manifold mesh. The package is downloadable at https://doi.org/10.6084/m9.figshare.5346169.v1 and can be run online at http://www.xyzgate.com. PMID- 28886111 TI - Evidence for an ancient whole genome duplication in the cycad lineage. AB - Contrary to the many whole genome duplication events recorded for angiosperms (flowering plants), whole genome duplications in gymnosperms (non-flowering seed plants) seem to be much rarer. Although ancient whole genome duplications have been reported for most gymnosperm lineages as well, some are still contested and need to be confirmed. For instance, data for ginkgo, but particularly cycads have remained inconclusive so far, likely due to the quality of the data available and flaws in the analysis. We extracted and sequenced RNA from both the cycad Encephalartos natalensis and Ginkgo biloba. This was followed by transcriptome assembly, after which these data were used to build paralog age distributions. Based on these distributions, we identified remnants of an ancient whole genome duplication in both cycads and ginkgo. The most parsimonious explanation would be that this whole genome duplication event was shared between both species and had occurred prior to their divergence, about 300 million years ago. PMID- 28886112 TI - Evaluating and implementing temporal, spatial, and spatio-temporal methods for outbreak detection in a local syndromic surveillance system. AB - The New York City Department of Health and Mental Hygiene has operated an emergency department syndromic surveillance system since 2001, using temporal and spatial scan statistics run on a daily basis for cluster detection. Since the system was originally implemented, a number of new methods have been proposed for use in cluster detection. We evaluated six temporal and four spatial/spatio temporal detection methods using syndromic surveillance data spiked with simulated injections. The algorithms were compared on several metrics, including sensitivity, specificity, positive predictive value, coherence, and timeliness. We also evaluated each method's implementation, programming time, run time, and the ease of use. Among the temporal methods, at a set specificity of 95%, a Holt Winters exponential smoother performed the best, detecting 19% of the simulated injects across all shapes and sizes, followed by an autoregressive moving average model (16%), a generalized linear model (15%), a modified version of the Early Aberration Reporting System's C2 algorithm (13%), a temporal scan statistic (11%), and a cumulative sum control chart (<2%). Of the spatial/spatio-temporal methods we tested, a spatial scan statistic detected 3% of all injects, a Bayes regression found 2%, and a generalized linear mixed model and a space-time permutation scan statistic detected none at a specificity of 95%. Positive predictive value was low (<7%) for all methods. Overall, the detection methods we tested did not perform well in identifying the temporal and spatial clusters of cases in the inject dataset. The spatial scan statistic, our current method for spatial cluster detection, performed slightly better than the other tested methods across different inject magnitudes and types. Furthermore, we found the scan statistics, as applied in the SaTScan software package, to be the easiest to program and implement for daily data analysis. PMID- 28886113 TI - The overlap between autistic spectrum conditions and borderline personality disorder. AB - BACKGROUND: Both people with autism spectrum conditions (ASC) and borderline personality disorder (BPD) are significantly challenged in terms of understanding and responding to emotions and in interpersonal functioning. AIMS: To compare ASC, BPD, and comorbid patients in terms of autistic traits, empathy, and systemizing. METHODS: 624 ASC, 23 BPD, and 16 comorbid (ASC+BPD) patients, and 2,081 neurotypical controls (NC) filled in the Autism Spectrum Quotient (AQ), the Empathy Quotient (EQ) and the Systemizing Quotient-Revised (SQ-R). RESULTS: On the AQ, the comorbid group scored higher than the ASC group, who in turn scored higher than the BPD group, who scored higher than controls. On the EQ, we found the comorbid and ASC groups scored lower than the BPD group, who were not different from controls. Finally, on the SQ-R, we found the ASC and BPD group both scored higher than controls. CONCLUSIONS: Similar to ASC, BPD patients have elevated autistic traits and a strong drive to systemize, suggesting an overlap between BPD and ASC. PMID- 28886114 TI - Delivery of mental health treatment to combat veterans with psychiatric diagnoses and TBI histories. AB - Traumatic brain injury (TBI) and mental health (MH) disorders are prevalent in combat veterans returning from Afghanistan and/or Iraq (hereafter referred to as returning veterans). Accurate estimates of service utilization for veterans with and without TBI exposure (referred to as TBI history) are imperative in order to provide high quality healthcare to returning veterans. We examined associations between TBI history and MH service utilization in a subsample of returning veterans who were newly diagnosed with posttraumatic stress disorder (PTSD), depression, and/or anxiety in the 2010 fiscal year (N = 55,458). Data were extracted from the Veterans Health Administration (VHA) National Patient Care Database. Veterans with MH diagnoses and TBI histories attended significantly more psychotherapy visits, (M = 8.32 visits, SD = 17.15) and were more likely to attend at least 8 psychotherapy visits, (15.7%) than veterans with MH diagnoses but no TBI history (M = 6.48 visits, SD = 12.12; 10.1% attended at least 8 sessions). PTSD and TBI history, but not depression or anxiety, were associated with a greater number of psychotherapy visits when controlling for demographic and clinical variables. PTSD, anxiety, depression, and TBI history were associated with number of psychotropic medication-management visits. TBI history was related to greater MH service utilization, independent of MH diagnoses. Future research should examine what MH services are being utilized and if these services are helping veterans recover from their disorders. PMID- 28886115 TI - Androgen receptor-mediated downregulation of microRNA-221 and -222 in castration resistant prostate cancer. AB - MicroRNAs (miRNAs) play important roles in cancer formation and progression by suppressing the production of key functional proteins at the post-transcriptional level in a sequence-specific manner. While differential expression of miRNAs is widely observed in cancers including prostate cancer (PCa), how these miRNAs are transcriptionally regulated is largely unknown. MiRNA-221 and miRNA-222 (miR-221/ 222) are well-established oncogenes and overexpressed in breast, liver, pancreas, and lung cancer, but their expression and biological functions in PCa remain controversial. Both up and down regulation have been observed in patient samples. Specifically, studies have demonstrated miR-221/-222 function as oncogenes, and promote PCa cell proliferation and the development of castration-resistant prostate cancer (CRPC). However, the expression level of miR-221/-222 is downregulated in several miRNA expression profiling studies. In this study, we demonstrate miR-221/-222 are androgen receptor (AR)-repressed genes and reside in a long primary transcript (pri-miRNA). Derepression of miR-221/-222 after androgen deprivation therapy (ADT) may enhance PCa cell proliferation potential through promoting G1/S phase transition. This function is likely transient but important in the development of CRPC. Downregulation of miR-221/-222 subsequently occurs once AR activity is restored through AR overexpression in CRPC. Our findings shed light on the complexity of transcriptional regulation of miRNAs in PCa and suggest context-dependent targeting of oncogenic miRNAs. PMID- 28886116 TI - Treatment with the WNT5A-mimicking peptide Foxy-5 effectively reduces the metastatic spread of WNT5A-low prostate cancer cells in an orthotopic mouse model. AB - Prostate cancer patients with high WNT5A expression in their tumors have been shown to have more favorable prognosis than those with low WNT5A expression. This suggests that reconstitution of Wnt5a in low WNT5A-expressing tumors might be an attractive therapeutic approach. To explore this idea, we have in the present study used Foxy-5, a WNT5A mimicking peptide, to investigate its impact on primary tumor and metastasis in vivo and on prostate cancer cell viability, apoptosis and invasion in vitro. We used an in vivo orthotopic xenograft mouse model with metastatic luciferase-labeled WNT5A-low DU145 cells and metastatic luciferase-labeled WNT5A-high PC3prostate cancer cells. We provide here the first evidence that Foxy-5 significantly inhibits the initial metastatic dissemination of tumor cells to regional and distal lymph nodes by 90% and 75%, respectively. Importantly, this effect was seen only with the WNT5A-low DU145 cells and not with the WNT5A-high PC3 cells. The inhibiting effect in the DU145-based model occurred despite the fact that no effects were observed on primary tumor growth, apoptosis or proliferation. These findings are consistent with and supported by the in vitro data, where Foxy-5 specifically targets invasion without affecting apoptosis or viability of WNT5A-low prostate cancer cells. To conclude, our data indicate that the WNT5A-mimicking peptide Foxy-5, which has been recently used in a phase 1 clinical trial, is an attractive candidate for complimentary anti metastatic treatment of prostate cancer patients with tumors exhibiting absent or low WNT5A expression. PMID- 28886117 TI - Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice. AB - Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer. PMID- 28886118 TI - In vivo experimental study of anterior cervical fusion using bioactive polyetheretherketone in a canine model. AB - BACKGROUND: Polyetheretherketone (PEEK) is a widely accepted biomaterial, especially in the field of spinal surgery. However, PEEK is not able to directly integrate with bone tissue, due to its bioinertness. To overcome this drawback, various studies have described surface coating approaches aimed at increasing the bioactivity of PEEK surfaces. Among those, it has been shown that the recently developed sol-gel TiO2 coating could provide PEEK with the ability to bond with bone tissue in vivo without the use of a bone graft. OBJECTIVE: This in vivo experimental study using a canine model determined the efficacy of bioactive TiO2 coated PEEK for anterior cervical fusion. METHODS: Sol-gel-derived TiO2 coating, which involves sandblasting and acid treatment, was used to give PEEK bone bonding ability. The cervical interbody spacer, which was designed to fit the disc space of a beagle, was fabricated using bioactive TiO2-coated PEEK. Both uncoated PEEK (control) and TiO2-coated PEEK spacers were implanted into the cervical intervertebral space of beagles (n = 5 for each type). After the 3-month survival period, interbody fusion success was evaluated based on MU-CT imaging, histology, and manual palpation analyses. RESULTS: Manual palpation analyses indicated a 60% (3/5 cases) fusion (no gap between bone and implants) rate for the TiO2-coated PEEK group, indicating clear advantage over the 0% (0/5 cases) fusion rate for the uncoated PEEK group. The bony fusion rate of the TiO2-coated PEEK group was 40% according to MUCT imaging; however, it was 0% of for the uncoated PEEK group. Additionally, the bone-implant contact ratio calculated using histomorphometry demonstrated a better contact ratio for the TiO2-coated PEEK group than for the uncoated PEEK group (mean, 32.6% vs 3.2%; p = 0.017). CONCLUSIONS: The TiO2-coated bioactive PEEK implant demonstrated better fusion rates and bone-bonding ability than did the uncoated PEEK implant in the canine anterior cervical fusion model. Bioactive PEEK, which has bone-bonding ability, could contribute to further improvements in clinical outcomes for spinal interbody fusion. PMID- 28886119 TI - Intimate partner violence-related hospitalizations in Appalachia and the non Appalachian United States. AB - The highly rural region of Appalachia faces considerable socioeconomic disadvantage and health disparities that are recognized risk factors for intimate partner violence (IPV). The objective of this study was to estimate the rate of IPV-related hospitalizations in Appalachia and the non-Appalachian United States for 2007-2011 and compare hospitalizations in each region by clinical and sociodemographic factors. Data on IPV-related hospitalizations were extracted from the State Inpatient Databases, which are part of the Healthcare Cost and Utilization Project. Hospitalization day, year, in-hospital mortality, length of stay, average and total hospital charges, sex, age, payer, urban-rural location, income, diagnoses and procedures were compared between Appalachian and non Appalachian counties. Poisson regression models were constructed to test differences in the rate of IPV-related hospitalizations between both regions. From 2007-2011, there were 7,385 hospitalizations related to IPV, with one-third (2,645) occurring in Appalachia. After adjusting for age and rurality, Appalachian counties had a 22% higher hospitalization rate than non-Appalachian counties (ARR = 1.22, 95% CI: 1.14-1.31). Appalachian residents may be at increased risk for IPV and associated conditions. Exploring disparities in healthcare utilization and costs associated with IPV in Appalachia is critical for the development of programs to effectively target the needs of this population. PMID- 28886121 TI - Correction: Complete chloroplast genome sequence of common bermudagrass (Cynodon dactylon (L.) Pers.) and comparative analysis within the family Poaceae. AB - [This corrects the article DOI: 10.1371/journal.pone.0179055.]. PMID- 28886120 TI - Chloride intracellular channel proteins respond to heat stress in Caenorhabditis elegans. AB - Chloride intracellular channel proteins (CLICs) are multi-functional proteins that are expressed in various cell types and differ in their subcellular location. Two CLIC homologs, EXL-1 (excretory canal abnormal like-1) and EXC-4 (excretory canal abnormal- 4), are encoded in the Caenorhabditis elegans genome, providing an excellent model to study the functional diversification of CLIC proteins. EXC-4 functions in excretory canal formation during normal animal development. However, to date, the physiological function of EXL-1 remains largely unknown. In this study, we demonstrate that EXL-1 responds specifically to heat stress and translocates from the cytoplasm to the nucleus in intestinal cells and body wall muscle cells under heat shock. In contrast, we do not observe EXC-4 nuclear translocation under heat shock. Full protein sequence analysis shows that EXL-1 bears a non-classic nuclear localization signal (NLS) that EXC-4 is lacking. All mammalian CLIC members have a nuclear localization signal, with the exception of CLIC3. Our phylogenetic analysis of the CLIC gene families across various animal species demonstrates that the duplication of CLICs in protostomes and deuterostomes occurred independently and that the NLS was subsequently lost in amniotes and nematodes, suggesting convergent evolution. We also observe that EXL-1 nuclear translocation occurs in a timely ordered manner in the intestine, from posterior to anterior regions. Finally, we find that exl-1 loss of function mutants are more susceptible to heat stress than wild-type animals, demonstrating functional relevance of the nuclear translocation. This research provides the first link between CLICs and environmental heat stress. We propose that C. elegans CLICs evolved to achieve different physiological functions through subcellular localization change and spatial separation in response to external or internal signals. PMID- 28886122 TI - Alteration of Endothelin 1, MCP-1 and Chromogranin A in patients with atrial fibrillation undergoing pulmonary vein isolation. AB - BACKGROUND: The relation between arrhythmias and stress is known. The aim of our current study was to elucidate whether plasma levels of previously described stress parameters are altered in highly symptomatic patients with atrial fibrillation (AF) per se and in patients undergoing ablation therapy by pulmonary vein isolation (PVI). METHODS: 96 patients with AF undergoing PVI were recruited. Plasma levels of Endothelin-1 (ET-1), MCP-1 and Chromogranin-A (CGA) were measured before and three months after ablation completed with clinical follow-up with respect to AF recurrence. Additionally, we examined 40 healthy age- and sex matched volunteers as a reference. RESULTS: Symptomatic AF patients showed increased levels of ET-1 compared to healthy controls (2.62pg/ml vs. 1.57pg/ml; p<0.01). Baseline levels of ET-1 were higher in patients presenting with AF after PVI (2.96pg/ml vs. 2.57pg/ml;p = 0.02). The temporal comparison revealed decreased ET-1 levels in patients without (2.57pg/ml vs. 2.33pg/ml; p<0.01) and unchanged ET-1 levels in patients with AF after PVI. Baseline MCP-1 was increased in AF patients vs. controls (268pg/ml vs. 227 pg/ml; p = 0.03). Both groups, with and without AF after PVI, showed an increase of MCP-1 compared to baseline (268pg/ml vs. 349pg/ml;p<0.01; 281pg/ml vs. 355pg/ml;p = 0.03). CGA was lower in AF patients compared to healthy controls (13.8ng/ml vs. 25.6ng/ml;p<0.01). Over time patients without AF after PVI showed an increase of CGA (14.2ng/ml vs. 20.7ng/ml;p<0.01). No change was observed in patients with AF after PVI. CONCLUSION: Our study demonstrated dysregulated levels of ET-1, MCP-1 and CGA in symptomatic AF patients. We could demonstrate an association between ET-1 to presence or absence of AF. Furthermore, we could show that a decrease of ET-1 as well as an increase of CGA after PVI, representing a trend towards control cohort levels, were both associated with restoration of sinus rhythm. These results provide new insights into the role of stress-related biomarkers in AF and AF treatment by ablation therapy. PMID- 28886123 TI - Increased medial olivocochlear reflex strength in normal-hearing, noise-exposed humans. AB - Research suggests that college-aged adults are vulnerable to tinnitus and hearing loss due to exposure to traumatic levels of noise on a regular basis. Recent human studies have associated exposure to high noise exposure background (NEB, i.e., routine noise exposure) with the reduced cochlear output and impaired speech processing ability in subjects with clinically normal hearing sensitivity. While the relationship between NEB and the functions of the auditory afferent neurons are studied in the literature, little is known about the effects of NEB on functioning of the auditory efferent system. The objective of the present study was to investigate the relationship between medial olivocochlear reflex (MOCR) strength and NEB in subjects with clinically normal hearing sensitivity. It was hypothesized that subjects with high NEB would exhibit reduced afferent input to the MOCR circuit which would subsequently lead to reduced strength of the MOCR. In normal-hearing listeners, the study examined (1) the association between NEB and baseline click-evoked otoacoustic emissions (CEOAEs) and (2) the association between NEB and MOCR strength. The MOCR was measured using CEOAEs evoked by 60 dB pSPL linear clicks in a contralateral acoustic stimulation (CAS) off and CAS-on (a broadband noise at 60 dB SPL) condition. Participants with at least 6 dB signal-to-noise ratio (SNR) in the CAS-off and CAS-on conditions were included for analysis. A normalized CEOAE inhibition index was calculated to express MOCR strength in a percentage value. NEB was estimated using a validated questionnaire. The results showed that NEB was not associated with the baseline CEOAE amplitude (r = -0.112, p = 0.586). Contrary to the hypothesis, MOCR strength was positively correlated with NEB (r = 0.557, p = 0.003). NEB remained a significant predictor of MOCR strength (beta = 2.98, t(19) = 3.474, p = 0.003) after the unstandardized coefficient was adjusted to control for effects of smoking, sound level tolerance (SLT) and tinnitus. These data provide evidence that MOCR strength is associated with NEB. The functional significance of increased MOCR strength is discussed. PMID- 28886124 TI - Identification and genomic comparison of temperate bacteriophages derived from emetic Bacillus cereus. AB - Cereulide-producing Bacillus cereus isolates can cause serious emetic (vomiting) syndrome and even acute lethality. As mobile genetic elements, the exploration of prophages derived from emetic B. cereus isolates will help in our understanding of the genetic diversity and evolution of these pathogens. In this study, five temperate phages derived from cereulide-producing B. cereus strains were induced, with four of them undergoing genomic sequencing. Sequencing revealed that they all belong to the Siphoviridae family, but presented in different forms in their hosts. PfNC7401 and PfIS075 have typical icosahedral heads, probably existing alone as phagemids in the host with self-replicating capability in the lysogenic state. PfEFR-4, PfEFR-5, and PfATCC7953 have elongated heads, with the genomes of the former two identified as linear dsDNA, which could be integrated into the host genome during the lysogenic state. Genomic comparison of the four phages with others also derived from emetic B. cereus isolates showed similar genome structures and core genes, thus displaying host spectrum specificity. In addition, phylogenic analysis based on the complete genome and conserved tail fiber proteins of 36 Bacillus species-derived phages confirmed that the phages derived from emetic B. cereus strains were highly similar. Furthermore, one endolysin LysPfEFR-4 was cloned and showed lytic activity against all tested emetic B. cereus strains and cross-lytic activity against some other pathogenic bacteria, implying a potential to control bacterial contamination in the food supply. PMID- 28886125 TI - Heterogeneous hybrid signcryption for multi-message and multi-receiver. AB - To achieve secure communication in heterogeneous cryptography systems, we present a heterogeneous hybrid signcryption scheme. The proposed scheme allows a sender in an identity-based cryptography system to send multi-message to multi-receiver in a certificateless cryptography system with different master keys. At the same time, all users are mapped to a distinct pseudo-identity for conditional identity privacy preservation. A trusted authority could trace the real identity when necessary. Compared with existing schemes, the proposed scheme is more practical for actual applications. In addition, the proposed scheme has indistinguishability against adaptive chosen ciphertext attacks and existential unforgeability against adaptive chosen message attacks under the random oracle model. PMID- 28886126 TI - Validation of the 18-gene classifier as a prognostic biomarker of distant metastasis in breast cancer. AB - We validated an 18-gene classifier (GC) initially developed to predict local/regional recurrence after mastectomy in estimating distant metastasis risk. The 18-gene scoring algorithm defines scores as: <21, low risk; >=21, high risk. Six hundred eighty-three patients with primary operable breast cancer and fresh frozen tumor tissues available were included. The primary outcome was the 5-year probability of freedom from distant metastasis (DMFP). Two external datasets were used to test the predictive accuracy of 18-GC. The 5-year rates of DMFP for patients classified as low-risk (n = 146, 21.7%) and high-risk (n = 537, 78.6%) were 96.2% (95% CI, 91.1%-98.8%) and 80.9% (74.6%-81.9%), respectively (median follow-up interval, 71.8 months). The 5-year rates of DMFP of the low-risk group in stage I (n = 62, 35.6%), stage II (n = 66, 20.1%), and stage III (n = 18, 10.3%) were 100%, 94.2% (78.5%-98.5%), and 90.9% (50.8%-98.7%), respectively. Multivariate analysis revealed that 18-GC is an independent prognostic factor of distant metastasis (adjusted hazard ratio, 5.1; 95% CI, 1.8-14.1; p = 0.0017) for scores of >=21. External validation showed that the 5-year rate of DMFP in the low- and high-risk patients was 94.1% (82.9%-100%) and 80.3% (70.7%-89.9%, p = 0.06) in a Singapore dataset, and 89.5% (81.9%-94.1%) and 73.6% (67.2%-79.0%, p = 0.0039) in the GEO-GSE20685 dataset, respectively. In conclusion, 18-GC is a viable prognostic biomarker for breast cancer to estimate distant metastasis risk. PMID- 28886128 TI - Psychological distress, health protection, and sexual practices among young men who have sex with men: Using social action theory to guide HIV prevention efforts. AB - The present study addresses gaps in the literature related to theory development for young men who have sex with men (YMSM) sexual practices through the application and modification of Social Action Theory. Data come from the Healthy Young Men study (N = 526), which longitudinally tracked a diverse cohort of YMSM ages 18-24 to characterize risk and protective factors associated with drug use and sexual practices. Structural equation modeling examined the applicability of, and any necessary modifications to a YMSM-focused version of Social Action Theory. The final model displayed excellent fit (CFI = 0.955, TLI = 0.947, RMSEA = 0.037) and suggested concordance between social support and personal capacity for sexual health promotion. For YMSM, practicing health promotion and avoiding practices that may put them at risk for HIV was associated with both social isolation and psychological distress (beta = -0.372, t = -4.601, p<0.001); psychological distress is an internalized response to environmental and cognitive factors and sexual practices are an externalized response. Results point to the utility of Social Action Theory as a useful model for understanding sexual practices among YMSM, the application of which shows health protective sexual practices are a function of sociocognitive factors that are influenced by environmental contexts. Social Action Theory can help prevention scientists better address the needs of this vulnerable population. PMID- 28886127 TI - Genome-wide miRNA response to anacardic acid in breast cancer cells. AB - MicroRNAs are biomarkers and potential therapeutic targets for breast cancer. Anacardic acid (AnAc) is a dietary phenolic lipid that inhibits both MCF-7 estrogen receptor alpha (ERalpha) positive and MDA-MB-231 triple negative breast cancer (TNBC) cell proliferation with IC50s of 13.5 and 35 MUM, respectively. To identify potential mediators of AnAc action in breast cancer, we profiled the genome-wide microRNA transcriptome (microRNAome) in these two cell lines altered by the AnAc 24:1n5 congener. Whole genome expression profiling (RNA-seq) and subsequent network analysis in MetaCore Gene Ontology (GO) algorithm was used to characterize the biological pathways altered by AnAc. In MCF-7 cells, 69 AnAc responsive miRNAs were identified, e.g., increased let-7a and reduced miR-584. Fewer, i.e., 37 AnAc-responsive miRNAs were identified in MDA-MB-231 cells, e.g., decreased miR-23b and increased miR-1257. Only two miRNAs were increased by AnAc in both cell lines: miR-612 and miR-20b; however, opposite miRNA arm preference was noted: miR-20b-3p and miR-20b-5p were upregulated in MCF-7 and MDA-MB-231, respectively. miR-20b-5p target EFNB2 transcript levels were reduced by AnAc in MDA-MB-231 cells. AnAc reduced miR-378g that targets VIM (vimentin) and VIM mRNA transcript expression was increased in AnAc-treated MCF-7 cells, suggesting a reciprocal relationship. The top three enriched GO terms for AnAc-treated MCF-7 cells were B cell receptor signaling pathway and ribosomal large subunit biogenesis and S-adenosylmethionine metabolic process for AnAc-treated MDA-MB-231 cells. The pathways modulated by these AnAc-regulated miRNAs suggest that key nodal molecules, e.g., Cyclin D1, MYC, c-FOS, PPARgamma, and SIN3, are targets of AnAc activity. PMID- 28886129 TI - Modulation of the endogenous omega-3 fatty acid and oxylipin profile in vivo-A comparison of the fat-1 transgenic mouse with C57BL/6 wildtype mice on an omega-3 fatty acid enriched diet. AB - Dietary intervention and genetic fat-1 mice are two models for the investigation of effects associated with omega-3 polyunsaturated fatty acids (n3-PUFA). In order to assess their power to modulate the fatty acid and oxylipin pattern, we thoroughly compared fat-1 and wild-type C57BL/6 mice on a sunflower oil diet with wild-type mice on the same diet enriched with 1% EPA and 1% DHA for 0, 7, 14, 30 and 45 days. Feeding led after 14-30 days to a high steady state of n3-PUFA in all tissues at the expense of n6-PUFAs. Levels of n3-PUFA achieved by feeding were higher compared to fat-1 mice, particularly for EPA (max. 1.7% in whole blood of fat-1 vs. 7.8% following feeding). Changes in PUFAs were reflected in most oxylipins in plasma, brain and colon: Compared to wild-type mice on a standard diet, arachidonic acid metabolites were overall decreased while EPA and DHA oxylipins increased with feeding more than in fat-1 mice. In plasma of n3 PUFA fed animals, EPA and DHA metabolites from the lipoxygenase and cytochrome P450 pathways dominated over ARA derived counterparts.Fat-1 mice show n3-PUFA level which can be reached by dietary interventions, supporting the applicability of this model in n3-PUFA research. However, for specific questions, e.g. the role of EPA derived mediators or concentration dependent effects of (individual) PUFA, feeding studies are necessary. PMID- 28886130 TI - Improving the antiprotozoal effect of saponins in the rumen by combination with glycosidase inhibiting iminosugars or by modification of their chemical structure. AB - The antiprotozoal effect of saponins is transitory, as when saponins are deglycosylated to sapogenins by rumen microorganisms they become inactive. We hypothesised that the combination of saponins with glycosidase-inhibiting iminosugars might potentially increase the effectiveness of saponins over time by preventing their deglycosylation in the rumen. Alternatively, modifying the structure of the saponins by substituting the sugar moiety with other small polar residues might maintain their activity as the sugar substitute would not be enzymatically cleaved. The aim of this in vitro study was to evaluate the acute antiprotozoal effect and the stability of this effect over a 24 h incubation period using ivy saponins, a stevia extract rich in iminosugars, ivy saponins with stevia extract, and a chemically modified ivy saponin, hederagenin bis succinate (HBS). The effects on fermentation parameters and rumen bacterial communities were also studied. Ivy saponins with stevia and HBS had a greater antiprotozoal effect than ivy saponins, and this effect was maintained after 24 h of incubation (P<0.001). The combination of ivy and stevia extracts was more effective in shifting the fermentation pattern towards higher propionate (+39%) and lower butyrate (-32%) and lower ammonia concentration (-64%) than the extracts incubated separately. HBS caused a decrease in butyrate (-45%) and an increase in propionate (+43%) molar proportions. However, the decrease in ammonia concentration (-42%) observed in the presence of HBS was less than that caused by ivy saponins, either alone or with stevia. Whereas HBS and stevia impacted on bacterial population in terms of community structure, only HBS had an effect in terms of biodiversity (P<0.05). It was concluded that ivy saponins with stevia and the modified saponin HBS had a strong antiprotozoal effect, although they differed in their effects on fermentation parameters and bacteria communities. Ivy saponins combined with an iminosugar-rich stevia extract and/or HBS should be evaluated to determine their antiprotozoal effect in vivo. PMID- 28886132 TI - A global view of shifting cultivation: Recent, current, and future extent. AB - Mosaic landscapes under shifting cultivation, with their dynamic mix of managed and natural land covers, often fall through the cracks in remote sensing-based land cover and land use classifications, as these are unable to adequately capture such landscapes' dynamic nature and complex spectral and spatial signatures. But information about such landscapes is urgently needed to improve the outcomes of global earth system modelling and large-scale carbon and greenhouse gas accounting. This study combines existing global Landsat-based deforestation data covering the years 2000 to 2014 with very high-resolution satellite imagery to visually detect the specific spatio-temporal pattern of shifting cultivation at a one-degree cell resolution worldwide. The accuracy levels of our classification were high with an overall accuracy above 87%. We estimate the current global extent of shifting cultivation and compare it to other current global mapping endeavors as well as results of literature searches. Based on an expert survey, we make a first attempt at estimating past trends as well as possible future trends in the global distribution of shifting cultivation until the end of the 21st century. With 62% of the investigated one-degree cells in the humid and sub-humid tropics currently showing signs of shifting cultivation-the majority in the Americas (41%) and Africa (37%)-this form of cultivation remains widespread, and it would be wrong to speak of its general global demise in the last decades. We estimate that shifting cultivation landscapes currently cover roughly 280 million hectares worldwide, including both cultivated fields and fallows. While only an approximation, this estimate is clearly smaller than the areas mentioned in the literature which range up to 1,000 million hectares. Based on our expert survey and historical trends we estimate a possible strong decrease in shifting cultivation over the next decades, raising issues of livelihood security and resilience among people currently depending on shifting cultivation. PMID- 28886131 TI - Histone deacetylase regulates insulin signaling via two pathways in pancreatic beta cells. AB - Recent studies demonstrated that insulin signaling plays important roles in the regulation of pancreatic beta cell mass, the reduction of which is known to be involved in the development of diabetes. However, the mechanism underlying the alteration of insulin signaling in pancreatic beta cells remains unclear. The involvement of epigenetic control in the onset of diabetes has also been reported. Thus, we analyzed the epigenetic control of insulin receptor substrate 2 (IRS2) expression in the MIN6 mouse insulinoma cell line. We found concomitant IRS2 up-regulation and enhanced insulin signaling in MIN6 cells, which resulted in an increase in cell proliferation. The H3K9 acetylation status of the Irs2 promoter was positively associated with IRS2 expression. Treatment of MIN6 cells with histone deacetylase inhibitors led to increased IRS2 expression, but this occurred in concert with low insulin signaling. We observed increased IRS2 lysine acetylation as a consequence of histone deacetylase inhibition, a modification that was coupled with a decrease in IRS2 tyrosine phosphorylation. These results suggest that insulin signaling in pancreatic beta cells is regulated by histone deacetylases through two novel pathways affecting IRS2: the epigenetic control of IRS2 expression by H3K9 promoter acetylation, and the regulation of IRS2 activity through protein modification. The identification of the histone deacetylase isoform(s) involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes. PMID- 28886133 TI - Phylogeographic pattern suggests a general northeastward dispersal in the distribution of Machilus pauhoi in South China. AB - Machilus pauhoi Kanehira is an important timber species in China. A provenance trial was recently set up to evaluate the growth performance of trees from different localities, with the aim of designing seed transfer guidelines. Here, we tested twelve nuclear microsatellite markers derived from other species of the Lauraceae family and investigated population genetic structure in M. pauhoi. Both the number of observed alleles per locus (Na) and the polymorphic information content (PIC) significantly decreased against the latitude, but showed an insignificant decrease against the longitude. Heterozygosity (Ho) and gene diversity (h) exhibited a weak correlation with geographic location. Private alleles were present in multiple populations, and a moderate level of population genetic differentiation was detected (Gst = 0.1691). The joint pattern of genetic diversity (Na, PIC, Ho, and h) suggests that general northeastward dispersal led to the current distribution of M. pauhoi. Significant but weak effects of isolation-by-distance (IBD) occurred, implicating the mountain ranges as the major barrier to gene flow. Both STRUCTURE and hierarchical clustering analyses showed three distinct groups of populations related to the physical connectivity among mountain ranges. A priority in designing genetic conservation should be given to the populations at the southwest side of the species' distribution. This conservation strategy can also be combined with the pattern of adaptive genetic variation from the provenance trial for comprehensive genetic resource management of native M. pauhoi. PMID- 28886134 TI - Clinical utility of the modified Glasgow prognostic score in lung cancer: A meta analysis. AB - OBJECTIVE: To perform a meta-analysis of prospective and retrospective studies exploring the association of the modified Glasgow prognostic score (mGPS) with overall survival (OS) in patients with lung cancer. METHODS: Relevant studies were identified by searching the Cochrane Library, Web of Science, Embase and PubMed until April 16, 2017. We combined hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the correlation between mGPS and OS in patients with lung cancer. RESULTS: Eleven studies involving 5817 participants from several countries were included in the meta-analysis. In a pooled analysis of all studies, elevated mGPS predicted poorer OS (HR = 1.77; 95% CI: 1.35-2.31; P<0.05). Subgroup analyses stratified by mGPS showed that mGPS of 1 or 2 and mGPS>=1 were predictive of poorer OS and that the HR for mGPS of 2 (HR = 5.82; 95% CI: 1.85-18.22; P = 0.003) was significantly greater than that for mGPS of 1 (HR = 1.74; 95% CI: 1.24-2.45; P = 0.001) and mGPS>=1 (HR = 1.42; 95% CI: 1.14 1.76; P = 0.002). Among patients undergoing surgery, elevated mGPS had a non significant correlation with reduced OS (HR = 2.48; 95% CI: 0.90-6.85; P = 0.079), whereas the correlation was significant for patients receiving chemotherapy or other palliative treatment (HR = 1.74; 95% CI: 1.31-2.30; P<0.05). CONCLUSIONS: Our findings indicate that mGPS may have prognostic value in lung cancer, as we detected a significant association between elevated mGPS and poorer OS. The association between mGPS and poorer OS was non-significant among patients undergoing surgery, which may be attributable to lower tumor load. However, further studies are warranted to draw firm conclusions. PMID- 28886136 TI - Relationship between the number of family members and stress by gender: Cross sectional analysis of the fifth Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: Due to gendered inequalities in the division of domestic work, women with paid employment and family caregiving responsibilities can feel extremely tired with general distress and depression. Therefore, the purpose of this study was to examine the association between the number of family members and stress level by gender among Korean adults using a nationally representative dataset. METHODS: We used a sample of 6,293 subjects aged 19 or older (3,629 female and 2,264 male) from the fifth Korea National Health and Nutrition Examination Survey. A multivariable logistic regression analysis with sociodemographic and health-related characteristics was conducted. Because there were gender differences, a stratified analysis was performed for each gender. RESULTS: Age, number of family members, education level, occupational status, depression, self rated health status, and chronic diseases were found to have a significant association with stress level in the study subjects (p<0.05). The probability of perceiving stress increased among females from family with two members (OR 1.521), three family members (OR 1.893), or four or more family members without spouse (OR 2.035) compared to those who live alone. CONCLUSION: We found that unmarried women are more likely to be stressed as the number of family members increases. Gender expectations giving women the main responsibility for domestic and care work may become a source of stress. Reconciliation of family and work remains women's responsibility in Korea. As family problems are recently becoming a big issue, our study shows the importance of considering gender difference in studies on stress according to family roles and functions. PMID- 28886135 TI - Differential regulation of innate immune cytokine production through pharmacological activation of Nuclear Factor-Erythroid-2-Related Factor 2 (NRF2) in burn patient immune cells and monocytes. AB - Burn patients suffer from immunological dysfunction for which there are currently no successful interventions. Similar to previous observations, we find that burn shock patients (>=15% Total Burn Surface Area (TBSA) injury) have elevated levels of the innate immune cytokines Interleukin-6 (IL-6) and Monocyte Chemoattractant Protein-1 (MCP-1)/CC-motif Chemokine Ligand 2(CCL2) early after hospital admission (0-48 Hours Post-hospital Admission (HPA). Functional immune assays with patient Peripheral Blood Mononuclear Cells (PBMCs) revealed that burn shock patients (>=15% TBSA) produced elevated levels of MCP-1/CCL2 after innate immune stimulation ex vivo relative to mild burn patients. Interestingly, treatment of patient PBMCs with the Nuclear Factor-Erythroid-2-Related Factor 2 (NRF2) agonist, CDDO-Me(bardoxolone methyl), reduced MCP-1 production but not IL-6 or Interleukin-10 (IL-10) secretion. In enriched monocytes from healthy donors, CDDO Me(bardoxolone methyl) also reduced LPS-induced MCP1/CCL2 production but did not alter IL-6 or IL-10 secretion. Similar immunomodulatory effects were observed with Compound 7, which activates the NRF2 pathway through a different and non covalent Mechanism Of Action (MOA). Hence, our findings with CDDO-Me(bardoxolone methyl) and Compound 7 are likely to reflect a generalizable aspect of NRF2 activation. These observed effects were not specific to LPS-induced immune responses, as NRF2 activation also reduced MCP-1/CCL2 production after stimulation with IL-6. Pharmacological NRF2 activation reduced Mcp-1/Ccl2 transcript accumulation without inhibiting either Il-6 or Il-10 transcript levels. Hence, we describe a novel aspect of NRF2 activation that may contribute to the beneficial effects of NRF2 agonists during disease. Our work also demonstrates that the NRF2 pathway is retained and can be modulated to regulate important immunomodulatory functions in burn patient immune cells. PMID- 28886137 TI - Fast sparse fractal image compression. AB - As a structure-based image compression technology, fractal image compression (FIC) has been applied not only in image coding but also in many important image processing algorithms. However, two main bottlenecks restrained the develop and application of FIC for a long time. First, the encoding phase of FIC is time consuming. Second, the quality of the reconstructed images for some images which have low structure-similarity is usually unacceptable. Based on the absolute value of Pearson's correlation coefficient (APCC), we had proposed an accelerating method to significantly speed up the encoding of FIC. In this paper, we make use of the sparse searching strategy to greatly improve the quality of the reconstructed images in FIC. We call it the sparse fractal image compression (SFIC). Furthermore, we combine both the APCC-based accelerating method and the sparse searching strategy to propose the fast sparse fractal image compression (FSFIC), which can effectively improve the two main bottlenecks of FIC. The experimental results show that the proposed algorithm greatly improves both the efficiency and effectiveness of FIC. PMID- 28886138 TI - Reproductive life history of sablefish (Anoplopoma fimbria) from the U.S. Washington coast. AB - Sablefish (Anoplopoma fimbria) is a marine groundfish that supports valuable fisheries in the North Pacific Ocean and holds promise for marine aquaculture. Limited information is available, however, about its reproductive biology. This study aimed to characterize the complete reproductive cycle, including seasonal changes in gonadal development (macroscopic and histological), plasma sex steroid levels (17beta-estradiol -E2-, and 11-ketotestosterone -11KT-), gonadosomatic and hepatosomatic indices (GSI, and HSI), and condition factor (K) of female and male sablefish captured off the Washington coast. Adult fish (209 females, 159 males) were caught by longline monthly from August 2012 to August 2013. Early signs of recruitment of ovarian follicles into secondary growth, indicated by oocytes containing small yolk granules and cortical alveoli, were first observed in March. Oogenesis progressed during spring and summer, and fully vitellogenic follicles were first observed in July. Vitellogenic growth was correlated with increases in plasma E2, GSI, HSI and K. Periovulatory females, indicated by fully grown oocytes with migrating germinal vesicles and hydrated oocytes, were found from November to February. At this stage, plasma E2 and GSI reached maximal levels. In males, proliferating cysts containing spermatocytes were first observed in April. Testicular development proceeded during spring and summer, a period during which all types of male germ cells were found. The first clusters of spermatozoa appeared in July, concomitant with a 5.2-fold increase in GSI. Spermiating males were observed from November to April; at this time, spermatids were absent or greatly reduced, and testis lobules were filled with spermatozoa. The highest levels of plasma 11KT were found in males at this stage. Postspawning ovaries and testes, and basal steroids levels were found in fish captured from February to April. These results suggest that sablefish in coastal Washington initiate their reproductive cycle in March/April and spawn primarily in January/February. PMID- 28886139 TI - Effect of pre-analytic variables on the reproducibility of qPCR relative telomere length measurement. AB - Telomeres, long nucleotide repeats and a protein complex at chromosome ends, shorten with each cell division and are susceptible to oxidative damage. Quantitative PCR (qPCR) is a widely-used technique to measure relative telomere length (RTL) in DNA samples but is challenging to optimize and significant lab-to lab variability has been reported. In this study, we evaluated factors that may contribute to qPCR RTL measurement variability including DNA extraction methods, methods used for removing potential residual PCR inhibitors, sample storage conditions, and sample location in the PCR plate. Our results show that the DNA extraction and purification techniques, as well as sample storage conditions introduce significant variability in qPCR RTL results. We did not find significant differences in results based on sample location in the PCR plate or qPCR instrument used. These data suggest that lack of reproducibility in published association studies of RTL could be, in part, due to methodological inconsistencies. This study illustrates the importance of uniform sample handling, from DNA extraction through data generation and analysis, in using qPCR to determine RTL. PMID- 28886141 TI - The impact of vehicle moving violations and freeway traffic flow on crash risk: An application of plugin development for microsimulation. AB - This paper presents the use of the Aimsun microsimulation program to simulate vehicle violating behaviors and observe their impact on road traffic crash risk. Plugins for violations of speeding, slow driving, and abrupt stopping were developed using Aimsun's API and SDK module. A safety analysis plugin for investigating probability of rear-end collisions was developed, and a method for analyzing collision risk is proposed. A Fuzzy C-mean Clustering algorithm was developed to identify high risk states in different road segments over time. Results of a simulation experiment based on the G15 Expressway in Shanghai showed that abrupt stopping had the greatest impact on increasing collision risk, and the impact of violations increased with traffic volume. The methodology allows for the evaluation and monitoring of risks, alerting of road hazards, and identification of hotspots, and could be applied to the operations of existing facilities or planning of future ones. PMID- 28886140 TI - Male-specific association of the FCGR2A His167Arg polymorphism with Kawasaki disease. AB - Kawasaki disease (KD) is an acute systemic vasculitis that can potentially cause coronary artery aneurysms in some children. KD occurs approximately 1.5 times more frequently in males than in females. To identify sex-specific genetic variants that are involved in KD pathogenesis in children, we performed a sex stratified genome-wide association study (GWAS), using the Illumina HumanOmni1 Quad BeadChip data (249 cases and 1,000 controls) and a replication study for the 34 sex-specific candidate SNPs in an independent sample set (671 cases and 3,553 controls). Male-specific associations were detected in three common variants: rs1801274 in FCGR2A [odds ratio (OR) = 1.40, P = 9.31 * 10-5], rs12516652 in SEMA6A (OR = 1.87, P = 3.12 * 10-4), and rs5771303 near IL17REL (OR = 1.57, P = 2.53 * 10-5). The male-specific association of FCGR2A, but not SEMA6A and IL17REL, was also replicated in a Japanese population (OR = 1.74, P = 1.04 * 10-4 in males vs. OR = 1.22, P = 0.191 in females). In a meta-analysis with 1,461 cases and 5,302 controls, a very strong association of KD with the nonsynonymous SNP rs1801274 (p.His167Arg, previously assigned as p.His131Arg) in FCGR2A was confirmed in males (OR = 1.48, P = 1.43 * 10-7), but not in the females (OR = 1.17, P = 0.055). The present study demonstrates that p.His167Arg, a KD associated FCGR2A variant, acts as a susceptibility gene in males only. Overall, the gender differences associated with FCGR2A in KD provide a new insight into KD susceptibility. PMID- 28886142 TI - Effects of ozone exposure on human epithelial adenocarcinoma and normal fibroblasts cells. AB - Previous studies show variable ozone cytotoxicity and genotoxicity in cell cultures, laboratory animals and humans directly exposed to tropospheric ozone. The aim of this study was therefore to investigate and compare the cyto and genotoxic effects of ozone using adenocarcinoma human alveolar basal epithelial cells A549 and normal human fibroblasts Hs27. A cell culture chamber with controlled atmosphere (a simulation reactor) was built to inject a flow of 120 ppb of ozone, which is two times the threshold value for the protection of human health, fixed by the EU legislation. Cell proliferation was evaluated by a luminescent cell viability assay while we assessed the genotoxic potential of ozone by the induction of micronuclei as well as evaluating DNA strand breaks by the induction of micronuclei evaluated by means of the cytokinesis-block micronucleus (CBMN) assay as well as evaluating DNA strand breaks by Alkaline Comet Assay (CA) or Comet Assay. A549 cells viability decreases significantly at 24 hours treatment with 120 ppb of O3 while at 48 hours and 72 hours O3 treated cells viability doesn't differ in respect to the control. However a significative decrease of A549 viability is shown at 72 hours vs. 48 hours in both treated and not-treated cells. The viability trend in the Hs27 cells did not show any significant changes in treated samples compared to the control in all conditions. The two genotoxicity biomarkers, the micronucleus and the comet tests, showed in both the cell types exposed to ozone, a significant increase in the number of micronuclei and in the tail DNA % in respect to the control even if at different times/cell type. Moreover, we found that O3 provokes genotoxic effects more evident in A549 cancer cells than in normal fibroblasts Hs27 ones. We applied a cell growth simulation model referred to ozone treated or not cell lines to confirm that the ozone exposure causes a slackening in the cells replication. PMID- 28886143 TI - Outbreak detection and evaluation of a school-based influenza-like-illness syndromic surveillance in Tianjin, China. AB - School-based influenza-like-illness (ILI) syndromic surveillance can be an important part of influenza community surveillance by providing early warnings for outbreaks and leading to a fast response. From September 2012 to December 2014, syndromic surveillance of ILI was carried out in 4 county-level schools. The cumulative sum methods(CUSUM) was used to detect abnormal signals. A susceptible-exposed-infectious/asymptomatic-recovered (SEIAR) model was fit to the influenza outbreak without control measures and compared with the actual influenza outbreak to evaluate the effectiveness of early control efforts. The ILI incidence rates in 2014 (14.51%) was higher than the incidence in 2013 (5.27%) and 2012 (3.59%). Ten school influenza outbreaks were detected by CUSUM. Each outbreak had high transmissibility with a median Runc of 4.62. The interventions in each outbreak had high effectiveness and all Rcon were 0. The early intervention had high effectiveness within the school-based ILI syndromic surveillance. Syndromic surveillance within schools can play an important role in controlling influenza outbreaks. PMID- 28886146 TI - Association between health literacy and patient experience of primary care attributes: A cross-sectional study in Japan. AB - Primary care is regarded as a setting that potentially mitigate patient health literacy (HL) related inequalities. However, there is a lack of evidence about influence of patient HL on the patients' perception of quality of primary care. We aimed to examine the association between HL and patient experience of primary care attributes. We conducted a cross-sectional survey, and sent questionnaires to adult residents who were randomly selected from a basic resident register in Yugawara Town, Kanagawa, Japan. We assessed HL using a 14-item Health Literacy Scale (HLS-14) and patient experience of primary care attributes using a Japanese version of Primary Care Assessment Tool (JPCAT), which comprises six domains: first contact, longitudinality, coordination, comprehensiveness (services available), comprehensiveness (services provided), and community orientation. We used a multivariable linear regression analyses to adjust individual covariates. Data were analyzed for 381 residents who had a usual source of care. After adjustment for patients' sociodemographic and health characteristics, patient HL was positively associated with the JPCAT total score (B = 4.49, 95% confidence interval: 0.27 to 8.65 for HLS-14 total score highest quartile, compared with the lowest quartile). Among primary care attributes, HL had significant associations with longitudinality and comprehensiveness (service provided). We found that HL was positively associated with patient experience of primary care attributes in Japanese people. Our findings indicated that greater efforts might be needed to improve patient-centered and tailored primary care to those with low HL. PMID- 28886145 TI - Application of a whole blood mycobacterial growth inhibition assay to study immunity against Mycobacterium tuberculosis in a high tuberculosis burden population. AB - The determinants of immunological protection against Mycobacterium tuberculosis (M.tb) infection in humans are not known. Mycobacterial growth inhibition assays have potential utility as in vitro surrogates of in vivo immunological control of M.tb. We evaluated a whole blood growth inhibition assay in a setting with high burden of TB and aimed to identify immune responses that correlate with control of mycobacterial growth. We hypothesized that individuals with underlying M.tb infection will exhibit greater M.tb growth inhibition than uninfected individuals and that children aged 4 to 12 years, an age during which TB incidence is curiously low, will also exhibit greater M.tb growth inhibition than adolescents or adults. Neither M.tb infection status, age of the study participants, nor M.tb strain was associated with differential control of mycobacterial growth. Abundance and function of innate or T cell responses were also not associated with mycobacterial growth. Our data suggest that this assay does not provide a useful measure of age-associated differential host control of M.tb infection in a high TB burden setting. We propose that universally high levels of mycobacterial sensitization (through environmental non-tuberculous mycobacteria and/or universal BCG vaccination) in persons from high TB burden settings may impart broad inhibition of mycobacterial growth, irrespective of M.tb infection status. This sensitization may mask the augmentative effects of mycobacterial sensitization on M.tb growth inhibition that is typical in low burden settings. PMID- 28886144 TI - Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors. AB - S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5 methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPA-PAM). S 47445 enhanced glutamate's action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants) (EC50 between 2.5-5.4 MUM), except a higher EC50 value for GluA4 flop (0.7 MUM) and a greater amount of potentiation on GluA1 flop. A low concentration of S 47445 (0.1 MUM) decreased receptor response decay time of GluA1flop/GluA2flip AMPA receptors and increased the sensitivity to glutamate. Furthermore, S 47445 (0.1 and 0.3 MUM) in presence of repetitive glutamate pulses induced a progressive potentiation of the glutamate-evoked currents from the second pulse of glutamate confirming a rapid enhancing effect of S 47445 at low concentrations. The potentiating effect of S 47445 (1 MUM) was concentration-dependently reversed by the selective AMPA receptor antagonist GYKI52466 demonstrating the selective modulatory effect of S 47445 on AMPA receptors. Using an AMPA-kainate chimera approach, it was confirmed that S 47445 binds to the common binding pocket of AMPA-PAMs. S 47445 did not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro, in contrast significantly protected rat cortical neurons at 10 MUM. S 47445 was shown to improve both episodic and spatial working memory in adult rodents at 0.3 mg/kg, as measured in the natural forgetting condition of object recognition and T-maze tasks. Finally, no deleterious effect on spontaneous locomotion and general behavior was observed up to 1000 mg/kg of S 47445 given acutely in rodents, neither occurrence of convulsion or tremors. Collectively, these results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties. This drug is currently evaluated in clinical phase 2 studies in Alzheimer's disease and in Major Depressive Disorder. PMID- 28886148 TI - Balancing anti-inflammatory and anti-oxidant responses in murine bone marrow derived macrophages. AB - RATIONALE: The underlying pathophysiology of bronchopulmonary dysplasia includes a macrophage-mediated host response orchestrated by anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARgamma) and anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf2). These have not yet been studied in combination. This study tested the hypothesis that combined inflammatory and oxidative stressors would interact and change PPARgamma- and Nrf2-regulated gene expression and antioxidant capacity. Therefore, we investigated the effect of dual stimulation with lipopolysaccharide and hyperoxia in murine bone marrow derived macrophages (BMDM). METHODS: Sub-confluent BMDM from wild-type C57BL/6J mice were treated with lipopolysaccharide (LPS) 1ug/mL for 2 hours followed by room air (21% oxygen) or hyperoxia (95% oxygen) for 24 hours. Taqman real time polymerase chain reaction gene expression assays, total antioxidant capacity assays, and Luminex assays were performed. RESULTS: Supernatants of cultured BMDM contained significant antioxidant capacity. In room air, LPS treatment decreased expression of PPARgamma and Nrf2, and increased expression of tumor necrosis factor-alpha and heme oxygenase-1; similar findings were observed under hyperoxic conditions. LPS treatment decreased cellular total antioxidant capacity in room air but not in hyperoxia. Increased expression of sulfiredoxin-1 in response to hyperoxia was not observed in LPS-treated cells. Dual stimulation with LPS treatment and exposure to hyperoxia did not have synergistic effects on gene expression. Cellular total antioxidant capacity was not changed by hyperoxia exposure. CONCLUSIONS: Our hypothesis was supported and we demonstrate an interaction between inflammatory and oxidative stressors in a model system of bronchopulmonary dysplasia pathogenesis. The protective anti-oxidant effect of cell culture media may have protected the cells from the most deleterious effects of hyperoxia. PMID- 28886147 TI - Detection of atypical network development patterns in children with autism spectrum disorder using magnetoencephalography. AB - Autism spectrum disorder (ASD) is a developmental disorder that involves developmental delays. It has been hypothesized that aberrant neural connectivity in ASD may cause atypical brain network development. Brain graphs not only describe the differences in brain networks between clinical and control groups, but also provide information about network development within each group. In the present study, graph indices of brain networks were estimated in children with ASD and in typically developing (TD) children using magnetoencephalography performed while the children viewed a cartoon video. We examined brain graphs from a developmental point of view, and compared the networks between children with ASD and TD children. Network development patterns (NDPs) were assessed by examining the association between the graph indices and the raw scores on the achievement scale or the age of the children. The ASD and TD groups exhibited different NDPs at both network and nodal levels. In the left frontal areas, the nodal degree and efficiency of the ASD group were negatively correlated with the achievement scores. Reduced network connections were observed in the temporal and posterior areas of TD children. These results suggested that the atypical network developmental trajectory in children with ASD is associated with the development score rather than age. PMID- 28886149 TI - Plasma sterols and depressive symptom severity in a population-based cohort. AB - Convergent evidence strongly suggests major depressive disorder is heterogeneous in its etiology and clinical characteristics. Depression biomarkers hold potential for identifying etiological subtypes, improving diagnostic accuracy, predicting treatment response, and personalization of treatment. Human plasma contains numerous sterols that have not been systematically studied. Changes in cholesterol concentrations have been implicated in suicide and depression, suggesting plasma sterols may be depression biomarkers. Here, we investigated associations between plasma levels of 34 sterols (measured by mass spectrometry) and scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS SR16) scale in 3117 adult participants in the Dallas Heart Study, an ethnically diverse, population-based cohort. We built a random forest model using feature selection from a pool of 43 variables including demographics, general health indicators, and sterol concentrations. This model comprised 19 variables, 13 of which were sterol concentrations, and explained 15.5% of the variation in depressive symptoms. Desmosterol concentrations below the fifth percentile (1.9 ng/mL, OR 1.9, 95% CI 1.2-2.9) were significantly associated with depressive symptoms of at least moderate severity (QIDS-SR16 score >=10.5). This is the first study reporting a novel association between plasma concentrations cholesterol precursors and depressive symptom severity. PMID- 28886150 TI - Fluorescence study of freeze-drying as a method for support the interactions between hyaluronan and hydrophobic species. AB - A freeze-drying method enabling solubilization of hydrophobic species in aqueous solutions of native hyaluronan is described. The method is based on opening the access to supposed hydrophobic patches on hyaluronan by disturbing its massive hydration shell. Hydrophobic and/or polarity-sensitive fluorescence probes were used as hydrophobic models or indicators of interactions with hydrophobic patches. Fluorescence parameters specific to individual probes confirmed the efficiency of the freeze-drying method. This work is the first step in developing biocompatible and biodegradable carriers for hydrophobic drugs with targeted distribution of the active compound from native, chemically non-modified hyaluronan. PMID- 28886151 TI - Label-free quantitative 1H NMR spectroscopy to study low-affinity ligand-protein interactions in solution: A contribution to the mechanism of polyphenol-mediated astringency. AB - Nuclear magnetic resonance (NMR) spectroscopy is well-established in assessing the binding affinity between low molecular weight ligands and proteins. However, conventional NMR-based binding assays are often limited to small proteins of high purity and may require elaborate isotopic labeling of one of the potential binding partners. As protein-polyphenol complexation is assumed to be a key event in polyphenol-mediated oral astringency, here we introduce a label-free, ligand focused 1H NMR titration assay to estimate binding affinities and characterize soluble complex formation between proteins and low molecular weight polyphenols. The method makes use of the effects of NMR line broadening due to protein-ligand interactions and quantitation of the non-bound ligand at varying protein concentrations by quantitative 1H NMR spectroscopy (qHNMR) using electronic reference to access in vivo concentration (ERETIC 2). This technique is applied to assess the interaction kinetics of selected astringent tasting polyphenols and purified mucin, a major lubricating glycoprotein of human saliva, as well as human whole saliva. The protein affinity values (BC50) obtained are subsequently correlated with the intrinsic mouth-puckering, astringent oral sensation imparted by these compounds. The quantitative NMR method is further exploited to study the effect of carboxymethyl cellulose, a candidate "anti-astringent" protein binding antagonist, on the polyphenol-protein interaction. Consequently, the NMR approach presented here proves to be a versatile tool to study the interactions between proteins and low-affinity ligands in solution and may find promising applications in the discovery of bioactives. PMID- 28886152 TI - Molecular cytogenetic identification of a novel wheat-Agropyron elongatum chromosome translocation line with powdery mildew resistance. AB - Agropyron elongatum (Host.) Neviski (synonym, Thinopyrum ponticum Podp., 2n = 70) has been used extensively as a valuable source for wheat breeding. Numerous chromosome fragments containing valuable genes have been successfully translocated into wheat from A. elongatum. However, reports on the transfer of powdery mildew resistance from A. elongatum to wheat are rare. In this study, a novel wheat-A. elongatum translocation line, 11-20-1, developed and selected from the progenies of a sequential cross between wheat varieties (Lankaoaizaoba, Keyu 818 and BainongAK 58) and A. elongatum, was evaluated for disease resistance and characterized using molecular cytogenetic methods. Cytological observations indicated that 11-20-1 had 42 chromosomes and formed 21 bivalents at meiotic metaphase I. Genomic in situ hybridization analysis using whole genomic DNA from A. elongatum as a probe showed that the short arms of a pair of wheat chromosomes were replaced by a pair of A. elongatum chromosome arms. Fluorescence in situ hybridization, using wheat D chromosome specific sequence pAs1 as a probe, suggested that the replaced chromosome arms of 11-20-1 were 5DS. This was further confirmed by wheat SSR markers specific for 5DS. EST-SSR and EST-STS multiple loci markers confirmed that the introduced A. elongatum chromosome arms belonged to homoeologous group 5. Therefore, it was deduced that 11-20-1 was a wheat-A. elongatum T5DL?5AgS translocation line. Both resistance observation and molecular marker analyses using two specific markers (BE443538 and CD452608) of A. elongatum in a F2 population from a cross between line 11-20-1 and a susceptible cultivar Yannong 19 verified that the A. elongatum chromosomes were responsible for the powdery mildew resistance. This work suggests that 11-20-1 likely contains a novel resistance gene against powdery mildew. We expect this line to be useful for the genetic improvement of wheat. PMID- 28886153 TI - Tumor size and proliferative marker geminin rather than Ki67 expression levels significantly associated with maximum uptake of 18F-deoxyglucose levels on positron emission tomography for breast cancers. AB - It has been well established that maximum standardized uptake value (SUVmax) for 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) is clinically useful for evaluating treatment efficacy as well as predicting prognosis of breast cancer patients. Although SUVmax reflects increased glucose uptake and metabolism possibly induced by activation of growth factor signaling or TP53 dysfunction, tumor characteristics of SUVmax-high breast cancers remain to be elucidated. For the present study, we used immunohistochemical staining to investigate expressions of phospho-ribosomal protein S6 (pS6, downstream molecule of phosphatidyl inositol 3 kinase/Akt/mammalian target of the rapamycin/S6K pathway) and phosphor-p44/42 mitogen-activated protein kinase (pMAPK). Expression levels of TP53 and proliferative marker geminin as well as Ki67 were also examined by means of immunostaining in 163 invasive breast cancers. Cutoff values were set at 10% for pS6, 20% for pMAPK and TP53, and 4% for geminin. The SUVmax levels were significantly higher in the pS6-positive (p = 0.0173), TP53-positive (p = 0.0207) and geminin-high cancers (p<0.0001), but there was no significant association between pMAPK expression levels and SUVmax levels. Multivariable analysis showed that a high geminin level (odds ratio: 6.497, 95% confidence interval: 2.427 19.202, p = 0.0001) and large tumor size (6.438, 2.224-20.946, p = 0.0005) were significantly and independently associated with SUVmax-high. Univariable but not multivariable analysis indicated that Ki67-high significantly correlated with SUVmax-high. Twenty of 23 (87.0%) breast cancers with tumor size >2cm and geminin high showed SUVmax-high, while only 6 of 49 (12.2%) breast cancers <=2cm in size and with low geminin levels were SUVmax-high. In conclusion, we could determine that breast cancers with a large tumor and a geminin-high rather than Ki67-high proliferative marker were significantly associated with high levels of SUVmax. These findings may signify that SUVmax reflects tumor characteristics with high proliferative activity but not activation of mTOR/S6K and MAPK pathways or increased glucose metabolism due to dysfunction of TP53. PMID- 28886154 TI - Validity and reliability of a novel 3D scanner for assessment of the shape and volume of amputees' residual limb models. AB - BACKGROUND: Objective assessment methods to monitor residual limb volume following lower-limb amputation are required to enhance practitioner-led prosthetic fitting. Computer aided systems, including 3D scanners, present numerous advantages and the recent Artec Eva scanner, based on laser free technology, could potentially be an effective solution for monitoring residual limb volumes. PURPOSE: The aim of this study was to assess the validity and reliability of the Artec Eva scanner (practical measurement) against a high precision laser 3D scanner (criterion measurement) for the determination of residual limb model shape and volume. METHODS: Three observers completed three repeat assessments of ten residual limb models, using both the scanners. Validity of the Artec Eva scanner was assessed (mean percentage error <2%) and Bland Altman statistics were adopted to assess the agreement between the two scanners. Intra and inter-rater reliability (repeatability coefficient <5%) of the Artec Eva scanner was calculated for measuring indices of residual limb model volume and shape (i.e. residual limb cross sectional areas and perimeters). RESULTS: Residual limb model volumes ranged from 885 to 4399 ml. Mean percentage error of the Artec Eva scanner (validity) was 1.4% of the criterion volumes. Correlation coefficients between the Artec Eva and the Romer determined variables were higher than 0.9. Volume intra-rater and inter-rater reliability coefficients were 0.5% and 0.7%, respectively. Shape percentage maximal error was 2% at the distal end of the residual limb, with intra-rater reliability coefficients presenting the lowest errors (0.2%), both for cross sectional areas and perimeters of the residual limb models. CONCLUSION: The Artec Eva scanner is a valid and reliable method for assessing residual limb model shapes and volumes. While the method needs to be tested on human residual limbs and the results compared with the current system used in clinical practice, it has the potential to quantify shape and volume fluctuations with greater resolution. PMID- 28886155 TI - Coronary heart disease and risk for cognitive impairment or dementia: Systematic review and meta-analysis. AB - AIMS/HYPOTHESIS: Accumulating evidence suggests an association between coronary heart disease and risk for cognitive impairment or dementia, but no study has systematically reviewed this association. Therefore, we summarized the available evidence on the association between coronary heart disease and risk for cognitive impairment or dementia. METHODS: Medline, Embase, PsycINFO, and CINAHL were searched for all publications until 8th January 2016. Articles were included if they fulfilled the inclusion criteria: (1) myocardial infarction, angina pectoris or coronary heart disease (combination of both) as predictor variable; (2) cognition, cognitive impairment or dementia as outcome; (3) population-based study; (4) prospective (>=1 year follow-up), cross-sectional or case-control study design; (5) >=100 participants; and (6) aged >=45 years. Reference lists of publications and secondary literature were hand-searched for possible missing articles. Two reviewers independently screened all abstracts and extracted information from potential relevant full-text articles using a standardized data collection form. Study quality was assessed with the Newcastle-Ottawa Scale. We pooled estimates from the most fully adjusted model using random-effects meta analysis. RESULTS: We identified 6,132 abstracts, of which 24 studies were included. A meta-analysis of 10 prospective cohort studies showed that coronary heart disease was associated with increased risk of cognitive impairment or dementia (OR = 1.45, 95%CI = 1.21-1.74, p<0.001). Between-study heterogeneity was low (I2 = 25.7%, 95%CI = 0-64, p = 0.207). Similar significant associations were found in separate meta-analyses of prospective cohort studies for the individual predictors (myocardial infarction, angina pectoris). In contrast, meta-analyses of cross-sectional and case-control studies were inconclusive. CONCLUSION/INTERPRETATION: This meta-analysis suggests that coronary heart disease is prospectively associated with increased odds of developing cognitive impairment or dementia. Given the projected worldwide increase in the number of people affected by coronary heart disease and dementia, insight into causal mechanisms or common pathways underlying the heart-brain connection is needed. PMID- 28886156 TI - Loss of SPRR3 in ApoE-/- mice leads to atheroma vulnerability through Akt dependent and independent effects in VSMCs. AB - Vascular smooth muscle cells (VSMCs) represent important modulators of plaque stability in advanced lesions. We previously reported that loss of small proline rich repeat protein 3 (Sprr3), leads to VSMC apoptosis in a PI3K/Akt-dependent manner and accelerates lesion progression. Here, we investigated the role of Sprr3 in modulating plaque stability in hyperlipidemic ApoE-/- mice. We show that loss of Sprr3 increased necrotic core size and reduced cap collagen content of atheromas in brachiocephalic arteries with evidence of plaque rupture and development of intraluminal thrombi. Moreover, Sprr3-/-ApoE-/- mice developed advanced coronary artery lesions accompanied by intraplaque hemorrhage and left ventricle microinfarcts. SPRR3 is known to reduce VSMC survival in lesions by promoting their apoptosis. In addition, we demonstrated that Sprr3-/- VSMCs displayed reduced expression of procollagen in a PI3K/Akt dependent manner. SPRR3 loss also increased MMP gelatinase activity in lesions, and increased MMP2 expression, migration and contraction of VSMCs independently of PI3K/Akt. Consequently, Sprr3 represents the first described VSMC modulator of each of the critical features of cap stability, including VSMC numbers, collagen type I synthesis, and protease activity through Akt dependent and independent pathways. PMID- 28886157 TI - A new approach to keratoconus detection based on corneal morphogeometric analysis. AB - PURPOSE: To characterize corneal structural changes in keratoconus using a new morphogeometric approach and to evaluate its potential diagnostic ability. METHODS: Comparative study including 464 eyes of 464 patients (age, 16 and 72 years) divided into two groups: control group (143 healthy eyes) and keratoconus group (321 keratoconus eyes). Topographic information (Sirius, CSO, Italy) was processed with SolidWorks v2012 and a solid model representing the geometry of each cornea was generated. The following parameters were defined: anterior (Aant) and posterior (Apost) corneal surface areas, area of the cornea within the sagittal plane passing through the Z axis and the apex (Aapexant, Aapexpost) and minimum thickness points (Amctant, Amctpost) of the anterior and posterior corneal surfaces, and average distance from the Z axis to the apex (Dapexant, Dapexpost) and minimum thickness points (Dmctant, Dmctpost) of both corneal surfaces. RESULTS: Significant differences among control and keratoconus group were found in Aapexant, Aapexpost, Amctant, Amctpost, Dapexant, Dapexpost (all p<0.001), Apost (p = 0.014), and Dmctpost (p = 0.035). Significant correlations in keratoconus group were found between Aant and Apost (r = 0.836), Amctant and Amctpost (r = 0.983), and Dmctant and Dmctpost (r = 0.954, all p<0.001). A logistic regression analysis revealed that the detection of keratoconus grade I (Amsler Krumeich) was related to Apost, Atot, Aapexant, Amctant, Amctpost, Dapexpost, Dmctant and Dmctpost (Hosmer-Lemeshow: p>0.05, R2 Nagelkerke: 0.926). The overall percentage of cases correctly classified by the model was 97.30%. CONCLUSIONS: Our morphogeometric approach based on the analysis of the cornea as a solid is useful for the characterization and detection of keratoconus. PMID- 28886158 TI - Correction: Insulin and diet-induced changes in the ubiquitin-modified proteome of rat liver. AB - [This corrects the article DOI: 10.1371/journal.pone.0174431.]. PMID- 28886159 TI - Directional migration of mesenchymal stem cells under an SDF-1alpha gradient on a microfluidic device. AB - Homing of peripheral stem cells is regulated by one of the most representative homing factors, stromal cell-derived factor 1 alpha (SDF-1alpha), which specifically binds to the plasma membrane receptor CXCR4 of mesenchymal stem cells (MSCs) in order to initiate the signaling pathways that lead to directional migration and homing of stem cells. This complex homing process and directional migration of stem cells have been mimicked on a microfluidic device that is capable of generating a chemokine gradient within the collagen matrix and embedding endothelial cell (EC) monolayers to mimic blood vessels. On the microfluidic device, stem cells showed directional migration toward the higher concentration of SDF-1alpha, whereas treatment with the CXCR4 antagonist AMD3100 caused loss of directionality of stem cells. Furthermore, inhibition of stem cell's main migratory signaling pathways, Rho-ROCK and Rac pathways, caused blockage of actomyosin and lamellipodia formation, decreasing the migration distance but maintaining directionality. Stem cell homing regulated by SDF-1alpha caused directional migration of stem cells, while the migratory ability was affected by the activation of migration-related signaling pathways. PMID- 28886161 TI - A morphological and functional basis for maximum prey size in piscivorous fishes. AB - Fish predation is important in shaping populations and community structure in aquatic systems. These predator-prey interactions can be influenced by environmental, behavioural and morphological factors. Morphological constraints influence the feeding performance of species, and interspecific differences can thus affect patterns of resource use. For piscivorous fishes that swallow prey whole, feeding performance has traditionally been linked to three key morphological constraints: oral gape, pharyngeal gape, and the cleithral gape. However, other constraints may be important. We therefore examine 18 potential morphological constraints related to prey capture and processing, on four predatory species (Cephalopholis urodeta, Paracirrhites forsteri, Pterois volitans, Lates calcarifer). Aquarium-based experiments were then carried out to determine capture and processing behaviour and maximum prey size in two focal species, C. urodeta and P. forsteri. All four species showed a progressive decrease in gape measurements from anterior to posterior with oral gape >= buccal >= pharyngeal >= pectoral girdle >= esophagus >= stomach. C. urodeta was able to process prey with a maximum depth of 27% of the predators' standard length; for P. forsteri it was 20%. C. urodeta captured prey head-first in 79% of successful strikes. In P. forsteri head-first was 16.6%, mid-body 44.4%, and tail-first 38.8%. Regardless of capture mode, prey were almost always swallowed head first and horizontally in both focal species. Most internal measurements appeared too small for prey to pass through. This may reflect the compressibility of prey, i.e. their ability to be dorsoventrally compressed during swallowing movements. Despite examining all known potential morphological constraints on prey size, horizontal maxillary oral gape in a mechanically stretched position appears to be the main morphological variable that is likely to affect maximum prey size and resource use by these predatory species. PMID- 28886160 TI - Effect of age on the diagnostic efficiency of HbA1c for diabetes in a Chinese middle-aged and elderly population: The Shanghai Changfeng Study. AB - BACKGROUND AND AIMS: Glycated hemoglobin A1c (HbA1c) >=6.5% (or 48mmol/mol) has been recommended as a new diagnostic criterion for diabetes; however, limited literature is available regarding the effect of age on the HbA1c for diagnosing diabetes and the causes for this age effect remain unknown. In this study, we investigated whether and why age affects the diagnostic efficiency of HbA1c for diabetes in a community-based Chinese population. METHODS: In total, 4325 participants without previously known diabetes were enrolled in this study. Participants were stratified by age. Receiver operating characteristic curve (ROC) was plotted for each age group and the area under the curve (AUC) represented the diagnostic efficiency of HbA1c for diabetes defined by the plasma glucose criteria. The area under the ROC curve in each one-year age group was defined as AUCage. Multiple regression analyses were performed to identify factors inducing the association between age and AUCage based on the changes in the beta and P values of age. RESULTS: The current threshold of HbA1c (>=6.5% or 48mmol/mol) showed low sensitivity (35.6%) and high specificity (98.9%) in diagnosing diabetes. ROC curve analyses showed that the diagnostic efficiency of HbA1c in the >=75 years age group was significantly lower than that in the 45-54 years age group (AUC: 0.755 vs. 0.878; P<0.001). Pearson correlation analysis showed that the AUCage of HbA1c was negatively correlated with age (r = -0.557, P = 0.001). When adjusting the red blood cell (RBC) count in the multiple regression model, the negative association between age and AUCage disappeared, with the regression coefficient of age reversed to 0.001 and the P value increased to 0.856. CONCLUSIONS: The diagnostic efficiency of HbA1c for diabetes decreased with aging, and this age effect was induced by the decreasing RBC count with age. HbA1c is unsuitable for diagnosing diabetes in elderly individuals because of their physiologically decreased RBC count. PMID- 28886162 TI - Inter-annual cascade effect on marine food web: A benthic pathway lagging nutrient supply to pelagic fish stock. AB - Currently, spatial and temporal changes in nutrients availability, marine planktonic, and fish communities are best described on a shorter than inter annual (seasonal) scale, primarily because the simultaneous year-to-year variations in physical, chemical, and biological parameters are very complex. The limited availability of time series datasets furnishing simultaneous evaluations of temperature, nutrients, plankton, and fish have limited our ability to describe and to predict variability related to short-term process, as species specific phenology and environmental seasonality. In the present study, we combine a computational time series analysis on a 15-year (1995-2009) weekly sampled time series (high-resolution long-term time series, 780 weeks) with an Autoregressive Distributed Lag Model to track non-seasonal changes in 10 potentially related parameters: sea surface temperature, nutrient concentrations (NO2, NO3, NH4 and PO4), phytoplankton biomass (as in situ chlorophyll a biomass), meroplankton (barnacle and mussel larvae), and fish abundance (Mugil liza and Caranx latus). Our data demonstrate for the first time that highly intense and frequent upwelling years initiate a huge energy flux that is not fully transmitted through classical size-structured food web by bottom-up stimulus but through additional ontogenetic steps. A delayed inter-annual sequential effect from phytoplankton up to top predators as carnivorous fishes is expected if most of energy is trapped into benthic filter feeding organisms and their larval forms. These sequential events can explain major changes in ecosystem food web that were not predicted in previous short-term models. PMID- 28886163 TI - Effectiveness of a training program for police officers who come into contact with people with mental health problems: A pragmatic randomised controlled trial. AB - INTRODUCTION: Police officers frequently come into contact with individuals with mental health problems. Specialist training in this area for police officers may improve how they respond to individuals with mental health problems; however, evidence to support this is sparse. This study evaluated the effectiveness of one bespoke mental health training package for frontline police officers relative to routine training. DESIGN: Pragmatic, two-armed cluster randomised controlled trial in one police force in England. Police stations in North Yorkshire were randomised with frontline police officers receiving either a bespoke mental health training package or routine training. The primary outcome was the number of incidents which resulted in a police response reported to the North Yorkshire Police control room up to six months after delivery of training. Secondary outcomes included: likelihood of incidents using Section 136 of the Mental Health Act; likelihood of incidents having a mental health tag applied; and number of individuals with a mental health warning marker involved in incidents. The appropriateness of mental health tags applied to a random sample of incidents was checked by an independent mental health professional. Routinely collected data were used. RESULTS: Twelve police stations were recruited and randomised (Intervention group n = 6; Control group n = 6), and 249 officers received the bespoke mental health training intervention. At follow-up, a median of 397 incidents were assigned to trial stations in the intervention group, and 498 in the control group. There was no evidence of a difference in the number of incidents with a police response (adjusted incidence rate ratio (IRR) 0.92, 95% CI 0.61 to 1.38, p = 0.69), or in the number of people with mental health warning markers involved in incidents (adjusted IRR 1.39, 95% CI 0.91 to 2.10, p = 0.13) between the intervention and control groups up to six months following the intervention; however, incidents assigned to stations in the intervention group were more likely to have a mental health tag applied to them than incidents assigned to control stations (adjusted odds ratio 1.41, 95% CI 1.16 to 1.71, p = 0.001). The review of 100 incidents suggests that there may be incidents involving individuals with mental health issues that are not being recorded as such (Kappa coefficient 0.65). There was no statistically significant difference in the likelihood of Section 136 of the Mental Health Act being applied to an incident. CONCLUSIONS: The bespoke one day mental health training delivered to frontline officers by mental health professionals did not reduce the number of incidents reported to the police control room up to six months after its delivery; however training may have a positive effect on how the police record incidents involving individuals with mental health problems. Our trial has shown that conducting pragmatic trials within the police setting is feasible and acceptable. There is a wealth of routinely collected police data that can be utilised for research and further collaboration between police forces and academia is encouraged. TRIAL REGISTRATION: ISRCTN (ISRCTN11685602). The authors confirm that all ongoing and related trials for this drug/intervention are registered. PMID- 28886164 TI - Variant genotyping with gap filling. AB - Although recent developments in DNA sequencing have allowed for great leaps in both the quality and quantity of genome assembly projects, de novo assemblies still lack the efficiency and accuracy required for studying genetic variation of individuals. Thus, efficient and accurate methods for calling and genotyping genetic variants are fundamental to studying the genomes of individuals. We study the problem of genotyping insertion variants. We assume that the location of the insertion is given, and the task is to find the insertion sequence. Insertions are the hardest structural variant to genotype, because the insertion sequence must be assembled from the reads, whereas genotyping other structural variants only requires transformations of the reference genome. The current methods for constructing insertion variants are mostly linked to variation calling methods and are only able to construct small insertions. A sub-problem in genome assembly, the gap filling problem, provides techniques that are readily applicable to insertion genotyping. Gap filling takes the context and length of a missing sequence in a genome assembly and attempts to assemble the intervening sequence. In this paper we show how tools and methods for gap filling can be used to assemble insertion variants by modeling the problem of insertion genotyping as filling gaps in the reference genome. We further give a general read filtering scheme to make the method scalable to large data sets. Our results show that gap filling methods are competitive against insertion genotyping tools. We further show that read filtering improves performance of insertion genotyping especially for long insertions. Our experiments show that on long insertions the new proposed method is the most accurate one, whereas on short insertions it has comparable performance as compared against existing tools. PMID- 28886165 TI - Low mother-to-child HIV transmission rate but high loss-to-follow-up among mothers and babies in Mandalay, Myanmar; a cohort study. AB - INTRODUCTION: Loss-to-follow-up (LTFU) throughout the Prevention of Mother-To Child Transmission (PMTCT) cascade remains one of the major threats to the success of PMTCT programs. In this study, we aimed to determine the mother-to child transmission rate in a programmatic setting and to determine factors associated with LTFU among enrolled mothers and unfavorable outcomes among HIV exposed babies which includes being HIV positive, death and LTFU. METHODS: A retrospective cohort study reviewing routinely collected data in an Integrated HIV care program, Mandalay, Myanmar in June 2016.LTFU means mother/infant missing appointed visit for more than three months. RESULTS: Of 678 pregnant women enrolled in PMTCT program between March 2011 and June 2014, one stillbirth and 607 live births were recorded in this cohort. Of 457 HIV-exposed babies with HIV test recorded at the end of the intervention, nine (2%) were HIV-positive. Pregnant women's and exposed-babies' LTFU rate was 7 per 1000 person-years, and 10 per 1000 person-years respectively. PMTCT option B protocol was found to be significantly associate with maternal LTFU [adjusted Hazard Ratio (aHR) 95% CI: 3.52 (1.38-8.96)] when compare to mothers receiving option B+/lifelong antiretroviral therapy (ART). Weight <2.5 Kg at enrolment, receiving mixed feeding, vaginal delivery and option B PMTCT protocol were significantly associated with unfavorable outcomes among exposed babies [aHR(95% CI): 5.40 (1.66-17.53), 5.91(1.68-20.84), 2.27 (1.22-4.22) and 2.33 (1.16-4.69) respectively]. CONCLUSION: Mother-to-child HIV transmission rate in this public hospital-based program was lower than the 5% national target, which indicates a successful PMTCT intervention. However, a high proportion of HIV-infected mothers and exposed babies LTFU was recorded. Lifelong ART provision to HIV-positive pregnant women was shown to reduce exposed babies' LTFU, death and transmission rate (unfavorable outcomes) in this setting. Lessons learned from this program could be used to inform policy and practice in the country, while the programmatic challenge of LTFU should be urgently addressed. PMID- 28886167 TI - Degradable transportation network with the addition of electric vehicles: Network equilibrium analysis. AB - Introducing electric vehicles (EVs) into urban transportation network brings higher requirement on travel time reliability and charging reliability. Specifically, it is believed that travel time reliability is a key factor influencing travelers' route choice. Meanwhile, due to the limited cruising range, EV drivers need to better learn about the required energy for the whole trip to make decisions about whether charging or not and where to charge (i.e., charging reliability). Since EV energy consumption is highly related to travel speed, network uncertainty affects travel time and charging demand estimation significantly. Considering the network uncertainty resulted from link degradation, which influences the distribution of travel demand on transportation network and the energy demand on power network, this paper aims to develop a reliability-based network equilibrium framework for accommodating degradable road conditions with the addition of EVs. First, based on the link travel time distribution, the mean and variance of route travel time and monetary expenses related to energy consumption are deduced, respectively. And the charging time distribution of EVs with charging demand is also estimated. Then, a nested structure is considered to deal with the difference of route choice behavior derived by the different uncertainty degrees between the routes with and without degradable links. Given the expected generalized travel cost and a psychological safety margin, a traffic assignment model with the addition of EVs is formulated. Subsequently, a heuristic solution algorithm is developed to solve the proposed model. Finally, the effects of travelers' risk attitude, network degradation degree, and EV penetration rate on network performance are illustrated through an example network. The numerical results show that the difference of travelers' risk attitudes does have impact on the route choice, and the widespread adoption of EVs can cut down the total system travel cost effectively when the transportation network is more reliable. PMID- 28886166 TI - Assigning ecological roles to the populations belonging to a phenanthrene degrading bacterial consortium using omic approaches. AB - The present study describes the behavior of a natural phenanthrene-degrading consortium (CON), a synthetic consortium (constructed with isolated strains from CON) and an isolated strain form CON (Sphingobium sp. AM) in phenanthrene cultures to understand the interactions among the microorganisms present in the natural consortium during phenanthrene degradation as a sole carbon and energy source in liquid cultures. In the contaminant degradation assay, the defined consortium not only achieved a major phenanthrene degradation percentage (> 95%) but also showed a more efficient elimination of the intermediate metabolite. The opposite behavior occurred in the CON culture where the lowest phenanthrene degradation and the highest HNA accumulation were observed, which suggests the presence of positive and also negative interaction in CON. To consider the uncultured bacteria present in CON, a metagenomic library was constructed with total CON DNA. One of the resulting scaffolds (S1P3) was affiliated with the Betaproteobacteria class and resulted in a significant similarity with a genome fragment from Burkholderia sp. HB1 chromosome 1. A complete gene cluster, which is related to one of the lower pathways (meta-cleavage of catechol) involved in PAH degradation (ORF 31-43), mobile genetic elements and associated proteins, was found. These results suggest the presence of at least one other microorganism in CON besides Sphingobium sp. AM, which is capable of degrading PAH through the meta-cleavage pathway. Burkholderiales order was further found, along with Sphingomonadales order, by a metaproteomic approach, which indicated that both orders were metabolically active in CON. Our results show the presence of negative interactions between bacterial populations found in a natural consortium selected by enrichment techniques; moreover, the synthetic syntrophic processing chain with only one microorganism with the capability of degrading phenanthrene was more efficient in contaminant and intermediate metabolite degradation than a generalist strain (Sphingobium sp. AM). PMID- 28886168 TI - Unraveling the human salivary microbiome diversity in Indian populations. AB - The importance of studying the salivary microbiome has been highlighted for its connection to health and disease and as a potential tool for supplementing human genetic diversity studies. While the salivary microbiome has been studied in various world populations, Indian populations have not been examined. We therefore analyzed microbiome diversity in saliva samples from 92 volunteers from eight different sampling locations in India by amplifying and sequencing variable regions (V1 and V2) of the bacterial 16S rRNA gene. The results showed immense bacterial richness in Indian populations; we identified 165 bacterial genera and 785 unique Operational Taxonomic Units (OTUs), with substantial sharing among the populations. There were small, but significant correlations in the abundance of bacterial genera in sampling locations from the same geographic region. Most of the core OTUs detected were also observed previously in other populations, but Solobacterium spp., Lachnoanaerobaculum spp. and Alloprevotella spp. were observed to be a component of the saliva microbiome unique to Indian populations. Importantly, nine bacterial genera were observed that were not listed in the Human Oral Microbiome Database (HOMD). These results highlight the importance of analyzing underrepresented populations like those of India. PMID- 28886169 TI - Endogenous temporal attention in the absence of stimulus-driven cues emerges in the second year of life. AB - Anticipating both where and when an object will appear is a critical ability for adaptation. Research in the temporal domain in adults indicate that dissociable mechanisms relate to endogenous attention driven by the properties of the stimulus themselves (e.g. rhythmic, sequential, or trajectory cues) and driven by symbolic cues. In infancy, we know that the capacity to endogenously orient attention progressively develops through infancy. However, the above-mentioned distinction has not yet been explored since previous studies involved stimulus driven cues. The current study tested 12- and 15-month-olds in an adaptation of the anticipatory eye movement procedure to determine whether infants were able to anticipate a specific location and temporal interval predicted only by symbolic pre-cues. In the absence of stimulus-driven cues, results show that only 15-month olds could show anticipatory behavior based on the temporal information provided by the symbolic cues. Distinguishing stimulus-driven expectations from those driven by symbolic cues allowed dissecting more clearly the developmental progression of temporal endogenous attention. PMID- 28886170 TI - Homoarginine-A prognostic indicator in adolescents and adults with complex congenital heart disease? AB - BACKGROUND: Homoarginine (hArg) has been shown to be of prognostic value in patients with chronic left heart failure. The present study aims to assess the clinical utility and prognostic value of hArg levels in patients with complex congenital heart disease (CHD). METHODS: Plasma hArg levels were measured in 143 patients with complex CHD and compared to clinical status, echocardiographic and laboratory parameters as well as the occurrence of adverse cardiac events. RESULTS: Median hArg levels were 1.5 MUmol/l in CHD patients as compared to 1.70 MUmol/l in healthy controls (p = 0.051). Median hArg levels were lowest in patients with Fontan palliation (1.27 MUmol/l) and Eisenmenger physiology (0.99 MUmol/l) and decreased with the severity of adverse cardiac events with lowest values found in patients prior to death or overt heart failure (0.89 MUmol/l). According to ROC analysis, the most important predictors of adverse cardiac events were hArg levels (AUC 0.837, p<0.001, CI 0.726-0.947), NYHA class (AUC 0.800, p<0.001, CI 0.672-0.928) and NT-proBNP levels (AUC 0.780, p<0.001, CI 0.669-0.891). The occurrence of overt heart failure or death due to progressive heart failure were best predicted by NYHA class (AUC 0.945, p<0.001, CI 0.898 0.992), hArg levels (AUC 0.911, p<0.001, CI 0.850-0.971) and NT-proBNP levels (AUC 0.877, p<0.001, CI 0.791-0.962), respectively. CONCLUSION: In patients with complex CHD, hArg levels can predict adverse cardiac events as reliably as or even better than NT-proBNP levels and thus might be of prognostic value in this subset of patients. PMID- 28886171 TI - Positive predictive value and effectiveness of measles case-based surveillance in Uganda, 2012-2015. AB - INTRODUCTION: Disease surveillance is a critical component in the control and elimination of vaccine preventable diseases. The Uganda National Expanded Program on Immunization strives to have a sensitive surveillance system within the Integrated Disease Surveillance and Response (IDSR) framework. We analyzed measles surveillance data to determine the effectiveness of the measles case based surveillance system and estimate its positive predictive value in order to inform policy and practice. METHODS: An IDSR alert was defined as >=1 suspected measles case reported by a district in a week, through the electronic Health Management Information System. We defined an alert in the measles case-based surveillance system (CBS) as >=1 suspected measles case with a blood sample collected for confirmation during the corresponding week in a particular district. Effectiveness of CBS was defined as having >=80% of IDSR alerts with a blood sample collected for laboratory confirmation. Positive predictive value was defined as the proportion of measles case-patients who also had a positive measles serological result (IgM +). We reviewed case-based surveillance data with laboratory confirmation and measles surveillance data from the electronic Health Management Information System from 2012-2015. RESULTS: A total of 6,974 suspected measles case-persons were investigated by the measles case-based surveillance between 2012 and 2015. Of these, 943 (14%) were measles specific IgM positive. The median age of measles case-persons between 2013 and 2015 was 4.0 years. Between 2013 and 2015, 72% of the IDSR alerts reported in the electronic Health Management Information System, had blood samples collected for laboratory confirmation. This was however less than the WHO recommended standard of >=80%. The PPV of CBS between 2013 and 2015 was 8.6%. CONCLUSION: In conclusion, the effectiveness of measles case-based surveillance was sub-optimal, while the PPV showed that true measles cases have significantly reduced in Uganda. We recommended strengthening of case-based surveillance to ensure that all suspected measles cases have blood samples collected for laboratory confirmation to improve detection and ensure elimination by 2020. PMID- 28886172 TI - Use of alcohol and drugs with addiction potential among older women and men in a population-based study. The Nord-Trondelag Health Study 2006-2008 (HUNT3). AB - BACKGROUND: Little is known about the consumption habits of older adults in Norway with respect to alcohol and the use of drugs with addiction potential, such as benzodiazepines, z-hypnotics and opioids, among regular drinkers. We studied the prevalence of self-reported consumption of alcohol on a regular basis in community-living older men and women (>= 65 years). Furthermore, we investigated the prevalence of dispensed prescribed drugs with addiction potential in older men and women who were regular drinkers. METHODS: We used data from the Nord-Trondelag Health Study 2006-2008 (HUNT3). Of 12,361 older adults in the HUNT3 study, 11,545 had answered the alcohol consumption item and were included in our study. Regular drinkers were defined as consuming alcohol one or more days a week. Data on dispensed drugs with addiction potential were drawn from the Norwegian Prescription Database. Addiction potential was defined as at least one prescription for benzodiazepines, z-hypnotics or opioids during one year for a minimum of two consecutive years. RESULTS: In total 28.2% of older Norwegian adults were regular drinkers. Men in the study were more likely to be regular drinkers than women. Drugs with addiction potential were used by 32.4% of participants, and were more commonly used by women. Nearly 12% of participants used benzodiazepines, 19% z-hypnotics and 12.4% opioids. Among regular drinkers, 29% used drugs with addiction potential, which was also more common among women. Adjusted for age, gender and living situation, use of z-hypnotics was associated with regular alcohol intake, while use of opioids was associated with no regular alcohol intake. CONCLUSION: The prevalence of the use of drugs with addiction potential was high in a Norwegian population of older adults who reported regular consumption of alcohol. Strategies should be developed to reduce or prevent alcohol consumption among older adults who use drugs with addiction potential. PMID- 28886173 TI - Prevalence of self-reported comorbidities in HIV positive and HIV negative men who have sex with men over 55 years-The Australian Positive & Peers Longevity Evaluation Study (APPLES). AB - In Australia, almost half of HIV-positive people are now aged over 50 and are predominately gay and bisexual men (GBM). Compared to the general HIV-negative population, GBM engage more in behaviours that may increase the risk of age related comorbidities, including smoking, high alcohol consumption and recreational drug use. The objective of APPLES was to compare comorbidities and risk factors in HIV-positive older GBM with an appropriate control group of HIV negative GBM. We undertook a prospectively recruited cross-sectional sample of HIV-positive and HIV-negative GBM >= 55 years. Detailed data collection included clinic data, a health and lifestyle survey, and blood sample collection. We report key demographic, laboratory markers and self-reported comorbidities by HIV status. For selected comorbidities we also adjust HIV status a priori for age, smoking and body mass index. Over 16 months 228 HIV-positive and 218 HIV-negative men were recruited. Median age was 63 years (IQR: 59-67). Although more HIV positive men reported having ever smoked, smoking status was not statistically different between HIV positive and HIV negative men (p = 0.081). Greater alcohol use was reported by HIV-negative men (p = 0.002), and recreational drug use reported more often by HIV-positive men (p<0.001). After adjustment, HIV-positive men had significantly increased odds of diabetes (adjusted Odds ratio (aOR): 1.97, p = 0.038), thrombosis (aOR: 3.08, p = 0.007), neuropathy (aOR: 34.6, P<0.001), and non-significantly increased odds for heart-disease (aOR: 1.71, p = 0.077). In conclusion, HIV-positive GBM have significantly increased odds for key self-reported comorbidities. This study underscores the importance of an appropriate HIV-negative control group for more accurate evaluation of the risk and attribution of age-related comorbidities in HIV-positive people. PMID- 28886174 TI - Development of hop transcriptome to support research into host-viroid interactions. AB - Viroids, the smallest known pathogens, unable to encode any proteins, can cause severe diseases in their host plants. One of the proposed mechanisms of their pathogenicity includes silencing the host's genes via viroid-derived small RNAs, which are products of the host's immune response to the viroid's double stranded RNA. Humulus lupulus (hop) plants are hosts to several viroids; two of them, HLVd and CBCVd, are interesting models for studying host-viroid interactions, due to the symptomless infection of the former and severe stunting disease caused by the latter. To study these interactions, we constructed a deep hop NGS transcriptome based on 35 Gb paired-end sequencing data assembled into over 74 Mb of contigs. These transcripts were used for in-silico prediction of target transcripts of vd sRNA of the two aforementioned viroids, using two different software tools. Prediction models revealed that 1062 and 1387 hop transcripts share nucleotide similarities with HLVd- and CBCVd-derived small RNAs, respectively, so they could be silenced in an RNA interference process. Furthermore, we selected 17 transcripts from 4 groups of targets involved in the metabolism of plant hormones, small RNA biogenesis, transcripts with high complementarity with viroid derived small RNAs and transcripts targeted by CBCVd-derived small RNAs with high cellular concentrations. Their expression was monitored by reverse transcription quantitative PCR performed using leaf, flower and cone samples. Additionally, the expression of 5 pathogenesis related genes was monitored. Expression analysis confirmed high expression levels of four pathogenesis related genes in leaves of HLVd and CBCVd infected hop plants. Expression fluctuations were observed for the majority of targets, with possible evidence of downregulation of GATA transcription factor by CBCVd- and of linoleate 13S-lipoxygenase by HLVd-derived small RNAs. These results provide a deep transcriptome of hop and the first insights into complex viroid-hop plant interactions. PMID- 28886175 TI - Cabozantinib versus everolimus, nivolumab, axitinib, sorafenib and best supportive care: A network meta-analysis of progression-free survival and overall survival in second line treatment of advanced renal cell carcinoma. AB - BACKGROUND: Relative effect of therapies indicated for the treatment of advanced renal cell carcinoma (aRCC) after failure of first line treatment is currently not known. The objective of the present study is to evaluate progression-free survival (PFS) and overall survival (OS) of cabozantinib compared to everolimus, nivolumab, axitinib, sorafenib, and best supportive care (BSC) in aRCC patients who progressed after previous VEGFR tyrosine-kinase inhibitor (TKI) treatment. METHODOLOGY & FINDINGS: Systematic literature search identified 5 studies for inclusion in this analysis. The assessment of the proportional hazard (PH) assumption between the survival curves for different treatment arms in the identified studies showed that survival curves in two of the studies did not fulfil the PH assumption, making comparisons of constant hazard ratios (HRs) inappropriate. Consequently, a parametric survival network meta-analysis model was implemented with five families of functions being jointly fitted in a Bayesian framework to PFS, then OS, data on all treatments. The comparison relied on data digitized from the Kaplan-Meier curves of published studies, except for cabozantinib and its comparator everolimus where patient level data were available. This analysis applied a Bayesian fixed-effects network meta-analysis model to compare PFS and OS of cabozantinib versus its comparators. The log normal fixed-effects model displayed the best fit of data for both PFS and OS, and showed that patients on cabozantinib had a higher probability of longer PFS and OS than patients exposed to comparators. The survival advantage of cabozantinib increased over time for OS. For PFS the survival advantage reached its maximum at the end of the first year's treatment and then decreased over time to zero. CONCLUSION: With all five families of distributions, cabozantinib was superior to all its comparators with a higher probability of longer PFS and OS during the analyzed 3 years, except with the Gompertz model, where nivolumab was preferred after 24 months. PMID- 28886176 TI - Material wealth in 3D: Mapping multiple paths to prosperity in low- and middle- income countries. AB - Material wealth is a key factor shaping human development and well-being. Every year, hundreds of studies in social science and policy fields assess material wealth in low- and middle-income countries assuming that there is a single dimension by which households can move from poverty to prosperity. However, a one dimensional model may miss important kinds of prosperity, particularly in countries where traditional subsistence-based livelihoods coexist with modern cash economies. Using multiple correspondence analysis to analyze representative household data from six countries-Nepal, Bangladesh, Ethiopia, Kenya, Tanzania and Guatemala-across three world regions, we identify a number of independent dimension of wealth, each with a clear link to locally relevant pathways to success in cash and agricultural economies. In all cases, the first dimension identified by this approach replicates standard one-dimensional estimates and captures success in cash economies. The novel dimensions we identify reflect success in different agricultural sectors and are independently associated with key benchmarks of food security and human growth, such as adult body mass index and child height. The multidimensional models of wealth we describe here provide new opportunities for examining the causes and consequences of wealth inequality that go beyond success in cash economies, for tracing the emergence of hybrid pathways to prosperity, and for assessing how these different pathways to economic success carry different health risks and social opportunities. PMID- 28886178 TI - Ethics approval in applications for open-access clinical trial data: An analysis of researcher statements to clinicalstudydatarequest.com. AB - Although there are a number of online platforms for patient-level clinical trial data sharing from industry sponsors, they are not very harmonized regarding the role of local ethics approval in the research proposal review process. The first and largest of these platforms is ClinicalStudyDataRequest.com (CSDR), which includes over three thousand trials from thirteen sponsors including GlaxoSmithKline, Novartis, Roche, Sanofi, and Bayer. CSDR asks applicants to state whether they have received ethics approval for their research proposal, but in most cases does not require that they submit evidence of approval. However, the website does require that applicants without ethical approval state the reason it was not required. In order to examine the perspectives of researchers on this topic, we coded every response to that question received by CSDR between June 2014 and February 2017. Of 111 applicants who stated they were exempt from ethics approval, 63% mentioned de-identification, 57% mentioned the use of existing data, 33% referred to local or jurisdictional regulations, and 20% referred to the approvals obtained by the original study. We conclude by examining the experience of CSDR within the broader context of the access mechanisms and policies currently being used by other data sharing platforms, and discuss how our findings might be used to help clinical trial data providers design clear and informative access documents. PMID- 28886177 TI - Inflammatory and non-inflammatory monocytes as novel prognostic biomarkers of survival in SOD1G93A mouse model of Amyotrophic Lateral Sclerosis. AB - Amyotrophic Lateral Sclerosis (ALS) has lately become a suitable scenario to study the interplay between the hematopoietic system and disease progression. Recent studies in C9orf72 null mice have demonstrated that C9orf72 is necessary for the normal function of myeloid cells. In this study, we aimed to analyze in depth the connection between the hematopoietic system and secondary lymphoid (spleen) and non-lymphoid (liver and skeletal muscle) organs and tissues along the disease progression in the transgenic SOD1G93A mice. Our findings suggested that the inflammatory response due to the neurodegeneration in this animal model affected all three organs and tissues, especially the liver and the skeletal muscle. However, the liver was able to compensate this inflammatory response by means of the action of non-inflammatory monocytes, while in the skeletal muscle inflammatory monocytes prompted a further inflammation process until the terminal state of the animals. Interestingly, in blood, a positive correlation was found between non-inflammatory monocytes and survival of the transgenic SOD1G93A mice, while the contrary (a negative correlation) was found in the case of inflammatory monocytes, supporting their potential role as biomarkers of disease progression and survival in this animal model. These findings could prompt future translational studies in ALS patients, promoting the identification of new reliable biomarkers of disease progression. PMID- 28886179 TI - Local overfishing may be avoided by examining parameters of a spatio-temporal model. AB - Spatial erosion of stock structure through local overfishing can lead to stock collapse because fish often prefer certain locations, and fisheries tend to focus on those locations. Fishery managers are challenged to maintain the integrity of the entire stock and require scientific approaches that provide them with sound advice. Here we propose a Bayesian hierarchical spatio-temporal modelling framework for fish abundance data to estimate key parameters that define spatial stock structure: persistence (similarity of spatial structure over time), connectivity (coherence of temporal pattern over space), and spatial variance (variation across the seascape). The consideration of these spatial parameters in the stock assessment process can help identify the erosion of structure and assist in preventing local overfishing. We use Atlantic cod (Gadus morhua) in eastern Canada as a case study an examine the behaviour of these parameters from the height of the fishery through its collapse. We identify clear signals in parameter behaviour under circumstances of destructive stock erosion as well as for recovery of spatial structure even when combined with a non-recovery in abundance. Further, our model reveals the spatial pattern of areas of high and low density persists over the 41 years of available data and identifies the remnant patches. Models of this sort are crucial to recovery plans if we are to identify and protect remaining sources of recolonization for Atlantic cod. Our method is immediately applicable to other exploited species. PMID- 28886180 TI - Health care utilization in general practice after HPV vaccination-A Danish nationwide register-based cohort study. AB - OBJECTIVE: The Human Papillomavirus (HPV) vaccine has increasingly been suspected of adverse effects in Denmark since 2013. By using consultations with the general practitioner (GP) as an indicator for morbidity, this study aims to examine the association between HPV vaccination and morbidity in girls in the Danish childhood immunization program. METHODS: The study is a nationwide register-based cohort study. Both the HPV and the Measles, Mumps and Rubella (MMR) vaccines were offered to 12-year-old girls in Denmark in the study period (2008-2015). Therefore, both vaccines were included as exposures to allow differentiation between potential effects. This resulted in four exposure groups: HPV only vaccinated, HPV+MMR vaccinated, MMR only vaccinated, and Non-vaccinated girls. Outcomes were: daytime consultation rates and frequent GP attendance (> 7 annual GP consultations). We estimated consultation rates by negative binomial regressions analysis and frequent GP attendance by logistic regression analysis. Both analyses were stratified on the years 2008-2013 versus 2014. RESULTS: The study included 214,240 girls born in 1996-2002. All vaccinated groups consulted the GP more often than the non-vaccinated group, both before and after the vaccination. After the vaccination, an increase in consultations was observed for all three vaccinated groups; most distinct for girls vaccinated in 2014. For girls vaccinated before 2014, we found a slightly higher risk of frequent GP attendance after vaccination in the HPV only group compared to the non-vaccinated group, whereas in 2014, frequent GP attendance was seen for all three vaccinated groups; most substantial for the MMR only vaccinated group. CONCLUSION: In this study, no exclusive increase in health care utilization was detected after HPV vaccination. However, a general difference in the health care utilization pattern was found between vaccinated and non-vaccinated girls, which increased after the time of vaccination, primarily for girls vaccinated after 2013. PMID- 28886182 TI - Toxoplasma gondii seroprevalence varies by cat breed. AB - Toxoplasma gondii is a widespread zoonotic parasite that is relevant for veterinary and public health. The domestic cat, the definitive host species with the largest worldwide population, has become evolutionarily and epidemiologically the most important host of T. gondii. The outcome of T. gondii infection is influenced by congenital and acquired host characteristics. We detected differences in T. gondii seroprevalence by cat breed in our previous studies. The aims of this study were to estimate T. gondii seroprevalence in selected domestic cat breeds, and to evaluate whether being of a certain breed is associated with T. gondii seropositivity, when the age and lifestyle of the cat are taken into account. The studied breeds were the Birman, British Shorthair, Burmese, Korat, Norwegian Forest Cat, Ocicat, Persian, and Siamese. Plasma samples were analyzed for the presence of immunoglobulin G antibodies against T. gondii with a commercial direct agglutination test at dilution 1:40. The samples were accompanied by owner-completed questionnaires that provided background data on the cats. Overall, 41.12% of the 1121 cats tested seropositive, and the seroprevalence increased with age. The Burmese had the lowest seroprevalence (18.82%) and the Persian had the highest (60.00%). According to the final multivariable logistic regression model, the odds to test seropositive were four to seven times higher in Birmans, Ocicats, Norwegian Forest Cats, and Persians when compared with the Burmese, while older age and receiving raw meat were also risk factors for T. gondii seropositivity. This study showed that T. gondii seroprevalence varies by cat breed and identified being of certain breeds, older age, and receiving raw meat as risk factors for seropositivity. PMID- 28886181 TI - Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury. AB - Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1 acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI). Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and enhances the expression of binding immunoglobulin protein BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of these endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3). These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI. PMID- 28886183 TI - Effectiveness of tori line use to reduce seabird bycatch in pelagic longline fishing. AB - Industrial longline fisheries cause the death of large numbers of seabirds annually. Various mitigation measures have been proposed, including the use of tori lines. In this study the efficiency of a single tori line to reduce seabird bycatch was tested on pelagic longline vessels (25-37m length). Thirteen fishing trips were carried out in the area and season of the highest bycatch rates recorded in the southwest Atlantic (2009-2011). We deployed two treatments in random order: sets with a tori line and without a tori line (control treatment). The use of a tori line significantly reduced seabird bycatch rates. Forty three and seven birds were captured in the control (0.85 birds/1,000 hooks, n = 49 sets) and in the tori line treatment (0.13 birds/1,000 hooks, n = 51 sets), respectively. In 47% of the latter sets the tori line broke either because of entanglement with the longline gear or by tension. This diminished the tori line effectiveness; five of the seven captures during sets where a tori line was deployed were following ruptures. Nine additional trips were conducted with a tori line that was modified to reduce entanglements (2012-2016). Seven entanglements were recorded in 73 longline sets. The chance of a rupture on these trips was 4% (95% c.l. = 1-18%) of that during 2009-2011. This work shows that the use of a tori line reduces seabird bycatch in pelagic longline fisheries and is a practice suitable for medium size vessels (~25-40m length). Because the study area has historically very high bycatch rates at global level, this tori line design is potentially useful to reduce seabird bycatch in many medium size pelagic longline vessel fishing in the southern hemisphere. PMID- 28886184 TI - Retraction: miR-122 Regulates Tumorigenesis in Hepatocellular Carcinoma by Targeting AKT3. PMID- 28886185 TI - Clinical features and seasonality of parechovirus infection in an Asian subtropical city, Hong Kong. AB - BACKGROUND: The epidemiology of human parechovirus (HPeV) in Asia remains obscure. We elucidated the prevalence, seasonality, type distribution and clinical presentation of HPeV among children in Hong Kong. METHODS: A 24-month prospective study to detect HPeV in children <=36 months hospitalized for acute viral illnesses. RESULTS: 2.3% of the 3911 children examined had HPeV infection, with most (87.5%) concentrated in September-January (autumn-winter). 81.3% were HPeV1 and 12.5% were HPeV4, while HPeV3 was rare (2.5%). HPeV was a probable cause of the disease in 47.7% (42/88), mostly self-limiting including acute gastroenteritis, upper respiratory tract infection and maculopapular rash. A neonate developed severe sepsis-like illness with HPeV3 as the only pathogen detected. A high proportion (60.0%) of children coinfected with HPeV and other respiratory virus(es) had acute bronchiolitis or pneumonia. Six children with HPeV coinfections developed convulsion / pallid attack. Most rash illnesses exhibited a generalized maculopapular pattern involving the trunk and limbs, and were more likely associated with HPeV4 compared to other syndrome groups (36.4% vs. 3.1%, p = 0.011). CONCLUSIONS: In Hong Kong, HPeV exhibits a clear seasonality (autumn-winter) and was found in a small proportion (2.3%) of young children (<=36 months) admitted with features of acute viral illnesses. The clinical presentation ranged from mild gastroenteritis, upper respiratory tract infection and febrile rash to convulsion and severe sepsis-like illness. HPeV3, which is reported to associate with more severe disease in neonates, is rare in Hong Kong. HPeV coinfection might associate with convulsion and aggravate other respiratory tract infections. PMID- 28886186 TI - The cardiac calsequestrin gene transcription is modulated at the promoter by NFAT and MEF-2 transcription factors. AB - Calsequestrin-2 (CASQ2) is the main Ca2+-binding protein inside the sarcoplasmic reticulum of cardiomyocytes. Previously, we demonstrated that MEF-2 and SRF binding sites within the human CASQ2 gene (hCASQ2) promoter region are functional in neonatal cardiomyocytes. In this work, we investigated if the calcineurin/NFAT pathway regulates hCASQ2 expression in neonatal cardiomyocytes. The inhibition of NFAT dephosphorylation with CsA or INCA-6, reduced both the luciferase activity of hCASQ2 promoter constructs (-3102/+176 bp and -288/+176 bp) and the CASQ2 mRNA levels in neonatal rat cardiomyocytes. Additionally, NFATc1 and NFATc3 over expressing neonatal cardiomyocytes showed a 2-3-fold increase in luciferase activity of both hCASQ2 promoter constructs, which was prevented by CsA treatment. Site-directed mutagenesis of the -133 bp MEF-2 binding site prevented trans-activation of hCASQ2 promoter constructs induced by NFAT overexpression. Chromatin Immunoprecipitation (ChIP) assays revealed NFAT and MEF-2 enrichment within the -288 bp to +76 bp of the hCASQ2 gene promoter. Besides, a direct interaction between NFAT and MEF-2 proteins was demonstrated by protein co immunoprecipitation experiments. Taken together, these data demonstrate that NFAT interacts with MEF-2 bound to the -133 bp binding site at the hCASQ2 gene promoter. In conclusion, in this work, we demonstrate that the Ca2+ calcineurin/NFAT pathway modulates the transcription of the hCASQ2 gene in neonatal cardiomyocytes. PMID- 28886187 TI - Evaluating the role of land cover and climate uncertainties in computing gross primary production in Hawaiian Island ecosystems. AB - Gross primary production (GPP) is the Earth's largest carbon flux into the terrestrial biosphere and plays a critical role in regulating atmospheric chemistry and global climate. The Moderate Resolution Imaging Spectrometer (MODIS)-MOD17 data product is a widely used remote sensing-based model that provides global estimates of spatiotemporal trends in GPP. When the MOD17 algorithm is applied to regional scale heterogeneous landscapes, input data from coarse resolution land cover and climate products may increase uncertainty in GPP estimates, especially in high productivity tropical ecosystems. We examined the influence of using locally specific land cover and high-resolution local climate input data on MOD17 estimates of GPP for the State of Hawaii, a heterogeneous and discontinuous tropical landscape. Replacing the global land cover data input product (MOD12Q1) with Hawaii-specific land cover data reduced statewide GPP estimates by ~8%, primarily because the Hawaii-specific land cover map had less vegetated land area compared to the global land cover product. Replacing coarse resolution GMAO climate data with Hawaii-specific high-resolution climate data also reduced statewide GPP estimates by ~8% because of the higher spatial variability of photosynthetically active radiation (PAR) in the Hawaii-specific climate data. The combined use of both Hawaii-specific land cover and high resolution Hawaii climate data inputs reduced statewide GPP by ~16%, suggesting equal and independent influence on MOD17 GPP estimates. Our sensitivity analyses within a heterogeneous tropical landscape suggest that refined global land cover and climate data sets may contribute to an enhanced MOD17 product at a variety of spatial scales. PMID- 28886189 TI - Phylogeny of the infectious hematopoietic necrosis virus in European aquaculture. AB - Infectious hematopoietic necrosis (IHN)-a highly lethal infectious salmonid disease-has caused substantial economic losses in the European production of rainbow trout (Oncorhynchus mykiss) since the late 1980s. The causal agent of IHN is the IHN virus (IHNV) introduced from overseas. However, until today, its phylogeographic spread in Europe remains poorly understood. We therefore sought to elucidate this unresolved topic by using the largest ever compiled dataset of European IHNV isolates (E isolates) (193 GenBank E isolates and 100 isolates from this study) for the complete glycoprotein (G) gene sequence. Our results clearly revealed that the active trout trade has left its traces in the E phylogeny. For example, the spread by trade of IHNV-infected trout was apparently the cause for the exposure of the E lineage to different local scenarios of selection and genetic drift, and therefore has led to the split of this lineage into various subordinated lineages. Accordingly, we also found evidence for E isolates being mixed Europe-wide by cross-border introduction events. Moreover, there were indications that this propagation of the E lineage within Europe corresponded with an extensive and rapid spread event, already during or shortly after its formation. Finally, in accordance with the high substitution rate of IHNV determined by previous studies, our dataset indicates that the mean period of occurrence of a single E haplotype is typically not longer than one calendar year. PMID- 28886188 TI - Alkylation induced cerebellar degeneration dependent on Aag and Parp1 does not occur via previously established cell death mechanisms. AB - Alkylating agents are ubiquitous in our internal and external environments, causing DNA damage that contributes to mutations and cell death that can result in aging, tissue degeneration and cancer. Repair of methylated DNA bases occurs primarily through the base excision repair (BER) pathway, a multi-enzyme pathway initiated by the alkyladenine DNA glycosylase (Aag, also known as Mpg). Previous work demonstrated that mice treated with the alkylating agent methyl methanesulfonate (MMS) undergo cerebellar degeneration in an Aag-dependent manner, whereby increased BER initiation by Aag causes increased tissue damage that is dependent on activation of poly (ADP-ribose) polymerase 1 (Parp1). Here, we dissect the molecular mechanism of cerebellar granule neuron (CGN) sensitivity to MMS using primary ex vivo neuronal cultures. We first established a high throughput fluorescent imaging method to assess primary neuron sensitivity to treatment with DNA damaging agents. Next, we verified that the alkylation sensitivity of CGNs is an intrinsic phenotype that accurately recapitulates the in vivo dependency of alkylation-induced CGN cell death on Aag and Parp1 activity. Finally, we show that MMS-induced CGN toxicity is independent of all the cellular events that have previously been associated with Parp-mediated toxicity, including mitochondrial depolarization, AIF translocation, calcium fluxes, and NAD+ consumption. We therefore believe that further investigation is needed to adequately describe all varieties of Parp-mediated cell death. PMID- 28886190 TI - Correlation among baseline variables yields non-uniformity of p-values. AB - A recent paper in Neurology used statistical techniques to investigate the integrity of the randomization in 33 clinical trials conducted by a group of investigators. Without justification, the approach assumed that there would be no impact of correlation among baseline variables. We investigated the impact of correlation on the conclusions of the approach in several large-scale simulation studies that replicated the sample sizes and baseline variables of the clinical trials in question and utilized proper randomization. Additionally, we considered scenarios with larger numbers of baseline variables. We found that, with even moderate correlation, there can be substantial inflation of the type I error of statistical tests of randomization integrity. This is also the case under no correlation, in the presence of some discrete baseline variables, with a large number of variables. Thus, statistical techniques for assessing randomization integrity should be applied with extreme caution given that very low p-values, which are taken as evidence against valid randomization, can arise even in the case of valid randomization, in the presence of correlation. More generally, the use of tests of goodness of fit to uniformity for the purpose of testing a global null hypothesis is not advisable in the presence of correlation. PMID- 28886191 TI - Clinical chemistry reference intervals of healthy adult populations in Gojjam Zones of Amhara National Regional State, Northwest Ethiopia. AB - BACKGROUND: Reference interval is crucial for disease screening, diagnosis, monitoring, progression and treatment efficacy. Due to lack of locally derived reference values for the parameters, clinicians use reference intervals derived from western population. But, studies conducted in different African countries have indicated differences between locally and western derived reference values. Different studies also indicated considerable variation in clinical chemistry reference intervals by several variables such as age, sex, geographical location, environment, lifestyle and genetic variation. OBJECTIVE: This study aimed to determine the reference intervals of common clinical chemistry parameters of the community of Gojjam Zones, Northwest Ethiopia. METHOD: Population based cross sectional study was conducted from November 2015 to December 2016 in healthy adult populations of Gojjam zone. Data such as, medical history, physical examination and socio-demographic data were collected. In addition, laboratory investigations were undertaken to screen the population. Clinical chemistry parameters were measured using Mindray BS 200 clinical chemistry autoanalyzer as per the manufacturer's instructions. Descriptive statistics was used to calculate mean, median and 95th percentiles. Independent sample T-test and one way ANOVA were used to see association between variables. RESULTS: After careful screening of a total of 799 apparently healthy adults who were consented for this study, complete data from 446 (224 females and 222 males) were included for the analysis. The mean age of both the study participants was 28.8 years. Males had high (P<0.05) mean and 2.5th-97.5th percentile ranges of ALT, AST, ALP, creatinine and direct bilirubin. The reference intervals of amylase, LDH, total protein and total bilirubin were not significantly different between the two sex groups (P>0.05). Mean, median, 95% percentile values of AST, ALP, amylase, LDH, creatinine, total protein, total bilirubin, and direct bilirubin across all age groups of participants were similar (P>0.05). But, there was a significant difference in the value of ALT (P<0.05). The reference intervals of ALT, total protein and creatinine were significantly (P<0.05) high in people having monthly income >1500 ETB compared to those with low monthly income. Significant (P<0.05) higher values of the ALT, ALP and total protein were observed in people living in high land compared to low land residences. CONCLUSION: The study showed that some of the common clinical chemistry parameters reference intervals of healthy adults in Gojjam zones were higher than the reference intervals generated from developed countries. Therefore, strict adherence to the reference values generated in developed countries could lead to inappropriate diagnosis and treatment of patients. There was also variation of reference interval values based on climate, gender, age, monthly income and geographical locations. Therefore, further study is required to establish reference intervals for Ethiopian population. PMID- 28886192 TI - Influence of weight status on 24-hour urine composition in adults without urolithiasis: A nationwide study based on a Chinese Han population. AB - OBJECTIVES: This study sought to explore the influence of different body weight statuses on 24-hour urine compositions in adults without urolithiasis based on a nationwide study of a Chinese Han population. MATERIAL AND METHODS: Twenty-four hour urine samples from 584 Chinese Han adults without urolithiasis in six cities were analyzed. The participants were divided into four body weight status types according to their body mass indices (BMIs) according to WHO guidelines. The baseline characteristics and 24-hour urine compositions of the standard weight group were compared with those of the underweight, overweight and obese groups. The influences of different body weight statuses on the 24-hour urine compositions were explored using univariate and multivariate logistic regressions. RESULTS: The numbers of participants in the underweight, standard weight, overweight and obese status groups were 24, 376, 149 and 35, respectively. The overweight and obese groups suffered significantly higher risks of hypertension and diabetes mellitus than the standard weight group. In the univariate analyses, compared with the standard weight group, the overweight group had significantly higher levels of urine citrate (mean difference [MD] = 0.51 mmol, 95% confidence interval [CI]: 0.15-0.87, P = 0.001), potassium (MD = 6.63 mmol, 95% CI: 1.13-12.14, P = 0.01) and magnesium (MD = 0.38 mmol, 95% CI: 0.08-0.69, P = 0.014). Significant increases in urine citrate (MD = 0.85 mmol, 95% CI: 0.01-1.68, P = 0.046), magnesium (MD = 0.69 mmol, 95% CI: 0.13-1.25, P = 0.016) and phosphate (MD = 2.28 mmol, 95% CI: 0.03-4.54, P = 0.047) were found in the obese group. No significant differences were detected between the standard weight and underweight groups. In the multivariate logistic regression analyses, we only observed significantly higher levels of urine potassium (odds ratio [OR] = 1.02, 95% CI: 1.00-1.04, P = 0.03) in the overweight group and phosphate (OR = 1.32, 95% CI: 1.05-1.66, P = 0.018) in the obese group when compared with the standard weight group. CONCLUSIONS: Nonstone-forming adults with overweight or obese statuses were at higher risks of hypertension and diabetes mellitus. Obese nonstone-formers might have a greater risk of urinary stone formation due to increased urinary phosphate excretion. Additionally, underweight status had no influence on 24-hour urine composition. PMID- 28886193 TI - Estimating the incidence of interstitial lung diseases in the Cree of Eeyou Istchee, northern Quebec. AB - BACKGROUND: Little is known about the epidemiology of interstitial lung disease (ILD) amongst Canada's Indigenous populations. Clinicians working in Eeyou Istchee (the Cree territory of the James Bay region of Quebec, population 17, 956) suspected that ILD was more common in this area. We sought to identify all prevalent and incident cases of ILD in Eeyou Istchee between 2006 and 2013, to describe characteristics of affected patients, distribution of subtypes, and estimate disease incidence. METHODS: Potential ILD cases amongst Eeyou Istchee residents were identified by searching hospitalization databases and lists of patients on long term home oxygen in the region's nine communities, and surveying physicians and nurses. Clinical, radiological and pathological data were reviewed. Potential cases were classified as 'Definite ILD' if an open lung biopsy demonstrated ILD or, in the absence of histopathologic confirmation, if their thoracic CT imaging was deemed consistent with ILD by a panel of two respirologists and a chest radiologist. Potential cases for whom CT images could not be retrieved for our review were not eligible for classification as Definite ILD, unless they had undergone open lung biopsy. The Definite ILD group was further categorized by subtype of ILD. For usual interstitial pneumonia and non specific interstitial pneumonitis patterns, we assumed cases were idiopathic in the absence of documentation of connective tissue disease or occupational exposures in the medical chart. For Definite ILD and the most common subtype, we calculated the average annual incidence rates, age-standardized to the province of Quebec, for 2006 to 2013, using a gamma distribution to calculate 95% confidence intervals. RESULTS: Of 167 potential cases, 52 were categorized as Definite ILD: 14 on the basis of histopathology and 38 on the basis of CT imaging alone. Six patients had a prior history of connective tissue disease. Information on occupation was recorded in the charts of 18/52 (35%) cases, and missing in the remainder. We found the most common subtype was idiopathic pulmonary fibrosis (27/52, 52%), followed by idiopathic non-specific interstitial pneumonia (13/52, 25%), and secondary usual interstitial pneumonia associated with connective tissue diseases (5/52, 10%). The age-standardized annual incidence between 2006 2013 was 80 per 100,000 person-years observed (PYO) for ILD, and 46 per 100,000 PYO for idiopathic pulmonary fibrosis. INTERPRETATION: The incidence of ILD and of idiopathic pulmonary fibrosis in Eeyou Istchee may be higher than rates reported in other populations; however, cautious interpretation is required due to the lack of histopathological confirmation in the majority of cases, and our reliance on chart review to exclude secondary causes. A prospective study of incident cases with standardized assessments to establish the types of ILD and to assess for potential causes could overcome some of the limitations of the present analysis. Studies evaluating ILD incidence and subtype distribution in other Indigenous populations would also be of interest. PMID- 28886194 TI - A new rabbit model of impaired wound healing in an X-ray-irradiated field. AB - Radiation is an important therapy for cancer with many benefits; however, its side effects, such as impaired wound healing, are a major problem. While many attempts have been made to overcome this particular disadvantage, there are few effective treatments for impaired wound healing in an X-ray-irradiated field. One reason for this deficiency is the lack of experimental models, especially animal models. We have previously reported a mouse model of impaired wound healing in which the irradiation area was restricted to the hindlimbs. In this mouse model, due to the size of the animal, a diameter of five millimeters was considered the largest wound size suitable for the model. In addition, the transplanted cells had to be harvested from other inbred animals. To investigate larger wounds and the impact of autologous specimen delivery, a rabbit model was developed. Rabbits were kept in a special apparatus to shield the body and hindlimbs while the irradiation field was exposed to radiation. Six weeks after irradiation, a 2 x 2 cm, full-thickness skin defect was made inside the irradiation field. Then, the wound area was observed over time. The wound area after irradiation was larger than that without irradiation at all time points. Both angiogenesis and collagen formation were reduced. For further study, as an example of using this model, the effect of autologous platelet-rich plasma (PRP) was observed. Autologous PRP from peripheral blood (pb-PRP) and bone marrow aspirate (bm-PRP) was processed and injected into the wounds in the irradiated field. Two weeks later, the wounds treated with bm-PRP were significantly smaller than those treated with phosphate buffer vehicle controls. In contrast, the wounds treated with pb-PRP were not significantly different from the controls. This rabbit model is useful for investigating the mechanism of impaired wound healing in an X-ray-irradiated field. PMID- 28886195 TI - Effect of dragon fruit on glycemic control in prediabetes and type 2 diabetes: A systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this study was to systematically determine the effect of dragon fruit on glycemic control in prediabetes and type 2 diabetes. METHODS: Electronic databases including MEDLINE, CENTRAL, CINAHL, Scopus, ScienceDirect(r), Proquest, Web of Science(r), LILACS, NAPRALERT, SciFinder, Clinicalkey, Herbmed, NCCIH and Google Scholar were searched from their earliest inception up to March 2017 for relevant randomized controlled trials (RCTs) which compared dragon fruit with placebo or no treatment in prediabetes or type 2 diabetes. Clinicaltrials.gov, clinicaltrialresults.org, and ISRCTN registry were also searched. Personal contact with experts and historical search of related articles was undertaken. Outcome of interest were fasting plasma glucose (FPG) and 2 hours post-prandial glucose (2HPP). Study selection, data extraction and study quality assessment were performed independently by two investigators. Disagreements were resolved by a third reviewer. Treatment effect was estimated with mean difference (MD). Effect estimates were pooled using inverse-variance weighted method. Heterogeneity was assessed with the Q statistic and quantified with the I2 statistic. DerSimonian and Laird random-effects model was used when the Q-statistic was significant at the level of 0.1, otherwise a fixed-effects model was used. RESULTS: Among 401 studies identified from literature search, 4 RCTs involving 36 prediabetes subjects and 109 type 2 diabetes patients were included in the analysis. In prediabetes, FPG reduction was significant with MD of -15.1 mg/dL (95% CI: -23.8 to -6.5 mg/dL, P-value = 0.0006). Meta-analysis in type 2 diabetes showed no effect of dragon fruit on FPG (MD -26.5 mg/dL, 95% CI: 72.6 mg/dL to 19.6 mg/dL) and in 2HPP (MD -30.5 mg/dL, 95% CI: -80.9 mg/dL to 19.9 mg/dL). CONCLUSION: The available evidence in prediabetes is interesting. This will shed some light on diabetes prevention. The effect in T2DM was not significant. However, a trend towards greater blood glucose reduction with higher dose was observed. PMID- 28886196 TI - Fully-coupled fluid-structure interaction simulation of the aortic and mitral valves in a realistic 3D left ventricle model. AB - In this study, we present a fully-coupled fluid-structure interaction (FSI) framework that combines smoothed particle hydrodynamics (SPH) and nonlinear finite element (FE) method to investigate the coupled aortic and mitral valves structural response and the bulk intraventricular hemodynamics in a realistic left ventricle (LV) model during the entire cardiac cycle. The FSI model incorporates valve structures that consider native asymmetric leaflet geometries, anisotropic hyperelastic material models and human material properties. Comparison of FSI results with subject-specific echocardiography data demonstrates that the SPH-FE approach is able to quantitatively predict the opening and closing times of the valves, the mitral leaflet opening and closing angles, and the large-scale intraventricular flow phenomena with a reasonable agreement. Moreover, comparison of FSI results with a LV model without valves reveals substantial differences in the flow field. Peak systolic velocities obtained from the FSI model and the LV model without valves are 2.56 m/s and 1.16 m/s, respectively, compared to the Doppler echo data of 2.17 m/s. The proposed SPH-FE FSI framework represents a further step towards modeling patient-specific coupled LV-valve dynamics, and has the potential to improve our understanding of cardiovascular physiology and to support professionals in clinical decision making. PMID- 28886197 TI - In vivo lineage tracing reveals Axin2-expressing, long-lived cortical thymic epithelial progenitors in the postnatal thymus. AB - In the thymus, cortical and medullary thymic epithelial cells (TECs) are instrumental for generating a repertoire of functional T cells. Hence, there has been much interest in the ontogeny of TECs. While medullary TEC (mTEC) and bipotent progenitors have been identified, the existence of a cortical TEC (cTEC) progenitor remains ambiguous. In this study, we used lineage tracing based on a target gene of the Wnt pathway, Axin2. We found that Axin2 initially labels cells in both the cortical and medullary compartments. Using Axin2-CreERT2 mice to track the fate of labelled cells, we identified long-lived cortical TEC progenitors that give rise to expanding clones and contribute to homeostasis in postnatal thymus. In contrast, no clonal expansion was found in the medullary or in the K5K8-double positive compartments. The identification of cTEC progenitors and their regulation by Wnt signaling have important implications for our understanding of thymus physiology during homeostasis and TEC-related disorders. PMID- 28886198 TI - TAT-mediated transduction of bacterial redox proteins generates a cytoprotective effect on neuronal cells. AB - Cell penetrating peptides, also known as protein transduction domains, have the capacity to ubiquitously cross cellular membranes carrying many different cargos with negligible cytotoxicity. As a result, they have emerged as a powerful tool for macromolecular delivery-based therapies. In this study, catalytically active bacterial Ferredoxin-NADP+ reductase (LepFNR) and Heme oxygenase (LepHO) fused to the HIV TAT-derived protein transduction peptide (TAT) were efficiently transduced to neuroblastoma SHSY-5Y cells. Proteins entered the cells through an endocytic pathway showing a time/concentration dependent mechanism that was clearly modulated by the nature of the cargo protein. Since ferredoxin-NADP+ reductases and heme oxygenases have been implicated in mechanisms of oxidative stress defense, neuroblastoma cells simultaneously transduced with TAT-LepFNR and TAT-LepHO were challenged by H2O2 incubations to judge the cytoprotective power of these bacterial enzymes. Accumulation of reactive oxygen species was significantly reduced in these transduced neuronal cells. Moreover, measurements of metabolic viability, membrane integrity, and cell survival indicated that these cells showed a better tolerance to oxidative stress. Our results open the possibility for the application of transducible active redox proteins to overcome the damage elicited by oxidative stress in cells and tissues. PMID- 28886199 TI - Quantitative analysis and comparison of 3D morphology between viable and apoptotic MCF-7 breast cancer cells and characterization of nuclear fragmentation. AB - Morphological changes in apoptotic cells provide essential markers for defining and detection of apoptosis as a fundamental mechanism of cell death. Among these changes, the nuclear fragmentation and condensation have been regarded as the important markers but quantitative characterization of these changes is yet to be achieved. We have acquired confocal image stacks of 206 viable and apoptotic MCF 7 cells stained by three fluorescent dyes. Three-dimensional (3D) parameters were extracted to quantify and compare their differences in morphology. To analyze nuclear fragmentation, a new method has been developed to determine clustering of nuclear voxels in the reconstructed cells due to fluorescence intensity changes in nuclei of apoptotic cells. The results of these studies reveal that the 3D morphological changes in cytoplasm and nuclear membranes in apoptotic cells provide sensitive targets for label-free detection and staging of apoptosis. Furthermore, the clustering analysis and morphological data on nuclear fragmentation are highly useful for derivation of optical cell models and simulation of diffraction images to investigate light scattering by early apoptotic cells, which can lead to future development of label-free and rapid methods of apoptosis assay based on cell morphology. PMID- 28886200 TI - Screening of transporters to improve xylodextrin utilization in the yeast Saccharomyces cerevisiae. AB - The economic production of cellulosic biofuel requires efficient and full utilization of all abundant carbohydrates naturally released from plant biomass by enzyme cocktails. Recently, we reconstituted the Neurospora crassa xylodextrin transport and consumption system in Saccharomyces cerevisiae, enabling growth of yeast on xylodextrins aerobically. However, the consumption rate of xylodextrin requires improvement for industrial applications, including consumption in anaerobic conditions. As a first step in this improvement, we report analysis of orthologues of the N. crassa transporters CDT-1 and CDT-2. Transporter ST16 from Trichoderma virens enables faster aerobic growth of S. cerevisiae on xylodextrins compared to CDT-2. ST16 is a xylodextrin-specific transporter, and the xylobiose transport activity of ST16 is not inhibited by cellobiose. Other transporters identified in the screen also enable growth on xylodextrins including xylotriose. Taken together, these results indicate that multiple transporters might prove useful to improve xylodextrin utilization in S. cerevisiae. Efforts to use directed evolution to improve ST16 from a chromosomally-integrated copy were not successful, due to background growth of yeast on other carbon sources present in the selection medium. Future experiments will require increasing the baseline growth rate of the yeast population on xylodextrins, to ensure that the selective pressure exerted on xylodextrin transport can lead to isolation of improved xylodextrin transporters. PMID- 28886201 TI - Extrinsically derived TNF is primarily responsible for limiting antiviral CD8+ T cell response magnitude. AB - TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As a consequence of the widespread expression of its receptors (TNFR1 and 2), TNF plays a role in many important biological processes. In the context of influenza A virus (IAV) infection, TNF has variably been implicated in mediating immunopathology as well as suppression of the immune response. Although a number of cell types are able to produce TNF, the ability of CD8+ T cells to produce TNF following viral infection is a hallmark of their effector function. As such, the regulation and role of CD8+ T cell-derived TNF following viral infection is of great interest. Here, we show that the biphasic production of TNF by CD8+ T cells following in vitro stimulation corresponds to distinct patterns of epigenetic modifications. Further, we show that a global loss of TNF during IAV infection results in an augmentation of the peripheral virus-specific CD8+ T cell response. Subsequent adoptive transfer experiments demonstrated that this attenuation of the CD8+ T cell response was largely, but not exclusively, conferred by extrinsic TNF, with intrinsically-derived TNF making only modest contributions. In conclusion, TNF exerts an immunoregulatory role on CD8+ T cell responses following IAV infection, an effect that is largely mediated by extrinsically derived TNF. PMID- 28886203 TI - A Novel Method for Repeatable Failure Testing of Annulus Fibrosus. AB - Tears in the annulus fibrosus (AF) of the intervertebral disk can result in disk herniation and progressive degeneration. Understanding AF failure mechanics is important as research moves toward developing biological repair strategies for herniated disks. Unfortunately, failure mechanics of fiber-reinforced tissues, particularly tissues with fibers oriented off-axis from the applied load, is not well understood, partly due to the high variability in reported mechanical properties and a lack of standard techniques ensuring repeatable failure behavior. Therefore, the objective of this study was to investigate the effectiveness of midlength (ML) notch geometries in producing repeatable and consistent tissue failure within the gauge region of AF mechanical test specimens. Finite element models (FEMs) representing several notch geometries were created to predict the location of bulk tissue failure using a local strain based criterion. FEM results were validated by experimentally testing a subset of the modeled specimen geometries. Mechanical testing data agreed with model predictions (~90% agreement), validating the model's predictive power. Two of the modified dog-bone geometries ("half" and "quarter") effectively ensured tissue failure at the ML for specimens oriented along the circumferential-radial and circumferential-axial directions. The variance of measured mechanical properties was significantly lower for notched samples that failed at the ML, suggesting that ML notch geometries result in more consistent and reliable data. In addition, the approach developed in this study provides a framework for evaluating failure properties of other fiber-reinforced tissues, such as tendons and meniscus. PMID- 28886202 TI - Fuchs' Endothelial Corneal Dystrophy and RNA Foci in Patients With Myotonic Dystrophy. AB - Purpose: The most common cause of Fuchs' endothelial corneal dystrophy (FECD) is an intronic CTG repeat expansion in TCF4. Expanded CUG repeat RNA colocalize with splicing factor, muscleblind-like 1 (MBNL1), in nuclear foci in endothelium as a molecular hallmark. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG repeat expansion in the 3'-untranslated region (UTR) of DMPK. In this study, we examine for RNA-MBNL1 foci in endothelial cells of FECD subjects with DM1, test the hypothesis that DM1 patients are at risk for FECD, and determine prevalence of TCF4 and DMPK expansions in a FECD cohort. Methods: Using FISH, we examined for nuclear RNA-MBNL1 foci in endothelial cells from FECD subjects with DM1. We examined 13 consecutive unrelated DM1 patients for FECD using slit-lamp and specular microscopy. We genotyped TCF4 and DMPK repeat polymorphisms in a FECD cohort of 317 probands using short-tandem repeat and triplet repeat-primed PCR assays. Results: We detected abundant nuclear RNA foci colocalizing with MBNL1 in endothelial cells of FECD subjects with DM1. Six of thirteen DM1 patients (46%) had slit-lamp and specular microscopic findings of FECD, compared to 4% disease prevalence (P = 5.5 * 10-6). As expected, 222 out of 317 (70%) FECD probands harbored TCF4 expansion, while one subject harbored DMPK expansion without prior diagnosis of DM1. Conclusions: Our work suggests that DM1 patients are at risk for FECD. DMPK mutations contribute to the genetic burden of FECD but are uncommon. We establish a connection between two repeat expansion disorders converging upon RNA-MBNL1 foci and FECD. PMID- 28886204 TI - Stress Analysis-Driven Design of Bilayered Scaffolds for Tissue-Engineered Vascular Grafts. AB - Continuing advances in the fabrication of scaffolds for tissue-engineered vascular grafts (TEVGs) are greatly expanding the scope of potential designs. Increasing recognition of the importance of local biomechanical cues for cell mediated neotissue formation, neovessel growth, and subsequent remodeling is similarly influencing the design process. This study examines directly the potential effects of different combinations of key geometric and material properties of polymeric scaffolds on the initial mechanical state of an implanted graft into which cells are seeded or migrate. Toward this end, we developed a bilayered computational model that accounts for layer-specific thickness and stiffness as well as the potential to be residually stressed during fabrication or to swell during implantation. We found that, for realistic ranges of parameter values, the circumferential stress that would be presented to seeded or infiltrating cells is typically much lower than ideal, often by an order of magnitude. Indeed, accounting for layer-specific intrinsic swelling resulting from hydrophilicity or residual stresses not relieved via annealing revealed potentially large compressive stresses, which could lead to unintended cell phenotypes and associated maladaptive growth or, in extreme cases, graft failure. Metrics of global hemodynamics were also found to be inversely related to markers of a favorable local mechanobiological environment, suggesting a tradeoff in designs that seek mechanical homeostasis at a single scale. These findings highlight the importance of the initial mechanical state in tissue engineering scaffold design and the utility of computational modeling in reducing the experimental search space for future graft development and testing. PMID- 28886205 TI - Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis. AB - BACKGROUND: It is important to minimize placebo rates in randomised controlled trials (RCTs) to efficiently detect treatment differences between interventions. Historically, high placebo rates have been observed in clinical trials of ulcerative colitis (UC). A better understanding of factors influencing placebo rates may lead to more informed clinical trial design. OBJECTIVES: A systematic review and meta-analysis was conducted to evaluate placebo response and remission rates in RCTs evaluating UC treatments in adult patients. SEARCH METHODS: Electronic databases (i.e. MEDLINE, EMBASE, and CENTRAL) were searched from inception to 1 March 2017 with no language restrictions applied. Reference lists and conference proceedings of major gastroenterology meetings were also handsearched to identify additional studies. SELECTION CRITERIA: Placebo controlled RCTs of adult patients with UC treated with corticosteroids, aminosalicylates, immunosuppressives or biologics were eligible, provided enrolment and outcome assessment was conducted using the Ulcerative Colitis Disease Activity Index (UCDAI) or the Mayo Clinic Score. The minimum trial duration was two weeks for induction trials and four months maintenance trials. DATA COLLECTION AND ANALYSIS: Pairs of authors independently determined study eligibility and extracted data with any disagreements resolved through consensus. Outcomes of interest included the proportion of patients with clinical response and remission. Trial characteristics such as the design, participant demographics and disease history, interventions, and enrolment and assessment criteria were also recorded. The methodological quality of the included studies was evaluated using the Cochrane risk of bias tool. Pooled placebo response and remission rates and 95% confidence intervals (95% CI) were calculated using a binomial normal model for proportions. Induction of remission and maintenance studies were pooled separately. The impact of study-level characteristics on placebo response and remission rates was investigated using mixed-effects meta-regression analyses with logits of event rates as the outcome variables. An assessment of pooled placebo rates over time was conducted using a cumulative meta-analysis based on date of publication. Publication bias was examined using funnel plots. MAIN RESULTS: The screening process identified 61 included studies which encompass 58 induction phases (5111 patients randomised to placebo) and 12 maintenance phases (1579 patients randomised to placebo). For induction trials, the pooled estimate of placebo response was 33% (95% CI 30% to 36%) while the pooled estimate of placebo remission was 12% (95% CI 9% to 15%). For maintenance trials, the pooled estimate of placebo response was 23% (95% CI 19% to 28%) while the pooled estimate of placebo remission was 17% (95% CI 10% to 27%).Studies enrolling patients with more active disease confirmed objectively by endoscopy were associated with significantly lower placebo remission and response rates than trials enrolling patients with less active disease (27% versus 4%, OR 2.60, 95% CI 1.25 to 5.42, P = 0.01 for UCDAI endoscopy sub score >=1 versus >= 2 for remission; and 27% versus 4%, OR 1.70, 95% CI 1.02 to 2.82, P = 0.02 for UCDAI endoscopy sub score greater than or equal to one versus greater than or equal to two for response). With respect to drug class, the lowest placebo response and remission rates were observed in trials evaluating corticosteroids (23%; 95% CI 19 to 29%, and 5%; 95% CI 2 to 11%, respectively). Trials of biologics had the highest placebo response rate (35%; 95% CI 30 to 41%), while trials evaluating aminosalicylates had the highest placebo remission rate (18%; 95% CI 12 to 24%). Disease duration of greater than five years prior to enrolment was associated with a significantly lower placebo response rate compared to disease duration of less than or equal to five years (29% versus 47%, respectively; OR 0.54, 95% CI 0.32 to 0.92, P = 0.02). The requirement of a minimum rectal bleeding score for study eligibility was associated with an increased placebo response rate compared to studies that did not use rectal bleeding for trial eligibility (37% versus 32%, respectively; OR 1.70, 95% CI 1.02 to 2.82, P = 0.02). Finally, the time point of primary outcome assessment was found to be significantly associated with placebo remission rates such that every one week increment in endpoint assessment was associated with a 6% increase in the placebo remission rate (OR 1.06, 95% CI 1.02 to 1.10, P = 0.01).Cumulative meta-analysis indicated a consistent increase in the placebo response rate from 1987 to 2007 (from 13% to 33%), although rates have remained constant from 2008 to 2015 (32% to 34%). Similarly, placebo remission rates increased from 1987 to 2007 (5% to 14%) but have remained constant from 2008 to 2015 (12 to 14%). On meta-regression, there were no statistically significant differences between the 1987-2007 and 2008-2015 point estimates for both response (P = 0.81) and remission (P = 0.32). AUTHORS' CONCLUSIONS: Placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, class of agent, disease duration, and the time point at which the primary outcome was measured. These observations have important implications for the design and conduct of future clinical trials in UC and will help researchers design trials, determine required sample sizes and also provide useful information about trial design features which should be considered when planning new trials. PMID- 28886206 TI - Inverse probability weighted Cox regression for doubly truncated data. AB - Doubly truncated data arise when event times are observed only if they fall within subject-specific, possibly random, intervals. While non-parametric methods for survivor function estimation using doubly truncated data have been intensively studied, only a few methods for fitting regression models have been suggested, and only for a limited number of covariates. In this article, we present a method to fit the Cox regression model to doubly truncated data with multiple discrete and continuous covariates, and describe how to implement it using existing software. The approach is used to study the association between candidate single nucleotide polymorphisms and age of onset of Parkinson's disease. PMID- 28886207 TI - The Biological Effects of Kambo: Is There a Relationship Between its Administration and Sudden Death? AB - Kambo is a substance obtained from the skin secretions of a frog, Phyllomedusa bicolor, popular in the Amazon region, which is administered via the transdermal route. We report a case of 42-year-old man found dead in his house. Near the corpse, a plastic box labeled as "Kambo sticks" was found. The man was a chronic consumer of Kambo and no previous pathology or genetic disease emerged in clinical history from the declaration of his general practitioner. Autopsy investigations and toxicological analysis were performed. The histopathological examination showed left ventricular hypertrophy. Toxicological screening was negative for ethanol and other drugs. Phyllocaerulein, phyllokinin, and deltorphin A were isolated from the Kambo sticks but, only deltorphin A was detected in blood sample. We describe the first forensic case of death associated with Kambo administration. We attempt to explain how its use could be related to the cause of sudden death in this case. PMID- 28886209 TI - Treatment of superficial basal cell carcinoma by topical photodynamic therapy with fractionated 5-aminolaevulinic acid 20% vs. two-stage topical methyl aminolaevulinate: results of a randomized controlled trial. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer and incidence rates are increasing. Photodynamic therapy (PDT) is a frequently used treatment, especially for superficial BCC (sBCC). Two topical photosensitizing agents are currently used to treat sBCC, namely 5-aminolaevulinic acid (ALA) and its ester, methyl aminolaevulinate (MAL). Previous research showed a high efficacy for ALA-PDT using a twofold fractionated illumination scheme in which two light fractions of 20 J cm-2 and 80 J cm-2 were delivered 4 h and 6 h after ALA application. OBJECTIVES: To evaluate whether twofold ALA-PDT is superior to conventional MAL-PDT for sBCC. METHODS: We performed a single-blind, randomized, multicentre trial in the Netherlands. RESULTS: Overall, 162 patients were randomized either to conventional MAL-PDT or twofold ALA-PDT. After 12 months, a total of six treatment failures occurred following ALA-PDT and 13 treatment failures occurred following MAL-PDT. The 12-month cumulative probability of remaining free from treatment failure was 92.3% [95% confidence interval (CI) (83.7-96.5)] for ALA-PDT and 83.4% (95% CI 73.1-90.0) for MAL-PDT (P = 0.091). CONCLUSIONS: The twofold ALA-PDT scheme resulted in fewer recurrences, although the difference between both treatment groups was not statistically significant. However, ALA-PDT resulted in higher pain scores and more post-treatment side effects compared with MAL-PDT. PMID- 28886208 TI - Interacting effects of unobserved heterogeneity and individual stochasticity in the life history of the southern fulmar. AB - Individuals are heterogeneous in many ways. Some of these differences are incorporated as individual states (e.g. age, size, breeding status) in population models. However, substantial amounts of heterogeneity may remain unaccounted for, due to unmeasurable genetic, maternal or environmental factors. Such unobserved heterogeneity (UH) affects the behaviour of heterogeneous cohorts via intra cohort selection and contributes to inter-individual variance in demographic outcomes such as longevity and lifetime reproduction. Variance is also produced by individual stochasticity, due to random events in the life cycle of wild organisms, yet no study thus far has attempted to decompose the variance in demographic outcomes into contributions from UH and individual stochasticity for an animal population in the wild. We developed a stage-classified matrix population model for the southern fulmar breeding on Ile des Petrels, Antarctica. We applied multievent, multistate mark-recapture methods to estimate a finite mixture model accounting for UH in all vital rates and Markov chain methods to calculate demographic outcomes. Finally, we partitioned the variance in demographic outcomes into contributions from UH and individual stochasticity. We identify three UH groups, differing substantially in longevity, lifetime reproductive output, age at first reproduction and in the proportion of the life spent in each reproductive state. -14% of individuals at fledging have a delayed but high probability of recruitment and extended reproductive life span. -67% of individuals are less likely to reach adulthood, recruit late and skip breeding often but have the highest adult survival rate. -19% of individuals recruit early and attempt to breed often. They are likely to raise their offspring successfully, but experience a relatively short life span. Unobserved heterogeneity only explains a small fraction of the variances in longevity (5.9%), age at first reproduction (3.7%) and lifetime reproduction (22%). UH can affect the entire life cycle, including survival, development and reproductive rates, with consequences over the lifetime of individuals and impacts on cohort dynamics. The respective role of UH vs. individual stochasticity varies greatly among demographic outcomes. We discuss the implication of our finding for the gradient of life-history strategies observed among species and argue that individual differences should be accounted for in demographic studies of wild populations. PMID- 28886210 TI - Can the extent of heart rate reduction predict the clinical response of infantile haemangiomas to propranolol? PMID- 28886211 TI - Homogeneity study of proton and carbon ion scanning beams using combinations of different spot sizes and grid sizes. AB - PURPOSE: Different scanning ion beam delivery systems have different delivery accuracies, and the resulting delivery errors will affect field homogeneity. This study was performed to determine an appropriate combination of spot size (FWHM) and spot grid size (GS), which can provide homogenous dose distributions for both proton and carbon ion scanning beam radiotherapy. The combination of the two parameters is represented by a combination factor named n, which is the quotient of FWHM divided by GS. METHODS: Delivery uncertainties of our beam delivery system were analyzed using log files from the treatment of 28 patients. Square fields for different n values were simulated with and without considering the delivery uncertainties, and the homogeneity of these square fields was analyzed. All spots were located on a rectilinear grid with equal spacing in the x and y directions. In addition to the simulations, we performed experimental measurements using both protons and carbon ions. We selected six energy levels for both proton and carbon ions. For each energy level, we created six square field plans with different n values (1, 1.5, 2, 2.5, 3, 3.5). These plans were delivered and the field homogeneity was determined using a film measurement. RESULTS: The simulations demonstrated that under ideal condition (i.e., the delivery system has no delivery errors), the homogeneity is within 3% when n >= 1.1. When delivery uncertainties were included in the simulation, the homogeneity is within 3% when n >= 2.3. For film measurements, homogeneity under 3% was achieved when n >= 2.5. CONCLUSION: A practical method to determine the appropriate combination of spot size and grid size is here presented. Considering the uncertainties of the beam delivery system, an n value of 2.5 is good enough to meet the lateral homogeneity requests in our center. The methods used here can be easily repeated in other particle therapy centers. PMID- 28886212 TI - Comparison of gadolinium nanoparticles and molecular contrast agents for radiation therapy-enhancement. AB - PURPOSE: Nanoparticles appear as a novel tool to enhance the effectiveness of radiotherapy in cancer treatments. Many parameters influence their efficacy, such as their size, concentration, composition, their cellular localization, as well as the photon source energy. The current Monte Carlo study aims at comparing the dose-enhancement in presence of gadolinium (Gd), either as isolated atoms or atoms clustered in nanoparticles (NPs), by investigating the role played by these physical parameters at the cellular and the nanometer scale. In parallel, in vitro assays were performed in presence of either the gadolinium contrast agent (GdCA) Magnevist(r) or ultrasmall gadolinium NPs (GdNPs, 3 nm) for comparison with the simulations. METHODS: PENELOPE Monte Carlo Code was used for in silico dose calculations. Monochromatic photon beams were used to calculate dose enhancements in different cell compartments and low-energy secondary electron spectra dependence with energy. Particular attention has been placed on the interplay between the X-ray beam energy, the Gd localization and its distance from cellular targets. Clonogenic assays were used to quantify F98 rat glioma cell survival after irradiation in the presence of GdNPs or GdCA, using monochromatic X-rays with energies in the 30 keV-80 keV range from a synchrotron and 1.25 MeV gamma photons from a cobalt-60 source. The simulations that correspond to the experimental conditions were compared with the experimental results. RESULTS: In silico, a highly heterogeneous and clustered Gd-atom distribution, a massive production of low energy electrons around GdNPs and an optimal X-ray beam energy, above the Gd K-edge, were key factors found to increase microscopic doses, which could potentially induce cell death. The different Gd localizations studied all resulted in a lower dose enhancement for the nucleus component than for cytoplasm or membrane compartments, with a maximum dose-enhancement factor (DEF) found at 65 keV and 58 keV, respectively. In vitro, radiosensitization was observed with GdNPs incubated 5 h with the cells (2.1 mg Gd/mL) at all energies. Experimental DEFs were found to be greater than computational DEFs but follow a similar trend with irradiation energy. However, an important radiosensitivity was observed experimentally with GdNPs at high energy (1.25 MeV), whereas no effect was expected from modeling. This effect was correlated with GdNPs incubation time. In vitro, GdCA provided no dose enhancement at 1.25 MeV energies, in agreement with computed data. CONCLUSIONS: These results provide a foundation on which to base optimizations of the physical parameters in Gd radiation-enhanced therapy. Strong evidence was provided that GdCA or GdNPs could both be used for radiation dose-enhancement therapy. There in vivo biological distribution, in the tumor volume and at the cellular scale, will be the key factor for providing large dose enhancements and determine their therapeutic efficacy. PMID- 28886213 TI - Prospective study of the effect of maternal body mass index on labor progress in nulliparous women in Egypt. AB - OBJECTIVE: To evaluate the impact of maternal body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) on labor progress in nulliparous women. METHODS: The present prospective cohort study enrolled primigravidae admitted to Kasr Al Ainy hospital, Cairo University, Egypt, during active labor between February 1, 2016, and February 28, 2017. Patients were classified into three equal groups using their BMI at admission: underweight (<18.5), normal weight (18.5-29.9), and obese (>=30). The primary outcome was the rate of cervical dilatation; secondary outcomes included the duration of the second stage of labor, neonatal delivery weight, and the mode of delivery. RESULTS: Among the 600 primigravidae enrolled (200 in each group), significant differences were recorded in the rates of cervical dilatation (P<0.001), and the duration of the active labor phase (P<0.001) and the whole of labor (P<0.001); in the obese group, the cervical dilatation rate was lowest and the durations of the active phase of labor and the whole of labor were longer. The incidence of intrapartum cesarean delivery (P<0.001) and neonatal delivery weight (P<0.001) also differed between the groups; both were highest in the obese group. CONCLUSIONS: Patterns in labor progress, including cervical dilatation rate and labor duration, differed among patients with different BMI. ClinicalTrials.gov: NCT02686073. PMID- 28886214 TI - Suicidal Decapitation by Hanging-A Population-based Study. AB - A prospective study was undertaken at Forensic Science SA over a 15-year period from July 2002 to June 2017 for all cases of adult (>18 years) suicidal hangings with decapitation. A total of 1446 cases of suicidal hangings were identified from a general population of approximately 1.5 million (1206 males-age range 18 97 years, average 42.6; and 240 females-age range 18-96 years, average 40.1). Only three cases of decapitation were found, all from long-drop hangings; these consisted of three males (ages 32-55 years; average 45 years). Spinal transections had occurred between the first and second, second and third, and third and fourth cervical vertebrae, respectively. In this study, the number of suicidal hangings with decapitation represented only 0.2% of the total number of hangings. These events are therefore extremely rare, most likely due to most suicidal hangings occurring from relatively low levels in a domestic environment. PMID- 28886215 TI - Clinical, histological and immunohistochemical markers of resistance to methyl aminolaevulinate photodynamic therapy in Bowen disease. PMID- 28886216 TI - Identification of 1-(2,3-dihydro-1H-inden-5-yl)-2-(ethylamino)pentan-1-one (bk IVP) in a Seized Drug Exhibit. AB - To circumvent the law by evading regulation and obscuring their identities in routine analyses, numerous substituted cathinones have entered the illicit drug market. These compounds have been coined "bath salts" by users. In the described case, the laboratory received an unknown white powder for controlled substances identification. The sample could not be immediately identified using standard methods and procedures. Ultimately, the structure was elucidated using GC-MS, NMR, FTIR, GC-SPIR, UV, and color tests to be 1-(2,3-dihydro-1H-inden-5-yl)-2 (ethylamino)pentan-1-one (bk-IVP), a cathinone analog with a rarely observed nonoxygenated bicyclic ring system. Features of spectra and chemical tests are reported that distinguish this class of cathinones from heterocyclic analogs. PMID- 28886217 TI - Analysis of restricted mean survival time for length-biased data. AB - In clinical studies with time-to-event outcomes, the restricted mean survival time (RMST) has attracted substantial attention as a summary measurement for its straightforward clinical interpretation. When the data are subject to length biased sampling, which is frequently encountered in observational cohort studies, existing methods to estimate the RMST are not applicable. In this article, we consider nonparametric and semiparametric regression methods to estimate the RMST under the setting of length-biased sampling. To assess the covariate effects on the RMST, a semiparametric regression model that directly relates the covariates and the RMST is assumed. Based on the model, we develop unbiased estimating equations to obtain consistent estimators of covariate effects by properly adjusting for informative censoring and length bias. Stochastic process theories are used to establish the asymptotic properties of the proposed estimators. We investigate the finite sample performance through simulations and illustrate the methods by analyzing a prevalent cohort study of dementia in Canada. PMID- 28886218 TI - CRISPR/Cpf1 enables fast and simple genome editing of Saccharomyces cerevisiae. AB - Cpf1 represents a novel single RNA-guided CRISPR/Cas endonuclease system suitable for genome editing with distinct features compared with Cas9. We demonstrate the functionality of three Cpf1 orthologues - Acidaminococcus spp. BV3L6 (AsCpf1), Lachnospiraceae bacterium ND2006 (LbCpf1) and Francisella novicida U112 (FnCpf1) for genome editing of Saccharomyces cerevisiae. These Cpf1-based systems enable fast and reliable introduction of donor DNA on the genome using a two-plasmid based editing approach together with linear donor DNA. LbCpf1 and FnCpf1 displayed editing efficiencies comparable with the CRISPR/Cas9 system, whereas AsCpf1 editing efficiency was lower. Further characterization showed that AsCpf1 and LbCpf1 displayed a preference for their cognate crRNA, while FnCpf1-mediated editing with similar efficiencies was observed using non-cognate crRNAs of AsCpf1 and LbCpf1. In addition, multiplex genome editing using a single LbCpf1 crRNA array is shown to be functional in yeast. This work demonstrates that Cpf1 broadens the genome editing toolbox available for Saccharomyces cerevisiae. (c) 2017 The Authors. Yeast published by John Wiley & Sons, Ltd. PMID- 28886219 TI - Comparison of outcomes of kidney transplantation from donation after brain death, donation after circulatory death, and donation after brain death followed by circulatory death donors. AB - BACKGROUND: There are three categories of deceased donors of kidney transplantation in China, donation after brain death (DBD), donation after circulatory death (DCD), and donation after brain death followed by circulatory death (DBCD) donors. The aim of this study was to compare the outcomes of kidney transplantation from these three categories of deceased donors. METHODS: We retrospectively reviewed 469 recipients who received deceased kidney transplantation in our hospital from February 2007 to June 2015. The recipients were divided into three groups according to the source of their donor kidneys: DBD, DCD, or DBCD. The primary endpoints were delayed graft function (DGF), graft loss, and patient death. RESULTS: The warm ischemia time was much longer in DCD group compared to DBCD group (18.4 minutes vs 12.9 minutes, P < .001). DGF rate was higher in DCD group than in DBD and DBCD groups (22.5% vs 10.2% and 13.8%, respectively, P = .021). Urinary leakage was much higher in DCD group (P = .049). Kaplan-Meier analysis showed that 1-, 2-, and 3-year patient survivals were all comparable among the three groups. CONCLUSION: DBCD kidney transplantation has lower incidences of DGF and urinary leakage than DCD kidney transplant. However, the overall patient and graft survival were comparable among DBD, DCD, and DBCD kidney transplantation. PMID- 28886220 TI - Anti-inflammatory effects of polyphenols in arthritis. AB - Polyphenols have been extensively investigated with regard to their antioxidant, anti-inflammatory, and immunomodulant properties in many inflammatory chronic conditions. The aim of this review is to summarise how these compounds can modulate the inflammatory pathways which characterise the most prevalent arthropathies including osteoarthritis, rheumatoid arthritis and crystal-induced arthritis. Among polyphenols, epigallocatechin gallate, carnosol, hydroxytyrosol, curcumin, resveratrol, kaempferol and genistein have been the most widely investigated in arthritis. The most important results of the studies outlined in this article show how polyphenolic compounds are able to inhibit the expression and the release of a number of pro-inflammatory mediators and proteolytic enzymes, the activity of different transcriptional factors and the production of reactive oxygen species in vitro. Studies on animal models of rheumatoid arthritis, osteoarthritis and gout show interesting results in terms of reduced tissue damage, restored cartilage homeostasis, and decreased levels of uric acid, respectively. Despite the multiple protective effects of polyphenols, there are no dietary recommendations for patients affected by rheumatic diseases. Future studies, including intervention trials, should be conducted to determine the relevance of polyphenols consumption or supplementation in arthritis. (c) 2017 Society of Chemical Industry. PMID- 28886221 TI - An Improved Version of a Tool Mark Comparison Algorithm. AB - Chumbley et al. (2010) described a statistically based algorithm for comparing pairs of tool marks. They presented empirical evidence that the algorithm produces well-separated similarity score values for "matching" and "non-matching" pairs of tool marks. However, the algorithm has two substantial weaknesses. First, it is "uncalibrated" in the sense that error rates can be determined only through empirical investigation. Second, it relies on a randomized test and can lead to different similarity scores when the algorithm is repeatedly applied to the same pair of tool marks. We present an improved version of the procedure, which eliminates the randomized scores and yields more consistent and predictable error rate control. This is accomplished by replacement of a random sampling step from the original algorithm with a deterministic process. We demonstrate the improved algorithm and compare its performance to the original by applying to known "matching" and "non-matching" pairs of tool marks. PMID- 28886222 TI - Polyclonal hyperglobulinaemia and elevated acute-phase reactants in hidradenitis suppurativa. PMID- 28886223 TI - Open standing castration in Thoroughbred racehorses in Hong Kong: Prevalence and severity of complications 30 days post-castration. AB - BACKGROUND: Complications following open standing castration (OSC) in Thoroughbred racehorses are well recognised but variation in their prevalence and severity between populations is not well documented. OBJECTIVES: To describe the prevalence and severity of complications in the 30 days following OSC. STUDY DESIGN: A retrospective cohort study of veterinary clinical records relating to horses that underwent OSC between July 2007 and July 2012. METHODS: Complications were graded on a severity score from N, no complications, to C3, severe complications. Additional data were accessed for each horse including age, import date, racing history, trainer and veterinarian performing the castration. Bacterial culture and antimicrobial sensitivities were performed on a limited number of castration wounds that became infected. RESULTS: In total, 250 horses were castrated in Hong Kong using the OSC technique over the period of the study. Sixty percent (150/250) of horses experienced some type of post-castration complication, with eight horses experiencing a severe (C3) complication requiring intensive veterinary treatment. Scrotal swelling, funiculitis and seroma formation were present in 70.0%, 36.7% and 24.7% of cases respectively. Most horses experiencing complications required wound reopening (87.3%; 131/150), and/or an extended course of first-line antimicrobials and/or nonsteroidal anti inflammatory drugs (75/150; 50.0%). Eight horses had cultures submitted for bacterial sensitivity, with 17 bacterial isolates grown. In vitro, the bacteria cultured were sensitive to enrofloxacin (76%; 13/17) and ceftiofur (100%; 17/17). Resistance was detected to penicillin, gentamicin, oxytetracycline, metronidazole and trimethoprim-sulfadiazine. MAIN LIMITATIONS: Differences in post-castration management cannot be accounted for in this study. CONCLUSIONS: Complications following OSC in horses in Hong Kong were common. The majority were mild and were successfully treated using antimicrobials and simple wound management. Given the high rate of complications and antimicrobial usage identified in this study, a review of the technique is warranted. PMID- 28886224 TI - Variation in dermoscopic features of basal cell carcinoma as a function of anatomical location and pigmentation status. PMID- 28886225 TI - The Role of Forensic Botany in Solving a Case: Scientific Evidence on the Falsification of a Crime Scene. AB - Forensic botany can provide useful information for pathologists, particularly on crime scene investigation. We report the case of a man who arrived at the hospital and died shortly afterward. The body showed widespread electrical lesions. The statements of his brother and wife about the incident aroused a large amount of suspicion in the investigators. A crime scene investigation was carried out, along with a botanical morphological survey on small vegetations found on the corpse. An autopsy was also performed. Botanical analysis showed some samples of Xanthium spinosum, thus leading to the discovery of the falsification of the crime scene although the location of the true crime scene remained a mystery. The botanical analysis, along with circumstantial data and autopsy findings, led to the discovery of the real crime scene and became crucial as part of the legal evidence regarding the falsity of the statements made to investigators. PMID- 28886226 TI - A systematic review and meta-analysis on fetal ovarian cysts: impact of size, appearance and prenatal aspiration. AB - OBJECTIVE: The objective of the study is to compare outcomes of ultrasound-guided aspiration of fetal ovarian cysts with conservative management. METHOD: A systematic review of MEDLINE and Web of Science included studies reporting outcomes (prenatal and postnatal torsion, spontaneous resolution and surgery) of fetuses with ovarian cysts. Subgroup analysis was performed according to cyst diameter at diagnosis and cysts >=40 mm. RESULTS: Ninety-two non-randomised studies reported on 380 cysts (324 observed and 56 aspirated in utero) in 365 fetuses. All studies were case reports or series with high heterogeneity and risk of bias. The overall spontaneous resolution rate of conservatively managed cysts was 46%, yet decreased with increasing cyst size. Risk of prenatal ovarian torsion in conservatively managed cases depended on cyst size and was particularly important in the range 30 to 59 mm (15-34%). The rate of prenatal torsion in simple cysts >=40 mm was lower in aspirated than conservatively managed cysts (0% vs 10%, p = 0.03). Aspirated cysts had lower rates of postnatal surgery (7%) compared with conservatively managed cysts (49%, p < 0.001). CONCLUSION: Cysts 30 to 59 mm were at highest risk of torsion. Simple cysts >40 mm had lower rates of torsion when aspirated prenatally. Randomised studies and safety data are needed prior to routine prenatal ovarian cyst aspiration. (c) 2017 John Wiley & Sons, Ltd. PMID- 28886227 TI - Lung transplantation in cystic fibrosis patients in Israel: The importance of ethnicity and nutritional status. AB - OBJECTIVES: To assess the characteristics that correlate with better outcomes after lung transplantation for patients with cystic fibrosis (CF). METHODS: We retrospectively reviewed the charts of all patients with CF who underwent lung transplantation between 1996 and 2014 at Rabin Medical Center, Israel. RESULTS: Fifty patients with CF underwent 55 lung transplantations. Eighteen patients (36%) died during the study period. Actuarial survival was 83%, 68%, 62%, and 39% at 1, 3, 5, and 10 years, respectively. Better survival correlated with: BMI at 6 months and 1 year after transplantation (P = .002 and P = .003, respectively), ischemic time of less than 300 minutes (P = .023), absence of liver disease (P = .012), and Jewish compared to Arab ethnicity (P = .007). Freedom from bronchiolitis obliterans syndrome (BOS) was 87%, 75%, and 72% at 1, 3, and 5 years, respectively. BOS was more common and appeared earlier in the Arab than in the Jewish population (P = .012, P = .007). Additionally, prolonged time free of BOS correlated with male gender (P = .039), older age (P < .001), absence of liver disease (P = .012), and higher BMI 1 year after transplantation (P < .001). CONCLUSIONS: Clinically important determinants for survival include BMI pre- and 1-year post-transplantation and improved freedom from BOS. Arab ethnicity correlated with higher incidence and earlier onset of BOS compared to Jewish ethnicity in Israel. PMID- 28886228 TI - The serum heavy/light chain immunoassay: A valuable tool for sensitive paraprotein assessment, risk, and disease monitoring in monoclonal gammopathies. AB - OBJECTIVE: The heavy/light chain (HLC)-immunoassay quantifies light chain types of each immunoglobulin class in patients with monoclonal gammopathies. METHODS: We assessed 147 consecutive patients with different forms and stages of plasma cell dyscrasias (PCD) who received standard tests (serum and urine protein electrophoresis [SPEP, UPEP], immunofixation [IFE], serum-free light chain [SFLC]), and HLC-immunoassay. Patients with multiple myeloma (MM, n = 102), smoldering MM (SMM, n = 5), monoclonal gammopathy of undetermined significance (MGUS, n = 28), and Waldenstrom's macroglobulinemia (WM, n = 12) were included. RESULTS: We verified a significant correlation between HLC- and standard monoclonal protein (mp)-parameters, and HLC-increases with higher disease stage and unfavorable remission status. In patients with difficult to quantify mp, more abnormal HLC- than SPEP-, immunoglobulin-, or SFLC-results were found. In WM, a pathological HLC kappa/lambda-ratio and M-component were observed in 95% and 58%, respectively. In 21/28 MGUS and 5/5 SMM patients, HLC kappa/lambda-ratios were abnormal. Testing different HLC cutoffs, patients with extreme HLC values showed impaired progression-free survival (PFS). CONCLUSIONS: Despite the fact that different PCD patients were included, the assessment of the HLC-immunoassay in MGUS, SMM, MM, and WM, our comparison with standard mp-assays, and relevant PFS differences may excite future applications, which should be confirmed in prospective multicenter trials. PMID- 28886229 TI - Structural insight into a partially unfolded state preceding aggregation in an intracellular lipid-binding protein. AB - Human ileal bile acid-binding protein (I-BABP) has a key role in the intracellular transport and metabolic targeting of bile salts. Similar to other members of the family of intracellular lipid-binding proteins (iLBPs), disorder order transitions and local unfolding processes are thought to mediate ligand entry and release in human I-BABP. To gain insight into the stability of various protein regions, the temperature response of human I-BABP was investigated using NMR, CD and fluorescence spectroscopy, as well as molecular dynamics (MD) simulations. A joint analysis of NMR thermal melting and relaxation dispersion data indicates a complex pattern of internal dynamics with a dominating single barrier and a likely presence of rapidly exchanging conformational substates on both sides of the barrier. Moreover, our residue-specific analysis uncovers a partially unfolded U* state in which part of the helical region with three proximate beta-strands contains a substantial amount of residual structure, whereas several segments of the C-terminal half exhibit a high susceptibility to temperature elevation. Cluster analysis of atomic temperature responses indicates a thermodynamic coupling between distant protein sites including the bottom of the beta-barrel, the E-F region and part of the helical cap. MD simulations up to 1 MUs show correlated motions in the same protein regions and together with the NMR data suggest a role for the highly dynamic D-E turn and E-F region in the initiation of unfolding. The response of human I-BABP to temperature elevation is discussed in the context of the folding/unfolding behaviour of different members of the iLBP family. PMID- 28886230 TI - Lipoprotein particle concentration measured by nuclear magnetic resonance spectroscopy is associated with gestational age at delivery: a prospective cohort study. AB - OBJECTIVE: To estimate the association between lipoprotein particle concentrations in pregnancy and gestational age at delivery. DESIGN: Prospective cohort study. SETTING: The study was conducted in the USA at the University of North Carolina. POPULATION: We assessed 715 women enrolled in the Pregnancy, Infection, and Nutrition study from 2001 to 2005. METHODS: Fasting blood was collected at two time points (<20 and 24-29 weeks of gestation). Nuclear magnetic resonance (NMR) quantified lipoprotein particle concentrations [low-density lipoprotein (LDL), high-density lipoprotein (HDL), very-low density lipoprotein (VLDL)] and 10 subclasses of lipoproteins. Concentrations were assessed as continuous measures, with the exception of medium HDL which was classified as any or no detectable level, given its distribution. Cox proportional hazards models estimated hazard ratios (HR) for gestational age at delivery adjusting for covariates. MAIN OUTCOME MEASURES: Gestational age at delivery, preterm birth (<37 weeks of gestation), and spontaneous preterm birth. RESULTS: At <20 weeks of gestation, three lipoproteins were associated with later gestational ages at delivery [large LDLNMR (HR 0.78, 95% CI 0.64-0.96), total VLDLNMR (HR 0.77, 95% CI 0.61-0.98), and small VLDLNMR (HR 0.78, 95% CI 0.62-0.98], whereas large VLDLNMR (HR 1.19, 95% CI 1.01-1.41) was associated with a greater hazard of earlier delivery. At 24-28 weeks of gestation, average VLDLNMR (HR 1.25, 95% CI 1.03-1.51) and a detectable level of medium HDLNMR (HR 1.90, 95% CI 1.19-3.02) were associated with earlier gestational ages at delivery. CONCLUSION: In this sample of pregnant women, particle concentrations of VLDLNMR , LDLNMR , IDLNMR , and HDLNMR were each independently associated with gestational age at delivery for all deliveries or spontaneous deliveries <37 weeks of gestation. These findings may help formulate hypotheses for future studies of the complex relationship between maternal lipoproteins and preterm birth. TWEETABLE ABSTRACT: Nuclear magnetic resonance spectroscopy may identify lipoprotein particles associated with preterm delivery. PMID- 28886231 TI - Gadoxetic acid disodium-enhanced magnetic resonance imaging outperformed multidetector computed tomography in diagnosing small hepatocellular carcinoma: A meta-analysis. AB - Early detection of small hepatocellular carcinoma (HCC) lesions can improve longterm patient survival. A systematic review and meta-analysis of the diagnostic performance of gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and multidetector computed tomography (MDCT) was performed in diagnosing small HCCs measuring up to 2 cm (<=2 cm). Two investigators searched multiple databases for studies in which the performances of either Gd-EOB-DTPA-enhanced MRI or MDCT were reported with sufficient data to construct 2 * 2 contingency tables for diagnosing HCCs up to 2 cm on a per-lesion or per-patient level. Diagnostic performances were quantitatively pooled by a bivariate random-effect model with further meta-regression and subgroup analyses. A total of 27 studies (14 on Gd-EOB-DTPA-enhanced MRI, 9 on MDCT, and 4 on both) were included, enrolling a total of 1735 patients on Gd-EOB-DTPA-enhanced MRI and 1781 patients on MDCT. Gd-EOB-DTPA-enhanced MRI demonstrated significantly higher overall sensitivity than did MDCT (0.96 versus 0.65; P < 0.01), without substantial loss of specificity (0.94 versus 0.98; P > 0.05). Area under the summary receiver operating characteristic curve was 0.97 with Gd-EOB-DTPA enhanced MRI and 0.85 with MDCT. Regarding Gd-EOB-DTPA-enhanced MRI, sensitivity was significantly higher for studies from non-Asian countries than Asian countries (0.96 versus 0.93; P < 0.01), for retrospective studies than prospective studies (0.95 versus 0.91; P < 0.01), and for those with Gd-EOB-DTPA injection rate >= 1.5 mL/s than that of <1.5 mL/s (0.97 versus 0.90; P < 0.01). In conclusion, Gd-EOB-DTPA-enhanced MRI demonstrated higher sensitivity and overall diagnostic accuracy than MDCT, and thus should be the preferred imaging modality for diagnosing small HCCs measuring up to 2 cm. Liver Transplantation 23 1505-1518 2017 AASLD. PMID- 28886232 TI - What type of rigorous experiments are needed to investigate the impact of artificial light at night on individuals and populations? PMID- 28886233 TI - Mistrust of physicians in China: society, institution, and interaction as root causes. AB - Based on two years' ethnographic research on doctor-patient relations in urban China, this paper examines the causes of patients' mistrust of physicians. I identify the major factors at the societal, institutional, and interpersonal levels that lead to patients' mistrust of physicians. First, I set the context by describing the extent of mistrust at the societal level. Then, I investigate the institutional sources of mistrust. I argue that the financing mechanism of public hospitals and physicians' income structures are the most crucial factors in inducing patients' mistrust. Hospitals' heavy reliance on self-finance has basically caused public hospitals to run like private hospitals, resulting in blatant conflicts of interest between hospitals and patients. Related to this is physicians' reliance on bonuses and commissions as part of their regular incomes, which has inevitably resulted in overtreatment and, hence, mistrust from the patients. At the interpersonal level, I describe how individual physicians' attitudes toward and interaction with patients may also affect patients' sense of trust or mistrust in physicians. In conclusion, I discuss the ethical implications of the mistrust problem, and suggest changes at the institutional and interpersonal levels to mitigate the problem. PMID- 28886235 TI - In the search for a lead structure among series of potent and selective hydantoin 5-HT7 R agents: The drug-likeness in vitro study. AB - Since the year 1993, when 5-HT7 receptor (5-HT7 R) was discovered, there is no selective 5-HT7 R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5-HT7 R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by "drug-likeness" estimation of the first series of selective and potent 5-HT7 R ligands among 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4 aryl-piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione derivatives (11-16). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test (FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2. The experiments showed promising drug like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13. The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant like activity in the FST. Taking into account the beneficial properties of 13, i.e., good drug-like parameters, the significant antagonistic action, high selectivity to 5-HT7 R, and its in vivo antidepressant-like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5-HT7 receptor. PMID- 28886236 TI - Waldenstrom's macroglobulinemia: Two malignant clones in a monoclonal disease? Molecular background and clinical reflection. AB - Waldenstrom's macroglobulinemia (WM) is a complex disease characterized by apparent morphological heterogeneity within the malignant clonal cells representing a continuum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. At the molecular level, the neoplastic B cell-derived clone has undergone somatic hypermutation, but not isotype switching, and retains the capability of plasmacytic differentiation. Although by classical definition, WM is formed by monoclonal expansion, long-lived clonal B lymphocytes are of heterogeneous origin. Even more, according to current opinion, plasma cells also conform certain population with pathogenic and clinical significance. In this article, we review the recent advances in the WM clonal architecture, briefly describe B-cell development during which the molecular changes lead to the malignant transformation and mainly focus on differences between two principal B lineage clones, including analysis of their genome and transcriptome profiles, as well as immunophenotype features. We assume that the correct identification of a number of specific immunophenotypic molecular and expression alterations leading to proper aberrant clone detection can help to guide patient monitoring throughout treatment and successfully implement therapy strategies directed against both B- and plasma cell tumor WM clones. PMID- 28886237 TI - Synthesis, quality control, and bio-evaluation of 99m Tc-cyclophosphamide. AB - Cancer is found to be the leading cause of death worldwide characterized by uncontrolled cell division. Nuclear medicines imaging using radiopharmaceuticals have pronounced potential for the diagnosis and treatment of cancers. Cyclophosphamide (CPH) is an antineoplastic drug which targets selectively cancer cells. In the present work, labeling of CPH with Tc-99m is performed for diagnostic purpose, which gave labeling yield as high as 99% using 20 MUg SnCl2 .2H2 O, 200 MUg of ligand at pH 7 for 10 min reaction time at room temperature. The characterization of the prepared complex was performed using ITLC, electrophoresis, and HPLC. In vitro stability was analyzed in the presence of human serum at 37 degrees C which has maximum value of 94 +/- 0.5. The biodistribution studies of 99m Tc-CPH were performed in normal and tumor bearing Swiss Webster mice. The high accumulation of 99m Tc-CPH was observed in liver and tumours respectively at 4 hr after injection. Biodistribution results revealed that 99m Tc-CPH may be a potential tumour diagnostic agent simultaneously with chemotherapy. PMID- 28886238 TI - SIRT7 deacetylates DDB1 and suppresses the activity of the CRL4 E3 ligase complexes. AB - Cullin 4 (CUL4) and small ring finger protein ROC1 assemble to form E3 ubiquitin ligase (CRL4) complexes. CUL4 interacts with WD-40 proteins through the adaptor protein DNA damage-binding protein 1 (DDB1) to target substrates for ubiquitylation. Very little is known on how the CUL4 and DDB1 interaction is regulated. Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction. Following inhibition of nucleolar function by actinomycin D or 5-fluorouracil treatment or knocking down the gene for the RNA polymerase I component UBF, SIRT7 is mobilized from the nucleolus to the nucleoplasm and promotes DDB1 deacetylation, leading to decreased DDB1-CUL4 association and CRL4 activity. This results in the accumulation or activation of CRL4 substrates including LATS1 and p73, which contribute to cell apoptosis induced by actinomycin D and 5-fluorouracil. Our study uncovers a novel regulation of CRL4 E3 ligase complexes. PMID- 28886239 TI - Terminal Alkyne Coupling on a Corrugated Noble Metal Surface: From Controlled Precursor Alignment to Selective Reactions. AB - Surface-templated covalent coupling of organic precursors currently emerges as a promising route to the atom-precise fabrication of low-dimensional carbon materials. Here, we investigate the adsorption and the coupling reactions of 4,4''-diethynyl-1,1':4',1''-terphenyl on Au(110) under ultra-high vacuum conditions by using scanning tunneling microscopy combined with density functional theory and kinetic Monte Carlo calculations. Temperature treatment induces both 1,2,4-asymmetric cyclotrimerization and homocoupling, resulting in various reaction products, including a previously unreported, surface-templated H shaped pentamer. Our analysis of the temperature-dependent relative product abundances unravels that 1,2,4-trimerization and homocoupling proceed via identical intermediate species with the final products depending on the competition of coupling to a third monomer versus dehydrogenation. Our study sheds light on the control of coupling reactions by corrugated surfaces and annealing protocols. PMID- 28886240 TI - A review of diffusion MRI of typical white matter development from early childhood to young adulthood. AB - Understanding typical, healthy brain development provides a baseline from which to detect and characterize brain anomalies associated with various neurological or psychiatric disorders and diseases. Diffusion MRI is well suited to study white matter development, as it can virtually extract individual tracts and yield parameters that may reflect alterations in the underlying neural micro-structure (e.g. myelination, axon density, fiber coherence), though it is limited by its lack of specificity and other methodological concerns. This review summarizes the last decade of diffusion imaging studies of healthy white matter development spanning childhood to early adulthood (4-35 years). Conclusions about anatomical location, rates, and timing of white matter development with age are discussed, as well as the influence of image acquisition, analysis, age range/sample size, and statistical model. Despite methodological variability between studies, some consistent findings have emerged from the literature. Specifically, diffusion studies of neurodevelopment overwhelmingly demonstrate regionally varying increases of fractional anisotropy and decreases of mean diffusivity during childhood and adolescence, some of which continue into adulthood. While most studies use linear fits to model age-related changes, studies with sufficient sample sizes and age range provide clear evidence that white matter development (as indicated by diffusion) is non-linear. Several studies further suggest that maturation in association tracts with frontal-temporal connections continues later than commissural and projection tracts. The emerging contributions of more advanced diffusion methods are also discussed, as they may reveal new aspects of white matter development. Although non-specific, diffusion changes may reflect increases of myelination, axonal packing, and/or coherence with age that may be associated with changes in cognition. PMID- 28886241 TI - Mentha suaveolens Ehrh. Chemotypes in Eastern Iberian Peninsula: Essential Oil Variation and Relation with Ecological Factors. AB - Essential oil (EO) extracts coming from two representative populations of Mentha suaveolens Ehrh. subesp. suaveolens in Eastern Iberian Peninsula were analyzed by gas chromatography coupled with mass spectrometry and flame ion detector. Plant sampling was carried out in the morning and evening in order to study diurnal variation in EO profiles. Likewise, leaves and inflorescences were analyzed separately. Two chemotypes corresponding to each one of the populations were identified, with piperitenone oxide (35.2 - 74.3%) and piperitone oxide (83.9 - 91.3%), respectively, as major compounds. Once different chemotypes were identified, canonical correspondence analysis was employed to evaluate the effect of the bioclimatic and edaphic factors recorded in each location on the observed differences. Statistical analysis suggested that these chemotypes were closely related to specific environmental factors, mainly the bioclimatic ones. Concretely, piperitenone oxide chemotype can be associated to supramediterranean bioclimatic conditions and soils with major salinity and water field capacity. On the other hand, the most volatile fraction (hydrocarbon monoterpenes) reached its higher level in the morning; specifically, a noticeable amount of limonene was found in morning samples of flowers (4.8 - 10.6%). This fact can be related to ecological role of volatile compounds in order to attract pollinator insects. PMID- 28886242 TI - Synthesis of Size-Tunable CO2-Philic Imprinted Polymeric Particles (MIPs) for Low Pressure CO2 Capture Using Oil-in-Oil Suspension Polymerization. AB - Highly selective molecularly imprinted poly[acrylamide-co-(ethylene glycol dimethacrylate)] polymer particles (MIPs) for CO2 capture were synthesized by suspension polymerization via oil-in-oil emulsion. Creation of CO2-philic, amide decorated cavities in the polymer matrix led to a high affinity to CO2. At 0.15 bar CO2 partial pressure, the CO2/N2 selectivity was 49 (corresponding to 91% purity of the gas stream after regeneration), and reached 97 at ultralow CO2 partial pressures. The imprinted polymers showed considerably higher CO2 uptakes compared to their nonimprinted counterparts, and the maximum equilibrium CO2 capture capacity of 1.1 mmol g-1 was achieved at 273 K. The heat of adsorption was below 32 kJ mol-1 and the temperature of onset of intense thermal degradation was 351-376 degrees C. An increase in monomer-to-cross-linker molar ratio in the dispersed phase up to 1:2.5 led to a higher affinity toward CO2 due to higher density of selective amide groups in the polymer network. MIPs are a promising option for industrial packed and fluidized bed CO2 capture systems due to large particles with a diameter up to 1200 MUm and irregular oblong shapes formed due to arrested coalescence during polymerization, occurring as a result of internal elasticity of the partially polymerized semisolid drops. PMID- 28886243 TI - Enantioselective Synthesis of 1,3-Disubstituted 1,3-Dihydroisobenzofurans via a Cascade Allylboration/Oxo-Michael Reaction of o-Formyl Chalcones Catalyzed by a Chiral Phosphoric Acid. AB - The first chiral Bronsted acid-catalyzed asymmetric cascade allylboration/oxo Michael reaction between o-formyl chalcones and allylboronate has been successfully discovered, which afforded chiral 1,3-disubstituted 1,3 dihydroisobenzofurans with a yield, diastereoselective ratio (dr) and enantioselective excess (ee) up to 94%, 2.5:1, and 98%, respectively. In addition, 2,3-dienylboronic pinacol ester was also applied into this cascade reaction with good catalytic results. PMID- 28886234 TI - Validation of the MASK-rhinitis visual analogue scale on smartphone screens to assess allergic rhinitis control. AB - BACKGROUND: Visual Analogue Scale (VAS) is a validated tool to assess control in allergic rhinitis patients. OBJECTIVE: The aim of this study was to validate the use of VAS in the MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) app (Allergy Diary) on smartphones screens to evaluate allergic rhinitis symptoms and disease control. METHODS: Each user filled 4 different VAS measuring overall, nasal, ocular, and asthma symptoms at least once. Following COSMIN guidelines, we evaluated internal consistency, (Cronbach's alpha coefficient and test-retest), reliability (intraclass correlation coefficients), sensitivity, and acceptability of the MASK-Rhinitis VAS. RESULTS: Between 1 August 2015 and 31 July 2016, the app was used 14 612 times in 15 countries. A total of 1225 users used it more than once, during the evaluated period. The tool resulted to be statistically satisfactory, showing excellent internal consistency (Cronbach's test > 0.84, test-retest > 0.7), reliability (>0.9), and acceptability. In addition, the tool had a good sensitivity when users (n = 521) answered the VAS twice in less than 3 hours. CONCLUSIONS AND CLINICAL RELEVANCE: The MASK-rhinitis VAS is a reliable and valid tool to assess allergic control on smartphone screens, at the population level. PMID- 28886244 TI - Full Protein Sequence Redesign with an MMGBSA Energy Function. AB - Computational protein design aims to create proteins with novel properties. A key element is the energy or scoring function used to select the sequences and conformations. We study the performance of an "MMGBSA" energy function, which combines molecular mechanics terms, a generalized Born and surface area (GBSA) solvent model, with approximations that make the model pairwise additive. Our approach is implemented in the Proteus software. The use of a physics-based energy function ensures a certain model transferability and explanatory power. As a first test, we redesign the sequence of nine proteins, one position at a time, with the rest of the protein having its native sequence and crystallographic conformation. As a second test, all positions are designed together. The contributions of individual energy terms are evaluated, and various parametrizations are compared. We find that the GB term significantly improves the results compared to simple Coulomb electrostatics but is affected by pairwise decomposition errors when all positions are designed together. The SA term, with distinct energy coefficients for nonpolar and polar atoms, makes a decisive contribution to obtain realistic protein sequences and can partially compensate for the absence of a GB term. With the best GBSA protocol, we obtain nativelike protein cores and Superfamily recognition of almost all of our sequences. PMID- 28886245 TI - Triquinanes and Related Sesquiterpenes Revisited Computationally: Structure Corrections of Hirsutanols B and D, Hirsutenol E, Cucumin B, Antrodins C-E, Chondroterpenes A and H, Chondrosterins C and E, Dichrocephone A, and Pethybrene. AB - NMR data for 90+ natural sesquiterpenes possessing triquinane cores were examined with the help of a relatively fast parametric/DFT hybrid computational method, DU8+. Thirteen of these compounds, i.e., approximately 14% of the sample, required structure correction. This rate of misassignment is similar to the percentage of misassigned halogenated sesquiterpenes reported previously. PMID- 28886246 TI - An Anion-pi Interaction Strongly Stabilizes the beta-Sheet Protein WW. AB - Anions have long been known to engage in stabilizing interactions with electron deficient arenes. However, the precise nature and energetic contribution of anion pi interactions to protein stability remains a subject of debate. Here, we show that placing a negatively charged Asp in close proximity to electron-rich Phe in a reverse turn within the WW domain results in a favorable interaction that increases WW conformational stability by -1.3 kcal/mol. PMID- 28886248 TI - Application of real-time PCR (qPCR) for characterization of microbial populations and type of milk in dairy food products. AB - Dairy foods represent an important sector of the food market for their nutritional qualities and their organoleptic characteristics, which are often linked to tradition and to region. These products are typically protected by labels such as PDO (Protected Designation of Origin) and PGI (Protected Geographical Indication). Real-time PCR (qPCR) is a fundamental tool in "Food Genomics;" a discipline concerned with the residual DNA in food, which, alongside traditional physical and chemical methods, is frequently used to determine product safety, quality and authenticity. Compared to conventional or "end-point" PCR, qPCR incorporates continuous monitoring of reaction progress, thereby enabling quantification of target DNA. This review describes qPCR applications to the analysis of microbiota, and to the identification of the animal species source of milk from which dairy products have been made. These are important aspects for ensuring safety and authenticity. The various applications of qPCR are discussed, as well as advantages and disadvantages in comparison with other analytical methods. PMID- 28886247 TI - H-Ferritin Enriches the Curcumin Uptake and Improves the Therapeutic Efficacy in Triple Negative Breast Cancer Cells. AB - Triple negative breast cancer (TNBC) is a highly aggressive, invasive, and metastatic tumor. Although it is reported to be sensitive to cytotoxic chemotherapeutics, frequent relapse and chemoresistance often result in treatment failure. In this study, we developed a biomimetic nanodrug consisting of a self assembling variant (HFn) of human apoferritin loaded with curcumin. HFn nanocage improved the solubility, chemical stability, and bioavailability of curcumin, allowing us to reliably carry out several experiments in the attempt to establish the potential of this molecule as a therapeutic agent and elucidate the mechanism of action in TNBC. HFn biopolymer was designed to bind selectively to the TfR1 receptor overexpressed in TNBC cells. HFn-curcumin (CFn) proved to be more effective in viability assays compared to the drug alone using MDA-MB-468 and MDA MB-231 cell lines, representative of basal and claudin-low TNBC subtypes, respectively. Cellular uptake of CFn was demonstrated by flow cytometry and label free confocal Raman imaging. CFn could act as a chemosensitizer enhancing the cytotoxic effect of doxorubicin by interfering with the activity of multidrug resistance transporters. In addition, CFn exhibited different cell cycle effects on these two TNBC cell lines, blocking MDA-MB-231 in G0/G1 phase, whereas MDA-MB 468 accumulated in G2/M phase. CFn was able to inhibit the Akt phosphorylation, suggesting that the effect on the proliferation and cell cycle involved the alteration of PI3K/Akt pathway. PMID- 28886249 TI - Chronic 5-HT2 receptor blockade unmasks the role of 5-HT1F receptors in the inhibition of rat cardioaccelerator sympathetic outflow. AB - Serotonin (5-hydroxytryptamine; 5-HT) inhibits the rat cardioaccelerator sympathetic outflow by 5-HT1B/1D/5 receptors. Because chronic blockade of sympatho-excitatory 5-HT2 receptors is beneficial in several cardiovascular pathologies, this study investigated whether sarpogrelate (a 5-HT2 receptor antagonist) alters the pharmacological profile of the above sympatho-inhibition. Rats were pretreated for 2 weeks with sarpogrelate in drinking water (30 mg/kg per day; sarpogrelate-treated group) or equivalent volumes of drinking water (control group). Animals were pithed and prepared for spinal stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or for intravenous (i.v.) bolus injections of noradrenaline. Both procedures produced tachycardic responses remaining unaltered after saline. Continuous i.v. infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT receptor agonists 5 carboxamidotryptamine (5-CT; 5-HT1/5A), CP 93,129 (5-HT1B), or PNU 142633 (5 HT1D), but not by indorenate (5-HT1A) in both groups; whereas LY344864 (5-HT1F) mimicked 5-HT only in sarpogrelate-treated rats. In sarpogrelate-treated animals, i.v. GR 127935 (310 MUg/kg; 5-HT1B/1D/1F receptor antagonist) attenuated 5-CT induced sympatho-inhibition and abolished LY344864-induced sympatho-inhibition; while GR 127935 plus SB 699551 (1 mg/kg; 5-HT5A receptor antagonist) abolished 5 CT-induced inhibition. These results confirm the cardiac sympatho-inhibitory role of 5-HT1B, 5-HT1D, and 5-HT5A receptors in both groups; nevertheless, sarpogrelate treatment specifically unmasked a cardiac sympatho-inhibition mediated by 5-HT1F receptors. PMID- 28886251 TI - Iron influences on the Gut-Brain axis and development of type 2 diabetes. AB - BACKGROUND: Microbiota/neuroendocrine interactions with health and disease are increasingly recognized. Main Body: Aging is associated with progressive iron storage and development of type 2 diabetes, which impacts on brain microstructure and function, mainly in obese subjects. Iron status is also mutually influencing the composition of the gut microbiota, which in turn may affect cognition through the gut-brain axis. Short Conclusion: In this article we update the possible role of iron in all these interactions. PMID- 28886250 TI - Dectin-2 Is a C-Type Lectin Receptor that Recognizes Pneumocystis and Participates in Innate Immune Responses. AB - Pneumocystis is an important fungal pathogen that causes life-threatening pneumonia in patients with AIDS and malignancy. Lung fungal pathogens are recognized by C-type lectin receptors (CLRs), which bind specific ligands and stimulate innate immune responses. The CLR Dectin-1 was previously shown to mediate immune responses to Pneumocystis spp. For this reason, we investigated a potential role for Dectin-2. Rats with Pneumocystis pneumonia (PCP) exhibited elevated Dectin-2 mRNA levels. Soluble Dectin-2 carbohydrate-recognition domain fusion protein showed binding to intact Pneumocystis carinii (Pc) and to native Pneumocystis major surface glycoprotein/glycoprotein A (Msg/gpA). RAW macrophage cells expressing V5-tagged Dectin-2 displayed enhanced binding to Pc and increased protein tyrosine phosphorylation. Furthermore, the binding of Pc to Dectin-2 resulted in Fc receptor-gamma-mediated intracellular signaling. Alveolar macrophages from Dectin-2-deficient mice (Dectin-2-/-) showed significant decreases in phospho-Syk activation after challenge with Pc cell wall components. Stimulation of Dectin-2-/- alveolar macrophages with Pc components showed significant decreases in the proinflammatory cytokines IL-6 and TNF-alpha. Finally, during infection with Pneumocystis murina, Dectin-2-/- mice displayed downregulated mRNA expression profiles of other CLRs implicated in fungal immunity. Although Dectin-2-/- alveolar macrophages had reduced proinflammatory cytokine release in vitro, Dectin-2-/- deficiency did not reduce the overall resistance of these mice in the PCP model, and organism burdens were statistically similar in the long-term immunocompromised and short-term immunocompetent PCP models. These results suggest that Dectin-2 participates in the initial innate immune signaling response to Pneumocystis, but its deficiency does not impair resistance to the organism. PMID- 28886253 TI - Female offspring born to obese and insulin-resistant dams are not at increased risk for obesity and metabolic dysfunction during early development. AB - The percentage of women who are obese at the time of conception or during pregnancy is increasing, with animal and human studies demonstrating that offspring born to obese dams or mothers are at increased risk for obesity and the metabolic syndrome. Our goal was to confirm in an experimental model of metabolic syndrome in the dam, whether the offspring would be at increased risk of obesity. Conversely, we observed that male offspring born to dams with metabolic syndrome had no alterations in their body mass profiles, whereas female offspring born to dams with metabolic syndrome were heavier at weaning, but exhibited no perturbations in energy metabolism. Moreover, they gained weight at a reduced rate versus female offspring born to healthy dams, and thus weighed less at study completion. Hence, our findings suggest that factors other than increased adiposity and insulin resistance during pregnancy are responsible for the increased risk of obesity in children born to obese mothers. PMID- 28886252 TI - Total Airway Count on Computed Tomography and the Risk of Chronic Obstructive Pulmonary Disease Progression. Findings from a Population-based Study. AB - RATIONALE: Studies of excised lungs show that significant airway attrition in the "quiet" zone occurs early in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine if the total number of airways quantified in vivo using computed tomography (CT) reflects early airway-related disease changes and is associated with lung function decline independent of emphysema in COPD. METHODS: Participants in the multicenter, population-based, longitudinal CanCOLD (Canadian Chronic Obstructive Lung Disease) study underwent inspiratory/expiratory CT at visit 1; spirometry was performed at four visits over 6 years. Emphysema was quantified as the CT inspiratory low-attenuation areas below -950 Hounsfield units. CT total airway count (TAC) was measured as well as airway inner diameter and wall area using anatomically equivalent airways. MEASUREMENTS AND MAIN RESULTS: Participants included never-smokers (n = 286), smokers with normal spirometry at risk for COPD (n = 298), Global Initiative for Chronic Obstructive Lung Disease (GOLD) I COPD (n = 361), and GOLD II COPD (n = 239). TAC was significantly reduced by 19% in both GOLD I and GOLD II compared with never smokers (P < 0.0001) and by 17% in both GOLD I and GOLD II compared with at-risk participants (P < 0.0001) after adjusting for low-attenuation areas below -950 Hounsfield units. Further analysis revealed parent airways with missing daughter branches had reduced inner diameters (P < 0.0001) and thinner walls (P < 0.0001) compared with those without missing daughter branches. Among all CT measures, TAC had the greatest influence on FEV1 (P < 0.0001), FEV1/FVC (P < 0.0001), and bronchodilator responsiveness (P < 0.0001). TAC was independently associated with lung function decline (FEV1, P = 0.02; FEV1/FVC, P = 0.01). CONCLUSIONS: TAC may reflect the airway-related disease changes that accumulate in the "quiet" zone in early/mild COPD, indicating that TAC acquired with commercially available software across various CT platforms may be a biomarker to predict accelerated COPD progression. PMID- 28886255 TI - A Tribute to Section Editor Prof. Julio C. Voltarelli. PMID- 28886254 TI - The research progress in mechanism and influence of biosorption between lactic acid bacteria and Pb(II): A review. AB - Currently, due to high surface to volume ratio; large availability, rapid kinetics of adsorption and desorption and low cost, the exploitation of microbial biosorption of heavy metals is regarded as a reliable alternative compared to the conventional bioremediation approaches. In parallel with the increasing attractiveness of biosorption research, its pace of advance is also boosted. The barrier that prevent biosorption as an effective method from being applied into wastewater purification is listed, (1) There is not enough data on multi component biosorption, (2) It remains to be seen that physical-chemical characteristics of different biomasses. (3) Studies on surface modification of strains for enhancement of heavy metals removal efficiency is lack. And extensive literatures involving the mechanism and model of biosorption for particular metal and microbial strains are not available. The present literatures lack systematization, the theory on interaction between lactic acid bacteria and Pb is far from complete. Therefore, the review tries to give a comprehensive explanation about the mechanism of Pb removal from Lactic acid bacteria and provide a brief overview of distinction between biosorption and bioaccumulation, biosorption technology, highlight the underlying features of biosorption and the various affecting factors such as pH, dose required, initial concentration, temperature, and treatment performance as a reference. Biosorption mechanisms can be briefly generalized into several pathways, which are ion exchange, complexation, precipitation, reduction and chelation. Many views holds that complexation is the major absorption mechanisms of Pb. Biosorption mechanisms can be roughly classified as biosorption and bioaccumulation, which have great differences between each other. Biosorption is metabolism-independent but fast, while bioaccumulation is metabolism-dependent but slow. The slight advantages of the bioaccumulation are the metabolite (lactic acid), lactobacillus surface layers, enzymes and so on. Many factors can greatly affect adsorption process, different factors have different influence and the effects of pretreatment, pH and temperature are relatively greater. Desorption is not a fully reversible process of biosorption, but could not only achieve the goal of the recycle of microorganism, but also contribute to release of trace metal elements. Also the technologies for observation of biosorbents characterics and effect on the metal binding process are reviewed. PMID- 28886256 TI - Advances in Cardiovascular Cell Therapy. PMID- 28886257 TI - Prevalence and Causes of Visual Impairment in Fundong District, North West Cameroon: Results of a Population-Based Survey. AB - PURPOSE: To estimate the prevalence and causes of visual impairment in Fundong Health District, North West Cameroon. METHODS: A total of 51 clusters of 80 people (all ages) were sampled with probability proportionate to size and compact segment sampling. Visual acuity (VA) was measured with a tumbling "E" chart. An ophthalmic nurse examined people with VA<6/18 in either eye. The presence of hearing and physical impairments were assessed using clinical examination, and self-reported visual problems using the Washington Group Short Set. RESULTS: In total, 4080 people were enumerated of whom 3567 were screened (response rate 87%). The overall prevalence of visual impairment was 2.3% (95% CI 1.8-3.0%) and blindness was 0.6% (0.3-1.0%). The prevalence of both blindness and visual impairment increased rapidly with age, so that the vast majority of cases of visual impairment (84%) and blindness (82%) were in people aged 50+. Posterior segment disease and cataract were the main causes of blindness and visual impairment, with refractive error also an important cause of visual impairment. Cataract surgical coverage (proportion of all cataracts that had received surgery) was relatively high (87% of people at VA<6/60). Post-surgery outcomes were poor, with 31% of operated eyes having VA<6/60. Among the 82 people with visual impairment, 22% had a physical impairment or epilepsy and 30% had a hearing impairment. Self-reported difficulties in vision were relatively closely related to clinical measures of visual impairment. CONCLUSIONS: Ophthalmic programmes in Cameroon need to incorporate control of posterior segment diseases while also working to improve outcomes after cataract surgery. PMID- 28886258 TI - A questionnaire survey of general practitioners in Japan's Kanagawa Prefecture for the Japanese Society of Hypertension Guidelines for the Management of Hypertension 2014. AB - To evaluate the Japanese Society of Hypertension Guidelines for the Management of Hypertension 2014 (JSH2014) among Japanese general practitioners (GPs), we used a questionnaire survey with 209 GPs from the Kanagawa Physicians Society. Overall, 93.6% of GPs felt that the contents of the JSH2014 were useful. Based on the results showing that 81.8% of GPs instructed the measurement of blood pressure (BP) in the early morning at home to most patients, GP's acceptance of home BP methods and their penetration among patients with hypertension were considerably high. Regarding the number of home BP measurements, percentages for "one time," "two times," "three times," and "as many times as the patient decides," were 20.2%, 44.9%, 12.2%, and 22.9%, respectively; as such, no consensus was reached. Overall, 80.6% of GPs instructed most patients on sodium restriction; however, the content and method of restriction varied. Furthermore, 14.7% collected spot urine to assess salt intake. Many GPs respected the JSH2014 and faithfully adopted the guidelines during medical care. However, GPs did not necessarily agree with all guidelines. GPs sometimes selected the appropriate method for the individual patients and careful observations of how the guidelines affect actual clinical practice may lead to better medical care. PMID- 28886259 TI - Addition of dexmedetomidine to QX-314 enhances the onset and duration of sciatic nerve block in rats. AB - An experimental set-up was designed to observe whether adding dexmedetomidine to QX-314 would enhance the onset and duration of sensory and motor function in a rat sciatic nerve block model. Fifty-six Sprague-Dawley rats received unilateral sciatic nerve blocks with 0.2 mL of 35 mmol/L QX-314 alone, dexmedetomidine (5.3 MUmol/L (1 MUg/kg), 26.4 MUmol/L (5 MUg/kg), 52.8 MUmol/L (10 MUg/kg)) alone, or a combination of the two. Thermal nociception and motor function were assessed by an investigator blinded to the drug treatment, and sciatic nerves and perineural tissues were harvested at 14 days after injection. In addition, we examined the effects of these solutions on compound action potentials in isolated frog sciatic nerves. Dexmedetomidine added to QX-314 enhanced the onset and duration of thermal nociception block and motor block (P < 0.05) without aggravating histopathological injuries. Furthermore, 52.8 MUmol/L dexmedetomidine added to 35 mmol/L QX-314 showed less inflammation than QX-314 alone at 14 days (P = 0.003). Dexmedetomidine plus QX-314 was shown to dose-dependently reduce the compound action potentials relative to QX-314 alone (P < 0.05). It was concluded that co administration of QX-314 with a clinical dose of dexmedetomidine produced a synergistic anesthetic effect to enhance the effect of sciatic nerve block. PMID- 28886260 TI - Avoidable Waste in Ophthalmic Epidemiology: A Review of Blindness Prevalence Surveys in Low and Middle Income Countries 2000-2014. AB - PURPOSE: Sources of avoidable waste in ophthalmic epidemiology include duplication of effort, and survey reports remaining unpublished, gaining publication after a long delay, or being incomplete or of poor quality. The aim of this review was to assess these sources of avoidable waste by examining blindness prevalence surveys undertaken in low and middle income countries (LMICs) between 2000 and 2014. METHODS: On December 1, 2016 we searched MEDLINE, EMBASE and Web of Science databases for cross-sectional blindness prevalence surveys undertaken in LMICs between 2000 and 2014. All surveys listed on the Rapid Assessment of Avoidable Blindness (RAAB) Repository website ("the Repository") were also considered. For each survey we assessed (1) availability of scientific publication, survey report, summary results tables and/or datasets; (2) time to publication from year of survey completion and journal attributes; (3) extent of blindness information reported; and (4) rigour when information was available from two sources (i.e. whether it matched). RESULTS: Of the 279 included surveys (from 68 countries) 186 (67%) used RAAB methodology; 146 (52%) were published in a scientific journal, 57 (20%) were published in a journal and on the Repository, and 76 (27%) were on the Repository only (8% had tables; 19% had no information available beyond registration). Datasets were available for 50 RAABs (18% of included surveys). Time to publication ranged from <1 to 11 years (mean, standard deviation 2.8 +/- 1.8 years). The extent of blindness information reported within studies varied (e.g. presenting and best-corrected, unilateral and bilateral); those with both a published report and Repository tables were most complete. For surveys published and with RAAB tables available, discrepancies were found in reporting of participant numbers (14% of studies) and blindness prevalence (15%). CONCLUSION: Strategies are needed to improve the availability, consistency, and quality of information reported from blindness prevalence surveys, and hence reduce avoidable waste. PMID- 28886262 TI - Effectiveness of antibiotic treatment in infertile patients with sterile leukocytospermia induced by tobacco use. AB - : Our study investigated whether antibiotic therapy in infertile tobacco users with sterile leukocytospermia and a history of former sexual transmitted disease (STD) has an advantage over cessation of smoking alone. For this study, 80 male infertile smokers were divided into two subgroups. The first group numbered 40 patients treated with a two week course of doxycycline, 100 mg, twice daily, while the second group simply ceased smoking. A control group of 20 patients with chronic abacterial prostatitis (CPPS III a) were treated with the same antibiotic for two weeks. Patients from the first group exhibited significantly higher values in semen volume, total motility, and progressive motility of spermatozoa, when compared with the second group, two weeks post treatment. The latter two measures persisted during the 12 week follow up period. In both groups of patients, the correlation coefficient between the number of leukocytes and progressive motility was determined as statistically significant. However, in the control group the correlation was not statistically significant; however progressive motility, total motility, and vitality were significantly improved after a two week course of antibiotics. Our study implies that antibiotic treatment is perhaps effective in treating sterile leukocytospermia in smokers with a former STD and is a more effective treatment option in improving sperm parameters over smoking cessation alone. ABBREVIATIONS: STD: sexual transmitted disease; CPPS IIIa: chronic abacterial prostatitis; PSA: prostatic specific antigen; EPS: expressed prostatic secretion; WBC: white blood count; LUTS: lower urinary tract symptoms; PPMT: pre-massage and post-massage urine test; VAS: visual analogue scale. PMID- 28886261 TI - Syndecan-2 Attenuates Radiation-induced Pulmonary Fibrosis and Inhibits Fibroblast Activation by Regulating PI3K/Akt/ROCK Pathway via CD148. AB - Radiation-induced pulmonary fibrosis is a severe complication of patients treated with thoracic irradiation. We have previously shown that syndecan-2 reduces fibrosis by exerting alveolar epithelial cytoprotective effects. Here, we investigate whether syndecan-2 attenuates radiation-induced pulmonary fibrosis by inhibiting fibroblast activation. C57BL/6 wild-type mice and transgenic mice that overexpress human syndecan-2 in alveolar macrophages were exposed to 14 Gy whole thoracic radiation. At 24 weeks after irradiation, lungs were collected for histological, protein, and mRNA evaluation of pulmonary fibrosis, profibrotic gene expression, and alpha-smooth muscle actin (alpha-SMA) expression. Mouse lung fibroblasts were activated with transforming growth factor (TGF)-beta1 in the presence or absence of syndecan-2. Cell proliferation, migration, and gel contraction were assessed at different time points. Irradiation resulted in significantly increased mortality and pulmonary fibrosis in wild-type mice that was associated with elevated lung expression of TGF-beta1 downstream target genes and cell death compared with irradiated syndecan-2 transgenic mice. In mouse lung fibroblasts, syndecan-2 inhibited alpha-SMA expression, cell contraction, proliferation, and migration induced by TGF-beta1. Syndecan-2 attenuated phosphoinositide 3-kinase/serine/threonine kinase/Rho-associated coiled-coil kinase signaling and serum response factor binding to the alpha-SMA promoter. Syndecan-2 attenuates pulmonary fibrosis in mice exposed to radiation and inhibits TGF-beta1-induced fibroblast-myofibroblast differentiation, migration, and proliferation by down-regulating phosphoinositide 3-kinase/serine/threonine kinase/Rho-associated coiled-coil kinase signaling and blocking serum response factor binding to the alpha-SMA promoter via CD148. These findings suggest that syndecan-2 has potential as an antifibrotic therapy in radiation-induced lung fibrosis. PMID- 28886263 TI - Functional peptides derived from rice bran proteins. AB - Rice bran has been predominantly used in the feed industry, and only recently it has attracted greater attention in terms of human nutrition with increasing knowledge of its bioactivity. A growing interest is the analysis of physiologically active peptides derived from rice bran proteins. In this paper, the bioactivities of rice bran proteins hydrolysates and peptides are reviewed based on recent studies. These enzymatic hydrolysates and peptides exert various biological activities including antioxidant, antidiabetic, anticancer and inhibitory activity for angiotensin converting enzyme (ACE), which may ultimately prevent certain chronic diseases. Nevertheless, these functionalities can be highly associated with their corresponding structural characteristics, in particular specific sequences and molecular weight distribution. This article may facilitate the expansion of the prospective applications of the bioactive peptides in a number of fields and provide some clues of the relationship between peptides structure and functionality for future research. PMID- 28886264 TI - Lack of asthma and rhinitis control in general practitioner-managed patients prescribed fixed-dose combination therapy in Australia. AB - OBJECTIVES: The first aim of the study (i) assess the current asthma status of general-practitioner-managed patients receiving regular fixed-dose combination inhaled corticosteroid and long-acting beta2 agonist (FDC ICS/LABA) therapy and (ii) explore patients' perceptions of asthma control and attitudes/behaviors regarding preventer inhaler use. METHODS: A cross-sectional observational study of Australian adults with a current physician diagnosis of asthma receiving >=2 prescriptions of FDC ICS/LABA therapy in the previous year, who were recruited through general practice to receive a structured in-depth asthma review between May 2012 and January 2014. Descriptive statistics and Chi-Square tests for independence were used for associations across asthma control levels. RESULTS: Only 11.5% of the patients had controlled asthma based on guideline-defined criteria. Contrarily, 66.5% of the patients considered their asthma to be well controlled. Incidence of acute asthma exacerbations in the previous year was 26.5% and 45.6% of the patients were without a diagnosis of rhinitis. Asthma medication use and inhaler technique were sub-optimal; only 41.0% of the preventer users reported everyday use. The side effects of medication were common and more frequently reported among uncontrolled and partially controlled patients. CONCLUSIONS: The study revealed the extent to which asthma management needs to be improved in this patient cohort and the numerous unmet needs regarding the current state of asthma care. Not only there is a need for continuous education of patients, but also education of health care practitioners to better understand the way in which patient's perceptions impact on asthma management practices, incorporating these findings into clinical decision making. PMID- 28886265 TI - Microvesicles releasing by oral cancer cells enhance endothelial cell angiogenesis via Shh/RhoA signaling pathway. AB - The present study aimed to investigate the significance of hedgehog signaling pathway in association with clinicopathology parameters and its effect on angiogenesis in oral squamous cell carcinoma (OSCC). The expression of Sonic Hh (Shh) and Gli1 were done on primary tumors and metastatic lymph nodes in OSCC samples from 80 patients by immunohistochemical analysis. The western blot was used to examine the expression of Shh in OSCC cell lines and OSCC-derived microvesicles (MVs). The role of Shh carried by MVs to induce endothelial cell angiogenesis was further investigated by matrigel assay. Our results indicated that the expression of Shh was positive associated with microvesseldentisty(MVD), TNM stage, tumor recurrence and lymph node metastasis. Moreover, Shh and Gli1 expression were higher in paired metastatic lymph nodes compared with expression of their primary tumors. The expression of Shh was abundant in Cal27, and present in SCC4, SCC9, and the amount of Shh protein in Cal27 targeting MVs was increased significantly than Cal27 cell group, up to ~ fifth-fold. The Cal27 derived MVs increased significantly angiogenesis of HUVECs in vitro, and this effect was blocked with exoenzyme C3 transferase (C3) and shRNA targeting RhoA by suppressing RhoA expression and activation. The data suggested that OSCC derived Shh carried by MVs may facilitate the tumor growth and modulate the preparation of a vascular network in primary tumor and/or premetastatic niche. PMID- 28886266 TI - Metastasis of esophageal small cell carcinoma to the appendix: A case report and literature review. AB - Primary small cell carcinoma (SCC) of the esophagus is characterized by high malignancy with a tendency to metastasize early through lymph and blood circulation. Metastasis of esophageal SCC frequently occurs to distant organs such as liver and lung. However, few cases of appendiceal metastasis have been reported. This paper first presents a pathologically confirmed case with metastasis of esophageal SCC to the appendix. This particular case highlights the importance of pathological diagnosis and provides new evidence of appendiceal metastasis from esophageal SCC. PMID- 28886267 TI - The effect of three novel feature extraction methods on the prediction of the subcellular localization of multi-site virus proteins. AB - Experimental methods play a crucial role in identifying the subcellular localization of proteins and building high-quality databases. However, more efficient, automated computational methods are required to predict the subcellular localization of proteins on a large scale. Various efficient feature extraction methods have been proposed to predict subcellular localization, but challenges remain. In this paper, three novel feature extraction methods are established to improve multi-site prediction. The first novel feature extraction method utilizes repetitive information via moving windows based on a dipeptide pseudo amino acid composition method (R-Dipeptide). The second novel feature extraction method utilizes the impact of each amino acid residue on its following residues based on pseudo amino acids (I-PseAAC). The third novel feature extraction method provides local information about protein sequences that reflects the strength of the physicochemical properties of residues (PseAAC2). The multi-label k-nearest neighbor algorithm (MLKNN) is used to predict the subcellular localization of multi-site virus proteins. The best overall accuracy values of R-Dipeptide, I-PseAAC, and PseAAC2 when applied to dataset S from Virus mPloc are 59.92%, 59.13%, and 57.94% respectively. PMID- 28886268 TI - Implanted hair-follicle-associated pluripotent (HAP) stem cells encapsulated in polyvinylidene fluoride membrane cylinders promote effective recovery of peripheral nerve injury. AB - Hair follicle-associated-pluripotent (HAP) stem cells are located in the bulge area of the hair follicle, express the stem-cell marker, nestin, and have been shown to differentiate to nerve cells, glial cells, keratinocytes, smooth muscle cells, cardiac muscle cells, and melanocytes. Transplanted HAP stem cells promote the recovery of peripheral nerve and spinal cord injuries and have the potential for heart regeneration as well. In the present study, we implanted mouse green fluorescent protein (GFP)-expressing HAP stem-cell spheres encapsulated in polyvinylidene fluoride (PVDF)-membrane cylinders into the severed sciatic nerve of immunocompetent and immunocompromised (nude) mice. Eight weeks after implantation, immunofluorescence staining showed that the HAP stem cells differentiated into neurons and glial cells. Fluorescence microscopy showed that the HAP stem cell hair spheres promoted rejoining of the sciatic nerve of both immunocompetent and immunodeficient mice. Hematoxylin and eosin (H&E) staining showed that the severed scatic nerves had regenerated. Quantitative walking analysis showed that the transplanted mice recovered the ability to walk normally. HAP stem cells are readily accessible from everyone, do not form tumors, and can be cryopreserved without loss of differentiation potential. These results suggest that HAP stem cells may have greater potential than iPS or ES cells for regenerative medicine. PMID- 28886269 TI - Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate. AB - In contrast to the progress that has been made toward understanding the genetic etiology of cleft lip with or without cleft palate, relatively little is known about the genetic etiology for cleft palate only (CPO). A common coding variant of grainyhead like transcription factor 3 ( GRHL3) was recently shown to be associated with risk for CPO in Europeans. Mutations in this gene were also reported in families with Van der Woude syndrome. To identify rare mutations in GRHL3 that might explain the missing heritability for CPO, we sequenced GRHL3 in cases of CPO from Africa. We recruited participants from Ghana, Ethiopia, and Nigeria. This cohort included case-parent trios, cases and other family members, as well as controls. We sequenced exons of this gene in DNA from a total of 134 nonsyndromic cases. When possible, we sequenced them in parents to identify de novo mutations. Five novel mutations were identified: 2 missense (c.497C>A; p.Pro166His and c.1229A>G; p.Asp410Gly), 1 splice site (c.1282A>C p.Ser428Arg), 1 frameshift (c.470delC; p.Gly158Alafster55), and 1 nonsense (c.1677C>A; p.Tyr559Ter). These mutations were absent from 270 sequenced controls and from all public exome and whole genome databases, including the 1000 Genomes database (which includes data from Africa). However, 4 of the 5 mutations were present in unaffected mothers, indicating that their penetrance is incomplete. Interestingly, 1 mutation damaged a predicted sumoylation site, and another disrupted a predicted CK1 phosphorylation site. Overexpression assays in zebrafish and reporter assays in vitro indicated that 4 variants were functionally null or hypomorphic, while 1 was dominant negative. This study provides evidence that, as in Caucasian populations, mutations in GRHL3 contribute to the risk of nonsyndromic CPO in the African population. PMID- 28886270 TI - Airway epithelial barrier dysfunction in the pathogenesis and prognosis of respiratory tract diseases in childhood and adulthood. AB - The lungs are in direct contact with the environment through the tubular structure that constitutes the airway. Starting from the nasal orifice, the airway is exposed to foreign particles including infectious agents, allergens, and other substances that can damage the airways. Therefore, the airway must have a functional epithelial barrier both in the upper and lower airways to protect against these threats. As with the skin, it is likely that the pathogenesis of respiratory diseases is a consequence of epithelial barrier defects in these airways. The characteristics of this system, starting from the beginning of life and extending into maturing and aging, determine the prognosis of respiratory diseases. In this article, we discuss the pathogenesis, clinical phenotype, and prognosis of respiratory diseases from newborns to adulthood in the context of epithelial barrier function and dysfunction. PMID- 28886272 TI - Expression of SESN1, UHRF1BP1, and miR-377-3p as prognostic markers in mutated TP53 squamous cell carcinoma of the head and neck. AB - The tumor suppressor gene TP53 is the most frequently mutated gene in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). It represents a known transcription factor that controls different microRNAs (miRNA) and target genes involved in the regulation of cellular stress, apoptosis and response to DNA damage. We used The Cancer Genome Atlas database to investigate the difference in transcriptome and proteome levels between mutated and wild-type TP53 HPV-negative HNSCC. Using different databases and an extensive literature review, we built the transcriptional and post-transcriptional network regulated by TP53. TP53 mutation was associated with poor overall survival in 203 HPV negative patients compared to 40 patients with TP53 wild-type tumors. Using the enrichment analysis, we found that UHRF1BP1 and SESN1 mRNA were linked to prognosis in the TP53 mutated group. This is also the case for miR-377-3p, an important miRNA regulator of SESN1. Our study shows that SESN1 mRNA, UHRF1BP11 mRNA and miRNA-377-3p levels are prognostically relevant in HPV-negative HNSCC patients. This finding may help with patient stratification and the development of potential new therapeutic targets to treat patients with HNSCC. PMID- 28886271 TI - MicroRNA signature in the chemoprevention of functionally-enriched stem and progenitor pools (FESPP) by Active Hexose Correlated Compound (AHCC). AB - PURPOSE: Many breast cancer patients use natural compounds in their battle against breast cancer. Active Hexose Correlated Compound (AHCC(r)) is a cultured mushroom mycelium extract shown to favorably modulate the immune system and alleviate cancer burden. Cancer Stem cells (CSCs) are a subset of highly tumorigenic cancer cells that are thought to be responsible for recurrence. CSCs can be epigenetically regulated by microRNAs (miRNAs). We hypothesized that AHCC may influence CSCs by modulating tumor-suppressor or oncogenic miRNAs. METHODS: Functionally-enriched stem and progenitor pools (FESPP) were isolated in the form of mammospheres from MDA-MB-231, MCF-7, and 4T1 cells, exposed to AHCC in both regular and primary culture from Balb/c mice, and analyzed by visual counting and flow cytometry. Cell motility was also observed in MDA-MB-231 cells. Profiling and RT-qPCR were performed to determine AHCC influence on miRNAs in MDA-MB-231 mammospheres. Additionally, Balb/c mice were orally gavaged with AHCC, and tumor growth parameters and miR-335 expression were analyzed. MDA-MB-231 cells were transfected with miR-335 and analyzed by western blot. RESULTS: We demonstrated that AHCC reduced mammosphere growth in three cell lines and in primary culture, prevented cell migration, and upregulated miR-335 expression in MDA-MB-231 cells and mouse tumor samples. Among the differentially regulated miRNAs in CSCs, we focused on tumor suppressor miR-335, known to target extracellular matrix protein Tenascin C (TNC). TNC is involved in CSC immune evasion pathways. In MDA-MB-231, inhibition of miR-335 increased TNC protein expression. CONCLUSIONS: These results support that AHCC limits FESPP growth, partly by targeting miRNA pathways. PMID- 28886273 TI - PARPi potentiates with current conventional therapy in MLL leukemia. AB - Acute myeloid leukemias driven by MLL fusion proteins are commonly associated with poor prognosis and refractory treatment. Here, we provide evidence that olaparib can potentiate sensitivity of MLL leukemia cells to conventional chemotherapy and DNMT inhibitors offering new potential therapeutic strategies for MLL rearranged leukemias Using the primary mouse leukemia cells and human MLL AF9 leukemic cell line, we demonstrate that treatment of MLL-AF9 leukemic cells with DNMT inhibitors or chemotherapies in combination with olaparib results in significant reduction in colony formation or cell growth while the single agent treatments had little impacts. Combining olaparib with DNMT inhibitor induce cell cycle block and apoptosis. Furthermore, we observe a significant increase in proportion of cells with >10 gammaH2AX DNA damage foci and double stranded breaks when treated with DNMT inhibitors or chemotherapy agents in combination with olaparib, thus providing possible mechanistic insights for the synergism. PMID- 28886274 TI - The plant RNA polymerase II elongation complex: A hub coordinating transcript elongation and mRNA processing. AB - Characterisation of the Arabidopsis RNA polymerase II (RNAPII) elongation complex revealed an assembly of a conserved set of transcript elongation factors associated with chromatin remodellers, histone modifiers as well as with various pre-mRNA splicing and polyadenylation factors. Therefore, transcribing RNAPII streamlines the processes of mRNA synthesis and processing in plants. PMID- 28886275 TI - Preclinical rationale for combination of crizotinib with mitomycin C for the treatment of advanced colorectal cancer. AB - Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. We analyzed 26 MSI-High and 558 non-MSI-High CRC tumors. BRCA2 mutations were highly enriched (50%) in MSI-High CRC. Immunohistochemistry showed that BRCA2-mutated MSI-High CRC had high c-MET (64%) expression compared with BRCA-WT (17%). We hypothesized a mechanistic link between BRCA2-deficiency and c-MET overexpression and synergistic interaction between drugs that treat BRCA deficient tumors (mitomycin C (MMC) or PARP inhibitors) and c-MET inhibitors (crizotinib). We tested CRC cell lines for sensitivity to MMC plus crizotinib or other drug combinations including PARP-inhibitors. Combined treatment of tumor cells with crizotinib and MMC led to increased apoptosis as compared with each drug alone. Additionally, combination treatment with increasing concentrations of both drugs demonstrated a synergistic anti-cancer effect (CI = 0.006-0.74). However, we found no evidence for c-MET upregulation upon effective BRCA2 knockdown in tumor cells -/+DNA damage. Although we found no mechanistic link between BRCA2 deficiency and c-MET overexpression, c-MET is frequently overexpressed in CRC and BRCA2 is mutated especially in MSI-H CRC. The combination of crizotinib with MMC appeared synergistic regardless of MSI or BRCA2 status. Using an in-vivo CRC xenograft model we found reduced tumor growth with combined crizotinib and MMC therapy (p = 0.0088). Our preclinical results support clinical testing of the combination of MMC and crizotinib in advanced CRC. Targeting cell survival mediated by c-MET in combination with targeting DNA repair may be a reasonable strategy for therapy development in CRC or other cancers. PMID- 28886277 TI - A comparison of multiple imputation methods for incomplete longitudinal binary data. AB - Longitudinal binary data are commonly encountered in clinical trials. Multiple imputation is an approach for getting a valid estimation of treatment effects under an assumption of missing at random mechanism. Although there are a variety of multiple imputation methods for the longitudinal binary data, a limited number of researches have reported on relative performances of the methods. Moreover, when focusing on the treatment effect throughout a period that has often been used in clinical evaluations of specific disease areas, no definite investigations comparing the methods have been available. We conducted an extensive simulation study to examine comparative performances of six multiple imputation methods available in the SAS MI procedure for longitudinal binary data, where two endpoints of responder rates at a specified time point and throughout a period were assessed. The simulation study suggested that results from naive approaches of a single imputation with non-responders and a complete case analysis could be very sensitive against missing data. The multiple imputation methods using a monotone method and a full conditional specification with a logistic regression imputation model were recommended for obtaining unbiased and robust estimations of the treatment effect. The methods were illustrated with data from a mental health research. PMID- 28886289 TI - Optimization of saccharification potential of recombinant xylanase from Bacillus licheniformis. AB - Saccharification potential of xylanase enzyme cloned from Bacillus licheniformis into E. coli BL21 (DE3) was evaluated against plant biomass for the production of bioethanol. The expression of cloned gene was studied and conditions were optimized for its large scale production. The parameters effecting enzyme production were examined in a fermenter. Recombinant xylanase has the ability to breakdown birchwood xylan to release xylose as well as the potential to treat plant biomass, such as wheat straw, rice straw, and sugarcane bagass. The saccharification ability of this enzyme was optimized by studying various parameters. The maximum saccharification percentage (84%) was achieved when 20 units of recombinant xylanase were used with 8% sugarcane bagass at 50 degrees C and 120 rpm after 6 hours of incubation. The results indicated that the bioconversion of natural biomass by recombinant xylanase into simple sugars can be used for biofuel (bioethanol) production. This process can replace the use of fossil fuels, and the use of bioethanol can significantly reduce the emission of toxic gases. Future directions regarding pre-treatment of cellulosic and hemicellulosic biomass and other processes that can reduce the cost and enhance the yield of biofuels are briefly discussed. PMID- 28886276 TI - Systems approach to the pharmacological actions of HDAC inhibitors reveals EP300 activities and convergent mechanisms of regulation in diabetes. AB - Given the skyrocketing costs to develop new drugs, repositioning of approved drugs, such as histone deacetylase (HDAC) inhibitors, may be a promising strategy to develop novel therapies. However, a gap exists in the understanding and advancement of these agents to meaningful translation for which new indications may emerge. To address this, we performed systems-level analyses of 33 independent HDAC inhibitor microarray studies. Based on network analysis, we identified enrichment for pathways implicated in metabolic syndrome and diabetes (insulin receptor signaling, lipid metabolism, immunity and trafficking). Integration with ENCODE ChIP-seq datasets identified suppression of EP300 target genes implicated in diabetes. Experimental validation indicates reversal of diabetes-associated EP300 target genes in primary vascular endothelial cells derived from a diabetic individual following inhibition of HDACs (by SAHA), EP300, or EP300 knockdown. Our computational systems biology approach provides an adaptable framework for the prediction of novel therapeutics for existing disease. PMID- 28886292 TI - Prime Time for Pancreas and Islet Transplantation at the Turn of the Millennium. PMID- 28886300 TI - Cell Therapy 2000: Introduction. PMID- 28886299 TI - Successful Retroviral Gene Transfer of Simian Virus 40 T Antigen and Herpes Simplex Virus-Thymidine Kinase into Human Hepatocytes 1. AB - Current clinical reports have indicated that hepatocyte transplantation (HTX) could be used in patients with liver failure and in children with liver-based metabolic diseases. One of the major limiting factors of HTX is a serious shortage of donor livers for hepatocyte isolation. To address this issue, we immortalized adult human hepatocytes with a retroviral vector SSR#69 expressing the genes of simian virus 40 large T antigen and herpes simplex virus-thymidine kinase simultaneously. One of the resulting clones, NKNT-3, grew steadily in chemically defined serum-free medium without any obvious crisis and showed the gene expression of differentiated liver functions. Under the administration of 5 MUM ganciclovir, NKNT-3 cells stopped proliferation and died in in vitro experiments. We have established a tightly regulated immortal human hepatocyte cell line. The cells could allow the need for immediate availability of consistent and functionally uniform cells in sufficient quantity and adequate quality. PMID- 28886301 TI - Acute Lethal Injury of Lung and Liver in Mice Transplanted with Ex Vivo-Expanded CTLs. AB - Clinical application of cytotoxic T lymphocytes (CTL) induced in vitro is extensively used for the treatment of viral infection and malignant diseases. We produced anti H-2d CTL in vitro from C57BL/6 (B6) splenocytes presensitized with (B6 * DBA/2) F1 (BDF1) splenocytes to establish a model system of CTL therapy. The specificity and cytotoxic activity were high enough (E/T ratio 1:1 = 38.8%) to induce graft versus host reaction. Though the total number of B6 splenocytes decreased by 0.27 during the 4 days of culture, the number of CD8+ lymphocytes increased 1.3-fold. When more than 5 * 106 cells of H-2d -reactive CTL were transplanted into BDF1 mice, mice died within 2 days postinduction. This lethal effect was not seen in the mice induced with ConA-stimulated T cells. Histological examination of the lungs and liver revealed massive infiltration of neutrophils in alveoli and the necrosis of hepatocytes. Therefore, this protocol was shown to be effective to produce alloantigen-specific CTLs and applicable to in vitro manipulation such as retrovirus-mediated gene transfer. PMID- 28886302 TI - Cre/loxP-Based Reversible Immortalization of Human Hepatocytes 1. AB - An ideal alternative to the primary human hepatocytes for hepatocyte transplantation would be to use a clonal cell line that grows economically in culture and exhibits the characteristics of differentiated, nontransformed hepatocytes following transplantation. The purpose of the present studies was to establish a reversibly immortalized human hepatocyte cell line. Human hepatocytes were immortalized with a retroviral vector SSR#69 expressing simian virus 40 large T antigen (SV40Tag) gene flanked by a pair of loxP recombination targets. One of the resulting clones, NKNT-3, showed morphological characteristics of liver parenchymal cells and expressed the genes of differentiated liver functions. NKNT-3 cells offered unlimited availability. After an adenoviral delivery of Cre recombinase and subsequent differential selection, efficient removal of SV40Tag from NKNT-3 cells was performed. Here we represent that elimination of the retrovirally transferred SV40Tag gene can be excised by adenovirus-mediated site-specific recombination. PMID- 28886303 TI - Helicases as transcription termination factors: Different solutions for a common problem. AB - Helicases are enzymes that remodel nucleic acids or protein-nucleic acid complexes in an ATP-dependent manner. They are ubiquitous and can play many diverse functions related to the metabolism of nucleic acids. A few helicases from both the prokaryotic and the eukaryotic worlds have the ability to induce transcription termination. Here we discuss how the same biological function is achieved by different helicases with quite divergent structures and mechanisms of action. PMID- 28886305 TI - Sample size determination for the current strategy in oncology Phase 3 trials that tests progression-free survival and overall survival in a two-stage design framework. AB - The selection of progression-free survival (PFS) or overall survival (OS) as the most suitable primary endpoint (PE) in oncology Phase 3 trials is currently under intense debate. Because of substantial limitations in the single use of PFS (or OS) as the PE, trial designs that include PFS and OS as co-primary endpoints are attracting increasing interest. In this article, we report on the formulation of determining the sample size for a trial that sequentially tests PFS and OS by treating them as co-PEs. Using a three-component model of OS, the proposed method overcomes the drawbacks of an existing method that requires unreasonable assumption of the exponential distribution for OS, although the hazard function is nonconstant because effective subsequent therapy has prolonged postprogression survival in recent oncology trials. Alternative estimation method of hazard ratio for OS under a three-component mode is also discussed by checking the appropriateness of assuming proportionality of hazards for OS. In order to examine the performance of our proposed method, we performed three numerical studies using both simulated and actual data of cancer Phase 3 trials. We find that the proposed method preserves a prespecified target value of power with a feasible increment of trial scale. PMID- 28886304 TI - The roles of vasohibin and its family members: Beyond angiogenesis modulators. AB - Vasohibin-1 is an intrinsic angiogenesis inhibitor, and is expressed in endothelial cells via induction by pro-angiogenesis factors. It is known to inhibit several processes of angiogenesis, with different mechanisms from extrinsic angiogenesis inhibitors. Vasohibin-2 is mainly expressed by mononuclear cells which have been mobilized from bone marrow. It not only promotes angiogenesis, but also modulates the releases of FGF-2 and VEGF, which are the two major inducers for vasohibin1. Hypoxic environment induces the expression of hypoxia-inducible Factor 1alpha with a result of VEGF release nearly in all tumor cell lines and tissues. However, it has been observed that hypoxia reduces the inducible effects of VEGF on vasohibin, which indicates that a complicated mechanism exists in the angiogenesis. Vasohibin and its family members play important roles in both the physiological and pathological procedures, in contrary but complementary patterns. Furthermore, human aortic smooth muscle cells and fibroblast have also been detected to express vasohibin on a moderate to weak scale range. Recently, the results of an increasing number of studies in vivo have shown that vasohibin can also be detected in several cancers, and is associated with micro-vessel densities, histology grades, invasions, poor clinical features, metastasis, and dissemination in abdominal cavities, as well as EMT. In more recent reports, it has been confirmed that, along with being angiogenesis regulators, a variety of other roles have been associated with this family. The focus of this study was the upstream regulatory mechanisms of vasohibin expressions, and their role in regard to the downstream target proteins of vasohibin, especially in carcinoma. Vasohibin is considered to be an original angiogenesis inhibitor, and has a much broader significance in pathological processes. It can be taken as an independent prognostic factor, as well as a potential strategy for cancer therapy programs. PMID- 28886306 TI - LncRNA H19 contributes to Rh2-mediated MC3T3-E1cell proliferation by regulation of osteopontin. AB - 20(R)-ginsenoside Rh2 (Rh2) is one of the most active components of red ginseng, possessing the beneficial effects in cancer prevention and metabolic diseases. However, the detailed mechanisms that contribute to Rh2-mediated bone formation remain largely unknown. In this study, we assessed the expression of 17 long non coding RNAs (lncRNAs) in cultured MC3T3-E1 cells under Rh2 treatments. We found that lncRNA H19 was significantly increased in Rh2-treated MC3T3-E1 cells. Expression of lncRNA H19 was promoted in a dose- and time-dependent manner after Rh2 treatments. Increased expression of lncRNA H19 resulted in osteopontin (OPN) overexpression in Rh2-treated MC3T3-E1 cells. Furthermore, knockdown of lncRNA H19 by specific siRNAs significantly abolished the Rh2-mediated cell proliferation effects. Knockdown of lncRNA H19 also decreased both mRNA and protein levels of OPN in the Rh2-treated cells, which was accomplished by inhibiting histones H3 and H4 acetylation of OPN promoter. Importantly, OPN knockdown fully blocked Rh2 induced MC3T3-E1 cell proliferation. Our results suggest that lncRNA H19 is an important contributor to Rh2-mediated MC3T3-E1 proliferation by regulation of OPN. PMID- 28886307 TI - Pleckstrin homology-like domain family B member 1 rs498872 polymorphism and glioma risk in Chinese Han population. AB - This case-control study aimed to investigate the association between PHLDB1 rs498872 polymorphism and the risk of glioma in a Chinese Han population. A total of 210 patients and 235 controls were enrolled in this study. The CT genotype and TT genotype were significantly associated with the risk of glioma (OR=1.48, 95%CI 1.00-2.19, P=0.05 and OR=2.40, 95%CI 1.06-4.10, P=0.03), respectively. In addition, T allele of PHLDB1 rs498872 polymorphism was significantly associated with an increased risk of glioma (OR=1.58, 95%CI 1.08-2.29, P=0.02). We also found that PHLDB1 rs498872 polymorphism was not associated with histology and tumor grade of glioma. In conclusion, this study found that PHLDB1 rs498872 polymorphism was significantly associated with glioma risk in Chinese Han population. PMID- 28886308 TI - Contribution of polymorphisms in the LEP, LEPR and RETN genes on serum leptin and resistin levels in young adults from Mexico. AB - Polymorphisms in the LEP (G-2548A and A19G), LEPR (A326G, A668G and G3057A) and RETN (C-420G and G+62A) genes were documented according to their association with alterations in biochemical parameters such as glucose, insulin and lipid profiles, along with serum leptin and resistin concentrations. The aim of the study was to establish any contribution of the G-2548A and A19G polymorphisms of the LEP gene, the A326G, A668G and G3057A polymorphisms of the LEPR gene, and the C-420G and G+62A polymorphisms of the RETN gene to serum leptin and resistin levels in Mexican young adults. Clinical and biochemical variables, serum leptin and resistin levels, and genotype profiles were analysed in 66 Mexican young adults. Seven polymorphisms in the LEP, LEPR and RETN genes were genotyped using polymerase chain reaction-restriction fragment length polymorphisms analysis. Individuals carrying allele 3057A of the G3057A polymorphism in the LEPR gene showed significantly higher leptin concentrations than those bearing the genotype G/G (43.78 +/- 39.11 vs 28.20 +/- 14.12 ng/mL; p = 0.021). There were no associations of serum leptin or resistin levels according to the genotype of the other six analysed polymorphisms. Our results suggest that the allele 3057A of the LEPR G3057A polymorphism contributes to increased serum leptin levels in Mexican young adults. PMID- 28886309 TI - The correlation between Pax5 deletion and patients survival in Iranian children with precursor B-cell acute lymphocytic leukemia. AB - Despite advances in treatment, children with acute lymphoblastic leukemia (ALL) still experience drug resistance and relapse. Several gene mutations are involved in the onset of this disease and resistance to therapy. The present study examines the incidence of IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1, RB1, JAK2, and Xp22.33 gene deletions/duplications associated with pediatric ALL in Iran and investigates the possible effect of these mutations on drug resistance. Three year disease-free survival (3DFS) was evaluated for children diagnosed with Philadelphia negative precursor-B-cell ALL hospitalized at Sayed-al-Shohada Hospital, Isfahan-Iran, from January 2009 until December 2012. DNA was extracted from bone marrow slides, and ALL correlated gene deletions and duplications were measured using Multiplex Ligation-dependent Probe Amplification (MLPA) method. The correlation between gene mutations and 3DFS was then assessed. Among the nine aforementioned investigated genes, 63% of samples showed at least one gene mutation. At least two concomitant genomic mutations were observed in 42% of samples. Pax5 deletion was the most prevalent gene mutation observed in 45% of cases, and showed significant negative impact on response to treatment. CDKN2A/B (9p21.3) gene deletion, and ETV6 (12p13.2) gene duplication also demonstrated negative effect on patient survival and contributed to a worse prognosis if concomitant with Pax5 gene deletion. ALL patients with one of the gene deletions including Pax5 and CDKN2A/B (9p21.3) or ETV6 (12p13.2) gene duplication are classified as high-risk patients and need more intensified protocols of treatment to improve their chance of survival. PMID- 28886310 TI - Risk factors associated with oral and maxillofacial benign tumors: A case-control study. AB - This study aimed to investigate the risk factors for oral and maxillofacial benign tumors (OMFBTs). A total of 138 patients diagnosed with OMFBTs between September 2010 and September 2015 were retrospectively analyzed. Clinical data including demographic characteristics, smoking and drinking status, dietary habit, oral hygiene and tumor related family history were collected and compared with 134 cases of healthy people who visited the hospital for physical examination during the same time. Logistic regression analysis was performed for multivariable regression analysis. OMFBTs was associated with smoking more than 20 cigarettes per day, accumulated cigarette consumption more than 30, accumulated cigarette package consumption more than 1000, present smoking and drinking, passive smoking before 18 years old, initial smoking age more than 20 years old and alcohol consumption more than 50 g/d (P < 0.05). Consumption of meat, fish, seafood, fruits and vitamin tablets were associated with lower risk of OMFBTs. Non-conditional logistic regression analyses indicated that the independent risk factors of OMFBTs included accumulated cigarette consumption, passive smoking before the age of 18, meat-free, fish-free, fruit-free, vitamin tablets-free, frequency of tooth brushing lower than once a day, not routinely attending oral examination, wearing denture and drinking alcohol (P < 0.05). Smoking and drinking should be discouraged in dental patients. Keeping a good dietary habit and routinely attending oral examination are highly encouraged. PMID- 28886311 TI - Effect of sucrose concentrations on Stevia rebaudiana Bertoni tissue culture and gene expression. AB - Stevia rebaudiana (Bert.) Bertoni is known as sweet plant which it contains a high level of steviol glycosides in the leaves. This plant has been used from centuries ago as a sweetener for tea. One of the most important steviol glycosides is stevioside that is attractive for diabetic persons. Tissue culture is the only rapid process for the mass propagation of stevia. One of the most important factors in the medium is sucrose that is a necessary for plant growth. In the present study, we use nodal segments of the stem as explants in mediums with different sucrose concentration (50 mM, 100mM and 150mM). Several morphological traits were measured in a 28 day period. Results analysis showed a significant variation between treatments. The highest growth rate, rooting and leaf production was obtained in medium with 100mM sucrose. The correlation between measured traits was significant at the 0.01 level. To investigation of UGT74G1, UGT76G1, UGT85C2 and KS genes expression that are involved in the synthesis of SGs, RT- PCR was done with the housekeeping gene of as internal control. There were significant differences between all media. The results showed thatsucrose 100 mM containing media was more desirable than others for expression of UGT76G1 and UGT85C2 genes. Whereas, the best medium for expression of UGT74G1 was sucrose 150 mM and sucrose 50 mM for KS gene. Totally, it seems that sucrose at a concentration of 100 mMprovides the best condition for stevia growth and steviol glycosides production. PMID- 28886312 TI - Differences in expression of serum protein in patients with psoriasis vulgaris and blood heat syndrome and healthy volunteers. AB - To explore the mechanism of psoriasis vulgaris (PV), serum protein expression profiles between PV patients with blood-heat syndrome and healthy volunteers were detected by isobaric tags for relative and absolute quantitation (iTRAQ). First, sera from 15 PV patients with blood-heat syndrome and 10 healthy volunteers were collected; then, serum proteins were separated and hydrolyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and a specific iTRAQ marker enzyme respectively after further purification and protein abundance treatment. Compared with the control group, differentially expressed proteins in PV patients with blood-heat syndrome were identified and analyzed by tandem mass spectrometry. A total of 787 proteins were identified and 718 proteins had a functional annotation with gene ontology (GO) by iTRAQ in the current study. Significant differences (P <0.05) and great differences (P <0.01) were found in 681 proteins and 536 proteins respectively between the patient group and healthy group. ). Different protein expression profiles in serum existed between PV patients with blood-heat syndrome and healthy volunteers; the differences largely involved immune-related proteins and lipoproteins. The proteins specific for PV with blood-heat syndrome deserves further investigation. PMID- 28886313 TI - Susceptibility of herpes simplex virus type 1 to monoterpenes thymol, carvacrol, p-cymene and essential oils of Sinapis arvensis L., Lallemantia royleana Benth. and Pulicaria vulgaris Gaertn. AB - : In recent years, with increased the prevalence of viral infections and having no specific for their treatment and also the continuous appearance of resistant viral strains, the finding of novel antiviral agents is necessary. In this study, monoterpenes of thymol, carvacrol, p-cymene and essential oils from Sinapis arvensis L., Lallemantia royleana Benth. and Pulicaria vulgaris Gaertn. were screened for their inhibitory effect against herpes simplex virus type 1 (HSV-1) in vitro on Vero cell line CCL-81-ATCC using a plaque reduction assay. The antiviral activity of three monoterpenes (thymol, carvacrol and p-cymene) and three essential oils were evaluated by cytotoxicity assay, direct plaque test. In addition, the modes of antiviral action of these compounds were investigated during the viral infection cycle. Results showed that the inhibitory concentrations (IC50) were determined at 0.002%, 0.037%, >0.1%, 0.035%, 0.018% and 0.001% for thymol, carvacrol, p-cymene, S. arvensis oil, L. royleana oil and P. vulgaris oil, respectively. A manifestly dose-dependent virucidal activity against HSV-1 could be exhibited for compounds tested. In order to determine the mode of the inhibitory effect, compounds were added at different stages during the viral infection cycle. At maximum noncytotoxic concentrations of the compounds, plaque formation was significantly reduced by more than 80% when HSV-1 was preincubated with p-cymene. However, no inhibitory effect could be observed when the compounds were added to the cells prior to infection with HSV-1 or after the adsorption period. CONCLUSION: These results indicate that compounds affected HSV-1 mostly before adsorption and might interact with the viral envelope. Thymol exhibited a high selectivity index and seems to be a promising candidate for topical therapeutic application as antiviral agent for treatment of herpetic infections. PMID- 28886314 TI - Alterations on high HbF levels may be associated with KLF1 gene mutations. AB - The KLF1 gene synthesizes a transcription factor in the zinc finger structure that regulates the transcription of beta-, gamma-globin, and Foxm1 genes. This factor plays an important role in the erythropoiesis mechanism by modifying the chromatin structure and is involved in the regulation of transcription in the opening of the beta-globin gene. beta-globin gene expression could be disrupted by a mutation, which may be a possible cause of a disruption in regulation of the promotor of the beta-globin gene where the KLF1 transcription factor binds. This can lead to an inherited high fetal hemoglobin (HbF) ratio in people. Therefore, the main aim of this study was to determine the effects of KLF1 mutations on these high levels of HbF. In this study, in order to determine the relationship between the KLF1 mutations and the high HbF levels three exons along with the 5' UTR and 3'-UTR regions of the KLF1 gene were sequenced of 53 volunteers. In this study, 3 variations in the non-coding regions of the KLF1 gene were not associated with a high level of HbF. Five variations were detected in the second exon of KLF1 gene. One of these is a frame shift that occurs when GG bases are inserted between the 59-60 codons, and the other four variations occur as a base substitution variations. No correlation was found between high HbF levels and neutral variants. Only polar-nonpolar amino acid changes were found at two points. At one of them, a significant drop in the high HbF levels was observed, while the other was observed to be high near to the critical limit. These findings suggested that variations in function of the KLF1 gene can alter the HbF levels. PMID- 28886315 TI - The protective effect of cinnamaldehyde on lipopolysaccharide induced acute lung injury in mice. AB - The study wasintended to examinethe protective effect of cinnamaldehyde (CM) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice model.The results of the investigation confirmed that, LPS induced inflammatory cytokines such as TNF-alpha, IL-6, IL-13 and IL-1beta were significantly decreased by CM. CM also up-regulated level of IL-10. We found that CM significantly attenuated LPS induced TLR4 expression, NF-kappaB activation and MPO activity in the lung tissues. It markedly reduced lung wet/dry ratio, and improved typical and severe pathological changes including pulmonary edema in the LPS induced ALI mice. Moreover, CM significantly inhibited neutrophils, macrophages and total cell number in the bronchoalveolar lavage fluid (BALF). In our study, we noted that TLR4-NF-kappaB signaling pathway was involved in acute lung injury.The results revealed the protective effects of CM in LPS-induced ALI, through suppressionTLR4 NF-kappaB signaling pathway. Our finding suggests that Cinnamaldehyde is a potential anti-inflammatory agent in treatment the acute lung injury. PMID- 28886316 TI - Is GDF5 gene promoter polymorphism +104T/C associated with osteoarthritis in the Eastern of Turkey population? AB - Osteoarthritis (OA) is the most common form of arthritis. Genetic factors have been shown to play important roles in the etiology of OA. The gene growth differentiation factor 5 (GDF5) has been implicated in skeletal development and joint morphogenesis in human and mice. A functional single nucleotide polymorphism (SNP) +104T/C in the 5'-UTR of GDF5 (rs143383) was reported to be associated with osteoarthritis susceptibility in Han Chinese and Japanese populations. Our objective was to assess whether this SNP was also associated with OA in the Eastern Turkey population.A total of 172 cases including 95 patients with idiopathic OA and 77 control cases were recruited into the study. DNA samples were extracted from peripheral blood lymphocytes of all cases by using salting out method. The +104T/C polymorphism was genotyped by PCR-RFLP method. In terms of genotype comparison there wasn't any correlation between patient and control groups. Frequency of C allele was found to be higher in patient group than control group and statistical analysis showed a poor correlation in allele frequencies of the +104T/C SNP of GDF5 gene between cases and controls (p<0.05). Significant correlation between GDF5 and OA has been reported in Asian population, especially T alleles were found in higher frequencies and related to OA. Our study did not confirm this association and also in term of T allele. Interestingly, we found higher frequency of C allele in patient group than control group and our results are compatible with the study carried out in Greek population. PMID- 28886317 TI - Potential of Laurencia obtusa as a substrate for the development of a probiotic Saccharomyces cerevisiae. AB - Laurencia obtusa (Ceramiales, Rhodophyta) has tremendous nutritional value, being high in proteins, oligosaccharides, vitamins, essential minerals, and fatty acids, and it is a rich source of amino acids and trace elements. In this study, L. obtusa was extracted and subjected to phenolic, sugar and flavonoid analyses.The fatty acid, vitamin and phytosterol contents in Saccharomyces cerevisiae were evaluated when it was incubated with L. obtusa dry biomass. The fatty acids in the lipid extract were analysed after converting them into methyl esters using gas chromatography, and vitamin concentrations were measured using high-performance liquid chromatography (HPLC). According to the achieved results, the total fatty acid levels and vitamin contents of the S. cerevisiae prepared with algal extract increased at different rates. Our results showed that alpha tocopherol decreased in the group in which the S. cerevisiae was added the algal extract. When compared to the control group, ergesterol increased in the group in which L. obtusa extract was added. Additionally, when compared to the control group in which L. obtusa extract was added, stearic acid (18:0), oleic acid (18:1) and linoleic acid (18:2) increased in the other groups. Palmitoleic acid (16:1) increased in the L. obtusa culture medium, but palmitic acid decreased in the L. obtusa culture medium. In conclusion, it was determined that the L. obtusa extract added to the development medium of S. cerevisiae caused differences in the synthesis of some vitamins and fatty acids. PMID- 28886318 TI - New insights into the expression profile of MicroRNA-34c and P53 in infertile men spermatozoa and testicular tissue. AB - Spermatogenesis is proliferation and differentiation processes of stem spermatogonia into mature spermatozoa controlled by the genes responsible for transcription and post transcription levels. MicroRNAs (miRNA) are the key factors during gene expression in RNA silencing and post-transcriptional regulation. They play main roles in regulation of early and late spermatogenesis, and reproduction. In this study, we investigate the role of miRNAs in infertile males.The patients were assigned to five groups based on semen analysis (n=55), including normozoospermic (N), moderate oligoasthenoteratozoospermic (MOAT), severe oligoasthenoteratozoospermic (SOAT), obstructive azoospermia (OA) and non obstructive azoospermia (NOA). Quantitative RT-PCR was recruited to study the expression of miR-34c and tumor suppressor p53 gene. In addition, malondialdehyde (MDA) and DNA fragmentation was measured. Network analysis was performed using Pathway Studio web tool (Elsevier). Our results revealed statistically significant increased expression of miR-34c in moderate oligoasthenoteratozoospermic, non-obstructive azoospermia and an increased expression of p53 in MOAT, SOAT and NOA males. Also, the percentage of DNA fragmentation and oxidative stress was significantly higher in infertile groups (MOAT and SOAT) than other groups. These findings provide a novel molecular mechanism of gene regulation during cell-cycle and apoptosis in sperm, which gives a new regulatory insight into male infertility in terms of molecular diagnosis. PMID- 28886319 TI - Morphokinetic analysis of human embryo development and its relationship to the female age: a retrospective time-lapse imaging study. AB - Time-lapse imaging technique has provided embryologists with a unique chance of studying the embryo morphokineticsto select the most viable embryos for implantation in the field of IVF (In vitro fertilization).The conventional method of morphological evaluations has proved that maternal age affects the human embryo quality. This retrospective study carried out at Islamabad Clinic Serving Infertile Couples, Islamabad, Pakistan mainly focuses on the effect of female age on human embryo morphokinetics. A total number of 200 patients undergoing ICSI treatment cycles at the clinic were selected for the study and divided into five age groups (< 26, 26-30, 31-35, 36-40, and > 40 years). Embryo culture was done at 37 degrees C, 6% CO2 and 5% oxygen for 5-6 days. Ten time-points were selected for kinetic analysis. The number of retrieved, matured, fertilized and cleaved oocytes showed highly significant difference (P<= 0.0001) when compared among different age groups. There was no significant difference in average morphokinetic time-points among young versus old women.Whereas timely cleaved embryos showed significant difference in tPNa i.e. time for pronuclear appearance (P<= 0.001), t4 and t5 i.e. time for 4 and 5-cell cleavage (P<= 0.05)among different age groups. The clinical pregnancy rates showed a decline with increasing age. These results indicate the effect of female age on time-lapse embryo morphokinetic parameters. In future the addition of time-lapse analysis in routine IVF can help to improve the success rate by selecting the most viable embryos for uterine transfer. PMID- 28886320 TI - Investigation of the irisin, preptin and adropin levels in the blood serum of Alburnus tarichi. AB - Irisin, preptin and adropin are three newly discovered peptides that play critical roles in regulating energy homeostasis in various vertebrates.The purposes of this study were to measure the serum concentrations of preptin, adropin and irisin in the Alburnus tarichi and to investigate the relationship of these peptides to the weight, gender and length of this the fish, which will provide useful information for future biotechnology purposes aimed at improvements in aquaculture production. This study used 12 adult A. tarichi (6 female and 6 male) obtained from Van Lake (Van, Turkey). The serum irisin, preptin and adropin levels were measured using a commercially available enzyme linked immunosorbent assay (ELISA) kit to determine correlations between the levels of these three hormones and fish body weight and length. No statistically significant correlations were detected between the serum irisin, adropin and preptin levels and A. tarichi body weight (p = 0.921, r = -0.031; p = 0.08, r = 0.519; p = 0.461, r = -0.235, respectively) or length (p = 0.901, r = -0.040; p = 0.105, r = 0.490; p = 0.236, r = -0.369, respectively).Thus, serum levels of these hormones are independent of fish gender, body weight and length. PMID- 28886321 TI - Relationship between MCP1 (-2518A>G) gene variants and ovarian cancer in Turkish population. AB - The monocyte chemoattractant protein-1 (MCP-1) gene polymorphism(-2518A>G) in the regulatory region of the MCP-1 protein has been reported to be associated with cancer risk. In this study we aimed to investigate the relationship of MCP-1 (-2518A>G) gene polymorphism and ovarian cancer. MCP-1 genotyping was performed using polymerase chain reaction from blood samples ofovarian cancer patient (n=56) and a control groups (n=52).There was a significant difference in MCP1 ( 2518A>G) genotypes between the patient and control groups (p=0.049; x2=6.042). AA carriers were significantly higher in the control group (p=0.014) whereas AG genotype and G allele carriers were significantly higher in the ovarian cancer group (p=0.029, p=0.014, respectively). This study suggests that MCP-1 (-2518A>G) AG genotype and G allele could be considered as risk factor for susceptibility to ovarian cancer. PMID- 28886322 TI - Carnosol inhibits Hedgehog signaling pathway in both LNCaP and DU145 prostate cancer cell lines. AB - To investigate the effect of carnosol on the Hedgehog (HH) signaling pathway in human hormone-dependent prostate cancer cell line LNCaP and hormone-independent prostate cancer cell line DU145. The expression levels of glioma-associated oncogene homolog 1 (Gli1) and Sonic hedgehog (Shh) in human prostate cancer tissues were detected by immunohistochemistry. After treated with carnosol (0.25 16 MUmol/L), the cell survival of LNCaP and DU145 cells were detected by MTT assay. The expression levels of Gli1 and Shh mRNA and protein in the two cells were detected by qRT-PCR and western blot, respectively. The apoptosis was determined by the caspase-3 activity assay. Results showed that Shh and Gli1 were upregulated in cancer tissues. The inhibitory effect of carnosol on cell survival was enhanced with concentration, suggesting both LNCaP and DU145 cells were sensitive to carnosol. The inhibitory effects of carnosol on Gli1 and Shh mRNAs in the hormone-dependent LNCaP prostate cancer cell was stronger than that in the hormone-independent DU145 prostate cancer cells. Carnosol downregulated the expression of Gli1 in nucleus, and Shh in cells. Greater carnosol concentration resulted in lower levels of Gli1 and Shh. Carnosol increased caspase-3 activity in a dose-dependent manner, suggesting that carnosol promotes cell apoptosis. Thus, carnosol can inhibit the proliferation and induce the apoptosis of prostate cancer cells in vitro, and its mechanism might be associated with the inhibiting of HH signaling pathway. Although the inhibitory effect of carnosol on hormone dependent LNCaP prostate cancer cells is stronger than hormone-independent DU145 prostate cancer cells, carnosol might be a potential drug for hormone-independent prostate cancer. PMID- 28886323 TI - Genotoxic and cytotoxic potential of Alternanthera Bettzickiana, an important ethno-medicinal plant. AB - The present study was carried out to investigate the mutagenic and cytotoxic potential of n-hexane and aqueous-methanolic whole plant extracts of Alternanthera bettzickiana. Aqueous-methanolic and n-hexane extracts of Alternanthera bettzickiana extracts were assessed for the mutagenic potential with Salmonella tester strains TA-100 and TA-102 in the presence and absence of the rodent enzyme activation system and cytotoxic potential was assessed by MTT assay. Aqueous-methanolic extract showed the presence of saponins, tannins, terpenoids, flavonoids and glycosides. However n-hexane extract revealed the presence of tannins and terpenoids only. It was found that a concentration as low as 15mg/mL of both extracts was more mutagenic to the TA 102 tester strain than TA-100. Hexane whole plant extract of Altenanthera bettzickiana was more mutagenic than aqueous-methanolic extract considering revertant colonies of TA 100 strain. Aqueous-methanolic and n-hexane whole plant extracts of Altenanthera bettzickiana showed higher mutagenic potential in the presence of the enzyme activation system. Mutagenicity of aqueous-methanolic extract increased with an enzyme activation system in case of TA 100 whereas mutagenicity of n-hexane extract decreased in the presence of the enzyme activation system with TA 100 and TA 102 strains. Aqueous-methanolic and n-Hexane whole plant extracts of Alternanthera bettzickiana showed an IC-50 of 493 and 456 ug/mL in BHK-21 cells respectively. It can be concluded that Altenanthera bettzickiana exhibited mutagenic activity in a bacterial reverse mutation assay with and without enzyme activation systems. However, it showed limited cytotoxicity to BHK-21 cells. PMID- 28886324 TI - Atypical bacterial etiology of acute respiratory infections and clinical characterizations among Iranian children. AB - Acute respiratory infections (ARIs) in children younger than 5 years of age are one of the leading causes of morbidity and mortality, particularly in developing countries. Mycoplasma pneumoniae and Chlamydophila pneumoniae are prevalent causative agents of ARIs, worldwide. We sought M. pneumoniae and C. pneumoniae in respiratory samples from Iranian children with ARIs. From November 2014 to April 2015, respiratory samples of 150 children aged 1 month to 15 years old were screened for presence of M. pneumoniae and C. pneumoniae. Polymerase chain reaction (PCR) and culture methods were used to detect these bacteria in respiratory samples in the form of throat swabs and nasopharyngeal aspirates. A questionnaire containing demographic and clinical information has been filled up for all participants in this study. Our obtained data showed that out of 150 tested samples, 7 (4.7%) were PCR positive for M. pneumoniae and only one (0.7%) positive sample for C. pneumoniae was detected. However, none of the tested samples was detected M. pneumoniae using the bacterial culture method. All patients with ARIs due to M. pneumoniae showed up with sore throat and flu like symptoms. According to our data, PCR method is more sensitive than culture for detection of M. pneumoniae. With regards to our results, it appears that M. pneumoniae and especially C. pneumoniae were infrequent causative agents in our studied population. PMID- 28886325 TI - Nullification of aspirin induced gastrotoxicity and hepatotoxicity by prior administration of wheat germ oil in Mus musculus: histopathological, ultrastructural and molecular studies. AB - Aspirin (acetyl salicylic acid) is used worldwide to treat various inflammatory conditions and prevent cardiovascular disease, along with reducing the risk of cancer. However, administration of aspirin causes toxic effects, especially in the stomach and liver. Thus, our study examined the protective effect of wheat germ oil on aspirin-induced toxicity in the stomach and liver tissues of Swiss albino mice. Administration of wheat germ oil before aspirin has restored normal hepatic and gastric tissue architecture and DNA integrity has become better than that of a negative health control group compared with the aspirin only treated group. The elevated gastric nitric oxide content in the aspirin only treated group was significantly decreased by wheat germ oil prior administration as a result of reduced the expression of inducible nitric synthase and increased the expression of endothelial nitric oxide synthase compared to their expression in the aspirin administered group. Wheat germ oil pre-administration significantly reduced the level of malondialdehyde, increased the level of glutathione and catalase and superoxide dismutase activities compared with those in aspirin only treated group. We conclude that wheat germ oil has a potential protective effect against aspirin induced gastro- and hepato-toxicity because of its free radical scavenging ability. PMID- 28886326 TI - miR-146a rs2910164 polymorphism might be associated with coronary artery disease risk in Asians. AB - Recently, several studies reported the association between miR-146a rs2910164 polymorphism and coronary artery disease (CAD) risk. However, the results were inconclusive. We therefore did a meta-analysis to investigate this association. Electronic databases, including PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) databases, were searched. The strength of association was assessed by calculating odds ratios (OR) and 95% confidence interval (CI). Five eligible studies included in this meta-analysis. The total sample size of this meta-analysis was 1565 cases and 1541 controls. We found that miR-146a rs2910164 polymorphism was significantly associated with an increased CAD risk (OR = 1.19; 95% CI 1.07 - 1.32; P = 0.002). In the subgroup analysis by race, miR-146a rs2910164 polymorphism was significantly associated with an increased CAD risk in Asians (OR = 1.18; 95% CI 1.04 - 1.33; P = 0.008). However, we did not find significant result in Caucasians (OR = 1.22; 95% CI 0.86 - 1.74; P = 0.25). In the subgroup analysis by age, we found that miR-146a rs2910164 polymorphism increased CAD risk in old population (OR = 1.22; 95% CI 1.09 - 1.38; P = 0.0008). In conclusion, this meta-analysis found that miR-146a rs2910164 polymorphism was significantly associated with CAD risk. PMID- 28886327 TI - Association between platelet to lymphocyte ratio (PLR) and overall survival (OS) of hepatocellular carcinoma (HCC): A meta-analysis. AB - Some studies investigated the association between platelet-to-lymphocyte ratio (PLR) and the survival of hepatocellular carcinoma (HCC). However, the results remained inconclusive. Thus, we performed this meta-analysis. Published studies were searched in PubMed and EMBASE. The strength of association was assessed by calculating odds ratios (OR) and 95% confidence interval (CI). In total, 6 studies with 1446 HCC patients were included in this meta-analysis. HCC with higher PLR showed an increased death risk (OR = 1.59; 95%CI, 1.15-2.20; P < 0.0001). However, the heterogeneity was high (I2=89.2%). When the study by Li et al. was excluded, the heterogeneity decreased (I2=20%). Further, the result was still positive (OR = 1.70; 95%CI, 1.42-2.04; P < 0.00001). In conclusion, this meta-analysis suggested that PLR was significantly associated with the OS of HCC. PMID- 28886328 TI - Angiotensin-converting enzyme (ACE) I/D polymorphism is a risk factor of allergic rhinitis. AB - Some previous studies and meta-analysis investigated the association between ACE I/D polymorphism and allergic rhinitis risk. However, the results were conflicting. This meta-analysis, therefore, was performed to evaluate the association between ACE I/D polymorphism and allergic rhinitis risk. Online electronic databases (PubMed and EMBASE) were searched. The strength was evaluated by calculating the OR and 95% CI. Five studies were finally included in this meta-analysis. These studies included 681 cases and 629 controls. ACE I/D polymorphism was significantly associated with allergic rhinitis risk (OR = 1.17; 95% CI 1.07 - 1.29; P = 0.001). In the subgroup analysis of race, Asians showed the increased allergic rhinitis risk (OR = 1.15; 95% CI 1.02 - 1.30; P = 0.03). In a stratified analysis by age, adults with ACE I/D polymorphism showed the increased allergic rhinitis risk (OR = 1.16; 95% CI 1.04 - 1.29; P = 0.006). However, children did not have the significantly increased allergic rhinitis risk (OR = 1.24; 95% CI 0.99 - 1.56; P = 0.06). In conclusion, this meta-analysis indicated that ACE I/D polymorphism was significantly associated with allergic rhinitis risk. PMID- 28886329 TI - A case of IgG4-related retroperitoneal fibrosis with multiple involvement. AB - To increase awareness of IgG4-related retroperitoneal fibrosis (IgG4-RRPF) and reduce clinical misdiagnosis. We report a 79-year-old man with multiple organs involvement of IgG4-RRPF, who developed right lower extremity edema, hemoptysis and fever. The abdomen computed tomography (CT) scan image showed lymph nodes enlargement. The positron emission tomography/CT scan image showed pancreatic malignancy with multiple nodal lymph node metastasis, lung fibroblast proliferation, and right lung apex bullae. The chest CT scan image showed pulmonary multiple lymph nodes with calcification in the mediastinum. Posterior peritoneum magnetic resonance imaging showed the body and tail of the pancreas parenchymatous mass. The serum IgG4 concentration was high. The fibrous connective tissue with IgG4-positive plasma cells infiltration in the left supraclavicular lymph node biopsy was found. Fiberoptic bronchoscopy showed diffuse alveolar hemorrhage, and the transbronchial lung biopsy found no cancer cells. The patient was treated with glucocorticoids and immunosuppressive agents. After 2 months treatment, the patient showed rapid improvement. This is a case of IgG4-RRPF with multiple organs involvement. Glucocorticoid is the first-line treatment. PMID- 28886330 TI - Cornelia de lange syndrome with thyroid agenesis of an indonesian patient. AB - Cornelia de Lange syndrome (CdLs), which is also called Brachmann de Lange syndrome, is a congenital disorder characterized by distinctive facial features, prenatal and postnatal growth deficiency, feeding difficulties, psychomotor delay, behavioral problems, and associated malformations that mainly involve the upper extremities. The prevalence ranges from 1:100,000 to as high as 1:10,000. Most cases (50-60%) were carried mutation in NIPBL gene. To our knowledge this is the first CdLs Indonesian case that reported with molecular analysis study. We present an 11 months old female Indonesian patient with classic CdLs with congenital hypothyroid. Genetics studies were performed in intron 1, exon 2, exon 10 and exon 22 of NIPBL gene. Thyroid studies (T3, T4, TSH and thyroid scan) were performed. Low level of T3 and T4, and high level of TSH were observed. Thyroid agenesis was found in thyroid scan examination. We detected thyroid agenesis which has been never reported in CdLs patients. We could not find any mutation in intron 1, exon 2, exon 10 and exon 22 of NIPBL gene. Further genetics examinations were necessary whether there is mutation in other locus. PMID- 28886331 TI - Towards carborane-functionalised structures for the treatment of brain cancer. AB - Boron neutron capture therapy (BNCT) is a promising targeted chemoradiotherapeutic technique for the management of invasive brain tumors, such as glioblastoma multiforme (GBM). A prerequisite for effective BNCT is the selective targeting of tumour cells with 10B-rich therapeutic moieties. To this end, polyhedral boranes, especially carboranes, have received considerable attention because they combine a high boron content with relative low toxicity and metabolic inertness. Here, we review progress in the molecular design of recently investigated carborane derivatives in light of the widely accepted performance requirements for effective BNCT. PMID- 28886332 TI - Evolving Models of Heterochromatin: From Foci to Liquid Droplets. AB - Two recent papers (Larson et al., 2017; Strom et al., 2017) in Nature propose that heterochromatic domains are organized into phase-separated liquid compartments. Here we highlight the main findings that support the liquid-like nature of HP1 domains and discuss their functional implications in gene silencing and genome organization. PMID- 28886333 TI - Mammalian Circadian Cogwheels Are Parts of Macromolecular Machines. AB - In this issue of Molecular Cell, two papers address the biochemical structure of a large protein complex containing components of the mammalian circadian clock (Aryal et al., 2017) and a mechanism rendering this molecular timekeeper temperature-compensated (Shinohara et al., 2017). PMID- 28886334 TI - New Insights into Genome Structure: Genes of a Feather Stick Together. AB - DNA structuring proteins such as CTCF facilitate DNA loop formation and are presumed to be among the major determinants of eukaryotic genome structure. Recent studies, including Rowley et al. (2017), suggest that gene activation and repression play fundamentally important roles in structuring the genome independently of CTCF. PMID- 28886335 TI - Macromolecular Assemblies of the Mammalian Circadian Clock. AB - The mammalian circadian clock is built on a feedback loop in which PER and CRY proteins repress their own transcription. We found that in mouse liver nuclei all three PERs, both CRYs, and Casein Kinase-1delta (CK1delta) are present together in an ~1.9-MDa repressor assembly that quantitatively incorporates its CLOCK BMAL1 transcription factor target. Prior to incorporation, CLOCK-BMAL1 exists in an ~750-kDa complex. Single-particle electron microscopy (EM) revealed nuclear PER complexes purified from mouse liver to be quasi-spherical ~40-nm structures. In the cytoplasm, PERs, CRYs, and CK1delta were distributed into several complexes of ~0.9-1.1 MDa that appear to constitute an assembly pathway regulated by GAPVD1, a cytoplasmic trafficking factor. Single-particle EM of two purified cytoplasmic PER complexes revealed ~20-nm and ~25-nm structures, respectively, characterized by flexibly tethered globular domains. Our results define the macromolecular assemblies comprising the circadian feedback loop and provide an initial structural view of endogenous eukaryotic clock machinery. PMID- 28886336 TI - Temperature-Sensitive Substrate and Product Binding Underlie Temperature Compensated Phosphorylation in the Clock. AB - Temperature compensation is a striking feature of the circadian clock. Here we investigate biochemical mechanisms underlying temperature-compensated, CKIdelta dependent multi-site phosphorylation in mammals. We identify two mechanisms for temperature-insensitive phosphorylation at higher temperature: lower substrate affinity to CKIdelta-ATP complex and higher product affinity to CKIdelta-ADP complex. Inhibitor screening of ADP-dependent phosphatase activity of CKIdelta identified aurintricarboxylic acid (ATA) as a temperature-sensitive kinase activator. Docking simulation of ATA and mutagenesis experiment revealed K224D/K224E mutations in CKIdelta that impaired product binding and temperature compensated primed phosphorylation. Importantly, K224D mutation shortens behavioral circadian rhythms and changes the temperature dependency of SCN's circadian period. Interestingly, temperature-compensated phosphorylation was evolutionary conserved in yeast. Molecular dynamics simulation and X-ray crystallography demonstrate that an evolutionally conserved CKI-specific domain around K224 can provide a structural basis for temperature-sensitive substrate and product binding. Surprisingly, this domain can confer temperature compensation on a temperature-sensitive TTBK1. These findings suggest the temperature-sensitive substrate- and product-binding mechanisms underlie temperature compensation. PMID- 28886338 TI - Hospitalizations for ambulatory care sensitive conditions and unplanned readmissions among Medicare beneficiaries with Alzheimer's disease. AB - INTRODUCTION: Medicare beneficiaries with Alzheimer's disease and related dementias (ADRDs) may have more potentially avoidable hospitalizations and readmissions than people without dementia. These hospitalizations may be indicative of access barriers, problems in continuity of care, inefficient resource use, and poor patient outcomes. METHODS: We examined national frequency and costs of ambulatory care sensitive condition hospitalizations and unplanned, all-cause, and condition-specific 30-day readmissions in >2.7 million fee-for service ADRD patients using 2013 Medicare claims data. RESULTS: In 2013, 410,000 Medicare ADRD patients had ambulatory care sensitive condition hospitalizations or unplanned 30-day readmissions costing $4.7 billion. One in 10 ADRD patients were hospitalized for a potentially avoidable condition. Almost one in five hospitalized ADRD patients had an unplanned 30-day readmission. Readmission rates were highest among ADRD patients initially hospitalized for heart failure (22%) and chronic obstructive pulmonary disease (21%). DISCUSSION: Our findings may suggest potential deficiencies in ambulatory care and postdischarge care related to managing comorbidities among Medicare fee-for-service ADRD patients. PMID- 28886337 TI - Replication Fork Slowing and Reversal upon DNA Damage Require PCNA Polyubiquitination and ZRANB3 DNA Translocase Activity. AB - DNA damage tolerance during eukaryotic replication is orchestrated by PCNA ubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitination activates an error-free pathway, elusive in mammals, enabling damage bypass by template switching. Fork reversal is driven in vitro by multiple enzymes, including the DNA translocase ZRANB3, shown to bind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and template switching in vivo was unknown. Here we show that damage induced fork reversal in mammalian cells requires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved in error-free damage tolerance. Fork reversal in vivo also requires ZRANB3 translocase activity and its interaction with polyubiquitinated PCNA, pinpointing ZRANB3 as a key effector of error-free DNA damage tolerance. Mutations affecting fork reversal also induced unrestrained fork progression and chromosomal breakage, suggesting fork remodeling as a global fork slowing and protection mechanism. Targeting these fork protection systems represents a promising strategy to potentiate cancer chemotherapy. PMID- 28886339 TI - Longitudinal Study of Insomnia Symptoms Among Women During Perimenopause. AB - OBJECTIVE: To describe the prevalence of insomnia symptoms among women during perimenopause and to examine differences in self-reported insomnia symptoms at different stages of perimenopause over 10 years. DESIGN: Secondary analysis of self-reported sleep symptoms and clinical variables using 10 years of publicly available data from the Study of Women Across the Nation (SWAN). SETTING: The data set of women's insomnia symptoms was obtained from publicly available data from the SWAN. The parent study settings included Detroit, Michigan; Northern New Jersey; Los Angeles, California; Boston, Massachusetts; Chicago, Illinois; and Pittsburgh, Pennsylvania. PARTICIPANTS: Multiethnic midlife women with a mean age of 46 years (N = 3,302) categorized as pre- and perimenopausal at baseline. METHODS: Dependent variables included self-reported insomnia symptoms: difficulty falling asleep (sleep latency), wake after sleep onset, early morning awakenings, and sleep quality. Descriptive analysis was completed for each 1-year study interval. Repeated measures logistic regression was used to identify whether insomnia symptoms changed over time by stage of perimenopause. RESULTS: Insomnia symptoms were present in 31% to 42% of perimenopausal women at any 1-year study interval. Insomnia symptoms were more prevalent in the late stage of perimenopause than the early stage (p < .001). The odds of having any insomnia symptoms were 1.3 times greater for women in the late stage of perimenopause than in the early stage (95% confidence interval [1.2, 1.5], p < .001). CONCLUSION: Insomnia symptoms are prevalent in women transitioning to menopause, and stage of perimenopause may heighten the risk to develop symptoms of insomnia disorder, which is associated with negative cardiometabolic outcomes. PMID- 28886340 TI - Variant Interpretation: Functional Assays to the Rescue. AB - Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of "lookup tables" of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis. PMID- 28886341 TI - CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. AB - In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development. PMID- 28886342 TI - A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis. AB - Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p <= 5 * 10-8. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research. PMID- 28886343 TI - Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44. AB - The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias. PMID- 28886344 TI - A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility. AB - Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Genome wide linkage analyses and whole-exome sequencing revealed a paternally transmitted heterozygous missense mutation of c.400 G>A (p.Ala134Thr) in zona pellucida glycoprotein 3 (ZP3). The same mutation was identified in an unrelated EFS pedigree. Haplotype analysis revealed that the disease allele of these two families came from different origins. Furthermore, in a cohort of 21 cases of EFS, two were also found to have the ZP3 c.400 G>A mutation. Immunofluorescence and histological analysis indicated that the oocytes of the EFS female had degenerated and lacked the zona pellucida (ZP). ZP3 is a major component of the ZP filament. When mutant ZP3 was co-expressed with wild-type ZP3, the interaction between wild-type ZP3 and ZP2 was markedly decreased as a result of the binding of wild-type ZP3 and mutant ZP3, via dominant negative inhibition. As a result, the assembly of ZP was impeded and the communication between cumulus cells and the oocyte was prevented, resulting in oocyte degeneration. These results identified a genetic basis for EFS and oocyte degeneration and, moreover, might pave the way for genetic diagnosis of infertile females with this phenotype. PMID- 28886347 TI - Editorial Comment. PMID- 28886346 TI - In Memoriam-Lawrence Lumeng, MD: Researcher, Clinician, Leader, Mentor, Family Man, and Friend. PMID- 28886348 TI - Personalized Treatment of Vesicoureteral Reflux-Where are We Now? PMID- 28886345 TI - RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes. AB - RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ~10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration. PMID- 28886350 TI - Editorial Comment. PMID- 28886352 TI - Benchmarking: An Effective Tool to Demystify the Academic Career. PMID- 28886351 TI - Does Dexamethasone Facilitate Neurosensory Function Regeneration After Zygomatic Fracture? A Randomized Controlled Trial. AB - PURPOSE: This study sought to clarify the rate of neurosensory disturbance (NSD) after zygomatic complex fractures in general, as well as the effect of perioperatively administered dexamethasone on neurosensory recovery. PATIENTS AND METHODS: This was a single-blinded randomized study aiming to clarify the benefits of perioperative dexamethasone after surgery. The patients were randomly assigned either to receive dexamethasone (up to a total dose of 10 or 30 mg) or to act as control patients (no glucocorticoid treatment). The outcome variable was NSD, the presence of which was established when patients had any sensory disturbance of the infraorbital nerve. Other predictor variables included in the analysis were age, gender, time span from accident to surgery, surgical approach to the fracture line, and relation of the fracture to the infraorbital foramen. The statistical significance of associations was evaluated with chi2 tests. RESULTS: We included 64 patients in the analyses. Of the patients in the dexamethasone group (either 10 or 30 mg), 58.3% had NSD at 6 months postoperatively, whereas in the control group, 66.7% of the patients had NSD. This finding was not statistically significant (P = .565). At the 1-month interval, the patients without a fracture through the infraorbital foramen had less NSD (P = .009); this finding was not significant at 3 and 6 months postoperatively. Age, gender, injury mechanism, surgical approach, and time span from accident to surgery were not significant predictors of NSD. In total, 64.4% of the patients still had NSD at 6 months postoperatively. CONCLUSIONS: This study showed no benefits of short-term, high-dose dexamethasone administration in the neurosensory recovery of patients with zygomatic complex fractures. The type of primary trauma is the main cause of NSD, but the precise predictors remain unknown. PMID- 28886353 TI - Initial Manifestation of Acquired Hemophilia A After a Routine Tooth Extraction. A Case Report and Literature Review. AB - Although surgical treatment of patients on anticoagulation regimens is common practice among oral and maxillofacial surgeons, unexpected and unknown coagulopathies can have devastating and catastrophic consequences for the most routine of procedures. Acquired hemophilia A (AHA) is an extremely rare life threatening bleeding disorder characterized by autoantibodies directed against circulating coagulation factor VIII. The effects of AHA can produce catastrophic bleeding and hematomas. The effect of this uncontrolled hemorrhage after dentoalveolar surgery can mimic severe head and neck infection by causing dysphagia, odynophagia, and acute airway complications. This report describes the case of a 64-year-old woman who was diagnosed with AHA after routine extraction of the mandibular left third molar. PMID- 28886354 TI - Closed Approach for Horizontal Augmentation of the Maxilla. AB - The narrow ridge in the anterior maxilla often requires horizontal augmentation for ideal implant placement. This article reviews the historical use of a closed, tunnel approach to augment deficient alveolar ridges and describes its application for augmentation of the narrow ridge in the anterior maxilla. The use of a tunnel approach through a vertical incision in the unattached mucosa provides access to the ridge while maintaining crestal attachments without displacement of the crestal attached gingiva. This approach is atraumatic and provides excellent access for placement of graft material for ridge augmentation. PMID- 28886355 TI - The Cervicofacial Flap in Cheek Reconstruction: A Guide for Flap Design. AB - PURPOSE: The cervicofacial (CF) flap is a random-pattern flap that provides an excellent match for cheek reconstruction. The design of the CF flap varies between different cheek subunits. In this report, the authors review their experience with this flap and present a guide for flap design for different cheek subunits. MATERIALS AND METHODS: Patients who had cheek reconstruction were screened using the database of the surgical procedures from 2011 to 2016. Seventy four patients were identified. Data on patient demographics, diagnosis, defect type, and outcome were retrospectively reviewed. Patients who did not have a clear description of the defect or flap design were excluded from the study. The authors divided the cheek into 3 zones and created a guide for flap design for each zone. RESULTS: Twenty-eight patients with CF flap for cheek reconstruction met the inclusion criteria (21 male [75%] and 7 female [25%]; mean age, 57 yr; range, 8 to 88 yr). Fifty-seven percent had zone A defects, 18% had zone B1 defects, 14% had zone B2 defects, and 11% had multiple-zone defects. Mean follow up was 4.6 months (0 to 17 months). Ninety-three percent had a successful outcome. Only 2 patients developed wound complications. CONCLUSION: The CF flap is a versatile flap that provides excellent skin color, thickness, and texture match in cheek reconstruction. Planning the flap design is essential to achieve a good outcome. The present algorithm provides a straightforward method to reliably design the CF flap for cheek reconstruction. PMID- 28886356 TI - African Americans in Oral and Maxillofacial Surgery: Factors Affecting Career Choice, Satisfaction, and Practice Patterns. AB - PURPOSE: There are few data available on the experience of minority surgeons in the field of oral and maxillofacial surgery (OMS). Therefore, the purpose of this study was to 1) explore factors that contribute to African Americans choosing OMS as a career, 2) examine satisfaction among minority oral and maxillofacial surgeons with the residency application and training process, 3) report on practice patterns among minority oral and maxillofacial surgeons, and 4) identify perceived bias for or against minority oral and maxillofacial surgeons in an attempt to aid the efforts of OMS residency organizations to foster diversity. MATERIALS AND METHODS: A 19-item survey was sent to 80 OMS practitioners by use of information from the mailing list of the National Society of Oral and Maxillofacial Surgeons, an American Association of Oral and Maxillofacial Surgeons-affiliated organization. All surveys were sent by mail and were followed by a reminder mailing after 8 weeks. Responses returned within 16 weeks were accepted for analysis. RESULTS: Of the 80 mailed surveys, 41 were returned within the 16-week parameter, representing a return rate of 51%. Most of the minority surgeon respondents were married men with a mean age of 60 years who worked as private practitioners. Most respondents practiced on the eastern and western coasts of the United States. Exposure in dental school was the most important factor in selecting OMS as a specialty. Location and prestige were the most important factors in selecting a residency program. Most respondents reported that race did not affect the success of their application to a residency program and did not currently affect the success of their practice. However, 25 to 46% of participants experienced race-related harassment, and 48 to 55% of participants believed there was a bias against African Americans in OMS. CONCLUSIONS: Our data suggest that a substantial number of minority oral and maxillofacial surgeons subjectively perceive race-based bias in their career, although it does not appear to affect professional success. PMID- 28886357 TI - A Retrospective Volume Matched Analysis of the Submental Artery Island Pedicled Flap as Compared to the Forearm Free Flap: Is It a Good Alternative Choice for the Reconstruction of Defects of the Oral Cavity and Oropharynx? AB - PURPOSE: The submental artery island pedicled flap (SMIF) is an underused alternative for reconstruction of head and neck defects after tumor ablation. The purpose of this study was to perform a comparative evaluation of reconstructive outcomes based on surgical site and ablative defect volume in patients who underwent reconstruction with the SMIF versus the forearm free flap (FFF). MATERIALS AND METHODS: A retrospective cohort study of all patients with oral cavity and oropharyngeal defects reconstructed with the SMIF and a cohort of patients with similar volume defects reconstructed with the FFF were compared for oncologic safety and viability of equivalent reconstructive outcomes. All statistical comparisons were assessed by analysis of variance and Fisher exact test. RESULTS: Average age was 61.8 years in the SMIF group versus 57.9 years in the FFF group. The most common defect was located in the tongue, with squamous cell carcinoma being the most common pathology identified. Flap volumes were similar (SMIF, 38.79 cm3; FFF, 39.77 cm3). Significant comparative outcomes identified with SMIF versus FFF reconstruction included shorter anesthesia times (815 vs 1,209 minutes; P < .001), shorter operative times (653 vs 1,031 minutes; P < .001), and less blood loss (223 vs 398 mL; P = .04). Postoperative Eastern Co operative Oncology Group performance score increased more for the FFF than for the SMIF group (+0.33 vs + 1.25; P = .0019). Recipient site complication rates were lower for the FFF group (0.17 vs 0.42 per patient) but were not statistically relevant. There were equal rates of recurrence at the local surgical site and no differences in speech and swallowing function. Mean follow up was 15.5 months. CONCLUSIONS: This is the first study to compare the SMIF with the FFF for reconstruction of oral cavity defects based on ablative volume deficit. The SMIF is a viable surgical option compared with the FFF that can be considered oncologically safe in the N0 neck, allowing for an excellent esthetic reconstruction, with decreased operative time, hospital stay, and donor site morbidity. PMID- 28886358 TI - Open Sesame: Open Chromatin Regions Shed Light onto Non-coding Risk Variants. AB - Human genetics and stem cell biology have advanced neurobiology for neurodevelopmental psychiatric disorders. In this issue of Cell Stem Cell, Forrest et al. (2017) demonstrate that studying the landscape of open chromatin regions in stem cell-derived neurons helps functional interpretation of non coding genetic variants associated with these diseases. PMID- 28886359 TI - The TREX1 Dinosaur Bites the Brain through the LINE. AB - In this issue of Cell Stem Cell, Thomas et al. (2017) define the nature of accumulated ssDNA present in the neuron and astrocyte cytoplasm of TREX1 mutated stem cell-derived organoids. Accumulated ssDNAs are derived from LINE-1 endogenous retroelements, providing new clues as to the development of Aicardi Goutieres syndrome in the neural system. PMID- 28886360 TI - Putting Two Heads Together to Build a Better Brain. AB - 3D organoids enable in vitro human brain development models, but they have not yet recapitulated some essential features of brain circuit formation. Recently, several studies appearing in Nature, Nature Methods, and Cell Stem Cell generated fused organoid models of inhibitory and excitatory neuron development, which can now achieve functional circuit integration. PMID- 28886361 TI - Survival of the Fittest: Darwinian Selection Underpins Chemotherapy Resistance in AML. AB - Intratumor heterogeneity driving therapeutic resistance is a major challenge in cancer management. Recently in Nature, Shlush et al. (2017) provide a tour de force of genomics coupled to functional assays to demonstrate that resistance emerges from a pre-existing subpopulation of acute myeloid leukemia (AML) cells with a stem cell transcription program. PMID- 28886362 TI - Hypothalamic Neurons Take Center Stage in the Neural Stem Cell Niche. AB - Neural stem cells (NSCs) are a heterogeneous population of cells that generate new neurons in adult animals. Recently in Science, Paul et al. (2017) show that hypothalamic neurons control activation of a subset of NSCs in response to feeding, providing insights into how physiological cues may influence stem cell activation. PMID- 28886363 TI - CRISPR: Established Editor of Human Embryos? AB - Off-target effects and mosaicism are major concerns for applying CRISPR-Cas9 to correct genetic mutations. A recent article in Nature by Ma et al. (2017) uses an elegant CRISPR-Cas9 approach that repairs a genetic mutation in human embryos with negligible mosaicism and no off-target effects, bringing this editing tool closer to clinical application. PMID- 28886364 TI - Synergistic Engineering: Organoids Meet Organs-on-a-Chip. AB - Organoid technology and organ-on-a-chip engineering have emerged as two distinct approaches for stem cell-derived 3D tissue preparation. Their strategic integration can address each approach's limitations and provide a path toward a superior, synergistic strategy of constructing tissues that will truly deliver on the promise of regenerative and precision medicine. PMID- 28886365 TI - Mitochondrial Replacement Techniques: Remaining Ethical Challenges. AB - Recent developments in the field of mitochondrial replacement technique (MRT) research and clinical practice have raised ethical concerns worldwide. We argue that the future use of MRTs requires a concerted effort among the global research and clinical community to implement and enforce responsible innovation and governance. PMID- 28886368 TI - ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells. PMID- 28886366 TI - MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype Specific Reprogramming of Adult Human Fibroblasts. AB - Directed reprogramming of human fibroblasts into fully differentiated neurons requires massive changes in epigenetic and transcriptional states. Induction of a chromatin environment permissive for acquiring neuronal subtype identity is therefore a major barrier to fate conversion. Here we show that the brain enriched miRNAs miR-9/9* and miR-124 (miR-9/9*-124) trigger reconfiguration of chromatin accessibility, DNA methylation, and mRNA expression to induce a default neuronal state. miR-9/9*-124-induced neurons (miNs) are functionally excitable and uncommitted toward specific subtypes but possess open chromatin at neuronal subtype-specific loci, suggesting that such identity can be imparted by additional lineage-specific transcription factors. Consistently, we show that ISL1 and LHX3 selectively drive conversion to a highly homogeneous population of human spinal cord motor neurons. This study shows that modular synergism between miRNAs and neuronal subtype-specific transcription factors can drive lineage specific neuronal reprogramming, providing a general platform for high-efficiency generation of distinct subtypes of human neurons. PMID- 28886367 TI - A Modular Platform for Differentiation of Human PSCs into All Major Ectodermal Lineages. AB - Directing the fate of human pluripotent stem cells (hPSCs) into different lineages requires variable starting conditions and components with undefined activities, introducing inconsistencies that confound reproducibility and assessment of specific perturbations. Here we introduce a simple, modular protocol for deriving the four main ectodermal lineages from hPSCs. By precisely varying FGF, BMP, WNT, and TGFbeta pathway activity in a minimal, chemically defined medium, we show parallel, robust, and reproducible derivation of neuroectoderm, neural crest (NC), cranial placode (CP), and non-neural ectoderm in multiple hPSC lines, on different substrates independently of cell density. We highlight the utility of this system by interrogating the role of TFAP2 transcription factors in ectodermal differentiation, revealing the importance of TFAP2A in NC and CP specification, and performing a small-molecule screen that identified compounds that further enhance CP differentiation. This platform provides a simple stage for systematic derivation of the entire range of ectodermal cell types. PMID- 28886369 TI - Two hybrid Au-ZnO aggregates with different hierarchical structures: A comparable study in photocatalysis. AB - Two hierarchical ZnO micro/nano-materials have been prepared by a short-time (45min) hydrothermal reaction without any surfactants. The different morphologies have been characterized comprehensively by XRD, SEM, TEM and XPS technologies. The hierarchical micro- and nano-structures are respectively consisted by the subordinate nano-pieces and nano-hexagonal-rods. Under the illumination of the simulated solar light, the nano-piece-aggregate spends 40min to degrade the 98% of rhodamine 6G solution (10-5mol/L), whereas the nano-rod-aggregate only degrades the 78% of the solution in the same condition. Moreover, the photocatalytic performances of the two ZnO aggregates are significantly improved by loading with Au nanoparticles (NPs) in the same assembly process. The nano piece-aggregate decorated with the Au NPs spends 24min to decompose the rhodamine 6G solution completely, while nano-rod-aggregate decorated with the Au NPs needs 28min. The related photocatalytic mechanisms are proposed in this paper. PMID- 28886370 TI - Synthesis of iron and copper cluster-grafted zinc oxide nanorod with enhanced visible-light-induced photocatalytic activity. AB - Design of visible-light-responsive photocatalyst employing simple and cost effective method is of great importance from commercial point of view. Herein, we report the synthesis of visible-light-sensitive ubiquitous nanoclusters of Fe3+/Cu2+-grafted ZnO nanorod using impregnation technique, which showed excellent photocatalytic activity towards the decomposition of Rhodamine B (RhB), 4-nitrophenol (4-NP) and paracetamol in aqueous suspension under atmospheric oxygen. Fe-grafted ZnO nanorod exhibited pronounced effect for the degradation of the above-mentioned pollutants compared to pure ZnO and Cu-grafted ZnO nanorod. The better activity could be due to the more positive redox potential of surface grafted Fe3+ species resulting in the generation of more hydroxyl radicals thereby, leading to higher photodegradation rate. PMID- 28886371 TI - One-pot fabrication of reduced graphene oxide supported dendritic core-shell gold@gold-palladium nanoflowers for glycerol oxidation. AB - Herein, a one-pot wet-chemical route was used to prepare well-defined dendritic core-shell gold@gold-palladium nanoflowers supported on reduced graphene oxide (Au@AuPd NFs/rGO), using 2, 4-dihydroxypyridine (2, 4-DHP) asa new stabilizer and structure-director. Their morphology, size, composition, and crystal structure were characterized by a set of characterization techniques. Control experiments demonstrated that the molar ratio of the metal precursors and the dosage of 2,4 DHP play essential roles in this synthesis. The growth mechanism of dendritic core-shell Au@AuPd nanoflowers was investigated in details. The synthesized branched architectures exhibited enlarged electrochemically active surface area (ECSA), improved catalytic properties, enhanced stability and durability toward glycerol oxidation in alkaline media when compared to the home-made Au26Pd74 nanocrystals (NCs)/rGO and Au78Pd22 NCs/rGO, along with commercially available Pd/C catalyst. PMID- 28886372 TI - Bismuth oxide decorated graphene oxide nanocomposites synthesized via sonochemical assisted hydrothermal method for adsorption of cationic organic dyes. AB - Bismuth oxide decorated graphene oxide (Bi2O3@GO) nanocomposites were successfully synthesized by sonochemical method followed by hydrothermal treatment. The structural, morphology/microstructure and functional groups were investigated through X-ray Diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM), Transmission Electron Microscopy (TEM) and Fourier Transform Infrared (FTIR) spectroscopy, respectively. In the FESEM and TEM studies, well dispersed Bi2O3 nanoparticles of size 3-5nm were found uniformly distributed throughout the surface and edges of GO sheets. The HRTEM measurements on the Bi2O3 nanoparticle decorated graphene oxide shows imaged lattice spacing of 3.2A corresponding to (111) plane of Bi2O3 which confirms the successful synthesis of bismuth oxide decorated graphene oxide (Bi2O3@GO) nanocomposite. The synthesized nanocomposite was employed for adsorption and removal of cationic organic dyes like RhB from industrial wastewater. The effect of various parameters, viz., contact time, temperature, pH and amount of adsorbent on the adsorption capability as well as dye removal capacity of the adsorbent was studied in detail. Under optimized conditions, like, contact time (65min), amount of adsorbent (5mg), temperature (35 degrees ) and pH (4), the adsorption capacity of GO and Bi2O3@GO were recorded and the percentage of removal was found to be 64% and 80.7% for GO and Bi2O3@GO, respectively. The Bi2O3@GO nanocomposite shows higher adsorption capacity (320mg/g) as compare to only GO (224mg/g). The adsorption isotherm follows both the Temkin as well as Langmuir isotherm having heat of sorption 65.88 with Langmuir constant of 13.13 corresponding to the complete monolayer coverage of 387.44mg/g. The adsorption kinetics also follow, both pseudo first order and intraparticle diffusion model with adsorption capacity of 84.91mg/g and intra particle diffusion rate constant of 10.53mg/g min1/2 for Bi2O3@GO nanocomposites. Our results suggest that the prepared Bi2O3@GO nanocomposites possess potential application as high-performance renewable adsorbent for removal of toxic dyes from wastewater. PMID- 28886373 TI - Global strain field mapping of a particle-laden interface using digital image correlation. AB - HYPOTHESIS: The ability to identify the stress-strain relations correctly is critical to understanding and modeling any rheological responses of an interface. Langmuir-Pockels (LP) trough is one of the most commonly used tools for studying an interface. Most, if not all, existing studies assume a 1D uniaxial compression during a LP-trough compression experiment. It is hypothesized that the deformation field is far more complex than what is typically assumed. EXPERIMENTS: To examine this hypothesis, we custom-built a glass-bottomed LP trough equipped with a camera to capture a series of optical images asa carbon nanotube (CNT)-laden interface is compressed. A digital image correlation (DIC) technique was then applied to the images to evaluate the global strain field during compression of the CNT laden interface. The DIC-corrected strain data were subsequently analyzed with the surface stress data to quantify the surface shear and dilatational moduli of the CNT-laden interface. FINDINGS: Our experimental findings clearly show, for the first time, the development of a non-uniform and complex 2D strain field during compression. The local strains were further quantified and compared with the usual assumption of 1D uniaxial compression. Although the compressive strain averaged over the whole trough area closely resembles the 1D uniaxial compression strain, the 1D compression assumption underestimates the local strain by about 36% at the center of the trough, where the surface stresses are measured. This is the first study in applying the DIC technique to map out the global strain field asa particle-laden interface is compressed. The method may also be applicable to other systems with similar optical texture, allowing the correct identification of stress-strain relationship of an interface. PMID- 28886374 TI - Seeing DNA Where It Lives. AB - It's the stuff of life, and we're fascinated by DNA and how it's packaged into chromatin and compacted into chromosomes. Advances in looking at chromatin organization in cells are letting us see this polymer, its packing, and its function with fresh eyes. PMID- 28886375 TI - Barbara McClintock's Final Years as Nobelist and Mentor: A Memoir. AB - September 2, 2017, marks the 25th year after the passing of Dr. Barbara McClintock, geneticist and recipient of the 1983 Nobel Prize in Physiology or Medicine for her discovery of transposable elements in maize. This memoir focuses on the last years of her life-after the prize-and includes personal recollections of how she mentored young scientists and inspired the age of genetics, epigenetics, and genomics. PMID- 28886376 TI - Converting Cold into Hot Tumors by Combining Immunotherapies. AB - In a small phase Ib study in this issue of Cell, Ribas et al. report that the combination of intralesional injection of a modified human herpes simplex virus and systemic anti-PD-1 treatment resulted in a 62% response rate in patients with metastatic melanoma, accompanied by enhanced T cell infiltration in virus injected lesions. PMID- 28886377 TI - Crowd Control: E7 Conservation Is the Key to Cancer. AB - Several human papillomavirus type 16 (HPV16) oncoproteins contribute to cellular transformation in vitro. In this issue of Cell, Mirabello and colleagues use high throughput sequencing data to assess the diversity of HPV16 isolates from human patients. These data suggest that the E7 oncoprotein is the fundamental contributor to in vivo carcinogenesis. PMID- 28886378 TI - Eukaryotic Sexual Reproduction Evoked "with a Little Help from My Friends". AB - Bacteria and eukaryotes interact in many ways-from the microbiome that educates the mammalian immune system and enhances nutrition to relationships that are commensal, symbiotic, or parasitic. Now in an unexpected twist, King and colleagues have expanded the repertoire of prokaryotic influence over eukaryotic physiology to include mating. PMID- 28886379 TI - Putting p53 in Context. AB - TP53 is the most frequently mutated gene in human cancer. Functionally, p53 is activated by a host of stress stimuli and, in turn, governs an exquisitely complex anti-proliferative transcriptional program that touches upon a bewildering array of biological responses. Despite the many unveiled facets of the p53 network, a clear appreciation of how and in what contexts p53 exerts its diverse effects remains unclear. How can we interpret p53's disparate activities and the consequences of its dysfunction to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might we restore its tumor-suppressive activities in cancer? PMID- 28886380 TI - NF-kappaB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer. AB - Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor kappaB (NF kappaB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-kappaB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. Our studies therefore establish inhibition of NF-kappaB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols. PMID- 28886381 TI - Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti PD-1 Immunotherapy. AB - Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, as well as IFN-gamma gene expression on several cell subsets in tumors after talimogene laherparepvec treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-gamma signature. These findings suggest that oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment. VIDEO ABSTRACT. PMID- 28886382 TI - Distinct Mesenchymal Lineages and Niches Promote Epithelial Self-Renewal and Myofibrogenesis in the Lung. AB - The lung is an architecturally complex organ comprising a heterogeneous mixture of various epithelial and mesenchymal lineages. We use single-cell RNA sequencing and signaling lineage reporters to generate a spatial and transcriptional map of the lung mesenchyme. We find that each mesenchymal lineage has a distinct spatial address and transcriptional profile leading to unique niche regulatory functions. The mesenchymal alveolar niche cell is Wnt responsive, expresses Pdgfralpha, and is critical for alveolar epithelial cell growth and self-renewal. In contrast, the Axin2+ myofibrogenic progenitor cell preferentially generates pathologically deleterious myofibroblasts after injury. Analysis of the secretome and receptome of the alveolar niche reveals functional pathways that mediate growth and self renewal of alveolar type 2 progenitor cells, including IL-6/Stat3, Bmp, and Fgf signaling. These studies define the cellular and molecular framework of lung mesenchymal niches and reveal the functional importance of developmental pathways in promoting self-renewal versus a pathological response to tissue injury. PMID- 28886383 TI - Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6. AB - The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo. Distinct Lgr5+ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung. PMID- 28886384 TI - HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis. AB - Although most cervical human papillomavirus type 16 (HPV16) infections become undetectable within 1-2 years, persistent HPV16 causes half of all cervical cancers. We used a novel HPV whole-genome sequencing technique to evaluate an exceptionally large collection of 5,570 HPV16-infected case-control samples to determine whether viral genetic variation influences risk of cervical precancer and cancer. We observed thousands of unique HPV16 genomes; very few women shared the identical HPV16 sequence, which should stimulate a careful re-evaluation of the clinical implications of HPV mutation rates, transmission, clearance, and persistence. In case-control analyses, HPV16 in the controls had significantly more amino acid changing variants throughout the genome. Strikingly, E7 was devoid of variants in precancers/cancers compared to higher levels in the controls; we confirmed this in cancers from around the world. Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research. PMID- 28886387 TI - Golgi-Resident Galphao Promotes Protrusive Membrane Dynamics. PMID- 28886385 TI - Combinatorial Signal Perception in the BMP Pathway. AB - The bone morphogenetic protein (BMP) signaling pathway comprises multiple ligands and receptors that interact promiscuously with one another and typically appear in combinations. This feature is often explained in terms of redundancy and regulatory flexibility, but it has remained unclear what signal-processing capabilities it provides. Here, we show that the BMP pathway processes multi ligand inputs using a specific repertoire of computations, including ratiometric sensing, balance detection, and imbalance detection. These computations operate on the relative levels of different ligands and can arise directly from competitive receptor-ligand interactions. Furthermore, cells can select different computations to perform on the same ligand combination through expression of alternative sets of receptor variants. These results provide a direct signal processing role for promiscuous receptor-ligand interactions and establish operational principles for quantitatively controlling cells with BMP ligands. Similar principles could apply to other promiscuous signaling pathways. PMID- 28886386 TI - Lis1 Has Two Opposing Modes of Regulating Cytoplasmic Dynein. AB - Regulation is central to the functional versatility of cytoplasmic dynein, a motor involved in intracellular transport, cell division, and neurodevelopment. Previous work established that Lis1, a conserved regulator of dynein, binds to its motor domain and induces a tight microtubule-binding state in dynein. The work we present here-a combination of biochemistry, single-molecule assays, and cryoelectron microscopy-led to the surprising discovery that Lis1 has two opposing modes of regulating dynein, being capable of inducing both low and high affinity for the microtubule. We show that these opposing modes depend on the stoichiometry of Lis1 binding to dynein and that this stoichiometry is regulated by the nucleotide state of dynein's AAA3 domain. The low-affinity state requires Lis1 to also bind to dynein at a novel conserved site, mutation of which disrupts Lis1's function in vivo. We propose a new model for the regulation of dynein by Lis1. PMID- 28886388 TI - SnapShot: Connexins and Disease. AB - The connexin family of membrane proteins enable gap junction formation and homeostasis, supporting communication between adjacent cells. This SnapShot highlights mutations in different connexins associated with human pathologies and how they affect gap junction function. PMID- 28886389 TI - Localized constrictive pericarditis compressing and obstructing the right ventricular inflow tract due to a giant anterior calcified cardiac mass. A case report. AB - INTRODUCTION: Localized pericardial constriction is a rare form of constrictive pericarditis CP. Depending on the CP location, clinical presentation may be variable, including compression and obstruction of right ventricular inflow tract(RVIT), coronary obstruction, or pulmonary stenosis. CASE PRESENTATION: A 72 year-old man presented a 2-year history of dyspnea and atrial fibrillation. A contrast enhanced angio computerized tomography clearly demonstrated a large spherical mass about 11*9*4cm in the anterior pericardium, presenting as a mediastinal tumor causing compression and obstruction of the RVIT. The patient underwent surgical procedure. The outer calcified layer of the pericardial mass was a thick layer of calcification surrounding an inner amorphous low density material. The inferior calcified layer of the pericardial mass which was extremely adherent with the epicardium, was carefully excised, without employment of cardiopulmonary bypass, from the aorta and pulmonary artery origin to the diaphragm and all areas between the right and left phrenic nerves. The final diagnosis was idiopathic CP. DISCUSSION: The clinical presentation was due to right ventricular free wall compression and obstruction of the RVIT by a giant calcified anterior cardiac mass. The differential diagnosis with other calcified masses in the anterior mediastinum such as teratoma, hemopericardium after blunt trauma and idiopathic or tuberculous CP should be considered. CONCLUSION: Herein we report a very rare case with localized CP causing compression and obstruction of RVIT due to a giant anterior calcified cardiac mass, treated successfully with pericardectomy. Careful dissection is mandatory for a successful procedure. PMID- 28886390 TI - Vascularized fibular graft as a surgical option for osteosarcoma of distal humerus: A case report. AB - INTRODUCTION: Distal humerus is a very rare predilection site of osteosarcoma. Limb salvage surgery has widely replaced amputation for surgical treatment of most types of malignant bone sarcomas. PRESENTATION OF CASE: We presented a 42 years old male with rapidly growing osteosarcoma on his right distal humerus. After induction chemotherapy, wide excision and reconstruction using free vascularized fibular graft followed with interpositional elbow arthroplasty technique was done. DISCUSSION: One of the option for surgical treatment for distal humerus osteosarcoma is limb salvage sugery with free vascularized fibular graft technique. Good functional outcome and no signs of local recurrence were found during 2,5 years follow up. CONCLUSION: Free vascularized fibular graft with interpositional elbow arthroplasty is a good option for management of bone sarcoma of distal humerus. PMID- 28886391 TI - Combined pancreatic and duodenal transection injury: A case report. AB - INTRODUCTION: Combined pancreatic-duodenal injuries in blunt abdominal trauma are rare. These injuries are associated with high morbidity and mortality, and their emergent management is a challenge. CASE PRESENTATION: We report a case of combined complete pancreatic (through the neck) and duodenal (first part) transections in a 24-year-old male secondary to blunt abdominal trauma following a motor vehicle crash. The duodenal stumps were closed separately and a gastrojejunostomy performed for intestinal continuity. The transacted head of pancreas main duct was suture ligated and parenchyma was over sewn and buttressed with omentum. The edge of the body and tail pancreatic segment was freshened and an end to side pancreatico-jejunostomy was fashioned. A drain was left in situ. Post operatively the patient developed a pancreatic fistula which resolved with conservative management. After ten months of follow up the patient was well and showed no signs and symptoms of pancreatic insufficiency. DISCUSSION: Lengthy, complex procedures in pancreatic injuries have been associated with poor outcomes. Distal pancreatectomy or Whipple's procedure for trauma are viable options for complete pancreatic transections. But when there is concern that the residual proximal pancreatic tissue is inadequate to provide endocrine or exocrine function, preservation of the pancreatic tissue distal to the injury becomes an option. CONCLUSION: Combined pancreatic and duodenal injuries are rare and often fatal. Early identification, resuscitation and surgical intervention is warranted. Because of the large number of possible combinations of injuries to the pancreas and duodenum, no one form of therapy is appropriate for all patients. PMID- 28886392 TI - How do you define body image? Exploring conceptual gaps in understandings of body image at an exercise facility. AB - The definition of body image has evolved within research; however, less is known about the layperson's understanding of the construct. This study explored how members and student trainees of an exercise facility (designed for older adults, people with physical disability, and those with cardiac complications) defined body image. Nineteen participants completed a one-on-one interview, and seven of those participants took part in six additional focus group meetings. The following main themes were found: stereotypical assumptions about body image (e.g., it is solely a person's weight or merely a woman's issue), body image continua for positive and negative body image, degree of complexity of body image dimensions, broad considerations of body image (e.g., it is self-esteem), and limited knowledge about body image. These findings suggest a need for knowledge translation between researchers and the general public which informs future body image program design. PMID- 28886393 TI - Body checking is associated with weight- and body-related shame and weight- and body-related guilt among men and women. AB - This study examined whether body checking was a correlate of weight- and body related shame and guilt for men and women. Participants were 537 adults (386 women) between the ages of 17 and 74 (Mage=28.29, SD=14.63). Preliminary analyses showed women reported significantly more body-checking (p<.001), weight- and body related shame (p<.001), and weight- and body-related guilt (p<.001) than men. In sex-stratified hierarchical linear regression models, body checking was significantly and positively associated with weight- and body-related shame (R2=.29 and .43, p<.001) and weight- and body-related guilt (R2=.34 and .45, p<.001) for men and women, respectively. Based on these findings, body checking is associated with negative weight- and body-related self-conscious emotions. Intervention and prevention efforts aimed at reducing negative weight- and body related self-conscious emotions should consider focusing on body checking for adult men and women. PMID- 28886394 TI - Challenging fat talk: An experimental investigation of reactions to body disparaging conversations. AB - Although "fat talk" is associated with increased eating disorder risk, the predictors of fat talk engagement and viable alternatives to these pervasive conversations remain unclear. The current experiment examined responses to fat talk versus feminist-oriented challenging fat talk scenarios. Undergraduate women (N=283) completed baseline questionnaires assessing body dissatisfaction, fat talk engagement, and positive impression management. One week later, they were randomized to view one of the two scenarios, followed by assessment of mood, fat talk engagement, social acceptability, and social likeability. Results indicated that the challenging fat talk vignette (versus the fat talk vignette) yielded less negative affect and fat talk and was perceived as more socially attractive with a more likeable target character. Baseline body dissatisfaction, baseline fat talk tendencies, and momentary negative affect predicted post-exposure fat talk engagement. Current findings highlight possibilities for implementing feminist language and psychoeducation in fat talk prevention efforts. PMID- 28886396 TI - Alcohol and depression: Evidence from the 2014 health survey for England. AB - BACKGROUND: A relatively large body of literature examines the association between depression and alcohol consumption, with evidence suggesting a bidirectional causal relationship. However, the endogeneity arising from this reverse causation has not been addressed in the literature. METHODS: Using data on 5828 respondents from the Health Survey for England (HSE), this study revisits the relationship between alcohol and depression and addresses the endogenous nature of this relationship. We use information on self-assessed depression, and control for endogeneity using the Lewbel two-staged least square (2SLS) estimation technique. RESULTS: We find that drinking alcohol promotes depression, and this is consistent across several measures of drinking behaviour including the amount of alcohol consumed, consumption intensity, alcohol dependence and risk of dependence. CONCLUSION: While drinking may be generally accepted and in the case of England, part of the culture, this has costs in terms of both physical and mental health that ought not to be ignored. While public policy has predominantly focused on the physical aspects of excessive alcohol consumption it is possible that these policies will also have a direct positive spillover in terms of the mental health costs, through the impact of lower alcohol consumption on quality of life and wellbeing. PMID- 28886395 TI - Individual, peer, and family factor modification of neighborhood-level effects on adolescent alcohol, cigarette, e-cigarette, and marijuana use. AB - BACKGROUND: Neighborhood factors reported subjectively by residents and measured objectively at the census tract are both associated with adolescent alcohol, tobacco (cigarette and electronic cigarette), and other drug (marijuana) (ATOD) use. Less clear is how these neighborhood factors are longitudinally associated with each substance. Equivocal findings may be due to lack of consideration of individual, peer, and family effect modifiers, which could help adolescents overcome exposure to stressful neighborhood environments. METHODS: We used multivariate logistic regressions with interaction terms to test whether parental monitoring, resistance self-efficacy (RSE) and being around peers who use ATOD modified the association between four subjective and objective neighborhood measures and odds of using each substance measured one year later among 2539 high school students and college freshmen originally recruited from middle schools in Southern California. RESULTS: Census tract-level disadvantage was not longitudinally associated with ATOD use. However, perceptions of higher neighborhood disorganization, less social cohesion, and more neighborhood problems with alcohol and drug use were associated with higher odds of ATOD use. Higher RSE and weaker affiliations with peers who use ATOD consistently buffered negative effects of neighborhood disorganization and neighborhood problems with alcohol and drugs on past year ATOD use. CONCLUSIONS: Community-level programs that increase social cohesion among neighbors, neighborhood monitoring of deviant behaviors, and better policing of open drug selling may prevent ATOD use. Programs should also target RSE and minimize affiliations with peers who use ATOD, which could reduce the magnitude of the association with ATOD, even for adolescents living in the most at-risk neighborhoods. PMID- 28886398 TI - Perceptions of women on workloads in health facilities and its effect on maternal health care: A multi-site qualitative study in Nigeria. AB - OBJECTIVE: of the study was to explore women's perception of maternal health care providers' workload and its effects on the delivery of maternal healthcare in secondary and tertiary hospitals in Nigeria. RESEARCH DESIGN, SETTING, PARTICIPANTS: five focus groups discussions (FGDs) were conducted with women in each of eight secondary and tertiary hospitals in 8 States in four geo-political zones of the country. In all, 40 FGDs were held with women attending antenatal and post-natal clinics in the hospitals. We elicited information on women's perceptions of workloads of maternal health providers and the effects of the workloads on maternity care. The discussions were audio-taped and transcribed while thematic analysis was carried out using Atlas.ti computer software. FINDINGS: the majority of the participants submitted that the health providers are burdened with heavy workloads in the provision of maternal health care. Examples of heavy workload cited included complaints from health providers, evidence of stress and strain in care provision by providers and the sheer numbers of patients that are left unattended to in health facilities. Poor quality care, insufficient time to carry out necessary investigations on patients, and prolonged waiting time experienced by women in accessing care featured as consequences of heavy workload, with the secondary result that women are reluctant to seek care in the health facilities because of the belief that they would spend a long time in receiving care. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: we conclude that women are concerned about heavy workloads experienced by healthcare providers and may partly account for the low utilization of referral health facilities for maternal health care in Nigeria. Efforts to address this problem should include purposeful human resource policy development, the development of incentives for health providers, and the proper re-organization of the health system. PMID- 28886397 TI - Directly alcohol-attributable mortality by industry and occupation in a Spanish Census cohort of economically active population. AB - AIMS: To assess disparities in directly alcohol-attributable (DAA) mortality by industry/occupation in Spain during 2002-2011 and the contribution of different socio-demographic factors, including socioeconomic position, to explain such disparity. METHODS: Nationwide cohort study covering 16 million economically active people living in Spain in 2001. Deaths at age 25-64 were analyzed. Subjects were classified by employment status, industry and occupation at baseline. Poisson regression models were built, calculating rate ratios (RRs) compared to all employees or those in the education sector. RESULTS: DAA mortality was much higher in the unemployed than in employees (Crude RR: 2.4; 95% CI: 2.3-2.6) and varied widely across industries/occupations. Crude RRs>3.0 (p<0.05) compared to teachers were found in employees in extractive industries/fishing, agriculture/livestock, construction, catering/accommodation and protective services. Socio-demographic factors, especially age, gender and educational attainment contributed more to explain risk disparities than other factors or potential selection bias. However, after exhaustive sociodemographic adjustment, including education attainment and material wealth, a RR>1.33 (p<0.05) remained in unemployed, catering/accommodation employees and unskilled construction workers. RRs were significantly larger in women than men (p<0.05) among mineworkers/fishworkers/sailors (RR=8.6 vs. 1.2) and drivers (RR=3.7 vs. 1.0). CONCLUSIONS: The results could be extrapolated to all alcohol-attributable mortality since disparities for other strongly alcohol-related deaths, although smaller, were in the same direction. Given the wide occupational disparities in alcohol-attributable mortality, implementation of special measures to reduce this mortality in the highest risk groups is fully justified. Future research should better characterize the explanatory factors of disparities and their role in the causal chain. PMID- 28886399 TI - Effectiveness of a measure program to prevent admission hypothermia in very low birth weight preterm infants. AB - OBJECTIVE: To evaluate the effectiveness of a thermoregulation bundle for preventing admission hypothermia in very low-birth weight preterm infants. METHODS: Interventional study with retrospective evaluation of data undertaken in a tertiary neonatal unit including all very low-birth weight preterm infants (<1500g) born at and admitted to the unit. Two periods were compared: before intervention (PI; 01/01/2012 to 02/28/2014_ and after intervention (PII; 04/01/2014 to 11/30/2016). The intervention started in March 2014. At PI procedures in the delivery room were: placement in a crib with a radiant heat source, doors always closed, polyethylene body plastic bag, double cap (plastic and cotton mesh), room temperature between 24 to 27 degrees C and transport to neonatal unit in a pre-heated incubator (36-37.0 degrees C). At PII, there was a reinforcement on not opening the plastic bag during the entire resuscitation process, even at an advanced stage, and the anthropometric measures and routine care were performed in the neonatal unit. Maternal, delivery, and neonatal variables were compared. Admission hypothermia was considered when admission axillary temperature was <36.0 degrees C. Periodic results were shown to the team every six months and results were discussed. RESULTS: The incidence of admission hypothermia was reduced significantly in PII (37.2 vs. 14.2%, p<0.0001) and admission temperature medians were higher (36.1 vs. 36.5 degrees C, p<0.001). At PII, there was an increase in the number of infants transported with oxygen (49.5 vs. 75.5%, p<0.0001). No differences were observed regarding birth weight and gestational age. CONCLUSION: There was a very important reduction in admission hypothermia incidence and a higher median admission temperature after continued protocol implementation. PMID- 28886400 TI - Breastfeeding increases microbial community resilience. AB - OBJECTIVE: Since the present group had already described the composition of the intestinal microbiota of Brazilian infants under low social economic level, the aim of the present study was to analyze the microbial community structure changes in this group of infants during their early life due to external factors. METHODS: Fecal samples were collected from 11 infants monthly during the first year of life. The infants were followed regarding clinical and diet information and characterized according to breastfeeding practices. DNA was extracted from fecal samples of each child and subjected to Polymerase Chain Reaction - Denaturing Gradient Gel Electrophoresis. RESULTS: The results revealed a pattern of similarity between the time points for those who were on exclusive breastfeeding or predominant breastfeeding. Although there were changes in intensity and fluctuation of some bands, the Denaturing Gradient Gel Electrophoresis patterns in the one-year microbial analysis were stable for breastfeeding children. There was uninterrupted ecological succession despite the influence of external factors, such as complementary feeding and antibiotic administration, suggesting microbiota resilience. This was not observed for those children who had mixed feeding and introduction of solid food before the 5th month of life. CONCLUSION: These results suggested an intestinal microbiota pattern resilient to external forces, due to the probiotic and prebiotic effects of exclusive breastfeeding, reinforcing the importance of exclusive breastfeeding until the 6th month of life. PMID- 28886401 TI - Factors associated with breastfeeding maintenance for 12 months or more: a systematic review. AB - OBJECTIVE: Synthesize the information about the factors associated with maintenance of breastfeeding for 12 months or more. DATA SOURCE: A systematic review was conducted in the Pubmed/Medline, Scielo, and Lilacs databases, including articles published in Portuguese or English since 2004 on the factors associated with breastfeeding maintenance for at least 12 months; review articles and those with qualitative design were excluded. The factors were organized into four levels, according to the chronological proximity to the outcome: distal, distal intermediate, proximal intermediate, and proximal; nationality and place/area of residence were considered contextual factors. SUMMARY OF DATA: 1174 articles were identified, of which 19 were included in this review, comprising seven cohort studies and 12 cross-sectional studies. A total of 39 of the 75 assessed factors were associated with the outcome at least once. The factors with the highest percentages of associations with maintenance of breastfeeding for 12 months or more, considering the number of times they were tested were: children whose parents are the caregivers (100%), none type of maternal exposure to smoke (54%), children and/or parents are immigrants/foreigners (50%), live in urban areas (42.9%), older maternal age (40%), married women (37.5%), higher level of maternal education (31.3%), greater parity (30.8%), and lower income (30%). CONCLUSIONS: The maintenance of breastfeeding for 12 months or more is associated with multiple factors, emphasizing the contextual factors and those related to some maternal sociodemographic characteristics. Associations differ in effect and magnitude between the different populations studied. PMID- 28886402 TI - Identification and initial management of intoxication by alcohol and other drugs in the pediatric emergency room. AB - OBJECTIVE: To review the screening, diagnosis, evaluation, and treatment of intoxication by alcohol and other drugs in children and adolescents in the emergency scenario. DATA SOURCE: This was a narrative literature review. DATA SUMMARY: The detection of this problem in the emergency room can be a challenge, especially when its assessment is not standardized. The intentional and episodic use of large amounts of psychoactive substances by adolescents is a usual occurrence, and unintentional intoxication is more common in children younger than 12 years. The clinical picture in adolescents and children differs from that in adults and some particularities are important in the emergency scenario. After management of the acute condition, interventions targeting the adolescent at risk may be effective. CONCLUSION: The diagnosis and treatment of intoxication by alcohol and other drugs in adolescents and children in the emergency scenario requires a systematic evaluation of the use of these drugs. There are few specific treatments for intoxication, and the management comprehends support measures and management of related clinical complications. PMID- 28886403 TI - Increased MAPK1/3 Phosphorylation in Luminal Breast Cancer Related with PIK3CA Hotspot Mutations and Prognosis. AB - INTRODUCTION: While mutations in PIK3CA are most frequently (45%) detected in luminal breast cancer, downstream PI3K/AKT/mTOR pathway activation is predominantly observed in the basal subtype. The aim was to identify proteins activated in PIK3CA mutated luminal breast cancer and the clinical relevance of such a protein in breast cancer patients. MATERIALS AND METHODS: Expression levels of 171 signaling pathway (phospho-)proteins established by The Cancer Genome Atlas (TCGA) using reverse phase protein arrays (RPPA) were in silico examined in 361 breast cancers for their relation with PIK3CA status. MAPK1/3 phosphorylation was evaluated with immunohistochemistry on tissue microarrays (TMA) containing 721 primary breast cancer core biopsies to explore the relationship with metastasis-free survival. RESULTS: In silico analyses revealed increased phosphorylation of MAPK1/3, p38 and YAP, and decreased expression of p70S6K and 4E-BP1 in PIK3CA mutated compared to wild-type luminal breast cancer. Augmented MAPK1/3 phosphorylation was most significant, i.e. in luminal A for both PIK3CA exon 9 and 20 mutations and in luminal B for exon 9 mutations. In 290 adjuvant systemic therapy naive lymph node negative (LNN) breast cancer patients with luminal cancer, high MAPK phosphorylation in nuclei (HR=0.49; 95% CI, 0.25 0.95; P=.036) and in tumor cells (HR=0.37; 95% CI, 0.18-0.79; P=.010) was related with favorable metastasis-free survival in multivariate analyses including traditional prognostic factors. CONCLUSION: Enhanced MAPK1/3 phosphorylation in luminal breast cancer is related to PIK3CA exon-specific mutations and correlated with favorable prognosis especially when located in the nuclei of tumor cells. PMID- 28886404 TI - Graph-based composite local Bregman divergences on discrete sample spaces. AB - This paper develops a general framework of statistical inference on discrete sample spaces, on which a neighborhood system is defined by an undirected graph. The scoring rule is a measure of the goodness of fit for the model to observed samples, and we employ its localized version, local scoring rules, which does not require the normalization constant. We show that the local scoring rule is closely related to a discrepancy measure called composite local Bregman divergence. Then, we investigate the statistical consistency of local scoring rules in terms of the graphical structure of the sample space. Moreover, we propose a robust and computationally efficient estimator based on our framework. In numerical experiments, we investigate the relation between the neighborhood system and estimation accuracy. Also, we numerically evaluate the robustness of localized estimators. PMID- 28886405 TI - Emotional recognition of dynamic facial expressions before and after cochlear implantation in adults with progressive deafness. AB - Visual processing has been extensively explored in deaf subjects in the context of verbal communication, through the assessment of speech reading and sign language abilities. However, little is known about visual emotional processing in adult progressive deafness, and after cochlear implantation. The goal of our study was thus to assess the influence of acquired post-lingual progressive deafness on the recognition of dynamic facial emotions that were selected to express canonical fear, happiness, sadness, and anger. A total of 23 adults with post-lingual deafness separated into two groups; those assessed either before (n = 10) and those assessed after (n = 13) cochlear implantation (CI); and 13 normal hearing (NH) individuals participated in the current study. Participants were asked to rate the expression of the four cardinal emotions, and to evaluate both their emotional valence (unpleasant-pleasant) and arousal potential (relaxing stimulating). We found that patients with deafness were impaired in the recognition of sad faces, and that patients equipped with a CI were additionally impaired in the recognition of happiness and fear (but not anger). Relative to controls, all patients with deafness showed a deficit in perceiving arousal expressed in faces, while valence ratings remained unaffected. The current results show for the first time that acquired and progressive deafness is associated with a reduction of emotional sensitivity to visual stimuli. This negative impact of progressive deafness on the perception of dynamic facial cues for emotion recognition contrasts with the proficiency of deaf subjects with and without CIs in processing visual speech cues (Rouger et al., 2007; Strelnikov et al., 2009; Lazard and Giraud, 2017). Altogether these results suggest there to be a trade-off between the processing of linguistic and non-linguistic visual stimuli. PMID- 28886406 TI - An investigation of potential neural correlates of intrusive retrieval of distressing memories. AB - BACKGROUND AND OBJECTIVES: Despite the prevalence of intrusive memories across psychological disorders, little is known about the neural networks that underpin this form of memory. This study used functional magnetic resonance imaging (fMRI) to identify neural circuits associated with the retrieval of intrusive memories. METHODS: Participants with moderate levels of anxiety (N = 30) underwent a cold pressor task to induce a physiological stress response, after which they viewed 10 neutral and 10 negative film clips. In a method designed to induce intrusive memories, participants then completed an fMRI scan in which they viewed short (2 s) depictions of neutral components from the original film clips. RESULTS: There were no significant differences in activations during intrusion and non-intrusion responses. Exploratory analyses comparing intrusive responses to neutral stimuli found the insula, inferior frontal gyrus, precuneus, right cerebellum and bilateral supplementary motor area were uniquely activated during experience of intrusions (compared to the neutral cue baseline), whereas no significant activations were in response to negative scenes that did not trigger intrusions. LIMITATIONS: This study did not compare the different neural processes implicated in intrusive and intentional emotional memories. The limited intrusions that could be elicited in the scanning environment restricted the number of trials that could be employed. CONCLUSIONS: Although no differences in neural activations were observed between intrusive and non-intrusive responses, the observation of precuneus involvement is consistent with models that propose that intrusive memories are impacted by the extent to which there is contextual integration of the relevant memories. PMID- 28886408 TI - The fate of distractors in working memory: No evidence for their active removal. AB - Not all the information processed in working memory (WM) must be retained. Due to the strict limitations of its capacity, the mechanisms that prevent WM from being cluttered and choked by no longer relevant information are of paramount importance. The present study tested the hypothesis put forward by the SOB-CS model of an active and attention-demanding mechanism that would remove no-longer relevant items from WM. Such a mechanism has been advocated to account for the well-known fact that, in complex span tasks, processing distractors at a slower pace results in better recall of memory items. According to the SOB-CS model, slow pace would free more time for removing distractors, thus alleviating the interference they create on target items. In direct contradiction with this hypothesis, a first experiment demonstrated that distractors are not less, but more accessible at the end of complex span task trials in which they have been processed at a slow rather than a fast pace. Using the repetition priming effect occurring in a lexical decision task inserted as processing component within a complex span task, a second experiment established that distractors processed at a slower pace do not elicit weaker, but stronger repetition priming effects, indicating that they have not been removed. Along with previous findings, the present study not only shows that there is no trace of distractor removal in the long term, in the short term, nor immediately after processing, but demonstrates that memory traces of distractors are stronger in situations assumed to involve a more complete removal by the SOB-CS model. These empirical evidence suggests that distractors are not actively removed from working memory after having been processed. PMID- 28886407 TI - Preparing for what might happen: An episodic specificity induction impacts the generation of alternative future events. AB - A critical adaptive feature of future thinking involves the ability to generate alternative versions of possible future events. However, little is known about the nature of the processes that support this ability. Here we examined whether an episodic specificity induction - brief training in recollecting details of a recent experience that selectively impacts tasks that draw on episodic retrieval (1) boosts alternative event generation and (2) changes one's initial perceptions of negative future events. In Experiment 1, an episodic specificity induction significantly increased the number of alternative positive outcomes that participants generated to a series of standardized negative events, compared with a control induction not focused on episodic specificity. We also observed larger decreases in the perceived plausibility and negativity of the original events in the specificity condition, where participants generated more alternative outcomes, relative to the control condition. In Experiment 2, we replicated and extended these findings using a series of personalized negative events. Our findings support the idea that episodic memory processes are involved in generating alternative outcomes to anticipated future events, and that boosting the number of alternative outcomes is related to subsequent changes in the perceived plausibility and valence of the original events, which may have implications for psychological well-being. PMID- 28886409 TI - Relationships among grit, academic performance, perceived academic failure, and stress in associate degree students. AB - The present study examined the relationships among grit, academic performance, perceived academic failure, and stress levels of Hong Kong associate degree students using path analysis. Three hundred and forty-five students from a community college in Hong Kong voluntarily participated in the study. They completed a questionnaire that measured their grit (operationalized as interest and perseverance) and stress levels. The students also provided their actual academic performance and evaluated their perception of their academic performance as a success or a failure. The results of the path analysis showed that interest and perseverance were negatively associated with stress, and only perceived academic failure was positively associated with stress. These findings suggest that psychological appraisal and resources are more important antecedents of stress than objective negative events. Therefore, fostering students' psychological resilience may alleviate the stress experienced by associate degree students or college students in general. PMID- 28886410 TI - A methodology to design heuristics for model selection based on the characteristics of data: Application to investigate when the Negative Binomial Lindley (NB-L) is preferred over the Negative Binomial (NB). AB - Safety analysts usually use post-modeling methods, such as the Goodness-of-Fit statistics or the Likelihood Ratio Test, to decide between two or more competitive distributions or models. Such metrics require all competitive distributions to be fitted to the data before any comparisons can be accomplished. Given the continuous growth in introducing new statistical distributions, choosing the best one using such post-modeling methods is not a trivial task, in addition to all theoretical or numerical issues the analyst may face during the analysis. Furthermore, and most importantly, these measures or tests do not provide any intuitions into why a specific distribution (or model) is preferred over another (Goodness-of-Logic). This paper ponders into these issues by proposing a methodology to design heuristics for Model Selection based on the characteristics of data, in terms of descriptive summary statistics, before fitting the models. The proposed methodology employs two analytic tools: (1) Monte-Carlo Simulations and (2) Machine Learning Classifiers, to design easy heuristics to predict the label of the 'most-likely-true' distribution for analyzing data. The proposed methodology was applied to investigate when the recently introduced Negative Binomial Lindley (NB-L) distribution is preferred over the Negative Binomial (NB) distribution. Heuristics were designed to select the 'most-likely-true' distribution between these two distributions, given a set of prescribed summary statistics of data. The proposed heuristics were successfully compared against classical tests for several real or observed datasets. Not only they are easy to use and do not need any post-modeling inputs, but also, using these heuristics, the analyst can attain useful information about why the NB-L is preferred over the NB - or vice versa- when modeling data. PMID- 28886411 TI - A preliminary investigation of textile fibers in smothering scenarios and alternative legitimate activities. AB - Was this group of target fibers transferred during a criminal action? Is it possible that it was transferred during another legitimate activity? Acquiring knowledge about the activity, whether legitimate or criminal, leading to the transfer of a group of fibers is a recurring challenge encountered throughout the evidence interpretation process. Trace evidence such as fibers may assist with generating a reasoning of the activity which produced the trace, but this assumes that one already has a thorough understanding of the transfer phenomenon. How to generate and then use such relevant knowledge? What are the influencing parameters and which ones should (or can) be controlled? The present work focuses on homicides by smothering using a pillow and the transfer of fibers on the face of the victim in such events. A legitimate activity - represented by a night's sleep on a pillow - was also investigated since such legitimate, alternative explanations concerning the presence of fibers could likely be formulated by the suspect. The number and distribution of fibers transferred onto the victim's face in either scenario were investigated and interpreted using a Bayesian approach. Results showed that the shedding capacity of the pillowcase strongly impact the number of fibers recovered. The nature of the action, modus operandi and amount of friction could not be excluded in their influence on the transfer of fibers. Finally, likelihood ratios indicating the number of fibers recovered from the victim's face can provide relevant information by supporting either criminal or legitimate proposition (i.e., smothering or night's sleep scenario). PMID- 28886412 TI - Re-evaluation of acute erythroid leukemia according to the 2016 WHO classification. AB - In the recent update of WHO classification, the definition of myeloid neoplasms with erythroid predominance has been modified shifting the main criteria for calculating blast percentage from non-erythroid cells (NEC) to all nucleated marrow cells (ANC). Thus, the cases previously classified as erythroid/myeloid subtype of acute erythroid leukemia (AEL) based on the 2008 WHO will now be categorized either as myelodysplastic syndrome with excess blasts (MDS-EB) or acute myeloid leukemia, not otherwise specified (AML-NOS). However, the clinical significance of this new classification has not been demonstrated. Thus, we reviewed a leukemia database and reclassified 38 cases previously diagnosed as AEL, erythroid/myeloid subtype, with the consideration of 2016 revision criteria. Twenty seven (71%) of them had >20% blasts in NEC but less than 20% blasts in ANC, and 11 (29%) had >20% in both NEC and ANC. There was no significant difference in overall survivals (OS) among AEL, MDS-EB, and AML-NOS (non erythroid predominance, NEP). However, AML with myelodysplasia-related changes showed significant shorter OS than AEL, MDS-EB and AML-NOS (NEP). Our results indicate that in myeloid neoplasm with erythroid predominance, patients with >20% blasts, of either NEC or ANC, share similar clinical laboratory features and survival outcomes with AML-NOS. PMID- 28886413 TI - Maternal residential air pollution and placental imprinted gene expression. AB - BACKGROUND: Maternal exposure to air pollution is associated with reduced fetal growth, but its relationship with expression of placental imprinted genes (important regulators of fetal growth) has not yet been studied. OBJECTIVES: To examine relationships between maternal residential air pollution and expression of placental imprinted genes in the Rhode Island Child Health Study (RICHS). METHODS: Women-infant pairs were enrolled following delivery between 2009 and 2013. We geocoded maternal residential addresses at delivery, estimated daily levels of fine particulate matter (PM2.5; n=355) and black carbon (BC; n=336) using spatial-temporal models, and estimated residential distance to nearest major roadway (n=355). Using linear regression models we investigated the associations between each exposure metric and expression of nine candidate genes previously associated with infant birthweight in RICHS, with secondary analyses of a panel of 108 imprinted genes expressed in the placenta. We also explored effect measure modification by infant sex. RESULTS: PM2.5 and BC were associated with altered expression for seven and one candidate genes, respectively, previously linked with birthweight in this cohort. Adjusting for multiple comparisons, we found that PM2.5 and BC were associated with changes in expression of 41 and 12 of 108 placental imprinted genes, respectively. Infant sex modified the association between PM2.5 and expression of CHD7 and between proximity to major roadways and expression of ZDBF2. CONCLUSIONS: We found that maternal exposure to residential PM2.5 and BC was associated with changes in placental imprinted gene expression, which suggests a plausible line of investigation of how air pollution affects fetal growth and development. PMID- 28886415 TI - Burden of higher lead exposure in African-Americans starts in utero and persists into childhood. AB - BACKGROUND: Recent public health lead crises in urban areas emphasize the need to better understand exposure to environmental toxicants, particularly in higher risk groups. Although African-American children have the highest prevalence of elevated blood lead levels in the United States, little is known about when this trajectory of disproportionate burden of lead exposure first emerges. OBJECTIVES: Using tooth-matrix biomarkers that directly measure fetal and early childhood metal levels, the primary goal of this study was to determine if there were racial disparities in lead levels during fetal development and early childhood. Manganese, an essential nutrient that modifies the neurotoxic effects of lead, was also measured. METHODS: Pregnant women served by the Henry Ford Health System and living in a predefined geographic area in and around Detroit, Michigan, were recruited during the second trimester or later into the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS), a population-based birth cohort. Offspring born between September 2003 and December 2007 were studied in childhood. Child race was parent-reported. Lead and manganese during the second and third trimesters, early postnatal life (birth through age 1year) and early childhood (age 1 through time of tooth shedding, which ranges from 6 to 12years) were measured via high-resolution microspatial mapping of dentin growth rings, a validated biomarker for prenatal and childhood metal exposure. RESULTS: African-American children (N=71) had 2.2 times higher lead levels in the second and third trimesters (both p<0.001) and 1.9 times higher lead levels postnatally in the first year of life (p=0.003) compared to white children (N=51). Lead levels in African-American children were also higher during childhood, but this effect was only marginally significant (p=0.066) and was attenuated after covariate adjustment. Additionally, we observed that African-American children had lower tooth-manganese levels during the third trimester (p=0.063) and postnatally (p=0.043), however these differences were attenuated after covariate adjustment. CONCLUSION: The disproportionate burden of lead exposure is vertically transmitted (i.e., mother-to-child) to African-American children before they are born and persists into early childhood. Our results suggest that testing women for lead during pregnancy (or in pre-conception planning), may be needed to identify the risk to their future offspring, particularly for African American women. PMID- 28886414 TI - Serum polychlorinated biphenyls and leukocyte telomere length in a highly-exposed population: The Anniston Community Health Survey. AB - BACKGROUND: Serum polychlorinated biphenyls (PCBs) have previously been associated with longer leukocyte telomere length (LTL) in most, but not all, of the few previous studies. PCBs were produced in Anniston, Alabama from 1929 to 1971 and participants of the Anniston Community Health Survey (ACHS) were highly exposed. OBJECTIVES: We evaluated serum levels of 35 PCBs and relative telomere length in 559 ACHS participants. METHODS: Relative LTL was measured in DNA extracted from blood clots. We assessed PCBs individually, grouped by chlorination, and summed PCBs. We used linear regression to assess the association between each PCB metric while adjusting for pertinent covariates. RESULTS: Serum PCBs were associated with longer LTL among white participants and the oldest age group of black participants. Among white participants, compared with those in the first quartile of sum PCBs those in the third quartile of sum PCBs had 8.09% longer relative LTL (95% CI: 1.99; 14.55) and those in the fourth had 7.58% longer relative LTL (95%CI: -0.01; 15.76) (p-quadratic=0.05). Among African American participants, serum PCBs were associated with longer relative LTL among those over age 64 only. Tests for interaction were not statistically significant. CONCLUSIONS: We observed a non-linear positive association between serum PCBs and LTL among white participants. Serum PCBs were associated with longer LTL in the oldest age group of African Americans. This association may provide insight into the cancers previously associated with exposure to PCBs, melanoma and non-Hodgkin lymphoma, which have been associated with long LTL in previous studies. PMID- 28886416 TI - Long-term exposure to particulate matter, NO2 and the oxidative potential of particulates and diabetes prevalence in a large national health survey. AB - BACKGROUND: The evidence from observational epidemiological studies of a link between long-term air pollution exposure and diabetes prevalence and incidence is currently mixed. Some studies found the strongest associations of diabetes with fine particles, other studies with nitrogen dioxide and some studies found no associations. OBJECTIVES: Our aim was to investigate associations between long term exposure to multiple air pollutants and diabetes prevalence in a large national survey in the Netherlands. METHODS: We performed a cross-sectional analysis using the 2012 Dutch national health survey to investigate the associations between the 2009 annual average concentrations of multiple air pollutants (PM10, PM2.5, PM10-2.5, PM2.5 absorbance, OPDTT, OPESR and NO2) and diabetes prevalence, among 289,703 adults. Air pollution exposure was assessed by land use regression models. Diabetes was defined based on a combined measure of self-reported physician diagnosis and medication prescription from an external database. Using logistic regression, we adjusted for potential confounders, including neighborhood- and individual socio-economic status and lifestyle related risk factors such as smoking habits, alcohol consumption, physical activity and BMI. RESULTS: After adjustment for potential confounders, all pollutants (except PM2.5) were associated with diabetes prevalence. In two pollutant models, NO2 and OPDTT remained associated with increased diabetes prevalence. For NO2 and OPDTT, single-pollutant ORs per interquartile range were 1.07 (95% CI: 1.05, 1.09) and 1.08 (95% CI: 1.05, 1.10), respectively. Stratified analysis showed no consistent effect modification by any of the included known diabetes risk factors. CONCLUSIONS: Long-term residential air pollution exposure was associated with diabetes prevalence in a large health survey in the Netherlands, strengthening the evidence of air pollution being an important diabetes risk factor. Most consistent associations were observed for NO2 and oxidative potential of PM2.5 measured by the DTT assay. The finding of an association with the oxidative potential of fine particles but not with PM2.5, suggests that particle composition may be important for a potential effect on diabetes. PMID- 28886418 TI - Chemically-induced photoreceptor degeneration and protection in mouse iPSC derived three-dimensional retinal organoids. AB - Induced pluripotent stem cells (iPSCs), which can be differentiated into various tissues and cell types, have been used for clinical research and disease modeling. Self-organizing three-dimensional (3D) tissue engineering has been established within the past decade and enables researchers to obtain tissues and cells that almost mimic in vivo development. However, there are no reports of practical experimental procedures that reproduce photoreceptor degeneration. In this study, we induced photoreceptor cell death in mouse iPSC-derived 3D retinal organoids (3D-retinas) by 4-hydroxytamoxifen (4-OHT), which induces photoreceptor degeneration in mouse retinal explants, and then established a live-cell imaging system to measure degeneration-related properties. Furthermore, we quantified the protective effects of representative ophthalmic supplements for treating the photoreceptor degeneration. This drug evaluation system enables us to monitor drug effects in photoreceptor cells and could be useful for drug screening. PMID- 28886417 TI - Is long-term particulate matter and nitrogen dioxide air pollution associated with incident monoclonal gammopathy of undetermined significance (MGUS)? An analysis of the Heinz Nixdorf Recall study. AB - BACKGROUND: Exposure to air pollution activates the innate immune system and influences the adaptive immune system in experimental settings. We investigated the association of residential long-term exposure to particulate matter (PM) and NO2 air pollution with monoclonal gammopathy of undetermined significance (MGUS) as a marker of adaptive immune system activation. METHODS: We used data from the baseline (2000-2003), 5-year (2006-2008) and 10-year (2011-2015) follow-up examinations of the German Heinz Nixdorf Recall cohort study of 4814 participants (45-75years). Residential exposure to PM size fractions and NO2 was estimated by land-use regression (ESCAPE-LUR, annual mean 2008/2009) and dispersion chemistry transport models (EURAD-CTM, 3-year mean at baseline). We used logistic regression to estimate the effects of air pollutants on incident MGUS, adjusting for age, sex, education, smoking status, physical activity, and BMI. As a non linear approach, we looked at quartiles (2-4) of the air pollutants in comparison to quartile 1. RESULTS: Of the 3949 participants with complete data, 100 developed MGUS during the 10-year follow-up. In the main model, only PMcoarse was associated with incident MGUS (OR per IQR (1.9MUg/m3): 1.32, 95% CI 1.04-1.67). We further found positive associations between PM size fractions estimated by ESCAPE-LUR and incident MGUS by quartiles of exposure (OR Q4 vs Q1: PM2.5 2.03 (1.08-3.80); PM10 1.97 (1.05-3.67); PMcoarse 1.98 (1.09-3.60)). CONCLUSIONS: Our results indicate that an association between long-term exposure to PM and MGUS may exist. Further epidemiologic studies are needed to corroborate this possible link. PMID- 28886419 TI - Mutation in an exonic splicing enhancer site causing chronic granulomatous disease. AB - In a male patient suffering from X-linked chronic granulomatous disease (CGD) we found a c.389G>T mutation in exon 5 of the CYBB gene. We have analyzed why 95% of the transcripts of this gene lacked exon 5, leading to a frameshift and premature termination codon. The mutation was located in a region comprising three putative exonic splicing enhancer binding sites, for SRSF1, SRFS2 and SRFS6, according to the ESEfinder Tool (http://rulai.cshl.edu/cgi-bin/tools/ESE3/esefinder.cgi). With the Analyser Splice Tool we calculated the probability of skipping of exon 5 in CYBB mRNA, and by means of Sroogle the number of putative binding motifs for splicing enhancer and splicing silencer proteins (http://astlab.tau.ac.il/index.php). These analyses clarify why this exon was skipped in the majority of the mRNA. The normally spliced transcript contains an amino acid change p.Arg130Leu. This poorly expressed transcript gives rise to a protein with low expression but presumably normal activity, leading to a respiratory burst activity in the patient's neutrophils of about 15% of normal. PMID- 28886421 TI - A method to describe inelastic gamma field distribution in neutron gamma density logging. AB - Pulsed neutron gamma density logging (NGD) is of great significance for radioprotection and density measurement in LWD, however, the current methods have difficulty in quantitative calculation and single factor analysis for the inelastic gamma field distribution. In order to clarify the NGD mechanism, a new method is developed to describe the inelastic gamma field distribution. Based on the fast-neutron scattering and gamma attenuation, the inelastic gamma field distribution is characterized by the inelastic scattering cross section, fast neutron scattering free path, formation density and other parameters. And the contribution of formation parameters on the field distribution is quantitatively analyzed. The results shows the contribution of density attenuation is opposite to that of inelastic scattering cross section and fast-neutron scattering free path. And as the detector-spacing increases, the density attenuation gradually plays a dominant role in the gamma field distribution, which means large detector spacing is more favorable for the density measurement. Besides, the relationship of density sensitivity and detector spacing was studied according to this gamma field distribution, therefore, the spacing of near and far gamma ray detector is determined. The research provides theoretical guidance for the tool parameter design and density determination of pulsed neutron gamma density logging technique. PMID- 28886420 TI - Discriminant validity, diagnostic utility, and parent-child agreement on the Screen for Child Anxiety Related Emotional Disorders (SCARED) in treatment- and non-treatment-seeking youth. AB - The Screen for Child Anxiety and Related Emotional Disorder (SCARED) may be differentially sensitive to detecting specific or comorbid anxiety diagnoses in treatment-seeking and non-treatment-seeking youth. We assessed the SCARED's discriminant validity, diagnostic utility, and informant agreement using parent- and self-report from healthy and treatment-seeking anxious youth (Study 1, N=585) and from non-treatment-seeking anxious youth (Study 2, N=331) diagnosed with generalized anxiety disorder (GAD), social anxiety disorder (SAD), or comorbid GAD+SAD. Among treatment-seeking youth, the SCARED showed good diagnostic utility and specificity, differentiating healthy, comorbid, and non-comorbid anxious youth. Child-parent agreement was modest: healthy child self-reports were higher than parent-reports whereas anxious child self-reports were similar or lower than parent-reports. Less consistent results emerged for diagnostic utility, specificity, and informant agreement among non-treatment-seeking youth. Given the number of non-treatment seeking anxious youth (N=33), generalizability of these findings may be limited. Together, results suggest informants may provide distinct information about children's anxiety symptoms. PMID- 28886422 TI - Initial evaluation of a 99mTc-cyclopentadienyltricarbonyl technetium complex as a potential 5-HT1A receptor imaging agent. PMID- 28886423 TI - Molecular Imaging of Colorectal Tumors by Targeting Colon Cancer Secreted Protein 2 (CCSP-2). AB - A versatile biomarker for detecting colonic adenoma and colon cancer has yet to be developed. Colon cancer secreted protein-2 (CCSP-2) is a protein specifically expressed and secreted in colon adenomas and cancers. We developed a fluorescent imaging method based on CCSP-2 targeting for a more sensitive and specific detection of colorectal tumors. CCSP-2 expression was evaluated in human colon adenoma and colorectal specimens. Anti-CCSP-2 antibody was labeled with a near infrared fluorescent dye, FPR-675, and molecular imaging of surgical human colorectal tumors was performed. Immunohistochemistry identified CCSP-2 expression in 87.0% of colorectal cancer specimens and 89.5% of colon adenoma specimens. Fluorescence imaging of surgical human colon specimens after spraying treatment with the probe permitted a clear distinction of cancer from paired normal colon tissue (target-to-background ratio, 4.09+/-0.42; P<.001). CCSP-2 targeting imaging was also evaluated in patient-derived colon cancer xenograft mouse and liver metastasis murine models. CCSP-2-positive colon cancer xenografts and liver metastases were visualized by near-infrared fluorescence imaging after intravenous injection of the probe, which showed significantly higher fluorescence. Our results show that CCSP-2 is a promising marker for colorectal tumor detection in clinical settings and that a CCSP-2-targeting molecular imaging strategy might improve the diagnosis of colorectal tumors in metastatic or recurrent cancers and aid in early colonoscopic detection of premalignant lesions. PMID- 28886424 TI - Emotional and behavioural needs in children with specific language impairment and in children with autism spectrum disorder: The importance of pragmatic language impairment. AB - BACKGROUND: Language problems may negatively affect children's behaviour and have detrimental effects on the development of peer-relations. AIMS: We investigated and compared emotional and behavioural profiles in children with SLI and in children with ASD aged 6-15 years and explored to what extent pragmatic language problems contributed to the emotional and behavioural needs (EBN) in these clinical groups. METHODS AND PROCEDURES: The ASD group consisted of 23 children (19 boys; 4 girls) and the SLI group consisted of 20 children (18 boys; 2 girls). In order to assess EBN and language abilities, the Strength and Difficulties Questionnaire (SDQ) and the Children's Communication Checklist -2 (CCC-2) were filled out by parents. OUTCOMES AND RESULTS: Our main findings were that although EBN was common in both groups; the children in the ASD group were significantly impaired relative to the children in the SLI group. However, in both groups pragmatic language problems were found to be significantly associated with EBN. IMPLICATIONS: A comprehensive assessment of EBN as well as pragmatic language abilities should be an integral part of the assessment procedure. Considering the substantial influence of pragmatic language abilities on social function and in resolving interpersonal conflicts with peers further development of therapy plans and interventions targeting pragmatics is strongly needed. PMID- 28886425 TI - Enhanced thymocyte apoptosis induced by maternal undernutrition in late gestation results in declined mature T cells in rat fetal thymus. AB - This study was designed to observe the effects of maternal food restriction (MFR) on the development of fetal thymus in different gestation periods. Timed pregnant rats were randomized into 3 groups: CN (free access to standard chow throughout gestation), MFR0-21 (50% MFR throughout gestation), MFR0-14 (50% MFR from gestational day (GD) 0 to GD14, early-mid gestation). Results showed that MFR during early-mid period had few impact on the fetal thymus and T cell subpopulations. However, MFR throughout gestation resulted in thymic atrophy, deceased frequency of both CD4+ and CD8+ single positive (SP) T cells and enhanced thymocyte apoptosis in fetus. Our results suggest the fetal thymus is more vulnerable to the adverse intrauterine environments in the late gestation period, and the decreased number of SP T cells could result from the enhanced thymocyte apoptosis. PMID- 28886426 TI - Synthesis, characterization and evaluation cytotoxic activity of silver nanoparticles synthesized by Chinese herbal Cornus officinalis via environment friendly approach. AB - Cornus officinalis has been widely used as a precious herb and as the tonic food to improve kidney function in China. Its fruits have been used in many traditional Chinese medicine prescriptions to treat kidney diseases, diabetes, cancer and shock. In this study, a new eco-friendly approach for green synthesis of silver nanoparticles (AgNPs) by using the fruits of Cornus officinalis aqueous extract as a reducing and stabilizing agent. The so-synthesized AgNPs showed quasi-spherical in shape with uniform dispersal and an average mean size of 11.7nm. Water soluble biomolecules such as flavonoids and/or anthocyanins from the extract played important roles in the nanoparticles formation. The AgNPs displayed distinctive cytotoxicity activities against human prostate cancer (PC 3) and human liver cancer (HepG2) cell lines. The results provided a low cost, nontoxic and eco-friendly approach for synthesizing metal nanoparticles to explore alternative anticancer agents on the way fighting against cancer in future. PMID- 28886427 TI - Tolerance to dichloroacetonitrile-induced neurotoxicity in streptozotocin-induced diabetic rats. AB - Diabetes mellitus has potential to alter the toxicity of hazardous chemicals. Dichloroacetonitrile (DCAN) is one of high-risk nitrogenous disinfection by products. This study evaluated the neurotoxicity of DCAN (11, 44 and 88mg/kg) in normoglycaemic and streptozotocin (STZ)-induced diabetic rats via orally for 28days. STZ diabetes prolonged the median survival time and total lethal time after DCAN (88mg/kg) exposure when compared with that observed in normoglycaemic rats. DCAN altered motor activity and induced anxiety behaviour in normoglycaemic rats; but it did not exaggerate behavioural changes in STZ diabetic rats. DCAN induced brain oxidative damage by compensatory increase glutathione content and decrease malonaldehyde levels; but it did not induce oxidative damage in diabetic rats. STZ diabetes slowed down the pathological pace of DCAN-induced brain mitochondrial dysfunction by decreasing reactive oxygen species and increasing cytochrome C oxidase activity. In conclusion, the present study indicated that STZ diabetic rats are resistant to DCAN-induced neurotoxicity at the dosage and with the dosage schedule in 28-day subacute toxicity test. PMID- 28886428 TI - Tris (2-chloroethyl) phosphate induces senescence-like phenotype of hepatocytes via the p21Waf1/Cip1-Rb pathway in a p53-independent manner. AB - Tris (2-chloroethyl) phosphate (TCEP) has been widely used as a plasticizer and flame retardant. TCEP as a potential carcinogen is often detected in the occupational and nature environments. To investigate effects of TCEP on human hepatocytes, we assessed cell growth rate, cellular membrane integrity, senescence-associated beta-galactosidase (SA-beta-Gal) activity and analyzed expression of regulators involved in the p53-p21Waf1/Cip1-Rb pathway in TCEP treated L02 cells. The results showed TCEP increased the percentage of SA-beta Gal positive cells, decreased IL-6 levels, down-regulated the regulators of p38MAPK-NF-kappaB pathways, but up-regulated the regulators of p21Waf1/Cip1-Rb pathway in L02 cells. Furthermore, we measured the SA-beta-Gal activity and expression of regulators involved in the p53-p21Waf1/Cip1-Rb pathway in L02-p53 cells and p53-null Hep3B cells. Similar results were found in L02-p53 cells and Hep3B cells. The findings demonstrated that TCEP induced senescence-like growth arrest via the p21Waf1/Cip1-Rb pathway in a p53-independent manner, without activation of the IL-6/IL6R, p38MAPK-NF-kappaB pathways in hepatocytes. PMID- 28886429 TI - Pre-treatment with melatonin decreases abamectin induced toxicity in a nocturnal insect Spodoptera litura (Lepidoptera: Noctuidae). AB - AIM: Oxidative stress is an important component of the mechanism of pesticide toxicity. The aim of the present study was to investigate the time-dependent melatonin effects against abamectin-induced oxidative stress in a S.litura model. Larvae were divided into 5 different groups; (1) control group,(2) Melatonin group (4.3*10-5M/100ml diet), (3) Abamectin group 1.5ml/L, (4) Pre-melatonin treated group (PM) (4.3*10-5M/100ml diet) before abamectin exposure 1.5ml/L, (5) Post-melatonin treated group (TM) after abamectin exposure. Melatonin was supplemented via artificial diet in PM and TM animals during 24h. MAIN METHODS: Midgut, fatbody, and hemolymph, were collected for the analysis of oxidative stress markers (Total ROS, GSH, nitrite, TBARS, LPO), antioxidant enzyme levels (SOD, GST, CAT, POX, APOX) in fifth instar larvae. Midgut damage was examined by using morphological analysis. KEY FINDINGS: Our results observed that ABA group showed significant changes (p<0.001) in the ROS and carbonyl content in midgut. The increase of antioxidant enzyme levels (SOD, CAT, POX, and APOX) in midgut was led by the continuous free radical scavenger cascade of melatonin. Significant (p<0.01) increases in CAT and APOX levels were seen in the fatbody of PM and TM treated insects. SIGNIFICANCE: In conclusion, the results of the study revealed that abamectin toxicity generates oxidative stress in the insect, while pre melatonin treatment reduces this damage due to its antioxidant properties, especially POX levels in midgut, fatbody, and hemolymph. Therefore, indoleamine can play a vital role curtailing the abamectin toxicity in time dependent manner in S.litura. PMID- 28886430 TI - Story grammar elements and causal relations in the narratives of Russian-Hebrew bilingual children with SLI and typical language development. AB - BACKGROUND: While there is general agreement regarding poor performance of children with Specific Language Impairment (SLI) on microstructure measures of narrative production, findings on macrostructure are inconsistent. PURPOSE: The present study analyzed narrative abilities of Russian-Hebrew bilingual preschool children with and without SLI, with a particular focus on story grammar (SG) elements and causal relations, in order to identify macrostructure features which distinguish bilingual children with SLI from those with typical development. METHOD: Narratives were collected from 35 typically developing bilinguals (BiTD) and 14 bilinguals with SLI (BiSLI) in both Russian/L1 and Hebrew/L2 using a retelling procedure (LITMUS-Multilingual Assessment Instrument for Narratives) (Gagarina, Klop, Kunnari, Tantele, Valimaa, Balciuniene, Bohnacker, & Walters, 2012). Each story contained three episodes, and each episode introduced a different protagonist with explicitly stated Goals (G), Attempts (A) and Outcomes (O). Causal relations assessed included Enabling, Physical, Motivational, and Psychological relations, following Trabasso & Nickels (1992). Each Goal-Attempt Outcome (GAO) episode was examined for the use of SG elements and causal relations. RESULTS: Group differences emerged for both aspects of macrostructure. For causal relations, narratives of BiSLI children contained fewer Enabling and Physical relations, and differed qualitatively from those of BiTD children. For SG elements, BiSLI children referred to fewer SG elements than BiTD children in the first episode, but performed like BiTD children in the second and the third episodes. CONCLUSIONS: Story grammar elements in specific episodes along with Enabling and Physical causal relations distinguish the narratives of children with BiSLI from those with BiTD, which stresses the importance of examining wider array of macrostructure features in narratives. PMID- 28886431 TI - The effect of phonetic complexity on the speed of single-word productions in adults who do and do not stutter. AB - PURPOSE: The purpose of this study was to investigate the influence of phonetic complexity as measured by the Word Complexity Measure (WCM) on the speed of single-word production in adults who do (AWS, n=15) and do not stutter (AWNS, n=15). METHOD: Participants were required to name pictures of high versus low phonetic complexity and balanced for lexical properties. Speech reaction time was recorded from initial presentation of the picture to verbal response of participant for each word type. Accuracy and fluency were manually coded for each production. RESULTS: AWS named pictures significantly slower than AWNS, but there were no significant differences observed in response latency when producing word of high versus low phonetic complexity as measured by the WCM. CONCLUSION: Findings corroborate past research of overall slowed picture naming latencies in AWS, compared to AWNS. Findings conflict with data that suggest that the phonetic complexity of words uniquely compromises the speed of production in AWS. The potential interaction between lexical and phonetic factors on single-word production within each group are discussed. PMID- 28886432 TI - Traumatic lower extremity and lumbosacral peripheral nerve injuries in adults: Electrodiagnostic studies and patients symptoms. AB - BACKGROUND: Peripheral nerve injuries (PNI) are relatively common pathologies in clinical practice. PNIs are rare in the lower extremity but have worse prognosis than those in the upper extremity. Electrodiagnostic studies could help better understanding PNIs. In this study, we aimed to evaluate the distribution of lower extremity PNI in traumatic patients in northwest of Iran. METHODS: In this prospective study, 74 patients (62 male and 12 female with mean age of 38.39 +/- 14.42 years) with possible lower or lumbosacral peripheral nerve injury were studied. Patients' demographic information and physical examination findings were recorded. Electrodiagnostic investigations including electromyography and Nerve Conduction Study were performed for all subjects. RESULTS: Common chief complaints were pain and weakness. Impairment in the sensory function was present in 59.5% and muscle force reduction in 47.3%. PNIs were present in 23.0% and mostly were severe. Injuries in sciatic nerve were the most common PNIs (16.2%). Electrodiagnostic studies showed radiculopathy in 48.7% and plexopathy in 8.10% of cases. In 52 patients (70.3%), the physical examination findings were compatible with Electrodiagnostic studies. CONCLUSION: Not all patients presenting with traumatic injuries have lower extremity PNIs. Due to the nature of the trauma and the anatomical course of the nerves, sciatic nerve is more susceptible to traumatic injuries. PMID- 28886433 TI - Sudden death in a child caused by a giant cavernous hemangioma of the anterior mediastinum. AB - A 4-year-old girl who had been treated for asthma since the age of 2 years had a severe coughing fit and died suddenly. The patient had a history of occasional severe coughing fits, and these fits had been worsening in severity during the week before her death. Prior to death, she was taken to a clinician, and thymic hypertrophy was suspected based on chest X-ray findings. The clinician recommended that she visit a general hospital at a later date; however, she died that night. Postmortem radiology and autopsy revealed a large mass in the anterior mediastinum compressing the heart and airway, and no other findings attributable to sudden death were observed. Therefore, we concluded that the patient's death was attributable to acute respiratory and cardiac circulatory failure secondary to the pressure induced by the mass. Microscopically, the mass showed a cavernous structure composed of cystically dilated, thin-walled large vessels filled with blood. The final diagnosis was a cavernous hemangioma. Hemangiomas are the most common benign vascular anomalies seen in young children; however, mediastinal hemangiomas are rare and can cause life-threatening complications because of their size and location. Therefore, forensic pathologists should include hemangioma as a differential diagnosis in children with anterior mediastinal masses. PMID- 28886434 TI - Prediction of lysine crotonylation sites by incorporating the composition of k spaced amino acid pairs into Chou's general PseAAC. AB - As one of the most important and common histones post-translational modifications, crotonylation plays a key role in regulating various biological processes. The accurate identification of crotonylation sites is crucial to elucidate the underlying molecular mechanisms of crotonylation. In this study, a novel bioinformatics tool named CKSAAP_CrotSite is developed to predict crotonylation sites. The highlight of CKSAAP_CrotSite is to adopt the composition of k-spaced amino acid pairs as input encoding, and the support vector machine is employed as the classifier. As illustrated by jackknife test, CKSAAP_CrotSite achieves a promising performance with a Sensitivity of 92.45%, a Specificity of 99.17%, an Accuracy of 98.11% and a Matthew's correlation coefficient of 0.9283, which is much better than those of the existing prediction methods. Feature analysis shows that some amino acid pairs such as 'KxG', 'KG' and 'PxP' may play an important role in the prediction of crotonylation sites. The results of analysis and prediction could offer useful information for elucidating the molecular mechanisms of crotonylation and related experimental validations. A user-friendly web-server for CKSAAP_CrotSite is available at 123.206.31.171/CKSAAP_CrotSite/. PMID- 28886435 TI - Using WWC sanctioned rigorous methods to develop comparison groups for evaluation. AB - Evaluation of program impact in the field of education has been a controversial topic over the years. Although randomized control trials have great advantages in causal inference, they often raise ethical and economic concerns in practice. As an alternative, quasi-experimental designs may provide valid evidence of influence if they are well-designed. In this article, we presented an evaluation case of a district-wide early learning improvement program. To strike a balance between practicability and academic rigor, we developed comparison groups from multiple perspectives, and used a series of tests consistent with WWC 3.0 standards to reach the most valid comparisons. Implications for evaluation practice were discussed. PMID- 28886436 TI - Devil is in the details: Using logic models to investigate program process. AB - Theory-based logic models are commonly developed as part of requirements for grant funding. As a tool to communicate complex social programs, theory based logic models are an effective visual communication. However, after initial development, theory based logic models are often abandoned and remain in their initial form despite changes in the program process. This paper examines the potential benefits of committing time and resources to revising the initial theory driven logic model and developing detailed logic models that describe key activities to accurately reflect the program and assist in effective program management. The authors use a funded special education teacher preparation program to exemplify the utility of drill down logic models. The paper concludes with lessons learned from the iterative revision process and suggests how the process can lead to more flexible and calibrated program management. PMID- 28886437 TI - Apple and blackcurrant polyphenol-rich drinks decrease postprandial glucose, insulin and incretin response to a high-carbohydrate meal in healthy men and women. AB - Postprandial glycemic responses to meals are inhibited by polyphenol-rich plant foods. Combinations of polyphenols may be particularly effective through complementary mechanisms. A randomized, controlled, double-blinded cross-over trial was conducted in healthy volunteers to test the hypothesis that apple and blackcurrant polyphenol-rich drinks would reduce postprandial blood glucose concentrations. Secondary outcomes included insulin and glucose-dependent insulinotropic polypeptide (GIP) secretion. Twenty men (mean age 26 y, SD 8) and 5 postmenopausal women (mean age 57 y, SD 3) consumed a placebo drink (CON) and 2 polyphenol-rich drinks containing fruit extracts: either 1200 mg apple polyphenols (AE), or 600 mg apple polyphenols+600 mg blackcurrant anthocyanins (AE+BE), in random order with a starch and sucrose meal. Incremental areas under the curve (iAUC) for plasma glucose concentrations were lower following AE+BE over 0-30 and 0-120 min compared with CON; mean differences (95% CI) -32 mmol/L.min (-41, -22, P<.0005) and -52 mmol/L min (-94, -9, P<.05), respectively. AE significantly reduced iAUC 0-30 min (mean difference -26 mmol/L min, -35, -18, P<.0005) compared with CON, but the difference over 120 min was not significant. Postprandial insulin, C-peptide and GIP concentrations were significantly reduced relative to CON. A dose response inhibition of glucose transport was demonstrated in Caco-2 cells, including total and GLUT-mediated transport, and SGLT1-mediated glucose transport was strongly inhibited at all doses in Xenopus oocytes, following 10 min incubation with 0.125-4 mg apple polyphenols/ml. In conclusion, ingestion of apple and blackcurrant polyphenols decreased postprandial glycemia, which may be partly related to inhibition of intestinal glucose transport. PMID- 28886438 TI - Daidzein down-regulates ubiquitin-specific protease 19 expression through estrogen receptor beta and increases skeletal muscle mass in young female mice. AB - Ubiquitin-specific protease 19 (USP19) is a key player in the negative regulation of muscle mass during muscle atrophy. Loss-of-function approaches demonstrate that 17beta-estradiol (E2) increases USP19 expression through estrogen receptor (ER) alpha and consequently decreases soleus muscle mass in young female mice under physiological conditions. Daidzein is one of the main isoflavones in soy, and activates ERbeta-dependent transcription. Here, we investigated the effects of daidzein on E2-increased USP19 expression and E2-decreased soleus muscle mass in young female mice. Daidzein stimulated the transcriptional activity of ERbeta in murine C2C12 cells and down-regulated USP19 expression. Consistently, daidzein inhibited E2-induced USP19 expression in a reporter activity using a functional half-estrogen response element (hERE) from Usp19. Daidzein inhibited E2-induced recruitment of ERalpha and promoted recruitment of ERbeta to the Usp19 hERE. Dietary daidzein down-regulated the expression of USP19 at the mRNA and protein levels and increased soleus muscle mass in female mice, but not in males. In soleus muscle from ovariectomized (OVX) female mice, dietary daidzein inhibited E2-increased USP19 mRNA expression and E2-decreased muscle mass. Furthermore, E2 induced the recruitment of ERalpha and ERbeta to the hERE, whereas daidzein inhibited E2-induced recruitment of ERalpha, and enhanced E2-increased recruitment of ERbeta, to the Usp19 hERE. These results demonstrate that dietary daidzein decreases USP19 mRNA expression through ERbeta and increases soleus muscle mass in young female mice, but not in male mice, under physiological conditions. PMID- 28886439 TI - Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice. AB - Excess carbohydrate intake causes obesity in humans. On the other hand, acute administration of fructose, glucose or sucrose in experimental animals has been shown to increase the plasma concentration of anti-obesity hormones such as glucagon-like peptide 1 (GLP-1) and Fibroblast growth factor 21 (FGF21), which contribute to reducing body weight. However, the secretion and action of GLP-1 and FGF21 in mice chronically fed a high-sucrose diet has not been investigated. To address the role of anti-obesity hormones in response to increased sucrose intake, we analyzed mice fed a high-sucrose diet, a high-starch diet or a normal diet for 15 weeks. Mice fed a high-sucrose diet showed resistance to body weight gain, in comparison with mice fed a high-starch diet or control diet, due to increased energy expenditure. Plasma FGF21 levels were highest among the three groups in mice fed a high-sucrose diet, whereas no significant difference in GLP 1 levels was observed. Expression levels of uncoupling protein 1 (UCP-1), FGF receptor 1c (FGFR1c) and beta-klotho (KLB) mRNA in brown adipose tissue were significantly increased in high sucrose-fed mice, suggesting increases in FGF21 sensitivity and energy expenditure. Expression of carbohydrate responsive element binding protein (ChREBP) mRNA in liver and brown adipose tissue was also increased in high sucrose-fed mice. These results indicate that FGF21 production in liver and brown adipose tissue is increased in high-sucrose diet and participates in resistance to weight gain. PMID- 28886440 TI - Pills in paradise: Exploring international lifestyle and retirement migrants' perceptions of the pharmaceutical sector on Cozumel Island, Mexico. AB - International lifestyle and retirement migration is a growing phenomenon, yet little is known about migrants' experiences of health care in destination countries. This includes use of and access to pharmaceutical selling establishments. This article explores international lifestyle and retirement migrants' experiences and perceptions of the local pharmaceutical sector on Cozumel Island, Mexico. Qualitative data, collected through semi-structured interviews (n = 26), finds that participants are concerned with accessibility, quality and communication within the island's pharmaceutical sector. Subsequent analysis suggests that these concerns arise through comparison with previous health care environments and that migrants attempt to remedy them by spatially reorganising their pharmacy engagements through practices which may contribute to adverse health outcomes. PMID- 28886441 TI - Place and recovery from alcohol dependence: A journey through photovoice. AB - It has been suggested that place, and interaction with the environment, may play a role in recovery from alcohol dependence. In this paper we report findings from a project that used an adapted photovoice methodology to better understand individuals' experience and perceptions of the role of place in recovery from alcohol dependence. Individuals attending a recovery cafe in central Scotland documented their environment and, in focus group settings, the individuals discussed and analysed their photographs. Here we report aspects of the environment, both therapeutic and risky, experienced by individuals negotiating the journey of dependence recovery. Elements of the natural environment were largely referred to as supportive and therapeutic, as were other more quotidian spaces, such as the home and cafe. The largest place-based risk faced by participants was the persistent availability and marketing of alcohol. The results demonstrate that the journey of recovery from alcohol dependence is contextually shaped, with place both supporting and hindering this journey. PMID- 28886442 TI - Four new cases of pediatric thoracic aortic aneurysm (TAA) with review of the molecular genetic basis, utilizing the newly published consensus nomenclature. AB - The majority of thoracic aortic aneurysms (TAA) in the pediatric population are due to post repair etiology (iatrogenic). Although rare, underlying inheritable disease and congenital cardiac anomalies represent the most common non-iatrogenic cause of TAA among patients in this age group (1-21 years of age). Herein, we present a case series of 9aortic aneurysms with varying underlying etiology. We discuss the molecular genetic basis of these syndromes in conjunction with the radiological findings and histological description utilizing the newly published consensus criteria article. PMID- 28886444 TI - Assessment of mental health status among school going adolescents in North East India: A cross sectional school based survey. AB - BACKGROUND: Adolescent emotional responses and behaviors are often passed off as growth pangs and academic stress, thereby missing those that need deeper understanding and mental health interventions. AIM: The aim of the study is to understand mental health status among the school adolescents in Tezpur, Assam. MATERIALS AND METHODS: The present study was a cross sectional study that used convenience sampling in selection of the schools. A total of 10 schools were selected for the purpose of the study. 1403 Adolescents were selected for data analysis. Socio-Demographic Performa and Strengths and Difficulties Questionnaire [SDQ] were administered to the participants. RESULTS: The results indicated that five predictors (gender, education, family type, academic performance, socio economic status in the family) explained 9.79% of the variance (F=5.040, P<0.000) in total difficulty levels: (Academic performance; beta=0.08; t=3.15; P=0.002) and (Socio economic status; beta=0.07, t=3.02, P=0.003). CONCLUSION: In the study less than one tenth of the participants have some mental health issues and this calls for concern. Schools should have standing operation procedures in place to periodically screen adolescents for mental health related issues. PMID- 28886443 TI - Antiplasmodial activities of dyes against Plasmodium falciparum asexual and sexual stages: Contrasted uptakes of triarylmethanes Brilliant green, Green S (E142), and Patent Blue V (E131) by erythrocytes. AB - The search for safe antimalarial compounds acting against asexual symptom responsible stages and sexual transmission-responsible forms of Plasmodium species is one of the major challenges in malaria elimination programs. So far, among current drugs approved for human use, only primaquine has transmission blocking activity. The discovery of small molecules targeting different Plasmodium falciparum life stages remains a priority in antimalarial drug research. In this context, several independent studies have recently reported antiplasmodial and transmission-blocking activities of commonly used stains, dyes and fluorescent probes against P. falciparum including chloroquine-resistant isolates. Herein we have studied the antimalarial activities of dyes with different scaffold and we report that the triarylmethane dye (TRAM) Brilliant green inhibits the growth of asexual stages (IC50 <= 2 MUM) and has exflagellation-blocking activity (IC50 <= 800 nM) against P. falciparum reference strains (3D7, 7G8) and chloroquine-resistant clinical isolate (Q206). In a second step we have investigated the antiplasmodial activities of two polysulfonated triarylmethane food dyes. Green S (E142) is weakly active against P. falciparum asexual stage (IC50 ? 17 MUM) whereas Patent Blue V (E131) is inactive in both antimalarial assays. By applying liquid chromatography techniques for the culture supernatant analysis after cell washings and lysis, we report the detection of Brilliant green in erythrocytes, the selective uptake of Green S (E142) by infected erythrocytes, whereas Patent Blue V (E131) could not be detected within non-infected and 3D7-infected erythrocytes. Overall, our results suggest that two polysulfonated food dyes might display different affinity with transporters or channels on infected RBC membrane. PMID- 28886445 TI - Unveiling the polarization of the multimode acoustic fields. AB - The spatial three dimensional variation of the polarization ellipse characterizing an elastic movement of the solid particles in the harmonically oscillating ultrasonic fields is studied. Such a variation comes into sight because of the interference of various elastic modes generated during the excitation and/or scattering of acoustic waves by the inhomogeneities located on the solid surface. In order to confirm this effect, an innovative method based on finite element approach is used showing a rule to find the form and orientation of the elastic polarization ellipse in general case. Polarization plane may have an arbitrary orientation in anisotropic crystals. The dispersive parameters of the spatially changeable ellipse of polarization in a substrate with perturbed boundary conditions depend on the polarization and on the relative complex-valued amplitudes of the partial elastic modes which contribute differently to the sum of acoustic fields at every point of analysis. Results of a detailed investigation of the mentioned effects in an interdigital transducer formed by aluminum electrodes on the ST-X cut of quartz substrate are presented. PMID- 28886446 TI - Interaction of zinc(II) with the non-steroidal anti-inflammatory drug niflumic acid. AB - The reaction of ZnCl2 with the non-steroidal anti-inflammatory drug niflumic acid (Hnif) resulted in the formation of complex [Zn(nif-O)2(MeOH)4], 1. When this reaction was performed in the presence of a N,N'-donor heterocyclic ligand such as 2,2'-bipyridine (bipy), 2,2'-bipyridylamine (bipyam), 1,10-phenanthroline (phen) and 2,2'-dipyridylketone oxime (Hpko), the complexes [Zn(nif O,O')(bipy)Cl], 2, [Zn(nif-O)(nif-O,O')2(bipyam)], 3, [Zn(nif-O,O')2(phen)], 4 and [Zn(nif-O)2(Hpko-N,N')2], 5 were formed, respectively. The complexes were characterized by physicochemical and spectroscopic techniques and X-ray crystallography (for complexes 1-3). The complexes can scavenge 1,1-diphenyl picrylhydrazyl, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals, may inhibit soybean lipoxygenase and are more active compounds than free Hnif. The interaction of the complexes with serum albumins was monitored by fluorescence emission spectroscopy and the corresponding binding constants were calculated. The affinity of the complexes with calf-thymus DNA was investigated by UV-vis spectroscopy, viscosity measurements and fluorescence emission spectroscopy for the competitive studies of the complexes with ethidium bromide revealing their interaction probably via intercalation. PMID- 28886447 TI - Early life experience contributes to the developmental programming of depressive like behaviour, neuroinflammation and oxidative stress. AB - This study used an animal model of depression induced by maternal care deprivation (MCD) to investigate whether depressive behaviour, neuroinflammation and oxidative stress were underlying factors in developmental programming after early life stress. At postnatal days (PND) 20, 30, 40, and 60, individual subsets of animals were evaluated in behavioural tests and then euthanized to assess cytokine levels and oxidative stress parameters in the prefrontal cortex (PFC), hippocampus and serum. The results showed that MCD did not induce behavioural changes at PND 30 and 40. However, at PND 20 and 60, the rats displayed a depressive-like behaviour in the forced swimming test, without changes in locomotor spontaneous activity. In the brain and serum, the levels of pro inflammatory cytokines (interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha)) were increased, and the anti inflammatory cytokine (interleukin-10) level was reduced throughout developmental programming (PND 20, 30, 40 and 60). Protein carbonyl levels increased in the brain at PND 30, 40 and 60. Superoxide dismutase (SOD) activity was decreased during all developmental programming phases evaluated in the brain. Catalase (CAT) activity was decreased at PND 20, 40 and 60 in the brain. Our results revealed that "critical episodes" in early life stressful events are able to induce behavioural alterations that persist into adulthood and can stimulate inflammation and oxidative damage in both central and peripheral systems, which are required for distinct patterns of resilience against psychiatric disorders later in life. PMID- 28886448 TI - Exploring hepsin functional genetic variation association with disease specific protein expression in bipolar disorder: Applications of a proteomic informed genomic approach. AB - In a prior discovery study, increased levels of serum Growth Differentiation Factor 15 (GDF15), Hepsin (HPN), and Matrix Metalloproteinase-7 (MMP7) were observed in bipolar depressed patients vs controls. This exploratory post-hoc analysis applied a proteomic-informed genomic research strategy to study the potential functional role of these proteins in bipolar disorder (BP). Utilizing the Genotype-Tissue Expression (GTEx) database to identify cis-acting blood expression quantitative trait loci (cis-eQTLs), five eQTL variants from the HPN gene were analyzed for association with BP cases using genotype data of cases from the discovery study (n = 58) versus healthy controls (n = 777). After adjusting for relevant covariates, we analyzed the relationship between these 5 cis-eQTLs and HPN serum level in the BP cases. All 5 cis-eQTL minor alleles were significantly more frequent in BP cases vs controls [(rs62122114, OR = 1.6, p = 0.02), (rs67003112, OR = 1.6, p = 0.02), (rs4997929, OR = 1.7, p = 0.01), (rs12610663, OR = 1.7, p = 0.01), (rs62122148, OR = 1.7, P = 0.01)]. The minor allele (A) in rs62122114 was significantly associated with increased serum HPN level in BP cases (Beta = 0.12, P = 0.049). However, this same minor allele was associated with reduced gene expression in GTEx controls. These exploratory analyses suggest that genetic variation in/near the gene encoding for hepsin protein may influence risk of bipolar disorder. This genetic variation, at least for the rs62122114-A allele, may have functional impact (i.e. differential expression) as evidenced by serum HPN protein expression. Although limited by small sample size, this study highlights the merits of proteomic informed functional genomic studies as a tool to investigate with greater precision the genetic risk of bipolar disorder and secondary relationships to protein expression recognizing, and encouraging in subsequent studies, high likelihood of epigenetic modification of genetic disease risk. PMID- 28886450 TI - Driving performance at lateral system limits during partially automated driving. AB - This study investigated driver performance during system limits of partially automated driving. Using a motion-based driving simulator, drivers encountered different situations in which a partially automated vehicle could no longer safely keep the lateral guidance. Drivers were distracted by a non-driving related task on a touch display or driving without an additional secondary task. While driving in partially automated mode drivers could either take their hands off the steering wheel for only a short period of time (10s, so-called 'Hands-on' variant) or for an extended period of time (120s, so-called 'Hands-off' variant). When the system limit was reached (e.g., when entering a work zone with temporary lines), the lateral vehicle control by the automation was suddenly discontinued and a take-over request was issued to the drivers. Regardless of the hands-off interval and the availability of a secondary task, all drivers managed the transition to manual driving safely. No lane exceedances were observed and the situations were rated as 'harmless' by the drivers. The lack of difference between the hands-off intervals can be partly attributed to the fact that most of the drivers kept contact to the steering wheel, even in the hands-off condition. Although all drivers were able to control the system limits, most of them could not explain why exactly the take-over request was issued. The average helpfulness of the take-over request was rated on an intermediate level. Consequently, providing drivers with information about the reason for a system limit can be recommended. PMID- 28886449 TI - Development and validation of the Questionnaire of Stressful Life Events (QSLE). AB - Stressful life events (SLEs) are important indicators prior to the onset of first episode psychosis (FEP). Although there are well-validated interviews and self reports for assessing SLE on proximate events, unfortunately there are no instruments to assess SLE covering an entire lifetime. This study includes detailed specific items of childhood, adolescence, and adulthood focused on the presence of SLE, emotional impact (stressfulness), and the age at which the event occurred. Our research describes 2 studies designed to develop and validate a new scale to assess SLE: the Questionnaire of Stressful Life Events (QSLE). In Study 1, an over-inclusive item pool was generated based on review of group of experts at Parc Sanitari Sant Joan de Deu and content validity was examined by an Expert Survey. The whole scale represents the content domain. In Study 2, item-level analyses revealed good distributional properties, intra-rater reliability, and convergent and discriminant validity. In the sensitivity and specificity analysis, 18 items had high relevance in the discriminability between patients with FEP and healthy controls. We note that there was an AUC of 0.676, indicating a good predictor. Using 7 as a cutoff to predict an individual as a patient would yield a sensitivity of 64.8% and a specificity of 65%. Overall, the QSLE displayed satisfactory psychometric characteristics in a Spanish population. These results suggest that QSLE gives us the opportunity to investigate childhood, adolescent, and adult life events by measuring the stress and age at the moment on a continuous scale. PMID- 28886451 TI - A comparative injury severity analysis of motorcycle at-fault crashes on rural and urban roadways in Alabama. AB - The research described in this paper explored the factors contributing to the injury severity resulting from the motorcycle at-fault accidents in rural and urban areas in Alabama. Given the occurrence of a motorcycle at-fault crash, random parameter logit models of injury severity (with possible outcomes of fatal, major, minor, and possible or no injury) were estimated. The estimated models identified a variety of statistically significant factors influencing the injury severities resulting from motorcycle at-fault crashes. According to these models, some variables were found to be significant only in one model (rural or urban) but not in the other one. For example, variables such as clear weather, young motorcyclists, and roadway without light were found significant only in the rural model. On the other hand, variables such as older female motorcyclists, horizontal curve and at intersection were found significant only in the urban model. In addition, some variables (such as, motorcyclists under influence of alcohol, non-usage of helmet, high speed roadways, etc.) were found significant in both models. Also, estimation findings showed that two parameters (clear weather and roadway without light) in the rural model and one parameter (on weekend) in the urban model could be modeled as random parameters indicating their varying influences on the injury severity due to unobserved effects. Based on the results obtained, this paper discusses the effects of different variables on injury severities resulting from rural and urban motorcycle at-fault crashes and their possible explanations. PMID- 28886452 TI - Underexpression of apoplastic polyamine oxidase improves thermotolerance in Nicotiana tabacum. AB - Polyamines (PAs) and hydrogen peroxide (H2O2), the product of PA oxidation by polyamine oxidase (PAO), are potential players affecting plant growth, development and responses to abiotic/biotic stresses. Genetically modified Nicotiana tabacum plants with altered PA/H2O2 homeostasis due to over/underexpression of the ZmPAO gene (S-ZmPAO/AS-ZmPAO, respectively) were assessed under heat stress (HS). Underexpression of ZmPAO correlates with increased thermotolerance of the photosynthetic machinery and improved biomass accumulation, accompanied by enhanced levels of the enzymatic and non-enzymatic antioxidants, whereas ZmPAO overexpressors exhibit significant impairment of thermotolerance. These data provide important clues on PA catabolism/H2O2/thermotolerance, which merit further exploitation. PMID- 28886453 TI - Patterns of low temperature induced accumulation of dehydrins in Rosaceae crops Evidence for post-translational modification in apple. AB - Important crop plants of Rosaceae family are often damaged during winter due to the lack of acclimation and cold hardiness. One of the cellular responses of plants to cold stress is the accumulation of dehydrin proteins. We studied the expression of dehydrins in several Rosaceae species during low temperature treatment in vitro. Microshoots of Pyrus communis, Malus*domestica, Fragaria vesca, Fragaria*ananassa, Prunus cerasus and Prunus avium cultivars were grown in low temperature conditions. Genotype -specific accumulation of dehydrins was detected by immunoblot analysis of the extracted proteins. Untargeted difference gel electrophoresis of Malus x domestica microshoots revealed an extensive accumulation of three dehydrins. In a protein phosphatase assay, MdDHN2 and MdDHN4, but not MdDHN6 proteins were found to be extensively phosphorylated. In terms of the amount of protein synthesized, dehydrins are a major protein-level adaptation mechanism to low temperature in M. x domestica. In addition to dehydrins, the induction of proteins involved in the response for oxidative stress were observed. Additionally, a Xero2 -like dehydrin of F. vesca was detected by difference gel electrophoresis and identified by nano LC-MS/MS. PMID- 28886454 TI - Effects of olive root warming on potassium transport and plant growth. AB - Young olive (Olea europaea L.) plants generated from seed were grown in liquid hydroponic medium exposing the roots system for 33days or 24h to high temperature (37 degrees C) while the aerial part to 25 degrees C aiming to determine the prolonged and immediate effects of root warming on K+(Rb+) transport in the root and consequently on plant growth. The exposition of the root system to 37 degrees C for 24h inhibited K+ (Rb+) transport from root to shoot having no effect on its uptake. However, when the root system was exposed permanently to 37 degrees C both the K+ (Rb+) uptake and translocation to the aerial part were inhibited as well as the growth in all plants organs. The ability of the root system to recover K+ (Rb+) uptake and transport capacity after being exposed to high temperature was also evaluated. Plants grown in a root medium at 37 degrees C for 31days were transferred to another at 25 degrees C for 48 or 96h. The recovery of K+ (Rb+) root transport capacity after high root temperature was slow. Any signal of recovery was observed after 48h without stress: both potassium root uptake and subsequent transport to above organs were inhibited yet. Whereas 96h without stress led to restore potassium upward transport capacity although the uptake was partially inhibited yet. The results obtained in this study have shown that the root system of young olive plants is very sensitive to high temperature related to root potassium transport and growth of the plant. Taking into account the two processes involved in root potassium transport, the discharge of K+ to the xylem vessels was more affected than the uptake at the initial phase of high root temperature stress. However, it was the first process to be re-established during recovery. All this could explain the symptoms frequently observed in olive orchards when dry and high temperature spells occur: a reduction in shoots growth and leaves with low levels of potassium contents and dehydration symptoms. PMID- 28886455 TI - Development of an electrochemical immunosensor for the diagnostic testing of spotted fever using synthetic peptides. AB - Spotted fever is a rare acute and multisystemic febrile infectious disease with a mortality rate of >=50% without adequate antibiotic treatment, and in diagnosed and treated cases, of approximately 2.5%. Currently, the applied test to diagnose this disease is the indirect immunofluorescence reaction, however two samples of paired sera are necessary to confirm the diagnosis, since using only one sample may allow for confusion with cross reactions. OmpA is an outer membrane protein present in the R. rickettsia, the etiological agent of spotted fever, able to activate dendritic and macrophage cells. It also presents immunogenicity properties, and is considered a target for the development of diagnostic tests for spotted fever. In this context, an amperometric immunosensor was developed for the identification of sera antibodies (human IgG) from patients with spotted fever aimed at improving sensitivity and minimize sample volume. The development of the immunosensor was conducted using a synthetic peptide, derivative from the H6PGA4 R. rickettsia protein, homologous to OmpA. Amperometric responses were generated at -0.6 to 0.6V, at a scan rate of 0.025Vs-1 for 20 cycles, a limit of detection of approximately 10ngmL-1 for the synthetic peptides and 0.01ugmL-1 for the humam serum, a sensitivity of 2.59uA, adequate for the detection of spotted fever antibodies. The construction of this immunosensor, capable of identifying circulating antibodies in real time, can also be applied in the diagnosis of other infectious-parasitic diseases. PMID- 28886457 TI - Competition-derived FRET-switching cationic conjugated polymer-Ir(III) complex probe for thrombin detection. AB - A novel, label-free and convenient strategy for thrombin assay has been developed based on the fluorescence resonance energy transfer (FRET) from a cationic conjugated polymer (CCP) to Ir(III) complex. The energy donor (CCP) and acceptor (Ir(III) complex) were taken into close proximity through pi-pi stacking interaction and electrostatic interaction, leading to the occurrence of FRET. However, the introduction of the thrombin aptamer upset the status and blocked the FRET process, but afterwards the reappearance of FRET phenomenon was confirmed by the special binding interaction between aptamer and thrombin, thus achieving the quantitative detection of thrombin. This assay could detect thrombin as low concentration as about 0.05pM and provided a highly specific selectivity among other nonspecific proteins. Moreover, the strategy may allow our platform to provide similar sensitivity toward different targets in an aptamer-structure-independent manner. Furthermore, the assay can be used to detect thrombin in diluted real urine or serum samples with a satisfactory recovery, implying its great potential for rapid detection of thrombin in the clinic. PMID- 28886456 TI - Broccoli-shaped biosensor hierarchy for electrochemical screening of noradrenaline in living cells. AB - Monitoring and determination of ultra-trace concentrations of monoamine neurotransmitter such as noradrenaline (NA) in living cells with simple, sensitive and selective assays are significantly interesting. We design NA electrode sensing system based on C-, N-doped NiO broccoli-like hierarchy (CNNB). The spherical broccoli-head umbrella architectures associated with nano-tubular arrangements enabled to tailor NA biosensor design. The homogenous doping and anisotropic dispersion of CN nanospheres along the entire NB head nanotubes lead to creating of abundant electroactive sites in the interior tubular vessels and outer surfaces for ultrasensitive detection of NA in living cells such as PC12. The CNNB biosensor electrodes showed efficient electrocatalytic activity, enhanced kinetics for electrooxidation of NA, and fast electron-transfer between electrode-electrolyte interface surfaces, enabling synergistic enhancement in sensitivity, and selectivity at a low-detectable concentration of ~ 6nM and reproducibility of broccoli-shaped NA-electrodes. The integrated CNNB biosensor electrodes showed evidence of monitoring and screening of NA released from PC12 cells under K+ ion-extracellular stimulation process. The unique features of CNNB in terms of NA-selectivity among multi-competitive components, long-term stability during the detection of NA may open their practical, in-vitro application for extracellular monoamine neurotransmitters detection in living cells. PMID- 28886458 TI - A novel psychoanalytical approach: An electrochemical ligand-binding assay to screen antipsychotics. AB - Schizophrenia treatment may see a paradigm shift due to development of new atypical antipsychotic drugs (APDs), with better tolerability due to more selective dopamine (DA) receptor blockade. Monitoring of these APD candidates in biological fluids is of great importance to reduce the development cost, to clarify the mechanism of action and ultimately to support the demonstration of efficacy of these molecules. Electrochemical approaches have attracted great attention for monitoring DA and APD levels but none of the methods developed so far aimed to screen APD candidates. Herein, by this work, we propose for the first time an electrochemical ligand-binding approach for antipsychotic drug screening where competitive binding of a novel APD and DA to a dopamine D3 receptor (D3R) was investigated by looking at electrochemical signals of DA and drug before and after D3R interaction. D3R peptide was incubated with DA and/or drug first and then changes in electrochemical oxidation signals of free DA and the drug was measured by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Circular Dichroism spectroscopy was used to investigate the secondary structure of the peptide upon binding with either drug and/or DA. PMID- 28886459 TI - Inner filter with carbon quantum dots: A selective sensing platform for detection of hematin in human red cells. AB - Hematin plays a crucial role in various physiological functions, and the determination of hematin in complex biological matrixes is a significant but difficult issue. Considering the unique photophysical/photochemical properties of carbon quantum dots (CQDs) prepared with p-aminobenzoic acid (PABA) and ethanol, a new strategy for the design of fluorescent probes for hematin has been achieved. The proposed sensor array is fabricated based on the inner filter effect (IFE) between hematin and CQDs with phenomenon of selective fluorescence quenching of CQDs which results from the strong absorption of the excitation and emission spectrum of CQDs by hematin. The fluorescence quenching of CQDs is closely related to the amount of hematin and there is a good linear relationship over the range of 0.5-10MUM with a detection limit of 0.25MUM. What's more, the fluorescence assay has been successfully applied for hematin sensing in healthy human red cells showing this sensing assay has a great potential prospect for detection of hematin in the complex matrixes. PMID- 28886461 TI - Time-dependent effects of olanzapine treatment on the expression of histidine decarboxylase, H1 and H3 receptor in the rat brain: The roles in olanzapine induced obesity. AB - Antipsychotic treatment, particularly olanzapine and clozapine, induces severe obesity. The Histamine H1 receptor is considered to be an important contributor to olanzapine-induced obesity, however how olanzapine modulates the histaminergic system is not sufficiently understood. This study examined the effect of olanzapine on key molecules of the histaminergic system, including histidine decarboxylase (HDC), H1 receptor (H1R) and H3 receptor (H3R), in the brain at different stages of olanzapine-induced obesity. During short-term treatment (8 day), olanzapine increased hypothalamic HDC mRNA expression and H1R binding in the arcuate nucleus (Arc) and ventromedial hypothalamus (VMH), without changing H3R binding density. HDC mRNA and Arc H1R binding were positively correlated with increased food intake, feeding efficiency and weight gain. When the treatment was extended to 16 and 36 days, H1R binding was increased not only in the hypothalamic Arc and VMH but also in the brainstem dorsal vagal complex (DVC). The H1R bindings in the Arc, VMH and DVC were positively correlated with weight gain induced by olanzapine treatment. However, the expression of HDC and H3R mRNA was not increased. These results suggest that olanzapine time-dependently modulates histamine neurotransmission, which suggested the different neuronal mechanisms underlying different stages of weight gain development. Treatment targeting the H1R may be effective for both short- and long-term olanzapine induced weight gain. PMID- 28886460 TI - Diurnal salivary cortisol and nativity/duration of residence in Latinos: The Multi-Ethnic Study of Atherosclerosis. AB - Latino immigrants have lower prevalence of depression, obesity and cardiovascular disease than US-born Latinos when they are recently arrived in the US, but this health advantage erodes with increasing duration of US residence. Cumulative exposure to psychosocial stress and its physiological sequelae may mediate the relationship between nativity and duration of US residence and poor health. We used data from Latino cohort study participants ages 45-84 to examine cross sectional (n=558) and longitudinal (n=248) associations between nativity and duration of US residence and features of the diurnal cortisol curve including: wake-up cortisol, cortisol awakening response (CAR, wake-up to 30min post awakening), early decline (30min to 2h post-awakening) and late decline (2h post awakening to bed time), wake-to-bed slope, and area under the curve (AUC). In cross-sectional analyses, US-born Latinos had higher wake-up cortisol than immigrants with fewer than 30 years of US residence. In the full sample, over 5 years the CAR and early decline became flatter and AUC became larger. Over 5 years, US-born Latinos had greater increases in wake-up cortisol and less pronounced flattening of the early diurnal cortisol decline than immigrants with fewer than 30 years of US residence. Immigrants with 30 or more years of US residence also had less pronounced flattening of the early decline relative to more recent immigrants, and also had a less pronounced increase in AUC. In sum, we saw limited cross-sectional evidence that US-born Latinos have more dysregulated cortisol than recently-arrived Latino immigrants, but over time US born Latinos had slower progression of cortisol dysregulation. PMID- 28886462 TI - Genetic polymorphism of thymidine kinase (TK) and DNA polymerase (pol) of clinical varicella-zoster virus (VZV) isolates collected over three decades. AB - BACKGROUND: Genotypic resistance testing of varicella-zoster virus (VZV) strains to antivirals is of high relevance in immunocompromised patients with VZV reactivations unresponsive to therapy. However, the knowledge on mutations associated with natural gene polymorphism or resistance is limited. OBJECTIVES: To examine the genotype of the thymidine kinase (TK) and DNA polymerase (pol) of unselected clinical VZV isolates collected between 1984 and 2014 and to verify the phenotype related to novel amino acid (aa) substitutions. STUDY DESIGN: The TK and DNA pol genes of 169 VZV isolates were analyzed by amplification and sequencing. Sequences were compared to that of the reference strain Dumas. The phenotype to acyclovir and other antivirals was examined in isolates with novel aa substitutions using modified plaque reduction assay. RESULTS: In the TK of four strains, four different aa substitutions were detected, apart from the known change S288L that was present in all strains compared to Dumas. All four substitutions have hitherto not been described in the literature and were phenotypically classified as natural gene polymorphisms although two out of them (S51L, K186R) were localized in conserved gene centers. The DNA pol of 34 isolates exhibited 19 different substitutions, 14 out of them were novel, and two (R753K, V777I) were within conserved gene regions. Again, these changes were characterized as natural gene polymorphisms. CONCLUSIONS: Non-synonymous mutations in VZV TK or DNA pol conferring natural gene polymorphism are rare events. Nevertheless, the phenotypic characterization of 18 novel polymorphisms can help to provide a better identification of resistance mutations. PMID- 28886463 TI - Treadmill based reference running data for healthy subjects is dependent on speed and morphological parameters. AB - OBJECTIVE: To obtain spatiotemporal and dynamic running parameters of healthy participants and to identify relationships between running parameters, speed, and physical characteristics. METHOD: A dynamometric treadmill was used to collect running data among 417 asymptomatic subjects during speeds ranging from 10 to 24km/h. Spatiotemporal and dynamic running parameters were calculated and measured. RESULTS: Results of the analyses showed that assessing running parameters is dependent on running speed. Body height correlated with stride length (r=0.5), cadence (r=-0.5) and plantar forefoot force (r=0.6). Body mass also had a strong relationship to plantar forefoot forces at 14 and 24km/h and plantar midfoot forces at 14 and 24km/h. CONCLUSION: This reference data base can be used in the kinematic and kinetic evaluation of running under a wide range of speeds. PMID- 28886464 TI - Muscle activity during backward and forward running with body weight support. AB - We investigated muscle activity during backward (BR) and forward (FR) running with body weight support (BWS). Ten participants completed BR and FR on a lower body positive pressure treadmill while selecting a preferred speed (PS) for different BWS conditions (0%, 20%, 40%, 60%, and 80%BWS). Muscle activity from the rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), and gastrocnemius (GA), rating of perceived exertion (RPE), preferred stride frequency (PSF), and PS were measured. Magnitude of muscle activity (BF, TA, and GA), RPE, PSF, and PS were not influenced by the interaction of direction and BWS (P>0.05). BF, TA, and GA were not different between directions (P>0.05) but were different between BWS conditions (P<0.01). RF was influenced by the interaction of direction and BWS (P<0.01). RF, BF, TA, and GA during BR were lower with increasing BWS. RF during BR was 59-86% higher than that of FR within BWS condition. RPE was lower with increasing BWS (P<0.001), regardless of direction of locomotion. PSF was lower and PS was higher during BR and FR with increasing BWS (both P<0.001). PSF during BR was 6-9% higher than that of FR. PS during BR was 24-31% lower than that of FR. These observations demonstrate that a change in BWS influences magnitude of muscle activity, PS, PSF, and RPE for both BR and FR. However, a change in direction of locomotion may not influence magnitude of muscle activity or RPE during running for a given BWS, even though muscle activity pattern, PS, and PSF were different between BR and FR. PMID- 28886465 TI - The interaction of pregnancy, substance use and mental illness on birthing outcomes in Australia. AB - BACKGROUND: this study aimed to (1) assess the prevalence, and demographic features of women with a history of mental illness during pregnancy and childbirth, (2) investigate maternal and perinatal outcomes in relation to mental illness and substance use, and (3) determine the effects of maternal characteristics, history of mental illness and substance use on birth outcomes. METHODS: the records of 22,193 pregnant women who gave birth at one tertiary level health service comprising three maternity settings in Victoria, Australia from 2009 to 2011 were reviewed.Univariate comparisons for socio-demographic and birthing outcome variables by substance use and mental illness category were performed. A multivariable logistic regression model was developed to examine the effects of maternal characteristics on birth outcomes. RESULTS: mental illness was recorded for 1.08/1,000 delivery hospitalisations.Mothers with a history of mental illness had a significantly higher proportion of babies born with low birth weight (OR = 1.85, 95% CI 1.64 -2.09) and low Apgar 1 scores<7 (OR = 1.47, 95% CI 1.26 - 1.70).Differences in health behaviours were also noted between the two groups.Babies born to women with an illicit and poly substance use history reported an average birth weight at 2,951 (SD 777) grams compared to birth weight of approximately 3,300 g of smoking and alcohol user groups, as well as shorter gestational age and lower birth weight. There was a statistically significant interaction between the effects of mental illness and substance use on birth weight. This interaction effect was not significant for gestational age. Logistic regression showed the strongest predictor of reporting a premature birth and low birth weight was using substances, recording an odds ratio of 1.95 (95% CI 1.50 2.53) and 2.73 (95% CI 2.15-3.47) respectively. CONCLUSIONS: mental health history should be highlighted as being a common morbidity and the increased risk of poorer birth outcomes especially when the women were also using substances, alcohol or tobacco should be acknowledged by the health practitioners. PMID- 28886466 TI - Beware of the gorilla: Effect of goal priming on inattentional blindness. AB - When people's attention is engaged in a visual task, they often are blind to unexpected events occurring in their environment. This phenomenon is known as inattentional blindness. In this study, we examine inattentional blindness with regard to goal priming, a technique allowing to unconsciously influence goal pursuit. After being primed with a detection goal, the name of the target to detect, or no prime, participants watched a short sequence in which they had to count passes made by basketball players. An unexpected event occurred during the video. Results indicated that when attentional demands of the monitoring task were moderate, goal priming improved the detection of the unexpected event. Implications for the understanding of nonconscious management of attention will be discussed. PMID- 28886467 TI - The relationship between fluid intelligence and sustained inattentional blindness in 7-to-14-year-old children. AB - Previous researches have shown that people with higher fluid intelligence are more likely to detect the unexpected stimuli. The current study systematically explored the relationship between fluid intelligence and sustained inattentional blindness in children. In Experiment 1, we measured one hundred and seventy-nine 7-to-14-year-old children's fluid intelligence and sustained inattentional blindness. The results showed that fluid intelligence was negatively related to sustained inattentional blindness only in 7-to-8-year-old children. In Experiment 2, we explored sustained inattentional blindness in sixty children with high Raven's scores. We found that compared with children who have average Raven's scores aged 11-to-12 years old, children with high Raven's scores were unable to better avoid sustained inattentional blindness. In general, this research implies that the relation between fluid intelligence and sustained inattentional blindness is weak. Fluid intelligence could predict sustained inattentional blindness only when children do not have enough perceptual capacities to complete the primary task. PMID- 28886468 TI - Do drives drive the train of thought?-Effects of hunger and sexual arousal on mind-wandering behavior. AB - Physiological needs that are currently unfulfilled are known to affect human cognition and behavior. The present study investigates whether and how the temporary activation of two primary physiological needs, namely hunger and sexual arousal, influence both the frequency and the contents of mind-wandering episodes. To induce hunger, one group of participants fasted for a minimum of five hours whereas another group of participants was exposed to audio material with explicit sexual content to provoke sexual arousal. Both groups as well as an additional control group, which had not received hunger instructions and had not been exposed to arousing material of any kind beforehand, performed a reading task during which mind wandering was assessed using a standard experience sampling method. Results showed that acute hunger but not elevated sexual arousal renders the occurrence of mind-wandering episodes more likely. Induction of both hunger and sexual arousal rendered the occurrence of need-related off-task thoughts more likely and changed time orientations of mind wandering. The present findings are well in line with the assumption that unfulfilled needs regularly achieve cognitive priority and extend the cognitive-priority idea to self generated thoughts. PMID- 28886469 TI - Phenomenological characteristics of autobiographical memory in Korsakoff's syndrome. AB - A body of research suggests compromise of autobiographical memory in Korsakoff's syndrome (KS). The present paper extends this literature by investigating the subjective experience of autobiographical recall in the syndrome. Patients with KS and controls were asked to retrieve autobiographical memories. After memory retrieval, participants were asked to rate phenomenological characteristics of their memories (i.e., reliving, back in time, remembering, realness, visual imagery, auditory imagery, language, emotion, rehearsal, importance, spatial recall and temporal recall). Analysis showed lower "Mean Phenomenological Experience" in the Korsakoff patients than in controls. However, the Korsakoff patients attributed relatively high emotional value and importance to their memories. Although our findings suggest compromised phenomenological reliving of autobiographical memory in patients with KS, affective characteristics such as emotion and importance are likely to play a main role in the subjective experience of the past in these patients. PMID- 28886470 TI - Exploring member perspectives on participation on child welfare Citizen Review Panels: A national study. AB - The year 2016 marked the 20th anniversary of the Child Abuse Prevention and Treatment Act (CAPTA) amendments (P.L. 104-235) that mandated Citizen Review Panels (CRPs). CRPs are citizen volunteer groups authorized by United States (U.S.) federal law to examine policies and procedures of state child welfare agencies. Despite the potential of CRPs to positively impact child welfare systems outcomes associated with child abuse and neglect, and the millions of dollars in resources allocated to these groups, there remains a dearth in the literature about CRPs. This exploratory study examined CRP member perceptions from across the United States. Researchers collected scaled survey data to examine member knowledge, engagement and assessment of panel influence and impact, membership composition, and meeting structure. Results revealed that panel members lack some knowledge related to the federal mandate guiding their work, and data suggest the need for panels to more adroitly recruit and retain members representative of the communities in which the panels are formed. After a brief review of background literature, this paper will explicate key results, discuss these findings, and identify salient practice, policy and research implications derived from the study. PMID- 28886471 TI - DNA damage by 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced p53-mediated apoptosis through activation of cytochrome P450/aryl hydrocarbon receptor. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; polycyclic aromatic hydrocarbon) is a persistent and ubiquitous environmental contaminant that causes a wide variety of deleterious effects. In this study, the DNA damage and apoptotic activity induced by TCDD was examined using in silico and in vitro approaches. In silico study showed that conformational changes and energies involved in the binding of TCDD to cytochrome P450 1B1 (CYP1B1) were crucial for its target proteins. Moreover, activated TCDD had high affinity to bind with aryl hydrocarbon receptor (AhR), with a binding energy of -564.7 Kcal/mol. Further, TCDD-CYP1B1 complex showed strong binding affinity for caspase 3, showing a binding energy of -518.5 Kcal/mol, and the docking of caspase inhibitors in the complex showed weak interaction with low binding energy as compared to TCDD-CYP1B1 caspase complexes. Interestingly, TCDD-induced apoptosis was significantly suppressed in Ac-DEVD-CMK pretreated cells. The DNA damage activity of TCDD was quantified by comet tail formation and gamma-H2AX foci formation in HaCaT cells. The role of CYP1B1 and AhR in DNA damage and apoptosis was demonstrated, and clotrimazole as well as knockdown of CYP1B1 and AhR could inhibit TCDD activation and suppress DNA damage followed by apoptosis in HaCaT cells. Moreover, TCDD increased expression of p53 and PUMA and our data showed that TCDD induced DNA damage followed by p53 mediated apoptosis. This study highlights the critical role of CYP1B1 and AhR in TCDD activity and proposes that inhibition of these key molecules might serve as a potential therapeutic approach for treatment of allergy and cancer. PMID- 28886472 TI - Factor VII Tokushima (Cys22->Gly) is not gamma-carboxylated due to a disrupted gamma-carboxylase recognition site. PMID- 28886473 TI - Strategies for injury prevention in Brazilian football: Perceptions of physiotherapists and practices of premier league teams. AB - OBJECTIVES: To describe the physiotherapists perceptions and the current practices for injury prevention in elite football (soccer) clubs in Brazil. DESIGN: Cross-sectional study. SETTING: Group of Science in Sports & Exercise, Federal University of Healthy Sciences of Porto Alegre (Brazil). PARTICIPANTS: 16 of the 20 football clubs involved in the Brazilian premier league 2015. MAIN OUTCOME MEASURES: Physiotherapists answered a structured questionnaire. RESULTS: Most physiotherapists (~88%) were active in design, testing and application of prevention programs. Previous injury, muscle imbalance, fatigue, hydration, fitness, diet, sleep/rest and age were considered "very important" or "important" injury risk factors by all respondents. The methods most commonly used to detect athletes' injury risk were: monitoring of biochemical markers (100% of teams), isokinetic dynamometry (81%), questionnaires (75%), functional movement screen (56%), fleximetry (56%) and horizontal jump tests (50%). All clubs used strength training, functional training, core exercises and balance/proprioception exercises in their injury prevention program; and Nordic hamstring exercise and other eccentric exercises were used by 94% of clubs. "FIFA 11+" prevention program was adapted by 88% of clubs. CONCLUSION: Physiotherapists perceptions and current practices of injury prevention within Brazilian elite football clubs were similar to those employed in developed countries. There remains a gap between clinical practice and scientific evidence in high performance football. PMID- 28886474 TI - Functional connectivity of the hippocampus to the thalamocortical circuitry in an animal model of absence seizures. AB - OBJECTIVE: Using the gamma-butyrolactone (GBL) rat model of absence seizures, this study investigated the functional connectivity of the hippocampus, thalamus and cerebral cortex before and during absence seizures. METHODS: Functional connectivity between the hippocampus, thalamus and sensory and motor cortecies, were examined by the temporal correlations of the resting state blood-oxygen level-dependent (BOLD) signal. Functional connectivity between these regions was calculated at baseline, 5min after saline injection, and at 5, 20 and 52min after GBL injection. This time interval spans the onset of behaviours including chewing and staring spells associated with GBL-induced absence seizures, along with the onset and suppression of spike-and-wave discharges (SWDs). RESULTS: Overall there was an increase in functional connectivity across most regions. The functional connectivity generally decreased over time and it returned to baseline 52min post GBL injection. Functional connectivity of the thalamus to the sensory and motor cortecies increased during absence seizure. The results revealed enhanced connectivity of the left dorsal hippocampus and the thalamus shortly after GBL injection, which coincided with the appearance of SWDs in this rat model. SIGNIFICANCE: Increased functional connectivity between the hippocampus and the thalamus suggests that the hippocampus participates in the GBL model of absence seizures. Involvement of the hippocampus during absence seizure has implications for studies into the mechanisms in cognitive impairments in patients with absence epilepsy. PMID- 28886475 TI - Accuracy of screening women at familial risk of breast cancer without a known gene mutation: Individual patient data meta-analysis. AB - INTRODUCTION: Women with a strong family history of breast cancer (BC) and without a known gene mutation have an increased risk of developing BC. We aimed to investigate the accuracy of screening using annual mammography with or without magnetic resonance imaging (MRI) for these women outside the general population screening program. METHODS: An individual patient data (IPD) meta-analysis was conducted using IPD from six prospective screening trials that had included women at increased risk for BC: only women with a strong familial risk for BC and without a known gene mutation were included in this analysis. A generalised linear mixed model was applied to estimate and compare screening accuracy (sensitivity, specificity and predictive values) for annual mammography with or without MRI. RESULTS: There were 2226 women (median age: 41 years, interquartile range 35-47) with 7478 woman-years of follow-up, with a BC rate of 12 (95% confidence interval 9.3-14) in 1000 woman-years. Mammography screening had a sensitivity of 55% (standard error of mean [SE] 7.0) and a specificity of 94% (SE 1.3). Screening with MRI alone had a sensitivity of 89% (SE 4.6) and a specificity of 83% (SE 2.8). Adding MRI to mammography increased sensitivity to 98% (SE 1.8, P < 0.01 compared to mammography alone) but lowered specificity to 79% (SE 2.7, P < 0.01 compared with mammography alone). CONCLUSION: In this population of women with strong familial BC risk but without a known gene mutation, in whom BC incidence was high both before and after age 50, adding MRI to mammography substantially increased screening sensitivity but also decreased its specificity. PMID- 28886476 TI - Phase I study of axitinib and everolimus in metastatic solid tumours and extension to metastatic renal cell carcinoma: Results of EVAX study. AB - PURPOSE: Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours. Reported combination of both drugs was deemed to be too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase I study combining everolimus (EV) and AX for solid tumours was explored. EXPERIMENTAL DESIGN: Patients (pts) with advanced cancers were enrolled in an escalation phase I study to investigate the safety of the combination. Pharmacokinetic profile and functional vascular imaging were performed. An extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored. RESULTS: 15 pts were included over three different dose levels (DLs); DL 0: AX 3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st line MRCC in the escalating phase. In the extension phase in naive MRCC treated at MTD, five pts had a PR and one pt had a prolonged stable disease. CONCLUSION: The recommended dose for phase II is AX 5 mg BID/EV 10 mg OD. PMID- 28886477 TI - Detection of 8-hydroxydeoxyguanosine (8-OHdG) as a biomarker of oxidative damage in peripheral leukocyte DNA by UHPLC-MS/MS. AB - 8-Hydroxydeoxyguanosine (8-OHdG) is a widely-used biomarker of oxidative DNA damages. 8-OHdG in peripheral blood leukocyte is associated with mutation and cancer risk. The level of 8-OHdG in peripheral blood leukocytes can indicate a long-term response to oxidative stress rather than that in urine. Accurate identification and quantification of leukocyte 8-OHdG are essential for understanding its mechanism of formation, repair, and biological consequences. In this study, a fast and accurate ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated to detect 8 OHdG in human peripheral leukocyte. DNA in blood samples were extracted and digested, then subjected onto UHPLC-MS/MS using an isocratic elution on a Zorbax Eclipse Plus C18 column (2.1*100mm, 1.8MUm). Multiple reaction monitoring (MRM) mode was adopted by using [15N5]-8-OHdG as an internal standard. The assay was linear over the concentration range of 1.0-100nM with R2=0.999. The accuracy for spiked samples was 90.9%-94.8%, and the intra-day precision was within 3.7%. The limit of detection (LOD) is 0.30nM and limit of quantification (LOQ) is 1.0nM with 5MUl of sample injection. By the analysis of human leukocyte 8-OHdG (n=121) using the developed UHPLC-MS/MS method, it demonstrates that the level of leukocyte 8-OHdG of the cancer patients group (n=46) is significantly higher than that of the health control (n=75). PMID- 28886478 TI - Chaihu-Shu-Gan-San regulates phospholipids and bile acid metabolism against hepatic injury induced by chronic unpredictable stress in rat. AB - Chaihu-Shu-Gan-San (CSGS) is a famous classic traditional Chinese medicines (TCM) formula for treatment of liver stagnancy recorded in a famous book of traditional Chinese medicine, Jing Yue Quan Shu published in 1624. It has been extensively accepted as an antidepressant in China and its mechanism of action is still not clear. Previously we have found that hepatic injury happens in chronic unpredicted mild stress (CUMS). Thus, the protection of CSGS against hepatic injury induced by CUMS treatment was explored by metabonomics study and gene expression of the rat liver tissue. The results indicated that CSGS improved 8 of the 18 perturbed potential biomarkers in liver tissues of rats treated with CUMS, and involved in regulating phospholipids and bile acid metabolism against hepatic injury induced by CUMS in rat. The expressions of two apoptosis associated genes (Bcl-2 and Bax) and four genes (Pnpla6, Pla2g15, Baat and Gad1) related to the perturbed metabolic pathways were further investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Both metabonomics and studies of genetic influences on metabolites demonstrated that CSGS inhibited hepatocyte apoptosis, and regulated phospholipids and bile acid metabolism against hepatic injury induced by CUMS in rat. Exploring the protection of CSGS against hepatic injury related to depression further clarify the relationship between CUMS-induced depression and hepatic injury, and also provide a novel insight to understand the underlying antidepressive mechanism of CSGS. PMID- 28886480 TI - Intelligent visual localization of wireless capsule endoscopes enhanced by color information. AB - Wireless capsule endoscopy (WCE) is performed with a miniature swallowable endoscope enabling the visualization of the whole gastrointestinal (GI) tract. One of the most challenging problems in WCE is the localization of the capsule endoscope (CE) within the GI lumen. Contemporary, radiation-free localization approaches are mainly based on the use of external sensors and transit time estimation techniques, with practically low localization accuracy. Latest advances for the solution of this problem include localization approaches based solely on visual information from the CE camera. In this paper we present a novel visual localization approach based on an intelligent, artificial neural network, architecture which implements a generic visual odometry (VO) framework capable of estimating the motion of the CE in physical units. Unlike the conventional, geometric, VO approaches, the proposed one is adaptive to the geometric model of the CE used; therefore, it does not require any prior knowledge about and its intrinsic parameters. Furthermore, it exploits color as a cue to increase localization accuracy and robustness. Experiments were performed using a robotic assisted setup providing ground truth information about the actual location of the CE. The lowest average localization error achieved is 2.70 +/- 1.62 cm, which is significantly lower than the error obtained with the geometric approach. This result constitutes a promising step towards the in-vivo application of VO, which will open new horizons for accurate local treatment, including drug infusion and surgical interventions. PMID- 28886479 TI - High sensitivity HPLC method for determination of the allysine concentration in tissue by use of a naphthol derivative. AB - Common to all fibrotic and metastatic diseases is the uncontrollable remodeling of tissue that leads to the accumulation of fibrous connective tissue components such as collagen and elastin. Build-up of fibrous tissue occurs through the cross linking of collagen or elastin monomers, which is initiated through the oxidation of lysine residues to form alpha-aminoadipic-delta-semialdehyde (allysine). To provide a measure of the extent of collagen oxidation in disease models of fibrosis or metastasis, a rapid, sensitive HPLC method was developed to quantify the amount of allysine present in tissue. Allysine was reacted with sodium 2 naphthol-7-sulfonate under conditions typically applied for acid hydrolysis of tissues (6M HCl, 110 degrees C, 24h) to prepare AL-NP, a fluorescent bis-naphthol derivative of allysine. High performance liquid chromatography was applied for analysis of allysine content. Under optimal reaction and detection conditions, successful separation of AL-NP was achieved with excellent analytical performance attained. Good linear relationship (R2=0.994) between peak area and concentration for AL-NP was attained for 0.35-175pmol of analyte. A detection limit of 0.02pmol in the standard sample with a 20MUL injection was achieved for AL-NP, with satisfactory recovery from 88 to 100% determined. The method was applied in the quantification of allysine in healthy and fibrotic mouse lung tissue, with the fibrotic tissue showing a 2.5 fold increase in the content of allysine. PMID- 28886482 TI - Area-based cell colony surviving fraction evaluation: A novel fully automatic approach using general-purpose acquisition hardware. AB - BACKGROUND: The current methodology for the Surviving Fraction (SF) measurement in clonogenic assay, which is a technique to study the anti-proliferative effect of treatments on cell cultures, involves manual counting of cell colony forming units. This procedure is operator-dependent and error-prone. Moreover, the identification of the exact colony number is often not feasible due to the high growth rate leading to the adjacent colony merging. As a matter of fact, conventional assessment does not deal with the colony size, which is generally correlated with the delivered radiation dose or the administered cytotoxic agent. METHOD: Considering that the Area Covered by Colony (ACC) is proportional to the colony number and size as well as to the growth rate, we propose a novel fully automatic approach exploiting Circle Hough Transform, to automatically detect the wells in the plate, and local adaptive thresholding, which calculates the percentage of ACC for the SF quantification. This measurement relies just on this covering percentage and does not consider the colony number, preventing inconsistencies due to intra- and inter-operator variability. RESULTS: To evaluate the accuracy of the proposed approach, we compared the SFs obtained by our automatic ACC-based method against the conventional counting procedure. The achieved results (r = 0.9791 and r = 0.9682 on MCF7 and MCF10A cells, respectively) showed values highly correlated with the measurements using the traditional approach based on colony number alone. CONCLUSIONS: The proposed computer-assisted methodology could be integrated in laboratory practice as an expert system for the SF evaluation in clonogenic assays. PMID- 28886481 TI - Identifying sleep spindles with multichannel EEG and classification optimization. AB - Researchers classify critical neural events during sleep called spindles that are related to memory consolidation using the method of scalp electroencephalography (EEG). Manual classification is time consuming and is susceptible to low inter rater agreement. This could be improved using an automated approach. This study presents an optimized filter based and thresholding (FBT) model to set up a baseline for comparison to evaluate machine learning models using naive features, such as raw signals, peak frequency, and dominant power. The FBT model allows us to formally define sleep spindles using signal processing but may miss examples most human scorers would agree are spindles. Machine learning methods in theory should be able to approach performance of human raters but they require a large quantity of scored data, proper feature representation, intensive feature engineering, and model selection. We evaluate both the FBT model and machine learning models with naive features. We show that the machine learning models derived from the FBT model improve classification performance. An automated approach designed for the current data was applied to the DREAMS dataset [1]. With one of the expert's annotation as a gold standard, our pipeline yields an excellent sensitivity that is close to a second expert's scores and with the advantage that it can classify spindles based on multiple channels if more channels are available. More importantly, our pipeline could be modified as a guide to aid manual annotation of sleep spindles based on multiple channels quickly (6-10 s for processing a 40-min EEG recording), making spindle detection faster and more objective. PMID- 28886483 TI - A window-based time series feature extraction method. AB - This study proposes a robust similarity score-based time series feature extraction method that is termed as Window-based Time series Feature ExtraCtion (WTC). Specifically, WTC generates domain-interpretable results and involves significantly low computational complexity thereby rendering itself useful for densely sampled and populated time series datasets. In this study, WTC is applied to a proprietary action potential (AP) time series dataset on human cardiomyocytes and three precordial leads from a publicly available electrocardiogram (ECG) dataset. This is followed by comparing WTC in terms of predictive accuracy and computational complexity with shapelet transform and fast shapelet transform (which constitutes an accelerated variant of the shapelet transform). The results indicate that WTC achieves a slightly higher classification performance with significantly lower execution time when compared to its shapelet-based alternatives. With respect to its interpretable features, WTC has a potential to enable medical experts to explore definitive common trends in novel datasets. PMID- 28886485 TI - Development of an epitope-based vaccine inhibiting immune cells rolling and migration against atherosclerosis using in silico approaches. AB - Atherosclerosis is a chronic inflammatory disease characterized by formation of pro-oxidative lipids in large and medium-sized vessels. Over the years, many treatments and drugs have entered the market to improve atherosclerosis and autoantigen-mediated active immunization is currently considered as a beneficial method. Therefore, this study was conducted to design a novel epitope-based vaccine against atherosclerosis employing CD99, CD81 and CD99L2 antigens. In this way, structural vaccinology approaches were used to design a novel multi-epitope vaccine against atherosclerosis. Six epitopes were predicted from CD99, CD81 and CD99L2 proteins. In addition, helper epitopes selected from Tetanus toxin fragment C (TTFrC)ion were applied to induce CD4+ helper T lymphocytes (HTLs) responses. Moreover, cholera toxin B (CTB) was employed as an adjuvant. Finally, EAAAK AND GPGPG sequences as linkers were considered to make a linkage between favorite peptide sequences. A multi-epitope construction was designed based on the predicted epitopes which was 270 residues in length. Further immunoinformatic analyses were carried out to assess physicochemical properties, secondary and tertiary structures, stability, intrinsic protein disorder, solubility, and allergenicity of this chimeric protein. Based on the obtained results, a soluble, and non-allergic protein with a molecular weight of 28.7kDa was designed. Further analyses revealed that the chimeric protein is a stable protein and the predicted epitopes indicated strong potential to induce B-cell and T-cell mediated immune response. Our immunoinformatic analyses revealed that the modeled multi-epitope vaccine had appropriate properties,which can properly stimulate the immune responses of both T and B cells. PMID- 28886484 TI - Augmentation of intracellular iron using iron sucrose enhances the toxicity of pharmacological ascorbate in colon cancer cells. AB - Pharmacological doses (> 1mM) of ascorbate (a.k.a., vitamin C) have been shown to selectively kill cancer cells through a mechanism that is dependent on the generation of H2O2 at doses that are safely achievable in humans using intravenous administration. The process by which ascorbate oxidizes to form H2O2 is thought to be mediated catalytically by redox active metal ions such as iron (Fe). Because intravenous iron sucrose is often administered to colon cancer patients to help mitigate anemia, the current study assessed the ability of pharmacological ascorbate to kill colon cancer cells in the presence and absence of iron sucrose. In vitro survival assays showed that 10mM ascorbate exposure (2h) clonogenically inactivated 40-80% of exponentially growing colon cancer cell lines (HCT116 and HT29). When the H2O2 scavenging enzyme, catalase, was added to the media, or conditionally over-expressed using a doxycycline inducible vector, the toxicity of pharmacological ascorbate was significantly blunted. When colon cancer cells were treated in the presence or absence of 250uM iron sucrose, then rinsed, and treated with 10mM ascorbate, the cells demonstrated increased levels of labile iron that resulted in significantly increased clonogenic cell killing, compared to pharmacological ascorbate alone. Interestingly, when colon cancer cells were treated with iron sucrose for 1h and then 10mM ascorbate was added to the media in the continued presence of iron sucrose, there was no enhancement of toxicity despite similar increases in intracellular labile iron. The combination of iron chelators, deferoxamine and diethylenetriaminepentaacetic acid, significantly inhibited the toxicity of either ascorbate alone or ascorbate following iron sucrose. These observations support the hypothesis that increasing intracellular labile iron pools, using iron sucrose, can be used to increase the toxicity of pharmacological ascorbate in human colon cancer cells by a mechanism involving increased generation of H2O2. PMID- 28886486 TI - The seed to success: The role of seminal plasma in pregnancy. AB - A lack of immunologic tolerance of the mother toward her child and in placentation can result in early or late pregnancy complications, including implantation failure, miscarriage, preeclampsia, and fetal growth restriction. Seminal plasma has the potential of influencing the maternal immune system for acceptance of the semi-allogeneic fetus. Here we elaborate on studies which provide evidence that an optimal balance of pro-inflammatory and immunomodulatory factors is necessary for the induction of immunologic tolerance and the process of implantation and placentation. Seminal plasma is a source of immunological mediators at conception, which can influence the function of maternal immune cells. Identifying the relevant factors in seminal plasma and the mechanisms by which they affect the maternal reproductive tract in relation to pregnancy outcome is a challenge for future research. PMID- 28886487 TI - Numerical modeling of specimen geometry for quantitative energy dispersive X-ray spectroscopy. AB - Transmission electron microscopy specimens typically exhibit local distortion at thin foil edges, which can influence the absorption of X-rays for quantitative energy dispersive X-ray spectroscopy (EDS). Here, we report a numerical, three dimensional approach to model the geometry of general specimens and its influence on quantification when using single and multiple detector configurations. As a function of specimen tilt, we show that the model correctly predicts the asymmetric nature of X-ray counts and ratios. When using a single detector, we show that complex specimen geometries can introduce significant uncertainty in EDS quantification. Further, we show that this uncertainty can be largely negated by collection with multiple detectors placed symmetrically about the sample such as the FEI Super-X configuration. Based on guidance provided by the model, we propose methods to reduce quantification error introduced by the sample shape. The source code is available at https://github.com/subangstrom/superAngle. PMID- 28886488 TI - Optimization of monochromated TEM for ultimate resolution imaging and ultrahigh resolution electron energy loss spectroscopy. AB - The performance of a monochromated transmission electron microscope with Wien type monochromator is optimized to achieve an extremely narrow energy spread of electron beam and an ultrahigh energy resolution with spectroscopy. The energy spread in the beam is improved by almost an order of magnitude as compared to specified values. The optimization involves both the monochromator and the electron energy loss detection system. We demonstrate boosted capability of optimized systems with respect to ultra-low loss EELS and sub-angstrom resolution imaging (in a combination with spherical aberration correction). PMID- 28886490 TI - Interleukin-6 in irritable bowel syndrome: A systematic review and meta-analysis of IL-6 (-G174C) and circulating IL-6 levels. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which presents with abdominal pain and alterations of the bowel habits. The pathophysiology of IBS is not well-recognized. Low grade inflammation has been suggested as one of the underlying mechanisms of IBS. Variations in the circulating pro-inflammatory interleukin-6 (IL-6) levels and IL 6 gene polymorphisms have been demonstrated in IBS. However, the results of published studies are not consistent, probably due to their small sample sizes. To address this inconsistency, we conducted the current systematic review and meta-analysis on serum/plasma IL-6 levels and IL-6 (-G174C; rs1800795) gene polymorphism in IBS. METHODS: PubMed was searched in July 2016. Case-control studies on serum/plasma IL-6 levels and IL-6 (-G174C) gene polymorphisms in IBS versus control were retrieved. The quality of studies was evaluated based on the modified Newcastle-Ottawa Scale (NOS) with 0 indicating the lowest and 9 as the highest score. Results were pooled using: (a) the standardized mean difference (SMD) for IL-6 levels which was considered statistically significant when the 0 value was not within the 95% confidence interval (CI), or (b) odds ratio (OR; 95% CI) through converting and pooling the IL-6 (-G174C) genotypes and alleles data into individual 2*2 tables. Heterogeneity was assessed based on I2 values; where I2<=50% and I2>50% designated using fixed and random effect models, respectively. RESULTS: Circulating IL-6 levels are higher in IBS patients compared to controls (SMD: 2.40 [95%CI: 0.53-4.28]; p=0.01). Categorizing data based on IBS subtypes, showed that IL-6 level is significantly higher in diarrhea predominant IBS (IBS D) compared to control (SMD: 2.62 [95%CI: 0.29-4.95]; p=0.03), while it is comparable in constipation predominant IBS (IBS-C) and alternating IBS (IBS-A) patients with healthy controls. The meta-analysis of IL-6 (-G174C) polymorphism in IBS and based on IBS subtypes showed no difference in the distribution of genotypes or alleles compared to control. CONCLUSION: The higher IL-6 levels in IBS and more specifically in IBS-D suggests a pro-inflammatory phenotype in these patients, while this phenomenon is not supported by the polymorphism of IL-6 ( G174C). Increased IL-6 in IBS might be an acquired phenomenon or mediated by other genotypes. Any potential association between gene polymorphisms and IL-6 levels in IBS should be tested by assessing both IL-6 levels and IL-6 (-G174C) simultaneously in the same IBS subjects compared to their healthy controls. Categorizing patients based on their circulating IL-6 levels may introduce a new opportunity for personalized anti-inflammatory therapies of IBS. PMID- 28886489 TI - Increased plasma sCXCL16 levels may have a relationship with Th1/Th2 imbalance in primary immune thrombocytopenia. AB - Primary immune thrombocytopenia (ITP) is a disease of autoimmunity in which there are Th1/Th2 imbalance and disordered cytokine profiles. CXC chemokine ligand 16 (CXCL16) was proved to implicate in some autoimmune diseases. Our research aimed to determine plasma soluble CXCL16 (sCXCL16) levels and its effects in ITP. We used ELISA to measure plasma sCXCL16, IFN-gamma and IL-4 and flow cytometry to determine expression of CXCR6 on lymphocyte subsets. We used real-time PCR to detect the CXCL16 and CXCR6 mRNA expression. Additionally, plasma sCXCL16, CXCL16 and CXCR6 mRNA levels of 8 patients were monitored before and after treatment. We found that patients with active ITP had higher circulating sCXCL16 in plasma than healthy controls and patients in remission. Meanwhile, negative relationships between sCXCL16 and platelet count, IL-4 and positive relationships between sCXCL16 and IFN-gamma, IFN-gamma/IL-4 ratio were observed. Besides, expression of CXCR6 on lymphocyte subsets and mRNA levels of CXCL16 and CXCR6 were all increased in active ITP. Additionally, plasma sCXCL16 and IFN-gamma levels and CXCR6 mRNA expression were down-regulated after effective treatment compared with those before treatment. Thus, increased plasma sCXCL16 might be implicated in the pathogenesis of ITP and have a relationship with Th1/Th2 imbalance. PMID- 28886491 TI - Interleukin 34, from pathogenesis to clinical applications. AB - Interleukin-34 (IL-34) is a hematopoietic cytokine that was described for the first time in 2008 as a second ligand of CSF1R in addition to M-CSF. IL-34 and M CSF share no sequence homology, but have similar functions, affecting the biology of myeloid cell lineage. In contrast to M-CSF, IL-34 shows unique signaling and expression patterns. Physiologically, IL-34 expression is restricted to epidermis and CNS, acting as a regulator of Langerhans cells and microglia, respectively. However, IL-34 expression can be induced and regulated by NF-kappaB under pathological conditions. Importantly, growing evidence indicates a correlation between IL-34 and disease severity, chronicity and progression. In addition to its promising roles as a novel diagnostic and prognostic biomarker of disease, IL 34 may also serve as a powerful target for therapeutic intervention. Here, we review the current knowledge regarding the emerging roles of IL-34 in disease, and focus on the clinical applications of IL-34 in medicine. PMID- 28886492 TI - The dynamics of prehospital/hospital care and modes of transport during civil conflict and terrorist incidents. AB - OBJECTIVE: Prehospital and hospital care during incidents of mass violence and civil conflict involve a number of aspects that distinguish it from care during times of peace. We aimed to analyze the dynamics and outcomes of prehospital and hospital care during ongoing conflicts. STUDY DESIGN: Multicentric prospective observational study. METHOD: Patients enrolled in the study, which was conducted in Turkey, were all injured in armed conflict and taken to level 1 trauma centers. On admittance, patients were requested to complete a semistructured questionnaire containing questions on patient demographics, transport type, weapons used, injury severity score (ISS), and other incident-related factors. We analyzed patient outcomes (mortality, morbidity, complications, and length of hospital stay) and transfers of patients between hospitals. The present study evaluated the cases of 390 victims enrolled over a 9-month period and followed up for 6 months. RESULTS: The majority of patients were transported by ambulances (n = 334, 85.6%); other transport modes were helicopters (n = 32, 8.2%) and private vehicles (n = 24, 6.2%). Nearly half of patients (48.7%) did not benefit by changing hospitals. During transport to hospitals, 4.1% of the vehicles in the study were involved in accidents. Using multiple regression analysis, only ISS (odds ratio [OR]: 1.098, 95% confidence interval [CI]: 1.044-1.156) and the Glasgow Coma Scale (OR: 0.744, 95% CI: 0.639-0.866) were found to affect mortality. In Receiver-operator characteristic analysis, a cutoff value of 22.5 for ISS had a sensitivity of 100% and a specificity of 89.6% for mortality. CONCLUSIONS: Despite lower ISS values, patient outcomes were worse in terror incidents/civil conflicts. Transport modes did not significantly affect outcomes, whereas hospital transport was found to be inefficiently used. PMID- 28886493 TI - The elderly and falls: Factors associated with quality of life A cross-sectional study using large-scale national data in Korea. AB - OBJECTIVE: To investigate the factors of fall injury and measuring the relationship between health-related quality of life in the elderly. METHODS: We analyzed the data on 38,627 persons of aged 65 years or older who have experienced falls drawn from the Korean Community Health Survey 2011. Binomial logistic regression analysis was performed with crude and adjusted odds ratios and 95% confidence intervals. RESULTS: It was found that sex (OR: 1.187), types of household (OR: 1.134), employment status (OR: 0.941), stress (OR: 1.260), comorbidities (OR: 1.308), and health-related quality of life were significantly related to falls among the elderly. Specifically, elderly women, greater stress, comorbidities, and poor health-related quality of life were strongly related to higher odds of falls. CONCLUSION: Health-related quality of life was significantly related with the risk of fall injuries in elderly households. Providing support for informal caregivers (e.g., friends or neighbors), not only family members could expect to positive effect. PMID- 28886494 TI - The elder physical abuse reflected in judicial authorities in Eskisehir. AB - AIM: Elder abuse is a health and human rights problem that may occur among every race and ethnic group all around the world. This study aims at describing all cases of physical abuse of elderly which have been reported to, and investigated by Eskisehir - a western city of Turkey. METHODS: Physical abuse incidents above 65 years of age which were evaluated by the Eskisehir Council of Forensic Medicine for expert witness opinion during 5year period between 01.01.2010 and 12.31.2014 are examined in this descriptive, cross-sectional study. RESULTS: 253 cases are found and evaluated in the scope of the study. It is determined that all aggressors are the acquaintance of the victim, and for 114 cases (45.1%) the aggressor is the victim's son. It is found that only investigation procedures of cases are completed, but no protection and rehabilitation program has been issued. CONCLUSION: In conclusion, it is determined that elder victims are abused by family members and relatives who are mostly the care givers. It is seen that emergency physicians play a great role in the detection of abuse. PMID- 28886495 TI - Assessing the environmental impact of phenanthrene in different types of land use based on the binding characteristics with dissolved organic matter. AB - The binding characteristics of phenanthrene with dissolved organic matter (DOM) were studied by the excitation emission matrix fluorescence spectroscopy with parallel factor analysis in four types of land use which derived from forest (F), meadow (M), cropland (C), and greenhouse (G). The results showed that the humification degree and binding characteristics of phenanthrene with DOM were distinct differences in the four soils. The binding capacities of humic-like components with phenanthrene were stronger than those of protein-like components. The log K derived from the Stern-Volmer equation significantly correlated with the humification degree of DOM (p < 0.05) in different types of land use. Besides, correlation analysis demonstrated that the potential binding index (Fk) obtained from the modified Stern-Volmer model was a more accurate parameter to describe the combination degree of DOM with phenanthrene than log K, which presented a decrease order of C > F > M > G. Therefore, the environmental impact of phenanthrene in different types of land use could be assessed deeply based on the Fk and DOM concentration. PMID- 28886496 TI - Convulsive status epilepticus in a quaternary hospital paediatric intensive care unit (PICU) in South Africa: An 8 year review. AB - PURPOSE: Convulsive status epilepticus (CSE) is associated with a high morbidity and mortality. This study aimed to describe the clinical profile, aetiology, neuroimaging and EEG findings as well as outcome of children with CSE in Sub Saharan Africa. METHODS: This was a retrospective analysis of electronic records of children with CSE admitted to the Paediatric Intensive Care Unit (PICU) over an 8-year period from January 2007 to December 2014. RESULTS: Seventy six patients were admitted to the PICU with CSE and 55(72%) had refractory status epilepticus. The median age at presentation was 15 months (IQR 6-37 months). The main aetiologies were meningoencephalitis and gastroenteritis in 33(43%) and 19(25%) patients respectively. The most frequently used antiepileptic drugs for CSE in PICU consisted of infusions of midazolam (96%) and thiopentone (22%). Neuroimaging findings were abnormal in 53(75%) patients with hypoxic changes in 17 patients. On multivariable regression, the predictors of poor outcome included the use of more than 3 antiepileptic drugs in PICU(RR-1.41(1.12-1.78), p=0.003), duration of mechanical ventilation for more than 3days (RR 1.98(1.22-3.20), p=0.005) and abnormal neuroimaging findings (RR 3.21(1.53-6.72), p=0.002). The mortality rate was 24%(n=18). Persistent seizures or a new neurological deficit occurred in 58%(n=44). The main cause of mortality was CSE related diffuse cortical and brainstem injury. Predominant neurological sequelae were cerebral palsy and persistent epilepsy. CONCLUSION: The high burden of infection related CSE is associated with high morbidity and mortality rates in contrast to the rates in developed countries. This highlights the need for early recognition and treatment of underlying conditions. PMID- 28886497 TI - Development of a 2-h suicide prevention program for medical staff including nurses and medical residents: A two-center pilot trial. AB - BACKGROUND: Suicide is a crucial global health concern and effective suicide prevention has long been warranted. Mental illness, especially depression is the highest risk factor of suicide. Suicidal risk is increased in people not only with mental illness but also with physical illnesses, thus medical staff caring for physically-ill patients are also required to manage people with suicidal risk. In the present study, we evaluated our newly developed suicide intervention program among medical staff. METHODS: We developed a 2-h suicide intervention program for medical staff, based on the Mental Health First Aid (MHFA), which had originally been developed for the general population. We conducted this program for 74 medical staff members from 2 hospitals. Changes in knowledge, perceived skills, and confidence in early intervention of depression and suicide-prevention were evaluated using self-reported questionnaires at 3 points; pre-program, immediately after the program, and 1 month after program. RESULTS: This suicide prevention program had significant effects on improving perceived skills and confidence especially among nurses and medical residents. These significant effects lasted even 1 month after the program. LIMITATIONS: Design was a single arm study with relatively small sample size and short-term follow up. CONCLUSIONS: The present study suggests that the major target of this effective program is nurses and medical residents. Future research is required to validate the effects of the program with control groups, and also to assess long-term effectiveness and actual reduction in suicide rates. PMID- 28886498 TI - The neurobiology of brain recovery from traumatic stress: A longitudinal DTI study. AB - BACKGROUND: Previous studies demonstrated decreased brain microstructure integrity in people that were exposed to extreme life stress but did not meet posttraumatic stress disorder (PTSD) diagnostic criteria. It is unclear how the brain recovers from traumatic stress in these trauma-exposed non-PTSD people (TENP). METHODS: Twenty-two TENP individuals were recruited from the most affected area of Wenchuan quake, and scanned twenty-five days after the quake and at a two-year follow-up. Tract-based spatial statistics was used to examine brain microstructure changes over the two years. Correlation analyses were conducted to investigate relationships between brain microstructure changes and both stress recovery and demographic factors. To assess DTI stability, fifteen healthy subjects were scanned twice in a year and analysed similarly. RESULTS: Significantly increased fractional anisotropy (FA) was found in the left posterior limb of internal capsule, left superior and posterior corona radiata (SCR and PCR), and left external capsule. The FA increase of these regions was primarily a result of radial diffusivity reduction. Recovery in symptoms was positively correlated with FA increase of SCR. Changes were related to participant age and sex. No DTI measures were changed for the healthy subjects. LIMITATIONS: Generalizability of the findings was constrained by the relatively small sample size. CONCLUSIONS: The TENP individuals showed a recovery from the trauma over the follow-up, and that was accompanied with increased brain microstructure integrity in fiber tracts primarily involving corticostriatal networks. These changes may contribute to the psychological resilience to a severe life stress that led to PTSD in quake victims. In particular,this study adds to Psychoradiology, which is a promising subspecialty for clinical radiology focusing on psychiatric disorders. PMID- 28886500 TI - Peripheral proinflammatory cytokines in Chinese patients with generalised anxiety disorder. AB - BACKGROUND: Inflammatory responses and inflammatory cytokines have been implicated in the pathogenesis of affective disorders, particularly major depression. Given the limited evidence relating to the potential role of proinflammatory cytokines in generalised anxiety disorder (GAD), we aimed to examine peripheral proinflammatory cytokines in Chinese patients with GAD. METHODS: A case-controlled cross-sectional study design, with recruitment of 48 patients with first episode GAD and 48 matched healthy controls. All participants completed measures of anxiety using well-established questionnaires, and serum levels of pro-inflammatory cytokines were measured using multiplex technology. RESULTS: Serum levels of CRP, IL-1alpha, IL-2, IL-6, IL-8, IL-12, IFN-gamma, and GM-CSF were significantly higher in the GAD group in comparison to the control group (p < 0.05). Pearson correlation revealed significant positive correlations between anxiety measures and serum levels of CRP, IL-1alpha, IL-6, IL-8, IFN gamma, and GM-CSF (p < 0.05). LIMITATIONS: The cross-sectional study design does not permit definite conclusions on causal directions between inflammation and GAD. The study was limited to a panel of 8 cytokines and does not exclude the possibility of other important cytokines being involved. CONCLUSIONS: These findings indicate an elevated peripheral proinflammatory response, and provide further support for low grade inflammation in GAD. Further research may identify an 'inflammatory signature' for diagnosis and treatment response, and guide the search for novel pharmacological interventions. PMID- 28886499 TI - Increased reward-oriented impulsivity in older bipolar patients: A preliminary study. AB - OBJECTIVE: Impulsivity is a well-established trait of bipolar disorder (BD) that persists across mood phases. It is, however, still unknown whether, in BD, impulsivity remains stable or varies in intensity over the lifespan. This cross sectional study compared impulsive behavior in older euthymic BD patients and healthy individuals using a range of self-rating and behavioral measures of impulsivity. METHODS: 28 BD patients (56.07 +/- 4.08 years, 16 women) and 15 healthy controls (HC; 55.1 +/- 3.95 years, 6 women) were administered the Barratt Impulsivity Scale (BIS) and selected tasks of the Cambridge Neuropsychological Test Automated Batter (CANTAB) reflecting impulsivity. Multivariate analysis of variance controlled for age compared impulsivity measures across BD and HC. RESULTS: BD patients displayed poor decision making, risk taking, and increased delay aversion. Other measures of impulsivity such as response inhibition, sustained cognitive control, and BIS scores were, overall, comparable between BD and HC. CONCLUSIONS: These preliminary findings suggest that, in BD, aspects of impulsivity related to reward-based decision making persist into late adulthood. Large scale, longitudinal studies are needed to evaluate the relationship of age to impulsivity over time, and explore the link between impulsivity and illness progression in elderly individuals with BD. PMID- 28886501 TI - Global grey matter volume in adult bipolar patients with and without lithium treatment: A meta-analysis. AB - OBJECTIVE: The goal of this meta-analysis was to quantitatively summarize the evidence available on the differences in grey matter volume between lithium treated and lithium-free bipolar patients. METHODS: A systematic search was conducted in Cochrane Central, Embase, MEDLINE, and PsycINFO databases for original peer-reviewed journal articles that reported on global grey matter volume in lithium-medicated and lithium-free bipolar patients. Standard mean difference and Hedges' g were used to calculate effect size in a random-effects model. Risk of publication bias was assessed using Egger's test and quality of evidence was assessed using standard criteria. RESULTS: There were 15 studies with a total of 854 patients (368 lithium-medicated, 486 lithium-free) included in the meta-analysis. Global grey matter volume was significantly larger in lithium-treated bipolar patients compared to lithium-free patients (SMD: 0.17, 95% CI: 0.01-0.33; z = 2.11, p = 0.035). Additionally, there was a difference in global grey matter volume between groups in studies that employed semi-automated segmentation methods (SMD: 0.66, 95% CI: 0.01-1.31; z = 1.99, p = 0.047), but no significant difference in studies that used fully-automated segmentation. No publication bias was detected (bias coefficient = - 0.65, p = 0.46). LIMITATIONS: Variability in imaging methods and lack of high-quality evidence limits the interpretation of the findings. CONCLUSIONS: Results suggest that lithium-treated patients have a greater global grey matter volume than those who were lithium free. Further study of the relationship between lithium and grey matter volume may elucidate the therapeutic potential of lithium in conditions characterized by abnormal changes in brain structure. PMID- 28886502 TI - Nature-Based Solutions in the EU: Innovating with nature to address social, economic and environmental challenges. AB - Contemporary societies are facing a broad range of challenges, from pressures on human health and well-being to natural capital depletion, and the security of food, water and energy. These challenges are deeply intertwined with global processes, such as climate change and with local events such as natural disasters. The EU's research & innovation (R&I) policy is now seeking to address these challenges from a new perspective, with Nature-Based Solutions, and turn them into innovation opportunities that optimise the synergies between nature, society and the economy. Nature-Based Solutions can be an opportunity for innovation, and are here promoted by both policymakers and practitioners as a cost-effective way of creating a greener, more sustainable, and more competitive economy. Since 2013, the European Commission has devoted particular attention to Nature-Based Solutions through consultations and dialogues that sought to make the concept of these solutions more concrete and to define the concept's place within the spectrum of ecosystem-based approaches. In 2014, the Commission launched an expert group, which conducted further analysis, and made recommendations to help increase the use of Nature-Based Solutions and bring nature back into cities. In 2015, a survey was conducted on citizens' views and perceptions of 'Nature in Cities' to provide further insight for future work. Based on these elements and on results from running EU projects, the Commission has developed an R&I agenda for Nature-Based Solutions and has published targeted calls for proposals for large-scale demonstration projects in this field in 2016 and 2017. Additional R&I actions at EU level that promote systemic Nature-Based Solutions and their benefits to cities and territories are planned with the aim to improve the implementation capacity and evidence base for deploying Nature Based Solutions and developing corresponding future markets. They are also expected to foster an interdisciplinary R&I and stakeholder community and the exchange of good practices in this field, as well as help shaping and implementing international R&I agendas on Nature-Based Solutions. PMID- 28886503 TI - Developing and testing transferability and feasibility of a model for educators using simulation-based learning - A European collaboration. AB - BACKGROUND: There is a pragmatic and often inconsistent approach of embedding simulation-based learning into nursing programmes. This paper details a European collaboration that designed a model for educator facilitation for educators utilizing simulation-based education. OBJECTIVES: The objectives of the study were to develop a model to educate the educators who deliver simulation-based learning and to test to which extent this model could be transferred to education providers in different national settings. METHODS: This model, its transferability and feasibility, was tested across three European countries. Educators from three Schools of Nursing participated in the study. Design-based Research was used as an overall methodology. Data were collected by the use of pre- and post-programme questionnaires and focus groups. RESULTS: The content of the NESTLED model is consistent with the needs of the participants. The testing also demonstrated that the model is transferable across-countries. Additionally, the participants' preferences regarding amount of time and pre-reading for the different sessions vary depending on the background and level of seniority of the individual participant. CONCLUSION: The testing of the NESTLED model demonstrated that participants gained confidence and knowledge from undertaking the programme. Delivering the NESTLED model across-countries was found to be feasible, but flexibility is required in terms of logistical delivery of the programme. PMID- 28886504 TI - Experiences of service users involved in recruitment for nursing courses: A phenomenological research study. AB - The aim of this study was to gain insight into service users' experiences of participating in recruitment for Adult, Mental Health and Child nursing studies at the authors' university; to establish potential motivations behind such participation; and to make suggestions for improved future practice. The involvement of service users in nurse education and recruitment has for some years been required by the Nursing and Midwifery Council, but there is a dearth of publications on the meaning of that involvement to participating service users. It is hoped that this study will contribute to this body of knowledge. A phenomenological approach was selected, field-specific focus groups of service users being facilitated using a semi-structured interview format; these were audio recorded and transcribed. The data was analysed using thematic analysis. Participation was subject to the service users having been involved in recruitment to nursing studies at the authors' university and the focus groups took place either at the university or at the child participants' school. Themes identified demonstrated largely positive experiences and a sense of meaningful involvement for all concerned. Findings indicated a close link between the values of the participants and those of the wider NHS, benefits to a sense of wellbeing and achievement, as well as the need for greater ownership of the recruitment process by service users. Potential lessons for academics wishing to promote greater service user involvement in student recruitment are articulated. PMID- 28886505 TI - A dual-responsive colorimetric and fluorescent chemosensor based on diketopyrrolopyrrole derivative for naked-eye detection of Fe3+ and its practical application. AB - A novel dual-responsive colorimetric and fluorescent chemosensor L based on diketopyrrolopyrrole derivative for Fe3+ detection was designed and synthesized. In presence of Fe3+, sensor L displayed strong colorimetric response as amaranth to rose pink and significant fluorescence enhancement and chromogenic change, which served as a naked-eye indicator by an obvious color change from purple to red. The binding constant for L-Fe3+ complex was found as 2.4*104 with the lower detection limit of 14.3nM. The sensing mechanism was investigated in detail by fluorescence measurements, IR and 1H NMR spectra. Sensor L for Fe3+ detection also exhibited high anti-interference performance, good reversibility, wide pH response range and instantaneous response time. Furthermore, the sensor L has been used to quantify Fe3+ ions in practical water samples with good recovery. PMID- 28886506 TI - Dual fluorescence of (E)-N-(4-(dimethylamino)benzylidene)-2H-1,2,4-triazol-3 amine (DMABA-Amtr): A ground state perspective. AB - We present the absorption and fluorescence spectra of (E)-N-(4 (dimethylamino)benzylidene)-2H-1,2,4-triazol-3-amine (DMABA-Amtr), an electron donor-pi-acceptor system. The molecule shows a single fluorescence emission band in non-polar solvents while dual emissions were observed in polar aprotic solvents. Although several researchers over the years provide different explanations for the mechanism of the phenomena, based on solvent assisted excited state geometry changes of such systems, it is still a matter of controversy since such systems are unique as they contradict Kasha's rule. The emission spectrum of the molecule shows strong dependence on solvent polarity and excitation wavelength. This observation together with a single iso-emissive point found in the area normalize emission spectra indicates the presence of two ground state equilibrium structures of the compound which are both fluorescent. Density functional theory (DFT) and time-dependent (TD-DFT) calculations also support the experimental findings. PMID- 28886507 TI - SERS study of surface plasmon resonance induced carrier movement in Au@Cu2O core shell nanoparticles. AB - A plasmon induced carrier movement enhanced mechanism of surface-enhanced Raman scattering (SERS) was investigated using a charge-transfer (CT) enhancement mechanism. Here, we designed a strategy to study SERS in Au@Cu2O nanoshell nanoparticles with different shell thicknesses. Among the plasmonically coupled nanostructures, Au spheres with Cu2O shells have been of special interest due to their ultrastrong electromagnetic fields and controllable carrier transfer properties, which are useful for SERS. Au@Cu2O nanoshell nanoparticles (NPs) with shell thicknesses of 48-56nm are synthesized that exhibit high SERS activity. This high activity originates from plasmonic-induced carrier transfer from Au@Cu2O to 4-mercaptobenzoic acid (MBA). The CT transition from the valence band (VB) of Cu2O to the second excited pi-pi* transition of MBA, and is of b2 electronic symmetry, which was enhanced significantly. The Herzberg-Teller selection rules were employed to predict the observed enhanced b2 symmetry modes. The system constructed in this study combines the long-range electromagnetic effect of Au NPs, localized surface plasmon resonance (LSPR) of the Au@Cu2O nanoshell, and the CT contribution to assist in understanding the SERS mechanism based on LSPR-induced carrier movement in metal/semiconductor nanocomposites. PMID- 28886508 TI - Effects of clinico-pathological risk factors on in-vitro mechanical properties of human dilated ascending aorta. AB - Ascending aorta aneurysms (AsAA) are associated with a degeneration of the aortic wall tissue, which leads to changes in tissue mechanical properties. Risk factors for the development of the AsAA disease are recognized in patient age and gender, valve type, hypertension, diabetes mellitus, smoking history, and a prior diagnosis of Marfan syndrome. The present study aims to assess how such clinico pathological factors can affect the mechanical properties of human dilated ascending aorta. Specimens of AsAA are excised from 68 patients who underwent elective AsAA surgical repair and stretched until rupture during the execution of uniaxial tensile tests. Experimental stress-stretch curves are used to determine tissue mechanical properties (stress and stretch at failure point and at transition point, low and high elastic modulus). Data are divided into groups according to region (anterior vs posterior), direction (circumferential vs longitudinal), and then according to age (young vs old), gender (male vs female), valve type (tricuspid aortic valve, TAV, vs bicuspid aortic valve, BAV), and presence of hypertension, diabetes mellitus, and/or Marfan syndrome (yes/no). Moreover, data are grouped according to the critical value of body mass index (BMI), maximum AsAA diameter, and aortic stiffness index (ASI), respectively. Finally, a non-parametric statistical analysis is performed to find possible significant differences and correlations between mechanical properties and clinico-pathological data. Our results confirm the anisotropy and heterogeneity of the AsAA tissue and highlight that ageing and hypertension make the AsAA tissue weaker and less extensible, whereas the valve type affects the tissue strength with higher values in BAV than in TAV patients. No effects of gender, critical BMI, critical maximum AsAA diameter, critical ASI, smoking status, and presence of diabetes mellitus, and Marfan syndrome are evidenced. PMID- 28886509 TI - Acridone-pyrimidine hybrids- design, synthesis, cytotoxicity studies in resistant and sensitive cancer cells and molecular docking studies. AB - Hybrid systems of acridones with substituted pyrimidines were designed with an objective of discovering next generation anticancer agents targeting multiple mechanisms in the cancer cell. Hybrid compounds were synthesized by simple and convenient methods in the lab, characterized by NMR and Mass spectral methods and screened for cytotoxicity against A549 (lung), Hela (cervical), MCF7 (breast) and MDA-MB-231 (breast) cancer cell lines respectively. Evaluation of compounds for cell proliferation identified active compounds 11b, 11d and 11h against MCF7, MDA MB-231 and A549 cell lines. Further absorption titrations with CT-DNA and gel electrophoresis identified that hybrid molecules displayed anticancer activity partly by DNA intercalation. Also further results of western blotting assay with Akt kinase identified that hybrid compounds have the ability to inhibit the Akt kinase activity and induce apoptosis, with ABCC1 suggests that active compounds too have the ability to modulate multidrug resistance (MDR) associated with ABCC1/MRP1. Selective Akt1 kinase assay have identified 11a, 11b, 11d and 11h as potential inhibitors. Molecular docking studies identified the orientation and binding interactions at the active site of Akt1 and DNA. Compounds 12e and 12f have shown good cytotoxicity profile against lung cancer cell lines of sensitive and resistant type. Acute toxicity study of compound 12f at the dose of 5000 mg/kg has identified no signs of clinical toxicity. Prediction of ADMET properties and oral toxicity of the drug likeness features of new hybrid systems were carried out using software's. This experimental data suggests that hybrid systems of acridone with substituted pyrimidines can be taken as a lead for the design of efficient inhibitors and active compounds which can be taken up for further studies. PMID- 28886510 TI - Polyamine-based analogs and conjugates as antikinetoplastid agents. AB - Naturally occurring polyamines: putrescine, spermidine and spermine are crucial for Kinetoplastid growth and persistence. These aliphatic polycations are either biosynthesized or internalized into Kinetoplastid by active transport. Impairing the polyamine metabolism using polyamine derivatives is an interesting path in the search of new antikinetoplastid chemotherapy. In the past 30 years, research interest in this field has been constantly expanding and recent results demonstrated that the discovery of a polyamine-based antikinetoplastid drug is undoubtedly possible. In this paper, all the polyamine derivatives previously described to present an antikinetoplastid activity are reported. This review is organized around three main parts which are diamine, triamine and tetramine derivatives. Each part includes the description of the series of molecules and, their in vitro and in vivo activity when available. Structure-activity relationships of these derivatives are discussed and the most promising structures for a positive outcome are eventually highlighted. PMID- 28886511 TI - Electrochemical nitric oxide biosensor based on amine-modified MoS2/graphene oxide/myoglobin hybrid. AB - Nitric oxide (NO) is one of the most important molecules in living things due to its role as a signaling molecule in influencing pathological and physiological mechanisms including neurotransmission. In this study, the electrochemical biosensor based on the amine-modified molybdenum disulfide nanoparticles (MoS2), graphene oxide (GO) and myoglobin (Mb) hybrid material (amine-modified MoS2/GO/Mb hybrid) is developed to achieve the accurate detection of NO with electrochemical signal improvement. For the first time, the synthesis of MoS2 accompanying the amine-modification of the surface of MoS2 is done to hybridize with GO efficiently through the short linkage. After the amine-modification of MoS2, it is enclosed with GO directly (amine-modified MoS2/GO). Then, Mb which can induce the reduction of NO is immobilized on the amine-modified MoS2/GO to fabricate the amine-modified MoS2/GO/Mb hybrid for NO detection. The prepared hybrid shows the signal improved redox properties relative to the result of the electrode prepared without hybrid. Furthermore, upon addition of NO, the electrode prepared with hybrid shows the improved amperometric response compared with that of the electrode without hybrid. This amine-modified MoS2/GO/Mb hybrid can be used in the development of the biosensor platform accompanying the electrochemical signal improvement and accurate detection of target materials. PMID- 28886512 TI - Physicochemical study of biomolecular interactions between lysosomotropic surfactants and bovine serum albumin. AB - The interactions between two cationic lysosomotropic surfactants (2 dodecanoyloxyethyl)trimethylammonium bromide (DMM-11) and (2 dodecanoyloxypropyl)trimethylammonium bromide (DMPM-11) with bovine serum albumin (BSA) in Hepes buffer (pH=7.4) were systematically studied by surface tension, fluorescence and circular dichroism (CD) spectroscopy and isothermal titration calorimetry (ITC). Furthermore, the size of the micellar aggregates and the polydispersity indexes of both cationic surfactants were studied by dynamic light scattering technique (DLS). The hydrodynamic radii, micellar volumes and aggregation numbers were calculated using a method based on density functional theory (DFT). The results showed that, in both cases, the surface tension was modified upon addition of BSA, and the critical micelle concentration (CMC) values of DMM-11 and DMPM-11 were higher in the presence of BSA. The fluorescence intensity of BSA decreased significantly as the concentration of both cationic surfactants increased and this effect was attributed to the formation of surfactant-BSA complexes. Synchronous fluorescence spectrometry showed the binding-induced conformational changes in BSA. Finally, CD and DLS results revealed the occurrence of changes in the secondary structure of the protein in the presence of both surfactants. In conclusion, understanding the interactions between lysosomotropic surfactants and BSA is required to explore their potential applications in medicine. PMID- 28886513 TI - Construction of genetically engineered M13K07 helper phage for simultaneous phage display of gold binding peptide 1 and nuclear matrix protein 22 ScFv antibody. AB - The most common techniques of antibody phage display are based on the use of M13 filamentous bacteriophages. This study introduces a new genetically engineered M13K07 helper phage displaying multiple copies of a known gold binding peptide on p8 coat proteins. The recombinant helper phages were used to rescue a phagemid vector encoding the p3 coat protein fused to the nuclear matrix protein 22 (NMP22) ScFv antibody. Transmission electron microscopy (TEM), UV-vis absorbance spectroscopy, and field emission scanning electron microscopy (FE-SEM) with energy dispersive X-ray spectroscopy (EDX) analysis revealed that the expression of gold binding peptide 1 (GBP1) on major coat protein p8 significantly enhances the gold-binding affinity of M13 phages. The recombinant bacteriophages at concentrations above 5*104 pfu/ml red-shifted the UV-vis absorbance spectra of gold nanoparticles (AuNPs); however, the surface plasmon resonance of gold nanoparticles was not changed by the wild type bacteriophages at concentrations up to 1012 pfu/ml. The phage ELISA assay demonstrated the high affinity binding of bifunctional bacteriophages to NMP22 antigen at concentrations of 105 and 106 pfu/ml. Thus, the p3 end of the bifunctional bacteriophages would be able to bind to specific target antigen, while the AuNPs were assembled along the coat of virus for signal generation. Our results indicated that the complex of antigen bacteriophages lead to UV-vis spectral changes of AuNPs and NMP22 antigen in concentration range of 10-80MUg/ml can be detected by bifunctional bacteriophages at concentration of 104 pfu/ml. The ability of bifunctional bacteriophages to bind to antigen and generate signal at the same time, makes this approach applicable for identifying different antigens in immunoassay techniques. PMID- 28886514 TI - Fabrication of polymer matrix-free nanocomposites based on Angelica gigas Nakai extract and their application to breast cancer therapy. AB - Nanocomposites (NCs) based on the ethanol extract of Angelica gigas Nakai (AGN EtOH ext) were developed for breast cancer therapy. Polymer matrix-free nano sized particles based on the extract of natural product were fabricated using a modified emulsification-solvent evaporation method. Without the use of polymer matrix, toxicity can be minimized and the clinical application may be assured. AGN NCs with approximately 200nm mean diameter, narrow size distribution, and negative zeta potential were prepared in this study. Sustained release of decursin (D) and decursinol angelate (DA) (as major components of AGN) from AGN NCs was observed at pH 7.4. Cellular accumulation efficiency and intracellular distribution of AGN NCs were evaluated in MCF-7 (human breast adenocarcinoma) cells. According to the results of antiproliferation assay in MCF-7 cells, IC50 value of AGN NCs group (27.4+/-4.0MUg/mL) was lower than that of AGN EtOH ext group (75.3+/-13.7MUg/mL) (p<0.05). Also, the percentage of apoptotic events of AGN NCs group was significantly higher than that of AGN EtOH ext group (p<0.05). All these findings suggest that developed AGN NCs can be used as one of promising nanosystems for the therapy of breast cancers. PMID- 28886515 TI - Development and characterization of cores-shell poly(lactide-co-glycolide) chitosan microparticles for sustained release of GDNF. AB - The microencapsulation of bioactive neurotrophic factors in biodegradable poly(lactide-co-glycolide) (PLGA) microspheres has been a promising tool in the treatment of various nervous system disorders. However, challenges still exist; the PLGA burst drug release and acidic degradation products often limit clinical application. In this study, cores-shell PLGA-chitosan microparticles (MPs) were fabricated with a single shell of chitosan and multi-cores of PLGA using a re emulsification method. The glial cell line-derived neurotrophic factor (GDNF) was encapsulated at the PLGA cores of the cores-shell MPs. The cores-shell MPs prepared by different chitosan concentrations showed a rough surface, and the particle mean size varied between 32.3 and 45.2MUm. The fluorescence images indicated that Nile red-stained PLGA microspheres were uniformly distributed in the cores-shell MPs. Compared with PLGA microspheres, the cores-shell MPs were able to reduce the initial burst release of GDNF and neutralize the acidity of PLGA degradation products, which could be modulated by changing the chitosan concentrations. Further differentiation of PC12 cells toward a neuronal phenotype in vitro indicated that the cores-shell MPs were capable of maintaining the bioactivity of GDNF during preparation. Taken together, these findings highlight the possibility of using cores-shell PLGA-chitosan MPs for the sustained release of GDNF, which offers potential applications in nerve injury repair. PMID- 28886516 TI - Biodegradation behavior and modelling of soil burial effect on degradation rate of PLA blended with starch and wood flour. AB - The biodegradation behavior of Poly (lactic acid) (PLA) blended with starch and wood flour in outdoor soil was investigated comprehensively. As a result, starch provided a biological fuel for the growth of microorganisms in the soil which accelerated the degradation rate of PLA more obviously than wood flour. With the increase of starch content, the weight loss increased and the morphology exhibited more gullies and cavities. X-ray Photoelectron Spectroscopy (XPS) analysis indicated that the variation of O/C ratio was controlled by starch biodegradation and PLA hydrolysis and they were a concomitant process. The mechanical strengths of all the blends showed similar trend and fitted a first order exponential decay model. The model is shown in good agreement with experimental results as the correlation coefficient is higher than 0.99, and the model can support an efficient method to estimate the durability of starch/wood flour/PLA blends. PMID- 28886517 TI - Tunable pH and redox-responsive drug release from curcumin conjugated gamma polyglutamic acid nanoparticles in cancer microenvironment. AB - Tunable pH and redox responsive polymer was prepared using gamma-polyglutamic acid (gamma-PGA) with linker 3-mercaptopropionic acid (3-MPA) (gamma-PGA_SH) via oxidation to obtain redox responsive disulfide (gamma-PGA_SS) backbone and adipic acid dihydrazide (ADH) (gamma-PGA_SS_ADH) with hydrazide functional group for pH responsiveness. Further curcumin (Cur) was conjugated through hydrazone bond of the gamma-PGA_SS_ADH via Schiff base reaction to obtain (gamma-PGA_SS_ADH_Cur). The prepared systems were characterized by Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, Electrospray ionization quadrupole time of-flight mass spectrometry (ESI-Qq-TOF-MS/MS) and Solid state nuclear magnetic resonance (SS NMR) techniques. gamma-PGA_SS_ADH_Cur formed self-assembled core shell nanoparticles (NPs) in existence of stabilized aqueous medium. gamma PGA_SS_ADH_Cur NPs maintained its stability in physiological condition. NPs tunable Cur release and cytotoxicity were observed for gamma-PGA_SS_ADH_Cur NPs in both acidic and redox conditions mimicking the cancer microenvironment. gamma PGA_SS_ADH_Cur NPs uptake study showed via endocytosis mechanism resulted in the lysosomal entrapment of these NPs within the cell. gamma-PGA_SS_ADH_Cur NPs exhibited a dual stimuli responsive drug delivery and can be used as a smart and potential drug delivery system in cancer microenvironment. PMID- 28886518 TI - Capillary electrophoresis study on the base-catalyzed formation of bioactive oxidized metabolites of 20-hydroxyecdysone. AB - A novel capillary electrophoretic method was developed for the analysis and monitoring of the base-catalyzed autoxidation of 20-hydroxyecdysone, a worldwide used non-hormonal anabolic food supplement. An effective separation of the starting material and its bioactive oxidized derivatives was achieved by using sulfobutyl-beta-cyclodextrin as selector at pH 11 and by fixing the separation voltage at +30kV. Only a dilution step was inserted before injecting the sample, taken from the crude reaction mixture, to the capillary electrophoresis instrument. The same alkaline pH was used for the analysis as for the reaction, unlike the previously reported HPLC study where sample neutralization was required prior to the measurement. Due to the very short analysis time (6min) in capillary electrophoresis, more frequent sampling and more detailed time scale analysis could be carried out. Furthermore, in contrast with the preceding HPLC results, the previously unobserved calonysterone could also be detected by capillary electrophoresis as a minor primary product. Our novel method demonstrated higher resolution than the one before. Baseline separation could be achieved and the resolution values were in the range of 1.9-7.0. The limit of detection was below 71MUg/ml, the relative standard deviation values of the migration time and peak area for intra- and inter-day precision were less than 10%. The more precise, direct monitoring of the time dependency of the oxidation process is expected to have a significant impact on yield optimization initiatives to allow related pharmacological studies in the near future. PMID- 28886519 TI - Development and validation of a liquid chromatography-tandem mass spectrometry method for pharmacokinetic study of TM-53, a novel transcriptional coactivator with PDZ-binding motif (TAZ) modulator. AB - Transcriptional coactivator with PDZ-binding motif (TAZ) is considered an attractive target for osteoporosis, obesity, and muscle regeneration. TM-53, a promising TAZ modulator, was recently introduced, and here, we developed a rapid, precise, and reliable analytical method for TM-53 and characterized its pharmacokinetic properties in rat plasma. The hybrid triple quadrupole/linear ion trap coupled to liquid chromatography method was developed and validated to quantify TM-53. Additionally, TM-53 concentrations in plasma were analyzed, and its pharmacokinetic parameters were calculated by non-compartmental analysis. Multiple reaction monitoring at m/z 569.4->207.1 showed the most sensitive signals for TM-53, and the linear scope of the standard curve was between 1.5ng/mL and 500ng/mL. The intra- and inter-day precisions of the quality control samples were <15%, and their accuracies were ranged from 86.2% to 111.0%. Furthermore, the matrix effects, extraction recoveries, and process efficiencies of this analytical method for evaluating TM-53 in rat plasma were 99.1%, 99.9%, and 99.1% respectively. In short- and long-term stability studies, TM-53 showed good stability under frozen conditions, but TM-53 hydrolysis in the plasma matrix was observed following storage at room temperature. This analytical method was successfully applied for pharmacokinetic analysis of TM-53 in rat plasma and demonstrated excellent sensitivity, selectivity, precision, and accuracy. These data indicated that this method can be applied for further preclinical studies of TM-53. PMID- 28886520 TI - Development of a sensitive LC-MS/MS method for quantification of coniferyl ferulate and its metabolite coniferyl alcohol in rat plasma: Application to a pharmacokinetic study. AB - A rapid and simple LC-MS/MS method was developed and validated for the simultaneous determination of coniferyl ferulate (CF) and its metabolite coniferyl alcohol (CA) using bavachromene as an internal standard (IS). A TSQ Quantum Access mass spectrometer was operated under selected-reaction monitoring mode using negative electrospray ionization. Extraction with ether was used in sample preparation. The plasma samples were prepared and then chromatographed on a Phenomenex Luna C18 column (2.1mm*50mm, 1.7MUm; Torrance, USA) at 35 degrees C, using acetonitrile: water (65:35, v/v) in an isocratic mode at a flow rate of 0.3mL/min. Method validation was performed as per the FDA guidelines and calibration curves showed good linearity over the concentration range of 2.5 1000ng/mL for both CF and CA. The intra- and inter-day precision and accuracy were within the acceptable limits. The developed assay was successfully applied to a pharmacokinetic study of CA in rats. PMID- 28886521 TI - Permeability through the Caco-2 cell monolayer of 42 bioactive compounds in the TCM formula Gegen-Qinlian Decoction by liquid chromatography tandem mass spectrometry analysis. AB - Caco-2 cell monolayer model was used to evaluate the intestinal permeability of 42 bioactive compounds in the famous traditional Chinese medicine (TCM) formula Gegen-Qinlian Decoction (GQD). These compounds include alkaloids, flavonoids and glycosides, triterpenoid saponins, and coumarins. Their transportations across the cell monolayers in the forms of herb extract and formula extract were monitored by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) analysis. Most alkaloids from Huang-Lian; flavonoid C-glycosides from Ge-Gen and Huang-Qin; O-glycosides from Ge-Gen, Huang-Qin and Gan-Cao; O glucuronides from Huang-Qin; and coumarins from Gan-Cao exhibited favorable permeability. Their PAB values were >1.05*10-5cm/s, and efflux ratios (ER, PBA/PAB) were<=1.0. In contrast, triterpenoid saponins showed poor permeability (PAB<=1.50*10-6cm/s, ER<=1.5), indicating a paracellular diffusion mechanism. Furthermore, GQD could remarkably improve the intestinal transport of alkaloids in Huang-Lian, flavonoid C-glycosides in Ge-Gen, as well as coumarins and flavonoid O-glycosides in Gan-Cao. These results indicate herb-herb interactions in GQD. PMID- 28886523 TI - A workflow for column interchangeability in liquid chromatography using modeling software and quality-by-design principles. AB - The goal of the present study was to develop a generic workflow to evaluate the chromatographic resolution in a large design space and easily find some replacement column for the method. To attain this objective from a limited number of initial experiments, modern LC modeling software (Drylab) was employed to study the behaviour of the compounds and visually compare the parts of design spaces obtained with different columns, where a given criterion of critical resolution is fullfilled. A zone of robust space can then easily be found by overlapping design spaces. By using 50*2.1mm columns packed with sub-2MUm fully porous particles (UHPLC), the resolution in the entire design space can be modeled on the basis of only 2-3h experimental work per column. To demonstrate the applicability of the developed procedure, amlodipine and its related pharmacopeia impurities were selected as a case study. It was demonstrated that two columns from different providers (Waters Acquity HSS C18, Thermo Hypersil Gold C18) can be interchanged, providing a sufficient resolution at the same working point and a high degree of robustness around this condition. PMID- 28886524 TI - Simultaneous quantification of arginine, alanine, methionine and cysteine amino acids in supplements using a novel bioelectro-nanosensor based on CdSe quantum dot/modified carbon nanotube hollow fiber pencil graphite electrode via Taguchi method. AB - A number of four amino acids have been simultaneously determined at CdSe quantum dot-modified/multi-walled carbon nanotube hollow fiber pencil graphite electrode in different bodybuilding supplements. CdSe quantum dots were synthesized and applied to construct a modified carbon nanotube hollow fiber pencil graphite electrode. FT-IR, TEM, XRD and EDAX methods were applied for characterization of the synthesized CdSe QDs. The electro-oxidation of arginine (Arg), alanine (Ala), methionine (Met) and cysteine (Cys) at the surface of the modified electrode was studied. Then the Taguchi's method was applied using MINITAB 17 software to find out the optimum conditions for the amino acids determination. Under the optimized conditions, the differential pulse (DP) voltammetric peak currents of Arg, Ala, Met and Cys increased linearly with their concentrations in the ranges of 0.287 33670MUM and detection limits of 0.081, 0.158, 0.094 and 0.116MUM were obtained for them, respectively. Satisfactory results were achieved for calibration and validation sets. The prepared modified electrode represents a very good resolution between the voltammetric peaks of the four amino acids which makes it suitable for the detection of each in presence of others in real samples. PMID- 28886522 TI - Quantification of the antimalarial drug pyronaridine in whole blood using LC MS/MS - Increased sensitivity resulting from reduced non-specific binding. AB - Malaria is one of the most important parasitic diseases of man. The development of drug resistance in malaria parasites is an inevitable consequence of their widespread and often unregulated use. There is an urgent need for new and effective drugs. Pyronaridine is a known antimalarial drug that has received renewed interest as a partner drug in artemisinin-based combination therapy. To study its pharmacokinetic properties, particularly in field settings, it is necessary to develop and validate a robust, highly sensitive and accurate bioanalytical method for drug measurements in biological samples. We have developed a sensitive quantification method that covers a wide range of clinically relevant concentrations (1.5ng/mL to 882ng/mL) using a relatively low volume sample of 100MUL of whole blood. Total run time is 5min and precision is within +/-15% at all concentration levels. Pyronaridine was extracted on a weak cation exchange solid-phase column (SPE) and separated on a HALO RP amide fused core column using a gradient mobile phase of acetonitrile-ammonium formate and acetonitrile-methanol. Detection was performed using electrospray ionization and tandem mass spectrometry (positive ion mode with selected reaction monitoring). The developed method is suitable for implementation in high-throughput routine drug analysis, and was used to quantify pyronaridine accurately for up to 42days after a single oral dose in a drug-drug interaction study in healthy volunteers. PMID- 28886525 TI - Perillyl alcohol protects human renal tubular epithelial cells from hypoxia/reoxygenation injury via inhibition of ROS, endoplasmic reticulum stress and activation of PI3K/Akt/eNOS pathway. AB - Ischemia/reperfusion (I/R) injury plays an essential role in renal transplantation, and represents a crucial risk factor for allograft dysfunction and acute renal failure. Modulation of oxidative stress is an effective therapeutic strategy for I/R injury. Perillyl alcohol (POH), a dietary monoterpene with antioxidant activity is found in a variety of plants. The study was carried out to investigate whether treatment of POH could reduce hypoxia/reoxygenation (H/R)-induced injury. H/R induced significant injury in HK 2 cells. H/R caused an increase in ROS level, apoptosis and ER stress. Meanwhile H/R also inhibited the cell viability and PI3K/Akt/eNOS signaling pathway. Pretreatment with POH prior to H/R improved cell viability, reduce ROS level, ER stress and apoptosis. Moreover, POH could also activate the PI3K/Akt/eNOS pathway. Therefore, POH may possess protective effects in H/R-induced cellular damage. PMID- 28886526 TI - Glycyrrhizic acid: A promising carrier material for anticancer therapy. AB - Drug delivery systems have become an integral part of anticancer drugs today. Design of novel drug carriers may lead to significant enhancement in antineoplastic therapy. Glycyrrhizic acid (GL), which is the most important active ingredient extracted from the licorice root shows great potential as a carrier material in this field. Recent studies have indicated that the combination of GL and first-line drugs had better therapeutic effects on cancers. GL showed a series of anti-cancer-related pharmacological activities, such as broad-spectrum anti-cancer ability, resistance to the tissue toxicity caused by chemotherapy and radiation, drug absorption enhancing effects and anti-multidrug resistance (MDR) mechanisms, as a carrier material in drug delivery systems. This review introduced the current research progress on pharmacological mechanisms of GL and development of GL-based drug carriers in anti-cancer field to provide basis for the application prospects of GL. The design of novel GL-based drug delivery systems will bring new opportunities and challenges to anti-cancer therapy. PMID- 28886527 TI - Cardioprotective effect of Malva sylvestris L. in myocardial ischemic/reprefused rats. AB - PURPOSE: The present investigation evaluated the cardioprotective effect of Malva sylvestris L. (MS) on myocardial ischemic/reperfusion (MI/R) in rats. METHODS: All animals were divided into four groups: the sham operated group, ischemia/reperfusion group (MI/R), and the MS (250 and 500mg/kg) treated groups, who received MS 250 and 500mg/kg intragastrically for 15 consecutive days, respectively. At the end of the protocol, concentrations of aspartate transaminase (AST), creatine kinase-MB fraction (CK-MB) and lactate dehydrogenase (LDH) were estimated in serum and the concentrations of other parameters, such as C-reactive protein, macrophage inflammatory protein 1 alpha (MIP-1alpha), and nitric oxide (NO) were also estimated in the blood. Tissue homogenate concentrations of inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interlukin-1beta (IL-1beta), IL-10 and IL-6 as well as oxidative stress parameters, such as lipid peroxidation, catalase, and superoxide dismutase were estimated in MI/R rats. RESULT: Significant decreases (p<0.01) in AST, LDH, and CK-MB levels were observed in the MS-treated group compared with those in the MI/R group. C-reactive protein and MIP-1alpha levels decreased in the MS-treated group compared with those in the MI/R group. Plasma NO level was significantly enhanced in the MS-treated group than in the MI/R group. Moreover, treatment with MS significantly reduced TNF-alpha, IL-1beta, and IL-6 levels and increased IL-10 levels in the MS group compared with the MI/R group. Treatment with MS also attenuated the altered oxidative stress parameters in MI/R rats. CONCLUSION: The present results indicate the cardioprotective effects of MS of reducing oxidative stress and the inflammatory response in MI/R rats. PMID- 28886528 TI - An increased expression of long non-coding RNA PANDAR promotes cell proliferation and inhibits cell apoptosis in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies worldwide. Emerging evidence indicates that aberrantly expressed long non-coding RNAs (lncRNAs) act as imperative roles in tumorigenesis and progression. PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) is a novel lncRNA that contributes to the development of various cancers. However, its clinical significance and potential effects on PDAC remains unknown. In the present study, qRT-PCR was performed to explore the expression levels of PANDAR in PDAC tissues and corresponding non-tumor tissues, the correlation between PANDAR expression and clinicopathological characteristics was also analyzed. The functional roles of lncRNA PANDAR in PDAC cells were evaluated both in vitro and in vivo. The results indicated that PANDAR was aberrantly overexpressed in PDAC tissues and cell lines, and this overexpression was closely associated with tumor stage and vascular invasion in PDAC patients. Besides, silencing of PANDAR exerted tumor suppressive effect via reducing cell proliferation, colony-forming ability, inducing cell cycle G0/G1 arrest and apoptosis in PANC1 and Capan-2 cells. Further in vivo study confirmed the oncogenesis role of PANDAR in PDAC cells. Overall, our findings may help to develop a potential therapeutic target for the patients with PDAC. PMID- 28886529 TI - Peroxisome proliferator-activated receptors as therapeutic targets for heart failure. AB - Heart failure (HF) is a common clinical syndrome that affects more than 23 million individuals worldwide. Despite the marked advances in its management, the mortality rates in HF patients have remained unacceptably high. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription regulators, involved in the regulation of fatty acid and glucose metabolism. PPAR agonists are currently used for the treatment of type II diabetes mellitus and hyperlipidemia; however, their role as therapeutic agents for HF remains under investigation. Preclinical studies have shown that pharmacological modulation of PPARs can upregulate the expression of fatty acid oxidation genes in cardiomyocytes. Moreover, PPAR agonists were proven able to improve ventricular contractility and reduce cardiac remodelling in animal models through their anti inflammatory, anti-oxidant, anti-fibrotic, and anti-apoptotic activities. Whether these effects can be replicated in humans is yet to be proven. This article reviews the interactions of PPARs with the pathophysiological mechanisms of HF and how the pharmacological modulation of these receptors can be of benefit for HF patients. PMID- 28886530 TI - A novel ventricular restraint device (ASD) repetitively deliver Salvia miltiorrhiza to epicardium have good curative effects in heart failure management. AB - A novel ventricular restraint is the non-transplant surgical option for the management of an end-stage dilated heart failure (HF). To expand the therapeutic techniques we design a novel ventricular restraint device (ASD) which has the ability to deliver a therapeutic drug directly to the heart. We deliver a Traditional Chinese Medicine (TCM) Salvia miltiorrhiza (Danshen Zhusheye) through active hydraulic ventricular support drug delivery system (ASD) and we hypothesize that it will show better results in HF management than the restraint device and drug alone. SD rats were selected and divided into five groups (n=6), Normal, HF, HF+SM (IV), HF+ASD, HF+ASD+SM groups respectively. Post myocardial infarction (MI), electrocardiography (ECG) showed abnormal heart function in all groups and HF+ASD+SM group showed a significant therapeutic improvement with respect to other treatment HF, HF+ASD, and HF+SM (IV) groups on day 30. The mechanical functions of the heart such as heart rate, LVEDP, and LVSP were brought to normal when treated with ASD+SM and show significant (P value<0.01) compared to other groups. BNP significantly declines in HF+ASD+SM group animals compared with other treatment groups. Masson's Trichrome staining was used to study histopathology of cardiac myocytes and quantification of fibrosis was assessed. The large blue fibrotic area was observed in HF, HF+ASD, and HF+SM (IV) groups while HF+ASD+SM showed negligible fibrotic myocyte at the end of study period (30days). This study proves that novel ASD device augments the therapeutic effect of the drug and delivers Salvia miltiorrhiza to the cardiomyocytes significantly as well as provides additional support to the dilated ventricle by the heart failure. PMID- 28886531 TI - Long non-coding RNA HOTTIP promotes hypoxia-induced epithelial-mesenchymal transition of malignant glioma by regulating the miR-101/ZEB1 axis. AB - Hypoxia is a universal characteristic of solid tumor and involving cancer metastasis via epithelial-mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) are known to regulate carcinogenesis and metastasis of various cancers. The aim of this study was to identify the function role of lncRNAs in the hypoxia induced EMT of malignant glioma. We used U87 and U251 cell lines were treated under hypoxia to induce EMT, then lncRNA microarray analyse was performed between U87-hypoxia and parental cell line. The relative expression of lncRNA and HIF 1alpha were detected by qRT-PCR between glioma tissues without metastasis and that with metastasis. Hypoxia could induce EMT and increase HOTTIP expression in glioma cells. Among the different expressions of lncRNAs, HOTTIP was the most upregulated lncRNA in glioma cells treated by hypoxia. High levels of HOTTIP and HIF-1alpha were correlated with glioma metastasis and poor patient prognosis. Knockdown of HIF-1alpha and HOTTIP blocked hypoxia-induced EMT, and suppressed invasion and migration of glioma cells. Finally, HOTTIP sponged endogenous miR 101 and inhibited its activity, which resulted in increased ZEB1 expression and promoted process of EMT. HIF-1alpha/HOTTIP/miR-101/ZEB1 axis plays essential role in hypoxia-induced EMT and metastasis of glioma, and HOTTIP may serve as a therapeutic target to reverse EMT and prevent glioma progression. PMID- 28886532 TI - Chemical characterization and sources of personal exposure to fine particulate matter (PM2.5) in the megacity of Guangzhou, China. AB - Concurrent ambient and personal measurements of fine particulate matter (PM2.5) were conducted in eight districts of Guangzhou during the winter of 2011. Personal-to-ambient (P-C) relationships of PM2.5 chemical components were determined and sources of personal PM2.5 exposures were evaluated using principal component analysis and a mixed-effects model. Water-soluble inorganic ions (e.g., SO42-, NO3-, NH4+, C2O42-) and anhydrosugars (e.g., levoglucosan, mannosan) exhibited median personal-to-ambient (P/C) ratios < 1 accompanied by strong P-C correlations, indicating that these constituents in personal PM2.5 were significantly affected by ambient sources. Conversely, elemental carbon (EC) and calcium (Ca2+) showed median P/C ratios greater than unity, illustrating significant impact of local traffic, indoor sources, and/or personal activities on individual's exposure. SO42- displayed very low coefficient of divergence (COD) values coupled with strong P-C correlations, implying a uniform distribution of SO42- in the urban area of Guangzhou. EC, Ca2+, and levoglucosan were otherwise heterogeneously distributed across individuals in different districts. Regional air pollution (50.4 +/- 0.9%), traffic-related particles (8.6 +/- 0.7%), dust-related particles (5.8 +/- 0.7%), and biomass burning emissions (2.0 +/- 0.2%) were moderate to high positive sources of personal PM2.5 exposure in Guangzhou. The observed positive and significant contribution of Ca2+ to personal PM2.5 exposure, highlighting indoor sources and/or personal activities, were driving factors determining personal exposure to dust-related particles. Considerable discrepancies (COD values ranging from 0.42 to 0.50) were shown between ambient concentrations and personal exposures, indicating caution should be taken when using ambient concentrations as proxies for personal exposures in epidemiological studies. PMID- 28886533 TI - Artificial light at night affects sleep behaviour differently in two closely related songbird species. AB - Artificial light at night (ALAN) or light pollution is an increasing and worldwide problem. There is growing concern that because of the disruption of natural light cycles, ALAN may pose serious risks for wildlife. While ALAN has been shown to affect many aspects of animal behaviour and physiology, few studies have experimentally studied whether individuals of different species in the wild respond differently to ALAN. Here, we investigated the effect of ALAN on sleep behaviour in two closely related songbird species inhabiting the same study area and roosting/breeding in similar nest boxes. We experimentally exposed free living great tits (Parus major) and blue tits (Cyanistes caeruleus) to artificial light inside their nest boxes and observed changes in their sleep behaviour compared to the previous night when the nest boxes were dark. In line with previous studies, sleep behaviour of both species did not differ under dark conditions. ALAN disrupted sleep in both great and blue tits. However, compared to blue tits, great tits showed more pronounced effects and more aspects of sleep were affected. Light exposed great tits entered the nest boxes and fell asleep later, woke up and exited the nest boxes earlier, and the total sleep amount and sleep percentage were reduced. By contrast, these changes in sleep behaviour were not found in light exposed blue tits. Our field experiment, using exactly the same light manipulation in both species, provides direct evidence that two closely related species respond differently to ALAN, while their sleep behaviour under dark conditions was similar. Our research suggests that findings for one species cannot necessarily be generalised to other species, even closely-related species. Furthermore, species-specific effects could have implications for community dynamics. PMID- 28886534 TI - Distribution of lead and mercury in Ontario peatlands. AB - While considerable attention has been given to the measurement of mercury (Hg) and lead (Pb) concentrations and accumulation in detailed peat cores in central Canada, the geographic distribution and density of sampling are generally limited. Here, we use the Ontario Peatland Inventory to examine broad patterns of Hg and Pb concentration with depth, based on 338 peat cores (containing >1500 analyzed samples) from 127 bogs, fens and swamps located in southeastern, northeastern and northwestern sections of Ontario. Overall, Hg concentrations averaged 0.05 MUg g-1 and that of Pb averaged 10.8 MUg g-1. Maximum values in the top 50 cm of the profiles are 0.08 MUg g-1 and 26.2 MUg g-1 for Hg and Pb, respectively. The ratio between these values (surface) and the values from below 100 cm (background), where peat likely accumulated before 1850 and industrial activities were limited, are 2.3 and 6.6 for Hg and Pb, respectively. The highest surface:background concentration ratios are generally found in the westernmost part of the province and in the southeast for Hg and around areas that are more heavily populated for Pb. Our results show that a vast amount of Hg and Pb are stored in Ontarian peatlands, although the spatial distribution of these stores varies. The rapid decomposition of peat in a changing climate could release these pollutants to the atmosphere. PMID- 28886535 TI - Groundwater assessment and environmental impact in the abandoned mine of Kettara (Morocco). AB - Many questions about the soil pollution due to mining activities have been analyzed by numerous methods which help to evaluate the dispersion of the Metallic Trace Elements (MTE) in the soil and stream sediments of the abandoned mine of Kettara (Morocco). The transport of these MTE could have an important role in the degradation of groundwater and the health of people who are living in the vicinity. The present paper aims to evaluate the groundwater samples from 15 hydrogeological wells. This evaluation concerns the hydrogeological parameters, pH, Electrical conductivity, temperature and the groundwater level, and the geochemical assessment of Mg, Ca, Ti, Cr, Mn, Fe, Co, Ni, Zn, Cu, As, Se, Cd, Sb, Tl and Pb. Furthermore, the Metallic Trace Elements are transported in the saturated zone via the fractures network. The groundwater flow is from the north east to south-west. The spatial distribution of As, Fe, Zn and Mn is very heterogeneous, with high values observed in the north, upstream, of the mine site. This distribution is maybe related to: i) the existence of hydrogeological structures (dividing and drainage axes); ii) the individualization of the fractures network that affects the shaly lithostratigraphical formation; iii) the transport of the contaminants from the soil towards groundwater; and iv) interaction water/rocks. Some MTE anomalies are linked to the lithology and the fracturation system of the area. Therefore, the groundwater contamination by Arsenic is detected in the hydrogeological wells (E1 and E2). This pollution which is higher than guideline standards of Moroccan drinking water could affect the public health. The hydrogeological and geochemical investigations favor the geological origin (mafic rocks) of this contamination rather than mining activities. PMID- 28886536 TI - Response of soil microbial communities and microbial interactions to long-term heavy metal contamination. AB - Due to the persistence of metals in the ecosystem and their threat to all living organisms, effects of heavy metal on soil microbial communities were widely studied. However, little was known about the interactions among microorganisms in heavy metal-contaminated soils. In the present study, microbial communities in Non (CON), moderately (CL) and severely (CH) contaminated soils were investigated through high-throughput Illumina sequencing of 16s rRNA gene amplicons, and networks were constructed to show the interactions among microbes. Results showed that the microbial community composition was significantly, while the microbial diversity was not significantly affected by heavy metal contamination. Bacteria showed various response to heavy metals. Bacteria that positively correlated with Cd, e.g. Acidobacteria_Gp and Proteobacteria_thiobacillus, had more links between nodes and more positive interactions among microbes in CL- and CH-networks, while bacteria that negatively correlated with Cd, e.g. Longilinea, Gp2 and Gp4 had fewer network links and more negative interactions in CL and CH-networks. Unlike bacteria, members of the archaeal domain, i.e. phyla Crenarchaeota and Euryarchaeota, class Thermoprotei and order Thermoplasmatales showed only positive correlation with Cd and had more network interactions in CH-networks. The present study indicated that (i) the microbial community composition, as well as network interactions was shift to strengthen adaptability of microorganisms to heavy metal contamination, (ii) archaea were resistant to heavy metal contamination and may contribute to the adaption to heavy metals. It was proposed that the contribution might be achieved either by improving environment conditions or by cooperative interactions. PMID- 28886537 TI - A probabilistic approach to assess antibiotic resistance development risks in environmental compartments and its application to an intensive aquaculture production scenario. AB - Estimating antibiotic pollution and antibiotic resistance development risks in environmental compartments is important to design management strategies that advance our stewardship of antibiotics. In this study we propose a modelling approach to estimate the risk of antibiotic resistance development in environmental compartments and demonstrate its application in aquaculture production systems. We modelled exposure concentrations for 12 antibiotics used in Vietnamese Pangasius catfish production using the ERA-AQUA model. Minimum selective concentration (MSC) distributions that characterize the selective pressure of antibiotics on bacterial communities were derived from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) Minimum Inhibitory Concentration dataset. The antibiotic resistance development risk (RDR) for each antibiotic was calculated as the probability that the antibiotic exposure distribution exceeds the MSC distribution representing the bacterial community. RDRs in pond sediments were nearly 100% for all antibiotics. Median RDR values in pond water were high for the majority of the antibiotics, with rifampicin, levofloxacin and ampicillin having highest values. In the effluent mixing area, RDRs were low for most antibiotics, with the exception of amoxicillin, ampicillin and trimethoprim, which presented moderate risks, and rifampicin and levofloxacin, which presented high risks. The RDR provides an efficient means to benchmark multiple antibiotics and treatment regimes in the initial phase of a risk assessment with regards to their potential to develop resistance in different environmental compartments, and can be used to derive resistance threshold concentrations. PMID- 28886538 TI - Groundwater vulnerability to climate change: A review of the assessment methodology. AB - Impacts of climate change on water resources, especially groundwater, can no longer be hidden. These impacts are further exacerbated under the integrated influence of climate variability, climate change and anthropogenic activities. The degree of impact varies according to geographical location and other factors leading systems and regions towards different levels of vulnerability. In the recent past, several attempts have been made in various regions across the globe to quantify the impacts and consequences of climate and non-climate factors in terms of vulnerability to groundwater resources. Firstly, this paper provides a structured review of the available literature, aiming to critically analyse and highlight the limitations and knowledge gaps involved in vulnerability (of groundwater to climate change) assessment methodologies. The effects of indicator choice and the importance of including composite indicators are then emphasised. A new integrated approach for the assessment of groundwater vulnerability to climate change is proposed to successfully address those limitations. This review concludes that the choice of indicator has a significant role in defining the reliability of computed results. The effect of an individual indicator is also apparent but the consideration of a combination (variety) of indicators may give more realistic results. Therefore, in future, depending upon the local conditions and scale of the study, indicators from various groups should be chosen. Furthermore, there are various assumptions involved in previous methodologies, which limit their scope by introducing uncertainty in the calculated results. These limitations can be overcome by implementing the proposed approach. PMID- 28886539 TI - Exposure to lead and mercury through breastfeeding during the first month of life: A CHECK cohort study. AB - Mercury and lead are naturally occurring toxicants and are responsible for various health issues including neurobehavioral and developmental disorders. Because of crucial synchronized developmental processes occurring at the early stage of life, infancy and childhood are considered as among the most susceptible windows to the exposure to these metals. Breastmilk is often the only source of nutrition during the first months of life. As breastmilk can be contaminated with these metals, breastfeeding may serve as a significant route of heavy metal exposure among infants. In order to understand current levels of exposure to mercury and lead through breastfeeding, and their associated risks, a total of 157 lactating mothers were recruited from Children's Health and Environmental Chemicals of Korea (CHECK) cohort, and breastmilk samples were collected at 15 and 30days after delivery (n=207). Mercury was detected from 100% of breastmilk with a median concentration of 0.59MUg/L, and lead was detected in 77% of the samples with a median at 4.71MUg/L. Higher concentrations of lead were found in the 30- day breastmilk than in the 15-day. Up to 45% of the breastmilk samples exceeded the normal range of the breastmilk lead suggested by WHO. Based on Monte Carlo simulation, about 71% of 15days old infants and 56% of 30days old infants were estimated at risk due to lead exposure through breastfeeding. Considering vulnerability of infants and well-known neurological toxicity of these metals, further studies to identify major exposure sources that contribute the lead concentration in breastmilk and health implication of early life stage exposure to lead among the breastfed infants are warranted. PMID- 28886540 TI - Paddy soil microbial communities driven by environment- and microbe-microbe interactions: A case study of elevation-resolved microbial communities in a rice terrace. AB - : Rice paddies are a significant source of the greenhouse gas methane, which mainly originates from microbial activity. Methane generation in anaerobic systems involves complex interactions of multiple functional microbial groups. Rice paddies installed in hilly terrain are often terraced, providing multiple quasi-independent plots differing primarily in their elevation up a hillside. This represents an excellent study site to explore the influence of environmental factors on microbial communities and interactions among microbial populations. In this study, we used a combination of geochemical analyses, high-throughput amplicon sequencing, and statistical methods to elucidate these interactions. Sulfate, total nitrogen, total iron, and total organic carbon were determined to be critical factors in steering the ecosystem composition and function. Sulfate reducing bacteria predominated in the rice terrace microbial communities, and Fe(III)-reducing and methane-oxidizing bacteria were abundant as well. Biotic interactions indicated by co-occurrence network analysis suggest mutualistic interactions among these three functional groups. Paddy-scale methane production may be affected by competition among methanogens and sulfate- and Fe(III) reducing bacteria, or by direct methane oxidation by methane-oxidizing bacteria. CAPSULE: Microbial communities were characterized in rice terrace. The environment- and microbe-microbe interactions indicated the mitigation of sulfate and Fe on methane production. PMID- 28886541 TI - Abiotic control of phytoplankton blooms in temperate coastal marine ecosystems: A case study in the South Atlantic Ocean. AB - Coastal waters of the South Atlantic Ocean (SAO) sustain one of the highest levels of production of the World's ocean, maintained by dense phytoplankton winter blooms that are dominated by large diatoms. These blooms have been associated to calm weather conditions that allow the formation of a shallow and well illuminated upper mixed layer. In Bahia Engano, a coastal site in Patagonia, Argentina (chosen as a model coastal ecosystem) winter blooms recurrently peaked on June and they were dominated almost entirely by the microplanktonic diatom Odontella aurita. However, during the year 2015, a new wind pattern was observed with many days of northerly high-speed winds, deviating from the calm winter days observed during a reference period (2001-2014) used for comparison. We determined that this new wind pattern was the most important factor that affected the phytoplankton dynamics, precluding the initiation of a June bloom during 2015 that instead occurred during late winter (August). Furthermore, the 2015 bloom had a higher proportion of nanoplanktonic cells (as compared to the reference period) and it was co-dominated by O. aurita and Thalassiossira spp. Other variables such as nutrient supply and incident solar radiation did not have an important role in limiting and/or initiating the June 2015 bloom, but temperature might have benefited the growth of small cells during August 2015. If these changes in the timing and/or the taxonomic composition of the bloom persist, they may have important consequences for the secondary production and economic services of the coastal SAO. PMID- 28886542 TI - Enhanced bioremediation of nutrient-amended, petroleum hydrocarbon-contaminated soils over a cold-climate winter: The rate and extent of hydrocarbon biodegradation and microbial response in a pilot-scale biopile subjected to natural seasonal freeze-thaw temperatures. AB - A pilot-scale biopile field experiment for nutrient-amended petroleum contaminated fine-grained soils was performed over the winter at a cold-climate site. The rate and extent of hydrocarbon biodegradation and microbial responses were determined and corresponded to the on-site soil phase changes (from unfrozen to partially frozen, deeply frozen, and thawed) associated with natural seasonal freeze-thaw conditions. Treated and untreated biopiles were constructed (~3500kg each) on an open outdoor surface at a remediation facility in Saskatoon, Canada. The treated biopile received N-P-K-based nutrient and humate amendments before seasonal freezing. Real-time field monitoring indicated significant unfrozen water content in the treated and untreated biopiles throughout the freezing period, from the middle of November to early March. Unfrozen water was slightly more available in the treated biopile due to the aqueous nutrient supply. Soil CO2 production and O2 consumption in the treated biopile were generally greater than in the untreated biopile. Total removal percentages for F2 (>C10-C16), F3 (>C16-C34), and total petroleum hydrocarbons (TPH) in the treated biopile were 57, 58, and 58%, respectively, of which 26, 39, and 33% were removed during seasonal freezing and early thawing between November to early March. F3 degradation largely occurred during freezing while F2 hydrocarbons were primarily removed during thawing. Biomarker-based hydrocarbon analyses confirmed enhanced biodegradation in the treated biopile during freezing. The soil treatment increased the first-order rate constants for F2, F3, and TPH degradation by a factor of 2 to 7 compared to the untreated biopile. Shifts in bacterial community appeared in both biopiles as the biopile soils seasonally froze and thawed. Increased alkB1 gene copy numbers in the treated biopile, especially in the partially thawed phase during early thawing, suggest extended hydrocarbon biodegradation to the seasonal freeze-thaw season, due to the nutrients supplied prior to seasonal freezing. PMID- 28886543 TI - Assessing river water quality using water quality index in Lake Taihu Basin, China. AB - Lake Taihu Basin, one of the most developed regions in China, has received considerable attention due to its severe pollution. Our study provides a clear understanding of the water quality in the rivers of Lake Taihu Basin based on basin-scale monitoring and a water quality index (WQI) method. From September 2014 to January 2016, four samplings across four seasons were conducted at 96 sites along main rivers. Fifteen parameters, including water temperature, pH, dissolved oxygen (DO), conductivity, turbidity (tur), permanganate index (CODMn), total nitrogen, total phosphorus, ammonium (NH4-N), nitrite, nitrate (NO3-N), calcium, magnesium, chloride, and sulfate, were measured to calculate the WQI. The average WQI value during our study period was 59.33; consequently, the water quality was considered as generally "moderate". Significant differences in WQI values were detected among the 6 river systems, with better water quality in the Tiaoxi and Nanhe systems. The water quality presented distinct seasonal variation, with the highest WQI values in autumn, followed by spring and summer, and the lowest values in winter. The minimum WQI (WQImin), which was developed based on a stepwise linear regression analysis, consisted of five parameters: NH4 N, CODMn, NO3-N, DO, and tur. The model exhibited excellent performance in representing the water quality in Lake Taihu Basin, especially when weights were fully considered. Our results are beneficial for water quality management and could be used for rapid and low-cost water quality evaluation in Lake Taihu Basin. Additionally, we suggest that weights of environmental parameters should be fully considered in water quality assessments when using the WQImin method. PMID- 28886544 TI - A new method for deriving trace gas emission inventories from satellite observations: The case of SO2 over China. AB - A method is developed that allows the construction of spatial emission inventories. The method is applied for anthropogenic SO2 over China (0.25 degrees *0.25 degrees ). The Enhancement Ratio Method (ERM) allows for the calculation of SO2 emissions using relationships between gridded satellite measurements of SO2 and NO2 at low wind speeds, and satellite-based NOx emission estimates. Here, we derive SO2 emissions for five years (2007-2011). A large decrease of emissions during 2007-2009 and a modest increase between 2010 and 2011 is observed. The evolution of emissions over time calculated here is in general agreement with bottom-up inventories, although differences exist, not only between the current inventory and other inventories but also among the bottom up inventories themselves. The ERM-derived emissions are consistent, spatially and temporally, with existing inventories. PMID- 28886545 TI - Occurrence and distribution of marine natural organic pollutants: Lipophilic marine algal toxins in the Yellow Sea and the Bohai Sea, China. AB - For the first time, the composition, concentration and distribution characteristics of typical lipophilic marine algal toxins (LMATs) are investigated in surface seawater, suspended particulate matter (SPM) and sediments from the Yellow Sea and the Bohai Sea, China. Pectenotoxin-2 (PTX2) and okadaic acid (OA) were detected in offshore surface seawater samples (n=67) of the Yellow and Bohai Seas, and PTX2 was found in higher concentrations than OA. The concentrations of PTX2 were between 0.49 and 14.14ng/L. OA, dinophysistoxin 1(DTX1), PTX2 and gymnodimine (GYM) were detected in the nearshore surface seawater samples (n=20) of the Haizhou Bay of the Yellow Sea. OA concentrations were between 11.47 and 55.85ng/L. There was a large degree of variation in the concentrations of DTX1, from 90%) for all techniques used, although only thermal treatment on BTEX (Benzene, Toluene, Ethylbenzene and Xylenes) reached 100% efficiency. The main limiting factors of each technique were: (i) for oxidation, the solubility of the substance limited the removal; (ii) for surfactant both the solubility in the surfactant and the type of surfactant are important; (iii) for sparging, the main factors are contaminant vapor pressure and porous media grain size; (iv) for thermal treatment, the limitation arises from the contaminant vapor pressure and the medium hydraulic conductivity. A comparison with literature data shows that the results are consistent with most of the studies conducted on one technique. PMID- 28886553 TI - An impact of moss sample cleaning on uncertainty of analytical measurement and pattern profiles of rare earth elements. AB - The main source of rare earth elements (REE) in mosses is atmospheric deposition of particles. Sample treatment operations including shaking, rinsing or washing, which are made in a standard way on moss samples prior to chemical analysis, may lead to removing particles adsorbed onto their tissues. This in turn causes differences in REE concentrations in treated and untreated samples. For the present study, 27 combined moss samples were collected within three wooded areas and prepared for REE determinations by ICP-MS using both manual cleaning by shaking and triple rinsing with deionized water. Higher concentrations of REE were found in manually cleaned samples. The comparison of REE signatures and shale-normalized REE concentration patterns showed that the treatment procedure did not lead to fractionation of REE. All the samples were enriched in medium rare earth elements, and the deltaMREE factor remained practically unchanged after rinsing. Positive anomalies of Nd, Sm, Eu, Gd, Er and Yb were observed in both, manually cleaned and rinsed samples. For all the elements examined, analytical uncertainty was below 3.0% whereas sample preparation uncertainty computed with ANOVA, RANOVA, modified RANOVA and range statistics methods varied from 3.5 to 29.7%. In most cases the lowest srprep values were obtained with the modified RANOVA method. PMID- 28886554 TI - Dependence of toxicity of silver nanoparticles on Pseudomonas putida biofilm structure. AB - Susceptibility of biofilms with different physical structures to silver nanoparticles (AgNPs) was studied. Biofilms of Pseudomonas putida KT2440 were formed in batch conditions under different carbon sources (glucose, glutamic acid, and citrate), glucose concentrations (5 and 50 mM), and incubation temperatures (25 and 30 degrees C). The biofilms were observed using confocal laser scanning microscopy for their physical characteristics (biomass amount, thickness, biomass volume, surface to volume ratio, and roughness coefficient). The biofilms forming under different growth conditions exhibited different physical structures. The biofilm thickness and the roughness coefficient were found negatively and positively correlated with the biofilm susceptibility to AgNPs, respectively. The effect of AgNPs on biofilms was low (1-log reduction of cell number) when the biofilms had high biomass amount, high thickness, high biomass volume, low surface to volume ratio, and low roughness coefficient. Furthermore, the extracellular polymeric substance (EPS) stripping process was applied to confirm the dependence of susceptibility to AgNPs on the structure of biofilm. After the EPS stripping process, the biofilms forming under different conditions showed reduction in thickness and biomass volume, and increases in surface to volume ratio and roughness coefficient, which led to more biofilm susceptibility to AgNPs. The results of this study suggest that controlling the growth conditions to alter the biofilm physical structure is a possible approach to reduce the impact of AgNPs on biofilms in engineered and natural systems. PMID- 28886555 TI - Effects of Fe(III) and quality of humic substances on As(V) distribution in freshwater: Use of ultrafiltration and Kohonen neural network. AB - Humic substances (HS) are ubiquitous organic compounds able to affect mobility and availability of arsenic (As) in aquatic systems. Although it is known that associations between HS and As occur mainly via iron (Fe)-cationic bridges, the behaviour and distribution of this metalloid in HS- and Fe-rich environments is still not fully understood. In this paper, the quality of HS from different rivers in Brazil and Germany and its influence on the behaviour of As(V) under different Fe(III) concentrations were investigated. HS were extracted from four different rivers (Cascatinha, Holtemme, Selke and Warme Bode), characterised and fractionated into different molecular weight sizes (10, 5 and 1 kDa). Complexation tests were performed using an ultrafiltration system and 1 kDa membranes. All data was analysed using the Kohonen neural network (SOM - Self organising maps). All samples, except Selke, exhibited similar results of free As (<1 kDa). The results suggested that associations between HS, Fe and As were dependent on nitrogen (N)-aromatic carbon (C), amount of sulphur (S) and the molecular size of the HS. Although all HS appeared to be similar after looking at most variables analysed, the SOM could discriminate them into three different groups. Characterisation of the HS indicated that they had terrestrial material (from C3 plants) as precursor material. Most of the As and Fe was distributed in the fractions of higher (>10 kDa) and lower (<1 kDa) size. HS quality is an important factor to take into account when studying the behaviour of As in HS rich environments. PMID- 28886556 TI - Developing an integrated 3D-hydrodynamic and emerging contaminant model for assessing water quality in a Yangtze Estuary Reservoir. AB - An integrated 3D-hydrodynamic and emerging contaminant model was developed for better understanding of the fate and transport of emerging contaminants in Qingcaosha Reservoir. The reservoir, which supplies drinking water for nearly half of Shanghai's population, is located in Yangtze Delta. The integrated model was built by Delft3D suite, a fully integrated multidimensional modeling software. Atrazine and Bisphenol A (BPA) were selected as two representative emerging contaminants for the study in this reservoir. The hydrodynamic model was calibrated and validated against observations from 2011 to 2015 while the integrated model was calibrated against observations from 2014 to 2015 and then applied to explore the potential risk of high atrazine concentrations in the reservoir driven by agriculture activities. Our results show that the model is capable of describing the spatial and temporal patterns of water temperature, salinity and the dynamic distributions of two representative emerging contaminants (i.e. atrazine and BPA) in the reservoir. The physical and biodegradation processes in this study were found to play a crucial role in determining the fate and transport of atrazine and BPA in the reservoir. The model also provides an insight into the potential risk of emerging contaminants and possible mitigation thresholds. The integrated approach can be a very useful tool to support policy-makers in the future management of Qingcaosha Reservoir. PMID- 28886557 TI - The phytoremediation potential of Plectranthus neochilus on 2,4 dichlorophenoxyacetic acid and the role of antioxidant capacity in herbicide tolerance. AB - The possible phytoremediation capacity of Plectranthus neochilus (boldo) exposed to the commercial pesticide (Aminol) in soil and water through consecutive extractions (days interval) was evaluated. After the exposure period, tea leaves from the plant were analyzed in terms of the presence of 2,4-D, total antioxidant capacity (DPPH), concentration of total polyphenols and flavonoids for plants exposed to soil and water. In water, 2,4-D remained up to 67% in the 60 days of experiment in the control group, which provided the use of two treatment groups with the plant (one group of plants for 30 days and another group in the remaining 30 days in the same system), thus, a decontamination up to 49% of the 2,4-D was obtained in this system with water. In both experiments (soil and water) the 2,4-D was not detected in tea leaves, the reduction of the antioxidant activity, polyphenols and flavonoids of plants exposed to the herbicide was also observed when compared to the non-exposed plants. In tea - plants in water - it was also possible to quantify the phenolic compounds and it was observed that in the group of plants of the first 30 days there was a decrease in caffeic acid and an increase in coumaric and ferulic acids, compared to the group of plants that were not exposed to 2,4-D. In the remaining 30 days with the new seedlings there was a decrease of the coumaric acid and an increase of the caffeic and ferulic acids. PMID- 28886558 TI - Glyphosate and AMPA passive sampling in freshwater using a microporous polyethylene diffusion sampler. AB - Glyphosate (PMG) is one of the most widely used herbicides with a reported 8.6 million tons applied globally in 2016. Due to widespread use and limited understanding of long-term environmental impacts, it is expected that future monitoring requirements for PMG and its primary metabolite aminomethyl phosphonic acid (AMPA) in aquatic environments will increase, along with the need for low cost monitoring and risk assessment strategies. The aim of this study was to investigate a microporous polyethylene tube (MPT; 2-mm thickness, 17.6 cm2 surface area, 35% porosity, 2.5 MUm pore size) as a diffusive layer for the passive sampling of PMG and AMPA. Levels of PMG and AMPA sorbed to MPT were low (Kmw close to 1 mL g-1), validating MPT as a diffusive layer. Uptake experiments were conducted first under controlled laboratory conditions (pH = 6.8, 6 days), followed by an in situ freshwater lake system deployment (pH = 7.3, 11 days). PMG and AMPA accumulated linearly (slope relative standard deviation < 6%) under laboratory conditions with sampling rates (Rs) of 18 and 25 mL d-1, respectively. PMG in situ Rs was 28 mL d-1, and was not different from the one found in the laboratory. AMPA was below the limit of quantification (LOQ, 1 ng mL-1) in grab water samples, but was detected (>LOQ) in all passive samplers. Results illustrate the gain in sensitivity provided by the passive sampling technique, and the applicability of the device developed for the passive sampling of PMG and AMPA. PMID- 28886559 TI - Sewage treatment effluents in Delhi: A key contributor of beta-lactam resistant bacteria and genes to the environment. AB - Rapid emergence of antibiotic resistance (AR) in developing countries is posing a greater health risk and increasing the global disease burden. Lack of access to safe drinking water, poor sanitation and inadequate sewage treatment facilities in these countries are fueling the problem associated with emergence of AR. Rapid proliferation of AR mediated by treated and untreated discharges from sewage treatment plants (STPs) is a prime public health concern. This study aims to understand the occurrence, fate, and routes of proliferation of carbapenem (KPC) and extended spectrum beta-lactam (ESBL) resistant bacteria, and selected resistant genes in the samples collected from different unit operations in 12 STPs in New Delhi over two seasons. Strong correlation observed between faecal coliform levels and KPC (R = 0.95, p = 0.005, n = 60) and ESBL (R = 0.94, p = 0.004, n = 60) resistant bacteria levels indicates possible association of resistant bacteria with faecal matter. Different unit operations in STPs proved inefficient in treating resistant bacteria and genes present in the wastewater. However, inclusion of tertiary treatment (chlorination) unit and anaerobic digester in the present STPs resulted in better removal of AR. Significant correlations between antibiotic resistant genes (ARGs) and integron levels indicates a potential for higher rate of AR proliferation in the environment. Microbial culturing indicated the presence of clinically significant drug resistant pathogens such as Escherichia coli, Pseudomonas putida, Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella oxytoca, Acinetobacter baumannii, Shigella dysentery and Aeromonas caviae in the STP effluents. The emergence and spread of resistant bacteria through STP effluents poses exposure risk for the residents of the city. PMID- 28886560 TI - Occurrence of nitrogenous and carbonaceous disinfection byproducts in drinking water distributed in Shenzhen, China. AB - A 12-month sampling program was conducted throughout a drinking water distribution system in Shenzhen and the data from 251 samples provide a comprehensive picture of the spatial and seasonal variability of 17 species disinfection by-products (DBPs) in a city with subtropical monsoon climate. The carbonaceous disinfection by-product (C-DBPs) included four trihalomethanes (THMs), three trihaloacetaldehydes (THAs) and two haloketones (HKs). Their median concentrations over the entire period were 19.9 MUg/L, 3.4 MUg/L and 1.4 MUg/L, respectively. The nitrogenous DBPs (N-DBPs) monitored were four haloacetonitriles (HANs) and four haloacetamides (HAcAms). Their median levels were 2.0 MUg/L and 1.5 MUg/L, respectively. Low levels of brominated DBP species (bromine substitution factors <= 0.5) were observed. The BSF of each DBP class followed the trend: THMs ~ DHAcAms > DHANs > THAs. All the DBP concentrations showed clear seasonal variations with the highest average concentrations in spring. Correlation analyses showed that the THMs and CH levels in Shenzhen drinking water could be used as statistical indicators of the levels of unregulated N-DBPs (0.4 < r < 0.7, p < 0.5). The results supplement the database of DBP occurrence in drinking water in China, and provide an important reference data set for DBP occurrence in cities with a subtropical monsoon climate around the world. PMID- 28886561 TI - Zinc protects against cadmium-induced toxicity by regulating oxidative stress, ions homeostasis and protein synthesis. AB - The widespread environmental toxin cadmium (Cd) is associated with numerous human diseases. The essential trace element zinc (Zn) strongly counteracts Cd-induced toxicity; however, the mechanism is incompletely understood. Here, we conducted RNA sequencing and bioinformatics analyses to determine the global gene expression profiles of yeast cells exposed to Cd or Cd plus Zn. We identified 912 Cd-induced and 627 Cd plus Zn-induced differentially expressed genes (DEGs). Adding Zn during Cd exposure efficiently reversed the expression of 92.1% of Cd induced DEGs; that of 48.7% was entirely reversed. Gene Ontology, Cluster of Orthologous Group and KEGG Ontology analyses revealed that the response of yeasts to Cd or Cd plus Zn was mainly involved in metal-specific oxidative stress; energy production and conversion; ion homeostasis and ribosome biogenesis and translation. Exposure of yeasts to Cd plus Zn protected them from oxidative stress by efficiently inhibiting the expression of genes associated with Cd triggered oxidative stress and preventing the disruption of Fe- and Zn-ion homeostasis and reduced glutathione and partially restored mitochondrial membrane potential. Moreover, Zn reduced the intracellular level of Cd to prevent the replacement by Cd of elements required for antioxidant enzyme activity and to protect protein sulphydryl groups against oxidation by free radicals. Further, Zn inhibited the synthesis alterations of Cd-induced ribosomal proteins, S containing amino acids, S-rich proteins and antioxidant enzymes. Conversely, the investigation results of our study on the yeast model revealed that the Cd treated protective effects of Zn on Cd-induced toxicity might be partially protective. PMID- 28886562 TI - Support of supervised injection facilities by emergency physicians in Canada. AB - BACKGROUND: Despite evidence supporting the implementation of supervised injection facilities (SIFs) by multiple stakeholders, no evaluation of emergency physicians' attitudes has ever been documented towards such facilities in Canada or internationally. The primary goal of our study was to determine the opinions and perceptions of emergency physicians regarding the implementation of SIFs in Canada. METHODS: We conducted a national electronic survey of staff and resident emergency physicians in Canada using an iteratively designed survey tool in consultation with content experts. Invitations to complete the survey were sent via email by the Canadian Association of Emergency Physicians. Inclusion criteria required respondents to have treated an adult patient in a Canadian emergency department within the preceding 6 months. The primary measure was the proportion of respondents who would support, not support or were unsure of supporting SIFs in their community with the secondary measure being the likelihood of respondents to refer patients to a SIF if available. RESULTS: We received 280 responses out of 1353 eligible physicians (20.7%), with the analysis conducted on 250 responses that met inclusion criteria (18.5%). The majority of respondents stated they would support the implementation of SIFs in their community (N=172; 74.5%) while 10.8% (N=25) would not and 14.7% (N=34) did not know. The majority of respondents said they would refer their patients to SIFs (N=198; 84.6%), with 4.3% (N=10) who would not and 11.1% (N=26) who were unsure. CONCLUSION: The findings from our study demonstrate that the majority of emergency physician respondents in Canada support the implementation of such sites (74.5%) while 84.6% of respondents would refer patients from the emergency department to such sites if they did exist. Given that many Canadian cities are actively pursuing the creation of SIFs or imminently opening such sites, it appears that our sample population of emergency physicians would both support this approach and would utilize such facilities in an effort to improve patient-centered outcomes for this often marginalized population. PMID- 28886563 TI - Prenatal anxiety effects: A review. AB - This review is based on literature on prenatal anxiety effects that was found on Pubmed and PsycINFO for the years 2010-2016. Prenatal anxiety is thought to have distinct features, although it has been measured both by specific prenatal anxiety symptoms as well as by standardized anxiety scales. Its prevalence has ranged from 21 to 25% and it has been predicted by a number of pregnancy - related variables such as unintended pregnancy, demographic variables such as low acculturation and income and psychosocial factors including pessimism and partner tension. Prenatal anxiety effects on pregnancy include increased cortisol levels, pro-inflammatory cytokines, obstetric problems and cesarean section. Effects on the neonate include lower gestational age, prematurity, less insulin-like growth factor in cord blood, less exclusive breast-feeding and less self-regulation during the heelstick procedure. Prenatal anxiety effects continue into infancy and childhood both on physiological development and emotional/mental development. Among the physiological effects are lower vagal activity across the first two years, and lower immunity, more illnesses and reduced gray matter in childhood. Prenatal anxiety effects on emotional/mental development include greater negative emotionality and in infants, lower mental development scores and internalizing problems. Anxiety disorders occur during childhood and elevated cortisol and internalizing behaviors occur during adolescence. Interventions for prenatal anxiety are virtually nonexistent, although stroking (massaging) the infant has moderated the pregnancy - specific anxiety effects on internalizing behaviors in the offspring. The limitations of this literature include the homogeneity of samples, the frequent use of anxiety measures that are not specific to pregnancy, and the reliance on self-report. Nonetheless, the literature highlights the negative, long-term effects of prenatal anxiety and the need for screening and early interventions. PMID- 28886564 TI - Efficient photodecomposition of herbicide imazapyr over mesoporous Ga2O3-TiO2 nanocomposites. AB - The unabated release of herbicide imazapyr into the soil and groundwater led to crop destruction and several pollution-related concerns. In this contribution, heterogeneous photocatalytic technique was employed utilizing mesoporous Ga2O3 TiO2 nanocomposites for degrading imazapyr herbicide as a model pollutant molecule. Mesoporous Ga2O3-TiO2 nanocomposites with varied Ga2O3 contents (0 5wt%) were synthesized through sol-gel process. XRD and Raman spectra exhibited extremely crystalline anatase TiO2 phase at low Ga2O3 content which gradually reduced with the increase of Ga2O3 content. TEM images display uniform TiO2 particles (10+/-2nm) with mesoporous structure. The mesoporous TiO2 exhibits large surface areas of 167m2g-1, diminished to 108m2g-1 upon 5% Ga2O3 incorporation, with tunable mesopore diameter in the range of 3-9nm. The photocatalytic efficiency of synthesized Ga2O3-TiO2 nanocomposites was assessed by degrading imazapyr herbicide and comparing with commercial photocatalyst UV 100 and mesoporous Ga2O3 under UV illumination. 0.1% Ga2O3-TiO2 nanocomposite is considered the optimum photocatalyst, which degrades 98% of imazapyr herbicide within 180min. Also, the photodegradation rate of imazapyr using 0.1% Ga2O3-TiO2 nanocomposite is nearly 10 and 3-fold higher than that of mesoporous Ga2O3 and UV 100, respectively. The high photonic efficiency and long-term stability of the mesoporous Ga2O3-TiO2 nanocomposites are ascribed to its stronger oxidative capability in comparison with either mesoporous TiO2, Ga2O3 or commercial UV-100. PMID- 28886565 TI - Size-separated particle fractions of stainless steel welding fume particles - A multi-analytical characterization focusing on surface oxide speciation and release of hexavalent chromium. AB - Welding fume of stainless steels is potentially health hazardous. The aim of this study was to investigate the manganese (Mn) and chromium (Cr) speciation of welding fume particles and their extent of metal release relevant for an inhalation scenario, as a function of particle size, welding method (manual metal arc welding, metal arc welding using an active shielding gas), different electrodes (solid wires and flux-cored wires) and shielding gases, and base alloy (austenitic AISI 304L and duplex stainless steel LDX2101). Metal release investigations were performed in phosphate buffered saline (PBS), pH 7.3, 37 degrees , 24h. The particles were characterized by means of microscopic, spectroscopic, and electroanalytical methods. Cr was predominantly released from particles of the welding fume when exposed in PBS [3-96% of the total amount of Cr, of which up to 70% as Cr(VI)], followed by Mn, nickel, and iron. Duplex stainless steel welded with a flux-cored wire generated a welding fume that released most Cr(VI). Nano-sized particles released a significantly higher amount of nickel compared with micron-sized particle fractions. The welding fume did not contain any solitary known chromate compounds, but multi-elemental highly oxidized oxide(s) (iron, Cr, and Mn, possibly bismuth and silicon). PMID- 28886566 TI - Textile dye biodecolourization and ammonium removal over nitrite in aerobic granular sludge sequencing batch reactors. AB - Biodecolourization of azo dye and removal of ammonium by aerobic granular sludge (AGS) was investigated under different growth conditions. AGS not previously exposed to azo dye was able to effectively decolourize azo dye under anaerobic and microaerophilic conditions. Azo dye, total organic carbon and ammoniacal nitrogen removal efficiencies of 89-100%, 79-95% and 92-100%, respectively, were achieved in the AGS reactor operated for 80days under microaerophilic conditions. Removal of carbon, nitrogen and phosphorus was not impacted by azo dye loading. Azo dye, organic carbon and ammonium were majorly removed in the anoxic period wherein bulk dissolved oxygen was ranged from 0.5 and <0.08mgL-1. Removal of 60mgL-1 NH4+-N was associated only with smaller amounts of nitrite build-up (~5mgL-1 NO2--N) and negligible nitrate concentrations. Profiles of nitrogen compounds in individual sequencing batch reactor cycles supported the occurrence of ammonium removal over nitrite pathway. Bacterial community analysis showed enrichment of specific microorganisms capable of decolourizing azo dyes in the dye-decolourizing AGS. Dye decolourization and nutrient removal by AGS under microaerophilic conditions is a novel finding and can be further developed for treating textile wastewaters onsite or after dilution with sewage. PMID- 28886567 TI - Expanding the application scope of on-farm biopurification systems: Effect and removal of oxytetracycline in a biomixture. AB - Antibiotic-containing wastewaters produced in agricultural activities may depress the pesticide-degrading capacity of biomixtures contained in biopurification systems. This work aimed to assay the effect of oxytetracycline (OTC) on the removal of carbofuran (CFN) in an optimized biomixture, and to determine the capacity of the system to dissipate OTC. During co-application of CFN+OTC, CFN removal and its accelerated degradation were not negatively affected. Similarly, different doses of OTC (10-500mgkg-1) did not significantly affect CFN mineralization, and the process even exhibited a hormetic-like effect. Moreover, the biomixture was able to remove OTC with a half-life of 34.0 d. DGGE-cluster analyses indicated that fungal and bacterial communities remained relatively stable during OTC application and CFN+OTC co-application, with similarities of over 70% (bacteria) and 80% (fungi). Overall, these findings support the potential use of this matrix to discard OTC-containing wastewater in this system originally intended for CFN removal. PMID- 28886568 TI - Synergistic degradation of pyrene by five culturable bacteria in a mangrove sediment-derived bacterial consortium. AB - A pyrene-degrading microbial consortium was obtained after enrichment with mangrove sediment collected from Thailand. Five cultivable bacteria (Mycobacterium spp. PO1 and PO2, Novosphingobium pentaromativorans PY1, Ochrobactrum sp. PW1, and Bacillus sp. FW1) were successfully isolated from the consortium. Draft genomes of them showed that two different morphotypes of Mycobacterium (PO1 and PO2), possessed a complete gene set for pyrene degradation. PY1 contained genes for phthalate assimilation via protocatechuate, a central intermediate, by meta-cleavage pathway, and PW1 possessed genes for protocatechuate degradation via ortho-cleavage pathway. The occurrence of biosurfactant-producing genes in FW1 suggests the involvement in enhancing the pyrene bioavailability. Biotransformation experiments revealed that Mycobacterium completely degraded 100mgL-1 pyrene within six days, whereas no significant degradation was observed with the others. Notably, PY1 and PW1 exhibited higher activity for protocatechuate degradation than the others. The artificially reconstructed consortia containing Mycobacterium with the other three strains (PY1, PW1 and FW1) showed three-fold higher degradation rate for pyrene than the individual Mycobacterium. The enhanced pyrene biodegradation achieved in the consortium was due to the cooperative interaction of bacterial mixture. Our findings showing that synergistic degradation of pyrene in the consortium will facilitate the application of the defined bacterial consortium in bioremediation. PMID- 28886569 TI - DNA incision evaluation, binding investigation and biocidal screening of Cu(II), Ni(II) and Co(II) complexes with isoxazole Schiff bases. AB - Two new series of binary metal complexes [M(L1)2] and [M(L2)2] where, M=Cu(II), Ni(II) & Co(II) and L1=4-((3,4-dimethylisoxazol-5-ylimino)methyl)benzene-1,3 diol; L2=2-((3,4-dimethylisoxazol-5-ylimino)methyl)-5-methoxyphenol were synthesized and characterized by elemental analysis, 1H NMR, 13C NMR, FT-IR, ESI mass, UV-Visible, magnetic moment, ESR, SEM and powder XRD studies. Based on these results, a square planar geometry is assigned for all the metal complexes where the Schiff base acts as uninegatively charged bidentate chelating agent via the hydroxyl oxygen and azomethine nitrogen atoms. DNA binding studies of all the complexes with calf thymus DNA have been comprehensively investigated using electronic absorption spectroscopy, fluorescence quenching and viscosity studies. The oxidative and photo cleavage affinity of metal complexes towards supercoiled pBR322 DNA has been ascertained by agarose gel electrophoresis assay. From the results, it is observed that all the metal complexes bind effectively to CT-DNA via an intercalative mode of binding and also cleave pBR322 DNA in a promising manner. Further the Cu(II) complexes have shown better binding and cleavage properties towards DNA. The antimicrobial activities of the Schiff bases and their metal complexes were studied on bacterial and fungal strains and the results denoted that the complexes are more potent than their Schiff base ligands. PMID- 28886570 TI - Daily light integral and day light quality: Potentials and pitfalls of nighttime UV treatments on cucumber powdery mildew. AB - Nighttime ultraviolet (UV) radiation, if applied properly, has a significant potential for management of powdery mildews in many crop species. In this study, the role of growth light duration, irradiance, a combination of both (daily light integral) and light spectral quality (blue or red) on the efficacy of UV treatments against powdery mildew caused by Podosphaera xanthii and the growth performance of cucumber plants was studied in growth chambers. Increasing daily light integral provided by high-pressure sodium lamps (HPS) decreased efficacy of nighttime UV treatments against P. xanthii, but it increased plant growth. Furthermore, the efficacy of nighttime UV decreased when day length was increased from 16 to 20h at a constant daily light integral. The efficacy of nighttime UV increased if red light was applied after UV treatment, showing the possibility of day length extension without reducing the effect of UV. Increasing the dose of blue light during daytime reduced the efficacy of nighttime UV in controlling the disease, whereas blue deficient growth light (<6% of blue) caused UV mediated curling of young leaves. Furthermore, application of blue light after nighttime UV reduced its disease control efficacy. This showed the importance of maintaining a minimum of blue light in the growth light before nighttime UV treatment. Findings from this study showed that optimization of nighttime UV for management of powdery mildew is dependent on the spectral composition of the photosynthetically active radiation. PMID- 28886571 TI - Adolescent social media use and mental health from adolescent and parent perspectives. AB - This study investigated adolescent and parent reports of adolescent social media use and its relation to adolescent psychosocial adjustment. The sample consisted of 226 participants (113 parent-adolescent dyads) from throughout the United States, with adolescents (55 males, 51 females, 7 unreported) ranging from ages 14 to 17. Parent and adolescent reports of the number of adolescents' social media accounts were moderately correlated with parent-reported DSM-5 symptoms of inattention, hyperactivity/impulsivity, ODD, anxiety, and depressive symptoms, as well as adolescent-reported fear of missing out (FoMO) and loneliness. Lastly, anxiety and depressive symptoms were highest among adolescents with a relatively high number of parent-reported social media accounts and relatively high FoMO. The implications of these findings and need for related longitudinal studies are discussed. PMID- 28886572 TI - Myristic acid in amniotic fluid produces appetitive responses in human newborns. AB - BACKGROUND: A mixture of eight fatty acids (lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid, and linoleic acid) that are contained in human amniotic fluid, colostrum, and milk produces appetitive responses in newborns, suggesting the existence of a transition of sensorial cues that guide newborns to the maternal breast. OBJECTIVE: To explore the ability of each of these eight fatty acids individually to produce appetitive responses in newborns. METHODS: The study included 12 healthy human newborns<24h after birth. Using a longitudinal design, cotton swabs that were impregnated with each of the eight fatty acids and control substances (i.e., vehicle, saline, and vanilla) were placed approximately 1cm from the newborns' nostrils for 30s. Positive responses that were suggestive of acceptance included appetitive movements (i.e., suckling) and sniffing that were directed toward the cotton swab. Lateral movements of the head away from the swab were considered negative responses. Remaining stationary with no changes in facial expressions was considered indifference. RESULTS: Compared with controls (i.e., vehicle, saline, and vanilla) and the other fatty acids tested, myristic acid produced the longest duration of positive facial responses (suckling and sniffing). No significant differences in negative facial responses were observed in response to the odoriferous stimuli. No reactions that were suggestive of disgust were observed. CONCLUSION: A complex combination of stimuli, including the odor of myristic acid, may integrate sensory cues that guide newborns to the maternal breast. PMID- 28886573 TI - Do restrictive omnibus immigration laws reduce enrollment in public health insurance by Latino citizen children? A comparative interrupted time series study. AB - In the United States, there is concern that recent state laws restricting undocumented immigrants' rights could threaten access to Medicaid and the Children's Health Insurance Program (CHIP) for citizen children of immigrant parents. Of particular concern are omnibus immigration laws, state laws that include multiple provisions increasing immigration enforcement and restricting rights for undocumented immigrants. These laws could limit Medicaid/CHIP access for citizen children in immigrant families by creating misinformation about their eligibility and fostering fear and mistrust of government among immigrant parents. This study uses nationally-representative data from the National Health Interview Survey (2005-2014; n = 70,187) and comparative interrupted time series methods to assess whether passage of state omnibus immigration laws reduced access to Medicaid/CHIP for US citizen Latino children. We found that law passage did not reduce enrollment for children with noncitizen parents and actually resulted in temporary increases in coverage among Latino children with at least one citizen parent. These findings are surprising in light of prior research. We offer potential explanations for this finding and conclude with a call for future research to be expanded in three ways: 1) examine whether policy effects vary for children of undocumented parents, compared to children whose noncitizen parents are legally present; 2) examine the joint effects of immigration-related policies at different levels, from the city or county to the state to the federal; and 3) draw on the large social movements and political mobilization literature that describes when and how Latinos and immigrants push back against restrictive immigration laws. PMID- 28886574 TI - Comparative transcriptome analysis of fast twitch muscle and slow twitch muscle in Takifugu rubripes. AB - Fast twitch muscle and slow twitch muscle are two important organs of Takifugu rubripes. Both tissues are of ectodermic origin, and the differences between the two muscle fibers reflect the differences in their myofibril protein composition and molecular structure. In order to identify and characterize the gene expression profile in the two muscle fibers of T. rubripes, we generated 54 million and 44 million clean reads from the fast twitch muscle and slow twitch muscle, respectively, using RNA-Seq and identified a total of 580 fast-muscle specific genes, 1533 slow-muscle-specific genes and 11,806 genes expressed by both muscles. Comparative transcriptome analysis of fast and slow twitch muscles allowed the identification of 1508 differentially expressed genes, of which 34 myosin and 30 ubiquitin family genes were determined. These differentially expressed genes (DEGs) were also analyzed by Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. In addition, alternative splicing analysis was also performed. The generation of larger-scale transcriptomic data presented in this work would enrich the genetic resources of Takifugu rubripes, which could be valuable to comparative studies of muscles. PMID- 28886575 TI - Changing social norms: The impact of normative feedback included in motivational enhancement therapy on cannabis outcomes among heavy-using adolescents. AB - INTRODUCTION: Heavy cannabis use is a problematic behavior, particularly among some adolescents. Adolescents are particularly prone to social influence. As such, injunctive norms (perceptions of others' approval of cannabis use) and descriptive norms (perception of frequency of others' cannabis use) influence cannabis behavior. Given that norms are not always accurate, motivational enhancement therapy aims to reduce cannabis use through normative feedback and correction of normative misconceptions. The purpose of this study was to evaluate the relationships between perceived norms (descriptive and injunctive) and cannabis-related outcomes (use, cannabis-related problems, and cannabis use disorder symptoms) in a heavy cannabis-using adolescent population receiving motivational enhancement therapy. METHODS: Heavy cannabis-using individuals (n=252, 68% male, mean age 13.38, 59% Caucasian) were recruited from six Seattle high schools for a motivational enhancement therapy-based intervention involving normative feedback. RESULTS: Participants perceived higher rates of cannabis use among close friends than other same age teens and reported a higher perception of approval for cannabis use from close friends as compared to perceived approval of other same aged peers. Personal approval and the perceived approval of other same age teens were reduced following the intervention but there was no evidence of change in normative perceptions for close friends following the normative feedback interventions. Changes in normative perceptions were related to decreases in cannabis use and -related outcomes. CONCLUSIONS: Results suggest the importance of normative feedback in changing behavior in adolescent cannabis users, but also highlight the ongoing influence of close friends. PMID- 28886576 TI - Change in college students' perceived parental permissibility of alcohol use and its relation to college drinking. AB - College students who perceive their parents to hold permissive views about their alcohol use engage in heavier drinking. However, few studies have assessed perceived parental permissibility of alcohol use (PPP) longitudinally across the later college years, and few have assessed variation in changes in PPP and whether or not these changes differentially predict drinking. This study assessed whether PPP changed across college and used two approaches to determine whether PPP predicted binge drinking frequency and peak drinking. Data on college students' daily lives and risk behaviors were collected from 687 students (51% female) in a large university in the Northeast United States over four years. Perceived parental permissibility of alcohol use increased from the last year of high school through the third year of college with males reporting significantly higher PPP by the third year of college. From 12th grade through the third year of college, between-person differences in mean PPP were positively associated with binge drinking frequency and peak drinking, and patterns of PPP change differentially predicted both drinking outcomes through fourth year. These findings suggest that PPP is a dynamic construct that may evidence important developmental changes across college and the transition to adulthood. More broadly, the results indicate that aspects of the parent-child relationship continue to change after high school and may be important as they are linked with college student risk behaviors. PMID- 28886577 TI - What's the harm? Alcohol and marijuana use and perceived risks of unprotected sex among adolescents and young adults. AB - : The link between substance use and risky sexual behavior, particularly unprotected sex, among adolescents and young adults has been well established in the literature; however, less is known regarding how different patterns and types of substance use differentially relate to unprotected sex and perceived risks of unprotected sex. The current study examined perceived risks and unprotected sex among adolescents and young adults, and examined whether marijuana use, alcohol use, and dual marijuana and alcohol use were differentially linked to unprotected sex and perceived risks of unprotected sex. METHOD: A sample of N=144 adolescents and young adults (Mage=18.77, SDage=3.4, range: 12-25) completed self-report questionnaires regarding past month substance use, unprotected sex, and perceived risks of having unprotected sex. RESULTS: In a hierarchical logistic regression, only alcohol use was related to having unprotected sex at last intercourse (b=0.25, p<0.001). The second multinomial logistic regression showed that the interaction of alcohol and marijuana use was significantly related to lower levels of perceived risk of unprotected sex (moderate risk: b=0.06, p=0.04, OR=1.07; no/slight risk: b=0.07, p=0.03). CONCLUSION: While dual marijuana and alcohol use was related to lower perceived risk of unprotected sex, only alcohol use only was associated with a higher likelihood of unprotected sex. PMID- 28886578 TI - Extraction time and temperature affect the extraction efficiencies of coumarin and phenylpropanoids from Cinnamomum cassia bark using a microwave-assisted extraction method. AB - Microwave-assisted extraction (MAE), an efficient extraction tool, was employed to extract a coumarin and five phenylpropanoids (cinnamic acid, cinnamyl alcohol, cinnamaldehyde, 2-hydroxycinnamadehyde, and 2-methoxycinnamaldehyde) from Cinnamomum cassia bark using water as the extraction solvent. Six marker compounds were quantified by high-performance liquid chromatography-diode array detector using a validated analytical method. To investigate the influences of temperature and time on the extraction yields of the six marker compounds, the water extracts of C. cassia bark were prepared using a MAE method at six different extraction temperatures (70, 75, 80, 85, 90, and 95 degrees C) and times (2, 4, 6, 8, 10, and 12min). Their influences were assessed by multiple regression analysis. The results obtained demonstrated that higher extraction temperature and longer extraction time positively affected coumarin and cinnamyl alcohol contents, but negatively affected extract contents of cinnamic acid, cinnamaldehyde and 2-hydroxycinnamaldehyde (all p-<0.05). The extraction of 2 methoxycinnamaldehyde was affected by both positively and negatively by increasing temperature and time. These changes during MAE were assumed by the chemical natures of the marker compounds with various functional groups. In conclusion, temperature and times significantly affected the extraction efficiencies of a coumarin and five phenylpropanoids from C. cassia bark when a water-based MAE method was used. This study provides a novel approach to the preparation of the water extract of C. cassia bark using MAE. PMID- 28886579 TI - Development, validation, and clinical pharmacokinetic application of ultra performance liquid chromatography/tandem mass spectrometry method for simultaneously determining a novel recombinant hirudin derivative (Neorudin) and its active metabolite in human serum. AB - Recombinant Neorudin (EPR-hirudin, EH), a novel, low-bleeding anticoagulant fusion protein, has been developed as an inactive prodrug that is converted to an active metabolite, hirudin variant 2-Lys47 (HV2), at the thrombus site and is undergoing Phase I clinical trials in China. The goal of our present research was to establish a novel ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for simultaneously quantifying EH and HV2 in human serum. Furthermore, the method was used in clinical pharmacokinetic study after validation. The stock and dilute working solutions were dissolved in methanol/water (1/1, v/v) to avoid their adsorption. The internal standard (IS) used, had a similar structure to that of EH. The serum sample pretreatment involved protein precipitation with methanol. The volume ratio of the precipitating solvent to the serum sample was 3:1 (300MUL methanol: 100MUL serum sample). The chromatographic separation was performed using a 300A C18 column using a multi-step gradient with a mobile phase consisting of acetonitrile:water containing 0.1% formic acid. The detection was carried out using an ESI source in the positive multiple reaction monitoring (MRM) mode. The within and between run precision were in the range of 3.5%-10.3% for EH and 3.3%-8.8% for HV2, and the accuracy of both EH and HV2 was between -4.6% and 2.1%. The extraction recoveries and matrix effect at three quality control (QC) levels for EH and HV2 were satisfactory. The stabilities of EH and HV2 during the storage, preparation, and analysis were confirmed, and the carryover also proved to be acceptable. This technique was efficiently used in Phase I clinical pharmacokinetic trials of EH following intravenous administration of 0.2mg/kg to healthy volunteers. PMID- 28886580 TI - A plasma metabonomic analysis on potential biomarker in pyrexia induced by three methods using ultra high performance liquid chromatography coupled with Fourier transform ion cyclotron resonance mass spectrometry. AB - Pyrexia usually is a systemic pathological process that can lead to metabolic disorders. Metabonomics as a powerful tool not only can reveal the pathological mechanisms, but also can give insight into the progression of pyrexia from another angle. Thus, an ultra high performance liquid chromatography combined with Fourier transform ion cyclotron resonance mass spectrometry (UHPLC-FT-ICR MS) metabonomic approach was employed for the first time to investigate the plasma biochemical characteristics of pyrexia induced by three methods and to reveal subtle metabolic changes under the condition of pyrexia so as to explore its mechanism. The acquired metabolic data of the models were subjected to principal component analysis (PCA) for allowing the clear separation of the pyrexia rats from the control rats. Variable importance for project values (VIP) and Student's t-test were used to screen the significant metabolic changes caused by pyrexia. Fifty-two endogenous metabolites were identified and putatively identified as potential biomarkers primarily associated with phospholipid metabolism, sphingolipid metabolism, fatty acid oxidation metabolism, fatty acid amides metabolism and amino acid metabolism, and related to bile acid biosynthesis and glycerolipid catabolism. LysoPC (14:0), LysoPC (18:3), LysoPC (20:4), LysoPC (16:0), phytosphingosine, Cer (d18:0/12:0), N-[(4E,8E)-1,3 dihydroxyoctadeca-4,8-dien-2-yl]hexadecanamide, oleamide, fatty acid amide C22:1, tryptophan, acetylcarnitine, palmitoylcarnitine and stearoylcarnitine were considered as common potential biomarkers of pyrexia rats induced by three methods: Our results revealed that the UHPLC-FT-ICR-MS-based metabolomic method is helpful for finding new potential metabolic markers for pyrexia detection and offers a good perspective in pyrexia research. PMID- 28886581 TI - Skullcapflavone II attenuates ovalbumin-induced allergic rhinitis through the blocking of Th2 cytokine production and mast cell histamine release. AB - Allergic rhinitis is a common heterogeneous chronic upper airway disorder and is an IgE-mediated inflammation characterized by one or more nasal symptoms such as sneezing, itching, nasal discharge, rhinorrhea, post nasal drainage and nasal blockage. In the present study, the effects of skullcapflavone II (SCFII) on upper airway inflammation, Th2 cytokines, and NF-kappaB signaling in an ovalbumin (OVA)-induced allergic rhinitis (AR) murine model in vivo were investigated. OVA induced AR mice increased nasal symptoms, eosinophils and mast cells infiltration into nasal cavity, OVA-specific IgE/IgG1 and histamine in serum, Th2 cytokines including IL-13 and GATA3, and NF-kappaB signaling in NALF and lung homogenate. Interestingly, treatment of SCFII reduced the levels of OVA-specific IgE/IgG1 and histamine in serum, of Th2 cytokines and of NF-kappaB signaling in the NALF and the lung homogenate, and histopathological changes in the nasal tissue and the lung. Also, dexamethasone suppressed such increases. The results of this study suggested that SCFII may ameliorate allergic inflammation of upper airway in AR mice model by blocking the Th2 cytokine production, the NF-kappaB signal pathway and the mast cell histamine release. Taken together, we suggest that SCFII may be used as a therapeutic agent for patients with Th2-mediated or mast cell-mediated allergic diseases. PMID- 28886582 TI - Protective effects of ghrelin in ventilator-induced lung injury in rats. AB - Ghrelin has exhibited potent anti-inflammatory effects on various inflammatory diseases. The aim of this study was to investigate the potential effects of ghrelin on a model of ventilator-induced lung injury (VILI) established in rats. Male Sprague-Dawley rats were randomly divided into three groups: low volume ventilation (LV, Vt=8ml/kg) group, a VILI group (Vt=30ml/kg), and a VILI group pretreated with ghrelin (GH+VILI). For the LV group, for the VILI and GH+VILI groups, the same parameters were applied except the tidal volume was increased to 40ml/kg. After 4h of MV, blood gas, lung elastance, and levels of inflammatory mediators, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL 1beta, and (MIP)-2 and total protein in bronchoalveolar lavage fluid (BALF) were analyzed. Myeloperoxidase (MPO), (TLR)-4, and NF-kappaB, were detected in lung tissues. Water content (wet-to-dry ratio) and lung morphology were also evaluated. The VILI group had a higher acute lung injury (ALI) score, wet weight to dry ratio, MPO activity, and concentrations of inflammatory mediators (TNF alpha, IL-6, IL-1beta, and MIP-2) in BALF, as well as higher levels of TLR4 and NF-kappaB expression than the LV group (P<0.05). All histopathologic ALI, the inflammatory profile, and pulmonary dynamics have been improved by ghrelin pretreatment (P<0.05). Ghrelin pretreatment also decreased TLR4 expression and NF kappaB activity compared with the VILI group (P<0.05). Ghrelin pretreatment attenuated VILI in rats by reducing MV-induced pulmonary inflammation and might represent a novel therapeutic candidate for protection against VILI. PMID- 28886583 TI - Protective effects of wogonin against disease progression in different hepatic pathological conditions. PMID- 28886584 TI - Human pulpal blood flow in different root formation stages measured with transmitted-light plethysmography. AB - OBJECTIVES: To determine the pulp vitality after traumatic injury, dentists often use pulp sensitivity tests, which can be ambiguous in young permanent teeth with incomplete root formation. Transmitted-light plethysmography (TLP) is a non invasive objective method that uses a 525-nm LED to detect blood volume change in the pulp. The present study aimed (1) to investigate pulpal blood flow with TLP and optical characteristics in healthy permanent maxillary incisors in different root formation stages, and (2) to assess the influences of body growth of the children and tooth color on the TLP amplitude. DESIGN: Seventy-eight fully erupted maxillary central incisors were divided into four groups, according to the root formation stages. Group 1: root with wide-open apex, Group 2: root completed in length with open apex, Group 3: root with half-closed apex, Group 4: root with complete formation. The TLP amplitude, optical density, electric pulp testing, and cervical tooth color measurements of each group were compared using a one-way analysis of variance followed by the Bonferroni method. The correlation between the weights/heights of children and TLP amplitudes was analyzed using Pearson coefficient. RESULTS: The TLP amplitude was significantly higher in Group 3 than in the other groups. The amplitude was correlated with the weights/heights of children, but not with the tooth color. Optical density and electric sensitivity increased with tooth maturation. CONCLUSION: The amplitude of TLP and optical density may be affected by growth and development in children and indicate changes in the vascular dynamics of the pulp and hard tissue maturation during root formation stages. PMID- 28886585 TI - Human papillomavirus infection in oral potentially malignant disorders and cancer. AB - Human papillomavirus (HPV) infects keratinocytes in the mucosa or skin, and persistent infection with HPV may lead to premalignant lesions and invasive cancer, especially cervical cancer. It has also been hypothesized that HPV infection is an etiological factor of oral squamous cell carcinoma and oral precancerous disorders such as lichen planus, leukoplakia, and erythroplakia. A high percentage of HPV in oral lesions supports the possible viral contribution, but an association of HPV infection with these lesions remains to be established. The current paper will update the latest progress of HPV infection in several oral potentially malignant disorders and oral squamous cell carcinoma and discuss the impact of HPV infection on the progression of oral potentially malignant disorders. PMID- 28886586 TI - A murine Ig light chain transgene reveals IGKV3 gene contributions to anti collagen types IV and II specificities. AB - A subset of autoimmune diseases result from autoantibodies targeting epitopes on matrix collagen. The most extensively studied are anti-glomerular basement membrane glomerulonephritis (or its systemic counterpart Goodpasture's disease) that destroys kidneys and lungs, and rheumatoid arthritis that leads to disabling arthritis. Autoantibodies in these disorders bind evolutionarily conserved conformational epitopes on the noncollagenous domain 1 (NC1) of the alpha3 chain of type IV [alpha3(IV)NC1] collagen in glomerular and alveolar basement membranes, and on native or citrullinated type II collagen (CII) in joint cartilage, respectively. The genetic origins of pathogenic anti-collagen B cells in these diseases is unknown, but observations from murine models raise the possibility that they overlap despite distinct in vivo immunopathologies. Monoclonal autoantibodies isolated from mice immunized with alpha3(IV)NC1 collagen or CII show a biased use of Ig light chains (LC) encoded by genes of the IGKV3 subgroup (previously Vk21 family), paired with diverse Ig heavy chains. To further explore this relationship and determine if a single murine IGKV3 LC independently predisposes to both anti-collagen responses, we generated a novel transgenic (Tg) C57BL/6 mouse that expresses a productively rearranged IGKV3 encoded LC, termed mLCV3-Tg, in conjunction with endogenously rearranged Ig heavy chains. Tg mice are also genetically deficient in endogenous kappa chains to permit tracking of the mLCV3 transgene. We show that mLCV3-Tg mice are susceptible to humoral autoimmunity against both collagen chains. Anti alpha3(IV)NC1 collagen, but not anti-CII, mLCV3-encoded Ig are detected in serum of unmanipulated Tg mice, while Toll-like receptor ligands induce secretion of mLCV3-Tg autoantibodies of both collagen specificities from splenocytes ex vivo. This indicates developmental survival of mLCV3-Tg B cells reactive with each antigen, and is consistent with production of the two anti-collagen autoIg from distinct B cell populations. Reduced B cell numbers, low serum Ig kappa levels, low cell surface Ig kappa density, and abundant endogenous lambda chain expression suggest that subsets of IGKV3-encoded B cells are regulated in vivo by mechanisms that include deletion, anergy, and LC editing. These results support the notion that murine IGKV3 LCs contribute structural fitness to antigen binding sites that support diverse anti-collagen autoimmune responses, that these responses are regulated in vivo, and that these cells can nonetheless readily escape immune regulation. PMID- 28886587 TI - Distinct pattern of immune tolerance in dendritic cells treated with lipopolysaccharide or lipoteichoic acid. AB - Cytokine induction is often critical for the host defense during acute immune responses while, if not tightly regulated, it may cause an immunological pathology coincident with tissue damage. Despite the fact that gram-positive bacterial infection has become increasingly prevalent, immune modulation induced by lipoteichoic acid (LTA), the major cell wall component of gram-positive bacteria has not been studied thoroughly at the cellular level. In the current study, tolerance induction in mouse bone marrow-derived dendritic cells (BMDCs) treated with single or repeated stimulation of Staphylococcus aureus LTA was compared with those of Escherichia coli lipopolysaccharide (LPS). The results showed that repeated LTA stimulation significantly suppressed pro-inflammatory cytokine (TNF-alpha and IL-6) production in BMDCs, comparable to that of LPS, but with less extent, down-regulated IL-10 and enhanced the inhibitory molecule, LAG 3-associated protein (LAP). Furthermore, we observed a sustained expression of unique negative regulators, Toll interacting protein (TOLLIP) and Indoleamine 2,3 dioxygenase (IDO), in BMDCs treated with LTA. A transient hyporesponsiveness period appeared when DCs were treated repeatedly with LTA or LPS showing a distinctive pattern. Intriguingly, LPS exposure induced cross tolerance to LTA while LTA exposure did not to LPS, implicating that a distinct signaling components are involved in response to LTA. Collectively, a distinct immune regulation appeared to be responsible for the LPS- and LTA-induced tolerance on cytokine production, expression of surface markers and intracellular proteins. PMID- 28886589 TI - Role of FKBP51 in the modulation of the expression of the corticosteroid receptors in bovine thymus following glucocorticoid administration. AB - The aim of this work was to study the transcriptional effects of glucocorticoids on corticosteroid hormone receptors, prereceptors (11beta-hydroxysteroid dehydrogenase 1 and 2, 11beta-HSD1 and 2), and chaperones molecules regulating intracellular trafficking of the receptors (FKBP51 and FKBP52) in thymus of veal calves. Moreover, the expression of FKBP51 and FKBP52 gene were investigated in beef cattle thymus. In the cervical thymus of veal calves, dexamethasone administration in combination with estradiol decreased FKBP51 expression (P < 0.01). The same treatment increased mineralocorticoid receptor (MR) (P < 0.01) and 11beta-HSD1 expression (P < 0.05) compared to control group in the cervical thymus of veal calves. The thoracic thymus of veal calves treated with dexamethasone and estradiol showed a decrease of FKBP51 (P < 0.05), FKBP52 (P < 0.05), glucocorticoid receptor (P < 0.05), and MR expression (P < 0.05) compared to control group in the thoracic thymus of veal calves. The gene expression of FKBP51 decreased both in cervical (P < 0.01) and thoracic thymus (P < 0.01) of beef cattle treated with dexamethasone and estradiol. In addition, also prednisolone administration reduced FKBP51 expression in the cervical thymus (P < 0.01) and in the thoracic thymus of beef cattle (P < 0.01). The gene expression of FKBP52 increased only in the cervical thymus following dexamethasone administration (P < 0.01). The decrease of FKBP51 gene expression in thymus could be a possible biomarker of illicit dexamethasone administration in bovine husbandry. Moreover, so far, an effective biomarker of prednisolone administration is not identified. In this context, the decrease of FKBP51 gene expression in thymus of beef cattle following prednisolone administration could play an important role in the indirect identification of animals illegally treated with prednisolone. PMID- 28886588 TI - Human beta-defensin 3 inhibits periodontitis development by suppressing inflammatory responses in macrophages. AB - Human beta-defensin 3 (hBD3) is a cationic peptide with immunomodulatory effects on both innate and acquired immune responses. Periodontitis, an inflammatory disease that extends deep into periodontal tissues, causes the loss of supporting structures around the tooth. The present study assessed the effects of hBD3 as a monotherapy for periodontitis in mice and explored its potential mechanism. In vivo, hBD3 inhibited the levels of tumour necrosis factor (TNF)-alpha, interleukin-6, and matrix metalloprotease-9 in periodontium exposed to Porphyromonas gingivalis (P.g) in a mouse periodontitis model; reduced osteoclast formation and lower alveolar bone loss were also observed. In addition, hBD3 was related to the expression of polarization signature molecules in circulating monocytes. In vitro, hBD3 notably suppressed the production of TNF-alpha and interleukin-6 in RAW 264.7 cells stimulated by the lipopolysaccharide of P.g. Moreover, hBD3 attenuated polarization of RAW 264.7 cells into the M1 phenotype, with reduced activation of nuclear factor-kappaB signal transduction. In conclusion, hBD3 exhibits potent anti-periodontitis properties both in vitro and in vivo, and this effect may be correlated to inhibition of the nuclear factor kappaB pathway and macrophage polarization. PMID- 28886590 TI - Corpora lutea in superovulated ewes fed different planes of nutrition. AB - The corpus luteum (CL) is an ovarian structure which is critical for the maintenance of reproductive cyclicity and pregnancy support. Diet and/or diet components may affect some luteal functions. FSH is widely used to induce multiple follicle development and superovulation. We hypothesized that FSH would affect luteal function in ewes fed different nutritional planes. Therefore, the aim of this study was to determine if FSH-treatment affects (1) ovulation rate; (2) CL weight; (3) cell proliferation; (4) vascularity; (5) expression of endothelial nitric oxide (eNOS) and soluble guanylate cyclase (sGC) proteins; and (6) luteal and serum progesterone (P4) concentration in control (C), overfed (O), and underfed (U) ewes at the early- and mid-luteal phases. In addition, data generated from this study were compared to data obtained from nonsuperovulated sheep and described by Bass et al. Ewes were categorized by weight and randomly assigned into nutrition groups: C (2.14 Mcal/kg; n = 11), O (2xC; n = 12), and U (0.6xC; n = 11). Nutritional treatment was initiated 60 d prior to day 0 of the estrous cycle. Ewes were injected with FSH on day 13-15 of the first estrous cycle, and blood samples and ovaries were collected at early- and mid-luteal phases of the second estrous cycle. The number of CL/ewe was determined, and CL was dissected and weighed. CL was fixed for evaluation of expression of Ki67 (a proliferating cell marker), CD31 (an endothelial cell marker), and eNOS and sGC proteins using immunohistochemistry and image analysis. From day 0 until tissue collection, C maintained, O gained, and U lost body weight. The CL number was greater (P < 0.03) in C and O than U. Weights of CL, cell proliferation, vascularity, and eNOS but not sGC expression were greater (P < 0.001), and serum, but not luteal tissue, P4 concentrations tended to be greater (P = 0.09) at the early- than mid-luteal phase. Comparisons of CL measurements demonstrated greater (P < 0.01) cell proliferation and serum P4 concentration, but less vascularity at the early and mid-luteal phases, and less CL weight at the mid-luteal phase in superovulated than nonsuperovulated ewes; however, concentration of P4 in luteal tissues was similar in both groups. Thus, in superovulated ewes, luteal cell proliferation and vascularity, expression of eNOS, and serum P4 concentration depend on the stage of luteal development, but not diet. Comparison to control ewes demonstrated several differences and some similarities in luteal functions after FSH-induced superovulation. PMID- 28886591 TI - Predictors of early dropout in treatment for gambling disorder: The role of personality disorders and clinical syndromes. AB - Several treatment options for gambling disorder (GD) have been tested in recent years; however dropout levels still remain high. This study aims to evaluate whether the presence of psychiatric comorbidities predicts treatment outcome according to Millon's evolutionary theory, following a six-month therapy for GD. The role of severity, duration of the disorder, typology of gambling (mainly online or offline) and pharmacological treatment were also analysed. The recruitment included 194 pathological gamblers (PGs) to be compared with 78 healthy controls (HCs). Psychological assessment included the South Oaks Gambling Screen and the Millon Clinical Multiaxial Inventory-III. The "treatment failure" group (n = 70) comprised PGs who prematurely dropped out of the treatment whereas the "abstinent group" (n = 124) included PGs who completed the treatment regardless of whether the outcome was successful or not. As expected, the presence of psychiatric comorbidities was highlighted as a significant predictor in dropping out of the therapy. Specifically negativistic personality disorder, antisocial personality disorder, drug dependence and PTSD were associated with early dropout. These variables were predictive of treatment outcome independently from the typology of gambling, severity, duration of the disorder and pharmacological treatment. Implications for psychological and psychiatric care are discussed. PMID- 28886592 TI - New Rodent Population Models May Inform Human Health Risk Assessment and Identification of Genetic Susceptibility to Environmental Exposures. AB - BACKGROUND: This paper provides an introduction for environmental health scientists to emerging population-based rodent resources. Mouse reference populations provide an opportunity to model environmental exposures and gene environment interactions in human disease and to inform human health risk assessment. OBJECTIVES: This review will describe several mouse populations for toxicity assessment, including older models such as the Mouse Diversity Panel (MDP), and newer models that include the Collaborative Cross (CC) and Diversity Outbred (DO) models. METHODS: This review will outline the features of the MDP, CC, and DO mouse models and will discuss published case studies investigating the use of these mouse population resources in each step of the risk assessment paradigm. DISCUSSION: These unique resources have the potential to be powerful tools for generating hypotheses related to gene-environment interplay in human disease, performing controlled exposure studies to understand the differential responses in humans for susceptibility or resistance to environmental exposures, and identifying gene variants that influence sensitivity to toxicity and disease states. CONCLUSIONS: These new resources offer substantial advances to classical toxicity testing paradigms by including genetically sensitive individuals that may inform toxicity risks for sensitive subpopulations. Both in vivo and complementary in vitro resources provide platforms with which to reduce uncertainty by providing population-level data around biological variability. https://doi.org/10.1289/EHP1274. PMID- 28886593 TI - Influence of Tetrabromobisphenol A, with or without Concurrent Triclosan, upon Bisphenol A and Estradiol Concentrations in Mice. AB - BACKGROUND: Humans are commonly exposed to multiple environmental chemicals, including tetrabromobisphenol A (TBBPA; a flame retardant), triclosan (an antimicrobial agent), and bisphenol A (BPA; polycarbonate plastics). These chemicals are readily absorbed and may interact with each other. OBJECTIVES: We sought to determine whether TBBPA, given alone or in combination with triclosan, can modulate the concentrations of BPA and 17beta-estradiol (E2). METHODS: Female and male CF-1 mice were each given a subcutaneous injection of 0-27mg TBBPA, with or without concurrent 0.33mg triclosan, followed by dietary administration of 50MUg/kg body weight 14C-BPA. Radioactivity was measured in blood serum and tissues through liquid scintillation counting. In subsequent experiments, female and male CF-1 mice were each given a subcutaneous injection of 0 or 1mg TBBPA and E2 was measured in urine 2-12 h after injection. RESULTS: Doses as low as 1mg TBBPA significantly elevated 14C-BPA concentrations in the uterus and ovaries of females; in the testes, epididymides, vesicular-coagulating glands, and preputial glands of males; and in blood serum, heart, lungs, and kidneys of both sexes; urinary E2 concentrations were also elevated. Lower doses of TBBPA or triclosan that had no effects on their own elevated 14C-BPA concentrations when the two substances were given concurrently. CONCLUSION: These data indicate that TBBPA, triclosan, and BPA interact in vivo, consistent with evidence that TBBPA and triclosan inhibit enzymes that are critical for BPA and E2 metabolism. https://doi.org/10.1289/EHP1329. PMID- 28886594 TI - Elemental Sulfur Use and Associations with Pediatric Lung Function and Respiratory Symptoms in an Agricultural Community (California, USA). AB - BACKGROUND: Elemental sulfur, "the oldest of all pesticides," is the most heavily used agricultural pesticide in California and Europe. Sulfur is considered relatively safe and is used in both conventional and organic farming systems. Adverse respiratory effects have been reported in applicators and animals, but the effect on residential populations, and especially on children living in proximity to fields treated with elemental sulfur, is not known. OBJECTIVES: We evaluated associations between residential proximity to elemental sulfur applications and respiratory symptoms and spirometry of children living in an agricultural community. METHODS: Participants were enrolled in the CHAMACOS longitudinal birth cohort. We collected respiratory symptomatology for 347 children at 7 y of age and measured spirometry on a subset of 279. Of these, estimations of proximity to sulfur application and relevant covariate data were available for 237 and 205 children for whom we had symptomatology information and FEV1 measurements, respectively. Data from the California Pesticide Use Reporting System were used to estimate the amount of elemental sulfur applied within 0.5, 1, and 3km of a child's residence during the week, month, and 12 mo prior to pulmonary evaluation. Regression models controlled for maternal smoking during pregnancy; season of birth; PM2.5 (particulate matter <=2.5mm in aerodynamic diameter); breast feeding duration; child's sex, age, and height; technician; and other covariates. RESULTS: Adverse associations with respiratory outcomes were found for sulfur applications within 0.5- and 1-km radii. Specifically, asthma medication usage and respiratory symptoms increased [OR=3.51; 95% confidence interval (CI): 1.50, 8.23, p=0.004; OR=2.09; 95% CI: 1.27, 3.46, p=0.004, respectively] and FEV1 decreased (beta=-0.143; 95% CI: -0.248, -0.039, p=0.008) per 10-fold increase in the estimated amount of sulfur used within 1 km of child residence during the year prior to pulmonary evaluation. CONCLUSIONS: This study suggests that elemental sulfur use, allowed in both organic and conventional farming, in close proximity to residential areas, may adversely affect children's respiratory health. https://doi.org/10.1289/EHP528. PMID- 28886595 TI - Personal Care Product Use in Men and Urinary Concentrations of Select Phthalate Metabolites and Parabens: Results from the Environment And Reproductive Health (EARTH) Study. AB - BACKGROUND: Personal care products (PCPs) are exposure sources to phthalates and parabens; however, their contribution to men's exposure is understudied. OBJECTIVES: We examined the association between PCP use and urinary concentrations of phthalate metabolites and parabens in men. METHODS: In a prospective cohort, at multiple study visits, men self-reported their use of 14 PCPs and provided a urine sample (2004-2015, Boston, MA). We measured urinary concentrations of 9 phthalate metabolites and methylparaben, propylparaben, and butylparaben. We estimated the covariate-adjusted percent change in urinary concentrations associated with PCP use using linear mixed and Tobit mixed regressions. We also estimated weights for each PCP in a weighted binary score regression and modeled the resulting composite weighted PCP use. RESULTS: Four hundred men contributed 1,037 urine samples (mean of 3/man). The largest percent increase in monoethyl phthalate (MEP) was associated with use of cologne/perfume (83%, p-value<0.01) and deodorant (74%, p-value<0.01). In contrast, the largest percent increase for parabens was associated with the use of suntan/sunblock lotion (66-156%) and hand/body lotion (79-147%). Increases in MEP and parabens were generally greater with PCP use within 6 h of urine collection. A subset of 10 PCPs that were used within 6 h of urine collection contributed to at least 70% of the weighted score and predicted a 254-1,333% increase in MEP and parabens concentrations. Associations between PCP use and concentrations of the other phthalate metabolites were not statistically significant. CONCLUSIONS: We identified 10 PCPs of relevance and demonstrated that their use within 6 h of urine collection strongly predicted MEP and paraben urinary concentrations. https://doi.org/10.1289/EHP1374. PMID- 28886596 TI - Assessing Exposure to Household Air Pollution: A Systematic Review and Pooled Analysis of Carbon Monoxide as a Surrogate Measure of Particulate Matter. AB - BACKGROUND: Household air pollution from solid fuel burning is a leading contributor to disease burden globally. Fine particulate matter (PM2.5) is thought to be responsible for many of these health impacts. A co-pollutant, carbon monoxide (CO) has been widely used as a surrogate measure of PM2.5 in studies of household air pollution. OBJECTIVE: The goal was to evaluate the validity of exposure to CO as a surrogate of exposure to PM2.5 in studies of household air pollution and the consistency of the PM2.5-CO relationship across different study settings and conditions. METHODS: We conducted a systematic review of studies with exposure and/or cooking area PM2.5 and CO measurements and assembled 2,048 PM2.5 and CO measurements from a subset of studies (18 cooking area studies and 9 personal exposure studies) retained in the systematic review. We conducted pooled multivariate analyses of PM2.5-CO associations, evaluating fuels, urbanicity, season, study, and CO methods as covariates and effect modifiers. RESULTS: We retained 61 of 70 studies for review, representing 27 countries. Reported PM2.5-CO correlations (r) were lower for personal exposure (range: 0.22-0.97; median=0.57) than for cooking areas (range: 0.10-0.96; median=0.71). In the pooled analyses of personal exposure and cooking area concentrations, the variation in ln(CO) explained 13% and 48% of the variation in ln(PM2.5), respectively. CONCLUSIONS: Our results suggest that exposure to CO is not a consistently valid surrogate measure of exposure to PM2.5. Studies measuring CO exposure as a surrogate measure of PM exposure should conduct local validation studies for different stove/fuel types and seasons. https://doi.org/10.1289/EHP767. PMID- 28886597 TI - Pesticide Use and Age-Related Macular Degeneration in the Agricultural Health Study. AB - BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of blindness in developed countries. Few studies have investigated its relationship to environmental neurotoxicants. In previous cross-sectional studies, we found an association between pesticide use and self-reported retinal degeneration. OBJECTIVE: We evaluated the association of pesticide use with physician-confirmed incident AMD. METHODS: The Agricultural Health Study (AHS) is a prospective cohort of pesticide applicators and their spouses enrolled from 1993-1997 in Iowa and North Carolina. Cohort members reported lifetime use of 50 specific pesticides at enrollment. Self-reports of incident AMD during follow-up through 2007 were confirmed by reports from participants' physicians and by independent evaluation of retinal photographs provided by the physicians. Confirmed cases (n=161) were compared with AHS cohort members without AMD (n=39,108). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression with adjustment for age, gender, and smoking. RESULTS: AMD was associated with ever use of organochlorine [OR=2.7 (95% CI: 1.8, 4.0)] and organophosphate [OR=2.0 (95% CI: 1.3, 3.0)] insecticides and phenoxyacetate herbicides [OR=1.9 (95% CI: 1.2, 2.8)]. Specific pesticides consistently associated with AMD included chlordane, dichlorodiphenyltrichloroethane (DDT), malathion, and captan; others with notable but slightly less consistent associations were heptachlor, diazinon, phorate, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and 2,4-dichlorophenoxyacetic acid (2,4-D). Results were similar for men and women. Some specific pesticides were associated with both early- and late-stage AMD, but others were associated with only one stage. CONCLUSIONS: Exposures to specific pesticides may be modifiable risk factors for AMD. https://doi.org/10.1289/EHP793. PMID- 28886598 TI - A Human Mixture Risk Assessment for Neurodevelopmental Toxicity Associated with Polybrominated Diphenyl Ethers Used as Flame Retardants. AB - BACKGROUND: The European Food Safety Authority recently concluded that the exposure of small children (1-3 y old) to brominated diphenyl ether (BDE)-99 may exceed acceptable levels defined in relation to neurodevelopmental toxicity in rodents. The flame retardant BDE-209 may release BDE-99 and other lower brominated BDEs through biotic and abiotic degradation, and all age groups are exposed not only to BDE-209 and -99 but also to a cocktail of BDE congeners with evidence of neurodevelopmental toxicity. The possible risks from combined exposures to these substances have not been evaluated. OBJECTIVES: We performed a congener-specific mixture risk assessment (MRA) of human exposure to combinations of BDE-209 and other BDEs based on estimated exposures via diet and dust intake and on measured levels in biologic samples. METHODS: We employed the Hazard Index (HI) method by using BDE congener-specific reference doses for neurodevelopmental toxicity. RESULTS: Our HI analysis suggests that combined exposures to polybrominated diphenyl ethers (PBDEs) may exceed acceptable levels in breastfeeding infants (0-3 mo old) and in small children (1-3 y old), even for moderate (vs. high) exposure scenarios. Our estimates also suggest that acceptable levels of combined PBDEs may be exceeded in adults whose diets are high in fish. Small children had the highest combined exposures, with some estimated body burdens that were similar to body burdens associated with developmental neurotoxicity in rodents. CONCLUSIONS: Our estimates corroborate reports from several recent epidemiological studies of associations between PBDE exposures and neurobehavioral outcomes, and they support the inclusion of BDE-209 in the persistent organic pollutant (POP) convention as well as the need for strategies to reduce exposures to PBDE mixtures, including maximum residue limits for PBDEs in food and measures for limiting the release of PBDEs from consumer waste. https://doi.org/10.1289/EHP826. PMID- 28886599 TI - Associations between Greenness, Impervious Surface Area, and Nighttime Lights on Biomarkers of Vascular Aging in Chennai, India. AB - BACKGROUND: India is undergoing rapid urbanization with simultaneous increases in the prevalence of cardiovascular disease (CVD). As urban areas become home to an increasing share of the world's population, it is important to understand relationships between the built environment and progression towards CVD. OBJECTIVE: We assessed associations between multiple measures of the built environment and biomarkers of early vascular aging (EVA) in the Population Study of Urban, Rural and Semiurban Regions for the Detection of Endovascular Disease and Prevalence of Risk Factors and Holistic Intervention Study (PURSE-HIS) in Chennai, India. METHODS: We performed a cross-sectional analysis of 3,150 study participants. EVA biomarkers included systolic and diastolic blood pressure (SBP and DBP), central pulse pressure (cPP) and flow-mediated dilatation (FMD). Multiple approaches were used to assign residential exposure to factors of the built environment: Moderate Resolution Imaging Spectroradiometer (MODIS)-derived normalized difference vegetation index (NDVI), a measure of vegetation health and greenness; Landsat-derived impervious surface area (ISA); and Visible Infrared Imaging Radiometer Suite (VIIRS)-derived nighttime lights (NTL). Multivariable regression models were used to assess associations between each built environment measure and biomarkers of EVA, adjusting for age, body mass index (BMI), cooking fuel type, energy intake, sex, physical activity, smoking, socioeconomic status, and stress. RESULTS: Residing in areas with higher ISA or NTL, or lower greenness, was significantly associated with elevated SBP, DBP, and cPP, and with lower FMD, adjusting for age, BMI, sex, smoking status, and other CVD risk factors. An interquartile range decrease in greenness had the largest increase in SBP [4.3 mmHg (95% CI: 2.9, 5.6)], DBP [1.2 mmHg (95% CI: 0.4, 2.0)] and cPP [3.1 mmHg (95% CI: 2.0, 4.1)], and the largest decrease in FMD [-1.5% (95%CI: -2.2%, 0.9%]. CONCLUSION: Greenness, ISA, and NTL were associated with increased SBP, DBP, and cPP, and with reduced FMD, suggesting a possible additional EVA pathway for the relationship between urbanization and increased CVD prevalence in urban India. https://doi.org/10.1289/EHP541. PMID- 28886600 TI - Outdoor Light at Night and Breast Cancer Incidence in the Nurses' Health Study II. AB - BACKGROUND: Animal and epidemiologic studies suggest that exposure to light at night (LAN) may disrupt circadian patterns and decrease nocturnal secretion of melatonin, which may disturb estrogen regulation, leading to increased breast cancer risk. OBJECTIVES: We examined the association between residential outdoor LAN and breast cancer incidence using data from the nationwide U.S.-based Nurses' Health Study II cohort. METHODS: We followed 109,672 women from 1989 through 2013. Cumulative LAN exposure was estimated using time-varying satellite data for a composite of persistent nighttime illumination at ~1 km2 scale for each residence during follow-up. Incident invasive breast cancer cases were confirmed by medical record review. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for anthropometric, reproductive, lifestyle, and socioeconomic risk factors. RESULTS: Over 2,187,425 person-years, we identified 3,549 incident breast cancer cases. Based on a fully adjusted model, the estimated HR for incident breast cancer with an interquartile range (IQR) (31.6 nW/cm2/sr) increase in cumulative average outdoor LAN was 1.05 (95% CI: 1.00, 1.11). An association between LAN and breast cancer appeared to be limited to women who were premenopausal at the time of a case [HR=1.07 (95% CI: 1.01, 1.14) based on 1,973 cases vs. HR=1.00 (95% CI: 0.91, 1.09) based on 1,172 cases in postmenopausal women; p-interaction=0.08]. The LAN-breast cancer association was observed only in past and current smokers at the end of follow-up [HR=1.00 (95% CI: 0.94, 1.07) based on 2,215 cases in never smokers; HR=1.10 (95% CI: 1.01, 1.19) based on 1,034 cases in past smokers vs. HR=1.21 (95% CI: 1.07, 1.37) for 300 cases in current smokers; p interaction=0.08]. CONCLUSIONS: Although further work is required to confirm our results and to clarify potential mechanisms, our findings suggest that exposure to residential outdoor light at night may contribute to invasive breast cancer risk. https://doi.org/10.1289/EHP935. PMID- 28886601 TI - Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II. AB - BACKGROUND: The International Agency for Research on Cancer classified both outdoor air pollution and airborne particulate matter as carcinogenic to humans (Group 1) for lung cancer. There may be associations with cancer at other sites; however, the epidemiological evidence is limited. OBJECTIVE: The aim of this study was to clarify whether ambient air pollution is associated with specific types of cancer other than lung cancer by examining associations of ambient air pollution with nonlung cancer death in the Cancer Prevention Study II (CPS-II). METHODS: Analysis included 623,048 CPS-II participants who were followed for 22 y (1982-2004). Modeled estimates of particulate matter with aerodynamic diameter <2.5um (PM2.5) (1999-2004), nitrogen dioxide (NO2) (2006), and ozone (O3) (2002 2004) concentrations were linked to the participant residence at enrollment. Cox proportional hazards models were used to estimate associations per each fifth percentile-mean increment with cancer mortality at 29 anatomic sites, adjusted for individual and ecological covariates. RESULTS: We observed 43,320 nonlung cancer deaths. PM2.5 was significantly positively associated with death from cancers of the kidney {adjusted hazard ratio (HR) per 4.4 MUg/m3=1.14 [95% confidence interval (CI): 1.03, 1.27]} and bladder [HR=1.13 (95% CI: 1.03, 1.23)]. NO2 was positively associated with colorectal cancer mortality [HR per 6.5 ppb=1.06 (95% CI: 1.02, 1.10). The results were similar in two-pollutant models including PM2.5 and NO2 and in three-pollutant models with O3. We observed no statistically significant positive associations with death from other types of cancer based on results from adjusted models. CONCLUSIONS: The results from this large prospective study suggest that ambient air pollution was not associated with death from most nonlung cancers, but associations with kidney, bladder, and colorectal cancer death warrant further investigation. https://doi.org/10.1289/EHP1249. PMID- 28886603 TI - Review of Epidemiological Studies of Drinking-Water Turbidity in Relation to Acute Gastrointestinal Illness. AB - BACKGROUND: Turbidity has been used as an indicator of microbiological contamination of drinking water in time-series studies attempting to discern the presence of waterborne gastrointestinal illness; however, the utility of turbidity as a proxy exposure measure has been questioned. OBJECTIVES: We conducted a review of epidemiological studies of the association between turbidity of drinking-water supplies and incidence of acute gastrointestinal illness (AGI), including a synthesis of the overall weight of evidence. Our goal was to evaluate the potential for causal inference from the studies. METHODS: We identified 14 studies on the topic (distinct by region, time period and/or population). We evaluated each study with regard to modeling approaches, potential biases, and the strength of evidence. We also considered consistencies and differences in the collective results. DISCUSSION: Positive associations between drinking-water turbidity and AGI incidence were found in different cities and time periods, and with both unfiltered and filtered supplies. There was some evidence for a stronger association at higher turbidity levels. The studies appeared to adequately adjust for confounding. There was fair consistency in the notable lags between turbidity measurement and AGI identification, which fell between 6 and 10 d in many studies. CONCLUSIONS: The observed associations suggest a detectable incidence of waterborne AGI from drinking water in the systems and time periods studied. However, some discrepant results indicate that the association may be context specific. Combining turbidity with seasonal and climatic factors, additional water quality measures, and treatment data may enhance predictive modeling in future studies. https://doi.org/10.1289/EHP1090. PMID- 28886602 TI - Heat Wave and Mortality: A Multicountry, Multicommunity Study. AB - BACKGROUND: Few studies have examined variation in the associations between heat waves and mortality in an international context. OBJECTIVES: We aimed to systematically examine the impacts of heat waves on mortality with lag effects internationally. METHODS: We collected daily data of temperature and mortality from 400 communities in 18 countries/regions and defined 12 types of heat waves by combining community-specific daily mean temperature >=90th, 92.5th, 95th, and 97.5th percentiles of temperature with duration >=2, 3, and 4 d. We used time series analyses to estimate the community-specific heat wave-mortality relation over lags of 0-10 d. Then, we applied meta-analysis to pool heat wave effects at the country level for cumulative and lag effects for each type of heat wave definition. RESULTS: Heat waves of all definitions had significant cumulative associations with mortality in all countries, but varied by community. The higher the temperature threshold used to define heat waves, the higher heat wave associations on mortality. However, heat wave duration did not modify the impacts. The association between heat waves and mortality appeared acutely and lasted for 3 and 4 d. Heat waves had higher associations with mortality in moderate cold and moderate hot areas than cold and hot areas. There were no added effects of heat waves on mortality in all countries/regions, except for Brazil, Moldova, and Taiwan. Heat waves defined by daily mean and maximum temperatures produced similar heat wave-mortality associations, but not daily minimum temperature. CONCLUSIONS: Results indicate that high temperatures create a substantial health burden, and effects of high temperatures over consecutive days are similar to what would be experienced if high temperature days occurred independently. People living in moderate cold and moderate hot areas are more sensitive to heat waves than those living in cold and hot areas. Daily mean and maximum temperatures had similar ability to define heat waves rather than minimum temperature. https://doi.org/10.1289/EHP1026. PMID- 28886604 TI - The Imperial County Community Air Monitoring Network: A Model for Community-based Environmental Monitoring for Public Health Action. AB - SUMMARY: The Imperial County Community Air Monitoring Network (the Network) is a collaborative group of community, academic, nongovernmental, and government partners designed to fill the need for more detailed data on particulate matter in an area that often exceeds air quality standards. The Network employs a community-based environmental monitoring process in which the community and researchers have specific, well-defined roles as part of an equitable partnership that also includes shared decision-making to determine study direction, plan research protocols, and conduct project activities. The Network is currently producing real-time particulate matter data from 40 low-cost sensors throughout Imperial County, one of the largest community-based air networks in the United States. Establishment of a community-led air network involves engaging community members to be citizen-scientists in the monitoring, siting, and data collection process. Attention to technical issues regarding instrument calibration and validation and electronic transfer and storage of data is also essential. Finally, continued community health improvements will be predicated on facilitating community ownership and sustainability of the network after research funds have been expended. https://doi.org/10.1289/EHP1772 PMID- 28886605 TI - Air Pollution and Risk of Parkinson's Disease in a Large Prospective Study of Men. AB - BACKGROUND: Exposure to air pollution has been implicated in a number of adverse health outcomes, and the effect of particulate matter (PM) on the brain is beginning to be recognized. OBJECTIVES: We aimed to examine whether exposure to PM air pollution is related to risk of Parkinson's disease (PD) in the Health Professionals Follow-up Study (HPFS), a large prospective cohort of U.S. men. METHODS: We prospectively followed 50,352 men in the HPFS, a large prospective cohort of U.S. men, and identified 550 incident PD cases. Cumulative average exposure to various size fractions of PM [PM10 (<=10MUm microns in diameter), PM2.5 (<=2.5MUm in diameter), and PM2.5-10 (between 2.5 and 10MUm in diameter)] up to 2 years before the onset of PD was estimated using a spatiotemporal model by linking each participant's place of residence throughout the study with location-specific PM levels. We used multivariable Cox proportional hazards models to independently estimate the risk of PD associated with each size fraction of PM. RESULTS: In models adjusted for age, smoking, region, and population density, we did not observe statistically significant associations between exposure to PM and PD risk. In analyses considering cumulative average PM exposure, the comparing the top to the bottom quintile of PM exposure was 0.85 [95% confidence interval (CI): (0.63, 1.15)] for PM10, 0.97 [95% CI: (0.72, 1.32)] for PM2.5, and 0.88 [95% CI: (0.64, 1.22)] for hazard ratio (HR) PM2.5-10. The results did not change markedly when restricted to men who did not move during the study or when stratified by smoking status or population density. CONCLUSIONS: In this study, we found no evidence that exposure to air pollution is a risk factor for PD in men. https://doi.org/10.1289/EHP259. PMID- 28886606 TI - High-Throughput Analysis of Ovarian Cycle Disruption by Mixtures of Aromatase Inhibitors. AB - BACKGROUND: Combining computational toxicology with ExpoCast exposure estimates and ToxCastTM assay data gives us access to predictions of human health risks stemming from exposures to chemical mixtures. OBJECTIVES: We explored, through mathematical modeling and simulations, the size of potential effects of random mixtures of aromatase inhibitors on the dynamics of women's menstrual cycles. METHODS: We simulated random exposures to millions of potential mixtures of 86 aromatase inhibitors. A pharmacokinetic model of intake and disposition of the chemicals predicted their internal concentration as a function of time (up to 2 y). A ToxCastTM aromatase assay provided concentration-inhibition relationships for each chemical. The resulting total aromatase inhibition was input to a mathematical model of the hormonal hypothalamus-pituitary-ovarian control of ovulation in women. RESULTS: Above 10% inhibition of estradiol synthesis by aromatase inhibitors, noticeable (eventually reversible) effects on ovulation were predicted. Exposures to individual chemicals never led to such effects. In our best estimate, ~10% of the combined exposures simulated had mild to catastrophic impacts on ovulation. A lower bound on that figure, obtained using an optimistic exposure scenario, was 0.3%. CONCLUSIONS: These results demonstrate the possibility to predict large-scale mixture effects for endocrine disrupters with a predictive toxicology approach that is suitable for high-throughput ranking and risk assessment. The size of the effects predicted is consistent with an increased risk of infertility in women from everyday exposures to our chemical environment. https://doi.org/10.1289/EHP742. PMID- 28886609 TI - [The Hospital Emergency Plan: Important Tool for Disaster Preparedness]. AB - Hospitals need to be prepared for any kind of disaster. The terrorist attacks and mass shootings that took place in Europe in recent years impressively demonstrated the capability of hospitals to manage such challenging and disastrous events. To be adequately prepared, the hospital emergency plan is a very important tool. In this article we describe the entire process of drafting the emergency plan. We discuss the theoretical background as well as different models of disaster planning and we give important practical hints and tips for those in charge of the hospital disaster planning. PMID- 28886608 TI - ? PMID- 28886607 TI - Impact of clinical registries on quality of patient care and clinical outcomes: A systematic review. AB - BACKGROUND: Clinical quality registries (CQRs) are playing an increasingly important role in improving health outcomes and reducing health care costs. CQRs are established with the purpose of monitoring quality of care, providing feedback, benchmarking performance, describing pattern of treatment, reducing variation and as a tool for conducting research. OBJECTIVES: To synthesise the impact of clinical quality registries (CQRs) as an 'intervention' on (I) mortality/survival; (II) measures of outcome that reflect a process or outcome of health care; (III) health care utilisation; and (IV) healthcare-related costs. METHODS: The following electronic databases were searched: MEDLINE, EMBASE, CENTRAL, CINAHL and Google Scholar. In addition, a review of the grey literature and a reference check of citations and reference lists within articles was undertaken to identify relevant studies in English covering the period January 1980 to December 2016. The PRISMA-P methodology, checklist and standard search strategy using pre-defined inclusion and exclusion criteria and structured data extraction tools were used. Data on study design and methods, participant characteristics attributes of included registries and impact of the registry on outcome measures and/or processes of care were extracted. RESULTS: We identified 30102 abstracts from which 75 full text articles were assessed and finally 17 articles were selected for synthesis. Out of 17 studies, six focused on diabetes care, two on cardiac diseases, two on lung diseases and others on organ transplantations, rheumatoid arthritis, ulcer healing, surgical complications and kidney disease. The majority of studies were "before after" design (#11) followed by cohort design (#2), randomised controlled trial (#2), experimental non randomised study and one cross sectional comparison. The measures of impact of registries were multifarious and included change in processes of care, quality of care, treatment outcomes, adherence to guidelines and survival. Sixteen of 17 studies demonstrated positive findings in their outcomes after implementation of the registry. CONCLUSIONS: Despite the large number of published articles using data derived from CQRs, few have rigorously evaluated the impact of the registry as an intervention on improving health outcomes. Those that have evaluated this impact have mostly found a positive impact on healthcare processes and outcomes. TRIAL REGISTRATION: PROSPERO CRD42015017319. PMID- 28886610 TI - [Disaster Control and Civil Protection in Germany]. AB - The train crash of Bad Aibling/Germany in February 2016 and the terrorist attacks of the recent years in Europe have demonstrated the urgent need to be prepared for such disastrous events. Disaster preparedness and disaster control are very important governmental duties, as are civil protection and civil defense. In Germany the responsibility for those tasks are divided between the 16 "Lander" and the Federation. While the Federation takes care of the civil protection and disaster assistance, the Lander are responsible for disaster control. The presented article focuses on these issues and gives valuable insights into the German system of disaster control and civil protection with a focus on health protection. PMID- 28886611 TI - [Mass casualty incident - special features of "threatening situations"]. AB - Terrorist attacks or amok runs may cause "threatening situations" for emergency medical services (EMS), fire fighters and physicians. Cooperation with the police is of paramount importance. In order to minimize the risk to rescue personnel and affected persons, emergency medical care has to follow tactical principles. So, the strategy in such "threatening situations" is "Stop the bleeding and clear the scene". The police define three areas of danger: unsafe, partly safe and secure. Medical care in these areas follows the concept of Tactical Combat Casualty Care. While only police should act in the unsafe area, the EMS can operate in the partly safe area after appropriate arrangements. Safety may only be achieved in emergency departments, which have to be made to secure areas by certain measures.The task force "Tactical Medicine" of the Scientific Working Group Emergency Medicine of the German Association for Anesthesiology and Intensive Care describes in this article essential criteria for a coordinated approach in "threatening situations". PMID- 28886612 TI - [Remifentanil up2date - Part 2]. AB - Remifentanil is a short-acting opioid of high analgetic potency and superior controllability. It is widely used in day-case surgery, procedural sedation, for reduction of recovery-times and obstetrics and whenever excellent controllability of opioid effects is needed. Especially in combination with propofol it is used for target controlled infusion (TCI). The second part of the article shows the differences between groups of patients regarding the use of remifentanil. PMID- 28886613 TI - [Acute Monkshood Intoxication Requiring Acute Resuscitation in Suicidal Intent]. AB - We report about an acute monkshood intoxication requiring acute resuscitation in suicidal intent in a 56-year-old patient. The Blue Monkshood (Aconitum napellus) is considered to be the most toxic plant in Europe. All plant parts contain the highly toxic alkonoid aconitin. The lethal dose in adults is 2 - 6 mg. Intoxications are often fatal. Asymptomatic patients with suspected monkshood intoxication should also be monitored on an ICU. First signs of intoxication are paraesthesia in the mouth and throat area, abdominal cramps, nausea, vomiting and severe pain in skeletal muscle. Affected patients die within hours after ingestion due to respiratory distress and/or cardiac arrhythmia.The most important measure after oral ingestion is to achieve a rapid primary poison elimination clearance (in the case of awareness clear patients, trigger vomiting, otherwise gastric lavage under protective intubation) and the subsequent carbonation. A specific antidote is not available. The management of an intoxication consists primarily of the therapy of the rhythm disturbances in the form of magnesium and amiodarone.Strict adherence to protective measures (gloves, masks) must be strictly observed. A direct skin contact with plant parts is to be avoided as well as the potential contact with vomit or aspirate. PMID- 28886614 TI - ? PMID- 28886615 TI - ? PMID- 28886616 TI - Association of change in waist circumference and dyslipidaemia risk: The rural Chinese cohort study. AB - OBJECTIVE: To investigate the association of change in waist circumference (WC) and incidence of dyslipidaemia in a cohort study of a rural Chinese population. METHODS: Change in WC (DeltaWC) was defined as the value at follow-up minus the corresponding value at baseline. Risk of dyslipidaemia associated with DeltaWC was assessed by odds ratios and 95% confidence intervals in a logistic regression model, and the odds ratios were transformed to relative risks (RRs). RESULTS: Among 7691 participants without dyslipidaemia at baseline, 3213 (41.78%) showed dyslipidaemia at 6 year follow-up. Risk of dyslipidaemia was decreased for participants with the first quartile of DeltaWC and normal baseline WC (adjusted RR [aRR] = 0.79 [95% confidence interval: 0.64-0.98]) and was increased with the fourth quartile of DeltaWC and male gender, age 18 to 30 years, age 31 to 50 years, or normal baseline WC (aRR = 1.55 [1.19-2.03], 2.40 [1.16-4.95], 1.32 [1.06-1.64], and 1.66 [1.35-2.04], respectively). The risk of dyslipidaemia increased with change in WC from normal at baseline to abnormal at follow-up for both genders (aRR = 1.88 [1.39-2.55] for men and 1.60 [1.30-1.97] for women) and decreased with abnormal baseline WC changed to normal WC for women (aRR = 0.61 [0.45-0.83]). CONCLUSIONS: Dynamic change in waist circumference was closely related to the incidence of dyslipidaemia in a rural Chinese population. Waist circumference reduction could decrease dyslipidaemia risk, whereas WC increase may increase the risk. Interventions to control or reduce WC to within the normal range are important for early prevention of dyslipidaemia. PMID- 28886617 TI - Viscous effects in pelvic floor muscles during childbirth: A numerical study. AB - During vaginal delivery, women sustain stretching of their pelvic floor, risking tissue injury and adverse outcomes. Realistic numerical simulations of childbirth can help in the understanding of the pelvic floor mechanics and on the prevention of related disorders. In previous studies, biomechanical finite element simulations of a vaginal delivery have been performed disregarding the viscous effects present on all biological soft tissues. The inclusion of the viscoelastic behaviour is fundamental, since it allows to investigate rate-dependent responses. The present work uses a viscohyperelastic constitutive model to evaluate how the childbirth duration affects the efforts sustained by the pelvic floor during delivery. It was concluded that viscoelasticity adds a stiffness component that leads to higher forces comparing with the elastic response. Viscous solutions are rate dependent, and precipitous labours could be associated to higher efforts, while lower reaction forces were denoted for normal and prolonged labours, respectively. The existence of resting stages during labour demonstrated the capability of the tissue to relax and recover some of the initial properties, which helped to lower the forces and stresses involved. The present work represents a step further in achieving a robust non-invasive procedure, allowing to estimate how obstetrical factors influence labour and its outcomes. PMID- 28886618 TI - Bcl10 synergistically links CEACAM3 and TLR-dependent inflammatory signalling. AB - The neutrophil-specific innate immune receptor CEACAM3 functions as a decoy to capture Gram-negative pathogens, such as Neisseria gonorrhoeae, that exploit CEACAM family members to adhere to the epithelium. Bacterial binding to CEACAM3 results in their efficient engulfment and triggers activation of an nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB)-dependent inflammatory response by human neutrophils. Herein, we report that CEACAM3 cross linking is not sufficient for induction of cytokine production and show that the inflammatory response induced by Neisseria gonorrhoeae infection is elicited by an integration of signals from CEACAM3 and toll-like receptors. Using neutrophils from a human CEACAM-expressing mouse line (CEABAC), we use a genetic approach to reveal a molecular bifurcation of the CEACAM3-mediated antimicrobial and inflammatory responses. Ex vivo experiments with CEABAC-Rac2-/- , CEABAC-Bcl10-/- , and CEABAC-Malt1-/- neutrophils indicate that these effectors are not necessary for gonococcal engulfment, yet all 3 effectors contribute to CEACAM3-mediated cytokine production. Interestingly, although Bcl10 and Malt1 are often inextricably linked, Bcl10 enabled synergy between toll-like receptor 4 and CEACAM3, whereas Malt1 did not. Together, these findings reveal an integration of the specific innate immune receptor CEACAM3 into the network of more conventional pattern recognition receptors, providing a mechanism by which the innate immune system can unleash its response to a relentless pathogen. PMID- 28886619 TI - 2017 ESC/EACTS Guidelines for the management of valvular heart disease. PMID- 28886620 TI - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). PMID- 28886623 TI - Near-IR Photoluminescence of C60. AB - We have observed that C60+ ions isolated in cryogenic matrices show distinct near IR photoluminescence upon excitation in the near-IR range. By contrast, UV photoexcitation does not lead to measurable luminescence. Near-IR C60+ photoluminescence is a one-photon process. The emission is mainly concentrated in one band and corresponds to 2A1u <- 2E1g relaxation. We present experimental data for the Stokes shift, power, and temperature dependencies as well as the quantum efficiency of the photoluminescence. Our findings may be relevant for astronomy, considering recent unequivocal assignment of five diffuse interstellar bands to near-IR absorption bands of C60+. PMID- 28886624 TI - Nanobubbles: An Effective Way to Study Gas-Generating Catalysis on a Single Nanoparticle. AB - Gas-generating catalysis is important to many energy-related research fields, such as photocatalytic water splitting, water electrolysis, etc. The technique of single-nanoparticle catalysis is an effective way to search for highly active nanocatalysts and elucidate the reaction mechanism. However, gas-generating catalysis remains difficult to investigate at the single-nanoparticle level because product gases, such as H2 and O2, are difficult to detect on an individual nanoparticle. Here, we successfully find that nanobubbles can be used to study the gas-generating catalysis, i.e., H2 generation from formic acid dehydrogenation on a single Pd-Ag nanoplate, with a high time resolution (50 ms) via dark-field microscopy. The research reveals that the nanobubble evolution process includes nucleation time and lifetime. The nucleation rate of nanobubbles is proportional to the catalytic activity of a single nanocatalyst. The relationship between the catalytic activity and the nucleation rate is quantitatively described by a mathematical model, which shows that an onset reaction rate (ronset) exists for the generation of nanobubbles on a single Pd-Ag nanoplate. The research also reveals that a Pd-Ag nanoplate with larger size usually has a higher activity. However, some large-sized ones still have low activities, indicating the size of the Pd-Ag nanoplate is not the only key factor for the activity. Notablely, further research shows that Pd content is the key factor for the activity of single Pd-Ag nanoplates with similar size. The methodology and knowledge acquired from this research are also applicable to other important gas-generating catalysis reactions at the single-nanoparticle level. PMID- 28886625 TI - Complete active space configuration interaction from state-averaged configuration interaction singles natural orbitals: Analytic first derivatives and derivative coupling vectors. AB - A new complete active space configuration interaction (CASCI) method was recently introduced that uses state-averaged natural orbitals from the configuration interaction singles method (configuration interaction singles natural orbital CASCI, CISNO-CASCI). This method has been shown to perform as well or better than state-averaged complete active space self-consistent field for a variety of systems. However, further development and testing of this method have been limited by the lack of available analytic first derivatives of the CISNO-CASCI energy as well as the derivative coupling between electronic states. In the present work, we present a Lagrangian-based formulation of these derivatives as well as a highly efficient implementation of the resulting equations accelerated with graphical processing units. We demonstrate that the CISNO-CASCI method is practical for dynamical simulations of photochemical processes in molecular systems containing hundreds of atoms. PMID- 28886621 TI - 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). PMID- 28886622 TI - 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). PMID- 28886626 TI - Observation of the de Vries behavior in SmA* phase of a liquid crystal using polarised Raman scattering and infrared spectroscopy. AB - Two approaches exist in the literature for describing the orientational distribution function (ODF) of the molecular directors in SmA* phase of liquid crystals, though several models are recently proposed in the literature for explaining the de Vries behaviour. These ODFs correspond to either the conventional unimodal arrangements of molecular directors arising from the mean field theory that leads to the broad or sugar-loaf like distribution or to the "diffuse-cone-shaped" type distribution proposed by de Vries. The hypothesis by de Vries provides for a realistic explanation as to how at a molecular level, a first-order SmA* to SmC* transition can occur where the uniform molecular director azimuthal distributions condense to values lying within a narrow range of angles; finally these condense to a single value while at the same time ensuring a little or no concomitant shrinkage in the layer spacing. The azimuthal distribution of the in-layer directors is probed using IR and polarized Raman spectroscopic techniques. The latter allows us to obtain the ODF and the various order parameters for the uniaxial and the biaxial phases. Based on the results of these measurements, we conclude that the "cone-shaped" (or volcano-shaped) de Vries type of distribution can most preferably describe SmA* where "a first-order phase transition from SmA* to SmC*" and a low layer shrinkage can both be easily explained. PMID- 28886627 TI - CO2 adsorption on the copper surfaces: van der Waals density functional and TPD studies. AB - We investigated the adsorption of CO2 on the flat, stepped, and kinked copper surfaces from density functional theory calculations as well as the temperature programmed desorption and X-ray photoelectron spectroscopy. Several exchange correlation functionals have been considered to characterize CO2 adsorption on the copper surfaces. We used the van der Waals density functionals (vdW-DFs), i.e., the original vdW-DF (vdW-DF1), optB86b-vdW, and rev-vdW-DF2, as well as the Perdew-Burke-Ernzerhof (PBE) with dispersion correction (PBE-D2). We have found that vdW-DF1 and rev-vdW-DF2 functionals slightly underestimate the adsorption energy, while PBE-D2 and optB86b-vdW functionals give better agreement with the experimental estimation for CO2 on Cu(111). The calculated CO2 adsorption energies on the flat, stepped, and kinked Cu surfaces are 20-27 kJ/mol, which are compatible with the general notion of physisorbed species on solid surfaces. Our results provide a useful insight into appropriate vdW functionals for further investigation of related CO2 activation on Cu surfaces such as methanol synthesis and higher alcohol production. PMID- 28886628 TI - Thermodynamic responses of electronic systems. AB - We present how the framework of the temperature-dependent chemical reactivity theory can describe the panorama of different types of interactions between an electronic system and external reagents. The key reactivity indicators are responses of an appropriate state function (like the energy or grand potential) to the variables that determine the state of the system (like the number of electrons/chemical potential, external potential, and temperature). We also consider the response of the average electron density to appropriate perturbations. We present computable formulas for these reactivity indicators and discuss their chemical utility for describing electronic, electrostatic, and thermal changes associated with chemical processes. PMID- 28886629 TI - Testing the nature of reaction coordinate describing interaction of H2 with carbonyl carbon, activated by Lewis acid complexation, and the Lewis basic solvent: A Born-Oppenheimer molecular dynamics study with explicit solvent. AB - Using Born-Oppenheimer molecular dynamics (BOMD), we explore the nature of interactions between H2 and the activated carbonyl carbon, C(carbonyl), of the acetone-B(C6F5)3 adduct surrounded by an explicit solvent (1,4-dioxane). BOMD simulations at finite (non-zero) temperature with an explicit solvent produced long-lasting instances of significant vibrational perturbation of the H-H bond and H2-polarization at C(carbonyl). As far as the characteristics of H2 are concerned, the dynamical transient state approximates the transition-state of the heterolytic H2-cleavage. The culprit is the concerted interactions of H2 with C(carbonyl) and a number of Lewis basic solvent molecules-i.e., the concerted C(carbonyl)?H2?solvent interactions. On one hand, the results presented herein complement the mechanistic insight gained from our recent transition-state calculations, reported separately from this article. But on the other hand, we now indicate that an idea of the sufficiency of just one simple reaction coordinate in solution-phase reactions can be too simplistic and misleading. This article goes in the footsteps of the rapidly strengthening approach of investigating molecular interactions in large molecular systems via "computational experimentation" employing, primarily, ab initio molecular dynamics describing reactants-interaction without constraints of the preordained reaction coordinate and/or foreknowledge of the sampling order parameters. PMID- 28886630 TI - Dissipative particle dynamics: Systematic parametrization using water-octanol partition coefficients. AB - We present a systematic, top-down, thermodynamic parametrization scheme for dissipative particle dynamics (DPD) using water-octanol partition coefficients, supplemented by water-octanol phase equilibria and pure liquid phase density data. We demonstrate the feasibility of computing the required partition coefficients in DPD using brute-force simulation, within an adaptive semi automatic staged optimization scheme. We test the methodology by fitting to experimental partition coefficient data for twenty one small molecules in five classes comprising alcohols and poly-alcohols, amines, ethers and simple aromatics, and alkanes (i.e., hexane). Finally, we illustrate the transferability of a subset of the determined parameters by calculating the critical micelle concentrations and mean aggregation numbers of selected alkyl ethoxylate surfactants, in good agreement with reported experimental values. PMID- 28886631 TI - Colloidal motion under the action of a thermophoretic force. AB - We present thermophoretic measurements in aqueous suspensions of three different polystyrene (PS) particles of varying negative charge, size, and surface coating. Our measurement technique is based on the observation of the colloidal steady state distribution using conventional bright-field microscopy, which avoids undesirable effects such as laser-induced convection or local heating. We find that the colloids with the weakest zeta potential exhibit the strongest thermophoretic effect, suggesting that the Soret coefficient has a more intricate dependence on surface functionality than predicted by existing theoretical approaches. We also study the relaxation of the colloids to steady-state and propose a model to quantify the relaxation speed, based on the time evolution of the colloidal center of mass. Our observations are well described by this model and show that the relaxation speed tends to increase with the magnitude of the thermophoretic force. PMID- 28886632 TI - Efficient molecular density functional theory using generalized spherical harmonics expansions. AB - We show that generalized spherical harmonics are well suited for representing the space and orientation molecular density in the resolution of the molecular density functional theory. We consider the common system made of a rigid solute of arbitrary complexity immersed in a molecular solvent, both represented by molecules with interacting atomic sites and classical force fields. The molecular solvent density rho(r,Omega) around the solute is a function of the position r=(x,y,z) and of the three Euler angles Omega=(theta,phi,psi) describing the solvent orientation. The standard density functional, equivalent to the hypernetted-chain closure for the solute-solvent correlations in the liquid theory, is minimized with respect to rho(r,Omega). The up-to-now very expensive angular convolution products are advantageously replaced by simple products between projections onto generalized spherical harmonics. The dramatic gain in speed of resolution enables to explore in a systematic way molecular solutes of up to nanometric sizes in arbitrary solvents and to calculate their solvation free energy and associated microscopic solvent structure in at most a few minutes. We finally illustrate the formalism by tackling the solvation of molecules of various complexities in water. PMID- 28886633 TI - IR spectroscopic study of the displacement of an SF6 monolayer on graphite by Xe. AB - We report a study of displacement by xenon of a monolayer of sulphur hexafluoride initially condensed on a graphite surface. Earlier work showed that, below 112 K, Xe displaces SF6 almost completely in a first-order transition. Working at higher temperatures, we show that this system has a simple eutectic-like phase diagram, at least for SF6 not too dilute. In our experiment, both adsorbates are in equilibrium with their respective vapors in a cold cell. In our infrared reflection-absorption spectroscopy measurements, the SF6 coverage on the surface is monitored by the frequency shift due to dynamic dipole coupling of the collective mode of the strong SF6 nu3 vibrational resonance. Simulations relate this frequency shift to the SF6 areal density. Below T ~ 134 K, with increasing Xe pressure, a small amount Xe dissolves in the solid SF6 monolayer preceding its displacement by a solid predominantly Xe monolayer in a first-order transition. Above 134 K, there is a weaker first-order transition to a mixed liquid monolayer, followed by continuous increase in Xe concentration. If the initial SF6 monolayer is near its melting line, the melting transition on adding Xe appears to become continuous. PMID- 28886634 TI - Coherent multi-dimensional spectroscopy at optical frequencies in a single beam with optical readout. AB - Ultrafast coherent multi-dimensional spectroscopies form a powerful set of techniques to unravel complex processes, ranging from light-harvesting, chemical exchange in biological systems to many-body interactions in quantum-confined materials. Yet these spectroscopies remain complex to implement at the high frequencies of vibrational and electronic transitions, thereby limiting their widespread use. Here we demonstrate the feasibility of two-dimensional spectroscopy at optical frequencies in a single beam. Femtosecond optical pulses are spectrally broadened to a relevant bandwidth and subsequently shaped into phase coherent pulse trains. By suitably modulating the phases of the pulses within the beam, we show that it is possible to directly read out the relevant optical signals. This work shows that one needs neither complex beam geometries nor complex detection schemes in order to measure two-dimensional spectra at optical frequencies. Our setup provides not only a simplified experimental design over standard two-dimensional spectrometers but its optical readout also enables novel applications in microscopy. PMID- 28886635 TI - Weak hydrogen bond topology in 1,1-difluoroethane dimer: A rotational study. AB - The rotational spectrum of the 1,1-difluoroethane dimer has been investigated by pulsed-jet Fourier transform microwave spectroscopy. Two most stable isomers have been detected, which are both stabilized by a network of three C-H?F-C weak hydrogen bonds: in the most stable isomer, two difluoromethyl C-H groups and one methyl C-H group act as the weak proton donors whilst in the second isomer, two methyl C-H groups and one difluoromethyl C-H group act as the weak proton donors. For the global minimum, the measurements have also been extended to its four 13C isotopologues in natural abundance, allowing a precise, although partial, structural determination. Relative intensity measurements on a set of MUa-type transitions allowed estimating the relative population ratio of the two isomers as NI/NII ~ 6/1 in the pulsed jet, indicating a much larger energy gap between these two isomers than that expected from ab initio calculation, consistent with the result from pseudo-diatomic dissociation energies estimation. PMID- 28886636 TI - Communication: Molecular near-infrared transitions determined with sub-kHz accuracy. AB - Precise molecular transition frequencies are needed in various studies including the test of fundamental physics. Two well isolated ro-vibrational transitions of 12C16O at 1.57 MUm, R(9) and R(10) in the second overtone band, were measured by a comb-locked cavity ring-down spectrometer. Despite the weakness of the lines (Einstein coefficient A?0.008 s-1), Lamb-dip spectra were recorded with a signal to-noise ratio over 1000, and the line positions were determined to be 191 360 212 761.1 and 191 440 612 662.2 kHz, respectively, with an uncertainty of 0.5 kHz (deltanu/nu=2.6*10-12). The present work demonstrates the possibility to explore extensive molecular lines in the near-infrared with sub-kHz accuracy. PMID- 28886637 TI - Ro-vibronic transition intensities for triatomic molecules from the exact kinetic energy operator; electronic spectrum for the C 1B2 <- X 1A1 transition in SO2. AB - A procedure for calculating ro-vibronic transition intensities for triatomic molecules within the Born-Oppenheimer approximation is reported. Ro-vibrational energy levels and wavefunctions are obtained with the DVR3D suite, which solves the nuclear motion problem with an exact kinetic energy operator. Absolute transition intensities are calculated both with the Franck-Condon approximation and with a full transition dipole moment surface. The theoretical scheme is tested on C 1B2 <- X 1A1 ro-vibronic transitions of SO2. Ab initio potential energy and dipole moment surfaces are generated for this purpose. The calculated ro-vibronic transition intensities and cross sections are compared with the available experimental and theoretical data. PMID- 28886638 TI - Dynamic Kerr effect in a strong uniform AC electric field for interacting polar and polarizable molecules in the mean field approximation. AB - Analytical formulas for the electric birefringence response of interacting polar and anisotropically polarizable molecules due to a uniform alternating electric field are derived using Berne's forced rotational diffusion model [B. J. Berne, J. Chem. Phys. 62, 1154 (1975)] in the nonlinear version described by Warchol and Vaughan [J. Chem. Phys. 71, 502 (1979)]. It is found for noninteracting molecules that the signal consists of a frequency-dependent DC component superimposed on an oscillatory part with a frequency twice that of the AC driving field. However, unlike noninteracting molecules, the AC part strongly deviates from its dilute counterpart. This suggests a possible way of motivating new experimental studies of intermolecular interactions involving electro-optical methods and complementary nonlinear dielectric relaxation experiments. PMID- 28886639 TI - Internal energy dependence of the photodissociation dynamics of O3- using cryogenic photoelectron-photofragment coincidence spectroscopy. AB - Photoelectron-photofragment coincidence (PPC) spectra of ozonide, O3-, were measured at 388 nm (Ehnu = 3.20 eV) using a newly constructed cryogenic octopole accumulation trap coupled to a PPC spectrometer. The photoelectron spectra reveal three processes consisting of a stable photodetachment channel, and two distinct photodissociation pathways yielding (1) O2 + O- or (2) O + O2-. The first photodissociation pathway is observed in the PPC spectra by photodetachment of the O- product by a second photon, and produces electronically excited O2(1Deltag). The O2- product of the second photodissociation pathway undergoes autodetachment for O2-(2Pig, v" > 4), a process greatly enhanced by vibrational excitation of the precursor O3-. Cooling anions thermalized at 300 K to <17 K in a cryogenic octopole accumulation trap essentially turns off this autodetachment pathway. The product kinetic energy distribution in coincidence with the autodetached electrons from O2-(v" = 4) exhibits resolved features consistent with bend (nu2), asymmetric stretch (nu3) and a stretching combination band (nu1 + nu3) in the intermediate electronic state, illustrating the insights that can be gained from kinematically complete measurements. These results are discussed in the context of the low-lying excited states of O3-. PMID- 28886640 TI - Communication: Microphase equilibrium and assembly dynamics. AB - Despite many attempts, ordered equilibrium microphases have yet to be obtained in experimental colloidal suspensions. The recent computation of the equilibrium phase diagram of a microscopic, particle-based microphase former [Zhuang et al., Phys. Rev. Lett. 116, 098301 (2016)] has nonetheless found such mesoscale assemblies to be thermodynamically stable. Here, we consider their equilibrium and assembly dynamics. At intermediate densities above the order-disorder transition, we identify four different dynamical regimes and the structural changes that underlie the dynamical crossovers from one disordered regime to the next. Below the order-disorder transition, we also find that periodic lamellae are the most dynamically accessible of the periodic microphases. Our analysis thus offers a comprehensive view of the dynamics of disordered microphases and a route to the assembly of periodic microphases in a putative well-controlled, experimental system. PMID- 28886641 TI - Length and sequence relaxation of copolymers under recombination reactions. AB - We describe the kinetics and thermodynamics of copolymers undergoing recombination reactions, which are important for prebiotic chemistry. We use two approaches: the first one, based on chemical rate equations and the mass-action law describes the infinite size limit, while the second one, based on the chemical master equation, describes systems of finite size. We compare the predictions of both approaches for the relaxation of thermodynamic quantities towards equilibrium. We find that for some choice of initial conditions, the entropy of the sequence distribution can be lowered at the expense of increasing the entropy of the length distribution. We consider mainly energetically neutral reactions, except for one simple case of non-neutral reactions. PMID- 28886642 TI - Microscopic flow around a diffusing particle. AB - We report here on the computation of the microscopic flow induced by the motion of a small tagged particle in a fluid from molecular dynamic simulations. It is found that the hydrodynamical Stokes solution with slip boundary conditions is recovered at only a few diameters away from the tagged particle. However, fluctuations of the diffusing particle itself induce a renormalization of the bath viscosity and, more strikingly, an apparent violation of the non penetrability of the particles in the laboratory frame. The expected zero normal velocity at contact is satisfied only in the particle frame, or for heavy particles. Further evidence of this generalized boundary condition is given by the evaluation of the flow in a granular gas using data from particle tracking experiments. PMID- 28886643 TI - A surface-hopping method for semiclassical calculations of cross sections for radiative association with electronic transitions. AB - A semiclassical method based on surface-hopping techniques is developed to model the dynamics of radiative association with electronic transitions. It can be proven that this method is an extension of the established semiclassical formula used in the characterization of diatomic molecule-formation. Our method is tested for diatomic molecules. It gives the same cross sections as the former semiclassical formula but, contrary to the former method, it allows us to follow the fate of the trajectories after the emission of a photon. This means that we can characterize the rovibrational states of the stabilized molecules. Using semiclassical quantization, we can obtain quantum state-resolved cross sections or emission spectra for the radiative association process. The calculated semiclassical state-resolved spectra show general agreement with the result of quantum mechanical perturbation theory. Furthermore, our surface-hopping model is not only applicable for the description of radiative association but it can be used for semiclassical characterization of any molecular process where spontaneous emission occurs. PMID- 28886644 TI - Knotting probability of self-avoiding polygons under a topological constraint. AB - We define the knotting probability of a knot K by the probability for a random polygon or self-avoiding polygon (SAP) of N segments having the knot type K. We show fundamental and generic properties of the knotting probability particularly its dependence on the excluded volume. We investigate them for the SAP consisting of hard cylindrical segments of unit length and radius rex. For various prime and composite knots, we numerically show that a compact formula describes the knotting probabilities for the cylindrical SAP as a function of segment number N and radius rex. It connects the small-N to the large-N behavior and even to lattice knots in the case of large values of radius. As the excluded volume increases, the maximum of the knotting probability decreases for prime knots except for the trefoil knot. If it is large, the trefoil knot and its descendants are dominant among the nontrivial knots in the SAP. From the factorization property of the knotting probability, we derive a sum rule among the estimates of a fitting parameter for all prime knots, which suggests the local knot picture and the dominance of the trefoil knot in the case of large excluded volumes. Here we remark that the cylindrical SAP gives a model of circular DNA which is negatively charged and semiflexible, where radius rex corresponds to the screening length. PMID- 28886645 TI - A multi-state coarse grained modeling approach for an intrinsically disordered peptide. AB - Many proteins display a marginally stable tertiary structure, which can be altered via external stimuli. Since a majority of coarse grained (CG) models are aimed at structure prediction, their success for an intrinsically disordered peptide's conformational space with marginal stability and sensitivity to external stimuli cannot be taken for granted. In this study, by using the LKalpha14 peptide as a test system, we demonstrate a bottom-up approach for constructing a multi-state CG model, which can capture the conformational behavior of this peptide in three distinct environments with a unique set of interaction parameters. LKalpha14 is disordered in dilute solutions; however, it strictly adopts the alpha-helix conformation upon aggregation or when in contact with a hydrophobic/hydrophilic interface. Our bottom-up approach combines a generic base model, that is unbiased for any particular secondary structure, with nonbonded interactions which represent hydrogen bonds, electrostatics, and hydrophobic forces. We demonstrate that by using carefully designed all atom potential of mean force calculations from all three states of interest, one can get a balanced representation of the nonbonded interactions. Our CG model behaves intrinsically disordered in bulk water, folds into an alpha-helix in the presence of an interface or a neighboring peptide, and is stable as a tetrameric unit, successfully reproducing the all atom molecular dynamics simulations and experimental results. PMID- 28886646 TI - Communication: Effect of density on the physical aging of pressure-densified polymethylmethacrylate. AB - The rate of physical aging of glassy polymethylmethacrylate (PMMA), followed from the change in the secondary relaxation with aging, is found to be independent of the density, the latter controlled by the pressure during glass formation. Thus, the aging behavior of the secondary relaxation is the same whether the glass is more compacted or less dense than the corresponding equilibrium liquid. This equivalence in aging of glasses formed under different pressures indicates that local packing is the dominant variable governing the glassy dynamics. The fact that pressure densification yields different glass structures is at odds with a model for non-associated materials having dynamic properties exhibited by PMMA, such as density scaling of the relaxation time and isochronal superposition of the relaxation dispersion. PMID- 28886647 TI - Signatures of vibronic coupling in two-dimensional electronic-vibrational and vibrational-electronic spectroscopies. AB - Two-Dimensional Electronic-Vibrational (2D EV) spectroscopy and Two-Dimensional Vibrational-Electronic (2D VE) spectroscopy are new coherent four-wave mixing spectroscopies that utilize both electronically resonant and vibrationally resonant field-matter interactions to elucidate couplings between electronic and vibrational degrees of freedom. A system Hamiltonian is developed here to lay a foundation for interpreting the 2D EV and 2D VE signals that arise from a vibronically coupled molecular system in the condensed phase. A molecular system consisting of one anharmonic vibration and two electronic states is modeled. Equilibrium displacement of the vibrational coordinate and vibrational frequency shifts upon excitation to the first electronic excited state are included in our Hamiltonian through linear and quadratic vibronic coupling terms. We explicitly consider the nuclear dependence of the electronic transition dipole moment and demonstrate that these spectroscopies are sensitive to non-Condon effects. A series of simulations of 2D EV and 2D VE spectra obtained by varying parameters of the system, system-bath, and interaction Hamiltonians demonstrate that one of the following conditions must be met to observe signals: (1) non-zero linear and/or quadratic vibronic coupling in the electronic excited state, (2) vibrational-coordinate dependence of the electronic transition dipole moment, or (3) electronic-state-dependent vibrational dephasing dynamics. We explore how these vibronic interactions are manifested in the positions, amplitudes, and line shapes of the peaks in 2D EV and 2D VE spectroscopies. PMID- 28886649 TI - Erratum: "Intense fluorescence of Au20" [J. Chem. Phys. 147, 074301 (2017)]. PMID- 28886650 TI - A general variational approach for computing rovibrational resonances of polyatomic molecules. Application to the weakly bound H2He+ and H2?CO systems. AB - The quasi-variational quantum chemical protocol and code GENIUSH [E. Matyus et al., J. Chem. Phys. 130, 134112 (2009) and C. Fabri et al., J. Chem. Phys. 134, 074105 (2011)] has been augmented with the complex absorbing potential (CAP) technique, yielding a method for the determination of rovibrational resonance states. Due to the effective implementation of the CAP technique within GENIUSH, the GENIUSH-CAP code is a powerful tool for the study of important dynamical features of arbitrary-sized molecular systems with arbitrary composition above their first dissociation limit. The GENIUSH-CAP code has been tested and validated on the H2He+ cation: the computed resonance energies and lifetimes are compared to those obtained with a previously developed triatomic rovibrational resonance-computing code, D2FOPI-CCS [T. Szidarovszky and A. G. Csaszar Mol. Phys. 111, 2131 (2013)], utilizing the complex coordinate scaling method. A unique feature of the GENIUSH-CAP protocol is that it allows the simple implementation of reduced-dimensional dynamical models. To prove this, resonance energies and lifetimes of the H2?CO van der Waals complex have been computed utilizing a four-dimensional model (freezing the two monomer stretches), and a related potential energy surface, of the complex. PMID- 28886648 TI - Critical size dependence of domain formation observed in coarse-grained simulations of bilayers composed of ternary lipid mixtures. AB - Model cellular membranes are known to form micro- and macroscale lipid domains dependent on molecular composition. The formation of macroscopic lipid domains by lipid mixtures has been the subject of many simulation investigations. We present a critical study of system size impact on lipid domain phase separation into liquid-ordered and liquid-disordered macroscale domains in ternary lipid mixtures. In the popular di-C16:0 PC:di-C18:2 PC:cholesterol at 35:35:30 ratio mixture, we find systems with a minimum of 1480 lipids to be necessary for the formation of macroscopic phase separated domains and systems of 10 000 lipids to achieve structurally converged conformations similar to the thermodynamic limit. To understand these results and predict the behavior of any mixture forming two phases, we develop and investigate an analytical Flory-Huggins model which is recursively validated using simulation and experimental data. We find that micro- and macroscale domains can coexist in ternary mixtures. Additionally, we analyze the distributions of specific lipid-lipid interactions in each phase, characterizing domain structures proposed based on past experimental studies. These findings offer guidance in selecting appropriate system sizes for the study of phase separations and provide new insights into the nature of domain structure for a popular ternary lipid mixture. PMID- 28886651 TI - Comparison of exciplex generation under optical and X-ray excitation. AB - Exciplex generation under optical and X-ray excitation in identical conditions is experimentally compared using a specially chosen model donor-acceptor system, anthracene (electron acceptor) and N,N-dimethylaniline (electron donor) in non polar solution, and the results are analyzed and interpreted based on analytically calculated luminescence quantum yields. Calculations are performed on the basis of kinetic equations for multistage schemes of bulk exciplex production reaction under optical excitation and combination of bulk and geminate reactions of radical ion pairs under X-ray excitation. These results explain the earlier experimentally found difference in the ratio of the quantum yields of exciplexes and excited electron acceptors (exciplex generation efficiency) and the corresponding change in the exciplex generation efficiency under X irradiation as compared to the reaction under optical excitation. PMID- 28886652 TI - Linear and nonlinear frequency- and time-domain spectroscopy with multiple frequency combs. AB - Two techniques that employ equally spaced trains of optical pulses to map an optical high frequency into a low frequency modulation of the signal that can be detected in real time are compared. The development of phase-stable optical frequency combs has opened up new avenues to metrology and spectroscopy. The ability to generate a series of frequency spikes with precisely controlled separation permits a fast, highly accurate sampling of the material response. Recently, pairs of frequency combs with slightly different repetition rates have been utilized to down-convert material susceptibilities from the optical to microwave regime where they can be recorded in real time. We show how this one dimensional dual comb technique can be extended to multiple dimensions by using several combs. We demonstrate how nonlinear susceptibilities can be quickly acquired using this technique. In a second class of techniques, sequences of ultrafast mode locked laser pulses are used to recover pathways of interactions contributing to nonlinear susceptibilities by using a photo-acoustic modulation varying along the sequences. We show that these techniques can be viewed as a time-domain analog of the multiple frequency comb scheme. PMID- 28886653 TI - A coherent discrete variable representation method on a sphere. AB - The coherent discrete variable representation (ZDVR) has been extended for constructing a multidimensional potential-optimized DVR basis on a sphere. In order to deal with the non-constant Jacobian in spherical angles, two direct product primitive basis methods are proposed so that the original ZDVR technique can be properly implemented. The method has been demonstrated by computing the lowest states of a two-dimensional (2D) vibrational model. Results show that the extended ZDVR method gives accurate eigenvalues and exponential convergence with increasing ZDVR basis size. PMID- 28886654 TI - Low-energy electron-induced dissociation in gas-phase nicotine, pyridine, and methyl-pyrrolidine. AB - Dissociative electron attachment to nicotine, pyridine, and N-methyl-pyrrolidine was studied in the gas phase in order to assess their stability with respect to low-energy electron interactions. Anion yield curves for different products at electron energies ranging from zero to 15 eV were measured, and the molecular fragmentation pathways were proposed. Nicotine does not form a stable parent anion or a dehydrogenated anion, contrary to other biological systems. However, we have observed complex dissociation pathways involving fragmentation at the pyrrolidine side accompanied by isomerization mechanisms. Combining structure optimization and enthalpy calculations, performed with the Gaussian09 package, with the comparison with a deuterium-labeled N-methyl-d3-pyrrolidine allowed for the determination of the fragmentation pathways. In contrast to nicotine and N methylpyrrolidine, the dominant pathway in dissociative electron attachment to pyridine is the loss of hydrogen, leading to the formation of an [M-H]- anion. The presented results provide important new information about the stability of nicotine and its constituent parts and contribute to a better understanding of the fragmentation mechanisms and their effects on the biological environment. PMID- 28886655 TI - Investigation of the ozone formation reaction pathway: Comparisons of full configuration interaction quantum Monte Carlo and fixed-node diffusion Monte Carlo with contracted and uncontracted MRCI. AB - The association/dissociation reaction path for ozone (O2 + O <-> O3) is notoriously difficult to describe accurately using ab initio electronic structure theory, due to the importance of both strong and dynamic electron correlations. Experimentally, spectroscopic studies of the highest lying recorded vibrational states combined with the observed negative temperature dependence of the kinetics of oxygen isotope exchange reactions confirm that the reaction is barrierless, consistent with the latest potential energy surfaces. Previously reported potentials based on Davidson-corrected internally contracted multireference configuration interaction (MRCI) suffer from a spurious reef feature in the entrance channel even when extrapolated towards the complete basis set limit. Here, we report an analysis of comparisons between a variety of electronic structure methods including internally contracted and uncontracted MRCI (with and without Davidson corrections), as well as full configuration interaction quantum Monte Carlo, fixed-node diffusion Monte Carlo, and density matrix renormalization group. PMID- 28886657 TI - Transferable coarse-grained model for perfluorosulfonic acid polymer membranes. AB - Perfluorosulfonic acid (PFSA) polymer membranes are widely used as proton exchange membranes. Because the structure of the aqueous domain within the PFSA membrane is expected to directly influence proton conductance, many coarse grained (CG) simulation studies have been performed to investigate the membrane morphology; these studies mostly used phenomenological models, such as dissipative particle dynamics. However, a chemically accurate CG model is required to investigate the morphology in realistic membranes and to provide a concrete molecular design. Here, we attempt to construct a predictive CG model for the structure and morphology of PFSA membranes that is compatible with the Sinoda-DeVane-Klein (SDK) CG water model [Shinoda et al., Mol. Simul. 33, 27 (2007)]. First, we extended the parameter set for the SDK CG force field to examine a hydrated PFSA membrane based on thermodynamic and structural data from experiments and all-atom (AA) molecular dynamics (MD) simulations. However, a noticeable degradation of the morphology motivated us to improve the structural properties by using the iterative Boltzmann inversion (IBI) approach. Thus, we explored a possible combination of the SDK and IBI approaches to describe the nonbonded interaction. The hybrid SDK/IBI model improved the structural issues of SDK, showing a better agreement with AA-MD in the radial distribution functions. The hybrid SDK/IBI model was determined to reasonably reproduce both the thermodynamic and structural properties of the PFSA membrane for all examined water contents. In addition, the model demonstrated good transferability and has considerable potential for application to realistic long-chained PFSA membranes. PMID- 28886656 TI - Multisequence algorithm for coarse-grained biomolecular simulations: Exploring the sequence-structure relationship of proteins. AB - We consider a generalized-ensemble algorithm for coarse-grained simulations of biomolecules which allows the thermodynamic behavior of two or more sequences to be determined in a single multisequence run. By carrying out a random walk in sequence space, the method also enhances conformational sampling. Escape from local energy minima is accelerated by visiting sequences for which the minima are more shallow or absent. We test the method on an intermediate-resolution coarse grained model for protein folding with 3 amino acid types and explore the potential for a large-scale coverage of sequence space by applying the method to sets of more than 1000 sequences. The resulting thermodynamic data are used to analyze the structures and stability properties of sequences covering the space between folds with different secondary structures. PMID- 28886658 TI - Communication: Hypothetical ultralow-density ice polymorphs. AB - More than 300 kinds of porous ice structures derived from zeolite frameworks and space fullerenes are examined using classical molecular dynamics simulations. It is found that a hypothetical zeolitic ice phase is less dense and more stable than the sparse ice structures reported by Huang et al. [Chem. Phys. Lett. 671, 186 (2017)]. In association with the zeolitic ice structure, even less dense structures, "aeroices," are proposed. It is found that aeroices are the most stable solid phases of water near the absolute zero temperature under negative pressure. PMID- 28886659 TI - Coarsening and aging of lattice polymers: Influence of bond fluctuations. AB - We present results for the nonequilibrium dynamics of collapse for a model flexible homopolymer on simple cubic lattices with fixed and fluctuating bonds between the monomers. Results from our Monte Carlo simulations show that, phenomenologically, the sequence of events observed during the collapse are independent of the bond criterion. While the growth of the clusters (of monomers) at different temperatures exhibits a non-universal power-law behavior when the bonds are fixed, the introduction of fluctuations in the bonds by considering the existence of diagonal bonds produces a temperature independent growth, which can be described by a universal nonequilibrium finite-size scaling function with a non-universal metric factor. We also examine the related aging phenomenon, probed by a suitable two-time density-density autocorrelation function showing a simple power-law scaling with respect to the growing cluster size. Unlike the cluster growth exponent alphac, the nonequilibrium autocorrelation exponent lambdaC governing the aging during the collapse, however, is independent of the bond type and strictly follows the bounds proposed by Majumder and Janke [Phys. Rev. E 93, 032506 (2016)] at all temperatures. PMID- 28886660 TI - A multi-plate velocity-map imaging design for high-resolution photoelectron spectroscopy. AB - A velocity map imaging (VMI) setup consisting of multiple electrodes with three adjustable voltage parameters, designed for slow electron velocity map imaging applications, is presented. The motivations for this design are discussed in terms of parameters that influence the VMI resolution and functionality. Particularly, this VMI has two tunable potentials used to adjust for optimal focus, yielding good VMI focus across a relatively large energy range. It also allows for larger interaction volumes without significant sacrifice to the resolution via a smaller electric gradient at the interaction region. All the electrodes in this VMI have the same dimensions for practicality and flexibility, allowing for relatively easy modifications to suit different experimental needs. We have coupled this VMI to a cryogenic ion trap mass spectrometer that has a flexible source design. The performance is demonstrated with the photoelectron spectra of S- and CS2-. The latter has a long vibrational progression in the ground state, and the temperature dependence of the vibronic features is probed by changing the temperature of the ion trap. PMID- 28886661 TI - Comment on: Excessive daytime sleepiness in chronic migraine and chronic tension type headache from the general population. PMID- 28886662 TI - Comment on: Relationship between serum levels of VIP, but not of CGRP, and cranial autonomic parasympathetic symptoms: A study in chronic migraine patients. PMID- 28886663 TI - Comment on: Role of adipocytokines in the pathophysiology of migraine: A cross sectional study. PMID- 28886664 TI - Effectiveness of Cognitive Processing Therapy and Prolonged Exposure in the Department of Veterans Affairs. AB - Objective This study evaluated the effectiveness of cognitive processing therapy and prolonged exposure in conditions reflective of current clinical practice within the Veterans Health Administration. Method This study involved a retrospective review of 2030 charts. A total of 750 veterans from 10 U.S. states who received cognitive processing therapy or prolonged exposure in individual psychotherapy were included in the study (participants in cognitive processing therapy, N = 376; participants in prolonged exposure, N = 374). The main dependent variable was self-reported posttraumatic stress disorder symptoms as measured by total scores on the Posttraumatic Stress Disorder Checklist. The study used multilevel modeling to evaluate the absolute and relative effectiveness of both treatments and determine the relationship between patient level variables and total Posttraumatic Stress Disorder Checklist scores during treatment. Results Cognitive processing therapy and prolonged exposure were equally effective at reducing total Posttraumatic Stress Disorder Checklist scores. Veterans who completed therapy reported significantly larger reductions in the Posttraumatic Stress Disorder Checklist than patients who did not complete therapy. There were no significant differences in the improvement of posttraumatic stress disorder symptoms with respect to age and three racial/ethnic groups (Caucasian, African American, and Hispanic). Conclusions Cognitive processing therapy and prolonged exposure were shown to be effective in conditions highly reflective of clinical practice and with a highly diverse sample of veterans. Challenges related to dropout from trauma focused therapy should continue to be researched. PMID- 28886665 TI - Development of carpal tunnel syndrome after repair of the median nerve in the distal forearm. PMID- 28886666 TI - The diagnostic accuracy of 1.5T magnetic resonance imaging for detecting root avulsions in traumatic adult brachial plexus injuries. AB - : Identification of root avulsions is of critical importance in traumatic brachial plexus injuries because it alters the reconstruction and prognosis. Pre operative magnetic resonance imaging is gaining popularity, but there is limited and conflicting data on its diagnostic accuracy for root avulsion. This cohort study describes consecutive patients requiring brachial plexus exploration following trauma between 2008 and 2016. The index test was magnetic resonance imaging at 1.5 Tesla and the reference test was operative exploration of the supraclavicular plexus. Complete data from 29 males was available. The diagnostic accuracy of magnetic resonance imaging for root avulsion(s) of C5-T1 was 79%. The diagnostic accuracy of a pseudomeningocoele as a surrogate marker of root avulsion(s) of C5-T1 was 68%. We conclude that pseudomeningocoles were not a reliable sign of root avulsion and magnetic resonance imaging has modest diagnostic accuracy for root avulsions in the context of adult traumatic brachial plexus injuries. LEVEL OF EVIDENCE: III. PMID- 28886667 TI - The effect of screw trajectory for the reduction and association of the scaphoid and lunate (RASL) procedure: a biomechanical analysis. AB - The purpose of this study was to determine if screw placement in the reduction and association of the scaphoid and the lunate (RASL) procedure affected the ability of the scapholunate joint to withstand force. After completely disrupting of the scapholunate ligament in 29 fresh-frozen cadaveric wrists, we placed the RASL screw either distal or proximal to the lateral aspect of the dorsal ridge of the scaphoid and into the dorsal or volar aspect of the lunate. Specimens were subjected to repeated cycles of transcarpal axial force, mimicking clenched-fist loading, until failure. Screw placement distal to the lateral aspect of the dorsal scaphoid ridge was significantly associated with failure when examined manually, radiographically (1.8 vs. 0.5 mm) and using real-time motion capture (diastasis: 1.6 vs. 0.4 mm; Euler angle: 4.5 degrees vs. 0.8 degrees ). The lateral aspect of the dorsal ridge is a reliable radiographic landmark on the scaphoid and provides surgeons with a convenient starting point to achieve the most biomechanically stable RASL construct, and, therefore, enhances the potential for an optimal clinical outcome. PMID- 28886668 TI - Conceptual origins, current practice, and views of wide awake hand surgery. AB - This article reviews historical background, essential practice principles, and the new emerging area of wide awake hand surgery. It outlines the reasons that wide awake, local anaesthesia, no tourniquet surgery has emerged so quickly in the last 10 years over the world. I explain the origin of the concepts and some of the challenges of getting the technique accepted; in particular, the debunking of the myth of epinephrine danger in the finger. I review the most recent developments in several operations in this rapidly changing field of the tourniquet-free approach. Finally, this review includes speculations on the future of this technique. PMID- 28886669 TI - Canadian Practice Guidelines for Comprehensive Community Treatment for Schizophrenia and Schizophrenia Spectrum Disorders. AB - OBJECTIVE: The objective of this review is to identify the features and components of a comprehensive system of services for people living with schizophrenia. A comprehensive system was conceived as one that served the full range of people with schizophrenia and was designed with consideration of the incidence and prevalence of schizophrenia. The system should provide access to the full range of evidence-based services, should be recovery oriented, and should provide patient-centred care. METHOD: A systematic search was conducted for published guidelines for schizophrenia and schizophrenia spectrum disorders. The guidelines were rated by at least 2 raters, and recommendations adopted were primarily drawn from the National Institute for Clinical Excellence (2014) Guideline on Psychosis and Schizophrenia in adults and the Scottish Intercollegiate Guidelines Network guidelines on management of schizophrenia. RESULTS: The recommendations adapted for Canada cover the range of services required to provide comprehensive services. CONCLUSIONS: Comprehensive services for people with schizophrenia can be organized and delivered to improve the quality of life of people with schizophrenia and their carers. The services need to be organized in a system that provides access to those who need them. PMID- 28886670 TI - Canadian Treatment Guidelines on Psychosocial Treatment of Schizophrenia in Children and Youth. AB - OBJECTIVE: A panel of experts, including researchers, clinicians and people with lived experience, was brought together to develop the new Canadian schizophrenia guidelines for the psychosocial treatment of children and youth with schizophrenia or psychotic disorders. METHOD: The ADAPTE process, which relies on adapting existing high-quality guidelines, was used. Existing guidelines for children and youth (mostly from the National Institute for Health and Care Excellence [NICE]), as well as CPA adult guidelines, were reviewed and discussed in terms of their adaptability to the Canadian context and their level of recommendation for children and youth. New treatments were also considered when recent meta-analyses suggested their usefulness. RESULTS: The children and youth psychosocial guidelines include many cross-sectional recommendations in terms of clinical and interpersonal skills needed to work with this clientele, setting and collaboration issues and needed adaptations for specific subpopulations. In terms of specific treatments, the treatments most strongly recommended are family intervention and cognitive behavior therapy. Also recommended, although with different degrees of support, are supported employment/supported education programs, patient education, cognitive remediation, and social skills training. Novel and upcoming psychosocial treatments are also briefly discussed. CONCLUSION: These novel Canadian guidelines for the psychosocial treatment of children and youth with schizophrenia or psychotic disorders report evidence based treatments as well as important considerations for providers who work with this clientele. More studies with children and youth with schizophrenia and psychotic disorders are warranted. If followed, these guidelines should facilitate the recovery of children and youth with schizophrenia or psychotic disorders as well as the recovery of their families. PMID- 28886671 TI - Canadian Schizophrenia Guidelines: Schizophrenia and Other Psychotic Disorders with Coexisting Substance Use Disorders. AB - OBJECTIVE: Persons with schizophrenia and other psychotic disorders frequently have coexisting substance use disorders that require modifications to treatment approaches for best outcomes. The objectives of this review were to identify evidence-based practices best practices that improve outcomes for individuals with schizophrenia and substance used disorders. METHOD: We reviewed guidelines that were published in the last 5 years and that included systematic reviews or meta-analyses. Most of our recommendations came from 2 publications from the National Institute for Health and Care Excellence (NICE): the 2011 guidance titled Coexisting Severe Mental Illness (Psychosis) and Substance Misuse: Assessment and Management in Healthcare Settings and the 2014 guidance titled Psychosis and Schizophrenia in Adults: Prevention and Management. We placed these recommendations into the Canadian context to create this guideline. RESULTS: Evidence supports the inclusion of individuals with coexisting substance use disorders in first-episode psychosis programs. The programs should integrate psychosis and substance use treatments, emphasizing ongoing monitoring of both substance use and patterns and symptoms. The best outcomes are achieved with combined use of antipsychotic medications and addiction-based psychosocial interventions. However, limited evidence is available to recommend using one antipsychotic medication over another or one psychosocial intervention over another for persons with schizophrenia and other psychotic disorders with coexisting substance use disorders. CONCLUSIONS: Treating persons who have schizophrenia and other psychotic disorders with coexisting substance use disorders can present clinical challenges, but modifications in practice can help engage and retain people in treatment, where significant improvements over time can be expected. PMID- 28886672 TI - Purification of Body and Soul for the Next Journey. Practices Surrounding Death and Dying Among Muslim Women. AB - This study aims, first, to compare normative Islamic practices toward death and dying and actual practices of Moroccan Muslim women. Second, it seeks to compare the views and practices of middle-aged and elderly women. Qualitative empirical research was conducted with 30 middle-aged and elderly Moroccan Muslim women living in Antwerp (Belgium) and with 15 experts in the field. Our study shows that religious beliefs and worldview have a great impact on Muslims' practices surrounding death and dying. More specifically, practices are strongly shaped by their eschatological beliefs. The rituals are perceived as preparations for the hereafter, entailing purification of both soul and body, and demonstrate the belief in a continued existence of the soul. We found striking similarities between our participants' views and normative Islamic views. We did not find a more secular understanding of death and dying among the middle-aged women. PMID- 28886674 TI - Cancer Caregivers' Preparedness for Loss and Bereavement Outcomes: Do Preloss Caregiver Attributes Matter? AB - Past studies examining the relationship between preparedness for loss and bereavement outcomes among caregivers of spouses/partners with life-limiting illness did not adequately account for preloss caregiver attributes that could potentially confound the relationship. Using a sample of spouse/partner cancer caregivers ( N = 226), we examined how preloss caregiver attributes were associated with how prepared one felt for loss and their role in the relationship between preparedness and later bereavement outcomes. Nearly half reported they were not emotionally prepared, and 35% were not prepared for the practical challenges associated with the loss. Although attributes such as depression, anxiety, competence in daily activities, and financial adequacy were associated with both preparedness and bereavement outcomes, regression analyses revealed that preparedness remained the strongest predictor in all models. We suggest that early interventions enhancing caregivers' preparedness for loss may hold considerable promise for improved bereavement outcome. PMID- 28886675 TI - Self-Criticism and Depressive Symptoms: Mediating Role of Self-Compassion. AB - Self-compassion is gaining recognition as a resilience factor with implications for positive mental health. This study investigated the role of self-compassion in alleviating the effect of self-criticism on depressive symptoms. Participants were 147 urban, low-income African Americans with a recent suicide attempt. They were administered measures of self-criticism, depressive symptoms, and self compassion. Results from this cross-sectional investigation showed that self criticism was positively associated with depressive symptoms and negatively associated with self-compassion, and self-compassion was negatively associated with depressive symptoms. Bootstrapping analysis revealed that self-compassion mediated the self-criticism-depressive symptoms link, suggesting that self compassion ameliorates the negative impact of self-criticism on depressive symptoms. Our findings suggest that low-income African Americans with recent suicide attempt histories may benefit from interventions that focus on enhancing self-compassion. These results also highlight self-compassion as a positive trait with promise to improve people's quality of life and suggest that self-compassion focused interventions are consistent with a positive psychology framework. PMID- 28886676 TI - Validity, reliability and minimal detectable change of the balance evaluation systems test (BESTest), mini-BESTest and brief-BESTest in patients with end-stage renal disease. AB - PURPOSE: This study determined the validity, test-retest reliability and minimal detectable change of the balance evaluation systems test (BESTest), mini-balance evaluation systems test (Mini-BESTest) and brief-balance evaluation systems test (Brief-BESTest) in patients with end-stage renal disease. METHODS: A cross sectional study with 74 patients with end-stage renal disease (male 66.2%; 63.9 +/- 15.1 years old) was conducted. Participants were asked to report the number of falls during the previous 12 months and to complete the activity-specific balance confidence (ABC) scale. The BESTest was administered, and the Mini BESTest and Brief-BESTest scores were computed based on the BESTest performance. Validity was assessed by correlating balance tests with each other and with the ABC scale. Test-retest relative reliability and agreement were explored with the intraclass correlation coefficient (ICC) equation (2,1) and the Bland and Altman method. Minimal detectable changes at the 95% confidence level were established. RESULTS: Balance test scores were significantly correlated with each other (spearman's correlation = 0.89-0.92) and with the ABC scale (spearman's correlation = 0.49-0.59). Balance tests presented high test-retest reliability (ICC = 0.84-0.94), with no evidence of bias. Minimal detectable change values were 10.8 (expressed as a percentage 13.5%), 5.3 (23.7%) and 5.6 (34%) points for the BESTest, Mini-BESTest and Brief-BESTest, respectively. CONCLUSIONS: All tests are valid and reliable to assess balance in patients with end-stage renal disease. Nevertheless, based on the minimal detectable changes found, BESTest and Mini-BESTest may be the most recommended tests for this specific population. Implications for Rehabilitation Balance evaluation systems test (BESTest), mini balance evaluation systems test (Mini-BESTest) and brief-balance evaluation systems test (Brief-BESTest) are reliable and valid in patients with end stage renal disease (ESRD). The minimal detectable changes of 10.8 for the BESTest, 5.3 for the Mini-BESTest and 5.6 for the Brief-BESTest can be used by clinicians to identify a true change in balance over time or in response to interventions. Based on the minimal detectable changes found, BESTest and Mini-BESTest may be the most recommended; and the selection of one of them may be based on time and equipment availability. PMID- 28886677 TI - Unplanned return to operating room after endovascular repair of abdominal aortic aneurysm (EVAR) is associated with increased risk of hospital readmission. AB - Objectives Hospital readmissions after surgical operations are considered serious events. Centers for Medicare and Medicaid (CMS) consider surgical readmissions as preventable and hold hospitals responsible for them. Endovascular abdominal aortic aneurysm (EVAR) has become the first line modality of treatment for suitable patients with abdominal aortic aneurysm (AAA). The purpose of this study is to retrospectively review the factors associated with hospital readmission after EVAR. Methods The 2013 EVAR targeted American College of Surgeons (ACS NSQIP) database and generalized 2013 general and vascular surgery ACS-NSQIP participant use files were used for this study. Patient, diagnosis, and procedure characteristics of patients undergoing EVAR surgery were assessed. Multivariate logistic regression analysis was used to determine independent risk factors for hospital readmission within 30 days after surgery. Results A total of 2277 patients (81% males, 19% females) underwent EVAR operations in the year 2013. Indications for operations included: asymptomatic large diameter (79%), symptomatic (5.7%), rupture without hypotension (4.3%), and rupture with hypotension (2.8%). Among these patients, 178 (7.8%) were readmitted to the hospital within 30 days after surgery. About 53% of all readmissions were within two weeks after the discharge. Risk factors, associated with readmission included: body mass index (per 5-units, OR 1.23, CI 1.06-1.42, p < 0.05), days from admission to operation (per 1 day, OR 1.26, CI 1.12-1.41, p < 0.05), prior abdominal aortic surgery (OR 1.60, CI 1.10-2.31, p < 0.05), urinary tract infection (OR 5.93, CI 2.09-16.88, p < 0.05), superficial surgical site infection (OR 6.57, CI 2.53-17.09, p < 0.05), unplanned return to the operating room (OR 11.29, CI 6.29-20.28, p < 0.05), myocardial infarction (OR 11.30, CI 4.42-28.89, p < 0.05), deep venous thrombosis (OR 11.52, CI 2.89-45.86, p < 0.05 and deep incisional surgical site infection (OR 38.0, CI 2.87-373.56, p < 0.05). Risk of readmission for patients with presence of all these seven factors was 99.9%. Conclusions Readmission after EVAR is a serious occurrence. Various factors predispose a patient at a high risk for readmission. Unplanned return to operating room after EVAR is associated with a 11-fold increase in hospital readmission. PMID- 28886678 TI - Introduction. PMID- 28886679 TI - Microbial Expansins. AB - Expansins are small proteins that loosen plant cell walls and cellulosic materials without lytic activity. First discovered in plants, expansin genes are found in the genomes of numerous bacteria and fungi that interact with plants in pathogenic and mutualistic patterns, as well as in microbes that feed on plant debris. Horizontal gene transfer from plants to microbes and between microbes accounts for expansins' irregular taxonomic distribution. Expansins facilitate plant colonization by Bacillus, Clavibacter, and Trichoderma species, a list likely to grow as knowledge of microbial expansin function deepens. Studies have documented a synergistic action of expansins for cellulose digestion by cellulases, but only rarely to an extent that is commercially relevant. Expansins' biophysical actions remain enigmatic because of limited understanding of cell wall structure. Deeper understanding of microbial expansins may lead to novel approaches for biomass deconstruction and biocontrol of plant diseases. PMID- 28886681 TI - Molecular Evolution of Antifungal Drug Resistance. AB - The fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have transitioned from a rare curiosity to a leading cause of human mortality. The management of infections caused by these organisms is intimately dependent on the efficacy of antifungal agents; however, fungi that are resistant to these treatments are regularly isolated in the clinic, impeding our ability to control infections. Given the significant impact fungal pathogens have on human health, it is imperative to understand the molecular mechanisms that govern antifungal drug resistance. This review describes our current knowledge of the mechanisms by which antifungal drug resistance evolves in experimental populations and clinical settings. We explore current antifungal treatment options and discuss promising strategies to impede the evolution of drug resistance. By tackling antifungal drug resistance as an evolutionary problem, there is potential to improve the utility of current treatments and accelerate the development of novel therapeutic strategies. PMID- 28886680 TI - Outer Membrane Biogenesis. AB - The hallmark of gram-negative bacteria and organelles such as mitochondria and chloroplasts is the presence of an outer membrane. In bacteria such as Escherichia coli, the outer membrane is a unique asymmetric lipid bilayer with lipopolysaccharide in the outer leaflet. Integral transmembrane proteins assume a beta-barrel structure, and their assembly is catalyzed by the heteropentameric Bam complex containing the outer membrane protein BamA and four lipoproteins, BamB-E. How the Bam complex assembles a great diversity of outer membrane proteins into a membrane without an obvious energy source is a particularly challenging problem, because folding intermediates are predicted to be unstable in either an aqueous or a hydrophobic environment. Two models have been put forward: the budding model, based largely on structural data, and the BamA assisted model, based on genetic and biochemical studies. Here we offer a critical discussion of the pros and cons of each. PMID- 28886682 TI - Copper Acquisition and Utilization in Fungi. AB - Fungal cells colonize and proliferate in distinct niches, from soil and plants to diverse tissues in human hosts. Consequently, fungi are challenged with the goal of obtaining nutrients while simultaneously elaborating robust regulatory mechanisms to cope with a range of availability of nutrients, from scarcity to excess. Copper is essential for life but also potentially toxic. In this review we describe the sophisticated homeostatic mechanisms by which fungi acquire, utilize, and control this biochemically versatile trace element. Fungal pathogens, which can occupy distinct host tissues that have their own intrinsic requirements for copper homeostasis, have evolved mechanisms to acquire copper to successfully colonize the host, disseminate to other tissues, and combat host copper bombardment mechanisms that would otherwise mitigate virulence. PMID- 28886683 TI - Neisseria gonorrhoeae: Drug Resistance, Mouse Models, and Vaccine Development. AB - Gonorrhea, an obligate human infection, is on the rise worldwide and gonococcal strains resistant to many antibiotics are emerging. Appropriate antimicrobial treatment and prevention, including effective vaccines, are urgently needed. To guide investigation, an experimental model of genital tract infection has been developed in female mice to study mechanisms by which Neisseria gonorrhoeae evades host-derived antimicrobial factors and to identify protective and immunosuppressive pathways. Refinements of the animal model have also improved its use as a surrogate host of human infection and accelerated the testing of novel therapeutic and prophylactic compounds against gonococcal infection. Reviewed herein are the (a) history of antibiotic usage and resistance against gonorrhea and the consequences of resistance mechanisms that may increase gonococcal fitness and therefore the potential for spread, (b) use of gonococcal infection in the animal model system to study mechanisms of pathogenesis and host defenses, and PMID- 28886684 TI - Elongation Factor P and the Control of Translation Elongation. AB - Elongation factor P (EF-P) binds to ribosomes requiring assistance with the formation of oligo-prolines. In order for EF-P to associate with paused ribosomes, certain tRNAs with specific d-arm residues must be present in the peptidyl site, e.g., tRNAPro. Once EF-P is accommodated into the ribosome and bound to Pro-tRNAPro, productive synthesis of the peptide bond occurs. The underlying mechanism by which EF-P facilitates this reaction seems to have entropic origins. Maximal activity of EF-P requires a posttranslational modification in Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis. Each of these modifications is distinct and ligated onto its respective EF-P through entirely convergent means. Here we review the facets of translation elongation that are controlled by EF-P, with a particular focus on the purpose behind the many different modifications of EF-P. PMID- 28886686 TI - A Life in Bacillus subtilis Signal Transduction. AB - This is a tale of how technology drove the discovery of the molecular basis for signal transduction in the initiation of sporulation in Bacillus subtilis and in bacterial two-component systems. It progresses from genetics to cloning and sequencing to biochemistry to structural biology to an understanding of how proteins evolve interaction specificity and to identification of interaction surfaces by statistical physics. This is about how the people in my laboratory accomplished this feat; without them little would have been done. PMID- 28886687 TI - "Fleaing" the Plague: Adaptations of Yersinia pestis to Its Insect Vector That Lead to Transmission. AB - Interest in arthropod-borne pathogens focuses primarily on how they cause disease in humans. How they produce a transmissible infection in their arthropod host is just as critical to their life cycle, however. Yersinia pestis adopts a unique life stage in the digestive tract of its flea vector, characterized by rapid formation of a bacterial biofilm that is enveloped in a complex extracellular polymeric substance. Localization and adherence of the biofilm to the flea foregut is essential for transmission. Here, we review the molecular and genetic mechanisms of these processes and present a comparative evaluation and updated model of two related transmission mechanisms. PMID- 28886685 TI - Bacterial Cell Size: Multifactorial and Multifaceted. AB - How cells establish, maintain, and modulate size has always been an area of great interest and fascination. Until recently, technical limitations curtailed our ability to understand the molecular basis of bacterial cell size control. In the past decade, advances in microfluidics, imaging, and high-throughput single-cell analysis, however, have led to a flurry of work revealing size to be a highly complex trait involving the integration of three core aspects of bacterial physiology: metabolism, growth, and cell cycle progression. PMID- 28886688 TI - Regulating Bacterial Virulence with RNA. AB - Noncoding RNAs (ncRNAs) regulating virulence have been identified in most pathogens. This review discusses RNA-mediated mechanisms exploited by bacterial pathogens to successfully infect and colonize their hosts. It discusses the most representative RNA-mediated regulatory mechanisms employed by two intracellular [Listeria monocytogenes and Salmonella enterica serovar Typhimurium (S. Typhimurium)] and two extracellular (Vibrio cholerae and Staphylococcus aureus) bacterial pathogens. We review the RNA-mediated regulators (e.g., thermosensors, riboswitches, cis- and trans-encoded RNAs) used for adaptation to the specific niches colonized by these bacteria (intestine, blood, or the intracellular environment, for example) in the framework of the specific pathophysiological aspects of the diseases caused by these microorganisms. A critical discussion of the newest findings in the field of bacterial ncRNAs shows how examples in model pathogens could pave the way for the discovery of new mechanisms in other medically important bacterial pathogens. PMID- 28886689 TI - Predator Versus Pathogen: How Does Predatory Bdellovibrio bacteriovorus Interface with the Challenges of Killing Gram-Negative Pathogens in a Host Setting? AB - Bdellovibrio bacteriovorus is a small deltaproteobacterial predator that has evolved to invade, reseal, kill, and digest other gram-negative bacteria in soils and water environments. It has a broad host range and kills many antibiotic resistant, clinical pathogens in vitro, a potentially useful capability if it could be translated to a clinical setting. We review relevant mechanisms of B. bacteriovorus predation and the physiological properties that would influence its survival in a mammalian host. Bacterial pathogens increasingly display conventional antibiotic resistance by expressing and varying surface and soluble biomolecules. Predators coevolved alongside prey bacteria and so encode diverse predatory enzymes that are hard for pathogens to resist by simple mutation. Predators do not replicate outside pathogens and thus express few transport proteins and thus few surface epitopes for host immune recognition. We explain these features, relating them to the potential of predatory bacteria as cellular medicines. PMID- 28886692 TI - Supernumerary phantom limb in a patient with basal ganglia hemorrhage - a case report and review of the literature. AB - BACKGROUND: Supernumerary phantom limb (SPL) is a rare neurologic phenomenon, in which a patient misperceives an extra limb in addition to the original set of limbs. We report a case of SPL in a patient with a right basal ganglia hemorrhage and review the previous literature about this peculiar phenomenon. CASE PRESENTATION: Two days after the event of a right basal ganglia hemorrhage, a 78 year-old male reported a phantom arm protruding from his left shoulder. He could not see or touch the phantom arm but he felt the presence of an addition arm lateral to his paretic arm. Pain or sensory discomfort were absent in either the paretic arm or the phantom arm. He stated that he could intentionally move the phantom arm independent of his paretic arm. The examination showed that the passive movement of his paretic arm did not elicit any movement of his phantom arm. We diagnosed the SPL as a complication of the hypertensive basal ganglia hemorrhage and treated him with anti-hypertensive medications. His phantom arm persisted for 3 weeks, and it gradually faded away. CONCLUSION: SPL had been reported as a rare complication of various types of cerebral lesions. Right hemispheric lesions were most frequently associated with the SPL. Considering the intentional movement of the phantom arm, we deduced that the SPL might result from the impairment of the sensory feedback system for both internal body image and motor movement. PMID- 28886691 TI - Impaired response of the bronchial epithelium to inflammation characterizes severe equine asthma. AB - BACKGROUND: Severe equine asthma is a naturally occurring lung inflammatory disease of mature animals characterized by neutrophilic inflammation, bronchoconstriction, mucus hypersecretion and airway remodeling. Exacerbations are triggered by inhalation of dust and microbial components. Affected animals eventually are unable of aerobic performance. In this study transcriptomic differences between asthmatic and non-asthmatic animals in the response of the bronchial epithelium to an inhaled challenge were determined. RESULTS: Paired endobronchial biopsies were obtained pre- and post-challenge from asthmatic and non-asthmatic animals. The transcriptome, determined by RNA-seq and analyzed with edgeR, contained 111 genes differentially expressed (DE) after challenge between horses with and without asthma, and 81 of these were upregulated. Genes involved in neutrophil migration and activation were in central location in interaction networks, and related gene ontology terms were significantly overrepresented. Relative abundance of specific gene products as determined by immunohistochemistry was correlated with differential gene expression. Gene sets involved in neutrophil chemotaxis, immune and inflammatory response, secretion, blood coagulation and apoptosis were overrepresented among up-regulated genes, while the rhythmic process gene set was overrepresented among down-regulated genes. MMP1, IL8, TLR4 and MMP9 appeared to be the most important proteins in connecting the STRING protein network of DE genes. CONCLUSIONS: Several differentially expressed genes and networks in horses with asthma also contribute to human asthma, highlighting similarities between severe human adult and equine asthma. Neutrophil activation by the bronchial epithelium is suggested as the trigger of the inflammatory cascade in equine asthma, followed by epithelial injury and impaired repair and differentiation. Circadian rhythm dysregulation and the sonic Hedgehog pathway were identified as potential novel contributory factors in equine asthma. PMID- 28886693 TI - Erratum to: the link between adjacent codon pairs and mRNA stability. PMID- 28886690 TI - Transcriptome profiling of antiviral immune and dietary fatty acid dependent responses of Atlantic salmon macrophage-like cells. AB - BACKGROUND: Due to the limited availability and high cost of fish oil in the face of increasing aquaculture production, there is a need to reduce usage of fish oil in aquafeeds without compromising farm fish health. Therefore, the present study was conducted to determine if different levels of vegetable and fish oils can alter antiviral responses of salmon macrophage-like cells (MLCs). Atlantic salmon (Salmo salar) were fed diets containing 7.4% (FO7) or 5.1% (FO5) fish oil. These diets were designed to be relatively low in EPA + DHA (i.e. FO7: 1.41% and FO5: 1%), but near the requirement level, and resulting in comparable growth. Vegetable oil (i.e. rapeseed oil) was used to balance fish oil in experimental diets. After a 16-week feeding trial, MLCs isolated from fish in these dietary groups were stimulated by a viral mimic (dsRNA: pIC) for 6 h (qPCR assay) and 24 h (microarray and qPCR assays). RESULTS: The fatty acid composition of head kidney leukocytes varied between the two dietary groups (e.g. higher 20:5n-3 in the FO7 group). Following microarray assays using a 44K salmonid platform, Rank Products (RP) analysis showed 14 and 54 differentially expressed probes (DEP) (PFP < 0.05) between the two diets in control and pIC groups (FO5 vs. FO7), respectively. Nonetheless, Significance Analysis of Microarrays (SAM, FDR < 0.05) identified only one DEP between pIC groups of the two diets. Moreover, we identified a large number (i.e. 890 DEP in FO7 and 1128 DEP in FO5 overlapping between SAM and RP) of pIC-responsive transcripts, and several of them were involved in TLR-/RLR-dependent and cytokine-mediated pathways. The microarray results were validated as significantly differentially expressed by qPCR assays for 2 out of 9 diet-responsive transcripts and for all of the 35 selected pIC responsive transcripts. CONCLUSION: Fatty acid-binding protein adipocyte (fabp4) and proteasome subunit beta type-8 (psmb8) were significantly up- and down regulated, respectively, in the MLCs of fish fed the diet with a lower level of fish oil, suggesting that they are important diet-responsive, immune-related biomarkers for future studies. Although the different levels of dietary fish and vegetable oils involved in this study affected the expression of some transcripts, the immune-related pathways and functions activated by the antiviral response of salmon MLCs in both groups were comparable overall. Moreover, the qPCR revealed transcripts responding early to pIC (e.g. lgp2, map3k8, socs1, dusp5 and cflar) and time-responsive transcripts (e.g. scarb1-a, csf1r, traf5a, cd80 and ctsf) in salmon MLCs. The present study provides a comprehensive picture of the putative molecular pathways (e.g. RLR-, TLR-, MAPK- and IFN-associated pathways) activated by the antiviral response of salmon MLCs. PMID- 28886694 TI - Comparative transcriptome analysis of cotton fiber development of Upland cotton (Gossypium hirsutum) and Chromosome Segment Substitution Lines from G. hirsutum * G. barbadense. AB - BACKGROUND: How to develop new cotton varieties possessing high yield traits of Upland cotton and superior fiber quality traits of Sea Island cotton remains a key task for cotton breeders and researchers. While multiple attempts bring in little significant progresses, the development of Chromosome Segment Substitution Lines (CSSLs) from Gossypium barbadense in G. hirsutum background provided ideal materials for aforementioned breeding purposes in upland cotton improvement. Based on the excellent fiber performance and relatively clear chromosome substitution segments information identified by Simple Sequence Repeat (SSR) markers, two CSSLs, MBI9915 and MBI9749, together with the recurrent parent CCRI36 were chosen to conduct transcriptome sequencing during the development stages of fiber elongation and Secondary Cell Wall (SCW) synthesis (from 10DPA and 28DPA), aiming at revealing the mechanism of fiber development and the potential contribution of chromosome substitution segments from Sea Island cotton to fiber development of Upland cotton. RESULTS: In total, 15 RNA-seq libraries were constructed and sequenced separately, generating 705.433 million clean reads with mean GC content of 45.13% and average Q30 of 90.26%. Through multiple comparisons between libraries, 1801 differentially expressed genes (DEGs) were identified, of which the 902 up-regulated DEGs were mainly involved in cell wall organization and response to oxidative stress and auxin, while the 898 down regulated ones participated in translation, regulation of transcription, DNA templated and cytoplasmic translation based on GO annotation and KEGG enrichment analysis. Subsequently, STEM software was performed to explicate the temporal expression pattern of DEGs. Two peroxidases and four flavonoid pathway-related genes were identified in the "oxidation-reduction process", which could play a role in fiber development and quality formation. Finally, the reliability of RNA seq data was validated by quantitative real-time PCR of randomly selected 20 genes. CONCLUSIONS: The present report focuses on the similarities and differences of transcriptome profiles between the two CSSLs and the recurrent parent CCRI36 and provides novel insights into the molecular mechanism of fiber development, and into further exploration of the feasible contribution of G. barbadense substitution segments to fiber quality formation, which will lay solid foundation for simultaneously improving fiber yield and quality of upland cotton through CSSLs. PMID- 28886695 TI - Cerebral microvascular dysfunction in metabolic syndrome is exacerbated by ischemia-reperfusion injury. AB - BACKGROUND: Metabolic syndrome (MetS) is associated with an increased risk of cerebrovascular diseases, including cerebral ischemia. Microvascular dysfunction is an important feature underlying the pathophysiology of cerebrovascular diseases. In this study, we aimed to investigate the impacts of ischemia and reperfusion (IR) injury on the cerebral microvascular function of rats with high fat diet-induced MetS. RESULTS: We examined Wistar rats fed a high-fat diet (HFD) or normal diet (CTL) for 20 weeks underwent 30 min of bilateral carotid artery occlusion followed by 1 h of reperfusion (IR) or sham surgery. Microvascular blood flow was evaluated on the parietal cortex surface through a cranial window by laser speckle contrast imaging, functional capillary density, endothelial function and endothelial-leukocyte interactions by intravital videomicroscopy. Lipid peroxidation was assessed by TBARs analysis, the expression of oxidative enzymes and inflammatory markers in the brain tissue was analyzed by real-time PCR. The cerebral IR in MetS animals induced a functional capillary rarefaction (HFD IR 117 +/- 17 vs. CTL IR 224 +/- 35 capillary/mm2; p < 0.05), blunted the endothelial response to acetylcholine (HFD IR -16.93% vs. CTL IR 16.19% from baseline inner diameter p < 0.05) and increased the endothelial-leukocyte interactions in the venules in the brain. The impact of ischemia on the cerebral microvascular blood flow was worsened in MetS animals, with a marked reduction of cerebral blood flow, exposing brain tissue to a higher state of hypoxia. CONCLUSIONS: Our results demonstrate that during ischemia and reperfusion, animals with MetS are more susceptible to alterations in the cerebral microcirculation involving endothelial dysfunction and oxidative stress events. PMID- 28886696 TI - Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors. AB - BACKGROUND: Phosphatase and Tensin homolog (PTEN) is a tumor suppressor gene. Loss of its function is the most frequent genetic alteration in endometrioid endometrial cancers (70-80%) and high grade tumors (90%). We assessed the sensitivity of endometrial cancer cell lines to PARP inhibitors (olaparib and BMN 673) and a PI3K inhibitor (BKM-120), alone or in combination, in the context of their PTEN mutation status. We also highlighted a direct pathway linking PTEN to DNA repair. METHODS: Using endometrial cancer cellular models with known PTEN status, we evaluated their homologous recombination (HR) functionality by RAD51 foci formation assay. The 50% Inhibitory concentration (IC50) of PI3K and PARP inhibitors in these cells was assessed, and western blotting was performed to determine the expression of proteins involved in the PI3K/mTOR pathway. Moreover, we explored the interaction between RAD51 and PI3K/mTOR by immunofluorescence. Next, the combination effect of PI3K and PARP inhibitors on cell proliferation was evaluated by a clonogenic assay. RESULTS: Cells with mutated PTEN showed over activation of the PI3K/mTOR pathway. These cells were more sensitive to PARP inhibition compared to PTEN wild-type cells. In addition, PI3K inhibitor treatment reduced RAD51 foci formation in PTEN mutated cells, and sensitized these cells to PARP inhibitor. CONCLUSION: Targeting both PARP and PI3K might lead to improved personalized therapeutic approaches in endometrial cancer patients with PTEN mutations. Understanding the complex interaction of PTEN mutations with DNA repair in endometrial cancer will help to better select patients that are likely to respond to some of the new and costly targeted therapies. PMID- 28886697 TI - Correlates of alcohol consumption among Germans in the second half of life. Results of a population-based observational study. AB - BACKGROUND: Several studies have investigated the predictors of alcohol consumption behavior among adolescents and young adults. However, the body of evidence about the relationship between in particular psychological factors and alcohol consumption among individuals in the second half of life is still limited. Hence, we aimed at identifying factors associated with alcohol consumption among individuals aged 40 and above, especially focusing on psychological correlates. METHODS: Data were derived from a population-based sample of community-dwelling individuals aged 40 to 95 years (n = 7820) in Germany. Alcohol consumption was rated as 'never' (never drinkers), 'rarer than once a month', 'one to three times a month', 'once a week', 'several times a week' (occasional drinkers), and 'daily' (daily drinkers). Socio-economic factors, the illness level and physical activity were considered as possible determinants of alcohol consumption. In addition, positive and negative affect, life satisfaction, optimism, self-esteem, self-efficacy, and self-regulation were included as psychological factors. Multinomial regressions were used to identify factors associated with drinking behavior. RESULTS: 12.0% of the individuals were daily drinkers, 76.5% were occasional drinkers, and 11.5% of the individuals never drank alcohol. After adjusting for various potential confounders, multinomial logistic regressions revealed that, compared with never drinking, occasional and daily drinking were positively associated with a decreased loneliness, a higher life satisfaction, a higher positive affect, a higher optimism, a higher self-efficacy (occasional drinkers), a higher self-esteem, and less perceived stress. In addition, occasional and daily drinking were positively associated with less physical illnesses, male gender, and income as compared with never drinking. CONCLUSIONS: The current study extends the existing literature on alcohol consumption behavior by new insights of correlates of drinking behavior among individuals in the second half of life. Since interventions are available to address this risk factor, this might help to identify individuals with increased alcohol consumption. PMID- 28886698 TI - Screening for anxiety and depression: reassessing the utility of the Zung scales. AB - BACKGROUND: While the gold standard for the diagnosis of mental disorders remains the structured clinical interview, self-report measures continue to play an important role in screening and measuring progress, as well as being frequently employed in research studies. Two widely-used self-report measures in the area of depression and anxiety are Zung's Self-Rating Depression Scale (SDS) and Self Rating Anxiety Scale (SAS). However, considerable confusion exists in their application, with clinical cut-offs often applied incorrectly. This study re examines the credentials of the Zung scales by comparing them with the Depression Anxiety Stress Scale (DASS) in terms of their ability to predict clinical diagnoses of anxiety and depression made using the Patient Health Questionnaire (PHQ). METHOD: A total sample of 376 adults, of whom 87 reported being in receipt of psychological treatment, completed the two-page version of the PHQ relating to depression and anxiety, together with the SDS, the SAS and the DASS. RESULTS: Overall, although the respective DASS scales emerged as marginally stronger predictors of PHQ diagnoses of anxiety and depression, the Zung indices performed more than acceptably in comparison. The DASS also had an advantage in discriminative ability. Using the current recommended cut-offs for all scales, the DASS has the edge on specificity, while the Zung scales are superior in terms of sensitivity. There are grounds to consider making the Zung cut-offs more conservative, and doing this would produce comparable numbers of 'Misses' and 'False Positives' to those obtained with the DASS. CONCLUSIONS: Given these promising results, further research is justified to assess the Zung scales ability against full clinical diagnoses and to further explore optimum cut-off levels. PMID- 28886699 TI - Research on advanced intervention using novel bone marrOW stem cell (RAINBOW): a study protocol for a phase I, open-label, uncontrolled, dose-response trial of autologous bone marrow stromal cell transplantation in patients with acute ischemic stroke. AB - BACKGROUND: Stroke is a leading cause of death and disability, and despite intensive research, few treatment options exist. However, a recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for treating stroke have been reported, certain problems remain unsolved. Recent studies have demonstrated that bone marrow stromal cells (BMSCs) have therapeutic potential against stroke. We investigated the use of autologous BMSC transplantation as a next-generation cell therapy for treating stroke. In this article, we introduce the protocol of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW). METHODS/DESIGN: RAINBOW is a phase 1, open-label, uncontrolled, dose-response study, with the primary aim to determine the safety of the autologous BMSC product HUNS001-01 when administered to patients with acute ischemic stroke. Estimated enrollment is 6-10 patients suffering from moderate to severe neurological deficits. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset. BMSCs are cultured with allogeneic human platelet lysate (PL) as a substitute for fetal calf serum and are labeled with superparamagnetic iron oxide for cell tracking using magnetic resonance imaging (MRI). HUNS001-01 is stereotactically administered around the area of infarction in the subacute phase. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking, 18F-fuorodeoxyglucose positron emission tomography, and 123I Iomazenil single-photon emission computed tomography will be performed for 1 year after the administration. DISCUSSION: This is a first-in-human trial for HUNS001 01 to the patients with acute ischemic stroke. We expect that intraparenchymal injection can be a more favorable method for cell delivery to the lesion and improvement of the motor function than intravenous infusion. Moreover, it is expected that the bio-imaging techniques can clarify the therapeutic mechanisms. TRIAL REGISTRATION: The trial was registered at The University Hospital Medical Information Network on February 22, 2017 (UNIN ID: UMIN000026130 ). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations. PMID- 28886700 TI - Internal limiting membrane peeling and gas tamponade for myopic foveoschisis: a systematic review and meta-analysis. AB - BACKGROUND: Myopic foveoschisis (MF) is among the leading causes of visual loss in high myopia. However, it remains controversial whether internal limiting membrane (ILM) peeling or gas tamponade is necessary treatment option for MF. METHODS: PubMed, EMBASE, CBM, CNKI, WANFANG DATA and VIP databases were systematically reviewed. Outcome indicators were myopic foveoschisis resolution rate, visual acuity improvement and postoperative complications. RESULTS: Nine studies that included 239 eyes were selected. The proportion of resolution of foveoschisis was higher in ILM peeling group than non-ILM peeling group (OR = 2.15, 95% CI: 1.06-4.35; P = 0.03). The proportion of postoperative complications was higher in Tamponade group than non-Tamponade group (OR = 10.81, 95% CI: 1.26 93.02; P = 0.03). However, the proportion of visual acuity improvement (OR = 1.63, 95% CI: 0.56-4.80; P = 0.37) between ILM peeling group and non-ILM peeling group and the proportion of resolution of foveoschisis (OR = 1.80, 95% CI: 0.76 4.28; P = 0.18) between Tamponade group and non-Tamponade group were similar. CONCLUSIONS: Vitrectomy with internal limiting membrane peeling could contribute to better resolution of myopic foveoschisis than non-peeling, however it does not significantly influence the proportion of visual acuity improvement and postoperative complications. Vitrectomy with gas tamponade is associated with more complications than non-tamponade and does not significantly influence the proportion of visual acuity improvement and resolution of myopic foveoschisis. PMID- 28886702 TI - Safety and effectiveness of oral misoprostol for induction of labour in a resource-limited setting: a dose escalation study. AB - BACKGROUND: Oral misoprostol as an induction of labour (IOL) agent is rapidly gaining popularity in resource-limited settings because it is cheap, stable at ambient temperatures, and logistically easier to administer compared to dinoprostone and oxytocin. We aim to investigate the safety and effectiveness of a regimen of oral misoprostol in Papua New Guinean women undergoing IOL. METHODS: As part of a prospective dose escalation study conducted at Modilon Hospital in Papua New Guinea, women with a singleton pregnancy in cephalic presentation and an unfavourable cervix who gave written informed consent were administered oral misoprostol, commencing at 25mcg once every 2 h for 4 doses and increased to 50mcg once every 2 h for 8 doses within 24 h. The primary outcomes studied were i) the proportion of women delivering within 24 h of oral misoprostol administration, and ii) rates of maternal and perinatal severe adverse events. RESULTS: Of 6167 labour ward screened admissions, 209 women (3%) fulfilled the study inclusion criteria and underwent IOL. Overall, 74% (155/209 [95% confidence interval 67.6-79.9]) delivered within 24 h. Most women (90%; 188/209; 95% CI [84.9-93.5]) delivered vaginally with 86% (180/209) having a good outcome for both the mother and baby. Of the 10% (21/209) who failed IOL and underwent caesarean section, a significant proportion of their babies were admitted to special-care nursery compared to babies delivered vaginally (20/21 [95%] versus 8/188 [4%]; Fisher Exact test P < 0.001), but their perinatal mortality rate was not significantly higher (1/21 [5%] versus 2/188 [1%]; P = 0.30). The only maternal death was not study related and occurred in a patient with post-partum haemorrhage, 15 h post-delivery. CONCLUSION: The oral misoprostol regimen for IOL described in the present study is safe, effective and logistically feasible to administer in a resource-limited setting. PMID- 28886701 TI - The loss-of-function disease-mutation G301R in the Na+/K+-ATPase alpha2 isoform decreases lesion volume and improves functional outcome after acute spinal cord injury in mice. AB - BACKGROUND: The Na+/K+-ATPases are transmembrane ion pumps important for maintenance of ion gradients across the plasma membrane that serve to support multiple cellular functions, such as membrane potentials, regulation of cellular volume and pH, and co-transport of signaling transmitters in all animal cells. The alpha2Na+/K+-ATPase subunit isoform is predominantly expressed in astrocytes, which us the sharp Na+-gradient maintained by the sodium pump necessary for astroglial metabolism. Prolonged ischemia induces an elevation of [Na+]i, decreased ATP levels and intracellular pH owing to anaerobic metabolism and lactate accumulation. During ischemia, Na+/K+-ATPase-related functions will naturally increase the energy demand of the Na+/K+-ATPase ion pump. However, the role of the alpha2Na+/K+-ATPase in contusion injury to the spinal cord remains unknown. We used mice heterozygous mice for the loss-of-function disease-mutation G301R in the Atp1a2 gene (alpha 2+/G301R ) to study the effect of reduced alpha2Na+/K+-ATPase expression in a moderate contusion spinal cord injury (SCI) model. RESULTS: We found that alpha 2+/G301R mice display significantly improved functional recovery and decreased lesion volume compared to littermate controls (alpha 2+/+ ) 7 days after SCI. The protein level of the alpha1 isoform was significantly increased, in contrast to the alpha3 isoform that significantly decreased 3 days after SCI in both alpha 2+/G301R and alpha 2+/+ mice. The level of the alpha2 isoform was significantly decreased in alpha 2+/G301R mice both under naive conditions and 3 days after SCI compared to alpha 2+/+ mice. We found no differences in astroglial aquaporin 4 levels and no changes in the expression of chemokines (CCL2, CCL5 and CXCL1) and cytokines (TNF, IL-6, IL-1beta, IL-10 and IL-5) between genotypes, just as no apparent differences were observed in location and activation of CD45 and F4/80 positive microglia and infiltrating leukocytes. CONCLUSION: Our proof of concept study demonstrates that reduced expression of the alpha2 isoform in the spinal cord is protective following SCI. Importantly, the BMS and lesion volume were assessed at 7 days after SCI, and longer time points after SCI were not evaluated. However, the alpha2 isoform is a potential possible target of therapeutic strategies for the treatment of SCI. PMID- 28886703 TI - Factors associated with foot ulceration and amputation in adults on dialysis: a cross-sectional observational study. AB - BACKGROUND: Adults on dialysis are at increased risk of foot ulceration, which commonly precedes more serious lower limb complications, including amputation. Limited data exist regarding the prevalence and factors associated with foot disease in this population. Hence, this study set out to investigate factors associated with foot ulceration and amputation in a dialysis cohort. METHODS: This study presents a cross-sectional analysis of baseline data from a multi center prospective cohort study. We recruited 450 adults with end-stage renal disease on dialysis from multiple satellite and home-therapy dialysis units in Melbourne, Australia from January to December 2014. Data collection consisted of a participant interview, medical record review, health-status questionnaire and non-invasive foot examination. Logistic regression analyses were conducted to evaluate associations between screened variables and study outcomes. RESULTS: Mean age was 67.5 (SD, 13.2) years, 64.7% were male, 94% were on hemodialysis, median dialysis duration was 36.9 (IQR, 16.6 to 70.1) months, and 50.2% had diabetes. There was a high prevalence of previous ulceration (21.6%) and amputation (10.2%), 10% had current foot ulceration, and 50% had neuropathy and/or peripheral arterial disease. Factors associated with foot ulceration were previous amputation (OR, 10.19), peripheral arterial disease (OR, 6.16) and serum albumin (OR, 0.87); whereas previous and/or current ulceration (OR, 167.24 and 7.49, respectively) and foot deformity (OR, 15.28) were associated with amputation. CONCLUSIONS: Dialysis patients have a high burden of lower limb complications. There are markedly higher risks of foot ulceration and/or amputation in those with previous and/or current ulceration, previous amputation, peripheral arterial disease, lower serum albumin, and foot deformity. Although not a major risk factor, diabetes in men was an important effect modifier for risk of ulceration. PMID- 28886704 TI - Differentiated transcriptional signatures in the maize landraces of Chiapas, Mexico. AB - BACKGROUND: Landrace farmers are the keepers of crops locally adapted to the environments where they are cultivated. Patterns of diversity across the genome can provide signals of past evolution in the face of abiotic and biotic change. Understanding this rich genetic resource is imperative especially since diversity can provide agricultural security as climate continues to shift. RESULTS: Here we employ RNA sequencing (RNA-seq) to understand the role that conditions that vary across a landscape may have played in shaping genetic diversity in the maize landraces of Chiapas, Mexico. We collected landraces from three distinct elevational zones and planted them in a midland common garden. Early season leaf tissue was collected for RNA-seq and we performed weighted gene co-expression network analysis (WGCNA). We then used association analysis between landrace co expression module expression values and environmental parameters of landrace origin to elucidate genes and gene networks potentially shaped by environmental factors along our study gradient. Elevation of landrace origin affected the transcriptome profiles. Two co-expression modules were highly correlated with temperature parameters of landrace origin and queries into their 'hub' genes suggested that temperature may have led to differentiation among landraces in hormone biosynthesis/signaling and abiotic and biotic stress responses. We identified several 'hub' transcription factors and kinases as candidates for the regulation of these responses. CONCLUSIONS: These findings indicate that natural selection may influence the transcriptomes of crop landraces along an elevational gradient in a major diversity center, and provide a foundation for exploring the genetic basis of local adaptation. While we cannot rule out the role of neutral evolutionary forces in the patterns we have identified, combining whole transcriptome sequencing technologies, established bioinformatics techniques, and common garden experimentation can powerfully elucidate structure of adaptive diversity across a varied landscape. Ultimately, gaining such understanding can facilitate the conservation and strategic utilization of crop genetic diversity in a time of climate change. PMID- 28886705 TI - Cognitive function in very old men does not correlate to biomarkers of Alzheimer's disease. AB - BACKGROUND: The Alzheimer's disease (AD) brain displays atrophy with amyloid-beta (Abeta) and tau deposition, whereas decreased Abeta42 and increased tau are measured in cerebrospinal fluid (CSF). The aim of this study was to relate cognitive performance to the degree of brain atrophy, CSF biomarker levels and neuropathology in a cohort of aged men. METHODS: Fifty-eight 86-92-year-old men from the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort underwent cognitive testing, brain computed tomography and lumbar puncture. Atrophy was graded with established scales. Concentrations of CSF Abeta42, t-tau and p-tau were measured by ELISA. Thirteen brains were examined post mortem. RESULTS: Forty six of the individuals were considered non-demented, whereas twelve were diagnosed with dementia, either at baseline (n = 4) or during follow-up (n = 8). When comparing subjects with and without dementia, there were no differences in the degree of atrophy, although the mini mental state examination (MMSE) scoring correlated weakly with the degree of medial temporal atrophy (MTA) (p = 0.04). Moreover, the CSF biomarker levels did not differ significantly between healthy (n = 27) and demented (n = 8) subjects (median values 715 vs 472 pg/ml for Abeta42, 414 vs 427 pg/ml for t-tau and 63 vs 60 pg/ml for p-tau). Similarly, there were no differences in the biomarker levels between individuals with mild (n = 24) and severe (n = 11) MTA (median values 643 vs 715 pg/ml for Abeta42, 441 vs 401 pg/ml for t-tau and 64 vs 53 pg/ml for p-tau). Finally, the neuropathological changes did not correlate with any of the other measures. CONCLUSION: In this cohort of aged men only a weak correlation could be seen between cognitive performance and MTA, whereas the various neuroradiological, biochemical and neuropathological measures did not correlate with each other. Thus, AD biomarkers seem to be less informative in subjects of an advanced age. PMID- 28886706 TI - Can Randall's plug composed of calcium oxalate form via the free particle mechanism? AB - BACKGROUND: The likelihood of a Randall's plug composed of calcium oxalate monohydrate (COM) forming by the free particle mechanism in a model of kidney with a structure recently described by Robertson was examined at the most favourable conditions for the considered mechanism. METHODS: The Robertson model of the kidney is used in the following development. The classical theory of crystallization was used for calculations. RESULTS: Initial COM nuclei were assumed to form at the beginning of the ascending loop of Henle where the supersaturation with respect to COM has been shown to reach the threshold level for spontaneous nucleation. Nucleation proceeds by a heterogeneous mechanism. The formed particles are transported in the nephron by a laminar flow of liquid with a parabolic velocity profile. Particles travel with a velocity dependent on their position in the cross-section of the nephron assumed to be straight tubule with smooth walls and without any sharp bends and kinks. These particles move faster with time as they grow as a result of being surrounded by the supersaturated liquid. Individual COM particles (crystals) can reach maximum diameter of 5.2 * 10-6 m, i.e. 5.2 MUm, at the opening of the CD and would thus always be washed out of the CD into the calyx regardless of the orientation of the CD. Agglomeration of COM crystals forms a fractal object with an apparent density lower than the density of solid COM. The agglomerate that can block the beginning of the CD is composed of more crystals than are available even during crystaluria. Moreover the settling velocity of agglomerate blocking the opening of the CD is lower than the liquid flow and thus such agglomerate would be washed out even from upward-draining CD. CONCLUSIONS: The free particle mechanism may be responsible for the formation of a Randall's plug composed by COM only in specific infrequent cases such as an abnormal structure of kidney. Majority of incidences of Randall's plug development by COM are caused by mechanism different from the free particle mechanism. PMID- 28886708 TI - Cancer heterogeneity: converting a limitation into a source of biologic information. AB - Analysis of spatial and temporal genetic heterogeneity in human cancers has revealed that somatic cancer evolution in most cancers is not a simple linear process composed of a few sequential steps of mutation acquisitions and clonal expansions. Parallel evolution has been observed in many early human cancers resulting in genetic heterogeneity as well as multilineage progression. Moreover, aneuploidy as well as structural chromosomal aberrations seems to be acquired in a non-linear, punctuated mode where most aberrations occur at early stages of somatic cancer evolution. At later stages, the cancer genomes seem to get stabilized and acquire only few additional rearrangements. While parallel evolution suggests positive selection of driver mutations at early stages of somatic cancer evolution, stabilization of structural aberrations at later stages suggests that negative selection takes effect when cancer cells progressively lose their tolerance towards additional mutation acquisition. Mixing of genetically heterogeneous subclones in cancer samples reduces sensitivity of mutation detection. Moreover, driver mutations present only in a fraction of cancer cells are more likely to be mistaken for passenger mutations. Therefore, genetic heterogeneity may be considered a limitation negatively affecting detection sensitivity of driver mutations. On the other hand, identification of subclones and subclone lineages in human cancers may lead to a more profound understanding of the selective forces which shape somatic cancer evolution in human cancers. Identification of parallel evolution by analyzing spatial heterogeneity may hint to driver mutations which might represent additional therapeutic targets besides driver mutations present in a monoclonal state. Likewise, stabilization of cancer genomes which can be identified by analyzing temporal genetic heterogeneity might hint to genes and pathways which have become essential for survival of cancer cell lineages at later stages of cancer evolution. These genes and pathways might also constitute patient specific therapeutic targets. PMID- 28886709 TI - Improving the production of applied health research findings: insights from a qualitative study of operational research. AB - BACKGROUND: Knowledge produced through applied health research is often of a form not readily accessible to or actionable by policymakers and practitioners, which hinders its implementation. Our aim was to identify research activities that can support the production of knowledge tailored to inform policy and practice. To do this, we studied an operational research approach to improving the production of applied health research findings. METHODS: A 2-year qualitative study was conducted of the operational research contribution to a multidisciplinary applied health research project that was successful in rapidly informing national policy. Semi-structured interviews (n = 20) were conducted with all members of the project's research team and advisory group (patient and health professional representatives and academics). These were augmented by participant (> 150 h) and non-participant (> 15 h) observations focusing on the process and experience of attempting to support knowledge production. Data were analysed thematically using QSR NVivo software. RESULTS: Operational research performed a knowledge mediation role shaped by a problem-focused approach and an intent to perform those tasks necessary to producing readily implementable knowledge but outwith the remit of other disciplinary strands of the project. Three characteristics of the role were found to support this: engaging and incorporating different perspectives to improve services by capturing a range of health professional and patient views alongside quantitative and qualitative research evidence; rendering data meaningful by creating and presenting evidence in forms that are accessible to and engage different audiences, enabling them to make sense of it for practical use; and maintaining perceived objectivity and rigour by establishing credibility, perceived neutrality and confidence in the robustness of the research in order to unite diverse professionals in thinking creatively about system-wide service improvement. CONCLUSIONS: Our study contributes useful empirical insights about knowledge mediation activities within multidisciplinary applied health research projects that support the generation of accessible, practice-relevant and actionable knowledge. Incorporating such activities, or a dedicated role, for mediating knowledge production within such projects could help to enhance the uptake of research findings into routine healthcare and warrants further consideration. PMID- 28886710 TI - Travel patterns and demographic characteristics of malaria cases in Swaziland, 2010-2014. AB - BACKGROUND: As Swaziland progresses towards national malaria elimination, the importation of parasites into receptive areas becomes increasingly important. Imported infections have the potential to instigate local transmission and sustain local parasite reservoirs. METHODS: Travel histories from Swaziland's routine surveillance data from January 2010 to June 2014 were extracted and analysed. The travel patterns and demographics of rapid diagnostic test (RDT) confirmed positive cases identified through passive and reactive case detection (RACD) were analysed and compared to those found to be negative through RACD. RESULTS: Of 1517 confirmed cases identified through passive surveillance, 67% reported travel history. A large proportion of positive cases reported domestic or international travel history (65%) compared to negative cases (10%). The primary risk factor for malaria infection in Swaziland was shown to be travel, more specifically international travel to Mozambique by 25- to 44-year old males, who spent on average 28 nights away. Maputo City, Inhambane and Gaza districts were the most likely travel destinations in Mozambique, and 96% of RDT-positive international travellers were either Swazi (52%) or Mozambican (44%) nationals, with Swazis being more likely to test negative. All international travellers were unlikely to have a bed net at home or use protection of any type while travelling. Additionally, paths of transmission, important border crossings and means of transport were identified. CONCLUSION: Results from this analysis can be used to direct national and well as cross-border targeting of interventions, over space, time and by sub-population. The results also highlight that collaboration between neighbouring countries is needed to tackle the importation of malaria at the regional level. PMID- 28886707 TI - Health outcomes of non-nutritive sweeteners: analysis of the research landscape. AB - BACKGROUND: Food products containing non-nutritive sweeteners (NNSs) instead of sugar have become increasingly popular in the last decades. Their appeal is obviously related to their calorie-free sweet taste. However, with the dramatic increase in their consumption, it is reasonable and timely to evaluate their potential health benefits and, more importantly, potential adverse effects. The main aim of this scoping review was to map the evidence about health outcomes possibly associated with regular NNS consumption by examining the extent, range, and nature of research activity in this area. METHODS: We systematically searched Ovid MEDLINE, EMBASE and the Cochrane CENTRAL databases for studies on NNSs (artificial sweeteners or natural, non-caloric sweeteners, either used individually or in combination) using text terms with appropriate truncation and relevant indexing terms. All human studies investigating any health outcomes of a NNS intervention or exposure were eligible for inclusion. No studies were excluded based on language, study design or methodological quality. Data for each health outcome were summarized in tabular form and were discussed narratively. RESULTS: Finally, we included 372 studies in our scoping review, comprising 15 systematic reviews, 155 randomized controlled trials (RCTs), 23 non-randomized controlled trials, 57 cohort studies, 52 case-control studies, 28 cross sectional studies and 42 case series/case reports. In healthy subjects, appetite and short term food intake, risk of cancer, risk of diabetes, risk of dental caries, weight gain and risk of obesity are the most investigated health outcomes. Overall there is no conclusive evidence for beneficial and harmful effects on those outcomes. Numerous health outcomes including headaches, depression, behavioral and cognitive effects, neurological effects, risk of preterm delivery, cardiovascular effects or risk of chronic kidney disease were investigated in fewer studies and further research is needed. In subjects with diabetes and hypertension, the evidence regarding health outcomes of NNS use is also inconsistent. CONCLUSIONS: This scoping review identifies the needs for future research to address the numerous evidence gaps related to health effects of NNSs use.It also specifies the research questions and areas where a systematic review with meta-analyses is required for the proper evaluation of health outcomes associated to regular NNSs consumption. PMID- 28886711 TI - Structure and functional impact of seed region variant in MIR-499 gene family in bronchial asthma. AB - BACKGROUND: Small non-coding RNAs (microRNAs) have been evolved to master numerous cellular processes. Genetic variants within microRNA seed region might influence microRNA biogenesis and function. The study aimed at determining the role of microRNA-499 (MIR-499) gene family polymorphism as a marker for susceptibility and progression of bronchial asthma and to analyze the structural and functional impact of rs3746444 within the seed region. METHODS: Genotyping for 192 participants (96 patients and 96 controls) in the discovery phase and 319 subjects (115 patients and 204 controls) in the replication phase was performed via Real Time-Polymerase Chain Reaction technology. Patients underwent the methacholine challenge test and biochemical analysis. Gene structural and functional analysis, target prediction, annotation clustering, and pathway enrichment analysis were executed. Predicted functional effect of rs37464443 SNP was analyzed. RESULTS: miR-499 gene family is highly implicated in inflammation related signaling pathways. Rs374644 (A > G) in MIR499A and MIR499B within the seed region could disrupt target genes and create new genes. The G variant was associated with high risk of developing asthma under all genetic association models (G versus A: OR = 3.27, 95% CI = 2.53-4.22; GG versus AA: OR = 9.52, 95% CI = 5.61-16.5; AG versus AA: OR = 2.13, 95% CI = 1.24-3.46; GG + AG versus AA: OR = 4.43, 95% CI = 2.88-6.82). GG genotype was associated with poor pre bronchodilator FEV1 (p = 0.047) and the worst bronchodilator response after Salbutamol inhalation, represented in low peaked expiratory flow rate (p = 0.035). CONCLUSIONS: miR-499 rs3746444 (A > G) polymorphism was associated with asthma susceptibility and bronchodilator response in Egyptian children and adolescents. Further functional analysis is warranted to develop more specific theranostic agents for selecting targeted therapy. PMID- 28886712 TI - The effect of alphacypermethrin-treated mesh protection against African horse sickness virus vectors on jet stall microclimate, clinical variables and faecal glucocorticoid metabolites of horses. AB - BACKGROUND: African horse sickness (AHS) is of importance to health and international trade in horses worldwide. During export from and transit through AHS endemic countries or zones, physical and chemical measures to protect horses from the vectors of AHS virus (AHSV) are recommended by the World Organization for Animal Health. Protection of containerized air transport systems for horses (jet stalls) with alphacypermethrin insecticide-treated high density polyethylene mesh is effective in reducing the Culicoides midge vector attack rate. In order to determine the effect of this mesh on jet stall ventilation and horse welfare under temperate climatic conditions, jet stall microclimate, clinical variables and faecal glucocorticoid metabolite (FGM) levels of 12 horses were monitored during overnight housing in either a treated or untreated stall in two blocks of a 2 * 3 randomized crossover design. RESULTS: Temperature difference between the treated stall and outside was significantly higher than the difference between the untreated stall and outside at 1/15 time points only (P = 0.045, r = 0.70). Relative humidity (RH) difference between the treated stall and outside did not differ from the untreated stall and outside. Temperature and RH in the treated stall were highly and significantly correlated with outside temperature (r = 0.96, P < 0.001) and RH (r = 0.95, P < 0.001), respectively. No significant differences were detected between rectal temperatures, pulse and respiratory rates of horses in the treated stall compared to the untreated stall. Mean FGM concentrations for horses housed in the treated stall peaked earlier (24 h) and at a higher concentration than horses housed in the untreated stall (48 h), but were not significantly different from baseline. No significant difference was detected in FGM concentrations when the treated and untreated stall groups were compared at individual time points up to 72 h after exiting the jet stall. CONCLUSIONS: Alphacypermethrin-treated HDPE mesh could be used under temperate climatic conditions to protect horses in jet stalls against AHSV vectors, without compromising jet stall microclimate and horse welfare. PMID- 28886713 TI - Increased activated regulatory T cells proportion correlate with the severity of idiopathic pulmonary fibrosis. AB - BACKGROUND: Regulatory T cells (Tregs) are crucial in maintaining immune tolerance and immune homeostasis, but their role in idiopathic pulmonary fibrosis (IPF) is unclear. This study was designed to explore the role of Tregs in IPF. METHODS: Percentages of Tregs and their subpopulations in peripheral blood (PB) and bronchoalveolar lavage (BAL) samples were determined by flow cytometry in 29 patients with IPF, 19 patients with primary Sjogren's syndrome-related interstitial pneumonia (pSS-IP), and 23 healthy controls (HCs). RESULTS: In peripheral blood, no difference was found in CD4+CD25+Foxp3+ Treg percentages among patients with IPF, pSS-IP, or HCs. However, activated Treg (aTreg) fractions among CD4+ T cells increased significantly in IPF compared with pSS-IP or HCs. Being consistent with the result from the PB, aTreg fractions among CD4+ T cells in IPF also increased significantly compared with pSS-IP or HCs, accompanied by increased fraction III compared with HCs in BAL. IPF patients had lower levels of resting Tregs (rTregs) from the thymus than did HCs, whereas aTreg levels originating from the thymus did not significantly differ from HCs. Both rTregs and aTregs proliferated in IPF, with aTregs being more proliferative than rTregs. Both rTregs and aTregs significantly inhibited proliferation of CD4+ T lymphocytes in vitro. The percentage of aTregs was correlated negatively with predicted diffusing capacity values for carbon monoxide and positively with GAP index in IPF. CONCLUSIONS: Our study showed the imbalance between subpopulations of Tregs in IPF. Increased aTregs proportion in the peripheral blood correlated inversely with disease severity. PMID- 28886714 TI - The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children. AB - BACKGROUND: Oxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initiation and resolution of inflammation during microbial infections. Metabolic complications in malaria are recognized contributors to severe and fatal malaria, but the impact of malaria infection on the production of small lipid derived signalling molecules is unknown. Knowledge of immunoregulatory patterns of these molecules in malaria is of great value for better understanding of the disease and improvement of treatment regimes, since the action of these classes of molecules is directly connected to the inflammatory response of the organism. METHODS: Detection of oxylipins and endocannabinoids from plasma samples from forty children with uncomplicated and severe malaria as well as twenty controls was done after solid phase extraction followed by chromatography mass spectrometry analysis. The stable isotope dilution method was used for compound quantification. Data analysis was done with multivariate (principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA(r)) and univariate approaches (receiver operating characteristic (ROC) curves, t tests, correlation analysis). RESULTS: Forty different oxylipin and thirteen endocannabinoid metabolites were detected in the studied samples, with one oxylipin (thromboxane B2, TXB2) in significantly lower levels and four endocannabinoids (OEA, PEA, DEA and EPEA) at significantly higher levels in infected individuals as compared to controls according to t test analysis with Bonferroni correction. Three oxylipins (13-HODE, 9-HODE and 13-oxo ODE) were higher in severe compared to uncomplicated malaria cases according to the results from multivariate analysis. Observed changes in oxylipin levels can be connected to activation of cytochrome P450 (CYP) and 5-lipoxygenase (5-LOX) metabolic pathways in malaria infected individuals compared to controls, and related to increased levels of all linoleic acid oxylipins in severe patients compared to uncomplicated ones. The endocannabinoids were extremely responsive to malaria infection with majority of this class of molecules found at higher levels in infected individuals compared to controls. CONCLUSIONS: It was possible to detect oxylipin and endocannabinoid molecules that can be potential biomarkers for differentiation between malaria infected individuals and controls and between different classes of malaria. Metabolic pathways that could be targeted towards an adjunctive therapy in the treatment of malaria were also pinpointed. PMID- 28886716 TI - Intralobar pulmonary sequestration displayed as localized emphysema on computed tomography image. AB - BACKGROUND: Pulmonary sequestration is a relatively rare condition in which a systemic artery supplies blood to an abnormal lung tissue and the normal connection with the bronchial tree is absent. It can be displayed as various signs on the computed tomography image, but emphysema is extremely rare. CASE PRESENTATION: We describe the case of a 35-year-old man with intralobar pulmonary sequestration that appeared as localized emphysema on the computed tomography image. The 3-D reconstruction revealed the presence of an anomalous feeding artery and the absence of normal connection with the bronchial tree. CONCLUSION: We presumed that it was a type between "anomalous systemic arterial supply to the normal lung" and the common type of pulmonary sequestration. Common pulmonary lobectomy was performed and the patient recovered well. PMID- 28886715 TI - Peroxisome proliferator-activated receptor-gamma: potential molecular therapeutic target for HIV-1-associated brain inflammation. AB - BACKGROUND: Despite the use of combination antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated brain inflammation. Primary cellular targets of HIV-1 in the brain are macrophages, microglia, and to a certain extent astrocytes which in response to infection release inflammatory markers, viral proteins [i.e., glycoprotein 120 (gp120)] and exhibit impaired glutamate uptake. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Compelling evidence suggests that PPARgamma exerts anti-inflammatory properties in neurological disorders. The goal of this study was to examine the role of PPARgamma in the context of HIV-1ADA gp120-induced inflammation in vitro, in primary cultures of rat astrocytes and microglia, and in vivo, in a rodent model of HIV-1ADA gp120-associated brain inflammation. METHODS: Primary mixed cultures of rat astrocytes and microglia were treated with PPARgamma agonists (rosiglitazone or pioglitazone) and exposed to HIV-1ADA gp120. Inflammatory cytokines and indicator of oxidative stress response (TNFalpha, IL-1beta, iNOS) were measured using qPCR, and glutamate transporter (GLT-1) was quantified by immunoblotting. In vivo, rats were administered an intracerebroventricular injection of HIV-1ADA gp120 and an intraperitoneal injection of PPARgamma agonist (rosiglitazone) or co-administration with PPARgamma antagonist (GW9662). qPCR and immunoblotting analyses were applied to measure inflammatory markers, GLT-1 and PPARgamma. RESULTS: In primary mixed cultures of rat astrocytes and microglia, HIV-1ADA gp120 exposure resulted in a significant elevation of inflammatory markers and a decrease in GLT-1 expression which were significantly attenuated with rosiglitazone or pioglitazone treatment. Similarly, in vivo, treatment with rosiglitazone reversed the gp120-mediated inflammatory response and downregulation of GLT-1. Furthermore, we demonstrated that the anti-inflammatory effects of PPARgamma agonist rosiglitazone were mediated through inhibition of NF kappaB. CONCLUSION: Our data demonstrate that gp120 can induce an inflammatory response and decrease expression of GLT-1 in the brain in vitro and in vivo. We have also successfully shown that these effects can be reversed by treatment with PPARgamma agonists, rosiglitazone or pioglitazone. Together our data suggest that targeting PPARgamma signaling may provide an option for preventing/treating HIV associated brain inflammation. PMID- 28886717 TI - The association between dietary protein intake and colorectal cancer risk: a meta analysis. AB - BACKGROUND: Association between dietary protein intake and colorectal cancer risk has not been fully quantified, while the results were controversial. This study aimed to evaluate the role of protein intake in the development of colorectal cancer. METHODS: PUBMED and EMBASE were searched up to December 2016. Two independent reviewers independently extracted data from eligible studies. Relative risk (RR) with 95% confidence intervals (CI) was pooled using random effects model to estimate the result. Besides, publication bias and sensitivity analysis were conducted. RESULTS: Thirteen articles involving 21 studies comprising 8187 cases were included in this report. The pooled RR of colorectal cancer was 1.006 (95% CI = 0.857-1.179) indicating that there is no significant association between dietary protein intake and colorectal cancer risk. Furthermore, the pooled RRs for colon cancer and rectum cancer were 1.135(95% CI = 0.871-1.480) and 0.773(95% CI = 0.538-1.111), respectively, with the highest category of dietary protein intake. The association was not significant either in subgroup analysis of study design, protein type (animal protein or vegetable protein), sex, and or geographic locations. CONCLUSIONS: The present study indicated that the highest category compared to the lowest category of protein intake had no significant association on colorectal cancer risk. Dose-response analysis was not conducted due to limited information provided. Therefore, more studies with large cases and participants as well as detailed amounts of dietary protein intake are wanted to confirm this result. PMID- 28886718 TI - Repositioning drugs for traumatic brain injury - N-acetyl cysteine and Phenserine. AB - Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults of less than 45 years of age and the elderly, and contributes to about 30% of all injury deaths in the United States of America. Whereas there has been a significant improvement in our understanding of the mechanism that underpin the primary and secondary stages of damage associated with a TBI incident, to date however, this knowledge has not translated into the development of effective new pharmacological TBI treatment strategies. Prior experimental and clinical studies of drugs working via a single mechanism only may have failed to address the full range of pathologies that lead to the neuronal loss and cognitive impairment evident in TBI and other disorders. The present review focuses on two drugs with the potential to benefit multiple pathways considered important in TBI. Notably, both agents have already been developed into human studies for other conditions, and thus have the potential to be rapidly repositioned as TBI therapies. The first is N-acetyl cysteine (NAC) that is currently used in over the counter medications for its anti-inflammatory properties. The second is (-)-phenserine ((-)-Phen) that was originally developed as an experimental Alzheimer's disease (AD) drug. We briefly review background information about TBI and subsequently review literature suggesting that NAC and (-)-Phen may be useful therapeutic approaches for TBI, for which there are no currently approved drugs. PMID- 28886719 TI - Self-reported eating rate is associated with weight status in a Dutch population: a validation study and a cross-sectional study. AB - BACKGROUND: Observational studies performed in Asian populations suggest that eating rate is related to BMI. This paper investigates the association between self-reported eating rate (SRER) and body mass index (BMI) in a Dutch population, after having validated SRER against actual eating rate. METHODS: Two studies were performed; a validation and a cross-sectional study. In the validation study SRER (i.e., 'slow', 'average', or 'fast') was obtained from 57 participants (men/women = 16/41, age: mean +/- SD = 22.6 +/- 2.8 yrs., BMI: mean +/- SD = 22.1 +/- 2.8 kg/m2) and in these participants actual eating rate was measured for three food products. Using analysis of variance the association between SRER and actual eating rate was studied. The association between SRER and BMI was investigated in cross-sectional data from the NQplus cohort (i.e., 1473 Dutch adults; men/women = 741/732, age: mean +/- SD = 54.6 +/- 11.7 yrs., BMI: mean +/- SD = 25.9 +/- 4.0 kg/m2) using (multiple) linear regression analysis. RESULTS: In the validation study actual eating rate increased proportionally with SRER (for all three food products P < 0.01). In the cross-sectional study SRER was positively associated with BMI in both men and women (P = 0.03 and P < 0.001, respectively). Self reported fast-eating women had a 1.13 kg/m2 (95% CI 0.43, 1.84) higher BMI compared to average-speed-eating women, after adjusting for confounders. This was not the case in men; self-reported fast-eating men had a 0.29 kg/m2 (95% CI 0.22, 0.80) higher BMI compared to average-speed-eating men, after adjusting for confounders. CONCLUSIONS: These studies show that self-reported eating rate reflects actual eating rate on a group-level, and that a high self-reported eating rate is associated with a higher BMI in this Dutch population. PMID- 28886720 TI - Development of an electrooculogram-based eye-computer interface for communication of individuals with amyotrophic lateral sclerosis. AB - BACKGROUND: Electrooculogram (EOG) can be used to continuously track eye movements and can thus be considered as an alternative to conventional camera based eye trackers. Although many EOG-based eye tracking systems have been studied with the ultimate goal of providing a new way of communication for individuals with amyotrophic lateral sclerosis (ALS), most of them were tested with healthy people only. In this paper, we investigated the feasibility of EOG based eye-writing as a new mode of communication for individuals with ALS. METHODS: We developed an EOG-based eye-writing system and tested this system with 18 healthy participants and three participants with ALS. We also applied a new method for removing crosstalk between horizontal and vertical EOG components. All study participants were asked to eye-write specially designed patterns of 10 Arabic numbers three times after a short practice session. RESULTS: Our system achieved a mean recognition rates of 95.93% for healthy participants and showed recognition rates of 95.00%, 66.67%, and 93.33% for the three participants with ALS. The low recognition rates in one of the participants with ALS was mainly due to miswritten letters, the number of which decreased as the experiment proceeded. CONCLUSION: Our proposed eye-writing system is a feasible human-computer interface (HCI) tool for enabling practical communication of individuals with ALS. PMID- 28886721 TI - Sex and gender considerations in transplantation research: protocol for a scoping review. AB - BACKGROUND: Despite the growing appreciation of the importance of sex and gender considerations in transplantation research, there is currently no framework or good practice guidelines for the appropriate handling of sex and gender issues in human allotransplantation research. METHODS: We will conduct a scoping review to synthesize the evidence on how matters of sex and gender have been handled in human allotransplantation research. We will survey the literature discussing sex and gender in relation to transplantation, including adult and pediatric patients, hematopoietic and solid organ transplant recipients as well as organ donors. We will search MEDLINE and Embase for literature discussing sex and gender in relation to transplantation. Two reviewers will independently evaluate the eligibility of all identified titles and abstracts for inclusion in the full text review, as well as data extraction. Descriptive data and information on how sex and gender have been considered in human transplantation research will be reported. DISCUSSION: This scoping review will be an important stepping stone towards the development of good practice guidelines on study design and analysis considerations when handling sex and gender issues in human transplantation research. This scoping review can also help identify methodological issues that restrict the translation of transplantation research findings into clinical practice related to underestimation of sex/gender differences. This review will ultimately identify major gaps, inform donor-recipient selection, guide personalized interventions, and prioritize research recommendations in human transplantation research. PMID- 28886722 TI - Tridax procumbens flavonoids: a prospective bioactive compound increased osteoblast differentiation and trabecular bone formation. AB - BACKGROUND: The Tridax procumbens extracts (TPE) are known for their ethno medicinal properties to increase osteogenic functioning in mesenchymal stem cells. Recently, we found that the T. procumbens flavonoids (TPF) significantly suppressed the RANKL-induced osteoclasts differentiation and bone resorption. The TPF also promoted osteoblasts differentiation and bone formation demonstrated by increasing bone formation markers in cultured mouse primary osteoblasts. However, the effects of the TPF on in vivo bone formation remain unclear. In this study, we investigated the effects of the TPF on in vivo bone formation, injected the TPF (20 mg/kg) twice a day in the low calcium diet mice and killed them after 21 day. Radiographic and histomorphometric analyses were performed on the dissected bones to determine the anabolic effects of the TPF. RESULTS: Bone mineral density and bone mineral content of the TPF-treated mice were significantly increased compared to the control mice. Bone formation-related indices like osteoblast number, osteoblast surface, bone volume, mineralizing surface, mineral apposition rate and bone formation rate were significantly increased in the TPF-treated mice compared to the control mice. CONCLUSION: Our findings point towards the stimulation of bone formation by TPF, suggested that the TPF could be a potential natural anabolic agent to treat patients with bone loss-associated diseases such as osteoporosis. PMID- 28886723 TI - Pancreatic injury in children: a case report and review of the literature. AB - BACKGROUND: Trauma is the main cause of morbidity and mortality in the pediatric population. Blunt trauma to the abdomen accounts for the majority of abdominal injuries in children. Pancreatic injury, although uncommon (2 to 9%), is the fourth most common solid organ injury. Unlike other solid organ injuries, pancreatic trauma may be subtle and difficult to diagnose. Computed tomography currently is the imaging modality of choice. As the incidence of pancreatic injury in children sustaining blunt abdominal trauma is low, management remains a challenge. CASE PRESENTATION: We present a 7-year-old Bahraini boy who sustained blunt trauma to his abdomen. He presented with abdominal pain and vomiting. His examination revealed abdominal distension and an epigastric bruise. Contrast enhanced computed tomography reported grade III liver injury, grade I bilateral renal injury, a suspicion of splenic injury, and a grade III to IV pancreatic injury. He was admitted to Pediatric Intensive Care Unit and was treated conservatively. Because he was stable, he was discharged to the surgical ward at day 3. At day 18 he developed a pancreatic pseudocyst that was aspirated and recurred at day 25 when a pigtail catheter was inserted. He was kept on total parenteral nutrition through a peripherally inserted central catheter. The pigtail catheter was removed on day 36 and a low fat diet was started by day 44. He was discharged home at day 55 in good health. Out-patient follow-up and serial abdominal ultrasound showed resolution of the cyst and normalization of blood tests. CONCLUSION: Non-operative management of pancreatic injury is effective and safe in hemodynamically stable patients with no other indication for surgery. PMID- 28886724 TI - Composition of Anopheles mosquitoes, their blood-meal hosts, and Plasmodium falciparum infection rates in three islands with disparate bed net coverage in Lake Victoria, Kenya. AB - BACKGROUND: Small islands serve as potential malaria reservoirs through which new infections might come to the mainland and may be important targets in malaria elimination efforts. This study investigated malaria vector species diversity, blood-meal hosts, Plasmodium infection rates, and long-lasting insecticidal net (LLIN) coverage on Mageta, Magare and Ngodhe Islands of Lake Victoria in western Kenya, a region where extensive vector control is implemented on the mainland. RESULTS: From trapping for six consecutive nights per month (November 2012 to March 2015) using CDC light traps, pyrethrum spray catches and backpack aspiration, 1868 Anopheles mosquitoes were collected. Based on their cytochrome oxidase I (COI) and intergenic spacer region PCR and sequencing, Anopheles gambiae s.l. (68.52%), Anopheles coustani (19.81%) and Anopheles funestus s.l. (11.67%) mosquitoes were differentiated. The mean abundance of Anopheles mosquitoes per building per trap was significantly higher (p < 0.001) in Mageta than in Magare and Ngodhe. Mageta was also the most populated island (n = 6487) with low LLIN coverage of 62.35% compared to Ngodhe (n = 484; 88.31%) and Magare (n = 250; 98.59%). Overall, 416 (22.27%) engorged Anopheles mosquitoes were analysed, of which 41 tested positive for Plasmodium falciparum infection by high resolution melting (HRM) analysis of 18S rRNA and cytochrome b PCR products. Plasmodium falciparum infection rates were 10.00, 11.76, 0, and 18.75% among blood-fed An. gambiae s.s. (n = 320), Anopheles arabiensis (n = 51), An. funestus s.s. (n = 29), and An. coustani (n = 16), respectively. Based on HRM analysis of vertebrate cytochrome b, 16S rRNA and COI PCR products, humans (72.36%) were the prominent blood-meal hosts of malaria vectors, but 20.91% of blood-meals were from non-human vertebrate hosts. CONCLUSIONS: These findings demonstrate high Plasmodium infection rates among the primary malaria vectors An. gambiae s.s. and An. arabiensis, as well as in An. coustani for the first time in the region, and that non-human blood-meal sources play an important role in their ecology. Further, the higher Anopheles mosquito abundances on the only low LLIN coverage island of Mageta suggests that high LLIN coverage has been effective in reducing malaria vector populations on Magare and Ngodhe Islands. PMID- 28886726 TI - Overviews of systematic reviews: great promise, greater challenge. AB - The proliferation of systematic reviews and escalating demand from policy makers has driven a newer form of evidence synthesis-overviews of systematic reviews. Systematic Reviews are publishing a special thematic series on overviews and are encouraging submissions on the development and evaluation of methods for this review type. The authors' of this editorial introduce the series by considering challenges that arise when conducting an overview and what methods guidance is available. They emphasise the importance of evaluating overview methods to understand the trade-offs of using different approaches and propose that a more systematic and coordinated approach to methods development would be beneficial. Finally, they consider the potential for overviews to drive improvements in the conduct and reporting of systematic reviews. PMID- 28886725 TI - Is it a supplementary benefit to use anti-inflammatory agents in the treatment of type 2 diabetes? AB - OBJECTIVE: The aim of this study was to investigate an independent correlation between high sensitivity C-reactive protein (hs-CRP) and glycated haemoglobin (HbA1c) on one side and between hs-CRP and arterial pressure in well glucose controlled type 2 diabetics on the other side. RESULTS: The mean of HbA1c was 6.37% in this study and 70.10% of participants had an HbA1c less than 7%. A positive correlation between hs-CRP and HbA1c was found in the current study (r = 0.232; P = 0.043) and we observed a decrease of 0.79% of HbA1c of the participants when their hs-CRP was less than 1 mg/l compared to that of the participants who had hs-CRP more than 1 mg/l (5.75 +/- 1.25% VS 6.54 +/- 1.42% P value = 0.04 Student). No correlation was found between hs-CRP and arterial pressure in this study. These results could justify the perspective use of anti inflammatory drugs in the management of T2D. However the presence of participants with HbA1c levels greater than 7% makes plausible the influence of confounding factors on the observed correlations. PMID- 28886727 TI - Antibody responses to P. falciparum blood stage antigens and incidence of clinical malaria in children living in endemic area in Burkina Faso. AB - BACKGROUND: High parasite-specific antibody levels are generally associated with low susceptibility to Plasmodium falciparum malaria. This has been supported by several studies in which clinical malaria cases of P. falciparum malaria were reported to be associated with low antibody avidities. This study was conducted to evaluate the role of age, malaria transmission intensity and incidence of clinical malaria in the induction of protective humoral immune response against P. falciparum malaria in children living in Burkina Faso. METHODS: We combined levels of IgG and IgG subclasses responses to P. falciparum antigens: Merozoite Surface Protein 3 (MSP3), Merozoite Surface Protein 2a (MSP2a), Merozoite Surface Protein 2b (MSP2b), Glutamate Rich Protein R0 (GLURP R0) and Glutamate Rich Protein R2 (GLURP R2) in plasma samples from 325 children under five (05) years with age, malaria transmission season and malaria incidence. RESULTS: We notice higher prevalence of P. falciparum infection in low transmission season compared to high malaria transmission season. While, parasite density was lower in low transmission than high transmission season. IgG against all antigens investigated increased with age. High levels of IgG and IgG subclasses to all tested antigens except for GLURP R2 were associated with the intensity of malaria transmission. IgG to MSP3, MSP2b, GLURP R2 and GLURP R0 were associated with low incidence of malaria. All IgG subclasses were associated with low incidence of P. falciparum malaria, but these associations were stronger for cytophilic IgGs. CONCLUSIONS: On the basis of the data presented in this study, we conclude that the induction of humoral immune response to tested malaria antigens is related to age, transmission season level and incidence of clinical malaria. PMID- 28886728 TI - Correlation of cord blood telomere length with birth weight. AB - BACKGROUND: Intrauterine growth restriction affects 3% of newborns; and the lightest 10% of whom are classified as small for gestational age (SGA). These low birth weight newborns are at increased risk of neonatal morbidity such as hypoxia and hypoglycaemia. In later life, they are at higher risk of several age-related diseases such as cardiovascular and metabolic disorders and dementia. As having short telomeres is also associated with these diseases, we tested if these newborns might already start with shorter telomeres at birth. FINDINGS: Relative telomere lengths were determined using quantitative real-time PCR in cord blood samples from 195 newborns of Chinese ancestry. Based on the telomere length normalised to a single copy gene and a reference DNA sample as internal control, we found statistically significant correlations between relative telomere length and both unadjusted and gestational age-adjusted birth weight, with the lighter newborns having shorter telomeres. The SGA birth weight group comprising the bottom 10% of the samples also had the shortest telomeres compared to the medium and heaviest birth weight groups. CONCLUSIONS: Our results indicate that there is reduction of cord blood telomere length for newborns with lower birth weight. PMID- 28886729 TI - Evaluation of Xpert MTB/RIF testing for rapid diagnosis of childhood pulmonary tuberculosis in children by Xpert MTB/RIF testing of stool samples in a low resource setting. AB - OBJECTIVE: Children with tuberculosis (TB) remain underdiagnosed due to difficulty in testing for Mycobacterium tuberculosis (MTB) infection. We evaluated the Xpert MTB/RIF assay for respiratory and stool testing in children for pulmonary TB through a cross-sectional study at tertiary care facilities in Karachi, Pakistan. Fifty children aged 0-15 years screened by a modified Kenneth Jones (KJ) score were included. Mycobacterial culture of respiratory samples was the microbiological standard against stool Xpert TB results. All positive TB cases were compared against a treatment response standard (TRS). RESULTS: Twelve study subjects were diagnosed by Xpert TB and nine by MTB culture. Compared with culture [gastric aspirates (GA)/sputum (spm)], stool Xpert TB had a sensitivity of 88.9% (95% CI 50.7-99.4) and a specificity of 95% (95% CI 81.8-99.1). Xpert TB stool versus GA/spm had sensitivity of 81.8% (95% CI 47.8-96.8) and specificity of 94.7% (95% CI 84.6-99.9). We found good agreement (kappa scores of >0.8) between stool Xpert, GA/spm Xpert and GA/spm culture. Stool Xpert PPV and NPV against TRS was 100 and 82.1% respectively. Stool Xpert TB is a relatively easy option for diagnosis for pulmonary childhood TB in a high burden low-resource setting. PMID- 28886730 TI - Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells. AB - BACKGROUND: Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. We previously identified that Annexin A2 is significantly up-regulated in cisplatin-resistant non-small cell lung cancer (NSCLC) A549/DDP cells. However, the exact function and molecular mechanism of Annexin A2 in cisplatin resistance of NSCLCs has not been determined. METHODS: Western blot and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. Immunohistochemistry was performed to analyze the expression of Annexin A2 in NSCLC tissue samples. MTS assay, Colony formation assays, AnnexinV/PI apoptosis assay, Luciferase Reporter Assay, Chromatin-immunoprecipitation, and nude mice xenograft assay were used to visualize the function of Annexin A2 on cisplatin resistance. RESULTS: Our results demonstrated that knockdown of Annexin A2 increased cisplatin sensitivity of cisplatin-resistant A549/DDP cells both in vitro and in vivo, whereas overexpression of Annexin A2 increased cisplatin resistance of A549, H460 and H1650 cells. Moreover, we found that Annexin A2 enhanced cisplatin resistance via inhibition of cisplatin-induced cell apoptosis. Our studies showed that Annexin A2 suppressed the expression of p53 through activation of JNK/c-Jun signaling, which in turn resulted in a decrease in the expression of p53 regulated apoptotic genes p21, GADD45 and BAX, as well as p53-dependent cell apoptosis. Furthermore, we found that in NSCLC cases that Annexin A2 is highly expressed; it is positively correlated with a poor prognosis, as well as correlated with short disease-free survival for patients who received chemotherapy after surgery. CONCLUSIONS: These data suggested that Annexin A2 induces cisplatin resistance of NSCLCs via regulation of JNK/c-Jun/p53 signaling, and provided an evidence that blockade of Annexin A2 could serve as a novel therapeutic approach for overcoming drug resistance in NSCLCs. PMID- 28886731 TI - Effects of bacitracin methylene disalicylate and diet change on gastrointestinal integrity and endotoxin permeability in the duodenum of broiler chicken. AB - OBJECTIVE: To determine the effect of bacitracin methylene disalicylate (BMD) and feed changes on gastrointestinal integrity, endotoxin permeability, and morphometric parameters in the duodenum of broilers. RESULTS: Birds were raised on a starter diet without growth promoting antibiotics for 31 days then switched to a grower diet. Four of the pens including 50 g/ton of BMD while 4 pens remained antibiotic free. Eight birds per treatment were sampled prior to the feed change and at 3 and 7 days following the feed change. Gastrointestinal integrity and endotoxin permeability in the duodenum were determined using a modified Ussing Chamber and an adjacent section fixed in 10% formalin for morphometric analysis. Data were analyzed using Proc Glimmix of SAS with the model fitting BMD treatment, time, and the interaction of BMD treatment and time as fixed effects. Intestinal integrity increased at d 3 and 7 compared to prior to the feed change and addition of BMD (P > 0.001) and villus height was decreased with BMD supplementation (P = 0.049). All other tested effects similar (P > 0.1). In conclusion, the practice of changing feed had a greater effect on intestinal health than addition of BMD. However, the factors driving these differences 42 are unclear. PMID- 28886732 TI - Optimized protocol for whole organ decellularization. AB - BACKGROUND: The idea of tissue decellularization to gain matrices for tissue engineering is promising. The aim of the present study is to establish a safe and reproducible protocol for solid tissue decellularization that prevents the architecture of the matrix with the inherent vascular network. METHODS: The study was performed in rat kidneys which were decellularized by a SDS-based perfusion protocol. Perfusion time and SDS concentration were systematically changed to obtain the shortest and most gentle protocol that leads to complete decellularization. RESULTS: We investigated kinetics of protein elution, decellularization success, and remaining cell toxicity. This resulted in a reproducible protocol, leading to safe decellularization with prevention of the inherent vascular network, without remaining detectable cell toxicity. The established protocol leads to solid tissue decellularization in only 7 h, which is by far shorter than the previously published methods. CONCLUSION: The established technique has the potential to become a relevant platform technology for tissue engineering of solid tissues. It provides a solution for the yet unsolved problem of vascularization. PMID- 28886734 TI - Promoting physical activity in worksite settings: results of a German pilot study of the online intervention Healingo fit. AB - BACKGROUND: Worldwide, one third of the adult population is insufficiently physically active. This fact has led to a strong demand for public health initiatives. Given the mixed evidence on the effectiveness of worksite interventions promoting physical activity (PA), a pedometer-based and gamified intervention, Healingo Fit, was developed and evaluated over a period of six weeks. METHODS: The effectiveness of Healingo Fit was evaluated as part of a randomized controlled trial (RCT) with two measurement points involving employees of an automobile manufacturer. Direct health promotion outcomes were assessed using self-developed items on PA knowledge, the HAPA brief scales and the exercise self-efficacy scale. IPAQ short version was used to assess different forms of PA behavior. Intervention effects were identified using a two-way analysis of variance (ANOVA) with repeated measurements. RESULTS: A total of 144 participants took part in the study (intervention group = 80, control group = 64). The results of the ANOVA show significant interaction effects (group x time) for health promotion outcomes (knowledge, intention, and self-efficacy), with medium to high effect sizes. In the health behavior related outcomes, there were significant improvements, with large effect sizes for low levels of PA, but not for moderate and high PA. Walking time increased by 125 min/week in the intervention group, corresponding to a percentage increase of 30% compared to baseline. CONCLUSIONS: Pedometer-based interventions using gamification elements can have positive effects not only on health promotion parameters but can also lead to an increase in PA behavior. The online format of Healingo Fit is suitable for reaching large numbers of people and achieving population effects. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00006105 , date of registration: 2017-03-24. PMID- 28886733 TI - Radix Puerariae and Fructus Crataegi mixture inhibits renal injury in type 2 diabetes via decreasing of AKT/PI3K. AB - BACKGROUND: Radix puerariae (RP) is a herbal medicines for diabetes, mainly because of anti-oxidative, insulin resistance and hypoglycemic effect. Fructus crataegi (FC) also possesses strong antioxidant activity in vitro. This study focused on the effects of herbal mixture of RP and FC (RPFC) on renal protection through a diabetic rat model. METHODS: Type 2 Diabetic model was established with high fat diet followed by injecting rats a low dose of STZ (25 mg/kg body weight). Rats were randomly divided into five groups: normal, high fat diet, diabetes mellitus, high fat diet plus RPFC prevention, and RPFC prevention before diabetes mellitus. RPFC was given to rats daily by intragastric gavage. The blood bio-chemical index and renal pathological changes were examined. The later includes hematoxylin and eosin staining, periodic acid schiff staining, and Masson trichrome staining. Protein levels of were determined by Western blot and immunohistochemical staining. mRNA levels were detected by RT-PCR. RESULTS: Rats prevented with RPFC resulted in decreasing blood glucose with corresponding vehicle treated rats. Glomerulus mesangial matrix expansion, renal capsule constriction, and renal tubular epithelial cell edema were less severe following RPFC prevention. Moreover, RPFC prevention reduced protein levels of PI3K, AKT, alpha-SMA and collagen IV in the kidney of diabetic rats. CONCLUSION: Combined prevention with RPFC may inhibit the PI3K/AKT pathway in the kidney, thereby prevent renal injury in diabetic rats. PMID- 28886735 TI - Sustainability in Health care by Allocating Resources Effectively (SHARE) 9: conceptualising disinvestment in the local healthcare setting. AB - BACKGROUND: This is the ninth in a series of papers reporting a program of Sustainability in Health care by Allocating Resources Effectively (SHARE) in a local healthcare setting. The disinvestment literature has broadened considerably over the past decade; however there is a significant gap regarding systematic, integrated, organisation-wide approaches. This debate paper presents a discussion of the conceptual aspects of disinvestment from the local perspective. DISCUSSION: Four themes are discussed: Terminology and concepts, Motivation and purpose, Relationships with other healthcare improvement paradigms, and Challenges to disinvestment. There are multiple definitions for disinvestment, multiple concepts underpin the definitions and multiple alternative terms convey these concepts; some definitions overlap and some are mutually exclusive; and there are systematic discrepancies in use between the research and practice settings. Many authors suggest that the term 'disinvestment' should be avoided due to perceived negative connotations and propose that the concept be considered alongside investment in the context of all resource allocation decisions and approached from the perspective of optimising health care. This may provide motivation for change, reduce disincentives and avoid some of the ethical dilemmas inherent in other disinvestment approaches. The impetus and rationale for disinvestment activities are likely to affect all aspects of the process from identification and prioritisation through to implementation and evaluation but have not been widely discussed. A need for mechanisms, frameworks, methods and tools for disinvestment is reported. However there are several health improvement paradigms with mature frameworks and validated methods and tools that are widely used and well-accepted in local health services that already undertake disinvestment-type activities and could be expanded and built upon. The nature of disinvestment brings some particular challenges for policy-makers, managers, health professionals and researchers. There is little evidence of successful implementation of 'disinvestment' projects in the local setting, however initiatives to remove or replace technologies and practices have been successfully achieved through evidence-based practice, quality and safety activities, and health service improvement programs. CONCLUSIONS: These findings suggest that the construct of 'disinvestment' may be problematic at the local level. A new definition and two potential approaches to disinvestment are proposed to stimulate further research and discussion. PMID- 28886736 TI - What do we know about the needs and challenges of health systems? A scoping review of the international literature. AB - BACKGROUND: While there is an extensive literature on Health System (HS) strengthening and on the performance of specific HSs, there are few exhaustive syntheses of the challenges HSs are facing worldwide. This paper reports the findings of a scoping review aiming to classify the challenges of HSs investigated in the scientific literature. Specifically, it determines the kind of research conducted on HS challenges, where it was performed, in which health sectors and on which populations. It also identifies the types of challenge described the most and how they varied across countries. METHODS: We searched 8 databases to identify scientific papers published in English, French and Italian between January 2000 and April 2016 that addressed HS needs and challenges. The challenges reported in the articles were classified using van Olmen et al.'s dynamic HS framework. Countries were classified using the Human Development Index (HDI). Our analyses relied on descriptive statistics and qualitative content analysis. RESULTS: 292 articles were included in our scoping review. 33.6% of these articles were empirical studies and 60.1% were specific to countries falling within the very high HDI category, in particular the United States. The most frequently researched sectors were mental health (41%), infectious diseases (12%) and primary care (11%). The most frequently studied target populations included elderly people (23%), people living in remote or poor areas (21%), visible or ethnic minorities (15%), and children and adolescents (15%). The most frequently reported challenges related to human resources (22%), leadership and governance (21%) and health service delivery (24%). While health service delivery challenges were more often examined in countries within the very high HDI category, human resources challenges attracted more attention within the low HDI category. CONCLUSIONS: This scoping review provides a quantitative description of the available evidence on HS challenges and a qualitative exploration of the dynamic relationships that HS components entertain. While health services research is increasingly concerned about the way HSs can adopt innovations, little is known about the system-level challenges that innovations should address in the first place. Within this perspective, four key lessons are drawn as well as three knowledge gaps. PMID- 28886737 TI - Students as anatomy near-peer teachers: a double-edged sword for an ancient skill. AB - BACKGROUND: A near-peer instructors (NPI) program was designed for 1st year medical students who successfully finished the Anatomy course, in order to develop their didactic ability and teaching skills, mostly for cadaver dissection. METHODS: Graduates of the training program were administered a voluntary survey at the end of the program, annually. Best graduates of the training program were offered a NPI position in the next academic year. They were evaluated by the first-year students, at the end of the Anatomy block. RESULTS: In a debriefing questionnaire at the end of the NPI training, on the five-point Likert scale (1 = lowest to 5 = highest), the overall rating ranged from 3.63 in 2013 to 3.71 in 2015. Learning prosection and anatomy demonstration skills scored on average from 4.30 to 4.36, respectively. The NPIs were then evaluated by first year students at the end of the next year's Anatomy block. On the Likert scale, the average score of NPIs ranged from 4.10 in 2014 to 4.75 in 2016, on the par with the general satisfaction score for the professional preclinical teachers during the same period (which ranged from 3.80 to 4.26). CONCLUSIONS: It is suggested that students as near-peer instructors can make a valuable contribution to the teaching faculty, especially in a new medical school. PMID- 28886738 TI - Gaps in care for patients with memory deficits after stroke: views of healthcare providers. AB - BACKGROUND: Stroke is a common cause of physical disability but is also strongly associated with cognitive impairment and a risk for future dementia. Despite national clinical guidelines, the service provided for stroke survivors with cognitive and memory difficulties varies across localities. This study critically evaluated the views of healthcare professionals about barriers and facilitators to their care. METHODS: Seventeen semi-structured individual interviews were conducted by a single interviewer with both primary and secondary care clinicians in regular contact with stroke-survivors. This included stroke medicine specialists, specialist nurses, physiotherapists, occupational therapists, general practitioners and primary care nurses. Topics included individual experiences of the current care offered to patients with cognitive impairment, assessment processes and inter-professional communication. Interviews were audio recorded and transcribed verbatim. Transcripts were thematically analysed and themes grouped into broad categories to facilitate interpretation. RESULTS: Data analysis identified four key themes as barriers to optimal care for stroke survivors with memory difficulties: 1) Less focus on memory and cognition in post stroke care; 2) Difficulties bringing up memory and cognitive problems post stroke; 3) Lack of clarity in current services; and, 4) Assumptions made by healthcare professionals introducing gaps in care. Facilitators included stronger links between primary and secondary care in addition to information provision at all stages of care. CONCLUSIONS: The care provided by stroke services is dominated by physical impairments. Clinicians are unsure who should take responsibility for follow-up of patients with cognitive problems. This is made even more difficult by the lack of experience in assessment and stigma surrounding potential diagnoses associated with these deficits. Service development should focus on increased cohesiveness between hospital and community care to create a clear care pathway for post-stroke cognitive impairment. PMID- 28886739 TI - An Australian general practice based strategy to improve chronic disease prevention, and its impact on patient reported outcomes: evaluation of the preventive evidence into practice cluster randomised controlled trial. AB - BACKGROUND: Implementing evidence-based chronic disease prevention with a practice-wide population is challenging in primary care. METHODS: PEP Intervention practices received education, clinical audit and feedback and practice facilitation. Patients (40-69 years) without chronic disease from trial and control practices were invited to participate in baseline and 12 month follow up questionnaires. Patient-recalled receipt of GP services and referral, and the proportion of patients at risk were compared over time and between intervention and control groups. Mean difference in BMI, diet and physical activity between baseline and follow up were calculated and compared using a paired t-test. Change in the proportion of patients meeting the definition for physical activity diet and weight risk was calculated using McNemar's test and multilevel analysis was used to determine the effect of the intervention on follow-up scores. RESULTS: Five hundred eighty nine patients completed both questionnaires. No significant changes were found in the proportion of patients reporting a BP, cholesterol, glucose or weight check in either group. Less than one in six at-risk patients reported receiving lifestyle advice or referral at baseline with little change at follow up. More intervention patients reported attempts to improve their diet and reduce weight. Mean score improved for diet in the intervention group (p = 0.04) but self-reported BMI and PA risk did not significantly change in either group. There was no significant change in the proportion of patients who reported being at-risk for diet, PA or weight, and no changes in PA, diet and BMI in multilevel linear regression adjusted for patient age, sex, practice size and state. There was good fidelity to the intervention but practices varied in their capacity to address changes. CONCLUSIONS: The lack of measurable effect within this trial may be attributable to the complexities around behaviour change and/or system change. This trial highlights some of the challenges in providing suitable chronic disease preventive interventions which are both scalable to whole practice populations and meet the needs of diverse practice structures. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12612000578808 (29/5/2012). This trial registration is retrospective as our first patient returned their consent on the 21/5/2012. Patient recruitment was ongoing until 31/10/2012. PMID- 28886741 TI - Taurine and tea polyphenols combination ameliorate nonalcoholic steatohepatitis in rats. AB - BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease, for which there is currently no safe and effective drug for therapy. In this study, we explored the effects of taurine, tea polyphenols (TPs), or a combination thereof, on NASH rats. METHODS: Rats were divided into a normal group, a high-fat diet induced model group and a treatment group (including taurine, TPs, or taurine + TPs treatment for 8 weeks). Twelve weeks later, all rats were sacrificed, and serum transaminase, lipid and lipopolysaccharide levels and hepatic oxidative stress levels were determined. Histological changes were evaluated. RESULTS: In NASH rats, hepatocyte damage, lipid disturbance, oxidative stress and elevated lipopolysaccharide levels were confirmed. Taurine treatment alleviated hepatocyte damage and oxidative stress. TPs treatment improved lipid metabolism and increased hepatic antioxidant activity. The therapeutic effects of taurine + TPs treatment on hepatocyte damage, lipid disturbance, and oxidative stress were superior to those of taurine and TPs treatment, respectively. Taurine, TPs and their combination all decreased serum lipopolysaccharide levels in NASH rats, but the combination of the compounds caused these levels to decrease more significantly than taurine or TPs treatment alone. CONCLUSION: Taurine combined with TPs treatment could relieve NASH by alleviating hepatocyte damage, decreasing oxidative stress and improving lipid metabolism and gut flora disturbance partly. Taurine and TPs combination may act as a new effective medicine for treating NASH patients. PMID- 28886740 TI - Sustainability in Health care by Allocating Resources Effectively (SHARE) 10: operationalising disinvestment in a conceptual framework for resource allocation. AB - BACKGROUND: This is the tenth in a series of papers reporting a program of Sustainability in Health care by Allocating Resources Effectively (SHARE) in a local healthcare setting. After more than a decade of research, there is little published evidence of active and successful disinvestment. The paucity of frameworks, methods and tools is reported to be a factor in the lack of success. However there are clear and consistent messages in the literature that can be used to inform development of a framework for operationalising disinvestment. This paper, along with the conceptual review of disinvestment in Paper 9 of this series, aims to integrate the findings of the SHARE Program with the existing disinvestment literature to address the lack of information regarding systematic organisation-wide approaches to disinvestment at the local health service level. DISCUSSION: A framework for disinvestment in a local healthcare setting is proposed. Definitions for essential terms and key concepts underpinning the framework have been made explicit to address the lack of consistent terminology. Given the negative connotations of the word 'disinvestment' and the problems inherent in considering disinvestment in isolation, the basis for the proposed framework is 'resource allocation' to address the spectrum of decision-making from investment to disinvestment. The focus is positive: optimising healthcare, improving health outcomes, using resources effectively. The framework is based on three components: a program for decision-making, projects to implement decisions and evaluate outcomes, and research to understand and improve the program and project activities. The program consists of principles for decision-making and settings that provide opportunities to introduce systematic prompts and triggers to initiate disinvestment. The projects follow the steps in the disinvestment process. Potential methods and tools are presented, however the framework does not stipulate project design or conduct; allowing application of any theories, methods or tools at each step. Barriers are discussed and examples illustrating constituent elements are provided. CONCLUSIONS: The framework can be employed at network, institutional, departmental, ward or committee level. It is proposed as an organisation-wide application, embedded within existing systems and processes, which can be responsive to needs and priorities at the level of implementation. It can be used in policy, management or clinical contexts. PMID- 28886742 TI - Patient involvement in the development of patient-reported outcome measures: The developers' perspective. AB - BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly used in health care. To capture the patient's perspective, patient involvement in PROM development is needed. As earlier research showed varying degrees of patient involvement in PROM development, this study aimed to investigate why PROM developers do or do not involve patients, how patients can be successfully involved and what the negative aspects and benefits of patient involvement are. METHODS: PROM developers who, according to an earlier scoping review, involved patients in at least two phases of PROM development or did not involve patients at all, were contacted for a telephone interview. The interviews were recorded, transcribed and analysed using a general inductive approach. RESULTS: From the PROM developers who involved patients, 21 developers were interviewed and three answered questions via e-mail. Most developers considered patient involvement necessary to create a valid questionnaire and relied on guidelines, personal experience and practical considerations for choosing a qualitative method. Negative aspects of patient involvement were mainly time investment and budget impact. One developer who did not involve patients was interviewed. Two developers sent back answers via e-mail. These developers did not involve patients because of limited resources or because no benefits were expected. CONCLUSION: Although PROM developers agree that patient involvement is necessary, a lack of resources can be a stumbling block. Most developers rely on guidelines, personal experience or practical considerations for choosing a qualitative method. Although this may be a good place to start, to optimize patient involvement developers should explicitly think about which methods would suit their study. PMID- 28886743 TI - Fatal poisonings in Northern Finland: causes, incidence, and rural-urban differences. AB - BACKGROUND: In this study we evaluate differences between rural and urban areas in the causes and incidence of fatal poisonings. METHODS: Data from all fatal poisonings that occurred in Northern Finland from 2007 to 2011 were retrieved from Cause of Death Registry death certificates provided by Statistics Finland. The demographics and causes of fatalities were compared between rural and urban areas. Incidences were calculated based on the population data. RESULTS: There were a total of 684 fatal poisonings during the study period and 57.9% (n = 396) occurred in the urban population. Ethanol was the most common primary poisoning agent in cases of fatal poisoning, accounting for 47.5% of cases in urban areas and 68.1% in rural areas (P < 0.001). Fatal poisonings caused by psychoactive pharmaceutical products and opioids were more common in urban areas (28.3% compared to 18.0%, P < 0.001). The crude incidence of fatal poisonings in the study area was 18.8 (17.4-20.2) per 100,000 inhabitants per year and there was no difference in incidence between urban and rural areas. In the youngest age group (15 to 24 years), the incidence of fatal poisonings observed in urban areas was two times higher than that in rural areas. DISCUSSION: Higher rate of fatal ethanol poisonings in rural areas could be linked to higher alcohol consumption in rural areas and also differences in drinking behaviour. Higher incidence of poisoning suicides in urban areas could be due to availability of different toxic agents as a suicidal method. Preventive measures could be key in reducing the number of fatal poisonings in both areas, as most of the fatal poisonings still occur outside hospital. CONCLUSION: There was a higher rate of fatal ethanol poisoning in rural areas and higher rate of fatal poisoning related to psychoactive pharmaceutical products and opioids in urban areas. There were twice as many fatal poisonings in the youngest age group (15-24 years) in urban areas compared to rural areas, and suicide was more common in urban areas. PMID- 28886744 TI - Identification of high-confidence RNA regulatory elements by combinatorial classification of RNA-protein binding sites. AB - Crosslinking immunoprecipitation sequencing (CLIP-seq) technologies have enabled researchers to characterize transcriptome-wide binding sites of RNA-binding protein (RBP) with high resolution. We apply a soft-clustering method, RBPgroup, to various CLIP-seq datasets to group together RBPs that specifically bind the same RNA sites. Such combinatorial clustering of RBPs helps interpret CLIP-seq data and suggests functional RNA regulatory elements. Furthermore, we validate two RBP-RBP interactions in cell lines. Our approach links proteins and RNA motifs known to possess similar biochemical and cellular properties and can, when used in conjunction with additional experimental data, identify high-confidence RBP groups and their associated RNA regulatory elements. PMID- 28886746 TI - Prevalence of antibodies to Brucella species in commercial raw bovine milk in Southwestern Uganda. AB - OBJECTIVES: The purpose and objective of this research was to explore the prevalence of antibodies against Brucella species in raw milk samples collected in Southwestern Uganda, one of the biggest milk producing regions in the Country. We hypothesized that there is a high level of antibodies in milk samples from this region. This builds more evidence to other studies in the region on the level contamination of raw milk. RESULTS: A total of 185 raw milk samples, collected from dairy farms and factories in southwestern region, were tested for antibodies to Brucella spp. using the milk ring test (MRT) and indirect Enzyme Linked Immunosorbent Assay (i-ELISA).We found a prevalence of 26.5% (49/185) by the two methods. This is related to previous reports in the region and adds more evidence on the need for further investigations to confirm the source of these antibodies and their relationship with disease in milk producing animals. PMID- 28886745 TI - Bayesian dose selection design for a binary outcome using restricted response adaptive randomization. AB - BACKGROUND: In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size. METHODS: To balance these challenges, a novel placebo controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage. RESULTS: For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data. CONCLUSIONS: Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy within the context of limited resources. While the design is general enough to apply to many situations, future work is needed to address interim analyses and the incorporation of models for dose response. PMID- 28886747 TI - Women's views and experiences of two alternative consent pathways for participation in a preterm intrapartum trial: a qualitative study. AB - BACKGROUND: The Cord Pilot Trial compared alternative policies for timing of cord clamping at very preterm birth at eight UK hospitals. In addition to standard written consent, an oral assent pathway was developed for use when birth was imminent. The aim of this study was to explore women's views and experiences of two alternative consent pathways to participate in the Cord Pilot Trial. METHODS: We conducted a qualitative study using semi-structured interviews. A total of 179 participants in the Cord Pilot Trial were sent a postal invitation to take part in interviews. Women who agreed were interviewed in person or by telephone to explore their experiences of two consent pathways for a preterm intrapartum trial. Data were analysed using inductive systematic thematic analysis. RESULTS: Twenty-three women who gave either written consent (n = 18) or oral assent followed by written consent (n = 5) to participate in the trial were interviewed. Five themes were identified: (1) understanding of the implications of randomisation, (2) importance of staff offering participation, (3) information about the trial and time to consider participation, (4) trial secondary in women's minds and (5) reasons for agreeing to take part in the trial. Experiences were similar for the two consent pathways. Women recruited by the oral assent pathway reported being given less information about the trial but felt it was sufficient to make a decision regarding participation. There were gaps in women's understanding of the trial and intervention, regardless of the consent pathway. CONCLUSIONS: Overall, women were positive about their experiences of being invited to participate in the trial. The oral assent pathway seems an acceptable option for women if the intervention is low-risk and time is limited. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN21456601 . Registered on 28 February 2013. PMID- 28886748 TI - ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation. AB - BACKGROUND: During pregnancy, as the mammary gland prepares for synthesis and delivery of milk to newborns, a luminal mammary epithelial cell (MEC) subpopulation proliferates rapidly in response to systemic hormonal cues that activate STAT5A. While the receptor tyrosine kinase ErbB4 is required for STAT5A activation in MECs during pregnancy, it is unclear how ErbB3, a heterodimeric partner of ErbB4 and activator of phosphatidyl inositol-3 kinase (PI3K) signaling, contributes to lactogenic expansion of the mammary gland. METHODS: We assessed mRNA expression levels by expression microarray of mouse mammary glands harvested throughout pregnancy and lactation. To study the role of ErbB3 in mammary gland lactogenesis, we used transgenic mice expressing WAP-driven Cre recombinase to generate a mouse model in which conditional ErbB3 ablation occurred specifically in alveolar mammary epithelial cells (aMECs). RESULTS: Profiling of RNA from mouse MECs isolated throughout pregnancy revealed robust Erbb3 induction during mid-to-late pregnancy, a time point when aMECs proliferate rapidly and undergo differentiation to support milk production. Litters nursed by ErbB3 KO dams weighed significantly less when compared to litters nursed by ErbB3 WT dams. Further analysis revealed substantially reduced epithelial content, decreased aMEC proliferation, and increased aMEC cell death during late pregnancy. Consistent with the potent ability of ErbB3 to activate cell survival through the PI3K/Akt pathway, we found impaired Akt phosphorylation in ErbB3 KO samples, as well as impaired expression of STAT5A, a master regulator of lactogenesis. Constitutively active Akt rescued cell survival in ErbB3-depleted aMECs, but failed to restore STAT5A expression or activity. Interestingly, defects in growth and survival of ErbB3 KO aMECs as well as Akt phosphorylation, STAT5A activity, and expression of milk-encoding genes observed in ErbB3 KO MECs progressively improved between late pregnancy and lactation day 5. We found a compensatory upregulation of ErbB4 activity in ErbB3 KO mammary glands. Enforced ErbB4 expression alleviated the consequences of ErbB3 ablation in aMECs, while combined ablation of both ErbB3 and ErbB4 exaggerated the phenotype. CONCLUSIONS: These studies demonstrate that ErbB3, like ErbB4, enhances lactogenic expansion and differentiation of the mammary gland during pregnancy, through activation of Akt and STAT5A, two targets crucial for lactation. PMID- 28886749 TI - Bacterial microbiota associated with Rhipicephalus sanguineus (s.l.) ticks from France, Senegal and Arizona. AB - BACKGROUND: Ticks of the group Rhipicephalus sanguineus (sensu lato) are distributed worldwide and are major pathogen vectors of both dogs and humans. Previous phylogenetic reconstructions have suggested the existence of two main lineages within this group, "Tropical" and "Temperate". Symbiotic interactions contribute to vector development, survival, reproduction and competence. The diversity of microbial communities associated with different populations of R. sanguineus (s.l.) remains poorly characterized, however, this knowledge will aid in future studies of hosts-microbiota-pathogen interactions. To gain insight into the bacterial communities associated with R. sanguineus (s.l.) ticks, 40 specimens from France, Senegal and Arizona were analyzed by high-throughput 16S amplicon sequencing. All tick specimens were taxonomically classified using the mitochondrial 12S rDNA gene, which provides sufficient phylogenetic resolution to discriminate different lineages of R. sanguineus. RESULTS: Rhipicephalus sanguineus (s.l.) samples from Senegal belonged to the "Tropical" lineage, samples from France belonged to the "Temperate" lineage, whereas both lineages were identified in samples from Arizona. Regardless of origin, each bacterial microbiota was dominated by three genera: Coxiella, Rickettsia and Bacillus. Rickettsia and Coxiella were the two main genera found in females whereas males had a higher proportion of Bacillus. Significant differences of relative abundances were evidenced between specimens from different geographical origins. CONCLUSIONS: This study highlights differences in the microbiota composition within R. sanguineus (s.l.) specimens from different genotypes, genders and geographical origins. This knowledge will help in future studies of the symbiotic interactions, biology and vector competence of the R. sanguineus (s.l.) complex. PMID- 28886750 TI - Evidence-based gene models for structural and functional annotations of the oil palm genome. AB - BACKGROUND: Oil palm is an important source of edible oil. The importance of the crop, as well as its long breeding cycle (10-12 years) has led to the sequencing of its genome in 2013 to pave the way for genomics-guided breeding. Nevertheless, the first set of gene predictions, although useful, had many fragmented genes. Classification and characterization of genes associated with traits of interest, such as those for fatty acid biosynthesis and disease resistance, were also limited. Lipid-, especially fatty acid (FA)-related genes are of particular interest for the oil palm as they specify oil yields and quality. This paper presents the characterization of the oil palm genome using different gene prediction methods and comparative genomics analysis, identification of FA biosynthesis and disease resistance genes, and the development of an annotation database and bioinformatics tools. RESULTS: Using two independent gene-prediction pipelines, Fgenesh++ and Seqping, 26,059 oil palm genes with transcriptome and RefSeq support were identified from the oil palm genome. These coding regions of the genome have a characteristic broad distribution of GC3 (fraction of cytosine and guanine in the third position of a codon) with over half the GC3-rich genes (GC3 >= 0.75286) being intronless. In comparison, only one-seventh of the oil palm genes identified are intronless. Using comparative genomics analysis, characterization of conserved domains and active sites, and expression analysis, 42 key genes involved in FA biosynthesis in oil palm were identified. For three of them, namely EgFABF, EgFABH and EgFAD3, segmental duplication events were detected. Our analysis also identified 210 candidate resistance genes in six classes, grouped by their protein domain structures. CONCLUSIONS: We present an accurate and comprehensive annotation of the oil palm genome, focusing on analysis of important categories of genes (GC3-rich and intronless), as well as those associated with important functions, such as FA biosynthesis and disease resistance. The study demonstrated the advantages of having an integrated approach to gene prediction and developed a computational framework for combining multiple genome annotations. These results, available in the oil palm annotation database ( http://palmxplore.mpob.gov.my ), will provide important resources for studies on the genomes of oil palm and related crops. REVIEWERS: This article was reviewed by Alexander Kel, Igor Rogozin, and Vladimir A. Kuznetsov. PMID- 28886751 TI - Uva-ursi extract and ibuprofen as alternative treatments of adult female urinary tract infection (ATAFUTI): study protocol for a randomised controlled trial. AB - BACKGROUND: Women with acute uncomplicated urine infection are usually treated with antibiotics. One trial has demonstrated that delayed antibiotic treatment offered without symptom relief results in a modest reduction in antibiotic use. There is some evidence that ibuprofen provides symptom relief and reduces antibiotic use. Uva-ursi, a herbal product, has a traditional use for urinary infection symptom relief. We set out to test: in adult women with suspected UTI who accept the delayed prescription strategy: Do NSAIDs or uva-ursi (a herbal product) provide relief from urinary symptoms and reduce antibiotic use. METHODS/DESIGN: Adult women with suspected urinary tract infection presenting to primary care will be randomised using a factorial trial design in which patients will be randomised to one of two interventions as below: Group 1 - Uva-ursi + advice to take ibuprofen Group 2 - Placebo + advice to take ibuprofen Group 3 - Uva-ursi + no advice to take ibuprofen Group 4 - Placebo + no advice to take ibuprofen Patients and physicians will be blinded to the randomised group for the herb. The main outcome is symptom severity at days 2-4 recorded in a validated, self-report diary used in previous studies. Secondary outcomes include antibiotic use and symptom duration. In total the trial will require 328 patients in order to achieve at least 90% power for the primary endpoint and 80% for the secondary endpoint. In accordance with CONSORT guidelines all comparative analyses will be conducted on an intention-to-treat basis using SPSS or similar package. DISCUSSION: The outcomes from this trial have the potential to modify the current approach to the management of acute urinary symptoms with less dependence on the use of antibiotics. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN43397016 . Registered on 11 February 2015. PMID- 28886752 TI - Protocol for the management of psychiatric patients with psychomotor agitation. AB - BACKGROUND: Psychomotor agitation (PMA) is a state of motor restlessness and mental tension that requires prompt recognition, appropriate assessment and management to minimize anxiety for the patient and reduce the risk for escalation to aggression and violence. Standardized and applicable protocols and algorithms can assist healthcare providers to identify patients at risk of PMA, achieve timely diagnosis and implement minimally invasive management strategies to ensure patient and staff safety and resolution of the episode. METHODS: Spanish experts in PMA from different disciplines (psychiatrists, psychologists and nurses) convened in Barcelona for a meeting in April 2016. Based on recently issued international consensus guidelines on the standard of care for psychiatric patients with PMA, the meeting provided the opportunity to address the complexities in the assessment and management of PMA from different perspectives. The attendees worked towards producing a consensus for a unified approach to PMA according to the local standards of care and current local legislations. The draft protocol developed was reviewed and ratified by all members of the panel prior to its presentation to the Catalan Society of Psychiatry and Mental Health, the Spanish Society of Biological Psychiatry (SEPB) and the Spanish Network Centre for Research in Mental Health (CIBERSAM) for input. The final protocol and algorithms were then submitted to these organizations for endorsement. RESULTS: The protocol presented here provides guidance on the appropriate selection and use of pharmacological agents (inhaled/oral/IM), seclusion, and physical restraint for psychiatric patients suspected of or presenting with PMA. The protocol is applicable within the Spanish healthcare system. Implementation of the protocol and the constituent algorithms described here should ensure the best standard of care of patients at risk of PMA. Episodes of PMA could be identified earlier in their clinical course and patients could be managed in the least invasive and coercive manner, ensuring their own safety and that of others around them. CONCLUSION: Establishing specialized teams in agitation and providing them with continued training on the identification of agitation, patient management and therapeutic alternatives might reduce the burden of PMA for both the patient and the healthcare system. PMID- 28886753 TI - Depletion of adult neurogenesis exacerbates cognitive deficits in Alzheimer's disease by compromising hippocampal inhibition. AB - BACKGROUND: The molecular mechanism underlying progressive memory loss in Alzheimer's disease is poorly understood. Neurogenesis in the adult hippocampus is a dynamic process that continuously changes the dentate gyrus and is important for hippocampal plasticity, learning and memory. However, whether impairments in neurogenesis affect the hippocampal circuitry in a way that leads to memory deficits characteristic of Alzheimer's disease is unknown. Controversial results in that regard were reported in transgenic mouse models of amyloidosis. METHODS: Here, we conditionally ablated adult neurogenesis in APPswe/PS1DeltaE9 mice by crossing these with mice expressing nestin-driven thymidine kinase (delta-HSV TK). RESULTS: These animals show impairment in performance in contextual conditioning and pattern separation tasks following depletion of neurogenesis. Importantly, these deficits were not observed in age-matched APPswe/PS1DeltaE9 or delta-HSV-TK mice alone. Furthermore, we show that cognitive deficits were accompanied by the upregulation of hyperphosphorylated tau in the hippocampus and in immature neurons specifically. Interestingly, we observed upregulation of the immediate early gene Zif268 (Egr-1) in the dentate gyrus, CA1 and CA3 regions of the hippocampus following learning in the neurogenesis-depleted delta-HSV-TK mice. This may suggest overactivation of hippocampal neurons in these areas following depletion of neurogenesis. CONCLUSIONS: These results imply that neurogenesis plays an important role in the regulation of inhibitory circuitry of the hippocampus. This study suggests that deficits in adult neurogenesis may contribute to cognitive impairments, tau hyperphosphorylation in new neurons and compromised hippocampal circuitry in Alzheimer's disease. PMID- 28886755 TI - Revisiting Coiled Flocculator Performance for Particle Aggregation. AB - This work summarizes recent studies evaluating the torsion and curvature parameters in flocculation efficiency using a hydraulic plug flow flocculator known as a Flocs Generator Reactor (FGR). Colloidal Fe(OH)3 and coal particles were used as suspension models and a cationic polyacrylamide was used for the flocculation. The effectiveness of the aggregation process (in the distinct curvature and torsion parameters, and hydrodynamic conditions) was evaluated by the settling rate of the Fe(OH)3 flocs, and flocs size by photographic analysis. As a result of curvature, a secondary flow is induced and the profiles of the flow quantities differ from those for a straight pipe. Results showed that the differences in the flocculator design influences the Fe(OH)3 flocs size and settling rates, reaching values of about 13 and 4 m/h, for the coiled and straight pipes respectively. Coal flocs generation was also shown to be dependent on the flocculator design and shear rate. Results showed that turbulent kinetic energy increases because of curvature when the torsion parameter is kept constant (pitch close to zero), enhancing the flocs formation. PMID- 28886754 TI - On-farm biosecurity practices and causes of preweaning mortality in Canadian commercial mink kits. AB - BACKGROUND: Mink are an important animal commodity group in Canada and excessive kit mortality represents a significant loss to production. National biosecurity standards have been developed for Canadian mink farms, but it is unclear how well these standards have been implemented as there are no studies correlating management practices of mink producers with causes of death in mink kits. To that end, we surveyed Ontario mink producers on their biosecurity and management practices and conducted almost 5660 post mortem examinations on found-dead, preweaned kits to characterize mink farm biosecurity practices and causes of death in preweaned kits. RESULTS: We found that very few biosecurity and management practices were uniformly used by producers, despite good awareness of appropriate practices. Use of personal protective equipment was implemented by fewer than 50% of respondents, while control of mink shed access, disinfection of feed containers after use, and use of a rodent control program were the only practices implemented by greater than 70% of respondents. Only 18% of producers reported regular use of antimicrobials in feed or water, although 91% stated they used antimicrobials for treatment of bacterial diseases on a regular basis. On post mortem examination, no gross abnormalities were noted in 71% of the kits, 45% were thought to be stillborn or aborted, 27% had some form of abnormal fluid distribution in the body, and 2% had a congenital malformation. A subset of 69 gastrointestinal tract samples was submitted for bacterial culture, of which 45 samples yielded sufficient growth. Most interesting was the identification of Salmonella enterica serovar Heidelberg in 11% of samples. CONCLUSIONS: The results of this study will provide a benchmark for Canadian mink producers and their veterinarians, defining the areas to which greater attention should be given to ensure more rigorous biosecurity practices are in place. Ultimately, these improvements in practices may contribute to increased mink production and animal well-being. PMID- 28886756 TI - A New Platform for Profiling Degradation-Related Impurities Via Exploiting the Opportunities Offered by Ion-Selective Electrodes: Determination of Both Diatrizoate Sodium and Its Cytotoxic Degradation Product. AB - Although the ultimate goal of administering active pharmaceutical ingredients (APIs) is to save countless lives, the presence of impurities and/or degradation products in APIs or formulations may cause harmful physiological effects. Today, impurity profiling (i.e., the identity as well as the quantity of impurity in a pharmaceutical) is receiving critical attention from regulatory authorities. Despite the predominant use of spectroscopic and chromatographic methods over electrochemical methods for impurity profiling of APIs, this work investigates the opportunities offered by electroanalytical methods, particularly, ion selective electrodes (ISEs), for profiling degradation-related impurities (DRIs) compared with conventional spectroscopic and chromatographic methods. For a meaningful comparison, diatrizoate sodium (DTA) was chosen as the anionic X-ray contrast agent based on its susceptibility to deacetylation into its cytotoxic and mutagenic degradation product, 3,5-diamino-2,4,6 triiodobenzoic acid (DTB). This cationic diamino compound can be also detected as an impurity in the final product because it is used as a synthetic precursor for the synthesis of DTA. In this study, four novel sensitive and selective sensors for the determination of both DTA and its cytotoxic degradation products are presented. Sensors I and II were developed for the determination of the anionic drug, DTA, and sensors III and IV were developed for the determination of the cationic cytotoxic impurity. The use of these novel sensors not only provides a stability-indicating method for the selective determination of DTA in the presence of its degradation product, but also permits DRI profiling. Moreover, a great advantage of these proposed ISE systems is their higher sensitivity for the quantification of DTB relative to other spectroscopic and chromatographic methods, so it can measure trace amounts of DTB impurities in DTA bulk powder and pharmaceutical formulation without a need for preliminary separation. PMID- 28886757 TI - Differentiation of Bovine, Porcine, and Fish Gelatins by Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIRS) Coupled with Pattern Recognition. AB - Bovine, porcine, and fish gelatins have been differentiated based on their spectra collected by attenuated total reflectance FTIR spectroscopy (ATR-FTIRS) coupled with pattern recognition. Three tree-based classification methods, a fuzzy rule-building expert system (FuRES), support vector machine classification trees (SVMTreeG and SVMTreeH), and one reference model, super partial least squares discriminant analysis (sPLS-DA), were evaluated with and without two preprocessing techniques, namely standard normal variate (SNV) and principal component orthogonal signal correction (PC-OSC). Validation of these methods was obtained with 95% confidence intervals with 10 bootstraps and 4 Latin partitions (10:4). The ATR-FTIR spectra were used with four different ranges: full spectra (4000-650 cm-1), fingerprint region (1731-650 cm-1), specified spectra (4000-800 cm-1), and narrow fingerprint region (1731-800 cm-1). Classification rates for the methods were improved with SNV and PC-OSC when they were used separately or together. The highest classification rates were obtained from the narrow fingerprint region with SNV and PC-OSC at 97.4 +/- 1.6% for FuRES, 100 +/- 0% for sPLS-DA, and 99.3 +/- 0.5% for both SVMTreeG and SVMTreeH. ATR-FTIRS combined with pattern recognition is a potential analytical technique for differentiating the sources of bovine, porcine, and fish gelatins with fast and reliable results. PMID- 28886758 TI - Evaluation of beclomethasone dipropionate (80 and 160 micrograms/day) delivered via a breath-actuated inhaler for persistent asthma. AB - BACKGROUND: Breath-actuated inhalers (BAI) may simplify the delivery of inhaled medications compared with other devices. OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate BAI versus matching placebo in adolescent and adult patients with persistent asthma. METHODS: This phase III, 12-week, double-blind study enrolled patients with asthma aged >=12 years who were previously treated with a stable dose of inhaled corticosteroid or noncorticosteroid therapy. After a run-in period of 14 to 21 days, patients were randomly assigned in a 1:1:1 ratio to beclomethasone dipropionate BAI 80 or 160 micrograms/day (40 or 80 micrograms twice daily) or placebo BAI. The primary end point was the standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from time 0 to 12 weeks (AUEC[0-12 weeks]). Secondary end points included peak expiratory flow, rescue medication use, asthma symptoms, and the time to withdrawal due to meeting predefined criteria for worsening asthma. Additional end points evaluated quality of life, instructions for use, and safety. RESULTS: The full analysis and the safety sets included 270 and 273 patients, respectively. Patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day had significant improvements in FEV1 AUEC(0-12 weeks) versus placebo (p <= 0.001). Improvements in secondary end points were also apparent in patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day compared with placebo. Patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day had greater increases in Asthma Quality of Life Questionnaire scores versus placebo patients at week 12. Of 98 patients who participated in the instructions for-use substudy, 87 (88.8%) used the inhaler successfully on their first attempt. Treatment was generally safe and well tolerated. CONCLUSION: Beclomethasone dipropionate BAI 80 and 160 micrograms/day were effective and well accepted treatments in patients with asthma, with safety comparable to beclomethasone dipropionate delivered via a metered-dose inhaler.Clinical trial NCT02040779, www.clinicaltrials.gov. PMID- 28886759 TI - Epigenetic Regulation of the Kappa Opioid Receptor by Child Abuse. AB - BACKGROUND: Experiences of abuse and neglect during childhood are major predictors of the emergence of depressive and suicidal behaviors throughout life. The underlying biological mechanisms, however, remain poorly understood. Here, we focused on the opioid system as a potential brain substrate mediating these effects. METHODS: Postmortem samples from three brain structures regulating social bonds and emotions were analyzed. Groups were constituted of depressed individuals who died by suicide, with or without a history of severe child abuse, and of psychiatrically healthy control subjects. Expression of opioid peptides and receptors was measured using real-time polymerase chain reaction. DNA methylation, a major epigenetic mark, was investigated using targeted bisulfite sequencing and characterized at functional level using in vitro reporter assays. Finally, oxidative bisulfite sequencing was used to differentiate methylation and hydroxymethylation of DNA. RESULTS: A history of child abuse specifically associated in the anterior insula with a downregulation of the kappa opioid receptor (Kappa), as well as decreased DNA methylation in the second intron of the Kappa gene. In vitro assays further showed that this intron functions as a genomic enhancer where glucocorticoid receptor binding regulates Kappa expression, unraveling a new mechanism mediating the well-established interactions between endogenous opioids and stress. Finally, results showed that child abuse is associated in the Kappa intron with a selective reduction in levels of DNA hydroxymethylation, likely mediating the observed downregulation of the receptor. CONCLUSIONS: Altogether, our findings uncover new facets of Kappa physiology, whereby this receptor may be epigenetically regulated by stressful experiences, in particular as a function of early social life. PMID- 28886760 TI - Network Mechanisms of Clinical Response to Transcranial Magnetic Stimulation in Posttraumatic Stress Disorder and Major Depressive Disorder. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) therapy can modulate pathological neural network functional connectivity in major depressive disorder (MDD). Posttraumatic stress disorder is often comorbid with MDD, and symptoms of both disorders can be alleviated with TMS therapy. This is the first study to evaluate TMS-associated changes in connectivity in patients with comorbid posttraumatic stress disorder and MDD. METHODS: Resting-state functional connectivity magnetic resonance imaging was acquired before and after TMS therapy in 33 adult outpatients in a prospective open trial. TMS at 5 Hz was delivered, in up to 40 daily sessions, to the left dorsolateral prefrontal cortex. Analyses used a priori seeds relevant to TMS, posttraumatic stress disorder, or MDD (subgenual anterior cingulate cortex [sgACC], left dorsolateral prefrontal cortex, hippocampus, and basolateral amygdala) to identify imaging predictors of response and to evaluate clinically relevant changes in connectivity after TMS, followed by leave-one-out cross-validation. Imaging results were explored using data-driven multivoxel pattern activation. RESULTS: More negative pretreatment connectivity between the sgACC and the default mode network predicted clinical improvement, as did more positive amygdala-to-ventromedial prefrontal cortex connectivity. After TMS, symptom reduction was associated with reduced connectivity between the sgACC and the default mode network, left dorsolateral prefrontal cortex, and insula, and reduced connectivity between the hippocampus and the salience network. Multivoxel pattern activation confirmed seed-based predictors and correlates of treatment outcomes. CONCLUSIONS: These results highlight the central role of the sgACC, default mode network, and salience network as predictors of TMS response and suggest their involvement in mechanisms of action. Furthermore, this work indicates that there may be network-based biomarkers of clinical response relevant to these commonly comorbid disorders. PMID- 28886761 TI - Corrigendum to "Shared decision making in contraceptive counseling" [Contraception (2017) 95:452-455]. PMID- 28886762 TI - The Tooth: Its Structure and Properties. AB - This article provides a brief review of recent investigations concerning the structure and properties of the tooth. The last decade has brought a greater emphasis on the durability of the tooth, an improved understanding of the fatigue and fracture behavior of the principal tissues, and their importance to tooth failures. The primary contributions to tooth durability are discussed, including the process of placing a restoration, the impact of aging, and challenges posed by the oral environment. The significance of these findings to the dental community and their importance to the pursuit of lifelong oral health are highlighted. PMID- 28886763 TI - Bioactive Dental Composites and Bonding Agents Having Remineralizing and Antibacterial Characteristics. AB - Current dental restorative materials are typically inert and replace missing tooth structures. This article reviews efforts in the development of a new generation of bioactive materials designed to not only replace the missing tooth volume but also possess therapeutic functions. Composites and bonding agents with remineralizing and antibacterial characteristics have shown promise in replacing lost minerals, inhibiting recurrent caries, neutralizing acids, repelling proteins, and suppressing biofilms and acid production. Furthermore, they have demonstrated a low cytotoxicity similar to current resins, with additional benefits to protect the dental pulp and promote tertiary dentin formation. This new class of bioactive materials shows promise in reversing lesions and inhibiting caries. PMID- 28886765 TI - An Overview of Dental Adhesive Systems and the Dynamic Tooth-Adhesive Interface. AB - From the conception of resin-enamel adhesion to today's contemporary dental adhesive systems, clinicians are no longer afraid of exploring the many advantages brought by adhesive restorative concepts. To maximize the performance of adhesive-based restorative procedures, practitioners must be familiar with the mechanism of adhesion, clinical indications, proper handling, the inherent limitations of the materials and the biological challenges. This review provides an overview of the current status of restorative dental adhesives, their mechanism of adhesion, mechanisms of degradation of dental adhesive interfaces, how to maximize performance, and future trends in adhesive dentistry. PMID- 28886764 TI - Advanced Scaffolds for Dental Pulp and Periodontal Regeneration. AB - No current therapy promotes root canal disinfection and regeneration of the pulp dentin complex in cases of pulp necrosis. Antibiotic pastes used to eradicate canal infection negatively affect stem cell survival. Three-dimensional easy-to fit antibiotic-eluting nanofibers, combined with injectable scaffolds, enriched or not with stem cells and/or growth factors, may increase the likelihood of achieving predictable dental pulp regeneration. Periodontitis is an aggressive disease that impairs the integrity of tooth-supporting structures and may lead to tooth loss. The latest advances in membrane biomodification to endow needed functionalities and technologies to engineer patient-specific membranes/constructs to amplify periodontal regeneration are presented. PMID- 28886767 TI - Light Curing in Dentistry. AB - The ability to light cure resins 'on demand' in the mouth has revolutionized dentistry. However, there is a widespread lack of understanding of what is required for successful light curing in the mouth. Most instructions simply tell the user to 'light cure for xx seconds' without describing any of the nuances of how to successfully light cure a resin. This article provides a brief description of light curing. At the end, some recommendations are made to help when purchasing a curing light and how to improve the use of the curing light. PMID- 28886766 TI - Polymer-Based Direct Filling Materials. AB - After a brief review of current restorative materials and classifications, this article discusses the latest developments in polymer-based direct filling materials, with emphasis on products and studies available in the last 10 years. This will include the more recent bulk fill composites and self-adhesive materials, for which clinical evidence of success, albeit somewhat limited, is already available. The article also introduces the latest cutting edge research topics on new materials for composite restorations, and an outlook for the future of how those may help to improve the service life of dental composite restorations. PMID- 28886768 TI - Dental Impression Materials and Techniques. AB - Dental impression making is the process of creating a negative form of the teeth and oral tissues, into which gypsum or other die materials can be processed to create working analogues. Contemporary dentistry generates new information every year and digital dentistry is becoming established and influential. Although dentists should stay abreast of new technologies, some of the conventional materials and time-tested techniques remain widely used. It is important to review the impression-making process to ensure that practitioners have up-to-date information about how to safely and effectively capture the exact form of the oral tissues to provide optimal patient management. PMID- 28886770 TI - Dental Cements for Luting and Bonding Restorations: Self-Adhesive Resin Cements. AB - Self-adhesive resin cements combine easy application of conventional luting materials with improved mechanical properties and bonding capability of resin cements. The presence of functional acidic monomers, dual cure setting mechanism, and fillers capable of neutralizing the initial low pH of the cement are essential elements of the material and should be understood when selecting the ideal luting material for each clinical situation. This article addresses the most relevant aspects of self-adhesive resin cements and their potential impact on clinical performance. Although few clinical studies are available to establish solid clinical evidence, the information presented provides clinical guidance in the dynamic environment of material development. PMID- 28886769 TI - Dental Ceramics for Restoration and Metal Veneering. AB - A survey of the development of dental ceramics is presented to provide a better understanding of the rationale behind the development and clinical indications of each class of ceramic material. Knowledge of the composition, microstructure, and properties of a material is critical for selecting the right material for specific applications. The key to successful ceramic restorations rests on material selection, manufacturing technique, and restoration design, including the balancing of several factors such as residual stresses, tooth contact conditions, tooth size and shape, elastic modulus of the adhesives and tooth structure, and surface state. PMID- 28886772 TI - Dental Implants. AB - Systematic reviews of literature over the period between 2008 and 2017 are discussed regarding clinical evidence for the factors affecting survival and failure of dental implants. The factors addressed include publication bias, tooth location, insertion torque, collar design, implant-abutment connection design, implant length, implant width, bone augmentation, platform switching, surface roughness, implant coatings, and the use of ceramic materials in the implant body and abutment. PMID- 28886773 TI - Biomaterials for Oral Health. PMID- 28886774 TI - [Back to the future]. PMID- 28886775 TI - The history of electrocardiography. PMID- 28886776 TI - Cuff Pressure Confusion: Solutions Are Abundant. PMID- 28886771 TI - Biomaterials for Craniofacial Bone Regeneration. AB - Functional reconstruction of craniofacial defects is a major clinical challenge in craniofacial sciences. The advent of biomaterials is a potential alternative to standard autologous/allogenic grafting procedures to achieve clinically successful bone regeneration. This article discusses various classes of biomaterials currently used in craniofacial reconstruction. Also reviewed are clinical applications of biomaterials as delivery agents for sustained release of stem cells, genes, and growth factors. Recent promising advancements in 3D printing and bioprinting techniques that seem to be promising for future clinical treatments for craniofacial reconstruction are covered. Relevant topics in the bone regeneration literature exemplifying the potential of biomaterials to repair bone defects are highlighted. PMID- 28886777 TI - Pulmonary Edema After Near Hanging: An Insight. PMID- 28886779 TI - Teaching: Tips and Costs. PMID- 28886780 TI - Vehicular Manslaughter. PMID- 28886784 TI - Development of a New Infusion Protocol for Austere Trauma Resuscitations. AB - Intravenous fluid therapy for hemorrhagic shock has undergone enormous changes since it was first conducted almost 200 years ago. In the past 40 years especially, practices have dramatically changed with regards to fluid resuscitation. In pre-hospital, combat, austere, and rural emergency medicine the stakes are especially high to deliver an effective and logical resuscitation fluid strategy to a patient that is suffering from hemorrhagic shock. This article follows a prior article published in July 2014. It highlights the development of new cutting edge intravenous therapy regimens that maximize hemodynamic outcomes that can be effected by those providers that care for injured patients without the benefit of ample resources. PMID- 28886785 TI - Reducing Door-in Door-out Intervals in Helicopter ST-segment Elevation Myocardial Infarction Interhospital Transfers. AB - BACKGROUND: Many health systems rely on helicopter EMS (HEMS) to transfer ST elevation myocardial infarction (STEMI) patients for percutaneous coronary intervention (PCI) to a hospital with a catheterization laboratory. Mortality rates increase with the time to reperfusion, so reducing delays is imperative. For interhospital STEMI transfers, the time spent in the initial hospital from arrival until departure (door-in to door-out interval or DIDO) should be minimized. OBJECTIVE: To evaluate the impact of a series of process improvements to reduce DIDO intervals for STEMI patients transferred via a hospital based HEMS program. METHODS: Changes made to the STEMI transfer protocol in March 2011 were: (a) allowing transferring facilities to request HEMS before identifying an accepting cardiologist or hospital, with one hospital serving as a default PCI center in the case of delays, (b) limiting continuous infusions to those absolutely necessary for the transfer flights and (c) training flight crews to minimize time at bedside. Trained dual abstractors conducted structured medical record reviews for all STEMI patients 18 years and older, transferred to a PCI facility by HEMS from March 2011 to December 2012. Discrepancies were adjudicated. We compared DIDO intervals to a historical control cohort from 2007. We used the Mann-Whitney U test to compare times, and calculated differences with 95% confidence intervals. RESULTS: Of 244 patients identified, six were excluded due to incomplete data. The historical cohort included 179 cases. Mean age was 59 (SD 14) years, 81% were white and 66% male. There were no differences in patient characteristics or door to EKG times between the cohorts. Median door-in to door out interval decreased from 83 minutes (IQR 43) to 68 minutes (IQR 31) (difference 15 minutes, 95% CI 8 to 21, P <.0001). EKG to HEMS request decreased 21 minutes (95% CI 17 to 25, P <.0001), and HEMS ground time decreased 3 minutes (95% CI 2 to 4, P <.0001). There was a 32% absolute increase in the proportion of patients with EKG to helicopter request interval <35 minutes (83% vs 51%, difference 32%, 95% CI 24% to 41%, P <.0001). CONCLUSION: HEMS-focused process improvements can significantly reduce the DIDO interval times for STEMI patients transferred for PCI. PMID- 28886786 TI - Infusion Pump in UH60L/M Flight in Afghanistan: Why Failures Occur. AB - The ALARIS MSIII Infusion Pump (CareFusion, San Diego, CA) uses 3 separate alarms designed to prevent air emboli: "check air sensor," "air in lower tubing," and "air in line." It is assumed that ambient pressure changes cause air emboli that lead to pump failure although evidence to support this is limited. In this small study, the MSIII proved to be highly resilient and able to maintain function even after large repetitive emboli. Although unproven, it is more likely that these alarms are usually caused by loosening of the intravenous tubing within the pump's collar. This disjointing of the tubing and the ultrasonic sensor can be perceived as an air embolus leading to severe consequences. If the user attempts the clear air function, the pump will not resume function. Problems such as this may have been related to at least 1 reported patient death. More research is needed to determine the cause of these alarms and determine the exact cause. Patient safety can potentially be improved at all levels including manufacturer modifications and operator training. It seems reasonable that the manufacturer should design a mode ("transport mode") that allows the pump to function even with air emboli. PMID- 28886787 TI - Evaluation of Intensive Care Unit Ventilators at Altitude. AB - INTRODUCTION: Devices may forgo US military air worthiness and safety testing in an attempt to expedite the availability of critical assets such as mechanical ventilators with a waiver for one-time use in extenuating circumstances. METHODS: We evaluated two Intensive Care Unit (ICU) level ventilators: Drager Evita XL and Puritan Bennett (PB) 840 in an altitude chamber at sea level and altitudes of 8,000 and 16,000 feet. RESULTS: Altitude affected delivered tidal volumes (VTs) in volume control mode (VCV) and Pressure Regulated Volume Controlled (PRVC) mode at altitude with the Evita XL but the differences were not considered clinically important with the PB 840. Sixty-seven percent of the VTs were outside the ASTM standard of +/- 10% of set VT with the Evita XL at altitude. CONCLUSION: The PB 840 did not deliver VTs that were larger than the ASTM standard up to an altitude of 16,000 feet while the majority of the delivered VTs with the Darger XL were greater than the ASTM standard. This could present a patient safety issue. Caregivers must be aware of the capabilities and limitations of ICU ventilators when utilized in a hypobaric environment in order to provide safe care. PMID- 28886788 TI - Logistical Concerns for Prehospital Blood Product Use by Air Medical Services. AB - Over the past few decades, reports have described favorable results from transfusion of blood products in helicopter EMS (HEMS). Nevertheless, the initiation of a HEMS transfusion program requires consideration of many factors, some unique to each clinical site. This paper describes our experience developing a HEMS transfusion program in an urban non-hospital based HEMS program with a history of long transport times. When considering blood use away from the hospital, major consideration must be given to safe storage and monitoring of blood products both on the ground and while in flight. PRBCs have been shown to generally be resilient to helicopter transit and have a prolonged storage duration. Transfusion of other blood products, such as plasma, involves additional challenges but has been achieved by some HEMS sites. Flight protocols should be developed addressing when and how many blood products should be transported, potentially considering patient factors, scene factors, and the regional availability of blood products during interfacility transport. Quality assurance and documentation protocols must also be developed for blood product use in flight. In our center's experience, we have so far transfused a limited number of patients with generally good results. Patient outcomes are described as below. PMID- 28886789 TI - Air Repatriation With a Medium-sized Pneumothorax Without Thoracic Tube: A Special Case of a Repatriation Accompanied by an Experienced Surgeon. AB - We report on the repatriation of a 28-year old female from Germany, who was involved in a serious bus accident and was transported to the nearest hospital in Oruro, Bolivia. CT scans and x-rays performed in this hospital demonstrated a complete pneumothorax right. Thorax drainage was inserted, which was removed after 5 days. Since the hospital refused to acknowledge the presence of a residual middle-sized pneumothorax on the repatriation day and did not want to insert another tube, the decision was made to repatriate the patient on commercial flight back home to Germany without a thoracic tube. PMID- 28886790 TI - Hemodynamic Deterioration in Lateral Compression Pelvic Fracture After Prehospital Pelvic Circumferential Compression Device Application. AB - Increased fracture displacement has previously been described with the application of pelvic circumferential compression devices (PCCDs) in patients with lateral compression-type pelvic fracture. We describe the first reported case of hemodynamic deterioration temporally associated with the prehospital application of a PCCD in a patient with a complex acetabular fracture with medial displacement of the femoral head. Active hemorrhage from a site adjacent to the acetabular fracture was subsequently demonstrated on angiography. Caution in the application of PCCDs to patients with lateral compression-type fractures is warranted. PMID- 28886791 TI - Foraminal enlargement with rotatory system increases postoperative pain up to 2 days in patients with necrotic teeth and apical lesions. PMID- 28886792 TI - Antibiotic prophylaxis probably reduces the risk of developing bacteremia in patients at risk of developing infective endocarditis who are undergoing dental extractions. PMID- 28886793 TI - Scalloped implant-abutment connections appear to have similar implant survival rates as flat implant-abutment connections but may be associated with greater marginal bone loss. PMID- 28886794 TI - No trustworthy evidence about the effectiveness of laser therapy or ibuprofen to minimize pain during orthodontic treatment with fixed appliances owing to major limitations in the process to conduct a systematic review. PMID- 28886795 TI - Use of definitive abutments may result in very small marginal bone-level change compared with use of provisional abutments in patients undergoing implant placement. PMID- 28886796 TI - Mandibular third molars increase the risk of developing angle fractures in patients with mandibular fractures. PMID- 28886797 TI - Clinical Diagnosis of Skin Cancer: Enhancing Inspection and Early Recognition. AB - The annual incidence rate for melanoma and nonmelanoma skin cancer continues to rise and morbidity and deaths from skin cancer are increasing. Despite advances in therapeutics, the factors that most impact prognosis remain early recognition and removal of neoplasms before deep invasion or metastatic disease can occur. There are numerous public health and screening initiatives that have been introduced to help recognize disease earlier and to increase patients' awareness of signs or changes of lesions that may represent skin cancers. Early recognition and removal of suspicious lesions remains critical in significantly reducing morbidity and mortality associated with skin cancers. PMID- 28886799 TI - Mole Mapping for Management of Pigmented Skin Lesions. AB - Identifying new or changing melanocytic lesions, particularly in patients with numerous or atypical nevi, can be challenging. Total-body photography and sequential digital dermoscopy imaging, together known as digital follow-up, are 2 prominent forms of noninvasive imaging technology used in mole mapping that have been found to improve diagnostic accuracy, detect earlier-stage melanomas, and reduce costs. Digital follow-up, in combination with direct-to-consumer applications and teledermatology, is already revolutionizing the ways in which physicians and patients participate in melanoma surveillance and will likely continue to enhance early detection efforts. PMID- 28886798 TI - Enhancing Skin Cancer Diagnosis with Dermoscopy. AB - Dermoscopy increases the sensitivity for skin cancer detection, decreases the number of benign lesions biopsied for each malignant diagnosis, and enables the diagnosis of thinner melanomas compared with naked eye examination. Multiple meta analyses have identified that dermoscopy improves the diagnostic accuracy for melanoma when compared with naked eye examination. In addition, studies have established that dermoscopy can aid in the detection of keratinocyte carcinomas. Dermoscopy triage algorithms have been developed to help novices decide when a biopsy or a referral is most appropriate. In this article, the authors illustrate the dermoscopic features that assist in identifying melanoma and keratinocyte carcinomas. PMID- 28886800 TI - Temporal Image Comparison (Serial Imaging) in Assessing Pigmented Lesions. AB - The large-scale deployment of low-cost, noninvasive mechanisms of early detection are needed to reduce the melanoma burden. A serial 2-step system could power mass screening efforts serving the uninsured and underinsured as well as the rural and remote US counties where melanoma mortality is doubled for lack of access to dermatologists. Furthermore, serial melanoma screening strategies, serial total body photography and serial digital dermatoscopy imaging may be performed as a telehealth service, and thus would be available in any location that can support activity compliant with the Health Insurance Portability and Accountability Act and has appropriate bandwidth. PMID- 28886801 TI - Noninvasive Technologies for the Diagnosis of Cutaneous Melanoma. AB - Multispectral analysis devices assess pigmented lesion disorganization at different levels using variable wavelengths of light. Computerized algorithms measure morphologic disorganization of the pigmented skin lesion. Aggregated data of 855 participants investigating the influence of multispectral digital skin lesion analysis (MSDSLA) on practitioner decisions to biopsy pigmented skin lesions revealed the overall sensitivity for detection of melanoma improved from 70% to 88%. Participant specificity increased from 52% to 58% after MSDSLA. Five studies using spectrophotometric intracutaneous analysis scope to evaluate suspicious pigmented skin lesions demonstrated an overall sensitivity and specificity of 85% and 81%, respectively, for the detection of melanoma. PMID- 28886802 TI - Using Reflectance Confocal Microscopy in Skin Cancer Diagnosis. AB - Biopsy and histologic evaluation have been the gold standard to diagnose skin tumors. Reflectance confocal microcopy (RCM) is a noninvasive, innovative diagnostic technique that enables visualization of different skin layers at an almost histologic resolution. RCM has been proven beneficial in management of various cutaneous lesions. This article highlights the clinical significance and future of RCM to diagnose common skin cancers. However, RCM cannot replace currently standard histopathologic diagnosis. More studies are required to better compare the sensitivity and specificity of skin cancer diagnosis using RCM. PMID- 28886803 TI - Optical Coherence Tomography in the Diagnosis of Skin Cancer. AB - Optical coherence tomography (OCT) has emerged as a novel noninvasive imaging device that allows for the real-time, in vivo, cross-sectional imaging of skin morphology. OCT has increased imaging depth and field of view compared with reflectance confocal microscopy, at the cost of decreased cellular resolution. Frequency domain OCT, dynamic OCT (D-OCT), and high-definition OCT (HD-OCT) are useful in the diagnosis, treatment planning, and treatment monitoring of nonmelanoma skin cancers. Research is currently underway to assess the utilization of these devices in distinguishing between malignant and benign melanocytic lesions based on vascular patterns on D-OCT and cellular information on HD-OCT. PMID- 28886804 TI - Electrical Impedance Spectroscopy in Skin Cancer Diagnosis. AB - Electrical impedance spectroscopy (EIS) is a noninvasive method that aims to help diagnose skin cancer. The EIS device consists of a handheld probe with a disposable electrode that is applied directly on the skin and uses electrical impendence differences to differentiate between normal and abnormal skin lesions. The EIS algorithm is best used on lesions that are deemed clinically or dermoscopically suspicious and has a high sensitivity in detecting malignant melanoma. The greatest usefulness of EIS is achieved in conjunction with a physician who has experience with this modality and excellent training in the clinical detection of suspicious lesions. PMID- 28886805 TI - Using Raman Spectroscopy to Detect and Diagnose Skin Cancer In Vivo. AB - Raman spectroscopy provides a noninvasive bedside tool that captures unique optical signals via molecular vibrations in tissue samples. Raman theory was discovered at the beginning of the twentieth century, but it was not until the past few decades that it has been used to differentiate skin neoplasms. We provide a brief description of Raman spectroscopy for in vivo skin cancer diagnosis, including the physical principles underlying Raman spectroscopy, its advantages, typical spectra of skin pathologies, and its clinical application for aiding skin cancer diagnosis. PMID- 28886806 TI - High-Frequency Ultrasound Examination in the Diagnosis of Skin Cancer. AB - Ultrasound above 14 MHz images epidermis, dermis, and subcutaneous tissues in real time. Tumor depth is ascertained with B-mode. Three-dimensional imaging depicts nonpalpable, in-transit, and satellite lesions. Doppler blood flow technologies measure tumor neovascularity and map vascular structures. Three dimensional Doppler histogram reconstruction measures tumor aggression and metastatic potential proportional to the percentage of malignant vessels. Subcutaneous investigation reveals nonpalpable metastatic disease and nodal basin lymphadenopathy. Adjacent nerves may be studied. Preservation of the fat-fascia border refines surgical staging of deeper malignancies. Image-guided biopsy is facilitated. Treatment under image guidance is optimized with radiation and various photo and thermal technologies. PMID- 28886807 TI - Proteomic Mass Spectrometry Imaging for Skin Cancer Diagnosis. AB - Mass spectrometry imaging can be successfully used for skin cancer diagnosis, particularly for the diagnosis of challenging melanocytic lesions. This method analyzes proteins within benign and malignant melanocytic tumor cells and, based on their differences, which constitute a unique molecular signature of 5 to 20 proteins, can render a diagnosis of benign nevus versus malignant melanoma. Mass spectrometry imaging may assist in the differentiation between metastases and nevi as well as between proliferative nodules in nevi and melanoma arising in a nevus. In the difficult area of atypical Spitzoid neoplasms, mass spectrometry diagnosis can predict clinical outcome better than histopathology. PMID- 28886808 TI - Assessing Skin Cancer Using Epidermal Genetic Information Retrieved by Adhesive Patch Skin Surface Sampling. AB - The detection of melanoma can be challenging. Many patients have clinically equivocal lesions in cosmetically sensitive areas or have multiple suspicious lesions. Epidermal genetic information retrieval is a noninvasive diagnostic method involving the application of adhesive tape onto the skin's surface to recover genomic material from the epidermis. This genomic material can then be used in assays to determine gene expression profiles. Studies have shown the potential of this technology to aid clinicians in differentiating between melanomas and nevi. Although this technology is not meant to replace a biopsy, it can help guide the decision whether to biopsy. PMID- 28886809 TI - Detection of Genetic Aberrations in the Assessment and Prognosis of Melanoma. AB - The assessment of melanoma by light microscopy with hematoxylin-eosin staining remains an often subjective process. However, there are additional diagnostic measures that may be of utility, such as immunohistochemical staining and genetic evaluation. Adjunctive genetic assessment to augment the diagnosis of melanoma includes comparative genomic hybridization or fluorescent in situ hybridization to assess for gains or losses in genetic material, or gene expression profiling in some form, to ascertain the expression of genes associated with malignancy. Although these techniques may bolster the dermatopathologic assessment of melanoma, none of them, at the present time, are singularly diagnostic. Additional developments in the genetic assessment and prognostication of melanoma are anticipated. PMID- 28886810 TI - Assessing Genetic Expression Profiles in Melanoma Diagnosis. AB - Most melanocytic tumors can be characterized as a benign nevus or a melanoma by a trained pathologist using traditional histopathological methods. However, a minority demonstrates ambiguous features and continues to be a diagnostic challenge. Genetic expression profiling (GEP) assays have been developed in an effort to resolve this dilemma. These assays measure mRNA levels of specified genes using reverse transcription quantitative polymerase chain reaction technology. The development of GEP assays, methodology, challenges associated with GEP validation and testing, and the suitability of a currently available GEP test for clinical use are reviewed. PMID- 28886811 TI - Assessing Genetic Expression Profiles in Melanoma Prognosis. AB - A 31-genetic expression profile (31-GEP) test (DecisionDx-Melanoma, Castle Biosciences Inc, Friendswood, TX, USA) was developed as a diagnostic test to assist physicians in the management of cutaneous malignant melanoma. Based on a patient's primary tumor expression levels of a panel of genes (28 discriminating genes and 3 control genes), a lesion is classified as "low risk" (class 1) or "high risk" (class 2) for metastasis. Studies evaluating the clinical utility and impact of the 31-GEP test showed it positively influenced clinical management and patient care, as clinicians incorporated the additional data to modify their clinical recommendations in a risk-appropriate manner. PMID- 28886812 TI - Smartphone-Based Applications for Skin Monitoring and Melanoma Detection. AB - With the advancement of mobile technologies, smartphone applications (apps) have become widely available and gained increasing attention as a novel tool to deliver dermatologic care. This article presents a review of various apps for skin monitoring and melanoma detection and a discussion of current limitations in the field of dermatology. Concerns regarding quality, transparency, and reliability have emerged because there are currently no established quality standards or regulatory oversight of mobile medical apps. Only a few apps have been evaluated clinically. Further research is needed to evaluate the utility and efficacy of smartphone apps in skin cancer screening and early melanoma detection. PMID- 28886813 TI - Teledermatology Applications in Skin Cancer Diagnosis. AB - Teledermatology has drawn interest in the dermatologic community, because it allows for earlier detection of skin cancer in patients with poor access to health care. Using a combination of dermoscopy and digital photography, teledermatology has demonstrated acceptable concordance with face-to-face clinical diagnoses in multiple settings for pigmented skin lesions. Additional studies on using teledermatology to assess nonpigmented skin lesions are needed. Future advances in mobile teledermatology may help make this technology more widespread and affordable. Although teledermatology is not a replacement for regular total body skin examinations, it is a useful tool to significantly reduce the burden of dermatologic malignancies. PMID- 28886815 TI - Erratum. PMID- 28886814 TI - Integrating Skin Cancer-Related Technologies into Clinical Practice. AB - Early diagnosis and treatment of melanoma improve survival. New technologies are emerging that may augment the diagnosis, assessment, and management of melanoma but penetrance into everyday practice is low. In the current health care climate, greater emphasis will be placed on the incorporation of technology for clinically suspicious pigmented lesions to facilitate better, more cost-effective management. PMID- 28886816 TI - The Importance of Early Recognition of Skin Cancer. PMID- 28886817 TI - Women in Sport: Historical Perspectives. AB - The history of women in sport in America was shaped by Victorian ideals and other belief systems prevalent during the nineteenth century. Medical experts of that era believed that intense exercise and competition could cause women to become masculine, threaten their ability to bear children, and create other reproductive health complications. Consequently, sport for women was reserved for upper-class women until the mid-twentieth century. Title IX of the Education Amendments had a significant and lasting impact on sport in America. Today, girls and women are enjoying sport at the interscholastic, intercollegiate, and professional levels comparable with their male counterparts. PMID- 28886818 TI - Cardiovascular Considerations in the Female Athlete. AB - Over several decades, much has been learned about the diverse physical impacts of exercise. Those who excel, such as elite athletes, have physiologic differences compared with the general population. There is a growing body of data suggesting that gender may play a role in these adaptations. Further, certain cardiac conditions may exhibit a gender predilection. This article explains the particular cardiac nuances of the female athlete. PMID- 28886819 TI - Nutritional Aspects of the Female Athlete. AB - Athletes have specific needs based on sex, size, sport, exercise intensity, duration of activity, phase of training, and the season in which the sport is played. Nutritionally, the female athlete is unique, with needs that may vary based on hormonal fluctuations related to the menstrual cycle. This article provides an overview of the distinct nutritional needs and concerns of the physically active female, including energy availability, macronutrient needs, micronutrient needs, hydration, supplements, and other nutritional issues. Although there is some research focusing specifically on the female athlete and her exceptional nutritional concerns, further gender-specific exploration is needed in all areas. PMID- 28886820 TI - Gastrointestinal Conditions in the Female Athlete. AB - Exercise can have significant effects on gastrointestinal diseases. Regular, moderate exercise can impart beneficial effects for the intestinal microbiome, irritable bowel syndrome symptoms, and inflammatory bowel disease. High-intensity training or prolonged endurance training, on the other hand, can have negative effects on these same entities. Female athletes report a higher prevalence of irritable bowel syndrome and celiac disease, and furthermore, have gastrointestinal symptoms modulated by the menstrual cycle. Management of gastrointestinal problems in the athletic population is widespread and includes training adjustments, dietary measures, and medicine management of symptoms. PMID- 28886822 TI - Osteopenia and Osteoporosis in Female Athletes. AB - Disorders of bone density are especially prevalent among athletic women. The severity of bone loss ranges from osteopenia to frank osteoporosis. In female athletes, a higher incidence of osteoporosis is due to a decreased rate of bone accretion in youth, often as a result of hormonal deficiency and/or excessive exercise. Low bone mass poses a particular challenge for athletes because it predisposes to stress-related bone injuries and increases the risk of osteoporosis and insufficiency fractures with aging. This article reviews the pathophysiology of bone thinning in premenopausal and postmenopausal women, the impact of exercise, and the treatment options presently available. PMID- 28886823 TI - Update on Anterior Cruciate Ligament Rupture and Care in the Female Athlete. AB - As female athlete sports participation has continued to increase, the rate of anterior cruciate ligament (ACL) rupture in female athletes has also increased. Individualized, patient-specific treatment is crucial to achieving optimal outcomes; ACL reconstruction must accurately restore native ACL anatomy and address any concomitant injury to secondary stabilizers. Rehabilitation programs should target hip, core, and trunk neuromuscular control; allow adequate time for graft ligamentization; and address the psychosocial needs of the athlete. PMID- 28886824 TI - Sport Concussion and the Female Athlete. AB - Sport concussion (SC) has emerged as a major health concern in the medical community and general public owing to increased research and media attention, which has primarily focused on male athletes. Female athletes have an equal, if not increased, susceptibility to SC. An ever-growing body of research continues to compare male and female athletes in terms of SC before and after an injury. Clinicians must be cognizant of this literature to make evidence-based clinical decision when providing care to female athletes and discern between dated and/or unsupported claims in terms of SC. PMID- 28886821 TI - Female Athlete Triad: Future Directions for Energy Availability and Eating Disorder Research and Practice. AB - Despite more than 3 decades of research on the Female Athlete Triad, research gaps remain. Although low energy availability (EA) is the key etiologic factor in the Triad and the pathways to low EA are varied, its effects can be modified by several factors. Accurate screening, diagnosis, and treatment of disordered eating are a challenge; however, recent techniques combined with novel educational and behavior interventions prove promising. Recently published practice-based guidelines have helped to translate Triad science and should improve as they are refined. This article identifies the current state of research and distinguishes areas that require further investigation. PMID- 28886825 TI - Exercise in Pregnancy. AB - Routine exercise should be recommended to healthy pregnant women after consultation with an obstetric provider. Even pregnant women who have not been exercising regularly can gradually increase their exercise during pregnancy. Regular exercise during pregnancy promotes overall wellness and helps maintain appropriate gestational weight gain and appropriate fetal weight gain. Exercise in pregnancy may also reduce hypertensive disorders of pregnancy and gestational diabetes, and may be associated with shorter first stage of labor and decreased risk for cesarean section. Exercise in pregnancy is safe for pregnant women and their fetuses and can have multiple health benefits. PMID- 28886826 TI - Foreword. PMID- 28886827 TI - The Female Athlete. PMID- 28886828 TI - ? PMID- 28886829 TI - ? PMID- 28886830 TI - [An overview of transition from child to adult psychiatry]. AB - The transition from child to adult psychiatry is a fundamental stage in an individual's development and in the care pathway of teenagers with mental health problems. The organisation of adult care is very different from that provided to children. There is often a lack of support provided to patients as they make the transition between these two systems, despite it being essential. Local initiatives must be developed to rethink this particularly vulnerable period. PMID- 28886831 TI - [From the perinatal period to adolescence: the three stages of coordination]. AB - The need for coordinated organisation between infant-child psychiatry and adult psychiatry is highlighted through key periods, with the aid of a clinical case: the perinatal period and the hospitalisation of a mother with her child; the psychiatric support of the unwell mother and that of her daughter; then the transition for the 16-year-old teenager towards adult psychiatry. Taking into consideration the mother-child bond is essential and requires collaborative care projects, the creation of opportunities for joint reflection and organisation, and the acknowledgement that internal institutional divisions exist which are too often denied. PMID- 28886832 TI - [Towards a partnership-based care approach to adolescence]. AB - The transition from child psychiatry to adult psychiatry is difficult. The need to reinforce this 'bridge' between the services is clear. A system focused on the assessment and orientation of adolescents, set up a year ago by Lille-Metropole public mental health service, aims to favour collaboration on a local level between the different players from the social, medical and educational sector working with young people aged between 12 and 21 in order to facilitate this transition. PMID- 28886833 TI - [Linking up medico-social care and psychiatry for adolescents with an intellectual disability]. AB - The medical-educational institute in Quimperle caters for teenagers aged between 13 and 16. While its missions are centred on the construction of a project and the provision of on-going and effective support for the young users, there are sometimes major difficulties relating to the links to be established with psychiatry. Young people with mental health conditions require shared and collective care. Three clinical cases reflect the successes and failures of this cross-disciplinary approach. PMID- 28886834 TI - [Joris or the story of a programmed break]. AB - The case of Joris, a young patient with an atypical clinical presentation, highlights the malaise present in our institutions. In this situation, the passage from paedopsychiatry to adult psychiatry could only end in alienation. This case study provides a basis to explore the clinical and institutional cogwheel of a transitional period that is often difficult. PMID- 28886835 TI - [Alex, an example of a successful transition to adult psychiatry]. AB - A successful transition between child psychiatry and adult psychiatry is the result of a joint project. To ensure the continuity of the adolescent's care, the two protagonists need a common and constructive clinical interpretation, and a shared understanding of the problems, without which the transition will be difficult. The story of Alex, a young teenager cared for since early childhood, illustrates the communication methods which must be put in place. PMID- 28886836 TI - [Occupational therapy: benefit of early intervention in the manic phase]. AB - When people experiencing a manic episode arrive in hospital, restrictive measures are often put in place. The priority is to avoid all sources of stimulation, especially anything likely to activate the patient. The prescribing of occupational therapy sessions in a well-defined framework may however be appropriate at an early stage in the care. Aside from its effect on the therapeutic alliance, occupational therapy can help on the cognitive and temporal level, increasing awareness of the condition and engagement in the care. PMID- 28886837 TI - [Benefit of mortality and morbidity reviews in psychiatry]. AB - A mortality and morbidity (M&M) review consists in analysing, collectively and retrospectively, the cases of patients whose evolution has been marked by a complication or death. This analysis must question whether such an outcome could have been avoided, making it possible to identify the causes and correct the factors having contributed to its occurrence. After a presentation of the methodological and organisational principles, as well as the M&M reviews carried out in France, attention is turned to those performed in psychiatry and identifying the main perspectives for the discipline. PMID- 28886838 TI - ? PMID- 28886840 TI - Cryptogenic Stroke and Patent Foramen Ovale Risk Assessment. AB - Stroke is a devastating condition. It is the fifth leading cause of death in the United States, and a leading cause of serious long-term disability. Stroke occurs at any age. Younger patients tend to have strokes of undetermined cause, termed cryptogenic. Herein, the authors describe the classification of stroke cause; the risk of recurrent cryptogenic stroke with patent foramen ovale (PFO); a risk assessment model to stratify incidental versus a pathogenic PFO in patients presenting with stroke; and patient selection for device occluder therapy in the context of the long-term follow-up of the RESPECT randomized clinical trial. PMID- 28886841 TI - Identification and Quantification of Patent Foramen Ovale-Mediated Shunts: Echocardiography and Transcranial Doppler. AB - Once deemed benign, patent foramen ovale (PFO)-mediated right-to-left shunting has now been linked to stroke, migraine, and hypoxemia. Contrast transesophageal echocardiography is considered the standard technique for identifying a PFO, allowing visualization of the atrial septal anatomy and differentiation from non PFO right-to-left shunts. Transthoracic echocardiography is the most common method for PFO imaging, being cost-effective, but has the lowest sensitivity. Transcranial Doppler is highly sensitive but is unable to differentiate cardiac from pulmonary shunts; it is the best method to quantitate shunt severity, being more sensitive than transthoracic or transesophageal echocardiography so is our preferred screening method for PFO. PMID- 28886839 TI - Analysis of Common Eligibility Criteria of Randomized Controlled Trials in Newly Diagnosed Multiple Myeloma Patients and Extrapolating Outcomes. AB - BACKGROUND: The performance of multiple myeloma (MM) therapies in a general patient population and specific eligibility criteria that might limit enrollment into randomized controlled trials (RCTs) have not been evaluated in depth. This study aimed to determine if improvements seen with MM therapies in RCTs are reflected in the general patient population and to identify eligibility criteria that can be modified to increase enrollment. PATIENTS AND METHODS: The Connect MM Registry is a prospective observational cohort study of patients with newly diagnosed MM (NDMM) in the United States. Using common RCT exclusion criteria collected from 16 published studies, patients in the registry were categorized according to their eligibility for inclusion in RCTs. RESULTS: On the basis of common criteria, 563 of 1406 of registry patients (40.0%) are ineligible for RCTs. Criteria leading to exclusion included M-protein <= 1.0 g/dL (25.2%), creatinine > 2.5 mg/dL (13.9%), low absolute neutrophil count (10.0%), and low hemoglobin (9.6%). Significantly more RCT-ineligible versus RCT-eligible patients had hypercalcemia (11.0% vs. 5.5%), elevated creatinine levels (38.9% vs. 6.2%), low hemoglobin levels (59.5% vs. 39.5%), or International Staging System stage III disease (40.1% vs. 22.1%; P < .001 for all comparisons). RCT-ineligible patients had a lower 3-year survival rate than RCT-eligible patients (63% vs. 70%). The incidence of serious adverse events was similar between groups. CONCLUSION: Of patients with NDMM enrolled in the Connect MM Registry, 40% are ineligible for RCTs. This study provides insight into potential modifications of standard eligibility criteria that can lead to improved RCT design and accelerated enrollment. PMID- 28886842 TI - Imaging Assessment of the Interatrial Septum for Transcatheter Atrial Septal Defect and Patent Foramen Ovale Closure. AB - Transcatheter closure of atrial septal defects and patent foramen ovale has become increasingly common with advances in device and imaging technology. The percutaneous approach is now the preferred method of closure when anatomically suitable. Two-dimensional and 3-dimensional echocardiography determines anatomic suitability by characterizing the interatrial defect and its surrounding structures, and is critical for intraprocedural guidance and postprocedure follow up. This article provides an overview of interatrial anatomy as it pertains to interventional considerations and discusses the transthoracic, transesophageal, and intracardiac echocardiographic modalities used for periprocedural and intraprocedural imaging of the interatrial septum. PMID- 28886843 TI - Current Dataset for Patent Foramen Ovale Closure in Cryptogenic Stroke: Randomized Clinical Trials and Observational Studies. AB - Approximately one-third of all strokes have no apparent cause. A patent foramen ovale (PFO) is present in as many as 60% of these patients with cryptogenic strokes, which is significantly more frequent than that of the general population. The presumed biologic mechanisms of ischemic stroke in the setting of a PFO are paradoxic embolism from the peripheral venous system through this interatrial shunt or embolism from in situ thrombosis. In this review, the authors summarize and critically assess the contemporary studies evaluating the efficacy and safety of PFO closure for prevention of recurrent cryptogenic strokes. PMID- 28886844 TI - Patent Foramen Ovale and Migraine Headache. AB - Migraine headache is a common and debilitating disease that has a demonstrable association with the presence of patent foramen ovale (PFO) in multiple case series. Closure of PFO has been performed to try to treat migraine with aura, with variable results. Although early trials suggested benefit to PFO closure, these were of poor quality, and subsequent randomized trials have failed to yield positive results. This article discusses the evidence of an association with PFO and migraine headache, and the trials that have so far been performed to assess the benefits of closure. PMID- 28886845 TI - Patent Foramen Ovale Closure for Hypoxemia. AB - A patent foramen ovale (PFO) is a common anatomic finding in 20% of the normal population. Significant hypoxemia can occur in circumstances in which hemodynamic or anatomic changes predispose to increased right-to-left intra-atrial shunting. The subsequent hypoxemia produces substantial dyspnea that may affect the patient's quality of life, independent of underlying pulmonary disease. Profound hypoxemia caused by right-to-left shunt across the interatrial septum usually responds to percutaneous PFO closure. An important impediment to successful treatment is the lack of awareness of the potential role of a PFO in this condition. PMID- 28886846 TI - Transcatheter Closure of Patent Foramen Ovale: Devices and Technique. AB - Transcatheter closure of a patent foramen ovale (PFO) reduces the risk of recurrent cryptogenic stroke compared with medical therapy. PFO closure is a prophylactic procedure, and will not provide the patient with symptomatic improvement, except in cases of hypoxemia due to right-to-left shunt or possibly migraine headaches. Therefore, appropriate patient selection is critical, and procedural safety is paramount. Herein, we review key characteristics of the devices currently available for transcatheter PFO closure within the United States, and highlight key technical aspects of the PFO closure procedure that will maximize procedural success. PMID- 28886847 TI - Transcatheter Closure of Patent Foramen Ovale. PMID- 28886848 TI - Preparing a Systematic Review for the American Journal of Ophthalmology: Updated Guidance. PMID- 28886849 TI - The Best and the Brightest. PMID- 28886850 TI - Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement in Lower-Surgical-Risk Patients With Chronic Obstructive Pulmonary Disease. AB - Respiratory complications are a major factor contributing to postoperative morbidity and mortality, especially in patients with chronic obstructive pulmonary disease (COPD). Our objective was to compare the rate of respiratory complications in patients with COPD with severe aortic stenosis who underwent transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement (SAVR). Low-to-intermediate surgical-risk patients with moderate or severe COPD who underwent TAVI or SAVR at 2 tertiary centers were included in this study. COPD was defined by the Global Initiative for Chronic Lung Disease classification. The primary end point was the 30-day composite of respiratory mortality, prolonged ventilation (>24 hours), the need for reintubation for respiratory causes, tracheostomy, acute respiratory distress syndrome, pneumonia, or pneumothorax. The inverse probability of treatment weighting was determined to reduce baseline imbalance between the 2 groups. A total of 321 patients (mean age 72.4 +/- 9.3 years old, 74.5% male, mean Society of Thoracic Surgeons predicted risk of mortality 3.8 +/- 1.9%, mean forced expiratory volume 1: 59 +/- 13%) were included in the analysis. TAVI was performed in 122 patients, whereas 199 underwent SAVR. There were no differences between the 2 groups regarding the composite respiratory primary end point (SAVR 10.6%, TAVR 7.4%, adjusted odds ratio 0.57, 95% confidence interval 0.20 to 1.65, p = 0.30). Transfemoral TAVI without general anesthesia (28 patients) was associated with the lowest rate of respiratory complications (3.6%). Among patients with moderate or severe COPD at low-to-intermediate surgical risk, TAVI patients had a similar rate of 30-day major pulmonary complications compared with SAVR patients despite a higher baseline risk profile. Future studies should further investigate whether TAVI is associated with reduced respiratory complications, comparing transfemoral TAVI recipients treated with local anesthesia with their SAVR counterparts. PMID- 28886851 TI - Meta-Analysis of Comparison of 5-Year Outcomes of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Patients With Unprotected Left Main Coronary Artery in the Era of Drug-eluting Stents. AB - Patients with unprotected left main coronary artery (ULMCA) disease are increasingly being treated with percutaneous coronary intervention (PCI) using drug-eluting stents (DES), but long-term outcomes comparing PCI with coronary artery bypass grafting (CABG) remain limited. We performed aggregate data meta analyses of clinical outcomes (all-cause death, nonfatal myocardial infarction, stroke, repeat revascularization, cardiac death, and major adverse cardiac and cerebrovascular events) in studies comparing 5-year outcomes of PCI with DES versus CABG in patients with ULMCA disease. A comprehensive literature search (January 1, 2003 to December 10, 2016) identified 9 studies (6,637 patients). Effect size for individual clinical outcomes was estimated using odds ratio (OR) with 95% confidence intervals (CI) using a random effects model. At 5 years, PCI with DES was associated with equivalent cardiac (OR 0.95, 95% CI 0.62 to 1.46) and all-cause mortality (OR 0.98, 95% CI 0.72 to 1.33), lower rates of stroke (OR 0.50, 95% CI 0.30 to 0.84), and higher rates of repeat revascularization (OR 2.52, 95% CI 1.63 to 3.91); compared with CABG, major adverse cardiac and cerebrovascular events showed a trend favoring CABG but did not reach statistical significance (OR 1.19, 95% CI 0.93 to 1.54). In conclusion, for ULMCA disease, PCI can be considered as a comparably effective and yet less invasive alternative to CABG given the comparable long-term mortality and lower incidences of stroke. PMID- 28886852 TI - Prevalence of Hypertension in Professional Drivers (from the RACER-ABPM Study). AB - Professional drivers are a group exposed to many cardiovascular risk factors. Nonsystematic working hours, stress, low physical activity, and unhealthy dietary habits are common among professional drivers. These translate into high risk of cardiovascular disease. The aim of the current analysis was to establish the prevalence of arterial hypertension in a group of continuous professional drivers. The RACER (Risk of Adverse Cardiovascular Events among professional dRivers in Poland) study is a prospective study focused on assessing cardiovascular risk factors in professional drivers. Patients included in the study were screened for the classical and nonclassical cardiovascular risk factors and had an ambulatory blood pressure monitoring (ABPM) performed. Of the RACER study population, 144 drivers were included into the RACER-ABPM study. Of this group 135 (95.7%) were male at mean age of 50.2 +/- 9.3 years, with mean body mass index of 32.3 +/- 3.0 kg/m2. In 21.3% of patients, family history of cardiovascular disease was noted, 28.1% were current smokers, and 2.9% had diabetes mellitus. Arterial hypertension was previously diagnosed in 39 patients (27.9%). In ABPM, the mean 24-hour blood pressure (BP) values were 130.3 +/- 14.3 and 80.9 +/- 9.9 for systolic and diastolic BP, respectively, and 46.1% of patients could be categorized as dippers. Based on the ABPM results, arterial hypertension was diagnosed in 104 of patients (73.8%). Patients with hypertension tend to be more often male and have a family history of cardiovascular disease. In conclusion, arterial hypertension is highly prevalent in professional drivers. Also abnormal day-to-night BP value patterns are often seen in this group. PMID- 28886853 TI - Comparison of Efficacy and Safety of Transcatheter Aortic Valve Implantation in Patients With Bicuspid Versus Tricuspid Aortic Valves. AB - Bicuspid aortic valve (BAV) stenosis has been considered a contraindication to transcatheter aortic valve implantation (TAVI). The aim of this study is to compare the efficacy and safety of TAVI in patients with BAV with those with tricuspid aortic valve (TAV) using balloon-expandable and self-expanding transcatheter heart valves. This retrospective study included 823 consecutive patients with severe, symptomatic aortic valve stenosis undergoing TAVI in 2 institutions, Baylor Heart and Vascular Hospital (Dallas, TX) and The Heart Hospital Baylor Plano (Plano, TX), from January 2012 to February 2016. Efficacy was evaluated by postprocedural valve function as mean gradient, peak velocity, effective orifice area, and >=moderate paravalvular leak. Safety end points included all-cause 30-day and 1-year mortality, immediate postprocedural mortality and 30-day cardiovascular mortality, procedural success, pacemaker implantation, and procedural complications. Of the 823 included patients, 735 had TAV and 77 had BAV. Baseline characteristics were similar between the 2 groups. Procedural success was high in both BAV and TAV (98.7% vs 99.1%, p = ns). There were no significant differences between groups in valve hemodynamics after TAVI, pacemaker implantation rate, or procedural complications. There were no differences regarding immediate postprocedural mortality (BAV vs TAV, 1.1% vs 0.8%, p = ns), nor 30-day cardiovascular mortality (3.4% vs 2.3%, p = ns). All cause mortality at 30 days (3.4% vs 3.1%, p = ns) and 1-year (8.5% vs 10.5%) were similar. Patients with BAV showed similar procedural and clinical outcomes to patients with TAV. Therefore, TAVI appears to be a safe and effective procedure for patients with BAVs as well as those with TAVs. PMID- 28886854 TI - Impact of Cardiorespiratory Fitness on Mortality in Black Male Veterans With Resistant Systemic Hypertension. AB - Patients with resistant systemic hypertension have poorer outcomes than nonresistant hypertensives. The purpose of this study was to evaluate the association between cardiorespiratory fitness and all-cause mortality in black male Veterans with resistant systemic hypertension. Patients were identified from a cohort undergoing exercise tolerance test at the department of Veterans Affairs Medical Center in Washington, DC. Patients were divided into 4 cardiorespiratory fitness categories based on age-specific peak metabolic equivalents achieved on a standard Bruce protocol. Multivariate Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality across all fitness categories. A total of 1,276 patients out of 9,068 hypertensives had resistant hypertension defined as systolic and/or diastolic blood pressure >140 and/or >90 mm Hg, respectively, on 3 antihypertensive medications, one of which was a diuretic or use of >4 antihypertensive medications. During a follow-up of 9.5 +/- 4.2 years, an inverse association was observed between cardiorespiratory fitness and all-cause mortality in patients with resistant hypertension. Compared with the least-fit group, mortality was reduced by 21% in the low-fit group (HR 0.79, CI 0.60 to 1.05; p value: 0.280), 36% in the moderate-fit group (HR 0.64, CI 0.48 to 0.87; p value 0.001), and 62% in the high-fit group (HR 0.38, CI 0.25 to 0.56; p value <0.001). In conclusion, an inverse association was observed between the level of cardiorespiratory fitness and all-cause mortality in patients with resistant systemic hypertension. Compared with the least-fit referent group, the high-fit group had a significant 62% lower risk of all-cause mortality. PMID- 28886855 TI - Effect of Ablation for Atrial Fibrillation on Heart Failure Readmission Rates. AB - Atrial fibrillation (AF) and heart failure (HF) cause numerous hospital admissions. We investigated if AF increases readmissions in patients with HF and whether AF ablation alters readmissions for HF exacerbations. The 2013 Nationwide Readmissions Database was analyzed for all-cause 90-day readmissions, after discharge for HF exacerbation. Kaplan-Meier analysis was used to compare hazard rates for readmissions due to HF exacerbation, after recent ablation versus no ablation. There were 885,270 admissions for HF exacerbation of which 364,447 had coexisting AF. All-cause 90-day readmission rates were higher in patients with HF with coexisting AF versus those without AF (41.4% vs 37.6%, p <0.0001). Associated factors increasing all-cause 90-day readmissions after ablation in patients without HF were female (odds ratio [OR] 1.44, p <0.001), complication of ablation (OR 1.44, p = 0.022), coronary artery disease (OR 1.56, p <0.001), chronic lung disease (OR 1.74, p <0.001), and malnutrition (OR 10.33, p <0.001). These factors were not significant for patients with HF. HF was not a significant risk factor for complications of ablation (adjusted OR 0.82, 95% confidence interval 0.57 to 1.18). Patients who underwent ablation versus patients who were discharged after HF exacerbation without ablation had a lower rate and length of stay for the 90-day readmission episode, due to HF exacerbation (27.5% vs 41.4%, p <0.0001, and 5.58 days vs 6.60 days, p = 0.031, respectively). In conclusion, AF increased 90-day readmissions in patients with HF, and ablation for AF in patients with HF was associated with reduced frequency, length of stay, and readmissions without an increase in complication rates. PMID- 28886856 TI - Outcome of Patients Receiving Thrombolytic Therapy While on Rivaroxaban for Nonvalvular Atrial Fibrillation (from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). AB - The safety of intravenous thrombolysis in patients taking rivaroxaban has not been well established. We retrospectively analyzed the outcomes of all patients who received thrombolytic therapy in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). A review of medical and adverse event records for patients receiving thrombolytic therapy while enrolled in ROCKET AF was performed to determine their baseline characteristics, indications for thrombolysis, and type of agent used. Safety end points were 30 day post-thrombolytic rates of stroke, bleeding, and mortality. A total of 28 patients in ROCKET AF received thrombolytic therapy, with 19 patients on rivaroxaban and 9 patients on warfarin. Ischemic stroke was the most common indication for thrombolysis (n = 10), and alteplase was the most commonly used fibrinolytic agent (n = 14). Of the 19 patients in the rivaroxaban group, there were 2 nonfatal bleeding events and 2 deaths, mostly occurring when thrombolytic therapy was administered within 48 hours of the last rivaroxaban dose. Of the 9 patients in the warfarin group, there was 1 nonfatal bleeding event and 3 deaths, most occurring when thrombolytic therapy was administered outside of 48 hours from the last warfarin dose. In conclusion, these observations suggest that careful assessment of the time since the last dose may be of clinical significance in patients on novel oral anticoagulants who require emergent thrombolysis. PMID- 28886857 TI - Impact of National Health Checkup Service on Hard Atherosclerotic Cardiovascular Disease Events and All-Cause Mortality in the General Population. AB - Whether health checkups favorably impact the occurrence of atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality in the general population remains in debate. We investigated further the impact of health checkups on hard ASCVD events and all-cause mortality. We compared the occurrence of hard ASCVD events and all-cause deaths for 4 years starting in 2010 between participants who used the National Health Checkup Service (NHCS) more than twice and nonparticipants who never used the NHCS from 2006 to 2009. From the 342,594 survivors aged 40 to 69 years old in 2006 listed in the National Health Insurance Service-National Sample Cohort, a total of 55,275 pairs were selected by propensity matching. Hard ASCVD events were defined as the composite of myocardial infarction and stroke. In the 55,275 matched pairs, we found a significant association between the use of the NHCS and the reduction in hard ASCVD events (adjusted hazard ratio = 0.84, 95% confidence interval 0.76 to 0.92, p <0.001) and all-cause deaths (adjusted hazard ratio = 0.50, 95% confidence interval 0.45 to 0.55, p <0.001). The participants had more medical care, including outpatient care and hospitalizations, and took more hypertension and dyslipidemia medications, whereas hospitalizations for more than 60 days were significantly more frequent in the nonparticipants. In the subgroup analysis, the reduction in hard ASCVD events for NHCS participants was significantly greater in patients without a previous history of dyslipidemia or who did not have outpatient care. In conclusion, the use of the NHCS was significantly associated with reduced hard ASCVD events and all-cause mortality in the general population. PMID- 28886859 TI - Static-dynamic hybrid communication scheduling and control co-design for networked control systems. AB - In this paper, the static-dynamic hybrid communication scheduling and control co design is proposed for the networked control systems (NCSs) to solve the capacity limitation of the wireless communication network. The analytical most regular binary sequences (MRBSs) are used as the communication scheduling function for NCSs. When the communication conflicts yielded in the binary sequence MRBSs, a dynamic scheduling strategy is proposed to on-line reallocate the medium access status for each plant. Under such static-dynamic hybrid scheduling policy, plants in NCSs are described as the non-uniform sampled-control systems, whose controller have a group of controller gains and switch according to the sampling interval yielded by the binary sequence. A useful communication scheduling and control co-design framework is proposed for the NCSs to simultaneously decide the controller gains and the parameters used to generate the communication sequences MRBS. Numerical example and realistic example are respectively given to demonstrate the effectiveness of the proposed co-design method. PMID- 28886860 TI - Primary Headache Disorders Part I- Migraine and the Trigeminal Autonomic Cephalalgias. AB - In Primary Headache Disorders, Part 1, we discuss three of the primary headache disorders using the headache definitions from ICHD-III (Beta): Migraine, with and without aura; its pathophysiology and treatment are discussed. We then discuss the Trigeminal Autonomic Cephalalgias (TACs), including Cluster Headache and Hemicrania Continua, two more primary headache disorders, as well as the other TAC Headaches. We discuss pathophysiology as well as diagnosis, treatment, and pharmacotherapeutic management of these headache diatheses. PMID- 28886861 TI - Primary Headache Disorders- Part 2: Tension-type headache and medication overuse headache. AB - In Part 2 of Primary Headache disorders, we discuss the fourth Primary Headache Disorder, Tension-Type Headache (TTHA). We are again using the ICHD-III (Beta) definitions of such headaches, taking into consideration episodic and chronic TTHA, as well as the presence or absence of pericranial muscle tenderness. We discuss the pathophysiology and pharmacotherapeutic treatment of TTHA, and the aspects of the Myofascial Pain Syndrome that enhance and help the development of TTHA. We then discuss Medication Overuse Headache (MOH), itself a Secondary headache disorder, but one that is extremely important as it assists with the chronification of both migraine and TTHA. Finally we discuss how to manage and treat those patients with MOH. Chronic migraine, which is TTHA, Migraine as well as, in many patients, MOH, is discussed along with the treatment of this multifaceted disorder. PMID- 28886862 TI - Understanding positive immigrant youth adaptation in the context of multiculturalism. AB - This commentary highlights some of the strengths of the papers in this special issue focusing on how they advance acculturation research; how they link immigrant youth research with positive youth development and how they provide some insights into understanding how immigrant youth thrive in their adoptive societies. The commentary takes as its point of departure the prototypical research question for immigrant youth research within the perspective of positive youth development and the ultimate goals of acculturation research, i.e., to (i) promote positive psychological acculturation and the well-being of individuals and (ii) the attainment of harmonious intercultural relations among all groups in contact, and argues that the four papers fall short in addressing the second goal. The second goal is subsequently linked to multiculturalism and suggest that to do full justice to the prototypical research question, more attention should be directed to incorporating indicators of multiculturalism in acculturation research. PMID- 28886863 TI - Critical role of mammalian target of rapamycin for IL-10 dendritic cell induction by a flagellin A conjugate in preventing allergic sensitization. AB - BACKGROUND: Fusion proteins incorporating the Toll-like receptor 5 ligand flagellin are currently undergoing clinical trials as vaccine candidates for many diseases. OBJECTIVE: We studied the mechanisms of immune modulation by a flagellin:allergen fusion protein containing the Toll-like receptor 5 ligand flagellin A from Listeria monocytogenes and the birch pollen allergen Bet v 1 (recombinant flagellin A [rFlaA]:Betv1). METHODS: BALB/c mice were vaccinated with rFlaA:Betv1 in an experimental Bet v 1 sensitization model. Myeloid dendritic cells (mDCs) were differentiated from mouse bone marrow, and PBMCs were isolated from subjects with birch pollen allergy. Cells were stimulated with equimolar amounts of rFlaA, rBet v 1, rFlaA plus rBet v 1, or the rFlaA:Betv1 conjugate and analyzed for cell activation, cytokine secretion, and metabolic state. RESULTS: rFlaA:Betv1 displayed strong immune-modulating properties both in vivo and in vitro, as characterized by secretion of both proinflammatory and anti inflammatory cytokines from murine mDCs and PBMCs from patients with birch allergy. rFlaA:Betv1 suppressed TH2 responses from Bet v 1-specific CD4+ T cells and prevented allergic sensitization in a mouse allergy model. Aggregation of rFlaA:Betv1 resulted in stronger protein uptake accompanied by an increased resistance to microsomal digestion. Remarkably, rFlaA:Betv1 induced activation of mammalian target of rapamycin, which increased the metabolic activity of the stimulated mDCs. rFlaA:Betv1-mediated IL-10 secretion, but not proinflammatory cytokine secretion, was inhibited by rapamycin in mDCs. CONCLUSION: These results provide evidence that mammalian target of rapamycin is a key player involved in prevention of TH2 responses by flagellin A conjugate vaccines. PMID- 28886864 TI - Analysis of the cranio-cervical curvatures in subjects with migraine with and without neck pain. AB - OBJECTIVE: To investigate the differences in head and cervical spine alignment between subjects with migraine and healthy people. DESIGN: A cross-sectional, observational study. PARTICIPANTS: Fifty subjects with migraine and 50 matched healthy controls. MAIN OUTCOMES MEASURES: The presence of neck pain and neck pain related disability was assessed. Four angles (high cervical angle, low cervical angle, atlas plane angle and cervical lordosis Cobb angle) as well as four distances (anterior translation distance, C0 to C1 distance, C2 to C7 posterior translation and hyoid triangle) were calculated using digitalised radiographs and analysed using K-Pacs(r) software. RESULTS: Subjects with migraine reported a longer history of neck pain symptoms, and higher pain intensity and neck-pain related disability than controls (P<0.01). Patients exhibited a smaller anterior translation distance (mean difference: 4.9mm, 95% confidence interval 1.8 to 8.8; P<0.001) and hyoid triangle (difference: 3.0mm, 95% confidence interval 1.0 to 5.0; P=0.02) than healthy controls. When the presence or the absence of neck pain was included in the analysis, the differences did not change. Differences in anterior translation and hyoid triangle distances were considered clinically relevant for subjects with migraine suffering from neck pain. CONCLUSION: Subjects with migraine exhibited straightening of cervical lordosis curvature. The presence of neck pain did not influence head posture in subjects with and without migraine. PMID- 28886858 TI - Trends and Impact of Door-to-Balloon Time on Clinical Outcomes in Patients Aged <75, 75 to 84, and >=85 Years With ST-Elevation Myocardial Infarction. AB - Guidelines strongly recommend patients with ST-elevation myocardial infarction (STEMI) receive timely mechanical reperfusion, defined as door-to-balloon time (DTBT) <=90 minutes. The impact of timely reperfusion on clinical outcomes in patients aged 75-84 and >=85 years is uncertain. We analysed 2,972 consecutive STEMI patients who underwent primary percutaneous coronary intervention from the Melbourne Interventional Group Registry (2005-2014). Patients aged <75 years were included in the younger group, those aged 75-84 years were in the elderly group and those >=85 years were in the very elderly group. The primary endpoints were 12-month mortality and major adverse cardiovascular events (MACE). 2,307 (77.6%) patients were <75 years (mean age 59 +/- 9 years), 495 (16.7%) were 75-84 years and 170 (5.7%) were >=85 years. There has been a significant decrease in DTBT over 10 years in younger and elderly patients (p-for-trend <0.01 and 0.03) with a trend in the very elderly (p-for-trend 0.08). Compared to younger and elderly patients, the very elderly had higher 12-month mortality (3.6% vs 10.7% vs. 29.4%; p = 0.001) and MACE (10.8% vs 20.6% vs 33.5%; p = 0.001). DTBT <=90 minutes was associated with improved outcomes on univariate analysis but was not an independent predictor of improved 12-month mortality (OR 0.84, 95% CI 0.54 1.31) or MACE (OR 0.89, 95% CI 0.67-1.16). In conclusion, over a 10-year period, there was an improvement in DTBT in patients aged <75 years and 75-84 years however DTBT <=90 minutes was not an independent predictor of 12-month outcomes. Thus assessing whether patients aged >=85 years are suitable for invasive management does not necessarily translate to worse clinical outcomes. PMID- 28886865 TI - Updated reliability and normative values for the standing heel-rise test in healthy adults. AB - OBJECTIVES: The heel-rise test is used to assess the strength and endurance of the plantar flexors in everyday clinical practice. However, several factors may affect outcomes, including sex, age, body mass index and activity level. The aims of this study were to revisit the reliability and normative values of this test, and establish normative equations accounting for several factors. DESIGN: Cross sectional observational study with test-retest. SETTING: Community. PARTICIPANTS: Volunteers (n=566, age 20 to 81 years). INTERVENTIONS: Subjects performed single legged heel rises to fatigue, standing on a 10 degrees incline, once on each leg. A subset of subjects (n=32) repeated the test 1 week later. Reliability was quantified using intraclass (ICC) correlation coefficients and Bland-Altman plots {mean difference [95% limits of agreement (LOA)]}, whereas the impact of sex, age, body mass index and activity level on the number of heel rises was determined using non-parametric regression models. RESULTS: The test showed excellent reliability (ICC=1.0 right leg, 1.0 left leg), with mean between-day differences in the total number of heel-rise repetitions of 0.2 (95% LOA -6.2 to 6.5) and 0.1 (95% LOA -6.1 to 6.2) for right and left legs, respectively. Overall, males completed more repetitions than females (median 24 vs 21). However, older females (age >60years) outperformed older males. According to the model, younger males with higher activity levels can complete the most heel rises. CONCLUSIONS: The heel-rise test is highly reliable. The regression models herein can be employed by clinicians to evaluate the outcomes of heel-rise tests of individuals against a comparable normative population. PMID- 28886866 TI - Genetics, hormonal influences, and preterm birth. AB - Prematurity is a devastating disease with high neonatal morbidity and mortality based on gestational age at birth. Genetic and hormonal signals impact directly on the maternal predisposition to preterm birth or sudden onset of myometrial contractility. Candidate gene or genome-wide approaches are beginning to identify potential variants for women at risk for premature delivery or increased responsiveness to hormonal signals including progesterone. However, a majority of these studies have not yielded definitive results to allow for at this stage for development of personalized therapy. PMID- 28886867 TI - Experiences of vulnerability and uncertainty during the Iraq and Afghanistan wars: Stories of wounded service members and the nurses who cared for them. AB - BACKGROUND: The findings reported in this paper were derived from a secondary analysis of selected data from a large clinical knowledge study designed to document the experiential learning of military and federal nurses caring for critically wounded service members (WSMs) of their experience of care from point of injury in the combat zone through their rehabilitation. FINDINGS: This article describes a picture of vulnerability and uncertainty in both WSMs and their nurses throughout the health care continuum. The concepts of vulnerability and uncertainty had distinct meanings for each group. In many cases, nurses who were deployed revealed a dual encounter with the vulnerability of war along with personal uncertainty about themselves and their patients. DISCUSSION: To support optimized health care of WSMs and the well-being of caregivers, health care professionals and policy makers must understand the effects and dynamics of serving in a warzone. PMID- 28886868 TI - Sharper angle, higher risk? The effect of cutting angle on knee mechanics in invasion sport athletes. AB - INTRODUCTION: Cutting is an important skill in team-sports, but unfortunately is also related to non-contact ACL injuries. The purpose was to examine knee kinetics and kinematics at different cutting angles. MATERIAL AND METHODS: 13 males and 16 females performed cuts at different angles (45 degrees , 90 degrees , 135 degrees and 180 degrees ) at maximum speed. 3D kinematics and kinetics were collected. To determine differences across cutting angles (45 degrees , 90 degrees , 135 degrees and 180 degrees ) and sex (female, male), a 4*2 repeated measures ANOVA was conducted followed by post hoc comparisons (Bonferroni) with alpha level set at alpha<=0.05a priori. RESULTS: At all cutting angles, males showed greater knee flexion angles than females (p<0.01). Also, where males performed all cutting angles with no differences in the amount of knee flexion 42.53 degrees +/-8.95 degrees , females decreased their knee flexion angle from 40.6 degrees +/-7.2 degrees when cutting at 45 degrees to -36.81 degrees +/ 9.10 degrees when cutting at 90 degrees , 135 degrees and 180 degrees (p<0.01). Knee flexion moment decreased for both sexes when cutting towards sharper angles (p<0.05). At 90 degrees , 135 degrees and 180 degrees , males showed greater knee valgus moments than females. For both sexes, knee valgus moment increased towards the sharper cutting angles and then stabilized compared to the 45 degrees cutting angle (p<0.01). Both females and males showed smaller vGRF when cutting to sharper angles (p<0.01). CONCLUSION: It can be concluded that different cutting angles demand different knee kinematics and kinetics. Sharper cutting angles place the knee more at risk. However, females and males handle this differently, which has implications for injury prevention. PMID- 28886870 TI - Children and young people's views on institutional safety: It's not just because we're little. AB - The Australian Royal Commission into Institutional Responses to Child Sexual Abuse has set in motion a number of systemic and organizational approaches to identify and respond to child sexual abuse. These include increased child abuse awareness, developing and enhancing child-safe organizational cultures and policies and more thorough screening and supervision of staff in child and youth serving organizations. Although these advances should be applauded, many of the concerns that children and young people have raised about interpersonal safety have not been fully addressed. There is therefore a risk that children's physical, relational, generational, and organizational powerlessness are reinforced through child-safe practices that restrict their meaningful participation, ignore their agency and capacity and fail to respond to their felt safety needs or wishes. This paper presents the findings of a qualitative research project conducted with 121 Australian children and young people and presents their perspectives on issues of vulnerability and the ways that they would like adults and institutions to respond to their safety concerns. The value of adult-child alliances, of formal mechanisms that are child-friendly and accessible and having external agencies monitor and review institutional strategies to preventing harm are discussed. PMID- 28886869 TI - Immunohistochemical study of arginases 1 and 2 in the olfactory bulbs of the Korean roe deer, Capreolus pygargus. AB - Arginases are enzymes of the urea cycle that catalyze the hydrolysis of l arginine to ornithine and urea. The enzymes are core components of the arginine ornithine-glutamate-gamma-amino butyric acid pathway of the central nervous system. In the present study, we immunohistochemically determined the localization of arginase 1 and 2 in the olfactory bulb (OB) of the roe dear (Capreolus pygargus). Reverse transcription PCR revealed that the mRNAs encoding both arginase 1 and 2 were expressed in the OB. Arginase 1 was localized to olfactory nerve axons, calcitonin gene-related peptide-positive mitral/tufted cells (excitatory neurons), and glutamate acid decarboxylase 65/67-immunopositive periglomerular cells of the main olfactory bulb. The arginase 2 immunoreactivities in the OB tissues were similar to those of arginase 1. Furthermore, both arginases were detected in the accessory olfactory bulb. These findings suggest that both arginase 1 and 2 are potentially associated with excitatory and inhibitory neurotransmitter activities in animal OBs, including those of the roe deer. PMID- 28886872 TI - [Benefits of volumetric to facial rejuvenation. Part 1: Fat grafting]. AB - For a number of years, a volumetric approach using autologous fat injection has been implemented to improve cosmetic outcome in face-lift procedures and to achieve lasting rejuvenation. Autologous fat as filling tissue has been used in plastic surgery since the late 19th century, but has only recently been associated to face lift procedures. The interest of the association lies on the one hand in the pathophysiology of facial aging, involving skin sag and loss of volume, and on the other hand in the tissue induction properties of grafted fat, "rejuvenating" the injected area. The strict methodology consisting in harvesting, treating then injecting an autologous fat graft is known as LipoStructure(r) or lipofilling. We here describe the technique overall, then region by region. It is now well known and seems simple, effective and reproducible, but is nevertheless delicate. For each individual, it is necessary to restore a harmonious face with well-distributed volumes. By associating volumetric to the face lift procedure, the plastic surgeon plays a new role: instead of being a tailor, cutting away excess skin, he or she becomes a sculptor, remodeling the face to restore the harmony of youth. PMID- 28886871 TI - DAF in diabetic patients is subject to glycation/inactivation at its active site residues. AB - Decay accelerating factor (DAF or CD55) is a cell associated C3 and C5 convertase regulator originally described in terms of protection of self-cells from systemic complement but now known to modulate adaptive T cell responses. It is expressed on all cell types. We investigated whether nonenzymatic glycation could impair its function and potentially be relevant to complications of diabetes mellitus and other conditions that result in nonenzymatic glycation including cancer, Alzheimer's disease, and aging. Immunoblots of affinity-purified DAF from erythrocytes of patients with diabetes showed pentosidine, glyoxal-AGEs, carboxymethyllysine, and argpyrimidine. HPLC/MS analyses of glucose modified DAF localized the sites of AGE modifications to K125 adjacent to K126, K127 at the junction of CCPs2-3 and spatially near R96, and R100, all identified as being critical for DAF's function. Functional analyses of glucose or ribose treated DAF protein showed profound loss of its regulatory activity. The data argue that de regulated activation of systemic complement and de-regulated activation of T cells and leukocytes could result from non-enzymatic glycation of DAF. PMID- 28886874 TI - Welcome to the New Age. Claude Bernard's "Introduction to the Study of Experimental Medicine" and the Shift of Medical Thought Towards Science: 150 Years Later. PMID- 28886873 TI - Estimation of air-to-grass mass interception factors for iodine. AB - Air-to-grass mass interception factors for radionuclide are important basic input parameter for the estimation of radiation dose to the public around a nuclear power plant. In this paper, we present the determination of air-to- grass mass interception factors for iodine using a 2 m * 2 m * 2 m (l * b * h) size environmental chamber. The temperature, humidity, and rainfall inside the environmental chamber was controlled to required values to simulate different environmental conditions. Grass (Pennisetum purpureum, Schum), grown in pots, was kept inside the environmental chamber and stable iodine in elemental form was sublimed quickly inside the chamber to simulate an accidental release of iodine to the environment. The concentration of iodine in the air was measured periodically by drawing air through a bubbling setup, containing 1% sodium carbonate solution. The mass interception factor for dry deposition varied in the range of 0.25-7.7 m2 kg-1 with mean value of 2.2 m2 kg-1 with respect to fresh weight of grass, and that due to wet deposition varied in the range of 0.6-4.8 m2 kg-1 with mean value of 2.3 m2 kg-1. The mass interception factor was inversely correlated with the total iodine deposited through dry deposition as well as with the rainfall. PMID- 28886875 TI - NF-kappaB Participates in the Stem Cell Phenotype of Ovarian Cancer Cells. AB - BACKGROUND: NF-kappaB is a transcription factor involved in cancer stem cells maintenance of many tumors. Little is known about the specific stem-associated upstream regulators of this pathway in ovarian cancer. The Aim of the study was to analyze the role of the canonical and non-canonical NF-kappaB pathways in stem cells of ovarian cancer cell lines. METHODS: Stem cells were isolated using sorting cytometry. Western blot and RT-PCR were used to quantify protein and messenger RNA levels. Loss and gain of function assays were performed using siRNAs and dominant-negative proteins, respectively. NF-kappaB binding activity was measured with a reporter gene assay. The stem phenotype was estimated with clonogenic assays using soft agar, colony formation, ovospheres formation and in vivo tumorigenicity assays. RESULTS: The CD44+ subpopulation of SKOV3 ovarian cancer cell line presented higher mRNA levels of key stemness genes, an increased tumorigenic capacity and higher expression of the RelA, RelB and IKKalpha. When the canonical pathway was inhibited by means of a dominant-negative version of IkBalpha, the stem cell population was reduced, as shown by a reduced CD44+ subpopulation, a decrease in the expression of the stemness genes and a reduction of the stem phenotype. In addition, IKKalpha, the main upstream non-canonical kinase, was highly expressed in the CSC population. Accordingly, when IKKalpha was inhibited using shRNAs, the expression of the stemness genes was reduced. CONCLUSIONS: This report is the first to show the importance of several elements of both NF-kappaB pathway in maintaining the ovarian cancer stem cell population. PMID- 28886876 TI - Reply to Letter to the Editor Re: "Ultrasound Findings on Hands and Wrists of Patients with Systemic Lupus Erythematosus: Relationship with Physical Examination". PMID- 28886877 TI - Functional sustainability of periphytic biofilms in organic matter and Cu2+ removal during prolonged exposure to TiO2 nanoparticles. AB - Responses of microbial communities to nanotoxicity in aquatic ecosystems are largely unknown, particularly with respect to relationship between community dynamics and functions. Here, periphytic biofilms were selected as a model of species-rich microbial communities to elucidate their responses when exposed to titanium dioxide nanoparticles (TiO2-NPs). Especially, the relationships between the functions (e.g. organic matter and Cu2+ removal) and community dynamics after long-term exposure to TiO2-NPs were assessed systematically. After 5days exposure to TiO2-NPs (5mgL-1), periphytic biofilms showed sustainable functions in pollutant removal and strong plasticity in defensing the toxic disturbance of TiO2-NPs, including photosynthesis and carbon metabolic diversity. The sustainable pollutant removal functions of periphytic biofilms were attributed to their functional redundancy. Specifically, periphytic biofilms altered their composition with cyanobacteria, Sphingobacteriia and Spirochaetes being the newly dominant taxa, and changed the carbon substrate utilization pattern to maintain high photosynthesis and metabolic rates. Moreover, extracellular polymeric substances (EPS) especially proteins were overproduced to bind the NPs and thereby reduce the nanotoxicity. The information obtained in this study may greatly help to understand the interactions between microbial community dynamics and function under NPs exposure conditions and functional redundancy is an important mechanism of periphytic biofilms to maintain sustainable functions. PMID- 28886878 TI - Divergently expressed gene identification and interaction prediction of long noncoding RNA and mRNA involved in duck reproduction. AB - Long noncoding RNAs (lncRNAs) and divergently expressed genes exist widely in different tissues of mammals and birds, in which they are involved in various biological processes. However, there is limited information on their role in the regulation of normal biological processes during differentiation, development, and reproduction in birds. In this study, whole transcriptome strand-specific RNA sequencing of the ovary from young ducks (60days), first-laying ducks (160days), and old ducks, i.e., ducks that stopped laying eggs (490days) was performed. The lncRNAs and mRNAs from these ducks were systematically analyzed and identified by duck genome sequencing in the three study groups. The transcriptome from the duck ovary comprised 15,011 protein-coding genes and 2905 lncRNAs; all the lncRNAs were identified as novel long noncoding transcripts. The comparison of transcriptome data from different study groups identified 2240 divergent transcription genes and 135 divergently expressed lncRNAs, which differed among the groups; most of them were significantly downregulated with age. Among the divergent genes, 38 genes were related to the reproductive process and 6 genes were upregulated. Further prediction analysis revealed that 52 lncRNAs were closely correlated with divergent reproductive mRNAs. More importantly, 6 remarkable lncRNAs were correlated significantly with the conversion of the ovary in different phases. Our results aid in the understanding of the divergent transcriptome of duck ovary in different phases and the underlying mechanisms that drive the specificity of protein-coding genes and lncRNAs in duck ovary. PMID- 28886879 TI - Analysis of putative biomarkers of undifferentiated spermatogonia in dog testis. AB - Spermatogenesis begins after puberty and continues throughout a male's life, and is regulated by spermatogonial stem cells in the seminiferous tubules. Markers of male germ cells, including undifferentiated spermatogonia to fully developed spermatozoa have been identified in rodents, but not in dogs. In this study, to characterize the markers of undifferentiated spermatogonia, histological and immunohistochemical analyses were performed on pre-pubertal (1-month-old), early pubertal (4-month-old), and post-pubertal (7-month-old) dog testes. Expression of chemokine receptor 4 (CXCR4), insulin-like growth factor binding protein 3 (IGFBP3), LIN28, and Sal-like protein 4 (SALL4) genes was confirmed by immunohistochemical analysis. In pre-pubertal and early pubertal dog testes, CXCR4, IGFBP4, and LIN28 genes were expressed in undifferentiated spermatogonia, whereas the SALL4 gene was not expressed in the pre-pubertal stage. In adult dog testes, CXCR4 and IGFBP3 gene expression was detected in undifferentiated spermatogonia and co-localized with protein gene product 9.5 (PGP9.5) near the basement membrane of the seminiferous tubules. The LIN28 and SALL4 genes were expressed in synaptonemal complex protein 3-positive spermatocytes. The CXCR4 and IGFBP3 gene expression is conserved among other species, while LIN28 and SALL4 gene expression varies. Based on results of the present study, it is suggested that undifferentiated spermatogonia markers detected in other species are conserved in dogs. These results may facilitate further studies of the cellular mechanisms of spermatogenesis in dogs. PMID- 28886880 TI - Choice of technological change for China's low-carbon development: Evidence from three urban agglomerations. AB - China's three urban agglomerations, namely, "Beijing-Tianjin-Hebei", "Yangtze River Delta", and "Pearl River Delta", are the most developed regions in China. These agglomerations are also expected to play a leading role in China's low carbon development. Energy-saving and carbon-free technological changes play key roles in the low-carbon development transformation of these regions. This study investigates the elasticities of the output and substitution of factors, and the biased technological change in the three urban agglomerations based on the stochastic frontier analysis with a translog production function. The results indicate that the economic growth of the three urban agglomerations is mainly driven by the increase in capital stock caused by investment, energy shortage, and environmental degradation. The relationship between electricity input and carbon dioxide emissions is affected by power generation and economic cycles and transforms from complementarity to substitution. However, this relationship varies among regions. Technological change is conducive to electricity saving, but it does not present an emission-reduction effect. PMID- 28886881 TI - PAHs accelerate the propagation of antibiotic resistance genes in coastal water microbial community. AB - Antibiotic resistance genes (ARGs) have been regarded as emerging contaminants and have attracted growing attention owing to their widespread presence in the environment. In addition to the well-documented selective pressure of antibiotics, ARGs have also become prevalent because of anthropogenic impacts. Coastal habitats are located between terrestrial and marine ecosystems, which are a hotspot for anthropogenic impacts. Excessive accumulation of polycyclic aromatic hydrocarbons (PAHs) has posed a serious threat to coastal habitats, but no information is available on the effect of PAHs on antibiotic resistance in the microbial community of coastal environments. In this study, the effect of two typical PAHs, naphthalene and phenanthrene, on antibiotic resistance propagation was investigated in a coastal microbial community. The results indicated that the presence of 100 mg/L of naphthalene or 10 mg/L of phenanthrene significantly enhanced the abundance of class I integrase gene (intI1), sulfanilamide resistance gene (sulI), and aminoglycosides resistance gene (aadA2) in the microbial community. Horizontal gene transfer experiment demonstrated that increased abundance of ARGs was primarily a result of conjugative transfer mediated by class I integrons. These findings provided direct evidence that coastal microbial community exposed to PAHs might have resulted in the dissemination of ARGs and implied that a more comprehensive risk assessment of PAHs to natural ecosystems and public health is necessary. PMID- 28886882 TI - Insights into defective serological memory after acute lymphoblastic leukaemia treatment: The role of the plasma cell survival niche, memory B-cells and gut microbiota in vaccine responses. AB - Acute lymphoblastic leukaemia (ALL) is the most common type of cancer in children, accounting for approximately 25% of childhood cancer cases. As a result of effective treatments over the past decades, paediatric ALL mortality has been greatly reduced. Chemotherapy, however, has a range of harmful side effects including the loss of protective antibodies against vaccine-preventable diseases. Since ALL survivors have an increased risk of health problems including organ insufficiencies, acquired vaccine-preventable infections subsequent to clinical remission could become life threatening to these individuals. This review will summarize clinical findings regarding defective humoral immunity in ALL survivors, identify current knowledge gaps and highlight mechanisms related to deficiencies in the B-cell compartment important for serological memory. Further, we illuminate the emerging evidence for a relationship between chemotherapy and gut microbiota, which could play an important role in vaccine responses and the shaping of a young immune system subjected to maturation and recovery. PMID- 28886883 TI - Alternative splicing of telomerase catalytic subunit hTERT generated by apoptotic endonuclease EndoG induces human CD4+ T cell death. AB - Telomerase activity is regulated by alternative splicing of its catalytic subunit human Telomerase Reverse Transcriptase (hTERT) mRNA. Induction of a non-active spliced hTERT leads to inhibition of telomerase activity. However, very little is known about the mechanism of hTERT mRNA alternative splicing. The aim of this study was to determine the role of the apoptotic endonuclease EndoG in alternative splicing of hTERT and telomerase activity. A strong correlation was identified between EndoG expression levels and hTERT splice variants in human CD4+ and CD8+ T lymphocytes. Overexpression of EndoG in CD4+ T cells down regulated the expression of the active full-length hTERT variant and up-regulated expression of the non-active spliced variant. A reduction in full-length hTERT transcripts down-regulated telomerase activity. Long-term in vitro cultivation of EndoG-overexpressing CD4+ T cells led to dramatically shortened telomeres, conversion of cells into a replicative senescence state, and activation of the BCL2/BAX-associated apoptotic pathway finally leading to cell death. These data indicated the participation of EndoG in alternative mRNA splicing of the telomerase catalytic subunit hTERT, regulation of telomerase activity and determination of cell fate. PMID- 28886884 TI - Diffusion lengths and partition coefficients of 131mXe and 85Kr in Makrofol N and Makrofol DE polycarbonates. AB - This work presents the results of an experimental study of the Makrofol(r) N and Makrofol(r) DE polycarbonate foils absorption properties of 85Kr and 131mXe. The diffusion lengths of 85Kr and 131mXe in both types of foils are determined. The partition coefficients of 85Kr from air and water and that of 131mXe from air in Makrofol(r) N are determined. The partition coefficients of 85Kr from water and 131mXe from air in Makrofol(r) DE are also determined. The parameters are determined for T = 22 degrees C and allow for the full characterization of sorption and desorption of 85Kr and 131mXe in the foils at this temperature. The results from this study highlight the remarkable absorption ability of Makrofol(r) and especially of the Makrofol(r) N foil and show that it surpasses the Makrofol DE(r) foil not only as a Rn absorber, but also as Kr and Xe absorber. PMID- 28886885 TI - Segmentation of the right ventricle in four chamber cine cardiac MR images using polar dynamic programming. AB - The four chamber plane is currently underutilized in the right ventricular segmentation community. Four chamber information can be useful to determine ventricular short axis stacks and provide a rough estimate of the right ventricle in short axis stacks. In this study, we develop and test a semi-automated technique for segmenting the right ventricle in four chamber cine cardiac magnetic resonance images. The three techniques that use minimum cost path algorithms were used. The algorithms are: Dijkstra's shortest path algorithm (Dijkstra), an A* algorithm that uses length, curvature and torsion into an active contour model (ALCT), and a variation of polar dynamic programming (PDP). The techniques are evaluated against the expert traces using 175 cardiac images from 7 patients. The evaluation first looks at mutual overlap metrics and then focuses on clinical measures such as fractional area change (FAC). The mean mutual overlap between the physician's traces ranged from 0.85 to 0.88. Using as reference physician 1's landmarks and traces (i.e., comparing the traces from physician 1 to the semi-automated segmentation using physician 1's landmarks), the PDP algorithm has a mean mutual overlap of 0.8970 compared to 0.8912 for ALCT and 0.8879 for Dijkstra. The mean mutual overlap between the BP regions generated by physician 1 and physician 2 landmarks are 0.9674, 0.9605 and 0.9531 for PDP, ALCT and Dijkstra, respectively. The FAC correlation coefficient between the physician's traces ranged from 0.73 to 0.93. PMID- 28886886 TI - Are changes in excitability in the hippocampus of adult male rats induced by prenatal methamphetamine exposure or stress? AB - Prenatal stress and drug exposure induce permanent alterations of the brain. Even though different brain structures are involved, alterations almost always refer to the hippocampus. The aim of this study was to investigate the excitability of hippocampal slices in low-magnesium epilepsy model of prenatally methamphetamine (MA, 5mg/kg sc.) or saline (sc., stress model) exposed animals in adult male rats. The second aim was to investigate, if a low dose of MA (1ml/kgs.c.) administered in adulthood changes the hippocampal activity of these animals. Adult Wistar male rats were divided into groups according to their prenatal treatment (C - naive control; Sa - saline; MA - MA administration). One half of the animals was treated with a challenge dose of MA (1mg/kg sc.) 45min before hippocampal slices were cut. The activity of 350MU thick transversal slices of CA1 hippocampi was recorded (latencies of the first epileptiform discharge and the regular epileptiform activity) and evaluated in ACSF with low-magnesium concentration. Effects of prenatal exposure: The highest excitability was found in the Sa (prenatally stressed) group in respect to C and MA groups. This group developed also the highest number of seizure-like events. In addition, the prenatally MA treated group had also higher excitability than C group. Effects of the MA challenge dose: The challenge dose decreased the excitability of prenatally SA- exposed group. To conclude, even a mild prenatal stress significantly increases hippocampal excitability in adulthood and a challenge dose of MA is able to dampen it. PMID- 28886887 TI - Making medicine; producing pleasure: A critical examination of medicinal cannabis policy and law in Victoria, Australia. AB - Several jurisdictions around the world have introduced policies and laws allowing for the legal use of cannabis for therapeutic purposes. However, there has been little critical discussion of how the object of 'medicinal cannabis' is enacted in policy and practice. Informed by Carol Bacchi's poststructuralist approach to policy analysis and the work of science and technology studies scholars, this paper seeks to problematise the object of 'medicinal cannabis' and examine how it is constituted through governing practices. In particular, we consider how the making of the object of 'medicinal cannabis' might constrain or enact discourses of pleasure. As a case example, we take the Victorian Law Reform Commission's review of law reform options to allow people in the Australian state of Victoria to be treated with medicinal cannabis. Through analysis of this case example, we find that although 'medicinal cannabis' is constituted as a thoroughly medical object, it is also constituted as unique. We argue that medicinal cannabis is enacted in part through the production of another object (so-called 'recreational cannabis') and the social and political meanings attached to both. Although both 'substances' are constituted as distinct, 'medicinal cannabis' relies on the 'absent presence' of 'recreational cannabis' to define and shape what it is. However, we find that contained within this rendering of 'medicinal cannabis' are complex enactments of health and wellbeing, which open up discourses of pleasure. 'Medicinal cannabis' appears to challenge the idea that the effects of 'medicine' cannot be understood in terms of pleasure. As such, the making of 'medicinal cannabis' as a medical object, and its invocation of broad notions of health and wellbeing, expand the ways in which drug effects can be acknowledged, including pleasurable and desirable effects, helping us to think differently about both medicine and other forms of drug use. PMID- 28886888 TI - Thinking with pleasure: Experimenting with drugs and drug research. AB - Within the field of drug and alcohol studies, researchers think about pleasure or against it; we analyse, consider, investigate, invoke or ignore it. The philosophically inclined may think of pleasure or write on it, but in each of these scenarios pleasure is kept at an arm's length while the researcher appears to remain unmoved - detached observers, objective scientists, conceptual experts, program directors, sharp critics, policy advocates - sober judges whose sovereignty is secured by the formal conventions of positivist research, established theory, institutional authority and/or disciplinary knowledge. This paper asks what happens when pleasure is allowed to emerge as a constitutive element in the relations of drug and alcohol research. What happens when we conceive our work as thinking with pleasure, rather than simply researching pleasure or thinking about it? I return to the later work of Foucault, reading it alongside conceptions of the experiment drawn from Science and Technology Studies, arguing that both the pleasures of drug consumption and drug research might be conceived more generatively as mutually implicated in events. PMID- 28886889 TI - Anti-influenza activity of diazaadamantanes combined with monoterpene moieties. AB - The antiviral activity of several diaza-adamantanes containing monoterpenoid moieties against a rimantadine-resistant strain of the influenza A/Puerto Rico/8/34 (H1N1) virus was studied. Hetero-adamantanes containing monoterpene moieties at the aminal position of the heterocycle were found to exhibit lower activity compared to compounds with a diaza-adamantane fragment and a monoterpene moiety linked via an amino group at the 6-position of the hetero-adamantane ring. The highest selectivity index (a ratio of the 50% cytotoxic concentration to the 50% inhibitory concentration) out of 30 was observed for compound 8d, which contains a citronellal monoterpenoid moiety. Diaza-adamantane 8d was superior to its adamantane-containing analog 5 both in its anti-influenza activity and selectivity. Furthermore, 8d has more balanced physicochemical properties than 5, making the former a more promising drug candidate. Modelling these compounds against an influenza virus M2 ion channel predicted plausible binding modes to both the wild-type and the mutant (S31N). PMID- 28886890 TI - Deficit of entropy modulation of the EEG in schizophrenia associated to cognitive performance and symptoms. A replication study. AB - Spectral entropy (SE) is a measurement from information theory field that provides an estimation of EEG regularity and may be useful as a summary of its spectral properties. Previous studies using small samples reported a deficit of EEG entropy modulation in schizophrenia during cognitive activity. The present study is aimed at replicating this finding in a larger sample, to explore its cognitive and clinical correlates and to discard antipsychotic treatment as the main source of that deficit. We included 64 schizophrenia patients (21 first episodes, FE) and 65 healthy controls. We computed SE during performance of an odd-ball paradigm, at the windows prior (-300 to 0ms) and following (150 to 450ms) stimulus presentation. Modulation of SE was defined as the difference between post- and pre-stimulus windows. In comparison to controls, patients showed a deficit of SE modulation over frontal and central regions, also shown by FE patients. Baseline SE did not differ between patients and controls. Modulation deficit was directly associated with cognitive deficits and negative symptoms, and inversely with positive symptoms. SE modulation was not related to antipsychotic doses. Patients also showed a smaller change of median frequency (i.e., smaller slowing of oscillatory activity) of the EEG from pre- to post stimulus windows. These results support that a deficit of fast modulation contributes to cognitive deficits and symptoms in schizophrenia patients. PMID- 28886891 TI - Gliadin-related antibodies in schizophrenia. PMID- 28886892 TI - The Atlantic divide in coronary heart disease: Epidemiology and patient care in the US and Portugal. AB - INTRODUCTION AND OBJECTIVES: We aimed to compare access to new health technologies to treat coronary heart disease (CHD) in the health systems of Portugal and the US, characterizing the needs of the populations and the resources available. METHODS: We reviewed data for 2000 and 2010 on epidemiologic profiles of CHD and on health care available to patients. Thirty health technologies (16 medical devices and 14 drugs) introduced during the period 1980 2015 were identified by interventional cardiologists. Approval and marketing dates were compared between countries. RESULTS: Relative to the US, Portugal has lower risk profiles and less than half the hospitalizations per capita, but fewer centers per capita provide catheterization and cardiothoracic surgery services. More than 70% of drugs were available sooner in the US, whereas 12 out of 16 medical devices were approved earlier in Portugal. Nevertheless, at least five of these devices were adopted first or diffused faster in the US. Mortality due to CHD and myocardial infarction (MI) was lower in Portugal (CHD: 72.8 vs. 168 and MI: 48.7 vs. 54.1 in Portugal and the US, respectively; age- and gender-adjusted deaths per 100000 population, 2010); but only CHD deaths exhibited a statistically significant difference between the countries. CONCLUSIONS: Differences in regulatory mechanisms and price regulations have a significant impact on the types of health technologies available in the two countries. However, other factors may influence their adoption and diffusion, and this appears to have a greater impact on mortality, due to acute conditions. PMID- 28886893 TI - The action of anti-inflammatory agents in healthy temporomandibular joint synovial tissues is sex-dependent. AB - This study evaluated the effects of dexamethasone, parecoxib, and glucosamine on cartilage thickness and cytokine levels in the temporomandibular joint (TMJ). Forty-eight rats (24 female, 24 male) were assigned to four treatments administered once daily for 7 days: control (saline intramuscularly), parecoxib (0.3mg/kg intramuscularly), dexamethasone (0.1mg/kg intramuscularly), and glucosamine (80mg/kg orally). The thickness of TMJ cartilage and levels of four cytokines were measured. Median cartilage thickness was higher in males than in females in the control (253.2 vs. 240.4MUm, P=0.0036), parecoxib (227.3 vs. 192.1MUm, P<0.0001), and dexamethasone (227.1 vs. 170.5MUm, P=0.017) groups, but was lower in males in the glucosamine group (214.5 vs. 239.6MUm, P=0.0001). IL 1beta was not detected. Median IL-1alpha levels differed between males and females in the parecoxib group (0.08 vs. 0.04ng/ml, P=0.0055), but not in the control (0.07 vs. 0.06ng/ml), dexamethasone (0.06 vs. 0.04ng/ml), or glucosamine (0.08ng/ml vs. 0.06ng/ml) groups (all P>0.05). Only dexamethasone induced lower IL-6 levels in males than in females (median 4.6 vs. 2.1ng/ml, P=0.0044). Median TNF-alpha levels did not differ between males and females in the control (0.07 vs. 0.05ng/ml) or parecoxib (0.07 vs. 0.05ng/ml) groups (both P>0.05), but dexamethasone (0.09 vs. 0.05ng/ml, P=0.0002) and glucosamine (0.09 vs. 0.07ng/ml, P=0.0259) induced higher TNF-alpha levels in females. Thus, the effects of the three treatments on the levels of cytokines and thickness of condylar cartilage were sex-dependent. PMID- 28886894 TI - Satisfaction with facial profile aesthetics: are norms overrated? AB - This study aimed to explore to what extent adults perceive deviations from the norm of a balanced profile with normal occlusion as reducing satisfaction with facial appearance and having a psychosocial impact. This cross-sectional study included 225 Caucasian subjects (64% women) aged 18-42 years. Their facial profiles were analyzed photogrammetrically and they were classified into three categories: within, below, or above the standard range for the Croatian population with a normal occlusion. Psychosocial issues were assessed by self reported satisfaction with facial appearance and domains from the Orthognathic Quality of Life Questionnaire: social aspects of dentofacial aesthetics (SA), facial aesthetics concern (FA), and awareness of dentofacial aesthetics (AW). Men with a concave profile were less satisfied with their faces than those with a flat or convex profile (P<0.05). A reduced upper lip height in men resulted in a lower level of satisfaction and increased FA score, when compared to men with a normal or increased upper lip height (P<0.05). In women, a reduced middle third of the face increased AW (P=0.045). Deviations from a well-balanced facial profile, as well as the morphology of the nose and lip, do not increase psychosocial issues to a great extent. The range of acceptable facial characteristics is evidently much broader than the norms. PMID- 28886895 TI - Comments on prospective study of metabolic syndrome as a mortality marker in chronic coronary heart disease patients. PMID- 28886896 TI - The Ire1 Twist that Links Proteostatic with Lipostatic Control of the Endoplasmic Reticulum. AB - The unfolded protein response (UPR) governs homeostasis of both luminal content and membrane of the endoplasmic reticulum (ER). In Molecular Cell, Halbleib et al. identified how a twist in the juxta-membrane amphipathic helix of the UPR transducer Ire1 in yeast is essential for responding to both proteostatic and lipostatic ER stress. PMID- 28886897 TI - Low adherence to antidepressants is associated with increased mortality following stroke: A large nationally representative cohort study. AB - Post stroke depression is common and pervasive. In the general population, there has been some controversy that antidepressant (AD) medication is associated with premature mortality. Data is still lacking regarding the association between adherence to antidepressants (AD) and all-cause mortality. In this retrospective analysis of a population-based cohort of patients, 32,361 post-stroke patients who purchased at least one AD were followed for all-cause mortality over 4-years. Adherence to AD was measured as a ratio between dispensed and prescribed durations and was modeled as: non-adherence (<20%, n=8619), poor (20-50%, n=5108), moderate (50-80%, n=5656), and good (>80%, n=12,978) adherence. Multivariable survival analyses, adjusted for demographic and clinical variables including physical comorbidities known to influence mortality, were conducted. Unadjusted mortality rates were 16.5%, 20.2%, 22.2% and 23.7% in those classified as non-adherent, poor, moderate and good adherence respectively (chi2=174.6, p<0.0001). In the adjusted model, the non-adherent and poor adherence groups had significantly increased mortality Hazard Ratios (HR) of 1.25 (95% CI: 1.17-1.33) and 1.17 (95% CI: 1.09-1.26) respectively compared to the good adherence group. This nationally representative data suggests that poor adherence to AD is associated with increased all-cause mortality among people who had a stroke. Given our findings and the high prevalence of anxiety and depression along with AD effectiveness, efforts to promote AD adherence in this population may be warranted in clinical practice. PMID- 28886898 TI - The differential organogenesis and functionality of two liver-draining lymph nodes in mice. AB - The liver is an immunological organ. However, fundamental knowledge concerning liver-draining lymph nodes (LNs), which have been newly identified in mice as the portal and celiac LNs, is still lacking. Here, we revealed that the portal LN and celiac LN drain liver lymph through different lymphatic vessels. Although both the portal LN and celiac LN possess typical structures, they have different cell compositions. Interestingly, these two LNs form at different times during fetal development. Moreover, the organogenesis of the celiac LN, but not the portal LN, is controlled by the transcription factor NFIL3. Furthermore, the portal LN and celiac LN also perform different functions. The celiac LN is the predominant site of liver antiviral immune responses, whereas the portal LN functions in the in situ induction of dietary antigen-specific regulatory T cells. In conclusion, the portal LN and celiac LN are two independent liver-draining LNs with different organogenesis histories and separate functions in maintaining immune homeostasis in the liver. PMID- 28886900 TI - Clinical and imaging differences between neonates and children with pyriform sinus fistula: which is preferred for diagnosis, computed tomography, or barium esophagography? AB - PURPOSE: Pyriform sinus fistula (PSF) is very rare. It is difficult to make an accurate diagnosis preoperatively. The aim of this study is to summarize the characteristics of clinical and radiologic presentations in neonates and children with PSF and to assess which examination is more helpful for diagnosis. METHODS: A retrospective review was performed in 29 patients with PSF at a single center from January 2013 to September 2016. The clinical presentation, computed tomography (CT) scan/magnetic resonance imaging (MRI), and barium esophagogram were evaluated between neonates and children. RESULTS: This study comprised 14 neonates and 15 children. Neonatal patients presented with cervical cyst, dyspnea, and stridor. However, the most common presentations of children were recurrent neck abscess and thyroiditis. All the neonates and 12 the children underwent CT scan/MRI, which showed the characteristic air pocket in the cervical lesion of 11 (78.6%) neonates and 4 (33.3%) children. The positive rates of barium esophagography in the neonates and children were 27.3% and 86.7%, respectively, the difference of which was statistically significant. CONCLUSION: To obtain an accurate diagnosis of PSF, the differences in clinical and radiologic presentation suggest that CT scan/MRI is preferred for neonates, and barium esophagography is preferred for children. CT scans performed immediately after barium swallow improve the positive rate. PMID- 28886899 TI - Frailty and subclinical coronary atherosclerosis: The Multicenter AIDS Cohort Study (MACS). AB - BACKGROUND AND AIMS: Frailty and cardiovascular disease share many risk factors. We evaluated whether frailty is independently associated with subclinical coronary atherosclerosis and whether any relationships differ by HIV-serostatus. METHODS: We studied 976 [62% HIV-infected] male participants of the Multicenter AIDS Cohort Study who underwent assessment of frailty and non-contrast cardiac CT scanning; of these, 747 men also underwent coronary CT angiography (CCTA). Frailty was defined as having >=3 of 5 of the following: weakness, slowness, weight loss, exhaustion, and low physical activity. Coronary artery calcium (CAC) was assessed by non-contrast CT, and total plaque score (TPS), mixed plaque score (MPS), and non-calcified plaque score (NCPS) by CCTA. Multivariable-adjusted regression was used to assess the cross-sectional associations between frailty and subclinical coronary atherosclerosis. RESULTS: Mean (SD) age of participants was 54 (7) years; 31% were black. Frailty existed in 7.5% and 14.3% of HIV uninfected and HIV-infected men, respectively. After adjustment for demographics, frailty was significantly associated with prevalence of any CAC (CAC>0), any plaque (TPS>0), and mixed plaque (MPS>0) in HIV-uninfected but not in HIV infected men (p-interactionHIV<0.05 for all). Among HIV-uninfected men, after adjustment for cardiovascular risk factors, frailty was significantly associated only with CAC>0 [Prevalence Ratio 1.27 (95%CI 1.02, 1.59)] and TPS>0 [1.19 (1.06, 1.35)]. No association was found for NCPS. CONCLUSIONS: Frailty was independently associated with subclinical coronary atherosclerosis among HIV-uninfected men, but not among HIV-infected men. Further work is needed to ascertain mechanisms underlying these differences and whether interventions that improve frailty (i.e. strength training) can improve cardiovascular outcomes. PMID- 28886902 TI - Measuring stability of cognitive impairment in inpatients with schizophrenia with alternate forms of the Montreal Cognitive Assessment during acute hospitalization. AB - Cognitive impairment is a core feature of schizophrenia. Measuring the stability of cognitive impairment is important for further understanding of this disorder. The Montreal Cognitive Assessment (MoCA) has been demonstrated to be a brief and effective screening tool in detecting cognitive impairment in patients with schizophrenia. It has alternative versions designed for longitudinal settings. The current study retrospectively analyzed the total and subscores of two versions of the MoCA, administered to a group of inpatients with severe schizophrenia at admission and discharge, to measure their cognitive stability during hospitalization. The results revealed that the test-retest reliability coefficient of the MoCA had good reliability, suggesting the two alternative versions of the MoCA are reliable measurements for assessing cognitive impairment repeatedly in patients with schizophrenia. The paired-samples t-test showed that the overall cognitive impairment of patients measured by two forms of the MoCA remained stable during acute hospital stay and across symptom changes. Furthermore, the results showed that patients' cognitive stability was not related to their symptom/illness severity improvement, age, education, or length of stay. PMID- 28886901 TI - Perceptual abnormalities in clinical high risk youth and the role of trauma, cannabis use and anxiety. AB - Recent research suggests that perceptual abnormalities are a group of diverse experiences, which have been associated with trauma, cannabis use, and anxiety. Of the attenuated psychotic symptoms that are present in youth at clinical high risk (CHR) of psychosis, perceptual abnormalities tend to be one of the most frequently endorsed symptoms. However, very few studies have explored perceptual abnormalities and their relationships with the above environmental and affective factors in a CHR sample. Four hundred and forty-one CHR individuals who met criteria for attenuated psychotic symptom syndrome (APSS) determined by the Structured Interview for Psychosis-risk Syndromes (SIPS) were assessed on the content of their perceptual abnormalities, early traumatic experience, cannabis use and self-reported anxiety. Logistic regression analyses suggested that both simple auditory and simple visual perceptual abnormalities were more likely to be reported by CHR who had early traumatic experiences, who are current cannabis users, and who have higher levels of anxiety. Multiple regression analysis revealed that only trauma and anxiety were independent predictors of both simple auditory and simple visual perceptual abnormalities. It is possible that examining subtypes of perceptual abnormalities in CHR leads to an improved understanding of the prevalence of such symptoms. PMID- 28886903 TI - The relationships of current suicidal ideation with inflammatory markers and heart rate variability in unmedicated patients with major depressive disorder. AB - Studies investigating inflammatory status and autonomic functioning simultaneously in depressed patients with current suicidal ideation (SI) are lacking. We recruited 58 unmedicated depressed patients with current SI but without lifetime history of suicidal behavior, as well as 61 equally depressed patients without lifetime history of SI or suicidal behavior. We measured serum cortisol, high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and autonomic functioning evaluated by frequency-domain measures of heart rate variability (HRV). The intensity of current SI was rated with the Columbia Suicide Severity Rating Scale. Chronic psychological stress was assessed using the Chinese version of the Perceived Stress Scale (PSS). Patients with current SI showed higher hs-CRP and ESR but lower variance (total HRV), low frequency (LF), and high frequency (HF) HRV than those without lifetime history of SI. We found no differences in cortisol levels and PSS scores. The intensity of current SI was negatively correlated with variance, LF, and HF but positively correlated with hs-CRP. Our results help improve the understanding of the relationships among current SI, inflammation, and autonomic functioning in depressed patients. The combined use of inflammatory markers and HRV indices may one day be applied in predicting and monitoring patients' suicide risk. PMID- 28886904 TI - Searching for suicide-related information on Chinese websites. AB - Growing concerns about cyber-suicide have prompted many studies on suicide information available on the web. However, very few studies have considered non English websites. We aimed to analyze online suicide-related information accessed through Chinese-language websites. We used Taiwan's two most popular search engines (Google and Yahoo) to explore the results returned from six suicide related search terms in March 2016. The first three pages listing the results from each search were analyzed and rated based on the attitude towards suicide (pro-suicide, anti-suicide, neutral/mixed, not a suicide site, or error). Comparisons across different search terms were also performed. In all, 375 linked webpages were included; 16.3% of the webpages were pro-suicide and 41.3% were anti-suicide. The majority of the pro-suicide sites were user-generated webpages (96.7%). Searches using the keywords 'ways to kill yourself' (31.7%) and 'painless suicide' (28.3%) generated much larger numbers of harmful webpages than the term 'suicide' (4.3%). We conclude that collaborative efforts with internet service providers and search engines to improve the ranking of anti-suicide webpages and websites and implement online suicide reporting guidelines are highly encouraged. PMID- 28886905 TI - Group differences in pain interference, psychiatric disorders, and general medical conditions among Hispanics and whites in the U.S. general population. AB - The cross-sectional retrospective study examined whether ethnicity moderates relationships between pain interference and both psychopathology and general medical conditions among Hispanic and non-Hispanic white adults. Participants comprised 32,574 (14% Hispanic; 86% white) National Epidemiologic Survey on Alcohol and Related Conditions respondents. While Hispanic respondents were less likely than white respondents to report severe pain interference (11.4% vs. 11.9%) or moderate pain interference (5.7% vs. 7.8%), and were more likely to report no or low pain interference (82.9% vs. 80.3%), the magnitude of these ethnic group differences was relatively small. Pain interference was associated with multiple past-year Axis-I psychiatric disorders and general medical conditions in both Hispanic and white respondents. Stronger relationships were observed in Hispanic compared to white respondents between moderate pain interference and any heart condition, tachycardia, and hypertension, and between severe pain interference and any mood disorder. Stronger relationships were observed in white compared to Hispanic respondents between severe pain interference and both social phobia and any stomach condition. Differences between Hispanic and white respondents on the prevalence of pain interference and on the strength of the associations between pain interference and specific psychiatric disorders and general medical conditions underscore the complexity of ethnic health disparities and suggest the importance of further study of underlying mechanisms. PMID- 28886906 TI - Nine-valent human papillomavirus vaccine: great science, but will it save lives? PMID- 28886908 TI - DNA Sensing across the Tree of Life. AB - From plants to mammals, pattern recognition receptors (PRRs) specifically recognize DNA, as a potential marker of either infection or damage. These receptors play critical roles in inflammation, immunity, and pathogen resistance. Importantly, given the ubiquity of DNA, its sensing must be tightly regulated. DNA localization plays a key role in recognition, as highlighted by Toll-like receptor 9 (TLR9) in the endosomal compartment and cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) in the cytoplasm. Sequence and structure also enhance recognition across species. Evidence in plants supports the sensing of extracellular DNA by PRRs, leading to calcium-dependent signaling, although no receptor has been definitively identified yet. Here, we review the shared and distinct features of DNA sensors, and their physiological functions, across the tree of life. PMID- 28886909 TI - Quantitative susceptibility mapping differentiates between parkinsonian disorders. AB - INTRODUCTION: It is often challenging to clinically distinguish between Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Quantitative susceptibility mapping (QSM) is an accurate indirect method for estimating brain iron levels in vivo. This method has yet to be applied in atypical parkinsonism. We aimed to investigate differences in brain iron accumulation parkinsonian disorders and healthy controls using QSM. METHODS: 15 patients with PSP, 11 patients with MSA, 62 patients with PD and 14 healthy controls were included in the study and their phase and magnitude data from susceptibility-weighted magnetic resonance imaging were retrospectively analyzed with an in-house pipeline to create susceptibility maps. Two-way ANCOVA were used to assess group differences. Pairwise comparisons within the ANCOVA were corrected for multiple comparisons. RESULTS: Red nucleus susceptibility was higher in PSP compared with PD (p < 0.001), MSA (p < 0.001) and controls (p < 0.001), which separated PSP from these groups with areas under receiver operating characteristic curve of 0.97, 0.75 and 0.98 respectively. PSP showed higher globus pallidus susceptibility compared with PD (p < 0.001), MSA (p = 0.006) and controls (p < 0.001). Putamen susceptibility was higher in MSA than in PD (p = 0.022) and controls (p = 0.026). Substantia nigra susceptibility was increased in PD compared to controls (p = 0.030). CONCLUSION: We show that all studied parkinsonian disorders have increased susceptibility subcortically, reflecting distinct topographical patterns of abnormal brain iron accumulation. QSM, particularly of the red nucleus, is a promising biomarker in differentiating parkinsonian disorders, and would be interesting to study longitudinally for monitoring disease progression and treatment effects. PMID- 28886910 TI - Challenges towards Revitalizing Hemp: A Multifaceted Crop. AB - Hemp has been an important crop throughout human history for food, fiber, and medicine. Despite significant progress made by the international research community, the basic biology of hemp plants remains insufficiently understood. Clear objectives are needed to guide future research. As a semi-domesticated plant, hemp has many desirable traits that require improvement, including eliminating seed shattering, enhancing the quantity and quality of stem fiber, and increasing the accumulation of phytocannabinoids. Methods to manipulate the sex of hemp plants will also be important for optimizing yields of seed, fiber, and cannabinoids. Currently, research into trait improvement is hindered by the lack of molecular techniques adapted to hemp. Here we review how addressing these limitations will help advance our knowledge of plant biology and enable us to fully domesticate and maximize the agronomic potential of this promising crop. PMID- 28886907 TI - Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial. AB - BACKGROUND: Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. METHODS: We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1.5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention to-treat population, and the primary evaluation of immunogenicity was a non inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. FINDINGS: Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0.5 cases per 10 000 person-years in the 9vHPV and 19.0 cases per 10 000 person-years in the qHPV groups, representing 97.4% efficacy (95% CI 85.0-99.9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. INTERPRETATION: The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. FUNDING: Merck & Co, Inc. PMID- 28886911 TI - Type-B ARABIDOPSIS RESPONSE REGULATORs Directly Activate WUSCHEL. AB - The WUSCHEL (WUS) gene is necessary for the maintenance of stem cells in the shoot apical meristem. Four recent reports show that cytokinin responsive type-B ARABIDOPSIS RESPONSE REGULATORs (ARRs) directly activate WUS expression, providing a long-awaited explanation for how cytokinin influences the maintenance of the stem cell niche. PMID- 28886912 TI - Divergence in How Genetic Pathways Respond to Environments. AB - An upstream gene in the pathway that induces flowering in response to cold has been identified. The gene, RVR1, occurs in several plant lineages and operates in a pathway that exhibits functional divergence across development and across taxa. Such divergence can provide insight into how genetic pathways evolve. PMID- 28886913 TI - Mucus plugging in allergic bronchopulmonary aspergillosis: Implication of the eosinophil DNA traps. PMID- 28886914 TI - Mapping eutrophication risk from climate change: Future phosphorus concentrations in English rivers. AB - Climate change is expected to increase eutrophication risk in rivers yet few studies identify the timescale or spatial extent of such impacts. Phosphorus concentration, considered the primary driver of eutrophication risk in English rivers, may increase through reduced dilution particularly if river flows are lower in summer. Detailed models can indicate change in catchment phosphorus concentrations but targeted support for mitigation measures requires a national scale evaluation of risk. In this study, a load apportionment model is used to describe the current relationship between flow and total reactive phosphorus (TRP) at 115 river sites across England. These relationships are used to estimate TRP concentrations for the 2050s under 11 climate change driven scenarios of future river flows and under scenarios of both current and higher levels of sewage treatment. National maps of change indicate a small but inconsistent increase in annual average TRP concentrations with a greater change in summer. Reducing the TRP concentration of final sewage effluent to 0.5mg/L P for all upstream sewage treatment works was inadequate to meet existing P standards required through the EU Water Framework Directive, indicating that more needs to be done, including efforts to reduce diffuse pollution. PMID- 28886915 TI - Immune failure reveals vulnerability of populations exposed to pollution in the bioindicator species Hediste diversicolor. AB - Human activities on the shoreline generate a growing pollution, creating deleterious habitats in coastal zones. Some species nevertheless succeed in such harsh milieus, raising the question of their tolerance to environmental stress. The annelid Hediste diversicolor lives buried in the sediments, directly exposed to contaminants trapped in the mud. After verifying the similarity of their genetic contexts, we compared reproductive output and individual immune resistance measures of populations living in polluted vs. 'clean' sediments, and related these assessments with measures of phthalates and metal pollution, and associated toxicity indices. Chemical analyses predicted no toxicity to the local infauna, and phenological studies evidenced no direct cost of living in noxious habitats. However, populations exposed to pollutants showed a significantly reduced survival upon infection with a local pathogen. Surprisingly, physiological studies evidenced a basal overinflammatory state in the most exposed populations. This over-activated baseline immune phenotype likely generates self-damage leading to enhanced immune cell death rate and immune failure. Monitoring the immune status of individual worms living in anthropic areas could thus be used as a reliable source of information regarding the actual health of wild populations. PMID- 28886916 TI - Annual variations of total and fractionated chlorophyll and phytoplankton groups in the Gulf of Cadiz. AB - Chlorophyll and phytoplankton distribution and concentration in the Gulf of Cadiz were studied during 2014 and 2015. In both years the highest chlorophyll concentrations are found at coastal stations during spring. Pico- and nanophytoplankton are the main contributors to total chlorophyll, with highest concentrations at the outer limit of the continental shelf. Microphytoplankton is responsible for most of the inshore chlorophyll. Picophytoplankton was analyzed to determine density, biomass and distribution. Prochlorococcus and Synechococcus show differences in distribution depending on distance from the coast and depth. Our results suggest temperature and consequent water stratification seem to be the main factors determining deep fluorescence maxima (DFM), mainly formed by picophytoplankton, especially Prochlorococcus. Pigment identification assisted by CHEMTAX analysis was carried out to analyze relative concentrations of larger phytoplankton. PMID- 28886917 TI - Effects of the phthalate exposure during three gestation periods on birth weight and their gender differences: A birth cohort study in China. AB - Phthalate has been widely used as a type of plasticiser in various consuming products in daily life. Recent studies have suggested that prenatal phthalate exposure may have adverse effects on fetal development. We aimed to identify the effects of in utero phthalate exposure on birth weight (BW). We evaluated a birth cohort comprising 3474 pregnant women and their single infants; 3103, 2975 and 2838 urine samples were collected in the first, second and third trimesters, respectively. Phthalate metabolites included monomethyl phthalate (MMP), monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEHHP), and mono-(2-ethyl-5-hydroxylhexyl) phthalate (MEOHP), which were analysed in the urine by using high performance liquid chromatography-tandem mass spectrometry. Mixed linear model was used in the statistical analysis. Generally, MMP and MEP exposure during pregnancy was associated with decreased birth weight of infants (MMP, beta=-12.192, p=0.009; MEP, beta=-11.876, p=0.014). Hierarchical analysis found that MMP and MEOHP exposure was associated with decreased infants' birth weight only in low birth weight groups (MMP, beta=-42.538, p=0.005; MEOHP, beta=-63.224, p=0.008); MEHP and MEHHP exposure was associated with decreased infants' birth weight in both low birth weight group (MEHP, beta=-42.348, p=0.035; MEHHP, beta=-50.485, p=0.006) and high birth weight group (MEHP, beta= 16.580, p=0.034; MEHHP, beta=-18.009, p=0.040), MBP and MEHP exposure were associated with increased infants' birth weight in male NBW group (MBP, beta=10.438, p=0.039; MEHP, beta=13.223, p=0.017). Moreover, the effect has sex difference. The reduction of birth weight associated with MEHP and MEOHP exposure was stronger in male infants, while MMP and MEP exposure was more significant in female infants. PMID- 28886918 TI - Complementary and alternative therapies for restless legs syndrome: An evidence based systematic review. AB - Restless legs syndrome (RLS) is defined as an irresistible urge to move the legs, which is usually accompanied by paresthesias or dysesthesias at least twice weekly, and affects 2%-4% of adults in Europe and North America. This systematic review assesses the current complementary and alternative options for RLS and the potential benefits of those treatments on sleep quality, mood disorder, and quality of life. A systematic search of the PubMed, Embase, Cochrane, and Web of Science databases was conducted. Eighteen studies met the inclusion criterion, which included the use of the international RLS study group criteria. Complementary and alternative therapies have been found to be effective in both primary and secondary RLS. The severity of primary RLS symptoms can be significantly ameliorated by exercise training, transcutaneous spinal direct current stimulation, pneumatic compression devices, light therapy, repetitive transcranial magnetic stimulation, and acupuncture. Pneumatic compression devices and yoga also improve RLS-related disorders. Exercise training is highly efficacious in the reduction of symptom severity in uremic RLS and related effects such as poor quality of life. Endovenous laser ablation may be a good choice for patients with concurrent RLS and superficial venous insufficiency. PMID- 28886919 TI - Kinetic and equilibrium based fractionation study of Pb in continental shelf sediment of India. AB - Two independent analytical methods (kinetic and sequential extraction protocols) were used to understand the distribution, stability, and lability of Pb-sediment complexes in Indian continental shelf. The concentrations of sedimentary Pb varied from 12.0+/-0.6 to 30.4+/-0.1mg.kg-1 and 15.9+/-0.3 to 36.7+/-0.4mg.kg-1 in the western and eastern shelf of India respectively. The kinetic extraction study showed that higher proportion of labile Pb-complexes were present in the eastern shelf sediments (~24% of total Pb) than the western shelf sediments (~14% of total Pb). The sedimentary organic matter was found to regulate lability of sedimentary Pb complexes. The sequential extraction study suggested that Fe/Mn oxyhydroxide were the primary hosting phase for labile Pb complexes. This study showed that water soluble, exchangeable, carbonate/bicarbonate-Pb complexes in the sediments was labile. This study provides a better physicochemical description of stability or lability of Pb complexes in the coastal sediment of India. PMID- 28886920 TI - Recovering microplastics from marine samples: A review of current practices. AB - An important component of microplastic research is development of reproducible methods for microplastic recovery and characterization. Presented is a review of the literature comparing microplastic separation and identification methodologies from seawater, sediment and marine organisms. The efficiency of methods was examined, including processing time, recovery rates, and potential destruction of microplastics. Visual examination and acid digestion were the most common separation methods for seawater samples and organisms, while density flotation was the primary method for sediment. Few studies reported recovery rates, or investigated the physical or chemical impact on plastics. This knowledge gap may lead to misidentification of plastic or unreliable pollution estimates. Further investigation of the impact chemical treatments have on plastic is warranted. Factors, i.e. biomass loading, recovery rates, and chemical compatibility, must be considered to allow for appropriate methodology. Standardizing this will contribute to efficient sample processing, and allow for direct comparison of microplastic contamination across environments. PMID- 28886921 TI - Concomitance of oligotrophy and low grazing pressure is essential for the resilience of Mediterranean subtidal forests. AB - The study aimed at investigating factors influencing the recovery of the canopy seaweed Cystoseira brachycarpa. A manipulative experiment was done to test if in barren patches the recovery of Cystoseira I) is enhanced by the removal of the urchins, II) is prevented by eutrophication, III) depends on the time of patch clearance and IV) decreases with the distance from Cystoseira bed edge within the barren patch. The effects of the same factors on the structure of the macroalgal assemblage were also tested. Cystoseira recovered abundantly only in clearings where nutrients were not added and urchins were removed. Furthermore, Cystoseira recovered irrespectively of the time the patches were cleared and the distance from the canopy edge. This study showed that the lack of sea urchins at oligotrophic conditions was essential for Cystoseira brachycarpa recruitment, providing evidence that interacting constraints are involved in the recovery of Cystoseira beds. PMID- 28886922 TI - Lumbar pseudo-tail associated with dermal sinus - A case report. AB - BACKGROUND: Lumbosacral and coccygeal skin covered appendages are a rare malformation, considered human-tails. CASE REPORT: The authors describe the case of a full term newborn girl with lumbar skin appendage and a normal neurologic examination. The magnetic resonance of the spine revealed a dermal sinus continuous with the skin appendage and with extension into to the spinal canal. Due to the infection risk, a surgery was performed on the third day of life, with dermal sinus ligation and appendage removal. At 12 months of follow-up the girl has a normal neurologic examination. CONCLUSIONS: With the description of this case the authors aim to emphasize that although rare, lumbar skin appendages can be associated with spinal dysraphism and other lesions, requiring extensive work up and long-term surveillance. PMID- 28886923 TI - The effect of 12-month participation in osteogenic and non-osteogenic sports on bone development in adolescent male athletes. The PRO-BONE study. AB - OBJECTIVES: Research investigating the longitudinal effects of the most popular sports on bone development in adolescent males is scarce. The aim is to investigate the effect of 12-month participation in osteogenic and non-osteogenic sports on bone development. DESIGN: A 12-month study was conducted in adolescent males involved in football, swimming and cycling and compared with an active control group. METHODS: 116 adolescent males (13.1+/-0.1years at baseline): 37 footballers, 37 swimmers, 28 cyclists and 14 active controls were followed for 12 months. Bone mineral content (BMC) was measured by dual-energy X-ray absorptiometry, and bone stiffness was measured by quantitative ultrasound. Bone outcomes at 12 months were adjusted for baseline bone status, age, height, lean mass and moderate to vigorous physical activity. RESULTS: Footballers had higher improvement in adjusted BMC at the total body, total hip, shaft, Ward's triangle, legs and bone stiffness compared to cyclists (6.3-8.0%). Footballers had significantly higher adjusted BMC at total body, shaft and legs compared to swimmers (5.4-5.6%). There was no significant difference between swimmers and cyclists for any bone outcomes. Swimming and cycling participation resulted in non-significant lower bone development at most sites of the skeleton compared to controls (-4.3 to -0.6%). CONCLUSIONS: Football participation induces significantly greater improvements in BMC and bone stiffness over 12 months compared to cycling and swimming. CLINICAL TRIAL REGISTRATION: ISRCTN17982776. PMID- 28886924 TI - Cryptic Female Choice Revisited: A Response to Firman et al. PMID- 28886925 TI - The NCDR ICD Registry: A Foundation for Quality Improvement. PMID- 28886927 TI - Suitability of cardiac resynchronisation therapy in patients with Fontan circulation and congenitally corrected transposition of the great arteries. AB - BACKGROUND: Cardiac resynchronisation therapy (CRT) is a well-recognised treatment in systolic heart failure. There is limited evidence in congenital patients with univentricular hearts or systemic right ventricles. In 2014 PACES/HRS published a consensus statement recommending CRT if ventricular ejection fraction (EF)<=35%, QRS duration>=150ms (with RBBB in systemic RV), NYHA II-IV and ventricular dilatation. The incidence of patients meeting these criteria in whom CRT is possible is not known. METHODS: Retrospective analysis of 203 patients with a univentricular Fontan circulation and 55 patients with ccTGA under specialist ACHD care. RESULTS: Univentricular functional data was available for 194 (96%), 10 (5%) having EF<=35%. QRS duration was available for 190 (94%) and was >=150ms in five (3%). EF data was available for 54 (98%) ccTGA patients, and was <=35% in 6 (11%). QRS duration was >=150ms in 13 (26%). Only four patients fulfilled recommendations and two received CRT. CONCLUSIONS: Only a small proportion of patients with single ventricles or ccTGA meet the criteria for CRT. In many of these patients there are significant anatomical barriers to CRT which limit its use in this population. The decision to implant CRT in complex ACHD requires discussion in a combined ACHD electrophysiology surgical multidisciplinary meeting and close collaboration with patients. PMID- 28886926 TI - 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. AB - In 2016, the American College of Cardiology published the first expert consensus decision pathway (ECDP) on the role of non-statin therapies for low-density lipoprotein (LDL)-cholesterol lowering in the management of atherosclerotic cardiovascular disease (ASCVD) risk. Since the publication of that document, additional evidence and perspectives have emerged from randomized clinical trials and other sources, particularly considering the longer-term efficacy and safety of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in secondary prevention of ASCVD. Most notably, the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial and SPIRE-1 and -2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), assessing evolocumab and bococizumab, respectively, have published final results of cardiovascular outcomes trials in patients with clinical ASCVD and in a smaller number of high-risk primary prevention patients. In addition, further evidence on the types of patients most likely to benefit from the use of ezetimibe in addition to statin therapy after acute coronary syndrome has been published. Based on results from these important analyses, the ECDP writing committee judged that it would be desirable to provide a focused update to help guide clinicians more clearly on decision making regarding the use of ezetimibe and PCSK9 inhibitors in patients with clinical ASCVD with or without comorbidities. In the following summary table, changes from the 2016 ECDP to the 2017 ECDP Focused Update are highlighted, and a brief rationale is provided. The content of the full document has been changed accordingly, with more extensive and detailed guidance regarding decision making provided both in the text and in the updated algorithms. Revised recommendations are provided for patients with clinical ASCVD with or without comorbidities on statin therapy for secondary prevention. The ECDP writing committee judged that these new data did not warrant changes to the decision pathways and algorithms regarding the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C <190 mg/dL with or without diabetes mellitus or patients without ASCVD and LDL-C >=190 mg/dL not due to secondary causes. Based on feedback and further deliberation, the ECDP writing committee down-graded recommendations regarding bile acid sequestrant use, recommending bile acid sequestrants only as optional secondary agents for consideration in patients intolerant to ezetimibe. For clarification, the writing committee has also included new information on diagnostic categories of heterozygous and homozygous familial hypercholesterolemia, based on clinical criteria with and without genetic testing. Other changes to the original document were kept to a minimum to provide consistent guidance to clinicians, unless there was a compelling reason or new evidence, in which case justification is provided. PMID- 28886928 TI - Geographic atrophy: Etiopathogenesis and current therapies. AB - Geographic atrophy is characterized by severe visual deficit whose etiology and pathophysiology are yet to be elucidated. As a working hypothesis, oxidative damage could trigger a chronic inflammation in Bruch's membrane-RPE choriocapillaris complex, mostly due to complement pathway overactivation. Some individuals with mutations in the complement system and other factors have diminished capacity in the modulation of the inflammatory response, which results in cell damage and waste accumulation. This accumulation of intracellular and extracellular waste products manifests as drusen and pigmentary changes that precede the atrophy of photoreceptors, RPE, choriocapillaris with an ischemic process with decreased choroid flow. All these processes can be detected as tomographic findings and autofluorescence signals that are useful in the evaluation of patients with atrophic AMD, which helps to establish an individualized prognosis. Anti-inflammatory, antioxidant and therapies that decrease the accumulation of toxins for the preservation of the RPE cells and photoreceptors are being investigated in order to slow down the progression of this disease. PMID- 28886929 TI - Indocyanine green angiography in anterior scleritis. PMID- 28886930 TI - Valsalva petaloid maculopathy. PMID- 28886931 TI - OCT angiography in solitary astrocitic hamartoma. PMID- 28886932 TI - Human immunodeficiency virus-associated giant conjunctival Kaposi's sarcoma: complete remission with antiretroviral therapy and systemic chemotherapy. AB - CASE REPORT: A 35-year-old male patient with a large unilateral haemorrhagic conjunctival tumour lesion and another contralateral haemorrhagic conjunctival flat lesion associated with violaceous cutaneous macules on the extremities and angiomatous lesions in the upper gastrointestinal tract as initial clinical manifestation of HIV-related immunodeficiency. Cutaneous, gastric mucosal and conjunctival biopsy was consistent with Kaposi's sarcoma with complete remission after highly active antiretroviral therapy and systemic chemotherapy. CONCLUSION: HIV-related conjunctival Kaposi's sarcoma, even a large one, can have a good response to antiretroviral therapy and systemic chemotherapy without any additional topical eye treatment. PMID- 28886933 TI - Characterization of Actinobacillus pleuropneumoniae field strains antigenically related to the 3-6-8-15 group from diseased pigs in Japan and Argentina. AB - The objectives of this study were to determine the serovar of a collection of Actinobacillus pleuropneumoniae strains within the 3-6-8-15 cross-reacting group and to analyze their phenotypic and genetic properties. Based on the serological tests, forty-seven field strains of Actinobacillus pleuropneumoniae isolated from lungs with pleuropneumonia lesions in Japan and Argentina were found to be serovars belonging to the 3-6-8-15 cross-reacting group. By using a capsule loci based PCR, twenty-nine (96.7%) and one (3.3%) from Japan were identified as serovars 15 and 8, respectively, whereas seventeen (100%) from Argentina were identified as serovar 8. The findings suggested that serovars 8 and 15 were prevalent within the 3-6-8-15 cross-reacting group, in Argentina and Japan, respectively. Phenotypic analyses revealed that the protein patterns observed on SDS-PAGE and the lipopolysaccharide antigen detected by immunoblotting of the reference and field strains of serovars 8 and 15 were similar to each other. Genetic (16S rDNA, apxIIA, apxIIIA, cps, cpx genes, apx and omlA patterns) analyses revealed that the apxIIA and apxIIIA genes of the field strains of serovars 8 and 15 were similar to those of the reference strains of serovars 3, 4, 6, 8 and 15. The results obtained in the present study may be useful for the development of more effective vaccines against disease caused by A. pleuropneumoniae by including the homologous antigens to the most prevalent serovars in specific geographical areas. PMID- 28886934 TI - Transglutaminase 6 antibodies in gluten neuropathy. AB - BACKGROUND: TG6 antibodies have been shown to be a marker of gluten ataxia but their presence in the context of other neurological manifestations of gluten sensitivity has not been explored. We investigated the presence of TG6 antibodies in gluten neuropathy (GN), defined as as an otherwise idiopathic peripheral neuropathy associated with serological markers of gluten sensitivity (one or more of antigliadin IgG and/or IgA, endomysial and transglutaminase-2 antibodies). METHODS: This was a cross-sectional study conducted at the Sheffield Institute of Gluten Related Diseases, Royal Hallamshire Hospital, Sheffield, UK. Blood samples were collected whilst the patients were on a gluten containing diet. Duodenal biopsies were performed to establish the presence of enteropathy. RESULTS: Twenty eight patients were recruited (mean age 62.5+/-13.7 years). Fifteen (53.6%) had sensory ganglionopathy, 12 (42.9%) had symmetrical axonal neuropathy and 1 had mononeuritis multiplex. The prevalence of TG6 antibodies was 14 of 28 (50%) compared to 4% in the healthy population. TG6 antibodies were found in 5/15 (33.3%) patients with sensory ganglionopathy and in 8/12 (66.7%) with symmetrical axonal neuropathy. Twenty-four patients underwent duodenal biopsy 11 (45.8%) of which had enteropathy. The prevalence of TG6 was not significantly different when comparing those with or without enteropathy. CONCLUSIONS: We found a high prevalence of antibodies against TG6 in patients with GN. This suggests that TG6 involvement is not confined to the central nervous system. The role of transglutaminase 6 in peripheral nerve function remains to be determined but TG6 antibodies may be helpful in the diagnosis of GN. PMID- 28886935 TI - Examination of Nondesignated Preliminary Surgery Residents Recruited Since the Inception of Supplementary Offer and Acceptance Program: Lessons Learned From a Large Academic Program. AB - PURPOSE: The majority of surgery programs roster non-designated preliminary (NDP) residents. We and others have reported on the success of NDP resident mentoring with regard to categorical position placement. Lacking is a focus on the candidates themselves and differences based on initial career of choice. METHODS: NDP residents' files since the institution of SOAP were reviewed for demographics, initial career choice, financial burden, region of medical school of origin, application and interview history, and pre-screen interview candidate score (high score of 22 - data includes USMLE scores, major clerkship grades, and AOA) used for categorical recruitment. RESULTS: From 2012-16 79 NDP residents have been recruited at UCDenver (82% via SOAP). Median age was 28 years, majority were single (73%), and male (82%). Thirty percent belonged to an under represented minority group. Mean debt was $156,000 but 20% owe over $250,000. 90% attended US medical schools with 65% from the NRMP "South" region. 86% were recruited as fourth year students. NDPs were categorized as failing to match in general surgery (38%), surgical subspecialties (47%), or other (15%). NDPs applied to median of 68 programs (range 7-200) and granted a median of 8 interviews (range 0-24). NDPs had a mean pre-screening interview score of 13 out of 22 and only 9% would have met the standard threshold to obtain a categorical surgery interview. There were no differences in pre-screening scores in the three groups. 95% NDPs (excluding present year) successfully completed their R1 year (three resigned - one obtained a general surgery spot mid-year and two after matching in non-general surgery fields). 68% NDPs placed in categorical positions after the R1 year. The placement was better for the surgical subspecialty group compared to the other two. CONCLUSIONS: The bias is that due to a more competitive applicant pool recruiting NDPs from surgical subspecialties would be optimal. However, those unmatched surgical subspecialty candidates are no better academically than the unmatched general surgery group, often have career interests that do not always align with scheduled rotations, and may not feel compelled to complete the year if they match. They place minimally better when accounting for those unmatched general surgery NDP R1s continuing as NDP R2s. Ultimately the success in a non-designated preliminary R1 surgery program is alignment of clinical educational opportunities with the needs of the trainee. PMID- 28886936 TI - Quantification of piperazine in chicken and pig tissues by gas chromatography electron ionization tandem mass spectrometry employing pre-column derivatization with acetic anhydride. AB - This paper describes a novel method that combines acetic anhydride derivatization with gas chromatography-electron ionization tandem mass spectrometry (GC EI/MS/MS) for the sensitive and selective determination of piperazine in chicken and pig tissues. Samples were extracted using an accelerated solvent extraction (ASE) apparatus, purified by solid-phase extraction (SPE) and derivatized with acetic anhydride. This optimized method was validated according to the requirements defined by the European Union and the Food and Drug Administration. At the limit of quantification (LOQ) spiked levels of 50.0, 100.0, 500.0, 1000.0 and 2000.0MUg/kg, the average recoveries of piperazine in chicken and pig tissues were 77.46-96.26%, with relative standard deviations (RSDs) of 1.55-6.64%. The intra-day RSDs were 1.39-5.92%, and the inter-day RSDs were 2.24-8.39%. The limits of detection (LODs) and the LOQs were 1.4-1.6MUg/kg and 4.8-5.2MUg/kg, respectively. The decision limits (CCalpha) were 102.02-105.17MUg/kg, and the detection capabilities (CCbeta) were 104.03-109.09MUg/kg. Finally, the new approach was verified for the quantitative determination of piperazine in 30 commercial chicken and pig tissues from local supermarkets. PMID- 28886938 TI - Enantioselective determination of (R)-zopiclone and (S)-zopiclone (eszopiclone) in human hair by micropulverized extraction and chiral liquid chromatography/high resolution mass spectrometry. AB - Zopiclone and its (S)-enantiomer (eszopiclone) are commonly prescribed for insomnia. Despite the high demand for enantioselective differentiation, the chiral analysis of zopiclone in hair has not been reported. In this study, a method for the enantioselective quantification of zopiclone in human hair was developed. The extraction medium and duration were optimized using real eszopiclone-positive hair samples. Specifically, micropulverized extraction with 3.0M ammonium phosphate buffer (pH 8.4) involving salting-out assisted liquid liquid extraction with acetonitrile was utilized to minimize the degradation of zopiclone and for rapid and facile operation. On the other hand, recovery of the conventional solid-liquid extraction involved overnight soaking in 3.0M ammonium phosphate buffer (pH 8.4) was only 0.58+/-0.12% of the maximum recovery achieved by the present method due to the decomposition in the phosphate buffer. An excellent chiral separation (Rs=5.0) was achieved using a chiral stationary phase comprising cellulose tris(3,5-dichlorophenylcarbamate) and a volatile mobile phase of 10mM ammonium carbonate (pH 8.0)-acetonitrile (25:75, v/v). Detection was carried out using liquid chromatography/high resolution mass spectrometry (LC/HRMS) with electrospray ionization. A Q Exactive mass spectrometer equipped with a quadrupole-Orbitrap analyzer was used for detection. The concentration of 0.50pg/mg was defined as the lowest limit of quantification using 5mg of hair sample. Using the developed approach, the concentration of eszopiclone in hair after a single 2-mg dose was found to be 441pg/mg, which was higher than all the reported values regarding a single administration of zopiclone. After daily administration of racemic zopiclone (3.75mg/day), the concentrations of (R) enantiomer and (S)-enantiomer in the black hair were 5.30-8.31ng/mg and 7.96 12.8ng/mg, respectively, and the concentration of the (S)-enantiomer was always higher than that of the (R)-enantiomer due to the enantioselective difference in the pharmacokinetics. PMID- 28886937 TI - Studies of drug interactions with alpha1-acid glycoprotein by using on-line immunoextraction and high-performance affinity chromatography. AB - A method that combined on-line immunoextraction with high-performance affinity chromatography was developed to examine the binding of drugs with alpha1-acid glycoprotein (AGP). Affinity microcolumns containing immobilized polyclonal anti AGP antibodies were developed that had a capture efficiency of up to 98.4% for AGP and a binding capacity of 0.72nmol AGP when using a 20mm*2.1mm i.d. microcolumn. These microcolumns were employed in various formats to examine the binding of drugs to normal AGP and AGP that had been adsorbed from serum samples for patients with systemic lupus erythematosus (SLE). Drugs that were screened in zonal elution experiments for their overall binding to these types of AGP included chlorpromazine, disopyramide, imipramine, propranolol, and warfarin. Most of these drugs showed an increase in their binding to the AGP from SLE serum when compared to normal AGP (i.e., an increase of 13-76%); however, disopyramide gave a 21-25% decrease in retention when the same AGP samples were compared. Frontal analysis was used to further evaluate the binding of disopyramide and imipramine to these forms of AGP. Both drugs gave a good fit to a model that involved a combination of saturable and non-saturable interactions with AGP. Changes in the non-saturable interactions accounted for most of variations seen in the binding of disopyramide and imipramine with the AGP samples. The methods used in this study could be adapted for use in personalized medicine and the study of other proteins or drugs using aqueous mixtures or clinical samples. PMID- 28886939 TI - Development of an on-line mixed-mode gel liquid chromatography*reversed phase liquid chromatography method for separation of water extract from Flos Carthami. AB - A novel on-line comprehensive two-dimensional liquid chromatography (2D-LC) method by coupling mixed-mode gel liquid chromatography (MMG-LC) with reversed phase liquid chromatography (RPLC) was developed. A mixture of 17 reference compounds was used to study the separation mechanism. A crude water extract of Flos Carthami was applied to evaluate the performance of the novel 2D-LC system. In the first dimension, the extract was eluted with a gradient of water/methanol over a cross-linked dextran gel Sephadex LH-20 column. Meanwhile, the advantages of size exclusion, reversed phase partition and adsorption separation mechanism were exploited before further on-line reversed phase purification on the second dimension. This novel on-line mixed-mode Sephadex LH-20*RPLC method provided higher peak resolution, sample processing ability (2.5mg) and better orthogonality (72.9%) versus RPLC*RPLC and hydrophilic interaction liquid chromatography (HILIC)*RPLC. To the best of our knowledge, this is the first report of a mixed-mode Sephadex LH-20*RPLC separation method with successful applications in on-line mode, which might be beneficial for harvesting targets from complicated medicinal plants. PMID- 28886940 TI - Incidence of bifid uvula and its relationship to submucous cleft palate and a family history of oral cleft in the Brazilian population. AB - INTRODUCTION: Bifid uvula is a frequently observed anomaly in the general population and can be regarded as a marker for submucous cleft palate. OBJECTIVE: In this study aimed to determine the frequency of bifid uvula and submucous cleft palate and their relationship with oral clefts in a Brazilian population. METHODS: We conducted a transversal, descriptive and quantitative study of 1206 children between August 2014 and December 2015. A clinical examination of the children was conducted by means of inspection of the oral cavity with the aid of a tongue depressor and directed light. After the clinical examination in children, parents answered a questionnaire with questions about basic demographic information and their family history of oral clefts in their first-degree relatives. After application of the questionnaires, the information collected was archived in a database and analyzed by the statistical program SPSS(r) version 19.0, by applying Chi-Square tests. Values with p<0.05 were considered statistically significant. RESULTS: Of the 1206 children included in this study, 608 (50.40%) were female and 598 (49.60%) were male (p=0.773). The average age of children was 3.75 years (standard deviation+/-3.78 years). Of the 1206 children studied, 6 (0.5%) presented with bifid uvula. Submucosal cleft palate was not found in any child. When the family histories of children were examined for the presence of nonsyndromic cleft lip and/or cleft palate, no first degree relatives presented with the congenital anomaly. CONCLUSION: This study revealed that the incidence of bifid uvula and submucous cleft palate in this population was quite similar to previously reported incidence rates. Our study suggests an intensification of new reviews, with broader and diverse populations, seeking to associate the occurrence of bifid uvula, submucous cleft palate and oral clefts. PMID- 28886941 TI - Should functional renal scans be obtained prior to upper abdominal IMRT for pancreatic cancer? AB - BACKGROUND: Upper abdominal irradiation for pancreatic cancer is administered in close proximity to the radiation-sensitive kidneys. There is difficulty in defining dose-volume parameters to predict late renal toxicity after partial kidney irradiation. Less than 10% of the general population is estimated to have asymmetrical kidney function; however, there are no studies that examine this in patients with pancreatic cancer. The primary purpose of this study was to determine the prevalence of asymmetrical kidney function in patients with pancreatic cancer. A secondary aim was to determine if asymmetrical kidney function was associated with abnormal laboratory values or kidney size on computed tomography scans. Finally, we aimed to develop recommendations for when a functional renal scan in patients with pancreatic cancer should be ordered. METHODS AND MATERIALS: We performed a retrospective review of patients with resectable, borderline resectable, and locally advanced pancreatic cancer who received abdominal radiation therapy and had preradiation functional renal scans between 2009 and 2015. Asymmetrical kidney function was defined as a difference between the 2 kidneys that was >=60%/40% on a functional renal scan. Serum studies (blood urea nitrogen [BUN], creatinine [Cr], and glomerular filtration rate [GFR]) and abdominal computed tomography scans were routinely obtained before simulation. RESULTS: Of the 204 patients examined, 23 (11.2%) had asymmetrical kidney function that was identified on preradiation functional renal scans. Elevated Cr or BUN, a GFR <60, or a medical history that suggested abnormal renal function were not significantly associated with asymmetrical kidney function. Only 6 of 23 patients (26%) with asymmetrical kidney function had a notable difference in kidney size. CONCLUSIONS: In our series, approximately 11% of patients with pancreatic cancer have asymmetrical kidney function that was not identified by kidney size, serum BUN, Cr, GFR, or a significant medical history. These data suggest that in cases in which renal radiation doses exceed a V18 of 20% to 30% or there is concern about baseline renal function, a functional renal scan should be considered. PMID- 28886942 TI - Remitting infections due to community-acquired Panton-Valentine leukocidin producing Staphylococcus aureus in the Milan area. AB - One of the most important Staphylococcus aureus virulence factors is Panton Valentine leukocidin (PVL). We describe an outbreak of recurrent cutaneous PVL infections in different members of three family clusters. Molecular investigations were performed to confirm the presence of the mecA and PVL genes and to assign the SCCmec type, sequence type (ST) and clonal relatedness. A strain of PVL-producing methicillin-resistant S. aureus (MRSA) was responsible for infection in two related families (A and B), and a third family (C) was infected with PVL-producing methicillin-sensitive S. aureus (MSSA). Molecular investigations revealed the same clone of community-acquired (CA)-MRSA, PVL positive ST8, and SCCmec IV in families A and B and CA-MSSA PVL positive ST15 in family C. S. aureus PVL may give rise to recurrent uncontrolled infections that are difficult to eradicate, and close family contacts are at high risk for transmission. PMID- 28886943 TI - Short- and long-term protective efficacy against clade 2.3.4.4 H5N2 highly pathogenic avian influenza virus following prime-boost vaccination in turkeys. AB - Highly pathogenic avian influenza virus (HPAIV) infections are frequently associated with systemic disease and high mortality in domestic poultry, particularly in chickens and turkeys. Clade 2.3.4.4 represents a genetic cluster within the Asian HPAIV H5 Goose/Guangdong lineage that has transmitted through migratory birds and spread throughout the world. In 2014, clade 2.3.4.4 strains entered the U.S. via the Pacific flyway, reassorted with local strains of the North American lineage, and produced novel HPAIV strains of the H5N1, H5N2, and H5N8 subtypes. By 2015, the H5N2 HPAIVs disseminated eastwards within the continental U.S. and Canada and infected commercial poultry, causing the largest animal health outbreak in recent history in the U.S. The outbreak was controlled by traditional mass depopulation methods, but the outbreak was of such magnitude that it led to the consideration of alternative control measures, including vaccination. In this regard, little information is available on the long-term protection of turkeys vaccinated against avian influenza. In this report, a vaccination study was carried out in turkeys using 3 prime-boost approaches with a combination of 2 different vaccines, an alphavirus-based replicon vaccine and an adjuvanted-inactivated reverse genetics vaccine. Vaccine efficacy was assessed at 6 and 16weeks of age following challenge with a prototypic novel clade 2.3.4.4 H5N2 HPAIV. All three vaccines protocols were protective with significantly reduced virus shedding and mortality after challenge at 6weeks of age. In contrast, significant variations were seen in 16-week old turkeys after challenge: priming with the alphavirus-based replicon followed by boost with the adjuvanted-inactivated vaccine conferred the best protection, whereas the alphavirus-based replicon vaccine given twice provided the least protection. Our study highlights the importance of studying not only different vaccine platforms but also vaccination strategies to maximize protection against HPAIV especially with regards to the longevity of vaccine-induced immune response. PMID- 28886944 TI - Attitudes towards Zika screening and vaccination acceptability among pregnant women in Malaysia. AB - The aim of this study was to examine the willingness of pregnant women to have prenatal screening for the Zika virus (ZIKV). Secondly, the study also assessed the acceptability of a hypothetical Zika vaccination and its association with the health belief model (HBM) constructs. A cross-sectional study was conducted from 4th October to 11th November 2016, among pregnant women who attended antenatal care at the University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia. The majority (81.8%) was willing to be tested for ZIKV and 78% felt that their spouse would be willing to be tested for ZIKV. A total of 94% expressed a willingness to receive a Zika vaccination if available. The participants expressed high perceived benefits of a ZIKV vaccination. Although many have a high perception of the severity of ZIKV, the proportion with a strong perception of their susceptibility to ZIKV was low. In the multivariate analysis of all the HBM constructs, cue-to-action, namely physician recommendation (odds ratio [OR]=2.288; 95% confidence interval [CI] 1.093-4.793) and recommendation from friends or relatives (OR=4.030; 95% CI 1.694-9.587), were significantly associated with a willingness to be vaccinated against ZIKV. The favourable response to a Zika vaccination implies that more research attention has to be given to develop a vaccine against ZIKV. Should the vaccine be available in the future, publicity and healthcare providers would play a vital role in ensuring vaccine uptake among pregnant women. PMID- 28886945 TI - Cost of a measles outbreak in a remote island economy: 2014 Federated States of Micronesia measles outbreak. AB - After 20years with no reported measles cases, on May 15, 2014 the Centers for Disease Control and Prevention (CDC) was notified of two cases testing positive for measles-specific immunoglobulin M (IgM) antibodies in the Federated States of Micronesia (FSM). Under the Compact of Free Association, FSM receives immunization funding and technical support from the United States (US) domestic vaccination program managed by the Centers for Disease Control and Prevention (CDC). In a collaborative effort, public health officials and volunteers from FSM and the US government worked to respond and contain the measles outbreak through an emergency mass vaccination campaign, contact tracing, and other outbreak investigation activities. Contributions were also made by United Nations Children's Emergency Fund (UNICEF) and World Health Organization (WHO). Total costs incurred as a result of the outbreak were nearly $4,000,000; approximately $10,000 per case. Direct medical costs (~$141,000) were incurred in the treatment of those individuals infected, as well as lost productivity of the infected and informal caregivers (~$250,000) and costs to contain the outbreak (~$3.5 million). We assessed the economic burden of the 2014 measles outbreak to FSM, as well as the economic responsibilities of the US. Although the US paid the majority of total costs of the outbreak (~67%), examining each country's costs relative to their respective economy illustrates a far greater burden to FSM. We demonstrate that while FSM was heavily assisted by the US in responding to the 2014 Measles Outbreak, the outbreak significantly impacted their economy. FSM's economic burden from the outbreak is approximately equivalent to their entire 2016 Fiscal Year budget dedicated to education. PMID- 28886946 TI - Postmarketing safety surveillance of trivalent recombinant influenza vaccine: Reports to the Vaccine Adverse Event Reporting System. AB - On January 16, 2013, the Food and Drug Administration approved recombinant hemagglutinin influenza vaccine (RIV3) (Spodoptera frugiperda cell line; Flublok), which is the first completely egg-free flu vaccine licensed in the United States. To improve our understanding of the safety profile of this vaccine, we reviewed and summarized reports to the Vaccine Adverse Event Reporting System (VAERS) following RIV3. Through June 30, 2016, VAERS received 88 reports. Allergic reactions, including anaphylaxis, were the most common type of adverse event. Based on medical review, 10 cases met the Brighton Collaboration case definition of anaphylaxis, 21 reports described allergic reactions other than anaphylaxis, and 11 reports described signs and symptoms that suggested hypersensitivity. Other adverse events included injection site reactions, fatigue, myalgia, headache, and fever. The occurrence of anaphylaxis and other allergic reactions in some individuals may reflect an underlying predisposition to atopy that may manifest itself after an exposure to any drug or vaccine, and it does not necessarily suggest a causal relationship with the unique constituents that are specific to the vaccine product administered. Further research may elucidate the mechanism of allergic reactions following influenza vaccination: it is possible that egg proteins and influenza hemagglutinin play little or no role. Vaccination remains the single best defense against influenza and its complications. The information summarized here may enable policy makers, health officials, clinicians, and patients to make a more informed decision regarding vaccination strategies. PMID- 28886947 TI - Using campaigns to improve perceptions of the value of adult vaccination in the United States: Health communication considerations and insights. AB - Vaccines have much relevance and promise for improving adult health in the United States, but to date, overall use and uptake remain far below desired levels. Many adults have not received recommended vaccinations and many healthcare providers do not strongly and actively encourage their use with patients. This has led some public health and medical experts to conclude that adult vaccines are severely undervalued by the U.S. public and healthcare providers and to call for campaigns and communication-based efforts to foster increased appreciation, and in turn, higher adult immunization rates. A narrative integrative review that draws upon the vaccine valuation and health communication literatures is used to develop a framework to guide campaign and communication-based efforts to improve public, provider, and policymakers' assessment of the value of adult vaccination. The review does this by: (1) distinguishing social psychological value from economic value; (2) identifying the implications of social psychological value considerations for adult vaccination-related communication campaigns; and (3) using five core health communication considerations to illustrate how social psychological notions of value can be integrated into campaigns or communication that are intended to improve adult vaccination value perceptions and assessments, and in turn, motivate greater support for and uptake of recommended adult vaccines. PMID- 28886948 TI - Preface. PMID- 28886949 TI - Low antigen dose formulated in CAF09 adjuvant Favours a cytotoxic T-cell response following intraperitoneal immunization in Gottingen minipigs. AB - The relationship between the antigen dose and the quality of an immune response generated upon immunization is poorly understood. However, findings show that the immune system is indeed influenced by the antigen dose; hence underlining the importance of correctly determining which dose to use in order to generate a certain type of immune response. To investigate this area further, we used Gottingen minipigs asan animal model especially due to the similar body size and high degree of immunome similarity between humans and pigs. In this study, we show that both a humoral and a cell-mediated immune (CMI) response can be generated following intraperitoneal immunization with tetanus toxoid (TT) formulated in the CAF09 liposomal adjuvant. Importantly, a low antigen dose induced more TT-specific polyfunctional T cells, whereas antigen-specific IgG production was observed upon high-dose immunization. Independent of antigen dose, intraperitoneal administration of antigen increased the amount of TT-specific cytotoxic CD8beta+ T cells within the cytokine-producing T-cell pool when compared to the non-cytokine producing T-cell compartment. Taken together, these results demonstrate that a full protein formulated in the CAF09 adjuvant and administered to pigs via the intraperitoneal route effectively generates a cytotoxic T-cell response. Moreover, we confirm the inverse relationship between the antigen dose and the induction of polyfunctional T cells in a large animal model. These finding can have implications for the design of upcoming vaccine trials aiming at establishing a cytotoxic T-cell response. PMID- 28886950 TI - Influence of thermo-mechanical cycling on porcelain bonding to cobalt-chromium and titanium dental alloys fabricated by casting, milling, and selective laser melting. AB - PURPOSE: The aim has been to determine the effect of thermo-mechanical cycling on shear-bond-strength (SBS) of dental porcelain to Co-Cr and Ti-based alloys fabricated by casting, computer-numerical-controlled milling, and selective-laser melting (SLM). METHODS: Seven groups (n=22/group) of metal cylinders were fabricated by casting (Co-Cr and commercially pure-cpTi), milling (Co-Cr, cpTi, Ti-6Al-4V) or by SLM (Co-Cr and Ti-6Al-4V) and abraded with airborne-particles. The average surface roughness (Ra) was determined for each group. Dental porcelain was applied and each metal-ceramic combination was divided into two subgroups - stored in deionized water (24-h, 37 degrees C), or subjected to both thermal (6000-cycles, between 5 and 60 degrees C) and mechanical cycling (105 cycles, 60N-load). SBS test-values and failure modes were recorded. Metal-ceramic interfaces were analyzed with a focused-ion-beam/scanning-electron-microscope (FIB/SEM) and energy-dispersive-spectroscopy (EDS). The elastic properties of the respective metal and ceramic materials were evaluated by instrumented-indentation testing. The oxide thickness on intact Ti-based substrates was measured with Auger-electron-spectroscopy (AES). Data were analyzed using ANOVA, Tukey's HSD and t-tests (alpha=0.05). RESULTS: The SBS-means differed according to the metal ceramic combination (p<0.0005) and to the fatigue conditions (p<0.0005). The failure modes and interface analyses suggest better porcelain adherence to Co-Cr than to Ti-based alloys. Values of Ra were dependent on the metal substrate (p<0.0005). Ti-based substrates were not covered with thick oxide layers following digital fabrication. CONCLUSIONS: Ti-based alloys are more susceptible than Co-Cr to reduction of porcelain bond strength following thermo-mechanical cycling. The porcelain bond strength to Ti-based alloys is affected by the applied metal processing technology. PMID- 28886951 TI - Strength comparison of anterior teeth restored with ceramic endocrowns vs custom made post and cores. AB - PURPOSE: The aim of the study was to compare strength of the anterior teeth restored with ceramic endocrowns versus custom-made post and core. METHODS: The investigation used the finite element analysis. Three 3-D models of maxillary central incisor were created: model A-tooth restored with metal post and core with ceramic crown; model B-tooth with leucite ceramic endocrown; model C-tooth with lithium disilicate ceramic endocrown. Each model was subjected to a 100N force applied at a distance of 5mm from the incisal edge, at the angle of 130 degrees to the long axis of the tooth. The modified von Mises failure criterion was used to evaluate the strength of the dentin, ceramic and resin cement, and Huber-Mises-Hencky failure criterion for cast alloy. Contact stresses in the cement-tissue adhesive interface were calculated. RESULTS: The lowest stresses occurred in the anterior tooth restored with custom post and core (model A). The mvM stress of 47.5MPa concentrated in leucite ceramic endocrown (model B) and its value was close to the tensile strength of this material. The maximal mvM stresses in the lithium disilicate ceramic endocrown (model C) were 4 times lower than tensile strength of this material. In all cases contact stresses in the adhesive interface under restorations did not exceed the resin cement bond strength to dentin. CONCLUSIONS: Leucite ceramic endocrowns in incisors may fracture during physiological loading. Endocrowns made of lithium disilicate ceramic are resistant to failure. Posts and prosthetic crowns are still recommended for anterior teeth restorations. PMID- 28886952 TI - Clinical manifestations of candidemia caused by uncommon Candida species and antifungal susceptibility of the isolates in a regional hospital in Taiwan, 2007 2014. AB - OBJECTIVE: This retrospective study investigated clinical manifestations of candidemia caused by uncommon Candida species and antifungal susceptibility of the isolates in a regional hospital in Taiwan. METHODS: The uncommon Candida species was initially defined as Candida species other than C. albicans, C. tropicalis, C. glabrata complex, C. parapsilosis complex and C. krusei. All uncommon Candida isolates were identified and confirmed by molecular methods. In vitro susceptibility testing of the uncommon Candida species to nine antifungal agents was conducted using the broth microdilution method with the Sensititre YeastOne (SYO) system (Trek Diagnostic Systems, Ltd., East Grimstead, UK). RESULTS: Twenty-one patients, comprising 11 males and 10 females with a median age of 69 years, were recruited. Cancer (n = 11) was the most common underlying disease, 19 (90.5%) cases had prior antibiotic exposure, and only two patients had prior antifungal use. The overall in-hospital mortality rate was 38.1% (n = 8). C. guilliermondii (n = 11) was the most common pathogen, followed by C. curvata (n = 3). C. guilliermondii isolates exhibited relatively high rates of azole minimum inhibitory concentrations (MICs) above epidemiological cut-off values (ECVs), whereas C. pelliculosa and C. lusitaniae isolates all remained susceptible to azoles. All three C. curvata isolates had high caspofungin (>8 mg/L) and fluconazole MICs (8 mg/L) and could be defined as multidrug-resistant. CONCLUSIONS: Uncommon Candida species frequently exhibit high rates of non susceptibility to antifungals. Identification of all Candida isolates at the species level from blood samples is of value for treatment. PMID- 28886953 TI - Activating or Inhibiting Nrf2? AB - Activating nuclear factor erythroid 2 (NF-E2)-related factor (Nrf2) is a widely recognized strategy for combating oxidative-stress-induced diseases. However, Nrf2 activation does not always bring advantageous effects. Therefore, before performing Nrf2-targeted therapy, we must pinpoint whether Nrf2 should be activated or inhibited. PMID- 28886954 TI - A systematic checklist approach to immunosuppression risk management: An audit of practice at two clinical neuroimmunology centers. AB - There is no consensus approach to safety screening for immune intervention in clinical neuroimmunology. An immunosuppression risk evaluation checklist was used as an audit tool to assess real-world immunosuppression risk management and formulate recommendations for quality improvements in patient safety. Ninety-nine patients from two centres with 27 non-MS diagnoses were included. An average of 1.9 comorbidities with the potential to adversely impact morbidity and mortality associated with immunosuppression were identified. Diabetes and smoking were the most common, however a range of rarer but potentially life-threatening co-morbid disorders in the context of immunosuppression were identified. Inadequate documentation of risk mitigation tasks was common at 40.1% of total tasks across both cohorts. A routine, systematic immunosuppression checklist approach should be considered to improve immunosuppression risk management in clinical neuroimmunology practice. PMID- 28886955 TI - Successful combined targeting of B- and plasma cells in treatment refractory anti NMDAR encephalitis. AB - We describe an extremely severe case of therapy refractory NMDA receptor encephalitis (NMDAe) in a 26-year-old woman. After rituximab, bilateral oophorectomy, repeated cycles of high dose methylprednisolone and plasma exchange, she received repeated cyclophosphamide, tocilizumab (interleukin-6 inhibitor) and finally bortezomib (plasma cell depleting drug) leading to remission after 204days in intensive care. Two years after disease onset her cognitive functions are still affected, but slowly improving and the cerebral atrophy has been partly reversed. The cerebrospinal fluid biomarker profile suggests an early synaptic/dendritic process, with subsequent neuroaxonal degeneration motivating aggressive treatment early on. PMID- 28886956 TI - Sepsis biomarkers reprofiling to predict stroke-associated infections. AB - We aimed to evaluate the usefulness of sepsis biomarkers to predict stroke associated infections. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), mid-regional pro-adrenomedullin (MR-proADM), presepsin (sCD14), and soluble urokinase-type plasminogen activator receptor (suPAR), were explored in 125 blood samples collected at different time-points. At baseline, MR-proADM was an independent predictor of infection [>0.94pg/mL, OR=3.63 (1.16-11.33), p=0.026], as well as suPAR at 24h [>2185.8pg/mL, OR=5.81 (1.05-32.26), p=0.044]. Both MR-proADM and suPAR were raised in patients with infections throughout the first week after stroke. These results are especially relevant for MR-proADM given its early elevation, which would allow early preventive interventions. PMID- 28886957 TI - Differential vulnerability of hippocampal subfields and anteroposterior hippocampal subregions in healthy cognitive aging. AB - In the present study, we investigated whether hippocampal subfields (cornu ammonis 1-3, dentate gyrus, and subiculum) and anteroposterior hippocampal subregions (head, body, and tail) follow the same trajectory with age using structural magnetic resonance imaging. We recruited 129 healthy volunteers, aged 18-85 years. Structural magnetic resonance imaging scans were acquired on a 4.7T system. Hippocampal subfields and subregions were manually segmented using reliable volumetric protocols. We found that all effects of age on the hippocampal volumes were nonlinear and were mainly found in the hippocampal body, while the hippocampal head and the tail volumes were not associated with age. The total subiculum and the total dentate gyrus volumes were associated with age, while the total cornu ammonis 1-3 was not. Significant associations with age for the cornu ammonis 1-3 and the dentate gyrus volumes were present only in the hippocampal body, while the subiculum volumes were associated with age throughout the entire hippocampus. Subiculum volumes were more negatively related to age in men than in women. PMID- 28886958 TI - Use of psychoactive substances in prison: Results of a study in the Lyon-Corbas prison, France. AB - BACKGROUND AND AIMS: In prison, in 2012, according to various sources, from 4 to 56% of the European inmate population used psychoactive substances (PAS). The aim of our study was to describe PAS consumption during incarceration in the prison of Lyon-Corbas, France. METHOD: A transversal descriptive study was conducted between September 23rd and September 27th 2013 among all inmates of this prison. We used an anonymous self-administered questionnaire, distributed at lunchtime and collected, the same day, at dinnertime, by the mental health service personnel. RESULTS: Among 785 inmates present at the time of the study in the prison of Lyon-Corbas, 710 were included and the response rate was 64.4% (95% CI [60.8-67.8]). Among 457 responding inmates, 16.4% (95% CI [13.2-20.0]) reported no PAS consumption. Among 382 consumers, 74.4% (95% CI [69.8-78.5]) used tobacco, 36.8% (95% CI [32.2-41.8]) cannabis, 30.4% (95% CI [25.9-35.1]) alcohol, 7.7% (95% CI [5.2-10.6]) heroin and 10.3% (95% CI [7.5-13.6]) cocaine. Furthermore, 15% of consumers had started PAS consumption during their incarceration. Among consumers of at least one PAS other than tobacco, cannabis and alcohol, the way of consumption was sniff for 60.0% (95% CI [48.5-70.2]) and injection for 31.0% (95% CI [21.6-42.1]). Use of several PAS at the same time and sharing sniffing and/or injection paraphernalia were other risky behaviors observed; 12% (95% CI [5.8-20.4]) of drug injectors declared using chlorine to sterilize their injection paraphernalia. CONCLUSION: Our study provides worrying data about PAS consumption in prison. The measures of prohibition do not prevent this consumption. There is even an initiation of consumption of PAS for 15% of the first-time incarcerated inmates. This finding should encourage public authorities to facilitate access of inmates to the care structures in prisons, to improve drug use prevention and care programs and to develop activities (sports, cultural, educational and vocational). PMID- 28886959 TI - [The psychiatric hospital discharge database (RIM-P): An essential tool for the surveillance of hospitalization after a suicide attempt]. AB - BACKGROUND: Epidemiological surveillance of suicide attempts is essential for monitoring indicator trends in the evaluation of prevention actions. As part of this surveillance, analysis of data from hospitalization for suicide attempts is particularly useful. METHODS: For the first time, data from two national hospital discharge databases, the "Programme de medicalisation des systemes d'information en medecine, chirurgie, obstetrique" (PMSI-MCO) and the " Recueil d'information medicalise en psychiatrie" (RIM-P) have been analyzed jointly. All patients aged 10 or more hospitalized in 2012 in medicine, surgery or psychiatry departments in metropolitan France have were included. RESULTS: Through 2012, 89,072 patients (62% females and 38% males) totalized 134,051 hospital stays following a suicide attempt, with 93.4% (n=83,196) in medicine or surgery wards and 32.1% (n=28,594) in psychiatry wards (solely or transferred after a stay in medicine or surgery). However, among the patients transferred to psychiatry after hospitalization in medicine or surgery for suicide attempt, 82.4% had no suicide attempt code noted at their discharge from psychiatry. One or more psychiatric diagnoses were observed in 75% of the patients hospitalized for suicide attempt. The most common diagnoses in men and in women were mood disorders (46%), particularly depression (42%; 44% in women and 38% in men). Mental disorders related to alcohol use were noted in more than a quarter of the patients, more frequently in men (37%) than in women (21%). Some diagnoses were rarely noted in medicine or surgery, such as anxiety disorders and disorders of adult personality and behavior. CONCLUSION: Improvement of the epidemiological surveillance of suicide attempts requires a systematic coding of hospitalizations in psychiatry as well as in medicine and surgery. Data from hospitalization in psychiatry yield a more precise identification of psychiatric co-morbidities associated with suicide attempts. The frequent presence of mental problems associated with suicide attempts should encourage clinicians to search for these symptoms systematically as soon as possible after admission of the patient. PMID- 28886961 TI - A feasibility study of using advanced external beam techniques to create a vaginal cuff brachytherapy-like endometrial boost plan. AB - The purpose of this study was to explore the feasibility of using advanced external beam radiation therapy (EBRT) planning techniques for creating plans that could be used as a possible alternative for high-dose rate (HDR) vaginal cuff brachytherapy (VCBT) boost in treating endometrial cancer. The computed tomography (CT) images of a total of 4 female patients who had endometrial cancer treated with HDR-VCBT were selected for this study. A typical HDR-VCBT target volume, 0.5-cm-thick shell volume around the cylinder applicator in the prescribed treatment length was contoured and used as the planning target volume (PTV) in both the HDR VCBT and the EBRT VCBT-like plans. HDR-VCBT plans were made based on the clinical protocol, 6 Gy given at the cylinder surface. The EBRT plans were generated using either a 7-field intensity-modulated radiation therapy (IMRT) or a 2-arc volumetric-modulated arc therapy (VMAT) techniques for different cylinder sizes and treatment lengths, with the prescription dose of 5 Gy. Organs at risk (OARs) such as bladder, femoral heads, rectum, and sigmoid were also contoured and used in dosimetric evaluations. Dose-to-target metrics included mean dose, the dose covering 90% of target volume (D90) and the percentage of target volume covered by 90% of prescription dose (V90 or V13.5 Gy). Dose to OAR metrics included the maximum dose received by 0.1 cc (D0.1cc), 1.0 cc (D1.0cc), and 2.0 cc (D2.0cc) of OARs. These metrics were calculated and compared between all techniques. After the EBRT plans were normalized to achieve a comparable mean dose to target as HDR-VCBT, the EBRT plans were found to have superior target coverage and increased dose homogeneity compared with HDR-VCBT. V90s of EBRT plans were 95%, compared with 50% to 58% of the HDR plans. However, D0.1cc, D1.0cc, and D2.0cc of OARs were 2% to 38% lower in HDR-VCBT than in EBRT. Although HDR-VCBT plans demonstrated superior normal tissue sparing, both EBRT and HDR-VCBT plans produce plans that met clinical dose constraints on normal tissues. Advanced EBRT techniques such as IMRT and VMAT are capable of making plans, which closely resemble HDR-VCBT. Although the doses of OARs are greater in EBRT than in HDR-VCBT, the prescription dose coverage and dose homogeneity of the EBRT plans are greater than that of HDR-VCBT plans at the similar mean dose, and the OAR dose is still acceptable with EBRT plans. The detailed dosimetric approaches are provided in the study. PMID- 28886960 TI - [Indoor air quality and parents of asthmatic children practices]. AB - BACKGROUND: Indoor air pollution can worsen asthma in children. Better knowledge of factors determining parents' reception of recommendations to limit pollution of indoor air in the homes of asthmatic children would be helpful to improve implementation. METHOD: A descriptive study evaluating practices known to have an impact on the quality of air in homes was conducted among parents of asthmatic children aged 3 to 16 years. From May to September 2013, parents answered anonymous self-administered questionnaires in waiting rooms of generalist practitioners, in the Nantes University pneumology pediatric outpatient clinic, and as part of therapeutic education sessions conducted by the Asthma-44 Network. RESULTS: There were 190 exploitable questionnaires: 88.2% of parents reported never smoking in the home; 48.4% used home fragrance in the living room at least once a week; 77.8% opened their children's bedroom windows more than 10minutes at least once a day; 32.6% used several cleaning products or bleach once or twice a week. Good practices concerning smoking in housing were applied less in homes where the child was monitored only by a general practitioner (OR=0.08; CI[0.02 0.34]). Good practices on the use of perfume were statistically linked to having an intermediate level occupation (OR=2.31; CI[1.01-5.32]) and being followed by the university hospital, by the asthma network or by a general practitioner if the child had already consulted a pneumo-pediatrician or an allergist (OR=0.24; CI[0.07-0.81]). Good ventilation practices forchildren's bedrooms were statistically linked to residing in a rural rather than urban setting (OR=4.72; CI[1.0-22.16]). CONCLUSION: Practices observed in parents of asthmatic children differ little from those of the general population. Recommendations on how to limit sources of chemical pollutants, with the exception of smoking, are still poorly applied. Specialist consultations and specific training for general practitioners should improve the penetration of public health messages to this vulnerable population. PMID- 28886962 TI - Endoscopy in inflammatory bowel disease: advances in disease management. PMID- 28886963 TI - Current High-Intensity Drinking Among Eighth and Tenth Grade Students in the U.S. AB - INTRODUCTION: This study assessed the prevalence of current high-intensity drinking (i.e., having ten or more drinks in a row in the past 2 weeks) among national samples of U.S. eighth and tenth grade students (at modal ages 14 and 16 years, respectively). METHODS: Data on high-intensity drinking were provided by 10,210 students participating in the nationally representative Monitoring the Future study in 2016, and analyzed in 2016-2017. Prevalence levels and interactions between grade and key covariates were estimated using procedures that adjusted for the Monitoring the Future study's complex sampling design. RESULTS: Approximately 2% of adolescents reported current high-intensity drinking, with significant differences by grade (1.2% of eighth graders; 3.1% of tenth graders) and gender (1.7% female; 2.3% male). High-intensity drinking was significantly higher among eighth and tenth grade students who reported any cigarette or marijuana use than among students who reported never using either substance. CONCLUSIONS: A meaningful percentage of young adolescents in the U.S. engage in high-intensity drinking. PMID- 28886965 TI - Circadian and economic factors affect food acquisition in rats restricted to discrete feeding opportunities. AB - The purpose of this study is to examine aspects of operant behavior-modeled economic choice for food in rats in closed economy protocols in which food is available for only a few discrete times per daily 23-h session, designed to emulate clustering of human food intake into meals. In the first experiment, rats performed lever press responses for food pellets in an ascending series of ratios or fixed unit prices (FUP) when food was available for four 40-min food opportunities (FO) per day. Daily intake at low FUP was comparable to ad libitum intakes. Intake declined as FUP increased and was not distributed equally among the four FOs. In particular, the last FO of a session (occurring at about lights on in a 12:12cycle) was the smallest, even when total intake was low due to the response requirement at high FUP. Within FOs, satiation was evident at low FUPs by a decrease in rate of intake across a 40min FO; at high FUPs responding was evenly distributed. In the second experiment, rats had a choice of responding on two levers for either intermittent inexpensive (II; low FUP according to a four FO schedule) or costly continuous (CC; 20-fold higher FUP but available throughout 23-h sessions) food. Most (73%) of the rats consistently chose almost all of their food from the II source. Further, as the timing of the four II FOs were changed relative to the light: dark Zeitgeber, the time of the smallest meal changed such that the smallest meal (s) were during the light period regardless of ordinal position within a session. These data are discussed in terms of economic and Zeitgeber effects on consumption when food is available intermittently, and are contrasted with results from comparable protocols in mice. PMID- 28886964 TI - Prevalence and Trends in Lifetime Obesity in the U.S., 1988-2014. AB - INTRODUCTION: Estimates of obesity prevalence based on current BMI are an important but incomplete indicator of the total effects of obesity on a population. METHODS: In this study, data on current BMI and maximum BMI were used to estimate prevalence and trends in lifetime obesity status, defined using the categories never (maximum BMI <=30 kg/m2), former (maximum BMI >=30 kg/m2 and current BMI <=30 kg/m2), and current obesity (current BMI >=30 kg/m2). Prevalence was estimated for the period 2013-2014 and trends for the period 1988-2014 using data from the National Health and Nutrition Examination Survey. Predictors of lifetime weight status and the association between lifetime weight categories and prevalent disease status were also investigated using multivariable regression. RESULTS: A total of 50.8% of American males and 51.6% of American females were ever obese in 2013-2014. The prevalence of lifetime obesity exceeded the prevalence of current obesity by amounts that were greater for males and for older persons. The gap between the two prevalence values has risen over time. By 2013-2014, a total of 22.0% of individuals who were not currently obese had formerly been obese. For each of eight diseases considered, prevalence was higher among the formerly obese than among the never obese. CONCLUSIONS: A larger fraction of the population is affected by obesity and its health consequences than is suggested in prior studies based on current BMI alone. Weight history should be incorporated into routine health surveillance of the obesity epidemic for a full accounting of the effects of obesity on the U.S. POPULATION: PMID- 28886966 TI - Monitoring training load and fatigue in soccer players with physiological markers. AB - The quantification and monitoring of training load (TL) has been the topic of many scientific works in the last fifteen years. TL monitoring helps coaches to individually prescribe, follow-up, analyse, adjust and programme training sessions. In particular, the aim of the present review was to provide a critical literature report regarding different physiological markers of TL monitoring, particularly in soccer, as the load is specific to individual sports. Therefore, the interests and limitations of heart rate (HR), HR variability (HRV) and biochemical variables (blood, urinary and hormonal variations) were analysed, with a special focus on daily measures (before, during and after training) and monitoring throughout a whole season. It appears that the most relevant markers were the resting HR before training, HR reserve during training, HRV during rest days, blood lactate, and blood and salivary immunological status in follow-ups throughout the season. Urinary markers indicative of the players' hydration status also deserve attention. However, these objective markers should be considered with a subjective marker of TL such as the rating of perceived exertion to give a more precise quantification of TL and its perception. Future research could be directed towards urinary marker analysis and the analysis of specific markers of TL, which could be related to injury occurrence and to performance during competition. PMID- 28886968 TI - [Neuromyelitis optica with anti-MOG antibodies: A case report]. PMID- 28886969 TI - [A case of Leber hereditary optic neuropathy in a black African patient]. PMID- 28886967 TI - Class I HDACs control a JIP1-dependent pathway for kinesin-microtubule binding in cardiomyocytes. AB - Class I histone deacetylase (HDAC) inhibitors block hypertrophy and fibrosis of the heart by suppressing pathological signaling and gene expression programs in cardiac myocytes and fibroblasts. The impact of HDAC inhibition in unstressed cardiac cells remains poorly understood. Here, we demonstrate that treatment of cultured cardiomyocytes with small molecule HDAC inhibitors leads to dramatic induction of c-Jun amino-terminal kinase (JNK)-interacting protein-1 (JIP1) mRNA and protein expression. In contrast to prior findings, elevated levels of endogenous JIP1 in cardiomyocytes failed to significantly alter JNK signaling or cardiomyocyte hypertrophy. Instead, HDAC inhibitor-mediated induction of JIP1 was required to stimulate expression of the kinesin heavy chain family member, KIF5A. We provide evidence for an HDAC-dependent regulatory circuit that promotes formation of JIP1:KIF5A:microtubule complexes that regulate intracellular transport of cargo such as autophagosomes. These findings define a novel role for class I HDACs in the control of the JIP1/kinesin axis in cardiomyocytes, and suggest that HDAC inhibitors could be used to alter microtubule transport in the heart. PMID- 28886970 TI - [Proptosis as presenting sign of Fahr's syndrome]. PMID- 28886971 TI - TRAF6: A player in CVB3-induced myocarditis? AB - Coxsackievirus B3 (CVB3) is an important inducer of myocarditis, which, in susceptible individuals, can chronify and eventually lead to the development of dilated cardiomyopathy and heart failure. The respective mechanisms are not completely understood. Here, we analyzed expression of the TRAF6 gene, encoding TNF receptor-associated factor 6 (TRAF6), a signal transduction scaffold protein that acts downstream of cytokine receptors, in heart tissue of susceptible and non-susceptible mouse strains. We found that after infection, TRAF6 expression was upregulated in both non-susceptible C57BL/6 wildtype and susceptible A.BY/SnJ and C57BL/6-TLR3 (-/-) mice, however, to different degrees. In infected HeLa cells, we also found moderately elevated TRAF6 levels after infection, in addition, activity of the transcription factor nuclear factor kappa B (NFkappaB), which can be activated downstream of TRAF6, was strongly enhanced in infected cells. To functionally analyze the role of TRAF6 with regard to infection progression, TRAF6 expression was knocked down in cultured HeLa cells using specific siRNAs. We found that reduction of TRAF6 expression had no effect on NFkappaB activation in response to infection. Taken together, our data suggest that CVB3 infection enhances TRAF6 levels, however, this induction might not be necessary for infection-induced NFkappaB activation. PMID- 28886972 TI - Benzene metabolite hydroquinone induces apoptosis of bone marrow mononuclear cells through inhibition of beta-catenin signaling. AB - The Akt/glycogen synthase kinase-3beta (GSK-3beta)/beta-catenin signaling pathway has been shown to play an important role in hematopoiesis, and hematopoietic cells are sensitive targets for benzene-induced hematotoxicity. We therefore hypothesized that dysregulation of the Akt/GSK-3beta/beta-catenin signaling was associated with benzene-induced hematotoxicity. Here, we showed that hydroquinone (HQ), a major metabolite of benzene in humans, significantly inhibited cell viability and colony formation while inducing apoptosis of human bone marrow mononuclear cells in vitro. Interestingly, we found that HQ inhibited the Akt affected beta-catenin signaling by activation of GSK-3beta, resulting in downregulation of beta-catenin and its targets Cyclin D1 and Survivin. HQ blocked nuclear translocation of beta-catenin and lymphoid enhancer-binding factor 1 (LEF 1), and importantly, HQ also reduced the interaction of beta-catenin and LEF-1 in the nucleus. As expected, blockage of GSK-3beta activity with a GSK-3beta inhibitor lithium chloride (LiCl) or activation of Akt signaling with an Akt agonist insulin-like growth factor-1 (IGF-1) could inhibit HQ-induced activation of GSK-3beta as well as hematotoxicity. Taken together, our results suggest that HQ-induced hematotoxicity in bone marrow mononuclear cells is associated with dysregulation of Akt/GSK-3beta/beta-catenin signaling due to the dissociation of beta-catenin/LEF-1 complex, and LiCl and IGF-1 may be two potential agents to ameliorate HQ-induced hematotoxicity. PMID- 28886973 TI - Vocal Tract Morphology in Inhaling Singing: Characteristics During Vowel Production-A Case Study in a Professional Singer. AB - BACKGROUND: A professional singer produced various vowels on a comfortable loudness and pitch in an inspiratory and expiratory phonation manner. The present study investigates the morphological differences and tries to find a link with the acoustical characteristics. OBJECTIVES/HYPOTHESIS: We hypothesize that features, constantly present over all vowels, characterize inhaling phonation and that the formant frequencies reflect the morphological findings. STUDY DESIGN: A prospective case study was carried out. METHODS: A female singer uttered the vowels /a/, /e/, /i/, /o/, and /u/ in a supine position under magnetic resonance imaging, on a comfortable loudness and pitch, in both inhaling and exhaling manner. The exact same parameters as in previous reports were measured (1-3). Acoustical analysis was performed with Praat. RESULTS: Wilcoxon directional testing demonstrates a statistically significant difference in (1) the distance between the lips, (2) the antero-posterior tongue diameter, (3) the distance between the lips and the tip of the tongue, (4) the distance between the epiglottis and the posterior pharyngeal wall, (5) the narrowing of the subglottic space, and (6) the oropharyngeal and the hypopharyngeal areas. Acoustical analysis reveals slightly more noise and irregularity during reverse phonation. The central frequency of F0 and F1 is identical, whereas that of F2 and F3 increases, and that of F4 varies. CONCLUSIONS: A smaller mouth opening, a narrowing of the subglottic space, a larger supralaryngeal inlet, and a smaller antero-posterior tongue diameter can be considered as morphological characteristics for reverse phonation. Acoustically, reverse phonation discretely contains more noise and perturbation. The formant frequency distribution concurs with a mouth narrowing and pharyngeal widening during inhaling. PMID- 28886974 TI - Informational needs during active surveillance for prostate cancer: A qualitative study. AB - OBJECTIVE: To understand the informational needs during active surveillance (AS) for prostate cancer from the perspectives of patients and providers. METHODS: We conducted seven focus groups with 37 AS patients in two urban clinical settings, and 24 semi-structured interviews with a national sample of providers. Transcripts were analyzed using applied thematic analysis, and themes were organized using descriptive matrix analyses. RESULTS: We identified six themes related to informational needs during AS: 1) more information on prostate cancer (biopsy features, prognosis), 2) more information on active surveillance (difference from watchful waiting, testing protocol), 3) more information on alternative management options (complementary medicine, lifestyle modification), 4) greater variety of resources (multiple formats, targeting different audiences), 5) more social support and interaction, and 6) verified integrity of information (trusted, multidisciplinary and secure). CONCLUSIONS: Patients and providers described numerous drawbacks to existing prostate cancer resources and a variety of unmet needs including information on prognosis, AS testing protocols, and lifestyle modification. They also expressed a need for different types of resources, including interaction and unbiased information. PRACTICAL IMPLICATIONS: These results are useful to inform the design of future resources for men undergoing AS. PMID- 28886975 TI - A review on technological options of waste to energy for effective management of municipal solid waste. AB - Approximately one-fourth population across the world rely on traditional fuels (kerosene, natural gas, biomass residue, firewood, coal, animal dung, etc.) for domestic use despite significant socioeconomic and technological development. Fossil fuel reserves are being exploited at a very fast rate to meet the increasing energy demands, so there is a need to find alternative sources of energy before all the fossil fuel reserves are depleted. Waste to energy (WTE) can be considered as a potential alternative source of energy, which is economically viable and environmentally sustainable. The present study reviewed the current global scenario of WTE technological options (incineration, pyrolysis, gasification, anaerobic digestion, and landfilling with gas recovery) for effective energy recovery and the challenges faced by developed and developing countries. This review will provide a framework for evaluating WTE technological options based on case studies of developed and developing countries. Unsanitary landfilling is the most commonly practiced waste disposal option in the developing countries. However, developed countries have realised the potential of WTE technologies for effective municipal solid waste management (MSWM). This review will help the policy makers and the implementing authorities involved in MSWM to understand the current status, challenges and barriers for effective management of municipal solid waste. This review concluded WTE as a potential renewable source of energy, which will partly meet the energy demand and ensure effective MSWM. PMID- 28886976 TI - The degradation processes of refractory substances in nanofiltration concentrated leachate using micro-ozonation. AB - Concentrated leachate (CL) is the byproduct of leachate treated by the membrane separation unit after bio-treatment processes, and contains many humic-like substances. Ozonation processes were applied and optimized for the further removal of those refractory matters in this work. Micro-bubble ozonation (MB-O3) possessed the best performance, and 76.0% and 69.9% of COD and TOC were found to be removed under the optimum conditions with ozone dosage of 2.4g/L, initial pH of 9 and reaction time of 120min. The reaction rate k in MB-O3 was 0.0104min-1, three times higher than that in normal O3. The percentages of humic acid and fulvic acid in CL decreased from 24.1% to 14.3% and 49.6% to 25.0%, while that of HyI substances increased from 26.3% to 60.7%, which was also found in the fraction of <2000Da, with the occupied percentage increased from 0 to 63.0%. The humic acid-like substances might be transformed to matters with carbonyl and carboxyl group, since a continuous blue-shift was observed from Em/Ex 475/390 to 410/325nm. MB-O3 could be a promising method for the advanced treatment of CL. PMID- 28886977 TI - An optimization model for collection, haul, transfer, treatment and disposal of infectious medical waste: Application to a Greek region. AB - The objective of this work was to develop an optimization model to minimize the cost of a collection, haul, transfer, treatment and disposal system for infectious medical waste (IMW). The model calculates the optimum locations of the treatment facilities and transfer stations, their design capacities (t/d), the number and capacities of all waste collection, transport and transfer vehicles and their optimum transport path and the minimum IMW management system cost. Waste production nodes (hospitals, healthcare centers, peripheral health offices, private clinics and physicians in private practice) and their IMW production rates were specified and used as model inputs. The candidate locations of the treatment facilities, transfer stations and sanitary landfills were designated, using a GIS-based methodology. Specifically, Mapinfo software with exclusion criteria for non-appropriate areas was used for siting candidate locations for the construction of the treatment plant and calculating the distance and travel time of all possible vehicle routes. The objective function was a non-linear equation, which minimized the total collection, transport, treatment and disposal cost. Total cost comprised capital and operation costs for: (1) treatment plant, (2) waste transfer stations, (3) waste transport and transfer vehicles and (4) waste collection bins and hospital boxes. Binary variables were used to decide whether a treatment plant and/or a transfer station should be constructed and whether a collection route between two or more nodes should be followed. Microsoft excel software was used as installation platform of the optimization model. For the execution of the optimization routine, two completely different software were used and the results were compared, thus, resulting in higher reliability and validity of the results. The first software was Evolver, which is based on the use of genetic algorithms. The second one was Crystal Ball, which is based on Monte Carlo simulation. The model was applied to the Region of East Macedonia - Thrace in Greece. The optimum solution resulted in one treatment plant located in the sanitary landfill area of Chrysoupolis, required no transfer stations and had a total management cost of 38,800 ?/month or 809 ?/t. If a treatment plant is sited in the most eastern part of the Region, i.e., the industrial area of Alexandroupolis, the optimum solution would result in a transfer station of 23 m3, located near Kavala General Hospital, and a total cost of 39,800 ?/month or 831 ?/t. A sensitivity analysis was conducted and two alternative scenarios were optimized. In the first scenario, a 15% rise in fuel cost and in the second scenario a 25% rise in IMW production were considered. At the end, a cost calculation in ?/t/km for every type of vehicle used for haul and transfer was conducted. Also, the cost of the whole system was itemized and calculated in ?/t/km and ?/t. The results showed that the higher percentage of the total cost was due to the construction of the treatment plant. PMID- 28886978 TI - Nursing Home Residents with Dementia and Very Frequent Agitation: A Particular Group. AB - OBJECTIVE: Although many nursing home residents with dementia show agitation, hardly any literature is published about very frequent agitation. The WAALBED-III study focuses on the 2-week prevalence and correlates of very frequent agitation in these residents. DESIGN: Cross-sectional study using combined data of four studies. SETTING: One hundred nineteen dementia special care units in twenty-six nursing homes in The Netherlands. PARTICIPANTS: Two thousand seventy-four residents with dementia. MEASUREMENTS: We operationally defined very frequent agitation as having a score of 6 (several times a day) or 7 (several times an hour) on at least five items of the Cohen Mansfield Agitation Inventory (CMAI) combined with a CMAI total score above the 90th percentile. To assess the association of demographic and behavioral characteristics with very frequent agitation, we performed a multivariate multilevel logistic regression analysis. RESULTS: The 2-week prevalence of very frequent agitation was 7.4% (95% CI: 6.374 8.634). Correlates for very frequent agitation were age (OR: 0.967, 95% CI: 0.942 0.992), dementia severity (GDS 6 = OR: 3.636, 95% CI: 1.929-6.875; GDS 7 = OR: 2.951, 95% CI: 1.321-6.588), delusions (OR: 2.480, 95% CI: 1.555-3.956), anxiety (OR: 1.904, 95% CI: 1.259-2.881), euphoria (OR: 3.712, 95% CI: 2.171-6.337) and irritability (OR: 4.411, 95% CI: 2.854-6.816). CONCLUSIONS: To our knowledge, this study is the first to report prevalence data and correlates about nursing home residents with very frequent agitation. We found several correlated factors for very frequent agitation. Still, further research is needed for a better understanding of the behavior of this group, and to identify good treatment options. PMID- 28886979 TI - Development of a Prediction Model for Diagnosis of Acute Poisoning in Patients with Altered Mental Status and Absent History of Alcohol/Drug Ingestion. AB - BACKGROUND: Diagnosis of acute poisoning in patients with altered mental status and absent history is a challenging diagnostic problem in clinical practice. OBJECTIVE: The aims of the study were to develop a simple clinical tool to stratify risk of acute poisoning in patients with altered mental states and no history of alcohol/drug ingestion, and develop a prediction model using initial observations from which a simple risk score could be derived. METHODS: The study was carried out on non-trauma patients aged 15 years and older admitted with altered mental states and no history of alcohol or drug ingestion. Univariate analysis and logistic regression were carried out and a score was derived and validated. RESULTS: There were 607 patients included, with mean age of 60.3 years and 54% were male. The regression model performed moderately well on both the training and validation sets with areas under the receiver operating characteristic curve of 0.834 and 0.844, respectively. The risk score correlated with the regression model (R2 = 0.969). At cutoff thresholds of 20% for the model and 2 for the score, sensitivity and specificity of the regression model (67.6% and 85.6%) and the score (67.6% and 85.4%) were moderate, while positive predictive values were low (43.4%) and negative predictive values were high (94.2%) for both the regression model and the score. CONCLUSIONS: A prediction model with a derived risk score was developed with a high negative predictive value and may have potential in assessing risk of poisoning in altered mental status and may have value in a prehospital environment or at triage. PMID- 28886980 TI - [Dose constraints to organs at risk for conformational and stereotactic radiotherapy: Small bowel and duodenum]. AB - Radiotherapy of abdominopelvic primary or secondary lesions in conformational or stereotactic techniques is in full development. The small bowel is highly sensitive to irradiation and is the main organ at risk limiting prescription doses. This literature review aims to define the dose constraints to the small bowel and the duodenum in conformational and stereotactic body radiotherapy. The small bowel including the duodenum, jejunum and ileum is delineated on the simulation scanner. The radio-induced intestinal toxicities are acute related to the cellular depopulation of the intestinal mucosa, and late of more complex pathophysiology associating depletion in stem cells, microangiopathy, chronic inflammation and fibrosis. The main predictive factor of intestinal toxicity is the dose-volume ratio. In conformational radiotherapy, the dose constraints to the duodenum are: V25Gy<45% and V35Gy<20%. The jejunum and ileum dose constraints are for delineation by intestinal loop or peritoneal cavity respectively: V15Gy<275mL or V15Gy<830mL and V45Gy<150mL. In stereotactic body radiotherapy, small bowel dose constraints depend on fractionation and are defined on a small volume and on a maximum dose at one point. Intestinal toxicity is also dependent on factors intrinsic to the patient and radiosensitizers such as targeted therapies or chemotherapies. With the development of new techniques allowing dose escalation on the tumour and the development of inverse planning, the definition of dose constraints to the small bowel is essential for current practice. PMID- 28886982 TI - Management of Epilepsy Due to Hypothalamic Hamartomas. AB - A hypothalamic hamartoma consists of hyperplastic heterotopic tissue growing in a disorganized fashion. These lesions occur in about one per 50,000 to 100,000 people. Hypothalamic hamartomas can cause intrinsic epileptogenesis leading to gelastic seizures. Surrounding cortical structures may also develop secondary epileptogenesis. Persistent seizures caused by hypothalamic hamartomas can be debilitating and result in significant cognitive and behavioral impairment. Early recognition and treatment is important in controlling seizures and in preventing further cognitive deterioration. Some patients experience improved cognition and behavior following early treatment, suggesting that hypothalamic hamartomas represent a reversible epileptic encephalopathy. The outcome of epilepsy associated with these lesions has significantly evolved with the availability of new treatment techniques and an improved understanding of its pathogenesis. Increasing evidence supporting the role of hypothalamic hamartomas as a cause of gelastic seizures and secondary epileptogenesis has led to more frequent use of surgery as the definitive treatment. Several minimally invasive procedures have been devised, including neuroendoscopic approaches and different stereotactic radio and laser ablation techniques. Each of these techniques can lead to unique adverse events. We review the various classification schemes used to characterize hypothalamic hamartomas and the recommended surgical approaches for each subtype. We also review the literature for currently available treatment modalities and compare their efficacy in controlling seizures and their safety profiles. PMID- 28886981 TI - [Lung dose constraints for normo-fractionated radiotherapy and for stereotactic body radiation therapy]. AB - Radiation-induced lung disease (RILD) is common after radiation therapy and represents cornerstone toxicities after treatment of thoracic malignancies. From a review of literature, the objective of this article was to summarize clinical and non-clinical parameters associated with the risk of RILD in the settings of normo-fractionated radiotherapy and stereotactic body radiation therapy (SBRT). For the treatment of lung cancers with a normo-fractionated treatment, the mean lung dose (MLD) should be below 15-20Gy. For a thoracic SBRT, V20Gy<10% and MLD<6Gy are recommended. One should pay attention to central tumors and respect specific dose constraints to the bronchial tree. The recent technological improvements may represent an encouraging way to decrease lung toxicities. Finally, our team developed a calculator in order to predict the risk of radiation pneumonitis. PMID- 28886983 TI - Organic degradation potential of a TiO2/H2O2/UV-vis system for dental applications. AB - OBJECTIVES: The combination of TiO2 and H2O2 under light activation constitutes a promising method for disinfection of dental prosthetics and implants, due to production of reactive oxygen species (ROS). The aim of this work was to investigate the organic degradation ability of TiO2 particles in combination with H2O2 and under light activation utilizing the organic dye rhodamine B (RhB). METHODS: Five different types of TiO2 particles, consisting of anatase, rutile, or a mixture of these crystalline phases, were combined with H2O2 and RhB, and subsequently exposed to UV (365nm) or visible (405nm) light at an irradiance of 2.1mW/cm2. RESULTS: It was found that rutile in combination with low concentrations of H2O2 (1.0-3.5mM) resulted in a degradation of RhB of 96% and 77% after 10min exposure to 365nm and 405nm light, respectively, which was the highest degradation of all test groups. Control measurements performed without light irradiation or irradiation at 470nm, or without TiO2 particles resulted in little or no degradation of RhB. CONCLUSIONS: Low H2O2 concentrations (1.0mM 3.5mM) and visible light (405nm) used in combination with rutile TiO2 particles showed the highest RhB degradation capacity. CLINICAL SIGNIFICANCE: A combination of TiO2 particles and H2O2 exposed to low energy UV or high energy visible light has an organic degradation capability that could be utilized in applications to kill or inactivate bacteria on medical devices such as dental implants for treatment against, e.g., peri-implantitis. PMID- 28886984 TI - The role of gap junctions in the C. elegans connectome. PMID- 28886985 TI - Pannexin-1 channels in epilepsy. AB - Pannexin-1 (Panx1) expression is raised in several animal seizure models and in resected human epileptic brain tissue, suggesting relevance to epilepsy. Multiple factors that are characteristic of seizures are thought to regulate Panx1 channel opening, including elevated levels of extracellular K+. Panx1, when open, 1) releases ATP, glutamate, and other metabolites into the extracellular medium, and 2) may depolarize the membrane due to a channel reversal potential around 0mV. Resultant ATP release from stimulated Panx1 can activate purinergic receptors, including P2X7 receptors. Glutamate and other signaling molecules released by Panx1 opening may have both excitatory and inhibitory actions on seizure generation. This review examines the critical and complex roles of Panx1 channels in epilepsy, which could provide a basis for future therapeutics. PMID- 28886986 TI - Role of Connexin and Pannexin containing channels in HIV infection and NeuroAIDS. AB - Neuron-Glia crosstalk is essential for efficient synaptic communication, cell growth and differentiation, neuronal activity, neurotransmitter recycling, and brain immune response. The master regulators of this neuron-glia communication are connexin containing Gap Junctions (GJs) and Hemichannels (HCs) as well as pannexin HCs. However, the role of these channels under pathological conditions, especially in infectious diseases is still in exploratory stages. Human Immunodeficiency Virus-1 (HIV) is one such infectious agent that takes advantage of the host intercellular communication systems, GJs and HCs, to exacerbate viral pathogenesis in the brain in spite of the antiretroviral therapy effectively controlling viral replication in the periphery. Although most infectious agents lead to total "shutdown" of gap junctional communication in parenchymal cells, HIV infection maintains and "hijacks" GJs and HCs to enable few infected cells to spread toxic intracellular agents to neighboring uninfected cells aggravating viral neuropathology even in the absence of viral replication. In this mini review, we present a comprehensive overview of the role of GJs and HCs in augmenting HIV neuropathogenesis. PMID- 28886987 TI - Consequences of the natural retinoid/retinoid X receptor ligands action in human breast cancer MDA-MB-231 cell line: Focus on functional proteomics. AB - The main intention of this study was the investigation of impact of natural biologically active ligands of nuclear retinoid/retinoid X receptors (all-trans and 9-cis retinoic acid) on proteomic pattern in human estrogen receptor negative breast cancer cell line MDA-MB-231. For this purpose, proteomic strategies based on bottom-up method were applied. The total cell proteins were extracted utilizing a commercially Radio-Immunoprecipitation Assay (RIPA) buffer and separated on 2D sodium dodecyl sulfate polyacrylamide gel electrophoresis (2D SDS PAGE). The proteins were subsequently digested in-gel by trypsin and their characterization was achieved by MALDI-TOF/TOF. By employing PDQuestTM software, we identified more than 50 proteins affected by retinoic acid isomers. For more information, 9 proteins which are associated with tumor process were selected. We determined that derivatives of retinoic acid led to significantly reduced level of proteins belonging to metabolic pathway (e.g. glyceraldehyde-3-phosphate dehydrogenase or pyruvate kinase 2) or to other cellular processes as apoptosis, regulation of transcription process or epithelial-mesenchymal transition (e.g. annexins, nucleoside diphosphate kinase B, vimentin). On the other hand all-trans retinoic acid treatment indicates up-regulated effect for heterogeneous nuclear ribonucleoprotein A2/B1. PMID- 28886988 TI - Perinatal ciclosporin A exposure elicits sex-related cardiac dysfunction and inflammation in the rat progeny. AB - Ciclosporin A (CSA) has been identified with harmful cardiotoxicity but little, if any, is known about the influence of perinatal exposure upon the cardiac function of the progeny. The present work examines the premise that perinatal contact with CSA undermines the cardiac function of sexually mature rats. Administration of CSA (15mg/kg/day sc) to pregnant rats from day 6 of conception till weaning led to a decrease in gradient of the end-systolic pressure-volume relationship by a factor of ten for male progeny and a factor of two for female progeny. Perinatally CSA-exposed male, but not female, progeny also demonstrated significantly increased systolic and diastolic blood pressure, along with significantly increased JT interval and a tendency towards increased QTc interval, indicating delayed left ventricular (LV) repolarization and perhaps arrhythmogenesis. Conversely, female, but not male, progeny exposed perinatally to CSA showed a delay in atrioventricular (AV) conduction, as demonstrated by significantly prolonged P duration and a tendency towards increased PR interval. CSA increased serum tumor necrosis factor alpha (TNFalpha) and decreased serum adiponectin levels and cardiac adiponectin receptor expression in male progeny, in contrast to no effects in female progeny. Signs of improved oxidative state (decreased 8-isoprostane and increased catalase activity) appeared only in CSA exposed female rats. Moreover, cardiac muscle degeneration and pyknosis was more observed in male than in female rats. In brief, the sex plays a key role in determining the extent of the deterioration in functional and inflammatory states of the heart that follow perinatal CSA exposure in rats. PMID- 28886989 TI - Factors Associated with Contralateral Deep Venous Thrombosis after Iliocaval Venous Stenting. AB - BACKGROUND: The majority of iliac venous obstructions occur on the left side, and endovascular therapy has become the first line treatment for this condition. A left common iliac venous stent will protrude into the inferior vena cava (IVC) to some extent, thereby covering the contralateral common iliac vein (CIV) outflow. This may increase the risk of thrombosis of the contralateral iliac vein. The aim of this paper was to determine the rate of, and factors associated with, contralateral lower limb venous thrombosis after stenting, and to evaluate the results of salvage revascularisation. METHODS: A total of 376 patients (102 from UCH, Galway, Ireland, 2008-16, and 274 from, CHU Nord, Marseille, France, 2000 15) with symptomatic acute or chronic left iliocaval venous obstruction were retrospectively evaluated. Either duplex ultrasound scanning (DUS) or computed tomographic venography (CTV) was used for pre- and post-operative imaging. Data were collected from the PACS system (IMPAX, Agfa, BE) of the Radiology Department, UCH, Galway, and from the electronic medical records of Vascular Surgery department, CHU Nord, Marseille. RESULTS: The median age of stented patients was 46 (range 15-86 years), 80% were female (301/376). Following left CIV stent placement, 10 patients later presented with a right (contralateral) iliac deep venous thrombosis (DVT) resulting in a cumulative incidence of contralateral DVT of 4% according to Kaplan-Meier analysis. Acute DVT (p=.001), non-compliance with the prescribed 6 months anticoagulation (p = 0.05), pre operative contralateral internal iliac vein (IIV) thrombosis (p = 0.001), and pre existing IVC filter placement (p = 0.003) were all statistically significantly associated with contralateral DVT. All patients with symptomatic contralateral iliac DVT underwent clot removal in the acute phase. The primary patency of these limbs was 100% at 3 years. CONCLUSION: Stent placement across the iliocaval confluence from the left CIV is associated with a low but definite rate of contralateral iliac vein thrombosis. Acute DVT, pre-operative contralateral IIV thrombosis, pre-existing IVC filters, and anticoagulation non-compliance are significant risk factors. PMID- 28886990 TI - Comparison of traditional diabetes risk scores and HbA1c to predict type 2 diabetes mellitus in a population based cohort study. AB - AIMS: Compare performances of diabetes risk scores and glycated hemoglobin (HbA1c) to estimate the risk of incident type 2 diabetes mellitus (T2DM) in Northeast Germany. METHODS: We studied 2916 subjects (20 to 81years) from the Study of Health in Pomerania (SHIP) in a 5-year follow-up period. Diabetes risk scores included the Cooperative Health Research in the Region of Augsburg (KORA) base model, the Danish diabetes risk score and the Data from the Epidemiological Study on the Insulin Resistance syndrome (D.E.S.I.R) clinical risk score. We assessed the performance of each of the diabetes risk scores and the HbA1c for 5 year risk of T2DM by the area under the receiver-operating characteristic curve (AUC) and calibration plots. RESULTS: In SHIP, the incidence of T2DM was 5.4% (n=157) in the 5-year follow-up period. Diabetes risk scores and HbA1c achieved AUCs ranging from 0.76 for the D.E.S.I.R. clinical risk score to 0.82 for the KORA base model. For diabetes risk scores, the discriminative ability was lower for the age group 55 to 74years. For HbA1c, the discriminative ability also decreased for the group 55 to 74years while it was stable in the age group 30 to 64years old. CONCLUSIONS: All diabetes risk scores and the HbA1c showed a good prediction for the risk of T2DM in SHIP. Which model or biomarker should be used is driven by its context of use, e.g. the practicability, implementation of interventions and availability of measurement. PMID- 28886992 TI - Study on the Effect of Irbesartan on Atrial Fibrillation Recurrence in Kumamoto: Atrial Fibrillation Suppression Trial (SILK study). AB - BACKGROUND: Experimental studies suggest that angiotensin II-receptor blockers can influence atrial remodeling and may prevent atrial fibrillation (AF). Therefore, we hypothesized that irbesartan may prevent the recurrence of AF following either catheter ablation or electrical cardioversion of AF. METHODS: Study on the Effect of Irbesartan on Atrial Fibrillation Recurrence in Kumamoto (SILK study) is a prospective, multicenter, randomized, and open-label comparative evaluation of the effects of irbesartan and amlodipine on AF recurrence in hypertensive patients with AF who are scheduled to undergo catheter ablation or electrical cardioversion of AF. The primary end point was either AF or atrial tachycardia (AT) recurrence. AF/AT recurrence was evaluated for 6 months using 24-h Holter electrocardiogram and portable electrocardiogram. The secondary endpoints included the change in blood pressure, the interval from the procedure to the first AF/AT recurrence, cardiovascular events, left atrial diameter (LAD), left ventricular ejection fraction (LVEF), and changes in the biomarkers [brain natriuretic polypeptide (BNP), high-sensitivity C-reactive protein (hs-CRP), urinary albumin/creatinine]. RESULTS: The study enrolled 98 patients (irbesartan; n=47, amlodipine; n=51). The recurrence of AF/AT was observed in 8 patients (17.0%) in the irbesartan group and in 10 patients (19.6%) in the amlodipine group. There was no significant difference in the AF/AT recurrence between the irbesartan and amlodipine groups. Blood pressure decreased similarly in both groups. There were no significant differences between the two groups as regards to the interval from the procedure to the first AF/AT recurrence, occurrence of cardiovascular events, changes in LAD and LVEF. BNP and urinary albumin/creatinine significantly decreased similarly in both groups, but no significant difference was found in hs-CRP between the two groups. CONCLUSIONS: In hypertensive patients with AF, treatment with irbesartan did not have any advantage over amlodipine in the reduction of AF/AT recurrence after catheter ablation or electrical cardioversion. PMID- 28886991 TI - Molecular mechanisms of nonalcoholic fatty liver disease: Potential role for 12 lipoxygenase. AB - Nonalcoholic fatty liver disease (NAFLD) is a spectrum of pathologies associated with fat accumulation in the liver. NAFLD is the most common cause of liver disease in the United States, affecting up to a third of the general population. It is commonly associated with features of metabolic syndrome, particularly insulin resistance. NAFLD shares the basic pathogenic mechanisms with obesity and insulin resistance, such as mitochondrial, oxidative and endoplasmic reticulum stress. Lipoxygenases catalyze the conversion of poly-unsaturated fatty acids in the plasma membrane-mainly arachidonic acid and linoleic acid-to produce oxidized pro-inflammatory lipid intermediates. 12-Lipoxygenase (12-LOX) has been studied extensively in setting of inflammation and insulin resistance. As insulin resistance is closely associated with development of NAFLD, the role of 12-LOX in pathogenesis of NAFLD has received increasing attention in recent years. In this review we discuss the role of 12-LOX in NAFLD pathogenesis and its potential role in emerging new therapeutics. PMID- 28886994 TI - Successful Treatment of Residual Curvature in Peyronie Disease in Men Previously Treated With Intralesional Collagenase Clostridium Histolyticum. AB - OBJECTIVE: To determine the success and feasibility of surgically correcting residual curvature after intralesional collagenase clostridium histolyticum (CCH) for the treatment of Peyronie disease (PD). METHODS: We performed a retrospective analysis of patients who had intralesional CCH treatment for PD and who subsequently underwent penile plication (PP), plaque incision and grafting (PIG), or inflatable penile prosthesis (IPP) placement. RESULTS: Ten men who underwent PP, PIG, or IPP for the treatment of residual curvature after intralesional CCH were identified. Six patients underwent PP; 1 patient underwent PIG; and 3 patients underwent IPP with ancillary straightening maneuvers. The mean time from the last CCH injection to surgical correction was 150.9 days, or 5 months. The mean pre-CCH curvature was 67 degrees and the mean post-CCH curvature was 51 degrees. Eight of 10 patients had no residual curvature after surgical treatment. The mean postprocedure curvature was 4.5 degrees. The mean operative time was 72.1 minutes. The mean estimated blood loss was 20 mL. Increased fibrosis with increased surgical difficulty was noted in 3 (all <6 months post CCH treatment) of 10 patients. No postoperative complications were noted. CONCLUSION: The surgical treatment of PD after intralesional CCH is safe and effective. If surgery is considered, this should be performed at least 6 months after the last CCH injection, given the potential for an increased inflammatory reaction in this area. PMID- 28886993 TI - Smoking and risk of atrial fibrillation in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. AB - BACKGROUND: Whether smoking increases the risk of atrial fibrillation (AF) remains debatable due to inconsistent reports. METHODS: We examined the association between smoking and incident AF in 11,047 participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, one of the largest biracial, population-based cohort studies in the USA. Baseline (2003 2007) cigarette smoking status and amount (pack-years) were self-reported. Incident AF was determined by electrocardiography and history of a prior physician diagnosis at a follow-up examination conducted after a median of 10.6 years. RESULTS: During follow-up, 954 incident AF cases were identified; 9.5% in smokers vs. 7.8% in non-smokers; p<0.001. In a model adjusted for socio demographics, smoking (ever vs. never) was associated with a 15% increased risk of AF [OR (95%CI): 1.15(1.00, 1.31)], but this association was no longer significant after further adjustment for cardiovascular risk factors [OR (95% CI): 1.12 (0.97, 1.29)]. However, heterogeneities in the association were observed among subgroups; the association was stronger in young vs. old participants [OR (95%CI): 1.31 (1.03, 1.67) vs. 0.99 (0.83-1.18) respectively; interaction p-value=0.005] and in those with vs. without prior cardiovascular disease [OR (95%CI): 1.18 (0.90, 1.56) vs. 1.06 (0.90, 1.25) respectively; interaction p-value 0.0307]. Also, the association was significant in blacks but not in whites [OR (95%CI): 1.51 (1.12, 2.05) vs. 0.99 (0.84, 1.16), respectively], but the interaction p-value did not reach statistical significance (interaction p-value=0.65). CONCLUSIONS: The association between smoking and AF is possibly mediated by a higher prevalence of cardiovascular risk factors in smokers, but there is marked heterogeneity in the strength of this association among subgroups which may explain the conflicting results in prior studies. PMID- 28886995 TI - Improving oral bioavailability of cyclic peptides by N-methylation. AB - The renaissance of peptides in pharmaceutical industry results from their importance in many biological functions. However, low metabolic stability and the lack of oral availability of most peptides is a certain limitation. Whereas metabolic instability may be often overcome by development of small cyclic peptides containing d-amino acids, the very low oral availability of most peptides is a serious limitation for some medicinal applications. The situation is complicated because a twofold optimization - biological activity and oral availability - is required to overcome this problem. Moreover, most simple "rules" for achieving oral availability are not general and are applicable only to limited cases. Many structural modifications for increasing biological activities and metabolic stabilities of cyclic peptides have been described, of which N-alkylation is probably the most common. This mini-review focuses on the effects of N-methylation of cyclic peptides in strategies to optimize bioavailabilities. PMID- 28886996 TI - A prodrug design for improved oral absorption and reduced hepatic interaction. AB - A series of estradiol-17-beta esters of N-(p-sulfomylbenzamide)-amino acids were prepared and evaluated for systemic and hepatic estrogenic activity after oral administration in ovariectomized rats. The alkyl substitution at nitrogen of amino acids such as proline or N-methyl-alanine produced compounds that exhibit potent oral activity. The proline analog (EC508) was further evaluated along with 17beta-estradiol (E2) and ethinyl-estradiol (EE) and compared their effects on the uterus, angiotensin and HDL-cholesterol after oral administration to ovariectomized female rats. Orally administered EC508 produced systemic estrogenic activity 10 times greater than EE and a 100 times higher activity than E2 with no influence on levels of angiotensin and HDL-cholesterol, whereas EE and E2 reduced the HDL-cholesterol and increased the angiotensine plasma levels. EC508 might offer significant advantages in indications like fertility control and HRT based on its high oral bioavailability and lack of hepatic estrogenicity. PMID- 28886997 TI - Analysis of the binding sites of vitamin D 1alpha-hydroxylase (CYP27B1) and vitamin D 24-hydroxylase (CYP24A1) for the design of selective CYP24A1 inhibitors: Homology modelling, molecular dynamics simulations and identification of key binding requirements. AB - A homology model of human CYP27B1 was built using MOE and was further optimised by molecular dynamics simulations of the hCYP27B1 homology model and a hCYP27B1 SDZ-88357 complex. Docking results from the hCYP27B1-SDZ-88357 complex showed amino acids Arg107, Asn387 and Asp320 have an important role in binding interaction, with Asp320 part of the important acid-alcohol pair situated in the I-helix with the conserved sequence (A/G) GX (E/D) (T/S), which assumes an essential role in the binding of an oxygen molecule for catalysis. Additional docking experiments with selective hCYP27B1 or hCYP24A1 inhibitors using both the hCYP27B1 model and a triple mutant hCYP24A1 model provided further support for the importance of H-bonding interactions with the three identified active site amino acids. To confirm the role of Arg107, Asn387 and Asp320 in the active site of hCYP27B1 compounds were designed that would form H-bonding interactions, as determined from docking experiments with the hCYP27B1 model. Subsequent synthesis and CYP24A1 and CYP27B1 enzyme assays of the designed compounds 1a and 1b showed a~5-fold selectivity for CYP27B1 confirming the importance of Asp320 in particular and also Asn387 and Arg107 as important amino acids for CYP27B1 inhibitory activity. PMID- 28886998 TI - Propolis reversed cigarette smoke-induced emphysema through macrophage alternative activation independent of Nrf2. AB - Chronic obstructive pulmonary disease (COPD) is an incurable and progressive disease. Emphysema is the principal manifestation of COPD, and the main cause of this condition is cigarette smoke (CS). Natural products have shown antioxidant and anti-inflammatory properties that can prevent acute lung inflammation and emphysema, but there are few reports in the literature regarding therapeutic approaches to emphysema. We hypothesized that supplementation with natural extracts would repair lung damage in emphysema caused by CS exposure. Mice were exposed to 60days of CS and then treated or not with three different natural extracts (mate tea, grape and propolis) orally for additional 60days. Histological analysis revealed significant improvements in lung histoarchitecture, with recovery of alveolar spaces in all groups treated with natural extracts. Propolis was also able to recovery alveolar septa and elastic fibers. Propolis also increased MMP-2 and decreased MMP-12 expression, favoring the process of tissue repair. Additionally, propolis recruited leukocytes, including macrophages, without ROS release. These findings led us to investigate the profile of these macrophages, and we showed that propolis could promote macrophage alternative activation, thus increasing the number of arginase positive cells and IL-10 levels and favoring an anti-inflammatory microenvironment. We further investigated the participation of Nrf2 in lung repair, but no Nrf2 translocation to the nucleus was observed in lung cells. Proteins and enzymes related to Nrf2 were not altered, other than NQO1, which seemed to be activated by propolis in a Nrf2-independent manner. Finally, propolis downregulated IGF1 expression. In conclusion, propolis promoted lung repair in a mouse emphysema model via macrophage polarization from M1 to M2 in parallel to the downregulation of IGF1 expression in a Nrf2-independent manner. PMID- 28886999 TI - Advances in macrocyclic peptide-based antibiotics. AB - Macrocyclic peptide-based natural products have provided powerful new antibiotic drugs, drug candidates, and scaffolds for medicinal chemists as a source of inspiration to design novel antibiotics. While most of those natural products are active mainly against Gram-positive pathogens, novel macrocyclic peptide-based compounds have recently been described, which exhibit potent and specific activity against some of the most problematic Gram-negative ESKAPE pathogens. This mini-review gives an up-date on recent developments. PMID- 28887000 TI - Development of sulfonamides incorporating phenylacrylamido functionalities as carbonic anhydrase isoforms I, II, IX and XII inhibitors. AB - A series of novel sulfonamides incorporating phenylacrylamido functionalities were synthesized and investigated for the inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The physiologically and pharmacologically relevant human (h) isoforms hCA I and II (cytosolic isozymes), as well as the transmembrane tumor-associated hCA IX and XII were included in the study. These compounds showed low nanomolar or sub-nanomolar inhibition constants against hCA II (KIs in the range of 0.50-50.5nM), hCA IX (KIs of 1.8-228.5nM), and hCA XII (KIs of 3.5-96.2nM) being less effective as inhibitors of the off target isoform hCA I. A detailed structure-activity relationship study demonstrates that the nature and position of substituents present on the aromatic part of the scaffold strongly influence the inhibition of CA isoforms. As hCA II, IX and XII are involved in pathologies such as glaucoma and hypoxic, and metastatic tumors, compounds of the type reported in this work may be useful preclinical candidates. PMID- 28887001 TI - Major findings and recent advances in virus-like particle (VLP)-based vaccines. AB - Virus-like particles (VLPs) have made giant strides in the field of vaccinology over the last three decades. VLPs constitute versatile tools in vaccine development due to their favourable immunological characteristics such as their size, repetitive surface geometry, ability to induce both innate and adaptive immune responses as well as being safe templates with favourable economics. Several VLP-based vaccines are commercially available including vaccines against Human Papilloma Virus (HPV) such as Cervarix(r), Gardasil(r) & Gardasil9(r) and Hepatitis B Virus (HBV) including the 3rd generation Sci-B-VacTM. In addition, the first licensed malaria-VLP-based vaccine MosquirixTM has been recently approved by the European regulators. Several other VLP-based vaccines are currently undergoing preclinical and clinical development. This review summarizes some of the major findings and recent advances in VLP-based vaccine development and technologies and outlines general principles that may be harnessed for induction of targeted immune responses. PMID- 28887002 TI - Optimized efflux assay for the NorA multidrug efflux pump in Staphylococcus aureus. AB - Real-time fluorescent efflux assays are commonly used for measuring the efflux of bacterial pumps. Here we describe an optimized protocol for the NorA efflux pump in S. aureus using DiOC3 instead of ethidium bromide. Glucose and sodium formate were tested as energy carriers. This novel method is fast and reproducible. PMID- 28887003 TI - Effects of acupuncture at the ST-36 point on muscle sympathetic nerve activity and blood pressure in normal adults. AB - The aim of the present study was to determine the effects of acupuncture on post ganglionic muscle sympathetic nerve activity (MSNA) in humans. MSNA was measured in 8 healthy adult males by microneurography evaluation of the left peroneal nerve. Blood pressure (BP) and heart rate (HR) were simultaneously recorded. MSNA was evaluated as the burst rate, with total MSNA, BP and HR normalized to their respective baseline values. After 10min of rest in the supine position, acupuncture was applied to the right ST-36 point in the tibialis anterior muscle for 15min, with recovery then monitored over a 20-min period. While the burst rate and total MSNA remained constant throughout the study, there was a significant decrease in BP during the real but not sham acupuncture procedure (p<0.05). HR did not significantly change throughout the study. The results rule out the role of MSNA in the BP fall during acupuncture at the ST-36 point, and suggest possible involvement of other factors in the fall of BP. PMID- 28887004 TI - [Mycological profile of hand onychomycosis amongs "Garba" sellers in Abidjan (Cote d'Ivoire)]. AB - OBJECTIVE: The aim of this study is to determine the prevalence and the fungi involved in onychomycosis located on fingers in Abidjan. MATERIAL AND METHODS: This study includes the sellers of cooked cassava semolina served with fried tuna fish called "garba". Fines squames specimen was processed with 30% KOH for a direct microscope examination. Serous collection were done in physiological serum. Part of the original sample was cultured on Sabouraud medium with antibiotics (chloramphenicol, actidione). Species distribution and antifungal susceptibility by the technique on agar were noted. RESULTS: A total of 205 male sellers were involved. The Onychomycosis prevalence was 6.3%; (95% CI : 3.6 10.3). Five species of yeasts were identified. Candida spp were the most frequent (84.6%) and Candida albicans represented 30.8% of isolated yeasts. Trichosporon cutaneum were isolated in two case (15.4%). Susceptibility for amphotericin-B was 92.3% contrary to 5-fluorocytosine 30.8%. The subjects aged between 15 to 24 (69.2%), with a higher seniority (84.6%) and illiterate (69.2%) were the most affected. The main risk factors of fungal infections were the presence of previous fingernail onychomycosis (P<0.0001) and the frequent fingernail cutting (P=0.0009). CONCLUSION: Onychomycosis caused by yeast is infrequent among "garba" sellers in Abidjan. The main fungi involved in fingernail onychomycosis were Candida species. It is nevertheless necessary to implement sensitization for them on contributing factors. PMID- 28887005 TI - [Fungal aetiologies and contributing factors of interdigital tinea pedis among policemen in Abidjan (Ivory Coast)]. AB - AIM OF THE STUDY: Fungal interdigital tinea pedis are poorly documented in Ivory Coast. This study aimed to determine the distribution of fungal species and contributing factors of the disease among policemen in Abidjan. PATIENTS AND METHODS: Our cross-sectional study was carried out at the police school in Abidjan. Our patients consisted of symptomatic or non-symptomatic police students. Samples of scales or serosities taken from inter-toes spaces were examinated with KOH mount and cultured on Sabouraud-chloramphenicol and Sabouraud chloramphenicol-actidione media. The method of identification depended on the observed fungus. RESULTS: Among the 303 police students with clinical lesions of the inter-toe folds, 233 (76.9%; IC 95%=71.9-81.4) had a positive diagnosis after mycological examination. Lesions were predominantly located in the 3rd and 4th interdigital plantar spaces, with desquamation (100%) followed by maceration (82.5%) as the predominant functional sign. Dermatophytes accounted for 86.3% of the strains isolated with as majority species : Trichophyton interdigitale (40.3%), Microsporum langeronii (30.0%) and Trichophyton rubrum (15.5%). Yeasts accounted for 13.7% of the strains with Candida albicans (7.7%) as the most found species. The duration at the police school (P=0.004) and the practice of sports activities (P=0.0001) were statistically associated with the occurrence of the disease. CONCLUSION: A good hygiene of feet would reduce the incidence of the disease among the defense and security forces. Also, investigations for the influence of the seasons in the occurrence of interdigital tinea pedis will allow a better understand of epidemiology of this dermatomycosis. PMID- 28887006 TI - A 3-month safety and efficacy study of travoprost 0.004% ophthalmic solution compared with timolol in pediatric patients with glaucoma or ocular hypertension. AB - PURPOSE: To evaluate efficacy and safety of travoprost in pediatric patients with ocular hypertension or glaucoma and demonstrate its noninferiority to timolol. METHODS: Patients aged 2 months to <18 years with glaucoma or ocular hypertension were randomized to receive travoprost (0.004%) or timolol eye drops (0.25% for patients aged 2 months to <3 years and 0.5% for patients >=3 years old) for 3 months in this double-masked, parallel-group study. Intraocular pressure (IOP) was measured and patients were evaluated at 2 weeks, 6 weeks, and 3 months after treatment. Change in IOP from baseline to 3 months was the primary endpoint, and the test of noninferiority was based on a margin of +3.0 mm Hg using the 95% 2 sided confidence interval of the mean change. RESULTS: Of 157 patients included (mean age, 9.6 years), 77 received travoprost and 75 timolol. All patients experienced a significant reduction in IOP in the study eye at 3 months: the mean IOP change from baseline was -5.4 mm Hg for travoprost; -5.3 mm Hg, for timolol. The mean difference between travoprost and timolol at month 3 was -0.1 mm Hg (95% CI, -1.5 to 1.4 mm Hg). The most common treatment-related adverse events for the travoprost group were ocular hyperemia and eyelash growth. No serious adverse events were reported. CONCLUSIONS: This study found travoprost to be noninferior to timolol in lowering IOP in patients with pediatric glaucoma or ocular hypertension. Travoprost was well-tolerated, and no treatment-related systemic adverse events were reported. PMID- 28887007 TI - Yersinia pestis detection by loop-mediated isothermal amplification combined with magnetic bead capture of DNA. AB - We developed a loop-mediated isothermal amplification (LAMP) assay for the detection of Y. pestis by targeting the 3a sequence on chromosome. All 11 species of the genus Yersinia were used to evaluate the specificity of LAMP and PCR, demonstrating that the primers had a high level of specificity. The sensitivity of LAMP or PCR was 2.3 or 23CFU for pure culture, whereas 2.3*104 or 2.3*106CFU for simulated spleen and lung samples. For simulated liver samples, the sensitivity of LAMP was 2.3*106CFU, but PCR was negative at the level of 2.3*107CFU. After simulated spleen and lung samples were treated with magnetic beads, the sensitivity of LAMP or PCR was 2.3*103 or 2.3*106CFU, whereas 2.3*105 or 2.3*107CFU for magnetic bead-treated liver samples. These results indicated that some components in the tissues could inhibit LAMP and PCR, and liver tissue samples had a stronger inhibition to LAMP and PCR than spleen and lung tissue samples. LAMP has a higher sensitivity than PCR, and magnetic bead capture of DNAs could remarkably increase the sensitivity of LAMP. LAMP is a simple, rapid and sensitive assay suitable for application in the field or poverty areas. PMID- 28887009 TI - Addressing quantification of "turbulence" in the "political replacement effect": Comment on "Modeling human behavior in economics and social science" by Marina Dolfin, Leone Leonida, and Nisrine Outada. PMID- 28887008 TI - Physiological response of Cucurbita pepo var. pepo mycorrhized by Sonoran desert native arbuscular fungi to drought and salinity stresses. AB - Plants response to symbiosis with arbuscular mycorrhizal fungi (AMF) under water stress is important to agriculture. Under abiotic stress conditions native fungi are more effective than exotics in improving plant growth and water status. Mycorrhization efficiency is related to soil fungi development and energy cost benefit ratio. In this study, we assessed the effect on growth, water status and energy metabolism of Cucurbita pepo var. pepo when inoculated with native AMF from the Sonoran desert Mexico (mixed isolate and field consortium), and compared with an exotic species from a temperate region, under drought, low and high salinity conditions. Dry weights, leaf water content, water and osmotic potentials, construction costs, photochemistry and mycorrhization features were quantified. Under drought and low salinity conditions, the mixed isolate increased plant growth and leaf water content. Leaf water potential was increased only by the field consortium under drought conditions (0.5-0.9MPa). Under high salinity, the field consortium increased aerial dry weight (more than 1g) and osmotic potential (0.54MPa), as compared to non-mycorrhized controls. Plants inoculated with native AMF, which supposedly diminish the effects of stress, exhibited low construction costs, increased photochemical capacity, and grew larger external mycelia in comparison to the exotic inoculum. PMID- 28887010 TI - Improved Performance of Adjunctive Ultrasonography After Mammography Screening for Breast Cancer Among Chinese Females. AB - INTRODUCTION: Until now, no studies have investigated whether women other than those with dense breasts are suitable for adjunctive ultrasonography after negative mammography, and investigated whether all women with negative mammography are suitable for adjunctive ultrasonography. METHODS: Based on the Multi-modality Independent Screening Trial in China, a total of 31,918 women aged 45 to 65 years underwent both ultrasonography and mammography. Physicians performed ultrasonography and mammography separately and were blinded to each other's findings until their interpretations had been recorded. For both ultrasonography and mammography, suspicious results and those highly suggestive of a malignancy were confirmed by pathologic examination, whereas other results were confirmed by 1-year follow-up after initial screening. RESULTS: Based on Breast Imaging Reporting and Data System (BIRADS) assessments, 84 (84.8%) of 99 cancers were identified on mammography (detection rate, 2.6/1000), and 61 (61.6%) of 99 cancers were identified on ultrasonography (detection rate, 1.9/1000). Integrated mammography with ultrasonography identified 94 (95.0%) of 99 cancers, with an increment of 11.9% in cancer detection rate (from 2.6/1000 to 2.9/1000) (P < .05). Moreover, among women with BIRADS 3, adjunctive ultrasonography detected no cancers. All 10 additional cancers detected by adjunctive ultrasonography were from women with BIRADS 0 to 2, at a cost of 207 women with false positives. Additionally, dense breasts and benign breast disease were significantly associated with positive ultrasonography after BIRADS 0 to 2 (all P values < .05). CONCLUSIONS: After negative mammography, adjunctive ultrasonography should only be recommended for BIRADS 0 to 2 but not BIRADS 3, especially for women with dense breasts or benign breast disease. PMID- 28887011 TI - Cell therapies for Chagas disease. AB - In this review of cell therapies in Chagas disease, we cover aspects related to the disease, its treatment and world demographics, before proceeding to describe the preclinical and clinical trials performed using cell therapies in the search for an alternative therapy for the most severe and lethal form of this disease, chronic chagasic cardiomyopathy. PMID- 28887012 TI - Chronic maladaptive pain in cats: A review of current and future drug treatment options. AB - Despite our increasing understanding of the pathophysiology underlying chronic or maladaptive pain, there is a significant gap in our ability to diagnose and treat the condition in domestic cats. Newer techniques being used to identify abnormalities in pain processing in the cat include validated owner questionnaires, measurement of movement and activity, and measurement of sensory thresholds and somatomotor responses. While some data are available evaluating possible therapeutics for the treatment of chronic pain in the cat, most data are limited to normal cats. This review details our current understanding of chronic or maladaptive pain, techniques for the detection and measurement of the condition and the associated central nervous changes, as well as an overview of the data evaluating potential therapeutics in cats. PMID- 28887013 TI - Morphine exposure and maternal deprivation during the early postnatal period alter neuromotor development and nerve growth factor levels. AB - The objective of this study was to verify whether repeated morphine administration and maternal deprivation in early life alter neurobehavioral development and central nerve growth factor (NGF) levels. A total of 58 male Wistar rat pups were used in our study. From postnatal day 1 (P1), litters were daily deprived of their mother for 3h; this was continued for the first 10days of life. Animals were divided into 5 groups: total control (C), did not receive any intervention; saline (S), received saline solution; morphine (M), received morphine; deprived-saline group (DS), were subjected to maternal deprivation and received saline solution; and deprived-morphine (DM), were subjected to maternal deprivation and received morphine. From P8, newborns received subcutaneous (s.c.) injections of morphine or saline (5MUg) once daily for 7days. Righting reflex, negative geotaxis and gait were chosen as postural parameters to evaluate neuromotor reflexes. In the righting reflex test, a delay in the development of animals was evidenced in the M group. Performance of negative geotaxis was slower in the M and DM groups. In the gait test, all groups showed a daily improvement in performance in terms of locomotion frequency. An increased frequency of rearing was observed in the M, DS, and DM groups from P16 to P20. The DM group presented an increase in NGF levels in the brainstem. An increase in cerebral cortex NGF levels in the M, DS, and DM groups was observed as well. Our results suggest that changes in environmental conditions and the disruption of mother infant interactions during the neonatal period can produce changes in the neurobiology, physiology, and emotional behavior of rats. This finding has important implications for the maternal-neonate interaction needed for normal brain development in newborns. PMID- 28887014 TI - Osiris9a is a major component of silk fiber in lepidopteran insects. AB - In a previous high-throughput proteomics study, it was found that the silkworm cocoon contains hundreds of complex proteins, many of which have unknown functions, in addition to fibroins, sericins, and some protease inhibitors. Osiris was one of the proteins with no known function. In this study, we identified the Osiris gene family members and constructed a phylogenetic tree based on the sequences from different species. Our results indicate that the Osiris9 gene subfamily contains six members; it is specifically expressed in lepidopteran insects and has evolved by gene duplication. An Osiris gene family member from Bombyx mori was designated as BmOsiris9a (BmOsi9a) on the basis of its homology to Drosophila melanogaster Osiris9. The expression pattern of BmOsi9a showed that it was highly expressed only in the middle silk gland of silkworm larvae, similar to Sericin1 (Ser1). BmOsi9a was visualized as two bands in western blot analysis, implying that it probably undergoes post-translational modifications. Immunohistochemistry analysis revealed that BmOsi9a was synthesized and secreted into the lumen of the middle silk gland, and was localized in the sericin layer in the silk fiber. BmOsi9a was found in the silk fibers of not only three Bombycidae species, viz. B. mori, B. mandarina, and B. huttoni, but also in the fibers collected from Saturniidae species, including Antheraea assama, Antheraea mylitta, and Samia cynthia. Although the exact biological function of Osi9a in the silk fibers is unknown, our results are important because they demonstrate that Osi9a is a common structural component of silk fiber and is expressed widely among the silk-producing Bombycidae and Saturniidae insects. Our results should help in understanding the role of Osi9a in silk fibers. PMID- 28887015 TI - Bedaquiline or delamanid for rifampin-resistant tuberculosis? PMID- 28887017 TI - Establishment and activity of the D quadrant organizer in the marine gastropod Crepidula fornicata. AB - During development in metazoan embryos, the fundamental embryonic axes are established by organizing centers that influence the fates of nearby cells. Among the spiralians, a large and diverse branch of protostome metazoans, studies have shown that an organizer sets up the dorsal-ventral axis, which arises from one of the four basic cell quadrants during development (the dorsal, D quadrant). Studies in a few species have also revealed variation in terms of how and when the D quadrant and the organizer are established. In some species the D quadrant is specified conditionally, via cell-cell interactions, while in others it is specified autonomously, via asymmetric cell divisions (such as those involving the formation of polar lobes). The third quartet macromere (3D) typically serves as the spiralian organizer; however, other cells born earlier or later in the D quadrant lineage can serve as the organizer, such as the 2d micromere in the annelid Capitella teleta or the 4d micromere in the mollusc Crepidula fornicata. Here we present work carried out in the snail C. fornicata to show that establishment of a single D quadrant appears to rely on a combination of both autonomous (via inheritance of the polar lobe) and conditional mechanisms (involving induction via the progeny of the first quartet micromeres). Through systematic ablation of cells, we show that D quadrant identity is established between 5th and 6th cleavage stages, as it is in other spiralians that use conditional specification. Subsequently, following the next cell cycle, organizer activity takes place soon after the birth of the 4d micromere. Therefore, unlike the case in other spiralians that use conditional specification, the specification of the D quadrant and the activity of the dorso-ventral organizer are temporally and spatially uncoupled. We also present data on organizer function in naturally-occurring and experimentally-induced twin embryos, which possess multiple D quadrants. We show that supernumerary D quadrants can arise in C. fornicata (either spontaneously or following polar lobe removal); when multiple D quadrants are present these do not exhibit effective organizer activity. We conclude that the polar lobe is not required for D quadrant specification, though it could play a role in effective organizer activity. We also tested whether the inheritance of the small polar lobe by the D quadrant is associated with the ability to laterally inhibit neighboring quadrants by direct contact in order to normally prevent supernumerary organizers from arising. Finally, we discuss the variation of spiralian organizers in a phylogenetic context. PMID- 28887016 TI - Myotome adaptability confers developmental robustness to somitic myogenesis in response to fibre number alteration. AB - Balancing the number of stem cells and their progeny is crucial for tissue development and repair. Here we examine how cell numbers and overall muscle size are tightly regulated during zebrafish somitic muscle development. Muscle stem/precursor cell (MPCs) expressing Pax7 are initially located in the dermomyotome (DM) external cell layer, adopt a highly stereotypical distribution and thereafter a proportion of MPCs migrate into the myotome. Regional variations in the proliferation and terminal differentiation of MPCs contribute to growth of the myotome. To probe the robustness of muscle size control and spatiotemporal regulation of MPCs, we compared the behaviour of wild type (wt) MPCs with those in mutant zebrafish that lack the muscle regulatory factor Myod. Myodfh261 mutants form one third fewer multinucleate fast muscle fibres than wt and show a significant expansion of the Pax7+ MPC population in the DM. Subsequently, myodfh261 mutant fibres generate more cytoplasm per nucleus, leading to recovery of muscle bulk. In addition, relative to wt siblings, there is an increased number of MPCs in myodfh261 mutants and these migrate prematurely into the myotome, differentiate and contribute to the hypertrophy of existing fibres. Thus, homeostatic reduction of the excess MPCs returns their number to normal levels, but fibre numbers remain low. The GSK3 antagonist BIO prevents MPC migration into the deep myotome, suggesting that canonical Wnt pathway activation maintains the DM in zebrafish, as in amniotes. BIO does not, however, block recovery of the myodfh261 mutant myotome, indicating that homeostasis acts on fibre intrinsic growth to maintain muscle bulk. The findings suggest the existence of a critical window for early fast fibre formation followed by a period in which homeostatic mechanisms regulate myotome growth by controlling fibre size. The feedback controls we reveal in muscle help explain the extremely precise grading of myotome size along the body axis irrespective of fish size, nutrition and genetic variation and may form a paradigm for wider matching of organ size. PMID- 28887019 TI - Are We Still Prescribing Opioids for Osteoarthritis? AB - BACKGROUND: The United States is in the midst of an opioid epidemic. These medications continue to be used to manage pain associated with osteoarthritis, despite mounting evidence questioning the benefits. The rate at which opioids are prescribed for osteoarthritis is largely unknown. We sought to identify rates of opioid prescriptions for osteoarthritis and identify factors associated with higher rates of prescribing. METHODS: We queried the Humana, Inc. administrative claims database from 2007 to 2014. Patients with osteoarthritis were identified using International Classification of Diseases 9th Revision codes and classified as having hip, knee, or any joint osteoarthritis. Claims data were reviewed to identify opioid prescriptions associated with a diagnosis of osteoarthritis. Rates of prescribing were trended over time and stratified by sex, age, and geographic region. RESULTS: From 2007 to 2014, 17.0% of patients with any joint osteoarthritis, 13.4% of patients with hip osteoarthritis, and 15.9% with knee osteoarthritis were prescribed an opioid for their condition. Yearly rates of prescription were fairly stable over this period. Patients in the South had the highest odds of opioid prescription, while those in the Northeast had the lowest. Patients <=49 years old were more likely to receive a prescription than those >=50 years old. CONCLUSION: This study provides important epidemiologic data about the use of opioids for osteoarthritis. Despite increasing evidence calling proposed benefits into question and increasing awareness of risks of opioids, prescribing rates remained stable between 2007 and 2014. This provides important baseline data as we work to combat excessive and inappropriate opioid use within the United States. PMID- 28887018 TI - DPP9 enzyme activity controls survival of mouse migratory tongue muscle progenitors and its absence leads to neonatal lethality due to suckling defect. AB - Dipeptidyl peptidase 9 (DPP9) is an intracellular N-terminal post-proline cleaving enzyme whose physiological function remains largely unknown. We investigated the role of DPP9 enzyme in vivo by characterizing knock-in mice expressing a catalytically inactive mutant form of DPP9 (S729A; DPP9ki/ki mice). We show that DPP9ki/ki mice die within 12-18h after birth. The neonatal lethality can be rescued by manual feeding, indicating that a suckling defect is the primary cause of neonatal lethality. The suckling defect results from microglossia, and is characterized by abnormal formation of intrinsic muscles at the distal tongue. In DPP9ki/ki mice, the number of occipital somite-derived migratory muscle progenitors, forming distal tongue intrinsic muscles, is reduced due to increased apoptosis. In contrast, intrinsic muscles of the proximal tongue and extrinsic tongue muscles, which derive from head mesoderm, develop normally in DPP9ki/ki mice. Thus, lack of DPP9 activity in mice leads to impaired tongue development, suckling defect and subsequent neonatal lethality due to impaired survival of a specific subset of migratory tongue muscle progenitors. PMID- 28887020 TI - Narcotic Use and Total Knee Arthroplasty. AB - BACKGROUND: Although the United States is in the midst of a narcotic epidemic, risk factors for use and the impact of perioperative narcotic use on total knee arthroplasty (TKA) outcomes is ill-defined. METHODS: A national database was queried for patients who underwent primary TKA from 2007 to 2015. Patients taking narcotics in the preoperative, and for a prolonged period of time postoperatively, were identified. The risk factors for prolonged narcotic use were analyzed with a regression analysis, in addition to evaluating preoperative and prolonged postoperative use as independent risk factors for short-term and long-term complications. RESULTS: In total, 113,337 patients met inclusion criteria, of which 31,733 patients were prescribed narcotics preoperatively and 35,770 patients were prescribed narcotics more than 3 months postoperatively. There are several independent risk factors for prolonged narcotic use postoperatively, the most significant being the number of narcotic prescriptions prescribed preoperatively. Preoperative narcotic use was independently associated with an increased risk of emergency room visits, readmission, infection, stiffness, and aseptic revision. Prolonged postoperative use was also associated with significantly increased rates of infection, stiffness, and aseptic revision. CONCLUSION: Preoperative and prolonged narcotic use following TKA was associated with an increased risk of short-term and long-term complications following TKA. The liberal use of narcotics in the perioperative period should be considered a modifiable risk factor when considering elective TKA. PMID- 28887021 TI - Improving Value in Total Joint Arthroplasty: A Comprehensive Patient Education and Management Program Decreases Discharge to Post-Acute Care Facilities and Post Operative Complications. AB - BACKGROUND: A step-by-step approach to creating a comprehensive patient education, expectation, and management program is described with the aim of reducing discharges to post-acute care centers (PACs) following total joint arthroplasty (TJA). We hypothesized that by lowering discharges to PACs, readmissions and reoperations would also decrease. METHODS: Following the implementation of a multi-faceted patient education and management program, we retrospectively reviewed 927 TJAs who underwent surgery 12 months before (n = 465) and after (n = 462) the program was implemented. To assess the exposure of the pathway on discharge disposition as well as institutional 30-day and 90-day readmissions and reoperations, a modified Poisson regression was used. RESULTS: There was a 20% absolute reduction in discharges to PACs (<0.001). The frequency of 30-day readmissions was greater in patients who underwent TJA before implementation (incidence rate ratio [IRR] 1.93, 95% confidence interval [CI] 1.01-3.69). The risk for 90-day readmissions (IRR 1.70, 95% CI 1.20-2.40) and reoperations (IRR 1.67, 95% CI 1.12-2.53) was greater prior to implementation. Discharge to PACs was associated with 2.4 and 3.10 times greater risk for 30-day readmissions (95% CI 1.28-4.56) and 30-day reoperations (95% CI 1.40-7.0), respectively. Patients discharged to PACs were also at greater risk for both 90 day readmissions (IRR 1.59, 95% CI 1.08-2.32) and 90-day reoperations (IRR 1.75, 95% CI 1.12-2.73). CONCLUSION: Our program led to a reduction in the number of patients being discharged to PACs following TJA, while also demonstrating a reduction in readmission and reoperations. Additionally, discharge to these facilities was an independent risk factor for these complications. PMID- 28887022 TI - Additive Influence of Hip Offset and Leg Length Reconstruction on Postoperative Improvement in Clinical Outcome After Total Hip Arthroplasty. AB - BACKGROUND: There is a lack of prospective studies investigating the additive effect of both acetabular and femoral reconstruction parameters on the functional outcome following total hip arthroplasty (THA). METHODS: The aim of this prospective cohort study was to determine the combined influence of hip geometry reconstruction and component positioning on the clinical outcome following primary THA for unilateral osteoarthritis. We prospectively assessed the clinical outcome and radiographic parameters for hip geometry reconstruction, component position, and orientation using validated measurements for the operated hip compared to the contralateral native hip in a consecutive series of 113 patients with primary unilateral cementless THA. The correlation of reconstruction parameters was investigated using a multivariate polynomial regression model for the dependent variable DeltaHHS (difference between the Harris hip scores preoperatively and 2.0-4.8 years postoperatively). Target zones for hip reconstruction and component positioning were investigated for an association with superior clinical outcome. RESULTS: The regression model demonstrated a significant correlation for the DeltaHHS and both hip offset (HO) reconstruction and leg length difference. Patients with accurate to slightly increased HO reconstruction combined with balanced leg length demonstrated a significantly higher DeltaHHS than patients outside this zone (HO: 5 +/- 5 and LLD: 0 +/-5 mm, P = .029). This finding could be confirmed for 2 enlarged zones (zone 1: HO, 7.5 +/- 7.5 and LLD, 2.5 +/- 7.5 mm, P = .028; zone 2: HO, 7.5 +/- 7.5 and LLD, 7.5 +/- 7.5 mm, P = .007). CONCLUSION: HO and leg length reconstruction demonstrated an additive effect on clinical outcome and surgeons should aim for high accuracy in the reconstruction of both factors. PMID- 28887023 TI - Chronic Kidney Diseases Among Patients Undergoing Elective Arthroplasty: Risk Groups and the Value of Serum Creatinine. AB - BACKGROUND: In arthroplasty clinics, we tend to evaluate patient's kidney function looking at serum creatinine (SCr), while estimated glomerular filtration rate (eGFR) is recommended. We reported the prevalence of chronic kidney disease (CKD; eGFR <60 mL/min/1.73 m2) in different patient groups and investigated whether CKD is missed by evaluation based on SCr. METHODS: Preoperative SCr values were used to calculate eGFR in 20,575 consecutive hip or knee arthroplasties. RESULTS: Prevalence of CKD was 9%-12%. It was higher among older women, knee arthroplasty patients, and patients with hypertension, diabetes, or coronary disease. Using SCr instead of eGFR leads to missing CKD in up to 7% of the cases. In older women and older patients with body mass index <25 kg/m2, half of CKD cases were missed. CONCLUSION: Use of eGFR instead of SCr to detect CKD more accurately is recommended. PMID- 28887024 TI - Are Trends in Total Hip Arthroplasty Bearing Surface Continuing to Change? 2007 2015 Usage in a Large Database Cohort. AB - BACKGROUND: Bearing surface issues related to trunnionosis or metal-on-metal (MoM) articulations have likely impacted recent trends in bearing surface choice. The purpose of this study is to evaluate trends in total hip arthroplasty (THA) bearing surface use, including 2015 data, with respect to the date of operation and patient demographics. METHODS: The Humana dataset was reviewed from 2007 through 2015 to analyze bearing surface usage in primary THA. Four bearing surface types were identified by International Classification of Disease, 10th Revision codes and trended throughout the years: metal-on-polyethylene (MoP), ceramic-on-ceramic (CoC), ceramic-on-polyethylene (CoP), and MoM. Prevalence was analyzed as a function of age and sex. RESULTS: Of the 28,504 primary THA procedures, the most commonly used bearing was MoP (46.1%), followed by CoP (33.2%), MoM (17.1%), and ceramic-on-ceramic (3.6%). The use of CoP bearings significantly increased from 6.4% in 2007 to 52.0% in 2015, while MoM bearings decreased during this period. MoP bearings decreased over 2012-2015 (P < .001). CoP usage decreased with age, while MoP bearings increased with a transition occurring at 65-69 years of age. Women were more likely to receive MoP bearings (odds ratio [OR] 1.2), while men were more likely to receive MoM and CoP bearings (OR 1.1). Multivariate logistic regression showed age to be an independent predictor of bearing surface choice with patients 65 and older more likely to receive MoP bearings (OR 3.2). CONCLUSION: Bearing surface choice in primary THA has changed tremendously from 2007 to 2015. MoM bearing use has decreased as a result of adverse effects. Age continues to remain a significant factor in bearing surface choice. PMID- 28887025 TI - Tryptone-stabilized gold nanoparticles target tubulin and inhibit cell viability by inducing an unusual form of cell cycle arrest. AB - Gold nanoparticles have been investigated extensively for their molecular mechanisms of action and anticancer potential. We report a novel, tubulin targeted antiproliferative mechanism of action of tryptone-stabilized gold nanoparticles (TsAuNPs). TsAuNPs, synthesized using HAuCl4.3H2O and tryptone and characterized by a variety of spectroscopic methods and transmission electron microscopy, were found to be inhibitory to viability of human pancreatic (PANC 1), cervical (HeLa), and breast (MDA-MB-231) cancer cell lines in a concentration dependent manner, with highest efficacy against PANC-1 cells. The particles strongly inhibited the clonogenic propagation of PANC-1 cells. TsAuNPs-mediated inhibition of cell viability involved an unusual mode of cell cycle arrest (arrest at both G0/G1 phase and S-phase) followed by apoptosis. In vitro, TsAuNPs bound purified tubulin, competitively inhibited anilinonaphthalene sulfonate binding to tubulin, and suppressed tubulin assembly. In cells, tubulin-TsAuNPs interactions were manifested as a disrupted microtubule network, defective reassembly of cold-disassembled microtubules, and induction of tubulin acetylation. Our data indicate that TsAuNPs inhibit cell viability by inducing differential cell cycle arrest possibly through disrupted dynamicity of cellular microtubules. PMID- 28887026 TI - Beyond Read-Counts: Ribo-seq Data Analysis to Understand the Functions of the Transcriptome. AB - By mapping the positions of millions of translating ribosomes in the cell, ribosome profiling (Ribo-seq) has established its role as a powerful tool to study gene expression. Several laboratories have introduced modifications to the experimental protocol and expanded the repertoire of biochemical methods to study translation transcriptome-wide. However, the diversity of protocols highlights a need for standardization. At the same time, different computational analysis strategies have used Ribo-seq data to identify the set of translated sequences with high confidence. In this review we present an overview of such methodologies, outlining their assumptions, data requirements, and availability. At the interface between RNA and proteins, Ribo-seq can complement data from multiple omics approaches, zooming in on the central role of translation in the molecular cell. PMID- 28887027 TI - Accurate eGFR reporting for children without anthropometric data. AB - INTRODUCTION: Reporting estimated glomerular filtration rate (eGFR) instead of serum concentrations is advised in current guidelines. Most creatinine-based eGFR equations for children require height, a parameter not readily available to laboratories. Combining height-dependent creatinine- and cystatin C-based eGFR improves performance. Recently, a height-independent creatinine-based eGFR equation has been developed. AIM: To compare the combination of height independent creatinine- and cystatin C-based equations with a combination of equations using anthropometric data. METHODS: Retrospective analysis of 408 pediatric inulin clearance studies with simultaneous height, creatinine, cystatin C and urea measurements. eGFR calculation using the recalibrated Schwartzcrea (height-dependent), FASage (height-independent) and the Schwartzcys equation. The means (Schwartzcrea+Schwartzcys)/2 and (FASage+Schwartzcys)/2 were compared with the CKiD3 equation incorporating cystatin C, creatinine, urea, height and gender in terms of %prediction error and accuracy. RESULTS: All three single parameter equations performed similarly (P30 accuracy around 80%). (FASage+Schwartzcys)/2 (P30 89.2%) and (Schwartzcrea+Schwartzcys)/2 (P30 89.0%), performed comparably to CKiD3 (P30 90.0%). If the difference between the creatinine- and the cystatine C based eGFR was <40%, P30 accuracy of the mean exceeded 90%. CONCLUSION: Combining the height-independent FASage and SchwartzCys equations substantially improves accuracy and performs comparably to height-dependent equations. This allows laboratories to directly report eGFR in children. PMID- 28887028 TI - FVIIa-antithrombin levels in early and late preeclampsia. AB - BACKGROUND: Preeclampsia (PE) is associated with a hypercoagulability state. According to the gestational age (GA) at the onset of the disease, PE has been classified as early (GA<34weeks) and late (GA>=34weeks). It has been admitted that early PE is associated with ischemic placental lesions, while in late PE an adequate or slightly impaired placentation occurs, which suggests that the two clinical forms have distinct etiology. Tissue factor (TF) binds and activates plasma factor VII triggering the coagulation. The inhibitor antithrombin (AT), along with tissue factor pathway inhibitor, acts as an inhibitor of the FVIIa-TF pathway. Once the TF-FVIIa complex is formed, the binding and transfer of FVIIa to AT is facilitated and FVIIa activity is inhibited. OBJECTIVE: We evaluated the FVIIa-AT complex levels in pregnant women with early and late severe PE (sPE), in order to verify if this biomarker can be useful for discriminating the two forms of the disease. METHODS: We evaluated 26 pregnant with severe early PE and 19 pregnant with severe late PE. FVIIa-AT levels were measured by STACLOT(r) (Diagnostica Stago). Statistical analysis was done by Mann-Whitney test. RESULTS: Increased FVIIa-AT levels were found in early sPE [148.4pM (137.1)] compared to late sPE [95.9pM (66.5)] (P=0.046), which suggests a higher pro-coagulant state when PE onset occurs before 34weeks of gestation. CONCLUSION: These pioneer data allow inferring the relevance of FVIIa-AT as a device for early sPE diagnosis. However, the clinical relevance of FVIIa-AT complex surely needs to be fully clarified. PMID- 28887029 TI - Urocortins: Actions in health and heart failure. AB - The urocortins (Ucns), endogenous peptides belonging to the corticotropin releasing factor (CRF) family, are increasingly recognized as having diverse and important multi-system functions, especially within the cardiovascular system. The biological actions of the three Ucns (Ucn1, Ucn2, Ucn3) are mediated via G protein-coupled CRF receptors, with both peptides and receptors widely distributed throughout tissues and organs contributing to pressure/volume homeostasis including the heart, vasculature, kidneys and adrenals. The Ucns activate a variety of signaling cascades in cardiomyocytes, vascular smooth muscle cells and endothelial cells including, but not limited to, adenyl cyclase/cAMP and several kinase pathways, with downstream effects comprising vasodilation, augmented cardiac contractility, and protection against hypoxic injury. Increasing evidence suggests the Ucns may be clinically significant molecules in the pathogenesis, treatment and/or management of several conditions, with some of the most compelling data demonstrating a therapeutic potential for the peptides in the setting of heart failure. Circulating levels of the Ucns are elevated in this setting, and antagonism of the endogenous peptides exacerbates manifestations of the syndrome in animal models. All three Ucns exert salutary hemodynamic, neurohormonal and renal effects in experimental heart failure and recent clinical trials have demonstrated hemodynamic benefits of Ucn2 administration. PMID- 28887030 TI - Association of Picky Eating With Weight Status and Dietary Quality Among Low Income Preschoolers. AB - BACKGROUND: Picky eating is common in children. Few studies have examined predictors of picky eating, and the association of picky eating with weight status and dietary quality is inconsistent in the literature. We aimed to identify predictors of picky eating and to test the association of picky eating with child body mass index z-score (BMIz), dietary quality, and micronutrient intake. METHODS: This was a cross-sectional analysis of baseline data from a randomized controlled trial to prevent obesity among 506 preschoolers attending Head Start. Parents completed questionnaires to assess picky eating and child temperament. Three 24-hour dietary recalls were collected to assess dietary intake. Multivariate regression models assessed child, parent, and family predictors of picky eating; additional models tested adjusted associations of picky eating with child BMIz, dietary quality (measured using the Healthy Eating Index-2010), and micronutrient intake. RESULTS: Picky eating was predicted by male sex, older child age, and more difficult temperament but not race/ethnicity, maternal body mass index, maternal depressive symptoms, household food insecurity, or single parent home. Picky eating was not associated with child BMIz or micronutrient deficiencies; it was inversely associated with total Healthy Eating Index-2010 score and servings of whole fruit, total vegetables, greens and beans, and total protein foods. CONCLUSIONS: Pediatric providers should support parents in expanding the number of healthy foods the child eats to improve dietary quality, but reassure parents that picky eating is not associated with children's weight status or micronutrient deficiencies. PMID- 28887031 TI - The C. elegans mRNA decapping enzyme shapes morphology of cilia. AB - Cilia and flagella are evolutionarily conserved organelles that protrude from cell surfaces. Most cilia and flagella are single rod-shaped but some cilia show a variety of shapes. For example, human airway epithelial cells are multiciliated, flagella of crayfish spermatozoon are star-like shaped, and fruit fly spermatozoon extends long flagella. In Caenorhabditis elegans, cilia display morphological diversity of shapes (single, dual rod-type and wing-like and highly branched shapes). Here we show that DCAP-1 and DCAP-2, which are the homologues of mammalian DCP1 and DCP2 mRNA decapping enzymes, respectively, are involved in formation of dual rod-type and wing-like shaped cilia in C. elegans. mRNA decapping enzyme catalyzes hydrolysis of 5' cap structure of mRNA, which leads to degradation of mRNA. Rescue experiments showed that DCAP-2 acts not in glial cells surrounding cilia but in neurons. This is the first evidence to demonstrate that mRNA decapping is involved in ciliary shape formation. PMID- 28887032 TI - Electrostatic differences: A possible source for the functional differences between MCF7 and brain microtubules. AB - Recent studies suggested a link between diversity of beta tubulin isotypes in microtubule structures and the regulatory roles that they play not only on microtubules' intrinsic dynamic, but also on the translocation characteristics of some of the molecular motors along microtubules. Remarkably, unlike porcine brain microtubules, MCF7 microtubules are structured from a different beta tubulin distribution. These types of cancer microtubules show a relatively stable and slow dynamic. In addition, the translocation parameters of some molecular motors are distinctly different along MCF7 as compared to those parameters on brain microtubules. It is known that the diversity of beta tubulin isotypes differ predominantly in the specifications and the electric charge of their carboxy terminal tails. A key question is to identify whether the negative electrostatic charge of tubulin isotypes and, consequently, microtubules, can potentially be considered as one of the sources of functional differences in MCF7 vs. brain microtubules. We tested this possibility experimentally by monitoring the electro orientation of these two types of microtubules inside a uniform electric field. Through this evaluation, we quantified and compared the average normalized polarization coefficient of MCF7 vs. Porcine brain microtubules. The higher value obtained for the polarization of MCF7 microtubules, which is associated to the higher negative charge of these types of microtubules, is significant as it can further explain the slow intrinsic dynamic that has been recently reported for single MCF7 microtubules in vitro. Furthermore, it can be potentially considered as a factor that can directly impact the translocation parameters of some molecular motors along MCF7 microtubules, by altering the mutual electrostatic interactions between microtubules and molecular motors. PMID- 28887033 TI - Long-term exposure to PM2.5 lowers influenza virus resistance via down-regulating pulmonary macrophage Kdm6a and mediates histones modification in IL-6 and IFN beta promoter regions. AB - Atmospheric particulates, especially PM2.5, not only damage the respiratory system, but also play important roles in pulmonary immunity. China is influenced by atmospheric diffusion conditions, industrial manufacturers, and heating and discharging. PM2.5 levels in the air rise substantially in the winter, which is also a period of flu high-incidence. Although an epidemiological link exists between PM2.5 and flu, we do not understand how long-term PM2.5 inhalation affects pulmonary immunity and the influenza virus response. Our study has prepared an in vivo PM2.5 mouse pharyngeal wall drop-in model and has found that PM2.5 exposure leads to mouse inflammatory injuries and furthers influenza A infection. Our results suggest that short-term exposure to PM2.5 significantly enhances the survival rate of influenza A-contaminated mice, while long-term PM2.5 inhalation lowers the capacity of pulmonary macrophages to secrete IL-6 and IFN-beta. A disorder in the pulmonary innate defense system results in increased death rates following influenza infection. On a macromolecular level, this mechamism involves Kdm6a down-regulation after long-term exposure to PM 2.5 and a resultant increase in H3K4 and H3K9 methylation in IL-6 and IFN-beta promoter regions. In summary, PM2.5 causes injuries of lung tissue cells and downregulates immune defense mechanisms in the lung. PMID- 28887034 TI - A novel gene, cilia flagella associated protein 44, encoding an enzyme cleaving FtsZ and tubulin contributes to the regulation of secretory pathway. AB - We identified a novel gene, encoding the central region of the cilia and flagella associated protein 44 (Cfap44), that regulates trafficking of cellular components and morphology via the cleavage of cellular proteins (particularly beta-tubulin). Although Cfap44 is registered in GenBank, the functions of both the central part and full-length protein are unknown except for a polymorphism associated with proprotein convertase 9 activity, the third gene of familiar hyper cholesterolemia. In mice and humans, both unspliced and spliced RNAs were transcribed, and the spliced form was predominantly transcribed in the brain and embryonic tissues. In transfectants carrying this gene, various cellular processes such as cell division, transport of cellular components, and proteolytic processing of several proteins were found to be affected. The cleavage of beta-tubulin was observed. A bacterial tubulin homolog, cell division protein FtsZ, was also cleaved in vivo and in vitro by the spliced form of Cfap44 product. Furthermore, the unspliced form showed proteolytic activity with low substrate specificity. Various biological activities of Cfap44 may be due to a direct effect of cleavage of beta-tubulin inhibiting microtubule formation, or an indirect effect with the cross-recognition of the cleavage site between beta tubulin and other molecules. PMID- 28887035 TI - Detergent-resistant oligomeric Leptosphaeria rhodopsin is a promising bio nanomaterial and an alternative to bacteriorhodopsin. AB - Bacteriorhodopsin has attracted remarkable attention as a photoactive bio nanomaterial in the last decades. However, its instability in the presence of detergents has restricted the extent to which bacteriorhodopsin may be applied. In this study, we investigated the oligomerization of a eukaryotic light-driven H+-pump, Leptosphaeria rhodopsin, using circular dichroism spectroscopy and other biophysical and biochemical methods. Our findings revealed that Leptosphaeria rhodopsin assembled into oligomers in the cell membrane and also in 0.05% DDM detergent micelles. Moreover, unlike bacteriorhodopsin in purple membrane, Leptosphaeria rhodopsin retained its oligomeric structure in 1% Triton X-100 and demonstrated strong resistance to other common detergents. A maximal photocurrent density of ~85 nA/cm2 was consistently generated, which was substantially larger than that of solubilized bacteriorhodopsin (~10 nA/cm2). Therefore, oligomeric Leptosphaeria rhodopsin may be a promising bio-nanomaterial, and an alternative to bacteriorhodopsin, especially with the use of detergents. PMID- 28887036 TI - Autocrine STIP1 signaling promotes tumor growth and is associated with disease outcome in hepatocellular carcinoma. AB - Stress-induced phosphoprotein 1 (STIP1) is an adaptor protein that bridges between HSP70 and HSP90 folding and a secretory protein which regulates malignant cell growth. However, the role of STIP1 in hepatocellular carcinoma (HCC) remains unknown. Here, we found high expression of STIP1 in tumors was associated with worse overall survival (41.3 vs 62.7 months, P < 0.001) in 231 HCC patients. STIP1 was overexpressed in HCC tissues compared to adjacent non-tumor liver tissue (64.9% vs 4.0% P < 0.001), and serum STIP1 levels of HCC patients were elevated compared to healthy controls (P < 0.001). Mechanistically, STIP1 promoted HCC growth through PI3K-AKT-dependent anti-apoptotic pathway. STIP1 mediated cell growth in an autocrine fashion, which could be suppressed either by neutralizing extracellular STIP1 or by knocking down intracellular STIP1. In xenograft mouse model, knockdown of STIP1 significantly reduced tumor growth (P < 0.001). In conclusion, STIP1 is upregulated in HCC and associated with poor clinical prognosis. Blocking STIP1 activity suppresses HCC cell growth, providing the rationale for STIP1 as a potential therapeutic target in HCC. PMID- 28887037 TI - Cholecalciterol cholesterol emulsion attenuates experimental autoimmune myocarditis in mice via inhibition of the pyroptosis signaling pathway. AB - 1,25-dihydroxyvitamin D3 and its analog (paricalcitol) have beneficial effects on multiple systems and diseases, including myocarditis. However, the therapeutic effect of cholecalciterol cholesterol emulsion (CCE) on myocarditis and the role of pyroptosis in the progress of myocarditis have not been determined. The objective of this study was to investigate the effect of CCE on experimental autoimmune myocarditis and its underlying mechanisms. The ratio of heart weight to body weight was decreased after CCE treatment compared with vehicle-treated controls. In addition, CCE improved the general status of mice, suppressed myocardial apoptosis, and inhibited the pyroptosis signaling pathway. Therefore, CCE can ameliorate experimental autoimmune myocarditis by downregulating the pyroptosis signaling pathway. PMID- 28887038 TI - Resveratrol protects against mitochondrial dysfunction through autophagy activation in human nucleus pulposus cells. AB - Intervertebral disc degeneration (IVDD) is closely related with aging, whereas mitochondrial damage is a common feature of aging that results in cell apoptosis. Resveratrol (RES) is a natural antioxidant that protects against mitochondrial dysfunction in various cells. This study aimed to investigate the protective role of RES against mitochondrial dysfunction and human nucleus pulposus cell (NPC) apoptosis. We found that mitochondrial dysfunction and NPC apoptosis could be induced under oxidative stress by 100 MUmol/l of H2O2. However, RES tended to attenuate the H2O2-mediated cytotoxicity. Therefore, autophagic state was evaluated in NPCs to further reveal the underlying mechanism. Results showed that RES reversed the impaired autophagy induced by H2O2, and this increased autophagic flux was confirmed by the addition of bafilomycin A1. Moreover, pretreatment with 3-methyladenine showed that the potential mechanism of RES to prevent deteriorating mitochondrial function and cell apoptosis was related to autophagy activation. Furthermore, MRI and histological detection were employed to provide more solid evidence that RES injection in an IVDD rabbit model effectively retards the degenerative process of the intervertebral discs in vivo. In summary, these results suggested that RES could alleviate mitochondrial dysfunction and cell apoptosis under oxidative stress and may delay the progression of disc degeneration, whose mechanism is associated with an advantageous role of autophagy induced by RES. PMID- 28887039 TI - Activation of the HMGB1-RAGE axis upregulates TH expression in dopaminergic neurons via JNK phosphorylation. AB - The derangement of tyrosine hydroxylase (TH) activity reduces dopamine synthesis and is implicated in the pathogenesis of Parkinson's disease. However, the extracellular modulator and intracellular regulatory mechanisms of TH have yet to be identified. Recently, high-mobility group box 1 (HMGB1) was reported to be actively secreted from glial cells and is regarded as a mediator of dopaminergic neuronal loss. However, the mechanism for how HMGB1 affects TH expression, particularly through the receptor for advanced glycation endproducts (RAGE), has not yet been investigated. We found that recombinant HMGB1 (rHMGB1) upregulates TH mRNA expression via simultaneous activation of JNK phosphorylation, and this induction of TH expression is blocked by inhibitors of RAGE and JNK. To investigate how TH expression levels change through the HMGB1-RAGE axis as a result of MPP+ toxicity, we co-treated SN4741 dopaminergic cells with MPP+ and rHMGB1. rHMGB1 blocked the reduction of TH mRNA following MPP+ treatment without altering cell survival rates. Our results suggest that HMGB1 upregulates TH expression to maintain dopaminergic neuronal function via activating RAGE, which is dependent on JNK phosphorylation. PMID- 28887040 TI - Roles of antibodies to influenza A virus hemagglutinin, neuraminidase, and M2e in conferring cross protection. AB - Although neuraminidase (NA) is the second major viral glycoprotein of influenza virus, its immune mechanism as a vaccine target has been less considered. Here we compared the properties of antibodies and the efficacy of cross protection by N1 and N2 NA proteins, inactivated split influenza vaccines (split), and tandem repeat extracellular domain M2 on virus-like particles (M2e5x VLP). Anti-NA immune sera could confer better cross-protection against multiple heterologous influenza viruses correlating with NA inhibition activity compared to split vaccine immune sera. Whereas split vaccine was superior to NA in conferring homologous protection. NA and M2e immune sera each showed comparable survival protection. Protective efficacy by NA immune sera was lower in Fc receptor common gamma-chain deficient mice but comparable in C3 complement deficient mice compared to that in wild type mice, suggesting a role of Fc receptor in NA immunity. PMID- 28887041 TI - Partial anomalous pulmonary venous connection in a dog. AB - A 2-year-old male intact Belgian Malinois was presented for exercise intolerance. A grade III/VI left basilar systolic murmur was detected. Echocardiography revealed moderate right atrial and ventricular dilation and increased pulmonic outflow velocity. Thoracic radiographs showed right heart enlargement and a dilated caudal vena cava. In addition, on the left lateral projection, an enlarged aberrant right cranial pulmonary lobar vein was suspected to be diverging ventrally from the course of the right cranial lobar bronchus and inserting more ventrally than normal in the region of the right atrium. A left-to right pulmonary vascular shunt was suspected, and the patient underwent further diagnostics under general anesthesia. An agitated saline study was positive, suggestive of a concurrent right to left shunt. A right heart catheterization was performed. Angiography was inconclusive. Oximetry testing revealed an increase in oxygen saturation within the right atrium at the level of the caudal cava supportive of a left-to-right shunt in this region. Computed tomography angiography revealed a large single pulmonary vein that anomalously entered into the caudolateral aspect of the right atrium (left-to-right shunt) and was suspicious for a small arteriovenous malformation between the right caudal pulmonary artery and the right pulmonary vein returning to the left atrium (right to left shunt). The patient was diagnosed with a partial anomalous pulmonary venous connection and a possible arteriovenous malformation. PMID- 28887042 TI - Hinokitiol copper complex inhibits proteasomal deubiquitination and induces paraptosis-like cell death in human cancer cells. AB - The ubiquitin-proteasome system (UPS) plays a central role in the regulation of proteins that control cell growth and apoptosis and has therefore become an important target for anticancer therapy. Several constitutive subunits of the 19S proteasome display deubiquitinase (DUB) activity, suggesting that ubiquitin modification of proteins is dynamically regulated. Our study and others have shown that metal complexes, such as copper complexes, can induce cancer cell apoptosis through inhibiting 19S proteasome-associated DUBs and/or 20S proteasome activity. In this study, we found that (1) Hinokitiol copper complex (HK-Cu) induces striking accumulation of ubiquitinated proteins in A549 and K562 cells (2) HK-Cu potently inhibits the activity of the 19S proteasomal DUBs much more effectively than it does to the chymotrypsin-like activity of the 20S proteasome (3) HK-Cu effectively induces caspase-independent and paraptosis-like cell death in A549 and K562 cells, and (4) HK-Cu-induced cell death depends on ATF4 assosiated ER stress but is apparently not related to ROS generation. Altogether, these data indicate that HK-Cu can inhibit the activity of the 19S proteasomal DUBs and induce paraptosis-like cell death, representing a new drug candidate for cancer treatment. PMID- 28887043 TI - Planar bile acids in health and disease. AB - Bile acids are the amphipathic primary end-products of cholesterol metabolism that aid in digestion as well as participate in signal transduction in several hepatic and enteric pathways. Despite the reputation of bile acids as signaling molecules implicated in disease states such as cancer and diabetes, there remain numerous bile acid species that are weakly characterized in either physiological or pathological conditions. This review presents one such group: the flat or planar bile acids, a set of bile acids found in humans during infancy and occurring again during certain diseases. As their name implies, these molecules are structurally distinct from the typical human bile acids, retaining the planar structure of their cholesterol predecessor instead of bending or twisting at the A ring. This review defines these species of bile acids in detail and describes their presence in infancy, gestation, and in disease. The large gaps in research regarding the flat bile acids are highlighted and all available experimental knowledge collected as far as 60years ago is summarized. Further, the potential for these molecules as endogenous biomarkers of liver disease and injury is discussed. Finally, the flat bile salts found in humans are compared to the ancestral and evolutionary older bile salts, which similarly have a flat steroidal structure, as mechanisms of flat bile acid biosynthesis are explored. PMID- 28887044 TI - Biochemical and biophysical properties of positively supercoiled DNA. AB - In this paper we successfully developed a procedure to generate the (+) supercoiled (sc) plasmid DNA template pZXX6 in the milligram range. With the availability of the (+) sc DNA, we are able to characterize and compare certain biochemical and biophysical properties of (+) sc, (-) sc, and relaxed (rx) DNA molecules using different techniques, such as UV melting, circular dichroism, and fluorescence spectrometry. Our results show that (+) sc, (-) sc, and rx DNA templates can only be partially melted due to the fact that these DNA templates are closed circular DNA molecules and the two DNA strands cannot be completely separated upon denaturation at high temperatures. We also find that the fluorescence intensity of a DNA-binding dye SYTO12 upon binding to the (-) sc DNA is significantly higher than that of its binding to the (+) sc DNA. This unique property may be used to differentiate the (-) sc DNA from the (+) sc DNA. Additionally, we demonstrate that E. coli topoisomerase I cannot relax the (+) sc DNA. In contrast, E. coli DNA gyrase can efficiently convert the (+) sc DNA to the (-) sc DNA. Furthermore, our dialysis competition assays show that DNA intercalators prefer binding to the (-) sc DNA. PMID- 28887045 TI - The molten-globule residual structure is critical for reflavination of glucose oxidase. AB - Glucose oxidase (GOX) is a homodimeric glycoprotein with tightly bound one molecule of FAD cofactor per monomer of the protein. GOX has numerous applications, but the preparation of biotechnologically interesting GOX sensors requires a removal of the native FAD cofactor. This process often leads to unwanted irreversible deflavination and, as a consequence, to the low enzyme recovery. Molecular mechanisms of reversible reflavination are poorly understood; our current knowledge is based only on empiric rules, which is clearly insufficient for further development. To develop conceptual understanding of flavin-binding competent states, we studied the effect of deflavination protocols on conformational properties of GOX. After deflavination, the apoform assembles into soluble oligomers with nearly native-like holoform secondary structure but largely destabilized tertiary structure presumambly due to the packing density defects around the vacant flavin binding site. The reflavination is cooperative but not fully efficient; after the binding the flavin cofactor, the protein directly disassembles into native homodimers while the fraction of oligomers remains irreversibly inactivated. Importantly, the effect of Hofmeister salts on the conformational properties of GOX and reflavination efficiency indicates that the native-like residual tertiary structure in the molten-globule states favorably supports the reflavination and minimizes the inactivated oligomers. We interpret our results by combining the ligand-induced changes in quaternary structure with salt-sensitive, non-equilibrated conformational selection model. In summary, our work provides the very first steps toward molecular understanding the complexity of the GOX reflavination mechanism. PMID- 28887046 TI - Effect of amino acids near the RGD sequence on binding activities between alphaIIbbeta3 integrin and fibrinogen in the presence of RGD-containing synthetic peptides from elegantin and angustatin. AB - Elegantin and angustatin, which were isolated from the snake venoms of Protobothrops elegans and Dendroaspis angusticeps, markedly inhibit binding between platelet integrins and fibrinogen via the Arg-Gly-Asp (RGD) sequence. Angustatin, which is a three-finger toxin containing the RGD sequence, inhibits platelet aggregation almost ten times more strongly than disintegrin isolated from the venoms of Viperidae and Crotalidae. The RGD sequences of both polypeptides are located at the top of hairpin loops, and the composition of the RGD loop is very important for binding to integrin. We investigated the effects of synthetic RGD loop peptides from angustatin and elegantin on ADP- or collagen induced platelet aggregation and alphaIIbbeta3-fibrinogen binding. Synthetic angustatin (PRGDMP)-type peptides inhibited platelet aggregation more strongly than elegantin (ARGDDX)-type peptides. In particular, the cyclic angustatin peptide (CPRGDMPC) inhibited ADP- and collagen-induced platelet aggregation at least 10-50 times more strongly than the other peptides. The cyclic angustatin peptide (CPRGDMPC) was also the strongest inhibitor of binding between alphaIIbbeta3 and fibrinogen, the IC50 of this peptide was approximately 2.58MUM. Regarding the inhibition of binding between alphaIIbbeta3 and fibrinogen, CPRGDMPC demonstrated a stronger inhibitory and more stable effect in the presence of Mg2+ than in the presence of Ca2+. PMID- 28887047 TI - Peptides from frog skin with potential for development into agents for Type 2 diabetes therapy. AB - Several frog skin peptides, first identified as result of their antimicrobial or immunomodulatory activities, have subsequently been shown to stimulate insulin release both in vitro and in vivo and so show potential for development into incretin-based drugs for treatment of patients with Type 2 diabetes mellitus. However, their therapeutic potential as anti-diabetic agents is not confined to this activity as certain frog skin-derived peptides, such as magainin-AM2 and CPF SE1 and analogs of hymenochirin-1B, tigerinin-1R, and esculentin-2CHa, have been shown to increase insulin sensitivity, promote beta-cell proliferation, suppress pancreatic and circulating glucagon concentrations, improve the lipid profile, and selectively alter expression of genes involved in insulin secretion and action in mice with diet-induced obesity, insulin resistance and impaired glucose tolerance. This review assesses the therapeutic possibilities of peptides from frogs belonging to the Pipidae, Dicroglossidae, and Ranidae families, focusing upon work that has been carried out since 2014. PMID- 28887048 TI - Nursing Staff's Perceptions of Quality of Care for Children in Emergency Departments-High Respect, Low Resources. AB - PURPOSE: To describe the quality of care for children in emergency departments (ED) as perceived by the nursing staff, and to compare the quality of care for children in a pediatric ED and in a general ED and to identify care quality factors that predict nursing staff's satisfaction with pediatric care in an ED. DESIGN AND METHODS: A cross-sectional survey study was performed using the 41 item Children Revised Humane Caring Scale (CRHCS) to collect data (n=147) from acute hospitals' pediatric EDs and general EDs in November 2015. The data were analyzed using descriptive statistics and multiple linear regression. RESULTS: Nurses evaluated the quality of professional practice to be high. Children were treated in a respectful and friendly fashion, and received help when needed. The nurses perceived a lack of human resources in the studied EDs. Nurses in pediatric EDs gave more positive evaluations of the quality of care for children than nurses in general EDs. Positive assessments of professional practice, interdisciplinary collaboration and human resources by nursing staff predicted higher satisfaction with the quality of ED care for children. CONCLUSIONS: The quality of children's care seemed to be higher in the pediatric ED than in the general ED. Key predictors of quality in children's care are professional practices of nursing staff, interdisciplinary collaboration and adequate human resources. PRACTICE IMPLICATIONS: In EDs, children should be treated by nursing staff and facilities designated for them. Pediatric nursing and teamwork skills should be maintained in the training of nurses. PMID- 28887049 TI - An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection. AB - We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naive patients to an MTD achieved with intra-patient dose escalation design may be unsafe. PMID- 28887052 TI - Comparing long-acting reversible contraception insertion rates in women with Medicaid vs. private insurance in a clinic with a two-visit protocol. AB - OBJECTIVE: This study examined whether women with Medicaid are less likely to receive long-acting reversible contraception (LARC) in a clinic requiring two visits for insertion. STUDY DESIGN: LARC insertion and pregnancy rates were compared among women with Medicaid vs. private insurance, along with other predictors, in a retrospective chart review (N=447). RESULTS: Univariately, fewer women with Medicaid vs. private insurance received LARC (66% vs. 79%, p<.01) and more become pregnant (18% vs. 6%, p<.001). Significant multivariate predictors of not receiving LARC were being unmarried and postpartum, both of which were associated with having Medicaid. CONCLUSION: Women with Medicaid are less likely than women with private insurance to have a requested LARC device inserted when a clinic requires two visits for insertion. PMID- 28887050 TI - Genome Engineering for Personalized Arthritis Therapeutics. AB - Arthritis represents a family of complex joint pathologies responsible for the majority of musculoskeletal conditions. Nearly all diseases within this family, including osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis, are chronic conditions with few or no disease-modifying therapeutics available. Advances in genome engineering technology, most recently with CRISPR Cas9, have revolutionized our ability to interrogate and validate genetic and epigenetic elements associated with chronic diseases such as arthritis. These technologies, together with cell reprogramming methods, including the use of induced pluripotent stem cells, provide a platform for human disease modeling. We summarize new evidence from genome-wide association studies and genomics that substantiates a genetic basis for arthritis pathogenesis. We also review the potential contributions of genome engineering in the development of new arthritis therapeutics. PMID- 28887053 TI - Modeling the impact of novel male contraceptive methods on reductions in unintended pregnancies in Nigeria, South Africa, and the United States. AB - OBJECTIVE: We modeled the potential impact of novel male contraceptive methods on averting unintended pregnancies in the United States, South Africa, and Nigeria. STUDY DESIGN: We used an established methodology for calculating the number of couple-years of protection provided by a given contraceptive method mix. We compared a "current scenario" (reflecting current use of existing methods in each country) against "future scenarios," (reflecting whether a male oral pill or a reversible vas occlusion was introduced) in order to estimate the impact on unintended pregnancies averted. Where possible, we based our assumptions on acceptability data from studies on uptake of novel male contraceptive methods. RESULTS: Assuming that only 10% of interested men would take up a novel male method and that users would comprise both switchers (from existing methods) and brand-new users of contraception, the model estimated that introducing the male pill or reversible vas occlusion would decrease unintended pregnancies by 3.5% to 5.2% in the United States, by 3.2% to 5% in South Africa, and by 30.4% to 38% in Nigeria. Alternative model scenarios are presented assuming uptake as high as 15% and as low as 5% in each location. Model results were sensitive to assumptions regarding novel method uptake and proportion of switchers vs. new users. CONCLUSION: Even under conservative assumptions, the introduction of a male pill or temporary vas occlusion could meaningfully contribute to averting unintended pregnancies in a variety of contexts, especially in settings where current use of contraception is low. IMPLICATIONS: Novel male contraceptives could play a meaningful role in averting unintended pregnancies in a variety of contexts. The potential impact is especially great in settings where current use of contraception is low and if novel methods can attract new contraceptive users. PMID- 28887054 TI - HLA-DPB1 matching in unrelated hematopoietic stem cell transplantation program contributes to a higher incidence of disease relapse. AB - The impact of patient/donor matching for HLA-A, -B, -C, -DRB1 and -DQB1 genes in hematopoietic stem cell transplantation (HSCT) is well-recognized, but typing for additional genes, such as HLA-DPB1, is still controversial. Based on defined T cell epitope (TCE) groups, all HLA-DPB1 mismatches can be classified as permissive or non-permissive. In this retrospective study we analysed 82 patient matched unrelated donor (MUD) pairs who underwent HSCT, and explored the impact of HLA-DPB1 matches, permissive and non-permissive mismatches on transplantation outcomes. Patient-MUD pairs matched for HLA-DPB1 alleles in univariate analysis were associated with a significantly higher incidence of disease relapse compared to pairs who were permissive/non-permissive HLA-DPB1 mismatched according to the TCE3 and TCE4 algorithms (P=0.025 and P=0.026, respectively), although the significance was lost in multivariate analysis. The analysis did not reveal any significant influence of HLA-DPB1 alleles on overall survival (OS), non-relapse mortality (NRM) or graft-versus-host disease (GvHD) incidence. In conclusion, our study presents evidence that HLA-DPB1 matching influenced the relapse rate in patients after HSCT so the HLA-DPB1 alleles should be implemented in the MUD search algorithm as a transplantation determinant. PMID- 28887051 TI - Precision Oncology: The Road Ahead. AB - Current efforts in precision oncology largely focus on the benefit of genomics guided therapy. Yet, advances in sequencing techniques provide an unprecedented view of the complex genetic and nongenetic heterogeneity within individual tumors. Herein, we outline the benefits of integrating genomic and transcriptomic analyses for advanced precision oncology. We summarize relevant computational approaches to detect novel drivers and genetic vulnerabilities, suitable for therapeutic exploration. Clinically relevant platforms to functionally test predicted drugs/drug combinations for individual patients are reviewed. Finally, we highlight the technological advances in single cell analysis of tumor specimens. These may ultimately lead to the development of next-generation cancer drugs, capable of tackling the hurdles imposed by genetic and phenotypic heterogeneity on current anticancer therapies. PMID- 28887055 TI - How to control an intracellular proteolytic system: Coordinated regulatory switches in the mycobacterial Pup-proteasome system. AB - Intracellular proteolysis is critical for the proper functioning of all cells, owing to its involvement in a wide range of processes. Because of the destructive nature of protein degradation, intracellular proteolysis is restricted by control mechanisms at almost every step of the proteolytic process. Understanding the coordination of such mechanisms is a challenging task, especially in systems as complex as the eukaryotic ubiquitin-proteasome system (UPS). In comparison, the bacterial analog of the UPS, the Pup-proteasome system (PPS) is much simpler and, therefore, allows for insight into the control of a proteolytic system. This review integrates available information to present a coherent picture of what is known of PPS regulatory switches and describes how these switches act in concert to enforce regulation at the system level. Finally, open questions regarding PPS regulation are discussed, providing readers with a sense of what lies ahead in the field. PMID- 28887057 TI - PPARgamma agonists: Potential treatments for exudative age-related macular degeneration. AB - Choroidal neovascularization (CNV) characterizes the progression of exudative age related macular degeneration (AMD) with the deterioration in the central vision. Vascular inflammation, and overproduction of inflammatory cytokines, growth factors and aberrant endothelial cell migration, initiate defective blood vessel proliferation in exudative AMD. CNV formation is initiated by the interplay between inflammation, the hallmark of exudative AMD, and the activation of WNT/beta-catenin pathway. Upregulation of WNT/beta-catenin pathway involves activation of PI3K/Akt pathway and then the Warburg effect to produce lactate. Lactate production generates VEGF expression and then participates to the initiation of CNV in exudative AMD. WNT/beta-catenin pathway and PPARgamma act in an opposite manner in several diseases. We focus this review on the interplay between PPARgamma and canonical WNT/beta-catenin pathway and the anti inflammatory role of PPARgamma in exudative AMD. In exudative AMD, PPARgamma agonists downregulate inflammation and the WNT/beta-catenin pathway. PPARgamma agonists can appear as promising treatment against the initiation and the progression of CNV in exudative AMD. PMID- 28887056 TI - Quantification of volume and lipid filling of intracellular vesicles carrying the ABCA3 transporter. AB - The ABCA3 lipid transporter is located in the limiting membrane of lamellar bodies (LBs) in type-II-pneumocytes. Mutations within the ABCA3 gene may functionally impair the transporter, causing lung diseases in newborns, children and adults. Assays to quantify volume and lipid filling of the LBs on the level of the vesicular structures and thereby assess the function of ABCA3 are still lacking. In the present study human influenza haemagglutinin- (HA-) tagged wild type and mutant ABCA3 proteins were stably expressed in lung A549 cells. Fluorescently-labelled TopFluor phosphatidylcholine (TopF-PC) incorporated in surfactant-like liposomes was delivered to the cells and visualized by confocal microscopy. Subsequently, a comprehensive image analysis method was applied to quantify volume and fluorescence intensity of TopF-PC in ABCA3-HA-positive vesicles. TopF-PC accumulated within the vesicles in a time and concentration dependent manner, whereas the volume remained unchanged, suggesting active transport into preformed ABCA3 containing vesicles. Furthermore, this finding was supported by a decrease of the fluorescence intensity within the vesicles when either the ATPase of the transporter was inhibited by vanadate, or when a disease causing mutation (K1388N) close to the ABCA3-nucleotide binding domain 2 was introduced. Conversely, a mutation (E292V) located in the first cytoplasmic loop of ABCA3 did not significantly affect lipid transport, but rather resulted in smaller vesicles. In addition to these findings, the assay used in this work for analysing the PC-lipid transport into ABCA3 positive vesicles will be useful to screen for compounds susceptible to restore function in mutated ABCA3 protein. PMID- 28887059 TI - Toll-like receptor 2 and its roles in immune responses against Legionella pneumophila. AB - Legionella pneumophila (L. pneumophila) is an intracellular bacterium which can be survived in the human macrophages phagosomes. The infectious agent is cleared in some cases and survived in others. The main mechanisms responsible for survival of L. pneumophila are yet to be clarified. It has been reported that innate immunity plays key roles in limitation and also eradication of bacterial infections. Toll like receptor 2 (TLR2) is an important cell membrane receptor which recognizes a wide range of bacterial antigens entitled pathogen associated molecular patterns (PAMPs). The aim of the current review article is to present recent data regarding the roles of TLR2 in induction of immune responses and consequently eradication of L. pneumophila. Additionally, the main mechanisms used by L. pneumophila to overcome TLR2 dependent immune responses are discussed in this review article. PMID- 28887058 TI - Does resistance exercise performed during dialysis modulate Nrf2 and NF-kappaB in patients with chronic kidney disease? AB - Studies have shown that nuclear factor erythroid 2-related factor 2 (Nrf2) can be modulated by physical exercise. However, the impact of resistance exercise has never been investigated in patients with chronic kidney disease (CKD). The aim of this study was to evaluate the effects of resistance exercise programs on the expression of transcription factors Nrf2 and nuclear factor kappaB (NF-kappaB) in CKD patients on hemodialysis (HD). Patients on an HD program were randomly assigned to an exercise group of 25 patients (54.5% women, aged 45.7+/-15.2years and time on dialysis=71.2+/-45.5months) or a control group of 19 patients who had no exercise intervention (61.5% women, aged 42.5+/-13.5years and time on dialysis=70.1+/-49.9months). A strength exercise program was performed 3 times a week during the HD sessions. Peripheral blood mononuclear cells were isolated and processed for the expression of Nrf2 and NF-kappaB by quantitative real-time polymerase chain reaction 3months before and after the exercise program. Using an enzyme-linked immunosorbent assay, the activity of glutathione peroxidase (GPx) as well as the products of high-sensitivity C-reactive protein and nitric oxide (NO) were assessed. Nrf2 expression (ranging from 0.86+/-0.4 to 1.76+/-0.8) and GPx activity were significantly increased after exercise intervention. In the exercise group, no difference in the levels of NO was observed; however, there was a significant reduction in the control group. In conclusion, these data suggest that resistance exercises seem to be capable of inducing Nrf2 activation in CKD patients on HD. PMID- 28887060 TI - Ethnicity in Pulmonary Arterial Hypertension: Possibilities for Novel Phenotypes in the Age of Personalized Medicine. AB - In the past decade and a half, the introduction of new therapeutic agents has revolutionized the management of pulmonary arterial hypertension (PAH). These new treatment options have improved the quality of life and survival in PAH. With an armamentarium of options available, the identification of unique phenotypes can help practitioners choose tailored treatment regimens. Experts in other cardiovascular diseases, such as congestive heart failure and hypertension, have recommended race-specific treatments in their fields based on data highlighting variations in response to therapies. With this perspective, we review evidence supporting the hypothesis that ethnicity or race plays an important role in the management of PAH. Preliminary research suggests that races/ethnicities have differences in the presentation and outcome of PAH and could respond to PAH specific medications with varying efficacy. Genetic, physiological, and anatomic differences exist between races, particularly regarding the structure and function of the right ventricle. Unfortunately, clinical trials have not adequately included minorities, and registry data often omit inclusion of this demographic information. Further studies are needed to characterize the role that ethnicity plays in the prevalence, presentation, outcomes, and optimal treatment of PAH. PMID- 28887061 TI - Advances in Audio-Based Systems to Monitor Patient Adherence and Inhaler Drug Delivery. AB - Hundreds of millions of people worldwide have asthma and COPD. Current medications to control these chronic respiratory diseases can be administered using inhaler devices, such as the pressurized metered dose inhaler and the dry powder inhaler. Provided that they are used as prescribed, inhalers can improve patient clinical outcomes and quality of life. Poor patient inhaler adherence (both time of use and user technique) is, however, a major clinical concern and is associated with poor disease control, increased hospital admissions, and increased mortality rates, particularly in low- and middle-income countries. There are currently limited methods available to health-care professionals to objectively and remotely monitor patient inhaler adherence. This review describes recent sensor-based technologies that use audio-based approaches that show promising opportunities for monitoring inhaler adherence in clinical practice. This review discusses how one form of sensor-based technology, audio-based monitoring systems, can provide clinically pertinent information regarding patient inhaler use over the course of treatment. Audio-based monitoring can provide health-care professionals with quantitative measurements of the drug delivery of inhalers, signifying a clear clinical advantage over other methods of assessment. Furthermore, objective audio-based adherence measures can improve the predictability of patient outcomes to treatment compared with current standard methods of adherence assessment used in clinical practice. Objective feedback on patient inhaler adherence can be used to personalize treatment to the patient, which may enhance precision medicine in the treatment of chronic respiratory diseases. PMID- 28887063 TI - The 50kDa metalloproteinase TvMP50 is a zinc-mediated Trichomonas vaginalis virulence factor. AB - Trichomonas vaginalis is a protozoan parasite that can adapt to the trichomonicidal Zn2+ concentrations of the male urogenital tract microenvironment. This adaptation is mediated by molecular mechanisms, including proteinase expression, that are regulated by cations such as Zn2+. Herein, we characterized the previously identified 50kDa metalloproteinase aminopeptidase P (M24 family) member TvMP50 as a new Zn2+-mediated parasite virulence factor. Quantitative RT-PCR and indirect immunofluorescence assays corroborated the positive regulation of both mp50 gene expression and native TvMP50 protein overexpression in the cytoplasm and secretion products of parasites grown in the presence of Zn2+. Furthermore, this active metalloproteinase was characterized as a new virulence factor by assaying cytotoxicity toward prostatic DU145 cell monolayers as well as the inhibition of parasite and secreted soluble protein proteolytic activity in the 50kDa proteolytic region by the specific metalloproteinase inhibitor 1,10-phenanthroline and the chelating agents EDTA and EGTA. Parasite and secreted soluble protein cytotoxicity toward DU145 cells were reduced by treatment with an alpha-rTvMP50 polyclonal antibody. Our results show that the metalloproteinase TvMP50 is a new virulence factor modulated by Zn2+, which is present during male trichomoniasis, possibly explaining T. vaginalis survival even within the adverse conditions of the male urogenital microenvironment. PMID- 28887064 TI - Top-down modulation of alpha power and pattern similarity for threatening representations in visual short-term memory. AB - Recent studies have shown that top-down attention biases task-relevant representations in visual short-term memory (VSTM). Accumulating evidence has also revealed the modulatory effects of emotional arousal on attentional processing. However, it remains unclear how top-down attention interacts with emotional memoranda in VSTM. In this study, we investigated the mechanisms of alpha oscillations and their spatiotemporal characteristics that underlie top down attention to threatening representations during VSTM maintenance with electroencephalography. Participants were instructed to remember a threatening object and a neutral object in a cued variant delayed response task. Retrospective cues (retro-cues) were presented to direct attention to the hemifield of a threatening object (i.e., cue-to-threat trials) or a neutral object (i.e., cue-to-neutral trials) during a retention interval prior to the probe test. We found a significant retro-cue-related alpha lateralisation over posterior regions during VSTM maintenance. The novel finding was that the magnitude of alpha lateralisation was greater for cue-to-threat objects compared to cue-to-neutral ones. These results indicated that directing attention towards threatening representations compared to neutral representations could result in greater regulation of alpha activity contralateral to the cued hemifield. Importantly, we estimated the spatiotemporal pattern similarity in alpha activity and found significantly higher similarity indexes for the posterior regions relative to the anterior regions and for the cue-to-threat objects relative to cue-to-neutral objects over the posterior regions. Together, our findings provided the oscillatory evidence of greater top-down modulations of alpha lateralisation and spatiotemporal pattern similarity for attending to threatening representations in VSTM. PMID- 28887062 TI - Diaphragm Dysfunction in Critical Illness. AB - The diaphragm is the major muscle of inspiration, and its function is critical for optimal respiration. Diaphragmatic failure has long been recognized as a major contributor to death in a variety of systemic neuromuscular disorders. More recently, it is increasingly apparent that diaphragm dysfunction is present in a high percentage of critically ill patients and is associated with increased morbidity and mortality. In these patients, diaphragm weakness is thought to develop from disuse secondary to ventilator-induced diaphragm inactivity and as a consequence of the effects of systemic inflammation, including sepsis. This form of critical illness-acquired diaphragm dysfunction impairs the ability of the respiratory pump to compensate for an increased respiratory workload due to lung injury and fluid overload, leading to sustained respiratory failure and death. This review examines the presentation, causes, consequences, diagnosis, and treatment of disorders that result in acquired diaphragm dysfunction during critical illness. PMID- 28887065 TI - Pulmonary function and thoracic deformities in adolescent idiopathic scoliosis 27 years or longer after spinal fusion with Harrington instrument. AB - BACKGROUND: The aim of this study was to conduct an investigation into spinal fusion with Harrington instrument (HI) in patients with adolescent idiopathic scoliosis (AIS) and to survey pulmonary function and thoracic deformity outcomes many years after surgery. METHODS: Subjects comprised 194 patients diagnosed with AIS and treated with spinal fusion using HI between 1968 and 1987. Patients who gave their informed consent were subjected to a complete standing spine X-ray, chest CT, and pulmonary function tests. Eighteen patients were eligible for inclusion. Mean age at the time of follow-up was 49.9 years and the mean duration of follow-up was 35.3 years. CT axial image was used at the apex of the main thoracic curve. Apical vertebral rotation was determined from RA sag measured by the method of Aaro et al. Thoracic cage deformities were measured as follows: Rib hump index (RHi) according to the method of Aaro et al. and posterior hemithoracic symmetry ratio (PHSr) according to the method of Campbell et al. RESULTS: Pulmonary function tests revealed mean forced vital capacity (FVC) of 2.28 (range: 1.00-3.04) L and mean %FVC of 83.5% (range: 35.6%-117.8%). Restrictive ventilation disorder with %FVC <80% was seen in 5 patients (27.7%). %FVC had strong negative correlations with RA sag (r = -0.798), RHi (r = -0.820, p < 0.001), PHSr (r = -0.705), and proximal thoracic curve (r = -0.721). Main thoracic curve (r = -0.674) and apical vertebral rotation of thoracic curve (r = 0.685) showed moderate negative correlations. Multiple regression analysis revealed RHi was a most significant factor on %FVC. CONCLUSIONS: In AIS patients examined 27 years or longer after surgery, restrictive ventilation defects were observed in 27.7%. Factors aggravating %FVC were large rib humps and large vertebral rotations. Three-dimensional correction of the spine and thoracic cage deformities is vital in order to avoid pulmonary function impairment many years after surgery. PMID- 28887066 TI - Neoadjuvant chemoradiation is associated with improved overall survival in older patients with esophageal cancer. AB - OBJECTIVES: The aim of this study was to characterize outcomes associated with neoadjuvant chemoradiation prior to esophagectomy, compared to esophagectomy alone, in older patients with esophageal cancer. MATERIALS AND METHODS: We conducted an observational cohort study in patients >=70years with locally advanced esophageal cancer undergoing esophagectomy +/- neoadjuvant chemoradiation between 2006 and 2012 using the National Cancer Database. A Cox proportional hazards model with inverse probability of treatment weighting (IPTW) using the propensity score was developed to assess the association between trimodality therapy and overall survival. Perioperative complications and pathologic outcomes associated with trimodality therapy were identified with multivariable logistic regression. RESULTS: 1364 patients were included; the mean age was 75 (range 70-90). 904 (66%) were treated with trimodality therapy and 460 (34%) were treated with esophagectomy alone. On IPTW Cox analysis, neoadjuvant chemoradiation was associated with improved overall survival (HR=0.76, 95%CI [0.70-0.82], p<=0.001). Further, trimodality therapy was associated with lower rates of margin-positive resection (5% vs. 18%; OR=0.26, 95%CI [0.18-0.37], p<0.001) and in 18% of trimodality patients, there was no detectable tumor at surgery. 90-day mortality rates were not statistically different (14% vs. 12%; OR=0.99, 95%CI [0.73-1.36], p=0.22). Neoadjuvant chemoradiation was associated with lower 30-day readmission rates (5% vs. 8%; OR=0.48, 95%CI [0.31-0.73], p=0.004) and shorter surgical hospital stay (median 10 vs. 12days, p<0.001) compared to esophagectomy alone. CONCLUSION: In older patients with esophageal cancer, trimodality therapy, compared to esophagectomy alone, is associated with improved overall survival and favorable pathologic and perioperative outcomes. Further studies are needed to identify which older patients are most suitable for trimodality therapy. PMID- 28887067 TI - Rush to the fire: FGF21 extinguishes metabolic stress, metaflammation and tissue damage. AB - FGF21 is a master regulator of homeostasis of local and systemic lipid, glucose and energy metabolism. Since its discovery a decade ago, significant progress has been made in understanding the basic molecular, cellular and physiological mechanisms underlying its metabolic roles, and characterizing its beneficial pharmacological activities and possible pathological roles in obesity, diabetes, dyslipidemia, fatty liver disease and their collateral complications and tissue damage. Under basal or normal conditions, FGF21 appears to play a dispensable role in metabolism. However, in response to a variety of cellular and metabolic stress, FGF21 is significantly upregulated to serve as a potent catabolic factor leading to the clearance of excessive lipids and glucose, and therefore, antagonizes metabolic and energy imbalance in a negative fashion. Furthermore, FGF21 treatment ameliorates tissue damage resulted from the harmful effects of metabolic abnormalities, which often ensue an oxidative, pro-inflammatory, inflammatory and/or immune stress state, the so-called metaflammation. Most notably, studies focusing on the liver, pancreas, cardio-vasculature and kidney have revealed its significant protective effects against the structural and functional damages induced by the obese, diabetic or other abnormal metabolic conditions. In this review, we will summarize the current progress on the roles of FGF21 against metaflammation and metabolic tissue damage. PMID- 28887068 TI - The rationale, design, and methods of a randomized, controlled trial to evaluate the effectiveness of collaborative telecare in preserving function among patients with late stage cancer and hematologic conditions. AB - Disablement affects over 40% of patients with advanced stage cancer, devastates their quality of life (QoL), and increases their healthcare costs. Proactively treating the causes of disablement; physical impairments, pain, and immobility, can prolong functional independence, improve QoL and, potentially, reduce utilization. However rehabilitation service delivery models are reactive in nature and focus on catastrophic rather than incipient disability. A validated collaborative approach, the Three Component Model (TCM), optimizes important clinical outcomes and may provide an ideal framework to overcome barriers to proactively integrating rehabilitation into cancer care. A novel expansion of the TCM that targets disablement by engaging local physical therapists to address physical impairments and immobility, the TCM-Rehabilitation Services (TCM-RS), benefits and is well received by patients. However, its effectiveness has not been rigorously assessed. The 3-arm randomized COllaborative Care to Preserve PErformance in Cancer (COPE) Trial compared: 1) enhanced usual care, 2) rehabilitation services targeting physical impairments and immobility via the TCM RS, and 3) TCM-RS plus conventional TCM pain management TCM-RS+Pain. Of the 516 participants, those randomized to arms 2 and 3 underwent an initial 4-week intervention period and were then followed for 6months with remote monitoring and monthly telephone calls. The trial's primary outcome, functional status, and secondary outcomes were assessed at baseline, 3, and 6months. Utilization was abstracted from clinical records. By estimating the effectiveness and cost utility implications of the TCM-RS and TCM-RS+Pain, COPE will inform future delivery research, practice and policy in the means to reduce disablement in chronically diseased populations. PMID- 28887069 TI - Better Respiratory Education and Treatment Help Empower (BREATHE) study: Methodology and baseline characteristics of a randomized controlled trial testing a transitional care program to improve patient-centered care delivery among chronic obstructive pulmonary disease patients. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of hospitalizations. Interventional studies focusing on the hospital-to-home transition for COPD patients are few. In the BREATHE (Better Respiratory Education and Treatment Help Empower) study, we developed and tested a patient and family-centered transitional care program that helps prepare hospitalized COPD patients and their family caregivers to manage COPD at home. METHODS: In the study's initial phase, we co-developed the BREATHE transitional care program with COPD patients, family-caregivers, and stakeholders. The program offers tailored services to address individual patients' needs and priorities at the hospital and for 3months post discharge. We tested the program in a single-blinded RCT with 240 COPD patients who were randomized to receive the program or 'usual care'. Program participants were offered the opportunity to invite a family caregiver, if available, to enroll with them into the study. The primary outcomes were the combined number of COPD-related hospitalizations and Emergency Department (ED) visits per participant at 6months post discharge, and the change in health related quality of life over the 6months study period. Other measures include 'all cause' hospitalizations and ED visits; patient activation; self-efficacy; and, self-care behaviors. DISCUSSION: Unlike 1month transitional care programs that focus on patients' post-acute care needs, the BREATHE program helps hospitalized COPD patients manage the post discharge period as well as prepare them for long term self-management of COPD. If proven effective, this program may offer a timely solution for hospitals in their attempts to reduce COPD rehospitalizations. PMID- 28887070 TI - Decreased serum sodium levels predict symptomatic vasospasm in patients with subarachnoid hemorrhage. AB - BACKGROUND: Symptomatic vasospasm is a major cause of morbidity and mortality in subarachnoid hemorrhage patients. Hyponatremia and dehydration due to natriuresis after subarachnoid hemorrhage are related to symptomatic vasospasm. Therefore, most institutions are currently targeting euvolemia and eunatremia in subarachnoid hemorrhage patients to avoid complications. We retrospectively investigated the predictors of symptomatic vasospasm with respect to water and sodium homeostasis, while maintaining euvolemia and eunatremia after subarachnoid hemorrhage. METHODS: We monitored changes in serum sodium levels, serum osmolarity, daily sodium intake, daily urine volume, and daily water balance for 14days after subarachnoid hemorrhage. Outcomes were assessed using the modified Rankin scale at 1month after subarachnoid hemorrhage. RESULTS: Among 97 patients, 27 (27.8%) had symptomatic vasospasm. Patients with symptomatic vasospasm were older than those without symptomatic vasospasm; the occurrence of symptomatic vasospasm affected outcomes. Serum sodium levels were sequentially significantly decreased, but within the normal range from 1day before the occurrence of symptomatic vasospasm. Serum osmolarity of the spasm group was lower than that of the non-spasm group. CONCLUSIONS: Symptomatic vasospasm occurs more often in older patients and affects outcomes. A decrease in serum sodium levels occurs a day before symptomatic vasospasm. This observation may help predict symptomatic vasospasm. PMID- 28887071 TI - Pathological crying induced by deep brain stimulation of the subthalamic nucleus in Parkinson's disease. AB - We report on a patient with deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) who developed pathologic crying (PC) immediately postoperatively. A spread of DBS current to adjacent cortico-ponto cerebellar pathways might be responsible. In contrast to the few cases published previously, there was no pre-existing additional lesion that would have favoured occurrence of PC. Treating physicians should be aware of DBS-induced PC. PMID- 28887072 TI - Minimum Clinically Important Difference of Montreal Cognitive Assessment in aneurysmal subarachnoid hemorrhage patients. AB - Cognitive impairment is a major factor contributing to poor functional outcome after subarachnoid hemorrhage caused by a ruptured cerebral aneurysm (aSAH). Montreal Cognitive Assessment (MoCA) has been shown to be superior to the Mini Mental State Examination in screening for cognitive domain deficit and correlating to functional outcome in aSAH patients. The aim of the current study was to determine the Montreal Cognitive Assessment (MoCA) score change that was associated with change of health in general in an aSAH patient cohort. We recruited aSAH patients from a regional neurosurgical center over a 3-year period. Patient assessments including MoCA and global rating of change (GRoC) were carried out at at 3 and 12months after aSAH. Anchor-based and distribution based approaches were adopted to calculate the Minimum Clinically Important Difference (MID). One hundred and seventy-five aSAH patients completed both 3 month and 1-year assessments and consented for participation. Employing the distribution-based approach for the 3-month and 1-year MoCA scores, the MID estimates equated to a change of 2.0 and 1.1 respectively. Employing the anchor based approach (with GRoC), the MID estimate of MoCA (median, IQR) was 2, 1-4. In conclusion, we found that the MID of MoCA score associated with change of health in general in aSAH patients was 2. The MID provides guidance for future clinical trial design targeting on cognitive dysfunction after aSAH. PMID- 28887073 TI - Bilateral suboccipital approach for a giant vertebral artery aneurysm. AB - Giant thrombosed aneurysms of the vertebral artery (VA) are difficult to treat. Moreover, marked tortuosity of the parent VA complicates determination of the surgical approach. We report the case of a 71-year-old male patient who presented with gait disturbance. Magnetic resonance imaging revealed a giant thrombosed aneurysm of approximately 4cm in diameter located in the ventral region and to the right of the medulla oblongata. Computed tomography angiography showed that the right VA had extreme tortuosity, and that the VA union was in contact with the left 7th and 8th cranial nerves. Given that the aneurysm was thrombosed and causing a mass effect, we sought to trap it. In this case, because of the tortuous VA, intravascular team considered intravascular therapy to be too difficult. We made a question mark-shaped skin incision and used a wide bilateral suboccipital approach. The VA proximal to the aneurysm was occluded with an aneurysm clip using an approach from the right of the brainstem, while the VA distal to the aneurysm was occluded using a lateral suboccipital approach. When the VA and basilar artery are atherosclerotic and extremely tortuous, the distal and proximal aspects of the aneurysm can exist on both sides of the midline. In difficult cases such as that reported here, in which a giant VA aneurysm exceeded the midline of the anterior surface of the medulla, we believe that it is useful to employ a bilateral approach from both sides of the brainstem. PMID- 28887074 TI - Paediatric aneurysms - Review of endovascular treatment strategies. AB - Paediatric aneurysms are rare and represent the end result of a variety of different pathological mechanisms. They have a varied presentation and features that are distinct from their adult counterparts. The appropriate management of these aneurysms requires a multi-disciplinary team approach and detailed analysis to deal with the underlying pathology. This can involve the use of coils, adjunctive devices such as neck-bridging devices, flow diverters and liquid embolic agents, as well as microsurgical clipping. In this paper we discuss the different types of aneurysms that can present in the paediatric population and present cases that highlight the entire spectrum of paediatric aneurysmal disease and the different treatment options currently available. Treatment of paediatric intracranial aneurysms requires individualized strategies. PMID- 28887075 TI - Role of cathepsin K in the development of chronic subdural hematoma. AB - Despite extensive investigations, the process of development of chronic subdural hematoma (CSDH) is not known. The present study aims to investigate CSDH by measuring biomarkers in it, gas analysis, and immunohistochemical examination. A total of 42 patients with symptomatic CSDH who underwent burr-hole drainage were enrolled. Intraoperatively, hematoma fluid and peripheral venous blood (PVCSDH) were simultaneously collected. As controls, peripheral venous blood (PVControl) and intracranial cerebrospinal fluid (CSF) were collected from other subjects during other surgeries. CatK, lipocalin-type prostaglandin D synthase (PGDS), and cystatin C (CysC) present in these specimens were measured using enzyme-linked immunosorbent assay. Data obtained were statistically analyzed after age correction. In 15 patients, gas analysis was performed for CSDH and PVCSDH. Furthermore, immunohistochemical examination for the outer membrane was performed for four patients. CatK, PGDS, and CysC levels were markedly elevated in the CSF and CSDH. CatK levels in PVCSDH were significantly higher than in PVControl (P<0.0001). In contrast, CysC levels in PVCSDH were significantly lower than in PVControl (P=0.004). The gas analysis revealed that the internal environment of CSDH is characterized by marked hypoxia, hypoglycemia, and lactic acidosis. Furthermore, the outer membrane consistently showed a diffuse staining for CatK. Based on these, CatK was thought to play a role in the development of CSDH, with the levels in peripheral venous blood elevated in patients with CSDH. PMID- 28887077 TI - Use of subdural drain for chronic subdural haematoma? A 4-year multi-centre observational study of 302 cases. PMID- 28887076 TI - Microstructural mechanisms of analgesia in percutaneous cervical cordotomy revealed by diffusion tensor imaging. AB - The purpose of this study is to demonstrate the potential of diffusion tensor imaging (DTI) to reveal structural mechanisms underlying spinal ablative procedures, including percutaneous radiofrequency cordotomy (PRFC). PRFC is a surgical procedure that produces analgesia through focal ablation of the lateral spinothalamic tract (STT), thereby interrupting the flow of pain information from the periphery to the brain. To date, studies regarding mechanisms of analgesia after PRFC have been limited to postmortem cadaveric dissection and histology. However, with recent advances in DTI, the opportunity has arisen to study the STT non-invasively in vivo. In this technical note, an individual with successful pain relief following unilateral STT PRFC was examined using DTI, with the contralateral STT serving as an internal control. PRFC substantially reduced rostrocaudal directional DTI signal in the STT from the lesion in the cervical spinal cord through the pons and mesencephalon. Our findings confirm that focal ablation and anterograde degeneration accompany the analgesic effects of PRFC. In vivo imaging of the STT with DTI may contribute to surgical targeting for PRFC procedures, better understanding of the therapeutic and untoward effects of PRFC, and a deeper understanding of spinothalamic contributions to nociception. PMID- 28887078 TI - Management of residual subdural hematoma after burr-hole evacuation. The role of fluid therapy and review of the literature. AB - A vast amount of literature has been published investigating the factors associated to the recurrence of a chronic subdural hematoma (SDH). However, little exists in the literature about the best medical management of the residual SDH in order to prevent the recurrence. Moreover only few studies quantitatively assess clinical and radiological outcomes of residual post-operative SDH. In this study, to our knowledge, we report the first series of chronic SDH with a quantitative outcomes analysis of the effects of fluid therapy on residual post operative SDH. Moreover we discuss the pertinent literature. We reviewed clinical and outcome data of 39 patients (44 SDH; 12 F, 27 M) submitted to a burr-hole evacuation of a SDH. The mean age was 76.97+/-7.77years. All patients had a minimum 3-month follow-up (FU). Post-operatively, an intravenous saline solution was started in all cases (2000ml in 24h) and administered for 3days. Then an oral hydration with 2l per day of water was started and continued as outpatients. Glasgow Coma Scale (GCS), Karnofsky Performance Status (KPS), SDH volume and midline shift were evaluated pre-operatively, post-operatively and at FU. We found a statistically significant improvement of post-operative and at FU GCS and KPS compared to the pre-operative. SDH volume and midline shift were also statistically significant reduced in the post-operative and at FU. No complication occurred. Only 1 patient required a reoperation at 3months FU for neurological worsening. Oral fluid therapy is a safe and effective treatment for residual SDH. PMID- 28887079 TI - Measuring the validation of assessing the non-dominant-hand function by ALSFRS-r in Chinese ALS patients. AB - ALSFRS-r is a widely accepted rating scale for measuring the global function of Amyotrophic Lateral Sclerosis (ALS) patients, but we found some limitations of ALSFRS-r in assessing the function of non-dominant hand in Chinese ALS patients. We reviewed 95 ALS patients who expressed upper-limb symptoms at first visit and analyzed the ALSFRS-r score and subscale. In both upper limb involved patients, the ALSFRS-r had no difference between dominant-hand and non-dominant-hand onset groups (39.15+/-5.55 vs 38.0+/-5.91, p=0.477). But in only one upper limb involved patients, the ALSFRS-r score in non-dominant-hand onset patients was higher than dominant-hand onset patients (43.94+/-3.44 vs 40.87+/-4.42, p<0.05), especially in item of handwriting, cutting food and handing utensils (3.56+/-0.89 vs 2.2+/-1.27 p=0.001, 3.44+/-1.03 vs 1.8+/-1.21 p=0.000). When the item of cutting food and handing utensils was replaced by using food bowl and chopsticks to assess the function of non-dominant-hand, the modified ALSFRS-r score was significantly lower than original ALSFRS-r (43.94+/-3.44 vs 42.88+/-3.07 p=0.001), the progression rate was slower (0.81+/-0.63 vs 0.64+/-0.63, p=0.001). So, for Chinese ALS patients, using food bowl and chopsticks should replace the item of cutting food and handling utensils to assess the non-dominant-hand function, especially in non-dominant-hand onset patients. PMID- 28887080 TI - A rare case of metastatic extramammary Paget disease of the spine and review of the literature. AB - Extramammary Paget disease is an intraepithelial neoplasm affecting cells rich in apocrine glands-often located in the vulvar, scrotal, or perianal region. It typically affects older patients, between the ages of 50 and 80years old, and is most often limited to the epidermis. A 47-year-old Asian male first presented with enlargement of the right inguinal lymph node. A subsequent biopsy revealed extrammamary Paget disease of the scrotum. The patient eventually developed significant worsening back pain with bilateral lower extremity numbness and weakness three months later. Imaging demonstrated a pathologic compression fracture of the L4 vertebral body with metastatic epidural spinal cord compression. The patient underwent surgical decompression of the spine with bilateral L4 laminectomy, resection of epidural tumor, and pedicle screw fixation from L2 to S1. Surgical pathology demonstrated metastatic adenocarcinoma consistent with extramammary Paget disease. Although two other case reports have described spinal metastases from extramammary Paget disease, to the author's knowledge, this represents the first report of surgical decompression and fusion for extramammary Paget disease of the spine. PMID- 28887081 TI - Ultrasound for the assessment of distal shunt malfunction in adults with internal ventricular shunts. AB - Shunts that are used for the treatment of hydrocephalus have a propensity towards malfunction, however, diagnosing a shunt malfunction can sometimes be a challenge. The purpose of this study was to investigate whether ultrasound technology can be safely and effectively used to assess for distal shunt malfunction. This was a prospective cohort study at a single institution. Eighteen adult patients that received a radionuclide shunt patency study also underwent an ultrasound shunt patency study. Ultrasound with Doppler technology was used to visualize flow through the shunt tubing following manual compression of the shunt reservoir. A peak flow speed was recorded and the results were compared to the results of the radionuclide shunt patency study. A Receiver Operating Characteristic (ROC) curve comparing the ultrasound to the radionuclide shunt patency study was generated, revealing an Area Under the Curve (AUC) of 0.95 (95% CI: 0.84-1.00). The ultrasound test performed maximally with a cutoff speed of <=10cm/s as the criteria for malfunction, with a sensitivity of 100.00%, specificity of 90.91%, accuracy of 94.44%, positive likelihood ratio of 11.000 and negative likelihood ratio of 0.000 using the radionuclide study results as criteria for comparison. Overall, ultrasound has the potential to be a safe, quick, available and cost-effective screening test for patients with suspected distal shunt malfunction. The high sensitivity of the test makes it an attractive option for use as a screening method that could potentially reduce the number of cases requiring radionuclide shunt patency study. PMID- 28887082 TI - Clinical outcomes after craniotomy for unruptured intracranial aneurysm in patients with coronary artery disease. AB - BACKGROUND: Coronary artery disease (CAD) patients receiving antiplatelet agents occasionally undergo craniotomy. We aimed to clarify clinical outcomes after craniotomy for unruptured intracranial aneurysm (UIA) in patients with CAD. We also aimed to identify the possible predictive factors for morbidity and surgical complications in patients on antiplatelet treatment. METHODS: We retrospectively analyzed 401 consecutive patients who had undergone craniotomy for UIA at our institution between January 2006 and December 2016. Forty-three patients (10.7%) received antiplatelet agents during the perioperative period. The underlying reasons for antiplatelet treatment were CAD in 12 patients and other diseases in 31 patients. RESULTS: Severe morbidity and intracranial hemorrhage occurred more commonly and symptomatic brain infarction occurred less frequently in patients with CAD compared to patients with other underlying diseases (16.7% versus 3.2%, 16.7% versus 9.7%, and 8.3% versus 16.1%, respectively), though differences between the two groups were not significant. Univariate analysis revealed that a low preoperative baseline platelet count was significantly correlated with the occurrence of intracranial hemorrhage (cutoff value, 16.5*104/uL; odds ratio (OR), 46.67; 95% confidence interval (CI), 3.88-561.95; p=0.0005), and a high baseline platelet count tended to correlate with severe morbidity (cutoff value, 29.8*104/uL; OR, 11.33; 95% CI, 0.88-145.52; p=0.0550). CONCLUSIONS: Our results suggest that surgical complications and clinical outcomes after craniotomy may depend on the underlying reason for antiplatelet treatment. Moreover, a preoperative platelet count can be useful in predicting the occurrence of intracranial hemorrhage and severe morbidity after craniotomy in patients receiving antiplatelet agents. PMID- 28887083 TI - PRES leading to the diagnosis of McArdle disease. AB - A 35year-old male developed myalgias after moving furniture and was hospitalized with acute renal failure and rhabdomyolysis requiring hemodialysis. He then had several generalized tonic-clonic seizures. Brain MRI showed findings of posterior reversible encephalopathy syndrome (PRES). Interval history revealed easy fatigability and exercise-induced myalgias in childhood but no preceding history of urine discoloration. Quadriceps biopsy showed absent muscle myophosphorylase reactivity consistent with the diagnosis of McArdle disease. With supportive care he improved and the PRES resolved. This case represents an extreme in the spectrum of complications that can occur in McArdle disease, including downstream central nervous system involvement and highlights the importance of early recognition and aggressive management of rhabdomyolysis. PMID- 28887084 TI - Tethered growth factors on biocompatible scaffolds improve stemness of cultured rat and human neural stem cells and growth of oligodendrocyte progenitors. AB - Currently, there is no widely accepted technique to efficiently and reproducibly grow stem and progenitor cells in vitro. Stem cells require contact with extracellular matrices as well as signals from growth factors to proliferate and to retain their stemness. We have shown a novel tissue culture platform (StemTrix cultureware) that transforms standard tissue culture plasticware into a multi functional chitosan-based scaffold that supports the expansion of neural stem cells. The StemTrix scaffold is comprised of chitosan with immobilized heparin which in turn tethers heparin-binding growth factors. The scaffold is also coated with an adhesive ECM protein. Here we demonstrate that fibronectin or the RGD peptide contained in fibronectin are equally effective in promoting the adhesion, viability and growth of rat and human neural stem cells. When FGF-2 and heparin binding EGF are tethered to the StemTrix cultureware neural stem cells grow ~3 times faster and remain in a more primitive state as determined by both Western Blot and gene expression analyses. Another important feature of this new culture platform is that the NSCs remain in a primitive and proliferative state for 4days without refreshing the culture medium or providing new growth factors, which represents a 20-fold extension of FGF-2's biological activity vs when it is freely soluble in the medium. To test the utility of this scaffold for propagating other types of stem cells and progenitors we tethered platelet derived growth factor (PDGF) and FGF-2 alone and in combination to the scaffold and tested the efficacy of this platform to maintain primary oligodendrocyte progenitors or the CG-4 cell line in a primitive state. Oligodendrocyte progenitors plated onto this multifunctional film proliferated for at least 3days without providing soluble growth factors while inhibiting the expression of the differentiation marker myelin-basic protein. Oligodendrocyte progenitors proliferated 3 times more rapidly than cells maintained on fibronectin-coated culture substrates in culture medium supplemented with soluble FGF-2 and PDGF. Finally, we show that StemTrix cultureware can be produced using clinical grade components, providing users with a fully defined platform suitable for clinical use that maintains stem cells or progenitors in a more uniform and primitive state. PMID- 28887085 TI - Visualizing omics and clinical data: Which challenges for dealing with their variety? AB - Life sciences are currently going through a great number of transformations raised by the in-going revolution in high-throughput technologies for the acquisition of data. The integration of their high dimensionality, ranging from omics to clinical data, is becoming one of the most challenging stages. It involves inter-disciplinary developments with the aim to move towards an enhanced understanding of human physiology for caring purposes. Biologists, bioinformaticians, physicians and other experts related to the healthcare domain have to accompany each step of the analysis process in order to investigate and expertise these various data. In this perspective, methods related to information visualization are gaining increasing attention within life sciences. The softwares based on these methods are now well recognized to facilitate expert users' success in carrying out their data analysis tasks. This article aims at reviewing the current methods and techniques dedicated to information visualisation and their current use in software development related to omics or/and clinical data. PMID- 28887086 TI - The effects of cinnamon supplementation on blood lipid concentrations: A systematic review and meta-analysis. AB - BACKGROUND: Cinnamon is a rich botanical source of polyphenols, whose positive effects on blood lipid concentrations have been hypothesized, but have not been conclusively studied. OBJECTIVE: The objective of the study was to systematically review and evaluate the effect of administration of cinnamon on blood lipid concentrations. METHODS: We assessed 13 randomized controlled trials with 750 participants investigating the effect of cinnamon supplementation on blood lipid concentrations. A meta-analysis was performed using random effect models, with weighted mean differences (WMDs; with 95% confidence interval [CI]) for endpoints calculated using a random effects model. RESULTS: No statistically significant effect of cinnamon was observed on blood low-density lipoprotein cholesterol (LDL C; WMD: -0.16 mmol/L [-6.19 mg/dL], 95% CI: -0.35, 0.03 [-13.53, 1.16], P = .10) and high-density lipoprotein cholesterol (HDL-C; WMD: 0.05 mmol/L [1.92 mg/dL], 95% CI: -0.03, 0.12 [-0.03, 4.64], P = .21) concentrations. However, a statistically significant reduction in blood triglycerides (WMD: -0.27 mmol/L [ 23.91 mg/dL], 95% CI: -0.39, -0.14 [-34.54, -12.40], P < .01) and total cholesterol concentrations (WMD: -0.36 mmol/L [-13.92 mg/dL], 95% CI: -0.63, 0.09 [-24.36, -3.48], P < .01) was observed. HDL-C was significantly elevated after the omission of 1 study (WMD: 0.04 mmol/L [1.54 mg/dL], 95% CI: 0.03, 0.06 [1.16, 2.32], P < .01) during our sensitivity analysis. A meta-regression analysis was conducted, and no significant association was found between changes in lipid parameters and cinnamon dose. In contrast, changes in blood levels of total cholesterol (slope: 0.09; 95% CI: 0.02, 0.16; P < .01), LDL-C (slope: 0.05; 95% CI: 0.001, 0.10; P = .05) and triglycerides (slope: 0.06; 95% CI: 0.04, 0.09; P < .01) were significantly and positively associated with the duration of supplementation. No statistically significant association was found between blood HDL-C changes and duration of supplementation. CONCLUSION: Cinnamon supplementation significantly reduced blood triglycerides and total cholesterol concentrations without any significant effect on LDL-C and HDL-C. PMID- 28887087 TI - A systematic study of the sensitivity of partial volume correction methods for the quantification of perfusion from pseudo-continuous arterial spin labeling MRI. AB - Arterial spin labeling (ASL) MRI is a non-invasive technique for the quantification of cerebral perfusion, and pseudo-continuous arterial spin labeling (PCASL) has been recommended as the standard implementation by a recent consensus of the community. Due to the low spatial resolution of ASL images, perfusion quantification is biased by partial volume effects. Consequently, several partial volume correction (PVEc) methods have been developed to reduce the bias in gray matter (GM) perfusion quantification. The efficacy of these methods relies on both the quality of the ASL data and the accuracy of partial volume estimates. Here we systematically investigate the sensitivity of different PVEc methods to variability in both the ASL data and partial volume estimates using simulated PCASL data and in vivo PCASL data from a reproducibility study. We examined the PVEc methods in two ways: the ability to preserve spatial details and the accuracy of GM perfusion estimation. Judging by the root-mean-square error (RMSE) between simulated and estimated GM CBF, the spatially regularized method was superior in preserving spatial details compared to the linear regression method (RMSE of 1.2 vs 5.1 in simulation of GM CBF with short scale spatial variations). The linear regression method was generally less sensitive than the spatially regularized method to noise in data and errors in the partial volume estimates (RMSE 6.3 vs 23.4 for SNR = 5 simulated data), but this could be attributed to the greater smoothing introduced by the method. Analysis of a healthy cohort dataset indicates that PVEc, using either method, improves the repeatability of perfusion quantification (within-subject coefficient of variation reduced by 5% after PVEc). PMID- 28887088 TI - Impact of the heart rate on the shape of the cardiac response function. AB - There is limited understanding about how heart rate (HR) influences the blood oxygen level dependent (BOLD) signal. While the mechanism by which respiration induces fluctuation in the BOLD signal is relatively well understood, the mechanisms regarding the HR remains unclear. The application of canonical cardiac response function (CRF), or subject-specific CRF, is an effective method for creating nuisance regressors, which can be used to remove cardiac-induced fluctuations in the BOLD signal. However, the relationship between physiological parameters and the characteristics of the CRF has not been systematically investigated. In the present investigation, we studied the relationship between the variations in mean HR and the shape of the cardiac response function in 84 healthy subjects with a wide range of HR lying between 47 and 97 beats per minute (bpm). Three groups (n = 28) were created based on the subject's mean HR. We demonstrated that the HR plays an important role in determining the shape of the CRFs. We also observed that the canonical CRF explains more variance in subjects with a slow HR, than in subjects exhibiting faster HR. We found that the amount of explained variance significantly increased in each group when a group-specific CRF was used. In a further analysis, we found two forms of a CRF, which explain a considerable amount of variance in subjects with a mean HR below and above 68 bpm. The shape of the CRF in subjects below 68 bpm is characterized by a shape similar to the canonical CRF, while in subjects with a HR above 68 bpm a well defined second maximum was identified around 17 s. Thus, in the present study, we provide evidence for the necessity to use mean HR-based CRFs, rather than one canonical CRF, in order to optimally describe the interaction between BOLD and HR signal in subjects with varying heart rates. PMID- 28887089 TI - Steviol, an aglycone of steviol glycoside sweeteners, interacts with the pregnane X (PXR) and aryl hydrocarbon (AHR) receptors in detoxification regulation. AB - Stevia rebaudiana Bertoni is a herb known for the high content of natural sweeteners in its leaves. Its main secondary metabolite stevioside is used as non caloric sweetener. No information, however, is available on whether stevioside or steviol interact with drug-metabolizing enzymes and pose the potential risk of food-drug interactions. Similarly, data are lacking on the interactions of steviol and stevioside with key nuclear receptors controlling the expression of the main drug metabolizing enzymes. We studied the interactions of steviol and stevioside with the pregnane X (PXR), vitamin D (VDR), constitutive androstane (CAR), farnesoid X (FXR), glucocorticoid (GR) and aryl hydrocarbon (AHR) receptors, which control expression of genes of xenobiotic metabolism. In addition, the inhibitory activities of steviol and stevioside towards the major cytochrome P450 enzymes CYP3A4, CYP2C9, CYP2D6, CYP1A2 and CYP2B6 were evaluated in vitro. We found that steviol moderately activated the PXR and AHR, resulting in the induction of their target genes including CYP3A4 and CYP1A2 in primary human hepatocytes. A weak inhibition of CYP3A4 and CYP2C9 with steviol was also found. Our results provide mechanistic data indicating that stevioside and stevia sweeteners may have the potential to induce food-drug interactions, a finding that warrants future prospective clinical investigation. PMID- 28887090 TI - Vitamin C partially prevents reproductive damage in adult male rats exposed to rosuvastatin during prepuberty. AB - Pediatric obesity is closely associated with dyslipidemias and environmental factors, such as diet and lack of physical exercises, which may alter lipid profile in children. Rosuvastatin decreases serum total cholesterol and triglycerides concentrations. Vitamin C (ascorbic acid) plays an important role on sperm integrity and fertility. Juvenile male rats were distributed into six experimental groups that received saline solution 0.9%, 3 or 10 mg/kg/day of rosuvastatin, 150 mg/day of ascorbic acid, or 3 or 10 mg/kg/day of rosuvastatin co-administered with 150 mg/day of ascorbic acid from PND23 until PND53 and then the rats were maintained until sexual maturity. Rosuvastatin-exposed groups showed lower sperm quality, androgen depletion and germ cell death. Ascorbic acid was capable to prevent partially the reproductive adverse effects provoked by rosuvastatin. In conclusion, prepubertal exposure to rosuvastatin provokes long term reproductive damages at sexual maturity and ascorbic acid supplementation at prepuberty may be a preventive mode against these reproductive adverse effects. PMID- 28887092 TI - Maternal cadmium exposure and impact on foetal gene expression through methylation changes. AB - Cadmium (Cd) exposure is not easily avoidable; it is a common contaminant found in many food sources, accumulates throughout life and, in high doses, is a significant health hazard for humans. Women are highly vulnerable to Cd because of their relatively higher absorption rate than men. High levels of Cd accumulated in the mother could potentially cause harm to both the mother and new born child. The foetal genome is vulnerable to external signals; Cd partially crosses the placental barrier and can impact on foetal development, potentially, through epigenetic mechanisms causing changes to foetal gene expression. This review explores current research on Cd induced methylation changes to maternal and foetal genomes. Cd is significantly associated with differential methylation of both maternal and foetal genomes. Some studies have described infant sex specific changes in DNA methylation in association with maternal Cd burden. However, research on methylation changes to the foetal genome due to prenatal Cd exposure is scarce. More research is required to explore the impact of maternal Cd accumulation on differential methylation of the foetal genome. PMID- 28887091 TI - RIFM fragrance ingredient safety assessment, 4-isopropyl-2-methoxy-1 methylbenzene, CAS Registry Number 6379-73-3. PMID- 28887093 TI - Repeated restraint stress increases seizure susceptibility by activation of hippocampal endoplasmic reticulum stress. AB - A growing body of evidence suggests that stress triggers a variety of pathophysiological responses. Recent studies show that stress produces enduring effects on structure and function of hippocampus, which is one of the most important structures involved in epilepsy. In the present study, we determined the effect of repeated restraint stress exposure on the susceptibility of pentylenetetrazole (PTZ)-induced seizures and the possible mechanisms involved using a rodent model. Our results show that mice subjected to repeated restraint stress exhibited shorter latency to PTZ-induced tonic-clonic seizures and higher seizure severity, suggesting chronic restraint stress increases seizure susceptibility. Following repeated restraint stress, we observed an increased level of endoplasmic reticulum (ER) stress as well as oxidative stress in the hippocampus. Moreover, our results show that chronic restraint stress exposure causes neuron loss in the hippocampus. Inhibition of ER stress with chemical chaperone, tauroursodeoxycholic acid (TUDCA), however, protects against chronic restraint stress-induced neuron loss, suggesting repeated restraint stress induced neuronal degeneration is dependent on ER stress activation. On the other hand, inhibition of ER stress with TUDCA suppresses restraint stress-induced seizure susceptibility. Taken together, these results indicate that repeated restraint stress increases seizure susceptibility by activation of hippocampal ER stress and ER stress mediated oxidative stress and neurodegeneration. Thus, attenuating ER stress may serve as a potential therapeutic strategy targeted to block stress-induced seizure activities. PMID- 28887094 TI - Salvianolic Acids for Injection (SAFI) promotes functional recovery and neurogenesis via sonic hedgehog pathway after stroke in mice. AB - There is a pressing need of developing approaches for delayed post-stroke therapy for patients who fail to receive thrombolysis within the narrow time window. Neuroprotection of Salvianolic Acids for Injection (SAFI) for cerebral ischemia reperfusion injury in acute phase has been well documented. The current study was to determine the influence of SAFI at the subacute phase after stroke in mice, and to elucidate the underlying mechanisms. Adult male C57BL/6 mice were subjected to permanent occlusion of the distal middle cerebral artery (dMCAO), followed by daily intraperitoneal injection of SAFI 24 h after stroke for 14 days. Motor behavior was measured by neurological function evaluations weekly, and proliferation, migration, survival and differentiation of neural progenitor cells (NPCs) were examined with immunohistochemistry. Sonic hedgehog (Shh) inhibitor cyclopamine (CYC) was injected to determine the involvement of Shh pathway in the therapeutic effects of SAFI. The results showed that SAFI led to dramatic brain functional improvement, elevated NPCs proliferation, and prompted long-term survival of newborn neurons in the subventricular zone (SVZ). Up regulation of Shh, Ptch and nuclear translocation of Gli1 were observed in the peri-infarct region, accompanied with robust production of Brain derived neurotrophic factor (BDNF) and Nerve growth factor (NGF). Simultaneous administration with CYC strikingly attenuated the beneficial outcomes of SAFI as well as abolished SAFI induced BDNF and NGF production. Collectively, our study demonstrated SAFI significantly promoted long-term functional recovery and neurogenesis, which might be dependent on Shh signaling mediated BDNF and NGF production. Therefore, SAFI might serve as a potential clinically translatable therapy during recovery stage after stroke. PMID- 28887095 TI - Psychological distress in patients undergoing surgery for urological cancer: A single centre cross-sectional study. AB - PURPOSE: Interest in the disease-specific psychological well-being of patients with cancer has increased, and it has been estimated that less than half of all patients with cancer are properly identified and subsequently treated for anxiety or depression. The aim of this study is to evaluate psychological distress in uro oncological patients undergoing different surgeries: radical cystectomy, radical prostatectomy, radical nephrectomy, or transurethral resection (TUR) before the surgery. MATERIALS AND METHODS: We performed a cross-sectional study in consecutively enrolled patients with bladder, kidney, or prostate cancer, scheduled for surgery. Demographic data, socioeconomic status, education level, and diagnoses were recorded. Patients with a previous diagnosis of depression or anxiety were excluded. We evaluated the level of clinically meaningful depression and anxiety assessed by 2 tools: the Hospital Anxiety and Depression Scale (HADS; score >=8 presence of anxiety and depression; score >=11 clinical anxiety and depression) and the State-Trait Anxiety Inventory (STAI). To determine variables related to depression and anxiety among the demographic variables, logistic regression analyses were conducted, with P<0.05 considered as statistically significant. RESULTS: A total of 207 patients were recruited, completed the questionnaires and were included in the study. Patients presented a mean age of 70.8 (+/-10.8) years, 89% were males (n = 184) and 19% of patients presented previous cancer. The majority of patients underwent surgery for bladder tumors (60.4%) and the most common type of surgery was TUR. The most frequent procedures were performed for bladder tumors (60.4%), being TUR the most common type of surgery (52.7%) followed by radical prostatectomy (24.6%). Mean STAI-State score was 19.3 (+/-10.3), and mean STAI-Trait score was 18.4 (+/-11.9) points. Clinical levels of anxiety and depression (HADS >= 11 points) were found in 19 (9.8%) and 7 (3.6%) cases. And HADS anxiety 8 to 10 points was present in 14.5% (n = 28) and HADS depression 8 to 10 points in 5.7% (n = 11) of the sample, representing presence of psychological distress. Female patients showed a higher level of anxiety and STAI-Trait compared to males. CONCLUSION: The present results show that our patients had lower levels of anxiety and depression than those described in the literature. Sex, tumor type, and surgical approach were significantly related to psychological distress in patients undergoing surgery for urological cancer. Females and patients with kidney tumor and patients undergoing radical nephrectomy presented higher levels of anxiety. Patients with radical cystectomy showed a higher level of STAI-State compared with other surgeries. PMID- 28887096 TI - Predicting local failure after radical cystectomy in patients with bladder cancer: Implications for the selection of candidates at adjuvant radiation therapy. AB - OBJECTIVE: To evaluate incidence and predictors of local failure (LF) after radical cystectomy (RC) due to bladder cancer. METHODS: We focused on 1,112 patients treated with RC, between 1990 and 2012, at a single center. LF was defined as imaging evidence of recurrence in the pelvic soft tissues or nodes below the aortic bifurcation at least 3 months before the detection of distant metastases. Competing risk analyses tested the relationship between clinical and pathological factors and the risk to develop LF. Regression tree analysis stratified patients into risk-groups based on their characteristics and the corresponding LF rate. RESULTS: Overall, 50 (4.5%) patients developed LF during a median follow-up period of 62 (35-92) months. On univariable competing risk regression analyses, pathological T stage (pT4 vs. pT3; hazard ratio [HR] = 2.55, P = 0.003), soft tissue surgical margin (STSM; HR = 2.95, P = 0.005), and variant histology (HR = 1.79, P = 0.03) were associated with an increased risk of developing LF. The cohort was stratified into 4 risk groups: very low (<=pT3a disease and pure urothelial histology), low (<=pT3a disease and variant histology), intermediate (pT4 disease), and high (positive STSM). CONCLUSIONS: LF is an important event in RC patients. We developed a new risk model based on bladder cancer characteristics. Our findings could help with the identification of the best candidate for consideration of adjuvant radiotherapy. PMID- 28887097 TI - Second-line systemic therapy in metastatic renal-cell carcinoma: A review. AB - Treatment in metastatic renal-cell carcinoma (mRCC) has evolved tremendously in the last decade. The development of newer targeted agents, like vascular endothelial growth factor inhibitors and immunotherapy have changed the treatment paradigm in mRCC patients. Axitinib and everolimus have been used extensively in patients who progressed on prior antiangiogenic therapy. The newer agents including nivolumab, cabozantinib, and lenvatinib in combination with everolimus have all demonstrated overall survival benefit over everolimus. However, with multiple treatment options, optimal choice and sequencing becomes challenging. This article provides an overview of different therapeutic options available as second-line treatment in patients with mRCC along with future directions. PMID- 28887098 TI - Investigation of a new pH-responsive nanoparticulate pore former for controlled release enteric coating with improved processability and stability. AB - Water-soluble polymers are often used as pore formers to tailor permeability of film-forming hydrophobic polymers on coated dosage forms. However, their addition to a coating formulation could significantly increase the viscosity thus making the coating process difficult. Moreover, the dissolution of pore formers after oral administration could compromise film integrity resulting in undesirable, inconsistent release profiles. Therefore, a non-leaching, pH-responsive nanoparticulate pore former is proposed herein to preserve film integrity and maintain pH-dependent permeability. Poly(methacrylic acid)-polysorbate 80-grafted starch terpolymer nanoparticles (TPNs) were incorporated within an ethylcellulose (EC) film (TPN-EC) by casting or spray coating. TPNs at 10%wt (pore former level) only increased viscosity of EC coating suspension slightly while conventional pore formers increased the viscosity by 490-11,700%. Negligible leaching of TPNs led to superior mechanical properties of TPN-EC films compared to Eudragit(r) L EC films. As pH increased from 1.2 to 6.8, TPN-EC films with 10% pore former level exhibited an 8-fold higher diltiazem permeability compared to Eudragit(r) L EC films. The pH-dependent drug release kinetics of diltiazem HCl beads coated with TPN-EC films was tunable by adjusting the pore former level. These results suggest that the TPNs are promising pH-sensitive nanoparticulate pore formers in EC-coated dosage forms. PMID- 28887100 TI - Verification of post-chemotherapeutic clearance of Theileria equi through concordance of nested PCR and immunoblot. AB - Certain countries including the United States remain non-endemic for particular infectious diseases such as equine piroplasmosis through import restrictions and surveillance. Endemic regions often employ premunition as the primary method to control disease, however in non-endemic countries, chemosterilization combined with methods to confirm parasite elimination are required to maintain disease free status. The ability of imidocarb diproprionate (ID) to clear persistent Theileria equi infection from infected horses has been shown through the inability of treated horses to transmit via blood transfer. However, the common lengthy persistence of anti-T. equi antibody causes regulatory tests such as cELISA or IFA to remain positive for extended periods. Persistence of positive testing creates challenges for regulatory veterinary medicine and international trade. Concordance between nested polymerase chain reaction (nPCR) targeting the ema1 gene and immunoblotting (IB) measuring declination in anti-EMA1 and anti EMA2 antibody were used to verify clearance of T. equi from 179 ID-treated horses. These data support the use of IB to demonstrate declining anti-EMA1 and EMA2 titers in T. equi-infected horses subsequent to successful ID treatment. Such data provide concordant support to a negative nPCR and allow for a more timely determination of effective ID clearance of T. equi. The post ID treatment results indicate that while nPCR was consistently negative by 14 days and cELISA generally remained positive after 1 year, immunoblot was on average negative after 4 months and 100% in agreement with nPCR. PMID- 28887099 TI - Enhancing biopharmaceutical performance of an anticancer drug by long chain PUFA based self-nanoemulsifying lipidic nanomicellar systems. AB - The aim of this study was to develop polyunsaturated fatty acid (PUFA) long chain glyceride (LCG) enriched self-nanoemulsifying lipidic nanomicelles systems (SNELS) for augmenting lymphatic uptake and enhancing oral bioavailability of docetaxel and compare its biopharmaceutical performance with a medium-chain fatty acid glyceride (MCG) SNELS. Equilibrium solubility and pseudo ternary phase studies facilitated the selection of suitable LCG and MCG. The critical material attributes (CMAs) and critical process parameters (CPPs) were earmarked using Placket-Burman Design (PBD) and Fractional Factorial Design (FFD) for LCG- and MCG-SNELS respectively, and nano micelles were subsequently optimized using I- and D-optimal designs. Desirability function unearthed the optimized SNELS with Temul <5min, Dnm <100nm, Rel15min >85% and Perm45min >75%. The SNELS demonstrated efficient biocompatibility and energy dependent cellular uptake, reduced P-gp efflux and increased permeability using bi-directional Caco-2 model. Optimal PUFA enriched LCG-SNELS exhibited distinctly superior permeability and absorption parameters during ex vivo permeation, in situ single pass intestinal perfusion, lymphatic uptake and in vivo pharmacokinetic studies over MCG-SNELS. PMID- 28887101 TI - Molecular, epidemiological, haematological and biochemical evaluation in asymptomatic Theileria annulata infected cattle from an endemic region in Spain. AB - Mediterranean theileriosis is one of the most fatal theilerioses, with considerable economic impact on livestock production. The potential consequences of asymptomatic infection on the animal's health and on the epidemiology in endemic regions are still unclear. The objectives of this study were to determine the molecular prevalence of T. annulata in a representative population of asymptomatic cattle in extensive management in Madrid, Central Spain, an area where practitioners frequently report cases of clinical theileriosis, and to evaluate the existence of associations between infection by this pathogen and haematological, biochemical and epidemiological data. T. annulata DNA was detected in 22.4% of the study population. The age was statistically associated with T. annulata prevalence rates, with a higher prevalence in cows older than 8 years (26.1%). Introduction of new cattle to the farm, grazing on pastures with other herds of cattle and previous history of clinical cases were statistically related to a higher prevalence of T. annulata infection. Herds with more than one ectoparasiticide treatment per year and that used more than one drug had significantly lower prevalences of infection with T. annulata. The location of farms in areas with a mean temperature higher than 17.1 degrees C and mean altitude lower than 962m was statistically associated with the presence of T. annulata. In our study, the mean values of haematological parameters were within the normal adult range, but it is noteworthy that some T. annulata-infected animals presented low values for red blood cell parameters. PMID- 28887102 TI - Molecular detection of vector-borne pathogens in Greek cats. AB - Infectious diseases have been increasingly recognized in cats worldwide. The objective of this study was the molecular investigation of the prevalence of selected pathogens in healthy and sick cats from Greece, a country highly endemic for several canine vector-borne pathogens. Blood and/or bone marrow samples from 50 clinically healthy and 50 sick adult (>1 year-old) cats were retrospectively examined for the amplification of Bartonella spp., haemoplasmas, Ehrlichia spp., Anaplasma spp., Babesia spp., and Cytauxzoon spp. DNA. Overall, 14.9% of the cats were found to be infected or co-infected by haemoplasmas, including Candidatus Mycoplasma haemominutum and M. haemofelis. In addition, 8.5% of the cats were infected by Bartonella henselae, Bartonella clarridgeiae or Bartonella koehlerae. In contrast, DNA of Ehrlichia spp., Anaplasma spp., Babesia spp. and Cytauxzoon spp. was not amplified from the blood or bone marrow of any cat. There was no significant difference in either haemoplasma or Bartonella infection rates when comparing healthy and sick cats. This study represents the first description of Bartonella koehlerae in Greek cats. PMID- 28887103 TI - Unusual glycosylation of proteins: Beyond the universal sequon and other amino acids. AB - BACKGROUND: Glycosylation of proteins is the most common, multifaceted co- and post-translational modification responsible for many biological processes and cellular functions. Significant alterations and aberrations of these processes are related to various pathological conditions, and often turn out to be disease biomarkers. Conventional N-glycosylation occurs through the recognition of the consensus sequon, asparagine (Asn)-X-serine (Ser)/threonine (Thr), where X is any amino acid except for proline, with N-acetylglucosamine (GlcNAc) as the first glycosidic linkage. Usually, O-glycosylation adds a glycan to the hydroxyl group of Ser or Thr beginning with N-acetylgalactosamine (GalNAc). SCOPE OF REVIEW: Protein glycosylation is further governed by additional diversifications in sequon and structure, which are yet to be fully explored. This review mainly focuses on the occurrence of N-glycosylation in non-consensus motifs, where Ser/Thr at the +2 position is substituted by other amino acids. Additionally, N glycosylation is also observed in other amide/amine group-containing amino acids. Similarly, O-glycosylation occurs at hydroxyl group-containing amino acids other than serine/threonine. The neighbouring amino acids and local structural features around the potential glycosylation site also play a significant role in determining the extent of glycosylation. All of these phenomena that yield glycosylation at the atypical sites are reported in a variety of biological systems, including different pathological conditions. CONCLUSION AND SIGNIFICANCE: Therefore, the discovery of more novel sequence patterns for N- and O-glycosylation may help in understanding the functions of complex biological processes and cellular functions. Taken together, all these information provided in this review would be helpful for the biological readers. PMID- 28887104 TI - Should we consider day-2 and day-3 embryo morphology before day-5 transfer when blastocysts reach a similar good quality? AB - Clinical outcomes of 291 day-5 blastocyst transfers carried out between January 2012 and March 2016 were retrospectively compared according to their quality at day 2 and 3. Inclusion criteria were female age younger than 37 years; first or second IVF and intracytoplasmic sperm injection cycle; quality of the transferred blastocyst: blastocoele B3 or higher; inner-cell-mass A/B; trophectoderm A/B; and known implantation outcome for each transferred blastocyst. Blastocysts were classified into good-quality and poor-quality embryo groups at day 2 and 3. Implantation (38.7% versus 41.4), clinical pregnancy (40.3% versus 45.9%), miscarriage (22.2% versus 26.7%;) and live birth rates (37.4% versus 38.8%) were comparable in day 2 good and poor-quality embryo groups. No signficiant differences in morphology of transferred blastocysts at day 3 were found. Multivariable analysis highlighted that poor or good embryo quality at day 2 and day 3 were not predictive of the implantation of good-quality blastocysts (at day 2: adjusted odds ratio = 0.82 CI 95% 0.49 to 1.38; at day 3: adjusted odds ratio = 1.39; CI 95% 0.77 to 2.52). Good-quality blastocyst transfer should, therefore, be carried out irrespective of embryo quality at cleavage stage, as it may not compromise success rates in a good-prognosis population. PMID- 28887105 TI - The significance of polymorphism and expression of oestrogen metabolism-related genes in Chinese women with premature ovarian insufficiency. AB - The aim of this study was to investigate whether polymorphism and expression of CYP17, CYP1A1, COMT and SULT1A1 affected the risk of idiopathic primary ovarian insufficiency (POI) in Chinese women. DNA sequencing and real-time PCR were used to detect these genes in 132 cases of idiopathic POI and 132 normal women. A significant increase in the C allele of CYP17 (rs743572) polymorphism was observed in women with POI compared with controls (PFDR = 0.046). A significant decrease was observed in the C allele of CYP1A1 (rs4646903) in women with POI compared with controls (PFDR = 0.004). The A allele of COMT (rs4680) polymorphism was more frequent in women with POI compared with controls (PFDR = 0.029). The genotypic frequency of SULT1A1 (rs9282861) was not significantly different between the two groups. For the relative expression of CYP17 and COMT were statistically significant (both PFDR = 0.066), with false discovery rate controlled at 0.1. No significant difference was observed in the RNA levels of CYP1A1 and SULT1A1 between the two groups. The frequency of expression of the CYP17 T/C variant tended to be higher and the A allele of COMT polymorphism together with down-regulation of its mRNA expression may be more frequent in Chinese women with idiopathic POI. PMID- 28887106 TI - Review the 'peer review'. AB - Peer review has been the main form of appraisal of scientific knowledge for over a century. In essence, this process involves the evaluation of a scientific finding by independent experts prior to its dissemination to the scientific community, in an attempt to ensure that both the research and conclusions meet the necessary standards regarding quality, accuracy, relevance and novelty. However, although 'peer review' is considered the current gold standard, it is far from perfect. A focus on the methodology of an article and reviewers' training are key messages for the scientific community. Guidelines on how to review an article are needed and may help reviewers deal with this difficult process. PMID- 28887107 TI - Efficacy of Systemic Treatments of Psoriasis on Pruritus: A Systemic Literature Review and Meta-Analysis. AB - In the course of the last 30 years, several studies have clearly documented that pruritus is a very frequent symptom of psoriasis and its impact on the patients' quality of life. The variety of available systemic treatments for psoriasis is increasing rapidly. Our objective was to assess their efficacy on pruritus based on a systematic literature review. A systematic literature search was performed using PubMed and Trip Database (from January 1990 to September 2016) to find published clinical trials for the treatments of psoriasis, and then a meta analysis was performed. Among 516 articles identified, 35 studies were retained in the systematic review. At baseline, the high prevalence of pruritus (80-100%) was confirmed. The meta-analysis included 13 trials using a 0 to 10 itch scale and highlighted that all treatments evaluated reduced pruritus. Anti-IL-17, JAK inhibitors, adalimumab, and apremilast were all shown to be effective in reducing pruritus in psoriasis with variable effect size magnitudes. Our systematic review highlights that systemic treatments, including UVB phototherapy, improve pruritus in psoriasis but that it is not necessarily correlated with lesion recovering. Nonetheless, these results must be displayed carefully because there are so many variable endpoints in different studies. PMID- 28887108 TI - Approach for the Derivation of Melanocytes from Induced Pluripotent Stem Cells. AB - Induced pluripotent stem (iPS) cells have the ability to differentiate into multiple cell types in the body and have an unlimited growth potential. However, iPS cell-derived melanocytes produced by existing protocols have significant limitations in developing novel strategies for regenerative medicine and cell therapies of pigmentation disorders in humans because they involve culture in media containing fetal bovine serum and nonphysiological agents. In this study, we established an in vitro approach to generate iPS cell-derived human melanocytes that have higher proliferation rates and increased melanin production compared with melanocytes prepared by previously reported approaches. Importantly, our iPS cell-derived human melanocytes are prepared in fetal bovine serum-free culture conditions that do not contain any nonphysiological agents. We designed two original methods, transferring black colonies by pipette and recovering black cell pellets from centrifuged medium, and numerous human iPS cell-derived melanocytes proliferated in gelatinous dishes coated with Matrigel after 12 days. We also succeeded in inducing melanin pigmentation in the nude mouse skin in vivo using those human iPS cell-derived melanocytes. We propose that this method using iPS cells established from T cells in the blood of normal human volunteers could be applied clinically to develop regenerative medicine and cell therapies for various forms of human pigmentation disorders. PMID- 28887109 TI - Early Identification of Patients With Acute Decompensated Heart Failure. AB - BACKGROUND: Interventions to reduce readmissions after acute heart failure hospitalization require early identification of patients. The purpose of this study was to develop and test accuracies of various approaches to identify patients with acute decompensated heart failure (ADHF) with the use of data derived from the electronic health record. METHODS AND RESULTS: We included 37,229 hospitalizations of adult patients at a single hospital during 2013-2015. We developed 4 algorithms to identify hospitalization with a principal discharge diagnosis of ADHF: 1) presence of 1 of 3 clinical characteristics, 2) logistic regression of 31 structured data elements, 3) machine learning with unstructured data, and 4) machine learning with the use of both structured and unstructured data. In data validation, algorithm 1 had a sensitivity of 0.98 and positive predictive value (PPV) of 0.14 for ADHF. Algorithm 2 had an area under the receiver operating characteristic curve (AUC) of 0.96, and both machine learning algorithms had AUCs of 0.99. Based on a brief survey of 3 providers who perform chart review for ADHF, we estimated that providers spent 8.6 minutes per chart review; using this this parameter, we estimated that providers would spend 61.4, 57.3, 28.7, and 25.3 minutes on secondary chart review for each case of ADHF if initial screening were done with algorithms 1, 2, 3, and 4, respectively. CONCLUSIONS: Machine learning algorithms with unstructured notes had the best performance for identification of ADHF and can improve provider efficiency for delivery of quality improvement interventions. PMID- 28887110 TI - Percutaneous Decommissioning of Left Ventricular Assist Device. AB - BACKGROUND: The left ventricular assist device (LVAD) has revolutionised our treatment of advanced stage heart failure, giving debilitated patients a new lease on life. A small proportion of these LVAD patients can be bridged-to recovery. The identification of these patients and decision to wean, however, can be challenging. METHODS: The need to fully explant the device upon recovery has evolved to a minimalist approach aiming to avoid injury to the 'recovered' heart. A review of the evolution of explant strategies was performed to guide our decision to wean the LVAD in our early experience. RESULTS: Between 2009 and 2014, two patients in our series of 69 LVAD implants (2.9%) were successfully weaned off their LVADs. The second patient had a minimal access implantation of his HeartWare Ventricular Assist Device (HVAD, Medtronic Inc, Framingham, MA, USA). His clinical variables and minimalist weaning strategy are described. CONCLUSIONS: A case of LVAD decommissioning by thrombosis of the outflow graft, using percutaneous Amplatzer Vascular Plug II (St. Jude Medical, St. Paul, MN, USA) without surgery is reported. PMID- 28887111 TI - Impairment of gill structural integrity by manganese deficiency or excess related to induction of oxidative damage, apoptosis and dysfunction of the physical barrier as regulated by NF-kappaB, caspase and Nrf2 signaling in fish. AB - This study is for the first time to explore the possible effects of dietary manganese (Mn) on structural integrity and the related signaling in the gills of fish. Grass carp (Ctenopharyngodon idella) were fed with six diets containing graded levels of Mn [3.65-27.86 mg Mn/kg diet] for 8 weeks. The results firstly demonstrated that Mn deficiency aggravated inflammation indicated by up regulation of pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin 8, and interleukin 1beta mRNA levels) and down-regulation of anti inflammatory cytokines (interleukin 10, transforming growth factor-beta1) mRNA levels, which might be partially related to the up-regulation of nuclear factor kappa B (NF-kappaB p65) and down-regulation of nuclear inhibitor factor kappaBalpha (ikappaBalpha) mRNA levels in the gills of fish. Meanwhile, Mn deficiency caused DNA fragmentation, which might be partially associated with the up-regulation of the apoptosis signaling (caspase-3, caspase-8 and caspase-9) in the gills of fish. Furthermore, Mn deficiency-caused apoptosis might be partly related to the increases of oxidative damage that indicated by increases of lipid peroxidation and protein oxidation, and decreases of antioxidant enzyme activities [included Mn superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST)]. However, Mn deficiency only down-regulated MnSOD and GST mRNA levels, which might be partially related to the up-regulation of NF-E2-related factor-2 (Nrf2) inhibitor (Keap1), and only down-regulated the gene expression of claudin b and claudin-15 to disrupt the TJ in the gills of fish. Excessive Mn led to negative effects on partial parameters studied in the gills of fish. The optimal levels of Mn based on protecting against ROS, MDA and PC in the gills of grass carp were 17.04, 16.86 and 21.20 mg/kg diet, respectively. Collectively, Mn deficiency or excess could cause inflammation, apoptosis, antioxidant system disruption and change tight junction protein (claudin-b and claudin-15) transcription abundances, which might be partially related to the NF-kappaB p65, caspase-(3,8,9) and Nrf2 signaling, in the gills of fish. PMID- 28887112 TI - Protein and lipid interactions - Modulating CFTR trafficking and rescue. AB - Different levels of CFTR regulation in the cell contribute to a stringent control of chloride secretion in epithelia. Tuning of chloride transport is achieved by modulating CFTR biogenesis, exit from the endoplasmic reticulum, trafficking, membrane stability and channel activity. In this short review, we summarize recent findings identifying interactions with other proteins - directly or through membrane lipids - and briefly discuss how these observations can provide clues to the design of better therapeutic approaches. PMID- 28887113 TI - Primary (Month-6) Outcomes of the STOP-Uveitis Study: Evaluating the Safety, Tolerability, and Efficacy of Tocilizumab in Patients With Noninfectious Uveitis. AB - PURPOSE: To report the primary endpoint analyses of the safety and efficacy of 2 different doses of intravenous (IV) infusions of tocilizumab (TCZ), an IL-6 inhibitor, in eyes with noninfectious intermediate uveitis, posterior uveitis, or panuveitis. DESIGN: Randomized, controlled, multicenter clinical trial. METHODS: STOP-Uveitis is a randomized, open-label safety, efficacy, and bioactivity clinical trial conducted at 5 clinical centers across the United States. The study evaluated the role of TCZ in patients with noninfectious uveitis (NIU). Thirty-seven patients with NIU were randomized into one of 2 treatment groups in a ratio of 1:1. Group 1 received IV infusions of 4 mg/kg TCZ and group 2 received IV infusions of 8 mg/kg TCZ. Infusions were given every 4 weeks in both groups until month 6 (primary endpoint). Primary outcome measure was incidence and severity of systemic and ocular adverse events through month 6. Secondary outcome measures included mean change in visual acuity (VA), vitreous haze (VH), and central macular thickness (CMT) at month 6. RESULTS: A total of 37 patients were randomized in the study. At month 6, 43.5% of patients who had the potential for a 2-step decrease in VH demonstrated a 2-step decrease (40% in Group 1 and 46.1% in Group 2). Mean change in CMT was -83.88 +/- 136.1 MUm at month 6 (-131.5 +/- 41.56 MUm in Group 1 and -38.92 +/- 13.7 MUm in Group 2). Mean change in VA was +8.22 +/- 11.83 ETDRS letters at month 6 (10.9 +/- 14.6 in Group 1 and 5.5 +/- 7.8 in Group 2). Repeated infusions of TCZ were well tolerated. CONCLUSIONS: Repeated IV administrations of TCZ are well tolerated. TCZ (both 4 and 8 mg/kg) is effective in improving VA and reducing VH and CMT in eyes with noninfectious intermediate uveitis, posterior uveitis, and panuveitis. PMID- 28887114 TI - Cataract Surgery From 1918 to the Present and Future-Just Imagine! AB - PURPOSE: To review the history of cataract surgery over the past 100 years, and to offer predictions about new developments that may occur during the next 50 years. DESIGN: Interpretive essay. METHODS: Review of historical literature and author experiences pertaining to cataract surgery, with commentary and perspective. RESULTS: By this time, cataract surgery has advanced to the point that Kelman's introduction of phacoemulsification and use of intraocular lenses (IOLs), both very controversial when initially introduced, have become state of the art. Outpatient surgery, minimally limited mobility, sutureless incisions, and topical anesthesia also have become key components of standard treatment. The author envisions availability of medications for nuclear sclerosis and presbyopia, expansion of lens surgery for refractive purposes with postsurgical adjustment and unprecedented precision, increased mechanization of lens removal with emphasis on uncomplicated surgery rather than refractive precision, and accommodating IOLs all becoming standard. CONCLUSIONS: Acknowledging and appreciating the past contributions of pioneers in cataract surgery is vital to understanding the development of today's clinical care. Clues as to the future do help give us a possible scenario worthy of such conjecture. PMID- 28887116 TI - Residual Angle Closure One Year After Laser Peripheral Iridotomy in Primary Angle Closure Suspects. AB - PURPOSE: To determine the incidence and baseline clinical and anterior segment optical coherence tomography (AS-OCT) predictors associated with residual angle closure as assessed by gonioscopy 1 year after laser peripheral iridotomy (LPI) in primary angle closure suspects (PACS). DESIGN: Subanalysis of randomized controlled trial data. METHODS: AS-OCT images from 181 PACS subjects >=50 years of age were analyzed using customized software before and 1 year after LPI. Other parameters assessed were intraocular pressure (IOP) and axial length (Axl). Residual angle closure was defined as the inability to see the posterior trabecular meshwork for at least 2 quadrants on gonioscopy after LPI. Multivariate regression analysis determined the baseline predictors of residual angle closure 1 year after LPI. RESULTS: The mean age of participants was 62.4 (standard deviation 9.9) years. The majority were female (137, 75.7%) and Chinese (174, 96.1%). At 1 year post LPI, 148 (81.8%) subjects had gonioscopic residual angle closure. Univariate analysis showed that baseline Axl, anterior chamber area, anterior chamber volume, angle opening distance at 750 MUm from the scleral spur, and angle recess area were smaller while baseline lens vault and iris curvature were larger in residual angle closure subjects (all P < .05). Multivariate analysis revealed that baseline iris volume (B = -0.08, P = .035) and baseline IOP (B = 0.23, P = .032) were predictors for residual angle closure. CONCLUSIONS: One year after LPI, >80% of PACS had gonioscopic residual angle closure. Greater baseline iris volume and higher IOP at baseline are independent risk factors for residual gonioscopic angle closure. PMID- 28887117 TI - Analysis of Cytokine Levels in Tears and Clinical Correlations After Intense Pulsed Light Treating Meibomian Gland Dysfunction. AB - PURPOSE: To investigate the change from baseline of inflammatory markers in tears of dry eye disease (DED) subjects owing to meibomian gland dysfunction (MGD) after intense pulsed light (IPL) treatment and meibomian gland expression (MGE) compared to sham treatment, and the correlations with ocular surface parameters. DESIGN: Randomized, double-masked, controlled study. METHODS: Those randomized into the active treatment arm received 3 consecutive treatments (14~16 J/cm2) approximately 4 weeks apart in the periocular region. Control eyes received 3 treatments in the same intervals of 0 J/cm2. Tear samples in all eyes were collected and analyzed at baseline, week 12, and/or week 4 for interleukin (IL) 17A, IL-6, and prostaglandin E2 (PGE2). The correlations between cytokines and ocular surface parameters were analyzed before and after IPL treatment. RESULTS: All of the inflammatory markers declined in value compared to baselines. IL-17A and IL-6 showed statistically significant decreases compared to sham treatment at each measured time point. PGE2 showed statistically significant decreases compared to sham at week 12. Results showed that the expressions of IL-17A and IL 6 correlated well with ocular surface parameters of the lower eyelid before IPL. The changed values of IL-6 and PGE2 in tears correlated with the changed values of partial ocular surface parameters after IPL treatment in study eyes, respectively. CONCLUSIONS: The study results suggest that IPL can significantly reduce inflammatory markers in tears of patients suffering with DED owing to MGD after IPL treatment. These findings indicate that IL-17A and IL-6 play roles in the pathogenesis of DED owing to MGD, and the reduction of the inflammatory factors is consistent with the improvement of partial clinical symptoms and signs. PMID- 28887115 TI - Blau Syndrome-Associated Uveitis: Preliminary Results From an International Prospective Interventional Case Series. AB - PURPOSE: Provide baseline and preliminary follow-up results in a 5-year longitudinal study of Blau syndrome. DESIGN: Multicenter, prospective interventional case series. METHODS: Baseline data from 50 patients from 25 centers worldwide, and follow-up data for patients followed 1, 2, or 3 years at the end of study enrollment. Ophthalmic data were collected at baseline and yearly visits by means of a standardized collection form. RESULTS: Median age at onset of eye disease was 60 months and duration of eye disease at baseline 145 months. At baseline 38 patients (78%) had uveitis, which was bilateral in 37 (97%). Eight patients (21%) had moderate to severe visual impairment. Panuveitis was found in 38 eyes (51%), with characteristic multifocal choroidal infiltrates in 29 eyes (39%). Optic disc pallor in 9 eyes (12%) and peripapillary nodules in 9 eyes (12%) were the commonest signs of optic nerve involvement. Active anterior chamber inflammation was noted in 30 eyes (40%) at baseline and in 16 (34%), 17 (57%), and 11 (61%) eyes at 1, 2, and 3 years, respectively. Panuveitis was associated with longer disease duration. At baseline, 56 eyes (75%) were on topical corticosteroids. Twenty-six patients (68%) received a combination of systemic corticosteroids and immunomodulatory therapy. CONCLUSIONS: Blau uveitis is characterized by progressive panuveitis with multifocal choroiditis, resulting in severe ocular morbidity despite continuous systemic and local immunomodulatory therapy. The frequency and severity of Blau uveitis highlight the need for close ophthalmologic surveillance as well as a search for more effective therapies. PMID- 28887118 TI - Trabecular Meshwork Height in Primary Open-Angle Glaucoma Versus Primary Angle Closure Glaucoma. AB - PURPOSE: To determine if trabecular meshwork (TM) height differs between primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) eyes. DESIGN: Prospective, cross-sectional clinical study. METHODS: Adult patients were consecutively recruited from glaucoma clinics at the University of California, San Francisco, from January 2012 to July 2015. Images were obtained from spectral domain optical coherence tomography (Cirrus OCT; Carl Zeiss Meditec, Inc, Dublin, California, USA). Univariate and multivariate linear mixed models comparing TM height and glaucoma type were performed to assess the relationship between TM height and glaucoma subtype. Mixed-effects regression was used to adjust for the use of both eyes in some subjects. RESULTS: The study included 260 eyes from 161 subjects, composed of 61 men and 100 women. Mean age was 70 years (SD 11.77). There were 199 eyes (123 patients) in the POAG group and 61 eyes (38 patients) in the PACG group. Mean TM heights in the POAG and PACG groups were 812 +/- 13 MUm and 732 +/- 27 MUm, respectively, and the difference was significant in univariate analysis (P = .004) and in multivariate analysis (beta = -88.7 [24.05 153.5]; P = .008). CONCLUSION: In this clinic-based population, trabecular meshwork height is shorter in PACG patients compared to POAG patients. This finding may provide insight into the pathophysiology of angle closure and provide assistance in future diagnosis, prevention, and management of the angle-closure spectrum of disorders. PMID- 28887119 TI - Respiratory syncytial virus associated hospitalizations in children with congenital diaphragmatic hernia. AB - BACKGROUND: To evaluate the risk of RSV infection in infants and children with congenital diaphragmatic hernia (CDH) over two consecutive RSV seasons. METHODS: Retrospective, single-center cohort study from southern Austria including infants with CDH born between 1993 and 2012. Infants were retrieved by searching via ICD 10 codes Q79.0 and Q79.1 and by using a local electronic database. Children were followed over 2 years of life including at least two consecutive RSV seasons (November to April). We also defined a group of hypothetical RSV infections with the following criteria: 70% of the admissions due to a respiratory infection (diagnosis of bronchiolitis and/or LRI score >=3) during the RSV seasons over the first 2 years of life, when no test for RSV was performed. RESULTS: Twenty-nine of 45 infants with CDH comprised the study population (6 were lost to follow-up and 10 died) of whom 9 (31%) exhibited 17 hospitalizations due to respiratory illness. Two hospitalized infants (6.9% of the study population) tested RSV positive, one during the first and the other during the second RSV season. Nine of 29 infants (31%) had documentation of palivizumab prophylaxis, none (0%) had proven RSV hospitalization compared to 1 of 20 (5%) without prophylaxis during the first RSV season (p = 0.256). Including the hypothetical cases, we calculated 0 of 9 (0%) in the palivizumab group and 4 of 20 (20%) in the group without prophylaxis (p = 0.079). CONCLUSIONS: We found a moderate rate of proven RSV hospitalizations in infants with CDH, and palivizumab prophylaxis led to a non significant reduction of proven and hypothesized RSV hospitalizations. PMID- 28887120 TI - Increased expression of interleukin-21 along colorectal adenoma-carcinoma sequence and its predicating significance in patients with sporadic colorectal cancer. AB - The role and significance of interleukin (IL)-21 in the development of sporadic CRC have not been well defined. The aim of this study is therefore to investigate the dynamics of the IL-21 along colorectal adenoma-carcinoma sequence and to evaluate the impact of IL-21 on clinicopathological parameters and CRC prognosis. The real-time PCR results showed that the level of IL-21 in adenomas (n=50) and sporadic CRC (n=50) were significantly higher than that in normal controls (n=18), which were predominately observed in the adenoma/CRC stroma. Analysis revealed that IL-21 level was correlated with the overall survival time in CRC patients. Double immunofluorescence observations confirmed that IL-21 positive cells were mostly natural killer cells and T lymphocytes in the tumor stroma. These results indicate that significant increased IL-21 expression present within the adenoma/CRC microenvironment might have a potential predicating significance for survival time in patients with CRC. PMID- 28887121 TI - Discovery of human scFvs that cross-neutralize the toxic effects of B. jararacussu and C. d. terrificus venoms. AB - Accidents involving venomous snakes are a public health problem worldwide, causing a large number of deaths per year. In Brazil, the majority of accidents are caused by the Bothrops and Crotalus genera, which are responsible for approximately 80% of severe envenoming cases. The cross-neutralization of snake venoms by antibodies is an important issue for development of more effective treatments. Our group has previously reported the construction of human monoclonal antibody fragments towards Bothrops jararacussu and Crotalus durissus terrificus' venoms. This study aimed to select human single-chain variable fragments (scFvs) that recognize both bothropic and crotalic crude venoms following venoms neutralizing capacity in vitro and in vivo. The cross-reactivity of Cro-Bothrumabs were demonstrated by ELISA and in vitro and in vivo experiments showed that a combination of scFvs neutralizes in vitro toxic activities (e.g. indirect hemolysis and plasma-clotting) of crotalic and bothropic venoms as well as prolonged survival time of envenomed animals. Our results may contribute to the development of the first human polyvalent antivenom against Bothrops jararacussu and Crotalus durissus terrificus venoms, overcoming some undesirable effects caused by conventional serotherapy. PMID- 28887122 TI - Blastocystis subtypes detected in long-tailed macaques in Thailand-Further evidence of cryptic host specificity. AB - Blastocystis is an enteric parasitic protist with a widespread distribution in a variety of human and non-human hosts and supposedly a source of zoonotic transmission. This study aimed to determine the frequency and distribution of Blastocystis subtypes in free-ranging Macaca fascicularis (long-tailed macaques, LTMs) in Thailand. A total of 628 faecal samples were collected from free-ranging LTMs inhabiting fourteen tourist attraction sites in Thailand. Fresh faecal samples were individually cultured in Jones' medium, and Blastocystis-positive samples were subtyped using nuclear small subunit ribosomal DNA (SSU rDNA) sequencing. Two hundred and sixty-three (41.87%) samples were positive by culture, and 197 and 154 were successfully SSU rDNA-amplified and sequenced, respectively. Three subtypes (ST1, ST2, and ST3) comprising 19 alleles were observed. ST3 was the most common subtype detected (36.55%), followed by ST2 and ST1 (24.37% and 17.26%, respectively). Some subtype alleles not previously observed were identified. A couple of strains appeared similar to those found in humans as evidenced by SSU rDNA allelic profiles, while further evidence of cryptic host specificity emerged. This study provides the first data on Blastocystis subtypes in non-human primates in Thailand and confirms the trend observed in other Old-World countries with regard to the colonization rate and subtype distribution. PMID- 28887123 TI - Third record of Rhodnius amazonicus and comparative study with R. pictipes (Hemiptera, Reduviidae, Triatominae). AB - Rhodnius amazonicus Almeida et al. (1973) is a triatomine of rare occurrence. This species was found for the third time in Breves city, Para state, Brazil. Morphometric and morphological studies were carried out on one male and one female. Lent and Wygodzinsky (1979) considered this species as a synonym of R. pictipes, until its revalidation after 23 years by Berenger and Pluot-Sigwalt (2002). Considering the synonym mentioned above, a comparative study between these two species was performed in order to report the third encounter of this species, and increase the number of morphological characters that distinguish R. amazonicus from R. pictipes. The dorsal side of the head, the dorsal and ventral portions of the thorax, the dorsal, ventral and posterior sides of the female genitalia, eggs and the median process of the pygophore were examined by scanning electronic microscopy (SEM). The head, thorax, abdomen and egg parameters of these two species were also measured. The identification of characters on the head, stridulatory sulcus, mesosternum, metasternum, scutellum, process of urotergite I, external female genitalia, pygophore and eggs made the distinction between R. amazonicus and R. pictipes possible. This study has shown the new characters recorded and described for the first time for R. amazonicus and R. pictipes by SEM here made it possible to confirm the morphological separation between these two species. The morphometric analysis also confirmed that the above two taxa are different at specific level. PMID- 28887124 TI - Impaired insulin signaling upon loss of ovarian function is associated with a reduction of tristetraprolin and an increased stabilization of chemokine in adipose tissue. AB - Loss of ovarian function can activate inflammation and lead to insulin resistance (IR). IR is also a core feature of obesity and obesity-associated metabolic dysfunction. Tristetraprolin/zinc finger protein 36 (TTP) interferes with TNF alpha production by destabilizing TNF-alpha mRNA, and mice deficient in TTP develop a complex syndrome of inflammatory disease (Carballo et al., 1998; Taylor et al., 1999). We hypothesized that ovariectomy (OVX) might also prime inflammation by reducing tristetraprolin/zinc finger protein 36 (TTP) levels. We used a mouse OVX model to study impaired insulin signaling due to loss of ovarian function by evaluating Akt activity upon insulin stimulus. Impaired insulin signaling was initially detected in adipose tissue (AT) at 4 weeks after OVX, and then spread to liver and muscle, finally resulting in systemic IR at 12 weeks after OVX. OVX decreased TTP protein levels and increased adipocyte size, oxidative stress, chemokine expression and fat mass in AT by 4 weeks after surgery. TTP deficiency due to TTP gene deletion induced aberrant insulin signaling and increased chemokine expression and macrophage numbers in AT but did not increase adipocyte size, oxidative stress, or fat mass, suggesting that it promotes insulin signaling by decreasing AT inflammation independent of oxidative stress and adiposity. OVX, like TTP deficiency, increased the stability of chemokine transcripts as assessed from their half-lives. Our data indicate that the impaired insulin signaling resulting from OVX is due to an OVX-induced reduction of TTP and the resulting stabilization of inflammatory chemokines. PMID- 28887125 TI - Initiatives to Achieve Excellence in the Care of Acute Coronary Syndrome. Response. PMID- 28887126 TI - Introduction: The European Association of Epilepsy Centers (EAEC). PMID- 28887127 TI - The Epilepsy-Center Berlin-Brandenburg, Germany. PMID- 28887128 TI - Introduction to the International Bureau for Epilepsy (IBE) platform and its newly elected president Martin Brodie. PMID- 28887129 TI - Disulfiram is a slow-binding partial noncompetitive inhibitor of 20S proteasome activity. AB - The alcohol abuse drug disulfiram has also been shown to exhibit potent cell growth inhibitory and anticancer activity. While a number of cellular and animal studies have suggested that disulfiram exhibits its anticancer activity through interaction with the proteasome, direct evidence for inhibition of proteasome activity is lacking. In this study we show that disulfiram potently inhibits the chymotrypsin-like activity of purified human 20S proteasome at low micromolar pharmacological concentrations. The enzyme progress curves displayed characteristics of a slow-binding reaction, similar to that observed for the FDA approved proteasomal-targeted anticancer drugs bortezomib and carfilzomib. The apparent second order rate constant for reaction with 20s proteasome that was derived from an analysis of the progress curves was about 250-fold smaller than for bortezomib and carfilzomib. The concentration dependence of the enzyme kinetics was consistent with partial noncompetitive inhibition, whereby the putative disulfiram-proteasome adduct retains, partial but decreased enzyme activity. Disulfiram, which is known to have a high affinity for protein thiols, likely reacted with a non-critical cysteine residue, and not at the proteasome substrate binding site. PMID- 28887130 TI - Gender-specific impairment of in vitro sinoatrial node chronotropic responses and of myocardial ischemia tolerance in rats exposed prenatally to betamethasone. AB - Excessive fetal glucocorticoid exposure has been linked to increased susceptibility to hypertension and cardiac diseases in the adult life, a process called fetal programming. The cardiac contribution to the hypertensive phenotype of glucocorticoid-programmed progeny is less known, therefore, we investigated in vitro cardiac functional parameters from rats exposed in utero to betamethasone. Pregnant Wistar rats received vehicle (VEH) or betamethasone (BET, 0.1mg/kg, i.m.) at gestational days 12, 13, 18 and 19. Male and female offspring were killed at post-natal day 30 and the right atrium (RA) was isolated to in vitro evaluation of drug-induced chronotropic responses. Additionally, whole hearts were retrograde-perfused in a Langendorff apparatus and infarct size in response to in vitro ischemia/reperfusion (I/R) protocol was evaluated. Male and female progeny from BET-exposed pregnant rats had reduced birth weight, a hallmark of fetal programming. Male BET-progeny had increased basal RA rate, impaired chronotropic responses to noradrenaline and adenosine, and increased myocardial damage to I/R. Though a 12-fold reduction in the negative chronotropic responses to adenosine, the effects of non-metabolisable adenosine receptor agonists 5'-(N ethylcarboxamido)adenosine or 2-Chloro-adenosine were not different between VEH- and BET-exposed male rats. BET-exposed female offspring presented no cardiac dysfunction. Prenatal BET exposure engenders male-specific impairment of sinoatrial node function and on myocardial ischemia tolerance resulting, at least in part, from an increased adenosine metabolism in the heart. In light of the importance of adenosine in the cardiac physiology our results suggest a link between reduced adenosinergic signaling and the cardiac dysfunctions observed in glucocorticoid-induced fetal programming. PMID- 28887131 TI - Prostacyclin mimetics afford protection against lipopolysaccharide/d galactosamine-induced acute liver injury in mice. AB - Prostacyclin (PGI2) serves as a protective, anti-inflammatory mediator and PGI2 mimetics may be useful as a hepatoprotective agent. We examined whether two PGI2 mimetics, ONO-1301 and beraprost, are beneficial in acute liver injury and attempted to delineate the possible mechanism underlying the hepatoprotective effect. Acute liver injury was induced by lipopolysaccharide/d-galactosamine (LPS/GalN) in mice. Mice were given an intraperitoneal injection of PGI2 mimetics 1h before LPS/GalN challenge. Both ONO-1301 and beraprost significantly declined the LPS/GalN-induced increase in serum aminotransferase activity. ONO-1301 and, to a lesser extent, beraprost inhibited hepatic gene expression levels of pro inflammatory cytokines, which were sharply elevated by LPS/GalN. The hepatoprotective effects of ONO-1301, to a lesser extent, of beraprost were also supported by liver histopathological examinations. The PGI2 receptor antagonist CAY10441 abrogated their hepatoprotective effects. The mechanisms behind the benefit of PGI2 mimetics in reducing LPS/GalN-induced liver injury involved, in part, their suppressive effects on increased generation of reactive oxygen species (ROS), since their ability to prevent LPS/GalN-induced hepatic apoptosis was mimicked by the antioxidant N-acetyl-l-cysteine. They significantly diminished LPS/GalN-induced activation of signal transducers and activators of transcription 3 (STAT3) in liver tissues, an effect which was highly associated with their hepatoprotective effects. We indicate that IP receptor activation with PGI2 mimetics can rescue the damage in the liver induced by LPS/GalN by undermining activation of STAT3 and leading to a lower production of ROS. Our findings point to PGI2 mimetics, especially ONO-1301, as a potential novel therapeutic modality for the treatment of acute liver injury. PMID- 28887132 TI - Structure and diversity of human dendritic spines evidenced by a new three dimensional reconstruction procedure for Golgi staining and light microscopy. AB - BACKGROUND: Different approaches aim to unravel detailed morphological features of neural cells. Dendritic spines are multifunctional units that reflect cellular connectivity, synaptic strength and plasticity. NEW METHOD: A novel three dimensional (3D) reconstruction procedure is introduced for visualization of dendritic spines from human postmortem brain tissue using brightfield microscopy. The segmentation model was based on thresholding the intensity values of the dendritic spine image along 'z' stacks. We used median filtering and removed false positives. Fine adjustments during image processing confirmed that the reconstructed image of the spines corresponded to the actual original data. RESULTS: Examples are shown for the cortical amygdaloid nucleus and the CA3 hippocampal area. Structure of spine heads and necks was evaluated at different angles. Our 3D reconstruction images display dendritic spines either isolated or in clusters, in a continuum of shapes and sizes, from simple to more elaborated forms, including the presence of spinule and complex 'thorny excrescences'. COMPARISON WITH EXISTING METHODS: The procedure has the advantages already described for the adapted "single-section" Golgi method, since it provides suitable results using human brains fixed in formalin for long time, is relatively easy, requires minimal equipment, and uses an algorithm for 3D reconstruction that provides high quality images and more precise morphological data. CONCLUSION: The procedure described here allows the reliable visualization and study of human dendritic spines with broad applications for normal controls and pathological studies. PMID- 28887133 TI - Potential of insulin nanoparticle formulations for oral delivery and diabetes treatment. AB - Nanoparticles have demonstrated significant advancements in potential oral delivery of insulin. In this publication, we review the current status of polymeric, inorganic and solid-lipid nanoparticles designed for oral administration of insulin. Firstly, the structure and physiological function of insulin are examined. Then, the efficiency and shortcomings of insulin nanoparticle are discussed. These include the susceptibility to digestive enzyme degradation, instability in the acidic pH environment, poor mucus diffusion and inadequate permeation through the gastrointestinal epithelium. In order to optimise the nanocarriers, the following considerations, including polymer nature, surface charge, size, polydispersity index and morphology of nanoparticles, have to be taken into account. Some novel designs such as chitosan based glucose-responsive nanoparticles, layer by layer technique-based nanoparticles and zwitterion nanoparticles are being adopted to overcome the physiological challenges. The review ends with some future directions and challenges to be addressed for the success of oral delivery of insulin-loaded nanoparticle formulation. PMID- 28887135 TI - Progress in brain targeting drug delivery system by nasal route. AB - : The blood-brain barrier (BBB) restricts the transport of potential therapeutic moieties to the brain. Direct targeting the brain via olfactory and trigeminal neural pathways by passing the BBB has gained an important consideration for delivery of wide range of therapeutics to brain. Intranasal route of transportation directly delivers the drugs to brain without systemic absorption, thus avoiding the side effects and enhancing the efficacy of neurotherapeutics. Over the last several decades, different drug delivery systems (DDSs) have been studied for targeting the brain by the nasal route. Novel DDSs such as nanoparticles (NPs), liposomes and polymeric micelles have gained potential as useful tools for targeting the brain without toxicity in nasal mucosa and central nervous system (CNS). Complex geometry of the nasal cavity presented a big challenge to effective delivery of drugs beyond the nasal valve. Recently, pharmaceutical firms utilized latest and emerging nasal drug delivery technologies to overcome these barriers. This review aims to describe the latest development of brain targeted DDSs via nasal administration. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE: Carbopol 934p (PubChem CID: 6581) Carboxy methylcellulose (PubChem CID: 24748) Penetratin (PubChem CID: 101111470) Poly lactic-co-glycolic acid (PubChem CID: 23111554) Tween 80 (PubChem CID: 5284448). PMID- 28887134 TI - Decreased non-specific adhesivity, receptor targeted (DART) nanoparticles exhibit improved dispersion, cellular uptake, and tumor retention in invasive gliomas. AB - The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, microvascular proliferation, immune system suppression, and brain tissue invasion. Delivering effective and sustained treatments to the invasive GBM cells intermixed with functioning neural elements is a major goal of advanced therapeutic systems for brain cancer. Previously, we investigated the nanoparticle characteristics that enable targeting of invasive GBM cells. This revealed the importance of minimizing non-specific binding within the relatively adhesive, 'sticky' microenvironment of the brain and brain tumors in particular. We refer to such nanoformulations with decreased non-specific adhesivity and receptor targeting as 'DART' therapeutics. In this work, we applied this information toward the design and characterization of biodegradable nanocarriers, and in vivo testing in orthotopic experimental gliomas. We formulated particulate nanocarriers using poly(lactic-co-glycolic acid) (PLGA) and PLGA-polyethylene glycol (PLGA-PEG) polymers to generate sub-100nm nanoparticles with minimal binding to extracellular brain components and strong binding to the Fn14 receptor - an upregulated, conserved component in invasive GBM. Multiple particle tracking in brain tissue slices and in vivo testing in orthotopic murine malignant glioma revealed preserved nanoparticle diffusivity and increased uptake in brain tumor cells. These combined characteristics also resulted in longer retention of the DART nanoparticles within the orthotopic tumors compared to non-targeted versions. Taken together, these results and nanoparticle design considerations offer promising new methods to optimize therapeutic nanocarriers for improving drug delivery and treatment for invasive brain tumors. PMID- 28887136 TI - Non-covalent formulation of active principles with dendrimers: Current state-of the-art and prospects for further development. AB - During the last three decades, dendrimers, nano-sized highly-branched fractal like symmetrical macromolecules, have been intensively studied as promising candidates for application as drug-delivery carriers. Among other important characteristics arising from their unique and highly-controlled architecture, size and surface properties, the possibility of hosting guest molecules in internal voids represents a key advantage underlying the potential of dendrimers as non-covalent drug-encapsulating agents. The impressive amount of accumulating experimental results to date allows researchers to identify the most important and promising theoretical and practical aspects of the use of dendrimers for this purpose. This review covers the main factors, phenomena, and mechanisms involved in this drug-vectorization approach, including mechanisms of non-covalent dendrimer-drug association, dendrimer-dendrimer interactions, as well as biological properties relevant to the host dendrimers. A discussion is then provided to illustrate some successful existing formulation strategies as well as to propose some new possible ones to optimize further development of the field. PMID- 28887137 TI - Effects of a high level of illumination before sleep at night on chorioretinal thickness and ocular biometry. AB - The choroid is affected by many factors. One of the factors, change in illumination has been suggested to influence choroidal thickness. However, the effects of bright light before sleep at night on the human eye are not well established. The purpose of this study was to investigate the effects of a high level of illumination in the evening on ocular measurements. Twenty-seven men with myopia spent seven consecutive nights in the sleep laboratory. During the first two nights, subjects were exposed to light at 150 lux between 20:00 and midnight. Then, for five consecutive nights, they were exposed to ambient light at 1000 lux between 20:00 and midnight. Ocular parameters and their diurnal variations were compared between the two periods and the effects of a high level of illumination were analyzed. After subjects were exposed to 1000 lux of illumination, axial length increased with borderline significance (p = 0.064). Macular volume and retinal thickness did not change. However, subfoveal choroidal thickness after exposure to 1000 lux of illumination (245.37 +/- 52.84 MUm) was significantly lower than that after 150 lux of illumination (268.00 +/- 57.10 MUm), (p < 0.001). Significant diurnal variations were found in mean keratometry (p = 0.039), intraocular pressure (IOP, p = 0.003), ocular perfusion pressure (OPP, p < 0.0001), macular volume (p = 0.019), and subfoveal choroidal thickness (p < 0.0001). A high level of illumination had significant effects on only IOP and OPP (p = 0.027 and 0.017, respectively). Bright light exposure before sleep at an intensity as high as 1000 lux reduced subfoveal choroidal thickness in healthy young men. In conclusion, diurnal variation in choroidal thickness can be affected by bright light exposure before sleep. PMID- 28887138 TI - The role of phacoemulsification in glaucoma therapy: A systematic review and meta analysis. AB - Cataract extraction is a safe and effective surgery that has been performed in its modern form for several decades. Many studies have noted that cataract extraction could also have a clinically significant role in the control of comorbid glaucoma. Lens extraction decreases the pressure within the eye, and intraocular pressure (IOP) is the only controllable risk factor in glaucoma proven to be effective. A systematic analysis of current evidence is needed to establish strong practice patterns and identify areas where further research is required. We performed systematic review and meta-analysis of the clinical data to estimate the net effect of cataract surgery on IOP. A total of 37 treatment arms from 32 different studies from January 1997 to January 2017 were included. IOP reduction was highly correlated across follow-up periods. For angle-closure glaucoma, results showed an IOP decrease of -6.4 mmHg (95% CI: -9.4 to -3.4) at final follow-up (12 months and longer). For the open-angle glaucoma group, there was an overall IOP change of -2.7 mmHg (95% CI -3.7 to -1.7) from baseline. For pseudoexfoliation glaucoma further research is needed to reach an adequate evidence-based conclusion. The influence of inherent sources of bias, including loss to follow-up, washout and medication use, and lack of a control group, was evaluated numerically. These sources of bias pulled the IOP estimate in opposite directions and are therefore unlikely to affect the main conclusions substantially. Future prospective clinical trials, including other outcomes such as quality of life, clinical severity information, and cost-effectiveness analysis, are needed to determine the role of phacoemulsification alone within the glaucoma treatment algorithm. PMID- 28887139 TI - Reducing the Variability of Medicaid Coverage Policies for Pregnant Women. PMID- 28887141 TI - Epilogue: Western science, reductionism and eastern perspectives. PMID- 28887142 TI - Marriages of mathematics and physics: A challenge for biology. AB - The human attempts to access, measure and organize physical phenomena have led to a manifold construction of mathematical and physical spaces. We will survey the evolution of geometries from Euclid to the Algebraic Geometry of the 20th century. The role of Persian/Arabic Algebra in this transition and its Western symbolic development is emphasized. In this relation, we will also discuss changes in the ontological attitudes toward mathematics and its applications. Historically, the encounter of geometric and algebraic perspectives enriched the mathematical practices and their foundations. Yet, the collapse of Euclidean certitudes, of over 2300 years, and the crisis in the mathematical analysis of the 19th century, led to the exclusion of "geometric judgments" from the foundations of Mathematics. After the success and the limits of the logico-formal analysis, it is necessary to broaden our foundational tools and re-examine the interactions with natural sciences. In particular, the way the geometric and algebraic approaches organize knowledge is analyzed as a cross-disciplinary and cross-cultural issue and will be examined in Mathematical Physics and Biology. We finally discuss how the current notions of mathematical (phase) "space" should be revisited for the purposes of life sciences. PMID- 28887143 TI - Mind-life continuity: A qualitative study of conscious experience. AB - There are two fundamental models to understanding the phenomenon of natural life. One is the computational model, which is based on the symbolic thinking paradigm. The other is the biological organism model. The common difficulty attributed to these paradigms is that their reductive tools allow the phenomenological aspects of experience to remain hidden behind yes/no responses (behavioral tests), or brain 'pictures' (neuroimaging). Hence, one of the problems regards how to overcome methodological difficulties towards a non-reductive investigation of conscious experience. It is our aim in this paper to show how cooperation between Eastern and Western traditions may shed light for a non-reductive study of mind and life. This study focuses on the first-person experience associated with cognitive and mental events. We studied phenomenal data as a crucial fact for the domain of living beings, which, we expect, can provide the ground for a subsequent third-person study. The intervention with Jhana meditation, and its qualitative assessment, provided us with experiential profiles based upon subjects' evaluations of their own conscious experiences. The overall results should move towards an integrated or global perspective on mind where neither experience nor external mechanisms have the final word. PMID- 28887140 TI - Envisioning Women-Centered HIV Care: Perspectives from Women Living with HIV in Canada. AB - BACKGROUND: Women comprise nearly one-quarter of people living with human immunodeficiency virus (HIV) in Canada. Compared with men, women living with HIV experience inequities in HIV care and health outcomes, prompting a need for gendered and tailored approaches to HIV care. METHOD: Peer and academic researchers from the Canadian HIV Women's Sexual and Reproductive Health Cohort Study conducted focus groups to understand women's experience of seeking care, with the purpose of identifying key characteristics that define a women-centered approach to HIV care. Eleven focus groups were conducted with 77 women living with HIV across Quebec, Ontario, and British Columbia, Canada. RESULTS: Women envisioned three central characteristics of women-centered HIV care, including i) coordinated and integrated services that address both HIV and women's health care priorities, and protect against exclusion from care due to HIV-related stigma, ii) care that recognizes and responds to structural barriers that limit women's access to care, such as violence, poverty, motherhood, HIV-related stigma, and challenges to safe disclosure, and iii) care that fosters peer support and peer leadership in its design and delivery to honor the diversity of women's experiences, overcome women's isolation, and prioritize women's ownership over the decisions that affect their lives. CONCLUSION: Despite advances in HIV treatment and care, the current care landscape is inadequate to meet women's comprehensive care needs. A women-centered approach to HIV care, as envisioned by women living with HIV, is central to guiding policy and practice to improve care and outcomes for women living with HIV in Canada. PMID- 28887144 TI - Sheaf theoretic formulation for consciousness and qualia and relationship to the idealism of non-dual philosophies. AB - Questions about the nature of reality, whether Consciousness is the fundamental reality in the universe, and what is Consciousness itself, have no answer in systems that assume an external reality independent of Consciousness. Ultimately, the ontological foundation of such systems is the absolute division of subject and object. We advocate instead what we consider to be an approach that is in agreement with the foundation of quantum reality, which is based on Ramanuja's version of Vedanta philosophy and non-dual Kashmir Saivism. Quantum mechanics opened the door to consciousness, but it cannot account for consciousness. However, the quantum measurement problem implies that we cannot remove subjective experience from the practice of science. It is then appropriate to seek mathematical formalisms for the workings of consciousness that don't rely on specific interpretations of quantum mechanics. Temporal topos provides such a framework. In the theory of temporal topos, which we outline here, the difference between a subject and an object involves the direction of a morphism in a category. We also note that in the dual category, the direction of the morphism is in the opposite direction compared with the original direction of the original category. The resulting formalism provides powerful ways to address consciousness and qualia, beyond attempts to account for consciousness through physical theories. We also discuss the implications of the mathematics presented here for the convergence of science and non-dualist philosophies, as an emerging science of Consciousness, that may bring out the underlying unity of physics, life and mind. PMID- 28887145 TI - Role of an estradiol regulatory factor-hydroxysteroid dehydrogenase (HSD) in Toxoplasma gondii infection and pathogenicity. AB - Toxoplasma gondii is an apicomplexan parasite that infects most species of warm blooded animals, including humans, and causes abortions and severe damage to the fetal central nervous system. During pregnancy, the prevalence of toxoplasmosis increases throughout the second and third quarter of gestation, while the hormones progesterone and estradiol simultaneously increase. Thus, it has been suggested that these hormones could affect parasite reproduction. This study was mainly focused on an estradiol regulatory factor-Hydroxysteroid dehydrogenase (HSD) gene in T. gondii. Our data showed that estradiol promoted Pru (Type II) and VEG (Type III) infection and thus significantly contributed to the pathogenicity of T. gondii in mice. Subsequently, we found that this phenomenon may relate to the interplay of T. gondii and estradiol. We reported that estradiol can enter T. gondii tachyzoites. Bioinformatics analysis showed that T. gondii may have a residual estradiol metabolism-related gene HSD. To verify the gene function, HEK293T cells were transiently transfected with Tg-HSD and gene expression was induced. Then, HPLC (high-performance liquid chromatography) analysis showed that Tg-HSD can efficiently transform estrone into estradiol. Moreover, Tg-HSD -overexpressing parasites showed significantly enhanced pathogenicity and upregulation of estradiol levels in mice. In conclusion, estradiol can promote T. gondii infection in vitro and in vivo, and this may be related to its Tg- HSD gene. PMID- 28887146 TI - Analysing the effect of multiple sclerosis on vitamin D related biochemical markers of bone remodelling. AB - The Irish population is at risk of vitamin D deficiency during the winter months, but the secular trend over the past 40 years is for marked improvement. Multiple sclerosis (MS) is common in Ireland with a latitudinal pattern favouring highest incidence in northern regions; MS is linked strongly with vitamin D status as a causal factor. We sought firstly to study the relationship between vitamin D status and vitamin D-related bone biochemistry, and secondly to evaluate if MS had an independent effect on vitamin D related markers of bone remodelling. Using a case-control design of 165 pairs (MS patient and matched control) residing in three different geographic regions during winter months, we measured serum 25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), C-terminal telopeptide of type I collagen (CTX) and total procollagen type I amino-terminal propeptide (PINP). Given the paired case-control design, associations were explored using mixed-effects linear regression analysis with the patient-control pair as a random effect and after log transformation of 25OHD. A two-way interaction effect was tested for vitamin D status (25OHD <30nmol/L) and the presence of MS on PTH, CTX, and PINP. In the total group, just over one-third (34.5%) had 25OHD <30nmol/L. PTH was elevated in 7.6%. CTX was not elevated in any case, and PINP was elevated in 4.5%. On mixed-effects linear regression analysis after adjusting for confounders (age, sex, renal function, and serum albumin), we demonstrated the principal determinant of 25OHD was geographical location (p<0.001), of PTH was 25OHD (p<0.001), of CTX was PTH (p<0.001), and of PINP was PTH (p<0.001). MS did not have an independent effect on PTH (p=0.921), CTX (p=0.912), or PINP (p=0.495). As regards an interaction effect, the presence of MS and 25OHD <30nmol/L was not significant but tended towards having lower PTH (p=0.207). In conclusion, in Ireland in winter only a minority had any abnormality in the secondary indices of vitamin D deficiency, and MS had no independent effect on parathyroid status or bone remodelling activity. PMID- 28887147 TI - Both ligand and VDR expression levels critically determine the effect of 1alpha,25-dihydroxyvitamin-D3 on osteoblast differentiation. AB - Previous studies have shown that 1alpha,25-dihydroxyvitamin D3 (1,25D) through vitamin D receptor (VDR) signalling has both catabolic and anabolic effects on osteoblast differentiation. However, the mechanism of these differential effects by 1,25D is not fully understood. In this study, mice with three different genetic backgrounds, representing a normal VDR level (wild-type, WT), VDR over expression specifically in mature osteoblasts (ObVDR-B6) and global VDR knockout (VDRKO), were utilised to generate primary osteoblast-like cultures to further elucidate the effects of 1,25D on osteoblast differentiation. Our data confirm the importance of VDR in the late stage of osteogenic differentiation and also for the expression of factors critical for osteoblastic support of osteoclast formation. This study also demonstrates the differential effects of a pharmacological level of 1,25D (1nM) on the expression of osteogenic differentiation markers, including Ocn and Sost, depending on the relative level of VDR. Our findings suggest that 1,25D plays an inhibitory role in matrix mineralisation, possibly through the modulation of the tissue non-specific alkaline phosphatase to ectonucleotide pyrophosphatase/phosphodiesterase 1 axis, in a VDR level-dependent manner. We conclude that the relative VDR level and the 1,25D availability to cells, are important co-determinants for whether 1,25D plays a promoting or suppressive role in osteoblast-mediated osteogenic activity. PMID- 28887148 TI - Objective choice of phylogeographic models. AB - Phylogeography seeks to discover the evolutionary processes that have given rise to organismal and genetic diversity. This requires explicit hypotheses (i.e., models) to be evaluated with genetic data in order to identify those hypotheses that best explain the data. In recent years, advancements in the model-based tools used to estimate phylogeographic parameters of interest such as gene flow, divergence time, and relationships among groups have been made. However, given the complexity of these models, available methods can typically only compare a handful of possible hypotheses, requiring researchers to specify in advance the small set of models to consider. Without formal quantitative approaches to model selection, researchers must rely on their intuition to formulate the model space to be explored. We explore the adequacy of intuitive choices made by researchers during the process of data analysis by reanalyzing 20 empirical phylogeographic datasets using PHRAPL, an objective tool for phylogeographic model selection. We show that the best models for most datasets include both gene flow and population divergence parameters, and that species tree methods (which do not consider gene flow) tend to be overly simplistic for many phylogeographic systems. Objective approaches to phylogeographic model selection offer an important complement to researcher intuition. PMID- 28887149 TI - Transcriptome and target DNA enrichment sequence data provide new insights into the phylogeny of vespid wasps (Hymenoptera: Aculeata: Vespidae). AB - The wasp family Vespidae comprises more than 5000 described species which represent life history strategies ranging from solitary and presocial to eusocial and socially parasitic. The phylogenetic relationships of the major vespid wasp lineages (i.e., subfamilies and tribes) have been investigated repeatedly by analyzing behavioral and morphological traits as well as nucleotide sequences of few selected genes with largely incongruent results. Here we reconstruct their phylogenetic relationships using a phylogenomic approach. We sequenced the transcriptomes of 24 vespid wasp and eight outgroup species and exploited the transcript sequences for design of probes for enriching 913 single-copy protein coding genes to complement the transcriptome data with nucleotide sequence data from additional 25 ethanol-preserved vespid species. Results from phylogenetic analyses of the combined sequence data revealed the eusocial subfamily Stenogastrinae to be the sister group of all remaining Vespidae, while the subfamily Eumeninae turned out to be paraphyletic. Of the three currently recognized eumenine tribes, Odynerini is paraphyletic with respect to Eumenini, and Zethini is paraphyletic with respect to Polistinae and Vespinae. Our results are in conflict with the current tribal subdivision of Eumeninae and thus, we suggest granting subfamily rank to the two major clades of "Zethini": Raphiglossinae and Zethinae. Overall, our findings corroborate the hypothesis of two independent origins of eusociality in vespid wasps and suggest a single origin of using masticated and salivated plant material for building nests by Raphiglossinae, Zethinae, Polistinae, and Vespinae. The inferred phylogenetic relationships and the open access vespid wasp target DNA enrichment probes will provide a valuable tool for future comparative studies on species of the family Vespidae, including their genomes, life styles, evolution of sociality, and co evolution with other organisms. PMID- 28887150 TI - Geography and past climate changes have shaped the evolution of a widespread lizard from the Chilean hotspot. AB - The complex orogenic history and structure of Southern South America, coupled with Pleistocene glacial cycles, have generated paleoclimatic and environmental changes that influenced the spatial distribution and genetic composition of natural populations. Despite the increased number of phylogeographic studies in this region and given the frequent idiosyncratic phylogeographic patterns, there is still the need to focus research especially on species that are currently distributed within a wide range of bioclimatic regimes, and that historically have been subject to contrasting scenarios. Liolaemus tenuis is a widely distributed lizard species inhabiting latitudinally in almost 1000km through central and southern Chile. Here we describe the geographical patterns of genetic variation and lineage diversification within L. tenuis, and their association with geography and Pleistocene glaciations, using sequences from one mitochondrial and two nuclear genes, and five microsatellite loci, and covering most of the species distributional range. Our results revealed a high diversity both within and among populations, as well as two phylogeographic breaks, which are consistent with two of the larger rivers of central Chile, the Maipo and Biobio Rivers. Liolaemus tenuis is characterized by several allopatric lineages, especially in its north and central range, which suggest a history of multiple vicariance processes. Conversely, populations found in the southern range, south of the Biobio River, show signatures of recent decreases in effective population sizes, coupled with recent range expansions and secondary contact. Niche "envelope" data are consistent with patterns of genetic variation; both suggest a history of discontinuous areas of relatively stable populations throughout all of the distribution of L. tenuis. These data are also consistent with higher probabilities of habitat suitability north of the Maipo River (ca. 33 degrees S), in both coastal areas and the "Intermediate Depression" between 34 degrees and 37 degrees S, as well as in the southern Coastal Cordillera between the Biobio and Araucania regions. Interestingly, both molecular and niche envelope modeling data suggest that some populations may have persisted in fragmented refugia in Andean valleys, within the limits of the ice sheet. Finally, our results suggest that several populations of L. tenuis colonized glaciated regions from refugial areas in lowlands and coastal regions, and in the southern distribution, historic migration events would have occurred from refugial areas within the limits of the ice sheet. PMID- 28887152 TI - Cerebral oximetry leading up to cardiac arrest: A marker of the impact of mean arterial pressure on the brain, but not time of death. PMID- 28887151 TI - Altered synaptobrevin-II trafficking in neurons expressing a synaptophysin mutation associated with a severe neurodevelopmental disorder. AB - Following exocytosis, synaptic vesicles (SVs) have to be reformed with the correct complement of proteins in the correct stoichiometry to ensure continued neurotransmission. Synaptophysin is a highly abundant, integral SV protein necessary for the efficient retrieval of the SV SNARE protein, synaptobrevin II (sybII). However the molecular mechanism underpinning synaptophysin-dependent sybII retrieval is still unclear. We recently identified a male patient with severe intellectual disability, hypotonia, epilepsy and callosal agenesis who has a point mutation in the juxtamembrane region of the fourth transmembrane domain of synaptophysin (T198I). This mutation had no effect on the activity-dependent retrieval of synaptophysin that was tagged with the genetically-encoded pH sensitive reporter (pHluorin) in synaptophysin knockout hippocampal cultures. This suggested the mutant has no global effect on SV endocytosis, which was confirmed when retrieval of a different SV cargo (the glutamate transporter vGLUT1) was examined. However neurons expressing this T198I mutant did display impaired activity-dependent sybII retrieval, similar to that observed in synaptophysin knockout neurons. Interestingly this impairment did not result in an increased stranding of sybII at the plasma membrane. Screening of known human synaptophysin mutations revealed a similar presynaptic phenotype between T198I and a mutation found in X-linked intellectual disability. Thus this novel human synaptophysin mutation has revealed that aberrant retrieval and increased plasma membrane localisation of SV cargo can be decoupled in human disease. PMID- 28887154 TI - Comparing the effects of two distinct eccentric modalities to traditional resistance training in resistance trained, higher functioning older adults. AB - BACKGROUND: The effects of eccentric resistance exercise are of interest in the older adult cohort, but to our knowledge, there is no research on the relative effects of different eccentric modalities on a range of outcomes in higher functioning, resistance trained older adults. METHODS: 33 resistance-trained older adults (aged 67+/-4.5years) were randomized into one of three supervised training groups: traditional (TRE), eccentric only (ERE) or eccentrically biased resistance exercise (EBRE) on a 45 degrees , plate-loaded leg press machine. Participants trained twice per week with maximal strength, functional capacity, body composition and blood biomarkers measured before and after the eight-week intervention. RESULTS: Both eccentric and concentric strength, and important functional tasks for independent living significantly improved independent of group. Body composition and blood biomarkers were found to significantly improve in the EBRE group only however, no statistical differences were found between groups. CONCLUSION: Compared to traditional resistance training, the two eccentric modalities investigated here were equally effective for improvements in maximum muscular strength, functional capacity, body composition and metabolic biomarkers. When training the resistance trained older adult, very heavy isoinertial external loads (at least 70% of one repetition maximum) are effective irrespective of contraction mode. With heavy strength training, resistance trained older adults can continue to expect improvements in health and function. PMID- 28887153 TI - The Eya phosphatase: Its unique role in cancer. AB - The Eya proteins were originally identified as essential transcriptional co activators of the Six family of homeoproteins. Subsequently, the highly conserved C-terminal domains of the Eya proteins were discovered to act as a Mg2+-dependent Tyr phosphatases, making Eyas the first transcriptional activators to harbor intrinsic phosphatase activity. Only two direct targets of the Eya Tyr phosphatase have been identified: H2AX, whose dephosphorylation directs cells to the DNA repair instead of the apoptotic pathway upon DNA damage, and ERbeta, whose dephosphorylation inhibits its anti-tumor transcriptional activity. The Eya Tyr phosphatase mediates breast cancer cell transformation, migration, invasion, as well as metastasis, through targets not yet identified. Intriguingly, the N terminal domain of Eya contains a separate Ser/Thr phosphatase activity implicated in innate immunity and in regulating c-Myc stability. Thus, Eya proteins are highly complex, containing two separable phosphatase domains and a transcriptional activation domain, thereby influencing tumor progression through multiple mechanisms. PMID- 28887155 TI - Corrigendum to 'Jack Nicholson: A Reel and Real-Life Contribution to Neurosciences' [World Neurosurgery 101 (2017) 718-721]. PMID- 28887156 TI - The association between FOXP3 gene variations and autism: True or false positive? PMID- 28887157 TI - Effect of a single nucleotide polymorphism in the growth hormone secretagogue receptor (GHSR) gene on growth rate in pigs. AB - The growth hormone secretagogue receptor (GHSR) gene controls growth hormone (GH) release by inducing a strong stimulatory effect on the endogenous ligand, ghrelin. In this study, we examined the possible role of GHSR in the growth traits of four pig breeds, namely Tibetan pigs (n=45), Diannan small-eared pigs (n=40), Yorkshire pigs (n=45), and New Huai pigs (n=122). Single nucleotide polymorphisms (SNPs) in these pigs were identified by polymerase chain reaction (PCR) sequencing and genotyping was performed using PCR-restriction fragment length polymorphisms (PCR-RFLPs). A SNP (C/A) named C-1595A (the "C" allele), which is located 1595bp upstream of the initiation codon of the GHSR gene, was found at a higher frequency in the fast-growing Yorkshire pigs than in the slow growing Tibetan and Diannan small-eared pigs. In preliminary assays, the C-1595A genotype was found to be associated with growth traits in New Huai pigs. Quantitative real-time PCR and western blotting assays were used to measure the levels of GHSR1a, a functionally active form of the GHSR protein, in the tissues of the growth axis. The estimated levels of mRNA and protein in pituitary and liver tissues were significantly higher in Yorkshire pigs than in Diannan small eared or Tibetan pigs (P<0.05). The results indicated that GHSR had a positive influence on the growth rate of pigs and suggested that the C-1595A SNP could be of value as a molecular marker for improving the production performance of pig breeds. PMID- 28887158 TI - Lack of association of CASC8 rs1447295 with colorectal cancer in Iranian population: A multicenter case-control study. AB - Several studies reported the potential role of the rs1447295 polymorphism in susceptibility to cancer. This variant located in the cancer susceptibility candidate 8 (CASC8) is a long noncoding RNA (lnRNA) gene and does not code protein. LnRNA transcripts play a potential regulatory role in the expression of key genes involved in multiple cellular pathways, including cell cycle, pluripotency, and immune response. The aim of this study is to evaluate this association with colorectal cancer (CRC) in a large case-control study of the Iranian population. After extraction of genomic DNA by the standard protocols, the rs1447295 was genotyped in 2416 subjects (46% patients). Results of this case control demonstrated no significant association between the rs1447295 polymorphism and risk of CRC or its characteristics under allele or alternative genotype models. In conclusion, it is unlikely that the rs1447295 polymorphism is a risk variant for the development of CRC in Iranian population. PMID- 28887159 TI - Integrative analysis of DNA methylation and mRNA expression during differentiation of umbilical cord blood derived mononuclear cells to endothelial cells. AB - Differentiation of umbilical cord blood derived mononuclear cells to endothelial cells is accompanied by massive changes in gene expression. Although methylation and demethylation of DNA likely play crucial roles in regulating gene expression, their interplay during differentiation remains elusive. To address this question, we performed deep sequencing of DNA methylation and mRNA expression to profile global changes in promoter methylation and gene expression during differentiation from mononuclear cells to outgrowing cells. We identified 61 downregulated genes with hypermethylation, including CD74, VAV1, TLR8, and NCF4, as well as 21 upregulated genes with hypomethylation, including ECSCR, MCAM, PGF, and ARHGEF15. Interestingly, gene ontology analysis showed that downregulated genes with hypermethylation were enriched in immune-related functions, and upregulated genes with hypomethylation were enriched in the developmental process and angiogenesis, indicating the important roles of DNA methylation in regulating differentiation. We performed polymerase chain reaction analyses and bisulfite sequencing of representative genes (CD74, VAV1, ECSCR, and MCAM) to verify the negative correlation between DNA methylation and gene expression. Further, inhibition of DNA methyltransferase and demethylase activities using 5'-aza-dc and shRNAs, specific for TET1 and TET2 mRNAs, respectively, revealed that DNA methylation was the main regulator of the reversible expression of functionally important genes. Collectively, our findings implicate DNA methylation as a critical regulator of gene expression during umbilical cord blood derived mononuclear cells to endothelial cell differentiation. PMID- 28887160 TI - Silencing of the pentose phosphate pathway genes influences DNA replication in human fibroblasts. AB - Previous reports and our recently published data indicated that some enzymes of glycolysis and the tricarboxylic acid cycle can affect the genome replication process by changing either the efficiency or timing of DNA synthesis in human normal cells. Both these pathways are connected with the pentose phosphate pathway (PPP pathway). The PPP pathway supports cell growth by generating energy and precursors for nucleotides and amino acids. Therefore, we asked if silencing of genes coding for enzymes involved in the pentose phosphate pathway may also affect the control of DNA replication in human fibroblasts. Particular genes coding for PPP pathway enzymes were partially silenced with specific siRNAs. Such cells remained viable. We found that silencing of the H6PD, PRPS1, RPE genes caused less efficient enterance to the S phase and decrease in efficiency of DNA synthesis. On the other hand, in cells treated with siRNA against G6PD, RBKS and TALDO genes, the fraction of cells entering the S phase was increased. However, only in the case of G6PD and TALDO, the ratio of BrdU incorporation to DNA was significantly changed. The presented results together with our previously published studies illustrate the complexity of the influence of genes coding for central carbon metabolism on the control of DNA replication in human fibroblasts, and indicate which of them are especially important in this process. PMID- 28887161 TI - Loss of discoidin domain receptor 1 (DDR1) via CpG methylation during EMT in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) can be stratified according to the stages of epithelial-mesenchymal transition (EMT). Here, we aim to identify tyrosine kinases (TKs) in EOC that correlate with the EMT subtypes. By gene expression microarray, we analyzed the expression levels of tyrosine kinases in EOC cell lines in correlation with EMT. Among the candidate TKs identified, DDR1 was expressed mainly in EOC cells with an Epithelial phenotype. Its expression was validated by qPCR, ELISA and western blotting. Using Infinium HumanMethylation27K BeadChip array and pyrosequencing, we further analyzed the CpG methylation levels at the DDR1 promoter in EOC cells and found that the CpG methylation levels of DDR1 promoter correlated negatively with the expression of DDR1 along the EMT spectrum. Therefore, EMT stratification could be a potential biomarker to predict patient response to DDR1-targeting drugs. PMID- 28887162 TI - Extrinsic nerves are not involved in branchial 5-HT dynamics or pulsatile urea excretion in Gulf toadfish, Opsanus beta. AB - Gulf toadfish (Opsanus beta) can switch from continuously excreting ammonia as their primary nitrogenous waste to excreting predominantly urea in distinct pulses. Previous studies have shown that the neurotransmitter serotonin (5-HT) is involved in controlling this process, but it is unknown if 5-HT availability is under central nervous control or if the 5-HT signal originates from a peripheral source. Following up on a previous study, cranial nerves IX (glossopharyngeal) and X (vagus) were sectioned to further characterize their role in controlling pulsatile urea excretion and 5-HT release within the gill. In contrast to an earlier study, nerve sectioning did not result in a change in urea pulse frequency. Total urea excretion, average pulse size, total nitrogen excretion, and percent ureotely were reduced the first day post-surgery in nerve-sectioned fish but recovered by 72h post-surgery. Nerve sectioning also had no effect on toadfish urea transporter (tUT), 5-HT transporter (SERT), or 5-HT2A receptor mRNA expression or 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) abundance in the gill, all of which were found consistently across the three gill arches except 5-HIAA, which was undetectable in the first gill arch. Our findings indicate that the central nervous system does not directly control pulsatile urea excretion or local changes in gill 5-HT and 5-HIAA abundance. PMID- 28887163 TI - Reply to: "Insufficient accuracy of computed tomography-based portal pressure assessment in hepatitis B virus-related cirrhosis: An analysis of data from CHESS 1601 trial". PMID- 28887164 TI - Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention. AB - Although epidemic jaundice was well known to physicians of antiquity, it is only in recent years that medical science has begun to unravel the origins of hepatitis A virus (HAV) and the unique pathobiology underlying acute hepatitis A in humans. Improvements in sanitation and the successful development of highly efficacious vaccines have markedly reduced the worldwide prevalence and incidence of this enterically-transmitted infection over the past quarter century, yet the virus persists in vulnerable populations and remains a common cause of food-borne disease outbreaks in economically-advantaged societies. Reductions in the prevalence of HAV have led to increases in the median age at which infection occurs, often resulting in more severe disease in affected persons and paradoxical increases in disease burden in some developing nations. Here, we summarize recent advances in the molecular virology of HAV, an atypical member of the Picornaviridae family, survey what is known of the pathogenesis of hepatitis A in humans and the host-pathogen interactions that typify the infection, and review medical and public health aspects of immunisation and disease prevention. PMID- 28887165 TI - Insufficient accuracy of computed tomography-based portal pressure assessment in hepatitis B virus-related cirrhosis: An analysis of data from CHESS-1601 trial. PMID- 28887166 TI - Dusp14 protects against hepatic ischaemia-reperfusion injury via Tak1 suppression. AB - BACKGROUND & AIMS: Hepatic ischaemia-reperfusion (I/R) injury is characterised by severe inflammation and extensive cell death. Multiple signalling pathways, including NF-kappaB and mitogen-activated protein kinase (MAPK)/c-Jun NH2 terminal kinase (JNK), have important roles in this process. Identifying the unknown critical regulators of these signalling pathways could provide potential targets for therapeutic application. Dual-specificity phosphatase 14 (DUSP14) acts as a negative regulator of NF-kappaB signalling. However, its function in hepatic I/R injury is unknown. METHODS: Hepatocyte-specific Dusp14 knockout (HKO) and transgenic (TG) mice were subjected to hepatic I/R surgery to examine Dusp14 function in vivo. Primary hepatocytes isolated from Dusp14-HKO and Dusp14-TG mice were cultured and subjected to hypoxia/reoxygenation insult in vitro. Inflammatory cytokine production was measured using quantitative reverse transcription PCR and ELISA. Liver damage was analysed using histopathology. Co immunoprecipitation and pull-down assays followed by Western blot were performed to detect Dusp14 and transforming growth factor (Tgf)-beta-activated kinase 1 (Tak1) interactions. RESULTS: Dusp14 was significantly downregulated in liver tissues from liver transplantation patients and mice subjected to hepatic I/R surgery. Dusp14-HKO and Dusp14-TG mouse models demonstrated that Dusp14 reduced cell death, ameliorated inflammation, and promoted hepatocyte proliferation and/or regeneration. Dusp14 also suppressed NF-kappaB and MAPK signalling via a physical interaction with Tak1, leading to its subsequent inhibition. Tak1 inhibition by 5Z-7-ox abolished Dusp14 function in vivo, indicating that TAK1 is required for Dusp14 function in hepatic I/R injury. Finally, mutant Dusp14 lost the ability to bind Tak1 and failed to protect against hepatic I/R injury. CONCLUSIONS: Dusp14 is a protective factor in hepatic I/R injury, and the Dusp14 Tak1-Jnk1/2 regulatory axis is important for the pathogenesis of hepatic I/R injury. Modulation of this axis could be a novel therapeutic strategy to prevent or interfere with this pathological process. LAY SUMMARY: Reductions in the level of the protein Dusp14 are closely associated with liver damage caused by inadequate blood supply followed by restoration of blood flow to the liver. Dusp14 protects against liver damage by suppressing the activity of Tak1. Targeting Dusp14 could be a strategy for prevention and treatment of this disease. PMID- 28887167 TI - Identification of Slug and SOX7 as transcriptional repressors binding to the hepatitis B virus core promoter. AB - BACKGROUND & AIMS: The Hepatitis B Virus (HBV) may gain entry into non-liver cells but does not actively replicate in them. We investigated the possibility that these cells possess mechanisms that block HBV core promoter (HBVCP) transcription, specifically absent in liver cells, which together with other liver-specific mechanisms, such as sodium-taurocholate cotransporting polypeptide mediated entry, enable liver cells to effectively produce HBV. METHODS: Liver and non-liver cell lines were screened for their capacity to activate the HBVCP and synthesize pre-genomic RNA (pgRNA). Transcription regulators differentially expressed between cells with active or inactive HBVCP were determined by human transcriptome array. Slug (SNAI2) and SRY-related HMG box 7 (SOX7) transcriptional repressors were identified and shown to bind specifically to the HBVCP by electrophoretic mobility shift assay. The resultant inhibitory effect on HBVCP transcription was validated using luciferase reporter and assays for pgRNA, HBcAg and cccDNA accumulation in cells with HBV replicon and HBV infection models. To further confirm their specific activity, short peptide mimetics generated from Slug zinc-finger domains and SOX7 HMG-box were generated. RESULTS: The HBVCP was found to be active in liver and selected non-liver cells. These cells have low/negligible expression of Slug and SOX7, which inhibit HBVCP transcription specifically by binding at the pgRNA initiator site and competitively displacing hepatocyte nuclear factor 4alpha, respectively. Overexpression of Slug and/or SOX7 specifically reduced HBVCP transcription, significantly diminishing pgRNA synthesis, HBcAg and cccDNA accumulation in HBV infected primary human hepatocytes. Similar results were obtained with Slug and SOX7 stapled peptides individually, which were even more potent in combination. CONCLUSIONS: Slug and SOX7 are transcriptional repressors that bind specifically to the HBVCP. Their absence or weak expression in liver cells contribute to the favorable host environment for the active and efficient production of HBV. LAY SUMMARY: Hepatitis B virus (HBV) replication occurs efficiently in human liver because of the specificity of viral uptake receptors and presence of numerous liver-enriched transcription activators. Herein, we show that the specific lack of transcriptional inhibitory mechanisms in liver cells also contribute to effective HBV production. HBV replication is kept low in non-liver cells as transcriptional repressors Slug and SRY-related HMG box 7 (SOX7) actively bind to the transcriptional initiator and displace transcription activators, respectively, within the HBV core promoter. PMID- 28887168 TI - HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. AB - BACKGROUND & AIMS: It is unclear whether direct-acting antiviral (DAA) treatment induced sustained virologic response (SVR) reduces the risk of hepatocellular carcinoma (HCC) in patients with HCV infection. Therefore, in the current study, our aim was to determine the impact of DAA-induced SVR on HCC risk. METHODS: We identified 62,354 patients who initiated antiviral treatment in the Veterans Affairs (VA) national healthcare system from 1 January 1999 to 31 December 2015, including 35,871 (58%) interferon (IFN)-only regimens, 4,535 (7.2%) DAA + IFN regimens, and 21,948 (35%) DAA-only regimens. We retrospectively followed patients until 15 June 2017 to identify incident cases of HCC. We used Cox proportional hazards regression to determine the association between SVR and HCC risk or between type of antiviral regimen (DAA-only vs. DAA + IFN vs. IFN-only) and HCC risk. RESULTS: We identified 3,271 incident cases of HCC diagnosed at least 180 days after initiation of antiviral treatment during a mean follow-up of 6.1 years. The incidence of HCC was highest in patients with cirrhosis and treatment failure (3.25 per 100 patient-years), followed by cirrhosis and SVR (1.97), no cirrhosis and treatment failure (0.87), and no cirrhosis and SVR (0.24). SVR was associated with a significantly decreased risk of HCC in multivariable models irrespective of whether the antiviral treatment was DAA-only (adjusted hazard ratio [AHR] 0.29; 95% CI 0.23-0.37), DAA + IFN (AHR 0.48; 95% CI 0.32-0.73) or IFN-only (AHR 0.32; 95% CI 0.28-0.37). Receipt of a DAA-only or DAA + IFN regimen was not associated with increased HCC risk compared with receipt of an IFN-only regimen. CONCLUSIONS: DAA-induced SVR is associated with a 71% reduction in HCC risk. Treatment with DAAs is not associated with increased HCC risk compared with treatment with IFN. LAY SUMMARY: It was unclear whether direct acting antiviral treatment-induced sustained virologic response reduces the risk of liver cancer in patients with HCV infection. We demonstrated that eradication of HCV infection with direct-acting antiviral agents reduces the risk of liver cancer by 71%. PMID- 28887169 TI - In vitro and in vivo exploration of palmitic acid from Synechococcus elongatus as an antibiofilm agent on the survival of Artemia franciscana against virulent vibrios. AB - Biofilm formation of Vibrio spp. has been demonstrated as a potentially important mechanism contributing antibiotic treatment failure in aquaculture. In the present study, the effect of palmitic acid (PA) identified from Synechococcus elongatus was assessed for the inhibition of quorum sensing (QS) regulated biofilm formation in aquatic bacterial pathogens. The biofilm inhibitory concentration (BIC) of PA against Vibrio spp. was found to be 100ugml-1. In this concentration, PA exhibited a significant inhibition in biofilm biomass of Vibrio harveyi MTCC 3438, V. parahaemolyticus ATCC 17802, V. vulnificus MTCC 1145 and V. alginolyticus ATCC 17749 without hindering their planktonic growth. Also, PA displayed gradual decrease in bioluminescence production of V. harveyi. The results of extracellular polymeric substances quantification, microbial adhesion to hydrocarbons and Fourier transform infrared spectroscopic (FT-IR) analyses suggested that PA positively interferes with the initial adhesion stages of biofilm formation. In addition, confocal and scanning electron microscopic analysis substantiates the antibiofilm efficacy of the PA. The transcriptomic analysis revealed the down-regulation of QS mediated response regulator genes expression in V. harveyi. Concomitantly, PA reduced the intestinal colonization of vibrios in brine shrimp larvae and thereby attenuates the biofilm assemblage and its associated virulence. In vivo studies using brine shrimp larvae manifested the reduction in adherence and virulence, which prompts further investigation about the potential of PA for the treatment of vibriosis. PMID- 28887170 TI - Synthesis and evaluation of antitumor, anti-inflammatory and analgesic activity of novel deoxycholic acid derivatives bearing aryl- or hetarylsulfanyl moieties at the C-3 position. AB - Novel deoxycholic acid (DCA) derivatives were stereoselectively synthesised with OH and -CH2SR moieties at the C-3 position, where R was a substituted aryl [2 aminophenyl (8) or 4-chlorophenyl (9)] or hetaryl [1-methylimidazolyl (5), 1,2,4 triazolyl (6), 5-amino-1,3,4-thiadiazolyl (7), pyridinyl (10) or pyrimidinyl (11)]. These compounds were prepared in good yields from the C-3beta-epoxy derivative 2 in the epoxide ring-opening reaction by S-nucleophiles. These derivatives were evaluated for their in vitro anti-proliferation activity in a panel of tumor cell lines. Data showed that: (i) heterocycle-containing derivatives displayed higher cytotoxicity profiles than the parent molecule; (ii) heterocyclic substituents were more preferable than aryl moieties for enhancing anti-proliferation activity; (iii) the sensitivity of tumor cell lines to analysed compounds decreased in the following order: HuTu-80 (duodenal carcinoma)>KB-3-1 (cervical carcinoma)>HepG2 (hepatocellular carcinoma)>MH-22a (hepatoma); (iv) compounds 5, 6 and 11 exhibited a high cytotoxic selectivity index (HuTu-80: SI>7.7, 38.5 and 12.0, respectively). Compounds 2 and 6-8 markedly inhibited NO synthesis by interferon gamma-induced macrophages. Screening for anti-inflammatory activity of these derivatives in vivo showed their high potency on histamine- (5, 10) and formalin- (2, 10, 11) induced paw edema models. PMID- 28887171 TI - Some observations on solasodine reactivity. AB - This article presents new transformations of solasodine - a representative steroid alkaloid sapogenin from the Solanum family. Oxidation of N,O-diacetylated solasodine with either NaNO2/BF3.Et2O or t-BuONO/BF3.Et2O resulted in partial degradation of the side chain to (20S)-3beta-acetoxypregn-5-ene-20,16beta carbolactone (vespertilin acetate). The same starting compound when treated with TMSOTf afforded the corresponding pseudosapogenin after aqueous work-up. However, when the crude reaction mixture was directly subjected to purification on a silica gel column, efficient autoxidation to pregna-5,16-dien-3beta-ol-20-one acetate was observed. One-step synthesis of this important drug intermediate from spirosolan alkaloids may be potentially exploited for large-scale production of steroid hormones. PMID- 28887172 TI - Synthesis and in vitro anticancer activity of 23(23')E-benzylidenespirostanols derived from steroid sapogenins. AB - Benzylidenespirostanols were prepared by two-step synthesis including BF3.Et2O catalyzed aldol condensation of several acetylated steroid sapogenins with benzaldehyde followed by saponification. The obtained compounds showed moderate cytotoxicity against three cancer cell lines (T-lymphoblastic leukemia cell line CEM, breast carcinoma cell line MCF7 and cervical carcinoma cell line HeLa) and normal human fibroblasts (BJ). The most active of the five tested substances was 3c (lowest IC50 for MCF7 cells 19.9+/-0.1uM) without any selectivity towards human cancer and normal cells, respectively. PMID- 28887173 TI - Adsorption effects of the doping relevant peptides Insulin Lispro, Synachten, TB 500 and GHRP 5. AB - The tendency of peptides to adsorb to surfaces can raise a concern in variety of analytical fields where the qualitative/quantitative measurement of low concentration analytes (ng/mL-pg/mL) is required. To demonstrate the importance of using the optimal glassware/plasticware, four doping relevant model peptides (GHRP 5, TB-500, Insulin Lispro, Synachten) were chosen and their recovery from various surfaces were evaluated. Our experiments showed that choosing expensive consumables with low-bind characteristics is not beneficial in all cases. A careful selection of the consumables based on the evaluation of the physico/chemical features of the peptide is recommended. PMID- 28887174 TI - Gas chromatography tandem mass spectrometry offers advantages for urinary steroids analysis. AB - Gas chromatography mass spectrometry has been the lynchpin of clinical assessment of steroid profiles for ~3 decades. The improvements in assay performance offered by tandem mass spectrometry were assessed. Across the spectrum of glucocorticoid and androgen analytes tested, limits of detection and quantitation were ~20 fold lower with triple than single quadrupole systems, but the more noticeable improvement was that signal to noise was substantially improved and the linear range wider. These benefits allowed more reliable and concomitant measurement of steroids with substantially different abundances and in smaller volumes of urine. PMID- 28887175 TI - Epigenetics in pediatric acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. ALL arises from the malignant transformation of progenitor B- and T-cells in the bone marrow into leukemic cells, but the mechanisms underlying this transformation are not well understood. Recent technical advances and decreasing costs of methods for high-throughput DNA sequencing and SNP genotyping have stimulated systematic studies of the epigenetic changes in leukemic cells from pediatric ALL patients. The results emerging from these studies are increasing our understanding of the epigenetic component of leukemogenesis and have demonstrated the potential of DNA methylation as a biomarker for lineage and subtype classification, prognostication, and disease progression in ALL. In this review, we provide a concise examination of the epigenetic studies in ALL, with a focus on DNA methylation and mutations perturbing genes involved in chromatin modification, and discuss the future role of epigenetic analyses in research and clinical management of ALL. PMID- 28887176 TI - Ecoacoustic codes and ecological complexity. AB - Multi-layer communication and sensing network assures the exchange of relevant information between animals and their umwelten, imparting complexity to the ecological systems. Individual soniferous species, the acoustic community, and soundscape are the three main operational levels that comprise this multi-layer network. Acoustic adaptation and acoustic niche are two more important mechanisms that regulate the acoustic performances at the first level while the acoustic community model explains the complexity of the interspecific acoustic network at the second level. Acoustic habitat and ecoacoustic events are two of the most relevant mechanisms that operate at the third level. The exchange of ecoacoustic information on each of these levels is assured by ecoacoustic codes. At the level of individual sonifeorus species, a dyadic intraspecific exchange of information is established between an emitter and a receiver. Ecoacoustic codes discriminate, identify, and label specific signals that pertain to the theme, variation, motif repetition, and intensity of signals. At the acoustic community level, a voluntarily or involuntarily communication is established between networks of interspecific emitters and receivers. Ecoacoustic codes at this level transmit information (e.g., recognition of predators, location of food sources, availability and location of refuges) between one species and the acoustically interacting community and impart cohesion to interspecific assemblages. At the soundscape level, acoustic information is transferred from a mosaic of geophonies, biophonies, and technophonies to different species that discriminate meaningful ecoacoustic events and their temporal dynamics during habitat selection processes. Ecoacoustic codes at this level operate on a limited set of signals from the environmental acoustic dynamic that are heterogeneous in time and space, and these codes are interpreted differently according to the species during habitat selection and the completion of phenological cycles. The process of ecoacoustic coding can be interpreted according to the eco-field theory, which describes the procedures utilized by a receiver to intercept and optimize acoustic information. The acoustic codes may be detected and identified using mathematical models that simulate their performances. The Acoustic Complexity Indices are an appropriate tool to investigate the acoustic codes in action on all three levels. Ecoacoustic codes are powerful agencies used by sound-adapted species to cope with environmental novelties, and their efficiency may represent an important divide between whether a species perpetuates or becomes extinct. PMID- 28887177 TI - A step into the RNA world: Conditional analysis of hydrogel formation of adenosine 5'-monophosphate induced by cyanuric acid. AB - Nucleotide polymerization occurs by the nucleophilic attack of 3'-oxygen of the 3'-terminal nucleotide on the alpha-phosphorus of the incoming nucleotide 5' triphosphate. The pi-stacking of mononucleotides is an important factor for prebiotic RNA polymerization in terms of attaining the proximity of two reacting moieties. Adenosine and adenosine 5'-monophosphate (AMP) are known to form hydrogel in the presence of cyanuric acid at neutral pH. However, we observed that other canonical ribonucleotides did not gel under the same condition. The pi stacking-induced hydrogel formation of AMP was destroyed at pH 2.0, suggesting that the protonation of N at position 1 of adenine abolished hydrogen bonding with the NH of cyanuric acid and resulted in the deformation of the hexad of adenine and cyanuric acid. A liquid-like gel was formed in the case of adenosine with cyanuric acid and boric acid, whereas AMP caused the formation of a solid gel, implying that the negative charge inherent to AMP prevented the formation of esters of boric acid with the cis-diols of ribose. Cyanuric acid-driven oligomerizations of AMP might have been the first crucial event in the foundation of the RNA world. PMID- 28887178 TI - Assessing standards used to review online health information. PMID- 28887179 TI - Reply. PMID- 28887180 TI - Gray matter volume showed dynamic alterations in methamphetamine users at 6 and 12months abstinence: A longitudinal voxel-based morphometry study. AB - BACKGROUND: Previous studies have demonstrated brain gray matter reduction in methamphetamine (MA) users; however, little is known about longitudinal brain structural alternations during abstinence. METHOD: Brain volumes were compared among 30 MA-dependent patients (average 6.3years of drug use) at 6months' abstinence and 27 drug-naive controls by voxel-based morphometry. A longitudinal analysis of MA subjects was performed from 6 to 12months' abstinence, and multiple regression analyses were performed between drug use patterns and gray matter volumes (GMV) at 6months' abstinence. RESULTS: Compared with drug-naive subjects, subjects with 6months' abstinent of MA showed significantly lower GMV in the precentral gyrus, caudate head, fusiform gyrus, and cerebellum. Compared to 6months' abstinence, GMV was greater in the cerebellum and lower in the cingulate gyrus at 12months' abstinence. Accumulated years of MA use negatively correlated with GMV in the right superior frontal gyrus, the right superior temporal cortex, and the right caudate nucleus (significant at the whole brain level, p<0.001; FWE cluster-corrected p<0.05). CONCLUSION: The present study suggested that heavy MA users' GMV could show dynamic alterations in different brain regions at different time lengths of abstinence. PMID- 28887181 TI - Treatment resistant schizophrenia and neurological soft signs may converge on the same pathology: Evidence from explanatory analysis on clinical, psychopathological, and cognitive variables. AB - Here, we investigated neurological soft signs (NSSs) in treatment resistant schizophrenia (TRS) vs treatment responder schizophrenia (SZ) patients. TRS is a severe condition, affecting approximately one-third of schizophrenia patients and representing a relevant clinical challenge. NSSs are neurological abnormalities reportedly described in schizophrenia patients and linked to dysregulated network connections. We explored the possibility that NSSs may be: i) more severe in TRS patients; ii) differentially associated to clinical/cognitive variables in TRS vs SZ; iii) predictive of having TRS. In addition, we evaluated whether diagnosis may mediate NSSs associations with the above-mentioned variables. Consecutive patients with schizophrenia diagnosis underwent stringent assessment for TRS diagnosis. Demographics and clinical variables were recorded. Psychopathology (by Positive and Negative Syndrome Scale, PANSS), cognitive performances, and NSSs (by Neurological Evaluation Scale, NES) were tested. TRS had higher scores than SZ patients in total NES score and in almost all NES subscales, even after correction for duration of illness and antipsychotic dose (ANCOVA, p<0.05). NSSs significantly correlated with multiple clinical, psychopathological, and cognitive variables (above all: duration of disease and negative symptoms) in TRS but not in SZ patients. Two-way ANOVA showed NSS-x-diagnosis interaction in determining outcomes on multiple cognitive performances, but not in other clinical variables. However, simple main effect analysis detected a significant relationship between high severity NSSs and TRS diagnosis on multiple clinical and cognitive outcomes. Hierarchical regression analysis showed that diagnosis was among a discrete number of predictors yielding significant increases in variance explained on NES total, Sensory Integration and Other Signs subscales' scores. NSSs, together with antipsychotic dose and disease severity, were found to be significantly predictive of TRS diagnosis in a binary logistic regression model. These results suggest a stringent association between NSSs and TRS diagnosis, and may imply that NSSs association with clinical, psychopathological, and cognitive variables may be in part mediated by TRS diagnosis. PMID- 28887183 TI - Electrical stimulation of the hippocampal fimbria facilitates neuronal nitric oxide synthase activity in the medial shell of the rat nucleus accumbens: Modulation by dopamine D1 and D2 receptor activation. AB - The medial shell region of the nucleus accumbens (msNAc) is a key center for the regulation of goal-directed behavior and is likely to be dysfunctional in neuropsychiatric disorders such as addiction, depression and schizophrenia. Nitric oxide (NO)-producing interneurons in the msNAc are potently modulated by dopamine (DA) and may play an important role in synaptic integration in msNAc networks. In this study, neuronal NO synthase (nNOS) activity was measured in anesthetized rats using amperometric microsensors implanted into the msNAc or via histochemical techniques. In amperometric studies, NO oxidation current was recorded prior to and during electrical stimulation of the ipsilateral fimbria. Fimbria stimulation elicited a frequency and intensity-dependent increase in msNAc NO efflux which was attenuated by systemic administration of the nNOS inhibitor NG-propyl-l-arginine. Parallel studies using NADPH-diaphorase histochemistry to assay nNOS activity produced highly complementary outcomes. Moreover, systemic administration of either a DA D1 receptor agonist or a DA D2 receptor antagonist potentiated nNOS activity in the msNAc elicited by fimbria stimulation. These observations demonstrate for the first time that NO synthesis in nNOS expressing interneurons in the msNAc is facilitated by robust activation of hippocampal afferents in a manner that is differentially modulated by DA D1 and D2 receptor activation. PMID- 28887184 TI - Chronic fluoxetine administration enhances synaptic plasticity and increases functional dynamics in hippocampal CA3-CA1 synapses. AB - Recent studies demonstrate that chronic administration of the widely used antidepressant fluoxetine (FLX) promotes neurogenesis, synaptogenesis and synaptic plasticity in the adult hippocampus, cortex and amygdala. However, the mechanisms underlying these effects and how are they related to the clinical antidepressant efficacy are still poorly understood. We show here that chronic FLX administration decreases hippocampus-associated neophobia in naive mice. In parallel, electrophysiological recordings in hippocampal CA3-CA1 circuitry revealed that the FLX treatment resulted in increased short- and long-term plasticity likely attributed to changes in presynaptic function. These changes were accompanied by enhancement in the expression of proteins related to vesicular trafficking and release, namely synaptophysin, synaptotagmin 1, MUNC 18 and syntaxin 1. Thus, chronic FLX administration is associated with enhanced synaptic dynamics atypical of mature CA1 synapses, elevated hippocampal plasticity, improved hippocampus-dependent behavior as well as altered expression of synaptic proteins regulating neurotransmitter trafficking and release. The results support the idea that antidepressants can promote neuronal plasticity and show that they can increase the functional dynamic range and information processing in synaptic circuitries. PMID- 28887185 TI - Role of monoaminergic systems and ambient temperature in bath salts constituent 3,4-methylenedioxypyrovalerone (MDPV)-elicited hyperthermia and locomotor stimulation in mice. AB - 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit bath salts products, and in vitro studies implicate monoamine transporters as mediators of its pharmacological effects. Locomotor and thermoregulatory effects of MDPV depend on ambient temperature, so the current studies aimed to gauge the involvement of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in MDPV induced locomotor stimulation and hyperthermia in the mouse at different ambient temperatures. Mice were pretreated with the selective 5-HT-reuptake inhibitor fluoxetine (3 mg/kg), the NE-reuptake inhibitor desipramine (3 mg/kg), the DA reuptake inhibitor bupropion (10 mg/kg), or saline, followed by 10 mg/kg MDPV while thermoregulation and locomotor activity were monitored via radiotelemetry. In other studies, mice were pretreated for three days with saline, 100 mg/kg of the tryptophan hydroxylase inhibitor para-chlorophenylalanine (p-CPA), or 100 mg/kg of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha MPT) before receiving 10 mg/kg MDPV on the fourth day. All manipulations were conducted at both 20 degrees C and 28 degrees C ambient temperatures. MDPV increased locomotor activity under both ambient conditions and modestly increased core body temperature at 20 degrees C; however, neither pretreatment with monoamine reuptake inhibitors nor monoamine synthesis inhibitors significantly altered these effects. At 28 degrees C, MDPV induced a more pronounced hyperthermic effect which was attenuated by bupropion, desipramine, or fluoxetine pretreatment, but not by the monoamine synthesis inhibitors. These results suggest that MDPV may have a more complex pharmacological profile than suggested by in vitro studies, perhaps extending beyond interactions with monoamine transporters. A more thorough binding profile of MDPV at various brain recognition sites should be developed. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 28887186 TI - To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis: a position paper of ESGBOR, the ESCMID study group for Lyme borreliosis. AB - BACKGROUND: Lyme borreliosis (LB) is a tick-borne infection caused by Borrelia burgdorferi sensu lato. The most frequent clinical manifestations are erythema migrans and Lyme neuroborreliosis. Currently, a large volume of diagnostic testing for LB is reported, whereas the incidence of clinically relevant disease manifestations is low. This indicates overuse of diagnostic testing for LB with implications for patient care and cost-effective health management. AIM: The recommendations provided in this review are intended to support both the clinical diagnosis and initiatives for a more rational use of laboratory testing in patients with clinically suspected LB. SOURCES: This is a narrative review combining various aspects of the clinical and laboratory diagnosis with an educational purpose. The literature search was based on existing systematic reviews, national and international guidelines and supplemented with specific citations. IMPLICATIONS: The main recommendations according to current European case definitions for LB are as follows. Typical erythema migrans should be diagnosed clinically and does not require laboratory testing. The diagnosis of Lyme neuroborreliosis requires laboratory investigation of the spinal fluid including intrathecal antibody production, and the remaining disease manifestations require testing for serum antibodies to B. burgdorferi. Testing individuals with non-specific subjective symptoms is not recommended, because of a low positive predictive value. PMID- 28887182 TI - Behavioral and neural mechanisms underlying habitual and compulsive drug seeking. AB - Addiction is characterized by compulsive drug use despite negative consequences. Here we review studies that indicate that compulsive drug use, and in particular punishment resistance in animal models of addiction, is related to impaired cortical control over habitual behavior. In humans and animals, instrumental behavior is supported by goal-directed and habitual systems that rely on distinct corticostriatal networks. Chronic exposure to addictive drugs or stress has been shown to bias instrumental response strategies toward habit learning, and impair prefrontal cortical (PFC) control over responding. Moreover, recent work has implicated prelimbic PFC hypofunction in the punishment resistance that has been observed in a subset of animals with an extended history of cocaine self administration. This may be related to a broader role for prelimbic PFC in mediating adaptive responding and behavioral flexibility, including exerting goal directed control over behavior. We hypothesize that impaired cortical control and reduced flexibility between habitual and goal-directed systems may be critically involved in the development of maladaptive, compulsive drug use. PMID- 28887187 TI - Different chemical groups modification on the surface of chitosan nonwoven dressing and the hemostatic properties. AB - The hemostatic properties of surface modified chitosan nonwoven had been investigated. The succinyl groups, carboxymethyl groups and quaternary ammonium groups were introduced into the surface of chitosan nonwoven (obtained NSCS, CMCS and TMCS nonwoven, respectively). For blood clotting, absorbance value (0.105+/ 0.03) of NSCS1 nonwoven was the smallest (CS 0.307+/-0.002, NSCS2 0.148+/-0.002, CMCS1 0.195+/-0.02, CMCS2 0.233+/-0.001, TMCS1 0.191+/-0.002, TMCS2 0.345+/ 0.002), which indicated the stronger hemostatic potential. For platelet aggregation, adenosine diphosphate agonist was added to induce the nonwoven to adhered platelets. The aggregation of platelet with TMCS2 nonwoven was highest (10.97+/-0.16%). Further research of blood coagulation mechanism was discussed, which indicated NSCS and CMCS nonwoven could activate the intrinsic pathway of coagulation to accelerate blood coagulation. NSCS1 nonwoven showed the shortest hemostatic time (147+/-3.7s) and the lowest blood loss (0.23+/-0.05g) in a rabbit ear artery injury model. These results demonstrated that these surface modified chitosan nonwoven dressings could use as a promising hemostatic intervention, especially NSCS nonwoven dressing. PMID- 28887188 TI - An extremely thermostable maltogenic amylase from Staphylothermus marinus: Bacillus expression of the gene and its application in genistin glycosylation. AB - The most extremely thermostable maltogenic amylase (SMMA) from archaeon Staphylothermus marinus has many potential applications in food processing. To ensure safety of microbial origin, a recombinant plasmid containing the enzymic gene and a constitutive promoter AmyR2 was constructed, and then transformed into a GRAS microorganism Bacillus subtilis. The purified SMMA from the liquid cultures of Bacillus has a specific activity of 66.96U/mg, two times more than that from Escherichia coli. SMMA was further employed to catalyze the genistion glycosylation using gamma-CD as both glucosyl donors and solubilizer. Glycosylated genistins with one to four additional alpha-glucosyls and a molar percentage of 69.87% in genistin reaction mixture were identified and quantified by HPLC-UV-MS. The glycosylated genistins at 0.2-1.2mM showed an enhanced DPPH free radical scavenging capacity. To our knowledge, this is the first report on the Bacillus expression of archaeal maltogenic amylase. PMID- 28887189 TI - Fluorescence spectroscopic analysis of the interaction of papain and bromelain with l-ascorbic acid, alpha-tocopherol, beta-carotene and astaxanthin. AB - In this study, the interaction between four classic dietary antioxidants (including l-ascorbic acid, alpha-tocopherol, beta-carotene and astaxanthin) and papain/bromelain was investigated by fluorescence spectroscopy. The results show that the quenching mechanisms are all static quenching at lower concentrations of antioxidants, but at higher concentrations of antioxidants, predominantly by the "sphere of action" quenching mechanisms. The binding processes of the four antioxidants to papain/bromelain are all synergistically driven by enthalpy and entropy, and the major driving forces are electrostatic effect and hydrophobic interactions. The binding constants of papain/bromelain with the four antioxidants are in the following order as: astaxanthin-papain >beta-carotene papain > astaxanthin-bromelain >l-ascorbic acid-papain >l-ascorbic acid-bromelain >beta-carotene-bromelain >alpha-tocopherol-papain >alpha-tocopherol-bromelain. Synchronous fluorescence spectroscopy shows the interaction between l-ascorbic acid/beta-carotene/astaxanthin and papain/bromelain decreases the hydrophobicity of the microenvironment of tryptophan (Trp) and tyrosine (Tyr) residues. The hydrophobicity of Trp is increased while the hydrophility of Tyr is increased in the presence of alpha-tocopherol. PMID- 28887190 TI - Rapid detection of fifteen known soybean viruses by dot-immunobinding assay. AB - A dot-immunobinding assay (DIBA) was optimized and used successfully for the rapid detection of 15 known viruses [Alfalfa mosaic virus (AMV), Bean pod mottle virus (BPMV), Bean yellow mosaic virus (BYMV), Cowpea mild mottle virus (CPMMV), Cowpea severe mosaic virus (CPSMV), Cucumber mosaic virus (CMV), Peanut mottle virus (PeMoV), Peanut stunt virus (PSV), Southern bean mosaic virus (SBMV), Soybean dwarf virus (SbDV), Soybean mosaic virus (SMV), Soybean vein necrosis virus (SVNV), Tobacco ringspot virus (TRSV), Tomato ringspot virus (ToRSV), and Tobacco streak virus (TSV)] infecting soybean plants in Oklahoma. More than 1000 leaf samples were collected in approximately 100 commercial soybean fields in 24 counties of Oklahoma, during the 2012-2013 growing seasons. All samples were tested by DIBA using polyclonal antibodies of the above 15 plant viruses. Thirteen viruses were detected, and 8 of them were reported for the first time in soybean crops of Oklahoma. The highest average incidence was recorded for PeMoV (13.5%) followed by SVNV (6.9%), TSV (6.4%), BYMV, (4.5%), and TRSV (3.9%), while the remaining seven viruses were detected in less than 2% of the samples tested. The DIBA was quick, and economical to screen more than 1000 samples against 15 known plant viruses in a very short time. PMID- 28887191 TI - Factors influencing participation in colorectal cancer screening programs in Spain. AB - To analyze the sociodemographic and organizational factors influencing participation in population-based colorectal cancer screening programs (CRCSP) in Spain, a retrospective study was conducted in a cohort of people invited to participate in the first 3 screening rounds of 6 CRCSP from 2000 to 2012. Mixed logistic regression models were used to analyze the relationship between sociodemographic and organizational factors, such as the type of fecal occult blood test (FOBT) used and the FOBT delivery type. The analysis was performed separately in groups (Initial screening-first invitation, Subsequent invitation for previous never-responders, Subsequent invitation-regular, Subsequent invitation-irregular intervals). The results showed that, in the Initial screening-first invitation group, participation was higher in women than in men in all age groups (OR 1.05 in persons aged 50-59years and OR 1.12 in those aged 60-69years). Participation was also higher when no action was required to receive the FOBT kit, independently of the type of screening (Initial screening-first invitation [OR 2.24], Subsequent invitation for previous never-responders [OR 2.14], Subsequent invitation-regular [OR 2.03], Subsequent invitation-irregular intervals [OR 9.38]) and when quantitative rather than qualitative immunological FOBT (FIT) was offered (Initial screening-first invitation [OR 0.70], Subsequent invitation for previous never-responders [OR 0.12], Subsequent invitation-regular [OR 0.20]) or guaiac testing (Initial screening-first invitation [OR 0.81], Subsequent invitation for previous never-responders [OR 0.88], Subsequent invitation-regular [OR 0.73]). In conclusion, the results of this study show that screening participation could be enhanced by inclusion of the FOBT kit with the screening invitation and the use of the quantitative FIT. PMID- 28887192 TI - Integrating smartphone technology, social support and the outdoor physical environment to improve fitness among adults at risk of, or diagnosed with, Type 2 Diabetes: Findings from the 'eCoFit' randomized controlled trial. AB - The risk and prevalence of Type 2 Diabetes (T2D) has dramatically increased over the past decade. The aim of this study was to develop, implement and evaluate a physical activity intervention to improve aerobic and muscular fitness among adults at risk of, or diagnosed with T2D. A 20-week, assessor blinded, parallel group randomized controlled trial (RCT) was conducted at the University of Newcastle (June-December 2015). Adults were randomized to the intervention (n=42) or wait-list control group (n=42). The theory-based intervention included: Phase 1 (weeks 1-10) integrated group sessions (outdoor physical activity and cognitive mentoring), and the eCoFit smartphone application (app). Phase 2 (weeks 11-20) only included the eCoFit app. Participants were assessed at baseline, 10weeks and 20weeks. Linear mixed models (intention-to-treat) were used to determine group-by time interactions at 10weeks (primary time-point) and 20weeks for the primary outcomes. Several secondary outcomes were also assessed. After 10weeks, significant group-by-time effects were observed for aerobic fitness (4.5mL/kg/min; 95% CI [1.3, 7.7], d=0.68) and muscular fitness (lower body) (3.4 reps, 95% CI [2.7, 4.2], d=1.45). Intervention effects for secondary outcomes included significant increased physical activity (1330steps/week), improved upper body muscular fitness (5 reps; arm-curl test), improved functionality (-1.8s; timed-up and go test) reduced waist circumference (2.8cm) and systolic blood pressure (-10.4mmHg). After 20weeks, significant effects were observed for lower body muscular fitness and health outcomes. eCoFit is an innovative lifestyle intervention which integrates smartphone technology, social support, and the outdoor environment to improve aerobic and muscular fitness. PMID- 28887193 TI - Variability in self-rated health trajectories from adolescence to young adulthood by demographic factors. AB - Self-rated health (SRH) is a robust measure of general health status and an indicator of where and when to target disease prevention efforts-especially in adolescent populations when clinical endpoints are rare. This study's purpose was to model SRH trajectories from ages 13 to 31 and identify whether and when differences between demographic groups emerge. We employed a conditional latent growth model of SRH in December 2016 using a nationally representative sample of 11,512 adolescents from the National Longitudinal Study of Adolescent to Adult Health data collected in 1994-2008. The average SRH trajectory is curvilinear: SRH increases until age 21 and then decreases. This trajectory contains significant between-individual variability in the intercept and linear slope. Males and self-identified non-Hispanic Blacks had higher SRH at age 13 but experienced steeper linear declines than their demographic counterparts. Individuals who grew up in households without two parents and whose parents did not graduate college had consistently lower SRH compared to those living in households with two parents and whose parents graduated college. Self-rated health is not stable over the span of early adolescence to young adulthood; demographic factors account for differences in individual variability around the starting point and overtime changes in SRH. Because these differences are apparent as early as age 13years, prevention efforts targeting demographic-based disparities should occur early in life. PMID- 28887194 TI - Hypoxia-inducible factor-1alpha is involved in isoflurane-induced blood-brain barrier disruption in aged rats model of POCD. AB - Prolonged exposure to inhaled anesthetics may lead to postoperative cognitive dysfunction (POCD). Nevertheless, the underlying mechanisms are not known. Hypoxia-inducible factor-1alpha (HIF-1alpha) and its target gene vascular endothelial growth factor (VEGF) were shown to be activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF-1alpha in isoflurane-induced blood-brain barrier (BBB) disruption and resultant cognitive impairment. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in vascular permeability, and disrupted BBB ultrastructure were accompanied by the degradation of tight junction proteins occludin and collagen type IV in brain blood vessels. Increases in HIF-1alpha and VEGF proteins and activation of MMP-2 in the hippocampus were also observed in the hippocamp of isoflurane-exposed rats compared with control rats. Pharmacological inhibition of HIF-1alpha activation by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) markedly suppressed the expression of HIF-1alpha, VEGF and MMP-2, and mitigated the severity of BBB disruption.YC-1 pretreatment also significantly attenuated isoflurane-induced cognitive deficits in the Morris water maze task. Overall, our results demonstrate that hippocampal HIF-1alpha/VEGF signaling seems to be the upstream mechanism of isoflurane-induced cognitive impairment, and provides apotential preventive and therapeutic target for POCD. PMID- 28887195 TI - Pharmacological activation of the Nrf2 pathway by 3H-1, 2-dithiole-3-thione is neuroprotective in a mouse model of Alzheimer disease. AB - Accumulating evidence suggests that oxidative stress induced by beta-amyloid (Abeta) is implicated in the pathlogical progression of Alzheimer's disease (AD). 3H-1,2-dithiole-3-thione (D3T), the simplest compound of the sulfur-containing dithiolethiones, has been proved to be a strongly active antioxidant factor by regulation of the nuclear factor E2-related factor 2 (Nrf2). Previous study reported that D3T confers protection to AD cell model in vitro, however, the neuroprotective effect of D3T in the AD mammalian model is unknown. In the present study, we aimed to evaluate the therapeutic potential of D3T in the Tg2576 AD mouse model and investigate the mechanisms underlying its beneficial effects. We showed that intraperitoneal administration of D3T significantly alleviated cognitive deficits in AD mice and dramatically decreased insoluble Abeta level and oxidative stress. Further mechanistic studies revealed that D3T significantly promoted hippocampal neurogenesis, and up-regulated levels of silent information regulator 1 (Sirt1), Nrf2 and heme oxygenase-1 (HO-1). Moreover, the positive effect of D3T on behavioral performance of AD mice was markedly attenuated by inhibition of the Sirt1/Nrf2 pathway by the antagonist EX527. In summary, our studies on a mouse AD model indicate that D3T could serve as a potential therapeutic agent for this devastating disease. PMID- 28887196 TI - Enhanced expression of heme oxygenase-1 in the locus coeruleus can be associated with anxiolytic-like effects. AB - Some researchers have shown that carbon monoxide (CO) plays a role in emotional behavior modulation through intracellular 3'-5'-guanosine monophosphate mechanisms in the locus coeruleus (LC). In fact, the LC region has a high expression of the heme-oxygenase (HO) enzymes, which are responsible for the production of CO. However, the physiological mechanism by which the HO-CO pathway participates in the modulation of emotional responses in the LC still needs clarification. This study evaluates whether a systemic intraperitoneal treatment is able to alter behavioral responses (in the elevated plus-maze and the light dark box test) and the expression of the HO-1 and HO-2 enzymes in the LC. The tested treatments are acute (3h before) or chronic (twice daily for 10days) and with a carbon monoxide releaser (tricarbonyldichlororuthenium [II] dimer, or CORM 2) or with a HO-1 inducer compound (cobalt protoporphyrin IX, CoPP). The results for the elevated plus-maze show that CO-for both acute or chronic administration of either drug-ncreased the number of entries into the open arms and the percentage of time spent in the open arms. Regarding the light-dark box test, chronic treatment with either drug increased the time spent in the light compartment. Additionally, treatment with CORM-2 or CoPP, either acutely or chronically, increased HO-1 enzyme expression in the LC cells. This study shows that systemic CO treatment can promote an anxiolytic-like effect and the expression of HO-1 enzymes in LC cells. PMID- 28887197 TI - Reduction in open field activity in the absence of memory deficits in the AppNL-G F knock-in mouse model of Alzheimer's disease. AB - The recent development of knock-in mouse models of Alzheimer's disease provides distinct advantages over traditional transgenic mouse models that rely on over expression of amyloid precursor protein. Two such knock-in models that have recently been widely adopted by Alzheimer's researchers are the AppNL-F and AppNL G-F mice. This study aimed to further characterise the behavioural phenotype and amyloid plaque distribution of AppNL-G-F/NL-G-F (C57BL/6J background) mice at six months of age. An attempt to replicate a previous study that observed deficits in working memory in the Y-maze, showed no difference between AppNL-G-F/NL-G-F and wild-type mice. Further assessment of these mice using the novel object recognition test and Morris water maze also revealed no differences between AppNL G-F/NL-G-F and wild-type mice. Despite a lack of demonstrated cognitive deficits, we report a reduction in locomotor/exploratory activity in an open field. Histological examination of AppNL-G-F/NL-G-F mice showed widespread distribution of amyloid plaques at this age. We conclude that whilst at six-months of age, memory deficits are not sufficiently robust to be replicated in varying environments, amyloid plaque burden is significant in AppNL-G-F/NL-G-F knock-in brain. PMID- 28887198 TI - Mindfulness and dynamic functional neural connectivity in children and adolescents. AB - BACKGROUND: Interventions that promote mindfulness consistently show salutary effects on cognition and emotional wellbeing in adults, and more recently, in children and adolescents. However, we lack understanding of the neurobiological mechanisms underlying mindfulness in youth that should allow for more judicious application of these interventions in clinical and educational settings. METHODS: Using multi-echo multi-band fMRI, we examined dynamic (i.e., time-varying) and conventional static resting-state connectivity between core neurocognitive networks (i.e., salience/emotion, default mode, central executive) in 42 children and adolescents (ages 6-17). RESULTS: We found that trait mindfulness in youth relates to dynamic but not static resting-state connectivity. Specifically, more mindful youth transitioned more between brain states over the course of the scan, spent overall less time in a certain connectivity state, and showed a state specific reduction in connectivity between salience/emotion and central executive networks. The number of state transitions mediated the link between higher mindfulness and lower anxiety, providing new insights into potential neural mechanisms underlying benefits of mindfulness on psychological health in youth. CONCLUSIONS: Our results provide new evidence that mindfulness in youth relates to functional neural dynamics and interactions between neurocognitive networks, over time. PMID- 28887199 TI - Temporal evolution of polymyxin B-resistant Klebsiella pneumoniae clones recovered from blood cultures in a teaching hospital during a 7-year period. AB - The polymyxins have become one of the last resorts to treat serious infections caused by KPC-2-producing Klebsiella pneumoniae worldwide. However, the increase of polymyxin consumption has favored the emergence of resistance to these compounds. In this study, we observed an increase in polymyxin B resistance rates from 0 to 30.6% among 224 K. pneumoniae isolates recovered from blood cultures between 2009 and 2015. Only gentamicin, tigecycline and fosfomycin remained active against the polymyxin B-resistant K. pneumoniae (PMB-R-KPN) isolates, which were classified as extensively drug-resistant (XDR; 83.3%), multidrug resistant (MDR; 13.9%), or pan-drug resistant (2.8%). Most PMB-R-KPN clones belonged to CC258 (ST11, ST258, ST340, and ST437). A C7/ST258 XDR clone carrying distinct resistance determinants (blaSHV-11, blaTEM-1, blaCTX-M-15, blaCTX-M-14, blaKPC-2, and rmtB-1) was introduced in 2014. Twelve of 36 PMB-R-KPN isolates showed disruption of mgrB. No mcr-1-positive isolate was found. The rapid detection of PMB-R-KPN isolates allied to implementation of effective infection control measures are of crucial importance to avoid the dissemination of high risk PMB-R-KPN clones. PMID- 28887200 TI - Purification and characterisation of a novel antistaphylococcal peptide (ASP-1) from Bacillus sp. URID 12.1. AB - A strong antistaphylococcal peptide (ASP-1) from Bacillus subtilis URID 12.1 strain that is active against cefoxitin- and methicillin-resistant Staphylococcus aureus clinical isolates was purified to homogeneity by solvent extraction, silica gel-based adsorption chromatography and reversed-phase high-performance liquid chromatography. The peptide sequence of ASP-1 as determined by MALDI TOF/MS and ESI-FTICR-MS was acetylated Phe-Thr-Ala-Val-Dhb-Phe-Ile/Leu. The peptide was further analysed by alkaline hydrolysis, ESI-Q-TOF-MS and an ion mobility assay, which detected the presence of a lactone ring in the intact peptide and a cyclic nature, subsequently revealing the linearised peptide sequence as acPhe-Leu-Phe-Thr-Val-Ala-Dhb. Based on the molecular mass (804.5 Da), peptide sequence and amino acid composition, ASP-1 was identified as a lactone ring-containing peptide similar to TL-119, a poorly studied cyclic depsipeptide. Circular dichroism spectroscopy revealed its predominantly random structure in aqueous solution and its beta-sheet conformation in methanol. Minimum inhibitory concentrations (MICs) of the purified peptide against S. aureus and methicillin-resistant S. aureus (MRSA) ranged from 2 ug/mL to 64 ug/mL. At sub-MICs and 1* MIC, ASP-1 showed a strong antibiofilm characteristic. ASP-1 at a concentration of 128 ug/mL did not show haemolytic activity, and no cytotoxicity was observed against hepatic carcinoma and breast carcinoma cell lines at the same concentration. Peptide ASP-1 with anti-MRSA and antibiofilm abilities and non-haemolytic and non-cytotoxic properties has not been reported previously. These findings suggest that it may serve as a lead molecule for developing alternative topical antibacterial agents. PMID- 28887201 TI - Reactive oxygen species: a novel antimicrobial. AB - The main solution to the global antibiotic resistance crisis is to reduce the volume of antibiotic use in medicine, agriculture and the environment. However, there is also a pressing need for novel antimicrobials. Despite much rhetoric, there are few entirely novel agents in development. One such therapy to reach clinical use is an agent using Reactive Oxygen Species (ROS), oxygen radicals, as an antimicrobial mechanism. ROS can be delivered to the site of infection in various formats. ROS are highly antimicrobial against Gram-positive and Gram negative bacteria, viruses and fungi. They also prevent and break down biofilm. These functions make ROS potentially highly suitable for chronic inflammatory conditions, where antibiotics are frequently overused and relatively ineffective, including: chronic wounds, ulcers and burns; chronic rhinosinusitis, chronic bronchitis, bronchiectasis, cystic fibrosis and ventilated airways; recurrent cystitis; and prosthetic device infection. ROS could have an important role in infection prevention and antimicrobial stewardship. Much clinical investigation remains to be delivered on ROS therapy, but in vitro work on infection models and early clinical evaluations are extremely promising. PMID- 28887202 TI - Hospital sewage water: a reservoir for variants of New Delhi metallo-beta lactamase (NDM)- and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. AB - New Delhi metallo-beta-lactamase (NDM)-producing Enterobacteriaceae have become a threat to public health. Hospital sewage is generally unexplored, having the potential to harbour bacteria causing healthcare-associated infections. Hence, this study was initiated to monitor NDM-producing Enterobacteriaceae in hospital sewage water. A total of 32 isolates with blaNDM variants were detected in hospital sewage water, including 17 Escherichia coli, 8 Citrobacter freundii, 4 Shigella boydii, 2 Citrobacter braakii and 1 Citrobacter farmeri, showing resistance to all antibiotics except colistin. All 32 isolates carried blaNDM (9 blaNDM-1, 11 blaNDM-4, 10 blaNDM-5 and 2 blaNDM-7), 24 isolates carried blaCMY variants (1 blaCMY-2, 3 blaCMY-4, 5 blaCMY-6, 11 blaCMY-42, 2 blaCMY-86 and 2 blaCMY-139), 20 isolates carried blaOXA-type (17 blaOXA-1 and 3 blaOXA-48), 19 isolates carried blaCTX-M and 9 isolates carried ampC on conjugative plasmids of IncFIA, IncFIB, IncFIC, IncP, IncY, IncHI1 and IncI1 types. In E. coli, coexistence of blaNDM-1 with blaCMY-6 and blaCMY-139, of blaNDM-4 with blaCMY-6, blaCMY-42 and blaCMY-86, of blaNDM-5 with blaCMY-6 and blaCMY-42, and of blaNDM-7 with blaCMY-6 was observed. NDM-5-producing S. boydii and NDM-7-producing C. freundii were identified as well as detection of an association of blaNDM-4 and blaOXA-48 in C. braakii and C. farmeri. A class 1 integron was also found on a plasmid. ISAba125 and bleomycin genes were found surrounding all blaNDM variants. The emergence and dissemination of blaNDM variants in hospital sewage water is a matter of concern, creating an endemic scenario leading to the level of an outbreak. PMID- 28887203 TI - Clinical relevance of metronidazole and peripheral neuropathy: a systematic review of the literature. AB - The objective of this paper was to review and evaluate the literature on metronidazole-associated peripheral neuropathy and determine the relevance in clinical practice. MEDLINE/PubMed, EBSCO, and Google Scholar were searched through February 2017 using the search terms metronidazole and peripheral neuropathy, or polyneuropathy, or paresthesia, or neurotoxicity. Relevant case reports, retrospective studies, surveys, and review articles were included. Bibliographies of all relevant articles were reviewed for additional sources. Overall, metronidazole is generally well tolerated, but serious neurotoxicity, including peripheral neuropathy, has been reported. The overall incidence of peripheral neuropathy associated with metronidazole is unknown. Our review found 36 case reports (40 unique patients) of metronidazole-associated peripheral neuropathy, with most cases (31/40) receiving a >42 g total (>4 weeks) of therapy. In addition, we reviewed 13 clinical studies and found varying rates of peripheral neuropathy from 0 to 50%. Within these clinical studies, we found a higher incidence of peripheral neuropathy in patients receiving >42 g total (>4 weeks) of metronidazole compared with those patients receiving <=42 g total (17.9% vs. 1.7%). Nearly all patients had complete resolution of symptoms. In conclusion, peripheral neuropathy is rare in patients who receive <=42 g total of metronidazole. Patients who receive higher total doses may be at higher risk of peripheral neuropathy, but symptoms resolve after discontinuation of therapy in most patients. Antimicrobial stewardship programs may consider use of antibiotic combinations that include metronidazole over broad-spectrum alternatives when treating with <=42 g total of the drug (<=4 weeks). PMID- 28887204 TI - Structural determinants in ApoA-I amyloidogenic variants explain improved cholesterol metabolism despite low HDL levels. AB - Twenty Apolipoprotein A-I (ApoA-I) variants are responsible for a systemic hereditary amyloidosis in which protein fibrils can accumulate in different organs, leading to their failure. Several ApoA-I amyloidogenic mutations are also associated with hypoalphalipoproteinemia, low ApoA-I and high-density lipoprotein (HDL)-cholesterol plasma levels; however, subjects affected by ApoA-I-related amyloidosis do not show a higher risk of cardiovascular diseases (CVD). The structural features, the lipid binding properties and the functionality of four ApoA-I amyloidogenic variants were therefore inspected in order to clarify the paradox observed in the clinical phenotype of the affected subjects. Our results show that ApoA-I amyloidogenic variants are characterized by a different oligomerization pattern and that the position of the mutation in the ApoA-I sequence affects the molecular structure of the formed HDL particles. Although lipidation increases ApoA-I proteins stability, all the amyloidogenic variants analyzed show a lower affinity for lipids, both in vitro and in ex vivo mouse serum. Interestingly, the lower efficiency at forming HDL particles is compensated by a higher efficiency at catalysing cholesterol efflux from macrophages. The decreased affinity of ApoA-I amyloidogenic variants for lipids, together with the increased efficiency in the cholesterol efflux process, could explain why, despite the unfavourable lipid profile, patients affected by ApoA-I related amyloidosis do not show a higher CVD risk. PMID- 28887205 TI - Approaches and techniques to characterize cancer metabolism in vitro and in vivo. AB - Cancer metabolism is wired to sustain uncontrollable cell proliferation and ensure cell survival. Given the multitude of available approaches to study metabolic alterations it remains a challenging task to select the most appropriate method. In this mini-review we describe how cancer metabolism can be studied in vitro and in vivo providing an overview of available approaches and techniques, discussing their advantages and drawbacks and guiding through selection of an appropriate method to address particular research needs. This work is particularly intended to those cancer researchers who are new in the field but want to investigate metabolic alterations in their cancer model systems. PMID- 28887206 TI - Reproducibility and relative stability in magnetic resonance imaging indices of tumor vascular physiology over a period of 24h in a rat 9L gliosarcoma model. AB - PURPOSE: The objective was to study temporal changes in tumor vascular physiological indices in a period of 24h in a 9L gliosarcoma rat model. METHODS: Fischer-344 rats (N=14) were orthotopically implanted with 9L cells. At 2weeks post-implantation, they were imaged twice in a 24h interval using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Data-driven model selection-based analysis was used to segment tumor regions with varying vascular permeability characteristics. The region with the maximum number of estimable parameters of vascular kinetics was chosen for comparison across the two time points. It provided estimates of three parameters for an MR contrast agent (MRCA): i) plasma volume (vp), ii) forward volumetric transfer constant (Ktrans) and interstitial volume fraction (ve, ratio of Ktrans to reverse transfer constant, kep). In addition, MRCA extracellular distribution volume (VD) was estimated in the tumor and its borders, along with tumor blood flow (TBF) and peritumoral MRCA flux. Descriptors of parametric distributions were compared between the two times. Tumor extent was examined by hematoxylin and eosin (H&E) staining. Picrosirus red staining of secreted collagen was performed as an additional index for 9L cells. RESULTS: Test-retest differences between population summaries for any parameter were not significant (paired t and Wilcoxon signed rank tests). Bland-Altman plots showed no apparent trends between the differences and averages of the test-retest measures for all indices. The intraclass correlation coefficients showed moderate to almost perfect reproducibility for all of the parameters, except vp. H&E staining showed tumor infiltration in parenchyma, perivascular space and white matter tracts. Collagen staining was observed along the outer edges of main tumor mass. CONCLUSION: The data suggest the relative stability of these MR indices of tumor microenvironment over a 24h duration in this gliosarcoma model. PMID- 28887207 TI - Extent of size, shape and systolic variability of the left ventricular outflow tract in aortic stenosis determined by phase-contrast MRI. AB - PURPOSE: Left ventricular outflow tract (LVOT) dimensions are important for calculation of aortic valve areas and planning of valve repair. Mostly, LVOT areas are calculated from echocardiographic longitudinal measurements with the assumption of a round shape. Here, orthogonal phase contrast (PC) MRI with dynamic assessment of LVOT was compared to standard longitudinal cine MRI and 2D echocardiography. METHODS: In 19 patients with aortic stenosis (5 female; 69+/ 10years), LVOT areas were determined on orthogonal PC images, either by planimetry (Aplan) or by two-diameter measurement (Aellip). Data were analyzed in early, middle and late systole (t1/t2/t3). Additionally, standard diameter-based calculation (A3CV) of LVOT on longitudinal three-chamber view (3CV) MRI images and 2D echocardiography was performed. RESULTS: Calculated PC LVOT areas strongly correlated to planimetry (r=0.95; p<0.001) with almost identical areas (Aplan 5.1+/-1.1cm2 vs. Aellip 5.3+/-1.0cm2). In PC changes of LVOT-eccentricity during systole were most pronounced in late systole (t1 vs. t3plan -7.4+/-18%). Cine 3CV calculation resulted in lower LVOT areas compared to Aplan (A3CV 3.7+/-0.9cm2; p<0.001), yet correlating to Aplan (r=0.66; p=0.002). 3CV LVOT areas correlated to echocardiography (r=0.56; p=0.014). CONCLUSIONS: Calculated LVOT areas seem to be sufficient for daily routine. Compared to the orthogonal view, standard long axis 3CV underestimates the LVOT size and overestimates the systolic reduction of LVOT-size. Systolic changes are most pronounced in late systole. PMID- 28887208 TI - Proteomic comparison of three clinical diarrhoeagenic drug-resistant Escherichia coli isolates grown on CHROMagarTMSTEC media. AB - : Shiga-toxin-producing Escherichia coli (STEC) and enteropathogenic Escherichia coli (EPEC) are key diarrhoea-causing foodborne pathogens. We used proteomics to characterize the virulence and antimicrobial resistance protein profiles of three clinical pathogenic E. coli isolates (two EPEC [one resistant to ciprofloxacin] and one STEC) cultured on CHROMagarTMSTEC solid media after minimal laboratory passage. We identified 4767 unique peptides from 1630 protein group across all three clinical E. coli strains. Label-free proteomic analysis allowed the identification of virulence and drug resistance proteins that were unique to each of the clinical isolates compared in this study. The B subunit of Shiga toxin, ToxB, was uniquely detected in the STEC strain while several other virulence factors including SheA, OmpF, OmpC and OmpX were significantly more abundant in the STEC strain. The ciprofloxacin resistant EPEC isolate possessed reduced levels of key virulence proteins compared to the ciprofloxacin susceptible EPEC and STEC strains. Parallel reaction monitoring assays validated the presence of biologically relevant proteins across biologically-replicated cultures. Propagation of clinical isolates on a relevant solid medium followed by mass spectrometry analysis represents a convenient means to quantify virulence factors and drug resistance determinants that might otherwise be lost through extensive in vitro passage in enteropathogenic bacteria. SIGNIFICANCE: Through the use of quantitative proteomics, we have characterized the virulence and antimicrobial resistance attributes of three clinically isolated, pathogenic E. coli strains cultured on solid media. Our results provide new, quantitative data on the expressed proteomes of these tellurite-resistant, diarrhoeagenic E. coli strains and reveal a subset of antimicrobial resistance and virulence proteins that are differentially abundant between these clinical strains. Our quantitative proteomics-based approach should thus have applicability in microbiological diagnostic labs for the identification of pathogenic/drug resistant E. coli in the future. PMID- 28887209 TI - Thyroid-associated orbitopathy and tears: A proteomics study. AB - : To date, Thyroid-Associated Orbitopathy (TAO), an autoimmune inflammatory disease affecting the eye, remains poorly characterised and its diagnosis challenging. The aim of this study was to investigate the tears of the TAO patients in order to identify potential biomarkers. Two independent quantitative Tandem Mass TagTM 6-plex experiments were done. After in-solution digestion and isoelectric fractionation, the 12 fractions were analysed with a LTQ Orbitrap Velos coupled to a liquid chromatography. Raw files were searched against Swiss Prot-AC database using Proteome Discoverer software, with a false discovery rate of 1% at peptide and protein levels. The differential proteins were then verified using orthogonal approaches in independent patients. Globally, 712 tear proteins were quantified with 2 unique peptides. Interestingly, cystatin c (TAO/controls ratio: 1.53), alpha-1 antichymotrypsin (ratio: 1.70) and retinal dehydrogenase (ratio: 0.68), displaying differential levels in the tears of TAO patients using proteomics experiments emerged as highly promising biomarkers after verification. In conclusion, this proteomics study supports the idea that tears reflect biological modifications occurring in a disease context and can therefore be a promising fluid for biomarker discovery. Moreover, our study identified three candidates that could in the future open new avenues in the diagnosis of TAO disease. SIGNIFICANCE: Thyroid associated orbitopathy (TAO) is the most common disease affecting the orbit. Moreover, the later, severe stages of the disease can be sight threating [1]. On the other hand, the early sign and symptoms can be mistaken with other ocular pathologies [2]. Here we explore the modification of the tear content of the TAO patients using proteomics strategies and we proposed three new biomarker candidates, which could allow the early diagnosis of the disease and prompt action to prevent more severe stages. Moreover, our findings could also help to better understand the pathophysiology of the disease. PMID- 28887210 TI - Can half-marathon affect overall health? The yin-yang of sport. AB - : Physical activity improves overall health and counteracts metabolic pathologies. Adipose tissue and bone are important key targets of exercise; the prevalence of diseases associated with suboptimal physical activity levels has increased in recent times as a result of lifestyle changes. Mesenchymal stem cells (MSCs) differentiation in either osteogenic or adipogenic lineage is regulated by many factors. Particularly, the expression of master genes such as RUNX2 and PPARgamma2 is essential for MSC commitment to osteogenic or adipogenic differentiation, respectively. Besides various positive effects on health, some authors have reported stressful outcomes as a consequence of endurance in physical activity. We looked for further clues about MSCs differentiation and serum proteins modulation studying the effects of half marathon in runners by means of gene expression analyses and a proteomic approach. Our results demonstrated an increase in osteogenic commitment and a reduction in adipogenic commitment of MSCs. In addition, for the first time we have analyzed the proteomic profile changes in runners after half-marathon activity in order to survey the related systemic adjustments. The shotgun proteomic approach, performed through the immuno-depletion of the 14 most abundant serum proteins, allowed the identification of 23 modulated proteins after the half marathon. Interestingly, proteomic data showed the activation of both inflammatory response and detoxification process. Moreover, the involvement of pathways associated to immune response, lipid transport and coagulation, was elicited. Notably, positive and negative effects may be strictly linked. Data are available via ProteomeXchange with identifier PXD006704. SIGNIFICANCE: We describe gene expression and proteomic studies aiming to an in-depth understanding of half marathon effects on bone and adipogenic differentiation as well as biological phenomena involved in sport activity. We believe that this novel approach suggests the physical effects on overall health and show the different pathways involved during half marathon. Contents of the paper have not been published or submitted for publication elsewhere. The authors declare no conflict of interest. PMID- 28887212 TI - Nanoscale mapping of refractive index by using scattering-type scanning near field optical microscopy. AB - We present a novel method for nanoscale reconstruction of complex refractive index by using scattering-type Scanning Near-field Optical Microscopy (s-SNOM). Our method relies on correlating s-SNOM experimental image data with computational data obtained through simulation of the classical oscillating point dipole model. This results in assigning a certain dielectric function for every pixel of the s-SNOM images, which further results in nanoscale mapping of the refractive index. This method is employed on human erythrocytes to demonstrate the approach in a biologically relevant manner. The presented results advance the current knowledge on the capabilities of s-SNOM to extract quantitative information with nanoscale resolution from optical data sets with biological application. PMID- 28887211 TI - Gold nanoparticles in injectable calcium phosphate cement enhance osteogenic differentiation of human dental pulp stem cells. AB - In this study, a novel calcium phosphate cement containing gold nanoparticles (GNP-CPC) was developed. Its osteogenic induction ability on human dental pulp stem cells (hDPSCs) was investigated for the first time. The incorporation of GNPs improved hDPSCs behavior on CPC, including better cell adhesion (about 2 fold increase in cell spreading) and proliferation, and enhanced osteogenic differentiation (about 2-3-fold increase at 14 days). GNPs endow CPC with micro nano-structure, thus improving surface properties for cell adhesion and subsequent behaviors. In addition, GNPs released from GNP-CPC were internalized by hDPSCs, as verified by transmission electron microscopy (TEM), thus enhancing cell functions. The culture media containing GNPs enhanced the cellular activities of hDPSCs. This result was consistent with and supported the osteogenic induction results of GNP-CPC. In conclusion, GNP-CPC significantly enhanced the osteogenic functions of hDPSCs. GNPs are promising to modify CPC with nanotopography and work as bioactive additives thus enhance bone regeneration. PMID- 28887213 TI - Bivalent mucosal peptide vaccines administered using the LCP carrier system stimulate protective immune responses against Streptococcus pyogenes infection. AB - Despite the broad knowledge about the pathogenicity of Streptococcus pyogenes there is still a controversy about the correlate of protection in GAS infections. We aimed in further improving the immune responses stimulated against GAS comparing different vaccine formulations including bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) and BPPCysMPEG, a derivative of the macrophage activating lipopeptide (MALP-2), as adjuvants, respectively, to be administered with and without the universal T helper cell epitope P25 along with the optimized B cell epitope J14 of the M protein and B and T cell epitopes of SfbI. Lipopeptide based nano carrier systems (LCP) were used for efficient antigen delivery across the mucosal barrier. The stimulated immune responses were efficient in protecting mice against a respiratory challenge with a lethal dose of a heterologous S. pyogenes strain. Moreover, combination of the LCP based peptide vaccine with c-di-AMP allowed reduction of antigen dose at the same time maintaining vaccine efficacy. PMID- 28887214 TI - Trypanocidal activity of polysaccharide extract from Genipa americana leaves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The parts of the Genipa americana (Rubiaceae) tree, also known as "jenipapo" or "jenipapeiro", has been used in traditional Medicine in parasitic and bacterial infections. Thus, the experimental evolution of the antiparasitic activity of polysaccharide extracts from Genipa americana leaves, and correlation with antiparasitic and popular use is important. AIM OF THE STUDY: To evaluate the effect of polysaccharide extract obtained from Genipa americana leaves on all Trypanosoma cruzi (Y strain: benznidazole-resistant) developmental forms, a protozoan that causes Chagas' disease. MATERIALS AND METHODS: An extract rich in polysaccharides was obtained from the leaves of Genipa americana (GaEPL) by associating depigmentation in methanol followed by extraction of polysaccharides in NaOH and precipitation with ethanol. Cytotoxicity to mammalian cells (LLC-MK2) was determined using an MTT assay. Antiparasitic activity was evaluated against epimastigote, trypomastigote and amastigote forms of T. cruzi. Cell-death mechanism was determined in epimastigote forms by flow cytometry analysis after FITC-annexin V (Ax), 7-AAD, and H2DCFDA staining. Striking morphological changes were observed by scanning electron microscope. RESULTS: GaEPL (6.5% yield; 54.6% total carbohydrate; 21.1% uronic acid and 12% protein), inhibited all T. cruzi developmental forms, epimastigotes after periods of 24h (IC50 = 740 +/- 0.075ug/mL), 48h (IC50 = 710 +/- 0.053ug/mL) and 72h (IC50 = 870 +/- 0.052ug/mL) of incubation; trypomastigotes (IC50 = 470 +/ 0.082ug/mL) after periods of 24h and intracellular amastigotes (IC50/2 = 235 or IC50 = 470ug/mL) after periods of 24 and 48h of incubation, with no toxicity on LLC-MK2 cells at the used concentrations. Analysis of the possible action mechanism in the parasites suggested cell death by necrosis with the involvement of reactive oxygen species (ROS). The scanning electron microscopy (SEM) confirmed T. cruzi death by necrosis. CONCLUSIONS: GaEPL showed significant activity against the epimastigote, trypomastigote and amastigote forms of T. cruzi, strain Y, suggesting cell death by necrosis with involvement of reactive oxygen species. PMID- 28887215 TI - Antiprotozoal activity of medicinal plants used by Iquitos-Nauta road communities in Loreto (Peru). AB - ETHNOPHARMACOLOGICAL RELEVANCE: In the Peruvian Amazon, the use of medicinal plants is a common practice. However, there is few documented information about the practical aspects of their use and few scientific validation. The starting point for this work was a set of interviews of people living in rural communities from the Peruvian Amazon about their uses of plants. Protozoan diseases are a public health issue in the Amazonian communities, who partly cope with it by using traditional remedies. Validation of these traditional practices contributes to public health care efficiency and may help identify new antiprotozoal compounds. AIMS OF STUDY: to inventory and validate the use of medicinal plants by rural people of Loreto region. MATERIALS AND METHODS: Rural mestizos were interviewed about traditional medication of parasite infections with medicinal plants. Ethnopharmacological surveys were undertaken in two villages along Iquitos-Nauta road (Loreto region, Peru), namely 13 de Febrero and El Dorado communities. Forty-six plants were collected according to their traditional use for the treatment of parasitic diseases, 50 ethanolic extracts (different parts for some of the plants) were tested in vitro on Plasmodium falciparum (3D7 sensitive strain and W2 chloroquine resistant strain), Leishmania donovani LV9 strain and Trypanosoma brucei gambiense. Cytotoxic assessment (HUVEC cells) of the active extracts was performed. Two of the most active plants were submitted to preliminary bioguided fractionation to ascertain and explore their activities. RESULTS: From the initial plants list, 10 were found to be active on P. falciparum, 15 on L. donovani and 2 on the three parasites. The ethanolic extract from Costus curvibracteatus (Costaceae) leaves and Grias neuberthii (Lecythidaceae) bark showed strong in vitro activity on P. falciparum (sensitive and resistant strain) and L. donovani and moderate activity on T. brucei gambiense. CONCLUSIONS: The Amazonian forest communities in Peru represents a source of knowledge on the use of medicinal plants. In this work, several extracts with antiprotozoal activity were identified. This work contributes to validate some traditional uses and opens subsequent investigations on active compounds isolation and identification. PMID- 28887216 TI - Phytochemistry, pharmacology, quality control and future research of Forsythia suspensa (Thunb.) Vahl: A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Forsythiae Fructus (called Lianqiao in Chinese), the fruit of Forsythia suspensa (Thunb.) Vahl, is utilized as a common traditional medicine in China, Japan and Korea. It is traditionally used to treat pyrexia, inflammation, gonorrhea, carbuncle and erysipelas. Depending on the different harvest time, Forsythiae Fructus can be classified into two forms, namely Qingqiao and Laoqiao. The greenish fruits that start to ripen are collected as Qingqiao, while the yellow fruits that are fully ripe are collected as Laoqiao. Both are applied to medical use. This review aims to provide a systematic summary of F. suspensa (Forsythia suspensa (Thunb.) Vahl) and to reveal the correlation between the traditional uses and pharmacological activities so as to offer inspiration for future research. MATERIALS AND METHODS: All corresponding information about F. suspensa was searched by Scifinder and obtained from scientific databases including Springer, Science Direct, Wiley, Pubmed and China Knowledge Resource Integrated (CNKI). Local dissertations and books were searched as well. RESULTS: According to classical Chinese herbal texts and Chinese Pharmacopoeia, Forsythiae Fructus dominantly displays heat-clearing and detoxifying effects in TCM prescriptions. In modern research, more than 230 compounds were separated and identified from F. suspensa. 211 Of them were isolated from fruits. Lignans and phenylethanoid glycosides are considered as the characteristic and active constituents of this herb, such as forsythiaside, phillyrin, rutin and phillygenin. They exhibited anti-inflammatory, antioxidant, antibacterial, anti-virus, anti-cancer and anti-allergy effects, etc. Currently, there is no report on the toxicity of Forsythiae Fructus, despite slight toxicity of forsythiaside reported in local publications. Compared to Laoqiao, Qingqiao contains higher levels of forsythiaside, forsythoside C, cornoside, rutin, phillyrin, gallic acid and chlorogenic acid and lower levels of rengyol, beta glucose and S-suspensaside methyl ether. CONCLUSION: Heat-clearing actions of Forsythiae Fructus are based on the anti-inflammatory and antioxidant properties of lignans and phenylethanoid glycosides. Detoxifying effects attribute to the antibacterial, antiviral and anti-cancer activities of Forsythiae Fructus. And traditional Chinese medicine (TCM) characteristics of Forsythiae Fructus (bitter flavor, slightly cold nature and lung meridian) supported its strong anti inflammatory effects. In addition, the remarkable anti-inflammatory and antioxidant capacities of Forsythiae Fructus contribute to its anti-cancer and neuroprotective activities. The higher proportion of lignans and phenylethanoid glycosides in Qingqiao than Laoqiao might explain the better antioxidant ability of Qingqiao and more frequent uses of Qingqiao in TCM prescriptions. For future research, more in vivo experiments and clinical studies are encouraged to further clarify the relation between traditional uses and modern applications. Regarding to Qingqiao and Laoqiao, they remain to be differentiated by all-round quality control methods, and the chemical compositions and clinical effects between them should be compared. PMID- 28887217 TI - Transcriptional factors Eaf1/2 inhibit endoderm and mesoderm formation via suppressing TGF-beta signaling. AB - Eaf family genes act in multiple cellular responses such as tumor suppression and embryonic development. In our previous work, Eaf1/2 was found to modulate convergence and extension (C&E) movements and pattern the embryonic anterior posterior axis during zebrafish embryogenesis. Here, we found that loss-of function of eaf1/2 caused expanded mesoderm and endoderm in zebrafish embryos and led to the recovery of endoderm specification in TGF-beta factor-mzoeptz257 mutants, while gain-of-function of eaf1/2 induced reduced mesoderm and endoderm. Analyses of gene expression profiles in Eaf deleted or over-expressed mammalian cells indicated that the roles of Eaf1 and Eaf2 in inhibiting TGF-beta signals were conserved from fish to mammals. By taking advantages of TGF-beta reporters, eaf1/2-fused engrailed proteins, and P53M214K mutant, we revealed that Eaf1 and Eaf2 might suppress TGF-beta transduction by synergistically inhibiting none-P53 and P53-required TGF-beta signaling. Furthermore, Eaf1/2 might co-localize and interact with TGF-beta transcriptional factors in the transcriptional complex as repressors to target and suppress TGF-beta signaling activity. Our study unveiled a previously unrecognized link of Eaf1/2 genes with TGF-beta and P53 in vertebrates and demonstrated a conservation of TGF-beta suppression activity for Eaf1/2 family genes from fish to mammals, which might shed some light on the molecular mechanistic basis of Eaf1 and Eaf2 in tumor suppression. PMID- 28887218 TI - The histone lysine methyltransferase Ezh2 is required for maintenance of the intestine integrity and for caudal fin regeneration in zebrafish. AB - The histone lysine methyltransferase EZH2, as part of the Polycomb Repressive Complex 2 (PRC2), mediates H3K27me3 methylation which is involved in gene expression program repression. Through its action, EZH2 controls cell-fate decisions during the development and the differentiation processes. Here, we report the generation and the characterization of an ezh2-deficient zebrafish line. In contrast to its essential role in mouse early development, loss of ezh2 function does not affect zebrafish gastrulation. Ezh2 zebrafish mutants present a normal body plan but die at around 12 dpf with defects in the intestine wall, due to enhanced cell death. Thus, ezh2-deficient zebrafish can initiate differentiation toward the different developmental lineages but fail to maintain the intestinal homeostasis. Expression studies revealed that ezh2 mRNAs are maternally deposited. Then, ezh2 is ubiquitously expressed in the anterior part of the embryos at 24 hpf, but its expression becomes restricted to specific regions at later developmental stages. Pharmacological inhibition of Ezh2 showed that maternal Ezh2 products contribute to early development but are dispensable to body plan formation. In addition, ezh2-deficient mutants fail to properly regenerate their spinal cord after caudal fin transection suggesting that Ezh2 and H3K27me3 methylation might also be involved in the process of regeneration in zebrafish. PMID- 28887219 TI - Novel freeze-dried DDA and TPGS liposomes are suitable for nasal delivery of vaccine. AB - There is a pressing need for effective needle-free vaccines that are stable enough for use in the developing world and stockpiling. The inclusion of the cationic lipid DDA and the PEG-containing moiety TPGS into liposomes has the potential to improve mucosal delivery. The aim of this study was to develop stable lyophilized cationic liposomes based on these materials suitable for nasal antigen delivery. Liposomes containing DDA and TPGS were developed. Size and zeta potential measurements, ex vivo, CLSM cell penetration study and cell viability investigations were made. Preliminary immunisation and stability studies using ovalbumin were performed. The liposomes exhibited suitable size and charge for permeation across nasal mucosa. DDA and TPGS increased tissue permeation in ex vivo studies and cell uptake with good cell viability. The liposomes improved immune response both locally and vaginally when compared to i.m administration or control liposomes delivered nasally. Additionally, the lyophilized products demonstrated good stability in terms of Tg, size and antigen retention. This study has shown that the novel liposomes have potential for development as a mucosal vaccine delivery system. Furthermore, the stability of the lyophilized liposomes offers potential additional benefits in terms of thermal stability over liquid formats. PMID- 28887221 TI - Modelling the primary drying step for the determination of the optimal dynamic heating pad temperature in a continuous pharmaceutical freeze-drying process for unit doses. AB - In the pharmaceutical industry, traditional freeze-drying of unit doses is a batch-wise process associated with many disadvantages. To overcome these disadvantages and to guarantee a uniform product quality and high process efficiency, a continuous freeze-drying process is developed and evaluated. The main differences between the proposed continuous freeze-drying process and traditional freeze-drying can be found firstly in the freezing step during which the vials are rotated around their longitudinal axis (spin freezing), and secondly in the drying step during which the energy for sublimation and desorption is provided through the vial wall by conduction via an electrical heating pad. To obtain a more efficient drying process, the energy transfer has to be optimised without exceeding the product and process limits (e.g. cake collapse, choked flow). Therefore, a mechanistic model describing primary drying during continuous lyophilisation of unit doses based on conduction via heating pads was developed allowing the prediction of the optimal dynamic power input and temperature output of the electric heating pads. The model was verified by experimentally testing the optimal dynamic primary drying conditions calculated for a model formulation. The primary drying endpoint of the model formulation was determined via in-line NIR spectroscopy. This endpoint was then compared with the predicted model based endpoint. The mean ratio between the experimental and model based predicted drying time for six verification runs was 1.05+/-0.07, indicating a good accordance between the model and the experimental data. PMID- 28887220 TI - Enhanced glioma therapy by synergistic inhibition of autophagy and tyrosine kinase activity. AB - Autophagy is a lysosomal degradation pathway that acts as a cytoprotective mechanism causing treatment resistance in various cancer cells. Recent studies showed that hydroxychloroquine can inhibit the latter step of autophagy and therefore enhance the anti-glioma efficiency of ZD6474, a tyrosine kinase inhibitor. However, the nonselective distribution of ZD6474 in vivo and the low penetrating ability of hydroxychloroquine when crossing the blood-brain barrier restrict their clinical use in glioma therapy. Here we coencapsulated ZD6474 and hydroxychloroquine into R6dGR peptide-modified liposomes (R6dGR-Lip) which can specifically recognize both integrin alphavbeta3 and neuropilin-1 receptors that are highly expressed on the endothelial cells and glioma cells. R6dGR significantly enhanced the brain targeting and overcame the blood-brain barrier. Our results confirmed that loading hydroxychloroquine into R6dGR-Lip blocked autophagic flux more efficiently than free hydroxychloroquine in glioma cells and significantly sensitized glioma cells to ZD6474-induced cell death in vitro and in vivo. The coencapsulated R6dGR-modified liposomes (ZD6474/HCQ-R6dGR-Lip) prolonged the medium survival time of intracranial C6 glioma bearing mice by 1.2 fold compared with ZD6474-R6dGR-Lip, 1.5-fold compared with free ZD6474/HCQ, and 1.8-fold compared with free ZD6474, exhibiting a synergistic therapeutic effect. Therefore, ZD6474/HCQ-R6dGR-Lip is presented as a potential strategy which could be further used for efficient anti-glioma therapy. PMID- 28887223 TI - Efficacy of erythrosine and cyanidin-3-glucoside mediated photodynamic therapy on Porphyromonas gingivalis biofilms using green light laser. AB - BACKGROUND: The purpose of this in vitro study was to evaluate the efficacy of erythrosine and cyanidin-3-glucoside as photosensitizers in PDT for the elimination of Porphyromonas gingivalis (P. gingivalis) biofilms. METHODS: P. gingivalis biofilms were prepared from a chronic periodontitis subject. Erythrosine and cyanidin-3-glucoside were prepared and randomly allocated as follows: 110, 220, 330, and 440MUM erythrosine; 101, 202, 303, and 404MUM anthocyanin; and 440MUM erythrosine+404MUM cyanidin-3-glucoside. There were 18 PDT experimental groups (non-irradiated/irradiated with a 532-nm green light diode laser at 1.29J/cm2 for 60s). The 3 controls were grouped as follows: biofilms exposed to the photosensitizers alone, biofilms exposed to the laser alone, and biofilms exposed to 0.12% chlorhexidine. All sample groups were cultured at 1, 3 and 6h after PDT and incubated in an anaerobic chamber at 37 degrees C for 4days. The surviving fraction was calculated from the log10 CFU/ml. The 330 and 440MUM erythrosine and the 440MUM erythrosine+404MUM cyanidin-3 glucoside were mixed with spin traps (TEMPO, DMPO), and the electron spin resonance spectra were evaluated. RESULTS: The log10 CFU/ml measurements showed that the PDT groups with 330MUM or 440MUM erythrosine and 440MUM erythrosine+404MUM cyanidin-3-glucoside had statistically significant differences from the other groups (one-way ANOVA and Bonferroni's multiple comparison test, p value<=0.05). CONCLUSIONS: PDT using 330MUM erythrosine, 440MUM erythrosine or 440MUM erythrosine+404MUM cyanidin-3-glucoside irradiated with the laser more effectively inhibited P. gingivalis in biofilms. PMID- 28887222 TI - Contrast enhanced ultrasound imaging can predict vascular-targeted photodynamic therapy induced tumor necrosis in small animals. AB - AIMS: To evaluate the accuracy of contrast-enhanced ultrasound (CEUS) for monitoring tumor necrosis following WST-11 vascular targeted photodynamic therapy (VTP) using imaging-pathology correlation. METHODS: Renal adenocarcinoma cells were injected into the hindlimb of 13 BalB/c mice resulting in tumors ranging from 9.8 to 194.3mm3. US guidance was used to place a laser fiber into the tumor, and VTP was performed. CEUS was performed prior to animal sacrifice, 24h post VTP. Whole tumors were extracted for histopathologic analysis using H&E and TUNEL staining. Pathology samples corresponding to the CEUS imaging plane were prepared in order to compare the size and extents of tumor necrosis. RESULTS: Tumor necrosis following VTP appeared as a central region of non-enhancement on CEUS, while viable tumor appeared as patchy regions of enhancement in the tumor periphery. The region of tumor necrosis measured in mean 66% and 64.8% of total tumor area on CEUS and pathology respectively (p=0.2). The size and location of the necrosis on CEUS images and pathology samples were found correlative with no inter-observer difference (weighted kappa of 0.771 and 0.823, respectively). CONCLUSION: CEUS allows accurate monitoring of VTP induced tumor necrosis in a small animal model. PMID- 28887224 TI - The zebrafish as a promising tool for modeling human brain disorders: A review based upon an IBNS Symposium. AB - The zebrafish represents an excellent compromise between system complexity and practical simplicity, features that make it useful for modeling and mechanistic analysis of complex brain disorders. Also promising are screens for psychoactive drugs with effects on larval and adult zebrafish behavior. This review, based upon a recent symposium held at the 2016 IBNS Congress, provides different perspectives on how the zebrafish may be utilized to advance research into human central nervous system disorders. It starts with a discussion on an important bottleneck in zebrafish research, measuring the behavior of this species (specifically shoaling), and continues with examples on research on autism spectrum disorder in larval zebrafish, on screening natural products for compounds with psychoactive properties in adult zebrafish, and on the development of a zebrafish model of fetal alcohol spectrum disorders. By providing information on a broad spectrum of brain disorders, experimental methods, and scientific approaches using both larval and adult zebrafish, the review is intended to showcase this underutilized laboratory species for behavioral neuroscience and psychopharmacology research. PMID- 28887225 TI - Substance P and neurotensin in the limbic system: Their roles in reinforcement and memory consolidation. AB - Substance P (SP) and neurotensin (NT) are neuropeptides isolated in the periphery and in the central nervous system. They are involved in various regulatory processes in the gastrointestinal tract, in the circulatory and respiratory systems, kidney and endocrine system. In addition to the peripheral effects, SP and NT act as neurotransmitters and neuromodulators in the central nervous system, regulating various behavioural actions, such as general and motor activity, pain, food and water intake, anxiety, reward/reinforcement and memory consolidation. In the limbic system SPergic and NTergic pathways, terminals and related receptors have been identified. According to several data of literature and to our recently published results, SP and NT have rewarding/reinforcing effects and facilitate memory consolidation in various limbic regions. In this report evidences are provided about the interaction of these neuropeptides with dopaminergic and acetylcholinergic systems. A hypothesis is presented that rewarding/reinforcing effects of SP and NT develop by modulating the mesencephalic dopaminergic system, while their mnemonic effects are mediated via the mesencephalic dopaminergic and the basal forebrain cholinergic systems. PMID- 28887226 TI - Reconciling the different faces of hippocampal theta: The role of theta oscillations in cognitive, emotional and innate behaviors. AB - The theta oscillation (5-10Hz) is a prominent behavior-specific brain rhythm. This review summarizes studies showing the multifaceted role of theta rhythm in cognitive functions, including spatial coding, time coding and memory, exploratory locomotion and anxiety-related behaviors. We describe how activity of hippocampal theta rhythm generators - medial septum, nucleus incertus and entorhinal cortex, links theta with specific behaviors. We review evidence for functions of the theta-rhythmic signaling to subcortical targets, including lateral septum. Further, we describe functional associations of theta oscillation properties - phase, frequency and amplitude - with memory, locomotion and anxiety, and outline how manipulations of these features, using optogenetics or pharmacology, affect associative and innate behaviors. We discuss work linking cognition to the slope of the theta frequency to running speed regression, and emotion-sensitivity (anxiolysis) to its y-intercept. Finally, we describe parallel emergence of theta oscillations, theta-mediated neuronal activity and behaviors during development. This review highlights a complex interplay of neuronal circuits and synchronization features, which enables an adaptive regulation of multiple behaviors by theta-rhythmic signaling. PMID- 28887227 TI - Probabilistic language models in cognitive neuroscience: Promises and pitfalls. AB - Cognitive neuroscientists of language comprehension study how neural computations relate to cognitive computations during comprehension. On the cognitive part of the equation, it is important that the computations and processing complexity are explicitly defined. Probabilistic language models can be used to give a computationally explicit account of language complexity during comprehension. Whereas such models have so far predominantly been evaluated against behavioral data, only recently have the models been used to explain neurobiological signals. Measures obtained from these models emphasize the probabilistic, information processing view of language understanding and provide a set of tools that can be used for testing neural hypotheses about language comprehension. Here, we provide a cursory review of the theoretical foundations and example neuroimaging studies employing probabilistic language models. We highlight the advantages and potential pitfalls of this approach and indicate avenues for future research. PMID- 28887229 TI - MAPK activation patterns of AT1R and CB1R in SHR versus Wistar astrocytes: Evidence of CB1R hypofunction and crosstalk between AT1R and CB1R. AB - BACKGROUND: Angiotensin (Ang) II and cannabinoids regulate physiologically relevant astroglial functions via receptor-mediated activation of Mitogen activated protein kinases (MAPKs). In this study, we investigated the consequences of astroglial Ang II type 1 receptor (AT1R) and Cannabinoid type 1 receptor (CB1R) activation, alone and in combination, on MAPK activation in the presence and absence of hypertensive states. In addition, we also investigated a novel unidirectional crosstalk mechanism between AT1R and CB1R, that involves PKC mediated phosphorylation of CB1R. METHODS: Astrocytes were isolated from the brainstem and cerebellum of Spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. The cells were treated with either 100nM Ang II or 10nM Arachidonyl-2'-chloroethylamide (ACEA), both alone and in combination, for varying time periods, and the extent of phosphorylation of MAPKs, ERK and p38, and the phosphorylated forms of CB1R (p-CB1R), were measured using western blotting. RESULTS: Ang II treatment resulted in a greater activation of MAPKs in SHR brainstem astrocytes, but not SHR cerebellar astrocytes when compared to Wistar rats. ACEA-mediated MAPK activation was significantly lower in brainstem astrocytes of SHRs when compared to Wistar rats. ACEA negatively modulates AT1R mediated MAPK activation in both cerebellar and brainstem astrocytes of both models. The effect however was diminished in brainstem astrocytes. Ang II caused a significant increase in phosphorylation of CB1R in cerebellar astrocytes, while its effect was diminished in brainstem astrocytes of both models. CONCLUSION: Both Ang II and ACEA-induced MAPK activation were significantly altered in SHR astrocytes when compared to Wistar astrocytes. A possible reduction in CB1R functionality, coupled with a hyperfunctional AT1R in the brainstem, could well be significant factors in the development of hypertensive states. AT1R-mediated phosphorylation of CB1R could be critical for impaired cerebellar development characterized by a hyperactive RAS. PMID- 28887228 TI - Leaf proteomics of drought-sensitive and -tolerant genotypes of fennel. AB - Fennel is attracted attention as a useful resource as researching medicinal plant for drought tolerance. To elucidate the response mechanism in drought-sensitive and -tolerant genotypes of fennel leaf, a gel-free/label-free proteomic technique was used. Fifty-day-old plants were subjected to drought stress for 60days. The relative water and proline contents were decreased and increased in sensitive genotypes, respectively; however, they were not a big change in tolerant genotypes. Photosynthesis was decreased in the sensitive genotypes under drought; however, it was increased in the tolerant genotype. In both drought-sensitive and -tolerant genotypes, proteins related to protein metabolism and cell organization were predominately affected under drought stress. The abundance of phosphoribulokinase and phosphoglycerate kinase enzymes were decreased and increased in drought-sensitive and -tolerant genotypes, respectively; however, the abundance of RuBisCO and glyceraldehyde-3-phosphate dehydrogenase enzymes were increased and decreased in drought-sensitive and -tolerant genotypes, respectively. Under drought stress, the abundance of glycolysis-related proteins was decreased in sensitive genotypes; however, they were increased in tolerance genotypes. Commonly changed proteins with polyethylene glycol fractionation such as cobalamin-independent methionine synthase were decreased and increased in drought-sensitive and -tolerant genotypes, respectively. These results suggest that cobalamin-independent methionine synthetase is involved in the tolerance of drought-tolerant fennel leaf under drought stress. PMID- 28887230 TI - Multiparticulate system combining taste masking and immediate release properties for the aversive compound praziquantel. AB - The taste of pharmaceuticals is of particular importance as it highly affects the compliance of patients, especially for patient groups like children. In view of oral solid dosage forms, various taste masking techniques can be applied encapsulating the active pharmaceutical ingredient (API) to prevent the interaction with the taste buds. Despite a delayed drug release in saliva, an immediate drug release in gastrointestinal media is desirable for efficient drug absorption. This combinatory approach is of particular interest for poorly soluble drugs still demonstrating an aversive, bitter taste, e.g. praziquantel (PZQ). It is an anthelmintic drug of current importance for adults and children as it is the recommended therapy against schistosomiasis. First, a small scale screen was conducted to identify the most suitable polymer for a combinatorial approach of taste masking and immediate release for PZQ. Among various PZQ polymer combinations Eudragit(r) E PO was chosen. Second, multiparticulate systems utilizing extrusion and spray-drying were generated comprising PZQ, Eudragit(r) E PO and a lipid as an additional taste masking agent. Spray-dried powders and ground extrudates showed as expected strong differences in terms of particle size distribution and morphological characteristics of the encapsulated PZQ. DSC and XRPD studies revealed the formation of an amorphous solid dispersion of PZQ after spray-drying in contrast to ground extrudates. This could be correlated to drug release studies. All formulations were subjected to non-sink dissolution studies in simulated salivary (SSF), gastric (spSGF) and intestinal (FaSSIF) media. Ground extrudates provided an efficient delayed release in SSF and immediate release and supersaturation in spSGF and FaSSIF for PZQ. Spray dried powders revealed fast solubility kinetics and up to 5-fold supersaturation in biorelevant media, contrary to a taste masking effect. Moreover, XRPD-patterns of spray-dried powders after storage detected recrystallized PZQ resulting in varied dissolution profiles. Solid lipid extrusion combined with Eudragit(r) E PO enabled a promising taste masking of PZQ in SSF through encapsulation of the crystalline PZQ and further, a fast and reproducible dissolution in simulated gastric and intestinal media. PMID- 28887231 TI - Therapeutic activity of superoxide dismutase-containing enzymosomes on rat liver ischaemia-reperfusion injury followed by magnetic resonance microscopy. AB - Liver ischaemia-reperfusion injury (IRI) may occur during hepatic surgery and is unavoidable in liver transplantation. Superoxide dismutase enzymosomes (SOD enzymosomes), liposomes where SOD is at the liposomal surface expressing enzymatic activity in intact form without the need of liposomal disruption, were developed with the aim of having a better insight into its antioxidant therapeutic outcome in IRI. We also aimed at validating magnetic resonance microscopy (MRM) at 7T as a tool to follow IRI. SOD-enzymosomes were characterized and tested in a rat ischaemia-reperfusion model and the therapeutic outcome was compared with conventional long circulating SOD liposomes and free SOD using biochemical liver injury biomarkers, histology and MRM. MRM results correlated with those obtained using classical biochemical biomarkers of liver injury and liver histology. Moreover, MRM images suggested that the therapeutic efficacy of both SOD liposomal formulations used was related to prevention of peripheral biliary ductular damage and disrupted vascular architecture. Therefore, MRM at 7T is a useful technique to follow IRI. SOD-enzymosomes were more effective than conventional liposomes in reducing liver ischaemia reperfusion injury and this may be due to a short therapeutic window. PMID- 28887232 TI - Dry powder inhalers: An overview of the in vitro dissolution methodologies and their correlation with the biopharmaceutical aspects of the drug products. AB - In vitro dissolution testing is routinely used in the development of pharmaceutical products. Whilst the dissolution testing methods are well established and standardized for oral dosage forms, i.e. tablets and capsules, there are no pharmacopoeia methods or regulatory requirements for testing the dissolution of orally inhaled powders. Despite this, a wide variety of dissolution testing methods for orally inhaled powders has been developed and their bio-relevance has been evaluated. This review provides an overview of the in vitro dissolution methodologies for dry inhalation products, with particular emphasis on dry powder inhalers, where the dissolution behavior of the respirable particles can have a role on duration and absorption of the drug. Dissolution mechanisms of respirable particles as well as kinetic models have been presented. A more recent biorelevant dissolution set-ups and media for studying inhalation biopharmaceutics were also reviewed. In addition, factors affecting interplay between dissolution and absorption of deposited particles in the context of biopharmaceutical considerations of inhalation products were examined. PMID- 28887233 TI - Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases. AB - BACKGROUND: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4 diamino-N10-methyl propyl-glutamic acid. METHODS: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. RESULTS: Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28bp copy number variation, SLCO1B1 T521C, DHFR C 1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19bp indel. Multivariate analysis showed that DHFR-1610G/T (OR=0.107, p=0.018) and MTHFR677T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR 1610CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. CONCLUSIONS: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours. PMID- 28887234 TI - Vaginal semisolid products: Technological performance considering physiologic parameters. AB - Vaginal semisolid products are frequently used to treat vaginal infections and atrophy-related symptoms of menopause. Formulations composition and the methods for their characterization, especially those developed concerning the target epithelia, are key tools to predict in vivo results at early stages of product development. However, recent studies on this subject have been almost exclusively focused on anti-HIV preparations. The aim of this work consists on improving traditional characterization methods by using physiological parameters in order to construct predictive tools to characterize a new ideal vaginal semisolid formulation whatever target it may have. Ten vaginal antimicrobial and hormonal products already available in the market were studied (Gino-Canesten(r), Sertopic(r), Dermofix(r), Gyno-pevaryl(r), Lomexin(r), Gino Travogen(r), Dalacin V(r), Ovestin(r), Blissel(r), Colpotrophine(r)). Furthermore, Universal Placebo gel and Replens(r) were used for comparison. Products were characterized in terms of: pH and buffering capacity in a vaginal fluid simulant (VFS); osmolality - directly and upon dilution in VFS; textural parameters (firmness, adhesiveness and bioadhesion) using vaginal ex vivo porcine epithelium; and viscosity (including VFS dilution at 37 degrees C and after administration on an ex vivo model). Interestingly, the majority of the tested commercial vaginal formulations did not present technological characteristics close to the ideal ones when tested under target biological conditions. The inclusion of such methodologic adaptations is expected to optimize cost-efficiency of new formulations development by predicting efficacy and safety profiles at early stages of product development. PMID- 28887235 TI - Impact of N-methylation of the substance P 1-7 amide on anti-allodynic effect in mice after peripheral administration. AB - Substance P 1-7 (SP1-7, Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7) is the major bioactive metabolite formed after proteolytic degradation of the tachykinin substance P (SP). This heptapeptide often opposes the effects of the mother peptide. Hence, SP1-7 is having anti-inflammatory, anti-nociceptive and anti hyperalgesic effects in experimental models. Despite all encouraging properties of SP1-7 its exact mode of action has not yet been elucidated which has hampered further development of this heptapeptide in drug discovery. Contrary to SP that mediates its biological activity via the NK-1 receptor, the N-terminal fragment SP1-7 acts through an unknown target that is distinct from all known opioid and tachykinin receptors. The SP1-7 amide 1 (Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-NH2) was previously shown to be superior to the endogenous SP1-7 in all experimental pain models where the two compounds were compared. Herein, we report that N methylation scan of the backbone of the SP1-7 amide (1) results in peptides that are significantly less prone to undergo proteolysis in plasma from both mouse and human. However, with the two exceptions of the [MeLys3]SP1-7 amide (3) and the [MeGln5]SP1-7 amide (4), the peptides with a methyl group attached to the backbone are devoid of significant anti-allodynic effects after peripheral administration in the spared nerve injury (SNI) mouse model of neuropathic pain. It is suggested that the N-methylation does not allow these peptides to form the accurate bioactive conformations or interactions required for efficient binding to the macromolecular target. The importance of intact N-terminal Arg1 and C terminal Phe7, anticipated to serve as address and message residues, respectively, for achieving the anti-allodynic effect is emphasized. Notably, the three heptapeptides: the SP1-7 amide (1), the [MeLys3]SP1-7 amide (3) amide and the [MeGln5]SP1-7 amide (4) are all considerably more effective in the SNI mouse model than gabapentin that is widely used in the clinic for treatment of neuropathic pain. PMID- 28887236 TI - Iatrogenic Major Venous Injury Is Associated with Increased Morbidity of Aortic Reconstruction. AB - BACKGROUND: Major venous injury during open aortic reconstruction though uncommon often result in sudden and massive blood loss resulting in increased morbidity and mortality. This study details the etiology, management, and outcome of such injuries. METHODS: A retrospective review of 945 patients (1981-2017) undergoing aortic reconstruction from 2 midsized (350 bed each) teaching hospitals was conducted. Seven hundred twenty-three patients (76.5%) underwent open abdominal aortic aneurysm (AAA) repair/iliac aneurysm repair, 222 patients (23.5%) underwent aortofemoral grafting (AFG). Patients sustaining major venous injury (sudden loss of more than 500 mL of blood) during major aortic reconstruction were studied. The number of units of packed red blood cells transfused, location of injured vessel, type of repair, postoperative morbidity, and mortality were collected in our vascular registry on a continuous basis. All patients identified with iliac vein/inferior vena cava/femoral vein injury had follow-up noninvasive venous examination of the lower extremities. RESULTS: Eighteen major venous injuries (1.9%) occurred during aortic reconstruction in 17 patients (1 patient had 2 major venous injuries): IVC (n = 4), iliac vein (n = 10), left renal vein (n = 4, this includes a posterior retroaortic renal vein injury n = 1). Of the 18 major venous injuries, 7 occurred during open AAA repair for ruptured AAA and another 9 occurred during repair of intact AAA (P = 0.001), 2 venous injuries occurred after AFG, and 1 after primary AFG (P = 0.05). Using multivariate regression analysis, periarterial inflammation had significant association with major venous injury (P < 0.001). The presence of associated iliac aneurysm with abdominal aortic aneurysm also increased the incidence of major venous injury during AAA surgery (P = 0.05). Two patients (11.8%) died, one from uncontrolled bleeding due to tear of right common iliac vein during ruptured AAA repair and second patient from disseminated intravascular complication following repair of ruptured AAA. Intraoperative transfusion requirements were 3-28 units, (median 8 units). Three of 9 (33%) surviving patients developed iliofemoral venous thrombosis following repair of iliac/femoral vein injury. CONCLUSIONS: Major venous injury during aortic reconstructions occurs more commonly during the repair of ruptured AAA and redo AFG. Following repair of iliac/femoral vein injury, surveillance for possible deep venous thrombosis by duplex imaging should be considered. PMID- 28887237 TI - Successful Use of Nellix and Endovascular Aortic Sealing Technology for Treatment of Aortic Rupture in a Porcine Model. AB - BACKGROUND: Endovascular aortic sealing (EVAS) represents a recent transformation in approach for treatment of aortic aneurysms. Initial reporting has shown that EVAS using the Nellix device is safe with similar complication rates to standard endovascular aortic repair (EVAR). What remains unknown is how EVAS technology will behave in the ruptured setting. The purpose of this report is to discuss how EVAS system and endobag technology behave when deployed in a porcine model of aortic rupture. METHODS: A controlled left retroperitoneal rupture was created in 20 large swine. Following rupture, an EVAS system was deployed across the rupture site to seal the area. The primary end point was seal from ongoing hemorrhage. Other parameters were examined to include endobag extravasation, aortic wall pressure measurements and device behavior in a live tissue model. RESULTS: Of the EVAS systems used, 15 Nellix (Endologix, Irvine, CA) devices and 5 novel EVAS systems were used. Of the correctly deployed devices, 100% sealed the rupture (n = 19). One device was deployed above the rupture site, and seal was not achieved secondary to malpositioning. Endobag extravasation was seen with an average protrusion of 7.7 mm. No other areas of aortic injury were noted secondary to endobag trauma. Pressure recording from behind the endobag indicates loss of pulsatile flow to the aortic wall with polymer curing. CONCLUSIONS: Endovascular aortic sealing for rupture is feasible and performs well in a porcine model of aortic rupture. Polymer extravasation is seen and may be controllable by the implanter. Once the polymer has cured, pulsatile aortic wall pressure is no longer present. EVAS represents an emerging technology for treatment of aortic rupture. PMID- 28887238 TI - Emergent Carotid Stent Removal after Carotid Stent Thrombosis. AB - BACKGROUND: Acute carotid stent thrombosis in patients undergoing CAS is a relatively rare and potentially devastating complication influencing significantly the quality of life. With the increasing use of stenting in clinical practice, it is expected to represent a more often encountered complication for physicians performing CAS. Emergent removal of the thrombosed stent and endarterectomy is indicated when the intrastent thrombosis is not associated with intracranial carotid branch thrombosis. METHODS: The technique and its peculiarities and tip and tricks of this carotid operation have not been described meticulously. We describe the steps of the surgical technique in detail, and we analyze crucial issues associated with the technique. RESULTS: We have performed this emergency operation in 2 patients with acute early stroke after CAS. Both patients presented recovery of their previous neurologic deficits and had uneventful postoperative course. CONCLUSIONS: We illustrate the technique of emergent removal of the thrombosed stent after CAS. If carotid stent thrombosis with no distal extension is documented post procedurally, emergency stent removal and endarterectomy is the preferred strategy. Special care should be taken to avoid risk of clot dislocation and consequent cerebral embolization during the surgical exposure of the carotid bifurcation and placement of the vascular clamps. PMID- 28887239 TI - Atorvastatin Protects Kidney from Remote Reperfusion Injury. AB - BACKGROUND: There is a need to find an effective treatment against reperfusion injury. The aim of the present study was to evaluate the capacity of the ischemic postconditioning and statin to prevent renal reperfusion injury. DESIGN AND SETTING: An experimental study developed at Universidade Anhanguera-Uniderp. METHODS: A total of 41 Wistar rats were distributed into 5 groups: ischemia and reperfusion (I/R), ischemic postconditioning (IPC), postconditioning + statin (IPC + S), statin (S), and sham. In the sham group, the infrarenal abdominal aorta was dissected and isolated; all others were submitted to aortic clamping for 70 min (ischemia) and posterior removal of the clamp (reperfusion, 70 min). In the IPC and IPC + S groups, postconditioning was performed in ischemia and reperfusion phases by 4 cycles of reperfusion and ischemia lasting 30 sec each. In the IPC + S and S groups, preceding the surgical procedure, atorvastatin was administered 3.4 mg/day for 7 days by gavage. After the procedure, the left kidney was removed for histological study. RESULTS: The mean renal lesion was 4 in the I/R group, 2.44 in the IPC group, 1.22 in the IPC + S group, 1.11 in the S group, and 1 in the sham group. The I/R group had a higher degree of tissue injury when compared to the others (P < 0.001) and the IPC + S and S groups improved protection against IPC alone (P < 0.05). CONCLUSIONS: Ischemic postconditioning and atorvastatin can minimize renal remote reperfusion injury. PMID- 28887240 TI - Temporal Trends, Determinants, and Outcomes of Inpatient versus Outpatient Arteriovenous Fistula Operations. AB - BACKGROUND: As high healthcare costs are increasing scrutinized, a movement toward reducing patient hospital admissions and lengths of stay has emerged, particularly for operations that may be performed safely in the outpatient setting. Our aim is to describe recent temporal trends in the proportion of dialysis access procedures performed on an inpatient versus outpatient basis and to determine the effects of these changes on perioperative morbidity and mortality. METHODS: The 2005-2008 American College of Surgeons National Surgical Quality Improvement Program database was queried for all primary arteriovenous fistula (AVF) procedures using current procedural terminology codes. Changes in the proportions of inpatient versus outpatient operations performed by year, as well as the associated 30-day postoperative morbidity and mortality, were analyzed using univariable statistics and multivariable logistic regression. RESULTS: Two thousand nine hundred fifty AVF procedures were performed over the study period. Overall, 71.7% (n = 2,114) were performed on an outpatient basis. Inpatient procedures were associated with higher 30-day morbidity (10.5% vs. 4.5%) and mortality (2.8% vs. 0.7%) than outpatient procedures (both, P < 0.001). There was a significant increase in the proportion of procedures performed on an outpatient basis over time (2005: 56% vs. 2008: 75%; P < 0.001). There were no changes in postoperative morbidity or mortality for inpatient or outpatient AVF over time (P >= 0.36). Independent determinants of having an inpatient procedure included younger age (OR 0.99), increasing ASA class (ASA IV OR 1.56), congestive heart failure (OR 3.32), recent ascites (OR 3.25), poor functional status (OR 3.22), the presence of an open wound (OR 1.91), and recent sepsis (OR 6.06) (all, P < 0.01). Acute renal failure (OR 2.60) and current dialysis (OR 1.44) were also predictive (P < 0.001). After correcting for baseline differences between groups, the adjusted OR for both morbidity (aOR 1.93, 95% CI 1.38-2.69) and mortality (aOR 2.85, 95% CI 1.36-5.95) remained significantly higher for inpatient versus outpatient AVF. CONCLUSIONS: Dialysis access operations are increasingly being performed on an outpatient basis, with stable perioperative outcomes. Inpatient procedures are associated with worse outcomes, likely because they are reserved for patients with acute illnesses, serious comorbidities, and poor functional status. Overall, for appropriately selected patients, the movement toward performing more elective dialysis access operations on an outpatient basis is associated with acceptable outcomes. PMID- 28887241 TI - Noninvasive Peripheral Artery Disease Screening Tools: A Deficient Knowledge among French Vascular Residents from 4 Medical Schools. AB - BACKGROUND: Ankle-brachial index (ABI) at rest, postexercise ABI, and toe brachial index (TBI) are essential diagnostic tools recommended for peripheral artery disease (PAD) diagnosis. Our study investigates the level of knowledge on these 3 tests among vascular medicine residents from 4 French medical schools in France. METHODS: We included 19 vascular medicine residents in a cross-sectional study. During an annual obligatory seminar, all residents accepted to fill 3 questionnaires concerning knowledge about these 3 tests. RESULTS: All residents accepted to fill 3 questionnaires. None of the residents correctly knows how to perform all pressure measurements (ABI, postexercise ABI, and TBI). Two residents had the knowledge to perform the whole ABI at rest procedure, whereas no resident had the knowledge to perform neither the postexercise ABI (P = 0.48) nor the TBI (P = 0.48). Twelve residents correctly completed the question regarding the interpretation of ABI at rest, whereas 2 correctly completed the postexercise ABI question (P = 0.001) and 4 the TBI question (P = 0.02). The number of residents who have performed more than 20 measurements is higher regarding ABI at rest than postexercise ABI and TBI (84%, 5%, and 37% respectively; P < 0.001 and P = 0.006 respectively) and significantly less often in postexercise ABI than TBI (5% vs. 37%; P = 0.04). CONCLUSIONS: This study shows for the first time that residents' knowledge of pressure measurements (resting-ABI, postexercise ABI, and TBI) of 4 French medical school are insufficient although the importance of pressure measurement has been strongly highlighted by the newly released PAD guidelines (2016) for PAD diagnosis. PMID- 28887242 TI - Rapid Methods for Routine Frailty Assessment during Vascular Surgery Clinic Visits. AB - BACKGROUND: Frailty assessment can help vascular surgeons predict perioperative risk and long-term mortality for their patients. Unfortunately, comprehensive frailty assessments take too long to integrate into clinic workflow. This study was designed to evaluate 2 rapid methods for assessing frailty during vascular clinics-a short patient-reported survey and a provider-reported frailty scale. METHODS: We prospectively enrolled 159 patients presenting to an academic medical center vascular surgery clinic between May and November 2016. Patients underwent frailty assessment using 2 rapid methods: (1) the Frail Nondisabled (FiND) survey (5 questions) and (2) the Clinical Frailty Scale (CFS; 9-point scale from robust to severely frail). These were followed by administering the Fried Index, a validated frailty assessment method with 5 measures (weight loss, exhaustion, grip strength, walking speed, and activity level). The correlation between Fried scores (reference standard) with frailty diagnoses derived from FiND and CFS was analyzed using the Spearman-rank test, Cohen's kappa, sensitivity/specificity tests, and receiver operating curves. RESULTS: The evaluated cohort included 87 (55%) females, a mean age of 61 years, 126 (79%) preoperative patients, and 32 (20%) categorized as frail using the Fried Index criteria. The FiND survey was very sensitive (91%) but less specific for diagnosing frailty. In comparison, the CFS was highly specific (96%) for diagnosing frailty and exhibited high inter rater reliability between surgeon and medical assistant scores (kappa: 0.79; 95% CI: 0.72-0.87; P < 0.001). There was moderate correlation between frailty assigned using the Fried Index and the CFS (rho: 0.41-0.44). CONCLUSIONS: Frailty can be quickly and effectively assessed during vascular surgery clinic using a combination of patient-reported (FiND) and provider-reported (CFS) methods to improve diagnostic accuracy. Implementing routine frailty assessment into clinic workflow can be a valuable tool for risk prediction and surgical decision-making. PMID- 28887243 TI - Superior 3-Year Value of Open and Endovascular Repair of Abdominal Aortic Aneurysm with High-Volume Providers. AB - BACKGROUND: Conflicting literature exists regarding resource utilization for cardiovascular care when stratified by provider volume. This study investigates the differences in value of abdominal aortic aneurysm (AAA) repair by high- and low-volume providers. The hypothesis of this study is that high-volume providers will provide superior value AAA repairs when compared to low-volume providers. METHODS: Using the New York Statewide Planning and Research Cooperative System database and its linked death database, patients undergoing intact open and endovascular aneurysm repair (EVAR) were identified over a 10-year period. Charge data were normalized to year 2016 dollars and the data stratified by repair modality and annual surgeon volume. Univariate technique was used to compare the 2 groups over a 3-year follow-up period. RESULTS: Nine hundred eleven surgeons performed open AAA repairs and 615 performed EVAR. For both repair modalities, and despite a patient population with more vascular risk factors, the cumulative adjusted charge for all aneurysm-related care was significantly less for high volume providers than low-volume providers. The calculated 3-year value-patient life years per cumulative charge-was also superior for high-volume providers compared to low-volume providers. This difference in charge and value persisted after propensity score matching for race, sex, insurance status, and common vascular comorbidities including hypertension, dyslipidemia, and a history of smoking. CONCLUSIONS: High-volume surgeons performing repair of aortic aneurysms provide superior value when compared to low-volume providers. The improved value margin is driven by both lower charge and improved survival, despite an increased incidence of cardiovascular comorbidities. This study adds support for the regionalization of care for patients with aortic aneurysm. PMID- 28887244 TI - External Validation of a Rapid Ruptured Abdominal Aortic Aneurysm Score. AB - BACKGROUND: The Rapid Ruptured Abdominal Aortic Aneurysm Score (RrAAAS) was developed from Vascular Study Group of New England (VSGNE) data (649 ruptured abdominal aortic aneurysm (rAAA) patients, repaired both open and endovascularly), using preoperative age, creatinine, and blood pressure. This study validates that model using the larger National Vascular Quality Initiative (VQI) data set and compares its performance to previous models. METHODS: The VQI registry was queried for patients undergoing rAAA repair from 2006 to 2016. The performance of our original model, RrAAAS, was tested on this data set excluding VSGNE patients (VQI minus VSGNE), and its performance was then compared to the performance of the Glasgow Aneurysm Score (GAS) and Edinburgh Ruptured Aneurysm Score (ERAS). RESULTS: VQI contained 2,704 eligible patients, of which 715 had been contributed by VSGNE. The discrimination of RrAAAS was similar to GAS or ERAS (area under a receiver operator characteristic curve = 0.66). Neither GAS nor ERAS provides a direct prediction of mortality; observed mortality in the VQI minus VSGNE cohort tended to be somewhat lower than predictions of the original RrAAAS. A recalibrated equation predicting the percent mortality was Mortality (%) = 16 + 12*(age > 76) + 8*(creatinine > 1.5) + 20*(systolic blood pressure < 70). CONCLUSIONS: The previously described RrAAAS has similar discrimination as the GAS and ERAS, is easier to obtain in an emergency setting, and has been recalibrated to reflect the experience of a large national sample. The RrAAAS could be useful for clinicians caring for these patients and could be used for risk adjustment when comparing regional differences in mortality associated with rAAA repair. PMID- 28887245 TI - A Pulsatile Fresh Frozen Human Cadaver Circulation Model for Endovascular Training: A Trial of Face Validity. AB - BACKGROUND: The authors have published their design of a pulsatile fresh frozen human cadaver circulation model (PHCM) for endovascular training the face validity of the PHCM for training endovascular practitioners was subsequently assessed. METHODS: Twelve endovascular clinicians performed the same 2 procedures (catheterization of the left renal artery and left subclavian artery) on PHCM and Simbionix angiomentor virtual reality simulator (SVR). They were randomized to begin on either the PHCM or SVR. A pretrial questionnaire determined participants' endovascular experience. After training, participants rated statements relating to their experience on a numerical scale from 1 to 5, with 1 representing the strongest agreement with the statement. RESULTS: When participants were asked to compare the realism of training modalities with live patients, PHCM scored significantly higher than SVR on statements regarding "realism of vascular access" (P = 0.002), "guide-wire manipulation" (P = 0.001), and "vessel catheterization" (P = 0.004). Candidates again favored PHCM as "a valuable learning exercise" (P = 0.016) and strongly favored PHCM as a "useful training model" compared to SVR (P = 0.004). CONCLUSIONS: This is the first published trial in world literature to assess the validity of a PHCM for training endovascular practitioners. The PHCM demonstrates good face validity when compared to both real patients and the SVR model and holds exciting potential. PMID- 28887246 TI - Novel Morphological Features for Prediction of Distal Thoracic Aortic Enlargement after Thoracic Endovascular Aortic Repair of DeBakey IIIb Aortic Dissection. AB - BACKGROUND: Identifying the risk factors predisposing to aortic enlargement after thoracic endovascular aortic repair (TEVAR) is needed for DeBakey IIIb aortic dissection. The aim of the study is to assess the novel morphological features for DeBakey IIIb aortic dissection in predicting distal thoracic aortic enlargement after TEVAR. METHODS: Sixty-seven patients who underwent TEVAR for DeBakey IIIb aortic dissection between January 2011 and December 2013 at our center were divided based on preoperative computer tomography angiography (CTA) features into 3 groups: I (n = 27) and III (n = 9), with true and false lumen, respectively, coursing closely along thoracic vertebral bodies and II, spiral configuration (n = 31). Distal thoracic aortic enlargement was determined using preoperative and postoperative CTA images. RESULTS: At median 12.2 (interquartile range, 4.3-26.6) months, 12 patients developed distal thoracic aortic enlargement, with estimated cumulative incidence tending to increase from categories I to III (P for trend < 0.01). Categories II and III versus I had more frequently concave location of primary entry tear (P < 0.01), larger dissection length and height index (L/Hi) (P = 0.05), and greater number of abdominal small branches involved preoperatively (P = 0.03), with otherwise similar baseline characteristics; and significantly greater total aortic diameter increase and lower false lumen regression up to 24 months, and lower true lumen expansion up to 12 months. In multivariable regression analysis, categories II and III were independently associated with distal thoracic aortic enlargement (hazard ratio, 19.95 [95% confidence interval, 2.14-186.09]; 41.23 [3.61-470.22], respectively) after adjustment for Society of Vascular Surgery score, preoperative maximum total aortic diameter, L/Hi, and number of abdominal small branches involved preoperatively. CONCLUSIONS: The CTA-based morphological features described in this study might improve preoperative risk stratification of DeBakey IIIb aortic dissection, with categories II and III having higher risk of distal thoracic aortic enlargement after TEVAR. PMID- 28887247 TI - Rare Presentation of a Syphilitic Aneurysm of the Infrarenal Aorta with Contained Rupture. AB - We report, to our knowledge, the first case of a rare syphilitic infrarenal aortouniiliac aneurysm with contained rupture that presented with midepigastric abdominal pain. Review of the patient's medical history revealed untreated syphilis and poorly treated congestive heart failure. Given his comorbidities, the patient was treated with an emergent endovascular aneurysm repair. His 30-day postoperative recovery period was uneventful, and follow-up imaging revealed complete resolution of the aneurysms. Syphilitic infrarenal aortic aneurysm is currently considered a rare entity in this era of antibiotics. The present article provides a brief case report and short review of literature pertaining to syphilitic aortic aneurysms. PMID- 28887248 TI - Positive Impact of an Aortic Center Designation. AB - BACKGROUND: In January 2015, we created a multidisciplinary Aortic Center with the collaboration of Vascular Surgery, Cardiac Surgery, Interventional Radiology, Anesthesia and Hospital Administration. We report the initial success of creating a Comprehensive Aortic Center. METHODS: All aortic procedures performed from January 1, 2015 until December 31, 2016 were entered into a prospectively collected database and compared with available data for 2014. Primary outcomes included the number of all aortic related procedures, transfer acceptance rate, transfer time, and proportion of elective/emergent referrals. RESULTS: The Aortic Center included 5 vascular surgeons, 2 cardiac surgeons, and 2 interventional radiologists. Workflow processes were implemented to streamline patient transfers as well as physician and operating room notification. Total aortic volume increased significantly from 162 to 261 patients. This reflected an overall 59% (P = 0.0167) increase in all aorta-related procedures. We had a 65% overall increase in transfer requests with 156% increase in acceptance of referrals and 136% drop in transfer denials (P < 0.0001). Emergent abdominal aortic cases accounted for 17% (n = 45) of our total aortic volume in 2015. The average transfer time from request to arrival decreased from 515 to 352 min, although this change was not statistically significant. We did see a significant increase in the use of air-transfers for aortic patients (P = 0.0041). Factorial analysis showed that time for transfer was affected only by air-transfer use, regardless of the year the patient was transferred. Transfer volume and volume of aortic related procedures remained stable in 2016. CONCLUSIONS: Designation as a comprehensive Aortic Center with implementation of strategic workflow systems and a culture of "no refusal of transfers" resulted in a significant increase in aortic volume for both emergent and elective aortic cases. Case volumes increased for all specialties involved in the center. Improvements in transfer center and emergency medical services communication demonstrated a trend toward more efficient transfer times. These increases and improvements were sustainable for 2 years after this designation. PMID- 28887249 TI - Chronic Nonatherosclerotic Occlusive Popliteal Artery Disease. AB - BACKGROUND: The outcomes of revascularization of nonatherosclerotic occlusive popliteal artery disease are unknown. Therefore, the objective of this study was to analyze the outcomes of recanalization of nonatherosclerotic occlusive popliteal artery disease, the results of which would be useful in creating surgical strategies for such cases. METHODS: From January 2000 to December 2015, a total of 22 patients with nonatherosclerotic occlusive popliteal artery disease underwent open surgical repair. We retrospectively analyzed the data of these patients. Thrombectomy with angioplasty on the occluded popliteal artery, graft interposition, and bypass surgery were conducted for revascularization of the affected region. We analyzed the overall primary patency rate, type of graft, and surgical approach. Furthermore, we compared the primary patency rate after surgical treatment. RESULTS: Of 22 patients, 3 (13.6%) had cystic adventitial disease, 16 (72.7%) had popliteal artery entrapment syndrome, and 3 (13.6%) were diagnosed as having thromboangiitis obliterans. Five patients (22.7%) underwent thrombectomy with patch angioplasty, 8 (36.3%) underwent bypass surgery, and 9 (40.9%) underwent graft interposition of the popliteal artery. All graft interpositions and thrombectomies with patch angioplasty were performed through a posterior approach, whereas all bypass surgeries were performed through a medial approach except in 1 case. The mean follow-up period was 54.95 +/- 42.99 months. The overall primary patency rate at 1, 3, and 10 years was 100%, 86.9%, and 69.5%, respectively. In the bypass group, the primary patency rate at 1, 3, and 10 years was 100%, 66.7%, and 44.4%, respectively. In the other groups, the primary patency rate was 100% during the follow-up period. The difference in primary patency rate was statistically significant (P <= 0.05). CONCLUSIONS: The result of surgical treatment for nonatherosclerotic occlusive popliteal artery disease was better than that of atherosclerotic popliteal artery disease. Direct popliteal artery reconstruction, such as graft interposition or thrombectomy with patch angioplasty, showed better short- and long-term patency than did bypass surgery. PMID- 28887250 TI - Analysis of Patients Undergoing Major Lower Extremity Amputation in the Vascular Quality Initiative. AB - BACKGROUND: Despite an aggressive climate of limb salvage and revascularization, 7% of patients with peripheral artery disease undergo major lower extremity amputation (LEA). The purpose of this study was to describe the current demographics and early outcomes of patients undergoing major LEA in the Vascular Quality Initiative (VQI). METHODS: The VQI amputation registry was reviewed to identify patients who underwent major LEAs. Patient factors, limb characteristics, procedure type, and intraoperative variables were analyzed by the level of amputation. Factors associated with amputation level, 30-day complications, and mortality were analyzed using chi-squared analysis for significance with associated P values. Propensity score adjustment was used to balance statistically significant differences observed in subject characteristics by amputation level for the associated relative risk of a given outcome. RESULTS: Between 2013 and 2015, 2,939 major LEAs were recorded in the VQI amputation registry. The ratio of below-knee to above-knee amputation (BKA:AKA) was 1.29:1. The mean age was 66 years, 64% were male, 84% lived at home before admission, and 68% were ambulatory. Comorbidities included diabetes (67%), coronary artery disease (32%), end-stage renal disease (22%), and chronic obstructive pulmonary disease (23%). The mean preoperative ankle-brachial index (ABI) was 0.78. Overall, 43% had a history of prior ipsilateral revascularization. Indications for amputation were ischemic rest pain or tissue loss (58%), uncontrolled infection (31%), acute ischemia (9%), and neuropathic tissue loss (2%). The overall perioperative complication rate was 15%, 25% were discharged home, and the 30-day mortality was 5%. Patients who received an AKA versus BKA were more likely to be female (40.61% vs. 31.70%), more than age 70 (48.79% vs. 32.55%), underweight (18.63% vs. 9.18%), nonambulatory (40.22% vs. 25.18%), have an ABI <0.6 (58.00% vs. 45.26%), and carry nonprivate insurance (77.40% vs. 69.08%) (all P < 0.001). Patients undergoing AKA were less likely to have 30-day postoperative complications (12.24% vs. 17.87%) but had higher 30-day mortality (6.70% vs. 3.09%) than BKA patients (all P < 0.001). CONCLUSIONS: In the VQI registry, major LEA was performed predominantly for ischemic rest pain and tissue loss with a BKA:AKA ratio of 1.29:1. Patients undergoing AKA versus BKA were older, had lower ABI, lower rates of 30-day postoperative complications but higher rates of 30-day mortality. This registry offers an important real-world resource for studies pertaining to vascular surgery patients undergoing major lower extremity amputation. PMID- 28887251 TI - Metabolic Syndrome but not Obesity Adversely Affects Outcomes after Open Aortoiliac Bypass Surgery. AB - BACKGROUND: Although the incident risk of peripheral artery disease increases in patients with metabolic syndrome, several authors report favorable outcomes in obese patients after arterial bypass surgery. We examine the effect of the so called "obesity paradox" and metabolic syndrome on outcomes after open aortoiliac bypass surgery. METHODS: We identified patients between 2004 and 2015 who had open surgical bypass for aortoiliac occlusive disease. We excluded patients with endovascular repair and those treated primarily for aneurysmal disease. Variables that were analyzed included preoperative medical history, Trans-Atlantic Inter Society Consensus Document on Management of Peripheral Arterial Disease II classification, Rutherford classification, intra-operative, and postoperative outcomes. Metabolic syndrome was defined by World Health Organization criteria: diabetes and 2 or more of dyslipidemia, hypertension, and obesity (body mass index > 30 kg/m2). Data were analyzed by stratified Kaplan-Meier and multiple Cox regression for outcomes including long-term mortality and reintervention rate. RESULTS: There were 154 open bypass surgery patients during the study period with a median age of 60 years (interquartile range [IQR] 53-68), median glomerular filtration rate 76.1 mL/min (IQR 54-102), and 58% female prevalence. In all, 53 patients had metabolic syndrome (4%), and 14 patients (9%) were obese but did not have metabolic syndrome. Primary bypass graft patency was 89.0 +/- 2.7% at 1 year and 77.4 +/- 4.1% at 5 years and was not significantly different between metabolic syndrome, obese, and nonmetabolic syndrome patients. Reintervention rate for the entire cohort was 25.3 +/- 3.7% at 1 year and 40.6 +/- 4.7% at 5 years. In those with and without metabolic syndrome, reintervention rate at 1 and 5 years was 33.0 +/- 6.8% vs. 21.1 +/- 4.2% and 56.1 +/- 7.9% vs. 30.7 +/- 5.4%, respectively (log-rank P = 0.003). In multivariable analyses, metabolic syndrome (hazard ratio [HR] 1.8, P = 0.036) and critical limb ischemia (CLI) (HR: 3.2, P = 0.001) were the only independent predictors of reintervention. Neither obesity nor the individual components comprising metabolic syndrome was a risk for reintervention. Multivariate analysis demonstrated age, female gender, CLI, and nonobesity as the independent risk factors for long-term mortality. CONCLUSIONS: Our study supports the "obesity paradox" that obesity by itself is not a risk factor for reintervention and was a protective factor for mortality after open aortoiliac bypass surgery. Bypass graft patency and major amputation rates were not affected. Although the individual components do not predispose to worse outcome, metabolic syndrome is a constellation of factors that, together, are associated with adverse events. PMID- 28887252 TI - Correlation of Intraluminal Thrombus Deposition, Biomechanics, and Hemodynamics with Surface Growth and Rupture in Abdominal Aortic Aneurysm-Application in a Clinical Paradigm. AB - BACKGROUND: The natural history of abdominal aortic aneurysm (AAA) can be investigated through longitudinal evaluation of localized aneurysm characteristics exploiting clinical images. The major challenge is to identify corresponding regions between follow-ups. We have recently developed an algorithm (VascForm) based on nonrigid registration that can obtain surface correspondence and quantify surface growth distribution. METHODS: A ruptured AAA with an initial computed tomography scan 2 years ago was studied. Following 3-dimensional reconstruction of outer wall and luminal surfaces, the wall/thrombus thickness was obtained. Wall stress distribution was computed with finite element analysis, and computational fluid dynamics simulation was performed. VascForm was applied and allowed for the ruptured wall site to be traced back to the initial wall surface and be correlated with local initial intraluminal thrombus thickness, wall stress, and hemodynamic parameters. It also allowed for the quantification of wall surface growth based on surface element growth. RESULTS: Rupture occurred at the posterolateral side. Initial wall surface growth was in most regions 40%. However, a large section of the posterior wall presented 110% growth. Initial thrombus deposition was more prevalent anteriorly, and a posterior thrombus-free isle was present. Peak wall stress (initial and follow-up) occurred at AAA neck. Nonrigid registration revealed that rupture originated from the vicinity of the initial thrombus-free isle. Furthermore, rupture occurred at the wall region with the largest growth (110%). No clear correlation between hemodynamics and rupture site could be identified. CONCLUSIONS: High local surface growth correlates with rupture site and could therefore potentially become a marker of rupture risk. The ongoing application of this methodology to a large cohort of AAA patients will focus on identifying characteristic features of AAA regions that present high surface growth in follow-up evaluations, to assist in improved rupture risk estimation. PMID- 28887254 TI - Factors Affecting Patency following Successful Percutaneous Intervention for Dysfunctional Hemodialysis Vascular Access. AB - BACKGROUND: This study aimed to investigate the patency following initial successful percutaneous transluminal angioplasty (PTA) for untreated dysfunctional hemodialysis vascular access and to identify predictors of PTA durability. METHODS: This retrospective observational study included data of 132 consecutive initial PTA of hemodialysis vascular access in 126 patients who showed immediate technical and clinical success and had at least 1 year of follow up data. RESULTS: The mean duration of primary and secondary patency post-PTA was 16 and 27 months, respectively. On multivariate adjusted Cox regression analysis, dyslipidemia (P < 0.001), use of insulin (P = 0.016), and arteriovenous graft (AVG) (P = 0.016) were significantly associated with shorter primary patency. Dyslipidemia (P < 0.001), use of antiplatelet medication (P = 0.013), and failed vascular access (P = 0.004) were significant predictors of secondary patency loss. Use of statin was the only clinical variable associated with increased primary and secondary patency (P < 0.001). According to a subgroup analysis on the type of vascular access and dysfunction, primary and secondary patency rates were significantly higher in the arteriovenous fistula (AVF) and failing vascular access groups than AVG and failed vascular access groups, respectively. Early dysfunction (within 6 months) was significantly higher in the AVG and failed vascular access groups after initial PTA, but there was no significant difference after multiple PTAs. CONCLUSIONS: Post-PTA primary and secondary patency rates were significantly higher with AVF and failing vascular access. The use of statin was associated with increased primary and secondary patency after initial successful PTA in this study. PMID- 28887253 TI - Comparison of Ultrasound-Guided Thrombin Injection of Iatrogenic Pseudoaneurysms Based on Neck Dimension. AB - BACKGROUND: Ultrasound-guided thrombin injection (UGTI) of femoral artery pseudoaneurysms after endovascular procedures is an effective therapy. There is controversy in the literature regarding injecting pseudoaneurysms with short and/or wide necks. This article reports our experience in UGTI of pseudoaneurysms in 1 hospital regarding the efficacy of this treatment in all pseudoaneurysms regardless of the size of the necks. METHODS: A retrospective review of 46 patients diagnosed between 2011 and 2016 with groin pseudoaneurysms using established duplex ultrasound criteria. Mean age was 68 years (range 27-87). Ten pseudoaneurysms thrombosed spontaneously, 5 were thrombosed by ultrasound-guided compression, and 2 were treated surgically due to disqualifying criteria. In this retrospective review, we analyzed the remaining 29 pseudoaneurysms regarding the dimensions of their neck lengths and outcomes after attempting thrombin injection. RESULTS: The mean aneurysm neck length and width were 1.03 +/- 0.9 cm and 0.30 +/- 0.1 cm, respectively. All 29 patients were evaluated with respect to pseudoaneurysm size, neck length, neck width, and complexity. Successful treatment of 29 pseudoaneurysms (2 external iliac, 20 common femoral, 2 deep femoral, and 5 superficial femoral) with UGTI was achieved without complications in 100% of the cases, regardless of pseudoaneurysm size, neck dimensions, or complexity. Anticoagulation status did not affect the efficacy of the procedure. Nine of the 29 pseudoaneurysms (31.0%) had neck length less than 0.5 cm. CONCLUSIONS: This study demonstrates the safety and efficacy of UGTI in treating iatrogenic pseudoaneurysm in 29 of 29 patients, even in patients with pseudoaneurysm with short neck lengths. Our experiences support injecting all pseudoaneurysms irrespective of dimension. PMID- 28887255 TI - Forced-Air Warming in Patients Undergoing Endovascular Procedures: Comparison between 2 Thermal Blanket Models. AB - BACKGROUND: The purpose of this study was to compare the efficiency between 2 thermal blanket models: the upper blanket and the underbody blanket in patient heating and hypothermia prevention during endovascular surgery. METHODS: Fifty patients, American Society of Anesthesiologists physical status 2-4, receiving endovascular surgery repair of infrarenal abdominal aortic aneurysm or lower limb angioplasty by endovascular technique were studied. Primary outcome was to determine which forced-air blanket is more warming effective during the surgeries. Age, type of surgery, gender, body mass index, surgery duration, and initial patient temperature were analyzed to determine possible hypothermia association as secondary outcomes. Patients were randomized and split into 2 groups based on blanket model. All patients received general anesthesia, and temperature was obtained by an esophageal thermometer inserted after tracheal intubation and registered at intervals of 15 min until extubation. RESULTS: Groups significantly differed in body temperature (P = 0.006) and hypothermia occurrence (P = 0.020). The underbody blanket group hada higher ratio of hypothermic patients and a lower average temperature at the end of surgery. The average temperature after 60 min in the underbody blanket group was lower than the upper blanket group,although this difference was only significant after 150 min (P = 0.020). CONCLUSIONS: We conclude that upper thermal blanket is more effective thanunderbody thermal blanket in patient warming and hypothermia prevention during endovascular abdominal aortic aneurysm repair and lower limb angioplasty after 150 min of anesthetic-surgical time duration. PMID- 28887256 TI - Remote Ischemic Preconditioning Decreases the Magnitude of Hepatic Ischemia Reperfusion Injury on a Swine Model of Supraceliac Aortic Cross-Clamping. AB - BACKGROUND: Temporary hepatic ischemia is inevitable during open aortic surgery when supraceliac clamping is necessary, as in thoracoabdominal or pararenal aneurysms. Remote ischemic preconditioning (RIPC) has been described as a potential protective means against ischemia-reperfusion injury (IRI) in various tissues including the liver. The aim of this experimental study was to detect the effect of RIPC on liver IRI in a model of supraceliac aortic cross-clamping. METHODS: An animal study was performed. Four groups of 6 swines each were examined: the control (sham) group, the ischemia-reperfusion (IR) group, and 2 remote ischemic preconditioning groups (RIPC I and RIPC II group). In the IR group, the animals underwent a complete cessation of the splanchnic arterial circulation for 30 min by a concomitant occlusion of the supraceliac and the infrarenal aorta. In the RIPC groups, a remote preconditioning was applied before the splanchnic ischemia. This consisted of a temporary occlusion of the infrarenal aorta for 15 min followed by 15 min of reperfusion (RIPC I group), and 3 cycles of 5 min similar ischemia, followed by 5 min of reperfusion each (RIPC II group). All animals were followed for 24 hr after the ischemia (reperfusion period). The liver ischemia-reperfusion injury was assessed by examining specific serum biomarkers indicating the magnitude of metabolic injury from selective blood samples of the hepatic circulation. In particular, the following parameters were examined: C-reactive protein, interleukin 6, tumor necrosis factor a, ferritin, and L-arginine. RESULTS: All parameters were affected in the IR group as compared to the sham group. Both RIPC groups developed a less serious change as compared to the IR group, in all examined parameters. CONCLUSIONS: In an animal study of splanchnic ischemia produced in a way to this produced during a supraceliac aortic aneurysm open repair, the remote ischemic preconditioning seemed to attenuate the effect of hepatic ischemia-reperfusion injury. CLINICAL RELEVANCE: Remote ischemic preconditioning produced with short bouts of ischemia of the lower body by temporary clamping of the infrarenal aorta might be used as a means of decreasing the detrimental effects of hepatic ischemia-reperfusion injury after supraceliac aortic cross-clamping. This was found in a swine model of suprarenal AAA open repair by studying the variance of certain biological biomarkers in selective blood samples retrieved from the hepatic vein. PMID- 28887257 TI - A Rare Presentation of Abdominal Aortic Aneurysm-Renal Pelvis Rupture Due to Compression. AB - Abdominal aortic aneurysms (AAAs) are usually asymptomatic. The compressive effects of internal iliac aneurysms are well described in the literature; however, we report what we believe to be the first case of rupture of the renal pelvis caused by compression by an infrarenal AAA. We describe the subsequent management and briefly review the literature. PMID- 28887258 TI - Severe Acute Type B Aortic Dissection Complicated by Acute Pancreatitis: A Case Report. AB - A 52-year-old man presented with sudden abdominal pain and intermittent vomiting. The patient underwent contrast-enhanced computed tomography scan and was diagnosed with an acute type B aortic dissection involving the celiac trunk superior mesenteric artery and extending to the renal artery. The patient was treated with thoracic endovascular aortic repair. After the procedure, the patient still complained of left upper abdomen abdominal pain, and an abdominal mass was detected on physical examination. Imaging revealed a 15-cm cystic lesion involving the pancreatic tail and serum amylase measured at 556 U/L. A definitive diagnosis of severe acute pancreatitis was made. The patient was treated with injection of somatostatin, ultrasound-guided puncture drainage, and jejunal nutrition tube placement. The patient was discharged with symptom free after 30 days and well recovered in subsequent follow-up 12 months later. PMID- 28887259 TI - Morphometric Assessment as a Predictor of Outcome in Older Vascular Surgery Patients. AB - BACKGROUND: Frailty is a recognized predictor of poor outcome in patients undergoing surgical intervention. Frailty is intricately linked with body morphology, which can be evaluated using morphometric assessment via computerized tomographic (CT) imaging. We aimed to assess the predictive power of such objective assessments in a broad cohort of vascular surgical patients. METHODS: A consecutive series of patients aged over 65 years admitted to a vascular unit, who had undergone CT imaging of the abdomen, were analyzed. Demographic and patient-specific data were collated alongside admission relevant information. Outcomes included mortality, length of stay, health care-related costs, and discharge destination. Images were analyzed for 4 morphometric measurements: (1) psoas muscle area, (2) mean psoas density, (3) subcutaneous fat depth, and (4) intra-abdominal fat depth, all taken at the level of the fourth lumbar vertebra. RESULTS: Two hundred and ten patients were initially analyzed. Forty-four patients had significant retroperitoneal and abdominal abnormalities that limited appropriate CT analysis. Decreased subcutaneous fat depth was significantly associated with mortality, readmission within 12 months, and increased cost of health care (P < 0.01, adjusted for confounders). Psoas muscle area was significantly associated with readmission-free survival. CONCLUSIONS: Morphometric analysis predicts poorer outcome in a broad cohort of vascular surgery patients. Such assessment is likely to enhance patient counseling regarding individual risk as well as enhancing the ability to undertake risk modified surgical audit. PMID- 28887260 TI - The Use of Smart Phone Thermal Imaging for Assessment of Peripheral Perfusion in Vascular Patients. AB - BACKGROUND: Ankle-brachial index (ABI) is a reliable method to evaluate extremity perfusion but can be prohibitive to obtain secondary to patient discomfort or extremity trauma. This study investigates smart phone-based forward looking infrared imaging to assess peripheral perfusion using thermal ABI (tABI). METHODS: ABIs were measured by a certified vascular laboratory. Thermographs of each extremity (hands/feet) were obtained, and maximum surface temperature was recorded. tABI was calculated by dividing the lower extremity (LE) temperature by the upper extremity (UE). ABI and tABI were compared using Pearson's correlation and Bland-Altman plot. RESULTS: Twenty-three patients (45 limbs) had ABI's and thermographs recorded on the same day. Median ABI was 0.89 (range 0.33-1.46, IQR 0.4). Median LE temperature was 83.0 degrees F (range 60.7-96.9 degrees F, IQR 14.1). Median UE temperature was 91.2 degrees F (range 81.9-94.6 degrees F, IQR 3.4). Median tABI was 0.93 (range 0.33-1.4, IQR 0.2). Positive correlation was seen between ABI and tABI with Pearson analysis (r = 0.83, P < 0.0001) and Bland Altman plot (bias -0.01, LOA -0.13 to -0.12). CONCLUSIONS: Thermal imaging correlates with ABI in the evaluation of extremity perfusion. Smart phone-based FLIR can be used to determine peripheral perfusion in clinical settings where ABI is difficult to obtain. PMID- 28887261 TI - Stenting of Subclavian Artery True and False Aneurysms: A Systematic Review. AB - BACKGROUND: Aneurysms of the subclavian artery are usually the result of trauma, atherosclerosis, or thoracic outlet syndrome. Until the 90s, open surgical repair was considered the only therapeutic choice, exhibiting high complication rates. Since the first report of endovascular repair of subclavian aneurysms in 1991, promising results have been published. The aim of this review was to summarize all available data on subclavian artery (SA) true and false aneurysm stenting to reach conclusions regarding morbidity, mortality, and other procedure-related characteristics. METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. Eligible studies were sought in the Medline (PubMed), ClinicalTrials.gov, and Cochrane library-Cochrane Central Register of Controlled Trials (CENTRAL) databases through February 2017 using the following MeSH terms: "endovascular", "hybrid", "aneurysm", "pseudo-aneurysm", "pseudo-aneurysm", "false aneurysm", "arterial injury", "subclavian artery", "axillo-subclavian," and "axillosubclavian artery". The reference lists of eligible articles and pertinent reviews were screened for potential relevant studies. RESULTS: Seventy three studies encompassing data on 142 patients who underwent endovascular or hybrid SA aneurysm repair were deemed eligible. One hundred forty-seven stents and stent grafts were used. Median age of all patients was 56 years, and males comprised 46% of the study sample. Trauma was the most common mechanism of injury. Pulsatile mass or hematoma was the most frequent presenting sign. Pseudoaneurysms were the most frequent type of aneurysms, followed by true aneurysms. Most authors used self-expanding polytetrafluoroethylene-covered stents. Access was obtained by either brachial, femoral, or both arteries. Through-and-through technique was also used in angulated vessels. All-cause mortality was 10.6%, slightly higher to that already reported in literature and lower to the respective rate of the open repair. Reintervention rate was 8.5% despite the high 15.5% complication rate. CONCLUSIONS: Endovascular SA aneurysm repair is a technically feasible technique, useful in both elective and emergency cases. Although preliminary results quote its safety and efficacy, larger cohort studies are warranted to elucidate its benefit in treating SA aneurysms. PMID- 28887262 TI - Late Rupture of a Totally Thrombosed Abdominal Aortic Aneurysm: A Case Report and Literature Review. AB - Chronic totally thrombosed abdominal aortic aneurysms (AAAs) comprise a rare medical situation, with only a few cases reported in literature. Optimal management has been controversial, although an early risk for rupture is present. Therefore, we present a rare case of late rupture in a patient with a totally thrombosed AAA, and we discuss proper treatment. PMID- 28887263 TI - Changes in Geometry and Cardiac Deformation of the Thoracic Aorta after Thoracic Endovascular Aortic Repair. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) has dramatically expanded treatment options for patients with thoracic aortic pathology. The interaction between endografts and the dynamic anatomy of the thoracic aorta is not well characterized for repetitive physiologic stressors and subsequent issues related to long-term durability. Through three-dimensional (3D) modeling we sought to quantify cardiac-induced aortic deformation before and after TEVAR to assess the impact of endografts on dynamic aortic anatomy. METHODS: Eight patients with acute (n = 4) or chronic (n = 3) type B dissections, or chronic arch aneurysm (n = 1), underwent TEVAR with a single (n = 5) or multiple (n = 3) Gore C-TAG(s). Cardiac-resolved thoracic CT images were acquired pre- and post-TEVAR. 3D models of thoracic aorta and branch vessels were constructed in systole and diastole. Axial length, mean, and peak curvature of the ascending aorta, arch, and stented lumens were computed from the aortic lumen centerline, delineated with branch vessel landmarks. Cardiac-induced deformation was computed from mid-diastole to end-systole. RESULTS: Pre-TEVAR, there were no significant cardiac-induced changes for aortic axial length or mean curvature. Post-TEVAR, the ascending aorta increased in axial length (2.7 +/- 3.1%, P < 0.05) and decreased in mean curvature (0.38 +/- 0.05 -> 0.36 +/- 0.05 cm-1, P < 0.05) from diastole to systole. From pre- to post-TEVAR, axial length change increased in the ascending aorta (P < 0.02), mean curvature decreased in the arch and stented aorta (P < 0.03), and peak curvature decreased in the stented aorta (P < 0.05). CONCLUSIONS: TEVAR for a range of indications not only causes direct geometric changes to the stented aorta but also results in dynamic changes to the ascending and stented aorta. In our cohort, endograft placement straightens the stented aorta and mutes cardiac-induced bending due to longitudinal stiffness. This is compensated by greater length and curvature changes from diastole to systole in the ascending aorta, relative to pre-TEVAR. PMID- 28887264 TI - Toe Pressures are Superior to Duplex Parameters in Predicting Wound Healing following Toe and Foot Amputations. AB - BACKGROUND: No criteria, including preamputation vascular diagnostic thresholds, have been established to reliably predict healing versus nonhealing following minor lower extremity amputations. Thus, the goal of our study was to identify clinical factors, including noninvasive vascular laboratory measures, associated with wound healing following toe, forefoot, and midfoot amputations. METHODS: We retrospectively examined records of patients receiving elective toe, forefoot, or midfoot amputation at our institution over a 5-year span (2010-2015). A total of 333 amputations received noninvasive vascular assessment of the lower extremity preamputation and follow-up at 90 days postamputation. Multivariate binomial logistic regression was used to identify variables predicting wound healing as defined as the absence of reamputation due to wound breakdown. RESULTS: Wound healing occurred in 81% of amputations. A total of 23 (7%) patients required revisions of the foot while 39 (12%) patients required major amputations by 90 days. Chi-squared analysis found that toe pressure at or above the value of 47 mm Hg (P = 0.04), bi/triphasic anterior tibial (P = 0.01), and posterior tibial artery (P = 0.01) waveforms were associated with wound healing. When these diagnostic parameters were examined in the presence of confounders (increasing age, chronic kidney disease, and concomitant revascularization), only toe pressure >= 47 mm Hg predicted amputation site healing (odds ratio: 3.1 [95% CI: 1.0-9.4], P = 0.04). CONCLUSION: Preamputation toe pressures of 47 mm Hg and above are associated with wound healing. No other noninvasive vascular studies predicted wound healing in the presence of confounders. Thus, toe pressures may assist in clinical decision-making and should be routinely obtained preamputation. PMID- 28887265 TI - Modified Staple Aneurysmorrhaphy for Treating Arteriovenous Fistula-Related Venous Aneurysms. AB - Autogenous arteriovenous fistulas (AVFs) are the preferred access for hemodialysis. AVF occasionally develop venous aneurysms, and we report a modified staple aneurysmorrhaphy technique for treatment. Briefly, the lateral wall of the venous aneurysm is dissected and a longitudinal staple resection performed. Adjunct procedures include inflow banding and outflow venous angioplasty with possible stenting. In this initial experience, 20 aneurysms were resected in 17 patients. The average AVF age at time of repair was 5.8 years. Sixteen of 17 AVF remained patent, and there were no recurrences or mortalities. One patient had a loss of thrill intraoperatively after stapling and was successfully treated with cephalic vein embolectomy. All AVF were cannulated for dialysis immediately following the procedure. The average follow-up period was 12.5 months. Given the benefits of uninterrupted fistula use and avoidance of temporary catheter placement, this technique is a promising therapy for arteriovenous fistula related venous aneurysms. PMID- 28887266 TI - Use of V-POSSUM and E-PASS Scores to Predict Acute Kidney Injury after Elective Open Abdominal Aortic Aneurysm Surgery. PMID- 28887267 TI - Patterns and Outcomes of Care in Children With Advanced Heart Disease Receiving Palliative Care Consultation. AB - CONTEXT: Although access to subspecialty pediatric palliative care (PPC) is increasing, little is known about the role of PPC for children with advanced heart disease (AHD). OBJECTIVES: The objective of this study was to examine features of subspecialty PPC involvement for children with AHD. METHODS: This is a retrospective single-institution medical record review of patients with a primary diagnosis of AHD for whom the PPC team was initially consulted between 2011 and 2016. RESULTS: Among 201 patients, 87% had congenital/structural heart disease, the remainder having acquired/nonstructural heart disease. Median age at initial PPC consultation was 7.7 months (range 1 day-28.8 years). Of the 92 patients who were alive at data collection, 73% had received initial consultation over one year before. Most common indications for consultation were goals of care (80%) and psychosocial support (54%). At initial consultation, most families (67%) expressed that their primary goal was for their child to live as long and as comfortably as possible. Among deceased patients (n = 109), median time from initial consultation to death was 33 days (range 1 day-3.6 years), and children whose families expressed that their primary goal was for their child to live as comfortably as possible were less likely to die in the intensive care unit (P = 0.03) and more likely to die in the setting of comfort care or withdrawal of life sustaining interventions (P = 0.008). CONCLUSION: PPC involvement for children with AHD focuses on goals of care and psychosocial support. Findings suggest that PPC involvement at end of life supports goal-concordant care. Further research is needed to clarify the impact of PPC on patient outcomes. PMID- 28887268 TI - Association of Advance Directives Completion With the Utilization of Life Sustaining Treatments During the End-of-Life Care in Older Patients. AB - CONTEXT: Evidence is mixed regarding the impact of advance directives (ADs) on the utilization of end-of-life treatments. OBJECTIVES: This study evaluated the effect of AD on the utilization of end-of-life treatments during the last month of life in older patients. METHODS: Taipei City Hospital initiated an advance care planning program to promote AD for admitted patients in 2015. This prospective study recruited deceased older patients who completed advance care planning communication between 2015 and 2016. Multiple logistic regression was used to determine the association of AD completion with utilization of life sustaining treatments. RESULTS: Of 1307 deceased older patients, overall mean age was 84.1 years and 78.7% of the subjects had AD completion. During the study follow-up period, 31 older patients received life-sustaining treatments during the last month of life, including 17 patients (1.7%) with AD completion and 14 patients (5.0%) without AD completion. After adjusting for the sociodemographic factors and co-morbidities, older patients with AD completion were less likely to receive life-sustaining treatments during the last month of life (adjusted odds ratio [AOR] = 0.32, 95% confidence interval [CI]: 0.16-0.67). Considering type of life-sustaining treatments, AD completion was associated with a lower likelihood of receiving cardiopulmonary resuscitation (AOR = 0.21, 95% CI: 0.06-0.70) as well as intubation and mechanical ventilation support (AOR = 0.32, 95% CI: 0.14 0.70) during the last month of life in older patients. CONCLUSION: AD completion was associated with a lower likelihood of receiving life-sustaining treatments during the last month of life in older patients. These findings support the continued use of AD in older population. PMID- 28887269 TI - Which Physicians' Behaviors on Death Pronouncement Affect Family-Perceived Physician Compassion? A Randomized, Scripted, Video-Vignette Study. AB - CONTEXT: Although the death of a loved one is a devastating family event, little is known about which behaviors positively affect families' perceptions on death pronouncements. OBJECTIVES: The objective of this study was to evaluate the effect of a compassionate death pronouncement on participant-perceived physician compassion, trust in physicians, and emotions. METHODS: In this randomized, video vignette study, 92 people (>=50 years) in Tokyo metropolitan area viewed two videos of death pronouncements by an on-call physician with or without compassion enhanced behaviors, including five components: waiting until the families calm themselves down, explaining that the physician has received a sign-out about information of the patient's condition, performing examination respectfully, ascertaining the time of death with a wristwatch (vs. smartphone), and reassuring the families that the patient did not experience pain. Main outcomes were physician compassion score, trust in physician, and emotions. RESULTS: After viewing the video with compassion-enhanced behaviors compared with the video without them, participants assigned significantly lower compassion scores (reflecting higher physician compassion) (mean 26.2 vs. 36.4, F = 33.1, P < 0.001); higher trust in physician (5.10 vs. 3.00, F = 39.7, P < 0.001); and lower scores for anger (2.49 vs. 3.78, F = 18.0, P < 0.001), sadness (3.42 vs. 3.85, F = 11.8, P = 0.001), fear (1.93 vs. 2.55, F = 15.8, P < 0.001), and disgust (2.45 vs. 3.71, F = 19.4, P < 0.001). CONCLUSION: To convey compassion on death pronouncement, we recommend that physicians initiate prompt examination, explain that the physician has received a sign-out, perform examination respectfully, ascertain the time of death with a wristwatch, and reassure the families that the patient did not experience pain. PMID- 28887270 TI - Temporal Trends Between 2010 and 2015 in Intensity of Care at End-of-Life for Patients With Chronic Illness: Influence of Age Under vs. Over 65 Years. AB - CONTEXT: Recent analyses of Medicare data show decreases over time in intensity of end-of-life care. Few studies exist regarding trends in intensity of end-of life care for those under 65 years of age. OBJECTIVES: To examine recent temporal trends in place of death, and both hospital and intensive care unit (ICU) utilization, for age-stratified decedents with chronic, life-limiting diagnoses (<65 vs. >=65 years) who received care in a large healthcare system. METHODS: Retrospective cohort using death certificates and electronic health records for 22,068 patients with chronic illnesses who died between 2010 and 2015. We examined utilization overall and stratified by age using multiple regression. RESULTS: The proportion of deaths at home did not change, but hospital admissions in the last 30 days of life decreased significantly from 2010 to 2015 (hospital b = -0.026; CI = -0.041, -0.012). ICU admissions in the last 30 days also declined over time for the full sample and for patients aged 65 years or older (overall b = -0.023; CI = -0.039, -0.007), but was not significant for younger decedents. Length of stay (LOS) did not decrease for those using the hospital or ICU. CONCLUSION: From 2010 to 2015, we observed a decrease in hospital admissions for all age groups and in ICU admissions for those over 65 years. As there were no changes in the proportion of patients with chronic illness who died at home nor in hospital or ICU LOS in the last 30 days, hospital and ICU admissions in the last 30 days may be a more responsive quality metric than site of death or LOS for palliative care interventions. PMID- 28887272 TI - Establishing benchmarks for the volume-outcome relationship for common lumbar spine surgical procedures. AB - BACKGROUND CONTEXT: The importance of surgeon volume as a quality measure has been defined for a number of surgical specialties. Meaningful procedural volume benchmarks have not been established, however, particularly with respect to lumbar spine surgery. PURPOSE: We aimed to establish surgeon volume benchmarks for the performance of four common lumbar spine surgical procedures (discectomy, decompression, lumbar interbody fusion, and lumbar posterolateral fusion). STUDY DESIGN: A retrospective review of data in the Florida Statewide Inpatient Dataset (2011-2014) was carried out. PATIENT SAMPLE: Patients who underwent one of the four lumbar spine surgical procedures under study comprised the study sample. OUTCOME MEASURE: The development of a complication or hospital readmission within 90 days of the surgical procedure was the surgical outcome. METHODS: For each specific procedure, individual surgeon volume was separately plotted against the number of complications and readmissions in a spline analysis that adjusted for co-variates. Spline cut-points were used to create a categorical variable of procedure volume for each individual procedure. Log-binomial regression analysis was then separately performed using the categorical volume-outcome metric for each individual procedure and for the outcomes of 90-day complications and 90-day readmissions. RESULTS: In all, 187,185 spine surgical procedures met inclusion criteria, performed by 5,514 different surgeons at 178 hospitals. Spline analysis determined that the procedure volume cut-point was 25 for decompressions, 40 for discectomy, 43 for interbody fusion, and 35 for posterolateral fusions. For surgeons who failed to meet the volume metric, there was a 63% increase in the risk of complications following decompressions, a 56% increase in the risk of complications following discectomy, a 15% increase in the risk of complications following lumbar interbody fusions, and a 47% increase in the risk of complications following posterolateral fusions. Findings were similar for readmission measures. CONCLUSIONS: The results of this work allow us to identify meaningful volume-based benchmarks for the performance of common lumbar spine surgical procedures including decompression, discectomy, and fusion-based procedures. Based on our determinations, readily achievable goals for individual surgeons would approximate an average of four discectomy and lumbar interbody fusion procedures per month, three posterolateral lumbar fusions per month, and at least one decompression surgery every other week. PMID- 28887271 TI - Comparing the Palliative Care Needs of Patients With Hematologic and Solid Malignancies. AB - CONTEXT: Hematologic cancer patients use palliative care services less frequently than their solid tumor counterparts. Prior work suggests that these patients have a sizable symptom burden, but comparisons between hematologic and solid tumor patients near the end of life are limited. OBJECTIVES: To compare unmet symptom needs in a cohort of hematologic and solid tumor patients referred to specialty palliative care services. METHODS: Using a novel data registry of initial palliative care encounters, we performed a cross-sectional analysis of cancer patients receiving care across 17 sites within the Global Palliative Care Quality Alliance. We compared clinically-significant symptoms (rated as four or greater in severity) between hematologic and solid tumor patients and performed multivariate logistic regression analyses examining the relationship between symptom burden and tumor type. RESULTS: We identified 1235 cancer patients, 108 of which had hematologic malignancies. Pain, dyspnea, nausea, and anorexia burden were as high among patients with hematologic as those with solid malignancies. Blood cancer patients had higher rates of clinically-significant tiredness (51% vs. 42%; P = 0.03) than solid tumor patients. Finally, blood cancer patients had greater odds of being tired (odds ratio 2.19; CI 1.22-3.91) and drowsy (odds ratio 1.81; CI 1.07-3.07) than solid tumor patients independent of age, gender, race, and performance status. CONCLUSIONS: Hematologic and solid tumor patients have significant symptom burden at time of referral to palliative care services. Blood cancer patients may have unique concerns warranting targeted attention, including substantial drowsiness and tiredness. Our findings suggest a need to optimize palliative care usage in the hematologic cancer population. PMID- 28887273 TI - Use of the "dual construct" for the management of complex spinal reconstructions. AB - BACKGROUND CONTEXT: Surgical management of complex spinal reconstructions remains a clinical challenge, as pseudoarthrosis with subsequent rod breakage can occur. Increased rod density in the form of "satellite" or "outrigger" rods have been described; however, rod-fracture above or below satellite rods persist and can result in dissociation of the construct, loss of correction, and recurrence of deformity. The use of four distinct and mechanically independent rods (dual construct) reduces this concern. Since the original case description in 2006, there have been no other studies that use the dual construct for the surgical management of complex spinal reconstructions. PURPOSE: The purpose of this study is to review the long-term experience and surgical technique using the dual construct, and to present our complications, rod fracture rates, and outcomes for the surgical management of complex spinal reconstructions. STUDY DESIGN: This study used a surgical technique with case series outcomes. PATIENT SAMPLE: Patients were from a single-institute who underwent dual construct between 2010 and 2014 and who were available for 2-year follow-up. OUTCOME MEASURES: Radiographic and functional outcomes, complications, rod fracture rates, and revision surgery rates were the outcome measures. METHODS: A retrospective review was conducted from a single institution between 2010 and 2014, with a subsequent 2-year follow-up period. Extensive review of patients' medical record, radiographs, and advanced imaging where available was performed. Medical record was evaluated for patient demographics, surgical procedure, and complications. Radiographic measurements included presence or absence of implant failure and proximal junctional kyphosis or distal junctional kyphosis. RESULTS: A total of 36 patients underwent surgical reconstruction. The average estimated blood loss was 1,856 cc (range, 400-4,000 cc). The average length of stay was 7.3 days (range, 4-22 days). Clinical follow-up reported 21 patients (58.3%) with no or minimal pain. There were six deaths during the follow-up unrelated to the index procedure. Radiographic follow-up revealed three patients (8.3%) with rod fracture; one patient with one rod fracture, and two patients with two rod fractures. No patient had three or all four rod fractures. There were no screw fractures. None of the patients with rod fractures required revision surgery. CONCLUSIONS: The biggest advantage of the dual construct is that rod breakage, although uncommon, is typically minimal, or asymptomatic, and more importantly does not result in loss of alignment, and therefore has not required revision surgery. The dual construct approach is a safe alternative to traditional two-rod constructs, with encouraging outcomes at follow-up. PMID- 28887274 TI - The qualitative grading of muscle fat infiltration in whiplash using fat and water magnetic resonance imaging. AB - BACKGROUND CONTEXT: The development of muscle fat infiltration (MFI) in the neck muscles is associated with poor functional recovery following whiplash injury. Custom software and time-consuming manual segmentation of magnetic resonance imaging (MRI) is required for quantitative analysis and presents as a barrier for clinical translation. PURPOSE: The purpose of this work was to establish a qualitative MRI measure for MFI and evaluate its ability to differentiate between individuals with severe whiplash-associated disorder (WAD), mild or moderate WAD, and healthy controls. STUDY DESIGN/SETTING: This is a cross-sectional study. PATIENT SAMPLE: Thirty-one subjects with WAD and 31 age- and sex-matched controls were recruited from an ongoing randomized controlled trial. OUTCOME MEASURES: The cervical multifidus was visually identified and segmented into eighths in the axial fat/water images (C4-C7). Muscle fat infiltration was assessed on a visual scale: 0 for no or marginal MFI, 1 for light MFI, and 2 for distinct MFI. The participants with WAD were divided in two groups: mild or moderate and severe based on Neck Disability Index % scores. METHODS: The mean regional MFI was compared between the healthy controls and each of the WAD groups using the Mann Whitney U test. Receiver operator characteristic (ROC) analyses were carried out to evaluate the validity of the qualitative method. RESULTS: Twenty (65%) patients had mild or moderate disability and 11 (35%) were considered severe. Inter- and intra-rater reliability was excellent when grading was averaged by level or when frequency of grade II was considered. Statistically significant differences (p<.05) in regional MFI were particularly notable between the severe WAD group and healthy controls. The ROC curve, based on detection of distinct MFI, showed an area-under-the curve of 0.768 (95% confidence interval 0.59-0.94) for discrimination of WAD participants. CONCLUSIONS: These preliminary results suggest a qualitative MRI measure for MFI is reliable and valid, and may prove useful toward the classification of WAD in radiology practice. PMID- 28887275 TI - FFA4 (GPR120) as a fatty acid sensor involved in appetite control, insulin sensitivity and inflammation regulation. AB - Unsaturated long-chain fatty acids have been suggested to be beneficial in the context of cardiovascular disorders based in epidemiologic studies conducted in Greenland and Mediterranean. DHA and EPA are omega-3 polyunsaturated fatty acids that are plentiful in fish oil, and oleic acid is an omega-9 monounsaturated fatty acid, rich in olive oil. Dietary intake of these unsaturated long-chain fatty acids have been associated with insulin sensitivity and weight loss, which contrasts with the impairment of insulin sensitivity and weight gain associated with high intakes of saturated long-chain fatty acids. The recent discovery that free fatty acid receptor 4 (FFA4, also known as GPR120) acts as a sensor for unsaturated long-chain fatty acids started to unveil the molecular mechanisms underlying the beneficial functions played by these unsaturated long-chain fatty acids in various physiological processes, which include the secretions of gastrointestinal peptide hormones and glucose homeostasis. In this review, the physiological roles and therapeutic significance of FFA4 in appetite control, insulin sensitization, and inflammation reduction are discussed in relation to obesity and type 2 diabetes from pharmacological viewpoints. PMID- 28887276 TI - Moyamoya Vasculopathy in PHACE Syndrome: Six New Cases and Review of the Literature. AB - BACKGROUND: PHACE syndrome (Posterior fossa malformations, large cervicofacial infantile Hemangiomas, Arterial anomalies, aortic coarctation and Cardiac abnormalities, and Eye abnormalities) is a neurocutaneous disorder including posterior fossa malformations, hemangiomas, arterial lesions, cardiac defects, and eye abnormalities. PHACE arteriopathies may be progressive and recently have been categorized based on the risk of acute ischemic stroke, increasing attention to the potentially devastating consequences of cerebrovascular complications in this syndrome. In contrast, the natural history of arteriopathy in PHACE syndrome remains poorly understood. At the moment, there are no established surgical guidelines for high-risk vasculopathies, including quasi-moyamoya, in this syndrome. CASE DESCRIPTION: We described the clinicoradiologic features of a small series of 6 patients with PHACE syndrome and quasi-moyamoya (5 female, age range 4 months to 12 years), focusing on the clinical course and surgical outcome of 3 children who were treated with encephaloduroarteriosynangiosis and encephalomyosynangiosis. In addition, we reviewed the radiologic, clinical, and surgical aspects of moyamoya vasculopathy in PHACE syndrome, providing information on 15 additional published cases. CONCLUSIONS: Although the natural history of arteriopathy in PHACE syndrome is poorly understood, patients with high-risk vasculopathies, such as quasi-moyamoya disease, may benefit of revascularization by using encephaloduroarteriosynangiosis and encephalomyosynangiosis. PMID- 28887277 TI - Single-Step Resection of an Intraosseous Meningioma and Cranial Reconstruction: Technical Note. AB - OBJECTIVE: Simultaneous tumor resection and cranial reconstruction can be a challenging task. Surgical navigation is an indispensable tool in making this single-step procedure possible. In this technical note, we describe a new technique for this procedure to ensure a precise resection and optimal fit of the implant in a patient with an intraosseous meningioma. METHODS: We generated a 3 dimensional (3D) model of the patient's skull based on a computed tomography scan and created a digital "resection line" object using 3D Studio Max 2016 software. Based on this object, the patient-specific implant was generated and printed with a 3D printer. Before surgery, the digital object was transferred to the neuronavigation system to enable a navigated resection of the lesion to ensure maximum precision. During surgery, the craniotomy was performed, and the custom made implant was fitted in a single step. RESULTS: The planned resection was achieved, and the implant could be fitted without need for further adjustments to the resection border. CONCLUSIONS: We provide a simple technique to digitally define a planned resection site and create a custom-made implant using specialized software and 3D printing to enable single-step resection of a skull lesion and cranial reconstruction, thereby reducing surgical time and costs and ensuring a good cosmetic result. PMID- 28887278 TI - Comparison of Unilateral and Bilateral Craniotomy for the Treatment of Bilateral Middle Cerebral Artery Aneurysms: Anatomic and Clinical Parameters and Surgical Outcomes. AB - OBJECTIVE: To compare 2 craniotomy approaches (unilateral and bilateral) in terms of anatomic and clinical parameters and surgical outcomes. METHODS: Between January 2011 and December 2014, 19 patients with bilateral unruptured middle cerebral artery (MCA) aneurysm were treated with unilateral craniotomy (group 1), and 10 patients were treated with bilateral mini-craniotomy (group 2). We compared demographic data, characteristics of aneurysms, radiologic and clinical parameters, postoperative complications, and surgical outcomes between the 2 groups. RESULTS: No statistically significant differences in aneurysm characteristics were found between the 2 groups. Radiologic parameters did not have any influence on surgical outcomes or the incidence of postoperative complications. Group 1 had a higher incidence of olfactory dysfunction (11 of 19; 58%) and residual neck at the contralateral aneurysm (10 of 19; 53%), whereas no patients in group 2 had olfactory dysfunction or residual neck at the contralateral aneurysm. All patients in group 2 had good surgical outcomes (modified Rankin scale score 0). The length of hospital stay was similar in the 2 groups. CONCLUSIONS: Bilateral mini-craniotomy for the treatment of bilateral MCA aneurysms was associated with better surgical outcomes and fewer complications. Bilateral mini-craniotomy does not require as much retraction of the frontal lobe to apply a clip completely at the contralateral aneurysm. Therefore, it represents a safe and effective therapeutic option for unruptured bilateral MCA aneurysms. PMID- 28887279 TI - Sacral-Alar-Iliac Fixation in Children with Neuromuscular Scoliosis: Minimum 5 Year Follow-Up. AB - OBJECTIVE: To investigate the 5-year outcomes of children with neuromuscular scoliosis treated with sacral-alar-iliac screws. METHODS: We reviewed clinical and radiographic records of patients aged <=18 years treated by 1 pediatric orthopedic surgeon for neuromuscular scoliosis with spinal fusion using sacral alar-iliac pelvic anchors. Thirty-eight patients with a minimum 5-year radiographic follow-up (mean, 6.0 +/- 1.2 years) were studied. The mean patient age was 13 +/- 2.0 years, and 47% were female. The mean number of levels fused was 18 +/- 0.7. Two-thirds (66%) of the patients were diagnosed with cerebral palsy. RESULTS: Between the preoperative period and final follow-up, the patients exhibited a mean correction of the major coronal curve of 79% (preoperative, 85 degrees to final, 18 degrees ) and a mean 57% correction of the pelvic obliquity (preoperative, 16 degrees to final, 7 degrees ). Patients maintained the correction of mean pelvic obliquity from the early postoperative period (6 degrees ) to final follow-up (7 degrees ). Preoperatively, 76% of the patients had a pelvic obliquity of >10 degrees , compared with 26% of patients postoperatively. There were no cases of neurologic or vascular complications or pseudarthrosis. Radiographs revealed bilateral sacral-alar-iliac screw lucency in 8 patients; 4 of these patients had deep wound infections, and the other 4 were asymptomatic. Unilateral screw fracture was found in 1 patient with an 8-mm diameter screw (1.3%; 1 of 76 screws); the patient was observed and remained asymptomatic. There were no cases of set screw displacement, screw back-out, or rod dislodgement. CONCLUSIONS: Sacral-alar-iliac screws are safe and effective pelvic anchors for use in children with neuromuscular scoliosis. PMID- 28887280 TI - Transsphenoidal Surgery for Mixed Pituitary Gangliocytoma-Adenomas. AB - BACKGROUND: Most sellar gangliocytomas are discovered with a concurrent pituitary adenoma, also known as a mixed gangliocytoma-adenoma (MGA). MGAs are rare, with fewer than 100 cases reported in the literature to date and only 1 previously documented surgical series. Because MGAs are radiologically indistinguishable from pituitary adenomas, they are often diagnosed after surgery. Combined with the paucity of clinical outcome data for these tumors, this makes their diagnosis and management challenging. Here we describe the clinical presentation and outcomes of 10 individuals who were diagnosed with a MGA at a single institution. METHODS: This retrospective case series study included patients diagnosed with a combined sellar MGA between 1993 and 2016. RESULTS: This series comprised 10 patients, mean age of 44 years (range, 28-63 years) diagnosed with an MGA. The mean tumor size was 1.6 cm (range, 0.4-2.4 cm). Five patients presented with acromegaly, and 1 patient had recurrent Cushing disease. Transsphenoidal surgery was performed in all cases, and gross total resection was achieved in 7 patients (70%). Histologically, 9 of the 10 MGAs were identified as mixed somatotroph adenoma-gangliocytomas. The median duration of follow-up was 74 months (range, 2 180 months). Following adjuvant treatment (n = 3), all patients with acromegaly (n = 4) achieved biochemical remission, and no patient experienced recurrence of the pituitary tumor with a median radiographic follow-up of 48 months. CONCLUSIONS: MGAs are often associated with a hypersecretory adenoma. Transsphenoidal surgery is well tolerated by most patients, and when performed in combination with adjuvant therapy, a low rate of recurrence and reversal of preoperative endocrinopathy can be expected. PMID- 28887281 TI - Cerebrospinal Fluid Leak Rhinorrhea after Systemic Erlotinib Chemotherapy for Metastatic Lung Cancer: A Familiar Problem from an Unfamiliar Culprit. AB - BACKGROUND: Cerebrospinal fluid (CSF) rhinorrhea after medical therapy for pituitary prolactinoma is a rare but well-described phenomenon. To our knowledge, no CSF leaks have been reported after targeted medical treatment of pituitary or anterior skull base metastases. We report this unusual case to raise awareness of spontaneous CSF leaks in the setting of skull base metastatic disease. CASE PRESENTATION: A 66-year-old woman presented with epidermal growth factor receptor mutant stage IV adenocarcinoma of the lung. Headache workup revealed a large sellar and clival lesion consistent with metastatic disease. Systemic erlotinib chemotherapy was initiated with a robust positive response. Approximately 1 week after chemotherapy initiation, the patient noted clear discharge from the right nostril. Her oncologist first diagnosed her with allergic rhinitis, but she presented with meningitis 4 days after diagnosis of CSF leak and was admitted for intravenous antibiotics and definitive repair of a CSF leak via an endoscopic endonasal approach. An erosion of bone and dura was found at the dorsum sellae where tumor had regressed due to the chemotherapy. A multilayer skull base repair was made uneventfully, and she recovered fully with no leakage seen at 2-month follow-up. CONCLUSIONS: All members of the treatment team should be aware of this possibility of CSF leak after initiation of systemic chemotherapy and tumor regression and urgently refer patients for repair if a leak should develop before the development of meningitis. PMID- 28887282 TI - Anterior Lumbar Corpectomy with Expandable Titanium Cage Reconstruction: A Case Series of 42 Patients. AB - BACKGROUND: Burst fractures involve the anterior and middle columns with an intact posterior column. Deforming forces are magnified at areas of transition, making the thoracolumbar junction highly susceptible to injury. METHODS: This is a retrospective review of 42 consecutive patients who underwent single-level anterior lumbar corpectomy using an obelisc expandable titanium cage and lateral fixation for traumatic lumbar burst fractures. RESULTS: Myelopathy and sensory dysfunction were the most frequent neurologic deficits initially, occurring in 16 (38%) and 15 (36%) patients, respectively, which both decreased to 5 (13%). At follow-up, 26 patients (68%) were able to ambulate independently. No patient had significant cage displacement or needed cage replacement. Subsidence was minimal in 32 of 39 patients (82%). There were no hardware infections or surgical site infections. Options for stabilization include posterior instrumentation and fusion, anterior corpectomy with interbody fusion, and combination procedures. We believe anterior stabilization is superior because the aim is structural restoration of anterior and middle columns. The aim of posterior fixation is to replace the posterior tension band, which is not affected. There are 3 major surgical components to consider. First is anterior versus posterior decompression of the spinal canal. Second is the choice of autograft or titanium graft. Third is whether to stabilize posteriorly or anterolateral. CONCLUSIONS: Anterior corpectomy with an expandable titanium cage and lateral rod fixation is safe and effective with minimal complications. It is a viable alternative to posterior decompression and instrumentation. PMID- 28887283 TI - Endoscopic Transsphenoidal Approach for Acromegaly with Remission Rates in 401 Patients: 2010 Consensus Criteria. AB - BACKGROUND: Transsphenoidal surgery is the first-choice treatment for acromegaly. Postoperative remission is an important predictor of outcome. Various factors have been described as markers of remission: preoperative mean growth hormone (GH) and insulin-like growth factor-1 levels, cavernous sinus invasion, tumor size, extrapseudocapsular resection, and experience of the surgeon. MATERIALS AND METHODS: A total of 401 patients underwent 432 endoscopic transsphenoidal surgeries between August 1997 and June 2016 at the Pituitary Research Centre of Kocaeli University. The remission rates were evaluated according to the 2010 consensus criteria using preoperative and postoperative data including overall remission, cavernous sinus invasiveness, extrapseudocapsular resection, resection rate, and preoperative and postoperative GH levels. RESULTS: Total resection was performed in 311 (77.56%) of 401 patients according to early (24-hour) postoperative magnetic resonance imaging. Overall, remission was achieved in 273 (68.1%) of 401 patients. Remission was achieved in 186 (63.3%) of 294 patients with macroadenomas, 87 (81.3%) of 107 patients with microadenomas, and 35 (40.7%) of 86 patients with cavernous sinus invasion. Remission was seen in 21 (75%) of 28 patients who underwent pseudocapsular resection. According to preoperative GH levels, remission was achieved in 205 (72.4%) of 273 patients with GH levels below 20 ng/mL but decreased to 11 (37.9%) of 29 patients with GH levels over 60 ng/mL. There was, conversely, a very strongly significant correlation with cavernous sinus invasion (P < 0.001; r: -0.953) and also a very strongly significant correlation with extrapseudocapsular resection (P < 0.001; r: 0.810). However, remission was very weakly but reversely significantly correlated with adenoma size and volume. CONCLUSION: The most significant factors for remission are cavernous sinus invasion and extrapseudocapsular resection. Higher remission rates can be achieved with the removal of small remnants by meticulous sweeping and by total resection. Preoperative and postoperative GH levels are predictive of remission. PMID- 28887284 TI - Quantitative Comparison of Three Endoscopic Approaches to the Parasellar Region: Laboratory Investigation. AB - BACKGROUND: Endoscopic endonasal transsphenoidal and contralateral sublabial transmaxillary approaches are used for approaching parasellar lesions. The aim of this anatomical study was to compare endoscopic endonasal uninostril and binostril (contralateral) and contralateral sublabial transmaxillary approaches via a quantitative analysis of exposure limits and instrument working avenues. METHODS: Six formalin-fixed silicone-injected adult cadaveric heads (12 sides) were studied. The surgical working area, depth of the surgical corridor, angle of attack, and surgical freedom were measured and compared for the 3 approaches. RESULTS: The endoscopic binostril endonasal approach to the parasellar area provided greater surgical freedom in the opticocarotid recess (OCR) and superior orbital fissure (SOF) compared with that of the uninostril endonasal approach (OCR, P < 0.01; SOF, P = 0.01) and the contralateral sublabial transmaxillary approach (OCR, P = 0.01; SOF, P = 0.03). The horizontal and vertical angles of attack with the binostril endonasal approach also were greater than those of the uninostril approach (OCR, P <= 0.05; SOF, P <= 0.01) and the contralateral transmaxillary approach (OCR, P <= 0.01; SOF, P <= 0.01). However, the contralateral sublabial transmaxillary approach provided more lateral exposure than the uninostril or binostril endonasal approach to the parasellar area, and it enabled a shorter surgical trajectory to the contralateral parasellar area (P < 0.01). CONCLUSIONS: An anatomical comparison of the 3 endoscopic approaches to the parasellar area showed that the binostril approach provides greater exposure and freedom for instrument manipulation. The contralateral transmaxillary route provided a more lateral view, increasing exposure on average by 48%, with shorter surgical depth; however, surgical freedom was inferior to that of the binostril approach. PMID- 28887285 TI - The Occipital Artery as an Alternative Donor for Low-Flow Bypass to Anterior Circulation After Internal Carotid Artery Occlusion Failure prior to Exenteration for an Atypical Cavernous Sinus Meningioma. AB - BACKGROUND: In skull base tumors involving the cavernous sinus, indications for aggressive resection are sparse and must be carefully examined because of their invasiveness. With careful evaluation, techniques including internal carotid artery sacrifice with or without extracranial-intracranial bypass may still be an option in some cases. Moreover, previous surgery with the sacrifice of potential donor vessels requires adjusting the revascularization strategy. We describe an occipital artery-middle cerebral artery bypass before skull base tumor resection. CASE DESCRIPTION: A 47-year-old woman with a recurrent cavernous sinus meningioma was referred to our department. Because of tumor recurrence after radiotherapy and its rapid progression, radical resection, including part of the cavernous sinus, was planned. A balloon test occlusion was performed and showed good tolerance. An endovascular internal carotid artery occlusion was performed. The patient eventually experienced motor deficits and aphasia after surgery. Therefore, bypass surgery using an occipital artery-middle cerebral artery anastomosis was performed. The patient showed no exacerbation of symptoms after bypass surgery and subsequently underwent tumor resection. CONCLUSIONS: The reliability of balloon test occlusion in the management of giant aneurysms may not be similarly applicable to skull base tumors. If hypoperfusion symptoms occur after occlusion of the internal carotid artery, a surgical revascularization procedure should be considered because of the risk of ischemic stroke following tumor resection. For patients whose superficial temporal artery is not available, the occipital artery can be a valuable alternative donor for low-flow bypass. PMID- 28887287 TI - Characterization of simvastatin acid uptake by organic anion transporting polypeptide 3A1 (OATP3A1) and influence of drug-drug interaction. AB - Human organic anion transporting polypeptide 3A1 (OATP3A1) is predominately expressed in the heart. The ability of OATP3A1 to transport statins into cardiomyocytes is unknown, although other OATPs are known to mediate the uptake of statin drugs in liver. The pleiotropic effects and uptake of simvastatin acid were analyzed in primary human cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. Treatment with simvastatin acid reduced indoxyl sulfate mediated reactive oxygen species and modulated OATP3A1 expression in cardiomyocytes and HEK293 cells transfected with the OATP3A1 gene. We observed a pH-dependent effect on OATP3A1 uptake, with more efficient simvastatin acid uptake at pH5.5 in HEK293 cells transfected with the OATP3A1 gene. The Michaelis Menten constant (Km) for simvastatin acid uptake by OATP3A1 was 0.017+/-0.002MUM and the Vmax was 0.995+/-0.027fmol/min/105 cells. Uptake of simvastatin acid was significantly increased by known (benzylpenicillin and estrone-3-sulfate) and potential (indoxyl sulfate and cyclosporine) substrates of OATP3A1. In conclusion, the presence of OATP3A1 in cardiomyocytes suggests that this transporter may modulate the exposure of cardiac tissue to simvastatin acid due to its enrichment in cardiomyocytes. Increases in uptake of simvastatin acid by OATP3A1 when combined with OATP substrates suggest the potential for drug-drug interactions that could influence clinical outcomes. PMID- 28887286 TI - Why Does the Health-Related Quality of Life in Idiopathic Normal-Pressure Hydrocephalus Fail to Improve Despite the Favorable Clinical Outcome? AB - OBJECTIVE: Occasionally, a favorable clinical disease-specific outcome does not reflect into improved generic health-related quality of life (HRQoL) in patients with idiopathic normal-pressure hydrocephalus (iNPH) at 1 year after the installation of a cerebrospinal fluid shunt. Our aim was to identify factors causing this discrepancy. METHODS: The 1-year HRQoL outcomes of 141 patients with iNPH were evaluated with the generic 15D instrument, in which the minimum clinically important change/difference on the 0-1 scale has been estimated to be +/-0.015. A 12-point iNPH grading scale (iNPHGS) was used as a clinical disease specific outcome measure, in which a 1-point decrease is considered to be clinically important. We identified 29 (21%) patients with iNPH from our prospective study whose HRQoL deteriorated or remained the same despite of a favorable iNPHGS outcome. We analyzed this discrepancy using patients' clinical variables and characteristics. RESULTS: Multivariate binary logistic regression analysis indicated that a greater (worse) iNPHGS score at baseline (adjusted odds ratio [OR], 1.7; 95% confidence interval [CI] 1.3-2.3; P < 0.001), comorbid chronic pulmonary disease (40% vs. 20%; adjusted OR 17.8; 95% CI 3.6-89.9; P < 0.001), and any comorbid nonmetastatic tumor (62% vs. 17%; adjusted OR 11.5; 95% CI 1.5-85.3; P = 0.017) predicted discrepancy between iNPHGS and 15D outcomes. CONCLUSIONS: Frail patients suffering from certain pre-existing comorbidities may not experience improvement in generic HRQoL despite of a favorable clinical disease-specific response. Acknowledging the comorbidity burden of the patient may help clinicians and the patients to understand the conflict between patient reported and clinical outcomes. PMID- 28887288 TI - Development of a quantitative cytotoxicity assay using mouse lymphoma TK cells. AB - We describe a new, quantitative, cytotoxicity method using mouse lymphoma L5178Y thymidine kinase+/- (TK) suspension cells for medical device safety assessment that has equivalent sensitivity, and greater efficiency compared to the colony formation assay (CFA) using adherent V79-4 cells. Assays were carried out in 24 well plates. TK cells were seeded on concave side of six types of contact lenses and cell growth rate after 72h determined using the Vi-Cell XR. Five of six contact lenses studied demonstrated the same results between the TK and the CFA methods. One lens showed a difference between the CFA and TK suspension cell methods (79% colony formation rate vs. 17% cell growth rate). Although colony size is not a CFA test criterion, colonies were smaller than control indicating a cytotoxic effect that is reflected in the TK suspension cell assay which measures cell number. The mouse lymphoma TK suspension cell assay performs as well as the CFA direct contact method with distinct advantages. This quantitative, automated method is not susceptible to mechanical damage from test materials, does not depend on cell adherence to test materials and represents a valuable tool to evaluate medical device cytotoxicity. PMID- 28887289 TI - Baseline resistance and cross-resistance among fluoroquinolones in multidrug resistant Mycobacterium tuberculosis isolates at a national reference laboratory in India. AB - OBJECTIVES: Pre-existing fluoroquinolone (FQ) resistance in multidrug-resistant tuberculosis (MDR TB) patients is a major threat in treating MDR-TB. This study was conducted to assess the percentage of FQ resistance among MDR-TB patients and to determine whether there is complete cross-resistance between FQs [ofloxacin (OFX), levofloxacin (LVX) and moxifloxacin (MXF)] used as second-line drugs in MDR-TB treatment. METHODS: Among 879 MDR-TB suspects tested, 68 were confirmed to be MDR-TB and rifampicin (RIF) monoresistant. Suspects were further analysed for FQ resistance by drug susceptibility testing (DST) using Mycobacterium Growth Indicator Tube (MGIT). Minimum inhibitory concentrations (MIC) were determined for OFX, LVX and MXF. RESULTS: Of 879 MDR-TB suspects, RIF resistance was observed in 70 patients (8.0%), among which pre-existing FQ resistance was detected in 32%. Moreover, 88% of isolates exhibited a similar DST pattern for all three FQs tested. Cross-resistance among FQs was not complete in eight isolates; the MIC of MXF was found to be much lower than the MICs of OFX and LVX. CONCLUSIONS: A huge proportion of MDR-TB strains (32%) exhibiting OFX resistance prior to treatment with second-line anti-TB drugs raises major concern. Detection of baseline drug resistance in TB patients helps in reducing the transmission of drug-resistant TB. The OFX MIC was higher than its critical concentration, indicating the prevalence of baseline resistance to FQs owing to irrational use of these drugs. PMID- 28887290 TI - Individual feedback to reduce inappropriate antimicrobial prescriptions for treating acute upper respiratory infections in an outpatient setting of a Thai university hospital. AB - OBJECTIVES: Excessive use of antimicrobial agents for acute upper respiratory infections (URIs) is one of the most common problems in clinical practice. Interventions are required to reduce antimicrobial overuse in these common infections. METHODS: During a 9-month study period (June 2014-February 2015), a quasi-experimental (pre-/post-) study was conducted among internal medicine residents and fellows in an outpatient setting of Siriraj Hospital, Thailand. The aim of the study was to determine the effectiveness of individual feedback to reduce inappropriate antimicrobial prescriptions for treating URIs. The administrative ICD-10 database was used to identify index physicians with at least one outpatient experience of URI. Data on antimicrobial prescriptions were extracted from the hospital pharmacy database. A confidential letter and SMS were sent to all index physicians about the extent of antimicrobial therapy they prescribed for treating URIs during the pre-intervention period. RESULTS: The proportion of antimicrobial use among the index encounters showed a significant reduction from 34.7% in the pre-intervention period to 26.1% in the post intervention period (P=0.02). Segmented logistic regression analysis confirmed the significant impact of the intervention on reducing antimicrobial prescriptions (P=0.02). CONCLUSION: This integrated intervention is simple and non-labour intensive and may therefore be used sustainably in resource-limited settings. PMID- 28887291 TI - Molecular epidemiology and antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus isolates in Xiangyang, China. AB - OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) is a public health problem worldwide. This study aimed to investigate the antimicrobial susceptibility and molecular epidemiological characteristics of MRSA strains in Xiangyang, China, during 2012-2014. METHODS: Eighty non-duplicate S. aureus isolates from clinical specimens were collected from four tertiary hospitals. MRSA strains were identified and were tested for antibacterial susceptibility. Staphylococcal cassette chromosome mec (SCCmec) typing, pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and staphylococcal protein A (spa) typing were performed to explore molecular characteristics. RESULTS: Among the 80 S. aureus isolates, 43 MRSA (53.8%) were detected. MRSA strains exhibited resistance against non-beta-lactam antibiotics to varying degrees. SCCmec type III was the predominant type (39/43; 90.7%), and the remainder were SCCmec type IVa (4/43; 9.3%). Thirteen MLST types were found, mainly ST239 (12/43; 27.9%) and ST59 (7/43; 16.3%). Fifteen spa types were found, mainly t437 (13/43; 30.2%) and t030 (6/43; 14.0%). PFGE grouped the 43 MRSA isolates into five types. SCCmecIII-ST239-t030/t632 and SCCmecIII-ST59/ST338-t437 were the dominant epidemic clones in this region. ST239-t030/t632/t037 was the epidemic clone with the most serious drug resistance. CONCLUSIONS: This region presented a high MRSA rate and the MRSA isolates demonstrated strong antimicrobial resistance. The existence of four strains of community-acquired MRSA (SCCmec type IVa) indicated the dissemination of MRSA strains from the community to hospitals. The epidemic situation and drug resistance of MRSA should be regularly monitored. Effective measures should be adopted to prevent and control the occurrence of infection in hospitals. PMID- 28887292 TI - Protocol for Usability Testing and Validation of the ISO Draft International Standard 19223 for Lung Ventilators. AB - BACKGROUND: Clinicians, such as respiratory therapists and physicians, are often required to set up pieces of medical equipment that use inconsistent terminology. Current lung ventilator terminology that is used by different manufacturers contributes to the risk of usage errors, and in turn the risk of ventilator associated lung injuries and other conditions. Human factors and communication issues are often associated with ventilator-related sentinel events, and inconsistent ventilator terminology compounds these issues. This paper describes our proposed protocol, which will be implemented at the University of Waterloo, Canada when this project is externally funded. OBJECTIVE: We propose to determine whether a standardized vocabulary improves the ease of use, safety, and utility as it relates to the usability of medical devices, compared to legacy medical devices from multiple manufacturers, which use different terms. METHODS: We hypothesize that usage errors by clinicians will be lower when standardization is consistently applied by all manufacturers. The proposed study will experimentally examine the impact of standardized nomenclature on performance declines in the use of an unfamiliar ventilator product in clinically relevant scenarios. Participants will be respiratory therapy practitioners and trainees, and we propose studying approximately 60 participants. RESULTS: The work reported here is in the proposal phase. Once the protocol is implemented, we will report the results in a follow-up paper. CONCLUSIONS: The proposed study will help us better understand the effects of standardization on medical device usability. The study will also help identify any terms in the International Organization for Standardization (ISO) Draft International Standard (DIS) 19223 that may be associated with recurrent errors. Amendments to the standard will be proposed if recurrent errors are identified. This report contributes a protocol that can be used to assess the effect of standardization in any given domain that involves equipment, multiple manufacturers, inconsistent vocabulary, symbology, audio tones, or patterns in interface navigation. Second, the protocol can be used to experimentally evaluate the ISO DIS 19223 for its effectiveness, as researchers around the world may wish to conduct such tests and compare results. PMID- 28887294 TI - Impact of At-Home Telemonitoring on Health Services Expenditure and Hospital Admissions in Patients With Chronic Conditions: Before and After Control Intervention Analysis. AB - BACKGROUND: Telemonitoring is becoming increasingly important for the management of patients with chronic conditions, especially in countries with large distances such as Australia. However, despite large national investments in health information technology, little policy work has been undertaken in Australia in deploying telehealth in the home as a solution to the increasing demands and costs of managing chronic disease. OBJECTIVE: The objective of this trial was to evaluate the impact of introducing at-home telemonitoring to patients living with chronic conditions on health care expenditure, number of admissions to hospital, and length of stay (LOS). METHODS: A before and after control intervention analysis model was adopted whereby at each location patients were selected from a list of eligible patients living with a range of chronic conditions. Each test patient was case matched with at least one control patient. Test patients were supplied with a telehealth vital signs monitor and were remotely managed by a trained clinical care coordinator, while control patients continued to receive usual care. A total of 100 test patients and 137 control patients were analyzed. Primary health care benefits provided to Australian patients were investigated for the trial cohort. Time series data were analyzed using linear regression and analysis of covariance for a period of 3 years before the intervention and 1 year after. RESULTS: There were no significant differences between test and control patients at baseline. Test patients were monitored for an average of 276 days with 75% of patients monitored for more than 6 months. Test patients 1 year after the start of their intervention showed a 46.3% reduction in rate of predicted medical expenditure, a 25.5% reduction in the rate of predicted pharmaceutical expenditure, a 53.2% reduction in the rate of predicted unscheduled admission to hospital, a 67.9% reduction in the predicted rate of LOS when admitted to hospital, and a reduction in mortality of between 41.3% and 44.5% relative to control patients. Control patients did not demonstrate any significant change in their predicted trajectory for any of the above variables. CONCLUSIONS: At-home telemonitoring of chronically ill patients showed a statistically robust positive impact increasing over time on health care expenditure, number of admissions to hospital, and LOS as well as a reduction in mortality. TRIAL REGISTRATION: Retrospectively registered with the Australian and New Zealand Clinical Trial Registry ACTRN12613000635763; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364030 (Archived by WebCite at http://www.webcitation.org/6sxqjkJHW). PMID- 28887293 TI - Influence of Fear of Pain and Coping Strategies on Health-Related Quality of Life and Patient-Anticipated Outcomes in Patients With Chronic Pain: Cross-Sectional Study Protocol. AB - BACKGROUND: Fear of pain and coping strategies are emotional-behavioral responses to pain and are known to play an important role in the development and maintenance of pain. It is highly likely that fear of pain and coping strategies influence each other, potentially affecting the course of chronic pain. To our knowledge, the relationship between pain, fear of pain and coping strategies, and how they influence patient-anticipated outcomes and health-related quality of life, have not been investigated. OBJECTIVE: The aims of this study are to test (1) if both fear of pain and/or coping strategies are sufficient causes for maintaining pain; and (2) whether fear of pain influences coping strategies and pain intensity. The study will also examine the impact of fear of pain and coping strategies on health-related quality of life and patient-anticipated outcomes. METHODS: The cross-sectional study will be conducted using an online survey. The Fear of Pain Questionnaire-III (FPQ-III), the Brief Coping Inventory (COPE), and EuroQoL-5d (EQ-5D) validated questionnaires will be used to collect data. Information pertaining to demographic factors, pain-related factors, and patient anticipated outcomes will also be collected. The study has ethics approval from the Human Research Ethics Committee of the University of Adelaide. Study participants will be individuals aged 18 years and above who are experiencing chronic pain (ie, pain lasting more than 6 months). Effect measure modification technique (EMMM) will be used to examine if fear of pain acts as a moderator or mediator between coping strategies and pain. Simple and multinomial logistic regression analysis will be used to examine the effect of fear of pain and coping strategies on health-related quality of life and patient-anticipated outcomes. RESULTS: Recruitment began July 2017 and it is anticipated that data collection will be completed by October 2017. Findings from this study will help to extend our understanding of fear of pain and coping strategies, their interaction, and their impact on health-related quality of life and patient-anticipated outcomes. CONCLUSIONS: Fear of pain and coping strategies have significant influence on the experience of chronic pain and its course. This study will help enhance our understanding of the relationship between fear of pain and coping strategies, which may help in developing patient-centered care practices. PMID- 28887296 TI - An Exploration of Changes in the Measurement of Mammography in the National Health Interview Survey. AB - Background: Using the National Health Interview Survey (NHIS), we examined the effect of question wording on estimates of past-year mammography among racially/ethnically diverse women ages 40-49 and 50-74 without a history of breast cancer.Methods: Data from one-part ("Have you had a mammogram during the past 12 months?") and two-part ("Have you ever had a mammogram"; "When did you have your most recent mammogram?") mammography history questions administered in the 2008, 2011, and 2013 NHIS were analyzed. chi2 tests provided estimates of changes in mammography when question wording was either the same (two-part question) or differed (two-part question followed by one-part question) in the two survey years compared. Crosstabulations and regression models assessed the type, extent, and correlates of inconsistent responses to the two questions in 2013.Results: Reports of past-year mammography were slightly higher in years when the one-part question was asked than when the two-part question was asked. Nearly 10% of women provided inconsistent responses to the two questions asked in 2013. Black women ages 50 to 74 [adjusted OR (aOR), 1.50; 95% confidence interval (CI), 1.16-1.93] and women ages 40-49 in poor health (aOR, 2.22; 95% CI, 1.09-4.52) had higher odds of inconsistent responses; women without a usual source of care had lower odds (40-49: aOR, 0.42; 95% CI, 0.21-0.85; 50-74: aOR, 0.42; 95% CI, 0.24 0.74).Conclusions: Self-reports of mammography are sensitive to question wording. Researchers should use equivalent questions that have been designed to minimize response biases such as telescoping and social desirability.Impact: Trend analyses relying on differently worded questions may be misleading and conceal disparities. Cancer Epidemiol Biomarkers Prev; 26(11); 1611-8. (c)2017 AACR. PMID- 28887295 TI - Photoaging Mobile Apps in School-Based Melanoma Prevention: Pilot Study. AB - BACKGROUND: Around 90% of melanomas are caused by exposure to ultraviolet (UV) radiation and are therefore eminently preventable. Tanning behavior is mostly initiated in early adolescence, often with the belief that it increases attractiveness; the problems related to malignant melanoma and other skin cancers are too far in the future to fathom. Given the substantial amount of time children and adolescents spend in schools, as well as with their mobile phones, addressing melanoma prevention via both of these ways is crucial. However, no school-based intervention using mobile apps has been evaluated to date. We recently released a photoaging mobile app, in which a selfie is altered to predict future appearance dependent on UV protection behavior and skin type. OBJECTIVE: In this pilot study, we aimed to use mobile phone technology to improve school-based melanoma prevention and measure its preliminary success in different subgroups of students with regard to their UV protection behavior, Fitzpatrick skin type and age. METHODS: We implemented a free photoaging mobile phone app (Sunface) in 2 German secondary schools via a method called mirroring. We "mirrored" the students' altered 3-dimensional (3D) selfies reacting to touch on mobile phones or tablets via a projector in front of their whole grade. Using an anonymous questionnaire capturing sociodemographic data as well as risk factors for melanoma we then measured their perceptions of the intervention on a 5-point Likert scale among 205 students of both sexes aged 13-19 years (median 15 years). RESULTS: We measured more than 60% agreement in both items that measured motivation to reduce UV exposure and only 12.5% disagreement: 126 (63.0%) agreed or strongly agreed that their 3D selfie motivated them to avoid using a tanning bed, and 124 (61.7%) to increase use of sun protection. However, only 25 (12.5%) disagreed with both items. The perceived effect on motivation was increased in participants with Fitzpatrick skin types 1-2 in both tanning bed avoidance (n=74, 71.8% agreement in skin types 1-2 vs n=50, 53.8% agreement in skin types 3-6) and increased use of sun protection (n=70, 68.0% agreement in skin types 1-2 vs n=52, 55.3% agreement in skin types 3-6), and also positively correlated with higher age. CONCLUSIONS: We present a novel way of integrating photoaging in school based melanoma prevention that affects the students' peer group, considers the predictors of UV exposure in accordance with the theory of planned behavior, and is particularly effective in changing behavioral predictors in fair-skinned adolescents (Fitzpatrick skin types 1-2). Further research is required to evaluate the intervention's prospective effects on adolescents of various cultural backgrounds. PMID- 28887297 TI - Defining Optimal Triage Strategies for hrHPV Screen-Positive Women-An Evaluation of HPV 16/18 Genotyping, Cytology, and p16/Ki-67 Cytoimmunochemistry. AB - Background: Several options for the triage of high-risk HPV screen-positive (hrHPV+) women were assessed.Methods: This study incorporated CIN2+ cases and controls, all of whom tested hrHPV+ and whose results of liquid-based cytology (LBC), HPV16/18 genotyping, and p16/Ki67 cytoimmunochemistry were available. Sensitivity and specificity for the CIN2+ of these triage tests were evaluated.Results: Absolute sensitivities of HPV 16/18 typing, LBC, and p16/Ki-67 cytoimmunochemistry for CIN2+ detection were 61.7%, 68.3%, and 85.0% for women with hrHPV+ clinician-taken samples. Respective specificities were 70.5%, 89.1%, and 76.7%. The absolute accuracy of the triage tests was similar for women with a hrHPV+ self-sample. P16/Ki-67 cyto-immunochemistry was significantly more sensitive than LBC although significantly less specific.Conclusions: All three single-test triage options, if positive, exceed the threshold of 20% risk at which colposcopy would be indicated. However, none of them conferred a post-test probability of CIN2+ <2%; which would permit routine recall. P16/Ki-67 cytoimmunochemistry on HPV16/18 negative women had a post-test probability of CIN2+ of 1.7% and 0.6% if also LBC negative.Impact: This is one of the few studies to directly compare the performance of triage strategies of hrHPV+ women, in isolation and combinations. It is the only study assessing triage strategies in women who test hrHPV+ in self-taken vaginal samples. A combined triage option that incorporated HPV 16/18 typing prior to p16/ki-67 cytoimmunochemistry in HPV 16/18-negative women yielded a post-test probability of CIN2+ of >20%, whereas women who tested negative had a probability of CIN2+ of <2%. Cancer Epidemiol Biomarkers Prev; 26(11); 1629-35. (c)2017 AACR. PMID- 28887298 TI - Tougher charging regime for "overseas" patients. PMID- 28887299 TI - The problem with US website for collecting adverse events after vaccination is resolved. PMID- 28887300 TI - Rules for NHS compensation are to change again after costs spiral. PMID- 28887301 TI - The phospholipase PNPLA7 functions as a lysophosphatidylcholine hydrolase and interacts with lipid droplets through its catalytic domain. AB - Mammalian patatin-like phospholipase domain-containing proteins (PNPLAs) are lipid-metabolizing enzymes with essential roles in energy metabolism, skin barrier development, and brain function. A detailed annotation of enzymatic activities and structure-function relationships remains an important prerequisite to understand PNPLA functions in (patho-)physiology, for example, in disorders such as neutral lipid storage disease, non-alcoholic fatty liver disease, and neurodegenerative syndromes. In this study, we characterized the structural features controlling the subcellular localization and enzymatic activity of PNPLA7, a poorly annotated phospholipase linked to insulin signaling and energy metabolism. We show that PNPLA7 is an endoplasmic reticulum (ER) transmembrane protein that specifically promotes hydrolysis of lysophosphatidylcholine in mammalian cells. We found that transmembrane and regulatory domains in the PNPLA7 N-terminal region cooperate to regulate ER targeting but are dispensable for substrate hydrolysis. Enzymatic activity is instead mediated by the C-terminal domain, which maintains full catalytic competence even in the absence of N terminal regions. Upon elevated fatty acid flux, the catalytic domain targets cellular lipid droplets and promotes interactions of PNPLA7 with these organelles in response to increased cAMP levels. We conclude that PNPLA7 acts as an ER anchored lysophosphatidylcholine hydrolase that is composed of specific functional domains mediating catalytic activity, subcellular positioning, and interactions with cellular organelles. Our study provides critical structural insights into an evolutionarily conserved class of phospholipid-metabolizing enzymes. PMID- 28887302 TI - Mechanisms of zinc binding to the solute-binding protein AztC and transfer from the metallochaperone AztD. AB - Bacteria can acquire the essential metal zinc from extremely zinc-limited environments by using ATP-binding cassette (ABC) transporters. These transporters are critical virulence factors, relying on specific and high-affinity binding of zinc by a periplasmic solute-binding protein (SBP). As such, the mechanisms of zinc binding and release among bacterial SBPs are of considerable interest as antibacterial drug targets. Zinc SBPs are characterized by a flexible loop near the high-affinity zinc-binding site. The function of this structure is not always clear, and its flexibility has thus far prevented structural characterization by X-ray crystallography. Here, we present intact structures for the zinc-specific SBP AztC from the bacterium Paracoccus denitrificans in the zinc-bound and apo states. A comparison of these structures revealed that zinc loss prompts significant structural rearrangements, mediated by the formation of a sodium binding site in the apo-structure. We further show that the AztC flexible loop has no impact on zinc-binding affinity, stoichiometry, or protein structure, yet is essential for zinc transfer from the metallochaperone AztD. We also found that 3 His residues in the loop appear to temporarily coordinate zinc and then convey it to the high-affinity binding site. Thus, mutation of any of these residues to Ala abrogated zinc transfer from AztD. Our structural and mechanistic findings conclusively identify a role for the AztC flexible loop in zinc acquisition from the metallochaperone AztD, yielding critical insights into metal binding by AztC from both solution and AztD. These proteins are highly conserved in human pathogens, making this work potentially useful for the development of novel antibiotics. PMID- 28887303 TI - Dynamic nuclear polarization facilitates monitoring of pyruvate metabolism in Trypanosoma brucei. AB - Dynamic nuclear polarization provides sensitivity improvements that make NMR a viable method for following metabolic conversions in real time. There are now many in vivo applications to animal systems and even to diagnosis of human disease. However, application to microbial systems is rare. Here we demonstrate its application to the pathogenic protozoan, Trypanosoma brucei, using hyperpolarized 13C1 pyruvate as a substrate and compare the parasite metabolism with that of commonly cultured mammalian cell lines, HEK-293 and Hep-G2. Metabolic differences between insect and bloodstream forms of T. brucei were also investigated. Significant differences are noted with respect to lactate, alanine, and CO2 production. Conversion of pyruvate to CO2 in the T. brucei bloodstream form provides new support for the presence of an active pyruvate dehydrogenase in this stage. PMID- 28887304 TI - Allostery between two binding sites in the ion channel subunit TRIP8b confers binding specificity to HCN channels. AB - Tetratricopeptide repeat (TPR) domains are ubiquitous structural motifs that mediate protein-protein interactions. For example, the TPR domains in the peroxisomal import receptor PEX5 enable binding to a range of type 1 peroxisomal targeting signal motifs. A homolog of PEX5, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), binds to and functions as an auxiliary subunit of hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Given the similarity between TRIP8b and PEX5, this difference in function raises the question of what mechanism accounts for their binding specificity. In this report, we found that the cyclic nucleotide-binding domain and the C terminus of the HCN channel are critical for conferring specificity to TRIP8b binding. We show that TRIP8b binds the HCN cyclic nucleotide-binding domain through a 37 residue domain and the HCN C terminus through the TPR domains. Using a combination of fluorescence polarization- and co-immunoprecipitation-based assays, we establish that binding at either site increases affinity at the other. Thus, allosteric coupling of the TRIP8b TPR domains both promotes binding to HCN channels and limits binding to type 1 peroxisomal targeting signal substrates. These results raise the possibility that other TPR domains may be similarly influenced by allosteric mechanisms as a general feature of protein-protein interactions. PMID- 28887305 TI - Structural analyses of the Haemophilus influenzae peptidoglycan synthase activator LpoA suggest multiple conformations in solution. AB - In many Gram-negative bacteria, the peptidoglycan synthase PBP1A requires the outer membrane lipoprotein LpoA for constructing a functional peptidoglycan required for bacterial viability. Previously, we have shown that the C-terminal domain of Haemophilus influenzae LpoA (HiLpoA) has a highly conserved, putative substrate-binding cleft between two alpha/beta lobes. Here, we report a 2.0 A resolution crystal structure of the HiLpoA N-terminal domain. Two subdomains contain tetratricopeptide-like motifs that form a concave groove, but their relative orientation differs by ~45 degrees from that observed in an NMR structure of the Escherichia coli LpoA N domain. We also determined three 2.0-2.8 A resolution crystal structures containing four independent full-length HiLpoA molecules. In contrast to an elongated model previously suggested for E. coli LpoA, each HiLpoA formed a U-shaped structure with a different C-domain orientation. This resulted from both N-domain twisting and rotation of the C domain (up to 30 degrees ) at the end of the relatively immobile interdomain linker. Moreover, a previously predicted hinge between the lobes of the LpoA C domain exhibited variations of up to 12 degrees . Small-angle X-ray scattering data revealed excellent agreement with a model calculated by normal mode analysis from one of the full-length HiLpoA molecules but even better agreement with an ensemble of this molecule and two of the partially extended normal mode analysis predicted models. The different LpoA structures helped explain how an outer membrane-anchored LpoA can either withdraw from or extend toward the inner membrane-bound PBP1A through peptidoglycan gaps and hence regulate the synthesis of peptidoglycan necessary for bacterial viability. PMID- 28887306 TI - The long noncoding RNA PCAT-1 links the microRNA miR-215 to oncogene CRKL mediated signaling in hepatocellular carcinoma. AB - The long non-coding RNA (lncRNA) PCAT-1 resides in the chromosome 8q24 cancer risk locus and acts as a vital oncogene during tumorigenesis and progression. However, how PCAT-1 is post-transcriptionally regulated, for example, by small ncRNAs, such as microRNAs (miRNAs) is largely unknown. Here, we report how miRNAs regulate PCAT-1 expression and also investigate the biological significance of this regulation in hepatocellular carcinoma (HCC). We found that miR-215, a P53 inducible miRNA, is a key regulator of PCAT-1 expression in HCC and identified an interaction between miR-215 and PCAT-1 in dual luciferase reporter gene assays. We also found that post-transcriptional silencing of PCAT-1 by miR-215 or PCAT-1 siRNAs significantly inhibited proliferation of HCC cells and, conversely, that inhibition of endogenous miR-215 up-regulated PCAT-1 expression and promoted cell viability. The tumor-suppressing role of miR-215 was further confirmed in an in vivo mouse HCC xenograft model. Of note, gene profiling assays suggested that the kinase CRK-like proto-oncogene, adaptor protein (CRKL), is a potential downstream target of the miR-215-PCAT-1 axis in HCC, and we demonstrated that CRKL silencing significantly suppresses cell proliferation. Taken together and considering the essential role of CRKL in cancer cells, we propose that the TP53-miR-215-PCAT-1 CRKL axis might represent an important regulatory pathway in HCC. In summary, our results highlight the involvement of several ncRNAs in HCC and thus provide critical insights into the molecular pathways operating in this malignancy. PMID- 28887308 TI - Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation. AB - Lysine methylation is an important and much-studied posttranslational modification of nuclear and cytosolic proteins but is present also in mitochondria. However, the responsible mitochondrial lysine-specific methyltransferases (KMTs) remain largely elusive. Here, we investigated METTL12, a mitochondrial human S-adenosylmethionine (AdoMet)-dependent methyltransferase and found it to methylate a single protein in mitochondrial extracts, identified as citrate synthase (CS). Using several in vitro and in vivo approaches, we demonstrated that METTL12 methylates CS on Lys-395, which is localized in the CS active site. Interestingly, the METTL12-mediated methylation inhibited CS activity and was blocked by the CS substrate oxaloacetate. Moreover, METTL12 was strongly inhibited by the reaction product S-adenosylhomocysteine (AdoHcy). In summary, we have uncovered a novel human mitochondrial KMT that introduces a methyl modification into a metabolic enzyme and whose activity can be modulated by metabolic cues. Based on the established naming nomenclature for similar enzymes, we suggest that METTL12 be renamed CS-KMT (gene name CSKMT). PMID- 28887307 TI - Dynamic feature of mitotic arrest deficient 2-like protein 2 (MAD2L2) and structural basis for its interaction with chromosome alignment-maintaining phosphoprotein (CAMP). AB - Mitotic arrest deficient 2-like protein 2 (MAD2L2), also termed MAD2B or REV7, is involved in multiple cellular functions including translesion DNA synthesis (TLS), signal transduction, transcription, and mitotic events. MAD2L2 interacts with chromosome alignment-maintaining phosphoprotein (CAMP), a kinetochore microtubule attachment protein in mitotic cells, presumably through a novel "WK" motif in CAMP. Structures of MAD2L2 in complex with binding regions of the TLS proteins REV3 and REV1 have revealed that MAD2L2 has two faces for protein protein interactions that are regulated by its C-terminal region; however, the mechanisms underlying the MAD2L2-CAMP interaction and the mitotic role of MAD2L2 remain unknown. Here we have determined the structures of human MAD2L2 in complex with a CAMP fragment in two crystal forms. The overall structure of the MAD2L2 CAMP complex in both crystal forms was essentially similar to that of the MAD2L2 REV3 complex. However, the residue interactions between MAD2L2 and CAMP were strikingly different from those in the MAD2L2-REV3 complex. Furthermore, structure-based interaction analyses revealed an unprecedented mechanism involving CAMP's WK motif. Surprisingly, in one of the crystal forms, the MAD2L2 CAMP complex formed a dimeric structure in which the C-terminal region of MAD2L2 was swapped and adopted an immature structure. The structure provides direct evidence for the dynamic nature of MAD2L2 structure, which in turn may have implications for the protein-protein interaction mechanism and the multiple functions of this protein. This work is the first structural study of MAD2L2 aside from its role in TLS and might pave the way to clarify MAD2L2's function in mitosis. PMID- 28887309 TI - Phosphorylation of the oncogenic transcription factor ERG in prostate cells dissociates polycomb repressive complex 2, allowing target gene activation. AB - In ~50% of prostate cancers, chromosomal rearrangements cause the fusion of the promoter and 5'-UTR of the androgen-regulated TMPRSS2 (transmembrane protease, serine 2) gene to the open reading frame of ERG, encoding an ETS family transcription factor. This fusion results in expression of full-length or N terminally truncated ERG protein in prostate epithelia. ERG is not expressed in normal prostate epithelia, but when expressed, it promotes tumorigenesis via altered gene expression, stimulating epithelial-mesenchymal transition, cellular migration/invasion, and transformation. However, limited knowledge about the molecular mechanisms of ERG function in prostate cells has hampered efforts to therapeutically target ERG. ERK-mediated phosphorylation of ERG is required for ERG functions in prostate cells, but the reason for this requirement is unknown. Here, we report a mechanism whereby ERK-mediated phosphorylation of ERG at one serine residue causes a conformational change that allows ERK phosphorylation at a second serine residue, Ser-96. We found that the Ser-96 phosphorylation resulted in dissociation of EZH2 and SUZ12, components of polycomb repressive complex 2 (PRC2), transcriptional activation of ERG target genes, and increased cell migration. Conversely, loss of ERG phosphorylation at Ser-96 resulted in recruitment of EZH2 across the ERG-cistrome and a genome-wide loss of ERG mediated transcriptional activation and cell migration. In conclusion, our findings have identified critical molecular mechanisms involving ERK-mediated ERG activation that could be exploited for therapeutic intervention in ERG-positive prostate cancers. PMID- 28887310 TI - Histone deacetylase 6 inhibition reduces cysts by decreasing cAMP and Ca2+ in knock-out mouse models of polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of multiple renal cysts, often leading to renal failure that cannot be prevented by a current treatment. Two proteins encoded by two genes are associated with ADPKD: PC1 (pkd1), primarily a signaling molecule, and PC2 (pkd2), a Ca2+ channel. Dysregulation of cAMP signaling is central to ADPKD, but the molecular mechanism is unresolved. Here, we studied the role of histone deacetylase 6 (HDAC6) in regulating cyst growth to test the possibility that inhibiting HDAC6 might help manage ADPKD. Chemical inhibition of HDAC6 reduced cyst growth in PC1-knock-out mice. In proximal tubule-derived, PC1-knock-out cells, adenylyl cyclase 6 and 3 (AC6 and -3) are both expressed. AC6 protein expression was higher in cells lacking PC1, compared with control cells containing PC1. Intracellular Ca2+ was higher in PC1-knock-out cells than in control cells. HDAC inhibition caused a drop in intracellular Ca2+ and increased ATP-simulated Ca2+ release. HDAC6 inhibition reduced the release of Ca2+ from the endoplasmic reticulum induced by thapsigargin, an inhibitor of endoplasmic reticulum Ca2+-ATPase. HDAC6 inhibition and treatment of cells with the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) reduced cAMP levels in PC1-knock-out cells. Finally, the calmodulin inhibitors W-7 and W-13 reduced cAMP levels, and W-7 reduced cyst growth, suggesting that AC3 is involved in cyst growth regulated by HDAC6. We conclude that HDAC6 inhibition reduces cell growth primarily by reducing intracellular cAMP and Ca2+ levels. Our results provide potential therapeutic targets that may be useful as treatments for ADPKD. PMID- 28887311 TI - Severe Hypoglycemia-Induced Fatal Cardiac Arrhythmias Are Augmented by Diabetes and Attenuated by Recurrent Hypoglycemia. AB - We previously demonstrated that insulin-mediated severe hypoglycemia induces lethal cardiac arrhythmias. However, whether chronic diabetes and insulin deficiency exacerbates, and whether recurrent antecedent hypoglycemia ameliorates, susceptibility to arrhythmias remains unknown. Thus, adult Sprague Dawley rats were randomized into four groups: 1) nondiabetic (NONDIAB), 2) streptozotocin-induced insulin deficiency (STZ), 3) STZ with antecedent recurrent (3 days) hypoglycemia (~40-45 mg/dL, 90 min) (STZ+RH), and 4) insulin-treated STZ (STZ+Ins). Following treatment protocols, all rats underwent hyperinsulinemic (0.2 units ? kg-1 ? min-1), severe hypoglycemic (10-15 mg/dL) clamps for 3 h with continuous electrocardiographic recordings. During matched nadirs of severe hypoglycemia, rats in the STZ+RH group required a 1.7-fold higher glucose infusion rate than those in the STZ group, consistent with the blunted epinephrine response. Second-degree heart block was increased 12- and 6.8-fold in the STZ and STZ+Ins groups, respectively, compared with the NONDIAB group, yet this decreased 5.4-fold in the STZ+RH group compared with the STZ group. Incidence of third-degree heart block in the STZ+RH group was 5.6%, 7.8-fold less than the incidence in the STZ group (44%). Mortality due to severe hypoglycemia was 5% in the STZ+RH group, 6.2-fold less than that in the STZ group (31%). In summary, severe hypoglycemia-induced cardiac arrhythmias were increased by insulin deficiency and diabetes and reduced by antecedent recurrent hypoglycemia. In this model, recurrent moderate hypoglycemia reduced fatal severe hypoglycemia induced cardiac arrhythmias. PMID- 28887313 TI - Celebrating 35 Years of the AJNR: September 1982 edition. PMID- 28887312 TI - Increased Lipolysis, Diminished Adipose Tissue Insulin Sensitivity, and Impaired beta-Cell Function Relative to Adipose Tissue Insulin Sensitivity in Obese Youth With Impaired Glucose Tolerance. AB - Despite evidence of insulin resistance and beta-cell dysfunction in glucose metabolism in youth with prediabetes, the relationship between adipose tissue insulin sensitivity (ATIS) and beta-cell function remains unknown. We investigated whole-body lipolysis, ATIS, and beta-cell function relative to ATIS (adipose disposition index [DI]) in obese youth with impaired glucose tolerance (IGT) versus normal glucose tolerance (NGT). Whole-body lipolysis (glycerol appearance rate [GlyRa], [2H5]glycerol at baseline and during a hyperinsulinemic euglycemic clamp), lipid oxidation (indirect calorimetry), insulin secretion (2-h hyperglycemic clamp), and body composition (dual-energy X-ray absorptiometry) were examined. Adipose DI was calculated as ATIS: (1/GlyRa * fasting insulin) * first-phase insulin secretion. Despite similar percent body fat, youth with IGT versus NGT had higher GlyRa, lower ATIS at baseline and during hyperinsulinemia, and higher lipid oxidation. Adipose DI was ~43% lower in youth with IGT and correlated positively with glucose DI. The lower ATIS and diminished adipose DI in IGT versus NGT is in line with the compromised glucose metabolism reflected in impaired beta-cell function relative to peripheral insulin resistance. We conclude that youth with IGT manifest a global decline in insulin sensitivity, including impaired insulin action in suppressing lipolysis and lipid oxidation, accompanied by beta-cell dysfunction in fat and glucose metabolism, enhancing their risk of type 2 diabetes. PMID- 28887314 TI - Novo Nordisk pays $58.7m to settle claims of mis-selling liraglutide. PMID- 28887316 TI - Prognostic Value of Aortic Stiffness in Patients After ST-Elevation Myocardial Infarction. AB - BACKGROUND: High aortic stiffness has been shown to be a strong predictor of morbidity and mortality in the general population and several patient cohorts. However, in patients after ST-elevation myocardial infarction, the prognostic value of high aortic stiffness is unknown so far. METHODS AND RESULTS: This prospective observational study included 160 consecutive patients with first acute ST-elevation myocardial infarction. Aortic pulse wave velocity (PWV) was measured 2 (interquartile range 2-4 days) days after infarction using cardiac magnetic resonance imaging. The primary end point was defined as a composite end point of major adverse cardiac and cerebrovascular events (MACCE) comprising death, nonfatal myocardial reinfarction, new congestive heart failure, and stroke. During a median follow-up of 1.2 years (interquartile range 1.0-3.1 years), 19 (12%) MACCE events occurred. Kaplan-Meier analysis showed a significantly lower MACCE-free survival in patients with high PWV (PWV >7.3 m/s, log-rank P=0.003). Multivariable Cox regression analysis revealed PWV >7.3 m/s to be an independent predictor of MACCE after adjustment for age, sex, mean blood pressure, N-terminal pro-brain natriuretic peptide levels, presence of multivessel disease, and left ventricular stroke volume (hazard ratios >=3.5; 95% confidence interval 1.4-13.3; all P<=0.018). In reclassification analysis the addition of PWV to a risk model comprising major clinical prognostic parameters led to a net reclassification improvement of 0.11 (95% confidence interval 0.06 0.17; P<0.001). CONCLUSIONS: Increased aortic stiffness is an independent predictor of MACCE after acute ST-elevation myocardial infarction. Moreover, the assessment of aortic stiffness in addition to classical risk factors significantly improved early risk stratification. PMID- 28887315 TI - Inorganic Nitrate in Angina Study: A Randomized Double-Blind Placebo-Controlled Trial. AB - BACKGROUND: In this double-blind randomized placebo-controlled crossover trial, we investigated whether oral sodium nitrate, when added to existing background medication, reduces exertional ischemia in patients with angina. METHODS AND RESULTS: Seventy patients with stable angina, positive electrocardiogram treadmill test, and either angiographic or functional test evidence of significant ischemic heart disease were randomized to receive oral treatment with either placebo or sodium nitrate (600 mg; 7 mmol) for 7 to 10 days, followed by a 2-week washout period before crossing over to the other treatment (n=34 placebo nitrate, n=36 nitrate-placebo). At baseline and at the end of each treatment, patients underwent modified Bruce electrocardiogram treadmill test, modified Seattle Questionnaire, and subgroups were investigated with dobutamine stress, echocardiogram, and blood tests. The primary outcome was time to 1 mm ST depression on electrocardiogram treadmill test. Compared with placebo, inorganic nitrate treatment tended to increase the primary outcome exercise time to 1 mm ST segment depression (645.6 [603.1, 688.0] seconds versus 661.2 [6183, 704.0] seconds, P=0.10) and significantly increased total exercise time (744.4 [702.4, 786.4] seconds versus 760.9 [719.5, 802.2] seconds, P=0.04; mean [95% confidence interval]). Nitrate treatment robustly increased plasma nitrate (18.3 [15.2, 21.5] versus 297.6 [218.4, 376.8] MUmol/L, P<0.0001) and almost doubled circulating nitrite concentrations (346 [285, 405] versus 552 [398, 706] nmol/L, P=0.003; placebo versus nitrate treatment). Other secondary outcomes were not significantly altered by the intervention. Patients on antacid medication appeared to benefit less from nitrate supplementation. CONCLUSIONS: Sodium nitrate treatment may confer a modest exercise capacity benefit in patients with chronic angina who are taking other background medication. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02078921. EudraCT number: 2012-000196-17. PMID- 28887317 TI - Biomarker-Stratified Phase III Clinical Trials: Enhancement with a Subgroup Focused Sequential Design. AB - Among various design approaches to phase III clinical trials with a predictive biomarker, the marker-stratified all-comers design is advantageous because it allows for establishing the utility of both treatment and biomarker, but it is often criticized for requiring large sample sizes, as the design includes both marker-positive and marker-negative patients. In this article, we propose a simple but flexible subgroup-focused design for marker-stratified trials that allow both sequential assessment across marker-defined subgroups and adaptive subgroup selection while retaining an assessment using the entire patient cohort at the final analysis stage, possibly using established marker-based multiple testing procedures. Numerical evaluations indicate that the proposed marker stratified design has a robustness property in preserving statistical power for detecting various profiles of treatment effects across the subgroups while effectively reducing the number of randomized patients in the marker-negative subgroup with presumably limited treatment efficacy. In contrast, the traditional all-comers and sequential enrichment designs could suffer from low statistical power for some possible profiles of treatment effects. The latter also needs long study durations and a large number of marker-screened patients. We also provide an application to SWOG S0819, a trial to assess the role of cetuximab in treating non-small cell lung cancers. These evaluations indicate that the proposed subgroup-focused approach can enhance the efficiency of the marker-stratified design for definitive evaluation of treatment and biomarker in phase III clinical trials. Clin Cancer Res; 24(5); 994-1001. (c)2017 AACR. PMID- 28887318 TI - UbcD1 regulates Hedgehog signaling by directly modulating Ci ubiquitination and processing. AB - The Hh pathway controls many morphogenetic processes in metazoans and plays important roles in numerous pathologies and in cancer. Hh signaling is mediated by the activity of the Gli/Ci family of transcription factors. Several studies in Drosophila have shown that ubiquitination by the ubiquitin E3 ligases Slimb and Rdx(Hib) plays a crucial role in controlling Ci stability dependent on the levels of Hh signals. If Hh levels are low, Slimb adds K11- and K48-linked poly ubiquitin chains on Ci resulting in partial degradation. Ubiquitin E2 enzymes are pivotal in determining the topologies of ubiquitin chains. However, which E2 enzymes participate in the selective ubiquitination-degradation of Ci remains elusive. Here, we find that the E2 enzyme UbcD1 negatively regulates Hh signaling activity in Drosophila wing disks. Genetic and biochemical analyses in wing disks and in cultured cells reveal that UbcD1 directly controls Ci stability. Interestingly, UbcD1 is found to be selectively involved in Slimb-mediated Ci degradation. Finally, we show that the homologs of UbcD1 play a conserved role in modulating Hh signaling in vertebrates. PMID- 28887319 TI - Cold stress-induced ferroptosis involves the ASK1-p38 pathway. AB - A wide variety of cell death mechanisms, such as ferroptosis, have been proposed in mammalian cells, and the classification of cell death attracts global attention because each type of cell death has the potential to play causative roles in specific diseases. However, the precise molecular mechanisms leading to cell death are poorly understood, particularly in ferroptosis. Here, we show that continuous severe cold stress induces ferroptosis and the ASK1-p38 MAPK pathway in multiple cell lines. The activation of the ASK1-p38 pathway is mediated by critical determinants of ferroptosis: MEK activity, iron ions, and lipid peroxide. The chemical compound erastin, a potent ferroptosis inducer, also activates the ASK1-p38 axis downstream of lipid peroxide accumulation and leads to ASK1-dependent cell death in a cell type-specific manner. These lines of evidence provide mechanistic insight into ferroptosis, a type of regulated necrosis. PMID- 28887320 TI - p53 gain-of-function mutations increase Cdc7-dependent replication initiation. AB - Cancer-associated p53 missense mutants confer gain of function (GOF) and promote tumorigenesis by regulating crucial signaling pathways. However, the role of GOF mutant p53 in regulating DNA replication, a commonly altered pathway in cancer, is less explored. Here, we show that enhanced Cdc7-dependent replication initiation enables mutant p53 to confer oncogenic phenotypes. We demonstrate that mutant p53 cooperates with the oncogenic transcription factor Myb in vivo and transactivates Cdc7 in cancer cells. Moreover, mutant p53 cells exhibit enhanced levels of Dbf4, promoting the activity of Cdc7/Dbf4 complex. Chromatin enrichment of replication initiation factors and subsequent increase in origin firing confirm increased Cdc7-dependent replication initiation in mutant p53 cells. Further, knockdown of CDC7 significantly abrogates mutant p53-driven cancer phenotypes in vitro and in vivo Importantly, high CDC7 expression significantly correlates with p53 mutational status and predicts poor clinical outcome in lung adenocarcinoma patients. Collectively, this study highlights a novel functional interaction between mutant p53 and the DNA replication pathway in cancer cells. We propose that increased Cdc7-dependent replication initiation is a hallmark of p53 gain-of-function mutations. PMID- 28887321 TI - LncRNA-PAGBC acts as a microRNA sponge and promotes gallbladder tumorigenesis. AB - Long noncoding RNAs (lncRNAs) play roles in the development and progression of many cancers; however, the contributions of lncRNAs to human gallbladder cancer (GBC) remain largely unknown. In this study, we identify a group of differentially expressed lncRNAs in human GBC tissues, including prognosis associated gallbladder cancer lncRNA (lncRNA-PAGBC), which we find to be an independent prognostic marker in GBC Functional analysis indicates that lncRNA PAGBC promotes tumour growth and metastasis of GBC cells. More importantly, as a competitive endogenous RNA (ceRNA), lncRNA-PAGBC competitively binds to the tumour suppressive microRNAs miR-133b and miR-511. This competitive role of lncRNA-PAGBC is required for its ability to promote tumour growth and metastasis and to activate the AKT/mTOR pathway. Moreover, lncRNA-PAGBC interacts with polyadenylate binding protein cytoplasmic 1 (PABPC1) and is stabilized by this interaction. This work provides novel insight on the molecular pathogenesis of GBC. PMID- 28887324 TI - Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development. AB - Strong epidemiologic evidence documents the protective effect of physical activity on breast cancer risk, recurrence, and mortality, but the underlying mechanisms remain to be identified. Using human exercise-conditioned serum for breast cancer cell incubation studies and murine exercise interventions, we aimed to identify exercise factors and signaling pathways involved in the exercise dependent suppression of breast cancer. Exercise-conditioned serum from both women with breast cancer (n = 20) and healthy women (n = 7) decreased MCF-7 (hormone-sensitive) and MDA-MB-231 (hormone-insensitive) breast cancer cell viability in vitro by 11% to 19% and reduced tumorigenesis by 50% when preincubated MCF-7 breast cancer cells were inoculated into NMRI-Foxn1nu mice. This exercise-mediated suppression of cell viability and tumor formation was completely blunted by blockade of beta-adrenergic signaling in MCF-7 cells, indicating that catecholamines were the responsible exercise factors. Both epinephrine (EPI) and norepinephrine (NE) could directly inhibit breast cancer cell viability, as well as tumor growth in vivo EPI and NE activate the tumor suppressor Hippo signaling pathway, and the suppressive effect of exercise conditioned serum was found to be mediated through phosphorylation and cytoplasmic retention of YAP and reduced expression of downstream target genes, for example, ANKRD1 and CTGF. In parallel, tumor-bearing mice with access to running wheels showed reduced growth of MCF-7 (-36%, P < 0.05) and MDA-MB-231 ( 66%, P < 0.01) tumors and, for the MCF-7 tumor, increased regulation of the Hippo signaling pathway. Taken together, our findings offer a mechanistic explanation for exercise-dependent suppression of breast cancer cell growth. Cancer Res; 77(18); 4894-904. (c)2017 AACR. PMID- 28887322 TI - Kinesin-2 motors adapt their stepping behavior for processive transport on axonemes and microtubules. AB - Two structurally distinct filamentous tracks, namely singlet microtubules in the cytoplasm and axonemes in the cilium, serve as railroads for long-range transport processes in vivo In all organisms studied so far, the kinesin-2 family is essential for long-range transport on axonemes. Intriguingly, in higher eukaryotes, kinesin-2 has been adapted to work on microtubules in the cytoplasm as well. Here, we show that heterodimeric kinesin-2 motors distinguish between axonemes and microtubules. Unlike canonical kinesin-1, kinesin-2 takes directional, off-axis steps on microtubules, but it resumes a straight path when walking on the axonemes. The inherent ability of kinesin-2 to side-track on the microtubule lattice restricts the motor to one side of the doublet microtubule in axonemes. The mechanistic features revealed here provide a molecular explanation for the previously observed partitioning of oppositely moving intraflagellar transport trains to the A- and B-tubules of the same doublet microtubule. Our results offer first mechanistic insights into why nature may have co-evolved the heterodimeric kinesin-2 with the ciliary machinery to work on the specialized axonemal surface for two-way traffic. PMID- 28887326 TI - Interferon-tau and fertility in ruminants. AB - Establishment of pregnancy in domestic ruminants includes pregnancy recognition signalling by the conceptus, implantation and placentation. Despite the high fertilisation success rate in ruminants, a significant amount of embryo loss occurs, primarily during early gestation. Interferon-tau (IFNT), a type I interferon that is exclusively secreted by the cells of the trophectoderm of the ruminant conceptus, has been recognised as the primary agent for maternal recognition of pregnancy in ruminants. It produces its antiluteolytic effect on the corpus luteum by inhibiting the expression of oxytocin receptors in the uterine epithelial cells, which prevents pulsatile, luteolytic secretion of prostaglandin F2alpha by the uterine endometrium. While the importance of IFNT in maternal recognition of pregnancy and prevention of luteolysis in ruminants is unequivocal, important questions, for example, relating to the threshold level of IFNT required for pregnancy maintenance, remain unanswered. This paper reviews data linking IFNT with measures of fertility in ruminants. PMID- 28887325 TI - At least 20% donor myeloid chimerism is necessary to reverse the sickle phenotype after allogeneic HSCT. AB - Novel curative therapies using genetic transfer of normal globin-producing genes into autologous hematopoietic stem cells (HSCs) are in clinical trials for patients with sickle cell disease (SCD). The percentage of transferred globin necessary to cure SCD is currently not known. In the setting of allogeneic nonmyeloablative HSC transplants (HSCTs), stable mixed chimerism is sufficient to reverse the disease. We regularly monitored 67 patients after HSCT. After initially robust engraftment, 3 of these patients experienced declining donor myeloid chimerism (DMC) levels with eventual return of disease. From this we discovered that 20% DMC is necessary to reverse the sickle phenotype. We subsequently developed a mathematical model to test the hypothesis that the percentage of DMC necessary is determined solely by differences between donor and recipient red blood cell (RBC) survival times. In our model, the required 20% DMC can be entirely explained by the large differences between donor and recipient RBC survival times. Our model predicts that the requisite DMC and therefore necessary level of transferred globin is lowest in patients with the highest reticulocyte counts and concomitantly shortened RBC lifespans. PMID- 28887323 TI - ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma. AB - Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of beta-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low beta-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5Ahigh cells decreased Wnt5A and increased beta-catenin. To define the physiologic relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5Ahigh cells were less sensitive to Lys05 and could be reverted by inducing beta-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account. Cancer Res; 77(21); 5873-85. (c)2017 AACR. PMID- 28887328 TI - Experimental evolution in photoautotrophic microorganisms as a means of enhancing chloroplast functions. AB - The term 'experimental evolution' refers to short-term evolutionary experiments with microorganisms under controlled conditions in which selection is expected to occur. In combination with whole-genome sequencing and genetic engineering, the method has become a powerful tool to study evolutionary mechanisms and engineer new microbial variants. It has been most extensively used in the model species Escherichia coli and Saccharomyces cerevisiae, but more recently photosynthetic microorganisms have been subjected to experimental evolution. In such assays, strains were generated that had become more tolerant to certain abiotic environmental factors or evolved new traits during co-propagation with other organisms. These strains were viable under conditions that were lethal to the non adapted progenitor and in a few cases, the causative mutations were identified. Because cyanobacteria like Synechocystis or green algae like Chlamydomonas reinhardtii share many features with crop plants - which are not amenable to such experiments - experimental evolution with photosynthetic microorganisms has the potential to identify novel targets for improving the capacity of plants to acclimate to environmental change. Here, I provide a survey of the experiments performed so far in cyanobacteria and green algae, focusing on Synechocystis and C. reinhardtii, and discuss the promise and the challenges of such approaches. PMID- 28887327 TI - Uterine flushings from women treated with levonorgestrel affect sperm functionality in vitro. AB - Levonorgestrel (LNG), a synthetic 19 nor-testosterone derivative, is widely used for emergency contraception. It is well known that LNG prevents ovulation only when given prior to the surge of serum luteinizing hormone (LH) during the periovulatory phase of the menstrual cycle. This observation suggests that LNG, given its contraceptive efficacy, has additional effects other than those affecting ovulation. In this study, we have evaluated the effects on human sperm functionality of uterine flushings (UF) obtained from women at day LH + 1 of a control cycle (CTR-LH + 1) and after receiving LNG (LNG-LH + 1) two days before the surge of LH. Human sperm from normozoospermic donors were incubated with UF and protein tyrosine phosphorylation, sperm motility, acrosome reaction as well as zona pellucida (ZP) binding capacity were assessed. A significant decrease in total motility and tyrosine phosphorylation accompanied by an increase on spontaneous acrosome reaction was observed when sperm were incubated in the presence of LNG-LH + 1. None of these effects were mimicked by purified glycodelin A (GdA). Moreover, the addition of UF obtained during the periovulatory phase from LNG-treated women or the presence of purified GdA significantly decreased sperm-ZP binding. The data were compatible with changes affecting sperm capacitation, motility and interaction with the ZP. These results may offer evidence on additional mechanisms of action of LNG as an emergency contraceptive. PMID- 28887329 TI - The Abdication of King Edward VIII: a study of estrangement between an adult son and elderly mother. AB - In this article the Abdication of King Edward VIII of Great Britain and his estrangement from the dowager Queen Mary are reconsidered as prototypes of intergenerational conflict arising from a collision of values between an adult child and an elderly mother. Historical materials on the Abdication and other respected secondary sources, including biographies of key individuals, were consulted, and the limited sociological and clinical literature on estrangement between elderly parents and adult children was referenced. Although estrangement was perpetuated by the rigid and incompatible positions taken up by both the former king and his widowed mother, the elderly Queen Mary, it was the latter who suffered the greater emotional consequences of the permanent separation that followed the Abdication. Most accounts of the Abdication have put forward views of the conflict of values at its centre that emphasise the vulnerability of the elderly mother. The clinical narrative supports a characterisation of estrangement as a subtype of bereavement with particular relevance to the geriatric population. PMID- 28887330 TI - Age- and strain-related aberrant Ca2+ release is associated with sudden cardiac death in the ACTC E99K mouse model of hypertrophic cardiomyopathy. AB - Patients with hypertrophic cardiomyopathy, particularly young adults, can die from arrhythmia, but the mechanism underlying abnormal rhythm formation remains unknown. C57Bl6 * CBA/Ca mice carrying a cardiac actin ( ACTC) E99K (Glu99Lys) mutation reproduce many aspects of human hypertrophic cardiomyopathy, including increased myofilament Ca2+ sensitivity and sudden death in a proportion (up to 40%) of young (28-40 day old) animals. We studied the hearts of transgenic (TG; ACTC E99K) mice and their non-TG (NTG) littermates when they were in their vulnerable period (28-40 days old) and when they were adult (8-12 wk old). Ventricular myocytes were isolated from the hearts of TG and NTG mice at these two time points. We also examined the hearts of mice that died suddenly (SCD). SCD animals had approximately four times more collagen compared with age-matched NTG mice, yet myocyte cell size was normal. Young TG mice had double the collagen content of NTG mice. Contraction and Ca2+ transients were greater in cells from young TG mice compared with their NTG littermates but not in cells from adult mice (TG or NTG). Cells from young TG mice had a greater propensity for Ca2+ waves than NTG littermates, and, despite similar sarcoplasmic reticulum Ca2+ content, a proportion of these cells had larger Ca2+ spark mass. We found that the probability of SCD in young TG mice was increased when the mutation was expressed in animals with a CBA/Ca2+ background and almost eliminated in mice bred on a C57Bl6 background. The latter TG mice had normal cellular Ca2+ homeostasis. NEW & NOTEWORTHY Mice with the actin Glu99Lys hypertrophic cardiomyopathy mutation ( ACTC E99K) are prone to sudden cardiac death around 40 days, associated with increased Ca2+ transients, spark mass, and fibrosis. However, adult survivors have normal Ca2+ transients and spark density accompanied by hypertrophy. Penetrance of the sudden cardiac death phenotype depends on the genetic background of the mouse. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/calcium-regulation-in-e99k mouse-heart/ . PMID- 28887332 TI - The cerebrocardiovascular response to periodic squat-stand maneuvers in healthy subjects: a time-domain analysis. AB - Squat-stand maneuvers (SSMs) have been used to improve the coherence of transfer function analysis (TFA) estimates during the assessment of dynamic cerebral autoregulation (dCA). There is a need to understand the influence of peripheral changes resulting from SSMs on cerebral blood flow, which might confound estimates of dCA. Healthy subjects ( n = 29) underwent recordings at rest (5-min standing) and 15 SSMs (0.05 Hz). Heart rate (three-lead ECG), end-tidal CO2 (capnography), blood pressure (Finometer), cerebral blood velocity (CBV; transcranial Doppler, middle cerebral artery), and the angle of the thigh (tilt sensor) were measured continuously. The response of CBV to SSMs was decomposed into the relative contributions of mean arterial pressure (MAP), resistance-area product (RAP), and critical closing pressure (CrCP). Upon squatting, a rise in MAP (83.6 +/- 21.1% contribution) was followed by increased CBV. A dCA response could be detected, determined by adjustments in RAP and CrCP (left hemisphere) with peak contributions of 24.8 +/- 12.7% and 27.4 +/- 22.8%, respectively, at different times during SSMs. No interhemispheric differences were detected. During standing, the contributions of MAP, RAP, and CrCP changed considerably. In conclusion, the changes of CBV subcomponents during repeated SSMs indicate a complex response of CBV to SSMs that can only be partially explained by myogenic mechanisms. More work is needed to clarify the potential contribution of other cofactors, such as breath-to-breath changes in Pco2, heart rate, stroke volume, and the neurogenic component of dCA. NEW & NOTEWORTHY Here, we describe the different contributions to the cerebral blood flow response after squat-stand maneuvers. Furthermore, we demonstrate the complex interaction of peripheral and cerebral parameters for the first time. Moreover, we show that the cerebral blood velocity response to squatting is likely to include a significant metabolic component. PMID- 28887331 TI - Shock and lethality with anthrax edema toxin in rats are associated with reduced arterial responsiveness to phenylephrine and are reversed with adefovir. AB - Although edema toxin (ETx) and lethal toxin (LTx) contribute to Bacillus anthracis shock and lethality, the mechanisms underlying their cardiovascular effects are unclear. We have previously shown that ETx but not LTx inhibited phenylephrine-stimulated contraction of aortic rings prepared from healthy rats and that adefovir, a selective inhibitor of ETx cAMP production, blocked this effect. Here, we examined arterial function in rats that received 24-h ETx or LTx infusions. Compared with control rats, ETx reduced mean arterial pressure (MAP) and survival over 48 h (P <= 0.0003) and increased plasma cAMP at 4, 24, and 48 h (P < 0.0001) and nitric oxide (NO) at 24 and 48 h (P <= 0.01). Compared with control animals, at 24- and 48-h phenylephrine stimulation of aortic rings from ETx animals produced decreased maximal contractile force (MCF; P = 0.05 and 0.006) and in vivo phenylephrine infusion in ETx animals produced decreased proportional increases in MAP (P < 0.0001 and P = 0.05). In ETx-treated animals, compared with placebo-treated animals, adefovir treatment prevented all lethality (P = 0.01), increased MAP (P <= 0.0001), decreased plasma and aortic tissue cAMP at 24 and 48 h, respectively (P <= 0.03), and plasma NO at both times (P <= 0.004), and increased phenylephrine-stimulated increases in MCF in aortic rings and MAP in vivo at 48 h (P = 0.02). LTx decreased MAP and survival also, but it did not alter the response to phenylephrine of MCF in aortic rings prepared from LTx animals or of MAP in vivo. In conclusion, in rats, hypotension and lethality are associated with reduced arterial contractile function with ETx but not LTx and adefovir improves ETx-induced hypotension and lethality.NEW & NOTEWORTHY The most important aspects of the present study are the findings that 1) in vivo challenge with anthrax edema but not lethal toxin depresses arterial contractile function measured both ex vivo and in vivo and 2) adefovir inhibits the effects of edema toxin on arterial hypotension and improves survival with lethal dose of edema toxin challenge. PMID- 28887334 TI - New Oregon law lets pharmacists prescribe formulary drugs, devices. PMID- 28887335 TI - FDA approves short-course hepatitis C product. PMID- 28887333 TI - Rapid estrogen receptor-alpha signaling mediated by ERK activation regulates vascular tone in male and ovary-intact female mice. AB - Estrogen has been shown to affect vascular reactivity. Here, we assessed the estrogen receptor-alpha (ERalpha) dependency of estrogenic effects on vasorelaxation via a rapid nongenomic pathway in both male and ovary-intact female mice. We compared the effect of a primary estrogen, 17beta-estradiol (E2) or 4,4',4"-(4-propyl-[1H]pyrazole-1,3,5-triyl)tris-phenol (PPT; selective ERalpha agonist). We found that E2 and PPT induced greater aortic relaxation in female mice than in male mice, indicating ERalpha mediation, which was further validated by using ERalpha antagonism. Treatment with 1,3-bis(4-hydroxyphenyl)-4-methyl-5 [4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP dihydrochloride; ERalpha antagonist) attenuated PPT-mediated vessel relaxation in both sexes. ERalpha-mediated vessel relaxation was further validated by the absence of significant PPT-mediated relaxation in aortas isolated from ERalpha knockout mice. Treatment with a specific ERK inhibitor, PD-98059, reduced E2-induced vessel relaxation in both sexes but to a lesser extent in female mice. Furthermore, PD-98059 prevented PPT-induced vessel relaxation in both sexes. Both E2 and PPT treatment activated ERK as early as 5-10 min, which was attenuated by PD-98059 in aortic tissue, cultured primary vascular smooth muscle cells (VSMCs), and endothelial cells (ECs). Aortic rings denuded of endothelium showed no differences in vessel relaxation after E2 or PPT treatment, implicating a role of ECs in the observed sex differences. Here, our results are unique to show estrogen-stimulated rapid ERalpha signaling mediated by ERK activation in aortic tissue, as well as VSMCs and ECs in vitro, in regulating vascular function by using side-by-side comparisons in male and ovary-intact female mice in response to E2 or PPT. NEW & NOTEWORTHY Here, we assessed the estrogen receptor-alpha dependency of estrogenic effects in vasorelaxation of both male and ovary-intact female mice by performing side-by-side comparisons. Also, we describe the connection between estrogen-stimulated rapid estrogen receptor-alpha signaling and downstream ERK activation in regulating vascular function in male and ovary intact female mice. PMID- 28887336 TI - In Spain, zoo animals boost drug adherence for young children. PMID- 28887338 TI - Asthma clinics combine pediatric care, pharmacy student education. PMID- 28887339 TI - Population health management: Challenges and opportunities for pharmacy. PMID- 28887340 TI - Population health management and the pharmacist's role. PMID- 28887341 TI - Rationale for postgraduate year 2 residencies in ambulatory care. PMID- 28887342 TI - Population health management: Review of concepts and definitions. AB - PURPOSE: The terms population health, population health improvement, and population health management are discussed. SUMMARY: A key concept in defining population health activities is clearly delineating the population(s) of focus. The Institute for Healthcare Improvement's (IHI's) Triple Aim Initiative uses the term population health management to describe the work by healthcare organizations to improve outcomes for individual patients to maximize population health. The National Academy of Medicine favors the term population health improvement and uses this term to describe work to identify and improve aspects of or contributors to population health, expanding the focus beyond traditional healthcare delivery systems. As organizations like IHI and the National Academy of Medicine continue to focus on population health, the terms and definitions used to describe these activities will continue to evolve. CONCLUSION: The use of consistent, clear definitions for population health activities is critical to the practice of pharmacy and healthcare delivery. PMID- 28887343 TI - Population health and medicine: Policy and financial drivers. AB - PURPOSE: The financial and policy levers of population health and potential opportunities for pharmacists are described. SUMMARY: Three long-standing problems drive the focus on population health: (1) the United States suffers far worse population health outcomes compared with those of other developed nations that spend significantly less on healthcare, (2) the U.S. healthcare system's focus on "sick care" fails to address upstream prevention and population health improvement, and (3) financial incentives for healthcare delivery are poorly aligned with improvements in population health outcomes. The Patient Protection and Affordable Care Act of 2010 (ACA) was arguably the first major healthcare legislation since 1965 and had 3 main strategies for improving population health: expand health insurance coverage, control healthcare costs, and improve the healthcare delivery system. Federal and state legislation as well as Medicare and Medicaid financing strategies have designated mechanisms to reward advances in population outcomes since the passage of the ACA. States are responsible for many of the factors that affect population health, and a bipartisan effort that builds upon state and federal collaboration will likely be needed to implement the necessary health policy initiative. Population health issues affect productivity in the United States; conversely, improvements in population health may increase productivity, helping to offset the rising federal debt. Employers are in a position to improve population health and consequently help reduce the federal debt by addressing lifestyle, chronic disease, poverty, and inequality. National pharmacy organizations, regulatory bodies, and journal editors need to collectively agree to a threshold of quality and rigor for publication and endorsement. CONCLUSION: Knowledge of the policy and financial drivers of population health may both support pharmacists' efforts to improve population outcomes and identify opportunities for professional advancement. PMID- 28887344 TI - Medication therapy disease management: Geisinger's approach to population health management. AB - PURPOSE: Pharmacists' involvement in a population health initiative focused on chronic disease management is described. SUMMARY: Geisinger Health System has cultivated a culture of innovation in population health management, as highlighted by its ambulatory care pharmacy program, the Medication Therapy Disease Management (MTDM) program. Initiated in 1996, the MTDM program leverages pharmacists' pharmacotherapy expertise to optimize care and improve outcomes. MTDM program pharmacists are trained and credentialed to manage over 16 conditions, including atrial fibrillation (AF) and multiple sclerosis (MS). Over a 15-year period, Geisinger Health Plan (GHP)-insured patients with AF whose warfarin therapy was managed by the MTDM program had, on average, 18% fewer emergency department (ED) visits and 18% fewer hospitalizations per year than GHP enrollees with AF who did not receive MTDM services, with 23% lower annual total care costs. Over a 2-year period, GHP-insured patients with MS whose pharmacotherapy was managed by pharmacists averaged 28% fewer annual ED visits than non-pharmacist-managed patients; however, the mean annual total care cost was 21% higher among MTDM clinic patients. CONCLUSION: The Geisinger MTDM program has evolved over 20 years from a single pharmacist-run anticoagulation clinic into a large program focused on managing the health of an ever-growing population. Initial challenges in integrating pharmacists into the Geisinger patient care framework as clinical experts were overcome by demonstrating the MTDM program's positive impact on patient outcomes. PMID- 28887345 TI - Design and implementation of population-based specialty care programs. AB - PURPOSE: The development, implementation, and scaling of 3 population-based specialty care programs in a large integrated healthcare system are reviewed, and the role of clinical pharmacy services in ensuring safe, effective, and affordable care is highlighted. SUMMARY: The Kaiser Permanente (KP) integrated healthcare delivery model allows for rapid development and expansion of innovative population management programs involving pharmacy services. Clinical pharmacists have assumed integral roles in improving the safety and effectiveness of high-complexity, high-cost care for specialty populations. These roles require an appropriate practice scope and are supported by an advanced electronic health record with disease registries and electronic surveillance tools for care-gap identification. The 3 specialty population programs described were implemented to address variation or unrecognized gaps in care for at-risk specialty populations. The Home Phototherapy Program has leveraged internal partnerships with clinical pharmacists to improve access to cost-effective nonpharmacologic interventions for psoriasis and other skin disorders. The Multiple Sclerosis Care Program has incorporated clinical pharmacists into neurology care in order to apply clinical guidelines in a systematic manner. The KP SureNet program has used clinical pharmacists and data analytics to identify opportunities to prevent drug-related adverse outcomes and ensure timely follow-up. CONCLUSION: Specialty care programs improve quality, cost outcomes, and the patient experience by appropriating resources to provide systematic and targeted care to high-risk patients. KP leverages an integration of people, processes, and technology to develop and scale population-based specialty care. PMID- 28887346 TI - Leveraging electronic medical record data for population health management in the Veterans Health Administration: Successes and lessons learned. AB - PURPOSE: The process and operational elements to establish a population health program using electronic medical record data in a Veterans Health Administration region are described. SUMMARY: Pharmacists are uniquely qualified to assume important roles in population health through the use of their clinical knowledge, assisted by electronic tools that consolidate and report patient-specific data for clinical care. Veterans Integrated Services Network (VISN) 21 has developed 300 dashboards and reports to improve the quality, safety, and value of healthcare to veterans. Within a group of specialty task forces, physicians, nurses, and pharmacists assist in the design and development of evidence-based tools to leverage timely electronic health information into metrics, benchmarks, and targets to assist with goal achievement. Examples of programs designed to improve care in 3 areas were selected for further description and review of outcomes. Population health improvement using Healthcare Effectiveness Data and Information Set and hepatitis C metrics were used to describe populations that may have an indication for evidence-based care but are not receiving it. Deprescribing efforts are described, as are medication safety monitoring efforts to prevent potential adverse events known to be associated with therapy. CONCLUSION: Quality, safety, and value outcomes are the measures of success for population health programs in VISN 21. Data-rich project dashboards and reports are developed by pharmacist data analysts and implemented and used by teams of clinicians who provide continuous feedback and support to improve population health. The use of task forces, metrics, benchmarks, targets, and teams is instrumental in the successful application of these tools. PMID- 28887347 TI - Pharmacists supporting population health in patient-centered medical homes. AB - PURPOSE: The integral role of pharmacists in supporting population health initiatives in the patient-centered medical home (PCMH) model of care is described. SUMMARY: Population health initiatives focus on the health outcomes of a group of patients; in the PCMH model, such groups of patients, known as panels, may be defined as patients assigned to a care team or provider. The basic characteristics of the PCMH model include physician-led, team-based practice; coordinated and integrated care within the PCMH and in the patient's community; provision of safe, evidence-based, high-quality care; incorporation of health information technology and continuous quality improvement strategies into panel identification, documentation, and care processes; improved access to care (e.g., through expanded scheduling and innovative communication methods); and value based payments for participating healthcare professionals. Pharmacists can assist in management of patient panels to help achieve quality and performance metrics through activities typically including comprehensive medication reviews, identification of medication-related problems, and development of care plans and individualized treatment goals. Pharmacists practicing in PCMH settings focus on evaluating and optimizing medication regimens, including therapy initiation and dosage adjustment, to achieve targeted therapeutic outcomes and prevent adverse events. Pharmacists' role in population health management varies according to the PCMH characteristics and setting. CONCLUSION: Pharmacists support population health in the PCMH by improving medication use, quality, and safety. Pharmacists' impact on PCMH quality measures and health outcomes of their patient panels should continue to be evaluated. PMID- 28887348 TI - Population health management in a small health system: Impact of controlled substance stewardship in a patient-centered medical home. AB - PURPOSE: The success of a patient-centered medical home in providing population health management (PHM) services through controlled substance stewardship is described. SUMMARY: In 2013, Penobscot Community Health Care (PCHC), in Bangor, Maine, was fully engulfed in the prescription opioid crisis. At PCHC, patients' opioid doses were startlingly high. Within the organization, measures to ensure that prescriptions were being used as prescribed, and not diverted, were underutilized. PCHC responded to these challenges by developing a comprehensive approach to controlled substance stewardship, defined as a coordinated effort to promote the appropriate use of controlled substances, improve patient outcomes, reduce misuse and abuse, and decrease patient morbidity and mortality attributed to these high-risk medications. Since the establishment of the program, over 1,300 patient reviews have been conducted. During this time, the number of PCHC patients receiving chronic opioids has decreased by 67.2% and continues to drop, with a corresponding 65.6% decrease in the number of patients receiving benzodiazepines. Premature deaths were reviewed to identify associations with opioids prescribed at the time of death, which revealed a decline of 50% between 2013 and 2015. Since program inception, the reviews conducted based on internal quality-improvement reports have been expanded to include patients on combinations of opioids and benzodiazepines, high-dose opioids, and carisoprodol. CONCLUSION: Systematic approaches addressing areas of critical need in high-risk populations are integral to PHM efforts in small health systems. The pharmacy team can serve a unique role in identifying, developing, and implementing key PHM services. Coupled with strategic community partnerships, successful PHM integration can assist in the financial survival of small health systems. PMID- 28887349 TI - Population health management: An independent physician organization approach. AB - PURPOSE: The role of clinical pharmacists and their impact on population health and value-based contracts within a multidisciplinary care management team are described. SUMMARY: The Greater Rochester Independent Practice Association (GRIPA) has promoted high-quality, value-based care since its foundation 20 years ago. One of several ways that GRIPA enables its physicians to succeed in shared savings agreements is by providing a community-based multidisciplinary care management team. The multidisciplinary team's primary goal is to help physicians manage the care of their most costly and complex patients. In addition, clinical pharmacists concentrate on lowering the amount of money spent on medications. The outcome goals for this team include (1) reducing hospitalizations, emergency room visits, and the use of unnecessary or inappropriate medications and (2) improving medication adherence and other measurable outcomes. Care management provided by clinical pharmacists for patients meeting GRIPA's high-risk criteria (>=2 inpatient or >=3 emergency room visits in the 12 months before care management engagement) between 2013 and August 2015 resulted in a 42% decrease in 30-day readmissions, a 45% decrease in hospital admissions, a 16% decrease in emergency room visits, and a 20% decrease in annual medical charges. Through individualized pharmacy reviews and a unique approach to managing high-cost drugs, the clinical pharmacists at GRIPA have been successful in reducing hospitalizations and emergency room visits as well as promoting appropriate use of medications while reducing pharmacy waste. CONCLUSION: As part of a multidisciplinary team, clinical pharmacists are able to optimize medication use and engage patients and physicians to reduce medical and medication costs for contracted patients. PMID- 28887350 TI - Institutional care paths: Development, implementation, and evaluation. AB - PURPOSE: The Cleveland Clinic experience with care paths, including their creation and implementation, challenges overcome during development and testing, and outcomes of selected care path evaluations, is described. SUMMARY: Care paths are tools to assist healthcare professionals in practicing evidence-based medicine. The Cleveland Clinic health system has implemented or is developing approximately 100 care paths, including care paths designed to optimize management of sepsis and septic shock and to promote timely use of i.v. tissue plasminogen activator and correct dosing of antithrombotics and statins in patients with stroke. Key steps in successful care path initiatives include (1) identifying key stakeholders, (2) achieving stakeholder consensus on a standardized approach to disease or condition management, (3) cultivating provider awareness of care paths, (4) incorporating care path tools into the electronic health record and workflow processes, and (5) securing the resources to develop, implement, and maintain care paths. Electronic health records facilitate the use of and adherence to care paths. After care path implementation, revisions are typically needed due to unexpected issues not initially identified and to optimize care path features and support resources for clinical practice. Ongoing evaluation is required to determine whether an implemented care path is producing the intended patient and quality performance outcomes. CONCLUSION: Care paths provide a standardized approach to treatment or prevention of a disease or condition, reducing unnecessary variability and expense while promoting optimal, cost-effective patient care. PMID- 28887351 TI - Using predictive analytics and big data to optimize pharmaceutical outcomes. AB - PURPOSE: The steps involved, the resources needed, and the challenges associated with applying predictive analytics in healthcare are described, with a review of successful applications of predictive analytics in implementing population health management interventions that target medication-related patient outcomes. SUMMARY: In healthcare, the term big data typically refers to large quantities of electronic health record, administrative claims, and clinical trial data as well as data collected from smartphone applications, wearable devices, social media, and personal genomics services; predictive analytics refers to innovative methods of analysis developed to overcome challenges associated with big data, including a variety of statistical techniques ranging from predictive modeling to machine learning to data mining. Predictive analytics using big data have been applied successfully in several areas of medication management, such as in the identification of complex patients or those at highest risk for medication noncompliance or adverse effects. Because predictive analytics can be used in predicting different outcomes, they can provide pharmacists with a better understanding of the risks for specific medication-related problems that each patient faces. This information will enable pharmacists to deliver interventions tailored to patients' needs. In order to take full advantage of these benefits, however, clinicians will have to understand the basics of big data and predictive analytics. CONCLUSION: Predictive analytics that leverage big data will become an indispensable tool for clinicians in mapping interventions and improving patient outcomes. PMID- 28887352 TI - A Single Amino Acid Substitution in the Third Transmembrane Region Has Opposite Impacts on the Selectivity of the Parasiticides Fluralaner and Ivermectin for Ligand-Gated Chloride Channels. AB - Fluralaner (Bravecto) is a recently marketed isoxazoline ectoparasiticide. This compound potently inhibits GABA-gated chloride channels (GABACls) and less potently glutamate-gated chloride channels (GluCls) in insects. The mechanism underlying this selectivity is unknown. Therefore, we sought to identify the amino acid residues causing the low potency of fluralaner toward GluCls. We examined the fluralaner sensitivity of mutant housefly (Musca domestica) GluCls in which amino acid residues in the transmembrane subunit interface were replaced with the positionally equivalent amino acids of Musca GABACls. Of these amino acids, substitution of an amino acid (Leu315) in the third transmembrane region (TM3) with an aromatic amino acid dramatically enhanced the potency of fluralaner in the GluCls. In stark contrast to the enhancement of fluralaner potency, this mutation eliminated the activation of currents and the potentiation but not the antagonism of glutamate responses that are otherwise all elicited by the macrolide parasiticide ivermectin (IVM). Our findings indicate that the amino acid Leu315 in Musca GluCls plays significant roles in determining the selectivity of fluralaner and IVM for these channels. Given the high sequence similarity of TM3, this may hold true more widely for the GluCls and GABACls of other insect species. PMID- 28887358 TI - First-Ever CAR T-cell Therapy Approved in U.S. AB - The first chimeric antigen receptor T-cell therapy, tisagenlecleucel, received FDA approval for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia who haven't responded to standard therapy or who have relapsed at least twice. PMID- 28887359 TI - Wearing humanism on your sleeve. PMID- 28887353 TI - A Nucleus-Localized Long Non-Coding RNA Enhances Drought and Salt Stress Tolerance. AB - Long noncoding RNAs (lncRNAs) affect gene expression through a wide range of mechanisms and are considered as important regulators in many essential biological processes. A large number of lncRNA transcripts have been predicted or identified in plants in recent years. However, the biological functions for most of them are still unknown. In this study, we identified an Arabidopsis (Arabidopsis thaliana) lncRNA, DROUGHT INDUCED lncRNA (DRIR), as a novel positive regulator of the plant response to drought and salt stress. DRIR was expressed at a low level under nonstress conditions but can be significantly activated by drought and salt stress as well as by abscisic acid (ABA) treatment. We identified a T-DNA insertion mutant, drirD , which had higher expression of the DRIR gene than the wild-type plants. The drirD mutant exhibits increased tolerance to drought and salt stress. Overexpressing DRIR in Arabidopsis also increased tolerance to drought and salt stress of the transgenic plants. The drirD mutant and the overexpressing seedlings are more sensitive to ABA than the wild type in stomata closure and seedling growth. Genome-wide transcriptome analysis demonstrated that the expression of a large number of genes was altered in drirD and the overexpressing plants. These include genes involved in ABA signaling, water transport, and other stress-relief processes. Our study reveals a mechanism whereby DRIR regulates the plant response to abiotic stress by modulating the expression of a series of genes involved in the stress response. PMID- 28887361 TI - Technical Considerations on Phase Mapping for Identification of Atrial Reentrant Activity in Direct- and Inverse-Computed Electrograms. AB - BACKGROUND: Phase mapping has become a broadly used technique to identify atrial reentrant circuits for ablative therapy guidance. This work studies the phase mapping process and how the signal nature and its filtering affect the reentrant pattern characterization in electrogram (EGM), body surface potential mapping, and electrocardiographic imaging signals. METHODS AND RESULTS: EGM, body surface potential mapping, and electrocardiographic imaging phase maps were obtained from 17 simulations of atrial fibrillation, atrial flutter, and focal atrial tachycardia. Reentrant activity was identified by singularity point recognition in raw signals and in signals after narrow band-pass filtering at the highest dominant frequency (HDF). Reentrant activity was dominantly present in the EGM recordings only for atrial fibrillation and some atrial flutter propagations patterns, and HDF filtering allowed increasing the reentrant activity detection from 60% to 70% of time in atrial fibrillation in unipolar recordings and from 0% to 62% in bipolar. In body surface potential mapping maps, HDF filtering increased from 10% to 90% the sensitivity, although provoked a residual false reentrant activity ~30% of time. In electrocardiographic imaging, HDF filtering allowed to increase <=100% the time with detected rotors, although provoked the apparition of false rotors during 100% of time. Nevertheless, raw electrocardiographic imaging phase maps presented reentrant activity just in atrial fibrillation recordings accounting for ~80% of time. CONCLUSIONS: Rotor identification is accurate and sensitive and does not require additional signal processing in measured or noninvasively computed unipolar EGMs. Bipolar EGMs and body surface potential mapping do require HDF filtering to detect rotors at the expense of a decreased specificity. PMID- 28887360 TI - Initial Clinical Experience With a New Automated Antitachycardia Pacing Algorithm: Feasibility and Safety in an Ambulatory Patient Cohort. AB - BACKGROUND: Antitachycardia pacing (ATP) in implantable cardioverter defibrillators (ICD) decreases patient shock burden but has recognized limitations. A new automated ATP (AATP) based on electrophysiological first principles was designed. The study objective was to assess the feasibility and safety of AATP in ambulatory ICD patients. METHODS AND RESULTS: Enrolled patients had dual chamber or cardiac resynchronization therapy ICDs, history of >=1 ICD treated ventricular tachycardias (VT)/ventricular fibrillation episode, or a recorded, sustained monomorphic VT. Detection was set to ventricular fibrillation number of intervals to detect=24/32, VT number of intervals to detect>=16, and a fast VT zone of 240 to 320 ms. AATP prescribed the components and delivery of successive ATP sequences in real time, using the same settings for all patients. ICD datalogs were uploaded every ~3 months, at unscheduled visits, exit, and death. Episodes and adverse events were adjudicated by separate committees. Results were adjusted (generalized estimating equations) for multiple episodes. AATP was downloaded into the ICDs of 144 patients (121 men), aged 67.4+/-11.9 years, left ventricular ejection fraction 33.1+/-13.6% (n=137), and treated 1626 episodes in 49 patients during 14.5+/-5.1 months of follow-up. Datalogs permitted adjudication of 702 episodes, including 669 sustained monomorphic VT, 20 polymorphic VT, 10 supraventricular tachycardia, and 3 malsensing episodes. AATP terminated 39 of 69 (59% adjusted) sustained monomorphic VT in the fast VT zone, 509 of 590 (85% adjusted) in the VT zone, and 6 of 10 in the ventricular fibrillation zone. No supraventricular tachycardias converted to VT or ventricular fibrillation. No anomalous AATP behavior was observed. CONCLUSIONS: The new AATP algorithm safely generated ATP sequences and controlled therapy progression in all zones without need for individualized programing. PMID- 28887362 TI - Resolving Bipolar Electrogram Voltages During Atrial Fibrillation Using Omnipolar Mapping. AB - BACKGROUND: Low-voltage-guided substrate modification is an emerging strategy in atrial fibrillation (AF) ablation. A major limitation to contemporary bipolar electrogram (EGM) analysis in AF is the resultant lower peak-to-peak voltage (Vpp) from variations in wavefront direction relative to electrode orientation and from fractionation and collision events. We aim to compare bipole Vpp with novel omnipolar peak-to-peak voltages (Vmax) in sinus rhythm (SR) and AF. METHODS AND RESULTS: A high-density fixed multielectrode plaque was placed on the epicardial surface of the left atrium in dogs. Horizontal and vertical orientation bipolar EGMs, followed by omnipolar EGMs, were obtained and compared in both SR and AF. Bipole orientation has significant impact on bipolar EGM voltages obtained during SR and AF. In SR, vertical values were on average 66+/ 119% larger than horizontal (P=0.004). In AF, vertical values were on average 31+/-96% larger than horizontal (P=0.07). Omnipole Vmax values were 99.9+/-125% larger than both horizontal (99.9+/-125%; P<0.001) and vertical (41+/-78%; P<0.0001) in SR and larger than both horizontal (76+/-109%; P<0.001) and vertical (52+/-70%; P value <0.0001) in AF. Vector field analysis of AF wavefronts demonstrates that omnipolar EGMs can account for collision and fractionation and record EGM voltages unaffected by these events. CONCLUSIONS: Omnipolar EGMs can extract maximal voltages from AF signals which are not influenced by directional factors, collision or fractionation, compared with contemporary bipolar techniques. PMID- 28887364 TI - Optimizing Antitachycardia Pacing: Back to the Roots. PMID- 28887363 TI - Rotors: How Do We Know When They Are Real? PMID- 28887365 TI - Omnipolar Mapping: A Method to Improve the Fidelity of Voltage Mapping to Guide Substrate-Based Atrial Fibrillation Ablation? PMID- 28887366 TI - Clearance Prediction Methodology Needs Fundamental Improvement: Trends Common to Rat and Human Hepatocytes/Microsomes and Implications for Experimental Methodology. AB - Although prediction of clearance using hepatocytes and liver microsomes has long played a decisive role in drug discovery, it is widely acknowledged that reliably accurate prediction is not yet achievable despite the predominance of hepatically cleared drugs. Physiologically mechanistic methodology tends to underpredict clearance by several fold, and empirical correction of this bias is confounded by imprecision across drugs. Understanding the causes of prediction uncertainty has been slow, possibly reflecting poor resolution of variables associated with donor source and experimental methods, particularly for the human situation. It has been reported that among published human hepatocyte predictions there was a tendency for underprediction to increase with increasing in vivo intrinsic clearance, suggesting an inherent limitation using this particular system. This implied an artifactual rate limitation in vitro, although preparative effects on cell stability and performance were not yet resolved from assay design limitations. Here, to resolve these issues further, we present an up-to-date and comprehensive examination of predictions from published rat as well as human studies (where n = 128 and 101 hepatocytes and n = 71 and 83 microsomes, respectively) to assess system performance more independently. We report a clear trend of increasing underprediction with increasing in vivo intrinsic clearance, which is similar both between species and between in vitro systems. Hence, prior concerns arising specifically from human in vitro systems may be unfounded and the focus of investigation in the future should be to minimize the potential in vitro assay limitations common to whole cells and subcellular fractions. PMID- 28887367 TI - Tfr cells lack IL-2Ralpha but express decoy IL-1R2 and IL-1Ra and suppress the IL 1-dependent activation of Tfh cells. AB - Follicular regulatory T (Tfr) cells from lymph node germinal centers control follicular helper T (Tfh) cell-dependent B cell activation. These scarce cells, often described and purified as CD25+ cells, are thought to be derived from thymic regulatory T (Treg) cells. However, we observed that mouse Tfr cells do not respond to interleukin-2 (IL-2), unlike Treg cells. Stringent immunophenotyping based on B cell lymphoma 6 (Bcl6), programmed cell death protein 1 (PD-1), and CXCR5 expression revealed that Tfr cells are actually CD25 , in mice and humans. Moreover, Tfr cell characterization based only on CXCR5 and PD-1 high expression without excluding CD25+ cells resulted in contamination with Treg cells. Transcriptome studies of CD4+CXCR5+PD-1+Bcl6+Foxp3+CD25- Tfr cells revealed that they express the IL-1 decoy receptor IL-1R2 and the IL-1 receptor antagonist IL-1Ra, whereas Tfh cells express the IL-1R1 agonist receptor. IL-1 treatment expanded Tfh cells in vivo and activated their production of IL-4 and IL-21 in vitro. Tfr cells suppressed the IL-1-induced activation of Tfh cells as efficiently as the IL-1 receptor antagonist Anakinra. Altogether, these results reveal an IL-1 axis in the Tfh cell control of B cell responses and an IL-2/IL-1 dichotomy for Treg cell control of effector T cells versus Tfr cell control of Tfh cells. PMID- 28887368 TI - Segment-specific responses of intestinal epithelium transcriptome to in-feed antibiotics in pigs. AB - Despite widespread use of antibiotics for treatment of human diseases and promotion of growth of agricultural animals, our understanding of their effects on the host is still very limited. We used a model in which pigs were fed with or without a cocktail of antibiotics and found, based on the denaturing gradient gel electrophoresis (DGGE) patterns, that the fecal bacteria from the treatment and control animals were distinct. Furthermore, the total bacterial population in the feces tended to be decreased by the antibiotic treatment (P = 0.07), and the counts of Lactobacillus and Clostridium XIVa were significantly reduced (P < 0.05). To explore the effects of antibiotics on host intestinal epithelium, we assessed gene expression profiles of the jejunum and ileum and their response to antibiotic administration. The results indicate that in-feed antibiotics increased expression of genes involved in immune functions in both the jejunum and ileum, some of which were clustered in the coexpression network. Gene ontology terms of metabolic processes were altered predominantly in the jejunum but not in the ileum. Notably, antibiotics diminished intestinal segment-specific transcriptional changes, especially for genes associated with metabolic functions. This study reveals segment-specific responses of host intestinal epithelium to in-feed antibiotics, which can be a valuable resource for deciphering antibiotic-microbiota-host interactions. PMID- 28887369 TI - Genetic mechanisms of human hypertension and their implications for blood pressure physiology. AB - Hypertension, or elevated blood pressure, constitutes a major public health burden that affects more than 1 billion people worldwide and contributes to ~9 million deaths annually. Hereditary factors are thought to contribute to up to 50% of interindividual blood pressure variability. Blood pressure in the general population approximately shows a normal distribution and is thought to be a polygenic trait. In rare cases, early-onset hypertension or hypotension are inherited as Mendelian traits. The identification of the underlying Mendelian genes and variants has contributed to our understanding of the physiology of blood pressure regulation, emphasizing renal salt handling and the renin angiotensin aldosterone system as players in the determination of blood pressure. Genome-wide association studies (GWAS) have revealed more than 100 variants that are associated with blood pressure, typically with small effect sizes, which cumulatively explain ~3.5% of blood pressure trait variability. Several GWAS associations point to a role of the vasculature in the pathogenesis of hypertension. Despite these advances, the majority of the genetic contributors to blood pressure regulation are currently unknown; whether large-scale exome or genome sequencing studies will unravel these factors remains to be determined. PMID- 28887370 TI - Genome reprogramming in Saccharomyces cerevisiae upon nonylphenol exposure. AB - Bioaccumulative environmental estrogen, nonylphenol (NP; 4-nonylphenol), is widely used as a nonionic surfactant and can affect human health. Since genomes of Saccharomyces cerevisiae and higher eukaryotes share many structural and functional similarities, we investigated subcellular effects of NP on S. cerevisiae BY4742 cells by analyzing genome-wide transcriptional profiles. We examined effects of low (1 mg/l; <15% cell number reduction) and high (5 mg/l; >65% cell number reduction) inhibitory concentration exposures for 120 or 180 min. After 120 and 180 min of 1 mg/l NP exposure, 187 (63 downregulated, 124 upregulated) and 103 genes (56 downregulated, 47 upregulated), respectively, were differentially expressed. Similarly, 678 (168 repressed, 510 induced) and 688 genes (215 repressed, 473 induced) were differentially expressed in cells exposed to 5 mg/l NP for 120 and 180 min, respectively. Only 15 downregulated and 63 upregulated genes were common between low and high NP inhibitory concentration exposure for 120 min, whereas 16 downregulated and 31 upregulated genes were common after the 180-min exposure. Several processes/pathways were prominently affected by either low or high inhibitory concentration exposure, while certain processes were affected by both inhibitory concentrations, including ion transport, response to chemicals, transmembrane transport, cellular amino acids, and carbohydrate metabolism. While minimal expression changes were observed with low inhibitory concentration exposure, 5 mg/l NP treatment induced substantial expression changes in genes involved in oxidative phosphorylation, cell wall biogenesis, ribosomal biogenesis, and RNA processing, and encoding heat shock proteins and ubiquitin-conjugating enzymes. Collectively, these results provide considerable information on effects of NP at the molecular level. PMID- 28887372 TI - The apolipoprotein C-III (Gln38Lys) variant associated with human hypertriglyceridemia is a gain-of-function mutation. AB - Recent cell culture and animal studies have suggested that expression of human apo C-III in the liver has a profound impact on the triacylglycerol (TAG)-rich VLDL1 production under lipid-rich conditions. The apoC-III Gln38Lys variant was identified in subjects of Mexican origin with moderate hypertriglyceridemia. We postulated that Gln38Lys (C3QK), being a gain-of-function mutation, promotes hepatic VLDL1 assembly/secretion. To test this hypothesis, we expressed C3QK in McA-RH7777 cells and apoc3-null mice to contrast its effect with WT apoC-III (C3WT). In both model systems, C3QK expression increased the secretion of VLDL1 TAG (by 230%) under lipid-rich conditions. Metabolic labeling experiments with C3QK cells showed an increase in de novo lipogenesis (DNL). Fasting plasma concentration of TAG, cholesterol, cholesteryl ester, and FA were increased in C3QK mice as compared with C3WT mice. Liver of C3QK mice also displayed an increase in DNL and expression of lipogenic genes as compared with that in C3WT mice. These results suggest that C3QK variant is a gain-of-function mutation that can stimulate VLDL1 production, through enhanced DNL. PMID- 28887373 TI - Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration. AB - OBJECTIVE: Whereas Alzheimer disease (AD) is associated with inner retina thinning visualized by spectral-domain optical coherence tomography (SD-OCT), we sought to determine if the retina has a distinguishing biomarker for frontotemporal degeneration (FTD). METHODS: Using a cross-sectional design, we examined retinal structure in 38 consecutively enrolled patients with FTD and 44 controls using a standard SD-OCT protocol. Retinal layers were segmented with the Iowa Reference Algorithm. Subgroups of highly predictive molecular pathology (tauopathy, TAR DNA-binding protein 43, unknown) were determined by clinical criteria, genetic markers, and a CSF biomarker (total tau: beta-amyloid) to exclude presumed AD. We excluded eyes with poor image quality or confounding diseases. SD-OCT measures of patients (n = 46 eyes) and controls (n = 69 eyes) were compared using a generalized linear model accounting for intereye correlation, and correlations between retinal layer thicknesses and Mini-Mental State Examination (MMSE) were evaluated. RESULTS: Adjusting for age, sex, and race, patients with FTD had a thinner outer retina than controls (132 vs 142 MUm, p = 0.004). Patients with FTD also had a thinner outer nuclear layer (ONL) (88.5 vs 97.9 MUm, p = 0.003) and ellipsoid zone (EZ) (14.5 vs 15.1 MUm, p = 0.009) than controls, but had similar thicknesses for inner retinal layers. The outer retina thickness of patients correlated with MMSE (Spearman r = 0.44, p = 0.03). The highly predictive tauopathy subgroup (n = 31 eyes) also had a thinner ONL (88.7 vs 97.4 MUm, p = 0.01) and EZ (14.4 vs 15.1 MUm, p = 0.01) than controls. CONCLUSIONS: FTD is associated with outer retina thinning, and this thinning correlates with disease severity. PMID- 28887371 TI - Germline genetic variants with implications for disease risk and therapeutic outcomes. AB - Genetic testing has multiple clinical applications including disease risk assessment, diagnosis, and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care. PMID- 28887374 TI - REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease. AB - OBJECTIVE: To determine whether REM sleep behavior disorder (RBD) in Parkinson disease (PD) is associated with lesions and dysfunctions of the autonomic nervous system by evaluating enteric phosphorylated alpha-synuclein histopathology (PASH) and permeability. METHODS: A total of 45 patients with PD were included in this cross-sectional study. RBD was diagnosed on the basis of a standardized clinical interview and confirmed by polysomnography. For each patient, 5 biopsies were taken at the junction between the sigmoid and descending colon during the course of a rectosigmoidoscopy. For the detection of enteric PASH, 2 colonic biopsies were analyzed by immunohistochemistry with antibodies against phosphorylated alpha-synuclein and PGP9.5 in 43 patients (2 patients were excluded because only 1 biopsy was available). The paracellular permeability and transcellular permeability were evaluated by measuring sulfonic acid and horseradish peroxidase flux, respectively, in the 3 remaining biopsies mounted in Ussing chambers. RESULTS: Enteric PASH was more frequent in the subgroup of patients with PD with RBD compared to patients without RBD (18 of 28, 64.3%, vs 2 of 15, 13.3%, respectively, p < 0.01). No differences were observed in intestinal permeability between patients with PD with and without RBD. CONCLUSIONS: Patients with PD and RBD have a greater frequency of synuclein pathology in the enteric nervous system, suggesting that RBD is associated with widespread synuclein neuropathology. PMID- 28887376 TI - Smoking cessation and secondary stroke prevention. PMID- 28887377 TI - Outcome after stroke thrombolysis in patients >80 years treated within 3 hours vs >3-4.5 hours. AB - OBJECTIVE: To determine outcomes and risks of IV thrombolysis (IVT) in patients with acute ischemic stroke (AIS) >80 years of age within 3 hours compared to >3 to 4.5 hours recorded in the Safe Implementation of Treatment in Stroke (SITS) International Stroke Thrombolysis Registry. METHODS: A total of 14,240 (year 2003 2015) patients >80 years of age with AIS were treated with IVT <=4.5 hours of stroke onset (3,558 in >3-4.5 hours). Of these, 8,658 (2,157 in >3-4.5 hours) were treated otherwise according to the European Summary of Product Characteristics (EU SmPC) criteria for alteplase. Outcomes were 3-month functional independence (modified Rankin Scale score 0-2), mortality, and symptomatic intracerebral hemorrhage (SICH)/SITS. Results were compared between the groups treated in >3 to 4.5 and <=3 hours. RESULTS: Median age was 84 years; 61% were female in both groups. Median NIH Stroke Scale score was 12 vs 14 in the >3- to 4.5- and <=3-hour group, respectively. Three-month functional independence was 34% vs 35% (adjusted odds ratio [aOR] 0.78, 95% confidence interval [CI] 0.69 0.89, p < 0.001); mortality was 31% vs 32% (aOR 1.10, 95% CI 0.97-1.25, p = 0.13); and SICH/SITS was 2.7% vs 1.6% (aOR 1.72, 95% CI 1.25-2.35, p = 0.001). In EU SmPC-compliant patients, 3-month functional independence was 36 vs 37% (aOR 0.79, 95% CI 0.68-0.92, p = 0.002), mortality was 29% vs 29.6% (aOR 1.10, 95% CI 0.95-1.28, p = 0.20), and SICH/SITS was 2.7% vs 1.6% (aOR 1.62, 95% CI 1.12-2.34, p = 0.01). CONCLUSIONS: In this observational study, unselected patients >80 years of age treated with IVT after 3 hours vs earlier had a slightly higher rate of SICH and similar unadjusted functional outcome but poorer adjusted outcome. The absolute difference between the treatment groups is small, and elderly patients should not be denied IVT in the later time window solely because of age without other contraindications. PMID- 28887375 TI - CSF inflammatory response after intraventricular hemorrhage. AB - OBJECTIVE: To investigate the temporal pattern and relevant associations of CSF inflammatory measures after intraventricular hemorrhage (IVH). METHODS: We analyzed prospectively collected CSF cell counts and protein and glucose levels from participants in the Clot Lysis Evaluation of Accelerated Resolution of IVH phase III (CLEAR III) trial. Corrected leukocyte count and cell index were calculated to adjust for CSF leukocytes attributable to circulating blood. Data were chronologically plotted. CSF inflammatory measures (daily, mean, median, maximum, and cases with highest quartile response) were correlated with initial IVH volume, IVH clearance rate, thrombolytic treatment, bacterial infection, and adjudicated clinical outcome at 30 and 180 days. RESULTS: A total of 11,376 data points of CSF results from 464 trial participants were analyzed. Measures of CSF inflammatory response evolved during the resolution of IVH. This was significantly more pronounced with initial IVH volume exceeding 20 mL. Intraventricular alteplase was associated with a significantly augmented inflammatory response compared to saline, even after correcting for initial IVH volume. There was an association but nonpredictive correlation of CSF inflammation measures with culture-positive CSF bacterial infection. None of the CSF inflammatory measures, including cases with upper quartile inflammatory response, was associated with a significant detrimental effect on 30 or 180 days functional outcome or mortality after multivariate adjustment for measures of disease severity. CONCLUSIONS: Aseptic CSF inflammation after IVH is primarily dependent on the volume of initial bleed. Thrombolysis intensifies the inflammatory response, with no apparent detrimental effect on clinical outcome. CLINICALTRIALSGOV IDENTIFIER: NCT00784134. PMID- 28887379 TI - A Comprehensive, Open-source Platform for Mass Spectrometry-based Glycoproteomics Data Analysis. AB - Glycosylation is among the most abundant and diverse protein post-translational modifications (PTMs) identified to date. The structural analysis of this PTM is challenging because of the diverse monosaccharides which are not conserved among organisms, the branched nature of glycans, their isomeric structures, and heterogeneity in the glycan distribution at a given site. Glycoproteomics experiments have adopted the traditional high-throughput LC-MSn proteomics workflow to analyze site-specific glycosylation. However, comprehensive computational platforms for data analyses are scarce. To address this limitation, we present a comprehensive, open-source, modular software for glycoproteomics data analysis called GlycoPAT (GlycoProteomics Analysis Toolbox; freely available from www.VirtualGlycome.org/glycopat). The program includes three major advances: (1) "SmallGlyPep," a minimal linear representation of glycopeptides for MSn data analysis. This format allows facile serial fragmentation of both the peptide backbone and PTM at one or more locations. (2) A novel scoring scheme based on calculation of the "Ensemble Score (ES)," a measure that scores and rank-orders MS/MS spectrum for N- and O-linked glycopeptides using cross-correlation and probability based analyses. (3) A false discovery rate (FDR) calculation scheme where decoy glycopeptides are created by simultaneously scrambling the amino acid sequence and by introducing artificial monosaccharides by perturbing the original sugar mass. Parallel computing facilities and user-friendly GUIs (Graphical User Interfaces) are also provided. GlycoPAT is used to catalogue site-specific glycosylation on simple glycoproteins, standard protein mixtures and human plasma cryoprecipitate samples in three common MS/MS fragmentation modes: CID, HCD and ETD. It is also used to identify 960 unique glycopeptides in cell lysates from prostate cancer cells. The results show that the simultaneous consideration of peptide and glycan fragmentation is necessary for high quality MSn spectrum annotation in CID and HCD fragmentation modes. Additionally, they confirm the suitability of GlycoPAT to analyze shotgun glycoproteomics data. PMID- 28887380 TI - Proteomic Signature Reveals Modulation of Human Macrophage Polarization and Functions Under Differing Environmental Oxygen Conditions. AB - Macrophages are innate immune cells which can react to a large number of environmental stimuli thanks to a high degree of plasticity. These cells are involved in a variety of tissue functions in homeostasis, and they play essential roles in pathological contexts. Macrophages' activation state, which determines their functional orientation, is strongly influenced by the cellular environment. A large body of macrophage literature is devoted to better defining polarizations from a molecular viewpoint. It is now accepted that a multidimensional model of polarization is needed to grasp the broad phenotype repertoire controlled by environmental signals. The study presented here aimed, among other goals, to provide a molecular signature of various polarizations in human macrophages at the protein level to better define the different macrophage activation states. To study the proteome in human monocyte-derived macrophages as a function of their polarization state, we used a label-free quantification approach on in-gel fractionated and LysC/Trypsin digested proteins. In total, 5102 proteins were identified and quantified for all polarization states. New polarization-specific markers were identified and validated. Because oxygen tension is an important environmental parameter in tissues, we explored how environmental oxygen tension, at either atmospheric composition (18.6% O2) or "tissue normoxia" (3% O2), affected our classification of macrophage polarization. The comparative results revealed new polarization-specific makers which suggest that environmental oxygen levels should be taken into account when characterizing macrophage activation states. The proteomic screen revealed various polarization-specific proteins and oxygen sensors in human macrophages. One example is arachidonate 15-lipoxygenase (ALOX15), an IL4/IL13 polarization-specific protein, which was upregulated under low oxygen conditions and is associated with an increase in the rate of phagocytosis of apoptotic cells. These results illustrate the need to consider physicochemical parameters like oxygen level when studying macrophage polarization, so as to correctly assess their functions in tissue. PMID- 28887381 TI - Global Analysis of Membrane-associated Protein Oligomerization Using Protein Correlation Profiling. AB - Membrane-associated proteins are required for essential processes like transport, organelle biogenesis, and signaling. Many are expected to function as part of an oligomeric protein complex. However, membrane-associated proteins are challenging to work with, and large-scale data sets on the oligomerization state of this important class of proteins is missing. Here we combined cell fractionation of Arabidopsis leaves with nondenaturing detergent solubilization and LC/MS-based profiling of size exclusion chromatography fractions to measure the apparent masses of >1350 membrane-associated proteins. Our method identified proteins from all of the major organelles, with more than 50% of them predicted to be part of a stable complex. The plasma membrane was the most highly enriched in large protein complexes compared with other organelles. Hundreds of novel protein complexes were identified. Over 150 proteins had a complicated localization pattern, and were clearly partitioned between cytosolic and membrane-associated pools. A subset of these dual localized proteins had oligomerization states that differed based on localization. Our data set is an important resource for the community that includes new functionally relevant data for membrane-localized protein complexes that could not be predicted based on sequence alone. Our method enables the analysis of protein complex localization and dynamics, and is a first step in the development of a method in which LC/MS profile data can be used to predict the composition of membrane-associated protein complexes. PMID- 28887382 TI - Identification of a Novel Salmonella Type III Effector by Quantitative Secretome Profiling. AB - Salmonella enterica serovar Typhimurium is arguably one of the most studied bacterial pathogens and successful infection requires the delivery of its virulence factors (effectors) directly into host cells via the type III secretion systems (T3SSs). Central to Salmonella pathogenesis, these effector proteins have been subjected to extensive studies over the years. Nevertheless, whether additional effectors exist remains unclear. Here we report the identification of a novel Salmonella T3SS effector STM1239 (which we renamed SopF) via quantitative secretome profiling. Immunoblotting and beta-lactamase reporter assays confirmed the secretion and translocation of SopF in a T3SS-dependent manner. Moreover, ectopic expression of SopF caused significant toxicity in yeast cells. Importantly, genetic ablation of sopF led to Salmonella strains defective in intracellular replication within macrophages and the mutant were also markedly attenuated in a mouse model of infection. Our study underscores the use of quantitative secretome profiling in identifying novel virulence factors for bacterial pathogens. PMID- 28887378 TI - Smoking cessation and outcome after ischemic stroke or TIA. AB - OBJECTIVE: To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. METHODS: We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. RESULTS: At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48 0.90). CONCLUSION: Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort. PMID- 28887383 TI - AtSPX1 affects the AtPHR1-DNA-binding equilibrium by binding monomeric AtPHR1 in solution. AB - Phosphorus is an essential macronutrient for plant growth and is deficient in ~50% of agricultural soils. The transcription factor phosphate starvation response 1 (PHR1) plays a central role in regulating the expression of a subset of phosphate starvation-induced (PSI) genes through binding to a cis-acting DNA element termed P1BS (PHR1-binding sequences). In Arabidopsis and rice, activity of AtPHR1/OsPHR2 is regulated in part by their downstream target SPX (Syg1, Pho81, Xpr1) proteins through protein-protein interaction. Here, we provide kinetic and affinity data for interaction between AtPHR1 and P1BS sites. Using surface plasmon resonance, a tandem P1BS sequence showed ~50-fold higher affinity for MBPAtdPHR1 (a fusion protein comprising the DNA-binding domain and coiled coil domain of AtPHR1 fused to maltose-binding protein) than a single site. The affinity difference was largely reflected in a much slower dissociation rate from the 2* P1BS-binding site, suggesting an important role for protein co operativity. Injection of AtSPX1 in the presence of phosphate or inositol hexakisphosphate (InsP6) failed to alter the MBPAtdPHR1-P1BS dissociation rate, while pre-mixing of these two proteins in the presence of either 5 mM Pi or 500 uM InsP6 resulted in a much lower DNA-binding signal from MBPAtdPHR1. These data suggest that, in the Pi-restored condition, AtSPX1 can bind to monomeric AtPHR1 in solution and therefore regulate PSI gene expression by tuning the AtPHR1-DNA binding equilibrium. This Pi-dependent regulation of AtPHR1-DNA-binding equilibrium also generates a negative feedback loop on the expression of AtSPX1 itself, providing a tight control of PSI gene expression. PMID- 28887384 TI - Constitutive activation of p46JNK2 is indispensable for C/EBPdelta induction in the initial stage of adipogenic differentiation. AB - Adipogenic differentiation plays a vital role in energy homeostasis and endocrine system. Several transcription factors, including peroxisome proliferator activated receptor gamma 2 and CCAAT-enhancer-binding protein (C/EBP) alpha, beta, and delta, are important for the process, whereas the stage-specific intracellular signal transduction regulating the onset of adipogenesis remains enigmatic. Here, we explored the functional role of c-jun N-terminal kinases (JNKs) in adipogenic differentiation using in vitro differentiation models of 3T3 L1 cells and primary adipo-progenitor cells. JNK inactivation with either a pharmacological inhibitor or JNK2-specific siRNA suppressed adipogenic differentiation, characterized by decreased lipid droplet appearance and the down regulation of Adiponectin, fatty acid protein 4 (Fabp4), Pparg2, and C/ebpa expressions. Conversely, increased adipogenesis was observed by the inducible overexpression of p46JNK2 (JNK2-1), whereas it was not observed by that of p54JNK2 (JNK2-2), indicating a distinct role of p46JNK2. The essential role of JNK appears restricted to the early stage of adipogenic differentiation, as JNK inhibition in the later stages did not influence adipogenesis. Indeed, JNK phosphorylation was significantly induced at the onset of adipogenic differentiation. As for the transcription factors involved in early adipogenesis, JNK inactivation significantly inhibited the induction of C/ebpd, but not C/ebpb, during the initial stage of adipogenic differentiation. JNK activation increased C/ebpd mRNA and protein expression through the induction and phosphorylation of activating transcription factor 2 (ATF2) that binds to a responsive element within the C/ebpd gene promoter region. Taken together, these data indicate that constitutive JNK activity is specifically required for the initial stage differentiation events of adipocytes. PMID- 28887385 TI - Prior Learning of Relevant Nonaversive Information Is a Boundary Condition for Avoidance Memory Reconsolidation in the Rat Hippocampus. AB - Reactivated memories can be modified during reconsolidation, making this process a potential therapeutic target for posttraumatic stress disorder (PTSD), a mental illness characterized by the recurring avoidance of situations that evoke trauma related fears. However, avoidance memory reconsolidation depends on a set of still loosely defined boundary conditions, limiting the translational value of basic research. In particular, the involvement of the hippocampus in fear motivated avoidance memory reconsolidation remains controversial. Combining behavioral and electrophysiological analyses in male Wistar rats, we found that previous learning of relevant nonaversive information is essential to elicit the participation of the hippocampus in avoidance memory reconsolidation, which is associated with an increase in theta- and gamma-oscillation power and cross frequency coupling in dorsal CA1 during reactivation of the avoidance response. Our results indicate that the hippocampus is involved in memory reconsolidation only when reactivation results in contradictory representations regarding the consequences of avoidance and suggest that robust nesting of hippocampal theta gamma rhythms at the time of retrieval is a specific reconsolidation marker.SIGNIFICANCE STATEMENT Posttraumatic stress disorder (PTSD) is characterized by maladaptive avoidance responses to stimuli or behaviors that represent or bear resemblance to some aspect of a traumatic experience. Disruption of reconsolidation, the process by which reactivated memories become susceptible to modifications, is a promising approach for treating PTSD patients. However, much of what is known about fear-motivated avoidance memory reconsolidation derives from studies based on fear conditioning instead of avoidance-learning paradigms. Using a step-down inhibitory avoidance task in rats, we found that the hippocampus is involved in memory reconsolidation only when the animals acquired the avoidance response in an environment that they had previously learned as safe and showed that increased theta- and gamma-oscillation coupling during reactivation is an electrophysiological signature of this process. PMID- 28887386 TI - Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis Entry into Central Neurons. AB - Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function.SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction. PMID- 28887387 TI - Neural Architecture of Selective Stopping Strategies: Distinct Brain Activity Patterns Are Associated with Attentional Capture But Not with Outright Stopping. AB - In stimulus-selective stop-signal tasks, the salient stop signal needs attentional processing before genuine response inhibition is completed. Differential prefrontal involvement in attentional capture and response inhibition has been linked to the right inferior frontal junction (IFJ) and ventrolateral prefrontal cortex (VLPFC), respectively. Recently, it has been suggested that stimulus-selective stopping may be accomplished by the following different strategies: individuals may selectively inhibit their response only upon detecting a stop signal (independent discriminate then stop strategy) or unselectively whenever detecting a stop or attentional capture signal (stop then discriminate strategy). Alternatively, the discrimination process of the critical signal (stop vs attentional capture signal) may interact with the go process (dependent discriminate then stop strategy). Those different strategies might differentially involve attention- and stopping-related processes that might be implemented by divergent neural networks. This should lead to divergent activation patterns and, if disregarded, interfere with analyses in neuroimaging studies. To clarify this crucial issue, we studied 87 human participants of both sexes during a stimulus-selective stop-signal task and performed strategy dependent functional magnetic resonance imaging analyses. We found that, regardless of the strategy applied, outright stopping displayed indistinguishable brain activation patterns. However, during attentional capture different strategies resulted in divergent neural activation patterns with variable activation of right IFJ and bilateral VLPFC. In conclusion, the neural network involved in outright stopping is ubiquitous and independent of strategy, while different strategies impact on attention-related processes and underlying neural network usage. Strategic differences should therefore be taken into account particularly when studying attention-related processes in stimulus-selective stopping.SIGNIFICANCE STATEMENT Dissociating inhibition from attention has been a major challenge for the cognitive neuroscience of executive functions. Selective stopping tasks have been instrumental in addressing this question. However, recent theoretical, cognitive and behavioral research suggests that different strategies are applied in successful execution of the task. The underlying strategy-dependent neural networks might differ substantially. Here, we show evidence that, regardless of the strategy used, the neural network involved in outright stopping is ubiquitous. However, significant differences can only be found in the attention-related processes underlying those different strategies. Thus, when studying attentional processing of salient stop signals, strategic differences should be considered. In contrast, the neural networks implementing outright stopping seem less or not at all affected by strategic differences. PMID- 28887388 TI - Minocycline in Acute Cerebral Hemorrhage: An Early Phase Randomized Trial. AB - BACKGROUND AND PURPOSE: Minocycline is under investigation as a neurovascular protective agent for stroke. This study evaluated the pharmacokinetic, anti inflammatory, and safety profile of minocycline after intracerebral hemorrhage. METHODS: This study was a single-site, randomized controlled trial of minocycline conducted from 2013 to 2016. Adults >=18 years with primary intracerebral hemorrhage who could have study drug administered within 24 hours of onset were included. Patients received 400 mg of intravenous minocycline, followed by 400 mg minocycline oral daily for 4 days. Serum concentrations of minocycline after the last oral dose and biomarkers were sampled to determine the peak concentration, half-life, and anti-inflammatory profile. RESULTS: A total of 16 consecutive eligible patients were enrolled, with 8 randomized to minocycline. Although the literature supports a time to peak concentration (Tmax) of 1 hour for oral minocycline, the Tmax was estimated to be at least 6 hours in this cohort. The elimination half-life (available on 7 patients) was 17.5 hours (SD+/-3.5). No differences were observed in inflammatory biomarkers, hematoma volume, or perihematomal edema. Concentrations remained at neuroprotective levels (>3 mg/L) throughout the dosing interval in 5 of 7 patients. CONCLUSIONS: In intracerebral hemorrhage, a 400 mg dose of minocycline was safe and achieved neuroprotective serum concentrations. However, oral administration led to delayed absorption in these critically ill patients and should not be used when rapid, high concentrations are desired. Given the safety and pharmacokinetic profile of minocycline in intracerebral hemorrhage and promising data in the treatment of ischemic stroke, intravenous minocycline is an excellent candidate for a prehospital treatment trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01805895. PMID- 28887389 TI - Response by Jadhav et al to Letter Regarding Article, "Interfacility Transfer Directly to the Neuroangiography Suite in Acute Ischemic Stroke Patients Undergoing Thrombectomy". PMID- 28887390 TI - Response by Aigner et al to Letter Regarding Article, "Contribution of Established Stroke Risk Factors to the Burden of Stroke in Young Adults". PMID- 28887391 TI - Direct Mechanical Thrombectomy Versus Combined Intravenous and Mechanical Thrombectomy in Large-Artery Anterior Circulation Stroke: A Topical Review. PMID- 28887392 TI - Response by Lee and Ovbiagele to Letter Regarding Article, "Antiplatelet Regimen for Patients With Breakthrough Strokes While on Aspirin: A Systematic Review and Meta-Analysis". PMID- 28887394 TI - Letter by Braillon Regarding Article, "Contribution of Established Stroke Risk Factors to the Burden of Stroke in Young Adults". PMID- 28887393 TI - White Matter Hyperintensity Volume and Outcome of Mechanical Thrombectomy With Stentriever in Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Finding of white matter hyperintensity (WMH) has been associated with an increased risk of parenchymal hematoma and poor clinical outcomes after mechanical thrombectomy using old-generation endovascular devices. Currently, no data exist with regard to the risk of mechanical thrombectomy using stentriever devices in patients with significant WMH. We hypothesized that WMH volume will not affect the hemorrhagic and clinical outcome in patients with acute ischemic stroke undergoing thrombectomy using new-generation devices. METHODS: A retrospective cohort of consecutive acute ischemic stroke patients >18 year-old receiving mechanical thrombectomy with stentriever devices at a single academic center was examined. WMH volume was assessed by a semiautomated volumetric analysis on T2 fluid attenuated inversion recovery-magnetic resonance imaging. Outcomes included the rate of any intracerebral hemorrhage, 90-day modified Rankin Score (mRS), the rate of good outcome (discharge mRS <=2), and the rate of successful reperfusion (thrombolysis in cerebral ischemia score 2b or 3). RESULTS: Between June 2012 and December 2015, 56 patients with acute ischemic stroke met the study criteria. Median WMH volume was 6.76 cm3 (4.84-16.09 cm3). Increasing WMH volume did not significantly affect the odds of good outcome (odds ratio [OR], 0.811; 95% confidence interval [CI], 0.456-1.442), intracerebral hemorrhage (OR, 1.055; 95% CI, 0.595-1.871), parenchymal hematoma (OR, 0.353; 95% CI, 0.061-2.057), successful recanalization (OR, 1.295; 95% CI, 0.704-2.383), or death (OR, 1.583; 95% CI, 0.84-2.98). CONCLUSIONS: Mechanical thrombectomy using stentrievers seems to be safe in selected patients with acute ischemic stroke with large vessel occlusion, nonwithstanding the severity of WMH burden in this population. Larger prospective studies are warranted to validate these findings. PMID- 28887395 TI - Letter by Lederer et al Regarding Article, "Interfacility Transfer Directly to the Neuroangiography Suite in Acute Ischemic Stroke Patients Undergoing Thrombectomy". PMID- 28887397 TI - Letter by Spence Regarding Article, "Antiplatelet Regimen for Patients With Breakthrough Strokes While on Aspirin: A Systematic Review and Meta-Analysis". PMID- 28887396 TI - Influence of Penumbral Reperfusion on Clinical Outcome Depends on Baseline Ischemic Core Volume. AB - BACKGROUND AND PURPOSE: In alteplase-treated patients with acute ischemic stroke, we investigated the relationship between penumbral reperfusion at 24 hours and clinical outcomes, with and without adjustment for baseline ischemic core volume. METHODS: Data were collected from consecutive acute ischemic stroke patients with baseline and follow-up perfusion imaging presenting to hospital within 4.5 hours of symptom onset at 7 hospitals. Logistic regression models were used for predicting the effect of the reperfused penumbral volume on the dichotomized modified Rankin Scale (mRS) at 90 days and improvement of National Institutes of Health Stroke Scale at 24 hours, both adjusted for baseline ischemic core volume. RESULTS: This study included 1507 patients. Reperfused penumbral volume had moderate ability to predict 90-day mRS 0 to 1 (area under the curve, 0.77; R2, 0.28; P<0.0001). However, after adjusting for baseline ischemic core volume, the reperfused penumbral volume was a strong predictor of good functional outcome (area under the curve, 0.946; R2, 0.55; P<0.0001). For every 1% increase in penumbral reperfusion, the odds of achieving mRS 0 to 1 at day 90 increased by 7.4%. Improvement in acute 24-hour National Institutes of Health Stroke Scale was also significantly related to the degree of reperfused penumbra (R2, 0.31; P<0.0001). This association was again stronger after adjustment for baseline ischemic core volume (R2, 0.41; P<0.0001). For each 1% of penumbra that was reperfused, the 24-hour National Institutes of Health Stroke Scale decreased by 0.069 compared with baseline. CONCLUSIONS: In patients treated with alteplase, the extent of the penumbra that is reperfused is a powerful predictor of early and late clinical outcomes, particularly when baseline ischemic core is taken into account. PMID- 28887398 TI - 64CuCl2 PET/CT in Prostate Cancer Relapse. AB - Our objective was to evaluate the biodistribution, kinetics, and radiation dosimetry of 64CuCl2 in humans and to assess the ability of 64CuCl2 PET/CT to detect prostate cancer (PCa) recurrence in patients with biochemical relapse. Methods: We prospectively evaluated 50 PCa patients with biochemical relapse after surgery or external-beam radiation therapy. All patients underwent 64CuCl2 PET/CT, 18F-choline PET/CT, and multiparametric MRI within 15 d of each other. Experienced readers interpreted the images, and the detection rate (DR) of each imaging modality was calculated. Histopathology, when available; clinical or laboratory response; and multidisciplinary follow-up were used to confirm the site of disease. In parallel, biodistribution, kinetics of the lesions, and radiation dosimetry of 64CuCl2 were evaluated. Results: From a dosimetric point of view, an administered dose of 200 MBq for 64CuCl2 translated into a 5.7-mSv effective dose. Unlike 18F-choline, 64CuCl2 was not excreted or accumulated in the urinary tract, thus allowing thorough pelvic exploration. The maximum 64CuCl2 uptake at the sites of PCa relapse was observed 1 h after tracer injection. In our cohort, 64CuCl2 PET/CT proved positive in 41 of 50 patients, with an overall DR of 82%. The DRs of 18F-choline PET/CT and multiparametric MRI were 56% and 74%, respectively. The difference between the DRs of 64CuCl2 PET/CT and 18F choline PET/CT was statistically significant (P < 0.001). Interestingly, on considering prostate-specific antigen (PSA) value, 64CuCl2 PET/CT had a higher DR than 18F-choline PET/CT in patients with a PSA of less than 1 ng/mL. Conclusion: The biodistribution of 64CuCl2 is more suitable than that of 18F-choline for exploring the pelvis and prostatic bed. The 64CuCl2 effective dose is like those of other established PET tracers. In patients with biochemical relapse and a low PSA level, 64CuCl2 PET/CT shows a significantly higher DR than 18F-choline PET/CT. PMID- 28887400 TI - RADAR Dose Estimate Report: A Compendium of Radiopharmaceutical Dose Estimates Based on OLINDA/EXM Version 2.0. AB - A compendium of about 100 radiopharmaceuticals, based on the OLINDA/EXM version 2.0 software, is presented. A new generation of voxel-based, realistic human computational phantoms developed by the RADAR committee of the Society of Nuclear Medicine and Molecular Imaging, based on 2007 recommendations of the International Commission on Radiological Protection, was used to develop the dose estimates, and the most recent biokinetic models were used as well. These estimates will be made available in electronic form and can be modified and updated as models are changed and as new radiopharmaceuticals are added. PMID- 28887399 TI - Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1. AB - A semiquantitative 123I-metaiodobenzylguanidine (123I-MIBG) scoring method (the Curie score, or CS) was previously examined in the Children's Oncology Group (COG) high-risk neuroblastoma trial, COG A3973, with a postinduction CS of more than 2 being associated with poor event-free survival (EFS). The validation of the CS in an independent dataset, International Society of Paediatric Oncology European Neuroblastoma/High-Risk Neuroblastoma 1 (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of 123I-MIBG scans obtained from patients who had been prospectively enrolled in SIOPEN/HR-NBL1 was performed. All patients exhibited 123I-MIBG-avid, International Neuroblastoma Staging System stage 4 neuroblastoma. 123I-MIBG scans were evaluated at 2 time points, diagnosis (n = 345) and postinduction (n = 330), before consolidation myeloablative therapy. Scans of 10 anatomic regions were evaluated, with each region being scored 0-3 on the basis of disease extent and a cumulative CS generated. Cut points for outcome analysis were identified by Youden methodology. CSs from patients enrolled in COG A3973 were used for comparison. Results: The optimal cut point for CS at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by CS noted (5-y EFS, 43.0% +/- 5.7% [CS <= 12] vs. 21.4% +/- 3.6% [CS > 12], P < 0.0001). The optimal CS cut point after induction was 2 in SIOPEN/HR NBL1, with a postinduction CS of more than 2 being associated with an inferior outcome (5-y EFS, 39.2% +/- 4.7% [CS <= 2] vs. 16.4% +/- 4.2% [CS > 2], P < 0.0001). The postinduction CS maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number. Conclusion: The prognostic significance of postinduction CSs has now been validated in an independent cohort of patients (SIOPEN/HR-NBL1), with a postinduction CS of more than 2 being associated with an inferior outcome in 2 independent large, cooperative group trials. PMID- 28887401 TI - Proposal for a Structured Reporting System for Prostate-Specific Membrane Antigen Targeted PET Imaging: PSMA-RADS Version 1.0. PMID- 28887403 TI - The functions of Reelin in membrane trafficking and cytoskeletal dynamics: implications for neuronal migration, polarization and differentiation. AB - Reelin is a large extracellular matrix protein with relevant roles in mammalian central nervous system including neurogenesis, neuronal polarization and migration during development; and synaptic plasticity with its implications in learning and memory, in the adult. Dysfunctions in reelin signaling are associated with brain lamination defects such as lissencephaly, but also with neuropsychiatric diseases like autism, schizophrenia and depression as well with neurodegeneration. Reelin signaling involves a core pathway that activates upon reelin binding to its receptors, particularly ApoER2 (apolipoprotein E receptor 2)/LRP8 (low-density lipoprotein receptor-related protein 8) and very low-density lipoprotein receptor, followed by Src/Fyn-mediated phosphorylation of the adaptor protein Dab1 (Disabled-1). Phosphorylated Dab1 (pDab1) is a hub in the signaling cascade, from which several other downstream pathways diverge reflecting the different roles of reelin. Many of these pathways affect the dynamics of the actin and microtubular cytoskeleton, as well as membrane trafficking through the regulation of the activity of small GTPases, including the Rho and Rap families and molecules involved in cell polarity. The complexity of reelin functions is reflected by the fact that, even now, the precise mode of action of this signaling cascade in vivo at the cellular and molecular levels remains unclear. This review addresses and discusses in detail the participation of reelin in the processes underlying neurogenesis, neuronal migration in the cerebral cortex and the hippocampus; and the polarization, differentiation and maturation processes that neurons experiment in order to be functional in the adult brain. In vivo and in vitro evidence is presented in order to facilitate a better understanding of this fascinating system. PMID- 28887404 TI - Flowering Versus Runnering: Uncovering the Protein Behind a Trait That Matters in Strawberry. PMID- 28887402 TI - Detection of long repeat expansions from PCR-free whole-genome sequence data. AB - Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions. PMID- 28887405 TI - Phosphorylation of Phosphoenolpyruvate Carboxylase Is Essential for Maximal and Sustained Dark CO2 Fixation and Core Circadian Clock Operation in the Obligate Crassulacean Acid Metabolism Species Kalanchoe fedtschenkoi. AB - Phosphoenolpyruvate carboxylase (PPC; EC 4.1.1.31) catalyzes primary nocturnal CO2 fixation in Crassulacean acid metabolism (CAM) species. CAM PPC is regulated posttranslationally by a circadian clock-controlled protein kinase called phosphoenolpyruvate carboxylase kinase (PPCK). PPCK phosphorylates PPC during the dark period, reducing its sensitivity to feedback inhibition by malate and thus enhancing nocturnal CO2 fixation to stored malate. Here, we report the generation and characterization of transgenic RNAi lines of the obligate CAM species Kalanchoe fedtschenkoi with reduced levels of KfPPCK1 transcripts. Plants with reduced or no detectable dark phosphorylation of PPC displayed up to a 66% reduction in total dark period CO2 fixation. These perturbations paralleled reduced malate accumulation at dawn and decreased nocturnal starch turnover. Loss of oscillations in the transcript abundance of KfPPCK1 was accompanied by a loss of oscillations in the transcript abundance of many core circadian clock genes, suggesting that perturbing the only known link between CAM and the circadian clock feeds back to perturb the central circadian clock itself. This work shows that clock control of KfPPCK1 prolongs the activity of PPC throughout the dark period in K. fedtschenkoi, optimizing CAM-associated dark CO2 fixation, malate accumulation, CAM productivity, and core circadian clock robustness. PMID- 28887407 TI - Erratum. Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived? Diabetes Care 2017;40:813-820. PMID- 28887406 TI - Maize NPF6 Proteins Are Homologs of Arabidopsis CHL1 That Are Selective for Both Nitrate and Chloride. AB - Nitrate uptake by plant cells requires both high- and low-affinity transport activities. Arabidopsis thaliana nitrate transporter 1/peptide transporter family (NPF) 6.3 is a dual-affinity plasma membrane transport protein that has both high and low-affinity functions. At-NPF6.3 imports and senses nitrate and is regulated by phosphorylation at Thr-101 (T101). A detailed functional analysis of two maize (Zea mays) homologs of At-NPF6.3 (Zm-NPF6.6 and Zm-NPF6.4) showed that Zm-NPF6.6 was a pH-dependent nonbiphasic high-affinity nitrate-specific transport protein. By contrast, maize NPF6.4 was a low-affinity nitrate transporter with efflux activity. When supplied chloride, NPF6.4 switched to a high-affinity chloride selective transporter, while NPF6.6 had only a low-affinity chloride transport activity. Structural predictions identified a nitrate binding His (H362) in NPF6.6 but not in NPF6.4. Mutation of NPF6.4 Tyr-370 to His (Y370H) resulted in saturable high-affinity nitrate transport activity and nitrate selectivity. Loss of H362 in NPF6.6 (H362Y) eliminated both nitrate and chloride transport. Furthermore, alterations to Thr-104, a conserved phosphorylation site in NPF6.6, resulted in a similar high-affinity nitrate transport activity with increased Km, whereas equivalent changes in NPF6.4 (T106) disrupted high-affinity chloride transport activity. NPF6 proteins exhibit different substrate specificity in plants and regulate nitrate transport affinity/selectivity using a conserved His residue. PMID- 28887408 TI - Erratum. Application of Zone Model Predictive Control Artificial Pancreas During Extended Use of Infusion Set and Sensor: A Randomized Crossover-Controlled Home Use Trial. Diabetes Care 2017;40:1096-1102. PMID- 28887409 TI - Longitudinal Change in Fasting Blood Glucose and Myocardial Infarction Risk in a Population Without Diabetes. AB - OBJECTIVE: To examine the change in fasting blood glucose (FBG) during repeated assessments over time and its potential impact on the risk of developing myocardial infarction (MI). RESEARCH DESIGN AND METHODS: This prospective cohort study included 68,297 participants without diabetes (mean age 49 years) who were free of MI, stroke, and cancer prior to or in 2010 (baseline of the current analysis). FBG concentrations were measured in 2006, 2008, and 2010. The FBG trajectories during 2006-2010, the primary exposure of the current study, were identified by latent mixture modeling. Incident MI cases were confirmed via review of medical records by cardiologists. RESULTS: We identified five discrete FBG trajectories according to FBG range and changing pattern over time: elevated stable (n = 3,877), elevated-decreasing (n = 7,060), moderate-increasing (n = 10,298), moderate-stable (n = 40,352), and low-stable (n = 6,710). During 4 years of follow-up, we documented 283 incident MI cases. Relative to the moderate stable pattern (FBG ranged from 4.9 to 5.1 mmol/L), adjusted hazard ratios (HRs) were 1.53 (95% CI 1.04, 2.26) for the elevated-stable pattern (FBG ranged from 6.1 to 6.3 mmol/L) and HR 0.61 (95% CI 0.38, 0.98) for the elevated-decreasing pattern (FBG decreased from 6.0 to 5.4 mmol/L), after adjustment for potential confounders such as age, sex, lifestyle factors, obesity, medical history, blood pressure, blood lipids, and C-reactive protein. Consistently, cumulative average and increasing rate of FBG during 2006-2010, but not a single baseline FBG, predicted future risk of MI. CONCLUSIONS: We found that discrete FBG trajectories were significantly associated with subsequent risk of MI in individuals without diabetes. These observations suggest that long-term trajectories of FBG may be important for risk prediction of MI and possibly other macrovascular diseases. PMID- 28887410 TI - A coarse-grained computational model of the nuclear pore complex predicts Phe-Gly nucleoporin dynamics. AB - The phenylalanine-glycine-repeat nucleoporins (FG-Nups), which occupy the lumen of the nuclear pore complex (NPC), are critical for transport between the nucleus and cytosol. Although NPCs differ in composition across species, they are largely conserved in organization and function. Transport through the pore is on the millisecond timescale. Here, to explore the dynamics of nucleoporins on this timescale, we use coarse-grained computational simulations. These simulations generate predictions that can be experimentally tested to distinguish between proposed mechanisms of transport. Our model reflects the conserved structure of the NPC, in which FG-Nup filaments extend into the lumen and anchor along the interior of the channel. The lengths of the filaments in our model are based on the known characteristics of yeast FG-Nups. The FG-repeat sites also bind to each other, and we vary this association over several orders of magnitude and run 100 ms simulations for each value. The autocorrelation functions of the orientation of the simulated FG-Nups are compared with in vivo anisotropy data. We observe that FG-Nups reptate back and forth through the NPC at timescales commensurate with experimental measurements of the speed of cargo transport through the NPC. Our results are consistent with models of transport where FG-Nup filaments are free to move across the central channel of the NPC, possibly informing how cargo might transverse the NPC. PMID- 28887411 TI - Age-related pacemaker deterioration is due to impaired intracellular and membrane mechanisms: Insights from numerical modeling. AB - Age-related deterioration of pacemaker function has been documented in mammals, including humans. In aged isolated sinoatrial node tissues and cells, reduction in the spontaneous action potential (AP) firing rate was associated with deterioration of intracellular and membrane mechanisms; however, their relative contribution to age-associated deficient pacemaker function is not known. Interestingly, pharmacological interventions that increase posttranslation modification signaling activities can restore the basal and maximal AP firing rate, but the identities of the protein targets responsible for AP firing rate restoration are not known. Here, we developed a numerical model that simulates the function of a single mouse pacemaker cell. In addition to describing membrane and intracellular mechanisms, the model includes descriptions of autonomic receptor activation pathways and posttranslation modification signaling cascades. The numerical model shows that age-related deterioration of pacemaker function is related to impaired intracellular and membrane mechanisms: HCN4, T-type channels, and phospholamban functions, as well as the node connecting these mechanisms, i.e., intracellular Ca2+ and posttranslation modification signaling. To explain the restored maximal beating rate in response to maximal phosphodiesterase (PDE) inhibition, autonomic receptor stimulation, or infused cyclic adenosine monophosphate (cAMP), the model predicts that phospholamban phosphorylation by protein kinase A (PKA) and HCN4 sensitivity to cAMP are altered in advanced age. Moreover, alteration in PKA and cAMP sensitivity can also explain age-reduced sensitivity to PDE inhibition and autonomic receptor stimulation. Finally, the numerical model suggests two pharmacological approaches and one gene manipulation method to restore the basal beating rate of aged pacemaker cells to that of normal adult cells. In conclusion, our numerical model shows that impaired membrane and intracellular mechanisms and the nodes that couple them can lead to deteriorated pacemaker function. By increasing posttranslation modification signaling, the deteriorated basal and maximal age-associated beating rate can be restored to adult levels. PMID- 28887412 TI - Enzymatic modules of the SAGA chromatin-modifying complex play distinct roles in Drosophila gene expression and development. AB - The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex is a transcriptional coactivator that contains four different modules of subunits. The intact SAGA complex has been well characterized for its function in transcription regulation and development. However, little is known about the roles of individual modules within SAGA and whether they have any SAGA-independent functions. Here we demonstrate that the two enzymatic modules of Drosophila SAGA are differently required in oogenesis. Loss of the histone acetyltransferase (HAT) activity blocks oogenesis, while loss of the H2B deubiquitinase (DUB) activity does not. However, the DUB module regulates a subset of genes in early embryogenesis, and loss of the DUB subunits causes defects in embryogenesis. ChIP seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analysis revealed that both the DUB and HAT modules bind most SAGA target genes even though many of these targets do not require the DUB module for expression. Furthermore, we found that the DUB module can bind to chromatin and regulate transcription independently of the HAT module. Our results suggest that the DUB module has functions within SAGA and independent functions. PMID- 28887413 TI - Dynamic assembly and activation of estrogen receptor alpha enhancers through coregulator switching. AB - Although many features of active transcriptional enhancers have been defined by genomic assays, we lack a clear understanding of the order of events leading to enhancer formation and activation as well as the dynamics of coregulator interactions within the enhancer complex. Here, we used selective loss- or gain of-function mutants of estrogen receptor alpha (ERalpha) to define two distinct phases of ligand-dependent enhancer formation. In the first phase (0-20 min), p300 is recruited to ERalpha by Mediator as well as p300's acetylhistone-binding bromodomain to promote initial enhancer formation, which is not competent for sustained activation. In the second phase (20-45 min), p300 is recruited to ERalpha by steroid receptor coregulators (SRCs) for enhancer maturation and maintenance. Successful transition between these two phases ("coregulator switching") is required for proper enhancer function. Failure to recruit p300 during either phase leads to abortive enhancer formation and a lack of target gene expression. Our results reveal an ordered and cooperative assembly of ERalpha enhancers requiring functional interplay among p300, Mediator, and SRCs, which has implications for hormone-dependent gene regulation in breast cancers. More broadly, our results demonstrate the unexpectedly dynamic nature of coregulator interactions within enhancer complexes, which are likely to be a defining feature of all enhancers. PMID- 28887414 TI - Progressive polarity loss and luminal collapse disrupt tissue organization in carcinoma. AB - Epithelial cancers (carcinoma) account for 80%-90% of all cancers. The development of carcinoma is associated with disrupted epithelial organization and solid ductal structures. The mechanisms underlying the morphological development of carcinoma are poorly understood, but it is thought that loss of cell polarity is an early event. Here we report the characterization of the development of human breast lesions leading to carcinoma. We identified a unique mechanism that generates solid ducts in carcinoma through progressive loss of polarity and collapse of the luminal architecture. This program initiates with asymmetric divisions of polarized cells that generate a stratified epithelium containing both polarized and depolarized cells. Stratified regions form cords that penetrate into the lumen, subdividing it into polarized secondary lumina. The secondary lumina then collapse with a concomitant decrease in RhoA and myosin II activity at the apical membrane and ultimately lose apical-basal polarity. By restoring RhoA activity in mice, ducts maintained lumen and cell polarity. Notably, disrupted tissue architecture through luminal collapse was reversible, and ducts with a lumen were re-established after oncogene suppression in vivo. This reveals a novel and common mechanism that contributes to carcinoma development by progressively disrupting cell and tissue organization. PMID- 28887415 TI - Inactivation of Human Norovirus Genogroups I and II and Surrogates by Free Chlorine in Postharvest Leafy Green Wash Water. AB - Human noroviruses (hNoVs) are a known public health concern associated with the consumption of leafy green vegetables. While a number of studies have investigated pathogen reduction on the surfaces of leafy greens during the postharvest washing process, there remains a paucity of data on the level of treatment needed to inactivate viruses in the wash water, which is critical for preventing cross-contamination. The objective of this study was to quantify the susceptibility of hNoV genotype I (GI), hNoV GII, murine norovirus (MNV), and bacteriophage MS2 to free chlorine in whole leaf, chopped romaine, and shredded iceberg lettuce industrial leafy green wash waters, each sampled three times over a 4-month period. A suite of kinetic inactivation models was fit to the viral reduction data to aid in quantification of concentration-time (CT) values. Results indicate that 3-log10 infectivity reduction was achieved at CT values of less than 0.2 mg . min/liter for MNV and 2.5 mg . min/liter for MS2 in all wash water types. CT values for 2-log10 molecular reduction of hNoV GI in whole leaf and chopped romaine wash waters were 1.5 and 0.9 mg . min/liter, respectively. For hNoV GII, CT values were 13.0 and 7.5 mg . min/liter, respectively. In shredded iceberg wash water, 3-log10 molecular reduction was not observed for any virus over the time course of experiments. These findings demonstrate that noroviruses may exhibit genogroup-dependent resistance to free chlorine and emphasize the importance of distinguishing between genogroups in hNoV persistence studies.IMPORTANCE Postharvest washing of millions of pounds of leafy greens is performed daily in industrial processing facilities with the intention of removing dirt, debris, and pathogenic microorganisms prior to packaging. Modest inactivation of pathogenic microorganisms (less than 2 log10) is known to occur on the surfaces of leafy greens during washing. Therefore, the primary purpose of the sanitizing agent is to maintain microbial quality of postharvest processing water in order to limit cross-contamination. This study modeled viral inactivation data and quantified the free-chlorine CT values that processing facilities must meet in order to achieve the desired level of hNoV GI and GII reduction. Disinfection experiments were conducted in industrial leafy green wash water collected from a full-scale fresh produce processing facility in the United States, and hNoV GI and GII results were compared with surrogate molecular and infectivity data. PMID- 28887416 TI - Identifying the Active Microbiome Associated with Roots and Rhizosphere Soil of Oilseed Rape. AB - RNA stable isotope probing and high-throughput sequencing were used to characterize the active microbiomes of bacteria and fungi colonizing the roots and rhizosphere soil of oilseed rape to identify taxa assimilating plant-derived carbon following 13CO2 labeling. Root- and rhizosphere soil-associated communities of both bacteria and fungi differed from each other, and there were highly significant differences between their DNA- and RNA-based community profiles. Verrucomicrobia, Proteobacteria, Planctomycetes, Acidobacteria, Gemmatimonadetes, Actinobacteria, and Chloroflexi were the most active bacterial phyla in the rhizosphere soil. Bacteroidetes were more active in roots. The most abundant bacterial genera were well represented in both the 13C- and 12C-RNA fractions, while the fungal taxa were more differentiated. Streptomyces, Rhizobium, and Flavobacterium were dominant in roots, whereas Rhodoplanes and Sphingomonas (Kaistobacter) were dominant in rhizosphere soil. "Candidatus Nitrososphaera" was enriched in 13C in rhizosphere soil. Olpidium and Dendryphion were abundant in the 12C-RNA fraction of roots; Clonostachys was abundant in both roots and rhizosphere soil and heavily 13C enriched. Cryptococcus was dominant in rhizosphere soil and less abundant, but was 13C enriched in roots. The patterns of colonization and C acquisition revealed in this study assist in identifying microbial taxa that may be superior competitors for plant-derived carbon in the rhizosphere of Brassica napusIMPORTANCE This microbiome study characterizes the active bacteria and fungi colonizing the roots and rhizosphere soil of Brassica napus using high-throughput sequencing and RNA-stable isotope probing. It identifies taxa assimilating plant-derived carbon following 13CO2 labeling and compares these with other less active groups not incorporating a plant assimilate. Brassica napus is an economically and globally important oilseed crop, cultivated for edible oil, biofuel production, and phytoextraction of heavy metals; however, it is susceptible to several diseases. The identification of the fungal and bacterial species successfully competing for plant-derived carbon, enabling them to colonize the roots and rhizosphere soil of this plant, should enable the identification of microorganisms that can be evaluated in more detailed functional studies and ultimately be used to improve plant health and productivity in sustainable agriculture. PMID- 28887417 TI - High substrate uptake rates empower Vibrio natriegens as production host for industrial biotechnology. AB - The productivity of industrial fermentation processes is essentially limited by the biomass specific substrate consumption rate (qS) of the applied microbial production system. Since qS depends on the growth rate (MU), we highlight the potential of the fastest growing non-pathogenic bacterium, Vibrio natriegens, as novel candidate for future biotechnological processes. V. natriegens grows rapidly in BHIN complex medium with a MU of up to 4.43 h-1 (doubling time of 9.4 min) as well as in minimal medium supplemented with various industrially relevant substrates. Bioreactor cultivations in minimal medium with glucose showed that V. natriegens possesses an exceptionally high qS under aerobic (3.90 +/- 0.08 g g-1 h-1) and anaerobic (7.81 +/- 0.71 g g-1 h-1) conditions. Fermentations with resting cells of genetically engineered V. natriegens under anaerobic conditions yielded an overall volumetric productivity of 0.56 +/- 0.10 g alanine L-1 min-1 (i.e. 34 g L-1 h-1). These inherent properties render V. natriegens a promising new microbial platform for future industrial fermentation processes operating with high productivity.Importance Low conversion rates are one major challenge to realize microbial fermentation processes for the production of commodities operating competitively to existing petrochemical approaches. For this reason, we screened for a novel platform organism possessing superior characteristics to traditionally employed microbial systems. We identified the fast growing Vibrio natriegens which exhibits a versatile metabolism and shows striking growth and conversion rates, as a solid candidate to reach outstanding productivities. Due to these inherent characteristics V. natriegens can speed up common laboratory routines, is suitable for already existing production procedures, and forms an excellent foundation to engineer next generation bioprocesses. PMID- 28887418 TI - Chitinase Expression in Listeria monocytogenes Is Influenced by lmo0327, Which Encodes an Internalin-Like Protein. AB - The chitinolytic system of Listeria monocytogenes thus far comprises two chitinases, ChiA and ChiB, and a lytic polysaccharide monooxygenase, Lmo2467. The role of the system in the bacterium appears to be pleiotropic, as besides mediating the hydrolysis of chitin, the second most ubiquitous carbohydrate in nature, the chitinases have been deemed important for the colonization of unicellular molds, as well as mammalian hosts. To identify additional components of the chitinolytic system, we screened a transposon mutant library for mutants exhibiting impaired chitin hydrolysis. The screening yielded a mutant with a transposon insertion in a locus corresponding to lmo0327 of the EGD-e strain. lmo0327 encodes a large (1,349 amino acids [aa]) cell wall-associated protein that has been proposed to possess murein hydrolase activity. The single inactivation of lmo0327, as well as of lmo0325 that codes for a putative transcriptional regulator functionally related to lmo0327, led to an almost complete abolishment of chitinolytic activity. The effect could be traced at the transcriptional level, as both chiA and chiB transcripts were dramatically decreased in the lmo0327 mutant. In accordance with that, we could barely detect ChiA and ChiB in the culture supernatants of the mutant strain. Our results provide new information regarding the function of the lmo0325-lmo0327 locus in L. monocytogenes and link it to the expression of chitinolytic activity.IMPORTANCE Many bacteria from terrestrial and marine environments express chitinase activities enabling them to utilize chitin as the sole source of carbon and nitrogen. Interestingly, several bacterial chitinases may also be involved in host pathogenesis. For example, in the important foodborne pathogen Listeria monocytogenes, the chitinases ChiA and ChiB and the lytic polysaccharide monooxygenase Lmo2467 are implicated in chitin assimilation but also act as virulence factors during the infection of mammalian hosts. Therefore, it is important to identify their regulators and induction cues to understand how the different roles of the chitinolytic system are controlled and mediated. Here, we provide evidence for the importance of lmo0327 and lmo0325, encoding a putative internalin/autolysin and a putative transcriptional activator, respectively, in the efficient expression of chitinase activity in L. monocytogenes and thereby provide new information regarding the function of the lmo0325-lmo0327 locus. PMID- 28887419 TI - Oxidative Stressors Modify the Response of Streptococcus mutans to Its Competence Signal Peptides. AB - The dental caries pathogen Streptococcus mutans is continually exposed to several types of stress in the oral biofilm environment. Oxidative stress generated by reactive oxygen species has a major impact on the establishment, persistence, and virulence of S. mutans Here, we combined fluorescent reporter-promoter fusions with single-cell imaging to study the effects of reactive oxygen species on activation of genetic competence in S. mutans Exposure to paraquat, which generates superoxide anion, produced a qualitatively different effect on activation of expression of the gene for the master competence regulator, ComX, than did treatment with hydrogen peroxide (H2O2), which can yield hydroxyl radical. Paraquat suppressed peptide-mediated induction of comX in a progressive and cumulative fashion, whereas the response to H2O2 displayed a strong threshold behavior. Low concentrations of H2O2 had little effect on induction of comX or the bacteriocin gene cipB, but expression of these genes declined sharply if extracellular H2O2 exceeded a threshold concentration. These effects were not due to decreased reporter gene fluorescence. Two different threshold concentrations were observed in the response to H2O2, depending on the gene promoter that was analyzed and the pathway by which the competence regulon was stimulated. The results show that paraquat and H2O2 affect the S. mutans competence signaling pathway differently, and that some portions of the competence signaling pathway are more sensitive to oxidative stress than others.IMPORTANCEStreptococcus mutans inhabits the oral biofilm, where it plays an important role in the development of dental caries. Environmental stresses such as oxidative stress influence the growth of S. mutans and its important virulence-associated behaviors, such as genetic competence. S. mutans competence development is a complex behavior that involves two different signaling peptides and can exhibit cell-to-cell heterogeneity. Although oxidative stress is known to influence S. mutans competence, it is not understood how oxidative stress interacts with the peptide signaling or affects heterogeneity. In this study, we used fluorescent reporters to probe the effect of reactive oxygen species on competence signaling at the single-cell level. Our data show that different reactive oxygen species have different effects on S. mutans competence, and that some portions of the signaling pathway are more acutely sensitive to oxidative stress than others. PMID- 28887420 TI - Flexibility-Rigidity Coordination of the Dense Exopolysaccharide Matrix in Terrestrial Cyanobacteria Acclimated to Periodic Desiccation. AB - A dense exopolysaccharide (EPS) matrix is crucial for cyanobacterial survival in terrestrial xeric environments, in which cyanobacteria undergo frequent expansion and shrinkage processes during environmental desiccation-rehydration cycles. However, it is unclear how terrestrial cyanobacteria coordinate the structural dynamics of the EPS matrix upon expansion and shrinkage to avoid potential mechanical stress while benefiting from the matrix. In the present study, we sought to answer this question by investigating the gene expression, protein dynamics, enzymatic characteristics, and biological roles of WspA, an abundantly secreted protein, in the representative terrestrial cyanobacterium Nostoc flagelliforme The results demonstrated that WspA is a novel beta-galactosidase that facilitates softening of the EPS matrix by breaking the polysaccharide backbone under substantial moisture or facilitates the thickening and relinkage of the broken matrix during the drying process, and thus these regulations are well correlated with moisture availability or desiccation-rehydration cycles. This coordination of flexibility and rigidity of the cyanobacterial extracellular matrix may contribute to a favorable balance of cell growth and stress resistance in xeric environments.IMPORTANCE How the exopolysaccharide matrix is dynamically coordinated by exoproteins to cope with frequent expansion and shrinkage processes in terrestrial colonial cyanobacteria remains unclear. Here we elucidated the biochemical identity and biological roles of a dominant exoprotein in these regulation processes. Our study thus gained insight into this regulative mechanism in cyanobacteria to combat periodic desiccation. In addition, the filamentous drought-adapted cyanobacterium Nostoc flagelliforme serves as an ideal model for us to explore this issue in this study. PMID- 28887421 TI - Impact of "Raised Without Antibiotics" Beef Cattle Production Practices On Occurrences of Antimicrobial Resistance. AB - The specific antimicrobial resistance (AMR) decreases that can be expected from reducing antimicrobial (AM) use in United States (US) beef production have not been defined. To address this data gap, feces were recovered from 36 lots of "raised without antibiotics" (RWA) and 36 lots of "conventional" (CONV) beef cattle. Samples (N = 719) were collected during harvest and distributed over a year. AMR was assessed by: i) culture of six AM-resistant bacteria (ARB); ii) qPCR for 10 AMR genes (ARGs); iii) an qPCR array of 84 ARGs; and iv) metagenomic sequencing. Generally, AMR levels were similar, but some were higher in CONV. The prevalence of third-generation cephalosporin-resistant (3GCr) Escherichia coli was marginally different between production systems (47.5 % CONV, 34.8% RWA, P = 0.04), but the seasonal effect (92.8% summer, 48.3% winter, P < 0.01) was greater. Erythromycin-resistant (ERYr) Enterococcus spp. concentrations significantly differed between production systems (CONV = 1.91 log10 CFU/g, RWA = 0.73 log10 CFU/g, P < 0.01). Levels of aadA1, ant(6)-I, blaACI, erm(A), erm(B), erm(C), erm(F), erm(Q), tet(A), tet(B), tet(M), and tet(X) ARGs were higher (P < 0.05) in CONV. Aggregate abundances of all 43 ARGs detected by metagenomic sequencing and the aggregate abundances of ARGs in the aminoglycoside, beta lactam, macrolide-lincosamide-streptogramin B (MLSB), and tetracycline AM classes did not differ (log2 fold change < 1.0) between CONV and RWA. These results suggest that further reductions of AM use in US beef cattle production may not yield significant AMR reductions beyond MLSB and tetracycline resistance.IMPORTANCE The majority of AM use in the US is for food-animal production, leading to concerns that typical AM use patterns during CONV beef cattle production in the US contribute broadly to AMR occurrence. In the present study, levels of AMR were generally similar between CONV and RWA cattle. Only a limited number of modest AMR increases were observed in CONV, primarily involving MLSB and tetracycline resistance. Macrolides (tylosin) and tetracyclines (chlortetracycline) are administered in-feed for relatively long durations to reduce liver abscesses. To ensure judicious AM use, the animal health, economic, and AMR impacts of shorter duration in-feed administration of these AMs should be examined. However, given the modest AMR reductions observed, further reductions of AM use in US beef cattle production may not yield significant AMR reductions beyond MLSB and tetracycline resistance. PMID- 28887423 TI - Forensic human identification using skin microbiomes. AB - The human microbiome contributes significantly to the genetic content of the human body. Genetic and environmental factors help shape the microbiome, and as such, the microbiome can be unique to an individual. Previous studies have demonstrated the potential to use microbiome profiling for forensic applications, however a method has yet to identify stable features of skin microbiomes that produce high classification accuracies for samples collected over reasonably long time intervals. A novel approach is described to classify skin microbiomes to their donors by comparing two features types, Propionibacterium acnes pangenome presence/absence features and nucleotide diversities of stable clade-specific markers. Supervised learning was used to attribute skin microbiomes from 14 skin body sites from 12 healthy individuals sampled at three time points over a >2.5 year period with accuracies up to 100% for three body sites. Feature selection identified a reduced subset of markers from each body site that are highly individualizing, identifying 187 markers from 12 clades. Classification accuracies were compared in a formal model testing framework, and the results of this indicate that learners trained on nucleotide diversity perform significantly better than those trained on presence/absence encodings. This study used supervised learning to identify individuals with high accuracy and associated stable features from skin microbiomes over a period of up to almost 3 years. These selected features provide a preliminary marker panel for future development of a robust and reproducible method for skin microbiome profiling for forensic human identification.Importance A novel approach is described to attribute skin microbiomes, collected over a period of >2.5 years, to their individual hosts with a high degree of accuracy. Nucleotide diversities of stable clade-specific markers with supervised learning was used to classify skin microbiomes from a particular individual with up to 100% classification accuracy for three body sites. Attribute selection was used to identify 187 genetic markers from 12 clades which provide the greatest differentiation of individual skin microbiomes from 14 skin sites. This study performs skin microbiome profiling from a supervised learning approach and obtains high classification accuracy for samples collected from individuals over a relatively long time period for potential application to forensic human identification. PMID- 28887422 TI - Glycolytic Functions Are Conserved in the Genome of the Wine Yeast Hanseniaspora uvarum, and Pyruvate Kinase Limits Its Capacity for Alcoholic Fermentation. AB - Hanseniaspora uvarum (anamorph Kloeckera apiculata) is a predominant yeast on wine grapes and other fruits and has a strong influence on wine quality, even when Saccharomyces cerevisiae starter cultures are employed. In this work, we sequenced and annotated approximately 93% of the H. uvarum genome. Southern and synteny analyses were employed to construct a map of the seven chromosomes present in a type strain. Comparative determinations of specific enzyme activities within the fermentative pathway in H. uvarum and S. cerevisiae indicated that the reduced capacity of the former yeast for ethanol production is caused primarily by an ~10-fold-lower activity of the key glycolytic enzyme pyruvate kinase. The heterologous expression of the encoding gene, H. uvarumPYK1 (HuPYK1), and two genes encoding the phosphofructokinase subunits, HuPFK1 and HuPFK2, in the respective deletion mutants of S. cerevisiae confirmed their functional homology.IMPORTANCEHanseniaspora uvarum is a predominant yeast species on grapes and other fruits. It contributes significantly to the production of desired as well as unfavorable aroma compounds and thus determines the quality of the final product, especially wine. Despite this obvious importance, knowledge on its genetics is scarce. As a basis for targeted metabolic modifications, here we provide the results of a genomic sequencing approach, including the annotation of 3,010 protein-encoding genes, e.g., those encoding the entire sugar fermentation pathway, key components of stress response signaling pathways, and enzymes catalyzing the production of aroma compounds. Comparative analyses suggest that the low fermentative capacity of H. uvarum compared to that of Saccharomyces cerevisiae can be attributed to low pyruvate kinase activity. The data reported here are expected to aid in establishing H. uvarum as a non-Saccharomyces yeast in starter cultures for wine and cider fermentations. PMID- 28887425 TI - To what extent and why adolescents do or do not support future tobacco control measures: a multimethod study in the Netherlands. AB - BACKGROUND: In the Netherlands, the adoption of new tobacco control measures is needed to further reduce rates of adolescent smoking. Adolescents' support for future measures could increase the likelihood of adoption as this provides political leverage for tobacco control advocates. There is, however, scant evidence about to what extent and why adolescents support future measures. We therefore assessed adolescents' support for a range of future measures and explored the criteria that adolescents use to underpin their support. METHODS: A mixed-method design involved surveys and group interviews with fourth-year students (predominantly 15-16 years). The survey, completed by 345 adolescents, included statements about future tobacco control measures and a smoke-free future where nobody starts or continues smoking. Thereafter, 15 adolescents participated in five group interviews to discuss their support for future measures. RESULTS: The survey showed that adolescents generally support a smoke-free future. They expressed most support for product measures, mixed support for smoke-free areas, ambivalent support for price increases and least support for sales restrictions. The group interviews revealed that differences in support were explained by adolescents' criteria that future measures should: have the potential to be effective, not violate individuals' right to smoke, protect children from pro smoking social influences and protect non-smokers from secondhand smoke. CONCLUSION: Adolescents' high support for a smoke-free future does not lead to categorical support for any measure. Addressing the underlying criteria may increase adolescents' support and therewith provide political leverage for the adoption of future measures. PMID- 28887424 TI - Acyl-Homoserine Lactone Production in Nitrifying Bacteria of the Genera Nitrosospira, Nitrobacter, and Nitrospira Identified via a Survey of Putative Quorum-Sensing Genes. AB - The genomes of many bacteria that participate in nitrogen cycling through the process of nitrification contain putative genes associated with acyl-homoserine lactone (AHL) quorum sensing (QS). AHL QS or bacterial cell-cell signaling is a method of bacterial communication and gene regulation and may be involved in nitrogen oxide fluxes or other important phenotypes in nitrifying bacteria. Here, we carried out a broad survey of AHL production in nitrifying bacteria in three steps. First, we analyzed the evolutionary history of AHL synthase and AHL receptor homologs in sequenced genomes and metagenomes of nitrifying bacteria to identify AHL synthase homologs in ammonia-oxidizing bacteria (AOB) of the genus Nitrosospira and nitrite-oxidizing bacteria (NOB) of the genera Nitrococcus, Nitrobacter, and Nitrospira Next, we screened cultures of both AOB and NOB with uncharacterized AHL synthase genes and AHL synthase-negative nitrifiers by a bioassay. Our results suggest that an AHL synthase gene is required for, but does not guarantee, cell density-dependent AHL production under the conditions tested. Finally, we utilized mass spectrometry to identify the AHLs produced by the AOB Nitrosospira multiformis and Nitrosospira briensis and the NOB Nitrobacter vulgaris and Nitrospira moscoviensis as N-decanoyl-l-homoserine lactone (C10 HSL), N-3-hydroxy-tetradecanoyl-l-homoserine lactone (3-OH-C14-HSL), a monounsaturated AHL (C10:1-HSL), and N-octanoyl-l-homoserine lactone (C8-HSL), respectively. Our survey expands the list of AHL-producing nitrifiers to include a representative of Nitrospira lineage II and suggests that AHL production is widespread in nitrifying bacteria.IMPORTANCE Nitrification, the aerobic oxidation of ammonia to nitrate via nitrite by nitrifying microorganisms, plays an important role in environmental nitrogen cycling from agricultural fertilization to wastewater treatment. The genomes of many nitrifying bacteria contain genes associated with bacterial cell-cell signaling or quorum sensing (QS). QS is a method of bacterial communication and gene regulation that is well studied in bacterial pathogens, but less is known about QS in environmental systems. Our previous work suggested that QS might be involved in the regulation of nitrogen oxide gas production during nitrite metabolism. This study characterized putative QS signals produced by different genera and species of nitrifiers. Our work lays the foundation for future experiments investigating communication between nitrifying bacteria, the purpose of QS in these microorganisms, and the manipulation of QS during nitrification. PMID- 28887426 TI - E-cigarettes and youth smoking: be alert but not alarmed. PMID- 28887427 TI - Tobacco industry tactics in preparing for menthol ban. PMID- 28887428 TI - Impact of plain packaging of cigarettes on the risk perception of Uruguayan smokers: an experimental study. AB - BACKGROUND: Uruguay, a South American country of 3.4 million inhabitants that has already banned tobacco advertising, prohibited such terms as light, mild and low tar and required graphic warnings covering 80% of cigarette packs, is considering the imposition of plain, standardised packaging. METHODS: We conducted an experimental choice-based conjoint analysis of the impact of alternative cigarette package designs on the risk perceptions of 180 adult current Uruguayan smokers. We compared plain packaging, with a standardised brand description and the dark brown background colour required on Australian cigarette packages, to two controls: the current package design with distinctive brand elements and colours; and a modified package design, with distinctive brand elements and the dark brown background colour. Graphic warnings were also varied. RESULTS: Plain packaging significantly reduced the probability of perceiving the stimulus cigarettes as less harmful in comparison to the current package design (OR 0.398, 95% CI 0.333 to 0.476, p<0.001) and the modified package design (OR 0.729, 95% CI 0.626 to 0.849, p<0.001). CONCLUSIONS: Plain packaging enhanced the perceived risk of cigarette products even in a highly regulated setting such as Uruguay. Both the elimination of distinctive brand elements and the use of Australia's dark brown background colour contributed to the observed effect. PMID- 28887430 TI - The Role of Leukocyte-Associated Ig-like Receptor-1 in Suppressing Collagen Induced Arthritis. AB - Several observations implicate a critical role for T cell dysregulation as a central problem in rheumatoid arthritis. We investigated a mechanism for suppressing T cell activation by stimulating a natural inhibitory receptor called leukocyte-associated Ig-like receptor-1 (LAIR-1). The collagen-induced arthritis (CIA) model and DR-1 transgenic mice were used to study the importance of LAIR-1 in autoimmune arthritis. Splenocytes from wild-type or LAIR-1-/- mice were stimulated with soluble anti-CD3 Ab in the presence or absence of alpha1(II) and supernatants were collected for cytokine analysis. B6.DR1 mice were immunized with type II collagen/CFA to induce arthritis and were treated with either the stimulatory mAb to LAIR-1 or a hamster IgG control. Finally, B6.DR1/LAIR-1-/- and B6.DR1/LAIR-1+/+ mice were challenged for CIA and mean severity scores were recorded thrice weekly. Using splenocytes or purified CD4+ cells that were sufficient in LAIR-1, CD3-induced cytokine secretion was significantly suppressed in the presence of collagen, whereas LAIR-1-deficient splenocytes had no attenuation. Treatment with a stimulatory mAb to LAIR-1 also significantly attenuated CIA in the LAIR+/+ mice. When B6.DR1/LAIR-1-/- mice were immunized with type II collagen they developed more severe arthritis and had a greater percentage of affected limbs than the wild-type mice. These data demonstrate that collagen can suppress the T cell cytokine response through the action of LAIR-1. Treatment with stimulating LAIR-1 Abs suppresses CIA whereas B6.DR1/LAIR-1-/- mice develop more severe arthritis than wild-type controls. These data suggest that LAIR-1 may be a potential therapeutic target for suppressing rheumatoid arthritis. PMID- 28887429 TI - NFM Cross-Reactivity to MOG Does Not Expand a Critical Threshold Level of High Affinity T Cells Necessary for Onset of Demyelinating Disease. AB - Of interest to the etiology of demyelinating autoimmune disease is the potential to aberrantly activate CD4+ T cells due to cross-recognition of multiple self epitopes such as has been suggested for myelin oligodendrocyte glycoprotein epitope 35-55 (MOG35-55) and neurofilament medium protein epitope 15-35 (NFM15 35). NFM15-35 is immunogenic in C57BL/6 mice but fails to induce demyelinating disease by polyclonal T cells despite having the same TCR contact residues as MOG35-55, a known encephalitogenic Ag. Despite reported cross-reactivity with MOG specific T cells, the polyclonal response to NFM15-35 did not expand threshold numbers of MOG38-49 tetramer-positive T cells. Furthermore, NFM lacked functional synergy with MOG to promote experimental autoimmune encephalomyelitis because NFM deficient synonymous with knockout mice developed an identical disease course to wild-type mice after challenge with MOG35-55 Single-cell analysis of encephalitogenic T cells using the peptide:MHC monomer-based two-dimensional micropipette adhesion frequency assay confirmed that NFM was not a critical Ag driving demyelinating disease because NFM18-30-specific T cells in the CNS were predominantly reactive to MOG38-49 The absence of NFM contribution to disease allowed mapping of the amino acids required for encephalitogenicity and expansion of high-affinity, MOG-specific T cells that defined the polyclonal response. Alterations of N-terminal residues outside of the NFM15-35 core nonamer promoted expansion of high-affinity, MOG38-49 tetramer-positive T cells and promoted consistent experimental autoimmune encephalomyelitis induction, unlike mice challenged with NFM15-35 Although NFM15-35 is immunogenic and cross-reactive with MOG at the polyclonal level, it fails to expand a threshold level of encephalitogenic, high-affinity MOG-specific T cells. PMID- 28887432 TI - Maternal Pregravid Obesity Remodels the DNA Methylation Landscape of Cord Blood Monocytes Disrupting Their Inflammatory Program. AB - Prepregnancy maternal obesity is associated with adverse outcomes for the offspring, including increased incidence of neonatal bacterial sepsis and necrotizing enterocolitis. We recently reported that umbilical cord blood (UCB) monocytes from babies born to obese mothers generate a reduced IL-6/TNF-alpha response to TLR 1/2 and 4 ligands compared to those collected from lean mothers. These observations suggest altered development of the offspring's immune system, which in turn results in dysregulated function. We therefore investigated transcriptional and epigenetic differences within UCB monocytes stratified by prepregnancy maternal body mass index. We show that UCB monocytes from babies born to obese mothers generate a dampened response to LPS stimulation compared with those born to lean mothers, at the level of secreted immune mediators and transcription. Because gene expression profiles of resting UCB monocytes from both groups were comparable, we next investigated the role of epigenetic differences. Indeed, we detected stark differences in methylation levels within promoters and regulatory regions of genes involved in TLR signaling in resting UCB monocytes. Interestingly, the DNA methylation status of resting cells was highly predictive of transcriptional changes post-LPS stimulation, suggesting that cytosine methylation is one of the dominant mechanisms driving functional inadequacy in UCB monocytes obtained from babies born to obese mothers. These data highlight a potentially critical role of maternal pregravid obesity associated epigenetic changes in influencing the function of an offspring's monocytes at birth. These findings further our understanding of mechanisms that explain the increased risk of infection in neonates born to mothers with high prepregnancy body mass index. PMID- 28887431 TI - Neutrophil-Derived Cytosolic PLA2alpha Contributes to Bacterial-Induced Neutrophil Transepithelial Migration. AB - Eicosanoids are a group of bioactive lipids that are shown to be important mediators of neutrophilic inflammation; selective targeting of their function confers therapeutic benefit in a number of diseases. Neutrophilic airway diseases, including cystic fibrosis, are characterized by excessive neutrophil infiltration into the airspace. Understanding the role of eicosanoids in this process may reveal novel therapeutic targets. The eicosanoid hepoxilin A3 is a pathogen-elicited epithelial-produced neutrophil chemoattractant that directs transepithelial migration in response to infection. Following hepoxilin A3-driven transepithelial migration, neutrophil chemotaxis is amplified through neutrophil production of a second eicosanoid, leukotriene B4 (LTB4). The rate-limiting step of eicosanoid generation is the liberation of arachidonic acid by phospholipase A2, and the cytosolic phospholipase A2 (cPLA2)alpha isoform has been specifically shown to direct LTB4 synthesis in certain contexts. Whether cPLA2alpha is directly responsible for neutrophil synthesis of LTB4 in the context of Pseudomonas aeruginosa-induced neutrophil transepithelial migration has not been explored. Human and mouse neutrophil-epithelial cocultures were used to evaluate the role of neutrophil-derived cPLA2alpha in infection-induced transepithelial signaling by pharmacological and genetic approaches. Primary human airway basal stem cell-derived epithelial cultures and micro-optical coherence tomography, a new imaging modality that captures two- and three-dimensional real-time dynamics of neutrophil transepithelial migration, were applied. Evidence from these studies suggests that cPLA2alpha expressed by neutrophils, but not epithelial cells, plays a significant role in infection-induced neutrophil transepithelial migration by mediating LTB4 synthesis during migration, which serves to amplify the magnitude of neutrophil recruitment in response to epithelial infection. PMID- 28887434 TI - Exosomes from uninfected cells activate transcription of latent HIV-1. PMID- 28887433 TI - The Neurobeachin-like 2 Protein Regulates Mast Cell Homeostasis. AB - The neurobeachin-like 2 protein (Nbeal2) belongs to the family of beige and Chediak-Higashi (BEACH) domain proteins. Loss-of-function mutations in the human NBEAL2 gene or Nbeal2 deficiency in mice cause gray platelet syndrome, a bleeding disorder characterized by macrothrombocytopenia, splenomegaly, and paucity of alpha-granules in megakaryocytes and platelets. We found that in mast cells, Nbeal2 regulates the activation of the Shp1-STAT5 signaling axis and the composition of the c-Kit/STAT signalosome. Furthermore, Nbeal2 mediates granule formation and restricts the expression of the transcription factors, IRF8, GATA2, and MITF as well as of the cell-cycle inhibitor p27, which are essential for mast cell differentiation, proliferation, and cytokine production. These data demonstrate the relevance of Nbeal2 in mast cells above and beyond granule biosynthesis. PMID- 28887435 TI - Potential dual function of PQ-loop proteins such as cystinosin. PMID- 28887436 TI - When Escherichia coli doesn't fit the mold: A pertussis-like toxin with altered specificity. AB - Bacterial toxins introduce protein modifications such as ADP-ribosylation to manipulate host cell signaling and physiology. Several general mechanisms for toxin function have been established, but the extent to which previously uncharacterized toxins utilize these mechanisms is unknown. A study of an Escherichia coli pertussis-like toxin demonstrates that this protein acts on a known toxin substrate but displays distinct and dual chemoselectivity, suggesting this E. coli pertussis-like toxin may serve as a unique tool to study G-protein signaling in eukaryotic cells. PMID- 28887437 TI - Cell-cell adhesion accounts for the different orientation of columnar and hepatocytic cell divisions. AB - Mitotic spindle alignment with the basal or substrate-contacting domain ensures that dividing epithelial cells remain in the plane of the monolayer. Spindle orientation with respect to the substratum is established in metaphase coincident with maximal cell rounding, which enables unobstructed spindle rotation. Misaligned metaphase spindles are believed to result in divisions in which one daughter loses contact with the basal lamina. Here we describe a rescue mechanism that drives substrate-parallel spindle alignment of quasi-diagonal metaphase spindles in anaphase. It requires a Rho- and E-cadherin adhesion-dependent, substrate-parallel contractile actin belt at the apex that governs anaphase cell flattening. In contrast to monolayered Madin-Darby canine kidney cells, hepatocytic epithelial cells, which typically feature tilted metaphase spindles, lack this anaphase flattening mechanism and as a consequence maintain their spindle tilt through cytokinesis. This results in out-of-monolayer divisions, which we propose contribute to the stratified organization of hepatocyte cords in vivo. PMID- 28887439 TI - Overexpression of Acyl-CoA Ligase 4 (ACSL4) in Patients with Hepatocellular Carcinoma and its Prognosis. AB - BACKGROUND Recently, accumulating studies have found that ACSL4 dysregulation is related to a great number of malignant tumors. The purpose of the present study was to explore the relationship between ACSL4 expression level and clinical prognosis of hepatocellular carcinoma (HCC) patients. MATERIAL AND METHODS The Oncomine and TCGA databases were used to predict the expression of ACSL4 mRNA in HCC and its association with HCC prognosis. Further, immunohistochemistry was performed to verify the ACSL4 protein expression in 116 paired HCC and adjacent normal tissues. Kaplan-Meier and cox analysis were performed to validate the correlation between ACSL4 expression and HCC prognosis. RESULTS We first used the Oncomine database to find that ACSL4 mRNA expression level was significantly higher in HCC tissues than that in normal tissues (p all <0.001). The results were consistent with those in the TCGA database. Then, immunohistochemical results demonstrated that the ACSL4 positive expression rate was 70.7% in HCC tissues. ACSL4 differential expression level was significantly related to Edmondson grade (p=0.010), AFP (p=0.001) and TNM stage (p=0.012). Survival analysis revealed that both overall survival (OS) and disease-free survival (DFS) time were remarkably reduced in HCC patients with ACSL4 high expression (p=0.001 and 0.000, respectively). Moreover, Cox multivariate analysis demonstrated that ACSL4 expression was the only independent prognostic factor for both OS and DFS (both p values=0.001). CONCLUSIONS Taken together, our study demonstrated that ACSL4 was overexpressed in HCC, and it will be a new potential therapeutic target for HCC as an independent adverse prognostic parameter. PMID- 28887438 TI - Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia. AB - A propensity for rewiring genetic and epigenetic regulatory networks, thus enabling sustained cell proliferation, suppression of apoptosis, and the ability to evade the immune system, is vital to cancer cell propagation. An increased understanding of how this is achieved is critical for identifying or improving therapeutic interventions. In this study, using acute myeloid leukemia (AML) human cell lines and a custom CRISPR/Cas9 screening platform, we identify the H3K9 methyltransferase SETDB1 as a novel, negative regulator of innate immunity. SETDB1 is overexpressed in many cancers, and loss of this gene in AML cells triggers desilencing of retrotransposable elements that leads to the production of double-stranded RNAs (dsRNAs). This is coincident with induction of a type I interferon response and apoptosis through the dsRNA-sensing pathway. Collectively, our findings establish a unique gene regulatory axis that cancer cells can exploit to circumvent the immune system. PMID- 28887440 TI - A global Staphylococcus aureus proteome resource applied to the in vivo characterization of host-pathogen interactions. AB - Data-independent acquisition mass spectrometry promises higher performance in terms of quantification and reproducibility compared to data-dependent acquisition mass spectrometry methods. To enable high-accuracy quantification of Staphylococcus aureus proteins, we have developed a global ion library for data independent acquisition approaches employing high-resolution time of flight or Orbitrap instruments for this human pathogen. We applied this ion library resource to investigate the time-resolved adaptation of S. aureus to the intracellular niche in human bronchial epithelial cells and in a murine pneumonia model. In epithelial cells, abundance changes for more than 400 S. aureus proteins were quantified, revealing, e.g., the precise temporal regulation of the SigB-dependent stress response and differential regulation of translation, fermentation, and amino acid biosynthesis. Using an in vivo murine pneumonia model, our data-independent acquisition quantification analysis revealed for the first time the in vivo proteome adaptation of S. aureus. From approximately 2.15 * 105 S. aureus cells, 578 proteins were identified. Increased abundance of proteins required for oxidative stress response, amino acid biosynthesis, and fermentation together with decreased abundance of ribosomal proteins and nucleotide reductase NrdEF was observed in post-infection samples compared to the pre-infection state. PMID- 28887441 TI - HIV-1-mediated insertional activation of STAT5B and BACH2 trigger viral reservoir in T regulatory cells. AB - HIV-1 insertions targeting BACH2 or MLK2 are enriched and persist for decades in hematopoietic cells from patients under combination antiretroviral therapy. However, it is unclear how these insertions provide such selective advantage to infected cell clones. Here, we show that in 30/87 (34%) patients under combination antiretroviral therapy, BACH2, and STAT5B are activated by insertions triggering the formation of mRNAs that contain viral sequences fused by splicing to their first protein-coding exon. These chimeric mRNAs, predicted to express full-length proteins, are enriched in T regulatory and T central memory cells, but not in other T lymphocyte subsets or monocytes. Overexpression of BACH2 or STAT5B in primary T regulatory cells increases their proliferation and survival without compromising their function. Hence, we provide evidence that HIV-1 mediated insertional activation of BACH2 and STAT5B favor the persistence of a viral reservoir in T regulatory cells in patients under combination antiretroviral therapy.HIV insertions in hematopoietic cells are enriched in BACH2 or MLK2 genes, but the selective advantages conferred are unknown. Here, the authors show that BACH2 and additionally STAT5B are activated by viral insertions, generating chimeric mRNAs specifically enriched in T regulatory cells favoring their persistence. PMID- 28887443 TI - Role of interfacial mode coupling of optical phonons on thermal boundary conductance. AB - We investigate the influence of optical phonon coupling across interfaces comprised of different materials with varying crystallographic orientations on the overall thermal boundary conductance. We show that for interfaces formed between a fcc solid and a L10 solid (where L10 solids exhibit alternating atomic layers in certain orientations), coupling between acoustic phonons in the fcc crystal and optical phonons on the L10-side of the interface leads to a highly anisotropic thermal boundary conductance, where optical phonons can considerably enhance the conductance in a preferred crystallographic orientation of the layered solid. We attribute this in part to directionally dependent group velocities of optical phonons in the different crystallographic directions. For interfaces comprised of materials exhibiting diamond cubic crystal structures, higher conductances are observed for interfaces where there is a better overlap of acoustic phonons on either side of the interface, whereas, acoustic phonons directly coupling with high frequency optical phonons is shown to lower the overall conductance, especially at high temperatures where anharmonic interactions become important. Unique to the interfaces formed between the materials with diamond cubic crystal structures studied in this work, the presence of localized interfacial optical modes mediate thermal conductance across these interfaces. PMID- 28887442 TI - Targeting Deficiencies in the TLR5 Mediated Vaginal Response to Treat Female Recurrent Urinary Tract Infection. AB - The identification of the host defence peptides as target effectors in the innate defence of the uro-genital tract creates new translational possibilities for immunomodulatory therapies, specifically vaginal therapies to treat women suffering from rUTI, particularly those carrying the TLR5_C1174T SNP. Urinary tract infections (UTIs) are a microbial disease reported worldwide. Women are particularly susceptible with many suffering debilitating recurrent (r) infections. Treatment is by antibiotics, but such therapy is linked to antibiotic resistance and re-infection. This study explored the innate protective mechanisms of the urogenital tract with the aim of boosting such defences therapeutically. Modelling UTIs in vitro, human vaginal and bladder epithelial cells were challenged with uropathogenic Escherichia coli (CFT073) and microbial PAMPs including flagellin, LPS and peptidoglycan. Flagellin functioning via the TLR5/NFkappaB pathway was identified as the key UPEC virulence factor causing a significant increase (P < 0.05) in the production of the host-defence peptide (HDP), BD2. BD2-depleted urine samples from bladder infected mice supported increased UPEC growth, strengthening the significance of the HDPs in protecting the urogenital tissues from infection. Clinically, vaginal-douche BD2 concentrations were reduced (p < 0.05) in women suffering rUTIs, compared to age matched healthy controls with concentrations further decreased (p < 0.05) in a TLR5392Stop SNP rUTI subgroup. Topical vaginal estrogen treatment increased (p < 0.001) BD2 concentrations in all women, including those carrying the SNP. These data identify therapeutic and antibiotic sparing roles for vaginal immunomodulatory agents that specifically target HDP induction, facilitate bacterial killing and disrupt the UPEC infection cycle. PMID- 28887444 TI - Insulin, glucagon and somatostatin stores in the pancreas of subjects with type-2 diabetes and their lean and obese non-diabetic controls. AB - In type-2 diabetes, both insufficient insulin and excessive glucagon secretion contribute to hyperglycemia. We compared insulin, glucagon and somatostatin stores in pancreas obtained at autopsy of 20 lean and 19 obese non-diabetic (ND), and 18 type-2 diabetic (T2D) subjects. From concentrations and pancreas weight, total content of hormones was calculated. Insulin content was 35% lower in T2D than ND subjects (7.4 versus 11.3 mg), whereas glucagon content was similar (0.76 versus 0.81 mg). The higher ratio of glucagon/insulin contents in T2D was thus explained by the decrease in insulin. With increasing BMI of ND subjects, insulin and glucagon contents respectively tended to increase and decrease, resulting in a lower glucagon/insulin ratio in obesity. With aging, insulin and glucagon contents did not significantly change in ND subjects but declined in T2D subjects, without association with the duration of diabetes or type of treatment. The somatostatin content was lower in T2D than ND subjects (0.027 versus 0.038 mg), but ratios somatostatin/insulin and somatostatin/glucagon were not different. In conclusion, insulin stores are about 1/3 lower in T2D than ND subjects, whereas glucagon stores are unchanged. Abnormal secretion of each hormone in type-2 diabetes cannot be attributed to major alterations in their pancreatic reserves. PMID- 28887446 TI - Effects of Host-rock Fracturing on Elastic-deformation Source Models of Volcano Deflation. AB - Volcanoes commonly inflate or deflate during episodes of unrest or eruption. Continuum mechanics models that assume linear elastic deformation of the Earth's crust are routinely used to invert the observed ground motions. The source(s) of deformation in such models are generally interpreted in terms of magma bodies or pathways, and thus form a basis for hazard assessment and mitigation. Using discontinuum mechanics models, we show how host-rock fracturing (i.e. non-elastic deformation) during drainage of a magma body can progressively change the shape and depth of an elastic-deformation source. We argue that this effect explains the marked spatio-temporal changes in source model attributes inferred for the March-April 2007 eruption of Piton de la Fournaise volcano, La Reunion. We find that pronounced deflation-related host-rock fracturing can: (1) yield inclined source model geometries for a horizontal magma body; (2) cause significant upward migration of an elastic-deformation source, leading to underestimation of the true magma body depth and potentially to a misinterpretation of ascending magma; and (3) at least partly explain underestimation by elastic-deformation sources of changes in sub-surface magma volume. PMID- 28887445 TI - Usb1 controls U6 snRNP assembly through evolutionarily divergent cyclic phosphodiesterase activities. AB - U6 small nuclear ribonucleoprotein (snRNP) biogenesis is essential for spliceosome assembly, but not well understood. Here, we report structures of the U6 RNA processing enzyme Usb1 from yeast and a substrate analog bound complex from humans. Unlike the human ortholog, we show that yeast Usb1 has cyclic phosphodiesterase activity that leaves a terminal 3' phosphate which prevents overprocessing. Usb1 processing of U6 RNA dramatically alters its affinity for cognate RNA-binding proteins. We reconstitute the post-transcriptional assembly of yeast U6 snRNP in vitro, which occurs through a complex series of handoffs involving 10 proteins (Lhp1, Prp24, Usb1 and Lsm2-8) and anti-cooperative interactions between Prp24 and Lhp1. We propose a model for U6 snRNP assembly that explains how evolutionarily divergent and seemingly antagonistic proteins cooperate to protect and chaperone the nascent snRNA during its journey to the spliceosome.The mechanism of U6 small nuclear ribonucleoprotein (snRNP) biogenesis is not well understood. Here the authors characterize the enzymatic activities and structures of yeast and human U6 RNA processing enzyme Usb1, reconstitute post-transcriptional assembly of yeast U6 snRNP in vitro, and propose a model for U6 snRNP assembly. PMID- 28887447 TI - interleukin-11 induces and maintains progenitors of different cell lineages during Xenopus tadpole tail regeneration. AB - Unlike mammals, Xenopus laevis tadpoles possess high ability to regenerate their lost organs. In amphibians, the main source of regenerated tissues is lineage restricted tissue stem cells, but the mechanisms underlying induction, maintenance and differentiation of these stem/progenitor cells in the regenerating organs are poorly understood. We previously reported that interleukin-11 (il-11) is highly expressed in the proliferating cells of regenerating Xenopus tadpole tails. Here, we show that il-11 knockdown (KD) shortens the regenerated tail length, and the phenotype is rescued by forced-il 11-expression in the KD tadpoles. Moreover, marker genes for undifferentiated notochord, muscle, and sensory neurons are downregulated in the KD tadpoles, and the forced-il-11-expression in intact tadpole tails induces expression of these marker genes. Our findings demonstrate that il-11 is necessary for organ regeneration, and suggest that IL-11 plays a key role in the induction and maintenance of undifferentiated progenitors across cell lineages during Xenopus tail regeneration. Xenopus laevis tadpoles have maintained their ability to regenerate various organs. Here, the authors show that interleukin-11 is necessary for organ regeneration, by inducing and maintaining undifferentiated progenitors across cell lineages during Xenopus tail regeneration. PMID- 28887448 TI - Remarkable preservation of terpenoids and record of volatile signalling in plant animal interactions from Miocene amber. AB - Plants produce and release a large array of volatile organic compounds that play many ecological functions. These volatile plant metabolites serve as pollinator attractants, herbivore and pathogen repellents and protect plants from abiotic stresses. To date, the geological evolution of these organic compounds remains unknown. The preservation potential of these metabolites in the fossil record is very poor due to their low boiling points. Here we report a series of volatile sesquiterpenoids, including delta-elemene, alpha-copaene, beta-elemene, beta caryophyllene, alpha-humulene, germacrene D, delta-cadiene and spathunenol, from early Miocene (~17 million year) amber from eastern India. The survival of these unaltered bioterpenoids can be attributed to the existence of extraordinary taphonomic conditions conducive to the preservation of volatile biomolecules through deep time. Furthermore, the occurrence of these volatiles in the early Miocene amber suggests that the plants from this period had evolved metabolic pathways to synthesize these organic molecules to play an active role in forest ecology, especially in plant-animal interactions. PMID- 28887449 TI - Realization of tunable artificial synapse and memory based on amorphous oxide semiconductor transistor. AB - Recently, advanced designs and materials emerge to study biologically inspired neuromorphic circuit, such as oxide semiconductor devices. The existence of mobile ions in the oxide semiconductors could be somewhat regarded to be similar with the case of the ions movements among the neurons and synapses in the brain. Most of the previous studies focus on the spike time, pulse number and material species: however, a quantitative modeling is still needed to study the voltage dependence of the relaxation process of synaptic devices. Here, the gate pulse stimulated currents of oxide semiconductor devices have been employed to mimic and investigate artificial synapses functions. The modeling for relaxation process of important synaptic behaviors, excitatory post-synaptic current (EPSC), has been updated as a stretched-exponential function with voltage factors in a more quantitative way. This quantitative modeling investigation of representative synaptic transmission bias impacts would help to better simulate, realize and thus control neuromorphic computing. PMID- 28887450 TI - Effects of low concentrations of erythromycin, penicillin, and virginiamycin on bacterial resistance development in vitro. AB - Distillers grains are co-products of the corn ethanol industry widely used in animal feed. We examined the effects of erythromycin, penicillin, and virginiamycin at low concentrations reflective of those detected in distillers grains on bacterial resistance selection. At 0.1 ug/ml erythromycin, macrolide resistant mutants were induced in one Campylobacter coli and one Enterococcus faecium strain, while these strains plus three additional C. coli, one additional E. faecium, and one C. jejuni also developed resistance when exposed to 0.25 ug/ml erythromycin. At 0.5 ug/ml erythromycin, a total of eight strains (four Campylobacter and four Enterococcus) obtained macrolide-resistant mutants, including two strains from each genus that were not selected at lower erythromycin concentrations. For penicillin, three of five E. faecium strains but none of five Enterococcus faecalis strains consistently developed resistance at all three selection concentrations. Virginiamycin at two M1:S1 ratios did not induce resistance development in four out of five E. faecium strains; however, increased resistance was observed in the fifth one under 0.25 and 0.5 ug/ml virginiamycin selections. Although not yet tested in vivo, these findings suggest a potential risk of stimulating bacterial resistance development in the animal gut when distillers grains containing certain antibiotic residues are used in animal feed. PMID- 28887451 TI - Evolution of protein-coupled RNA dynamics during hierarchical assembly of ribosomal complexes. AB - Assembly of 30S ribosomes involves the hierarchical addition of ribosomal proteins that progressively stabilize the folded 16S rRNA. Here, we use three color single molecule FRET to show how combinations of ribosomal proteins uS4, uS17 and bS20 in the 16S 5' domain enable the recruitment of protein bS16, the next protein to join the complex. Analysis of real-time bS16 binding events shows that bS16 binds both native and non-native forms of the rRNA. The native rRNA conformation is increasingly favored after bS16 binds, explaining how bS16 drives later steps of 30S assembly. Chemical footprinting and molecular dynamics simulations show that each ribosomal protein switches the 16S conformation and dampens fluctuations at the interface between rRNA subdomains where bS16 binds. The results suggest that specific protein-induced changes in the rRNA dynamics underlie the hierarchy of 30S assembly and simplify the search for the native ribosome structure.Ribosomes assemble through the hierarchical addition of proteins to a ribosomal RNA scaffold. Here the authors use three-color single molecule FRET to show how the dynamics of the rRNA dictate the order in which multiple proteins assemble on the 5' domain of the E. coli 16S rRNA. PMID- 28887452 TI - Scalable carbon dioxide electroreduction coupled to carbonylation chemistry. AB - Significant efforts have been devoted over the last few years to develop efficient molecular electrocatalysts for the electrochemical reduction of carbon dioxide to carbon monoxide, the latter being an industrially important feedstock for the synthesis of bulk and fine chemicals. Whereas these efforts primarily focus on this formal oxygen abstraction step, there are no reports on the exploitation of the chemistry for scalable applications in carbonylation reactions. Here we describe the design and application of an inexpensive and user friendly electrochemical set-up combined with the two-chamber technology for performing Pd-catalysed carbonylation reactions including amino- and alkoxycarbonylations, as well as carbonylative Sonogashira and Suzuki couplings with near stoichiometric carbon monoxide. The combined two-reaction process allows for milligram to gram synthesis of pharmaceutically relevant compounds. Moreover, this technology can be adapted to the use of atmospheric carbon dioxide.Electroreduction of CO2 to CO is a potential valorisation pathway of carbon dioxide for fine chemicals production. Here, the authors show a user friendly device that couples CO2 electroreduction with carbonylation chemistry for up to gram scale synthesis of pharmaceuticals even under atmospheric CO2. PMID- 28887453 TI - Hyaluronic acid based extracellular matrix regulates surface expression of GluN2B containing NMDA receptors. AB - Cortical areas of the juvenile rodent brain display a high degree of structural and functional plasticity, which disappears later in development. Coincident with the decline of plasticity 1) the hyaluronic acid-based extracellular matrix (ECM) of the brain, which stabilizes synapses and neuronal circuit is formed and 2) N methyl-D-aspartate subtype of ionotropic glutamate receptors (NMDARs) implied in synaptic plasticity switch from mainly GluN2B to GluN2A subunit-containing receptors. Here we tested the hypothesis that ECM influences the NMDAR subunit composition in dissociated neuronal cultures. Experimental removal of ECM using hyaluronidase induced an increase in surface expression of GluN2B. This was due to decreased endocytosis of surface GluNB-containing receptors. We further found a reduction in phosphorylation at Tyr1472, which negatively regulates their binding to the endocytotic AP2 complex. We propose that maturation of ECM could induce switch in NMDAR composition necessary for normal adult synaptic plasticity and that increased expression of GluN2B contributes to rejuvenation of plasticity after ECM removal in vivo. PMID- 28887454 TI - The intestinal phosphate transporter NaPi-IIb (Slc34a2) is required to protect bone during dietary phosphate restriction. AB - NaPi-IIb/Slc34a2 is a Na+-dependent phosphate transporter that accounts for the majority of active phosphate transport into intestinal epithelial cells. Its abundance is regulated by dietary phosphate, being high during dietary phosphate restriction. Intestinal ablation of NaPi-IIb in mice leads to increased fecal excretion of phosphate, which is compensated by enhanced renal reabsorption. Here we compared the adaptation to dietary phosphate of wild type (WT) and NaPi-IIb-/- mice. High phosphate diet (HPD) increased fecal and urinary excretion of phosphate in both groups, though NaPi-IIb-/- mice still showed lower urinary excretion than WT. In both genotypes low dietary phosphate (LDP) resulted in reduced fecal excretion and almost undetectable urinary excretion of phosphate. Consistently, the expression of renal cotransporters after prolonged LDP was similar in both groups. Plasma phosphate declined more rapidly in NaPi-IIb-/- mice upon LDP, though both genotypes had comparable levels of 1,25(OH)2vitamin D3, parathyroid hormone and fibroblast growth factor 23. Instead, NaPi-IIb-/- mice fed LDP had exacerbated hypercalciuria, higher urinary excretion of corticosterone and deoxypyridinoline, lower bone mineral density and higher number of osteoclasts. These data suggest that during dietary phosphate restriction NaPi-IIb-mediated intestinal absorption prevents excessive demineralization of bone as an alternative source of phosphate. PMID- 28887455 TI - Neonicotinoids act like endocrine disrupting chemicals in newly-emerged bees and winter bees. AB - Accumulating evidence suggests that neonicotinoids may have long-term adverse effects on bee health, yet our understanding of how this could occur is incomplete. Pesticides can act as endocrine disrupting chemicals (EDCs) in animals providing characteristic multiphasic dose-response curves and non-lethal endpoints in toxicity studies. However, it is not known if neonicotinoids act as EDCs in bees. To address this issue, we performed oral acute and chronic toxicity studies including concentrations recorded in nectar and pollen, applying acetamiprid, clothianidin, imidacloprid, and thiamethoxam to bumble bees, honey bees and leafcutter bees, the three most common bee species managed for pollination. In acute toxicity studies, late-onset symptoms, such as ataxia, were recorded as non-lethal endpoints for all three bee species. Clothianidin and thiamethoxam produced biphasic dose-response curves for all three bee species. Clothianidin and thiamethoxam were extremely toxic to winter worker honey bees prior to brood production in spring, making this the most sensitive bee stage identified to date. Chronic exposure to field-realistic levels of neonicotinoids reduced bee survival and caused significant late-onset symptoms for all three bee species. Given these findings, neonicotinoid risk should be reevaluated to address the EDC-like behavior and the sensitivity of winter worker honey bees. PMID- 28887456 TI - Demonstration of a beam loaded nanocoulomb-class laser wakefield accelerator. AB - Laser-plasma wakefield accelerators have seen tremendous progress, now capable of producing quasi-monoenergetic electron beams in the GeV energy range with few femtoseconds bunch duration. Scaling these accelerators to the nanocoulomb range would yield hundreds of kiloamperes peak current and stimulate the next generation of radiation sources covering high-field THz, high-brightness X-ray and gamma-ray sources, compact free-electron lasers and laboratory-size beam driven plasma accelerators. However, accelerators generating such currents operate in the beam loading regime where the accelerating field is strongly modified by the self-fields of the injected bunch, potentially deteriorating key beam parameters. Here we demonstrate that, if appropriately controlled, the beam loading effect can be employed to improve the accelerator's performance. Self truncated ionization injection enables loading of unprecedented charges of ~0.5 nC within a mono-energetic peak. As the energy balance is reached, we show that the accelerator operates at the theoretically predicted optimal loading condition and the final energy spread is minimized.Higher beam quality and stability are desired in laser-plasma accelerators for their applications in compact light sources. Here the authors demonstrate in laser plasma wakefield electron acceleration that the beam loading effect can be employed to improve beam quality by controlling the beam charge. PMID- 28887457 TI - Spinal miRNA-124 regulates synaptopodin and nociception in an animal model of bone cancer pain. AB - Strong breakthrough pain is one of the most disabling symptoms of cancer since it affects up to 90% of cancer patients and is often refractory to treatments. Alteration in gene expression is a known mechanism of cancer pain in which microRNAs (miRNAs), a class of non-coding regulatory RNAs, play a crucial role. Here, in a mouse model of cancer pain, we show that miR-124 is down-regulated in the spinal cord, the first relay of the pain signal to the brain. Using in vitro and in vivo approaches, we demonstrate that miR-124 is an endogenous and specific inhibitor of synaptopodin (Synpo), a key protein for synaptic transmission. In addition, we demonstrate that Synpo is a key component of the nociceptive pathways. Interestingly, miR-124 was down-regulated in the spinal cord in cancer pain conditions, leading to an up-regulation of Synpo. Furthermore, intrathecal injections of miR-124 mimics in cancerous mice normalized Synpo expression and completely alleviated cancer pain in the early phase of the cancer. Finally, miR 124 was also down-regulated in the cerebrospinal fluid of cancer patients who developed pain, suggesting that miR-124 could be an efficient analgesic drug to treat cancer pain patients. PMID- 28887458 TI - Increased 15-PGDH expression leads to dysregulated resolution responses in stromal cells from patients with chronic tendinopathy. AB - The mechanisms underpinning the failure of inflammation to resolve in diseased musculoskeletal soft tissues are unknown. Herein, we studied bioactive lipid mediator (LM) profiles of tendon-derived stromal cells isolated from healthy donors and patients with chronic tendinopathy. Interleukin(IL)-1beta treatment markedly induced prostaglandin biosynthesis in diseased compared to healthy tendon cells, and up regulated the formation of several pro-resolving mediators including 15-epi-LXA4 and MaR1. Incubation of IL-1beta stimulated healthy tendon cells with 15-epi-LXA4 or MaR1 down-regulated PGE2 and PGD2 production. When these mediators were incubated with diseased cells, we only found a modest down regulation in prostanoid concentrations, whereas it led to significant decreases in IL-6 and Podoplanin expression. In diseased tendon cells, we also found increased 15-Prostaglandin Dehydrogenase (15-PGDH) expression as well as increased concentrations of both 15-epi-LXA4 and MaR1 further metabolites, 15-oxo LXA4 and 14-oxo-MaR1. Inhibition of 15-PGDH using either indomethacin or SW033291 significantly reduced the further conversion of 15-epi-LXA4 and MaR1 and regulated expression of IL-6, PDPN and STAT-1. Taken together these results suggest that chronic inflammation in musculoskeletal soft tissues may result from dysregulated LM-SPM production, and that inhibition of 15-PGDH activity together with promoting resolution using SPM represents a novel therapeutic strategy to resolve chronic tendon inflammation. PMID- 28887459 TI - The unexpected role of bioaerosols in the Oxidative Potential of PM. AB - Bioaerosols represent up to 15-25% of PM by mass, but there is currently no assessment of their impact on Oxidative Potential (OP), or capacity of particulate matter (PM) to produce damaging oxidative reactions in the human lungs. Here, the OP of selected bioaerosols (bacteria cells vs fungal spores) was assessed through the cell-free DTT assay. Results show that bioaerosols induce Reactive Oxygen Species (ROS) production, varying along the microorganism type, species, and concentration. Fungal spores show up to 10 times more ROS generation than bacterial cells. At the highest concentrations, fungal spores present as much oxidative reactivity as the most redox-active airborne chemicals (Copper, Naphtoquinone). Moreover, bioaerosols substantially influence OP of ambient PM and that of its chemical constituents: in presence of A. fumigatus spores, the OP of Cu/NQ is increased by a factor of 2 to 5, whereas, 104 and 105 S. epidermidis bacterial cells.mL-1 halves the OP of Cu/NQ. Finally, viable and gamma-rays killed model bioaerosols present similar oxidative reactivity, suggesting a metabolism-independent cellular mechanism. These results reveal the importance of bioaerosols for PM reactivity. PM toxicity can be modified due to bioaerosols contribution or by their ability to modulate the OP of toxic chemicals present in PM. PMID- 28887461 TI - On the consistency of seismically imaged lower mantle slabs. AB - The geoscience community is increasingly utilizing seismic tomography to interpret mantle heterogeneity and its links to past tectonic and geodynamic processes. To assess the robustness and distribution of positive seismic anomalies, inferred as subducted slabs, we create a set of vote maps for the lower mantle with 14 global P-wave or S-wave tomography models. Based on a depth dependent threshold metric, an average of 20% of any given tomography model depth is identified as a potential slab. However, upon combining the 14 models, the most consistent positive wavespeed features are identified by an increasing vote count. An overall peak in the most robust anomalies is found between 1000-1400 km depth, followed by a decline to a minimum around 2000 km. While this trend could reflect reduced tomographic resolution in the middle mantle, we show that it may alternatively relate to real changes in the time-dependent subduction flux and/or a mid-lower mantle viscosity increase. An apparent secondary peak in agreement below 2500 km depth may reflect the degree-two lower mantle slow seismic structures. Vote maps illustrate the potential shortcomings of using a limited number or type of tomography models and slab threshold criteria. PMID- 28887462 TI - Evaluating strategies for reversing CRISPR-Cas9 gene drives. AB - A gene drive biases inheritance of a gene so that it increases in frequency within a population even when the gene confers no fitness benefit. There has been renewed interest in environmental releases of engineered gene drives due to recent proof of principle experiments with the CRISPR-Cas9 system as a drive mechanism. Release of modified organisms, however, is controversial, especially when the drive mechanism could theoretically alter all individuals of a species. Thus, it is desirable to have countermeasures to reverse a drive if a problem arises. Several genetic mechanisms for limiting or eliminating gene drives have been proposed and/or developed, including synthetic resistance, reversal drives, and immunizing reversal drives. While predictions about efficacy of these mechanisms have been optimistic, we lack detailed analyses of their expected dynamics. We develop a discrete time model for population genetics of a drive and proposed genetic countermeasures. Efficacy of drive reversal varies between countermeasures. For some parameter values, the model predicts unexpected behavior including polymorphic equilibria and oscillatory dynamics. The timing and number of released individuals containing a genetic countermeasure can substantially impact outcomes. The choice among countermeasures by researchers and regulators will depend on specific goals and population parameters of target populations. PMID- 28887460 TI - Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand- and structure-based virtual screening approach. AB - Transient receptor potential melastatin 8 (TRPM8), a nonselective cation channel, is the predominant mammalian cold temperature thermosensor and it is activated by cold temperatures and cooling compounds, such as menthol and icilin. Because of its role in cold allodynia, cold hyperalgesia and painful syndromes TRPM8 antagonists are currently being pursued as potential therapeutic agents for the treatment of pain hypersensitivity. Recently TRPM8 has been found in subsets of bladder sensory nerve fibres, providing an opportunity to understand and treat chronic hypersensitivity. However, most of the known TRPM8 inhibitors lack selectivity, and only three selective compounds have reached clinical trials to date. Here, we applied two virtual screening strategies to find new, clinics suitable, TRPM8 inhibitors. This strategy enabled us to identify naphthyl derivatives as a novel class of potent and selective TRPM8 inhibitors. Further characterization of the pharmacologic properties of the most potent compound identified, compound 1, confirmed that it is a selective, competitive antagonist inhibitor of TRPM8. Compound 1 also proved itself active in a overreactive bladder model in vivo. Thus, the novel naphthyl derivative compound identified here could be optimized for clinical treatment of pain hypersensitivity in bladder disorders but also in different other pathologies. PMID- 28887463 TI - Functional Characterization of Two Elongases of Very Long-Chain Fatty Acid from Tenebrio molitor L. (Coleoptera: Tenebrionidae). AB - The elongases of very long chain fatty acid (ELOVL or ELO) are essential in the biosynthesis of fatty acids longer than C14. Here, two ELO full-length cDNAs (TmELO1, TmELO2) from the yellow mealworm (Tenebrio molitor L.) were isolated and the functions were characterized. The open reading frame (ORF) lengths of TmELO1 and TmELO2 were 1005 bp and 972 bp, respectively and the corresponding peptide sequences each contained several conserved motifs including the histidine-box motif HXXHH. Phylogenetic analysis demonstrated high similarity with the ELO of Tribolium castaneum and Drosophila melanogaster. Both TmELO genes were expressed at various levels in eggs, 1st and 2nd instar larvae, mature larvae, pupae, male and female adults. Injection of dsTmELO1 but not dsTmELO2 RNA into mature larvae significantly increased mortality although RNAi did not produce any obvious changes in the fatty acid composition in the survivors. Heterologous expression of TmELO genes in yeast revealed that TmELO1 and TmELO2 function to synthesize long chain and very long chain fatty acids. PMID- 28887464 TI - RNAseq revealed the important gene pathways controlling adaptive mechanisms under waterlogged stress in maize. AB - Waterlogging causes yield penalty in maize-growing countries of subtropical regions. Transcriptome analysis of the roots of a tolerant inbred HKI1105 using RNA sequencing revealed 21,364 differentially expressed genes (DEGs) under waterlogged stress condition. These 21,364 DEGs are known to regulate important pathways including energy-production, programmed cell death (PCD), aerenchyma formation, and ethylene responsiveness. High up-regulation of invertase (49-fold) and hexokinase (36-fold) in roots explained the ATP requirement in waterlogging condition. Also, high up-regulation of expansins (42-fold), plant aspartic protease A3 (19-fold), polygalacturonases (16-fold), respiratory burst oxidase homolog (12-fold), and hydrolases (11-fold) explained the PCD of root cortical cells followed by the formation of aerenchyma tissue during waterlogging stress. We hypothesized that the oxygen transfer in waterlogged roots is promoted by a cross-talk of fermentative, metabolic, and glycolytic pathways that generate ATPs for PCD and aerenchyma formation in root cortical cells. SNPs were mapped to the DEGs regulating aerenchyma formation (12), ethylene-responsive factors (11), and glycolysis (4) under stress. RNAseq derived SNPs can be used in selection approaches to breed tolerant hybrids. Overall, this investigation provided significant evidence of genes operating in the adaptive traits such as ethylene production and aerenchyma formation to cope-up the waterlogging stress. PMID- 28887465 TI - Host immune status-specific production of gliotoxin and bis-methyl-gliotoxin during invasive aspergillosis in mice. AB - Delayed diagnosis in invasive aspergillosis (IA) contributes to its high mortality. Gliotoxin (GT) and bis-methyl-gliotoxin (bmGT) are secondary metabolites produced by Aspergillus during invasive, hyphal growth and may prove diagnostically useful. Because IA pathophysiology and GT's role in virulence vary depending on the underlying host immune status, we hypothesized that GT and bmGT production in vivo may differ in three mouse models of IA that mimic human disease. We defined temporal kinetics of GT and bmGT in serum, bronchoalveolar lavage fluid (BALF) and lungs of A. fumigatus-infected chronic granulomatous disease (CGD), hydrocortisone-treated, and neutropenic mice. We harvested lungs for assessment of fungal burden, histology and GT/bmGT biosynthetic genes' mRNA induction. GT levels were higher in neutropenic versus CGD or steroid-treated lungs. bmGT was persistently detected only in CGD lungs. GT, but not bmGT, was detected in 71% of sera and 50% of BALF of neutropenic mice; neither was detected in serum/BALF of CGD or steroid-treated mice. Enrichment of GT in Aspergillus infected neutropenic lung correlated with fungal burden and hyphal length but not induction of GT biosynthetic genes. In summary, GT is detectable in mouse lungs, serum and BALF during neutropenic IA, suggesting that GT may be useful to diagnose IA in neutropenic patients. PMID- 28887467 TI - Long-term impact of Amazon river runoff on northern hemispheric climate. AB - Amazon discharges a large volume of freshwater into the ocean, yet its impact on climate is largely unknown. Climate projections show that a warmer northern tropical Atlantic Ocean together with a warmer equatorial Pacific lead to extreme droughts in the Amazonia, considerably reducing the Amazon runoff. Here we present results from coupled model simulations and observations on the climatic response to a significant reduction in Amazon runoff into the Atlantic Ocean. Climate model simulation without Amazon runoff resulted in cooler equatorial Atlantic, weakening the Hadley cell and thereby the atmospheric meridional cells. Consequently, the extratropical westerlies turned weaker, leading to prevalent negative North Atlantic Oscillation (NAO) like climate, similar to the observed anomalies during Amazon drought years. This study reaffirms that spatial signature of NAO is in part driven by sea surface temperature (SST) anomalies in the tropical Atlantic. Winters of northern Europe and eastern Canada turned cooler and drier whereas southern Europe and the eastern United States experienced warmer and wetter winters without Amazon runoff. Significant warming over the Arctic reduced the local sea-ice extent and enhanced the high latitude river runoff. More importantly, our simulations caution against extreme exploitation of rivers for its far-reaching consequences on climate. PMID- 28887466 TI - HPLC-based quantification of bacterial housekeeping nucleotides and alarmone messengers ppGpp and pppGpp. AB - Here we describe an HPLC-based method to quantify bacterial housekeeping nucleotides and the signaling messengers ppGpp and pppGpp. We have replicated and tested several previously reported HPLC-based approaches and assembled a method that can process 50 samples in three days, thus making kinetically resolved experiments feasible. The method combines cell harvesting by rapid filtration, followed by acid extraction, freeze-drying with chromatographic separation. We use a combination of C18 IPRP-HPLC (GMP unresolved and co-migrating with IMP; GDP and GTP; AMP, ADP and ATP; CTP; UTP) and SAX-HPLC in isocratic mode (ppGpp and pppGpp) with UV detection. The approach is applicable to bacteria without the requirement of metabolic labelling with 32P-labelled radioactive precursors. We applied our method to quantify nucleotide pools in Escherichia coli BW25113 K12 strain both throughout the growth curve and during acute stringent response induced by mupirocin. While ppGpp and pppGpp levels vary drastically (40- and >=8 fold, respectively) these changes are decoupled from the quotients of the housekeeping pool and guanosine and adenosine housekeeping nucleotides: NTP/NDP/NMP ratio remains stable at 6/1/0.3 during both normal batch culture growth and upon acute amino acid starvation. PMID- 28887468 TI - The network of plants volatile organic compounds. AB - Plants emission of Volatile Organic Compounds (VOCs) is involved in a wide class of ecological functions, as VOCs play a crucial role in plants interactions with biotic and abiotic factors. Accordingly, they vary widely across species and underpin differences in ecological strategy. In this paper, VOCs spontaneously emitted by 109 plant species (belonging to 56 different families) have been qualitatively and quantitatively analysed in order to provide an alternative classification of plants species. In particular, by using bipartite networks methodology from Complex Network Theory, and through the application of community detection algorithms, we show that is possible to classify species according to chemical classes such as terpenes and sulfur compounds. Such complex network analysis allows to uncover hidden plants relationships related to their evolutionary and adaptation to the environment story. PMID- 28887469 TI - Analysis of mutual couplings in a concentric circular ring plasmonic optical antenna array. AB - In this paper, we report the analysis of a concentric circular ring plasmonic optical antenna (POA) array using a simple lumped coupled circuit (LCC) model. The currents in the circular rings of the POA array and their mutual couplings are analyzed using the LCC model. The results agree well with the numerical simulation using CST's Microwave Studio(r). The LCC model reveals the mutual couplings between the antenna rings. It is found that the mutual couplings are not only between the adjacent antenna rings, but also involve their second (2nd) nearest or farther neighbors. Since the near-fields of the optical antennas are related to the currents in the optical antennas, the LCC model provides a useful tool for the analysis of the near-field and their mutual interactions in the circular ring POA array. PMID- 28887471 TI - Spatially encoded fast single-molecule fluorescence spectroscopy with full field of-view. AB - We report a simple single-molecule fluorescence imaging method that increases the temporal resolution of any type of array detector by >5-fold with full field-of view. We spread single-molecule spots to adjacent pixels by rotating a mirror in the detection path during the exposure time of a single frame, which encodes temporal information into the spatial domain. Our approach allowed us to monitor fast blinking of an organic dye, the dissociation kinetics of very short DNA and conformational changes of biomolecules with much improved temporal resolution than the conventional method. Our technique is useful when a large field-of-view is required, for example, in the case of weakly interacting biomolecules or cellular imaging. PMID- 28887470 TI - Direct measurement of individual phonon lifetimes in the clathrate compound Ba7.81Ge40.67Au5.33. AB - Engineering lattice thermal conductivity requires to control the heat carried by atomic vibration waves, the phonons. The key parameter for quantifying it is the phonon lifetime, limiting the travelling distance, whose determination is however at the limits of instrumental capabilities. Here, we show the achievement of a direct quantitative measurement of phonon lifetimes in a single crystal of the clathrate Ba7.81Ge40.67Au5.33, renowned for its puzzling 'glass-like' thermal conductivity. Surprisingly, thermal transport is dominated by acoustic phonons with long lifetimes, travelling over distances of 10 to 100 nm as their wave vector goes from 0.3 to 0.1 A-1. Considering only low-energy acoustic phonons, and their observed lifetime, leads to a calculated thermal conductivity very close to the experimental one. Our results challenge the current picture of thermal transport in clathrates, underlining the inability of state-of-the-art simulations to reproduce the experimental data, thus representing a crucial experimental input for theoretical developments.Phonon lifetime is a fundamental parameter of thermal transport however its determination is challenging. Using inelastic neutron scattering and the neutron resonant spin-echo technique, Lory et al. determine the acoustic phonon lifetime in a single crystal of clathrate Ba7.81Ge40.67Au5.33. PMID- 28887472 TI - Radial arrangement of apical adhesive sites promotes contact self-alignment of fruits in Commicarpus plants (Nyctaginaceae). AB - Fruits of the plants from the genus Commicarpus (Nyctaginaceae) use their adhesive properties for dispersal. They can readily stick to various surfaces including skin, fur, and feathers of potential dispersal vectors using the secretion provided by the set of glands arranged radially at the distal end of the cut-cone-shaped fruit. Field observations show that this particular geometry promotes self-alignment of the fruit to various surfaces after initial contact just by one gland is established. Such self-alignment in turn leads to an increase of the number of contacting points and to the enhancement of adhesive contact area. Here, we study this particular geometry from a theoretical point of view, by probing adhesion ability of geometries having from 2 to 7 radially distributed attachment points. The results show that the radial arrangement provides rapid alignment to the surface. The robust adhesion can be reached already at 5 adhesive points and their further increase does not substantially improve the performance. This study is important not only for our understanding of the functional morphology of biological adhesive systems, but also for the development of technical self-aligning adhesive devices. PMID- 28887473 TI - Complete sequence-based pathway analysis by differential on-chip DNA and RNA extraction from a single cell. AB - We demonstrate on-chip, differential DNA and RNA extraction from a single cell using a microfluidic chip and a two-stage lysis protocol. This method enables direct use of the whole extract, without additional washing steps, reducing sample loss. Using this method, the tumor driving pathway in individual cells from a colorectal cancer cell line was determined by applying a Bayesian computational pathway model to sequences obtained from the RNA fraction of a single cell and, the mutations driving the pathway were determined by analyzing sequences obtained from the DNA fraction of the same single cell. This combined functional and mutational pathway assessment of a single cell could be of significant value for dissecting cellular heterogeneity in tumors and analyzing single circulating tumor cells. PMID- 28887474 TI - Body Fat Distribution and the Risk of Incident Metabolic Syndrome: A Longitudinal Cohort Study. AB - The effect of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) area on metabolic syndrome (MS) has been debated. We aimed to evaluate the effects of VAT and SAT on the incidence of MS and its components in a large and apparently healthy Asian population. We performed a longitudinal cohort study of 1,964 subjects who received health screenings over a 5-year follow-up period; 317 incidents of MS (16.1%) were observed during a median follow-up of 4.5 years. The VAT area was significantly associated with a higher incidence of MS; the adjusted HR for incident MS per 1 SD of VAT was 1.50 (95% CI 1.29-1.74), and the adjusted HR of the 5th VAT quintile compared with the 1st quintile was 3.73 (95% CI 2.22 6.28). However, the SAT area was not associated with incident MS. Although the VAT area was longitudinally associated with the incidence of each component of MS, the SAT area was inversely associated with the risk of high blood pressure, fasting blood sugar, and triglycerides, with marginal significance. In conclusion, the VAT area is longitudinally associated with an increased risk of incident MS, while SAT may have a protective effect against the incidence of individual MS components. PMID- 28887475 TI - Noble UV protective agent for Bacillus thuringiensis based on a combination of graphene oxide and olive oil. AB - The focus of this study is investigating the performance of graphene oxide (GO) in the protective effect of olive oil on Bacillus thuringiensis (Bt) after being exposed to UV radiations. Biological pesticides Bt subsp. Kurstaki is one of the most important biological control agents. We compared the protective effect of two UV protectant; GO and olive oil and also the combination of both, on the stability of the formulation of Bt after exposure to UV radiations. Spore viability was measured for protective effect and bioassay test was performed on the formulations of Bt. The combination of GO and olive oil revealed the highest viabilities of 50.62% after 96 h exposure to UV radiation, while viabilities of free spore, olive oil formulation and GO formulation were 32.54%, 37.19%,and 45.20%, respectively. The mortality of irradiated combination formulation on second-instar larvae Ephestia Kuehniella was 68.89%, while the same parameter for free spore, olive oil formulation and GO formulation were 40%, 46.66%,and 56%, respectively. PMID- 28887476 TI - The C-terminal residue of phage Vp16 PDF, the smallest peptide deformylase, acts as an offset element locking the active conformation. AB - Prokaryotic proteins must be deformylated before the removal of their first methionine. Peptide deformylase (PDF) is indispensable and guarantees this mechanism. Recent metagenomics studies revealed new idiosyncratic PDF forms as the most abundant family of viral sequences. Little is known regarding these viral PDFs, including the capacity of the corresponding encoded proteins to ensure deformylase activity. We provide here the first evidence that viral PDFs, including the shortest PDF identified to date, Vp16 PDF, display deformylase activity in vivo, despite the absence of the key ribosome-interacting C-terminal region. Moreover, characterization of phage Vp16 PDF underscores unexpected structural and molecular features with the C-terminal Isoleucine residue significantly contributing to deformylase activity both in vitro and in vivo. This residue fully compensates for the absence of the usual long C-domain. Taken together, these data elucidate an unexpected mechanism of enzyme natural evolution and adaptation within viral sequences. PMID- 28887477 TI - Neuropilin-1 is upregulated by Wnt/beta-catenin signaling and is important for mammary stem cells. AB - Wnt/beta-catenin signaling is instrumental for the development of mammary gland and the properties of mammary stem cells (MaSCs). The Wnt signaling downstream effectors that engage in regulating MaSCs have not been extensively studied. Here, we report that Neuropilin-1 (Nrp1) expression is induced by Wnt/beta catenin signaling in MaSCs, and its function is critical for the activity of MaSCs. Nrp1 is particularly expressed in MaSCs that are marked by the expression of Protein C Receptor (Procr). Knockdown of Nrp1 by shRNA diminishes MaSCs' in vitro colony formation and in vivo mammary gland reconstitution ability. Similar results are seen when antagonizing Nrp1 using a dominant negative peptide. In genetic experiments, deletion of Nrp1 results in delay of mammary development. In addition, knockdown of Nrp1 inhibits MMTV-Wnt1 tumor growth in xenograft. Our data demonstrate that Nrp1 is critical for mammary development and tumorigenesis, revealing new insights into MaSC regulation and targeting stem cells in treatment of breast cancer. PMID- 28887478 TI - Stat3 as a potential therapeutic target for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a multi-factorial disease characterized by chronic inflammation and destruction of multiple joints. To date, various biologic treatments for RA such as anti-tumor necrosis factor alpha antibodies have been developed; however, mechanisms underlying RA development remain unclear and targeted therapy for this condition has not been established. Here, we provide evidence that signal transducer and activator of transcription 3 (Stat3) promotes inflammation and joint erosion in a mouse model of arthritis. Stat3 global KO mice show early embryonic lethality; thus, we generated viable Stat3 conditional knockout adult mice and found that they were significantly resistant to collagen induced arthritis (CIA), the most common RA model, compared with controls. We then used an in vitro culture system to screen ninety-six existing drugs to select Stat3 inhibitors and selected five candidate inhibitors. Among them, three significantly inhibited development of arthritis and joint erosion in CIA wild type mice. These findings suggest that Stat3 inhibitors may serve as promising drugs for RA therapy. PMID- 28887479 TI - Field-Effect Transistor Biosensor for Rapid Detection of Ebola Antigen. AB - The Ebola virus transmits a highly contagious, frequently fatal human disease for which there is no specific antiviral treatment. Therefore, rapid, accurate, and early diagnosis of Ebola virus disease (EVD) is critical to public health containment efforts, particularly in developing countries where resources are few and EVD is endemic. We have developed a reduced graphene oxide-based field-effect transistor method for real-time detection of the Ebola virus antigen. This method uses the attractive semiconductor characteristics of graphene-based material, and instantaneously yields highly sensitive and specific detection of Ebola glycoprotein. The feasibility of this method for clinical application in point-of care technology is evaluated using Ebola glycoprotein suspended in diluted PBS buffer, human serum, and plasma. These results demonstrate the successful fabrication of a promising field-effect transistor biosensor for EVD diagnosis. PMID- 28887480 TI - Deep Neural Network Probabilistic Decoder for Stabilizer Codes. AB - Neural networks can efficiently encode the probability distribution of errors in an error correcting code. Moreover, these distributions can be conditioned on the syndromes of the corresponding errors. This paves a path forward for a decoder that employs a neural network to calculate the conditional distribution, then sample from the distribution - the sample will be the predicted error for the given syndrome. We present an implementation of such an algorithm that can be applied to any stabilizer code. Testing it on the toric code, it has higher threshold than a number of known decoders thanks to naturally finding the most probable error and accounting for correlations between errors. PMID- 28887481 TI - Glycosylation-dependent galectin-1/neuropilin-1 interactions promote liver fibrosis through activation of TGF-beta- and PDGF-like signals in hepatic stellate cells. AB - Concomitant expressions of glycan-binding proteins and their bound glycans regulate many pathophysiologic processes, but this issue has not been addressed in liver fibrosis. Activation of hepatic stellate cells (HSCs) is a rate-limiting step in liver fibrosis and is an important target for liver fibrosis therapy. We previously reported that galectin (Gal)-1, a beta-galactoside-binding protein, regulates myofibroblast homeostasis in oral carcinoma and wound healing, but the role of Gal-1 in HSC migration and activation is unclear. Herein, we report that Gal-1 and its bound glycans were highly expressed in fibrotic livers and activated HSCs. The cell-surface glycome of activated HSCs facilitated Gal-1 binding, which upon recognition of the N-glycans on neuropilin (NRP)-1, activated platelet-derived growth factor (PDGF)- and transforming growth factor (TGF)-beta like signals to promote HSC migration and activation. In addition, blocking endogenous Gal-1 expression suppressed PDGF- and TGF-beta1-induced signaling, migration, and gene expression in HSCs. Methionine and choline-deficient diet (MCD)-induced collagen deposition and HSC activation were attenuated in Gal-1 null mice compared to wild-type mice. In summary, we concluded that glycosylation dependent Gal-1/NRP-1 interactions activate TGF-beta and PDGF-like signaling to promote the migration and activation of HSCs. Therefore, targeting Gal-1/NRP-1 interactions could be developed into liver fibrosis therapy. PMID- 28887482 TI - Preliminary evidence of olfactory signals of women's fertility increasing social avoidance behavior towards women in pair-bonded men. AB - Previous studies suggest that women's body odor is perceived as more attractive during ovulation and that exposure to women's chemical signals of high fertility leads to increased mating motivation. Given that pair-bonded men react differently than single men to unfamiliar women, we investigated whether women's chemical signals of fertility influence approach behavior among pair-bonded and single men. In the first experiment, men performed the Comfortable Interpersonal Distance task while exposed to body odor samples from women who were ovulating and from the same women during their luteal phase. We found that in the presence of the body odor from ovulation, pair-bonded, but not single men, maintained greater distance from different protagonists, particularly from women. In a second experiment we exposed men to women's body odors while they rated the attractiveness and beauty of women's faces. Although the ratings of women's beauty did not differ across odor conditions, when the pair-bonded men were exposed to the high fertility odor they rated highly attractive women as less sexually attractive. The results suggest that exposure to fertility cues from unfamiliar women may trigger social avoidance in pair-bonded men, an outcome that may result from identifying such cues as threats to their relationship. PMID- 28887483 TI - Responses of plant species diversity and soil physical-chemical-microbial properties to Phragmites australis invasion along a density gradient. AB - The invasion of ecosystems by strongly colonising plants such as Phragmites australis is viewed as one of the greatest threats to plant diversity and soil properties. This study compared a range of diversity measures including soil properties and mycorrhizal potential under different degrees of Phragmites density among three populations in coastal wetland, Victoria, Australia. Species richness, evenness and Shanon-Wiener index had significantly higher values in low degree of Phragmites density in all populations. Higher densities had the lowest diversity, with Shannon-Wiener index = 0 and Simpson's index = 1 indicating its mono-specificity. Significant alterations in soil properties associated with different degrees of Phragmites density were noticed. These had interactive effects (population * density) on water content, dehydrogenase activity, microbial biomass (C, N and P) but not on pH, electrical conductivity, phenolics, organic carbon, and spore density. Furthermore, the study elucidated decrease of competitive abilities of native plants, by interfering with formation of mycorrhizal associations and biomass. Overall, our results suggest that significant ecological alterations in vegetation and soil variables (including mycorrhizal potential) were strongly dependent on Phragmites density. Such changes may lead to an important role in process of Phragmites invasion through disruption of functional relationships amongst those variables. PMID- 28887484 TI - Differential degeneration of the ACTAGT sequence among Salmonella: a reflection of distinct nucleotide amelioration patterns during bacterial divergence. AB - When bacteria diverge, they need to adapt to the new environments, such as new hosts or different tissues of the same host, by accumulating beneficial genomic variations, but a general scenario is unknown due to the lack of appropriate methods. Here we profiled the ACTAGT sequence and its degenerated forms (i.e., hexa-nucleotide sequences with one of the six nucleotides different from ACTAGT) in Salmonella to estimate the nucleotide amelioration processes of bacterial genomes. ACTAGT was mostly located in coding sequences but was also found in several intergenic regions, with its degenerated forms widely scattered throughout the bacterial genomes. We speculated that the distribution of ACTAGT and its degenerated forms might be lineage-specific as a consequence of different selection pressures imposed on ACTAGT at different genomic locations (in genes or intergenic regions) among different Salmonella lineages. To validate this speculation, we modelled the secondary structures of the ACTAGT-containing sequences conserved across Salmonella and many other enteric bacteria. Compared to ACTAGT at conserved regions, the degenerated forms were distributed throughout the bacterial genomes, with the degeneration patterns being highly similar among bacteria of the same phylogenetic lineage but radically different across different lineages. This finding demonstrates biased amelioration under distinct selection pressures among the bacteria and provides insights into genomic evolution during bacterial divergence. PMID- 28887485 TI - Direct comparison of performance of single nucleotide variant calling in human genome with alignment-based and assembly-based approaches. AB - Complementary to reference-based variant detection, recent studies revealed that many novel variants could be detected with de novo assembled genomes. To evaluate the effect of reads coverage and the accuracy of assembly-based variant calling, we simulated short reads containing more than 3 million of single nucleotide variants (SNVs) from the whole human genome and compared the efficiency of SNV calling between the assembly-based and alignment-based calling approaches. We assessed the quality of the assembled contig and found that a minimum of 30X coverage of short reads was needed to ensure reliable SNV calling and to generate assembled contigs with a good coverage of genome and genes. In addition, we observed that the assembly-based approach had a much lower recall rate and precision comparing to the alignment-based approach that would recover 99% of imputed SNVs. We observed similar results with experimental reads for NA24385, an individual whose germline variants were well characterized. Although there are additional values for SNVs detection, the assembly-based approach would have great risk of false discovery of novel SNVs. Further improvement of de novo assembly algorithms are needed in order to warrant a good completeness of genome with haplotype resolved and high fidelity of assembled sequences. PMID- 28887486 TI - Propagation of superconducting coherence via chiral quantum-Hall edge channels. AB - Recently, there has been significant interest in superconducting coherence via chiral quantum-Hall (QH) edge channels at an interface between a two-dimensional normal conductor and a superconductor (N-S) in a strong transverse magnetic field. In the field range where the superconductivity and the QH state coexist, the coherent confinement of electron- and hole-like quasiparticles by the interplay of Andreev reflection and the QH effect leads to the formation of Andreev edge states (AES) along the N-S interface. Here, we report the electrical conductance characteristics via the AES formed in graphene-superconductor hybrid systems in a three-terminal configuration. This measurement configuration, involving the QH edge states outside a graphene-S interface, allows the detection of the longitudinal and QH conductance separately, excluding the bulk contribution. Convincing evidence for the superconducting coherence and its propagation via the chiral QH edge channels is provided by the conductance enhancement on both the upstream and the downstream sides of the superconducting electrode as well as in bias spectroscopy results below the superconducting critical temperature. Propagation of superconducting coherence via QH edge states was more evident as more edge channels participate in the Andreev process for high filling factors with reduced valley-mixing scattering. PMID- 28887489 TI - Hardware emulation of stochastic p-bits for invertible logic. AB - The common feature of nearly all logic and memory devices is that they make use of stable units to represent 0's and 1's. A completely different paradigm is based on three-terminal stochastic units which could be called "p-bits", where the output is a random telegraphic signal continuously fluctuating between 0 and 1 with a tunable mean. p-bits can be interconnected to receive weighted contributions from others in a network, and these weighted contributions can be chosen to not only solve problems of optimization and inference but also to implement precise Boolean functions in an inverted mode. This inverted operation of Boolean gates is particularly striking: They provide inputs consistent to a given output along with unique outputs to a given set of inputs. The existing demonstrations of accurate invertible logic are intriguing, but will these striking properties observed in computer simulations carry over to hardware implementations? This paper uses individual micro controllers to emulate p-bits, and we present results for a 4-bit ripple carry adder with 48 p-bits and a 4-bit multiplier with 46 p-bits working in inverted mode as a factorizer. Our results constitute a first step towards implementing p-bits with nano devices, like stochastic Magnetic Tunnel Junctions. PMID- 28887488 TI - The Chemical Form of Metal Species Released from Corroded Taper Junctions of Hip Implants: Synchrotron Analysis of Patient Tissue. AB - The mechanisms of metal release from the articulation at the head cup bearing and the tapered junctions of orthopaedic hip implants are known to differ and the debris generated varies in size, shape and volume. Significantly less metal is lost from the taper junction between Cobalt-Chromium-Molybdenum (CoCrMo) and Titanium (Ti) components (fretting-corrosion dominant mechanism), when compared to the CoCrMo bearing surfaces (wear-corrosion dominant mechanism). Corrosion particles from the taper junction can lead to Adverse Reactions to Metal Debris (ARMD) similar to those seen with CoCrMo bearings. We used synchrotron methods to understand the modes underlying clinically significant tissue reactions to Co, Cr and Ti by analysing viable peri-prosthetic tissue. Cr was present as Cr2O3 in the corroded group in addition to CrPO4 found in the metal-on-metal (MoM) group. Interestingly, Ti was present as TiO2 in an amorphous rather than rutile or anatase physical form. The metal species were co-localized in the same micron scale particles as result of corrosion processes and in one cell type, the phagocytes. This work gives new insights into the degradation products from metal devices as well as guidance for toxicological studies in humans. PMID- 28887487 TI - TrkB-enhancer facilitates functional recovery after traumatic brain injury. AB - Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the post-traumatic activation of JNK in a rodent model of TBI. The recordings of field excitatory post-synaptic potentials in the hippocampal CA1 subfield demonstrate that TBI inhibits the expression of long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals, and that CN2097 attenuates this LTP impairment. Lastly, we demonstrate that CN2097 significantly improves the complex auditory processing deficits, which are impaired after injury. The multifunctionality of CN2097 strongly suggests that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma. PMID- 28887490 TI - Organic-Silica Interactions in Saline: Elucidating the Structural Influence of Calcium in Low-Salinity Enhanced Oil Recovery. AB - Enhanced oil recovery using low-salinity solutions to sweep sandstone reservoirs is a widely-practiced strategy. The mechanisms governing this remain unresolved. Here, we elucidate the role of Ca2+ by combining chemical force microscopy (CFM) and molecular dynamics (MD) simulations. We probe the influence of electrolyte composition and concentration on the adsorption of a representative molecule, positively-charged alkylammonium, at the aqueous electrolyte/silica interface, for four electrolytes: NaCl, KCl, MgCl2, and CaCl2. CFM reveals stronger adhesion on silica in CaCl2 compared with the other electrolytes, and shows a concentration-dependent adhesion not observed for the other electrolytes. Using MD simulations, we model the electrolytes at a negatively-charged amorphous silica substrate and predict the adsorption of methylammonium. Our simulations reveal four classes of surface adsorption site, where the prevalence of these sites depends only on CaCl2 concentration. The sites relevant to strong adhesion feature the O- silica site and Ca2+ in the presence of associated Cl-, which gain prevalence at higher CaCl2 concentration. Our simulations also predict the adhesion force profile to be distinct for CaCl2 compared with the other electrolytes. Together, these analyses explain our experimental data. Our findings indicate in general how silica wettability may be manipulated by electrolyte concentration. PMID- 28887491 TI - The Aging of the Social Mind - Differential Effects on Components of Social Understanding. AB - Research in younger adults dissociates cognitive from affective facets of social information processing, rather than promoting a monolithic view of social intelligence. An influential theory on adult development suggests differential effects of aging on cognitive and affective functions. However, this dissociation has not been directly tested in the social domain. Employing a newly developed naturalistic paradigm that disentangles facets of the social mind within an individual, we show multi-directionality of age-related differences. Specifically, components of the socio-cognitive route - Theory of Mind and metacognition - are impaired in older relative to younger adults. Nevertheless, these social capacities are still less affected by aging than factual reasoning and metacognition regarding non-social content. Importantly, the socio-affective route is well-functioning, with no decline in empathy and elevated compassion in the elderly. These findings contribute to an integrated theory of age-related change in social functioning and inform interventions tailored to specifically reinstate socio-cognitive skills in old age. PMID- 28887492 TI - Freeform fabrication of tissue-simulating phantom for potential use of surgical planning in conjoined twins separation surgery. AB - Preoperative assessment of tissue anatomy and accurate surgical planning is crucial in conjoined twin separation surgery. We developed a new method that combines three-dimensional (3D) printing, assembling, and casting to produce anatomic models of high fidelity for surgical planning. The related anatomic features of the conjoined twins were captured by computed tomography (CT), classified as five organ groups, and reconstructed as five computer models. Among these organ groups, the skeleton was produced by fused deposition modeling (FDM) using acrylonitrile-butadiene-styrene. For the other four organ groups, shell molds were prepared by FDM and cast with silica gel to simulate soft tissues, with contrast enhancement pigments added to simulate different CT and visual contrasts. The produced models were assembled, positioned firmly within a 3D printed shell mold simulating the skin boundary, and cast with transparent silica gel. The produced phantom was subject to further CT scan in comparison with that of the patient data for fidelity evaluation. Further data analysis showed that the produced model reassembled the geometric features of the original CT data with an overall mean deviation of less than 2 mm, indicating the clinical potential to use this method for surgical planning in conjoined twin separation surgery. PMID- 28887493 TI - Molecular characterization of cell-free eccDNAs in human plasma. AB - Extrachromosomal circular DNAs (eccDNAs) have been reported in most eukaryotes. However, little is known about the cell-free eccDNA profiles in circulating system such as blood. To characterize plasma cell-free eccDNAs, we performed sequencing analysis in 26 libraries from three blood donors and negative controls. We identified thousands of unique plasma eccDNAs in the three subjects. We observed proportional eccDNA increase with initial DNA input. The detected eccDNAs were also associated with circular DNA enrichment efficiency. Increasing the sequencing depth in an additional sample identified many more eccDNAs with highly heterogenous molecular structure. Size distribution of eccDNAs varied significantly from 31 bp to 19,989 bp. We found significantly higher GC content in smaller eccDNAs (<500 bp) than the larger ones (>500 bp) (p < 0.01). We also found an enrichment of eccDNAs at exons and 3'UTR (enrichment folds from 1.36 to 3.1) as well as the DNase hypersensitive sites (1.58-2.42 fold), H3K4Me1 (1.23 1.42 fold) and H3K27Ac (1.33-1.62 fold) marks. Junction sequence analysis suggested fundamental role of nonhomologous end joining mechanism during eccDNA formation. Further characterization of the extracellular eccDNAs in peripheral blood will facilitate understanding of their molecular mechanisms and potential clinical utilities. PMID- 28887494 TI - Sulfonolipids as novel metabolite markers of Alistipes and Odoribacter affected by high-fat diets. AB - The gut microbiota generates a huge pool of unknown metabolites, and their identification and characterization is a key challenge in metabolomics. However, there are still gaps on the studies of gut microbiota and their chemical structures. In this investigation, an unusual class of bacterial sulfonolipids (SLs) is detected in mouse cecum, which was originally found in environmental microbes. We have performed a detailed molecular level characterization of this class of lipids by combining high-resolution mass spectrometry and liquid chromatography analysis. Eighteen SLs that differ in their capnoid and fatty acid chain compositions were identified. The SL called "sulfobacin B" was isolated, characterized, and was significantly increased in mice fed with high-fat diets. To reveal bacterial producers of SLs, metagenome analysis was acquired and only two bacterial genera, i.e., Alistipes and Odoribacter, were revealed to be responsible for their production. This knowledge enables explaining a part of the molecular complexity introduced by microbes to the mammalian gastrointestinal tract and can be used as chemotaxonomic evidence in gut microbiota. PMID- 28887496 TI - Differential gene expression profiling linked to tumor progression of splenic marginal zone lymphoma. AB - The genetic events that lead to aggressive transformation of cases of splenic marginal zone lymphoma (SMZL) after the chronic clinical stage have not been well understood. We aimed to find candidate genes associated with aggressive features of SMZL. We have successfully established two SMZL cell lines, designated SL-15 and SL-22, derived from the same patient's tumor clone in chronic and aggressive phases, respectively. Microarray analysis identified cell cycle-associated genes specifically PLK1-as the most significantly upregulated in primary aggressive SMZL cells compared with cells from chronic phase. EPHA4 and MS4A1 (CD20) were found to be downregulated dramatically. These gene expression patterns were reproduced in both cell lines. Genetic knockdown of PLK1 resulted in inhibition of cell proliferation and induction of apoptosis in SL-22 cells, which expressed higher levels of PLK1 than SL-15 cells. SL-22 cells needed higher concentrations of chemical PLK1 inhibitors to achieve greater effects. In addition, we found homozygous deletion of the MS4A1 gene as a newly identified molecular mechanism of CD20-negative conversion. Our findings are expected to stimulate further studies on whether PLK1 could be a potential therapeutic target for this tumor. Furthermore, cases with CD20-negatively converted lymphomas should be screened for the genomic loss of MS4A1. PMID- 28887495 TI - Integration of deep transcriptome and proteome analyses of salicylic acid regulation high temperature stress in Ulva prolifera. AB - To investigate changes in transcript and relative protein levels in response to salicylic acid regulation of the thermotolerance in U. prolifera, complementary transcriptome and proteome analyses were performed with U. prolifera grown at 35 degrees C (UpHT) and with the addition of SA at high temperature (UpSHT). At mRNA level,12,296 differentially expressed genes (DEGs) were obtained from the comparison of UpSHT with UpHT. iTRAQ-labeling proteome analysis showed that a total of 4,449 proteins were identified and reliably quantified. At mRNA level, the up-regulated genes involved in antioxidant activity were thioredoxin,peroxiredoxin,FeSOD, glutathione peroxidase, partion catalase and MnSOD. The down-regulated genes were ascorbate peroxidase, glutathione S transferase, catalase and MnSOD. In addition, the DEGs involved in plant signal transduction pathway (such as auxin response factors, BRI1 and JAZ) were down regulated. At protein level, the up-regulated proteins involved in carbon fixation and the down-regulated protein mainly were polyubiquitin, ascorbate peroxidase. The expression of Ca2+-binding protein, heat shock protein and photosynthesis-related proteins, EDS1 were also significantly regulated both at mRNA and protein level. The results indicated that SA alleviated the high temperature stimulus through partion antioxidant related proteins up-regulated, JA signal pathway enchanced, Ca2+-binding proteins, photosynthesis-related proteins significantly changed, antioxidant enzyme activities increased and photosynthesis index changed. PMID- 28887497 TI - Interaction between G-Quadruplex and Zinc Cationic Porphyrin: The Role of the Axial Water. AB - The interaction of ligands with G-quadruplexes has attracted considerable attention due to its importance in molecular recognition and anticancer drugs design. Here, we utilize triplet excited state as a sensitive reporter to study the binding interaction of zinc cationic porphyrin (ZnTMPyP4) with three G quadruplexes, AG3(T2AG3)3, (G4T4G4)2, and (TG4T)4. By monitoring the triplet decay dynamics of ZnTMPyP4 with transient absorption spectroscopy, the coexisted binding modes via pi-pi stacking of porphyrin macrocycle and the G-quartets are allowed to be identified quantitatively, which involve intercalation (25% and 36%) versus end-stacking (75% and 64%) for AG3(T2AG3)3 and (G4T4G4)2, and end stacking (23%) versus partial intercalation (77%) for (TG4T)4. It is shown that the steric hindrance of the axial water decreases greatly the percentage of intercalation. Further, a rapid assessment of binding stoichiometry is fulfilled by measuring the triplet decay dynamics under various [G-quadruplex]/[ZnTMPyP4] ratios. The binding stoichiometric ratios of G-quadruplex/ZnTMPyP4 are 1:2 for AG3(T2AG3)3, 1:1 for (G4T4G4)2, and 1:2 for (TG4T)4, which agree well with results obtained by the conventional method of continuous variation analysis. These results reveal a clear scenario of G-quadruplex/ZnTMPyP4 interaction and provide mechanistic insights for the application of anticancer drug designs using G-quadruplex as target. PMID- 28887498 TI - New Insight into the Concept of Carbonization Degree in Synthesis of Carbon Dots to Achieve Facile Smartphone Based Sensing Platform. AB - Direct pyrolysis of citric acid (CA) has been proved to be a facile bottom-up technique for making pristine carbon dots (CD) with homogenous size distribution. However, limited reports are available on systematic optimization of carbonization degree. In this investigation, pyrolysis temperatures between 160 degrees C and 220 degrees C were studied, based on CA thermal decomposition path, using various heating durations. The effect of the formation of more carbonized carbon particles (MCCPs), as the major byproduct of this method, on photoluminescence properties of CDs was also considered. The NaOH amount that neutralizes the solution and the effect of dilution on the emission intensity, were introduced as simple and accessible factors for monitoring carbonization degree, and an estimate of MCCP/CD ratio, respectively. The results show that the CDs fabricated at 160 degrees C, 50 minutes attain almost twice higher quantum yield (QY) of 29% than highest QY reported based on pyrolysis of CA. The so prepared CDs can be employed as excellent candidates for turn-off sensing. As a proof of concept, detection limit of 50 nM for Hg2+ was achieved using a facile and inexpensive smartphone set-up that is able to quantify and compare fluorescent intensity in several samples simultaneously. PMID- 28887499 TI - Transcription factors NRF2 and HSF1 have opposing functions in autophagy. AB - Autophagy plays a critical role in the maintenance of cellular homeostasis by degrading proteins, lipids and organelles. Autophagy is activated in response to stress, but its regulation in the context of other stress response pathways, such as those mediated by heat shock factor 1 (HSF1) and nuclear factor-erythroid 2 p45-related factor 2 (NRF2), is not well understood. We found that the Michael acceptor bis(2-hydoxybenzylidene)acetone (HBB2), a dual activator of NRF2 and HSF1, protects against the development of UV irradiation-mediated cutaneous squamous cell carcinoma in mice. We further show that HBB2 is an inducer of autophagy. In cells, HBB2 increases the levels of the autophagy-cargo protein p62/sequestosome 1, and the lipidated form of microtubule-associated protein light chain 3 isoform B. Activation of autophagy by HBB2 is impaired in NRF2 deficient cells, which have reduced autophagic flux and low basal and induced levels of p62. Conversely, HSF1-deficient cells have increased autophagic flux under both basal as well as HBB2-induced conditions, accompanied by increased p62 levels. Our findings suggest that NRF2 and HSF1 have opposing roles during autophagy, and illustrate the existence of tight mechanistic links between the cellular stress responses. PMID- 28887500 TI - MicroRNA Profiling Reveals Distinct Profiles for Tissue-Derived and Cultured Endothelial Cells. AB - Endothelial plasticity enables the cells to switch their phenotype according to the surrounding vascular microenvironment. MicroRNAs (miRNAs) are small noncoding RNAs that control endothelial plasticity. The objective of this study was to investigate the differences in miRNA profiles of tissue-derived cells and cultured endothelial cells. To this end, miRNA expression was profiled from freshly isolated tissue-derived human vascular endothelial cells and endothelial cells cultured until cellular senescence using miRNA sequencing. In addition, the data was searched for putative novel endothelial miRNAs and miRNA isoforms. The data analysis revealed a striking change in endothelial miRNA profile as the cells adapted from tissue to cell culture environment and the overall miRNA expression decreased significantly in cultured compared to tissue-derived endothelial cells. In addition to changes in mechanosensitive miRNA expression, alterations in senescence-associated and endothelial-to-mesenchymal-transition associated miRNAs were observed in aging cells. Collectively, the data illustrates the adaptability of endothelial cell miRNA expression that mirrors prevailing cellular environment. PMID- 28887501 TI - Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. AB - We investigated the haemodynamic effects of two-week liquorice exposure (glycyrrhizin dose 290-370 mg/day) in 22 healthy volunteers during orthostatic challenge. Haemodynamics were recorded during passive 10-minute head-up tilt using radial pulse wave analysis, whole-body impedance cardiography, and spectral analysis of heart rate variability. Thirty age-matched healthy subjects served as controls. Liquorice ingestion elevated radial systolic (p < 0.001) and diastolic (p = 0.018) blood pressure and systemic vascular resistance (p = 0.037). During orthostatic challenge, heart rate increased less after the liquorice versus control diet (p = 0.003) and low frequency power of heart rate variability decreased within the liquorice group (p = 0.034). Liquorice intake increased central pulse pressure (p < 0.001) and augmentation index (p = 0.002) supine and upright, but in the upright position the elevation of augmentation index was accentuated (p = 0.007). Liquorice diet also increased extracellular fluid volume (p = 0.024) and aortic to popliteal pulse wave velocity (p = 0.027), and aortic characteristic impedance in the upright position (p = 0.002). To conclude, in addition to increased extracellular fluid volume and large arterial stiffness, two weeks of liquorice ingestion elevated systemic vascular resistance and augmentation index. Measurements performed at rest may underestimate the haemodynamic effects of liquorice ingestion, as enhanced central wave reflection and reduced chronotropic response were especially observed in the upright position. PMID- 28887502 TI - Synergies between Urban Heat Island and Heat Waves in Athens (Greece), during an extremely hot summer (2012). AB - Heat waves (HWs) are recognized as a serious threat for human health worldwide, with urban areas being more vulnerable due to the urban heat island (UHI) effect and population density. Yet, in the climate change context, HWs are becoming more frequent, stronger and longer, which, coupled with intensifying urbanization exacerbates thermal risk for urban residents. Despite the profound impact of this global phenomenon there is no clear consensus so far on possible synergies between UHIs and HWs. The study sheds light on the complex synergies between UHIs and HWs focusing on coastal sites. A quite challenging period comprising five HW episodes during summer 2012 in Athens (Greece) was selected for analysis. A positive feedback between UHIs and HWs was found, with intensification of the average UHI magnitude by up to 3.5 degrees C during HWs, compared to summer background conditions. Our results contribute significantly to understanding synergies between UHIs and HWs that may strongly increase thermal risk in cities and vulnerability of urban population. PMID- 28887503 TI - Stretchable conductive elastomer for wireless wearable communication applications. AB - Wearable devices have provided noninvasive and continuous monitoring of physiological parameters in healthcare applications. However, for the comfortable applications of wearable devices on human body, two key requirements are to replace conventional bulky devices into soft and deformable ones and to have wireless wearable communication. In this paper we present a simple, low-cost and highly efficient all-elastomeric conductor that can be used in a soft radio frequency (RF) transmission line and antenna. We show a stretchable transmission line and two stretchable antennas fabricated with conventional screen printing. The stretchable conductor used in this fabrication method, which is a mixture of Ag and Polydimethylsiloxane (PDMS), can be stretched at high strains while maintaining a high conductivity, low attenuation and feasible radiation performance. The measured conductivity of the stretchable conductor reaches 1000 S/cm. Additionally, the highly conductive printed Ag-PDMS is utilized to construct transmission lines and antennas. The performance of these stretchable components, especially under different conditions of bending, stretching and twisting, are experimentally examined in common wireless-communication frequency bands. Our results demonstrate that printed Ag-PDMS enabled RF passive components have the desired property and quality for wireless wearable communication applications, which would provide new opportunities for wearable healthcare electronics. PMID- 28887504 TI - Macrophages unlock progression of breast cancer cells experiencing matrigel segregation in transplantation models. AB - Basement membrane matrix proteins, such as matrigel, are able to improve the efficiency of tumour transplantation. This assay represents the gold standard to measure tumour initiation potential in vivo of a limited number of cancer cells. However, in culture conditions, matrigel directly signals to cancer cells altering their phenotype. We here investigate how matrigel influences the tumour reconstitution dynamics of breast cancer cells in vivo. This is particularly relevant in the setting of limiting dilution assay where cells are transplanted in a relatively high amount of Matrigel. We show that matrigel initially induces a normalized growth of transplanted MMTV-PyMT breast tumours cells. This occurs in the context of a matrigel-segregation effect where cancer cells are transiently isolated from host tissue. We identify macrophages as gatekeepers of the cancer-host cell interaction: depriving transplants from macrophages locked cancer cells in this isolated environment where they fail to form tumours despite retaining their intrinsic tumorigenic potential. This is a decisive proof of concept that cancer cells' malignant behaviour can be dominated by their microenvironment. Moreover, considering that diverse breast cancer cells are differently subjected to a segregation effect, this needs to be considered when comparing tumour initiation potential of different cancer cells. PMID- 28887505 TI - Impaired fibrinolysis and lower levels of plasma alpha2-macroglobulin are associated with an increased risk of severe asthma exacerbations. AB - Recently we have reported that asthma is associated with enhanced plasma thrombin formation, impaired fibrinolysis and platelet activation. In the present study we investigated whether described prothrombotic blood alterations might predispose to thromboembolic events or asthma exacerbations. In 164 adult asthmatics we assessed clinical events during 3-year follow-up and analyzed their associations with measured at baseline prothrombotic blood parameters. Data were obtained from 157 (95.7%) of the asthma patients. We documented 198 severe asthma exacerbations (64/year), which occurred in 53 subjects (34%). These patients were older (p = 0.004), had worse asthma control (p = 0.02) and lower spirometry values (p = 0.01), at baseline. Interestingly, this subgroup had longer clot lysis time (CLT), as well as lower alpha2-macroglobulin (p = 0.038 and p = 0.04, respectively, after adjustment for potential confounders). Increased CLT and lower alpha2-macroglobulin were demonstrated as independent predictors of asthma exacerbation in multiple regression model. Moreover, we documented two episodes of deep vein thrombosis (1.3%), and eight acute coronary syndromes (5.1%). Patients who experienced thromboembolic events (n = 10, 6.4%, 2.1%/year) had lower alpha2-macroglobulin (p = 0.04), without differences in efficiency of fibrinolysis and thrombin generation. Impaired fibrinolysis and lower levels of alpha2-macroglobulin might predispose to a higher rate of asthma exacerbations, suggesting new links between disturbed hemostasis and asthma. PMID- 28887506 TI - Introduced ascidians harbor highly diverse and host-specific symbiotic microbial assemblages. AB - Many ascidian species have experienced worldwide introductions, exhibiting remarkable success in crossing geographic borders and adapting to local environmental conditions. To investigate the potential role of microbial symbionts in these introductions, we examined the microbial communities of three ascidian species common in North Carolina harbors. Replicate samples of the globally introduced species Distaplia bermudensis, Polyandrocarpa anguinea, and P. zorritensis (n = 5), and ambient seawater (n = 4), were collected in Wrightsville Beach, NC. Microbial communities were characterized by next generation (Illumina) sequencing of partial (V4) 16S rRNA gene sequences. Ascidians hosted diverse symbiont communities, consisting of 5,696 unique microbial OTUs (at 97% sequenced identity) from 47 bacterial and three archaeal phyla. Permutational multivariate analyses of variance revealed clear differentiation of ascidian symbionts compared to seawater bacterioplankton, and distinct microbial communities inhabiting each ascidian species. 103 universal core OTUs (present in all ascidian replicates) were identified, including taxa previously described in marine invertebrate microbiomes with possible links to ammonia-oxidization, denitrification, pathogenesis, and heavy-metal processing. These results suggest ascidian microbial symbionts exhibit a high degree of host specificity, forming intimate associations that may contribute to host adaptation to new environments via expanded tolerance thresholds and enhanced holobiont function. PMID- 28887507 TI - Carnosic acid prevents dextran sulfate sodium-induced acute colitis associated with the regulation of the Keap1/Nrf2 pathway. AB - Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBDs) with high prevalence in humans. Carnosic acid (CA) has been reported to possess antioxidative properties; however, its role in IBDs has not been determined. In the present study, we found that CA significantly prevented the loss of body weight and shortening of colon length in acute colitis induced by dextran sodium sulfate (DSS). Pronounced infiltration of immune cells and a loss of crypt architecture and goblet cells were ameliorated by CA. CA significantly decreased the activity of MPO and infiltration of F4/80+ macrophages in the colon. DSS induced pro-inflammatory cytokine mRNA and protein levels in the colon were also attenuated by CA. CA decreased the activation of p65 and c-Jun signalling. CA inhibited DSS-induced NLRP3 inflammasome activation by reducing caspase 1 activity. In addition, CA increased the level of Nrf2 and prevented the degradation of Nrf2 via ubiquitination by blocking the interaction between Cullin3 and Keap1, which resulted in the decrease of Nrf2 target genes. Finally, GSH levels and SOD activity were increased after CA treatment, while MDA and iNOS levels were significantly reduced. Taken together, our data showed that CA may be useful as a potential therapeutic candidate for IBDs. PMID- 28887508 TI - Lattice light sheet imaging of membrane nanotubes between human breast cancer cells in culture and in brain metastases. AB - Membrane nanotubes are cytosolic protrusions with diameters <1 um that extend between cells separated by tens of um. They mediate several forms of intercellular communication and are upregulated in diverse diseases. Difficulties in visualizing and studying nanotubes within intact tissues have, however, prompted skepticism regarding their in vivo relevance, and most studies have been confined to cell culture systems. Here, we introduce lattice-light sheet imaging of MDA-MB-231 human breast cancer cells genetically engineered to brightly express membrane-targeted GFP as a promising approach to visualize membrane nanotubes in vitro and in situ. We demonstrate that cultured cells form multiple nanotubes that mediate intercellular communication of Ca2+ signals and actively traffic GFP-tagged membrane vesicles along their length. Furthermore, we directly visualize nanotubes in situ, interconnecting breast cancer cells in live acute brain slices from an experimental mouse model of breast cancer brain metastasis. This amenable experimental system should facilitate the transition of the study of intercellular communication by membrane nanotubes from cell culture to the whole animal. PMID- 28887509 TI - Optimal stress and deformation partition in gradient materials for better strength and tensile ductility: A numerical investigation. AB - Inspired by recent progress in developing gradient materials with excellent performances, here we report a systematic finite-element based investigation to show how the strength and tensile ductility of gradient crystalline metals depend on their microstructure characteristics. We reveal that the yielding strength of polycrystalline metals with gradient grain size can be significantly enhanced at no reduction in ductility. By employing a representative 3D voronoi gradient sample, we demonstrate that the redistribution of stress and deformation in the gradient structure - stronger grains carry more load and ductile ones share more deformation - accounts for the realized optimal property in strength and ductility. In addition, the hardenability of the ductile domain is beneficial to circumvent pre-mature plastic instability in gradient samples. PMID- 28887510 TI - MiRNA-target network analysis identifies potential biomarkers for Traditional Chinese Medicine (TCM) syndrome development evaluation in hepatitis B caused liver cirrhosis. AB - Hepatitis B is one of most etiologies of Liver cirrhosis in China, and clinically lacks the effective strategy for Hepatitis B caused cirrhosis (HBC) therapy. As a complementary and alternative medicine, Chinese Traditional Medicine (TCM) has special therapeutic effects for HBC. Here, we focus on the evolution process of HBC TCM syndromes, which was from Excessive (Liver-Gallbladder Dampness-Heat Syndrome, LGDHS) to Deficient (Liver-Kidney Deficiency Syndrome, LKYDS) via Excessive-Deficient syndrome (Liver-Depression and Spleen-Deficiency Syndrome, LDSDS). Using R package, 16 miRNAs in LGDHS/Normal, 48 miRNAs in LDSDS/LGDHS, and 16 miRNAs in LKYDS/LDSDS were identified, respectively. The miRNA-target networks show that the LDSDS was most stability and complicated. Subsequently, 4 kernel miRNAs with LGDHS-LDSDS process, and 5 kernel miRNAs with LDSDS-LKYDS process were screened. Using RT-qPCR data, p1 (hsa-miR-17-3p, -377-3p, -410-3p and -495) and p2 miRNA panel (hsa-miR-377-3p, -410-3p, -27a-3p, 149-5p and 940) were identified by Logistic Regression Model, which clearly improve the accuracy of TCM syndrome classification. The rebuilt miRNA-target network shows that the LDSDS is a critical point and might determine the evolution directions of HBC TCM syndrome. This study suggests that the identified kernel miRNAs act as potential biomarkers and benefit to evaluate the evolution tendency of HBC TCM syndromes. PMID- 28887511 TI - Hemoglobin level, a prognostic factor for nasal extranodal natural killer/T-cell lymphoma patients from stage I to IV: A validated prognostic nomogram. AB - Although nasal extranodal natural killer/T-cell lymphoma (nasal ENKL) shares some prognostic factors with other lymphomas, seldom studies had explored the prognostic value of hemoglobin. The ENKL cases in stage I-IV during 2000 to 2015 were collected from two medical centers (group A, n = 192), and were randomly divided into the group B (n = 155) and C (n = 37). Although the significant factors identified by the univariate analysis differed between the group A and B, the multivariate Cox regression indicated the same factors. C-index of the model was slightly better than Yang's, but its integrated Brier score (IBS) was obviously lower than Yang's both in the group A and B. Additionally, minimal depth of random survival forest (RSF) classifier confirmed that the prognostic ability of hemoglobin was better than age both in the group A and B. In the calibration of the nomogram, the predicted 3-year or 5-year OS of our nomogram well agreed with the corresponding actual OS. In conclusion, Hemoglobin is a prognostic factor for nasal ENKL patients in stage I - IV, and integrating it into a validated prognostic nomogram, whose generalization error is the smallest among the evaluated models, can be used to predict the patients' outcome. PMID- 28887512 TI - LNA effects on DNA binding and conformation: from single strand to duplex and triplex structures. AB - The anti-gene strategy is based on sequence-specific recognition of double-strand DNA by triplex forming (TFOs) or DNA strand invading oligonucleotides to modulate gene expression. To be efficient, the oligonucleotides (ONs) should target DNA selectively, with high affinity. Here we combined hybridization analysis and electrophoretic mobility shift assay with molecular dynamics (MD) simulations to better understand the underlying structural features of modified ONs in stabilizing duplex- and triplex structures. Particularly, we investigated the role played by the position and number of locked nucleic acid (LNA) substitutions in the ON when targeting a c-MYC or FXN (Frataxin) sequence. We found that LNA containing single strand TFOs are conformationally pre-organized for major groove binding. Reduced content of LNA at consecutive positions at the 3'-end of a TFO destabilizes the triplex structure, whereas the presence of Twisted Intercalating Nucleic Acid (TINA) at the 3'-end of the TFO increases the rate and extent of triplex formation. A triplex-specific intercalating benzoquinoquinoxaline (BQQ) compound highly stabilizes LNA-containing triplex structures. Moreover, LNA substitution in the duplex pyrimidine strand alters the double helix structure, affecting x-displacement, slide and twist favoring triplex formation through enhanced TFO major groove accommodation. Collectively, these findings should facilitate the design of potent anti-gene ONs. PMID- 28887513 TI - Coherent diffractive imaging of single helium nanodroplets with a high harmonic generation source. AB - Coherent diffractive imaging of individual free nanoparticles has opened routes for the in situ analysis of their transient structural, optical, and electronic properties. So far, single-shot single-particle diffraction was assumed to be feasible only at extreme ultraviolet and X-ray free-electron lasers, restricting this research field to large-scale facilities. Here we demonstrate single-shot imaging of isolated helium nanodroplets using extreme ultraviolet pulses from a femtosecond-laser-driven high harmonic source. We obtain bright wide-angle scattering patterns, that allow us to uniquely identify hitherto unresolved prolate shapes of superfluid helium droplets. Our results mark the advent of single-shot gas-phase nanoscopy with lab-based short-wavelength pulses and pave the way to ultrafast coherent diffractive imaging with phase-controlled multicolor fields and attosecond pulses.Diffraction imaging studies of free individual nanoparticles have so far been restricted to XUV and X-ray free - electron laser facilities. Here the authors demonstrate the possibility of using table-top XUV laser sources to image prolate shapes of superfluid helium droplets. PMID- 28887514 TI - Dormant 5-lipoxygenase in inflammatory macrophages is triggered by exogenous arachidonic acid. AB - The differentiation of resident tissue macrophages from embryonic precursors and that of inflammatory macrophages from bone marrow cells leads to macrophage heterogeneity. Further plasticity is displayed through their ability to be polarized as subtypes M1 and M2 in a cell culture microenvironment. However, the detailed regulation of eicosanoid production and its involvement in macrophage biology remains unclear. Using a lipidomics approach, we demonstrated that eicosanoid production profiles between bone marrow-derived (BMDM) and peritoneal macrophages differed drastically. In polarized BMDMs, M1 and M2 phenotypes were distinguished by thromboxane B2, prostaglandin (PG) E2, and PGD2 production, in addition to lysophospholipid acyltransferase activity. Although Alox5 expression and the presence of 5-lipoxygenase (5-LO) protein in BMDMs was observed, the absence of leukotrienes production reflected an impairment in 5-LO activity, which could be triggered by addition of exogenous arachidonic acid (AA). The BMDM 5-LO regulatory mechanism was not responsive to PGE2/cAMP pathway modulation; however, treatment to reduce glutathione peroxidase activity increased 5-LO metabolite production after AA stimulation. Understanding the relationship between the eicosanoids pathway and macrophage biology may offer novel strategies for macrophage-associated disease therapy. PMID- 28887516 TI - Linking primary producer diversity and food quality effects on herbivores: A biochemical perspective. AB - Biodiversity can strongly influence trophic interactions. The nutritional quality of prey communities and how it is related to the prey diversity is suspected to be a major driver of biodiversity effects. As consumer growth can be co-limited by the supply of several biochemical components, biochemically diverse prey communities should promote consumer growth. Yet, there is no clear consensus on how prey specific diversity is linked to community biochemical diversity since previous studies have considered only single nutritional quality traits. Here, we demonstrate that phytoplankton biochemical traits (fatty acids and sterols) can to a large extent explain Daphnia magna growth and its apparent dependence on phytoplankton species diversity. We find strong correlative evidence between phytoplankton species diversity, biochemical diversity, and growth. The relationship between species diversity and growth was partially explained by the fact that in many communities Daphnia was co-limited by long chained polyunsaturated fatty acids and sterols, which was driven by different prey taxa. We suggest that biochemical diversity is a good proxy for the presence of high food quality taxa, and a careful consideration of the distribution of the different biochemical traits among species is necessary before concluding about causal links between species diversity and consumer performance. PMID- 28887515 TI - Sacral Neuromodulation for Refractory Bladder Pain Syndrome/Interstitial Cystitis: a Global Systematic Review and Meta-analysis. AB - Bladder pain syndrome/interstitial cystitis (BPS/IC) is a common debilitating disease and there has not been consistently effective treatment. We aimed to evaluate all available literature regarding the efficacy and safety of sacral neuromodulation (SNM) for refractory BPS/IC. A comprehensive search of Pubmed, Web of Science and Cochrane Library through May 2016 was conducted. A total of 17 studies enrolling 583 patients were identified. Pooled analyses demonstrated that SNM was associated with great reduction in pelvic pain (weighted mean difference [WMD] -3.99; 95% confidence interval [CI] -5.22 to -2.76; p < 0.00001), Interstitial Cystitis Problem and Symptom Index scores (WMD -6.34; 95% CI -9.57 to -3.10; p = 0.0001; and WMD -7.17; 95% CI -9.90 to -4.45; p < 0.00001, respectively), daytime frequency (WMD -7.45; 95% CI -9.68 to -5.22; p < 0.00001), nocturia (WMD -3.01; 95% CI -3.56 to -2.45; p < 0.00001), voids per 24 hours (WMD -9.32; 95% CI -10.90 to -7.74; p < 0.00001) and urgency (WMD -1.08; 95% CI -1.79 to -0.37; p = 0.003) as well as significant improvement in average voided volume (WMD 95.16 ml; 95% CI 63.64 to 126.69; p < 0.0001). The pooled treatment success rate was 84% (95% CI 76% to 91%). SNM-related adverse events were minimal. Current evidence indicates that SNM might be effective and safe for treating refractory BPS/IC. PMID- 28887517 TI - Densification of the interlayer spacing governs the nanomechanical properties of calcium-silicate-hydrate. AB - Calciuam-silicate-hydrate (C-S-H) is the principal binding phase in modern concrete. Molecular simulations imply that its nanoscale stiffness is 'defect driven', i.e., dominated by crystallographic defects such as bridging site vacancies in its silicate chains. However, experimental validation of this result is difficult due to the hierarchically porous nature of C-S-H down to nanometers. Here, we integrate high pressure X-ray diffraction and atomistic simulations to correlate the anisotropic deformation of nanocrystalline C-S-H to its atomic scale structure, which is changed by varying the Ca-to-Si molar ratio. Contrary to the 'defect-driven' hypothesis, we clearly observe stiffening of C-S-H with increasing Ca/Si in the range 0.8 <= Ca/Si <= 1.3, despite increasing numbers of vacancies in its silicate chains. The deformation of these chains along the b axis occurs mainly through tilting of the Si-O-Si dihedral angle rather than shortening of the Si-O bond, and consequently there is no correlation between the incompressibilities of the a- and b-axes and the Ca/Si. On the contrary, the intrinsic stiffness of C-S-H solid is inversely correlated with the thickness of its interlayer space. This work provides direct experimental evidence to conduct more realistic modelling of C-S-H-based cementitious material. PMID- 28887519 TI - Decoding the Morphological Differences between Himalayan Glacial and Fluvial Landscapes Using Multifractal Analysis. AB - Himalayas is the home to nearly 10,000 glaciers which are mostly located at high and inaccessible region. Digital Elevation Model (DEM) can be effective in the study of these glaciers. This paper aims at providing an automated distinction of glacial and fluvial morphologies using multifractal technique. We have studied the variation of elevation profile of Glacial and Fluvial landscapes using Multifractal Detrended Fluctuation Analysis (MFDFA). Glacial landscapes reveal more complex structure compared to the fluvial landscapes as indicated by fractal parameters degree of multifractality, asymmetry index. PMID- 28887518 TI - Monitoring storage induced changes in the platelet proteome employing label free quantitative mass spectrometry. AB - Shelf life of platelet concentrates is limited to 5-7 days due to loss of platelet function during storage, commonly referred to as the platelet storage lesion (PSL). To get more insight into the development of the PSL, we used label free quantitative mass spectrometry to identify changes in the platelet proteome during storage. In total 2501 proteins were accurately quantified in 3 biological replicates on at least 1 of the 7 different time-points analyzed. Significant changes in levels of 21 proteins were observed over time. Gene ontology enrichment analysis of these proteins revealed that the majority of this set was involved in platelet degranulation, secretion and regulated exocytosis. Twelve of these proteins have been shown to reside in alpha-granules. Upon prolonged storage (13-16 days) elevated levels of alpha-2-macroglobulin, glycogenin and Ig MU chain C region were identified. Taken together this study identifies novel markers for monitoring of the PSL that may potentially also be used for the detection of "young" and "old" platelets in the circulation. PMID- 28887520 TI - The life-span trajectory of visual perception of 3D objects. AB - Deriving a 3D structural representation of an object from its 2D input is one of the great challenges for the visual system and yet, this type of representation is critical for the successful recognition of and interaction with objects. Perhaps reflecting the importance of this computation, infants have some sensitivity to 3D structural information, and this sensitivity is, at least, partially preserved in the elderly population. To map precisely the life-span trajectory of this key visual computation, in a series of experiments, we compared the performance of observers from ages 4 to 86 years on displays of objects that either obey or violate possible 3D structure. The major findings indicate that the ability to derive fine-grained 3D object representations emerges after a prolonged developmental trajectory and is contingent on the explicit processing of depth information even in late childhood. In contrast, the sensitivity to object 3D structure remains stable even through late adulthood despite the overall reduction in perceptual competence. Together, these results uncover the developmental process of an important perceptual skill, revealing that the initial, coarse sensitivity to 3D information is refined, automatized and retained over the lifespan. PMID- 28887521 TI - Sex differences in the C57BL/6 model of Mycobacterium tuberculosis infection. AB - Globally, tuberculosis (Tb) notification data show a male-to-female ratio of 1.7 and higher, but the underlying reasons for the male bias remain elusive. Despite the well-known gender bias in human pulmonary Tb, a majority of experimental animal studies either do not separate and analyze data by sex or do not report the sex of their subjects at all. In the present study, we report increased male susceptibility in one of the most commonly used mouse models for Tb, C57BL/6 mice. Our study revealed that disease progression upon aerosol infection with Mycobacterium tuberculosis (Mtb) was accelerated in males resulting in increased morbidity and mortality compared to females. Elevated Mtb loads in males were associated with an early exaggerated pulmonary inflammatory response which likely was detrimental to the host, as reflected by exacerbated pathology and increased mortality. Our data emphasis the urgent need to include and separately analyze both sexes in future animal studies of Tb in order to appreciate the differences in immune responses and disease pathogenesis between males and females. PMID- 28887522 TI - Urban PM2.5 exacerbates allergic inflammation in the murine lung via a TLR2/TLR4/MyD88-signaling pathway. AB - Nevertheless its mechanism has not been well explained yet, PM2.5 is recognized to exacerbate asthma. In the present study, the roles of toll-like receptor (TLR) 2, TLR4 and MyD88, in exacerbation of allergen-induced lung eosinophilia caused by urban PM2.5 was investigated. TLR2-, TLR4-, MyD88-deficient and WT BALB/c mice were intratracheally challenged with PM2.5 +/- ovalbumin (OVA) four times at 2 week intervals. PM2.5 increased neutrophil numbers and KC in bronchoalveolar lavage fluid and caused slight peribronchiolar inflammation in WT mice. However, these changes were attenuated, but not completely suppressed in gene-deficient mice, especially in MyD88-/- mice. In WT mice, PM2.5 + OVA exacerbated OVA related lung eosinophilia. This exacerbation includes increase of IL-5, IL-13, eotaxin and MCP-3; infiltration of eosinophils into the airway submucosa; proliferation of goblet cells in the airway epithelium; and the production of antigen-specific IgE and IgG1 in serum. All these effects were stronger in TLR2-/ mice than in TLR4-/- mice. In MyD88-/- mice, this pro-inflammatory mediator inducing ability was considerably weak and lung pathology was negligible. These results suggest that urban PM2.5 may exacerbate allergic inflammation in the murine lung via a TLR2/TLR4/MyD88-signaling pathway. PM2.5-bound trace microbial elements, such as lipopolysaccharide may be a strong candidate for exacerbation of murine lung eosinophilia. PMID- 28887523 TI - The Role of High Frequency Ultrasonography in Diagnosis of Acute Closed Mallet Finger Injury. AB - To evaluate the role of high frequency ultrasonography in diagnosis of acute closed mallet finger injury. 36 patients diagnosed with mallet finger were included in this study. All patients underwent ultrasonography, magnetic resonance imaging(MRI) and X-ray examinations. A new kind of classification of acute mallet finger injury based on ultrasonography findings was described. The difference in terms of extensor tendon injury and bony fragment identification ability among the three types of examinations were described respectively. Either an injury of extensor digital tendon or an avulsion fracture of distal phalangeal base was identified clearly on ultrasonography. Among the 36 cases, avulsion fracture of the distal phalangeal base was found without extensor tendon rupture in Type A, complete rupture of the extensor tendon was found without avulsion fracture in Type B, and contusion of the extensor tendon was found in Type C. Compared with X-ray, ultrasonography and MRI could show the extensor tendon injury clearly. While compared with MRI, ultrasonography and X-ray was more sensitive in showing bony fragment. High frequency ultrasonography could be an accurate, reliable, and non-invasive diagnostic imaging method in diagnosis of acute close mallet finger injury. PMID- 28887524 TI - Selective uptake of epidermal growth factor-conjugated gold nanoparticle (EGF GNP) facilitates non-thermal plasma (NTP)-mediated cell death. AB - Non-thermal atmospheric pressure plasma (NTP) has been shown to induce cell death in various mammalian cancer cells. Accumulated evidence also shows that NTP could be clinically used in cancer therapy. However, the current NTP-based applications lack target specificity. Here, a novel method in NTP-mediated cancer therapeutics was described with enhanced target specificity by treating EGF (epidermal growth factor)-conjugated GNP (gold nanoparticle). The treatment with EGF-conjugated GNP complex, followed by NTP irradiation showed selective apoptosis of cells having receptor-mediated endocytosis. NTP triggered gamma-H2AX elevation which is a typical response elicited by DNA damage. These results suggest that EGF conjugated GNP functions as an important adjuvant which gives target specificity in applications of conventional plasma therapy. PMID- 28887525 TI - MIER3 suppresses colorectal cancer progression by down-regulating Sp1, inhibiting epithelial-mesenchymal transition. AB - Mesoderm induction early response 1, family member 3 (MIER3) has recently been identified as a potential cancer susceptibility gene. However, the expression pattern and the role of MIER3 in the progression of colorectal cancer (CRC) have not yet been well characterized. Here, we reported that MIER3 was significantly reduced in human primary colorectal cancer and was associated with CRC metastasis and poor prognosis. Moreover, the up-regulation of MIER3 expression significantly inhibited CRC cell proliferation, migration and invasion in vitro and repressed tumor growth and metastasis in vivo. In contrast, down-regulation of MIER3 could promote the aggressive behaviors of CRC cells. Furthermore, our study showed that MIER3 inhibited cell proliferation and invasion partially via reduction of Sp1 and subsequent suppression of epithelial-mesenchymal transition (EMT). In conclusion, our data suggested that MIER3 plays a potential tumor suppressor role in CRC progression and may be a potentially valuable clinical prognostic marker of this disease. PMID- 28887526 TI - Thin zeolite laminates for rapid and energy-efficient carbon capture. AB - Thin, binder-less zeolite NaX laminates, with thicknesses ranging between 310 to 750 MUm and widths exceeding 50 mm and biaxial tensile strength in excess of 3 MPa, were produced by pulsed current processing. The NaX laminates displayed a high CO2 adsorption capacity and high binary CO2-over-N2 and CO2-over-CH4 selectivity, suitable for CO2 capture from flue gas and upgrading of raw biogas. The thin laminates displayed a rapid CO2 uptake; NaX laminates with a thickness of 310 MUm were saturated to 40% of their CO2 capacity within 24 seconds. The structured laminates of 310 MUm thickness and 50 mm thickness would offer low pressure drop and efficient carbon capture performance in a laminate-based swing adsorption technology. PMID- 28887527 TI - Pan-genome analysis of Bacillus for microbiome profiling. AB - Recent advances in high-throughput sequencing technology allow for in-depth studies on microbial genomes and their communities. While multiple strains of the same species could display genomic variations with different gene contents in diverse habitats and hosts, the essential functions for a specific species are conserved as core genes that are shared among strains. We have comprehensively analyzed 238 strains of five different Bacillus species to identify the properties of core and strain-specific genes. Core and strain-specific genes in each Bacillus species show significant differences in their functions and genomic signatures. Using the core genes defined in this study, we have precisely identified the Bacillus species that exist in food microbiomes. Without resorting to culture-based whole genome sequencing, an unexpectedly large portion of the core genes, 98.22% of core genes in B. amyloliquefaciens and 97.77% of B. subtilis, were reconstructed from the microbiome. We have performed a pan-genome analysis on the core gene data of multiple Bacillus species to investigate the Bacillus species in food microbiome. Our findings provide a comprehensive genetic landscape of the Bacillus species, which is also consistent with previous studies on a limited number of strains and species. Analysis based on comprehensive core genes should thus serve as a powerful profiling tool to better understand major constituents in fermented food microbiomes. PMID- 28887529 TI - Production of high-resolution forest-ecosite maps based on model predictions of soil moisture and nutrient regimes over a large forested area. AB - Forest ecosite reflects the local site conditions that are meaningful to forest productivity as well as basic ecological functions. Field assessments of vegetation and soil types are often used to identify forest ecosites. However, the production of high-resolution ecosite maps for large areas from interpolating field data is difficult because of high spatial variation and associated costs and time requirements. Indices of soil moisture and nutrient regimes (i.e., SMR and SNR) introduced in this study reflect the combined effects of biogeochemical and topographic factors on forest growth. The objective of this research is to present a method for creating high-resolution forest ecosite maps based on computer-generated predictions of SMR and SNR for an area in Atlantic Canada covering about 4.3 * 106 hectares (ha) of forestland. Field data from 1,507 forest ecosystem classification plots were used to assess the accuracy of the ecosite maps produced. Using model predictions of SMR and SNR alone, ecosite maps were 61 and 59% correct in identifying 10 Acadian- and Maritime-Boreal-region ecosite types, respectively. This method provides an operational framework for the production of high-resolution maps of forest ecosites over large areas without the need for data from expensive, supplementary field surveys. PMID- 28887528 TI - Transcriptional analysis of genes involved in competitive nodulation in Bradyrhizobium diazoefficiens at the presence of soybean root exudates. AB - Nodulation competition is a key factor that limits symbiotic nitrogen fixation between rhizobia and their host legumes. Soybean root exudates (SREs) are thought to act as signals that influence Bradyrhizobium ability to colonize roots and to survive in the rhizosphere, and thus they act as a key determinant of nodulation competitiveness. In order to find the competitiveness-related genes in B. diazoefficiens, the transcriptome of two SREs treated B. diazoefficiens with completely different nodulation abilities (B. diazoefficiens 4534 and B. diazoefficiens 4222) were sequenced and compared. In SREs treated strain 4534 (SREs-4534), 253 unigenes were up-regulated and 204 unigenes were down-regulated. In SREs treated strain 4534 (SREs-4222), the numbers of up- and down-regulated unigenes were 108 and 185, respectively. There were considerable differences between the SREs-4534 and SREs-4222 gene expression profiles. Some differentially expressed genes are associated with a two-component system (i.g., nodW, phyR sigmaEcfG), bacterial chemotaxis (i.g., cheA, unigene04832), ABC transport proteins (i.g., unigene02212), IAA (indole-3-acetic acid) metabolism (i.g., nthA, nthB), and metabolic fitness (i.g., put.), which may explain the higher nodulation competitiveness of B. diazoefficiens in the rhizosphere. Our results provide a comprehensive transcriptomic resource for SREs treated B. diazoefficiens and will facilitate further studies on competitiveness-related genes in B. diazoefficiens. PMID- 28887530 TI - Persistence of a stage-structured food-web. AB - Contrary to a theoretical prediction, natural communities comprise many interacting species, thereby developing complex ecosystems. Earlier theoretical studies assumed that each component species within an ecological network has a simple life history, despite the fact that the interaction partners of many species, such as their predators and resources, change during the developmental stages. This poses an open question on the effect of life history complexity on the dynamics of communities. Here using a food web model, I showed that species with a stage-structured life cycle greatly changes the relationship between community complexity and persistence. Without stage-structured species, an increase in species diversity and interaction links decreases the community persistence, whereas in the presence of stage-structured species, community complexity can increase the community persistence. Therefore, life history complexity may be a key element of biodiversity that is self-maintaining. PMID- 28887531 TI - Homogeneity and High Concordance of ALK Translocation in Primary Lung Adenocarcinoma and Paired Lymph Node Metastasis. AB - Translocation of anaplastic lymphoma kinase (ALK) gene is an important determinator for the response to ALK tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients. The existence of genetic heterogeneity will affect the results of molecular testing, especially in biopsy samples from primary or metastatic sites of patients with advanced stage NSCLC. We intended to explore the heterogeneity of ALK gene translocation in excision specimens and to examine the existence of discordance of ALK status between primary tumours and corresponding lymph node metastases. A total of 106 ALK positive lung adenocarcinoma cases were collected for assessment of intratumour heterogeneity of ALK gene translocation, which were stained by the fully automated Ventana ALK D5F3 immunohistochemistry (IHC) analysis. In addition, the ALK gene translocations were evaluated in a series of 53 primary tumours and their paired lymph node metastases using ALK D5F3 IHC staining. The concordance rate between primary tumours and paired metastatic lymph nodes was 100%. ALK status was homogeneous in lung adenocarcinoma samples and was generally stable during metastasis. Therefore, ALK gene translocation can be measured reliably in material from either primary or metastatic tumours in lung adenocarcinoma patients. PMID- 28887532 TI - Nano-Integrated Suspended Polymeric Microfluidics (SPMF) Platform for Ultra Sensitive Bio-Molecular Recognition of Bovine Growth Hormones. AB - The development of sensitive platforms for the detection of biomolecules recognition is an extremely important problem in clinical diagnostics. In microcantilever (MC) transducers, surface-stress is induced upon bimolecular interaction which is translated into MC deflection. This paper presents a cost effective and ultra-sensitive MC-based biosensing platform. To address these goals, the need for costly high-resolution read-out system has been eliminated by reducing the cantilever compliance through developing a polymer-based cantilever. Furthermore a microfluidic system has been integrated with the MC in order to enhance sensitivity and response time and to reduce analytes consumption. Gold nanoparticles (AuNPs) are synthesized on the surface of suspended microfluidics as the selective layer for biomolecule immobilization. The biosensing results show significant improvement in the sensitivity of the proposed platform compared with available silicon MC biosensor. A detection limit of 2 ng/ml (100pM) is obtained for the detection of bovine growth hormones. The results validated successful application of suspended polymeric microfluidics (SPMF) as the next generation of biosensing platforms which could enable femtomolar (fM) biomolecular recognition detection. PMID- 28887533 TI - Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways. AB - The polymorphic CagA toxin is associated with Helicobacter pylori-induced disease. Previous data generated using non-isogenic strains and transfection models suggest that variation surrounding the C-terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs as well as the number of EPIYA motifs influence disease outcome. To investigate potential CagA-mediated effects on host cell signaling, we constructed and characterized a large panel of isogenic H. pylori strains that differ primarily in the CagA EPIYA region. The number of EPIYA-C motifs or the presence of an EPIYA-D motif impacted early changes in host cell elongation; however, the degree of elongation was comparable across all strains at later time points. In contrast, the strain carrying the EPIYA-D motif induced more IL-8 secretion than any other EPIYA type, and a single EPIYA-C motif induced comparable IL-8 secretion as isolates carrying multiple EPIYA-C alleles. Similar levels of ERK1/2 activation were induced by all strains carrying a functional CagA allele. Together, our data suggest that polymorphism in the CagA C-terminus is responsible for differential alterations in some, but not all, host cell signaling pathways. Notably, our results differ from non-isogenic strain studies, thus highlighting the importance of using isogenic strains to study the role of CagA toxin polymorphism in gastric cancer development. PMID- 28887534 TI - Phylogeographic studies of schizothoracine fishes on the central Qinghai-Tibet Plateau reveal the highest known glacial microrefugia. AB - Pleistocene climatic oscillations have greatly influenced the evolutionary history and distribution pattern of most extant species. However, their effects on species on the Qinghai-Tibet Plateau (QTP) are not well understood. To investigate the effects of past climatic shifts, particularly the Last Glacial Maximum (LGM), on plateau fish, we analysed the phylogeographic structure and demographic history of five closely related taxa of the subfamily Schizothoracinae, a representative endemic taxon of the QTP, from nine endorheic lakes on the central QTP and three peripheral exorheic rivers using the mitochondrial control region (D-loop) sequence and 12 microsatellite (SSR) markers. Phylogram from D-loop haplotypes revealed two well-supported lineages (North and South) separated by the Tanggula Mountains. The results from the D loop and SSR revealed that endorheic populations possess high genetic diversity and a unique genetic structure. The most recent demographic expansion occurred post-LGM for most endorheic populations and in the last interglacial period for Siling Co and all exorheic populations. Phylogeographic structure, together with species distribution modelling, supports the scenario of multiple glacial refugia on the QTP during the LGM and suggests that Siling Co (4540 m asl) is a cryptic glacial microrefugia for plateau fish, which would be the highest glacial microrefugia known. PMID- 28887535 TI - Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signaling. AB - The prevalence of cardiomyopathy from metabolic stress has increased dramatically; however, its molecular mechanisms remain elusive. Here, we show that extracellular signal-regulated protein kinase 5 (Erk5) is lost in the hearts of obese/diabetic animal models and that cardiac-specific deletion of Erk5 in mice (Erk5-CKO) leads to dampened cardiac contractility and mitochondrial abnormalities with repressed fuel oxidation and oxidative damage upon high fat diet (HFD). Erk5 regulation of peroxisome proliferator-activated receptor gamma co-activator-1alpha (Pgc-1alpha) is critical for cardiac mitochondrial functions. More specifically, we show that Gp91phox activation of calpain-1 degrades Erk5 in free fatty acid (FFA)-stressed cardiomyocytes, whereas the prevention of Erk5 loss by blocking Gp91phox or calpain-1 rescues mitochondrial functions. Similarly, adeno-associated virus 9 (AAV9)-mediated restoration of Erk5 expression in Erk5-CKO hearts prevents cardiomyopathy. These findings suggest that maintaining Erk5 integrity has therapeutic potential for treating metabolic stress-induced cardiomyopathy.The mechanistic link between metabolic stress and associated cardiomyopathy is unknown. Here the authors show that high fat diet causes calpain-1-dependent degradation of ERK5 leading to mitochondrial dysfunction, suggesting the maintenance of cardiac ERK5 as a therapeutic approach for cardiomyopathy prevention and/or treatment. PMID- 28887536 TI - Efficiency of newly formulated camptothecin with beta-cyclodextrin-EDTA-Fe3O4 nanoparticle-conjugated nanocarriers as an anti-colon cancer (HT29) drug. AB - Camptothecin (CPT) is an anti-cancer drug that effectively treats various cancers, including colon cancer. However, poor solubility and other drawbacks have restricted its chemotherapeutic potential. To overcome these restrictions, CPT was encapsulated in CEF (cyclodextrin-EDTA-FE3O4), a composite nanoparticle of magnetic iron oxide (Fe3O4), and beta-cyclodextrin was cross-linked with ethylenediaminetetraacetic acid (EDTA). This formulation improved CPT's solubility and bioavailability for cancer cells. The use of magnetically responsive anti-cancer formulation is highly advantageous in cancer chemotherapy. The chemical characterisation of CPT-CEF was studied here. The ability of this nano-compound to induce apoptosis in HT29 colon cancer cells and A549 lung cancer cells was evaluated. The dose-dependent cytotoxicity of CPT-CEF was shown using MTT. Propidium iodide and Annexin V staining, mitochondrial membrane depolarisation (JC-1 dye), and caspase-3 activity were assayed to detect apoptosis in CPT-CEF-treated cancer cells. Cell cycle analysis also showed G1 phase arrest, which indicated possible synergistic effects of the nano-carrier. These study results show that CPT-CEF causes a dose-dependent cell viability reduction in HT29 and A549 cells and induces apoptosis in colon cancer cells via caspase-3 activation. These data strongly suggest that CPT could be used as a major nanocarrier for CPT to effectively treat colon cancer. PMID- 28887537 TI - LNGFR targets the Wnt/beta-catenin pathway and promotes the osteogenic differentiation in rat ectomesenchymal stem cells. AB - Considerable evidence has shown that the Wnt/beta-catenin pathway is involved in osteogenic differentiation in various stem cells. However, the role of Wnt/beta catenin pathway in regulating the osteogenic differentiation of rat ectomesenchymal stem cells (EMSCs), which are considered to be the progenitors of dental mesenchymal stem cells, remains unknown. In this study, we demonstrated that nuclear beta-catenin was upregulated during EMSC osteogenic differentiation. The Wnt signalling inhibitor IWR-1-endo inhibited EMSC osteogenic differentiation, while the Wnt signalling agonist SKL2001 promoted it. Moreover, nuclear beta-catenin was further upregulated by the overexpression of low affinity nerve growth factor receptor (LNGFR) during EMSC osteogenic differentiation. Further experiments demonstrated that LNGFR overexpression enhanced EMSC osteogenic differentiation, while LNGFR silencing decreased it. Additionally, IWR-1-endo attenuated LNGFR-enhanced EMSC osteogenic differentiation. Collectively, our data reveal that LNGFR targets the Wnt/beta catenin pathway and positively regulates EMSC osteogenic differentiation, suggesting that Wnt/beta-catenin pathway may be involved in the development of teeth and that the targeting Wnt/beta-catenin pathway may have great potential for applications in dental tissue engineering regeneration. PMID- 28887538 TI - Melt fluxing to elevate the forming ability of Al-based bulk metallic glasses. AB - Salt-fluxing treatment is an effective technique to improve the glass-forming ability (GFA) of bulk metallic glass (BMG)-forming melts, as demonstrated before in Pd- and Fe-based systems. However, it has been challenging to develop similar fluxing protocol for more reactive melts, such as Al-rich BMG-forming systems. Here we design new fluxing agents, from a thermodynamics perspective that takes into account combined effects of physical absorption and chemical absorption (reaction) between the fluxing agents and oxide inclusions. MgCl2-CaCl2 composite salts were selected, and their fluxing effects were systematically studied on an Al86Ni6.75Co2.25Y3.25La1.75 alloy, the best BMG-forming composition reported thus far for Al-rich alloy systems. The oxygen content was found to continuously decrease in the master alloy with increasing cycles of salt-fluxing treatment, with chlorate products on the surface suggesting concurrent physical absorption and chemical reaction. The fluxing treatment developed has enabled a record critical size (diameter) of 2.5 mm for Al-based BMGs. Our finding is thus an advance in developing highly desirable Al-based BMGs, and also provides guidance for designing processing protocol to produce larger-sized BMGs in other reactive systems. PMID- 28887539 TI - Neurogenetic plasticity and sex influence the link between corticolimbic structural connectivity and trait anxiety. AB - Corticolimbic pathways connecting the amygdala and ventral prefrontal cortex (vPFC) are linked with trait anxiety, but it remains unclear what potential genetic moderators contribute to this association. We sought to address this by examining the inter-individual variability in neuroplasticity as modeled by a functional polymorphism (rs6265) in the human gene for brain derived neurotrophic factor (BDNF). Amygdala-vPFC pathway fractional anisotropy (FA) from 669 diffusion magnetic resonance images was used to examine associations with trait anxiety as a function of rs6265 genotype. We first replicated the inverse correlation between trait anxiety and amygdala-vPFC pathway FA in women. Furthermore, we found a moderating influence of rs6265 genotype such that the association between trait anxiety and right amygdala-vPFC pathway FA was strongest in women carrying the Met allele, which is linked with decreased activity-dependent neuroplasticity. Results indicate that the microstructural integrity of pathways supporting communication between the amygdala and vPFC help shape the expression of trait anxiety in women, and that this association is further modulated by genetically driven variability in neuroplasticity. PMID- 28887540 TI - Interleukin-22 level is negatively correlated with neutrophil recruitment in the lungs in a Pseudomonas aeruginosa pneumonia model. AB - Pseudomonas aeruginosa is a major threat for immune-compromised patients. Bacterial pneumonia can induce uncontrolled and massive neutrophil recruitment ultimately leading to acute respiratory distress syndrome and epithelium damage. Interleukin-22 plays a central role in the protection of the epithelium. In this study, we aimed to evaluate the role of interleukin-22 and its soluble receptor IL-22BP in an acute Pseudomonas aeruginosa pneumonia model in mice. In this model, we noted a transient increase of IL-22 during Pseudomonas aeruginosa challenge. Using an antibody-based approach, we demonstrated that IL-22 neutralisation led to increased susceptibility to infection and to lung damage correlated with an increase in neutrophil accumulation in the lungs. On the contrary, rIL-22 administration or IL-22BP neutralisation led to a decrease in mouse susceptibility and lung damage associated with a decrease in neutrophil accumulation. This study demonstrated that the IL-22/IL-22BP system plays a major role during Pseudomonas aeruginosa pneumonia by moderating neutrophil accumulation in the lungs that ultimately leads to epithelium protection. PMID- 28887541 TI - Evaluation of single-cell genomics to address evolutionary questions using three SAGs of the choanoflagellate Monosiga brevicollis. AB - Single-cell genomics (SCG) appeared as a powerful technique to get genomic information from uncultured organisms. However, SCG techniques suffer from biases at the whole genome amplification step that can lead to extremely variable numbers of genome recovery (5-100%). Thus, it is unclear how useful can SCG be to address evolutionary questions on uncultured microbial eukaryotes. To provide some insights into this, we here analysed 3 single-cell amplified genomes (SAGs) of the choanoflagellate Monosiga brevicollis, whose genome is known. Our results show that each SAG has a different, independent bias, yielding different levels of genome recovery for each cell (6-36%). Genes often appear fragmented and are split into more genes during annotation. Thus, analyses of gene gain and losses, gene architectures, synteny and other genomic features can not be addressed with a single SAG. However, the recovery of phylogenetically-informative protein domains can be up to 55%. This means SAG data can be used to perform accurate phylogenomic analyses. Finally, we also confirm that the co-assembly of several SAGs improves the general genomic recovery. Overall, our data show that, besides important current limitations, SAGs can still provide interesting and novel insights from poorly-known, uncultured organisms. PMID- 28887542 TI - Genome-wide analysis of health-related biomarkers in the UK Household Longitudinal Study reveals novel associations. AB - Serum biomarker levels are associated with the risk of complex diseases. Here, we aimed to gain insights into the genetic architecture of biomarker traits which can reflect health status. We performed genome-wide association analyses for twenty serum biomarkers involved in organ function and reproductive health. 9,961 individuals from the UK Household Longitudinal Study were genotyped using the Illumina HumanCoreExome array and variants imputed to the 1000 Genomes Project and UK10K haplotypes. We establish a polygenic heritability for all biomarkers, confirm associations of fifty-four established loci, and identify five novel, replicating associations at genome-wide significance. A low-frequency variant, rs28929474, (beta = 0.04, P = 2 * 10-10) was associated with levels of alanine transaminase, an indicator of liver damage. The variant is located in the gene encoding serine protease inhibitor, low levels of which are associated with alpha 1 antitrypsin deficiency which leads to liver disease. We identified novel associations (rs78900934, beta = 0.05, P = 6 * 10-12; rs2911280, beta = 0.09, P = 6 * 10-10) for dihydroepiandrosterone sulphate, a precursor to major sex hormones, and for glycated haemoglobin (rs12819124, beta = -0.03, P = 4 * 10-9; rs761772, beta = 0.05, P = 5 * 10-9). rs12819124 is nominally associated with risk of type 2 diabetes. Our study offers insights into the genetic architecture of well-known and less well-studied biomarkers. PMID- 28887543 TI - The Oxidative State of Cysteine Thiol 144 Regulates the SIRT6 Glucose Homeostat. AB - Control of glucose homeostasis plays a critical role in health and lifespan and its dysregulation contributes to inflammation, cancer and aging. NAD + dependent Sirtuin 6 (SIRT6) is a glucose homeostasis regulator in animals and humans and its regulation at the molecular level is unknown. Here, we report that a cysteine thiol redox sensor contributes to the role of SIRT6 in controlling glucose homeostasis. Sulfenylation of SIRT6 occurs in THP1 cells and primary human promonocytes during inflammation and in splenocytes from mice with sepsis. Inhibiting xanthine oxidase, a major reactive oxygen species (ROS) contributor during acute inflammation, reduces sulfenylation of SIRT6, glucose transporter Glut1 expression, glucose uptake, and glycolysis. A block in glycolysis associated with monocyte deactivation by endotoxin, a process contributing to immunometabolic paralysis in human and mouse sepsis monocytes, can be reversed by increasing H2O2 and sulfenylating SIRT6. Mutation analysis of SIRT6 Cys144, which lies in its phylogenetically conserved zinc-associated Cys-X-X-Cys motif near the catalytic domain of the protein, decreases SIRT6 deacetylase activity and promotes glycolysis. These results suggest that direct and reversible cysteine thiol 144 may play a functional role in SIRT6-dependent control over monocyte glycolysis, an important determinant of effector innate immune responses. PMID- 28887544 TI - Analysis of bacterial and fungal communities in Marcha and Thiat, traditionally prepared amylolytic starters of India. AB - Marcha and thiat are traditionally prepared amylolytic starters use for production of various ethnic alcoholic beverages in Sikkim and Meghalaya states in India. In the present study we have tried to investigate the bacterial and fungal community composition of marcha and thiat by using high throughput sequencing. Characterization of bacterial community depicts phylum Proteobacteria is the most dominant in both marcha (91.4%) and thiat (53.8%), followed by Firmicutes, and Actinobacteria. Estimates of fungal community composition showed Ascomycota as the dominant phylum. Presence of Zygomycota in marcha distinguishes it from the thiat. The results of NGS analysis revealed dominance of yeasts in marcha whereas molds out numbers in case of thiat. This is the first report on microbial communities of traditionally prepared amylolytic starters of India using high throughput sequencing. PMID- 28887545 TI - Human-to-human closed-loop control based on brain-to-brain interface and muscle to-muscle interface. AB - Novel communication techniques have always been fascinating for humankind. This pilot study presents an approach to human interaction by combining direct brain to-brain interface (BBI) and muscle-to-muscle interface (MMI) in a closed-loop pattern. In this system, artificial paths (data flows) functionally connect natural paths (nerves). The intention from one subject (sender) is recognized using electroencephalography (EEG) based brain-computer interface (BCI), which is sent out to trigger transcranial magnetic stimulation (TMS) on the other subject (receiver) and induce hand motion; meanwhile TMS results in a significant change on the motor evoked potentials (MEP) recorded by electromyography (EMG) of the receiver's arm, which triggers functional electrical stimulation (FES) applied to the sender's arm and generates hand motion. Human-controlled loop and automatic control loop experiments were performed with 6 pairs of healthy subjects to evaluate the performance of the introduced mechanism. The results indicated that response accuracy during human-controlled experiments was 85% which demonstrates the feasibility of the proposed method. During the automatic control test, two subjects could accomplish repetitive and reciprocal hand motion control up to 85 times consecutively. PMID- 28887546 TI - Metabolomics differences between silkworms (Bombyx mori) reared on fresh mulberry (Morus) leaves or artificial diets. AB - Silkworms (Bombyx mori) reared on artificial diets have great potential applications in sericulture. However, the mechanisms underlying the enhancement of metabolic utilization by altering silkworm nutrition are unclear. The aim of this study was to investigate the mechanisms responsible for the poor development and low silk protein synthesis efficiency of silkworms fed artificial diets. After multi-generational selection of the ingestive behavior of silkworms to artificial diets, we obtained two strains, one of which developed well and another in which almost all its larvae starved to death on the artificial diets. Subsequently, we analyzed the metabolomics of larval hemolymph by gas chromatography/liquid chromatography-mass spectrometry, and the results showed that vitamins were in critically short supply, whereas the nitrogen metabolic end product of urea and uric acid were enriched substantially, in the hemolymph of the silkworms reared on the artificial diets. Meanwhile, amino acid metabolic disorders, as well as downregulation of carbohydrate metabolism, energy metabolism, and lipid metabolism, co-occurred. Furthermore, 10 male-dominant metabolites and 27 diet-related metabolites that differed between male and female silkworms were identified. These findings provide important insights into the regulation of silkworm metabolism and silk protein synthesis when silkworms adapt to an artificial diet. PMID- 28887547 TI - Uncovering the effect of low-frequency static magnetic field on tendon-derived cells: from mechanosensing to tenogenesis. AB - Magnetotherapy has been receiving increased attention as an attractive strategy for modulating cell physiology directly at the site of injury, thereby providing the medical community with a safe and non-invasive therapy. Yet, how magnetic field influences tendon cells both at the cellular and molecular levels remains unclear. Thus, the influence of a low-frequency static magnetic field (2 Hz, 350 mT) on human tendon-derived cells was studied using different exposure times (4 and 8 h; short-term studies) and different regimens of exposure to an 8h-period of magnetic stimulation (continuous, every 24 h or every 48 h; long-term studies). Herein, 8 h stimulation in short-term studies significantly upregulated the expression of tendon-associated genes SCX, COL1A1, TNC and DCN (p < 0.05) and altered intracellular Ca2+ levels (p < 0.05). Additionally, every 24 h regimen of stimulation significantly upregulated COL1A1, COL3A1 and TNC at day 14 in comparison to control (p < 0.05), whereas continuous exposure differentially regulated the release of the immunomodulatory cytokines IL-1beta and IL-10 (p < 0.001) but only at day 7 in comparison to controls. Altogether, these results provide new insights on how low-frequency static magnetic field fine-tune the behaviour of tendon cells according to the magnetic settings used, which we foresee to represent an interesting candidate to guide tendon regeneration. PMID- 28887548 TI - Label-free and real-time monitoring of single cell attachment on template stripped plasmonic nano-holes. AB - Leveraging microfluidics and nano-plasmonics, we present in this paper a new method employing a micro-nano-device that is capable of monitoring the dynamic cell-substrate attachment process at single cell level in real time without labeling. The micro-nano-device essentially has a gold thin film as the substrate perforated with periodic, near-cm2-area, template-stripped nano-holes, which generate plasmonic extraordinary optical transmission (EOT) with a high sensitivity to refractive index changes at the metal-dielectric interface. Using this device, we successfully demonstrated label-free and real-time monitoring of the dynamic cell attachment process for single mouse embryonic stem cell (C3H10) and human tumor cell (HeLa) by collecting EOT spectrum data during 3-hour on-chip culture. We further collected the EOT spectral shift data at the start and end points of measurement during 3-hour on-chip culture for 50 C3H10 and 50 HeLa cells, respectively. The experiment results show that the single cell attachment process of both HeLa and C3H10 cells follow the logistic retarded growth model, but with different kinetic parameters. Variations in spectral shift during the same culture period across single cells present new evidence for cell heterogeneity. The micro-nano-device provides a new, label-free, real-time, and sensitive, platform to investigate the cell adhesion kinetics at single cell level. PMID- 28887549 TI - SATB2/beta-catenin/TCF-LEF pathway induces cellular transformation by generating cancer stem cells in colorectal cancer. AB - Recent studies have demonstrated the involvement of colorectal cancer (CRC) stem cells (CSC) in transformation, cancer progression and metastasis. The main goal of this paper was to examine the molecular mechanisms by which SATB2 induced malignant transformation of colorectal epithelial cells. SATB2 induced malignant transformation and these transformed cells gained the characteristics of CSCs by expressing stem cell markers (CD44, CD133, LGR5 and DCLK1) and transcription factors (c-Myc, Nanog and Sox2). Overexpression of SATB2 in normal colorectal epithelial cells increased cell motility, migration and invasion, which were associated with an increase in N-cadherin and Zeb1, and decrease in E-cadherin expression. SATB2 overexpression also upregulated XIAP and cyclin D1, suggesting its role in cell survival and cell cycle. Furthermore, the expression of SATB2 was positively correlated with beta-catenin expression in CRC. In contrary, depletion of SATB2 inhibited cell proliferation, colony formation, cell motility and expression of beta-catenin, Snail, Slug, Zeb1 and N-cadherin, and upregulated E-cadherin. Furthermore, SATB2 silencing inhibited the expression of stem cell markers, pluripotency maintaining transcription factors, cell cycle and cell proliferation/survival genes and TCF/LEF targets. Finally, beta-catenin/TCF-LEF pathway mediated the biological effects of SATB2 in CSCs. These studies support the role of SATB2/beta-catenin/TCF-LEF pathway in transformation and carcinogenesis. PMID- 28887550 TI - Identification of immunity-related genes in Plutella xylostella in response to fungal peptide destruxin A: RNA-Seq and DGE analysis. AB - Plutella xylostella has become the major lepidopteran pest of Brassica owing to its strong ability of resistance development to a wide range of insecticides. Destruxin A, a mycotoxin of entomopathogenic fungus, Metarhizium anisopliae, has broad-spectrum insecticidal effects. However, the interaction mechanism of destruxin A with the immune system of P. xylostella at genomic level is still not well understood. Here, we identified 129 immunity-related genes, including pattern recognition receptors, signal modulators, few members of main immune pathways (Toll, Imd, and JAK/STAT), and immune effectors in P. xylostella in response to destruxin A at three different time courses (2 h, 4 h, and 6 h). It is worthy to mention that the immunity-related differentially expressed genes (DEGs) analysis exhibited 30, 78, and 72 up-regulated and 17, 13, and 6 down regulated genes in P. xylostella after destruxin A injection at 2 h, 4 h, and 6 h, respectively, compared to control. Interestingly, our results revealed that the expression of antimicrobial peptides that play a vital role in insect immune system was up-regulated after the injection of destruxin A. Our findings provide a detailed information on immunity-related DEGs and reveal the potential of P. xylostella to limit the infection of fungal peptide destruxin A by increasing the activity of antimicrobial peptides. PMID- 28887551 TI - Graphene Improves the Biocompatibility of Polyacrylamide Hydrogels: 3D Polymeric Scaffolds for Neuronal Growth. AB - In tissue engineering strategies, the design of scaffolds based on nanostructures is a subject undergoing intense research: nanomaterials may affect the scaffolds properties, including their ability to interact with cells favouring cell growth and improving tissue performance. Hydrogels are synthetic materials widely used to obtain realistic tissue constructs, as they resemble living tissues. Here, different hydrogels with varying content of graphene, are synthesised by in situ radical polymerization of acrylamide in aqueous graphene dispersions. Hydrogels are characterised focusing on the contribution of the nanomaterial to the polymer network. Our results suggest that graphene is not a mere embedded nanomaterial within the hydrogels, rather it represents an intrinsic component of these networks, with a specific role in the emergence of these structures. Moreover, a hybrid hydrogel with a graphene concentration of only 0.2 mg mL-1 is used to support the growth of cultured brain cells and the development of synaptic activity, in view of exploiting these novel materials to engineer the neural interface of brain devices of the future. The main conclusion of this work is that graphene plays an important role in improving the biocompatibility of polyacrylamide hydrogels, allowing neuronal adhesion. PMID- 28887552 TI - Formaldehyde Hemiacetal Sampling, Recovery, and Quantification from Electronic Cigarette Aerosols. AB - The electronic cigarette solvents propylene glycol and glycerol are known to produce toxic byproducts such as formaldehyde, acetaldehyde and acrolein. However, the aerosol toxin yield depends upon a variety of chemical and physical variables. The formaldehyde hemiacetals derived from these solvents were reported as major electronic cigarette aerosol components by us in 2015. In the study described herein, the formaldehyde hemiacetals were found at higher levels than those of free formaldehyde via an orthogonal sample collection protocol. In addition, the common aldehyde collection methods for electronic cigarettes, such as impingers and sorbent tubes containing DNPH, significantly underestimate the levels of formaldehyde. The reason for this is that formaldehyde hemiacetals follow other reaction pathways, such as the formation of a less reactive full cyclic acetal catalyzed by the acidity of the DNPH solution and the silica. We found that formaldehyde hemiacetals are a considerable fraction of the total formaldehyde produced in electronic cigarette that cannot be determined accurately by DNPH derivatization methods. Although the health effects of the hemiacetals are not yet known, they warrant further investigation. PMID- 28887553 TI - Insight into shark magnetic field perception from empirical observations. AB - Elasmobranch fishes are among a broad range of taxa believed to gain positional information and navigate using the earth's magnetic field, yet in sharks, much remains uncertain regarding the sensory receptors and pathways involved, or the exact nature of perceived stimuli. Captive sandbar sharks, Carcharhinus plumbeus were conditioned to respond to presentation of a magnetic stimulus by seeking out a target in anticipation of reward (food). Sharks in the study demonstrated strong responses to magnetic stimuli, making significantly more approaches to the target (p = < 0.01) during stimulus activation (S+) than before or after activation (S-). Sharks exposed to reversible magnetosensory impairment were less capable of discriminating changes to the local magnetic field, with no difference seen in approaches to the target under the S+ and S- conditions (p = 0.375). We provide quantified detection and discrimination thresholds of magnetic stimuli presented, and quantify associated transient electrical artefacts. We show that the likelihood of such artefacts serving as the stimulus for observed behavioural responses was low. These impairment experiments support hypotheses that magnetic field perception in sharks is not solely performed via the electrosensory system, and that putative magnetoreceptor structures may be located in the naso-olfactory capsules of sharks. PMID- 28887554 TI - Near-optimal integration of facial form and motion. AB - Human perception consists of the continuous integration of sensory cues pertaining to the same object. While it has been fairly well shown that humans use an optimal strategy when integrating low-level cues proportional to their relative reliability, the integration processes underlying high-level perception are much less understood. Here we investigate cue integration in a complex high level perceptual system, the human face processing system. We tested cue integration of facial form and motion in an identity categorization task and found that an optimal model could successfully predict subjects' identity choices. Our results suggest that optimal cue integration may be implemented across different levels of the visual processing hierarchy. PMID- 28887555 TI - Monitoring the colonization and infection of legume nodules by Micromonospora in co-inoculation experiments with rhizobia. AB - The discovery that the actinobacterium Micromonospora inhabits nitrogen-fixing nodules raised questions as to its potential ecological role. The capacity of two Micromonospora strains to infect legumes other than their original host, Lupinus angustifolius, was investigated using Medicago and Trifolium as test plants. Compatible rhizobial strains were used for coinoculation of the plants because Micromonospora itself does not induce nodulation. Over 50% of nodules from each legume housed Micromonospora, and using 16S rRNA gene sequence identification, we verified that the reisolated strains corresponded to the microorganisms inoculated. Entry of the bacteria and colonization of the plant hosts were monitored using a GFP-tagged Lupac 08 mutant together with rhizobia, and by using immunogold labeling. Strain Lupac 08 was localized in plant tissues, confirming its capacity to enter and colonize all hosts. Based on studying three different plants, our results support a non-specific relationship between Micromonospora and legumes. Micromonospora Lupac 08, originally isolated from Lupinus re-enters root tissue, but only when coinoculated with the corresponding rhizobia. The ability of Micromonospora to infect and colonize different legume species and function as a potential plant-growth promoting bacterium is relevant because this microbe enhances the symbiosis without interfering with the host and its nodulating and nitrogen-fixing microbes. PMID- 28887556 TI - Biodegradation of gentamicin by bacterial consortia AMQD4 in synthetic medium and raw gentamicin sewage. AB - Gentamicin, a broad spectrum antibiotic of the aminoglycoside class, is widely used for disease prevention of human beings as well as animals. Nowadays the environmental issue caused by the disposal of wastes containing gentamicin attracts increasing attention. In this study, a gentamicin degrading bacterial consortia named AMQD4, including Providencia vermicola, Brevundimonas diminuta, Alcaligenes sp. and Acinetobacter, was isolated from biosolids produced during gentamicin production for the removal of gentamicin in the environment. The component and structure of gentamicin have a great influence on its degradation and gentamicin C1a and gentamicin C2a were more prone to being degraded. AMQD4 could maintain relatively high gentamicin removal efficiency under a wide range of pH, especially in an alkaline condition. In addition, AMQD4 could remove 56.8% and 47.7% of gentamicin in unsterilized and sterilized sewage in a lab-scale experiment, respectively. And among the isolates in AMQD4, Brevundimonas diminuta BZC3 performed the highest gentamicin degradation about 50%. It was speculated that aac3iia was the gentamicin degradation gene and the main degradation product was 3'-acetylgentamicin. Our results suggest that AMQD4 and Brevundimonas diminuta BZC3 could be important candidates to the list of superior microbes for bioremediation of antibiotic pollution. PMID- 28887557 TI - Identification of Purple Acid Phosphatases in Chickpea and Potential Roles of CaPAP7 in Seed Phytate Accumulation. AB - Purple acid phosphatases (PAPs) play important roles in phosphate (Pi) acquisition and utilization. These PAPs hydrolyze organic Phosphorus (P) containing compounds in rhizosphere as well as inside the plant cell. However, roles of PAPs in one of the most widely cultivated legumes, chickpea (Cicer arietnum L.), have not been unraveled so far. In the present study, we identified 25 putative PAPs in chickpea (CaPAPs) which possess functional PAP motifs and domains. Differential regulation of CaPAPs under different nutrient deficiencies revealed their roles under multiple nutrient stresses including Pi deficiency. Interestingly, most of the CaPAPs were prominently expressed in flowers and young pods indicating their roles in flower and seed development. Association mapping of SNPs underlying CaPAPs with seed traits revealed significant association of low Pi inducible CaPAP7 with seed weight and phytate content. Biochemical characterization of recombinant CaPAP7 established it to be a functional acid phosphatase with highest activity on most abundant organic-P substrate, phytate. Exogenous application of recombinant CaPAP7 enhanced biomass and Pi content of Arabidopsis seedlings supplemented with phytate as sole P source. Taken together, our results uncover the PAPs in chickpea and potential roles of CaPAP7 in seed phytate accumulation. PMID- 28887558 TI - Dramatically Enhanced Superconductivity in Elemental Bismuth from Excitonic Fluctuation Exchange. AB - Motivated by the remarkable discovery of superconductivity in elemental Bismuth at ambient pressure, we study its normal state in detail using a combination of tight-binding (TB) band-structure supplemented by dynamical mean-field theory (DMFT). We show that a two-fluid model composed of preformed and dynamically fluctuating excitons coupled to a tiny number of carriers provides a unified rationalization of a range of ill-understood normal state spectral and transport data. Based on these, we propose that resonant scattering involving a very low density of renormalized carriers and the excitonic liquid drives logarithmic enhancement of vertex corrections, boosting superconductivity in Bi. A confirmatory test for our proposal would be the experimental verification of an excitonic semiconductor with electronic nematicity as a 'competing order' on inducing a semi-metal-to semiconductor transition in Bi by an external perturbation like pressure. PMID- 28887559 TI - Delayed hypersensitivity to nanosecond pulsed electric field in electroporated cells. AB - We demonstrate that conditioning of mammalian cells by electroporation with nanosecond pulsed electric field (nsPEF) facilitates their response to the next nsPEF treatment. The experiments were designed to unambiguously separate the electroporation-induced sensitization and desensitization effects. Electroporation was achieved by bursts of 300-ns, 9 kV/cm pulses (50 Hz, n = 3 100) and quantified by propidium dye uptake within 11 min after the nsPEF exposure. We observed either sensitization to nsPEF or no change (when the conditioning was either too weak or too intense, or when the wait time after conditioning was too short). Within studied limits, conditioning never caused desensitization. With settings optimal for sensitization, the second nsPEF treatment became 2.5 times (25 degrees C) or even 6 times (37 degrees C) more effective than the same nsPEF treatment delivered without conditioning. The minimum wait time required for sensitization development was 30 s, with still longer delays increasing the effect. We show that the delayed hypersensitivity was not mediated by either cell swelling or oxidative effect of the conditioning treatment; biological mechanisms underlying the delayed electrosensitization remain to be elucidated. Optimizing nsPEF delivery protocols to induce sensitization can reduce the dose and adverse side effects of diverse medical treatments which require multiple pulse applications. PMID- 28887560 TI - Simulation of head and neck cancer oxygenation and doubling time in a 4D cellular model with angiogenesis. AB - Tumor oxygenation has been correlated with treatment outcome for radiotherapy. In this work, the dependence of tumor oxygenation on tumor vascularity and blood oxygenation was determined quantitatively in a 4D stochastic computational model of head and neck squamous cell carcinoma (HNSCC) tumor growth and angiogenesis. Additionally, the impacts of the tumor oxygenation and the cancer stem cell (CSC) symmetric division probability on the tumor volume doubling time and the proportion of CSCs in the tumor were also quantified. Clinically relevant vascularities and blood oxygenations for HNSCC yielded tumor oxygenations in agreement with clinical data for HNSCC. The doubling time varied by a factor of 3 from well oxygenated tumors to the most severely hypoxic tumors of HNSCC. To obtain the doubling times and CSC proportions clinically observed in HNSCC, the model predicts a CSC symmetric division probability of approximately 2% before treatment. To obtain the doubling times clinically observed during treatment when accelerated repopulation is occurring, the model predicts a CSC symmetric division probability of approximately 50%, which also results in CSC proportions of 30-35% during this time. PMID- 28887561 TI - Enhancement of extinction memory by pharmacological and behavioral interventions targeted to its reactivation. AB - Extinction is a process that involves new learning that inhibits the expression of previously acquired memories. Although temporarily effective, extinction does not erase an original fear association. Since the extinction trace tends to fade over time, the original memory can resurge. On the other hand, strengthening effects have been described in several reconsolidation studies using different behavioral and pharmacological manipulations. In order to know whether an extinction memory can be strengthened by reactivation-based interventions in the contextual fear conditioning task, we began by replicating the classic phenomenon of spontaneous recovery to show that brief reexposure sessions can prevent the decay of the extinction trace over time in a long-lasting way. This fear attenuation was shown to depend both on L-type calcium channels and protein synthesis, which suggests a reconsolidation process behind the reactivation induced strengthening effect. The extinction trace was also susceptible to enhancement by a post-reactivation infusion of a memory-enhancing drug (NaB), which was also able to prevent rapid fear reacquisition (savings). These findings point to new reactivation-based approaches able to strengthen an extinction memory to promote its persistence. The constructive interactions between extinction and reconsolidation may represent a promising novel approach in the realm of fear-related disorder treatments. PMID- 28887562 TI - Metformin Improves Endothelial Function and Reduces Blood Pressure in Diabetic Spontaneously Hypertensive Rats Independent from Glycemia Control: Comparison to Vildagliptin. AB - Metformin confers vascular benefits beyond glycemia control, possibly via pleiotropic effects on endothelial function. In type-1-diabetes-mellitus (T1DM )patients metformin improved flow-mediated dilation but also increased prostaglandin(PG)-F2alpha, a known endothelial-contracting factor. To explain this paradoxical finding we hypothesized that metformin increased endothelial vasodilator mediators (e.g. NO and EDHF) to an even larger extent. Spontaneously hypertensive-rats (SHR) display impaired endothelium-dependent relaxation (EDR) involving contractile PGs. EDR was studied in isolated SHR aortas and the involvement of PGs, NO and EDHF assessed. 12-week metformin 300 mg/kg/day improved EDR by up-regulation of NO and particularly EDHF; it also reduced blood pressure and increased plasma sulphide levels (a proxy for H2S, a possible mediator of EDHF). These effects persisted in SHR with streptozotocin (STZ) induced T1DM. Vildagliptin (10 mg/kg/day), targeting the incretin axis by increasing GLP-1, also reduced blood pressure and improved EDR in SHR aortas, mainly via the inhibition of contractile PGs, but not in STZ-SHR. Neither metformin nor vildagliptin altered blood glucose or HbA1c. In conclusion, metformin reduced blood pressure and improved EDR in SHR aorta via up-regulation of NO and particularly EDHF, an effect that was independent from glycemia control and maintained during T1DM. A comparison to vildagliptin did not support effects of metformin mediated by GLP-1. PMID- 28887563 TI - The most active Cu facet for low-temperature water gas shift reaction. AB - Identification of the active site is important in developing rational design strategies for solid catalysts but is seriously blocked by their structural complexity. Here, we use uniform Cu nanocrystals synthesized by a morphology preserved reduction of corresponding uniform Cu2O nanocrystals in order to identify the most active Cu facet for low-temperature water gas shift (WGS) reaction. Cu cubes enclosed with {100} facets are very active in catalyzing the WGS reaction up to 548 K while Cu octahedra enclosed with {111} facets are inactive. The Cu-Cu suboxide (CuxO, x >= 10) interface of Cu(100) surface is the active site on which all elementary surface reactions within the catalytic cycle proceed smoothly. However, the formate intermediate was found stable at the Cu CuxO interface of Cu(111) surface with consequent accumulation and poisoning of the surface at low temperatures. Thereafter, Cu cubes-supported ZnO catalysts are successfully developed with extremely high activity in low-temperature WGS reaction.Nanocrystals display a variety of facets with different catalytic activity. Here the authors identify the most active facet of copper nanocrystals relevant to the low-temperature water gas shift reaction and further design zinc oxide-copper nanocubes with exceptionally high catalytic activity. PMID- 28887565 TI - Rapid synthesis and decoration of reduced graphene oxide with gold nanoparticles by thermostable peptides for memory device and photothermal applications. AB - This article presents novel, rapid, and environmentally benign synthesis method for one-step reduction and decoration of graphene oxide with gold nanoparticles (NAuNPs) by using thermostable antimicrobial nisin peptides to form a gold nanoparticles-reduced graphene oxide (NAu-rGO) nanocomposite. The formed composite material was characterized by UV/Vis spectroscopy, X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy, field emission scanning electron microscopy, and high-resolution transmission electron microscopy (HR TEM). HR-TEM analysis revealed the formation of spherical AuNPs of 5-30 nm in size on reduced graphene oxide (rGO) nanosheets. A non-volatile-memory device was prepared based on a solution-processed ZnO thin-film transistor fabricated by inserting the NAu-rGO nanocomposite in the gate dielectric stack as a charge trapping medium. The transfer characteristic of the ZnO thin-film transistor memory device showed large clockwise hysteresis behaviour because of charge carrier trapping in the NAu-rGO nanocomposite. Under positive and negative bias conditions, clear positive and negative threshold voltage shifts occurred, which were attributed to charge carrier trapping and de-trapping in the ZnO/NAu rGO/SiO2 structure. Also, the photothermal effect of the NAu-rGO nanocomposites on MCF7 breast cancer cells caused inhibition of ~80% cells after irradiation with infrared light (0.5 W cm-2) for 5 min. PMID- 28887564 TI - Inhibition of Y1 receptor signaling improves islet transplant outcome. AB - Failure to secrete sufficient quantities of insulin is a pathological feature of type-1 and type-2 diabetes, and also reduces the success of islet cell transplantation. Here we demonstrate that Y1 receptor signaling inhibits insulin release in beta-cells, and show that this can be pharmacologically exploited to boost insulin secretion. Transplanting islets with Y1 receptor deficiency accelerates the normalization of hyperglycemia in chemically induced diabetic recipient mice, which can also be achieved by short-term pharmacological blockade of Y1 receptors in transplanted mouse and human islets. Furthermore, treatment of non-obese diabetic mice with a Y1 receptor antagonist delays the onset of diabetes. Mechanistically, Y1 receptor signaling inhibits the production of cAMP in islets, which via CREB mediated pathways results in the down-regulation of several key enzymes in glycolysis and ATP production. Thus, manipulating Y1 receptor signaling in beta-cells offers a unique therapeutic opportunity for correcting insulin deficiency as it occurs in the pathological state of type-1 diabetes as well as during islet transplantation.Islet transplantation is considered one of the potential treatments for T1DM but limited islet survival and their impaired function pose limitations to this approach. Here Loh et al. show that the Y1 receptor is expressed in beta- cells and inhibition of its signalling, both genetic and pharmacological, improves mouse and human islet function. PMID- 28887566 TI - The syntactic organization of pasta-eating and the structure of reach movements in the head-fixed mouse. AB - Mice are adept in the use of their hands for activities such as feeding, which has led to their use in investigations of the neural basis of skilled-movements. We describe the syntactic organization of pasta-eating and the structure of hand movements used for pasta manipulation by the head-fixed mouse. An ethogram of mice consuming pieces of spaghetti reveals that they eat in bite/chew bouts. A bout begins with pasta lifted to the mouth and then manipulated with hand movements into a preferred orientation for biting. Manipulation involves many hand release-reach movements, each with a similar structure. A hand is advanced from a digit closed and flexed (collect) position to a digit extended and open position (overgrasp) and then to a digit closed and flexed (grasp) position. Reach distance, hand shaping, and grasp patterns featuring precision grasps or whole hand grasps are related. To bite, mice display hand preference and asymmetric grasps; one hand (guide grasp) directs food into the mouth and the other stabilizes the pasta for biting. When chewing after biting, the hands hold the pasta in a symmetric resting position. Pasta-eating is organized and features structured hand movements and so lends itself to the neural investigation of skilled-movements. PMID- 28887567 TI - Signatures of the Kondo effect in VSe2. AB - VSe2 is a transition metal dichaclogenide which has a charge- density wave transition that has been well studied. We report on a low-temperature upturn in the resistivity and, at temperatures below this resistivity minimum, an unusual magnetoresistance which is negative at low fields and positive at higher fields, in single crystals of VSe2. The negative magnetoresistance has a parabolic dependence on the magnetic field and shows little angular dependence. The magnetoresistance at temperatures above the resistivity minimum is always positive. We interpret these results as signatures of the Kondo effect in VSe2. An upturn in the susceptibility indicates the presence of interlayer V ions which can provide the localized magnetic moments required for scattering the conduction electrons in the Kondo effect. The low-temperature behaviour of the heat capacity, including a high value of gamma, along with a deviation from a Curie Weiss law observed in the low-temperature magnetic susceptibility, are consistent with the presence of magnetic interactions between the paramagnetic interlayer V ions and a Kondo screening of these V moments. PMID- 28887568 TI - The Arabidopsis MTP8 transporter determines the localization of manganese and iron in seeds. AB - Understanding how seeds obtain and store nutrients is key to developing crops with higher agronomic and nutritional value. We have uncovered unique patterns of micronutrient localization in seeds using synchrotron X-ray fluorescence (SXRF). Although all four members of the Arabidopsis thaliana Mn-CDF family can transport Mn, here we show that only mtp8-2 has an altered Mn distribution pattern in seeds. In an mtp8-2 mutant, Mn no longer accumulates in hypocotyl cortex cells and sub-epidermal cells of the embryonic cotyledons, but rather accumulates with Fe in the cells surrounding the vasculature, a pattern previously shown to be determined by the vacuolar transporter VIT1. We also show that MTP8, unlike the other three Mn-CDF family members, can transport Fe and is responsible for localization of Fe to the same cells that store Mn. When both the VIT1 and MTP8 transporters are non-functional, there is no accumulation of Fe or Mn in specific cell types; rather these elements are distributed amongst all cell types in the seed. Disruption of the putative Fe binding sites in MTP8 resulted in loss of ability to transport Fe but did not affect the ability to transport Mn. PMID- 28887569 TI - Spatial features of synaptic adaptation affecting learning performance. AB - Recent studies have proposed that the diffusion of messenger molecules, such as monoamines, can mediate the plastic adaptation of synapses in supervised learning of neural networks. Based on these findings we developed a model for neural learning, where the signal for plastic adaptation is assumed to propagate through the extracellular space. We investigate the conditions allowing learning of Boolean rules in a neural network. Even fully excitatory networks show very good learning performances. Moreover, the investigation of the plastic adaptation features optimizing the performance suggests that learning is very sensitive to the extent of the plastic adaptation and the spatial range of synaptic connections. PMID- 28887571 TI - EUROSPINE 2017 Dublin, Ireland, 11-13 October. PMID- 28887572 TI - EUROSPINE Meetings 2017: e-Poster Abstracts. PMID- 28887570 TI - The salivary microbiome is consistent between subjects and resistant to impacts of short-term hospitalization. AB - In recent years, a growing amount of research has begun to focus on the oral microbiome due to its links with health and systemic disease. The oral microbiome has numerous advantages that make it particularly useful for clinical studies, including non-invasive collection, temporal stability, and lower complexity relative to other niches, such as the gut. Despite recent discoveries made in this area, it is unknown how the oral microbiome responds to short-term hospitalization. Previous studies have demonstrated that the gut microbiome is extremely sensitive to short-term hospitalization and that these changes are associated with significant morbidity and mortality. Here, we present a comprehensive pipeline for reliable bedside collection, sequencing, and analysis of the human salivary microbiome. We also develop a novel oral-specific mock community for pipeline validation. Using our methodology, we analyzed the salivary microbiomes of patients before and during hospitalization or azithromycin treatment to profile impacts on this community. Our findings indicate that azithromycin alters the diversity and taxonomic composition of the salivary microbiome; however, we also found that short-term hospitalization does not impact the richness or structure of this community, suggesting that the oral cavity may be less susceptible to dysbiosis during short-term hospitalization. PMID- 28887574 TI - EUROSPINE 2017 Scientific Programme Quick Fire presentations. PMID- 28887573 TI - Index: Abstracts EUROSPINE 2017 Dublin, Ireland, 11-13 October. PMID- 28887575 TI - Contents: EUROSPINE 2017 Dublin, Ireland, 11-13 October. PMID- 28887578 TI - [Topical antiseptic agents]. AB - Topical therapy is an important domain in the treatment of dermatological diseases in the 21st century. Because multiresistant bacteria are becoming an increasing issue in medical care of chronic diseases, it is important to develop appropriate therapeutic management for acute and chronic dermatoses. The current discussion about the skin microbiota shows the importance of preserving the resident skin flora. There is a need for alternatives to topical antibiotics, e. g. topical antiseptics, which should be safe, fast, and effective but not allergenic or toxic. Even with frequent and prolonged application it is important that they do not develop a resistance. This article focusses on the use of antiseptics for medical indications. Mechanisms of action, tolerability, maximum concentrations, and possible contraindications are discussed and examples of extemporaneous antiseptic preparations are provided. PMID- 28887579 TI - [Impact factor and reader satisfaction]. PMID- 28887577 TI - Periostin and its interacting proteins in the construction of extracellular architectures. AB - Periostin is a matricellular protein that is composed of a multi-domain structure with an amino-terminal EMI domain, a tandem repeat of four FAS 1 domains, and a carboxyl-terminal domain. These distinct domains have been demonstrated to bind to many proteins including extracellular matrix proteins (Collagen type I and V, fibronectin, tenascin, and laminin), matricellular proteins (CCN3 and betaig-h3), and enzymes that catalyze covalent crosslinking between extracellular matrix proteins (lysyl oxidase and BMP-1). Adjacent binding sites on periostin have been suggested to put the interacting proteins in close proximity, promoting intermolecular interactions between each protein, and leading to their assembly into extracellular architectures. These extracellular architectures determine the mechanochemical properties of connective tissues, in which periostin plays an important role in physiological homeostasis and disease progression. In this review, we introduce the proteins that interact with periostin, and discuss how the multi-domain structure of periostin functions as a scaffold for the assembly of interacting proteins, and how it underlies construction of highly sophisticated extracellular architectures. PMID- 28887580 TI - Removal of Two High Molecular Weight PAHs from Soils with Different Water Content. AB - Polycyclic aromatic hydrocarbons (PAHs) such as benz[a]anthracene (BA) and dibenz[a,h]anthracene (DBA), which are considered toxic, are frequently found in contaminated soils in Mexico. A laboratory-scale study monitored the degradation of the mixture of these two PAHs in three soils from different Mexican states (Tabasco, Morelos and Veracruz), each with different organic matter content, particle size distribution and incubated under different water content conditions. The hydrocarbons were extracted using microwave digestion and quantified by GC/MS. The removal of the PAHs, the growth of aerobic bacteria and microbial activity were determined in soil samples with and without a bacterial growth inhibitor (HgCl2). The conclusion is that more than 90% of both contaminants was removed from the three soils, independently of the soil water content or the application of a bacterial growth inhibitor. Biological properties of the soils showed changes at the end of the experiment, but the results of the removal of PAHs were similar in the three soils. PMID- 28887582 TI - Decline of rheumatologic care of nursing home residents with rheumatoid arthritis. PMID- 28887581 TI - Multiple skeletal muscle metastases revealing a cardiac intimal sarcoma. AB - We report the case of a 59-year-old female with progressive bilateral painful swelling of the thighs. MRI revealed multiple intramuscular necrotic masses with similar morphologic patterns. Whole-body CT and 18-FDG PET-CT scans demonstrated additional hypermetabolic muscular masses and a lobulated lesion within the left atrial cavity. As biopsy of a muscular mass was compatible with a poorly differentiated sarcoma with MDM2 oncogene amplification, two diagnoses were discussed: a dedifferentiated liposarcoma with muscle and heart metastases or a primary cardiac sarcoma, mainly a cardiac intimal sarcoma, with muscular metastases, which was finally confirmed by array-comparative genomic hybridization (aCGH) in a sarcoma reference center. This case emphasizes the potential for intimal sarcoma to disseminate in skeletal muscle prior to any other organ and the need for a genomic approach in addition to classical radiopathologic analyses to distinguish primary from secondary locations facing simultaneous tumors of the heart and skeletal muscles with MDM2 amplification. PMID- 28887583 TI - MiR-608 regulating the expression of ribonucleotide reductase M1 and cytidine deaminase is repressed through induced gemcitabine chemoresistance in pancreatic cancer cells. AB - PURPOSE: Gemcitabine resistance is the main problem in pancreatic adenocarcinoma patients. Hence, we aimed to identify the correlation between expression of RRM1 and CDA as the resistance genes and their predicted targeting miR-608 in the resistant pancreatic cancer cell lines to gemcitabine. METHODS: Dual luciferase assay was performed to determine whether both RRM1 and CDA are targeted by miR 608 in 293T and pancreatic cancer cell lines. AsPC-1 and MIA PaCa-2 cell lines became gradually resistant to gemcitabine by exposing to the increasing doses of gemcitabine. After RNA and miRNAs extraction and cDNA conversion, the expressions of RRM1, CDA and miR-608 in all cell lines were studied by quantitative PCR. Pre miR-608 transfection to the cell lines was done by calcium phosphate method. MTT assay was performed for analyzing the chemo sensitivity of different cell lines to gemcitabine. RESULTS: Luciferase assays showed that miR-608 targeted RRM1 and CDA genes in 293T, AsPC-1 and MIA PaCa-2 cell lines. Compared to parental cell line, resistant MIA PaCa-2 and AsPC-1 cells demonstrated increased expression of RRM1 and CDA. On the other hand the expression of miR-608 in resistant MIA PaCa-2 and AsPC-1 cells was lower than parental cells. Furthermore, transfection of MIA PaCa-2 and AsPC-1 cells by miR-608 lead to decreased expression of RRM1 and CDA and lowered viability of the cells in comparison with scrambled microRNA transfected cells. CONCLUSION: During resistance induction in pancreatic cancer cells, miR-608 which is targeting RRM1 and CDA is downregulated which leads to upregulation of these genes. PMID- 28887584 TI - Ocular perfusion pressure control during pars plana vitrectomy: testing a novel device. AB - PURPOSE: To study the efficacy of a novel device intended to control infusion pressure based on mean ocular perfusion pressure (MOPP) during pars plana vitrectomy (PPV). METHODS: An arm blood pressure cuff connected to a vitrectomy machine calculated mean arterial pressure (MAP), while a pressure sensor close to the infusion trocar measured intraocular pressure (IOP). MOPP was calculated in real time in 36 consecutive patients undergoing PPV, who were divided into two groups. The device lowered IOP every time that calculated MOPP fell below 30 mmHg in the Control ON group (18 patients), while no action was taken in the Control OFF group (18 patients). RESULTS: Baseline IOP and blood pressure were similar between groups. The Control ON group had significantly lower average intraoperative IOP (30.5 +/- 2.1 vs. 35.9 +/- 6.9 mmHg; p = 0.002) and higher MOPP (56.4 +/- 5.9 vs. 49.7 +/- 6.1 mmHg) than the Control OFF group. The Control ON group also spent less time at MOPP < 10 mmHg and < 30 mmHg: 0 vs. 3.40 +/- 2.38 min (p < 0.001) and 9.91 +/- 7.15 vs. 16.13 +/- 8.12 min (p = 0.02), respectively. CONCLUSIONS: The MOPP control device effectively maintained lower IOP and higher MOPP throughout surgery. It also helped avoid dangerous IOP peaks and MOPP dips, allowing patients to spend less time at MOPP of < 10 and < 30 mmHg. PMID- 28887585 TI - Biomechanical properties and cellular biocompatibility of 3D printed tracheal graft. AB - The goals of our study were to evaluate the biomechanical properties and cellular biocompatibility of 3D printed tracheal graft fabricated by polycaprolactone (PCL). Compared with native tracheal patch, there was a significant increase in maximum stress and elastic modulus for 3DP tracheal graft (p < 0.05). BMSCs were co-cultured under four different conditions to investigate cytotoxicity of the graft: (1) co-cultured with normal culture medium, as blank control; (2) co cultured with perfluoropropylene, as negative control; (3) co-cultured with 3DP tracheal graft; and (4) co-cultured with polyvinyl chloride, as positive control. Moreover, the results of SRB assay showed that compared with blank and negative control group, there was no significant difference in the cell proliferation of 3DP tracheal graft group for 21 days (p > 0.05). These results revealed that 3DP tracheal graft in our study has favorable cellular biocompatibility and biomechanical properties, and, therefore, will be a promising alternative for tissue-engineered trachea. PMID- 28887586 TI - Increased genomic prediction accuracy in wheat breeding using a large Australian panel. AB - KEY MESSAGE: Genomic prediction accuracy within a large panel was found to be substantially higher than that previously observed in smaller populations, and also higher than QTL-based prediction. In recent years, genomic selection for wheat breeding has been widely studied, but this has typically been restricted to population sizes under 1000 individuals. To assess its efficacy in germplasm representative of commercial breeding programmes, we used a panel of 10,375 Australian wheat breeding lines to investigate the accuracy of genomic prediction for grain yield, physical grain quality and other physiological traits. To achieve this, the complete panel was phenotyped in a dedicated field trial and genotyped using a custom AxiomTM Affymetrix SNP array. A high-quality consensus map was also constructed, allowing the linkage disequilibrium present in the germplasm to be investigated. Using the complete SNP array, genomic prediction accuracies were found to be substantially higher than those previously observed in smaller populations and also more accurate compared to prediction approaches using a finite number of selected quantitative trait loci. Multi-trait genetic correlations were also assessed at an additive and residual genetic level, identifying a negative genetic correlation between grain yield and protein as well as a positive genetic correlation between grain size and test weight. PMID- 28887587 TI - A deletion of the gene encoding amino aldehyde dehydrogenase enhances the "pandan like" aroma of winter melon (Benincasa hispida) and is a functional marker for the development of the aroma. AB - KEY MESSAGE: The gene conferring a "pandan-like" aroma of winter melon was identified. The sequence variation (804-bp deletion) found in the gene was used as the target for functional marker development. Winter melon (Benincasa hispida), a member of the Cucurbitaceae family, is a commonly consumed vegetable in Asian countries that is popular for its nutritional and medicinal value. A "pandan-like" aroma, which is economically important in crops including rice and soybean, is rarely found in most commercial varieties of winter melon, but is present in some landraces. This aroma is a value-added potential trait in breeding winter melon with a higher economic value. In this study, we confirmed that the aroma of winter melon is due to the potent volatile compound 2-acetyl-1 pyrroline (2AP) as previously identified in other plants. Based on an analysis of public transcriptome data, BhAMADH encoding an aminoaldehyde dehydrogenase (AMADH) was identified as a candidate gene conferring aroma of winter melon. A sequence comparison of BhAMADH between the aromatic and non-aromatic accessions revealed an 804-bp deletion encompassing exons 11-13 in the aromatic accession. The deletion caused several premature stop codons and could result in a truncated protein with a length of only 208 amino acids compared with 503 amino acids in the normal protein. A functional marker was successfully developed based on the 804-bp deletion and validated in 237 F2 progenies. A perfect association of the marker genotypes and aroma phenotypes indicates that BhAMADH is the major gene conferring the aroma. The recently developed functional marker could be efficiently used in breeding programs for the aroma trait in winter melon. PMID- 28887588 TI - Exploring Institutional Mechanisms for Scientific Input into the Management Cycle of the National Protected Area Network of Peru: Gaps and Opportunities. AB - Understanding how to improve decision makers' use of scientific information across their different scales of management is a core challenge for narrowing the gap between science and conservation practice. Here, we present a study conducted in collaboration with decision makers that aims to explore the functionality of the mechanisms for scientific input within the institutional setting of the National Protected Area Network of Peru. First, we analyzed institutional mechanisms to assess the scientific information recorded by decision makers. Second, we developed two workshops involving scientists, decision makers and social actors to identify barriers to evidence-based conservation practice. Third, we administered 482 questionnaires to stakeholders to explore social perceptions of the role of science and the willingness to collaborate in the governance of protected areas. The results revealed that (1) the institutional mechanisms did not effectively promote the compilation and application of scientific knowledge for conservation practice; (2) six important barriers hindered scientific input in management decisions; and (3) stakeholders showed positive perceptions about the involvement of scientists in protected areas and expressed their willingness to collaborate in conservation practice. This collaborative research helped to (1) identify gaps and opportunities that should be addressed for increasing the effectiveness of the institutional mechanisms and (2) support institutional changes integrating science-based strategies for strengthening scientific input in decision-making. These insights provide a useful contextual orientation for scholars and decision makers interested in conducting empirical research to connect scientific inputs with operational aspects of the management cycle in other institutional settings around the world. PMID- 28887589 TI - Assessment of CT dose to the fetus and pregnant female patient using patient specific computational models. AB - PURPOSE: This work provides detailed estimates of the foetal dose from diagnostic CT imaging of pregnant patients to enable the assessment of the diagnostic benefits considering the associated radiation risks. MATERIALS AND METHODS: To produce realistic biological and physical representations of pregnant patients and the embedded foetus, we developed a methodology for construction of patient specific voxel-based computational phantoms based on existing standardised hybrid computational pregnant female phantoms. We estimated the maternal absorbed dose and foetal organ dose for 30 pregnant patients referred to the emergency unit of Geneva University Hospital for abdominal CT scans. RESULTS: The effective dose to the mother varied from 1.1 mSv to 2.0 mSv with an average of 1.6 mSv, while commercial dose-tracking software reported an average effective dose of 1.9 mSv (range 1.7-2.3 mSv). The foetal dose normalised to CTDIvol varies between 0.85 and 1.63 with an average of 1.17. CONCLUSION: The methodology for construction of personalised computational models can be exploited to estimate the patient specific radiation dose from CT imaging procedures. Likewise, the dosimetric data can be used for assessment of the radiation risks to pregnant patients and the foetus from various CT scanning protocols, thus guiding the decision-making process. KEY POINTS: * In CT examinations, the absorbed dose is non-uniformly distributed within foetal organs. * This work reports, for the first time, estimates of foetal organ-level dose. * The foetal brain and skeleton doses present significant correlation with gestational age. * The conceptus dose normalised to CTDI vol varies between 0.85 and 1.63. * The developed methodology is adequate for patient-specific CT radiation dosimetry. PMID- 28887590 TI - Transcriptome and phytohormone analysis reveals a comprehensive phytohormone and pathogen defence response in pear self-/cross-pollination. AB - KEY MESSAGE: Candidate genes were identified and the role of phytohormones such as JA-Me and ABA in the synthesis of S-RNase was emphasized in pear self incompatibility. Self-incompatibility (SI) occurs widely in flowering plants as an intraspecific reproductive barrier. This phenomenon promotes variation within species, but for some species such as Pyrus, SI is a nuisance rather than a benefit in agricultural production. Although many studies have been conducted on SI in pears, its mechanism remains unclear. In this study, high-throughput Illumina RNA sequencing (RNA-seq) was used to identify SI-related genes in pear styles. Using transcriptome comparisons, differentially expressed genes of unpollinated (UP), cross-pollinated (CP), and self-pollinated (SP) styles were identified after 48 h. A total of 1796 and 1890 genes were identified in DSC (UP vs. CP) and DSI (UP vs. SP), respectively. KEGG analysis revealed that genes involved in the "plant hormone signal transduction pathway" and "plant-pathogen interaction pathway" were significantly enriched in DSI (UP vs. SP) compared to those in DSC (UP vs. CP). The expression level of S-glycoprotein ribonuclease (S RNase) was dramatically reduced in cross-pollinated (CP) styles. To better understand the relationship between the expression patterns of S-RNase and two major KEGG pathways, the concentrations of phytohormones were measured, and the expression pattern of S-RNase was analysed using qRT-PCR. Our results demonstrate that methyl jasmonate and abscisic acid may enhance the expression level of S RNase, and pollination can affect the synthesis of methyl jasmonate and abscisic acid in pear styles. Overall, this study is a global transcriptome analysis of SI in pear. A relationship between self-rejection, plant hormones, and pathogen defence was shown in pear. PMID- 28887591 TI - Emergent Macrophytes Support Zooplankton in a Shallow Tropical Lake: A Basis for Wetland Conservation. AB - Understanding the biodiversity value of littoral zones of lakes is a priority for aquatic biodiversity conservation. However, less emphasis has been given to the littoral part of tropical African lakes, with many of the previous researches focusing only on the open water side. The aim of the present study was, therefore, to investigate the impact of the littoral zone of a shallow freshwater tropical lake (Ziway, Ethiopia), dominated by two emergent macrophytes, on zooplankton community structure. We hypothesized that the wetland vegetation serves as a preferred microhabitat for zooplankton communities. A lake with substantial coverage of emergent macrophytes was monitored monthly from January to August, 2016. The monitoring included the measurements of physical, chemical, and biological parameters. Sampling sites were selected to represent areas of the macrophyte vegetation (Typha latifolia and Phragmites australis) and the open water part of the lake. Sites with macrophyte vegetation were found to be the home of more dense and diverse zooplankton community. However, during the period of high vegetation loss, the density of crustacean zooplankton showed significant reduction within the patches of macrophytes. From biodiversity conservation perspective, it was concluded that the preservation of such small areas of macrophytes covering the littoral zone of lakes could be as important as protecting the whole lake. However, the rapid degradation of wetland vegetation by human activities is a real threat to the lake ecosystem. In the not-too-far future, it could displace and evict riparian vegetation and the biota it supports. PMID- 28887592 TI - The (Surprising) Impact of Televised Antidepressant Direct-to-Consumer Advertising on the Stigmatization of Mental Illness. AB - This study tests the effect of pharmaceutical Direct-to-Consumer Advertising (DTCA) for antidepressants on perceived stigma surrounding mental disorders. We randomly assigned participants into one of three experimental conditions: antidepressant DTCA with portrayals of discrimination, cognitive separation, and stereotyping (DCSS), antidepressant DTCA without these representations, or a no exposure control. Contrary to study hypotheses, participants who viewed ads containing portrayals of DCSS were significantly less likely to want to socially distance themselves from those with mental illnesses than those assigned to the no-exposure control condition, even when controlling for demographics and personal experience with mental illness. We discuss plausible explanations for the unexpected pattern of effects and resulting implications for future research on the topic. PMID- 28887594 TI - Do long telomeres affect cellular fitness? AB - Telomeres protect the chromosome ends and maintain the genome stability; they, therefore, play important roles in aging and cancer. Despite the wide variability in telomere length among eukaryotes, in all telomerase-expressing cells telomere length is strictly controlled within a very narrow range. In humans, telomeres shorten with age, and it has been proposed that telomere shortening may play a causal role in aging. Using yeast strains with genetically or physiologically generated differences in telomere length, we have explored the question of whether having long telomeres affects telomere function and fitness or cellular lifespan. We found no effect of long telomeres on vegetative cell division, meiosis, or in cellular lifespan. No positive or negative effect on fitness was observed either under stressful conditions. PMID- 28887595 TI - Spectral, Electrochemical and Computational Investigations of Binding of n-(4 Hydroxyphenyl)-imidazole with p-Sulfonatocalix[4]arene. AB - The interaction of n-(4-hydroxyphenyl)-imidazole with p-sulfonatocalix[4]arene is studied using fluorescence technique. The quenching of fluorescence intensity explains the efficiency of binding via binding constant and quenching constant. The excited state lifetime of n-(4-hydroxyphenyl)-imidazole is decreased upon interaction with p-sulfonatocalix[4]arene. The cyclic voltametric studies emphasized the interaction of n-(4-hydroxyphenyl)-imidazole with p sulfonatocalix[4]arene. Quantum chemical calculations are carried out to study the interactions as well as charge transfer between the host and the guest upon complexation. The simulations revealed that the n-(4-hydroxyphenyl)-imidazole interacts with p-sulfonatocalix[4]arene with horizontal orientation with in the p sulfonatocalix[4]arene cavity. PMID- 28887593 TI - v-SNARE function in chromaffin cells. AB - Vesicle fusion is elementary for intracellular trafficking and release of signal molecules, thus providing the basis for diverse forms of intercellular communication like hormonal regulation or synaptic transmission. A detailed characterization of the mechanisms underlying exocytosis is key to understand how the nervous system integrates information and generates appropriate responses to stimuli. The machinery for vesicular release employs common molecular players in different model systems including neuronal and neuroendocrine cells, in particular members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) protein family, Sec1/Munc18-like proteins, and other accessory factors. To achieve temporal precision and speed, excitable cells utilize specialized regulatory proteins like synaptotagmin and complexin, whose interplay putatively synchronizes vesicle fusion and enhances stimulus-secretion coupling. In this review, we aim to highlight recent progress and emerging views on the molecular mechanisms, by which constitutively forming SNAREpins are organized in functional, tightly regulated units for synchronized release. Specifically, we will focus on the role of vesicle associated membrane proteins, also referred to as vesicular SNAREs, in fusion and rapid cargo discharge. We will further discuss the functions of SNARE regulators during exocytosis and focus on chromaffin cell as a model system of choice that allows for detailed structure-function analyses and direct measurements of vesicle fusion under precise control of intracellular [Ca]i. PMID- 28887596 TI - Cross-cultural adaptation and measurement properties of generic and cancer related patient-reported outcome measures (PROMs) for use with cancer patients in Brazil: a systematic review. AB - PURPOSE: This systematic review (1) identifies the current generic and cancer related patient-reported outcome measures (PROMs) that have been cross-culturally adapted to Brazilian Portuguese and applied to cancer patients and (2) critically evaluates their cross-cultural adaptation (CCA) and measurement properties. METHODS: Seven databases were searched for articles regarding the translation and evaluation of measurement properties of generic and cancer-related PROMs cross culturally adapted to Brazilian Portuguese that are applied in adult (>=18 years old) cancer patients. The methodological quality of included studies was assessed using the COSMIN checklist. RESULTS: The bibliographic search retrieved 1674 hits, of which seven studies analysing eight instruments were included in this review. Data on the interpretability of scores were poorly reported. Overall, the quality of the CCA process was inconsistent throughout the studies. None of the included studies performed a cross-cultural validation. The evidence concerning the quality of measurement properties is limited by poor or fair methodological quality. Moreover, limited information regarding measurement properties was provided within the included papers. CONCLUSIONS: This review aids the selection process of Brazilian Portuguese PROMs for use in cancer patients. After acknowledging the methodological caveats and strengths of each tool, our opinion is that for quality of life and symptoms assessment the adapted FACT-G version and the ESAS could be recommended, respectively. Future research should rely on the already accepted standards of CCA and validation studies. PMID- 28887598 TI - Removal of Anabaena spiroides by potassium permanganate pre-oxidation: effect on photosynthetic capacity and molecular weight distribution. AB - Bench scale tests were conducted to investigate the effect of potassium permanganate pre-oxidation on the photosynthetic activity and molecular weight distribution of Anabaena spiroides. Different concentrations of potassium permanganate were added into the suspension of Anabaena spiroides, one of the dominant algae in water bloom, and after pre-oxidation of permanganate for 1 h, the results show that the removal rate significantly increases by 33.99~36.35% compared to direct coagulation. Then, the algal characteristics, including photosynthetic ability, the changes in extracellular organic matter three dimensional fluorescence, and the distribution of molecular weight were conducted and the results show that along with increasing concentration of potassium permanganate, the photosynthetic ability of algae decreases, more extracellular organic matter is secreted, and large molecular weight matter (humic-like and fulvic-like substances) are generated. Therefore, this study demonstrates that potassium permanganate could be used in addressing the algae-rich water. PMID- 28887597 TI - SALL4 suppresses PTEN expression to promote glioma cell proliferation via PI3K/AKT signaling pathway. AB - Spalt-like transcription factor 4 (SALL4), a oncogene, is known to participate in multiple carcinomas, and is up-regulated in glioma. However, its actual role and underlying mechanisms in the development of glioma remain unclear. The present study explored the molecular functions of SALL4 in promoting cell proliferation in glioma. The expression level of SALL4 in 69 human glioma samples and six non tumor brain tissues was determined using real-time polymerase chain reaction (PCR). Then, we transfected U87 and U251 cell lines with siRNA, and assessed cellular proliferation and cell cycle to understand the function of SALL4, and the relationship between SALL4, PTEN and PI3K/AKT pathway. PCR confirmed that the expression of SALL4 was higher in the glioma samples than non-tumor brain tissues. Cellular growth and proliferation were dramatically reduced following inhibition of SALL4 expression. Western blot showed increase in PTEN expression when SALL4 was silenced, which in turn depressed the activation of PI3K/AKT pathway, suggesting that PTEN was a downstream target of SALL4 in glioma development. Therefore, SALL4 could act as a proto-oncogene by regulating the PTEN/PI3K/AKT signaling pathway, thereby facilitating proliferation of glioma cells. PMID- 28887599 TI - Uptake of AV-1451 in meningiomas. AB - AIM: AV-1451 is an imaging agent labeled with the positron-emitting radiolabel Fluorine-18. 18F-AV-1451 binds paired helical filament tau (PHF-tau), a pathology related to Alzheimer's disease. In our study of AV-1451 uptake in the brains of cognitively normal subjects, we noted a case of a meningioma with visually significant uptake of AV-1451. OBJECTIVE: We initiated the present retrospective study to further examine cases of meningioma that underwent AV-1451 imaging. METHODS: We searched the patient records of 650 patients who had undergone AV 1451 at our institution for the keyword "meningioma" to identify potential cases. PET/CT and MRI results were visually reviewed and semi-quantitative analysis of PET was performed. A paired student's t test was run between background and tumor standard uptake values. Fisher's exact test was used to examine the association between AV-1451 uptake and presence of calcifications on CT. RESULTS: We identified 12 cases of meningioma, 58% (7/12) of which demonstrated uptake greater than background using both visual analysis and tumor-to-normal cortex ratios (T/N + 1.90 +/- 0.83). The paired student's t test revealed no statistically significant difference between background and tumor standard uptake values (p = 0.09); however, cases with a T/N ratio greater than one showed statistically higher uptake in tumor tissue (p = 0.01). A significant association was noted between AV-1451 uptake and presence of calcifications (p = 0.01). CONCLUSION: AV-1451 PET imaging should be reviewed concurrently with anatomic imaging to prevent misleading interpretations of PHF-tau distribution due to meningiomas. PMID- 28887600 TI - Strong, sudden cooling alleviates the inflammatory responses in heat-stressed dairy cows based on iTRAQ proteomic analysis. AB - This study was designed to investigate the effects of sudden cooling on the physiological responses of 12 heat-stressed Holstein dairy cows using an isobaric tags for relative and absolute quantification (iTRAQ) labeling approach. Plasma samples were collected from these cows during heat stress (HS), and after strong, sudden cooling in the summer (16 days later). We compared plasma proteomic data before and after sudden cooling to identify the differentially abundant proteins. The results showed that sudden cooling in summer effectively alleviated the negative consequences of HS on body temperature and production variables. Expressions of plasma hemoglobin alpha and hemoglobin beta were upregulated, whereas lipopolysaccharide-binding protein (LBP) and haptoglobin were downregulated in this process. The increase of hemoglobin after cooling may improve oxygen transport and alleviate the rise in respiration rates in heat stressed dairy cows. The decrease of LBP and haptoglobin suggests that the inflammatory responses caused by HS are relieved after cooling. Our findings provide new insight into the physiological changes that occur when heat-stressed dairy cows experience strong, sudden cooling. PMID- 28887601 TI - Is there a role for epithelial-mesenchymal transition in adrenocortical tumors? AB - PURPOSE: Epithelial-mesenchymal transition (EMT) is a biological dynamic process by which epithelial cells lose their epithelial phenotype and acquire mesenchymal invasive and migratory characteristics. This has been postulated as an essential step during cancer progression and metastasis. Although this is well described in other tumors, the role of EMT in adrenocortical tumors (ACT) has yet to be addressed. METHODS: The aim of this study was to evaluate the expression of EMT markers e-cadherin, vimentin, and fibronectin, along with EMT-transcription factors (EMT-TFs), TWIST1, SIP1, and SNAIL in 24 adrenocortical carcinoma (ACC), 19 adrenocortical adenomas (ACA), 27 childhood-onset adrenocortical tumors (CAT), and 12 normal adrenal glands. The association of EMT and EMT-TFs with clinical outcomes and pathology features were also evaluated. RESULTS: Cytoplasmic vimentin expression was increased among CAT samples when compared to ACC, ACA, and normal adrenal samples (p < 0.001). There was no difference in e-cadherin and fibronectin expression observed between groups. Nuclear and cytoplasmic expression of TWIST1 and SIP1 was stronger in CAT and ACC vs. ACA and normal tissue samples (all, p < 0.05). ACT, regardless of classification, exhibited increased SNAIL expression when compared to normal tissue (p < 0.05). A significant correlation was observed between vimentin and TWIST1 (r s = 0.44, p < 0.001); SIP1 (r s = 0.51, p < 0.001); and SNAIL (r s = 0.23, p < 0.05). TWIST1 and SIP1 expressions demonstrated a significant correlation (r s = 0.56, p < 0.001). High SIP1 expression was associated with a lower survival rate among ACC cases (p < 0.05). CONCLUSIONS: Vimentin, TWIST1, and SIP1 expressions are increased in aggressive ACT. Therefore, EMT may play a relevant role in adrenal tumorigenesis. PMID- 28887602 TI - Correlation between immunohistochemical staining of CEACAM1 and clinicopathological findings in oral pre-neoplastic lesions and squamous cell carcinoma. AB - Squamous cell carcinoma of the oral cavity represents the sixth most common cancer worldwide and it is often preceded by pre-neoplastic lesions. Sometimes it is still difficult for pathologists to make objective differential diagnoses only on histological characteristics. Tumorigenesis is accompanied by altered expression of cell adhesion molecules, like carcinoembryonic antigen cell adhesion molecule (CEACAM)1. We wanted to investigative CEACAM1 in oral dysplastic lesions, carcinoma in situ (CIS) and oral squamous cell carcinoma (OSCC). We examined immunohistochemical CEACAM1 expression in 50 OSCC, 30 oral CIS and 40 pre-neoplastic lesions and assessed its correlation with clinical and pathological parameters. CEACAM1 was not expressed in normal mucosa, significantly expressed in CIS while it was negative in all the dysplastic lesions. In OSCC, high CEACAM1 expression was associated with tumor grade and inversely correlated with both overall and disease-specific 5-year survival. We showed that CEACAM1 expression is very dynamic: absent in dysplastic lesions, up regulated in CIS and OSCC. We suggest that CEACAM1 could be a prognostic marker of OSCC and oral CIS. Our most important finding was that it could help pathologists diagnosing oral carcinoma in situ. PMID- 28887604 TI - Correspondence to "Role of neutrophil to lymphocyte and monocyte to lymphocyte ratios in the diagnosis of bacterial infection in patients with fever". PMID- 28887603 TI - Molecular Signature of Tumors with Monoallelic 13q14 Deletion: a Case Series of Spindle Cell Lipoma and Genetically-Related Tumors Demonstrating a Link Between FOXO1 Status and p38 MAPK Pathway. AB - Spindle cell/pleomorphic lipomas (SCLs), cellular angiofibromas (CAFs) and mammary-type myofibroblastomas (MFBs) are rare benign mesenchymal tumors with monoallelic 13q14 deletion. They are predicted to have a common pathogenic mechanism due to shared similar histological and immunohistochemical features; however, pathological consequences of monoallelic 13q14 deletion remain unknown. We previously reported a CAF case with monoallelic 13q14 deletion in which the tumor expressed decreased levels of FOXO1 and RB1, both of which were encoded in 13q14, and increased reactive oxygen species (ROS) levels. We further demonstrated the activation of p38 mitogen-activated protein kinase (p38 MAPK) pathway induced by oxidative stress. We hypothesized that SCLs, CAFs and MFBs would share common molecular signatures involving FOXO1, ROS and p38 MAPK and that their expression patterns were different from those tumors without monoallelic 13q14 deletion such as solitary fibrous tumors (SFTs). We compared the expression levels of FOXO1, RB1, ROS markers and several signal transduction factors between SCLs and SFTs. SCLs expressed decreased levels of FOXO1 and RB1, whereas SFTs showed no change. Both tumor types exhibited increased markers of ROS; however, nuclear localization of phosphorylated p38 was significantly more frequent in SCLs than that in SFTs, suggesting p38 MAPK activation by oxidative stress. SFTs showed lower p38 MAPK activity and higher beta-catenin expression, implying that oxidative stress was caused by increased cellular proliferation stress. Finally, CAFs and MFBs showed changes similar to those observed in SCLs. Overall, tumors with monoallelic 13q14 deletion showed shared molecular signatures that might be associated with pathogenesis. PMID- 28887605 TI - The Possible Protective Effect of Marital Status in Quality of Life Among Elders in a U.S.-Mexico Border City. AB - The purpose of this study was to determine how marital status may have an impact on quality of life in a group of older adults living in a U.S.-Mexico border city. Two-hundred and seventy-six older adults completed the Spanish version of the World Health Organization Quality of Life Assessment, composed of four domains: physical health, psychological health, social relationships, and environment. Participants answered a measure of sociodemographic variables. In the psychological health component of quality of life, single and married older adults had the highest scores as compared to widowed and divorced. Similarly, married older adults had the highest quality of life in social relationships. Marital status may play an important role when analyzing quality of life among older adults, this study suggests that being married may offer a protective mechanism against depressive symptoms and therefore against mental illnesses during late adulthood. PMID- 28887606 TI - MiR-221/222 promote chemoresistance to cisplatin in ovarian cancer cells by targeting PTEN/PI3K/AKT signaling pathway. AB - Cisplatin resistance is one of the main limitations in the treatment of ovarian cancer, and its mechanism has not been fully understood. The objectives of this study were to determine the role of miR-221/222 and its underlying mechanism in chemoresistance of ovarian cancer. We demonstrated that miR-221/222 expression levels were higher in A2780/CP cells compared with A2780 S cells. An in vitro cell viability assay showed that downregulation of miR-221/222 sensitized A2780/CP cells to cisplatin-induced cytotoxicity. Moreover, we found that knockdown of miR-221/222 by its specific inhibitors promoted the cisplatin induced apoptosis in A2780/CP cells. Using bioinformatic analysis and luciferase reporter assay, miR-221/222 were found to directly target PTEN. Moreover, knockdown of miR-221/222 in A2780/CP cells significantly upregulated PTEN and downregulated PI3KCA and p-Akt expression. In conclusion, our results demonstrated that miR-221/222 induced cisplatin resistance by targeting PTEN mediated PI3K/Akt pathway in A2780/CP cells, suggesting that miR 221/222/PTEN/PI3K/Akt may be a promising prognostic and therapeutic target to overcome cisplatin resistance and treat ovarian cancer in the future. PMID- 28887607 TI - Respiratory distress syndrome in preterm infants and risk of epilepsy in a Danish cohort. AB - Infant respiratory distress syndrome (IRDS) may be complicated by intracerebral hemorrhage, a known trigger of epilepsy. However, few data exist on long term epilepsy risk following IRDS. We therefore examined the association between IRDS in preterm infants and childhood epilepsy. We conducted a population-based cohort study using individual-level data linkage among nationwide registries. All infants born at 32-36 weeks of gestation in 1978-2009 were identified in the Medical Birth Registry. We identified children with IRDS and those with epilepsy using the Danish National Patient Registry. We computed the cumulative incidence of epilepsy with follow-up from birth until epilepsy, emigration, death, age 15, or December 31, 2014. We used Cox's regression analysis to compute hazard ratios comparing children with and without IRDS, adjusting for sex, birth year, gestational age, multiplicity, major malformations, and maternal age. We identified 95,026 infants, of whom 6426 (6.8%) had IRDS. The cumulative incidence of epilepsy was 3.4% by age 15 in children with IRDS and 2.1% in children without IRDS. The adjusted hazard ratio of epilepsy among children with IRDS compared to those without was 1.4 (95% CI 1.2-1.6). When we restricted the IRDS cohort to children with no simultaneous morbidities that had clinical symptoms overlapping with IRDS, the overall adjusted HR was 1.1 (95% CI 0.9-1.4). In children born preterm at 32-36 weeks' gestation, IRDS was associated with increased risk of childhood epilepsy. PMID- 28887608 TI - Erratum to: Interactive Effects of Prenatal Antidepressant Exposure and Likely Gene Disrupting Mutations on the Severity of Autism Spectrum Disorder. PMID- 28887609 TI - Post-Synthetic Modification Nanoscale Metal-Organic Frameworks for Targeted Drug Delivery in Cancer Cells. AB - PURPOSE: Metal-organic frameworks (MOFs) have shown great potentials as drug delivery carriers, but the conventional methods for MOFs synthesis limited their use in biomedicine. The aim of this study was engineered tumor-targeted zinc nanoscale MOFs encapsulating chemotherapy drug. METHODS: We employed post synthetic modification to construct tumor cell-targeted nanoscale zinc MOFs (nanoMOFs) functionalized with folate as the targeting ligand that binds specifically to folate receptors on tumor cells. The cytoctoxicity of drug-loaded nanoMOFs was measured by MTT assay. The cell target was tested by cell compete assay. RESULTS: The successful synthesis of folate-targeted nanoMOFs was confirmed by FTIR, 1H-NMR and ESI-MS analysis. In the drug loading test, the zinc nanoMOFs functionalized with folate quickly adsorbed up to 24 wt % 5-fluorouracil (5-FU) without causing obvious changes in the supramolecular crystalline organization of the material. The in vitro drug release profile of this nanoMOFs in phosphate buffered saline exhibited a biphasic pattern. The drug sustained release is the effect mainly of diffusion of 5-FU molecules, while the degradation of the carrier itself plays a minor role in this process. The drug loaded nanoMOFs showed a stronger cytotoxicity than free 5-FU against three cancer cell lines in vitro with a distinct selectivity between folate receptors positive and negative cells. CONCLUSIONS: These results encourage further in vivo studies of this nanoMOFs as candidates for tumor-targeted, sustained-release delivery of chemotherapeutic agents. PMID- 28887610 TI - Exploring the concept of patient centred communication for the pharmacy practice. AB - Background Patient centred communication can improve pharmaceutical care, but is not well described for pharmacists. Aim of the review To provide a comprehensive and accessible overview of the concept of patient centred communication for the pharmacy practice. Method A scoping review and thematic analysis was undertaken to synthesize the extracted data and present it in a model. Results Literature search and selection resulted in eighteen articles. Thematic analysis of the extracted data led to five categories regarding patient centred communication. Two categories refer to phases of a pharmaceutical consultation: (1) shared problem defining and (2) shared decision making; three refer to underlying concepts and assumptions about patient centredness regarding (3) the patient, (4) the pharmacist and (5) the therapeutic relation. The categories were modelled in the so called Utrecht's Model for Patient centred communication in the Pharmacy. Conclusion Although there might be barriers to implement patient centred communication in the pharmacy, the concept of patient centred communication as described in the literature is relevant for the pharmacy practice. PMID- 28887611 TI - Toxicity, uptake, and accumulation of nano and bulk cerium oxide particles in Artemia salina. AB - Although the toxicological impact of metal oxide nanoparticles has been studied for the last few decades on aquatic organisms, the exact mechanism of action is still unclear. The fate, behavior, and biological activity of nanoparticles are dependent on physicochemical factors like size, shape, surface area, and stability in the medium. This study deals with the effect of nano and bulk CeO2 particles on marine microcrustacean, Artemia salina. The primary size was found to be 15 +/- 3.5 and 582 +/- 50 nm for nano and bulk CeO2 (TEM), respectively. The colloidal stability and sedimentation assays showed rapid aggregation of bulk particles in seawater. Both the sizes of CeO2 particles inhibited the hatching rate of brine shrimp cyst. Nano CeO2 was found to be more toxic to A. salina (48 h LC50 38.0 mg/L) when compared to bulk CeO2 (48 h LC50 92.2 mg/L). Nano CeO2 treated A. salina showed higher oxidative stress (ROS) than those treated with the bulk form. The reduction in the antioxidant activity indicated an increase in oxidative stress in the cells. Higher acetylcholinesterase activity (AChE) was observed upon exposure to nano and bulk CeO2 particles. The uptake and accumulation of CeO2 particles were increased with respect to the concentration and particle size. Thus, the above results revealed that nano CeO2 was more lethal to A. salina as compared to bulk particles. PMID- 28887612 TI - Effect of acute exposure to PFOA on mouse liver cells in vivo and in vitro. AB - Increasingly, epidemiological evidences indicate chemosynthetic perfluorooctanoic acid (PFOA), an environmental pollutant, induces potential adverse effect on human health after long-term exposure. However, less study has been performed for assessment of acute effect of PFOA exposure on metabolic homeostasis. In experimental designs, PFOA-exposed liver cells in vivo and in vitro were used to discuss underlying mechanism related to PFOA-induced metabolic dysfunction. In serological tests, PFOA-exposed mice showed increased treads of liver functional enzymes in alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (T-BIL), trypsinase, low density lipoprotein-cholesterol (LDL-C), and insulin, while blood glucose, high density lipoprotein-cholesterol (HDL-C), and glucagon levels were reduced. In histocytological observations, PFOA-exposed liver showed visible cytoplasmic vesicles, and intact pancreatic islets were observed in PFOA-exposed pancreas. Additionally, increased insulin-positive cells and reduced glucagon-positive cells were detected in PFOA-exposed islets. As shown in immunoassays, PFOA-exposed liver resulted in elevations of cluster of differentiation 36 (CD36)-labeled cells and CD36 protein. In mouse liver cell study, PFOA-exposed cells showed increased cell apoptotic count, and increased phosphorylated levels of Bcl-2 and Bad in the cells. Furthermore, PFOA-exposed liver cells exhibited elevations of CD36-labeled cells and CD36 protein. Taken together, the present data demonstrate that acute exposure to PFOA-impaired liver function is associated with inducting CD36 expression and apoptosis, as well as disrupting key hormones in the pancreas. PMID- 28887613 TI - Theoretical method for evaluation of therapeutic effects and adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors in clinical treatment. AB - Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for non-small cell lung cancer patients with an EGFR gene mutation. However, skin disorders are known as adverse events. In the present study, we investigated whether EGFR-TK occupancy is useful as an index for assessing clinical efficacy and adverse events for the proper use and development of EGFR-TKIs. Average binding occupancies (Phi ss) of EGFR-TKIs, gefitinib and erlotinib, for the EGFR TK of cancer or skin cells were calculated. The relationships of Phi ss with response rate (RR) or frequency of rash were analyzed using the ternary complex model. Then, the relationships between the dose of EGFR-TKIs and RR or frequency of rash were examined. Gefitinib showed a greater difference for Phi ss value for both wild-type and mutant EGFR as compared to erlotinib at usual dose. The RR increased in a nonlinear manner rapidly rising when Phi ss exceeded 95%. It was thought that a very high Phi ss value might be needed to obtain the therapeutic effect of EGFR-TKIs. Meanwhile, the frequency of rash increased in a linear manner along with elevation of Phi ss. It was shown that the K d ratio (K d for mutant/K d for wild type) was less than 0.001, when the high RR and low frequency of rash were obtained simultaneously. The results showed that the therapeutic effects and skin disorder can be assessed by using Phi ss. Furthermore, it is likely that a proper choice of drug and dose can be made by using Phi ss in EGFR TKI therapy. PMID- 28887615 TI - [Reconsideration of radiosurgery for resection cavities following complete resection of 1-3 brain metastases]. PMID- 28887616 TI - Amitriptyline plays important roles in modifying the ovarian morphology and improving its functions in rats with estradiol valerate-induced polycystic ovary. AB - Previous studies demonstrated that depression is more prevalent in women with polycystic ovary syndrome (PCOS). In this study, we aimed to determine whether amitriptyline (AMT), an antidepressant drug, plays a role in preventing PCOS. The results showed that AMT modified ovarian morphology improved the ovarian functions and estrus cycle in estradiol valerate (EV)-induced polycystic ovary (PCO). AMT restored the levels of estradiol (E2), testosterone (T) and progesterone (P4) to normal, and elevated the level of luteinizing hormone (LH) in EV-induced PCO. No significant changes in follicle stimulating hormone (FSH) levels were observed in rats with EV or AMT treatment. The restoration of norepinephrine (NE) level was detected in rats with EV-induced PCO. AMT also altered the expression levels of steroidogenesis genes and beta2-adrenoceptor (beta2-AR) in EV-induced PCO. Our data revealed that AMT improves the ovarian morphology and modifies ovarian expression of beta2-AR and steroidogenesis genes in rats with EV-induced rat PCO. Our data provide support for the hypothesis that AMT is considered as a candidate drug for preventing and treating PCOS along with depression. PMID- 28887614 TI - The pro-fibrotic connective tissue growth factor (CTGF/CCN2) correlates with the number of necrotic-regenerative foci in dystrophic muscle. AB - Connective tissue growth factor (CTGF/CCN2) has strong inflammatory and profibrotic activities. Its expression is enhanced in skeletal muscular dystrophies such as Duchenne muscular dystrophy (DMD), a myopathy characterized by exacerbated inflammation and fibrosis. In dystrophic tissue, necrotic regenerative foci, myofibroblasts, newly-regenerated muscle fibers and necrosis all occur simultaneously. To determine if CCN2 is involved in the appearance of the foci, we studied their presence and characteristics in mdx mice (DMD mouse model) compared to mdx mice hemizygous for CCN2 (mdx-Ccn2+/-). We used laser capture microdissection followed by gene expression and immunofluorescence analyses to investigate fibrotic, inflammation and regeneration markers in damaged and non-damaged areas in mdx and mdx-Ccn2+/- skeletal muscle. Mdx mice foci express elevated mRNAs levels of transforming growth factor type beta, collagen, fibronectin, the myofribroblast marker alpha-SMA, and the myogenic transcription factor myogenin. Mdx foci also show elevated levels of MCP-1 and CD 68 positive cells, indicating that CCN2 could be inducing an inflammatory response. We found a significant reduction in the number of foci in mdx-Ccn2+/- mice muscle. Fibrotic and inflammatory markers were also decreased in these foci. We did not observe any difference in Pax7 mRNA levels, a marker for satellite cells, in mdx mice compared to mdx-Ccn2+/- mice. Thus, CCN2 appears to be involved in the fibrotic response as well as in the inflammatory response in the dystrophic skeletal muscle. PMID- 28887617 TI - FDG PET/CT appearance of local osteosarcoma recurrences in pediatric patients. AB - BACKGROUND: Osteosarcoma is the most common pediatric malignant bone tumor, frequently surgically managed with limb salvage rather than amputation. Local recurrences are seen in up to 9% of osteosarcoma patients, with CT and MRI imaging often limited by metal artifacts. OBJECTIVE: To describe the [F-18]2 fluoro-2-deoxyglucose (FDG) PET/CT appearance of local osteosarcoma recurrences with correlation to findings on other imaging modalities. MATERIALS AND METHODS: A retrospective review of pediatric osteosarcoma patients imaged with FDG PET/CT was performed in patients with pathologically proven local recurrences. FDG PET/CT findings were reviewed and correlated with available comparison imaging studies. RESULTS: Ten local osteosarcoma recurrences in eight pediatric osteosarcoma patients were imaged with FDG PET/CT. All eight patients had a local recurrence after limb salvage; two patients had a second local recurrence after amputation. All local recurrences were seen with FDG PET/CT, demonstrating solid (n=5) or peripheral/nodular (n=5) FDG uptake patterns. Maximum standard uptake values (SUVs) ranged from 3.0 to 15.7. In five recurrences imaged with FDG PET/CT and MRI, MRI was limited or nondiagnostic in three. In four recurrences imaged with FDG PET/CT and bone scan, the bone scan was negative in three. CONCLUSION: Local osteosarcoma recurrences are well visualized by FDG PET/CT, demonstrating either solid or peripheral/nodular FDG uptake with a wide range of maximum SUVs. FDG PET/CT demonstrates the full extent of local recurrences, while MRI can be limited by artifact from metallic hardware. PET/CT appears to be more sensitive than bone scan in detecting local osteosarcoma recurrences. PMID- 28887618 TI - Diagnostic value of 3D time-of-flight magnetic resonance angiography for detecting intracranial aneurysm: a meta-analysis. AB - PURPOSE: This meta-analysis is to comprehensively evaluate the diagnostic performance of three-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA) for detecting intracranial aneurysm (IA). METHODS: PubMed, Embase, Web of Science, and the Cochrane library were systematically searched for retrieving eligible studies. Study inclusion, data extraction, and risk of bias assessment were performed by two researchers independently. Pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated to assess the diagnostic value. In addition, heterogeneity and subgroup analysis were carried out. RESULTS: In total, 18 studies comprising 3463 patients were selected. The results of 3D-TOF-MRA for diagnosing IA were SEN 0.89 (95% CI 0.82-0.94), SPE 0.94 (0.86-0.97), PLR 13.79 (5.92-32.12), NLR 0.11 (0.07 0.19), DOR 121.90 (38.81-382.94), and AUC 0.96 (0.94-0.98), respectively. In the subgroup analysis, studies without subarachnoid hemorrhage (SAH) tend to perform statistical significantly better (P < 0.05) in detecting IAs than studies with SAH 0.99 (0.98-1.00) vs. 0.89 (0.86-0.91). The diagnostic value of studies with a two-image reconstruction method was higher than studies with only one image reconstruction method: 0.99 (0.98-1.00) vs. 0.91 (0.89-0.94) with P < 0.05. The 3D-TOF-MRA had better SEN in aneurysms > 3 mm than the aneurysms <= 3 mm in diameter: 0.89 (0.87-0.92) vs. 0.78 (0.71-0.84) with P < 0.05. CONCLUSION: This study demonstrated that 3D-TOF-MRA has an excellent diagnostic performance for the overall assessment of IA and may serve as an alternative for further patient management with IA. PMID- 28887619 TI - [Psychodynamics in organisation and cooperation of child and adolescents institutions]. AB - According to underlying law (Krankenanstaltengesetz) the internal structure of Departments of Child and Adolescent Psychiatry (CAP) represents a matrix structure, defining formal roles and tasks of the personel. In contrast, external cooperation is defined in several different laws. Furthermore, patients and their systems are exhibiting a high tensional potential. These different influences can cause more or less severe enmeshments. Thus, during the treatment of this patients it is necessary to take into account the possibility of these enmeshments. It should be answered by special forms of care of the relationship between professionals and families. These special forms of relational care can be delivered by clear organizational structures and must undergo reflective processes on a regular basis. The planning and delivery of those structures is clearly seen as a central responsibility of the management of a CAP-Department. PMID- 28887620 TI - Bilateral parotid gland hemorrhage after intravenous thrombolysis for stroke treatment. PMID- 28887621 TI - Comparison of Prescribing Practices with Direct Acting Oral Anticoagulant Protocols. AB - BACKGROUND: The goal of anticoagulation management programs is to prevent thrombosis while minimizing the risks of hemorrhage. Direct acting oral anticoagulants (DOACs) selectively inhibit coagulation proteins to inhibit thrombosis. Previous studies suggest patient monitoring and education provided through anticoagulation services enhance adherence and decrease adverse outcomes in patients receiving DOAC therapy. OBJECTIVE: The objectives of this study were to describe DOAC prescribing adherence to anticoagulation service protocols and to observe whether enrollment in an anticoagulation service resulted in greater prescribing adherence to DOAC protocols. METHODS: A retrospective cohort study evaluated all initial prescriptions of apixaban, dabigatran, and rivaroxaban at Marshfield Clinic from 19 October 2010 to 21 August 2014. Three algorithms analyzed patient and prescription data extracted from the organization's electronic health record and classified prescriptions as per protocol or not per protocol. The algorithms classified not per protocol prescriptions as off-label indication, renal impairment [estimated glomerular filtration rate (eGFR) <30 ml/min], hepatic impairment (rivaroxaban and apixaban), advanced age >74 years (dabigatran), dose too low, or dose too high. The analysis assessed whether enrollment in the Marshfield Clinic Anticoagulation Service DOAC monitoring process was associated with increased adherence to protocols. RESULTS: In aggregate, 72% of apixaban prescriptions, 52% of dabigatran prescriptions, and 70% of rivaroxaban prescriptions were per protocol. Off-label indications and dosage too low were the most common not per protocol reasons for apixaban and rivaroxaban prescriptions. Age >=75 years and off-label indication were the most common not per protocol reasons for dabigatran prescriptions. Enrollment in the anticoagulation service process was not associated with increased adherence to protocols. CONCLUSION: A significant proportion of DOAC prescriptions did not adhere to protocol expectations. While enrollment in DOAC management through the Marshfield Clinic Anticoagulation Service was not associated with increased adherence to protocols, opportunities exist to optimize DOAC prescribing. Defining ideal DOAC management requires additional research. PMID- 28887624 TI - China in action: national strategies to combat against emerging infectious diseases. PMID- 28887622 TI - Non-invasive prenatal testing (NIPT): Europe's first multicenter post-market clinical follow-up study validating the quality in clinical routine. AB - PURPOSE: Non-invasive prenatal tests (NIPT) for the determination of fetal aneuploidies from maternal blood are firmly established in clinical routine. For the first time, the accuracy of an NIPT for the determination of trisomies 21, 18 and 13 in singleton pregnancies was assessed by means of a prospective German wide multicenter post-market clinical follow-up study, to reliably evaluate the quality in clinical routine. METHODS: The study covered the indications for testing, the test results, the rate of invasive diagnostics and the pregnancy outcome. 2232 cases were tested for trisomy 21. Of these, 1946 cases were additionally examined for trisomy 18 and 13. RESULTS: Sensitivity and specificity for trisomy 21 (43/43) and for trisomy 13 (2/2) were 100%, for trisomy 18 the sensitivity was 80% (4/5) with a specificity of 99.8%. Three false-positive results for trisomy 18 were observed (FPR 0.15%). The no-call rate was 0.5%. In this subgroup, 27.3% (3/11) aneuploidies were diagnosed. The rate of invasive procedures was 2.6%. CONCLUSION: NIPT provides a very high quality for the fetal trisomies 21, 13 and 18 in clinical routine. The results support the recommendation that NIPT should be offered after genetic counseling and only in conjunction with a qualified ultrasound examination. PMID- 28887625 TI - Overexpressed BRH1, a RING finger gene, alters rosette leaf shape in Arabidopsis thaliana. AB - Leaves are the most important plant parts for photosynthesis and respiration. Many genes are involved in determining leaf shape; however, little is known about the effects of brassinosteroid (BR) signaling-pathway genes on the development of leaf shape. Here, the brassinosteroid-responsive RING-H2 (BRH1) gene, which is suppressed by 24-epi-brassinolide treatment, was isolated from Arabidopsis thaliana. The amino acid sequence contained a highly conserved RING finger domain. In a phylogenetic analysis, BRH1 clustered closely with GLYMA11G02470.1. The leaves of brh1 mutant plants were not much different to those of the wild type, while transgenic plants with high BRH1 expression levels had rounder rosette leaves. Mutants of the BR synthesis pathway also had a similar round leaf phenotype, and greater BRH1 expression levels. Moreover, the related marker genes KNAT1, AtHB13 and ROT4, which are known to control leaf shape, altered transcriptional levels in both transgenic BRH1 and BR-synthesis mutant lines. Thus, BRH1 may be involved in the BR signaling pathway and regulate the growth and development of rosette leaves. Research on BRH1 may prove valuable for understanding the regulatory mechanism of leaf shape and improving the leaf shapes of ornamental plants. PMID- 28887627 TI - [Sepsis masquerading as delirium]. AB - A previously healthy 60-year-old patient presented to the emergency department with severe headache, altered personality and fever. He was treated for bacterial meningitis with delirium of unknown cause but presumed to be due to alcohol withdrawal. Despite receiving the antibiotic therapy regimen recommended for bacterial meningitis the patient's condition rapidly deteriorated with profound delirium and tachypnea. The intensivist who was consulted immediately suspected sepsis-associated organ failure and admitted the patient to the intensive care unit (ICU). The blood culture was positive for Listeria. After 10 days the patient could be discharged from the ICU and ultimately recovered completely. In patients presenting with unexplained delirium or altered personality the suspicion of septic encephalopathy should always be considered. They should be admitted to the ICU and sepsis treatment should be initiated without delay. PMID- 28887626 TI - Probability differently modulating the effects of reward and punishment on visuomotor adaptation. AB - Recent human motor learning studies revealed that punishment seemingly accelerated motor learning but reward enhanced consolidation of motor memory. It is not evident how intrinsic properties of reward and punishment modulate the potentially dissociable effects of reward and punishment on motor learning and motor memory. It is also not clear what causes the dissociation of the effects of reward and punishment. By manipulating probability of distribution, a critical property of reward and punishment, the present study demonstrated that probability had distinct modulation on the effects of reward and punishment in adapting to a sudden visual rotation and consolidation of the adaptation memory. Specifically, two probabilities of monetary reward and punishment distribution, 50 and 100%, were applied during young adult participants adapting to a sudden visual rotation. Punishment and reward showed distinct effects on motor adaptation and motor memory. The group that received punishments in 100% of the adaptation trials adapted significantly faster than the other three groups, but the group that received rewards in 100% of the adaptation trials showed marked savings in re-adapting to the same rotation. In addition, the group that received punishments in 50% of the adaptation trials that were randomly selected also had savings in re-adapting to the same rotation. Sensitivity to sensory prediction error or difference in explicit process induced by reward and punishment may likely contribute to the distinct effects of reward and punishment. PMID- 28887628 TI - Development of a set of PCR markers specific to Aegilops longissima chromosome arms and application in breeding a translocation line. AB - KEY MESSAGE: Transcriptome data were used to develop 134 Aegilops longissima specific PCR markers and their comparative maps were constructed by contrasting with the homologous genes in the wheat B genome. Three wheat- Ae. longissima 1BL.1S l S translocation lines were identified using the correspondence markers. Aegilops longissima is an important wild species of common wheat that harbors many genes that can be used to improve various traits of common wheat (Triticum aestivum L.). To efficiently transfer the traits conferred by these Ae. longissima genes into wheat, we sequenced the whole expression transcript of Ae. longissima. Using the transcriptome data, we developed 134 specific polymerase chain reaction markers located on the 14 chromosome arms of Ae. longissima. These novel molecular markers were assigned to specific chromosome locations based on a comparison with the homologous genes in the B genome of wheat. Annotation of these genes showed that most had functions related to metabolic processes, hydrolase activity, or catalytic activity. Additionally, we used these markers to identify three wheat-Ae. longissima 1BL.1SlS translocation lines in somatic variation populations resulting from a cross between wheat cultivar Westonia and a wheat-Ae. longissima substitution line 1Sl(1B). The translocation lines had several low molecular weight glutenin subunits encoding genes beneficial to flour processing quality that came from Ae. longissima 1SlS. The three translocation lines were also confirmed by genomic in situ hybridization. These translocation lines will be further evaluated for potential quality improvement of bread-making properties of wheat. PMID- 28887629 TI - MicroRNA-143 promotes cardiac ischemia-mediated mitochondrial impairment by the inhibition of protein kinase Cepsilon. AB - The cardioprotection of protein kinase Cepsilon (PKCepsilon) against myocardial infarction (MI) mediated by its anti-apoptotic property and underlying mechanism of targeted regulation by microRNA (miRNA) are not established. MI-induced injury, PKCepsilon expression, and targeted regulation of miRNA-143 (miR-143) to PKCepsilon have been evaluated using animal MI and cellular hypoxic models conjugated with series of state-of-art molecular techniques. The results demonstrated that PKCepsilon significantly downregulated along with increased infarcted area and apoptotic and necrotic damage in MI model, and the targeted relationship and potential binding profile were established between miR-143 and PKCepsilon. Both in vivo and in vitro ischemic tests showed that miR-143 induced apoptosis and necrosis, which was reversed by antagomiR-143 or AMO-143. The upregulation of miR-143 by transfection of miR-143 in vitro also induced cell loss, and this effect of miR-143 was completely reversed by co-transfection of miR-143 with AMO-143. The identically deleterious action of miR-143 on mitochondrial membrane potential and ATP synthesis was also observed in both animal MI and cellular hypoxic models, as well as miR-143 overexpressed models and converted by either antagomiR or AMO. Importantly, overexpression of miR-143 downregulated PKCepsilon in all tested models and this downregulation was reversed in the presence of antagomiR or AMO. The direct targeted regulation of miR-143 on PKCepsilon was confirmed by luciferase reporter and miRNA-masking tests. In conclusion, MI-mediated upregulation of miR-143 inhibits PKCepsilon expression and consequently interference with the cardioprotection of PKCepsilon to mitochondrial, and leads to mitochondrial membrane potential dissipation and myocardial death eventually. PMID- 28887630 TI - NCB5OR Deficiency in the Cerebellum and Midbrain Leads to Dehydration and Alterations in Thirst Response, Fasted Feeding Behavior, and Voluntary Exercise in Mice. AB - Cytosolic NADH-cytochrome-b5-oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues. We have previously reported that global ablation of NCB5OR in mice results in early-onset lean diabetes with decreased serum leptin levels and increased metabolic and feeding activities. The conditional deletion of NCB5OR in the mouse cerebellum and midbrain (conditional knock out, CKO mice) results in local iron dyshomeostasis and altered locomotor activity. It has been established that lesion to or removal of the cerebellum leads to changes in nutrient organization, visceral response, feeding behavior, and body weight. This study assessed whether loss of NCB5OR in the cerebellum and midbrain altered feeding or metabolic activity and had an effect on serum T3, cortisol, prolactin, and leptin levels. Metabolic cage data revealed that 16 week old male CKO mice had elevated respiratory quotients and decreased respiratory water expulsion, decreased voluntary exercise, and altered feeding and drinking behavior compared to wild type littermate controls. Most notably, male CKO mice displayed higher consumption of food during refeeding after a 48-h fast. Echo MRI revealed normal body composition but decreased total water content and hydration ratios in CKO mice. Increased serum osmolality measurements confirmed the dehydration status of male CKO mice. Serum leptin levels were significantly elevated in male CKO mice while prolactin, T3, and cortisol levels remain unchanged relative to wild-type controls, consistent with elevated transcript levels for leptin receptors (short form) in the male CKO mouse cerebellum. Taken together, these findings suggest altered feeding response post starvation as a result of NCB5OR deficiency in the cerebellum. PMID- 28887631 TI - The efficient removal of thallium from sintering flue gas desulfurization wastewater in ferrous metallurgy using emulsion liquid membrane. AB - The removal of thallium ions in flue gas desulfurization wastewater from ferrous metallurgic industry was studied by emulsion liquid membrane (ELM) method using 2 ethylhexyl phosphoric acid-2-ethylhexyl ester (P507) as carrier, aviation kerosene (AK) as organic solvent, polyisobutylene succinimide (T154) as surfactant, polyisobutylene (PIB) as additive, and sulfuric acid as internal reagent. Some important influence parameters such as concentrations of carrier, surfactant and stripping agent, agitation speed, extraction time, volume ratios of feed solution to emulsion phase and internal phase to membrane phase, and their effects on the removal efficiency of Tl in the ELM process were investigated and optimized. Under the optimum operating conditions of 2% of carrier, 5% of surfactant, 0.5 M of stripping agent, 350 rpm of agitation speed, 12.5:1 of volume ratio of feed solution to emulsion phase, and 3:1 volume ratio of membrane to internal phase, the maximum extraction efficiency of thallium reached 99.76% within 15-min reaction time. The ICP-MS analysis indicated that the thallium concentration in treated wastewater was below 5 MUg/L and could meet the emission standard demand for industrial wastewater enacted by the local government of Hunan province of China. Meanwhile, the extraction of impurity ions calcium and magnesium in the ELM system was investigated. The result showed that an acidic environment would be in favor of the removal of Tl from calcium and magnesium contained in wastewater. Graphical abstract ?. PMID- 28887632 TI - Multipeptide-coupled nanoparticles induce tolerance in 'humanised' HLA-transgenic mice and inhibit diabetogenic CD8+ T cell responses in type 1 diabetes. AB - AIMS/HYPOTHESIS: Induction of antigen-specific immunological tolerance may provide an attractive immunotherapy in the NOD mouse model but the conditions that lead to the successful translation to human type 1 diabetes are limited. In this study, we covalently linked 500 nm carboxylated polystyrene beads (PSB) with a mixture of immunodominant HLA-A*02:01-restricted epitopes (peptides-PSB) that may have high clinical relevance in humans as they promote immune tolerance; we then investigated the effect of the nanoparticle-peptide complexes on T cell tolerance. METHODS: PSB-coupled mixtures of HLA-A*02:01-restricted epitopes were administered to HHD II mice via intravenous injection. The effects on delaying the course of the disease were verified in NOD.beta2m null HHD mice. The diabetogenic HLA-A*02:01-restricted cytotoxic lymphocyte (CTL) responses to treatment with peptides-PSB were validated in individuals with type 1 diabetes. RESULTS: We showed that peptides-PSB could induce antigen-specific tolerance in HHD II mice. The protective immunological mechanisms were mediated through the function of CD4+CD25+ regulatory T cells, suppressive T cell activation and T cell anergy. Furthermore, the peptides-PSB induced an activation and accumulation of regulatory T cells and CD11c+ dendritic cells through a rapid production of CD169+ macrophage-derived C-C motif chemokine 22 (CCL22). Peptides-PSB also prevented diabetes in 'humanised' NOD.beta2m null HHD mice and suppressed pathogenic CTL responses in people with type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our findings demonstrate for the first time the potential for using multipeptide-PSB complexes to induce T cell tolerance and halt the autoimmune process. These findings represent a promising platform for an antigen-specific tolerance strategy in type 1 diabetes and highlight a mechanism through which metallophilic macrophages mediate the early cell-cell interactions required for peptides-PSB-induced immune tolerance. PMID- 28887634 TI - CRISPR/Cas9-based genome editing of the filamentous fungi: the state of the art. AB - In recent years, a variety of genetic tools have been developed and applied to various filamentous fungi, which are widely applied in agriculture and the food industry. However, the low efficiency of gene targeting has for many years hampered studies on functional genomics in this important group of microorganisms. The emergence of CRISPR/Cas9 genome-editing technology has sparked a revolution in genetic research due to its high efficiency, versatility, and easy operation and opened the door for the discovery and exploitation of many new natural products. Although the application of the CRISPR/Cas9 system in filamentous fungi is still in its infancy compared to its common use in E. coli, yeasts, and mammals, the deep development of this system will certainly drive the exploitation of fungal diversity. In this review, we summarize the research progress on CRISPR/Cas9 systems in filamentous fungi and finally highlight further prospects in this area. PMID- 28887633 TI - Periostin in inflammation and allergy. AB - We found for the first time that IL-4 and IL-13, signature type 2 cytokines, are able to induce periostin expression. We and others have subsequently shown that periostin is highly expressed in chronic inflammatory diseases-asthma, atopic dermatitis, eosinophilc chronic sinusitis/chronic rhinosinusitis with nasal polyp, and allergic conjunctivitis-and that periostin plays important roles in the pathogenesis of these diseases. The epithelial/mesenchymal interaction via periostin is important for the onset of allergic inflammation, in which periostin derived from fibroblasts acts on epithelial cells or fibroblasts, activating their NF-kappaB. Moreover, the immune cell/non-immune cell interaction via periostin may be also involved. Now the significance of periostin has been expanded into other inflammatory or fibrotic diseases such as scleroderma and pulmonary fibrosis. The cross-talk of periostin with TGF-beta or pro-inflammatory cytokines is important for the underlying mechanism of these diseases. Because of its pathogenic importance and broad expression, diagnostics or therapeutic drugs can be potentially developed to target periostin as a means of treating these diseases. PMID- 28887635 TI - The Prognostic Impact of Controlling Nutritional Status (CONUT) in Intrahepatic Cholangiocarcinoma Following Curative Hepatectomy: A Retrospective Single Institution Study. AB - BACKGROUND: Several studies have examined controlling nutritional status (CONUT), which is one of the useful biomarkers for predicting patients' prognosis following cancer treatment. The aim of this study was to evaluate the value of CONUT as a postoperative prognostic marker in patients with intrahepatic cholangiocarcinoma (ICC) following curative hepatectomy. METHODS: We retrospectively analyzed 71 patients who underwent curative hepatectomy for ICC between May 2002 and November 2016. Patients were divided into two groups according to their preoperative CONUT score (i.e., CONUT ? 2 or CONUT < 2). RESULTS: The number of patients assigned to the normal, mild, moderate, or severe malnutrition groups was 40, 28, two, and one, respectively. The high CONUT group (CONUT ? 2) consisted of 31 patients (43.7%) and had a poor prognosis with regard to overall survival (OS) (p = 0.0149). A high CONUT score is also identified as one of the independent predictors of poor prognosis in OS (hazard ratio 3.02; 95% confidence interval 1.4-6.8; p = 0.007). However, in the current study, a high CONUT score was not associated with postoperative complications (Clavien-Dindo classification ? III or more). CONCLUSIONS: CONUT may be useful for the preoperative assessment of prognosis in patients with ICC who have undergone curative hepatectomy. PMID- 28887636 TI - MiR-184 Retarded the Proliferation, Invasiveness and Migration of Glioblastoma Cells by Repressing Stanniocalcin-2. AB - To investigate the repression of miR-184 on Stanniocalcin-2 (STC2) and how this axis affects the propagation, invasiveness and migration ability of glioblastoma cells. RT-PCR was employed to determine the miR-184 and STC2 mRNA expression both in tissues and cells. Western blot was employed to determine the protein expression levels. The cells were transfected via lipofection. MTT, colony formation, invasion and scratch healing assays were conducted to study the propagation, invasiveness and migratory ability of glioblastoma cells, respectively. The dual luciferase reporter gene assay was conducted to determine whether miR-184 could directly bind to STC2 mRNA 3'UTR. MiR-184 was under expressed whereas STC2 was over-expressed in glioblastoma tissues and cell line. The up-regulation of miR-184 significantly suppressed the propagation, migratory ability and invasion of glioblastoma cells, whereas the over-expression of STC2 restored this effect. MiR-184 was confirmed to directly target STC2. MiR-184 could retard the propagation, invasiveness and migratory ability of glioblastoma cells by suppressing STC2. PMID- 28887637 TI - Epigenetic regulation in cell senescence. AB - Cell senescence, which is an irreversible state of cell proliferative arrest, has emerged as a potentially important contributor to tissue dysfunction and organismal ageing. Cell senescence is triggered by a variety of senescence stressors, which affect gene expression and multiple signalling pathways that give rise to various senescence phenotypes. Epigenetic mechanisms, as critical regulators of chromosomal architecture and gene expression, have added an extra dimension to the molecular mechanisms of cell senescence. Cell senescence is accompanied by changes in DNA methylation, histone-associated epigenetic processes, chromatin remodelling and ncRNA expression. Those senescence associated epigenetic alterations interact with the senescence regulatory programme networks and lead to various cell senescence phenotypes. This review provides a comprehensive overview of epigenetic changes and their effects on cell senescence. The differences in epigenetic alterations among different types of senescence are also discussed. Furthermore, we summarise the interactions among different epigenetic mechanisms during cell senescence and analyse the possibility of using epigenetic signatures as biomarkers and therapeutic targets for the treatment of senescence-associated diseases. PMID- 28887638 TI - A new strategy to sustained release of ocular drugs by one-step drug-loaded microcapsule manufacturing in hydrogel punctal plugs. AB - PURPOSE: To design an injectable hyaluronate (HA)-based hydrogel system that contains drug-loaded microcapsules as resorbable plugs to deliver ocular drugs. METHODS: In-situ drug-loaded, core-shell-structured chitosan (CS)@HA microcapsules were fabricated via HA hydrosol collecting in electrospun bead-rich CS fibers under continuous stirring. An injectable and cytocompatible hydrogel system with different degrees of chemical crosslinking maintained viscoelastic and sustained drug release for a long-term period of time at body temperature in vitro. RESULTS: With the addition of adipic dihydrazide (ADH) or 1-Ethyl-3-(3 dimethyllaminopropyl) carbodiimide hydrochloride (EDCI), HA hydrosols transited from liquid to solid state at the gel point, with the G'/G" ratio varying between 1.43 and 5.32 as a function of crosslinker concentration in the hydrogel phase. Ofloxacin (OFL) release from the mechanically mixed hydrosol system (CS-HA-A0-E0) and the micro-encapsulated hydrosol formulation (CS@HA-A0-E0) were respectively over 80% and 51% of the total drug load leaching out within 24 h. As for the drug mixed hydrogel systems with low (CS-HA-A0.06-E0.15) and high (CS-HA-A0.06-E0.30) crosslinking density, the OFL release rate reached 38.5 and 46.6% respectively, while the micro-encapsulated hydrogel systems with low (CS@HA-A0.06-E0.15) and high (CS@HA-A0.6-E0.30) showed only (11.9 +/- 2.7)% and (17.4 +/- 3.5)% drug release respectively. CONCLUSIONS: A one-step in-situ drug-capsulizing method is developed to fabricate a resorbable hydrogel punctal plug with extended drug release. The chemistry of the crosslinking reaction involves the formation of highly biocompatible HA derivatives. Thus, the hydrogel can be used directly in the tear drainage canalicular system. PMID- 28887639 TI - A Double-Blinded Randomized Clinical Study on the Therapeutic Effect of Gastrografin in Prolonged Postoperative Ileus After Elective Colorectal Surgery: Reply. PMID- 28887640 TI - Clinical and instrumental evaluation of two different regimens of tranexamic acid in total hip arthroplasty: a single-centre, prospective, randomized study with 80 patients. AB - PURPOSE: The use of tranexamic acid (TXA) in total hip arthroplasty (THA) can significantly reduce blood losses with many clinical and economical advantages. However, no consensus has been reached regarding the optimal regimen for TXA administration. The aim of this study is to analyse and compare the haemostatic effect of two different intravenous (IV) regimens of TXA. MATERIALS AND METHODS: We planned a single-centre, prospective, randomized study including 80 patients who underwent primary unilateral minimally invasive THA because of a hip osteoarthritic degeneration. We divided patients into two groups: the G10 group received two IV doses of 10 mg/kg of TXA, and the G20 group received two doses of 20 mg/kg. RESULTS: No significant differences in mean minimum levels of Hb and HcT stratified by days after surgery were uncovered between the two groups despite the use of two different dosages of TXA. Also the mean blood volume loss was statistically similar between two groups. No differences were also observed regarding the occurrence of adverse effects. CONCLUSIONS: In two IV bolus regimens of TXA administration, the use of a dose of 10 or 20 mg/kg provides statistically similar results in blood loss sparing. Therefore, the use of two 10 mg/kg doses could be considered more advisable in order to reduce the potential thromboembolic risks related to this drug. PMID- 28887641 TI - Interference effects of transcranial direct current stimulation over the right frontal cortex and adrenergic system on conditioned fear. AB - RATIONALE: The effects of pharmacological interventions on fear memory have widely been studied, but there are very few studies about the effects of brain electrical stimulation on fear memory function. OBJECTIVE: Therefore, our aim was to determine whether anodal/cathodal transcranial direct current stimulation (tDCS) over the right frontal cortex would modify propranolol-induced contextual and auditory fear memory deficits, before or after training. METHODS: The adult NMRI male mice were randomly assigned into three groups: the sham group, the anodal tDCS group, and the cathodal tDCS group. Fear memories were evaluated using a classical fear conditioning apparatus. RESULTS: While the anodal stimulation did not affect fear retrieval, post-training cathodal stimulation improved fear memory retrieval. Regardless of when propranolol (0.1 mg/kg) was administered, it impaired fear memory retrieval. However, when anodal stimulation and propranolol were applied prior to the training, contextual fear memory retrieval was increased and auditory fear memory was reversed. An enhanced contextual retrieval was also observed when propranolol was administered prior to the training and stimulation occurred after the training. Only when the stimulation occurred prior to the training and propranolol was administered after the training was there a selective improvement in contextual fear memory retrieval, leaving the auditory fear memory retrieval impaired. Interestingly, cathodal stimulation improved the effects of propranolol on auditory fear memory only when it occurred prior to the training. CONCLUSION: The results highlight possible improving effects for anodal/cathodal tDCS on propranolol-induced deficits on fear memories. The timing of the interventions related to the specific phases of memory formation is important in modulating fear behaviors. PMID- 28887642 TI - Evaluation of the Functional Capacity of NK Cells of Melanoma Patients in an In Vitro Model of NK Cell Contact with K562 and FemX Tumor Cell Lines. AB - NK cells of metastatic melanoma (MM) patients display impaired function, making them incapable to mount an effective antitumor response. In this study, we evaluated immunophenotypic characteristics and functional capacity of CD3-CD16+ NK cells of MM patients in an in vitro model based on NK cell contact with an NK sensitive, K562, and a tumor-specific, melanoma FemX tumor cell line. Although our results indicate similar NK cell antitumor cytotoxic potential of MM patients in contact with both cell lines based on the expression of CD107a degranulation marker, there is a discrepancy in NK cell IFNgamma production, as it is not significantly induced by FemX tumor cells, found to be, contrary to K562, HLA class I positive. Furthermore, we show NKG2D receptor downregulation by K562 tumor cell line, only. This may result from the obtained higher gene expression of TGFbeta and VEGFA growth factors in K562 tumor cells that can negatively regulate NKG2D expression. Additionally, aside from postcontact downmodulation of activating CD16 receptor, there are no significant changes in the expression of CD161, CD158a, and CD158b NK cell receptors. Therefore, the applied in vitro model shows that, compared to the full NK cell functional capacity of MM patients displayed in a tumor-sensitive setting represented by contact with K562 cells, tumor-specific melanoma setting provided by FemX tumor cells leads to reduced NK functional potential. The obtained insight into NK cell capacity may be of use for evaluation of the state of disease and can help in selecting effective immunotherapeutic agents for MM patients. PMID- 28887643 TI - Clinical predictors of methicillin-resistant Staphylococcus aureus in nosocomial and healthcare-associated pneumonia: a multicenter, matched case-control study. AB - The situations in which coverage for methicillin-resistant Staphylococcus aureus (MRSA) in the empirical treatment of nosocomial pneumonia (NP) or severe healthcare-associated pneumonia (HCAP) is needed are poorly defined, particularly outside intensive care units (ICUs). Our aim was to characterize if the risk of MRSA NP/HCAP can be defined by clinical variables. We designed an observational, retrospective, multicenter, case-control study to analyze the association between defined clinical variables and risk of MRSA NP/HCAP in non-ICU patients using conditional multivariable logistic regression. Cases and controls (1:2) with microbiological diagnosis were included. Controls were matched for hospital, type of pneumonia (NP or HCAP), and date of isolation. A total of 140 cases (77 NP and 63 HCAP) and 280 controls were studied. The variables associated with the risk of MRSA pneumonia were: (i) respiratory infection/colonization caused by MRSA in the previous year [odds ratio (OR) 14.81, 95% confidence interval (CI) 4.13-53.13, p < 0.001]; (ii) hospitalization in the previous 90 days (OR 2.41, 95% CI 1.21 4.81, p = 0.012); and (iii) age (OR 1.02, 95% CI 1.001-1.05, p = 0.040). The area under the receiver operating characteristic (ROC) curve for the multivariable model was 0.72 (95% CI 0.66-0.78). The multivariate model had a sensitivity of 74.5% (95% CI 65.3-83.6), a specificity of 63.3% (95% CI 56.0-70.6), a positive predictive value of 52.5% (95% CI 43.9-61.2), and a negative predictive value of 82.0% (95% CI 75.3-88.8) for the observed data. Clinical predictors of MRSA NP/HCAP can be used to define a low-risk population in whom coverage against MRSA may not be needed. PMID- 28887644 TI - Habitat fragmentation leads to reduced pollinator visitation, fruit production and recruitment in urban mangrove forests. AB - Mangrove forests worldwide undergo anthropogenic fragmentation that may threaten their existence, and yet there have been few tests of the effects of fragmentation on demographic processes critical for mangrove regeneration. Predicting the effects of habitat fragmentation on mangroves is problematic as pollinators may move more freely across water than terrestrial habitat, and propagules can be widely dispersed by water. Here, within each of two estuaries, we compared pollinator diversity and activity, reproductive effort and output, and rates of recruitment for sets of three large (>1500 trees), medium (300-500) and small (<50) stands. As predicted, most measures of reproductive activity and success were inversely related to stand size with large stands typically producing significantly more and larger fruit, and significantly more seedlings. Most strikingly, we found the effect of fragmentation on the abundance of pollinators (honeybees), the production and quality of fruit and the survival rate of seedlings to be similar, showing significant reduction of recruitment in small stands. This study provides the first rigorous evidence that recruitment of mangroves, like for many terrestrial plants, is negatively impacted by habitat fragmentation. From a management perspective, we argue that in the short term our data imply the importance of conserving the largest possible stands. However, additional work is needed to determine (1) the proportion of recruits within small stands that originate within large stands, (2) how seedling performance varies with fruit size and genotype, and (3) how seedling size and performance vary with the abundance and diversity of pollen. PMID- 28887645 TI - Pitfalls in soft tissue sarcoma imaging: chronic expanding hematomas. AB - Solid or nodular enhancement is typical of soft tissue sarcomas although high grade soft tissue sarcomas and those with internal hemorrhage often appear heterogeneous with areas of nonenhancement and solid or nodular enhancement. These MRI findings often prompt an orthopedic oncology referral, a biopsy or surgery. However, not all masses with these imaging findings are malignant. We report the multimodality imaging findings of two surgically proven chronic expanding hematomas (CEH) with imaging features that mimicked sarcomas. A third case of nonenhancing CEH of the lower extremity is also presented as a comparison. It is important that in the correct clinical scenario with typical imaging findings, the differential diagnosis of a chronic expanding hematoma be included in the workup of these patients. An image-guided biopsy of nodular tissue within such masses that proves to be negative for malignancy should not necessarily be considered discordant. A correct diagnosis may prevent a morbid unnecessary surgery and may indicate the need for a conservative noninvasive follow-up with imaging. PMID- 28887646 TI - Cancer in First Nations people living in British Columbia, Canada: an analysis of incidence and survival from 1993 to 2010. AB - BACKGROUND: For First Nations (FN) peoples living in British Columbia (BC), little is known regarding cancer in the population. The aim of this study was to explore cancer incidence and survival in the FN population of BC and compare it to the non-FN population. METHODS: All new cancers diagnosed from 1993 to 2010 were linked to the First Nations Client File (FNCF). Age-standardized incidence rates (ASIR) and rate ratios, and 1- and 5-year cause-specific survival estimates and hazard ratios were calculated. Follow-up end date for survival was December 31, 2011 and follow-up time was censored at a maximum of 15 years. RESULTS: ASIR of colorectal cancer (male SRR = 1.42, 95% CI 1.25-1.61; female SRR = 1.21, 95% CI 1.06-1.38) and cervical cancer (SRR = 1.84, 95% CI 1.45-2.33) were higher overall in FN residents in BC, compared to non-FN residents. Incidence rates of almost all other cancers were generally similar or lower in FN populations overall and by sex, age, and period categories, compared to non-FN residents. Trends in ASIR over time were similar except for lung (increasing for FN, decreasing for non-FN) and colorectal cancers (increasing for FN, decreasing for non-FN). Conversely, survival rates were generally lower for FN, with differences evident for some cancer sites at 1 year following diagnosis. CONCLUSION: FN people living in BC face unique cancer issues compared to non-FN people. Higher incidence and lower survival associated with certain cancer types require further research to look into the likely multifaceted basis for these findings. PMID- 28887647 TI - A Comparative Evaluation Study of Growth Conditions for Culturing the Isolates of Campylobacter spp. AB - Campylobacter is one of the leading causes of foodborne travelers' diarrhea worldwide. Although a large number cases of campylobacteriosis go undiagnosed or unreported, it is considered as the second most common foodborne illness in the USA affecting over 1.3 million individuals every year. Of various Campylobacter species, C. jejuni, C. coli, and C. lari have been accounted for causing more than 99% of human infections. Thus, there is a need to have efficient isolation method to protect public health on food safety and monitoring the burden of campylobacteriosis. Nevertheless, it is a challenging task as the exposure of environmental stress during isolation process makes Campylobacter species less culturable. Sixteen Campylobacter spp. were used to evaluate the current protocols used in Campylobacter isolation. For optimal recovery, a range of growth media (Bolton, Columbia, Muller Hinton, CVA Campy and mCCDA), incubation temperatures, and additional supplements (including antibiotics) were tested. Blood agars without antibiotics were sufficient for the initial recovery. Afterward, the isolates could grow on agars without any supplements, and in some cases growth was observed in the presence of antibiotics. Incubation at 37 degrees C was found to be the optimal temperature for the recovery and the growth of most species. Additionally, a food adulteration study was also carried out by artificially contaminating three food matrices that included egg, milk, and infant cereal, with two isolates of C. jejuni and C. coli. Results of this study should provide the insight for culturing and isolation of Campylobacter from food and other sources. PMID- 28887648 TI - Evaluation of donor site morbidity after medial triceps brachii free flap for lower limb reconstruction. AB - INTRODUCTION: The medial head of the triceps brachii muscle (MTB)-free flap is an attractive solution to cover small-to-medium defects of the lower limb. This muscular head has no well-identified function, suggesting minimal impact of its removal on elbow mobility. The aim of this study was to evaluate the safety and reliability of the harvest procedure and the functional and cosmetic morbidity of this donor site. MATERIALS AND METHODS: Twenty-four consecutive MTB-free flaps were performed for reconstructive surgery of the lower limb between 2011 and 2015. Patients and their records were retrospectively examined. Functional results were evaluated by assessing elbow extension strength using a dynamometer and with a QuickDASH questionnaire. Cosmetic results were assessed using the POSAS observer and patient scales. RESULTS: Twenty-four patients were followed up postoperatively for an average of 33.9 [min 12-max 59] months. No major complication (in particular, no ulnar or radial nerve injury) occurred during harvest. No patient complained of elbow pain or reduction in strength. Elbow extension was complete in all patients and the mean strength was calculated at 89 [61.1-112.5] % of the opposite arm. The POSAS scale scored an average 8.6 [7-21] for the observer and 10 [7-26] for the patient. Cosmetic results using the POSAS scale were satisfactory in all patients. CONCLUSIONS: Objective evaluation of patients who underwent an MTB-free flap for limb reconstruction shows no impact of the harvesting procedure on elbow extension. Patient satisfaction with the donor site was high. From this retrospective study, it appears that this surgery is safe, aesthetically acceptable, and has minimal impact on donor site elbow function. PMID- 28887649 TI - Metal Concentrations and Responses of Chironomid Larvae Exposed to Thailand Pulp and Paper Mill Effluent. AB - Pulp and paper mills (PPM) may discharge insufficiently treated waste into rivers and give rise to serious effects with aquatic life. This study investigated the biological response of the chironomid (Chironomus javanus, Kieffer) when exposed to PPM effluent. Effluent concentrations of BOD, COD, TKN, TS, Cr, Cu, Pb and Zn were high. Cd and Cr concentrations in chironomid were the most accumulated. Whole effluent toxicity on the chironomid test organism was significant as expressed by the percent survival and decreased with increasing concentration. Highest dry weight, head capsule and length of the chironomid test organism corresponded to 100% effluent at a specific time. Effect of dilution was assessed by using glutathione S-transferase activity on chironomid and corresponded to 6.25% effluent during 48-96 h which was significantly increased in the chironomid. The results showed that the chironomid was sensitive to PPM effluent and toxicity tests can be used for assessing the effect of effluent on aquatic species. PMID- 28887650 TI - Microbial diversity of the Tibetan tick Haemaphysalis tibetensis (Acari: Ixodidae). AB - The Tibetan tick Haemaphysalis tibetensis is widely distributed in the Tibetan Plateau, and is recognized as one of the primary parasites affecting domestic and wild animals. No information is available on its microbial diversity. In the current study, the microbiomes in H. tibetensis were explored using Illumina MiSeq sequencing. Results indicate that a total of 28 phyla and 38 genera were characterized from this tick, and most of the microbes were classified in the phylum Proteobacteria. Female and male H. tibetensis harbored similar composition of the microbes, with dominant bacteria from the genus Coxiella accounting for 87.5 and 66.5% in females and males, respectively. The abundance of bacteria belonging to the genus Rickettsia in females and males was 6.9 and 23.7%, respectively. These findings may help understand the relationship between this tick and its symbiontic microorganisms. PMID- 28887652 TI - Disruption of adenylyl cyclase type 5 mimics exercise training. AB - Exercise training is key to healthful longevity. Since exercise training compliance is difficult, it would be useful to have a therapeutic substitute that mimicked exercise training. We compared the effects of exercise training in wild type (WT) littermates with adenylyl cyclase type 5 knock out (AC5 KO) mice, a model of enhanced exercise performance. Exercise performance, measured by maximal distance and work to exhaustion, was increased in exercise-trained WT to levels already attained in untrained AC5 KO. Exercise training in AC5 KO further enhanced their exercise performance. The key difference in untrained AC5 KO and exercise-trained WT was the beta-adrenergic receptor signaling, which was decreased in untrained AC5 KO compared to untrained WT but was increased in WT with exercise training. Despite this key difference, untrained AC5 KO and exercise-trained WT mice shared similar gene expression, determined by deep sequencing, in their gastrocnemius muscle with 183 genes commonly up or down regulated, mainly involving muscle contraction, metabolism and mitochondrial function. The SIRT1/PGC-1alpha pathway partially mediated the enhanced exercise in both AC5 KO and exercise-trained WT mice, as reflected in the reduced exercise responses after administering a SIRT1 inhibitor, but did not abolish the enhanced exercise performance in the AC5 KO compared to untrained WT. Increasing oxidative stress with paraquat attenuated exercise performance more in untrained WT than untrained AC5 KO, reflecting the augmented oxidative stress protection in AC5 KO. Blocking nitric oxide actually reduced the enhanced exercise performance in untrained AC5 KO and trained WT to levels below untrained WT, demonstrating the importance of this mechanism. These results suggest that AC5 KO mice, without exercise training, share similar mechanisms responsible for enhanced exercise capacity with chronic exercise training, most importantly increased nitric oxide, and demonstrate more reserve with the addition of exercise training. A novel feature of the enhanced exercise performance in untrained AC5 KO mice is their decreased sympathetic tone, which is also beneficial to patients with cardiovascular disease. PMID- 28887651 TI - A cell culture model for investigation of synapse influenceability: epigenetics, expression and function of gene targets important for synapse formation and preservation in SH-SY5Y neuroblastoma cells differentiated by retinoic acid. AB - SH-SY5Y neuroblastoma cells are frequently used for different neuronal cell culture models. As there is no "gold-standard", miscellaneous protocols exist to differentiate these cells into a neuronal cell type. Here, the aim was to find a differentiation condition making cells suitable for investigation of influenceability of synapses by environmental conditions in pharmacologic experiments. For this purpose, effects on synapse molecules should be somehow rateable and cells should be usable for functional analysis like calcium imaging. A system like this is desirable for example in basic research concerning schizophrenia, depression, autism or neurodegeneration as synaptic plasticity and neuronal maturation are known to have a significant impact in these diseases. Cells grown on laminin-coated glass cover slips and treated with 50 uM retinoic acid (RA) turned out to show most convincing morphological signs of neuronal differentiation and attached strongly to the ground, thereby also fulfilling preconditions for functional analysis. Systematic characterisation of this differentiation condition in comparison to non-treated controls revealed lower methylation rates and higher expression of most candidate molecules relevant for formation, preservation and function of synapses as well as differential function. In conclusion, this combination of differentiation strategy and markers seems to be a suitable system to estimate synapse modifications in basic research as it could help to identify possible dedifferentiating effects. To our knowledge, differentiation of SH-SY5Y has not been described as systematic before regarding comprehensiveness of the set of investigated synapse molecules and coverage of applied methods spanning from epigenetics to protein function. Furthermore, this is the first time that SH-SY5Y cells were differentiated on glass cover slips to an extent making them suitable for investigation of synapse molecules as part of stable intercellular connections in downstream functional analyses. PMID- 28887653 TI - Rodent herbivory differentially affects mortality rates of 14 native plant species with contrasting life history and growth form traits. AB - Ecosystems are transformed by changes in disturbance regimes including wildfire and herbivory. Rodent consumers can have strong top-down effects on plant community assembly through seed predation, but their impacts on post-germination seedling establishment via seedling herbivory need better characterization, particularly in deserts. To test the legacy effects of fire history, and native rodent consumers on seedling establishment, we evaluated factorial combinations of experimental exclusion of rodents and fire history (burned vs. unburned) on seedling survival of 14 native plant species that vary in their life history strategies and growth form in the Mojave Desert. Seedlings were placed into the experimental plots, and seedling survival was monitored daily for 8 days. The legacy effects of fire history had minimal effects on seedling survival, but rodent exclusion, year, and their interaction were strongly significant. Seedling survival rates were nearly sixfold greater in rodent exclusion plots compared to control plots in 2012 (53 vs. 9%) and 17-fold greater in 2013 (17 vs. 1%). The dramatic increase in seedling mortality from 2012 to 2013 was likely driven by an increase in rodent abundance and an outbreak of grasshoppers that appears to have intensified the rodent effect. There was strong variability in plant species survival in response to rodent herbivory with annual plants and forb species showing lower survival than perennial plants and shrub species. These results indicate that rodent consumers can strongly regulate seedling survival of native plant species with potentially strong regulatory effects on plant community development. PMID- 28887654 TI - [Critical consideration of ipsilateral axillary recurrence after breast conservative surgery and the protective effect of whole breast radiotherapy]. PMID- 28887656 TI - IUGA terminology and standardization: creating and using this expanding resource. PMID- 28887655 TI - Freezing shortens the lifetime of DNA molecules under tension. AB - DNA samples are commonly frozen for storage. However, freezing can compromise the integrity of DNA molecules. Considering the wide applications of DNA molecules in nanotechnology, changes to DNA integrity at the molecular level may cause undesirable outcomes. However, the effects of freezing on DNA integrity have not been fully explored. To investigate the impact of freezing on DNA integrity, samples of frozen and non-frozen bacteriophage lambda DNA were studied using optical tweezers. Tension (5-35 pN) was applied to DNA molecules to mimic mechanical interactions between DNA and other biomolecules. The integrity of the DNA molecules was evaluated by measuring the time taken for single DNA molecules to break under tension. Mean lifetimes were determined by maximum likelihood estimates and variances were obtained through bootstrapping simulations. Under 5 pN of force, the mean lifetime of frozen samples is 44.3 min with 95% confidence interval (CI) between 36.7 min and 53.6 min while the mean lifetime of non-frozen samples is 133.2 min (95% CI: 97.8-190.1 min). Under 15 pN of force, the mean lifetimes are 10.8 min (95% CI: 7.6-12.6 min) and 78.5 min (95% CI: 58.1-108.9 min). The lifetimes of frozen DNA molecules are significantly reduced, implying that freezing compromises DNA integrity. Moreover, we found that the reduced DNA structural integrity cannot be restored using regular ligation process. These results indicate that freezing can alter the structural integrity of the DNA molecules. PMID- 28887657 TI - Fine mapping of the soybean aphid-resistance genes Rag6 and Rag3c from Glycine soja 85-32. AB - KEY MESSAGE: Rag6 and Rag3c were delimited to a 49-kb interval on chromosome 8 and a 150-kb interval on chromosome 16, respectively. Structural variants in the exons of candidate genes were identified. The soybean aphid, an invasive species, has significantly threatened soybean production in North America since 2000. Host plant resistance is known as an ideal management strategy for aphids. Two novel aphid-resistance loci, Rag6 and Rag3c, from Glycine soja 85-32, were previously detected in a 10.5-cM interval on chromosome 8 and a 7.5-cM interval on chromosome 16, respectively. Defining the exact genomic position of these two genes is critical for improving the effectiveness of marker-assisted selection for aphid resistance and for identification of the functional genes. To pinpoint the locations of Rag6 and Rag3c, four populations segregating for Rag6 and Rag3c were used to fine map these two genes. The availability of the Illumina Infinium SoySNP50K/8K iSelect BeadChip, combined with single-nucleotide polymorphism (SNP) markers discovered through the whole-genome re-sequencing of E12901, facilitated the fine mapping process. Rag6 was refined to a 49-kb interval on chromosome 8 with four candidate genes, including three clustered nucleotide-binding site leucine-rich repeat (NBS-LRR) genes and an amine oxidase encoding gene. Rag3c was refined to a 150-kb interval on chromosome 16 with 11 candidate genes, two of which are a LRR gene and a lipase gene. Moreover, by sequencing the whole-genome exome-capture of the resistant source (E12901), structural variants were identified in the exons of the candidate genes of Rag6 and Rag3c. The closely linked SNP markers and the candidate gene information presented in this study will be significant resources for integrating Rag6 and Rag3c into elite cultivars and for future functional genetics studies. PMID- 28887658 TI - Genetic dissection of grain traits in Yamadanishiki, an excellent sake-brewing rice cultivar. AB - KEY MESSAGE: The grain traits of Yamadanishiki, an excellent sake-brewing rice cultivar in Japan, are governed by multiple QTLs, namely, a total of 42 QTLs including six major QTLs. Japanese rice wine (sake) is produced using brewing rice (Oryza sativa L.) that carries traits desirable for sake-brewing, such as a larger grain size and higher white-core expression rate (WCE) compared to cooking rice cultivars. However, the genetic basis for these traits in brewing rice cultivars is still unclear. We performed analyses of quantitative trait locus (QTL) of grain and days to heading over 3 years on populations derived from crosses between Koshihikari, a cooking rice, and Yamadanishiki, an excellent sake brewing rice. A total of 42 QTLs were detected for the grain traits, and the Yamadanishiki alleles at 16 QTLs contributed to larger grain size. Two major QTLs essential for regulating both 100-grain weight (GWt) and grain width (GWh) were harbored in the same regions on chromosomes 5 and 10. An interaction was noted between the environment and the QTL associated with WCE on chromosome 6, which was detected in two of 3 years. In addition, two QTLs for WCE on chromosomes 3 and 10 overlapped with the QTLs for GWt and GWh, suggesting that QTLs associated with grain size also play an important role in the formation of white-core. Despite differences in the rate of grain growth in both Koshihikari and Yamadanishiki across 2 years, the WCE in Yamadanishiki remained consistent, thus demonstrating that the formation of white-core does not depend on grain filling speed. These data can be informative for programs involved in breeding better cooking and brewing rice cultivars. PMID- 28887659 TI - Ligand-biased ensemble receptor docking (LigBEnD): a hybrid ligand/receptor structure-based approach. AB - Ligand docking to flexible protein molecules can be efficiently carried out through ensemble docking to multiple protein conformations, either from experimental X-ray structures or from in silico simulations. The success of ensemble docking often requires the careful selection of complementary protein conformations, through docking and scoring of known co-crystallized ligands. False positives, in which a ligand in a wrong pose achieves a better docking score than that of native pose, arise as additional protein conformations are added. In the current study, we developed a new ligand-biased ensemble receptor docking method and composite scoring function which combine the use of ligand based atomic property field (APF) method with receptor structure-based docking. This method helps us to correctly dock 30 out of 36 ligands presented by the D3R docking challenge. For the six mis-docked ligands, the cognate receptor structures prove to be too different from the 40 available experimental Pocketome conformations used for docking and could be identified only by receptor sampling beyond experimentally explored conformational subspace. PMID- 28887660 TI - Urinary interleukin 22 binding protein as a marker of lupus nephritis in Egyptian children with juvenile systemic lupus erythematosus. AB - Juvenile systemic lupus erythematosus (JSLE) is a multi-system autoimmune inflammatory disease. Generally, 60% of patients will develop lupus nephritis (LN); thus, early recognition and treatment is associated with better outcome. Interleukin 22 (IL-22) is involved in tissue inflammation and is regulated by interleukin 22 binding protein (IL-22BP). This study aimed to use IL-22BP as a non-invasive marker for disease activity in JSLE and LN. This is a cross sectional study conducted on 82 subjects: 51 JSLE patients and 31 healthy controls of matched age and gender. Urinary IL-22BP was measured using enzyme linked immunosorbent assay, and its level was correlated with different clinical and laboratory data in JSLE as well as Systemic Lupus Erythematous Disease Activity Index 2000 (SLEDAI-2k), renal SLEDAI-2k, and Systemic Lupus International Collaborating Clinics (SLICC) renal activity score which were used to assess overall disease and renal activity. Our results showed that urinary IL 22BP level was significantly higher in JSLE patients with mean level of 4.13 +/- 1.10, as compared to controls 1.63 +/- 0.61 (P value < 0.001); also, patients with active LN had urinary levels of IL-22BP (5.47 +/- 1.03) higher than patients with active JSLE without LN (4.23 +/- 0.72) and patients with non-active JSLE/LN (3.5 +/- 0.65) with a highly significant P value < 0.001. There was a positive correlation with SLEDAI-2k, renal SLEDAI, and renal activity scores (P < 0.001). Urinary IL-22BP may be used as a non-invasive marker for assessment of disease activity in children with JSLE and LN. PMID- 28887661 TI - Widening the spectrum of deletions and molecular mechanisms underlying alpha thalassemia. AB - Inherited deletions of alpha-globin genes and/or their upstream regulatory elements (MCSs) give rise to alpha-thalassemia, an autosomal recessive microcytic hypochromic anemia. In this study, multiplex ligation-dependent probe amplification performed with commercial and synthetic engineered probes, Gap-PCR, and DNA sequencing were used to characterize lesions in the sub-telomeric region of the short arm of chromosome 16, possibly explaining the alpha-thalassemia/HbH disease phenotype in ten patients. We have found six different deletions, in heterozygosity, ranging from approximately 3.3 to 323 kb, two of them not previously described. The deletions fall into two categories: one includes deletions which totally remove the alpha-globin gene cluster, whereas the other includes deletions removing only the distal regulatory elements and keeping the alpha-globin genes structurally intact. An indel was observed in one patient involving the loss of the MCS-R2 and the insertion of 39 bp originated from a complex rearrangement spanning the deletion breakpoints. Finally, in another case, no alpha-globin gene cluster deletion was found and the patient revealed to be a very unusual case of acquired alpha-thalassemia-myelodysplastic syndrome. This study further illustrates the diversity of genomic lesions and underlying molecular mechanisms leading to alpha-thalassemia. PMID- 28887663 TI - Presumptive diagnosis of multinodular vacuolating tumor: "more than meets the eye!" PMID- 28887662 TI - Coronary artery assessment using self-navigated free-breathing radial whole-heart magnetic resonance angiography in patients with congenital heart disease. AB - OBJECTIVES: To evaluate a self-navigated free-breathing three-dimensional (SNFB3D) radial whole-heart MRA technique for assessment of main coronary arteries (CAs) and side branches in patients with congenital heart disease (CHD). METHODS: SNFB3D-MRA datasets of 109 patients (20.1+/-11.8 years) were included. Three readers assessed the depiction of CA segments, diagnostic confidence in determining CA dominance, overall image quality and the ability to freeze cardiac and respiratory motion. Vessel sharpness was quantitatively measured. RESULTS: The percentages of cases with excellent CA depiction were as follows (mean score): left main, 92.6 % (1.92); left anterior descending (LAD), 88.3 % (1.88); right (RCA), 87.8 % (1.85); left circumflex, 82.8 % (1.82); posterior descending, 50.2 % (1.50) and first diagonal, 39.8 % (1.39). High diagnostic confidence for the assessment of CA dominance was achieved in 56.2 % of MRA examinations (mean score, 1.56). Cardiac motion freezing (mean score, 2.18; Pearson's r=0.73, P<0.029) affected image quality more than respiratory motion freezing (mean score, 2.20; r=0.58, P<0.029). Mean quantitative vessel sharpness of the internal thoracic artery, RCA and LAD were 53.1, 52.5 and 48.7 %, respectively. CONCLUSIONS: Most SNFB3D-MRA examinations allow for excellent depiction of the main CAs in young CHD patients; visualisation of side branches remains limited. KEY POINTS: * Self-navigated free-breathing three-dimensional magnetic resonance angiography (SNFB3D-MRA) sufficiently visualises coronary arteries (CAs). * Depiction of main CAs in patients with congenital heart disease is excellent. * Visualisation of CA side branches using SNFB3D-MRA is limited. * SNFB3D-MRA image quality is especially correlated to cardiac motion freezing ability. PMID- 28887664 TI - South Asian men have lower expression of IFN signalling genes in white adipose tissue and skeletal muscle compared with white men. PMID- 28887665 TI - Impact of radiation technique, radiation fraction dose, and total cisplatin dose on hearing : Retrospective analysis of 29 medulloblastoma patients. AB - PURPOSE: To analyze the incidence and degree of sensorineural hearing loss (SNHL) resulting from different radiation techniques, fractionation dose, mean cochlear radiation dose (Dmean), and total cisplatin dose. MATERIAL AND METHODS: In all, 29 children with medulloblastoma (58 ears) with subclinical pretreatment hearing thresholds participated. Radiotherapy (RT) and cisplatin had been applied sequentially according to the HIT MED Guidance. Audiological outcomes up to the latest follow-up (median 2.6 years) were compared. RESULTS: Bilateral high frequency SNHL was observed in 26 patients (90%). No significant differences were found in mean hearing threshold between left and right ears at any frequency. A significantly better audiological outcome (p < 0.05) was found after tomotherapy at the 6 kHz bone-conduction threshold (BCT) and left-sided 8 kHz air-conduction threshold (ACT) than after a combined radiotherapy technique (CT). Fraction dose was not found to have any impact on the incidence, degree, and time-to-onset of SNHL. Patients treated with CT had a greater risk of SNHL at high frequencies than tomotherapy patients even though Dmean was similar. Increase in severity of SNHL was seen when the total cisplatin dose reached above 210 mg/m2, with the highest abnormal level found 8-12 months after RT regardless of radiation technique or fraction dose. CONCLUSION: The cochlear radiation dose should be kept as low as possible in patients who receive simultaneous cisplatin-based chemotherapy. The risk of clinically relevant HL was shown when Dmean exceeds 45 Gy independent of radiation technique or radiation regime. Cisplatin ototoxicity was shown to have a dose-dependent effect on bilateral SNHL, which was more pronounced in higher frequencies. PMID- 28887666 TI - The potential of multi-compound nanoparticles to bypass drug resistance in cancer. AB - PURPOSE: The therapeutic efficacy of conventional chemotherapy against several solid tumors is generally limited and this is often due to the development of resistance or poor delivery of the drugs to the tumor. Mechanisms of resistance may vary between cancer types. However, with current development of genetic analyses, imaging, and novel delivery systems, we may be able to characterize and bypass resistance, e.g., by inhibition of the right target at the tumor site. Therefore, combined drug treatments, where one drug will revert or obstruct the development of resistance and the other will concurrently kill the cancer cell, are rational solutions. However, drug exposure of one drug will defer greatly from the other due to their physicochemical properties. In this sense, multi compound nanoparticles are an excellent modality to equalize drug exposure, i.e., one common physicochemical profile. In this review, we will discuss novel approaches that employ nanoparticle technology that addresses specific mechanisms of resistance in cancer. METHODS: The PubMed literature was consulted and reviewed. RESULTS: Nanoparticle technology is emerging as a dexterous solution that may address several forms of resistance in cancer. For instance, we discuss advances that address mechanisms of resistance with multi-compound nanoparticles which co-deliver chemotherapeutics with an anti-resistance agent. Promising anti resistance agents are (1) targeted in vivo gene silencing methods aimed to disrupt key resistance gene expression or (2) protein kinase inhibitors to disrupt key resistance pathways or (3) efflux pumps inhibitors to limit drug cellular efflux. PMID- 28887667 TI - APE1 modulates cellular responses to organophosphate pesticide-induced oxidative damage in non-small cell lung carcinoma A549 cells. AB - Monocrotophos (MCP) and chlorpyrifos (CP) are widely used organophosphate pesticides (OPPs), speculated to be linked with human pathologies including cancer. Owing to the fact that lung cells are most vulnerable to the environmental toxins, the development and progression of lung cancer can be caused by the exposure of OPPs. The present study investigates the oxidative DNA damage response evoked by MCP and CP in human non-small cell lung carcinoma A549 cells. A549 cells were exposed to MCP and CP; cytotoxicity and reactive oxygen species (ROS) generation were measured to select the non-toxic dose. In order to establish whether MCP and CP can initiate the DNA repair and cell survival signalling pathways in A549 cells, qRT-PCR and Western blotting techniques were used to investigate the mRNA and protein expression levels of DNA base excision repair (BER)-pathway enzymes and transcription factors (TFs) involved in cell survival mechanisms. A significant increase in cell viability and ROS generation was observed when exposed to low and moderate doses of MCP and CP at different time points (24, 48 and 72 h) studied. A549 cells displayed a dose-dependent accumulation of apurinic/apyrimidinic (AP) sites after 24 h exposure to MCP advocating for the activation of AP endonuclease-mediated DNA BER-pathway. Cellular responses to MCP- and CP-induced oxidative stress resulted in an imbalance in the mRNA and protein expression of BER-pathway enzymes, viz. PARP1, OGG1, APE1, XRCC1, DNA pol beta and DNA ligase III alpha at different time points. The treatment of OPPs resulted in the upregulation of TFs, viz. Nrf2, c jun, phospho-c-jun and inducible nitric oxide synthase. Immunofluorescent confocal imaging of A549 cells indicated that MCP and CP induces the translocation of APE1 within the cytoplasm at an early 6 h time point, whereas it promotes nuclear localization after 24 h of treatment, which suggests that APE1 subcellular distribution is dynamically regulated in response to OPP-induced oxidative stress. Furthermore, nuclear colocalization of APE1 and the TF c-jun was observed in response to the treatment of CP and MCP for different time points in A549 cells. Therefore, in this study we demonstrate that MCP- and CP-induced oxidative stress alters APE1-dependent BER-pathway and also mediates cell survival signalling mechanisms via APE1 regulation, thereby promoting lung cancer cell survival and proliferation. PMID- 28887668 TI - Low body mass index correlates with low left ventricular mass index in patients with severe anorexia nervosa. AB - The patients with anorexia nervosa (AN) are known to be associated with high mortality, but the actual causes of death are still undefined. We tested the hypothesis that AN patients had cardiac disorders, including left ventricular (LV) dysfunction and LV atrophy. This study is a cross-sectional study at St. Luke's International Hospital, Tokyo. We analyzed 13 female inpatients with AN. We assessed cardiac function and heart volume in AN by echocardiography, LV ejection fraction (LVEF), LV mass, and LV mass index (LVMI). We assessed the correlations between body mass index (BMI) and heart volume (LV mass and LVMI). The mean age and BMI were 34.8 +/- 11.2 years and 15.5 +/- 3.1 kg/m2, respectively. There was no patient with mitral valve prolapse, but 3 patients had trivial to small amount of pericardial effusion. The mean LVEF was 67.7 +/- 6.5%, and 12 out of 13 patients had normal LVEF. Their LV mass (89.0 +/- 27.3 g) and LVMI (66.3 +/- 16.4 g/m2) were small. BMI positively correlated with LVMI (r = 0.58, p = 0.040), as well as LV mass (r = 0.74, p = 0.004). Lower BMI reflects lower LVMI, as well as smaller LV mass. These issues suggest that heart volume is initially decreased in severe AN conditions. Low LVMI could be a good marker of severity of AN. PMID- 28887669 TI - Association of Cannabis, Stimulant, and Alcohol use with Mortality Prognosis Among HIV-Infected Men. AB - Questionnaires over a 9-year study period (2002-2010) were used to characterize cannabis, stimulant, and alcohol use among 3099 HIV-infected men participating in the Veterans Aging Cohort Study (VACS) to determine whether use of these substances is associated with changes in the VACS Index, a validated prognostic indicator for all-cause mortality. At baseline, 18% of participants reported no substance use in the past year, 24% lower risk alcohol use only, 18% unhealthy alcohol use only, 15% cannabis use (with or without alcohol), and 24% stimulant use (with or without alcohol or cannabis). In adjusted longitudinal analyses, cannabis use [beta = -0.97 (95% CI -1.93, 0.00), p = 0.048] was not associated with mortality risk, while stimulant use [1.08 (0.16, 2.00), p = 0.021] was associated with an increased mortality risk, compared to lower risk alcohol use. Our findings show no evidence of a negative effect of cannabis use on mortality risk, while stimulant use was associated with increased mortality risk among HIV infected men. Interventions to reduce stimulant use in this patient population may reduce mortality. PMID- 28887670 TI - Comparison of Two Endovascular Steerable Robotic Catheters for Percutaneous Robot Assisted Fibroid Embolization. AB - PURPOSE: To compare outcomes of percutaneous robot-assisted uterine fibroid embolization (UFE) using two different endovascular robotic catheters. METHODS: Twenty-one patients with a symptomatic uterine fibroid were prospectively enrolled in a single-center study to be treated with a percutaneous robot assisted embolization using the Magellan system. Fourteen patients were treated using a first generation steerable robotic catheter, version 1.0 (group 1), and seven were treated using the new version 1.1 (group 2). Demographic, pathologic, and procedural variables were recorded. Dose Area Product (DAP) and physician equivalent doses were registered for each procedure. Procedural related complications and clinical midterm outcomes were also evaluated. RESULTS: Successful robot-assisted UFE was obtained in eight patients (57.1%) in group 1 and 7 patients (100%) in group 2 (p = 0.01). A successful robot-assisted catheterization of the internal iliac artery anterior branch was performed in all patients of both groups. Median selective target vessel catheterization time was 21.0 +/- 12.8 vs 13.4 +/- 7 min (p = 0.04) and total fluoroscopy time was 30.3 +/ 11.2 vs 19.3 +/- 5.9 min, respectively, in group 1 and 2. Mean DAP decreased from 18472.6 +/- 15622 to 5469.1 +/- 4461.0 cGy.cm2 (p = 0.04). All patients obtained a symptoms relief at 6 months follow-up. CONCLUSIONS: Robot-assisted uterine fibroid embolization is safe and effective. New version of steerable robotic catheter allows performing a faster procedure without related adverse events compared to old version. PMID- 28887671 TI - Histamine 2 receptor antagonism elicits protection against doxorubicin-induced cardiotoxicity in rodent model. AB - Doxorubicin (DOX), an anthracycline-based antibiotic, is regularly used in the management of carcinomas, and haematological malignancies have been downplayed in chemotherapy because of its ability to induce dilated cardiomyopathy (DCM). Dexrazoxane is approved to combat the cardiotoxicity, but limited by its adverse effects. Redox imbalance and reactive oxygen species generation plays major role in DOX-induced cardiotoxicity. Histamine, known to mediate various cardiovascular effects, but nevertheless the role of histamine or its receptors in DOX-induced DCM is remained obscure. Hence, this study is aimed to examine the effect of Famotidine (FAM), a H2 receptor antagonist on DOX-induced DCM in Wistar rats. Myocardial antioxidant status, stress and apoptosis markers, myocardial morphology and function were evaluated as the end points. Treatment with FAM has alleviated DOX doxorubicin-induced cardiotoxicity by reducing oxidative and nitrosative stress evident from lipid peroxidation and total nitrate-to-nitrite ratio, and enhanced the activity of super oxide dismutase. Cardiac stress markers like LDH and Na+-K+ATPase activities as well as CK-MB and Cardiac troponin levels were reduced by FAM treatment. It also normalised the myocardial function as assessed by 2D echocardiography and myocardial index. Treatment imparted anti apoptotic effect as evident from decrease in myocardial caspase 3 and 9 activity and cleaved PARP expression. Effect of FAM is found to be comparable to the standard ACE inhibitor Captopril (CAP). The results from this study collectively suggest H2 receptor antagonism as a novel therapeutic strategy to impart biochemical, structural and functional improvement indicating its cardio protective activity. PMID- 28887672 TI - The impact of sustained hot weather on risk of acute work-related injury in Melbourne, Australia. AB - It has been reported that weather-related high ambient temperature is associated with an increased risk of work-related injury. Understanding this relationship is important because work-related injuries are a major public health problem, and because projected climate changes will potentially expose workers to hot days, including consecutive hot days, more often. The aim of this study was to quantify the impact of exposure to sustained periods of hot weather on work-related injury risk for workers in Melbourne, Australia. A time-stratified case crossover study design was utilised to examine the association between two and three consecutive days and two and three consecutive nights of hot weather and the risk of work related injury, using definitions of hot weather ranging from the 60th to the 95th percentile of daily maximum and minimum temperatures for the Melbourne metropolitan area, 2002-2012. Workers' compensation claim data was used to identify cases of acute work-related injury. Overall, two and three consecutive days of hot weather were associated with an increased risk of injury, with this effect becoming apparent at a daily maximum temperature of 27.6 degrees C (70th percentile). Three consecutive days of high but not extreme temperatures were associated with the strongest effect, with a 15% increased risk of injury (odds ratio 1.15, 95% confidence interval 1.01-1.30) observed when daily maximum temperature was >=33.3 degrees C (90th percentile) for three consecutive days, compared to when it was not. At a threshold of 35.5 degrees C (95th percentile), there was no significant association between temperature and injury for either two or three consecutive days of heat. These findings suggest that warnings to minimise harm to workers from hot weather should be given, and prevention protocol initiated, when consecutive warm days of temperatures lower than extreme heat temperatures are forecast, and well before the upper ranges of ambient daytime temperatures are reached. PMID- 28887673 TI - [Intraocular pressure after implantation of an ICL with aquaport : Development of intraocular pressure after implantation of an ICL (model V4c) with aquaport without iridotomy]. AB - BACKGROUND AND OBJECTIVE: The latest version of the intraocular lens (ICL V4c) has a central hole (aquaport) that avoids a pupillary block. Due to this laser iridotomy or intraoperative surgical peripheral iridectomy are no longer required. In this study, we examined the intraocular pressure (IOP) after implantation of the ICL with aquaport, with special reference to the development of a possible pupillary block glaucoma. MATERIAL AND METHODS: This retrospective non-randomized study included 87 eyes from 46 patients (consecutive case series). These patients had the ICL model V4c (without a laser iridotomy or peripheral iridectomy) implanted between January 2013 and October 2014. The preoperative IOP values were compared with the postoperative values 1-2 h, 1 day, 1 week and 1 month after implantation. RESULTS: The median intraocular pressure was 14 +/- 2 mm Hg before implantation of the ICL, palpatory normotensive 1-2 h after implantation, 13 +/- 3 mm Hg 1 day after implantation, 15 +/- 3 mm Hg 1 week after implantation and 16 +/- 4 mm Hg 1 month after implantation (a slight statistically significant increase of the intraocular pressure, p < 0.05). In 2 patients there was a steroid response in both eyes with IOP reaching up to a maximum of 28 mm Hg. There were no peaks of intraocular pressure due to a pupillary block. CONCLUSION: It is possible to implant the latest ICL V4c with a central hole (Aquaport) without a laser iridotomy or peripheral iridectomy or development of a pupillary block. PMID- 28887674 TI - Robot-Assisted Transaxillary Thyroidectomy (RATT): A Series Appraisal of More than 250 Cases from Europe. AB - BACKGROUND: Robot-assisted transaxillary thyroidectomy (RATT) is widely accepted in Asian countries. However, concerns regarding the balance between its real advantages and safety and cost have been raised by North American authorities. In Europe, assessments have been limited by small numbers since now. The purpose here is to report a large European experience with RATT. METHODS: A retrospective analysis was conducted of 257 patients who underwent RATT for nodular disease between February 2012 and September 2016. Data collected included patient demographics, diagnosis, ultrasound-estimated mean thyroid volume and nodule size, type of resection, operative time, postoperative pain and morbidity, and the hospital length of stay. Pain was assessed by visual analog scale score 12 h postoperatively (on the first postoperative day, before discharge). Feasibility, effectiveness, and safety were the outcomes of interest. Follow-up of thyroid carcinoma patients was carried out measuring thyroglobulin levels and ultrasound examination (median follow-up 24 months (6-48 months)). First control after 12 months and successively once a year. RESULTS: There were 253 women and 4 men, with a mean age of 37.3 years. Indications included benign disease in 116, papillary carcinoma in 56, and indeterminate nodule in 85. Mean thyroid volume was 16.8 mL, and nodule size was 25.3 mm. A hemithyroidectomy was performed in 138 patients and total thyroidectomy in 118. The mean operative time was 77.5 min for the former and 99.7 min for the latter. One conversion was required. Complications included transient hypoparathyroidism in 7/118 (total thyroidectomy) patients (5.9%), transient vocal fold palsy in 3/257 (1.1%), 1 delayed tracheal injury (0.4%), and 3 postoperative hematoma (1.1%). Mean visual analog scale score was 1.79, and the mean length of stay was 1.6 days for hemithyroidectomy and 1.9 days for total thyroidectomy. CONCLUSION: RATT is safe and effective and could serve as a viable treatment modality in selected cases. PMID- 28887675 TI - How Bad Is Aluminum Exposure to Reproductive Parameters in Rats? AB - Aluminum (Al) is the most widely distributed metal in the environment and is extensively used in human daily life without any known biological function. It is known that exposure to high concentrations of Al impacts negatively on serum testosterone levels, testicular histomorphometry, and sperm parameters; however, no information is available about the effects of low exposure levels on reproduction. International organizations have established the Al concentration tolerated in drinking water as 3.35 * 10-4 mg/kg. Therefore, we aimed to compare the effects of long-term exposure to low and high concentrations of Al on male reproductive functions, focusing on testis, epididymis, and sperm parameters. Adult Wistar rats were exposed to aluminum chloride (AlCl3) at 6.7 * 10-5, 3.35 * 10-4, 10, and 40 mg/kg for 112 days by gavage. Al-exposed animals presented low values of testis and epididymis weight, and serum testosterone levels when compared to controls. The stereology of Leydig cells, epididymis histomorphometry, sperm motility, and structural integrity of sperm membranes changed depending on the Al concentration. In regard to epididymis histomorphometry, the initial segment and caput regions were more affected by Al exposure than distal regions. Otherwise, the histology of testis and epididymis did not alter after the Al exposure, as well as sperm morphology. In summary, we concluded that the consequences of Al exposure at low levels were as negative as high levels on reproductive parameters, suggesting adverse impact on male fertility. PMID- 28887676 TI - Learning Curve Characteristics for Caesarean Section Among Associate Clinicians: A Prospective Study from Sierra Leone. AB - BACKGROUND: In response to the high maternal mortality ratio, Sierra Leone has adopted an associate clinician postgraduate surgical task-sharing training programme. Little is known about learning curve characteristics for caesarean sections among associate clinicians. The aim of this study is to evaluate the number of caesarean sections needed to be performed by associate clinicians until there is no further significant reduction in operation time. METHODS: This prospective study evaluates the first 50 caesarean sections performed by trainees between January 2011 and June 2016. Primary outcome was total operating time in minutes (incision to suturing time). Secondary outcomes were length of hospital stay, surgical site infections, estimated operative bloodloss and in-hospital postoperative mortality. RESULTS: A total of 1174 caesarean sections performed by 24 trainees were analysed. Total operation time significantly reduced during the first 15 operations from mean (SD) operation time 72 (27)-51 (18) min after 15 procedures (p < 0.001). Estimated bloodloss did not significantly vary among the first 50 caesarean sections. Surgical site infections were reported in 3.7% of the operations, which was higher during the first 15 operations (6.8%) compared to the following 35 operations (2.3%). Length of stay reduced from median (range) 9 (2-39)-6 (2-127) days after 15 operations, but there was no reduction in maternal mortality. CONCLUSION: While gaining experience, the operation time of associate clinicians significantly reduced during the first 15 caesarean sections. Estimated bloodloss is not related to trainees experience. PMID- 28887678 TI - Reply to Dijemeni et al.'s comments concerning: "The comparability of drug induced sedation classification systems". PMID- 28887677 TI - Evolutionary and functional characterization of leucoanthocyanidin reductases from Camellia sinensis. AB - MAIN CONCLUSION: LARs promoted the biosynthesis of catechin monomers and inhibited their polymerization. The accumulation of catechin monomers and polymers was increased by up-regulating the expression of NtLAR and NtANR s in CsMYB5b transgenic tobacco. Tea is rich in polyphenolic compounds, and catechins are the major polyphenols in tea. The biosynthesis of polyphenols is closely related to the expression of the leucoanthocyanidin reductase (LAR) and anthocyanidin reductase (ANR) genes. In this paper, an evolutionary analysis and functional characterization of three CsLARs were performed. The phylogenetic tree showed that plant LARs could be grouped into three, including gymnosperms, monocotyledons and dicotyledons (clusters I and II). The eighth amino acid residue in a conserved LAR-specific motif is changeable due to a transversion (G > T) and transition (G -> C) that occur in the corresponding codon. Therefore, plant LARs can be classified as G-type, A-type and S-type LARs due to this variable amino acid residue. Although (2R, 3S)-trans-flavan-3-ols were the products of recombinant CsLARs proteins expressed in Escherichia coli, both (2R, 3S)-trans and (2R, 3R)-cis-flavan-3-ols were detected in tobacco overexpressing CsLARs. However, a butanol/HCl hydrolysis assay indicated that overexpression of the CsLARs caused a decrease in polymerized catechins. A hybridization experiment with CsLARc + AtPAP1 also showed that no polymers other than epicatechin, catechin and glycoside were detected, although the accumulation of anthocyanins was markedly decreased. CsMYB5b promoted the biosynthesis of both flavan-3-ols and proanthocyanidins (PAs). Therefore, LARs promoted the biosynthesis of catechin monomers and inhibited their polymerization. The accumulation of catechin monomers and polymers was increased by up-regulating the expression of the NtLAR and NtANRs in CsMYB5b transgenic tobacco. PMID- 28887679 TI - Microbiological studies of hot springs in India: a review. AB - The earliest microbiological studies on hot springs in India date from 2003, a much later date compared to global attention in this striking field of study. As of today, 28 out of 400 geothermal springs have been explored following both culturable and non-culturable approaches. The temperatures and pH of the springs are 37-99 degrees C and 6.8-10, respectively. Several studies have been performed on the description of novel genera and species, characterization of different bio-resources, metagenomics of hot spring microbiome and whole genome analysis of few isolates. 17 strains representing novel species and many thermostable enzymes, including lipase, protease, chitinase, amylase, etc. with potential biotechnological applications have been reported by several authors. Influence of physico-chemical conditions, especially that of temperature, on shaping the hot spring microbiome has been established by metagenomic investigations. Bacteria are the predominant life forms in all the springs with an abundance of phyla Firmicutes, Proteobacteria, Actinobacteria, Thermi, Bacteroidetes, Deinococcus-Thermus and Chloroflexi. In this review, we have discussed the findings on all microbiological studies that have been carried out to date, on the 28 hot springs. Further, the possibilities of extrapolating these studies for practical applications and environmental impact assessment towards protection of natural ecosystem of hot springs have also been discussed. PMID- 28887680 TI - Cervical vertebroplasty under sedoanalgesia using combined ultrasonography and fluoroscopy guidance: a novel technique. AB - PURPOSE: The aim of this report was to describe a case using combined USG and fluoroscopy for cervical VP via a percutaneous route under sedoanalgesia. METHODS: A 70-year-old male patient had severe neck pain for 6 weeks because of metastatic mass lesions in C6. After the decision to VP, the patient was placed on the operating table and 2 mg midazolam and 75 ug fentanyl were administered for conscious sedation. Localisation of the carotid artery, internal jugular vein, and trachea had been determined with USG. 3 mL of 2% lidocaine was infiltrated after proceeding a needle from the axis of the trochar to the C6 vertebra corpus. The trochar entered into the vertebra corpus between the carotid artery and trachea right-antero-laterally under C-arm and USG guidance. 6 mL of PMMA was injected into this field. Then C6 VP procedure had been completed without complications. RESULTS: This case has three differences from studies in the literature. First, cervical VP was conducted under sedoanalgesia. The second important feature of this case is that cervical VP was performed via a percutaneous route. A third important feature of this case is that it was performed under USG guidance for the first time in the literature. CONCLUSION: We consider that the combined use of C-arm fluoroscopy and USG should improve success rates and prevent vascular and neural injuries and dura perforation. PMID- 28887682 TI - Opacification of the C-flex 570C intraocular lens after sulcus fixation. AB - PURPOSE: To report a case of diffuse intraocular lens (IOL) opacification in a patient who started complaining of blurred vision in his left eye over the course of three years after having phacoemulsification surgery combined with capsular bag fixation of a C-flex 570C IOL. The IOL had been repositioned in the ciliary sulcus following its subluxation. METHOD: An IOL exchange was performed, and the explanted IOL was sent for histopathological analysis. RESULTS: Scanning electron microscopy identified multiple crystalline-like deposits on both sides of the IOL. The optic was more extensively involved than the haptics. Energy-dispersive X-ray spectroscopy confirmed the predominance of calcium within the deposits. CONCLUSIONS: The breakdown of the blood-aqueous barrier seems to be a key component of this calcification process. Ciliary sulcus fixation is not a suitable option for C-flex 570C IOLs. PMID- 28887681 TI - Pediatric spine imaging post scoliosis surgery. AB - Many orthopedic articles describe advances in surgical techniques and implants used in pediatric scoliosis surgery. However, even though postoperative spine imaging constitutes a large portion of outpatient musculoskeletal pediatric radiology, few, if any, radiology articles discuss this topic. There has been interval advancement over the last decades of the orthopedic procedures used in the treatment of spinal scoliosis in adolescents with idiopathic scoliosis. The goal of treatment in these patients is to stop the progression of the curve by blocking the spinal growth and correcting the deformity as much as possible. To that end, the authors in this paper discuss postoperative imaging findings of Harrington rods, Luque rods, Luque-Galveston implants and segmental spinal fusion systems. Regarding early onset scoliosis, the guiding principles used for adolescent idiopathic scoliosis do not apply to a growing spine because they would impede lung development. As a result, other devices have been developed to correct the curve and to allow spinal growth. These include spine-based growing rods, vertically expandable prosthetic titanium rods (requiring repetitive surgeries) and magnetically controlled growing rods (with a magnetic locking/unlocking system). Other more recent systems are Shilla and thoracoscopic anterior vertebral body tethering, which allow guided growth of the spine without repetitive interventions. In this paper, we review the radiologic appearances of different orthopedic implants and techniques used to treat adolescent idiopathic scoliosis and early onset scoliosis. Moreover, we present the imaging findings of the most frequent postoperative complications. PMID- 28887683 TI - Lethal outcome after pelvic salvage radiotherapy in a patient with prostate cancer due to increased radiosensitivity : Case report and literature review. AB - BACKGROUND: In general, late side effects after salvage radiotherapy (RT) for prostate cancer are below 10%. Patients with impaired DNA repair ability and genetic instability can have significantly increased reactions after RT. CASE, CLINICAL FOLLOW-UP, AND EXAMINATION: We present a patient who experienced severe side effects after additive RT for prostate cancer and died from the complications 25 months after RT. Imaging (MR) is shown as well as three-color fluorescence in situ hybridization. The blood sample testing revealed that radiosensitivity was increased by 35-55%. We undertook a review of the literature to give an overview over the tests established that are currently considered useful. CONCLUSION: This case highlights that the identification of patients with increased radiosensitivity is an important task in radiation protection. Groups of patients who should be screened have to be found and corresponding research facilities have to be set up. PMID- 28887686 TI - The effect of stimulus frequency, spectrum, duration, and location on temporal order judgment thresholds: distribution analysis. AB - The present study aimed to examine whether the judgments of temporal order are made by the same "central processor" regardless of the characteristics of the sound stimuli. The influence of stimulus parameters (e.g., frequency, spectrum, duration, location) on auditory temporal order judgment (TOJ) thresholds was tested in seven groups with a total of 192 participants received two-tone sequences of different: frequencies (3 groups); spectrum widths, via a pure tone and a Gaussian noise burst (1 group); durations (2 groups); or locations, via asynchronous presentation to each ear (1 group). No difference in the mean rankings of TOJ thresholds was found for frequency, spectrum, and location parameters. TOJ thresholds for the duration condition, however, were significantly longer than for any of the other conditions. Notably, the threshold distributions for all the parameters (frequency, spectrum, duration, location) differed in shape. These findings raise the question as to whether we can rely upon the mean or median threshold as truly representative of TOJ threshold data. Furthermore, the data suggest that temporal order judgments for the different stimulus parameters are processed differently. The differences observed when analyzing the data with central tendency measures, as compared to analyzing the threshold distributions, may explain some of the mixed results reported in the literature on the mechanisms involved in temporal processing of different parameters. Stimulus parameters influence TOJ threshold distributions and response patterns, and may provide additional cues, beyond the standard temporal cue inherent in the TOJ procedure, by which participants may judge the order of the stimuli. PMID- 28887685 TI - Isolation of a fungus Pencicillium sp. with zinc tolerance and its mechanism of resistance. AB - A zinc (Zn)-tolerant fungus, designated BC109-2, was isolated from rhizosphere soil and was identified as Penicillium janthinellum BC109-2 based on ITS sequence analysis. To understand its Zn tolerance mechanisms, a series of studies was carried out addressing the subcellular distribution of Zn, its chemical forms, and the antioxidant system (superoxide dismutase, catalase, peroxidase, glutathione reductase, glutathione S-transferase, reduced glutathione, oxidized glutathione and malondialdehyde) of the fungus. The maximum level of resistance to Zn for strain BC109-2 is 2100 mg L-1. The Zn contents and percentages of cell wall and soluble fraction increased with increasing Zn concentration in the medium, which indicated extracellular accumulation/precipitation and vacuolar compartmentation mechanism might play significant role in the detoxificating process. The proportion of inactive forms of Zn was higher in the fungus, which indicated that BC109-2 mainly formed inactive Zn and stored it in the cell walls and vacuoles to decrease Zn toxicity. Furthermore, changes in antioxidant enzyme activities at various concentrations of Zn showed that the addition of Zn could cause oxidative stress in the fungal cells and that antioxidant enzymes in fungi played important roles in resistance to Zn toxicity. Moreover, the high level of lipid peroxidation showed that the protective effects of the antioxidant system were not sufficient at the high concentrations of Zn even though the antioxidant enzyme activity levels were very high. The purpose of this work is to figure out the heavy metal tolerance mechanisms of microorganisms in soil and the microbial isolate could be potentially used in bioremediation of Zn-contaminated environments. PMID- 28887684 TI - Plant-Based Nutrition: An Essential Component of Cardiovascular Disease Prevention and Management. AB - PURPOSE OF REVIEW: This review aims to summarize and discuss the role of plant based nutrition as an adjunct to the management of cardiovascular disease (CVD). Discussion of nutrition and the benefits of a plant-based diet should be highlighted during healthcare provider visits as an essential part of the overall CVD prevention and management care plan. RECENT FINDINGS: Evidence from prospective cohort studies indicates that a high consumption of predominantly plant-based foods, such as fruit and vegetables, nuts, and whole grains, is associated with a significantly lower risk of CVD. The protective effects of these foods are likely mediated through their multiple beneficial nutrients, including mono- and polyunsaturated fatty acids, omega-3 fatty acids, antioxidant vitamins, minerals, phytochemicals, fiber, and plant protein. In addition, minimizing intake of animal proteins has been shown to decrease the prevalence of CVD risk factors. Substantial evidence indicates that plant-based diets can play an important role in preventing and treating CVD and its risk factors. Such diets deserve more emphasis in dietary recommendations. PMID- 28887687 TI - Kaiso is highly expressed in TNBC tissues of women of African ancestry compared to Caucasian women. AB - PURPOSE: Triple-negative breast cancer (TNBC) is most prevalent in young women of African ancestry (WAA) compared to women of other ethnicities. Recent studies found a correlation between high expression of the transcription factor Kaiso, TNBC aggressiveness, and ethnicity. However, little is known about Kaiso expression and localization patterns in TNBC tissues of WAA. Herein, we analyze Kaiso expression patterns in TNBC tissues of African (Nigerian), Caribbean (Barbados), African American (AA), and Caucasian American (CA) women. METHODS: Formalin-fixed and paraffin embedded (FFPE) TNBC tissue blocks from Nigeria and Barbados were utilized to construct a Nigerian/Barbadian tissue microarray (NB TMA). This NB-TMA and a commercially available TMA comprising AA and CA TNBC tissues (AA-CA-YTMA) were subjected to immunohistochemistry to assess Kaiso expression and subcellular localization patterns, and correlate Kaiso expression with TNBC clinical features. RESULTS: Nigerian and Barbadian women in our study were diagnosed with TNBC at a younger age than AA and CA women. Nuclear and cytoplasmic Kaiso expression was observed in all tissues analyzed. Analysis of Kaiso expression in the NB-TMA and AA-CA-YTMA revealed that nuclear Kaiso H scores were significantly higher in Nigerian, Barbadian, and AA women compared with CA women. However, there was no statistically significant difference in nuclear Kaiso expression between Nigerian versus Barbadian women, or Barbadian versus AA women. CONCLUSIONS: High levels of nuclear Kaiso expression were detected in patients with a higher degree of African heritage compared to their Caucasian counterparts, suggesting a role for Kaiso in TNBC racial disparity. PMID- 28887688 TI - Adenoid hypertrophy in children and allergic rhinitis. PMID- 28887690 TI - Cervical sagittal alignment after different anterior discectomy procedures for single-level cervical degenerative disc disease: randomized controlled trial. AB - BACKGROUND: The effect of anterior cervical discectomy without fusion (ACD), ACD with fusion by stand-alone cage (ACDF) or with arthroplasty (ACDA) on cervical sagittal alignment is not known and is the subject of this study. METHODS: A total of 142 adult patients with single-level cervical disease were at random allocated to different procedures: ACD (45), ACDF (47) and ACDA (50). Upright cervical spine radiographs were obtained. Angles of the involved angle and the angle between C2 and C7 were determined. RESULTS: After a mean follow-up of 25.4 +/- 18.4 months, the angles of the involved level comparing ACD with ACDA and ACD with ACDF were different, reaching statistical significance. However, the angle between C2 and C7 did not differ between groups or between preoperative values and at follow-up. CONCLUSIONS: Irrespective of the technique used for anterior cervical discectomy for single-level degenerative disc disease, the alignment of the cervical spine is unaltered. PMID- 28887691 TI - Relationships among leaf functional traits, litter traits, and mass loss during early phases of leaf litter decomposition in 12 woody plant species. AB - Litter 'quality' or decomposability has historically been estimated through measuring chemical attributes, such as concentrations of nitrogen or 'lignin'. More recently, foliar functional traits, which may incorporate indications of the physical structures of tissues, have been found to correlate with litter mass loss rates. However, these traits may not be adequate to predict early rates of mass loss, in which two factors are crucial: the amount of material quickly lost through leaching, and the ease of access of decomposer organisms to the more labile tissues in the interior of the litter. We investigated relationships among physical and chemical traits in foliage and litter of 12 species native to British Columbia and then observed how these traits related to mass loss during the first 3 months (Phase I) and between 3 and 12 months (Phase II). Novel traits measured in this study include cuticle thickness, litter leaching loss, and litter water uptake. Foliar and litter traits both co-varied along spectra, but several chemical traits, such as nitrogen concentration, changed from foliage to litter, i.e., during senescence. Phase I mass loss was best predicted by leaching loss and traits relating to leaching, such as cuticle thickness and specific leaf area. Phase II mass loss was predicted by traits that may relate to decomposer access and activity, such as leaf dry matter content and foliar nitrogen. Physical traits predicted mass loss as well or better than chemical traits, suggesting that physical characteristics of litter are important in determining early rates of decomposition. PMID- 28887692 TI - Molecular and biochemical evidence on the protective role of ellagic acid and silybin against oxidative stress-induced cellular aging. AB - Aging is a natural process in living organisms that is defined by some molecular and cellular changes with time. Various causes such as mitochondrial DNA aberrations, aggregation of proteins, telomere shortening, and oxidative stress have an influential role in aging of the cells. Natural antioxidants are compounds that are potent to protect the body from detrimental effects of molecules such as free radicals. The aim of this study was to evaluate the anti aging properties of ellagic acid (EA) and silybin (SIL), as natural antioxidant compounds on rat embryonic fibroblast (REF) cells. These cells were pre-incubated with EA and SIL, thereafter were exposed to hydrogen peroxide (H2O2). Then, the cell viability, SA-beta-GAL activity, distribution of cell cycle, NF-kappaB, and mitochondrial complex I, II/IV enzyme activity were measured. The results of this study revealed the protective effects of EA and SIL in H2O2-treated REF cells, which confirm the previous achieved data on antioxidant and anti-inflammatory characteristics of EA and SIL against H2O2 in the treated REF cells. However, more new in vivo experiments are required to discover the anti-aging effects and mechanism of action of such compounds. PMID- 28887693 TI - Staying cool or staying safe in a human-dominated landscape: which is more relevant for brown bears? AB - Pigeon et al. (2016) Staying cool in a changing landscape: the influence of maximum daily ambient temperature on grizzly bear habitat selection. Oecologia 181:1101. doi: 10.1007/s00442-016-3630-5 analyzed the effect of ambient temperature on the habitat selection of grizzly bears (Ursus arctos) in Alberta, Canada. They concluded that temperature played a significant role in bear habitat selection and that it was unlikely that human activity introduced biases to the habitat selection of bears. However, Pigeon et al. did not consider variables related to human activities in their analyses. They also misinterpreted previous research that has accounted for temperature in the habitat selection of brown bears. There is much literature published on the negative effects of human disturbance on wildlife in general and on bears in particular. Downplaying the role of human disturbance could have important negative consequences if, in fact, human disturbance were a more important factor than thermoregulation. Indeed, dismissing the importance of human influence, in the face of contradictory evidence, could tempt managers to disregard an important factor that is difficult and often unpopular to deal with in their conservation plans. PMID- 28887694 TI - Contribution of auditory P300 test to the diagnosis of mild cognitive impairment in Parkinson's disease. AB - Abnormalities in auditory P300 test have been observed in patients with Parkinson's disease (PD). We aimed to investigate whether or not additional electrophysiological tests assist in making the clinical diagnosis of mild cognitive impairment in Parkinson's disease (PD-MCI), and we evaluated P300 changes in patients with non-demented PD and analyzed the correlation between the cognitive features and P300 changes. Twenty patients with PD who had been diagnosed with mild cognitive impairment (PD-MCI group) according to the Movement Disorder Society (MDS) 2012 PD-MCI level II criteria, 21 patients with PD without cognitive impairment (PD-Normal group), and 20 control subjects (control group) who were neurologically normal were examined by the standard auditory oddball paradigm. The N100, P200, N200, and P300 latencies and N100-P200, P200-N200, and N200-P300 amplitudes were measured and analyzed. P300 latencies recorded from Fz, Cz, and Pz and N200 latency recorded from Fz were significantly longer in the PD MCI group than in the PD-Normal and the control group (respectively p < 0.001, p = 0.041). P300 amplitude recorded from Fz was significantly lower in PD-MCI group than those in the other groups (p = 0.038). While P300 was obtained in all patients in the PD-Normal and the control group, it was lost in 35% of PD-MCI patients. The results show that P300 provides a diagnostic tool for detecting PDMCI. We suggest that P300 prolongation and loss of P300 potential could be used as supportive parameter in the diagnosis of PD-MCI. PMID- 28887695 TI - A "NIRS" death experience: a reduction in cortical oxygenation by time-resolved near-infrared spectroscopy preceding cardiac arrest. AB - Near-infrared spectroscopy (NIRS) has been used effectively post-cardiac-arrest to gauge adequacy of resuscitation and predict the likelihood of achieving a return of spontaneous circulation. However, preempting hemodynamic collapse is preferable to achieving ROSC through advanced cardiac life support. Minimizing "time down" without end-organ perfusion has always been a central pillar of ACLS. In many critically ill patients there is a prolonged phase of end-organ hypoperfusion preceding loss of palpable pulses and initiation of ACLS. Due to the relative infrequency of in-hospital cardiac arrest, NIRS has not previously evaluated the period immediately prior to hemodynamic collapse. Here we report a young man who suffered a pulseless electrical activity (PEA) arrest while cortical oxygenation was monitored using time-resolved near-infrared spectroscopy. The onset of cortical deoxygenation preceded the loss of palpable pulses by 15 min, suggesting that TRS-NIRS monitoring might provide a means of preempting PEA arrest. Our experience with this patient represents a promising new direction for continuous NIRS monitoring and has the potential to not only predict clinical outcomes, but affect them to the patient's benefit as well. PMID- 28887697 TI - Meta-analysis: diagnostic accuracy of antibody against peptidylarginine deiminase 4 by ELISA for rheumatoid arthritis. AB - The antibody against peptidylarginine deiminase (PAD) 4 is a biomarker that might be helpful in the diagnosis of rheumatoid arthritis (RA). We aim to estimate the diagnostic value of anti-PAD4 antibody for RA by meta-analysis. We searched PubMed, Embase, the Cochrane Library, Web of Science, and Scopus for studies published in any languages in March 1, 2017 that evaluated the diagnostic accuracy of the anti-PAD4 antibody for the diagnosis of RA. The articles that detected the anti-PAD4 antibody by enzyme-linked immunosorbent assay (ELISA) and used healthy donors or patients without arthritis or arthralgia as controls were included for meta-analysis. The articles were assessed by Quality Assessment of Diagnostic Accuracy Studies tool. A bivariate mixed-effects model was used to summarize the diagnostic indexes from eight eligible studies. The pooled sensitivity, specificity, and positive and negative likelihood ratios for anti PAD4 antibody were 38% (95% CI 30.0-46.0%), 96% (95% CI 93.0-98.0%), 8.96 (95% CI 5.00-16.05), and 0.65 (95% CI 0.57-0.74), respectively. The summary diagnostic odds ratios were 13.74 (95% CI 7.23-26.09), and the area under the summary receiver operator characteristic curve was 86% (95% CI 83-89%). Anti-PAD4 antibody detected by ELISA shows a high value in the diagnosis of RA with high specificity, but relatively low sensitivity. PMID- 28887696 TI - Lessons from single-cell transcriptome analysis of oxygen-sensing cells. AB - The advent of single-cell RNA-sequencing (RNA-Seq) technology has enabled transcriptome profiling of individual cells. Comprehensive gene expression analysis at the single-cell level has proven to be effective in characterizing the most fundamental aspects of cellular function and identity. This unbiased approach is revolutionary for small and/or heterogeneous tissues like oxygen sensing cells in identifying key molecules. Here, we review the major methods of current single-cell RNA-Seq technology. We discuss how this technology has advanced the understanding of oxygen-sensing glomus cells in the carotid body and helped uncover novel oxygen-sensing cells and mechanisms in the mice olfactory system. We conclude by providing our perspective on future single-cell RNA-Seq research directed at oxygen-sensing cells. PMID- 28887698 TI - The Effect of Salts in Promoting Specific and Competitive Interactions between Zinc Finger Proteins and Metals. AB - Specific protein-metal interactions (PMIs) fulfill essential functions in cells and organic bodies, and activation of these functions in vivo are mostly modulated by the complex environmental factors, including pH value, small biomolecules, and salts. Specifically, the role of salts in promoting specific PMIs and their competition among various metals has remained untapped mainly due to the difficulty to distinguish nonspecific PMIs from specific PMIs by classic spectroscopic techniques. Herein, we report Hofmeister salts differentially promote the specific PMIs by combining nanoelectrospray ionization mass spectrometry and spectroscopic techniques (fluorescence measurement and circular dichroism). Furthermore, to explore the influence of salts in competitive binding between metalloproteins and various metals, we designed a series of competitive experiments and applied to a well-defined model system, the competitive binding of zinc (II) and arsenic (III) to holo-promyelocytic leukemia protein (PML). These experiments not only provided new insights at the molecular scale as complementary to previous NMR and spectroscopic results, but also deduced the relative binding ability between zinc finger proteins and metals at the molecular scale, which avoids the mass spectrometric titration-based determination of binding constants that is frequently affected and often degraded by variable solution conditions including salt contents. Graphical Abstract ?. PMID- 28887699 TI - Lifestyle Intervention Has to Be Part of the Strategy in Kidney Transplant Candidate with Obesity. PMID- 28887700 TI - Lack of evidence of a relationship between magnetic resonance signal intensity changes in the globus pallidus and dentate nucleus, and repeated administrations of gadoterate meglumine in children. PMID- 28887701 TI - Morphological and molecular identification of Rhipicephalus (Boophilus) microplus in Nigeria, West Africa: a threat to livestock health. AB - The cattle tick Rhipicephalus (Boophilus) microplus was first reported in West Africa in Ivory Coast, in 2007. Since then it has made an aggressive eastward advancement having been reported in four other West African countries: Mali, Burkina Faso, Togo and Benin. We herein report the first molecular identification of this tick species in Nigeria, West Africa, and highlight the threat it poses to livestock health. A nation-wide tick survey was conducted in 12 out of 36 states across the various agro ecological zones of Nigeria over a 1 year period (April 2014-March 2015). In total 1498 ticks belonging to three genera collected from cattle were morphologically identified. Overall, Amblyomma species constituted the highest percentage of sampled ticks, 50.2% (752/1498), followed by Rhipicephalus (including the subgenus Boophilus) species, 29.4% (440/1498) and Hyalomma species, 20.4% (306/1498). The presence of Rh. (B.) microplus was identified morphologically from four out of the 12 states. This finding was confirmed for the first time in Nigeria using a molecular method targeting the ITS-2 region of the ticks in three of the 12 states. This study ascertained the presence of Rh. (B.) microplus in Nigeria in addition to a broad variety of cattle tick species, most of which are of veterinary importance. The implication of this finding is that there may be additional economic burden to livestock farmers due to increased cost of tick control occasioned by the acaricide resistance by this tick species widely reported from different climes. Additionally, there may be a potential upsurge in incidence of hemoparasitic infections in cattle leading to increased morbidity, cost of treatment and mortalities. PMID- 28887702 TI - Necroptosis may be a novel mechanism for cardiomyocyte death in acute myocarditis. AB - In this study, we investigated the roles of RIP1/RIP3 mediated cardiomyocyte necroptosis in CVB3-induced acute myocarditis. Serum concentrations of creatinine kinase (CK), CK-MB, and cardiac troponin I were detected using a Hitachi Automatic Biochemical Analyzer in a mouse model of acute VMC. Histological changes in cardiac tissue were observed by light microscope and expression levels of RIP1/RIP3 in the cardiac tissue were detected via Western blot and immunohistochemistry. The data showed that RIP1/RIP3 was highly expressed in cardiomyocytes in the acute VMC mouse model and that the necroptosis pathway specific blocker, Nec-1, dramatically reduced the myocardial damage by downregulating the expression of RIP1/RIP3. These findings provide evidence that necroptosis plays a significant role in cardiomyocyte death and it is a major pathway for cell death in acute VMC. Blocking the necroptosis pathway may serve as a new therapeutic option for the treatment of acute viral myocarditis. PMID- 28887703 TI - Examining the Impact of Intimate Partner Violence Type and Timing on Pre-exposure Prophylaxis Awareness, Interest, and Coercion. AB - Previous research suggests that intimate partner violence (IPV) is associated with acceptability of and adherence to pre-exposure prophylaxis (PrEP). However, very few studies have examined whether the type (i.e., physical, sexual, and psychological IPV) and timing (i.e., lifetime, past-year) of IPV experiences differentially relate to PrEP awareness, interest, and perceived PrEP coercion. Therefore, the objective of this study is to examine associations between lifetime and past-year physical, sexual, and psychological IPV experiences on PrEP awareness, interest, and perceived PrEP coercion. Data were collected from an online survey administered to 210 women and men. Past-year physical IPV experiences (AOR 4.53, 95% CI 1.85, 11.11) were significantly associated with being interested in using PrEP. Lifetime sexual (AOR 3.69, 95% CI 1.62, 8.40), psychological IPV (AOR 4.70, 95% CI 1.01, 21.89), and past-year sexual IPV experiences (AOR 3.01, 95% CI 1.10, 8.27) were also significantly associated with believing a recent partner would attempt to control the participant's use of PrEP, if she or he were currently using it. Understanding that engaging in PrEP care is influenced differently by the type and timing of IPV has potential implications for PrEP candidacy guidelines and interventions. PMID- 28887704 TI - [Indication and limitations of meniscus replacement]. AB - BACKGROUND: Meniscal lesions are among the most important musculoskeletal disorders and are the most common indication for knee joint arthroplasty. However, the structural integrity and function is rarely retained, and a loss of tissue results. Thus, there is a huge demand for meniscal replacement options. CURRENT PROCEDURES: Autografts were used in the past but did not fulfill expectations. Meniscus allografts have been developed to be a viable treatment option. However, availability is limited and evidence of a long-term chondroprotective effect scarce. Artificial scaffolds made from either collagen or PCU foam are available, which aid the regeneration of meniscal tissue and are rather intended as a partial replacement with an intact peripheral rim. Those implants thus have a limited spectrum of indication. While they seem to be symptomatically effective, it remains unclear whether they can reduce secondary cartilage damage. Newer developments aim at a permanent replacement of lost meniscal tissue. LIMITATIONS: In summary, there is currently no meniscal replacement available for a broad range of indications and with a solid scientific foundation. Prophylactic use should be limited to cases with a high chance of progression to osteoarthritis, like a lateral total meniscectomy. Otherwise meniscal replacement should be considered in younger, symptomatic patients with mild to moderate secondary changes. Potential causes of the initial meniscal injury like instability or deformities should be carefully assessed and addressed. In many cases, osteotomy might be a viable alternative to meniscus replacement. PMID- 28887705 TI - Population data and mutation rates of 20 autosomal STR loci in a Chinese Han population from Yunnan Province, Southwest China. AB - The genetic polymorphisms of 20 autosomal short tandem repeat (STR) loci included in the PowerPlex(r) 21 kit were evaluated from 2068 unrelated, healthy individuals from the Chinese Han population of Yunnan Province in southwest China. All of the loci reached Hardy-Weinberg equilibrium. These loci were examined to determine allele frequencies and forensic statistical parameters. The genetic relationships among the Yunnan Han and other Chinese populations were also estimated. The combined discrimination power and probability of excluding paternity of the 20 STR loci were 0.99999999999999999999999126 and 0.999999975, respectively. In addition, mutation rates from 4363 parentage cases (2215 trios and 2148 duos) were investigated in this study. A total of 164 mutations were observed in 6578 meioses from the 20 loci. The highest mutation rate was observed in D12S391 (0.30%), and the lowest mutation rates were observed in D13S317 (0.03%) and TPOX (0.03%). The average mutation rate for the 20 loci was estimated to be 1.246 * 10-3 per meiosis. The mutations were primarily single-step and paternal mutations. PMID- 28887706 TI - Computational study on acetophenone in amorphous polyethylene. AB - Polyethylene (PE) is widely used as an electrical insulating material. Acetophenone (AP) is a major residue in PE and is considered one of the causes of insulation deterioration. However, the physicochemical explanation of the influence of AP is still unknown. Therefore, in the present study, the behavior of AP molecules in amorphous PE was investigated using molecular dynamics (MD) simulations and quantum chemical calculation. First, the basic properties of the AP molecule were evaluated from the viewpoint of molecular electrostatic potential (MEP), molecular orbitals, and energy levels. Subsequently, an amorphous PE system containing AP molecules was studied using MD simulations. The results clearly indicate that AP does not greatly change the density and radius of gyration of amorphous PE. Quantum computations were performed using a part of the structure obtained from the MD simulations, suggesting that AP acts as a trap site in amorphous PE. It was also revealed that under the external electric field, the total density of state (DOS) changes with a dependence on the applied direction. Results of these calculations help in explaining previous experimental results. PMID- 28887707 TI - Correlations Between Patient-Reported Dysphagia Screening and Penetration Aspiration Scores in Head and Neck Cancer Patients Post-oncological Treatment. AB - Dysphagia is a common and severe toxicity after oncological treatment of head and neck cancer (HNC). The study aim was to investigate relationships between patient reported dysphagia and clinically measured swallowing function in HNC after modern curative radiotherapy with or without chemotherapy to identify possible alarm symptoms for clinically manifest dysphagia. Patients with tumors of the tonsil, base of tongue, hypopharynx, and larynx treated in 2007-2015 were assessed for dysphagia post-treatment by telephone interview and videofluoroscopy (VFS). A study-specific categorized symptom score was used to determine patient reported dysphagia (DESdC = presence of Drinking, Eating, Swallowing difficulties, and Coughing when eating/drinking (any combination); scores between 0 and 4 with 0 = no symptom); the penetration-aspiration scale (PAS) to determine swallowing function by VFS. Swallowing difficulties were defined as DESdC >= 1 and PAS >= 2. Relationships between clinically relevant cut-offs for DESdC and PAS were determined by Pearson's correlation coefficient (Pr). Swallowing difficulties according to DESdC were reported by 89% of the patients and according to PAS by 60% at a median of 7 months post-treatment. Averaged correlations between DESdC score 1/2/3/4 and PAS were 0.16/0.10/0.27/0.18. Almost one in two patients with DESdC score >=3 had severe swallowing difficulties according to PAS. Correlations between individual DESdC:s were highest for swallowing and eating (Pr = 0.53) and lowest for swallowing and coughing (Pr = 0.11). Our data suggest that if a patient reports having swallowing difficulties, it is likely that he or she also has eating difficulties but not necessarily coughing problems when eating/drinking. However, if all these three symptoms are reported, it is likely that the patient will present with moderate or severe impaired swallowing function according to PAS and thus should be referred for further evaluation and treatment. PMID- 28887708 TI - Long-term clinical results of acute myocardial infarction at the left main trunk requiring percutaneous cardiopulmonary support. AB - The clinical results of patients with acute myocardial infarction (AMI) at the left main trunk (LMT) remain unclear, especially in cases requiring percutaneous cardiopulmonary support (PCPS). Twenty seven cases of AMI at the LMT requiring emergent PCPS were retrospectively investigated. These 27 patients were aged 44 83 years (65.6 +/- 8.6 years) and 20 (81.5%) were men. Peak creatine kinase (CK) leakage ranged from 538 to 34,010 IU/l (13,553 +/- 7656 IU/l). Eight (29.6%) patients were discharged without mechanical support. Ten (37.0%) patients underwent left ventricular assist device (LVAD) implantation, five of whom with preoperative organ failure could not survive more than 6 months after implantation. The other nine (33.3%) patients died of low output syndrome or brain damage. The overall survival rates were 53.7, 41.3, 33.0, and 28.3% at 3 months, 6 months, 1 year, and 2 years, respectively. Multivariate analysis showed that Killip class 3/4 at hospital arrival was an independent risk factor for hospital mortality (odds ratio 20.4). Patients with more than 5 days of PCPS support period (n = 6), >= 4 h to revascularization (n = 6) or maximum CK leakage >=20,000 IU/dl (n = 3) were not associated with successful PCPS or IABP weaning. The long-term clinical outcomes of patients with LMT disease requiring PCPS is devastating. Rapid cardiopulmonary resuscitation and coronary revascularization and timely insertion of LVAD before the onset of complications might lead to better survival. PMID- 28887709 TI - Mapping and comparative proteomic analysis of the starch biosynthetic pathway in rice by 2D PAGE/MS. AB - KEY MESSAGE: Our results not only provide a comprehensive overview of the starch biosynthetic pathway in the developing endosperm but also reveal some important protein markers that regulate the synthesis of starch. In human diets, rice (Oryza sativa L.) is an important source of starch, a substantial amount of which is accumulated in developing endosperm. A better understanding of the complicated pathways involved in starch biosynthesis is needed to improve the yield and quality of rice and other cereal crops through breeding. One pure line rice mutant, SA0419, was induced from a wild-type rice, TNG67, by sodium azide mutagenesis; therefore, TNG67 and SA0419 share the same genetic background. SA0419 is, however, a unique glutinous rice with a lower amylose content (8%) than that of TNG67 (20%), and the grains of SA0419 develop earlier and faster than those of TNG67. In this study, we used a comparative proteomic analysis to identify the differentially expressed proteins that may explain the differences in starch biosynthesis and the characteristics of TNG67 and SA0419. A gel-based proteomic approach was applied to profile the expressed proteome in the developing endosperm of these two rice varieties by nano-LC/MS/MS. Several over expressed proteins were found in SA0419, such as plastidial ADP-glucose pyrophosphorylase (AGPase), phosphoglucomutase (PGM), pyrophosphate-fructose 6 phosphate 1-phosphotransferase (PFP), 6-phosphofructokinase (PFK), pyruvate phosphate dikinase (PPDK), starch branching enzymes (SBE) and starch debranching enzyme (SDBE), with those proteins mainly being involved in the pathways of starch metabolism and PPDK-mediated gluconeogenesis. Those over-expressed enzymes may contribute to the relatively early development, similar starch accumulation and rapid grain filling of SA0419 as compared with TNG67. This study provides a detailed biochemical description of starch biosynthesis and related information regarding a unique starch mutant that may assist future research efforts to improve the yield and quality of grain and starch in rice through breeding. PMID- 28887710 TI - Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center. AB - PURPOSE: To compare long-term outcomes in patients with adrenal incidentalomas (AIs) with the response to a 1 mg overnight dexamethasone suppression test (DST). METHODS: Consecutive patients with "non-functional" AIs (n = 365) were examined. Patients with overt hormone excess, adrenocortical cancer and known malignancy had been excluded. Patients were classified to normal cortisol secretion group (n = 204, DST <= 50 nmol/l), possible autonomous cortisol secretion group (n = 128, DST 51-138 nmol/l) and autonomous cortisol secretion group (n = 33, DST >= 138 nmol/l). RESULTS: Thirty-seven patients (10.1%) deceased during the follow-up period (5.2 +/- 2.3 years): 16(7.8%) in the non-secreting group (time from diagnosis to death: 3.9 +/- 2.9 years), 15 in the possible autonomous cortisol secretion group (11.7%, 3.2 +/- 1.8 years) and 6 in the autonomous cortisol secretion group (18.2%, 2.3 +/- 1.5 years), respectively (P = 0.019). Multivariate analysis only found significant association with age and the tumour size but if cortisol levels post-DST were analysed as a continuous variable it was significant as well. All deaths in autonomous cortisol secretion group were due to cancer not related to adrenal glands. Hypertension, cardiovascular disease and medications were more common in the possible and autonomous cortisol secretion group, especially in the former. More bilateral AIs and larger AI size were found in the two latter groups. CONCLUSIONS: Patients with autonomous cortisol secretion had higher mortality than those with non-functioning AIs though cortisol levels post-DST as a continuous variable, age and tumour size were better predictor of mortality. Cardiovascular disease and osteoporosis medication seemed more prevalent in the possible and autonomous cortisol secretion groups, especially in the former. PMID- 28887711 TI - In vitro remodeling and structural characterization of degradable polymer scaffold-based tissue-engineered vascular grafts using optical coherence tomography. AB - Non-destructive imaging strategies to monitor long-term cultures is essential for vascular engineering. The goal of this study is to investigate whether optical coherence tomography (OCT) can be a suitable approach to monitor the long-term remodeling process of biodegradable polymeric scaffold-based tissue-engineered vascular grafts (TEVG) after pulsatile stimulation and to observe polymeric scaffold degradation during bioreactor cultivation. In the present study, a perfusion system driven by a ventricular assist device was provided for a three dimensional culture system as a pulsatile force. We characterized the structural features of wall thickness and polyglycolic acid degradation based on optical signal attenuation using catheter-based OCT. Scanning electron microscopy confirmed morphological changes. Also, polymer degradation and the detection of different types of collagen was visualized after 4 weeks of culture by means of polarized microscopy. Findings on OCT imaging correlated with those on histological examination and revealed the effects of pulsatile stimulation on the development of engineered vessels. This finding demonstrated that real-time imaging with OCT may be a promising tool for monitoring the growth and remodeling characterization of TEVG and provide a basis to promote the ideal and long-term culture of vascular tissue engineering. PMID- 28887712 TI - Higher incidence of pancreatic fistula in laparoscopic gastrectomy. Real-world evidence from a nationwide prospective cohort study. AB - BACKGROUND: Laparoscopic distal gastrectomy (LDG) is becoming the standard procedure for gastric cancer. However, supporting evidence thus far has been derived primarily from randomized control trials conducted by centers of excellence. In the present study we used the National Clinical Database (NCD) in Japan to prospectively accumulate data from diverse types of hospitals and examine whether LDG is a safe and valid standard procedure. METHODS: From the NCD, 169 institutions were selected to form a cohort that was considered to be representative of Japan. From August 2014 to July 2015, 5288 patients who underwent LDG were registered prospectively, and clinical data were acquired through the NCD. To compare surgical outcomes between open distal gastrectomy (ODG) and LDG, we adjusted for confounding factors using propensity score matching, ultimately retrieving data from 1067 patients in each group. RESULTS: There were no significant differences in the number of in-hospital deaths in the ODG and LDG groups (3/1067 vs. 6/1067; P = 0.51) or in the number of reoperations (20/1067 vs. 29/1067; P = 0.19). However, the length of hospital stay was significantly shorter in the LDG. Although wound infection and dehiscence were more common in the ODG group, LDG was more often associated with grade B or higher pancreatic fistulas. CONCLUSION: The safety and minimal invasiveness of LDG were confirmed in the present Japanese nationwide survey. However, care must be taken to prevent the formation of pancreatic fistulas with LDG, and further improvements in surgical quality are warranted in this regard. PMID- 28887713 TI - Determinants of slow flow following stent implantation in intravascular ultrasound-guided primary percutaneous coronary intervention. AB - Slow flow is a serious complication in primary percutaneous coronary intervention (PCI) and is associated with poor clinical outcomes. Intravascular ultrasound (IVUS)-guided PCI may improve clinical outcomes after drug-eluting stent implantation. The purpose of this study was to seek the factors of slow flow following stent implantation, including factors related to IVUS-guided primary PCI. The study population consisted of 339 ST-elevation myocardial infarction patients, who underwent stent deployment with IVUS. During PCI, 56 patients (16.5%) had transient or permanent slow flow. Multivariate logistic regression analysis showed age (OR 1.04, 95% CI 1.01-1.07, P = 0.01), low attenuation plaque on IVUS (OR 3.38, 95% CI 1.70-6.72, P = 0.001), initial Thrombolysis In Myocardial Infarction (TIMI) flow grade 2 (vs. TIMI 0: OR 0.44, 95% CI 0.20-0.99, P = 0.046), and the ratio of stent diameter to vessel diameter (per 0.1 increase: OR 2.63, 95% CI 1.84-3.77, P < 0.001) were significantly associated with slow flow. A ratio of stent diameter to vessel diameter of 0.71 had an 80.4% sensitivity and 56.9% specificity to predict slow flow. There was no significant difference in ischemic-driven target vessel revascularization between the modest stent expansion (ratio of stent diameter to vessel diameter <0.71) and aggressive stent expansion (ratio of stent diameter to vessel diameter >=0.71) strategies. Unlike other variables, the ratio of stent diameter to vessel diameter was the only modifiable factor. The modest stent expansion strategy should be considered to prevent slow flow following stent implantation in IVUS-guided primary PCI. PMID- 28887714 TI - Is it time for one-step nucleic acid amplification (OSNA) in colorectal cancer? A systematic review and meta-analysis. AB - BACKGROUND: Lymph node metastasis (LNM) is prognostic in colorectal cancer (CRC). However, evaluation by routine haematoxylin and eosin histology (HE) limits nodal examination and is subjective. Missed LNMs from tissue allocation bias (TAB) might under-stage disease, leading to under-treatment. One-step nucleic acid amplification (OSNA) for CK19 messenger ribonucleic acid (mRNA), a marker of LNM, analyses the whole node. The aim of the present systematic review and meta analysis was to assess recent studies on OSNA versus HE and its implications for CRC staging and treatment. METHODS: Databases including OVID, Medline and Google Scholar were searched for OSNA, LNM and CRC. Study results were pooled using a random-effects model. Summary receiver operator curves (SROC) assessed OSNA's performance in detecting LNM when compared to routine HE histology. RESULTS: Five case-control studies analysing 4080 nodes from 622 patients were included. The summary estimates of pooled results for OSNA were sensitivity 0.90 [95% confidence interval (CI) 0.86-0.93], specificity 0.94 (95% CI 0.93-0.95) and diagnostic odds ratio 179.5 (CI 58.35-552.2, p < 0.0001). The SROC curve indicated a maximum joint sensitivity and specificity of 0.88 and area under the curve of 0.94, p < 0.0001. On average, 5.4% HE-negative nodes were upstaged by OSNA. CONCLUSIONS: OSNA is as good as routine HE. It may avoid TAB and offer a more objective and standardised assay of LNM. However, for upstaging, its usefulness as an adjunct to HE or superiority to HE requires further assessment of the benefits, if any, of adjuvant therapy in patients upstaged by OSNA. PMID- 28887715 TI - Tissue microarray analysis for epithelial membrane protein-2 as a novel biomarker for gliomas. AB - Epithelial membrane protein-2 (EMP2) expression is noted in many human cancers. We evaluated EMP2 as a biomarker in gliomas. A large tissue microarray of lower grade glioma (WHO grades II-III, n = 19 patients) and glioblastoma (GBM) (WHO grade IV, n = 50 patients) was stained for EMP2. EMP2 expression was dichotomized to low or high expression scores and correlated with clinical data. The mean EMP2 expression was 1.68 in lower grade gliomas versus 2.20 in GBMs (P = 0.01). The percentage of samples with high EMP2 expression was greater in GBMs than lower grade gliomas (90.0 vs. 52.6%, P = 0.001). No significant difference was found between median survival among patients with GBM tumors exhibiting high EMP2 expression and survival of those with low EMP2 expression (8.38 vs. 10.98 months, P = 0.39). However, EMP2 expression >=2 correlated with decreased survival (r = 0.39, P = 0.001). The EMP2 expression level also correlated with Ki-67 positivity (r = 0.34, P = 0.008). The mortality hazard ratio for GBM patients with EMP2 score of 3 or higher was 1.92 (CI 0.69-5.30). Our findings suggest that elevated EMP2 expression is associated with GBM. With other biomarkers, EMP2 may have use as a molecular target for the diagnosis and treatment of gliomas. PMID- 28887716 TI - Inhibitory effect and molecular mechanism of mesenchymal stem cells on NSCLC cells. AB - Non-small-cell lung cancer (NSCLC) is still the main threat of cancer-associated death. Current treatment of NSCLC has limited effectiveness, and unfortunately, the prognosis of NSCLC remains poor. Therefore, a novel strategy for cancer therapy is urgently needed. Stem cell therapy has significant potential for cancer treatment. Mesenchymal stem cells (MSCs) with capacity for self-renewal and differentiation into various cells types exhibit the feature of homing to tumor site and immunosuppression, have been explored as a new treatment for various cancers. Studies revealed that the broad repertoire of trophic factors secreted by MSCs extensively involved in the interplay between MSCs and tumor cells. In this study, we confirmed that MSCs do have the paracrine effect on proliferation and migration of NSCLC cells (A549, NCI-H460, and SK-MES-1). Co culture system and conditioned medium experiments results showed that soluble factors secreted by MSCs inhibited the proliferation of NSCLC cells in vitro. The scratch assay showed that conditioned medium of MSCs could suppress the migration of NSCLC cells in vitro. Western blot results showed that the expression of proteins relevant to cell proliferation, anti-apoptosis, and migration was remarkably decreased via MAPK/eIF4E signaling pathway. We speculated that soluble factors secreted by MSCs might be responsible for inhibitory mechanism of NSCLC cells. By Human Gene Expression Microarray Assay and recombinant Vascular Endothelial Growth Factor 165 (VEGF165) neutralizing experiment, we verified that VEGF might be responsible for the down-regulation of proteins related to cell proliferation, anti-apoptosis, and migration by suppressing translation initiation factor eIF4E via MAPK signaling pathway. Taken together, our study demonstrated that a possible trophic factor secreted by MSCs could manipulate translation initiation of NSCLC cells via MAPK signaling pathway, and significantly affect the fate of tumor cells, which will be a new strategy for cancer therapy. PMID- 28887717 TI - Prognostic importance of temozolomide-induced neutropenia in glioblastoma, IDH wildtype patients. AB - Standard treatment for patients with primary glioblastoma (GBM) includes surgery, radiotherapy, and concomitant and adjuvant temozolomide (TMZ). Recent reports have demonstrated that TMZ-induced myelosuppression correlates with survival in patients with GBM. However, those results were evaluated before the 2016 revision of the World Health Organization classification. This study examined whether myelosuppression during concomitant TMZ phase correlates with prognosis in GBM, IDH-wildtype patients. We examined circulating blood cell counts in 50 patients with GBM, IDH-wildtype who received the standard treatment protocol between August 2005 and November 2015. We assessed relationships between rates of decrease in blood cells (white blood cells (WBC), neutrophils, lymphocytes, red blood cells, and platelets) during the concomitant TMZ phase and overall survival (OS) using univariate and multivariate analyses including other clinicopathological factors (age, sex, Karnofsky Performance Status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase (MGMT) status). Log-rank testing revealed that age, KPS, extent of resection, MGMT status, and decrease rates of WBC, neutrophils, and platelets correlated significantly with OS. On multivariate analysis, age, MGMT status, and decrease rate of neutrophils correlated significantly with OS. Patients with a >= 40% decrease in neutrophils showed significantly longer OS than those with < 40% (hazard ratio = 2.815; 95% confidence interval = 1.177-7.038; P = 0.0196). A decrease of >= 40% in neutrophils represents a predictor of good prognosis for GBM, IDH-wildtype. Blood cell counts during the concomitant TMZ phase can help predict OS in patients with GBM, IDH-wildtype receiving the standard treatment protocol. PMID- 28887718 TI - Measurement of hemodynamic changes with the axial flow blood pump installed in descending aorta. AB - We have developed various axial flow blood pumps to realize the concept of the Valvo pump, and we have studied hemodynamic changes under cardiac assistance using an axial flow blood pump in series with the natural heart. In this study, we measured hemodynamic changes of not only systemic circulation but also cerebral circulation and coronary circulation under cardiac support using our latest axial flow blood pump placed in the descending aorta in an acute animal experiment. The axial flow blood pump was installed at the thoracic descending aorta through a left thoracotomy of a goat (43.8 kg, female). When the pump was on, the aortic pressure and aortic flow downstream of the pump increased with preservation of pulsatilities. The pressure drop upstream of the pump caused reduction of afterload pressure, and it may lead to reduction of left ventricular wall stress. However, cerebral blood flow and coronary blood flow were decreased when the pump was on. The axial flow blood pump enables more effective blood perfusion into systemic circulation, but it has the potential risk of blood perfusion disturbance into cerebral circulation and coronary circulation. The results indicate that the position before the coronary ostia might be suitable for implantation of the axial flow blood pump in series with the natural heart to avoid blood perfusion disturbances. PMID- 28887719 TI - Protective effects of carbenoxolone, an 11beta-HSD1 inhibitor, against chemical induced dry eye syndrome. AB - Dry eye syndrome (DES) is a disorder of the eye due to tear deficiency or excessive evaporation that causes damage to the eye and is associated with discomfort and dryness. 11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) is an enzyme that converts inactive cortisone to active cortisol. Recently, 11beta-HSD1 has been expressed in human and rodent eyes and has been recognized as a target of glaucoma. In this study, the therapeutic effects and underlying mechanisms of topical carbenoxolone, an 11beta-HSD1 inhibitor, were investigated in benzalkonium chloride (BAC)-treated human conjunctival epithelial cells and a rat DES model. In the in vitro study, carbenoxolone dose-dependently inhibited cell death and 11beta-HSD1 activity in BAC-treated human conjunctival epithelial cells. For the in vivo study, carbenoxolone or a solvent was administered to the BAC-induced DES model twice daily. BAC-treated rat eyes showed significant increases in ocular surface damage, a reduction of tears, decrease corneal thickness, corneal basement membrane destruction, apoptosis in the conjunctival epithelium, and expression of pro-inflammatory cytokines (TNF-alpha and IL-6) and 11beta-HSD1. These effects of BAC were reversed by topical carbenoxolone treatment. These results demonstrate that carbenoxolone can prevent DES by inhibiting pro-inflammatory cytokine expression and cell death of the corneal and conjunctival epithelium via inhibition of both 11beta-HSD1 activity and expression in the eyes of BAC-treated rats. It is suggested that topical 11beta HSD1 inhibitors may provide a new therapeutic window in the prevention and/or treatment of DES. PMID- 28887720 TI - Early Folic Acid Supplement Initiation and Risk of Adverse Early Childhood Respiratory Health: A Population-based Study. AB - Objectives Folate plays a vital role in biologic functions yet women often do not meet the recommended dietary intake in pregnancy. It has been suggested that high folic acid intake during pregnancy may increase the risk of respiratory diseases in offspring. However, findings from observational studies in human populations are inconclusive. Methods In this population-based study, we collected self reported folic acid and prenatal vitamin supplement use during pregnancy 3-6 months postpartum from mothers in Los Angeles whose children were born in 2003. Supplement initiation was based on whichever supplement, either folic acid or prenatal supplements, the women initiated first. In a 2006 follow-up survey, approximately 50% of women were re-contacted to gather information on the child's respiratory health, including symptoms and diagnoses, at approximately 3.5 years of age. Results Overall, timing of folic acid supplement initiation was not associated with wheeze or lower respiratory tract infection, even after accounting for preterm births and censoring at follow-up. However, children born to mothers with a history of atopy (hay fever, eczema or asthma) who initiate folic acid supplements in late pregnancy, compared to first trimester initiators, have 1.67 (95% CI 1.12, 2.49) times the risk of wheeze in the first 3 years of life and 1.88 (95% CI 1.05, 3.34) times the risk of wheeze in the past year. No association was found among children of non-atopic mothers. Conclusions These findings suggest that early folic acid or prenatal supplementation among atopic women may be important to prevent wheeze among offspring. PMID- 28887721 TI - Narrow implants (2.75 and 3.25 mm diameter) supporting a fixed splinted prostheses in posterior regions of mandible: one-year results from a prospective cohort study. AB - BACKGROUND: Can multiple splinted narrow-diameter implants be used as definitive implants in patients with insufficient bone ridge thickness in posterior regions of the mandible? With this aim, we evaluated their outcomes in this set up to 1 year after loading. METHODS: Forty-two patients with a mean age of 61.3 years old (range 49-73) in need of fixed prosthetic implant-supported rehabilitations in the posterior region of the mandible, presenting a thin alveolar crest, were selected. One hundred twenty-four narrow-diameter implants (2.75 and 3.25 mm diameter) were placed and splinted with a bridge. One implant for each missing tooth was requested to be inserted. Outcomes measured were implant survival, complications, and marginal bone level changes up to 1 year after loading. RESULTS: At the 12-month follow-up, three implants failed. Two 2.75 mm diameter implants and one 3.2 mm diameter implant failed. The implant survival rate was 97.6%. Peri-implant bone resorption was 0.20 mm (CI 95% 0.14: 0.26) after 6 months and 0.47 mm (CI 95% 0.29; 0.65) after 12 months of loading, not different between 2.75 and 3.25 mm diameter groups (p = 0.786). Of the 42 cases, three had an episode of peri-implant mucositis (7.1%). CONCLUSIONS: Within the limits of this study, preliminary short-term data (1 year post-loading) suggested that narrow-diameter implants (2.75 to 3.25 mm) can be successfully used as a minimally invasive alternative to horizontal bone augmentation in the posterior mandible. However, larger and longer follow-ups of 5 years or more are needed. PMID- 28887722 TI - Dental anomalies in pediatric patients with familial adenomatous polyposis. AB - Familial adenomatous polyposis patients often present with non-malignant extra intestinal manifestations which include dental anomalies that may be evident prior to the appearance of the colonic adenomas. The aims of this study were to describe the prevalence and type of dental anomalies and the relationships between gene mutations and dental anomalies in these patients. Twenty-two pediatric familial adenomatous polyposis patients and 46 controls, who were age and gender matched participated. Familial adenomatous polyposis patient's had a dental examination with panoramic radiograph and medical record review for age at diagnosis, the presence of the adenomatous polyposis coli gene mutation, and determination of other extra-intestinal manifestations on the body. The control group was identified from a retrospective chart review and selected if there was a current panoramic radiograph. The only significant difference between familial adenomatous polyposis patients and controls were the presence of jaw osteomas and sclerosis (p = .0001). Patients with a mutation in, or upstream of codon 1309 had a higher frequency of osteomas (77.8%) and jaw-bone sclerosis (44.4%), and 77% of these had at least one dental anomaly. This preliminary study showed an association between a genetic variant at, or upstream of codon 1309, and radiographic dental anomalies. PMID- 28887723 TI - Endoscopic Doppler Ultrasound Probe: Useful in the Management of Gastric Varices? PMID- 28887724 TI - Reviewers should have known better. PMID- 28887725 TI - Recombinant flagellin-PAL fusion protein of Legionella pneumophila induced cell mediated and protective immunity against bacteremia in BALB/c mice. AB - We report a new recombinant fusion protein composed of full-length Legionella pneumophila flagellin A and peptidoglycan-associated lipoprotein (PAL), rFLA-PAL, capable of inducing protective immunity against L. pneumophila. The recombinant protein was over expressed in Escherichia coli strain BL21 (DE3) using pET-28a (+) expression vector (pET28a-flaA-pal) and purified by Ni2+ exchange chromatography. Immunological properties of rFLA-PAL were assessed in a mouse model. Female BALB/c mice, immunized with rFLA-PAL, exhibited a rapid increase in serum antibody concentration against each of its protein portions. Furthermore, a strong activation of both innate and adaptive cell-mediated immunity was observed as indicated by antigen-specific splenocyte proliferation, IFN-gamma and IL-12 production, and early production of TNF-alpha in the serum and in splenocyte cultures which were separately assessed against PAL and FLA. BALB/c mice were challenged with a lethal dose of L. pneumophila intravenously. In a 10-days follow-up after intravenous lethal challenge with L. pneumophila, a 100% survival rate was observed for mice immunized with rFLA-PAL, same as for those immunized with a sublethal dose of L. pneumophila. Based on the potent immune responses observed in mice immunized with rFLA-PAL, this recombinant fusion protein could be a potential vaccine candidate against the intracellular pathogen L. pneumophila. PMID- 28887726 TI - Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF-03084014, an Oral Gamma Secretase Inhibitor. AB - BACKGROUND: Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in beta-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral gamma secretase inhibitor, PF-03084014. METHODS: PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated. RESULTS: Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0 96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5-21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily. CONCLUSIONS: PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0 96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation. PMID- 28887728 TI - Comment on: "Nominal Mass?" by Athula B. Attygalle and Julius Pavlov, J. Am. Soc. Mass Spectrom. 28, 1737-1738 (2017). PMID- 28887727 TI - Predictors of primary lung cancer in a solitary pulmonary lesion after a previous malignancy. AB - OBJECTIVE: A solitary pulmonary lesion in patients with a history of malignancy may be either primary lung cancer or a metastatic lung tumor or benign nodule. We retrospectively examined the preoperative predictive factors for determining the type of pathology. METHODS: We used an exact logistic regression analysis to identify radiological and clinical predictors of primary lung cancer. The study included 187 patients who underwent pulmonary resection for a solitary pulmonary lesion and had received previous treatment for a malignancy. RESULTS: There were 107 patients with primary lung cancer, 74 with metastatic lung tumors, and 6 with benign lesions. The previous malignancy included colorectal cancer in 71 patients. A disease-free interval exceeding 5 years and ground-glass opacity were found in 27.0% (20/74) and 1.4% (1/74) of metastatic lung tumors, respectively. Multivariate logistic regression analysis demonstrated that spiculation [adjusted odds ratio (a-OR), 1.74; 95% confidence interval (CI), 1.09-2.86], pleural indentation (a-OR 1.99, 95% CI 1.24-3.29), and ground-glass opacity (a-OR 5.28, 95% CI 2.61-13.1) on high-resolution computed tomography, maximum standardized uptake value (a-OR 1.14, 95% CI 1.02-1.29), current and former smokers (a-OR 1.96, 95% CI 1.21-3.30), and previous malignancy other than colorectal cancer (a OR 2.02, 95% CI 1.26-3.37) were associated with primary lung cancer. CONCLUSIONS: A combination of radiological findings, smoking history, and type of previous malignancy can improve the ability to predict primary lung cancer in the presence of a solitary pulmonary lesion that appears after previous treatment for a malignancy. PMID- 28887729 TI - Intestinal microbiome-gut-brain axis and irritable bowel syndrome. AB - Psychological comorbidity is highly present in irritable bowel syndrome (IBS). Recent research points to a role of intestinal microbiota in visceral hypersensitivity, anxiety, and depression. Increased disease reactivity to psychological stress has been described too. A few clinical studies have attempted to identify features of dysbiosis in IBS. While animal studies revealed strong associations between stress and gut microbiota, studies in humans are rare. This review covers the most important studies on intestinal microbial correlates of psychological and clinical features in IBS, including stress, anxiety, and depression. PMID- 28887730 TI - An exploration of the reflow technique for the fabrication of an in vitro microvascular system to study occlusive clots. AB - Embolic ischemia and pulmonary embolism are health emergencies that arise when a particle such as a blood clot occludes a smaller blood vessel in the brain or the lungs, and restricts flow of blood downstream of the vessel. In this work, the reflow technique (Wang et al. Biomed. Microdevices 2007, 9, 657) was adapted to produce a microchannel network that mimics the occlusion process. The technique was first revisited and a simple geometrical model was developed to quantitatively explain the shapes of the resulting microchannels for different reflow parameters. A critical modification was introduced to the reflow protocol to fabricate nearly circular microchannels of different diameters from the same master, which is not possible with the traditional reflow technique. To simulate the phenomenon of occlusion by clots, a microchannel network with three generations of branches with different diameters and branching angles was fabricated, into which fibrin clots were introduced. At low constant pressure drop (DeltaP), a clot blocked a branch entrance only partially, while at higher DeltaP, the branch was completely blocked. Instances of simultaneous blocking of multiple channels by clots, and the consequent changes in the flow rates in the unblocked branches of the network, were also monitored. This work provides the framework for a systematic study of the distribution of clots in a network, and the rate of dissolution of embolic clots upon the introduction of a thrombolytic drug into the network. PMID- 28887731 TI - Are Indigenous Determinants of Health Associated with Self-Reported Health Professional-Diagnosed Anxiety Disorders Among Canadian First Nations Adults?: Findings from the 2012 Aboriginal Peoples Survey. AB - We estimated the prevalence of self-reported health professional-diagnosed anxiety disorders among Canadian First Nations adults living off-reserve, and assessed the relationship between anxiety disorders and Indigenous determinants of health (Status Indian, residential school attendance, knowledge of Indigenous language, and participation in traditional activities) using the 2012 Aboriginal Peoples Survey. Multivariable logistic regression models were performed using bootstrap weights. The prevalence of anxiety disorders was 14.5% among off reserve First Nations adults. There was an increased odds of anxiety disorders among those participating in traditional activities compared to their counterparts (aOR 1.46, 95% CI 1.12-1.90). No association was found between anxiety disorders and other Indigenous determinants of health. There is a high prevalence of self-reported anxiety among First Nations adults living off reserve. However, further studies are warranted to identify and assess the role of Indigenous determinants of health for anxiety disorders and other prevalent mental health conditions in this population. PMID- 28887732 TI - Clinical outcomes of concurrent chemoradiotherapy with volumetric modulated arc therapy in patients with locally advanced nasopharyngeal carcinoma. AB - PURPOSE: The purpose of this study was to analyze the clinical results of concurrent chemoradiotherapy (CCRT) with volumetric modulated arc therapy (VMAT) for nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: Patients with stage II-IVB NPC who received CCRT with VMAT between 2010 and 2014 were included in this study. The planned dose was 70 Gy in 35 fractions. RESULTS: Twenty patients aged between 28 and 85 years (median 60 years) were assessed. With a median follow-up time of 47 months, the 3-year overall survival and progression free survival rates were 85 and 65%, respectively. The 3-year local, regional and distant control rates were 78, 88 and 79%, respectively. At 0, 3, 6 and 12 months from CCRT, 19, 6, 3, and 1 patients had grade 2 dry mouth, respectively. No cases of grade 3 or worse dry mouth were observed. The severity of dry mouth was downgraded from grade 2 to grade 0 or 1 significantly earlier in younger patients (<70 years, p = 0.02) or patients in whom the mean dose to one parotid gland was lower (<26 Gy, p = 0.04). CONCLUSIONS: Our clinical results regarding CCRT with VMAT for NPC patients showed favorable survival rates while maintaining organ function. PMID- 28887733 TI - Computational design of bio-inspired carnosine-based HOBr antioxidants. AB - During a respiratory burst the enzyme myeloperoxidase generates significant amounts of hypohalous acids (HOX, X = Cl and Br) in order to inflict oxidative damage upon invading pathogens. However, excessive production of these potent oxidants is associated with numerous inflammatory diseases. It has been suggested that the endogenous antioxidant carnosine is an effective HOCl scavenger. Recent computational and experimental studies suggested that an intramolecular Cl+ transfer from the imidazole ring to the terminal amine might play an important role in the antioxidant activity of carnosine. Based on high-level ab initio calculations, we propose a similar reaction mechanism for the intramolecular Br+ transfer in carnosine. These results suggest that carnosine may be an effective HOBr scavenger. On the basis of the proposed reaction mechanism, we proceed to design systems that share similar structural features to carnosine but with enhanced HOX scavenging capabilities for X = Cl and Br. We find that (i) elongating the beta-alanyl-glycyl side chain by one carbon reduces the reaction barriers by up to 44%, and (ii) substituting the imidazole ring with strong electron-donating groups reduces the reaction barriers by similar amounts. We also show that the above structural and electronic effects are largely additive. In an antioxidant candidate that involves both of these effects the reaction barriers are reduced by 71%. PMID- 28887734 TI - Mating of natural Saccharomyces cerevisiae strains for improved glucose fermentation and lignocellulosic inhibitor tolerance. AB - Natural Saccharomyces cerevisiae isolates from vineyards in the Western Cape, South Africa were evaluated for ethanol production in industrial conditions associated with the production of second-generation biofuels. The strains displayed high phenotypic diversity including the ability to grow at 45 degrees C and in the presence of 20% (v/v) ethanol, strain YI13. Strains HR4 and YI30 were inhibitor-tolerant under aerobic and oxygen-limited conditions, respectively. Spore-to-spore hybridization generated progeny that displayed heterosis, including increased ethanol productivity and improved growth in the presence of a synthetic inhibitor cocktail. Hybrid strains HR4/YI30#6 and V3/YI30#6 were able to grow at a high salt concentration (2 mol/L NaCl) with V3/YI30#6 also able to grow at a high temperature (45 degrees C). Strains HR4/YI30#1 and #3 were inhibitor-tolerant, with strain HR4/YI30#3 having similar productivity (0.36 +/- 0.0036 g/L per h) as the superior parental strain, YI30 (0.35 +/- 0.0058 g/L per h). This study indicates that natural S. cerevisiae strains display phenotypic variation and heterosis can be achieved through spore to-spore hybridization. Several of the phenotypes (temperature-, osmo-, and inhibitor tolerance) displayed by both the natural strains and the generated progeny were at the maximum conditions reported for S. cerevisiae strains. PMID- 28887735 TI - An automated sampling importance resampling procedure for estimating parameter uncertainty. AB - Quantifying the uncertainty around endpoints used for decision-making in drug development is essential. In nonlinear mixed-effects models (NLMEM) analysis, this uncertainty is derived from the uncertainty around model parameters. Different methods to assess parameter uncertainty exist, but scrutiny towards their adequacy is low. In a previous publication, sampling importance resampling (SIR) was proposed as a fast and assumption-light method for the estimation of parameter uncertainty. A non-iterative implementation of SIR proved adequate for a set of simple NLMEM, but the choice of SIR settings remained an issue. This issue was alleviated in the present work through the development of an automated, iterative SIR procedure. The new procedure was tested on 25 real data examples covering a wide range of pharmacokinetic and pharmacodynamic NLMEM featuring continuous and categorical endpoints, with up to 39 estimated parameters and varying data richness. SIR led to appropriate results after 3 iterations on average. SIR was also compared with the covariance matrix, bootstrap and stochastic simulations and estimations (SSE). SIR was about 10 times faster than the bootstrap. SIR led to relative standard errors similar to the covariance matrix and SSE. SIR parameter 95% confidence intervals also displayed similar asymmetry to SSE. In conclusion, the automated SIR procedure was successfully applied over a large variety of cases, and its user-friendly implementation in the PsN program enables an efficient estimation of parameter uncertainty in NLMEM. PMID- 28887736 TI - A comparison among three different apheretic techniques for treatment of hyperbilirubinemia. AB - Liver failure is associated to high mortality due to the accumulation of protein bound metabolites, such as bilirubin, not removed by conventional hemodialysis. Different methods can efficiently remove them, such as the molecular adsorbent recirculating system (MARS), plasma exchange (PEX), and bilirubin or plasma adsorption perfusion (PAP). No direct comparison exists between MARS, PEX and PAP, and current guidelines do not specify which method (and when) to use. We have retrospectively evaluated MARS, PEX and PAP in their effectiveness in lowering plasma bilirubin concentration, and their effects on liver and kidney function. A total of 98 patients have been recruited, which comprised 68 patients treated with PAP (177 sessions), 16 patients with PEX (41 sessions) and 11 patients with MARS (21 sessions). Bilirubin, creatinine, liver enzymes were analyzed before and after the first treatment with each technique. The three methods did not differ for bilirubin lowering efficiency, with MARS showing only slightly less effective reductions. Finally, the three techniques did not differ in the amount of change of cholinesterase, but a lower reduction in AST was found using PAP. Our retrospective observation is one of the largest case series of hepatic failure treated with bilirubin absorption. The choice of the technique cannot be based on the desired reduction in bilirubin concentration. Based on costs and duration of treatment, we suggest that PAP could be considered as a first-line approach. In case of kidney involvement, MARS remains a valuable option. PMID- 28887737 TI - Child with Vomiting. AB - Vomiting is a common problem in children for which parents seek health care consultation. It has a varied etiology encompassing many organ systems, ranging from a benign physiological behavior to a life-threatening systemic disease. Most often, it is benign and self-limiting. Infections within and outside the gastrointestinal tract are the commonest causes. A good history and meticulous physical examination can discern the cause and help in delineating the benign cause from the sinister. Red flags include unstable vital signs, acidotic breathing, presence of bile or blood stained vomitus, features of gastrointestinal (GI) obstruction, encephalopathy and papilledema. Blood pressure, hydration status, careful abdominal examination including genitalia and hernial orifices and fundus form important components of the physical examination. Signs of GI obstruction should prompt an abdominal X-ray and surgical consultation. Recognition and treatment of the underlying cause is important. Mere symptomatic treatment may delay specific diagnosis and therapy. If the cause is not apparent after initial assessment, observation and/or admission would be appropriate. Vomiting may need symptomatic relief with antiemetics, if it is persistent and impedes oral intake. Domperidone and ondansetron are the commonly used antiemetics. Since most causes are benign, parental reassurance with or without symptomatic treatment may suffice. PMID- 28887738 TI - Ripe Banana Flour as a Source of Antioxidants in Layer and Sponge Cakes. AB - About one-fifth of all bananas harvested become culls that are normally disposed of improperly. However, ripe banana pulp contains significant amounts of fibre and polyphenol compounds as well as a high content of simple sugars (61.06 g/100 g), making it suitable for sucrose replacement in bakery products. This work studied the feasibility of incorporating ripe banana flour (20 and 40% of replacement) in cake formulation. Physical, nutritional and sensory attributes of sponge and layer cakes were evaluated. The inclusion of ripe banana flour generally led to an increased batter consistency that hindered cake expansion, resulting in a slightly lower specific volume and higher hardness. This effect was minimised in layer cakes where differences in volume were only evident with the higher level of replacement. The lower volume and higher hardness contributed to the decline of the acceptability observed in the sensory test. Unlike physical attributes, the banana flour inclusion significantly improved the nutritional properties of the cakes, bringing about an enhancement in dietary fibre, polyphenols and antioxidant capacity (up to a three-fold improvement in antioxidant capacity performance). Therefore, results showed that sugar replacement by ripe banana flour enhanced the nutritional properties of cakes, but attention should be paid to its inclusion level. PMID- 28887739 TI - An evaluation of a handheld spectroradiometer for the near real-time measurement of cyanobacteria for bloom management purposes. AB - A commercially available handheld spectroradiometer, the WISP-3, was assessed as a tool for monitoring freshwater cyanobacterial blooms for management purposes. Three small eutrophic urban ponds which displayed considerable within-pond and between-pond variability in water quality and cyanobacterial community composition were used as trial sites. On-board algorithms provide field measurements of phycocyanin (CPC) and chlorophyll-a (Chl-a) from surface reflectance spectra measured by the instrument. These were compared with laboratory measurements. Although significant but weak relationships were found between WISP-3 measured CPC and cyanobacterial biovolume measurements and WISP-3 and laboratory Chl-a measurements, there was considerable scatter in the data due likely to error in both WISP-3 and laboratory measurements. The relationships generally differed only slightly between ponds, indicating that different cyanobacterial communities had little effect on the pigment retrievals of the WISP-3. The on-board algorithms need appropriate modification for local conditions, posing a problem if it is to be used extensively across water bodies with differing optical properties. Although suffering a range of other limitations, the WISP-3 has a potential as a rapid screening tool for preliminary risk assessment of cyanobacterial blooms. However, such field assessment would still require adequate support by sampling and laboratory-based analysis. PMID- 28887740 TI - Editor's Comments. PMID- 28887741 TI - Effects of Lectins on initial attachment of cariogenic Streptococcus mutans. AB - Oral bacteria initiate biofilm formation by attaching to tooth surfaces via an interaction of a lectin-like bacterial protein with carbohydrate chains on the pellicle. This study aimed to find naturally derived lectins that inhibit the initial attachment of a cariogenic bacterial species, Streptococcus mutans (S. mutans), to carbohydrate chains in saliva in vitro. Seventy kinds of lectins were screened for candidate motifs that inhibit the attachment of S. mutans ATCC 25175 to a saliva-coated culture plate. The inhibitory effect of the lectins on attachment of the S. mutans to the plates was quantified by crystal violet staining, and the biofilm was observed under a scanning electron microscope (SEM). Surface plasmon resonance (SPR) analysis was performed to examine the binding of S. mutans to carbohydrate chains and the binding of candidate lectins to carbohydrate chains, respectively. Moreover, binding assay between the biotinylated-lectins and the saliva components was conducted to measure the lectin binding. Lectins recognizing a salivary carbohydrate chain, Galbeta1 3GalNAc, inhibited the binding of S. mutans to the plate. In particular, Agaricus bisporus agglutinin (ABA) markedly inhibited the binding. This inhibition was confirmed by SEM observation. SPR analysis indicated that S. mutans strongly binds to Galbeta1-3GalNAc, and ABA binds to Galbeta1-3GalNAc. Finally, the biotinylated Galbeta1-3GalNAc-binding lectins including ABA demonstrated marked binding to the saliva components. These results suggest that ABA lectin inhibited the attachment of S. mutans to Galbeta1-3GalNAc in saliva and ABA can be useful as a potent inhibitor for initial attachment of oral bacteria and biofilm formation. PMID- 28887742 TI - Efficacy of ganglionated plexi ablation in addition to pulmonary vein isolation for paroxysmal versus persistent atrial fibrillation: a meta-analysis of randomized controlled clinical trials. AB - PURPOSE: Adjunctive ganglionated plexi (GP) ablation may improve success rates for treatment of atrial fibrillation (AF) when combined with pulmonary vein (PV) isolation. Existing meta-analyses on GP ablation have included observational studies and have not incorporated more recent randomized clinical trial data. Moreover, the impact of AF subtype (paroxysmal vs. persistent) on outcomes of GP ablation has not been well established. METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) comparing GP ablation + pulmonary vein (PV) isolation versus PV isolation alone according to the subtype of AF. The primary endpoint was freedom from sustained AF or atrial tachyarrhythmia (AT) after a single procedure. RESULTS: Across four RCTs, 718 patients (358 and 360 that underwent GP ablation + PV isolation [intervention] vs. PV isolation alone [control], respectively) were included in the study. Mean left atrial size and left ventricular ejection fraction were 45.7 mm and 54.8%, respectively. Among paroxysmal AF patients, GP ablation was linked to significantly higher freedom from AT/AF (75.8 vs. 60.0% for the intervention vs. control arms respectively; OR [95% CI]: 2.22 [1.36-3.61], P = 0.001). Among persistent AF patients, GP ablation was associated with a non-significant trend towards higher rates of freedom from AT/AF (54.7 vs. 43.3% for the intervention vs. control arms respectively; OR [95% CI]: 1.55 [0.96-2.52], P = 0.08). In all cases, heterogeneity was found to be low (I 2 of 32% or lower). CONCLUSIONS: Compared to PV isolation alone, GP ablation + PV isolation is associated with better outcomes in patients with paroxysmal AF and without significant structural heart disease. PMID- 28887743 TI - New Colorimetric and Fluorometric Fluoride Ion Probe Based on Anthra[1,9 cd]pyrazol-6(2H)-one. AB - New colorimetric and fluorometric fluoride ion probe, anthra[1,9-cd]pyrazol- 6(2H)-one (1), was synthesized by one-step condensation. The probe 1 shows F- selective color change from colorless to pink and appearance of red fluorescence. The fluorescence quantum yield of free probe 1 in DMSO was calculated to be 0.03. After addition of 15 equiv. of F-, its fluorescence quantum yield can be increased to 0.37. The analytical detection limit for F- was 2.8 * 10- 7 M. 1H NMR analysis and DFT calculation show that the F--induced colorimetric and fluorometric responses of 1 are driven by deprotonation process. Graphical Abstract. PMID- 28887744 TI - MicroRNA-203 suppresses proliferation in liver cancer associated with PIK3CA, p38 MAPK, c-Jun, and GSK3 signaling. AB - Primary liver cancer (hepatocellular carcinoma, HCC) is a leading cause of cancer related deaths, and alternative ways to treat this disease are urgently needed. In recent years, novel approaches to cancer treatment have been based on microRNAs, small non-coding RNA molecules that play a crucial role in cancer progression by regulating gene expression. Overexpression of some microRNAs has shown therapeutic potential, but whether or not this was the case for microRNA 203 (miR-203) in liver cancer was unknown. Therefore, the aim of this study was to investigate the effect of miR-203 overexpression in liver cancer and explore the related mechanisms. Liver cancer cells from the HepG2 and Hep3B cell lines were transfected with either miR-203 mimics or negative control RNA, and then the cells were subjected to cell viability, cell proliferation, and Western blotting assays. As a result of microRNA-203 overexpression, HepG2 and Hep3B cell viability and cell proliferation significantly declined. Furthermore, microRNA 203 overexpression led to inhibited expression of phosphatidylinositol-4,5 bisphosphate 3-kinase (PIK3)/protein kinase B (Akt), c-Jun, and p38 mitogen activated protein kinases (p38 MAPK), and restored glycogen synthase kinase 3 (GSK 3) activity in HepG2 cells. Our results suggest that c-Jun, p38 MAPK, PIK3CA/Akt, and GSK3 signaling involved in the effect of miR-203 on the proliferation of HCC cells. PMID- 28887745 TI - Modeling Human Mortality from All Diseases in the Five Most Populated Countries of the European Union. AB - Age affects mortality from diseases differently than it affects mortality from external causes, such as accidents. Exclusion of the latter leads to the "all diseases" category. The age trajectories of mortality from all diseases are studied in the five most populated countries of the EU, and the shape of these 156 age trajectories is investigated in detail. The arithmetic mean of ages where mortality reaches a minimal value is 8.47 years with a 95% confidence interval of [8.08, 8.85] years. Two simple deterministic models fit the age trajectories on the two sides of the mortality minimum. The inverse relationship is valid in all cases prior to this mortality minimum and death rates exactly decreased to three thousandths of its original size during the first 3000 days. After the mortality minimum, the standard Gompertz model fits the data in 63 cases, and the Gompertz model extended by a small quadratic element fits the remaining 93 cases. This analysis indicates that the exponential increase begins before the age of 15 years and that it is overshadowed by non-biological causes. Therefore, the existence of a mechanism switching that would explain the exponential increase in mortality after the age of 35 years is unlikely. PMID- 28887746 TI - Diagnosis of multiple sclerosis from EEG signals using nonlinear methods. AB - EEG signals have essential and important information about the brain and neural diseases. The main purpose of this study is classifying two groups of healthy volunteers and Multiple Sclerosis (MS) patients using nonlinear features of EEG signals while performing cognitive tasks. EEG signals were recorded when users were doing two different attentional tasks. One of the tasks was based on detecting a desired change in color luminance and the other task was based on detecting a desired change in direction of motion. EEG signals were analyzed in two ways: EEG signals analysis without rhythms decomposition and EEG sub-bands analysis. After recording and preprocessing, time delay embedding method was used for state space reconstruction; embedding parameters were determined for original signals and their sub-bands. Afterwards nonlinear methods were used in feature extraction phase. To reduce the feature dimension, scalar feature selections were done by using T-test and Bhattacharyya criteria. Then, the data were classified using linear support vector machines (SVM) and k-nearest neighbor (KNN) method. The best combination of the criteria and classifiers was determined for each task by comparing performances. For both tasks, the best results were achieved by using T-test criterion and SVM classifier. For the direction-based and the color luminance-based tasks, maximum classification performances were 93.08 and 79.79% respectively which were reached by using optimal set of features. Our results show that the nonlinear dynamic features of EEG signals seem to be useful and effective in MS diseases diagnosis. PMID- 28887747 TI - Reliability and Validity of the Work and Well-Being Inventory (WBI) for Employees. AB - Purpose The purpose of this study is to measure the psychometric properties of the Work and Wellbeing Inventory (WBI) (in Dutch: VAR-2), a screening tool that is used within occupational health care and rehabilitation. Our research question focused on the reliability and validity of this inventory. Methods Over the years seven different samples of workers, patients and sick listed workers varying in size between 89 and 912 participants (total: 2514), were used to measure the test retest reliability, the internal consistency, the construct and concurrent validity, and the criterion and predictive validity. Results The 13 scales displayed good internal consistency and test-retest reliability. The constructive validity of the WBI could clearly be demonstrated in both patients and healthy workers. Confirmative factor analyses revealed a CFI >.90 for all scales. The depression scale predicted future work absenteeism (>6 weeks) because of a common mental disorder in healthy workers. The job strain scale and the illness behavior scale predicted long term absenteeism (>3 months) in workers with short-term absenteeism. The illness behavior scale moderately predicted return to work in rehab patients attending an intensive multidisciplinary program. Conclusions The WBI is a valid and reliable tool for occupational health practitioners to screen for risk factors for prolonged or future sickness absence. With this tool they will have reliable indications for further advice and interventions to restore the work ability. PMID- 28887748 TI - Hypolipidemic Activity of Camellia euphlebia Flower Extract in High-fat-fed Mice. AB - Camellia euphlebia (family, Theaceae) has been used for the prevention and treatment of cardiovascular diseases in Southern China. However, there has been no report on the hypolipidemic activity of Camellia euphlebia flower. This study evaluated the hypolipidemic activity of different preparation of Camellia euphlebia flower extracts using in vivo models. Mice intragastrically administered aqueous extract at 400 mg/kg dose or ethanol extract at 100 and 400 mg/kg doses of Camellia euphlebia flower for 28 days exhibited significant decreases in the levels of total cholesterol, triglycerides and low-density lipoprotein cholesterol, while displaying increased level of high-density lipoprotein cholesterol in the serum. The Camellia euphlebia flower extracts also improved the antioxidant ability of hyperlipidemic mice as well as protecting the animals against liver damage by lowering the level of glutamic-pyruvic transaminase activity. Furthermore, 400 mg/kg ethanol extract effectively down regulated the mRNA levels of fatty acid synthase, 3-hydroxy-3-methylglutaryl CoA reductase and glycerol-3-phosphate acyl transferase, suggesting that Camellia euphlebia flower extract may potentially inhibit lipid accumulation in the liver by regulating the expression of fatty acid synthase, 3-hydroxy-3-methylglutaryl CoA reductase and glycerol-3-phosphate acyl transferase. These results provided support for the potential hypolipidemic activity of Camellia euphlebia flower and could partly explain the basis of using Camellia euphlebia for the treatment of hyperlipidemia. PMID- 28887749 TI - Perceived medication adherence barriers mediating effects between gastrointestinal symptoms and health-related quality of life in pediatric inflammatory bowel disease. AB - OBJECTIVES: The primary objective was to investigate the mediating effects of patient-perceived medication adherence barriers in the relationship between gastrointestinal symptoms and generic health-related quality of life (HRQOL) in adolescents with inflammatory bowel disease (IBD). The secondary objective explored patient health communication and gastrointestinal worry as additional mediators with medication adherence barriers in a serial multiple mediator model. METHODS: The Pediatric Quality of Life InventoryTM Gastrointestinal Symptoms, Medicines, Communication, Gastrointestinal Worry, and Generic Core Scales were completed in a 9-site study by 172 adolescents with IBD. Gastrointestinal Symptoms Scales measuring stomach pain, constipation, or diarrhea and perceived medication adherence barriers were tested for bivariate and multivariate linear associations with HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of perceived medication adherence barriers as an intervening variable between gastrointestinal symptoms and HRQOL. RESULTS: The predictive effects of gastrointestinal symptoms on HRQOL were mediated in part by perceived medication adherence barriers. Patient health communication was a significant additional mediator. In predictive analytics models utilizing multiple regression analyses, demographic variables, gastrointestinal symptoms (stomach pain, constipation, or diarrhea), and perceived medication adherence barriers significantly accounted for 45, 38, and 29 percent of the variance in HRQOL (all Ps < 0.001), respectively, demonstrating large effect sizes. CONCLUSIONS: Perceived medication adherence barriers explain in part the effects of gastrointestinal symptoms on HRQOL in adolescents with IBD. Patient health communication to healthcare providers and significant others further explain the mechanism in the relationship between gastrointestinal symptoms, perceived medication adherence barriers, and HRQOL. PMID- 28887751 TI - HIV Prevention Among Women Who Use Substances And Report Sex Work: Risk Groups Identified Among South African Women. AB - : This cross-sectional study presents baseline data from women (n = 641) in a community-based randomized trial in Pretoria, South Africa. Women were eligible if they reported recent alcohol or other drug (AOD) use and condomless sex. Latent class analyses were conducted separately for those who reported sex work and those who did not. Among those who reported sex work, a Risky Sex class (n = 72, 28%) and Low Sexual Risk class (n = 190, 73%) emerged. Those in the Risky Sex class were more likely to report that their last episode of sexual intercourse was with their boyfriend (vs. a client/other partner) compared with the Low Sexual Risk class (p < 0.001). Among participants who did not report sex work, a Drug-Using, Violence-Exposed, and Impaired Sex class (n = 53; 14%) and Risky Sex and Moderate Drinking class (n = 326; 86%) emerged. The findings suggest that interventions for women who engage in sex work should promote safer sexual behavior and empowerment with main partners. Women who use AODs, experience physical or sexual violence, and have impaired sex may be a key population at risk for HIV and should be considered for tailored behavioral interventions in conjunction with South Africa's plan to disseminate HIV prevention methods to vulnerable women. TRIAL REGISTRATION: ClinicalTrials.gov registration NCT01497405. PMID- 28887750 TI - Direct-Acting Antiviral Therapy for Chronic HCV Infection Results in Liver Stiffness Regression Over 12 Months Post-treatment. AB - BACKGROUND: Liver fibrosis stage determines risk of morbidity and mortality from chronic hepatitis C virus (HCV) infection. Prior data have shown long-term reversal of liver fibrosis, measured by vibration-controlled transient elastography (VCTE), in patients successfully treated with interferon-based therapies. AIM: Our study sought to determine the effect of treatment with modern HCV direct-acting antiviral (DAA) therapy on noninvasive liver fibrosis measurements. METHODS: A total of 70 patients had VCTE-based liver stiffness measurement (LSM) taken before treatment, directly after treatment completion, and at least 12 months after completion of DAA therapy. Our primary outcome was a >30% improvement in VCTE score at the end of follow-up, relative to baseline. RESULTS: The sustained virologic response rate in our cohort was 95.7%. In our cohort, 34 (48.6%) met the primary outcome. Those who had baseline elevated alanine aminotransferase (OR 3.27; 95% CI 1.13-9.47) and genotype 1 (OR 14.63; 95% CI 1.70-125.83) had higher odds of meeting that outcome, and this remained significant after adjusting for age, baseline body mass index, gender, baseline elevated alkaline phosphatase levels, treatment experience, liver transplant status, smoking, and baseline liver stiffness. CONCLUSION: Treatment of chronic HCV with modern DAA therapy was associated with a significant improvement in LSM by VCTE measurement, suggesting possible early improvement in liver fibrosis along with resolution of inflammation over the first year after treatment completion. PMID- 28887752 TI - Comparison of Antipyretic Efficacy of Intravenous (IV) Acetaminophen versus Oral (PO) Acetaminophen in the Management of Fever in Children. AB - OBJECTIVE: To assess the dynamics of the onset of antipyretic efficacy of intravenous (IV) acetaminophen vs. oral (PO) acetaminophen in the management of fever in children. METHODS: This observational single-dose study was conducted at Department of Pedriatrics, Army Hospital (Research and Referral), a multispecialty tertiary care center in New Delhi in fever patients to assess the antipyretic efficacy of IV acetaminophen 15 mg/kg/dose vs. PO acetaminophen 15 mg/kg/dose over 6 h. Subjects were randomly assigned to receive either IV acetaminophen (n = 200) or PO acetaminophen (n = 200). RESULTS: Demographics and baseline characteristics were similar between the two groups and were normally distributed. Allergic reaction was found in 7 (3.5%) patients in IV acetaminophen group and was absent in PO acetaminophen group. Onset of constipation and dry mouth was found in 8 patients (4%) in IV acetaminophen group and was absent in PO acetaminophen group. Additional dose was required in 6 patients (3%) in intravenous acetaminophen group and 10 patients (5%) in oral acetaminophen group respectively. Statistically significant differences in the rate of fall in temperature through 180 min were observed in favor of the IV acetaminophen group when compared to those receiving PO acetaminophen. CONCLUSIONS: A single dose of intravenous acetaminophen is safe and effective in reducing fever where patients are unable to tolerate oral administration or when rapid reduction of temperature is desirable. PMID- 28887753 TI - Can an Infusion of Federal Funds Result in Sustainable Projects? An Evaluation of Suicide Prevention Programs. AB - Our study evaluated the sustainability of programs in early cohorts of the Garrett Lee Smith (GLS) Memorial Act suicide prevention initiative, a major source of federal funding for youth suicide prevention among states, tribes, and institutions of higher education. We sought to: (1) determine whether suicide prevention activities initiated with federal support continued after funding ended, and (2) identify factors associated with sustainment. Thirty-three sites between 1 and 4 years beyond the end of their GLS grant participated in a retrospective online survey assessing their level of suicide prevention activity 1 year before, during (during-GLS), and 1 year after funding (after-GLS). We found that, on average, sites experienced a 6% decrease in their overall level of activity from during- to after-GLS. Twenty-two (67% of responding sites) exhibited either an increase in activity level or no more than a 10% decline from during- to after-GLS periods. After-GLS scores for the 11 remaining sites declined between 11 and 30% from their during-GLS levels. We conducted semi structured follow-up interviews with 13 sites that successfully continued their activities to explore factors associated with sustainability. Our findings indicate that program actions in the during-GLS period associated with sustainability included: maintaining a sustainability mindset, developing and nurturing partnerships and relationships, embedding services in parent organizations, pursuing new and diversified funding, and implementing cost reduction efficiencies. Actions in the after-GLS period associated with sustainability included: obtaining funding from other sources, reconfiguring, and maintaining continuous leadership. PMID- 28887754 TI - Lichen-derived caperatic acid and physodic acid inhibit Wnt signaling in colorectal cancer cells. AB - Lichens are a source of secondary metabolites which possess important biological activities, including antioxidant, antibacterial, anti-inflammatory, and cytotoxic effects. The anticancer activity of lichens was shown in many types of tumors, including colorectal cancers (CRC). Several studies revealed that the application of lichen extracts diminished the proliferation of CRC cells and induced apoptosis. Colon carcinogenesis is associated with aberrations in Wnt signaling. Elevated transcriptional activity of beta-catenin induces cell survival, proliferation, and migration. Thus, the inhibition of Wnt signaling is a promising therapeutic strategy in colorectal cancer. The aim of this study was the evaluation of the effects of lichen-derived depsides (atranorin, lecanoric acid, squamatic acid) and depsidones (physodic acid, salazinic acid) and a poly carboxylic fatty acid-caperatic acid, on Wnt signaling in HCT116 and DLD-1 colorectal cancer cell lines. HCT116 cells were more sensitive to the modulatory effects of the compounds. PKF118-310, which was used as a reference beta-catenin inhibitor, dose-dependently reduced the expression of the classical beta-catenin target gene-Axin2 in both cell lines. Lecanoric acid slightly reduced Axin2 expression in HCT116 cells while caperatic acid tended to reduce Axin2 expression in both cell lines. Physodic acid much more potently decreased Axin2 expression in HCT116 cells than in DLD-1 cells. Physodic acid and caperatic acid also diminished the expression of survivin and MMP7 in a cell line and time-dependent manner. None of the compounds affected the nuclear translocation of beta-catenin. This is the first report showing the ability of caperatic acid and physodic acid to modulate beta-catenin-dependent transcription. PMID- 28887756 TI - Development of the Pediatric Neuro-Oncology Rating of Treatment Intensity (PNORTI). AB - Measures of treatment intensity for childhood cancer are needed in research in order to control for variability in treatments. Existing measures of treatment intensity for childhood cancers do not reflect the complexities of treatment protocols for central nervous system (CNS) tumors. This paper describes the development of the Pediatric Neuro-Oncology Rating of Treatment Intensity (PNORTI). PNORTI development occurred in three phases. Phase 1: five experts in pediatric neuro-oncology created a 5-point scale of treatment intensity and 42 pediatric neuro-oncology providers completed a three-part online questionnaire to evaluate the classification system and apply the rating system to 16 sample patients. Validity was determined by respondents classifying therapy modalities into intensity levels. Inter-rater reliability was calculated from ratings of the 16 sample patients. Phase 2: three experts revised the PNORTI based on survey results and 18 pediatric neuro-oncology providers evaluated the classification system. Phase 3: ten experts in pediatric neuro-oncology refined and finalized the PNORTI and rated 10 sample patients using the PNORTI. Agreement between median ratings of the survey respondents and criterion raters for chemotherapy intensity (r's = .82 and 1.0) and overall treatment intensity level (r's = .91 and .94) were high in Phases 1 and 2. Inter-rater reliability also was very high when using the PNORTI to classify the 16 sample patients in Phase 1 (median agreement of r = .93 and rICC = .99) and the 10 sample patients in Phase 3 (median agreement of r = .92 and rICC = .98). The PNORTI is a valid and reliable method for classifying the intensity of different treatment modalities used in pediatric neuro-oncology. PMID- 28887757 TI - Survival in idursulfase-treated and untreated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS). AB - Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a life limiting, multisystemic disease with varying presentation and severity. Enzyme replacement therapy with intravenous idursulfase (EC 3.1.6.13) has been available since 2006. Data from the Hunter Outcome Survey (July 2016) were used to compare survival in idursulfase-treated (n = 800) and untreated (n = 95) male patients followed prospectively in this multinational, observational registry. Median age at symptom onset was similar for the treated and untreated groups (1.6 and 1.5 years, respectively), as was median age at diagnosis (3.3 and 3.2 years) and the proportion of patients with cognitive impairment (58.0%; 57.9%). The proportion of idursulfase-treated patients differed according to geographical region. Overall, 124/800 (15.5%) treated and 28/95 (29.5%) untreated patients had died. Respiratory failure was the most common cause of death (treated, 43/124 [34.7%]; untreated, 10/28 [35.7%]). Median survival (95% confidence interval [CI]) was 33.0 (30.4, 38.4) years in treated patients and 21.2 (16.1, 31.5) years in untreated patients; median follow-up time from birth to death or last visit was 13.0 and 15.1 years, respectively. A Cox model adjusted for treatment status, cognitive impairment, region and age at diagnosis indicated a 54% lower risk of death in treated compared with untreated patients: hazard ratio (HR), 0.46 (95% CI: 0.29, 0.72). Patients with cognitive impairment had nearly a fivefold higher risk of death than those without (HR, 4.84 [3.13, 7.47]). This analysis in a large population of patients with MPS II indicates for the first time that idursulfase treatment is associated with increased survival. PMID- 28887758 TI - Perceived Sodium Reduction Barriers Among Patients with Chronic Kidney Disease: Which Barriers Are Important and Which Patients Experience Barriers? AB - PURPOSE: The purposes of this study were to assess the importance of perceived sodium reduction barriers among patients with chronic kidney disease (CKD) and identify associated sociodemographic, clinical, and psychosocial factors. METHOD: A total of 156 patients with CKD completed a questionnaire assessing sodium reduction barriers (18 self-formulated items), depressive symptoms (Beck Depression Inventory), perceived autonomy support (Modified Health Care Climate Questionnaire), and self-efficacy (Partners in Health Questionnaire). Factor analysis was used to identify barrier domains. Correlation coefficients were computed to examine relationships between barrier domains and patient characteristics. RESULTS: Nine barrier domains were identified. Barriers perceived as important were as follows: high sodium content in products, lack of sodium feedback, lack of goal setting and discussing strategies for sodium reduction, and not experiencing CKD-related symptoms (mean scores > 3.0 on 5 point scales, ranging from 1 'no barrier' to 5 'very important barrier'). Other barriers (knowledge, attitude, coping skills when eating out, and professional support) were rated as moderately important (rated around midpoint), and the barrier 'intrinsic motivation' was rated as somewhat important (mean score = 1.9). Sodium reduction barrier domains were not associated with gender and kidney function, but were associated with age, level of education, number of comorbidities, perceived autonomy support, depressive symptoms, and self-efficacy (range r = 0.17-0.35). Patients with lower self-efficacy and perceived autonomy support scores experienced most sodium reduction barriers. CONCLUSION: Patients with CKD experience multiple important sodium reduction barriers and could benefit from support strategies that target various sodium reduction barriers and strengthen beliefs regarding self-efficacy and autonomy support. Additionally, environmental interventions should be implemented to reduce sodium levels in processed foods. PMID- 28887755 TI - Prokinetics in the Management of Functional Gastrointestinal Disorders. AB - PURPOSE OF REVIEW: The goal of this review is to review the current status of prokinetics and to place it in historical context. Impaired motility and thus propulsion have long been thought to play important roles in the pathogenesis of a number of gastrointestinal disorders including gastroesophageal reflux disease (GERD), gastroparesis, chronic idiopathic pseudo-obstruction, and constipation. Historically, disordered motility was also thought to contribute to a number of functional gastrointestinal disorders such as functional dyspepsia (FD) and irritable bowel syndrome (IBS). RECENT FINDINGS: As we learn more of the pathophysiology of FD, IBS, GERD, constipation, and gastroparesis, the limitations of a therapeutic strategy based on the stimulation of motility (i.e., the use of a prokinetic) have become apparent and the disappointments of the past explained. The development of prokinetic drugs has also been hampered by the non selective nature of many of the agents studied to date which resulted in some unexpected side effects. There is still an unmet need for an effective and safe prokinetic, but drug development in this area must be mindful of the challenges of the area and the need for selectivity for a given target receptor. PMID- 28887759 TI - Factors Contributing to Chronic Ankle Instability: A Systematic Review and Meta Analysis of Systematic Reviews. AB - BACKGROUND: Many factors are thought to contribute to chronic ankle instability (CAI). Multiple systematic reviews have synthesised the available evidence to identify the primary contributing factors. However, readers are now faced with several systematic reviews that present conflicting findings. OBJECTIVE: The aim of this systematic review and meta-analysis was to establish the statistical significance and effect size of primary factors contributing to CAI and to identify likely reasons for inconsistencies in the literature. METHODS: Relevant health databases were searched: CINAHL, MEDLINE, PubMed, Scopus and SPORTDiscus. Systematic reviews were included if they answered a focused research question, clearly defined the search strategy criteria and study selection/inclusion and completed a comprehensive search of the literature. Included reviews needed to be published in a peer-reviewed journal and needed to review observational studies of factors and/or characteristics of persons with CAI, with or without meta analysis. There was no language restriction. Studies using a non-systematic review methodology (e.g. primary studies and narrative reviews) were excluded. Methodological quality of systematic reviews was assessed using the modified R AMSTAR tool. Meta-analysis on included primary studies was performed. RESULTS: Only 17% of primary studies measured a clearly defined CAI population. There is strong evidence to support the contribution of dynamic balance, peroneal reaction time and eversion strength deficits and moderate evidence for proprioception and static balance deficits to non-specific ankle instability. CONCLUSIONS: Evidence from previous systematic reviews does not accurately reflect the CAI population. For treatment of non-specific ankle instability, clinicians should focus on dynamic balance, reaction time and strength deficits; however, these findings may not be translated to the CAI population. Research should be updated with an adequately controlled CAI population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2016, CRD42016032592. PMID- 28887760 TI - Sialadenoma Papilliferum: Analysis of Seven New Cases and Review of the Literature. AB - Sialadenoma papilliferum (SP) is a rare benign salivary gland neoplasm that comprises from 0.4 to 1.2% of all salivary gland tumors. The tumor is so named because of its microscopic resemblance to the syringocystadenoma papilliferum, an uncommon benign tumor of sweat gland origin. The purpose of this paper is to report the clinical and microscopic features of seven new cases of SP and combine them with cases previously reported in the English language literature to further define this unusual lesion. Combining our cases with acceptable cases from the literature, the palate (especially the hard palate) was the most common site, with 80% of the cases occurring in this location. Other locations in decreasing order were buccal mucosa, upper lip, retromolar pad, and parotid gland. Age at diagnosis ranged from 18 to 87 years with a peak in the 6th decade and an average age of 56.4 years. Microscopically, the lesions demonstrated a papillary surface morphology, and the papillary projections varied from long and pointed to short and blunted. The supporting connective tissue contained a variable number of convoluted ductal structures, which often fused with the overlying surface epithelium. The ductal structures exhibited papillary infoldings and were lined by a double layer of epithelium consisting of basal cell layer and a luminal layer of cuboidal-to-columnar ductal cells. Immunohistochemical reactivity with p63 and p40 indicated that the basal cell layer was comprised predominantly of neoplastic myoepithelial cells. The luminal cells were immunoreactive with epithelial membrane antigen characteristic of ductal cell differentiation. Conservative surgical treatment was accomplished in most cases and appears to be adequate treatment as only two recurrences were documented. Several case reports of purported malignant transformation in SP have been reported in the literature, but in our opinion, there is insufficient evidence in the publications to unequivocally determine whether any of the malignancies truly originated within a pre-existing SP. PMID- 28887761 TI - Textural features and SUV-based variables assessed by dual time point 18F-FDG PET/CT in locally advanced breast cancer. AB - AIM: To study the influence of dual time point 18F-FDG PET/CT in textural features and SUV-based variables and their relation among them. METHODS: Fifty six patients with locally advanced breast cancer (LABC) were prospectively included. All of them underwent a standard 18F-FDG PET/CT (PET-1) and a delayed acquisition (PET-2). After segmentation, SUV variables (SUVmax, SUVmean, and SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained. Eighteen three-dimensional (3D) textural measures were computed including: run-length matrices (RLM) features, co-occurrence matrices (CM) features, and energies. Differences between all PET-derived variables obtained in PET-1 and PET-2 were studied. RESULTS: Significant differences were found between the SUV-based parameters and MTV obtained in the dual time point PET/CT, with higher values of SUV-based variables and lower MTV in the PET-2 with respect to the PET-1. In relation with the textural parameters obtained in dual time point acquisition, significant differences were found for the short run emphasis, low gray-level run emphasis, short run high gray-level emphasis, run percentage, long run emphasis, gray-level non-uniformity, homogeneity, and dissimilarity. Textural variables showed relations with MTV and TLG. CONCLUSION: Significant differences of textural features were found in dual time point 18F-FDG PET/CT. Thus, a dynamic behavior of metabolic characteristics should be expected, with higher heterogeneity in delayed PET acquisition compared with the standard PET. A greater heterogeneity was found in bigger tumors. PMID- 28887762 TI - Evolution of the Staging System in Breast Cancer. PMID- 28887763 TI - Population-level intervention and information collection in dynamic healthcare policy. AB - We develop a general framework for optimal health policy design in a dynamic setting. We consider a hypothetical medical intervention for a cohort of patients where one parameter varies across cohorts with imperfectly observable linear dynamics. We seek to identify the optimal time to change the current health intervention policy and the optimal time to collect decision-relevant information. We formulate this problem as a discrete-time, infinite-horizon Markov decision process and we establish structural properties in terms of first and second-order monotonicity. We demonstrate that it is generally optimal to delay information acquisition until an effect on decisions is sufficiently likely. We apply this framework to the evaluation of hepatitis C virus (HCV) screening in the general population determining which birth cohorts to screen for HCV and when to collect information about HCV prevalence. PMID- 28887764 TI - Humanitarianism in surgery. AB - PURPOSE: Humanitarianism is by definition a moral of kindness, benevolence and sympathy extended to all human beings. In our view as surgeons working in underserved countries, humanitarianism means performing the best operation in the best possible circumstances with high income country (HIC) results and training in-country surgeons to do the same. Hernia Repair for the Underserved (HRFU), a not for profit organization, is developing a long term public health initiative for hernia surgery in Western Hemisphere countries. We report the progress of HRFUs methods to render humanitarian care. METHODS: In a collaborative effort, Creighton University and the Institute for Latin American Concern developed an outpatient surgery site for hernia surgery in Santiago, Dominican Republic. Based on this experience, we developed a sustainable care model by recruiting American and European Hernia Society expert surgeons, staff members they recommended, building relationships with local and industry partners, and selecting local surgeons to be trained in mesh hernioplasty. HRFU then extended the care model to other Western Hemisphere countries. RESULTS: Between 2004 and 2015, the HRFU elective hernia morbidity and mortality rates for 2052 hernia operations were 0.7 and 0%, respectively. This is consistent with outcomes from HICs and confirms the feasibility of a public health initiative based on the principles of the Preferential Option for the Poor. CONCLUSIONS: HRFU has recorded HIC morbidity and mortality rates for hernia surgery in low and middle income countries and has initiated a new surgical training model for sustainability of effect. PMID- 28887765 TI - Heartbeat detection in multimodal physiological signals using signal quality assessment based on sample entropy. AB - This paper presents a novel technique to identify heartbeats in multimodal data using electrocardiogram (ECG) and arterial blood pressure (ABP) signals. Multiple physiological signals such as ECG, ABP, and Respiration are often recorded in parallel from the activity of heart. These signals generally possess related information as they are generated by the same physical system. The ECG and ABP correspond to the same phenomenon of contraction and relaxation activity of heart. Multiple signals acquired from various sensors are generally processed independently, thus discarding the information from other measurements. In the estimation of heart rate and heart rate variability, the R peaks are generally identified from ECG signal. Efficient detection of R-peaks in electrocardiogram (ECG) is a key component in the estimation of clinically relevant parameters from ECG. However, when the signal is severely affected by undesired artifacts, this becomes a challenging task. Sometimes in clinical environment, other physiological signals reflecting the cardiac activity such as ABP signal are also acquired simultaneously. Under the availability of such multimodal signals, the accuracy of R peak detection methods can be improved using sensor-fusion techniques. In the proposed method, the sample entropy (SampEn) is used as a metric for assessing the noise content in the physiological signal and the R peaks in ECG and the systolic peaks in ABP signals are fused together to enhance the efficiency of heartbeat detection. The proposed method was evaluated on the 100 records from the computing in cardiology challenge 2014 training data set. The performance parameters are: sensitivity (Se) and positive predictivity (PPV). The unimodal R peaks detector achieved: Se gross = 99.40%, PPV gross = 99.29%, Se average = 99.37%, PPV average = 99.29%. Similarly unimodal BP delineator achieved Se gross = 99.93%, PPV gross = 99.99%, Se average = 99.93%, PPV average = 99.99% whereas, the proposed multimodal beat detector achieved: Se gross = 99.65%, PPV gross = 99.91%, Se average = 99.68%, PPV average = 99.91%. PMID- 28887766 TI - Short-term effects of passive mobilization on the sublingual microcirculation and on the systemic circulation in patients with septic shock. AB - BACKGROUND: Active mobilization is not possible in patients under deep sedation and unable to follow commands. In this scenario, passive therapy is an interesting alternative. However, in patients with septic shock, passive mobilization may have risks related to increased oxygen consumption. Our objective was to evaluate the impact of passive mobilization on sublingual microcirculation and systemic hemodynamics in patients with septic shock. METHODS: We included patients who were older than 18 years, who presented with septic shock, and who were under sedation and mechanical ventilation. Passive exercise was applied for 20 min with 30 repetitions per minute. Systemic hemodynamic and microcirculatory variables were compared before (T0) and up to 10 min after (T1) passive exercise. p values <0.05 were considered significant. RESULTS: We included 35 patients (median age [IQR 25-75%]: 68 [49.0-78.0] years; mean (+/-SD) Simplified Acute Physiologic Score (SAPS) 3 score: 66.7 +/- 12.1; median [IQR 25-75%] Sequential Organ Failure Assessment (SOFA) score: 9 [7.0 12.0]). After passive mobilization, there was a slight but significant increase in proportion of perfused vessels (PPV) (T0 [IQR 25-75%]: 78.2 [70.9-81.9%]; T1 [IQR 25-75%]: 80.0 [75.2-85.1] %; p = 0.029), without any change in other microcirculatory variables. There was a reduction in heart rate (HR) (T0 (mean +/ SD): 95.6 +/- 22.0 bpm; T1 (mean +/- SD): 93.8 +/- 22.0 bpm; p < 0.040) and body temperature (T0 (mean +/- SD): 36.9 +/- 1.1 degrees C; T1 (mean +/- SD): 36.7 +/ 1.2 degrees C; p < 0.002) with no change in other systemic hemodynamic variables. There was no significant correlation between PPV variation and HR (r = -0.010, p = 0.955), cardiac index (r = 0.218, p = 0.215) or mean arterial pressure (r = 0.276, p = 0.109) variation. CONCLUSIONS: In patients with septic shock after the initial phase of hemodynamic resuscitation, passive exercise is not associated with relevant changes in sublingual microcirculation or systemic hemodynamics. PMID- 28887768 TI - Population Model of Quorum Sensing with Multiple Parallel Pathways. AB - Quorum sensing (QS) is a bacterial communication mechanism that uses signal receptor binding to regulate gene expression based on cell density, resulting in group behaviors such as biofilm formation, bioluminescence and stress response. In certain bacterial species such as Vibrio harveyi, several parallel QS signaling pathways drive a single phosphorylation-dephosphorylation cycle, which in turn regulates QS target genes. In this paper, we investigate the possible role of parallel signaling pathways by developing a mathematical model of QS in V. harveyi at both the single-cell and population levels. First we explore how signal integration may be achieved at the single-cell level, and how different model parameters influence the process. We then consider two examples of signal integration at the population level: a one-population model responding to two environmental cues (cell density and mass transfer), and a two-population model with distinct cell densities. In each case, we use contraction analysis to reduce the population model to an effective single-cell model. PMID- 28887767 TI - Management of Spontaneous Intracerebral Hemorrhage. AB - PURPOSE OF REVIEW: We review the current evidence for medical and surgical treatments of spontaneous intracerebral hemorrhage (ICH). RECENT FINDINGS: Therapy with hemostatic agents (e.g. factor VIIa and tranexamic acid) if started early after bleeding onset may reduce hematoma expansion, but their clinical effectiveness has not been shown. Rapid anticoagulation reversal with prothrombin concentrates (PCC) plus vitamin K is the first choice in vitamin K antagonist related ICH. In ICH related to dabigatran, anticoagulation can be rapidly reversed with idarucizumab. PCC are recommended for ICH related to FXa inhibitors, whereas specific reversal agents are not yet approved. While awaiting ongoing trials studying minimally invasive approaches or hemicraniectomy, the role of surgery in ICH remains to be defined. Therapies targeting downstream molecular cascades in order to prevent secondary neuronal damage are promising, but the complexity and multi-phased nature of ICH pathophysiology is challenging. Finally, in addition to blood pressure control, antithrombotic prevention after ICH has to consider the risk of recurrent bleeding as well as the risk of ischemic events. Treatment of acute ICH remains challenging, and many promising interventions for acute ICH await further evidence from trials. PMID- 28887769 TI - alpha-Synuclein Interacts with Lipoproteins in Plasma. AB - Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by dopaminergic neural cell death in the substantia nigra of the brain and alpha-synuclein (alpha-syn) accumulation in Lewy bodies. alpha-Syn can be detected in blood and is a potential biomarker for PD. It has been shown recently that alpha-syn can pass through the blood-brain barrier (BBB), but the mechanism is not yet understood. We hypothesized that alpha-syn could interact with lipoproteins, and in association with these particles, could pass through the BBB. Here, we show that apoE, apoJ, and apoA1, but not apoB, were co immunocaptured along with alpha-syn from human blood plasma, suggesting that alpha-syn is associated with high-density lipoproteins (HDL). This association was also supported by experiments involving western blotting of plasma fractions separated by gel filtration, which revealed that alpha-syn was found in fractions identified as HDL. Interestingly, we could also detect alpha-syn and ApoJ in the intermediate fraction between HDL and LDL, referred to as lipoprotein (a) (Lp(a)), which has an important role in cholesterol metabolism. Overall, the results provide best support for the hypothesis that alpha-syn interacts with HDL, and this has potential implications for transport of alpha-syn from the brain to peripheral blood, across the BBB. PMID- 28887771 TI - Antimalarial drugs available in the city Cabinda (Angola) in 2016. AB - Antimalarial drug offerings in the city of Cabinda (Angola) were assessed during the fourth quarter of 2016. Combinations of artemisinin with other effective antimalarial drugs were available free of charge in public health centres, theoretically after a biological validation of the diagnosis of a malaria attack. Private pharmacies offered many products without medical prescription, most of them being ACT (Artemisinin Combined Therapy) but some being Artemisia derivatives alone. The cost of treatment for a presumptive attack varied from 14 to 44 ?. The diversity of antimalarial drugs and of their dosages makes it difficult for sellers to provide appropriate recommendations for their use. In the informal sector, sellers offered the same products at similar prices as the formal sector but with the option of purchasing only a part of the treatment. Analgesics and herbal medicine not validated as antimalarial drugs were also available. PMID- 28887770 TI - Optimization of 1H decoupling eliminates sideband artifacts in 3D TROSY-based triple resonance experiments. AB - TROSY-based triple resonance experiments are essential for protein backbone assignment of large biomolecular systems by solution NMR spectroscopy. In a survey of the current Bruker pulse sequence library for TROSY-based experiments we found that several sequences were plagued by artifacts that affect spectral quality and hamper data analysis. Specifically, these experiments produce sidebands in the 13C(t 1) dimension with inverted phase corresponding to 1HN resonance frequencies, with approximately 5% intensity of the parent 13C crosspeaks. These artifacts originate from the modulation of the 1HN frequency onto the resonance frequency of 13Calpha and/or 13Cbeta and are due to 180 degrees pulses imperfections used for 1H decoupling during the 13C(t 1) evolution period. These sidebands can become severe for CAi, CAi-1 and/or CBi, CBi-1 correlation experiments such as TROSY-HNCACB. Here, we implement three alternative decoupling strategies that suppress these artifacts and, depending on the scheme employed, boost the sensitivity up to 14% on Bruker spectrometers. A class of comparable Agilent/Varian pulse sequences that use WALTZ16 1H decoupling can also be improved by this method resulting in up to 60-80% increase in sensitivity. PMID- 28887772 TI - Fortuitous Detection of cmy-2 and dha-1 from ESBL-producing Escherichia coli in Senegal. AB - Cephalosporinases, which are naturally present in some enterobacterial species, can be mobilized by transposons, migrate to plasmids, and spread into other species such as Escherichia coli. The aim of this study was to characterize genes responsible for the production of extended-spectrum beta-lactamases (ESBL) in E. coli isolates from urinary origin isolated in two hospitals in Senegal. Thus, a fortuitous discovery of plasmidic cephalosporinase in two isolates was noted. One of the isolates produced dha-1 associated with ESBL CTX-M-14, the other produced cmy-2, ESBL CTXM-15, tem-1 penicillinase, and oxa-1. This confirms the circulation of multidrug-resistant bacteria producing plasmidic cephalosporinase in Senegal. However, a large study is needed to better understand the prevalence and the nature of the genes involved. PMID- 28887773 TI - Percutaneous embolization of a colonic fistula using n-butyl-2 cyanoacrylate (Histoacryl(r)). PMID- 28887774 TI - Social Inequality, Life Course Transitions, and Adolescent Development: Introduction to the Special Issue. AB - Conceptualizing adolescent development within a life course framework that links the perspectives on social inequality and early life course transitions has largely been absent from previous research. Such a conceptual model is needed, however, in order to understand how the individual development of agentic capacities and the opportunities and constraints inherent in the social contexts of growing up interact and jointly affect young people's trajectories across the adolescent life stage. We present the corner stones of the conceptual "trident" of social inequality, life course transitions, and adolescent development and identify three major themes the eleven contributions to this special issue address within this conceptual framework: social and individual prerequisites and consequences of coping with life course transitions; intergenerational transmission belts of social inequality; socialization of agency in and outside the family home. These three themes exemplify the great analytical potential inherent in this framework. PMID- 28887775 TI - Imaging cardiac innervation in amyloidosis. AB - Cardiac amyloidosis is a form of restrictive cardiomyopathy resulting in heart failure and potential risk on arrhythmia, due to amyloid infiltration of the nerve conduction system and the myocardial tissue. The prognosis in this progressive disease is poor, probably due the development of cardiac arrhythmias. Early detection of cardiac sympathetic innervation disturbances has become of major clinical interest, because its occurrence and severity limits the choice of treatment. The use of iodine-123 labelled metaiodobenzylguanidine ([I-123]MIBG), a chemical modified analogue of norepinephrine, is well established in patients with heart failure and plays an important role in evaluation of sympathetic innervation in cardiac amyloidosis. [I-123]MIBG is stored in vesicles in the sympathetic nerve terminals and is not catabolized like norepinephrine. Decreased heart-to-mediastinum ratios on late planar images and increased wash-out rates indicate cardiac sympathetic denervation and are associated with poor prognosis. Single photon emission computed tomography provides additional information and has advantages for evaluating abnormalities in regional distribution in the myocardium. [I-123]MIBG is mainly useful in patients with hereditary and wild type ATTR cardiac amyloidosis, not in AA and AL amyloidosis. The potential role of positron emission tomography for cardiac sympathetic innervation in amyloidosis has not yet been identified. PMID- 28887776 TI - Does hypodontia of primary canines result in delayed dental development? PMID- 28887777 TI - Global RNA association with the transcriptionally active chromosome of chloroplasts. AB - KEY MESSAGE: Processed chloroplast RNAs are co-enriched with preparations of the chloroplast transcriptionally active chromosome. Chloroplast genomes are organized as a polyploid DNA-protein structure called the nucleoid. Transcriptionally active chloroplast DNA together with tightly bound protein factors can be purified by gel filtration as a functional entity called the transcriptionally active chromosome (TAC). Previous proteomics analyses of nucleoids and of TACs demonstrated a considerable overlap in protein composition including RNA binding proteins. Therefore the RNA content of TAC preparations from Nicotiana tabacum was determined using whole genome tiling arrays. A large number of chloroplast RNAs was found to be associated with the TAC. The pattern of RNAs attached to the TAC consists of RNAs produced by different chloroplast RNA polymerases and differs from the pattern of RNA found in input controls. An analysis of RNA splicing and RNA editing of selected RNA species demonstrated that TAC-associated RNAs are processed to a similar extent as the RNA in input controls. Thus, TAC fractions contain a specific subset of the processed chloroplast transcriptome. PMID- 28887779 TI - Assessment of flexible bronchoscopic intubation through the AuraGainTM laryngeal mask versus a slit Guedel tube. PMID- 28887778 TI - Mapping sites of reef vulnerability along lagoons of Lakshadweep archipelago, Indian Ocean. AB - Tissue degradation and mediated mortality have turned into a major threat to coral reef systems around the world. Detailed knowledge on interactions of prime biological factors that mediate tissue loss and mortality is of paramount importance in understanding the prevailing reef health scenario and to trial management actions. In the present study, a series of benthic surveys were conducted in Lakshadweep islands to understand the interactions of plausible biological factors in causing tissue loss and mediated mortality. Interactions of biological scenarios were prioritized using hierarchical regression analysis. The hierarchical regression model analysis revealed black band disease (beta = 0.59; p < 0.001) and algal interactions (beta = 0.48; p < 0.001) as the major factors responsible for tissue-loss-mediated coral mortality in the region. The observations from the hierarchical analysis were used to derive vulnerability maps based on weighted overlay analysis. The vulnerability mapping revealed that lagoon of Kalpeni Island is very highly vulnerable to coral degradation with 683.5 ha followed by Kavaratti (70.2 ha), Bangaram (70 ha), and Amini (47 ha). Chethalath and Agatti lagoons were inferred as low vulnerable sites where coral reefs can sustain. The vulnerability maps derived can be used as a baseline observation to identify areas of very high vulnerability and specific stressor prevalent in those sites. This will be helpful in defining stressor and site specific management plans. PMID- 28887780 TI - Skin Cancer-Sun Knowledge and Sun Protection Behaviors of Liver Transplant Recipients in Turkey. AB - The aim of this study was to compare liver transplant recipients (LTRs) with the general population regarding their knowledge of skin cancer, sun health, sun protection behaviors, and affecting factors. This cross-sectional study was conducted in Turkey between March 2016 and September 2016 with 104 LTRs and 100 participants from the general population group (GPG). The mean age of the LTRs was 53.2 +/- 11.8 and that of the GPG was 42.7 +/- 14.5. The LTRs' skin cancer and sun knowledge were significantly lower than in the GPG, but there was no difference between the two groups in terms of their sun protection behavior scores. The most commonly used sun protection behaviors of LTRs were not being outside and not sunbathing between 10 a.m. and 4 p.m., wearing clothing that covers the skin, and avoiding the solarium. Behaviors commonly practiced by the GPG were wearing sunglasses, wearing sunscreen with a sun protection factor of 15 or higher before going outside, wearing sunscreen at the beach, while swimming or doing physical activity outside, and reapplying it every 2 h. Results of our study will contribute to the development of education and training programs for LTRs on skin cancer. The results also demonstrated the importance of practicing adequate sun protection behaviors which will certainly impact their future health. PMID- 28887781 TI - Antiapoptotic effects of caspase inhibitors on H2O2-treated lung cancer cells concerning oxidative stress and GSH. AB - Exogenous hydrogen peroxide (H2O2) induces oxidative stress and apoptosis in cancer cells. This study evaluated the antiapoptotic effects of pan-caspase and caspase-3, -8, or -9 inhibitors on H2O2-treated Calu-6 and A549 lung cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH). Treatment with 50-500 MUM H2O2 inhibited the growth of Calu-6 and A549 cells at 24 h and induced apoptosis in these cells. All the tested caspase inhibitors significantly prevented cell death in H2O2-treated lung cancer cells. H2O2 increased intracellular ROS levels, including that of O 2.- , at 1 and 24 h. It also increased the activity of catalase but decreased the activity of SOD. In addition, H2O2 triggered GSH deletion in Calu-6 and A549 cells at 24 h. It reduced GSH levels in Calu-6 cells at 1 h but increased them at 24 h. Caspase inhibitors decreased O 2.- levels in H2O2-treated Calu-6 cells at 1 h and these inhibitors decreased ROS levels, including that of O 2.- , in H2O2-treated A549 cells at 24 h. Caspase inhibitors partially attenuated GSH depletion in H2O2 treated A549 cells and increased GSH levels in these cells at 24 h. However, the inhibitors did not affect GSH deletion and levels in Calu-6 cells at 24 h. In conclusion, H2O2 induced caspase-dependent apoptosis in Calu-6 and A549 cells, which was accompanied by increases in ROS and GSH depletion. The antiapoptotic effects of caspase inhibitors were somewhat related to the suppression of H2O2 induced oxidative stress and GSH depletion. PMID- 28887782 TI - Development of ACRODAT(r), a new software medical device to assess disease activity in patients with acromegaly. AB - PURPOSE: Despite availability of multimodal treatment options for acromegaly, achievement of long-term disease control is suboptimal in a significant number of patients. Furthermore, disease control as defined by biochemical normalization may not always show concordance with disease-related symptoms or patient's perceived quality of life. We developed and validated a tool to measure disease activity in acromegaly to support decision-making in clinical practice. METHODS: An international expert panel (n = 10) convened to define the most critical indicators of disease activity. Patient scenarios were constructed based on these chosen parameters. Subsequently, a panel of 21 renowned endocrinologists at pituitary centers (Europe and Canada) categorized each scenario as stable, mild, or significant disease activity in an online validation study. RESULTS: From expert opinion, five parameters emerged as the best overall indicators to evaluate disease activity: insulin-like growth factor I (IGF-I) level, tumor status, presence of comorbidities (cardiovascular disease, diabetes, sleep apnea), symptoms, and health-related quality of life. In the validation study, IGF-I and tumor status became the predominant parameters selected for classification of patients with moderate or severe disease activity. If IGF-I level was <=1.2x upper limit of normal and tumor size not significantly increased, the remaining three parameters contributed to the decision in a compensatory manner. CONCLUSION: The validation study underlined IGF-I and tumor status for routine clinical decision-making, whereas patient-oriented outcome measures received less medical attention. An Acromegaly Disease Activity Tool (ACRODAT) is in development that might assist clinicians towards a more holistic approach to patient management in acromegaly. PMID- 28887783 TI - A novel integration of spectral-domain optical-coherence-tomography and laser ablation system for precision treatment. AB - PURPOSE: Complete resection of diseased lesions reduces the recurrence of cancer, making it critical for surgical treatment. However, precisely resecting residual tumors is a challenge during operation. A novel integrated spectral-domain optical-coherence-tomography (SD-OCT) and laser-ablation therapy system for soft biological-tissue resection is proposed. This is a prototype optical integrated diagnosis and therapeutic system as well as an optical theranostics system. METHODS: We develop an optical theranostics system, which integrates SD-OCT, a laser-ablation unit, and an automatic scanning platform. The SD-OCT image of biological tissue provides an intuitive and clear view for intraoperative diagnosis and monitoring in real time. The effect of laser ablation is analyzed using a quantitative mathematical model. The automatic endoscopic scanning platform combines an endoscopic probe and an SD-OCT sample arm to provide optical theranostic scanning motion. An optical fiber and a charge-coupled device camera are integrated into the endoscopic probe, allowing detection and coupling of the OCT-aiming beam and laser spots. RESULTS: The integrated diagnostic and therapeutic system combines SD-OCT imaging and laser-ablation modules with an automatic scanning platform. OCT imaging, laser-ablation treatment, and the integration and control of diagnostic and therapeutic procedures were evaluated by performing phantom experiments. Furthermore, SD-OCT-guided laser ablation provided precision laser ablation and resection for the malignant lesions in soft biological-tissue-lesion surgery. The results demonstrated that the appropriate laser-radiation power and duration time were 10 W and 10 s, respectively. In the laser-ablation evaluation experiment, the error reached approximately 0.1 mm. Another validation experiment was performed to obtain OCT images of the pre- and post-ablated craters of ex vivo porcine brainstem. CONCLUSION: We propose an optical integrated diagnosis and therapeutic system. The primary experimental results show the high efficiency and feasibility of our theranostics system, which is promising for realizing accurate resection of tumors in vivo and in situ in the future. PMID- 28887784 TI - Pancreatic neuroendocrine tumor in a patient with a TSC1 variant: case report and review of the literature. AB - The majority of pancreatic neuroendocrine tumors (PNETs) are sporadic while 10 15% are attributable to one of several familial cancer syndromes. Hereditary forms are more commonly associated with Multiple Endocrine Neoplasia Type I and von Hippel Lindau Syndrome. However, patients with Tuberous sclerosis complex also have an increased incidence of PNETs. More often this has been reported in patients with TSC2 variants. In this case report, we summarize the literature regarding PNETs associated with Tuberous sclerosis complex, as well as present a case of a patient with a TSC1 variant and a PNET. This case highlights the association of TSC1 gene variants with these tumors and emphasizes the importance of considering such diagnoses in this patient population. PMID- 28887786 TI - Assessing Psycho-social Barriers to Rehabilitation in Injured Workers with Chronic Musculoskeletal Pain: Development and Item Properties of the Yellow Flag Questionnaire (YFQ). AB - Purpose To develop a multidimensional scale to asses psychosocial beliefs-the Yellow Flag Questionnaire (YFQ)-aimed at guiding interventions for workers with chronic musculoskeletal (MSK) pain. Methods Phase 1 consisted of item selection based on literature search, item development and expert consensus rounds. In phase 2, items were reduced with calculating a quality-score per item, using structure equation modeling and confirmatory factor analysis on data from 666 workers. In phase 3, Cronbach's alpha, and Pearson correlations coefficients were computed to compare YFQ with disability, anxiety, depression and self-efficacy and the YFQ score based on data from 253 injured workers. Regressions of YFQ total score on disability, anxiety, depression and self-efficacy were calculated. Results After phase 1, the YFQ included 116 items and 15 domains. Further reductions of items in phase 2 by applying the item quality criteria reduced the total to 48 items. Phase factor analysis with structural equation modeling confirmed 32 items in seven domains: activity, work, emotions, harm & blame, diagnosis beliefs, co-morbidity and control. Cronbach alpha was 0.91 for the total score, between 0.49 and 0.81 for the 7 distinct scores of each domain, respectively. Correlations between YFQ total score ranged with disability, anxiety, depression and self-efficacy was .58, .66, .73, -.51, respectively. After controlling for age and gender the YFQ total score explained between R2 27% and R2 53% variance of disability, anxiety, depression and self-efficacy. Conclusions The YFQ, a multidimensional screening scale is recommended for use to assess psychosocial beliefs of workers with chronic MSK pain. Further evaluation of the measurement properties such as the test-retest reliability, responsiveness and prognostic validity is warranted. PMID- 28887785 TI - Bioplausible multiscale filtering in retino-cortical processing as a mechanism in perceptual grouping. AB - Why does our visual system fail to reconstruct reality, when we look at certain patterns? Where do Geometrical illusions start to emerge in the visual pathway? How far should we take computational models of vision with the same visual ability to detect illusions as we do? This study addresses these questions, by focusing on a specific underlying neural mechanism involved in our visual experiences that affects our final perception. Among many types of visual illusion, 'Geometrical' and, in particular, 'Tilt Illusions' are rather important, being characterized by misperception of geometric patterns involving lines and tiles in combination with contrasting orientation, size or position. Over the last decade, many new neurophysiological experiments have led to new insights as to how, when and where retinal processing takes place, and the encoding nature of the retinal representation that is sent to the cortex for further processing. Based on these neurobiological discoveries, we provide computer simulation evidence from modelling retinal ganglion cells responses to some complex Tilt Illusions, suggesting that the emergence of tilt in these illusions is partially related to the interaction of multiscale visual processing performed in the retina. The output of our low-level filtering model is presented for several types of Tilt Illusion, predicting that the final tilt percept arises from multiple-scale processing of the Differences of Gaussians and the perceptual interaction of foreground and background elements. The model is a variation of classical receptive field implementation for simple cells in early stages of vision with the scales tuned to the object/texture sizes in the pattern. Our results suggest that this model has a high potential in revealing the underlying mechanism connecting low-level filtering approaches to mid- and high-level explanations such as 'Anchoring theory' and 'Perceptual grouping'. PMID- 28887787 TI - Pneumococcal Vaccines - How Many Serotypes are Enough? AB - Streptococcus pneumoniae causes meningitis, pneumonia, septicemia, arthritis, sinusitis and otitis media specially in children and over 65 y age groups. It contributes significantly to under-five mortality and morbidity worldwide as well as in India. Use of pneumococcal vaccine seems to be the most effective measure to decrease the disease burden and reduction of under-five mortality. Many countries have already included Pneumococcal Conjugate Vaccines (PCV) in their National Immunization Programmes (NIP). Government of India has announced recently to include PCV13 in NIP in a phased manner. Superiority of a vaccine over the other depends upon serotype coverage, vaccine efficacy, cost effectiveness and safety profile. These facts will be discussed for the vaccines available in India. Further research is warranted to know the disease burden and develop vaccines to have more serotype coverage. PMID- 28887788 TI - The Clinical and Serological Profile of Pediatric Dengue. AB - OBJECTIVE: To classify suspected dengue into dengue, dengue with warning signs and severe dengue, based on clinical features as per the revised WHO guidelines with special emphasis on serology. METHODS: It was a prospective cross-sectional study for five years from 2011-2016 in a tertiary care medical college hospital in Bangalore. All cases of fever of three to five days duration with symptoms like dengue were enrolled for the study. They were categorized into three groups as per the Revised WHO 2012 criteria. Laboratory parameters, serology, ultrasound abdomen and X-ray were done in almost all patients. Data was analysed by SPSS software, version 16, and different groups were compared with Chi square test. RESULTS: Five hundred sixty eight children were diagnosed to have dengue fever; 4.2% of the sample belonged to infancy. Majority were in the age group of 5-10 y (42.6%). Fever and flushing were present in majority of the children. Gastrointestinal bleed was more commonly seen in the severe dengue group. Dengue nonstructural protein antigen (NS1Ag) was positive in 78%, immunoglobulin M (IgM) in 15.8% and immunoglobulin G (IgG) in 14.6%. Children with IgG had more complications, though not statistically significant. Mortality was reported in 1.2%. Dengue serology helped to confirm the diagnosis, however did not help in patient management. CONCLUSIONS: There is a considerable overlap in the symptomatology of dengue with warning signs and severe dengue. More studies are required on the severity and type of response to treatment in infants and obese adoloscents with severe dengue. PMID- 28887789 TI - Deaths from Opioid Overdosing: Implications of Coroners' Inquest Reports 2008 2012 and Annual Rise in Opioid Prescription Rates: A Population-Based Cohort Study. AB - INTRODUCTION: In the late 1990s multiple physicians and advocacy organizations promoted increased use of opioids for the treatment of acute, chronic and cancer pain. There has been an exponential growth in opioid prescribing in the last 20 years in the United States of America, in Australia, and in other developed Western countries. There are negative consequences associated with the liberal use of opioids. The primary aim of this population-based cohort study is to investigate the opioid-related death rate in New Zealand between 1 January 2008 and 31 December 2012. The secondary aims of this cohort study are: (1) to compare the opioid-related death rate per population in New Zealand in 2001/2002 with that between 2011/2012; (2) to investigate the number of opioid prescriptions in New Zealand between 2001 and 2012; (3) to compare the opioid-related death rate per population in New Zealand between 2001 and 2012 with the number of opioid prescriptions in New Zealand between 2001 and 2012. METHODS: Permission to access records from the Coronial Services Office in Wellington for 2008-2012 was acquired. Permission to access records for prescriptions containing opioids (dose and formulation) was obtained from the Pharmaceutical Collection. RESULTS: The rate of opioid-related deaths in New Zealand has increased by 33% from 2001 to 2012. More than half of the opioid-related deaths between 2008 and 2012 were unintentional opioid overdoses. Opioid analgesic deaths were most likely due to methadone, morphine and codeine prescribed by healthcare professionals. That 179 of these opioid-related deaths between 2008 and 2012 were unintentional opioid overdoses, and thus could have been avoided, is tragic. This study shows that there was a steady annual increases in opioid prescriptions in New Zealand from 2001 to 2012. This rise in opioid analgesic deaths was associated with the increases in the numbers of opioid prescriptions. CONCLUSION: A multifaceted national public health approach is needed to bring together the various stakeholders involved with pain management, opioid dependence, opioid availability and opioid diversion. There needs to be a targeted approach to educate current and future medical practitioners regarding the appropriate use of opioid prescriptions for the management of pain, as well as a strengthening of primary, secondary and tertiary resources to support medical practitioners managing their patients who suffer with pain. PMID- 28887791 TI - Pearls: The Mobile Segment in Sarcoma Resections. PMID- 28887790 TI - Polyspecificity of Anti-lipid A Antibodies and Its Relevance to the Development of Autoimmunity. AB - The process of natural selection favours germ-line gene segments that encode CDRs that have the ability to recognize a range of structurally related antigens. This presents an immunological advantage to the host, as it can confer protection against a common pathogen and still cope with new or changing antigens. Cross reactive and polyspecific antibodies also play a central role in autoimmune responses, and a link has been shown to exist between auto-reactive B cells and certain bacterial infections. Bacterial DNA, lipids, and carbohydrates have been implicated in the progression of autoimmune diseases such as systemic lupus erythematosus. As well, reports of anti-lipid A antibody polyspecificity towards single-stranded DNA together with the observed sequence homology amongst isolated auto- and anti-lipid A antibodies has prompted further study of this phenomenon. Though the lipid A epitope appears cryptic during Gram-negative bacterial infection, there have been several reported instances of lipid A-specific antibodies isolated from human sera, some of which have exhibited polyspecificity for single stranded DNA. In such cases, the breakdown of negative selection through polyspecificity can have the unfortunate consequence of autoimmune disease. This review summarizes current knowledge regarding such antibodies and emphasizes the features of S1-15, A6, and S55-5, anti-lipid A antibodies whose structures were recently determined by X-ray crystallography. PMID- 28887792 TI - Liver Failure as the Presentation of Ornithine Transcarbamylase Deficiency in a 13-Month-Old Female. AB - Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder with variable expressivity in heterozygous females. While liver function testing is often abnormal in patients with OTCD, liver failure is uncommon on presentation. A 13-month-old female with no significant past medical history presented with irritability, right arm weakness, and decreased appetite. Initial workup revealed hepatic dysfunction with an INR of 3.4, ammonia level of 75 MUmol/L, and abnormal brain MRI with gyral edema with restricted diffusion, and patchy signal abnormality in basal ganglia. The MRI findings led to a putative diagnosis of acute disseminated encephalomyelitis prompting corticosteroid treatment. As steroid treatment was begun, she developed significant hepatocellular dysfunction with ALT 2,222 U/L, AST 630 U/L, prolonged INR, and elevated ammonia (213 MUmol/L). Neurologic signs resolved and her ammonia level decreased (43 MUmol/L) without further intervention; however, she had ongoing acute liver failure with coagulopathy and episodic irritability, managed as seronegative autoimmune hepatitis with partial response to corticosteroid therapy. At 18 months of age she presented with severe irritability with markedly increased ammonia (417 MUmol/L). Plasma amino acids obtained several days prior to this acute episode demonstrated elevation in glutamine (2,725 MUmol/L) and alanine (1,459 MUmol/L). Biochemical testing demonstrated elevation of urine orotic acid (>240.6 mmol/mol creatinine). Genetic testing confirmed a heterozygous nonsense mutation in the OTC gene (c.958C>T, R320X). After treatment with ammonia scavengers and a protein-restricted diet, hepatic function normalized and irritability resolved. The diagnosis of a urea cycle disorder should be considered in patients with unexplained hepatic dysfunction. PMID- 28887793 TI - ALG13-CDG with Infantile Spasms in a Male Patient Due to a De Novo ALG13 Gene Mutation. AB - A boy presented at the age of 3.5 months with a developmental delay. He developed infantile spasms with hypsarrhytmia on EEG 1 month later. Additional symptoms were delayed visual development, asymmetrical hearing loss, hypotonia, and choreoathetoid movements. He also had some dysmorphic features and was vulnerable for infections. He was treated successively with vigabatrin, prednisolone, valproic acid, nitrazepam, and lamotrigine without a lasting clinical effect, but showed a treatment response to levetiracetam. Cerebral MRI showed hypoplasia of the corpus callosum and a mild delay in myelination. Further investigations including metabolic screening and glycosylation studies by transferrin isoelectric focusing were all considered to be normal. Whole-exome sequencing identified a de novo mutation in the ALG13 gene (c.320A>G, p.(Asn107Ser)). Mutations in this gene, which is located on the X-chromosome, are associated with congenital disorders of glycosylation type I (CDG-I). Mass spectrometric analysis of transferrin showed minor glycosylation abnormalities. The c.320A>G mutation in ALG13 has until now only been described in girls and was thought to be lethal for boys. All girls with this specific mutation presented with a similar phenotype of developmental delay and severe early onset epilepsy. In two girls glycosylation studies were performed which showed a normal glycosylation pattern. This is the first boy presenting with an epileptic encephalopathy caused by the c.320A>G mutation in the ALG13 gene. Since glycosylation studies are near-normal in patients with this mutation, the diagnosis of ALG13-CDG can be missed if genetic studies are not performed. PMID- 28887794 TI - In reply: Assessing flexible bronchoscopic intubation through the AuraGainTM laryngeal mask versus a slit Guedel tube. PMID- 28887795 TI - Social anxiety and attentional biases: A top-down contribution? AB - Selective attention toward threatening facial expressions has been found to precipitate and maintain symptoms of social anxiety. However, the automaticity of this bias is under debate. In the present study, we aimed to test whether top down (controlled) engagement and disengagement of attention toward threatening faces is associated with social anxiety. This was examined by testing the impact of a secondary working memory (WM) load on attentional biases. In a variation of the dot-probe task, participants' attention was initially cued to the left or right of fixation before an upright face paired with an inverted face was presented (displaying a disgust or neutral expression), and participants responded to a subsequently presented probe. The task was performed under no load, low-load (one-digit memory task), and high-load (six-digit memory task) conditions. Social anxiety was not found to be associated with delayed disengagement from threat. However, surprisingly, high social anxiety was associated with an engagement bias away from threat, whereas low social anxiety was associated with a bias toward threat. These results were unaffected by the WM load manipulation. This indicates that engagement with threatening facial expressions has minimal contributions from top-down mechanisms, since it is likely that orienting to facial expressions occurs relatively automatically. PMID- 28887798 TI - Processing language in face-to-face conversation: Questions with gestures get faster responses. AB - The home of human language use is face-to-face interaction, a context in which communicative exchanges are characterised not only by bodily signals accompanying what is being said but also by a pattern of alternating turns at talk. This transition between turns is astonishingly fast-typically a mere 200-ms elapse between a current and a next speaker's contribution-meaning that comprehending, producing, and coordinating conversational contributions in time is a significant challenge. This begs the question of whether the additional information carried by bodily signals facilitates or hinders language processing in this time pressured environment. We present analyses of multimodal conversations revealing that bodily signals appear to profoundly influence language processing in interaction: Questions accompanied by gestures lead to shorter turn transition times-that is, to faster responses-than questions without gestures, and responses come earlier when gestures end before compared to after the question turn has ended. These findings hold even after taking into account prosodic patterns and other visual signals, such as gaze. The empirical findings presented here provide a first glimpse of the role of the body in the psycholinguistic processes underpinning human communication. PMID- 28887797 TI - Cell-shaped silicon-on-insulator microdosimeters: characterization and response to 239PuBe irradiations. AB - This work tested the feasibility of a silicon-on-insulator microdosimeter, which mimics the size and shape of specific cells within the human body, to determine dose equivalent from neutron irradiation. The microdosimeters were analyzed in terms of their basic diode characteristics, i.e., leakage current as a function of bias voltage. Lineal energy spectra were acquired using two different converter layers placed atop the microdosimeter: a tissue-substitute converter made from high-density polyethylene, and a boron converter consisting of epoxy coated with boron powder. The spectra were then converted into absorbed dose and dose equivalent. Experimental results were compared to Monte Carlo simulations of the neutron irradiations, revealing good agreement. Uncertainty in the dose equivalent determinations was 7.5% when using the cell-shaped microdosimeter with the tissue-substitute converter and 13.1% when using the boron converter. This work confirmed that the SOI approach to cell-mimicking microdosimetry is feasible. PMID- 28887799 TI - Study of polar organic compounds in airborne particulate matter of a coastal urban city. AB - Two classes of polar organic compounds, dicarboxylic acids (DCAs) and sugars/sugar anhydrides (S/SAs), were measured in airborne particulate matter in the area of Thessaloniki, northern Greece. The target compounds were measured simultaneously in two particle fractions PM10 and PM2.5 during cold and warm periods by employing extraction in an ultrasonic bath with a mixture of MeOH/DCM (1:2 v/v), derivatization with BSTFA-TMCS and GC-MS for analysis. At both fractions, phthalic was the predominant carboxylic acid during cold season and a ketoglutaric acid in warm season, followed by maleic and malic. Levoglucosan was the dominant sugar anhydride during the cold and arabitol during the warm season. In total, the distribution of DCAs seemed to favor the PM2.5 particle fraction, probably due to anthropogenic emissions and photochemical formation. The relative contribution of DCAs to PM2.5 fraction was 0.9-3.2% in cold and 0.9-7.0% in warm period. Regarding S/SAs, levoglucosan was also predominantly distributed in fine particles, with relative contribution to this fraction 0.1-6.3% in cold and <0.65% in warm season, suggesting impact of biomass burning emissions. In contrast, arabitol, fructose, and glucose were mainly found in coarse fraction, possibly due to their biogenic origin. Negative correlation of target compounds with temperature and total solar radiation suggested the contribution of seasonal dependant local sources. Positive relationship with NO and NO2 oxidants and relative humidity showed secondary formation of polar compounds or enhanced gas to-particle conversion. PMID- 28887796 TI - Enabling Work: Occupational Therapy Interventions for Persons with Occupational Injuries and Diseases: A Scoping Review. AB - Purpose This review aims to map the scope of published research on occupational therapy (OT) interventions and pertinent work and work-related outcomes for persons with occupational injuries and diseases. Methods The scoping review adapted Arksey and O'Malley's framework. Six electronic databases were searched. Ancestral search was also done on five systematic reviews. The search was conducted from September 2015 to October 2015. Interventions and outcomes were coded using the International Classification of Functioning, Disability and Health Core Set for Vocational Rehabilitation to plot trends. Results Forty-six articles were included in the review. The top five intervention approaches included: acquiring skills (12.27%), health services, systems, and policies (10.43%), products and technology for employment (9.20%), handling stress and other psychological demands (7.98%), and apprenticeship (6.74%). The top five outcomes targeted included: remunerative employment (15.71%); sensation of pain (10.99%); emotional functions (5.76%); handling stress and other psychological demands (5.76%); economic self-sufficiency (4.71%); muscle endurance functions (4.71%); exercise tolerance functions (4.71%); undertaking multiple tasks (4.19%); acquiring, keeping, and terminating a job (4.19%); and looking after one's health (4.19%). Conclusion The trend in interventions show the use of activities and environment facilitators which are attuned to the conceptual nature of OT. Furthermore, the trend in outcomes show that there is substantial evidence that supports the use of OT to target work. This review may provide a platform for collaboration with other professionals and also help identify research directions to strengthen the evidence base for OT in work-related practice. PMID- 28887800 TI - Acipensericola glacialis n. sp. (Digenea: Aporocotylidae) from heart of lake sturgeon Acipenser fulvescens Rafinesque (Acipenseriformes: Acipenseridae) in the Great Lakes Basin, Lake Winnebago System, USA. AB - Acipensericola glacialis n. sp. infects the heart of lake sturgeon, Acipenser fulvescens (Rafinesque), in the Lake Winnebago System and differs from its only congener, Acipensericola petersoni Bullard, Snyder, Jensen & Overstreet, 2008, by having a dendritic intestine, deeply-lobed testes, a post-ovarian ootype, and a common genital pore that is medial to the dextral caecum. Acipensericola petersoni has a non-dendritic intestine, testes that are not deeply lobed, an ootype that is at level of the ovary (ventral to the ovary), and a common genital pore that is dorsal to the dextral caecum. Comparison of the large (28S) and small (18S) sub-unit ribosomal DNA and internal transcribed spacer 2 (ITS2) regions between specimens of A. glacialis n. sp. and A. petersoni revealed 13 (of 1,621 nt; 99.2% similarity in the 28S), 8 (of 1,841 nt; 99.9% similarity in the 18S), and 11 (of 442 nt; 97.5% similarity in the ITS2) nucleotide differences. Collectively, these results comprise an unexpectedly high degree of morphological and molecular similarity given the geographical (Mississippi River Basin vs Great Lakes Basin) and phylogenetic (Polyodontidae vs Acipenseridae) separation of these hosts but seemingly did not reject a previous hypothesis concerning lake sturgeon dispersal from the Mississippi Refugium following the Wisconsin glaciation ~18,000 years ago. The new species is the first nominal blood fluke described from a sturgeon. PMID- 28887801 TI - Population Pharmacokinetic and Pharmacodynamic Analysis of Belimumab Administered Subcutaneously in Healthy Volunteers and Patients with Systemic Lupus Erythematosus. AB - BACKGROUND: Intravenous belimumab 10 mg/kg every 4 weeks is indicated in patients with active, autoantibody-positive systemic lupus erythematosus receiving standard systemic lupus erythematosus care. Subcutaneous 200-mg weekly administration, which may prove more convenient for patients and improve adherence, is currently under investigation. OBJECTIVE: The objective of this study was to characterize the population pharmacokinetics and exposure-efficacy response of subcutaneous belimumab in a pooled analysis of pharmacokinetic data [phase I: BEL114448 (NCT01583530) and BEL116119 (NCT01516450) in healthy subjects (n = 134); phase III: BEL112341 (NCT01484496) in adults with systemic lupus erythematosus (n = 554)] and pharmacodynamic data [BEL112341 in adults with systemic lupus erythematosus (n = 833)]. METHODS: Non-linear mixed-effects modeling (NONMEM(r)) was used to develop a population pharmacokinetic model and perform a covariate analysis. Subsequently, exploratory exposure-response analysis and logistic regression modeling was performed based on the individual parameter estimates of the population pharmacokinetic model. RESULTS: Population pharmacokinetic parameters for subcutaneous belimumab were consistent with those for intravenous belimumab and other immunoglobulin G1 monoclonal antibodies. Pharmacokinetic parameters and subcutaneous belimumab exposure were consistent between healthy subjects and patients with systemic lupus erythematosus, and no evidence for target-mediated disposition of belimumab was found. Subcutaneous belimumab steady-state exposure was achieved after ~11 weeks; subcutaneous belimumab steady-state minimum concentration exceeded that of intravenous belimumab after <4 weeks, and average steady-state concentration was similar to that achieved following intravenous administration. In patients with moderate-to severe systemic lupus erythematosus, subcutaneous belimumab 200 mg once weekly plus standard of care significantly improved the systemic lupus erythematosus responder index. However, at this dose, the systemic lupus erythematosus responder index response was not significantly associated with belimumab exposure concentrations. CONCLUSION: The analysis demonstrates that a 200-mg once-weekly dose of belimumab is appropriate for subcutaneous administration in patients with systemic lupus erythematosus and that no dose adjustments are required for adult patients to maintain efficacy and safety. PMID- 28887802 TI - Small Molecule Inhibitors of the Hedgehog Pathway in the Treatment of Basal Cell Carcinoma of the Skin. AB - Basal cell carcinoma (BCC) is the most common type of skin cancer, with rising incidence rates primarily attributed to an aging population and ultraviolet radiation exposure. While the majority of BCCs are localized and respond to standard therapies, a very small minority of these tumors become locally destructive or metastasize. These advanced BCCs may not be amenable to localized treatment with surgery and/or radiation therapy. Most BCCs result from mutations in key receptors in the Hedgehog (HH) signaling pathway. As a result, identification of drugs that inhibit the receptor Smoothened (SMO) in the HH pathway has resulted in novel therapeutic approaches to treating patients with advanced BCC. These HH-pathway inhibiting medications have shown efficacy in clinical trials, and two medications, vismodegib and sonidegib, have received FDA approval. However, several limitations of these drugs have been identified, including treatment-limiting adverse events, drug resistance, and the formation of additional malignancies. This paper aims to summarize the clinical trials leading to the approval of SMO inhibitors, as well as reviewing potential mechanisms driving tumor resistance and the formation of cutaneous squamous cell carcinomas. Strategies to overcome some of these challenges, including the development of drugs that inhibit other downstream targets in the HH pathway, are the subject of ongoing clinical trials. PMID- 28887803 TI - Psychosis in Spinocerebellar Ataxias: a Case Series and Study of Tyrosine Hydroxylase in Substantia Nigra. AB - Spinocerebellar ataxias are a genetically heterogeneous group of degenerative diseases typically characterized by progressive ataxia and to various degrees, neuropathy, amyotrophy, and ocular abnormalities. There is increasing evidence for non-motor manifestations associated with cerebellar syndromes including cognitive and psychiatric features. We studied a retrospective clinical case series of eight subjects with spinocerebellar ataxias (SCAs) 2, 3, 7, and 17, all displaying features of psychosis, and also measured tyrosine hydroxylase (TH) staining of the substantia nigra (SN) at autopsy, among four of the subjects. We hypothesized that increased dopamine production in the SN may underlie the pathophysiology of psychosis in SCAs, given evidence of increased dopamine production in the SN in schizophrenia, as measured by TH staining. We analyzed differences in TH staining between the SCA psychosis cohort (n = 4), a heterogeneous ataxic cohort without psychosis (n = 22), and non-diseased age- and sex-matched control group (n = 12). SCA subjects with psychosis did not differ significantly in TH staining versus ataxic cases without psychosis. There was, however, increased TH staining in the ataxic cohort with and without psychosis (n = 26), compared to non-diseased controls (n = 12). Psychotic features were similar across subjects, with the presence of delusions, paranoia, and auditory hallucinations. Our findings are preliminary because of small numbers of subjects and variable neuropathology; however, they suggest that psychosis is a clinical feature of SCAs and may be under-recognized. While the underlying pathophysiology remains to be fully established, it may be related to extra-cerebellar pathology, including a possible propensity for increased dopamine activity in the SN. PMID- 28887804 TI - Identification of major quantitative trait loci for root diameter in synthetic hexaploid wheat under phosphorus-deficient conditions. AB - Synthetic hexaploid wheat (SHW) possesses numerous genes for resistance to stress, including phosphorus (P) deficiency. Root diameter (RDM) plays an important role in P-deficiency tolerance, but information related to SHW is still limited. Thus, the objective of this study was to investigate the genetic architecture of RDM in SHW under P-deficient conditions. To this end, we measured the RDM of 138 F9 recombinant inbred lines derived from an F2 population of a synthetic hexaploid wheat line (SHW-L1) and a common wheat line (Chuanmai32) under two P conditions, P sufficiency (PS) and P deficiency (PD), and mapped quantitative trait loci (QTL) for RDM using an enriched high-density genetic map, containing 120,370 single nucleotide polymorphisms, 733 diversity arrays technology markers, and 119 simple sequence repeats. We identified seven RDM QTL for P-deficiency tolerance that individually explained 11-14.7% of the phenotypic variation. Five putative candidate genes involved in root composition, energy supply, and defense response were predicted. Overall, our results provided essential information for cloning genes related to P-deficiency tolerance in common wheat that might help in breeding P-deficiency-tolerant wheat cultivars. PMID- 28887805 TI - Quantitative analysis of effects of hemodynamic stress on temporal variations of cardiac phases in models of human carotid bulbs. AB - In this study, we evaluated the hemodynamics of carotid artery models with carotid bulbs of various sizes using computational fluid dynamics (CFD) and the Fluent CFD software. The oscillatory shear index (OSI) and flow velocity distribution were evaluated in carotid models without a carotid bulb and with carotid bulbs of known geometry (major axis of 10, 11, 12, 13, and 14 mm; carotid bifurcation angle of 50 degrees ). Furthermore, the diameters of the common carotid artery, the external carotid artery, and the internal carotid artery were defined as 7.2, 4.0, and 4.5 mm, respectively. The accuracy of the CFD analysis in this study was verified using a flow phantom and measuring velocities with phase-contrast cine magnetic resonance imaging. The CFD parameters were defined as follows: rigid and no-slip walls, pulsatile flow, and 0 Pa of peripheral pressure. The OSI in the carotid bulb tended to show a high value during the expansion of the carotid bulb (maximum and minimum OSI: 0.11 +/- 0.08 at d bulb: 14 mm; 0.0013 +/- 0.0011 at no bulb), and the region of high OSI expanded with the expansion of the carotid bulb. The flow separated near the carotid bulb, and the flow deceleration expanded downstream as the size of the bulb increased. These findings suggest that the size of the carotid bulbs contributed to the OSI because the larger bulbs exhibited higher OSI values. The relation between the OSI and the carotid bulb size could serve as a risk indicator for atherosclerosis. PMID- 28887806 TI - Erratum to: Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer. PMID- 28887807 TI - Feasibility of multiplane microtransoesophageal echocardiographic guidance in structural heart disease transcatheter interventions in adults. AB - INTRODUCTION: Structural heart interventions are guided by transoesophageal or intracardiac echocardiography (TEE/ICE). MicroTEE, developed for paediatric purposes, is smaller and therefore less invasive and traumatic, avoiding the need for general anaesthesia. We aimed to show feasibility of procedural guidance by comparing image quality of microTEE with standard TEE and ICE during adult transcatheter interventions, and assess the accuracy in obtaining left atrial appendage (LAA) measurements between the microTEE probe and standard TEE. METHODS AND RESULTS: We prospectively included 49 patients (20 women, 64 +/- 18 years). Intraprocedural images were obtained by using the microTEE probe and standard (2D and 3D) TEE (LAA closure, MitraClip implantation) or ICE (interatrial communication closure, transseptal puncture for left atrial ablation). Two echocardiographers independently assessed image quality from 1 (excellent) to 4 (poor) and performed LAA measurements. Use of microTEE was not related to significant discomfort. Image quality obtained with the microTEE probe was lower than with standard TEE (2 [1-2] vs. 1 [1-2]; p = 0.04) and comparable with ICE images (2 [1-2] vs. 2 [1-2], p = 0.13). MicroTEE showed a wider field of view than ICE. LAA measurements on images obtained by microTEE were strongly associated with standard TEE. CONCLUSIONS: MicroTEE seems feasible for guidance during transcatheter heart interventions in adults. MicroTEE imaging offers a wider field of view than ICE, and its accuracy is comparable with TEE. In transcatheter interventions performed under conscious sedation, microTEE might be a viable and advantageous alternative to standard TEE or ICE. PMID- 28887808 TI - Comparison of reference values for immune recovery between event-free patients receiving haploidentical allografts and those receiving human leukocyte antigen matched sibling donor allografts. AB - To establish optimal reference values for recovered immune cell subsets, we prospectively investigated post-transplant immune reconstitution (IR) in 144 patients who received allogeneic stem cell transplantation (allo- SCT) and without showing any of the following events: poor graft function, grades II-IV acute graft-versus-host disease (GVHD), serious chronic GVHD, serious bacterial infection, invasive fungal infection, or relapse or death in the first year after transplantation. IR was rapid in monocytes, intermediate in lymphocytes, CD3+ Tcells, CD8+ T cells, and CD19+ B cells, and very slow in CD4+ T cells in the entire patient cohort. Immune recovery was generally faster under HLA-matched sibling donor transplantation than under haploidentical transplantation. Results suggest that patients with an IR comparable to the reference values display superior survival, and the levels of recovery in immune cells need not reach those in healthy donor in the first year after transplantation.We suggest that data from this recipient cohort should be used as reference values for post transplant immune cell counts in patients receiving HSCT. PMID- 28887809 TI - Effect of comprehensive therapy based on Chinese medicine patterns on self efficacy and effectiveness satisfaction in chronic obstructive pulmonary disease patients. AB - OBJECTIVE: To evaluate the effect of comprehensive therapy based on Chinese medicine (CM) patterns on self-efficacy and satisfaction with its effectiveness in patients with chronic obstructive pulmonary disease (COPD). METHODS: A total of 216 patients were randomly divided into the trial group (n =108) and the control group (n =108) based on the stratified and block randomization design. Patients in the trial group were treated with conventional Western medicine combined with Bufei Jianpi Granules (), Bufei Yishen Granules (), and Yiqi Zishen Granules () according to the CM patterns respectively, and patients in the control group were treated with conventional Western medicine. The COPD Self Efficacy Scale (CSES) and the Effectiveness Satisfaction Questionnaire for COPD (ESQ-COPD) were employed in a 6-month treatment and in further 6 month follow-up visit. RESULTS: Among the 216 patients, 191 patients (97 in the trial group and 94 in the control group) fully completed the study. After 12-month treatment and follow-up, the mean scores of the trial group all continued to increase over time, which were significantly higher than those of the control group (P <0.05), and the improvement in the following trial group domain: negative affect domain (12.13%), intense emotional arousal domain (12.21%), physical exertion domain (11.72%), weather/environmental domain (13.77%), behavioral risk domain (7.67%) and total score (10.65%). The trial group also exhibited significantly higher mean scores in the ESQ-COPD (P <0.05) and the improvement in the following domain: capacity for life and work domain (30.59%), clinical symptoms domain (53.52%), effect of therapy domain (35.95%), convenience of therapy domain (35.54%), and whole effect domain (52.47%). CONCLUSIONS: Bufei Jianpi Granules, Bufei Yishen Granules and Yiqi Zishen Granules can improve the self-efficacy and satisfaction of COPD patients. PMID- 28887811 TI - Great ape gestures: intentional communication with a rich set of innate signals. AB - Great apes give gestures deliberately and voluntarily, in order to influence particular target audiences, whose direction of attention they take into account when choosing which type of gesture to use. These facts make the study of ape gesture directly relevant to understanding the evolutionary precursors of human language; here we present an assessment of ape gesture from that perspective, focusing on the work of the "St Andrews Group" of researchers. Intended meanings of ape gestures are relatively few and simple. As with human words, ape gestures often have several distinct meanings, which are effectively disambiguated by behavioural context. Compared to the signalling of most other animals, great ape gestural repertoires are large. Because of this, and the relatively small number of intended meanings they achieve, ape gestures are redundant, with extensive overlaps in meaning. The great majority of gestures are innate, in the sense that the species' biological inheritance includes the potential to develop each gestural form and use it for a specific range of purposes. Moreover, the phylogenetic origin of many gestures is relatively old, since gestures are extensively shared between different genera in the great ape family. Acquisition of an adult repertoire is a process of first exploring the innate species potential for many gestures and then gradual restriction to a final (active) repertoire that is much smaller. No evidence of syntactic structure has yet been detected. PMID- 28887810 TI - Advantages of Chinese Medicine for Patients with Acquired Immunodeficiency Syndrome in Rural Central China. AB - OBJECTIVE: To analyze the effect of Chinese medicine (CM) on mortality and quality of life (QOL) of acquired immunodefificiency syndrome (AIDS) patients treated with combined antiretroviral therapy (cART). METHODS: A random sample of AIDS patients enrolled in the National Chinese Medicine Treatment Trial Program (NCMTP) that met the inclusion criteria was included in this study. NCMTP patients were included as the CM+cART group, and those not in the NCMTP were included as the cART group. Survival from September 2004 to September 2012 was analyzed by retrospective cohort study. QOL was analyzed by cross-sectional study. RESULTS: The retrospective cohort study included 528 AIDS patients, 322 in the CM+cART group and 206 in the cART group. After 8 years, the mortality in the CM+cART group was 3.3/100 person-years, which was lower than the cART group of 5.3/100 person-years (P<0.05). The hazard ratio (HR) for mortality in the cART group was 1.6 times that of the CM+cART group by Cox proportional hazard model analysis. After controlling for gender, age, marital status, education, and CD4+ T-cell count, the HR was 1.9 times higher in the cART group compared with the CM+cART group (P<0.05). The cross-sectional study investigated 275 AIDS patients. The mean scores of all QOL domains except spirituality/personal beliefs were higher in the CM+cART group than in the cART group (P<0.05). CONCLUSIONS: For AIDS patients, CM could help to prolong life, decrease mortality, and improve QOL. However, there were limitations in the study, so prospective studies should be carried out to confifirm our primary results. PMID- 28887812 TI - A comprehensive approach to evaluating and classifying sun-protective clothing. AB - BACKGROUND: National standards for clothing designed to protect the wearer from the harmful effects of solar ultraviolet radiation (UVR) have been implemented in Australia/New Zealand, Europe and the U.S.A. Industry standards reflect the need to protect the skin by covering a considerable proportion of the potentially exposed body surface area (BSA) and by reducing UVR-transmission through fabric (the Ultraviolet Protection Factor; UPF). OBJECTIVES: This research aimed to develop a new index for rating sun-protective clothing that incorporates the BSA coverage of the garment in addition to the UPF of the fabric. METHODS: A mannequin model was fixed to an optical bench and marked with horizontal lines at 1-cm intervals. An algorithm (the Garment Protector Factor; GPF) was developed based on the number of lines visible on the clothed vs. unclothed mannequin and the UPF of the garment textile. This data was collected in 2015/16 and analysed in 2016. RESULTS: The GPF weights fabric UPF by BSA coverage above the minimum required by international sun-protective clothing standards for upper-body, lower body and full-body garments. The GPF increases with BSA coverage of the garment and fabric UPF. Three nominal categories are proposed for the GPF: 0 <= GPF < 3 for garments that 'meet' minimum standards; 3 <= GPF < 6 for garments providing 'good' sun protection; and GPF >= 6 indicating 'excellent' protection. CONCLUSIONS: Adoption of the proposed rating scheme should encourage manufacturers to design sun-protective garments that exceed the minimum standard for BSA coverage, with positive implications for skin cancer prevention, consumer education and sun-protection awareness. PMID- 28887813 TI - Progression of care among women who use a midwife for prenatal care: Who remains in midwife care? AB - BACKGROUND: Prenatal care provided by midwives provides a safe and cost-effective alternative to care provided by physicians. However, no studies have evaluated the frequency of women who leave midwifery care, in a hospital setting. Our study objectives were to measure the frequency of transfers of care to physicians, to describe the sociodemographic and pregnancy-related characteristics of women who transferred to the care of a physician during prenatal care and at delivery, and to assess correlates of these transfers. METHODS: We used electronic medical records to perform a retrospective cohort study of women who delivered at The Ohio State University Wexner Medical Center (OSUWMC) and had at least one prenatal care visit within OSUWMC's network. We report descriptive findings, using proportions and means with standard deviations. We used logistic regression, with Firth's bias correction as necessary, to assess correlates of transferring to a physician during prenatal care and at delivery. RESULTS: Most women who initiated prenatal care with a midwife remained in midwifery care throughout delivery, with 4.7% transferring to a physician during prenatal care, and an additional 21.4% transferring to a physician during delivery. After adjusting for pregnancy-related factors, the black race was statistically significantly associated with leaving midwifery care during prenatal care (adjusted odds ratio AOR 3.0 [95% CI 1.4-6.6]) and delivery (AOR 2.5 [95% CI 1.5 4.3]). CONCLUSION: Findings indicate that most women remain in midwifery care throughout pregnancy, but raise important questions with respect to the possible role that race has in pregnancy care. PMID- 28887814 TI - Construction and application of an electrochemical biosensor based on an endotoxin aptamer. AB - An electrochemical biosensor that used an aptamer as a biological element was constructed to detect endotoxin. Biolayer interferometry was used to obtain the affinity constant of an aptamer for lipopolysaccharide, which had an equilibrium dissociation constant of 22.9 nM. The amine-terminated aptamer was then assembled on a gold electrode surface using 3-mercaptopropionic acid as an intermediate linker. The modification of the gold electrode was confirmed by cyclic voltammetry and electrochemical impedance spectroscopy. In the range of 0.001-1 EU/mL, the increase in electron transfer resistance of the biosensor was linear with the logarithmic value of the endotoxin concentration. The constructed biosensor exhibits sensitivity and a low limit of detection. PMID- 28887815 TI - Systematic review and meta-analysis of the efficacy of interventions for people with Type 1 diabetes mellitus and disordered eating. AB - AIM: To examine the types of interventions currently available for people with Type 1 diabetes mellitus and their effectiveness. BACKGROUND: The prevalence of disordered eating in people with Type 1 diabetes mellitus is twice that in their counterparts without diabetes, and is associated with worse biomedical outcomes and greater mortality. METHODS: Medline, Embase, PsycINFO, the Cochrane Library, PubMed and OpenGrey databases were searched up to August 2016 to identify studies on interventions in people with Type 1 diabetes-associated disordered eating. For the systematic review, intervention components were identified and their effectiveness was examined. For the meta-analysis, the pooled effect sizes of glycaemic control (HbA1c ) between pre- and post-treatment in treatment and comparison groups were calculated using a random effects model. RESULTS: Of 91 abstracts reviewed, six studies met the inclusion criteria, of which three had appropriate data for the meta-analysis (n = 118). The pooled effect size was 0.21 95% CI (-0.58 to 0.16; where negative values represent an improvement in HbA1c levels), indicating no statistically significant improvement in the treatment group compared with comparison group. Inpatient therapy appeared to be the most effective treatment, and this had multiple components including cognitive behavioural therapy, psychoeducation and family therapy. CONCLUSION: Limited or no improvement in glycaemic control and disordered eating symptoms was observed in people with Type 1 diabetes-associated disordered eating who were receiving currently available interventions. The present review suggests that developing an intensive intervention with a joint focus on both disordered eating and diabetes management is needed for this complex patient group. PMID- 28887816 TI - The little things that run: a general scaling of invertebrate exploratory speed with body mass. AB - Speed is a key trait of animal movement, and while much is already known about vertebrate speed and how it scales with body mass, studies on invertebrates are sparse, especially across diverse taxonomic groups. Here, we used automated image based tracking to characterize the exploratory (voluntary) speed of 173 invertebrates comprising 57 species across six taxonomic groups (Arachnida, Chilopoda, Diplopoda, Entognatha, Insecta, Malacostraca) and four feeding types (carnivore, detritivore, herbivore, omnivore). Across all individuals, exploratory speed (mm/s) scaled with body mass (g) following a power-law relationship with a scaling exponent of 0.19 +/- 0.04 (mean +/- SE) and an intercept of 14.33 +/- 1.2. These parameters varied substantially with taxonomic group and feeding type. For the first time, we provide general empirically derived allometric scaling relationships of exploratory speed across broad taxonomic groups of invertebrates. As exploratory speed drives key components of species interactions, such as encounter and attack rates, or competition, our study contributes to a deeper understanding of the role of individual movement in population and community level processes. PMID- 28887817 TI - Modulation of hERG potassium channels by a novel small molecule activator. PMID- 28887818 TI - Monitoring UV-induced signalling pathways in an ex vivo skin organ culture model using phospho-antibody array. AB - We investigated UV-induced signalling in an ex vivo skin organ culture model using phospho-antibody array. Phosphorylation modulations were analysed in time course experiments following exposure to solar-simulated UV and validated by Western blot analyses. We found that UV induced P-p38 and its substrates, P ERK1/2 and P-AKT, which were previously shown to be upregulated by UV in cultured keratinocytes and in vivo human skin. This indicates that phospho-antibody array applied to ex vivo skin organ culture is a relevant experimental system to investigate signalling events following perturbations. As the identified proteins are components of pathways implicated in skin tumorigenesis, UV-exposed skin organ culture model could be used to investigate the effect on these pathways of NMSC cancer drug candidates. In addition, we found that phospho-HCK is induced upon UV exposure, producing a new candidate for future studies investigating its role in the skin response to UV and UV-induced carcinogenesis. PMID- 28887819 TI - Climate Change, Global Health, and Nursing Scholarship. PMID- 28887820 TI - The epidemiology of mandibular fractures in Caracas, Venezuela: Incidence and its combination patterns. AB - BACKGROUND/AIM: As reported in the literature by several authors, there is a great variation between countries in terms of etiology and patterns of mandibular fractures. The aim of this study was to determine the incidence of mandibular fractures at the Oral and Maxillofacial Surgery Unit, "Dr. Domingo Luciani" Hospital, Venezuela, during the period January 2010 to March 2013. MATERIALS AND METHODS: A retrospective study was conducted to assess the etiology of trauma, age group, gender, anatomic distribution of injury, and combination patterns by reviewing patients records. RESULTS: There were 334 patients with 522 mandibular fractures averaging 1.56 fractures per patient. Eighty-five percent of the patients were males with an overall male: female ratio of 6.15:1. The highest occurrence of trauma was in the 20-29 years (43.4%) age group. The etiology most frequently observed was motorcycle traffic accidents in 94 patients (28.1%), and the parasymphysis region was the most common location with 144 (27.6%) fractures. Almost half (48.8%) of the injuries were combined mandibular fractures with 29 different combinations, and the most common was a mandibular body fracture + parasymphysis fracture (22.1%). CONCLUSION: Mandibular fracture is a common facial injury with variable incidence and etiology across gender and age range. The findings of this study are similar to other studies and provide important clinical information that will assist in the treatment planning of these types of injuries. PMID- 28887821 TI - SERPINA1 and MAN1B1 polymorphisms are not linked to severe liver disease in a French cohort of alpha-1 antitrypsin deficiency children. AB - BACKGROUND & AIMS: Fifteen to twenty percent of alpha-1 antitrypsin deficiency patients (A1ATD) have a severe liver outcome (portal hypertension - PHT) during childhood. Since they all share the same ZZSERPINA1 genotype and that environmental factors such as alcohol cannot be advanced, the presence of modifier genes is now well recognized. SNPs located on the SERPINA1 and MAN1B1 genes have already been tested in very few studies with contradictory or not replicated results. METHODS: Our genotype-phenotype correlation study, performed on 92 ZZ children, aimed at determining once and for all if SERPINA1 and MAN1B1 polymorphisms may be implied in the onset of PHT. To do so, we also performed for the first time a complete haplotype reconstruction for data analysis. RESULTS: The two genetic associations with severe liver disease that had been suspected previously (one SNP for SERPINA1 and another for MAN1B1) were not confirmed in our cohort. Moreover, the haplotype analysis identified only one major genetic background for the SERPINA1 Z-allele, allowing us to exclude the presence of a frequent modifier SNP within. For MAN1B1, four major haplotypes were identified but the prevalence of PHT did not significantly differ between them. CONCLUSION: We conclude that genetic polymorphisms in these two genes probably do not influence the onset of severe liver disease in A1ATD. PMID- 28887822 TI - Paracrine crosstalk between endothelial cells and melanocytes through clusterin to inhibit pigmentation. AB - Cutaneous vasculature systems play a role in regulating skin pigmentation. We analysed RNA sequencing data to identify novel antimelanogenic factors secreted from endothelial cells and found that one of the secreted factors, clusterin, is highly expressed by HDMECs. To investigate the paracrine effect of clusterin from HDMECs on the regulation of melanogenesis, HDMECs were infected with clusterin or sh-clusterin lentivirus and the HDMEC-derived conditioned media were used to treat normal human melanocytes. It was found that HDMEC-derived clusterin inhibits melanogenesis through MITF/tyrosinase downregulation. The findings here suggest that HDMECs secrete copious amounts of clusterin and that the clusterin is a factor contributing to the inhibitory effect of endothelial cells on melanogenesis via paracrine crosstalk between endothelial cells and melanocytes. PMID- 28887823 TI - Variation of the epidermal expression of glucocorticoid receptor-beta as potential predictive marker of bullous pemphigoid outcome. AB - Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease in Western countries. Although topical and/or systemic glucocorticoids treatment efficacy is widely recognized, up to 30% of patients with BP may undergo a relapse during the first year of treatment. We investigated the protein expression of the total glucocorticoid receptor and GRbeta isoform in the skin biopsy specimens from patients with BP and wondered whether such investigation at baseline provided a tool to predict disease outcome. Total GR and GRbeta protein expressions were detected by immunohistochemistry at baseline on 12 patients who later relapse and 11 patients who remained on remission in comparison with 14 control patients. The expression of GRbeta in the epidermis of patients with BP who later relapse was significantly higher than that in the epidermis of patients with BP controlled upon corticosteroid treatment, which was also higher than control patients. Thus, our results suggest that increased protein expression of GRbeta in skin epithelial cells is predictive of reduced steroid treatment efficacy, and therefore of increased risk of disease relapse in patients with BP. PMID- 28887824 TI - Structural proteins of the dermal-epidermal junction targeted by autoantibodies in pemphigoid diseases. AB - The dermal-epidermal junction consists of a network of several interacting structural proteins that strengthen adhesion and mediate signalling events. This structural network consists of hemidesmosomal-anchoring filament complexes connecting the basal keratinocytes to the basement membrane. The anchoring filaments in turn interact with the anchoring fibrils to attach the basement membrane to the underlying dermis. Several of these structural proteins are recognized by autoantibodies in pemphigoid diseases, a heterogeneous group of clinically and immunopathologically diverse entities. Targeted proteins include the two intracellular plakins, plectin isoform 1a and BP230 (also called bullous pemphigoid antigen (BPAG) 1 isoform e (BPAG1e)). Plectin 1a and BP230 are connected to the intermediate filaments and to the cell surface receptor alpha6beta4 integrin, which in turn is connected to laminin 332, a component of the anchoring filaments. Further essential adhesion proteins are BP180, a transmembrane protein, laminin gamma1 and type VII collagen. Latter protein is the major constituent of the anchoring fibrils. Mutations in the corresponding genes of these adhesion molecules lead to inherited epidermolysis bullosa emphasizing the importance of these proteins for the integrity of the dermal epidermal junction. This review will provide an overview on the structure and function of the proteins situated in the dermal-epidermal junction targeted by autoantibodies. PMID- 28887825 TI - Performance of a multi leaf collimator system for MR-guided radiation therapy. AB - PURPOSE: The purpose of this study was to investigate and characterize the performance of a Multi Leaf Collimator (MLC) designed for Cobalt-60 based MR guided radiation therapy system in a 0.35 T magnetic field. METHODS: The MLC design and unique assembly features in the ViewRay MRIdian system were first reviewed. The RF cage shielding of MLC motor and cables were evaluated using ACR phantoms with real-time imaging and quantified by signal-to-noise ratio. The dosimetric characterizations, including the leaf transmission, leaf penumbra, tongue-and-groove effect, were investigated using radiosensitive films. The output factor of MLC-defined fields was measured with ionization chambers for both symmetric fields from 2.1 * 2.1 cm2 to 27.3 * 27.3 cm2 and asymmetric fields from 10.5 * 10.5 cm2 to 10.5 * 2.0 cm2 . Multi leaf collimator (MLC) positional accuracy was assessed by delivering either a picket fence (PF) style pattern on radiochromic films with wire-jig phantom or double and triple-rectangular patterns on ArcCheck-MR (Sun Nuclear, Melbourne, FL, USA) with gamma analysis as the pass/fail indicator. Leaf speed tests were performed to assess the capability of full range leaf travel within manufacture's specifications. Multi leaf collimator plan delivery reproducibility was tested by repeatedly delivering both open fields and fields with irregular shaped segments over 1-month period. RESULTS: Comparable SNRs within 4% were observed for MLC moving and stationary plans on vendor-reconstructed images, and the direct k-space reconstructed images showed that the three SNRs are within 1%. The maximum leaf transmission for all three MLCs was less than 0.35% and the average leakage was 0.153 +/- 0.006%, 0.151 +/- 0.008%, and 0.159 +/- 0.015% for head 1, 2, and 3, respectively. Both the leaf edge and leaf end penumbra showed comparable values within 0.05 cm, and the measured values are within 0.1 cm with TPS values. The leaf edge TG effect indicated 10% underdose and the leaf end TG showed a shifted dose distribution with 0.3 cm offset. The leaf positioning test showed a 0.2 cm accuracy in the PF style test, and a gamma passing rate above 96% was observed with a 3%/2 mm criteria when comparing the measured double/triple-rectangular pattern fluence with TPS calculated fluence. The average leaf speed when executing the test plan fell in a range from 1.86 to 1.95 cm/s. The measured and TPS calculated output factors were within 2% for squared fields and within 3% for rectangular fields. The reproducibility test showed the deviation of output factors were well within 2% for square fields and the gamma passing rate within 1.5% for fields with irregular segments. The Monte Carlo predicted output factors were within 2% compared to TPS values. 15 out of the 16 IMRT plans have gamma passing rate more than 98% compared to the TPS fluence with an average passing rate of 99.1 +/- 0.6%. CONCLUSION: The MRIdian MLC has a good RF noise shielding design, low radiation leakage, good positioning accuracy, comparable TG effect, and can be modeled by an independent Monte Carlo calculation platform. PMID- 28887826 TI - Job contenders: roles of the beta-barrel assembly machinery and the translocation and assembly module in autotransporter secretion. AB - In Gram-negative bacteria, autotransporters secrete effector protein domains that are linked to virulence. Although they were once thought to be simple and autonomous secretion machines, mounting evidence reveals that multiple factors of the bacterial envelope are necessary for autotransporter assembly. Secretion across the outer membrane of their soluble effector "passenger domain" is promoted by the assembly of an outer membrane-spanning "beta-barrel domain". Both reactions require BamA, an essential component of the beta-barrel assembly machinery (BAM complex) that catalyzes the final reaction step by which outer membrane proteins are integrated into the lipid bilayer. A large amount of data generated in the last decade has shed key insights onto the mechanistic coordination of autotransporter beta-barrel domain assembly and passenger domain secretion. These results, together with the recently solved structures of the BAM complex, offer an unprecedented opportunity to discuss a detailed model of autotransporter assembly. Importantly, some autotransporters benefit from the presence of an additional machinery, the translocation and assembly module (TAM), a two-membrane spanning complex, which contains a BamA-homologous subunit. Although it remains unclear how the BAM complex and the TAM cooperate, it is evident that multiple preparatory steps are necessary for efficient autotransporter biogenesis. PMID- 28887827 TI - A universal parameterized gradient-based method for photon beam field size determination. AB - PURPOSE: To propose a universal, parameterized gradient-based method (PGM) for radiation field size determination. METHODS: The PGM locates the beam profile's edge by parameterizing its penumbra region with a modified sigmoid function where the inflection point can be determined in a closed form. The parametrization was validated with filter-flattened (FF), flattening-filter-free (FFF) and wedged profiles measured on two Elekta linac models (Synergy and Versa HD). Gamma analysis with the delta dose function set to zero was used to quantitatively assess the parameterization accuracy. Field sizes of FF beams were calculated with the PGM and the full width at half maximum (FWHM) methods for comparison. To assess the consistency of the PGM and the FWHM method with geometric scaling across different depths, the calculated field size at a reference depth was scaled to other depths and compared with the field sizes calculated from the measured profiles. The method was also validated against a maximum-slope method (MSM) with wedge and FFF profiles. We also evaluated the robustness of the three methods with respect to measurement noise, varying scanning step sizes, detector characteristics, and beam energy/modality. RESULTS: Small distance-to-agreement (0.02 +/- 0.02 mm) between the measured and parameterized penumbra region was observed for all profiles. The differences between the field sizes calculated with the FWHM method and the PGM were consistent (0.9 +/- 0.3 mm), with the FWHM method yielding larger values. With geometrical scaling, the PGM and the FWHM method produced maximum differences of 0.26 and 1.16 mm, respectively. For wedge and FFF beams, the mean differences relative to FF fields were 0.15 +/- 0.09 mm and 0.57 +/- 0.91 mm for the PGM and the MSM, respectively. The PGM was also found to produce more consistent results than the FWHM method and the MSM when measurement noise, scanning step size, detector characteristics, and beam energy/modality changed. CONCLUSION: The proposed PGM is universally applicable to all beam modalities (FF, wedge and FFF) for accurate field size determination. Compared to the FWHM and the MSM, it is more robust to variations in measurement condition and detection system. PMID- 28887828 TI - Opportunities for Students to Prescribe: An Evaluation of 185 Consultations in the Student-run Cardiovascular Risk Management Programme. AB - Involving students in cardiovascular risk management (CVRM) could offer patients a structured CVRM programme and students a valuable learning opportunity. We describe and evaluate a student-run CVRM programme that was set up to offer primary prevention to patients with known risk factors in a general practitioner's practice. During a consultation, two undergraduate medical students assessed the patients' actual risk and formulated a CVRM plan, which they discussed with the patient after approval by a GP. After the consultations, patients were asked to complete evaluation/feedback questionnaires. From December 2014 to December 2015, 185 consultations were carried out by 46 students. Feedback questionnaires of 153 consultations were returned, in which patient satisfaction was 8.43 (1-10, min-max). The cardiovascular risk of 95 patients was determined, and in >50% patients, it was 'high'. Participating students and GPs were enthusiastic about the (pharmacotherapy) learning opportunities and improved CVRM care while contributing to real patient care in this CVRM programme. PMID- 28887829 TI - Using Public Data for Comparative Proteome Analysis in Precision Medicine Programs. AB - PURPOSE: Maximizing the clinical utility of information obtained in longitudinal precision medicine programs would benefit from robust comparative analyses to known information to assess biological features of patient material toward identifying the underlying features driving their disease phenotype. Herein, the potential for utilizing publically deposited mass-spectrometry-based proteomics data to perform inter-study comparisons of cell-line or tumor-tissue materials is investigated. EXPERIMENTAL DESIGN: To investigate the robustness of comparison between MS-based proteomics studies carried out with different methodologies, deposited data representative of label-free (MS1) and isobaric tagging (MS2 and MS3 quantification) are utilized. RESULTS: In-depth quantitative proteomics data acquired from analysis of ovarian cancer cell lines revealed the robust recapitulation of observable gene expression dynamics between individual studies carried out using significantly different methodologies. The observed signatures enable robust inter-study clustering of cell line samples. In addition, the ability to classify and cluster tumor samples based on observed gene expression trends when using a single patient sample is established. With this analysis, relevant gene expression dynamics are obtained from a single patient tumor, in the context of a precision medicine analysis, by leveraging a large cohort of repository data as a comparator. CONCLUSION AND CLINICAL RELEVANCE: Together, these data establish the potential for state-of-the-art MS-based proteomics data to serve as resources for robust comparative analyses in precision medicine applications. PMID- 28887830 TI - Atom-Transfer Radical Addition to Unactivated Alkenes by using Heterogeneous Visible-Light Photocatalysis. AB - Heterogeneous visible-light photocatalysis represents an important route toward the development of sustainable organic synthesis. In this study visible light induced, heavy metal-free atom-transfer radical addition to unactivated terminal olefins is carried out by using the combination of heterogeneous titanium dioxide as photocatalyst and a hypervalent iodine(III) reagent as co-initiator. The reaction can be applied to a range of substrates with good functional-group tolerance under very mild conditions. In addition to a number of commonly used atom-transfer reagents, the relatively challenging chloroform is also suitable. PMID- 28887831 TI - Quality improvement in rhinology. PMID- 28887832 TI - Extracellular vesicles from oral squamous carcinoma cells display pro- and anti angiogenic properties. AB - BACKGROUND: A new intercellular communication mode established by neoplastic cells and tumor microenvironment components is based on extracellular vesicles (EVs). However, the biological effects of the EVs released by tumor cells on angiogenesis are not completely understood. Here, we aimed to understand the biological effects of EVs isolated from two cell lines of oral squamous cell carcinoma (OSCC) (SCC15 and HSC3) on endothelial cell tubulogenesis. METHODS: OSCC-derived EVs were isolated with a polymer-based precipitation method, quantified using nanoparticle tracking analysis and verified for EV markers by dot blot. Functional assays were performed to assess the angiogenic potential of the OSCC-derived EVs. RESULTS: The results showed that EVs derived from both cell lines displayed typical spherical-shaped morphology and expressed the EV markers CD63 and Annexin II. Although the average particle concentration and size were quite similar, SCC15-derived EVs promoted a pronounced tubular formation associated with significant migration and apoptosis rates of the endothelial cells, whereas EVs derived from HSC3 cells inhibited significantly endothelial cell tubulogenesis and proliferation. CONCLUSION: The findings of this study reveal that EVs derived from different OSCC cell lines by a polymer-based precipitation method promote pro- or anti-angiogenic effects. PMID- 28887833 TI - Gas-Phase Synthesis of the Elusive Cyclooctatetraenyl Radical (C8 H7 ) via Triplet Aromatic Cyclooctatetraene (C8 H8 ) and Non-Aromatic Cyclooctatriene (C8 H8 ) Intermediates. AB - The 1,2,4,7-cyclooctatetraenyl radical (C8 H7 ) has been synthesized for the very first time via the bimolecular gas-phase reaction of ground-state carbon atoms with 1,3,5-cycloheptatriene (C7 H8 ) on the triplet surface under single collision conditions. The barrier-less route to the cyclic 1,2,4,7 cyclooctatetraenyl radical accesses exotic reaction intermediates on the triplet surface, which cannot be synthesized via classical organic chemistry methods: the triplet non-aromatic 2,4,6-cyclooctatriene (C8 H8 ) and the triplet aromatic 1,3,5,7-cyclooctatetraene (C8 H8 ). Our approach provides a clean gas-phase synthesis of this hitherto elusive cyclic radical species 1,2,4,7 cyclooctatetraenyl via a single-collision event and opens up a versatile, unconventional path to access this previously largely obscure class of cyclooctatetraenyl radicals, which have been impossible to access through classical synthetic methods. PMID- 28887834 TI - Comparison of anatomic and non-anatomic hepatic resection for hepatocellular carcinoma. AB - BACKGROUND: The aim of the present study was to compare the prognostic impact of anatomic resection (AR) versus non-anatomic resection (NAR) on patient survival after resection of a single hepatocellular carcinoma (HCC). METHODS: To control for confounding variable distributions, a 1-to-1 propensity score match was applied to compare the outcomes of AR and NAR. Among 710 patients with a primary, solitary HCC of <5.0 cm in diameter that was resectable by either AR or NAR from 2003 to 2007 in Japan and Korea, 355 patients underwent NAR and 355 underwent AR of at least one section with complete removal of the portal territory containing the tumor. RESULTS: Overall survival (OS) was better in the AR than NAR group (hazard ratio 1.67, 95% confidence interval 1.28-2.19, P < 0.001) while disease free survival showed no significant difference. Significantly fewer patients in the AR than NAR group developed intrahepatic HCC recurrence and multiple intrahepatic recurrences. Patients with poorly differentiated HCC who underwent AR had improved disease-free survival and OS. CONCLUSIONS: Anatomic resection decreases the risk of tumor recurrence and improves OS in patients with a primary, solitary HCC of <5.0 cm in diameter. PMID- 28887835 TI - Prenatal attitudes toward vaginal delivery and actual delivery mode: Variation by race/ethnicity and socioeconomic status. AB - OBJECTIVES: Researchers documenting persistent racial/ethnic and socioeconomic status disparities in chances of cesarean delivery have speculated that women's birth attitudes and preferences may partially explain these differences, but no studies have directly tested this hypothesis. We examined whether women's prenatal attitudes toward vaginal delivery differed by race/ethnicity or socioeconomic status, and whether attitudes were differently related to delivery mode depending on race/ethnicity or socioeconomic status. METHODS: Data were from the First Baby Study, a cohort of 3006 women who gave birth to a first baby in Pennsylvania between 2009 and 2011. We used regression models to examine (1) predictors of prenatal attitudes toward vaginal delivery, and (2) the association between prenatal attitudes and actual delivery mode. To assess moderation, we estimated models adding interaction terms. RESULTS: Prenatal attitudes toward vaginal delivery were not associated with race/ethnicity or socioeconomic status. Positive attitudes toward vaginal delivery were associated with lower odds of cesarean delivery (AOR=0.60, P < .001). However, vaginal delivery attitudes were only related to delivery mode among women who were white, highly educated, and privately insured. CONCLUSIONS: There are racial/ethnic differences in chances of cesarean delivery, and these differences are not explained by birth attitudes. Furthermore, our findings suggest that white and high-socioeconomic status women may be more able to realize their preferences in childbirth. PMID- 28887836 TI - A novel method for quantification of beam's-eye-view tumor tracking performance. AB - PURPOSE: In-treatment imaging using an electronic portal imaging device (EPID) can be used to confirm patient and tumor positioning. Real-time tumor tracking performance using current digital megavolt (MV) imagers is hindered by poor image quality. Novel EPID designs may help to improve quantum noise response, while also preserving the high spatial resolution of the current clinical detector. Recently investigated EPID design improvements include but are not limited to multi-layer imager (MLI) architecture, thick crystalline and amorphous scintillators, and phosphor pixilation and focusing. The goal of the present study was to provide a method of quantitating improvement in tracking performance as well as to reveal the physical underpinnings of detector design that impact tracking quality. The study employs a generalizable ideal observer methodology for the quantification of tumor tracking performance. The analysis is applied to study both the effect of increasing scintillator thickness on a standard, single layer imager (SLI) design as well as the effect of MLI architecture on tracking performance. METHODS: The present study uses the ideal observer signal-to-noise ratio (d') as a surrogate for tracking performance. We employ functions which model clinically relevant tasks and generalized frequency-domain imaging metrics to connect image quality with tumor tracking. A detection task for relevant Cartesian shapes (i.e., spheres and cylinders) was used to quantitate trackability of cases employing fiducial markers. Automated lung tumor tracking algorithms often leverage the differences in benign and malignant lung tissue textures. These types of algorithms (e.g., soft-tissue localization - STiL) were simulated by designing a discrimination task, which quantifies the differentiation of tissue textures, measured experimentally and fit as a power law in trend (with exponent beta) using a cohort of MV images of patient lungs. The modeled MTF and NPS were used to investigate the effect of scintillator thickness and MLI architecture on tumor tracking performance. RESULTS: Quantification of MV images of lung tissue as an inverse power-law with respect to frequency yields exponent values of beta = 3.11 and 3.29 for benign and malignant tissues, respectively. Tracking performance with and without fiducials was found to be generally limited by quantum noise, a factor dominated by quantum detective efficiency (QDE). For generic SLI construction, increasing the scintillator thickness (gadolinium oxysulfide - GOS) from a standard 290 MUm to 1720 MUm reduces noise to about 10%. However, 81% of this reduction is appreciated between 290 and 1000 MUm. In comparing MLI and SLI detectors of equivalent individual GOS layer thickness, the improvement in noise is equal to the number of layers in the detector (i.e., 4) with almost no difference in MTF. Further, improvement in tracking performance was slightly less than the square root of the reduction in noise, approximately 84-90%. In comparing an MLI detector with an SLI with a GOS scintillator of equivalent total thickness, improvement in object detectability is approximately 34-39%. CONCLUSIONS: We have presented a novel method for quantification of tumor tracking quality and have applied this model to evaluate the performance of SLI and MLI EPID designs. We showed that improved tracking quality is primarily limited by improvements in NPS. When compared to very thick scintillator SLI, employing MLI architecture exhibits the same gains in QDE, but by mitigating the effect of optical Swank noise, results in more dramatic improvements in tracking performance. PMID- 28887837 TI - Characterization of proton pencil beam scanning and passive beam using a high spatial resolution solid-state microdosimeter. AB - PURPOSE: This work aims to characterize a proton pencil beam scanning (PBS) and passive double scattering (DS) systems as well as to measure parameters relevant to the relative biological effectiveness (RBE) of the beam using a silicon on insulator (SOI) microdosimeter with well-defined 3D sensitive volumes (SV). The dose equivalent downstream and laterally outside of a clinical PBS treatment field was assessed and compared to that of a DS beam. METHODS: A novel silicon microdosimeter with well-defined 3D SVs was used in this study. It was connected to low noise electronics, allowing for detection of lineal energies as low as 0.15 keV/MUm. The microdosimeter was placed at various depths in a water phantom along the central axis of the proton beam, and at the distal part of the spread out Bragg peak (SOBP) in 0.5 mm increments. The RBE values of the pristine Bragg peak (BP) and SOBP were derived using the measured microdosimetric lineal energy spectra as inputs to the modified microdosimetric kinetic model (MKM). Geant4 simulations were performed in order to verify the calculated depth-dose distribution from the treatment planning system (TPS) and to compare the simulated dose-mean lineal energy to the experimental results. RESULTS: For a 131 MeV PBS spot (124.6 mm R90 range in water), the measured dose-mean lineal energy yD- increased from 2 keV/MUm at the entrance to 8 keV/MUm in the BP, with a maximum value of 10 keV/MUm at the distal edge. The derived RBE distribution for the PBS beam slowly increased from 0.97 +/- 0.14 at the entrance to 1.04 +/- 0.09 proximal to the BP, then to 1.1 +/- 0.08 in the BP, and steeply rose to 1.57 +/- 0.19 at the distal part of the BP. The RBE distribution for the DS SOBP beam was approximately 0.96 +/- 0.16 to 1.01 +/- 0.16 at shallow depths, and 1.01 +/- 0.16 to 1.28 +/- 0.17 within the SOBP. The RBE significantly increased from 1.29 +/- 0.17 to 1.43 +/- 0.18 at the distal edge of the SOBP. CONCLUSIONS: The SOI microdosimeter with its well-defined 3D SV has applicability in characterizing proton radiation fields and can measure relevant physical parameters to model the RBE with submillimeter spatial resolution. It has been shown that for a physical dose of 1.82 Gy at the BP, the derived RBE based on the MKM model increased from 1.14 to 1.6 in the BP and its distal part. Good agreement was observed between the experimental and simulation results, confirming the potential application of SOI microdosimeter with 3D SV for quality assurance in proton therapy. PMID- 28887838 TI - Diagnostic accuracy of optical coherence tomography inter-eye percentage difference for optic neuritis in multiple sclerosis. AB - BACKGROUND AND PURPOSE: Multiple sclerosis-associated optic neuritis (MSON) causes atrophy of the inner retinal layers, which can be quantified by optical coherence tomography. It has been suggested that the inter-eye percentage difference (IEPD) of atrophy may be of diagnostic value in MSON. METHODS: This was a prospective, cross-sectional study in patients with multiple sclerosis and healthy controls (HCs). Spectral-domain optical coherence tomography of both eyes was performed, followed by automated retinal layer segmentation of the peri papillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (mGCIPL). Receiver operator characteristics curves were plotted and the area under the curve was calculated for group comparisons of the IEPD of the pRNFL and mGCIPL. RESULTS: There were 39 patients with bilateral MSON, 62 patients with unilateral MSON, 106 patients without MSON and 63 HCs. Diagnostic accuracy (area under the curve) of the IEPD was 0.73-0.86 for the pRNFL and 0.75 0.94 for the mGCIPL. The diagnostic sensitivity of the mGCIPL IEPD was 70% with a specificity of 97% for distinguishing unilateral MSON from HCs. For the comparison of bilateral MSON with HCs, sensitivity was 86% with a specificity of 97%. CONCLUSIONS: The IEPD of the pRNFL, and more particularly the IEPD of the mGCIPL, is a useful diagnostic measure for MSON. The IEPD is a dimensionless unit and may therefore contribute to overcome device and proprietary segmentation algorithm limitations. PMID- 28887839 TI - Anti-inflammatory effect of astaxanthin in phthalic anhydride-induced atopic dermatitis animal model. AB - In this study, we investigated anti-dermatitic effects of astaxanthin (AST) in phthalic anhydride (PA)-induced atopic dermatitis (AD) animal model as well as in vitro model. AD-like lesion was induced by the topical application of 5% PA to the dorsal skin or ear of Hos:HR-1 mouse. After AD induction, 100 MUL of 1 mg/mL and 2 mg/mL of AST (10 MUg or 20 MUg/cm2 ) was spread on the dorsum of ear or back skin three times a week for four weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB) activity. We also measured tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and immunoglobulin E (IgE) concentration in the blood of AD mice by enzyme-linked immunosorbent assay (ELISA). AST treatment attenuated the development of PA induced AD. Histological analysis showed that AST inhibited hyperkeratosis, mast cells and infiltration of inflammatory cells. AST treatment inhibited expression of iNOS and COX-2, and NF-kappaB activity as well as release of TNF-alpha, IL 1beta, IL-6 and IgE. In addition, AST (5, 10 and 20 MUM) potently inhibited lipopolysaccharide (LPS) (1 MUg/mL)-induced nitric oxide (NO) production, expression of iNOS and COX-2 and NF-kappaB DNA binding activities in RAW 264.7 macrophage cells. Our data demonstrated that AST could be a promising agent for AD by inhibition of NF-kappaB signalling. PMID- 28887840 TI - Pre-clinical evaluation of N-acetylcysteine reveals side effects in the mdx mouse model of Duchenne muscular dystrophy. AB - KEY POINTS: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation and oxidative stress. The antioxidant N acetylcysteine (NAC) has been proposed as a therapeutic intervention for DMD boys, but potential adverse effects of NAC have not been widely investigated. We used young (6 weeks old) growing mdx mice to investigate the capacity of NAC supplementation (2% in drinking water for 6 weeks) to improve dystrophic muscle function and to explore broader systemic effects of NAC treatment. NAC treatment improved normalised measures of muscle function, and decreased inflammation and oxidative stress, but significantly reduced body weight gain, muscle weight and liver weight. Unexpected significant adverse effects of NAC on body and muscle weights indicate that interpretation of muscle function based on normalised force measures should be made with caution and careful consideration is needed when proposing the use of NAC as a therapeutic treatment for young DMD boys. ABSTRACT: Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle wasting disease characterised by severe muscle weakness, necrosis, inflammation and oxidative stress. The antioxidant N-acetylcysteine (NAC) has been proposed as a potential therapeutic intervention for DMD boys. We investigated the capacity of NAC to improve dystrophic muscle function in the mdx mouse model of DMD. Young (6 weeks old) mdx and non-dystrophic C57 mice receiving 2% NAC in drinking water for 6 weeks were compared with untreated mice. Grip strength and body weight were measured weekly, before the 12 week old mice were anaesthetised and extensor digitorum longus (EDL) muscles were excised for functional analysis and tissues were sampled for biochemical analyses. Compared to untreated mice, the mean (SD) normalised grip strength was significantly greater in NAC-treated mdx [3.13 (0.58) vs 4.87 (0.78) g body weight (bw)-1 ; P < 0.001] and C57 mice [3.90 (0.32) vs 5.32 (0.60) g bw-1 ; P < 0.001]. Maximum specific force was significantly greater in NAC-treated mdx muscles [9.80 (2.27) vs 13.07 (3.37) N cm-2 ; P = 0.038]. Increased force in mdx mice was associated with reduced thiol oxidation and inflammation in fast muscles, and increased citrate synthase activity in slow muscle. Importantly, NAC significantly impaired body weight gain in both strains of young growing mice, and reduced liver weight in C57 mice and muscle weight in mdx mice. These potentially adverse effects of NAC emphasise the need for caution when interpreting improvements in muscle function based on normalised force measures, and that careful consideration be given to these effects when proposing NAC as a potential treatment for young DMD boys. PMID- 28887841 TI - Evidence for a contributory role of a xenogeneic immune response in experimental epidermolysis bullosa acquisita. AB - Autoimmune diseases affect a large fraction of the population in Western countries. To elucidate the underlying causes, autoantibody transfer-induced mouse models have been established that greatly contributed to the understanding of the pathophysiology of these diseases. However, the role of a potentially co occurring murine xenogeneic immune response to commonly utilized rabbit anti mouse IgG remains poorly understood. Using the established rabbit anti-mouse type VII collagen (COL7) IgG-induced mouse model of the mucocutaneous blistering disorder epidermolysis bullosa acquisita (EBA), we found in this study a profound T- and B-cell response along with an altered cytokine expression profile in draining lymph nodes of mice injected with the xenogeneic IgG. This was associated with the formation of circulating and skin-bound mouse anti-rabbit IgG in wild-type but not CD154-deficient or B-cell-deficient JHT mice challenged with pathogenic rabbit IgG. Development of EBA skin lesions was attenuated in the two mouse strains lacking a B-cell response at later observation time points, but was not affected in mice treated with the T-cell trafficking blocker FTY720. Collectively, our results implicate a host's xenoreactive immune response to rabbit anti-mouse COL7 IgG, a confounding effect that may contribute to immune complex-driven inflammation and tissue damage in this antibody transfer-induced EBA mouse model, especially at later time points. In this regard, it may be recommended to finish the evaluation of results obtained by experiments employing antibody-transferred mouse models within the first 2 weeks after the pathogenic antibody injection. PMID- 28887842 TI - Seasonally-induced alterations of some facial signs in Caucasian women and their changes induced by a daily application of a photo-protective product. AB - OBJECTIVES: These were two-fold: (i) to assess the possible changes in some facial signs induced in a 6-month period by the periodical shift from winter to summer in Caucasian women and (ii) to appraise the preventive effects of a strong photo-protective product. METHODS: The facial signs of two cohorts of French women (N= 40 and 42), of comparable ages were graded between winter to summer. One group was left unprotected whereas the other daily applied a strong photo protective product for 6 months. Facial signs (structural and pigmentation related) were graded in blind by a panel of 12 experts from photographs taken under standard conditions. A global and focused analysis of the skin colour or dark spots, when present, was carried out through spectro-radiometry under diffuse and standardized visible light, using the L*, a*, b* referential system. RESULTS: The unprotected group showed significant changes in summer as compared to winter on 10 facial signs (two-third of the studied signs) that presented an increased severity, of variable respective amplitude. Five signs among the 10 were particularly and significantly affected by the seasonal transition, of an amplitude above the precision of the grading scale. Three of these five signs concerned structural elements (wrinkles), the two others being related to vascular disorders (redness). These season-induced alterations appear efficiently reduced in the photo-protected group. The colour of the facial skin then appears more homogeneous, less red, less dull, all criteria being quantified by the L*, a*, b* referential system. The comparison with a previous work carried out on Chinese women, through a similar protocol, shows that the photo-protective product brings, in Caucasian women, a more important effect upon structural and vascular features than upon pigmentation disorders, inversely to the results previously observed in Chinese women. CONCLUSION: The alterations in some facial signs occurring in a 6-month period between winter and summer are confirmed in Caucasian women, mostly related to structural (wrinkles) and vascular elements. Such changes appear alleviated or prevented by daily applications of a strong sun photo-protective product. PMID- 28887844 TI - House dust mite allergens Der f and Der p induce IL-31 production by blood derived T cells from atopic dermatitis patients. AB - Aero-allergens, such as house dust mite (HDM), have been suggested to play a role in the initiation of atopic dermatitis (AD)-related skin inflammation. Here, we analysed the proliferation and the cytokine expression of blood-derived T cells from AD and healthy individuals upon HDM-allergen stimulation. The proliferating cells from healthy individuals and AD patients had a significantly different, distinct cytokine profile: in AD blood, we found increased frequencies of HDM reactive IL-31-producing T cells, as well as a decreased Th1/Th2 and Tc1/Tc2 ratio, suggesting that allergen-specific T cells in blood of chronic AD patients are subject to pre-existent Th2-Tc2 and "Th31-Tc31" programming. PMID- 28887845 TI - Contemporary Issues in Women's Health. PMID- 28887843 TI - Determinants of HDL Cholesterol Efflux Capacity after Virgin Olive Oil Ingestion: Interrelationships with Fluidity of HDL Monolayer. AB - SCOPE: Cholesterol efflux capacity of HDL (CEC) is inversely associated with cardiovascular risk. HDL composition, fluidity, oxidation, and size are related with CEC. We aimed to assess which HDL parameters were CEC determinants after virgin olive oil (VOO) ingestion. METHODS AND RESULTS: Post-hoc analyses from the VOHF study, a crossover intervention with three types of VOO. We assessed the relationship of 3-week changes in HDL-related variables after intervention periods with independence of the type of VOO. After univariate analyses, mixed linear models were fitted with variables related with CEC and fluidity. Fluidity and Apolipoprotein (Apo)A-I content in HDL was directly associated, and HDL oxidative status inversely, with CEC. A reduction in free cholesterol, an increase in triglycerides in HDL, and a decrease in small HDL particle number or an increase in HDL mean size, were associated to HDL fluidity. CONCLUSIONS: HDL fluidity, ApoA-I concentration, and oxidative status are major determinants for CEC after VOO. The impact on CEC of changes in free cholesterol and triglycerides in HDL, and those of small HDL or HDL mean size, could be mechanistically linked through HDL fluidity. Our work points out novel therapeutic targets to improve HDL functionality in humans through nutritional or pharmacological interventions. PMID- 28887846 TI - Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism. AB - Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remains unsolved in many cases. In a Chinese Han family segregated with sensorineural hearing loss and leukoencephalopathy, candidate pathogenic variants were identified by targeted next-generation sequencing of 144 genes associated with deafness and 108 genes with leukoencephalopathy. Novel compound heterozygous mutations p.R477H and p.P505S were identified in KARS, which encodes lysyl-tRNA synthetase (LysRS), as the only candidate causative variants. These two mutations were functionally characterized by enzymatic assays, immunofluorescence, circular dichroism analysis, and gel filtration chromatography. Despite no alteration in the dimer-tetramer oligomerization and cellular distribution by either mutation, the protein structure was notably influenced by the R477H mutation, which subsequently released the protein from the multiple-synthetase complex (MSC). Mutant LysRSs with the R477H and P505S mutations had decreased tRNALys aminoacylation and displayed a cumulative effect when introduced simultaneously. Our studies showed that mutations in KARS lead to a newly defined subtype of leukoencephalopathy associated with sensorineural hearing impairment. The combined effect of reduced aminoacylation and release of LysRS from the MSC likely underlies the pathogenesis of the KARS mutations identified in this study. PMID- 28887847 TI - Fournier's gangrene in a man on empagliflozin for treatment of Type 2 diabetes. AB - BACKGROUND: Sodium-glucose cotransporter 2 (SLGT2) inhibitors has been associated with an increased risk of genital infections secondary to increased glycosuria. CASE REPORT: We report a case of a 41-year-old man with type 2 diabetes treated with empagliflozin and metformin who presented with scrotal swelling. He described multiple preceding episodes of genital thrush for which he self administered over-the-counter anti-fungal treatment. On examination, he was afebrile and hemodynamically stable. Perineal examination revealed grossly swollen and indurated scrotum with bilateral inguinal lymphadenopathy. Investigations showed elevated inflammatory markers and HbA1c of 99 mmol/mol (11.2%). Computed tomography revealed features consistent with Fournier's gangrene. He underwent emergency exploration and debridement under anaesthetic with a later return to theatre for further exploration, washout and application of a vacuum dressing. He then received a split skin graft to his perineum. He required a 2-week course of intravenous antibiotics and was discharged home on oral antibiotics. Empagliflozin was ceased on admission and he was commenced on a basal bolus insulin regimen for glycaemic optimisation. CONCLUSION: There is a wide clinical spectrum of genital infections associated with SGLT2 inhibitors with most being generally mild and easily treated. However, risk factors such as diabetes, obesity, immunosuppressed states, smoking, alcohol abuse and end-stage renal or liver failure may increase the risk of potentially more severe infections such as Fournier's gangrene. Timely cessation of SGLT2 inhibitors in individuals with multiple risk factors may help prevent progression to more severe genital infections. PMID- 28887848 TI - A numerical classification system for cleft lip and palate in the dog. AB - An easy-to-use classification that enables an accurate record of canine cleft lip and palate is fundamental for effective communication between professionals and researchers and optimal use of published information. Here we present how a classification system for human cleft lip and palate can be used to register spontaneous cases in dogs, highlighting its advantages. This system is based on four topographic areas with a numerical representation of the severity of the cleft in each area. The use of spontaneous cases has the advantage of providing clefts that are naturally similar to their human counterparts for surgical, genetic and genomic studies and, furthermore, will reduce the need for experimental models of this condition. PMID- 28887849 TI - Extended Ladder-Type Benzo[k]tetraphene-Derived Oligomers. AB - Well-defined, fused-ring aromatic oligomers represent promising candidates for the fundamental understanding and application of advanced carbon-rich materials, though bottom-up synthesis and structure-property correlation of these compounds remain challenging. In this work, an efficient synthetic route was employed to construct extended benzo[k]tetraphene-derived oligomers with up to 13 fused rings. The molecular and electronic structures of these compounds were clearly elucidated. Precise correlation of molecular sizes and crystallization dynamics was established, thus demonstrating the pivotal balance between intermolecular interaction and molecular mobility for optimized processing of highly ordered solids of these extended conjugated molecules. PMID- 28887850 TI - Wear profile of canal wall surfaces and bond strength of endodontic sealers after in situ acid challenge. AB - AIM: To evaluate the wear of root wall surfaces, the bond strength of sealers to dentine and the demineralization around root filling materials after canals were exposed to acid challenge in situ. METHODOLOGY: Eighty-seven roots of mandibular incisors were selected. Thirty-two were used in the laboratory bond strength study (n = 8), and 55 in the in situ study (n = 11). Root canals were prepared biomechanically and then filled with gutta-percha and AH Plus, MTA Fillapex, Sealapex or Endofill. For 14 days, 11 participants used intra-oral devices with five sterilized roots (four experimental and one control - only canal prepared). Drops of sucrose were dripped onto roots allowing the accumulation of biofilm on canal surfaces. Roots were removed, sectioned and analysed for the following: bond strength of filling material using a push-out test and also wear profile and dentine demineralization using confocal microscopy. Bond strength (MPa) was evaluated by two-way anova and Tukey test (alpha = 0.05), and wear profile was assessed by Kruskal-Wallis and t-tests (alpha = 0.05). RESULTS: AH Plus had the highest bond strength values. Intermediate results were found in roots with MTA Fillapex and Endofill, whilst Sealapex had inferior results (P < 0.05). No significant differences were found amongst root thirds (P > 0.05). For wear profile, samples were associated with degradation of the filling materials after exposure to the oral environment (P < 0.05). Roots had signs of demineralization around the filling material when Sealapex and Endofill were used. CONCLUSIONS: Sealers were not able to prevent degradation of the adhesive interface and dentine. AH Plus and MTA Fillapex had superior bond strength to dentine and less intense demineralization around the root filling. PMID- 28887851 TI - Comparison of four extraction methods for analysis of volatile hop-derived aroma compounds in beer. AB - The volatile organic compound profile in beer is derived from hops, malt, yeast, and interactions between the ingredients, making it very diverse and complex. Due to the range and diversity of the volatile organic compounds present, the choice of the extraction method is extremely important for optimal sensitivity and selectivity. This study compared four extraction methods for hop-derived compounds in beer late hopped with Nelson Sauvin. Extraction capacity and variation were compared for headspace solid-phase micro extraction, stir bar sorptive extraction, headspace sorptive extraction, and solvent-assisted flavor evaporation. Generally, stir bar sorptive extraction was better suited for acids, headspace sorptive extraction for esters and aldehydes, while headspace solid phase microextraction was less sensitive overall, extracting 40% fewer compounds. Solvent-assisted flavor evaporation with dichloromethane was not suitable for the extraction of hop-derived volatile organic compounds in beer, as the profile was strongly skewed towards alcohols and acids. Overall, headspace sorptive extraction is found to be best suited, closely followed by stir bar sorptive extraction. PMID- 28887852 TI - CD8+ lineage dendritic cells determine adaptive immune responses to inflammasome activation upon sterile skin injury. AB - The molecular links between sterile inflammation and induction of adaptive immunity have not been fully identified. Here, we examine how damage-associated molecular patterns (DAMPs), as opposed to pathogen-associated molecules (PAMPs), regulate the immune response to non-self-antigens presented at the site of a physical injury. Heat applied briefly to the skin invokes sterile inflammation, characterized by local cell death and caspase-1 activation without demonstrably disrupting skin integrity. Co-delivery of ovalbumin (OVA) with heat injury induces OVA-specific CD8+ T-cell responses, and this is dependent on caspase-1 activation and MyD88 signalling. Using Id2flox/flox-CD11cCre+ mice, we demonstrate that CD8+ lineage DCs are required to induce OVA-specific CD8+ T-cell responses following heat injury. Consistent with this observation, intradermal administration of CD8+ lineage DCs but not CD11b+ lineage DCs restores priming of CD8+ T-cell responses in Casp-1-/- mice. Thus, we conclude that a sterile injury induces CD8+ T-cell immune responses to local antigen through caspase-1 activation and requires CD8+ lineage DCs, a finding of significance for immunotherapy and for the pathogenesis of autoimmunity. PMID- 28887853 TI - Neuroendocrine mechanisms underlying bariatric surgery: Insights from human studies and animal models. AB - Obesity has reached epidemic proportions and, to date, bariatric surgery remains the only effective treatment for morbid obesity in terms of its capacity to achieve durable weight loss. Bariatric surgery procedures, including Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB) and sleeve gastrectomy (SG), have been the primary procedures conducted over the past decade, with SG increasing in popularity over the past 5 years at the expense of both RYGB and AGB. Although these procedures were initially proposed to function via restrictive or malabsorptive mechanisms, it is now clear that profound physiological changes underlie the metabolic improvements in patients who undergo bariatric surgery. Data generated in human patients and animal models highlight the rapid and sustained changes in gut hormones that coincide with these procedures. Furthermore, recent studies highlight the involvement of the nervous system, specifically the vagus nerve, in mediating the reduction in appetite and food intake following bariatric surgery. What is unclear is where these pathways converge and interact within the gut-brain axis and whether vagally-mediated circuits are sufficient to drive the metabolic sequalae following bariatric surgery. PMID- 28887854 TI - Human tissue inhibitor of metalloproteinases-1 improved wound healing in diabetes through its anti-apoptotic effect. AB - Impaired wound healing accompanies severe cell apoptosis in diabetic patients. Tissue inhibitor of metalloproteinases-1 (TIMP-1) was known to have effects on promoting growth and anti-apoptosis for cells. We aimed to determine the actual levels of TIMP-1 and cell apoptosis in: (i) the biopsies of diabetic and non diabetic foot tissue and (ii) the human fibroblasts with or without treatments of advanced glycation end-products (AGEs). Next, we aimed to determine the improved levels of cell apoptosis and wound healing after the treatments of either active protein of TIMP-1 or in vivo expression of gene therapy vector-mediated TIMP-1 in both the human fibroblasts and the animal model of diabetic rats. The levels of TIMP-1 were significantly reduced in diabetic skin tissues and in AGEs-treated fibroblasts. Both AGEs-treated cells were effectively protected from apoptosis by active protein of TIMP-1 at appropriate dose level. So did the induced in vivo TIMP-1 expression after gene delivery. Similar effects were also found on the significant improvement of impaired wound healing in diabetic rats. We concluded that TIMP-1 improved wound healing through its anti-apoptotic effect. Treatments with either active protein TIMP-1 or TIMP-1 gene therapy delivered in local wound sites may be used as a strategy for accelerating diabetic wound healing. PMID- 28887855 TI - Effects of Anhydrous Lanolin versus Breast Milk Combined with a Breast Shell for the Treatment of Nipple Trauma and Pain During Breastfeeding: A Randomized Clinical Trial. AB - INTRODUCTION: The purpose of this study was to compare the effect of anhydrous lanolin with the effect of breast milk combined with a breast shell for treatment of nipple trauma and pain during breastfeeding. METHODS: A randomized clinical trial was conducted in a maternity ward in a hospital accredited as a Baby Friendly Hospital located in the middle-western region of Brazil. Breastfeeding women with obvious nipple trauma were randomized into 2 groups. In both groups, breastfeeding education was conducted. For up to 10 days, in Group 1, anhydrous lanolin was applied daily after each breastfeeding session, whereas in Group 2, breast milk combined with a breast shell was applied. Trauma was assessed using the Nipple Trauma Score, and pain was assessed using a numerical scale and sensory descriptors from the McGill Questionnaire. RESULTS: One hundred women participated, with 50 women in each of the 2 groups. The healing of nipple trauma was faster in the group treated with breast milk combined with a breast shell, starting on the third day of intervention (P = .032). The intensity of pain was lower in the group treated with breast milk combined with a breast shell starting on the fifth day of treatment (P = .008). The use of anhydrous lanolin had a progressively reduced treatment efficacy, with values of 86.4% on the third day (95% confidence interval [CI], -4.5%-98.2%), 58.3% on the fifth day (95% CI, 20.1%-78.3%), 48.1% on the seventh day (95% CI, 20.1%-66.2%), and 26.9.% on the tenth day (95% CI, 6.4%-43%) of intervention. The resolution of nipple trauma was significantly associated with the use of the nipple shell on all intervention days. DISCUSSION: The intervention with breast milk combined with a breast shell was more effective than anhydrous lanolin for the treatment of nipple trauma and pain in breastfeeding women. This treatment should be encouraged among breastfeeding women to promote healing and reduce pain. PMID- 28887857 TI - Development of a patient-specific atrial phantom model for planning and training of inter-atrial interventions. AB - BACKGROUND: Several authors have presented cardiac phantoms to mimic the particularities of the heart, making it suitable for medical training and surgical planning. Although the initial models were mainly focused on the ventricles, personalized phantoms of the atria were recently presented. However, such models are typically rigid, the atrial wall is not realistic and they are not compatible with ultrasound (US), being sub-optimal for planning/training of several interventions. METHODS: In this work, we propose a strategy to construct a patient-specific atrial model. Specifically, the target anatomy is generated using a computed tomography (CT) dataset and then constructed using a mold-cast approach. An accurate representation of the inter-atrial wall (IAS) was ensured during the model generation, allowing its application for IAS interventions. Two phantoms were constructed using different flexible materials (silicone and polyvinyl alcohol cryogel, PVA-C), which were then compared to assess their appropriateness for US acquisition and for the generation of complex anatomies. RESULTS: Two experiments were set up to validate the proposed methodology. First, the accuracy of the manufacturing approach was assessed through the comparison between a post-production CT and the virtual references. The results proved that the silicone-based model was more accurate than the PVA-C-based one, with an error of 1.68 +/- 0.79, 1.36 +/- 0.94, 1.45 +/- 0.77 mm for the left (LA) and right atria (RA) and IAS, respectively. Second, an US acquisition of each model was performed and the obtained images quantitatively and qualitatively assessed. Both models showed a similar performance in terms of visual evaluation, with an easy detection of the LA, RA, and the IAS. Furthermore, a moderate accuracy was obtained between the atrial surfaces extracted from the US and the ideal reference, and again a superior performance of the silicone-based model against the PVA-C phantom was observed. CONCLUSIONS: The proposed strategy proved to be accurate and feasible for the correct generation of complex personalized atrial models. PMID- 28887858 TI - Liver transplantation equity: Supply, demand, and access. PMID- 28887856 TI - Cassava brown streak disease: historical timeline, current knowledge and future prospects. AB - Cassava is the second most important staple food crop in terms of per capita calories consumed in Africa and holds potential for climate change adaptation. Unfortunately, productivity in East and Central Africa is severely constrained by two viral diseases: cassava mosaic disease (CMD) and cassava brown streak disease (CBSD). CBSD was first reported in 1936 from northeast Tanzania. For approximately 70 years, CBSD was restricted to coastal East Africa and so had a relatively low impact on food security compared with CMD. However, at the turn of the 21st century, CBSD re-emerged further inland, in areas around Lake Victoria, and it has since spread through many East and Central African countries, causing high yield losses and jeopardizing the food security of subsistence farmers. This recent re-emergence has attracted intense scientific interest, with studies shedding light on CBSD viral epidemiology, sequence diversity, host interactions and potential sources of resistance within the cassava genome. This review reflects on 80 years of CBSD research history (1936-2016) with a timeline of key events. We provide insights into current CBSD knowledge, management efforts and future prospects for improved understanding needed to underpin effective control and mitigation of impacts on food security. PMID- 28887859 TI - Association between mode of delivery and astigmatism in preschool children. AB - PURPOSE: To determine whether mode of delivery has any impact on astigmatism. METHODS: This case-control study was performed in the Department of Ophthalmology in 2015. Exposure was mode of delivery [vaginal delivery (VD) or caesarean section (CS), which here included both elective and emergency CS]. Outcome was astigmatism (>=2.5 D), which was determined by cycloplegic refraction. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed to assess the associations between mode of delivery and astigmatism from logistic regression models. RESULTS: Of the 659 children studied here (341 boys; mean age, 4.37 years), 440 were born by CS and 219 by VD. The incidence of severe astigmatism (>=2.5 D) in the CS and VD groups was 22.06% and 13.24%, respectively. Children delivered by CS had a 77.9% higher risk of severe astigmatism compared with vaginally delivered children (OR = 1.779; 95% CI, 1.121 to 2.824). After dividing CS into elective CS and emergency CS, children delivered by elective CS had an 87.3% increased risk of severe astigmatism (OR = 1.873; 95% CI, 1.157 to 3.032), but children delivered by emergency CS did not differ from vaginally delivered children. In addition, the children whose mothers had histories of breastfeeding had a 44.6% lower risk of severe astigmatism than children whose mother did not breastfeed them (OR = 0.554, 95% CI, 0.335-0.914). CONCLUSION: Birth by CS, especially elective CS, increases the risk of severe astigmatism (>=2.50 D) in childhood. PMID- 28887860 TI - Regulation of radial glial process growth by glutamate via mGluR5/TRPC3 and neuregulin/ErbB4. AB - Radial glial cells play an essential role through their function as guides for neuronal migration during development. Disruption of metabotropic glutamate receptor 5 (mGluR5) function retards the growth of radial glial processes in vitro. Neuregulins (NRG) are activated by proteolytic cleavage and regulate (radial) glial maintenance via ErbB3/ErbB4 receptors. We show here that blocking ErbB4 disrupts radial process extension. Soluble NRG acting on ErbB4 receptors is able to promote radial process extension in particular where process elongation has been impeded by blockade of mGluR5, the nonselective cation channel canonical transient receptor potential 3 (TRPC3), or matrix metalloproteases (MMP). NRG does not restore retarded process growth caused by ErbB4 blockade. Stimulation of muscarinic receptors restores process elongation due to mGluR5 blockade but not that caused by TRPC3, MMP or ErbB4 blockade suggesting that muscarinic receptors can replace mGluR5 with respect to radial process extension. Additionally, NRG/ErbB4 causes Ca2+ mobilization in a population of cells through cooperation with ErbB1 receptors. Our results indicate that mGluR5 promotes radial process growth via NRG activation by a mechanism involving TRPC3 channels and MMPs. Thus neurotransmitters acting on G-protein coupled receptors could play a central role in the maintenance of the radial glial scaffold through activation of NRG/ErbB4 signaling. PMID- 28887861 TI - Ultrasound-Guided Intratumoral Radiofrequency Ablation Coagulation to Facilitate Meningioma Resection: Preliminary Experience. AB - OBJECTIVES: This study aimed to explore the feasibility and safety of intratumoral radiofrequency ablation (RFA) in meningioma resection. METHODS: This study was approved by the Xijing Ethics Committee, and informed consent was obtained from all of the patients. Thirteen patients with meningiomas were recruited in the Neurosurgery Department of Xijing Hospital. These patients were treated with intratumoral RFA and surgery. We also chose 13 patients with meningiomas treated with traditional surgery as the control group. Two dimensional ultrasound, color Doppler flow imaging, contrast-enhanced ultrasound, and magnetic resonance imaging were used to identify the location, border, and blood supply of the meningiomas preoperatively and to assess the therapeutic effect intraoperatively. Finally, the meningiomas were dissected and removed by surgery. RESULTS: All procedures were technically successful without serious complications. Intraoperative ultrasound was able to provide a clear display of the location, shape, size, and boundary of the tumor and its relationship with other tissues and reveal the vascular distribution in and around the tumors. With intratumoral RFA, coagulative necrosis was induced, and the meningiomas became hard in texture with a decreased blood supply. Blood loss was significantly lower in the RFA group versus control group (320.0 +/- 24.8 versus 390.4 +/- 36.8 mL; P < .001). The RFA group spent fewer days in the hospital (6.0 +/- 0.9 versus 7.0 +/- 1.2 days; P = .022). However, the surgical time of the RFA group was relatively longer (3.5 +/- 0.5 versus 3.0 +/- 0.3 hours, P = .007). CONCLUSIONS: The application of intratumoral RFA in meningioma resection is effective and safe. It may be a useful adjunct for meningioma treatment. PMID- 28887862 TI - Systolic blood pressure targets, diastolic J curve and cuff artefact in blood pressure measurement: a note of caution. PMID- 28887863 TI - Fate of transplanted lungs is controlled by immune cells encounter within pulmonary allografts. PMID- 28887864 TI - Oral-maxillofacial trauma of a geriatric population in a super-ageing country. AB - BACKGROUND/AIM: World population has been ageing, and oral-maxillofacial trauma of geriatric population is expected to increase. The aim of this study was to analyse the characteristic features of oral-maxillofacial trauma in the geriatric population. MATERIALS AND METHODS: Data from 127 patients aged 65 years old or older, who were treated for oral-maxillofacial trauma at the Department of Oral and Maxillofacial Surgery, Hirosaki University, from 2000 to 2014, were retrospectively analysed. The data from 292 patients aged 20-64 years were used as a comparison. RESULTS: Oral-maxillofacial trauma in the geriatric population had been increasing over 15-year period. The male to female ratio was 1.05:1 in the older group and 2.3:1 in the younger group. In the older group, 117 patients (92.1%) had one or more underlying systemic diseases, and 16 (12.6%) had suffered injuries in association with acute medical disorders. The most common injuries in the older group were bone fractures (46.5%). The ratio of fractures in the older group was lower than in the younger group (69.2%). Trauma in the older group most frequently occurred because of falls from a standing height or lower (52.0%), and the mandible was the most common site of fracture (74.6%). A conservative form of treatment for maxillofacial fractures was most commonly (86.4%) chosen for the older group, whilst surgical treatment was most commonly in the younger group (55.0%). CONCLUSION: Oral-maxillofacial trauma in the geriatric population shows characteristic features in terms of aetiology, patterns and treatment modalities. PMID- 28887865 TI - Platelet-rich plasma, the ultimate secret for youthful skin elixir and hair growth triggering. AB - The clinical application of platelet-rich plasma (PRP) is based on the increase in the concentration of growth factors that are released from alpha-granule of the concentrated platelets and in the secretion of proteins which are able to capitalize on the healing process at the cellular level. It has been invented to restore the natural beauty by starting the natural rejuvenation process of the skin and aiming to make it function as a younger one and to keep the skin youthful and maintain it. Besides that, it is also emerged to include hairs as a new injectable procedure to enable stimulating hair growth locally and topically; preventing its fall; improving hair shaft, hair stem, and its caliber; increasing its shine, vitality, and pliability; and declining hair splitting and breakage. Thus, youth is in your blood as it has a magical power imposed in the platelet factors. There is, however, no standardization of the techniques besides insufficient description of the adopted procedures. Not long, autologous platelet rich plasma (PRP) has surfaced strongly in diverse medical specialties including plastic, wound healing and diabetic ulcers, orthopedic, trauma, ocular surgery, dry eye for eyelid injection, urology for urinary incontinence, sexual wellness, cutaneous surgery, sport medicine, dentistry and dermatology, and aesthetic applications. PRP proved to promote wound healing and aid in facelift, volumetric skin, skin rejuvenation, regeneration, and reconstruction; improve wrinkling; stimulate hair growth; increase hair follicle viability and its survival rate; prevent apoptosis; increase and prolong the anagen hair growth stage; and delay the progression to catagen hair cycle stage with increased density in hair loss and hair transplantation. The aims of this extensive review were to cover all PRP application aspects that are carried out in aesthetic dermatology and to assess the literature on platelet-rich plasma outcomes on main aesthetic practices of general dermatology. A literature review was conducted by searching through PubMed, Biomedical Library database, Google Scholar, and Research Gate for the terms PRP, platelet-rich plasma, platelet-rich fibrin matrix, platelet preparations, platelet application therapy, platelet growth factors, platelet facial, platelet facial rejuvenation, platelet hairs, and platelet wound healing, from inception till 2017, and they were combined using Boolean operators. All those retrieved articles in English language were looked at and explored thoroughly. PMID- 28887866 TI - A Monte Carlo evaluation of masked visual analysis in response-guided versus fixed-criteria multiple-baseline designs. AB - We developed masked visual analysis (MVA) as a structured complement to traditional visual analysis. The purpose of the present investigation was to compare the effects of computer-simulated MVA of a four-case multiple-baseline (MB) design in which the phase lengths are determined by an ongoing visual analysis (i.e., response-guided) versus those in which the phase lengths are established a priori (i.e., fixed criteria). We observed an acceptably low probability (less than .05) of false detection of treatment effects. The probability of correctly detecting a true effect frequently exceeded .80 and was higher when: (a) the masked visual analyst extended phases based on an ongoing visual analysis, (b) the effects were larger, (c) the effects were more immediate and abrupt, and (d) the effects of random and extraneous error factors were simpler. Our findings indicate that MVA is a valuable combined methodological and data-analysis tool for single-case intervention researchers. PMID- 28887867 TI - Pushing the haystack aside for efficient gene targeting in human cells. AB - Gene targeting, i.e., the disruption of a specific gene via homologous recombination, is one of the key techniques to study gene function. However, researchers have faced the difficulty that, in human cells, the frequency of correct targeted integration is quite low compared to non-targeted (or random) integration. Adachi and colleagues investigated the factors that influence the ratio of targeted integration to non-targeted integration. PMID- 28887868 TI - Scientific career paths - part II. AB - In the second part of our Words of Advice on science careers, we bring you the perspectives of established scientists who enjoy successful, fulfilling careers in academia, the patent office and a publishing company. We also get the thoughts of a PhD student on her internship at The FEBS Journal's Editorial Office. Get inspired by these scientists and trace your own path towards a rewarding science career. PMID- 28887870 TI - Activation of NLRP3 signalling accelerates skin wound healing. AB - The process of skin wound healing involves the following three steps: inflammation, tissue formation and tissue remodelling. These optimal steps are required for the development of normal wound healing. Recent reports demonstrated that inflammasomes are involved in the innate immune response. In the present study, we examined whether the activation of inflammasomes affects the process of skin wound repair. The skin wound repair model was established using wild-type (WT), NACHT, LRR and PYD domains-containing protein 3 (NALP3) knockout (KO) and ASC-KO mice. The wounds were observed every other day, and changes in wound size over time were calculated using photography. Wound repair in NALP3-KO and ASC-KO mice was significantly impaired compared with WT mice. Isoliquiritigenin, an inhibitor of NALP3, decreased the rate of wound repair in WT mice. mRNA expression of pro-inflammatory cytokines in the wound sites of NALP3-KO mice was markedly decreased compared with WT mice. Treatment with adenosine triphosphate (ATP), a ligand of NALP3, upregulated the mRNA expression of pro-inflammatory cytokines at the wound site and accelerated wound healing in the WT mice. Scratch assay revealed that ATP accelerated wound closure in mouse embryonic fibroblasts from WT mice but not from NALP3-KO mice. In conclusion, the present study demonstrated that NALP3 pathway activation is involved in wound repair, and the topical use of ATP may be useful as an effective treatment for accelerating wound healing. PMID- 28887872 TI - Pressure injuries in people with darker skin tones: A literature review. AB - AIMS AND OBJECTIVES: In this article, we aimed to explore the literature to ascertain what research evidence exists in relation to the identification of pressure injuries in people with dark skin tones. BACKGROUND: Pressure injuries development has been widely researched and documented; however, much of this work does not address ethnicity or race and assumes Caucasian-ness. Thus, the perceptions of people with dark skin tones and the influence of skin pigmentation on identification and management of pressure injuries is under examined. DESIGN: Literature review. METHODS: A comprehensive electronic database search was undertaken of PubMed, Cumulative Index for Nursing and Allied Health Literature, Cochrane and British Nursing Index (BNI) between 1990-July 2016. Alongside the electronic data, journals, books, papers from conferences, relevant national and international organisations and reference lists were also used to help source key studies. RESULTS: A search of the literature revealed 11 relevant articles. The foci of studies included the following: risk of sustaining a pressure injuries based on skin tones, identification of pressure injuries amongst people with dark skin tones, pressure injuries and place of care and socio-economic impact on pressure injuries development. Overall, findings indicate that people with darker skin tones are more likely to develop higher stage pressure injuries. Reasons for this are not fully elucidated; however, it may be associated with current skin assessment protocols being less effective for people who have darker skin tones resulting in early damage arising from pressure not being recognised. CONCLUSION: From the literature reviewed, it can be seen that there is a lack of guidance and evidence, and people with darker skin tones are more likely in comparison with people presenting as Caucasian to develop higher stage pressure injuries. RELEVANCE TO CLINICAL PRACTICE: The current literature suggests a need for researchers and clinicians to consider skin tone variances rather than ethnicity when exploring comprehensive skin assessment. PMID- 28887871 TI - The hypothalamic regulation of metabolic adaptations to exercise. AB - Our modern lifestyle is characterised by easy access to nutrient dense foods combined with limited physical activity. A sedentary lifestyle is one of several factors that have contributed to the global obesity epidemic and it also predisposes to chronic illnesses such as diabetes and cardiovascular disease. Although many studies have focused on the benefits of exercise in peripheral tissues, the contributions of the central nervous system to these exercise induced metabolic adaptations are relatively unknown. The present review highlights the role of the ventromedial hypothalamus in regulating the metabolic response to exercise. PMID- 28887873 TI - The Translational Science Benefits Model: A New Framework for Assessing the Health and Societal Benefits of Clinical and Translational Sciences. AB - We report the development of the Translational Science Benefits Model (TSBM), a framework designed to support institutional assessment of clinical and translational research outcomes to measure clinical and community health impacts beyond bibliometric measures. The TSBM includes 30 specific and potentially measurable indicators that reflect benefits that accrue from clinical and translational science research such as products, system characteristics, or activities. Development of the TSBM was based on literature review, a modified Delphi method, and in-house expert panel feedback. Three case studies illustrate the feasibility and face validity of the TSBM for identification of clinical and community health impacts that result from translational science activities. Future plans for the TSBM include further pilot testing and a resource library that will be freely available for evaluators, translational scientists, and academic institutions who wish to implement the TSBM framework in their own evaluation efforts. PMID- 28887875 TI - Fast subsurface fingerprint imaging with full-field optical coherence tomography system equipped with a silicon camera. AB - Images recorded below the surface of a finger can have more details and be of higher quality than the conventional surface fingerprint images. This is particularly true when the quality of the surface fingerprints is compromised by, for example, moisture or surface damage. However, there is an unmet need for an inexpensive fingerprint sensor that is able to acquire high-quality images deep below the surface in short time. To this end, we report on a cost-effective full field optical coherent tomography system comprised of a silicon camera and a powerful near-infrared LED light source. The system, for example, is able to record 1.7 cm*1.7 cmen face images in 0.12 s with the spatial sampling rate of 2116 dots per inch and the sensitivity of 93 dB. We show that the system can be used to image internal fingerprints and sweat ducts with good contrast. Finally, to demonstrate its biometric performance, we acquired subsurface fingerprint images from 240 individual fingers and estimated the equal-error-rate to be ~0.8%. The developed instrument could also be used in other en face deep-tissue imaging applications because of its high sensitivity, such as in vivo skin imaging. PMID- 28887874 TI - Small-molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia. AB - BACKGROUND: Muscle ring finger 1 (MuRF1) is a muscle-specific ubiquitin E3 ligase activated during clinical conditions associated with skeletal muscle wasting. Yet, there remains a paucity of therapeutic interventions that directly inhibit MuRF1 function, particularly in vivo. The current study, therefore, developed a novel compound targeting the central coiled coil domain of MuRF1 to inhibit muscle wasting in cardiac cachexia. METHODS: We identified small molecules that interfere with the MuRF1-titin interaction from a 130 000 compound screen based on Alpha Technology. A subset of nine prioritized compounds were synthesized and administrated during conditions of muscle wasting, that is, to C2C12 muscle cells treated with dexamethasone and to mice treated with monocrotaline to induce cardiac cachexia. RESULTS: The nine selected compounds inhibited MuRF1-titin complexation with IC50 values <25 MUM, of which three were found to also inhibit MuRF1 E3 ligase activity, with one further showing low toxicity on cultured myotubes. This last compound, EMBL chemical core ID#704946, also prevented atrophy in myotubes induced by dexamethasone and attenuated fibre atrophy and contractile dysfunction in mice during cardiac cachexia. Proteomic and western blot analyses showed that stress pathways were attenuated by ID#704946 treatment, including down-regulation of MuRF1 and normalization of proteins associated with apoptosis (BAX) and protein synthesis (elF2B-delta). Furthermore, actin ubiquitinylation and proteasome activity was attenuated. CONCLUSIONS: We identified a novel compound directed to MuRF1's central myofibrillar protein recognition domain. This compound attenuated in vivo muscle wasting and contractile dysfunction in cardiac cachexia by protecting de novo protein synthesis and by down-regulating apoptosis and ubiquitin-proteasome-dependent proteolysis. PMID- 28887876 TI - Cell-specific gain modulation by synaptically released zinc in cortical circuits of audition. AB - In many excitatory synapses, mobile zinc is found within glutamatergic vesicles and is coreleased with glutamate. Ex vivo studies established that synaptically released (synaptic) zinc inhibits excitatory neurotransmission at lower frequencies of synaptic activity but enhances steady state synaptic responses during higher frequencies of activity. However, it remains unknown how synaptic zinc affects neuronal processing in vivo. Here, we imaged the sound-evoked neuronal activity of the primary auditory cortex in awake mice. We discovered that synaptic zinc enhanced the gain of sound-evoked responses in CaMKII expressing principal neurons, but it reduced the gain of parvalbumin- and somatostatin-expressing interneurons. This modulation was sound intensity dependent and, in part, NMDA receptor-independent. By establishing a previously unknown link between synaptic zinc and gain control of auditory cortical processing, our findings advance understanding about cortical synaptic mechanisms and create a new framework for approaching and interpreting the role of the auditory cortex in sound processing. PMID- 28887877 TI - Epidemiological and ecological determinants of Zika virus transmission in an urban setting. AB - The Zika virus has emerged as a global public health concern. Its rapid geographic expansion is attributed to the success of Aedes mosquito vectors, but local epidemiological drivers are still poorly understood. Feira de Santana played a pivotal role in the Chikungunya epidemic in Brazil and was one of the first urban centres to report Zika infections. Using a climate-driven transmission model and notified Zika case data, we show that a low observation rate and high vectorial capacity translated into a significant attack rate during the 2015 outbreak, with a subsequent decline in 2016 and fade-out in 2017 due to herd-immunity. We find a potential Zika-related, low risk for microcephaly per pregnancy, but with significant public health impact given high attack rates. The balance between the loss of herd-immunity and viral re-importation will dictate future transmission potential of Zika in this urban setting. PMID- 28887879 TI - Orbital floor fracture repair: the endonasal approach. AB - To avoid the dangers associated with lower eyelid approaches to the orbital floor and to improve visualization, we propose an endoscopic procedure for orbital floor fracture reduction and osteosynthesis using endonasal access via the medial maxillary sinus wall. The technique of endoscopic, endonasal transantral surgery is described, together with a retrospective analysis of 17 patients who had undergone this surgical procedure in the Department of Otorhinolaryngology, University of Regensburg, between July 2013 and June 2016. Fractures without infraorbital margin involvement were successfully repaired and enophthalmos and/or diplopia were corrected in all cases. The endonasal approach described here allows orbital floor fractures to be repaired without injury to the eyelid apparatus. Visualization, in particular across the orbital floor as far as the palatine process, appears to be superior to that achieved with other approaches. The increased time required for the procedure and the difficulties of manipulation within a confined space are offset by rapid wound healing without ocular swelling and a minimal risk of complications. PMID- 28887878 TI - Simultaneous activation of parallel sensory pathways promotes a grooming sequence in Drosophila. AB - A central model that describes how behavioral sequences are produced features a neural architecture that readies different movements simultaneously, and a mechanism where prioritized suppression between the movements determines their sequential performance. We previously described a model whereby suppression drives a Drosophila grooming sequence that is induced by simultaneous activation of different sensory pathways that each elicit a distinct movement (Seeds et al., 2014). Here, we confirm this model using transgenic expression to identify and optogenetically activate sensory neurons that elicit specific grooming movements. Simultaneous activation of different sensory pathways elicits a grooming sequence that resembles the naturally induced sequence. Moreover, the sequence proceeds after the sensory excitation is terminated, indicating that a persistent trace of this excitation induces the next grooming movement once the previous one is performed. This reveals a mechanism whereby parallel sensory inputs can be integrated and stored to elicit a delayed and sequential grooming response. PMID- 28887880 TI - Allergy rhinitis: similarities and differences between children and adults. AB - BACKGROUND: Allergic rhinitis (AR) is a highly prevalent disease worldwide. Although a number of studies have described AR, no studies compared children and adult AR populations. The objective was to compare the AR characteristics between two AR cohorts of children and adults. METHODS: Two AR cohorts (children and adults) from Spain were studied through observational cross-sectional multicentre studies. AR was classified based on classical (allergen exposure), original (o ARIA), and modified (m-ARIA) ARIA criteria. AR was evaluated by Total 4-Symptoms Score (T4SS), and disease severity by Visual Analogue Scale (VAS, 0-100 mm). AR comorbidities were also evaluated. RESULTS: A total of 5,405 patients (1,275 children, 4,130 adults) were studied. According to symptoms duration, intermittent AR was more frequent in children than in adults. Using o-ARIA severity, more children than adults had moderate/severe AR while, using m-ARIA, more children than adults had severe AR. T4SS was higher in adults than in children. Moreover, VAS was also higher in adults than in children. In addition, asthma atopic dermatitis and conjunctivitis were more associated to children than adults with AR, the frequency of this comorbidities increasing according to higher severity. CONCLUSIONS: AR in children was more intermittent, severe, with less symptoms but with more comorbidities than in adults. These results suggest AR has similarities but also significant differences between children and adults. PMID- 28887881 TI - Rapid development of bilateral necroses of the upper extremity. PMID- 28887882 TI - Homogeneous processing in the striatal direct and indirect pathways: single body part sensitive type IIb neurons may express either dopamine receptor D1 or D2. AB - Striatal medium spiny projection neurons (MSNs) output through two diverging circuits, the 'direct and indirect pathways' which originate from minimally overlapping populations of MSNs expressing either the dopamine receptor D1 or the dopamine receptor D2. One modern theory of direct and indirect pathway function proposes that activation of direct pathway MSNs facilitates output of desired motor programs, while activation of indirect pathway MSNs inhibits competing motor programs. A separate theory suggests that coordinated timing or synchrony of the direct and indirect pathways is critical for the execution of refined movements. These hypotheses are made testable by a common type of striatal neuron known as type IIb MSNs. Clusters of these MSNs exhibit phasic increases in firing rate related to sensorimotor activity of single body parts. If these MSNs were to reside in only the direct pathway, evidence would be provided that D1 MSNs are 'motor program' specific, which would lend credence to the 'competing motor programs' hypothesis. However, if type IIb MSNs reside in both pathways, evidence would be provided for the 'coordinated timing or synchrony' hypothesis. Our results show that type IIb neurons may express either D1 or D2. This evidence supports the theory that the coordinated timing or synchrony of the direct and indirect pathways is critical for refined movements. We also propose a model in which the direct and indirect pathways act as a differentiator circuit, providing a possible mechanism by which coordinated activity of D1 and D2 neurons may output meaningful somatosensorimotor information to downstream structures. PMID- 28887883 TI - Early screening and prevention of preterm pre-eclampsia with aspirin: time for clinical implementation. PMID- 28887884 TI - Clear cell sarcoma-like tumor of the gastrointestinal tract: A clinicopathological review. PMID- 28887886 TI - Unusually recalcitrant reticular skin lesions in a young woman. PMID- 28887887 TI - Evaluating the essential role of RONS in vivo in exercised human muscle. PMID- 28887885 TI - Unveiling neural coupling within the sensorimotor system: directionality and nonlinearity. AB - Neural coupling between the central nervous system and the periphery is essential for the neural control of movement. Corticomuscular coherence is a popular linear technique to assess synchronised oscillatory activity in the sensorimotor system. This oscillatory coupling originates from ascending somatosensory feedback and descending motor commands. However, corticomuscular coherence cannot separate this bidirectionality. Furthermore, the sensorimotor system is nonlinear, resulting in cross-frequency coupling. Cross-frequency oscillations cannot be assessed nor exploited by linear measures. Here, we emphasise the need of novel coupling measures, which provide directionality and acknowledge nonlinearity, to unveil neural coupling in the sensorimotor system. We highlight recent advances in the field and argue that assessing directionality and nonlinearity of neural coupling will break new ground in the study of the control of movement in healthy and neurologically impaired individuals. PMID- 28887888 TI - Neurocognitive Impairment: Addressing Couple and Family Challenges. AB - Conditions involving neurocognitive impairment pose enormous challenges to couples and families. However, research and practice tend to focus narrowly on immediate issues for individual caregivers and their dyadic relationship with the affected member. A broad family systems approach with attention to family processes over time is needed in training, practice, and research. In this paper, Rolland's Family Systems Illness model provides a guiding framework to consider the interaction of different psychosocial types of neurocognitive conditions and their evolution over time with individual, couple, and family life-course development. Discussion addresses key family and couple issues with mild-to severe cognitive impairment and progressive dementias, including: communication, multigenerational legacies, threatened future neurocognitive disability, ambiguous loss, decisional capacity, reaching limits, placement decisions, issues for adult children and spousal caregivers, and the transformation of intimate bonds. Principles and guidelines are offered to help couples and families master complex challenges, deepen bonds, and forge positive pathways ahead. PMID- 28887889 TI - The genetic basis for most patients with pustular skin disease remains elusive. AB - BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN. PMID- 28887890 TI - Optimization of capillary zone electrophoresis for charge heterogeneity testing of biopharmaceuticals using enhanced method development principles. AB - CZE is a well-established technique for charge heterogeneity testing of biopharmaceuticals. It is based on the differences between the ratios of net charge and hydrodynamic radius. In an extensive intercompany study, it was recently shown that CZE is very robust and can be easily implemented in labs that did not perform it before. However, individual characteristics of some examined proteins resulted in suboptimal resolution. Therefore, enhanced method development principles were applied here to investigate possibilities for further method optimization. For this purpose, a high number of different method parameters was evaluated with the aim to improve CZE separation. For the relevant parameters, design of experiments (DoE) models were generated and optimized in several ways for different sets of responses like resolution, peak width and number of peaks. In spite of product specific DoE optimization it was found that the resulting combination of optimized parameters did result in significant improvement of separation for 13 out of 16 different antibodies and other molecule formats. These results clearly demonstrate generic applicability of the optimized CZE method. Adaptation to individual molecular properties may sometimes still be required in order to achieve optimal separation but the set screws discussed in this study [mainly pH, identity of the polymer additive (HPC versus HPMC) and the concentrations of additives like acetonitrile, butanolamine and TETA] are expected to significantly reduce the effort for specific optimization. PMID- 28887891 TI - The involvement of centralized and distributed processes in sub-second time interval adaptation: an ERP investigation of apparent motion. AB - Accumulating evidence suggests that the timing of brief stationary sounds affects visual motion perception. Recent studies have shown that auditory time interval can alter apparent motion perception not only through concurrent stimulation but also through brief adaptation. The adaptation after-effects for auditory time intervals was found to be similar to those for visual time intervals, suggesting the involvement of a central timing mechanism. To understand the nature of cortical processes underlying such after-effects, we adapted observers to different time intervals using either brief sounds or visual flashes and examined the evoked activity to the subsequently presented visual apparent motion. Both auditory and visual time interval adaptation led to significant changes in the ERPs elicited by the apparent motion. However, the changes induced by each modality were in the opposite direction. Also, they mainly occurred in different time windows and clustered over distinct scalp sites. The effects of auditory time interval adaptation were centred over parietal and parieto-central electrodes while the visual adaptation effects were mostly over occipital and parieto-occipital regions. Moreover, the changes were much more salient when sounds were used during the adaptation phase. Taken together, our findings within the context of visual motion point to auditory dominance in the temporal domain and highlight the distinct nature of the sensory processes involved in auditory and visual time interval adaptation. PMID- 28887892 TI - Recoupling in Mid-Life and Beyond: From Love at Last to Not So Fast. AB - Divorce rates have dropped in the United States, except for couples over 50 where they are rising steeply, along with rates of late-life recoupling. Both stepcouples and their young adult and adult children in new older stepfamilies are often surprised to find themselves facing many of the same challenges that younger stepfamilies do. Some challenges are even intensified by the decades-long relationships and additional layers of extended family that come with recoupling after mid-life. Stepfamilies formed in later life must also negotiate decisions about estate planning and elder care among stakeholders who often have sharply divergent agendas before there is time to establish trusting relationships. This article describes the "normal" challenges facing stepcouples who come together over age 50. It provides evidence-informed guidance for therapists in meeting these challenges on three levels of clinical work: Psychoeducational, Interpersonal, and Intrapsychic/Intergenerational. As in younger stepfamilies, "family therapy" must usually begin in subsystems-often the adult stepcouple and parent-adult child. The article then describes a particularly fraught subgroup of recouplers: over-50 fathers and their new partners, where the dad's young adult or adult daughter is very unhappy with his new relationship. In these latter stepfamilies, father-daughter repair must precede stepfamily bonding. Stepfamilies that are preceded by a partner's death and those that begin with affairs are also discussed. Finally, some "easy wrong turns" for therapists are described. PMID- 28887894 TI - Interobserver Variation in the Diagnosis of Neurologic Abnormalities in the Horse. AB - BACKGROUND: The diagnosis of equine protozoal myeloencephalitis (EPM) relies heavily on the clinical examination. The accurate identification of neurologic signs during a clinical examination is critical to the interpretation of laboratory results. OBJECTIVE: To investigate the level of agreement between board-certified veterinary internists when performing neurologic examinations in horses. ANIMALS: Ninety-seven horses admitted to the Veterinary Teaching Hospital at The Ohio State University from December 1997 to June 1998. METHODS: A prospective epidemiologic research design was used. Horses enrolled in the study were examined by the internist responsible for care of the horse, and later by an internist who was not aware of the presenting complaint or other patient history. Data were analyzed by descriptive statistics, and kappa (K) statistics were calculated to assess interobserver agreement. RESULTS: Ninety-seven horses were enrolled in the study. Overall, examiners, also referred to as observers, agreed that 60/97 (61.9%) were clinically abnormal, 21/97 (21.6%) were clinically normal, and the status of 16/97 (16.5%) of horses was contested. There was complete agreement among the examiners with regard to cranial nerve signs and involuntary movements. Disagreement involving severity of clinical signs occurred in 31 horses, and 25 of those horses (80.6%) were considered either normal or mildly affected by the primary observer. When examining the results of all paired clinical examinations for 11 different categories, there was wide variability in the results. When examiners rated the presence or absence of any neurologic abnormalities, lameness, or ataxia, the agreement among observers was either good or excellent for 80% of horses. When assessing truncal sway, the agreement among observers was good or excellent for 60% of the horses. When examining the horses for asymmetry of deficits, agreement was either good or excellent for 40% of the horses. Agreement among observers was excellent or good for only 20% of the horses when assessing muscle atrophy, spasticity (hypermetria), and overall assessment of the severity of neurologic abnormalities. CONCLUSIONS AND CLINICAL IMPORTANCE: This study underscores the subjectivity of the neurologic examination and demonstrates a reasonable level of agreement that may be achieved when different clinicians examine the same horse. PMID- 28887895 TI - Impact of climate change on vector transmission of Trypanosoma cruzi (Chagas, 1909) in North America. AB - Climate change can influence the geographical range of the ecological niche of pathogens by altering biotic interactions with vectors and reservoirs. The distributions of 20 epidemiologically important triatomine species in North America were modelled, comparing the genetic algorithm for rule-set prediction (GARP) and maximum entropy (MaxEnt), with or without topographical variables. Potential shifts in transmission niche for Trypanosoma cruzi (Trypanosomatida: Trypanosomatidae) (Chagas, 1909) were analysed for 2050 and 2070 in Representative Concentration Pathway (RCP) 4.5 and RCP 8.5. There were no significant quantitative range differences between the GARP and MaxEnt models, but GARP models best represented known distributions for most species [partial receiver operating characteristic (ROC) > 1]; elevation was an important variable contributing to the ecological niche model (ENM). There was little difference between niche breadth projections for RCP 4.5 and RCP 8.5; the majority of species shifted significantly in both periods. Those species with the greatest current distribution range are expected to have the greatest shifts. Positional changes in the centroid, although reduced for most species, were associated with latitude. A significant increase or decrease in mean niche elevation is expected principally for Neotropical 1 species. The impact of climate change will be specific to each species, its biogeographical region and its latitude. North American triatomines with the greatest current distribution ranges (Nearctic 2 and Nearctic/Neotropical) will have the greatest future distribution shifts. Significant shifts (increases or decreases) in mean elevation over time are projected principally for the Neotropical species with the broadest current distributions. Changes in the vector exposure threat to the human population were significant for both future periods, with a 1.48% increase for urban populations and a 1.76% increase for rural populations in 2050. PMID- 28887893 TI - Trial-by-trial co-variation of pre-stimulus EEG alpha power and visuospatial bias reflects a mixture of stochastic and deterministic effects. AB - Human perception of perithreshold stimuli critically depends on oscillatory EEG activity prior to stimulus onset. However, it remains unclear exactly which aspects of perception are shaped by this pre-stimulus activity and what role stochastic (trial-by-trial) variability plays in driving these relationships. We employed a novel jackknife approach to link single-trial variability in oscillatory activity to psychometric measures from a task that requires judgement of the relative length of two line segments (the landmark task). The results provide evidence that pre-stimulus alpha fluctuations influence perceptual bias. Importantly, a mediation analysis showed that this relationship is partially driven by long-term (deterministic) alpha changes over time, highlighting the need to account for sources of trial-by-trial variability when interpreting EEG predictors of perception. These results provide fundamental insight into the nature of the effects of ongoing oscillatory activity on perception. The jackknife approach we implemented may serve to identify and investigate neural signatures of perceptual relevance in more detail. PMID- 28887896 TI - Lesion evidence for a critical role of left posterior but not frontal areas in alpha-beta power decreases during context-driven word production. AB - Different frequency bands in the electroencephalogram are postulated to support distinct language functions. Studies have suggested that alpha-beta power decreases may index word-retrieval processes. In context-driven word retrieval, participants hear lead-in sentences that either constrain the final word ('He locked the door with the') or not ('She walked in here with the'). The last word is shown as a picture to be named. Previous studies have consistently found alpha beta power decreases prior to picture onset for constrained relative to unconstrained sentences, localised to the left lateral-temporal and lateral frontal lobes. However, the relative contribution of temporal versus frontal areas to alpha-beta power decreases is unknown. We recorded the electroencephalogram from patients with stroke lesions encompassing the left lateral-temporal and inferior-parietal regions or left-lateral frontal lobe and from matched controls. Individual participant analyses revealed a behavioural sentence context facilitation effect in all participants, except for in the two patients with extensive lesions to temporal and inferior parietal lobes. We replicated the alpha-beta power decreases prior to picture onset in all participants, except for in the two same patients with extensive posterior lesions. Thus, whereas posterior lesions eliminated the behavioural and oscillatory context effect, frontal lesions did not. Hierarchical clustering analyses of all patients' lesion profiles, and behavioural and electrophysiological effects identified those two patients as having a unique combination of lesion distribution and context effects. These results indicate a critical role for the left lateral-temporal and inferior parietal lobes, but not frontal cortex, in generating the alpha-beta power decreases underlying context driven word production. PMID- 28887898 TI - Beta-band oscillations during passive listening to metronome sounds reflect improved timing representation after short-term musical training in healthy older adults. AB - Sub-second time intervals in musical rhythms provide predictive cues about future events to performers and listeners through an internalized representation of timing. While the acuity of automatic, sub-second timing as well as cognitively controlled, supra-second timing declines with ageing, musical experts are less affected. This study investigated the influence of piano training on temporal processing abilities in older adults using behavioural and neuronal correlates. We hypothesized that neuroplastic changes in beta networks, caused by training in sensorimotor coordination with timing processing, can be assessed even in the absence of movement. Behavioural performance of internal timing stability was assessed with synchronization-continuation finger-tapping paradigms. Magnetoencephalography (MEG) was recorded from older adults before and after one month of one-on-one training. For neural measures of automatic timing processing, we focused on beta oscillations (13-30 Hz) during passive listening to metronome beats. Periodic beta-band modulations in older adults before training were similar to previous findings in young listeners at a beat interval of 800 ms. After training, behavioural performance for continuation tapping was improved and accompanied by an increased range of beat-induced beta modulation, compared to participants who did not receive training. Beta changes were observed in the caudate, auditory, sensorimotor and premotor cortices, parietal lobe, cerebellum and medial prefrontal cortex, suggesting that increased resources are involved in timing processing and goal-oriented monitoring as well as reward-based sensorimotor learning. PMID- 28887897 TI - Opportunistic Invasive Cutaneous Fungal Infections Associated with Administration of Cyclosporine to Dogs with Immune-mediated Disease. AB - BACKGROUND: Opportunistic invasive fungal infections (OIFIs) occur in dogs administered immunosuppressive medications. However, the epidemiology of OIFIs among dogs undergoing immunosuppressive treatment is poorly understood. The aims of this study were to (1) estimate the incidence of OIFIs among dogs diagnosed with certain immune-mediated diseases and treated with immunosuppressive drugs, and (2) determine if administration of particular drug(s) was a risk factor for OIFIs. HYPOTHESIS: Dogs receiving cyclosporine treatment (alone or as part of a multidrug protocol) are at higher risk of developing OIFIs. ANIMALS: One hundred and thirteen client-owned dogs diagnosed with select immune-mediated diseases: 42 with IMHA, 29 with ITP, 34 with IMPA, and 8 with Evans syndrome. METHODS: Retrospective cohort study. Medical records of dogs presenting to the Texas A&M University, Veterinary Medical Teaching Hospital between January 2008 and December 2015, and treated for 1 or more of IMHA, IMPA, ITP, or Evans syndrome were retrospectively reviewed. Dogs that did not develop an OIFI were excluded if they died, were euthanized, or were lost to follow-up within 120 days of initiation of immunosuppressive treatment. RESULTS: Fifteen dogs of 113 (13%) were diagnosed with an OIFI based on 1 or more of cytology, culture, or histopathology. The odds of developing an OIFI were greater among dogs that were treated with cyclosporine (OR = 7.1, P = 0.017; 95% CI, 1.5-34.4) and among male dogs (OR = 5.1, P = 0.018; 95% CI, 1.4-17.9). CONCLUSIONS AND CLINICAL IMPORTANCE: OIFIs were significantly more likely in male dogs and those receiving cyclosporine. It is important to consider OIFIs as a potential complication of immunosuppressive treatment, particularly cyclosporine. PMID- 28887900 TI - Atypical brain responses to auditory spatial cues in adults with autism spectrum disorder. AB - The auditory processing atypicalities experienced by many individuals on the autism spectrum disorder might be understood in terms of difficulties parsing the sound energy arriving at the ears into discrete auditory 'objects'. Here, we asked whether autistic adults are able to make use of two important spatial cues to auditory object formation - the relative timing and amplitude of sound energy at the left and right ears. Using electroencephalography, we measured the brain responses of 15 autistic adults and 15 age- and verbal-IQ-matched control participants as they listened to dichotic pitch stimuli - white noise stimuli in which interaural timing or amplitude differences applied to a narrow frequency band of noise typically lead to the perception of a pitch sound that is spatially segregated from the noise. Responses were contrasted with those to stimuli in which timing and amplitude cues were removed. Consistent with our previous studies, autistic adults failed to show a significant object-related negativity (ORN) for timing-based pitch, although their ORN was not significantly smaller than that of the control group. Autistic participants did show an ORN to amplitude cues, indicating that they do not experience a general impairment in auditory object formation. However, their P400 response - thought to indicate the later attention-dependent aspects of auditory object formation - was missing. These findings provide further evidence of atypical auditory object processing in autism with potential implications for understanding the perceptual and communication difficulties associated with the condition. PMID- 28887899 TI - The anterior insula bidirectionally modulates cost-benefit decision-making on a rodent gambling task. AB - Deficits in cost-benefit decision-making, as assessed in the Iowa Gambling Task (IGT), are commonly observed in neuropsychiatric disorders such as addiction. There is considerable variation in the maximization of rewards on such tasks, both in the general population and in rodent models, suggesting individual differences in decision-making may represent a key endophenotype for vulnerability to neuropsychiatric disorders. Increasing evidence suggests that the insular cortex, which is involved in interoception and emotional processes in humans, may be a key neural locus in the control of decision-making processes. However, the extent to which the insula contributes to individual differences in cost-benefit decision-making remains unknown. Using male Sprague Dawley rats, we first assessed individual differences in the performance over the course of a single session on a rodent analogue of the IGT (rGT). Rats were matched for their ability to maximize reward and received bilateral excitotoxic or sham lesions of the anterior insula cortex (AIC). Animals were subsequently challenged on a second rGT session with altered contingencies. Finally, animals were also assessed for instrumental conditioning and reversal learning. AIC lesions produced bidirectional alterations on rGT performance; rats that had performed optimally prior to surgery subsequently showed impairments, and animals that had performed poorly showed improvements in comparison with sham-operated controls. These bidirectional effects were not attributable to alterations in behavioural flexibility or in motivation. These data suggest that the recruitment of the AIC during decision-making may be state-dependent and help guide response selection towards subjectively favourable options. PMID- 28887901 TI - Meta-analysis of accuracy of intraocular lens power calculation formulas in short eyes. AB - IMPORTANCE: Intraocular lens (IOL) power selection is a critical factor affecting visual outcome after IOL implantation in short eyes. Many formulas have been developed to achieve a precise prediction of the IOL power. However, controversy regarding the accuracy remains. BACKGROUND: To investigate the accuracy of different IOL power calculation formulas in short eyes. DESIGN: Meta-analysis. PARTICIPANTS: Patients with the axial length of eyes less than 22 mm from previously reported studies. METHODS: A comprehensive search in Pubmed, EMBASE, Cochrane Data Base of Systematic Reviews and the Cochrane Central Register of Controlled Trials was conducted by October 2016. We assessed the methodological quality using a modified QUADAS-2 tool and performed analysis on weighted mean differences of mean absolute errors (MAE) among different formulas. MAIN OUTCOMES MEASURES: The between-group difference of MAE was evaluated with weighted mean difference and 95% confidence intervals. RESULTS: Ten observational studies, involving 1161 eyes, were enrolled to compare six formulas: Haigis, Holladay 2, Hoffer Q, Holladay 1, SRK/T and SRK II. Among them, the Holladay 2 introduced the smallest overall MAE (0.496D) without statistical significance. The difference of MAE is statistically significant between Haigis and Hoffer Q (mean difference = 0.07D, P = 0.003), Haigis and SRK/T (mean difference = -0.07D, P = 0.009), Haigis and SRK II (mean difference = -0.41D, P = 0.01). For publication bias and small study effect, neither funnel plot nor egger's test detected statistical finding. CONCLUSION AND RELEVANCE: The overall evidence from the studies confirmed the superiority of Haigis over Hoffer Q, SRK/T and SRK II in prediction IOL power in short eyes. PMID- 28887903 TI - Catalytic Asymmetric Mannich Reaction with N-Carbamoyl Imine Surrogates of Formaldehyde and Glyoxylate. AB - N,O-acetals (NOAcs) were developed as bench stable surrogates for N-carbamoyl, (Boc, Cbz and Fmoc) formaldehyde and glyoxylate imines in asymmetric Mannich reactions. The NOAcs can be directly utilized in the chiral primary amine catalyzed Mannich reactions of both acyclic and cyclic beta-ketocarbonyls with high yields and excellent stereoselectivity. The current reaction offers a straightforward approach in the asymmetric synthesis of alpha- or beta-amino carbonyls bearing chiral quaternary centers in a practical and highly stereocontrolled manner. PMID- 28887902 TI - Atropinic (anticholinergic) burden in antipsychotic-treated patients. AB - Antipsychotic drugs possess side atropinic (anticholinergic) properties that may induce several adverse drug reactions (ADRs), such as memory loss or cognitive impairment. The aim of this study was to investigate anticholinergic burden in patients treated with antipsychotic drugs. All ADR reports including at least one antipsychotic and registered between 2000 and 2015 in the Midi-Pyrenees PharmacoVigilance Database were extracted and analyzed using the Anticholinergic Duran's list. The primary objective of this cross-sectional study was to calculate anticholinergic burden in antipsychotic-treated patients; the secondary one was to investigate associated factors. Among the 1948 reports, the average number of atropinic drugs per report was 2.4 +/- 1.4. At least one atropinic drug was found in 59.4% of reports (1158), in addition to antipsychotic drugs. The mean anticholinergic burden per report was 3.9 +/- 2.9. A value >=3 was found in 61.7% of the reports. A significant association between anticholinergic burden, age, and male gender of patients was found. The mean value of anticholinergic burden remained stable during the study period. This study showed high values of anticholinergic burden in patients receiving antipsychotics. Thus, considering the potential noxious clinical impact of atropinic properties on cognitive functions, an appropriate approach should be used to reduce prescription of antipsychotics with a high anticholinergic burden but also coprescription of other frequently associated atropinic drugs, such as antiparkinsonians, H1 antihistamines, or imipraminic antidepressants in these patients. PMID- 28887904 TI - Thirty first annual symposium on etiology, pathogenesis, and treatment of Parkinson disease and other movement disorders: Presented by the Parkinson study group, huntington study group, dystonia study group, tourette syndrome study group, cooperative ataxia group, and tremor research group. PMID- 28887906 TI - Sphingosine-1-phosphate and renal vasoconstriction. PMID- 28887908 TI - Top scorers of 2015. PMID- 28887907 TI - Characterization of Wild Blueberry Polyphenols Bioavailability and Kinetic Profile in Plasma over 24-h Period in Human Subjects. AB - SCOPE: Understanding the metabolic fate of polyphenols from plant foods can aid in developing dietary recommendations that maximize their health benefits. Wild blueberries (WBB) provide a distinctive composition of dietary anthocyanins and chlorogenic acid (CGA). METHODS AND RESULTS: This is a single blind, randomized, two-arm crossover controlled study. Human subjects ingested a WBB beverage (25 g freeze dried WBB powder) or placebo beverage with a meal and plasma was collected over 24 h. Anthocyanins, CGA and their metabolites were characterized and quantified in beverages and in plasma using targeted and non-targeted mass analyses. Bioavailability of WBB anthocyanins and 3-CGA was 1.1 and 0.2%, respectively. Parent anthocyanins and 3-CGA peaked ~2 h post ingestion, while phase II metabolites, including glucuronide conjugates of peonidin, delphinidin, cyanidin and petunidin peaked ~ 2.6, 6.3, 7 and 8.8 h, respectively. Phenolic acids (metabolites) peaked between 0.5 and 24 h. Biphasic responses were evident suggesting preferential enterohepatic recycling for some compounds. CONCLUSION: The data indicate bioavailability of early and late phase WBB metabolites peaking at different times during the 24 h period, which may be important for maximizing their biological activity. PMID- 28887909 TI - Fluorescence Lifetime and UV-Vis Spectroscopy to Evaluate the Interactions Between Quercetin and Its Yeast Microcapsule. AB - Quercetin is a fragile bioactive compound. Several works have tried to preserve it by encapsulation but the form of encapsulation (mono- or supra-molecular structure, tautomeric form), though important for stability and bioavailability, remains unknown. The present work aims at developing a fluorescence lifetime technique to evaluate the structure of quercetin during encapsulation in a vector capsule that has already proven efficiency, yeast cells. Molecular stabilization was observed during a 4-month storage period. The time-correlated single-photon counting (TCSPC) technique was used to evaluate the interaction between quercetin molecules and the yeast capsule. The various tautomeric forms, as identified by UV-Vis spectroscopy, result in various lifetimes in TCSPC, although they varied also with the buffer environment. Quercetin in buffer exhibited a three-to-four longer long-time after 24 h (changing from 6-7 to 18-23 ns), suggesting an aggregation of molecules. In yeast microcapsules, the long-time population exhibited a longer lifetime (around 27 ns) from the beginning and concerned about 20% of molecules compared to dispersed quercetin. This shows that lifetime analysis can show the monomolecular instability of quercetin in buffer and the presence of interactions between quercetin molecules and their microcapsules. PMID- 28887910 TI - Robust Multi-Objective Global Optimization of Stochastic Processes With a Case Study in Gradient Elution Chromatography. AB - A novel algorithm for robust multi-objective process optimization under stochastic variability of environmental variables is introduced and applied to a case study in gradient elution chromatography. Process variability is accounted for by simultaneously optimizing several scenarios with random but fixed values of the environmental variables. These iterative optimizations are synchronized by planning the same experiments for all scenarios. Experiments are designed by maximizing the cumulative expected hypervolume improvement as predicted by several Gaussian process regression models. A straightforward method is presented for estimating the expected Pareto front and its variability based on the resulting data that maintains traceability of the corresponding process parameters. This information is required for robust process optimization, that is, determination of Pareto optimal processes that fulfil specific minimal criteria with a certain confidence. The presented algorithm can generally be applied to both in silico and wet lab experiments but involves an increased experimental effort as compared to the deterministic case. PMID- 28887911 TI - Deep capillary plexus impairment in patients with type 1 diabetes mellitus with no signs of diabetic retinopathy revealed using optical coherence tomography angiography. PMID- 28887912 TI - Safety Profile of Good Manufacturing Practice Manufactured Interferon gamma Primed Mesenchymal Stem/Stromal Cells for Clinical Trials. AB - Mesenchymal stem/stromal cells (MSCs) are widely studied by both academia and industry for a broad array of clinical indications. The collective body of data provides compelling evidence of the clinical safety of MSC therapy. However, generally accepted proof of therapeutic efficacy has not yet been reported. In an effort to generate a more effective therapeutic cell product, investigators are focused on modifying MSC processing protocols to enhance the intrinsic biologic activity. Here, we report a Good Manufacturing Practice-compliant two-step MSC manufacturing protocol to generate MSCs or interferon gamma (IFNgamma) primed MSCs which allows freshly expanded cells to be infused in patients on a predetermined schedule. This protocol eliminates the need to infuse cryopreserved, just thawed cells which may reduce the immune modulatory activity. Moreover, using (IFNgamma) as a prototypic cytokine, we demonstrate the feasibility of priming the cells with any biologic agent. We then characterized MSCs and IFNgamma primed MSCs prepared with our protocol, by karyotype, in vitro potential for malignant transformation, biodistribution, effect on engraftment of transplanted hematopoietic cells, and in vivo toxicity in immune deficient mice including a complete post-mortem examination. We found no evidence of toxicity attributable to the MSC or IFNgamma primed MSCs. Our data suggest that the clinical risk of infusing MSCs or IFNgamma primed MSCs produced by our two-step protocol is not greater than MSCs currently in practice. While actual proof of safety requires phase I clinical trials, our data support the use of either cell product in new clinical studies. Stem Cells Translational Medicine 2017;6:1868 1879. PMID- 28887913 TI - Preface: Nanoformulations for combination or cascade anticancer therapy. PMID- 28887905 TI - Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. AB - This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28887914 TI - Curcumin attenuates the scurfy-induced immune disorder, a model of IPEX syndrome, with inhibiting Th1/Th2/Th17 responses in mice. AB - BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is a lethal autoimmune disease caused by mutations in the Foxp3 gene scurfin (scurfy). Immunosuppressive therapy for IPEX patients has been generally ineffective and has caused severe side effects, however curcumin has shown immune regulation properties for inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases without side effects. OBJECTIVE: The aim of this study was to investigate whether curcumin would attenuate symptoms of IPEX in mouse model and would prolong its survival period. METHODS: C57BL/6 mice were separated into scurfy or wild-type litter mate groups by genotyping, and each group subsequently was separated into 2 subgroups that were fed a 1% curcumin containing or normal diet from the last day of breast-feeding. After weaning, pups were fed either a 1% curcumin containing or normal diet until all scurfy mice die for survival data. To elucidate immune cell proportions in spleen and lymph nodes, cells were analyzed by flowcytometry. Cellular cytokine production was accessed to investigate the effects of curcumin in T cell differentiation in vitro. RESULTS: Scurfy mice fed a 1% curcumin diet survived 4.0-fold longer compared to scurfy (92.5 days) mice fed a normal diet (23 days). A curcumin diet decreased all of the Th1/Th2/Th17 cell populations and attenuated diverse symptoms such as splenomegaly in scurfy mice. In vitro experiments showed that curcumin treatment directly decreased the Th1/Th2/Th17 cytokine production of IFN-gamma, IL-4, and IL-17A in CD4+ T cells. CONCLUSIONS: Curcumin diet attenuated the scurfy-induced immune disorder, a model of IPEX syndrome, by inhibiting Th1/Th2/Th17 responses in mice. These results have implications for improving clinical therapy for patients with IPEX and other T cell related autoimmune diseases. PMID- 28887915 TI - Hepatoprotective naphthalene diglucoside from Neanotis wightiana aerial parts. AB - BACKGROUND: Neanotis wightiana (Wall. ex Wight & Arn) W.H. Lewis has been used in traditional medicine in India for the treatment of liver disorders. In fact, this plant is frequently used by the local people of Tripura for the treatment of liver disorder problems. In previous study on this plant we have isolated a hepatoprotective saponin, neanoside A. PURPOSE: Evaluation of in vivo hepatoprotective effects of isolated compounds from N. wightiana aerial parts on serum hepatic-biomarkers in CCl4- induced hepatotoxicity in rats to validate the traditional use of the plant. STUDY DESIGN: This study was designed to isolate more hepatoprotective compounds from N. wightiana aerial parts and evaluate their in vivo hepatoprotective activity in animal model. METHODS: The phytochemicals from the polar n-butanol fraction of methanolic extract of N. wightiana aerial parts were isolated by repeated column chromatography over Diaion HP-20 and silica gel. Among the isolated three compounds, two were known triterpenoids, ursolic acid and oleanolic acid. The new compound was named neanoside B and its structure was established as naphthalene diglucoside 1 on the basis of extensive spectroscopic (including 2D NMR) analysis. Furthermore, the hepatoprotective activity of 1 was evaluated on CCl4 -induced hepatic injured rats by oral administration at three doses (5, 10 mg and 20 mg/kg) for 7 d and the assay of serum hepatic injury marker enzymes, SGPT, SGOT, ALP and bilirubin contents and histopathological changes of injured liver tissue after 7 d The herbal hepatoprotective drug, silymarin (100 mg/kg) was as positive control. RESULTS: The structure of the new compound, neanoside B (1) was elucidated as 1,4 dihydroxy-2-(methoxymethyl)naphthalen-3-yl-methyl-3-beta-d-glucopyranosyl-(1->6) beta-d-glucopyranoside on the basis of extensive spectroscopic (including 2D-NMR) and chemical studies. The compound 1 exhibited significant in vivo hepatoprotective effect at the tested doses of 5, 10 and 20 mg/kg bw in CCl4 induced hepatotoxicity in rats. In a dose-dependent manner, 1 normalized the elevated levels of hepatic injury marker enzymes, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and total bilirubin and ameliorated the damage of liver tissue by reducing the necrosis and vacuoles. Possibly compound 1 ameliorated the hepatic damage in hepatotoxic rats by improving the antioxidant status. The higher dose (20 mg/kg) showed more hepatoprotective effect by reducing the elevated levels of SGPT, SGOT, ALP and bilirubin content to 388.5 +/- 2.156, 160.7 +/- 3.00, 198.6 +/- 4.562 and 0.652 +/- 0.036 IU/ml, respectively, compared to the levels in the control group (583.2 +/- 6.922, 324.6 +/- 4.711, 263.9 +/- 4.939 and 1.533 +/- 0.042 IU/ml, respectively) and the effect was comparable to that of the positive control silymarin (100 mg/kg bw) (389.4 +/- 6.348, 167.9 +/- 4.289, 203.3 +/- 4.448 and 0.816 +/- 0.030 IU/ml, respectively). CONCLUSIONS: This study indicated that isolated neanoside B (1) from Neanotis wightiana could be a potential drug in liver disorders. Further study in pharmacokinetics and long-term toxicity of compound 1 is requested for its clinical setting as effective drug in liver disorders. PMID- 28887916 TI - Angelica polysaccharides inhibit the growth and promote the apoptosis of U251 glioma cells in vitro and in vivo. AB - BACKGROUND: Angelica sinensis (Oliv) Diels (Apiaceae) is a traditional medicine that has been used for more than 2000 years in China. It exhibits various therapeutic effects including neuroprotective, anti-oxidant, anti-inflammatory, and immunomodulatory activities. Angelica polysaccharides (APs), bioactive constituents of Angelica have been shown to be responsible for these effects; however, the utility of APs for the treatment of glioma and their mechanism of action remain to be elucidated. PURPOSE: In this study, we investigated the inhibitory effects of APs on a glioma cell line and their molecular mechanism of action. STUDY DESIGN: U251 cells were utilized to confirm the effects of APs on glioma. METHODS: The human glioblastoma cell line U251 was utilized for both in vitro and in vivo models, in which we tested the effects of APs. Flow cytometry, gene expression analysis, western blotting, and MTT assays were used to elucidate the effects of APs on cell proliferation, cell cycle, and apoptosis. RESULTS: The results demonstrated that APs significantly inhibited the growth and proliferation of U251 cells and induced their apoptosis. Furthermore, APs effectively reduced the expression of several cell cycle regulators: cyclins D1, B, and E. The apoptosis suppressor protein Bcl-2 was also downregulated, and the expression of pro-apoptotic proteins Bax and cleaved-caspase-3 increased. Additionally, APs inhibited the transforming growth factor (TGF)-beta signaling pathway and stimulated the expression of E-cadherin, thus prohibiting cell growth. CONCLUSION: In conclusion, the results indicate that APs attenuate the tumorigenicity of glioma cells and promote their apoptosis by suppressing the TGF beta signaling pathway. The present study therefore provides evidence of the inhibitory effects of APs against glioma progression, and proposes their potential application as alternative therapeutic agents for glioma. PMID- 28887917 TI - Hepatoprotective effects of Yulangsan flavone against carbon tetrachloride (CCl4) induced hepatic fibrosis in rats. AB - BACKGROUND: Yulangsan flavone (YLSF) was extracted from the root of Millettia pulchra Kurz var-laxior (Dunn) Z. Wei, which has been widely used for liver disease treatment in the Guangxi province of China. HYPOTHESIS/PURPOSE: The study was conducted to demonstrate the hepatoprotective effects of YLSF against CCl4 induced hepatic fibrosis in rats, meanwhile revealing the potential mechanism. STUDY DESIGN: Sprague-Dawley (SD) rats of both sexes were randomly divided into two groups: hepatic fibrosis group and normal control (NC) group. The rats in the hepatic fibrosis group were given 1 ml/kg 50% CCl4 (1:1 mixed with peanut oil), while those in the NC group were given 1 ml/kg normal saline (NS), both via intragastric administration. The established experimental rat model from the hepatic fibrosis group was confirmed by pathological inspection and randomly divided into five groups: three YLSF groups (20 mg/kg, 40 mg/kg and 80 mg/kg), a colchicine group (0.20 mg/kg) and a model group (10 ml/kg NS). All rats were treated with corresponding drugs or NS once a day for four consecutive weeks. Twenty-four hours after the last administration, blood serum and hepatic tissue were collected. METHODS: The activities of ALT and AST in the serum and the levels of SOD, MDA, GSH and GSH-Px in hepatic tissue were analysed, the indexes of liver, spleen and thymus were counted, the degree of hepatic injury was examined using HE and Masson staining, and the mRNA expression of Col-1, TIMP-1 and TGF-beta1 in hepatic tissues was detected. RESULTS: Compared with the model group, experimental results showed that YLSF and colchicine could reduce the levels of AST, ALT and MDA, increase the levels of SOD, GSH and GSH-Px, enhance rat survivability, decrease the liver, spleen and thymus index, significantly lessen collagen deposition and tissue damage and down-regulate the mRNA expression of Col-1, TIMP-1 and TGF-beta1. CONCLUSIONS: Our findings confirm that YLSF has a certain curative effect on rats with liver fibrosis induced by CCl4, and its mechanism may include attenuating free radicals, inhibiting lipid peroxidation and accelerating extracellular matrix degradation by down-regulating expression of related genes. PMID- 28887918 TI - Hepatoprotective and hypoglycemic effects of a tannin rich extract from Ximenia americana var. caffra root. AB - BACKGROUND: Liver diseases and diabetes are serious health disorders associated with oxidative stress and ageing. Some plant polyphenols can lower the risk of these diseases. PURPOSE: We investigated the phytochemical profiling of a root extract from Ximenia americana var. caffra using HPLC-PDA-ESI-MS/MS. The antioxidant activities in vitro were investigated. The hepatoprotective activities were studied in rat models with d-galactosamine (d-GaIN)-induced hepatotoxicity and the antidiabetic activities in STZ-diabetic rats were also investigated. MATERIALS AND METHODS: HPLC-PDA-ESI-MS/MS was used to identify plant phenolics. The antioxidant activities in vitro were determined using DPPH and FRAP assays. The in vivo hepatoprotective activities were determined for d GaIN-induced hepatotoxicity in rats. We determined the liver markers alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyltransferase (GGT), liver peroxidation product malondialdehyde (MDA), glutathione content (GSH), albumin and total bilirubin concentration. The histopathological changes in rat liver were also studied. The antidiabetic activities were also investigated in STZ-diabetic rats and serum glucose, serum insulin hormone, and lipid peroxides were determined. RESULTS: The root extract is rich in tannins with 20 compounds including a series of stereoisomers of (epi)catechin, (epi)catechin-(epi)catechin, (epi)catechin-(epi)catechin (epi)catechin, and their galloyl esters. Promising antioxidant potential was observed in vitro in DPPH assay with EC50 of 6.5 ug extract / 26 ug raw material and in FRAP assay with 19.54 mM FeSO4 compared with ascorbic acid (EC50 of 2.92 ug/ml) and quercetin (FeSO4 24.04 mM/mg), respectively. Significant reduction of serologic enzymatic markers and hepatic oxidative stress markers such as ALT, AST, MDA, GGT, and total bilirubin, as well as elevation of GSH and albumin were observed in rats with d-galactosamine-induced liver damage treated with the extract. These findings agree with a histopathological examination suggesting a hepatoprotective potential for the root extract. The root extract can mediate an antidiabetic effect by reducing elevated blood glucose and serum lipid peroxides levels and by increasing insulin in STZ-diabetic rats by -107, -31.1, +11.3%, respectively. CONCLUSIONS: The results of this study suggest that the tannin-rich extract from Ximenia americana var. caffra could be an interesting candidate for the treatment of several health disorders associated with oxidative stress such as hepatocellular injury and diabetes. PMID- 28887919 TI - Cassia tora Linn.: A boon to Alzheimer's disease for its anti-amyloidogenic and cholinergic activities. AB - BACKGROUND: Drug discovery from natural products as alternatives for Alzheimer's disease (AD) is a current trend. For which plant is an alternative for searching potential molecule for treating AD. Availability of Cassia tora as weed and abundance in nature makes it as potential source. Many plants group under Leguminosae family has potential medicinal property of which Cassia tora is an appropriate choice, to know potency against AD. Etiology of AD is described by senile plaques and neurofibrillary tangles. The Abeta42 has key major role in forming plaques by forming structures like protobirils, oligomers and final fibrilar like structures. Even at in vitro conditions, the peptides have a fibrilar like structure, which was exploited to preliminary screening of natural sources that may be effective in treating AD. HYPOTHESIS/PURPOSE: The design of the study was to unravel the potential medicinal property of Cassia tora for its antioxidant, cholinergic and aggregation inhibition activity. STUDY DESIGN: We evidenced that the methanol (MeOH), n-hexane (n-hex), petroleum ether (PE) and aqueous (aq) extracts from the leaves of Cassia tora (C. tora) were investigated for their inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and anti-amyloidogenic assays. The antioxidant effect using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, total phenolic and flavonoid contents of the extracts were determined using Folin Ciocaltaeu's and aluminum chloride (AlCl3) reagents, respectively. RESULTS: The methanol extract of C. tora exerted the highest inhibition against AChE (55.38 +/ 2.28%) and BChE inhibition (50.02 +/- 0.79%) at 100ug/ml concentration. The methanol extract was also found more active in the antioxidant test. The aggregation kinetics was monitored using thioflavin-T (ThT) assay and transmission electron microscopy (TEM) technique. CONCLUSION: The results showed that C. tora methanol extract is able to inhibit the Abeta42 aggregation from monomers and oligomers and also able to dis-aggregate the pre-formed fibrils. The study provides an insight on finding new natural products for AD therapeutics. PMID- 28887920 TI - Isolation of natural products with anti-ageing activity from the fruits of Platanus orientalis. AB - BACKGROUND: Ageing is defined as the time-dependent decline of functional capacity and stress resistance resulting in increased morbidity and mortality. HYPOTHESIS/PURPOSE: Reportedly, these effects can be delayed by mild genetic or pharmacological activation of the main modules of the proteostasis network. STUDY DESIGN-METHODS: By employing advanced phytochemical methods we isolated natural products from the fruits of Platanus orientalis and studied (via a bio-guided approach) their effects in Drosophila flies, as well as in normal human fibroblasts. RESULTS: We report herein that dietary administration in Drosophila flies of a phenolics-enriched methanol extract from the fruits of Platanus orientalis exerted antioxidant effects; activated proteostatic mechanisms and mildly extended flies' longevity. We then isolated the two major compounds of the extract, namely Platanoside and Tiliroside and found that enrichment of the total extract with these compounds decreased oxidative stress and (in the case of the Tiliroside enriched extract) activated proteostatic mechanisms. Administration of purified Tiliroside in flies activated proteostatic genes, enhanced proteasome and lysosomal-cathepsin activities and decreased tissues' oxidative load; moreover, it delayed the rate of age-related decrease in flies' locomotion activity and increased flies' longevity. Notably, Tiliroside also activated proteasome in normal human fibroblasts and delayed progression of cellular senescence indicating that it may also impact on human cells rate of senescence. CONCLUSION: Our presented findings highlight the potential anti-ageing activity of naturals products derived from the fruits of P. orientalis. PMID- 28887921 TI - Cytotoxicity and mode of action of a naturally occurring naphthoquinone, 2-acetyl 7-methoxynaphtho[2,3-b]furan-4,9-quinone towards multi-factorial drug-resistant cancer cells. AB - INTRODUCTION: Malignacies are still a major public concern worldwide and despite the intensive search of new chemotherapeutic agents, treatment still remains a challenging issue. The present study was designed to evaluate the cytotoxicity of 2-acetyl-7-methoxynaphtho[2,3-b]furan-4,9-quinone (AMNQ) isolated from the bark of Milletia versicolor towards a panel of drug-sensitive and multidrug-resistant (MDR) cancer cell lines. METHODS: The resazurin reduction assay was used to evaluate the cytotoxicity of AMNQ against 9 drug-sensitive and multidrug resistant (MDR) cancer cell lines. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species were all analyzed by flow cytometry. RESULTS: Following resazurin assay, the naphthoquinone AMNQ displayed IC50 values ranging from 0.79 uM (against HepG2 hepatocarcinoma cells) to 3.26 uM (against MDA-MB231/BCRP breast cancer cells) on 9 tested cancer cell lines, whilst doxorubicin showed IC50 values ranging from 0.40 uM (against CCRF-CEM leukemia cells) to 91.37 uM (against CEM/ADR5000 leukemia cells). IC50 values below 1 uM were recorded with AMNQ towards CCRF-CEM cells (0.57 uM), U87MG.DeltaEGFR gliobastoma multiforme cells (0.96 uM cells) and HepG2 cells (0.76 uM). Compared to its corresponding sensitive cell lines U87MG, sensitivity was observed in epidermal growth factor receptor-transfected U87MG.DeltaEGFR cells to AMNQ. MMP was found to be the main mode of action of induction of apoptosis by AMNQ. CONCLUSIONS: The results of this work demonstrate the cytotoxicity of AMNQ towards various types of cancer cell lines, including MDR phenotypes. AMNQ is a potential antiproliferative natural compound that deserves more investigations to develop novel cytotoxic drugs against sensitive and MDR cancers. PMID- 28887922 TI - Gramine inhibits angiogenesis and induces apoptosis via modulation of TGF-beta signalling in 7,12 dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinoma. AB - BACKGROUND: Transforming growth factor-beta (TGF-beta) and its receptors are considered as a novel target in cancer chemotherapy. Gramine, an indole alkaloid, possesses various pharmacological properties including antiproliferative and anticancer. However, the anti-angiogenic property remains unexplored. PURPOSE: The present study was designed to evaluate the anti-angiogenic and apoptosis induction properties of gramine through inhibiting TGF-beta on DMBA induced oral squamous cell carcinoma (OSCC) in the hamster buccal pouch (HBP). METHODS: The effects of gramine on TGF-beta signalling in DMBA induced carcinogenic events such as angiogenesis and apoptosis were analysed by studying the mRNA expression using RT-PCR, protein expression by western blot and histopathological analysis using haematoxylin and eosin (H & E) staining. RESULTS: Gramine significantly inhibited phosphorylation and nuclear translocation of Smad2 and Smad4 by blocking activity of the TGFbeta-RII, RI and activation of inhibitory Smad7. Gramine inhibited angiogenic markers such as MMP-2, MMP-9, HIF-1alpha, VEGF, and VEGF-R2 as well as increased TIMP-2 expression. Furthermore, gramine induced apoptosis in DMBA induced tumour bearing animals by up regulating the pro apoptotic proteins Bax, cytochrome C, apaf-1, caspase-9 caspase-3 and PARP. CONCLUSION: In this study, we clearly demonstrated that gramine treatment diminishes angiogenesis and induces apoptosis in hamster buccal pouch (HBP) carcinogenesis by modulating TGF-beta signals. PMID- 28887923 TI - Anti-adipogenesis mechanism of pterostilbene through the activation of heme oxygenase-1 in 3T3-L1 cells. AB - BACKGROUND: Pterostilbene is a stilbenoid and major compound and has diverse biological activities, such as antioxidant, anti-cancer, and anti-inflammatory. However, it has not been shown whether pterostilbene affects the mitotic clonal expansion during adipogenesis in 3T3-L1 cells. PURPOSE: In the present study, we aimed to demonstrate the detailed mechanism of pterostilbene on anti-adipogenesis in 3T3-L1 cells. METHODS: Preadipocytes were converted to adipocytes through treatment with MDI (IBMX; 3-isobutyl-1-methylxanthine, DEX; dexamethasone, insulin) in 3T3-L1 cells. Oil Red O staining was performed to measure intracellular lipid accumulation. Western blot analysis was conducted to analyze protein expressions. RESULTS: Our results showed that pterostilbene decreased the lipid accumulation compared to MDI-induced differentiation, using Oil Red O staining. Next, we found that pterostilbene suppressed the expression of C/EBPalpha, PPARgamma, and aP2 as well as the mitotic clonal expansion-associated proteins CHOP10 and C/EBPbeta, by western blot analysis. Our results indicated that pterostilbene may repress adipocyte differentiation through the activation of HO-1 expression prior to entering into the mitotic clonal expansion in 3T3-L1 cells. RNA interference was used to determine whether HO-1 acts as a regulator of CHOP10. CONCLUSION: Our results revealed that pterostilbene induced HO-1 expression which acts as a regulator of CHOP10. Together, we demonstrated that pterostilbene suppresses the initiation of mitotic clonal expansion via up regulation of HO-1 expression during adipocyte differentiation of 3T3-L1 cells. PMID- 28887924 TI - In memoriam Prof. Dr. med. Dr. h.c. mult. Fritz H. Kemper (1927-2017). PMID- 28887925 TI - Introduction to Extracorporeal Membrane Oxygenation. AB - Renewed interest in extracorporeal membrane oxygenation (ECMO) support of critically ill patients has led to a large expansion of its use across the world. This article reviews the long history of ECMO and introduces the early pioneers. The idea of team planning and team work is introduced in this article. There is an emphasis on understanding that ECMO care varies across institutions but is slowly growing to more uniform protocols. PMID- 28887926 TI - Developing an Extracorporeal Membrane Oxygenation Program. AB - The development of a successful extracorporeal membrane oxygenation (ECMO) program requires an institutional commitment and the multidisciplinary cooperation of trained specialty personnel from nursing, internal medicine, anesthesiology, pulmonology, emergency medicine, critical care, and surgery and often pediatrics as well. The specialized training necessary to cultivate an integrated team capable of providing life-saving ECMO cannot be underestimated. The development of a successful ECMO program is best suited to a tertiary medical center that is centrally/regionally located and capable of financially supporting the level of expertise required as well as managing the program's overall cost effectiveness. PMID- 28887928 TI - Management Strategies for Severe Respiratory Failure: As Extracorporeal Membrane Oxygenation Is Being Considered. AB - Pulmonary and critical care physicians must be facile in recognition and management of patients with acute respiratory distress syndrome (ARDS). Part of the current critical care knowledge base must include an understanding of how extracorporeal membrane oxygenation fits into the paradigm of ARDS management without using it as a "salvage therapy." This article provides a basic understanding of the evolution of ARDS to multiple organ dysfunction syndrome, recognizing benefits and limits of rescue therapies, indications and contraindications of extracorporeal membrane oxygenation, and coordination of care for severe respiratory failure. PMID- 28887929 TI - Vascular Complications in Extracoporeal Membrane Oxygenation. AB - Venoarterial extracorporeal membrane oxygenation is a rescue therapy in patients with severe cardiopulmonary failure. Often, cannulation is done emergently and the femoral vessels are most readily accessible for venous and arterial access. Unfortunately, complications with arterial femoral access can lead to devastating complications, primarily related to limb ischemia. A coordinated protocol of diligent limb examination by trained intensive care unit staff, near infrared spectroscopy monitoring of limbs, and placement of a distal perfusion catheter at the time of femoral cannulation or when signs of ischemia develop, can lead to successful limb salvage. PMID- 28887927 TI - Cardiac Support: Emphasis on Venoarterial ECMO. AB - Major advances have been made in mechanical circulatory support in recent years. Venoarterial (VA) extracorporeal membrane oxygenation (ECMO) provides both pulmonary and circulatory support for critically ill patients with hemodynamic compromise, serving as a bridge to recovery or definitive therapy in the form of transplant or a durable ventricular assist device. In the past, VA ECMO support was used in cases of cardiogenic shock or failure to wean from cardiopulmonary bypass; however, the technology is now being applied to an ever-expanding list of conditions, including massive pulmonary embolism, cardiac arrest, drug overdose, and hypothermia. PMID- 28887930 TI - Pediatric Extracorporeal Membrane Oxygenation. AB - Extracorporeal life support is a modified form of cardiopulmonary bypass. Experience in extracorporeal membrane oxygenation (ECMO) has come largely from the neonatal population. Most centers have transitioned the ECMO pumps from roller pumps to centrifugal technology. Modes of support include venovenous for respiratory support and venoarterial for cardiac support. "Awake" ECMO is the trend with extubation and tracheostomy on the rise. Fluid overload is common and managed with diuretics or hemofiltration. Nutrition is important and provided enterally or via total parenteral nutrition. Overall survival for pediatric cardiac and respiratory ECMO has remained at approximately 50% to 60%. PMID- 28887931 TI - Extracorporeal Membrane Oxygenation Management: Techniques to Liberate from Extracorporeal Membrane Oxygenation and Manage Post-Intensive Care Unit Issues. AB - Extracorporeal membrane oxygenation (ECMO) is a life-saving technique when patients require pulmonary and/or cardiac support for days to weeks for recovery, bridge to decision, or transplantation. Due to complications associated with ECMO, it is best to stay on ECMO as little time as necessary. Foremost is weaning from ECMO, but the post-ECMO period recapitulates the entire field of critical care. Identified issues include (1) potential for systemic inflammatory response syndrome post-decannulation; (2) post-ECMO complications, such as deep vein thrombosis, wounds, renal failure, and stroke; (3) delirium; (4) posttraumatic stress disorder; (5) rehabilitation; and (6) end of life. PMID- 28887932 TI - Issues in the Intensive Care Unit for Patients with Extracorporeal Membrane Oxygenation. AB - The care of patients on extracorporeal corporeal oxygenation support takes a coordinated effort among the team of nurses, midlevel providers, perfusionists, respiratory therapists, pharmacists, and physicians. Attention on the details of the circuitry and its interactions with the patient, the resolution of the disease process and the ongoing plan of care, and unique issues in the intensive care unit are crucial for success. PMID- 28887933 TI - Staffing, Equipment, Monitoring Considerations for Extracorporeal Membrane Oxygenation. AB - Although the reasons for the recent growth in adult extracorporeal membrane oxygenation (ECMO) are multifactorial, much of the success may be attributed to the development of well-trained staff and the technological innovations in equipment and monitoring devices used during extracorporeal support. In this article, the authors discuss general educational formats for the ECMO bedside provider, staffing support models, and devices designed to best meet the needs of the patient while simultaneously ensuring the proper delivery of ECMO-related care. PMID- 28887934 TI - Transport While on Extracorporeal Membrane Oxygenation Support. AB - Extracorporeal membrane oxygenation (ECMO) support for severe acute respiratory failure has been increasing. Evidence suggests that higher volume centers have better outcomes, leading to a need for specialized ECMO transport teams. The inherent nature of the prehospital environment adds an additional layer of complexity; however, the experience of multiple centers has demonstrated that cannulating and transporting a patient on ECMO can be performed safely. The purpose of this review article is to discuss the state of knowledge with respect to ECMO transport with special emphasis given to how to actually undertake such complex transports. PMID- 28887935 TI - Medication Complications in Extracorporeal Membrane Oxygenation. AB - The need for extracorporeal membrane oxygenation (ECMO) therapy is a marker of disease severity for which multiple medications are required. The therapy causes physiologic changes that impact drug pharmacokinetics. These changes can lead to exposure-driven decreases in efficacy or increased incidence of side effects. The pharmacokinetic changes are drug specific and largely undefined for most drugs. We review available drug dosing data and provide guidance for use in the ECMO patient population. PMID- 28887936 TI - Extracorporeal Membrane Oxygenation. PMID- 28887937 TI - Mars science laboratory radiation assessment detector (MSL/RAD) modeling workshop proceedings. PMID- 28887938 TI - Measurements of the neutral particle spectra on Mars by MSL/RAD from 2015-11-15 to 2016-01-15. AB - The Radiation Assessment Detector (RAD), onboard the Mars Science Laboratory (MSL) rover Curiosity, has been measuring the energetic charged and neutral particles and the radiation dose rate on the surface of Mars since the landing of the rover in August 2012. In contrast to charged particles, neutral particles (neutrons and gamma-rays) are measured indirectly: the energy deposition spectra produced by neutral particles are complex convolutions of the incident particle spectra with the detector response functions. An inversion technique has been developed and applied to jointly unfold the deposited energy spectra measured in two scintillators of different types (CsI for high gamma detection efficiency, and plastic for neutrons) to obtain the neutron and gamma-ray spectra. This result is important for determining the biological impact of the Martian surface radiation contributed by neutrons, which interact with materials differently from the charged particles. These first in-situ measurements on Mars provide (1) an important reference for assessing the radiation-associated health risks for future manned missions to the red planet and (2) an experimental input for validating the particle transport codes used to model the radiation environments within spacecraft or on the surface of planets. Here we present neutral particle spectra as well as the corresponding dose and dose equivalent rates derived from RAD measurement during a period (November 15, 2015 to January 15, 2016) for which the surface particle spectra have been simulated via different transport models. PMID- 28887939 TI - The radiation environment on the surface of Mars - Summary of model calculations and comparison to RAD data. AB - The radiation environment at the Martian surface is, apart from occasional solar energetic particle events, dominated by galactic cosmic radiation, secondary particles produced in their interaction with the Martian atmosphere and albedo particles from the Martian regolith. The highly energetic primary cosmic radiation consists mainly of fully ionized nuclei creating a complex radiation field at the Martian surface. This complex field, its formation and its potential health risk posed to astronauts on future manned missions to Mars can only be fully understood using a combination of measurements and model calculations. In this work the outcome of a workshop held in June 2016 in Boulder, CO, USA is presented: experimental results from the Radiation Assessment Detector of the Mars Science Laboratory are compared to model results from GEANT4, HETC-HEDS, HZETRN, MCNP6, and PHITS. Charged and neutral particle spectra and dose rates measured between 15 November 2015 and 15 January 2016 and model results calculated for this time period are investigated. PMID- 28887940 TI - Evaluation of HZETRN on the Martian surface: Sensitivity tests and model results. AB - The Mars Science Laboratory Radiation Assessment Detector (MSLRAD) is providing continuous measurements of dose, dose equivalent, and particle flux on the surface of Mars. These measurements have been highly useful in validating environmental and radiation transport models that will be heavily relied upon for future deep space missions. In this work, the HZETRN code is utilized to estimate radiation quantities of interest on the Martian surface. A description of the modeling approach used with HZETRN is given along with the various input models and parameters used to define the galactic cosmic ray (GCR) environment and Martian geometry. Sensitivity tests are performed to gauge the impact of varying several input factors on quantities being compared to MSLRAD data. Results from these tests provide context for inter-code comparisons presented in a companion paper within this issue. It is found that details of the regolith and atmospheric composition have a minimal impact on surface flux, dose, and dose equivalent. Details of the density variation within the atmosphere and uncertainties associated with specifying the vertical atmospheric thickness are also found to have minimal impact. Two widely used GCR models are used as input into HZETRN and it is found that the associated surface quantities are within several percent of each other. PMID- 28887941 TI - The charged particle radiation environment on Mars measured by MSL/RAD from November 15, 2015 to January 15, 2016. AB - The Radiation Assessment Detector (RAD) on board the Mars Science Laboratory (MSL) Curiosity rover has been measuring the radiation environment in Gale crater on Mars since August, 2012. These first in-situ measurements provide an important data set for assessing the radiation-associated health risks for future manned missions to Mars. Mainly, the radiation field on the Martian surface stems from Galactic Cosmic Rays (GCRs) and secondary particles created by the GCRs' interactions with the Martian atmosphere and soil. RAD is capable of measuring differential particle fluxes for lower-energy ions and isotopes of hydrogen and helium (up to hundreds of MeV/nuc). Additionally, RAD also measures integral particle fluxes for higher energies of these ions. Besides providing insight on the current Martian radiation environment, these fluxes also present an essential input for particle transport codes that are used to model the radiation to be encountered during future manned missions to Mars. Comparing simulation results with actual ground-truth measurements helps to validate these transport codes and identify potential areas of improvements in the underlying physics of these codes. At the First Mars Radiation Modeling Workshop (June 2016 in Boulder, CO), different groups of modelers were asked to calculate the Martian surface radiation environment for the time of November 15, 2015 to January 15, 2016. These model results can then be compared with in-situ measurements of MSL/RAD conducted during the same time frame. In this publication, we focus on presenting the charged particle fluxes measured by RAD between November 15, 2015 and January 15, 2016, providing the necessary data set for the comparison to model outputs from the modeling workshop. We also compare the fluxes to initial GCR intensities, as well as to RAD measurements from an earlier time period (August 2012 to January 2013). Furthermore, we describe how changes and updates in RAD on board processing and the on ground analysis tools effect and improve the flux calculations. An in-depth comparison of modeling results from the workshop and RAD fluxes of this publication is presented elsewhere in this issue (Matthia et al., 2017). PMID- 28887942 TI - Radiation transport simulation of the Martian GCR surface flux and dose estimation using spherical geometry in PHITS compared to MSL-RAD measurements. AB - Planetary bodies and spacecraft are predominantly exposed to isotropic radiation environments that are subject to transport and interaction in various material compositions and geometries. Specifically, the Martian surface radiation environment is composed of galactic cosmic radiation, secondary particles produced by their interaction with the Martian atmosphere, albedo particles from the Martian regolith and occasional solar particle events. Despite this complex physical environment with potentially significant locational and geometric dependencies, computational resources often limit radiation environment calculations to a one-dimensional or slab geometry specification. To better account for Martian geometry, spherical volumes with respective Martian material densities are adopted in this model. This physical description is modeled with the PHITS radiation transport code and compared to a portion of measurements from the Radiation Assessment Detector of the Mars Science Laboratory. Particle spectra measured between 15 November 2015 and 15 January 2016 and PHITS model results calculated for this time period are compared. Results indicate good agreement between simulated dose rates, proton, neutron and gamma spectra. This work was originally presented at the 1st Mars Space Radiation Modeling Workshop held in 2016 in Boulder, CO. PMID- 28887943 TI - Simulation of the GCR spectrum in the Mars curiosity rover's RAD detector using MCNP6. AB - The paper presents results from MCNP6 simulations of galactic cosmic ray (GCR) propagation down through the Martian atmosphere to the surface and comparison with RAD measurements made there. This effort is part of a collaborative modeling workshop for space radiation hosted by Southwest Research Institute (SwRI). All modeling teams were tasked with simulating the galactic cosmic ray (GCR) spectrum through the Martian atmosphere and the Radiation Assessment Detector (RAD) on board the Curiosity rover. The detector had two separate particle acceptance angles, 4pi and 30 degrees off zenith. All ions with Z = 1 through Z = 28 were tracked in both scenarios while some additional secondary particles were only tracked in the 4pi cases. The MCNP6 4pi absorbed dose rate was 307.3 +/- 1.3 uGy/day while RAD measured 233 uGy/day. Using the ICRP-60 dose equivalent conversion factors built into MCNP6, the simulated 4pi dose equivalent rate was found to be 473.1 +/- 2.4 uSv/day while RAD reported 710 uSv/day. PMID- 28887944 TI - A calculation of the radiation environment on the Martian surface. AB - In this work, the radiation environment on the Martian surface, as produced by galactic cosmic radiation incident on the atmosphere, is modeled using the Monte Carlo radiation transport code, High Energy Transport Code-Human Exploration and Development in Space (HETC-HEDS). This work is performed in participation of the 2016 Mars Space Radiation Modeling Workshop held in Boulder, CO, and is part of a larger collaborative effort to study the radiation environment on the surface of Mars. Calculated fluxes for neutrons, protons, deuterons, tritons, helions, alpha particles, and heavier ions up to Fe are compared with measurements taken by Radiation Assessment Detector (RAD) instrument aboard the Mars Science Laboratory over a period of 2 months. The degree of agreement between measured and calculated surface flux values over the limited energy range of the measurements is found to vary significantly depending on the particle species or group. However, in many cases the fluxes predicted by HETC-HEDS fall well within the experimental uncertainty. The calculated results for alpha particles and the heavy ion groups Z = 3-5, Z = 6-8, Z = 9-13 and Z > 24 are in the best agreement, each with an average relative difference from measured data of less than 40%. Predictions for neutrons, protons, deuterons, tritons, Helium-3, and the heavy ion group Z = 14-24 have differences from the measurements, in some cases, greater than 50%. Future updates to the secondary light particle production methods in the nuclear model within HETC-HEDS are expected to improve light ion flux predictions. PMID- 28887945 TI - The radiation environment on the surface of Mars - Numerical calculations of the galactic component with GEANT4/PLANETOCOSMICS. AB - Galactic cosmic radiation and secondary particles produced in the interaction with the atmosphere lead to a complex radiation field on the Martian surface. A workshop ("1st Mars Space Radiation Modeling Workshop") organized by the MSL-RAD science team was held in June 2016 in Boulder with the goal to compare models capable to predict this radiation field with each other and measurements from the RAD instrument onboard the curiosity rover taken between November 15, 2015 and January 15, 2016. In this work the results of PLANETOCOSMICS/GEANT4 contributed to the workshop are presented. Calculated secondary particle spectra on the Martian surface are investigated and the radiation field's directionality of the different particles in dependence on the energy is discussed. Omnidirectional particle fluxes are used in combination with fluence to dose conversion factors to calculate absorbed dose rates and dose equivalent rates in a slab of tissue. PMID- 28887946 TI - Comparing HZETRN, SHIELD, FLUKA and GEANT transport codes. AB - For the first time, the American (NASA) and Russian (ROSCOSMOS) space radiation transport codes, HZETRN and SHIELD respectively, are directly compared to each other. Calculations are presented for Galactic Cosmic Ray (GCR) minimum Hydrogen, Oxygen and Iron projectiles incident on a uniform Aluminum cylinder of varying thickness. Comparisons are made for the flux spectra of neutrons, light ions (Z<= 2), heavy ions (Z> 2) and pions emitted from the back of the Aluminum cylinder. In order to provide more benchmark comparisons, some calculations with the GEANT and FLUKA transport codes are also shown. PMID- 28887947 TI - Therapeutic pipeline for atopic dermatitis: End of the drought? AB - Until the past year, our therapeutic armamentarium for treating atopic dermatitis (AD) was still primarily topical corticosteroids and, for more severe disease, systemic immunosuppressants. The pipeline of more targeted topical and systemic therapies is expanding based on our growing understanding of the mechanism for AD and is particularly focused on suppressing the skewed immune activation. Most agents are in phase 2 clinical trials. Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, became available in late 2016 in the United States for mild-to moderate AD, with other PDE4 inhibitors, an agonist of the aryl hydrocarbon receptor, Janus kinase inhibitors, and commensal organisms also in trials for topical application. The first highly effective mAb for AD, dupilumab, targets the IL-4/IL-13 receptor and was approved in early 2017 in the United States for moderate-to-severe adult AD. Other biologics similarly inhibit TH2 cytokines (thymic stromal lymphopoietin, IL-4, IL-5, IL-13, and the itch-specific cytokine IL-31 and their receptors) or TH22/TH17 cytokines, levels of which are increased in lesional skin. Orally administered small-molecule inhibitors that suppress inflammation (targeting chemoattractant receptor-homologous molecules expressed on TH2 lymphocytes, PDE4, the histamine 4 receptor, and Janus kinase) or specifically itching (eg, NK1R inhibitors) are also being studied. Comparing biomarkers with individual responses to experimental agents will help to determine subphenotypes within AD that predict prognosis and treatment responses. PMID- 28887950 TI - Correction. PMID- 28887948 TI - Psoriasis pathogenesis and the development of novel targeted immune therapies. AB - Psoriasis is caused by a complex interplay between the immune system, psoriasis associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell-mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management. PMID- 28887951 TI - Injectable hyaluronan-methylcellulose composite hydrogel crosslinked by polyethylene glycol for central nervous system tissue engineering. AB - Spontaneous recovery ability of central nerves has inspired researchers to focus on tissue engineering techniques, especially scaffolds. To obtain a material with an appropriate degrading rate, an injectable composite hydrogel HAMC consisting of hyaluronic acid and methylcellulose was prepared using polyethylene glycol as a cross linker in this study. HAMC combined the advantages of two components to be fast-gelling, injectable, degradable, biocompatible, and it was able to meet some special shape requirement for injured tissue by in-situ forming. Moreover, due to the crosslinking effects polyethylene glycol brought to methylcellulose, the rheological properties and stability of HAMC were greatly improved, which could prolong the residence time of this hydrogel effectively. Cell viability results showed HAMC was cytocompatible for further applications in vivo, and would be a promising choice for neural tissue engineering in the future. PMID- 28887952 TI - Evaluating adhesion and alignment of dental pulp stem cells to a spider silk substrate for tissue engineering applications. AB - A proposed source of stem cells for nerve regeneration are dental pulp stem cells (DPSCs), based on their close embryonic origin to neurons and the ease with which DPSCs can be obtained from a donor. This study evaluated the response of human DPSCs to spider dragline silk fibers, a potential substrate material for tissue regeneration. The DPSCs' morphology and spread pattern were characterized after these cells were plated onto Nephila clavipes dragline fibers in media. In addition, the responses of two other well established cell lines, osteoblasts (7F2s), and fibroblasts (3T3s), were also studied under identical conditions. The inclusion of 3T3s and 7F2s in this study allowed for both direct comparisons to prior published work and a qualitative comparison to the morphology of the DPSCs. After twelve days, the DPSCs exhibited greater relative alignment and adherence to the spider dragline fibers than the 3T3s and 7F2s. The impact of a common sterilization method (ultraviolet light) on the spider dragline fiber surface and subsequent cell response to this modified surface was also characterized. Exposure of the silk to ultraviolet light did not have a measureable effect on cell alignment, but it did eliminate bacterial growth and changed fiber surface roughness. Spiders' exposure to stressful environments did not have an effect on silk to impair cell alignment or adhesion. Synthetic recombinant protein silk did not act as a substrate for cell adhesion or alignment but hydrogels with similar composition supported cell attachment, growth and proliferation. In all cases, natural drawn spider silk acted as an effective substrate for cellular adhesion and alignment of DPSCs and could be used in neural differentiation applications. PMID- 28887953 TI - Synthesis and biological evaluation of an anticancer drug delivery system: Poly(l gamma-glutamyl-l-carbocisteine)-paclitaxel nanoconjugate. AB - This study is intended to develop and evaluate a novel, highly water-soluble polymer drug conjugate poly(l-gamma-glutamyl-l-carbocisteine)-paclitaxel (PGSC PTX) which can trigger drug release in tumor acidic microenvironment and improve the therapeutic index of paclitaxel (PTX). PGSC-PTX is formed by introducing an additional carbocisteine into each glutamic side chain of poly(l-glutamic acid) paclitaxel (PGA-PTX) conjugate. PGSC-PTX self-assembles into nanoparticles, whose size remains in the range of 15-20nm. PGSC-PTX demonstrated sensitive to pH and released PTX rapidly in low pH. PGSC-PTX shows significant in vitro cytotoxicity to NH460 cancer cell line, which has less toxic and side effect of than PTX. Meanwhile, the hemolytic test indicated that the nanoparticles could be used for intravenous injection. It was concluded that the maximum tolerated dose of PGSC PTX achieved to be 250mg PTX/kg, which is extremely maximum tolerated providing a significant foundation in the clinical research. PMID- 28887954 TI - Fabrication, self-assembly and biomedical applications of luminescent sodium hyaluronate with aggregation-induced emission feature. AB - Organic dyes with aggregation-induced emission (AIE) feature have recently attracted much research attention for biomedical applications due to their inimitable optical superiority. Although many reports have demonstrated for fabricating AIE-active nanoprobes, the synthesis of AIE-active natural polymers is still very limited. In this work, fluorescent organic nanoparticles (FONs) with AIE feature have been prepared through formation of Schiff base interaction between amino-terminated AIE dye (PhE) and oxidation sodium hyaluronate (OSH). The final copolymers (denoted as PhE-OSH) were characterized by means of 1H nuclear magnetic resonance spectroscopy, transmission electron microscopy, fluorescent spectroscopy and X-ray photoelectron spectroscopy. The potential of using PhE-OSH in biomedical applications were examined by cell viability assay as well as confocal imaging capability. Results suggested that PhE can facilely conjugate with OSH through formation of Schiff base. The synthesized PhE-OSH FONs exhibited well dispersibility in aqueous solution, small size, strong fluorescence and good biocompatibility. Taken together, we developed a novel strategy for fabrication of AIE-active FONs, which showed great potential for biomedical applications. PMID- 28887955 TI - Engineered electrospun polycaprolactone (PCL)/octacalcium phosphate (OCP) scaffold for bone tissue engineering. AB - The main challenge in bone tissue engineering is to find suitable biological substitutes which act as scaffolds. Hence, in this work, a novel scaffold composed of octacalcium phosphate (OCP) particles fabricated by co-precipitation method and polycaprolactone (PCL) using electrospinning technique was introduced. The electrospun scaffolds were characterized by SEM, FTIR, XRD, DSC and TGA analysis. The mechanical properties of the composite scaffolds including maximum tensile stress, strain at break and Young modulus were measured. The bioactivity of the scaffolds was determined by soaking in simulated body fluid (SBF). The osteoblast human G-292 cells were seeded on the scaffold's surface for in vitro studies including cell culture and MTT assay. The FTIR and XRD results showed that OCP component has an appropriate incorporation into the polymeric PCL matrix. The SEM analysis exhibited a significant reduction in the fiber size thanks to the OCP. The results of tensile test confirmed that the PCL/OCP composite introduced suitable mechanical properties. Furthermore, the OCP particles led to form hydroxyapatite layer on the scaffold's surface in the vicinity of SBF solution. The obtained results from the MTT assay described that OCP particles have a positive impact on the growth of the osteoblast human G-292 cells on the scaffolds. Overall, aforesaid features of the PCL/OCP composite scaffold make it a great candidate for the bone tissue engineering application. PMID- 28887956 TI - Layer-by-layer assembled biopolymer microcapsule with separate layer cavities generated by gas-liquid microfluidic approach. AB - In this work, a layer-by-layer (LbL) assembled biopolymer microcapsule with separate layer cavities is generated by a novel and convenient gas-liquid microfluidic approach. This approach exhibits combined advantages of microfluidic approach and LbL assembly method, and it can straightforwardly build LbL assembled capsules in mild aqueous environments at room temperature. In particular, using this approach we can build the polyelectrolyte multilayer capsule with favorable cavities in each layer, and without the need for organic solvent, emulsifying agent, or sacrificial template. Various components (e.g., drugs, proteins, fluorescent dyes, and nanoparticles) can be respectively encapsulated in the separate layer cavities of the LbL-assembled capsules. Moreover, the encapsulated capsules present the ability as colorimetric sensors, and they also exhibit the interesting release behavior. Therefore, the LbL assembled biopolymer capsule is a promising candidate for biomedical applications in targeted delivery, controlled release, and bio-detection. PMID- 28887957 TI - Accelerated healing of full thickness dermal wounds by macroporous waterborne polyurethane-chitosan hydrogel scaffolds. AB - Wound healing is a dynamic process wherein cells, and macromolecules work in consonance to facilitate tissue regeneration and restore tissue integrity. In the case of full-thickness (FT) wounds, healing requires additional support from native or synthetic matrices to aid tissue regeneration. In particular, a matrix with optimum hydrophilic-hydrophobic balance which will undergo adequate swelling as well as reduce bacterial adhesion has remained elusive. In the present study, polyurethane diol dispersion (PUD) and the anti-bacterial chitosan (Chn) were blended in different ratios which self-organized to form macroporous hydrogel scaffolds (MHS) at room temperature on drying. SEM and AFM micrographs revealed the macroporosity on top and fracture surfaces of the MHS. FTIR spectra revealed the intermolecular as well as intra-molecular hydrogen bonding interactions between the two polymers responsible for phase separation, which was also observed by micrographs of blend solutions during the drying process. The effect of phase separation on mechanical properties and in vitro degradation (hydrolytic, enzymatic and pH dependent) of MHS were studied and found to be suitable for wound healing. In vitro cytocompatibility was demonstrated by the proliferation of primary rat fibroblast cells on MHS. Selected MHS was subjected to in vivo FT wound healing study in Wistar rats and compared with an analogous polyurethane containing commercial dressing i.e. TegadermTM. The MHS-treated wounds demonstrated accelerated healing with increased wound contraction, higher collagen synthesis, and vascularization in wound area compared to TegadermTM. Thus, it is concluded that the developed MHS is a promising candidate for application as FT wound healing dressings. PMID- 28887959 TI - alpha-TCP cements prepared by syringe-foaming: Influence of Na2HPO4 and surfactant concentration. AB - The lack of intrinsic open porosity in calcium phosphate cements slows down the resorption rate and bone ingrowth when implanted In Vivo. In this study, macroporous structures were obtained by mixing alpha-TCP cement with a foamed liquid phase containing different concentrations of sodium hydrogen phosphate and a nonionic surfactant. The cement paste was prepared by hand mixing in a novel system of two syringes connected by a tube. Two different liquid to powder (L/P) ratios were used to prepare the cement paste. The cement samples showed open macropores with diameters>100MUm. The specimens prepared with lower L/P ratio showed smaller porosity, macroporosity and pore size distribution. The cohesion of the cement paste in liquid solutions was assessed by adding 2wt% sodium alginate to the liquid phase. This study suggests that the final macrostructure of the foamed cements can be controlled by varying the phosphate and surfactant concentrations in the liquid phase and the L/P ratio. PMID- 28887958 TI - Photoelastic analysis of mandibular full-arch implant-supported fixed dentures made with different bar materials and manufacturing techniques. AB - PURPOSE: To compare the stress distribution of mandibular full dentures supported with implants according to the bar materials and manufacturing techniques using a qualitative photoelastic analysis. MATERIAL AND METHODS: An acrylic master model simulating the mandibular arch was fabricated with four Morse taper implant analogs of 4.5*6mm. Four different bars were manufactured according to different material and techniques: fiber-reinforced resin (G1, Trinia, CAD/CAM), commercially pure titanium (G2, cpTi, CAD/CAM), cobalt-chromium (G3, Co-Cr, CAD/CAM) and cobalt-chromium (G4, Co-Cr, conventional cast). Standard clinical and laboratory procedures were used by an experienced dental technician to fabricate 4 mandibular implant-supported dentures. The photoelastic model was created based on the acrylic master model. A load simulation (150N) was performed in total occlusion against the antagonist. RESULTS: Dentures with fiber reinforced resin bar (G1) exhibited better stress distribution. Dentures with machined Co-Cr bar (G3) exhibited the worst standard of stress distribution, with an overload on the distal part of the posteriors implants, followed by dentures with cast Co-Cr bar (G4) and machined cpTi bar (G2). CONCLUSION: The fiber reinforced resin bar exhibited an adequate stress distribution and can serve as a viable alternative for oral rehabilitation with mandibular full dentures supported with implants. Moreover, the use of the G1 group offered advantages including reduced weight and less possible overload to the implants components, leading to the preservation of the support structure. PMID- 28887960 TI - Electrochemical preparation and characterization of PNIPAM-HAp scaffolds for bone tissue engineering. AB - In the last decade, a variety of methods for fabrication of three-dimensional biomimetic scaffolds based on hydrogels have been developed for tissue engineering. However, many methods require the use of catalysts which compromises the biocompatibility of the scaffolds. The electrochemical polymerization (ECP) of acrylic monomers has received an increased attention in recent years due to its versatility in the production of highly biocompatible coatings for the electrodes used in medical devices. The main aim of this work was the use of ECP as scaffold fabrication technique to produce highly porous poly(N isopropylacrylamide) (PNIPAM)/hydroxyapatite (HAp) composite for bone tissue regeneration. The prepared PNIPAM-HAp porous scaffolds were characterized by SEM, FTIR, water swelling, porosity measurements and X-ray diffraction (XRD) techniques. FTIR indicates that ECP promotes a successful conversion of NIPAM to PNIPAM. The water swelling and porosity were shown to be controlled by the HAp content in PNIPAM-HAp scaffolds. The PNIPAM-HAp scaffolds exhibited no cytotoxicity to MG63 cells, showing that ECP are potentially useful for the production of PNIPAM-HAp scaffolds. To address the osteomyelitis, a significant complication in orthopedic surgeries, PNIPAM-HAp scaffolds were loaded with the antibiotic oxacillin. The oxacillin release and the bacterial killing activity of the released oxacillin from PNIPAM-HAp against S. aureus and P. aeruginosa were demonstrated. These observations demonstrate that ECP are promising technique for the production of non-toxic, biocompatible PNIPAM-HAp scaffolds for tissue engineering. PMID- 28887961 TI - Biopolymers/poly(epsilon-caprolactone)/polyethylenimine functionalized nano hydroxyapatite hybrid cryogel: Synthesis, characterization and application in gene delivery. AB - Nano-hydroxyapatite (nHAp), surface functionalized with linear polyethylenimine (LPEI), was used for the preparation of biocomposites in combination with biopolymers and poly(epsilon-caprolactone) (PCL), by cryogelation technique, to yield biomimetic scaffolds with controlled interconnected macroporosity, mechanical stability, and predictable degradation behavior. The structural characteristics, swelling and degradation behavior of hydroxyapatite and hydroxyapatite/beta-tricalcium phosphate (beta-TCP) filled matrices were investigated as compared to the corresponding naked polymer 3D system. It was found that the homogeneity and cohesivity of the composite are significantly dependent on the size and amount of the included inorganic particles, which are thus determining the structural parameters. Surface modification with LPEI and nanodimensions favored the nHAp integration in the organic matrix, with preferential location along protein fibers, while beta-TCP microparticles induced an increased disorder in the hybrid system. The biocomposite including nHAp only was further investigated targeting biomedical uses, and proved to be non cytotoxic and capable of acting as gene-activated matrix (GAM). It allowed sustained delivery over time (until 22days) of embedded PEI25-pDNA polyplexes at high levels of transgene expression, while insuring a decrease in cytotoxicity as compared to polyplexes alone. Experimental data recommend such biocomposite as an attractive material for regenerative medicine. PMID- 28887963 TI - Facile-one pot-green synthesis, antibacterial, antifungal, antioxidant and antiplatelet activities of lignin capped silver nanoparticles: A promising therapeutic agent. AB - The current work portrays the green synthesis of Lignin Capped Silver Nanoparticles (LCSN) and their antibacterial, antifungal, antioxidant and antiplatelet potential. The LCSN was synthesized in water using a carbohydrate based polymer 'lignin' as the reducing and capping agents. The peak at 406nm (lambdamax) in the UV-Vis., spectrum and EDX analysis confirmed 1.68% (w/w) of silver was found to be loaded on lignin. The characteristic sharp peaks appeared in the PXRD spectrum showed fcc crystalline structure LCSN. SEM and TEM images indicated that the spherical Ag-NPs were well dispersed on lignin with an average particle size of ~10-15nm. LCSN showed antibacterial and antifungal activity against human pathogens S. aureus, E. coli and A. niger and the percentage of zone of inhibition was found to be 10%, 12% and 80% respectively. Further, LCSN was evaluated for antioxidant potential using DPPH scavenging assay, interestingly it showed antioxidant activity and the percentage against positive control vitamin C was found to be 70%. Furthermore, LCSN did not interfere in plasma coagulation; however, it found to inhibit agonist ADP induced platelet aggregation of human platelet rich plasma. The observed inhibition was found to be 37% and the calculated IC50 value was found to be 9mg/mL. LCSN did not lyses RBC membrane when assayed hemolytic activity suggesting its non-toxic nature. PMID- 28887964 TI - In vitro co-culture of epithelial cells and smooth muscle cells on aligned nanofibrous scaffolds. AB - Esophagus is a complex, hollow organ consisting of epithelial cells in the inner mucosal layer and smooth muscle cells in the outer muscle layer. In the present study, we have evaluated the in vitro co-culture of epithelial cells and smooth muscle cells on the aligned nanofibrous scaffold made of PHBV, PHBV-gelatin, PCL and PCL-gelatin developed through electrospinning using rotating drum collector. Epithelial cells were labeled with cell tracker green while the smooth muscle cells were labeled with cell tracker red. Labeled cells were seeded on the aligned nanofibers matrices and tracked using laser scanning confocal microscopy. The results demonstrate that both epithelial and smooth muscle cells attach, extend, and proliferate over these nanofibrous matrices. Confocal z-sectioning shows that epithelial and smooth muscle cells tend to separate into two distinct layers on a single nanofiber system mimicking the in vivo anatomy. Cell viability assay showed that both types of cells are viable and also interact with each other. The functional gene expression of respective cell types demonstrates that both epithelial and smooth muscle cells are phenotypically as well as functionally active when they were co-cultured. Thus the study highlighted that aligned nanofibrous scaffolds could be potential alternative graft for esophageal tissue regeneration. PMID- 28887962 TI - A simple, compact, low-cost, highly efficient thermometer based on green fluorescence of Er3+/Yb3+-codoped NaYF4 microcrystals. AB - We developed a highly efficient optical thermometer based on intensity ratio of upconversion green fluorescence of Er3+/Yb3+-codoped NaYF4 microcrystals. The sensor consists simply of a 980nm laser diode, one narrow-band interference filter, two lenses, one Si-photocell and one multimeter, while being without use of spectrometer and additional electronics. The device not only has a simple, compact structure (hence a low cost), but also displays highly efficient sensing performance, characterized by large signal-to-noise ratio due to strong fluorescence intensity, high thermal resolution and sensitivity, which have the values 1.3K and 1.24*10-2K-1, respectively, at the physiological temperature 310K. The excellent sensing performance of the device was further confirmed by the results of the measurements repeated using a spectrometer. The thermometer is highly generalized that can be applied to other luminescent materials, and shows great potential for the physiological temperature sensing in biological tissues and cells. PMID- 28887965 TI - Preparation, characterization and anti-colitis activity of curcumin-asafoetida complex encapsulated in turmeric nanofiber. AB - Ulcerative colitis (UC) is a main form of inflammatory bowel disease (IBD). Asafoetida (ASF) and turmeric have traditionally been used for the treatment of various inflammatory diseases, including UC, because ASF is rich in sulfur compounds and turmeric contains curcumin (CUR). Turmeric nanofiber (TNF), the modified cell wall component of turmeric is considered to play important role in the human diet, health and can be used as a carrier agent to encapsulate bioactive components. A novel gut health product (GHP) was formulated by encapsulation of ASF and CUR complex onto TNF. The GHP was characterized by UPLC, GC-MS, FTIR, XRD, SEM with EDS and DSC studies. GHP was evaluated for anti colitis activity in a rat model of 5% dextran sulfate sodium (DSS) induced UC. Treatment with GHP significantly attenuated the disease activity index, colitis score, histopathological changes and myeloperoxidase activity. GHP has significant protective effects against DSS induced colitis. PMID- 28887966 TI - Core-shell structured polypyrrole/mesoporous SiO2 nanocomposite capped with graphene quantum dots as gatekeeper for irradiation-controlled release of methotrexate. AB - A core-shell structured nanocomposite of polypyrrole/mesoporous SiO2 (PPy/mSiO2) is rationally designed as the nanocarrier for methotrexate (MTX), a chemotherapeutic drug for cancer treatment. Graphene quantum dots (GQDs) are introduced to the outer surface of PPy/mSiO2, and it functions as a gatekeeper for the loaded MTX through the formation of H-bonds with the functionalized mSiO2. In the proposed nanocarrier for MTX, the mesopores in mSiO2 are beneficial for the accommodation of MTX, resulting in enhanced encapsulation capacity of the nanocarrier; on the other hand, PPy can effectively convert the near-infrared (NIR) light to heat. Under the irradiation of NIR light, the H-bonds between GQDs and mSiO2 are broken due to the gradually increased temperature, and therefore the GQDs cap is removed and consequently the encapsulated MTX is released from the nanocarrier. In this study, NIR irradiation-controlled drug delivery is achieved successfully owing to the synergistic effects of PPy, mSiO2 and GQDs, which opens a new window for the construction of smart drug delivery systems. PMID- 28887967 TI - Efficient synthesis of highly fluorescent carbon dots by microreactor method and their application in Fe3+ ion detection. AB - Rapidly obtaining strong photoluminescence (PL) of carbon dots with high stability is crucial in all practical applications of carbon dots, such as cell imaging and biological detection. In this study, we proposed a rapid, continuous carbon dots synthesis technique by using a microreactor method. By taking advantage of the microreactor, we were able to rapidly synthesized CDs at a large scale in less than 5min, and a high quantum yield of 60.1% was achieved. This method is faster and more efficient than most of the previously reported methods. To explore the relationship between the microreactor structure and CDs PL properties, Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) were carried out. The results show the surface functional groups and element contents influence the PL emission. Subsequent ion detection experiments indicated that CDs are very suitable for use as nanoprobes for Fe3+ ion detection, and the lowest detection limit for Fe3+ is 0.239MUM, which is superior to many other research studies. This rapid and simple synthesis method will not only aid the development of the quantum dots industrialization but also provide a powerful and portable tool for the rapid and continuous online synthesis of quantum dots supporting their application in cell imaging and safety detection. PMID- 28887968 TI - Polyethyleneimine grafted short halloysite nanotubes for gene delivery. AB - Inorganic nanoparticles have attracted much attentions in gene delivery because of their desirable characteristics including low toxicity, well-controlled characteristics, high gene delivery efficiency, and multi-functionalities. Here, natural occurred halloysite nanotubes (HNTs) were developed as a novel non-viral gene vector. To increase the efficiency of endocytosis, HNTs were firstly shortened into an appropriate size (~200nm). Then polyethyleneimine (PEI) was grafted onto HNTs to bind green fluorescence protein (GFP) labeled pDNA. The structure and physical-chemical properties of PEI grafted HNTs (PEI-g-HNTs) were characterized by various methods. PEI-g-HNTs show lower cytotoxicity than PEI. PEI-g-HNTs are positively charged and can bind DNA tightly at designed N/P ratio from 5:1 to 40:1. PEI-g-HNTs/pDNA complexes show much higher transfection efficiency towards both 293T and HeLa cells compared with PEI/pDNA complexes at the equivalent N/P ratio. The transfection efficiencies of PEI-g-HNTs/pDNA complex towards HeLa cell can reach to 44.4% at N/P ratio of 20. PEI-g-HNTs/pDNA complexes possess a higher GFP protein expression than PEI/pDNA from simple western immunoblots. So, PEI-g-HNTs are potential gene vectors with good biocompatibility and high transfection efficiency, which have promising applications in cancer gene therapy. PMID- 28887969 TI - Viability of HEK 293 cells on poly-beta-hydroxybutyrate (PHB) biosynthesized from a mutant Azotobacter vinelandii strain. Cast film and electrospun scaffolds. AB - Sterilization, cytotoxicity and cell viability are essential properties defining a material for medical applications and these characteristics were investigated for poly(beta-hydroxybutyrate) (PHB) of 230kDa obtained by bacterial synthesis from a mutant strain of Azotobacter vinelandii. Cell viability was investigated for two types of PHB scaffolds, solution cast films and non-woven electrospun fibrous membranes, and the efficiency was compared against a culture dish. The biosynthesized PHB was sterilized by ultraviolet radiation and autoclave, it was found that the thermal properties and intrinsic viscosity remained unchanged indicating that the sterilization methods did not degrade the polymer. Sterilized scaffolds were then seeded with human embryonic kidney 293 (HEK 293) cells to evaluate the cytotoxic response. The cell viability of these cells was evaluated for up to six days, and the results showed that the cell morphology was normal, with no cytotoxic effects. The films and electrospun membranes exhibited over 95% cell viability whereas the viability in culture dishes reached only ca. 90%. The electrospun membrane, however, exhibited significantly higher cell density than the cast film suggesting that the fibrous morphology enables better nutrients transfer. The results indicate that the biosynthesized PHB stands UV and autoclave sterilization methods, it is biocompatible and non-toxic for cell growth of human cell lines. Furthermore, cell culture for up to 18 days showed that 62% and 90% of mass was lost for the film and fibrous electrospun scaffold, respectively. This is a favorable outcome for use in tissue engineering where material degradation, as tissue regenerates, is desirable. PMID- 28887971 TI - 808nm light triggered black TiO2 nanoparticles for killing of bladder cancer cells. AB - The black TiO2 nanoparticles are synthesized via a facile calcination method combined with an in-situ controllable solid-state reaction approach. The results indicate that the photocatalyst with a narrow band gap of ~2.32 eV extends the photoresponse to visible light and near infrared region. And thus more reactive oxygen species can be obtained to induce the cell-killing under 808 nm light triggering. The as-obtained black TiO2 nanoparticles exhibiting low toxicity, good biocompatibility and high anticancer effect in vitro, is demonstrated as efficient photosensitizers for phototherapy to kill the bladder cancer cells. These findings suggest that the facile synthetic black TiO2 nanomaterials will have broad application in biomedicine. PMID- 28887970 TI - Fabrication and characterization of nanofibers of honey/poly(1,4-cyclohexane dimethylene isosorbide trephthalate) by electrospinning. AB - We report the fabrication of novel nanofibers using naturally occurring antimicrobial honey incorporated in poly(1,4-cyclohexane dimethylene isosorbide trephthalate) (PICT) for the potential wound dressing applications. We fabricated PICT/honey using three blend ratios 90:10, 85:15 and 80:20 respectively. Morphology of PICT nanofibers and PICT/honey nanofibers was observed under Scanning Electron Microscope and it showed bead-free nanofibers. Fourier Transform Infrared Spectroscope was used to confirm the presence of honey in PICT electrospun nanofibers. Tensile strength of PICT/honey nanofibers was slightly reduced with variation in effect of elongation. Water contact angle measurements were done with the static contact angle by a contact angle meter, which showed that hydrophobicity was decreased by adding the honey. The XPS spectra showed that honey was present in the PICT/honey nanofibers. The release behavior of honey was investigated by UV-visible Spectrophotometer. The release was complete in 15min and the maximum release of honey was 72mg/L in 10min. Therefore, PICT/honey nanofibers having 15% concentration of honey are suitable for good elastic behavior and tensile strength as compared to other concentrations of honey. PMID- 28887972 TI - Dual targeting hyaluronic acid - RGD mesoporous silica coated gold nanorods for chemo-photothermal cancer therapy. AB - This work reports a multifunctional nanoplatform (GNRs@mSiO2-HA-RGD) by conjugating targeting ligand hyaluronic acid (HA) and RGD with mesoporous silica coated gold nanorods (GNRs@mSiO2) for dual-targeted chemo-photothermal therapy. Doxorubicin hydrochloride (DOX) was used as the model drug to investigate the drug loading, in vitro drug release profiles and cell evaluation. The nanoplatform has demonstrated a good photothermal effect and excellent drug loading capacity of about 20.16%. It also had pH-enzyme sensitive and NIR triggered drug release properties. Cellular uptake experiment results indicated that DOX-GNRs@mSiO2-HA-RGD can be dual-targeted to ovarian cancer cells via CD44 and integrin receptor mediated endocytosis pathway. Cytotoxicity experiments demonstrated that combined therapy exhibited a better therapy effect compared to that of single chemotherapy or photothermal therapy. Our study demonstrates that DOX-GNRs@mSiO2-HA-RGD may be a new promising dual-targeted delivery system for chemo-photothermal therapy. PMID- 28887973 TI - Controlled release of a hydrophilic drug from electrospun amyloid-like protein blend nanofibers. AB - In this study, a controlled drug release platform, amyloid-like bovine serum albumin (AL-BSA) with ampicillin sodium salt (amp), was developed. To develop this platform, 5%, 10%, and 20% (w/w) ratios of amp:BSA were used with electrospinning to prepare nanofibers with average diameters of 132+/-69, 159+/ 60, and 179+/-42nm, respectively. Fourier transform infrared spectroscopy demonstrated that AL-BSA could entrap large amounts of drug inside the nanofibers, which was attributed to the antimicrobial activity of the released drug against Escherichia coli and Staphylococcus aureus. The amount of drug released was measured by UV-VIS spectrophotometry. The nanofibrous matrix of the electrospun membrane showed controlled release behavior in all samples. The transport mechanism was Fickian for the low ratio of amp:BSA (5% w:w). When the drug ratio was increased to >10% (w:w), thicker fiber structures formed, suggesting that the drug traveled a longer distance to reach the fiber surface; thus, the mechanism of transport shifted from Fickian to non-Fickian. PMID- 28887974 TI - Mechanical properties and osteogenic activity of poly(l-lactide) fibrous membrane synergistically enhanced by chitosan nanofibers and polydopamine layer. AB - To synergistically improve the mechanical properties and osteogenic activity of electrospinning poly(l-lactide) (PLLA) membrane, chitosan (CS) nanofibers were firstly introduced to prepare sub-micro and nanofibers interpenetrated PLLA/CS membrane, which was further surface modified with a polydopamine (PDA) layer to obtain PLLA/CS-PDA. Surface morphology, porosity, surface area and hydrophilicity of the obtained fibrous membranes were studied in detail. As compared to pure PLLA, the significant increase in the mechanical properties of the PLLA/CS, and especially of the PLLA/CS-PDA, was confirmed by tensile testing both in dry and wet states. Cells culture results indicated that both the PLLA/CS and PLLA/CS-PDA membranes, especially the latter, were more beneficial to adhesion, spreading and proliferation, as well as up-regulating alkaline phosphate activity and calcium deposition of MC3T3-E1 cells than PLLA membrane. Results suggested there was a synergistic effect of the CS nanofibers and PDA layer on the mechanical properties and osteogenic activity of PLLA membrane. PMID- 28887975 TI - Synthesis of silk fibroin-g-PAA composite using H2O2-HRP and characterization of the in situ biomimetic mineralization behavior. AB - Silk fibroin (SF) as a bioactive protein can offer growth substrates for hydroxyapatite (HAp) deposition. In the current work, graft copolymerization of acrylic acid (AA) onto fibroin chains was carried out using hydrogen peroxide horseradish peroxidase (H2O2-HRP) catalytic system, SF-g-polyacrylic acid (PAA) membranes was prepared subsequently, followed by in situ biomimetic mineralization in the Ca/P solutions, aiming at promoting the deposition of HAp and endowing the fibroin-based biocomposite with enhanced bioactivity. Meanwhile, p-hydroxyphenylacetamide (PHAD) and methyl acrylate (MA), as the model compounds of tyrosine residues in SF and vinyl monomer were used to disclose the mechanism of graft copolymerization. The data from FTIR and SEC chromatograms indicated that vinyl monomer was successfully graft copolymerized with SF during H2O2-HRP treatment. According to the results of XRD, SEM patterns and EDS-Mapping, mineral phases on the surfaces of SF-g-PAA membranes were detected after different cycles of biomimetic mineralization, and the mechanical property of SF-g-PAA/HAp membrane was noticeably improved. Cell viability and adhesion assays revealed that the composite of SF-g-PAA/HAp exhibited acceptable biocompatibility and outstanding adhesion property. The present work provides a novel method for preparation of the fibroin-based biomaterial for bone tissue engineering. PMID- 28887976 TI - Nanoclay cross-linked semi-IPN silk sericin/poly(NIPAm/LMSH) nanocomposite hydrogel: An outstanding antibacterial wound dressing. AB - High antibacterial and skin-like hydrogels have always been the perfect wound dressing for human to protect wound from infection. Here, based on silk sericin, we design a series of nanoclay lithium magnesium silicate hydrate (LMSH) cross linked semi-IPN sericin/poly(NIPAm/LMSH) (HSP) nanocomposite hydrogels and demonstrate advantages in serving as antibacterial wound dressing in comparison with gauze. Firstly, the effect of mass ratios of sericin/(sericin+NIPAm) upon pore structure, feasibility of mechanics and gas permeability of HSP nanocomposite hydrogels were evaluated. Then, the relationship between nanocomposite hydrogel and histological/antimicrobial properties was systematically analyzed. It was found that, the introduction of sericin increased internal pore size, leading to obvious transition from honeycomb to layered structure. Furthermore, as mass ratio of sericin/(sericin+NIPAm) is 20%, the wound healing area treated with nanocomposite hydrogels at 6th day reached up to 83%, 3 times of gauze, and almost recovered at 13th day. Especially, antibacterial mechanism can be thought to be the results that the macromolecular sericin embedded in the nanocomposite hydrogel adsorbed bacteria by charge interaction and micromolecular sericin dissociating out from nanocomposite hydrogels can be adsorbed onto bacteria. PMID- 28887977 TI - Magnetic electrospun short nanofibers wrapped graphene oxide as a promising biomaterials for guiding cellular behavior. AB - Magnetic particles show extremely wide application prospects in the biomedical field, particularly in the success of cellular manipulation, drug delivery systems, magnetic hyperthermia and NRI contrast enhancement. Graphene oxide with functional groups has a promising biological effect. In this work, we develop magnetic short-fibers wrapped graphene oxide for guiding cellular behavior with the aid of high-speed shear of nanofibers fabricated through electrospinning technique. The diameter and the length of short-fibers are about 300nm and 80MUm, respectively. The short-fibers exhibit superior magnetic properties (saturation magnetization value: 50.33emu/g), which has a strong response appearance to the NdFeB magnet. SEM images and laser confocal images display that there has an extremely tight adhesion between the short-fibers wrapped graphene oxide and cells. The control of cell-fibers structure behavior can be realized by applying external magnet. The results may provide an attractive perspective on the treatment of disease with magnetic field. PMID- 28887978 TI - Neuro-differentiated Ntera2 cancer stem cells encapsulated in alginate beads: First evidence of biological functionality. AB - The present communication investigates an application of alginate encapsulation technology to the differentiation of the embryonic cancer stem NTera2 cells (NT2) into dopamine-producing cells. The encapsulation of cells in polymeric beads allows their immune isolation and makes them eligible for transplantation, thus representing a promising biotech tool for the delivery of biologically active compounds to the brain. The polysaccharide alginate is one of the most commonly used material for this procedure since it is well tolerated by various tissues, including the brain. Two different initial cell concentrations (i.e. 0.5*106/ml and 1.0*106/ml) were tested, in order to identify which one could better reflect the homogeneous cell distribution into the alginate beads and guarantee a good cell viability at different times of culture. As evidenced, the higher number of cells promoted the formation of clusters resulting in a better interaction among encapsulated cells and the subsequent promotion of mitotic activity. The distribution of alive/dead cells into the alginate beads was verified and followed at different time points through the fluorescein diacetate/propidium iodide (FDA/PI) staining, confirming the presence of living neuronal positive cells, as determined from fluorescence microscopy imaging. The functionality of the encapsulated NT2 cells was confirmed by their dopamine production capability as assessed by UV-Vis spectrophotometric analysis and by liquid chromatography mass spectrometry (LC-MS). The NT2/microspheres system can be considered a groundbreaking experimental procedure, a functionally active platform, able to produce and release dopamine, and thus potentially exploitable for therapy in Parkinson's disease. PMID- 28887979 TI - Antibacterial zinc oxide hybrid with gelatin coating. AB - ZnO has been widely investigated as important biomaterials and antibacterial materials. However, the aggregation of nanoparticles and its potential toxicity may hinder its final application. Herein, biocompatible gelatin chains were grafted on the surface of ZnO via mussel inspired method to prevent the aggregation of the ZnO nanoparticles. The in vitro test showed that the gelatin can greatly improve the biocompatibility of ZnO, while the antibacterial properties of ZnO against both E. coli and S. aureus were maintained. PMID- 28887980 TI - Development and characterization of miltefosine-loaded polymeric micelles for cancer treatment. AB - Miltefosine presents antineoplastic activity but high hemolytic potential. Its use in cancer has been limited to treating cutaneous metastasis of breast cancer. To decrease hemolytic potential, we developed a formulation of miltefosine-loaded polymeric micelles (PM) of the copolymer Pluronic-F127. A central composite design was applied and the analysis of variance showed that the optimum level of hydrodynamic diameter and polydispersity index predicted by the model and experimentally confirmed were 29nm and 0.105, respectively. Thermal analyses confirmed that miltefosine was molecularly dispersed within PM. Pluronic-F127 PM with miltefosine 80MUM presented a significant reduction of hemolytic effect (80%, p<0.05) in comparison to free drug. In vitro assays against HeLa carcinoma cells demonstrated similar cytotoxicity to free miltefosine and PM. Our results suggest that, by lowering hemolytic potential, miltefosine-loaded Pluronic-F127 PM a promising alternative to broaden this drug use in cancer therapy, as well as of other alkylphosphocholines. PMID- 28887981 TI - Design and fabrication of auxetic PCL nanofiber membranes for biomedical applications. AB - The main objective of this study was to fabricate poly (epsilon-caprolactone) (PCL)-based auxetic nanofiber membranes and characterize them for their mechanical and physicochemical properties. As a first step, the PCL nanofibers were fabricated by electrospinning with two different thicknesses of 40MUm (called PCL thin membrane) and 180MUm (called PCL thick membrane). In the second step, they were tailored into auxetic patterns using femtosecond laser cut technique. The physicochemical and mechanical properties of the auxetic nanofiber membranes were studied and compared with the conventional electrospun PCL nanofibers (non-auxetic nanofiber membranes) as a control. The results showed that there were no significant changes observed among them in terms of their chemical functionality and thermal property. However, there was a notable difference observed in the mechanical properties. For instance, the thin auxetic nanofiber membrane showed the magnitude of elongation almost ten times higher than the control, which clearly demonstrates the high flexibility of auxetic nanofiber membranes. This is because that the auxetic nanofiber membranes have lesser rigidity than the control nanofibers under the same load which could be due to the rotational motion of the auxetic structures. The major finding of this study is that the auxetic PCL nanofiber membranes are highly flexible (10-fold higher elongation capacity than the conventional PCL nanofibers) and have tunable mechanical properties. Therefore, the auxetic PCL nanofiber membranes may serve as a potent material in various biomedical applications, in particular, tissue engineering where scaffolds with mechanical cues play a major role. PMID- 28887982 TI - The negative effect of silica nanoparticles on adipogenic differentiation of human mesenchymal stem cells. AB - Nanoparticles have drawn much attention for a wide variety of applications in biomedical and bioengineering fields. The combined use of nanoparticles and human mesenchymal stem cells (hMSCs) in tissue engineering and regenerative medicine requires more knowledge of the influence of nanoparticles on cell viability and differentiation potential of hMSCs. The objective of this study is to investigate the in vitro uptake of silica nanoparticles (silica NPs) and their effect on adipogenic differentiation of hMSCs. After exposure of hMSCs to silica NPs, the uptake and localization of silica NPs were assessed using transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM). The adipogenic differentiation potential of hMSCs was examined by analyzing the formation and accumulation of lipids droplets, triglyceride (TG) content and the expression of adipogenic marker genes/proteins. The results showed that silica NPs did not affect the cell viability but significantly decreased the differentiation of hMSCs to adipocytes. These findings improve the understanding of the influence of silica NPs on adipogenic differentiation of hMSCs and will provide a reference for the applications of silica NPs in biomedical and bioengineering fields. PMID- 28887983 TI - Effect of pores formation process and oxygen plasma treatment to hydroxyapatite formation on bioactive PEEK prepared by incorporation of precursor of apatite. AB - When bioinert substrates with fine-sized pores are immersed in a simulated body fluid (SBF) and the pH value or the temperature is increased, fine particles of calcium phosphate, which the authors denoted as 'precursor of apatite' (PrA), are formed in the pores. By this method, hydroxyapatite formation ability can be provided to various kinds of bioinert materials. In this study, the authors studied fabrication methods of bioactive PEEK by using the above-mentioned process. First, the fine-sized pores were formed on the surface of the PEEK substrate by H2SO4 treatment. Next, to provide hydrophilic property to the PEEK, the surfaces of the PEEK were treated with O2 plasma. Finally, PrA were formed in the pores by the above-mentioned process, which is denoted as 'Alkaline SBF' treatment, and the bioactive PEEK was obtained. By immersing in SBF with the physiological condition, hydroxyapatite formation was induced on the whole surface of the substrate within 1day. The formation of PrA directly contributed to hydroxyapatite formation ability. By applying the O2 plasma treatment, hydroxyapatite formation was uniformly performed on the whole surface of the substrate. The H2SO4 treatment contributed to a considerable enhancement of adhesive strength of the formed hydroxyapatite layer formed in SBF because of the increase of surface areas of the substrate. As a comparative study, the sandblasting method was applied as the pores formation process instead of the H2SO4 treatment. Although hydroxyapatite formation was provided also in this case, however, the adhesion of the formed hydroxyapatite layer to the substrate was not sufficient even if the O2 plasma treatment was conducted. This result indicates that the fine-sized pores should be formed on the whole surface of the substrate uniformly to achieve high adhesive strength of the hydroxyapatite layer. Therefore, it is considered that the H2SO4 treatment before the O2 plasma and the 'Alkaline SBF' treatment is an important factor to achieve high adhesive strength of hydroxyapatite layer to the PEEK substrate. This material is expected to be a candidate for next-generation implant materials with high bioactivity. PMID- 28887984 TI - Electrospun gelatin/sodium bicarbonate and poly(lactide-co-epsilon caprolactone)/sodium bicarbonate nanofibers as drug delivery systems. AB - In this work, we report electrospun nanofibers made of model hydrophobic (poly(lactide-co-epsilon-caprolactone); PLCL) and hydrophilic (gelatin) polymers. We explored the effect on drug release of the incorporation of sodium bicarbonate (SB) into these fibers, using the potent antibacterial agent ciprofloxacin as a model drug. The fibers prepared are smooth and have relatively uniform diameters lying between ca. 600 and 850nm. The presence of ciprofloxacin in the fibers was confirmed using IR spectroscopy. X-ray diffraction showed the drug to be incorporated into the fibers in the amorphous form. In vitro drug release studies revealed that, as expected, more rapid drug release was seen with gelatin fibers than those made of PLCL, and a greater final release percentage was obtained. The inclusion of SB in the gelatin fibers imparts them with pH sensitivity: gelatin/SB fibers showed faster release at pH5 than pH7.4, while fibers without SB gave the same release profiles at both pHs. The PLCL fibers have no pH sensitivity, even when SB was included, as a result of their hydrophobic structure precluding the ingress of solvent. In vitro cell culture studies showed that all the fibers are able to promote cell proliferation. The ciprofloxacin loaded fibers are effective in inhibiting Escherichia coli and Staphylococcus aureus growth in antibacterial tests. Thus, the gelatin-based fibers can be used as pH-responsive drug delivery systems, with potential applications for instance in the treatment of tumor resection sites. Should these become infected, the pH would drop, resulting in ciprofloxacin being released and the infection halted. PMID- 28887985 TI - Cerium oxide nanoparticle-containing poly (epsilon-caprolactone)/gelatin electrospun film as a potential wound dressing material: In vitro and in vivo evaluation. AB - In the present study, cerium oxide (CeO2) nanoparticles were incorporated into poly (epsilon-caprolactone)/gelatin films in order to develop a potential wound dressing material. The wound dressings were prepared by electrospinning of poly (epsilon-caprolactone)/gelatin (1:1 (w/w)) solutions containing 1.50%, 3% and 6% (w/w) CeO2 nanoparticles. The electrospun films were evaluated regarding their morphology, contact angle, water-uptake capacity, water vapor transmission rate, tensile strength and cellular response. The film containing 1.50% CeO2 nanoparticles was chosen as the optimal dressing for the in vivo study on full thickness excisional wounds of rats. The study showed that after 2weeks, the wounds treated with the CeO2 nanoparticle-containing dressing achieved a significant closure to nearly 100% compared with the sterile gauze with the nearly 63% of wound closure. Our results provided evidence supporting the possible applicability of CeO2 nanoparticle-containing wound dressing for a successful wound treatment. PMID- 28887986 TI - Biomineralized diamond-like carbon films with incorporated titanium dioxide nanoparticles improved bioactivity properties and reduced biofilm formation. AB - Recently, the development of coatings to protect biomedical alloys from oxidation, passivation and to reduce the ability for a bacterial biofilm to form after implantation has emerged. Diamond-like carbon films are commonly used for implanted medical due to their physical and chemical characteristics, showing good interactions with the biological environment. However, these properties can be significantly improved when titanium dioxide nanoparticles are included, especially to enhance the bactericidal properties of the films. So far, the deposition of hydroxyapatite on the film surface has been studied in order to improve biocompatibility and bioactive behavior. Herein, we developed a new route to obtain a homogeneous and crystalline apatite coating on diamond-like carbon films grown on 304 biomedical stainless steel and evaluated its antibacterial effect. For this purpose, films containing two different concentrations of titanium dioxide (0.1 and 0.3g/L) were obtained by chemical vapor deposition. To obtain the apatite layer, the samples were soaked in simulated body fluid solution for up to 21days. The antibacterial activity of the films was evaluated by bacterial eradication tests using Staphylococcus aureus biofilm. Scanning electron microscopy, X-ray diffraction, Raman scattering spectroscopy, and goniometry showed that homogeneous, crystalline, and hydrophilic apatite films were formed independently of the titanium dioxide concentration. Interestingly, the diamond-like films containing titanium dioxide and hydroxyapatite reduced the biofilm formation compared to controls. A synergism between hydroxyapatite and titanium dioxide that provided an antimicrobial effect against opportunistic pathogens was clearly observed. PMID- 28887987 TI - In situ cross-linking carbodiimide-modified chitosan hydrogel for postoperative adhesion prevention in a rat model. AB - BACKGROUND: Postoperative intra-abdominal adhesion often causes many complications. Chitosan fluid has been used in clinic to prevent intra-abdominal adhesion. However, fluid can be easily diluted and cannot stay on the wound site. As hydrogel is able to form stable physical barrier to separate injured tissues, we developed a chitosan hydrogel for better prevention of intra-abdominal adhesion in this study. METHODS: We synthesized a carbodiimide-derivatized chitosan gelatin (cd-CS-gelatin) hydrogel and investigated its rheological properties. A rat model was used to compare the anti-adhesion effect of chitosan hydrogel and fluid. The wounds were created with damage of the underlying muscle of the abdominal wall and the serosal layer of the cecum. They were coated with chitosan fluid or cd-CS-gelatin hydrogel. At day 14 after surgery, the animals were euthanized and intra-abdominal adhesion was assessed. RESULTS: The cd-CS gelatin hydrogel solidified within 3min after the mixing of the reagents. The cecum-abdomen adhesion occurred in all rats without anti-adhesion treatment. The application of cd-CS-gelatin significantly reduced the adhesion rate from 100% to 50%, compared the chitosan fluid only to 88%. The decrease of adhesion breaking strength also manifested that cd-CS-gelatin was more effective than chitosan fluid to reduce postsurgical intra-abdominal adhesion formation. CONCLUSIONS: Chitosan hydrogel is more effective than chitosan fluid to prevent postoperative cecum-abdomen adhesion. It indicates that hydrogel could be a more promising state than liquid to prevent postoperative intra-abdominal adhesion. PMID- 28887988 TI - Enhanced bovine serum albumin absorption on the N-hydroxysuccinimide activated graphene oxide and its corresponding cell affinity. AB - By successively reacting with N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), the carboxyl on the graphene oxide (GO) surface was successfully activated into NHS active ester. In this study, bovine serum albumin (BSA) was selected as a model protein, used for studying the protein absorption capacity of the NHS activated GO (GO-EDC-NHS). Approximately 12.75mg of BSA could be covalent bonded onto the GO-EDC-NHS surface (BSA-CB-GO), whereas only 6.83mg of BSA physical absorbed onto the GO surface (BSA-NB-GO). With a 168h of phosphate buffer saline (PBS) soaking, the BSA accumulative desorption ratio, which was accordingly assigned to the BSA-NB-GO and the BSA-CB-GO, was separately 29.91wt% and 2.95wt%. Consequently, it proved GO-EDC-NHS exhibited more stable and stronger BSA absorption capacity. As compared to the mouse bone marrow mesenchymal stem cells (mBMSCs) cultivated on the BSA-NB-GO surface, the immunofluorescence staining images showed that more vinculins and integrin alpha5 were visible in the mBMSCs cultivated on the BSA-CB GO surface, they also produced more distinct stress fibers and actin-containing microfilaments. In summary, BSA-CB-GO possesses an excellent cell affinity, which can be considered as a promising functional material used for promoting the bone remodeling. PMID- 28887989 TI - Biomimetic microenvironment complexity to redress the balance between biodegradation and de novo matrix synthesis during early phase of vascular tissue engineering. AB - Physiological functionality of a tissue engineered vascular construct depends on the phenotype of smooth muscle cells (SMCs) cultured into the scaffold and mechanical robust of the construct relies on two simultaneous mechanisms including scaffold biodegradation and de novo matrix synthesis by SMCs which both can be influenced by scaffold properties and culture condition. Our focus in this study was to provide an appropriate environmental condition within tissue engineering context to meet foregoing requisites for a successful vascular regeneration. To this end, SMCs seeded onto electrospun Tecophilic/gelatin (TP(70)/gel(30)) scaffolds were subjected to orbital shear stress. Given the improvement in mechanical properties of dynamically stimulated cell-seeded constructs after a span of 10days, effect of fluctuating shear stress on scaffold biodegradation and SMC behavior was investigated. Compared to static condition, SMCs proliferated more rapidly and concomitantly built up greater collagen content in response to dynamic culture, suggesting a reasonable balance between scaffold biodegradation and matrix turnover for maintaining the structural integrity and mechanical support to seeded cells during early phase of vascular tissue engineering. Despite higher proliferation of SMCs under dynamic condition, cells preserved nearly spindle like morphology and contractile protein expression likely thanks to composition of the scaffold. PMID- 28887990 TI - Synthesis and characterization of magnetite nanoparticles having different cover layer and investigation of cover layer effect on the adsorption of lysozyme and bovine serum albumin. AB - In this study, differently coated superparamagnetic Fe3O4 (magnetite) nanoparticles were synthesized, characterized and used for lysozyme (Ly) and bovine serum albumin (BSA) adsorption. SiO2, carbon nanotubes (CNTs) and graphene were used for covering the readily synthesized magnetite nanoparticles to elucidate the effect of cover layer on the protein adsorption kinetics and capacities of nanostructure. XRD, FTIR, AFM, SEM, VSM and fluorescence measurements were used for the characterization of the samples and investigating the adsorption kinetics of Ly and BSA by these nanoparticles. The average particle size of the Fe3O4 nanoparticles are approximately found as 10nm and VSM measurement shows that the Fe3O4 particles have superparamagnetic behavior with no hysteresis and remnant. The adsorption kinetic of proteins on nanosized material is followed via fluorescence method. All the nanostructures with different cover layers obey pseudo first order kinetics and SiO2 coated nanoparticles show the fastest kinetics and capabilities for Ly and BSA adsorption. PMID- 28887991 TI - Superparamagnetic iron oxide nanoparticles modified with dimyristoylphosphatidylcholine and their distribution in the brain after injection in the rat substantia nigra. AB - The subcellular distributions of nanoparticles in the brain are important for their biological application. We synthesized and characterized the superparamagnetic iron oxide nanoparticles (SPIONs) modified with poly (ethylene glycol) (PEG) and polyethylenimine (PEI) (PEG/PEI-SPIONs), and with dimyristoylphosphatidylcholine (DMPC) (DMPC-SPIONs). The nanoparticles were unilaterally injected into the left substantia nigra of rat brains. The distributions of the nanoparticles in the left brains of the rats were examined by ICP-OES (inductively coupled plasma optical emission spectrometer) and TEM (transmission electron microscopy) at 24h after the injection. Iron was found in the olfactory bulb, temporal lobe, frontal cortex, thalamus and brain stem at 24h after the injection of DMPC-SPIONs and PEG/PEI-SPIONs. In the rat substantia nigra, most DMPC-SPIONs were distributed in and on the myelin sheath around axons or on cell membranes, some were in cells. As a comparison, less iron was found in the rat brains at 24h after the injection of PEG/PEI-SPIONs. Our experiments suggest DMPC modification on SPIONs be a safe and effective method for increasing SPIONs distribution on the cell membranes. This work is encouraging for further study on using DMPC-SPIONs for efficient drug delivery or for deep brain stimulation of neurons in a magnetic field. PMID- 28887992 TI - Electrospun vein grafts with high cell infiltration for vascular tissue engineering. AB - Demand is increasing for functional small-diameter vascular grafts (diameter<6mm) for clinical arterial replacement. In the present study, we develop a bilayer poly(epsilon-caprolactone, PCL) fibrous vascular graft consisting of a thin internal layer made of longitudinally aligned fibers and a relatively thick highly porous external layer. The internal layer provides a scaffold with the necessary mechanical strength and enhances the growth of endothelial cells, whereas the external layer enhances cell motility through the scaffold bulk. The biocompatibility and biological performance of bilayer fibrous scaffolds are evaluated by in vivo experiments, molecular biology, and histology studies. Our bilayer scaffolds demonstrate much better fiber alignment and higher porosity than do normal electrospun vascular grafts with randomly distributed fibers. The results suggest that the proposed grafts can overcome limitations owing to the inadequate porosity, small pores, and poor cell infiltration of scaffolds fabricated by conventional electrospinning. The unique structure of bilayer scaffolds is satisfactory and promotes cell proliferation, collagen-fiber deposition, and ingrowth of smooth muscle cells and endothelial cells in vivo. The results of this study illustrate the strong potential of such bilayer fibrous scaffolds for vascular tissue engineering and regeneration. PMID- 28887993 TI - A facile one-pot Mannich reaction for the construction of fluorescent polymeric nanoparticles with aggregation-induced emission feature and their biological imaging. AB - Multicomponent reactions (MCRs) have recently attracted great attention as one of the most important tools for the construction of various organic compounds in modern organic chemistry. In this work, we introduced an efficient one-pot strategy to successfully fabricate the fluorescent polymeric nanoparticles (FPNs) with aggregation-induced emission (AIE) characteristic via the conjugation of hyperbranched polyamino compound polyethyleneimine (PEI), AIE dye (named as PhE OH) and paraformaldehyde (PF) through a Mannich reaction. The final amphiphilies (PEI-PF-PhE) can self-assemble into micelles in aqueous solution. We demonstrated PEI-PF-PhE FPNs showed high water dispersity, intense orange-yellow fluorescence, excellent photostability, low toxicity and high cell imaging performance. As compared with other construction strategies, the one-pot Mannich reaction possesses a number of advantages, such as simplicity, atom economy, high efficiency and multifunctional potential. Combined with the remarkable properties of the AIE-active FPNs and the one-pot Mannich reaction, we could expect that the strategy developed in this work should be a useful tool for construction of various AIE-active functional materials for biomedical applications. PMID- 28887994 TI - Luminomagnetic Eu3+- and Dy3+-doped hydroxyapatite for multimodal imaging. AB - Multimodal imaging has recently attracted much attention due to the advantageous combination of different imaging modalities, like photoluminescence (PL) and magnetic resonance imaging (MRI). In the present study, luminescent and magnetic hydroxyapatites (HAp) were prepared via doping with europium (Eu3+) and dysprosium (Dy3+), respectively. Co-doping of Eu3+ and Dy3+ was used to combine the desired physical properties. Both lanthanide ions were successfully incorporated in the HAp crystal lattice, where they preferentially occupied calcium(I) sites. While Eu-doped HAp (Eu:HAp) exhibits dopant concentration dependent persistent PL properties, Dy-doped HAp (Dy:HAp) shows paramagnetic behavior due to the high magnetic moment of Dy3+. Co-doped HAp (Eu:Dy:HAp) nanoparticles combine both properties in one single crystal. Remarkably, multimodal co-doped HAp features enhanced PL properties due to an energy transfer from Dy3+ sensitizer to Eu3+ activator ions. Eu:Dy:HAp exhibits strong transverse relaxation effects with a maximum transverse relaxivity of 83.3L/(mmol.s). Due to their tunable PL, magnetic properties and cytocompatibility Eu:-, Dy:- and Eu:Dy:HAp represent promising biocompatible ceramic materials for luminescence imaging that simultaneously may serve as a contrast agent for MRI in permanent implants or functional coatings. PMID- 28887995 TI - Supramolecular assemblies of alkane functionalized polyethylene glycol copolymers for drug delivery. AB - Surfactants are commonly used drug carriers, however, there is a lack of understanding regarding the relationship between drug loading, drug release kinetics, and cell internalization with the physicochemical properties of the drug carriers, preventing rational design. The effects of altering hydrophobic and hydrophilic chain lengths on a poly[poly-(oxyethylene)-oxy-5 hydroxyisophthaloyl] (Ppeg) platform for delivering hydrophobic drugs was examined. The synthesized polymers were characterized by nuclear magnetic resonance spectroscopy (NMR), dynamic light scattering (DLS), and zeta potential. The resulting polymer particles were able to form micelles in aqueous solution and encapsulate pyrene, a highly hydrophobic model drug, with a loading capacity up to 8wt%, corresponding to a 50% loading efficiency. The ability to sustain drug release from these micelles over several days was also observed. RAW 264.7 macrophage uptake of the micelles was measured quantitatively and was found to be substantially higher than internalization of the unencapsulated drug. The loading capacity of the drug in the various micelles did not correlate with the internalization of the particles into the cells. Factorial analysis was used to develop predictive equations for drug loading, drug release kinetics, and cell internalization. These models were validated with newly synthesized compounds. PMID- 28887997 TI - Electrochemical dopamine sensor based on P-doped graphene: Highly active metal free catalyst and metal catalyst support. AB - Heteroatom doping is an effective strategy to enhance the catalytic activity of graphene and its hybrid materials. Despite a growing interest of P-doped graphene (P-G) in energy storage/generation applications, P-G has rarely been investigated for electrochemical sensing. Herein, we reported the employment of P-G as both metal-free catalyst and metal catalyst support for electrochemical detection of dopamine (DA). As a metal-free catalyst, P-G exhibited prominent DA sensing performances due to the important role of P doping in improving the electrocatalytic activity of graphene toward DA oxidation. Furthermore, P-G could be an efficient supporting material for loading Au nanoparticles, and resulting Au/P-G hybrid showed a dramatically enhanced electrocatalytic activity and extraordinary sensing performances with a wide linear range of 0.1-180MUM and a low detection limit of 0.002MUM. All these results demonstrated that P-G might be a very promising electrode material for electrochemical sensor applications. PMID- 28887996 TI - PEGylated stereocomplex polylactide coating of stent for upregulated biocompatibility and drug storage. AB - Treatment of coronary heart disease by percutaneous coronary intervention (PCT) is usually limited to the high restenosis rate after implantation of bare-metal stent. To solve the problem, the coating of PEGylated stereocomplex poly(l lactide) (PEG-cPLA) was utilized on the surface modification of stainless steel (SS) sheet. Specifically, the 3-aminopropyltriethoxysilane (APTES)-modified methoxy-poly(ethylene glycol)-poly(d-lactide) (mPEG-PDLA) was grafted onto the surface of hydroxylated SS sheet through coupling reaction, and poly(l-lactide) poly(ethylene glycol)-poly(l-lactide) (PLLA-PEG-PLLA) was coated onto the surface through stereocomplex interaction between DLA and LLA units. The increase of contact angle firstly confirmed the changes of surface composition and hydrophilicity for the PEG-scPLA-modified SS sheet. The decreased fibrinogen adsorption, down-regulated platelet activation, and improved adhesion of human umbilical vein endothelial cells (HUVECs) indicated the excellent biocompatibility of PEG-scPLA-modified SS sheet. In addition, the drug loading capability of SS sheet was greatly upregulated through the formation of scPLA coating on the surface, where fluorescein (FLU) was chosen as a model molecule. Overall, the surface modification of SS sheet with PEG-scPLA could enhance the comprehensive performances, such as biocompatibility and drug loading capability, demonstrating that PEG-scPLA is a promising coating of coronary stent for PCT. PMID- 28887998 TI - Novel poly(epsilon-caprolactone)/gelatin wound dressings prepared by emulsion electrospinning with controlled release capacity of Ketoprofen anti-inflammatory drug. AB - In the present study, a single and binary Ketoprofen-loaded mats of ultrathin fibers were developed by electrospinning and their physical properties and drug release capacity was analyzed. The single mat was prepared by solution electrospinning of poly(epsilon-caprolactone) (PCL) with Ketoprofen at a weight ratio of 5wt%. This Ketoprofen-containing PCL solution was also used as the oil phase in a 7:3 (wt/wt) emulsion with gelatin dissolved in acidified water. The resultant stable oil-in-water (O/W) emulsion of PCL-in-gelatin, also containing Ketoprofen at 5wt%, was electrospun to produce the binary mat. Cross-linking process was performed by means of glutaraldehyde vapor on the electrospun binary mat to prevent dissolution of the hydrophilic gelatin phase. The performed characterization indicated that Ketoprofen was successfully embedded in the single and binary electrospun mats, i.e. PCL and PCL/gelatin, and both mats showed high hydrophobicity but poor thermal resistance. In vitro release studies interestingly revealed that, in comparison to the single PCL electrospun mat, the binary PCL/gelatin mat significantly hindered Ketoprofen burst release and exhibited a sustained release capacity of the drug for up to 4days. In addition, the electrospun Ketoprofen-loaded mats showed enhanced attachment and proliferation of L929 mouse fibroblast cells, presenting the binary mat the highest cell growth yield due to its improved porosity. The here-developed electrospun materials clearly show a great deal of potential as novel wound dressings with an outstanding controlled capacity to release drugs. PMID- 28887999 TI - Preferential killing of bacterial cells by hybrid carbon nanotube-MnO2 nanocomposite synthesized by novel microwave assisted processing. AB - We present a comprehensive study on the enhanced effect of CNT addition on the structural, optical, morphological and antibacterial properties of CNT-MnO2 nanocomposite synthesized by microwave assisted processing. X-ray diffraction pattern of the hybrid CNT/MnO2 nanocomposite revealed the shifting of highly oriented MnO2 preferential planes. SEM images show porous MnO2 nanospheres uniformly and discretely attached on the walls of carbon nanotube network. Significant variation in the peak shape and IR absorption intensity with CNT addition, indicate the interaction of CNT ions with MnO2 nanoparticles. Optical studies reveal a decrease in energy band gap caused by a significative reduction of electron-hole recombination in manganese activated CNT nanocomposite favouring photocatalytic activity. The antibacterial activity of pure MnO2 and the CNT/MnO2 hybrid was investigated by using both Gram positive and Gram negative bacteria as test organisms. The hybrid nanocomposite revealed higher antibacterial activity compared with pure MnO2 nanoparticles, due to reduced particle size and high specific surface area of CNT. Also, compared to Gram positive bacteria, Gram negative bacteria shows enhanced antibacterial activity due to the improved particle surface reactivity to visible light through effective charge transfer between MnO2 and CNT content of the nanopowder synthesized through microwave processing. Owing to the high surface area, large inner volume and other important physico-chemical properties, the antibacterial activity of carbon-based nanocomposites may interestingly be studied in the near future. PMID- 28888000 TI - pH and redox dual stimulate-responsive nanocarriers based on hyaluronic acid coated mesoporous silica for targeted drug delivery. AB - In this work, we developed a drug-conjugated nanocarrier with "zero premature release" property for actively targeted drug delivery. The pH and redox dual responsive nanocarrier was fabricated based on hyaluronic acid (HA) modified the mesoporous silica nanoparticles (MSNs). Doxorubicin (DOX) was conjugated to MSNs via hydrazone bonds, which can be cleaved in tumor tissue (acidic conditions). To improve specific cellular uptake and stability of nanocarriers, HA was equipped with an outer shell on the nanoparticle surface via a disulfide crosslinker. Stimulus-induced release of the DOX was studied in the different pH and GSH, which showed the embedded DOX can be controlled release from MSN channels. The dual-triggered drug release system provides an efficient targeted drug delivery system into the cytosol of cancer cells. The results of flow cytometry and confocal laser scanning microscopy (CLSM) showed that the HA-functionalized DOX conjugated nanoparticles presented much better cellular uptake and higher cytotoxicity to tumor cells. This drug delivery system has great potential for tumor-trigged drug release for cancer therapy. PMID- 28888001 TI - A targeted nanocarrier based on polyspermine for the effective delivery of methotrexate in nasopharyngeal carcinoma. AB - Antitumor efficacy of methotrexate (MTX) is seriously limited due to its poor water solubility, nonspecific tumor distribution and low bioavailability. To overcome these obstacles, polyspermine (PSP) conjugated with MTX and folic acid (FA) as a novel targeted prodrug was designed and has been successfully synthesized using the amidation reaction. The strong hydrophilic properties of PSP made MTX well dispersed in water and the cellular uptake study indicated that the presence of FA enhanced uptake of the FA-PSP-MTX in folate receptor (FR) over expressing human nasopharyngeal carcinoma HNE-1 cells. 1H NMR spectra and UV-Vis spectral analysis were carried out to confirm the MTX and FA content in FA-PSP MTX, respectively. In CCK-8 assay and apoptosis analysis, the prodrug showed significantly enhanced anticancer efficacy than free MTX in HNE-1 cells. These results suggested that the prodrug has the potential for targeted delivery of MTX into cancer cells to improve its anti-tumor efficacy. PMID- 28888002 TI - Construction of multifunctional porous silica nanocarriers for pH/enzyme responsive drug release. AB - pH/enzyme-responsive nanocarriers based on porous silica (pSiO2) nanospheres (NSs) were developed for controlled release of drug. The pSiO2 NSs present uniform spheres and have an average diameter of 100nm. The pSiO2 NSs with high specific surface area (835m2.g-1) and the pore volume (1.24cm3.g-1) are suitable for drug loading and the loading capacity reaches to 29% for amoxicillin (AMX) model drug. In this system, protocatechuic acid (PCA) and L-glutamic acid (Glu) as linkers were grafting onto the surface of pSiO2 NSs to conjugate the capping lids. Acid-decomposable ZnO quantum dots (QDs) were introduced to block the partial pores of pSiO2 via amido bonds, which could act as gates and fluorescence probes. To minimize the premature release, hyaluronic acid (HA) was further coating on the outer surface of pSiO2, which would be degraded by over-expressed hyaluronidase (Hyal-1) in the tumor microenvironment. The controlled release of the drug from the ZnO/HA-gated delivery system was realized by the acidic dissolution of ZnO QDs and enzymatic hydrolysis of HA. The obtained ZnO/HA-gated pSiO2 delivery system would achieve minimized premature release and responsive release under a physiological environment. PMID- 28888004 TI - Cardiomyocyte coculture on layered fibrous scaffolds assembled from micropatterned electrospun mats. AB - Challenges remain in engineering cardiac tissues with functional and morphological properties similar to those of native myocardium. In the current study, micropatterned fibrous mats are obtained by deposition of electrospun fibers on lithographic collectors to reproduce the anisotropic structure of myocardium, and carbon nanotubes are included in fibers to provide conductivities at the same level of cardiac muscles. The patterned mats are assembled layer-by layer into patterned scaffolds for coculture of primary cardiomyocytes (CMs) with cardiac fibroblasts (CFs) and endothelial cells (ECs). CMs are organized along the fibers with clear cardiac strips of sarcomeric alpha-actinin and belt-like connexin-43, showing strong cellular extraction forces and intercellular communications. Compared with square and rectangle patterns, honeycomb (Hc) patterned scaffolds shows higher ultimate tensile strength and strain to failure. The finite element analysis indicates no apparent stress concentration under stress application in the two orthogonal directions. The Hc-patterned coculture demonstrates significantly higher CM viabilities, deeper penetrations of cells into scaffolds, stronger expression of troponin I, connexin-43 and sarcomeric alpha-actinin by CMs and more abundant formations of capillary-like networks by ECs than other scaffolds. CMs on Hc-patterned scaffolds display spontaneous beating rates at 101+/-12times/min after coculture for 5days and remain synchronously beating at 94+/-8times/min after 15days, which is close to those of adult and neonatal rats. The layered and patterned coculture strategy achieves the spatial arrangement of multiple types of cells and vascularization potential, providing a biomimetic strategy for engineering functional cardiac patches in vitro. PMID- 28888003 TI - Cross-linked branched polyethylenimine used as a nitric oxide donor for prolonged nitric oxide release. AB - In order to prolong NO release and enhance the antibacterial effect, N-Carboxy propionyl chitosan sodium (CPCS) was cross-linked to branched polyethylenimine (bPEI) (CPCS-bPEI) and used as a NO donor. The CPCS-bPEI has been successfully synthesized at different molar ratios of CPCS to bPEI, followed with the reaction with NO gas under a parr high-pressure reactor to yield CPCS-bPEI-NO. Successful preparation of CPCS-bPEI-NO was confirmed by elemental analysis, FITR and SEM. The effective release of NO was determined by in vitro release. The antibacterial assay showed that CPCS-bPEI-NO can effectively inhibit Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus). We found that the NO loading amount and antibacterial effect can be adjusted by the molar ratio of CPCS to bPEI, and there was no significant toxicity of CPCS-bPEI-NO, suggesting that it may serve as an ideal antimicrobial agent. PMID- 28888005 TI - Synthesis, mechanical properties and corrosion behavior of powder metallurgy processed Fe/Mg2Si composites for biodegradable implant applications. AB - Recently, Fe and Fe-based alloys have shown their potential as degradable materials for biomedical applications. Nevertheless, the slow corrosion rate limits their performance in certain situations. The shift to iron matrix composites represents a possible approach, not only to improve the mechanical properties, but also to accelerate and tune the corrosion rate in a physiological environment. In this work, Fe-based composites reinforced by Mg2Si particles were proposed. The initial powders were prepared by different combinations of mixing and milling processes, and finally consolidated by hot rolling. The influence of the microstructure on mechanical properties and corrosion behavior of Fe/Mg2Si was investigated. Scanning electron microscopy and X-ray diffraction were used for the assessment of the composite structure. Tensile and hardness tests were performed to characterize the mechanical properties. Potentiodynamic and static corrosion tests were carried out to investigate the corrosion behavior in a pseudo-physiological environment. Samples with smaller Mg2Si particles showed a more homogenous distribution of the reinforcement. Yield and ultimate tensile strength increased when compared to those of pure Fe (from 400MPa and 416MPa to 523MPa and 630MPa, respectively). Electrochemical measurements and immersion tests indicated that the addition of Mg2Si could increase the corrosion rate of Fe even twice (from 0.14 to 0.28mm.year-1). It was found that the preparation method of the initial composite powders played a major role in the corrosion process as well as in the corrosion mechanism of the final composite. PMID- 28888006 TI - Chitosan membrane dressings toughened by glycerol to load antibacterial drugs for wound healing. AB - Transparent and flexible chitosan-based membranes containing antibacterial drugs were prepared through a casting/solvent evaporation method from suspension of chitosan floccule. To enhance mechanical properties, glycerin was incorporated into the floccule suspension to conjugate chitosan as a plasticizer. The mechanism of membrane formation is attributed to inter- and intro-hydrogen bonding between chitosan and glycerol molecules. The results showed that incorporation of glycerol has a significant influence on the properties of the chitosan membranes. With the increase of glycerol content, the tensile strength, swelling rate, water vapor permeability and wettability of membranes were significantly improved. In vitro enzymatic degradation revealed that the chitosan membrane had long-term stability regardless of the glycerol content. To enhance antibacterial properties, tetracycline hydrochloride (TH) and silver sulfadiazine (AgSD), representing the water-soluble and water-insoluble drug models, were integrated into the membranes, respectively. The results of controlled-release efficacy and inhibition zone indicate that the glycerol toughened chitosan membranes containing drugs have a promising future in treatment of bacterial infection as wound dressing. PMID- 28888007 TI - Nano-calcium phosphate bone cement based on Si-stabilized alpha-tricalcium phosphate with improved mechanical properties. AB - This study aimed to develop nano-calcium phosphate cement (nCPC) and evaluate the effect of nanosized precursors on mechanical, physical and handling properties (injectability and setting time) as well as conversion rate of nano-reactants into nano-hydroxyapatite (nHA). In this study, while alpha tricalcium phosphate (alpha-TCP, 98wt%) and HA (2wt%) were applied as the powder phase, 2.5wt% NaH2PO4 solution was used as liquid phase of cement. Before nano-CPC preparation, Si stabilized alpha-TCP nanopowder with particle size of 10+/-3.6nm was firstly synthesized in a two-step process of sol-gel followed by mechanical alloying. Moreover, HA nanopowder with particle size of 32+/-3.6nm was synthesized using sol-gel process. Our results revealed that after 3days of immersion in ringer's solution, reactants almost completely converted to nHA. Moreover, the initial and final setting time of nano-CPC was obtained 6.3+/-2.1min and 14.3+/-4.0min, respectively. Furthermore, injectability of this formulation was reached 87.90+/ 2.60%. In addition, our results confirmed that the compressive strength and modulus of nano-CPC enhanced with increasing immersion time in ringer's solution from 9.50+/-1.27MPa and 0.38+/-0.07GPa (at 1day) to 18.70+/-2.23MPa and 0.57+/ 0.15GPa (at 5days), respectively. Finally, in order to evaluate cellular responses to nano-CPC, MG63 cells were cultured on it and cell morphology and cytotoxicity were evaluated. Results revealed that nano-CPC enhanced proliferation and spreading of osteoblast like cells compared to control (tissue culture plate) which could be due to both appropriate physical and chemical properties of nano-CPC which stimulate cell proliferation. Our findings suggest the formation of an injectable nano-CPC with appropriate mechanical, physical and degradation rate which can potentially utilized for filling bone defects. PMID- 28888008 TI - Injectable methotrexate loaded polycaprolactone microspheres: Physicochemical characterization, biocompatibility, and hemocompatibility evaluation. AB - In this study, bare polycaprolactone microspheres (PCL MPs) and methotrexate (MTX) loaded PCL microspheres (MTX-PCL MPs) have been developed by oil-in-water emulsion solvent evaporation method using hydroxypropyl methylcellulose (HPMC) as an emulsifier. Encapsulation efficiency and loading capacity of methotrexate were found to be 51.28%+/-0.52 and 2.8%+/-0.06 respectively. Environmental scanning electron microscopy showed the PCL MPs and MTX-PCL MPs to have a spherical shape and smooth surface morphology. The mean size of microspheres (23MUm) was found within injectability criteria. High-Resolution X-ray diffraction of microspheres revealed that PCL retained its semi-crystalline nature after processing in microspheres, but the drug looses its crystallinity. Fourier transmittance infrared spectroscopy and thermogravimetry analysis of the microspheres indicated that no physicochemical modification occurred. In vitro, MTX release study from MTX-PCL MPs in phosphate buffer saline (pH7.4) showed controlled release profile and only 31% of MTX released in 306h. The microspheres in lyophilized form are physicochemically stable for 8months. Furthermore, L929 cells treated with microspheres showed cell viability >80%. The different concentrations of microspheres found hemocompatible and did not affect the biconcave shape of red blood cells (RBCs). The physiochemical and biological evaluation of microspheres suggests their further use for drug delivery application. PMID- 28888009 TI - Synthesis and evaluation of the cytotoxic and anti-proliferative properties of ZnO quantum dots against MCF-7 and MDA-MB-231 human breast cancer cells. AB - Current trends in therapeutic research are the application of nanomaterial carriers for cancer therapy. One such molecule, ZnO, originally used in diagnosis and as a drug carrier, is gaining importance for its biological properties. Here, we report for the first time, the scope of ZnO QDs for enhanced cytotoxicity against MCF-7 and metastatic MDA-MB-231 human breast cancer cells. Unlike other ZnO nanostructures, ZnO QDs are dispersed and small sized (8-10nm) which is believed to greatly increase the cellular uptake. Furthermore, the acidic tumor microenvironment attracts ZnO QDs enhancing targeted therapy while leaving normal cells less affected. Results from MTT assay demonstrated that ZnO QDs induced cytotoxicity to MCF-7 and metastatic MDA-MB-231 breast cancer cells at very low concentrations (10 and 15MUg/ml) as compared to other reported ZnO nanostructures. HEK-293 cells showed less toxicity at these concentrations. Confocal microscope images from DAPI staining and TUNEL assay demonstrated that ZnO QDs induced nuclear fragmentation and apoptosis in MCF-7 and MDA-MB-231. FACS results suggested ZnO QDs treatment induced cell cycle arrest at the G0/G1 phase in these cells. ZnO QDs drastically decreased the proliferation and migration of MCF-7 and MDA-MB-231 as seen from the results of the clonogenic and wound healing assays respectively. Furthermore, our data suggested that ZnO QDs regulated apoptosis via Bax and Bcl-2 proteins as validated by immunofluorescence and western blot. Taken together, our findings demonstrate that these ultra-small sized ZnO QDs destabilize cancer cells by using its acidic tumor microenvironment thereby inducing apoptosis and controlling the cell proliferation and migration at low dosages. PMID- 28888010 TI - Decoration of gold nanoparticles with thiolated pH-responsive polymeric (PEG-b p(2-dimethylamio ethyl methacrylate-co-itaconic acid) shell: A novel platform for targeting of anticancer agent. AB - The aim of this study was to design and develop a new pH-responsive nano-platform for controlled and targeted delivery of anticancer drugs. Engineering of pH responsive nanocarriers was prepared via decoration of gold nanoparticles (NPs) by thiolated (methoxy-poly(ethylene glycol)-b-poly((2-dimethylamino) ethyl methacrylate-co-itaconic acid) (mPEG-b-p(DMAEMA-co-IA) copolymer and fully characterized by various techniques and subsequently used for loading and targeted delivery of anticancer agent, methotrexate (MTX). By conjugation of MTX with the amino groups of polymeric shell of gold NPs (with the high loading capacity of 31%), since MTX is also the target ligand of folate receptors, the targeted performance of NPs examined through the cell uptake study. The results indicated that MTX-loaded NPs showed 1.3 times more cell internalization than MTX free NPs. Cell cytotoxicity studies pointed out ~1.5 and 3 times higher cell cytotoxicity after 24h for MTX-loaded nanoparticles than MTX in MTT assay and cell cycle arrest experiments, respectively. Additionally, mPEG was used as the outer shell of NPs which caused the long-term dispersibility of the NPs even under high ionic strength. The in-vitro pH-triggered drug release of MTX showed that MTX released more than three times in simulated cancerous tissue (40 degrees C, pH5.3) than physiologic condition (37 degrees C, pH7.4) during 48h. The results of various experiments determined that the developed smart nanocarrier proposed as a promising nanocarrier for active and passive targeting of anionic anti-cancer agents such as MTX. PMID- 28888011 TI - Surface PEGylation of mesoporous silica materials via surface-initiated chain transfer free radical polymerization: Characterization and controlled drug release. AB - As a new type of mesoporous silica materials with large pore diameter (pore size between 2 and 50nm) and high specific surface areas, SBA-15 has been widely explored for different applications especially in the biomedical fields. The surface modification of SBA-15 with functional polymers has demonstrated to be an effective way for improving its properties and performance. In this work, we reported the preparation of PEGylated SBA-15 polymer composites through surface initiated chain transfer free radical polymerization for the first time. The thiol group was first introduced on SBA-15 via co-condensation with gamma mercaptopropyltrimethoxysilane (MPTS), that were utilized to initiate the chain transfer free radical polymerization using poly(ethylene glycol) methyl ether methacrylate (PEGMA) and itaconic acid (IA) as the monomers. The successful modification of SBA-15 with poly(PEGMA-co-IA) copolymers was evidenced by a series of characterization techniques, including 1H NMR, FT-IR, TGA and XPS. The final SBA-15-SH- poly(PEGMA-co-IA) composites display well water dispersity and high loading capability towards cisplatin (CDDP) owing to the introduction of hydrophilic PEGMA and carboxyl groups. Furthermore, the CDDP could be released from SBA-15-SH-poly(PEGMA-co-IA)-CDDP complexes in a pH dependent behavior, suggesting the potential controlled drug delivery of SBA-15-SH-poly(PEGMA-co-IA). More importantly, the strategy should be also useful for fabrication of many other functional materials for biomedical applications owing to the advantages of SBA-15 and well monomer adoptability of chain transfer free radical polymerization. PMID- 28888012 TI - Characterization and degradation study of chitosan-siloxane hybrid microspheres synthesized using a microfluidic approach. AB - Chitosan microspheres can address challenges associated with poor bioavailability or unsustained drug release when used as drug delivery systems thanks to their mucoadhesiveness, which allows the drug dosage to be retained in the gastrointestinal track for extended periods. Chitosan-3 glycidoxypropyltrimethoxysilane-beta-glycerophosphate (chitosan-GPTMS-beta-GP) hybrid microspheres were synthetized through sol-gel processing using a microfluidic approach. Microspheres with uniform spherical shapes and sizes of approximately 650MUm were obtained. The microstructures of the microspheres consisted of four different siloxane structures. The degradation behaviors of the hybrid microspheres were examined under acidic pH conditions mimicking those found in the gastrointestinal track. Microspheres with different GPTMS molar ratios were incubated under several pH conditions for 2weeks. The microspheres incubated at pH7.4 extended the lowest weight loss (27%-32%), whereas those incubated at pH1.7 and pH5.4 showed greater weight losses of 43-59% and 69-77%, respectively. The inhibition of the degradation at low pH was dependent on the siloxane network in the chitosan matrix. Phosphate was mostly released in early stages, and the released amount of silicon was dependent on the composition. GPTMS was released with a chitosan chain via the hydrolysis of a chitosan molecule. The pelargonidin was incorporated in the microspheres and the slow releasing was observed at acidic condition. The resistance of these hybrid microspheres to low-pH conditions for longer than a full digestion cycle is promising for gastrointestinal drug delivery applications. PMID- 28888013 TI - Novel tetraphenylethylene diol amphiphile with aggregation-induced emission: self assembly, cell imaging and tagging property. AB - In this study, we reported a novel tetraphenylethylene diol amphiphile (2) with aggregation-induced emission property which self-assembled to form unique 3D cubic superstructure. This TPE amphiphile with strong bluish green emission exhibited high biocompatibility and improved cellular uptake. Moreover, this highly fluorescent molecule was conjugated with gold nanoparticles and used as a fluorescent tagging agent. Altogether, results supported the cell-imaging and fluorescent tagging properties of tetraphenylethylene diol amphiphile. PMID- 28888014 TI - Development and evaluation of thymol-chitosan hydrogels with antimicrobial antioxidant activity for oral local delivery. AB - Nowadays, the research of innovative drug delivery devices is focused on the design of multiple drug delivery systems, the prevention of drug side effects and the reduction of dosing intervals. Particularly, new mucosal delivery systems for antimicrobials, antioxidants and anti-inflammatory drugs has a growing development, regards to the avoidance of side effects, easy administration and a suitable drug concentration in the mucosa. In this work, chitosan hydrogels are evaluated as a biodegradable scaffold and as a bioactive agent carrier of an antioxidant-antimicrobial compound called thymol. Throughout the study, swelling behavior, viscoelastic properties and thermal analysis are highlighted to present its advantages for a biomedical application. Furthermore, the in vitro results obtained indicate that thymol-chitosan hydrogels are biocompatible when exposed to [3T3] fibroblasts, exhibit antimicrobial activity against Staphylococcus aureus and Streptococcus mutans for 72h and antioxidant activity for 24h. These are desirable properties for a mucosal delivery system for an antimicrobial antioxidant dual therapy for periodontal disease. PMID- 28888015 TI - Functionalization of titanium dioxide nanotubes with biomolecules for biomedical applications. AB - Titanium (Ti) and its alloys are extensively used in the manufacture of implants because they have biocompatibility. The production of a nanostructured surface can be achieved by means of titanium dioxide nanotubes (TNTs) which can have dimensions equivalent to the nanometric components of human bone, in addition to increasing the efficiency of such implants. The search is ongoing for ways to improve the performance of these TNTs in terms of their functionalization through coating these nanotubular matrices with biomolecules. The biocompatibility of the functionalized TNTs can be improved by promoting rapid osseointegration, by preventing the adhesion of bacteria on such surfaces and/or by promoting a more sustained local release of drugs that are loaded into such TNTs. In addition to the implants, these nanotubular matrices have been used in the manufacture of high-performance biosensors capable of immobilizing principally enzymes on their surfaces, which has possible use in disease diagnosis. The objective of this review is to show the main techniques of immobilization of biomolecules in TNTs, evidencing the most recent applications of bioactive molecules that have been functionalized in the nanotubular matrices for use in implants and biosensors. This surveillance also proposes a new class of biomolecules that can be used to functionalize these nanostructured surfaces, lectins. PMID- 28888016 TI - Albumin based versatile multifunctional nanocarriers for cancer therapy: Fabrication, surface modification, multimodal therapeutics and imaging approaches. AB - Albumin is a versatile protein used as a carrier system for cancer therapeutics. As a carrier it can provide tumor specificity, reduce drug related toxicity, maintain therapeutic concentration of the active moiety like drug, gene, peptide, protein etc. for long period of time and also reduce drug related toxicities. Apart from cancer therapy, it is also utilized in the imaging and multimodal therapy of cancer. This review highlights the important properties, structure and types of albumin based nanocarriers with regards to their use for cancer targeting. It also provides brief discussion on methods of preparation of these nanocarriers and their surface modification. Applications of albumin nanocarriers for cancer therapy, gene delivery, imaging, phototherapy and multimodal therapy have also been discussed. This review also provides brief discussion about albumin based marketed nano formulations and those under clinical trials. PMID- 28888017 TI - Corrigendum to "ice-templating of anisotropic structures with high permeability" [Mater. Sci. Eng. C 76 (2017) 628-636]. PMID- 28888018 TI - Preparation and characterization of photocured poly (epsilon-caprolactone) diacrylate/poly (ethylene glycol) diacrylate/chitosan for photopolymerization type 3D printing tissue engineering scaffold application. AB - Because of its biocompatible, biodegradable and antimicrobial properties, chitosan is an attractive biomaterial for use in tissue engineering scaffolds. This work builds on previous research by incorporating 95% DD chitosan into a visible-light curable resin which is compatible with a digital light processing (DLPTM) projection additive manufacturing (3D printing) system. Different concentrations of chitosan were added to a poly (epsilon-caprolactone) diacrylate/poly (ethylene glycol)-diacrylate baseline resin and the samples were extensively characterized. Thermal and mechanical analysis conformed to established scaffold requirements. L929 cells were cultured on the photo crosslinked films and MTT assays were performed at 1, 3, and 5days to assess cytocompatibility of the resins. Data and SEM images verified a correlation between the concentration of chitosan in the photocurable resin and the adhesion, proliferation, and viability of cell cultures. Finally, the processability of the resins with the dynamic masking DLP system was demonstrated by constructing multi layer scaffolds with actual measurements that were consistent with the CAD models. These findings encourage the use of chitosan as an additive in visible light curable resins to improve desired properties in tissue engineering scaffolds. PMID- 28888019 TI - In-vivo characterization of a 3D hybrid scaffold based on PCL/decellularized aorta for tracheal tissue engineering. AB - INTRODUCTION: As common treatments for long tracheal stenosis are associated with several limitations, tracheal tissue engineering is considered as an alternative treatment. AIM OF STUDY: This study aimed at preparing a hybrid scaffold, based on biologic and synthetic materials for tracheal tissue engineering. MATERIALS AND METHODS: Three electrospun polycaprolactone (PCL) scaffolds, namely E1 (pure PCL), E2 (collagen-coated PCL) and E3 (PCL blended with collagen) were prepared. Allogeneic aorta was harvested and decellularized. A biodegradable PCL stent was fabricated and inserted into the aorta to prevent its collapse. RESULT: Scaffold characterization results revealed that the 2-h swelling ratio of E2 was significantly higher than those of E1 and E3. In the first 3months, E2 and E3 exhibited almost equal degradabilities (significantly higher than that of E1). Moreover, tensile strengths of all samples were comparable with those of human trachea. Using rabbit's adipose-derived mesenchymal stem cells (AMSCs) and primary chondrocytes, E3 exhibited the highest levels of GAG release within 21days as well as collagen II and aggrecan expression. Fot the next step, AMSC chondrocyte co-culture seeded scaffold was sutured to the acellular aorta, implanted into rabbits' muscle, and finally harvested after 4weeks of follow up. CONCLUSION: Harvested structures were totally viable due to the angiogenesis created by the muscle. H&E and alcian blue staining results revealed the presence of chondrocytes in the structure and GAG in the produced extracellular matrix. Since tracheal replacement using biologic and synthetic scaffolds usually results in tracheal collapse or granulation formation, a hybrid construct may provide the required rigidity and biocompatibility for the substitute. PMID- 28888020 TI - Biocompatible beta-SrHPO4 clusters with dandelion-like structure as an alternative drug carrier. AB - Recent researches about calcium phosphate (CaP) biomaterials used as drug delivery systems are focusing on the better understanding of the microenvironment around the implant-host tissue interface, with the aim to provide a bone response in pathological ones. Towards the improvement of the osteogenic potential of CaP drug carriers, dandelion-like beta-SrHPO4 clusters (Phi10-20MUm) has been prepared by a homogeneous precipitation method under the hydrolysis of carbamide. Adhesion, spreading, proliferation, osteogenic differentiation and mRNA expression of bone mesenchymal stem cells (BMSCs) mediated by beta-SrHPO4 clusters were investigated. Highly osteoconductive and biodegradable octacalcium phosphate with similar structure was employed as the control. By contrast, beta SrHPO4 clusters exhibited remarkably better affinity, enhanced proliferation and osteogenic differentiation of BMSCs, providing a promising alternative bioactive bone substitute and drug carrier for tissue repair. With the unique dandelion like microstructure, we believe that our as-prepared material will open up new avenues for applicability of CaP drug delivery systems in the near future. PMID- 28888021 TI - Simultaneous monitoring of single cell and of micro-organ activity by PEDOT:PSS covered multi-electrode arrays. AB - Continuous and long-term monitoring of cellular and micro-organ activity is required for new insights into physiology and novel technologies such as Organs on-Chip. Moreover, recent advances in stem cell technology and especially in the field of diabetes call for non-invasive approaches in quality testing of the large quantities of surrogate pancreatic islets to be generated. Electrical activity of such a micro-organ results in single cell action potentials (APs) of high frequency and in low frequency changes in local field potentials (slow potentials or SPs), reflecting coupled cell activity and overall organ physiology. Each of them is indicative of different physiological stages in islet activation. Action potentials in islets are of small amplitude and very difficult to detect. The use of PEDOT:PSS to coat metal electrodes is expected to reduce noise and results in a frequency-dependent change in impedance, as shown here. Whereas detection of high-frequency APs improves, low frequency SPs are less well detected which is, however, an acceptable trade off in view of the strong amplitude of SPs. Using a dedicated software, recorded APs and SPs can be automatically diagnosed and analyzed. Concomitant capture of the two signals will considerably increase the diagnostic power of monitoring islets and islet surrogates in fundamental research as well as drug screening or the use of islets as biosensors. PMID- 28888022 TI - Effective induction of death in mesothelioma cells with magnetite nanoparticles under an alternating magnetic field. AB - With the objective of finding an avenue for development of magnetic hyperthermia as an effective mesothelioma treatment, the influence of heating by magnetite nanoparticles (MNPs) with a diameter of ~40nm, which were incorporated into cells and then subjected to AC magnetic field, on induction of cell death was investigated in all three histological subtypes of human mesothelioma cells (i.e., epithelioid NCI-H28, sarcomatoid NCI-H2052, and biphasic MSTO-211H cells). Cellular uptake of MNPs was observed in all cell types, but the amount of MNPs incorporated per cell into MSTO-211H cells was smaller than in NCI-H28 and NCI H2052 cells. On the other hand, cell death induced by cellular uptake of MNPs was observed specifically in MSTO-211H cells. Hence, when cells are heated by intracellular MNPs under AC magnetic field, a high degree of cell mortality in NCI-H28 and NCI-H2052 cells is induced by the temperature increase derived from the high amount of intracellular MNPs, but the combination of intracellular heating and cell-type-specific toxicity of MNPs induced high rates of cell death in MSTO-211H cells even at a lower temperature. Almost all of the heated cells were dead after 24-h incubation at 37 degrees C in all histological subtypes. Additionally, higher mortalities were observed in all three types of mesothelioma cells after MNPs-heating, as compared to the heating with a thermostatic bath. Herein, the significance of cellular uptake of MNPs for effectively inducing cell death in mesothelioma has been demonstrated in vitro. PMID- 28888023 TI - Innovative micro-textured hydroxyapatite and poly(l-lactic)-acid polymer composite film as a flexible, corrosion resistant, biocompatible, and bioactive coating for Mg implants. AB - The utility of a novel ceramic/polymer-composite coating with a micro-textured microstructure that would significantly enhance the functions of biodegradable Mg implants is demonstrated here. To accomplish this, bioactive hydroxyapatite (HA) micro-dots can be created by immersing a Mg implant with a micro-patterned photoresist surface in an aqueous solution containing calcium and phosphate ions. The HA micro-dots can then be surrounded by a flexible poly(l-lactic)-acid (PLLA) polymer using spin coating to form a HA/PLLA micro-textured coating layer. The HA/PLLA micro-textured coating layer showed an excellent corrosion resistance when it was immersed in a simulated body fluid (SBF) solution and good biocompatibility, which was assessed by in vitro cell tests. In addition, the HA/PLLA micro-textured coating layer had high deformation ability, where no apparent changes in the coating layer were observed even after a 5% elongation, which would be unobtainable using HA and PLLA coating layers; furthermore, this allowed the mechanically-strained Mg implant with the HA/PLLA micro-textured coating layer to preserve its excellent corrosion resistance and biocompatibility in vitro. PMID- 28888024 TI - Airflow and symptom outcomes between allergic and non-allergic rhinitis patients from turbinoplasty. AB - BACKGROUND: Inferior turbinate procedures are applied to relieve medically refractory nasal obstruction. However, the nature of congestion differs between allergic(AR) and non-allergic rhinitis(NAR). This study compares surgical outcomes between AR and NAR patients. METHODOLOGY: A case-control study of patients undergoing turbinate with or without septoplasty surgery for nasal obstruction was performed. Patient reported outcomes were: nasal obstruction, global nasal function(GNF), and sino-nasal outcome test(SNOT-22) with rhinitis, facial symptom, sleep and psychological sub-scores. Nasal peak inspiratory flow(NPIF) assessed nasal airflow. Measurements were obtained preoperatively and 3 months postoperatively. RESULTS: 190 patients were assessed. AR had worse obstruction and worse GNF. All outcomes improved post-surgery; nasal obstruction, GNF, SNOT-22, rhinitis-symptoms, facial-symptoms, sleep-function, psychological function and NPIF. GNF improvement was greater in AR. NPIF improvement was similar between groups. CONCLUSIONS: Both AR and NAR patients gained benefit from surgery to relieve nasal obstruction. AR patients demonstrate greater improvement in GNF score but allergy management may contribute to this. PMID- 28888025 TI - Comparison of different endoscopic scoring systems in patients with chronic rhinosinusitis: reliability, validity, responsiveness and correlation. AB - OBJECTIVES: Previous studies have proposed various endoscopic scoring systems to assess disease severity of patients with chronic rhinosinusitis (CRS). However, those assessments have not been validated. This study was designed to assess the Modified Lund - Kennedy (MLK) and the discharge, inflammation, and polyps/oedema (DIP) endoscopic scoring systems in patients with CRS. METHODS: A prospective study including 144 patients who underwent functional endoscopic sinus surgery (FESS). All participants were asked to finish SNOT-22, Lund-Mackay CT score and endoscopic examination evaluations before surgery and at 6 months after surgery. Endoscopic examination videos were evaluated using 3 scoring systems by two blinded rhinologists. The scores were compared in terms of responsiveness, validity, reliability and correlation with other scores. RESULTS: The MLK and DIP endoscopic scoring systems showed high test-retest reliability and inter-rater reliability. All endoscopic scoring systems showed significant differences between the scores recorded at each time point (all P lower than 0.90 when compared with the Lund - Kennedy (LK) endoscopic scoring system and showed a statistically significant difference in discriminant validity between symptomless and symptomatic cases. The MLK and DIP systems showed high correlations with other subject assessments and no correlation with SNOT-22. CONCLUSION: MLK and DIP exhibit substantial responsiveness, validity and reliability. MLK and DIP may be well suited for clinical and research use. PMID- 28888026 TI - Regional recurrence in a case series of patients with carcinoma of the nasal cavity - therapeutic implications. AB - INTRODUCTION: Surgery is the primary treatment option for squamous cell carcinomas of the nasal cavity (NCSCC). Nodal involvement is rare at the time of initial diagnosis, and the role of diagnostic neck dissection as well as potential adjuvant irradiation of the neck remains controversial. The objective of this study was to assess the oncologic outcomes of patients with NCSCC with special emphasis on cervical lymph node treatment and recurrence. METHODS: 37 previously untreated patients were included in this study. Demographic data, tumor characteristics, therapeutic management, and clinical outcome were analyzed. RESULTS: Patients with advanced stage tumors were slightly overrepresented in this study and overall 3-year disease-free survival was 63%. A surgical treatment approach was pursued in 89% (n=33) of patients. After total rhinectomy, there were no cases of local recurrence. Overall, 12% (n=4) of all surgically treated patients developed local recurrence. While in 45% of patients (n=15), neck dissection was performed at the time of tumor resection, initial lymph node metastasis was histologically confirmed in only 6% (n=2) of surgically treated patients. Cervical lymph node recurrence occurred in 18% (n=6) of patients, predominantly those with advanced stage tumors, despite prior treatment of the neck. CONCLUSION: Excellent local control is achievable for patients with NCSCC, especially with radical tumor resection. While cervical lymph node metastasis is rare at the time of diagnosis, regional lymph node recurrence needs to be taken into consideration when planning therapy and follow-up. Multimodal treatment of the neck may be required for patients with advanced stage tumors. PMID- 28888027 TI - Dermatopathic lymphadenopathy with Langerhans cell chimerism in graft-versus-host disease of the skin. AB - Dermatopathic lymphadenopathy (DL) is well-known in inflammatory skin disease; however, it has not been reported in graft-versus-host disease (GvHD) after allogeneic stem cell transplantation. Here, we report 2 cases of DL in patients with acute GvHD of the skin and demonstrate complete donor chimerism of Langerhans cells within the lymph nodes. PMID- 28888028 TI - Effect of reduced-intensity conditioning and the risk of late-onset non infectious pulmonary complications in pediatric patients. AB - OBJECTIVE: Late-onset non-infectious pulmonary complications (LONIPCs) contribute to higher morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we investigated the risk factors of LONIPCs in pediatric patients. METHOD: Between 2001 and 2011, 74 pediatric patients (range, 7 months to 22.7 years old; median 6.5 years old), including 29 with a primary immunodeficiency, underwent 80 allo-HSCTs at our institution. Sixty-seven patients who survived more than 3 months after allo-HSCT were analyzed retrospectively. The median follow-up period was 1 973 days (range, 126 5 145 days). RESULTS: Nine patients (13.4%) developed LONIPCs between 90 and 3 578 days after allo-HSCT. A myeloablative conditioning (MAC) regimen and chronic GVHD were determined as significant risk factors of LONIPCs. None of 18 patients who received the reduced-intensity conditioning (RIC) regimen developed LONIPCs, although there was no difference in overall survival between the MAC and RIC regimen. Notably, two immunodeficient patients who received busulfan-based MAC regimen under 2 years old developed LONIPC with no history of chronic GVHD after 5 years and 10 years from SCT, respectively, suggesting the direct toxicity of busulfan. CONCLUSION: Our study's findings indicate that the RIC regimen reduces the risk of LONIPCs in pediatric patients. PMID- 28888031 TI - Disconnection of hippocampal networks contributes to memory dysfunction in individuals with temporal lobe epilepsy. AB - A deficit in declarative memory function is common among individuals with temporal lobe epilepsy. The purpose of this study is to evaluate the relationship between the volume of the hippocampus, entorhinal cortex along with the surrounding parahippocampal white matter and memory performance in those with temporal lobe epilepsy. T1 weighted MRI scans were acquired using a 3-D pulse sequence in 50 individuals with temporal lobe epilepsy. Hippocampal and entorhinal cortex volumes were derived by manually tracing consecutive coronal slices aligned perpendicular to the long axis of the hippocampus. In addition, parahippocampal white matter volumes were determined using voxel based morphometry. Finally, declarative memory was assessed using immediate and delayed verbal and visual memory tests from the Wechsler Memory Scale third edition. Significant correlations were seen between right and left hippocampal volumes and delayed verbal memory test scores. In addition, left parahippocampal white matter showed positive correlations with immediate and delayed verbal and visual recall. Furthermore, regression models found that the right hippocampus and left parahippocampal white matter were the best predictors of immediate and delayed verbal and visual memory performance. These results show that a decrease in white matter fibers projecting to the hippocampus may cause a disruption of incoming multi-modal sensory information, contributing to the memory decline seen in individuals with temporal lobe epilepsy. PMID- 28888029 TI - Expression of DNA repair genes is important molecular findings in CD34 + stem cells of myelodysplastic syndrome. PMID- 28888030 TI - Increased sign-tracking behavior in adolescent rats. AB - An autoshaping procedure was used to test the notion that conditioned stimuli (CSs) gain greater incentive salience during adolescence than young adulthood under conditions of social isolation rearing and food restriction. Rats were single-housed and placed on food restriction during 10 daily training sessions in which a lever (CS+ ) was presented then followed immediately by a food unconditioned stimulus (US). A second lever (CS- ) was presented on intermixed trials and was not reinforced. Despite the fact that food delivery was not contingent on the rats' behavior, all rats exhibited behaviors directed towards the lever (i.e., sign-tracking). In the adolescent group, the rate of lever pressing and the percentage of trials with a lever press were higher than in young adults. Initially, group differences were observed when rats were retrained when the adolescents had reached young adulthood. These findings support the hypothesis that cues that come to predict reward become imbued with excessive motivational value in adolescents, perhaps contributing to the hyper responsiveness to reward-related stimuli typically observed during this period of development. PMID- 28888032 TI - Close but no cigar: Spatial precision deficits following medial temporal lobe lesions provide novel insight into theoretical models of navigation and memory. AB - : Increasing evidence suggests that the human hippocampus contributes to a range of different behaviors, including episodic memory, language, short-term memory, and navigation. A novel theoretical framework, the Precision and Binding Model, accounts for these phenomenon by describing a role for the hippocampus in high resolution, complex binding. Other theories like Cognitive Map Theory, in contrast, predict a specific role for the hippocampus in allocentric navigation, while Declarative Memory Theory predicts a specific role in delay-dependent conscious memory. Navigation provides a unique venue for testing these predictions, with past results from research with humans providing inconsistent findings regarding the role of the human hippocampus in spatial navigation. Here, we tested five patients with lesions primarily restricted to the hippocampus and those extending out into the surrounding medial temporal lobe cortex on a virtual water maze task. Consistent with the Precision and Binding Model, we found partially intact allocentric memory in all patients, with impairments in the spatial precision of their searches for a hidden target. We found similar impairments at both immediate and delayed testing. Our findings are consistent with the Precision and Binding Model of hippocampal function, arguing for its role across domains in high-resolution, complex binding. SIGNIFICANCE STATEMENT: Remembering goal locations in one's environment is a critical skill for survival. How this information is represented in the brain is still not fully understood, but is believed to rely in some capacity on structures in the medial temporal lobe. Contradictory findings from studies of both humans and animals have been difficult to reconcile with regard to the role of the MTL, specifically the hippocampus. By assessing impairments observed during navigation to a goal in patients with medial temporal lobe damage we can better understand the role these structures play in such behavior. Utilizing virtual reality and novel analysis techniques, we have more precisely assessed the impact that medial temporal lobe damage has on spatial memory and navigation. PMID- 28888033 TI - Modulation of gammadelta T-cell activation by neutrophil elastase. AB - gammadelta T cells are non-conventional, innate-like T cells, characterized by a restricted T-cell receptor repertoire. They participate in protective immunity responses against extracellular and intracellular pathogens, tumour surveillance, modulation of innate and adaptive immune responses, tissue healing, epithelial cell maintenance and regulation of physiological organ function. In this study, we investigated the role of neutrophils during the activation of human blood gammadelta T cells through CD3 molecules. We found that the up-regulation of CD69 expression, and the production of interferon-gamma and tumour necrosis factor alpha induced by anti-CD3 antibodies was potentiated by neutrophils. We found that inhibition of caspase-1 and neutralization of interleukin-18 did not affect neutrophil-mediated modulation. By contrast, the treatment with serine protease inhibitors prevented the potentiation of gammadelta T-cell activation induced by neutrophils. Moreover, the addition of elastase to gammadelta T-cell culture increased their stimulation, and the treatment of neutrophils with elastase inhibitor prevented the effect of neutrophils on gammadelta T-cell activation. Furthermore, we demonstrated that the effect of elastase on gammadelta T cells was mediated through the protease-activated receptor, PAR1, because the inhibition of this receptor with a specific antagonist, RWJ56110, abrogated the effect of neutrophils on gammadelta T-cell activation. PMID- 28888035 TI - Analysis of earthworm sublethal toxic responses to atrazine exposure using 1 H nuclear magnetic resonance (NMR)-based metabolomics. AB - Atrazine toxicity to earthworms is still not fully understood, particularly at sublethal concentrations. Because of the ubiquity of atrazine in the environment, it is imperative to understand the impacts of atrazine presence to soil-dwelling organisms. To examine this in detail, we used 1 H nuclear magnetic resonance (NMR)-based metabolomics to elucidate earthworm (Eisenia fetida) responses after 48 h of atrazine exposure in contact tests. Earthworms were exposed to 4 sublethal concentrations of 362.4, 181.2, 90.6, and 45.3 ng/cm2 , which correspond to 1/8th, 1/16th, 1/32nd, and 1/64th of the median lethal concentration (LC50) values, respectively. After exposure, polar metabolites were isolated from earthworm tissues and analyzed using 1 H NMR spectroscopy. Sublethal atrazine exposure induced a nonmonotonic response with respect to exposure concentration and caused an overall suppression in earthworm metabolism. Maltose, fumarate, malate, threonine/lactate, adenosine-5'-triphosphate (ATP), betaine, scyllo-inositol, glutamate, arginine, and glutamine were the metabolites identified as most sensitive to atrazine exposure. These observed fluctuations in the metabolic profile suggest that atrazine reduced ATP synthesis and negatively impacted the health of earthworms after acute sublethal exposure. Our study also demonstrates the utility of NMR-based metabolomics for the basic assessment of sublethal toxicity, which can then be used for more targeted approaches with other molecular techniques. Environ Toxicol Chem 2018;37:473-480. (c) 2017 SETAC. PMID- 28888034 TI - Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR. AB - The relatively low efficacy of ACE-inhibitors in the treatment of heart failure in women after estrogen loss may be due to their inability to reach the intracellular sites at which angiotensin (Ang) II is generated and/or the existence of cell-specific mechanisms in which ACE is not the essential processing pathway for Ang II formation. We compared the metabolic pathway for Ang II formation in freshly isolated myocytes (CMs) and non-myocytes (NCMs) in cardiac membranes extracted from hearts of gonadal-intact and ovariectomized (OVX) adult WKY and SHR rats. Plasma Ang II levels were higher in WKY vs. SHR (strain effect: WKY: 62 +/- 6 pg/ml vs. SHR: 42 +/- 9 pg/ml; p < 0.01), independent of OVX. The enzymatic activities of chymase, ACE, and ACE2 were higher in NCMs versus CMs, irrespective of whether assays were performed in cardiac membranes from WKY or SHR or in the presence or absence of OVX. E2 depletion increased chymase activity, but not ACE activity, in both CMs and NCMs. Moreover, cardiac myocyte chymase activity associated with diastolic function in WKYs and cardiac structure in SHRs while no relevant functional and structural relationships between the classic enzymatic pathway of Ang II formation by ACE or the counter-regulatory Ang-(1-7) forming path from Ang II via ACE2 were apparent. The significance of these novel findings is that targeted cell-specific chymase rather than ACE inhibition may have a greater benefit in the management of HF in women after menopause. PMID- 28888036 TI - Exploring the interaction between Mycobacterium tuberculosis enolase and human plasminogen using computational methods and experimental techniques. AB - Surface localized microbial enolases' binding with human plasminogen has been increasingly proven to have an important role in initial infection cycle of several human pathogens. Likewise, surface localized Mycobacterium tuberculosis (Mtb) enolase also binds to human plasminogen, and this interaction may entail crucial consequences for granuloma stability. The current study is the first attempt to explore the plasminogen interacting residues of enolase from Mtb. Beginning with the structural modeling of Mtb enolase, the binding pose of Mtb enolase and human plasminogen was predicted using protein-protein docking simulations. The binding pose revealed the interface region with interacting residues and molecular interactions. Next, the interacting residues were refined and ranked by using various criteria. Finally, the selected interacting residues were tested experimentally for their involvement in plasminogen binding. The two consecutive lysine residues, Lys-193 and Lys-194, turned out to be active residues for plasminogen binding. These residues when substituted for alanine along with the most active residue Lys-429, that is, the triple mutant (K193A + K194A + K429A) Mtb enolase, exhibited 40% reduction in plasminogen binding. It is worth noting that Mtb enolase lost nearly half of the plasminogen binding activity with only three simultaneous substitutions, without any significant secondary structure perturbation. Further, the sequence comparison between Mtb and human enolase isoforms suggests the possibility of selective targeting of Mtb enolase to obstruct binding of human plasminogen. PMID- 28888038 TI - Influence of littoral periphyton on whole-lake metabolism relates to littoral vegetation in humic lakes. AB - The role of littoral habitats in lake metabolism has been underrated, especially in humic lakes, based on an assumption of low benthic primary production (PP) due to low light penetration into water. This assumption has been challenged by recent recognition of littoral epiphyton dominance of whole-lake PP in a small highly humic lake and of epiphyton as an important basal food source for humic lake biota. However, as these studies have mostly concerned single lakes, there is a need to test their wider generality. We studied the whole-lake PP and community respiration (CR) in eight small humic lakes in southern Finland during July 2015 using 14 C incorporation to measure pelagic PP and the changes in dissolved inorganic carbon in light and dark in situ incubations to measure CR and littoral PP by epiphyton. Changes in O2 concentration in both pelagic and littoral surface water were measured periodically from each lake and, additionally, continuously with a data logger from one lake during the study period. The results revealed that the littoral dominated whole-lake net primary production (NPP) in five of the eight lakes, which was supported by observed O2 supersaturation in the littoral surface water in most of the lakes. Calculated pelagic:littoral ratios by area correlated negatively with both littoral NPP and littoral contribution to whole-lake NPP. Moreover, there was a significant positive relationship between littoral proportion of whole-lake NPP and the fraction of lake surface area covered by littoral aquatic vegetation. This demonstrates that increased aquatic littoral vegetation cover increases the overall importance of the littoral to whole-lake PP in highly humic lakes. Littoral NPP also correlated strongly with littoral O2 saturation, and the continuously measured O2 revealed substantial temporal variation in O2 saturation, particularly in the littoral zone. Whole-lake gross primary production:community respiration (GPP:CR) ratios revealed that accounting for littoral metabolism produced a marked shift towards lake metabolic balance, although all the eight lakes remained net heterotrophic. This study emphasizes that littoral metabolism needs to be accounted for when estimating whole-lake C fluxes in all lakes, even in highly colored humic waters. PMID- 28888037 TI - MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer. AB - Telomerase consists of at least two essential elements, an RNA component hTR or TERC that contains the template for telomere DNA addition and a catalytic reverse transcriptase (TERT). While expression of TERT has been considered the key rate limiting component for telomerase activity, increasing evidence suggests an important role for the regulation of TERC in telomere maintenance and perhaps other functions in human cancer. By using three orthogonal methods including RNAseq, RT-qPCR, and an analytically validated chromogenic RNA in situ hybridization assay, we report consistent overexpression of TERC in prostate cancer. This overexpression occurs at the precursor stage (e.g. high-grade prostatic intraepithelial neoplasia or PIN) and persists throughout all stages of disease progression. Levels of TERC correlate with levels of MYC (a known driver of prostate cancer) in clinical samples and we also show the following: forced reductions of MYC result in decreased TERC levels in eight cancer cell lines (prostate, lung, breast, and colorectal); forced overexpression of MYC in PCa cell lines, and in the mouse prostate, results in increased TERC levels; human TERC promoter activity is decreased after MYC silencing; and MYC occupies the TERC locus as assessed by chromatin immunoprecipitation (ChIP). Finally, we show that knockdown of TERC by siRNA results in reduced proliferation of prostate cancer cell lines. These studies indicate that TERC is consistently overexpressed in all stages of prostatic adenocarcinoma and that its expression is regulated by MYC. These findings nominate TERC as a novel prostate cancer biomarker and therapeutic target. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28888039 TI - Role of ALDH1 in the prognosis of esophageal cancer and its relationship with tumor microenvironment. AB - Aldehyde dehydrogenase 1 (ALDH1) is associated with tumorigenesis, and significantly increased in cancer stem-like cells. In the present study, the role of ALDH1 in esophageal squamous cell carcinoma (ESCC) was investigated. We retrospectively analyzed the clinical outcomes of 148 ESCC and examined its correlation with ALDH1 levels. Furthermore, we preformed cellular and animal experiments to investigate the role of ALDH1 in tumor progression and microenvironment. Our data revealed that ALDH1 staining was positively linked to a higher clinical stage, higher loco-regional failure rate, and shorter survival time. Furthermore, there was a positive link between ALDH1 expression and IL-6 signaling according to the data of clinical specimens and cellular experiments. Using animal model, ALDH1-positive tumors were associated with aggressive tumor growth, increased IL-6, augmented epithelial-mesenchymal transition (EMT), and activation of myeloid-derived suppressor cells (MDSCs). Blockade of COX-2 attenuated the aggressive tumor growth of ALDH1-positive cancer cells. In conclusion, our findings suggested that ALDH1 played an important role in tumor aggressiveness and associated with a tumor-promoting microenvironment in esophageal cancer. Directly targeting ALDH1 or using a COX-2 inhibitor could be a promising strategy for the treatment of ESCC. PMID- 28888040 TI - Phenotypic variation of an ALK-positive large-cell neuroendocrine lung carcinoma with carcinoid morphology during treatment with ALK inhibitors. PMID- 28888042 TI - Effect of a multinutrient intervention after ischemic stroke in female C57Bl/6 mice. AB - Stroke can affect females very differently from males, and therefore preclinical research on underlying mechanisms and the effects of interventions should not be restricted to male subjects, and treatment strategies for stroke should be tailored to benefit both sexes. Previously, we demonstrated that a multinutrient intervention (Fortasyn) improved impairments after ischemic stroke induction in male C57Bl/6 mice, but the therapeutic potential of this dietary treatment remained to be investigated in females. We now induced a transient middle cerebral artery occlusion (tMCAo) in C57Bl/6 female mice and immediately after surgery switched to either Fortasyn or an isocaloric Control diet. The stroke females performed several behavioral and motor tasks before and after tMCAo and were scanned in an 11.7 Tesla magnetic resonance imaging (MRI) scanner to assess brain perfusion, integrity, and functional connectivity. To assess brain plasticity, inflammation, and vascular integrity, immunohistochemistry was performed after killing of the mice. We found that the multinutrient intervention had diverse effects on the stroke-induced impairments in females. Similar to previous observations in male stroke mice, brain integrity, sensorimotor integration and neurogenesis benefitted from Fortasyn, but impairments in activity and motor skills were not improved in female stroke mice. Overall, Fortasyn effects in the female stroke mice seem more modest in comparison to previously investigated male stroke mice. We suggest that with further optimization of treatment protocols more information on the efficacy of specific interventions in stroked females can be gathered. This in turn will help with the development of (gender-specific) treatment regimens for cerebrovascular diseases such as stroke. This article is part of the Special Issue "Vascular Dementia". PMID- 28888041 TI - Supplementation with the Methyl Donor Betaine Prevents Congenital Defects Induced by Prenatal Alcohol Exposure. AB - BACKGROUND: Despite decades of public education about dire consequences of prenatal alcohol exposure (PAE), drinking alcohol during pregnancy remains prevalent. As high as 40% of live-born infants exposed to alcohol during gestation and diagnosed with fetal alcohol syndrome have congenital heart defects that can be life-threatening. In animal models, the methyl donor betaine, found in foods such as wheat bran, quinoa, beets, and spinach, ameliorated neurobehavioral deficits associated with PAE, but effects on heart development are unknown. METHODS: Previously, we modeled a binge drinking episode during the first trimester in avian embryos. Here, we investigated whether betaine could prevent adverse effects of alcohol on heart development. Embryos exposed to ethanol (EtOH) with and without an optimal dose of betaine (5 MUM) were analyzed at late developmental stages. Cardiac morphology parameters were rapidly analyzed and quantified using optical coherence tomography. DNA methylation at early stages was detected by immunofluorescent staining for 5-methylcytosine in sections of embryos treated with EtOH or cotreated with betaine. RESULTS: Compared to EtOH-exposed embryos, betaine-supplemented embryos had higher late stage survival rates and fewer gross head and body defects than seen after alcohol exposure alone. Betaine also reduced the incidence of late-stage cardiac defects such as absent vessels, abnormal atrioventricular (AV) valves, and hypertrophic ventricles. Furthermore, betaine cotreatment brought measurements of great vessel diameters, interventricular septum thickness, and AV leaflet volumes in betaine-supplemented embryos close to control values. Early-stage 5 methycytosine staining revealed that DNA methylation levels were reduced by EtOH exposure and normalized by co-administration with betaine. CONCLUSIONS: This is the first study demonstrating efficacy of the methyl donor betaine in alleviating cardiac defects associated with PAE. These findings highlight the therapeutic potential of low-concentration betaine doses in mitigating PAE-induced birth defects and have implications for prenatal nutrition policies, especially for women who may not be responsive to folate supplementation. PMID- 28888043 TI - SIRT1 deacetylates KLF4 to activate Claudin-5 transcription in ovarian cancer cells. AB - Malignant cancers are distinguished from more benign forms of cancers by enhanced ability to disseminate. A number of factors aid the migration and invasion of malignant cancer cells. Epithelial-to-mesenchymal transition (EMT), which greatly facilitates the dissemination of cancer cells, is characterized by the loss of epithelial markers and the acquisition of mesenchymal markers thereby rendering the cells more migratory and invasive. We have previously shown that the class III lysine deacetylase SIRT1 plays a critical role curbing the metastasis of ovarian cancer cells partly by blocking EMT. Here we investigated the mechanism by which SIRT1 regulates the transcription of Claudin 5 (CLDN5), an epithelial marker gene, in ovarian cancer cells. SIRT1 activation or over-expression up regulated CLDN5 expression while SIRT1 inhibition or depletion down-regulated CLDN5 expression. SIRT1 interacted with and deacetylated Kruppel-like factor 4 (KLF4), a known transcriptional activator for CLDN5. Deacetylation by SIRT1 promoted nuclear accumulation of KLF4 and enhanced the binding of KLF4 to the CLDN5 promoter in the nucleus. SIRT1-mediated up-regulation of CLDN5 was abrogated in the absence of KLF4. In accordance, KLF4 depletion by siRNA rendered ovarian cancer cells more migratory and invasive despite of SIRT1 activation or over-expression. In conclusion, our data suggest that SIRT1 activates CLDN5 transcription by deacetylating and potentiating KLF4. PMID- 28888044 TI - Novel mutations in Thai patients with glanzmann thrombasthenia. AB - OBJECTIVES: Glanzmann thrombasthenia (GT) is an autosomal recessive platelet disorder, caused by defects of the platelet integrin alphaIIbbeta3 (GPIIb/IIIa) resulting from pathogenic mutations in either ITGA2B or ITGB3. It is characterized by spontaneous mucocutaneous bleeding. The molecular features of GT in Thailand have not been identified. This study aimed to determine the clinical and molecular features of unrelated Thai patients with GT. METHODS: Four patients with clinically suspected GT were recruited at the Division of Pediatric Hematology/Oncology, King Chulalongkorn Memorial Hospital. The diagnosis was based on clinical and hematological parameters as well as genetic analysis. Whole exome sequencing (WES) was performed in all cases. RESULTS: Of the four patients studied, the median age at first suspicion of GT was 2.5 years. All presented with severe bleeding symptoms (WHO bleeding scale 3). Flow cytometry to assess the surface GPIIb/IIIa complex showed reduced expression. By WES, we successfully identified seven mutant alleles in ITGA2B. One alteration, the c.2915dup (p.Leu973Alafs*63), was detected in two unrelated families. One patient was homozygous for the c.617T>A (p.Val206Asp). Of the five different mutations, three have never been previously described. These include a missense, c.617T>A (p.Val206Asp), a deletion, c.1524_1533del (p.Gln508Hisfs*3), and a nonsense, c.2344C>T (p.Arg782Ter). CONCLUSION: This study reported three novel mutations expanding the genotypic spectrum of ITGA2B causing GT. PMID- 28888045 TI - Tracking pyrethroid toxicity in surface water samples: Exposure dynamics and toxicity identification tools for laboratory tests with Hyalella azteca (Amphipoda). AB - Pyrethroid insecticides are commonly used in pest control and are present at toxic concentrations in surface waters of agricultural and urban areas worldwide. Monitoring is challenging as a result of their high hydrophobicity and low toxicity thresholds, which often fall below the analytical methods detection limits (MDLs). Standard daphnid bioassays used in surface water monitoring are not sensitive enough to protect more susceptible invertebrate species such as the amphipod Hyalella azteca and chemical loss during toxicity testing is of concern. In the present study, we quantified toxicity loss during storage and testing, using both natural and synthetic water, and presented a tool to enhance toxic signal strength for improved sensitivity of H. azteca toxicity tests. The average half-life during storage in low-density polyethylene (LDPE) cubitainers (Fisher Scientific) at 4 degrees C of 5 pyrethroids (permethrin, bifenthrin, lambda cyhalothrin, cyfluthrin, and esfenvalerate) and one organophosphate (chlorpyrifos; used as reference) was 1.4 d, and piperonyl butoxide (PBO) proved an effective tool to potentiate toxicity. We conclude that toxicity tests on ambient water samples containing these hydrophobic insecticides are likely to underestimate toxicity present in the field, and mimic short pulse rather than continuous exposures. Where these chemicals are of concern, the addition of PBO during testing can yield valuable information on their presence or absence. Environ Toxicol Chem 2018;37:462-472. (c) 2017 SETAC. PMID- 28888046 TI - Gap junctional intercellular communication in adipose-derived stromal/stem cells is cell density-dependent and positively impacts adipogenic differentiation. AB - Adipose-derived stromal/stem cells (ASCs) represent a widely used cell source with multi-lineage differentiation capacity in approaches for tissue engineering and regenerative medicine. Despite the multitude of literature on their differentiation capacity, little is reported about the physiological properties contributing to and controlling the process of lineage differentiation. Direct intercellular communication between adjacent cells via gap junctions has been shown to modulate differentiation processes in other cell types, with connexin 43 (Cx43) being the most abundant isoform of the gap junction-forming connexins. Thus, in the present study we focused on the expression of Cx43 and gap junctional intercellular communication (GJIC) in human ASCs, and its significance for adipogenic differentiation of these cells. Cx43 expression in ASCs was demonstrated histologically and on the gene and protein expression level, and was shown to be greatly positively influenced by cell seeding density. Functionality of gap junctions was proven by dye transfer analysis in growth medium. Adipogenic differentiation of ASCs was shown to be also distinctly elevated at higher cell seeding densities. Inhibition of GJIC by 18alpha-glycyrrhetinic acid (AGA) significantly compromised adipogenic differentiation, as demonstrated by histology, triglyceride quantification, and adipogenic marker gene expression. Flow cytometry analysis showed a lower proportion of cells undergoing adipogenesis when GJIC was inhibited, further indicating the importance of GJIC in the differentiation process. Altogether, this study demonstrates the impact of direct cell-cell communication via gap junctions on the adipogenic differentiation process of ASCs, and may contribute to further integrate direct intercellular crosstalk in rationales for tissue engineering approaches. PMID- 28888048 TI - Involvement of nutrients and nutritional mediators in mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase gene expression. AB - Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) catalyses the first step of ketogenesis and is critical in various metabolic conditions. Several nutrient molecules were able to differentially modulate HMGCS2 expression levels. Docosahexaenoic acid (DHA, C22:6, n-3), eicosapentaenoic acid (EPA, C20:5, n-3), arachidonic acid (AA, C20:4, n-6), and glucose increased HMGCS2 mRNA and protein levels in HepG2 hepatoma cells, while fructose decreased them. The effect of n-6 AA resulted significantly higher than that of n-3 PUFA, but when combined all these molecules were far less efficient. Insulin reduced HMGCS2 mRNA and protein levels in HepG2 cells, even when treated with PUFA and monosaccharides. Several nuclear receptors and transcription factors are involved in HMGCS2 expression regulation. While peroxysome proliferator activated receptor alpha (PPAR-alpha) agonist WY14643 increased HMGCS2 expression, this treatment was unable to affect PUFA-mediated regulation of HMGCS2 expression. Forkhead box O1 (FoxO1) inhibitor AS1842856 reduced HMGCS2 expression and suppressed induction promoted by fatty acids. Cells treatment with liver X receptor alpha (LXRalpha) agonist T0901317 reduced HMGCS2 mRNA, indicating a role for this transcription factor as suppressor of HMGCS2 gene. Previous observations already indicated HMGCS2 expression as possible nutrition status reference: our results show that several nutrients as well as specific nutritional related hormonal conditions are able to affect significantly HMGCS2 gene expression, indicating a relevant role for PUFA, which are mostly derived from nutritional intake. These insights into mechanisms of its regulation, specifically through nutrients commonly associated with disease risk, indicate HMGCS2 expression as possible reference marker of metabolic and nutritional status. PMID- 28888047 TI - Toddler hand preference trajectories predict 3-year language outcome. AB - A growing body of work suggests that early motor experience affects development in unexpected domains. In the current study, children's hand preference for role differentiated bimanual manipulation (RDBM) was measured at monthly intervals from 18 to 24 months of age (N = 90). At 3 years of age, children's language ability was assessed using the Preschool Language Scales 5th edition (PLSTM-5). Three distinct RDBM hand preference trajectories were identified using latent class growth analysis: (1) children with a left hand preference but a moderate amount of right hand use; (2) children with a right hand preference but a moderate amount of left hand use; and (3) children with a right hand preference and only a mild amount of left hand use. Stability over time within all three trajectories indicated that children did not change hand use patterns from 18 to 24 months. Children with the greatest amount of preferred (i.e., right) hand use demonstrated higher expressive language scores compared to children in both trajectories with moderate levels of non-preferred hand use. Children with the greatest amount of right hand use also had higher scores for receptive language compared to children with a right hand preference but moderate left hand use. Results support that consistency in handedness as measured by the amount of preferred hand use is related to distal language outcomes in development. PMID- 28888049 TI - Interindividual differences in the intraindividual association of competence and well-being: Combining experimental and intensive longitudinal designs. AB - OBJECTIVE: The aim of the present study is to assess whether people differ in the degree to which their well-being is affected by fulfillment of the need for competence. Specifically, we want to examine (a) whether interindividual differences in the within-person coupling of competence satisfaction and well being (competence satisfaction effect) and of competence dissatisfaction and well being (competence dissatisfaction effect) exist, and (b) whether these differences moderate the effects of an experimentally induced frustration of the need for competence. METHOD: A daily diary study (N = 89) and a laboratory based experiment (N = 150) were conducted to investigate interindividual differences in need effects. In a third study, participants of an additional daily diary study (N = 129) were subsequently subjected to an experimental frustration of the need for competence. RESULTS: Including interindividual differences in the within person coupling of need fulfillment and well-being improved model fit significantly, indicating that there were statistically meaningful interindividual differences in need effects. The interaction of competence satisfaction effect and competence dissatisfaction effect moderated the effect of an experimental competence frustration on negative affect. CONCLUSION: Results show that interindividual differences in the association of competence fulfillment and well-being are a matter of degree, but not quality. They also support the claim that need satisfaction and dissatisfaction are more than psychometric opposites. PMID- 28888050 TI - Significance of perivascular tumour cells defined by CD109 expression in progression of glioma. AB - In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole genome sequencing analysis of tissues from human glioma. The importance of CD109 positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28888051 TI - Orthogonal fitness benefits of nitrogen and ants for nitrogen-limited plants in the presence of herbivores. AB - Predictable effects of resource availability on plant growth-defense strategies provide a unifying theme in theories of direct anti-herbivore defense, but it is less clear how resource availability modulates plant indirect defense. Ant-plant hemipteran interactions produce mutualistic trophic cascades when hemipteran tending ants reduce total herbivory, and these interactions are a key component of plant indirect defense in most terrestrial ecosystems. Here we conducted an experiment to test how ant-plant-hemipteran interactions depend on nitrogen (N) availability by manipulating the presence of ants and aphids under different N fertilization treatments. Ants increased plant flowering success by decreasing the densities of herbivores, and the effects of ants on folivores were positively related to the density of aphids. Unexpectedly, N fertilization produced no changes in plant N concentrations. Plants grown in higher N grew and flowered more, but aphid honeydew chemistry stayed the same, and neither the density of aphids nor the rate of ant attraction per aphid changed with N addition. The positive effects of ants and N addition on plant fitness were thus independent of one another. We conclude that N was the plant's limiting nutrient and propose that addition of the limiting nutrient is unlikely to alter the strength of mutualistic trophic cascades. PMID- 28888052 TI - MiR-21-Mediated Suppression of Smad7 Induces TGFbeta1 and Can Be Inhibited by Activation of Nrf2 in Alcohol-Treated Lung Fibroblasts. AB - BACKGROUND: We previously demonstrated that chronic alcohol ingestion augments TGFbeta1 expression in the lung fibroblast and increases the risk of fibroproliferative disrepair in a mouse model of acute lung injury. The effect of alcohol on TGFbeta1 is mitigated by treatment with sulforaphane (SFP), which can activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, the mechanisms by which alcohol amplifies, or SFP attenuates, TGFbeta1 expression in the fibroblast are not known. MicroRNA (miR)-21 has been shown to inhibit Smad7, a TGFbeta1 signaling inhibitor. In this study, we hypothesized that alcohol augments TGFbeta1 expression through up-regulation of miR-21, which subsequently inhibits Smad7. METHODS: Primary mouse lung fibroblasts were cultured +/- alcohol +/- SFP and assessed for gene expression of miR-21, and gene and/or protein expression of Nrf2, Nrf2-regulated antioxidant enzymes, Smad7, STAT3, and TGFbeta1. NIH 3T3 fibroblasts were transfected with a miR-21 inhibitor and cultured +/- alcohol. alpha-SMA, Smad7, and TGFbeta1 protein expression were then assessed. In parallel, NIH 3T3 lung fibroblasts were transfected with Nrf2 silencing RNA (siRNA) and cultured +/- alcohol +/- SFP. Gene expression of miR 21, Nrf2, Smad7, and TGFbeta1 was assessed. RESULTS: MiR-21 gene expression was increased by 12-fold at 48 hours, and Smad7 gene expression and protein expression were reduced by ~30% in alcohol-treated fibroblasts. In parallel, inhibition of miR-21 attenuated alcohol-mediated decrease in Smad7 and increase in TGFbeta1 and alpha-SMA protein expression. Treatment with SFP mitigated the effect of alcohol on miR-21, Smad7 and total and phosphorylated STAT3, and restored Nrf2-regulated antioxidant gene expression. Silencing of Nrf2 prevented the effect of SFP on miR-21, Smad7, and TGFbeta1 gene expression in alcohol treated NIH 3T3 fibroblasts. CONCLUSIONS: Alcohol treatment increases TGFbeta1 in fibroblasts, at least in part, through augmentation of miR-21, which then inhibits Smad7 expression. These effects can be attenuated by activation of Nrf2 with SFP. PMID- 28888053 TI - Mesenchymal Stem Cells Overexpressing Interleukin-35 Propagate Immunosuppressive Effects in Mice. AB - To explore generation of interleukin (IL)-35-expressing mouse adipocyte-derived mesenchymal stem cells (Ad-MSCs) using lentiviral vector and their potential immunosuppressive effects in mice. Ad-MSCs were isolated and cultured in vitro and transfected with a lentivirus vector for overexpression of the therapeutic murine IL-35 gene. IL-35 expression in transfected MSCs (IL-35-MSCs) was quantified by enzyme-linked immunosorbent assay (ELISA). The lymphocytes subsets after one-way mixed lymphocyte culture and in vivo intravenous transplantation were analysed by flow cytometry to evaluate the immunosuppressive effects of IL 35-MSCs. ELISA was performed to examine IL-10, IL-17A and IL-35 expression in lymphocyte culture. Mouse Ad-MSCs were isolated and cultured. IL-35 was expressed in the MSC supernatant and serum after IL-35 transduction into Ad-MSCs by lentiviral vector transfection in vitro and in vivo. The percentage of CD4+ CD25+ T regulatory (Treg) cells in mice treated with IL-35-MSCs significantly increased. IL-35-MSCs upregulated the CD4+ CD25+ Treg cells in the allogeneic mixed lymphocyte reaction system, and lowered the percentage of CD4+ T cells compared with the other two control groups (P < 0.01). IL-17A expression significantly decreased and IL-10 expression significantly increased in IL-35 MSCs and MSCs when compared by ELISA to the control groups (P < 0.01). IL-35 transduced Ad-MSCs in vivo can enhance proliferation of CD4+ CD25+ Treg cells and suppress the function of effector T cells such as T helper (Th) 1, Th2 and Th17 cells and may reduce the development of allograft rejection. Our data suggest that transduced Ad-MSCs overexpressing IL-35 may provide a useful approach for basic research on cell-based immunotolerance therapy for inducing transplantation tolerance. PMID- 28888054 TI - Maternal salivary testosterone in pregnancy and fetal neuromaturation. AB - Testosterone exposure during pregnancy has been hypothesized as a mechanism for sex differences in brain and behavioral development observed in the postnatal period. The current study documents the natural history of maternal salivary testosterone from 18 weeks gestation of pregnancy to 6 months postpartum, and investigates associations with fetal heart rate, motor activity, and their integration. Findings indicate maternal salivary testosterone increases with advancing gestation though no differences by fetal sex were detected. High intra individual stability in prenatal testosterone levels extend into the postnatal period, particularly for pregnancies with male fetuses. With respect to fetal development, by 36 weeks gestation higher maternal prenatal salivary testosterone was significantly associated with faster fetal heart rate and less optimal somatic-cardiac integration. Measurement of testosterone in saliva is a useful tool for repeated-measures studies of hormonal concomitants of pregnancy. Moreover, higher maternal testosterone levels are associated with modest interference to fetal neurobehavioral development. PMID- 28888056 TI - Comparison of genome-wide analysis techniques to DNA methylation analysis in human cancer. AB - DNA methylation was the first epigenetic modification to be detected in human cancers with specific relation to aberrant gene expression. Herein, DNA methylation analysis explains how epigenetic patterns affect gene expression level. Hypermethylation at tumor suppressor gene loci leads to increased tumorigenesis due to tumor suppressor gene silencing, whereas global hypomethylation of CpG islands (CGIs) is followed by genomic instability and aberrant activation of multiple oncogenes. Therefore, characterization of the genes which silenced or activated epigenetically in human tumor cells can improve our understanding of cancer biology. Different genome-wide methodologies are applied to evaluate methylation status. Various commonly conducted techniques for this evaluation are reviewed in this paper. We provided comparative description of the procedures, advantages, and drawbacks of genome-wide DNA methylation analysis methods and biological applications, to give information on selecting the appropriate method for different methylation studies. PMID- 28888055 TI - Evaluation of loading parameters for murine axial tibial loading: Stimulating cortical bone formation while reducing loading duration. AB - Classic studies in bone mechanobiology have established the importance of loading parameters on the anabolic response. Most of these early studies were done using loading methods not currently in favor, and using non-murine species. Our objective was to re-examine the effects of several loading parameters on the response of cortical bone using the contemporary murine axial tibial compression model. We subjected tibias of 5-month old, female C57Bl/6 mice to cyclic (4 Hz) mechanical loading and examined bone formation responses using dynamic and static histomorphometry. First, using a reference protocol of 1,200 cycles/day, 5 days/week for 2 weeks, we confirmed the significant influence of peak strain magnitude on periosteal mineralizing surface (Ps.MS/BS) and bone formation rate (Ps.BFR/BS) (p < 0.05, ANOVA). There was a significant induction of periosteal lamellar bone at a lower threshold of approx. -1,000 MUepsilon and a transition from lamellar-woven bone near -2,000 MUepsilon. In contrast, on the endocortical surface, bone formation indices did not exhibit a load magnitude-dependent response and no incidence of woven bone. Next, we found that reducing daily cycle number from 1,200 to 300 to 60 did not diminish the bone formation response (p > 0.05). On the other hand, reducing the daily frequency of loading from 5 consecutive days/week to 3 alternate days/week significantly diminished the periosteal response, from a loading-induced increase in Ps.MS/BS of 38% (loaded vs. control) for 5 days/week to only 15% for 3 days/week (p < 0.05). Finally, we determined that reducing the study duration from 2 to 1 weeks of loading did not affect bone formation outcomes. In conclusion, cyclic loading to -1,800 MUepsilon peak strain, at 4 Hz and 60 cycles/day for 5 consecutive days (1 week) induces an increase in periosteal lamellar bone formation with minimal incidence of woven bone in 5-month-old C57Bl/6 female mice. Our results provide a basis for reduction of loading duration (daily cycles and study length) without loss of anabolic effect as measured by dynamic histomorphometry. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:682-691, 2018. PMID- 28888057 TI - Glucocorticoid treatment earlier in childhood and adolescence show dose-response associations with diurnal cortisol levels. AB - Heightened levels of glucocorticoids in children and adolescents have previously been linked to prolonged changes in the diurnal regulation of the stress-hormone cortisol, a glucocorticoid regulated by the hypothalamic-pituitary-adrenal-axis (HPA-axis). To address this question, we examined the salivary cortisol awakening response (CAR) and daily cortisol output in 36 children and adolescents (25 girls/11 boys) aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder and 36 healthy controls. Patients and controls did not significantly differ in the CAR or diurnal cortisol output; however, sex-dependent group differences were observed. Specifically, female patients had a higher CAR relative to female controls, while male patients had higher daily cortisol levels compared to male controls. Notably, CAR in female patients and daily cortisol levels in male patients showed a positive linear relationship with the mean daily glucocorticoid doses administered during treatment. The observed dose-response associations suggest that glucocorticoid therapy during childhood and adolescence might trigger long-term changes in HPA axis regulation, which may differ for males and females. PMID- 28888058 TI - Increased Expression of Programmed Cell Death-1 in Regulatory T Cells of Patients with Severe Sepsis and Septic Shock: An Observational Clinical Study. AB - While regulatory T cells (Tregs) constitutively express programmed cell death-1 (PD-1), the role of PD-1 expression in Tregs of patients with sepsis remains unclear. Thus, we determined PD-1 expression in Tregs from the peripheral blood of patients with severe sepsis and septic shock. Seventy-eight patients with severe sepsis and 40 with septic shock, as well as 21 healthy subjects, were enrolled in this study. The percentage of peripheral blood PD-1+ Tregs, as well as absolute Treg counts, were compared between these three groups. PD-1 expression in Tregs and absolute Treg counts were also compared between survivors and non-survivors in patients with sepsis. PD-1 expression in Tregs increased in patients with sepsis compared to healthy controls. Conversely, absolute Treg counts were significantly decreased in patients with sepsis compared to healthy controls; patients with septic shock had the lowest absolute Treg counts. Among patients with sepsis, survivors had lower levels of PD-1 expression in Tregs, as well as higher absolute Treg counts, than non-survivors. Additionally, the percentage of PD-1+ Tregs correlated positively with lactate levels as well as the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in patients with sepsis. PD-1 was upregulated in Tregs of patients with sepsis and may indicate a state of immune dysfunction. Overexpression of PD-1 in Tregs was associated with more severe sepsis as well as poor outcomes. PMID- 28888059 TI - Levetiracetam-induced rhabdomyolysis: Analysis of reports from the Food and Drug Administration's Adverse Event Reporting System database. PMID- 28888060 TI - Unidirectional growth of heavy meromyosin clusters along actin filaments revealed by real-time fluorescence microscopy. AB - Heavy meromyosin (HMM) forms clusters along actin filaments under low ATP concentrations. Here, we observed the growth of HMM clusters under low concentrations of ATP in real time using fluorescence microscopy. When actin filaments were loosely immobilized on positively charged lipid bilayers, clusters of HMM-GFP were readily formed. Time-lapse observation revealed that the clusters grew unidirectionally. When we used a mixture of actin filaments and copolymers of actin and acto-S1dC, a chimeric protein of actin and the myosin motor domain, HMM-GFP preferentially formed clusters along the copolymers. We thus suggest that binding of myosin motors carrying ADP and Pi induces unidirectional conformational changes in actin filaments and allosterically recruits more myosin binding. In contrast, when actin filaments and copolymers were anchored to glass substrate via stable biotin-avidin linkage, higher concentrations of HMM-GFP were required to form clusters than on the lipid bilayer. Moreover, actin filaments and copolymers were not discriminated regarding preferential cluster formation. This is presumably because the myosin-induced cooperative conformational changes in actin filaments involve changes in the helical twist. Consistent with this, cofilin clusters, which supertwist the helix, were readily formed along loosely immobilized actin filaments, but not along those anchored via biotin-avidin linkage. PMID- 28888061 TI - Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis. AB - To synthesize evidence from available randomized controlled trials (RCT) to compare the efficacies of dopaminergic drugs (pramipexole, ropinirole and rotigotine) and alpha-2-delta ligands (gabapentin enacarbil and pregabalin) for the treatment of restless legs syndrome (RLS). We searched PubMed for all eligible RCTs. Network meta-analysis using frequentist methodology with random effect models was performed for mean changes in scores on the International RLS Study Group Rating Scale (IRLS) and for responder rates on Clinical Global Impressions-Improvement (CGI-I); analyzed as odds ratio (OR). Network meta analysis of mean changes in IRLS data from 35 studies with 7333 participants showed that all treatments, in specific gabapentin enacarbil, followed by pregabalin and rotigotine were superior to placebo [mean reduction in IRLS scores: -5.31 (-6.74 to -3.87), -5.20 (-6.91 to -3.49), 5.17 (3.73-6.61), respectively] but there were no significant differences between active treatments. Network meta-analysis of 5137 participants from 24 studies showed that gabapentin enacarbil and rotigotine were associated with the highest CGI-I response rates [ORs: 5.68; (95% CI, 4.14-7.21); and 4.68 (2.87-6.49), compared to placebo, respectively]. No significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropinirole. Based on IRLS scores and CGI-I response rates, while gabapentin enacarbil, pregabalin and rotigotine stand out as the most efficacious of all examined drugs, it is noteworthy that no significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropiniriole (for CGI-I response rates). PMID- 28888062 TI - Epigenetic regulation - contribution to herbicide resistance in weeds? AB - Continuous use of herbicides has resulted in the evolution of resistance to all major herbicide modes of action worldwide. Besides the well-documented cases of newly acquired resistance through genetic changes, epigenetic regulation may also contribute to herbicide resistance in weeds. Epigenetics involves processes that modify the expression of specific genetic elements without changes in the DNA sequence, and play an important role in re-programming gene expression. Epigenetic modifications can be induced spontaneously, genetically or environmentally. Stress-induced epigenetic changes are normally reverted soon after stress exposure, although in specific cases they can also be carried over multiple generations, thereby having a selective benefit. Here, we provide an overview of the basis of epigenetic regulation in plants and discuss the possible effect of epigenetic changes on herbicide resistance. The understanding of these epigenetic changes would add a new perspective to our knowledge of environmental and management stresses and their effects on the evolution of herbicide resistance in weeds. (c) 2017 Society of Chemical Industry. PMID- 28888063 TI - SUMO co-expression modifies KV 11.1 channel activity. AB - AIM: The voltage-gated potassium channel KV 11.1 is the molecular basis for the IKr current, which plays an important role in cardiac physiology. Its malfunction is associated with both inherited and acquired cardiac arrhythmias. Native currents differ from those in experimental models, suggesting additional regulatory mechanisms. We hypothesized that the post-translational modification sumoylation fine-tunes channel activity. METHODS: The functional effects of sumoylation on KV 11.1 were addressed by employing two-electrode voltage-clamp (TEVC) experiments in Xenopus laevis oocytes. Site-directed mutagenesis enabled a further analysis of the SUMO-target amino acids. We assessed protein expression levels and used confocal imaging for localization studies. RESULTS: Co-expression with Ubc9 and SUMO alters the electrophysiological properties of KV 11.1 leading to a decrease in steady-state current amplitude largely due to faster inactivation and alteration of deactivation kinetics. We identified three lysines (K21, K93 and K116) in the PAS domain as the putative SUMO-targets. CONCLUSION: This study indicates KV 11.1 as a sumoylation target and offers three main targets: K21, K93, and K116. Furthermore, it proposes an underlying mechanism for the observed kinetic impact of the PAS domain. PMID- 28888064 TI - The cytopathology of Actinomyces, Nocardia, and their mimickers. AB - Nocardia species and Actinomyces species are 2 of the most commonly diagnosed filamentous bacteria in routine cytopathology practice. These genera share many overlapping cytomorphologic features, including their thin, beaded, branching, Gram-positive, GMS-positive filamentous structures that fragment at their peripheries into bacillary- and coccoid-appearing forms. Features that help distinguish between these 2 microorganisms include the width of their filamentous structures, the angles at which they branch, and their ability or lack thereof to retain a modified acid-fast stain. In addition to cytomorphologic overlap, overlap in clinical presentation is frequent with pulmonary and mucocutaneous presentations seen in both. Differentiating between Nocardia and Actinomyces is essential because patients with these infections require different approaches to medical management. Both antibiotic susceptibilities and the need for early surgical intervention as part of the treatment plan vary greatly among these 2 groups. This review focuses on the clinical presentation, cytomorphology and staining characteristics that can be useful in identifying and distinguishing between Nocardia and Actinomyces infections, as well as their mimickers. PMID- 28888065 TI - Synthesizing value-added products from methane by a new Methylomonas. AB - AIMS: Methane and methanol are potential carbon sources of industrial micro organisms in addition to crop-derived bio-carbon sources. Methanotrophs that can utilize these simple, stable and large amounts chemicals are expected to be developed into 'cell factories' for the production of specific chemicals. In this study, a methanotroph that can synthesize lycopene, C30 carotenoid and exopolysaccharides (EPS) with relative better performances from C1 substrates was isolated, and its performances were evaluated. METHODS AND RESULTS: The isolated strain was identified as Methylomonas sp. ZR1 based on 16S rRNA sequence analysis. Its maximum specific growth rate achieved 0.200 h-1 under flask culture conditions, and 0.386 h-1 in bubble column reactors. ZR1 was able to utilize 35 g l-1 of methanol and even exhibited slight growth in the presence of 40 g l-1 of methanol. Furthermore, ZR1 was proved to synthesize lycopene (C40 carotenoids) besides the C30 carotenoids through HPLC-DAD and HPLC-MS/MS analysis methods. Its carotenoid extracts exhibited excellent antioxidative activities measured by the ABTS+ method. Plenty of polysaccharides were also synthesized by ZR1, the components of the polysaccharides were identified as glucose, mannose and galactose with a proportion of 1 : 2 : 1 by GC-MS, and its yield achieved 0.13 g g-1 cell dry weight. CONCLUSIONS: The isolated strain has great potential for the production of value-added bioproducts from C1 compounds because of its excellent C1 substrate utilizing abilities and its abilities to naturally synthesize lycopene, C30 carotenoids and EPS. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, we isolated a fast-growing methanotroph, its C1 carbon substrate utilizing ability is excellent in comparison with reported methanotrophs. Furthermore, besides polysaccharides and C30 carotenoids which were commonly synthesized by methanotrophs, our findings suggested that C40 lycopene could also be naturally synthesized from methane by methanotrophs. PMID- 28888066 TI - The interactions between gut microbiota and entomopathogenic fungi: a potential approach for biological control of Blattella germanica (L.). AB - BACKGROUND: Metarhizium anisopliae and Beauveria bassiana mainly infect insects through the cuticle; gut infection occasionally occurs. Micro-organisms existing in the gut may play a crucial role in the evolution and ecology of host defenses against fungal pathogens. To evaluate whether the gut bacteria participate in antifungal activity, and to determine their role in host protection, the interactions between gut bacteria and M. anisopliae and the diversity of gut microbiota in cockroaches were studied. RESULTS: An oral feeding test showed that the mortality of conventional cockroaches was significantly lower than that of germ-free cockroaches; both gut homogenates and aqueous fecal extracts showed antifungal activity, but the samples from germ-free cockroaches did not. Twenty two bacterial strains with antifungal activity and siderophore-producing ability were isolated from the gut and feces of cockroaches. Using high-throughput sequencing techniques, a total of 23 different phyla and 212 genera were detected. The composition of the microbiota of the hindgut was vastly different from those of the foregut and midgut; higher diversity and abundance of Bacteroides and Pseudomonas were found in the hindgut. CONCLUSION: The gut microbiota of German cockroaches may play a critical role in protecting cockroaches from fungal invasion and colonization. Removing certain bacteria from the B. germanica microbiota may facilitate microbial control using fungal pathogens. (c) 2017 Society of Chemical Industry. PMID- 28888067 TI - Injectable thermosensitive alginate/beta-tricalcium phosphate/aspirin hydrogels for bone augmentation. AB - In this study, an injectable and thermo-sensitive alginate/beta-tricalcium phosphate hydrogel (TSAH/beta-TCP) was prepared for aspirin release to a bone defect. Aspirin was dissolved into a mixture of poly(N-isopropylacrylamide) (PNIPAAm), an aminated alginate-g-PNIPAAm co-polymer, and beta-TCP powders. Scanning electron microscopy showed that TSAH/beta-TCP had an interconnected porous microstructure with a porosity of 86.78%. The cross-linked hydrogel released approximately 40% of the aspirin in the first 3 days and then slowly released the remainder. At a low concentration (<=100 MUg/mL), aspirin did not promote cell proliferation, but enhanced the alkaline phosphatase activity, and osteocalcin (OCN) and collagen I expression of human bone marrow-derived mesenchymal stem cells. The TSAH/beta-TCP/aspirin hydrogel was injected into the periosteum of the rat cranial bone, and its in vivo bone-forming ability was evaluated at 12 weeks. A bone morphogenetic protein 2 (BMP-2)-loaded TSAH/beta TCP hydrogel was injected as a control. Micro-computed tomography showed that the percentage of mineralized tissue in the TSAH/beta-TCP/BMP-2 and TSAH/beta TCP/aspirin groups were similar and significantly higher than that in the TSAH/beta-TCP group. Immunohistochemical staining showed considerable expression of OCN, especially in the TSAH/beta-TCP/BMP-2 and TSAH/beta-TCP/aspirin groups. These results suggest that the injectable TSAH/beta-TCP/aspirin hydrogel has great potential for bone regeneration. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1739-1751, 2018. PMID- 28888068 TI - Thymic enteric type adenocarcinoma: A case report with cytological features. AB - Primary thymic adenocarcinoma is an extremely rare tumor, and thymic enteric type adenocarcinoma has recently been proposed as a distinct pathological entity. Herein, we report the first cytological description of thymic enteric type adenocarcinoma. A 29-year-old Japanese female without a significant past medical history was found to have an abnormal chest shadow. Chest computed tomography demonstrated a well-circumscribed tumor in the anterior mediastinum, and thymectomy was performed. The Papanicolaou staining of the touch smear of the resected tumor demonstrated tightly cohesive epithelial cell clusters in a necrotic background. These cells were cuboidal to columnar in shape and had large round to oval nuclei with conspicuous nucleoli. Some of these neoplastic cells had intracytoplasmic mucin. Immunocytochemically, the neoplastic cells were positive for cytokeratin 20 and CDX-2. Histopathological study revealed tubular and papillotubular neoplastic growth composed of cuboidal to columnar neoplastic cells that contained large round to oval nuclei. Some of the neoplastic cells had intracytoplasmic mucin. Immunohistochemical study confirmed the expression of cytokeratin 20 and CDX-2. The final diagnosis of thymic enteric type adenocarcinoma was made. The cytological and immunocytochemical features of this case led to a diagnosis of enteric type adenocarcinoma. However, these features alone cannot be differentiated from a metastatic adenocarcinoma arising from the gastrointestinal tract. Cytological examination of a fine-needle aspiration of the mediastinal tumor has been reported to be useful in making a diagnosis. Therefore, an awareness of this new pathological entity is important for differentiating a thymic tumor from a metastatic carcinoma in the thymus. PMID- 28888069 TI - A novel missense mutation in AIFM1 results in axonal polyneuropathy and misassembly of OXPHOS complexes. AB - BACKGROUND AND PURPOSE: Apoptosis-inducing factor mitochondrion-associated-1 (AIFM1) in mitochondria has captured a great deal of attention due to its well described function in apoptosis. Mutations in AIFM1 have resulted in multiple clinical phenotypes, including X-linked Charcot-Marie-Tooth disease type 4. These syndromes usually involve multiple locations within the nervous system and/or multiple organs. This study describes a novel missense mutation in AIFM1 and its associated peripheral nerve disease. METHODS: Patients with AIFM1 mutation were characterized clinically, electrophysiologically, genetically and by magnetic resonance imaging. The fibroblasts were isolated from the patients to study mitochondrial OXPHOS complexes. RESULTS: We identified a family with a novel missense mutation (Phe210Leu) in AIFM1 who developed an isolated late-onset axonal polyneuropathy in which the central nervous system and other organs were spared. Interestingly, this Phe210Leu mutation resulted in abnormal assembly of mitochondrial complex I and III, and failed to disrupt AIFM1 binding with mitochondrial intermembrane space import and assembly protein 40 (MIA40) in the patients' cells. Deficiency of either AIFM1 or MIA40 is known to impair the assembly of mitochondrial complex I and IV. However, levels of both AIFM1 and MIA40 were unchanged. CONCLUSIONS: Phe210Leu mutation in AIFM1 induces an axonal polyneuropathy that might be contributed by the misassembly of mitochondrial complex I and III. This misassembly appears to be independent of the traditional mechanism via AIFM1/MIA40 deficiency. PMID- 28888070 TI - Using Virtual Reality Simulation Environments to Assess Competence for Emergency Medicine Learners. AB - Immersive learning environments that use virtual simulation (VS) technology are increasingly relevant as medical learners train in an environment of restricted clinical training hours and a heightened focus on patient safety. We conducted a consensus process with a breakout group of the 2017 Academic Emergency Medicine Consensus Conference "Catalyzing System Change Through Health Care Simulation: Systems, Competency, and Outcomes." This group examined the current uses of VS in training and assessment, including limitations and challenges in implementing VS into medical education curricula. We discuss the role of virtual environments in formative and summative assessment. Finally, we offer recommended areas of focus for future research examining VS technology for assessment, including high-stakes assessment in medical education. Specifically, we discuss needs for determination of areas of focus for VS training and assessment, development and exploration of virtual platforms, automated feedback within such platforms, and evaluation of effectiveness and validity of VS education. PMID- 28888071 TI - The effect of ventricular assist device-associated biomaterials on human blood leukocytes. AB - Ventricular assist devices (VADs) are an effective bridging or destination therapy for patients with advanced stage heart failure. These devices remain susceptible to adverse events including infection, bleeding, and thrombus; events linked to the foreign body response. Therefore, the biocompatibility of all biomaterials used is crucial to the success of medical devices. Biomaterials common in VADs-DLC: diamond-like carbon coated stainless steel; Sap: single crystal sapphire; SiN: silicon nitride; Ti: titanium alloy; and ZTA: zirconia toughened alumina-were tested for their biocompatibility through incubation with whole human blood for 2 h with mild agitation. Blood was then removed and used for: complete cell counts; leukocyte activation and death, and the production of key inflammatory cytokines. All were compared to time 0 and an un-exposed 2 h sample. Monocyte numbers were lower after exposure to DLC, SiN, and ZTA and monocytes showed evidence of activation with DLC, Sap, and SiN. Neutrophils and lymphocytes were unaffected. This approach allows comprehensive analysis of the potential blood damaging effects of biomaterials. Monocyte activation by DLC, Sap, ZTA, and SiN warrants further investigation linking effects on this cell type to unfavorable inflammatory/thrombogenic responses to VADs and other blood handling devices. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1730-1738, 2018. PMID- 28888072 TI - Characterization of isolated amyloid myopathy. AB - BACKGROUND AND PURPOSE: Amyloid myopathy frequently occurs in the setting of systemic amyloidosis and less commonly in isolation (isolated amyloid myopathy). Anoctaminopathy-5 and dysferlinopathy were recently recognized as causes of isolated amyloid myopathy. The present study aimed to characterize the isolated amyloid myopathy and to compare it with amyloid myopathy associated with systemic amyloidosis. METHODS: We searched the Muscle Laboratory database to identify patients with pathologically confirmed amyloid myopathy seen in neurology clinics between January 1998 and September 2016. Patients with monoclonal gammopathy, peripheral neuropathy, organomegaly or symptoms or pathologic evidence of amyloid deposition outside skeletal muscle were classified as having systemic amyloidosis associated myopathy. RESULTS: Fifty-two patients were identified, including 14 with isolated amyloid myopathy (eight anoctaminopathy-5, two dysferlinopathy and four genetically unknown) and 38 with systemic amyloidosis (32 immunoglobulin light-chain amyloidosis, four familial amyloid polyneuropathy and two senile systemic amyloidosis). Compared with patients with systemic amyloidosis, patients with isolated amyloid myopathy had a younger age of onset (median, 41.5 vs. 65 years), no dysphagia (0% vs. 26%) or weight loss (0% vs. 26%), but more frequent calf atrophy (57% vs. 0%), small collections of inflammatory cells on muscle biopsy (43% vs. 0%) and asymptomatic hyperCKemia at onset (21% vs. 0%). All patients with isolated amyloid myopathy had creatine kinase (CK) values >2.5 times the upper limit of normal. CONCLUSIONS: Isolated amyloid myopathy accounts for 27% of patients with amyloid myopathy, mostly due to anoctaminopathy-5. There are various clinical and laboratory parameters that can help to differentiate isolated amyloid myopathy from systemic amyloidosis. PMID- 28888074 TI - Early recovery of circulating immature B cells in B-lymphoblastic leukemia patients after CD19 targeted CAR T cell therapy: A pitfall for minimal residual disease detection. AB - BACKGROUND: CD19-targeted chimeric-antigen receptor-modified T-cells (CAR-T) are promising in the treatment of refractory B-lymphoblastic leukemia (B-ALL). Minimal residual disease (MRD) detection by multicolor flow cytometry (FCM) is critical to distinguish B-ALL MRD from regenerating, non-neoplastic B-cell populations. METHODS: FCM was performed on samples from 9 patients with B-ALL treated with CAR-T. RESULTS: All 9 patients showed response to CAR-T. Additionally, FCM revealed circulating CD10 + B cells, potentially mimicking MRD. Circulating CD10+ B-cells were detected in blood from 3 days to 3 months after CAR-T, comprising 73% (median) of B-cells (52-83%, 95%CI). They expressed CD19, CD10, CD20, bright CD9, CD22, CD24, moderate CD38 and dim CD58, but were CD34 ( ), with bright CD45 and polyclonal surface light chain immunoglobulin (sIg) expression. A similar CD10 + B-cell subpopulation was detected by marrow FCM, amidst abundant B-cell precursors. CONCLUSIONS: These circulating CD10 + B-cells are compatible with immature B-cells, and are a reflection of B-cell recovery within the marrow. They are immunophenotypically distinguishable from residual B ALL. Expression of light chain sIg and key surface antigens characterizing regenerating B-cell precursors can distinguish immature B-cells from B-ALL MRD and prevent misdiagnosis. (c) 2017 International Clinical Cytometry Society. PMID- 28888073 TI - Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease. AB - Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and neurotrophin receptor gene expression within microdissected CA1 neurons along with regional hippocampal dissections from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD using laser capture microdissection (LCM), custom-designed microarray analysis, and qPCR of CA1 subregional dissections. Gene expression levels were correlated with cognitive test scores and AD neuropathology criteria. We found a significant downregulation of several neurotrophin genes (e.g., Gdnf, Ngfb, and Ntf4) in CA1 pyramidal neurons in MCI compared to NCI and AD subjects. In addition, the neurotrophin receptor transcripts TrkB and TrkC were decreased in MCI and AD compared to NCI. Regional hippocampal dissections also revealed select neurotrophic gene dysfunction providing evidence for vulnerability within the hippocampus proper during the progression of dementia. Downregulation of several neurotrophins of the NGF family and cognate neurotrophin receptor (TrkA, TrkB, and TrkC) genes correlated with antemortem cognitive measures including the Mini-Mental State Exam (MMSE), a composite global cognitive score (GCS), and Episodic, Semantic, and Working Memory, Perceptual Speed, and Visuospatial domains. Significant correlations were found between select neurotrophic expression downregulation and neuritic plaques (NPs) and neurofibrillary tangles (NFTs), but not diffuse plaques (DPs). These data suggest that dysfunction of neurotrophin signaling complexes have profound negative sequelae within vulnerable hippocampal cell types, which play a role in mnemonic and executive dysfunction during the progression of AD. PMID- 28888075 TI - Intravenous thrombolysis for patients with in-hospital stroke onset: propensity matched analysis from the Safe Implementation of Treatments in Stroke-East registry. AB - BACKGROUND AND PURPOSE: Recent cross-sectional study data suggest that intravenous thrombolysis (IVT) in patients with in-hospital stroke (IHS) onset is associated with unfavorable functional outcomes at hospital discharge and in hospital mortality compared to patients with out-of-hospital stroke (OHS) onset treated with IVT. We sought to compare outcomes between IVT-treated patients with IHS and OHS by analysing propensity-score-matched data from the Safe Implementation of Treatments in Stroke-East registry. METHODS: We compared the following outcomes for all propensity-score-matched patients: (i) symptomatic intracranial hemorrhage defined with the safe implementation of thrombolysis in stroke-monitoring study criteria, (ii) favorable functional outcome defined as a modified Rankin Scale (mRS) score of 0-1 at 3 months, (iii) functional independence defined as an mRS score of 0-2 at 3 months and (iv) 3-month mortality. RESULTS: Out of a total of 19 077 IVT-treated patients with acute ischaemic stroke, 196 patients with IHS were matched to 5124 patients with OHS, with no differences in all baseline characteristics (P > 0.1). Patients with IHS had longer door-to-needle [90 (interquartile range, IQR, 60-140) vs. 65 (IQR, 47 95) min, P < 0.001] and door-to-imaging [40 (IQR, 20-90) vs. 24 (IQR, 15-35) min, P < 0.001] times compared with patients with OHS. No differences were detected in the rates of symptomatic intracranial hemorrhage (1.6% vs. 1.9%, P = 0.756), favorable functional outcome (46.4% vs. 42.3%, P = 0.257), functional independence (60.7% vs. 60.0%, P = 0.447) and mortality (14.3% vs. 15.1%, P = 0.764). The distribution of 3-month mRS scores was similar in the two groups (P = 0.273). CONCLUSIONS: Our findings underline the safety and efficacy of IVT for IHS. They also underscore the potential of reducing in-hospital delays for timely tissue plasminogen activator delivery in patients with IHS. PMID- 28888076 TI - A Contribution to the Morphology and Phylogeny of Chlamydodon, with Three New Species from China (Ciliophora, Cyrtophoria). AB - Three new cyrtophorian ciliates isolated from coastal areas of China were described based on morphological and genetic data. The Chlamydodon mnemosyne-like species Chlamydodon similis sp. n. differs from its congeners mainly by its number of somatic kineties. Chlamydodon oligochaetus sp. n. is distinguished from its congeners mainly by having fewer somatic kineties, and/or an elongated body shape. Chlamydodon crassidens sp. n. is characterized mainly by an inverted triangular body shape, a posteriorly interrupted cross-striated band (5-6 MUm wide), and a large cytostome. Moreover, we provided small-subunit (SSU) rDNA sequences of C. similis sp. n. and C. oligochaetus sp. n. Maximum likelihood (ML) and Bayesian inference (BI) consistently placed C. similis sp. n. as a sister to C. paramnemosyne, but showed different branching position of C. oligochaetus sp. n., which may be due to a low taxon sampling in the Chlamydodontidae and/or an insufficient resolution of the marker gene at species level. PMID- 28888077 TI - MicroRNA-214-3p: A link between autophagy and endothelial cell dysfunction in atherosclerosis. AB - AIM: Endothelial cell injury assumes a fundamental part in the pathogenesis of atherosclerosis, and endothelial cell autophagy has protective effects on the development of atherosclerosis, although the underlying molecular regulation mechanism is indistinct. This study aimed to investigate whether microRNA-214-3p (miR-214-3p) is involved in the endothelial cell autophagy regulation of atherosclerosis. METHODS: We utilized ApoE-/- mice provided with a high-fat diet (HFD) as atherosclerosis model. We analysed the level of miR-214-3p and the levels of autophagy-related protein 5 (ATG5) and autophagy-related protein 12 (ATG12) in the purified CD31+ endothelial cells from mouse aorta. Bioinformatics analysis and a dual-luciferase reporter assay were performed to confirm the binding target of miR-214-3p. In vitro study, human umbilical vein endothelial cells (HUVECs) were transfected with miR-214-3p mimics/inhibitor and stimulated with 100 MUg/mL oxidized low-density lipoprotein (ox-LDL) for 12 hours to initiate a stress-repairing autophagic process. RESULTS: In mouse models, we identified an inverse correlation between miR-214-3p, ATG5 and ATG12. We observed that in young HUVECs, ox-LDL-initiated autophagy was repressed by miR-214-3p overexpression, as evaluated by autophagic protein analysis, microtubule associated protein 1 light chain 3B-II (LC3B-II) immunofluorescence assay and transmission electron microscopy (TEM). Also, miR-214-3p promoted ox-LDL accumulation in HUVECs and THP-1 monocyte adhesion. Conversely, in old HUVECs, suppression of miR-214-3p preserved the ability to initiate a protective autophagy reaction to the ox-LDL stimulation. CONCLUSION: miR-214-3p regulates ox LDL-initiated autophagy in HUVECs by directly targeting the 3'UTR of ATG5 and may have a suitable role in the pathogenesis of atherosclerosis. PMID- 28888078 TI - Healing of soft tissue lacerations in diabetic-induced rats. AB - BACKGROUND/AIM: Prevalence and incidence of diabetes are increasing and many dental trauma patients today have diabetes. The implications of delayed wound healing, associated with diabetes mellitus, on oral mucosal wound healing have not been investigated extensively. The aim of this study was to investigate the implications of diabetes mellitus on the cellular, vascular, and fibroblastic changes induced by laceration on the oral mucosa of Wistar rats. MATERIALS AND METHODS: Sixteen female Wistar rats were randomly assigned into two groups: 1. Experimental Streptozotocin-induced diabetic group (8 rats). 2. Control group (8 rats). A standardized laceration injury was induced from the corner of the mouth to the mid-check penetrating through dermal and oral mucosal contaminated by saliva. Samples were taken from the rats after sacrificing them on days 1,3,7, and 10. Inflammation was evaluated both qualitatively and quantitatively. Two investigators evaluated samples in a blinded manner. RESULTS: Histology reports indicated delayed wound healing patterns in diabetic rats through days 1, 3, 7, and 10 when compared to controls. Inflammation was also noted to be consistently present more often in diabetic rats. Furthermore, polymorphonuclear cell count was consistently higher in diabetic rats. CONCLUSION: The results suggest that oral mucosa wound healing is delayed in diabetic Wistar rats compared to non diabetic rats in terms of wound closure, angiogenesis, and polymorphonuclear cells number. Furthermore, it is also suggested that wound healing is impaired both in the early and late stages of soft tissue wound healing. PMID- 28888079 TI - Bioabsorbable nerve conduits coated with induced pluripotent stem cell-derived neurospheres enhance axonal regeneration in sciatic nerve defects in aged mice. AB - Aging influences peripheral nerve regeneration. Nevertheless, most basic research of bioabsorbable nerve conduits including commercial products have been performed in very young animals. Results from these studies may not provide information about axonal regeneration in aged tissue, because young nerve tissue holds sufficient endogenous potential for axonal regeneration. The clinical target age for nerve conduit application is most likely going to increase with a rapidly growing elderly population. In the present study, we examined axonal regeneration after sciatic nerve defects in aged and young mice. 5-mm sciatic nerve defects in young (6 weeks old) and aged (92 weeks old) mice were reconstructed using nerve conduits (composed of a poly lactide and caprolactone) or autografts. In addition, in aged mice, sciatic nerve defects were reconstructed using nerve conduits coated with mouse induced pluripotent stem cell (iPSc)-derived neurospheres. Using electrophysiological and histological techniques, we demonstrated axonal regeneration was significantly less effective in aged than in young mice both for nerve conduits and for nerve autografts. However, despite the low regenerative capacity of the peripheral nerve in aged mice, axonal regeneration significantly increased when nerve conduits coated with iPSc-derived neurospheres, rather than nerve conduits alone, were used. The present study shows that aging negatively affects peripheral nerve regeneration based on nerve conduits in mice. However, axonal regeneration using nerve conduits was improved when supportive iPSc-derived neurospheres were added in the aged mice. We propose that tissue-engineered bioabsorbable nerve conduits in combination with iPSc derived neurospheres hold therapeutic potential both in young and elderly patients. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1752-1758, 2018. PMID- 28888081 TI - Study of the sleep quality and psychological state of patients with hepatitis B liver cirrhosis. AB - AIM: We aimed to investigate sleep quality, mild hepatic encephalopathy, anxiety, and depression in patients with hepatitis B cirrhosis by using a variety of scales and questionnaires. METHOD: A cohort of 341 patients with hepatitis B liver cirrhosis were categorized by Child-Pugh grading (A, B, and C) in this cross-sectional study. Pittsburgh Sleep Quality Index (PSQI), Number Connection Test-A (NCT-A), and Hospital Anxiety and Depression (HAD) evaluated the questionnaires and statistically analyzed the intrinsic correlation. The control group included 50 healthy individuals. Of 341 patients, 213 had a PSQI index >5 points. RESULTS: The PSQI, NCT-A, anxiety scale (HAD [a]), and depression scale (HAD [d]) of the patients were significantly different. The NCT-A-positive patients revealed 214 cases of possible minimal hepatic encephalopathy (MHE) during a preliminary screening of patients. The PSQI score of NCT-A-positive patients was significantly elevated compared to NCT-A-negative patients (P < 0.001). HAD (a) and HAD (d) were significantly different between the NCT-A positive and NCT-A-negative groups (P = 0.002 and P = 0.006, respectively). Univariate Pearson's correlation analysis found that NCT-A and HAD (a) were positively correlated with PSQI (P < 0.001 and P = 0.045, respectively); however, Child-Pugh score and HAD (d) were not correlated with PSQI (P = 0.061 and P = 0.059, respectively). CONCLUSION: These results indicated that patients with hepatitis B liver cirrhosis have a disturbed sleep, which might be an MHE symptom, further causing considerable anxiety. Thus, the evaluation of sleep quality and psychological state of patients with hepatitis B liver cirrhosis necessitates further investigation to guide positive intervention. PMID- 28888080 TI - Tokyo Guidelines 2018: management strategies for gallbladder drainage in patients with acute cholecystitis (with videos). AB - Since the publication of the Tokyo Guidelines in 2007 and their revision in 2013, appropriate management for acute cholecystitis has been more clearly established. Since the last revision, several manuscripts, especially for alternative endoscopic techniques, have been reported; therefore, additional evaluation and refinement of the 2013 Guidelines is required. We describe a standard drainage method for surgically high-risk patients with acute cholecystitis and the latest developed endoscopic gallbladder drainage techniques described in the updated Tokyo Guidelines 2018 (TG18). Our study confirmed that percutaneous transhepatic gallbladder drainage should be considered the first alternative to surgical intervention in surgically high-risk patients with acute cholecystitis. Also, endoscopic transpapillary gallbladder drainage or endoscopic ultrasound-guided gallbladder drainage can be considered in high-volume institutes by skilled endoscopists. In the endoscopic transpapillary approach, either endoscopic naso gallbladder drainage or gallbladder stenting can be considered for gallbladder drainage. We also introduce special techniques and the latest outcomes of endoscopic ultrasound-guided gallbladder drainage studies. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included. PMID- 28888082 TI - How can the Perioperative Surgical Home be applied to pediatric anesthesia practice? PMID- 28888083 TI - An antero-lateral approach to ultrasound-guided lumbar plexus block in supine position combined with quadratus lumborum block using single-needle insertion for pediatric hip surgery. PMID- 28888085 TI - Performance of different prostate specific antibodies in the cytological diagnosis of metastatic prostate adenocarcinoma. AB - BACKGROUND: Diagnosis of metastatic prostate adenocarcinoma (metPA) in cytology specimens can be challenging and frequently requires the use of immunohistochemistry (IHC). Prostate specific membrane antigen (PSMA) and NKX3.1 have emerged as promising IHC markers to determine prostatic origin of metPA in surgical specimens. Our goal is to evaluate the performance of PSMA and NKX3.1 and compare them with those of prostate-specific antigen (PSA) and prostate specific alkaline phosphatase (PSAP) in the cytological diagnosis of metPA MATERIALS: Cytology specimens from patients with a history of prostate adenocarcinoma at our institution between January 01, 2005 and December 31, 2015 were retrieved. IHC stains were performed on the cell blocks. In addition to the staining pattern and intensity, the sensitivity, and specificity of PSMA and NKX3.1 were assessed and compared to those of PSA and PSAP markers. RESULTS: A total of 56 cytology cases were retrieved with the following diagnoses: 13 metPA, 37 metastatic carcinomas from other origins, 4 rare atypical cells, and 2 benign. Additional 9 cases were re-classified as metPA based on positive PSMA and/or NKX3.1 immunostains. In our cohort of 22 cases of metPA, 18 were positive for PSMA (82%), 15 for NKX3.1 (68%), 9 for PSA (41%), and 9 for PSAP (41%). PSMA and NKX3.1 were negative in all 6 cases of metastatic carcinoma of nonprostate origin (specificity 100%). PSMA demonstrated strong membranous staining pattern, and NKX3.1 exhibited moderate nuclear staining pattern. CONCLUSION: Because of their higher sensitivity and specificity, PSMA and NKX3.1 are valuable surrogate markers for metPA in cytology specimens, when compared with PSA and PSAP markers. PMID- 28888086 TI - Stability of routine biochemical analytes in whole blood and plasma/serum: focus on potassium stability from lithium heparin. AB - BACKGROUND: Blood specimens are transported from clinical departments to the biochemistry laboratory by hospital courier service, sometimes over long distances. The aim of this study was to assess the stability of common biochemical analytes in venous blood under our routine transport conditions and to evaluate analyte stability after prompt or delayed centrifugation. METHODS: We investigated pre- and postanalytical contributions of 32 biochemical analytes in plasma and serum samples from 10 patients (healthy adults and patients from intensive care units). Differences in analyte concentrations between baseline (T0) and different time intervals (2, 4, 6, 8, 12 and 24 h) following storage after prompt and delayed centrifugation were reported. Evaluation was against the total change limit as described by Oddoze et al. (Oddoze C, Lombard E, Portugal H. Stability study of 81 analytes in human whole blood, in serum and in plasma. Clin Biochem 2012;45:464-9). RESULTS: The majority of analytes were stable with delayed separation up to 12 h, except for potassium, C-peptide, osteocalcin, parathyroid hormone (PTH), bicarbonate and LDH. After prompt centrifugation and storage at 4 degrees C, stability was greatly increased up to 48 h for most analytes. LDH and bicarbonate had the lowest stability after centrifugation; therefore, no reanalysis of these analytes in a centrifuged tube can be allowed. CONCLUSIONS: Knowledge of analyte stability is crucial to interpret biological analysis with confidence. However, centrifugation prior to transport is time consuming, and the transfer of plasma or serum from a primary tube to a secondary tube increases the risk of preanalytical errors. For analytes that are stable in whole blood for 24 h or more, it seems that there is no benefit to centrifuge before transport. PMID- 28888088 TI - Possible modulation of PPAR-gamma cascade against depression caused by neuropathic pain in rats. AB - BACKGROUND: Sciatic nerve ligation causes neuropathic pain with chronic constriction injury (CCI). However, there is no published report on the effect of pioglitazone as an antidepressant in the treatment of depression induced by neuropathic pain with CCI in rats. The aim of this study was to evaluate the effect of pioglitazone as an antidepressant by targeting oxidative stress by the peripheral neuropathic pain model using the CCI of the sciatic nerve. METHODS: Behavioral studies were carried out to measure thermal hyperalgesia and cold allodynia as markers of neuropathic pain and force swim test for depression. These were followed by estimation of biochemical parameters which include lipid peroxidation (LPO), reduced glutathione, catalase, nitrite and superoxide dismutase (SOD) in the rat brains as a measure of oxidative stress. We administered two intraperitoneal doses of pioglitazone (4.5 and 9.0 mg/kg, i.p.) to the treated group for 28 consecutive days from the day of injury and behavioral as well as biochemical evaluations were performed. RESULTS: The results suggested that the administration of pioglitazone significantly countered the neuropathic pain induced depression as interpreted through elevated pain threshold of tactile allodynia and thermal hyperalgesia followed by decreased immobility time in the 9.0 mg/kg dose group. CONCLUSIONS: It may be concluded that the oxidative stress plays a critical role in the pathogenesis of neuropathic pain and depression as evidenced by the behavioral studies and the changes in the levels of lipid peroxidase, nitrite, catalase, and glutathione and SOD. PMID- 28888087 TI - Modulation of transforming growth factor-beta/follistatin signaling and white adipose browning: therapeutic implications for obesity related disorders. AB - Obesity is a major risk factor for the development of diabetes, insulin resistance, dyslipidemia, cardiovascular disease and other related metabolic conditions. Obesity develops from perturbations in overall cellular bioenergetics when energy intake chronically exceeds total energy expenditure. Lifestyle interventions based on reducing total energy uptake and increasing activities including exercise have proved ineffective in the prevention and treatment of obesity because of poor adherence to such interventions for an extended period of time. Brown adipose tissue (BAT) has an extraordinary metabolic capacity to burn excess stored energy and holds great promise in combating obesity and related diseases. This unique ability to nullify the effects of extra energy intake of these specialized tissues has provided attractive perspectives for the therapeutic potential of BAT in humans. Browning of white adipose tissue by promoting the expression and activity of key mitochondrial uncoupling protein 1 (UCP1) represents an exciting new strategy to combat obesity via enhanced energy dissipation. Members of the transforming growth factor-beta (TGF-beta) superfamily including myostatin and follistatin have recently been demonstrated to play a key role in regulating white adipose browning both in in-vitro and in vivo animal models and thereby present attractive avenues for exploring the therapeutic potential for the treatment of obesity and related metabolic diseases. PMID- 28888089 TI - Antidiabetic potential of polyphenolic-rich fraction of Tamarindus indica seed coat in alloxan-induced diabetic rats. AB - BACKGROUND: Tamarindus is a monotypic genus and belongs to the subfamily Caesalpinioideae of the family Leguminosae (Fabaceae), Tamarindus indica L., commonly known as Tamarind tree is one of the most important multipurpose tropical fruit tree species in the India, Sudan, Nigeria, Bangladesh and entire subcontinent. METHODS: Hydroethanolic seed coat extract of Tamarindus indica (HETI) was assessed for presence of phytoconstituents and selection of optimum dose through acute and sub acute toxicity study. The single and multidose (14 days) study were conducted to evaluate antidiabetic potential of HETI in alloxan induced rats via determine of blood glucose level, body weight, hematological profile, extra-pancreatic glucose utilization of isolated rat hemi-diaphragm as well as histopathology of rat pancreas. RESULTS: Phytochemical analysis of HETI showed the presence of polyphenol like flavonoids. Single and multidose of HETI significantly (p<0.05; p<0.001) reduced blood glucose level in normoglycaemic, glucose loaded and alloxan induced hyperglycaemic animals. HETI exerts the protective effect on pancreatic beta-cells as per results obtained from histopathology of animals. Moreover, HETI increased glucose uptake in isolated rat hemi-diaphragm and prevents decrease in body weight along with recovery of altered hematological parameters. CONCLUSIONS: The study revealed that HETI have potent hypoglycaemic action by virtue of its phytoconstituents and it can be used as a herbal medicine for diabetes. PMID- 28888090 TI - Type 3 renal tubular acidosis associated with growth hormone deficiency. AB - BACKGROUND: We identified two boys with type 3 renal tubular acidosis (RTA) and growth hormone deficiency and we sought to differentiate them from children with classic type 1 distal RTA. METHODS: We reviewed all children <6 years of age with RTA referred over a 13-year period and compared the growth response to alkali therapy in these two boys and in 28 children with only type 1 distal RTA. RESULTS: All children with type 1 RTA reached the 5th percentile or higher on CDC growth charts within 2 years of alkali therapy. Their mean height standard deviation score (SDS) improved from -1.4 to -0.6 SDS and their mean mid-parental height (MPH) SDS improved from -0.6 to 0 SDS after 2 years. In contrast, the boys with growth hormone deficiency had a height SDS of -1.4 and -2.4 SDS after 2 years of alkali and the MPH SDS were both -2.6 SDS after 2 years of alkali therapy. Growth hormone therapy accelerated their growth to normal levels and led to long-term correction of RTA. CONCLUSIONS: A child with type 1 RTA whose height response after 2 years of alkali therapy is inadequate should undergo provocative growth hormone testing. PMID- 28888091 TI - Body weight misperception and health-related factors among Iranian children and adolescents: the CASPIAN-V study. AB - BACKGROUND: Along with increased prevalence of obesity, body weight misperception has also increased among adolescents. This study aims to evaluate the proportion of weight misperception among Iranian children and adolescents and its association with some health-related factors. METHODS: Data were collected from 14,440 Iranian students, aged 7-18 years, who participated in the national school based surveillance program (CASPIAN-V). The students' anthropometric indices and blood pressure were measured using standardized methods, and valid questionnaires were used to assess their weight perception, eating patterns, physical activity and sedentary behaviors. According to agreements between the real weight and self perceived weight status, participants were classified as underestimated, accurate and overestimated weight. RESULTS: The rates of underestimated, accurate and overestimated weight were 30.8%, 40.8% and 28.4%, respectively. In comparison with the accurate-weight group, both the underestimated- and overestimated-weight groups were less likely to have daily consumption of sugar-sweetened beverages (OR: 0.83, 95% CI: 0.74-0.93 and OR: 0.39, 95% CI: 0.34-0.44, respectively), sweets (OR: 0.81, 95% CI: 0.73-0.90 and OR: 0.68, 95% CI: 0.61-0.76, respectively) and salty snacks (OR: 0.78, 95% CI: 0.66-0.92 and OR: 0.30, 95% CI: 0.24-0.38, respectively). In the overestimated-weight group, the odds of daily intake of fast food decreased by 67% and the odds of low physical activity declined by 38% in comparison with the accurate-weight group. CONCLUSIONS: Weight misperception had a high prevalence among Iranian children and adolescents and is associated with their dietary patterns and physical activity behaviors. Suitable education programs need to be developed to correct the children and adolescents' insight about their weight status. PMID- 28888092 TI - Neurodevelopmental outcome at the age of 4 years according to the planned mode of delivery in term breech presentation: a nationwide, population-based record linkage study. AB - PURPOSE: To evaluate whether a trial of planned vaginal breech labor affects neurologic development in children. METHODS: This is a nationwide, Finnish, population-based record linkage study. An odds ratio with 95% confidence intervals was used to estimate the relative risk that a child delivered by planned vaginal breech labor would be diagnosed with adverse neurodevelopmental outcome (cerebral palsy, epilepsy, intellectual disability, sensor neural developmental outcome, hyperactivity, speech and language problems) at the age of 4 years. The reference group were children born by planned cesarean section. RESULTS: During a study period of 7 years, 8374 infants were delivered in breech position. Among them, 3907 (46.7%) had an attempted labor and 4467 (53.3%) infants were delivered by planned cesarean section. There were no differences in the neurodevelopmental outcome. In the planned vaginal labor group, 133 (3.4%) children had an abnormal neurodevelopmental outcome at the age of 4 years compared to 142 (3.2%) in the planned cesarean section group. CONCLUSION: The absolute risk of abnormal neurological outcome in breech deliveries at term was low, regardless of planned mode of birth. Planned vaginal breech labor did not increase the risk for abnormal neurological outcome compared to planned cesarean section. PMID- 28888093 TI - Models used in the study of traumatic brain injury. AB - Traumatic brain injury (TBI) is a contemporary health problem and a leading cause of mortality and morbidity worldwide. Survivors of TBI frequently experience disabling long-term changes in cognition, sensorimotor function, and personality. A crucial step in understanding TBI and providing better treatment has been the use of models to mimic the event under controlled conditions. Here, we describe the known head injury models, which can be classified as whole animal (in vivo), in vitro, and mathematical models. We will also review the ways in which these models have advanced the knowledge of TBI. PMID- 28888094 TI - Low-Dose Scanning Technology Combined with Low-Concentration Contrast Material in Renal Computed Tomography Angiography (CTA): A Preliminary Study. AB - BACKGROUND This study is to investigate the feasibility of low iodine concentration contrast material (CM) combined with low tube voltage and adaptive statistical iterative reconstruction (ASIR) in renal computed tomography angiography (CTA). MATERIAL AND METHODS A total of 136 patients were enrolled in this prospective trial, and randomly divided into two groups: group A (n=68) and group B (n=68). Group A received 120-kVp and iopromide (370 mg/mL) with filtered back projection (FBP) reconstruction, and group B received 100-kVp and iodixanol (270 mg/mL) with ASIR 40% (ASIR40). An equal iodine dose (300 mg/kg body weight) and the same iodine delivery rate (1,500 mg I/s) were given to all patients. Density, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured, and the image quality and visualization of renal arteries were scored. Dose-length product (DLP) and CT dose index volume (CTDIvol) were recorded, and effective doses (ED) were calculated. RESULTS There was no significant difference in image noise between groups A and B (p>0.05). The vessel attenuation, SNR, and CNR were significantly higher in group B than group A (all p<0.05). The subjective image quality and visualization of renal artery branches were similar in these two groups (p>0.05). Compared with group A, the CTDIvol, DLP, and ED in group B were decreased by 38.58%, 37.24%, and 37.24%, respectively (p=0.000). CONCLUSIONS Compared with 120-kVp with FBP reconstruction, the protocol of 100-kVp with ASIRP40 reconstruction provided high-quality renal CTA results, which allowed for reduced iodine concentration and decreased radiation dose. PMID- 28888096 TI - Exploration of thioxothiazolidinone-sulfonate conjugates as a new class of aldehyde/aldose reductase inhibitors: A synthetic and computational investigation. AB - In the present study, the pharmacophore integration methodology provided an efficient access to a new library of thioxothiazolidinone-sulfonate conjugates (8a-r) from easily available synthetic precursors. The approach was excellently high yielding with flexible structural sites for chemical modifications. The designed hybrid scaffolds were assessed for aldehyde/aldose reductase inhibition activities. The results for the in vitro bioassays were promising with the identification of compound 8e as the lead and selective candidate for ALR2 inhibition with an IC50 value of 0.468+/-0.003uMas compared to 3.1+/-0.2uM for the standard (sorbinil), whereas compound 8o demonstrated high inhibitory potency for both ALR2 and ALR1 enzymes. Molecular modeling analysis of the potent compounds provided further insight into the biological properties where detailed binding mode analysis revealed that the conjugates (8a-r) were found stabilized in the active site of the enzymes through the development of a number of interactions with catalytic residues. PMID- 28888095 TI - Magnesium therapy improves outcome in Streptococcus pneumoniae meningitis by altering pneumolysin pore formation. AB - BACKGROUND AND PURPOSE: Streptococcus pneumoniae is the most common cause of bacterial meningitis in adults and is characterized by high lethality and substantial cognitive disabilities in survivors. Here, we have studied the capacity of an established therapeutic agent, magnesium, to improve survival in pneumococcal meningitis by modulating the neurological effects of the major pneumococcal pathogenic factor, pneumolysin. EXPERIMENTAL APPROACH: We used mixed primary glial and acute brain slice cultures, pneumolysin injection in infant rats, a mouse meningitis model and complementary approaches such as Western blot, a black lipid bilayer conductance assay and live imaging of primary glial cells. KEY RESULTS: Treatment with therapeutic concentrations of magnesium chloride (500 mg.kg-1 in animals and 2 mM in cultures) prevented pneumolysin-induced brain swelling and tissue remodelling both in brain slices and in animal models. In contrast to other divalent ions, which diminish the membrane binding of pneumolysin in non-therapeutic concentrations, magnesium delayed toxin-driven pore formation without affecting its membrane binding or the conductance profile of its pores. Finally, magnesium prolonged the survival and improved clinical condition of mice with pneumococcal meningitis, in the absence of antibiotic treatment. CONCLUSIONS AND IMPLICATIONS: Magnesium is a well-established and safe therapeutic agent that has demonstrated capacity for attenuating pneumolysin triggered pathogenic effects on the brain. The improved animal survival and clinical condition in the meningitis model identifies magnesium as a promising candidate for adjunctive treatment of pneumococcal meningitis, together with antibiotic therapy. PMID- 28888097 TI - N-Sulfamoylphenyl- and N-sulfamoylphenyl-N-thiazolyl-beta-alanines and their derivatives as inhibitors of human carbonic anhydrases. AB - A series of N-substituted and N,N-disubstituted beta-amino acids and their derivatives bearing benzenesulfonamide moiety were designed and synthesized in search of compounds that would be high-affinity and selective inhibitors of human carbonic anhydrases (CA). There are 12 catalytically active human CA isoforms, the cytosolic CA I, CA II, CA III, CA VII, and CA XIII, secreted CA VI, the mitochondrial CA VA and CA VB, membrane-associated CA IV, and transmembrane CA IX, CA XII, and CA XIV. The di-bromo meta-substituted compounds exhibited low nanomolar dissociation constants and over 10-fold selectivity for mitochondrial isozyme CA VB, implicated in diseases of the central nervous system and obesity. These compounds can be used for further development as inhibitors of significant binding affinity and selectivity towards CA VB isozyme. PMID- 28888098 TI - Wave propagation through a flexoelectric piezoelectric slab sandwiched by two piezoelectric half-spaces. AB - Reflection and transmission of plane waves through a flexoelectric piezoelectric slab sandwiched by two piezoelectric half-spaces are studied in this paper. The secular equations in the flexoelectric piezoelectric material are first derived from the general governing equation. Different from the classical piezoelectric medium, there are five kinds of coupled elastic waves in the piezoelectric material with the microstructure effects taken into consideration. The state vectors are obtained by the summation of contributions from all possible partial waves. The state transfer equation of flexoelectric piezoelectric slab is derived from the motion equation by the reduction of order, and the transfer matrix of flexoelectric piezoelectric slab is obtained by solving the state transfer equation. By using the continuous conditions at the interface and the approach of partition matrix, we get the resultant algebraic equations in term of the transfer matrix from which the reflection and transmission coefficients can be calculated. The amplitude ratios and further the energy flux ratios of various waves are evaluated numerically. The numerical results are shown graphically and are validated by the energy conservation law. Based on these numerical results, the influences of two characteristic lengths of microstructure and the flexoelectric coefficients on the wave propagation are discussed. PMID- 28888099 TI - Polydrug use and its association with drug treatment outcomes among primary heroin, methamphetamine, and cocaine users. AB - BACKGROUND: Polydrug use may challenge effective treatment for substance use disorders. We evaluate whether secondary substance use modifies the association between treatment and primary drug use among primary heroin, cocaine and methamphetamine (MA) users. METHODS: Data were obtained from prospective cohort studies on people who use illicit drugs (PWUD) in California, USA. Using repeated monthly data on self-reported secondary substance use (heroin, cocaine, MA, alcohol or marijuana; >=1day in a month), primary drug use (>=1day in a month), and treatment participation, collected via timeline follow-back, we fitted generalized linear mixed multiple regression models controlling for potential confounders to examine the interactions between treatment and secondary substance use on the odds of primary heroin, cocaine and MA use, respectively. RESULTS: Included in our study were 587 primary heroin, 444 primary MA, and 501 primary cocaine users, with a median of 32.4, 13.3 and 18.9 years of follow-up, respectively. In the absence of secondary substance use, treatment was strongly associated with decreased odds of primary drug use (adjusted odds ratios (aORs): 0.25, 95% CI: 0.24, 0.27, 0.07 (0.06, 0.08), and 0.07 (0.07, 0.09)) for primary heroin, MA, and cocaine users, respectively. Secondary substance use of any kind moderated these associations (0.82 (0.78, 0.87), 0.25 (0.21, 0.30) and 0.53 (0.45, 0.61), respectively), and these findings were consistent for each type of secondary substance considered. Moreover, we observed different associations in terms of direction and magnitude between secondary substance use and primary drug use during off-treatment periods across substance types. CONCLUSION: This study demonstrates secondary substance use moderates the temporal associations between treatment and primary drug use among primary heroin, MA and cocaine users. Disparate patterns of polydrug use require careful measurement and analysis to inform targeted treatment for polydrug users. PMID- 28888101 TI - What's New in SCLC? A Review. AB - A few years ago the answer to the question in the title of this review would have been, "unfortunately not much" or even "nothing", likely eliciting knowing nods of agreement from oncologists. For the last 3 decades, SCLC has been notorious for its lack of progress, as drug after drug, over 60 of them, in fact, including inhibitors of VEGF, IGFR, mTOR, EGFR and HGF has failed and fallen by the wayside due to little or no impact on PFS or OS, while SCLC's cousin, NSCLC, has notched success after success with a spate of targeted treatment and immunotherapy regulatory approvals. However, a paradigm shift or, more appropriately, a 'paradigm nudge' is quietly underway in extensive stage SCLC with a series of agents that in early clinical trials have shown the potential to 'lift the curse' in SCLC, heretofore referred to as "a graveyard for drug development". These agents, constituting the "best of what's new" in SCLC, and discussed in this review following a brief overview of the classification, epidemiology, prognosis and current treatment of SCLC, include checkpoint inhibitors, antibody-drug conjugates, PARP inhibitors, epigenetic inhibitor/innate immune activator, and an inhibitor of RNA polymerase II. Compared to NSCLC, the therapeutic options are still limited but with one or more successes to build momentum and drive long overdue R&D and clinical investment the hope is that the approval floodgates may finally open. PMID- 28888100 TI - Chk1 Inhibitor SCH900776 Effectively Potentiates the Cytotoxic Effects of Platinum-Based Chemotherapeutic Drugs in Human Colon Cancer Cells. AB - Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate the ability of one of the most specific Chk1 inhibitors, SCH900776 (MK-8776), to enhance human colon cancer cell sensitivity to the cytotoxic effects of platinum(II) cisplatin and platinum(IV)- LA-12 complexes. The combined treatment with SCH900776 and cisplatin or LA-12 results in apparent increase in G1/S phase-related apoptosis, stimulation of mitotic slippage, and senescence of HCT116 cells. We further show that the cancer cell response to the drug combinations is significantly affected by the p21, p53, and PTEN status. In contrast to their wt counterparts, the p53- or p21-deficient cells treated with SCH900776 and cisplatin or LA-12 enter mitosis and become polyploid, and the senescence phenotype is strongly suppressed. While the cell death induced by SCH900776 and cisplatin or LA-12 is significantly delayed in the absence of p53, the anticancer action of the drug combinations is significantly accelerated in p21-deficient cells, which is associated with stimulation of apoptosis beyond G2/M cell cycle phase. We also show that cooperative killing action of the drug combinations in HCT116 cells is facilitated in the absence of PTEN. Our results indicate that SCH900776 may act as an important modulator of cytotoxic response triggered by platinum-based drugs in colon cancer cells. PMID- 28888102 TI - A new mechanism of resistance to ABL1 tyrosine kinase inhibitors in a BCR-ABL1 positive cell line. AB - Tyrosine kinase inhibitors (TKI) constitute the frontline treatment for chronic myeloid leukemia patients. Dasatinib, a second-generation TKI, was developed to overcome TKI resistances. However, dasatinib resistances are also described but remain less characterized. To mimic in vivo acquired dasatinib resistance, the BCR-ABL1-positive cell line K562 was transiently treated with a pharmacological concentration of dasatinib, for a short time in the presence of stem cell factor. A dasatinib resistant counterpart (K562 RES) was developed. Investigation of resistance mechanisms using kinase substrate arrays revealed that FYN was overactivated in K562 RES. The FYN inhibitor KX2-391 cooperated with dasatinib to block K562 RES proliferation. Cell tracking experiments showed that activated FYN support cell proliferation independently of BCR-ABL1 in K562 RES cells. Moreover, the MEK-ERK pathway was found hyper-phosphorylated in K562 RES cells even in the presence of dasatinib. Actually, ERK1/2 activity supported viability in K562 RES only in the absence of BCR-ABL1 activity. Finally, BCR-ABL1 and MEK inhibitor combination was sufficient to induce cell death even in non-proliferating resistant cells. Considering the conditions used to generate this dasatinib resistant cell line, such a resistance mechanism could be found in dasatinib treated patients. Consequently, it is valuable to know that inhibition of the MEK ERK1/2 axis can overcome this resistance. PMID- 28888103 TI - Using CRISPR-Cas systems as antimicrobials. AB - Although CRISPR-Cas systems naturally evolved to provide adaptive immunity in bacteria and archaea, Cas nucleases can be co-opted to target chromosomal sequences rather than invasive genetic elements. Although genome editing is the primary outcome of self-targeting using CRISPR-based technologies in eukaryotes, self-targeting by CRISPR is typically lethal in bacteria. Here, we discuss how DNA damage introduced by Cas nucleases in bacteria can efficiently and specifically lead to plasmid curing or drive cell death. Specifically, we discuss how various CRISPR-Cas systems can be engineered and delivered using phages or phagemids as vectors. These principles establish CRISPR-Cas systems as potent and programmable antimicrobials, and open new avenues for the development of CRISPR based tools for selective removal of bacterial pathogens and precise microbiome composition alteration. PMID- 28888104 TI - Effects of ultraviolet light emitting diodes (LEDs) on microbial and enzyme inactivation of apple juice. AB - In this study, the effects of Ultraviolet light-emitting diodes (UV-LEDs) on the inactivation of E. coli K12 (ATCC 25253), an indicator organism of E. coli O157:H7, and polyphneoloxidase (PPO) in cloudy apple juice (CAJ) were investigated. The clear (AJ) and cloudy apple juice were exposed to UV rays for 40min by using a UV device composed of four UV-LEDs with peak emissions at 254 and 280nm and coupled emissions as follows: 254/365, 254/405, 280/365, 280/405 and 254/280/365/405nm. UV-LEDs at 254nm achieved 1.6+/-0.1 log10 CFU/mL inactivation of E. coli K12 at UV dose of 707.2mJ/cm2. The highest inactivation of E. coli K12 (2.0+/-0.1log10 CFU/mL and 2.0+/-0.4log10CFU/mL) was achieved when the cloudy apple juice was treated with both 280nm and 280/365nm UV-LEDs. For clear apple juice the highest inactivation 4.4log10CFU/mL obtained for E. coli K12 was achieved using 4 lamps emitting light at 280nm for 40min exposure time. For the same treatment time, the experiments using a combination of lamps emitting light at 280 and 365nm (2lamp/2lamp) were resulted in 3.9+/ 0.2log10CFU/mL reductions. UV-A and UV-C rays in combination showed a better inactivation effect on PPO than UV-C rays used separately. Residual activity of PPO in CAJ was reduced to 32.58% when treated with UV-LED in combination of UV-C (280nm) and UV-A (365nm) rays. Additionally, the total color change (DeltaE) of CAJ subjected to combined UV-LED irradiation at 280/365nm was the lowest compared to other studied processing conditions. This study provides key implications for the future application of UV-LEDs to fruit juice pasteurization. PMID- 28888105 TI - CryoEM structures of spliceosomal complexes reveal the molecular mechanism of pre mRNA splicing. AB - The spliceosome is an intricate molecular machine which catalyses the removal of introns from eukaryotic mRNA precursors by two trans-esterification reactions (branching and exon ligation) to produce mature mRNA with uninterrupted protein coding sequences. The structures of the spliceosome in several key states determined by electron cryo-microscopy have greatly advanced our understanding of its molecular mechanism. The catalytic RNA core is formed during the activation of the fully assembled B to Bact complex and remains largely unchanged throughout the splicing cycle. RNA helicases and step specific factors regulate docking and undocking of the substrates (branch site and 3' splice site) to the single RNA based active site to catalyse the two trans-esterification reactions. PMID- 28888106 TI - Stereo-vision three-dimensional reconstruction of curvilinear structures imaged with a TEM. AB - Deriving accurate three-dimensional (3-D) structural information of materials at the nanometre level is often crucial for understanding their properties. Tomography in transmission electron microscopy (TEM) is a powerful technique that provides such information. It is however demanding and sometimes inapplicable, as it requires the acquisition of multiple images within a large tilt arc and hence prolonged exposure to electrons. In some cases, prior knowledge about the structure can tremendously simplify the 3-D reconstruction if incorporated adequately. Here, a novel algorithm is presented that is able to produce a full 3 D reconstruction of curvilinear structures from stereo pair of TEM images acquired within a small tilt range that spans from only a few to tens of degrees. Reliability of the algorithm is demonstrated through reconstruction of a model 3 D object from its simulated projections, and is compared with that of conventional tomography. This method is experimentally demonstrated for the 3-D visualization of dislocation arrangements in a deformed metallic micro-pillar. PMID- 28888107 TI - Comparison of dislocation characterization by electron channeling contrast imaging and cross-correlation electron backscattered diffraction. AB - In this work, the relative capabilities and limitations of electron channeling contrast imaging (ECCI) and cross-correlation electron backscattered diffraction (CC-EBSD) have been assessed by studying the dislocation distributions resulting from nanoindentation in body centered cubic Ta. Qualitative comparison reveals very similar dislocation distributions between the CC-EBSD mapped GNDs and the ECC imaged dislocations. Approximate dislocation densities determined from ECC images compare well to those determined by CC-EBSD. Nevertheless, close examination reveals subtle differences in the details of the distributions mapped by these two approaches. The details of the dislocation Burgers vectors and line directions determined by ECCI have been compared to those determined using CC EBSD and reveal good agreement. PMID- 28888108 TI - Analytical modeling of electron energy loss spectroscopy of graphene: Ab initio study versus extended hydrodynamic model. AB - We present an analytical modeling of the electron energy loss (EEL) spectroscopy data for free-standing graphene obtained by scanning transmission electron microscope. The probability density for energy loss of fast electrons traversing graphene under normal incidence is evaluated using an optical approximation based on the conductivity of graphene given in the local, i.e., frequency-dependent form derived by both a two-dimensional, two-fluid extended hydrodynamic (eHD) model and an ab initio method. We compare the results for the real and imaginary parts of the optical conductivity in graphene obtained by these two methods. The calculated probability density is directly compared with the EEL spectra from three independent experiments and we find very good agreement, especially in the case of the eHD model. Furthermore, we point out that the subtraction of the zero loss peak from the experimental EEL spectra has a strong influence on the analytical model for the EEL spectroscopy data. PMID- 28888109 TI - Biomechanical compensations of the trunk and lower extremities during stepping tasks after unilateral transtibial amputation. AB - BACKGROUND: Lower extremity movement compensations following transtibial amputation are well-documented and are likely influenced by trunk posture and movement. However, the biomechanical compensations of the trunk and lower extremities, especially during high-demand tasks such as step ascent and descent, remain unclear. METHODS: Kinematic and kinetic data were collected during step ascent and descent tasks for three groups of individuals: diabetic/transtibial amputation, diabetic, and healthy. An ANCOVA was used to compare peak trunk, hip and knee joint angles and moments in the sagittal and frontal planes between groups. Paired t-tests were used to compare peak joint angles and moments between amputated and intact limbs of the diabetic/transtibial amputation group. FINDINGS: During step ascent and descent, the transtibial amputation group exhibited greater trunk forward flexion and lateral flexion compared to the other two groups (P<0.016), which resulted in greater low back moments and asymmetric loading patterns in the lower extremity joints. The diabetic group exhibited similar knee joint loading patterns compared to the amputation group (P<0.016), during step descent. INTERPRETATION: This study highlights the biomechanical compensations of the trunk and lower extremities in individuals with dysvascular transtibial amputation, by identifying low back, hip, and knee joint moment patterns unique to transtibial amputation during stepping tasks. In addition, the results suggest that some movement compensations may be confounded by the presence of diabetes and precede limb amputation. The increased and asymmetrical loading patterns identified may predispose individuals with transtibial amputation to the development of secondary pain conditions, such as low back pain or osteoarthritis. PMID- 28888110 TI - Association of toll-like receptor polymorphisms with susceptibility to chikungunya virus infection. AB - Chikungunya virus (CHIKV) infection leads to activation of innate immune response by triggering Toll-like receptor (TLR) pathways resulting in elevated cytokines and type-I interferon levels. Genetic variations of these genes may influence human CHIKV-susceptibility and disease progression. Present study aimed to identify role of TLR polymorphisms in CHIKV-susceptibility and their association with cytokines and clinical symptoms. This is the first study illustrating certain genotypes of TLR-7 and TLR-8 SNPs viz. CT(p = 0.002)]; rs3853839[GC(p < 0.001), CC(p = 0.039)] and rs3764879[GC(p < 0.001)] were considerably associated with CHIKV susceptibility. Increased risk of CHIKV infection among male patients with CC-genotype (rs179010) (p = 0.028) and female patients with GT-genotype (rs5741880) (p = 0.019) was observed. Significant higher IFN-alpha (P = 0.002) levels among chikungunya TNF-alpha (P = 0.034) patients was reported. Chikungunya patients with rs179010-CC genotype showed significantly high IFN-alpha level(p = 0.003). Thus, these TLR variants might act as potential prognostic biomarkers for predicting CHIKV susceptibility among uninfected individuals. PMID- 28888112 TI - Isolate fitness and tissue-tropism determine superinfection success. AB - The mechanism of cross-protection, the deliberate infection of plants with a "mild" virus isolate to protect against "severe" isolates, has long been a topic of debate. In our model system, Citrus tristeza virus (CTV), this appears to be genotype-specific superinfection-exclusion, suggesting a simple recipe for cross protection. However, this concept failed in field trials, which led us to examine the process of superinfection-exclusion more closely. We found that exclusion relies on the relative fitness of the primary versus the challenge isolates, and the host infected, and that significant differences in superinfection success could occur between isolates that differ by as few as 3 nucleotides. Furthermore, we found that exclusion was not uniform throughout the plant, but was tissue specific. These data suggest that cross-protection is not a simple like-for-like process but a complex interaction between the primary and challenge isolates and the host. PMID- 28888111 TI - An influenza A virus (H7N9) anti-neuraminidase monoclonal antibody protects mice from morbidity without interfering with the development of protective immunity to subsequent homologous challenge. AB - The emergence of A(H7N9) virus strains with resistance to neuraminidase (NA) inhibitors highlights a critical need to discover new countermeasures for treatment of A(H7N9) virus-infected patients. We previously described an anti-NA mAb (3c10-3) that has prophylactic and therapeutic efficacy in mice lethally challenged with A(H7N9) virus when delivered intraperitoneally (i.p.). Here we show that intrananasal (i.n.) administration of 3c10-3 protects 100% of mice from mortality when treated 24h post-challenge and further characterize the protective efficacy of 3c10-3 using a nonlethal A(H7N9) challenge model. Administration of 3c10-3 i.p. 24h prior to challenge resulted in a significant decrease in viral lung titers and deep sequencing analysis indicated that treatment did not consistently select for viral variants in NA. Furthermore, prophylactic administration of 3c10-3 did not inhibit the development of protective immunity to subsequent homologous virus re-challenge. Taken together, 3c10-3 highlights the potential use of anti-NA mAb to mitigate influenza virus infection. PMID- 28888113 TI - Tissue-engineered human 3D model of bladder cancer for invasion study and drug discovery. AB - The tumour microenvironment is critical to both the initiation and maintenance of tumorigenesis. Reconstitution of the microenvironment is a major challenge for in vitro cancer models. Indeed, conventional 2D culture systems cannot replicate the complexity, diversity and dynamic nature of the tumour microenvironment. In this study, we have developed a 3D endotheliazed vesical equivalent by using tissue engineering from primary human cells in which non-invasive or invasive bladder cancer (BCa) cell lines, cultured as compact spheroids, were incorporated. Invasive BCa cells cross the basement membrane and invade the stromal compartment whereas non-invasive BCa cells are confined to the urothelium. Our 3D BCa model could be used as a reliable model for assessing drug responses, potentially reducing or partially replacing animal experiments, and thus should have applications in the identification of novel targets as well as toxicological evaluation of anti-cancer therapies. PMID- 28888114 TI - Carotid stiffness, extra-media thickness and visceral adiposity in young adults. AB - BACKGROUND AND AIMS: Carotid extra-media thickness (EMT) encompasses arterial adventitia and perivascular adipose tissue (PAT). Adventitial remodeling and PAT may contribute independently to functional (stiffness) and structural (remodeling) changes in artery wall properties. Visceral adiposity may contribute to PAT, thereby affecting artery stiffness. We investigated the relationships between carotid artery stiffness, EMT, and visceral adiposity in young, healthy individuals. METHODS: 135 healthy males (20 +/- 2 yr, body mass index [BMI] 24.8 +/- 3.3 kg/m2) underwent anthropometric and vascular measures on two separate days. Visceral adiposity was assessed using waist circumference and sagittal abdominal diameter (SAD). Brachial and carotid systolic, diastolic, and pulsatile (PP) blood pressures were assessed using an oscillometric cuff and applanation tonometry, respectively. Carotid intima-media thickness (IMT) and EMT were assessed using Doppler ultrasound. Carotid artery stiffness was calculated as beta-stiffness and calibrated to carotid pressures. RESULTS: Separate stepwise multiple regression models demonstrated that carotid PP (beta = 0.205) and EMT (beta = 0.267) accounted for 12.6% of variance in beta-stiffness, while carotid PP (beta = 0.195) and SAD (beta = 0.226) accounted for 10.5% of variance in EMT (p < 0.05). Mediation analyses revealed carotid PP partially mediated the relationship between a) EMT and beta-stiffness, and b) SAD and EMT (p < 0.05). CONCLUSIONS: Carotid PP and EMT, but not IMT, are related to carotid beta stiffness. Carotid PP and visceral adiposity (SAD) are related to EMT. Carotid PP partially mediates the association between a) EMT and carotid beta-stiffness, and b) SAD and EMT. Our findings suggest visceral adiposity may detrimentally affect subclinical markers of cardiovascular disease risk (carotid PP, EMT) and contribute to artery stiffness. PMID- 28888115 TI - Influence of a Roundup formulation on glyphosate effects on steroidogenesis and proliferation of bovine granulosa cells in vitro. AB - Glyphosate (N-phosphonomethyl-glycine) is a non-selective systemic herbicide widely used worldwide. The purpose of this study is to determine if glyphosate alone (GLPH) or in formulation with Roundup (G-RU) can affect granulosa cell proliferation and steroid production. Four experiments were conducted. In Exp. 1, 10 and 300 MUg/mL of GLPH had no effect (P > 0.05) on cell numbers, estradiol or progesterone production, whereas 10 and 300 MUg/mL of G-RU dramatically decreased (P < 0.05) cell numbers and estradiol and progesterone production. In Exp. 2, G RU at 0.1 MUg/mL had no significant effect whereas G-RU at 10 MUg/mL decreased (P < 0.05) GC numbers, progesterone and estradiol production. In the absence of IGF1 but presence of FSH, 1 MUg/mL of G-RU decreased (P < 0.05) estradiol production, whereas in the presence of IGF1 and FSH, 1 MUg/mL of G-RU increased (P < 0.05) cell numbers, progesterone and estradiol production. In Exp. 3, IGF1 significantly increased cell numbers (by 2.8-fold) and estradiol (by 17.8-fold) and progesterone (by 6.1-fold) production. GLPH at 10 MUg/mL alone had no significant effect on FSH-induced (i.e., basal) or FSH plus IGF1-induced cell numbers, estradiol or progesterone production. However, G-RU at 10 MUg/mL significantly inhibited FSH plus IGF1-induced cell numbers, estradiol and progesterone production by 65%-91%. In Exp. 4, 48 h treatment of G-RU had no significant effect on viability of attached cells. In conclusion, the present studies demonstrate that GLPH and particularly G-RU may have the potential to impair reproductive function in cattle. PMID- 28888116 TI - Comprehensive review on toxicity of persistent organic pollutants from petroleum refinery waste and their degradation by microorganisms. AB - Control and prevention of environmental pollution has become a worldwide issue of concern. Aromatic hydrocarbons including benzene, toluene, ethyl benzene, xylene (BTEX) and polyaromatic hydrocarbons (PAHs) are persistent organic pollutants (POPs), released into the environment mainly by exploration activities of petroleum industry. These pollutants are mutagenic, carcinogenic, immunotoxic and teratogenic to lower and higher forms of life i.e. microorganisms to humans. According to the International Agency for Research on Cancer (IARC) and United States Environmental Protection Agency (U.S. EPA), Benzo[a]pyrene (BaP) is carcinogenic in laboratory animals and humans. Aromatic hydrocarbons are highly lipid soluble and thus readily absorbed from environment in gastrointestinal tract of mammals. Treatment and remediation of petroleum refinery waste have been shown either to reduce or to eliminate genotoxicity of these pollutants. Bioremediation by using microorganisms to treat this waste is showing a promising technology as it is safe and cost-effective option among various technologies tested. The main aim of this review is to provide contemporary information on variety of aromatic hydrocarbons present in crude oil (with special focus to mono and poly-aromatic hydrocarbons), exposure routes and their adverse effects on humans. This review also provides a synthesis of scientific literature on remediation technologies available for aromatic hydrocarbons, knowledge gaps and future research developments in this field. PMID- 28888117 TI - Biotransformation, antioxidant and histopathological biomarker responses to contaminants in European and American yellow eels from the Gironde and St. Lawrence estuaries. AB - Since the early 1980s, populations of American (Anguilla rostrata) and European eels (Anguilla anguilla) have suffered a sharp decline. The causes of their decline are likely multifactorial and include chemical pollution. A field study was conducted in eight sites varying in organic and metal contamination along the St. Lawrence (Eastern Canada) and Gironde (France) systems to investigate the relationships among contaminants, biological characteristics and biotransformation, antioxidant and histopathological biomarkers in eels from both species. For A. rostrata, no major influences of persistent organic contaminants on biomarkers were identified. For A. anguilla, eels from the most contaminated site expressed higher surface of MelanoMacrophage Centers (MMCs) and eels from another contaminated site expressed higher amount of spleen lipofuscin pigment. These two histopathological biomarkers were also associated with aging. Compared to eels from the cleanest French site, higher hepatic catalase activity and density of MMC in eels from contaminated sites was related to higher concentration of organic (DDT and metabolites, sum of PCBs, sum of PBDEs) and inorganic (Hg and Cd) contaminants. In both species, a higher deposition of spleen hemosiderin pigment was measured in eels from the most brackish sites compared to eels living in freshwater environments. Our results suggest an association between higher hemosiderin pigment and metal contamination (As for A. anguilla and Pb for A. rostrata). Parasitism by A. crassus was observed in European eels from freshwater sites but not in eels from brackish habitats. Overall, contamination may pose a greater risk for the health of European compared to American eels. PMID- 28888118 TI - Electrical energy per order and current efficiency for electrochemical oxidation of p-chlorobenzoic acid with boron-doped diamond anode. AB - Electrochemical oxidation (EO) is an advanced oxidation process for water treatment to mineralize organic contaminants. While proven to degrade a range of emerging pollutants in water, less attention has been given to quantify the effect of operational variables such applied current density and pollutant concentration on efficiency and energy requirements. Particular figures of merit were mineralization current efficiency (MCE) and electrical energy per order (EEO). Linear increases of applied current exponentially decreased the MCE due to the enhancement of undesired parasitic reactions that consumed generated hydroxyl radical. EEO values ranged from 39.3 to 331.8 kW h m-3 order-1. Increasing the applied current also enhanced the EEO due to the transition from kinetics limited by current to kinetics limited by mass transfer. Further increases in current did not influence the removal rate, but it raised the EEO requirement. The EEO requirement diminished when decreasing initial pollutant loading with the increase of the apparent kinetic rate because of the relative availability of oxidant per pollutant molecule in solution at a defined current. Oxidation by products released were identified, and a plausible degradative pathway has been suggested. PMID- 28888119 TI - Multiple-endpoints gene alteration-based (MEGA) assay: A toxicogenomics approach for water quality assessment of wastewater effluents. AB - Wastewater effluents contain a significant number of toxic contaminants, which, even at low concentrations, display a wide variety of toxic actions. In this study, we developed a multiple-endpoints gene alteration-based (MEGA) assay, a real-time PCR-based transcriptomic analysis, to assess the water quality of wastewater effluents for human health risk assessment and management. Twenty-one genes from the human hepatoblastoma cell line (HepG2), covering the basic health relevant stress responses such as response to xenobiotics, genotoxicity, and cytotoxicity, were selected and incorporated into the MEGA assay. The genes related to the p53-mediated DNA damage response and cytochrome P450 were selected as markers for genotoxicity and response to xenobiotics, respectively. Additionally, the genes that were dose-dependently regulated by exposure to the wastewater effluents were chosen as markers for cytotoxicity. The alterations in the expression of an individual gene, induced by exposure to the wastewater effluents, were evaluated by real-time PCR and the results were validated by genotoxicity (e.g., comet assay) and cell-based cytotoxicity tests. In summary, the MEGA assay is a real-time PCR-based assay that targets cellular responses to contaminants present in wastewater effluents at the transcriptional level; it is rapid, cost-effective, and high-throughput and can thus complement any chemical analysis for water quality assessment and management. PMID- 28888120 TI - Impact of pyrene and cadmium co-contamination on prokaryotic community in coastal sediment microcosms. AB - Acute ecological impacts of co-contamination of polycyclic aromatic hydrocarbons (PAHs) and heavy metals on diversity and composition of coastal benthic prokaryotes were unclear. We took pyrene (Pyr) and cadmium (Cd) as the representatives and mimicked an eight-week exposure of moderate and high levels of Pyr, Cd and their mixtures. 16S rRNA amplicon sequencing was used to investigate interaction of the contaminants in temporal succession of prokaryotes. Generally, concentrations of Pyr and HCl-extractable Cd in the sediments were stable over time. Effects and interaction of Pyr and Cd on prokaryotic alpha-diversity were temporally- and dose-dependent with a decreasing trend in richness and Shannon index under various contamination regimes, particularly in the single-Cd contaminated groups at the early stage. Temporal variability and Pyr-induced pattern in prokaryotic composition were observed. However, Pyr and Cd showed a persistent interaction in prokaryotic composition after 7 days, altering successional trajectories of communities. The communities under Pyr contamination regardless of Cd could be at a developing stage for an active PAH-degrading community with appearance of a pioneer Cycloclasticus phylotype, persistently showing a strong correlation with Pyr level. The associations of phylotypes and Cd level were short-lived and weak, corresponding to the overall resistance of prokaryotic composition to Cd. In the high throughput sequencing era, using microcosm experiment, we renewed the knowledge about how prokaryotes vary in terms of alpha-diversity, composition and specific taxa in response to co-contamination of model contaminants at a temporal scale. PMID- 28888121 TI - Occurrence, distribution, ecological and resistance risks of antibiotics in surface water of finfish and shellfish aquaculture in Bangladesh. AB - The present study for the first time reports the occurrence, distribution, ecological and resistance risks of antibiotics in the surface water of freshwater finfish and brackish water shellfish aquaculture in Bangladesh. Among the nine targets, seven antibiotics were detected in finfish aquaculture, whereas four in shellfish aquaculture. The concentrations (ranges) and overall detection frequency of sulfamethoxazole (SMX) (nd-20.02 ng L-1 and 73%), trimethoprim (TMP) (nd-41.67 ng L-1 and 60%), tylosin (TYL) (nd-39.34 ng L-1 and 60%), sulfadiazine (SDZ) (nd-17.97 ng L-1 and 53%), sulfamethazine (SMT) (nd-11.71 ng L-1 and 33%), sulfamethizole (SMZ) (nd-10.81 ng L-1 and 40%) and penicillin G (PC_G) (nd-7.83 ng L-1, 7%) were found in finfish aquaculture. In case of shellfish aquaculture, the concentrations (ranges) and overall detection frequency were for SMX (nd 16.77 ng L-1 and 67%), TMP (nd-11.39 ng L-1 and 20%), TYL (nd-0.16 ng L-1 and 20%) and erythromycin-H2O (ERY-H2O) (nd-3.91 ng L-1 and 20%). The present findings revealed that finfish aquaculture is more contaminated with the higher numbers and concentrations of antibiotics. The preliminary ecological and resistance risks assessment showed that the calculated risk quotients (RQs) were lower than one (RQs<1) for all the detected antibiotics in both aquaculture. Preliminary ecological and resistance risks assessment revealed that there were no adverse ecological and resistance risks, however, our study suggests that it is imperative to pay due attention to monitor the antibiotics contamination in rapid growing aquaculture sector of Bangladesh for the reduction of potential risks of antibiotics on aquatic organisms as well as human health. PMID- 28888122 TI - Interferon-tau induced gene expression in bovine hepatocytes during early pregnancy. AB - Interferon-tau (IFNtau) is the conceptus derived specific early pregnancy signal in bovidae. Locally, IFNtau induces an IFNtau specific gene expression (ISG) in endometrial cells and by this it averts luteolysis of the corpus luteum (CL) by suppressing prostaglandin production. Moreover, it was shown that IFNtau also induces ISG in the liver in pregnant sheep and in liver biopsies from Holstein Friesian heifers on Day 18 of pregnancy. The objective of the present study was to confirm increased hepatic ISG in vivo on Day 18 of pregnancy and to prove if hepatocytes and not non-parenchymal cells react to IFNtau by using immunohistochemistry and primary bovine hepatocytes stimulated in vitro with recombinant bovine IFNtau. For the animal experiment, Angus heifers (n = 12) were cycle synchronized and the Day of ovulation (Day 0) was defined by ovarian ultrasonography and verified by progesterone < 0.1 ng/ml. Heifers were artificially inseminated either with sperm (n = 9) or with seminal plasma (mock control, n = 3). Early pregnancy was defined and detected by progesterone and pregnancy associated glycoprotein (PAG) concentration in blood before and after induced luteolysis by a PGF-injection on Day 21 in n = 3 inseminated heifers. A liver biopsy was taken on Day 18 for the analysis of gene (ISG 15, MX 1, MX 2 and OAS 1) and protein (OAS1) expression using qPCR and immunohistochemistry, respectively. Primary bovine hepatocytes were collected from bull liver using a two-step collagenase perfusion, cultured short-term in a monolayer and stimulated with IFNtau. Thereafter, gene expression was measured by qPCR. In liver biopsies obtained from pregnant heifers ISG was numerically higher expressed compared to biopsies from non-pregnant heifers. Furthermore, the OAS 1 protein expression was localized in hepatocytes on Day 18 of pregnancy. In vitro, primary bovine hepatocytes showed an increased mRNA expression of ISG after IFNtau stimulation. In conclusion, the findings confirm that IFNtau induces ISG in the parenchymal part of the liver in early pregnancy of cattle. PMID- 28888123 TI - The effect of imidazolium based ionic liquids on wheat and barley germination and growth: Influence of length and oxygen functionalization of alkyl side chain. AB - In this work five different imidazolium based ionic liquids, namely: 1-(2 oxybutyl)-3-methylimidazolium chloride, [C2OC2mIm][Cl]; 1-(2-oxypropyl)-3 methylimidazolium chloride, [C1OC2mIm][Cl]; 1-(3-hydroxypropyl)-3 ethylimidazolium chloride, [OHC3eIm][Cl]; 1-(3-hydroxypropyl)-3-methylimidazolium chloride, [OHC3mIm][Cl]; 1-(2-hydroxyethyl)-3-methylimidazolium chloride, [OHC2mIm][Cl], together with commercial 1-butyl-3-methylimidazolium chloride, [bmim][Cl] and synthesized protic imidazolium chloride, [Im][Cl], were prepared and their toxicity examined towards wheat and barley germination and growth. Introduction of the polar groups (in the form of hydroxyde and/or ether group) in the alkyl side chain of the imidazolium cation and their influence on the reduction of the ionic liquid's toxicity is demonstrated. The results indicate that toxicity of oxygen functionalized ILs is significantly lower against wheat comparing to non-functionalized analogues. In the case of barley, influence on germination follow the same trend as in the case of wheat, but for seedlings growth different trend is observed with more pronounced toxicity of ether functionalized ILs. From these results it was also shown that alkylation in the position N-3 atom of the imidazole significantly reduces toxicity of cation. PMID- 28888124 TI - Sperm viability assessment in marine invertebrates by fluorescent staining and spectrofluorimetry: A promising tool for assessing marine pollution impact. AB - The viability of spermatozoa is a crucial parameter to evaluate their quality that is an important issue in ecotoxicological studies. Here, a new method has been developed to rapidly determine the viability of spermatozoa in three marine invertebrates: the ascidian Ciona intestinalis, the sea urchin Paracentrotus lividus and the mollusc Mytilus galloprovincialis. This method employed the dual DNA fluorescent staining coupled with spectrofluorimetric analysis. The dual fluorescent staining used the SYBR-14 stained live spermatozoa and propidium iodide stained degenerated cells that had lost membrane integrity. Stain uptake was assessed by confocal microscopy and then the percentage of live and dead spermatozoa was quantified by spectrofluorimetric analysis. The microscopic examination revealed three populations of spermatozoa: living-SYBR-14 stained, dead-PI stained, and dying-doubly stained spermatozoa. The fluorescence emission peak values recorded in a spectrofluorimeter provide the portion of live and dead spermatozoa showing a significant negative correlation. The stain combination was further validated using known ratios of live and dead spermatozoa. The present study demonstrated that the dual DNA staining with SYBR-14 and propidium iodide was effective in assessing viability of spermatozoa in marine invertebrates and that spectrofluorimetric analysis can be successfully employed to evaluate the percentage of live and dead spermatozoa. The method develop herein is simple, accurate, rapid, sensitive, and cost-effective, so it could be a useful tool by which marine pollutants may be screened for spermiotoxicity. PMID- 28888125 TI - Interactive effects of microcystin and ammonia on the reproductive performance and phenotypic traits of the rotifer Brachionus calyciflorus. AB - Elevated microcystin-LR (MC-LR) and ammonia (NH3-N) concentrations co-occur during the degradation of Microcystis blooms, and are toxic to aquatic organisms. The freshwater rotifer, Brachionus calyciflorus, was exposed to mixtures of MC-LR (0, 10, 30, and 100ugL-1) and NH3-N (0, 270, and 540ugL-1) to assess the combined effects of the two toxicants on reproductive performance and phenotype traits. Single solutions of MC-LR (100ugL-1) and NH3-N (540ugL-1) had negative effects on rotifer reproductive timing and fecundity. Pre- and post-reproductive periods fluctuated with MC-LR and NH3-N concentrations, while reproductive period and total offspring per female were reduced in mixtures of MC-LR and NH3-N (p < 0.05). Grazing rate of rotifers decreased with grazing time and concentrations of the two toxicants (p < 0.001). MC-LR in combination with NH3-N had negative effects on swimming speed and body length but positively stimulated posterolateral spine development (p < 0.001). MC-LR and NH3-N had synergetic interactive effects on pre-reproductive period, reproductive period, total offspring per female, grazing rate, swimming speed, and body length (p < 0.05). In contrast, these effects were antagonistic on post-reproductive period and posterolateral spine length (p > 0.05). These results indicate that MC-LR and NH3 N act synergistically and antagonistically in causing toxicity to B. calyciflorus regarding reproductive performance and the formation of defensive phenotypes. PMID- 28888126 TI - Rural-urban disparities in unmet long-term care needs in China: The role of the hukou status. AB - This article studies rural-urban disparities in unmet long-term care (LTC) needs in China. Firstly, it investigates the prevalence of unmet LTC needs for three populations which differ according to the extent of LTC needs. Secondly, it examines the impact of having rural or urban hukou registration status and rural or urban residence. The analysis is based on the China Health and Retirement Longitudinal Study (CHARLS) 2013. The broadly, intermediately and narrowly defined LTC population comprises, respectively, 3,682, 1002 and 446 functionally disabled people aged 45 and older. The role of hukou status and rural/urban residence on unmet needs are examined by applying four logistic regression models for each population. We find that rural hukou holders are significantly more likely to have unmet needs in all three populations regardless of their residency. With narrower definitions of the population in need of care, the effects of rural hukou status on unmet needs strengthen. In contrast to earlier studies, our results indicate that it is hukou status rather than place of residence which exacerbates rural-urban disparities in unmet LTC needs. Reducing unmet LTC needs and existing rural-urban disparities therefore requires not only more universal LTC coverage, but also a reduction of the specific access barriers arising from the hukou system. PMID- 28888127 TI - Environmental injustice and sexual minority health disparities: A national study of inequitable health risks from air pollution among same-sex partners. AB - Air pollution is deleterious to human health, and numerous studies have documented racial and socioeconomic inequities in air pollution exposures. Despite the marginalized status of lesbian, gay, bisexual, and transgender (LGBT) populations, no national studies have examined if they experience inequitable exposures to air pollution. This cross-sectional study investigated inequities in the exposure of same-sex partner households to hazardous air pollutants (HAPs) in the US. We examined cancer and respiratory risks from HAPs across 71,207 census tracts using National Air Toxics Assessment and US Census data. We calculated population-weighted mean cancer and respiratory risks from HAPs for same-sex male, same-sex female and heterosexual partner households. We used generalized estimating equations (GEEs) to examine multivariate associations between sociodemographics and health risks from HAPs, while focusing on inequities based on the tract composition of same-sex, same-sex male and same-sex female partners. We found that mean cancer and respiratory risks from HAPs for same-sex partners are 12.3% and 23.8% greater, respectively, than for heterosexual partners. GEEs adjusting for racial/ethnic and socioeconomic status, population density, urban location, and geographic clustering show that living in census tracts with high (vs. low) proportions of same-sex partners is associated with significantly greater cancer and respiratory risks from HAPs, and that living in same-sex male partner enclaves is associated with greater risks than living in same-sex female partner enclaves. Results suggest that some health disparities experienced by LGBT populations (e.g. cancer, asthma) may be compounded by environmental exposures. Findings highlight the need to extend the conceptual framework for explaining LGBT health disparities beyond psycho-behavioral mechanisms translating social stress into illness to include environmental mechanisms. Because psycho-behavioral and environmental factors may together exacerbate health disparities, we call for a shift toward interdisciplinary research on LGBT health that takes into account cumulative risks, including the role of environmental exposures. PMID- 28888128 TI - When knowledge activated from memory intrudes on probabilistic inferences from description - the case of stereotypes. AB - To make decisions in probabilistic inference tasks, individuals integrate relevant information partly in an automatic manner. Thereby, potentially irrelevant stimuli that are additionally presented can intrude on the decision process (e.g., Sollner, Broder, Glockner, & Betsch, 2014). We investigate whether such an intrusion effect can also be caused by potentially irrelevant or even misleading knowledge activated from memory. In four studies that combine a standard information board paradigm from decision research with a standard manipulation from social psychology, we investigate the case of stereotypes and demonstrate that stereotype knowledge can yield intrusion biases in probabilistic inferences from description. The magnitude of these biases increases with stereotype accessibility and decreases with a clarification of the rational solution. PMID- 28888130 TI - Chiral supramolecular order revealed during the formation of calf thymus and phage DNA crystals. AB - The control of DNA packaging has been reported to be dependent on an ordered liquid-crystalline state. However, the textural characteristics that are typical of crystals and that resemble mesophases have not been reported for highly polymerized or even shorter types of DNA filaments under in vitro conditions that favor crystallization. Because DNA crystals are expected to exhibit particular textural optical anisotropies, pure and highly polymerized calf thymus DNA and simpler lambda phage DNA were crystallized from solution drops and were analyzed using high-performance polarization microscopy with and without differential interference contrast (DIC) optics. Both types of DNA formed crystals that exhibited chiral supramolecular textures resembling the twist-grain boundary (TGB) columnar mesophases described for liquid crystals and exhibited intrinsic negative birefringence. To the best of our knowledge, this is the first observation using polarization/interference optics of pure DNA crystals that have TGB columnar mesophase-like textural characteristics. A comparison of the crystals formed from the highly polymerized calf thymus DNA and those formed from the shorter phage DNA strands revealed textural differences. Compared to the phage DNA crystals, the crystals of highly polymerized thymus DNA exhibited a more intertwisted columnar distribution and a fibrous texture between their columnar structures. In addition, a form birefringence phenomenon was detected only in the thymus DNA crystals. These characteristics are presumed to reflect the higher level of supramolecular order, self-assembly and chirality in highly polymerized calf thymus DNA crystals relative to that of crystals formed from the simpler, shorter, lambda phage DNA. The higher-order supramolecular organization revealed here for in vitro DNA preparations raises the possibility that this structure could also occur, possibly to a smaller degree, during DNA self aggregation under specific in vivo conditions. Whether the DNA crystal properties presently described play a role in the establishment of higher-order levels of hierarchical chromatin structure and consequently in chromatin physiology, should be further investigated. PMID- 28888129 TI - Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis. AB - CD4+ T cells have been long known to play an important role in the pathogenesis of rheumatoid arthritis (RA), but the specific cell populations and states that drive the disease have been challenging to identify with low dimensional single cell data and bulk assays. The advent of high dimensional single cell technologies-like single cell RNA-seq or mass cytometry-has offered promise to defining key populations, but brings new methodological and statistical challenges. Recent single cell profiling studies have revealed a broad diversity of cell types among CD4+ T cells, identifying novel populations that are expanded or altered in RA. Here, we will review recent findings on CD4+ T cell heterogeneity and RA that have come from single cell profiling studies and discuss the best practices for conducting these studies. PMID- 28888131 TI - Health of newly arrived immigrants in Canada and the United States: Differential selection on health. AB - Canada and the U.S. are two major immigrant-receiving countries characterized by different immigration policies and health care systems. The present study examines whether immigrant health selection, or the "healthy immigrant effect", differs by destination and what factors may account for differences in immigrant health selection. We use 12 years of U.S. National Health Interview Survey and Canadian Community Health Survey data to compare the risks of overweight/obesity and chronic health conditions among new immigrants in the two countries. Results suggest a more positive health selection of immigrants to Canada than the U.S. Specifically, newly arrived U.S. immigrants are more likely to be overweight or obese and have serious chronic health conditions than their Canadian counterparts. The difference in overweight/obesity was explained by differences in source regions and educational levels of immigrants across the two countries. But this is not the case for serious chronic conditions. These results suggest that immigration-related policies can potentially shape immigrant health selection. PMID- 28888132 TI - Entropy factor for randomness quantification in neuronal data. AB - A novel measure of neural spike train randomness, an entropy factor, is proposed. It is based on the Shannon entropy of the number of spikes in a time window and can be seen as an analogy to the Fano factor. Theoretical properties of the new measure are studied for equilibrium renewal processes and further illustrated on gamma and inverse Gaussian probability distributions of interspike intervals. Finally, the entropy factor is evaluated from the experimental records of spontaneous activity in macaque primary visual cortex and compared to its theoretical behavior deduced for the renewal process models. Both theoretical and experimental results show substantial differences between the Fano and entropy factors. Rather paradoxically, an increase in the variability of spike count is often accompanied by an increase of its predictability, as evidenced by the entropy factor. PMID- 28888134 TI - Organizations of food redistribution and rescue. AB - OBJECTIVE: Food insecurity affects 13.4% of the USA population, despite the fact that 30-40% of all food is deposited in a landfill. Food rescue nutrition is the process of redistribution of surplus food to the impoverished. The aim of this study is to document the extent of involvement of organizations in food rescue nutrition. STUDY DESIGN: In this cross-sectional study, a survey about organizations involved in food rescue nutrition was developed, validated, and then tested. METHOD: Directors of 100 organizations involved in food rescue nutrition from eight Southwestern States in the USA participated in this research. RESULTS: These organizations provided an average of 2 million kg of food to more than 40,000 clients each month. Food assistance programs had an average of eight workers and 3081 volunteers. In addition to food, these organizations provided other services such as clothing, clinical, and childcare. The agencies encountered several challenges, including lack of resources that resulted in reducing food portions and turning away clients. CONCLUSIONS: The extent of involvement of community-based programs in food rescue nutrition was strong in eight Southwestern states in the USA. Organizations involved in food redistribution helped alleviate food insecurity in their clients. Sustainability of these charitable networks was dependent on availability of resources and sufficient volunteers. Health professionals should encourage these organizations by providing support through donations of time, money, and/or food. PMID- 28888133 TI - Rhesus monkeys for a nonhuman primate model of cytomegalovirus infections. AB - Human cytomegalovirus (HCMV) is the leading opportunistic viral infection in solid organ transplant patients and is the most common congenitally transmitted pathogen worldwide. Despite the significant burden of disease HCMV causes in immunosuppressed patients and infected newborns, there are no licensed preventative vaccines or effective immunotherapeutic treatments for HCMV, largely due to our incomplete understanding of the immune correlates of protection against HCMV infection and disease. Though CMV species-specificity imposes an additional challenge in defining a suitable animal model for HCMV, nonhuman primate (NHP) CMVs are the most genetically related to HCMV. In this review, we discuss the advantages and applicability of rhesus monkey models for studying HCMV infections and pathogenesis and ultimately informing vaccine development. PMID- 28888135 TI - STRSeq: A catalog of sequence diversity at human identification Short Tandem Repeat loci. AB - The STR Sequencing Project (STRSeq) was initiated to facilitate the description of sequence-based alleles at the Short Tandem Repeat (STR) loci targeted in human identification assays. This international collaborative effort, which has been endorsed by the ISFG DNA Commission, provides a framework for communication among laboratories. The initial data used to populate the project are the aggregate alleles observed in targeted sequencing studies across four laboratories: National Institute of Standards and Technology (N=1786), Kings College London (N=1043), University of North Texas Health Sciences Center (N=839), and University of Santiago de Compostela (N=944), for a total of 4612 individuals. STRSeq data are maintained as GenBank records at the U.S. National Center for Biotechnology Information (NCBI), which participates in a daily data exchange with the DNA DataBank of Japan (DDBJ) and the European Nucleotide Archive (ENA). Each GenBank record contains the observed sequence of a STR region, annotation ("bracketing") of the repeat region and flanking region polymorphisms, information regarding the sequencing assay and data quality, and backward compatible length-based allele designation. STRSeq GenBank records are organized within a BioProject at NCBI (https://www.ncbi.nlm.nih.gov/bioproject/380127), which is sub-divided into: commonly used autosomal STRs, alternate autosomal STRs, Y-chromosomal STRs, and X-chromosomal STRs. Each of these categories is further divided into locus-specific BioProjects. The BioProject hierarchy facilitates access to the GenBank records by browsing, BLAST searching, or ftp download. Future plans include user interface tools at strseq.nist.gov, a pathway for submission of additional allele records by laboratories performing population sample sequencing and interaction with the STRidER web portal for quality control (http://strider.online). PMID- 28888136 TI - Activating attachment representations during memory retrieval modulates intrusive traumatic memories. AB - Although priming mental representations of attachment security reduces arousal, research has not examined the effect of attachment on the retrieval of emotionally arousing memories. This study investigated the effect of priming attachment security on the retrieval of emotional memories. Seventy-five participants viewed negative and neutral images, and two days later received either an attachment prime or a control prime immediately prior to free recall of the images. Two days later, participants reported how frequently they experienced intrusions of the negative images. The attachment group had less distress, and reported fewer subsequent intrusions than the control group. Attachment style moderated these effects such that individuals with an avoidant attachment style were not impacted by the attachment prime. These findings suggest that priming attachment security decreases distress during memory reactivation, and this may reduce subsequent intrusive memories. PMID- 28888137 TI - Independent self-construal mediates the association between CYP19A1 gene variant and subjective well-being. AB - Testosterone and estrogen are involved in self-related behavioral dispositions and experiences of subjective well-being. In this study, we investigated to what extent the aromatase (CYP19A1) gene, which encodes an enzyme in converting testosterone into estrogen, contributes to subjective well-being and in another self-related disposition: independent and interdependent self-construal. In study 1, a meta-analysis showed that the GG genotype of CYP19A1 (a G/A substitution at Val80, rs700518) was associated with higher testosterone and lower estradiol. In study 2, an empirical study of individuals with the GG (n=115), AG (n=286) and AA (n=193) genotypes indicated that individuals with the GG genotype exhibited higher independent self-construal and higher subjective well-being. The association between the GG genotype of CYP19A1 Val80 and subjective well-being was mediated by the independent self-construal. Our findings reinforce the idea that personality traits such as independent self-construal explain the link between genetic variant and subjective well-being. PMID- 28888138 TI - Personality disorder is an excess risk factor for physical multimorbidity among women with mental state disorders. AB - We examined whether mental state disorders (lifetime mood, anxiety, eating, substance misuse) with comorbid personality disorder are associated with physical multimorbidity in a population-based sample of women. Mental state and personality disorders were assessed using semi-structured diagnostic interviews. Clinical measures were performed and medical conditions, medication use and lifestyle factors were documented by questionnaire. Mental state disorders were associated with higher odds of physical multimorbidity; risk was especially high for those with comorbid personality disorder. These findings suggest that mental state and physical comorbidity might be worsened by the additional comorbidity of personality disorder. PMID- 28888140 TI - Difficult extubation of an electromyographic endotracheal tube in an underweight patient. PMID- 28888139 TI - TET proteins in natural and induced differentiation. AB - The ten-eleven-translocation (TET) proteins oxidize 5-methylcytosine in DNA. Alterations in TET protein function have been linked to cancer, but TETs have also been observed to influence many cell differentiation processes. Here we review recent work assessing the contribution of TET proteins to natural and induced differentiation. Altogether these analyses have helped characterize how TETs and their enzymatic products influence DNA methylation patterns, regulatory element activity, DNA binding protein specificity and gene expression. PMID- 28888141 TI - Chest wall rigidity due to high dose sugammadex. PMID- 28888142 TI - Interrelationships between electrical, mechanical and hydration properties of cortical bone. AB - Interrelationship between electrical and mechanical properties of cortical bone and the role of bone composition in this interrelationship are not comprehensively investigated to date. This study aimed to investigate associations of electrical properties (i.e., specific impedance, dielectric constant, and conductivity) with mechanical properties (i.e., toughness, strength and elastic modulus) of wet and sequentially dehydrated cortical bone. Bovine cortical bone samples (N = 24) were subjected to three-point bending test. A sequential heat treatment protocol ensued to tease out contributions of unbound water and bound water. Demineralization was performed to understand contributions of organic matrix and the mineral phase to the electrical properties of cortical bone. Raman-spectroscopy based water measurement was used to investigate involvement of collagen- and mineral-bound water in the electrical properties. Our results showed statistically significant correlations between electrical and mechanical properties of cortical bone. Toughness and ultimate strength were negatively correlated with impedance and positively correlated with conductivity and dielectric constant. The highest correlations between electrical and mechanical properties of cortical bone were typically found at the frequencies of 0.2, 0.5 and 1MHz. The electrical properties of bone changed significantly as a result of sequential dehydration, indicating that unbound and bound water compartments are the key determinants of the electrical properties. Comparison of porosity matched bone samples with high and low amount of bound water showed that bound water compartments may have an independent role in determining electrical properties of cortical bone. Furthermore, the results indicated that collagen and mineral-bound water may contribute differentially to the electrical properties of a bone. In the overall, our results suggest that electrical properties of cortical bone may be used to assess bone toughness and strength, and also underline the necessity for developing techniques to measure these electrical properties in vivo. PMID- 28888143 TI - Synthetic zwitterionic polysaccharides. AB - Zwitterionic polysaccharides (ZPSs) are a unique class of polysaccharides that are capable of eliciting a T-cell response after being processed by antigen presenting cells and presented on MHC II molecules. In addition, they have also been shown to be potent stimulators of the innate arm of the immune system. To unravel the molecular details of their remarkable immunological activity, various synthetic approaches to assemble fragments towards these polysaccharides have been reported. This review describes these efforts, illustrating the immense challenges presented by these inspiring structures. PMID- 28888144 TI - Previously undescribed fridooleanenes and oxygenated labdanes from the brown seaweed Sargassum wightii and their protein tyrosine phosphatase-1B inhibitory activity. AB - Previously undescribed fridooleanene triterpenoids 2alpha-hydroxy-(28,29)-frido olean-12(13), 21(22)-dien-20-propyl-21-hex-4'(Z)-enoate, 2alpha-hydroxy-(28,29) frido-olean-12(13), 21(22)-dien-20-prop-2(E)-en-21-butanoate and oxygenated labdane diterpenoids 2alpha-hydroxy-8(17), (12E), 14-labdatriene, 3beta, 6beta, 13alpha-tri hydroxy 8(17), 12E, 14-labdatriene were purified from the ethyl acetate-methanol and dichloromethane fractions of the air-dried thalli of Sargassum wightii (Sargassaceae), a brown seaweed collected from the Gulf-of Mannar of Penninsular India. Inhibitory potential of Delta12 oleanenes towards protein tyrosine phosphatase-1B, the critical regulator of insulin-receptor activity were found to be significantly greater (IC50 0.1 * 10-2 and 0.09 * 10-2 mg/mL, respectively) than the standard sodium metavanadate (IC50 0.31 * 10-2 mg/mL). Fridooleanene triterpenoids displayed greater antioxidant activities (IC50DPPH 0.16-0.18 mg/mL) than the commercially available antioxidants, butylated hydroxytoluene and alpha-tocopherol (IC50DPPH 0.25 and 0.63 mg/mL, respectively). In general, the oxygenated labdane diterpenoids displayed significantly lesser antioxidant and tyrosine phosphatase-1B inhibitory properties than those exhibited by the fridooleanenes. Bioactivities of the titled compounds were primarily determined by the electronic and lipophilic parameters and not by the steric descriptors. Molecular docking simulations and kinetic studies were employed to describe the tyrosine phosphatase-1B inhibitory mechanism. The previously undescribed fridooleanene triterpenoids might be used as potential anti-hyperglycaemic pharmacophore leads to reduce the risk of elevated postprandial glucose levels. PMID- 28888145 TI - NMR-based identification of the major bioactive molecules from an Italian cultivar of Lycium barbarum. AB - Lycium barbarum (Solanaceae), long known to the traditional Chinese medicine because of its many health-promoting effects, has of late spread widely across the Western hemisphere, mainly on account of the nutritional richness in vitamins, minerals and antioxidant metabolites of its fruits. Data on bioactive metabolites from fruits and leaves, which are commonly consumed in soups and salads, are scarce and sometimes even contradictory. By means of NMR, the present study identified the specialised products contained in an Italian cultivar of L. barbarum. Kaempeferol, caffeic acid, 3,4,5-trihydroxycinnamic acid and 5 hydroxyferulic acid were found in fresh fruits; rutin and chlorogenic acid were detected in leaves and flowers; also, a previously undescribed N,N dicaffeoylspermidine derivative was identified in flowers, while N feruloyltyramine derivatives, for which interesting anti-inflammatory properties have been reported, turned out to be the major bioactive molecules in stems. The plethora of the detected bioactive molecules amplifies the nutraceutical value of berries and leaves and prompts the exploitation of L. barbarum flowers and pruned stems as sources of beneficial compounds. PMID- 28888146 TI - Is there much discrepancy between glycated hemoglobin and glycated albumin? PMID- 28888147 TI - Overweight, hyperglycemia and tobacco use are modifiable risk factors for onset of retinopathy 9 and 17years after the diagnosis of diabetes - A retrospective observational nation-wide cohort study. AB - BACKGROUND: The aims of this study were to estimate the risk for diabetic retinopathy (DR) and to identify risk factors. We investigated a nationwide population-based cohort with diabetes diagnosed at age 15-34years. PATIENTS AND METHODS: Of 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) 444 (56%) patients with retinal photos available for classification of retinopathy participated in a follow-up study 15-19 (median 17) years after diagnosis. Mean age was 42.3+/-5.7years, BMI 26.1+/-4.1kg/m2, 62% were male and 91% had type 1 diabetes. A sub-study was performed in 367 patients with retinal photos from both the 9 and 17year follow up and the risk for development of retinopathy between 9 and 17years of follow up was calculated. RESULTS: After median 17years 324/444 (73%, 67% of T1D and 71% of T2D), had developed any DR but only 5.4% proliferative DR. Male sex increased the risk of developing retinopathy (OR 1.9, 95% CI 1.2-2.9). In the sub-study obesity (OR 1.2, 95% CI 1.04-1.4), hyperglycemia (OR 2.5, 95% CI 1.6-3.8) and tobacco use (OR 2.9, 95% CI 1.1-7.3) predicted onset of retinopathy between 9 and 17years after diagnosis of diabetes. CONCLUSION: The number of patients with severe retinopathy after 17years of diabetes disease was small. The risk of developing retinopathy with onset between 9 and 17years after diagnosis of diabetes was strongly associated to modifiable risk factors such as glycemic control, obesity and tobacco use. PMID- 28888148 TI - Hypoglycemia awareness among insulin-treated patients with diabetes in Malaysia: A cohort subanalysis of the HAT study. AB - AIMS: The present Malaysian cohort analysis determined the prevalence of hypoglycemia among patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) attending primary care- or hospital-based diabetes clinics in Malaysia and their awareness of the symptoms of hypoglycemia. METHODS: The Hypoglycemia Assessment Tool (HAT) study was a non-interventional, 6-month retrospective and 4-week prospective analysis of hypoglycemic events in 24 countries, using self-assessment questionnaires and diaries among patients with T1DM/T2DM aged >=18years, using insulin for >12months. This report focuses on prospective data, as they are less prone to recall bias. RESULTS: There were 1153 participants in the Malaysian cohort (114 T1DM; 1039 T2DM). In the prospective period, 50.4% and 33.4% of patients reported >=1 hypoglycemic events, with estimated rates of 20.3 and 13.1 events per patient-year of exposure in patients with T1DM and T2DM, respectively. 24.8% and 16.1% of patients with T1DM or T2DM, respectively, reported >=1 nocturnal hypoglycemic event. The majority of patients (96.5%, T1DM; 91.8%, T2DM) knew what hypoglycemia was prior to the study. Impaired awareness was present in 48.0% (T1DM) and 36.9% (T2DM) of patients. In the prospective period, 50% of patients with T1DM or T2DM consulted a doctor or nurse following a hypoglycemia episode. CONCLUSIONS: Half of patients with T1DM and a third of patients with T2DM reported >=1 hypoglycemic event during the prospective period. Although the majority of patients knew the typical features of hypoglycemia, many reported impaired ability to recognize symptoms in real life. The present findings highlight the importance of patient education and physician awareness in dealing with hypoglycemia, in particular the burden of hypoglycemic unawareness. CLINICAL TRIAL NUMBER: This trial was registered at www.clinicaltrials.gov as NCT01696266 on 26 September 2012. PMID- 28888149 TI - The impact of alcohol policies on alcohol-attributable diseases in Taiwan-A population-based study. AB - BACKGROUND: Taiwan has some of the strictest alcohol-related driving laws in the world. However, its laws continue to be toughened to reduce the ever-increasing social cost of alcohol-related harm. AIM: This study assumes that alcohol-related driving laws show a spillover effect such that behavioral changes originally meant to apply behind the wheel come to affect drinking behavior in other contexts. The effects of alcohol driving laws and taxes on alcohol-related morbidity are assessed; incidence rates of alcohol-attributable diseases (AAD) serve as our measure of morbidity. METHODS: Monthly incidence rates of alcohol attributable diseases were calculated with data from the National Health Insurance Research Database (NHIRD) from 1996 to 2011. These rates were then submitted to intervention analyses using Seasonal Autoregressive Integrated Moving Average models (ARIMA) with multivariate adaptive regression splines (MARS). ARIMA is well-suited to time series analysis while MARS helps fit the regression model to the cubic curvature form of the irregular AAD incidence rates of hospitalization (AIRH). RESULTS: Alcoholic liver disease, alcohol abuse and dependence syndrome, and alcohol psychoses were the most common AADs in Taiwan. Compared to women, men had a higher incidence of AADs and their AIRH were more responsive to changes in the laws governing permissible blood alcohol. The adoption of tougher blood alcohol content (BAC) laws had significant effects on AADs, controlling for overall consumption of alcoholic beverages. CONCLUSION: Blood alcohol level laws and alcohol taxation effectively reduced alcohol attributable morbidities with the exception of alcohol dependence and abuse, a disease to which middle-aged, lower income people are particularly susceptible. Attention should be focused on this cohort to protect this vulnerable population. PMID- 28888150 TI - Gender differences in trajectories of alcohol use from ages 13 to 33 across Latina/o ethnic groups. AB - BACKGROUND: Research examining alcohol use trajectories among Latina/os is scarce. Further, prior findings on alcohol use by ethnic group and gender is mixed. The purpose of this study was twofold: (a.) to examine developmental trajectories for two types of alcohol (drunkenness and heavy drinking) use across four Latina/o ethnic groups (Cubans, Puerto Ricans, Central/South American, and Mexican Americans) and, (b.) to examine the role of gender and ethnicity in developmental trajectories of drunkenness and heavy drinking among Latina/os. METHODS: Data were drawn from Waves I-IV of the National Longitudinal Study of Adolescent to Adult Health. The sample consisted of 1670 Latina/os that were followed from adolescence into adulthood. Multi-level logistic regression models were used to estimate drunkenness and heavy drinking trajectories and trajectories by gender. RESULTS: indicate that, for all four ethnic groups examined, the probability of drunkenness and heavy drinking gradually increased in adolescence, peaked in "emerging adulthood", and decreased as they transitioned into adulthood. Findings also show divergent age trajectories by gender, but patterns varied across ethnicity and alcohol use outcome. CONCLUSIONS: Key findings from this study demonstrate that among Latina/os, there are critical developmental periods for reported drunkenness and heavy drinking in the last 12 months, and that ethnicity and gender play substantial roles in the development of hazardous alcohol use over the life course. PMID- 28888151 TI - Evaluation of the AC-OK mental health and substance abuse screening measure in an international sample of Latino immigrants. AB - BACKGROUND: Early detection and intervention in primary care is integral to behavioral health. Valid, practical screening assessments are scarce, particularly for non-English speaking populations. We address this need by evaluating the psychometric properties of the Spanish version of the AC-OK Screen for Co-occurring Disorders for first and second generation immigrant Latinos in Massachusetts, USA, and Madrid and Barcelona, Spain. METHODS: 567 Latino participants were recruited in waiting areas of clinics or by referral from Primary Care, Mental Health, Substance Use, and HIV Treatment Clinics, as well as Community Agencies. We use confirmatory factor analyses to evaluate the factor structure, correlation analysis to examine concurrent and discriminant validity, and receiver operating curves (ROC) to determine the ability of the AC-OK to approximate a composite of established instruments designed to measure depression, generalized anxiety, post-traumatic stress disorder symptoms, alcohol, and drugs (including benzodiazepines) as external criteria. RESULTS: The original two factor structure was replicated in samples of Latino respondents in the US and Spain. Correlations with other measures followed the expected pattern. In both the US and Spain, ROC analyses suggested that the AC-OK scale was an adequate approximation to other specific measures of mental health (ROC=0.90) and substance abuse problems (ROC=0.83). CONCLUSIONS: The Spanish version of the AC OK Screen has good to excellent psychometric properties in both its subscales. These findings are robust across sites, gender, and type of clinic. We recommend its use for clinical research and for routine screening at treatment centers. PMID- 28888152 TI - Altered functional connectivity to stressful stimuli in prenatally cocaine exposed adolescents. AB - BACKGROUND: Prenatal cocaine exposure (PCE) is linked to addiction and obesity vulnerability. Neural responses to stressful and appetitive cues in adolescents with PCE versus those without have been differentially linked to substance-use initiation. However, no prior studies have assessed cue-reactivity responses among PCE adolescents using a connectivity-based approach. METHODS: Twenty-two PCE and 22 non-prenatally drug-exposed (NDE) age-, sex-, IQ- and BMI-matched adolescents participated in individualized guided imagery with appetitive (favorite-food), stressful and neutral-relaxing cue scripts during functional magnetic resonance imaging. Subjective favorite-food craving scores were collected before and after script exposure. A data-driven voxel-wise intrinsic connectivity distribution analysis was used to identify between-group differences and examine relationships with craving scores. RESULTS: A group-by-cue interaction effect identified a parietal lobe cluster where PCE versus NDE adolescents showed less connectivity during stressful and more connectivity during neutral-relaxing conditions. Follow-up seed-based connectivity analyses revealed that, among PCE adolescents, the parietal seed was positively connected to inferior parietal and sensory areas and negatively connected to corticolimbic during both stress and neutral-relaxing conditions. For NDE, greater parietal connectivity to parietal, cingulate and sensory areas and lesser parietal connectivity to medial prefrontal areas were found during stress compared to neutral-relaxing cueing. Craving scores inversely correlated with corticolimbic connectivity in PCE, but not NDE adolescents, during the favorite-food condition. CONCLUSIONS: Findings from this first data-driven intrinsic connectivity analysis of PCE influences on adolescent brain function indicate differences relating to PCE status and craving. These findings provide insight into the developmental impact of in utero drug exposure. PMID- 28888153 TI - Life events and alcohol use disorder clinical course: Modeling the dynamic association. AB - BACKGROUND: Despite over 35 years of study, the relationship between life events (LEs) and alcohol use disorder (AUD) treatment outcome lacks consistent empirical support, which may be due to a lack of theoretically driven designs and corresponding statistical analyses. The purpose of this study was to elucidate the LEs-AUD treatment outcome relationship by statistically modeling the dynamic relationship between negative LEs and alcohol use post-treatment, as it is conceptualized within the dynamic model of relapse. METHODS: Existing longitudinal data from 417 AUD treatment-seeking adults were randomly assigned to two demographically comparable samples. One sample (N=208) was used to estimate a series of dynamic bivariate latent change score models that differentially relate latent indicators of distal and proximal negative LEs (i.e., events subjectively rated as negative) and percent heavy drinking days across 12 months. Cross validation was conducted on the second sample (N=209). RESULTS: Findings indicated that distal negative LEs were positively associated with a greater increase in negative LEs, but not heavy drinking, over the subsequent 12 months. Proximal negative LEs were significantly associated with subsequent increases in heavy drinking, though heavy drinking was not a determinant of change in negative LEs. These findings were cross-validated with the second sample. CONCLUSIONS: This study provides initial justification for the further study of the LEs alcohol use relationship as it is described in the dynamic model of relapse. PMID- 28888154 TI - Factors associated with an evidence-based measure of implementation for the Adolescent Community Reinforcement Approach. AB - BACKGROUND: An evidence-based measure of implementation (EBMI) is an implementation outcome measure shown to have predictive validity with one or more future-measured constructs of importance. The current study sought to identify correlates and predictors of an EBMI called procedure exposure. Garner et al. (2016) found procedure exposure to be an EBMI for the Adolescent Community Reinforcement Approach (A-CRA). METHODS: The dataset included 76 community-based substance use treatment organizations located across the United States. Organizational-level regression analyses, which were framed within the context of Chaudoir et al. (2013) framework for predicting implementation outcomes, were used to examine predictors of A-CRA procedure exposure RESULTS: The Washington Circle's treatment initiation performance measure (B=5.05 [SE=1.60], p=0.002), as well as session exposure (B=0.18 [SE=0.06], p=0.003), were significant predictors of A-CRA procedure exposure in the backward stepwise regression analysis (Adjusted R-square=0.55). The Washington Circle's treatment engagement performance measure (B=7.93 [SE=0.77], p<0.001), as well as time-to-proficiency (B=-0.04 [SE=0.02], p=0.02), each had significant bivariate relationships with A CRA procedure exposure but were not retained in the final model. CONCLUSIONS: Organizations implementing A-CRA are encouraged to make the following high priorities: (a) scheduling and completing a subsequent treatment session within 14days of their index session (treatment initiation) and (b) providing a targeted number of treatment sessions to each client (session exposure). To the extent organizations do this, they may be more likely to achieve higher levels of A-CRA procedure exposure. PMID- 28888155 TI - Pupil response and attention skills in Down syndrome. AB - Down syndrome (DS) is characterized by attentional problems. Little is known about the neural correlates of attention problems in DS due to difficulties in evaluation. Pupil dilation, associated with an increase in cognitive load and locus coeruleus-noradrenaline system activity in humans, is a neurophysiological measurement that may help to characterize such problems. The aim of this research was to investigate the link between a phasic pupil dilation response and target detection in people with DS, as compared with a control group with typical development (TD) matched by mental age. Participants performed an "oddball" task by means of an eye-tracker and a series of neuropsychological tests. Although the DS and control group demonstrated similar attentional skills and behavioral performance, the participants with DS showed greater pupil dilation. This result suggests that people with DS expend extra cognitive effort to achieve performance similar to those with TD. This finding is discussed in light of the attentional process in DS and the reliability of pupil dilation measurement in the study of attention and other cognitive processes in DS. PMID- 28888156 TI - Exploring the oxygen supply and demand framework as a learning tool in undergraduate nursing education. AB - In nursing education, physiological concepts are typically presented within a body 'systems' framework yet learners are often challenged to apply this knowledge in the holistic and functional manner needed for effective clinical decision-making and safe patient care. A nursing faculty addressed this learning challenge by developing an advanced organizer as a conceptual and integrative learning tool to support learners in diverse learning environments and practice settings. A mixed methods research study was conducted that explored the effectiveness of the Oxygen Supply and Demand Framework as a learning tool in undergraduate nursing education. A pretest/post-test assessment and reflective journal were used to gather data. Findings indicated the Oxygen Supply and Demand Framework guided the development of pattern recognition and thinking processes and supported knowledge development, knowledge application and clinical decision making. The Oxygen Supply and Demand Framework supports undergraduate students learning to provide safe and effective nursing care. PMID- 28888157 TI - Nursing students' evaluation of a new feedback and reflection tool for use in high-fidelity simulation - Formative assessment of clinical skills. A descriptive quantitative research design. AB - : Clinical skills training is an important part of nurses' education programmes. Clinical skills are complex. A common understanding of what characterizes clinical skills and learning outcomes needs to be established. The aim of the study was to develop and evaluate a new reflection and feedback tool for formative assessment. The study has a descriptive quantitative design. 129 students participated who were at the end of the first year of a Bachelor degree in nursing. After highfidelity simulation, data were collected using a questionnaire with 19 closed-ended and 2 open-ended questions. The tool stimulated peer assessment, and enabled students to be more thorough in what to assess as an observer in clinical skills. The tool provided a structure for selfassessment and made visible items that are important to be aware of in clinical skills. CONCLUSIONS: This article adds to simulation literature and provides a tool that is useful in enhancing peer learning, which is essential for nurses in practice. The tool has potential for enabling students to learn about reflection and developing skills for guiding others in practice after they have graduated. PMID- 28888158 TI - Predicting motorcycle crash injury severity using weather data and alternative Bayesian multivariate crash frequency models. AB - Motorcycle crashes constitute a very high proportion of the overall motor vehicle fatalities in the United States, and many studies have examined the influential factors under various conditions. However, research on the impact of weather conditions on the motorcycle crash severity is not well documented. In this study, we examined the impact of weather conditions on motorcycle crash injuries at four different severity levels using San Francisco motorcycle crash injury data. Five models were developed using Full Bayesian formulation accounting for different correlations commonly seen in crash data and then compared for fitness and performance. Results indicate that the models with serial and severity variations of parameters had superior fit, and the capability of accurate crash prediction. The inferences from the parameter estimates from the five models were: an increase in the air temperature reduced the possibility of a fatal crash but had a reverse impact on crashes of other severity levels; humidity in air was not observed to have a predictable or strong impact on crashes; the occurrence of rainfall decreased the possibility of crashes for all severity levels. Transportation agencies might benefit from the research results to improve road safety by providing motorcyclists with information regarding the risk of certain crash severity levels for special weather conditions. PMID- 28888159 TI - Reduction of liver tumerogenic effect of N-nitrosodiethylamine by treatment with gamma-oryzanol in Balb/C mice. AB - In recent years, naturally occurring phytochemicals with antioxidant capacity have generated surmount interest in their therapeutic usage against a wide range of pathological and toxicological conditions. The present study was designed to evaluate potential of gamma-oryzanol (OZ), a bio-active natural antioxidant against hepatocellular carcinoma effect of the carcinogen N-nitrosodiethylamine in Balb/c mice. OZ inhibited the proliferation of Hep-3B cell line in concentration dependent manner. Administration of OZ to N-nitrosodiethylamine induced Balb/c mice for 16 and 32 weeks showed reduction in levels of liver injury markers, restored the levels of liver tumor markers, suppressed the hepatic nodular incidence and multiplicity, and favorably modulated the liver antioxidant status in a time dependent manner. Histologically, no obvious signs of neoplasia in the liver tissues were observed in OZ supplemented rats with N nitrosodiethylamine induced liver tumerogenesis. OZ was found to be effective for reduction of N-nitrosodiethylamine induced hepatocellular carcinoma. PMID- 28888160 TI - Nicotiana benthamiana Matrix Metalloprotease 1 (NMMP1) gene confers disease resistance to Phytophthora infestans in tobacco and potato plants. AB - We previously isolated Nicotiana benthamiana matrix metalloprotease 1 (NMMP1) from tobacco leaves. The NMMP1 gene encodes a highly conserved, Zn-containing catalytic protease domain that functions as a factor in the plant's defense against bacterial pathogens. Expression of NMMP1 was strongly induced during interactions between tobacco and one of its pathogens, Phytophthora infestans. To elucidate the role of the NMMP1 in defense of N. benthamiana against fungal pathogens, we performed gain-of-function and loss-of-function studies. NMMP1 overexpressing plants had stronger resistance responses against P. infestans infections than control plants, while silencing of NMMP1 resulted in greater susceptibility of the plants to the pathogen. This greater susceptibility correlated with fewer NMMP1 transcripts than the non-silenced control. We also examined cell death as a measure of disease. The amount of cell death induced by the necrosis-inducing P. infestans protein 1, PiNPP1, was dependent on NMMP1 in N. benthamiana. Potato plants overexpressing NMMP1 also had enhanced disease resistance against P. infestans. RT-PCR analysis of these transgenic potato plants revealed constitutive up-regulation of the potato defense gene NbPR5. NMMP1-overexpressing potato plants were taller and produced heavier tubers than control plants. We suggest a role for NMMP1in pathogen defense and development. PMID- 28888161 TI - Glyphosate-induced oxidative stress in Arabidopsis thaliana affecting peroxisomal metabolism and triggers activity in the oxidative phase of the pentose phosphate pathway (OxPPP) involved in NADPH generation. AB - Glyphosate is a broad-spectrum systemic herbicide used worldwide. In susceptible plants, glyphosate affects the shikimate pathway and reduces aromatic amino acid synthesis. Using Arabidopsis seedlings grown in the presence of 20MUM glyphosate, we analyzed H2O2, ascorbate, glutathione (GSH) and protein oxidation content as well as antioxidant catalase, superoxide dismutase (SOD) and ascorbate glutathione cycle enzyme activity. We also examined the principal NADPH generating system components, including glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), NADP-malic enzyme (NADP-ME) and NADP-isocitrate dehydrogenase (NADP-ICDH). Glyphosate caused a drastic reduction in growth parameters and an increase in protein oxidation. The herbicide also resulted in an overall increase in GSH content, antioxidant enzyme activity (catalase and all enzymatic components of the ascorbate-glutathione cycle) in addition to the two oxidative phase enzymes, G6PDH and 6PGDH, in the pentose phosphate pathway involved in NADPH generation. In this study, we provide new evidence on the participation of G6PDH and 6PGDH in the response to oxidative stress induced by glyphosate in Arabidopsis, in which peroxisomal enzymes, such as catalase and glycolate oxidase, are positively affected. We suggest that the NADPH provided by the oxidative phase of the pentose phosphate pathway (OxPPP) should serve to maintain glutathione reductase (GR) activity, thus preserving and regenerating the intracellular GSH pool under glyphosate-induced stress. It is particularly remarkable that the 6PGDH activity was unaffected by pro-oxidant and nitrating molecules such as H202, nitric oxide or peroxynitrite. PMID- 28888162 TI - Improved short-term drought response of transgenic rice over-expressing maize C4 phosphoenolpyruvate carboxylase via calcium signal cascade. AB - To understand the link between long-term drought tolerance and short-term drought responses in plants, transgenic rice (Oryza sativa L.) plants over-expressing the maize C4-pepc gene encoding phosphoenolpyruvate carboxylase (PC) and wild-type (WT) rice plants were subjected to PEG 6000 treatments to simulate drought stress. Compared with WT, PC had the higher survival rate and net photosynthetic rate after 16days of drought treatment, and had higher relative water content in leaves after 2h of drought treatment as well, conferring drought tolerance. WT accumulated higher amounts of malondialdehyde, superoxide radicals, and H2O2 than PC under the 2-h PEG 6000 treatment, indicating greater damages in WT. Results from pretreatments with a Ca2+ chelator and/or antagonist showed that the regulation of the early drought response in PC was Ca2+-dependent. The NO and H2O2 levels in PC lines were also up-regulated via Ca2+ signals, indicating that Ca2+ in PC lines also reacted upstream of NO and H2O2. 2-h drought treatment increased the transcripts of CPK9 and CPK4 in PC via positive up-regulation of Ca2+. The transcripts of NAC6 [NACs (NAM, ATAF1, ATAF2, and CUC2)] and bZIP60 (basic leucine zipper, bZIP) were up-regulated, but those of DREB2B (dehydration responsive element-binding protein, DREB) were down-regulated, both via Ca2+ signals in PC. PEPC activity, expressions of C4-pepc, and the antioxidant enzyme activities in PC lines were up-regulated via Ca2+. These results indicated that Ca2+ signals in PC lines can up-regulate the NAC6 and bZIP60 and the downstream targets for early drought responses, conferring drought tolerance for the long term. PMID- 28888163 TI - Overexpression of GhDof1 improved salt and cold tolerance and seed oil content in Gossypium hirsutum. AB - A homologous GhDof1, which belongs to a large family of plant-specific transcription factor DOF, was isolated from Upland cotton (Gossypium hirsutum L.). GhDof1 protein was located in the nucleus of onion epidermal cells, the core domain of transcriptional activity existed in the C-terminal, and the activity elements of GhDof1 promoter existed in the regions of -645~ -469bp and -286~ 132bp of transcriptional start codon. GhDof1 constitutively expressed in leaves, roots and stems, accumulated highest in leaves. The salinity and cold treatments induced GhDof1 transcript accumulation. The GhDof1-overexpressed cotton showed significantly higher salt and cold tolerance over the wild-type plants. Under salt stress, the root growth of overexpressed GhDof1 lines was promoted. The expression levels of stress-responsive genes, GhP5CS, GhSOD and GhMYB, were differently up-regulated in transgenic lines. Oil contents increased in some transgenic plants, and protein contents reduced compared with transformed receptor. These results suggested that GhDof1 was a functional transcription factor for improving the abiotic tolerance and seed oil content in Upland cotton. PMID- 28888164 TI - Retooling microorganisms for the fermentative production of alcohols. AB - Bioengineering and synthetic biology approaches have revolutionised the field of biotechnology, enabling the introduction of non-native and de novo pathways for biofuels production. This 'retooling' of microorganisms is also applied to the utilisation of mixed carbon components derived from lignocellulosic biomass, a major technical barrier for the development of economically viable fermentations. This review will discuss recent advances in microorganism engineering for efficient production of alcohols from waste biomass. These advances span the introduction of new pathways to alcohols, host modifications for more cost effective utilisation of lignocellulosic waste and modifications of existing pathways for generating new fuel additives. PMID- 28888165 TI - Microbial production of alka(e)ne biofuels. PMID- 28888166 TI - Sub-lethal effects of waterborne exposure to copper nanoparticles compared to copper sulphate on the shore crab (Carcinus maenas). AB - The toxicity of soluble copper (Cu) to marine organisms is reasonably well described. However, the hazard of Cu engineered nanomaterial (ENMs) is poorly understood. The aim of the present study was to compare the toxicity of Cu ENMs to Cu as CuSO4 in the shore crab, Carcinus maenas. The crabs were exposed via the water using a semi-static approach to 0.2 or 1mgL-1 of Cu ENMs or 1mgL-1 of Cu as CuSO4. Gills, hepatopancreas, chela muscle and haemolymph were collected at days 0, 4 and 7 for the body burden of Cu, histology and biochemical analysis [thiobarbituric acid reactive substances (TBARS) and total glutathione (GSH)]. Nominal exposure concentrations of both the ENMs and the metal salt were maintained at over 80% in each treatment throughout the experiment. By day 7, 54% mortality was recorded in the 1mgL-1 CuSO4 treatment, compared to just 21% in the 1mgL-1 Cu ENM-exposed crabs. The target organs for Cu accumulation were similar for both forms of Cu with highest concentrations in the gills, particularly the posterior gills; followed by the hepatopancreas, and with the lowest concentrations in the chela muscle. No changes were observed in the osmolarity of the haemolymph (ANOVA, P>0.05). TBARS were measured as an indicator of lipid peroxidation and showed the greatest change in the anterior and posterior gills and hepatopancreas of animals exposed to 1mgL-1 Cu ENMs (ANOVA or Kruskal-Wallis, P<0.05). No statistically significant changes in total GSH were observed (ANOVA, P>0.05; n=6 crabs per treatment). Histological analysis revealed organ injuries in all treatments. The types of pathologies observed in the Cu ENM treatments were broadly similar to those of the Cu as CuSO4 treatment. Overall, the target organs and Cu accumulation from Cu ENMs were comparable to that following exposure to Cu as CuSO4, and although there were some differences in the sub lethal effects, the metal salt was more acutely toxic. PMID- 28888167 TI - Protective effect of 5, 7-dihydroxyflavone on brain of rats exposed to acrylamide or gamma-radiation. AB - 5, 7-Dihydroxyflavone (DHF), a natural plant flavonoid, have shown a variety of beneficial effects. Neurotoxic effects of acrylamide (ACR) or gamma irradiation (IR) have been established in humans and animals. The current study was designed to evaluate whether DHF could restrain ACR or IR induced neurotoxicity in rats and to explore the underlying mechanisms. The study was carried out by investigating some biochemical and biophysical parameters as well as histopathological examination. The daily oral administration of ACR (25mg/kg b.wt.) for 21days or exposure to single dose of IR (5Gy) induced brain damage throughout the significant decrease in catecholamine contents and brain derived neurotrophic factor (BDNF) in brain tissue with a concomitant significant decrease in serum activity of creatinine kinase-BB. Moreover, the brain levels of MDA and beta-amyloid and activities of acetylcholinesterase and caspase-3 were remarkably augmented in ACR-induced rats. Additionally, the electrical properties of erythrocytes membrane were significantly disturbed. The administration of DHF (50mg/kg b.wt. daily for 21day) to rats exposed to either ACR or IR significantly reversed the alteration in all studied parameters. Histopathological investigation of brain tissues supported the neuroprotective effect of DHF on brain. From the obtained data, it can be concluded that the DHF has neuroprotective effect against ACR or IR induced-neurotoxicity. PMID- 28888168 TI - Triazine-based covalent organic frameworks for photodynamic inactivation of bacteria as type-II photosensitizers. AB - With the increase of antibiotic resistances in microorganisms, photodynamic inactivation (PDI) as a clinically proven antibacterial therapy is gaining increasing attention in recent years due to its high efficacy. Herein, we reported two covalent organic frameworks (COFs) materials, namely COFs-Trif-Benz and COF-SDU1, as effective type-II photosensitizers for photodynamic inactivation of bacteria. COFs-Trif-Benz and COF-SDU1 are synthesized through a facile solvothermal reaction between tri-(4-formacylphenoxy)-1,3,5-triazine (trif) and benzidine or p-phenylenediamine with high yield. Their highly ordered and porous structures were confirmed by Fourier transform infrared (FT-IR) spectra, solid state 13C CP/MAS NMR spectrum, powder X-ray diffraction (PXRD) and Brunauer Emmett-Teller (BET) analyses. The electronic absorption spectra and electrochemical experiments revealed that the extensive pi-conjugation over COFs Trif-Benz and COF-SDU1 greatly enhance their absorbance capability for visible light and make them have a lower band gap. The photocatalytic antibacterial assay was studied against both Gram-positive Staphylococcus aureus (S. aureus) and Gram negative Escherichia coli O86:B7 (E. coli O86) bacteria. Two materials can kill more than 90% bacteria at concentrations of 100MUgmL-1 after 60-90min of illumination. Thus, both COFs are effective photosensitizers. Mechanism investigation revealed the antibacterial characteristics of the COFs-Trif-Benz and COF-SDU1 can generate reactive oxygen species (ROS) by energy transfer to molecular oxygen (3O2) to produce a highly reactive singlet oxygen (1O2). Hence, the two materials during the photodynamic were mainly via mechanism type II. PMID- 28888169 TI - Green synthesis of Si-incorporated hydroxyapatite using sodium metasilicate as silicon precursor and in vitro antibiotic release studies. AB - The aim of the current study is to synthesize nanosized silicon incorporated HAp (Si-HAP) using sodium metasilicate as the silicon source. The sol-gel derived samples were further subjected to microwave irradiation. Incorporation of Si into HAp did not alter the HAp phase, as confirmed by the X-ray diffraction analysis (XRD). Moreover, variation in the lattice parameters of the Si-incorporated HAp indicates that Si is substituted into the HAp lattice. The decrease in the intensity of the peaks attributed to hydroxyl groups, which appeared in the FTIR and Raman spectra of Si-HAp, further confirms the Si substitution in HAp lattices. The silicon incorporation enhanced the nanorods length by 70%, when compared to that of pure HAp. Microwave irradiation improved the crystallinity of Si-HAp when compared to as-synthesized Si-HAp samples. As-synthesized Si incorporated HAp sample showed an intense blue emission under UV excitation. Microwave irradiation reduced the intensity of blue emission and exhibited red shift due to the reduction of defects in the Si-HAp crystal. The morphological change from rod to spherical and ribbon-like forms was observed with an increase in silicon content. Further, Si-HAp exhibited better bioactivity and low dissolution rate. Initially there was a burst release of amoxicillin from all the samples, subsequently it followed a sustained release. The microwave-irradiated HAp showed extended period of sustained release than that of as-synthesized HAp and Si-HAp. Similarly, the microwave-irradiated Si-incorporated samples exhibited prolonged drug release, as compared to that of the as-synthesized samples. Hence, Si-HAp is rapidly synthesized by a simple and cost effective method without inducing any additional phases, as compared to the conventional sintering process. This study provides a new insight into the rapid green synthesis of Si HAp. Si-HAp could emerge as a promising material for the bone tissue replacement and as a drug delivery system. PMID- 28888170 TI - CorteXpert: A model-based method for automatic renal cortex segmentation. AB - This paper introduces a model-based approach for a fully automatic delineation of kidney and cortex tissue from contrast-enhanced abdominal CT scans. The proposed framework, named CorteXpert, consists of two new strategies for kidney tissue delineation: cortex model adaptation and non-uniform graph search. CorteXpert was validated on a clinical data set of 58 CT scans using the cross-validation evaluation strategy. The experimental results indicated the state-of-the-art segmentation accuracies (as dice coefficient): 97.86% +/- 2.41% and 97.48% +/- 3.18% for kidney and renal cortex delineations, respectively. PMID- 28888171 TI - Discriminative confidence estimation for probabilistic multi-atlas label fusion. AB - Quantitative neuroimaging analyses often rely on the accurate segmentation of anatomical brain structures. In contrast to manual segmentation, automatic methods offer reproducible outputs and provide scalability to study large databases. Among existing approaches, multi-atlas segmentation has recently shown to yield state-of-the-art performance in automatic segmentation of brain images. It consists in propagating the labelmaps from a set of atlases to the anatomy of a target image using image registration, and then fusing these multiple warped labelmaps into a consensus segmentation on the target image. Accurately estimating the contribution of each atlas labelmap to the final segmentation is a critical step for the success of multi-atlas segmentation. Common approaches to label fusion either rely on local patch similarity, probabilistic statistical frameworks or a combination of both. In this work, we propose a probabilistic label fusion framework based on atlas label confidences computed at each voxel of the structure of interest. Maximum likelihood atlas confidences are estimated using a supervised approach, explicitly modeling the relationship between local image appearances and segmentation errors produced by each of the atlases. We evaluate different spatial pooling strategies for modeling local segmentation errors. We also present a novel type of label-dependent appearance features based on atlas labelmaps that are used during confidence estimation to increase the accuracy of our label fusion. Our approach is evaluated on the segmentation of seven subcortical brain structures from the MICCAI 2013 SATA Challenge dataset and the hippocampi from the ADNI dataset. Overall, our results indicate that the proposed label fusion framework achieves superior performance to state-of-the-art approaches in the majority of the evaluated brain structures and shows more robustness to registration errors. PMID- 28888172 TI - Simultaneous extraction of propofol and propofol glucuronide from hair followed by validated LC-MS/MS analyses. AB - Besides its clinical application, the anaesthetic agent propofol is being increasingly misused, mostly by healthcare professionals, and its abuse potential gained worldwide attention after the tragic death of Michael Jackson in 2009. Due to the short duration of its narcotic effects, propofol abuse is especially easy to hide compared with the use of other recreational drugs. However, propofol possesses a very narrow therapeutic window between the desired effect and potentially fatal toxicity, making abuse of the drug extremely dangerous even in experienced physicians. Consequently, it is important that forensic laboratories possess a sensitive and specific method for the detection of chronic propofol abuse. We present a simple, fast and reliable method to simultaneously extract propofol and its main metabolite propofol glucuronide from hair, followed by sensitive LC-MS/MS analyses, allowing to determine a chronic propofol abuse. Difficulties regarding the detection of propofol using LC-MS/MS were solved by using a derivatization reaction with 2-fluoro-1-methylpyridinium-p-toluene sulfonate and triethylamine. Reliability of extraction method and subsequent LC MS/MS analyses was confirmed under consideration of the validation parameters selectivity, linearity, accuracy and precision, analytical limits, processed sample stability, matrix effects and recovery. Appropriate quantification (LLOQ=10pg/mg hair) and detection limits (3.6pg/mg hair for propofol and 7.8 pg/mg hair for propofol glucuronide) could be achieved, enabling to detect even small amounts of both analytes. Applicability of the method was confirmed by analysis of three human hair samples from deceased with suspicion of chronic propofol abuse. PMID- 28888174 TI - Repetitive negative thinking and suicide: a burgeoning literature with need for further exploration. AB - Extant research has found a significant overlap between various repetitive negative thinking (RNT) patterns, such as rumination and worry, across different affective disorders implicating that the process of repetitive negative thinking is likely trans-diagnostic. Furthermore, RNT patterns at the core of psychiatric disorders associated with suicide (e.g., rumination and worry) have been found to be associated with suicide even after accounting for the disorder. A synthesis of existing literature on repetitive negative thoughts suggest that following negative emotional experiences, RNTs may lead to a sense of entrapment and hopelessness that may contribute to the onset of suicidal ideation and then facilitate the transition from thinking about suicide to making a suicide attempt by increasing an individual's capability for suicide through repetitive exposure to violent thoughts and imagery associated with suicide. PMID- 28888173 TI - LC-MS/MS assay for the quantitation of the ATR kinase inhibitor VX-970 in human plasma. AB - DNA damaging chemotherapy and radiation are widely used standard-of-care modalities for the treatment of cancer. Nevertheless, the outcome for many patients remains poor and this may be attributed, at least in part, to highly effective DNA repair mechanisms. Ataxia-telangiectasia mutated and Rad3-related (ATR) is a key regulator of the DNA-damage response (DDR) that orchestrates the repair of damaged replication forks. ATR is a serine/threonine protein kinase and ATR kinase inhibitors potentiate chemotherapy and radiation. The ATR kinase inhibitor VX-970 (NSC 780162) is in clinical development in combination with primary cytotoxic agents and as a monotherapy for tumors harboring specific mutations. We have developed and validated an LC-MS/MS assay for the sensitive, accurate and precise quantitation of VX-970 in human plasma. A dilute-and-shoot method was used to precipitate proteins followed by chromatographic separation with a Phenomenex Polar-RP 80A (4MUm, 50*2mm) column and a gradient acetonitrile water mobile phase containing 0.1% formic acid from a 50MUL sample volume. Detection was achieved using an API 4000 mass spectrometer using electrospray positive ionization mode. The assay was linear from 3 to 5,000ng/mL, proved to be accurate (94.6-104.2%) and precise (<8.4% CV), and fulfilled criteria from the FDA guidance for bioanalytical method validation. This LC-MS/MS assay will be a crucial tool in defining the clinical pharmacokinetics and pharmacology of VX-970 as it progresses through clinical development. PMID- 28888175 TI - Solitary drinking is associated with specific alcohol problems in emerging adults. AB - Hazardous drinking in emerging adulthood is associated with multiple domains of alcohol problems, which range in type and severity. Alcohol problems at the severe end of the spectrum (e.g., impaired control) may be early warning signs of alcohol use disorders (AUDs) among emerging adults. However, given the emphasis in the literature on predictors of overall problem risk, we still know very little about predictors of these specific (and severe) domains of alcohol problems in emerging adults. Many emerging adults drink at social events (e.g., parties), but an estimated 15% engage in solitary drinking. Solitary drinking - a developmentally atypical behavior in emerging adulthood - may be especially risky. Data suggests that frequent solitary drinking may reflect a loss of control over drinking, leading to hazardous use and subsequent problems. Accordingly, we expected that frequent solitary drinking among emerging adults would predict severe alcohol problems that map onto diagnostic criteria for AUDs and these effects would be mediated by hazardous alcohol use. Undergraduates (N=118) completed self-report measures as a part of a larger study on motivation and alcohol use. As predicted, path analysis showed that solitary drinking positively predicted hazardous alcohol use, and this in turn predicted severe alcohol problems associated with diagnostic criteria for AUDs, particularly risky behaviors and blackout drinking. Solitary drinking also positively predicted less severe problems of diminished self-perception and poor self-care through hazardous use. Though comparatively smaller, some indirect effects were observed from social drinking (at parties, but not at bars) to alcohol problems, via hazardous alcohol use. Overall, our results suggest that solitary drinking is particularly harmful in emerging adulthood. PMID- 28888176 TI - Novel mechanisms in immune tolerance to allergens during natural allergen exposure and allergen-specific immunotherapy. AB - Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a clinical tolerance-inducing and immune tolerance-inducing therapy for allergic diseases and represents a potentially curative method of treatment. AIT functions through multiple mechanisms including early desensitization of basophils and mast cells, regulating T-cell and B-cell responses, changing antibody isotypes, and decreasing activation, mediator release and affected tissue migration of eosinophils, basophils, and mast cells. Similar molecular and cellular mechanisms have been observed in subcutaneous AIT, sublingual AIT and peptide immunotherapy as well as natural tolerance to high doses of allergen exposure in beekeepers and cat owners. PMID- 28888177 TI - A label-free cardiac biomarker immunosensor based on phase-shifted microfiber Bragg grating. AB - Fiber optics evanescent field based biosensor is an excellent candidate for label free detection of cardiac biomarkers which is of great importance in rapid, early, and accurate diagnosis of acute myocardial infarction (AMI). In this paper, we report a compact and sensitive cardiac troponin I (cTn-I) immunosensor based on the phase-shifted microfiber Bragg grating probe which is functionalized. The fine reflective signal induced by the phase shift in modulation significantly improves the spectral resolution, enabling the ability of the sensor in perceiving an ultra-small refractive index change due to the specific capture of the cTn-I antigens. In buffer, a log-linear sensing range from 0.1 to 10ng/mL and a limit of detection (LOD) of 0.03ng/mL (predicted to be as low as 10.8pg/mL) are obtained. Furthermore, with good specificity, the sensor can be applied in test of cTn-I in human serum samples. The proposed sensor presents superiorities such as improved integratability and portability, easy fabrication and operation, and intrinsic compatibility to the fiber-optic network, and thus has a promising prospect in "point-of-care" test for cardiac biomarkers and preclinical diagnosis. PMID- 28888178 TI - Novel amine-functionalized iron trimesates with enhanced peroxidase-like activity and their applications for the fluorescent assay of choline and acetylcholine. AB - We herein describe novel amine-grafted metal-organic frameworks (MOFs) as a promising alternative to natural peroxidase enzyme and their applications for a fluorescent assay of choline (Cho) and acetylcholine (ACh). Among diverse amine functionalized MOFs, N,N,N',N'-tetramethyl-1,4-butanediamine (TMBDA) functionalized MIL-100(Fe) (TMBDA-MIL-100(Fe)) exhibited the highest peroxidase activity by developing intense fluorescence from Amplex UltraRed (AUR) in the presence of H2O2, which was presumably due to the synergetic effect of the enhanced negative potential and precisely controlled molecular size of the grafted diamine. Based on the excellent peroxidase-like activity of TMBDA-MIL 100(Fe), choline and ACh were reliably determined down to 0.027 and 0.036uM, respectively. Furthermore, practical applicability of this strategy was successfully demonstrated by detecting choline and ACh in spiked samples of milk and serum, respectively. This work highlights the advantages of amine-grafted MOFs for the preparation of biomimetic catalysts, extending their scope to biosensor applications. PMID- 28888179 TI - A novel immunosensor based on excessively tilted fiber grating coated with gold nanospheres improves the detection limit of Newcastle disease virus. AB - A novel immunosensor for detecting Newcastle disease virus (NDV) was developed using excessively tilted fiber grating (Ex-TFG) coated with gold nanospheres (AuNs). AuNs were coated on the Ex-TFG surface via Au-S bonds using 3 mercaptopropyltrimethoxysilane (MPTMS), and the activated staphylococcal protein A (SPA) was linked to AuNs by covalent bonds via cysteamine. AuNs greatly enhanced the impact of the analyte on the fiber cladding mode through the local surface Plasmon resonance (LSPR) effect, thus improving the detection limit and sensitivity of the immunosensor. Meanwhile, SPA enhanced the bioactivity of anti NDV monoclonal antibodies (MAbs), thus promoting the effectiveness of specific binding events on the fiber surface. Immunoassays were performed by monitoring the resonance wavelength shift of the proposed sensor under NDV samples containing different particle amounts. Specificity was assessed, and clinical tests for NDV were performed by contrast experiments. Experimental results showed that the detection limit for NDV was about 5~10 times improved compared to that of reference Ex-TFG without AuN treatment. Moreover, the novel biosensor was reusable and could potentially be applied in clinic. PMID- 28888180 TI - Density of tubal ring vascularization: A new marker for prediction of success of medical treatment in tubal ectopic pregnancy. AB - OBJECTIVES: The diagnosis of ectopic pregnancy has been facilitated especially by the use of Doppler ultrasonography. In previous studies the presence of peri trophoblastic blood flow by Doppler ultrasound and the detection of a low resistance, high-velocity flow pattern were defined as specific signs for trophoblastic tissue. The aim of this study was to evaluate the efficacy of Doppler ultrasonography in the prediction of treatment success in tubal pregnancies being treated with single dose conservative methotrexate. STUDY DESIGN: A total of 104 patients with non-ruptured ectopic pregnancy who were hemodynamically stable and eligible for methotrexate treatment were included in the study. The spectral wave form of the mass was classified according to the vascularization density by Power Doppler. It was defined as Grade 1, 2 and 3, respectively. All patients received a single 50mg/m2 dose of systemic methotrexate. Serum beta-hCG levels were measured on the 4th and 7th days of treatment. The treatment was considered unsuccessful in patients without a decrease of 15% or more in the serum beta-hCG levels between days 0 and 7. RESULTS: Twenty-four patients with grade I vascularity, 11 patients with grade II vascularity and 13 patients with grade III vascularity were referred as Group I, II and III, respectively, according to the degree of adnexal vascularity assessed by Doppler ultrasonography. Overall success rate of MTX treatment was found to be 72.9%. The response rates to systemic MTX treatment in cases with Grade I, II and III ectopic pregnancy mass vascularization were found to be 58.3%, 81.8% and 92.3%, respectively. Comparison of the groups' treatment responses revealed a linear-by-linear correlation with the Chi-square test. Increased vascularization grade of ectopic pregnancy was associated with a higher likelihood of responding to MTX treatment. CONCLUSIONS: Detection of the vascularization grade with Doppler ultrasound could be considered a remarkable parameter in predicting treatment success considering its ease of utilization and low cost. PMID- 28888181 TI - External validation of preexisting first trimester preeclampsia prediction models. AB - OBJECTIVE: To validate the increasing number of prognostic models being developed for preeclampsia using our own prospective study. STUDY DESIGN: A systematic review of literature that assessed biomarkers, uterine artery Doppler and maternal characteristics in the first trimester for the prediction of preeclampsia was performed and models selected based on predefined criteria. Validation was performed by applying the regression coefficients that were published in the different derivation studies to our cohort. We assessed the models discrimination ability and calibration. RESULTS: Twenty models were identified for validation. The discrimination ability observed in derivation studies (Area Under the Curves) ranged from 0.70 to 0.96 when these models were validated against the validation cohort, these AUC varied importantly, ranging from 0.504 to 0.833. Comparing Area Under the Curves obtained in the derivation study to those in the validation cohort we found statistically significant differences in several studies. CONCLUSION: There currently isn't a definitive prediction model with adequate ability to discriminate for preeclampsia, which performs as well when applied to a different population and can differentiate well between the highest and lowest risk groups within the tested population. The pre-existing large number of models limits the value of further model development and future research should be focussed on further attempts to validate existing models and assessing whether implementation of these improves patient care. PMID- 28888182 TI - Instrumentation for cryogenic magic angle spinning dynamic nuclear polarization using 90L of liquid nitrogen per day. AB - Cryogenic sample temperatures can enhance NMR sensitivity by extending spin relaxation times to improve dynamic nuclear polarization (DNP) and by increasing Boltzmann spin polarization. We have developed an efficient heat exchanger with a liquid nitrogen consumption rate of only 90L per day to perform magic-angle spinning (MAS) DNP experiments below 85K. In this heat exchanger implementation, cold exhaust gas from the NMR probe is returned to the outer portion of a counterflow coil within an intermediate cooling stage to improve cooling efficiency of the spinning and variable temperature gases. The heat exchange within the counterflow coil is calculated with computational fluid dynamics to optimize the heat transfer. Experimental results using the novel counterflow heat exchanger demonstrate MAS DNP signal enhancements of 328+/-3 at 81+/-2K, and 276+/-4 at 105+/-2K. PMID- 28888183 TI - Periodic population codes: From a single circular variable to higher dimensions, multiple nested scales, and conceptual spaces. AB - Across the nervous system, neurons often encode circular stimuli using tuning curves that are not sine or cosine functions, but that belong to the richer class of von Mises functions, which are periodic variants of Gaussians. For a population of neurons encoding a single circular variable with such canonical tuning curves, computing a simple population vector is the optimal read-out of the most likely stimulus. We argue that the advantages of population vector read outs are so compelling that even the neural representation of the outside world's flat Euclidean geometry is curled up into a torus (a circle times a circle), creating the hexagonal activity patterns of mammalian grid cells. Here, the circular scale is not set a priori, so the nervous system can use multiple scales and gain fields to overcome the ambiguity inherent in periodic representations of linear variables. We review the experimental evidence for this framework and discuss its testable predictions and generalizations to more abstract grid-like neural representations. PMID- 28888184 TI - Early prosocial development across cultures. AB - Human prosociality is ubiquitous, even though it may be manifested differently across cultures. Low cost helping and sharing emerge early in development, and at similar levels, across cultures having vastly different sociocultural niches. Developmental trajectories for costly sharing diverge across cultures around middle childhood, in line with differences in the sociocultural niches that children experience. Cultural developmental research has focussed primarily on the emergence and development of prosocial behaviour, and would benefit from an examination of the interplay between psychological (cognitive, motivational) and sociocultural (norms, developmental niche) foundations over ontogeny. PMID- 28888186 TI - Acquired body marks: A mode of identification in Forensics. AB - Each individual regardless of sex, age and caste has a particular identification mark present on their body. This study is mainly an attempt to understand the distribution pattern of different types of acquired body marks present on the body which can be used as a marker for individual identification in Forensics. Data was collected by means of observation, interview schedule and interviews from 160 individuals of 6 multi-caste villages of Udaipur in Rajasthan, India. A wide variation was observed in the distribution patterns of various acquired body marks. Scars were the most prevalent (87.5%) followed by body piercing (66%), occupational marks (38.5%), tattoo marks (27.5%) and body deformity (5%). There is a strong association between sex of an individual and presence of tattoo and occupational marks. Type of occupation is associated with the presence of scar and occupational marks. Age also has its influence on the presence and type of - tattoo and occupational marks. This wide variation in the distribution of acquired body marks based on sex, age, educational status, occupation, religion etc. of an individual need to be considered and included as a method of identification of unknown in Forensic Science. PMID- 28888185 TI - Helicobacter pylori serological biomarkers of gastric cancer risk in the MCC Spain case-control Study. AB - BACKGROUND: Helicobacter pylori infection is one of the main risk factors for non cardia gastric cancer. However, only a minority of infected persons develop the disease. This study aims at identifying H. pylori related serological biomarkers of risk for gastric cancer. METHODS: Incident gastric cancer cases and population controls (age, sex and region frequency-matched) from the MCC-Spain multicase control Study were included. Seroreactivities against 16H. pylori proteins were determined using multiplex serology. Infection was defined as seropositivity against>=4 proteins. Relation of serological results to non-cardia and cardia gastric cancer was assessed using multivariable mixed logistic regression and principal components analysis. RESULTS: Seroprevalence was 88% among 2071 controls, 95% among 202 non-cardia gastric cancer cases (OR=1.9 (95% CI: 1.0 3.6)) and 85% among 62 cardia cancer cases (OR=0.5 (95% CI: 0.3-1.1)). In infected subjects, seropositivity for UreA, HP231, NapA and Cagdelta was associated with lower non-cardia gastric cancer risk, while seropositivity for CagA and VacA was associated with higher risk. Seropositivity for CagA and seronegativity for Cagdelta maintained the association after additional adjustment by serostatus of significant proteins. We identified two antibody reactivity patterns: the "virulent-pattern", related to a threefold higher risk of non-cardia gastric cancer and the "non-virulent pattern", related to a 60% decreased risk (4th vs. first quartile). CONCLUSIONS: In our population, people seropositive for H. pylori were characterized by two patterns of antibody reactivity against H. pylori proteins: 1) Combined high seroreactivity against several proteins, associated with a lower non-cardia gastric cancer risk, and 2) High seroreactivity against CagA and VacA, associated with an increased risk. PMID- 28888187 TI - Effect of tank diameter on thermal behavior of gasoline and diesel storage tanks fires. AB - Studies on fire behavior are extremely important as they contribute in a firefighting situation or even to avoid such hazard. Experimental studies of fire in real scale are unfeasible, implying that reduced-scale experiments must be performed, and results extrapolated to the range of interest. This research aims to experimentally study the fire behavior in tanks of 0.04m, 0.20m, 0.40m, 0.80m and 4.28m diameter, burning regular gasoline or diesel oil S-500. The following parameters were here obtained: burning rates, burning velocities, heat release rates, flame heights, and temperature distributions adjacent to the tank. Such parameters were obtained for each tank diameter with the purpose of correlating the results and understanding the relationship of each parameter for the different geometrical scale of the tanks. Asymptotic results for larger tanks were found as (regular gasoline and diesel oil S-500, respectively): burning rates 0.050kg/(m2s) and 0.031kg/(m2s), burning velocities 4.0mm/min and 2.5mm/min, heat release rates per unit area 2200kW/m2 and 1500kW/m2, normalized averaged flame heights (Hi/D, where Hi is the average flame height, D is the tank diameter) 0.9 and 0.8. Maximum temperatures for gasoline pools were higher than for diesel oil pools, and temperature gradients close to the tanks were also higher for the former fuel. The behavior of the maximum temperature was correlated as a function of the tank diameter, the heat release rate of each fuel and the dimensionless distance from the tank. PMID- 28888189 TI - A new three-dimensional bis(benzimidazole)-based cadmium(II) coordination polymer. AB - A new coordination polymer (CP), formulated as [Cd(L)(DCTP)]n (1) (L=1,1'-(1,4 butanediyl)bis(2-methylbenzimidazole), H2DCTP=2,5-dichloroterephthalic acid), was synthesized under hydrothermal conditions and the performance as luminescent probe was also investigated. Single-crystal X-ray diffraction reveals CP 1 is a 3D 3-fold interpenetrated dia network with large well-defined pores. It is found that CP 1 revealed highly sensitive luminescence sensing for Fe3+ ions in acetonitrile solution with a high quenching efficiency of KSV=2541.238L.mol-1 and a low detection limit of 3.2MUM (S/N=3). Moreover, the photocatalytic efficiency of 1 for degradation of methylene blue could reach 82.8% after 135min. Therefore, this coordination polymer could be viewed as multifunctional material for selectively sensing Fe3+ ions and effectively degrading dyes. PMID- 28888188 TI - Effect of extracellular electron shuttles on arsenic-mobilizing activities in soil microbial communities. AB - Microbially mediated arsenate (As(V)) and Fe(III) reduction play important roles in arsenic (As) cycling in nature. Extracellular electron shuttles can impact microbial Fe(III) reduction, yet little is known about their effects on microbial As mobilization in soils. In this study, microcosm experiments consisting of an As-contaminated soil and microbial communities obtained from several pristine soils were conducted, and the effects of electron shuttles on As mobilization were determined. Anthraquinone-2,6-disulfonate (AQDS) and riboflavin (RF) were chosen as common exogenous and biogenic electron shuttles, respectively, and both compounds significantly enhanced reductive dissolution of As and Fe. Accumulation of Fe(II)-bearing minerals was also observed, which may lead to re-immobilization of As after prolonged incubation. Interestingly, Firmicutes-related bacteria became predominant in all microcosms, but their compositions at the lower taxonomic level were different in each microcosm. Putative respiratory As(V) reductase gene (arrA) analysis revealed that bacteria closely related to a Clostridia group, especially those including the genera Desulfitobacterium and Desulfosporosinus, might play significant roles in As mobilization. These results indicate that the natural soil microbial community can use electron shuttles for enhanced mobilization of As; the use of this type of system is potentially advantageous for bioremediation of As-contaminated soils. PMID- 28888190 TI - Study of hydrogen bonding in ethanol-water binary solutions by Raman spectroscopy. AB - Raman spectra of ethanol-water binary solutions have been observed at room temperature and atmospheric pressure. We find that with increasing ethanol concentration, the symmetric and asymmetric OH stretching vibrational mode (3286 and 3434cm-1) of water are shifted to lower frequency and the weak shoulder peak at 3615cm-1 (free OH) disappears. These results indicate that ethanol strengthens hydrogen bonds in water. Simultaneously, our experiment shows that Raman shifts of ethanol reverses when the volume ratio of ethanol and the overall solution is 0.2, which demonstrates that ethanol-water structure undergoes a phase transition. PMID- 28888191 TI - The effect of glycation on bovine serum albumin conformation and ligand binding properties with regard to gliclazide. AB - Albumin, the major serum protein, plays a variety of functions, including binding and transporting endogenous and exogenous ligands. Its molecular structure is sensitive to different environmental modifiers, among which glucose is one of the most significant. In vivo albumin glycation occurs under physiological conditions, but it is increased in diabetes. Since bovine serum albumin (BSA) may serve as a model protein in in vitro experiments, we aimed to investigate the impact of glucose-mediated BSA glycation on the binding capacity towards gliclazide, as well as the ability of this drug to prevent glycation of the BSA molecule. To reflect normo- and hyperglycemia, the conditions of the glycation process were established. Structural changes of albumin after interaction with gliclazide (0-14MUM) were determined using fluorescence quenching and circular dichroism spectroscopy. Moreover, thermodynamic parameters as well as energy transfer parameters were determined. Calculated Stern-Volmer quenching constants, as well as binding constants for the BSA-gliclazide complex, were lower for the glycated form of albumin than for the unmodified protein. The largest, over 2 fold, decrease in values of binding parameters was observed for the sample with 30mM of glucose, reflecting the poorly controlled diabetic state, which indicates that the degree of glycation had a critical influence on binding with gliclazide. In contrast to significant changes in the tertiary structure of BSA upon binding with gliclazide, only slight changes in the secondary structure were observed, which was reflected by about a 3% decrease of the alpha-helix content of glycated BSA (regardless of glucose concentration) in comparison to unmodified BSA. The presence of gliclazide during glycation did not affect its progress. The results of this study indicate that glycation significantly changed the binding ability of BSA towards gliclazide and the scale of these changes depended on glucose concentration. It may have a direct impact on the free drug fraction and its pharmacokinetic behavior, including the risk of hypoglycemic episodes or unexpected interactions with other ligands. The use of BSA in examining binding effects upon glycation seems to be good model for preliminary research and may be used to identify a potential drug response in a diabetic state. PMID- 28888192 TI - What counts in preschool number knowledge? A Bayes factor analytic approach toward theoretical model development. AB - Preschool children vary tremendously in their numerical knowledge, and these individual differences strongly predict later mathematics achievement. To better understand the sources of these individual differences, we measured a variety of cognitive and linguistic abilities motivated by previous literature to be important and then analyzed which combination of these variables best explained individual differences in actual number knowledge. Through various data-driven Bayesian model comparison and selection strategies on competing multiple regression models, our analyses identified five variables of unique importance to explaining individual differences in preschool children's symbolic number knowledge: knowledge of the count list, nonverbal approximate numerical ability, working memory, executive conflict processing, and knowledge of letters and words. Furthermore, our analyses revealed that knowledge of the count list, likely a proxy for explicit practice or experience with numbers, and nonverbal approximate numerical ability were much more important to explaining individual differences in number knowledge than general cognitive and language abilities. These findings suggest that children use a diverse set of number-specific, general cognitive, and language abilities to learn about symbolic numbers, but the contribution of number-specific abilities may overshadow that of more general cognitive abilities in the learning process. PMID- 28888193 TI - Children's perception of action boundaries and how it affects their climbing behavior. AB - There are some concerns that children today may be less calibrated to their action capabilities because of the "risk-free" culture that has proliferated during recent decades. This study investigated the extent to which judgments of reaching affordances presented in different directions (i.e., overhead, diagonal, and horizontal) are related to children's climbing behavior on a climbing wall. A sample of 30 schoolchildren from 6 to 11years old (20 boys and 10 girls) estimated maximum reach and grasp distances and subsequently attempted to climb across an indoor climbing wall. Children who perceived the extents of their reach more accurately completed the climb more often and more quickly. Judgments in the primary directions of climbing locomotion (horizontal and diagonal) were better predictors of success than vertical judgments. Judgments about whether objects are reachable and graspable are complex and influenced by various dynamic factors (including perceptual-motor calibration), and as such different levels of accuracy are likely in different reaching directions. It appears that young children are relatively sensitive to their action boundaries for climbing and, therefore, may be able to make informed decisions themselves about whether a surface is climbable. PMID- 28888194 TI - Visual scanning of male and female bodies in infancy. AB - This study addressed the development of attention to information that is socially relevant to adults by examining infants' (N=64) scanning patterns of male and female bodies. Infants exhibited systematic attention to regions associated with sex-related scanning by adults, with 3.5- and 6.5-month-olds looking longer at the torsos of females than of males and looking longer at the legs of males than of females. However, this pattern of looking was not found when infants were tested on headless bodies in Experiment 2, suggesting that infants' differential gaze pattern in Experiment 1 was not due to low-level stimulus features, such as clothing, and also indicating that facial/head information is necessary for infants to exhibit sex-specific scanning. We discuss implications for models of face and body knowledge development. PMID- 28888195 TI - Children's and adults' understanding of death: Cognitive, parental, and experiential influences. AB - This study explored the development of understanding of death in a sample of 4- to 11-year-old British children and adults (N=136). It also investigated four sets of possible influences on this development: parents' religion and spiritual beliefs, cognitive ability, socioeconomic status, and experience of illness and death. Participants were interviewed using the "death concept" interview that explores understanding of the subcomponents of inevitability, universality, irreversibility, cessation, and causality of death. Children understood key aspects of death from as early as 4 or 5years, and with age their explanations of inevitability, universality, and causality became increasingly biological. Understanding of irreversibility and the cessation of mental and physical processes also emerged during early childhood, but by 10years many children's explanations reflected not an improved biological understanding but rather the coexistence of apparently contradictory biological and supernatural ideas religious, spiritual, or metaphysical. Evidence for these coexistent beliefs was more prevalent in older children than in younger children and was associated with their parents' religious and spiritual beliefs. Socioeconomic status was partly related to children's biological ideas, whereas cognitive ability and experience of illness and death played less important roles. There was no evidence for coexistent thinking among adults, only a clear distinction between biological explanations about death and supernatural explanations about the afterlife. PMID- 28888196 TI - The impact of prenatal exposure to air pollution on childhood wheezing and asthma: A systematic review. AB - BACKGROUND AND OBJECTIVES: There has been no clear consensus about whether prenatal exposure to air pollution contributes to the development of wheezing and asthma in children. We conducted a systematic review to analyze the association between exposure to different pollutants during pregnancy and the development of childhood wheezing and asthma. METHODS: We systematically reviewed epidemiological studies published through June 6, 2017 available in the MEDLINE and Web of Science databases. We included studies that examined the association between prenatal exposure to any air pollutants except tobacco smoke and the incidence or prevalence of "wheezing" or "asthma" from birth to 14 years of age. We extracted key characteristics of each included study using a template of predefined data items. We used the Critical Appraisal Skills Programme checklists to assess the validity of each included study. We conducted overall and subgroup meta-analyses for each summary exposure-outcome association. Pooled odds ratios (OR) with 95% confidence intervals (CI) were estimated by using a random effects model. RESULTS: Eighteen studies met our eligibility criteria. There was notable variability in exposure assessment methods. The overall random effects risk estimates (95% CI) of different pollutants were 1.04 (0.94-1.15) aromatic hydrocarbons (PAH), 1.04 (1.01-1.07) NO2, 1.4 (0.97-2.03) PM2.5 for childhood wheeze and 1.07 (1.01-1.14) NO2, 1 (0.97-1.03) PM2.5, 1.02 (0.98-1.07) SO2, 1.08 (1.05-1.12) PM10 for childhood asthma. Minimal heterogeneity was seen for PAH and SO2, while some heterogeneity was observed for PM10, PM2.5 and NO2. CONCLUSIONS: The overall and subgroup risk estimates from the meta-analyses showed statistically significant associations between prenatal exposures to NO2, SO2, and PM10 and the risk of wheezing and asthma development in childhood. There is insufficient evidence to show an effect of prenatal exposure to BC, CO, and O3 on childhood wheezing and asthma. Further studies are needed to examine the individual compounds' effects. PMID- 28888197 TI - Does a lag-structure of temperature confound air pollution-lag-response relation? Simulation and application in 7 major cities, Korea (1998-2013). AB - BACKGROUND: Temperature must be controlled when estimating the associations of short-term exposure to air pollution and mortality. Given that multi-country studies have implied temperature has lagged effects, we aim to explore confounding by temperature-lag-response and investigate PM10-lag-mortality relation in 7 cities, Korea. METHODS: In a simulation study, we compared the performance of different methods to control for: the same day temperature, a lagged temperature and distributed lags of temperature. In a real data study, we explored PM10-lag-mortality relation in 7 cities using these different methods. RESULTS: We confirmed that a model with insufficient control of temperature offers a biased estimate of PM10 risk. The degree of bias was from -82% to 95% in simulation settings. A real data study shows estimates among different models by temperature adjustments and PM10 lag variables ranging from -0.3% to 0.4% increase in the risk of all-cause mortality, with a 10MUg/m3 increase in PM10. Controlling for temperature as distributed lags for 21 days provided 0.25% (95% CI: 0.1, 0.4) increase in the risk of all-cause mortality. CONCLUSIONS: A lag structure of temperature can confound the air pollution-lag-response relation. Temperature-lag-response relation should be evaluated when estimating air pollution-lag-response relation. As a corollary, air pollution and temperature risk in mortality can be estimated using the same regression model. PMID- 28888198 TI - Effects of NO2 exposure on daily mortality in Sao Paulo, Brazil. AB - BACKGROUND: Recent reports have suggested that air pollution mixtures represented by nitrogen dioxide (NO2) may have effects on human health, which are independent from those of particulate matter mass. We evaluate the association between NO2 and daily mortality among elderly using one- and multipollutant models. METHODS: This study was a daily time series of non-accidental and cause-specific mortality among the elderly living in Sao Paulo, Brazil, between 2000 and 2011. Effects of NO2, particulate matter smaller than 10um (PM10), carbon monoxide (CO) and ozone (O3) were estimated in Poisson generalized additive models. The single lag effect at lags 0 and 1 days and the cumulative effect from 0 to lag 10 days were evaluated in one-, two-, three- and four-pollutant models. The cumulative risk index (CRI) recently proposed to analyze associations with health of multiple correlated pollutants was additionally estimated for each multipollutant model. RESULTS: An association between NO2, PM10, CO and O3 exposures and non-accidental and cause-specific deaths was found in one-pollutant models. NO2 effects remained significant in multipollutant models for non-accidental and circulatory deaths. The estimated CRIs suggested that circulatory deaths were mainly associated with NO2, and respiratory deaths mainly with CO and O3, regardless the lag. For non accidental deaths, multipollutant models were associated with the highest CRI, with the main pollutants depending on the chosen lag. CONCLUSIONS: The results suggest that air pollution mixtures represented by NO2 have an effect on non accidental and circulatory mortality, which is independent from PM10, CO and O3. The CRI was always larger than the risks associated with single pollutants. PMID- 28888199 TI - Chlorambucil labelled with the phenosafranin scaffold as a new chemotherapeutic for imaging and cancer treatment. AB - Here we report the first of the phenosafranin-chlorambucil conjugate as a new type of a chemotherapeutic agent suitable for dual detection methods (spectrophotometric and fluorescence) in imaging systems and cancer treatment. The synthetic cationic dye (3,7-diamino-5-phenylphenazinium chloride) is used as a fluorescent light-triggered scaffold that acts as a carrier for an anti-cancer drug. The chlorambucil was attached covalently via amide bonds to the bifunctional fluorophore, which facilitates tracking with visible light. Our studies revealed that the new photosensitive compound exhibits improved intrinsic activity in vitro in HeLa cells culture experiments; thus it could be a potential anti-cancer candidate in theranostic drug-delivery systems. In light of the urgent need for in vivo monitoring of the biodistribution of anti-cancer drugs, this strategy for the synthesis of innovative conjugates based on the phenosafranin backbone offers a promising possibility for drug control in anti cancer therapy and diagnosis. This aspect makes the phenosafranin-chlorambucil conjugate unique among currently available biomarkers. PMID- 28888200 TI - Emulsification efficacy of Quillaja saponins at very low concentration: Model development and role of alcohols. AB - The present study aims at quantifying interfacial coverage of a biosurfactant (Quillaja saponins) and understanding the impact of flavor and fragrance alcohols on emulsification efficacy of the biosurfactant in a surfactant-oil-matrix system. Emulsions were prepared using limonene, alkanes (C8, C12, and C16) or limonene alcohol (linalool and C6C10 alcohols) mixtures at different ratios as oil phase stabilized by Quillaja saponins at very low concentrations (0.005-0.05% w/w). Droplet size was measured and size distributions were numerized to determine surface and volume average droplet diameters of bimodal emulsions. Using a model developed in the present study, Quillaja saponins showed an interfacial coverage of 5.0*106cm2/g and a head surface of 1.37nm2 with a lay-on configuration at interface. The model proved to discriminate between surface active (alcohols) and non-active (alkanes) compounds. The apparent interfacial coverage of saponins increased linearly with increasing alcohol concentration. The type of alcohol (terpene alcohol vs. medium chain alcohols) and alcohol chain length (C6C10) showed little impact on emulsification efficacy of Quillaja saponins. The molar ratio of heptanol to saponin at interface increased from 0 to 8.6 corresponding to 0-30% w/w heptanol in limonene. This study revealed that the distribution of alcohol at interface was mainly driven by partitioning in the surfactant-oil-matrix system. The practical implication of the present study is to enhance emulsification efficacy of Quillaja Saponins at very low concentration by incorporating surface active compounds, i.e. flavor or fragrance alcohols. PMID- 28888201 TI - TGF-beta1 presenting enzymatically cross-linked injectable hydrogels for improved chondrogenesis. AB - In this work, we developed a novel enzymatically cross-linked injectable hydrogel composed of carboxymethyl cellulose (CMC), sulfated carboxymethyl cellulose (sCMC) and gelatin for delivery of infrapatellar fat pad derived MSCs and articular chondrocytes to a cartilage defect site while enabling TGF-beta1 mediated chondrogenesis. The sCMC component in the hydrogel served the purpose of mimicking heparan sulfate and thus enabled strong binding with TGF-beta1 and its consequential long term presentation to the encapsulated cells. We demonstrated that amongst CMC/sCMC/gelatin hydrogels cross-linked with 1 and 2mM H2O2, the latter demonstrated significantly higher compressive modulus and supported better in vitro cartilage formation. Thereafter, we explored the utility of this system to present TGF-beta1 to encapsulated cells for prolonged time period. It was observed that these hydrogels could sequester >90% of encapsulated TGF-beta1 for at least 4 weeks. The encapsulated TGF-beta1 was shown to be bioactive and supported significantly better cell survival over control hydrogels. Further, the TGF loaded hydrogels demonstrated good sulfated GAG and collagen deposition which was higher than control hydrogels and comparable to those treated with soluble TGF-beta1 through media. Interestingly, incorporation of TGF-beta1 in hydrogels not only enhanced the expression and deposition of hyaline cartilage markers, but it also significantly reduced the deposition of fibrocartilage and hypertrophy markers. Overall, it was concluded that TGF-beta1 immobilized CMC/sCMC/gelatin injectable hydrogels encapsulated with IFP MSCs and ACs present a promising, cost effective and easily translatable strategy for cartilage tissue engineering. PMID- 28888204 TI - Electrokinetic treatment of high saline petrochemical wastewater: Evaluation and scale-up. AB - High total dissolved solids (TDS) wastewater containing high amounts of organics with toxic and recalcitrant characteristics is a major concern in some petrochemical industries. This study was designed to evaluate a novel electrokinetic process for chemical oxygen demand (COD) removal. The removal of COD was carried out in some batch experiments in lab scale and effect of experimental factors such as the pH, current intensity, time, electrodes distances and TDS on the COD removal was evaluated. Also scale-up of the process was done in order to evaluate energy consumption. The obtained findings indicated that best conditions for COD removal were achieved in pH 5, current intensity of 0.5 A and electrodes distance of 2 cm. Pseudo-first-order kinetic model with rate constant of 0.0093 min-1 and significant coefficient of correlation (R2) 0.948 was the best fitted with experimental results. Energy consumption was 32 KWh.m-3 while 80 fold scaling up the reactor resulted in lower energy consumption of 2.1 KWh.m-3. Biodegradability improvement confirmed by BOD5/COD, average oxidation state (AOS) and carbon oxidation state (COS) indicators, Also GC chromatogram of the raw and treated wastewater showed removal and/or degradation of recalcitrant organics to more degradable and simpler compounds. PMID- 28888202 TI - Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. AB - Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins. For instance, ferritin (iron storage) levels provided a robust biomarker of cellular senescence, for associated iron accumulation and for resistance to iron-induced toxicity. Cellular senescence preceded iron accumulation and was not perturbed by sustained iron chelation (deferiprone). Iron accumulation in senescent cells was driven by impaired ferritinophagy, a lysosomal process that promotes ferritin degradation and ferroptosis. Lysosomal dysfunction in senescent cells was confirmed through several markers, including the build-up of microtubule-associated protein light chain 3 (LC3-II) in autophagosomes. Impaired ferritin degradation explains the iron accumulation phenotype of senescent cells, whereby iron is effectively trapped in ferritin creating a perceived cellular deficiency. Accordingly, senescent cells were highly resistant to ferroptosis. Promoting ferritin degradation by using the autophagy activator rapamycin averted the iron accumulation phenotype of senescent cells, preventing the increase of TfR1, ferritin and intracellular iron, but failed to re-sensitize these cells to ferroptosis. Finally, the enrichment of senescent cells in mouse ageing hepatic tissue was found to accompany iron accumulation, an elevation in ferritin and mirrored our observations using cultured senescent cells. PMID- 28888203 TI - Role of glutathione biosynthesis in endothelial dysfunction and fibrosis. AB - Glutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice). In murine lung endothelial cells (MLEC) derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177) and increased eNOS S glutathionylation, compared to MLEC from wild type (WT) mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+) male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH4. To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+) mice. We observed that obstructed kidneys from Gclc(e/+) mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses. PMID- 28888205 TI - Measuring geomorphological vulnerability on beaches using a set of indicators (GVI): A tool for management. AB - A system of indicators has been developed to evaluate beach geomorphological vulnerability (GVI) through: intrinsic susceptibility, the agents that model them, and their ability to remain stable over time. The method is applied to 34 beaches on the island of Gran Canaria (Spain) that experience different levels and conditions of human occupation, marine incidence, landforms and sediments, and spatial evolution that have been recorded since 1960. In contrast with other studies, the analysis of these dimensions (and their relationships) allows a diagnosis of the geomorphology of the beaches with an integrated approach. The results illustrate the numerous causes that generate geomorphological vulnerability, such as wave intensity, the presence of dikes or breakwaters, coastline variations, the absence of foredunes and embryonic dunes, the width of the intertidal zone, or the absence of beachrocks or lavic stones outcropping onto the shore. These variables combine and operate differently in five defined groups of beaches with different management needs. The most vulnerable ones were those with strong marine incidence, which require maintenance of their landforms in order to guarantee their stability. The opposite situation is found in beaches with little impact from anthropic and marine components. These beaches are less vulnerable since they have moderate susceptibility and high resilience. Their management requirements consist of soft measures since they have a strong geomorphological robustness. In this context, the proposed indicator system is a potentially relevant contribution to the management of beaches, especially for those that are under threat. PMID- 28888206 TI - Riverine discharges to Chesapeake Bay: Analysis of long-term (1927-2014) records and implications for future flows in the Chesapeake Bay basin. AB - The Chesapeake Bay (CB) basin is under a total maximum daily load (TMDL) mandate to reduce nitrogen, phosphorus, and sediment loads to the bay. Identifying shifts in the hydro-climatic regime may help explain observed trends in water quality. To identify potential shifts, hydrologic data (1927-2014) for 27 watersheds in the CB basin were analyzed to determine the relationships among long-term precipitation and stream discharge trends. The amount, frequency, and intensity of precipitation increased from 1910 to 1996 in the eastern U.S., with the observed increases greater in the northeastern U.S. than the southeastern U.S. The CB watershed spans the north-to-south gradient in precipitation increases, and hydrologic differences have been observed in watersheds north relative to watersheds south of the Pennsylvania-Maryland (PA-MD) border. Time series of monthly mean precipitation data specific to each of 27 watersheds were derived from the Precipitation-elevation Regression on Independent Slopes Model (PRISM) dataset, and monthly mean stream-discharge data were obtained from U.S. Geological Survey streamgage records. All annual precipitation trend slopes in the 18 watersheds north of the PA-MD border were greater than or equal to those of the nine south of that border. The magnitude of the trend slopes for 1927-2014 in both precipitation and discharge decreased in a north-to-south pattern. Distributions of the monthly precipitation and discharge datasets were assembled into percentiles for each year for each watershed. Multivariate correlation of precipitation and discharge within percentiles among the groups of northern and southern watersheds indicated only weak associations. Regional-scale average behaviors of trends in the distribution of precipitation and discharge annual percentiles differed between the northern and southern watersheds. In general, the linkage between precipitation and discharge was weak, with the linkage weaker in the northern watersheds compared to those in the south. On the basis of simple linear regression, 26 of the 27 watersheds are projected to have higher annual mean discharge in 2025, the target date for implementation of the TMDL for the CB basin. PMID- 28888207 TI - Acute changes of hip joint range of motion using selected clinical stretching procedures: A randomized crossover study. AB - BACKGROUND: Hip adductor flexibility and strength is an important component of athletic performance and many activities of daily living. Little research has been done on the acute effects of a single session of stretching on hip abduction range of motion (ROM). OBJECTIVES: The aim of this study was to compare 3 clinical stretching procedures against passive static stretching and control on ROM and peak isometric maximal voluntary contraction (MVC). DESIGN: Using a randomized crossover study design, a total of 40 participants (20 male and 20 female) who had reduced hip adductor muscle length attended a familiarization session and 5 testing sessions on non-consecutive days. METHOD: Following the warm-up and pre-intervention measures of ROM and MVC, participants were randomly assigned 1 of 3 clinical stretching procedures (modified lunge, multidirectional, and joint mobilization) or a static stretch or control condition. Post intervention measures of ROM and MVC were taken immediately following completion of the assigned condition. RESULTS: An ANOVA using a repeated measure design with the change score was conducted. All interventions resulted in small but statistically significant (p < 0.05) increases (1.0 degrees -1.7 degrees ) in ROM with no inter-condition differences except one. Multidirectional stretching was greater than control (p = 0.031). CONCLUSIONS: These data suggest that a single session of stretching has only a minimal effect on acute changes of hip abduction ROM. Although hip abduction is a frontal plane motion, to effectively increase the extensibility of the structures that limit abduction, integrating multi planar stretches may be indicated. PMID- 28888208 TI - Prophetic medicine as potential functional food elements in the intervention of cancer: A review. AB - Amounting scientific evidences have revealed the antitumor, antimetastatic, antiangiogenic, antiproliferative, chemopreventive and neo-adjuvant efficacy of Prophetic Medicine in various in vitro, in vivo and clinical cancer models. Prophetic Medicine includes plants, dietary materials or spices that were used as remedy recipes and nutrition by the great Prophet Mohammed (peace be upon him) to treat various ailments. Prophetic medicine is the total authentic Hadith narrated by the Prophet (PBUH) in relation to medicine, whether Qur'anic verses or honourable Prophetic Hadith. The ability of functional foods from Prophetic Medicine to modulate various signalling pathways and multidrug resistance conferring proteins with low side-effects exemplify their great potential as neo adjuvants and/or chemotherapeutics. The present review aims to provide the collective in vitro, in vivo, clinical and epidemiology information of Prophetic Medicines, and their bioactive constituents and molecular mechanisms as potential functional foods for the management of cancer. PMID- 28888209 TI - Development of 1,3,4-oxadiazole thione based novel anticancer agents: Design, synthesis and in-vitro studies. AB - A series of new 1,3,4-oxadiazole-2(3H)-thione analogues (3a to 3o) have been designed, synthesized and evaluated for their anticancer activity. Four different cancerous cell lines viz. HeLa (cervical), U-87 (glioblastoma), Panc (pancreatic) and MCF-7 (breast) were used to assess the potency of the synthesized compounds as anticancer agents. Among them 3i and 3j showed promising cytotoxicity against HeLa cell line. Further, 3i and 3j successfully inhibited cell cycle progression and displayed cell death in HeLa cells via apoptosis as visualized by Annexin V APC and DNA fragmentation assay. 3i and 3j induced caspase-3 activation, PARP cleavage, increase in expression of proapoptotic protein Bax and decrease in the expression of antiapoptotic protein Bcl-2. Also, 3i and 3j induced overexpression of p21 and decreased expression of cyclin B1 indicating the arrest of cells in G2 M phase of the cell cycle. Therefore, new lead compounds are being suggested having anticancer activity through cell cycle inhibition and apoptosis. PMID- 28888210 TI - Antibody-cytokine fusion proteins for improving efficacy and safety of cancer therapy. AB - Cytokines are key players in the regulation of immune responses both in physiological and pathological states. A number of cytokines have been evaluated in clinical trials and shown promising results in the treatment of different malignancies. Despite this, the clinical application of these molecules may be plagued by undesirable side effects The development of recombinant antibody cytokine fusion proteins, which offer a means for target delivery of cytokines toward the tumor site, has significantly improved the therapeutic index of these immunomodulatory molecules. Selective tumor localization is provided by the monoclonal antibody component of the fusion protein that binds to the molecules present on the surface of tumor cells or accumulated preferentially in the diseased site. In this manner, the cytokine element is specifically located at the tumor site and can stimulate immune cells with appropriate cytokine receptors. Over the recent years, several antibody-cytokine fusion proteins have been developed with the capacity to target a wide variety of cancers whose application, in some cases, has led to complete rejection of the tumor. These findings support the notion that antibody-cytokine fusion proteins represent huge potential for cancer therapy. This review presents an overview of the advances made in the field of targeted cytokine delivery, which is made possible by genetically engineering antibody-cytokine fusion proteins. PMID- 28888211 TI - MDR1 polymorphisms affect the outcome of Chinese multiple myeloma patients. AB - OBJECTIVE: To illustrate the association of MDR1 (Multidrug Resistance 1) polymorphisms at loci 1236, 2677, 3435 and the prognosis of multiple myeloma (MM) in Jiangsu population. METHODS: A total of 129 MM patients were recruited from Jiangsu Province, China. The DNA was extracted from white blood cells (WBC) of peripheral blood and was amplified by polymerase chain reaction-allele specific primers (PCR-ASP). MDR1 polymorphisms at 3 loci were analyzed by electrophoresis followed by photograph or DNA direct sequencing. The association between the MDR1 and clinical outcomes were calculated by Graphpad and SPSS. RESULTS: MDR1 alleles at locus C1236T with T had significant lower calcium level in MM patients compared with C. The genotype CT had a significantly prolonged progress free survival (PFS) compared genotype CC at locus C1236T (median time: 48 months vs. 28 months, respectively; p=0.0062; HR=0.21; 95%CI0.061-0.715) while patients carrying T allele (CT and TT) at locus C3435T had a longer PFS than patients without T allele (CC) (median time: 60 months vs. 29 months, respectively; p=0.038; HR=0.508; 95%CI 0.264-0.978). And a borderline significance was found in haplotype at loci 2677-3435 and PFS. No significant findings were revealed between OS and MDR1 polymorphisms. CONCLUSION: MDR1 polymorphisms could affect the prognosis of multiple myeloma whereas more samples and a longer follow-up are also needed. PMID- 28888212 TI - Reducing N2O and NO emissions while sustaining crop productivity in a Chinese vegetable-cereal double cropping system. AB - High nitrogen (N) inputs in Chinese vegetable and cereal productions played key roles in increasing crop yields. However, emissions of the potent greenhouse gas nitrous oxide (N2O) and atmospheric pollutant nitric oxide (NO) increased too. For lowering the environmental costs of crop production, it is essential to optimize N strategies to maintain high crop productivity, while reducing the associated N losses. We performed a 2 year-round field study regarding the effect of different combinations of poultry manure and chemical N fertilizers on crop yields, N use efficiency (NUE) and N2O and NO fluxes from a Welsh onion-winter wheat system in the North China Plain. Annual N2O and NO emissions averaged 1.14 3.82 kg N ha-1 yr-1 (or 5.54-13.06 g N kg-1 N uptake) and 0.57-1.87 kg N ha-1 yr 1 (or 2.78-6.38 g N kg-1 N uptake) over all treatments, respectively. Both N2O and NO emissions increased linearly with increasing total N inputs, and the mean annual direct emission factors (EFd) were 0.39% for N2O and 0.19% for NO. Interestingly, the EFd for chemical N fertilizers (N2O: 0.42-0.48%; NO: 0.07 0.11%) was significantly lower than for manure N (N2O: 1.35%; NO: 0.76%). Besides, a negative power relationship between yield-scaled N2O, NO or N2O + NO emissions and NUE was observed, suggesting that improving NUE in crop production is crucial for increasing crop yields while decreasing nitrogenous gas release. Compared to the current farmers' fertilization rate, alternative practices with reduced chemical N fertilizers increased NUE and decreased annual N2O + NO emissions substantially, while crop yields remained unaffected. As a result, annual yield-scaled N2O + NO emissions were reduced by > 20%. Our study shows that a reduction of current application rates of chemical N fertilizers by 30-50% does not affect crop productivity, while at the same time N2O and NO emissions would be reduced significantly. PMID- 28888213 TI - Occurrence, fate and transformation of emerging contaminants in water: An overarching review of the field. AB - Many of the products and drugs used commonly contain chemical components which may persist through sewage treatment works (STW) and eventually enter the aquatic environment as parent compounds, metabolites, or transformation products. Pharmaceuticals and personal care products (PPCPs) and other emerging contaminants (ECs) have been detected in waters (typically ng/L) as well as more recently bound to sediment and plastic particles (typically ng/g). Despite significant advancement of knowledge since the late 1990s, the fate of these contaminants/transformation products once introduced into the aquatic environment remains relatively unresolved. This review provides a unique focus on the fate of seven major groups of PPCPs/ECs in the aquatic environment, which is frequently not found in similar works which are often compound or topic-specific and limited in background knowledge. Key findings include: a) some replacements for regulation precluded/banned chemicals may be similarly persistent in the environment as those they replace, b) the adsorption of potentially bioactive chemicals to micro- and nanoplastics is a significant topic with risks to aquatic organisms potentially greater than previously thought, and c) micro-/nanoplastics are likely to remain of significant concern for centuries after regulatory limitations on their use become active due to the slow degradation of macro plastics into smaller components. An interdisciplinary perspective on recent advances in the field is presented here in a unique way which highlights both the principle science and direction of research needed to elucidate the fate and transport patterns of aquatic PPCPs/ECs. Unlike similar reviews, which are often topic-specific, here we aim to present an overarching review of the field with focus on the occurrence, transformation and fate of emerging contaminants. Environmental presence of seven major classes of contaminants (analygesics, antibiotics, antineoplastics, beta-blockers, perfluorinated compounds, personal care products and plasticisers), factors affecting contaminant fate, association with plastic micro-/nanoparticles and photochemical transformation are comprehensively evaluated. PMID- 28888214 TI - Catching new targets in metabolic disease with a zebrafish. AB - Traditionally, the development of novel therapeutics for metabolic diseases has relied mainly on high-throughput screening using biochemical or cell-based assays. While this approach represents a driving force in drug discovery, there is also a need to perform large-scale screens without disrupting inter-organ communication and tissue architecture, essential components for understanding the complexity of metabolic regulation and the identification of small molecules with appropriate biological activities in vivo. Hence, the zebrafish Danio rerio is gaining popularity in metabolic research and drug discovery, as this animal model allows screening of small molecules in the context of the whole-organism. Moreover, the zebrafish exhibits conserved function of the pancreas, liver and adipose tissue, which can be leveraged to identify novel targets in metabolic regulation, as well as to study the role of conserved genes associated with the risk of metabolic diseases in humans. Here we highlight recent advances in the identification of targets in metabolic regulation using the zebrafish as a model. PMID- 28888215 TI - The role of presurgical EEG parameters and of reoperation for seizure outcome in temporal lobe epilepsy. AB - PURPOSE: After surgery for intractable mesiotemporal lobe epilepsy (mTLE) seizures recur in 30-40%. One predictor for seizure recurrence is the distribution of seizure onset and interictal epileptiform discharges (IED). Our study focused on lateralization and extent of epileptiform activity regarding postoperative seizure persistence and the effect of reoperation. METHODS: This study comprises 426 consecutive patients operated for intractable mTLE. Impact of preoperative seizure onset and IED on the persistence of seizures and results of reoperation were analyzed. RESULTS: One year after surgery, 27% of patients with mTLE experienced persistent seizures (Engel II-IV). Preoperative bilateral seizure onset in EEG was predictive for postoperative seizure recurrence (Engel II-IV: 64%). Seizure foci and IED exceeding the temporal lobe in the ipsilateral hemisphere were not found to be associated with worse seizure outcome (Engel I: 72% and 75%) compared to patients with seizure foci confined to the ipsilateral temporal lobe (Engel I: 75% and 76%). Moreover, IED exceeding the affected temporal lobe in the ipsilateral hemisphere or even bilateral IED did not negatively affect seizure freedom if seizure onset was strictly limited to the affected temporal lobe (Engel I: 85% and 65%, respectively). 60% of patients reoperated in the ipsilateral temporal lobe for persistent seizures became seizure free. CONCLUSIONS: Preoperative bilateral ictal foci are a negative predictor for seizure outcome. Contrarily, IED exceeding the affected temporal lobe in the ipsilateral hemisphere or even bilateral IED had favorable seizure outcome if seizure onset is strictly limited to the affected temporal lobe. Reoperation for seizure persistence constitutes a promising therapeutic option. PMID- 28888216 TI - Vitamin B Derivative (Nicotinamide)Appears to Reduce Skin Cancer Risk. AB - Nicotinamide, an amide form of vitamin B3, has shown the potential to treat a variety of dermatological conditions, including acne, rosacea, and atopic dermatitis. Recent studies have demonstrated the role of nicotinamide, in both topical and oral forms, as a chemopreventive agent against skin cancer. Its anti carcinogenic role may be due to its ability to enhance DNA repair and prevent ultraviolet (UV)-induced immunosuppression, which is known to contribute to the progression of pre-malignant lesions. Furthermore, nicotinamide is a precursor of essential coenzymes for many important reactions in the body, including the production of nicotinamide adenine dinucleotide (NAD). NAD is a key coenzyme in the synthesis of adenosine triphosphate (ATP), which transports chemical energy within cells. Therefore, nicotinamide plays a significant role in supporting energy-dependent cellular processes, including DNA repair. PMID- 28888217 TI - Epidermal Growth Factor Receptor Inhibitors: Cutaneous Side Effects and Their Management. AB - Epidermal growth factor receptor (EGFR) inhibitors are part of an emerging class of anticancer medicines known as "targeted therapy," which target pathways more specific to neoplastic proliferation than traditional chemotherapeutic agents. Adverse effects of such treatments are thought to be less severe, but can still be significant. Because EGFR is preferentially expressed in epithelial tissues, including the skin and hair follicle, cutaneous side effects of these agents are quite common. Not only can these toxicities severely affect patients' quality of life, but in some specific instances, they can be associated with increased response to therapy. It is of paramount importance that clinicians familiarize themselves with and understand the basic management of the range of cutaneous adverse effects caused by these drugs. PMID- 28888218 TI - Impact of non-adherence on the safety and efficacy of uric acid-lowering therapies in the treatment of gout. AB - AIMS: Dual-urate-lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosuric agents can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of the present study were to simulate the relationship between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono- and dual-ULTs. METHODS: The impact of poor medication adherence was studied using two-compartment pharmacokinetic (PK) models based on published evidence, and a semi-mechanistic four-compartment pharmacodynamic (PD) model. The PKPD model was used to simulate mono and dual-ULT in gout patients with either under-excretion (lowered clearance) or overproduction of uric acid, with suboptimal adherence modelled as either a single drug holiday of increasing duration or doses taken at random. RESULTS: Simulation results showed a surge in urinary uric acid occurring when dosing is restarted following missed doses. For under-excreters taking a 20-day drug holiday, the addition of 200 mg (or 400 mg) lesinurad to 80 mg febuxostat increased the percentage of patients experiencing hyperuricosuria from 0% to 1.4% (or 3.1%). In overproducers, restarting ULTs following drug holidays of more than 5 days leads to over 60% of patients experiencing hyperuricosuria. CONCLUSIONS: Suboptimal medication adherence may compromise the safety and efficacy of mono- and dual-ULTs, especially in patients with gout resulting from an overproduction of uric acid. Clinicians and pharmacists should consider counselling patients with respect to the risks associated with partial adherence, and offer interventions to improve adherence or tailor treatments, where appropriate. PMID- 28888219 TI - Factor Xa inhibition by rivaroxaban in the trough steady state can significantly reduce thrombin generation. AB - AIMS: The aim of the present study was to demonstrate evidence of reduced thrombin generation at the trough plasma rivaroxaban concentration. METHODS: A single-centre, prospective, nonrandomized, drug-intervention, self-controlled study was conducted in 51 anticoagulation therapy-naive patients with nonvalvular atrial fibrillation. Plasma rivaroxaban concentration was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and the anti-factor Xa chromogenic assay. Partial thrombin time (PT), protein C activity, and protein S antigen, prothrombin fragment 1 + 2 (F1 + 2), D-dimer, thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor-1 (PAI-1) and tissue factor pathway inhibitor (TFPI) levels were also measured at the trough steady state after 4 weeks of rivaroxaban treatment and compared with baseline. RESULTS: Plasma concentrations obtained by the LC-MS/MS and anti-Xa assays were correlated (r = 0.841, P < 0.001). The mean concentration of rivaroxaban at the trough steady state was 23.6 ng ml-1 , at which F1 + 2, TAT and D-dimer had decreased from the baseline values (P < 0.0001, P = 0.029 and P < 0.005, respectively). PT was prolonged (+0.59 s, P < 0.0001). TFPI increased from baseline to the trough steady state in the first to third quartile groups (+0.79 pg ml-1 , P = 0.048). By contrast, PAI-1, protein C activity, protein S antigen and TM remained within the normal range at the trough steady state. CONCLUSIONS: Residual plasma rivaroxaban at the trough steady state may explain the antithrombin effect of rivaroxaban in patients with nonvalvular atrial fibrillation. PMID- 28888221 TI - Transcatheter aortic valve-in-valve implantation of a CoreValve in a JenaValve prosthesis: a case report. AB - BACKGROUND: Transcatheter aortic valve implantation has become an accepted treatment modality for inoperable or high-risk surgical patients with symptomatic severe aortic stenosis. CASE PRESENTATION: We report the case of a 70-year-old white man who was treated for severe symptomatic aortic regurgitation using transcatheter aortic valve implantation from the apical approach. Because of recurrent cardiac decompensation 4 weeks after implantation he underwent the implantation of a left ventricular assist device system. A year later echocardiography showed a severe transvalvular central insufficiency. Our heart team decided to choose a valve-in-valve approach while reducing the flow rate of left ventricular assist device to minimum and pacing with a frequency of 140 beats/minute. There was an excellent result and our patient is doing well with no relevant insufficiency of the aortic valve at 12-month follow-up. CONCLUSION: This is the first report about a successful treatment of a stenotic JenaValve using a CoreValve Evolut R; the use of a CoreValve Evolut R prosthesis may be an optimal option for valve-in-valve procedures. PMID- 28888220 TI - Pharmacokinetics of multiple doses of co-crystal of tramadol-celecoxib: findings from a four-way randomized open-label phase I clinical trial. AB - AIM: We compared the pharmacokinetic (PK) profiles of co-crystal of tramadol celecoxib (CTC) vs. each reference product (alone and in open combination) after single (first dose) and multiple dosing. METHODS: Healthy adults aged 18-50 years received, under fasted conditions, 15 twice-daily doses of the following treatments (separated by >=14-day washout): 200 mg immediate-release (IR) CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; treatment 1); 100 mg IR tramadol (treatment 2), 100 mg celecoxib (treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (treatment 4). The treatment sequence was assigned by computer-generated randomization. PK parameters were calculated using non compartmental analysis. Parameters for CTC were adjusted according to reference product dose. RESULTS: A total of 30 subjects (20 males, mean age 35 years) were included. Multiple-dose tramadol PK parameters for treatments 1, 2 and 4, respectively, were 551, 632 and 661 ng ml-1 [mean maximum plasma concentration (Cmax )]; 4796, 4990 and 5284 ng h ml-1 (area under the plasma concentration-time curve over the dosing interval at steady state); and 3.0, 2.0 and 2.0 h (median time to Cmax at steady state). For treatments 1, 3 and 4, multiple-dose celecoxib PK parameters were 445, 536 and 396 ng ml-1 ; 2803, 3366 and 2897 ng h ml-1 ; and 2.0, 2.0 and 3.0 h. Single-dose findings were consistent with multiple-dose data. Types of adverse events were consistent with known reference product safety profiles. CONCLUSION: After single (first dose) and multiple dosing, PK parameters for each active pharmaceutical ingredient in CTC were modified by co crystallization compared with reference products alone or in open combination. PMID- 28888222 TI - Primary hyperparathyroidism caused by enormous unilateral water-clear cell parathyroid hyperplasia. AB - BACKGROUND: Parathyroid water-clear cell hyperplasia (WCCH) and water-clear cell adenoma (WCCA) are rare causes of primary hyperparathyroidism. The frequency of WCCH seems to be less than 1% of all primary hyperplasia. CASE PRESENTATION: We report a 53-year-old woman with a large unilateral water clear cell parathyroid hyperplasia associated with primary hyperparathyroidism and severe osteoporosis. Ultrasonography showed a 5.4 cm multilobulated hypoechoic well defined mass localized in the lower half of the left thyroid lobe. Technetium sestamibi scanning showed a persistent very large area of increased activity possibly corresponding to a left inferior double parathyroid adenoma. At surgery, two large merged lobulated parathyroid glands were removed from the left superior and inferior aspects of the adjacent thyroid extending to the sub-clavicular area. Histopathology showed polygonal hyperplastic vacuolated cells with abundant water clear cytoplasm. The lesion had lack of capsule or rim of parathyroid tissue and immunohistochemistry was positive for PTH staining. These findings were consistent with diffused water clear cell hyperplasia. After parathyroidectomy, iPTH and calcium levels dropped immediately. CONCLUSION: The clinical presentation of the patients with water clear cells parathyroid content and hyperparathyroidism is indistinguishable from that of the more common causes of primary hyperparathyroidism of adenoma or hyperplasia and the diagnosis is made only on pathological examination. In conclusion, the distinction of water clear cell hyperplasia from water clear cell adenoma can be challenging in many cases, although clinically significant as far as treatment and follow-up. PMID- 28888223 TI - Assessment of transition readiness in adolescents and young adults with chronic health conditions. AB - BACKGROUND: Transition from pediatric to adult health care is a vulnerable period for adolescents and young adults. Challenges include paucity of validated measures to assess patients' transition readiness. We evaluated the Transition Readiness Assessment Questionnaire (TRAQ) in adolescents and young adults with rheumatic, gastrointestinal, and endocrine disorders. We examined whether baseline TRAQ scores and other demographic variables predicted transition to adult care over a three year follow up period. METHODS: In this descriptive study at a single institution, eighty-nine adolescents at a single pediatric academic medical center completed demographic and medical history surveys and the TRAQ and were followed over 3 years by telephone interview to determine whether they had transitioned to adult subspecialty care. Transition was defined as attending at least one adult subspecialty appointment. Multivariable logistic regression and Cox proportional hazards regression models were used to determine whether TRAQ scores predicted time to transition. RESULTS: Of the participants, 56% had rheumatic, 21% endocrine, and 23% gastrointestinal conditions. The TRAQ self management domain score was not significantly associated with age, gender, socioeconomic status, or specialty. The TRAQ self-advocacy score increased with age. Baseline TRAQ scores did not predict transition or time to transition over three years. CONCLUSION: In this cohort of adolescents and young adults who were 16 to 23 years of age at enrollment, 48% transitioned to adult care over three years of follow up. Nearly half reported not discussing transition with provider or seeing provider independently for part of visit. Older age but not other demographic variables nor baseline TRAQ score predicted transition or time to transition to an adult subspecialty provider; however, a there was a trend towards shorter time to transition with the highest quartile TRAQ scores. PMID- 28888224 TI - Long-term patient reported outcomes following radiation therapy for oropharyngeal cancer: cross-sectional assessment of a prospective symptom survey in patients >=65 years old. AB - BACKGROUND: Given the potential for older patients to experience exaggerated toxicity and symptoms, this study was performed to characterize patient reported outcomes in older patients following definitive radiation therapy (RT) for oropharyngeal cancer (OPC). METHODS: Cancer-free head and neck cancer survivors (>6 months since treatment completion) were eligible for participation in a questionnaire-based study. Participants completed the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN). Those patients >=65 years old at treatment for OPC with definitive RT were included. Individual and overall symptom severity and clinical variables were analyzed. RESULTS: Of the 79 participants analyzed, 82% were male, 95% white, 41% T3/4 disease, 39% RT alone, 27% induction chemotherapy, 52% concurrent, and 18% both, and 96% IMRT. Median age at RT was 71 yrs. (range: 65-85); median time from RT to MDASI-HN was 46 mos. (2/3 > 24 mos.). The top 5 MDASI-HN items rated most severe in terms of mean (+/ SD) ratings (0-10 scale) were dry mouth (3.48 +/- 2.95), taste (2.81 +/- 3.29), swallowing (2.59 +/- 2.96), mucus in mouth/throat (2.04 +/- 2.68), and choking (1.30 +/- 2.38) reported at moderate-severe levels (>=5) by 35, 29, 29, 18, and 13%, respectively. Thirty-nine % reported none (0) or no more than mild (1-4) symptoms across all 22 MDASI-HN symptoms items, and 38% had at least one item rated as severe (>=7). Hierarchical cluster analysis resulted in 3 patient groups: 1) ~65% with ranging from none to moderate symptom burden, 2) ~35% with moderate-severe ratings for a subset of classically RT-related symptoms (e.g. dry mouth, mucus, swallowing) and 3) 2 pts. with severe ratings of most items. CONCLUSIONS: The overall long-term symptom burden seen in this older OPC cohort treated with modern standard therapy was largely favorable, yet a higher symptom group (~35%) with a distinct pattern of mostly local and classically RT-related symptoms was identified. PMID- 28888225 TI - Towards evidence-based computational statistics: lessons from clinical research on the role and design of real-data benchmark studies. AB - BACKGROUND: The goal of medical research is to develop interventions that are in some sense superior, with respect to patient outcome, to interventions currently in use. Similarly, the goal of research in methodological computational statistics is to develop data analysis tools that are themselves superior to the existing tools. The methodology of the evaluation of medical interventions continues to be discussed extensively in the literature and it is now well accepted that medicine should be at least partly "evidence-based". Although we statisticians are convinced of the importance of unbiased, well-thought-out study designs and evidence-based approaches in the context of clinical research, we tend to ignore these principles when designing our own studies for evaluating statistical methods in the context of our methodological research. MAIN MESSAGE: In this paper, we draw an analogy between clinical trials and real-data-based benchmarking experiments in methodological statistical science, with datasets playing the role of patients and methods playing the role of medical interventions. Through this analogy, we suggest directions for improvement in the design and interpretation of studies which use real data to evaluate statistical methods, in particular with respect to dataset inclusion criteria and the reduction of various forms of bias. More generally, we discuss the concept of "evidence-based" statistical research, its limitations and its impact on the design and interpretation of real-data-based benchmark experiments. CONCLUSION: We suggest that benchmark studies-a method of assessment of statistical methods using real-world datasets-might benefit from adopting (some) concepts from evidence-based medicine towards the goal of more evidence-based statistical research. PMID- 28888226 TI - Modulation of hippocampal neuronal activity by So-ochim-tang-gamibang in mice subjected to chronic restraint stress. AB - BACKGROUND: So-ochim-tang-gamibang (SOCG) is a decoction formula which has been used to improve mental activity in traditional Korean medicine. The present study was performed to evaluate whether the treatment of SOCG was involved in activating hippocampal neurons in mice which were subjected to chronic restraint stress (CRS). METHODS: Mice were subjected to CRS for 2 weeks to induce depressive-like behaviors. SOCG was orally administered for the same period. mRNA expression in the hippocampus was analyzed by RT-PCR. Levels of serotonin receptor 5-HT1AR in the hippocampus were determined by western blotting and by immunofluorescence staining in coronal brain sections. Cultured neurons were prepared from the dorsal root ganglia (DRG) in mice to examine the effects of CRS and SOCG treatment on neurite outgrowth. Depressive-like behaviors of experimental animals were measured by open field test (OFT) and forced swimming test (FST). RESULTS: mRNA levels of serotonin 1A and 1B receptors (5-HT1AR and 5 HT1BR) were decreased in the hippocampus of CRS animals and increased by SOCG treatment. Signals of 5-HT1AR protein in CA3 pyramidal cells were decreased by CRS but elevated back to levels in control animals after SOCG treatment. Phospho Erk1/2 protein in CA3 cells showed similar pattern of changes as in 5-HT1AR, suggesting coordinated regulation after SOCG treatment in CRS animals. Axonal growth-associated protein GAP-43 levels were also decreased by CRS and then increased by SOCG treatment. In vivo administration of SOCG improved neurite outgrowth of primary DRG neurons from CRS animals and also increased 5-HT1AR protein signals. Behavioral tests of open field and forced swimming showed that immobility time periods were significantly decreased by SOCG treatment. CONCLUSIONS: Our data suggest that SOCG treatment may increase synaptic responsiveness to serotonergic neuronal inputs by upregulating 5-HT1AR in the hippocampal neurons. PMID- 28888227 TI - Conversion of an inactive xylose isomerase into a functional enzyme by co expression of GroEL-GroES chaperonins in Saccharomyces cerevisiae. AB - BACKGROUND: Second-generation ethanol production is a clean bioenergy source with potential to mitigate fossil fuel emissions. The engineering of Saccharomyces cerevisiae for xylose utilization is an essential step towards the production of this biofuel. Though xylose isomerase (XI) is the key enzyme for xylose conversion, almost half of the XI genes are not functional when expressed in S. cerevisiae. To date, protein misfolding is the most plausible hypothesis to explain this phenomenon. RESULTS: This study demonstrated that XI from the bacterium Propionibacterium acidipropionici becomes functional in S. cerevisiae when co-expressed with GroEL-GroES chaperonin complex from Escherichia coli. The developed strain BTY34, harboring the chaperonin complex, is able to efficiently convert xylose to ethanol with a yield of 0.44 g ethanol/g xylose. Furthermore, the BTY34 strain presents a xylose consumption rate similar to those observed for strains carrying the widely used XI from the fungus Orpinomyces sp. In addition, the tetrameric XI structure from P. acidipropionici showed an elevated number of hydrophobic amino acid residues on the surface of protein when compared to XI commonly expressed in S. cerevisiae. CONCLUSIONS: Based on our results, we elaborate an extensive discussion concerning the uncertainties that surround heterologous expression of xylose isomerases in S. cerevisiae. Probably, a correct folding promoted by GroEL-GroES could solve some issues regarding a limited or absent XI activity in S. cerevisiae. The strains developed in this work have promising industrial characteristics, and the designed strategy could be an interesting approach to overcome the non-functionality of bacterial protein expression in yeasts. PMID- 28888228 TI - Transperineal cryotherapy for unresectable muscle invasive bladder cancer: preliminary experience with 7 male patients. AB - BACKGROUND: Radical cystectomy (RC) with pelvic lymph node dissection (PLND) and urinary diversion (UD) is considered the standard treatment for muscle invasive bladder cancer (MIBC). In a part of patients, RC procedure is aborted due to unresectable disease, other followed treatment like systemic chemotherapy, radiotherapy or cryotherapy may be a better option. The aim of present study was to report the preliminary results of transperineal cryotherapy for unresectable muscle invasive bladder cancer. METHODS: From January 2011 to August 2013, 7 male patients with pT4b unresectable bladder cancer underwent bilateral ureterocutaneostomy. Two performed a pelvic lymph node dissection (PLND). Then primary transperineal cryosurgery for preserved bladder at the guidance of transrectal ultrasound (TRUS) was performed. All patients underwent a dual freeze thaw cycle using third-generation cryotechnology with ultrathin 17-gauge cryoneedles. Computer tomography (CT) and/or magnetic resonance image (MRI)were performed at 3 month intervals after cryosurgery to determine whether progression or recurrence occurred. RESULTS: All cryosurgery was performed successfully, mean operation time was 76.43 +/- 25.12 min (range 50-120 min), mean blood loss was 19.29 +/- 15.92 ml (range 5-50 ml). Mean hospital stay was 3.86 +/- 1.68 day (range 2-7 days). No operative related deaths occurred. Four patients dead due to the metastasis disease at the follow up time of 8, 15, 18 and 37 months, respectively. Six patients received postoperative therapy, of whom 5 patients were treated with combined chemoradiation, and the other one received chemotherapy alone. The progression free survival (PFS) of the 7 patients was 22.00 +/- 14.61 months (range 3-40 months). The one, two and three year overall survival (OS) was 85.7%, 57.1% and 42.9%, respectively. CONCLUSION: Our results suggest that cryosurgery combination with chemoradiotherapy provide a safe and effective alternative method for unresectable pT4b bladder cancer. Longer follow up is necessary to determine the sustained efficacy. PMID- 28888229 TI - Changes in ankle joint motion after Supramalleolar osteotomy: a cadaveric model. AB - BACKGROUND: Malalignment of the ankle joint has been found after trauma, by neurological disorders, genetic predisposition and other unidentified factors, and results in asymmetrical joint loading. For a medial open wedge supramalleolar osteotomy(SMO), there are some debates as to whether concurrent fibular osteotomy should be performed. We assessed the changes in motion of ankle joint and plantar pressure after supramalleolar osteotomy without fibular osteotomy. METHODS: Ten lower leg specimens below the knee were prepared from fresh-frozen human cadavers. They were harvested from five males (10 ankles)whose average age was 70 years. We assessed the motion of ankle joint as well as plantar pressure for SS(supra-syndesmotic) SMO and IS(intra-syndesmotic) SMO. After the osteotomy, each specimen was subjected to axial compression from 20 N preload to 350 N representing half-body weight. For the measurement of the motion of ankle joint, the changes in gap and point, angles in ankle joint were measured. The plantar pressure were also recorded using TekScan sensors. RESULTS: The changes in the various gap, point, and angles movements on SS-SMO and IS-SMO showed no statistically significant differences between the two groups. Regarding the shift of plantar center of force (COF) were noted in the anterolateral direction, but not statistically significant. CONCLUSIONS: SS-SMO and IS-SMO with intact fibula showed similar biomechanical effect on the ankle joint. We propose that IS-SMO should be considered carefully for the treatment of osteoarthrosis when fibular osteotomy is not performed because lateral cortex fracture was less likely using the intrasyndesmosis plane because of soft tissue support. PMID- 28888230 TI - Effect of supercritical carbon dioxide on the enzymatic production of biodiesel from waste animal fat using immobilized Candida antarctica lipase B variant. AB - BACKGROUND: Waste animal fat is a promising feedstock to replace vegetable oil that widely used in commercial biodiesel process, however the high content of free fatty acid in waste fat makes it unfeasible to be processed with commercial base-catalytic process. Enzymatic process is preferable to convert waste fat into biodiesel since enzyme can catalyze both esterification of free fatty acid and transesterification of triglyceride. However, enzymatic reaction still has some drawbacks such as lower reaction rates than base-catalyzed transesterification and the limitation of reactant concentration due to the enzyme inhibition of methanol. Supercritical CO2 is a promising reaction media for enzyme-catalyzed transesterification to overcome those drawbacks. RESULT: The transesterification of waste animal fat was carried out in supercritical CO2 with varied concentration of feedstock and methanol in CO2. The CO2 to feedstock mass ratio of 10:1 showed the highest yield compared to other ratios, and the highest FAME yield obtained from waste animal fat was 78%. The methanol concentration effect was also observed with variation 12%, 14%, and 16% of methanol to feedstock ratio. The best yield was 87% obtained at the CO2 to feedstock ratio of 10: 1 and at the methanol to feedstock ratio of 14% after 6 h of reaction. CONCLUSION: Enzymatic transesterification to produce biodiesel from waste animal fat in supercritical fluid media is a potential method for commercialization since it could enhance enzyme activity due to supercritical fluid properties to remove mass transfer limitation. The high yield of FAME when using high mass ratio of CO2 to oil showed that supercritical CO2 could increase the reaction and mass transfer rate while reducing methanol toxicity to enzyme activity. The increase of methanol concentration also increased the FAME yield because it might shift the reaction equilibrium to FAME production. This finding describes that the application of supercritical CO2 in the enzymatic reaction enables the application of simple process such as a packed-bed reactor. PMID- 28888231 TI - Preface to glyco-neuroscience. PMID- 28888232 TI - Small non-coding RNAs in endocrinology. PMID- 28888233 TI - Asian Urban Environment and Climate Change: Preface. AB - The Asian Network on Climate Science and Technology (www.ancst.org), in collaboration with Tsinghua University, held a conference on environmental and climate science, air pollution, urban planning and transportation in July 2015, with over 40 Asian experts participating and presentation. This was followed by a meeting with local government and community experts on the practical conclusions of the conference. Of the papers presented at the conference a selection are included in this special issue of Journal of Environmental Science, which also reflects the conclusions of the Paris Climate meeting in Dec 2015, when the major nations of the world agreed about the compelling need to reduce the upward trend of adverse impacts associated with global climate change. Now is the time for urban areas to work out the serious consequences for their populations, but also how they should work together to take action to reduce global warming to benefit their own communities and also the whole planet! PMID- 28888234 TI - Disseminating near-real-time hazards information and flood maps in the Philippines through Web-GIS. AB - The Philippines being a locus of tropical cyclones, tsunamis, earthquakes and volcanic eruptions, is a hotbed of disasters. These natural hazards inflict loss of lives and costly damage to property. Situated in a region where climate and geophysical tempest is common, the Philippines will inevitably suffer from calamities similar to those experienced recently. With continued development and population growth in hazard prone areas, it is expected that damage to infrastructure and human losses would persist and even rise unless appropriate measures are immediately implemented by government. In 2012, the Philippines launched a responsive program for disaster prevention and mitigation called the Nationwide Operational Assessment of Hazards (Project NOAH), specifically for government warning agencies to be able to provide a 6hr lead-time warning to vulnerable communities against impending floods and to use advanced technology to enhance current geo-hazard vulnerability maps. To disseminate such critical information to as wide an audience as possible, a Web-GIS using mashups of freely available source codes and application program interface (APIs) was developed and can be found in the URLs http://noah.dost.gov.ph and http://noah.up.edu.ph/. This Web-GIS tool is now heavily used by local government units in the Philippines in their disaster prevention and mitigation efforts and can be replicated in countries that have a proactive approach to address the impacts of natural hazards but lack sufficient funds. PMID- 28888235 TI - Predicting vehicle fuel consumption patterns using floating vehicle data. AB - The status of energy consumption and air pollution in China is serious. It is important to analyze and predict the different fuel consumption of various types of vehicles under different influence factors. In order to fully describe the relationship between fuel consumption and the impact factors, massive amounts of floating vehicle data were used. The fuel consumption pattern and congestion pattern based on large samples of historical floating vehicle data were explored, drivers' information and vehicles' parameters from different group classification were probed, and the average velocity and average fuel consumption in the temporal dimension and spatial dimension were analyzed respectively. The fuel consumption forecasting model was established by using a Back Propagation Neural Network. Part of the sample set was used to train the forecasting model and the remaining part of the sample set was used as input to the forecasting model. PMID- 28888236 TI - Urban air quality, meteorology and traffic linkages: Evidence from a sixteen-day particulate matter pollution event in December 2015, Beijing. AB - A heavy 16-day pollution episode occurred in Beijing from December 19, 2015 to January 3, 2016. The mean daily AQI and PM2.5 were 240.44 and 203.6MUg/m3. We analyzed the spatiotemporal characteristics of air pollutants, meteorology and road space speed during this period, then extended to reveal the combined effects of traffic restrictions and meteorology on urban air quality with observational data and a multivariate mutual information model. Results of spatiotemporal analysis showed that five pollution stages were identified with remarkable variation patterns based on evolution of PM2.5 concentration and weather conditions. Southern sites (DX, YDM and DS) experienced heavier pollution than northern ones (DL, CP and WL). Stage P2 exhibited combined functions of meteorology and traffic restrictions which were delayed peak-clipping effects on PM2.5. Mutual information values of Air quality-Traffic-Meteorology (ATM-MI) revealed that additive functions of traffic restrictions, suitable relative humidity and temperature were more effective on the removal of fine particles and CO than NO2. PMID- 28888237 TI - Street floods in Metro Manila and possible solutions. AB - Urban floods from thunderstorms cause severe problems in Metro Manila due to road traffic. Using Light Detection and Ranging (LiDAR)-derived topography, flood simulations and anecdotal reports, the root of surface flood problems in Metro Manila is identified. Majority of flood-prone areas are along the intersection of creeks and streets located in topographic lows. When creeks overflow or when rapidly accumulated street flood does not drain fast enough to the nearest stream channel, the intersecting road also gets flooded. Possible solutions include the elevation of roads or construction of well-designed drainage structures leading to the creeks. Proposed solutions to the flood problem of Metro Manila may avoid paralyzing traffic problems due to short-lived rain events, which according to Japan International Cooperation Agency (JICA) cost the Philippine economy 2.4billionpesos/day. PMID- 28888238 TI - GIS-based analysis of population exposure to PM2.5 air pollution-A case study of Beijing. AB - PM2.5, formally defined as particulate matter with diameter less than 2.5MUm, is one of most harmful air pollutants threatening human health. Numerous epidemiological studies have shown that both short-term and long-term exposures to PM2.5 are strongly linked with respiratory diseases. In this study, various types of spatio-temporal data were collected and used to estimate the spatio temporal variation of PM2.5 exposure in Beijing in 2014. The seasonal and daily variation of the population-weighted exposure level (PWEL) in 2014 was estimated and compared. The results show that the population exposure to ambient air pollution differs significantly in the four seasons, and the exposure levels in winter and spring are notably higher than the other seasons; the exposure level changes greatly from North to South, and each sub-district maintains similarity to neighboring sub-districts. PMID- 28888239 TI - Urban climate in the Tokyo metropolitan area in Japan. AB - Long-term climate changes related with urbanization in Tokyo, Japan, and recent temperature and heavy rainfall distribution in the Tokyo metropolitan area are reviewed. A relatively high temperature increase in annual mean temperature at the rate of 3.0 degrees C/century was detected in Tokyo for the period 1901-2015. Some observational evidence showed the existence of both thermal and mechanical effects of urbanization on recent heavy rainfall occurrences, and modeling studies also support precipitation enhancement. Urban influences were recognized in other climatological elements, such as number of fog days, relative humidity, and wind circulation. PMID- 28888240 TI - Sensitivity of precipitation statistics to urban growth in a subtropical coastal megacity cluster. AB - This short paper presents an investigation on how human activities may or may not affect precipitation based on numerical simulations of precipitation in a benchmark case with modified lower boundary conditions, representing different stages of urban development in the model. The results indicate that certain degrees of urbanization affect the likelihood of heavy precipitation significantly, while less urbanized or smaller cities are much less prone to these effects. Such a result can be explained based on our previous work where the sensitivity of precipitation statistics to surface anthropogenic heat sources lies in the generation of buoyancy and turbulence in the planetary boundary layer and dissipation through triggering of convection. Thus only mega cities of sufficient size, and hence human-activity-related anthropogenic heat emission, can expect to experience such effects. In other words, as cities grow, their effects upon precipitation appear to grow as well. PMID- 28888241 TI - Buoyancy and turbulence-driven atmospheric circulation over urban areas. AB - In the buoyancy and turbulence-driven atmospheric circulations (BTDAC) that occur over urban areas where the approach means wind speeds are very low (less than turbulent fluctuations and typically <3m/sec), the surface temperatures are significantly higher than those in the external rural areas, and the atmosphere above the mixing layer is stably stratified. In this paper, the mechanisms of BTDAC formation are studied through laboratory experiments and modelling, with additional low-level inflow from external rural areas and a divergent outflow in the opposite direction in the upper part of the mixed layer. Strong turbulent plumes in the central region mix the flow between lower and higher levels up to the inversion height. There are shear-driven turbulent eddies and weaker buoyant plumes around the periphery of the urban area. As the approach flow is very weak, the recirculating streamlines within the dome restrict the ventilation, and the dispersion of pollution emitted from sources below the inversion height leading to a rise in the mean concentration. Low-level air entrained from rural areas can, however, improve ventilation and lower this concentration. This trend can also be improved if the recirculating structure of the BTDAC flow pattern over urban areas breaks down as a result of the surface temperature distribution not being symmetrical, or as the approach wind speed increases to a level comparable with the mean velocity of circulation, or (except near the equator) the urban area is large enough that the Coriolis acceleration is significant. PMID- 28888242 TI - Surface ozone scenario and air quality in the north-central part of India. AB - Tropospheric pollutants including surface ozone (O3), nitrogen dioxide (NO2), carbon monoxide (CO) and meteorological parameters were measured at a traffic junction (78 degrees 2' E and 27 degrees 11' N) in Agra, India from January 2012 to December 2012. Temporal analysis of pollutants suggests that annual average mixing ratios of tropospheric pollutants were: O3 - 22.97+/-23.36ppbV, NO2 - 19.84+/-16.71ppbV and CO - 0.91+/-0.86ppmV, with seasonal variations of O3 having maximum mixing ratio during summer season (32.41+/-19.31ppbV), whereas lowest was found in post-monsoon season (8.74+/-3.8ppbV). O3 precursors: NO2 and CO, showed inverse relationship with O3. Seasonal variation and high O3 episodes during summer are associated with meteorological parameters such as high solar radiation, atmospheric temperature and transboundary transport. The interdependence of these variables showed a link between the daytime mixing ratios of O3 with the nighttime level of NO2. The mixing ratios of CO and NO2 showed tight correlations, which confirms the influence of vehicular emissions combined with other anthropogenic activities due to office/working hours, shallowing, and widening of boundary layer. FLEXTRA backward trajectories for the O3 episode days clearly indicate the transport from the NW and W to S/SE and SW direction at Agra in different seasons. PMID- 28888243 TI - Challenges to quantitative applications of Landsat observations for the urban thermal environment. AB - Since the launch of its first satellite in 1972, the Landsat program has operated continuously for more than forty years. A large data archive collected by the Landsat program significantly benefits both the academic community and society. Thermal imagery from Landsat sensors, provided with relatively high spatial resolution, is suitable for monitoring urban thermal environment. Growing use of Landsat data in monitoring urban thermal environment is demonstrated by increasing publications on this subject, especially over the last decade. Urban thermal environment is usually delineated by land surface temperature (LST). However, the quantitative and accurate estimation of LST from Landsat data is still a challenge, especially for urban areas. This paper will discuss the main challenges for urban LST retrieval, including urban surface emissivity, atmospheric correction, radiometric calibration, and validation. In addition, we will discuss general challenges confronting the continuity of quantitative applications of Landsat observations. These challenges arise mainly from the scan line corrector failure of the Landsat 7 ETM+ and channel differences among sensors. Based on these investigations, the concerns are to: (1) show general users the limitation and possible uncertainty of the retrieved urban LST from the single thermal channel of Landsat sensors; (2) emphasize efforts which should be done for the quantitative applications of Landsat data; and (3) understand the potential challenges for the continuity of Landsat observation (i.e., thermal infrared) for global change monitoring, while several climate data record programs being in progress. PMID- 28888244 TI - New and Anticipated Therapies for Severe Asthma. AB - Asthma is frequently undertreated, resulting in a relatively high prevalence of patients with uncontrolled disease, characterized by the presence of symptoms and risk of adverse outcomes. Patients with uncontrolled asthma have a higher risk of morbidity and mortality, underscoring the importance of identifying uncontrolled disease and modifying management plans to improve control. Several assessment tools exist to evaluate control with various cutoff points and measures, but these tools do not reliably correlate with physiological measures and should be considered a supplement to physiological tests. When attempting to improve control in patients, nonpharmacological interventions should always be attempted before changing or adding pharmacotherapies. Among patients with severe, uncontrolled asthma, individualized treatment based on asthma phenotype and eosinophil presence should be considered. The efficacy of the anti-IgE antibody omalizumab has been well established for patients with allergic asthma, and novel biologic agents targeting IL-5, IL-13, IL-4, and other allergic pathways have been investigated for patients with allergic or eosinophilic asthma. Fevipiprant (a CRTH2 [chemokine receptor homologous molecule expressed on Th2 cells] antagonist) and imatinib (a tyrosine kinase inhibition) are examples of nonbiologic therapies that may be useful for patients with severe, uncontrolled asthma. Incorporation of new and emerging treatment into therapeutic strategies for patients with severe asthma may improve outcomes for this patient population. PMID- 28888245 TI - Metabolic adventures in aging research. PMID- 28888246 TI - Correction. PMID- 28888248 TI - Epinephrine Autoinjectors: New Data, New Problems. AB - Epinephrine is the first-line treatment for anaphylaxis. Despite this, there have been identified gaps in the management of anaphylaxis including infrequent or delayed use of epinephrine for acute allergic reactions, as well as inadequate epinephrine autoinjector (EAI) training, and prescription rates of these devices for patients at risk. This paper reviews new data, and new problems in recently published literature on EAIs. A database search was conducted for publications between January 2015 and February 2017 using keywords related to EAIs including their functionality and features, carriage, prescription rates, barriers, and side effects. Eligibility criteria included patients at risk for anaphylaxis, caregivers, and health care professionals. Experimental studies and observational studies were included. Of 1,737 potentially relevant articles, 19 were used for analysis. These articles addressed specific aspects of an EAI, including (1) information on features and functionality; (2) prescriptions; (3) training on their use; and (4) carriage and use at the time of reaction by patients, schools, camps, emergency departments, and paramedics. Our review highlights that existing gaps in anaphylaxis management remain unaddressed. Patient needs are largely unmet, and very few studies are being designed to clarify and instill best practice, and to determine how to increase adherence to existing anaphylaxis guidelines through integrated knowledge translation strategies. PMID- 28888247 TI - Fatal Anaphylaxis: Mortality Rate and Risk Factors. AB - Up to 5% of the US population has suffered anaphylaxis. Fatal outcome is rare, such that even for people with known venom or food allergy, fatal anaphylaxis constitutes less than 1% of total mortality risk. The incidence of fatal anaphylaxis has not increased in line with hospital admissions for anaphylaxis. Fatal drug anaphylaxis may be increasing, but rates of fatal anaphylaxis to venom and food are stable. Risk factors for fatal anaphylaxis vary according to cause. For fatal drug anaphylaxis, previous cardiovascular morbidity and older age are risk factors, with beta-lactam antibiotics, general anesthetic agents, and radiocontrast injections the commonest triggers. Fatal food anaphylaxis most commonly occurs during the second and third decades. Delayed epinephrine administration is a risk factor; common triggers are nuts, seafood, and in children, milk. For fatal venom anaphylaxis, risk factors include middle age, male sex, white race, cardiovascular disease, and possibly mastocytosis; insect triggers vary by region. Upright posture is a feature of fatal anaphylaxis to both food and venom. The rarity of fatal anaphylaxis and the significant quality of life impact of allergic conditions suggest that quality of life impairment should be a key consideration when making treatment decisions in patients at risk for anaphylaxis. PMID- 28888249 TI - Do Corticosteroids Prevent Biphasic Anaphylaxis? AB - Anaphylaxis is a severe hypersensitivity reaction that is rapid in onset and can result in death. The pattern of an anaphylactic reaction can be uniphasic (or monophasic), biphasic (also called delayed or late phase), or refractory in nature. The most widely cited definition of biphasic anaphylaxis is a recurrence of anaphylactic symptoms after initial resolution despite no further exposure to the trigger. Corticosteroids are thought by some to prevent the development of biphasic symptoms and, therefore, commonly used in the emergency treatment of anaphylaxis but this has not been systemtically analyzed. In this review, Ovid MEDLINE, Ovid EMBASE, Web of Science, and Scopus were searched for articles using "anaphylaxis" combined with the key terms "biphasic" and/or "corticosteroids" and/or "epinephrine." A total of 31 appropriate studies were identified. Biphasic anaphylactic reactions are more likely to occur in moderate to severe anaphylaxis or when anaphylaxis is not treated with timely epinephrine. Because of the potential detrimental adverse effects of corticosteroids and lack of compelling evidence demonstrating an effective role in reducing anaphylaxis severity or preventing biphasic anaphylaxis, we do not advocate for their routine use in anaphylaxis. PMID- 28888250 TI - Latex Allergy: Where Are We Now and How Did We Get There? AB - Latex allergy emerged as an epidemic of anaphylaxis, occupational asthma, and clinical dilemmas in the 1980s. A systematic recognition, investigation, discovery, epidemiology, and prevention strategy followed. International attention and collaborations of investigators, government agencies, manufacturing, and health policy resulted in near elimination of a global epidemic. This article summarizes nearly 4 decades of work in control of this epidemic and focuses attention on future problems that still require resolution. PMID- 28888251 TI - Anaphylaxis: Recognizing Risk and Targeting Treatment. PMID- 28888252 TI - Anaphylaxis and Clinical Utility of Real-World Measurement of Acute Serum Tryptase in UK Emergency Departments. AB - BACKGROUND: British guidelines recommend that serial acute serum tryptase measurements be checked in all adults and a subset of children presenting with anaphylaxis. This is the first study reporting the clinical utility of acute serum tryptase in a "real-world" emergency department (ED) setting following the publication of the World Allergy Organization (WAO) criteria for anaphylaxis. OBJECTIVES: To (1) assess sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of acute serum tryptase in anaphylaxis; (b) determine factors associated with higher acute serum tryptase levels; and (c) audit compliance of acute serum tryptase measurement in the ED. METHODS: The methods used were retrospective electronic search for ED admissions to 3 acute care hospitals in Birmingham, UK, with anaphylaxis in 2012 using wide search terms followed by scrutiny of electronic clinical records and application of the WAO diagnostic criteria for anaphylaxis. Patients with an acute serum tryptase measurement were included in the analysis. RESULTS: Acute serum tryptase level was measured in 141 of 426 (33.1%) cases. Mean time from the onset of symptoms to the measurement of acute serum tryptase level was 4 hours 42 minutes (SD +/- 05:03 hours) and no patients had serial measurements conforming to British guidelines. Acute serum tryptase level of more than 12.4 ng/mL (75th centile) was associated with a sensitivity, specificity, PPV, and NPV of 28%, 88%, 0.93, and 0.17, respectively. Multiple regression analysis showed that male sex (odds ratio, 2.66; P = .003) and hypotension (odds ratio, 7.08; P = .001) predicted higher acute serum tryptase level. CONCLUSIONS: An acute serum tryptase level of more than 12.4 ng/mL in an ED setting carries high PPV and specificity, but poor sensitivity and NPV. PMID- 28888254 TI - In-season Dosage Adjustment for Pollen Subcutaneous Immunotherapy: The Controversy Continues. PMID- 28888253 TI - Further Evaluation of Factors That May Predict Biphasic Reactions in Emergency Department Anaphylaxis Patients. AB - BACKGROUND: Anaphylaxis is a systemic allergic reaction that is commonly treated in the emergency department (ED). The risk of a biphasic reaction is the rationale for observation. OBJECTIVE: To derive a prediction rule to stratify ED anaphylaxis patients at risk of a biphasic reaction. METHODS: We conducted an observational study of a cohort of patients presenting to an academic ED with signs and symptoms of anaphylaxis. We collected clinical data on biphasic reactions meeting National Institutes of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network diagnostic criteria. Logistic regression analyses were conducted to identify predictors of biphasic reactions, and odds ratios (ORs) with 95% CIs are reported. The predictive ability of the model features is summarized using the area under a receiver operating characteristics curve, or AUC. Internally validated AUCs were obtained using bootstrap resampling. RESULTS: We identified 872 anaphylaxis-related visits. Thirty-six (4.1%) visits resulted in biphasic reactions. Multivariable analysis showed that prior anaphylaxis (OR, 2.74; 95% CI, 1.33-5.63), unknown inciting trigger (OR, 2.40; 95% CI, 1.14-4.99), and first epinephrine administration more than 60 minutes after symptom onset (OR, 2.29; 95% CI, 1.09-4.79) were statistically significantly associated with biphasic reactions. The AUC of this model was 0.70 (95% CI, 0.61-0.79), with an internally validated AUC of 0.67 (95% CI, 0.59-0.76). The P value from the goodness-of-fit test was .91. CONCLUSIONS: Our study demonstrated a 4.1% rate of biphasic reactions and found that prior anaphylaxis, unknown inciting trigger, and delayed epinephrine use were risk factors for biphasic reactions. PMID- 28888255 TI - What Does Screening Newborns for T-Cell Lymphopenia Find? PMID- 28888256 TI - Vaccine Reactions. PMID- 28888257 TI - Gelatin Anaphylaxis During Surgery: A Rare Cause of Perioperative Anaphylaxis. PMID- 28888258 TI - Actually Calling and Talking with Your Patient. PMID- 28888259 TI - Is treatment of serological ABPA similar to that of ABPA with bronchiectasis? PMID- 28888260 TI - Reply. PMID- 28888261 TI - Erratum to "Photomodified fluoranthene exerts more harmful effects as compared to intact fluoranthene by inhibiting growth and photosynthetic processes in wheat" [Ecotoxicol. Environ. Saf. 122 (2015), 31-36]. PMID- 28888262 TI - Introduction. PMID- 28888263 TI - Epidemiology of racial/ethnic disparities in severe maternal morbidity and mortality. AB - The literature abounds with examples of racial/ethnic disparities in both obstetric outcomes and care. Disparities in maternal mortality are well documented with non-Hispanic blacks carrying the burden of the highest maternal mortality rates. Maternal deaths likely represent only the "tip of the iceberg" with respect to pregnancy complications, leading many to explore risk factors and disparities in severe maternal morbidity, a more common precursor to maternal mortality. This review article explores commonly cited indicators of severe maternal morbidity and includes a review of the epidemiological literature supporting or refuting disparities among each indicator. PMID- 28888264 TI - Availability of patient decision aids for stroke prevention in atrial fibrillation: A systematic review. AB - BACKGROUND: Atrial fibrillation is a common irregular heart rhythm that increases patients' risk of stroke. Aspirin, warfarin, direct oral anticoagulants, and an implantable device can reduce this risk. Given the availability of multiple comparable options, this decision depends on patient preferences and is appropriate for the use of decision aids and other efforts to promote shared decision making. The objective of this review was to examine the existence and accessibility of, as well as select outcomes associated with, published, formally evaluated patient decision aids for stroke prevention in atrial fibrillation. METHODS: Six databases were searched from inception to March 2016 with a research librarian. Two authors independently reviewed potential articles, selected trials meeting inclusion criteria, and assessed outcome measures. Outcomes included patient knowledge, involvement, choice, and decisional conflict. RESULTS: The search resulted in 666 articles; most were excluded for not examining stroke prevention in atrial fibrillation and 7 studies were eventually included. Six decision aids displayed combinations of aspirin, warfarin, or no therapy; 1 included a direct oral anticoagulant. Interventions were associated with increased patient knowledge, increased likelihood of making a choice, and low decisional conflict. Use of decision aids in this review was associated with less selection of warfarin. None of the tested decision aids are currently available. DISCUSSION: Published patient decision aids for stroke prevention in atrial fibrillation are not accessible for clinical use. Given the availability of multiple comparable options, there is a need to develop and test new patient decision aids in this context. PMID- 28888265 TI - Temporal changes in myocardial infarction incidence rates are associated with periods of perceived psychosocial stress: A SWEDEHEART national registry study. AB - BACKGROUND: Psychosocial stress might trigger myocardial infarction (MI). Increased MI incidence coincides with recurrent time periods during the year perceived as particularly stressful in the population. METHODS: A stress triggering hypothesis on the risk of MI onset was investigated with Swedish population data on MI hospital admission date and symptom onset date (N=156,690; 148,176) as registered from 2006 through 2013 in the national quality registry database Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART). Poisson regression was applied to analyze daily MI rates during days belonging to the Christmas and New Year holidays, turns of the month, Mondays, weekends, and summer vacation in July compared with remaining control days. RESULTS: Adjusted incidence rate ratios (IRRs) for MI rates were higher during Christmas and New Year holidays (IRR=1.07 [1.04-1.09], P<.001) and on Mondays (IRR=1.11 [1.09 1.13], P<.001) and lower in July (IRR=0.92 [0.90-0.94], P<.001) and over weekends (IRR=0.88 [0.87-0.89], P<.001), yet not during the turns of the month (IRR=1.01 [1.00-1.02], P=.891). These findings were also predominantly robust with symptom onset as alternative outcome, when adjusting for both established and some suggested-but-untested confounders, and in 8 subgroups. CONCLUSIONS: Fluctuations in daily MI incidence rates are systematically related to time periods of presumed psychosocial stress. Further research might clarify mechanisms that are amenable to clinical alteration. PMID- 28888266 TI - New York Heart Association class and the survival benefit from primary prevention implantable cardioverter defibrillators: A pooled analysis of 4 randomized controlled trials. AB - BACKGROUND: Primary prevention implantable cardioverter defibrillator (ICD) reduce all-cause mortality by reducing sudden cardiac death. There are conflicting data regarding whether patients with more advanced heart failure derive ICD benefit owing to the competing risk of nonsudden death. METHODS: We performed a patient-level meta-analysis of New York Heart Association (NYHA) class II/III heart failure patients (left ventricular ejection fraction <=35%) from 4 primary prevention ICD trials (MADIT-I, MADIT-II, DEFINITE, SCD-HeFT). Bayesian-Weibull survival regression models were used to assess the impact of NYHA class on the relationship between ICD use and mortality. RESULTS: Of the 2,763 patients who met study criteria, 68% (n=1,867) were NYHA II and 52% (n=1,435) were randomized to an ICD. In a multivariable model including all study patients, the ICD reduced mortality (hazard ratio [HR] 0.65, 95% posterior credibility interval [PCI]) 0.40-0.99). The interaction between NYHA class and the ICD on mortality was significant (posterior probability of no interaction=.036). In models including an interaction term for the NYHA class and ICD, the ICD reduced mortality among NYHA class II patients (HR 0.55, PCI 0.35 0.85), and the point estimate suggested reduced mortality in NYHA class III patients (HR 0.76, PCI 0.48-1.24), although this was not statistically significant. CONCLUSIONS: Primary prevention ICDs reduce mortality in NYHA class II patients and trend toward reducing mortality in the heterogeneous group of NYHA class III patients. Improved risk stratification tools are required to guide patient selection and shared decision making among NYHA class III primary prevention ICD candidates. PMID- 28888267 TI - Sex-based differences in quality of care and outcomes in a health system using a standardized STEMI protocol. AB - BACKGROUND: Recent data from the National Cardiovascular Data Registry indicate that women with ST-segment-elevation myocardial infarction (STEMI) continue to have higher mortality and reported delays in treatment compared with men. We aimed to determine whether the sex difference in mortality exists when treatment disparities are reduced. METHODS: Using a prospective regional percutaneous coronary intervention (PCI)-based STEMI system database with a standardized STEMI protocol, we evaluated baseline characteristics, treatment, and clinical outcomes of STEMI patients stratified by sex. RESULTS: From March 2003 to January 2016, 4,918 consecutive STEMI patients presented to the Minneapolis Heart Institute at Abbott Northwestern Hospital regional STEMI system including 1,416 (28.8%) women. Compared with men, women were older (68.4 vs 60.9 years) with higher rates of hypertension (66.7% vs 55.7%), diabetes (21.7% vs 17.4%), and cardiogenic shock (11.5% vs 8.0%) (all P < .001). Pre-revascularization medications and PCI were performed with same frequencies, but women were less likely to receive statin or antiplatelet therapy at discharge. After age adjustment, women had similar in hospital mortality to men (5.1% vs 4.8%, P = .60) despite slightly longer door-to balloon time (95 vs 92 minutes, P = .004). Five-year follow-up confirmed absence of a sex disparity in age-adjusted survival post-STEMI. CONCLUSIONS: Previously reported treatment disparities between men and women are diminished in a regional PCI-based STEMI system using a standardized STEMI protocol. No sex differences in short-term or long-term age-adjusted mortality are present in this registry despite some treatment disparities. These results suggest that STEMI health care disparities and mortality in women can be improved using STEMI protocols and systems. PMID- 28888269 TI - Depression is associated with recurrent chest pain with or without coronary artery disease: A prospective cohort study in the emergency department. AB - BACKGROUND: Only a small fraction of acute chest pain in the emergency department (ED) is due to obstructive coronary artery disease (CAD). ED chest pain remains associated with high rates of recidivism, often in the presence of nonobstructive CAD. Psychological states such as depression, anxiety, and elevation of perceived stress may account for this finding. The objective of the study was to determine whether psychological states predict recurrent chest pain (RCP). METHODS: We conducted a prospective cohort study of low- to moderate-cardiac risk ED patients admitted to the Yale Chest Pain Center with acute chest pain. Depression, anxiety, and perceived stress were assessed in each patient using multistudy validated screening scales: Patient Health Questionnaire (PHQ8), Clinical Anxiety Scale (CAS), and Perceived Stress Scale (PSS), respectively. All patients ruled out for infarction underwent appropriate cardiac stress testing. Primary outcome was RCP at 30 days evaluated by phone follow-up and medical record. The relationship between each psychological scale and RCP was evaluated using ordinal logistic regressions, controlling for known sociodemographic and cardiac risk factors. Depression (PHQ8>=10), anxiety (CAS>=30), and perceived stress (PSS>=15) were considered positive. RESULTS: Between August 2013 and May 2015, 985 patients were screened at the Yale Chest Pain Center. Of 500 enrolled patients, 483 patients had complete data and 365 (76%) patients completed follow-up. Thirty-six percent (n=131) had RCP within 1 month. On multivariable regression models, depression (odds ratio [OR]=2.11, 95% CI 1.18-3.79) was a significant independent predictor of 30-day chest pain recurrence after adjustment, whereas PSS (OR=0.96, 95% CI 0.60-1.53) and anxiety (OR=1.59, 95% CI 0.80-3.20) were not. Similarly, there was a direct relationship between psychometric evaluation of depression (via PHQ8) and the frequency of chest pain. CONCLUSIONS: Depression is independently associated with RCP regardless of significant cardiac ischemia on stress testing. Identification and targeted interventions may curtail recidivism with RCP. PMID- 28888268 TI - A randomized, multicenter, open-label, blinded end point trial comparing the effects of spironolactone to chlorthalidone on left ventricular mass in patients with early-stage chronic kidney disease: Rationale and design of the SPIRO-CKD trial. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with increased left ventricular (LV) mass and arterial stiffness. In a previous trial, spironolactone improved these end points compared with placebo in subjects with early-stage CKD, but it is not known whether these effects were specific to the drug or secondary to blood pressure lowering. AIM: The aim was to investigate the hypothesis that spironolactone is superior to chlorthalidone in the reduction of LV mass while exerting similar effects on blood pressure. DESIGN: This is a multicenter, prospective, randomized, open-label, blinded end point clinical trial initially designed to compare the effects of 40weeks of treatment with spironolactone 25mg once daily to chlorthalidone 25mg once daily on the co-primary end points of change in pulse wave velocity and change in LV mass in 350 patients with stages 2 and 3 CKD on established treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Because of slow recruitment rates, it became apparent that it would not be possible to recruit this sample size within the funded time period. The study design was therefore changed to one with a single primary end point of LV mass requiring 150 patients. Recruitment was completed on 31 December 2016, at which time 154 patients had been recruited. Investigations included cardiac magnetic resonance imaging, applanation tonometry, 24-hour ambulatory blood pressure monitoring, and laboratory tests. Subjects are assessed before and after 40weeks of randomly allocated drug therapy and at 46weeks after discontinuation of the study drug. PMID- 28888271 TI - Clinical event adjudication in cardiovascular device trials: An Food and Drug Administration perspective. PMID- 28888270 TI - Soluble endothelial cell-selective adhesion molecule and incident cardiovascular events in a multiethnic population. AB - BACKGROUND: Cell adhesion molecules are key regulators of atherosclerotic plaque development, but circulating levels of soluble fragments, such as intercellular adhesion molecule (sICAM-1) and vascular cell adhesion molecule (sVCAM-1), have yielded conflicting associations with atherosclerotic cardiovascular disease (ASCVD). Endothelial cell-selective adhesion molecule (ESAM) is expressed exclusively in platelets and endothelial cells, and soluble ESAM (sESAM) levels have been associated with prevalent subclinical atherosclerosis. We therefore hypothesized that sESAM would be associated with incident ASCVD. METHODS: sESAM, sICAM-1, and sVCAM-1 were measured in 2,442 participants without CVD in the Dallas Heart Study, a probability-based population sample aged 30-65 years enrolled between 2000 and 2002. ASCVD was defined as first myocardial infarction, stroke, coronary revascularization, or CV death. A total of 162 ASCVD events were analyzed over 10.4 years. RESULTS: Increasing sESAM was associated with ASCVD, independent of risk factors (HR Q4 vs Q1: 2.7, 95% CI 1.6-4.6). Serial adjustment for renal function, sICAM-1, VCAM-1, and prevalent coronary calcium did not attenuate these associations. Continuous ESAM demonstrated similar findings (HR 1.31, 95% CI 1.2-1.4). Addition of sESAM to traditional risk factors improved discrimination and reclassification (delta c-index: P = .009; integrated discrimination-improvement index P = .001; net reclassification index = 0.42, 95% CI 0.15-0.68). Neither sICAM-1 nor sVCAM-1 was independently associated with ASCVD. CONCLUSIONS: sESAM but not sICAM-1 or sVCAM-1 levels are associated with incident ASCVD. Further studies are warranted to investigate the role of sESAM in ASCVD. PMID- 28888272 TI - Gender differences in coronary angiography, subsequent interventions, and outcomes among patients with acute coronary syndromes. AB - BACKGROUND: The objective was to investigate whether gender disparities are found in referrals of patients with acute coronary syndromes to percutaneous coronary interventions (PCIs) or coronary artery bypass grafting (CABG) and, furthermore, to study gender differences in complications and mortality. METHODS: All consecutive coronary angiographies (CAs) and PCIs performed in Sweden and Iceland are prospectively registered in the Swedish Coronary Angiography and Angioplasty Registry. For the present analysis, data of patients with acute coronary syndromes, enrolled in 2007-2011, were used to analyze gender differences in revascularization, in-hospital complications, and 30-day mortality. RESULTS: A total of 106,881 CAs were performed during the study period. In patients with significant coronary artery disease, the adjusted odds ratio (OR) for women to undergo PCI compared with men was 0.95 (95% CI 0.92-0.99) and 0.81 (0.76-0.87) for referrals to CABG. In patients with 1-vessel disease, women were less likely to undergo PCI than men, but women with 2- or 3-vessel or left main stem disease were more likely to undergo PCI. All in-hospital complications after CA followed by PCI were more frequent among women (adjusted OR 1.58 [1.47-1.70]). There was no gender difference in adjusted 30-day mortality after PCI (1.02 [0.92-1.12]) and after CABG (0.97 [0.72-1.31]). CONCLUSIONS: After CA showing 1-vessel disease, women as compared with men were less likely to undergo PCI. In the group with 2- or 3-vessel disease or left main stem stenosis, women were more likely to undergo PCI but less likely to undergo CABG. However, there was no gender difference in 30-day mortality. PMID- 28888274 TI - Blood pressure reactivity to psychological stress is associated with clinical outcomes in patients with heart failure. AB - INTRODUCTION: Cardiovascular (CV) reactivity to psychological stress has been implicated in the development and exacerbation of cardiovascular disease (CVD). Although high CV reactivity traditionally is thought to convey greater risk of CVD, the relationship between reactivity and clinical outcomes is inconsistent and may depend on the patient population under investigation. The present study examined CV reactivity in patients with heart failure (HF) and its potential association with long-term clinical outcomes. METHODS: One hundred ninety-nine outpatients diagnosed with HF, with ejection fraction <=40%, underwent an evaluation of blood pressure (BP) and heart rate reactivity to a laboratory-based simulated public-speaking stressor. Cox proportional hazards regression models were used to examine the prospective association between BP and heart rate reactivity on a combined end point of death or CV hospitalization over a 5-year median follow-up period. RESULTS: Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) reactivity, quantified as continuous variables, were inversely related to risk of death or CV hospitalization (Ps < .01) after controlling for established risk factors, including HF disease severity and etiology. In similar models, heart rate reactivity was unrelated to outcome (P = .12). In models with tertiles of reactivity, high SBP reactivity, compared with intermediate SBP reactivity, was associated with lower risk (hazard ratio [HR] = .498, 95% CI .335-.742, P =.001), whereas low SBP reactivity did not differ from intermediate reactivity. For DBP, high reactivity was marginally associated with lower risk compared with intermediate DBP reactivity (HR = .767, 95% CI .515 1.14, P =.193), whereas low DBP reactivity was associated with greater risk (HR = 1.49, 95% CI 1.027-2.155, P =.0359). No relationship of heart rate reactivity to outcome was identified. CONCLUSIONS: For HF patients with reduced ejection fraction, a robust increase in BP evoked by a laboratory-based psychological challenge was associated with lower risk for adverse CVD events and may be a novel and unique marker of left ventricular systolic reserve that is accompanied by a more favorable long-term prognosis. PMID- 28888276 TI - Protocol changes to the TRIUMPH study. PMID- 28888275 TI - Mean arterial pressure of 65 mm Hg versus 85-100 mm Hg in comatose survivors after cardiac arrest: Rationale and study design of the Neuroprotect post-cardiac arrest trial. AB - BACKGROUND: Post-cardiac arrest (CA) patients admitted to the intensive care unit (ICU) have a poor prognosis, with estimated survival rates of around 30%-50%. On admission, these patients have a large cerebral penumbra at risk for additional damage in case of suboptimal brain oxygenation during their stay in the ICU. The aim of the Neuroprotect post-CA trial is to investigate whether forcing mean arterial blood pressure (MAP) and mixed venous oxygen saturation (SVO2) in a specific range (MAP 85-100 mm Hg, SVO2 65%-75%) with additional pharmacological support (goal-directed hemodynamic optimization) may better salvage the penumbra, reduce cerebral ischemia, and improve functional outcome when compared with current standard of care (MAP 65 mm Hg). DESIGN: The Neuroprotect post-CA trial (NCT02541591) is a multicenter, randomized, parallel-group, open-label, assessor blinded, monitored, and investigator-driven clinical trial. The trial will be conducted in 2 tertiary care hospitals in Belgium (UZ Leuven and ZOL-Genk). A total of 112 eligible patients will be randomly assigned in a 1:1 ratio to goal directed hemodynamic optimization or standard care strategy by an interactive voice response system. Patients will be stratified according to the presence of an initial shockable rhythm. Adult patients (>=18 years) resuscitated from out-of hospital CA of a presumed cardiac cause who are unconscious upon hospital admission are eligible for inclusion. Patients can be included irrespective of their presenting heart rhythm but need to have a sustained return of spontaneous circulation. Trial interventions will take 36 hours starting from ICU admission. The primary outcome is the extent of cerebral ischemia as quantified by the apparent diffusion coefficient on diffusion-weighted magnetic resonance imaging to be performed at day 4-5 post-CA. Secondary outcomes include surrogate biomarkers of brain injury (neuron specific enolase) at day 1-5, neuropsychological and functional testing at hospital discharge, a Short Form-36 health questionnaire at 180 days, and outcome as assessed with cerebral performance category scores at ICU discharge and at 180 days. CONCLUSIONS: The Neuroprotect post-CA trial will investigate whether a more aggressive hemodynamic strategy to obtain a MAP 85-100 mm Hg and SVO2 65%-75% reduces brain ischemia and improves outcome when compared with standard treatment (MAP 65 mm Hg) in comatose post-CA survivors. PMID- 28888277 TI - Erratum for "Specific RNA-Binding Antibodies with a Four-Amino-Acid Code" [J. Mol. Biol.426 (2014) 2145-2157]. PMID- 28888273 TI - Multinational and multiethnic variations in health-related quality of life in patients with chronic heart failure. AB - BACKGROUND: Assessing health-related quality of life (HRQoL) in patients with heart failure (HF) is an important goal of clinical care and HF research. We sought to investigate ethnic differences in perceived HRQoL and its association with mortality among patients with HF and left ventricular ejection fraction <=35%, controlling for demographic characteristics and HF severity. METHODS AND RESULTS: We compared 5697 chronic HF patients of Indian (26%), white (23%), Chinese (17%), Japanese/Koreans (12%), black (12%), and Malay (10%) ethnicities from the HF-ACTION and ASIAN-HF multinational studies using the Kansas City Cardiomyopathy Questionnaire (KCCQ; range 0-100; higher scores reflect better health status). KCCQ scores were lowest in Malay (58+/-22) and Chinese (60+/-23), intermediate in black (64+/-21) and Indian (65+/-23), and highest in white (67+/ 20) and Japanese or Korean patients (67+/-22) after adjusting for age, sex, educational status, HF severity, and risk factors. Self-efficacy, which measures confidence in the ability to manage symptoms, was lower in all Asian ethnicities (especially Japanese/Koreans [60+/-26], Malay [66+/-23], and Chinese [64+/-28]) compared to black (80+/-21) and white (82+/-19) patients, even after multivariable adjustment (P<.001). In all ethnicities, KCCQ strongly predicted 1 year mortality (HR 0.45, 95% CI 0.30-0.67 for highest vs lowest quintile of KCCQ; P for interaction by ethnicity .101). CONCLUSIONS: Overall, HRQoL is inversely and independently related to mortality in chronic HF but is not modified by ethnicity. Nevertheless, ethnic differences exist independent of HF severity and comorbidities. These data may have important implications for future global clinical HF trials that use patient-reported outcomes as endpoints. PMID- 28888278 TI - Are all jobs created equal? A cross-national analysis of women's employment and child malnutrition in developing countries. AB - Using multi-level models, the analysis examines female employment and child stunting across 49 developing countries. At the country level, female labor force participation is not associated with malnutrition after controlling for economic development. At the individual level, a binary measure of employment is not significantly associated with malnutrition. However, a more nuanced measure of seven occupational categories shows that certain types of employment improve malnutrition. Professional, clerical, sales, and domestic jobs are associated with reduced stunting. These effects are only partially mediated by wealth, perhaps suggesting that some jobs may bring benefits to the household beyond the sheer acquisition of tangible resources. Agricultural jobs are associated with increased malnutrition. Manual labor and service work do not have an effect on malnutrition, compared to unemployment. Thus, women's employment is not necessarily a mechanism for empowerment and wellbeing. Not all jobs are created equal, and many of them do not confer the benefits that are typically associated with working outside the home. PMID- 28888279 TI - A social ecology of civil conflict: Shifting allegiances in the conflict in Sierra Leone. AB - Drawing on data from a survey of 1043 ex-combatants who took part in the civil war in Sierra Leone (1991-2002) this paper explores the conditions that predict a key outcome in the conflict literature: defection, or side-switching between the various organizations at war. This paper advances arguments drawn from the organizational ecology school and works to extend key theories related to "Blau Space" to the study of civil war. Using a series of logistic regression procedures, this paper tests various competing hypotheses against key contributions of the organizational ecology school. Key findings of this work suggest support for major hypotheses in this literature as net of important theoretical conditions, defections are most likely when individuals are either demographically atypical of their organization (niche edge) or most susceptible to competition for their services by other groups (niche overlap). PMID- 28888280 TI - Intergenerational transmission of parent-child relationship quality: Evidence from a multi-actor survey. AB - Intergenerational transmission is a long-standing interest of social science research. However, little attention has been devoted to the study of transmission of relationship quality between several generations of family members. Exploiting multigenerational multi-actor data from the German Family Panel (pairfam), we estimate multilevel models to investigate whether, in three-generation families, relationship quality between the middle generation and the oldest (that is, grandparent) generation predicts relationship quality between the youngest generation of adolescent children and the middle generation. Our results reveal evidence of intergenerational transmission of emotional closeness, conflict, and ambivalence. Transmission was more consistently observed when emanating from ties to grandfathers than from ties to grandmothers. A hypothesis concerning differences in the strength of transmission between East Germany and West Germany found no support. The paper concludes with a discussion of limitations and perspectives for future research. PMID- 28888281 TI - Intergenerational relations before and after offspring arrive: A within-person investigation. AB - The birth of a child may re-orientate the relations between adult children and their parents; however, the previous studies on the topic are both scarce and methodologically limited. The current study investigates whether younger adults' entry into parenthood (i.e., the birth of the first child) is associated with increased contact frequency, emotional closeness, intimacy and conflict with their own parents. The participants are from the German Panel Analysis of Intimate Relationships and Family Dynamics, which is a prospective survey of younger adults with six annual follow-up waves between 2009 and 2014 (n = 17,662 person-observations from 4821 persons). Within-person regression with a focus on each individual's variation over time was used to detect changes in intergenerational relations. The contact frequency between daughters and mothers increased after the arrival of their first child. In contrast, the emotional closeness and intimacy between sons and mothers decreased after the birth of their first child. The results are discussed with reference to gender-based differences in intergenerational relations. PMID- 28888282 TI - Market transformation and the opportunity structure for gender inequality: A cohort analysis using linked employer-employee data from Slovenia. PMID- 28888283 TI - In-home firearm access among US adolescents and the role of religious subculture: Results from a nationally representative study. AB - Religious participation is linked to numerous positive safety outcomes for adolescents. Scant attention, however, has been paid to associations between religious participation and safety risks among adolescents. Using data from Add Health (N = 18,449), a nationally representative school-based sample of US adolescents, this study examines the relationship between adolescents' religious affiliation and easy access to firearms at home. Regression analyses adjust for complex sampling design and compare easy firearm access at home among conservative Protestant adolescents to adolescent firearm access in other religious traditions. Conservative Protestant adolescents have a substantially greater likelihood of easy access to a gun at home compared to adolescents of all other major religious traditions in the United States. Recognizing differences in adolescent firearm access between subcultural groups can help public health interventions more effectively identify and address the needs of vulnerable populations. The paper's conclusion considers suggestions for effective policy and programmatic initiatives. PMID- 28888284 TI - Long-term consequences of youth volunteering: Voluntary versus involuntary service. AB - Despite the renewed interest in youth volunteering in recent years, there remain major gaps in our knowledge of its consequences. Drawing data from the National Longitudinal Study of Adolescent to Adult Health, we examine the long-term effects of youth volunteering on the civic and personal aspects of volunteers' lives. Our results suggest that youth volunteering has a positive return on adult volunteering only when it is voluntary, and that net of contextual factors neither voluntary nor involuntary youth service has a significant effect on adult voting. Regarding personal outcomes, our findings indicate that the psychological benefits of youth volunteering accrue only to voluntary participants, whereas both voluntary and involuntary youth service are positively associated with educational attainment and earnings in young adulthood. Taken together, these results lend support to the case for youth volunteer programs, though the civic benefits of these programs appear to be less dramatic than generally suggested. PMID- 28888285 TI - The stratification of college-going Latinos' postsecondary destinations. PMID- 28888286 TI - Applying to college: Do information deficits lower the likelihood of college eligible students from less-privileged families to pursue their college intentions?: Evidence from a field experiment. AB - Information deficits are considered an important source of why students from less privileged families do not enroll in college, even when they are college-eligible and intend to go to college. In this paper, we examine whether correct and detailed information on the costs of and returns to higher education increases the likelihood of college applications of less-privileged high school graduates who expressed college intentions in their junior high school year. We employ an experimental design with a randomly assigned 25-minute information treatment about funding opportunities for, and returns to, higher education given at Berlin schools awarding university entrance qualifications. Our analyses show that our information treatment indeed substantially increases the likelihood of treated less-privileged students to apply to college. Our study indicates that our low cost provision of financial information not only increased their college knowledge but also substantially changed their college application behavior, despite other existing barriers, like economic constraints. PMID- 28888287 TI - The optimism trap: Migrants' educational choices in stratified education systems. AB - Immigrant children's ambitious educational choices have often been linked to their families' high level of optimism and motivation for upward mobility. However, previous research has mostly neglected alternative explanations such as information asymmetries or anticipated discrimination. Moreover, immigrant children's higher dropout rates at the higher secondary and university level suggest that low performing migrant students could have benefitted more from pursuing less ambitious tracks, especially in countries that offer viable vocational alternatives. We examine ethnic minority's educational choices using a sample of academically low performing, lower secondary school students in Germany's highly stratified education system. We find that their families' optimism diverts migrant students from viable vocational alternatives. Information asymmetries and anticipated discrimination do not explain their high educational ambitions. While our findings further support the immigrant optimism hypothesis, we discuss how its effect may have different implications depending on the education system. PMID- 28888288 TI - The effect of sociodemographic (mis)match between interviewers and respondents on unit and item nonresponse in Belgium. AB - Interviewer characteristics affect nonresponse and measurement errors in face-to face surveys. Some studies have shown that mismatched sociodemographic characteristics - for example gender - affect people's behavior when interacting with an interviewer at the door and during the survey interview, resulting in more nonresponse. We investigate the effect of sociodemographic (mis)matching on nonresponse in two successive rounds of the European Social Survey in Belgium. As such, we replicate the analyses of the effect of (mis)matching gender and age on unit nonresponse on the one hand, and of gender, age and education level (mis)matching on item nonresponse on the other hand. Recurring effects of sociodemographic (mis)match are found for both unit and item nonresponse. PMID- 28888289 TI - Measuring multiple discrimination through a survey-based methodology. AB - This paper focuses on the concept of multiple discrimination and its measurement through survey methods. The study was designed as a quasi-experimental comparison of survey mode effects on the quality of discrimination measurement: the traditional 'face-to-face' survey, the conventional self-completed mode and CAWI (finally deleted due to its non-comparability). Consistent with our hypothesis, some support was obtained for the social desirability bias and survey mode effects: 1) self-administration of questionnaires favours the declaration of discriminatory attitudes and personal experiences of discrimination; 2) the effect of privacy is greater in direct indicators of discriminatory attitudes; 3) perceptions and experiences of discrimination are more frequently reported by highly educated respondents. Nevertheless, contrary to our expectations, less educated respondents are also affected by survey mode and continue to be underrepresented in self-completed methods. The current research aims to serve as a basis for further research in this area. PMID- 28888290 TI - Experiencing discrimination in Los Angeles: Latinos at the intersection of legal status and socioeconomic status. AB - Despite its recent slowdown, immigration from Latin America continues to be a controversial issue. Some scholars argue that the social climate is increasingly inhospitable to Latinos, potentially fueling discriminatory attitudes and behaviors. However, little research has examined Latinos' experiences with discrimination, especially variation by nativity and legal status. We address this issue with research on perceived discrimination among Mexican and Central American residents of Los Angeles County, a major destination for Latin American immigrants. Using data from the Los Angeles Family and Neighborhood Survey and the American Community Survey, the analyses consider immigrants' legal status, intersectionality, and competing perspectives on assimilation. The results show that undocumented immigrants do not report especially high levels of discrimination. Instead, young U.S.-born Latinos are the most likely to report mistreatment in interpersonal and institutional domains. Neighborhood ethnoracial and income diversity also have implications for perceived exposure to different types of discrimination. PMID- 28888291 TI - Ultimatum bargaining over losses and gains - An experimental comparison. AB - Subjects in the loss domain tend to split payoffs equally when bargaining. The ultimatum game offers an ideal mechanism through which social scientists can investigate whether equal splits are the consequence of the proposers' generosity or due to their anticipation that the responders will reject lower offers. This paper experimentally compares ultimatum bargaining that takes place in a loss domain with that under a gains domain. The results reveal that, although responders do not expect more in the loss domain, proposers do make higher offers. As such, proposers reach agreements more often in the loss domain than they do in the gains domain, and responders receive higher payoffs. PMID- 28888292 TI - Racial identity and the quality of life among blacks and whites in the U.S. AB - Social identity theory and research on mental health among racial minority groups suggest that a stronger, more positive racial identity will be related to a higher subjective quality of life. We investigate how ingroup closeness, ingroup evaluation, and ingroup bias are associated with happiness, positive affect about life, and generalized trust for blacks and whites, using partial proportional odds models. Data came from the 1996-2014 General Social Surveys (N = 6553). Ingroup closeness and more favorable ingroup evaluation had mostly positive associations with the quality of life dimensions. Contrary to what social identity theory would predict, ingroup bias was either unrelated or negatively related to them. Racial identity functions somewhat differently for blacks and whites. Ingroup evaluation and ingroup bias were related to greater positive affect about life for blacks but lower positive affect about life for whites. PMID- 28888293 TI - Too much of a good thing? Economic growth and human rights, 1960 to 2010. AB - Despite widespread belief in the benefits of economic growth, some scholars emphasize the potentially negative consequences of growth-and especially rapid growth-for social and political outcomes. Using data for 149 countries between 1960 and 2010, I analyze the effect of economic growth on fundamental human rights conditions. Dynamic random-effects and two-way fixed-effects estimators, both with and without instrumental variables, yield several conclusions. First, economic growth is causally prior to rights conditions. Second, economic growth has a modest positive effect on human rights, albeit with diminishing returns at high growth rates. Third, low-income countries account for much of this relationship: growth improves rights conditions for most low-income countries, but extremely rapid growth is inimical. Growth has little effect among middle income countries, while for high-income countries the relationship is positive but not robust. I bring these findings to bear on long-standing debates between proponents and critics of modernization theory. PMID- 28888294 TI - Occupy the government: Analyzing presidential and congressional discursive response to movement repression. AB - I examine the role of Occupy Wall Street in shifting presidential and congressional discourse on economic fairness and inequality. Using data from 4646 presidential speeches and 1256 congressional records from 2009 to 2015, I test different mechanisms, including repression, media coverage, public opinion, and presidential agenda-setting by applying a novel combination of web scraping, natural language processing, and time series models. I suggest that movement success can be measured in its ability to shape discursive opportunity structures, and I argue that the role of the president should be at the forefront of social movements research. Ultimately, I demonstrate (1) that the repression of Occupy protesters not only predicts media coverage but also increases discursive opportunities through President Obama and Congress, (2) that media coverage of Occupy predicts presidential discourse, (3) that the president's rhetorical shift increases congressional response, and (4) that this change persists after the movement faltered. PMID- 28888295 TI - Rehabilitation of the Complex Burn Patient with Multiple Injuries or Comorbidities. AB - Patients with complex burn injuries require interdisciplinary rehabilitation to maximize their functional recovery. Successful rehabilitation from burn injuries starts with addressing the loss of the protective, mechanical, and cosmetic function of the skin and underlying structures. However, other injuries, particularly to the nervous and musculoskeletal systems, need to be identified and managed as part of the rehabilitation plan. Burn injuries can cause losses of functional mobility, self-care skills, psychological well-being, and community participation, which require comprehensive rehabilitation interventions throughout the recovery process. PMID- 28888296 TI - Current Concepts Burn Rehabilitation, Part I: Care During Hospitalization. AB - This article summarizes current interventions for several of the most common challenges faced by patients during their rehabilitation from burn injury. These include preservation of range of motion through scar contracture management, and achieving maximal independence through exercise, and training in activities of daily living. PMID- 28888297 TI - Current Concepts Burn Rehabilitation, Part II: Long-Term Recovery. AB - This article summarizes current interventions for several of the most common challenges faced by patients during their rehabilitation from burn injury. These challenges include range of motion preservation through scar contracture management, achieving maximal independence through exercise and activities of daily living training, and psychological recovery through nonpharmacologic approaches pain and anxiety. PMID- 28888299 TI - Principles of Burn Pain Management. AB - This article describes pathophysiology of burn injury-related pain and the basic principles of burn pain management. The focus is on concepts of perioperative and periprocedural pain management with extensive discussion of opioid-based analgesia, including patient-controlled analgesia, challenges of effective opioid therapy in opioid-tolerant patients, and opioid-induced hyperalgesia. The principles of multimodal pain management are discussed, including the importance of psychological counseling, perioperative interventional pain procedures, and alternative pain management options. A brief synopsis of the principles of outpatient pain management is provided. PMID- 28888298 TI - Rehabilitation in the Acute Versus Outpatient Setting. AB - Rehabilitation of patients with burn injuries aims to restore strength, coordination, and mobility as closely to normal as possible and should begin immediately after initial admission. In the acute phase, baseline assessments are made against which all subsequent rehabilitation success is held. In the intermediate phase, active, full range-of-motion movement, ambulation of steadily increasing distances, and resistive exercise and stretching aid in the prevention of muscle and bone atrophy and preserve muscle memory and coordination. In the long-term outpatient rehabilitation phase, individualized patient-centered exercise programs can be advantageous in achieving measurable and lasting positive rehabilitation outcomes. PMID- 28888301 TI - Laser Modulation of Hypertrophic Scars: Technique and Practice. AB - In this review, the authors discuss the use of laser photothermolysis and laser resurfacing in the management of hypertrophic burn scars. They provide details regarding preoperative selection, intraoperative decision making, and postoperative care. PMID- 28888300 TI - Heterotopic Ossification and Hypertrophic Scars. AB - Burns and trauma cause superficial and deep soft tissue wounds that cannot heal to the preinjury state. Healing requires cell proliferation and differentiation into the injured tissue type, laying down extracellular matrix, often as collagens. Heterotopic ossification causes severe pain, nonhealing wounds, and restricted range of motion. Treatment includes radiation therapy, nonsteroidal anti-inflammatory drugs, bisphosphonates, and possibly surgical excision and prophylactic measures. Hypertrophic scars, nonosseous lesions caused by excessive collagen deposition, are often painful, functionally limiting, and aesthetically displeasing. Treatment includes CO2 laser application, steroid injections, and excision with skin grafting. This article reviews the management of these pathologic wounds. PMID- 28888302 TI - A Systematic Review of the Effectiveness of Laser Therapy for Hypertrophic Burn Scars. AB - The objective of this systematic review was to assess the effectiveness of laser therapy for the treatment of hypertrophic burn scars. Improvements in scar symptoms following laser treatment were reported in 11 of the 12 included studies. However, issues related to overall quality and risk of bias were present in all studies. As a result, there is insufficient scientific evidence to determine the effectiveness of laser therapy from this systematic review. Future studies that use more rigorous study designs such as randomized controlled trials are needed to support the use of laser therapy for hypertrophic burn scars. PMID- 28888303 TI - Fat Grafting for Burn, Traumatic, and Surgical Scars. AB - Fat grafting provides a reliable modality with expanding usefulness in reconstructive plastic surgery. Owing to its mechanical and theorized regenerative properties, adipose tissue can improve scar qualities and scar related symptoms when grafted adjacent to or within a scar. In this article, the literature describing the effect of fat grafting on various types of scars, current scientific understanding of fat grafting for scars, and our current approach to the management of problematic burn scars are reviewed. PMID- 28888305 TI - Tissue Rearrangements: The Power of the Z-Plasty. AB - The z-plasty is a highly versatile standard technique of reconstructive burn surgery. Variations of the classic z-plasty with limbs of equal length at 60 degrees angles can accommodate specific reconstruction needs. Opposing z plasties can be used when available tissue is limited; series of z-plasties can be linked to elongate tissue over a longer distance with smaller individual incisions, and a z-plasty with varying limb angles and lengths can provide tissue coverage in areas with special distributions of scarred and normal skin. PMID- 28888306 TI - The Use of Prefabricated Flaps in Burn Reconstruction. AB - This article describes the use of prefabricated flaps in burn reconstruction. Several case examples are provided that demonstrate the versatility and power of this approach to restoration of form and function after burn injury. PMID- 28888304 TI - Peripheral Neuropathy and Nerve Compression Syndromes in Burns. AB - Peripheral neuropathy and nerve compression syndromes lead to substantial morbidity following burn injury. Patients present with pain, paresthesias, or weakness along a specific nerve distribution or experience generalized peripheral neuropathy. The symptoms manifest at various times from within one week of hospitalization to many months after wound closure. Peripheral neuropathy may be caused by vascular occlusion of vasa nervorum, inflammation, neurotoxin production leading to apoptosis, and direct destruction of nerves from the burn injury. This article discusses the natural history, diagnosis, current treatments, and future directions for potential interventions for peripheral neuropathy and nerve compression syndromes related to burn injury. PMID- 28888307 TI - Microsurgical Burn Reconstruction. AB - The treatment of burn-related wounds requires consideration of several factors, including defect size, available donor sites, exposure of critical structures, and the ultimate functional and aesthetic result of reconstruction. Although skin grafts and locoregional flaps are workhorses in burn reconstruction, they have inherent limitations that can directly impact reconstructive outcomes. Microsurgical free tissue transfer represents a viable option for the reconstruction of burn-related wounds in certain patients. Each anatomic region of the body has unique challenges that must be addressed to achieve a successful reconstruction. Therefore, the choice of free flap must be individualized to the wound and patients. PMID- 28888308 TI - Hand Reconstruction After Burn Injury: Functional Results. AB - Frequently burns of the hand occur as part of a major thermal injury, but appropriate treatment of the hands has high priority, because even small burns of the hand may result in severely limited function and compromised aesthetic appearance. The functional importance of the hand cannot be overemphasized, because the patient's ability to perform useful work after recovery or the ability to care for themselves is to a great degree determined by residual hand function. This article describes the management of burn injuries involving the hand, stressing the importance of appropriate initial treatment. A comprehensive review of hand reconstruction and rehabilitation, to optimize form and function, is provided. PMID- 28888309 TI - Head and Neck Reconstruction. AB - Management of head and neck burns involves acute and intermediate phases. Acutely, the goals are establish a secure airway and treat life-threatening injuries. Then, optimize nutrition, assess extent of the burn, perform local wound care, and provide eye protection. Management depends on the degree of the head and neck burn. Postinjury splinting and rehabilitation are vital to healing. After the acute inflammation has resolved and the scars have matured, reconstruction begins with the goals of restoring both function and aesthetics. Reconstruction ranges from simple scar release, to skin grafting, and possibly free flap reconstruction. PMID- 28888310 TI - Role of Facial Vascularized Composite Allotransplantation in Burn Patients. AB - Face transplantation can provide improved quality of life to patients with extensive burn injuries. Facial vascularized composite allotransplantation (VCA) offers a new paradigm of treatment options, serving as a powerful reconstructive tool to restore facial form and function. Although currently facial VCA patients must follow a lifelong regimen of immunosuppression medications and suffer a risk of rejection, in properly selected patients, facial VCA can be a transformative operation and can improve quality of life. Research efforts continue to optimize immunosuppression and surgical technique and serve as evidence of the procedure's growing role in reconstructive surgery for critically injured patients. PMID- 28888311 TI - Pediatric Burn Reconstruction: Focus on Evidence. AB - In this article, the author surveys the best available evidence to guide decision making in pediatric burn reconstruction. Evidence-based protocols are examined in the context of optimizing form and function in children who have sustained burn injury. PMID- 28888312 TI - Burn Management in the Developing World: International Volunteerism. AB - The burden of burn injury falls predominantly on the world's poor, with low income and middle-income countries accounting for 96% of burn injuries. These vulnerable populations are the least likely to have access to adequate medical care and are the most reliant on volunteer organizations. Every underserved area has a unique set of needs, circumstances, customs, resources, and challenges. The authors' intent is to provide an additional resource for volunteer surgeons who are interested in treating burns. This article reviews planning, organizing, and participating in a burn surgical mission trip. PMID- 28888313 TI - Aftercare, Survivorship, and Peer Support. AB - Burn recovery includes addressing any emotional, psychological, and social needs of the survivor and family. Providing support and resources is essential for a smooth transition from the acute phase of injury to rehabilitation and successful social and community reintegration. Priority psychosocial target areas are developing social skills, addressing body image concerns, and providing peer support. Peer support provides a unique perspective of shared experience that can instill hope and assist coping efforts of survivors and family. Health care professionals can be instrumental in connecting survivors to community support organizations. Discussed are considerations for aftercare planning and peer support's role. PMID- 28888314 TI - Of These, Faith, Hope, and Love: Assessing and Providing for the Psychosocial and Spiritual Needs of Burn Patients. AB - Burn treatment has grown increasingly advanced and technologically capable. Clinicians must take into account, however, multidimensional patient needs that factor into long-term burn recovery. Important psychosocial factors associated with burn care include psychiatric comorbidities, such as anxiety and depression, healthy family relationships, social support, and community involvement. Spiritual factors and resources, such as time spent praying and/or meditating and access to pastoral services, are also important to consider. Further study is needed to identify specific psychosocial and spiritual needs of patients and to develop interventions or therapies that specifically provide for these needs. PMID- 28888315 TI - Ethics in the Setting of Burned Patients. AB - This article considers multiple ethical principles in the context of patients with burns. It explores the application of these principles to burn care and the impact on medical decision making, through several clinical vignettes. PMID- 28888316 TI - Outcome Metrics After Burn Injury: From Patient-Reported Outcome Measures to Value-Based Health Care. AB - Outcomes research is important because it allows us to critically evaluate our results and strive for quality improvement, share our experiences with our colleagues, and improve the care and results delivered to the patient. This article focuses on outcomes research in burns from a historical perspective, highlights some of the current innovations, and previews future directions for outcomes-based research in burn care. PMID- 28888317 TI - Hypertrophic Burn Scar Research: From Quantitative Assessment to Designing Clinical Sequential Multiple Assignment Randomized Trials. AB - This article explores the current options for the quantitative assessment of hypertrophic burn scars. It also introduces a novel type of randomized, controlled trial, which relies on heterogeneity of the subject population to improve the predictive value of personalized treatment strategies. PMID- 28888318 TI - Under Pressure: Applying Practice-Based Learning and Improvement to the Treatment of Chronic Neuropathic Pain in Patients with Burns. AB - Chronic neuropathic pain after burn injury may have multiple causes, such as direct nerve injury, nerve compression, or neuroma formation, and can significantly impair quality of life and limit functional recovery. Management includes a team-based approach that involves close collaboration between occupational and physical therapists, plastic surgeons, and experts in chronic pain, from neurology, anesthesia, psychiatry, and physiatry. Carefully selected patients with an anatomic cause of chronic neuropathic pain unequivocally benefit from surgical intervention. Self-reflection and analysis yield improvement in both efficiency and effectiveness when managing patients with burns with chronic neuropathic pain. PMID- 28888319 TI - Systems-based Practice in Burn Care: Prevention, Management, and Economic Impact of Health Care-associated Infections. AB - Health care-associated infections in burn patients, from ventilator-associated pneumonia to skin and soft tissue infections, can substantially compromise outcomes, because these complications are associated with longer lengths of stay, increased morbidity and mortality, and greater direct medical costs. Health care associated infections are largely preventable, through surveillance, education, appropriate hand hygiene, and culture change, especially for device-related infections. Systems-based practice, which allows individuals and clinical microsystems to navigate and improve the macro health care system, may be one of the most powerful skill sets to effect change, permitting a shift in culture toward patient safety and quality improvement. PMID- 28888320 TI - Wellness and Burnout in Burn Care Providers: Professionalism, the Social Covenant, and the 7 Habits of Highly Effective Teams. AB - This article explores the functioning of highly effective teams in burn care. Critical to the success of the team is the health of burn care providers, who can experience burnout. Wellness must be promoted by health care organizations, which, in turn, are responsible for the health of the populations they serve. Professionalism not only frames the social covenant between patients and burn care physicians but may also serve as a critical force in protecting against burnout and promoting wellness. PMID- 28888321 TI - Volume 2: Rehabilitation, Reconstruction, and Recovery. PMID- 28888322 TI - TOR, the Gateway to Cellular Metabolism, Cell Growth, and Disease. AB - Michael N. Hall is this year's recipient of the Lasker Basic Medical Research Award for the identification of the target of rapamycin, TOR. TOR is a master regulator of the cell's growth and metabolic state, and its dysregulation contributes to a variety of diseases, including diabetes, obesity, neurodegenerative disorders, aging, and cancer, making the TOR pathway an attractive therapeutic target. PMID- 28888323 TI - Two Basic Scientists Walk into a Translational Space. AB - When John Schiller first joined Douglas Lowy's lab at the National Cancer Institute of the NIH, he could have not predicted that their common interest in the molecular biology of oncogenes would set them in path for discoveries that ultimately enabled the development of a vaccine for the human papillomavirus, which causes the majority of cervical cancers worldwide. John and Doug, the recipients of the 2017 Lasker-DeBakey Clinical Award, have joined Cell editor Joao Monteiro in a Conversation about science, public health, and the joys and challenges of being basic scientists in a translational space. Annotated excerpts from this conversation are presented below. PMID- 28888324 TI - A Prize for Cancer Prevention. AB - This year's Lasker-DeBakey Prize for Clinical Research to Douglas Lowy and John Schiller celebrates the science behind one of the greatest advances in the history of cancer research: the development of vaccines that prevent infection and thus prevent tumor induction by pathogenic strains of human papilloma virus (HPV). PMID- 28888325 TI - An Amazing Turn of Events. AB - How the master regulator of cell growth, TOR, came to be identified and understood, from the perspective of its discoverer, Michael N. Hall. PMID- 28888326 TI - Artists Create Puzzles, Scientists Solve Them. AB - The Spanish artist Diego Velazquez created a puzzle-painting 360 years ago that to this day remains unsolved, but still mystifies and intrigues. Unlike artists who get their thrills by creating puzzles that stimulate the imagination, scientists get their kicks by solving puzzles that advance biomedical research. PMID- 28888327 TI - Vicarious Social Defeat Stress Induces Depression-Related Outcomes in Female Mice. AB - BACKGROUND: Stress is a prevailing risk factor for mood-related illnesses, wherein women represent the majority of those affected by major depression. Despite the growing literature suggesting that affective disorders can arise after a traumatic event is vicariously experienced, this relationship remains understudied in female subjects at the preclinical level. Thus, the objective of the current investigation was to examine whether exposure to emotional and/or psychological stress (ES) mediates depression-related outcomes in female mice. METHODS: Female C57BL/6 mice (8 weeks old, null parity) vicariously experienced the defeat bout of a male conspecific, by a male CD1 aggressor, for 10 consecutive days. Twenty-four hours after the last stress exposure, female mice were tested in the social interaction, sucrose preference, tail suspension, or elevated plus maze tests. Furthermore, we examined whether ketamine and chlordiazepoxide, pharmacological agents used to treat mood-related disorders in the clinical population, would reverse the ES-induced social dysfunction. RESULTS: When compared with control mice, female mice exposed to ES displayed decreased social behavior and preference for sucrose, along with increased immobility in the tail suspension test. Also, they displayed higher levels of blood serum corticosterone, as well as decreased body weight. Lastly, the ES induced avoidance-like phenotype was ameliorated by both ketamine and chlordiazepoxide. CONCLUSIONS: Our data indicate that female mice exposed to ES display a behavioral and physiologic profile that mimics symptoms of depression in the clinical population. As such, this experimental model may be adopted to examine vicarious stress-induced mood-related disorders, as well as pharmacological antidepressant response, in a sex-specific manner. PMID- 28888328 TI - A population-based approach to assess the heritability and distribution of renal handling of electrolytes. AB - The handling of electrolytes by the kidney is essential for homeostasis. However, the heritability of these processes, the first step in gene discovery, is poorly known. To help clarify this, we estimated the heritability of serum concentration, urinary excretion, renal clearance, and fractional excretion of sodium, potassium, magnesium, calcium, phosphate, and chloride in a population based study. Nuclear families were randomly selected from the general population in Lausanne, Geneva, and Bern, Switzerland, and urine collected over 24-hour periods. We used the ASSOC program (S.A.G.E.) to estimate narrow sense heritability, including sex, age, body mass index, and study center as covariates in the model. The 1128 participants, from 273 families, had a mean age of 47 years, body mass index of 25.0 kg/m2, and an estimated glomerular filtration rate (CKD-EPI) of 98 mL/min/1.73 m2. The heritability of serum concentration was highest for calcium, 37% and lowest for sodium, 13%. The heritability of 24-hour urine clearances, excretions, and fractional excretions ranged from 15%, 10%, and 16%, respectively, for potassium to 45%, 44%, and 51%, respectively, for calcium. All probability values were significant. The heritability for phosphate-related phenotypes was lower than that for calcium. Thus, the serum and urine concentrations as well as urinary excretion and renal handling of electrolytes are heritable in the general adult population. The phenotypic variance attributable to additive genetic factors was variable and was higher for calcium. These results pave the way for identifying genetic variants involved in electrolyte homeostasis in the general population. PMID- 28888329 TI - Lasker foundation announces award winners for 2017. PMID- 28888330 TI - Saddle pulmonary embolism in hemodynamically stable patients: To lyse or not to lyse? An issue in no guidelines land. PMID- 28888331 TI - Hamartia in hippocampal sclerosis-associated mesial temporal lobe epilepsy. AB - Hamartia are small collections of rounded glioneuronal cells that are thought to be due to aberrant cell migration. Their presence has been recognized in association with mesial temporal lobe epilepsy; their prevalence among cases of hippocampal sclerosis (HS) and any potential association with patient demographics and outcomes is unknown. This study examines hamartia in a series of 292 patients with pathologically confirmed HS. Medical records were reviewed for pertinent patient clinical information (follow-up mean 5years). Hamartia were identified in 96 cases (33%) and were seen primarily in the amygdala (n=88) and less commonly in the hippocampus (n=10) and temporal lobe (n=4). A statistically significant relationship was found between the presence of hamartia and male gender, younger age of seizure onset, and history of childhood febrile seizures and developmental delay. It is unclear if these associations represent a real association or are a result of the underlying pathologies related to chronic epilepsy. At follow-up, there were no significant differences between patients who had hamartia and those who lacked this finding. Hamartia were observed in all subtypes of HS and there was a significant difference found in subtype distribution as well as proportion of cases between subtypes, but no association with any specific subtype overall. The presence of hamartia was not associated with the coexistence of focal cortical dysplasia or any specific histologic pattern of dysplasia. Hamartia are a common concomitant finding in HS and indicates evidence of aberrant cell migration in the hippocampal and parahippocampal regions in these patients. PMID- 28888332 TI - Machine-Learning-Based Electronic Triage More Accurately Differentiates Patients With Respect to Clinical Outcomes Compared With the Emergency Severity Index. AB - STUDY OBJECTIVE: Standards for emergency department (ED) triage in the United States rely heavily on subjective assessment and are limited in their ability to risk-stratify patients. This study seeks to evaluate an electronic triage system (e-triage) based on machine learning that predicts likelihood of acute outcomes enabling improved patient differentiation. METHODS: A multisite, retrospective, cross-sectional study of 172,726 ED visits from urban and community EDs was conducted. E-triage is composed of a random forest model applied to triage data (vital signs, chief complaint, and active medical history) that predicts the need for critical care, an emergency procedure, and inpatient hospitalization in parallel and translates risk to triage level designations. Predicted outcomes and secondary outcomes of elevated troponin and lactate levels were evaluated and compared with the Emergency Severity Index (ESI). RESULTS: E-triage predictions had an area under the curve ranging from 0.73 to 0.92 and demonstrated equivalent or improved identification of clinical patient outcomes compared with ESI at both EDs. E-triage provided rationale for risk-based differentiation of the more than 65% of ED visits triaged to ESI level 3. Matching the ESI patient distribution for comparisons, e-triage identified more than 10% (14,326 patients) of ESI level 3 patients requiring up triage who had substantially increased risk of critical care or emergency procedure (1.7% ESI level 3 versus 6.2% up triaged) and hospitalization (18.9% versus 45.4%) across EDs. CONCLUSION: E-triage more accurately classifies ESI level 3 patients and highlights opportunities to use predictive analytics to support triage decisionmaking. Further prospective validation is needed. PMID- 28888333 TI - Maternal long chain polyunsaturated fatty acid status and pregnancy complications. AB - Maternal nutrition plays a crucial role in influencing fetal growth and birth outcome. Any nutritional insult starting several weeks before pregnancy and during critical periods of gestation is known to influence fetal development and increase the risk for diseases during later life. Literature suggests that chronic adult diseases may have their origin during early life - a concept referred to as Developmental Origins of Health and Disease (DOHaD) which states that adverse exposures early in life "program" risks for later chronic disorders. Long chain polyunsaturated fatty acids (LCPUFA), mainly omega-6 and omega-3 fatty acids are known to have an effect on fetal programming. The placental supply of optimal levels of LCPUFA to the fetus during early life is extremely important for the normal growth and development of both placenta and fetus. Any alteration in placental development will result in adverse pregnancy outcome such as gestational diabetes mellitus (GDM), preeclampsia, and intrauterine growth restriction (IUGR). A disturbed materno-fetal LCPUFA supply is known to be linked with each of these pathologies. Further, a disturbed LCPUFA metabolism is reported to be associated with a number of metabolic disorders. It is likely that LCPUFA supplementation during early pregnancy may be beneficial in improving the health of the mother, improving birth outcome and thereby reducing the risk of diseases in later life. PMID- 28888334 TI - Preparation, characterization and application of long-acting FSH analogs for assisted reproduction. AB - Assisted reproduction technologies are widely used in humans and domestic animals and often include follicle stimulating hormone (FSH) in the protocol. One limitation with most of the available FSH preparations is the relative short half life in the circulation that dictates multiple daily injections for the desired follicle development and superovulation. The development of bioactive long-acting structurally modified FSH analogs is desirable for human and veterinary use. In addition, optimal preparations and/or formulations are expected to improve the regimen and efficiency of the treatment. This review briefly describes the approaches that have been explored to extend the half-life of FSH in the circulation. These include strategies to increase the mass and/or charge of FSH and to prevent the dissociation of the hormone to inactive subunits components. Most of these strategies, except one that led to a registered drug (Elonva) indicated for controlled ovarian stimulation protocols in humans, are still in experimental stage. PMID- 28888336 TI - Pediatric Firearm Deaths and Injuries in the United States. PMID- 28888335 TI - Dramatic relapse of seizures after everolimus withdrawal. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant multisystemic disorder caused by deregulation of the mTOR pathway, and represents one of the leading genetic causes of epilepsy. mTOR inhibitors (Sirolimus and Everolimus) are currently approved only for the treatment of growing subependymal giant cell astrocytomas, renal angiomyolipomas and lymphangioleiomyomatosis in TSC. However, preclinical and clinical evidence supports their potential role in effectively treating TSC-associated epilepsy, but no consensus on its use in seizures has been reached yet and there are few data on epilepsy outcome after the suspension of mTOR inhibitors treatment. We report for the first time on a patient in whom discontinuation of Everolimus (prescribed for growing subependymal giant cell astrocytomas) was associated with a relapse of seizures twice, and control of seizures was regained after reintroducing the medicine. This clinical report supports the promising potential of Everolimus in treating epilepsy in TSC, and specifically underlines the non-permanent effect on seizures after withdrawal. PMID- 28888337 TI - Recommendations for the Establishment of Disorders/Differences of Sex Development Interdisciplinary Care Clinics for Youth. AB - PURPOSE: Provide recommendations for the development of an interdisciplinary care (IDC) clinic for the treatment of youth with disorders/differences of sex development (DSD). DSD consist of a group of complex congenital medical disorders in which the development of chromosomal, gonadal, or anatomical sex is atypical. Youth with DSD require care from multiple specialized healthcare disciplines, including several medical specialties, surgery, nursing, and mental health. METHOD: Recommendations are based on an interdisciplinary care clinic model that allows for a team of relevant professionals who share knowledge, ideas, and responsibility of care. The framework established in this article is based largely on experiences at an established DSD clinic, as well as observations of multiple clinics across the United States. RESULTS: Preliminary outcome data on clinic adherence to treatment protocol under an IDC model are provided. CONCLUSIONS: To meet the diverse healthcare needs of youth with DSD, comprehensive care clinics are recommended; however, few such clinics exist in the United States. Establishing new comprehensive DSD clinics can be challenging due to the highly unique treatment of DSD, but the current paper expands the literature available to guide clinic development in the United States. PMID- 28888338 TI - South Asian floods and Hurricane Harvey: diabetes in crisis. PMID- 28888339 TI - Correction. PMID- 28888340 TI - Proteomic analysis of influenza haemagglutinin-specific antibodies following vaccination reveals convergent immunoglobulin variable region signatures. AB - Analysis of the anti-haemagglutinin serum antibody proteome from six H1N1pdm09 influenza A vaccinated subjects demonstrated restricted IgG1 heavy chain species encoded by IGHV5-51 and IGHV3-7 gene families in 2 subjects and either IGHV5-51 or IGHV3-7 in 4 individuals. All subjects exhibited a dominant IGKV3-20 light chain, however 5 subjects also exhibited IGKV3-11 and IGKV4-1 families. Sequences were closely aligned with the matched germline sequence, with few shared mutations. This study illustrates the feasibility of using a proteomic approach to determine the expressed V region signatures of serum antibodies induced by vaccination. PMID- 28888341 TI - HLA based selection of epitopes offers a potential window of opportunity for vaccine design against HIV. AB - The pace of progression to AIDS after HIV infection varies from individual to individual. While some individuals develop AIDS quickly, others are protected from the onset of disease for more than a decade (elite controllers and long term non-progressors). The mechanisms of protection are not yet clearly understood, though various factors including host genetics, immune components and virus attenuation have been elucidated partly. The influence of HLA alleles on HIV-1 infection and disease outcome has been studied extensively. Several HLA alleles are known to be associated with resistance to infection or delayed progression to AIDS after infection. Similarly, certain HLA alleles are reported to be associated with rapid progression to disease. Since HLA alleles influence the outcome of HIV infection differentially, selection of epitopes specifically recognized by protective alleles could serve asa rational means for HIV vaccine design. In this review article, we discuss existing knowledge on HLA alleles and their association with resistance/susceptibility to HIV and its relevance to vaccine design. PMID- 28888342 TI - Risk of venous thromboembolism following influenza vaccination in adults aged 50years and older in the Vaccine Safety Datalink. AB - BACKGROUND: Influenza-like illness and inflammation are known risk factors for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). However, few studies have characterized the risk of VTE following influenza vaccination. We examined VTE risk after vaccination in adults 50years old and older within the Vaccine Safety Datalink (VSD). METHODS: We used the self-controlled case series method to determine the risk of VTE among age eligible adults who received influenza vaccine (with or without pandemic H1N1) and experienced a VTE during the months of September through December in 2007 through 2012. Presumptive VTE cases were identified among VSD participants using diagnostic codes, diagnostic tests, and oral anticoagulant prescription. Potential cases were validated by medical record review. The VTE incidence rate ratio was calculated among confirmed cases for the risk window 1 to 10days after vaccination relative to all other person-time from September through December. RESULTS: Of the 1,488 presumptive cases identified, 508 were reviewed, of which 492 (97%) were confirmed cases of VTE. The analysis included 396 incident, confirmed cases. Overall, there was no increased risk of VTE in the 1 to 10days after influenza vaccination (IRR=0.89, 95% CI 0.69-1.17) compared to the control period. Results were similar when all person-time was censored before vaccination. A post hoc analysis showed an increased risk among current tobacco smokers (IRR=2.57, 95% CI 1.06-6.23). No clustering of VTE was observed in the 1 42days after vaccination. DISCUSSION: Overall, there was no evidence that inactivated influenza vaccine was associated with VTE in adults >=50years old. An increased risk was found among current smokers in a post hoc analysis. These findings are consistent with previous research and support the safety of annual vaccination in this population. PMID- 28888343 TI - Is midazolam a constitutional or pharmacological alternative in lethal injections? PMID- 28888345 TI - Erratum to "Contralesional Cathodal versus Dual Transcranial Direct Current Stimulation for Decreasing Upper Limb Spasticity in Chronic Stroke Individuals: A Clinical and Neurophysiological Study". PMID- 28888344 TI - Plasma Retinol-Binding Protein 4 Levels and the Risk of Ischemic Stroke among Women. AB - BACKGROUND: Plasma retinol-binding protein 4 (RBP4) levels have been associated with cardiovascular risk factors and risk of coronary heart disease, but little is known about the association between RBP4 and the risk of ischemic stroke. We hypothesized that elevated RBP4 levels would be associated with an increased risk of ischemic stroke among women. METHODS: We performed a nested case-control study among women enrolled in the Nurses' Health Study who provided blood samples between 1989 and 1990 and were free of prior stroke and cancer. We measured prediagnostic RBP4 levels in 471 ischemic stroke cases who were confirmed by medical record review and in 471 controls who were matched 1:1 to the cases on age, race, blood collection date, menopausal status, postmenopausal hormone use, and smoking status. We analyzed the association between RBP4 levels and ischemic stroke using multivariable conditional logistic regression conditional on the matching factors and adjusted for physical activity, body mass index, aspirin use, alcohol consumption, diet, history of diabetes, high cholesterol, high blood pressure, or heart disease, and cholesterol and hemoglobin A1C levels. RESULTS: Median levels of RBP4 were similar in cases (31.1 ug/mL) and controls (31.0 ug/mL; P value from the Wilcoxon rank-sum test = .82). Quartiles of RBP4 were not associated with an increased risk of ischemic stroke (highest quartile compared to lowest quartile: multivariate-adjusted odds ratio, .75; 95% confidence interval, .48, 1.17). We also did not observe associations between RBP4 and ischemic stroke of thrombotic or embolic origin. CONCLUSIONS: Elevated levels of RBP4 were not associated with an increased risk of ischemic stroke. PMID- 28888346 TI - The Safety of Carotid Artery Stenting for Patients in the Acute Poststroke Phase. AB - BACKGROUND: The efficacy of carotid artery stenting (CAS) for patients in the acute poststroke phase has not been established. We investigated the outcome of CAS for patients with symptomatic internal carotid artery (ICA) stenosis in the acute poststroke phase. METHODS: We performed a retrospective analysis of all patients who underwent CAS for symptomatic ICA stenosis in our institution. Patients in whom the time interval between neurological deterioration and the CAS procedure was less than 3 days were included in the early group, and the other patients were included in the delayed group. Perioperative complications including major adverse events (MAEs) were compared between the early and the delayed groups. RESULTS: One hundred five patients were included in the study. Forty patients were assigned to the early group and 65 patients were assigned to the delayed group. The overall MAE rate was 4.8%. There was no significant increase in the perioperative MAE in the early group compared with the delayed group (early group 2.5% versus delayed group 6.5%, P = .65). In the early group, 25 of 40 patients (62.5%) were functionally independent (modified Rankin scale [mRS] score of 0-2) at discharge. Significant differences between the independent patients and the disabled patients (mRS score of 3-6) included age (independent 72 versus disabled 79, P < .01) and prevalence of transient ischemic attack (36.0% versus .0%, P = .02). CONCLUSIONS: CAS performed within 3 days from the last ischemic event did not increase the risk of perioperative complication. Early CAS may be a useful option for the treatment of symptomatic carotid artery stenosis. PMID- 28888347 TI - Safety and efficacy of prasugrel in East Asian patients with acute coronary syndromes. PMID- 28888349 TI - Trump administration halts mountaintop coal mining health study. PMID- 28888348 TI - Nursing Across the Lifespan: Implications of Lifecourse Theory for Nursing Research. AB - Despite the lifecourse focus of nursing clinical care, nursing research largely remains cross-sectional or process-oriented within silos determined by patient characteristics such as age, acuity, or disease process. Incorporating interdisciplinary lifecourse theory into pediatric nursing research provides the opportunity to expand nursing theories and research beyond practice, age, and disease silos. One such theory is the Lifecourse Health Development (LCHD) framework. LCHD takes a more expansive view of health development from preconception through old age based on the premise that health is a consequence of transactions between genetic, biological, behavioral, social, and economic contexts that change as a child develops over time (Halfon & Hochstein, 2002). LCHD also explains how intergenerational influences and prevention during early life help predict health development and disease over the lifespan. The preventive and lifecourse focus of LCHD is well-aligned with the lifespan wellness foci of pediatric nurses. The purpose of this article is to introduce pediatric nurse researchers to LCHD and discuss proposed augmentations and implications related to expanding LCHD into pediatric nursing research. PMID- 28888351 TI - Correction. PMID- 28888350 TI - Anterior cingulate cortex grey matter volume abnormalities in adolescents with PTSD after childhood sexual abuse. AB - Adverse childhood experiences (ACE) substantially increase the risk of later psychiatric and somatic pathology. While neurobiological factors are likely to play a mediating role, specific insights are lacking. The scarce neuroimaging studies in traumatised pediatric populations have provided inconsistent results, potentially due to the inclusion of different types of trauma. To further improve our understanding of the neurobiology of pediatric psychotrauma, this study seeks to investigate abnormalities in grey matter volume (GMV) in a homogeneous group of adolescents with posttraumatic stress disorder (PTSD) due to childhood sexual abuse (CSA) and the relationship between GMV and symptom severity. We performed a voxel based morphometry (VBM) analysis in 21 adolescents with CSA-related PTSD and 25 matched non-traumatised, non-clinical adolescents. Hippocampus, amygdala, anterior cingulate cortex (ACC), medial PFC (mPFC) and superior temporal gyrus (STG) were chosen as regions of interest (ROIs). Trauma symptomatology was measured with the Trauma Symptom Checklist for Children (TSCC) and dissociation symptoms with the Adolescent Dissociative Experiences Scale (A-DES). The ROI analysis showed that the CSA-related PTSD group had significant smaller volumes of the dorsal ACC as compared to healthy controls. However, no correlations were found between GMV and scores on the TSCC and A-DES. The smaller ACC volume is partly in line with previous studies in traumatised youth and is a consistent finding in traumatised adults. Taken together our results suggest that the dorsal ACC is implicated in the neurobiological sequelae of CSA, potentially associated with an altered evaluative processing of emotion, but not directly with PTSD severity. PMID- 28888352 TI - High fat diet aggravates atrial and ventricular remodeling of hypertensive heart disease in aging rats. AB - BACKGROUND/PURPOSE: Left ventricular hypertrophy is a major cause of heart failure in aging population. This study is to determine whether an excess dietary fat is lipotoxic or lipoprotein to the hypertrophic aging heart. METHODS: At 44 week-old, a normal chow (12% fat) was replaced a high-fat diet (HFD; 45% fat) for randomly selective spontaneously hypertensive rats (SHR + HFD, n = 6) and Wistar Kyoto rats (WKY + HFD, n = 6, normotensive control). Others (SHR, n = 11; WKY, n = 10) were continuously fed with normal diets. After 27 weeks, electrocardiogram, echocardiography, and femoral arterial catheterization were performed before rats being sacrificed for molecular biology analyses. RESULTS: HFD aggravated cardiac atrial, ventricular dilation and hypertrophy in SHR (LV mass: SHR + HFD 2026.0 +/ 424.9 vs SHR 1449 +/- 461.1 mg, unpaired t test P < 0.05). HFD caused significant atrial dilatation in both WKY (LA diameter, 5.38 +/- 0.36 vs 4.11 +/- 0.42 mm, P < 0.001) and SHR (6.13 +/- 0.79 vs 4.69 +/- 1.00, P < 0.01). Only in SHR, HFD induced significant left ventricular dilatation (LV diameter, 8.87 +/- 1.25 vs 7.08 +/- 1.00 mm, P < 0.01) and reduced ejection fraction (LVEF, 62.8 +/- 11.6 vs 75.1 +/- 9.2 mm, P < 0.05). The alpha-myosin heavy chain was significantly upregulated in atria and ventricles of HFD groups. HFD induced significant upregulation of PPARalpha, ACADM, and TNFalpha transcripts in atrial tissues (P < 0.05). CONCLUSION: Hypertensive heart disease in aging rats was aggravated by HFD with worse atrial, ventricular remodeling and associated with left ventricular systolic function impairment. PMID- 28888353 TI - Preimplantation genetic diagnosis and screening: Current status and future challenges. AB - Preimplantation genetic diagnosis (PGD) is a clinically feasible technology to prevent the transmission of monogenic inherited disorders in families afflicted the diseases to the future offsprings. The major technical hurdle is it does not have a general formula for all mutations, thus different gene locus needs individualized, customized design to make the diagnosis accurate enough to be applied on PGD, in which the quantity of DNA is scarce, whereas timely result is sometimes requested if fresh embryo transfer is desired. On the other hand, preimplantation genetic screening (PGS) screens embryo with aneuploidy and was also known as PGD-A (A denotes aneuploidy) in order to enhance the implantation rates as well as livebirth rates. In contrasts to PGD, PGS is still under ferocious debate, especially recent reports found that euploid babies were born after transferring the aneuploid embryos diagnosed by PGS back to the womb and only very few randomized trials of PGS are available in the literature. We have been doing PGD and/or PGS for more than 10 years as one of the core PGD/PGS laboratories in Taiwan. Here we provide a concise review of PGD/PGS regarding its current status, both domestically and globally, as well as its future challenges. PMID- 28888354 TI - Reply to "Daily egg consumption should be still limited in hypercholesterolemic patients". PMID- 28888355 TI - The correlation of controlled attenuation parameter results with ultrasound identified steatosis in real-world clinical practice. AB - BACKGROUND/PURPOSE: Controlled attenuation parameter (CAP) is a method for measuring steatosis based on FibroScan. Despite observer dependency, ultrasound (US) robustly diagnoses moderate and severe steatosis. Here, we aimed to evaluate the correlation of CAP with US-identified steatosis in real-world clinical practice. METHODS: CAP and US were performed for 1554 chronic liver disease (CLD) patients. CAP was performed by two technicians, and US was performed by 30 hepatologists. The performance of the CAP as compared with the US results was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: 532 (34.2%) of the patients had hepatitis C virus (HCV) infection, 723 (46.5%) of the patients had hepatitis B virus (HBV) infection, and the rest were patients with metabolic risk factors. CAP values were significantly correlated with the steatosis grades identified by US for all the patients (rho = 0.497, P < 0.001), for the HBV-infected patients (rho = 0.495, P < 0.001), for the HCV-infected patients (rho = 0.343, P < 0.001), and for the patients with metabolic risk factors (rho = 0.515, P < 0.001). Using CAP, the AUROC values were 0.759, 0.795, 0.715, and 0.716 for >=moderate steatosis identified by US in, respectively, all the patients, the HBV-infected patients, the HCV-infected patients, and the patients with metabolic risk factors. The AUROC values were 0.791, 0.868, 0.807 and 0.701 for severe steatosis identified by US in, respectively, all the patients, the HBV-infected patients, the HCV-infected patients, and the patients with metabolic risk factors. CONCLUSION: CAP values were well correlated with the steatosis grades assessed by US in real-world clinical practice. PMID- 28888356 TI - Predicting response to rTMS for auditory hallucinations: Younger patients and females do better. PMID- 28888357 TI - Bullying victimization and perpetration in a community sample of youth with psychotic like experiences. AB - Prior studies indicate an association between psychotic-like experiences (PLEs) and bullying victimization; however, the most frequent types of bullying victimization and the association with bullying perpetration are unclear. A community sample of 1563 adolescents completed questionnaires examining PLEs and frequency of bullying victimization and perpetration. Compared to adolescents scoring below the psychosis-risk cut-off (n=1294), those with PLEs (who are putatively at-risk) (n=269) were more likely to report being the victims of overt, relational, and reputational bullying and to have perpetrated bullying against others. Increased bullying perpetration among youth with PLEs may reflect reactive aggression in response to being bullied. PMID- 28888358 TI - Prediction of self-stigma in early psychosis: 3-Year follow-up of the randomized controlled trial on extended early intervention. AB - BACKGROUND: Self-stigma represents a major barrier to recovery in people with psychotic disorders but is understudied in early illness stage. Longitudinal investigation of prediction for self-stigma is scarce and none is conducted in early psychosis. We aimed to prospectively examine baseline predictors of self stigma in early psychosis patients in the context of a 3-year follow-up of a randomized-controlled trial (RCT) comparing 1-year extension of early intervention (EI) with step-down psychiatric care for first-episode psychosis (FEP). METHOD: One hundred sixty Chinese patients were recruited from a specialized EI program for FEP in Hong Kong after they had completed this 2-year EI service, and underwent a 12-month RCT. Participants were followed up and reassessed 3years after inclusion to the trial. Comprehensive evaluation encompassing clinical, functional, subjective quality of life and treatment related variables were conducted. Data analysis was based on 136 participants who completed self-stigma assessment at 3-year follow-up. RESULTS: Fifty patients (36.8%) had moderate to high levels of self-stigma at 3-year follow-up. Multivariate regression analysis revealed that female gender, prior psychiatric hospitalization, longer duration of untreated psychosis and greater positive symptom severity at study intake independently predicted self-stigma at the end of 3-year study period. CONCLUSION: Our results of more than one-third of early psychosis patients experienced significant self-stigma underscore the clinical needs for early identification and intervention of self-stigmatization in the initial years of psychotic illness. Further research is warranted to clarify prediction profile and longitudinal course of self-stigma in the early illness phase. PMID- 28888359 TI - Patients with psychosis struggle with scalar implicatures. AB - Pragmatic language difficulties in people with psychosis have been demonstrated repeatedly but one of the most studied types of pragmatic language, i.e. scalar implicatures (SIs), has not yet been examined in this population. SIs are a special kind of pragmatic inferences, based on linguistic expressions like some, or, must. Such expressions are part of a scale of informativeness organized by informativity (e.g. some/many/all). Although semantically the less informative expressions imply the more informative ones, pragmatically people generally infer that the use of a less informative expression implies that the more informative option is not applicable. Based on the pragmatic language difficulties of people with psychosis we hypothesized that they may be less likely to derive these pragmatic SIs. We conducted two studies in which the ability of people with psychosis to derive SIs was compared to that of healthy controls matched for age and educational level. In the second study we additionally explored the possible link between the capacity to derive SIs and theory of mind (ToM) ability. In general, people with psychosis were less likely to derive SIs than controls. However, the patient group was not homogeneous: half had problems deriving SIs, the other half did not. This dichotomization seems linked to ToM ability because in the patient group, better ToM was associated with a higher ability to derive SIs. Based on the nature of the stimuli used in the SI-task we speculate that this link may not be a direct but an indirect one. PMID- 28888360 TI - An examination of components of recovery after five years of treatment in an early intervention program for psychosis. AB - Recovery from psychotic disorders includes both symptomatic and functional components. Progress in understanding recovery requires careful replication and extension of findings using comparable measures. In the current paper, we present a study of five year recovery rates in an early intervention program in London, Canada with the same operational criteria as those used in a previous report from the OPUS cohort in Denmark. Our analysis extends the OPUS reports by including additional potential predictors of overall recovery, such as cognitive functioning, adherence to medication and early social support, and examining rates and predictors of individual components of recovery at five year follow-up. Consistent with reports from OPUS, we found younger age of onset and lower initial severity of negative symptoms to predict greater likelihood of overall recovery. Different patterns of predictors emerge when we examine individual components of recovery. Adherence to medication during the first year was the sole independent predictor of remission of positive symptoms, while early social adjustment and social support were more likely to predict negative symptom and functional aspects of recovery at five years. Cognitive functioning, as represented by IQ, did not predict any aspects of recovery. Our findings suggest the importance of examining the predictors of individual components in the quest to improve overall recovery. PMID- 28888361 TI - Increased platelet glycogen sysnthase kinase 3beta in first-episode psychosis. AB - Past studies have linked intracellular pathways related to psychotic disorders to the GSK3B enzyme. This study aimed to investigate GSK3B protein expression and phosphorylation in drug-naive first-episode psychosis patients (n=43) at baseline and following symptom remission, and in healthy controls (n=77). At baseline GSK3B total level was higher in patients (p<0.001). In schizophrenia spectrum patients (n=25) GSK3B total and phosphorylated levels were higher than in controls and patients with other non-affective psychotic disorders (n=18) (p<0.001; p=0.027; p=0.05 respectively). No enzyme changes were found after clinical remission. The implication of this finding for the biology of psychoses warrants further studies to clarify whether increased GSK3B may be useful as a biomarker for psychosis in general, and schizophrenia in particular. PMID- 28888363 TI - Effect of complete or partial proteinuria recovery on long-term outcomes of lupus nephritis. AB - BACKGROUND/PURPOSE: We aimed to evaluate the effect of complete recovery (CR), partial recovery (PR), and no recovery (NR) of proteinuria at 2 years from the diagnosis of LN on long-term renal and extra-renal outcomes. METHODS: Patients with LN and proteinuria attending the Lupus Center from 1970 to 2015 were analyzed. At 2 years from diagnosis of LN, patients were divided into three groups (CR, PR, and NR), and long-term outcomes were studied up to 15 years or last visit available. CR was defined as resolution of proteinuria, PR as a reduction >=50% in baseline proteinuria, and NR as a reduction <50% compared to baseline. Long-term outcomes examined included renal outcomes [low eGFR, ESRD, and composite renal (low eGFR, ESRD, and dialysis/transplant)], cardiovascular outcomes, damage, and death. Kaplan-Meier plots, time-independent and time dependent Cox proportional hazards models were applied to examine the effect of CR, PR, or NR on long-term outcomes. RESULTS: Of 277 patients, 71.8% achieved CR, 18.4% PR, and 9.8% NR at 2 years. CR compared to NR and CR compared to PR were protective against low eGFR and composite renal outcome in time-independent and time-dependent analyses. CR compared to PR protected against damage in the time independent analysis. Overall, the comparison of CR and PR favored CR for long term renal outcomes. CONCLUSION: CR at 2 years from diagnosis of LN protected against renal outcomes (low eGFR, ESRD/dialysis, and transplant). CR is more favorable compared to PR and clinicians should aim for CR to improve long-term outcomes in LN. PMID- 28888364 TI - VDAC electronics: 4. Novel electrical mechanism and thermodynamic estimations of glucose repression of yeast respiration. AB - Inhibition of cell respiration by high concentrations of glucose (glucose repression), known as "Crabtree effect", has been demonstrated for various cancerous strains, highly proliferating cells and yeast lines. Although significant progress in understanding metabolic events associated with the glucose repression of cell respiration has been achieved, it is not yet clear whether the Crabtree effect is the result of a limited activity of the respiratory chain, or of some glucose-mediated regulation of mitochondrial metabolic state. In this work we propose an electrical mechanism of glucose repression of the yeast S. cerevisiae, resulting from generation of the mitochondrial outer membrane potential (OMP) coupled to the direct oxidation of cytosolic NADH in mitochondria. This yeast-type mechanism of OMP generation is different from the earlier proposed VDAC-hexokinase-mediated voltage generation of cancer-type, associated with the mitochondrial outer membrane. The model was developed assuming that VDAC is more permeable to NADH than to NAD+. Thermodynamic estimations of OMP, generated as a result of NADH(2-)/NAD+(1-) turnover through the outer membrane, demonstrated that the values of calculated negative OMP match the known range of VDAC voltage sensitivity, thus suggesting a possibility of OMP-dependent VDAC-mediated regulation of cell energy metabolism. According to the proposed mechanism, we suggest that the yeast-type Crabtree effect is the result of a fast VDAC-mediated electrical repression of mitochondria due to a decrease in the outer membrane permeability to charged metabolites and owing their redistribution between the mitochondrial intermembrane space and the cytosol, both controlled by metabolically-derived OMP. PMID- 28888362 TI - Risk factors for increased duration of untreated psychosis. Results from the FACE SZ dataset. AB - OBJECTIVES: Reducing the duration of untreated psychosis (DUP) may improve the prognosis of schizophrenia. This study investigated the prevalence, and associated risk factors, of long DUP in a large, non-selected sample of community dwelling schizophrenia patients (SZ). METHOD: 478 community-dwelling stable SZ participants (122 women and 356 men; mean age 32.37+/-9.86years) were recruited between 2010 and 2016. The mean retrospective DUP was evaluated from both patient and family reports, as well as hospital/psychiatrists records. Long DUP was defined as >2years. RESULTS: The mean DUP was 1.5years. 80 participants (16.7%) had a DUP>2years. In multivariate analyses, after adjustment for sex, education level, history of childhood trauma and history of maternal schizophrenia or bipolar disorder, long DUP was associated with a younger age of illness onset (19.3+/-6.67years vs. 22.0+/-6.51years, adjusted odd ratio aOR=0.91, 95%CI [0.86; 0.97], p=0.003) and cannabis use disorder (20.0% vs. 10.3%, aOR=2.41, 95%CI [1.14 5.09], p=0.02). CONCLUSION: A high proportion of SZ patients still have a long DUP. The present results suggest that illness onset before age 19years and cannabis use are associated with long DUP in schizophrenia patients. Early psychosis detection programs should prioritize the targeting of these populations. PMID- 28888365 TI - Functional reconstitution of cell-free synthesized purified Kv channels. AB - The study of ion channel activity and the screening of possible inhibitor molecules require reliable methods for production of active channel proteins, their insertion into artificial membranes and for the measurement of their activity. Here we report on cell-free expression of soluble and active Kv1.1 and Kv1.3 channels and their efficient insertion into liposomes. Two complementary methods for the determination of the electrical activity of the proteoliposome embedded channels were compared using Kv1.1 as a model system: (1) single channel recordings in droplet interface bilayers (DIB) and (2) measurement of the membrane voltage potential generated by a potassium ion diffusion potential using the voltage-sensitive fluorescent dye oxonol VI. Single channel recordings in DIBs proved unreliable because of the non-reproducible fusion of proteoliposomes with an artificial membrane. Therefore, the use of the optical indicator oxonol VI was adapted for 96 well microtiter plates using the ionophore valinomycin as a positive control. The activity of Kv1.1 and Kv1.3 channels was then monitored in the absence and presence of different venom toxins, demonstrating that fluorescent dyes can be used very efficiently when screening small molecules for their channel blocking activity. PMID- 28888366 TI - Lipopolysaccharides promote binding and unfolding of the antibacterial colicin E3 rRNAse domain. AB - Nuclease colicins are antibacterial proteins produced by certain strains of E. coli to reduce competition from rival strains. These colicins are generally organized with an N-terminal transport (T)-domain, a central receptor binding (R) domain, and a C-terminal cytotoxic nuclease domain. These colicins are always produced in complex with an inhibitory immunity protein, which dissociates prior entrance of the cytotoxic domain in the target cell. How exactly colicins traverse the cell envelope is not understood, yet this knowledge is important for the design of new antibacterial therapies. In this report, we find that the cytotoxic rRNAse domain of colicin E3, lacking both T- and R-domains, is sufficient to inhibit cell growth provided the immunity protein Im3 has been removed. Thus, while the T-domain is needed for dissociation of Im3, the rRNAse alone can associate to the cell surface without R-domain. Accordingly, we find a high affinity interaction (Kd ~1-2MUM) between the rRNAse domain and lipopolysaccharides (LPS). Furthermore, we show that binding of ColE3 to LPS destabilizes the secondary structure of the toxin, which is expectedly crucial for transport through the narrow pore of the porin OmpF. The effect of LPS on binding and unfolding of ColE3 may be indicative of a broader role of LPS for transport of colicins in general. PMID- 28888367 TI - Attenuation of ischemia/reperfusion-induced inhibition of the rapid component of delayed rectifier potassium current by Isosteviol through scavenging reactive oxygen species. AB - Isosteviol has been demonstrated to play a protective role during ischemia reperfusion (I/R) myocardial infarction. However, the underlying electrophysiological mechanisms of isosteviol are still unknown. Our previous study showed that the rapid component of the delayed rectifier potassium channel (IKr) plays an important role in the prolongation of I/R-induced QT interval related arrhythmia. This study aimed to investigate whether isosteviol could attenuate I/R-induced prolongation of the action potential duration (APD) along with inhibition of IKr, and we aimed to clarify the electrophysiological mechanism of isosteviol to determine its cardioprotective effects in guinea pigs. We observed that the APD90 were 298.5+/-41.6ms in control, 528.6+/-56.7ms during I/R, and reduced to 327.8+/-40.5ms after 10MUmol/L of isosteviol treatment. The IKr currents were 1.44+/-0.06 pA.pF-1in the control group, 0.50+/-0.07pA.pF 1during I/R, and recovered to 1.20+/-0.12pA.pF-1after 10MUmol/L of isoteviol treatment. Moreover, isosteviol reduced the over-production of reactive oxygen species (ROS) during I/R. Importantly, isosteviol does not affect the IKr and human ether-a-go-go-related gene currents of normal cardiomyocytes. It attenuated the I/R-induced inhibition of IKr due to reduced over-production of ROS. Furthermore, isosteviol is safe and has no cardiotoxicity, and it might be beneficial for coronary reperfusion therapy. PMID- 28888368 TI - Involvement of scavenger receptor class B type 1 and low-density lipoprotein receptor in the internalization of liposomes into HepG2 cells. AB - In this study, HepG2 cells, an in vitro model system for human hepatocytes, were used to evaluate the interaction of lipoprotein receptors with liposomes carrying fluorescently labeled cholesterol and their subsequent intracellular uptake. In these experiments, two lipoprotein receptors, scavenger receptor class B type 1 (SR-B1) and low-density lipoprotein receptor (LDLR), accounted for approximately 20% and 10%, respectively, of the intracellular uptake of the labeled liposomes. These findings indicate that additional mechanisms contributed to liposomal internalization. Liposomes modified with both apolipoproteins A-I and E were internalized in HepG2 cells in FBS-depleted culture medium at the same levels as unmodified liposomes in FBS-containing culture medium, which indicates that apolipoproteins A-I and E were the major serum components involved in liposomal binding to SR-B1 or LDLR (or both). These results increase our understanding of the disposition of liposomes, processes that can directly affect the efficacy and safety of drug products. PMID- 28888369 TI - Structure analysis of the membrane-bound dermcidin-derived peptide SSL-25 from human sweat. AB - SSL-25 (SSLLEKGLDGAKKAVGGLGKLGKDA) is one of the shortest peptides present in human sweat and is produced after the proteolytic processing of the parent peptide dermcidin. Both peptides are reported to have antimicrobial function. To determine the structure of SSL-25 in lipid bilayers, a series of 19F-labeled SSL 25 analogs were synthesized. Circular dichroism (CD) analysis showed that SSL-25 and all of its analogs formed alpha-helices in the presence of lipid vesicles, thus allowing a detailed analysis via oriented CD and solid-state NMR. The results suggest that SSL-25 resides on the membrane surface with a slight helix tilt angle. A detailed 19F NMR analysis revealed that SSL-25 does not form a continuous helix. The alpha-helical structure of the N-terminal part of the peptide was preserved in membranes of different lipid compositions and at various peptide-to-lipid molar ratios, but the C-terminus was disordered and did not fold into a well-defined alpha-helical conformation. Furthermore, the NMR results showed that SSL-25 resides on the membrane surface and does not re-orient into the membrane in response to changes in either peptide concentration or membrane composition. SSL-25 does not aggregate and remains fully mobile within the membrane bilayer, as shown by 19F NMR. SSL-25 has a high binding affinity toward bilayers mimicking bacterial lipid compositions, but does not bind to mammalian model membranes containing cholesterol. These observations may explain the selectivity of this peptide for bacterial membranes, and they are also in line with basic biophysical considerations on spontaneous lipid curvature and the general effect of cholesterol on peptide/lipid interactions. PMID- 28888371 TI - The "bespoke" recovery: Available when the tailoring is guided by experience and high-quality data. PMID- 28888370 TI - Biophysical and biological properties of small linear peptides derived from crotamine, a cationic antimicrobial/antitumoral toxin with cell penetrating and cargo delivery abilities. AB - Crotamine is a natural polypeptide from snake venom which delivers nucleic acid molecules into cells, besides having pronounced affinity for negatively charged membranes and antifungal activity. We previously demonstrated that crotamine derived short linear peptides were not very effective as antifungal, although the non-structured recombinant crotamine was overridingly more potent compared to the native structured crotamine. Aiming to identify the features necessary for the antifungal activity of crotamine, two linear short peptides, each comprising half of the total positively charged amino acid residues of the full-length crotamine were evaluated here to show that these linear peptides keep the ability to interact with lipid membrane model systems with different phospholipid compositions, even after forming complexes with DNA. Interestingly, the presence of cysteine residues in the structure of these linear peptides highly influenced the antifungal activity, which was not associated to the lipid membrane lytic activity. In addition to the importance of the positive charges, the crucial role of cysteine residues was noticed for these linear analogs of crotamine, although the tridimensional structure and lipid membrane lytic activity observed only for native crotamine was not essential for the antifungal activity. As these peptides still keep the ability to form complexes with DNA molecules with no prejudice to their ability to bind to lipid membranes, they may be potentially advantageous as membrane translocation vector, as they do not show lipid membrane lytic activity and may harbor or not antifungal activity, by keeping or not the semi-essential amino acid cysteine in their sequence. PMID- 28888372 TI - The arithmetic of a successful mitral valve repair. PMID- 28888373 TI - A nondystopian alternative history? PMID- 28888374 TI - Racing to the Rubicon. PMID- 28888375 TI - D-dimer and early coronary graft closure: Not so fast. PMID- 28888376 TI - Clamping improves your judgment. PMID- 28888377 TI - Rapid-deployment valves: Finally the fog is lifting-benefits beyond crossclamp and bypass times. PMID- 28888378 TI - Unplanned left ventricular assist device insertion for dissecting intramyocardial hematoma during biventricular assist device explantation. PMID- 28888379 TI - Video-assisted thoracoscopic lobectomy is associated with greater recurrence-free survival than stereotactic body radiotherapy for clinical stage I lung cancer. AB - OBJECTIVE: Stereotactic body radiotherapy is the standard treatment for medically inoperable early-stage non-small cell lung cancer. Recent data suggest that in operable patients, stereotactic body radiotherapy produces outcomes comparable to those of surgical resection. In veterans with early non-small cell lung cancer, we compared the outcomes of stereotactic body radiotherapy and video-assisted thoracoscopic lobectomy. METHODS: We retrospectively reviewed data from 183 patients (94.0% male) with clinical stage I non-small cell lung cancer who underwent stereotactic body radiotherapy (n = 56) or video-assisted thoracoscopic lobectomy (n = 127) from 2009 to 2014. Propensity matching was used to produce more comparable groups. Primary end points were tumor control and overall, recurrence-free, and lung-cancer-specific survival, as estimated by Kaplan-Meier actuarial analysis. Multivariable analysis was used to identify independent predictors. RESULTS: In the overall cohort, the patients who received stereotactic body radiotherapy were older than the patients who received video assisted thoracoscopic lobectomy (median age, 79.5 vs 64 years) and had more comorbidities. In the 37 propensity-matched pairs, the 3-year actuarial tumor control rate was 54.3% after stereotactic body radiotherapy and 90.6% after video assisted thoracoscopic lobectomy (P = .0038). Actuarial lung cancer-specific 3 year survival was 78.1% (stereotactic body radiotherapy) versus 93.6% (video assisted thoracoscopic lobectomy) (P = .055). One-year overall, 3-year overall, and 3-year recurrence-free survivals were 89.2%, 52.9%, and 38.5% after stereotactic body radiotherapy and 94.6%, 85.7%, and 82.8% after video-assisted thoracoscopic lobectomy (P < .005 for all), respectively. In multivariable analysis, stereotactic body radiotherapy independently predicted recurrence and poorer survival. CONCLUSIONS: In veteran patients with early-stage non-small cell lung cancer, video-assisted thoracoscopic lobectomy resulted in better disease control and survival than stereotactic body radiotherapy. Although prior reports suggest that stereotactic body radiotherapy is a suitable alternative to surgery in early-stage lung cancer, a prospective randomized trial is needed. Nevertheless, stereotactic body radiotherapy remains a suitable option for medically inoperable patients. PMID- 28888380 TI - A minimally invasive right ventricular assist device insertion late after a continuous-flow left ventricular assist device implantation. PMID- 28888382 TI - Correction. PMID- 28888381 TI - Long-term Observation of CT-guided Radiofrequency Ablation of Lung Neoplasm in 476 Consecutive Patients by a Thoracic Surgical Service: A Single-institutional Experience. AB - RATIONALE AND OBJECTIVES: The aim of the study was to evaluate the overall survival (OS) rate, progression survival rate, and local control rate over 10 years of medically inoperable patients with lung cancer undergoing computed tomography (CT)-guided radiofrequency ablation (RFA). MATERIALS AND METHODS: Between September 2004 to March 2016, 668 neoplasms were treated in 476 medically inoperable patients (294 men, 60 women; median age 74 years; range 29-84) who underwent CT-guided RFA. All patients had clinical or pathologic evidence of the neoplastic lesion: 22.1% patients with primary non-small cell lung cancer (NSCLC), 22.3% patients with recurrent NSCLC, 45.2% with metastases, and 10.3% with small cell lung cancer. The mean size of the lesions was 3.8 cm (range of 1 16 cm). Twenty-one lesions were re-treated from one to as many as four times. RESULTS: The procedure was technically successful in all cases. No procedure related deaths occurred in the RFA procedures. Major complications consisted in 104 (21.8%) cases of low-grade fever, 46 (9.6%) of the pneumothorax. The mean follow-up was 32 months. The probabilities of 1-, 2-, 3-, 5-, and 10-year OS rate were 98.1%, 86.6%, 68.9% 34.5%, and 9.5% for primary NSCLC; 59.7%, 18.5%, 8%, 3.4%, and 1.5% for metastases; 93.3%, 59.1%, 49.6%, 19.7%, and 0% for recurrence; and 89.4%, 67.5%, 39.1%, 16.5%, and 0% for small cell lung cancer. In primary NSCLC, progression-free survival (PFS) and OS were significantly related to tumor size, but there was no significant difference in recurrent NSCLC, metastasis, and peripheral SCLC. The median OS of metastases of NSCLC was significantly related to nodal or distant metastases. The most common pattern of recurrence was local; any type of recurrence at 1-year follow-up imaging was seen in 7.1% of primary NSCLC diameter less than 3 cm. CONCLUSIONS: Our experience indicates that CT guided RFA done by the thoracic surgeons is feasible and safe in high-risk patients. Maximum tumor diameter less than 3 cm and lack of extrapulmonary metastasis are all positive prognostic factors of survival after RFA. RFA offers good local control of recurrent NSCLC, lung metastases, and SCLC, also in the long-term period. RFA should continue to offer an alternative option in medically inoperable patients. PMID- 28888383 TI - Developing Item Response Theory-Based Short Forms to Measure the Social Impact of Burn Injuries. AB - OBJECTIVE: To develop self-reported short forms for the Life Impact Burn Recovery Evaluation (LIBRE) Profile. DESIGN: Short forms based on the item parameters of discrimination and average difficulty. SETTING: A support network for burn survivors, peer support networks, social media, and mailings. PARTICIPANTS: Burn survivors (N=601) older than 18 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The LIBRE Profile. RESULTS: Ten-item short forms were developed to cover the 6 LIBRE Profile scales: Relationships with Family & Friends, Social Interactions, Social Activities, Work & Employment, Romantic Relationships, and Sexual Relationships. Ceiling effects were <=15% for all scales; floor effects were <1% for all scales. The marginal reliability of the short forms ranged from .85 to .89. CONCLUSIONS: The LIBRE Profile-Short Forms demonstrated credible psychometric properties. The short form version provides a viable alternative to administering the LIBRE Profile when resources do not allow computer or Internet access. The full item bank, computerized adaptive test, and short forms are all scored along the same metric, and therefore scores are comparable regardless of the mode of administration. PMID- 28888384 TI - Ulnar Nerve Cross-Sectional Area for the Diagnosis of Cubital Tunnel Syndrome: A Meta-Analysis of Ultrasonographic Measurements. AB - OBJECTIVE: To examine the performance of sonographic cross-sectional area (CSA) measurements in the diagnosis of cubital tunnel syndrome (CuTS). DATA SOURCES: Electronic databases, comprising PubMed and EMBASE, were searched for the pertinent literature before July 1, 2017. STUDY SELECTION: Fourteen trials comparing the ulnar nerve CSA measurements between participants with and without CuTS were included. DATA EXTRACTION: Study design, participants' demographic characteristics, diagnostic reference of CuTS, and methods of CSA measurement. DATA SYNTHESIS: Among different elbow levels, the between-group difference in CSA was the largest at the medial epicondyle (6.0mm2; 95% confidence interval [CI], 4.5-7.4mm2). The pooled mean CSA in participants without CuTS was 5.5mm2 (95% CI, 4.4-6.6mm2) at the arm level, 7.4mm2 (95% CI, 6.7-8.1mm2) at the cubital tunnel inlet, 6.6mm2 (95% CI, 5.9-7.2mm2) at the medial epicondyle, 7.3mm2 (95% CI, 5.6 9.0mm2) at the cubital tunnel outlet, and 5.5mm2 (95% CI, 4.7-6.3mm2) at the forearm level. The sensitivities, specificities, and diagnostic odds ratios pooled from 5 studies, using 10mm2 as the cutoff point, were .85 (95% CI, .78 .90), .91 (95% CI, .86-.94), and 53.96 (95% CI, 14.84-196.14), respectively. CONCLUSIONS: The ulnar nerve CSA measured by ultrasound imaging is useful for the diagnosis of CuTS and is most significantly different between patients and participants without CuTS at the medial epicondyle. Because the ulnar nerve CSA in healthy participants, at various locations, rarely exceeds 10mm2, this value can be considered as a cutoff point for diagnosing ulnar nerve entrapment at the elbow region. PMID- 28888385 TI - Something Old, Something New, Something Borrowed, and Something Blue. PMID- 28888386 TI - Pediatric chronic osteomyelitis in the outskirts of Al-Ushbuna (Carnide, Lisboa, Portugal). AB - The skeletal remains of seven individuals (five non-adults and two adults) were recovered during an archeological intervention in the township of Carnide (Lisbon, Portugal). Funerary anthropology strongly suggests that the sample is from the Medieval Islamic period (8th - 12th centuries AD). This report presents a case of chronic osteomyelitis in a non-adult individual. The diagnostic is substantiated by the presence of pathognomonic signs of osteomyelitis, including the presence of cloacae and a sequestrum in the left tibia. The bone infection is discussed in the context of inadequate socioeconomic conditions. This case from a relatively unfamiliar chronology and cultural context supplements the uncommon paleopathological descriptions of osteomyelitis in non-adults from historical populations. PMID- 28888387 TI - Scurvy at the agricultural transition in the Atacama desert (ca 3600-3200 BP): nutritional stress at the maternal-foetal interface? AB - Studies of contemporary populations have demonstrated an association between decreased dietary diversity due to resource scarcity or underutilization and an increase in diseases related to poor micronutrient intake. With a reduction of dietary diversity, it is often the women and children in a population who are the first to suffer the effects of poor micronutrient status. Scurvy, a disease of prolonged vitamin C deficiency, is a micronutrient malnutrition disorder associated with resource scarcity, low dietary diversity, and/or dependence on high carbohydrate staple-foods. The aim of this paper is to assess the potential impact of nutritional transition on the prevalence of diseases of nutritional insufficiency in an archaeological sample. Here, we report palaeopathological findings from an Early Formative Period transitional site located in coastal Northern Chile (Quiani-7). The subadult cohort from this site is composed of four perinates who exhibit a number of non-specific skeletal changes suggestive of a systemic pathological condition. One of these is associated with an adult female exhibiting diagnostic skeletal lesions of scurvy. We argue that the lesions exhibited by these perinates may represent maternal transmission of vitamin C deficiency but acknowledge that there are difficulties in applying current diagnostic criteria for scurvy to individuals this young. PMID- 28888388 TI - A case of concrescent tooth-A developmental anomaly in a 19th century skull from Uganda. AB - Dental abnormalities in archeological material such us concrescence or odontoma are rare cases often found accidentally, mostly during routine X-ray analysis or during macroscopic examination of the mastication apparatus. In this study, we present a rare case of concrescence between an upper left third molar and a supernumerary fourth molar in a 19th century skull from Uganda. Simultaneously, it is a critical revision of earlier studies on the same object (which considered this abnormality as an odontoma), using dental X-ray imaging and histological analysis. Concrescence is a rare dental anomaly and this specimen is, to the best of our knowledge, the first such case reported in paleopathological studies of Eastern Africa. It may contribute to recognition and identification of etiopathogenetic factors in dental developmental defects in historical and contemporary populations of Africa. PMID- 28888389 TI - Scheuermann's disease in a juvenile male from the late Roman necropolis of Torrenueva (3rd-4th century CE, Granada, Spain). AB - This study details a severe case of Scheuermann's disease (SD) in a well preserved skeleton of a juvenile male (designated TOR302), dated to 3rd-4th century CE, from the late Roman necropolis of Torrenueva (Granada, Spain). Individual TOR302 shows an evident kyphotic curve in the thoraco-lumbar spine, which is characterised by: (i) vertebral bodies of thoracic vertebra T2, thoracic segment T4-T9, and thoraco-lumbar segment T12-L2 wedged at >5 degrees ; (ii) slight anterior extensions of the epiphyseal ring; (iii) Schmorl's nodes on the superior and/or inferior plates; and (iv) a Cobb angle of 75 degrees , derived from thoracic segments T4-T9. In addition, TOR302 shows other skeletal malformations as the secondary results of abnormal growth, due to altered biomechanical forces imposed by the spinal deformity, including: (i) lateral distortion of the spine that causes a slight secondary scoliotic curve; (ii) pelvic obliquity; and (iii) discrepancy in the length of the limbs. We argue that the secondary skeletal abnormalities allowed the individual to adapt to his spinal deformity meaning he was able to walk without the aid of a stick. Despite SD being a common modern clinical finding, few cases have been reported in ancient skeletal remains. This case therefore represents an important contribution to the palaeopathological literature. PMID- 28888390 TI - Ovarian teratoma: A case from 15th-18th century Lisbon, Portugal. AB - This paper discusses the differential diagnosis of an unusual calcified mass found in the pelvic cavity of 45+-year-old female excavated from 15th-18th century Lisbon (Portugal). The mass is relatively large, irregularly shaped, and exhibits a concave base with malformed teeth embedded within its inner surface. Considering its macroscopic and radiological characteristics, several conditions were considered in the differential diagnosis, namely eccyesis, fetus in fetu, lithopaedion, and ovarian teratoma. However, the morphological features of the specimen, such as its structure, morphology, and dimensions, are diagnostic of a teratoma. Its location and the sex of the individual are more specifically compatible with a calcified ovarian teratoma. With regional and temporal variations in the frequency of tumours, the report of new cases becomes imperative, especially from geographic regions where few cases have been identified. In fact, this appears to be the first case of ovarian teratoma detected in the Portuguese archaeological record and adds to the few palaeopathological cases described in the osteoarchaeological literature worldwide. PMID- 28888391 TI - Osteocytes and the bone lacunar-canalicular system: Insights into bone biology and skeletal function using bone tissue microstructure. PMID- 28888393 TI - Hypertrophic osteoarthropathy in a young adult male from Berber, Sudan (2nd-3rd century CE). AB - Hypertrophic osteoarthropathy (HOA) is a pathological condition characterised by extensive periosteal new bone formation (NBF) on the diaphyses of the long bones, metacarpal and metatarsal bones. In modern clinical contexts, the secondary form of the disease is common and most often occurs secondary to intra-thoracic cancer and other forms of chronic pulmonary disease. Paleopathological evidence for HOA on the other hand has only occasionally been reported. Here we report a young adult male from the Meriotic cemetery at Berber in Sudan (2nd-3rd century CE) displaying widespread NBF on the diaphyses of the upper and lower limb bones, metacarpal and metatarsal bones, as well as the pelvis and scapulae. While several pathological conditions have to be considered as differential diagnostic options for NBF in the post-cranial skeleton, HOA is the most likely diagnosis, based on the distribution of the changes observed in this individual, as well as their macroscopic and radiographic characteristics. A chronic pulmonary condition as indicated by NBF on the visceral side of the ribs may represent the underlying cause for the HOA. This individual represents the first paleopathological case of HOA reported from an archaeological site in Africa. PMID- 28888392 TI - Toxocara eggs in an 18th century Franciscan from Portugal. The challenge of differentiating between parasitism and chance in Paleoparasitology. AB - In 2005, an adult male was excavated in the cloister of the former Convent of the Holy Spirit, in the Franciscan Province of Holy Mary of Arrabida, Lisbon district. From the anterior part of the sacrum, a darker organic agglomeration was collected and studied for intestinal parasites. Samples were rehydrated with Lycopodium tablets in a Na3PO4 5% solution for 72h, followed by the swirl technique. Organic material was concentrated at 2500rpm. At least 20 slides of each sample were examined using a light/polarized microscope. A control sample from outside the pelvis revealed no biological remains. A sample collected inside the pelvic girdle was positive for pollen grains, other plant remains and Toxocara eggs, perhaps T. cati (2766 eggs/gram sediment). This finding, although exciting, cannot be explained in a simple way because humans are not definitive hosts for Toxocara species. Ingestion of feces-contaminated food or water, geophagy, or true infection are hypotheses considered in this study, which demonstrates the difficulty of interpreting the presence of animal parasites in human remains. This is the first time Toxocara eggs are found associated with human remains. PMID- 28888394 TI - Three cases of feet and hand amputation from Medieval Estremoz, Portugal. AB - Peri-mortem limb amputations are rarely reported in the paleopathological literature. The cases reported here concern severing of both hands and feet observed in three adult male skeletons, exhumed from the medieval Portuguese necropolis of Rossio do Marques de Pombal, Estremoz, Portugal. The fact that they were found in the same site, in graves placed side by side, that all are young males, and that the three skeletons show similar perimortem injuries, make this a unique case meriting detailed analysis. Considering the lesions' location and pattern, as well as historical data, we hypothesize that this is a case of amputation as a consequence of judicial punishment. Estremoz was an important city in sustaining the Royal power at a regional scale during the medieval period. PMID- 28888395 TI - Dental adaptations of Bronze Age Harappans: Occlusal wear, crown size, and dental pathology. AB - Systematic study of dental attributes yields insights regarding diet and subsistence that cannot be gained from the archaeological record alone. This analysis documents occlusal tooth wear, tooth crown dimensions and dental pathology of an expanded dental sample from Harappa (2550-2030cal BC; Pakistan). New floral and faunal evidence of subsistence indicates a mix of agriculture and pastoralism that can be integrated with evidence of dental attributes and disease to reveal the impact of Harappan diet on oral health. An enlarged dental sample (58 specimens, 910 teeth) from mature phase Harappa was analyzed using Scott's quadrant wear system, measures of crown size, and prevalence of seven pathological dental lesions. All data were collected by the author using standard methods. Sex differences were found in wear, tooth size and prevalence of dental diseases. Females exhibit greater caries prevalence and antemortem tooth loss than men, an attribute associated with higher rates of pulp exposure and abscesses in women. At Harappa antemortem tooth loss results from penetrating caries, while in foragers the cause is severe occlusal wear. In contrast to early Holocene foragers of north India (Damdama, 8800-8600 BP), Harappans have greater occlusal wear, smaller teeth, and a distinct dental pathology profile. PMID- 28888396 TI - Middle and late holocene micromammal pathologies from Cueva Tixi (Tandilia Range, Buenos Aires Province, Argentina). AB - Paleopathology in bones of very small mammals has rarely been studied. Different types of osseous lesions of mammals weighing under 0.2kg, recovered from the Holocene strata of Cueva Tixi archaeological and paleontological site (Tandilia range, province of Buenos Aires, Argentina), are described and discussed in this report. Several types of trauma, entheseal changes, degenerative joint diseases, and probable osteomyelitis were identified. The lesions were chronic, indicating that the animals were able to survive a period of convalescence, although in many cases the decreased capacity for locomotion likely was significant. These pathological findings open research avenues for very small mammals that usually are not considered in archaeological disease studies. PMID- 28888397 TI - Social reorganization and biological change: An examination of stature variation among Iron Age Samnites from Abruzzo, central Italy. AB - Stature is a sensitive indicator of overall environmental quality experienced during growth and development, and can provide insights on a population's 'well being'. This study investigated changes in estimated adult stature in a large (N=568) sample of Samnite Iron Age (800-27 BCE) people from central Italy, during a period of increasing sociopolitical complexity. Stature was analyzed diachronically, between sexes, and across social strata inferred using the 'Status Index' based on funerary treatment. It was expected: 1) a decrease in stature from the Orientalizing-Archaic period (O-A) to the fifth century BC (V SEC) and the following Hellenistic period (ELL), due to population increase and urbanization; 2) social status to positively influence the attainment of the full stature potential; 3) sexual dimorphism to be higher in more stratified groups. Results revealed no significant diachronic changes in stature (females: O-A: 154.2cm,V SEC: 154.2cm, and ELL: 153.6cm; males: O-A: 165.0cm,V SEC: 165.2cm, and ELL: 165.0cm) or sexual dimorphism. High-status males were taller than low-status (p=0.021), possibly due to a better diet, but only in the Orientalizing-Archaic period. Nonsignificant changes in females suggest either differential access to resources in women, or a better buffering from environmental optima or crises. The results of this study highlight the complex interrelation between social factors and human growth, and stress the importance of understanding the specific mechanisms leading to variation in adult stature. PMID- 28888398 TI - Basilar portion porosity: A pathological lesion possibly associated with infantile scurvy. AB - Recent analysis of the juvenile (<=12 years) human remains from a 19th century site in Wolverhampton, England revealed a relatively high level of nutritional deficiency diseases within the population. Indeed, 41.7% of the 48 juvenile skeletons analysed exhibited a combination of porous and proliferative bone lesions consistent with the pathological alterations associated with nutritional stress. This paper describes a pathological lesion on the inferior surface of the basilar portion of the occipital bone, not previously reported in association with infantile scurvy, but which was exhibited by 90% (N=9) of the 10 scorbutic individuals identified during this study. PMID- 28888399 TI - Overlapping genetic pathways in the skeletal dysplasias of a middle woodland individual: A case study. AB - Studies of interacting/overlapping genetic skeletal disorders are rare for populations today, but even more so for archaeological contexts. The skeletal remains of an adult female (EZ 3-7-1) were excavated in the 1980s from the Middle Woodland (50BC-AD400) context of the Elizabeth site (11PK512) in the lower Illinois Valley (LIV), USA. Reported here are the standard score (z-score) comparisons of the measured skeletal differences of EZ 3-7-1 with a reference sample and a re-analysis of the individual's pathological changes, with special consideration placed on refining the disease diagnosis. The impressive preservation and meticulous recovery of these skeletal remains have provided the opportunity to identify the first and earliest archaeological example of an individual (EZ 3-7-1) with a combined genetic skeletal dysplasia, Leri-Weill dyschondrosteosis and achondroplasia. PMID- 28888400 TI - Characterization of inflammasome-related genes in urine sediments of patients receiving intravesical BCG therapy. AB - BACKGROUND: Nowadays, the intravesical Bacillus Calmette-Guerin (BCG) instillation is the method of choice for the postsurgical treatment of high-grade nonmuscle-invasive bladder cancer , to reduce both recurrence rate and risk of progression. BCG is hypothesized to correct the immune system disequilibrium occurring during carcinogenesis, through an immunostimulation with detrimental effects for tumoral cells. Inflammation plays a crucial role in tumor progression. The deregulation of inflammasomes upon carcinogenesis underlines its importance both in physiologic and pathologic human conditions. Nucleotide oligomerization domain-like receptors (NLRs) are key components of this molecular platform and the increase in expression of some members of nucleotide oligomerization domain-like receptors family (NLRP3, NLRP4, NLRP9, and NLR family apoptosis inhibitory protein [NAIP]) in urothelial carcinoma was already demonstrated in our previous work. The first aim of the present work was to estimate whether these inflammasome-related genes show alterations during BCG instillations. The expression levels of NLRP3, NLRP4, NLRP9, and NAIP were assessed in the urine sediments from patients, which underwent surgery for superficial high-grade bladder cancer and further subjected to serial BCG instillations. The eventual association between NLR expression and recurrence was also evaluated. The expression of CK20 mRNA as confirmed marker of bladder cancer was also assayed. METHODS: Urine were sampled from patients harboring high-grade superficial bladder cancer and treated postsurgically with weekly BCG instillations for 6 weeks (induction cycle, I). Urine sediments were processed and resulting RNA was reverse transcribed and used for amplification by real-time PCR. RESULTS: After surgery, CK20 levels decreased significantly whereas NLRP4 and NLRP9 genes showed an increase. NLRP3 and NAIP remained substantially unmodified. CK20 mRNA decreased at the end of the induction cycle. NLRP3 did not show relevant modifications. The expression levels of NLRP4 and NLRP9 decreased significantly after 2 BCG administrations and remained substantially downregulated during the whole induction cycle. CK20 was higher in recurrence cases before BCG administration compared to the recurrence-free group, while no significant difference after BCG therapy was recorded. NLRP4 and NLRP9 were higher in patients with recurrence before BCG administration. CONCLUSIONS: The study underlines the importance of NLRP4 and NLRP9 in urothelial carcinoma and if these preliminary data will be confirmed in larger cohort studies, the assessment of NLRP4 and NLRP9 expression levels could help to predict the BCG failure, playing a relevant role in decision making for early radical surgery. PMID- 28888401 TI - Detection of carbapenemases and other mechanisms of enzymatic resistance to beta lactams in Enterobacteriaceae with diminished susceptibility to carbapenems in a tertiary care hospital. AB - INTRODUCTION: Our objective was to characterize the enzymatic beta-lactam resistance in clinical Enterobacteriaceae isolates with diminished susceptibility to carbapenems from 2013 to 2014 at Hospital Universitario Miguel Servet. MATERIAL/METHODS: A total of 63 clinical isolates were analyzed for the presence of carbapenemases (KPC, OXA-48 and MBL), ESBLs and AmpC enzymes by combined disk methods and PCR detection of carbapenemase-encoding and beta-lactamase-encoding genes. RESULTS: Fifteen isolates had a phenotypic test compatible with carbapenemase production; two of these were confirmed by PCR as OXA-48 producers. ESBL detection was positive in 27 isolates (43%); plasmid-mediated AmpC was detected in nine isolates (14.2%) and derepressed AmpC beta-lactamase was present in 18 isolates (28%). CONCLUSION: During the study period, the decreased susceptibility to carbapenems in Enterobacteriaceae in our area was not due to true carbapenemases but rather to beta-lactamase activity (82.5% were ESBL or AmpC producers), probably in combination with decreased permeability of the outer membrane. PMID- 28888402 TI - Investigating the potential of multiwalled carbon nanotubes based zinc nanocomposite as a recognition interface towards plant pathogen detection. AB - The emergence of nanotechnology has opened new horizons for constructing efficient recognition interfaces. This is the first report where the potential of a multiwalled carbon nanotube based zinc nanocomposite (MWCNTs-Zn NPs) investigated for the detection of an agricultural pathogen i.e. Chili leaf curl betasatellite (ChLCB). Atomic force microscope analyses revealed the presence of multiwalled carbon nanotubes (MWCNTs) having a diameter of 50-100nm with zinc nanoparticles (Zn-NPs) of 25-500nm. In this system, these bunches of Zn-NPs anchored along the whole lengths of MWCNTs were used for the immobilization of probe DNA strands. The electrochemical performance of DNA biosensor was assessed in the absence and presence of the complementary DNA during cyclic and differential pulse voltammetry scans. Target binding events occurring on the interface surface patterned with single-stranded DNA was quantitatively translated into electrochemical signals due to hybridization process. In the presence of complementary target DNA, as the result of duplex formation, there was a decrease in the peak current from 1.89*10-04 to 5.84*10-05A. The specificity of this electrochemical DNA biosensor was found to be three times as compared to non-complementary DNA. This material structuring technique can be extended to design interfaces for the recognition of the other plant viruses and biomolecules. PMID- 28888403 TI - Transitioning From a Level II to Level I Trauma Center Increases Resident Patient Exposure. AB - Increased patient exposure has been shown to improve residency training as determined by better patient outcomes. The transition of John Peter Smith Hospital from a level II to a level I trauma center in 2009 provided a unique opportunity to investigate the direct effects of increased patient exposure on residency training in a relatively controlled setting. We evaluated the effect of the transition to a level I trauma center on residency training. In 2014, we examined the annual facility reports and separated the data into 2 groups: level II (2001 to 2008) and level I (2010 to 2013). The primary outcome measures were patient volume, surgical volume, patient acuity, and scholarly activity by the residents. The patient volume in all units increased significantly (p < .05 for all) after the transition to a level I center. The surgical volume increased significantly for the general surgery, orthopedics, and podiatry departments (p < .05 for all) but remained unchanged in the gynecology and oral maxillofacial surgery departments. The volume measures were performed on all 98 residents (100%). Patient acuity and scholarly activity increased by 17% and 52%, respectively; however, the differences in these data were not statistically significant. The scholarly activity per resident was measured for the orthopedic and podiatry departments. For those departments, the total number of residents was 30, and scholarly activity was measured for 100% of them. Overall, resident education improved when the hospital transitioned to a level I trauma center, although certain subspecialties benefited more than did others from this transition. PMID- 28888404 TI - Expert Tibial Nails for Treating Distal Tibial Fractures With Soft Tissue Damage: A Patient Series. AB - Distal tibial fractures with soft tissue damage are relatively difficult to treat. We assessed the outcomes of patients with these fractures treated with the Expert Tibial Nail(r) (DePuy Synthes, Raynham, MA) from March 2012 to December 2014. At 6 months postoperatively, the general health quality of patients was assessed using operative time, interval to return to work, American Orthopaedic Foot and Ankle Society ankle scale score, pain measured using a visual analog scale, and short-form health outcomes 36-item survey physical functioning and mental health dimension scores. Of 11 cases, 7 (63.6%) were open fractures (3 [27.3%] Gustilo-Anderson type II, 3 [27.3%] type IIIA, and 1 [9.1%] type IIIB) and 4 (36.4%) were closed fractures with Tscherne-Oestern type II tissue damage. Their mean age was 52.2 (range 28 to 66) years. The mean operative time was 83 (range 65 to 105) minutes. The mean follow-up period was 16.3 (range 14 to 18) months. The median short-form 36-item survey scores were 79.1 (range 68.9 to 89.0) for the physical function dimension and 77.0 (range 64.3 to 90.0) for the mental health dimension. The mean postoperative ankle score was 88.6 (range 84 to 94). The mean pain score was 1.6 (range 0 to 4) mm. The mean interval to return to work was 14 (range 11 to 17) months. No patient showed evidence of neurovascular damage, malunion, nonunion, or shortening of the tibia. Taken together, we have confirmed that Expert Tibial Nails can effectively treat distal tibial fractures with soft tissue damage. PMID- 28888405 TI - Anatomic Locking Plate for Displaced Intraarticular Calcaneal Fracture: Design and Application. AB - Calcaneal fracture can lead to long-term disability and have a considerable economic effect. Most calcaneal fractures are intraarticular fractures involving the posterior facet of the subtalar joint. Treating displaced intraarticular calcaneal fractures is complicated because of the lack of an optimal treatment option. Internal fixation typically involves screw-and-plate implants, which can be unfavorable owing to the lack of an anatomic design and the intraoperative bending required for the plate to contour to the irregular surface of the calcaneus. We assessed the outcomes of 30 patients treated using innovative, anatomically designed calcaneal locking plates and the perceived advantages for surgeons. Postoperative computed tomography images of the affected feet were obtained, and the functional performance was recorded. The mean average Bohler angle had increased significantly from 16.8 degrees +/- 14.9 degrees to 28.5 degrees +/- 9.4 degrees (p < .001). The mean average maximal fracture gap and maximal step-off in the posterior facet of the subtalar joint in the coronal computed tomography images also decreased significantly from 2.8 +/- 3.7 mm to 0.8 +/- 1.3 mm (p < .01) and from 3.3 +/- 2.8 mm to 0.8 +/- 1.2 mm (p < .001), respectively. The mean average American Orthopaedic Foot and Ankle Ankle-Hindfoot scale score was 93.9 +/- 7.1 at the final follow-up visit. In addition, the surgical time was reduced because bending the plate was not required and the quality of reduction could be assessed easily by examining the gap between the cortex and the plate. The results were promising, revealing that the anatomic locking plate can be used effectively in the treatment of displaced intraarticular calcaneal fractures using simple reduction techniques with a potentially shortened operating time. PMID- 28888406 TI - Temporal Trends in the Prevalence, Severity, and Localization of Myocardial Ischemia and Necrosis at Myocardial Perfusion Imaging After Myocardial Infarction. AB - The definition, presentation, and management of myocardial infarction (MI) have changed substantially in the last decade. Whether these changes have impacted on the presence, severity, and localization of necrosis at myocardial perfusion imaging (MPI) has not been appraised to date. Subjects undergoing MPI and reporting a history of clinical MI were shortlisted. We focused on the presence, severity, and localization of necrosis at MPI with a retrospective single-center analysis. A total of 10,476 patients were included, distinguishing 5 groups according to the period in which myocardial perfusion scintigraphy had been performed (2004 to 2005, 2006 to 2007, 2008 to 2009, 2010 to 2011, 2012 to 2013). Trend analysis showed over time a significant worsening in baseline features (e.g., age, diabetes mellitus, and Q waves at electrocardiogram), whereas medical therapy and revascularization were offered with increasing frequency. Over the years, there was also a lower prevalence of normal MPI (from 16.8% to 13.6%) and ischemic MPI (from 35.6% to 32.8%), and a higher prevalence of ischemic and necrotic MPI (from 12.0% to 12.7%) or solely necrotic MPI (from 35.7% to 40.9%, p <0.001). Yet the prevalence of severe ischemia decreased over time from 11.4% to 2.0%, with a similar trend for moderate ischemia (from 15.9% to 11.8%, p <0.001). Similarly sobering results were wound for the prevalence of severe necrosis (from 19.8% to 8.2%) and moderate necrosis (from 8.5% to 7.8%, p = 0.028). These trends were largely confirmed at regional level and after propensity score matching. In conclusion, the outlook of stable patients with previous MI has substantially improved in the last decade, with a decrease in the severity of residual myocardial ischemia and necrosis, despite an apparent worsening in baseline features. PMID- 28888407 TI - Comparison of Outcome of Transcatheter Aortic Valve Implantation for Severe Aortic Stenosis in 3 Age Groups (<=70; 71 to 80, and >=81 Years). AB - Transcatheter aortic valve implantation (TAVI) has been widely used for the treatment of aortic stenosis. Most pivotal studies of TAVI included patients with a mean age of over 80 years old. Many young patients may also be considered for TAVI because of severe co-morbidities. We sought to describe a group of patients undergoing TAVI at an age below 70 and to compare them with older patients undergoing the procedure. This study included 1,324 consecutive patients from a 3 center TAVI registry from 2008 to 2014. Patients were divided according to age into 3 groups: patients aged 70 years and below, patients between the ages of 71 and 80, and patients 81 years and older. Patients in the younger group had higher body mass index (p <0.001), higher proportion of previous stroke (p = 0.05), peripheral vascular disease (p = 0.03), and diabetes mellitus (p <0.001). Thirty percent of patients in the younger group had functional class IV. Corticosteroids treatment was 5-fold higher in the younger group (p <0.001). Average valve area was lower in the older group (p = 0.004). Thirty-day mortality was similar between the 3 groups. We found no difference in the rate of in-hospital complications. One-year all-cause mortality rate of patients aged 70 years, 71 to 80 years, and >80 years was 7.6%, 7.5%, and 12.6%, respectively, p = 0.01. In conclusion, younger patients undergoing TAVI exhibited higher prevalence of risk factors and co-morbidities that probably explain the decision to perform TAVI rather than surgical aortic valve replacement. Nevertheless, the 1-year mortality of these patients was significantly lower than in older patients. PMID- 28888408 TI - Atrial Fibrillation and Stent Selection (Bare Metal vs Drug Eluting) (from Medicare Claims). AB - In treating coronary artery disease, many factors influence the choice of bare metal stent (BMS) or drug-eluting stent (DES), including bleed risk and suitability for prolonged dual antiplatelet therapy. Atrial fibrillation (AF) further complicates this choice, due to common use of anticoagulation. We examined stent selection in the United States by AF status and across academic medical centers (AMCs) to explore how cardiologists are managing this complex choice. Using a 100% Medicare denominator file and associated claims (2008 to 2012), we identified patients over age 65 receiving inpatient coronary artery stents. We measured BMS and DES use in patients with AF and in patients without AF and assessed variation in stent choice across AMCs, adjusting for differences in age, gender, and race. We identified 898,788 stent episodes among elderly Medicare beneficiaries. BMS, as a percentage of total inpatient stent episodes, decreased from 2008 to 2012, in patients with AF (42% to 34%) and in patients without AF (32% to 23%). Across AMCs, adjusted stent choice varied substantially, but more so for patients with AF (2008 to 2012 median BMS 44% to 39%, annual interquartile ratios range 1.8 to 2.3) than patients without AF (2008 to 2012 median BMS 33% to 25%, annual interquartile ratios range 2.0 to 1.8). In conclusion, among stent recipients, patients with AF are more likely to receive BMS than patients without AF but treatment varies across systems, suggesting a lack of consensus. Studies of stent choice and outcomes among patients with AF are needed to guide care decisions and optimize outcomes. PMID- 28888410 TI - Three-dimensional printing in contemporary fixed prosthodontics: A technique article. AB - Digital dentistry has gained in popularity among clinicians and laboratory technicians because of its versatile applications. Three-dimensional (3D) printing has been applied in many areas of dentistry as it offers efficiency, affordability, accessibility, reproducibility, speed, and accuracy. This article describes a technique where 3D printing is used to fabricate a die-trimmed cast and to replicate gingival tissue and implant analogs. The digital workflow that replaces the conventional laboratory procedure is outlined. PMID- 28888409 TI - Maxillofacial prosthetic treatment factors affecting oral health-related quality of life after surgery for patients with oral cancer. AB - STATEMENT OF PROBLEM: After oral cancer surgery, tissue defects can cause deformity and limited mobility, complicating many essential functions. For patients with mandibular, tongue, and oral floor defects, evidence regarding the effects of maxillofacial prosthetics on their oral health-related quality of life (OHRQoL) is lacking. Therefore, maxillofacial prosthetic reconstruction has been implemented with no clear treatment goals. PURPOSE: The purpose of this clinical study was to identify factors affecting the improvement of OHRQoL by using maxillofacial prosthetic treatment after surgery to repair maxillary, mandibular, tongue, and oral floor defects. MATERIAL AND METHODS: All individuals who agreed to maxillofacial prosthetics after surgery for oral cancer were enrolled. Oral function and OHRQoL were evaluated before maxillofacial prosthesis placement and 1 month after final adjustments. The oral functions evaluated included masticatory function, swallowing function, and articulatory function. The Oral Health Impact Profile (OHIP-J54) was used to evaluate OHRQoL. Factors affecting changes in the OHIP-J54 score for participants' background and oral functions before and after treatment were analyzed through logistic regression analysis (stepwise method). RESULTS: Participants included 34 men and 16 women with an average age of 72.4 +/-8.7 years. "Psychological discomfort" was correlated with the patient's sex and masticatory function. "Physical disability" was related to articulatory function. "Handicap" was related to the swallowing function. "Additional Japanese questions" were related to the patient's sex. CONCLUSIONS: Participants' sex and their oral functions, including masticatory, swallowing, and articulatory functions, were associated with improved OHRQoL because of maxillofacial prosthetics after surgery for oral cancer. PMID- 28888411 TI - 3D-printed cone-beam computed tomography scans: A tool for patient education. PMID- 28888412 TI - A risk-based decision making tree for managing fractured abutment and prosthetic screws: A systematic review. AB - STATEMENT OF PROBLEM: In implant dentistry, a variety of techniques are used to manage fractured abutment and prosthetic screws. All of them pose various degrees of difficulty to both the clinician and patient and risk involving damage to the implants and prostheses. PURPOSE: The purpose of this systematic review was to classify and organize the various reported techniques for managing fractured abutment and or prosthetic screws into a risk-based, decision making tree that could be used to guide the clinician through this difficult and time-consuming clinical procedure. MATERIAL AND METHODS: A systematic search of the PubMed/MEDLINE database for articles published before June 2016 was performed by 2 independent reviewers. Studies published in English that described a clinical technique to retrieve or manage a fractured abutment or prosthetic screws were included. Techniques were classified according to risk of irreversible damage to the implant. Low-risk techniques were defined as those involving the use of basic hand instruments and instrument modification; moderate-risk techniques were defined as those involving the use of screw retrieval kits, rotary instruments, and screw modification; and high-risk techniques were defined as those involving modification of the implant. Published techniques were then organized into a decision-making tree. RESULTS: A total of 35 articles were included. The reported techniques ranged from straightforward instrumentation and instrument modification to screw or implant modifications. Seven techniques were considered low risk, 17 moderate risk, and 11 high risk. CONCLUSIONS: The proposed risk based decision tree is a useful tool in helping clinicians choose the most appropriate strategy or sequence of strategies that offers maximum benefit to the patient while minimizing associated risks. PMID- 28888413 TI - Digital intraoral scanning technique for edentulous jaws. AB - Few studies have evaluated direct digital scans of edentulous jaws using intraoral scanners because it is difficult to scan edentulous sites that are smooth and devoid of features. A scanning technique is introduced for making direct digital scans of edentulous jaws with intraoral scanners in patients with a broad palate. PMID- 28888414 TI - Use of silver diamine fluoride for the maintenance of dental prostheses in a high caries-risk patient: A medical management approach. AB - A technique for using silver diamine fluoride (SDF) as part of a regimen to help maintain dental prostheses in a patient with scleroderma and at high risk of caries is presented. Medically compromised, xerostomic, or elderly patients generally face greater risk of caries and specifically with prosthetic retainer teeth. SDF is a minimally invasive solution to this problem. A technique is described for using SDF to arrest and prevent new caries with the goal of maintaining fixed and removable prostheses and supporting teeth in a cost effective manner. PMID- 28888415 TI - A chairside technique to add customized anterior acrylic resin teeth to a surgical obturator. AB - A surgical obturator may need to be modified during the healing process after tissue resection. Apart from relining the fitting surfaces to accommodate the healing wound and changes in the surrounding tissues, other modifications such as adding teeth are sometimes required to improve esthetics and speech. This article describes a chairside technique to add customized acrylic resin teeth to an existing surgical obturator. PMID- 28888416 TI - Toll Like Receptors in systemic sclerosis: An emerging target. AB - Pattern Recognition Receptors are critical receptors that elicit an immune response upon their activation that culminates in activation of NF-KB and cytokine secretion. Key among these receptors are the Toll-Like Receptors (TLRs). These evolutionary conserved receptors form a key part in the defence against various pathogens and comprise a key part of the innate immune system. Systemic sclerosis is an autoimmune disease in which a breach of tolerance has occurred and leads to fulminant autoimmunity, dysregulated cytokines, pro-fibrotic mediators and activation of fibroblasts leading to fibrosis via collagen deposition. It has become apparent in recent years that the innate immune system and specifically TLRs are important in disease pathogenesis; responding to internal ligands to initiate an innate immune response ultimately leading to release of a variety of factors that initiate and perpetuate fibrosis. This review will examine the recent evidence of TLR signalling in systemic sclerosis and the internal danger associated molecules that may mediate the fibrotic cascade. Evaluation of their contribution to disease in systemic sclerosis and possible therapeutic targeting will be discussed. PMID- 28888417 TI - American Brachytherapy Society recurrent carcinoma of the endometrium task force patterns of care and review of the literature. AB - PURPOSE: The purpose of this American Brachytherapy Society task force is to present a literature review and patterns of care by a panel of experts for the management of vaginal recurrence of endometrial cancer. METHODS AND MATERIALS: In 2016, the American Brachytherapy Society Board selected a panel of experts in gynecologic brachytherapy to update our current state of knowledge for managing vaginal recurrence of endometrial cancer. Practice patterns were evaluated via an online survey and clinical updates occurred through a combination of literature review and clinical experience and/or expertise. RESULTS: There are various retrospective series of patients treated with radiation for vaginal recurrence of endometrial cancer, which include a varied group of patients, multiple treatment techniques, and a range of total doses and demonstrate a wide scope of local control and overall survival outcomes. In the era of image-guided brachytherapy, high local control rates with low significant late-term morbidities can be achieved. Lower rates of local control and higher late-term toxicity are reported in the retreatment setting. In patients with no previous history of radiation treatment, external beam radiation therapy followed by brachytherapy boost should be used. There are varying practices with regard to the definition and appropriate doses of both the high-risk clinical target volume and the intermediate-risk clinical target volume in the setting of vaginal recurrence of endometrial cancer. There are limited data to provide appropriate dose constraints for some organs at risk with the majority of guidance taken from the definitive cervical cancer literature. CONCLUSIONS: A summary of literature and expert practice patterns for patient selection, dose recommendations, and constraints are provided as guidance for practitioners. PMID- 28888418 TI - Vitamin D supplementation in adult critically ill patients: Should we trust it? PMID- 28888419 TI - Clinical Skills and Professionalism: Assessing Orthopaedic Residents With Unannounced Standardized Patients. AB - OBJECTIVE: We developed a series of orthopedic unannounced standardized patient (USP) encounters for the purpose of objective assessment of residents during clinic encounters. DESIGN: Consecutive case-series. SETTING: NYU-Langone Multi center Academic University Hospital System. PARTICIPANTS: NYU-Langone/Hospital for Joint Diseases Orthopedic Surgery residents; 48 consecutive residents assessed. METHODS: Four orthopedic cases were developed. USPs presented themselves as patients in outpatient clinics. Residents were evaluated on communication skills (information gathering, relationship development, and education and counseling). USPs globally rated whether they would recommend the resident. RESULTS: Forty-eight USP encounters were completed over a 2-year period. Communication skills items were rated at 51% (+/-30) "well done." Education and counseling skills were rated as the lowest communication domain at 33% (+/-33). Residents were globally recommended based on communication skills in 63% of the encounters recommended in 70% of encounters based on both professionalism and medical competence. CONCLUSIONS: The USP program has been useful in assessing residents' clinical skills, interpersonal and communications skills, and professionalism. Use of USP in orthopedic surgery training programs can be an objective means for trainee assessment. PMID- 28888420 TI - Transition to Residency: The Successful Development and Implementation of a Nonclinical Elective in Perioperative Management. AB - OBJECTIVE: Few medical school programs in Canada address challenges related to the significant increase in responsibility for patient care between medical school and residency. This is particularly important in surgery and anesthesia due to the high-acuity care required during the perioperative period. The purpose of this study was to develop and assess a program that would help students transition to surgical and anesthesia residencies, in terms of knowledge acquisition, clinical decision-making skills, and subjective preparedness. DESIGN: The authors developed a 1-week nonclinical Perioperative Management Elective for students matching to surgical or anesthesia residencies. Clinical decision-making training was incorporated using a simulated pager called the MedsOnCall Pager app. A study was conducted to evaluate knowledge acquisition and development of clinical decision-making skills in students completing the elective. A mixed-effects model analysis of the proportion of pages answered correctly during the elective was used as a marker of their progression. Students were asked to complete entry and exit questionnaires to provide subjective information regarding their elective experience. SETTING: The study ran for 2 iterations of the elective in 2016 and 2017 at the University of Ottawa. PARTICIPANTS: A total of 20 University of Ottawa fourth-year medical students completed the elective. RESULTS: There was a significant increase in the proportion of correctly answered pages over the course of the elective week (p = 0.04). Results from entry and exit questionnaires revealed that students felt more knowledgeable, comfortable, and prepared for residency after completing the elective (p < 0.001). CONCLUSIONS: The Perioperative Management Elective has completed 2 successful iterations with confirmed knowledge acquisition and improved clinical decision-making skills among elective students. Participating students perceived that the experience was beneficial and fulfilled a gap in their medical school training. We believe that this elective framework could be employed by other schools to help graduating students' transition smoothly into residency. PMID- 28888422 TI - Exome Sequencing Landscape Analysis in Ovarian Clear Cell Carcinoma Shed Light on Key Chromosomal Regions and Mutation Gene Networks. AB - Previous studies have reported genome-wide mutation profile analyses in ovarian clear cell carcinomas (OCCCs). This study aims to identify specific novel molecular alterations by combined analyses of somatic mutation and copy number variation. We performed whole exome sequencing of 39 OCCC samples with 16 matching blood tissue samples. Four hundred twenty-six genes had recurrent somatic mutations. Among the 39 samples, ARID1A (62%) and PIK3CA (51%) were frequently mutated, as were genes such as KRAS (10%), PPP2R1A (10%), and PTEN (5%), that have been reported in previous OCCC studies. We also detected mutations in MLL3 (15%), ARID1B (10%), and PIK3R1 (8%), which are associations not previously reported. Gene interaction analysis and functional assessment revealed that mutated genes were clustered into groups pertaining to chromatin remodeling, cell proliferation, DNA repair and cell cycle checkpointing, and cytoskeletal organization. Copy number variation analysis identified frequent amplification in chr8q (64%), chr20q (54%), and chr17q (46%) loci as well as deletion in chr19p (41%), chr13q (28%), chr9q (21%), and chr18q (21%) loci. Integration of the analyses uncovered that frequently mutated or amplified/deleted genes were involved in the KRAS/phosphatidylinositol 3-kinase (82%) and MYC/retinoblastoma (75%) pathways as well as the critical chromatin remodeling complex switch/sucrose nonfermentable (85%). The individual and integrated analyses contribute details about the OCCC genomic landscape, which could lead to enhanced diagnostics and therapeutic options. PMID- 28888421 TI - Neural crest and cancer: Divergent travelers on similar paths. AB - Neural crest cells are multipotent progenitors that dynamically interpret diverse microenvironments to migrate significant distances as a loosely associated collective and contribute to many tissues in the developing vertebrate embryo. Uncovering details of neural crest migration has helped to inform a general understanding of collective cell migration, including that which occurs during cancer metastasis. Here, we discuss several commonalities and differences of neural crest and cancer cell migration and behavior. First, we focus on some of the molecular pathways required for the initial specification and potency of neural crest cells and the roles of many of these pathways in cancer progression. We also describe epithelial-to-mesenchymal transition, which plays a critical role in initiating both neural crest migration and cancer metastasis. Finally, we evaluate studies that demonstrate myriad forms of cell-cell and cell-environment communication during neural crest and cancer collective migration to highlight the remarkable similarities in their molecular and cell biological regulation. PMID- 28888424 TI - Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein. AB - MRPP2 (also known as HSD10/SDR5C1) is a multifunctional protein that harbours both catalytic and non-catalytic functions. The protein belongs to the short chain dehydrogenase/reductases (SDR) family and is involved in the catabolism of isoleucine in vivo and steroid metabolism in vitro. MRPP2 also moonlights in a complex with the MRPP1 (also known as TRMT10C) protein for N1-methylation of purines at position 9 of mitochondrial tRNA, and in a complex with MRPP1 and MRPP3 (also known as PRORP) proteins for 5'-end processing of mitochondrial precursor tRNA. Inherited mutations in the HSD17B10 gene encoding MRPP2 protein lead to a childhood disorder characterised by progressive neurodegeneration, cardiomyopathy or both. Here we report two patients with novel missense mutations in the HSD17B10 gene (c.34G>C and c.526G>A), resulting in the p.V12L and p.V176M substitutions. Val12 and Val176 are highly conserved residues located at different regions of the MRPP2 structure. Recombinant mutant proteins were expressed and characterised biochemically to investigate their effects towards the functions of MRPP2 and associated complexes in vitro. Both mutant proteins showed significant reduction in the dehydrogenase, methyltransferase and tRNA processing activities compared to wildtype, associated with reduced stability for protein with p.V12L, whereas the protein carrying p.V176M showed impaired kinetics and complex formation. This study therefore identified two distinctive molecular mechanisms to explain the biochemical defects for the novel missense patient mutations. PMID- 28888423 TI - Transposons As Tools for Functional Genomics in Vertebrate Models. AB - Genetic tools and mutagenesis strategies based on transposable elements are currently under development with a vision to link primary DNA sequence information to gene functions in vertebrate models. By virtue of their inherent capacity to insert into DNA, transposons can be developed into powerful tools for chromosomal manipulations. Transposon-based forward mutagenesis screens have numerous advantages including high throughput, easy identification of mutated alleles, and providing insight into genetic networks and pathways based on phenotypes. For example, the Sleeping Beauty transposon has become highly instrumental to induce tumors in experimental animals in a tissue-specific manner with the aim of uncovering the genetic basis of diverse cancers. Here, we describe a battery of mutagenic cassettes that can be applied in conjunction with transposon vectors to mutagenize genes, and highlight versatile experimental strategies for the generation of engineered chromosomes for loss-of-function as well as gain-of-function mutagenesis for functional gene annotation in vertebrate models, including zebrafish, mice, and rats. PMID- 28888425 TI - Prevalence and incidence of urinary tract and genital infections among patients with and without type 2 diabetes. AB - OBJECTIVE: Epidemiological data on genitourinary infections (GUIs) comparing patients with and without type 2 diabetes (T2DM) is scant. We aimed to estimate the incidence of urinary tract infections (UTIs), genital infections (GIs), or any GUI in total and stratified by history of GUI and sex. RESEARCH DESIGN AND METHODS: We identified 39,295 patients in the Kaiser Permanente Northwest health plan with T2DM and an equal number of age and sex matched patients without diabetes. The cohort was followed for up to 9years (2006-2014). We calculated incidence rates and corresponding 95% confidence intervals (CI) of any GUI, UTIs and GIs adjusting for age, sex, race, BMI, presence of chronic kidney disease, annual number of outpatient visits, and diuretic use. RESULTS: Adjusted incidence of any GUI was 97.2/1000person-years (p-y) (95% CI 95.5-98.8) among the T2DM cohort vs. 79.7/1000 p-y (78.3-81.2) among those without diabetes. T2DM was associated with an adjusted 25% increased risk of UTI (rate ratio 1.25, 95% CI 1.22-1.29), a 26% increased risk of GI (1.26, 1.22-1.31) and a 22% increased risk of any GUI (1.22, 1.19-1.25). Incidence rates were lower among those with no GUI history, but the relative risks were similar. Women in both groups had higher incidence rates of GUIs than men. CONCLUSIONS: T2DM was associated with increased risks of any GUI, UTIs and GIs. Incidence rates of UTIs were higher than rates of GIs, but the relative risk of GIs was essentially identical. A similar pattern was observed when stratifying by sex. SIGNIFICANCE OF THE STUDY: RESEARCH QUESTIONS. PMID- 28888426 TI - Sudden sensorineural hearing loss in children and adolescents: Clinical characteristics and age-related prognosis. AB - OBJECTIVE: Although many studies have investigated sudden sensorineural hearing loss (SSNHL) in adults, there were few studies on SSNHL in the pediatric population; especially research on treatment and prognosis of pediatric SSNHL was limited. The aim of this study was to evaluate clinical characteristics, treatment outcomes and prognostic factors in children and adolescents with SSNHL. METHODS: A retrospective review of medical records of 67 pediatric patients (67 ears) who had diagnosed with SSNHL at our hospitals was performed to analyze patients' clinical manifestations and audiograms. All patients were treated with high-dose systemic prednisolone (1mg/kg), and 17 of them underwent intratympanic steroid injection therapy. Audiological evaluation was carried out before and after treatment, and hearing recovery was defined as complete recovery and partial recovery according to Siegel's criteria. Patients were divided into two groups: childhood group (ages between 4 and 12 years old) and adolescence group (age>12years), and clinical characteristics and treatment outcomes were investigated. In addition, patients were divided into two groups according to degree of hearing recovery, and evaluation was made regarding possible prognostic factors. RESULTS: The recovery rate in total 67 patients was 55.2%. The recovery rate of the childhood group was significantly lower than that of the adolescence group (p=0.038). While the presence of vertigo did not significantly correlate with prognosis (p=0.219), the presence of tinnitus was significantly associated with hearing recovery (p=0.005). Audiological assessment revealed that a low initial hearing threshold, high speech discrimination score, and descending type of audiogram were positively associated with hearing recovery (p=0.002, p=0.003, and p=0.029, respectively). CONCLUSION: The childhood group had worse treatment outcomes than the adolescence group. High initial hearing threshold and absence of tinnitus were poor prognostic factors of hearing recovery. Active treatment is required for patients with these poor prognostic factors and childhood patients with SSNHL. PMID- 28888427 TI - Scientific considerations for the regulatory evaluation of cell therapy products. AB - Cell therapy involves the administration of a viable somatic cell preparation to a patient for the treatment of a disease or traumatic damage. Because cell therapies are complex and very different from traditional biological products, they present significant challenges for regulatory authorities, manufacturers, developers, health care providers, and patients involved in their application. Like other emerging areas of biomedical research and development, there are many issues where regulatory views and decisions among countries and regions may differ due to minimal scientific evidence to support safety and efficacy, and lack of experience with these novel treatments. A brief overview of the current regulatory landscape for cell-based therapies is presented, and the need for a global effort to develop a set of common principles that may serve to facilitate the regulatory evaluation and market availability of these products is identified. In addition, a number of elements that could form a core consensus package of requirements for evaluating human cell therapy products is presented in the supplemental material which should be read in conjunction with the manuscript. PMID- 28888429 TI - Taste receptors in the gut - A new target for health promoting properties in diet. AB - In this review we describe a new target for food functionality, the taste receptors in the gastrointestinal tract. These receptors are involved in an intricate signalling network for monitoring of taste and nutrient intake, homeostasis and energy metabolism, and they are also an early warning system for toxic substances in our diet. Especially the receptors for bitter taste provide a new possibility to activate a number of health related signalling pathways, already at low concentrations of the active substance, without requiring uptake into the body and transport via the circulation. When ligands bind to these receptors, signalling is induced either via peptide hormones into the circulation to other organs in the body, or via nerve fibers directly to the brain. PMID- 28888428 TI - Displacement comparison of CAD-CAM titanium and zirconia abutments to implants with different conical connections. AB - PURPOSE: To compare the displacements of CAD-CAM zirconia and titanium abutments into different internal connection systems after torquing. METHODS: OsseoSpeed EV and OsseoSpeed TX implants (n=10) were placed in resin blocks. Zirconia and titanium abutments (n=5) were first hand tightened and then tightened to the recommended torque (20Ncm for TX and 25Ncm for EV). Displacements of abutments between screw tightening by hand and torque driver was measured using three dimensional digital image correlation (3D DIC) technique. Displacements were measured in U (front/back), V (into/outward), W (right/left) directions and 3 dimensionally (3D). ANOVA with restricted maximum likelihood estimation method was used to analyze the data. Bonferroni-corrected t tests was used to determine the statistical differences (alpha=0.05). RESULTS: 3D displacement of zirconia and titanium abutments was significantly greater in OsseoSpeed EV implant (P<0.001). Displacement of zirconia and titanium abutments was not significantly different within implant systems, 3D (P>=0.386) and in each direction (P>=0.382). In U and V directions, zirconia and titanium abutments displaced significantly more towards negative in OsseoSpeed EV implant (P<0.019). Within the OsseoSpeed TX system, abutments displaced significantly more in V direction compared to the U and W (P<=0.005), and within the Osseospeed EV system, abutment displacements were significantly different amongst directions and displacements in V were the greatest (P<0.001). CONCLUSION: Abutments displaced more in the implant that required higher torque values to tighten the abutment. The amount of displacement in both systems was clinically small. Abutment material did not affect the magnitude of displacement. PMID- 28888430 TI - Vacuum facilitated infusion of bioactives into yeast microcarriers: Evaluation of a novel encapsulation approach. AB - Encapsulation into yeast microcarriers provides an appealing alternative to biomimetic systems by employing natural, pre-formed vehicles for the stabilization and delivery of bioactives compounds. However, current (diffusion limited) methods of encapsulation using yeast require long time scales and heating which lead to poor encapsulation efficiencies and yields. This study evaluates the usage of vacuum infusion to encapsulate two model bioactives, curcumin and fisetin, into yeast and yeast cell wall particles and the physical parameters, e.g. vacuum level, concentration of carrier solvent, log p value of bioactive, etc., which facilitate the process of vacuum infusion. Encapsulation efficiencies were determined using UV-vis spectrophotometry. Localization of bioactives within yeast microcarriers was determined using confocal and multiphoton (two-photon) microscopy. 99% vacuum, or 1.0kPa, and 35% ethanol (v/v) provide the optimal conditions for the encapsulation of both curcumin and fisetin; compared to the diffusion-limited method, vacuum infusion is able to encapsulate 3* more curcumin and 2* more fisetin into yeast microcarrier and requires 288-fold less time. Enhanced encapsulation efficiencies and yield as well as rapid encapsulation process technology presented in this study can transform the use of cell based carriers for encapsulation and delivery of bioactives. PMID- 28888431 TI - Thermal Pest Control in 'Tannat' grapes: Effect on anthocyanins, sensory and color of one-year-old wines. AB - Thermal pest control (TPC) is a technology that applies heated air in the vineyard to reduce pests. However, it can also alter grape anthocyanin synthesis in answer to temperature stress. The aim of this work was to determine the impact of TPC in 'Tannat' grape vineyards on wine quality. The major makers of quality considered in this study were the wine anthocyanin characterization by HPLC-PDA MSn, beverage's sensory evaluation by descriptive analysis, and color parameters by instrumental analysis. A total of three experiments were performed in different harvesting years. In 2011/12 (Experiment I), four applications were performed from the flowering to fruiting. For the second experiment (2012/13), five applications were used only during fruiting. TPC treatment performed in 2013/14 (Experiment III) had a total of 19 applications from the flowering to harvesting. In the first experiment, TPC had increased wine pigments, color, and sensorial descriptors for visual (translucence) and gustatory (woody and body) perceptions. However, in the second experiment none of the evaluated wine quality parameters was affected by TPC (p<=0.05). In the last and longest experiment (19 applications), TPC has significantly increased some wine pigments content. Nonetheless, wine sensorial parameters were not affected. Since the climate was different among the years, it seems that TPC effect does not depend on the applications number and vegetable cycle period only, but also it can be affected by the weather conditions in which the vine is being cultivated. However, when TPC treatment has resulted in the greatest anthocyanin increment (Experiment I) some wine sensory descriptors were also improved. PMID- 28888432 TI - Incorporation of water-in-oil-in-water (W1/O/W2) double emulsion in a set-type yogurt model. AB - The effect of W1/O/W2 emulsion incorporation in set-type yogurt on the acidification process, physicochemical properties, bacterial growth kinetics and structural characteristics was investigated. The W1/O/W2 emulsion was formed by using a two-step homogenisation process and milk as the W1 and W2 phases, and stability was monitored with optical microscopy and cryo-SEM. Adding the W1/O/W2 emulsions reduced the acidification rate, viscosity and water retention capacity. Texture (adhesiveness, cohesiveness, hardness, and gumminess) differed in yogurts containing W1/O/W2 emulsion compared to controls during the acidification process, however, trends became stable during storage. The growth of S. thermophilus during the acidification process of yogurt was reduced in the presence of W1/O/W2 emulsion while L. bulgaricus trended higher during storage. This study shows that yogurts containing W1/O/W2 emulsion are feasible subject to processing modification. PMID- 28888433 TI - Apple pectin-derived oligosaccharides produce carbon dioxide radical anion in Fenton reaction and prevent growth of Escherichia coli and Staphylococcus aureus. AB - Pectin is the main soluble fiber in apples or citruses. It may be fermented by gut microbiota to metabolites showing local intestinal and systemic effects. A wide range of beneficial effects of dietary pectin includes impacts on the redox milieu and microbiota profile. We prepared pectin-derived oligosaccharides (apple (APDO) and citrus) and polygalacturonic acid-derived oligosaccharides, using alkaline hydrolysis by hydrogen peroxide, and analyzed them by Fourier Transform Infrared spectrometry. Furthermore, we analyzed the effects of pectin-derived oligosaccharides on hydroxyl radical (HO)-generating Fenton reaction using electron paramagnetic resonance spin-trapping spectroscopy, and the effects on the growth of Escherichia coli and Staphylococcus aureus in the presence of dietary-relevant HO-generating system (iron+ascorbate). The oligosaccharides react with HO radical to produce carbon dioxide radical anion (CO2-). A comparative analysis showed that APDO has the most prominent bacteriostatic effect. This might be at least partially related to the higher capacity of APDO to produce CO2-, which specifically targets proteins and appears to have a longer lifetime and larger diffusion radius in biological systems compared to HO. PMID- 28888434 TI - Ensuring food safety in food donations: Case study of the Belgian donation/acceptation chain. AB - The food donation process in Belgium is mapped and analyzed to identify bottlenecks in compliance with the legal framework and implementation of food safety management, based on literature search and interviews with stakeholders (donors, acceptors, regulators and facilitators) in Belgium and at EU level. The study revealed that the food donation/acceptation chain is far less structured and organized than the conventional food supply chain. The fragmented landscape of many small food banks and charity organizations (acceptors), often directed by and working with volunteers without training in food safety and lack of knowledge of legal food hygiene requirements is a bottleneck to generate trust among food donors and restricts the provision of perishable products in food donations. Lack of refrigerated transport and insufficient cold/freezing capacity in food banks and charity organizations was identified as a barrier to distribute perishable products. Furthermore, in two cities in Flanders (Belgium), at some food donation centers, donated perishable food samples (n=72) were taken and subjected to microbiological analysis to determine their overall food quality, hygiene and food safety status. Twenty-two of 72 analyzed samples showed marginal microbiological quality based on numbers of yeast, lactic acid bacteria or total viable count. In three samples Listeria monocytogenes was detected per 25g among which one ready-to-eat cooked meat product which showed increased numbers of L. monocytogenes (3.5logCFU/g) and Enterobacteriaceae (6.7logCFU/g). Overall, in Belgium, most of the donated foods considers nonperishable foods, with more or less half of the food collected by the food banks being purchased with funds from FEAD (Fund for European Aid to the Most Deprived) and thus not derived from food losses. Efforts are being made by facilitators to provide a platform for better coordination of donors and acceptors to make more efficient use of food losses. Regulators at the national level are taking action to clarify and provide some flexibility in food hygiene regulation and initiatives on EU level to facilitate food donation in the combat of food losses are pending. As from the side of the acceptors, it is recommended to professionalize the acceptation chain in Belgium and seek for a more harmonized approach and concerted action. PMID- 28888435 TI - Resuscitation and growth kinetics of sub-lethally injured Listeria monocytogenes strains following fluorescence activated cell sorting (FACS). AB - This study investigated the effect of acid (pH4.2), osmotic (10% NaCl) and heat (55 degrees C for 30min) stress induced injury on Listeria monocytogenes strains ATCC19115, 69, 159/10 and 243 using differential plating and flow cytometry coupled with membrane integrity indicators, thiazole orange (TO) and propidium iodide (PI) staining. Growth kinetics of injured cells sorted by fluorescence activated cell sorting (FACS) were studied at 4, 25 and 37 degrees C. The percentage of cell injury detectable by both flow cytometry and differential plating varied significantly among strains and stress treatments (p<0.0001). Based on flow cytometry and TO/PI staining, acid stress caused the highest level of injury followed by heat and osmotic stress. Following cell sorting, acid and osmotic stress injured cells were capable of resuscitation and re-growth while heat injured cells (except for strain 69) were incapable of re-growth despite having a high level of membrane intact cells. The lag phase duration (lambda) of sorted stress injured cells resuscitated in brain heart infusion (BHI) broth was significantly influenced by strain variations (p<0.0001), stress treatments (p=0.007) and temperature of resuscitation (p<=0.001). Following repair, the maximum specific growth rate (MUmax) of resuscitated cells was not different from untreated control cells regardless of strain differences and stress treatments. Only temperature had a significant effect (p<0.0001) on growth rate. Sorted cells were also capable of growth at 4 degrees C, with the time to detectable growth (>=1.40Log10CFUml-1) ranging from 3 to 15days. Overall, re-growth potential of sorted cells showed that while membrane integrity was a good indicator of cell injury and viability loss for acid and osmotic stress, it was not a sufficient indicator of heat stress injury. Once injured cells repair the cellular damage, their growth rate is not different from non-injured cells regardless of form of stress and strain differences. Thus highlighting the potential food safety risks of stress injured L. monocytogenes cells. PMID- 28888436 TI - The influence of ripening stage and region on the chemical compounds in mulberry fruits (Morus atropurpurea Roxb.) based on UPLC-QTOF-MS. AB - Mulberries (Morus atropurpurea Roxb.) are rich in beneficial nutrients and secondary metabolites. Dramatic climate differences between western and eastern China lead to differences among the fruiting habits of mulberries grown in these regions. In this study, Xinjiang and Jiangsu, two regions in western and eastern China, respectively, were selected as sites where mulberry fruits (MFs) at different ripening stages were sampled. Their individual components, including both targeted and non-targeted chemical compounds, were detected by rapid ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Multivariate statistical analyses, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS DA) were used to compare MFs during ripening from these two regions. Potential biomarkers, which significantly contributed to the differentiation of the samples, were further identified or tentatively identified to determine the effects of ripening stages and regions on the chemical compounds in MFs. The results show that 43 compounds classified into nine different groups were identified in the MF samples from both the Xinjiang and Jiangsu regions. Among the compounds, all anthocyanins, carbohydrates and dihydroflavonols increased while phenolic acids and hydroxycoumarins decreased during ripening. Caffeoylquinic acids and some of anthocyanins could be regarded as important markers for MF ripening, and the accumulation of organic acids differentiated the samples from the two regions. Together, UPLC-QTOF-MS coupled with multivariate statistical analyses may be effective for metabolite profiling and identification of ripening degrees and cultivation regions. PMID- 28888437 TI - Differences in the metabolic profiles and antioxidant activities of wild and cultivated black soybeans evaluated by correlation analysis. AB - Wild soybeans are considered a potential resource for soybean domestication and an important source of genetic diversity for soybean crop improvement. Understanding metabolite-caused bioactivity differences between cultivated and wild soybeans is essential for designing a soybean with enhanced nutritional traits. In this study, the non-targeted metabolic profiling of 26 soybean varieties, 15 wild black soybeans (WBS) and 11 cultivated black soybeans (CBS), using liquid chromatography-mass spectrometry (LC-MS) in combination with multivariate analysis revealed significant differences in 25 differential metabolites. Among these, the soyasaponins Ab and Bb were found to be characteristic metabolites expressed more substantially in CBS than in WBS. Three different antioxidant assays and correlation analysis identified major and minor antioxidants that contributed to WBS having an antioxidant activity 4- to 8-fold stronger than that of CBS. Epicatechin, procyanidin B2, and cyanidin-3-O glucoside were identified by both association analysis and the online LC-ABTS radical scavenging assay as being major antioxidants. PMID- 28888438 TI - Impact of legume protein type and location on lipid oxidation in fish oil-in water emulsions: Lentil, pea, and faba bean proteins. AB - Emulsion-based delivery systems are being developed to incorporate omega-3 fatty acids into functional foods and beverages. There is interest in formulating these delivery systems from more sustainable and label-friendly ingredients. The aim of this study was therefore to examine the impact of plant-protein emulsifiers on the oxidative stability of 1wt% fish oil-in-water emulsions. Fish oil emulsions stabilized by three types of legume protein (lentil, pea, and faba bean) were produced using a high-pressure microfluidizer. The formation of primary (peroxides) and secondary (TBARS) lipid oxidation products was measured when the emulsions were stored at 37 degrees C under accelerated (+100MUM iron sulfate) or non-accelerated (no added iron) conditions for 21 or 33days, respectively. The particle size, charge and microstructure of the emulsions were monitored during storage using light scattering and microscopy to detect changes in physical stability. Emulsions stabilized by whey protein isolate, a commonly used animal based protein, were utilized as a control. The emulsions formed using whey protein had smaller initial particle sizes, better physical stability, and slightly better stability to lipid oxidation than the ones formed using plant based proteins. The impact of protein location (adsorbed versus non-adsorbed) on the oxidative stability of the emulsions was also investigated. The presence of non-adsorbed proteins inhibited lipid oxidation, presumably by binding transition metals and reducing their ability to interact with omega-3 fatty acids in the lipid droplets. Overall, these results have important implications for fabricating emulsion-based delivery systems for bioactive lipids, e.g., they indicate that including high levels of non-adsorbed proteins could improve oxidative stability. PMID- 28888439 TI - Preparation, characterization and alcoholic liver injury protective effects of algal oligosaccharides from Gracilaria lemaneiformis. AB - Oligosaccharides derived from seaweeds possess diverse biological functions. However, little is known about their effects on liver damage. In this study, algal oligosaccharides (AOS) were prepared from Gracilaria lemaneiformis by biodegradation approaches. HPLC analysis showed AOS were composed of agarooligosaccharides and neoagarooligosaccharides. In vivo animal studies showed AOS significantly attenuated alcohol-induced hepatopathy in mice to some extent, as revealed by the normalization of several serum liver-damage markers. Besides, AOS increased antioxidant levels of hepatic glutathione (GSH) and superoxide dismutase (SOD), and ameliorated the elevated formation of malonaldehyde (MDA), suggesting AOS attenuated hepatopathy mainly through their antioxidant activities. Interestingly, AOS could also enhance the activities of hepatic alcohol dehydrogenase (ADH). Histological examination of liver tissues showed AOS reduced the alcohol-induced liver injury in a dose-dependent manner. Moreover, the comparison of different administration strategies suggested AOS were best taken 2h before alcohol consumption. Therefore, our study provided a novel nutritional strategy for reducing alcohol-induced hepatotoxicity. PMID- 28888440 TI - Current applications and new opportunities for the thermal and non-thermal processing technologies to generate berry product or extracts with high nutraceutical contents. AB - The demand from consumer for safe and nutritious berry and berry products has promoted the rapid development of non-conventional processing technologies. This review summarizes the recent advances of thermal and non-thermal processing technologies in berry and berry products, including microwave, ohmic heating, high pressure processing, irradiation, dense phase carbon dioxide, ultrasonic processing, pulsed electric field, ozone, membrane processing technologies, cold plasma, and hydrothermodynamic cavitation. These technologies individually or in combination have shown great potential for extraction, sterilization, drying, concentration and deacidfication. They could decrease processing time and temperature, improve processing efficiency and minimize nutritional losses, as well as reduce energy consumption. Given the nutritional benefits of anthocyanins and other polyphenols in berry, their content and compositional change during processing were highlighted, as well as the primarily studies of the underlying mechanisms. The advantage and limitation of these technologies are also discussed along with the perspective insight of their future development. PMID- 28888441 TI - Effect of clarified Brazilian native fruit juices on postprandial glycemia in healthy subjects. AB - Brazilian native fruits have been shown as excellent sources of polyphenols which are associated with multiple biological activities including inhibition of carbohydrate-hydrolyzing enzymes, alpha-amylase and alpha-glucosidase. Postmeal blood glucose elevations and high glycemic index diets can play a major role in the development of type 2 diabetes, therefore alternative approaches to reduce postprandial hyperglycemia are of growing interest in order to reduce diabetes risk. Here we investigated the effect of six Brazilian native clarified fruit juices from Amazon, Savannah and Atlantic Forest biomes on postprandial glycemia after consumption of a carbohydrate meal. For this, 23 healthy subjects were selected to consume seven meal tests, with a 1-week interval among them, consisting in 50g white bread plus 300mL of water (control) or cambuci, cagaita, maracuja-alho, cupuacu, camu-camu and jaboticaba clarified fruit juices. The results showed that serum glucose concentrations were significantly lower after consumption of cambuci, cagaita, camu-camu and jaboticaba juices, whereas maracuja-alho and cupuacu juices did not decrease the amount of glucose absorbed, compared to control (p<0.05). In addition, cagaita, cambuci, cupuacu and jaboticaba juices increased the oxygen radical absorbance capacity in plasma, whereas all juices augmented the ferric reducing ability of plasma, except for cambuci (p<0.05). These results indicate that juices from Brazilian native fruits may be considered as adjuvant treatment for reduction of postprandial glycemia in healthy subjects. PMID- 28888442 TI - Fermented pearl millet (Pennisetum glaucum) with in vitro DNA damage protection activity, bioactive compounds and antioxidant potential. AB - In the present study, pearl millet cultivar PUSA-415 was fermented by solid state fermentation (SSF) process using Aspergillus sojae (MTCC-8779) as starter culture. The fermentation was carried out for the period of ten days. The effect of SSF on phenolic content, condensed tannin content, antioxidant potential and DNA damage protection of pearl millet during different fermentation period was determined. Results showed that SSF and thermal processing significantly affect the bioactive profile and antioxidant potential of bio-transformed pearl millet. Extracts prepared from 6th days fermented pearl millet flour exhibited the highest TPC, antioxidant potential and DNA damage protection activity. Qualitative and quantitative analysis of bioactive compounds were done by HPLC. During SSF, production of enzymes (alpha-amylase, beta-glucosidase and xylanase) as well as specific bioactive compounds (ascorbic acid, gallic acid and p Coumaric acid) was significantly increased. Thus, bio-transformed Aspergillus sojae fermented pearl millet could be used in preparation of functional foods and novel nutraceuticals in health promotions. Chapatti was formulated from unfermented as well as fermented flour and the effect of thermal processing on bioactive compounds and antioxidant potential was studied. Thermal processing resulted in decrease in TPC of both, AFM and UFM by 4.75-16.27% and increase in CTC by 38.52-67.41%. PMID- 28888443 TI - Flow properties and chemical composition of carob (Ceratonia siliqua L.) flours as related to particle size and seed presence. AB - Due to abundance in carbohydrates, dietary fibres and bioactive compounds, as well as for its outspread and low prices, carob (Ceratonia siliqua L.) flour has a great potential of use as a functional ingredient. The aim of this study was to analyse this potential by physical and chemical properties assessment of different particle sizes of carob flour with and without seeds. The influence of seed presence on physical and chemical properties of flour was also investigated. Seed presence in carob flour led to higher cohesivity and cake strength. It also affected the extraction efficiency of polyphenols, which was confirmed by the ranking of samples according to their procyanidin and tannins contents. With regard to the carbohydrate content, significant differences (P<0.05) between the contents of fructose and glucose was established in samples differing by the presence of carob seeds. Spearman rank order correlations revealed a significant difference (P<0.05) between physical and chemical properties of carob flours. These findings confirm the importance of understanding physical and chemical properties of carob flours in order to use them efficiently as a functional food ingredient. PMID- 28888444 TI - Metal ions accelerated phytosterol thermal degradation on Ring A & Ring B of steroid nucleus in oils. AB - This study aimed to investigate the effect of metal ions on the degradation of phytosterols in oils. The oil was heated at 180 degrees C for 1h with/without addition of Fe3+, Fe2+, Cu2+, Mn2+, Zn2+, Na+, Al3+ and Mg2+. Variations of beta sitosterol, stigmasterol, campesterol, brassicasterol and their degradation products were confirmed by the GC-MS analysis. In general, the increase of the metal ion concentration resulted in more phytosterol degradation, and the ability of metal ions following decreasing order: Fe3+>Fe2+>Mn2+>=Cu2+>=Zn2+>Na+>=Mg2+>Al3+. Metal ions significantly induced phytosterol autoxidation on C5, C6 and C7 on Ring B of steroid nucleus at even a low concentration, and induced dehydration on the C3 hydroxyl to form dienes and trienes at high concentration. The metal ions in oils are accounted for increasing phytosterol degradation, which decreases food nutritional quality and gives rise to the formation of undesirable compounds. PMID- 28888445 TI - Eating flowers? Exploring attitudes and consumers' representation of edible flowers. AB - Edible flowers have gained more attention in recent years thanks to their perceived health benefits. Despite this attention, it seems that edible flowers are not popularized for consumption in South America, being considered unfamiliar for some cultures from this continent. In this context, the general goal of the present study was to investigate the three dimensions of social representation theory, the representational field, the information and the attitude of the two conditions of edible flowers: a more general "food made with flowers" and more directional product "yoghurt made with flowers", using Brazilian consumers. To achieve this goal, a free word association task was applied. A total of 549 consumers participated in this study. Participants were divided into two conditions, in which the inductor expressions for the free word association task changed: (a) food products made with flowers and (b) yoghurt made with flowers. Results showed a very positive attitude to both situations, and consumers associated Food products made with flowers to "health care" while the central core of yoghurt made with flowers reflected the innovative condition of this product, supported here by their unpredictable character (information generated). PMID- 28888446 TI - Changes in anthocyanins and volatile components of purple sweet potato fermented alcoholic beverage during aging. AB - Purple sweet potato was fermented into alcoholic beverage. By using LC-MS analysis, 12 types of anthocyanins were found in the purple sweet potato alcoholic beverage (PSPFAB); these were based on cyanidin and peonidin as aglycones. The anthocyanins in young PSPFAB mainly consisted of acylates. The acylated anthocyanins, however, degraded gradually with aging. Cyanidin 3 sophoroside-5-glucoside and peonidin 3-sophoroside-5-glucoside were found to be major anthocyanins in the PSPFAB after two years of aging. Moreover, 52 kinds of volatile components were detected in PSPFAB by GC-MS analysis. Alcohol and ester substances constituted a major proportion of these volatile components of PSPFAB. After two years of aging, levels of high-alcohols such as 1-pentanol remarkably decreased to below the detection limit, while the level of total esters increased significantly. Such variation of aromas enriched and improved the flavor of PSPFAB. PMID- 28888447 TI - Projective mapping based on choice or preference: An affective approach to projective mapping. AB - This work explores a new affective approach to projective mapping, based on consumers' choices or preferences. Two sessions, one week apart, were performed with the same consumers, using whole bread as a case study. Overall liking ratings (OL) were gathered in blind conditions and samples were also profiled by a trained panel using generic descriptive analysis. Three projective mapping tests were performed in different scenarios. Consumers' categorization and product descriptions were explored when consumers based their positioning on the products' similarities and differences (analytical approach, "classic napping") both in blind and informed conditions, and when consumers were focusing on their preference or choice (affective approach). The affective approach to projective mapping successfully revealed consumers' drivers of liking and choice from a holistic perspective, where consumers summarized their main drivers for categorizing products as they would do when choosing in real life situations, based on their preferences. PMID- 28888448 TI - Effect of explosion-puffed coffee on locomotor activity and behavioral patterns in Drosophila melanogaster. AB - We hypothesized that the administration of explosion-puffed coffee, containing gamma-aminobutyric acid (GABA) and 5-hydroxytryptophan (5-HTP), would be associated with a reduction of the caffeine effect on sleep behavior and behavioral patterns, which was investigated in a Drosophila model. The effects of feeding roasted coffee beans (RB), explosion-puffed coffee beans puffed at 0.75MPa and 0.9MPa (PB 7.5 and PB 9.0, respectively), or decaffeinated coffee beans (DeRB) on locomotor activity and behavioral patterns of Drosophila was analyzed. In the decreasing order, the total chlorogenic acid (caffeoylquinic acids, CQA) content was PB 7.5>PB 9.0>RB. PB content analysis showed high levels of GABA and 5-HTP, compared with that of RB, which corresponded with the sleep wake behavior of Drosophila. The RB and PB (PB 7.5 and PB 9.0) groups were not significantly different with respect to an activity count during the subjective night and day period compared with the normal controls. Sleep bout numbers of the normal, PB, and DeRB groups showed significant differences as compared with the caffeine and RB groups (p<0.05). The PB and DePB groups showed a significantly increased transcript levels for the GABA receptors compared to the caffeine group. The caffeine and RB groups displayed better climbing ability than the other groups, covering an average distance 6cm in the related test; the average distance covered by the normal, PB 7.5, and DeRB groups was <4cm. The normal and DeRB groups showed similar behavior patterns with respect to total distance, velocity, moving, not moving, and meander. However, the PB 7.5 group significantly regulated not moving and meander of flies compared to flies receiving only caffeine and RB. Suppression of the stimulating effect of caffeine by explosion-puffed coffee administration was indicated in the above results, which can be attributed to the increased content of GABA and 5-HTP with explosive puffing process carried out at 0.75MPa. Results of the underlying mechanism of the behavioral change patterns of explosive puffed with or without caffeine in Drosophila models, transcript level for the Dop1-R1 receptor in caffeine group was significantly higher than normal, PB, and DePB groups. Flies exposed to the caffeine had significantly decreased transcript levels for the GABA receptors. PB 7.5 and DePB showed higher level of GABA content than RB. PMID- 28888449 TI - Understanding the effect of pulsed electric fields on thermostability of connective tissue isolated from beef pectoralis muscle using a model system. AB - Brisket is a low value/tough meat cut that contains a large amount of connective tissue. Conversion of collagen into gelatin during heating reduces the toughness of the connective tissue however this conversion is slow at low cooking temperatures (around 60 degrees C). The objective of this project was to determine the ability of pulsed electric field (PEF) processing to reduce the thermal stability of connective tissue. To achieve this, a novel model system was designed in which connective tissue obtained from beef deep pectotalis muscle (brisket) was exposed to PEF at combinations of electric field strength (1.0 and 1.5kV/cm) and specific energy (50 and 100kJ/kg) within an agar matrix at electrical conductivities representing the electrical conductivity found in brisket. Differential scanning calorimetry showed that PEF treatment significantly (p<0.05) decreased the denaturation temperature of connective tissue compared to untreated samples. Increasing electric field strength and the specific energy increased the Ringer soluble collagen fraction. PEF treated samples showed higher solubilization compared to the untreated samples at both 60 degrees C and 70 degrees C in heat solubility test. SEM examination of PEF treated (at 1.5kV/cm and 100kJ/kg) and untreated samples revealed that PEF appeared to increase the porosity of the connective tissue structure. These finding suggest that PEF processing is a technology that could be used to improve the tenderness and decrease the cooking time of collagen rich, meat cuts. PMID- 28888451 TI - Application of gamma radiation for the reduction of norovirus and the quality stability in optimally ripened cabbage kimchi. AB - Optimally ripened commercial cabbage kimchi is considered the main cause of enteric norovirus (NoV) outbreaks in Korea. This study investigated the effect of 1-10kGy gamma radiation on the inactivation of murine norovirus-1 (MNV-1; initial inoculum of 5-6log10PFU/ml), used as a human NoV surrogate, in kimchi. The effects of gamma radiation on the pH and acidity were also examined to address the index of quality and fermentation, respectively. Titers of MNV-1 significantly reduced (p<0.05) in kimchi subjected to increasing gamma radiation doses: MNV-1 titers in kimchi after 1, 3, 5, 7, and 10kGy were 4.82 (0.34-log10 reduction), 4.45 (0.71-log10 reduction), 4.18 (0.98-log10 reduction), 3.71 (1.45 log10 reduction), and 3.40 (1.76-log10 reduction) log10 PFU/ml, respectively. However, the values of pH (4.5-4.6) and acidity (0.6-0.7%) were not significantly different between non-irradiated and irradiated kimchi (p>0.05). The D-value (1 log reduction) for MNV-1 in kimchi, calculated using first-order kinetics, was 5.75kGy (R2=0.98, RMSE=0.10). Therefore, this study suggests that the use of >=5.75kGy gamma radiation in the kimchi manufacturing industry could be very effective in reducing NoV contamination by >90% (1 log), without causing changes in quality and fermentation. PMID- 28888450 TI - Formation of amyloid fibrils from soy protein hydrolysate: Effects of selective proteolysis on beta-conglycinin. AB - The soy protein hydrolysate subjected to selective proteolysis on beta conglycinin (referred to as DbetaH, contrast group) and a control soy protein isolate sample without addition of protease (referred to as CSPI, blank group) were adopted as experimental samples. By employing the "subtraction" mode of logical thinking, we aimed to compare the differences between CSPI and DbetaH on fibrillation at pH2.0 with heating at 95 degrees C. The results showed when heated for 60min, CSPI tended to form short worm-like fibrils while DbetaH long semiflexible fibrils. When heating time was prolonged to 360min, the fibrils formed from them both exhibited cluster. Whereas when heated for 720min, no fibrillar aggregates appeared from them. This study would help explore the effects of beta-conglycinin on the fibril formation of soy protein isolate by a new way. PMID- 28888452 TI - Inactivation mechanism of Vibrio parahaemolyticus via supercritical carbon dioxide treatment. AB - The effects of supercritical carbon dioxide (SC-CO2) treatments on Vibrio parahaemolyticus cells were determined using viable plate count method at different treatment times (10 and 40min), pressures (10-25MPa), and temperature (40 degrees C). Using the changes in the physical (absorbance, transmission electron microscope and contents of fatty acids) and chemical indexes (pH value, activity of Na+K+-ATPase, SDS-PAGE) were for further understand the mechanisms of bacterial inactivation under SC-CO2. The result showed that 25MPa treatment for 40min in 40 degrees C could significantly (P<0.05) enhance inactivation of V. parahaemolyticus. The pH value and activity of Na+K+-ATPase of SC-CO2 treated groups significantly (P<0.05) decreased compared with blank group. Damage to the cell membrane and cytoplasmic components can be observed on transmission electron microscope images. Results of SDS-PAGE and UV-absorbing substances also showed that the leakage of proteins and cytoplasmic materials increased with the SC-CO2 treatment time and pressure. Therefore, our results indicate that SC-CO2 can be applied to inactivate V. parahaemolyticus by causing a low pH, as well as severe damage to key substances and structures. PMID- 28888453 TI - Effect of microwave and conventional heating on structural, functional and antioxidant properties of bovine serum albumin-maltodextrin conjugates through Maillard reaction. AB - In present study, effect of conventional heating (CH) and microwave heating (MH) on Maillard reaction (MR) progression and structural, functional and antioxidant properties of glycated protein was investigated. The glycation process was carried out at 90 degrees C, in bovine serum albumin-maltodextrin system. The extent of glycation was assessed by ortho-phthaldialdehyde and absorbance at 420nm. Afterwards, K-means clustering was applied to classify all treatments into three levels of glycation (low, medium, high). Subsequently, SDS-PAGE, structural (surface hydrophobicity and circular dichroism), functional and antioxidant (DPPH radical scavenging) properties were measured within chosen treatments. Results showed that MH was more effective on the reduction of free amino groups and increase in absorbance at 420nm more than CH (p<0.05). On the other hand, higher values in solubility, emulsion activity and foam capacity were obtained during MH heating which could be attributed to different structural changes of proteins under MH and CH. PMID- 28888454 TI - Technological characteristics of cold-set gelled double emulsion enriched with n 3 fatty acids: Effect of hydroxytyrosol addition and chilling storage. AB - A study was carried out to analyse the technological characteristics and microbiological content of gelled double emulsions (GDE) formulated with perilla oil (as lipid phase and source of n-3 fatty acids) combined or not with hydroxytyrosol (Hyt) (in the inner aqueous phase) over 30days storage at 4 degrees C. Both the control sample without Hyt (GDE-C) and the sample containing Hyt (GDE-Hyt) had an appropriate whitish solid-like structure with rheological (elastic and viscous moduli, and phase angle) and textural (hardness and chewiness) properties of strong gels. In comparison with GDE-C, the presence of Hyt promoted the formation of weaker gels, as evidenced by lower hardness and chewiness values and elastic modulus. Overall, GDEs presented excellent water and fat binding properties irrespective of the formulation and storage time. Changes in hydroperoxides and TBARs contents over storage indicated that GDEs were little prone to oxidation after 30days. Nevertheless, Hyt increased GDE antioxidant capacity by up to 12 times after preparation, although this declined with storage. Most of the antimicrobial activity of Hyt was observed during the first two weeks of storage. PMID- 28888455 TI - Extraordinarily soft, medium-hard and hard Indian wheat varieties: Composition, protein profile, dough and baking properties. AB - Hard wheat (HW), medium-hard wheat (MHW) and extraordinarily soft wheat (Ex-SW) varieties with grain hardness index (GHI) of 83 to 95, 72 to 80, 17 to 29 were evaluated for pasting, protein molecular weight (MW) distribution, dough rheology and baking properties. Flours from varieties with higher GHI had more protein content, ash content and paste viscosities. Ex-SW had more glutenins proportion as compared to HW and MHW. Flours from Ex-SW varieties showed lower NaSRC, WA and mixographic parameters as compared to HW and MHW. Dough from flours milled from Ex-SW had higher Intermolecular-beta-sheets (IM-beta-sheets) than those from MHW and HW. Muffins volume increased with decrease in GHI, Ex-SW varieties had more muffin volume and less air space. The accumulation of polypeptides (PPs) varied significantly in different varieties. Ex-SW variety (QBP12-10) showed accumulation of 98, 90, 81 and 79kDa PPs, which was unique and was different from other varieties. PMID- 28888456 TI - Dry heating of whey proteins. AB - Whey protein products are of widespread use as food ingredients because of their high nutritional, biological and functional properties. Whey proteins are important structural components in many foods as used in their native form, for example for their heat-induced gelation abilities. Furthermore, they also offer reliable functionalities when modified by heating processes as denatured or aggregated proteins. Heat treatment of whey proteins in a liquid state has received much attention in recent years. While dry heating of whey proteins, say heating whey proteins in the dry state, is frequently cited in the literature as a potential and efficient means to improve the functional properties of proteins, it has received very little attention. We report first on the dry heating of whey products as applied to promote glycation of whey proteins with a low denaturation, and second, to promote their denaturation and aggregation and on their consequences on the functional properties of whey proteins. PMID- 28888457 TI - Effects of phosphorylation on MU-calpain activity at different incubation temperature. AB - The study investigated the effects of alkaline phosphatase (AP) dephosphorylation and protein kinase A (PKA) phosphorylation on MU-calpain activity and its sensitivity to temperature. The purified MU-calpain was treated with AP or PKA for 30min at 30 degrees C to modulate its phosphorylation level. Samples were then incubated at controlled freezing point (-1), 4, 25 and 37 degrees C, respectively. The results showed that PKA and AP had no influence on pH values of incubation solution. At -1 and 4 degrees C, the degradation rate of MU-calpain was maximum in AP group and minimum in control group. Low temperature of controlled freezing point prevented dephosphorylation and phosphorylation progression and delayed MU-calpain degradation. Increased incubation temperature of 4, 25 and 37 degrees C increased MU-calpain degradation. Two about 50kDa degradation products from MU-calpain were identified, of which the intensity was also lower in control group than in the other two groups. These observations demonstrated that AP dephosphorylation and PKA phosphorylation of MU-calpain promoted MU-calpain autolysis and activation. PMID- 28888459 TI - Structural characterization and formation mechanism of zein-propylene glycol alginate binary complex induced by calcium ions. AB - Effect of calcium ions (Ca2+) on characteristics of zein-propylene glycol alginate (PGA) binary complex was studied in this work. Ca2+ induced the formation of zein aggregates with decreased fluorescence intensity and a significant alpha-helix loss of zein. Zein-PGA binary complex with Ca2+ showed the decreased dimension and the minimum size was observed at 50.0mM Ca2+. Ca2+ resulted in the formation of strong hydrogen bonds between zein and PGA, strengthened their hydrophobic interactions, and induced a new peak at the diffraction angle of 30 degrees in the pattern of Zein-PGA binary complex. PGA fortified with Ca2+ exhibited an overall plane-like structure, also an interwoven flat profile appeared in Zein-PGA binary complex with Ca2+. Three potential mechanisms were proposed to explain the morphological changes of samples after Ca2+ addition: (i) particle-particle collision and aggregation of particles; (ii) chain-chain association and further cross-linking of associated chains; (iii) simultaneous cross-linking coupled with aggregation. PMID- 28888458 TI - The high content of beta-carotene present in orange-pulp fruits of Carica papaya L. is not correlated with a high expression of the CpLCY-beta2 gene. AB - We investigated the transcriptional regulation of six genes involved in carotenoid biosynthesis, together with the carotenoid accumulation during postharvest ripening of three different papaya genotypes of contrasting pulp color. Red-pulp genotype (RPG) showed the lowest content of yellow pigments (YP), such as beta-cryptoxanthin, zeaxanthin, and violaxanthin, together with the lowest relative expression levels (REL) of CpLCY-beta2 and CpCHX-beta genes. On the contrary, the yellow-pulp genotype (YPG) showed the highest content of YP and the highest REL of CpLCY-beta2 and CpCHX-beta genes. Interestingly, the orange pulp genotype (OPG) showed intermediate content of YP and intermediate REL of CpLCY-beta2 and CpCHX-beta genes. The highest content of beta-carotene shown by OPG despite having an intermediate REL of the CpLCY-beta2 genes, suggests a post transcriptional regulation. Thus, the transcriptional level of the genes, directing the carotenoid biosynthesis pathway, can partially explain the accumulation of carotenoids during the postharvest ripening in C. papaya genotypes of contrasting pulp color. PMID- 28888460 TI - Impact of boiling on free and bound phenolic profile and antioxidant activity of commercial gluten-free pasta. AB - Cooking by boiling dry pasta could have varying degrees of influence on nutritional and functional components. In the present study, its effect on total phenolic content and antioxidant capacity, as well as on the comprehensive profile of free and bound phenolics, was investigated in six commercial gluten free (GF) pasta products. Overall, the heat treatment caused a significant reduction (P<0.01) of the total phenolic content as well as FRAP reducing power and ORAC radical scavenging, with significant differences among the pasta samples considered. The highest values were recorded in free phenolic fraction remaining in black rice (41mggallic acid equivalents100g-1 and 25mmolTrolox Equivalents100g 1) and quinoa (24mggallic acid equivalents100g-1 and 14mmolTrolox Equivalents100g 1) cooked GF pasta. Significant correlations (P<0.01) could be found between total phenolics and both the antioxidant capacity assays performed. UHPLC ESI/QTOF-MS mass profiling allowed confirming the spectrophotometric results, while identifying the amount of free and bound fractions. Among phenolic classes, lignans exhibited the highest decrease during the cooking process, followed by stilbenes and flavonoids. However, phenolic acids and other phenolics showed the highest stability. Furthermore, cooking by boiling strongly lowered the bound-to free ratio of phenolic compounds, by an averaged factor ranging from 14-folds for flavonoids to 5-folds for other classes of phenolics. PMID- 28888461 TI - A high fat-high sucrose diet enriched in blue mussels protects against systemic inflammation, metabolic dysregulation and weight gain in C57BL/6 mice. AB - High fat-high sucrose (HF-HS) diet, known as the western diet, has been shown to induce the onset of obesity via increasing metabolic inflammation, insulin resistance and adipose tissue dysfunction. Hyperleptinemia, hyperglycemia and dyslipidemia are also the primary observations of obesogenic diet induced obesity. We have previously reported anti-adipogenic and insulin sensitizing effects of blue mussels (BM) using 3T3-L1 cells. BM is a rich source of omega-3 polyunsaturated fatty acids, phytosterols and other micronutrients that has been shown to elicit benefits under obese conditions using in-vitro cell culture models. However, no studies to date have established the anti-obesity effects, safety and efficacy of BM in an in-vivo animal model. In the present study, we fed a HF-HS diet supplemented with different concentrations of BM freeze-dried powder (1.25, 2.5 and 5% w/w) to C57BL/6 mice for 12weeks. A HF-HS diet caused rapid weight gain, hyperglycemia, dyslipidemia, hyperleptinemia, and increased plasma levels of inflammatory cytokines; interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. Incorporating 2.5% BM in the HF-HS diet prevented weight gain, dyslipidemia, hyperglycemia and reduced the levels of inflammatory cytokines and leptin mRNA expression. Furthermore, plasma from 2.5% BM increased cholesterol efflux capacity of J774 macrophage cells, compared to plasma from HF HS diet. There was no effect of 1.25% BM on any tested parameters, while 5% BM was not palatable after four weeks. In conclusion, our findings have established the efficacy and safety of BM using C57BL/6 mice, demonstrating that BM has the potential to target obesity and related complications. PMID- 28888462 TI - Control of protein digestion under simulated gastrointestinal conditions using biopolymer microgels. AB - Controlling the rate and extent of protein digestion within different regions of the human gastrointestinal tract (GIT) is important for regulating hormonal responses (such as hunger, satiety, and satiation) and immune responses (such as allergenicity). In this study, hydrogel beads (biopolymer microgels) were fabricated by injecting a solution of anionic alginate molecules into a solution of cationic calcium ions using a vibrating extrusion device. A model food protein (whey protein isolate, WPI) was mixed with the alginate solution prior to bead formation. The impact of thermal processing (80 degrees C, 15min) of the WPI before or after microgel formation was examined to determine the impact of protein denaturation and aggregation on encapsulation efficiency and retention. Heat-denaturation of the protein prior to microgel formation led to the highest encapsulation efficiency and retention, which was attributed to the formation of a cold-set protein gel inside the beads. Simulated GIT studies indicated that protein encapsulation in the microgels retarded its digestion in the stomach (around 3.7% digested), but not in the small intestine (around 19.6% digested). The denatured and native proteins were digested differently in different GIT regions: denatured protein digested faster in the stomach (around 11% digested), whereas native protein digested faster in the small intestine (around 41% digested). These results could provide valuable information for the design of microgel-based delivery systems to regulate protein digestion and peptide release in the GIT. PMID- 28888463 TI - Brazil nuts: Nutritional composition, health benefits and safety aspects. AB - Brazil nuts are among the richest selenium food sources, and studies have considered this Amazonian nut as an alternative for selenium supplementation. Besides selenium, Brazil nuts present relevant content of other micronutrients such as magnesium, copper, and zinc. The nutritional composition of nuts, also characterized by adequate fatty acid profile and high content of protein and bioactive compounds, has many health benefits. In the present review, we examine the nutritional composition of Brazil nuts, comparing it with other nuts, and describe the relevance of possible contaminants and metal toxicants observed in this nut for human health. Furthermore, we report different trials available in the literature, which demonstrate positive outcomes such as modulation of the lipid serum profile, enhancement of the antioxidant system and improvement of anti-inflammatory response. These effects have been assessed under different conditions, such as cognitive impairment, dyslipidemia, cancer, and renal failure. PMID- 28888464 TI - Minerals profile of two globe artichoke cultivars as affected by NPK fertilizer regimes. AB - Globe artichoke is a proven source of various minerals (such as K, Fe and Zn) in the Mediterranean diet, but their content in response to fertilizer regime has not yet been investigated sufficiently. Thus, we monitored the effect of two contrasting nitrogen/phosphorus/potassium (NPK) fertilizer regimes (one balanced and the other excessive) on the minerals accumulation of 'Apollo' and 'Tema 2000' cultivars, grown in three Sicilian locations ('Landolina', 'Iannarello' and 'Zotto') - South Italy. Except for total nitrogen, the balanced fertilizer regime favoured the accumulation of both macro- and micro-minerals, but with a different extent depending especially on trial location. Particularly, plants grown at 'Iannarello' responded more strongly to the fertilizer regime with respect to K, P, Ca, Fe and Zn accumulation, as a result of its different soil characteristics than the other locations. Providing a balanced supply of nitrogen/phosphorus/potassium via fertilization can enhance the nutritive value of globe artichoke, but taking into account especially soil characteristics. PMID- 28888465 TI - Predicting and evaluation the severity in acute pancreatitis using a new modeling built on body mass index and intra-abdominal pressure. AB - OBJECT: Acute pancreatitis (AP) keeps as severe medical diagnosis and treatment problem. Early evaluation for severity and risk stratification in patients with AP is very important. Some scoring system such as acute physiology and chronic health evaluation-II (APACHE-II), the computed tomography severity index (CTSI), Ranson's score and the bedside index of severity of AP (BISAP) have been used, nevertheless, there're a few shortcomings in these methods. The aim of this study was to construct a new modeling including intra-abdominal pressure (IAP) and body mass index (BMI) to evaluate the severity in AP. METHODS: The study comprised of two independent cohorts of patients with AP, one set was used to develop modeling from Jinling hospital in the period between January 2013 and October 2016, 1073 patients were included in it; another set was used to validate modeling from the 81st hospital in the period between January 2012 and December 2016, 326 patients were included in it. The association between risk factors and severity of AP were assessed by univariable analysis; multivariable modeling was explored through stepwise selection regression. The change in IAP and BMI were combined to generate a regression equation as the new modeling. Statistical indexes were used to evaluate the value of the prediction in the new modeling. RESULTS: Univariable analysis confirmed change in IAP and BMI to be significantly associated with severity of AP. The predict sensitivity, specificity, positive predictive value, negative predictive value and accuracy by the new modeling for severity of AP were 77.6%, 82.6%, 71.9%, 87.5% and 74.9% respectively in the developing dataset. There were significant differences between the new modeling and other scoring systems in these parameters (P < 0.05). In addition, a comparison of the area under receiver operating characteristic curves of them showed a statistically significant difference (P < 0.05). The same results could be found in the validating dataset. CONCLUSIONS: A new modeling based on IAP and BMI is more likely to predict the severity of AP. PMID- 28888466 TI - Effects of Electronic Medical Record Display on Provider Ordering Behavior: Leveraging the EMR to Improve Quality and Costs. PMID- 28888467 TI - Early electrophysiological findings in Fisher-Bickerstaff syndrome. AB - INTRODUCTION: The term Fisher-Bickerstaff syndrome (FBS) has been proposed to describe the clinical spectrum encompassing Miller-Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis. The pathophysiology of FBS and the nature of the underlying neuropathy (demyelinating or axonal) are still subject to debate. This study describes the main findings of an early neurophysiological study on 12 patients diagnosed with FBS. PATIENTS AND METHODS: Retrospective evaluation of clinical characteristics and electrophysiological findings of 12 patients with FBS seen in our neurology department within 10 days of disease onset. Follow-up electrophysiological studies were also evaluated, where available. RESULTS: The most frequent electrophysiological finding, present in 5 (42%) patients, was reduced sensory nerve action potential (SNAP) amplitude in one or more nerves. Abnormalities were rarely found in motor neurography, with no signs of demyelination. The cranial nerve exam revealed abnormalities in 3 patients (facial neurography and/or blink reflex test). Three patients showed resolution of SNAP amplitude reduction in serial neurophysiological studies, suggesting the presence of reversible sensory nerve conduction block. Results from cranial MRI scans were normal in all patients. CONCLUSION: An electrophysiological pattern of sensory axonal neuropathy, with no associated signs of demyelination, is an early finding of FBS. Early neurophysiological evaluation and follow-up are essential for diagnosing patients with FBS. PMID- 28888468 TI - Effect of visual biofeedback cycling training on gait in patients with multiple sclerosis. AB - INTRODUCTION: Gait alterations are present in a high percentage of patients with multiple sclerosis (MS). They appear from early stages of the disease and can limit patients' capacity to perform basic activities of daily living, affecting their quality of life. Visual biofeedback cycling training appears to be a useful tool in treating these impairments. This study aims to evaluate the short-term effect of visual biofeedback cycling training on gait in patients with MS. MATERIAL AND METHODS: A total of 61 patients with mild to moderate MS were randomly assigned to a control group and an intervention group. The intervention group received visual biofeedback cycling training (MOTOmed viva2 system) once per week for 3 months, and a home exercise program. The control group only received the home exercise program. Both groups were evaluated using the GAITRite(r) Walkway gait assessment system before the intervention, during the first month of the programme, and after the intervention. RESULTS: In the intervention group, the analysis revealed statistically significant differences between Functional Ambulation Profile (FAP) scores before and during the intervention (P=.014), and before and after the intervention (P=.002). A statistically significant improvement was observed in step length in the intervention group between pre- and post-intervention scores (P=.001) and between first-month and post-intervention scores (P=.004). CONCLUSIONS: Visual biofeedback cycling training improved specific gait parameters in the short term and appears to be a therapeutic option for gait retraining in patients with MS. PMID- 28888470 TI - Functional and biochemical adaptations of elite level futsal players from Brazil along a training season. AB - BACKGROUND AND OBJECTIVE: Although hard training is mandatory in elite level futsal training, few studies have proposed a biochemical follow up in futsal players during a whole season. Therefore, the aim of this study was to compare functional and biochemical markers in Brazilian elite level futsal players throughout a competition season. MATERIALS AND METHODS: Eight players aged 25.5+/ 5.4 years were evaluated at three time points: preseason (T1), immediately before the FIFA(r)-Intercontinental-Futsal-Cup (T2), and at the end of the season (T3), with a tapering period of 1 week before T2. Functional parameters (weight, height, body fat, VO2max, heart rate, and distance ran) and blood sampling for cell count and lipid profile (cholesterol, HDL-C, LDL-C, triglycerides) were assessed at each time point. After, a Yo-Yo R2 test was carried out in each time point (T1, T2 and T3) and blood samples to assess skeletal muscle damage (creatine kinase [CK], lactate dehydrogenase [LDH]), inflammation (C-reactive protein [CRP]) and oxidative stress markers (ischemia modified albumin [IMA], and advanced oxidation protein products [AOPP]) were obtained before and after the tests. RESULTS: Although functional parameters did not change throughout the season, greater total number of erythrocytes (P<=0.05), and hemoglobin (P<=0.05) were found at T2 compared to T1. Similarly, lower LDH (P<=0.05) and CK (P<=0.05) levels were found at T2 compared to T1. CPR levels were also decreased at T2 in comparison to T1 both before and after Yo-Yo R2 test (P<=0.05), while IMA and AOPP levels showed only a season effect (P<=0.05). CONCLUSIONS: The tapering strategy was successful considering players presented lower levels of muscle damage, inflammation and oxidative stress makers before T2, which preceded the main championship of the year. These results are of great relevance, considering the team won the FIFA(r)-Intercontinental-Futsal-Cup, which happened at T2. Thus, it seems that routine-based biochemical markers may be useful as training control means in this population. PMID- 28888469 TI - Cut and Paste: Efficient Homology-Directed Repair of a Dominant Negative KRT14 Mutation via CRISPR/Cas9 Nickases. AB - With the ability to induce rapid and efficient repair of disease-causing mutations, CRISPR/Cas9 technology is ideally suited for gene therapy approaches for recessively and dominantly inherited monogenic disorders. In this study, we have corrected a causal hotspot mutation in exon 6 of the keratin 14 gene (KRT14) that results in generalized severe epidermolysis bullosa simplex (EBS-gen sev), using a double-nicking strategy targeting intron 7, followed by homology-directed repair (HDR). Co-delivery into EBS keratinocytes of a Cas9 D10A nickase (Cas9n), a predicted single guide RNA pair specific for intron 7, and a minicircle donor vector harboring the homology donor template resulted in a recombination efficiency of >30% and correction of the mutant KRT14 allele. Phenotypic correction of EBS-gen sev keratinocytes was demonstrated by immunofluorescence analysis, revealing the absence of disease-associated K14 aggregates within the cytoplasm. We achieved a promising safety profile for the CRISPR/Cas9 double nicking approach, with no detectable off-target activity for a set of predicted off-target genes as confirmed by next generation sequencing. In conclusion, we demonstrate a highly efficient and specific gene-editing approach for KRT14, offering a causal treatment option for EBS. PMID- 28888472 TI - Integra(r) as a single-stage dermal regeneration template in reconstruction of large defects of the scalp. AB - Dermal regeneration templates may be used in the reconstruction of large defects after the excision of cutaneous malignancies. We describe the successful use of Integra(r) (Integra Lifesciences Corporation, Plainsboro, NJ, USA) as a single stage regeneration template after the excision of multiple lesions of the scalp with a surface area of 96.7cm2. Second-stage epidermal autografting was precluded because of an unforeseen deterioration in the patient's condition, and the wound re-epithelialised over a period of six months. To the best of our knowledge there are no published reports on the use of this procedure after excision of cutaneous malignancies of the scalp of similar dimensions, without subsequent epidermal autografting (Johnson and Wong, 2016).1. PMID- 28888471 TI - Altered expression of the FMR1 splicing variants landscape in premutation carriers. AB - FMR1 premutation carriers (55-200 CGG repeats) are at risk for developing Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), an adult onset neurodegenerative disorder. Approximately 20% of female carriers will develop Fragile X-associated Primary Ovarian Insufficiency (FXPOI), in addition to a number of clinical problems affecting premutation carriers throughout their life span. Marked elevation in FMR1 mRNA levels have been observed with premutation alleles resulting in RNA toxicity, the leading molecular mechanism proposed for the FMR1 associated disorders observed in premutation carriers. The FMR1 gene undergoes alternative splicing and we have recently reported that the relative abundance of all FMR1 mRNA isoforms is significantly increased in premutation carriers. In this study, we characterized the transcriptional FMR1 isoforms distribution pattern in different tissues and identified a total of 49 isoforms, some of which observed only in premutation carriers and which might play a role in the pathogenesis of FXTAS. Further, we investigated the distribution pattern and expression levels of the FMR1 isoforms in asymptomatic premutation carriers and in those with FXTAS and found no significant differences between the two groups. Our findings suggest that the characterization of the expression levels of the different FMR1 isoforms is fundamental for understanding the regulation of the FMR1 gene as imbalance in their expression could lead to an altered functional diversity with neurotoxic consequences. Their characterization will also help to elucidating the mechanism(s) by which "toxic gain of function" of the FMR1 mRNA may play a role in FXTAS and/or in the other FMR1-associated conditions. PMID- 28888473 TI - Acupuncture for temporomandibular joint syndrome. PMID- 28888474 TI - Recent advances in the genomic and molecular biology of Giardia. AB - Giardia duodenalis is the most common gastrointestinal protozoan parasite of humans and a significant contributor to the global burden of both diarrheal disease and post-infectious chronic disorders. Robust tools for analyzing gene function in this parasite have been developed and a range of genetic tools are now available. These together with public databases have provided insights on the function of different genes in Giardia. In this review we provide a current perspective on different molecular aspects of Giardia related to genomics, regulation of encystation, trophozoite transcriptional responses to physiological and xenobiotic (drug-induced) stress, and mechanisms of drug resistance. We also examine recent insights that have contributed to gain knowledge in the study of VSPs, antigenic variation, epigenetics, DNA repair and in the direct manipulation of gene function in Giardia, with a particular focus on the inducible Cre/loxP system. PMID- 28888475 TI - Promoter methylation status of the TIMP2 and ADAMTS4 genes and patellar tendinopathy. AB - OBJECTIVES: Patellar tendinopathy (PT) is a debilitating and prevalent condition that tends to affect those who are physically active or engaged in jumping sports. Although tendinopathies are known to have a genetic basis, the role of DNA methylation as an epigenetic factor and risk determinant for human PT has never been described. We sought to determine whether differences existed between the methylation profiles of both the TIMP2 and ADAMTS4 gene promoter sequences in a cohort of males having undergone surgery for patellar tendinopathy compared to controls. DESIGN: Case-control epigenetic study using DNA from 10 males with PT and 10 males with healthy tendons. METHODS: We used PCR and targeted pyrosequencing to interrogate the methylation profiles of CpG sites upstream of both the TIMP2 (4 sites) and ADAMTS4 (6 sites) genes. We compared methylation differences between the two groups using t-tests. RESULTS: We report no significant (p>0.05) methylation differences within the TIMP2 gene promoter between the PT group and controls across the 4 CpG sites investigated. In contrast, we detected a significant (p=0.016) difference in the methylation status of 1 CpG site, approximately 3kb upstream of the ADAMTS4 gene between the PT group and controls. CONCLUSIONS: To our knowledge, this is the first study to investigate how DNA methylation impacts on the risk of human tendinopathy. Our data indicate that the methylation status of the ADAMTS4 gene is altered in patellar tendinopathy and we speculate on how this change might modify the patellar tendon extra-cellular matrix environment. PMID- 28888477 TI - WITHDRAWN: Health Policy Research May Ensure the Future of Oral and Maxillofacial Surgery. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.joms.2017.03.056. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28888476 TI - Computational sensitivity investigation of hydrogel injection characteristics for myocardial support. AB - Biomaterial injection is a potential new therapy for augmenting ventricular mechanics after myocardial infarction (MI). Recent in vivo studies have demonstrated that hydrogel injections can mitigate the adverse remodeling due to MI. More importantly, the material properties of these injections influence the efficacy of the therapy. The goal of the current study is to explore the interrelated effects of injection stiffness and injection volume on diastolic ventricular wall stress and thickness. To achieve this, finite element models were constructed with different hydrogel injection volumes (150uL and 300 uL), where the modulus was assessed over a range of 0.1kPa to 100kPa (based on experimental measurements). The results indicate that a larger injection volume and higher stiffness reduce diastolic myofiber stress the most, by maintaining the wall thickness during loading. Interestingly, the efficacy begins to taper after the hydrogel injection stiffness reaches a value of 50kPa. This computational approach could be used in the future to evaluate the optimal properties of the hydrogel. PMID- 28888478 TI - Mandibular Coronoidectomy Could Significantly Accelerate the Healing Process of Infratemporal Fossa Abscess. AB - PURPOSE: Management of an infratemporal fossa abscess (IFA), which is a specific form of severe and advanced deep fascial space infection (DFI), is based mainly on traditional methods. The purpose of this study was to investigate the role of mandibular coronoidectomy in accelerating IFA healing. PATIENTS AND METHODS: This research is a single-center retrospective study composed of 23 patients with IFA. The predictor variables were gender, age, diabetes, severity score, and mandibular coronoidectomy. The outcome variables included hospitalization time (HT) and irrigating time (IT). A comparison of treatment outcomes between the improved and traditional surgical interventions for IFA was performed. RESULTS: Compared with patients who did not receive mandibular coronoidectomy (NC group; HT, 17.54 +/- 1.80 days; IT, 38.54 +/- 3.73 days), patients who underwent mandibular coronoidectomy (AC group) had significantly decreased HT (7.20 +/- 1.19 days) and IT (15.10 +/- 1.27 days; P < .01). In addition, 4 patients (31%) in the NC group received reoperation for osteomyelitis, whereas no osteomyelitis and DFI recurrence occurred in the AC group. CONCLUSIONS: Mandibular coronoidectomy with extra intraoral drainage could considerably accelerate the healing process of IFAs and obviously decrease the reoperation rate for osteomyelitis. PMID- 28888479 TI - Letter to the Editor concerning "One and a half syndrome following penetrating head injury: Case report" by Mathew R. Voisin, Sanskriti Sasikumar, Jeremy H. Russell, Gelareh Zadeh, Journal of Clinical Neuroscience 41 (2017) 88-90. PMID- 28888480 TI - The clinical characteristics and microsurgical therapy of pituitary adenomas in elderly patients: A retrospective study of 130 cases. AB - OBJECTIVE: To investigate the clinical characteristics and microsurgical therapy of pituitary adenomas in elderly patients. METHOD: This article describes a retrospective study of 130 pituitary adenomas in elderly patients over 65years of age who underwent a microsurgical operation using the transsphenoidal approach and were admitted to Peking Union Medical College Hospital (PUMCH) from January 2010 to December 2012. RESULTS: A total of 60 (46.2%) males and 70 females (53.8%) were included, and the mean age of the patients was 68.38years. The main clinical manifestation was visual defects (35.4%), and the levels of growth hormone (GH), insulin-like growth factor-1 (IGF-1), adrenocorticotropic hormone (ACTH), and prolactin (PRL) were increased by 11.5%, 11.5%, 6.2%, and 7.7%, respectively. All patients underwent the transsphenoidal approach. The main comorbidity prior to surgery was hypertension (45.0%), and the average duration of follow-up was 39.6+/-10.6months. Tumor recurrence was observed in 19 patients, 17 of which received radiological therapy, and two patients underwent an additional operation at our hospital. The rate of loss to follow-up was 15.9%. CONCLUSION: There was no significant difference in the surgical outcome, mortality in the perioperative period or complications between the elderly patients and the general population. However, the indications for pituitary adenomas in elderly patients still require further age-specific guidelines. PMID- 28888481 TI - Spatial distribution of conduction disorders during sinus rhythm. AB - BACKGROUND: Length of lines of conduction block (CB) during sinus rhythm (SR) at Bachmann's bundle (BB) is associated with atrial fibrillation (AF). However, it is unknown whether extensiveness of CB at BB represents CB elsewhere in the atria. We aim to investigate during SR 1) the spatial distribution and extensiveness of CB 2) whether there is a predilection site for CB and 3) the association between CB and incidence of post-operative AF. METHODS: During SR, epicardial mapping of the right atrium (RA), BB and left atrium was performed in 209 patients with coronary artery disease. The amount of conduction delay (CD, Deltalocal activation time >=7ms) and CB (Delta>=12ms) was quantified as % of the mapping area. Atrial regions were compared to identify potential predilection sites for CD/CB. Correlations between CD/CB and clinical characteristics were tested. RESULTS: Areas with CD or CB were present in all patients, overall prevalence was respectively 1.4(0.2-4.0) % and 1.3(0.1-4.3) %. Extensiveness and spatial distribution of CD/CB varied considerably, however occurred mainly at the superior intercaval RA. Of all clinicalcharacteristics, CD/CB only correlated weakly with age and diabetes (P<0.05). A 1% increase in CD or CB caused a 1.1 1.5ms prolongation of the activation time (P<0.001). There was no correlation between CD/CB and post-operative AF. CONCLUSION: CD/CB during SR in CABG patients with electrically non-remodeled atria show considerable intra-atrial, but also inter-individual variation. Despite these differences, a predilection site is present at the superior intercaval RA. Extensiveness of CB at the superior intercaval RA or BB does not reflect CB elsewhere in the atria and is not associated with post-operative AF. PMID- 28888483 TI - Correction. PMID- 28888482 TI - Exercise training and cardiac autonomic function in type 2 diabetes mellitus: A systematic review. AB - Cardiac autonomic neuropathy (CAN) is a common complication of type 2 diabetes mellitus (T2DM). It has been found to independently predict all cause and cardiovascular disease (CVD) mortality. It remains unclear whether exercise training could improve autonomic control in T2DM patients. The purpose of this study was to systematically review the effects of exercise training on cardiac autonomic function in T2DM patients. Electronic databases (MEDLINE, CENTRAL, PEDro, Scopus and Web of science) were systematically searched to retrieve relevant evidence. Clinical trials administering exercise training for at least 4 weeks and examining either heart rate variability (HRV), baroreflex sensitivity (BRS), heart rate recovery (HRR) as outcome measures were eligible. Eighteen articles were found to be relevant and were then assessed for characteristics and quality. Fifteen studies out of 18 found that exercise training leads to positive improvements in autonomic function of T2DM patients. Exercise participation enhances cardiac autonomic function of type 2 diabetics and therefore should be implemented in their management programs. PMID- 28888484 TI - Prediction of human efficacious antidepressant doses using the mouse forced swim test. AB - The forced swim test (FST) is a commonly used preclinical animal behavioural model for prediction of antidepressant activity in humans. While the FST may qualitatively predict efficacy, less is known about the quantitative translation of FST data to human efficacious doses. Assessing quantitative translation allows better predictions of human efficacious doses and a higher chance of success in the drug development process. Dose-response and time-course FST experiments were carried out on mice using four marketed antidepressants (citalopram, desipramine, bupropion, desvenlafaxine) in addition to ketamine, all with varying mechanisms of action. Population pharmacokinetic (PK)/pharmacodynamic (PD) analysis methods were applied to analyse the PK and immobility data, and the accuracy of the translation of FST data to human doses was evaluated using both area under the curve (AUC) and concentration-based approaches. The results showed that for the five antidepressants, average human AUC at clinically relevant doses were up to 38-fold higher than mouse AUC at doses associated with 50% of maximal efficacy in the FST (ED50). Using a concentration approach, human peak and trough drug concentrations at clinically relevant doses were generally associated with concentrations of at least 65% (EC65) and 20% (EC20) of maximal effect in mice, respectively. The FST is a useful tool to predict antidepressant efficacy across a variety of drugs with different mechanisms of actions. However, human doses can be over-or under-predicted many fold when using the traditional approach of estimating based upon ED50 AUC in mice. It is recommended that a concentration approach be used, where concentrations associated with 80% (EC80) and 30% (EC30) of maximal effect in the mouse are used as general targets for human maximum and trough concentrations, respectively, in the prediction of clinically efficacious doses of new, potential antidepressant agents. PMID- 28888486 TI - Subungual melanoma: Management in the modern era. AB - Subungual melanoma is a rare subtype of cutaneous melanoma that arises from the structures of the nail apparatus. It presents most commonly in older patients and at an advanced stage. A retrospective review of all patients with subungual melanoma in a single institution over a 15-year period was performed. In total, 54 patients were included (26 males, average age 62.9 years), of which 28 cases involved the upper limb. Median tumour thickness was 4.5 mm. Eighteen patients had lymph node metastasis at diagnosis, including 11 of 36 patients with positive sentinel lymph node biopsy. Median survival was 4.6 years. Subungual melanoma has a poor prognosis that is strongly associated with presence of nodal disease at diagnosis. Sentinel lymph node biopsy should be considered to determine stage and prognosis. PMID- 28888485 TI - Immunobiology of the IL-15/IL-15Ralpha complex as an antitumor and antiviral agent. AB - Interleukin (IL)-15 is essential for natural killer (NK), NKT and memory (m) CD8+ T cell development and function, and is currently under investigation as an immunotherapeutic agent for the treatment of cancer. Recently, the creation of IL 15 superagonist by complexing IL-15 and its high affinity receptor alpha (IL-15 Ralpha) in solution, inspired by the natural trans-presentation of IL-15, advances the potential of IL-15-based tumor immunotherapy. IL-15 superagonist shows promising advantages over monomeric IL-15 such as sustaining high circulating concentrations due to prolonged half-life and more potently stimulating NK and CD8+ T effector lymphocytes. So far, there are three different forms of recombinant IL-15 superagonist fusion protein based on configurational modifications. Gene therapy using engineered cells co-expressing IL-15/IL-15 Ralpha complex for cancer treatment is also emerging. All forms have demonstrated efficacy in causing tumor regression in animal studies, which provides strong rationale for advancing IL-15 superagonist through clinical trials. To date, there are fourteen phase I/II IL-15 superagonist trials in cancer patients and one phase I trial in HIV patients. Information generated by ongoing trials regarding the toxicity and efficacy of IL-15 superagonist is awaited. Finally, we elaborate on immunotoxicity caused by IL-15 superagonist in preclinical studies and discuss important safety considerations. PMID- 28888487 TI - Impaired autophagic flux and p62-mediated EMT are involved in arsenite-induced transformation of L-02 cells. AB - Autophagy is a catabolic process essential for preserving cellular homeostasis, and the epithelial-to-mesenchymal transition (EMT) is involved during tissue development and cancer progression. In arsenite-treated human hepatic epithelial (L-02) cells, arsenite reduced the autophagic flux, which caused accumulation of p62, an adaptor and receptor of autophagy. Further, in arsenite-transformed L-02 cells, the levels of E-cadherin were attenuated, but the levels of vimentin, which is expressed in mesenchymal cells, and Snail, a transcription regulator of the EMT, were up-regulated. Thus, after chronic exposure of L-02 cells to arsenite, the impaired autophagic flux induced the accumulation of p62, which up regulated the expression of Snail, a protein involved in arsenite-induced EMT of these cells. Knockdown of p62 by siRNA reversed the arsenite-induced EMT and decreased the capacities of arsenite-transformed L-02 cells for colony formation and invasion and migration. Therefore, in arsenite-induced transformation of L-02 cells, the accumulation of p62, by impairing autophagic flux, mediates the EMT via Snail. These results provide a previously unknown mechanism underlying arsenic toxicity and carcinogenicity. PMID- 28888488 TI - Cognitive Interviews for Validating the Family Nutrition Physical Activity Instrument for Korean-American Families With Young Children. AB - PURPOSE: Childhood obesity is a growing health concern for Korean-Americans (KA). The purpose of this study was to develop a culturally appropriate Korean-language version of the Family Nutrition Physical Activity (FNPA) instrument and evaluate its comprehensibility and cultural appropriateness of the FNPA for KAs. DESIGN AND METHODS: The FNPA was translated into Korean and cognitive interviews were conducted with 19 KA mothers in the Chicago metropolitan area. RESULTS: Overall, participants reported that the FNPA is easy to understand and said they had no difficulty answering items using a 4-point Likert scale. Six out of 20 items had minor revisions due to: items that were not specific enough, had confusing wording, or led to incorrect interpretations. CONCLUSIONS: Cognitive interviews confirmed the cultural appropriateness of the translated FNPA in the KA context. It is crucial that child's age and cultural aspects of a child's household routines should be taken into consideration when the original FNPA is being used with culturally diverse populations. PRACTICE IMPLICATIONS: Health care professionals may use the FNPA when assessing family environment in their efforts to prevent and control childhood obesity among KAs. PMID- 28888489 TI - Mental Health and Quality of Life Among Spanish-born and Immigrant Children in Years 2006 and 2012. AB - BACKGROUND: One of every five children and adolescents in the European Union suffers from behavioural, and emotional disturbances. OBJECTIVES: To compare factors associated with the quality of life and mental health of immigrant and Spanish children aged 4-14years both during the years 2006 and 2012 and to evaluate changes over this time period. DESIGN AND METHODS: An epidemiologic age and sex matched case-control study (1:2) was conducted. The study group were 677 immigrant children and 1354 matched Spanish children (controls). This study was conducted using data obtained from the Spanish National Health Surveys done in 2006 and 2012. We used the Strengths and Difficulties Questionnaire to obtain the score for variables derived from mental health and the Kidscreen-10 questionnaire to score the Health-Related Quality of Life. RESULTS: Spanish girls scored higher in conduct problems (2.04+/-0.1) and better in problems with peers (1.21+/-0.08) regarding immigrant girls (1.82+/-0.12-1.92+/-0.13 respectively). Concerning total scores, immigrant children obtained significantly lower scores in quality of life (81.29+/-0.76) and in problems with peers (2.04+/-0.09) than their matched Spanish children (84.4+/-0.45 and 1.26+/-0.06) in 2006. Immigrant children had lower total scores in prosocial behaviour (8.62+/-0.11) compared to the matched Spanish children (8.92+/-0.06) in 2012. The total average scores of immigrant children in terms of quality of life, emotional symptoms, behavioural problems, hyperactivity and problems with peers were significantly better in 2012 (86.58; 1.84; 1.46; 3.77 and 1.48 respectively) than in 2006 (81.29; 2.15; 1.90; 4.58 and2.04). CONCLUSIONS: Immigrant children had a poorer quality of life and mental health than matched Spanish children in 2006. PMID- 28888490 TI - Type 2 Diabetes in Canadian Aboriginal Adolescents: Risk Factors and Prevalence. AB - PURPOSE: To identify the risk factors and prevalence rates of prediabetes and type 2 diabetes among northern Canadian Aboriginal adolescents. DESIGN AND METHODS: In this novel exploratory, quantitative study, 160 high school students (aged 13-21) from three northern, predominantly Canadian Aboriginal communities were screened for risk for prediabetes and type 2 diabetes including demographic data, family medical history, anthropometric measurements, blood pressure, and hemoglobin A1c (HbA1c). Descriptive and inferential statistics, in addition to chi-square analysis, were used to establish risk and prevalence rates for prediabetes and type 2 diabetes in Aboriginal adolescents. RESULTS: At least half of the adolescents presented with multiple risk factors for type 2 diabetes. In this sample, 10% had an HbA1c>5.7%, 22.5% were overweight, 17.5% were obese, and 26.6% had prehypertension or hypertension. CONCLUSIONS: Prediabetes and type 2 diabetes are emerging as serious health concerns for young Aboriginal Canadians. This is troubling because both result from modifiable risk factors. As this study is the first to examine the prevalence of prediabetes in Canadian Aboriginal adolescents in the last decade, the findings underscore the necessity for early screening of Aboriginal adolescents for both prediabetes and type 2 diabetes. PRACTICE IMPLICATIONS: Recommendations toward positive health outcomes include the introduction of early age screening programs, followed by culturally relevant interventions, specific to the modifiable risk factors (overweight/obesity and hypertension), and developed in collaboration with the communities. Such approaches have the potential to prevent the progression of prediabetes to diabetes and reduce complications related to type 2 diabetes. PMID- 28888491 TI - Breakfast Eating Habits Among Schoolchildren. AB - BACKGROUND: A healthy breakfast provides school-age children with the essential nutrients needed for their activities and is correlated with improving a person's general nutritional status. METHODS: A cross-sectional study was conducted over a period of two months in 2015, involving 1798 Jordanian schoolchildren from grade 1 to grade 6. The study data sheet covered the breakfast habits of those children. Descriptive measures and Pearson's chi-square test were computed. Multivariate regression was calculated to assess the predictors' factors for breakfast consumption. The p value was considered significant at p<0.05. RESULTS: Findings show a prevalence for breakfast consumption of 80.4%. Furthermore, 52.1% of the breakfast eaters indicated that it was a family habit; half of them ate breakfast in order to be active and energetic and to alleviate hunger during the morning. Live with both parents, age groups of 6-9years and boys were the predictors of breakfast consumption among schoolchildren. CONCLUSION: Breakfast skipping among schoolchildren was initially high and increased with age. The findings suggest a community health education programme, conducted by school nurses, nutritionists and other health professionals, is needed. PMID- 28888492 TI - Physio-psychological Burdens and Social Restrictions on Parents of Children With Technology Dependency are Associated With Care Coordination by Nurses. AB - PURPOSE: To determine the association between parental care burdens and care coordination provided by nurses for children with technology dependency, specifically regarding physio-psychological burdens and social restrictions. DESIGN AND METHODS: A cross-sectional study was conducted between October and November 2015. Participants were recruited via home-visit nursing stations, social worker offices, and special-needs schools. A total of 246 parents of children with technology dependency completed anonymous self-report questionnaires. Parental burden was measured using the Zarit Burden Interview. Care coordination for children with technology dependency was examined using items extracted from focus group interviews involving three nursing administrators at home-visit nursing stations, two social workers, and a coordinator of school education for children with special health care needs. Multiple regression analysis was performed to examine the relationship between parental burden and care coordination among 172 parents who contracted with visiting nurses. RESULTS: Parents and children with nursing support were significantly younger and had higher medical care needs and higher parental role strain than those without nursing support. Care coordination from nurses predicted reduced parental burden, role strain, and personal strain (beta=-0.247, p=0.002; beta=-0.272, p=0.001; beta=-0.221, p=0.009, respectively). CONCLUSION: Nurses' care coordination appears to be associated with a reduction in parents' care burden resulting from home medical care of children with technology dependency, especially the social restrictions and physio-psychological burdens. PRACTICE IMPLICATIONS: Strengthening nursing functioning as care coordinators may contribute to reducing care burdens for parents of children with technology dependency. PMID- 28888493 TI - The Effects of Smartphone-based Nebulizer Therapy Education on Parents' Knowledge and Confidence of Performance in Caring for Children with Respiratory Disease. AB - PURPOSE: This study aimed to identify the effects of smartphone-based nebulizer therapy education on the knowledge and confidence of parents while performing care for their children with respiratory disease. DESIGN AND METHODS: This quasi experimental study employed a pretest-posttest design using a nonequivalent control group. Data were collected from children's parents who had not used nebulizer therapy for their children previously. Both the groups were given nebulizer therapy education using the same content but different learning methods. The experimental group (n=36) was taught using smartphones, while the control group (n=36) was taught using verbal and paper-based methods. The data were analyzed using the Chi Square test, repeated measures analysis of variance, and t-test. RESULTS: The mean scores on knowledge improvement (F=100.949, p<0.001) and confidence in performing care (t=-6.959, p<0.001) were significantly higher for the experimental group as compared to the control group. Further, the scores on satisfaction with the learning method were significantly higher for the experimental group as compared to the control group (t=-5.819, p<0.001). Our results suggest that smartphone-based education on nebulizer therapy might be effective in improving parents' knowledge and confidence in performing care for their children. CONCLUSION: This study suggests that smartphone-based education needs to be considered as an effective educational intervention in providing nursing support for parents of children with respiratory disease. PMID- 28888494 TI - Stress, Anxiety, Depression and Sleep Disturbance among Jordanian Mothers and Fathers of Infants Admitted to Neonatal Intensive Care Unit: A Preliminary Study. AB - PURPOSE: To investigate the stressors and stress levels among Jordanian parents of infants in the NICU and their relationship to three factors: anxiety, depression and sleep disturbance. DESIGN AND METHODS: A cross-sectional survey was conducted in two hospitals in Jordan among 310 parents of infants in the NICU by using PSS: NICU and PROMIS. RESULTS: Both parents experienced high levels of stress, anxiety, depression and sleep disturbance. There was a significant difference in stress level between mothers and fathers [t (308)=3.471, p=0.001], with the mothers experiencing higher stress than the fathers [mean: mothers=108.58; fathers=101.68]. The highest and lowest sources of stress were infant behavior and appearance (M=4.09) and sights and sounds in the NICU (M=3.54), respectively. The correlation between stress levels with anxiety (r=0.79) and depression (r=0.75) was strong and positive while sleep disturbance was significant and moderate (r=0.43). CONCLUSIONS: The mothers experienced higher levels of stress compared to fathers, with positive correlations between stress and anxiety, depression and sleep disturbance. PRACTICAL IMPLICATIONS: The findings of this study create nursing awareness of parent stress and its impact, which will help them to improve nursing care for parents. PMID- 28888495 TI - Teachers' Experiences With and Perceptions of Students With Attention Deficit/hyperactivity Disorder. AB - PURPOSE: The purpose of this research was to examine teacher experiences with and perceptions of students with attention deficit/hyperactivity disorder (ADHD). Teachers are integral in helping these children learn effectively and foster healthy relationships, yet little is known about their interactions with these children. DESIGN AND METHOD: Semi structured interviews were conducted with a purposive sample of fourteen currently practicing or retired elementary and middle schools teachers in North Carolina and South Carolina. All interviews were audio-recorded then analyzed for common themes. RESULTS: Participants obtained ADHD information from in-services or peer interaction, rather than formal education. Culture and gender influenced teacher perceptions, and ADHD classroom strategies were based on anecdotal experience. Teachers experienced guilt and worry while negotiating student needs, school system constraints, and family issues. CONCLUSIONS: While teachers have developed effective coping mechanisms through informal means, formal education and support will help teachers better serve students with ADHD. PRACTICE IMPLICATIONS: Pediatric nurses in many settings can benefit from better understanding how teachers perceive and interact with students who have attentional issues. PMID- 28888496 TI - "Mission Impossible"; the Mothering of a Child With Type 1 Diabetes - From the Perspective of Mothers Experiencing Burnout. AB - PURPOSE: To explore how mothers experiencing burnout describe their mothering of a child with type 1 diabetes mellitus (T1DM), with a focus on their experienced need for control and self-esteem. METHODS: This study used a qualitative, descriptive design and aimed to reveal the experience of mothering a child with diabetes when experiencing burnout. Twenty-one mothers of children with T1DM who were experiencing burnout participated in this study. Data were collected via semi-structured interviews, and content analysis was performed. RESULTS: The main results (latent content of the data) were interpreted in one theme, Mission impossible, an inner feeling derived from an extremely challenging experience of mothering, encompassing involuntary responsibility and constant evaluation. Two sub-themes emerged: Forced to provide extraordinary mothering and Constant evaluation of the mothering. CONCLUSIONS: In addition to monitoring the health of the child with T1DM, it is important for clinicians to pay attention to how mothers experience their daily life in order to support those who are at risk of developing burnout, as well as those who are experiencing burnout. The wellbeing of the mother could influence the wellbeing of the child, as well as the entire family. Further research on perceived parental responsibility, gender differences, psychosocial factors, and burnout is needed. PRACTICE IMPLICATIONS: Knowledge and understanding of how mothers suffering from burnout experience mothering a child with diabetes could help nurses, social workers, psychologists and counselors conducting pediatric diabetes care become more attentive to the mother's situation and have procedures for counseling interventions. PMID- 28888497 TI - Urban-Rural Differences in School Nurses' Asthma Training Needs and Access to Asthma Resources. AB - PURPOSE: Few studies have examined school nurses preferences' for asthma training. Our purpose was to: 1) assess school nurses' perceived asthma training needs, 2) describe nurses' access to asthma educational resources, and 3) identify urban-rural differences in training needs and access to resources in southern states. DESIGN AND METHODS: A convenience sample of school nurses (n=162) from seven counties (two urban and five rural) in North Carolina and South Carolina completed an online, anonymous survey. Chi-square tests were used to examine urban-rural differences. RESULTS: Although most nurses (64%) had received asthma training within the last five years, urban nurses were more likely to have had asthma training than rural nurses (chi2=10.84, p=0.001). A majority of nurses (87%) indicated they would like to receive additional asthma training. Approximately half (45%) of nurses reported access to age-appropriate asthma education materials, but only 16% reported that their schools implemented asthma education programs. Urban nurses were more likely than rural nurses to have access to asthma education programs (chi2=4.10, p=0.04) and age-appropriate asthma education materials (chi2=8.86, p=0.003). CONCLUSIONS: Few schools are implementing asthma education programs. Rural nurses may be disadvantaged in terms of receiving asthma training and having access to asthma education programs and materials. PRACTICE IMPLICATIONS: Schools are an ideal setting for delivering age-appropriate asthma education. By providing school nurses with access to age appropriate asthma education resources and additional asthma training, we can help them overcome several of the barriers that impede their ability to deliver asthma care to their students. PMID- 28888499 TI - The Efficacy of Art Therapy in Pediatric Oncology Patients: An Integrative Literature Review. AB - PROBLEM: Children undergoing cancer treatment experience detrimental adverse side effects that may be addressed with complementary and alternative medicine (CAM) such as art therapy. The purpose of this research was to examine the effects of art therapy in pediatric patients living with cancer. ELIGIBILITY CRITERIA: An integrative literature review was conducted using the CINAHL, OVID Medline, and PsycINFO databases. Studies were included if they were a primary source utilizing an art therapy intervention in children with cancer age birth to 18years old, was published between the year 2000 and 2016, and written in the English language. SAMPLE: Seven primary sources met inclusion criteria. RESULTS: Few studies were reported in this review. Findings of this review suggest that children who participated in various forms of drawing interventions exhibited enhanced communication with family members and healthcare providers. Additionally, children were able to better express underlying emotions, developed more effective coping skills, and experienced a reduction in adverse side effects. CONCLUSIONS: Implementing a drawing intervention or other forms of art into the holistic care of a pediatric oncology patient may assist in maximizing quality of life and allow for a more tolerable lifestyle. IMPLICATIONS: Acquiring a means of proper communication with children through art allows nurses to gain insight on the needs of this special patient population, resulting in a higher quality plan of care. PMID- 28888498 TI - Parental expectations of support from healthcare providers during pediatric life threatening illness: A secondary, qualitative analysis. AB - PURPOSES: To explain parental expectations of support from healthcare providers for their parenting roles and goals during a child's life-threatening illness (LTI). DESIGN AND METHODS: Qualitative interpretive study guided by the Family Adjustment and Adaptation Response Model. Thematic analyses were conducted with data from 31 semi-structured interviews of parents of children with LTI using systematic strategies to ensure rigor including audit trails and prolonged engagement. RESULTS: We identified three themes and one meta-theme or overall theme: (1) "Help us survive this," (2) "Let's fight together: please fight with me, not against me, to care for my family," and (3) "Guide me through the darkness: I am suffering." Overall, the parents conveyed that they expect mutuality with the health care providers and system in order to keep Fighting together for my family survival. CONCLUSIONS: In the daily work of caring for their families, parents of children with LTI consider survival on multiple levels. They consider the life, illness, and potential death of one child while considering the on-going survival and sustenance of family relationships. PRACTICE IMPLICATIONS: Parents are distressed and grapple with conflicted feelings about managing competing needs of various family members. Relationships with health care providers can influence parents' management of the situation and be a source of support as their parenting role changes over the illness trajectory, time, and in response to adversity. PMID- 28888500 TI - Evaluating the Reliability and Validity of the Arabic Version of the Parents Perceptions of Uncertainty Scale (A-PPUS). AB - BACKGROUND: Uncertainty often accompanies illness and may be a major aversive component of the patients' treatment process. There is evidence that parental uncertainty has a negative impact on their own and on their child's coping strategies and may affect family functioning. Key to the provision of competent care, to address uncertainty, is the use of an appropriate validated assessment tool to understand key parental concerns. The 'Parent Perception of Uncertainty Scale' (PPUS) has been widely used for this purpose. AIM: This study reports on the validity and reliability testing of the Arabic version of the Parents Perception of Uncertainty Scale (A-PPUS). METHODS: The scale was translated to Arabic using the translation-back-translation method. Appropriate statistical tests were performed including measurements of internal consistency, item to total scale correlation, and univariate and multivariate analyses. RESULTS: The study included 240 parents of children with chronic illnesses. Cronbach's alpha coefficient of the whole scale was 0.93. All the items were positively correlated to the total score. The univariate and multivariate analysis supported the previous tests and the assertion that the Arabic version of the PPUS provided a relevant measure of the uncertainty level. CONCLUSION: This study has identified that the A-PPUS is a reliable tool for parent report of their uncertainty, in the UAE and Arabic population. PMID- 28888501 TI - The effectiveness of assertiveness training for school-aged children on bullying and assertiveness level. AB - PURPOSE: The aim of this study was to determine the effectiveness of an assertive training for school-aged children on peer bullying and assertiveness. DESIGN AND METHODS: A quasi-experimental design using pre- and post-testing was conducted. Data were collected using a demographic questionnaire, an assertiveness scale, and the peer victimization scale. The training program was comprised of eight sessions which were implemented to intervention group. RESULTS: Descriptive characteristics were not statistically different between the groups (p>0.05). The peer victimization victim dimension results show that post-test mean scores of the students in the intervention group were lower than the pre-test mean scores (p<0.05). For the control group, no significant change was found in the pre-test and post-test mean scores (p>0.05). A comparison of the mean pre-test/post-test scores of peer-victimization bully dimension of the students' intervention and control groups revealed that the mean post-test scores of the students in the each group decreased (p>0.05). CONCLUSIONS: An assertiveness training program increased the assertiveness level and reduced the state of being victims, but did not affect the state of being bullies. PRACTICE IMPLICATIONS: The results of this study can help children acquire assertive behaviors instead of negative behaviors such as aggression and shyness, and help them to build effective social communication. PMID- 28888502 TI - Health Literacy in Adolescents With Sickle Cell Disease. AB - PURPOSE: To evaluate health literacy in a cohort of 75 adolescents with sickle cell disease (SCD). DESIGN AND METHODS: This cross-sectional, descriptive correlational study included assessment of demographic measures and appraisal of data resulting from completion of the REALM-Teen and Newest Vital Sign (NVS) instruments by 75 Black, non-Hispanic adolescents with SCD. Convenience sampling was utilized. Inclusion criteria were a diagnosis of one of the four primary genotypes of SCD and age 10-19years. RESULTS: Thirty-seven males and 38 females were recruited for the study. Their mean age was 14.7years (SD=2.2; range 8.1). Their grade level ranged from 4 to 12 (mean 8.7; SD=2.2). Scores on the REALM Teen ranged from 12 to 66 (mean 53.7; SD=12.8). Scores on the NVS ranged from 0 to 6 (mean 2.37; SD=1.33). These health literacy scores were lower using both the REALM-Teen and the NVS instruments when compared to scores in all healthy adolescents and adults. Current grade level and health literacy scores showed a moderately high positive correlation (r=0.52, p<0.01). Health literacy scores were also significantly positively correlated with age (r=0.49, p<0.01) and income (r=0.37, p<0.01). CONCLUSIONS: Health literacy in adolescents with SCD is suboptimal. Future research should include identifying facilitators and barriers to health literacy levels in a larger cohort of adolescents with SCD. PRACTICE IMPLICATIONS: Health literacy is a potential facilitator of successful health outcomes for all adolescents. This study lays a solid foundation for future adolescent health literacy initiatives. PMID- 28888503 TI - Adolescent Smoking Prevention: Feasibility and Effect of Participatory Video Production. AB - PURPOSE: This study tested whether a youth participatory video production program for smoking prevention is feasible and effective. DESIGN AND METHODS: A participatory video production program was implemented in eight twice-weekly sessions at a youth summer camp in a community center in a low-income neighborhood. Twenty-three youths participated. Descriptive statistics and a qualitative analysis were conducted to test the feasibility of the program by assessing attendance rates, the time and resources required, reasons for participation, and program satisfaction using checklists and interviews. Smoking intention was measured via pre- and post-intervention surveys and a quantitative analysis utilizing a Wilcoxon Signed Rank test to detect differences in intention for non-smoking. RESULTS: Participants worked in groups to produce four video clips containing anti-smoking messages. Three main themes (active engagement, participation for community health, and personal growth and healthy development) emerged from the qualitative interview data. >75% of the participants considered the program excellent and stated that it met their expectations. Significant positive changes were also found from baseline to post-intervention in intention not to smoke. CONCLUSIONS: This study demonstrated the effect of a participatory digital media production approach and confirmed its feasibility for youth health promotion and health education. Participants' active involvement in producing anti-smoking videos for a community health-promotion campaign decreased their intention to smoke and empowered them as advocates for a non-smoking community. PRACTICE IMPLICATIONS: These findings confirm the feasibility and utility of digital media use and interactive technology for actively engaging young people in health promotion. PMID- 28888504 TI - Parenting Practices of African Immigrants in Destination Countries: A Qualitative Research Synthesis. AB - PROBLEM: While studies have discussed the parenting practices and challenges of African immigrants, no paper has synthesized the results of these qualitative studies. We conducted a qualitative synthesis of the literature to summarize and interpret knowledge of African immigrants' parenting practices and challenges in destination countries to identify future directions for research, policy, and practice. ELIGIBILITY: We used a qualitative research synthesis method involving meta-summary and meta-synthesis of the literature. A research librarian assisted in searching ten databases. Two members of the research team independently reviewed 1794 articles. We included articles that: (a) reported a qualitative research study; (b) was written in English; and (c) provided the perspective of African immigrant parents on their parenting practices and/or challenges. SAMPLE: A total of 24 articles met our inclusion criteria. RESULTS: Our results indicate that parenting practices of African immigrants include the following: changes in discipline practices across transnational borders and the use of physical discipline, respect as a deeply embedded value of parenting, integration of cultural values into parenting, and integration of religious practices into parenting. We also found gender differences in parenting. Challenges faced by African immigrants in parenting their children in destination countries include lack of informal/community support, access to services and lack of formal support, cultural conflict in parenting, fear related to social services, and language barriers. CONCLUSION AND IMPLICATIONS: Our study identifies a need for culturally appropriate policies and practices that build on the strengths of African immigrants in destination countries while addressing their unique challenges. PMID- 28888505 TI - Mindfulness for Novice Pediatric Nurses: Smartphone Application Versus Traditional Intervention. AB - PURPOSE: The current study compares the effects of a traditionally delivered mindfulness (TDM) intervention to a smartphone delivered mindfulness (SDM) intervention, Headspace, an audio-guided mindfulness meditation program, in a group of novice nurses. DESIGN AND METHODS: Novice nurses participating in a pediatric nurse residency program were asked to participate in either a TDM or SDM intervention. Participants (N=95) completed self-administered pencil and paper questionnaires measuring mindfulness skills, and risk and protective factors at the start of their residency and three months after entering the program. RESULTS: Nurses in the SDM group reported significantly more "acting with awareness" and marginally more "non-reactivity to inner experience" skills compared to the TDM group. The smartphone intervention group also showed marginally more compassion satisfaction and marginally less burnout. Additionally, nurses in the SDM group had lower risk for compassion fatigue compared to the TDM group, but only when the nurses had sub-clinical posttraumatic symptoms at the start of the residency training program. CONCLUSIONS: Smartphone delivered mindfulness interventions may provide more benefits for novice nurses than traditionally delivered mindfulness interventions. However, the smart-phone intervention may be better indicated for nurses without existing symptoms of posttraumatic stress. PRACTICE IMPLICATIONS: Mindfulness interventions delivered through smartphone applications show promise in equipping nurses with important coping skills to manage stress. Because of the accessibility of smartphone applications, more nurses can benefit from the intervention as compared to a therapist delivered intervention. However, nurses with existing stress symptoms may require alternate interventions. PMID- 28888506 TI - The Perspective of Families With a Ventilator-Dependent Child at Home. A Literature Review. AB - This literature review gives an overview about the existing research concerning the experiences of families with a child with ventilation at home. The number of children with home-ventilation is increasing. Children who receive homecare have the possibility of growing up in their familiar environment and participate in social life. In comparison to children living in institutions, children at home show advantages in their physical, psychological, emotional, social and cognitive development. However, homecare of a child with ventilation places high demands on all family members. Parents assume divergent roles and live with losses. Especially mothers feel isolated, partially through self-imposed isolation. While parents are concerned about this dilemma, talk about their anxieties and strive for stability, children focus on other aspects of their life. They see the ventilator as a positive technique that helps them breathe. The children underline the importance of friends and would like to meet them without nurses in attendance. They strive for normalcy and independence like healthy children, asking for acceptance of themselves and their wishes. There are only few studies about the experience of families with a child with ventilator. Most studies are from the mother's perspective. Parents and children ascribe different importance to the ventilation. Further research should usefully explore the experiences of families with children using home-ventilation. The different perspectives of all family members have to be taken into consideration. PMID- 28888507 TI - Pediatric Nurses' Perspectives on Medication Teaching in a Children's Hospital. AB - PURPOSE: To explore inpatient pediatric nurses' current experiences and perspectives on medication teaching. DESIGN AND METHODS: A descriptive qualitative study was conducted at a Midwest pediatric hospital. Using convenience sampling, 26 nurses participated in six focus groups. Data were analyzed in an iterative group coding process. RESULTS: Three themes emerged. 1) Medication teaching is an opportunity. 2) Medication teaching is challenging. Nurses experienced structural and process challenges to deliver medication teaching. Structural challenges included the physical hospital environment, electronic health record, and institutional discharge workflow while process challenges included knowledge, relationships and interactions with caregivers, and available resources. 3) Medication teaching is amenable to improvement. CONCLUSION: Effective medication teaching with caregivers is critical to ensure safe, quality care for children after discharge. Nursing teaching practices have not changed, despite advances in technology and major changes in hospital care. Nurses face many challenges to conduct effective medication teaching. Improving current teaching practices is imperative in order to provide the best and safest care. PRACTICE IMPLICATIONS: This study generated knowledge regarding pediatric nurses' teaching practices, values and beliefs that influence teaching, barriers, and ideas for how to improve medication teaching. Results will guide the development of targeted interventions to promote successful medication teaching practices. PMID- 28888508 TI - Functional Independence of Children With Myelomeningocele: Is It Associated With the Informal Caregivers' Burden? AB - PURPOSE: This study aims to evaluate the association between the functional independence of children after postnatal spinal dysraphism correction and informal caregivers' burden. DESIGN AND METHODS: This is a cross-sectional study conducted in a child neurosurgery clinic at a University hospital. We included informal caregivers of children between six months and seven-and-a-half years old who were operated on for spinal dysraphism correction due to myelomeningocele. Functional independence was assessed using the Pediatric Evaluation of Disability Inventory (PEDI). Caregivers' burden was assessed through the Caregiver Burden Scale (CBS). RESULTS: Twenty-six caregivers were assessed, all mothers, aged 18 42years. Five provided child care and engaged in paid work. Regarding functional independence, 23.1% of the children were classified as needing supervision, 23.1% moderate assistance, 42.3% maximal assistance, and 11.5% total assistance. Median value for the overall CBS was 27.0 (22.0-53.0). The mean global CBS score was 1.42 and the mean PEDI score was 1.95. Correlations between PEDI and CBS scores were very close to zero. CONCLUSIONS: We found no association between the functional independence of children with myelomeningocele from 0 to 7years old and the burden of informal caregivers. PRACTICE IMPLICATIONS: The effect of functional independence of children with myelomeningocele may be balanced by the caregivers' resilience so that caregivers' burden is not dependent upon the child's independence. PMID- 28888509 TI - Tummy Time for Latinos With Limited English Proficiency: Evaluating the Feasibility of a Cultural and Linguistically Adapted Parent Education Intervention. AB - PURPOSE: Tummy Time is preventive positioning designed to strengthen an infant's neck and upper body muscles and minimize musculoskeletal disorders, including positional plagiocephaly. Latino parents with limited English proficiency (LEP) may experience barriers to receiving instruction on this important health promotion strategy. Study aims included 1) adaptation and implementation of a Spanish-language version of Tummy Time; 2) evaluation of participant Tummy Time knowledge; and 3) assessment of efficacy and acceptability of the Spanish language intervention. DESIGN AND METHODS: This feasibility study involved translation of educational materials into Spanish, creation of Spanish-language print materials, and training of bilingual research assistants to deliver the educational intervention. Participants were 21 Latino expectant and current parents with self-identified LEP. Participants completed brief pre- and post tests and performed a return demonstration. RESULTS: Participant knowledge of Tummy Time increased post-intervention. Program evaluation and on-site observations supported feasibility and acceptability. CONCLUSIONS: The cultural and linguistic tailoring of targeted educational interventions is a feasible and potentially effective strategy to overcome barriers experienced by parents with limited English proficiency and may contribute to improved infant health outcomes. PRACTICE IMPLICATIONS: To be effective, health education programs must be tailored to the target population. Pediatric nurses and nurse practitioners should be aware that populations with LEP face many barriers that may inhibit their ability to participate in and understand health promotion educational activities. While translating interventions can mitigate language barriers, providers should also evaluate and address other barriers such as time constraints, transportation issues, and trust. PMID- 28888510 TI - Improving the Patient Experience: Call Light Intervention Bundle. AB - PURPOSE: Delays in call light response are a significant patient quality and safety concern. Research on call light interventions and patient outcomes has focused exclusively on adult inpatients. This project examined the impact of increasing staff awareness and workflow redesign to improve the pediatric patient experience and outcomes based on timely response. DESIGN AND METHODS: A quality improvement project was conducted on two pediatric medical surgical units' (31 and 35 beds respectively) at a large Midwest academic medical center with patients' ages from to young adults. Data on staff knowledge, patient satisfaction, and fall rates was examined pre- and post-intervention of an evidence-based call light intervention bundle which included: 1) unit-based patient experience committees, 2) purposeful rounding, 3) pod buddy assignments, and 4) staff education. RESULTS: Post-intervention both units demonstrated improvement in staff knowledge on call light interventions and exhibited sustained improvement in patient satisfaction scores for promptness to call. Likelihood to recommend the hospital and satisfaction with pain control improved for one of the two units. No impact on fall rates was noted over time for either unit. CONCLUSIONS: A call light intervention bundle can positively impact patient satisfaction with promptness to call lights in pediatric medical surgical hospitalized patients and their families. Unlike adult patients, a call light intervention bundle did not impact fall rates in children and further study in pediatric fall reduction strategies is needed. PMID- 28888511 TI - The Influence of Peers on Diet and Exercise Among Adolescents: A Systematic Review. AB - Adolescents' diet and exercise are modifiable factors contributing to high rates of adolescent obesity. Diverse contextual factors, including family, social environment, and peers, affect adolescents' diet and exercise behaviors. Because peer influence increases during adolescence, peers' contributions to adolescents' diet and exercise behaviors should be examined as potential targets for intervention to reduce the prevalence of adolescent obesity. The purpose of this systematic review is to identify research examining the contribution of peers to diet and exercise of adolescents. The electronic databases PubMed, CINAHL, Web of Science, and SCOPUS were searched. A total of 24 unique articles were included: seven examined diet only, fourteen studied exercise only, and three explored diet and exercise. This review provided evidence that diet and exercise of adolescents were significantly associated with those of their peers. However, these associations differed depending on gender, the type of diet and exercise, and closeness of friends. Findings from this review suggest that peers could be possible targets for interventions to promote healthier diet and exercise among adolescents; however, more studies are needed to identify specific peer influences and develop tailored interventions. PMID- 28888512 TI - Caring for a Child With an Obstetric Brachial Plexus Injury: A Metaphor Analysis. AB - PURPOSE: The purpose of this study was to examine the metaphors used by mothers to describe their experiences caring for their children with obstetric brachial plexus injuries. DESIGN AND METHODS: A secondary qualitative data analysis was conducted from the primary data set of a phenomenological study of mothers' experiences caring for their children with obstetric brachial plexus injuries. The type of secondary qualitative data analysis approach used was analytic expansion. Metaphor Identification Procedure was used to analyze the corpus of 132 pages of typed transcription. RESULTS: This metaphorical analysis yielded seven metaphors mothers used to describe their experiences caring for their children with obstetric brachial plexus injuries. These metaphors portrayed mothers' lives as involving a heavy weight, a maze, a juggling act, a simmering pot, a dagger to the heart, a rollercoaster, and a constant battle. CONCLUSION: The seven metaphors helped women express what they could not completely capture using only medical jargon and provide valuable insight for clinicians. Using secondary qualitative data analysis to mine for any metaphors in a primary data set gives researchers another valuable and creative opportunity to discover new knowledge from the data they had previously collected. PRACTICE IMPLICATIONS: Specific interventions can be developed to target each of these seven metaphors to help mothers in their daily care for their children with obstetric brachial plexus injuries. PMID- 28888513 TI - Enhancing Pediatric Asthma Care and Nursing Education Through an Academic Practice Partnership. AB - BACKGROUND: Home environmental assessments and interventions delivered via academic practice partnerships (APP) between clinics and schools of nursing may be a low or no cost delivery model of pediatric asthma care and professional education. Patients receive enhanced clinical resources that can improve self management and healthcare utilization. Additionally, students can practice chronic disease management skills in actual patient encounters. OBJECTIVE: To describe outcomes of the implementation of an APP between a school of nursing and a pediatric asthma specialty clinic (PASC) to deliver a home visit program (HVP). The HVP was designed to reduce emergency department visits and asthma related hospitalizations in PASC patients and provide clinical experiences for nursing students. METHODS: PASC referred patients to the HVP based on their level of asthma control. Students provided an individualized number of home visits to 17 participants over a nine month period. A 12-month pre- and post-HVP comparison of emergency department visits and asthma related hospitalizations was conducted. Additional information was gathered from stakeholders via an online survey, and interviews with APP partners and HVP families. OUTCOMES: Children had fewer asthma related hospitalizations post HVP. Findings suggest a reduction in exposure to environmental triggers, improved patient and family management of asthma, and increased PASC knowledge of asthma triggers in the home and increased student knowledge and skills related to asthma management. CONCLUSIONS: Multiple clinical and educational benefits may be realized through the development of APPs as an infrastructure supporting targeted interventions in home visits to pediatric asthma patients and their families. PMID- 28888514 TI - Indicators of Non-adherence to Asthma Treatment in Pediatric Primary Care. AB - PURPOSE: Chronic disease management represents an ongoing challenge, as many childhood illnesses require complex medical management by primary care providers. Asthma is one such illness, and today there is evidence to support primary care based management strategies that will benefit patients with asthma throughout a lifetime. This study seeks to find significant indicators of asthma non-adherence in pediatric primary care, with potential for utilization in the medical home model. DESIGN AND METHODS: Potential indicators included in a chart review process of one large Southeastern U.S. primary care pediatric practice were reviewed from the previous calendar year for asthma patients. The study retroactively looks at the incidence of six indicators in relation to asthma related emergency department visits and hospitalizations, and number of missed appointments for clinically relevant associations. RESULTS: Strong associations were found between emergency department visits and hospitalizations and many of the indicators of non-adherence with high statistical significance. No associations were found between number of missed appointments and the selected indicators. CONCLUSIONS: The data analysis performed from the collected patient information can be helpful to guide practices in further discussions on the topic. Results were analyzed and reported to the practice in review as recommendations for a new medical home asthma documentation protocol that is in development. PRACTICAL IMPLICATIONS: The indicators of non-adherence to asthma treatments identified may be useful in developing markers of disease severity in primary care pediatrics. Medical home access to knowledge of target populations can lead to better patient outcomes with lower cost to stakeholders. PMID- 28888515 TI - "Treat Me Like a Normal Person!" A Meta-Ethnography of Adolescents' Expectations of Their Health Care Providers. AB - PURPOSE: Preventive health care services provide an important opportunity to assist adolescents to establish and maintain a healthy lifestyle and assume an increasing independent role in their health care. National guidelines emphasize the importance of an annual wellness visit to identify and address risk-behaviors that contribute significantly to the morbidity and mortality in this population. Despite these recommendations, adolescents utilize preventive health care at declining rates throughout adolescence. The purpose of this study was to capture a more holistic view of what adolescents, as consumers of health care services, expect from their primary health care providers (HCPs). METHOD: A metasynthesis of 12 qualitative research studies was conducted using Noblit and Hare's (1988) meta-ethnographic approach. RESULTS: Five overarching metaphors, Talk with Me- Not at Me, Accept Me, Respect My Privacy and Confidentiality, Show Me You Are a Professional, and A Trusted Relationship described adolescents' expectations of their HCPs. CONCLUSIONS: This study provides a more holistic view of adolescents' expectations of their HCPs. Clinical strategies are suggested to assist HCPs to meet adolescents' expectations. PMID- 28888516 TI - Effects of Animal-assisted Activities on Biobehavioral Stress Responses in Hospitalized Children: A Randomized Controlled Study. AB - PURPOSE: This study assessed the effectiveness of animal-assisted activities (AAA) on biobehavioral stress responses (anxiety, positive and negative affect, and salivary cortisol and C-reactive protein [CRP] levels) in hospitalized children. DESIGN AND METHODS: This was a randomized, controlled study. METHOD: Forty-eight participants were randomly assigned to receive a 10-minute AAA (n=24) or a control condition (n=24). Anxiety, positive and negative affect, and levels of salivary biomarkers were assessed before and after the intervention. RESULTS: Although increases in positive affect and decreases in negative affect were larger in the AAA condition, pre- and post-intervention differences between the AAA and control conditions were not significant. In addition, pre- and post intervention differences between the conditions in salivary cortisol and CRP were not statistically significant. Baseline levels of anxiety, cortisol, and CRP had a significant and large correlation to the corresponding post-intervention measures. Scores on the Pet Attitude Scale were high but were not associated with changes in anxiety, positive affect, negative affect, or stress biomarkers. CONCLUSIONS: Although changes were in the expected direction, the magnitude of the effect was small. Future randomized controlled trials with larger recruitment are needed to determine the effectiveness of AAAs in reducing biobehavioral stress responses in hospitalized children. PRACTICE IMPLICATIONS: Nurses are positioned to recommend AAA as a beneficial and safe experience for hospitalized children. PMID- 28888517 TI - Beliefs Regarding Asthma Management Relating to Asthma Action Plans (AAPs) of African American Caregivers Residing in Newark, New Jersey Public Housing Communities. AB - PURPOSE: The purpose of this study was to explore the beliefs regarding asthma management and Asthma Action Plans (AAPs) of African American caregivers residing in three New Jersey public housing communities in Newark, New Jersey. DESIGN: A qualitative methods design was accomplished using semi-structured interviews with a purposive sample of nine African American caregivers of children with asthma. Information was coded using N'VIVOTM; the textual analysis combined codes into categories, which were then assembled into themes. RESULTS: Self-determination was found to be a fundamental goal of asthma management; however, three themes emerged as barriers and facilitators to this goal: challenges in the urban environment, preference of familial methods, and access to medical care. CONCLUSIONS: Findings from this study regarding minority caregivers' beliefs regarding difficulty navigating the health care system coupled with insurance instability, leading to use of Emergency Departments, are consistent with past research. Although caregivers expressed belief in use of prescribed medications as indicated on AAPs, familial methods, found to provide a sense of control over asthma, were preferred. PMID- 28888518 TI - The Effect of Oral Care Using an Oral Health Care Guide on Preventing Mucositis in Pediatric Intensive Care. AB - OBJECTIVES: To evaluate the effectiveness of standard-of-care oral care guides developed specifically for children in intensive care to prevent mucositis. DESIGN AND METHODS: This prospective, interventional and single-group study design was performed in the pediatric intensive care unit of a university hospital in Istanbul between January and December 2014. Daily oral care was implemented to pediatric patients in the study group in line with an oral care guide developed by the researchers. Data were collected using the data collection form and oral mucositis assessment scale published by the World Health Organization (WHO). RESULTS: Oral mucositis occurred in 16 (5.2%) patients in the pre-intervention group and 7 (2.5%) in the post-intervention group, 10 patients had grade 1, and 6 patients had grade 2 oral mucositis in the pre-intervention group, and in the post-intervention group, three patients had grade 1, and four patients had grade 2 oral mucositis. Although more patients in the pre intervention group had mucositis than in the post-intervention group, the differences were not statistically significant (P=0.067). CONCLUSIONS: Oral mucositis can be reduced through the practice of administering oral care in accordance with oral healthcare guidelines. PRACTICE IMPLICATIONS: Oral care implemented in line with an evidence-based oral care guide and frequent observation of patients are the most important steps in preventing oral mucositis. PMID- 28888519 TI - An Integral Component of Pediatric Nursing Practice. PMID- 28888520 TI - Are Outcomes Related to Left Ventricular Assist Device Center Volume?: Too Complex to Answer. PMID- 28888522 TI - Sleep Disordered Breathing and Heart Failure: What Does the Future Hold? AB - Most patients with heart failure (HF) have sleep-disordered breathing (SDB), with central (rather than obstructive) sleep apnea becoming the predominant form in patients with more severe disease. Cyclical apnea and hypopneas are associated with sleep disturbance, hypoxemia, hemodynamic changes, and sympathetic activation. These patients have a worse prognosis than those without SDB. Mask based therapies of positive airway pressure targeted at SDB can improve measures of sleep quality and can partially normalize the sleep and respiratory physiology. However, recent randomized trials of cardiovascular outcomes in central sleep apnea in chronic HF with reduced ejection fraction have had neutral findings or suggested the possibility of harm, likely from an increased rate of sudden death. Further randomized outcome studies are required to determine whether mask-based treatment is appropriate for patients with chronic HF with reduced ejection fraction and obstructive sleep apnea, for patients with heart failure with preserved ejection fraction, and for patients with decompensated heart failure. New therapies for sleep apnea (e.g., implantable phrenic nerve stimulators) also require robust assessment. No longer can the surrogate endpoints of improvement in respiratory and sleep metrics be taken as adequate therapeutic outcome measures in patients with HF and sleep apnea. PMID- 28888521 TI - Impact of Center Left Ventricular Assist Device Volume on Outcomes After Implantation: An INTERMACS Analysis. AB - OBJECTIVES: This study examined patient outcomes after left ventricular assist device (LVAD) implantation across a range of center surgical volumes. BACKGROUND: In order for a center to qualify for reimbursement, Centers for Medicare and Medicaid Services (CMS) requires it to implant >=10 LVADs or total artificial hearts over a 3-year period. The impact of center LVAD surgical volumes on patient outcomes has not been thoroughly scrutinized. METHODS: Center volumes were provided for 7,416 patients undergoing LVAD implantation who were enrolled in INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). Center LVAD volume was categorized as either very low (<=10 implants/year, n = 617), low (11 to 30 implants/year, n = 2,561), medium (31 to 50 implants/year, n = 2,458), or high (>50 implants/year, n = 1,750). The main outcome of interest was patient survival based on center volume derived from Kaplan-Meier and multivariate Cox regression. RESULTS: Overall survival was associated with center volume (p = 0.003), as follows: 71 +/- 1.8% (very low volume), 81 +/- 0.8% (low volume), 83 +/- 0.8% (medium volume), and 79 +/- 1.0% (high volume) at 1 year. Compared with medium volume centers, the 90-day mortality was higher in very low volume (odds ratio [OR]: 1.35; p = 0.04) and high volume (OR: 1.28; p = 0.018) VAD centers. The adjusted hazard ratios (HRs) for mortality were 1.32 (95% confidence interval [CI]: 1.11 to 1.56), 1.07 (95% CI: 0.95 to 1.21), and 1.17 (95% CI: 1.03 to 1.30) for very low, low, and high volume centers, respectively. Center volume did not predict mortality (p = 0.25; n = 3,688) in INTERMACS profile 1 patients (patients who had sustained cardiogenic shock) and profile 2 patients (patients with progressive hemodynamic decline despite inotropes). CONCLUSIONS: Center volume correlates with post-VAD survival, with worse survival noted at very-low volume centers. These findings suggest that current U.S. VAD center standards warrant reconsideration. PMID- 28888523 TI - Mechanical alignment technique for TKA: Are there intrinsic technical limitations? AB - BACKGROUND: Mechanically aligned (MA) total knee arthroplasty (TKA) is affected by disappointing functional outcomes in spite of the recent improvements in surgical precision and implant designs. This might suggest the existence of intrinsic technical limitations. Our study aims to compare the prosthetic and native trochlear articular surfaces and to estimate the extent of collateral ligament imbalance, which is technically uncorrectable by collateral ligament release when TKA implants are mechanically aligned. STUDY HYPOTHESIS: Conventional MA technique generates a high rate of prosthetic overstuffing of the distal groove, distal lateral trochlear facet and distal lateral femoral condyle (Hypothesis 1), and technically uncorrectable collateral ligament imbalance (hypothesis 2)? Disregarding the distal femoral joint line obliquity (DFJLO) when performing femoral cuts explains distal lateral femoral prosthetic stuffing and uncorrectable imbalance (hypothesis 3)? METHODS: Twenty patients underwent a conventional MA TKA. Pre-operative MRI-based 3D knee models were generated and MA TKA was simulated. Native and prosthetic trochlear articular surfaces were compared using in-house analysis software. Following the automatic determination by the planning software of the size of the extension and flexion gaps, an algorithm was applied to balance the gaps and the frequency and amplitude of technically uncorrectable knee imbalance were estimated. RESULTS: The conventional MA technique generates a significant slight distal lateral femoral prosthetic overstuffing (mean 0.6mm, 0.8mm, 1.25mm for the most distal lateral facet point, groove, and at the most distal point of lateral femoral condyle, respectively) and a high rate of type 1 and 2 uncorrectable knee imbalance (30% and 40%, respectively). The incidence of distal lateral prosthetic overstuffing (trochlea and condyle) and uncorrectable knee imbalance were strongly to very strongly correlated with the DFJLO (r=0.53 to 0.89). CONCLUSION: Conventional MA technique for TKA generates frequent lateral distal femoral prosthetic overstuffing and technically uncorrectable knee imbalance secondary to disregarding the DFJLO when adjusting the femoral component frontal and axial rotations, respectively. LEVEL OF EVIDENCE: level 4. PMID- 28888524 TI - Total knee arthroplasty after opening- versus closing-wedge high tibial osteotomy. A 135-case series with minimum 5-year follow-up. AB - INTRODUCTION: High tibial osteotomy (HTO) is effective in treating isolated medial osteoarthritis of the knee, but subsequent deterioration is inevitable, and total knee arthroplasty (TKA) is then an option. The present study sought to compare TKA following medial opening-wedge HTO (OW-HTO) versus lateral closing wedge HTO (CW-HTO) in terms of intraoperative data and clinical results. The study hypothesis was that there is no significant difference in clinical results or complications in TKA following OW-HTO or CW-HTO. MATERIAL AND METHOD: A retrospective multicenter (9 centers) study was conducted for the French Society of Orthopedic Surgery and Traumatology (SoFCOT), including 135 TKAs following HTO (58 OW and 77 CW) at a minimum 5 years' follow-up. Mean interval between HTO and TKA was 134 months and was longer in case of CW-HTO (P<0.0001). Mean age at TKA was 65.4 years and older in case of CW-HTO (P=0.021). Tibial slope was greater in case of OW-HTO (P=0.024). Prior to TKA, 55.7% of patients could walk without canes, 98.4% found stairs difficult or impossible and only 19.1% could manage a walking distance greater than 1000m. Mean flexion was 110 degrees ; 54.2% of patients showed frontal knee stability and 87.8% sagittal stability; 60.1% had a mechanical axis in varus, without difference according to OW- or CW-HTO. RESULTS: Hardware was almost systematically removed (in 98.5% of cases): in the same step for OW-HTO (P=0.018) or often in 2 steps for CW-HTO. The primary approach was generally re-used (54.2%), but less frequently in the CW-HTO group (P=0.0004). Lateral or medial ligament release was not associated in respectively 78.2% and 79.7% of cases. The TKA implant was usually without stem (87.2%) and was fitted using a conventional technique (74.4%). At a mean 87 months' follow-up, 78.5% of patients could walk without canes, stairs were still difficult or impossible for 67%, and 74.1% could now walk further than 1000m; mean flexion was 110.5 degrees . Overall, 91.5% of patients showed frontal knee stability and 98.2% sagittal stability, without difference according to OW- or CW-HTO. There were 15 complications within 3 months, more often in the OW-HTO group (12.3%) although not significantly, and with no difference in severity. Late complications comprised loosening (5.5%) and infection (3.6%) and were more frequent in the CW HTO group (12%) (P<0.05). DISCUSSION: The study hypothesis was partially confirmed. The only technical differences concerned hardware removal, often performed in two steps in case of CW-HTO, and TKA approach, which differed from the primary approach in case of CW-HTO. Clinical results were comparable between OW- and CW-HTO, but late complications were more frequent in the CW-HTO group. LEVEL OF EVIDENCE: III; comparative retrospective study. PMID- 28888525 TI - Clinical and radiological outcomes following radioscapholunate fusion. AB - INTRODUCTION: Radioscapholunate (RSL) fusion is typically performed following wrist trauma. It addresses the pain caused by radiocarpal osteoarthritis but reduces the wrist's mobility. The objective of this study was to determine the long-term clinical and radiological outcomes of this procedure. MATERIALS AND METHODS: This was a retrospective study of all wrists operated for RSL fusion in our surgery unit over a 12-year period. The clinical analysis consisted of joint amplitudes, grip strength, pain (VAS) and functional scores (PRWE, QuickDash, Mayo Wrist Score). The radiological analysis focused on bone fusion and the presence of midcarpal osteoarthritis. RESULTS: This surgery procedure was performed on 48 wrists. Of these, 34 patients were available for review, including 6 who had subsequently undergone total wrist fusion after the RSL procedure. The average follow-up was 53 months. Flexion/extension and radioulnar deviation were 56 degrees and 30 degrees , respectively. Grip strength in the operated wrist was 71% of the contralateral wrist. The mean pain level was 3 out of 10. The PRWE, QuickDash and Mayo Wrist Score were 35.7, 44.5 and 57.2, respectively. Seventy-nine percent of patients were satisfied with the outcome. The fusion rate was 71%, the midcarpal osteoarthritis rate was 64% and the STT osteoarthritis rate was 46%. DISCUSSION: Reduced wrist range of motion in patients who have undergone RSL fusion helps to preserve satisfactory function in the majority of patients; however, the functional outcome scores point to some hindrance in day-to-day activities. Nonunion occurred in nearly one-quarter of patients and appears to be preventable by excision of the distal pole of the scaphoid (DPS). Midcarpal osteoarthritis develops in most wrists over the long term and appears to be inevitable. CONCLUSION: RSL fusion is a palliative procedure that preserves some of the wrist's mobility. However, it is a difficult procedure that has a significant nonunion rate. Excision of the DPS may contribute to lowering the nonunion rate. PMID- 28888526 TI - Posterior shoulder instability managed by arthroscopic acromial pediculated bone block. Technique. AB - : In posterior shoulder instability (recurrent dislocation, involuntary posterior subluxation or voluntary subluxation that has become involuntary), surgery may be considered in case of failure of functional treatment if there are no psychological contraindications. Acromial bone-block with pediculated deltoid flap, as described by Kouvalchouk, is an alternative to iliac bone-block, enabling triple shoulder locking by the blocking effect, the retention hammock provided by the deltoid flap and posterior capsule repair. Arthroscopy allows shoulder joint exploration and diagnosis of associated lesions, with opening and conservation of the posterior capsule; it greatly facilitates bone-block positioning and capsule reinsertion. The present report describes the procedure in detail. LEVEL OF EVIDENCE: Technical note. PMID- 28888528 TI - Redefining knee replacement. PMID- 28888527 TI - Complications following harvesting of patellar tendon or hamstring tendon grafts for anterior cruciate ligament reconstruction: Systematic review of literature. AB - : Anterior cruciate ligament (ACL) reconstruction can be performed with an autograft, which is most often harvested from the patient's hamstring tendon (HT) or patellar tendon (PT). However, autograft harvesting leads to morbidity that is by no means insignificant. A systematic review of literature was performed to define the incidence of complications related to graft harvesting and the methods to prevent these complications. In March 2017, a systemic review of literature was performed using the keywords"harvesting", "harvest", "morbidity", "complication", "cruciate ligament". No time limit was applied. The studies had to be written in French or English with their abstract available online. This initial search based on the title and abstract identified 133 articles. Two independent observers analyzed each article entirely, including the references. In all, 36 articles were retained. The main complication of HT harvesting was sensory deficit because of damage to the infrapatellar branches of the saphenous nerve. This complication occurred in 39.7% to 88% of patients. This risk can be reduced by using a horizontal or oblique incision. The main complication following PT harvesting is anterior knee pain, reported in up to 46% of patients. There are substantial numbers of short-, medium- and long-term complications related to the harvesting of the two main ACL autografts. Effective means of prevention exist to reduce the risk of these complications. LEVEL OF EVIDENCE: II Systematic review of literature. PMID- 28888529 TI - Eyelid inflammation: An uncommon cause in occidental countries. AB - BACKGROUND: Myiasis designates the infestation of live human and vertebrate animals with dipterous (two-winged) larvae (maggots) and is the fourth most common travel-associated skin disease. Furuncle is the most common aspect of cutaneous myiasis. CASE PRESENTATION: A 24-year-old Caucasian female had been back from Cap-Vert. She described pruritus, slight pain, and the sensation of a foreign body moving in the eyelid. Physical examination showed a single furuncle like nodule with surrounding erythema and a central pore of the upper eyelid through which a serosanguinous fluid was exuding. A larval end was visible to the naked eye through the aforementioned pore. Treatment consisted of the application of petroleum jelly (Vaseline(r)) to produce localized hypoxia. A transparent occlusive dressing was set for a duration of 2 h. The larva, Cordylobia antropophaga, spontaneously externalized to breathe and was extracted. DISCUSSION: There is an increase in travelers returning from tropical countries. Consequently, travel-associated dermatoses are increasing in non-endemic countries. Context of travel and typical clinical presentation strongly suggested to evoke a cutaneous myiasis. The typical furuncular lesion is a papule or nodule with a central punctum that exudes serosanguinous or purulent fluid. Ultrasound can be used to confirm the diagnosis. Treatment consists of three techniques: methods producing localized hypoxia to force emergence of the larvae, application of toxic substances to the eggs and larvae, and mechanical or surgical debridement. Surgery and antibiotics are usually unnecessary. Prevention of furunculous myiasis is based on vector control and individual actions to improve hygiene. PMID- 28888530 TI - Economic implications of unintentional carbon monoxide poisoning in the United States and the cost and benefit of CO detectors. AB - BACKGROUND: Unintentional non-fire-related (UNFR) carbon monoxide (CO) poisoning has been among the leading causes of poisoning in the United States. Current estimation of its economic burden is important for an optimal allocation of resources for UNFR CO poisoning prevention. OBJECTIVE: This study was to estimate the morbidity costs of UNFR CO poisoning. We also compared the costs and benefits of installing CO detectors in residences. METHODS: We used 2010-2014 charges and cost data from Healthcare Cost and Utilization Project (HCUP), and Truven(c) Health MarketScan Commercial Claims and Encounters and Medicare Supplemental data. We directly measured the morbidity cost as the summation of costs for different healthcare services. Benefit of installing CO detector was estimated by summing up the avoidable morbidity cost and mortality cost (value of life). Cost of CO detectors was calculated using the average market price of CO detectors. We also calculated the benefit-to-cost ratio by dividing the benefit by its cost. All expenditures were converted into 2013 U.S. dollars. RESULTS: For UNFR CO poisoning, total annual medical cost ranged from $33.6 to $37.7 million. Annual non-health-sector costs varied from $3.7 to almost $4.4 million. The benefit-to cost ratio can be as high as 7.2 to 1. CONCLUSION: UNFR CO poisoning causes substantial economic burden in the U.S. The benefit of using CO detectors in homes to prevent UNFR CO poisoning can considerably exceed the cost of installation. Public health programs could use these findings to promote broad installation of CO detectors in homes. PMID- 28888531 TI - Post-cardiac injury syndrome: an atypical case following percutaneous coronary intervention. AB - Post-cardiac injury syndrome (PCIS) is a syndrome characterized by pericardial and/or pleural effusion, triggered by a cardiac injury, usually a myocardial infarction or cardiac surgery, rarely a minor cardiovascular percutaneous procedure. Nowadays, the post-cardiac injury syndrome, is regaining importance and interest as an emerging cause of pericarditis, especially in developed countries, due to a great and continuous increase in the number and complexity of percutaneous cardiologic procedures. The etiopathogenesis seems mediated by the immunitary system producing immune complexes, which deposit in the pericardium and pleura and trigger an inflammatory response. We present the atypical case of a 76-year-old man presenting with a hydro-pneumothorax, low-grade fever and elevated inflammation markers, after two complex percutaneous coronary interventions, executed 30 and 75 days prior. The clinical features of our case are consistent with the diagnostic criteria of PCIS: prior injury of the pericardium and/or myocardium, fever, leucocytosis, elevated inflammatory markers, remarkable steroid responsiveness and latency period. Only one element does not fit with this diagnosis and does not find any further explanation: the air accompanying the pleural effusion, determining a hydro-pneumothorax and requiring a pleural drainage catheter positioning. PMID- 28888532 TI - Soft tissue oxygen saturation prediction of admission from the ED. PMID- 28888533 TI - An overview of posttraumatic stress disorder genetic studies by analyzing and integrating genetic data into genetic database PTSDgene. AB - Posttraumatic stress disorder (PTSD) is a debilitating psychiatric syndrome with complex etiology. Studies aiming to explore genetic susceptibility and environmental triggers of PTSD have been increasing. However, the results are limited and highly heterogeneous. To understand the genetic study status of PTSD and explore more reliable candidates, we obtained 105 PTSD related genetic studies by comprehensively literature searching and filtering 1762 studies. Detailed phenotype and sample information for each study and association results for each genetic marker were extracted. Based on the extracted data, we reviewed the PTSD genetic research status and further conducted bioinformatics analyses for the genetic data. Our analyses summarized the landscape of PTSD genetic studies, identified the genes with most genetic evidence, discovered the biological function of the candidate variants/genes and enlarged the overall candidates for future investigations. All the data were stored in the PTSDgene database (http://ptsdgene.psych.ac.cn). We hope PTSDgene could be a platform for the rapid growth of PTSD genetic data and provide new insights into the pathogenesis of PTSD. PMID- 28888534 TI - Psychiatric phenotypes in chronic traumatic encephalopathy. AB - Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder involving cognitive, motor, and psychiatrically-relevant symptoms resulting from repetitive head impacts. Psychiatric phenotypes of CTE, including depression and suicidality, present particular challenges for CTE research, given that the diagnosis requires postmortem neuropathological examination. The pathognomonic lesion of CTE is the perivascular accumulation of hyperphosphorylated tau (ptau) protein at the depths of cortical sulci. These lesions are found in the earliest disease stages, and with advancing pathological severity, ptau deposition occurs in widespread brain regions in a four-stage scheme of severity. We review the psychiatric phenotypes of individuals neuropathologically diagnosed with CTE, and suggest that earlier CTE stages hold particular interest for psychiatric CTE research. In the early CTE stages, there is ptau pathology in frontal cortex and axonal loss in the frontal white matter, followed by progressive ptau neurofibrillary degeneration in the amygdala and hippocampus. Neuropathological changes in the frontal and medial temporal lobes may underlie psychiatric phenotypes. Additional insight into the association between CTE pathology and psychiatric sequelae may come from advancements in in vivo methods of CTE detection. Further epidemiological, clinical, and postmortem studies are needed to validate the nature of psychiatric sequelae in CTE. PMID- 28888535 TI - From psychological moments to mortality: A multidisciplinary synthesis on heart rate variability spanning the continuum of time. AB - Heart rate variability (HRV) indexes functioning of the vagus nerve, arguably the most important nerve in the human body. The Neurovisceral Integration Model has provided a structural framework for understanding brain-body integration, highlighting the role of the vagus in adaptation to the environment. In the present paper, we emphasise a temporal framework in which HRV may be considered a missing, structural link between psychological moments and mortality, a proposal we label as Neurovisceral Integration Across a Continuum of Time (or NIACT). This new framework places neurovisceral integration on a dimension of time, highlighting implications for lifespan development and healthy aging, and helping to bridge the gap between clearly demarcated disciplines such as psychology and epidemiology. The NIACT provides a novel framework, which conceptualizes how everyday psychological moments both affect and are affected by the vagus in ways that have long-term effects on mortality risk. We further emphasize that a longitudinal approach to understanding change in vagal function over time may yield novel scientific insights and important public health outcomes. PMID- 28888536 TI - In vitro immunostimulatory potential of fungal beta-glucans in pacific red snapper (Lutjanus peru) cells. AB - This study attempts to describe the immunostimulatory effects of three fungal glucans on innate immunity responses in an in vitro assays using Pacific red snapper leukocytes. First, the yield glucans obtained was higher in Aspergillus niger, follow by Aspergillus ochraceus and Alternaria botrytis (40, 20 and 10%, respectively). Structural characterization of these fungal glucans by proton nuclear magnetic resonance (NMR) indicated structures containing (1-6)-branched (1-3)-beta-D-glucan. The immunostimulatory activity of fungal glucans were assessed in head-kidney leukocytes at 24 h using colorimetric assays and molecular gene expression. In addition, the response against bacterial infection using Aeromonas hydrophila was evaluated by flow cytometry with annexin V/propidium iodide. Leukocytes responded positively to fungal glucans where the viability was higher than 80%. Interestingly, A. niger beta-glucans enhanced the phagocytic ability and capacity in head-kidney leukocytes. Immunological assays reveled an increased in nitric oxide production, myeloperoxidase, superoxide dismutase and catalase activities, in fish stimulated with A. niger beta-glucans. Induction of cytokines (IL-1beta, TNF-alpha, IL-6, IL-8 and IL-12) were more pronounced in A. niger beta-glucans leukocytes stimulated compared to other group. Finally, flow cytometry assay showed that A. botrytis and A. niger beta glucans were able to inhibit apoptosis caused by Aeromonas hydrophila in the Pacific red snapper leukocytes indicating an immunostimulant potent response by fungi derived-glucans. These results strongly support the idea that fungal beta glucans can stimulate the immune mechanism in head-kidney leukocytes and that Aspergillus niger beta-glucan possess immunostimulatory properties cell increasing viability, and reducing necrotic cell death caused by Aeromonas hydrophila. PMID- 28888537 TI - A GTP-dependent Phosphoenolpyruvate Carboxykinase from Crassostrea gigas Involved in Immune Recognition. AB - Phosphoenolpyruvate carboxykinase (PEPCK) is well known as a key enzyme involved in the metabolic pathway of gluconeogenesis in organisms, but the information about its involvement in immune response is still very limited. In the present study, a novel PEPCK homolog named CgPEPCK was identified from oyster Crassostrea gigas. The deduced amino acid sequence of CgPEPCK shared 52%-74% similarities with those from other known PEPCKs. There were one conserved guanosine triphosphate (GTP) binding site, one substrate binding site, one metal binding site and one active site in CgPEPCK. The mRNA transcripts of CgPEPCK were constitutively expressed in all the tested tissues including hemolymph, mantle, gill, muscle, gonad and hepatopancreas. CgPEPCK proteins were mainly distributed in adductor muscle, gonad, gill and mantle, and rarely detected in hepatopancreas by using immunohistochemical analysis. After the stimulations with lipopolysaccharide (LPS), peptidoglycan (PGN), Vibrio splendidus and V. anguillarum, CgPEPCK transcripts in hemocytes were significantly up-regulated and peaked at 6 h (LPS, 9.62-fold, p < 0.01), 9 h (PGN, 4.25-fold, p < 0.01), 12 h (V. splendidus, 5.72-fold, p < 0.01), 3 h (V. anguillarum, 2.87-fold, p < 0.01), respectively. The recombinant CgPEPCK protein (rCgPEPCK) exhibited Mn2+/Mg2+ dependent GTP binding activity, and the activities to bind LPS and PGN, but not beta-1,3-glucan (GLU), lipoteichoic acid (LTA), mannan (MAN) nor polyinosinic polycytidylic (Poly I: C). It could also bind Escherichia coli, Staphylococcus aureus, Micrococcus luteus and significantly inhibit their growth. All these results collectively suggested that CgPEPCK could not only exert GTP binding activity involved in gluconeogenesis, but also mediate the bacteria recognition and clearance in immune response of oysters. PMID- 28888538 TI - The self-activation and LPS binding activity of executioner caspase-1 in oyster Crassostrea gigas. AB - Executioner caspases play important roles in apoptotic pathway and immune defense, which is considered to coordinate the execution phase of apoptosis by cleaving multiple structural and repair proteins. However, the knowledge about the activation mechanism and function of executioner caspases in mollusks, especially marine bivalves is limited. In the present study, the full-length cDNA sequence of caspase-1 was cloned from oyster Crassostrea gigas, which encoded a predicted protein containing a small subunit (p10) and large subunit (p20) with a conserved caspase active site QACRG similar to that of human executioner caspase 3/7. SDS-polyacrylamide gel electrophoresis and western blot results demonstrated that the CgCaspase-1 zymogen could be cleaved into p20p10, p20 and p10 in prokaryotic expression systems, and the C-terminus of CgCaspase-1 was also cleaved into p20 and p10. Both of the recombinant CgCaspase-1 (rCgCaspase-1) and the C-terminus of CgCaspase-1 (rCgCaspase-1-C) exhibited similar caspase activity towards proteolytic substrate Ac-DMQD-pNA and Ac-DEVD-pNA. However, the recombinant N-terminus of CgCaspase-1 (rCgCaspase-1-N) did not display any caspase activity. Moreover, the inhibitor of both caspase-3/7 and pan-caspase could significantly inhibit the proteolytic activity of rCgCaspase-1. The strong binding activities towards lipopolysaccharide (LPS) of both rCgCaspase-1 and rCgCaspase-1-C were revealed by ELISA techniques and western blotting. A high level of CgCaspase-1 mRNA transcripts was detected in the gills and hemocytes by quantitative real-time PCR, and the CgCaspase-1 protein was mainly located in the cytoplasm of oyster hemocytes by immunofluorescence assay. These results collectively suggested that CgCaspase-1 was a homolog of executioner caspase-3/7, which could be self-activated through proteolytic cleavage in prokaryotic expression systems, and performed caspase and LPS binding activities in the innate immune response of oyster. PMID- 28888539 TI - Variation in type II endometrial cancer risk by Hispanic subpopulation: An exploratory analysis. AB - BACKGROUND: Minorities have demonstrated an increased risk for type II endometrial cancers, but no data exists about risk among minority subpopulations. Our objective was to evaluate heterogeneity in risk of type II endometrial cancer (EC) histologies across race and Hispanic sub-groups using data from Florida's statewide cancer registry (FCDS). METHODS: FCDS contains data on N=26,416 women diagnosed with EC from 2004 to 2013. Our analysis included women >=18years of age who were classified as non-Hispanic White (NHW), non-Hispanic Black (NHB) or belonged to one of five Hispanic sub-groups, and had a histology code consistent with type I or type II EC. Binary logistic regression analyses were performed to model risk of type II versus type I ECs across racial and ethnic groups relative to NHW. RESULTS: Relative to NHW, overall odds of being diagnosed with a type II EC were significantly higher in NHB (OR=2.64, 95%CI: 2.38-2.92), Cubans (OR=1.35, 95%CI: 1.08-1.68) and South and Central Americans (SCA) (OR=1.84, 95%CI: 1.40 2.43). Compared to NHW, odds of serous EC were significantly higher in Cubans (OR=2.15, 95% CI: 1.51-3.05) and NHB (OR=2.51, 95% CI: 2.11-2.97); odds of carcinosarcoma (CS) were significantly higher in NHB (OR=2.97, 95% CI: 2.47-3.57) and Puerto Ricans (OR=2.35, 95%CI: 1.32-4.17); and odds of grade III adenocarcinoma (AG3) were significantly higher in NHB (OR=1.60, 95% CI: 1.42 1.81) and SCA (OR=1.76, 95%CI: 1.29-2.40). CONCLUSION: Risk of type II EC varies considerably across Hispanic sub-groups, with Cubans, Puerto Ricans and SCA characterized by elevated odds for specific type II histologies. PMID- 28888540 TI - Feasibility, safety and clinical outcomes of cardiophrenic lymph node resection in advanced ovarian cancer. AB - OBJECTIVES: Surgical resection of enlarged cardiophrenic lymph nodes (CPLNs) in primary treatment of advanced ovarian cancer has not been widely studied. We report on a cohort of patients undergoing CPLN resection during primary cytoreductive surgery (CRS), examining its feasibility, safety, and potential impact on clinical outcomes. METHODS: We identified all patients undergoing primary CRS/CPLN resection for Stages IIIB-IV high-grade epithelial ovarian cancer at our institution from 1/2001-12/2013. Clinical and pathological data were collected. Statistical tests were performed. RESULTS: 54 patients underwent CPLN resection. All had enlarged CPLNs on preoperative imaging. Median diameter of an enlarged CPLN: 1.3cm (range 0.6-2.9). Median patient age: 59y (range 41 74). 48 (88.9%) underwent transdiaphragmatic resection; 6 (11.1%) underwent video assisted thoracic surgery. A median of 3 nodes (range 1-23) were resected. A median of 2 nodes (range 0-22) were positive for metastasis. 51/54 (94.4%) had positive nodes. 51 (94.4%) had chest tube placement; median time to removal: 4d (range 2-12). 44 (81.4%) had peritoneal carcinomatosis. 19 (35%) experienced major postoperative complications; 4 of these (7%) were surgery-related. Median time to adjuvant chemotherapy: 40d (range 19-205). All patients were optimally cytoreduced, 30 (55.6%) without visible residual disease. Median progression-free survival: 17.2mos (95% CI 12.6-21.8); median overall survival: 70.1mos (95% CI 51.2-89.0). CONCLUSIONS: Enlarged CPLNs can be identified on preoperative imaging and may indicate metastases. Resection can identify extra-abdominal disease, confirm Stage IV disease, obtain optimal cytoreduction. In the proper setting it is feasible, safe, and does not delay chemotherapy. In select patients, it may improve survival. PMID- 28888541 TI - Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. AB - OBJECTIVES: Given the lack of adequate screening modalities, knowledge of ovarian cancer risks for carriers of pathogenic alterations in predisposition genes is important for decisions about risk-reduction by salpingo-oophorectomy. We sought to determine which genes assayed on multi-gene panels are associated with ovarian cancer, the magnitude of the associations, and for which clinically meaningful associations could be ruled out. METHODS: 7768 adult ovarian cancer cases of European ancestry referred to a single clinical testing laboratory underwent multi-gene panel testing for detection of pathogenic alterations in known or suspected ovarian cancer susceptibility genes. A targeted capture approach was employed to assay each of 19 genes for the presence of pathogenic or likely pathogenic alterations. Mutation frequencies in ovarian cancer cases were compared to mutation frequencies in individuals from the Exome Aggregation Consortium (ExAC). Analyses stratified by family and personal history of other cancers and age at diagnosis were also performed. RESULTS: Significant associations (p<0.001) were identified between alterations in 11 genes and ovarian cancer, with eight of these displaying >=5-fold increased risk (BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, RAD51D). Relative risks of ovarian cancer greater than two-fold were also observed for ATM, but could reliably be ruled out for RAD50 and CHEK2. CONCLUSIONS: These results will inform clinical management of women found to carry pathogenic alterations in genes tested on multi-gene panels. The knowledge that some genes are not associated with OC can reduce concerns of women found to carry pathogenic alterations in those genes. PMID- 28888542 TI - Values and worries of ovarian cancer patients. AB - INTRODUCTION: Older women with ovarian cancer (OC) are less likely to receive guideline concordant treatment. Differences in values and worries about treatment may explain why. METHODS: Women with OC in 2013-2015 were surveyed about values and worries at the time of initial treatment. Existing values (11 item, e.g., maintaining quality of life) and worries (12 items, e.g., treatment side effects) scales were adapted based on OC literature. Responses were very/somewhat/a little/not at all important or worried. Principal Component Analyses (PCA) identified groups of values and worries that best explained scales' variation. We examined proportions reporting very/somewhat important/worried on >=1 item in each component by age (older >=65years, younger <65years). RESULTS: Of 170 respondents, 42.3% were older. PCA components for values were: functional well being (3 survey items, proportion of variance explained [PoVE] 26.3%), length of life and sexual functioning (3 items, PoVE 20.1%), attitudes (3 items, PoVE 14.2%), and not becoming a burden (2 items, PoVE 13.7%). PCA components for worries were: economic (4 items, PoVE 27.2%), uncertainty (6 items, PoVE 26.0%), and family impact (2 items, PoVE 16.3%). Older women were less likely to indicate very/somewhat worried to >=1 item in the economic (51.4% vs 72.4%, p=0.006), uncertainty (80.6% vs. 98.0%, p=0.001), and family impact component (55.6% vs. 70.4%, p=0.03). No other age differences were found. CONCLUSIONS: While worry during OC treatment decision-making may differ across age groups, values do not. Research should assess how differences in worry might affect OC medical decision making for older and younger women. PMID- 28888543 TI - Preparation and characterization of bio-nanocomposite films based on cassava starch or chitosan, reinforced with montmorillonite or bamboo nanofibers. AB - In this study, films based on two different polysaccharides (chitosan and cassava starch) were produced by casting technique and nanostructured by montmorillonite (MMTNPs) or bamboo nanofibers (BNFs) at two different concentrations: 0.5g/100g and 1.0g/100g of polymer, using glycerol as plasticizer at concentration of 30g/100g of polymer. The particle size and surface charge of the MMTNPs and BNFs nanoparticles were 315+/-14nm and 60+/-3nm and -31.78mV and -20.77mV, respectively. In relation to the mechanical properties, the nanofibers increased the tensile strength in 50% of starch films, while the elongation at break shows a similar increase (66%) for both types of nanoparticles at concentration of 1.0g/100g. Cassava starch films showed a better response to nanostructure process, noticed through by the mechanical properties. XRD analyses showed good interaction between the polymer matrix and bamboo nanofibers. PMID- 28888544 TI - Xylanase immobilization on modified superparamagnetic graphene oxide nanocomposite: Effect of PEGylation on activity and stability. AB - In order to utilize the advantages of immobilization such as improvement of stability, increasing the catalytic activity, ability to recovery and reuse of enzyme from reaction medium, xylanase enzyme was immobilized on superparamagnetic garphene oxide nanosheets (GOMNP). Xylanase, as a hydrolytic enzyme of xylan has widely used in industry. Since the xylan is bulk, for enhance accessibility of active sites of the immobilized xylanase, polyethylene glycol bis amine (PEGA) was used as a spacer for functionalization of GOMNP. The modified GOMNP and immobilized xylanase on PEGA-GOMNP (PEGA-GOMNP/Xy) were characterized through different analysis tools. The results showed that xylanase was attached to the functionalized nanocomposite with a yield of 273mg enzyme per gram PEGA-GOMNP. Thermal stability, pH stability, reusability and storage stability were determined for immobilized enzyme. The free and immobilized xylanase displayed an optimal enzymatic activity at 60 degrees C and pH 6.5 and 7.5, respectively. The immobilized enzyme retained about 40% of the initial activity after 8 cycles with xylan substrate at 60 degrees C. Also immobilized and free enzymes retained 35% and 20% of the initial catalytic activity after 90days storage at 4 degrees C, respectively. Consequently, PEGA- modified GOMNP can be introduced as a biodegradable and suitable support for bioengineering. PMID- 28888545 TI - Next generation sequencing for the investigation of an outbreak of Salmonella Schwarzengrund in Nanjing, China. AB - INTRODUCTION: Salmonella Schwarzengrund is most frequently isolated from poultry meat and can cause human infections. S. Schwarzengrund was isolated from diarrheal patients in a food poisoning event in Nanjing, China. METHODS: Three strains isolated from patients were microbiologically confirmed as S. Schwarzengrund. Salmonella strains from spiced donkey meat were also confirmed as S. Schwarzengrund. Epidemiology investigation showed evidence of a correlation between the consumption of spiced donkey meat and those cases. Pulsed field gel electrophoresis, antibiotic susceptibility test and next generation sequencing (NGS) were employed to investigate this food poisoning event. RESULTS: The 3 strains isolated from patients and the strain isolated from the spiced donkey meat showed same results in PFGE, antibiotic susceptibility test and no SNPs were observed between these 4 strains in NGS analysis. DISCUSSION: NGS data could be used in the confirmation of an outbreak and in the tracing of contamination. However, this standard of defining an outbreak with NGS remained a challenge in practice. And the NGS data should be used in combination with other data in epidemiological investigation. PMID- 28888546 TI - Glyoxal-induced modification enhances stability of hemoglobin and lowers iron mediated oxidation reactions of the heme protein: An in vitro study. AB - Glyoxal, a reactive alpha-oxoaldehyde, increases in diabetic condition. It reacts with different proteins to form advanced glycation end products (AGEs) following Maillard-like reaction. Considering the significance of AGE-mediated protein modification by glyoxal, here we have investigated the in vitro effect of the reactive alpha-oxoaldehyde (10, 20MUM) on the heme protein hemoglobin (HbA0) (100MUM) after incubation for one week at 25 degrees C. In comparison with HbA0, glyoxal-treated HbA0 exhibited decreased absorbance around 280nm, reduced intrinsic fluorescence and lower surface hydrophobicity. Glyoxal treatment was found to increase the stability of HbA0 without significant perturbation of the secondary structure of the heme protein. In addition, H2O2-mediated iron release and subsequent iron-mediated oxidative (Fenton) reactions were found to be lower in presence of glyoxal-treated HbA0 compared to HbA0. Mass spectrometric studies revealed modification of arginine residues of HbA0 (Arg-31alpha, Arg-40beta) to hydroimidazolone adducts. AGE-induced modifications thus appear to be associated with the observed changes of the heme protein. Considering the increased level of glyoxal in diabetes mellitus as well as its high reactivity, glyoxal-derived AGE adducts might thus be associated with modifications of the protein including physiological significance. PMID- 28888547 TI - Green Nanotechnology for Synthesis and characterization of poly(3-hydroxybutyrate co-3-hydroxyhexanoate) nanoparticles for sustained bortezomib release using supercritical CO2 assisted particle formation combined with electrodeposition. AB - Carbon dioxide assisted particle formation combined with electrospraying using supercritical CO2 (scCO2) as an aid (Carbon Dioxide Assisted Nebulization Electrodeposition, CAN-ED) was used to produce Bortezomib loaded poly(3 hydroxybutyrate-co-3-hydroxyhexanoate) P(3HB-co-3HHx) nanoparticles for sustained release. The morphology and structure of the prepared nanoparticles were investigated by SEM, TEM and FT-IR spectroscopy. Average diameter of particles obtained was 155nm and the average core sizes of P(3HB-co-3HHx) nanoparticles were between 6 and 13nm. The drug loading capacity, drug release and stability of Bortezomib loaded P(3HB-co-3HHx) nanoparticles were analyzed. The maximum loading capacity was achieved at pH=6.0 in phosphate buffer (K2HPO4/KH2PO4). It was found that temperature did not affect the stability of Bortezomib loaded nanoparticles and it was good both at 37 degrees C and 4 degrees C. This study pointed out that CAN-ED is a green method to produce P(3HB-co-3HHx) nanoparticles for pH responsive targeting of Bortezomib especially to parts of the body where size exclusion is not crucial. PMID- 28888548 TI - A Novel approach for the morphology controlled synthesis of rod-shaped nano hydroxyapatite using semi-IPN and IPN as a template. AB - Present work offers use of semi-interpenetrating network (semi-IPN) and interpenetrating network (IPN) as the template for the synthesis of nano hydroxyapatites. Semi-IPN and IPN of agar-gelatin were prepared and successfully used to synthesize nano-hydroxyapatite. Graft copolymerization technique was used to alter the properties of the hybrid backbone using ammonium persulphate as an initiator and N,N'methylene-bisacrylamide (MBA) as a crosslinker. The first step was to synthesize cross-linked semi-IPN of agar-gelatin blend which was converted to a cross-linked interpenetrating polymer. Semi-IPN and IPN showed 4786% and 4896% swelling, respectively. In the second step in situ synthesis of rod-shaped nano-hydroxyapatites was carried out. Ca/P ratio for hydroxyapatite formed was found to be 1.67 for semi-IPN and 1.63 for IPN with the particle size of 50-100nm (length) and 6-15nm (diameter). These results were than compared with the literature findings of synthesizing n-HA (nano-hydroxyapatite) without using templates and results were better for n-HA synthesized using templates. Thus, the use of semi-IPN and IPN for the controlled growth of rod-shaped nano hydroxyapatite was a novel approach. PMID- 28888549 TI - Amination of biorefinery technical lignins using Mannich reaction synergy with subcritical ethanol depolymerization. AB - The alcoholic depolymerization and Mannich reaction were conducted to improve the chemical activity of biorefinery technical lignins and introduce amino groups into lignins, respectively. To understand the chemical structural transformations and examine the reaction mechanism, GPC and solution-state NMR techniques were performed. Element analysis was also used to quantify the amount of amine groups. The NMR characterization the depolymerized lignins indicated of the depolymerization, demethoxylation, and bond cleavage of linkages occurred during the depolymerization process. Results showed that the depolymerization temperature instead of the addition of capping reagents was the main factor for improving the reactivity of lignin under the given conditions. The Mannich reaction was very selective, primarily occurred at H3,5 and G5 positions, and the H units present a higher chemical reactivity. It is believed that the understanding of the fundamental chemistry of lignin during depolymerization and Mannich reaction process will contribute to the extension of high value-added applications of biorefinery lignin. PMID- 28888550 TI - ISSR marker-assisted genetic diversity analysis of Dioscorea hispida and selection of the best variety for sustainable production. AB - Plant breeding is a way of selection of a particular individual for the production of the progeny by separating or combining desired characteristics. The objective of this study was to justify different characteristics of Dioscorea hispida (Ubi gadong) varieties using molecular techniques to select the best variety for sustainable production at the farmer's level. A total of 160 germplasms of Ubi gadong were collected from different locations at the Terengganu and Kelantan states of Malaysia. Forty eight (48) out of 160 germplasms were selected as "primary" selection based on yield and other qualitative characters. Selected collections were then grown and maintained for ISSR marker-assisted genetic diversity analysis. Overall plant growth and yield of tubers were also determined. A total of 12 ISSR markers were tested to justify the characteristics of Ubi gadong varieties among which three markers showed polymorphic bands and on average 57.3% polymorphism were observed representing the highest variation among germplasms. The ISSR marker based on UPGMA cluster analysis grouped all 48 D. hispida into 10 vital groups that proved a vast genetic variation among germplasm collections. Therefore, hybridization should be made between two distant populations. The D. hispida is already proved as the highest starch content tuber crops and very rich in vitamins with both micro and macro minerals. Considering all these criteria and results from marker-assisted diversity analysis, accessions that are far apart based on their genetic coefficient (like DH27 and DH71; DH30 and DH70; DH43 and DH62; DH45 and DH61; DH77 and DH61; DH78 and DH57) could be selected as parents for further breeding programs. This will bring about greater diversity, which will lead to high productive index in terms of increase in yield and overall quality and for the ultimate target of sustainable Ubi gadong production. PMID- 28888551 TI - Amino acids production focusing on fermentation technologies - A review. AB - Amino acids are attractive and promising biochemicals with market capacity requirements constantly increasing. Their applicability ranges from animal feed additives, flavour enhancers and ingredients in cosmetic to specialty nutrients in pharmaceutical and medical fields. This review gives an overview of the processes applied for amino acids production and points out the main advantages and disadvantages of each. Due to the advances made in the genetic engineering techniques, the biotechnological processes, and in particular the fermentation with the aid of strains such as Corynebacterium glutamicum or Escherichia coli, play a significant role in the industrial production of amino acids. Despite the numerous advantages of the fermentative amino acids production, the process still needs significant improvements leading to increased productivity and reduction of the production costs. Although the production processes of amino acids have been extensively investigated in previous studies, a comprehensive overview of the developments in bioprocess technology has not been reported yet. This review states the importance of the fermentation process for industrial amino acids production, underlining the strengths and the weaknesses of the process. Moreover, the potential of innovative approaches utilizing macro and microalgae or bacteria are presented. PMID- 28888552 TI - Chassis and key enzymes engineering for monoterpenes production. AB - Microbial production of monoterpenes is often limited by their cytotoxicity and in vivo conversion. Therefore, alleviating cytotoxicity and reducing conversion by chassis engineering are highly desirable. On the other hand, engineering key enzymes is also critical for improving monoterpenes production through facilitating the biosynthesis process. Here we critically review recent advances in cytotoxicity alleviation, reducing in vivo conversion, selecting geranyl diphosphate synthase and engineering monoterpene synthases. These achievements would lead to the development of superior chassis with improved tolerance to cytotoxicity and rationally tailored metabolites profiles to improve titer, yield and productivity for the production of monoterpenes by microbial cells. PMID- 28888553 TI - NutriCancer: A French observational multicentre cross-sectional study of malnutrition in elderly patients with cancer. AB - OBJECTIVES: To compare the prevalence of malnutrition and nutritional management between elderly (>=70years old) and younger patients (<70years) with cancer. PATIENTS AND METHODS: This is a post-hoc analysis of NutriCancer 2012 study; a one-day cross-sectional nationwide survey conducted to assess malnutrition in adult patients with cancer in France. Patients diagnosed with cancer at the study date in both inpatient and outpatient settings were included. Data collection was performed by means of questionnaires completed by the physician, the patient and the caregiver. RESULTS: This post-hoc analysis compared 578 elderly patients (27.6%) vs. 1517 younger patients (72.4%). There were significant differences in cancer localization between the groups particularly in gastrointestinal cancer (27% in younger patients vs. 42% in elderly), breast cancer (17% vs 8% in elderly) and oropharyngeal (15% vs. 9% in elderly). Weight loss was significantly more reported in the elderly than in younger patients (73.6% vs. 67.6%, p=0.009). Elderly patients were more frequently malnourished than younger patients (44.9% vs. 36.7%, p=0.0006). Food intake was comparable between the groups; however, physicians overestimated the food intake, particularly in the elderly. The malnutrition management was more frequently proposed in elderly, as dietary advice and oral nutritional supplements, than in younger patients; however, enteral nutrition was significantly less undertaken in the elderly. CONCLUSION: Malnutrition is prevalent in elderly patients with cancer, and more frequent than in younger patients. There is a need for an early integration of the nutritional counselling in patients with cancer, and particularly in the elderly. PMID- 28888555 TI - Functional impairment prior to major non-cardiac surgery is associated with mortality within one year in elderly patients with gastrointestinal, gynaecological and urogenital cancer: A prospective observational cohort study. AB - OBJECTIVE: To investigate the prognostic value of elements of the Geriatric Assessment, in particular the Timed Up and Go (TUG) Test and the Barthel Index of Activities of Daily Living (ADL) for one-year post-operative mortality in elderly patients with cancer. MATERIALS AND METHODS: This prospective cohort study included patients 65years of age or older undergoing elective major surgery for cancer between June 2008 and June 2010. Preoperative functional status was measured by the TUG Test and the Barthel Index of ADL Cognitive state was assessed by the Mini Mental State Examination (MMSE). Complications were recorded prospectively. The degree of resection was noted. RESULTS: Data from 131 patients (56% women; median age, 71years) were analysed at 1year of follow-up. Mortality after 1year was 28.2%. Twenty-nine patients (22.3%) were dependent in ADLs, and 43 (35.2%) impaired in TUG. Thirteen patients (10.7%) were both, dependent in ADLs and impaired in TUG. Short-term complications after surgery occurred in 66% of patients, and major complications occurred in 29%. Patients who were dependent in ADLs and impaired in TUG had significantly higher 1-year mortality (OR, 4.5; 95% CI, 1.21-18.25; p=0.034). Lower scores on the MMSE (OR, 0.64; 95% CI, 0.43 0.95; p=0.048) and incomplete surgical resection (OR, 3.25; 95% CI, 1.15-9.20; p=0.026) were independently associated with higher 1-year mortality. CONCLUSION: Functional assessments, such as ADL and TUG scores, as well as mild cognitive impairment, are predictors of long-term outcome in elderly cancer patients. TRIAL REGISTRATION: German Clinical Trials Register (DRKS 00005150). PMID- 28888554 TI - How to treat pancreatic adenocarcinoma in elderly: How far can we go in 2017? AB - Pancreatic adenocarcinoma is one of the most fatal cancers that frequently affects older patients. Limited data suggest that older patients are as likely to benefit from surgery, radiation, and chemotherapy as younger patients. The only potentially curative approach for pancreatic cancer is surgery but this is only performed in less than 20% of patients considered resectable. With improvements in surgical techniques, older patients without major comorbidities show a course of disease after resection similar to that of younger patients. The use of adjuvant chemotherapy in an attempt to prolong survival is therefore reasonable for this population of patients. Historically, patients with locally-advanced disease will be offered gemcitabine as standard chemotherapy, with radiotherapy considered at a later time. In the majority, metastatic patients will preferably be offered gemcitabine chemotherapy, which can be used at a lower dose in frail or very old patients. In some cases in patients in a very good health condition, two recent intensive chemotherapies can be proposed with modified doses and a close follow-up: the 5-fluoroucil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) regimen and the combination of gemcitabine plus nab-paclitaxel. For older patients with terminal disease and palliative needs, which is the majority of cases, better use of pain control and palliative measures can be beneficial. Each of these issues will be examined in detail in this review. PMID- 28888556 TI - Telehealth in older adults with cancer in the United States: The emerging use of wearable sensors. AB - As the aging and cancer populations in the world continue to increase, the need for complements to traditional geriatric assessments and the logical incorporation of fast and reliable telehealth tools have become interlinked. In the United States, studies examining the use of telehealth for chronic disease management have shown promising results in small groups. The implementation of health technology on a broader scale requires older adults to both accept and adapt such innovation into routine medical care. Though the commercial and recreational use of new technology has increased in older individuals, the transition into creating a smart and connected home that can interface with both patients and healthcare professionals is in its early phases. Current limitations include an inherent digital divide, as well as concerns regarding privacy, data volume, rapid change, cost and reimbursement. The emergence of low-cost, high fidelity wearable sensors with a spectrum of clinical utility may be the key to increased use and adaptation by older adults. An opportunity to utilize wearable sensors for objective and real-time assessment of older patients with cancer for baseline functional status and treatment toxicity may be on the horizon. PMID- 28888557 TI - Robust current control-based generalized predictive control with sliding mode disturbance compensation for PMSM drives. AB - This paper addresses the current control of permanent magnet synchronous motor (PMSM) for electric drives with model uncertainties and disturbances. A generalized predictive current control method combined with sliding mode disturbance compensation is proposed to satisfy the requirement of fast response and strong robustness. Firstly, according to the generalized predictive control (GPC) theory based on the continuous time model, a predictive current control method is presented without considering the disturbance, which is convenient to be realized in the digital controller. In fact, it's difficult to derive the exact motor model and parameters in the practical system. Thus, a sliding mode disturbance compensation controller is studied to improve the adaptiveness and robustness of the control system. The designed controller attempts to combine the merits of both predictive control and sliding mode control, meanwhile, the controller parameters are easy to be adjusted. Lastly, the proposed controller is tested on an interior PMSM by simulation and experiment, and the results indicate that it has good performance in both current tracking and disturbance rejection. PMID- 28888559 TI - Work Equity and Investment-based Pediatric Departmental Reorganization. PMID- 28888558 TI - Elimination of hepatitis C virus infection among PWID: The beginning of a new era of interferon-free DAA therapy. PMID- 28888560 TI - Unintentional Cannabis Ingestion in Children: A Systematic Review. AB - OBJECTIVE: To analyze published reports of unintentional cannabis ingestions in children to determine presenting signs and symptoms, route of exposure, treatment, and outcome. STUDY DESIGN: PubMed, OpenGrey, and Google Scholar were systematically searched. Articles were selected, reviewed, and graded using Oxford Center for Evidence-Based Medicine guidelines. RESULTS: Of 3316 articles, 44 were included (3582 children age <=12 years). We found no high quality (Oxford Center for Evidence-Based Medicine level I or II) studies and 10 level III studies documenting lethargy as the most common presenting sign and confirming increasing incidence of unintentional ingestion in states having decriminalized medical and recreational cannabis. We identified 16 level IV case series, and 28 level V case reports with 114 children, mean age 25.2 +/- 18.7 months, range 8 months to 12 years, and 50 female children (44%). The most common ingestion (n = 43, 38%) was cannabis resin, followed by cookies and joints (both n = 15, 13%). Other exposures included passive smoke, medical cannabis, candies, beverages, and hemp oil. Lethargy was the most common presenting sign (n = 81, 71%) followed by ataxia (n = 16, 14%). Tachycardia, mydriasis, and hypotonia were also commonly observed. All cases were cared for in the emergency department or admitted, and mean length of stay was 27.1 +/- 27.0 hours. Twenty (18%) were admitted to the pediatric intensive care unit, and 7 (6%) were intubated. CONCLUSIONS: Unintentional cannabis ingestion by children is a serious public health concern and is well-documented in numerous studies and case reports. Clinicians should consider cannabis toxicity in any child with sudden onset of lethargy or ataxia. PMID- 28888561 TI - Delayed Presentation and Prolonged Survival of a Child with Surfactant Protein B Deficiency. AB - Surfactant protein B encoding gene mutations have been related to early onset fatal respiratory distress in full-term neonates. We report a school-aged male child homozygous for a surfactant protein B encoding gene missense mutation who presented after the neonatal period. His respiratory insufficiency responded to high dose intravenous methylprednisolone and hydroxychloroquine. PMID- 28888564 TI - Everolimus for the Treatment of Tuberous Sclerosis Complex-Related Cardiac Rhabdomyomas in Pediatric Patients. PMID- 28888563 TI - Bilirubin Uridine Diphosphate-glucuronosyltransferase Polymorphism as a Risk Factor for Prolonged Hyperbilirubinemia in Japanese Preterm Infants. AB - OBJECTIVE: To determine whether a variant of the bilirubin uridine diphosphate glucuronosyltransferase gene (UGT1A1*6) is a risk factor for prolonged hyperbilirubinemia in preterm infants. STUDY DESIGN: UGT1A1 genotypes in 46 Japanese preterm infants (<37 weeks of gestation) were compared with UGT1A1 genotypes in 38 control infants, using polymerase chain reaction-direct sequencing. Prolonged unconjugated hyperbilirubinemia was defined as serum total bilirubin concentration of >150 umol/L (8.77 mg/dL) beyond 14 days of life. RESULTS: In the case group, 41 of 46 infants (89.1%) had a polymorphic variant, c.211G>A, p.G71R (UGT1A1*6). In the control group, 7 of 38 (18.4%) had UGT1A1*6. The allele frequency of UGT1A1*6 was 0.641 in the prolonged hyperbilirubinemia group, which was significantly higher than in the control group (0.092; P < .001). In total, 39 of 46 infants in the case group were breast fed, and only 10 infants in the control group were breast fed. CONCLUSIONS: These data suggest that UGT1A1*6 is a risk factor for prolonged unconjugated hyperbilirubinemia in preterm infants in Japan. Given the different rate of breast feeding in this study, additional data are necessary for drawing a definitive conclusion. PMID- 28888562 TI - Timing and Chronicity of Maternal Depression Symptoms and Children's Verbal Abilities. AB - OBJECTIVE: To test the associations between the timing and chronicity of maternal depression symptoms (MDS) and children's long-term verbal abilities. STUDY DESIGN: Participants were 1073 mother-child pairs from a population-based birth cohort in Canada. MDS were assessed at ages 5 months, 1.5, 3.5, and 5 years using the Center for Epidemiologic Studies Depression Scale. Verbal abilities were measured at 5, 6, and 10 years using the Peabody Picture Vocabulary Test-Revised (PPVT-R). Multiple linear regression models were used to estimate the association between timing (early: 5 months and/or 1.5 years vs late 3.5 and/or 5 years) and chronicity (5 months, 1.5, 3.5, and 5 years) of exposure to elevated MDS and children's mean PPVT-R scores. RESULTS: Children exposed to chronic MDS had lower PPVT-R scores than children never exposed (mean difference = 9.04 [95% CI = 2.28 15.80]), exposed early (10.08 [3.33-16.86]) and exposed late (8.69 [1.85-15.53]). There were no significant differences between scores of children in the early compared with the late exposure group. We adjusted for mother-child interactions, family functioning, socioeconomic status, PPVT-R administration language, child's birth order, and maternal IQ, psychopathology, education, native language, age at birth of child, and parenting practices. Maternal IQ, (eta2 = 0.028), native language (eta2 = 0.009), and MDS (eta2 = 0.007) were the main predictors of children's verbal abilities. CONCLUSIONS: Exposure to chronic MDS in early childhood is associated with lower levels of verbal abilities in middle childhood. Further research is needed in larger community samples to test the association between MDS and children's long-term language skills. PMID- 28888565 TI - The Use of Echocardiography for Pediatric Patients Presenting with Syncope. AB - OBJECTIVES: To assess the frequency, yield, and cost of echocardiograms meeting "rarely appropriate" criteria. STUDY DESIGN: Retrospective, single-center study of pediatric patients presenting with syncope. Patients were categorized according to the appropriate use criteria and based upon location of care (emergency department only, primary care setting only, or referred to a pediatric cardiologist). Multivariable regression was used to determine factors associated with performance of a "rarely appropriate" echocardiogram. Costs were calculated using fair market values from the Healthcare Bluebook. RESULTS: The cohort included 637 patients presenting with syncope during the 1-year study. Echocardiograms were ordered for 127 of 637 (20.1%) including 0 of 328 emergency department patients, 1 of 66 (1.5%) primary care setting patients, and 127 of 243 (52.3%) patients evaluated by a pediatric cardiologist. Use of echocardiography by pediatric cardiologists was categorized as "appropriate" in 92 of 127 (72.4%), "maybe appropriate" in 6 of 127 (4.7%), and "rarely appropriate" in 29 of 127 (22.8%). Abnormal findings were seen in 6 of 127 (4.7%) echocardiograms but in none of the "rarely appropriate" studies. In multivariable analysis, female sex and younger age were the only factors associated with performance of a "rarely appropriate" echocardiogram. "Rarely appropriate" echocardiograms cost an estimated $16 704.00 ($576.00 per patient) in the 1-year study. CONCLUSIONS: "Rarely appropriate" echocardiograms performed for syncope do not contribute management changing diagnostic information. However, they burden patients with additional cost and perhaps contribute to increased need for follow-up. PMID- 28888566 TI - Tendon Tissue Engineering: Mechanism and Effects of Human Tenocyte Coculture With Adipose-Derived Stem Cells. AB - PURPOSE: Adipose-derived stem cells (ASCs) are a potential candidate for cell based therapy targeting tendon injury; however, their therapeutic benefit relies on their ability to interact with native tenocytes. This study examines the mechanism and effects of coculturing human tenocytes and ASCs. METHODS: Tenocytes (T) were directly cocultured with either ASCs (A) or fibroblasts (F) (negative control) in the following ratios: 50% T/50% A or F; 25% T/75% A or F; and 75% T/25% A or F. Cells were indirectly cocultured using a transwell insert that allowed for exchange of soluble factors only. Proliferation and collagen I production were measured and compared with monoculture controls. Synergy was quantified using the interaction index (II), which normalizes measured values by the expected values assuming no interaction (no synergy when II = 1). The ability of ASCs to elicit tenocyte migration was examined in vitro using a transwell migration assay and ex vivo using decellularized human flexor tendon explants. RESULTS: Compared with monoculture controls, II of proliferation was greater than 1 for all tenocyte and ASC direct coculture ratios, but not for tenocyte and fibroblast direct coculture ratios or for tenocyte and ASC indirect coculture. The ASCs elicited greater tenocyte migration in vitro and ex vivo. The II of collagen I production was greater than 1 for direct coculture groups with 25% T/75% A and 75% T/25% A. CONCLUSIONS: Direct coculture of ASCs and tenocytes demonstrated synergistic proliferation and collagen I production, and ASCs elicited tenocyte migration in vitro and ex vivo. These interactions play a key role in tendon healing and were absent when ASCs were replaced with fibroblasts, supporting the use of ASCs for cell-based therapy targeting tendon injuries. CLINICAL RELEVANCE: When ASCs are delivered for cell-based therapy, they directly interact with native tenocytes to increase cell proliferation, collagen I production, and tenocyte migration, which may enhance tendon healing. PMID- 28888567 TI - Biomechanics of the Acute Boutonniere Deformity. AB - PURPOSE: To demonstrate which structures of the extensor mechanism create a boutonniere deformity, when damaged, in a cadaver model. An analysis of how damage to these anatomical structures affects the biomechanical performance of the extensor mechanism was also performed. METHODS: We secured 18 fresh cadaveric hands onto an apparatus consisting of a computer-controlled motor and tensiometer attached in series to the extensor communis tendon of the ring and middle digits. The central slip, transverse, and oblique fibers of the interosseous hood and the triangular ligament were sequentially divided. After each structure was divided, the motors were activated to provide a constant tendon displacement force. The angular displacement at the proximal interphalangeal (PIP) and distal interphalangeal joints was recorded. RESULTS: In all digits, detachment of the central slip from the middle phalanx produced a decrease in extension of the PIP joint. When the transverse and oblique fibers of the interosseous hood were also divided, extension at the PIP joint was further decreased. A boutonniere deformity occurred only when all 3 structures were damaged. CONCLUSIONS: The boutonniere deformity requires subluxation of the lateral bands volar to the axis of rotation of the PIP joint. This study demonstrates that damage to the central slip alone does not cause the deformity. Combined injury of the central slip, triangular ligament, and transverse and oblique fibers of the interosseous hood causes a boutonniere deformity. CLINICAL RELEVANCE: Division of the central slip leads to loss of extension at the PIP joint. A more substantial loss of extension after injury or development of a boutonniere deformity should alert clinicians that other structures of the extensor mechanism are also damaged. PMID- 28888568 TI - In Vivo 3-Dimensional Kinematics of Thumb Carpometacarpal Joint During Thumb Opposition. AB - PURPOSE: This study primarily aimed to demonstrate the screw-home rotation of the thumb carpometacarpal (CMC) joint and the function of surrounding ligaments during thumb oppositional motion. METHODS: A 3-dimensional kinematic analysis of the thumb CMC joint was conducted using data derived from computed tomography of 9 healthy volunteers. Scans were obtained in the neutral forearm and wrist position and the thumb in maximum radial abduction, maximum palmar abduction, and maximum opposition. The movements of the first metacarpal and the palmar and dorsal bases on the trapezium during thumb oppositional motion from radial abduction through palmar abduction were quantified using a coordinate system originating on the trapezium. In addition to the kinematic analyses, the length of virtual ligaments, including the anterior oblique, ulnar collateral, dorsal radial, dorsal central (DCL), and posterior oblique ligament (POL), were calculated at each thumb position. RESULTS: From radial abduction to opposition of the thumb through palmar abduction, the first metacarpal was abducted, internally rotated, and flexed on the trapezium. The palmar base of the first metacarpal moved in the palmar-ulnar direction, and the dorsal base moved in the palmar-distal direction along the concave surface of the trapezium. Although the DCL and POL lengthened, the lengths of other ligaments did not change significantly. CONCLUSIONS: During thumb oppositional motion, internal rotation of the first metacarpal occurred, with the palmar base rotating primarily with respect to the dorsal base. The DCL and POL may be strained in thumb functional positions. CLINICAL RELEVANCE: Kinematic variables indicated a screw-home rotation of the thumb CMC joint and the contribution of the dorsal ligaments to the stability of the rotation on the pivot point. PMID- 28888569 TI - A Biomechanical Analysis of 2 Constructs for Metacarpal Spiral Fracture Fixation in a Cadaver Model: 2 Large Screws Versus 3 Small Screws. AB - PURPOSE: Surgeons confronted with a long spiral metacarpal fracture may choose to fix it solely with lagged screws. A biomechanical analysis of a metacarpal spiral fracture model was performed to determine whether 3 1.5-mm screws or 2 2.0-mm screws provided more stability during bending and torsional loading. METHODS: Second and third metacarpals were harvested from 12 matched pairs of fresh-frozen cadaveric hands and spiral fractures were created. One specimen from each matched pair was fixed with 2 2.0-mm lagged screws whereas the other was fixed with 3 1.5 mm lagged screws. Nine pairs underwent combined cyclic cantilever bending and axial compressive loading followed by loading to failure. Nine additional pairs were subjected to cyclic external rotation while under a constant axial compressive load and were subsequently externally rotated to failure under a constant axial compressive load. Paired t tests were used to compare cyclic creep, stiffness, displacement, rotation, and peak load levels. RESULTS: Average failure torque for all specimens was 7.2 +/- 1.7 Nm. In cyclic torsional testing, the group with 2 screws exhibited significantly less rotational creep than the one with 3 screws. A single specimen in the group with 2 screws failed before cyclic bending tests were completed. No other significant differences were found between test groups during torsional or bending tests. CONCLUSIONS: Both constructs were biomechanically similar except that the construct with 2 screws displayed significantly less loosening during torsional cyclic loading, although the difference was small and may not be clinically meaningful. CLINICAL RELEVANCE: Because we found no obvious biomechanical advantage to using 3 1.5-mm lagged screws to fix long spiral metacarpal fractures, the time efficiency and decreased implant costs of using 2-2.0 mm lagged screws may be preferred. PMID- 28888570 TI - Revision of the Failed Thumb Carpometacarpal Arthroplasty. AB - PURPOSE: To evaluate the outcome of revision surgery for failed thumb carpometacarpal (CMC) arthroplasty. METHODS: We retrospectively analyzed 32 patients with failed thumb CMC arthroplasty. The primary reason for revision was pain caused by metacarpal subsidence. Revision surgery included soft tissue interposition and distraction pinning to address the metacarpal subsidence. Additional ligament reconstruction was performed in patients with thumb instability. Eight patients required additional metacarpophalangeal joint fusion for concomitant joint hyperextension. Eleven required additional partial excision of the trapezoid for concomitant scaphotrapezoidal joint arthritis. All patients were evaluated clinically and radiographically. RESULTS: Mean follow-up was 57 months (range, 24-121 months). Pain levels evaluated by visual analog scale were significantly reduced in all patients after revision surgery. Mean grip strength and key pinch strength significantly increased. Twenty-seven patients achieved good functional results; those for 5 patients were fair. CONCLUSIONS: This study showed that revision surgery with distraction pinning and soft tissue interposition with or without ligament reconstruction was an effective treatment for failed CMC arthroplasty of the thumb. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28888571 TI - Accuracy and Early Clinical Outcome of 3-Dimensional Planned and Guided Single Cut Osteotomies of Malunited Forearm Bones. AB - PURPOSE: To investigate the reduction accuracy of 3-dimensional planned single cut osteotomies (SCOTs) of the forearm that were performed using patient-specific guides. METHODS: A retrospective analysis of SCOTs performed between 2012 and 2014 was performed. Ten patients (age, 15-59 years) with 6 malunions of the ulna and 6 malunions of the radius were identified. The reduction accuracy was assessed by comparing the 3-dimensional preoperative plan of each osteotomy with the superimposed bone model extracted from postoperative computed tomography data. The difference was assessed by 3-dimensional angle and in all 6 degrees of freedom (3 translations, 3 rotations) with respect to an anatomical coordinate system. Wrist range of motion and grip strength was assessed after a mean of 16.7 months and compared with the preoperative measurements. RESULTS: On average, the 12 SCOTs demonstrated excellent accuracy of the reduction with respect to rotation (ie, pronation/supination, 4.9 degrees ; flexion/extension, 1.7 degrees ; ulnar/radial angulation, 2.0 degrees ) and translation (ie, proximal/distal, 0.8 mm; radial/ulnar, 0.8 mm; dorsal/palmar, 0.8 mm). A mean residual 3 dimensional angle of 5.8 degrees (SD, 3.6 degrees ) was measured after surgery. All 6 patients operated on for reasons of a reduced range of motion demonstrated improved symptoms and increased movement (from 20 degrees to 80 degrees ). In the patients with unstable/painful distal radioulnar joint, 3 were totally free of complaints and 1 patient showed residual pain during sports. CONCLUSIONS: A SCOT combined with patient-specific guides is an accurate and reliable technique to restore normal anatomy in multiplanar deformities of the forearm. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28888572 TI - Risk Factors of Lunate Collapse in Kienbock Disease. AB - PURPOSE: Not all patients with Kienbock disease progress to collapse of the lunate and carpal malalignment, but it is difficult to determine which patients are at risk. We aimed to identify demographic or anatomical factors associated with more advanced stages of Kienbock disease. METHODS: We included all 195 eligible patients with Kienbock disease and available preoperative posteroanterior and lateral radiographs. We compared the mean age, sex distribution, mean ulnar variance, radial height, radial (ulnarward) inclination, palmar tilt, anteroposterior distance, and lunate type among the different Lichtman stages of Kienbock disease and performed ordinal logistic regression analysis. RESULTS: We found that patients with more negative ulnar variance had more advanced stages of Kienbock disease (adjusted odds ratio, 1.4). An increase in age was also independently associated with a higher Lichtman stage of Kienbock disease (adjusted odds ratio, 1.02). CONCLUSIONS: Our findings suggest that more negative ulnar variance may be related to a greater magnitude of lunate collapse in Kienbock disease. Additional long-term study is needed to confirm the longitudinal relationship of negative ulnar variance with progressive Kienbock disease. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 28888573 TI - An Extradigital Glomus Tumor of the Median Antebrachial Vein. AB - Glomus tumors are benign vascular neoplasms that arise from specialized dermal arteriovenous anastomoses called glomus bodies. These tumors are most often found in the digital pulp and subungual region of the fingertips; however, a review of the literature suggests that extradigital glomus tumors may occur more often than is generally recognized. Although most extradigital glomus tumors arise within subcutaneous tissues, glomus tumors have occasionally been found within bones, nerves, and blood vessels. An intravascular glomus tumor of the forearm is a very rare occurrence and only a few cases have been reported in the literature. Here we describe a 55-year-old right-handed man with a 10-year history of exquisite tenderness and dysesthesia of his right proximal forearm. Surgical exploration revealed the presence of a mass arising from the median antebrachial vein, which was confirmed histologically to be a glomus tumor. PMID- 28888574 TI - Patient- and Disease-Specific Factors Associated With Operative Management of de Quervain Tendinopathy. AB - PURPOSE: It remains unclear which factors, patient- or disease-specific, are associated with electing to undergo operative management for de Quervain tendinopathy. Our null hypothesis was that no patient- or disease-specific factors would be associated with the choice of surgical treatment of de Quervain tendinopathy. METHODS: We performed a retrospective review of consecutive patients diagnosed with de Quervain tendinopathy over 3 years by 1 of 3 fellowship-trained hand surgeons at an urban academic institution. Descriptive statistics were calculated for patient baseline and disease-specific characteristics. Cohorts were compared using bivariate analysis for all collected variables. Binary logistic regression with backward stepwise term selection was performed including independent predictors identified by bivariate analysis. RESULTS: A total of 200 patients were identified for inclusion. Bivariate analysis revealed that surgically treated patients were significantly more likely to have Medicaid insurance, psychiatric illness history, and disabled work status. Regression analysis revealed an association between surgical treatment and 2 of the factors evaluated: Medicaid insurance status and psychiatric illness history. CONCLUSIONS: Psychiatric illness and Medicaid insurance status are associated with undergoing surgical release of the first dorsal compartment. These findings support the use of a biopsychosocial framework when treating patients with de Quervain tendinopathy. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 28888575 TI - Fascaplysin inhibit ovarian cancer cell proliferation and metastasis through inhibiting CDK4. AB - OBJECTIVE: Cyclin-dependent kinases (CDKs) are important regulators of the cell cycle; previous studies have shown that misregulation of CDK4 (cyclin-dependent kinase 4) activity can lead to cancer. The present study investigated the anti tumor effects of a highly selective CDK4 inhibitor fascaplysin in ovarian carcinoma cell lines. MATERIALS AND METHODS: In our study, cell proliferation, cell cycle, cell apoptosis, cell invasion, and cell migration relative assays were performed in ovarian cancer cell lines A2780 and OVCAR3 in the presence of different concentrations of fascaplysin. The protein expression levels of CDK4, cyclin D1, Bcl-2 (B-cell lymphoma-2), and VEGFA (vascular endothelial growth factor A) were determined by western blot. RESULTS: Our results showed that fascaplysin inhibited ovarian cancer cell proliferation, invasion and migration, as well as inducing S arrest and cell apoptosis. Treatment with fascaplysin also suppressed CDK4, cyclin D1, Bcl-2, and VEGFA expression at protein levels. CONCLUSIONS: Above all, our results showed that fascaplysin has anti-tumor activity against ovarian cancer cell lines through inhibiting CDK4, and may be a therapeutic target for the treatment of ovarian carcinomas. PMID- 28888576 TI - Association of vitamin D and vitamin D binding protein (DBP) gene polymorphism with susceptibility of type 2 diabetes mellitus in Bangladesh. AB - AIMS: Polymorphism in vitamin D binding protein gene may have an impact on serum vitamin D transport and thus may have relation with type 2 diabetes mellitus. In our study, we investigated the association of serum vitamin D level and vitamin D binding protein gene polymorphism with the onset of type 2 diabetes mellitus. MATERIALS AND METHODS: Blood samples were collected from 104 type 2 diabetic patients and 107 healthy volunteers. Serum vitamin D was measured by high performance liquid chromatography. Genetic analysis of vitamin D-binging protein gene was carried out by polymerase chain reaction - restriction fragment length polymorphism method. RESULTS: We found significantly (p<0.001) lower level of vitamin D in type 2 diabetic patients compared to control subjects. A significantly negative correlation (r=-0.25, p<0.05) between vitamin D level and fasting blood glucose level was found among type 2 diabetic subjects. The Glu/Glu at codon 416 (rs7041) (p<0.05) and Lys/Lys at codon 420 (rs4588) (p<0.01) variants of vitamin D binding protein gene was significantly higher in type 2 diabetic subjects than controls. The patients with Glu/Glu and Lys/Lys genotypes respectively at codon 416 (odds ratio=2.87; 95% confidence interval=1.19 to 6.95) and 420 (odds ratio=8.9; 95% confidence interval=1.89 to 41.99) were at high risk of developing type 2 diabetes. CONCLUSIONS: Our present study strongly suggests that there might have an association of vitamin D, and vitamin D-binding protein gene (codon 416 & 420) polymorphisms with the occurrence of type 2 diabetes mellitus. PMID- 28888577 TI - CRISPR knock out CTLA-4 enhances the anti-tumor activity of cytotoxic T lymphocytes. AB - T cell-mediated anti-tumor immunity plays a pivotal role in cancer immune surveillance. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a protein receptor mainly expressed in activated T cells and regulatory T cells. CTLA-4 competes with CD28 for ligand binding and generates inhibitory signals to attenuate T cell activation. The blockade of CTLA-4 mediated immune inhibitory checkpoint has been associated with enhanced anti-tumor immunity. In this study, we use CRISPR-Cas9 system to knock out (KO) CTLA-4 from cytotoxic T lymphocytes (CTLs) and evaluate its effect on the anti-tumor activity of the CTLs. CTLA-4 KO CTLs robustly enhanced tumor cell death by 40% compared to the control and facilitated apoptosis and caspase activities in tumor cells. The knockout of CTLA 4 also increased TNF-alpha and IFN-gamma secretion of the CTLs by approximately 2 fold. The effectiveness of CTLA-4 KO in enhancing anti-tumor activity of the CTLs was verified in vivo using mouse xenograft model. The xenografted mice treated with CTLA-4 KO CTLs demonstrated repressed tumor growth and prolonged survival compared to the control group. Our data suggest that CRISPR targeting CTLA-4 immune checkpoint could significantly improve the anti-tumor activity of CTLs. PMID- 28888578 TI - When figures and data contradict text: MiR346 is apparently reduced in breast cancer tissue, contrary to claims by a paper's author. AB - A recent article in Gene highlighted potential function of miR-346 in human breast cancer (Yang et al., 2017). We request an explanation or correction of the report. In its current state, the text will certainly create confusion in the field and lead to incorrect assumptions. The authors made several critical errors. The abstract stated "we found that the expression of miR-346 was higher in breast cancer tissues than in their paired corresponding non-cancerous tissues" and the main text and legend for Fig. 1A stated "miR-346 expression was significantly higher in breast cancer tissues than in their paired corresponding non-cancerous tissues (Fig. 1A, Yang et al., 2017)" and "miR-346 was upregulated in breast cancer tissues and cell lines. (A)", respectively. It was also stated that "SRCIN1 expression levels were significantly down-regulated in breast cancer compared to the adjacent normal tissues (Fig. 5B, Yang et al., 2017)". The problem with these statements is that they contradict the actual data presented in the paper! This misrepresentation of the effects of miR-346 in breast cancer could prove harmful by sidetracking future research. Further, clinical trials may be incorrectly directed towards lowering miR-346 without a complete and fair assessment of the internal contradictions in the data. Inaccurately-presented data impede progress of biomedical research, deplete scientific resources and compromise public trust. PMID- 28888579 TI - Reliability of Self-reported Treatment Data by Patients With Breast Cancer Compared With Medical Record Data. AB - OBJECTIVES: Medical records are considered the gold standard for accurate treatment information. However, treatment data are increasingly obtained from questionnaires. It can be questioned whether self-reported treatment data are reliable, particularly because patients have to process a lot of information during their diagnosis and treatment process. The present study assesses the reliability of self-reported treatment data compared with medical records. METHODS: All patients with stage I, II, and III breast cancer (n = 606) in 5 hospitals in the west of the Netherlands were invited to complete a questionnaire 9 to 18 months after surgery. We calculated kappa statistics, proportion correct, sensitivity, specificity, and positive and negative predictive values to assess agreement. RESULTS: Three hundred fifty patients completed the questionnaire (58%). Agreement was good for type of surgery and receiving chemotherapy, endocrine therapy, and radiation therapy, with sensitivity and specificity of 95% or higher and kappa above 0.90. However, only moderate agreement was seen for sentinel node biopsy, including the pathologic results and axillary lymph node dissection (kappa between 0.60 and 0.80). Lack of agreement was more often found for patients who had received endocrine therapy (odds ratio, 1.85; 95% confidence interval, 1.11-3.10) but not influenced by age (odds ratio, 1.00; 95% confidence interval, 0.98-1.02). CONCLUSION: Accuracy of self-reported data is high for type of surgery, chemotherapy, endocrine therapy, and radiation therapy, but much lower for sentinel node biopsy including the pathologic results and axillary lymph node dissection. This is relevant for clinicians given the time spent explaining these procedures, and for researchers to help decide what information to obtain from patients or medical records. PMID- 28888580 TI - Predicting Brain Metastasis in Breast Cancer Patients: Stage Versus Biology. AB - BACKGROUND: Brain metastasis (BM) is a life-threatening event in breast cancer patients. Identifying patients at a high risk for BM can help to adopt screening programs and test preventive interventions. We tried to identify the incidence of BM in different stages and subtypes of breast cancer. PATIENTS AND METHODS: We reviewed the clinical records of 2193 consecutive breast cancer patients who presented between January 1999 and December 2010. We explored the incidence of BM in relation to standard clinicopathological factors, and determined the cumulative risk of BM according to the disease stage and phenotype. RESULTS: Of the 2193 included women, 160 (7.3%) developed BM at a median follow-up of 5.8 years. Age younger than 60 years (P = .015), larger tumors (P = .004), lymph node (LN) positivity (P < .001), high tumor grade (P = .012), and HER2 positivity (P < .001) were associated with higher incidence of BM in the whole population. In patients who presented with locoregional disease, 3 factors independently predicted BM: large tumors (hazard ratio [HR], 3.60; 95% confidence interval [CI], 1.54-8.38; P = .003), axillary LN metastasis (HR, 4.03; 95% CI, 1.91-8.52; P < .001), and HER2 positivity (HR, 1.89; 95% CI, 1.0-3.41; P = .049). A Brain Relapse Index was formulated using those 3 factors, with 5-year cumulative incidence of BM of 19.2% in those having the 2 or 3 risk factors versus 2.5% in those with no or 1 risk factor (P < .001). In metastatic patients, 3 factors were associated with higher risk of BM: HER2 positivity (P = .007), shorter relapse free interval (P < .001), and lung metastasis (P < .001). CONCLUSION: Disease stage and biological subtypes predict the risk for BM and subsequent treatment outcome. PMID- 28888581 TI - Treatment Outcomes and Prognostic Factors in Male Patients With Stage IV Breast Cancer: A Population-based Study. AB - PURPOSE: Male breast cancer (MBC) represents < 1% of breast cancer patients, and limited data exists regarding metastatic MBC. To better characterize this patient subset, we performed a population-based study examining prognostic factors among patients with stage IV MBC. METHODS: Patients with stage IV MBC diagnosed between 1988 and 2012 were selected from the Surveillance, Epidemiology, and End Results database. Prognostic factors for overall survival (OS) and cause-specific survival (CSS) were evaluated. RESULTS: Overall, 394 patients had metastatic disease meeting inclusion criteria. The median follow-up was 21 months. The 5 year OS and CSS rates were 21.1% and 38.3%, respectively. Of those with known progesterone receptor (PR) status, 52% were PR-positive, which was associated with better OS (P < .001) and CSS (P = .003). Overall, 197 patients (50%) received surgery for the primary tumor, and 197 (50%) did not. Patients undergoing surgery had longer median CSS than those who did not (36 vs. 21 months; P < .001). Additional factors that correlated with prolonged OS and CSS were smaller tumor size (<= 2 cm; P < .05) and younger age (<= 65 years; P < .05). In multivariate analysis, smaller tumor size, PR-positivity, younger age, and resection of the primary tumor were associated with longer OS and CSS (P < .05). CONCLUSIONS: Although stage IV MBC has poor OS and CSS, patients with PR positive disease, younger age (<= 65 years), tumor size <= 2 cm, or who undergo surgery of the primary tumor have better OS and CSS. This is the largest study of stage IV MBC to date, and these findings address some of the questions regarding this rare presentation of breast cancer. PMID- 28888582 TI - Hydroxychloroquine as additional treatment in pregnant patients with refractory APS. PMID- 28888583 TI - Food and Drug Administration warning on anesthesia and brain development: implications for obstetric and fetal surgery. AB - There has been growing concern about the detrimental effects of certain anesthetic agents on the developing brain. Preclinical studies in small animal models as well as nonhuman primates suggested loss or death of brain cells and consequent impaired neurocognitive function following anesthetic exposure in neonates and late gestation fetuses. Human studies in this area are limited and currently inconclusive. On Dec. 14, 2016, the US Food and Drug Administration issued a warning regarding impaired brain development in children following exposure to certain anesthetic agents used for general anesthesia, namely the inhalational anesthetics isoflurane, sevoflurane, and desflurane, and the intravenous agents propofol and midazolam, in the third trimester of pregnancy. Furthermore, this warning recommends that health care professionals should balance the benefits of appropriate anesthesia in young children and pregnant women against potential risks, especially for procedures that may last >3 hours or if multiple procedures are required in children <3 years old. The objective of this article is to highlight how the Food and Drug Administration warning may impact the anesthetic and surgical management of the obstetric patient. Neuraxial anesthesia (epidural or spinal anesthesia) is more commonly administered for cesarean delivery than general anesthesia. The short duration of fetal exposure to general anesthesia during cesarean delivery has not been associated with learning disabilities. However, the fetus can also be exposed to both intravenous and inhalation anesthetics during nonobstetric or fetal surgery in the second and third trimester; this exposure is typically longer than that for cesarean delivery. Very few studies address the effect of anesthetic exposure on the fetus in the second trimester when most nonobstetric and fetal surgical procedures are performed. It is also unclear how the plasticity of the fetal brain at this stage of development will modulate the consequences of anesthetic exposure. Strategies that may circumvent possible untoward long-term neurologic effects of anesthesia in the baby include: (1) use of nonimplicated (nongamma-aminobutyric acid agonist) agents for sedation such as opioids (remifentanil, fentanyl) or the alpha-2 agonist, dexmedetomidine, when appropriate; (2) minimizing the duration of exposure to inhalational anesthetics for fetal, obstetric, and nonobstetric procedures in the pregnant patient, as much as possible within safe limits; and (3) commencing surgery promptly and limiting the interval between induction of anesthesia and surgery start time will help decrease patient exposure to inhalational agents. While the Food and Drug Administration warning was based on duration and repetitive nature of exposure rather than concentration of inhalational agents, intravenous tocolytics can be considered for intraoperative use, to provide uterine relaxation for fetal surgery, in lieu of high concentrations of inhalational anesthetic agents. Practitioners should consider the type of anesthesia that will be administered and the potential risks when scheduling patients for nonobstetric and fetal surgery. PMID- 28888584 TI - Reply. PMID- 28888585 TI - Reply. PMID- 28888586 TI - Lessons learned from domestic and international human papillomavirus vaccination programs: a review. AB - Since the development of the human papillomavirus vaccine, many countries have created implementation programs to bolster vaccination rates and protect their populations. Despite demonstrated efficacy with decreased human papillomavirus related disease abroad, the vaccine's potential to prevent morbidity and mortality in the United States is not being met. The purpose of this review is to discuss strategies of both international and domestic vaccination programs, their impact on human papillomavirus-related diseases, the unique obstacles faced by the United States, and future directions for success. PMID- 28888587 TI - Reply. PMID- 28888588 TI - Variation in waiting period for Medicaid postpartum sterilizations: results of a national survey of obstetricians-gynecologists. PMID- 28888590 TI - Effective evidence-based medicine: considering factors not included in research studies. PMID- 28888589 TI - Beyond the traditional models of group prenatal care: the case for Moms2B. PMID- 28888591 TI - Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia. AB - BACKGROUND: The Aspirin for Evidence-Based Preeclampsia Prevention trial was a multicenter study in women with singleton pregnancies. Screening was carried out at 11-13 weeks' gestation with an algorithm that combines maternal factors and biomarkers (mean arterial pressure, uterine artery pulsatility index, and maternal serum pregnancy-associated plasma protein A and placental growth factor). Those with an estimated risk for preterm preeclampsia of >1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg/d) vs placebo from 11-14 until 36 weeks' gestation. Preterm preeclampsia with delivery at <37 weeks' gestation, which was the primary outcome, occurred in 1.6% (13/798) participants in the aspirin group, as compared with 4.3% (35/822) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74). OBJECTIVE: We sought to examine the influence of compliance on the beneficial effect of aspirin in prevention of preterm preeclampsia in the Aspirin for Evidence-Based Preeclampsia Prevention trial. STUDY DESIGN: This was a secondary analysis of data from the trial. The proportion of prescribed tablets taken was used as an overall measure of compliance. Logistic regression analysis was used to estimate the effect of aspirin on the incidence of preterm preeclampsia according to compliance of <90% and >=90%, after adjustment for the estimated risk of preterm preeclampsia at screening and the participating center. The choice of cut-off of 90% was based on an exploratory analysis of the treatment effect. Logistic regression analysis was used to investigate predictors of compliance >=90% among maternal characteristics and medical history. RESULTS: Preterm preeclampsia occurred in 5/555 (0.9%) participants in the aspirin group with compliance >=90%, in 8/243 (3.3%) of participants in the aspirin group with compliance <90%, in 22/588 (3.7%) of participants in the placebo group with compliance >=90%, and in 13/234 (5.6%) of participants in the placebo group with compliance <90%. The odds ratio in the aspirin group for preterm preeclampsia was 0.24 (95% confidence interval, 0.09-0.65) for compliance >=90% and 0.59 (95% confidence interval, 0.23-1.53) for compliance <90%. Compliance was positively associated with family history of preeclampsia and negatively associated with smoking, maternal age <25 years, Afro-Caribbean and South Asian racial origin, and history of preeclampsia in a previous pregnancy. CONCLUSION: The beneficial effect of aspirin in the prevention of preterm preeclampsia appears to depend on compliance. PMID- 28888593 TI - Digestibility and clover proportion determine milk production when silages of different grass and clover species are fed to dairy cows. AB - This study examined how silages of different grass and clover species affect dry matter (DM) intake, milk production, and eating behavior in dairy cows. The primary growth of perennial ryegrass (early and late harvested), festulolium, tall fescue, red clover, and white clover swards were cut, wilted, and ensiled without additives. Thirty-six Danish Holstein cows were fed ad libitum with total mixed rations containing 70% forage on DM basis in an incomplete Latin square design. The forage source was either 1 of the 6 pure silages or late perennial ryegrass silage mixed (50:50 on DM basis) with either red clover or white clover silage. Intake of DM, milk yield, and milk lactose concentration were higher, whereas milk fat and protein concentrations were lower when cows were fed clover compared with grass. No differences in DM intake and milk composition were detected between cows fed red clover and white clover, but white clover resulted in higher milk yield than red clover. Lower body weight, probably caused by lower rumen fill, in cows fed pure white clover compared with the other treatments indicated that intake was regulated physiologically instead of physically. Cows fed early perennial ryegrass, which had the highest silage organic matter digestibility (OMD), did not produce the expected amount of energy-corrected milk (ECM) compared with the other treatments based on the amount of OM digested in the gastrointestinal tract, but the reason was unclear. Across all other grass species, ECM was related to OMD. Inclusion of 50% clover in the diet increased ECM with 2.3 kg/d, and the response to OMD was comparable to the response for the grass silages. In situ fiber degradation profile parameters indicated that fiber in festulolium differed compared with fiber in the other grass species and resembled fiber in clover. Drinking and eating behavior differed markedly in cows fed pure white clover compared with the other treatments. Water intake per drinking bout was comparable among treatments, but cows fed pure white clover had higher drinking bout duration and reduced drinking rate. Additionally, meal size was smaller for cows fed pure white clover compared with the other treatments, for which meal size was similar. In conclusion, differences in ECM between different grass species can be explained by differences in OMD, and at a given OMD level inclusion of clover in the diet increased ECM. PMID- 28888592 TI - Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment. AB - Although nonsteroidal antiinflammatory drugs can alleviate menstrual pain, about 18% of women with dysmenorrhea are unresponsive, leaving them and their physicians to pursue less well-studied strategies. The goal of this review is to provide a background for treating menstrual pain when first-line options fail. Research on menstrual pain and failure of similar drugs in the antiplatelet category suggested potential mechanisms underlying nonsteroidal antiinflammatory drug resistance. Based on these mechanisms, alternative options may be helpful for refractory cases. This review also identifies key pathways in need of further study to optimize menstrual pain treatment. PMID- 28888594 TI - Plasma concentrations of glucagon-like peptide 1 and 2 in calves fed calf starters containing lactose. AB - The objective of this study was to evaluate the effects of lactose inclusion in calf starters on plasma glucagon-like peptide (GLP)-1 and GLP-2 concentrations and gastrointestinal tract development in calves. Holstein bull calves (n = 45) were raised on an intensified nursing program using milk replacer containing 28.0% CP and 15.0% fat, and were fed a texturized calf starter containing 0 (control), 5.0 (LAC5), or 10.0% (LAC10; n = 15 for each treatment) lactose on a DM basis. Lactose was included in the starter by partially replacing dry ground corn in pelleted portion of the starter. All calf starters were formulated with 23.1% CP. The ethanol-soluble carbohydrate concentrations of the control, LAC5, and LAC10 starters were 7.3, 12.3, and 16.8% on a DM basis, respectively. Starch concentrations of the control, LAC5, and LAC10 starters were 29.7, 27.0, and 21.4% on a DM basis, respectively. All calves were fed treatment calf starters ad libitum. Blood samples were obtained weekly from 1 to 11 wk of age, and used to measure plasma GLP-1, GLP-2, and insulin concentrations, serum beta hydroxybutyrate (BHB) concentration, and blood glucose concentration. At 80 d of age, calves were euthanized, and weights of the reticulorumen, omasum, abomasum, small intestine, and large intestine tissue were measured. Serum BHB concentration was higher for calves fed the LAC10 (171 MUmol/L) starter than for those fed the control (151 MUmol/L) and LAC5 (145 MUmol/L) starters. Plasma GLP-1 and GLP-2 concentrations did not differ between treatments. However, relative to the baseline (1 wk of age), the plasma GLP-1 concentration was higher for the LAC10 (125.9%) than for the LAC5 (68.2%) and control (36.8%), and for the LAC5 than for the control (36.8%). Moreover, similar differences between treatments were observed for GLP-2 concentration relative to the baseline (88.2, 76.9, and 74.9% for LAC10, LAC5, and control treatments, respectively). The serum BHB concentration was positively correlated with the plasma GLP-1 concentration (r = 0.428). Furthermore, the plasma GLP-1 concentration was positively correlated with the insulin concentration (r = 0.793). The weights of the reticulorumen, omasum, abomasum, small intestine, and large intestine were not affected by the treatments. In conclusion, inclusion of lactose in calf starters resulted in higher plasma GLP-1 and GLP-2 concentrations, and BHB might be associated with higher plasma GLP-1 concentration. PMID- 28888595 TI - Short communication: The diurnal intake and behavior of dairy cows when access to a feed of consistent nutritive value is restricted. AB - The diurnal variation in pasture nutritive value adds a confounding factor to studies elucidating the effect of time of day on behavior. Our work separates the effect of time of day on both feeding and lying patterns for cows outdoors to enable the alignment of feeding behavior with feed management. We determined the diurnal intake patterns and behavior of dairy cows when the nutritive value of feed remained constant throughout 24 h in an outdoor environment, and when feed access was restricted. Nine nonlactating Holstein-Friesian cows (live weight 626 +/- 53 kg, age 96 +/- 33 mo; mean +/- SD) were split into 3 groups of 3 and offered lucerne hay cubes (cube volume 32 mm3) ad libitum according to 3 treatments: full access (FA, feed access 24 h), day access (DA, feed access between 0600 and 1800 h), and night access (NA, feed access between 1800 and 0600 h). Treatments were applied to individual cows in a crossover design with 7-d periods. During the last 4 d of each period, data were collected on feed intake, as well as feeding and lying behaviors. Total daily intake was greater for cows on the FA treatment (3.5% of BW) compared with the DA and NA treatments at 3.1 and 2.9% of BW, respectively. The cows with FA consumed 69% of their total intake during the day (0600-1800 h), with the greatest intake (39%) occurring during 1200 to 1800 h and only 12% of intake occurring during 2400 to 0600 h. Cows with DA consumed 56% of feed during 0600 to 1200 h and 44% during 1200 to 1800 h. In contrast, NA cows consumed more feed (74%) during the first 6 h period (1800-2400 h), thus maximizing lying time between 2400 and 0600 h. The time spent lying throughout daylight periods varied between treatments; however, total daily lying time was similar across the 3 treatments. This experiment shows the feeding and lying behaviors of cows when feed quality remains constant throughout 24 h, which will assist the formulation of variable feed allocation strategies for future testing in both robotic and conventional milking systems. Varying the quantity of feed offered throughout 24 h may benefit robot utilization at night in automatic milking systems through increased feeding activity, and as we observed, is likely to have little effect on lying time or DMI, with cows readily adapting to changes in feed management. Conversely, aligning feed on offer with preferred feeding time in conventional milking systems may increase the intake of high quality pasture. PMID- 28888596 TI - Relative importance of herd-level risk factors for probability of infection with paratuberculosis in Irish dairy herds. AB - Control of paratuberculosis is challenging due to the relatively poor performance of diagnostic tests, a prolonged incubation period, and protracted environmental survival. Prioritization of herd-level interventions is not possible because putative risk factors are often not supported by risk factor studies. The objective for this study was to investigate the relative importance of risk factors for an increased probability of herd paratuberculosis infection. Risk assessment data, comprehensive animal purchase history, and diagnostic test data were available for 936 Irish dairy herds. Both logistic regression and a Bayesian beta regression on the outcome of a latent class analysis were conducted. Population attributable fractions and proportional reduction in variance explained were calculated for each variable in the logistic and Bayesian models, respectively. Routine use of the calving area for sick or lame cows was found to be a significant explanatory covariate in both models. Purchasing behavior for the previous 10 yr was not found to be significant. For the logistic model, length of time calves spend in the calving pen (25%) and routine use of the calving pen for sick or lame animals (14%) had the highest attributable fractions. For the Bayesian model, the overall R2 was 16%. Dry cow cleanliness (7%) and routine use of the calving area for sick or lame cows (6%) and had the highest proportional reduction in variance explained. These findings provide support for several management practices commonly recommended as part of paratuberculosis control programs; however, a large proportion of the observed variation in probability of infection remained unexplained, suggesting other important risks factors may exist. PMID- 28888597 TI - Symposium review: Mechanisms linking metabolic stress with innate immunity in the endometrium. AB - Bacterial infections of the uterus after parturition are ubiquitous in dairy cattle and often cause uterine disease, such as metritis or endometritis. However, the metabolic stress associated with milk production increases the risk of developing disease. Resolution of bacterial infections requires rapid and robust innate immune responses, which depend on host cell receptors recognizing pathogen-associated molecular patterns, such as lipopolysaccharide (LPS) from gram-negative bacteria. Here, we argue that metabolic stress impairs the inflammatory response to pathogens. Glucose and glutamine are the major energy sources for cells, but their abundance is reduced in postpartum dairy cows. Furthermore, inflammatory responses exacerbate metabolic stress, with animals and tissues consuming more glucose when challenged with LPS. However, depriving endometrial tissue of glucose or glutamine impairs the secretion of IL-1beta, IL 6, and IL-8 in response to pathogen-associated molecular patterns. Glycolysis and the intracellular sensor of energy, AMP-activated protein kinase, are important for the response to LPS because perturbing glycolysis or AMP-activated protein kinase activity reduces the secretion of IL-1beta, IL-6, and IL-8 in the endometrium. The mevalonate pathway for cellular cholesterol synthesis may also be linked to immunity, as inhibition of the terminal enzyme in the pathway, squalene synthase, reduces inflammatory responses to pathogenic bacteria and LPS. In contrast, only modest effects on inflammation are found when modulating the sensor of cellular nutrient satiety, mammalian target of rapamycin, or the endocrine regulator of metabolism, insulin-like growth factor-1. We suggest that stressing cellular metabolism increases the risk of uterine disease by impairing endometrial defenses. PMID- 28888598 TI - Effect of hoof trimmer intervention in moderately lame cows on lameness progression and milk yield. AB - The objective of this study was to evaluate the effect of hoof trimmer intervention (HTI) in moderately lame cows on lameness progression and milk yield. Two freestall Holstein herds were enrolled. Cows were milked 2 (herd A: 2,374 cows) or 3 (herd B: 2,800 cows) times a day. Within each dairy, moderately lame cows [locomotion score (LS) = 3 on a 5-point scale] were randomly assigned to control group (CON; herd A = 66, herd B = 84) or treatment group (HTI; evaluated and treated by the hoof trimmer under researchers' supervision; herd A = 73; herd B = 75). Enrollment criteria were <350 d in milk, <180 d pregnant, >10 kg/d of milk yield, not selected for therapeutic trimming 2 mo before enrollment, and >14 observations of daily milk yield during the study period. Biweekly lameness scoring (LS <=2, LS = 3, LS >=4) was conducted up to 6 wk post intervention. Lesion type and severity records were collected at intervention from HTI cows and up to 6 wk post-intervention from all enrolled cows identified as lame by farm employees. Daily milk yield data were collected from -1 to 6 wk relative to intervention using Afifarm (Afimilk Ltd., Kibbutz Afikim, Israel) records. No treatment effect was detected on the predicted probability of locomotion score, but the predicted probability of LS >=3 decreased over time in herd B, whereas in herd A, it initially decreased but later increased. A tendency for a treatment by time interaction was observed in herd A; at 2 wk post intervention, the predicted probability for LS >=3 was higher for HTI (0.69) than for CON (0.43), but similar at 4 wk (0.41 HTI, 0.49 CON) and 6 wk (0.77 HTI, 0.73 CON). At intervention, most study cows had no lesions (41.2%), sole hemorrhages (28.4%), thin soles (8.8%), or vertical fissure (6.8%). During the 6 wk following intervention, a similar proportion of cows were identified as lame in CON (8.7%) and HTI (6.7%) groups. In herd A, milk yield (least squares means +/- standard error) was similar for CON (42.0 +/- 0.77 kg/d) and HTI (42.3 +/- 0.75 kg/d) cows, whereas in herd B, it tended to be lower for HTI (43.7 +/- 0.61 kg/d) than for CON (45.2 +/- 0.59 kg/d) cows. A significant effect of time was detected on both dairies, with milk yield decreasing over the study period. In our study, implementing HTI on moderately lame cows resulted in no improvement in gait or milk yield. The low presence of severe lesions amenable to therapy may partially explain our findings. PMID- 28888599 TI - Management, operational, animal health, and economic characteristics of large dairy herds in 4 states in the Upper Midwest of the United States. AB - Recent trends in dairy farm structure in the United States have included a decreasing number of farms, although farm size has increased, especially the share of milk production from very large herds (>2,500 cows). The objectives of this observational study were to describe common management practices; to characterize labor and operational structure; to measure some aspects of animal health, including lameness, hock lesions, mortality, and mastitis incidence; and to summarize cost of production on farms with more than 2,500 cows in 4 states in the Upper Midwest of the United States. The study included 15 dairy farms in Minnesota, Wisconsin, Iowa, and South Dakota. Farms were visited twice, once each year, and on-farm herd records were collected for those 2 yr. On-farm herd records were used to investigate mortality, culling, pregnancy rate, and clinical mastitis incidence. At least 1 high-producing pen of mature cows and 1 pen of fresh cows were scored for locomotion. Likewise, at least 1 pen of high-producing mature cows was scored for cleanliness and hock lesions. Median herd size was 3,975 cows (range = 2,606-13,266). Milk sold per employee was 1,120,745 kg and the number of cows per employee was 105. Eighty percent of the farms had Holstein cows, 13% had Jersey, and 7% had Jersey-Holstein crosses. All farms used artificial insemination as the sole form of breeding and 100% of the farms used hormonal synchronization or timed artificial insemination programs in their reproductive protocols; 21-d pregnancy rate was 21.7%. Median lameness prevalence was 18.3% and median severe lameness prevalence was 5.1%. Median hock lesion prevalence was 17.4% and median severe hock lesion prevalence was 1.9%; mortality rate was 7.4%. Clinical mastitis incidence was 62.5 cases per 100 cow-years. Feed costs accounted for approximately 53% of the total cost of producing milk, followed by labor at 11%, interest and depreciation expenses at 10%, and replacement costs at 9.5%. Herds in the top 50th percentile for profitability had a net income of $2.40 per hundredweight of milk sold compared with $0.95 per hundredweight for herds in the bottom 50th percentile. Although results of this study were helpful in understanding how large dairy systems operate in the Upper Midwest, more research is yet needed with a larger number of farms and wider variety of management practices to identify factors within these large farms that promote optimal animal health and profitability. PMID- 28888600 TI - Effects of egg yolk inclusion, milk replacer feeding rate, and low-starch (pelleted) or high-starch (texturized) starter on Holstein calf performance through 4 months of age. AB - The objectives of this research were to evaluate milk replacer (MR) feeding rates, alternative protein and fat sources in MR, and calf starter starch concentration and their effects on calf performance to 4 mo of age. Male Holstein calves (42.6 +/- 1.2 kg of body weight; n = 192) were assigned at 3 d of age to 1 of 8 treatments in a randomized complete block design with a 2 * 2 * 2 factorial arrangement of treatments. Factors tested from d 0 to 56 (nursery) were low or high MR feeding rates, 0 or 10% inclusion of spray-dried egg yolks in MR, and low or high-starch calf starter. The low MR rate was 0.66 kg of dry matter (DM) fed for 39 d followed by 0.33 kg of DM for 3 d. The high MR rate was 0.87 kg of DM fed for 5 d, 1.08 kg of DM for 37 d, and 0.43 kg of DM for 7 d. The MR contained 27.5% crude protein and 19.6% fat (DM basis) and starters were 21.2% crude protein; low starch was a complete pellet with 10.2% starch, and high starch was textured using whole corn and oats with 43.3% starch. From d 56 to 112 (grower), calves were randomly assigned to pens (4 calves/pen) maintaining MR rate and starch content while stratifying yolk treatments within pen, resulting in a 2 * 2 factorial arrangement. Starter was blended with 5% chopped hay during the grower trial. Fecal scores and medical treatments were recorded daily. In the nursery trial, calves were weighed initially and weekly thereafter. Hip width and body condition score (BCS) were measured initially and every 2 wk thereafter. In the grower trial, body weight, hip width, and BCS were measured on d 56, 84, and 112. Data were analyzed as repeated measures with calf (nursery) or pen (grower) as the experimental unit. Calf average daily gain, hip width, and BCS change were greater for calves fed high versus low MR, 0 versus 10% yolk, and high versus low starch in the nursery. In the grower trial, calves fed low MR and high starch had the greatest average daily gain (1.09 vs. 0.87 kg/d) and hip width change (5.4 vs. 3.9 cm) compared with calves fed low MR and low starch with other treatments intermediate. From 0 to 112 d, calves fed high MR had 9% greater body weight gain and 4% greater hip width change than calves fed low MR, yet nutrient efficiency was similar despite 80% more MR intake than calves fed low MR. Additionally, calves fed high-starch starter achieved 18% greater body weight gain and 17% greater hip width than calves fed low starch starter overall, a more than 2-fold greater response than the effect of MR feeding rate. PMID- 28888601 TI - Interaction of potassium carbonate and soybean oil supplementation on performance of early-lactation dairy cows fed a high-concentrate diet. AB - Potassium carbonate supplementation is known to improve milk fat synthesis and to modify milk mineral composition in dairy cows. The objective of the current experiment was to evaluate the effect of K2CO3 on production performance, biohydrogenation of fatty acids (FA), and mineral composition of milk in early lactation dairy cows fed a high-concentrate diet with or without soybean oil (SBO), as a source of polyunsaturated FA. Twenty-eight ruminally fistulated Holstein cows were used in a randomized complete block design. The experiment lasted 33 d, including a 5-d pretreatment collection period used as a covariate. Experimental treatments were arranged as a 2 * 2 factorial with 0 or 1.5% K2CO3 and with 0 or 2% SBO, and balanced to contain 40% forage (57% corn silage + 43% grass silage) and 60% concentrate. Preplanned orthogonal contrasts were used to assess the effects of K2CO3, SBO, and their interaction. Feeding K2CO3 did not affect milk yield, but tended to increase 4% fat-corrected milk and fat yield when combined with SBO. However, adding SBO to diets increased milk yield. Dietary K2CO3 supplementation did not affect milk fat concentration of trans-10 18:1 or any other identified biohydrogenation intermediates. Soybean oil supplementation decreased milk fat concentration of C16 and de novo synthesized FA, and increased preformed FA. Among the other effects of SBO supplementation observed, concentrations of cis-9,trans-11 18:2 increased, as well as most of the cis and trans isomers of 18:1 and 18:0. Milk urea N decreased in cows fed K2CO3 as compared with unsupplemented diets. A positive relation was established between milk Cl concentration and milk yield, suggesting that the equilibrium of this ion is linked to the efficiency of lactogenesis. The effect of K2CO3 on this mineral equilibrium in the mammary gland remains to be established. Overall, results have shown that potential effect of K2CO3 on milk fat synthesis is dependent on the levels of dietary polyunsaturated FA. PMID- 28888602 TI - Properties of acid gels made from sodium caseinate-maltodextrin conjugates prepared by a wet heating method. AB - Covalent attachment of polysaccharides to proteins (conjugation) via the Maillard reaction has been extensively studied. Conjugation can lead to a significant improvement in protein functionality (e.g., solubility, emulsification, and heat stability). Caseins have previously been successfully conjugated with maltodextrin (Md), but the effect on the detailed acid gelation properties has not been examined. We studied the effect of conjugating sodium caseinate (NaCN) with 3 different sized Md samples via the Maillard reaction in aqueous solutions. The Md samples had dextrose equivalents of 4 to 7, 9 to 12, and 20 to 23 for Md40, Md100, and Md200, respectively. The conjugation reaction was performed in mixtures with 5% NaCN and 5% Md, which were heated at 90 degrees C for 10 h. The degree of conjugation was estimated from the reduction in free amino groups as well as color changes. Sodium dodecyl sulfate-PAGE analysis was performed to confirm conjugation by employing staining of both protein and carbohydrate bands. The molar mass of samples was determined by size-exclusion chromatography coupled with multi-angle laser light scattering. After the conjugation reaction, samples were then gelled by the addition of 0.63% (wt/vol) glucono-delta-lactone at 30 degrees C, such that samples reached pH 4.6 after about 13 h. The rheological properties of samples during acidification was monitored by small-strain dynamic oscillatory rheology. The microstructure of acid gels at pH 4.6 was examined by fluorescence microscopy. Conjugation resulted in a loss of 10.8, 8.8, and 11.9% of the available amino groups in the protein for the NaCN-Md40 conjugates (C40), NaCN-Md100 conjugates (C100), and NaCN-Md100 conjugates (C200), respectively. With a decrease in the size of the type of Md, an increase occurred in the molar mass of the resultant conjugate. The weight average molar masses of NaCN-Md samples were 340, 368, and 425 kDa for the conjugates C40, C100, and C200, respectively. Addition of Md to NaCN dispersion resulted in slightly shorter acid gelation times even without the conjugation reaction. The storage modulus (G') of acid gels was significantly lower in conjugated samples compared with the corresponding (unreacted) mixtures of Md and NaCN. The sample with the lowest G' value at pH 4.6 was the C40 conjugate. Fluorescence microscopy showed that gels made by conjugates had slightly larger pores. These results indicate that conjugation of casein modified its acid gelation properties, presumably by the Md polysaccharide moiety hindering aggregation and rearrangements of the casein network. PMID- 28888603 TI - Potential factors involved in virulence of Cronobacter sakazakii isolates by comparative transcriptome analysis. AB - Cronobacter species are important foodborne pathogens causing severe infections in neonates through consumption of contaminated powdered infant formula. However, the virulence-associated factors in Cronobacter are largely unknown. In this study, the transcriptome analysis between highly virulent Cronobacter sakazakii G362 and attenuated L3101 strains was used to reveal the potential factors involved in virulence. The total transcripts were grouped into 20 clusters of orthologous group categories and summarized in 3 gene ontology categories (biological process, cellular component, and molecular function). In addition, the differentially expressed genes (DEG) between these isolates were analyzed using Volcano plots and gene ontology enrichment. The predominant DEG were flagella-associated genes such as flhD, motA, flgM, flgB, and fliC. Furthermore, the expression abundance of outer membrane protein or lipoprotein genes (ompW, slyB, blc, tolC, and lolA), potential virulence-related factors (hlyIII and hha), and regulation factors (sdiA, cheY, Bss, fliZ) was also significantly different between G362 and L3101. Interestingly, 3 hypothetical protein genes (ESA_01022, ESA_01609, and ESA_00609) were found to be expressed only in G362. Our findings provide valuable transcriptomic information about potential virulence factor genes, which will be needed in future molecular biology studies designed to understand the pathogenic mechanism of Cronobacter. PMID- 28888604 TI - Neglect of lactation stage leads to naive assessment of residual feed intake in dairy cattle. AB - Residual feed intake (RFI) is a candidate trait for feed efficiency in dairy cattle. We investigated the influence of lactation stage on the effect of energy sinks in defining RFI and the genetic parameters for RFI across lactation stages for primiparous dairy cattle. Our analysis included 747 primiparous Holstein cows, each with recordings on dry matter intake (DMI), milk yield, milk composition, and body weight (BW) over 44 lactation weeks. For each individual cow, energy-corrected milk (ECM), metabolic BW (MBW), and change in BW (DeltaBW) were calculated in each week of lactation and were taken as energy sinks when defining RFI. Two RFI models were considered in the analyses; RFI model [1] was a 1-step RFI model with constant partial regression coefficients of DMI on energy sinks (ECM, MBW, and DeltaBW) over lactation. In RFI model [2], data from 44 lactation weeks were divided into 11 consecutive lactation periods of 4 wk in length. The RFI model [2] was identical to model [1] except that period-specific partial regressions of DMI on ECM, MBW, and DeltaBW in each lactation period were allowed across lactation. We estimated genetic parameters for RFI across lactation by both models using a random regression method. Using RFI model [2], we estimated the period-specific effects of ECM, MBW, and DeltaBW on DMI in all lactation periods. Based on results from RFI model [2], the partial regression coefficients of DMI on ECM, MBW, and DeltaBW differed across lactation in RFI. Constant partial regression coefficients of DMI on energy sinks over lactation was not always sufficient to account for the effects across lactation and tended to give roughly average information from all period-specific effects. Heritability for RFI over 44 lactation weeks ranged from 0.10 to 0.29 in model [1] and from 0.10 to 0.23 in model [2]. Genetic variance and heritability estimates for RFI from model [2] tended to be slightly lower and more stable across lactation than those from model [1]. In both models, RFI was genetically different over lactation, especially between early and later lactation stages. Genetic correlation estimates for RFI between early and later lactation tended to be higher when using model [2] compared with model [1]. In conclusion, partial regression coefficients of DMI on energy sinks differed across lactation when modeling RFI. Neglect of lactation stage when defining RFI could affect the assessment of RFI and the estimation of genetic parameters for RFI across lactation. PMID- 28888605 TI - Effects of profound acidemia on the dynamic glucose and insulin response and plasma potassium and phosphorus concentrations during an intravenous glucose tolerance test in neonatal calves. AB - Acidemia and electrolyte imbalances such as hyperkalemia are common in neonatal calves with diarrhea. Acidemia negatively affects the cellular response to insulin and may therefore result in deranged glucose, potassium, and phosphorus homeostasis. The primary aim of this study was to compare indices that characterize the dynamic glucose and insulin response between acidemic and nonacidemic neonatal diarrheic calves and a healthy control group during an intravenous glucose tolerance test (IVGTT) that consisted of i.v. administration of 0.3 g of glucose per kg of body weight. Secondary aims were to characterize the associated changes in plasma potassium and phosphorus concentrations. The effect of correction of profound acidemia with a sodium bicarbonate containing infusion on these parameters was also assessed. Thirty calves (age <=21 d) were purposively assigned to one of the following groups: 10 calves with diarrhea and profound acidemia (venous blood pH <7.20) where an IVGTT was performed before and after treatment with sodium bicarbonate, 10 calves with diarrhea and minimal acid base disturbance (venous blood pH >7.35), and 10 healthy control calves. Profoundly acidemic diarrheic calves (jugular venous blood pH 6.99 +/- 0.10) had a similar initial increase in plasma insulin concentration to that in healthy control calves or nonacidemic calves with diarrhea. However, insulin concentrations remained relatively stable in acidemic calves between 15 and 60 min after the start of the IVGTT, whereas a marked decrease in plasma insulin concentrations occurred in all other groups during the same period of time. We conclude that acidemia does not alter cell glucose availability or the dynamic response of glucose, phosphorus, and potassium to insulin; however, acidemia markedly prolongs plasma insulin concentrations following an IVGTT through an unidentified mechanism. Results of this study emphasize the importance of correcting acidemia and metabolic acidosis in neonatal calves with diarrhea. PMID- 28888606 TI - Preovulatory follicle characteristics and oocyte competence in repeat breeder dairy cows. AB - The varied and elusive etiology of repeat breeding (RB) in dairy cows necessitates evaluation of oocytes and follicles, which have not previously been assessed together. Accordingly, we evaluated characteristics of preovulatory follicles and the competence of oocytes in control (CTL) and RB cows. The estrous cycles of 35 cows (18 CTL and 17 RB) were synchronized using PGF2alpha and estrus detection. Cows with a corpus luteum were treated with PGF2alpha and, 14 to 15 d after a visible behavioral estrus, they were administered a second PGF2alpha, followed 48 h later by follicular fluid (FF) aspiration of the preovulatory follicles. Estradiol (E2)-active preovulatory follicles did not differ in diameter between the 2 groups of cows. However, FF of RB cows had higher E2 concentrations than that of CTL cows: 1,854.9 and 1,073.6 ng/mL, respectively, but similar androstenedione and progesterone concentrations. In the second part of the study, 14 consecutive ovum pick-ups (OPU) were performed in 5 CTL and 5 RB cows, at 3- to 4-d intervals. The RB and CTL cows did not differ in average numbers of follicles available per cow per session (7.1 and 7.3, respectively), oocyte recovery rates (42.2 and 44.1%, respectively), or cleavage rates (57.6 and 63.4%, respectively), but blastocyst production was markedly less in RB than in CTL cows (12.5 and 29.2%, respectively). We conclude that part of the RB cows' etiology occurs at an earlier phase of folliculogenesis, thereby impairing oocyte competence, and subsequently reducing the probability of normal fertilization, which diminish embryo vitality and development. PMID- 28888607 TI - Effect of increasing amounts of milk replacer powder added to whole milk on postweaning performance, reproduction, glucose metabolism, and mammary fat pad in dairy heifers. AB - The aim of this study was to evaluate the effects of increasing the total solids (TS) content of liquid feed, by adding increasing amounts of milk replacer powder to whole milk, on age at puberty and postweaning performance, glucose metabolism, and mammary fat pad of dairy heifers. Crossbreed Holstein * Gyr heifers (n = 58) were distributed into 4 different treatments during the preweaning period. Treatments consisted of liquid feeds with TS content of 12.5 (actual TS = 13.5 +/ 0.53%; n = 15), 15.0 (actual TS = 16.1 +/- 0.03%; n = 15), 17.5 (actual TS = 18.2 +/- 0.14%; n = 13), or 20.0% (actual TS = 20.4 +/- 0.24%; n = 15), which were provided up to 59 d old. From 60 to 89 d old, the animals received the same starter offered during the preweaning period in addition to corn silage ad libitum starting at 70 d old. From 90 to 104 d old, the animals were adapted to a total mixed ration. At 105 d old, the animals were distributed in 4 paddocks equipped with electronic feed and water bins and were fed the same total mixed ration ad libitum. A period of adaptation to the electronic feed bins occurred from 105 to 119 d old. Feed and water intake and body weight and body frame development were assessed until puberty. Mammary gland evaluations were performed monthly by ultrasonography from 120 d of age until puberty onset. Puberty onset was determined as plasma progesterone concentration greater than 1 ng/mL in 2 consecutive samples collected 7 d apart. The date of puberty onset was recorded as the collection day of the first of these samples. A glucose tolerance test was performed at 280 d of age. The increased TS content of the liquid feed fed during the preweaning period did not affect dry matter intake, performance, age at puberty, glucose metabolism, or mammary gland fat pad at later stages of rearing process. Conversely, hip width and heart girth increased linearly up to 150 and 240 d of age, respectively, as a result of the increased TS concentration of the liquid feed during the preweaning period. PMID- 28888608 TI - Effect of dietary flax seed and oil on milk yield, gross composition, and fatty acid profile in dairy cows: A meta-analysis and meta-regression. AB - Several experiments were conducted over the past few years to evaluate the feeding value of flax seed and oil in dairy cow diets. The current meta-analysis and meta-regression was undertaken to assess the overall effect of different forms of flax, as a source of trienoic (cis-9,cis-12,cis-15 18:3) fatty acids (FA), on lactation performance and on transfer efficiency of its constituent n-3 FA from diet to milk fat. Comparisons were first conducted with nonsupplemented controls or with diets containing either saturated (mainly 16:0 or 18:0 or both), monoenoic (mainly cis-9 18:1), or dienoic (mainly cis-9,cis-12 18:2) FA. Results indicate that supplementing flax seed and oil decreased dry matter intake, as well as actual and energy-corrected milk yield without affecting the efficiency of utilization of dietary dry matter or energy as compared with nonsupplemented iso-energetic controls. When compared with the other 3 types of dietary fat evaluated, flax rich in trienoic FA supported a yield of energy-corrected milk similar to supplements rich in saturated, monoenoic, or dienoic FA. Greater milk fat concentration and feed efficiency were observed with saturated supplements. However, milk fat concentration and yield were lower with dienoic FA than with flax supplements. Further analyses were conducted to compare the effect of different forms of flax oil, seed, or fractions of seed. Among the 6 categories evaluated, mechanically processed whole seed (rolled or ground) allowed the greatest yield of energy-corrected milk and the best feed efficiency when compared with free oil, intact or extruded whole seed, protected flax, and flax hulls. Feeding protected flax and flax hulls allowed the greatest milk fat concentration of cis-9,cis-12,cis-15 18:3. Moreover, the greatest transfer efficiencies of this fatty acid from diet to milk were recorded with the same 2 treatments, plus the mechanically processed whole seed. These results make this last category the most suitable treatment, among the 6 flax forms evaluated, to combine optimum lactation performance and protection of flax constituent cis 9,cis-12,cis-15 18:3. PMID- 28888609 TI - Consumers' perceptions toward 3 different fermented dairy products: Insights from focus groups, word association, and projective mapping. AB - Yogurts, fermented milk beverages, and fermented milks have great similarity and are widely accepted by Brazilian population, but the factors that influence their choice and consumption are unknown. In this sense, the present study aimed to identify the main aspects involved in consumers' perception of 3 different products, comparing the findings by using the 2 fast qualitative methods, word association and projective mapping, and a standard method, focus group. The tasks were performed by different participants through graphic stimuli (word association and projective mapping) and focus interviews (focus group). Results showed that all the 3 methodologies identified numerous intrinsic and extrinsic factors that influence the consumer choices regarding fermented dairy products. Major dimensions were closely related to the sensory aspects, emotional factors, perception of benefits, and composition, among others. It is noteworthy that the stimuli related to fermented milk beverages evoked rejecting responses, possibly due to the dissociation between information and consumers' expectation. Although minor differences were observed between the number and type of dimensions that were obtained, similar conclusions can be drawn from all 3 sensory methods, which shows the relevance of qualitative and projective methods for investigation of consumers' perception. These findings can help dairy companies to provide subsidies and guidelines for the reformulation of their products, marketing strategies, and improvement in the communication between producers and consumers from different fermented dairy products. PMID- 28888610 TI - Effects of monensin on glucose metabolism in transition dairy cows. AB - Eight multiparous periparturient Holstein cows fitted with ruminal cannula were used in a split plot design to evaluate the effects of monensin on plasma glucose metabolism. Diets were top-dressed daily with 0 mg/cow of monensin (control) or 300 mg/cow of monensin (MON) both pre- and postpartum. Plasma glucose kinetic parameters on d -13 +/- 2.0 and 19 +/- 1.6 relative to parturition were determined by using stable isotopes. Na-1-13C3-Propionate (labeled propionate) was infused into the rumen to measure glucose synthesis originating from ruminal propionate, and U-13C-glucose (labeled glucose) was injected into the jugular vein to determine total glucose kinetics. A sampling period of 480 min following labeled glucose injection was implemented. A compartmental analysis was employed to determine steady state glucose kinetic parameters. To develop a steady state glucose model, the Windows version of SAAM software (WinSAAM) was used. A 4 compartment model was adequate to comprehensively describe plasma glucose metabolism. The main model compartments consisted of propionate and plasma glucose. The time frame of the 480-min sampling period post-tracer glucose infusion allowed accurate quantification of glucose metabolism. The model estimated that glucose input from sources other than ruminal propionate decreased with MON, from 2.26 to 1.09 g/min postpartum. Gluconeogenesis, expressed as the propionate contribution to the plasma glucose pool, increased in cows fed MON (22 vs. 31%), whereas glucose oxidation, expressed as the glucose disposal rate, significantly decreased (1.67 vs. 0.92 g/min). In conclusion, MON may improve the energy status of transition cows by (1) improving the efficiency of propionate to produce glucose and (2) decreasing glucose oxidation in body tissues. PMID- 28888611 TI - Comparison of mammary lipid metabolism in dairy cows and goats fed diets supplemented with starch, plant oil, or fish oil. AB - A direct comparison of cow and goat performance and milk fatty acid (FA) responses to diets known to induce milk fat depression in the bovine has suggested interspecies differences in rumen and mammary lipid metabolism. Thus, this study was conducted to infer some potential mechanisms responsible for the differences in mammary lipogenesis due to diet and ruminant species. To meet this objective, 12 cows and 15 goats were fed a basal diet (control), a similar diet supplemented with 2.2% fish oil (FO), or a diet containing 5.3% sunflower oil and additional starch (+38%; SOS) according to a 3 * 3 Latin square design with 26-d experimental periods. Milk yield, milk composition, FA profile, and FA secretion were measured. On the last day of each period, the mRNA abundance of 19 key genes in mammary metabolism or the enzyme activity or both were measured in mammary tissue sampled by biopsy or at slaughter or both. The results show significant differences in the response of cows and goats to the dietary treatments. In cows, milk fat content and yield were lowered by FO and SOS (-31%), whereas only FO decreased milk fat content in goats (-21%) compared with the control. In cows and to a lesser extent in goats, FO and SOS decreased the secretion of C16 FA output (mmol/kg of BW). However, SOS increased the secretion of >C16 FA in goats. These changes in milk fat content and FA secretion were not associated with modifications in mammary expression or the activity of 19 proteins involved in the major lipogenic pathways. This absence of variation may be attributable to posttranscriptional regulation for these genes or related to the time of sampling of the mammary tissue relative to the previous meal and milking. Otherwise, the abundances of 15 mRNA among the 19 encoding for genes involved in lipid metabolism in the mammary gland were different among species, with 9 more abundant in cows (FASN, FADS1, SCD1, GPD1, LALBA, SREBF1, LXRA, PPARA, and PPARG1) and 6 more abundant in goats (G6PD, GPAM, SCD5, XDH, CSN2, and SP1). Similarly, a significant effect of the species was observed in the 4 enzyme activities measured; glycerol-3-phosphate dehydrogenase and malic enzyme were higher in cows, and FA synthase and glucose-6-phosphate dehydrogenase activities were higher in goats. In conclusion, the differences between cow and goat performance and milk FA responses to the FO and SOS treatments were not related to changes in the measured mammary lipogenic gene expression. Furthermore, the data provide evidence that the major mammary lipogenic pathways differ between the caprine and the bovine, whose biological significance remains to be unraveled. PMID- 28888612 TI - Evaluation of a gas in vitro system for predicting methane production in vivo. AB - Methane production from ruminant livestock varies with the diet as a result of factors such as dry matter intake, diet composition, and digestibility. To estimate the effect of dietary composition and feed additives, CH4 production can be measured in vitro as a first step because large numbers of samples can be incubated and analyzed at the same time. This study evaluated a recently developed in vitro method for prediction of in vivo CH4 production by examining the relationship between predicted and observed CH4 production values. A total of 49 different diets (observations), used in previous 13 in vivo studies, were selected to include diets varying in nutrient composition. Methane production was measured in all in vivo studies by respiration chambers or the GreenFeed system (C-Lock Inc., Rapid City, SD). Overall, the in vitro system predicted CH4 production well (R2 = 0.96), but the values obtained were slightly underestimated compared with observed in vivo values (mean 399 L/d compared with 418 L/d: root mean square prediction error = 51.6 L/d or 12.3% of observed mean). Further analysis of the effect on residuals showed no significant relationship between CH4 production and most factors known to affect CH4 production such as dry matter intake, digestibility, and dietary concentrations of fat and starch. However, some factors included in the model were not well predicted by the system, with residuals negatively related to neutral detergent fiber concentration and positively related to concentrate proportion. The in vitro system can thus be useful for screening diets and evaluation of feed additives as a first step that can be best interpreted when feeding cows at maintenance level. PMID- 28888613 TI - Intimate partner violence and breastfeeding practices: a systematic review of observational studies. AB - OBJECTIVE: To review the association between intimate partner violence and breastfeeding practices in the literature. DATA SOURCES: The search was carried out in five databases, including MEDLINE, LILACS, SCOPUS, PsycoINFO, and Science Direct. The search strategy was carried out in February 2017. The authors included original studies with observational design, which investigated forms of intimate partner violence (including emotional, physical, and/or sexual) and breastfeeding practices. The quality of the studies was assessed based on the bias susceptibility through criteria specifically developed for this review. SUMMARY OF DATA: The study included 12 original articles (10 cross-sectional, one case-control, and one cohort study) carried out in different countries. The forms of intimate partner violence observed were emotional, physical, and/or sexual. Breastfeeding was investigated by different tools and only assessed children between 2 days and 6 months of life. Of the 12 studies included in this review, eight found a lower breastfeeding intention, breastfeeding initiation, and exclusive breastfeeding during the first six months of the child's life, and a higher likelihood of early termination of exclusive breastfeeding among women living at home where violence was present. The quality varied between the studies and six were classified as having low bias susceptibility based on the assessed items. CONCLUSIONS: Intimate partner violence is associated with inadequate breastfeeding practices of children aged 2 days to 6 months of life. PMID- 28888614 TI - Curricular intervention increases adolescents' knowledge about asthma: a randomized trial. AB - OBJECTIVES: To evaluate the impact of a curricular intervention concerning the knowledge about asthma among adolescents from a public school. METHODS: This was a randomized, controlled trial study on a curricular intervention in asthma, carried out with asthmatic and non-asthmatic adolescents. The study participants were divided into a curricular intervention group for asthma (IG), and a control group with traditional curriculum (CG). Topics related to asthma were included in the curriculum, such as the disease concept, triggering factors, treatment, symptoms, action plan, and beliefs in popular myths about the disease. These topics were evaluated through a questionnaire with scores ranging from 0 to 20 points, expressed by the mean score. The acquisition of knowledge was evaluated 90 days and 540 days after the start of the intervention (baseline), by applying the mixed linear model for analysis of associations. RESULTS: 181 students participated in the study (IG=101 and CG=80). As shown by their scores before the intervention; the students were unaware about asthma (IG: x-=10.7+/-2.9vs. CG: x =11.5+/-2.7 points), its treatment (IG: x-=1.6+/-0.9vs. CG: x-=1.6+/-0.8 points), and reported beliefs in popular myths about the disease (IG: x-=1.5+/-1.1vs. CG: x-=1.7+/-1.1 points). After the intervention, the IG showed higher overall knowledge (GI: x-=15.5+/-3.1 points), as well as knowledge about the treatment (GI: x-=2.5+/-1.0 points), and two times more knowledge in the field "beliefs in popular myths about the disease" when compared to the CG. A greater probability of achieving satisfactory knowledge about asthma was noted in the IG (RR=3.5), with NTT=2.0. CONCLUSION: The inclusion of the asthma topic in the curriculum improved knowledge about the disease in a subgroup of students. PMID- 28888615 TI - Who cares for adolescents and young adults with cancer in Brazil? AB - OBJECTIVE: Approximately 6% of all cancers arise in adolescents and young adults. Currently, the ward type best placed to treat this patient group remains controversial. The aim of this study was to evaluate exactly where adolescents and young adults with cancer are treated in Brazil. METHODS: Data were extracted from 271 Brazilian hospital-based cancer registries (2007-2011), including all five national regions (North, Northeast, Midwest, South, and Southeast). Variables included gender, age, ethnicity, National Code of Health Establishment, hospital unit state, and region. Tumors were classified according to the World Health Organization classification for adolescents and young adults with cancer. Odds ratios with 95% confidence intervals were computed by unconditional logistic regression. RESULTS: Most patients were managed on medical oncology wards, followed by pediatric oncology and then by non-specialist wards. Of patients aged 15-19 years, 49% were managed on pediatric wards; most of the older patients (96%; aged 20-24) were managed on adult wards. Patients were more likely to be seen in medical oncology wards as their age increased (OR=2.03 [1.98-2.09]), or if they were based in the South (OR=1.50 [1.29-1.73]). Conversely, bone tumors were less likely to be treated (decreased OR) on medical oncology wards, regardless of age, gender, and region. CONCLUSION: An elevated risk of treatment on medical oncology wards was observed for older patients and those treated in the South. Bone tumors were generally treated in pediatric oncology wards, while skin cancers were treated in medical oncology wards, regardless of age, gender, and region. PMID- 28888616 TI - Physical functioning and risk for sleep disorders in US adults: results from the National Health and Nutrition Examination Survey 2005-2014. AB - OBJECTIVES: Sleep disorders (SDs), particularly problems with falling asleep or daytime sleepiness, have negative impact on health and longevity. Sleep deprivation is also associated with a decline in physical functioning (PF) that mediates the ability to perform activities of daily living. But it remains unknown if deterioration in PF can predict the risk of having a SD. Therefore, the purpose of the present study is to assess the risk of SD associated with PF status in the US adult population. STUDY DESIGN: Cross-sectional study design with data from the National Health and Nutrition Examination Survey from year 2005 to year 2014. METHODS: PF limitation is assessed by reported difficulty in performing 10 tasks selected from PF questionnaire. SD is identified by subjective description of presence of doctor diagnosed SD. Also, five categories of comorbidities that caused difficulty in carrying out these tasks were created. RESULTS: The adults with self-reported PF limitation have 41% higher odds of having a SD (odds ratio [OR] = 1.41, 95% confidence interval [CI] = 1.22-1.59). Moreover, participants having cognitive problems and cardiovascular and pulmonary disorders as secondary conditions that cause difficulty in PF have 145% and 28% higher odds (OR = 2.45 and 1.28; 95% CI = 2.01-3.01 and 1.08-1.53, respectively) of having a SD. Also, females have a 27% lower odds of having a SD than males (OR = 0.73, 95% CI = 0.63-0.83). CONCLUSION: Risk for SD is associated with increasing level of functional disability. We advocate the importance of engagement in physical activities to prevent or delay the onset of SD. PMID- 28888617 TI - Relationships between bone mass and dietary/lifestyle habits in Japanese women at 3-4 months postpartum. AB - OBJECTIVES: The relationships between calcaneal bone mass and dietary/lifestyle habits in women at 3-4 months postpartum were examined in the context of osteoporosis prevention. STUDY DESIGN: Cross-sectional survey. METHODS: We measured bone mass using calcaneal ultrasound in mothers who brought their 3- to 4-month-old babies to healthcare centers in Japan for health examination and administered a self-report questionnaire on physical characteristics and dietary/lifestyle habits to those who agreed to participate in the survey. Valid data were available for 1220 women (valid response rate, 97.5%). RESULTS: Based on their stiffness score, a measure of bone mass, 70.9% (n = 865) of the participants were classified as 'no apparent abnormality (stiffness score >=78.8)' (low-risk group), 18.2% (n = 222) as 'guidance required (>=70.1-<78.8)' (intermediate-risk group), and 10.9% (n = 133) as 'complete examination required (<70.1)' (high-risk group), according to the criteria for osteoporosis screening test results. The percentage of individuals with a history of fracture was higher in the guidance required/complete examination required than in the no apparent abnormality group (P = 0.016). The analysis of relationships between the consumption frequency of certain foods, such as calcium-rich foodstuffs, and bone mass found that women who reported lower frequencies of milk and dark-colored (beta-carotene rich) vegetables for breakfast consumption had a significantly lower bone mass than those who consumed these foods more often. Furthermore, the guidance required/complete examination required group had a significantly lower calcium intake than the no apparent abnormality group (P = 0.022). CONCLUSIONS: These results indicate the need to provide postpartum women with dietary education programs to promote healthy eating habits, such as increased consumption of calcium-rich foods, and prevent osteoporosis. PMID- 28888618 TI - Feedback intervention to doctors improves patient satisfaction among outpatients in Inner Mongolia Autonomous Region, China. AB - OBJECTIVES: The doctor-patient relationship (DPR) in China is known to be tense. We tested whether an intervention program providing individualized feedback to doctors by patients could improve patients' satisfaction in an outpatient setting. STUDY DESIGN: A non-randomized controlled prepost intervention study in a tertiary hospital. Six surgery clinics were chosen as the intervention group and eight internal medicine clinics as the control group. METHODS: Before the program started, patients attending each group of clinics were asked to fill in the Short-Form Patient Satisfaction Questionnaire (PSQ-18). In the experimental period, patients attending the intervention clinics were requested to rate their perception of the doctor's quality of care in various domains on an 8-question feedback card immediately after exiting from the examination room and to drop the completed card into the feedback box for the particular doctor. The cards were then collected by the doctor confidentially at the end of each day. There was no feedback in the control clinics. After the experimental period ended, the doctors in both groups of clinics were reassessed by a new series of patients using PSQ 18. The PSQ-18 scores were compared within the same group of clinics over time, and the changes in satisfaction score compared between intervention and control clinics. RESULTS: There were 189 and 190 responders in the intervention group and 190 and 200 in the control group, before and after the intervention period, respectively. Scores in all domains increased significantly (P < 0.001) in the intervention group but not in the control group. Significant improvement in the patient satisfaction scores in the intervention clinics compared with the control clinics was confirmed by mixed-effects linear regression controlling for the effects of gender, age, marital status, education, and household income in the domains of general satisfaction, technical quality, communication, and accessibility and convenience. CONCLUSIONS: Timely feedback to doctors of patients' perception of quality of care received can improve outpatient satisfaction in a Chinese hospital. PMID- 28888619 TI - Natural killer cell-mediated immunosurveillance of human cancer. AB - The contribution of natural killer (NK) cells to immunosurveillance of human cancer remains debatable. Here, we discuss advances in several areas of human NK cell research, many of which support the ability of NK cells to prevent cancer development and avoid relapse following adoptive immunotherapy. We describe the molecular basis for NK cell recognition of human tumor cells and provide evidence for NK cell-mediated killing of human primary tumor cells ex vivo. Subsequently, we highlight studies demonstrating the ability of NK cells to migrate to, and reside in, the human tumor microenvironment where selection of tumor escape variants from NK cells can occur. Indirect evidence for NK cell immunosurveillance against human malignancies is provided by the reduced incidence of cancer in individuals with high levels of NK cell cytotoxicity, and the significant clinical responses observed following infusion of human NK cells into cancer patients. Finally, we describe studies showing enhanced tumor progression, or increased cancer incidence, in patients with inherited and acquired defects in cellular cytotoxicity. All these observations have in common that they, either indirectly or directly, suggest a role for NK cells in mediating immunosurveillance against human cancer. This opens up for exciting possibilities with respect to further exploring NK cells in settings of adoptive immunotherapy in human cancer. PMID- 28888621 TI - Patient-reported outcomes in acute myeloid leukemia: Where are we now? AB - Outcomes for acute myeloid leukemia remain poor, and treatment decisions must consider not just quantity, but also quality of life (QOL). We conducted a systematic review of studies in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome that incorporated patient-reported outcome (PRO) measures. PubMed and PsycINFO were searched for articles published from January 2000 through June 2016. Forty-one were relevant for our review with more published in recent years. There was considerable inter-study heterogeneity in which instruments were used, and many studies employed multiple (often overlapping) instruments. Longitudinal studies in particular suffered from both high attrition rates due to disease-related mortality as well as waning compliance with questionnaire completion. There remain significant challenges to incorporation of PROs into leukemia trials. Despite these limitations, however, well-implemented PROs can provide important information beyond objective response outcomes and highlight areas of focus for clinicians caring for patients and for future research endeavors. PMID- 28888620 TI - The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production. AB - Ligation of the death receptors for TNF-alpha, FasL, and TRAIL triggers two common pathways, caspase-dependent intrinsic apoptosis and intracellular reactive oxygen species (ROS) generation. The apoptotic pathway is well characterized; however, a signaling linker between the death receptor and ROS production has not been clearly elucidated. Here, we found that death receptor-induced ROS generation was strongly inhibited by mitochondrial complex I and II inhibitors, but not by inhibitors of NADPH oxidase, lipoxygenase, cyclooxygenase or xanthine oxidase, indicating that ROS are mostly generated by the impairment of the mitochondrial respiratory chain. ROS generation was accompanied by caspase-8 activation, Bid cleavage, and cytochrome c release; it was blocked in FADD- and caspase-8-deficient cells, as well as by caspase-8 knockdown and inhibitor. Moreover, Bid knockdown abrogated TNF-alpha- or TRAIL-induced ROS generation, whereas overexpression of truncated Bid (tBid) or knockdown of cytochrome c spontaneously elevated ROS production. In addition, p53-overexpressing cells accumulated intracellular ROS via cytochrome c release mediated by the BH3-only protein Noxa induction. In a cell-free reconstitution system, caspase-8-mediated Bid cleavage and recombinant tBid induced mitochondrial cytochrome c release and ROS generation, which were blocked by Bcl-xL and antioxidant enzymes. These data suggest that anti-apoptotic Bcl-2 proteins play an important role in mitochondrial ROS generation by preventing cytochrome c release. These data provide evidence that the FADD/caspase-8/Bid/cytochrome c axis is a crucial linker between death receptors and mitochondria, where they play a role in ROS generation and apoptosis. PMID- 28888622 TI - The utility of thromboelastography and thrombin generation in assessing the prothrombotic state of adults with sickle cell disease. AB - INTRODUCTION: Previous studies have suggested a chronic hypercoagulable state in SCD, and that thrombosis also plays a role in the pathophysiology of sickle cell vaso-occlusive pain crises (VOC). Studies looking at thrombin generation have produced conflicting results. In this study we aimed to assess and compare whole blood thromboelastography (TEG) and plasma Calibrated Automated Thrombogram (CAT) in SCD versus healthy controls and in four different SCD subgroups. MATERIALS AND METHODS: In this prospective observational study, TEG and 1pM TF activated CAT assays were performed in citrated blood samples from 77 adult (18-66years old) SCD patients (HbSS and HbSB) and 22 healthy (HbAA) ethnically-matched controls. RESULTS AND CONCLUSIONS: SCD was associated with a prothrombotic state in all TEG parameters. CAT results showed that the upslope of the CAT in SCD displayed a hypercoagulable state with shorter time to peak and higher velocity index, but the downslope was also faster leading to an overall lower endogenous thrombin potential (ETP) compared to healthy controls. TEG subgroup analyses showed that during VOC the prothrombotic state is greater compared to patients on disease ameliorating therapy. CAT did not display statistically significant differences between the SCD subgroups. This study shows that the prothrombotic state in SCD is best displayed with TEG, and suggests the hypercoagulable changes of SCD rely at least in part in the cellular components of blood, which can only be detected in whole blood assays. PMID- 28888623 TI - Effect of different oral oxytetracycline treatment regimes on selection of antimicrobial resistant coliforms in nursery pigs. AB - A major concern derived from using antimicrobials in pig production is the development of resistance. This study aimed to assess the impact of selected combinations of oral dose and duration of treatment with oxytetracycline (OTC) on selection of tetracycline resistant (TET-R) coliforms recovered from swine feces. The work encompassed two studies: 1) OTC 5mg/kg and 20mg/kg were administered to nursery pigs for 3 and 10days, respectively, under controlled experimental conditions, and 2) 10mg/kg, 20mg/kg and 30mg/kg OTC were given to a higher number of pigs for 6, 3 and 2days, respectively, under field conditions. Statistical modeling was applied to analyze trends in the proportion of TET-R coliforms. In the experimental study, no statistical difference in proportion of TET-R coliforms was observed between treatments at the end of the trial (day 18) and compared to day 0. In the field study, treatment had a significant effect on the proportion of TET-R bacteria two days after the end of treatment (2dAT) with the regimes "low dose-six days" and "medium dose-three days" yielding the highest and lowest proportions of TET-R strains, respectively. No indication of co-selection for ampicillin- and sulphonamide -R bacteria was observed for any treatment at 2dAT. By the end of the nursery period, the proportion of TET-R bacteria was not significantly different between treatments and compared to day 0. Our results suggest that similar resistance levels might be obtained by using different treatment regimes regardless of the combinations of oral dose-duration of treatment. PMID- 28888624 TI - Changes in the population structure of canine methicillin-resistant Staphylococcus pseudintermedius in Poland. AB - Methicillin-resistant Staphylococcus pseudintermedius (MRSP) is being reported with an increasing frequency in small animal veterinary practice. The molecular typing of MRSP isolates revealed that the dominating European multidrug-resistant lineage is the sequence type 71 (ST71), associated with staphylococcal chromosomal cassette SCCmec type II-III. However, the recent reports indicated the emergence of other clones. The study aimed to determine the genetic properties of MRSP isolates obtained from dogs in Poland over a ten-year period. A total of 42 clinical MRSP isolates were subjected to multilocus-sequence typing (MLST) and SCCmec typing. MLST typing of 42 MRSP isolates yielded six STs belonging to two major clonal complexes (CCs): CC71 and CC551, associated with SCCmec element II-III and V, respectively. CC71 comprising ST71 and its newly described single locus variant (SLV) ST680. The second dominating CC551was represented by ST551 and newly described SLV ST771. The other, ST258 and ST85 were detected in single MRSP isolates. This is the first report concerning MLST typing of MRSP isolates in Poland. The results confirmed the domination of ST71 among MRSP until 2015, and the emergence of ST551 in 2015. Furthermore, in 2016 ST551 was identified in the majority of the strains, indicating the changes in the population structure of MRSP in Poland. Polish clinical MRSP isolates showed a shift in the population structure during the period of 2007 and 2016. The dominating MRSP lineage until 2015 was multidrug-resistant ST71-SCCmecII-III. The other lineage ST551-SCCmecV emerged in Poland since 2015, and in 2016 was found in the majority of MRSP isolates. PMID- 28888625 TI - Fine mapping and conservation analysis of linear B-cell epitopes of peste des petits ruminants virus hemagglutinin protein. AB - Hemagglutinin protein (H), one of the two glycoproteins of peste des petits ruminants virus (PPRV), binds to its receptor on the host cell and acts as a major antigen that induces and confers highly protective immunity in the host. In order to delineate the epitopes on H protein, fine epitope mapping and conservation analysis of linear B-cell epitopes (BCEs) on PPRV H has been undertaken using biosynthetic peptides and rabbit anti-PPRV H sera. Thirteen linear BCEs were identified and their corresponding minimal motifs were located on the H protein of PPRV China/Tibet/Geg/07-30. Conservation analysis indicated that two of the 13 minimal motifs were conserved among 52 PPRV strains. Nine of the 13 peptides containing the minimal motifs were recognized using anti-PPRV serum from a goat immunized with PPRV vaccine strain Nigeria 75/1. Identified epitopes and their motifs improve our understanding of the antigenic characteristics of PPRV H and provide a basis for the development of epitope based diagnostic assays and multiple epitopes vaccine. PMID- 28888626 TI - Prevalence and antimicrobial susceptibility of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni isolated from the lower respiratory tract of healthy feedlot cattle and those diagnosed with bovine respiratory disease. AB - Current information on prevalence and antimicrobial resistance (AMR) of bacterial respiratory pathogens is crucial to guide antimicrobial choice for control and treatment of bovine respiratory disease (BRD). The objectives were to describe the prevalence of three BRD-associated bacteria (Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni) in the lower airways of feedlot cattle, and to analyze AMR in these bacteria. Cattle with (n=210) and without (n=107) BRD were sampled by trans-tracheal aspiration at four feedlots (Nov. 15 Jan. 16). These cattle had received 2.5mg/kg of tulathromycin on arrival at the feedlot for BRD control and two in-feed pulses of chlortetracycline (5g/animal/day for 5days) within the first 21days on feed to prevent histophilosis. Bacteria were detected by culture and AMR was tested by microdilution. Pasteurella multocida was the most frequent bacterium isolated in cattle with BRD (54.8%), followed by M. haemolytica (30.5%) and H. somni (22.9%). Compared to those with BRD, healthy cattle were less likely to be positive for P. multocida (OR=0.27), M. haemolytica (OR=0.32), or H. somni (OR=0.25). There were high levels of resistance (>70%) against tulathromycin and oxytetracycline in M. haemolytica and P. multocida isolates and high levels of resistance against oxytetracycline (67%) and penicillin (52%) in H. somni isolates. None or few isolates were resistant to florfenicol, enrofloxacin and ceftiofur. The high prevalence of resistance against tulathromycin and oxytetracycline suggests that these antimicrobials should not be repeatedly used for both control and treatment of BRD and/or histophilosis. PMID- 28888627 TI - Genetic and pathogenic characterization of a novel reassortant mammalian orthoreovirus 3 (MRV3) from a diarrheic piglet and seroepidemiological survey of MRV3 in diarrheic pigs from east China. AB - Mammalian orthoreoviruses (MRVs), which cause gastrointestinal and respiratory illness, have been isolated from a wide variety of mammalian species including bats, minks, pigs and humans. Here we report the isolation and genetic and pathogenic characterization of a novel MRV type 3 (MRV3), named MRV-ZJ2013, from the diarrheic feces of piglets in Zhejiang province, China. Genomic and phylogenetic analysis shows that MRV-ZJ2013 may have originated from reassortments among mink, bat, and pig MRVs, suggesting the hypothesis that interspecies transmission has occurred in pig herds. Neonatal piglets infected with MRV-ZJ2013 displayed mild clinical signs such as poor appetite and soft feces, but vomiting and diarrhea were not observed. Fecal virus shedding was detected only in three out of six piglets, each for one- or two-day post infection. In contrast, piglets inoculated with a virulent porcine epidemic diarrhea virus (PEDV) strain as the control group had severe signs characterized by acute vomiting and watery diarrhea. These findings suggest that the virulence of MRV-ZJ2013, if any, was likely not significant compared to that of PEDV. A seroepidemiological survey of MRV by means of an indirect enzyme-linked immune sorbent assay (ELISA) based on a recombinant MRV3 capsid protein sigma1 as antigen revealed a high seroprevalence (77%) in 1037 samples from diarrheic pigs of different ages from 24 herds in seven provinces of east China between 2015 and 2016, indicating that MRV3 is endemic in pig herds in China, and may contribute collectively to enteric disease along with other porcine pathogens. PMID- 28888628 TI - Neuropathological survey reveals underestimation of the prevalence of neuroinfectious diseases in cattle in Switzerland. AB - Neuroinfectious diseases in livestock represent a severe threat to animal health, but their prevalence is not well documented and the etiology of disease often remains unidentified. The aims of this study were to generate baseline data on the prevalence of neuroinfectious diseases in cattle in Switzerland by neuropathological survey, and to identify disease-associated pathogens. The survey was performed over a 1-year period using a representative number of brainstem samples (n=1816) from fallen cattle. In total, 4% (n=73) of the animals had significant lesions, the most frequent types of which were indicative of viral (n=27) and bacterial (n=31) etiologies. Follow-up diagnostics by immunohistochemistry, PCR protocols and next-generation sequencing identified infection with Listeria monocytogenes (n=6), ovine herpesvirus 2 (n=7), bovine astrovirus CH13 (n=2), bovine herpesvirus 6 (n=6), bovine retrovirus CH15 (n=2), posavirus 1 (n=2), and porcine astroviruses (n=2). A retrospective questionnaire based investigation indicated that animals' owners observed clinical signs of neurological disease in about one-third of cases with lesions, which was estimated to correspond to approximately 85 cases per year in the adult fallen cattle population in Switzerland. This estimate stands in sharp contrast to the number of cases reported to the authorities and reveals a gap in disease surveillance. Systematic neuropathological examination and follow-up molecular testing of neurologically diseased cattle could significantly enhance the efficiency of disease detection for the purposes of estimating the prevalence of endemic diseases, identifying new or re-emerging pathogens, and providing "early warnings" of disease outbreaks. PMID- 28888629 TI - Prevalence of lapine rotavirus, astrovirus, and hepatitis E virus in Canadian domestic rabbit populations. AB - Lapine rotavirus and astrovirus have been associated with disease in rabbits, and there is strong evidence of zoonotic transmission of lapine hepatitis E virus (HEV). Outbreaks of enteritis are common on commercial meat farms, resulting in poor welfare, high rabbit mortality, and significant financial losses for rabbit producers. Currently, none of these viruses are routinely tested by diagnostic laboratories. In this study, we assessed the prevalence of rotavirus, astrovirus, and HEV RNA in 205 pooled and individual fecal samples from healthy Canadian laboratory, companion, shelter and commercial meat rabbit populations. Viral RNA were extracted and amplified via RT-PCR using virus-specific primers. Positive samples from the first cohort of samples tested were sequenced and aligned to previously identified viruses to confirm the products. Almost 45% (13/29) of the surveyed commercial rabbit farms were astrovirus-positive. Three commercial meat rabbit samples were positive for rotavirus, and either astrovirus or HEV RNA was also detected. Three companion rabbit samples also tested positive for lapine HEV. Samples from specific pathogen-free laboratory animals were negative for all viruses. Sequencing results showed highest identity to rotavirus A strain 30-96, lapine astrovirus strain 2208 and lapine HEV strain CMC-1. These results permit a better understanding of the prevalence of rotavirus, astrovirus, and hepatitis E virus in Canadian domestic rabbit populations, and continued screening for viruses may help to reduce risk of zoonotic agent transmission as well as providing a better understanding of potential causative agents of rabbit enteritis. PMID- 28888630 TI - A novel recombinant porcine reproductive and respiratory syndrome virus with significant variation in cell adaption and pathogenicity. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an important pathogen that causes huge economic losses to the swine industry worldwide. In this study, a type 2 PRRSV strain was isolated from primary porcine alveolar macrophage cells and designated as GD1404. Interestingly, this strain was unable to grow in MARC-145 cells. Analysis of the full-length genome sequence revealed that strain GD1404 was an inter-subgenotype recombinant of strains QYYZ and JXA1. The C-terminus of the GP2 protein of strain GD1404 had an amino acid deletion. Also, the ORF5a protein had 51 codons, five more than most other highly pathogenic (HP-PRRSV) strains. Phylogenetic analysis based on ORF5 gene sequences showed that strain GD1404 and five others isolated in China formed a new subgenotype represented by strain QYYZ. Challenge experiments with piglets showed that the GD1404 and HP-PRRSV BB0907 strains caused similar rates of mortality and interstitial pneumonia. However, strain GD1404 infection resulted in lower viremia and viral loads in the lungs, as compared with strain BB0907. The results of this study provide evidence of the circulation of type 2 PRRSV QYYZ-like strains in China with variations in cell adaption and pathogenic abilities. PMID- 28888631 TI - Incidence of elephant endotheliotropic herpesvirus in Asian elephants in India. AB - Elephant endotheliotropic herpesviruses (EEHVs) are the cause of acute hemorrhagic disease in endangered Asian and African elephants. In the present study, we report the incidence of EEHV infection and associated mortality in the captive elephant of Assam, India. Our result showed the gross morphology and histopathological changes of EEHV infection in the elephant. Moreover, the phylogenetic analysis of the polymerase, helicase, and GPCR genes from the infected tissue samples suggested the presence of EEHV1A virus. PMID- 28888632 TI - Genotypic and geographical distribution of porcine reproductive and respiratory syndrome viruses in mainland China in 1996-2016. AB - Porcine reproductive and respiratory syndrome (PRRS) has caused huge economic losses to Chinese swine industry and remains a major threat since it was first reported in 1996. However, investigations of molecular epidemiological and genetic diversity of PRRS viruses (PRRSVs) in China were limited to a small number of representative strains collected in several areas. Moreover, lineage classifications reported by individual researchers were quite different. In the present study, we sequenced ORF5 sequences of 217 PRRSVs from clinical samples, retrieved all the available ORF5 sequences of PRRSVs isolated in China in 1996 2016 (n=2213) from GenBank, and systematically analyzed corresponding epidemiological data. NA-type PRRSVs in China were classified into five lineages: lineage 1, lineage 3, lineage 5, lineage 8, and lineage 9. Most strains in China belonged to lineage 8 (85.6%), with dominant strains being classified as sublineage 8.3 (78.3%). Importantly, the emerging lineage 1 and lineage 3 strains spread rapidly, and their proportions among circulating PRRSVs have significantly increased in recent years. The geographical distribution of different PRRSV lineages in each province was analyzed and possible inter-province transmission routes were outlined for main lineages and sublineages. To our knowledge, this study is the most comprehensive and extensive phylogeographical analysis of PRRSVs in China since PRRS outbreak in 1996. Our dataset can serve as a canonical standard for PRRSV classification and will help to study genetic evolution of PRRSV. The results of the present study may also improve prevention of PRRS in China. PMID- 28888633 TI - Erratum to 'Antimicrobial susceptibility monitoring of Mycoplasma hyopneumoniae and Mycoplasma bovis isolated in Europe' [Vet. Microbiol. 204C (2017)188-193]. PMID- 28888634 TI - Development of improved enzyme-based and lateral flow immunoassays for rapid and accurate serodiagnosis of canine brucellosis. AB - Brucellosis is a widespread zoonotic disease caused by Brucella spp. Brucella canis is the etiological agent of canine brucellosis, a disease that can lead to sterility in bitches and dogs causing important economic losses in breeding kennels. Early and accurate diagnosis of canine brucellosis is central to control the disease and lower the risk of transmission to humans. Here, we develop and validate enzyme and lateral flow immunoassays for improved serodiagnosis of canine brucellosis using as antigen the B. canis rough lipopolysaccharide (rLPS). The method used to obtain the rLPS allowed us to produce more homogeneous batches of the antigen that facilitated the standardization of the assays. To validate the assays, 284 serum samples obtained from naturally infected dogs and healthy animals were analyzed. For the B. canis-iELISA and B. canis-LFIA the diagnostic sensitivity was of 98.6%, and the specificity 99.5% and 100%, respectively. We propose the implementation of the B. canis-LFIA as a screening test in combination with the highly accurate laboratory g-iELISA. The B. canis-LFIA is a rapid, accurate and easy to use test, characteristics that make it ideal for the serological surveillance of canine brucellosis in the field or veterinary laboratories. Finally, a blind study including 1040 serum samples obtained from urban dogs showed a prevalence higher than 5% highlighting the need of new diagnostic tools for a more effective control of the disease in dogs and therefore to reduce the risk of transmission of this zoonotic pathogen to humans. PMID- 28888635 TI - Infection dynamics and genetic variability of Mycoplasma hyopneumoniae in self replacement gilts. AB - The aim of this study was to assess the longitudinal pattern of M. hyopneumoniae detection in self-replacement gilts at various farms and to characterize the genetic diversity among samples. A total of 298 gilts from three M. hyopneumoniae positive farms were selected at 150days of age (doa). Gilts were tested for M. hyopneumoniae antibodies by ELISA, once in serum at 150 doa and for M. hyopneumoniae detection in laryngeal swabs by real time PCR two or three times. Also, 425 piglets were tested for M. hyopneumoniae detection in laryngeal swabs. A total of 103 samples were characterized by Multiple Locus Variable-number tandem repeats Analysis. Multiple comparison tests were performed and adjusted using Bonferroni correction to compare prevalences of positive gilts by ELISA and real time PCR. Moderate to high prevalence of M. hyopneumoniae in gilts was detected at 150 doa, which decreased over time, and different detection patterns were observed among farms. Dam-to-piglet transmission of M. hyopneumoniae was not detected. The characterization of M. hyopneumoniae showed 17 different variants in all farms, with two identical variants detected in two of the farms. ELISA testing showed high prevalence of seropositive gilts at 150 doa in all farms. Results of this study showed that circulation of M. hyopneumoniae in self replacement gilts varied among farms, even under similar production and management conditions. In addition, the molecular variability of M. hyopneumoniae detected within farms suggests that in cases of minimal replacement gilt introduction bacterial diversity maybe farm specific. PMID- 28888636 TI - Efficacy of oral BCG vaccination in protecting free-ranging cattle from natural infection by Mycobacterium bovis. AB - Vaccination of cattle against bovine tuberculosis could be a valuable control strategy, particularly in countries faced with intractable ongoing infection from a disease reservoir in wildlife. A field vaccination trial was undertaken in New Zealand. The trial included 1286 effectively free-ranging cattle stocked at low densities in a remote 7600ha area, with 55% of them vaccinated using Mycobacterium bovis BCG (Danish strain 1311). Vaccine was administered orally in all but 34 cases (where it was injected). After inclusion, cattle were exposed to natural sources of M. bovis infection in cattle and wildlife, most notably the brushtail possum (Trichosurus vulpecula). Cattle were slaughtered at 3-5 years of age and were inspected for tuberculous lesions, with mycobacteriological culture of key tissues from almost all animals. The prevalence of M. bovis infection was 4.8% among oral BCG vaccinates, significantly lower than the 11.9% in non vaccinates. Vaccination appeared to both reduce the incidence of detectable infection, and to slow disease progression. Based on apparent annual incidence, the protective efficacy of oral BCG vaccine was 67.4% for preventing infection, and was higher in cattle slaughtered soon after vaccination. Skin-test reactivity to tuberculin was high in vaccinates re-tested 70days after vaccination but not in non-vaccinates, although reactor animals had minimal response in gamma interferon blood tests. In re- tests conducted more than 12 months after vaccination, skin-test reactivity among vaccinates was much lower. These results indicate that oral BCG vaccination could be an effective tool for greatly reducing detectable infection in cattle. PMID- 28888637 TI - High abundance and diversity of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in faeces and tonsils of pigs at slaughter. AB - This cross-sectional study investigates the abundance of cefotaxime-resistant Escherichia coli (CREC) in the faeces and tonsils of 96 pigs during slaughter. Moreover, different isolates from a selected number of pigs were tested to study the diversity of blaESBL genes within E. coli isolates from one pig. Cefotaxime resistant bacteria (based on enumeration results on MacConkey agar supplemented with 1mg/L cefotaxime) were found in the faeces of 77 pigs (80%; 95% CI: 70-87%) and the tonsils of 91 pigs (95%; 95% CI: 88%-98%). Cefotaxime-resistant E. coli (based on enumeration results on Tryptone Bile X-glucuronide agar supplemented with 1mg/L cefotaxime) were detected in 72 faecal samples (75%; 95% CI: 64-83%) and 45 tonsil samples (47%; 95% CI: 35-59%), in numbers up to 5.5 and 5.6log10 CFU/g, respectively. On average, around 1/10,000 E. coli in both faeces and tonsils were cefotaxime-resistant, though large variations were observed between pigs. Within one sample, CREC isolates with up to five different combinations of ESBL genes were observed. In three out of 16 faecal samples and six out of 14 tonsil samples, only one ESBL gene profile was found. The high numbers of CREC that are occasionally found in the faeces and tonsils of pigs during slaughter may represent an important source of contamination of carcasses and subsequently pork. PMID- 28888638 TI - The response of red deer to oral administration of heat-inactivated Mycobacterium bovis and challenge with a field strain. AB - Deer species (family Cervidae) are often part of the Mycobacterium tuberculosis complex maintenance host community, and tuberculosis (TB) control in deer, including vaccination, is consequently an area of ongoing research. However, most research into deer vaccination against TB is focused on using the live bacillus Calmette Guerin (BCG). Oral inactivated vaccines represent an interesting alternative to either oral or parenteral BCG, since neither diagnostic cross reactions nor vaccine strain survival are likely to occur. In order to describe the red deer response to heat-inactivated M. bovis (IV) as compared to BCG and to unvaccinated controls (n=5/group), we ran an experiment with five month-old vaccinated red deer, which were challenged with a virulent M. bovis strain 70days later and necropsied at 60days post-challenge. A reduction in the IV group infection burden was discovered. There were significant differences between the IV group and the control group (53% lesion reduction) as regards to the TB lesion scores, but not between other pairs. Complement component 3 plasma levels increased after challenge, and there were no differences between groups. The plasma cytokines (IL-1beta, TNFalpha, IFNgamma, IL-10 and IL-12) levels did not change after vaccination, but IL-1beta, TNFalpha and IL-10 did so following the challenge. The IL-1beta level increased in all the groups while TNFalpha levels had a distinct response pattern in the IV group and IL-10 had a distinct response pattern in control group. The results showed that oral vaccination with IV reduces the TB lesion score in red deer challenged with a M. bovis field strain without interfering with the in vivo diagnosis of infection in this species. PMID- 28888639 TI - Increased microbiome diversity at the time of infection is associated with improved growth rates of pigs after co-infection with porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2). AB - Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) are two of the most important pathogens affecting the swine industry worldwide. Co-infections are common on a global scale, resulting in pork production losses through reducing weight gain and causing respiratory disease in growing pigs. Our initial work demonstrated that the fecal microbiome was associated with clinical outcome of pigs 70days post-infection (dpi) with PRRSV and PCV2. However, it remained uncertain if microbiome characteristics could predispose response to viral infection. The purpose of this study was to determine if microbiome characteristics present at the time of virus exposure were associated with outcome after co-infection. Using the Lawrence Livermore Microbial Detection Array, we profiled the microbiome in feces prior to infection from pigs identified retrospectively as having high or low growth rates after co infection. High growth rate pigs had less severe interstitial pneumonia, reduced virus replication, and a significant increase in average daily weight gain throughout the study. At the level of the fecal microbiome, high growth rate pigs had increased microbial diversity on both a family and species level. Shifts in the microbiome composition of high growth rate pigs included reduced Methanobacteriaceae species, increased Ruminococcaceae species, and increased Streptococcaceae species when compared to low growth rate pigs. The results indicate that both microbiome diversity and composition at the time of virus exposure may play a role in the subsequent response of pigs to PRRSV/PCV2 co infection. PMID- 28888640 TI - A bovine botulism outbreak associated with a suspected cross-contamination from a poultry farm. AB - In October 2014, an outbreak of botulism type D/C occurred on two cattle farms in close proximity. A poultry farm located nearby with no history of botulism had transferred poultry manure to both bovine farms before the beginning of the outbreak. Given this context, epidemiological investigation was conducted to determine if the poultry farm was a reservoir of C. botulinum type D/C and to identify the source of contamination on the cattle farms. Environmental samples were collected at three houses on the poultry farm (boot swabs from the surroundings, swabs from the ventilation system, boot swabs from the poultry litter and darkling beetles samples), and on the two cattle farms (silage samples, boot swabs from the cattle stalls, boot swabs from the cattle pasture and poultry manure samples). These samples were analyzed using real-time PCR after an enrichment step to detect C. botulinum type D/C. On the poultry farm, three boot swabs from the surroundings, two swabs from the ventilation system, one boot swab from the litter and one sample of darkling beetles were detected positive. On one cattle farm, C. botulinum type D/C was identified in a sample of silage made from grass grown on a field on which the poultry manure had previously been stored and in a boot swab from a pasture. On the other cattle farm, C. botulinum type D/C was detected in a sample of poultry manure stored on the cattle farm and in a boot swab from a pasture. This investigation shows that the healthy poultry farm might have been the reservoir of C. botulinum type D/C and that cross-contamination between poultry and cattle likely occurred, resulting in the botulism outbreak on the two cattle farms. PMID- 28888641 TI - A molecular survey of small ruminant hemotropic mycoplasmosis in Turkey, including first laboratory confirmed clinical cases caused by Mycoplasma ovis. AB - Hemotropic mycoplasmas are emerging zoonotic pathogens that cause mild to severe hemolytic anemia. Blood samples and thin blood smears were collected from six sheep exhibiting clinical symptoms typical of hemolytic anemia. Coccoid and ring shaped M. ovis were found on the surface of erythrocytes of infected sheep. Parasitemia ranged from 0.7% to 3.7% in individual smears. Clinical cases caused by Mycoplasma ovis were evaluated, and prevalence, based on DNA screening for the 16S rRNA gene of hemoplasmas in apparently healthy sheep (n=328) and goats (n=272) from the same area, was 11.3% (CI 8.1-15.2) and 6.2% (CI 3.7-9.8), respectively, a significant difference between species (p<0.05). Sequences of the nearly complete 16S rRNA gene shared 99% identity with the corresponding published sequences for M. ovis and Mycoplasma wenyonii. The overall M. ovis prevalence in healthy animals was 9% (CI 6.8-11.6) with no significant differences in infection rate between young and adults (p>0.05). The proportion of hemoplasma-positive small ruminants was higher with tick infestation (p<0.05). The presence of tick-borne Babesia spp. and Theileria spp. was also significantly associated with ovine hemoplasma infection (p<0.05) in the healthy sample. This is the first report of M. wenyonii in sheep. M. ovis should be considered in differential diagnosis in cases of high fever and anorexia in pastured sheep and goats. PMID- 28888642 TI - Spatio-temporal variations and genetic diversity of Anaplasma spp. in cattle from the North of Tunisia. AB - In cattle, anaplasmosis is a tick-borne rickettsial disease caused by Anaplasma marginale, A. centrale, A. phagocytophilum, and A. bovis. To date, no information concerning the seasonal dynamics of single and/or mixed infections by different Anaplasma species in bovines are available in Tunisia. In this work, a total of 1035 blood bovine samples were collected in spring (n=367), summer (n=248), autumn (n=244) and winter (n=176) from five different governorates belonging to three bioclimatic zones from the North of Tunisia. Molecular survey of A. marginale, A. centrale and A. bovis in cattle showed that average prevalence rates were 4.7% (minimum 4.1% in autumn and maximum 5.6% in summer), 7% (minimum 3.9% in winter and maximum 10.7% in autumn) and 4.9% (minimum 2.7% in spring and maximum 7.3% in summer), respectively. A. phagocytophilum was not detected in all investigated cattle. Seasonal variations of Anaplasma spp. infection and co infection rates in overall and/or according to each bioclimatic area were recorded. Molecular characterization of A. marginale msp4 gene indicated a high sequence homology of revealed strains with A. marginale sequences from African countries. Alignment of 16S rRNA A. centrale sequences showed that Tunisian strains were identical to the vaccine strain from several sub-Saharan African and European countries. The comparison of the 16S rRNA sequences of A. bovis variants showed a perfect homology between Tunisian variants isolated from cattle, goats and sheep. These present data are essential to estimate the risk of bovine anaplasmosis in order to develop integrated control policies against multi species pathogen communities, infecting humans and different animal species, in the country. PMID- 28888644 TI - Genetic diversity of porcine circovirus type 2 (PCV2) in Thailand during 2009 2015. AB - Porcine circovirus type 2 (PCV2), the essential cause of porcine circovirus associated disease (PCVAD), has evolved rapidly and it has been reported worldwide. However, genetic information of PCV2 in Thailand has not been available since 2011. Herein, we studied occurrence and genetic diversity of PCV2 in Thailand and their relationships to the global PCV2 based on ORF2 sequences. The results showed that 306 samples (44.09%) from 56 farms (80%) were PCV2 positive by PCR. Phylogenetic trees constructed by both neighbor-joining and Bayesian Inference yielded similar topology of the ORF2 sequences. Thai PCV2 comprise four clusters: PCV2a (5.5%), PCV2b (29.41%), intermediate clade 1 (IM1) PCV2b (11.03%) and PCV2d (54.41%). Genetic shift of PCV2 in Thailand has occurred similarly to the global situation. The shift from PCV2b to PCV2d was clearly observed during 2013-2014. The viruses with genetically similar to the first reported PCV2 in 2004 have still circulated in Thailand. The first Thai PCV2b and PCV2d were closely related to the neighboring countries. The haplotype network analysis revealed the relationship of PCV2 in Thailand and other countries. These results indicate that genetic diversity of PCV2 in Thailand is caused by genetic drift of the local strains and intermittent introduction of new strains or genotypes from other countries. Genetic evolution of PCV2 in Thailand is similar to that occurs globally. PMID- 28888645 TI - Eradication of bovine viral diarrhea virus in Germany-Diversity of subtypes and detection of live-vaccine viruses. AB - Bovine viral diarrhea (BVD) causes high economic losses in the cattle population worldwide. In Germany, an obligatory control program with detection and removal of persistently infected animals is in force since 2011. For molecular tracing of virus transmission, a comprehensive sequence data base of the currently circulating BVD viruses was established. Partial sequences of 1007 samples collected between 2008 and 2016 were generated. As dominant viruses, subtypes 1b (47.0%) and 1d (26.5%) could be identified with no marked geographic or sampling year effect, a much higher amount of BVDV-2c was detected in 2013 compared to other years, predominantly in Western Germany. In addition, subtypes 1a, 1e, 1f, 1h, 1g, 1k, and 2a were found. Interestingly, besides field-viruses, two different live-vaccine viruses were detected in tissue samples of newborn calves (n=37) whose mothers were immunized during pregnancy. PMID- 28888643 TI - Nasal carriage of methicillin-resistant coagulase-negative staphylococci in healthy humans is associated with occupational pig contact in a dose-response manner. AB - This study aimed to explore the association between occupational pig contact and human methicillin-resistant coagulase-negative staphylococci (MRCoNS) carriage. We conducted a cross-sectional study of pig exposed participants and controls in Guangdong, China, using a multi-stage sampling design. Participants provided a nasal swab for MRCoNS analysis and resulting isolates were tested for antibiotic susceptibility. The dose-response relation was examined using log binomial regression or Poisson regression models. The adjusted prevalence of MRCoNS carriage in pig exposed participants was 1.67 times (95% CI: 1.32-2.11) higher than in controls. The adjusted average number of resistance to different antibiotic classes of MRCoNS isolates from pig exposed participants was 1.67 times (95% CI: 1.46-1.91) higher than those from controls. Notably, we found the frequency and duration of occupational pig contact was associated with increased prevalence and increased number of resistance to different antibiotic classes of MRCoNS in a dose-response manner. When examining these relations by MRCoNS species, there was still evidence of similar exposure-response relations. Additionally, the proportion of tetracycline-resistant and tet(M)-containing MRCoNS isolates was significantly higher in pig exposed participants than in controls. These findings suggested a potential transmission of MRCoNS from livestock to humans by occupational livestock contact, and the presence of phenotypic and genotypic tetracycline resistance may aid in the differentiation of animal origins of MRCoNS isolates. PMID- 28888646 TI - Disparity in the nasopharyngeal microbiota between healthy cattle on feed, at entry processing and with respiratory disease. AB - Bovine respiratory disease (BRD) is one of the most serious causes of health and economic problems in the beef production industry, especially in recently weaned, intensely raised and newly transported feedlot cattle. While the importance of upper airway structure and function in the susceptibility of the lower respiratory tract to colonization with potential pathogens is well established, the role of the mucosal microbiota in respirtatory health is less well defined. The objective of this study was to characterize the nasopharyngeal microbiota of feedlot cattle at entry into a commercial feedlot, during initial management processing, and to compare the dynamics of change in these microbial communities between clinically healthy calves and those that develop BRD within the first month after entry. Deep nasopharyngeal swabs were collected from randomly selected healthy calves (n=66) during initial handling and processing at the feedlot, and again at the initial diagnosis of BRD (n=22). Clinically healthy pen matched controls calves (n=10) were sampled at the same time as the BRD affected animals. Genomic DNA was extracted from each sample, and the 16S rRNA gene V1-V3 hypervariable region was amplified and sequenced using the Illumina MiSeq platform. Across all the samples, the predominant bacterial phyla were Proteobacteria, Firmicutes and Actinobacteria. While the predominant genera were Moraxella, Mycoplasma and Acinetobacter. Linear discriminant analysis (LDA) effect size (LEfSe) revealed significant differences in bacterial taxa between healthy and BRD affected calves. Discriminant analysis revealed that the nasopharyngeal microbiota in feedlot calves at entry and in BRD affected calves were distinct from pen matched healthy calves. While the temporal dynamics of this shift were not examined in this study, it is possible that the observed changes in mucosal microbiota are linked to the increased susceptibility of calves to BRD during the first month after entry in to the feedlot. Additional studies are needed to examine the trajectory of change in nasopharyngeal microbial communities from entry to disease onset, and to explore the impact of other factors such as diet transition, commingling, vaccination and housing on the nasopharyngeal microbiota of growing cattle. PMID- 28888647 TI - Fibronectin-/fibrinogen-binding protein (FBPS) is not a critical virulence factor for the Streptococcus suis serotype 2 strain ZY05719. AB - Fibronectin-/fibrinogen-binding protein (FBPS) of Streptococcus suis serotype 2 (SS2) is an atypical anchorless microbial surface components recognizing adhesive matrix molecules (MSCRAMM) for which the role in bacterial infection are not clearly established. To investigate the biological functions of FBPS, an fbps knockout mutant was constructed in SS2 strain ZY05719 to explore the phenotypic changes between the wild-type and mutant strains. Cell morphology analyses combined with the basic growth curves showed that deletion of fbps does not significantly influence neither the thickness of the capsule of SS2 nor the cell growth characteristic. In addition to three previously identified host components fibronectin (FN), factor H (FH) and fibrinogen (FG), we also found that both laminin (LN) and immunoglobulin G (IgG) could bind specifically to FBPS. Furthermore, we confirmed that FBPS play an important role in adherence of SS2 to host cells. The in vitro assays demonstrated that an inactivation of fbps does not inhibit the intracellular survival of SS2 in RAW246.7 macrophages, attenuate the ability of invasion of host cells or the growth ability in pig blood. Additionally, the fbps mutation failed to decrease the virulence of SS2 in both BALB/c mice and zebrafish. Finally, immunization with recombinant FBPS showed no significant difference from the control groups in terms of murine viability after SS2 challenge. Taken together, we concluded that FBPS is not a critical virulence factor for the SS2 strain ZY05719. PMID- 28888648 TI - Evaluation of the effect of a porcine reproductive and respiratory syndrome (PRRS) modified-live virus vaccine on sow reproductive performance in endemic PRRS farms. AB - The efficacy of a porcine reproductive and respiratory syndrome (PRRS) modified live virus vaccine in reproductive performance was evaluated under field conditions. Three PRRS endemic farms were selected based on their history of PRRS associated reproductive failures. On each farm, a total of 40 sows were randomly allocated to either vaccinated (n=20) or unvaccinated (n=20) groups. Sows were vaccinated six weeks prior to breeding. Clinical data showed a significant improvement in reproductive performance in vaccinated sows. Sows in the vaccinated groups had a significantly (P<0.05) reduced number of stillborn piglets in all 3 farms. Sows in the vaccinated groups also had a significantly (P<0.05) higher number of live-born piglets in one of the farms. Sows in the vaccinated groups had a significantly (P<0.05) higher number of weaned piglets in two of the farms. Premature farrowing, one of the late gestation symptoms of PRRS, was also reduced due to vaccination as suggested by the increase in gestation length and the reduction in the number of stillborn piglets. No adverse systemic or local side effects relative to vaccination were observed during the entire gestation. No vaccine strain was detected in the vaccinated sows from all three farms at 70 and 114days post vaccination and in live-born piglets at the time of farrowing. Vaccination of sows with this PRRS vaccine was effective in improving reproductive performance in endemic PRRS farms. PMID- 28888649 TI - Identification of two novel avian influenza a (H5N6) viruses in wild birds, Shanghai, in 2016. AB - The H5N6 avian influenza virus (AIV) has been continuously reported in wild birds, which may contribute to further geographical spread during their long distance migrations. Active AIV surveillance in wild birds was conducted during October and November 2016 in Shanghai, China. Two novel influenza A (H5N6) viruses were detected in samples from migratory waterfowl that are genetically similar to recent South Korea and Japan H5N6 viruses collected in 2016 and 2017, highlighting the role of migratory waterfowl in the dissemination of H5N6 viruses along migratory flyways. PMID- 28888650 TI - Detection of rat hepatitis E virus in wild Norway rats (Rattus norvegicus) and Black rats (Rattus rattus) from 11 European countries. AB - Rat hepatitis E virus (HEV) is genetically only distantly related to hepeviruses found in other mammalian reservoirs and in humans. It was initially detected in Norway rats (Rattus norvegicus) from Germany, and subsequently in rats from Vietnam, the USA, Indonesia, China, Denmark and France. Here, we report on a molecular survey of Norway rats and Black rats (Rattus rattus) from 12 European countries for ratHEV and human pathogenic hepeviruses. RatHEV-specific real-time and conventional RT-PCR investigations revealed the presence of ratHEV in 63 of 508 (12.4%) rats at the majority of sites in 11 of 12 countries. In contrast, a real-time RT-PCR specific for human pathogenic HEV genotypes 1-4 and a nested broad-spectrum (NBS) RT-PCR with subsequent sequence determination did not detect any infections with these genotypes. Only in a single Norway rat from Belgium a rabbit HEV-like genotype 3 sequence was detected. Phylogenetic analysis indicated a clustering of all other novel Norway and Black rat-derived sequences with ratHEV sequences from Europe, the USA and a Black rat-derived sequence from Indonesia within the proposed ratHEV genotype 1. No difference in infection status was detected related to age, sex, rat species or density of human settlements and zoological gardens. In conclusion, our investigation shows a broad geographical distribution of ratHEV in Norway and Black rats from Europe and its presence in all settlement types investigated. PMID- 28888651 TI - Necrotic enteritis locus 1 diguanylate cyclase and phosphodiesterase (cyclic-di GMP) gene mutation attenuates virulence in an avian necrotic enteritis isolate of Clostridium perfringens. AB - Necrotic enteritis (NE) caused by netB-positive strains of Clostridium perfringens is an important disease of intensively-reared broiler chickens. It is widely controlled by antibiotic use, but this practice that has come under increasing scrutiny and alternative approaches are required. As part of the search for alternative approaches over the last decade, advances have been made in understanding its pathogenesis but much remains to be understood and applied to the control of NE. The objective of this work was to assess the effect on virulence of mutation of the cyclic-di-GMP signaling genes present on the large pathogenicity locus (NELoc-1) in the tcp-encoding conjugative virulence plasmid, pNetB. For this purpose, the diguanylate cyclase (dgc) and phosphodiesterase (pde) genes were individually insertionally inactivated and the two mutants were subsequently complemented with their respective genes. Southern blotting showed that a single gene insertion was present. Mutation of either gene resulted in almost total attenuation of the mutants to cause NE in experimentally-infected broiler chickens, which was fully restored in each case by complementation of the respective mutated gene. Production of NetB-associated cytotoxicity for Leghorn male hepatoma (LMH) cells was unaffected in mutants. We conclude that the cyclic di-GMP signaling system is important in controlling virulence in a NE C. perfringens strain and might be a target for control of the disease. PMID- 28888652 TI - Erratum to "Antimicrobials used for surgical prophylaxis by companion animal veterinarians in Australia" [Vet. Microbiol. 203C (2017) 301-307]. PMID- 28888653 TI - Porcine epidemic diarrhea virus does not replicate in porcine monocyte-derived dendritic cells, but activates the transcription of type I interferon and chemokine. AB - Porcine epidemic diarrhea virus (PEDV) belongs to the alphacoronavirus of the Coronaviridae. It is the major etiological agent of the recent outbreaks of piglet diarrhea and death in the US. Limited knowledge is currently available regarding the role of dendritic cells in PEDV infection. Here, we observed that PEDV did not replicate in monocyte-derived dendritic cells as evidenced by the decrease of viral gene transcript copies in infected cells by qRT-PCR and the absence of viral proteins by immunofluorescence staining as well as the absence of virus particles in infected cells by transmission electron microscopy. In addition, PEDV did not compromise cell viability at 48, 72, and 96h after infection at either a MOI of 2.5 or 5. Interestingly, an increased transcription of type I interferon including interferon-alpha and beta was observed in infected cells compared to mock infected cells. Surprisingly, we did not detect any interferon-beta in the supernatants of infected cells. A slight increase in interferon-alpha protein production in the supernatants of PEDV-infected cells was observed compared to mock infected cells. We also observed a markedly increased transcription of interferon inducible protein -10 (IP-10). Overall, PEDV does not replicate in porcine Mo-DC, but activates the transcription of type I interferon and chemokine IP-10. PMID- 28888654 TI - Shiga toxin-producing Escherichia coli (STEC) O22:H8 isolated from cattle reduces E. coli O157:H7 adherence in vitro and in vivo. AB - PROBLEM ADDRESSED: Shiga toxin-producing Escherichia coli (STEC) are a group of bacteria responsible for food-associated diseases. Clinical features include a wide range of symptoms such as diarrhea, hemorrhagic colitis and the hemolytic uremic syndrome (HUS), a life-threatening condition. OBJECTIVE: Our group has observed that animals naturally colonized with STEC strains of unknown serotype were not efficiently colonized with E. coli O157:H7 after experimental infection. In order to assess the basis of the interference, three STEC strains were isolated from STEC persistently-colonized healthy cattle from a dairy farm in Buenos Aires, Argentina. METHODS AND RESULTS: The three isolated strains are E. coli O22:H8 and carry the stx1 and stx2d genes. The activatable activity of Stx2d was demonstrated in vitro. The three strains carry the adhesins iha, ehaA and lpfO113. E. coli O22:H8 formed stronger biofilms in abiotic surface than E. coli O157:H7 (eae+, stx2+) and displayed a more adherent phenotype in vitro towards HeLa cells. Furthermore, when both serotypes were cultured together O22:H8 could reduce O157:H7 adherence in vitro. When calves were intragastrically pre challenged with 108 CFU of a mixture of the three STEC strains and two days later challenged with the same dose of the strain E. coli O157:H7 438/99, the shedding of the pathogen was significantly reduced. CONCLUSIONS: These results suggest that E. coli O22:H8, a serotype rarely associated with human illness, might compete with O157:H7 at the bovine recto-anal junction, making non-O157 carrying calves less susceptible to O157:H7 colonization and shedding of the bacteria to the environment. PMID- 28888655 TI - The matrix protein of vesicular stomatitis virus inhibits host-directed transcription of target genes via interaction with the TFIIH subunit p8. AB - In response to viral infection, the host innate antiviral response is elicited to limit viral replication. Many viruses have evolved various strategies to circumvent the host antiviral response. It has been reported that matrix (M) protein of vesicular stomatitis virus (VSV) can inhibit host gene expression to evade the host innate immune response. However, the molecular mechanism remains unclear. Here, we demonstrated that VSV M protein inhibited transcription of a reporter gene transfected into BSR-T7/5 cells. To further investigate the underlying mechanism, a yeast two-hybrid screen was performed to search for host proteins that interact with the M protein. The subunit of transcription/repair factor TFIIH, p8, was identified as an M binding partner, and the interaction was validated with a GST pull-down assay and laser confocal microscopy. Through a mutagenesis analysis, we found that the p8-M interaction was impaired when I96, E156, R159 and R160 residues on M were replaced with Ala. These mutants reduced the inhibitory effect on transcription of the reporter gene. Furthermore, the transcription inhibition mediated by M was impaired when co-expressed with p8. These results indicate that the p8-M interaction plays an important role in inhibiting transcription of host genes. PMID- 28888656 TI - Molecular characterization of circulating Foot and mouth disease virus (FMDV) serotype O topotype EA-3 and serotype A (African topotype) genotype IV in Egypt, 2016. AB - In January-April 2016, cattle and buffalo farm owners and veterinarians reported clinical signs suggestive of foot and mouth disease virus (FMDV) outbreaks among non-vaccinated cattle and buffalo herds in Egypt. The clinical disease observed was either mild (small oral lesions and speedy recovery) or severe (extensive oral lesions and/or mortalities), and the form of the disease (either mild or severe) segregated by farm. This study aimed to confirm the presence of FMDV and to characterize the circulating strains associated with the outbreaks. Vesicular epithelia were collected from 41 animals representing 15 affected cattle and buffalo farms in five governorates (Behira, Cairo, Daqahlia, Giza and Ismailia), and tested by real time (rt) RT-PCR. Consequently, 92% (38/41) of examined samples were positive. Furthermore, the VP1 coding region of 60% (23/38) of positive specimens were amplified by RT-PCR and sequenced. The phylogenetic analysis identified two distinct strains characterized as serotype O topotype EA 3 and serotype A (African topotype) of genotype IV in the severe and mild disease forms, respectively. The newly identified strains clustered in distinct clades in the phylogenetic trees, indicating the likelihood of new incursions into Egypt. Those strains were most closely related to previously described Sudanese strains. PMID- 28888657 TI - Spontaneous listeriosis in grey mouse lemurs (Microcebus murinus), but not in Goodman's mouse lemurs (Microcebus lehilahytsara) of the same colony. AB - Listeriosis is a zoonotic infection with the gram positive, facultative intracellular bacterium Listeria (L.) monocytogenes. Infections mainly occur in ruminants, but also in other species, including humans. Case fatality rate usually is high. The incidence of listeriosis in captive non-human primates is very low. We report the first spontaneous, fatal, and likely food-born outbreak of listeriosis in a population of captive grey mouse lemurs (Microcebus murinus). Conspicuously, none of the closely related Goodman's mouse lemurs (Microcebus lehilahytsara) in the same facility were affected. PMID- 28888658 TI - Variations in glycoprotein B contribute to immunogenic difference between PRV variant JS-2012 and Bartha-K61. AB - A newly emerged pseudorabies virus (PRV) variant has been identified in many Bartha-K61-vaccinated pig farms. This variant has caused great economic losses to the swine industry in China since 2011. Sequence analysis demonstrated that the gB gene of the emerging PRV variant JS-2012 had multiple variations compared with the vaccine strain Bartha-K61. In the study, a specific CRISPR/Cas9 system combined with homologous recombination was used to construct two recombinant viruses, BJB (Bartha-K61+JS-2012gB) and JBJ (JS-2012-DeltagE/gI+Bartha-K61gB), by interchanging the full-length gB genes between Bartha-K61 and JS-2012-DeltagE/gI. The two recombinant viruses showed similar characteristics in growth kinetics in vitro and similar pathogenicity in mice, as compared to their parental strains. Immunization of mice with inactivated BJB or JBJ followed by challenge of JS-2012 showed that BJB could increase protective efficacy to 80%, compared to only 40% protection by the parental Bartha-K61 strain. JBJ had a decreased protective efficacy of 65%, as compared to 90% protection by its parental JS-2012-DeltagE/gI strain. Exchange of the gB gene markedly altered the immunogenicity of the recombinant PRV. These data suggest that variations in gB might play an important role in the virulence of the reemergent PRV variant in China. Our results demonstrate the importance of gB in protective immunity and suggest that the recombinant virus BJB could be a promising vaccine candidate for eradication of the PRV variant. PMID- 28888659 TI - Development of a luminescent mutagenicity test for high-throughput screening of aquatic samples. AB - The Salmonella reversion based Ames test is the most widely used method for mutagenicity testing. For rapid toxicity assessment of e.g. water samples and for effect-directed analysis, however, the Ames test suffers from lack of throughput and is regarded as a laborious, time consuming method. To achieve faster analysis, with increased throughput, a (downscaled) luminescent derivative of the Ames Salmonella/microsome fluctuation test has been developed through expression of the Photorhabdus luminescens luciferase in the Salmonella TA98 and TA100 strains. The applicability of this test is demonstrated by analysis of environmentally relevant compounds, a suspended particulate matter extract and an industrial effluent sample. Use of the luminescent reporter reduced the required detection time from 48 to 28h with a specificity of 84% for responses reported in the literature to a set of 14 mutagens as compared to 72% in the unmodified fluctuation test. Testing of the same compounds in a downscaled luminescent format resulted in an 88% similarity with the response found in the regular luminescent format. The increase in throughput, faster analysis and potential for real-time bacterial quantification that luminescence provides, allows future application in the high-throughput screening of large numbers of samples or sample fractions, as required in effect-directed analysis in order to accelerate the identification of (novel) mutagens. PMID- 28888660 TI - Time for a change in how new antibiotics are reimbursed: Development of an insurance framework for funding new antibiotics based on a policy of risk mitigation. AB - Healthcare systems depend on the availability of new antibiotics. However, there is a lack of treatments for infections caused by multidrug resistant (MDR) pathogens and a weak development pipeline of new therapies. One core challenge to the development of new antibiotics targeting MDR pathogens is that expected revenues are insufficient to drive long-term investment. In the USA and Europe, financial incentives have focussed on supporting R&D, reducing regulatory burden, and extending market exclusivity. Using resistance data to estimate global revenues, we demonstrate that the combined effects of these incentives are unlikely to rekindle investment in antibiotics. We analyse two supplemental approaches: a commercial incentive (a premium price model) and a new business model (an insurance model). A premium price model is familiar and readily implemented but the required price and local budget impact is highly uncertain and sensitive to cross-sectional and longitudinal variation in prevalence of antibiotic resistance. An insurance model delivering risk mitigation for payers, providers and manufacturers would provide an incentive to drive investment in the development of new antibiotics while also facilitating antibiotic conservation. We suggest significant efforts should be made to test the insurance model as one route to stimulate investment in novel antibiotics. PMID- 28888661 TI - Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4 tetrahydroisoquinoline derivatives as potential PDE4 inhibitors. AB - Improvement of subtype selectivity of an inhibitor's binding activity using the conformational restriction approach has become an effective strategy in drug discovery. In this study, we applied this approach to PDE4 inhibitors and designed a series of novel oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally restricted analogues of rolipram. The bioassay results demonstrated the oxazolidinone-fused tetrahydroisoquinoline derivatives exhibited moderate to good inhibitory activity against PDE4B and high selectivity for PDE4B/PDE4D. Among these derivatives, compound 12 showed both the strongest inhibition activity (IC50=0.60MUM) as well as good selectivity against PDE4B and good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary SAR study showed that restricting the conformation of the catechol moiety in rolipram with the scaffold of oxazolidinone-fused tetrahydroisoquinoline could lead to an increase in selectivity for PDE4B over PDE4D, which was consistent with the observed docking simulation. PMID- 28888662 TI - Candida auris: An emerging multidrug-resistant pathogen. AB - Candida aurisis an emerging multidrug-resistant pathogen that can be difficult to identify using traditional biochemical methods. C. auris is capable of causing invasive fungal infections, particularly among hospitalized patients with significant medical comorbidities. Echinocandins are the empiric drugs of choice for C. auris, although not all isolates are susceptible and resistance may develop on therapy. Nosocomial C. auris outbreaks have been reported in a number of countries and aggressive infection control measures are paramount to stopping transmission. PMID- 28888663 TI - Impact of air manganese on child neurodevelopment in East Liverpool, Ohio. AB - BACKGROUND: East Liverpool, Ohio, the site of a hazardous waste incinerator and a manganese (Mn) processor, has had air Mn concentrations exceeding United States Environmental Protection Agency reference levels for over a decade. Save Our County, Inc., a community organization, was formed to address community environmental health concerns related to local industry. Researchers from the University of Cincinnati partnered with Save Our County to determine if air Mn had an impact on the neurocognitive function of children in the community. METHODS: Children 7-9 years of age from East Liverpool and its surrounding communities, were enrolled (N=106) in the Communities Actively Researching Exposure Study from between March 2013-June 2014. Blood and hair were analyzed for Mn and lead, and serum was analyzed for cotinine. We used linear regression to assess associations between biological measures and IQ subscale scores. RESULTS: Geometric mean blood lead (n=67), blood Mn (n=66), hair Mn (n=98), and serum cotinine (n=69) concentrations were 1.13+/-1.96MUg/dL, 10.06+/-1.30MUg/L, and 360.22+/-2.17ng/g, 0.76+/-6.12MUg/L respectively. After adjusting for potential confounders, hair Mn was negatively associated with Full Scale IQ. CONCLUSIONS: Hair Mn was negatively associated with child IQ scores. Community partners were instrumental in the conception and implementation of this study. PMID- 28888664 TI - Regulatory T cells and TLR9 activation shape antibody formation to a secreted transgene product in AAV muscle gene transfer. AB - Adeno-associated viral (AAV) gene delivery to skeletal muscle is being explored for systemic delivery of therapeutic proteins. To better understand the signals that govern antibody formation against secreted transgene products in this approach, we administered an intramuscular dose of AAV1 vector expressing human coagulation factor IX (hFIX), which does not cause antibody formation against hFIX in C57BL/6 mice. Interestingly, co-administration of a TLR9 agonist (CpG deoxyoligonucleotide, ODN) but not of lipopolysaccharide, caused a transient anti hFIX response. ODN activated monocyte-derived dendritic cells and enhanced T follicular helper cell responses. While depletion of regulatory T cells (Tregs) also caused an antibody response, TLR9 activation combined with Treg depletion instead resulted in prolonged CD8+ T cell infiltration of transduced muscle. Thus, Tregs modulate the response to the TLR9 agonist. Further, Treg re population eventually resolved humoral and cellular immune responses. Therefore, specific modes of TLR9 activation and Tregs orchestrate antibody formation in muscle gene transfer. PMID- 28888665 TI - Fish scale-derived collagen patch promotes growth of blood and lymphatic vessels in vivo. AB - : In this study, Type I collagen was extracted from fish scales asa potential alternative source of collagen for tissue engineering applications. Since unmodified collagen typically has poor mechanical and degradation stability both in vitro and in vivo, additional methylation modification and 1,4-butanediol diglycidyl ether (BDE) crosslinking steps were used to improve the physicochemical properties of fish scale-derived collagen. Subsequently, in vivo studies using a murine model demonstrated the biocompatibility of the different fish scale-derived collagen patches. In general, favorable integration of the collagen patches to the surrounding tissues, with good infiltration of cells, blood vessels (BVs) and lymphatic vessels (LVs) were observed under growth factor free conditions. Interestingly, significantly higher (p<0.05) number of LVs was found to be more abundant around collagen patches with methylation modification and BDE crosslinking. Overall, we have demonstrated the potential application of fish scale-derived collagen as a promising scaffolding material for various biomedical applications. STATEMENT OF SIGNIFICANCE: Currently the most common sources of collagen are of bovine and porcine origins, although the industrial use of collagen obtained from non-mammalian species is growing in importance, particularly since they have a lower risk of disease transmission and are not subjected to any cultural or religious constraints. However, unmodified collagen typically has poor mechanical and degradation stability both in vitro and in vivo. Hence, in this study, Type I collagen was successfully extracted from fish scales and chemically modified and crosslinked. In vitro studies showed overall improvement in the physicochemical properties of the material, whilst in vivo implantation studies showed improvements in the growth of blood and lymphatic host vessels in the vicinity of the implants. PMID- 28888666 TI - Perceptual Differences between Novice and Professional Music Theater Singers. AB - OBJECTIVE: Research examining contemporary commercial music styles of singing has increased significantly over the last 10 years. While acoustic analysis has helped determine which characteristics define various vocal genres, a discrepancy still exists in how those acoustic characteristics are perceived, described, and evaluated. METHODS: The current study recorded seven novice and four professional musical theater singers performing belt, legit, and mix vocal samples. Novice singers were defined as first- and second-year students in an undergraduate musical theater program, while professional singers were defined as having played at least one major role in a music theater production in regional Equity theaters. Five regional Equity casting directors listened to the recordings and rated each sample on the basis of style (belt versus legit) and tone quality (brassy versus fluty and bright versus dark). Results were compared across experience level (novice/professional) and pitch. Additionally, relationships between style (belt/legit) and quality (brassy/fluty, bright/dark) were examined. RESULTS: The statistically significant correlation emerged between the raters' perceived singing style and the singers' indicated singing style. Auditors identified the style (belt/legit) more reliably for the professional singers than for novice singers, and ratings of other qualities varied significantly between raters. CONCLUSIONS: The singers were successfully able to produce voicing styles that matched the perceptual expectations of the casting directors. Not surprisingly, professional singers were somewhat more successful in this regard than were the novices. There appears to be little consensus among the auditors, however, about which acoustical qualities define a belt, mix, or legit style. PMID- 28888667 TI - Preimmunization with a heat-killed preparation of Mycobacterium vaccae enhances fear extinction in the fear-potentiated startle paradigm. AB - The hygiene hypothesis or "Old Friends" hypothesis proposes that inflammatory diseases are increasing in modern urban societies, due in part to reduced exposure to microorganisms that drive immunoregulatory circuits, and a failure to terminate inappropriate inflammatory responses. Inappropriate inflammation is also emerging as a risk factor for trauma-related, anxiety, and affective disorders, including posttraumatic stress disorder (PTSD), which is characterized as persistent re-experiencing of the trauma after a traumatic experience. Traumatic experiences can lead to long-lasting fear memories and exaggerated fear potentiation of the acoustic startle reflex. The acoustic startle reflex is an ethologically relevant reflex and can be potentiated in both humans and rats through Pavlovian conditioning. Mycobacterium vaccae NCTC 11659 is a soil-derived bacterium with immunoregulatory and anti-inflammatory properties that has been demonstrated to confer stress resilience in mice. Here we immunized adult male Sprague Dawley rats 3*, once per week, with a heat-killed preparation of M. vaccae NCTC 11659 (0.1mg, s.c., in 100ul borate-buffered saline) or vehicle, and, then, 3weeks following the final immunization, tested them in the fear potentiated startle paradigm; controls were maintained under home cage control conditions throughout the experiment (n=11-12 per group). Rats were tested on days 1 and 2 for baseline acoustic startle, received fear conditioning on days 3 and 4, and underwent fear extinction training on days 5-10. Rats were euthanized on day 11 and brain tissue was sectioned for analysis of mRNA expression for genes important in control of brain serotonergic signaling, including tph2, htr1a, slc6a4, and slc22a3, throughout the brainstem dorsal and median raphe nuclei. Immunization with M. vaccae had no effect on baseline acoustic startle or fear expression on day 5. However, M. vaccae-immunized rats showed enhanced between-session and within-session extinction on day 6, relative to vehicle immunized controls. Immunization with M. vaccae and fear-potentiated startle altered serotonergic gene expression in a gene- and subregion-specific manner. These data are consistent with the hypothesis that immunoregulatory strategies, such as preimmunization with M. vaccae, have potential for prevention of stress- and trauma-related psychiatric disorders. PMID- 28888668 TI - Effects of obesity on depression: A role for inflammation and the gut microbiota. AB - Depression is a mental disorder associated with environmental, genetic and psychological factors. Recent studies indicate that chronic neuro-inflammation may affect brain physiology and alter mood and behavior. Consumption of a high fat diet leads to obesity and chronic systemic inflammation. The gut microbiota mediates many effects of a high-fat diet on human physiology and may also influence the mood and behavior of the host. We review here recent studies suggesting the existence of a link between obesity, the gut microbiota and depression, focusing on the mechanisms underlying the effects of a high-fat diet on chronic inflammation and brain physiology. This body of research suggests that modulating the composition of the gut microbiota using prebiotics and probiotics may produce beneficial effects on anxiety and depression. PMID- 28888669 TI - Thyroid hormones decrease the proinflammatory TLR4/NF-kappabeta pathway and improve functional parameters of the left ventricle of infarcted rats. AB - Myocardial infarction leads to oxidative stress and promotes activation of the TLR4/NF-kappabeta proinflammatory pathway. Thyroid hormones (TH) are known to be cardioprotective after infarction. However, there are no studies evaluating whether TH could modulate this pathway in the heart. This study aimed to verify the effect of thyroid hormones on the TLR4/NF-kappabeta pathway after myocardial infarction. Male Wistar rats were allocated into the following groups: Sham operated (SHAM), sham-operated + TH (SHAMT), infarcted (AMI) and infarcted + TH (AMIT). The treated rats received T4 and T3 (8 and 2 MUg 100 g-1 day-1) for 12 days by gavage. Subsequently, the animals were evaluated by echocardiography and euthanized, and the left ventricle was collected for biochemical and molecular analyses. TH modulates TLR4/NF-kappabeta expression in the infarcted hearts of rats and decreases xanthine oxidase expression. These effects were related to cardiac functional improvement after infarction. The cardioprotective effects of T3 and T4 seem to involve an anti-inflammatory action. PMID- 28888670 TI - Reliability, validity, and responsiveness of the Balance Evaluation Systems Test (BESTest) in individuals with multiple sclerosis. AB - BACKGROUND: The Balance Evaluation Systems Test (BESTest) measures various aspects of postural control, but little data exist in persons with multiple sclerosis (MS). The purpose of this study was to determine the psychometrics of the BESTest in MS. DESIGN: Observational study. METHODS: 21 ambulatory subjects with MS participated. In the first session, demographic data was collected; each subject completed a questionnaire of self-perceived disability level and the BESTest. The BESTest was re-administered 1 week later. RESULTS: Test-retest reliability (ICC 3,1) for the total BESTest was 0.94, ranging 0.66 to 0.93 for the subsections. Internal consistency (Chronbach's alpha) for the total BESTest was 0.97; subsections scores ranged 0.79 to 0.96. Minimal detectable change (MDC) scores ranged from 2.25 to 4.58 for subsections with 9.47 points for total BESTest. Weak to moderate correlations were found between individual subsection scores (0.12 to 0.78), and BESTest total and subsection scores to fall (-0.08 to 0.62) frequency and self-perceived disability level (-0.24 to -0.64). Strongest correlations were found between BESTest total and individual subsection scores. No floor effects were found; five BESTest subsections had ceiling effects. CONCLUSIONS: The BESTest is reliable and valid in individuals with MS. Total BESTest scores demonstrated higher reliability and a lack of a ceiling effect as compared to subsection scores, suggesting that clinicians use the BESTest in its entirety. The correlations among subsection scores indicate that each assesses a unique aspect of balance, supporting its construct validity. The MDC scores will assist clinicians in assessing patient change. PMID- 28888671 TI - Dicistroviridae: A new viral purification technique. AB - The family Dicistroviridae comprises three genera and about twenty species of RNA virus, most of them with health or agricultural importance. The Triatoma virus (TrV) is the only entomopathogenic virus identified in triatomine bugs up to the present. TrV replicates within the intestinal epithelial cells, causing high mortality rate and delayed development of the molt of these bugs. TrV has been proposed as a biological control agent for vectors of Chagas disease. Viral particles were purified from feces of 1, 5 and 10 insects from an experimental colony of Triatoma infestans infected with TrV. Viral concentration and infectivity were corroborated using polyacrylamide gels and RT-PCR, respectively. In this work we report a method of viral purification that allows to reduce necessary reagents and time, using a very small amount of fecal matter. PMID- 28888672 TI - Student support in accelerated nursing programs: Gender-based perspectives and impact on academic outcomes. AB - BACKGROUND: Factors that contribute to student success in accelerated degree nursing programs are poorly understood and may vary by gender. PURPOSE: Examine associations between satisfaction with peer and mentor support, gender, and academic outcomes among students in accelerated degree nursing programs. METHODS: We used data (demographic variables, satisfaction with peer and mentor support, graduation, and attempts of National Council Licensure Examination for Registered Nurses) from the American Association of Colleges of Nursing and Robert Wood Johnson Foundation's New Career in Nursing Program. Multivariable mixed effects regression models were used to examine associations among gender, satisfaction with support, and academic outcomes. FINDINGS: Males had an increased probability of reporting high satisfaction with peer support. Both males and females who were very dissatisfied with peer support were less likely to graduate than students who were very satisfied with peer support. Gender did not moderate the relationships between satisfaction with peer and mentor support and academic outcomes. CONCLUSION: Peer support is an important aspect of graduation among students in accelerated degree nursing programs. Continuous quality improvement strategies to improve student peer support may be warranted. PMID- 28888673 TI - Relationship between bacteriology report time in the morning and length of stay in hospital after the report. AB - We studied the relationship between the time of day bacteriology reports were available in the electronic medical record (Epic, Verona, WI) and subsequent length of stay (LOS) following the last report before discharge. All patients >=18years admitted to the UF Health Shands Hospital between 1/1/2014-2/29/2016 were included. We calculated the mean LOS following the report for each half-hour time period between 6AM and 1PM (N=14, 95.6% of all results) and tested the relationship to subsequent LOS. For patients whose total LOS was <=168hours (N=13,830) there was a highly significant positive linear relationship between the report time and LOS following the last report (r=0.8813, P=0.00001556). For those patients with total LOS>168h, there was no clear relationship between report time in the morning and LOS after the last bacteriology report. The relationship between bacteriology report time in the morning and use of this information by physicians in discharge decision-making is likely to be complex and multi-factorial, but for those patients with a total hospital LOS <=168h, there is a strong relationship between an earlier report and earlier patient discharge. PMID- 28888676 TI - Editorial Comment. PMID- 28888674 TI - Geographic variations in clinical presentation and outcomes of decompressive surgery in patients with symptomatic degenerative cervical myelopathy: analysis of a prospective, international multicenter cohort study of 757 patients. AB - BACKGROUND CONTEXT: Degenerative cervical myelopathy (DCM) is a progressive degenerative spine disease and the most common cause of spinal cord impairment in adults worldwide. Few studies have reported on regional variations in demographics, clinical presentation, disease causation, and surgical effectiveness. PURPOSE: The objective of this study was to evaluate differences in demographics, causative pathology, management strategies, surgical outcomes, length of hospital stay, and complications across four geographic regions. STUDY DESIGN/SETTING: This is a multicenter international prospective cohort study. PATIENT SAMPLE: This study includes a total of 757 symptomatic patients with DCM undergoing surgical decompression of the cervical spine. OUTCOME MEASURES: The outcome measures are the Neck Disability Index (NDI), the Short Form 36 version 2 (SF-36v2), the modified Japanese Orthopaedic Association (mJOA) scale, and the Nurick grade. MATERIALS AND METHODS: The baseline characteristics, disease causation, surgical approaches, and outcomes at 12 and 24 months were compared among four regions: Europe, Asia Pacific, Latin America, and North America. RESULTS: Patients from Europe and North America were, on average, older than those from Latin America and Asia Pacific (p=.0055). Patients from Latin America had a significantly longer duration of symptoms than those from the other three regions (p<.0001). The most frequent causes of myelopathy were spondylosis and disc herniation. Ossification of the posterior longitudinal ligament was most prevalent in Asia Pacific (35.33%) and in Europe (31.75%), and hypertrophy of the ligamentum flavum was most prevalent in Latin America (61.25%). Surgical approaches varied by region; the majority of cases in Europe (71.43%), Asia Pacific (60.67%), and North America (59.10%) were managed anteriorly, whereas the posterior approach was more common in Latin America (66.25%). At the 24-month follow-up, patients from North America and Asia Pacific exhibited greater improvements in mJOA and Nurick scores than those from Europe and Latin America. Patients from Asia Pacific and Latin America demonstrated the most improvement on the NDI and SF-36v2 PCS. The longest duration of hospital stay was in Asia Pacific (14.16 days), and the highest rate of complications (34.9%) was reported in Europe. CONCLUSIONS: Regional differences in demographics, causation, and surgical approaches are significant for patients with DCM. Despite these variations, surgical decompression for DCM appears effective in all regions. Observed differences in the extent of postoperative improvements among the regions should encourage the standardization of care across centers and the development of international guidelines for the management of DCM. PMID- 28888675 TI - Radiation dose and cardiac risk in breast cancer treatment: An analysis of modern radiation therapy including community settings. AB - PURPOSE: Adjuvant radiation therapy (RT) for breast cancer improves outcomes, but prior studies have documented substantive cardiac dose and cardiac risk. We assessed the mean heart dose (MHD) of RT and estimated the risk of RT-associated cardiac toxicity in women undergoing adjuvant RT for breast cancer in contemporary (predominantly) community practice. METHODS AND MATERIALS: We identified women with left-sided breast cancer receiving adjuvant RT between 2012 and 2014 from 94 centers across 16 states. We used bivariate analyses and multivariable linear regression to assess associations between RT techniques and MHD. Excess RT-related cardiac risk by age 80 was estimated for women diagnosed at age 60 using the previously reported relationship between MHD and cardiac risk. RESULTS: Among 1161 women, 77.3% were treated in community practice and with breast conservation (77.8%). The most common techniques were free-breathing (92.2%), supine (94.8%), and fixed gantry intensity modulated RT (FG-IMRT; 46.9%). The median MHD was 2.76 Gy (interquartile range, 1.47-5.03). In multivariable analyses, the predicted median MHD with deep inspiration breath hold was 2.41 Gy compared with 3.86 Gy with free-breathing (P < .001). Three dimensional conformal RT (3D-CRT) was associated with a lower predicted median MHD (2.78 Gy) than FG-IMRT (4.02 Gy) or rotational IMRT, 6.60 Gy, P < .001). For 60-year-old women with the median MHD of the study population (2.76 Gy) and no cardiovascular risk factors, the 20-year predicted excess risk of death from ischemic heart disease attributable to radiation was 3.5 excess events/1000 patients, in contrast to estimates of 8 events/1000 from prior analyses. The predicted risk of cardiac events varied based on radiation technique, with 4 excess events/1000 with 3D-CRT, 5 excess events/1000 with FG-IMRT, and 8 excess events/1000 with rotational IMRT. CONCLUSIONS: MHD varies substantially across patients and is influenced by technique in predominantly community settings. Overall risk of cardiac toxicity is modest. PMID- 28888677 TI - Quantitation of lanosterol in the vitreous humor of rabbits after ocular administration of lanosterol/thermogel formulation by ultra high performance liquid chromatography-tandem mass spectrometry with the electrospray ionization mode. AB - Cataracts are the most common cause of blindness worldwide affecting tens of millions of people. Here, we report a simple, rapid, sensitive and specific method by ultra performance liquid chromatography-tandem mass spectrometry with the electrospray ionization mode (UPLC-ESI-MS/MS) for quantitation of lanosterol, a possible effective drug for cataracts, in the vitreous humor of rabbits after ocular administration. The injected lanosterol was prepared by dispersing lanosterol molecules into the poly-(dl-lactic acid-co-glycolic acid) poly(ethylene glycol)-poly-(dl-lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) thermogel solution. The analyte and internal standard (IS, panaxadiol) were extracted by the simple protein precipitation with methanol. The chromatographic separation used an Agilent RRHD SB-C18 column with a methanol mobile phase containing 50mM of ammonium acetate aqueous solution (with 0.1% formic acid) (95:5, v/v). The protonated analyte was quantitated in positive ionization by multiple reaction monitoring (MRM) with a mass spectrometer. The mass transitions m/z 443.5->235 and m/z 461->127 were used to measure the analyte and IS, respectively. The assay exhibited a linear dynamic range of 1-1250ngmL-1 for lanosterol in vitreous samples. The lower limit of quantitation (LLOQ) was 1ngmL 1 with a relative standard deviation (RSD) of less than 15%. Acceptable precision and accuracy were obtained for concentrations over the standard curve ranges. A run time of 5min per sample offered a throughput of more than 200 samples per day. This validated method was used to analyze vitreous samples of New Zealand white rabbits for pharmacokinetic studies. The results provided useful information on pharmacological action mechanism of lanosterol and were meaningful for cataract treatment among the elderly population. PMID- 28888678 TI - Preparation of a magnetic porous organic polymer for the efficient extraction of phenylurea herbicides. AB - A magnetic porphyrin-based porous organic polymer (M-PPOP) with good porosity, high surface area and strong magnetism was prepared and employed as the adsorbent for the magnetic solid phase extraction of the phenylurea herbicides (metoxuron, monolinuron, chlorotoluron, and buturon) from bottled grape juice and tomato samples prior to their determination by high performance liquid chromatography. Under the optimized conditions, the developed method exhibited a good linear range, low limits of detection, low relative standard deviations (<6.8%), good method recoveries between 80.8% and 117%, and high enrichment factors (51-106). For a better elucidation of the adsorption of the M-PPOP towards the analytes, the extraction performance of the M-PPOP for different types of organic compounds including polycyclic aromatic hydrocarbons, phenylurea insecticides, phenylurea herbicides and phenols was studied. The results indicated that the pi- stacking, hydrogen-bonding and hydrophobic interactions between the M-PPOP and the analytes played a main role for the adsorption. The results revealed that the M-PPOP material had a great potential for the enrichment of more organic pollutants from real samples. PMID- 28888679 TI - Assessment of the removal of side nanoparticulated populations generated during one-pot synthesis by asymmetric flow field-flow fractionation coupled to elemental mass spectrometry. AB - Coupling of asymmetric flow field-flow fractionation (AF4) to an on-line elemental detection (inductively coupled plasma-mass spectrometry, ICP-MS) has been recently proposed as a powerful diagnostic tool for characterization of the bioconjugation of CdSe/ZnS core-shell Quantum Dots (QDs) to antibodies. Such approach has been used herein to demonstrate that cap exchange of the native hydrophobic shell of core/shell QDs with the bidentate dihydrolipoic acid ligands directly removes completely the eventual side nanoparticulated populations generated during simple one-pot synthesis, which can ruin the subsequent final bioapplication. The critical assessment of the chemical and physical purity of the surface-modified QDs achieved allows to explain the transmission electron microscopy findings obtained for the different nanoparticle surface modification assayed. PMID- 28888680 TI - The reciprocal iso-inhibition volume concept: A procedure for the evaluation in effect-directed analysis with thin-layer chromatography - using the thin-layer chromatography-luminescent bacteria assay as an example. AB - In effect-directed analysis (EDA) with high-performance thin-layer chromatography (HPTLC), the effect is often detected using images. Thus, an approach to create inhibition chromatograms from these images was developed using the example of the HPTLC- bioluminescence inhibition test. A comparison between the cuvette test and the HPTLC test shows that the test on the plate is significantly more sensitive. To describe the strength of the effect, the EC50 value is determined from the dose-response relationship. However, the inhibiting compounds are generally unknown and thus their concentrations are also unknown. Therefore, instead of the concentration, the known application volumes are used. This enables the calculation of the application volume necessary to achieve 50% inhibition. Since the volume is inversely proportional to the concentration, the reciprocal value of the calculated volume is indicated and is referred to as the reciprocal iso inhibition volume (RIV). Using this RIV-concept, it is now possible to compare inhibition bands within and between plates. The entire evaluation is described by the means of two samples from a contaminated site using the bioluminescence inhibition. PMID- 28888681 TI - Nano reversed phase versus nano hydrophilic interaction liquid chromatography on a chip in the analysis of hemopexin glycopeptides. AB - Analysis of the glycosylation of proteins is a challenge that requires orthogonal methods to achieve separation of the diverse glycoforms. A combination of reversed phase chromatography with tandem mass spectrometry (RP-LC-MS/MS) is one of the most powerful tools for glycopeptide analysis. In this work, we developed and compared RP-LC and hydrophilic interaction liquid chromatography (HILIC) in nanoscale on a chip combined with MS/MS in order to separate glycoforms of two peptides obtained from the tryptic digest of hemopexin. We observed reduction of the retention time with decreasing polarity of glycans attached to the same peptide backbone in HILIC. The opposite effect was observed for RP-LC. The presence of sialic acids prolonged the retention of glycopeptides in both chromatographic modes. The nanoHILIC method provided higher selectivity based on the composition of glycan, compared to nanoRP-LC but a lower sensitivity. The nanoHILIC method was able to partially separate linkage isomers of fucose (core and outer arm) on bi-antennary glycoform of SWPAVGDCSSALR glycopeptide, which is beneficial in the elucidation of the structure of the fucosylated glycoforms. PMID- 28888682 TI - Rapid capillary electrophoresis approach for the quantification of ewe milk adulteration with cow milk. AB - The substitution of ewe milk with more economic cow milk is a common fraud. Here we present a capillary electrophoresis method for the quantification of ewe milk in ovine/bovine milk mixtures, which allows for the rapid and inexpensive recognition of ewe milk adulteration with cow milk. We utilized a routine CE method for human blood and urine proteins analysis, which fulfilled the separation of skimmed milk proteins in alkaline buffer. Under this condition, ovine and bovine milk exhibited a recognizable and distinct CE protein profiles, with a specific ewe peak showing a reproducible migration zone in ovine/bovine mixtures. Based on ewe specific CE peak, we developed a method for ewe milk quantification in ovine/bovine skimmed milk mixtures, which showed good linearity, precision and accuracy, and a minimum amount of detectable fraudulent cow milk equal to 5%. PMID- 28888683 TI - Adult spinal deformity treated with minimally invasive surgery. Description of surgical technique, radiological results and literature review. AB - The prevalence of adult spinal deformity has been increasing exponentially over time. Surgery has been credited with good radiological and clinical results. The incidence of complications is high. MIS techniques provide good results with fewer complications. This is a retrospective study of 25 patients with an adult spinal deformity treated by MIS surgery, with a minimum follow-up of 6 months. Radiological improvement was SVA from 5 to 2cm, coronal Cobb angle from 31 degrees to 6 degrees , and lumbar lordosis from 18 degrees to 38 degrees . All of these parameters remained stable over time. We also present the complications that appeared in 4 patients (16%). Only one patient needed reoperation. We describe the technique used and review the references on the subject. We conclude that the MIS technique for treating adult spinal deformity has comparable results to those of the conventional techniques but with fewer complications. PMID- 28888684 TI - Prognostic factors after a traumatic hip dislocation. A long-term retrospective study. AB - INTRODUCTION: Traumatic hip dislocations can have devastating complications such as osteoarthritis or osteonecrosis. The aim of this study was to identify the variables and prognostic factors associated with clinical and radiological outcome after a traumatic hip dislocation at long-term follow-up. MATERIAL AND METHODS: A review was performed of all dislocations and fracture-dislocations of the hip from January 1999 to December 2012. A computed tomography scan was performed after reduction in all cases. The Harris Hip Score and modified Merle d'Aubigne-Postel method were used for clinical evaluation and radiological assessment was performed according to the Thompson and Epstein classification. RESULTS: There were 30 cases in 29 patients with a mean follow-up of 11 years (range, 4-17). The great majority were simple dislocations (21; 70%) vs. complex dislocations (9; 30%). Closed reduction was performed in less than 6h in all except one case (29; 96.7%). All of the patients with simple dislocations had an excellent outcome without radiological signs of osteoarthritis at the end of the follow-up (P<.01). Overall, arthritic signs had developed in 4 patients (13.3%) and avascular necrosis was noted in 3 patients (10%). Five patients with intraarticular fragments were treated non-operatively, and 3 of them developed arthritic changes (P<.05). CONCLUSION: Our study suggests that complex dislocations are associated with poorer functional and radiological outcomes than simple dislocations. We also found a strong association between intraarticular fragments and osteoarthritis, so surgical fragment removal could be considered in these cases. PMID- 28888685 TI - Predictive factors of hospital stay, mortality and functional recovery after surgery for hip fracture in elderly patients. AB - OBJECTIVES: Due to its high prevalence and serious consequences it is very important to be well aware of factors that might be related to medical complications, mortality, hospital stay and functional recovery in elderly patients with hip fracture. MATERIAL AND METHODS: A prospective study of a group of 130 patients aged over 75 years admitted for osteoporotic hip fracture. Their medical records, physical and cognitive status prior to the fall, fracture type and surgical treatment, medical complications and functional and social evolution after hospitalization were evaluated. RESULTS: Patients with greater physical disability, more severe cognitive impairment and those who lived in a nursing home before the fracture had worse functional recovery after surgery. Treatment with intravenous iron to reduce transfusions reduced hospital stay and improved walking ability. Infections and heart failure were the most frequent medical complications and were related to a longer hospital stay. The prescription of nutritional supplements for the patients with real indication improved their physical recovery after the hip fracture CONCLUSIONS: Evaluation of physical, cognitive and social status prior to hip fracture should be the basis of an individual treatment plan because of its great prognostic value. Multidisciplinary teams with continuous monitoring of medical problems should prevent and treat complications as soon as possible. Intravenous iron and specific nutritional supplements can improve functional recovery six months after hip fracture. PMID- 28888687 TI - Rapid screening of abused drugs by direct analysis in real time (DART) coupled to time-of-flight mass spectrometry (TOF-MS) combined with ion mobility spectrometry (IMS). AB - Increasing in cases involving drugs of abuse leads to heavy burden for law enforcement agencies, exacerbating demand for rapid screening technique. In this study, atmospheric pressure ionization technologies including direct analysis in real time (DART) ion source coupled to a time-of-flight mass spectrometer (DART TOF-MS)as well asdopant-assisted positive photoionization ion mobility spectrometry (DAPP-IMS) without radioactivity were utilized together as the powerful analytical tool for the rapid screening and identification of 53 abused drugs.The limits of detection (LOD) were 0.05-2MUg/mL when using DART-TOF-MS and 0.02-2MUg when using DAPP-IMS which could satisfy the actual requirement in forensic science laboratory. The advantages of this method included fast response, high-throughput potential, high specificity, and minimal sample preparation. A screening library of reduced mobility (K0), accurate mass of informative precursor ion ([M+H]+) and fragment ions was established respectively by employing a bench-top DAPP-IMS and TOF-MS in-source collision induced dissociation (CID) mode. Then the standardized screening procedure was developed with criteria for the confirmation of positive result. A total of 50 seized drug samples provided by local forensic laboratory we reanalyzed to testify the utility of the method. This study suggests that a method combing DART-TOF-MS and DAPP-IMS is promising for the rapid screening and identification of abused drugs with minimal sample preparation and absence of chromatography. PMID- 28888686 TI - Fibroblast-derived HGF drives acinar lung cancer cell polarization through integrin-dependent RhoA-ROCK1 inhibition. AB - The formation of lumens in epithelial tissues requires apical-basal polarization of cells, and the co-ordination of this individual polarity collectively around a contiguous lumen. Signals from the Extracellular Matrix (ECM) instruct epithelia as to the orientation of where basal, and thus consequently apical, surfaces should be formed. We report that this pathway is normally absent in Calu-3 human lung adenocarcinoma cells in 3-Dimensional culture, but that paracrine signals from MRC5 lung fibroblasts can induce correct orientation of polarity and acinar morphogenesis. We identify HGF, acting through the c-Met receptor, as the key polarity-inducing morphogen, which acts to activate beta1-integrin-dependent adhesion. HGF and ECM-derived integrin signals co-operate via a c-Src-dependent inhibition of the RhoA-ROCK1 signalling pathway via p190A RhoGAP. This occurred via controlling localization of these signalling pathways to the ECM-abutting surface of cells in 3-Dimensional culture. Thus, stromal derived signals can influence morphogenesis in epithelial cells by controlling activation and localization of cell polarity pathways. PMID- 28888688 TI - Comparing the Centering Ability of Different Pathfinding Systems and Their Effect on Final Instrumentation by Hyflex CM. AB - INTRODUCTION: Recently, different rotary glide path systems have been introduced. The aim of this study was to compare the centering ability of different rotary pathfinding systems and their effect on the final preparation by Hyflex CM files. METHODS: Sixty endodontic training blocks with J-shaped canals were divided into 3 groups according to the pathfinding system used. Instrumentation was done with G-File + Hyflex CM (G-File group), PathFile + Hyflex CM (PathFile group), and Hyflex GPF + Hyflex CM (GPF group). Three images were taken: initial, after glide path preparation, and after final instrumentation. Pre-instrumentation and post instrumentation images were superimposed, and centering ratio along the J-shaped canal was measured to evaluate the occurrence of deviation. Statistical analysis of the data was performed by using one-way analysis of variance, followed by Tukey test (alpha = 0.05). RESULTS: The ability of instruments to remain centered in canals at 0-mm level (apex) was significantly lower in PathFile group (P < .05). No significant difference was found at other levels. After final preparation by Hyflex CM no significant difference was found at any level. CONCLUSIONS: The centering abilities of Hyflex GPF and G-Files are better than that of PathFile at apex, but it has no significant effect on final preparation by Hyflex CM. PMID- 28888689 TI - Exercise training improves exercise capacity and quality of life in people with interstitial lung disease [commentary]. PMID- 28888690 TI - Pelvic physiotherapy in addition to standard care is more effective than standard medical care alone for children with functional constipation [synopsis]. PMID- 28888691 TI - Exercise training improves exercise capacity and quality of life in people with interstitial lung disease [synopsis]. PMID- 28888692 TI - Canadian Study of Health and Aging Clinical Frailty Scale: Does It Predict Adverse Outcomes among Geriatric Trauma Patients? AB - BACKGROUND: The Canadian Study of Health and Aging Clinical Frailty Scale (CFS) and the laboratory Frailty Index (FI-lab) are validated tools based on clinical and laboratory data, respectively. Their utility as predictors of geriatric trauma outcomes is unknown. Our primary objective was to determine whether pre admission CFS is associated with adverse discharge destination. Secondary objectives were to evaluate the relationships between CFS and in-hospital complications and between admission FI-lab and discharge destination. STUDY DESIGN: We performed a 4-year (2011 to 2014) retrospective cohort study with patients 65 years and older admitted to a level I trauma center. Admission FI-lab was calculated using 23 variables collected within 48 hours of presentation. The primary outcome was discharge destination, either adverse (death or discharge to a long-term, chronic, or acute care facility) or favorable (home or rehabilitation). The secondary outcome was in-hospital complications. Multivariable logistic regression was used to evaluate the relationship between CFS or FI-lab and outcomes. RESULTS: There were 266 patients included. Mean age was 76.5 +/- 7.8 years and median Injury Severity Score was 17 (interquartile range 13 to 24). There were 260 patients and 221 patients who had sufficient data to determine CFS and FI-lab scores, respectively. Pre-admission frailty as per the CFS (CFS 6 or 7) was independently associated with adverse discharge destination (odds ratio 5.1; 95% CI 2.0 to 13.2; p < 0.001). Severe frailty on admission, as determined by the FI-lab (FI-lab > 0.4), was not associated with adverse outcomes. CONCLUSIONS: Pre-admission clinical frailty independently predicts adverse discharge destination in geriatric trauma patients. The CFS may be used to triage resources to mitigate adverse outcomes in this population. The FI-lab determined on admission for trauma may not be useful. PMID- 28888693 TI - N-terminus determines activity and specificity of styrene monooxygenase reductases. AB - Styrene monooxygenases (SMOs) are two-enzyme systems that catalyze the enantioselective epoxidation of styrene to (S)-styrene oxide. The FADH2 co substrate of the epoxidase component (StyA) is supplied by an NADH-dependent flavin reductase (StyB). The genome of Rhodococcus opacus 1CP encodes two SMO systems. One system, which we define as E1-type, displays homology to the SMO from Pseudomonas taiwanensis VLB120. The other system, originally reported as a fused system (RoStyA2B), is defined as E2-type. Here we found that E1-type RoStyB is inhibited by FMN, while RoStyA2B is known to be active with FMN. To rationalize the observed specificity of RoStyB for FAD, we generated an artificial reductase, designated as RoStyBart, in which the first 22 amino acid residues of RoStyB were joined to the reductase part of RoStyA2B, while the oxygenase part (A2) was removed. RoStyBart mainly purified as apo-protein and mimicked RoStyB in being inhibited by FMN. Pre-incubation with FAD yielded a turnover number at 30 degrees C of 133.9+/-3.5s-1, one of the highest rates observed for StyB reductases. RoStyBart holo-enzyme switches to a ping-pong mechanism and fluorescence analysis indicated for unproductive binding of FMN to the second (co-substrate) binding site. In summary, it is shown for the first time that optimization of the N-termini of StyB reductases allows the evolution of their activity and specificity. PMID- 28888694 TI - Analyzing the effects of co-expression of chick (Gallus gallus) melanocortin receptors with either chick MRAP1 or MRAP2 in CHO cells on sensitivity to ACTH(1 24) or ACTH(1-13)NH2: Implications for the avian HPA axis and avian melanocortin circuits in the hypothalamus. AB - In order to better understand the roles that melanocortin receptors (cMCRs) and melanocortin-2 receptor accessory proteins (cMRAP1 and cMRAP2) play in the HPA axis and hypothalamus, adrenal gland and hypothalamus mRNA from 1day-old white leghorn chicks (Gallus gallus), were analyzed by real-time PCR. mRNA was also made for kidney, ovary, and liver. Mrap1 mRNA could be detected in adrenal tissue, but not in any of the other tissues, and mrap2 mRNA was also detected in the adrenal gland. Finally, all five melanocortin receptors mRNAs could be detected in the adrenal gland; mc2r and mc5r mRNAs were the most abundant. To evaluate any potential interactions between MRAP1 and the MCRs that may occur in adrenal cells, individual chick mcr cDNA constructs were transiently expressed in CHO cells either in the presence or absence of a chick mrap1 cDNA, and the transfected cells were stimulated with hACTH(1-24) at concentrations ranging from 10-13M to 10-6M. As expected, MC2R required co-expression with MRAP1 for functional expression; whereas, co-expression of cMC3R with cMRAP1 had no statistically significant effect on sensitivity to hACTH(1-24). However, co expression of MC4R and MC5R with MRAP1, increased sensitivity for ACTH(1-24) by approximately 35 fold and 365 fold, respectively. However, co-expressing of cMRAP2 with these melanocortin receptors had no effect on sensitivity to hACTH(1 24). Since the real-time PCR analysis detected mrap2 mRNA and mc4r mRNA in the hypothalamus, the interaction between cMC4R and cMRAP2 with respect to sensitivity to ACTH(1-13)NH2 stimulation was also evaluated. However, no effect, either positive or negative, was observed. Finally, the highest levels of mc5r mRNA were detected in liver cells. This observation raises the possibility that in one-day old chicks, activation of the HPA axis may also involve a physiological response from liver cells. PMID- 28888695 TI - Characterization of seasonal reproductive and stress steroid hormones in wild Radiated Tortoises, Astrochelys radiata. AB - The critically endangered Radiated Tortoise (Astrochelys radiata) is endemic to the southern coastlines of Madagascar. Once common, wild populations of this tortoise have undergone dramatic declines in recent years. Although there have been studies documenting reproductive activities, reproductive physiological parameters are unknown yet may be crucial in the recovery of the species. Over four research seasons in remote field locations native to A. radiata, we surveyed for, radio-tracked, and sampled wild, free ranging tortoises. We sampled and measured stress and reproductive parameters (corticosterone [CORT], testosterone [T], estradiol-17beta [E2], and progesterone [P]) in 311 plasma samples from 203 wild A. radiata, capturing their active period. Generally, hormone concentrations were associated with body condition, temperature, and humidity. There was wide variation in CORT that varied monthly and by group. Juvenile tortoises maintained more than twice the mean basal CORT concentrations than either adult sex, with the most dramatic distinctions in the middle of the wet season. For adult sex hormones, the last months of the dry season and into the wet season when ground humidities are low and just begin to rise prior to temperature declines, male T concentrations gradually increased to a peak before returning to near undetectable values into the dry season. We had limited data for T concentrations in females, but found average T concentrations were much lower than in males and positively correlated with larger female home range sizes. For female hormone cycles, E2 also peaked in the early 1/3 of the wet season along with male T, and was followed by an uptick in P which correlates to the putative ovulatory cycle. Females tracked over four years showed variation in patterns of P, indicating that number and frequency of clutches vary. Our results suggest that 1) there is high species plasticity in response to stress; 2) A. radiata reproductive cycling is somewhat dissociated with courtship timing and is instead triggered by environmental cues; and 3) individual female reproductive output is irregular. This study is oone of the first to document and describe multi-year seasonal stress and reproductive hormones in a free-ranging Malagasy chelonian. These data may be used to identify key high-production habitats for conservation, and aide in captive management and reproduction in assurance colonies for species health and survival. PMID- 28888696 TI - Characterization of NvLWamide-like neurons reveals stereotypy in Nematostella nerve net development. AB - The organization of cnidarian nerve nets is traditionally described as diffuse with randomly arranged neurites that show minimal reproducibility between animals. However, most observations of nerve nets are conducted using cross reactive antibodies that broadly label neurons, which potentially masks stereotyped patterns produced by individual neuronal subtypes. Additionally, many cnidarians species have overt structures such as a nerve ring, suggesting higher levels of organization and stereotypy exist, but mechanisms that generated that stereotypy are unknown. We previously demonstrated that NvLWamide-like is expressed in a small subset of the Nematostella nerve net and speculated that observing a few neurons within the developing nerve net would provide a better indication of potential stereotypy. Here we document NvLWamide-like expression more systematically. NvLWamide-like is initially expressed in the typical neurogenic salt and pepper pattern within the ectoderm at the gastrula stage, and expression expands to include endodermal salt and pepper expression at the planula larval stage. Expression persists in both ectoderm and endoderm in adults. We characterized our NvLWamide-like::mCherry transgenic reporter line to visualize neural architecture and found that NvLWamide-like is expressed in six neural subtypes identifiable by neural morphology and location. Upon completing development the numbers of neurons in each neural subtype are minimally variable between animals and the projection patterns of each subtype are consistent. Furthermore, between the juvenile polyp and adult stages the number of neurons for each subtype increases. We conclude that development of the Nematostella nerve net is stereotyped between individuals. Our data also imply that one aspect of generating adult cnidarian nervous systems is to modify the basic structural architecture generated in the juvenile by increasing neural number proportionally with size. PMID- 28888697 TI - Response to unfairness across the suicide risk spectrum. AB - Suicidal behavior is frequently triggered by social crises, such as familial, romantic, social or work-related conflict. A variety of cognitive and social functioning impairments has been associated with suicidal thoughts and acts. One of the precipitating and perpetuating factors of social conflict is the desire for retribution after a perceived offense, even at one's own detriment. We utilized the Ultimatum Game-a behavioral economic task which examines the behavioral response to perceived unfairness-in order to characterize the response to unfairness across the acute suicide risk spectrum. We examined five groups of adult individuals of both genders (n = 204): High- and Low-Lethality recent Suicide Attempters, Suicidal Ideators, Non-Suicidal Depressed Patients; and Healthy Controls. We also measured demographic and clinical variables. Even though all depressed groups showed similar rejection rates in the Ultimatum Game, there was a higher likelihood of rejecting offers in the low stakes condition in all acutely suicidal groups compared with healthy controls. Stake size, offer, education, and gender of the proposer were significantly associated with rejection rates. Acutely suicidal patients may be more vulnerable to adverse interpersonal interactions. Further characterization of social behavior may provide targets for secondary and tertiary prevention for high-risk individuals. PMID- 28888698 TI - [Ultra wide field imaging of a retinal detachment caused by desinsertion of the ora serrata]. PMID- 28888699 TI - Endometrial Ablation. AB - The destruction of the endometrium in women with heavy menstrual bleeding has been used for well over a century, and the various techniques of delivering forms of thermal energy have been modified over the years to ensure a safe and effective treatment approach. Today, 6 nonresectoscopic devices are approved for use in the United States in addition to resectoscopic techniques that rely on the skillful use of the operative hysteroscope. Regardless of the technique used, endometrial ablation uniformly reduces menstrual blood loss, improves general and menstrual-related quality of life, and prevents hysterectomy in 4 of 5 women who undergo the procedure. When patients are appropriately selected, outcomes are optimized, and risks of serious complications are minimized. This article reviews the literature with singular reference to nonresectoscopic endometrial ablation procedures including historical background, appropriate patient selection, clinical outcomes data, complications, and special or unique considerations. PMID- 28888700 TI - Surgical Repair of Rectovaginal Fistula Using the Modified Martius Procedure: A Step-by-Step Guide. AB - STUDY OBJECTIVE: To demonstrate the surgical repair of a rectovaginal fistula (RVF) using the modified Martius procedure. DESIGN: A step-by-step presentation of the procedure using video (Canadian Task Force classification III). SETTING: RVF is abnormal epithelialized connections between the vagina and rectum. Causes of RVF include obstetric trauma, Crohn disease, pelvic irradiation, and postsurgical complications. Many surgical interventions have been developed, from the laparoscopic technique to muscle transposition and even rectal resection. However, the treatment of RVF is a great challenge to gynecologic surgeons because the incidence of RVF is low and there is no high evidence for the best surgical approach to this disease. When RVF is persistent or recurrent, the surrounding tissue is always scarred or damaged, so the interposition of a healthy and well-perfused tissue is an appropriate approach to fistula management. The modified Martius procedure using adipose tissue from the labia major places well-vascularized pedicle in the place of the RVF. Limited studies involving the procedure present favorable successful rates. PATIENT: Consent was obtained from the patient. The study was approved by the local ethics committee. INTERVENTION: The surgical repair of rectovaginal fistula by the modified Martius procedure is described as follows: The patient is placed in the high lithotomy position. A temporary transurethral urinary catheter is placed preoperatively to keep the operative site clean. The rectovaginal fistula is identified by a fistula probe. A 4-cm incision is made vertically over the left labium majus from the level of the mons pubis to the bottom of the labium to harvest pedicle. It is imperative to ensure adequate length on the flap before transection. Blood supply to the fat-muscle flap is provided superiorly by the external pudendal artery, posteriorly by the internal posterior and laterally by the obturator artery. The fat-muscle flap is dissected in a lateral-to-medial direction and divided in the upper section by two clamps, preserving its posterior aspect intact to maintain its blood supply. After that the fistula is circumcised with a scalpel through the vaginal wall with a margin of healthy tissue. During the process, the rectovaginal septum is opened and wide mobilized so that a multilayer closure can be performed without any tension. Then a subcutaneous tunnel is made from the labium majus to the fistula with a forcep. It is also important to make the tunnel wide enough to easily accommodate the flap. The fat-muscle flap is pulled through the tunnel gently, ensuring proper orientation without kinking the blood supply. The rectal mucosa is sutured in one layer with 3-0 Vicryl in interrupted fashion. The flap is then sutured down to the rectal wall with four single sutures in interrupted fashion. So the rectal and vaginal walls are separated with a healthy, well-vascularized pedicle. In addition, the flap fills in the dead space and enhances granulation tissue. The vaginal mucosa is then closed over the pedicle with 1-0 Vicryl in interrupted suture without tension. The labial incision is closed in layers with absorbable suture. Neither incision is drained. MEASUREMENTS AND MAIN RESULTS: In this video, we describe the modified Martius procedure for the management of RVF. We present a 26-year-old woman who suffered from RVF caused by obstetric trauma. She complained of passing flatus and feces through the vagina 1 week after vaginal delivery. Clinical examination performed in the local hospital confirmed RVF 1 cm in diameter located in the lower third of the vagina. The fistula was present for about 6 months, which brought psychosocial dysfunction to the patient. She was transferred to our clinic. After examination, the anal sphincter was intact. After mechanical bowel preparation with polyethylene glycol solution, the patient was presented for surgery. The operating time was about 40 minutes. No recurrence or complications were observed at the 4-month follow-up. A protective ileostomy or colostomy was avoided. The patient reestablished intestinal continuity. The functional and cosmetic results were excellent with high patient satisfaction and greatly improved quality of life. CONCLUSION: The Martius flap is easy to harvest with minimal external disfigurement and a minimal recovery time. The modified Martius procedure is a feasible adjuvant technique for RVF with excellent postoperative outcomes. PMID- 28888701 TI - Direct Mass Spectrometry Differentiation of Ectopic and Eutopic Endometrium in Patients with Endometriosis. AB - STUDY OBJECTIVE: To introduce a method for the rapid assessment of endometriotic tissues using direct mass spectrometry (MS)-based lipidomics. DESIGN: A prospective observational cohort study (Canadian Task Force classification II2). SETTING: Department of Operative Gynecology of the Research Centre for Obstetrics, Gynecology and Perinatology. PATIENTS: Fifty patients with ovarian cysts and peritoneal endometriosis who underwent laparoscopic surgery between 2014 and 2016. INTERVENTION: Differences in mass spectrometric profiles of ectopic endometria (endometriosis) and eutopic endometria were analyzed for each patient in combination with morphohistologic evaluation. The lipidomic approach was applied using a direct high-resolution MS method. MEASUREMENTS AND MAIN RESULTS: Of 148 metabolites, 15 showed significant differences between endometriotic tissue and a healthy endometrium of the same patient, considered as a control in this study. The main lipids prevalent in endometriotic tissues were phosphoethanolamine (PE O-20:0), sphingomyelin (SM 34:1), diglycerides (DG 44:9), phosphatidylcholines (PC 32:1, PC O-36:3, PC 38:7, PC 38:6, PC 40:8, PC 40:7, PC 40:6, PC 40:9, and PC O-42:1), and triglycerides (TG 41:2, TG 49:4, and TG 52:3). Using partial least squares discriminant analysis models, MS showed that the lipidomic profile of endometriotic tissue (peritoneal endometriosis and ovarian endometriomas) was clearly separated from the eutopic endometrium, indicating tissue-type differentiation. CONCLUSION: Our results suggest that direct MS may play an important role for endometriotic tissue identification. Such an approach has potential usefulness for real-time tissue determination and differentiation during surgical treatment. Lipids of 3 important classes, sphingolipids, phospholipids, and the fatty acids (di- and triglycerides), were identified. Validation is required to determine whether these lipids can be used to discriminate between patients with endometriosis and those with other gynecologic diseases. PMID- 28888703 TI - Electrochemically assisted photocatalysis: Highly efficient treatment using thermal titanium oxides doped and non-doped electrodes for water disinfection. AB - Electrochemically assisted photocatalysis (by electronic drainage) is a highly promising method for disinfection of water. In this research, the efficiency of photolytic oxidation using UV-A radiation and electrochemically assisted photocatalysis (with electric potential of 1.5 V) was studied by using electrodes prepared by thermal treatment and doped with silver, for inactivation of Escherichia coli and Staphylococcus aureus. The Chick-Watson microorganism inactivation model was applied and the electrical energy consumption of the process was calculated. It was observed no significant inactivation of microorganisms when UV-A light or electric potential were applied separately. However, the electrochemically assisted photocatalytic process, with Ag-doped electrode completely inactivated the microbial population after 10 (E. coli) and 60 min (S. aureus). The best performing non-doped electrodes achieved 52.74% (E. coli) and 44.09% (S. aureus) inactivation rates after 60 min. Thus, electrochemically assisted photocatalytic activity was not only effective for the inactivation of microorganisms, but also notably low on electrical energy consumption during the treatment due to small current and low electric potential applied. PMID- 28888704 TI - Preparation of a novel resin with acyl and thiourea groups and its properties for Cu(II) removal from aqueous solution. AB - In this paper, a new resin (PIDTR) containing acyl and thiourea chelating groups was synthesized and its adsorption performances and mechanism to Cu(II) were investigated by adsorption tests, BET, SEM, FTIR and XPS analyses. Equilibrium data were fitted well with Langmuir model with the maximum adsorption capacity of 1.1608 mmol g-1 for Cu(II) at pH 5.0. The regeneration and reusability test showed that the adsorption capacities decreased from 0.917 mmol g-1 to 0.88 mmol g-1 after five cycles of adsorption and desorption. The thermodynamics showed that the adsorption process was spontaneous and endothermic. The adsorption dynamic demonstrated that two stages in the adsorption process: liquid film diffusion and chemical adsorption. The studies of SEM indicated that Cu(II) ions were adsorbed on the surface of PIDTR. FTIR and XPS analysis further proved that Cu(II) ions were chemisorbed on the surface of PIDTR by formation of CuN, CuO and CuS bonds with the breakage of NH, C=O and S=C bonds in PIDTR. PMID- 28888702 TI - Molecular Mechanisms Determining Lifespan in Short- and Long-Lived Species. AB - Aging is a global decline of physiological functions, leading to an increased susceptibility to diseases and ultimately death. Maximum lifespans differ up to 200-fold between mammalian species. Although considerable progress has been achieved in identifying conserved pathways that regulate individual lifespan within model organisms, whether the same pathways are responsible for the interspecies differences in longevity remains to be determined. Recent cross species studies have begun to identify pathways responsible for interspecies differences in lifespan. Here, we review the evidence supporting the role of anticancer mechanisms, DNA repair machinery, insulin/insulin-like growth factor 1 signaling, and proteostasis in defining species lifespans. Understanding the mechanisms responsible for the dramatic differences in lifespan between species will have a transformative effect on developing interventions to improve human health and longevity. PMID- 28888705 TI - Regulated expression of the lncRNA TERRA and its impact on telomere biology. AB - The telomere protects against genomic instability by minimizing the accelerated end resection of the genetic material, a phenomenon that results in severe chromosome instability that could favor the transformation of a cell by enabling the emergence of tumor-promoting mutations. Some mechanisms that avoid this fate, such as capping and loop formation, have been very well characterized; however, telomeric non-coding transcripts, such as long non-coding RNAs (lncRNAs), should also be considered in this context because they play roles in the organization of telomere dynamics, involving processes such as replication, degradation, extension, and heterochromatin stabilization. Although the mechanism through which the expression of telomeric transcripts regulates telomere dynamics is not yet clear, a non-coding RNA component opens the research options in telomere biology and the impact that it can have on telomere-associated diseases such as cancer. PMID- 28888706 TI - Molecular radiation biology/oncology and its impact on preclinical and clinical research in radiotherapy. PMID- 28888707 TI - The value of laparoscopy in the management of chronic groin pain. AB - BACKGROUND: Chronic groin pain problem represents a diagnostic and management challenge. This study is reporting all patients who underwent laparoscopic exploration of the groin and pelvis for undiagnosed chronic groin pain. MATERIALS AND METHODS: A retrospective cohort study. Evaluators were not involved in the operations. Laparoscopic exploration and mesh insertion using Trans-Abdominal Pre Preitoneal (TAPP) approach was performed for all patients. Follow up in the; clinic at 2 weeks and 6 months was arranged. This was a consecutive series of patients who were presented with chronic groin pain and no pre-operative radiological, orthopedic, gynecological or urologic abnormalities. Patients who were diagnosed with clinical hernia or other positive finding were excluded. RESULTS: Data were collected and analyzed for 92 patients. The operation had successfully managed the groin pain in 81 patients (88.04%), and the pain was improved in another 3 patients (3.26%). Six patients (6.52%) had no change in their symptoms, and worse pain was reported in two patient (2.17%). CONCLUSION: Laparoscopic groin exploration is an effective method to diagnose the chronic groin pain that under diagnosed by clinical, ultrasound and MRI tests. Laparoscopic management had resulted in resolution of the pain in the majority of the patients. The procedure is effective in athletes' patients who did not have clinical, radiological and laparoscopic evidence of groin hernia. PMID- 28888708 TI - Ureteric-urethral engraftment as a new surgical technique for management of incontinence in bladder exstrophy complex: A retrospective cohort. AB - OBJECTIVES: To report the results of a novel surgical technique for achieving urinary continence in patients with bladder exstrophy complex (BEC) by ureteric urethral engraftment (UUE) technique. PATIENTS AND METHODS: Sixteen female patients with BEC and a mean +/- SD age of 3.48 +/- 1.75 years were referred for primary exstrophy repair from 2009 to 2012. From these, 9 patients were operated by single-stage bladder closure (group I); while 7 patients underwent the novel technique of UUE to compare the continence achievement (group II). In UUE technique, distal ureter was applied for total urethral replacement while the lower part of engraft was fixed in external genitalia. No osteotomy was performed in none of the groups. Continence and upper urinary tract evaluation were performed in the follow-ups with 3 months intervals for the first year and biannually thereafter. The patients were followed-up for a mean +/- SD duration of 72 +/- 6 months. RESULTS: All patients in both groups experienced an uneventful postoperative period. In group II, 5 patients were continent day and night and voided per urethra without need for augmentation or intermittent catheterization technique (71.42%); while 55.55% of patients in group I achieved total continence (n = 5). Partial continence was achieved in 4 (44.44%) and 2 (28.57%) patients in group I and II, respectively. However, 3 patients in UUE group had postoperative vesicoureteral reflux that was successfully managed by Deflux injection. CONCLUSION: The eventual clinical outcomes of BEC children undergoing the UUE technique were promising. This practicable, safe, and reproducible option will add one complementary stage to the previously used reconstruction techniques. These patients would necessitate further surveillance with upper urinary tract evaluations during the adult life. PMID- 28888709 TI - Modelling and assessment of accidental oil release from damaged subsea pipelines. AB - This paper develops a 3D, transient, mathematical model to estimate the oil release rate and simulate the oil dispersion behavior. The Euler-Euler method is used to estimate the subsea oil release rate, while the Eulerian-Lagrangian method is employed to track the migration trajectory of oil droplets. This model accounts for the quantitative effect of backpressure and hole size on oil release rate, and the influence of oil release rate, oil density, current speed, water depth and leakage position on oil migration is also investigated in this paper. Eventually, the results, e.g. transient release rate of oil, the rise time of oil and dispersion distance are determined by above-mentioned model, and the oil release and dispersion behavior under different scenarios is revealed. Essentially, the assessment results could provide a useful guidance for detection of leakage positon and placement of oil containment boom. PMID- 28888710 TI - Fast assessment of bioaccessible metallic contamination in marine sediments. AB - A fast (16min) procedure to assess the bioaccessible metallic fraction of Cd, Cr, Cu, Ni, Pb and Zn simultaneously extracted (SEM) from marine sediments plus an indirect approach to determine acid volatile sulfides (AVS) are presented. For the extraction process magnetic agitation was compared with ultrasonic stirring (using a bath and a probe), and several stirring times were assayed. The proposed SEM procedure uses an ultrasonic probe and 1mL of HCl. It dramatically minimizes the turnaround time and the residues. AVS were evaluated as the difference between the amounts of sulphur in the solid residue after the extraction and total sulphur in the original sample. These procedures are fast, easy to implement and cost-effective to assess the potential risk posed by metals in marine sediments. They were tested using several CRMs and applied to sediments from two Galician Rias (NW Spain); their SEM-AVS differences indicated no biological risk. PMID- 28888711 TI - Fluorescence characteristics in the deep waters of South Gulf of Mexico. AB - Vertical profiles of deep-water fluorescence determined by the chlorophyll sensor, polycyclic aromatic hydrocarbons, biomarkers, and other miscellaneous parameters measured in the southern Gulf of Mexico are reported. In the course of the survey, unexpected deep fluorescences were recorded (>1100m depth) in half of the 40 stations studied, a novel finding in this area of the Gulf. Currently, the deep-water fluorescence phenomenon is not completely understood, however we observe linear correlation between the fluorescence intensity and chlorophyll alpha concentrations and coincidence of higher number of hydrocarbonoclastic bacteria in samples collected precisely in the deep-water fluorescence. This information is particularly interesting in relation to the Deepwater Horizon oil spill in 2010, in view that the aftermaths of the spill can be observed till today as oil plumes trapped in deep water layers that may disturb the natural water ecosystem. PMID- 28888712 TI - Simultaneous optimization of pH and binary organic composition by grid form modeling of the retention behavior in reversed-phase ultra high-performance liquid chromatography. AB - A novel computer-assisted methodology for the simultaneous optimization of aqueous pH and binary organic eluent composition through a broad range of analytical conditions of reversed-phase ultra high-performance liquid chromatography is proposed. Two of nonlinear prediction models were employed to fit into the retention time (tR) on a linear gradient elution with a predefined slope. One model was derived from Bernoulli-type probability distribution to predict the value of tR against the pH value of the aqueous eluent. This sigmoid shaped model was successfully fitted for tR value shift in the presence of three levels of organic eluent compositions (volumetric mixing of acetonitrile/methanol ratios 1:0, 1:1, and 0:1). The resultant pH versus tR value models were subsequently combined into grid form by quadratic multiple regression models based on the solubility parameter theory and their binary organic composition axes. The predicted tR values afforded from grid models were highly accurate for 13 different acidic non-steroidal anti-inflammatory drugs [root mean square error (RMSE) <=0.030] and 16 basic histamine H1-receptor blockers (RMSE <=0.067) in a pH ranging from 2.5 to 9.0 and an acetonitrile/methanol volumetric mixing ratio ranging from 1:0 to 0:1. Each compatibility score was defined as the indicator of the peak separation. Scores were calculated for all combinations of aqueous pH values and binary organic compositions via the predicted tR values. A colored map generated from the calculated scores was greatly effective in determining optimal combinations of both mobile phase conditions. By employing this predictive data, all analytes in both acidic and basic sample mixtures were finally separated at their respective optimized conditions. PMID- 28888713 TI - Simple and rapid LC-MS/MS method for the absolute determination of cetuximab in human serum using an immobilized trypsin. AB - Proteomic approaches using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) without an immunopurification technique have not been applied to the determination of serum cetuximab. This study developed a simple and rapid LC-MS/MS method for the absolute determination of cetuximab in human serum and applied it to clinical settings. Surrogate peptides derived from cetuximab digests were selected using a Fourier transform mass spectrometer. Reduced-alkylated serum cetuximab without immunopurification was digested for 20minutes using immobilized trypsin, and the digestion products were purified by solid-phase extraction. The LC-MS/MS was run in positive ion multiple reaction monitoring mode. This method was applied to the determination of serum samples in head and neck cancer patients treated with cetuximab. The chromatographic run time was 10minutes and no peaks interfering with surrogate peptides in serum digestion products were observed. The calibration curve of absolute cetuximab in serum was linear over the concentration range of 4-200MUg/mL. The lower limit of quantification of cetuximab in human serum was 4MUg/mL. The intra-assay and inter assay precision and accuracy were less than 13.2% and 88.0-100.7%, respectively. The serum concentration range of cetuximab was 19-140MUg/mL in patients. The serum cetuximab concentrations in LC-MS/MS were correlated with those in ELISA (r=0.899, P <0.01) and the mean bias was 1.5% in cancer patients. In conclusion, the present simple and rapid method with acceptable analytical performance can be helpful for evaluating the absolute concentration of serum cetuximab in clinical settings. PMID- 28888714 TI - The Diagnosis and Management of Bipolar I and II Disorders: Clinical Practice Update. AB - Bipolar disorders, including bipolar I disorder (BP-I) and bipolar II disorder (BP-II), are common, potentially disabling, and, in some cases, life-threatening conditions. Bipolar disorders are characterized by alternating episodes of mania or hypomania and depression, or mixtures of manic and depressive features. Bipolar disorders present many diagnostic and therapeutic challenges for busy clinicians. Adequate management of bipolar disorders requires pharmacotherapy and psychosocial interventions targeted to the specific phases of illness. Effective treatments are available for each illness phase, but mood episode relapses and incomplete responses to treatment are common, especially for the depressive phase. Mood symptoms, psychosocial functioning, and suicide risk must, therefore, be continually reevaluated, and, when necessary, the plan of care must be adjusted during long-term treatment. Many patients will require additional treatment of comorbid psychiatric and substance use disorders and management of a variety of commonly co-occurring chronic general medical conditions. PMID- 28888715 TI - Acute traumatic rupture of the patellar tendon in pediatric population: Case series and review of the literature. AB - BACKGROUND: Intact knee extensor mechanism is required for the normal function of the lower extremity. Patellar tendon rupture is a relatively rare injury with peak age incidence around 40 years and usually occurs midsubstance. The occurrence of pure patellar tendon rupture without bony avulsion is an extremely rare injury in the pediatric population with few cases reported in the literature with limited information regarding frequency, complications, and outcomes in children. However, due to increased participation in sports and high-energy recreational activities during childhood, the frequency of such injuries has progressively increased. OBJECTIVE: To evaluate the frequency of pediatric patellar tendon rupture injuries and describe the radiological findings, treatment modalities, and outcome of such injuries. METHODS: Demographic and clinical data on a series of patients who sustained patellar tendon rupture were reviewed. These data included age at time of injury, sex, laterality, mechanism of injury, associated injuries, complications, presence or absence of Osgood Schlatter disease, diagnostic imaging such as plain radiographs and magnetic resonance images (MRI), surgical technique, method of fixation, period of postoperative immobilization, total duration of physiotherapy, time to return to sports activities and follow-up duration. Insall-Salvati ratio was calculated on the preoperative lateral x-ray. The functional outcome was evaluated with regard to final knee active range of motion (AROM), manual quadriceps muscle testing, and presence or the absence of terminal extension lag. Clinical outcome rating using knee society score (KSS) was performed and functional outcome was further classified according to the calculated score. RESULTS: Five male patients with patellar tendon rupture (7%) were identified among 71 pediatric patients who sustained acute traumatic injury of the knee extensor mechanism. The mean age at the time of injury was 13.6 years (range: 12-15 years). The injury occurred in relation to sports activities in 4 patients. Osteogenesis imperfecta and Osgood Schlatter disease were identified in 2 patients. High riding patella is the hallmark diagnostic sign detected in plain x-ray with preoperative Insall-Salvati ratio ranged from 1.7 to 2.5. Three patients had pure soft tissue avulsion distally from the proximal tibia, 1 patient had pure soft tissue avulsion proximally from the inferior patellar pole, and 1 patient with midsubstance tendinous disruption. No associated intra-articular lesions were identified. Suture bridge double row technique, transpatellar suturing, and transosseous suturing through the proximal tibia were used for patellar tendon reinsertion. After a mean follow-up period of 18. 4 weeks (range: 10-30 weeks), patients achieved AROM ranging from 0 to 120 degrees to 0-137 degrees without terminal extension lag. The mean time to return to sports activity was 22 weeks (range: 13 30 weeks). Quadriceps muscle strength was 5/5 at the final follow-up visit in all patients; however, relative muscle atrophy was noted in comparison to the other side in one patient. The mean KSS was 91.8 points (range: 79-100 points) with excellent outcome in 4 patients and good outcome in 1 patient. CONCLUSION: Patellar tendon rupture is rare in the pediatric population and represents 7% of pediatric patients who sustained acute traumatic injury of the knee extensor mechanism. Ruptures may occur midsubstance, or from proximal or distal insertions. High riding patella is the hallmark diagnostic sign for such injury. Although rare, it is considered a serious injury that necessitates early diagnosis and surgical intervention. Functional range of motion was obtained in all patients with different modalities of treatment. PMID- 28888716 TI - Ideal angle of syndesmotic screw fixation: A CT-based cross-sectional image analysis study. AB - Without clear reference, the precision of syndesmotic screw placement cannot be guaranteed and malposition of these screws leads to poor results. Therefore, to prevent malpositioning of syndesmotic screws, an improved understanding of the orientation of tibiofibular syndesmosis is essential. We analyzed cross-sectional computed tomography (CT) scans of the foot and ankle to identify precise screw positions for the treatment of syndesmotic injuries. A total of 134 calcaneal fractures with intact tibiofibular syndesmosis were enrolled in this retrospective study. We measured the angle between the perpendicular line of the second proximal phalanx and the line start apex of the lateral cortex of the fibula bisecting the tibial incisura and crossing the center of the tibia in neutral ankle joints, with the second toe positioned anteriorly using a short leg splint. The second toe was used as the reference for clarity and applicability. The ideal angle of syndesmotic screw placement in cross-sectional CT images was 18.8+/-5.6 degrees (mean+/-standard deviation) and did not differ according to independent variables (P>0.05). In neutral ankle joints with the second toe positioned anteriorly, the ideal angle of syndesmotic screw placement is 18.8 degrees , which is less than that currently in used in conventional methods. PMID- 28888717 TI - Role of biomarkers in acute traumatic lung injury. AB - In severely injured patients severe thoracic trauma is common and can significantly influence the outcome of these critically ill patients by increased rates of mainly pulmonary complications. Furthermore, patients who sustained thoracic trauma are at increased risk for Acute Lung Injury (ALI) or Adult Respiratory Distress Syndrome (ARDS). Therapeutic options are limited, basically consisting of prophylactic antibiotic therapy and changing patient's positions. It is known, that ALI and ARDS differ clinically and pathobiologically from ALI/ARDS caused by other reasons, but the exact pathology remains elusive. Due to that no reliable predictive or surveillance biomarkers could be established for clinical diagnosis and identification of patients at high risk for acute traumatic lung injury. Nevertheless, there are plenty of promising markers that need to be further elucidated in larger case numbers and multicenter studies. This article sums up the recent status of those promising clinical biomarkers. PMID- 28888718 TI - The frail fail: Increased mortality and post-operative complications in orthopaedic trauma patients. AB - OBJECTIVE: The burgeoning elderly population calls for a robust tool to identify patients with increased risk of mortality and morbidity. This paper investigates the utility of the MFI as a predictor of morbidity and mortality in orthopaedic trauma patients. DESIGN: Retrospective review of the NSQIP database to identify patients age 60 and above who underwent surgery for pelvis and lower extremity fractures between 2005 and 2014. MAIN OUTCOMES AND MEASURES: For each patient, an MFI score was calculated using NSQIP variables. The relationship between the MFI score and 30-day mortality and morbidity was determined using chi-square analysis. MFI was compared to age, American Society of Anesthesiologists physical status classification, and wound classifications in multiple logistic regression. RESULTS: Study sample consisted of 36,424 patients with 27.8% male with an average age of 79.5 years (SD 9.3). MFI ranged from 0 to 0.82 with mean MFI of 0.12 (SD 0.09). Mortality increased from 2.7% to 13.2% and readmission increased from 5.5% to 18.8% with increasing MFI score. The rate of any complication increased from 30.1% to 38.6%. Length of hospital stay increased from 5.3days (+/ 5.5days) to 9.1days (+/-7.2days) between MFI score 0 and 0.45+. There was a stronger association between 30-day mortality and MFI (aOR for MFI 0.45+: 2.6, 95% CI: 1.7-3.9) compared to age (aOR for age: 1.1, 95% CI: 1.1-1.1) and ASA (aOR 2.5, 95% CI: 2.3-2.7). CONCLUSIONS AND RELEVANCE: MFI was a significant predictor of morbidity and mortality in orthopaedic trauma patients. The use of MFI can provide an individualized risk assessment tool that can be used by an interdisciplinary team for perioperative counseling and to improve outcomes. PMID- 28888719 TI - Insulin complexed with cyclodextrins stimulates epithelialization and neovascularization of skin wound healing in rats. AB - INTRODUCTION: Skin lesions are a significant public health problem, above all that wounds fail to heal properly and become chronic. Due to its reepithelization action, insulin has the potential to heal skin lesions, by stimulating the proliferation and migration of keratinocytes, angiogenic stimulus, and increasing collagen deposition. In the present study insulin was complexed with 2 hydroxypropyl-beta-cyclodextrin (HPbetaCD) and its wound healing effect and inclusion complex (HPbetaCD-I) were evaluated in excisional wounds in the skin of rats. MATERIAL AND METHODS: Three different gel based pharmaceutical forms were created: carbopol 940(r) base gel, an insulin gel comprising the base gel plus 50 IU of insulin and a gel complex comprising the base gel plus (HPbetaCD) complexed with insulin (HPbetaCD-I) were used to verify wound healing in vitro and in vivo assays. RESULTS: The wounds in the skin of rats were treated with gel containing HPbetaCD-I not cytoxically irritating and cytotoxic. Analysis of cell proliferation and measurement of the length and thickness of the epidermis showed that HPbetaCD-I prolonged the proliferation and migration of keratinocytes. Revascularization analysis of lesions treated with HPbetaCD-I compared to those treated with insulin found that angiogenic stimulus was less intense, but more constant and prolonged in the modified release process. There was increased deposition of type I and III collagen fibers in accordance with the treatment time. CONCLUSION: Therefore, the slow release of complexed insulin modulated the reepithelialization process by stimulating cell proliferation and migration of keratinocytes, favoring greater concentration of serum insulin, modulating inflammatory response, matrix remodeling and promoting neovascularization. Angiogenesis extended by the steady release of insulin can be effective in the treatment of chronic wounds. PMID- 28888720 TI - Aged chimpanzees exhibit pathologic hallmarks of Alzheimer's disease. AB - Alzheimer's disease (AD) is a uniquely human brain disorder characterized by the accumulation of amyloid-beta protein (Abeta) into extracellular plaques, neurofibrillary tangles (NFT) made from intracellular, abnormally phosphorylated tau, and selective neuronal loss. We analyzed a large group of aged chimpanzees (n = 20, age 37-62 years) for evidence of Abeta and tau lesions in brain regions affected by AD in humans. Abeta was observed in plaques and blood vessels, and tau lesions were found in the form of pretangles, NFT, and tau-immunoreactive neuritic clusters. Abeta deposition was higher in vessels than in plaques and correlated with increases in tau lesions, suggesting that amyloid build-up in the brain's microvasculature precedes plaque formation in chimpanzees. Age was correlated to greater volumes of Abeta plaques and vessels. Tangle pathology was observed in individuals that exhibited plaques and moderate or severe cerebral amyloid angiopathy, a condition in which amyloid accumulates in the brain's vasculature. Amyloid and tau pathology in aged chimpanzees suggests these AD lesions are not specific to the human brain. PMID- 28888721 TI - TMEM106B and ApoE polymorphisms in CHMP2B-mediated frontotemporal dementia (FTD 3). AB - Single-nucleotide polymorphisms in the TMEM106B gene have been identified as a risk factor in frontotemporal dementia (FTD). The major allele of SNP rs3173615 is a risk factor in sporadic FTD, whereas the minor allele seems protective in GRN- and C9orf72-mediated FTD. The role of apolipoprotein E (ApoE) in FTD is uncertain, though an established risk factor in Alzheimer's disease. In a unique Danish family, inherited FTD is caused by a mutation in the CHMP2B gene located on chromosome 3 (FTD-3). In this family, both risk factors TMEM106B and ApoE were analyzed and correlated to age at onset (AAO) and progression in terms of age at institutionalization (AAI) and age at death (AAD). Although TMEM106B and CHMP2B share cellular function in that both localize to endolysosomes, TMEM106B genotypes appeared to have no influence on the clinical disease course. ApoE epsilon4 was found to be a protective factor with later AAO and AAI, whereas epsilon2 seemed to aggravate the disease with earlier AAO and AAD. These results indicate ApoE epsilon2 as a risk factor in FTD-3 and suggest a protective role of epsilon4. PMID- 28888722 TI - Breast Cancer Risk After Radiation Therapy for Hodgkin Lymphoma: Influence of Gonadal Hormone Exposure. AB - BACKGROUND: Young women treated with chest radiation therapy (RT) for Hodgkin lymphoma (HL) experience a strongly increased risk of breast cancer (BC). It is unknown whether endogenous and exogenous gonadal hormones affect RT-associated BC risk. METHODS: We conducted a nested case-control study among female 5-year HL survivors treated before age 41. Hormone exposure and HL treatment data were collected through medical records and questionnaires for 174 BC case patients and 466 control patients. Radiation dose to breast tumor location was estimated based on RT charts, simulation films, and mammography reports. RESULTS: We observed a linear radiation dose-response curve with an adjusted excess odds ratio (EOR) of 6.1%/Gy (95% confidence interval [CI]: 2.1%-15.4%). Women with menopause <30 years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR, 0.13; 95% CI, 0.03-0.51) than did women with menopause >=50 years. BC risk increased by 6.4% per additional year of post-RT intact ovarian function (P<.001). Among women with early menopause (<45 years), hormone replacement therapy (HRT) use for >=2 years did not increase BC risk (OR, 0.86; 95% CI, 0.32 2.32), whereas this risk was nonsignificantly increased among women without early menopause (OR, 3.69; 95% CI, 0.97-14.0; P for interaction: .06). Stratification by duration of post-RT intact ovarian function or HRT use did not statistically significantly modify the radiation dose-response curve. CONCLUSIONS: BC risk in female HL survivors increases linearly with radiation dose. HRT does not appear to increase BC risk for HL survivors with therapy-induced early menopause. There are no indications that endogenous and exogenous gonadal hormones affect the radiation dose-response relationship. PMID- 28888723 TI - Isolated Biceps Reflection Pulley Tears Treated With Subpectoral Biceps Tenodesis: Minimum 2-Year Outcomes. AB - PURPOSE: To investigate if patients younger than 50 years old had improved functional outcomes after subpectoral biceps tenodesis (BT) for the treatment of biceps reflection pulley (BRP) lesions at minimum 2-year postoperative follow-up. METHODS: Patients who had arthroscopically confirmed BRP tears that were treated with subpectoral BT and were at least 2 years out from surgery were included; patients were excluded if they had concomitant reconstructive or reparative procedures at index surgery. Patient-centered outcomes including return to activity, American Shoulder and Elbow Surgeons (ASES), Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), and Short Form-12 Physical Component Summary (SF-12 PCS) scores, and patient satisfaction were collected. The pre- and postoperative scores were compared with a Wilcoxon test. Failure was defined as revision BT. RESULTS: Between January 2006 and July 2014, of 1,184 patients who underwent open subpectoral BT, 14 patients (6 male, 8 female) with mean age 37 (range, 16-49 years) met the inclusion criteria. Minimum 2-year outcomes data were available for all 14 patients (100% follow-up). The mean follow-up was 3.6 +/- 1.3 years. There were significant improvements postoperatively for all outcome scores (P = .017 ASES, P = .002 QuickDASH, P = .003 SF-12 PCS). There was no correlation between age and outcome scores (P > .05). Median patient satisfaction was 9 of 10. Five patients (36%) reported return to recreational activity with no modifications; 9 (64%) indicated a return to activity with modifications. The 5 patients who returned to recreational activity with no modification had significantly less time from initial injury/onset of symptoms until surgery in comparison with the 9 patients who modified their activity (P = .028). No complications or reoperations were reported. CONCLUSIONS: Patients younger than 50 years old with a symptomatic isolated BRP lesion experienced excellent results, high return to recreational activity, little postoperative pain, and high degrees of satisfaction when treated with subpectoral BT. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28888724 TI - [Stellate ganglion radiofrequency ablation in arrhythmic storm management]. PMID- 28888725 TI - [Impact of rotational coronary angiography in the amount of iodinated contrast and the exposure to ionising radiations in patients undergoing invasive coronary procedures: A systematic review and meta-analysis]. AB - BACKGROUND: Invasive coronary procedures involve the administration of iodinated contrast and the exposure to ionising radiations, increasing morbidity and mortality. The rotational coronary angiography (RCA) allows acquiring multiple projections with a unique injection of iodinated contrast. To date, there are no meta-analyses specifically comparing RCA and conventional coronary angiography (CCA) in patients undergoing invasive coronary procedures, whether diagnostic or diagnostic and therapeutic. The aim of this meta-analysis is to assess the impact of RCA on the amount of iodinated contrast and the exposure to ionising radiations during invasive coronary procedures. METHODS: A search in PubMed and Ovid databases was conducted to identify studies, including diagnostic and diagnostic and therapeutic studies, comparing RCA and CCA. The manuscripts were evaluated on quality and biases, and were included if they analysed any of the following endpoints: volume of contrast and exposure to ionising radiations measured as dose-area product, and Kerma-air or fluoroscopy time. RESULTS: Sixteen studies, with a total of 2,327 patients, were included in the final analysis (1,146 patients underwent RCA and 1,181 patients underwent CCA), with significant differences being detected in volume of contrast (standard difference in means [95% confidence interval] -1.887 [-2.472 to -1.302]; P<.001), dose-area product (-0.726 [-1.034 to -0.418]; P<.001), Kerma-air (-0.842 [-1.104 to 0.581]; P<.001), and fluoroscopy time (0.263 [-0.496 to -0.030]; P=.027). CONCLUSIONS: RCA reduces the volume of contrast and the exposure to radiation, evaluated as dose-area product, Kerma-air, and fluoroscopy time, in patients undergoing invasive coronary procedures. PMID- 28888726 TI - Complementary analyses of hollow cylindrical unioriented permanent magnet (HCM) with high permeability external layer. AB - In this article, several studies based on analytical expressions and computational simulations on Hollow Cylindrical Magnets with an external soft ferromagnetic material (HCM magnets) are presented. Electromagnetic configurations, as well as permanent-magnet-based structures, are studied in terms of magnetic field strength and homogeneity. Permanent-magnet-based structures are further analyzed in terms of the anisotropy of the magnetic permeability. It was found that the HCM magnets produce a highly homogeneous magnetic field as long as the magnetic material is isotropic. The dependency of the magnetic field strength and homogeneity in terms of the anisotropy of the magnetic permeability is also explored here. These magnets can potentially be used in medium-resolution NMR spectrometers and high-field NMR spectrometers. PMID- 28888727 TI - Genome-wide characterization of Toll-like receptor gene family in common carp (Cyprinus carpio) and their involvement in host immune response to Aeromonas hydrophila infection. AB - The Toll-like receptor (TLR) gene family is a class of conserved pattern recognition receptors, which play an essential role in innate immunity providing efficient defense against invading microbial pathogens. Although TLRs have been extensively characterized in both invertebrates and vertebrates, a comprehensive analysis of TLRs in common carp is lacking. In the present study, we have conducted the first genome-wide systematic analysis of common carp (Cyprinus carpio) TLR genes. A set of 27 common carp TLR genes were identified and characterized. Sequence similarity analysis, functional domain prediction and phylogenetic analysis supported their annotation and orthologies. By examining the gene copy number of TLR genes across several vertebrates, gene duplications and losses were observed. The expression patterns of TLR genes were examined during early developmental stages and in various healthy tissues, and the results showed that TLR genes were ubiquitously expressed, indicating a likely role in maintaining homeostasis. Moreover, the differential expression of TLRs was examined after Aeromons hydrophila infection, and showed that most TLR genes were induced, with diverse patterns. TLR1, TLR4-2, TLR4-3, TLR22-2, TLR22-3 were significantly up-regulated at minimum one timepoint, whereas TLR2-1, TLR4-1, TLR7 1 and TLR7-2 were significantly down-regulated. Our results suggested that TLR genes play critical roles in the common carp immune response. Collectively, our findings provide fundamental genomic resources for future studies on fish disease management and disease-resistance selective breeding strategy development. PMID- 28888728 TI - Can attentional bias modification inoculate people to withstand exposure to real world food cues? AB - Two experiments investigated whether attentional bias modification can inoculate people to withstand exposure to real-world appetitive food cues, namely television advertisements for chocolate products. Using a modified dot probe task, undergraduate women were trained to direct their attention toward (attend) or away from (avoid) chocolate pictures. Experiment 1 (N = 178) consisted of one training session; Experiment 2 (N = 161) included 5 weekly sessions. Following training, participants viewed television advertisements of chocolate or control products. They then took part in a so-called taste test as a measure of chocolate consumption. Attentional bias for chocolate was measured before training and after viewing the advertisements, and in Experiment 2 also at 24-h and 1-week follow-up. In Experiment 2, but not Experiment 1, participants in the avoid condition showed a significant reduction in attentional bias for chocolate, regardless of whether they had been exposed to advertisements for chocolate or control products. However, this inoculation effect on attentional bias did not generalise to chocolate intake. Future research involving more extensive attentional re-training may be needed to ascertain whether the inoculation effect on attentional bias can extend to consumption, and thus help people withstand exposure to real-world palatable food cues. PMID- 28888729 TI - Easy-going, rational, susceptible and struggling eaters: A segmentation study based on eating behaviour tendencies. AB - Eating behaviour tendencies, emotional eating (EE), uncontrolled eating (UE) and cognitive restraint (CR), are associated with various indicators of physical and mental health. Therefore, it is important to understand these tendencies in order to design interventions to improve health. Previous research has mostly examined eating behaviour tendencies individually, without considering typical combinations of these tendencies or their manifestation in well-being and food choices. This study aimed to understand the interactive occurrence of EE, UE and CR in two independent populations. Finnish (n = 1060) and German (n = 1070) samples were segmented on the basis of their responses to a modified Three-Factor Eating Questionnaire (TFEQ-R15). Well-being, coping strategies and food consumption habits of the segments were studied. Segmentation revealed four segments: "Susceptible", "Easy-going", "Rational" and "Struggling". These segments were similar in both countries with regard to well-being, coping strategies and food choices. EE and UE co-occurred, and these tendencies were mainly responsible for differentiating the segments. Members of the "Rational" and "Easy-going" segments, who had low scores for EE and UE, tended to experience vitality and positive emotions in life, and contentment with their eating. By contrast, the "Susceptible" and "Struggling" segments, with more pronounced tendencies towards EE and UE, experienced lower levels of vitality and less frequently positive emotions, applied less adaptive coping strategies and experienced more discontent with eating. The results of the current study suggest that it is possible to identify segments, with differing eating habits, coping strategies and well-being on the basis of the eating behaviour tendencies EE, UE and CR. We discuss possible viewpoints for the design of interventions and food products to help people towards psychologically and physiologically healthier eating styles. PMID- 28888730 TI - DNA methylation patterns at sweet taste transducing genes are associated with BMI and carbohydrate intake in an adult population. AB - Individual differences in taste perception may influence appetite, dietary intakes, and subsequently, disease risk. Correlations of DNA methylation patterns at taste transducing genes with BMI and dietary intakes were studied. A nutriepigenomic analysis within the Methyl Epigenome Network Association (MENA) project was conducted in 474 adults. DNA methylation in peripheral white blood cells was analyzed by a microarray approach. KEGG pathway analyses were performed concerning the characterization and discrimination of genes involved in the taste transduction pathway. Adjusted FDR values (p < 0.0001) were used to select those CpGs that showed best correlation with BMI. A total of 29 CpGs at taste transducing genes met the FDR criteria. However, only 12 CpGs remained statistically significant after linear regression analyses adjusted for age and sex. These included cg15743657 (TAS1R2), cg02743674 (TRPM5), cg01790523 (SCN9A), cg15947487 (CALHM1), cg11658986 (ADCY6), cg04149773 (ADCY6), cg02841941 (P2RY1), cg02315111 (P2RX2), cg08273233 (HTR1E), cg14523238 (GABBR2), cg12315353 (GABBR1) and cg05579652 (CACNA1C). Interestingly, most of them were implicated in the sweet taste signaling pathway, except CACNA1C (sour taste). In addition, TAS1R2 methylation at cg15743657 was strongly correlated with total energy (p < 0.0001) and carbohydrate intakes (p < 0.0001). This study suggests that methylation in genes related to sweet taste could be an epigenetic mechanism associated with obesity. PMID- 28888731 TI - Mechanism for detecting NAPL using electrical resistivity imaging. AB - The detection of non-aqueous phase liquid (NAPL) related impacts in freshwater environments by electrical resistivity imaging (ERI) has been clearly demonstrated in field conditions, but the mechanism generating the resistive signature is poorly understood. An electrical barrier mechanism which allows for detecting NAPLs with ERI is tested by developing a theoretical basis for the mechanism, testing the mechanism in a two-dimensional sand tank with ERI, and performing forward modeling of the laboratory experiment. The NAPL barrier theory assumes at low bulk soil NAPL concentrations, thin saturated NAPL barriers can block pore throats and generate a detectable electrically resistive signal. The sand tank experiment utilized a photographic technique to quantify petroleum saturation, and to help determine whether ERI can detect and quantify NAPL across the water table. This experiment demonstrates electrical imaging methods can detect small quantities of NAPL of sufficient thickness in formations. The bulk volume of NAPL is not the controlling variable for the amount of resistivity signal generated. The resistivity signal is primarily due to a zone of high resistivity separate phase liquid blocking current flow through the fully NAPL saturated pores spaces. For the conditions in this tank experiment, NAPL thicknesses of 3.3cm and higher in the formation was the threshold for detectable changes in resistivity of 3% and greater. The maximum change in resistivity due to the presence of NAPL was an increase of 37%. Forward resistivity models of the experiment confirm the barrier mechanism theory for the tank experiment. PMID- 28888732 TI - Are all phytochemicals useful in the preventing of DNA damage? AB - Phytochemicals derived from natural plants have been used commonly for the prevention and/or treatment of different diseases due to the belief of their safety. Many plant species synthesize toxic chemicals. New natural chemicals are being discovered but their toxic effects are unknown. Phytochemicals have been regarded as possible antioxidants. But on the other hand it is suggested that various phenolic antioxidants can display pro-oxidant properties at high doses. In this review, the role of some phytochemicals (epigallocathecin gallate, carvacrol, galangin, limonene, lycopene, naringin, puerarin, terpinene, thymol and ursolic acid) on the prevention of DNA damage will be discussed. PMID- 28888733 TI - Exposure risk assessment to ochratoxin A through consumption of juice and wine considering the effect of steam extraction time and vinification stages. AB - The goals of this study were (i) to verify the effect of steam extraction used in juice production and the stages of vinification on the ochratoxin A (OTA) levels found in grapes naturally contaminated, and (ii) evaluate the risk of exposure to this toxin when the daily consumption of juice and wine is followed to prevent cardiovascular disease. OTA-producing fungi were isolated from Cabernet Sauvignon, Moscato Italico and Concord grapes harvested from the same vineyard and intended to produce red wine, white wine and juice, respectively. The highest levels of this toxin were found in the Concord grapes used for juice production. Although greater reduction in OTA levels occurred during juice production (73%) compared to winemaking (66 and 44%, for red and white, respectively), the estimated OTA exposure through juice was higher than the tolerable intake established for this toxin by JECFA. The risk associated with juice consumption, rather than wine, can be explained by (i) higher OTA levels found in Concord must than those of Cabernet and Moscato, indicating that Concord grapes appear to be more susceptible to OTA production by toxigenic fungi; and (ii) the daily recommended juice consumption is higher than those proposed to red wine. PMID- 28888734 TI - Influence of the container on the consumption of cosmetic products. AB - The container, also known as primary package or inner package, could be defined as the packaging designed to come into direct contact with the cosmetic product. To author's knowledge, no study was available regarding the effect of the primary package on the consumption of cosmetic products. The aim of the study was to assess the impact of the container on the consumption of three cosmetic products widely used, i.e. shampoo, shower gel and emollient cream. The three products were contained in a tube with a flip top cap and in a bottle with a pump. The study was conducted on 221 French adults: 108 women and 113 men. Results showed that the consumption of each cosmetic product was slightly higher when the product was packaged in tube with a flip top cap than in bottle with a pump. The difference of consumption could vary from 5 % to 23 % when calculated with mean values. This information could be interesting for safety evaluators, safety agencies and commercial services of cosmetic manufacturers. PMID- 28888735 TI - UPLC-MS/MS analysis of ochratoxin A metabolites produced by Caco-2 and HepG2 cells in a co-culture system. AB - Ochatoxin A (OTA) is one of the most important mycotoxins based on its toxicity. The oral route is the main gateway of entry of OTA into the human body, and specialized epithelial cells constitute the first barrier. The present study investigated the in vitro cytotoxic effect of OTA (5, 15 and 45 MUM) and production of OTA metabolities in Caco-2 and HepG2 cells using a co-culture Transwell System to mimic the passage through the intestinal epithelium and hepatic metabolism. The results derived from MTS cell viability assays and transepithelial electrical resistance measurements showed that OTA was slightly cytotoxic at the lowest concentration at 3 h, but significant toxicity was observed at all concentrations at 24 h. OTA metabolites generated in this co culture were ochratoxin B (OTB), OTA methyl ester, OTA ethyl ester and the OTA glutathione conjugate (OTA-GSH). OTA methyl ester was the major metabolite found in both Caco-2 and HepG2 cells after all treatments. Our results showed that OTA can cause cell damage through several mechanisms and that the OTA exposure time is more important that the dosage in in vitro studies. OTA methyl ester is proposed as an OTA exposure biomarker, although future studies should be conducted. PMID- 28888736 TI - Distinct urinary metabolite profiles of two pharmacologically active N methylanthranilates: Three approaches to xenobiotic metabolite identification. AB - Two volatile alkaloids, isopropyl N-methylanthranilate (IMA) and methyl N methylanthranilate (MMA), present in the human diet and cosmetic products, were recently demonstrated to possess important pharmacological activities. While MMA is considered to be phototoxic, there is scarce data on the toxicity of IMA. Herein, we analyzed urinary metabolites of IMA and MMA in rats (200 mg kg-1, i.p., 7 days) by combining three different approaches: 1) preparative chromatography, 2) synthesis, and 3) SPR. The preparative approach, Sephadex LH 20 chromatography of the extract of urine samples of IMA treated animals, in conjunction with NMR, enabled the identification of 16 different anthranilate derivatives, among which products of aromatic core hydroxylation (isopropyl 5 hydroxy-N-methylanthranilate, isopropyl 5-hydroxyantranilate, isopropyl 3 hydroxyantranilate) were the major ones. The first application of the synthetic/combinatorial approach led to a successful identification of MMA metabolites, where 2-(methylamino)benzamide and N-methylanthranilic acid were the principal ones, among 14 others. Generally, MMA and IMA undergo analogous biotransformation pathways; however, MMA predominantly underwent chemical conversions of the ester group, i.e. transformation into derivatives of anthranilamide and anthranilic acid, while the major metabolic pathway of IMA was hydroxylation of the aromatic core. Additionally, pathohistological examinations revealed no signs of liver toxicity, or other signs of toxicity. PMID- 28888737 TI - Epigenetic toxicity of environmental chemicals upon exposure during development - Bisphenol A and valproic acid may have epigenetic effects. AB - As of 2017, chemical substances registered in Chemical Abstracts Service (CAS) exceed 100 million, which is increasing yearly. The safety of chemical substances is adequately managed by regulations based on scientific information from toxicity tests. However, there are substances reported to have "biological effects" even though they are judged to be nontoxic in conventional toxicity tests. Therefore, it is necessary to consider a new concept on toxicity, "epigenetic toxicity". In this review, we explain about epigenetic toxicity using bisphenol A (BPA) and valproic acid (VPA) as examples. We also discuss the problems associated with the judgment of epigenetic toxicity. Currently, epigenetic changes can only be detected by biochemical methods, which are labor intensive. Therefore, we are developing reporter mice that can be used to detect epigenetic toxicity during conventional toxicity tests. In addition, we consider that linking epigenomic changes with phenotypic changes is important, because causality is important for toxicity evaluation. Therefore, we are developing an artificial epigenome-editing technology. If we can develop a safety-assessment system by incorporating epigenetic evaluation into toxicity tests, we can increase the safety of both food and environmental chemical substances. The practical application of such a new safety-assessment system will be increasingly important in the future. PMID- 28888738 TI - Three-dimensional analysis of accuracy of patient-matched instrumentation in total knee arthroplasty: Evaluation of intraoperative techniques and postoperative alignment. AB - BACKGROUND: It is questionable that the accuracies of patient-matched instrumentation (PMI) have been controversial, even though many surgeons follow manufacturers' recommendations. The purpose of this study was to evaluate the accuracy of intraoperative procedures and the postoperative alignment of the femoral side using PMI with 3-dimensional (3D) analysis. METHODS: Eighteen knees that underwent total knee arthroplasty using MRI-based PMI were assessed. Intraoperative alignment and bone resection errors of the femoral side were evaluated with a CT-based navigation system. A conventional adjustable guide was used to compare cartilage data with that derived by PMI intraoperatively. Postoperative alignment was assessed using a 3D coordinate system with a computer assisted design software. We also measured the postoperative alignments using conventional alignment guides with the 3D evaluation. RESULTS: Intraoperative coronal alignment with PMI was 90.9 degrees +/- 1.6 degrees . Seventeen knees (94.4%) were within 3 degrees of the optimal alignment. Intraoperative rotational alignment of the femoral guide position of PMI was 0.2 degrees +/- 1.6 degrees compared with the adjustable guide, with 17 knees (94.4%) differing by 3 degrees or less between the two methods. Maximum differences in coronal and rotation alignment before and after bone cutting were 2.0 degrees and 2.8 degrees , respectively. Postoperative coronal and rotational alignments were 89.4 degrees +/- 1.8 degrees and -1.1 degrees +/- 1.3 degrees , respectively. In both alignments, 94.4% of cases were within 3 degrees of the optimal value. The PMI group had less outliers than conventional group in rotational alignment (p = 0.018). CONCLUSIONS: Our 3D analysis provided evidence that PMI system resulted in reasonably satisfactory alignments both intraoperatively and postoperatively. Surgeons should be aware that certain surgical techniques including bone cutting, and the associated errors may affect postoperative alignment despite accurate PMI positioning. PMID- 28888739 TI - Impingement between medial plica against femoral condyle osteophyte after high tibial osteotomy. PMID- 28888740 TI - Can the hip joint center be estimated from pelvic dimensions in dysplastic hips? AB - BACKGROUND: We aimed to determine correlations between the hip joint center position and pelvic dimensions and whether the three-dimensional position of the original hip joint center could be estimated from pelvic landmarks in dysplastic and normal hips. METHODS: We reviewed the pelvic CT scans of 70 patients (70 hips) with hip dysplasia. Seventy-seven normal hips were used as controls. The hip joint center coordinates (Cx, Cy, and Cz) and pelvic dimensions were measured with reference to the anterior pelvic plane coordinate system. Multiple regression formulas were used to estimate the original hip joint center. RESULTS: The hip center for both dysplastic and normal hip was highly correlated with the distance between the anterior superior iliac spine (ASIS) in the coronal plane (r = 0.76 and 0.84), the distance from the ASIS to the pubic tubercle in the sagittal plane (r = 0.81 and 0.76), and distance from the pubic tubercle to the most posterior point of the ischium on the transverse plane (r = 0.76 and 0.78). The hip joint center could be estimated within a 5-mm error for more than 80% of hips on their respective axes in both dysplastic and normal hips. CONCLUSIONS: The three-dimensional position of the original hip joint center was correlated with pelvic dimensions, and can be estimated with substantial accuracy using pelvic landmarks as references. Although these results are preliminary, this estimation method may be useful for surgeons planning total hip arthroplasties. PMID- 28888741 TI - Magnetic Resonance Signal Abnormalities Within the Pericruciate Fat Pad: A Possible Secondary Sign for Acute Anterior Cruciate Ligament Tears. AB - PURPOSE: The study sought to investigate the presence of magnetic resonance (MR) signal alterations within the pericruciate fat pad in patients with an acute anterior cruciate ligament (ACL) tear as well as evaluate its diagnostic value in comparison with the main secondary signs of ACL tears. METHODS: Two musculoskeletal radiologists retrospectively reviewed knee MR examinations performed from May to October 2015. The ACL was considered as torn or intact based on either previous arthroscopic findings or unequivocal MR imaging interpretation if arthroscopic correlation was unavailable. Abnormalities of the pericruciate fat pad were evaluated as increased signal on the fluid-sensitive sequences; the main secondary signs of ACL tears were identified. Sensitivity and specificity were calculated for each sign. RESULTS: A total of 182 patients entered this study: 22 with an acute ACL tear, 160 with intact ACL. Signal hyperintensity of the pericruciate fat pad was demonstrated in all patients with an acutely torn ACL, resulting significantly different between individuals with intact ACL and those with ligament tear (P < .0001). This sign was much more sensitive (100%) but less specific (72.5%-75%) than other secondary signs. CONCLUSIONS: Signal hyperintensity of the pericruciate fat pad on the fluid sensitive sequences is associated with acute ACL tears and could be considered as a possible indicator of these injuries. PMID- 28888742 TI - Brain Diffusion Changes in Polycystic Ovary Syndrome. PMID- 28888743 TI - HTLV-1-infected thymic epithelial cells convey the virus to CD4+ T lymphocytes. AB - The human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4+T cells are the main target of HTLV-1, but other cell types are known to be infected, including immature lymphocytes. Developing T cells undergo differentiation in the thymus, through migration and interaction with the thymic microenvironment, in particular with thymic epithelial cells (TEC) the major component of this three dimensional meshwork of non-lymphoid cells. Herein, we show that TEC express the receptors for HTLV-1 and can be infected by this virus through cell-cell contact and by cell-free virus suspensions. The expression of anti-apoptosis, chemokine and adhesion molecules genes are altered in HTLV-1-infected TEC, although gene expression of antigen presentation molecules remained unchanged. Furthermore, HTLV-1-infected TEC transmitted the virus to a CD4+ T cell line and to CD4+ T cells from healthy donors, during in vitro cellular co-cultures. Altogether, our data point to the possibility that the human thymic epithelial cells play a role in the establishment and progression of HTLV-1 infection, functioning as a reservoir and transmitting the virus to maturing CD4+ T lymphocytes, which in turn will cause disease in the periphery. PMID- 28888744 TI - [Stereotactic body radiotherapy for liver tumors: State of the art]. AB - Thanks to the improvement in radiotherapy physics, biology, computing and imaging, patients presenting with liver tumors can be efficiently treated by radiation. Radiotherapy has been included in liver tumors treatment guidelines at all disease stages. Liver stereotactic radiotherapy has to be preferred to standard fractionated radiotherapy whenever possible, as potentially more efficient because of higher biological equivalent dose. Liver stereotactic radiotherapy planning and delivery require extensive experience and optimal treatment quality at every step, thus limiting its availability to specialized centres. Multicentre studies are difficult to develop due to a large technical heterogeneity. Respiratory management, image guidance and immobilization are considerations as important as machine type. The use of multimodal planning imaging is compulsory to achieve expected contouring quality. Treatment efficacy is difficult to assess following liver stereotactic radiotherapy, but local control is high and toxicity unusual. As a consequence, liver stereotactic radiotherapy is part of multimodal and multidisciplinary management of liver tumors. PMID- 28888745 TI - [Repair and time-dose factor: The example of spinal cord irradiation]. AB - The question whether a reirradiation is possible, with either curative of palliative intent, is a frequent issue and a true therapeutic challenge, in particular for a critical organ sensitive to cumulative dose, such as the spinal cord. Preclinical experimental data, based on debatable models that are hardly transferable to patients, suggest that there is a possibility of reirradiation, beyond the classical threshold for dose constraints, taking into account the "time-dose factor". Although the underlying biological mechanisms are however uncertain, scarce clinical data seem to confirm that the tolerance of spinal cord to reirradiation does exist, provided that a particular attention to total dose is given. In the context where modern stereotactic irradiation facilities expand therapeutic perspectives, we review the literature on possibilities of reirradiation, through the example of spinal cord reirradiation. PMID- 28888746 TI - [Toxicity and quality of life comparison of iodine 125 brachytherapy and stereotactic radiotherapy for prostate cancers]. AB - Quality of life is a major issue for good prognostic prostate cancer, for which brachytherapy is one of the reference treatments. Stereotactic Body Radiotherapy (SBRT) is a recent alternative however not yet validated as a standard treatment. This review of the literature reports and compares the toxicities and the quality of life, either after exclusive brachytherapy with iodine 125 or after SBRT. The comparison is made with the limitations of the absence of randomized trial comparing the two treatment techniques. Acute toxicity appears to be lower after SBRT compared to brachytherapy (from 10 to 40 % versus 30 to 40 %, respectively). Conversely, acute and late gastrointestinal toxicity (from 0 to 21 % and from 0 to 10 % of grade 2, respectively) appears more frequent with SBRT. Late urinary toxicity seems identical between both techniques (from 20 to 30 % of grade 2), with a possible urinary flare syndrome. Both treatments have an impact on erectile dysfunction, although it is not possible to conclude that a technique is superior because of the limited data on SBRT. SBRT has better bowel and urinary (irritation or obstruction) quality of life scores than brachytherapy; while sexual and urinary incontinence remain the same. The absence of randomized trial comparing SBRT with brachytherapy for prostate cancers does not allow to conclude on the superiority of one technique over another, thus justifying a phase III medicoeconomic evaluation. PMID- 28888747 TI - Corrigendum to "Reducing implant loss rates in immediate breast reconstructions" [The Breast 31 (2017) 208-213]. PMID- 28888748 TI - Editorial commentary: Modulation of the QT interval by gender and age. PMID- 28888749 TI - Complete Penile Disassembly for Repair of Epispadias Causes Erectile Tissue Alteration Through Transforming Growth Factor Beta 1 Overexpression in a Rabbit Model. AB - OBJECTIVE: To investigate corporal tissue viability and changes in endothelial content following current techniques used for epispadias repair in an animal model. MATERIALS AND METHODS: Sixty rabbits were allocated into 3 groups: sham operation (penile degloving), complete disassembly model, and Cantwell-Ransley model. On weeks 2, 4, 12, and 24 postoperation, the penile tissue was harvested and processed for (1) Masson's trichrome staining for smooth muscle cell (SMC)-to collagen ratios, (2) immunohistochemical staining for endothelial factor (CD31), and transforming growth factor beta 1 (TGF-beta1) (3) terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick-end labeling (TUNEL) assay to detect apoptosis. RESULTS: Masson trichrome staining of corporal tissue showed significant decrease in SMC-to-collagen ratio in complete disassembly group compared with sham operation group. The expression of CD31 was significantly lower (P <.05) in complete disassembly group compared with the other groups at all time points, whereas no significant difference was observed between the Cantwell-Ransley group and the sham operation group. Moreover, apoptotic index was markedly higher in the complete disassembly group compared with the 2 other operation groups (P <.05). Immunohistochemistry also showed a significantly higher expression of TGF-beta1 in the penile tissue after complete disassembly than Cantwell-Ransley or sham operation. CONCLUSION: Complete detachment of the urethra from the corpus cavernosa may result in endothelial dysfunction, alteration of SMC content of erectile tissue, and replacement of the native cavernosal tissue with fibrotic tissue. An increased expression of TGF beta1, following the complete disassembly technique, might be one of the important factors causing the abovementioned alterations. PMID- 28888750 TI - Primary Mediastinal Pure Seminomatous Germ Cell Tumor (Germinoma) as a Rare Cause of Precocious Puberty in a 9-Year-Old Patient. AB - Less than 5%-7% of germ cell tumors are extragonadal, with the central nervous system being the most common location in children, followed by retroperitoneum and mediastinum. Only 10% of mediastinal tumors are malignant and one-third of these are pure seminomas (germinomas). We report the case of a 9-year-old boy with development of secondary sexual characteristics. Beta-human chorionic gonadotropin was elevated and a mediastinal mass was found. Final histology showed a pure seminomatous germ cell tumor. To our knowledge, this is the first report of a boy with precocious puberty secondary to a mediastinal germinoma. PMID- 28888751 TI - Female Outlet Obstruction After Anti-incontinence Surgery. AB - Numerous surgical options are available for the management of stress urinary incontinence in women, including urethral bulking agents, pubovaginal slings, retropubic bladder neck suspensions, midurethral slings, and even artificial urinary sphincters. We discuss the incidence, etiology, diagnosis, evaluation, and management of bladder outlet obstruction after anti-incontinence surgery in women. This problem presents with a wide range of symptoms. Urodynamic evaluation is not always diagnostic but can be helpful. Management options range from conservative to invasive. The optimal timeline for intervention is still not well defined, but general guiding principles of management are presented and a comprehensive review of current literature is presented. PMID- 28888752 TI - Incidence of Clinically Significant Prostate Cancer After a Diagnosis of Atypical Small Acinar Proliferation, High-grade Prostatic Intraepithelial Neoplasia, or Benign Tissue. AB - OBJECTIVE: To assess the incidence of clinically significant and insignificant prostate cancer after an initial biopsy that revealed either atypical small acinar proliferation (ASAP), high-grade prostatic intraepithelial neoplasia (HGPIN), or benign tissue. MATERIALS AND METHODS: We retrospectively identified patients diagnosed with ASAP, HGPIN, or benign tissue who had a repeat prostate biopsy within 1 year of diagnosis during 1987-2015. We compared the incidence of any prostate cancer and clinically significant prostate cancer (based on Gleason score, prostate-specific antigen (PSA), number of positive cores, and core volume) for each diagnostic group. RESULTS: A total of 17,016 biopsies were performed in 12,817 patients during 1987-2015. Among the 615 patients who had a repeat biopsy within 1 year of their first, 261 (42.4%), 208 (33.8%), and 146 (23.8%) had ASAP, HGPIN, or benign tissue on the initial biopsy, respectively. The second biopsy demonstrated significant differences in prostate cancer detection rates between these 3 groups (34.1%, 20.2%, and 15.8%, respectively; P <.001), with cancer detected significantly more often in the ASAP group relative to other groups (P <.001 vs benign and P = .001 vs HGPIN). The rates of clinically significant prostate cancer did not differ between groups (8.0%, 6.7%, and 4.1%, respectively, P = .31). CONCLUSION: On repeat biopsy, rates of clinically significant prostate cancer did not differ between patients initially diagnosed with ASAP, HGPIN, or benign tissue. Elevated rates of prostate cancer after a diagnosis of ASAP appear to be largely due to differences in the rate of clinically insignificant disease. PMID- 28888753 TI - The Role of Gut Microbiome in the Pathogenesis of Prostate Cancer: A Prospective, Pilot Study. AB - OBJECTIVE: To elucidate potential biomarkers or mechanistic principles involved with the gut microbiota and its impact on prostate cancer pathogenesis. MATERIALS AND METHODS: We performed a prospective case-control pilot study evaluating the gut microbiome of 20 men with either benign prostatic conditions (n = 8) or intermediate or high risk clinically localized prostate cancer (Gleason >=4 + 3 cN0M0) (n = 12) undergoing care at tertiary referral center from September 1, 2015 to March 1, 2016. Key exclusion criteria included recent antibiotic use, significant gastrointestinal disorders, hormonal or systemic therapy for prostate cancer. Computational genomics analysis was performed on collected stool samples using MetaPhlAn2 and HUMAnN2 platforms. Linear discriminant analysis effect size method was used to support high-dimensional class comparisons to find biologically relevant features. Kruskal-Wallis sum-rank test was used to detect features with significant differential abundance with respect to class, with biological consistency investigated using a set of pairwise tests among subclasses using the Wilcoxon rank-sum test, both to an alpha <=0.05. RESULTS: Higher relative abundance of Bacteriodes massiliensis was seen in prostate cancer cases compared to controls. Faecalibacterium prausnitzii and Eubacterium rectalie had higher relative abundance among controls. Biologically significant differences were also found in relative gene, pathway, and enzyme abundance. CONCLUSION: Biologically significant differences exist in the gut microbial composition of men with prostate cancer compared to benign controls. These differences may play a role in the pathobiology of prostate cancer, and warrant further exploration. PMID- 28888754 TI - Effect of antioxidant supplementation on the auditory threshold in sensorineural hearing loss: a meta-analysis. AB - INTRODUCTION: Hearing loss is conceptualized as any impairment of the ability to hear and/or detect speech or environment sounds, regardless of cause, type, or degree. It may occur at different stages of life; during pregnancy or childbirth, in childhood, adulthood or old age. It should be noted that aging is the most common cause of sensorineural hearing loss followed by noise-induced hearing loss, and both are closely related to the formation of reactive oxygen species. Dietary antioxidant supplementation has been employed as a therapeutic strategy to prevent and/or delay the risks of major human diseases. OBJECTIVE: To assess randomized clinical trials to determine the effect of antioxidant supplementation on the auditory thresholds in patients of different age groups with sensorineural hearing loss. METHODS: This systematic review consisted of a search in the following databases: MEDLINE, CENTRAL, ScienceDirect, Scopus, Web of Science, LILACS, SciELO and ClinicalTrials.gov. Additionally, the gray literature was also searched. The search strategy included terms related to the intervention (antioxidant supplementation), primary outcome (sensorineural hearing loss), as well as terms related to randomized clinical trials to improve search sensitivity. RESULTS: Based on 977 potentially relevant records identified through the search in the databases, ten full-text publications were retrieved for further evaluation. The increase in threshold at the 4kHz frequency was statistically higher in the control group (1.89 [1.01-2.78], p<0.0001) when compared to the NAC group and the ginseng group, whereas at 6kHz, the threshold increase was higher in the control group (1.42 [-1.14-3.97], p=0.28), but no statistically significant differences were found between groups. CONCLUSION: Ginseng was the antioxidant agent that showed the best effect in preventing auditory threshold worsening at the frequency of 4kHz, but not at 6kHz in patients with sensorineural hearing loss caused by exposure to high sound pressure levels. There was no improvement in the thresholds with vitamin E supplementation. PMID- 28888755 TI - An atmospheric pressure chemical ionisation liquid chromatographic-tandem mass spectrometry method for the analysis of benzodiazepines in urine. AB - The objective of this work was to establish an analytical method for the analysis of 7 Benzodiazepines (diazepam, oxazepam, temazepam, nordiazepam, desalkylflurazepam, alprazolam and alpha-hydroxyalprazolam) in urine specimens taken from drivers suspected of driving under the influence of drugs. The specimen, calibrator and control preparation involved hydrolysis of conjugated benzodiazepines using beta-glucuronidase in sodium acetate buffer, with incubation at 60 degrees C for 2h. Specimens were then centrifuged, before being diluted 1 in 5 (total dilution 1 in 10), with 10% acetonitrile in water. Specimens were analysed using a Shimadzu Prominence UPLC coupled to an AB Sciex 4000 QTrap LC-MS-MS. The chromatographic column was a Shim-pack XR ODS 2.2MUm. 3.0*50mm column and the mobile phase was a binary gradient system comprising of mobile phase A which was an ammonium formate/formic acid buffer dissolved in water and mobile phase B which was an ammonium formate/formic acid buffer dissolved in Acetonitrile. APCI was selected as the ionisation technique and the MS was operated in MRM mode, monitoring 2 transitions per analyte. The validation of the method is described. The method was found to be linear, accurate and precise (within day and between day) for diazepam, oxazepam, temazepam, nordiazepam, desalkylflurazepam, alprazolam and alpha-hydroxyalprazolam. The results of 480 cases are reviewed and show that alprazolam use was found in 35% of cases. Use of benzodiazepines resulting in oxazepam, nordiazepam or temazepam were found ca. 70% of cases analysed. PMID- 28888756 TI - Renoprotective effect of the xanthine oxidoreductase inhibitor Topiroxostat under decreased angiotensin II type 1a receptor expression. AB - The aim of this study was to confirm the renoprotective effect of xanthine oxidoreductase (XOR) inhibitor, topiroxostat, compared with another XOR inhibitor, febuxostat, under decreased angiotensin II type 1a (AT1a) receptor expression in the model of renal injury caused by adenine. To evaluate the degree of tubular damage using urinary liver-type fatty acid-binding protein (L-FABP) under decreased AT1a expression, we used AT1a receptor knockdown hetero and human L-FABP chromosomal transgenic (Tg) mice (AT1a+/-L-FABP+/-). Male AT1a+/-L-FABP+/- mice were divided into two groups: the adenine diet group (n = 40) was given a diet containing only 0.2% w/w adenine, and the normal diet group (n = 5) was given a normal diet. When renal dysfunction was confirmed in the adenine diet group 4 weeks after starting the diet, the adenine diet group was further divided into five groups. The adenine diet group (n = 8) was continuously given only the adenine diet. Each group receiving high-dose (3mg/kg) or low-dose (1mg/kg) topiroxostat (Topiroxostat-H group, n = 8, Topiroxostat-L group, n = 8) or febuxostat (Febuxostat-H group, n = 8, Febuxostat-L group, n = 8) was given the adenine diet including the drug for another 4 weeks. The levels of renal XOR, renal dysfunction, urinary L-FABP, tubulointerstitial damage, hypoxia, and oxidative stress were decreased or attenuated after treatment with topiroxostat or febuxostat compared with the adenine diet group. Furthermore, antioxidant capacity was maintained owing to these treatments. In conclusion, topiroxostat and febuxostat attenuated renal damage under decreased AT1a expression in the adenine-induced renal injury model. PMID- 28888757 TI - Single-step purification of recombinant Gaussia luciferase from serum-containing culture medium of mammalian cells. AB - A dihydrofolate reductase-deficient Chinese hamster ovary (CHO-K1/dhfr-) cell line stably expressing Gaussia luciferase with a histidine-tag sequence at the carboxyl terminus (GLase-His) was established. Recombinant GLase-His was purified from serum-containing culture medium by single-step Ni-chelate column chromatography in the presence of 2 M NaCl and 0.01% Tween 20. The protein yield of GLase-His with over 95% purity was 0.5 mg from 0.9 L of the cultured medium. The enzymatic properties of purified GLase-His were characterized. Interestingly, non-ionic detergent Tween 20 stabilized and stimulated GLase-His activity and its luminescence activity was stimulated 2-fold by the synergistic effect of 0.01% Tween 20 and 150 mM NaCl. PMID- 28888758 TI - Large area alpha sources with a lip: Integral counting and spectral distortions. AB - The detection efficiency for large area alpha sources with adjustable heights of a raised lip around the edge were measured by 2pi gas-filled proportional counter. The variations in low-energy spectral shape were modeled using a Geant4 radiation and charge transport Monte Carlo simulation, to enable extrapolation of the spectrum to zero energy. COMSOL Multiphysics finite-element analysis was used to explore changes in the spectrum gain in the presence of a lip. It qualitatively reproduced an increase in peak height due to an increasing height of the source lip. A spectrum analysis procedure was developed to perform integral counting on sources with a lip. The experimental results were used to validate the model, which was then used to predict the changes in 2pi counting efficiency for other source-lip geometries. PMID- 28888759 TI - Impact of iliac artery anatomy on the outcome of fenestrated and branched endovascular aortic repair. AB - OBJECTIVE: Fenestrated and branched endovascular aneurysm repair (FB-EVAR) is a valid option to treat juxtarenal and pararenal abdominal aortic aneurysms and thoracoabdominal aortic aneurysms. Because successful deployment depends on complex maneuvers, hostile iliac artery anatomy (HIA) can prejudice the FB-EVAR outcome. The aim of the study was to evaluate the impact of HIA on FB-EVAR outcome. METHODS: Between 2010 and 2015, all patients undergoing FB-EVAR were prospectively categorized according to iliac anatomy (friendly iliac artery anatomy [FIA] or HIA). HIA was defined as the presence of one of the following: severe (>90-degree) iliac angle, extensive (>50%) iliac circumferential calcification, hemodynamic iliac stenosis or obstruction, external iliac artery diameter <7 mm, or previous aortoiliac/femoral graft. Early end points were technical success (absence of type I or type III endoleak, target visceral vessel [TVV] loss, conversion to open repair), intraoperative adjunctive maneuvers (IAMs; iliac percutaneous transluminal angioplasty/stenting, surgical iliac conduit, intra-aortic graft rotations, several attempts of TVV cannulation), intraoperative technical problems (iliac rupture, significant endograft twisting, difficult TVV cannulations, TVV injuries, TVV loss), and 30-day mortality. Follow up end points were survival, TVV patency, and freedom from reintervention. RESULTS: Ninety-four patients (male, 87%; age, 73 +/- 6 years) with 59 (63%) juxtarenal and pararenal abdominal aortic aneurysms and 35 (37%) thoracoabdominal aortic aneurysms underwent FB-EVAR, for a total of 324 TVVs; 60 (64%) patients had HIA and 34 (36%) had FIA. Patients with HIA and FIA had similar preoperative clinical characteristics, except for coronary artery disease, peripheral artery occlusive disease, and American Society of Anesthesiologists class 4 (47% vs 24% [P = .03], 12% vs 0% [P = .04], and 28% vs 9% [P = .03], respectively). Technical success was 96% (HIA, 97%; FIA, 95%; P = .6). In HIA, adjunctive iliac procedures were performed in 32 cases (surgical conduit, 14 [15%]; percutaneous transluminal angioplasty/stenting, 27 [29%]). Endograft twisting and difficult TVV cannulation occurred in 13 (14%) and 33 (35%) cases, respectively (HIA 18% vs FIA 15% [P = .09]; HIA 28% vs FIA 21% [P = .03]). TVV cannulation failed in nine cases and injury occurred in five (TVV patency rate, 97.8%; HIA 94.7% vs FIA 98.3%; P = .3). One (1%) iliac rupture occurred in HIA, needing surgical repair. Overall, 44 (47%; HIA 55% vs FIA 25%; P = .03) IAMs were necessary. Perioperative mortality was 4% (HIA 3% vs FIA 5%; P = .9). At multivariate analysis, predictors of IAMs were external iliac diameter <7 mm (odds ratio [OR], 12.5; 95% confidence interval [CI], 2.2-71.4; P = .004) and extensive iliac calcifications (OR, 8.3; 95% CI, 1.4-50.0; P = .02). The mean follow-up was 24 +/- 17 months, with an overall survival of 87% and 71% at 1 year and 3 years, respectively, significantly lower in HIA compared with FIA (at 3 years, HIA 60% vs FIA 92%; P = .02). On multivariate analysis, HIA was a significant predictor of late mortality (OR, 3.6; 95% CI, 1.1-13.2; P = .04). Freedom from reintervention (87%) and 3 year TVV patency (92%) were similar in the two groups. CONCLUSIONS: HIA does not significantly affect the early outcome of FB-EVAR. However, in patients with HIA, procedures are technically more demanding and late mortality is increased. Iliac characteristics should be taken into account to correctly stratify the surgical risk in FB-EVAR. PMID- 28888760 TI - An in vitro investigation of indigenous South African medicinal plants used to treat oral infections. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Over a 120 South African medicinal plants are used for the treatment of oral diseases. Despite the vast collection of antimicrobial studies being done on South African plants, there is still limited research on pathogens associated with oral infections. In consultation with the available ethnobotanical literature, this study investigates the antimicrobial efficacy of some South African medicinal plants against oral pathogens. AIM OF THE STUDY: To provide a detailed account of the antimicrobial properties of selected South African medicinal plants used traditionally to treat oral infections. The effect on Streptococcus mutans biofilm formation and the toxicity profiles of these plants are also investigated. MATERIALS AND METHODS: A total of 136 aqueous and organic extracts and six essential oils were prepared from 31 different plant species. These plant samples were screened for antimicrobial efficacy against nine oral pathogens using the micro-titre plate dilution assay. Plant extracts that were found to have noteworthy antimicrobial activity against S. mutans were further evaluated on the effect on S. mutans biofilm formation using the glass slide technique. The toxicity profiles of plant samples that were found to have noteworthy antimicrobial activity were evaluated using the brine shrimp lethality assay. RESULTS: The organic extract of Cissampelos torulosa stems displayed the lowest MIC value of 0.05mg/mL against both Lactobacillus spp. This high antimicrobial activity was also observed with the organic extract of Spirostachys africana leaves against Candida albicans. In some instances, a direct relationship was found between the traditional use of the plant and the antimicrobial activity observed. For example, noteworthy activity (MIC < 1.00mg/mL) was observed against all three Candida spp. when tested against Clematis brachiata (leaves), a plant traditionally used to treat oral thrush. Englerophytum magalismonatanum stems displayed notable activity against both Streptococcus spp. (MIC 0.83mg/mL against S. mutans and MIC 0.67mg/mL against S. sanguis). Spirostachys africana leaves displayed the greatest anti-adherent properties against S. mutans biofilm formation at both 24 and 48h, reducing the biofilm by 97.56% and 86.58% respectively. The majority of plant samples tested in the brine shrimp lethality assay (BSLA) were considered safe, however, 13 plant samples were considered toxic, at a concentration of 1mg/mL. CONCLUSION: Noteworthy antimicrobial activity for plants species such as C. brachiata and E. magalismonatnum provides validation for the traditional use of these plants. Spirostachys africana displayed the greatest reduction of adherent S. mutans cells. The BSLA results revealed that the majority of the plant samples were not toxic in nature. The findings from the results favour the potential use of these plants in treating oral diseases such as dental caries, periodontal diseases and oral thrush. PMID- 28888761 TI - Associations Between TNFAIP3 Gene Polymorphisms and Rheumatoid Arthritis Risk: A Meta-analysis. AB - BACKGROUND AND AIMS: A host of studies investigated the associations between tumor necrosis factor alpha inducible protein 3 (TNFAIP3) gene rs2230926 and rs5029937 polymorphisms and rheumatoid arthritis (RA) susceptibility, but with conflicting findings. Therefore, we explored whether TNFAIP3 gene rs2230926 and rs5029937 polymorphisms are associated with RA by meta-analysis. MATERIAL AND METHODS: We performed out a comprehensive literature search of PubMed, Elsevier, Embase, and CNKI databases to identify relevant studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. RESULTS: Literature search identified 10 case-control studies involving 18,014 cases and 20,112 controls in this meta-analysis. Our data supported an association between TNFAIP3 gene rs2230926 and rs5029937 polymorphisms and RA risk. Stratification analysis of ethnicity indicated that rs5029937 polymorphism increased the risk of RA among Caucasians, while rs2230926 polymorphism increased the risk of RA among Asians and Caucasians. CONCLUSIONS: In conclusion, this meta-analysis demonstrates that TNFAIP3 gene polymorphisms (rs2230926 and rs5029937) are associated with the increased risk of RA. PMID- 28888762 TI - Probiotic Supplementation in Chronic Kidney Disease: A Double-blind, Randomized, Placebo-controlled Trial. AB - OBJECTIVE: The objective of the study was to evaluate the effects of probiotic supplementation on the gut microbiota profile and inflammatory markers in chronic kidney disease patients undergoing maintenance hemodialysis (HD). DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled study. Forty-six HD patients were assigned to receive 1 of 2 treatments: probiotic (n = 23; Streptococcus thermophilus, Lactobacillus acidophilus e Bifidobacterialongum, 90 billion colony-forming units per day) or placebo (n = 23) daily for 3 months. Blood and feces were collected at baseline and after intervention. The inflammatory markers (C-reactive protein and interleukin-6) were analyzed by immunoenzymatic assay (enzyme-linked immunosorbent assay). Uremic toxins plasma levels (indoxyl sulfate, p-cresyl sulfate, and indole-3-acetic acid) were obtained by Reversed-Phase High-Performance Liquid Chromatography. Routine laboratory parameters were measured by standard techniques. Fecal pH was measured by the colorimetric method, and the gut microbiota profile was assessed by Denaturing Gradient Gel Electrophoresis analysis. RESULTS: Sixteen patients remained in the probiotic group (11 men, 53.6 +/- 11.0 year old, 25.3 +/- 4.6 kg/m2) and 17 in the placebo group (10 men, 50.3 +/- 8.5 year old, 25.2 +/- 5.7 kg/m2). After probiotic supplementation there was a significant increase in serum urea (from 149.6 +/- 34.2 mg/dL to 172.6 +/- 45.0 mg/dL, P = .02), potassium (from 4.4 +/- 0.4 mmol/L to 4.8 +/- 0.4 mmol/L, P = .02), and indoxyl sulfate (from 31.2 +/- 15.9 to 36.5 +/- 15.0 mg/dL, P = .02). The fecal pH was reduced from 7.2 +/- 0.8 to 6.5 +/- 0.5 (P = .01). These parameters did not change significantly in placebo group. Changes in the percentage delta (Delta) between groups were exhibited with no statistical differences observed. The inflammatory markers and gut profile were not altered by supplementation. CONCLUSIONS: Aprobiotic supplementation failed to reduce uremic toxins and inflammatory markers. Therefore, probiotic therapy should be chosen with caution in HD patients. Further studies addressing probiotic therapy in chronic kidney disease patients are needed. PMID- 28888764 TI - Rehabilitating cardiac rehabilitation after heart transplantation. PMID- 28888763 TI - miR-155 targets Est-1 and induces ulcerative colitis via the IL-23/17/6-mediated Th17 pathway. AB - BACKGROUND: Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) affecting millions of people worldwide. miR-155 has been reported to be upregulated in various inflammatory diseases and is a positive regulator of the T cell response. IL-17 secreting helper T (Th17) cells have been heavily implicated in tissue-specific immune pathology, including UC. METHODS AND RESULTS: Therefore, we targeted miR-155 and investigated its expression levels in a DSS induced UC mouse model, revealing increased expression. Est-1 expression was found to have decreased, but the levels of IL-23/17/6 were raised significantly and Th17 had experienced an obvious increase. We overexpressed miR-155 using a lentiviral treatment. Increased miR-155 expression induced a more severe damage to colon tissues. In this case, the level of Est-1 decreased even further, thereby enhancing IL-23/17/6-mediated Th17 differentiation. CONCLUSION: miR-155 seems to target Est-1 and induces UC via the IL-23/17/6-mediated Th17 pathway. PMID- 28888765 TI - Donor bronchial wash bile acid and suitability of donor lungs for transplantation. PMID- 28888766 TI - A natural hybrid of a Bacillus thuringiensis Cry2A toxin implicates Domain I in specificity determination. AB - A PCR-RFLP method was used to identify cry2A toxin genes in a collection of 300 strains of Bacillus thuringiensis. From 81 genes identified, the vast majority appeared to be cry2Aa or cry2Ab, however three showed a different pattern and were subsequently cloned and sequenced. The gene cloned from strain HD395 was named cry2Ba2. Since the proteins encoded by the genes cloned from LS5115-3 and DS415 shared >95% sequence identity with existing toxins their genes were named cry2Aa17 and cry2Ab29 respectively by the toxin nomenclature committee. Despite this overall similarity these two toxins resembled natural hybrids, with Cry2Ab29 resembling Cry2Ab for the majority of the protein but then showing identity to Cry2Aa for the last 66 amino acids. For Cry2Aa17, Domains II and III most closely resembled Cry2Aa (99% identity) whilst Domain I was identical to that of Cry2Ab. The toxicity of the recombinant toxins was tested against Aedes aegypti and Spodoptera exigua, and it was found that the toxicity profile of Cry2Aa17 more closely matched the profile of Cry2Ab than that of Cry2Aa, thus implicating Domain I in specificity determination. This association of Domain I with toxicity was confirmed when hybrids were made between Cry2Aa and Cry2Ab. PMID- 28888767 TI - Recent acute crayfish mortality reveals Aphanomyces astaci presence in Bosnia and Herzegovina. AB - Although the introduction of the crayfish plague pathogen Aphanomyces astaci to Europe is responsible for substantial declines in native crayfish populations throughout the whole continent, its presence has never been officially confirmed in many European regions, including most of the Balkan Peninsula. We demonstrate that the recent crayfish mortality observed in Bosnia and Herzegovina (Mostarsko blato karst field, Neretva river drainage) was caused by A. astaci. The causative strain is known only from European crayfish, indicating that A. astaci poses a threat to native species in this region, even in the absence of its main vectors, the North American crayfish. PMID- 28888768 TI - Assessment of a cricket, Acheta domesticus, bioassay for Chequa Iflavirus and bunya-like virus from redclaw crayfish Cherax quadricarinatus. AB - Chequa iflavirus and a bunya-like virus infect redclaw crayfish (Cherax quadricarinatus) and they may cause mortality reaching 20-40% after about three weeks after a stress event. To complete River's postulates for viruses, virus free animals are needed. Due to a lack of chequa iflavirus and bunya-like virus free crayfish (testing shows>85% infection rate) coupled with the facts that iflavirus and bunyaviruses are found in insects and that crickets had been successful alternate hosts for crustacean viruses before, Acheta domesticus was trialled asa bioassay animal. There was no significant difference (P>0.05) in mortality rates between uninfected control crickets and infected crickets. Reverse transcriptase polymerase chain reaction for both viruses failed to find any trace of the RNA viruses in fed or inoculated crickets after 30days. The search for an alternative bioassay host will have to be widened. PMID- 28888769 TI - Inter-vender and test-retest reliabilities of resting-state functional magnetic resonance imaging: Implications for multi-center imaging studies. AB - This prospective multi-center study aimed to evaluate the inter-vendor and test retest reliabilities of resting-state functional magnetic resonance imaging (RS fMRI) by assessing the temporal signal-to-noise ratio (tSNR) and functional connectivity. Study included 10 healthy subjects and each subject was scanned using three 3T MR scanners (GE Signa HDxt, Siemens Skyra, and Philips Achieva) in two sessions. The tSNR was calculated from the time course data. Inter-vendor and test-retest reliabilities were assessed with intra-class correlation coefficients (ICCs) derived from variant component analysis. Independent component analysis was performed to identify the connectivity of the default-mode network (DMN). In result, the tSNR for the DMN was not significantly different among the GE, Philips, and Siemens scanners (P=0.638). In terms of vendor differences, the inter-vendor reliability was good (ICC=0.774). Regarding the test-retest reliability, the GE scanner showed excellent correlation (ICC=0.961), while the Philips (ICC=0.671) and Siemens (ICC=0.726) scanners showed relatively good correlation. The DMN pattern of the subjects between the two sessions for each scanner and between three scanners showed the identical patterns of functional connectivity. The inter-vendor and test-retest reliabilities of RS-fMRI using different 3T MR scanners are good. Thus, we suggest that RS-fMRI could be used in multicenter imaging studies as a reliable imaging marker. PMID- 28888771 TI - C-terminal hydrazide modification changes the spinal antinociceptive profiles of endomorphins in mice. AB - Previously, we have demonstrated that endomorphins (EMs) analogs with C-terminal hydrazide modification retained the MU-opioid receptor affinity and selectivity, and exhibited potent antinociception after intracerebroventricular (i.c.v.) administration. In the present study, we extended our studies to evaluate the antinociceptive profiles of EMs and their analogs EM-1-NHNH2, EM-2-NHNH2 given spinally in the radiant heat paw withdrawal test. Following intrathecal (i.t.) administration, EM-1, EM-2, EM-1-NHNH2 and EM-2-NHNH2 dose-dependently increased the latency for paw withdrawal response. EM-1-NHNH2 displayed the highest antinociceptive effects, with the ED50 values being 1.63 nmol, more potent than the parent EM-1 (1.96 nmol), but with no significant difference. By contrast, the analgesic activities of EM-2 and its analog EM-2-NHNH2 were almost equivalent (P>0.05). Naloxone and beta-funaltrexamine (beta-FNA) almost completely attenuated the antinociceptive effects of EMs and their analogs EM-1-NHNH2, EM-2 NHNH2 (10 nmol, i.t.), indicating the involvement of MU-opioid receptors. Notably, the antinociception of EM-1 was not significantly antagonized by naloxonazine, a selective MU1-opioid receptor antagonist, but partially reversed the effects of EM-2, suggesting that EM-1 and EM-2 may produce antinociception through distinct MU1- and MU2-opioid receptor subtypes. Moreover, naloxonazine didn't significantly block the antinociceptive effects of EM-1-NHNH2 and EM-2 NHNH2, and nor-BNI, the kappa-opioid receptor antagonist, attenuated the analgesic effects of EM-2, but not EM-1, EM-1-NHNH2 or EM-2-NHNH2. These results indicated that C-terminal amide to hydrazide conversion changed the antinociceptive opioid mechanisms of EM-2 but not EM-1 at the spinal level. Herein, the acute antinociceptive tolerance were further determined and compared. EM-1-NHNH2 and EM-2-NHNH2 shifted the dose-response curve rightward by only 2.8 and 1.5-fold as determined by tolerance ratio, whereas EM-1 and EM-2 by 3.4 and 4.6-fold, respectively, indicating substantially reduced antinociceptive tolerance. The present study demonstrated that C-terminal hydrazide modification changes the spinal antinociceptive profiles of EMs. PMID- 28888770 TI - Test-retest reliability of cerebral blood flow in healthy individuals using arterial spin labeling: Findings from the EMBARC study. AB - INTRODUCTION: Previous investigations of test-retest reliability of cerebral blood flow (CBF) at rest measured with pseudo-continuous Arterial Spin Labeling (pCASL) demonstrated good reliability, but are limited by the use of similar scanner platforms. In the present study we examined test-retest reliability of CBF in regions implicated in emotion and the default mode network. MATERIAL AND METHODS: We measured absolute and relative CBF at rest in thirty-one healthy subjects in two scan sessions, one week apart, at four different sites and three different scan platforms. We derived CBF from pCASL images with an automated algorithm and calculated intra-class correlation coefficients (ICCs) across sessions for regions of interest. In addition, we investigated site effects. RESULTS: For both absolute and relative CBF measures, ICCs were good to excellent (i.e. >0.6) in most brain regions, with highest values observed for the subgenual anterior cingulate cortex and ventral striatum. A leave-one-site-out cross validation analysis did not show a significant effect for site on whole brain CBF and there was no proportional bias across sites. However, a significant site effect was present in the repeated measures ANOVA. CONCLUSIONS: The high test retest reliability of CBF measured with pCASL in a range of brain regions implicated in emotion and salience processing, emotion regulation, and the default mode network, which have been previously linked to depression symptomatology supports its use in studies that aim to identify neuroimaging biomarkers of treatment response. PMID- 28888773 TI - Reply by Authors. PMID- 28888772 TI - Re: Magnetic Resonance Imaging Underestimation of Prostate Cancer Geometry: Use of Patient Specific Molds to Correlate Images with Whole Mount Pathology: A. Priester, S. Natarajan, P. Khoshnoodi, D. J. Margolis, S. S. Raman, R. E. Reiter, J. Huang, W. Grundfest and L. S. Marks J Urol 2017;197:320-326. PMID- 28888774 TI - Impact of body mass index in liver transplantation for nonalcoholic fatty liver disease and alcoholic liver disease. AB - BACKGROUND: This study evaluates long-term outcomes and body mass index (BMI) following liver transplantation (LT) for non-alcoholic fatty liver disease (NAFLD) in comparison with alcoholic liver disease (ALD). METHODS: Patient and graft survival were compared using Kaplan Meier curves and log rank test. Multivariable analysis of recipient and donor characteristics was performed as determinants of patient survival. BMI at listing was compared with BMI post-LT. RESULTS: Patient survival at 1-, 3-, 5- and 10 years post-LT was similar in the ALD group (n = 195) compared with the NAFLD group (n = 84) (93% vs. 93%, 91% vs. 89%, 86% vs. 77%, 64% vs. 66% respectively, p = 0.21). One patient in the NAFLD group was re-transplanted and none in the ALD group therefore graft survival was also similar (p = 0.20). Multivariable analysis didn't identify any significant predictors of reduced survival. In comparison with the ALD group, BMI was significantly higher in the NAFLD group at listing (31 vs. 27, p < 0.001), 3 months post-LT (28 vs. 26, p < 0.05) and 6-months post-LT (29 vs. 27, p < 0.05) but was equivalent by 5-years post-LT (29 vs. 30, p = 0.80). CONCLUSIONS: NAFLD patients had similar patient and graft survival post-LT compared to ALD. NAFLD patients returned to listing BMI by one-year post-LT but by 5-years post-LT there was no difference in BMI between the groups. PMID- 28888775 TI - Simultaneous versus delayed hepatectomy for synchronous colorectal liver metastases: a systematic review and meta-analysis. AB - OBJECTIVE: This was a systematic review and meta-analysis to compare outcomes between patients undergoing simultaneous or delayed hepatectomy for synchronous colorectal liver metastases. BACKGROUND: The optimal strategy for treating liver disease among patients with resectable synchronous colorectal liver metastases (CRLM) is unclear. Simultaneous resection of primary tumour and liver metastases may improve patient experience by reducing the number of interventions. However, there are concerns of increased morbidity compared to delayed resections. METHODS: A systematic literature search was performed using EMBASE, Medline, Cochrane library and Google scholar databases. Meta-analyses were performed using both random-effects and fixed-effect models. Publication and patient selection bias were assessed with funnel plots and sensitivity analysis. RESULTS: Thirty studies including 5300 patients were identified. There were no statistically significant differences in parameters relating to safety and efficacy between the simultaneous and delayed hepatectomy cohorts. Patients undergoing delayed surgery were more likely to have bilobar disease or undergo major hepatectomy. The average length of hospital stay was six days shorter with simultaneous approach [MD = -6.27 (95% CI: -8.20, -4.34), p < 0.001]. Long term survival was similar for the two approaches [HR = 0.97 (95%CI: 0.88, 1.08), p = 0.601]. CONCLUSION: In selected patients, simultaneous resection of liver metastases with colorectal resection is associated with shorter hospital stay compared to delayed resections, without adversely affecting perioperative morbidity or long-term survival. PMID- 28888776 TI - Living donor liver transplantation for hepatocellular carcinoma: results of prospective patient selection by Kyushu University Criteria in 7 years. AB - BACKGROUND: Expanding patient selection beyond the Milan criteria in living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) has long been a matter for debate. We have used the Kyushu University Criteria - maximum tumor diameter <5 cm or des-gamma-carboxy prothrombin <300 mAU/ml - in LDLT for HCC since June 2007. The aim of the present study was to present the results of our prospective patient selection by Kyushu University Criteria and to confirm whether or not our criteria were justified. METHODS: The entire study period was divided into the pre-Kyushu era (July 1999-May 2007) and the Kyushu era (June 2007-November 2014). Eighty-nine and 90 patients underwent LDLT for HCC in the pre-Kyushu era and the Kyushu era, respectively. RESULTS: In the pre-Kyushu era, there were significant differences in recurrence-free and disease-specific survival between the beyond-Milan and the within-Milan patients. In the Kyushu era, however, the differences in recurrence-free and disease-specific survival between the beyond-Milan and the within-Milan patients disappeared. The 5-year overall patient survival in the Kyushu era was 89.4%. CONCLUSION: Our selection criteria enabled a considerable number of beyond-Milan patients to undergo LDLT without jeopardizing the recurrence-free, and disease-specific, and overall patient survival. PMID- 28888777 TI - Evaluation of hepatocellular carcinoma spread via the portal system by 3 dimensional mapping. AB - BACKGROUND/PURPOSE: The pattern of tumor cell spread via the portal system has not been fully clarified in patients with hepatocellular carcinoma (HCC). This study aimed to evaluate the intrahepatic distribution of cancer cells derived from the main tumor by assessing histological portal invasion and/or intrahepatic metastasis (vp/im). METHODS: In 14 patients who underwent anatomical resection of primary solitary HCC <= 50 mm in diameter, vp/im were examined pathologically, and the sites of the lesions were reproduced on preoperative 3D-CT images. The number of vp/im and the distance of each lesion from the tumor margin were also determined. RESULTS: The tumor diameter was <30 mm in seven patients (smaller HCCs) and 30-50 mm in seven patients (larger HCCs). 3D mapping revealed that almost all vp/im were localized to the peritumoral area within one cm of the tumor margin in smaller HCCs, whereas vp/im seemed to spread extensively to the feeding 3rd level portal branches in larger HCCs. The number of vp/im was greater in patients with larger HCCs than in those with smaller HCCs. CONCLUSIONS: 3D mapping suggested tumor cells of HCC spread via the portal vein extensively in several cases. PMID- 28888778 TI - Mincle inhibits neutrophils and macrophages apoptosis in A. fumigatus keratitis. AB - PURPOSE: To determine whether macrophage inducible C-type lectin (Mincle) regulates neutrophils and macrophages apoptosis in A. fumigatus keratitis. MATERIALS AND METHODS: A murine model (C57BL/6) of fungal keratitis (AF) was established by gently scraping corneal central epithelium, smearing A. fumigatus on the epithelium surface and covering the eye with contact lenses. AF cell model was established by extracting neutrophils (PMN) and macrophages, and then infecting cells with A. fumigatus. Animals and cells were randomly divided into control and A. fumigatus keratitis group, which were treated with Mincle ligand Trehalose-6,6-dibehenate (TDB), Mincle neutralizing antibody (MincleAb) or PBS before infection. The cornea infection was monitored using a slit lamp and further analyzed using H&E assay. PCR, Western blot, immunostaining, TUNEL staining and flow cytometry were used to examine the expression of Mincle and apoptosis factors, PMN infiltration and cell apoptosis, respectively. RESULTS: Higher levels of Mincle mRNA and protein, as well as epithelial thickness and presence of inflammatory cells in the stroma, were observed in the AF group compared to control. In addition, higher Mincle mRNA levels were observed in normal and stimulated neutrophils and macrophages. Furthermore, Fas, FasL and CASP3 mRNA levels, neutrophils infiltration rate and TUNEL-positive cells were significantly increased in AF+MincleAb mice compared with the control. Similar results, as well as significantly higher neutrophils and macrophages apoptosis, were observed by treating cells with MincleAb in vitro. Most importantly, opposite results i.e. lower mRNA levels, neutrophils infiltration rate and TUNEL positive cells, as well as lower cell apoptosis in vitro, were observed in mice and cells treated with TDB. CONCLUSION: Mincle-participated in inflammatory process which inhibits neutrophils and macrophages apoptosis induced by A. fumigatus involved in Fas-dependent apoptotic pathways. PMID- 28888779 TI - Anti-inflammatory and antioxidant potential of Guaianolide isolated from Cyathocline purpurea: Role of COX-2 inhibition. AB - BACKGROUND: Inflammation activated by oxidative stress can cause various diseases, such as asthma, rheumatoid arthritis, cancer, diabetes, etc. Plant constituents with sesquiterpene lactones possess antioxidant and anti inflammatory properties. AIM: To determine the antioxidant and anti-inflammatory potential of isolated phytoconstituent from Cyathocline purpurea Buch-Ham ex D (CP). Don in laboratory animals. Furthermore, to understand the interactions involved in the binding of this compound to cyclooxygenase-2 (COX-2) via computational docking. METHODS: Phytoconstituent was isolated, purified and well characterized (using IR, NMR, and MS) from ethyl acetate fraction of CP methanolic extract. It was then evaluated for its in-vitro antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2) and hydroxyl (OH) radical assays as well as in-vivo anti-inflammatory potential against carrageenan-induced paw edema model in rats. The molecular docking study was performed against the crystal structure of COX-2 to evaluate the binding potential of phytoconstituent towards this enzyme. RESULTS: The isolated compound 6alpha-hydroxy-4 [14], 10 [15]-guainadien-8alpha, 12-olide (HGN) showed significant (p<0.001) antioxidant activity with IC50 values of 76MUg/mL. Administration of HGN (10 and 20mg/kg) significantly (p<0.001) reduced the increased paw volume after subplantar administration of carrageenan. It also exhibits good binding affinity towards with COX-2 with a docking score of -8.98 and Glide binding energy of -36.488kcal/mol shedding light on the potential mechanism of anti-inflammatory action. CONCLUSIONS: The presence of hydroxyl group in HGN provides a credential to its in-vivo anti-inflammatory and in-vitro antioxidant activities. Furthermore, the good binding affinity of HGN for the active site of COX-2 may open novel vistas in therapeutic option with natural antioxidants like Cyathocline purpurea to treat various inflammatory disorders. PMID- 28888780 TI - Berberine suppresses LPS-induced inflammation through modulating Sirt1/NF-kappaB signaling pathway in RAW264.7 cells. AB - Chronic inflammation is a major contributing factor in the pathogenesis of many diseases. Natural product berberine (BBR) exhibits potent anti-inflammatory effect in vitro and in vivo, while the underlying mechanisms remain elusive. Sirt1, a NAD+-dependent protein deacetylase, was recently found to play an important role in modulating the development and progression of inflammation. Thus, we speculate that Sirt1 might mediate the inhibitory effect of BBR on inflammation. In LPS-stimulated RAW264.7 macrophages, BBR treatment significantly downregulated the expression of proinflammatory cytokines such as MCP-1, IL-6 and TNF-alpha. Importantly, BBR potently reversed LPS-induced down-regulation of Sirt1. Consistently, the inhibitory effects of BBR on proinflammatory cytokines expression was largely abrogated by Sirt1 inhibition either by EX527, a Sirt1 inhibitor or Sirt1 siRNA. Further mechanistic studies revealed that BBR-induced inhibition of NF-kappaB is Sirt1-dependent, as either pharmacologically or genetically inactivating Sirt1 enhanced the IkappaBetaalpha degradation, IKK phosphorylation, NF-kappaB p65 acetylation and DNA-binding activity. Taken together, our results provide the first evidence that BBR potently suppressed inflammatory responses in macrophages through inhibition of NF-kappaB signaling via Sirt1-dependent mechanisms. PMID- 28888782 TI - TNF-alpha-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or neutrophilic asthma. AB - BACKGROUND: It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in TH2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with TH17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both TH2 and TH17 cell differentiation and is mediated through nuclear factor kappaB activation. Ablation of TNF-alpha-induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor kappaB activation in myeloid cells and DCs, was shown to control DC activation. OBJECTIVE: In this study we investigated the precise role of TNFAIP3 in myeloid cells for the development of TH2- and TH17-cell mediated asthma. METHODS: We exposed mice with conditional deletion of the Tnfaip3 gene in either myeloid cells (by using the lysozyme M [LysM] promotor) or specifically in DCs (by using the Cd11c promotor) to acute and chronic house dust mite (HDM)-driven asthma models. RESULTS: We demonstrated that reduced Tnfaip3 gene expression in DCs in either Tnfaip3CD11c or Tnfaip3LysM mice dose-dependently controlled development of TH17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely TH2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific TH17 cell differentiation through increased expression of the TH17-instructing cytokines IL 1beta, IL-6, and IL-23, whereas HDM-specific TH2 cell differentiation was hampered by increased IL-12 and IL-6 production. CONCLUSIONS: These data show that the extent of TNFAIP3 expression in DCs controls TH2/TH17 cell differentiation. This implies that reducing DC activation could be a new pharmacologic intervention to treat patients with severe asthma who present with TH17-mediated neutrophilic inflammation. PMID- 28888781 TI - Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8) is an activating receptor mediating beta2-integrin-dependent function in human eosinophils. AB - BACKGROUND: Siglec-8 is a CD33 subfamily cell-surface receptor selectively expressed on human eosinophils. After cytokine priming, Siglec-8 mAb or glycan ligand binding causes eosinophil apoptosis associated with reactive oxygen species (ROS) production. Most CD33-related Siglecs function as inhibitory receptors, but the ability of Siglec-8 to stimulate eosinophil ROS production and apoptosis suggests that Siglec-8 might instead function as an activating receptor. OBJECTIVE: We sought to determine the role of IL-5 priming and identify the signaling molecules involved in Siglec-8 function for human eosinophils. METHODS: We used an mAb and/or a multimeric synthetic sulfated sialoglycan ligand recognizing Siglec-8 in combination with integrin blocking antibodies, pharmacologic inhibitors, phosphoproteomics, and Western blot analysis to define the necessity of various proteins involved in Siglec-8 function for human eosinophils. RESULTS: Cytokine priming was required to elicit the unanticipated finding that Siglec-8 engagement promotes rapid beta2-integrin-dependent eosinophil adhesion. Also novel was the finding that this adhesion was necessary for subsequent ROS production and apoptosis. Siglec-8-mediated ROS was generated through reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation because pretreatment of eosinophils with catalase (an extracellular superoxide scavenger) or NSC 23766 (a Rac GTPase inhibitor) completely inhibited Siglec-8-mediated eosinophil apoptosis. Finally, engagement of Siglec-8 on IL-5 primed eosinophils resulted in increased phosphorylation of Akt, p38, and c-Jun N terminal kinase 1 that was also beta2-integrin dependent; pharmacologic inhibition of these kinases completely prevented Siglec-8-mediated eosinophil apoptosis. CONCLUSIONS: These data demonstrate that Siglec-8 functions uniquely as an activating receptor on IL-5-primed eosinophils through a novel pathway involving regulation of beta2-integrin-dependent adhesion, NADPH oxidase, and a subset of protein kinases. PMID- 28888783 TI - Phytochemical study of Juglans regia L. leaves. AB - A methanolic extract of Juglans regia L. leaves was fractioned by various chromatographic techniques yielding a total of 40 metabolites belonging to megastigmane, tetralone, phenylpropanoid, neolignane and juglone glycosides. Ten unknown megastigmane glucoside derivatives (juglanionosides A-K, 1-10) and six unknown tetralone glucoside derivatives (juglanosides J-O, 11-16) together with 24 known compounds - among them 16 described for the first time in Juglans - were isolated. As characteristic structural feature, the previously undescribed compounds showed acylation of the sugar units with sinapic, ferulic, coumaric, benzoic or salicylic acid. Their chemical structures were elucidated on the basis of 1D and 2D NMR techniques, HRESIMS as well as CD spectroscopy. Absolute stereochemistry was revealed by mild alkaline hydrolysis and comparison of CD and polarimetric data to literature values. PMID- 28888784 TI - Malignant ascites determine the transmesothelial invasion of ovarian cancer cells. AB - The exact role of malignant ascites in the development of intraperitoneal ovarian cancer metastases remains unclear. In this report we sought to establish if ascites can determine the efficiency of transmesothelial invasion of ovarian cancer cells, and, if so, whether the fluid generated by highly aggressive serous and undifferentiated tumors will promote the invasion more effectively than ascites from less aggressive clear cell and endometrioid cancers. The study showed that the invasion of ovarian cancer cells (SKOV-3 and primary cancer cells) across monolayered peritoneal mesothelial cells was elevated upon mesothelial cell exposure to fluid produced by serous and undifferentiated cancers, as compared with cells subjected to ascites from clear cell and endometrioid tumors. This effect coincided with decreased mesothelial expression of junctional proteins: connexin 43, E-cadherin, occludin, and desmoglein. Moreover, it was accompanied by transforming growth factor beta1-dependent overproduction of reactive oxygen species by these cells. The activity of ascites from serous and undifferentiated tumors was mediated by p38 mitogen-activated protein kinase and nuclear factor kappaB. When the mesothelial cells were protected against oxidative stress, both deterioration of junctional proteins and intensification of cancer cell invasion in response to ascites from serous and undifferentiated tumors were effectively prevented. In conclusion, our findings indicate that the high aggressiveness of some histotypes of ovarian cancer may be related to the ability of malignant ascites generated by these cells to oxidative stress-dependent impairment of mesothelial cell integrity and the resulting increase in their transmesothelial invasion. PMID- 28888785 TI - Infrared spectroscopic imaging: Label-free biochemical analysis of stroma and tissue fibrosis. AB - Infrared spectroscopic tissue imaging is a potentially powerful adjunct tool to current histopathology techniques. By coupling the biochemical signature obtained through infrared spectroscopy to the spatial information offered by microscopy, this technique can selectively analyze the chemical composition of different features of unlabeled, unstained tissue sections. In the past, the tissue features that have received the most interest were parenchymal and epithelial cells, chiefly due to their involvement in dysplasia and progression to carcinoma; however, the field has recently turned its focus toward stroma and areas of fibrotic change. These components of tissue present an untapped source of biochemical information that can shed light on many diverse disease processes, and potentially hold useful predictive markers for these same pathologies. Here we review the recent applications of infrared spectroscopic imaging to stromal and fibrotic regions of diseased tissue, and explore the potential of this technique to advance current capabilities for tissue analysis. PMID- 28888786 TI - Microwave-assisted synthesis of ruthenium(II) complexes with alkynes as potential inhibitor by selectively recognizing c-myc G-quadruplex DNA. AB - Herein, two polypyridyl ruthenium(II) complexes with alkynes, [Ru(bpy)2L](ClO4)2 (L=p-TEPIP (1) and p-BEPIP (2); bpy=2,2'-bipyridine; p-TEPIP=2-(4 trimethylsilylpropargyl)-1H-imidazo[4,5f][1,10]phenanthroline; p-BEPIP=2-(4 phenyacetylenephenyl)-1H-imidazo[4,5f][1,10]phenanthroline) have been successfully achieved in yields of 32%-89% by a Sonogashira coupling reaction under microwave irradiation. We studied these complexes as potential stabilizers of c-myc G-quadruplex DNA. Observations revealed that both complexes could selectively bind to and stabilize c-myc G-quadruplex DNA with a constant of approximately 1.61+/-0.78 and 9.47+/-4.20*103M-1, respectively, as determined from ITC (isothermal ttitration calorimetry) experiments, FRET (fluorescence resonance energy ttransfer) assay and competitive FRET assay. Moreover, the melting point (Tm) of the c-myc G-quadruplex DNA increased in the presence of 1 and 2 ([Ru]=0.2MUM) by approximately 9 and 19.9 degrees C, respectively. It is noteworthy that the conformation of the c-myc G-quadruplex DNA appeared to change when titrated with 1 and 2, which was accompanied by a negative-induced CD (circular dichroism) signal that appeared at a wavelength of 295nm. Furthermore, the conformational change in c-myc G-quadruplex DNA induced by 1 and 2have also been confirmed by TEM (transmission electron microscopy) and AFM (atomic force microscopy). Consequently, the replication of c-myc DNA was blocked by 1 and 2, and especially by 2, as verified by PCR (polymerase chain reaction) -stop assay and Western-blot assay. Thus, these ruthenium(II) complexes can be developed as potential inhibitors in chemotherapy through their binding and stabilization of c myc G-quadruplex DNA. PMID- 28888787 TI - Radiographic cup anteversion measurement corrected from pelvic tilt. AB - The purpose of this study was to develop a novel technique to improve the accuracy of radiographic cup anteversion measurement by correcting the influence of pelvic tilt. Ninety virtual total hip arthroplasties were simulated from computed tomography data of 6 patients with 15 predetermined cup orientations. For each simulated implantation, anteroposterior (AP) virtual pelvic radiographs were generated for 11 predetermined pelvic tilts. A linear regression model was created to capture the relationship between radiographic cup anteversion angle error measured on AP pelvic radiographs and pelvic tilt. Overall, nine hundred and ninety virtual AP pelvic radiographs were measured, and 90 linear regression models were created. Pearson's correlation analyses confirmed a strong correlation between the errors of conventional radiographic cup anteversion angle measured on AP pelvic radiographs and the magnitude of pelvic tilt (P < 0.001). The mean of 90 slopes and y-intercepts of the regression lines were -0.8 and -2.5 degrees , which were applied as the general correction parameters for the proposed tool to correct conventional cup anteversion angle from the influence of pelvic tilt. The current method proposes to measure the pelvic tilt on a lateral radiograph, and to use it as a correction for the radiographic cup anteversion measurement on an AP pelvic radiograph. Thus, both AP and lateral pelvic radiographs are required for the measurement of pelvic posture-integrated cup anteversion. Compared with conventional radiographic cup anteversion, the errors of pelvic posture-integrated radiographic cup anteversion were reduced from 10.03 (SD = 5.13) degrees to 2.53 (SD = 1.33) degrees. Pelvic posture-integrated cup anteversion measurement improves the accuracy of radiographic cup anteversion measurement, which shows the potential of further clarifying the etiology of postoperative instability based on planar radiographs. PMID- 28888788 TI - Experimental and modelling characterisation of adjustable hollow Micro-needle delivery systems. AB - BACKGROUND: Hollow micro-needles have been used increasingly less in practice because the infusion into the skin is limited by the tissue resistance to flow. The relationship between the infusion flow rate and tissue resistance pressure is not clear. METHODS: A custom-made, hollow micro-needle system was used in this study. The driving force and infusion flow rate were measured using a force transducer attached to an infusion pump. Evans blue dye was injected into the air, polyacrylamide gel and in-vivo mouse skin at different flow rates. Two different micro-needle lengths were used for in-vivo infusion into the mouse. A model was derived to calculate the driving force of the micro-needle infusion into the air, and the results were compared to experimental data. RESULTS: The calculated driving forces match the experimental results with different infusion flow rates. The pressure loss throughout the micro-needle delivery system was found to be two orders smaller than the resistance pressure inside the gel and mouse skin, and the resistance pressure increased with increasing flow rate. A portion of liquid backflow was observed when the flow rate was relatively larger, and the backflow was associated with a sudden larger increase in resistance pressure at a higher flow rate. CONCLUSIONS: The current micro-needle delivery system is capable of administering liquid into the mouse skin at a flow rate of up to 0.15 ml/min, without causing significant backflow on the surface. The resistance pressure increases with increasing flow rate, causing infusion restriction at higher flow rates. PMID- 28888789 TI - Modal analysis for the assessment of cementless hip stem primary stability in preoperative THA planning. AB - This numerical vibration finite element (FE) study introduces resonance three dimensional planning (RP3D) to assess preoperatively the primary stability of a cementless stem for total hip arthroplasty. Based on a patient's CT-scan and a numerical model of a stem, RP3D aims at providing mechanical criteria indicative of the achievable primary stability. We investigate variations of the modal response of the stem to changes of area and apparent stiffness of the bone implant interface. The model is computationally cheap as it does not include a mesh of the bone. The apparent stiffness of the bone is modeled by springs attached to the nodes of the stem's mesh. We investigate an extended range of stiffness values while, in future works, patient's specific Hounsfield values could be used to define stiffness. We report modal frequencies, shapes, and a ratio of elastic potential energies (rEPE) that quantifies the proximal motion that should be minimum for a stable stem. The modal response exhibits a clear transition between loose and tight contact as area and stiffness of the interface increase. rEPE thresholds that could potentially discriminate preoperatively between stable and unstable stems are given for a Symbios SPS(r) size C stem. PMID- 28888790 TI - Evolution in Australia's mesic biome under past and future climates: Insights from a phylogenetic study of the Australian Rock Orchids (Dendrobium speciosum complex, Orchidaceae). AB - The Australian mesic biome spans c. 33 degrees of latitude along Australia's east coast and ranges and is dissected by historical and contemporary biogeographical barriers. To investigate the impact of these barriers on evolutionary diversification and to predict the impact of future climate change on the distribution of species and genetic diversity within this biome, we inferred phylogenetic relationships within the Dendrobium speciosum complex (Orchidaceae) across its distribution and undertook environmental niche modelling (ENM) under past, contemporary and projected future climates. Neighbor Joining tree inference, NeighborNet and Structure analyses of Amplified Fragment Length Polymorphism (AFLP) profiles for D. speciosum sampled from across its distribution showed that the complex consists of two highly supported main groups that are geographically separated by the St. Lawrence gap, an area of dry sclerophyll forest and woodland. The presence of several highly admixed individuals identified by the Structure analysis provided evidence of genetic exchange between the two groups across this gap. Whereas previous treatments have recognised between one to eleven species, the molecular results support the taxonomic treatment of the complex as a single species with two subspecies. The ENM analysis supported the hypothesis that lineage divergence within the complex was driven by past climatic changes. The St. Lawrence gap represented a stronger biogeographic barrier for the D. speciosum complex during the cool and dry glacial climatic conditions of the Pleistocene than under today's interglacial conditions. Shallow genetic divergence was found within the two lineages, which mainly corresponded to three other biogeographic barriers: the Black Mountain Corridor, Glass House Mountains and the Hunter Valley. Our ENM analyses provide further support for the hypothesis that biogeographic barriers along Australia's east coast were somewhat permeable to genetic exchange due to past episodic range expansions and contractions caused by climatic change resulting in recurrent contact between previously isolated populations. An overall southward shift in the distribution of the complex under future climate scenarios was predicted, with the strongest effects on the northern lineage. This study contributes to our understanding of the factors shaping biodiversity patterns in Australia's mesic biome. PMID- 28888791 TI - A multilocus view on Mediterranean aeolid nudibranchs (Mollusca): Systematics and cryptic diversity of Flabellinidae and Piseinotecidae. AB - Recent molecular studies revealed high level of endemism and numerous cryptic species within opisthobranchs, with Mediterranean taxa clearly understudied. Here we used genetic data from both mitochondrial and nuclear gene fragments as well as morphological data from taxonomically relevant characters to investigate the phylogenetic relationships and systematics of Mediterranean taxa of the Flabellinidae and Piseinotecidae families. Phylogenetic analyses based on Bayesian and Maximum-Likelihood methods indicate that Flabellinidae and Pisenotecidae taxa and species within the genera Flabellina, Calmella and Piseinotecus do not form monophyletic clades. These results are supported by our morphological analyses which allowed the re-evaluation of the triseriate radula condition in Pisenotecidae and Calmella taxa and their inclusion in the genus Flabellina as Flabellina gaditanacomb. nov. (synonym of F. confusa), Flabellina gabiniereicomb. nov. and Flabellina cavolinicomb. nov. Species delimitation and barcoding gap analyses allowed uncovering cryptic species within Flabellina gracilis (Alder and Hancock, 1844), F. trophina (Bergh, 1890), F. verrucosa (M. Sars, 1829) and F. ischitana Hirano and Thompson, 1990, the latter with an Atlantic form which is under description. This study corroborates the relevance of combining molecular and morphological data from multiple populations and species in the assessment of nudibranch diversity and classification. PMID- 28888792 TI - Bisphenol A regulates rare minnow testicular vitellogenin expression via reducing its promoter Er recruitment. AB - Vitellogenins (Vtgs) are major precursor of the egg-yolk proteins. They are synthesized in liver of adult female ovipara, but normally silent in males. For their sensitive response to estrogen, Vtgs are usually used as biomarkers for environmental estrogenic compounds. In the present study, three vtg subtypes (vtg1, vtg2 and vtg3) were proved to present in the testis of rare minnow Gobiocypris rarus for the first time. Immunohistochemistry result showed that Vtg proteins mainly deposit in spermatogonium and spermatocytes. Following 225MUg/L bisphenol A (BPA) exposure 1, 3 and 9 weeks, testicular vtg mRNAs were mostly significantly decreased. The further chromatin immunoprecipitation showed that BPA could decrease estrogen receptor (Er) recruitment in vtg promoter, which possibly reduced Er's transcription activation effect on vtgs. However, different from the continuously decreased vtg mRNA levels, testicular Vtg protein levels were recovered at week 9. Considering the induced hepatic Vtg expression, testicular Vtgs may be replenished by the induced hepatic Vtgs under BPA exposure. PMID- 28888793 TI - Metal bioavailability in ecological risk assessment of freshwater ecosystems: From science to environmental management. AB - Metal contamination in freshwater ecosystems is a global issue and metal discharges to aquatic environments are monitored in order to protect aquatic life and human health. Bioavailability is an important factor determining metal toxicity. In aquatic systems, metal bioavailability depends on local water and sediment characteristics, and therefore, the risks are site-specific. Environmental quality standards (EQS) are used to manage the risks of metals in aquatic environments. In the simplest form of EQSs, total concentrations of metals in water or sediment are compared against pre-set acceptable threshold levels. Now, however, the environmental administration bodies have stated the need to incorporate metal bioavailability assessment tools into environmental regulation. Scientific advances have been made in metal bioavailability assessment, including passive samplers and computational models, such as biotic ligand models (BLM). However, the cutting-edge methods tend to be too elaborate or laborious for standard environmental monitoring. We review the commonly used metal bioavailability assessment methods and introduce the latest scientific advances that might be applied to environmental management in the future. We present the current practices in environmental management in North America, Europe and China, highlighting the good practices and the needs for improvement. Environmental management has met these new challenges with varying degrees of success: the USA has implemented site-specific environmental risk assessment for water and sediment phases, and they have already implemented metal mixture toxicity evaluation. The European Union is promoting the use of bioavailability and BLMs in ecological risk assessment (ERA), but metal mixture toxicity and sediment phase are still mostly neglected. China has regulation only for total concentrations of metals in surface water. We conclude that there is a need for (1) Advanced and up-to-date guidelines and legislation, (2) New and simple scientific methods for assessing metal bioavailability and (3) Improvement of knowledge and skills of administrators. PMID- 28888794 TI - Rutin: Exploitation of the flavonol for health and homeostasis. PMID- 28888795 TI - Comment on: Long-term nutritional impact of sleeve gastrectomy. PMID- 28888796 TI - Laparoscopic treatment of gastroparesis: a single center experience. AB - BACKGROUND: Gastroparesis (GP) is a chronic disorder of gastric motility with delayed gastric emptying. Gastric electrical stimulator (GES) implantation and Roux-en-Y gastric bypass (RYGB) are surgical options for medically refractory GP. OBJECTIVE: Evaluate operational outcomes and symptom improvement of patients with diabetic (DM) and idiopathic (IP) GP. SETTING: University Hospital, United States. METHODS: A retrospective chart review was performed of all patients who underwent surgical treatment of GP from February 2003 to December 2014. Subgroup analysis was performed based on etiology of GP (DM versus IP) and procedure received (GES versus RYGB). Postoperative outcomes and postoperative symptom improvements were compared between groups. RESULTS: Of 93 patients, 47 (50.5%) had IP and 46 (49.5%) had DM. The majority underwent GES implantation (83.8%, n = 78), and 15 patients (16%) underwent RYGB. There were significant differences in hospital stay (2 versus 3 days) and reoperation rate (30% versus 7%) between IP and DM. Operation time, complication rate, and 30-day readmission rate were similar in both groups. DM patients significantly improved GP-related complaints compared with preoperatively. IP patients also improved nausea and vomiting and had no change in abdominal pain between pre- and postoperative period. GES showed significant improvement of nausea, vomiting, and abdominal pain. RYGB showed improvement of nausea, but not vomiting or abdominal pain. CONCLUSIONS: Surgery is a feasible intervention for GP for both DM and IP patients; however, based on the data presented in this manuscript and the current literature, the use of gastric bypass as an effective treatment modality for patients with intractable GP remains highly controversial. Care must be taken for IP patients in the postoperative period due to high incidence of reoperation. Although both procedures offer some degree of symptomatic improvement, GES seems to provide improvement of more GP symptoms. However, there is no significant difference in the need for postoperative medications regardless of the procedure used. PMID- 28888797 TI - Will molecular target agents enable the multidisciplinary treatment in stage IV gastric cancer? AB - A detailed molecular characterization of gastric cancer has been revealed by global initiatives and a number of new molecular agents are under investigation. Currently only trastuzumab, a monoclonal antibody for human epidermal growth factor receptor 2 (HER2), is clinically used for HER2 positive advanced gastric cancer patients and ramucirumab, a monoclonal antibody directed against the extracellular ligand-binding domain of vascular endothelial growth factor receptor (VEGFR)2, can be used in second line. However, despite the progress in gastric cancer treatment, the prognosis of stage IV gastric cancer patients remains dismal. To achieve a remarkable improvement in the prognosis of patients, a multidisciplinary treatment approach with the help of effective molecular target agents should be considered. So far the role of multidisciplinary treatment for stage IV gastric cancer is still uncertain due to limited available data and absence of long-lasting tumor control with systemic therapy. Herein, an overview of the latest developments of molecular targeted agents for gastric cancer in advanced stages, in the perioperative setting and in oligometastatic disease is provided. The possibility of a multidisciplinary strategy using molecular target agents and surgery for stage IV gastric cancer is also assessed. PMID- 28888798 TI - Impact of body mass index on treatment outcome of neoadjuvant chemoradiotherapy in locally advanced rectal cancer. AB - AIM: To determine the effect of obesity, measured by body mass index (BMI), on tumor response and surgical outcome in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (nCRT) and radical surgery. METHOD: LARC patients undergoing nCRT and radical surgery from 2008 to 2014 were included and divided into three groups: non-obese (BMI < 25.0 kg/m2), obese I (BMI 25.0-29.9 kg/m2), and obese II (BMI >= 30.0 kg/m2). Tumor response, surgical and oncological outcome were compared between groups. Multivariate analyses were performed to identify risk factors for local recurrence. RESULTS: A total of 522 LARC patients were analyzed (407 non-obese, 93 obese I, 22 obese II). Post-operative complications did not differ between groups. Increased BMI was associated with poorer T downstaging and Rectal Cancer Regression Grade (P = 0.116, P = 0.036). With a mean follow-up of 57 months, the 5-year overall survival and distant metastasis rates did not differ between groups (P = 0.861, P = 0.116). The 5-year local recurrence rate in obese II patients was 14.6%, higher than that in non-obese and obese I groups (P = 0.015). Cox regression analysis demonstrated that BMI >=30 kg/m2 (HR = 6.187, P = 0.010) was significantly associated with increased risk for local recurrence. CONCLUSION: Obesity was associated with poorer T downstaging and Rectal Cancer Regression Grade, and thus poor local control in LARC following nCRT in Asian patients. More effective treatment strategies to improve treatment outcome for obese patients with LARC are warranted. PMID- 28888799 TI - Patterns of care and the survival of elderly patients with high-risk endometrial cancer: A case-control study from the FRANCOGYN group. AB - BACKGROUND: The standard of care of endometrial cancer involves complex procedures such as pelvic and para-aortic lymphadenectomy and omentectomy, particularly for high-risk endometrial cancer. Few data are available about these complex surgical procedures and adjuvant therapy in elderly women. We aim to examine treatment and survival of elderly women diagnosed with high-risk endometrial cancer. STUDY DESIGN: We performed a case-control study of women diagnosed between 2001 and 2013 with high-risk endometrial cancers. Women older than 70 years (n = 198) were compared with patients <70 years (n = 198) after matching on high-risk for recurrence and LVSI status. RESULTS: Elderly patients had lymphadenectomies less frequently compared with younger patients (76% vs 96%, p < 0.001) and no adjuvant treatment more frequently (17% vs 8%, p = 0.005) due to less chemotherapy being administered (23% vs 46%, p < 0.001). The 3-year DFS, CSS and OS of patients >=70 years was 52% (43-61), 81% (74-88) and 61% (53-70), respectively. These were significantly lower than the 3-year DFS, CSS, and OS of younger patients, which was 75% (68-82) (p < 0.001), 92% (87-96) (p < 0.008) and 75% (69-82) (p = 0.018), respectively. Cox proportional hazard models found that elderly women had 57% increased risk of recurrence (hazard ratio 1.57, 95% CI 1.04-2.39) compared with younger patients. CONCLUSION: Although we found an independently significant lower DFS in elderly patients with high-risk endometrial cancer when compared with young patients, elderly women are less likely to be treated with lymphadenectomy and chemotherapy. Specific guidelines for management of elderly patients with high-risk endometrial cancer are required to improve their prognosis. PMID- 28888800 TI - Percutaneous lung ablation of pulmonary recurrence may improve survival in selected patients undergoing cytoreductive surgery for colorectal cancer with peritoneal carcinomatosis. AB - PURPOSE: To analyze the outcomes of patients developing pulmonary metastases (PM) following cytoreductive surgery (CRS) and perioperative intra-peritoneal chemotherapy (IPC) for colorectal cancer (CRC) with peritoneal carcinomatosis. PATIENTS AND METHODS: A retrospective analysis of patients undergoing CRS/IPC for CRC from 1996 to 2016 was performed. Lung-specific disease-free and patient overall survival was analyzed. Patients undergoing percutaneous lung ablative therapy (PLAT) for PM were compared to patients receiving systemic chemotherapy alone. RESULTS: 273 patients underwent CRS/IPC for CRC. Of these, 61 (22%) developed PM. Median time to development of PM was 8 months (range 0-52 months) and 41 patients (67%) had metachronous lesions. Twenty-one PM patients underwent PLAT, either by radio-frequency or micro-wave ablation, for an average of 3 lesions (range 1-12) and 13 (62%) had bilobar disease. The most common post interventional complication was the development of pneumothorax (71%). Overall survival following development of PM was 18 months and higher in patients undergoing PLAT compared to those treated with systemic chemotherapy (26 vs. 14 months, p = 0.03). In eight cases (38%) local tumor recurrence developed post PLAT. A peritoneal carcinomatosis index >10 (HR 3.48, 95% CI 1.69-7.19), presence of liver metastases (HR 2.49, 95% CI 1.24-5.03) and PLAT (HR 0.43, 95% CI 0.20 0.93) were identified as significant predictors of overall survival following diagnosis of PM. CONCLUSION: PM develop in approximately a fourth of patients undergoing CRS/IPC for CRC. Of these, about 1/3 may be eligible for PLAT. PLAT is a valuable treatment option providing good local control and potentially prolongation of overall survival. PMID- 28888801 TI - Curative-intent treatment of recurrent colorectal liver metastases: A comparison between ablation and resection. AB - BACKGROUND: Liver-limited recurrence after resection of colorectal liver metastases is a frequent occurrence, and can in some cases be treated with curative intent. Although surgical re-resection remains standard of care, there is growing interest in the role of ablation in this setting. The aim of this study was to compare the outcomes after curative-intent ablation and resection in patients with recurrent colorectal liver metastases. METHODS: We retrospectively analysed data from 366 consecutive patients who underwent liver resection for colorectal liver metastases between June 2010 and August 2015. Sixty-four developed liver-limited recurrence which was treated with curative intent, thirty three (51.6%) by ablation and 31 (48.4%) by repeat resection. RESULTS: Patient groups were well matched, with surgically resected patients showing higher pre operative carcinoembryonic antigen levels and larger metastases. There were fewer post-operative complications and shorter length of stay in the ablation group (p < 0.02). After a median follow-up of 36.2 months, median overall survival was the same for both the resected and ablated groups at 33.3 months. Median progression free survival was longer for patients treated with surgery (10.2 months) compared to ablation (4.3 months) (p = 0.002). CONCLUSIONS: Ablation or resection for liver-limited recurrence after surgery for colorectal liver metastases is associated with improved overall survival compared with systemic chemotherapy alone, and should always be considered for patients with resectable liver recurrence. Although ablation seemed to be associated with a shorter progression free survival, post-procedure morbidity was significantly lower. The choice between ablation and resection should therefore be made on a personalised basis. PMID- 28888802 TI - Yamamoto New Scalp Acupuncture for postoperative pain management in cats undergoing ovariohysterectomy. AB - OBJECTIVE: To evaluate the analgesic efficacy of Yamamoto New Scalp Acupuncture (YNSA) as an adjuvant for postoperative pain management in cats. STUDY DESIGN: Prospective, randomized, blinded, clinical study. ANIMALS: Twenty cats aged (mean +/- standard deviation) 25 +/- 9 months and weighing 2.7 +/- 0.6 kg undergoing ovariohysterectomy. METHODS: The cats were sedated with intramuscular (IM) ketamine (5 mg kg-1), midazolam (0.5 mg kg-1) and tramadol (2 mg kg-1). The cats were randomly distributed before induction of anesthesia into two groups of 10 cats each: group YNSA, in which bilateral basic D points were stimulated with a dry needle from 20 minutes prior to anesthetic induction to the end of the surgery; group Control, in which no acupuncture was applied. Postoperative analgesia was assessed at 1, 2, 4, 8, 12, 18 and 24 hours postextubation using an Interactive Visual Analog Scale and Universidade Estadual Paulista-Botucatu Multidimensional Composite Pain Scale (UNESP-Botucatu MCPS). Rescue analgesia was provided with IM tramadol (2 mg kg-1), and the pain scores were reassessed 30 minutes after rescue intervention. If the analgesia remained insufficient, meloxicam (0.2 mg kg-1 as a single dose) was administered IM. Data were analyzed using Student t-test, Fisher exact test, Mann-Whitney U test and Friedman test (p < 0.05). RESULTS: Significantly lower pain scores were observed in YNSA when compared with Control at 1-4 hours based on the UNESP-Botucatu MCPS scores. Although significant differences were not identified between groups requiring rescue analgesia, additional postoperative analgesia was administered to four of 10 cats in Control and no cats in YNSA. CONCLUSION AND CLINICAL RELEVANCE: Perioperative YNSA resulted in decreased pain scores and a reduction in postoperative requirement for rescue analgesia in cats. This method should be considered a viable option as an adjuvant analgesic therapy for cats undergoing ovariohysterectomy. PMID- 28888803 TI - Effects of pneumoperitoneum and of an alveolar recruitment maneuver followed by positive end-expiratory pressure on cardiopulmonary function in sheep anesthetized with isoflurane-fentanyl. AB - OBJECTIVE: To investigate the effects of pneumoperitoneum alone or combined with an alveolar recruitment maneuver (ARM) followed by positive end-expiratory pressure (PEEP) on cardiopulmonary function in sheep. STUDY DESIGN: Prospective, randomized, crossover study. ANIMALS: A total of nine adult sheep (36-52 kg). METHODS: Sheep were administered three treatments (>=10-day intervals) during isoflurane-fentanyl anesthesia and volume-controlled ventilation (tidal volume: 12 mL kg-1) with oxygen: CONTROL (no intervention); PNEUMO (120 minutes of CO2 pneumoperitoneum); PNEUMOARM/PEEP (PNEUMO protocol with an ARM instituted after 60 minutes of pneumoperitoneum). The ARM (5 cmH2O increases in PEEP of 1 minute duration until 20 cmH2O of PEEP) was followed by 10 cmH2O of PEEP until the end of anesthesia. Cardiopulmonary data were recorded until 30 minutes after abdominal deflation. RESULTS: PaO2 was decreased from 435-462 mmHg (58.0-61.6 kPa) (range of mean values in CONTROL) to 377-397 mmHg (50.3-52.9 kPa) in PNEUMO (p < 0.05). Quasistatic compliance (Cqst, mL cmH2O-1 kg-1) was decreased from 0.85-0.92 in CONTROL to 0.52-0.58 in PNEUMO. PaO2 increased from 383-385 mmHg (51.1-51.3 kPa) in PNEUMO to 429-444 mmHg (57.2-59.2 kPa) in PNEUMOARM/PEEP (p < 0.05) and Cqst increased from 0.52-0.53 in PNEUMO to 0.70-0.74 in PNEUMOARM/PEEP. Abdominal deflation in PNEUMO did not restore PaO2 and Cqst to control values. Cardiac index (L minute-1 m2) decreased from 4.80-4.70 in CONTROL to 3.45-3.74 in PNEUMO and 3.63-3.76 in PNEUMOARM/PEEP. Compared with controls, ARM/PEEP with pneumoperitoneum decreased mean arterial pressure from 81 to 68 mmHg and increased mean pulmonary artery pressure from 10 to 16 mmHg. CONCLUSIONS AND CLINICAL RELEVANCE: Abdominal deflation did not reverse the pulmonary function impairment associated with pneumoperitoneum. The ARM/PEEP improved respiratory compliance and reversed the oxygenation impairment induced by pneumoperitoneum with acceptable hemodynamic changes in healthy sheep. PMID- 28888804 TI - Study of the physicochemical effects on the separation of the non-metallic fraction from printed circuit boards by inverse flotation. AB - Recycling printed circuit boards using green technology is increasingly important due to the metals these contain and the environmental care that must be taken when separating the different materials. Inverse flotation is a process that can be considered a Green Technology, which separates metallic from non-metallic fractions. The degree of separation depends on how much material is adhered to air bubbles. The contact angle measurement allows to determine, in an easy way, whether the flotation process will occur or not and thus establish a material as hydrophobic or not. With the material directly obtained from the milling process, it was found that the contact angle of the non-metallic fraction-liquid-air system increases as temperature increases. In the same way, the increments in concentration of frother in the liquid increase the contact angle of the non metallic fraction-liquid-air system. 10ppm of Methyl Isobutyl Carbinol provides the highest contact angle as well as the highest material charging in the bubble. PMID- 28888805 TI - Hydrothermal carbonization of food waste for nutrient recovery and reuse. AB - Food waste represents a rather large and currently underutilized source of potentially available and reusable nutrients. Laboratory-scale experiments evaluating the hydrothermal carbonization of food wastes collected from restaurants were conducted to understand how changes in feedstock composition and carbonization process conditions influence primary and secondary nutrient fate. Results from this work indicate that at all evaluated reaction times and temperatures, the majority of nitrogen, calcium, and magnesium remain integrated within the solid-phase, while the majority of potassium and sodium reside in the liquid-phase. The fate of phosphorus is dependent on reaction times and temperatures, with solid-phase integration increasing with higher reaction temperature and longer time. A series of leaching experiments to determine potential solid-phase nutrient availability were also conducted and indicate that, at least in the short term, nitrogen release from the solids is small, while almost all of the phosphorus present in the solids produced from carbonizing at 225 and 250 degrees C is released. At a reaction temperature of 275 degrees C, smaller fractions of the solid-phase total phosphorus are released as reaction times increase, likely due to increased solids incorporation. Using these data, it is estimated that up to 0.96% and 2.30% of nitrogen and phosphorus based fertilizers, respectively, in the US can be replaced by the nutrients integrated within hydrochar and liquid-phases generated from the carbonization of currently landfilled food wastes. PMID- 28888806 TI - Kinetic study of dry anaerobic co-digestion of food waste and cardboard for methane production. AB - Dry anaerobic digestion is a promising option for food waste treatment and valorization. However, accumulation of ammonia and volatile fatty acids often occurs, leading to inefficient processes and digestion failure. Co-digestion with cardboard may be a solution to overcome this problem. The effect of the initial substrate to inoculum ratio (0.25 to 1gVS.gVS-1) and the initial total solids contents (20-30%) on the kinetics and performance of dry food waste mono digestion and co-digestion with cardboard was investigated in batch tests. All the conditions produced methane efficiently (71-93% of the biochemical methane potential). However, due to lack of methanogenic activity, volatile fatty acids accumulated at the beginning of the digestion and lag phases in the methane production were observed. At increasing substrate to inoculum ratios, the initial acid accumulation was more pronounced and lower cumulative methane yields were obtained. Higher amounts of soluble organic matter remained undegraded at higher substrate loads. Although causing slightly longer lag phases, high initial total solids contents did not jeopardize the methane yields. Cardboard addition reduced acid accumulation and the decline in the yields at increasing substrate loads. However, cardboard addition also caused higher concentrations of propionic acid, which appeared as the most last acid to be degraded. Nevertheless, dry co digestion of food waste and cardboard in urban areas is demonstrated asan interesting feasible valorization option. PMID- 28888807 TI - Assessing the costs of municipal solid waste treatment technologies in developing Asian countries. AB - The management of municipal solid waste (MSW) is one of the main costs incurred by local authorities in developing countries. According to some estimates, these costs can account for up to 50% of city government budgets. It is therefore of importance that policymakers, urban planners and practitioners have an adequate understanding of what these costs consist of, from collection to final waste disposal. This article focuses on a specific stage of the MSW value chain, the treatment of waste, and it aims to identify cost patterns associated with the implementation and operation of waste treatment approaches in developing Asian countries. An analysis of the capital (CAPEX) and operational expenditures (OPEX) of a number of facilities located in countries of the region was conducted based on a database gathering nearly 100 projects and which served as basis for assessing four technology categories: composting, anaerobic digestion (AD), thermal treatment, and the production of refuse-derived fuel (RDF). Among these, it was found that the least costly to invest, asa function of the capacity to process waste, are composting facilities, with an average CAPEX per ton of 21,493 USD2015/ton. Conversely, at the upper end featured incineration plants, with an average CAPEX of 81,880 USD2015/ton, with this treatment approach ranking by and large as the most capital intensive of the four categories assessed. OPEX figures of the plants, normalized and analyzed in the form of OPEX/ton, were also found to be higher for incineration than for biological treatment methods, although on this component differences amongst the technology groups were less pronounced than those observed for CAPEX. While the results indicated the existence of distinct cost implications for available treatment approaches in the developing Asian context, the analysis also underscored the importance of understanding the local context asa means to properly identify the cost structure of each specific plant. Moreover, even though CAPEX and OPEX figures are important elements to assess the costs of a waste treatment system, these should not be considered on a standalone basis for decision making purposes. In complement to this internal cost dimension, the broader impacts - to the economy, society and the environment - resulting from the adoption of a certain treatment approach should be properly understood and, ideally, measured and expressed in monetary terms. PMID- 28888808 TI - Association of high-density lipoprotein cholesterol concentration with different types of stroke and coronary heart disease: The Japan Public Health Center-based prospective (JPHC) study. AB - BACKGROUND AND AIMS: Although low high-density lipoprotein (HDL) cholesterol concentration is an established risk factor for coronary heart disease (CHD), information regarding subtypes of stroke is very limited, especially in Asian populations. METHODS: A prospective study was conducted among 30,736 individuals aged 40-69 years, who lived in nine communities in Japan and did not have a history of cardiovascular disease (CVD). CHD and stroke, including its subtypes, were assessed, and sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were estimated according to quintiles of HDL cholesterol using Cox proportional models adjusted for other CVD risk factors. RESULTS: We identified 296 CHD and 1712 stroke events over a median 15 yr of follow-up. HDL cholesterol concentration showed an inverse association with CHD in men and women. A low HDL cholesterol concentration slightly raised the risk for total strokes in men, but not in women. When analyzed by subtypes, we observed an inverse relationship between HDL cholesterol concentration and the incidence of lacunar infarction, with an adjusted HR for the lowest quintile of HDL cholesterol concentration compared with the highest quintile of 1.63 (95% CI, 1.00-2.66) in men and 1.97 (95% CI, 1.19-3.26) in women. HDL cholesterol concentration was positively associated with the risk of intracerebral hemorrhage (ICH) in a linear manner in women (p for trend = 0.028), but not in men. CONCLUSIONS: The associations of HDL cholesterol concentration with lacunar infarction and ICH may be related to different functional properties of HDL rather than to its protective function against lipid-rich atherosclerosis. PMID- 28888809 TI - Childhood maltreatment, psychological resources, and depressive symptoms in women with breast cancer. AB - Childhood maltreatment is associated with elevated risk for depression across the human lifespan. Identifying the pathways through which childhood maltreatment relates to depressive symptoms may elucidate intervention targets that have the potential to reduce the lifelong negative health sequelae of maltreatment exposure. In this cross-sectional study, 271 women with early-stage breast cancer were assessed after their diagnosis but before the start of adjuvant treatment (chemotherapy, radiation, endocrine therapy). Participants completed measures of childhood maltreatment exposure, psychological resources (optimism, mastery, self esteem, mindfulness), and depressive symptoms. Using multiple mediation analyses, we examined which psychological resources uniquely mediated the relationship between childhood maltreatment and depressive symptoms. Exposure to maltreatment during childhood was robustly associated with lower psychological resources and elevated depressive symptoms. Further, lower optimism and mindfulness mediated the association between childhood maltreatment and elevated depressive symptoms. These results support existing theory that childhood maltreatment is associated with lower psychological resources, which partially explains elevated depressive symptoms in a sample of women facing breast cancer diagnosis and treatment. These findings warrant replication in populations facing other major life events and highlight the need for additional studies examining childhood maltreatment as a moderator of treatment outcomes. PMID- 28888810 TI - Bystander automated external defibrillator use and clinical outcomes after out-of hospital cardiac arrest: A systematic review and meta-analysis. AB - AIM: To systematically review studies comparing bystander automated external defibrillator (AED) use to no AED use in regard to clinical outcomes in out-of hospital cardiac arrest (OHCA), and to provide a descriptive summary of studies on the cost-effectiveness of bystander AED use. METHODS: We searched Medline, Embase, the Web of Science, and the Cochrane Library for randomized trials and observational studies published before June 1, 2017. Meta-analyses were performed for patients with all rhythms, shockable rhythms, and non-shockable rhythms. RESULTS: Forty-four observational studies, 3 randomized trials, and 13 cost effectiveness studies were included. Meta-analysis of 6 observational studies without critical risk of bias showed that bystander AED use was associated with survival to hospital discharge (all rhythms OR: 1.73 [95%CI: 1.36, 2.18], shockable rhythms OR: 1.66 [95%CI: 1.54, 1.79]) and favorable neurological outcome (all rhythms OR: 2.12 [95%CI: 1.36, 3.29], shockable rhythms OR: 2.37 [95%CI: 1.58, 3.57]). There was no association between bystander AED use and neurological outcome for non-shockable rhythms (OR: 0.76 [95%CI: 0.10, 5.87]). The Public-Access Defibrillation trial found higher survival rates when volunteers were equipped with AEDs. The other trials found no survival difference, although their study settings differed. The quality of evidence was low for randomized trials and very low for observational studies. AEDs were cost effective in settings with high cardiac arrest incidence, with most studies reporting ratios < $100,000 per quality-adjusted life years. CONCLUSIONS: The evidence supports the association between bystander AED use and improved clinical outcomes, although the quality of evidence was low to very low. PMID- 28888811 TI - Outcome after cardiac arrest, time will matter. PMID- 28888812 TI - Use of automated chest compression devices after out-of-hospital cardiac arrest in Sweden. AB - OBJECTIVE: To evaluate the implementation of automated chest compression cardiopulmonary resuscitation (ACC-CPR) after out-of-hospital cardiac arrest (OHCA) in Sweden during the years 2011 through 2015. The association between ACC CPR and 30-day survival was studied as a secondary objective. METHODS: The Swedish cardiopulmonary resuscitation registry is a prospectively recorded nationwide registry of modified Utstein parameters including all patients with attempted resuscitation after OHCA. Propensity score matching (PSM) was used to adjust for known confounders in the secondary analysis. RESULTS: Of the 24,316 patients included in the study population, 32.4% received ACC-CPR, with substantial regional variation ranging from 0.8% to 78.8%. Male gender and an initial shockable rhythm were associated with ACC-CPR, whereas crew witnessed status was associated with manual CPR. Potential markers of prolonged resuscitation attempts (drug administration and endotracheal intubation) were more prevalent in the ACC-CPR group. The unadjusted 30-day survival rate was 6.3% for ACC-CPR patients. The adjusted odds ratio for 30-day survival regarding use of an ACC device was 0.72 (95% CI 0.62-0.84, p<0.001, n=13922). CONCLUSION: The use of ACC devices varied significantly between Swedish regions and overall survival to 30days was low among patients receiving ACC-CPR. Although measured and unmeasured confounding might explain our finding of lower survival rates for patients exposed to ACC-CPR, specific guidelines recommending when and how ACC CPR should be used are warranted as there might be circumstances where these devices do more harm than good. PMID- 28888813 TI - Gender-specific Differences in Recurrence of Non-muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis. AB - CONTEXT: The incidence of urothelial carcinoma of the bladder (UCB) is lower in women; however, women tend to present with more advanced disease. To date, there is no quantitative synthesis of studies reporting gender-specific outcomes in non muscle-invasive UCB. OBJECTIVE: To conduct a meta-analysis evaluating gender specific differences in recurrence of non-muscle-invasive urinary bladder cancer (NMIBC). EVIDENCE ACQUISITION: An unrestricted systematic literature search of the MEDLINE, EMBASE, and Cochrane libraries was conducted. Studies evaluating the impact of gender on disease recurrence after local treatment of NMIBC using multivariable Cox proportional hazard models were included. Random effect meta analysis, subgroup analyses, meta-influence, and cumulative meta-analyses were conducted. Publication bias was assessed via a funnel plot and Eggers test. EVIDENCE SYNTHESIS: Of 609 studies screened, 27 comprising 23 754 patients were included. Random effect meta-analyses indicated women at increased risk for UCB recurrence compared with men (hazard ratio [HR]=1.11, 95% confidence interval [CI]: 1.01-1.23, p=0.03). Subgroup analyses yielded estimates between HR=0.99 and HR=1.68. Gender-specific differences in UCB recurrence were most pronounced in studies administering exclusively bacillus Calmette-Guerin (BCG; HR=1.64, 95% CI: 1.13-2.39, p=0.01), especially in a long-term treatment regimen (HR=1.68, 95% CI: 1.32-2.15, p<0.001). Sensitivity analyses confirmed female patients at increased risk for UCB recurrence. CONCLUSIONS: Women are at increased risk for disease recurrence after local treatment of NMIBC compared with male patients. Reduced effectiveness of BCG treatment might underlie this observation. Gender-specific differences were evident across various subgroups and proved robust upon sensitivity analyses. PATIENT SUMMARY: In this report, we combined several studies on gender-specific differences in relapse of superficial bladder cancer. Women were more likely to experience cancer relapse than men. PMID- 28888814 TI - Primary and Secondary Enuresis: Pathophysiology, Diagnosis, and Treatment. AB - CONTEXT: Enuresis is a common and possibly underestimated condition. While 5-10% of school-aged children suffer from the condition, a lack of background knowledge may impede timely child-adapted and successful therapy. OBJECTIVE: To provide a comprehensive overview of the pathophysiology, diagnosis, and treatment of enuresis. EVIDENCE ACQUISITION: Guideline and position papers from the European Society of Pediatric Urology, the European Association of Urology, and the International Children's Continence Society were acquired. PubMed was searched for literature on enuresis, and all papers published in the last 5 yr were considered. The most relevant information from the papers with the highest level of evidence was extracted and incorporated into the review. EVIDENCE SYNTHESIS: An altered antidiuretic hormone profile, arousal failure, and delayed bladder maturation are the main pathophysiological factors in primary enuresis. Coexisting constipation, obstructive airway disease, attention deficit hyperactivity disorder, obesity, and genetic preconditions influence its prevalence. Diagnosis relies on history-taking and simple noninvasive examinations to differentiate monosymptomatic enuresis and patients with daytime symptoms. It is essential to exclude daytime voiding symptoms, overactive bladder, dysfunctional voiding, and urinary tract infections. Further imaging is indicated in complex cases with a suspicion of underlying congenital malformations or systemic or endocrine diseases and in children refractory to initial therapy. In secondary enuresis, psychological causes should also be taken into consideration. While desmopressin melt tablets and alarm systems constitute the mainstays of treatment in monosymptomatic enuresis, anticholinergics and urotherapy play an additional role in nonmonosymptomatic enuresis. For therapy refractory cases, after a thorough re-investigation to identify any missed comorbidities and anatomical or functional causes of enuresis, combination therapy and stationary urotherapy might be promising options. CONCLUSIONS: While enuresis seems to be an often underestimated condition in terms of the suffering that children and their families, there are efficacious therapy options once a correct and full diagnosis is made. PATIENT SUMMARY: This article reviews primary and secondary nocturnal enuresis, which is the medical term for the condition whereby children wet their beds regularly after their first birthday. We describe the background of enuresis,including its complex underlying mechanisms, as well as diagnosis and treatment in the light of current scientific publications. We conclude that while enuresis seems to be an often underestimated condition in terms of the suffering that children and their families may undergo, there are efficacious therapy options once a correct and full diagnosis is made. PMID- 28888815 TI - Neurogenic Bladder in a Girl After Surgery for Cloacal Malformation: The Importance of informing Patients and Parents of All Various Options. AB - Management of neurogenic bladder in pediatric patients is complex. Treatment options must be individualized to not only address the clinical parameters but also take into account the social factors that directly impact the ability to achieve a successful outcome. PMID- 28888816 TI - The repeat structure of two paralogous genes, Yersinia ruckeri invasin (yrInv) and a "Y. ruckeri invasin-like molecule", (yrIlm) sheds light on the evolution of adhesive capacities of a fish pathogen. AB - Inverse autotransporters comprise the recently identified type Ve secretion system and are exemplified by intimin from enterohaemorrhagic Escherichia coli and invasin from enteropathogenic Yersiniae. These proteins share a common domain architecture and promote bacterial adhesion to host cells. Here, we identified and characterized two putative inverse autotransporter genes in the fish pathogen Yersinia ruckeri NVH_3758, namely yrInv (for Y. ruckeri invasin) and yrIlm (for Y. ruckeri invasin-like molecule). When trying to clone the highly repetitive genes for structural and functional studies, we experienced problems in obtaining PCR products. PCR failures and the highly repetitive nature of inverse autotransporters prompted us to sequence the genome of Y. ruckeri NVH_3758 using PacBio sequencing, which produces some of the longest average read lengths available in the industry at this moment. According to our sequencing data, YrIlm is composed of 2603 amino acids (7812bp) and has a molecular mass of 256.4kDa. Based on the new genome information, we performed PCR analysis on four non sequenced Y. ruckeri strains as well as the sequenced. Y. ruckeri type strain. We found that the genes are variably present in the strains, and that the length of yrIlm, when present, also varies. In addition, the length of the gene product for all strains, including the type strain, was much longer than expected based on deposited sequences. The internal repeats of the yrInv gene product are highly diverged, but represent the same bacterial immunoglobulin-like domains as in yrIlm. Using qRT-PCR, we found that yrIlm and yrInv are differentially expressed under conditions relevant for pathogenesis. In addition, we compared the genomic context of both genes in the newly sequenced Y. ruckeri strain to all available PacBio-sequenced Y. ruckeri genomes, and found indications of recent events of horizontal gene transfer. Taken together, this study demonstrates and highlights the power of Single Molecule Real-Time technology for sequencing highly repetitive proteins, and sheds light on the genetic events that gave rise to these highly repetitive genes in a commercially important fish pathogen. PMID- 28888818 TI - Consequences of perinatal hypoxia in developing brain: Changes in GABA transporter functioning in cortical, hippocampal and thalamic rat nerve terminals. AB - Perinatal hypoxia leads to behavioral abnormalities, cognitive disabilities, and epilepsy resulting from alterations in neurodevelopment, maturation and construction of the network. Considering a particular role of gamma-aminobutyric acid (GABA) for an immature brain, we analysed transporter-mediated [3H]GABA uptake in the cortical, hippocampal and thalamic nerve terminals isolated from rats of different age in the control and after perinatal hypoxia. The state of hypoxia was induced by exposure of rats at the age of 10 postnatal days (pd) (that corresponds approximately to the time of birth in humans) to a respiratory medium with low O2 content (4% O2 and 96%N2) for 12min (up to the initiation of clonico-tonic seizures). Here, we found that the initial rate of [3N]GABA uptake was higher in the young rats (pd 17-19) as compared to the older ones (pd 24-26, 38-40 and 66-73) in both control and hypoxia groups. It decreased abruptly by 50% in the thalamus and by 25% in the cortex for the period from pd 17-19 to pd 66 73. In the hippocampus, a decrease in the rate during the same time interval was 25%. Exposure to hypoxia had no effect on the intensity of [3N]GABA uptake by the cortical and thalamic nerve terminals, but caused a significant age-dependent attenuation (by 35%) of the uptake intensity in the hippocampal ones. Significant age-dependent hypoxia-independent decrease in [3N]GABA uptake with step-like dynamics of changes was shown in the thalamus and cortex. Gradual age-dependent hypoxia-dependent decrease in [3N]GABA uptake was revealed in the hippocampus, and so a particular vulnerability of the latest structure to hypoxia as compared to the cortex and thalamus was revealed. PMID- 28888817 TI - Mate choice, sexual selection, and endocrine-disrupting chemicals. AB - Humans have disproportionately affected the habitat and survival of species through environmental contamination. Important among these anthropogenic influences is the proliferation of organic chemicals, some of which perturb hormone systems, the latter referred to as endocrine-disrupting chemicals (EDCs). EDCs are widespread in the environment and affect all levels of reproduction, including development of reproductive organs, hormone release and regulation through the life cycle, the development of secondary sexual characteristics, and the maturation and maintenance of adult physiology and behavior. However, what is not well-known is how the confluence of EDC actions on the manifestation of morphological and behavioral sexual traits influences mate choice, a process that requires the reciprocal evaluation of and/or acceptance of a sexual partner. Moreover, the outcomes of EDC-induced perturbations are likely to influence sexual selection; yet this has rarely been directly tested. Here, we provide background on the development and manifestation of sexual traits, reproductive competence, and the neurobiology of sexual behavior, and evidence for their perturbation by EDCs. Selection acts on individuals, with the consequences manifest in populations, and we discuss the implications for EDC contamination of these processes, and the future of species. PMID- 28888819 TI - Synthesis and evaluation of biological activities of vibsanin A analogs. AB - Vibsanin A is an 11-membered vibsane diterpenoid and is reported to induce myeloid cell differentiation via activation of protein kinase C (PKC) without tumor-promoting activity. Therefore, vibsanin A is thought to be an attractive compound for acute myeloid leukemia (AML) therapy. In this study, we synthesized vibsanin A analogs and compared the activity of these compounds for PKC activation and myeloid cell differentiation. We found that the hydroxymethyl group in vibsanin A is an important substituent to induce differentiation of AML cells. Collectively, our results showed the biochemical features of vibsanin A and provided new insights into the development of new antileukemic drugs. PMID- 28888820 TI - Design and synthesis of 2-phenylpyrimidine coumarin derivatives as anticancer agents. AB - A series of 2-phenylpyrimidine coumarin derivatives with potential telomerase inhibiting activity was designed and synthesized. All of the compounds were screened for antiproliferative activity against CNE2, KB, and Cal27 cell lines in vitro. The results showed that most of the derivatives had a favorable effect on resisting tumor cell proliferation; compound 13, 3-(4-amino-5-oxo-5H-chromeno[4,3 d]pyrimidin-2-yl)phenyl 4-(dimethylamino)benzenesulfonate, exhibited the best activity. Flow cytometry revealed that compound 13 can inhibit CNE2 proliferation. Telomerase inhibition and in vitro antitumor activity were consistent among the compounds, but compound 13 showed the best telomerase inhibiting activity and could inhibit telomere extension. Molecular docking results indicated that compound 13 bonded with telomerase reverse transcriptase (TERT) through multiple interactions, including hydrogen bonding and hydrophobic interactions. The results of the study provide further information on 2 phenylpyrimidine coumarins, expanding the types of telomerase inhibitors as the parent structures. PMID- 28888821 TI - [11C]BCTC: Radiosynthesis and in vivo binding to transient receptor potential vanilloid subfamily member 1 (TRPV1) receptor in the mouse trigeminal nerve. AB - The purpose of this study was to synthesize a new positron emission tomography radiotracer, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine 1(2H)-[11C]carboxamide ([11C]BCTC, [11C]1), and assess its in vivo binding to the transient receptor potential vanilloid subfamily member 1 (TRPV1) receptor in mice. [11C]BCTC was synthesized by reacting the hydrochloride of 4 tertiarybutylaniline (2.HCl) with [11C]phosgene ([11C]COCl2) to give isocyanate [11C]4, followed by reaction with 4-(3-chloropyridin-2-yl)tetrahydropyrazine (3). [11C]BCTC was obtained at a 16-20% radiochemical yield, based on the cyclotron produced [11C]CO2 (decay-corrected to the end of bombardment), with >98% radiochemical purity and 65-110GBq/MUmol specific activity at the end of synthesis. An ex vivo biodistribution study in mice confirmed the specific binding of [11C]BCTC to TRPV1 in the trigeminal nerve, which is a tissue with high TRPV1 expression. PMID- 28888822 TI - Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists. AB - Emerging from an HTS campaign, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H3 receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future. PMID- 28888823 TI - Comparing percentages and ranks of adolescent weight-related outcomes among U.S. states: Implications for intervention development. AB - Understanding statistical differences in states' percentages and ranks of adolescents meeting health behavior guidelines can guide policymaking. Data came from 531,777 adolescents (grades 9-12) who completed the Youth Risk Behavior Surveillance System survey in 2011, 2013, or 2015. We measured the percentage of adolescents in each state that met guidelines for physical activity, fruit and vegetable (F&V) consumption, and healthy weight status. Then we ranked states and calculated the ranks' 95% CI's using a Monte Carlo method with 100,000 simulations. We repeated these analyses stratified by sex (female or male) or race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic/Latino, or other). Pearson's and Spearman's correlation coefficients examined consistency in the percentages and ranks (respectively) across behaviors and subgroups. Meeting the physical activity and F&V consumption guidelines was relatively rare among adolescents (25.8% [95% CI=25.2%-26.4%] and 8.0% [95% CI=7.6%-8.3%], respectively), while meeting the healthy weight guideline was common (71.5% [95% CI=70.7%-72.3%]). At the state level, percentages of adolescents meeting these guidelines were statistically similar; states' ranks had wide CI's, resulting in considerable overlap (i.e., statistical equivalence). For each behavior, states' percentages and ranks were moderately to highly correlated across adolescent subgroups (Pearson's r=0.33-0.96; Spearman's r=0.42-0.96), but across behaviors, only F&V consumption and healthy weight were correlated (Pearson's r=0.34; Spearman's r=0.37). Adolescents in all states could benefit from initiatives to support cancer prevention behaviors, especially physical activity and F&V consumption. Programs in states that ranked highly on all assessed health behaviors could be adapted for dissemination in lower-performing states. PMID- 28888824 TI - Associations of 100% fruit juice versus whole fruit with hypertension and diabetes risk in postmenopausal women: Results from the Women's Health Initiative. AB - The objective of this study was to determine whether consumption of 100% fruit juice as compared to whole fruit is associated with increased risk of hypertension or diabetes. We analyzed postmenopausal women in the United States enrolled in the Women's Health Initiative between 1993 and 1998. Whole fruit and 100% fruit juice intake were assessed by baseline food frequency questionnaire. Standardized questionnaires assessed outcomes every 6-12months during a mean 7.8years of follow-up. Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for incident hypertension (n=36,314 incident cases/80,539 total participants) and diabetes (n=11,488 incident cases/114,219 total participants). In multivariable analyses there was no significant association comparing the highest to lowest quintiles of 100% fruit juice consumption (8oz/day compared to none) and incident hypertension (HR 1.00, 95% CI 0.97-1.03) or diabetes (HR 0.96, 95% CI 0.90-1.03). There was also no significant association between whole fruit consumption (2.4servings/day compared to 0.3servings/day) and incident hypertension (HR 1.02, 95% CI 0.98-1.05) or diabetes (HR 1.03, 95% CI 0.96-1.10). Consuming moderate amounts of 100% fruit juice or whole fruit was not significantly associated with risk of hypertension or diabetes among postmenopausal US women. PMID- 28888825 TI - Multimodal interventions for bundle implementation to decrease central line associated bloodstream infections in adult intensive care units in a teaching hospital in Taiwan, 2009-2013. AB - BACKGROUND: Central line (CL)-associated bloodstream infection (CLABSI) poses a major threat to patient safety and is associated with additional cost. This study investigated the sustained effect of multimodal interventions focusing on CL bundle improvement in the adult intensive care units (ICUs) of a teaching hospital in Taiwan. METHODS: A before-after prospective study was conducted in 17 adult ICUs of a medical center in northern Taiwan from January 2009 to December 2013. Many interventions that aimed to facilitate CL bundle implementation were initiated in January 2011. The incidence rates of CLABSI and catheter-related bloodstream infection (CRBSI) were compared between the baseline and intervention periods. Catheter utilization ratios and microbiological characteristics were also analyzed. RESULTS: The incidence rates of both CLABSI and CRBSI decreased significantly from the baseline to the intervention periods (from 9.27 to 7.66 per 1000 CL-days and from 1.51 to 0.89 per 1000 CL-days, respectively). The yearly incidence rate decreased by up to 31% (incidence rate ratio [IRR], 0.69; 95% confidence interval [CI], 0.59-0.81) for CLABSI and 59% (IRR, 0.41; 95% CI, 0.26-0.65) for CRBSI since the initiation of the interventions. The catheter utilization ratio also decreased from 0.71 to 0.63 (p < 0.001). Microbiological analysis showed that among all CLABSI isolates, the proportion of coagulase negative staphylococci significantly decreased during the intervention period. CONCLUSION: Implementing multimodal interventions focusing on CL bundle improvement was effective in reducing the incidence rates of CLABSI and CRBSI in Taiwan's adult ICUs. PMID- 28888826 TI - Intramural duodenal hematoma post EUS-guided placement of fiducial radiopaque markers. PMID- 28888827 TI - Tumor Dose Response in Yttrium-90 Resin Microsphere Embolization for Neuroendocrine Liver Metastases: A Tumor-Specific Analysis with Dose Estimation Using SPECT-CT. AB - PURPOSE: To evaluate dose-response relationship in yttrium-90 (90Y) resin microsphere radioembolization for neuroendocrine tumor (NET) liver metastases using a tumor-specific dose estimation based on technetium-99m-labeled macroaggregated albumin (99mTc MAA) single photon emission computed tomography (SPECT)-CT. MATERIALS AND METHODS: Fifty-five tumors (mean size 3.9 cm) in 15 patients (10 women; mean age 57 y) were evaluated. Tumor-specific absorbed dose was estimated using a partition model. Initial (median 2.3 months) follow-up data were available for all tumors; last (median 7.6 months) follow-up data were available for 45 tumors. Tumor response was evaluated using Modified Response Evaluation Criteria in Solid Tumors (mRECIST) on follow-up CT. Tumors with complete or partial response were considered responders. Mean tumor absorbed dose was 231.4 Gy +/- 184.3, and mean nontumor liver absorbed dose was 39.0 Gy +/- 18.0. RESULTS: Thirty-six (65.5%) and 30 (66.7%) tumors showed response at initial and last follow-up, respectively. Mean absorbed doses in responders and nonresponders at initial and last follow-up were 285.8 Gy +/- 191.1 and 128.1 Gy +/- 117.1 (P = .0004) and 314.3 Gy +/- 195.8 and 115.7 Gy +/- 117.4 (P = .0001). Cutoff value of >= 191.3 Gy for tumor-specific absorbed dose predicted tumor response with 93% specificity, whereas < 72.8 Gy predicted nonresponse with 100% specificity at last follow-up. Estimated mean absorbed tumor dose per patient was significantly higher in responders versus nonresponders over the follow-up period (224.5 Gy +/- 90.3 vs 70.0 Gy +/- 28.0; P = .007). CONCLUSIONS: Tumor-specific absorbed dose, estimated with a partition model, was significantly associated with tumor response in NET liver metastases. An estimated dose >= 191.3 Gy predicted treatment response with high sensitivity and specificity. PMID- 28888828 TI - Contribution of dark septate fungi to the nutrient uptake and growth of rice plants. AB - The use of dark septate fungi (DSE) to promote plant growth can be beneficial to agriculture, and these organisms are important allies in the search for sustainable agriculture practices. This study investigates the contribution of dark septate fungi to the absorption of nutrients by rice plants and their ensuing growth. Four dark septate fungi isolates that were identified by Internal transcribed spacer phylogeny were inoculated in rice seeds (Cv. Piaui). The resulting root colonization was estimated and the kinetic parameters Vmax and Km were calculated from the nitrate contents of the nutrient solution. The macronutrient levels in the shoots, and the NO3--N, NH4+-N, free amino-N and soluble sugars in the roots, sheathes and leaves were measured. The rice roots were significantly colonized by all of the fungi, but in particular, isolate A103 increased the fresh and dry biomass of the shoots and the number of tillers per plant, amino-N, and soluble sugars as well as the N, P, K, Mg and S contents in comparison with the control treatment. When inoculated with isolates A103 and A101, the plants presented lower Km values, indicating affinity increases for NO3 -N absorption. Therefore, the A103 Pleosporales fungus presented the highest potential for the promotion of rice plant growth, increasing the tillering and nutrients uptake, especially N (due to an enhanced affinity for N uptake) and P. PMID- 28888829 TI - Sensitivity, specificity and comparison of three commercially available immunological tests in the diagnosis of Cryptosporidium species in animals. AB - The study was conducted to compare the specificity of immunological diagnostic methods used for the diagnosis of Cryptosporidium species capable of causing life threatening infection in both immunosuppressed and immunocompetent patients. For the detection of Cryptosporidium species in 79 animals with diarrhoea, we used three Copro-antigen tests: RIDASCREEN(r)Cryptosporidium test, Cryptosporidium 2nd Generation (ELISA) and RIDA(r)QUICK Cryptosporidium. For immunoassays we used positive and negative samples detected by means of polymerase chain reaction and validated by sequencing and nested polymerase chain reaction to confirm the presence six different species of Cryptosporidium species. Prevalence of cryptosporidiosis in the entire group determined by enzyme immunoassay, enzyme linked immunosorbent assay, immuno-chromatographic test and polymerase chain reaction was 34.17%, 27.84%, 6.33% and 27.84%, respectively. Sensitivity of animal samples with enzyme immunoassay, enzyme linked immunosorbent assay, and immuno-chromatographic test was 63.6%, 40.9% and 22.7%, resp., when questionable samples were considered positive, whereas specificity of enzyme immunoassay, enzyme linked immunosorbent assay and immuno-chromatographic test was 75.9%, 78.9% and 100%, respectively. Positive predictive values and negative predictive values were different for all the tests. These differences results are controversial and therefore reliability and reproducibility of immunoassays as the only diagnostic method is questionable. The use of various Cryptosporidium species in diagnosis based on immunological testing and different results obtained by individual tests indicate potential differences in Copro-antigens produced by individual Cryptosporidium species. PMID- 28888830 TI - The isolation of pentose-assimilating yeasts and their xylose fermentation potential. AB - For the implementation of cellulosic ethanol technology, the maximum use of lignocellulosic materials is important to increase efficiency and to reduce costs. In this context, appropriate use of the pentose released by hemicellulose hydrolysis could improve de economic viability of this process. Since the Saccharomyces cerevisiae is unable to ferment the pentose, the search for pentose fermenting microorganisms could be an alternative. In this work, the isolation of yeast strains from decaying vegetal materials, flowers, fruits and insects and their application for assimilation and alcoholic fermentation of xylose were carried out. From a total of 30 isolated strains, 12 were able to assimilate 30gL 1 of xylose in 120h. The strain Candida tropicalis S4 produced 6gL-1 of ethanol from 56gL-1 of xylose, while the strain C. tropicalis E2 produced 22gL-1 of xylitol. The strains Candida oleophila G10.1 and Metschnikowia koreensis G18 consumed significant amount of xylose in aerobic cultivation releasing non identified metabolites. The different materials in environment were source for pentose-assimilating yeast with variable metabolic profile. PMID- 28888831 TI - Steryl ester synthesis, storage and hydrolysis: A contribution to sterol homeostasis. AB - Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set on mammals and the yeast Saccharomyces cerevisiae. The contribution of imbalanced cholesterol homeostasis to several human diseases, namely Wolman disease, cholesteryl ester storage disease, atherosclerosis and Alzheimer's disease, Niemann-Pick type C and Tangier disease is described. PMID- 28888832 TI - Ageing sensitized by iPLA2beta deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids. AB - Ageing is a major risk factor for various forms of liver and gastrointestinal (GI) disease and genetic background may contribute to the pathogenesis of these diseases. Group VIA phospholipase A2 or iPLA2beta is a homeostatic PLA2 by playing a role in phospholipid metabolism and remodeling. Global iPLA2beta-/- mice exhibit aged-dependent phenotypes with body weight loss and abnormalities in the bone and brain. We have previously reported the abnormalities in these mutant mice showing susceptibility for chemical-induced liver injury and colitis. We hypothesize that iPLA2beta deficiency may sensitize with ageing for an induction of GI injury. Male wild-type and iPLA2beta-/- mice at 4 and 20-22months of age were studied. Aged, but not young, iPLA2beta-/-mice showed increased hepatic fibrosis and biliary ductular expansion as well as severe intestinal atrophy associated with increased apoptosis, pro-inflammation, disrupted tight junction, and reduced number of mucin-containing globlet cells. This damage was associated with decreased expression of intestinal endoplasmic stress XBP1 and its regulator HNF1alpha, FATP4, ACSL5, bile-acid transport genes as well as nuclear receptors LXRalpha and FXR. By LC/MS-MS profiling, iPLA2beta deficiency in aged mice caused an increase of intestinal arachidonate-containing phospholipids concomitant with a decrease in ceramides. By the suppression of intestinal FXR/FGF-15 signaling, hepatic bile-acid synthesis gene expression was increased leading to an elevation of secondary and hydrophobic bile acids in liver, bile, and intestine. In conclusions, ageing sensitized by iPLA2beta deficiency caused a decline of key intestinal homeostatic genes resulting in the development of GI disease in a gut to-liver manner. PMID- 28888833 TI - Iron depletion induces hepatic secretion of biliary lipids and glutathione in rats. AB - Iron depletion (ID) has been shown to induce the liver expression of Cyp7a1, the rate-limiting enzyme initiating conversion of cholesterol to bile acids (BA), although the effect on bile acids metabolism and bile production is unknown. Therefore, we investigated changes in bile secretion and BA synthesis during diet induced iron depletion (ID) in rats. ID increased bile flow along with augmented biliary excretion of bile acids, glutathione, cholesterol and phospholipids. Accordingly, we found transcriptional upregulation of the Cyp7a1, Cyp8b1, and Cyp27a1 BA synthetic enzymes, as well as induction of the Abcg5/8 cholesterol transporters in ID rat livers. In contrast, intravenous infusion of 3H taurocholate failed to elicit any difference in biliary secretion of this compound in the ID rats. This corresponded with unchanged expression of canalicular rate-limiting transporters for BA as well as glutathione. We also observed that ID substantially changed the spectrum of BA in bile and decreased plasma concentrations of BA and cholesterol. Experiments with differentiated human hepatic HepaRG cells confirmed human CYP7A1 orthologue upregulation resulting from reduced iron concentrations. Results employing a luciferase reporter gene assay suggest that the transcriptional activation of the CYP7A1 promoter under ID conditions works independent of farnesoid X (FXR), pregnane X (PXR) and liver X (LXRalpha) receptors activation. It can be concluded that this study characterizes the molecular mechanisms of modified bile production as well as cholesterol as along with BA homeostasis during ID. We propose complex upregulation of BA synthesis, and biliary cholesterol secretion as the key factors affected by ID. PMID- 28888834 TI - Season of birth and primary central nervous system tumors: a systematic review of the literature with critical appraisal of underlying mechanisms. AB - PURPOSE: Season of birth has been considered a proxy of seasonally varying exposures around perinatal period, potentially implicated in the etiology of several health outcomes, including malignancies. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we have systematically reviewed published literature on the association of birth seasonality with risk of central nervous system tumors in children and adults. RESULTS: Seventeen eligible studies using various methodologies were identified, encompassing 20,523 cases. Eight of 10 studies in children versus four of eight in adults showed some statistically significant associations between birth seasonality and central nervous system tumor or tumor subtype occurrence, pointing to a clustering of births mostly in fall and winter months, albeit no consistent pattern was identified by histologic subtype. A plethora of perinatal factors might underlie or confound the associations, such as variations in birth weight, maternal diet during pregnancy, perinatal vitamin D levels, pesticides, infectious agents, immune system maturity, and epigenetic modifications. CONCLUSIONS: Inherent methodological weaknesses of to-date published individual investigations, including mainly underpowered size to explore the hypothesis by histological subtype, call for more elegant concerted actions using primary data of large datasets taking also into account the interplay between the potential underlying etiologic factors. PMID- 28888835 TI - Disparities in gestational age-specific fetal mortality rates in the United States, 2009-2013. AB - PURPOSE: Although studies have examined overall temporal changes in gestational age-specific fetal mortality rates, there is little information on the current status of racial/ethnic differences. We hypothesize that differences exist between racial/ethnic groups across gestational age and that these differences are not equally distributed. METHODS: Using the 2009-2013 data from US fetal death and live birth files for non-Hispanic white (NHW); non-Hispanic black (NHB); Hispanic; and American Indian/Alaska Native (AIAN) women, we conducted analyses to examine fetal mortality rates and estimate adjusted prevalence rate ratios and 95% confidence intervals (CIs). RESULTS: There were lower risks of fetal mortality among NHB women (aPRR = 0.76; 95% CI = 0.71-0.81) and Hispanic women (aPRR = 0.89; 95% CI = 0.83-0.96) compared with NHWs at 22-23 weeks' gestation. For NHB women, the risk was higher starting at 32-33 weeks (aPRR = 1.11; 95% CI = 1.04-1.18) and continued to increase as gestational age increased. Hispanic and AIAN women had lower risks of fetal mortality compared with NHW women until 38-39 weeks. CONCLUSIONS: Further examination is needed to identify causes of fetal death within the later pregnancy period and how those causes and their antecedents might differ by race and ethnicity. PMID- 28888836 TI - Transcriptome sequencing and characterization of Symbiodinium muscatinei and Elliptochloris marina, symbionts found within the aggregating sea anemone Anthopleura elegantissima. AB - There is a growing body of literature using transcriptomic data to study how tropical cnidarians and their photosynthetic endosymbionts respond to environmental stressors and participate in metabolic exchange. Despite these efforts, our understanding of how essential genes function to facilitate symbiosis establishment and maintenance remains limited. The inclusion of taxonomically and ecologically diverse endosymbionts will enhance our understanding of these interactions. Here we characterize the transcriptomes of two very different symbionts found within the temperate sea anemone Anthopleura elegantissima: the chlorophyte Elliptochloris marina and the dinoflagellate Symbiodinium muscatinei. We use a multi-level approach to assess the diversity of genes found across S. muscatinei and E. marina transcriptomes, and compare their overall protein domains with other dinoflagellates and chlorophytes. Our analysis identified several genes that are potentially involved in mitigating stress response (e.g., heat shock proteins pathways for mediating reactive oxygen species) and metabolic exchange (e.g., ion transporters). Finally, we show that S. muscatinei and other Symbiodinium strains are equipped with a high salt peridinin-chl-protein (HSPCP) gene previously identified only in free-living dinoflagellates. The addition of these transcriptomes to the cnidarian-symbiont molecular toolkit will aid in understanding how these vitally important symbiotic relationships are established and maintained across a variety of environmental conditions. PMID- 28888837 TI - Left Ventricular Device Implantation Impacts on Hospitalisation Rates, Length of Stay and Out of Hospital Time. AB - BACKGROUND: Widespread application of left ventricular assist devices (LVADs) in advanced heart failure, is limited by costs, and access to technical expertise. Hospitalisation drives both cost and inversely, quality of life - but cross institutional and pre-surgical inpatient length of stay data is missing in the Australian literature. We describe changes in hospitalisation rates, in the year before and after bridge to transplant LVAD therapy and preceding heart transplant (HTX). METHODS: Hospitalisation, Australian refined diagnosis group (ArDRG), and clinical data were assessed for 77/100 consecutive patients listed for heart transplant between July of 2009 and June of 2012. Twenty-five of the patients required ventricular assist device (VAD) therapy whilst waitlisted. Hospitalisation was defined as the proportion of "days at risk" that were spent in hospital and included all public and private admissions identified in the year before and after VAD implant, or before HTX, in a linked administrative dataset of admissions across New South Wales. RESULTS: Patients requiring VADs were clinically more unstable and spent proportionally more time in hospital than pre HTX patients, (13% (IQR 10-20%) vs 4% (IQR1-10%), p<0.01). During the index admission, they spent 22days (IQR 10-33) in hospital before implantation, including 13 days in non-transplant centres (IQR 7-20). Following implantation, median inpatient stay was 31(IQR 26-70) - including rehabilitation in 8 of the 25 patients. The number of admissions per patient reduced in the year after VAD implant to two (IQR1-3), from five pre-implant (IQR 3-7) p=0.002. This was similar to the pre-HTX group's three admissions (IQR1-6), p=0.33. Overall hospitalisation decreased in VAD patients beyond the first year - from 14% (IQR 10-20%) at 1-year to 0.5% (IQR 0-10%) at 2-years (p=0.002). A high percentage of hospitalisation prior to VAD (41%) and HTX (66%) occurred outside the transplant centre. CONCLUSIONS: A high proportion of activity in the pre-implant and transplant year occurs outside the implanting hospital with higher pre-implant hospitalisation in VAD patients reflecting clinical severity. Ventricular assist device implantation is significantly associated with reduced admissions, and hospitalisation once reconditioning has occurred. PMID- 28888838 TI - Space for human connection in antenatal education: Uncovering women's hopes using Participatory Action Research. AB - OBJECTIVE: the aim of this research was to initiate active consultation with women and antenatal educators in the development and delivery of antenatal education that was mutually relevant. DESIGN: a Participatory Action Research approach influenced by feminist concerns was used to guide the research. Data were analysed by the researcher and participants using a Voice Centred Relational Method of Analysis. SETTING: an Antenatal Education service in a consultant-led tertiary referral unit in Ireland. FINDINGS: research findings revealed women's desires to build relationships through ANE to cope with anticipated loneliness and isolation after birth; however, environmental, structural, and organisational factors prohibited opportunity to build space for human connection. Participating women valued external and authoritative knowledge as truth, but concomitantly sought opportunity and space through classes to learn from the real life experiences of other mothers. Women lacked confidence in embodied knowing and their power to birth and demonstrated unquestioning acceptance of the predetermined nature of hospital birth and biomedical model of maternity care. KEY CONCLUSIONS: in this research, we envisioned that hospital-based ANE, relevant and grounded in the needs and life experiences of women, could be developed, with a view to supporting women's decision-making processes, and understanding of pregnancy, birth and early motherhood. Participatory Action Research using a Voice Centred Relational Method of Analysis offered an opportunity to foster ethical and dialogic activity between learner and facilitator, underpinned by acknowledgement of the value of women's experiences; however, space for expression of new and useful knowledge in preparation for motherhood was limited by institutional context. PMID- 28888839 TI - Oxidative stress and antioxidant defenses during blood processing and storage of erythrocyte concentrates. AB - Oxidative lesions start accumulating in cells when the oxidant attacks overwhelm the antioxidant defenses. This review will briefly describe red blood cell storage lesions with emphasis on the consequences of oxidation and the cellular defense mechanisms, as well as the methods that can be used to monitor them. The sources of variability in red blood cell storage capacity depend on the donor characteristics, the product processing and the storage conditions. Suggestions to improve the product quality in order to ensure the best efficacy and safety for the transfused patient are also discussed. PMID- 28888840 TI - Teneligliptin Prevents Cardiomyocyte Hypertrophy, Fibrosis, and Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats. AB - BACKGROUND: We investigated the effects of the dipeptidyl peptidase 4 inhibitor teneligliptin on cardiac function and hemodynamics during heart failure in hypertensive model rats. METHODS AND RESULTS: Fifty-five male Dahl salt-sensitive rats were divided into 4 groups: control group (0.3% NaCl chow; n = 13), hypertension (HT) group (8% NaCl chow; n = 20), HT-early TNL group (8% NaCl chow and teneligliptin from 6 weeks; n = 10), and HT-late TNL group (8% NaCl chow and teneligliptin from 10 weeks; n = 12). Hemodynamic measurement and tissue analyses were performed at 18 weeks. In all of the HT groups, systolic blood pressures were similarly elevated (P = .66) and heart weights similarly increased (P = .36) with and without TNL administration. LV end-diastolic dimension was significantly enlarged only in the HT-early TNL group compared with the control group (P = .025). Histologic analysis showed less fibrosis (P = .008) and cardiomyocyte widths (P = .009) in the HT-early TNL group compared with the HT group. On hemodynamic analysis, only the HT group showed significant LV end-diastolic pressure elevation (P = .049) and lung congestion (P < .001) compared with the control group. CONCLUSIONS: These results suggest that teneligliptin prevents concentric LV hypertrophy, fibrosis, and development of congestive heart failure in Dahl salt-sensitive rats. Teneligliptin may inhibit pressure-overload hypertrophic adaption and result in LV eccentric hypertrophy with reduced LV ejection fraction. PMID- 28888841 TI - Implications of the N-terminal heterogeneity for the neuronal K-Cl cotransporter KCC2 function. AB - The neuron-specific K-Cl cotransporter KCC2 maintains the low intracellular chloride concentration required for the fast hyperpolarizing responses of the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine. The two KCC2 isoforms, KCC2a and KCC2b differ by their N-termini as a result of alternative promoter usage. Whereas the role of KCC2b in mediating the chloride transport is unequivocal, the physiological role of KCC2a in neurons has remained obscure. We show that KCC2a isoform can decrease the intracellular chloride concentration in cultured neurons and attenuate calcium responses evoked by application of the GABAA receptor agonist muscimol. While the biotinylation assay detected both KCC2 isoforms at the cell surface of cultured neurons, KCC2a was not detected at the plasma membrane in immunostainings, suggesting that the N terminal KCC2a epitope is masked. Confirming this hypothesis, KCC2a surface expression was detected by the C-terminal KCC2 pan antibody but not by the N terminal KCC2a antibody in KCC2b-deficient neurons. One possible cause for the epitope masking is the binding site of Ste20-related proline-alanine-rich kinase (SPAK) in the KCC2a N-terminus. SPAK, a known regulator of K-Cl cotransporters, was co-immunoprecipitated in a complex with KCC2a but not KCC2b isoform. Moreover, SPAK overexpression decreased the transport activity of KCC2a but not that of KCC2b, as revealed by rubidium flux assay in HEK293 cells. Thus, our data indicate that both KCC2 isoforms perform as chloride cotransporters in neuronal cells, while their N-terminal heterogeneity could play an important role in fine tuning of the K-Cl transport activity. PMID- 28888843 TI - Food protein-induced enterocolitis syndrome to peanut with early introduction: a clinical dilemma. PMID- 28888842 TI - Evidence Refuting the Existence of Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA). AB - Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) was described in 2011. Over time the condition and its triggers have broadened to include several autoimmune disorders, the macrophagic myofasciitis syndrome, the Gulf war syndrome, the sick building syndrome, siliconosis, and the chronic fatigue syndrome. The aluminum-containing adjuvants in the hepatitis B vaccine and the human papillomavirus vaccine in particular have been stated to be the major causes of the disorder. Here, we review the specificity of the diagnostic criteria for ASIA. We also examine relevant human data, pertaining to causation, particularly from patients undergoing allergen-specific immunotherapy (IT). Patients undergoing allergen-specific IT receive 100 to 500 times more injected aluminum over 3 to 5 years, compared with hepatitis B and human papillomavirus vaccine recipients. In a large pharmacoepidemiological study, in contrast to case series of ASIA, patients receiving aluminum-containing allergen IT preparations were shown to have a lower incidence of autoimmune disease. In another clinical trial, there were no increases in exacerbations in a cohort of patients with systemic lupus erythematosus immunized with the hepatitis B vaccine. Current data do not support the causation of ASIA by vaccine adjuvants containing aluminum, which should be of reassurance to patients undergoing routine immunizations as well as to those undergoing allergen-specific IT. PMID- 28888844 TI - Recurrence of Chronic Urticaria: Incidence and Associated Factors. AB - BACKGROUND: Chronic urticaria (CU) is urticaria that has been present continuously or intermittently for at least 6 weeks. Although the prevalence and characteristics of CU are well established, little is known about recurrent CU (RCU). OBJECTIVES: We sought to establish a definition, determine the frequency, and evaluate risk factors for RCU. METHODS: A retrospective chart review of adult patients with CU evaluated at the University of Texas Southwestern allergy and immunology clinic was performed. RCU was defined as CU recurring at least 6 months after cessation of controller therapy and resolution of prior CU symptoms. Charts were reviewed for symptom resolution and recurrence, subtypes of CU (idiopathic, physical, and urticarial vasculitis), and medication usage (first line agents, alternative agents, and steroid dependence). RESULTS: Forty-five of 341 patients (13%) had RCU. The recurrence group had a higher frequency of alternative agent use at 57.8% (n = 26) compared with the nonrecurrence group at 34.8% (n = 103), which was statistically significant (P < .01). The rate of steroid dependence was similar in both groups (13.3% in the recurrence group vs 14.5%) and not statistically significant. Individuals exposed to anti inflammatory agents, immunosuppressants, and omalizumab had a significantly higher relative risk of recurrence compared with those who only used first-line agents (relative risk [RR] 2.32, P < .01; RR 2.69, P < .01; and RR 2.18, P = .05, respectively). CONCLUSIONS: RCU occurs in approximately 13% of patients with CU in our clinic population. Alternative agent use and antihistamine refractoriness appear to place patients at increased risk for recurrence compared with first line agent use alone. PMID- 28888845 TI - Eosinophilic esophagitis linked to pollen food syndrome. PMID- 28888846 TI - Diagnostic Accuracy of Urinary LTE4 Measurement to Predict Aspirin-Exacerbated Respiratory Disease in Patients with Asthma. AB - BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) are distinguished from patients with aspirin-tolerant asthma (ATA) by significantly higher baseline concentrations of urinary leukotriene E4 (uLTE4). However, an overlap between the individual values of the groups exists. OBJECTIVE: The objective of this study was to estimate the discriminative value of uLTE4 concentration in differentiating between patients with AERD and patients with ATA and evaluate the diagnostic accuracy of uLTE4 measurement alone and added to clinical parameters to predict AERD diagnosis in patients with asthma. METHODS: Clinical data were collected from questionnaires. Spirometry, skin prick tests, total IgE, and blood eosinophilia were evaluated. ULTE4 concentrations were measured in morning urine samples by enzyme-linked immune assay (ELISA). RESULTS: Patients with AERD (n = 247) had significantly higher uLTE4 concentrations than those with ATA (n = 239). The uLTE4 concentration of 800.0 pg/mg creatinine as measured by ELISA on a spot sample best discriminated the 2 groups (area under the curve 0.7; 95% confidence interval 0.66-0.74, sensitivity 49%, specificity 81%). The positive predictive value and negative predictive value (NPV), after considering the prevalence of AERD in the population of asthmatics, were 16% and 96%, respectively. Nasal polyps, upper airway symptoms, nasal corticosteroid treatment, asthma exacerbations, forced expiratory volume in the 1 second predicted, and age of asthma onset were independent predictors of AERD diagnosis. The addition of elevated uLTE4 concentration to the set of clinical parameters enhanced slightly the prediction of AERD diagnosis beyond the level predicted by clinical parameters (P = .036). CONCLUSIONS: A set of typical clinical parameters has a superior accuracy in prediction of AERD diagnosis than the measurement of uLTE4 concentration alone. The addition of uLTE4 concentration to clinical parameters slightly enhances the prediction of AERD diagnosis, especially due to a high NPV. PMID- 28888847 TI - Hereditary angioedema in 2 sisters due to paternal gonadal mosaicism. PMID- 28888848 TI - Prevention of oxytosis-induced c-Raf down-regulation by (arylthio)cyclopentenone prostaglandins is neuroprotective. AB - Prolonged exposure to high concentrations of glutamate leads to cell type specific glutathione depletion and resulting oxidative stress, known as oxytosis. As a result of glutathione depletion, accumulation of reactive oxygen species and Ca2+ influx are increased; however, the specific target of oxytosis has yet to be identified. In the present study, we focused on the effect of glutamate-induced oxidative stress on the extracellular-regulated protein kinase (ERK) pathway using the murine hippocampal HT22 cell line. Although the contribution of the ERK pathway to glutamate-induced oxytosis in HT22 cells is controversial, Western blot analysis revealed that glutamate caused down-regulation of mitogen-activated protein kinase kinase kinase (c-Raf) and a resulting decrease in the phosphorylation of c-Raf, as well as of mitogen-activated protein kinase kinase1/2 (MEK1/2) and ERK1/2, downstream components of the c-Raf/MEK/ERK pathway. Furthermore, neuroprotective (arylthio)cyclopentenone prostaglandins prevented glutamate-induced c-Raf down-regulation and consequently maintained the basal activity of c-Raf and its downstream signaling components. A pull-down assay using biotin-labeled cyclopentenone prostaglandins revealed that they preferentially bound to c-Raf relative to other signaling molecules of the ERK pathway, including Ras, MEK1/2, and ERK. These results suggest that neuroprotective (arylthio)cyclopentenone prostaglandins directly bind to c-Raf protein and protect cells from down-regulation of the c-Raf protein itself, resulting in neuroprotection against oxidative stress. PMID- 28888849 TI - Outcomes in non-metastatic treatment naive extremity osteosarcoma patients treated with a novel non-high dosemethotrexate-based, dose-dense combination chemotherapy regimen 'OGS-12'. AB - PURPOSE: High-dose methotrexate (HDMTX)-based regimens are widely used in osteosarcoma. However, mandatory in-patient treatment with complex pharmacokinetic monitoring requirement precludes its use, especially in resource constrained settings of low- and middle-income countries (LMICs). METHODS: All treatment naive consecutive patients of osteosarcoma were prospectively treated on a novel institutional regimen (named OGS-12) comprising of eight sequential doublets of the following drugs: doxorubicin, cisplatin and ifosfamide in four courses each, given in the neoadjuvant and adjuvant settings. Data were prospectively collected on baseline characteristics, histological response to neoadjuvant chemotherapy (NACT), toxicity, event-free survival (EFS) and overall survival (OS). RESULTS: Between 2011 and 2014, 317 treatment naive patients with extremity osteosarcoma were seen, of whom 237 (75%) were non-metastatic. Majority had high tumour burden, with mean tumour size of 10.45 cm, high serum lactate dehydrogenase (LDH) and serum alkaline phosphatase (SAP) in 71% and 88% respectively. A significant number (34%) were nutritionally challenged. Two hundred ten of 237 patients were analysable for histological response of which 58% had good response (viable cells <=10%). At the median follow-up of 34.31 (2 60) months, in intention-to-treat (ITT) analysis, the 5-year EFS and OS were 56% and 75% respectively; the same were 60% and 80% in per-protocol analysis. There was febrile neutropenia (FN) in 56%, grade 3/4 thrombocytopaenia in 22% and anaemia in 47% with two chemotoxic deaths. Ten percent of the patients had grade 3/4 diarrhoea and stomatitis and one patient developed grade 4 acute kidney injury requiring dialysis. Baseline SAP (per-protocol) for EFS and performance status (ITT) for OS were found to be independent variables. Histological response was an independent predictor for EFS and OS in both the analyses. CONCLUSIONS: In treatment naive patients with non-metastatic osteosarcoma, OGS-12 protocol, a dose-dense, non-HDMTX-based, novel, economic and easy to administer regimen produces comparable outcomes to international standards, with acceptable toxicity and is worthy of wider clinical application. PMID- 28888850 TI - Ultrasound-based follow-up does not increase survival in early-stage melanoma patients: A comparative cohort study. AB - INTRODUCTION: Different protocols have been used to follow up melanoma patients in stage I-II. However, there is no consensus on the complementary tests that should be requested or the appropriate intervals between visits. Our aim is to compare an ultrasound-based follow-up with a clinical follow-up. PATIENTS AND METHODS: Analysis of two prospectively collected cohorts of melanoma patients in stage IB-IIA from two tertiary referral centres in Barcelona (clinical-based follow-up [C-FU]) and Turin (ultrasound-based follow-up [US-FU]). Kaplan-Meier curves were used to evaluate distant metastases-free survival (DMFS), disease free interval (DFI), nodal metastases-free survival (NMFS) and melanoma-specific survival (MSS). RESULTS: A total of 1149 patients in the American Joint Committee on Cancer stage IB and IIA were included in this study, of which 554 subjects (48%) were enrolled for a C-FU, and 595 patients (52%) received a protocolised US FU. The median age was 53.8 years (interquartile range [IQR] 41.5-65.2) with a median follow-up time of 4.14 years (IQR 1.2-7.6). During follow-up, 69 patients (12.5%) in C-FU and 72 patients (12.1%) in US-FU developed disease progression. Median time to relapse for the first metastatic site was 2.11 years (IQR 1.14 4.04) for skin metastases, 1.32 (IQR 0.57-3.29) for lymph node metastases and 2.84 (IQR 1.32-4.60) for distant metastases. The pattern of progression and the total proportion of metastases were not significantly different (P = .44) in the two centres. No difference in DFI, DMFS, NMFS and MSS was found between the two cohorts. CONCLUSION: Ultrasound-based follow-up does not increase the survival of melanoma patients in stage IB-IIA. PMID- 28888851 TI - Long term longitudinal study of muscle function in patients with glycogen storage disease type IIIa. AB - Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme. Current therapy is based on dietary adaptations but new preclinical therapies are emerging. The identification of outcome measures which are sensitive to disease progression becomes critical to assess the efficacy of new treatments in upcoming clinical trials. In order to prepare future longitudinal studies or therapeutic trials with large cohorts, information about disease progression is required. In this study we present preliminary longitudinal data of Motor Function Measure (MFM), timed tests, Purdue pegboard test, and handgrip strength collected over 5 to 9years of follow-up in 13 patients with GSDIII aged between 13 and 56years old. Follow-up for nine of the 13 patients was up to 9years. Similarly to our previous cross-sectional retrospective study, handgrip strength significantly decreased with age in patients older than 37years. MFM scores started to decline after the age of 35. The Purdue pegboard score also significantly reduced with increasing age (from 13years of age) but with large inter-visit variations. The time to stand up from a chair or to climb 4 stairs increased dramatically in some but not all patients older than 30years old. In conclusion, this preliminary longitudinal study suggests that MFM and handgrip strength are the most sensitive muscle function outcome measures in GSDIII patients from the end of their third decade. Sensitive muscle outcome measures remain to be identified in younger GSDIII patients but is challenging as muscle symptoms remain discrete and often present as accumulated fatigue. PMID- 28888852 TI - Renal endoplasmic reticulum stress is coupled to impaired autophagy in a mouse model of GSD Ia. AB - GSD Ia (von Gierke Disease, Glycogen Storage Disease Type Ia) is a devastating genetic disorder with long-term sequelae, such as non-alcoholic fatty liver disease and renal failure. Down-regulated autophagy is involved in the development of hepatic metabolic dysfunction in GSD Ia; however, the role of autophagy in the renal pathology is unknown. Here we show that autophagy is impaired and endoplasmic reticulum (ER) stress is increased in the kidneys of a mouse model of GSD Ia. Induction of autophagy by rapamycin also reduces this ER stress. Taken together, these results show an additional role for autophagy down regulation in the pathogenesis of GSD Ia, and provide further justification for the use of autophagy modulators in GSD Ia. PMID- 28888853 TI - Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. AB - Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures. Asfotase alfa is a human, recombinant enzyme replacement therapy that is approved in many countries for the treatment of patients with HPP. To address the unmet need for guidance in the monitoring of patients receiving asfotase alfa, an international panel of physicians with experience in diagnosing and managing HPP convened in May 2016 to discuss treatment monitoring parameters. The panel discussions focused on recommendations for assessing and monitoring patients after the decision to treat with asfotase alfa had been made and did not include recommendations for whom to treat. Based on the consensus of panel members, this review provides guidance on the monitoring of patients with HPP during treatment with asfotase alfa, including recommendations for laboratory, efficacy, and safety assessments and the frequency with which these should be performed during the course of treatment. Recommended assessments are based on patient age and include regular monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life. Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient focused approach is recommended in the management of patients receiving asfotase alfa. Monitoring of efficacy and safety outcomes must be tailored to the individual patient, depending on medical history, clinical manifestations, availability of resources in the clinical setting, and the clinician's professional judgment. PMID- 28888854 TI - Quantitation of phenylbutyrate metabolites by UPLC-MS/MS demonstrates inverse correlation of phenylacetate:phenylacetylglutamine ratio with plasma glutamine levels. AB - Urea cycle disorders (UCDs) are genetic conditions characterized by nitrogen accumulation in the form of ammonia and caused by defects in the enzymes required to convert ammonia to urea for excretion. UCDs include a spectrum of enzyme deficiencies, namely n-acetylglutamate synthase deficiency (NAGS), carbamoyl phosphate synthetase I deficiency (CPS1), ornithine transcarbamylase deficiency (OTC), argininosuccinate lyase deficiency (ASL), citrullinemia type I (ASS1), and argininemia (ARG). Currently, sodium phenylbutyrate and glycerol phenylbutyrate are primary medications used to treat patients with UCDs, and long-term monitoring of these compounds is critical for preventing drug toxic levels. Therefore, a fast and simple ultra-performance liquid chromatography (UPLC-MS/MS) method was developed and validated for quantification of phenylbutyrate (PB), phenylacetate (PA), and phenylacetylglutamine (PAG) in plasma and urine. The separation of all three analytes was achieved in 2min, and the limits of detection were <0.04MUg/ml. Intra-precision and inter-precision were <8.5% and 4% at two quality control concentrations, respectively. Average recoveries for all compounds ranged from 100% to 106%. With the developed assay, a strong correlation between PA and the PA/PAG ratio and an inverse correlation between PA/PAG ratio and plasma glutamine were observed in 35 patients with confirmed UCDs. Moreover, all individuals with a ratio >=0.6 had plasma glutamine levels<1000MUmol/l. Our data suggest that a PA/PAG ratio in the range of 0.6-1.5 will result in a plasma glutamine level<1000MUmol/l without reaching toxic levels of PA. PMID- 28888855 TI - Cytomegalovirus associated severe pneumonia, multi-organ failure and Ganciclovir associated arrhythmia in immunocompetent child. AB - Cytomegalovirus (CMV) can rarely cause severe manifestations in immunocompetent individuals. Hereby, we report a twelve-year-old boy who presented with tachycardia, tachypnea, fever and leukocytosis, which progressed to hypoxemic respiratory failure and severe acute respiratory distress syndrome (ARDS). Subsequently, he developed multi-organ failure despite the ongoing full supportive care and empiric broad spectrum antibiotics. Cytomegalovirus infection was diagnosed by Polymerase Chain Reaction (PCR) in blood and histopathological examination of lung biopsy. Immunological work up for the child was unremarkable. Ganciclovir therapy was introduced and showed significant improvement until full recovery. However, our patient developed transient heart block as a rare complication for Ganciclovir therapy throughout his course. We present this case with literature review for the CMV infection associated morbidity and mortality among immunocompetent children. PMID- 28888856 TI - Computational models of basal ganglia dysfunction: the dynamics is in the details. AB - The development, simulation, and analysis of mathematical models offer helpful tools for integrating experimental findings and exploring or suggesting possible explanatory mechanisms. As models relating to basal ganglia dysfunction have proliferated, however, there has not always been consistency among their findings. This work points out several ways in which biological details, relating to ionic currents and synaptic pathways, can influence the dynamics of models of the basal ganglia under parkinsonian conditions and hence may be important for inclusion in models. It also suggests some additional useful directions for future modeling studies relating to basal ganglia dysfunction. PMID- 28888857 TI - Modelling plasticity in dendrites: from single cells to networks. AB - One of the key questions in neuroscience is how our brain self-organises to efficiently process information. To answer this question, we need to understand the underlying mechanisms of plasticity and their role in shaping synaptic connectivity. Theoretical neuroscience typically investigates plasticity on the level of neural networks. Neural network models often consist of point neurons, completely neglecting neuronal morphology for reasons of simplicity. However, during the past decades it became increasingly clear that inputs are locally processed in the dendrites before they reach the cell body. Dendritic properties enable local interactions between synapses and location-dependent modulations of inputs, rendering the position of synapses on dendrites highly important. These insights changed our view of neurons, such that we now think of them as small networks of nearly independent subunits instead of a simple point. Here, we propose that understanding how the brain processes information strongly requires that we consider the following properties: which plasticity mechanisms are present in the dendrites and how do they enable the self-organisation of synapses across the dendritic tree for efficient information processing? Ultimately, dendritic plasticity mechanisms can be studied in networks of neurons with dendrites, possibly uncovering unknown mechanisms that shape the connectivity in our brains. PMID- 28888859 TI - Determination of heavy metal toxicity by using a micro-droplet hydrodynamic voltammetry for microalgal bioassay based on alkaline phosphatase. AB - We developed an electrochemical microalgal bioassay for the determination of heavy metal toxicity in water on the basis of the alkaline phosphatase (ALP) enzyme inhibition of Chlamydomonas reinhardtii. Five heavy metals were chosen as toxicants: Hg, Cd, Pb, Zn, and Cu. The induced ALP activity of C. reinhardtii was inhibited using the phosphate starvation method, and the results were evaluated by measuring the electrochemical oxidation of p-aminophenol (PAP) following the enzymatic conversion of p-aminophenyl phosphate (PAPP) as a substrate. The rapid determination of enzymatic activity was achieved using hydrodynamic voltammetry in a 50 MUL micro-droplet with a rotating disk electrode (RDE). Enzymatic activity over a PAPP substrate is affected by heavy metal ions, and this phenomenon decreases the chronoamperometric current signal. The concentrations of Hg, Cd, Pb, Zn, and Cu in which the ALP activity was half that of the control (EC50) were found to be 0.017, 0.021, 0.27, 1.30, and 1.36 MUM, respectively. The RDE system was demonstrated to be capable of detecting enzymatic activity by using a small amount of regent, a reaction time of only 60 s, and a detection limit of 5.4 * 10-7 U. PMID- 28888861 TI - Development of nanohybrid adsorbent for defluoridation from aqueous systems. AB - The objective of present study is advancement of an efficient nanomaterial which was investigated to substantiate its efficiency, using kinetic studies to ensnare fluoride in order to make water potable. A new crystalline ZrAlCa nanohybrid adsorbent for fluoride removal was successfully synthesized by a co-precipitation method in this study. The prepared adsorbents were characterized by XRD, FT-IR, TGA, BET and FESEM and EDX. The adsorption properties of the developed adsorbent were studied using batch adsorption method which shown the noticeable fluoride removal efficiency up to 99% at near neutral pH as well as in acidic pH range. The reaction kinetics for adsorption of fluoride was established using reaction based kinetic models which fitted well with Avarami kinetic model as compared to pseudo-first-order, pseudo second-order and power function rate expression. The equilibrium isotherm modelling described adsorption process and Langmuir, Jovanovic, Temkin and Freundlich isotherms provides best fit to experimental data. The fluoride loaded adsorbent was efficiently regenerated by using an alkali solution and has no significant counter ion effect on fluoride adsorption efficiency. Interestingly, the developed nanomaterial has fluoride removal efficacy over varied concentration ranges. It has capability of reanimate and reuse the nanohybrid adsorbent makes it an attractive sustainable material. PMID- 28888860 TI - Natural soil mediated photo Fenton-like processes in treatment of pharmaceuticals: Batch and continuous approach. AB - This paper manifests the potential viability of soil as a cost-free catalyst in photo-Fenton-like processes for treating pharmaceuticals at large scale. Naturally available soil without any cost intensive modification was utilized as a catalyst to degrade pharmaceuticals, specifically ornidazole (ORZ) and ofloxacin (OFX). Soil was characterized and found enriched with various iron oxides like hematite, magnetite, goethite, pyrite and wustite, which contributes toward enhanced dissolution of Fe3+ than Fe2+ in the aqueous solution resulting in augmented rate of photo-Fenton reaction. The leached iron concentration in solution was detected during the course of experiments. The degradation of ORZ and OFX was assessed in solar induced batch experiments using H2O2 as oxidant and 95% ORZ and 92% OFX removal was achieved. Elevated efficiencies were achieved due to Fe2+/Fe3+ cycling, producing more hydroxyl radical leading to the existence of homogeneous and heterogeneous reactions simultaneously. The removal efficiency of solar photo-Fenton like process was also compared to photo-Fenton process with different irradiation sources (UV-A and UV-B) and were statistically analysed. Continuous-scale studies were conducted employing soil either in the form of soil beads or as a thin layer spread on the surface of baffled reactor. Soil beads were found to have satisfactory reusability and stability. 84 and 79% degradation of ORZ and OFX was achieved using soil as thin layer while with soil beads 71 and 68% degradation, respectively. HPLC and TOC study confirmed the efficient removal of both the compounds. Toxicity assessment demonstrates the inexistence of toxic intermediates during the reaction. PMID- 28888862 TI - Nitrogen dioxide radicals mediated mineralization of perfluorooctanoic acid in aqueous nitrate solution with UV irradiation. AB - Effective decomposition of perfluorooctanoic acid (PFOA) has received increasing attention in recent years because of its global occurrence and resistance to most conventional treatment processes. In this study, the complete mineralization of PFOA was achieved by the UV-photolysis of nitrate aqueous solution (UV/Nitrate), where the in-situ generated nitrogen dioxide radicals (NO2) efficiently mediated the degradation of PFOA. In particular, when the twinborn hydroxyl radicals were scavenged, the production of more NO2 radicals realized the complete mineralization of PFOA. DFT calculations further confirm the feasibility of PFOA removal with NO2. Near-stoichiometric equivalents of fluoride released rather than the related intermediates were detected in solution after decomposition of PEOA, further demonstrating the complete degradation of PFOA. Possible PFOA degradation pathways were proposed on the basis of experimental results. This work offers an efficient strategy for the complete mineralization of perfluorinated chemicals, and also sheds light on the indispensable roles of nitrogen dioxide radicals for environmental pollutants removal. PMID- 28888863 TI - Increased insulin resistance in men with unexplained infertility. AB - This prospective case-control study aimed to test the presence of insulin resistance (IR) in men with unexplained infertility. We included two groups: the study group including 160 infertile men with unexplained oligozoospermia (sperm count <10 * 106/ml) and normal hormonal profile, and the control group of 79 men with proven fertility within the preceding year. A fasting blood test measured IR, FSH, LH, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides. Insulin level was significantly higher in the study group (13.67 +/- 10.44) compared with the control group (5.46 +/- 3.15), P < 0.0001, and IR was significantly higher in the study group, P < 0.0001. FSH was significantly (P < 0.0001) higher in the study group (4.71 +/- 2.57) than the control group (3.15 +/- 1.92). LH was significantly higher in the study group (4.98 +/- 2.41) compared with the control group (3.15 +/- 1.12), P < 0.0001. Total cholesterol was significantly higher in the study group (198.29 +/- 37.52) than the control group (182.45 +/- 35.92), P < 0.05. In conclusion, IR in men with unexplained infertility may be a cause of reproductive and metabolic abnormalities. The benefit of insulin-sensitizing agents for these patients should be tested. PMID- 28888864 TI - Predictors of supplementation for breastfed babies in a Baby-Friendly hospital. AB - PROBLEM: Supplementation of breastfed babies is common during the hospital stay. BACKGROUND: The Baby Friendly Hospital Initiative (BFHI) optimises practices to support exclusive breastfeeding, yet supplementation is still prevalent. OBJECTIVE: To determine predictors for supplementation in a cohort of breastfed babies in a Baby-Friendly hospital. METHODS: Electronic hospital records of 1530 healthy term or near term singleton infants and their mothers were examined retrospectively and analysed to identify factors associated with in-hospital supplementation using Poisson regression (unadjusted and adjusted). FINDINGS: Fifteen percent of breastfed infants were supplemented during their hospital stay. Analysis by multivariable Poisson regression found that supplementation was independently associated with overweight (reference normal weight) (aRR [adjusted relative risk]=1.46; 95% CI: 1.11-1.93); primiparity (aRR=1.40; 95% CI: 1.09 1.80); early term gestation (37-376 weeks, aRR=2.79; 95% CI: 1.88-4.15; 38-386 weeks, aRR=2.03, 95%CI: 1.46-2.82); birthweight less than 2500 grams (reference 3000-3499 grams) (aRR=3.60; 95% CI: 2.32-5.60) and use of postpartum uterotonic (aRR=2.47; 95% CI: 1.09-5.55). Greater than 65 minutes of skin-to-skin contact at birth reduced the risk of supplementation (aRR=0.66; 95% CI; 0.48-0.92). CONCLUSION: These identified predictors for supplementation, can inform the development of interventions for mother-infant pairs antenatally or in the early postpartum period around increased breastfeeding education and support to reduce supplementation. It may also be possible to reduce supplementation through judicious use of postpartum uterotonics and facilitation of mother-infant skin-to skin contact at birth for greater than one hour duration. PMID- 28888865 TI - Changes in foot posture during pregnancy and their relation with musculoskeletal pain: A longitudinal cohort study. AB - AIM: To examine foot posture changes during the three trimesters of pregnancy and to determine whether there is a relationship between these changes and the pain experienced in this period. METHODS: The study sample consisted of 62 pregnant women who attended the Gynaecology Service at Hospital Santa Maria del Puerto (Cadiz, Spain), between January 2013 and May 2014. In their first visit, the following sociodemographic and anthropometric data were recorded: age, weight, height and foot size. In addition, information was obtained regarding pain in the lower back, knees, ankles and feet. In this first visit, too, the Foot Posture Index (FPI) was assessed, and three subsequent controls were performed during the first, second and third months of pregnancy (termed Stages 1, 2 and 3, respectively). RESULTS: In Stage 1, the average foot size (i.e., shoe size) was 38.3 (SD 1.5). This size did not change between Stages 1, 2 and 3. However, body weight and BMI did present statistically significant changes during this period (p<0.0001). The FPI varied during pregnancy but no relation was observed between these changes and the onset of pain. CONCLUSIONS: During pregnancy, pronation increases but this does not appear to influence the onset of pain in the lower limbs. PMID- 28888866 TI - Everolimus Versus Axitinib as Second-line Therapy in Metastatic Renal Cell Carcinoma: Experience From Institut Gustave Roussy. AB - BACKGROUND: Everolimus (E) and axitinib (A) have been standard treatments for patients with metastatic renal cell carcinoma after failure of first-line therapy (1L) with vascular endothelial growth factor-targeted therapy. This study aims to compare both drugs in a large comprehensive cancer center. METHODS: Patient characteristics and outcome data from all patients with metastatic renal cell carcinoma who received E or A as second-line therapy at Gustave Roussy from April 2007 to May 2015 have been recorded. RESULTS: A total of 81 patients were treated with E and 45 patients with A. There were no major differences between the 2 groups. The most common 1L was sunitinib (79% in the E group and 82.2% in the A group). The median follow-up was 29 months; 26 months for A and 33 months for E (P = .046). The median overall survival (OS) was 21.5 months for E and 14.9 months for A (P = .23). The median progression-free survival (PFS) was 5.3 and 7.7 months for E and A, respectively (P = .39). Partial response was achieved in 4% and in 24% of patients (P = .002) in the E and A cohort, respectively. In the A group, the median PFS and OS were statistically different according to response, tumor burden, and 1L duration. No differences were found in the E arm. CONCLUSION: In this series, there are no significant differences for PFS and OS with E and A. A appears to provide more objective response. A appears to be more effective in patients with small tumor burden, responders to 1L, and 1L therapy > 12 months. PMID- 28888867 TI - PICK1 facilitates lasting reduction in GluA2 concentration in the hippocampus during chronic epilepsy. AB - Overstimulation of glutamate receptors resulting in excessive intracellular calcium concentrations is a major cause of neuronal cell death in epilepsy. The main source of increased calcium concentration during this excitotoxicity is an influx through NMDA subtype of glutamate receptors. The GluR2 (GluA2) hypothesis states that following a neurological insult such as an epileptic seizure, the AMPA receptor subunit GluR2 protein is downregulated. This increases the likelihood of the formation of GluR2-lacking, calcium-permeable AMPA receptor which might further enhance the toxicity of the neurotransmitter, glutamate. The cytosolic protein, PICK1, facilitates the removal of GluA2 subunits from the synaptic plasma membrane. High calcium concentrations may cause PICK1 to bind to the GluA2 subunit of calcium-impermeable AMPARs, leading to an increased internalization of these receptor subunits and a relative increase of GluA2 lacking, calcium-permeable AMPARs. This further escalates the cytosolic calcium concentration. In order to test this hypothesis, we have used kainic acid to induce epilepsy in rats. Using semi-quantitative western blotting combined with univariate and multivariate statistical analyses, we found that both GluA2 and PICK1 were down-regulated in kainate-treated rats for as long as eight weeks after induction of epilepsy. An interesting finding was that statistical analysis indicates that the functional role of PICK1 in our material is to increase GluA2 concentrations in the cells. The observed reduction in PICK1 concentration may thus be an independent contributor to the observed GluA2 reduction. This reduction may possibly be an adaptive mechanism, serving to prevent further loss of GluA2 from the synapses. PMID- 28888868 TI - Acute Right Upper Quadrant Abdominal Pain. PMID- 28888869 TI - Development of a set of multiplex PCRs for detection of genes encoding cell wall associated proteins in Staphylococcus pseudintermedius isolates from dogs, humans and the environment. AB - Staphylococcus pseudintermedius commonly colonizes the skin of dogs, whilst nasal carriage may occur in humans who are in contact with dogs or the environment of veterinary hospitals. Genes encoding cell wall-associated (CWA) proteins have been described in Staphylococcus aureus but knowledge of their occurrence in S. pseudintermedius is still limited. The aim of the study was to develop a method to detect S. pseudintermedius surface protein genes (sps) encoding CWA proteins, and to examine the distribution of the genes in isolates from different sources. Four multiplex PCR assays (mPCR) were developed for detection of 18 sps genes, with 4-5 genes detected per mPCR. These were applied to 135 S. pseudintermedius isolates from carriage sites (n=35) and infected sites (n=35) in dogs, from the nasal cavity of humans (n=25), and from the environment of a veterinary hospital (n=40). The mPCRs were shown to detect all 18 known sps genes, and no discrepancies were found between uniplex and mPCR results. The mPCRs could detect at least 1pg/MUl of DNA template. A total of 23 sps gene profiles were found among the 135 isolates, with diverse gene combinations. Only spsD, spsF, spsI, spsO, spsP, and spsQ were not detected in all isolates. spsP and spsQ were more frequently detected in the canine isolates from infected sites than from carriage sites. This finding suggests that these two genes may play a role in pathogenicity, whereas the presence of the 12 sps genes may contribute to adherence function at all surfaces where carriage occurs. PMID- 28888870 TI - Efficient differentiation of Corynebacterium striatum, Corynebacterium amycolatum and Corynebacterium xerosis clinical isolates by multiplex PCR using novel species-specific primers. AB - A multiplex-PCR (mPCR) assay was designed with species-specific primers which generate amplicons of 226bp, 434bp and 106bp for differentiating the species C. striatum, C. amycolatum, and C. xerosis, respectively. mPCR results were 100% in agreement with identifications achieved by 16S rRNA and rpoB gene sequencing and by VITEK-MS. PMID- 28888871 TI - Interplay of mitochondria apoptosis regulatory factors and microRNAs in valvular heart disease. AB - Valvular heart disease (VHD) is an active process involving a wide range of pathological changes. The major complications of VHD are stenosis and regurgitation, which are macroscopic phenomena, induced in part through cellular changes. Altered expression of mitochondria associated genes causes membrane potential depolarization, leading to the increased levels of apoptosis observed in cardiac dysfunction. Objective of this study is to find molecular medicine candidates that can control expression of the key mitochondria apoptosis regulatory genes. Present study aims to assess the way microRNA are involved in regulating mitochondrial apoptosis regulatory genes and observation of their expression in the heart valve dysfunction. Apoptotic genes PUMA and DRP1 were found to be highly expressed, whereas anti-apoptotic gene ARC was down regulated. The expression level of GATA-4 transcription factor was also reduced in cardiac valve tissues. MicroRNAs miR-15a and miR-29a were repressed, while miR-214 was up regulated. Furthermore, study showed that PUMA, DRP1 and ARC expression might be attenuated by their respective miRNAs. Our results indicate that mitochondria regulatory genes might be controlled by miR-15a, miR-29a and miR-214, in VHD patients. Present study may provide platform for future research regarding potential therapeutic role of miRNAs in CVDs. PMID- 28888872 TI - The catalytic activity of a recombinant single chain variable fragment nucleic acid-hydrolysing antibody varies with fusion tag and expression host. AB - The antigen-binding properties of single chain Fv antibodies (scFvs) can vary depending on the position and type of fusion tag used, as well as the host cells used for expression. The issue is even more complicated with a catalytic scFv antibody that binds and hydrolyses a specific antigen. Herein, we investigated the antigen-binding and -hydrolysing activities of the catalytic anti-nucleic acid antibody 3D8 scFv expressed in Escherichia coli or HEK293f cells with or without additional amino acid residues at the N- and C-termini. DNA-binding activity was retained in all recombinant forms. However, the DNA-hydrolysing activity varied drastically between forms. The DNA-hydrolysing activity of E. coli-derived 3D8 scFvs was not affected by the presence of a C-terminal human influenza haemagglutinin (HA) or His tag. By contrast, the activity of HEK293f derived 3D8 scFvs was completely lost when additional residues were included at the N-terminus and/or when a His tag was incorporated at the C-terminus, whereas a HA tag at the C-terminus did not diminish activity. Thus, we demonstrate that the antigen-binding and catalytic activities of a catalytic antibody can be separately affected by the presence of additional residues at the N- and C termini, and by the host cell type. PMID- 28888874 TI - A kinetic approach to conflict theory and aggregation/secession of countries: Comment on "Modeling human behavior in economics and social science" by Marina Dolfin, Leone Leonida, and Nisrina Outada. PMID- 28888873 TI - Comparison of regadenoson and nitroprusside to adenosine for measurement of fractional flow reserve: A systematic review and meta-analysis. AB - BACKGROUND: FFR is useful in defining the physiological significance of intermediate coronary stenosis and requires induction of maximal hyperemia and measurement of pressure proximal and distal to the stenosis. Hyperemia normally is induced by either IV or IC adenosine, a medication associated with short-term side effects. IV regadenoson and IC nitroprusside have been suggested as viable alternatives. This meta-analysis aims to identify all studies comparing use of intravenous (IV) regadenoson or intracoronary (IC) nitroprusside with IV adenosine to determine differences related to the agent utilized for assessment of fractional flow reserve (FFR). METHODS: We searched PubMed, EMBASE, Web of Science, SCOPUS, ClinicalTrials.gov and the Cochrane Library databases for studies comparing IV regadenoson or IC nitroprusside to IV adenosine for FFR assessment. The main outcome was difference in mean FFR measurement. The main secondary outcomes were composite side-effect profile and reclassification of lesions. RESULTS: Seven studies were included in the analysis, with a total of 375 patients. Compared to IV adenosine, there was no difference in the mean FFR derived from IV regadenoson (p=1.0) or IC nitroprusside (p=0.48). IV regadenoson was associated with 53% lower risk of pooled side effects compared to IV adenosine (p=0.05). IC nitroprusside was associated with 97% lower risk of pooled side effects compared to IV adenosine (p<0.001). CONCLUSIONS: IV regadenoson and IC nitroprusside produce similar pressure-derived FFR measurements compared to IV adenosine and have a favorable side effect profile. Both can be considered as alternative agents to IV adenosine for FFR measurement. Further clinical validation is warranted. PMID- 28888875 TI - Imazalil exposure induces gut microbiota dysbiosis and hepatic metabolism disorder in zebrafish. AB - The fungicide imazalil (IMZ) is used extensively to preserve freshness, prevent decay and control fungal infections in fruits, vegetables or other plants. Recently, some studies have reported that the real in aquatic systems have reached very high levels. Here, male adult zebrafish were exposed to 100 and 1000MUg/L IMZ for 1, 7, 21days, and the gut microbiota and hepatic metabolism were evaluated. Exposure to a high concentration of IMZ for 21days decreased mucin secretion in the gut. Sequencing of the V3-V4 region of the bacterial 16S rRNA gene revealed a significant increase in the diversity of gut microbiota in male zebrafish. At the phylum level, the composition of Proteobacteria and Bacteroidetes was decreased, while those Fusobacteria and Firmicutes increased in the gut after exposure to 1000MUg/L IMZ for 21days. At the genus level, 29 species of microorganisms were significantly changed after IMZ exposure. Based on GC/MS metabolomics analysis, 101 metabolites were observably significantly altered in the 1000MUg/L IMZ-treatment group. These changed metabolites were mainly associated with the pathway of glycolysis, amino acid metabolism, and lipid metabolism. In addition, the transcription of some genes related to glycolysis and lipid metabolism, including Aco, Cpt1, Acc1, Srebp1a and Fas, was decreased significantly in the liver of zebrafish when exposed to 100 and 1000MUg/L IMZ for 7 or 21days. These results indicated that exposure to IMZ could cause gut microbiota dysbiosis and metabolic disorders in adult zebrafish. PMID- 28888876 TI - Hemolymph and gill carbonic anhydrase are more sensitive to aquatic contamination than mantle carbonic anhydrase in the mangrove oyster Crassostrea rhizophorae. AB - Carbonic anhydrase (CA) is a ubiquitous metalloenzyme of great importance in several physiological processes. Due to its physiological importance and sensitivity to various pollutants, CA activity has been used as biomarker of aquatic contamination. Considering that in bivalves the sensitivity of CA to pollutants seems to be tissue-specific, we proposed here to analyze CA activity of hemolymph, gill and mantle of Crassostrea rhizophorae collected in two tropical Brazilian estuaries with different levels of anthropogenic impact, in dry and rainy season. We found increased carbonic anhydrase activity in hemolymph, gill and mantle of oysters collected in the Paraiba Estuary (a site of high anthropogenic impact) when compared to oysters from Mamanguape Estuary (inserted in an area of environmental preservation), especially in the rainy season. CA of hemolymph and gill were more sensitive than mantle CA to aquatic contamination. This study enhances the suitability of carbonic anhydrase activity for field biomarker applications with bivalves and brings new and relevant information on hemolymph carbonic anhydrase activity as biomarker of aquatic contamination. PMID- 28888877 TI - The role of charge in the toxicity of polymer-coated cerium oxide nanomaterials to Caenorhabditis elegans. AB - This study examined the impact of surface functionalization and charge on ceria nanomaterial toxicity to Caenorhabditis elegans. The examined endpoints included mortality, reproduction, protein expression, and protein oxidation profiles. Caenorhabditis elegans were exposed to identical 2-5nm ceria nanomaterial cores which were coated with cationic (diethylaminoethyl dextran; DEAE), anionic (carboxymethyl dextran; CM), and non-ionic (dextran; DEX) polymers. Mortality and reproductive toxicity of DEAE-CeO2 was approximately two orders of magnitude higher than for CM-CeO2 or DEX-CeO2. Two-dimensional gel electrophoresis with orbitrap mass spectrometry identification revealed changes in the expression profiles of several mitochondrial-related proteins and proteins that are expressed in the C. elegans intestine. However, each type of CeO2 material exhibited a distinct protein expression profile. Increases in protein carbonyls and protein-bound 3-nitrotyrosine were also observed for some proteins, indicating oxidative and nitrosative damage. Taken together the results indicate that the magnitude of toxicity and toxicity pathways vary greatly due to surface functionalization of CeO2 nanomaterials. PMID- 28888878 TI - Effect of vitamin D supplementation on knee osteoarthritis: A systematic review and meta-analysis of randomized clinical trials. AB - OBJECTIVE: To provide evidence regarding the effect of vitamin D supplementation on symptomatic knee osteoarthritis (OA). METHODS: A systematic review and meta analysis was performed to quantitatively pool the results from randomized clinical trials. Studies were identified from a search of the Embase, MEDLINE and Web of Science databases up to January 22, 2017, and also from conference abstracts, ClinicalTrials.gov and the reference lists of identified studies. A standardized mean difference (SMD) was used to assess effect sizes, as outcomes were reported on different scales. Depending on the degree of heterogeneity, random-effects or fixed-effects models were used to pool outcomes. RESULTS: Up to January 22, 2017, four clinical trials containing 570 subjects in the vitamin D supplementation group and 560 subjects in the placebo group were identified. All of the included studies were of high quality and had a low risk of bias for each domain. The results indicated that vitamin D supplementation had a statistically significant but small-to-moderate effect on pain control in patients with knee OA (SMD=-0.32, 95% CI: -0.63 to -0.02). However, no effects were observed for the change in tibial cartilage volume (SMD=0.12, 95% CI: -0.05 to 0.29) or joint space width (SMD=0.07, 95% CI: -0.08 to 0.23). The subgroup analysis indicated that vitamin D supplementation had no significant effect regardless of whether patients had sufficient or insufficient serum 25(OH)D levels at baseline. CONCLUSIONS: The results of this study indicate that vitamin D supplementation may not have a clinically significant effect on pain control or structure progression among patients with knee OA. Longer-term clinical trials with rigorous measurement of symptom and radiologic changes are required to further clarify the effect of vitamin D supplementation in patients with symptomatic knee OA and low serum 25(OH)D levels. PMID- 28888879 TI - Fast form alpha-2-macroglobulin - A marker for protease activation in plasma exposed to artificial surfaces. AB - OBJECTIVES: Investigation of the blood compatibility requires a number of sensitive assays to quantify the activation of the blood protein cascades and cells induced by biomaterials. A global assay measuring the blood compatibility of biomaterials could be a valuable tool in such regard. In this study, we investigated whether an enzyme-linked immunosorbent assay (ELISA), that specifically measures the electrophoretic "fast form" of alpha2-macroglobulin (F alpha2M), could be a sensitive and global marker for activation of calcium dependent and in-dependent proteases in plasma exposed to biomaterials in vitro. METHODS: A F-alpha2M specific monoclonal antibody was generated and applied in an ELISA setup. Using the F-alpha2M ELISA, we investigated activation of calcium dependent and in-dependent proteases by polyvinylchloride (n=10), polytetrafluoroethylene (n=10) and silicone (n=10) tubings as well as glass tubes (n=10). RESULTS: We found that F-alpha2M is a sensitive marker for activation of both calcium dependent and in-dependent proteases. A significant difference between F-alpha2M concentrations in the control sample and plasma exposed to the artificial surfaces was found (p>0.001). This was observed both in the presence and absence of calcium. Furthermore, the highest F-alpha2M concentration was in both cases found in plasma incubated with glass. CONCLUSIONS: Our findings demonstrate that F-alpha2M is a sensitive marker for detection of protease activation in plasma by artificial surfaces. Potentially, levels of F-alpha2M could be a global marker of the blood compatibility of biomaterials. PMID- 28888880 TI - Nutritional support in preterm infants. PMID- 28888881 TI - Prevalence and genetic profiling of tetracycline resistance (Tet-R) genes and transposable element (Tn916) in environmental Enterococcus species. AB - Resistance against antimicrobial agents in enterococci is a global concern that not only challenges infection therapy but also make them reservoir of antibiotic resistance in human and animal alike. This study was conducted to establish tetracycline resistance profiles, prevalence of tet genes and transposable element (Tn916) in enterococcal soil and clinical isolates. Enterococci (n = 1210) from different environmental niche were collected and subjected to molecular identification. In total, 361 isolates showed tetracycline resistance at the breakpoint of 32 MUg ml-1. MICs (32-512 MUg ml-1) were established by both agar and micro-broth dilution methods. Soil isolates (n = 76) were further investigated for Tet genes (tet-A, C, K, L, M, S, O) and Tn916. Major resistance was observed in E. faecium 67% followed by E. faecalis 22%, E. hirae 8% and E. casseliflavus 2.6%. Results revealed that tet(L) was more frequently found in E. faecium 74.5%, while tet(M) was in high prevalence in E. faecalis 82.3%. Tn916 was detected in both clinical and soil isolates (i.e. 43.3% and 19.7%, respectively). RAPD-PCR analysis showed high diversity among the investigated isolates. Cumulatively, our results revealed high-level tetracycline resistance and the presence of multiple Tet genes and transposable element Tn916 in enterococci. PMID- 28888882 TI - Genome-wide sequence transposon insertion sites and analyze the essential genes of Brucella melitensis. AB - A transposon mutant library of B. melitensis NI including 32,640 transposon mutants was established. By sequencing the transposon insertion sites, 10,832 mutants were successfully defined for their insertion sites. Analysis of the mutants with defined transposon insertion sites (DTIS) indicated that the insertions were well spread through the two genomes. In addition, 948 genes with no detectable transposon insertions were taken as the candidate for identification of essential genes. In comparison with the Bacterial Database of Essential Genes and by using comparative genomics analysis, 183 potential essential genes of B. melitensis NI cultured in vitro were found and they were conserved in the common bacteria. This work was focused on screening of the essential genes of B. melitensis NI, which may provide a foundation for identification of the novel drug targets against brucellosis. Besides, the sequence-defined transposon library should serve as a resource for screening of different function genes of Brucella. PMID- 28888883 TI - Host responses and bacterial colonization following inoculation of Pasteurella multocida P52 strain into unvaccinated and aluminum hydroxide gel hemorrhagic septicemia vaccinated mice. AB - Hemorrhagic septicemia is a highly infectious and contagious disease caused by Pasteurella multocida serogroup B:2 in tropical Asian and African countries. The acute inflammatory responses induced by Pasteurella multocida are the main cause of death in hemorrhagic septicemia. Therefore, present study was undertaken to examine the blood cytokine expression profiles (TNF-alpha, IL-1beta, and IL-6), bacterial colonization and histopathological changes of intraperitoneally and subcutaneously challenged vaccinated and unvaccinated mice with 102 CFU of P. multocida P52. The observations were made at 6, 12, 18, 24 h and 48 h intervals. Real-time PCR based blood cytokine profiles (TNF-alpha, IL-1beta, and IL-6) measurement revealed a significantly higher amount of pro-inflammatory cytokines expression in the unvaccinated challenged group of mice than the vaccinated challenged group. There was heavy bacterial load in all organs of mice viz. trachea, lung, spleen, within 6 h of challenge in both vaccinated and unvaccinated group of mice, but bacterial load increased in the unvaccinated challenged group of mice with respect to time whereas the load were constant in the vaccinated challenged group. Histopathological changes were mild in the vaccinated challenged group of mice in comparison to the unvaccinated challenged group. There was no significant difference in the bacterial load, histopathological changes and cytokines expression when challenged through different routes. PMID- 28888884 TI - Prevalence of antimicrobial resistance and integron gene cassettes in Escherichia coli isolated from yaks (Poephagus grunniens) in Aba Tibetan Autonomous Prefecture, China. AB - BACKGROUND: Escherichia coli (E. coli) is one of the most relevant opportunistic pathogenic bacteria as it may cause severe morbidity and mortality in yaks (poephagus grunniens). In recent years, several kinds of antibiotics have been widely used in Tibetan areas to treat the bacterial diseases, resulting in serious repercussions on the bacterial antibiotic resistance in yaks. This investigation was conducted in order to determine the prevalence of antimicrobial resistance and integron gene cassettes in E. coli isolated from yaks in Aba Tibetan Autonomous Prefecture (Aba TAP), China. METHODS: A total of 278 non duplicated fresh samples were collected from the yaks in Aba TAP for the isolation and identification of E. coli isolates. Antimicrobial susceptibility testing is performed by using the disc diffusion method according to the Clinical and Laboratory Standards Institute guidelines (CLSI, 2013). Various antibiotic resistance genes and integron gene cassettes were detected by polymerase chain reaction (PCR) and sequencing. RESULTS: Overall, a total of 228 E. coli bacteria were isolated from the fresh faeces of yaks in four different geographical regions. 58% of those isolates showed multi-drug resistance capabilities (MDR) in our study. These isolated bacteria showed a high resistance rate to streptomycin (84%), cefotaxime (79%), amikacin (61%) and trimethoprim-sulfamethoxazole (54%). The most common antimicrobial resistance genes in the isolates were blaCTX-M, sul1, aph (3')-IIa, aac (3)-IIa, aac (6')-Ib, tetB, with respective detection rates of 65%, 46%, 35%, 13%, 11%, and 10%. Furthermore, 66% and 6% of the strains carried Class 1 and 2 integrons, respectively. However, the class 3 integron was not detected. Gene cassette arrays in the class 1 integron included aadA1, aadA7, aadA5, aadA17, dfrA1, dfrA5, dfrA1-aadA1, dfrA12-aadA2 and dfrA17-aadA5. The most prevalent gene cassette was aadA1 (20%). For the class 2 integron, dfrA1-sat2 aadA1 (6%) and dfrA1-sat1-aadA1 (0.4%) were also detected as part of this research. CONCLUSION: High multi-drug resistance rates have been discovered, as well as a prevalence of antibiotic resistance genes and integron gene cassettes in the E. coli isolated from the faeces of yak. This might create a potential problem for treatment of the yaks' bacterial infections as well as food hygiene for humans. It is therefore urgently necessary to begin continuous surveillance and analysis of antibiotic resistance and integron cassettes in other bacteria from yaks. PMID- 28888885 TI - A mitogen-activated protein kinase gene (VmPmk1) regulates virulence and cell wall degrading enzyme expression in Valsa mali. AB - Mitogen-activated protein kinases (MAPKs) play critical roles in the regulation of different developmental processes and hydrolytic enzyme production in many fungal plant pathogens. In this study, an FUS3/KSS1-related MAPK gene, VmPmk1, was identified and characterized in Valsa mali, which causes a highly destructive canker disease on apple. VmPmk1 deletion mutant showed a significant reduction in growth rate in vitro, and could not produce pycnidium, indicating that the MAPK gene is important for growth and asexual development. Also, VmPmk1 played a significant role in response to oxidative stress and in the maintenance of cell wall integrity. More importantly, when deletion mutant was inoculated onto detached apple leaves and twigs, an obvious decrease in lesion size was observed. Furthermore, expression of many cell wall degrading enzyme (CWDE) genes declined in the VmPmk1 deletion mutant during infection. VmPmk1 deletion mutant also showed a significant reduction in activities of CWDEs in both induced media and infection process. Finally, the determination of immunogold labeling of pectin demonstrated that the capacity of degradation pectin was attenuated due to the deletion of VmPmk1. These results indicated that VmPmk1 plays important roles in growth, asexual development, response to oxidative stress, and maintenance of cell wall integrity. More importantly, VmPmk1 is involved in pathogenicity of V. mali mainly by regulating CWDE genes expression. PMID- 28888886 TI - The recombinant EHV-1 vector producing CDV hemagglutinin as potential vaccine against canine distemper. AB - Canine distemper virus (CDV), is a pantropic agent of morbillivirus that causes fetal disease in dogs. Base on a broad host rang of CDV, the continued vaccines inoculation is unavoidable to pose gene recombination risk in vaccine virus and wild virus. The current study presents the construction of novel vectors, using equine herpesvirus type 1 (EHV-1) expressing the canine distemper virus (CDV). The recent field strain hemagglutinin protein and nucleoprotein were used for the construction of the viral vector vaccines. Based on the Bacterial artificial chromosome (BAC) genomes of EHV-1 RacH strain, the recombinant EHV-1 vaccine virus encoding CDV hemagglutinin protein (EHV-H) or CDV nucleoprotein (EHV-N) was constructed separately. The constructed BACs were rescued after 72 h post infection, and the expression of H or N in the recombinant viruses was confirmed by western-blotting. Furthermore, high levels of neutralizing antibodies were induced persistently following vaccination in the groups EHV-H&EHV-N and EHV-H, but the EHV-N group. The groups of vaccinated EHV-H and EHV-H&EHV-N pups were monitored for clinical signs, whereas the vaccinated EHV-N group developed moderate symptoms. The present study demonstrated that EHV-1 based recombinant virus carrying CDV H could be a promising vaccine candidate against canine distemper. PMID- 28888887 TI - The novel loop-mediated isothermal amplification based confirmation methodology on the bacteria in Viable but Non-Culturable (VBNC) state. AB - As a self-protection mechanism, the viable but non-culturable (VBNC) state provides the ability against conventional detection methods among various foodborne pathogens. The ability of forming colonies is lost while metabolism is still maintaining in VBNC state cells. Recently, ethidium monoazide (EMA) and propidium monoazide (PMA) have been widely applied on the detection of foodborne pathogens in VBNC state. Combined with loop-mediated isothermal amplification (LAMP), the PMA/EMA-LAMP showed a significant priority in high sensitivity, specificity and rapidity over conventional PCR based assays. Particularly, PMA/EMA-LAMP has been proved as an effective method in the detection of Escherichia coli, Vibrio parahaemolyticus and Staphylococcus in VBNC state. Based on the current investigations, the VBNC mechanism and current detection method for VBNC-state foodborne pathogens were introduced and discussed in this review. PMID- 28888888 TI - Sepsis induced by cecal ligation and perforation (CLP) alters nucleotidase activities in platelets of rats. AB - Sepsis is a potentially lethal condition, and it is associated with platelet alterations. The present study sought to investigate the activity of ecto nucleoside triphosphate diphosphohydrolase (E-NTPDase), E-5'-nucleotidase, and ecto-adenosine deaminase (E-ADA) in the platelets of rats that were induced with sepsis. Male Wistar rats were divided into three groups of ten animals each: a negative control group (normal; NC); a group that underwent surgical procedures (sham); and a group that underwent cecal ligation and perforation (CLP). The induction of sepsis was confirmed by bacteremia, and the causative pathogen identified was Escherichia coli. Hematological parameters showed leukocytosis and thrombocytopenia in animals in the septic group. The results also revealed that there were significant (p < 0.05) increases in adenosine triphosphate (ATP) and adenosine monophosphate (AMP) hydrolyses, and in the deamination of adenosine in the CLP group compared to the sham and control groups. Conversely, ADP hydrolysis was significantly decreased (p < 0.05) in the CLP group compared to the sham and control groups. Purine levels were analyzed by high-performance liquid chromatography (HPLC) in serum samples from control, sham, and CLP groups. Increased concentrations of ATP, adenosine, and inosine were found in the CLP group compared to the sham and control groups. Conversely, the concentrations of ADP and AMP in the CPL group were not significantly altered. We suggest that alterations in hematological parameters, nucleotide hydrolysis in platelets, and nucleotide concentrations in serum samples of rats with induced sepsis may be related to thromboembolic events. PMID- 28888889 TI - Biofabrication of polyphenols coated Nano palladium and its in-vitro cytotoxicity against human leukemia cell lines (K562). AB - The biofabrication of palladium nanoparticles (PdNPs) using aqueous leaf extract of Pelargonium graveolens is reported herein. The polyphenols present in the Pelargonium graveolens extract are mainly responsible for reduction and subsequent stabilization of formed PdNPs. UV-Visible spectroscopy (UV-Vis) absorption and reaction color change from yellow to brown indicated the formation of PdNPs. The as synthesized PdNPs were studied by using characterization techniques such as Fourier transform infrared spectroscopy (FTIR), Transmission electron microscopy (TEM), Energy dispersive spectroscopy (EDS), Zeta potential measurements and Selected area electron diffraction (SAED). FTIR analysis and Zeta potential measurements showed the capping of polyphenols onto the surface of PdNPs, which further responsible for preventing aggregation of PdNPs. TEM image showed that the PdNPs exists in the range from 50 to 150nm. Also, XRD pattern revealed the crystalline nature of as synthesized PdNPs. The in vitro cytotoxicity studies of Pelargonium graveolens extract capped PdNPs was conducted using human leukemia cell lines (K562) by following an MTT cell viability assay and is found that the cytotoxicity is dose dependent. Further, the synthesized PdNPs will open a new opportunities in the field of biomedicine. Also, the produced method is an alternative to the chemical synthetic approaches that are being used nowadays. PMID- 28888890 TI - Spatial variations and determinants of infant and under-five mortality in Bangladesh. AB - Reducing child mortality is a Sustainable Development Goal yet to be achieved by many low-income countries. We applied a subnational and spatial approach based on publicly available datasets and identified permanent insolvency, urbanicity, and malaria endemicity as factors associated with child mortality. We further detected spatial clusters in the east of Bangladesh and noted Sylhet and Jamalpur as those districts that need immediate attention to reduce child mortality. Our approach is transferable to other regions in comparable settings worldwide and may guide future studies to identify subnational regions in need for public health attention. Our study adds to our understanding where we may intervene to more effectively improve health, particularly among disadvantaged populations. PMID- 28888891 TI - Investigating the role of temporal lobe activation in speech perception accuracy with normal hearing adults: An event-related fNIRS study. AB - Functional near infrared spectroscopy (fNIRS) is a safe, non-invasive, relatively quiet imaging technique that is tolerant of movement artifact making it uniquely ideal for the assessment of hearing mechanisms. Previous research demonstrates the capacity for fNIRS to detect cortical changes to varying speech intelligibility, revealing a positive relationship between cortical activation amplitude and speech perception score. In the present study, we use an event related design to investigate the hemodynamic response in the temporal lobe across different listening conditions. We presented participants with a speech recognition task using sentences in quiet, sentences in noise, and vocoded sentences. Hemodynamic responses were examined across conditions and then compared when speech perception was accurate compared to when speech perception was inaccurate in the context of noisy speech. Repeated measures, two-way ANOVAs revealed that the speech in noise condition (-2.8dB signal-to-noise ratio/SNR) demonstrated significantly greater activation than the easier listening conditions on multiple channels bilaterally. Further analyses comparing correct recognition trials to incorrect recognition trials (during the presentation phase of the trial) revealed that activation was significantly greater during correct trials. Lastly, during the repetition phase of the trial, where participants correctly repeated the sentence, the hemodynamic response demonstrated significantly higher deoxyhemoglobin than oxyhemoglobin, indicating a difference between the effects of perception and production on the cortical response. Using fNIRS, the present study adds meaningful evidence to the body of knowledge that describes the brain/behavior relationship related to speech perception. PMID- 28888892 TI - Alpha-band transcranial alternating current stimulation modulates precision, but not gain during whole-body spatial updating. AB - Spatial updating is essential to maintain an accurate representation of our visual environment when we move. A neural mechanism that contributes to this ability is called remapping: the transfer of visual information from neural populations that code a location before the motion to those that encode it after the motion. While there is ample evidence for neural remapping in conjunction with eye movements, only recent findings suggest a role of this mechanism for whole-body motion updating, based on the observation that alpha band (10Hz) activity is selectively reorganized during remapping. This study tested whether alpha oscillations directly contribute to whole-body motion updating using transcranial alternating current stimulation (tACS). In a double blind sham controlled design, healthy volunteers received 10Hz tACS at an intensity of 1mA over either the left or right posterior hemisphere during a whole-body motion updating task. Updating performance was assessed psychometrically and indices of gain and precision were obtained. No tACS-related effects on updating gain were found, irrespective of whether the remapping was across or within the hemispheres. In contrast, updating precision was enhanced when a target representation had to be internally remapped to the stimulated hemisphere, but not in other remapping conditions. Our observations suggest that alpha band oscillations do not directly affect the transfer of target representations during remapping, but increase the fidelity of the updated representation by attenuating interference of afferent information. PMID- 28888893 TI - Face working memory deficits in developmental prosopagnosia: Tests of encoding limits and updating processes. AB - Developmental prosopagnosia (DP) is a condition in which individuals experience life-long problems recognising faces. In recent years, unpacking the nature of the impairments of this population has been the focus of numerous studies. One focus has been on the nature of face-based memory impairments for such individuals, with the onus being mainly on long-term memory deficits. Far fewer have considered the nature of face-based working memory (WM) impairments for DP cases, and the current study seeks to address this. One recent WM study (Shah et al., 2015) reported that the maintenance of faces over time in WM was spared among DPs, and argued instead that face encoding was limited in some way. Here we further explore the nature of face-based WM impairments in DP across two experiments designed to probe encoding limits (Experiment 1) and WM updating processes (Experiment 2). In Experiment 1 we manipulated the number of faces (1 4) to encode into WM and presented these simultaneously. We reasoned that if face encoding among DPs was inefficient or imprecise, then increasing encoding demands (WM load) would disproportionately impair WM accuracy compared to controls. However, we found that DP cases were consistently poorer than controls across all face load conditions, suggesting that front-end encoding problems are only part of the deficit. In Experiment 2, to measure updating four faces were shown sequentially for encoding into WM and accuracy was analysed as a function of whether the test face had been presented first, second, third or last in the encoding sequence. DPs had significantly poorer WM than controls for later faces but not the first face encoded in the sequence, and showed an attenuated recency effect. To account for these findings, we discuss the potential role of comparison processes at retrieval, impairments in configural face processing, and the impact of noise in the face identification system of individuals with DP. PMID- 28888894 TI - Exercise intervention attenuates hyperhomocysteinemia-induced aortic endothelial oxidative injury by regulating SIRT1 through mitigating NADPH oxidase/LOX-1 signaling. AB - Coronary artery disease (CAD) is a critical cardiovascular disease and a cause of high morbidity and mortality in this world. Hyperhomocysteinemia (HHcy) has been suggested as a risk factor for CAD. In addition, SIRT1 (sirtuin 1) has been reported to play a protective role in a variety of diseases, especially in the cardiovascular system. The main purpose of this study was to investigate the effects of exercise training on apoptosis and inflammation in HHcy animals. We also tested whether exercise protected against Hhcy-induced dysfunction of endothelium through modulation of SIRT1. C57BL mice (8 in each group) were fed with or without 1% L-methionine (w/w) in water for 4 months to induce HHcy. We found that Hhcy repressed SIRT1 and AMPK expression and increased NADPH oxidase activity. Plasma MDA, endothelium LOX-1 and p-p38 were up-regulated by Hhcy induction. NF-kappaB and it downstream molecules were activated under Hhcy situation, thereby promoting pro-inflammatory responses. Moreover, we also reported that Hhcy caused endothelium apoptosis involving Akt inhibition and mitochondria-dependent apoptotic pathways. Exercise training significantly protected against endothelium from Hhcy caused oxidative injuries. In addition, EX527 (SIRT1 inhibitor) reduced the therapeutic effects by exercise. Our results had indicated that exercise training prevent the development of atherosclerosis through SIRT1 activation and oxidative stress inhibition under Hhcy situation. PMID- 28888896 TI - Hormonal profile and follicular dynamics concurrent with CIDR and insulin modified Ovsync TAI programs and their impacts on the fertility response in buffaloes. AB - Fifty one cyclic Egyptian buffaloes were used to study the hormonal profile and follicular dynamics concurrent with CIDR and insulin modified Ovsync TAI programs and their impacts on the consequent fertility responses. The buffaloes were randomly assigned into 3 ovulation synchronization protocols: Ovsync-alone (n = 13, control) CIDR-sync (n = 20) and Insulin-sync (n = 18). Ovsync-alone protocol consisted of two im injections of 20 MUg bueserlin (GnRHa) on Day 0 (GnRH 1) and on Day 9 (GnRH 2) with an im injection of 500 MUg of cloprostenol sodium (PGF2 alpha) on Day 7. The CIDR-sync protocol consisted of the same treatment protocol as in Ovsync in addition to intra-vaginal insertion of CIDR (contains 1.38 gm of progesterone) on Day 0 followed by removal on Day 7. The Insulin-sync protocol consisted of the same treatment protocol as in Ovsync plus 3 sc injections of insulin at a dose of 0.25 i.u/1 kg, on Days 7, 8, and 9. Buffaloes in all groups were inseminated 16 h after GnRH2 by the same inseminator using frozen semen in straws. Blood samples were collected on Days 0, 3, 5 for serum progesterone assay and on Day 9 to measure serum concentrations of estradiol, insulin and IGF-1. Transrectal ultrasonographic scanning of the ovaries was conducted on Days 7, 8 and 9 to record the diameter of the largest follicle. Pregnancy diagnosis was conducted on Day 30 post-TAI by trans-rectal ultrasonographic scanning of the uterus to calculate conception rate. The serum progesterone concentration showed an increase (p < 0.01) in pregnant compared with non-pregnant buffaloes in both Ovsync-alone and Insulin-sync groups, but not in CIDR-sync group (p > 0.05) on Days 3 and 5. The serum estradiol concentration on Day 9 showed an increase (p < 0.01) in pregnant compared with the non-pregnant buffaloes in all of the treated groups. In Insulin-sync and Ovsync-alone groups, the diameter of the largest follicle (LF) was larger (p < 0.01) in pregnant compared with non-pregnant buffaloes, but in CIDR-sync, the diameter of the (LF) was larger (p < 0.01) in non-pregnant compared with pregnant buffaloes. Also, the results showed that the greatest diameter of LF was observed in pregnant buffaloes in Insulin-sync compared with either pregnant or non-pregnant buffaloes in all groups. It is concluded that modified CIDR-sync and Insulin-sync could improve fertility response through modulating hormonal profile and follicular dynamics in buffaloes during low breeding season. PMID- 28888895 TI - Regulation of platelet activation and thrombus formation by reactive oxygen species. AB - Reactive oxygen species (ROS) are generated within activated platelets and play an important role in regulating platelet responses to collagen and collagen mediated thrombus formation. As a major collagen receptor, platelet-specific glycoprotein (GP)VI is a member of the immunoglobulin (Ig) superfamily, with two extracellular Ig domains, a mucin domain, a transmembrane domain and a cytoplasmic tail. GPVI forms a functional complex with the Fc receptor gamma chain (FcRgamma) that, following receptor dimerization, signals via an intracellular immunoreceptor tyrosine-based activation motif (ITAM), leading to rapid activation of Src family kinase signaling pathways. Our previous studies demonstrated that an unpaired thiol in the cytoplasmic tail of GPVI undergoes rapid oxidation to form GPVI homodimers in response to ligand binding, indicating an oxidative submembranous environment in platelets after GPVI stimulation. Using a redox-sensitive fluorescent dye (H2DCF-DA) in a flow cytometric assay to measure changes in intracellular ROS, we showed generation of ROS downstream of GPVI consists of two distinct phases: an initial Syk-independent burst followed by additional Syk-dependent generation. In this review, we will discuss recent findings on the regulation of platelet function by ROS, focusing on GPVI dependent platelet activation and thrombus formation. PMID- 28888897 TI - Hepatobiliary disease in children and adolescents with cystic fibrosis. AB - OBJECTIVES: The aims of the study were to determine the frequency of hepatobiliary disease in patients with cystic fibrosis and to describe the sociodemographic, clinical, and laboratory profile of these patients. METHODS: This was a retrospective, descriptive, and analytical study of 55 patients diagnosed with cystic fibrosis, aged between 3 months and 21 years, followed-up from January 2008 to June 2016 in a referral center. Medical records were consulted and sociodemographic, clinical and laboratory data, including hepatobiliary alterations, imaging studies, genetic studies, liver biopsies, and upper digestive endoscopies were registered. RESULTS: Hepatobiliary disease was diagnosed in 16.4% of the patients and occurred as an initial manifestation of cystic fibrosis in 55.6% of these cases. The diagnosis of hepatopathy occurred before or concomitantly with the diagnosis of cystic fibrosis in 88.9% of the children. All patients with hepatobiliary disease were considered non-white, with a predominance of females (77.8%) and median (IQR) of 54 (27-91) months. Compared with the group without hepatobiliary disease, children with liver disease had a higher frequency of severe mutations identified in the CFTR gene (77.8% vs. 39.6%, p=0.033) and severe pancreatic insufficiency (88.9% vs. 31.6%, p=0.007). CONCLUSION: The frequency of hepatobiliary disease was high, with a very early diagnosis of the disease and its complications in the studied series. A statistical association was observed between the occurrence of hepatobiliary disease and the presence of pancreatic insufficiency and severe mutations in the CFTR gene. It is emphasized that cystic fibrosis is an important differential diagnosis of liver diseases in childhood. PMID- 28888898 TI - Duodenal pathologies in children: a single-center experience. AB - OBJECTIVE: Several studies have been performed concerning pathologies of the stomach and esophagus in the pediatric age group. However, there have been very few studies of duodenal pathologies in children. The authors aimed to examine the clinical, endoscopic, and histopathological characteristics, as well as the etiology of duodenal pathologies in children. METHOD: Patients aged between 1 and 17 years undergoing esophagogastroduodenoscopy during two years at this unit, were investigated retrospectively. Demographic, clinical, endoscopic data, and the presence of duodenal pathologies, gastritis, and esophagitis were recorded in all of the children. RESULTS: Out of 747 children who underwent endoscopy, duodenal pathology was observed in 226 (30.3%) patients. Pathology was also present in the esophagus in 31.6% of patients and in the stomach in 58.4%. The level of chronic diarrhea was higher in patients with duodenal pathology when compared with those without duodenal pathology (p=0.002, OR: 3.91, 95% CI: 1.59 9.57). Helicobacter pylori infection was more common in patients with pathology in the duodenum (59.3%). CONCLUSION: Duodenal pathology was detected in 30.3% of the present patients. A significantly higher level of chronic diarrhea was observed in subjects with duodenal pathologies compared to those with no such pathology. The rate of Helicobacter pylori infection was considerably higher than that in previous studies. In addition, there is a weak correlation between endoscopic appearance and histology of duodenitis. PMID- 28888899 TI - Association between body mass index and individual characteristics and the school context: a multilevel study with Portuguese children. AB - OBJECTIVE: The aim of this study was to examine the association between individual and school context characteristics with the body mass index of Portuguese children. METHODS: The sample comprised 1641 children (847 boys) aged 6-10 years from the North and Central regions of Portugal. Regarding the individual characteristics, age, gender, city of residence, levels of physical activity, and physical fitness were assessed. Concerning the school context characteristics, the surrounding environment, school size, presence of recreational characteristics and space, and presence of a sports court and of physical education classes were considered. Children's body mass index was the dependent variable. The multilevel analysis was carried out in HLM 7.0 software. RESULTS: The predictors of the child and the school context explained, respectively, 97.3% and 2.7% of the total body mass index variance. Regarding the individual characteristics, older children, boys, and those who had lower performance at the 1-mile run/walk, curl-up, push-up, and higher performance in trunk lift tests showed higher BMI. Further, urban schools with higher recreational spaces were positively associated with children's body mass index. CONCLUSION: School context variables have a reduced effect on body mass index variation compared to the children's biological and behavioral characteristics. The authors therefore encourage strategies that aim to increasing children's physical fitness levels to help prevent excess weight. PMID- 28888900 TI - Sliding enhances fluid and solute transport into buried articular cartilage contacts. AB - OBJECTIVE: Solutes and interstitial water are naturally transported from cartilage by load-induced interstitial fluid pressures. Fluid and solute recovery during joint articulation have been primarily attributed to passive diffusion and mechanical 'pumping' from dynamic loading. This paper tests if the sliding action of articulation is a significant and independent driver of fluid and solute transport in cartilage. DESIGN: The large osteochondral samples utilized in the present study preserve the convergent wedges necessary for physiological hydrodynamics. Following static load-induced fluid exudation and prior to sliding, a fluorescent solute (AlexaFluor 633) was added to the lubricant bath. In situ confocal microscopy was used to quantify the transport of solute from the bath into the buried stationary contact area (SCA) during sliding. RESULTS: Following static exudation, significant reductions in friction and strain during sliding at 60 mm/s were accompanied by significant solute transport into the inaccessible center of the buried contact; no such transport was detected for the 0- or 1 mm/s sliding conditions. The results suggest that external hydrodynamic pressures from sliding induced advective flows that carried solutes from the bath toward the center of contact. CONCLUSIONS: These results provide the first direct evidence that the action of sliding is a significant contributor to fluid and solute recovery by cartilage. Furthermore, they indicate that the sliding-induced transport of solutes into the buried interface was orders of magnitude greater than that attributable to diffusion alone, a result with critical implications for disease prevention and tissue engineering. PMID- 28888901 TI - Oral administration of undenatured native chicken type II collagen (UC-II) diminished deterioration of articular cartilage in a rat model of osteoarthritis (OA). AB - OBJECTIVE: The aim of this study was to determine the ability of undenatured native chicken type II collagen (UC-II) to prevent excessive articular cartilage deterioration in a rat model of osteoarthritis (OA). METHODS: Twenty male rats were subjected to partial medial meniscectomy tear (PMMT) surgery to induce OA. Immediately after the surgery 10 rats received vehicle and another 10 rats oral daily dose of UC-II at 0.66 mg/kg for a period of 8 weeks. In addition 10 naive rats were used as an intact control and another 10 rats received sham surgery. Study endpoints included a weight-bearing capacity of front and hind legs, serum biomarkers of bone and cartilage metabolism, analyses of subchondral and cancellous bone at the tibial epiphysis and metaphysis, and cartilage pathology at the medial tibial plateau using histological methods. RESULTS: PMMT surgery produced moderate OA at the medial tibial plateau. Specifically, the deterioration of articular cartilage negatively impacted the weight bearing capacity of the operated limb. Immediate treatment with the UC-II preserved the weight-bearing capacity of the injured leg, preserved integrity of the cancellous bone at tibial metaphysis and limited the excessive osteophyte formation and deterioration of articular cartilage. CONCLUSION: Study results demonstrate that a clinically relevant daily dose of UC-II when applied immediately after injury can improve the mechanical function of the injured knee and prevent excessive deterioration of articular cartilage. PMID- 28888903 TI - Appropriateness and total knee arthroplasty: an examination of the American Academy of Orthopaedic Surgeons appropriateness rating system. AB - OBJECTIVE: The American Academy of Orthopaedic Surgeons (AAOS) recently published appropriateness criteria for patients with knee osteoarthritis (OA) who are being considered for total knee arthroplasty (TKA). We evaluated the extent to which predictor variables used by the AAOS contribute to final classification, rated as "appropriate," "may be appropriate" or "rarely appropriate." METHODS: The RAND/UCLA Appropriateness method was used by AAOS to develop 864 clinical vignettes, each incorporating eight evidence-based variables associated with TKA outcome or need. Variables included function-limiting pain severity, knee OA severity, knee motion and age among others. The contribution of each variable to the overall classification was determined using multinomial regression. A classification tree method was applied to determine the combinations of variables that contributed to final classification for each vignette. RESULTS: Multinomial regression indicated that patient age, knee motion, OA severity and location were the four most powerful predictors of final classification. Function limiting pain, knee instability and lower limb alignment contributed little to the final classification. The classification tree had an accuracy of 86.7% and the most important contributors to classification were age, knee OA severity and pattern. CONCLUSION: Function limiting pain, the most frequent reason endorsed by patients seeking TKA does not meaningfully contribute to the newly developed AAOS appropriateness criteria. The system is highly dependent on traditional variables that surgeons consider when evaluating patients for TKA: patient age, knee OA severity, knee OA pattern and knee motion. PMID- 28888902 TI - A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. AB - OBJECTIVES: Osteoarthritis (OA) is a degenerative disease characterized by loss of cartilage and increased subchondral bone within synovial joints. Wnt signaling affects the pathogenesis of OA as this pathway modulates both the differentiation of osteoblasts and chondrocytes, and production of catabolic proteases. A novel small-molecule Wnt pathway inhibitor, SM04690, was evaluated in a series of in vitro and in vivo animal studies to determine its effects on chondrogenesis, cartilage protection and synovial-lined joint pathology. DESIGN: A high throughput screen was performed using a cell-based reporter assay for Wnt pathway activity to develop a small molecule designated SM04690. Its properties were evaluated in bone-marrow-derived human mesenchymal stem cells (hMSCs) to assess chondrocyte differentiation and effects on cartilage catabolism by immunocytochemistry and gene expression, and glycosaminoglycan breakdown. In vivo effects of SM04690 on Wnt signaling, cartilage regeneration and protection were measured using biochemical and histopathological techniques in a rodent acute cruciate ligament tear and partial medial meniscectomy (ACLT + pMMx) OA model. RESULTS: SM04690 induced hMSC differentiation into mature, functional chondrocytes and decreased cartilage catabolic marker levels compared to vehicle. A single SM04690 intra-articular (IA) injection was efficacious in a rodent OA model, with increased cartilage thickness, evidence for cartilage regeneration, and protection from cartilage catabolism observed, resulting in significantly improved Osteoarthritis Research Society International (OARSI) histology scores and biomarkers, compared to vehicle. CONCLUSIONS: SM04690 induced chondrogenesis and appeared to inhibit joint destruction in a rat OA model, and is a candidate for a potential disease modifying therapy for OA. PMID- 28888904 TI - Changes in biomechanical risk factors for knee osteoarthritis and their association with 5-year clinically important improvement after limb realignment surgery. AB - OBJECTIVE: To evaluate 5-year outcomes after lower limb realignment and test the hypothesis that surgery-induced changes in selected biomechanical risk factors for medial knee osteoarthritis (OA) are associated with clinically important improvements. DESIGN: We prospectively evaluated patient-reported outcomes, full limb standing radiographs and gait biomechanics before, 6 months (surgery-induced change) and 5 years after medial opening wedge high tibial osteotomy (HTO) in 170 patients (46.4 +/- 8.9 years, 135 males) with knee OA and varus alignment. Logistic regression tested the associations of 6-month changes in mechanical axis angle and knee adduction moment with achieving an increase of >=10 points in the Knee injury and Osteoarthritis Outcome Score (KOOS)4 at 5 years, with and without adjusting for covariates. Gait data were also compared to existing data from healthy controls. RESULTS: Mean 5-year changes (95% confidence interval (CI)) were: KOOS4: +14.2 (10.8, 17.6); mechanical axis angle: +8.21 degrees (7.58, 8.83); knee adduction moment: -1.49 %BW*Ht (-1.35, -1.63). The postoperative knee adduction moments were typically lower than values for healthy controls. When divided into quartiles, although all strata improved significantly, patients with reductions in knee adduction moment of 1.14-1.74 %BW*Ht (neither largest nor smallest changes) had highest 5-year KOOS4 scores. The 6-month change in knee adduction moment (odds ratios (OR) = 0.38; 95% CI: 0.22, 0.67), preoperative KOOS4 (OR = 0.96; 95% CI: 0.94, 0.99) and preoperative medial tibiofemoral narrowing grade (OR = 0.62; 95% CI: 0.37, 1.00) were negatively associated with having a 5-year clinically important improvement (C-statistic = 0.70). CONCLUSIONS: Substantial improvements in biomechanical risk factors and patient reported outcomes are observed 5 years after medial opening wedge HTO. The surgery-induced change in load distribution during walking is significantly associated with long-term clinically important improvement. PMID- 28888906 TI - The comparison of ground reaction forces and lower limb muscles correlation and activation time delay between forward and backward walking. AB - This study aimed to compare the ground reaction forces (GRF) and lower limb muscles correlation and activation time delay between Forward (FW) and Backward (BW) walking. Twenty-four male students participated in this research. Electromyogram activities of gluteus medius, biceps femoris, medial gastrocnemius, soleus and anterior tibialis muscles along with GRFs were measured. Each participant performed two FW and two BW trials bare foot. Statistical parametric mapping (SPM) analysis was performed over anterior posterior and vertical GRFs time series. The paired t-test was used in SPM analysis. Cross-correlation analysis compared similarity in shape and time delay of EMG pattern. SPM analysis of GRFs showed that these two walking modes have asymmetrical kinetic behavior during most parts of stance phase. Based on cross correlation analysis, the shape of EMG activation profiles differed, where a phase shift in the muscle activation pattern of approximately 60% occurred. This shift may indicate different control mechanisms, at the spinal level, underpin FW and BW walking modalities. PMID- 28888905 TI - Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy induction. AB - OBJECTIVE: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates nutrients to execute cell growth and protein synthesis. We hypothesized that mTOR is essential for the intervertebral disc, the largest avascular, low-nutrient organ. Our objective was to elucidate roles of mTOR signaling in human disc cells. DESIGN: The mTOR exists in two complexes: mTORC1 containing the regulatory-associated protein of mTOR (RAPTOR) and mTORC2 containing the rapamycin-insensitive companion of mTOR (RICTOR). To analyze their functions in human disc nucleus pulposus cells, RNA interference (RNAi) of mTOR targeting mTORC1 and mTORC2, RAPTOR targeting mTORC1, or RICTOR targeting mTORC2 or rapamycin, a pharmacological mTORC1 inhibitor, was applied. First, mTOR signaling including Akt, p70/ribosomal S6 kinase (p70/S6K), and autophagy were assessed. Then, apoptosis, senescence, and matrix metabolism were evaluated under pro-inflammatory interleukin-1 beta (IL-1beta) stimulation. RESULTS: Western blotting showed significant decreases in specific proteins by each RNAi (all P < 0.0001). In mTOR signaling, RNAi of mTOR and RICTOR decreased p70/S6K and Akt phosphorylation, whereas RAPTOR RNAi decreased p70/S6K but increased Akt phosphorylation. All RNAi treatments increased light chain 3 (LC3)-II and decreased p62/sequestosome 1 (p62/SQSTM1), indicating enhanced autophagy. In apoptosis, IL-1beta-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and poly (ADP-ribose) polymerase (PARP) and caspase-9 cleavage decreased by RAPTOR RNAi. In senescence, IL-1beta-induced senescence-associated beta-galactosidase (SA-beta-gal)-positive cells and p16/INK4A expression also decreased by RAPTOR RNAi. In matrix metabolism, RAPTOR RNAi reduced IL-1beta-induced catabolic matrix metalloproteinase (MMP) release and activation and up-regulated anabolic gene expression. These findings were all consistent with rapamycin administration. Additional disc-tissue analysis detected expression and phosphorylation of mTOR-signaling molecules in varying ages. CONCLUSION: Selective interference of mTORC1/RAPTOR protects against inflammation-induced apoptosis, senescence, and matrix catabolism possibly through Akt and autophagy induction in human disc cells. PMID- 28888907 TI - A robotic system for delivering novel real-time, movement dependent perturbations. AB - Perturbations are often used to study movement control and balance, especially in the context of falling. Most often, discrete perturbations defined prior to the experiment are used to mimic external disturbances to balance. However, the largest proportion of falls is due to self-generated errors in weight shifting. Inspired by self-generated weight shifting errors, we created a novel, continuous mediolateral perturbation proportional to subjects' mediolateral center of mass movement with minimal delays. This perturbation was delivered by a robotic platform controlled by a real time Matlab Simulink model using kinematic data from a marker positioned at subjects' L5 as input. Fifteen healthy young adults stood as still as possible atop the robotic platform with their eyes closed. We evaluated the performance of the perturbation in terms of accuracy and delay relative to the input signal by using cross-correlations. The perturbations were accurate (r=-0.984), with delays of 154 ms. Such systematic perturbation significantly affected mediolateral sway, increasing its range (from 5.56+/-3.72 to 9.58 +/-4.83 mm, p=0.01), SD (from 1.08+/-0.74 to 1.72+/-0.74 mm, p = 0.02), and mean power frequency (from 0.08+/-0.05 to 0.25+/-0.17 Hz, p<0.01). These perturbation characteristics enable inducing systematic, movement-dependent perturbations and open the door for future studies investigating self-generated movement errors. PMID- 28888908 TI - Quick foot placement adjustments during gait are less accurate in individuals with focal cerebellar lesions. AB - Online gait corrections are frequently used to restore gait stability and prevent falling. They require shorter response times than voluntary movements which suggests that subcortical pathways contribute to the execution of online gait corrections. To evaluate the potential role of the cerebellum in these pathways we tested the hypotheses that online gait corrections would be less accurate in individuals with focal cerebellar damage than in neurologically intact controls and that this difference would be more pronounced for shorter available response times and for short step gait corrections. We projected virtual stepping stones on an instrumented treadmill while some of the approaching stepping stones were shifted forward or backward, requiring participants to adjust their foot placement. Varying the timing of those shifts allowed us to address the effect of available response time on foot placement error. In agreement with our hypothesis, individuals with focal cerebellar lesions were less accurate in adjusting their foot placement in reaction to suddenly shifted stepping stones than neurologically intact controls. However, the cerebellar lesion group's foot placement error did not increase more with decreasing available response distance or for short step versus long step adjustments compared to the control group. Furthermore, foot placement error for the non-shifting stepping stones was also larger in the cerebellar lesion group as compared to the control group. Consequently, the reduced ability to accurately adjust foot placement during walking in individuals with focal cerebellar lesions appears to be a general movement control deficit, which could contribute to increased fall risk. PMID- 28888909 TI - Association of varus thrust with prevalent patellofemoral osteoarthritis: A cross sectional study. AB - This cross-sectional study investigated (i) the association of varus thrust during gait with the presence of patellofemoral osteoarthritis (PFOA) in patients with medial knee osteoarthritis (OA) and (ii) patellar alignment in the knees with varus thrust. Participants from orthopedic clinics (n=171; mean age, 73.4 years; 71.9% female) diagnosed with radiographic medial knee OA (Kellgren/Lawrence [K/L] grade >=1) were included in this study, and underwent gait observation for varus thrust assessment using 2D video analysis. A radiographic skyline view was used to assess the presence of medial PFOA using the grading system from the Osteoarthritis Research Society International Atlas. The tibiofemoral joint K/L grade, patellar alignment (i.e., lateral shift and tilting angle), and knee pain intensity were also evaluated as covariates. Thirty two (18.7%) of 171 patients exhibited varus thrust and they presented significantly higher knee pain (46.0+/-3.04mm vs. 32.4+/-2.73mm; P=0.024), a lower patellar tilting angle (P=0.024), and a higher prevalence of PFOA compared with those without varus thrust. A logistic regression analysis with adjustment of covariates showed that varus thrust was significantly associated with higher odds of the presence of mixed and medial PFOA, and trended to significantly associate with any PFOA, including lateral PFOA. This indicates that varus thrust was associated with PFOA in a compartment-nonspecific manner in patients with medial knee OA. Varus thrust may represent a clinical disease feature of more advanced and multicompartmental disease. PMID- 28888910 TI - The influence of adherent cell morphology on hydrodynamic recruitment of leukocytes. AB - Innate immunity is characterized by the coordinated activity of multiple leukocytes mobilizing at or near the site of tissue injury. Slow rolling and/or adherent leukocytes have been shown to hydrodynamically recruit free-stream leukocytes to a model of inflamed tissue. In this paper, we numerically investigate the hydrodynamic recruitment of free-stream leukocytes due to the presence of a nearby adherent, deformed leukocyte by using a computational model developed from first principles to simulate these types of interactions. For free stream cells at least one diameter above the surface and subsequently involved in a glancing (out-of-plane) collision with one or more adherent cell, the simulation indicated that the free-stream cell was driven closer to the surface as a function of increasing glancing distance. Further, with increasing deformation of the adherent cell a similar effect was observed beginning at smaller glancing offsets. The influence of binary interactions on the trajectories of free-stream cells that were less than one diameter above the surface was also examined. For fixed glancing distance, increased adherent cell deformation led to enhanced recruiting effectiveness which was quantified by determining the time needed for the free-stream cell to enter the reactive zone; that is, a membrane separation distance such that receptor-ligand binding was possible. This effectiveness was only moderately influenced by variations in shear rate and cell buoyancy. Finally, for large glancing offset the domain of influence of the adherent cell diminished and the trajectory of the free-stream cell was unaffected by the adherent cell, with regard to hydrodynamic recruitment. PMID- 28888911 TI - Photobiomodulation with 670 nm light ameliorates Muller cell-mediated activation of microglia and macrophages in retinal degeneration. AB - Muller cells, the supporting cells of the retina, play a key role in responding to retinal stress by releasing chemokines, including CCL2, to recruit microglia and macrophages (MG/MPhi) into the damaged retina. Photobiomodulation (PBM) with 670 nm light has been shown to reduce inflammation in models of retinal degeneration. In this study, we aimed to investigate whether 670 nm light had an effect on Muller cell-initiated inflammation under retinal photo-oxidative damage (PD) in vivo and in vitro. Sprague-Dawley rats were pre-treated with 670 nm light (9J/cm2) once daily over 5 days prior to PD. The expression of inflammatory genes including CCL2 and IL-1beta was analysed in retinas. In vitro, primary Muller cells dissociated from neonatal rat retinas were co-cultured with 661W photoreceptor cells. Co-cultures were exposed to PD, followed by 670 nm light treatment to the Muller cells only, and Muller cell stress and inflammation were assessed. Primary MG/MPhi were incubated with supernatant from the co-cultures, and collected for analysis of inflammatory activation. To further understand the mechanism of 670 nm light, the expression of COX5a and mitochondrial membrane potential (DeltaPsim) were measured in Muller cells. Following PD, 670 nm light treated Muller cells had a reduced inflammatory activation, with lower levels of CCL2, IL-1beta and IL-6. Supernatant from 670 nm light-treated co-cultures reduced activation of primary MG/MPhi, and lowered the expression of pro inflammatory cytokines, compared to untreated PD controls. Additionally, 670 nm light-treated Muller cells had an increased expression of COX5a and an elevated DeltaPsim following PD, suggesting that retrograde signaling plays a role in the effects of 670 nm light on Muller cell gene expression. Our data indicates that 670 nm light reduces Muller cell-mediated retinal inflammation, and offers a potential cellular mechanism for 670 nm light therapy in regulating inflammation associated with retinal degenerations. PMID- 28888913 TI - The renaissance of lipoprotein(a): Brave new world for preventive cardiology? AB - Lipoprotein(a) [Lp(a)] is a highly heritable cardiovascular risk factor. Although discovered more than 50 years ago, Lp(a) has recently re-emerged as a major focus in the fields of lipidology and preventive cardiology owing to findings from genetic studies and the possibility of lowering elevated plasma concentrations with new antisense therapy. Data from genetic, epidemiological and clinical studies have provided compelling evidence establishing Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease. Nevertheless, major gaps in knowledge remain and the identification of the mechanistic processes governing both Lp(a) pathobiology and metabolism are an ongoing challenge. Furthermore, the complex structure of Lp(a) presents a major obstacle to the accurate quantification of plasma concentrations, and a universally accepted and standardized approach for measuring Lp(a) is required. Significant progress has been made in the development of novel therapeutics for selectively lowering Lp(a). However, before these therapies can be widely implemented further investigations are required to assess their efficacy, safety, and cost-efficiency in the prevention of cardiovascular events. We review recent advances in molecular and biochemical aspects, epidemiology, and pathobiology of Lp(a), and provide a contemporary update on the significance of Lp(a) in clinical medicine. "Progress lies not in enhancing what is, but in advancing toward what will be." (Khalil Gibran). PMID- 28888912 TI - Chemotherapy induces secretion of exosomes loaded with heparanase that degrades extracellular matrix and impacts tumor and host cell behavior. AB - : The heparan sulfate-degrading enzyme heparanase promotes the progression of many cancers by driving tumor cell proliferation, metastasis and angiogenesis. Heparanase accomplishes this via multiple mechanisms including its recently described effect on enhancing biogenesis of tumor exosomes. Because we recently discovered that heparanase expression is upregulated in myeloma cells that survive chemotherapy, we were prompted to investigate the impact of anti-myeloma drugs on exosome biogenesis. When myeloma cells were exposed to the commonly utilized anti-myeloma drugs bortezomib, carfilzomib or melphalan, exosome secretion by the cells was dramatically enhanced. These chemotherapy-induced exosomes (chemoexosomes) have a proteome profile distinct from cells not exposed to drug including a dramatic elevation in the level of heparanase present as exosome cargo. The chemoexosome heparanase was not found inside the chemoexosome, but was present on the exosome surface where it was capable of degrading heparan sulfate embedded within an extracellular matrix. When exposed to myeloma cells, chemoexosomes transferred their heparanase cargo to those cells, enhancing their heparan sulfate degrading activity and leading to activation of ERK signaling and an increase in shedding of the syndecan-1 proteoglycan. Exposure of chemoexosomes to macrophages enhanced their secretion of TNF-alpha, an important myeloma growth factor. Moreover, chemoexosomes stimulated macrophage migration and this effect was blocked by H1023, a monoclonal antibody that inhibits heparanase enzymatic activity. These data suggest that anti-myeloma therapy ignites a burst of exosomes having a high level of heparanase that remodels extracellular matrix and alters tumor and host cell behaviors that likely contribute to chemoresistance and eventual patient relapse. SUMMARY: We find that anti-myeloma chemotherapy dramatically stimulates secretion of exosomes and alters exosome composition. Exosomes secreted during therapy contain high levels of heparanase on their surface that can degrade ECM and also can be transferred to both tumor and host cells, altering their behavior in ways that may enhance tumor survival and progression. PMID- 28888914 TI - Acute diffuse peritonitis due to spontaneous rupture of a primary gastrointestinal stromal tumor of the jejunum: A case report. AB - INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Overt peritonitis caused by GIST rupture is very uncommon. Three types of GIST rupture have been described: closed perforation due to abscess (abscess type), hemoperitoneum leading to rupture of the hematoma capsule in the tumor (hemoperitoneum type), and perforation of the digestive tract via a fistula leading to central necrosis of the tumor (bowel perforation type). This report describes a patient with spontaneous tumor rupture and diffuse peritonitis, a variant of the bowel perforation type of GIST rupture. PRESENTATION OF CASE: A 74-year-old man presented with symptoms of vomiting and abdominal pain. Computed tomography (CT) scan revealed an approximately 10*7-cm mass in the pelvis with free air and fluid collection. Emergency laparotomy revealed a tumor in the jejunum, which was ruptured with a hole measuring 5mm in diameter. The tumor and part of the jejunum were resected. Immunohistochemically, the mass was diagnosed as a GIST originating from the gastrointestinal tract. Despite chemotherapy with imatinib mesylate, the patient died 22 months after surgery. CONCLUSIONS: This report describes a patient with acute diffuse peritonitis due to spontaneous rupture of a primary GIST of the jejunum. PMID- 28888915 TI - A case report of locally advanced triple negative breast cancer showing pathological complete response to weekly paclitaxel with bevacizumab treatment following disease progression during anthracycline-based neoadjuvant chemotherapy. AB - INTRODUCTION: Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced triple negative breast cancer, however, approximately 5% of cases show disease progression during NAC. Although downstaging is essential to create an opportunity for curative surgery and to improve the local control outcome in such a case, no additional line of chemotherapy has been established. CASE PRESENTATION: A 60-year-old woman was referred to our hospital for an axillary mass presenting three weeks ago and was diagnosed as having right locally advanced (T2N2M0, stage IIIA) triple negative breast cancer. After two courses of epirubicine and cyclophosphamide as NAC, disease progression was recognized and curative resection was considered impossible due to enlarged axillary lymph nodes showing invasion to surrounding tissue. As second-line chemotherapy, weekly paclitaxel with bevacizumab treatment was initiated and significant shrinkage was immediately obtained. A clinically complete response was diagnosed after four courses of weekly paclitaxel with bevacizumab and she underwent a right breast mastectomy with axillary lymph node dissection without major complications. Histopathological examination of surgical specimens showed no residual invasive or noninvasive disease and she was diagnosed as having a pathological complete response. CONCLUSIONS: Although the addition of bevacizumab to standard adjuvant chemotherapy is not recommended in unselected triple negative breast cancer, the potent effect on tumor shrinkage should be considered in the treatment of locally advanced triple negative breast cancer showing disease progression during standard NAC. PMID- 28888916 TI - Blue finger: An unusual clinical presentation. PMID- 28888917 TI - Light-switchable systems for remotely controlled drug delivery. AB - Light-switchable systems have recently received attention as a new mode of remotely controlled drug delivery. In the past, a multitude of nanomedicine studies have sought to enhance the specificity of drug delivery to target sites by focusing on receptors overexpressed on malignant cells or environmental features of diseases sites. Despite these immense efforts, however, there are few clinically available nanomedicines. We need a paradigm shift in drug delivery. One strategy that may overcome the limitations of pathophysiology-based drug delivery is the use of remotely controlled delivery technology. Unlike pathophysiology-based active drug targeting strategies, light-switchable systems are not affected by the heterogeneity of cells, tissue types, and/or microenvironments. Instead, they are triggered by remote light (i.e., near infrared) stimuli, which are absorbed by photoresponsive molecules or three dimensional nanostructures. The sequential conversion of light to heat or reactive oxygen species can activate drug release and allow it to be spatio temporally controlled. Light-switchable systems have been used to activate endosomal drug escape, modulate the release of chemical and biological drugs, and alter nanoparticle structures to control the release rates of drugs. This review will address the limitations of pathophysiology-based drug delivery systems, the current status of light-based remote-switch systems, and future directions in the application of light-switchable systems for remotely controlled drug delivery. PMID- 28888918 TI - Effects of psychopharmacological treatment with antipsychotic drugs on the vascular system. AB - Psychopharmacological treatment with antipsychotic drugs is an essential part of guideline-based treatment strategies in psychotic disorders, such as schizophrenia, schizoaffective disorders, and delusional disorders. Other mental disorders frequently treated with antipsychotic drugs are bipolar disorders, and major depressive disorder. Furthermore, antipsychotic drugs are often given in emergency and surgical units for the treatment of metabolic or postoperative delirium. Antipsychotic drugs can exert direct and indirect effects on the vascular system, potentially leading to severe complications such as thromboembolism. Therefore, knowledge of vascular side effects of antipsychotic drugs is important for clinicians. This clinical orientated review article covers direct and indirect effects of antipsychotics on the vascular system. PMID- 28888920 TI - Comprehensive Integrated Care Model to Improve Maternal Mental Health. AB - In this article, we describe an integrated care model in a perinatal psychiatry program to improve access to care for women who experience mood changes during the perinatal period. A nurse-practitioner trained in psychiatry and obstetrics is embedded in the obstetric clinic, and perinatal nurses, often the first professionals to recognize women who are experiencing mood changes, can easily refer women for follow-up. Barriers, lessons learned, and goals for implementation are described. PMID- 28888919 TI - Patterns of Symptoms of Perinatal Depression and Stress in Late Adolescent and Young Adult Mothers. AB - OBJECTIVE: To compare symptoms of depression, maternal adjustment, and perceived stress in late adolescent and young adult mothers and to examine the patterns of these symptoms during the first 3 months after birth. DESIGN: Secondary analysis of existing longitudinal data. SETTING: San Francisco Bay Area, with participants in their home environments. PARTICIPANTS: Ethnically diverse women expecting their first infants recruited during the third trimester from childbirth education classes and antenatal clinics. The final sample included 34 participants in the late adolescent group (18-20 years) and 48 participants in the young adult group (21-24 years). METHODS: The Center for Epidemiologic Studies Depression Scale was used to assess depression symptoms, the Maternal Adjustment and Maternal Attitudes Scale was used to assess maternal adjustment, and the 10-item Perceived Stress Scale was used to assess perceived stress. Repeated-measures analyses of variance were used to examine changes over time in depression, maternal adjustment, and perceived stress scores. RESULTS: Compared with young adult participants, late adolescent participants had greater mean depression scores (F(1, 61) = 8.02, p = .006) and perceived stress scores (F(1, 62) = 9.45, p = .003) at all time points. Scores for maternal adjustment could not be compared because of the low internal validity of the instrument. CONCLUSION: Our results indicated that late adolescent mothers may have more symptoms of depression and stress in late pregnancy and the early postpartum period than young adult mothers. Clinicians in maternity and pediatric settings should be vigilant in screening for depression and stress in this vulnerable population during their transitions to motherhood. PMID- 28888921 TI - N(4)-[B-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan)methyl]-2'-deoxycytidine as a potential boron delivery agent with respect to glioblastoma. AB - Glioblastoma multiforme (GBM) is a central nervous system tumor of grade IV, according to the WHO classification, extremely resistant to all currently used forms of therapy, including resection, radiotherapy, chemotherapy or combined therapy. Therefore, more effective treatment strategies of this tumor are needed, with boron neutron capture therapy (BNCT) being a potential solution, provided a proper cancer cells-targeted 10B delivery agent is found. In search of such an agent, toxicity and capacity to target DNA of a boronated derivative of 2' deoxycytidine, N(4)-[B-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan)methyl]-2' deoxycytidine (1), was tested against human tumor vs. normal cells. The present in vitro results revealed 1 to show low toxicity for human U-118 MG glioma cells (in the mM range) and even by 3-4 - fold lower against normal human fibroblasts. In accord, induction of apoptosis dependent on caspase-3 and caspase-7 was detected at high (>20mM) concentration of 1. Although demonstrated to be susceptible to phosphorylation by human deoxycytidine kinase and to undergo incorporation in cellular DNA, the boron analogue did not disturb cell proliferation when applied at non-toxic concentrations and showed low toxicity to a model metazoan organism, Caenorhabditis elegans. Thus, N(4)-[B-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan)methyl]-2'-deoxycytidine appears a promising candidate for a 10B delivery agent to be used in BNCT, with C. elegans indicated as a good model for in vivo studies. PMID- 28888922 TI - MicroRNA-20a participates in the aerobic exercise-based prevention of coronary artery disease by targeting PTEN. AB - BACKGROUND: Exercise can reduce the coronary artery disease (CAD) incidence. MiRNA-20a has been reported to distinctly expressed after sustain physical activity. However, its expression and regulation pattern in CAD model with or without exercise has not been reported. OBJECTIVE: In present study, we aim to investigate regulatory mechanism of miR-20a in exercise-associated reduced-CAD incidence and miR-20a-dependent signaling pathways. METHODS: Eight weeks old male ApoE/LDLR double knock out mice were recruited for this study. CAD model was established in mice fed with or without western diet and cholesterol levels were measured using detection kit as well as fast protein liquid chromatography. Relative mRNA levels were determined using quantitative RT-PCR while the protein levels were analyzed using western blotting. Luciferase assay was used to determine the miRNA binding site on target genes. CCK-8 assay and flow cytometry (FCM) were used for assessing the proliferative and apoptotic rate. RESULTS: Overall cholesterol level was significantly increased in CAD model group, compared to normal control group. Expression of miR-20 was significantly lower in CAD group where the VEGF and PTEN were upregulated, compared to non-CAD group. Increased miR-20a was induced after exercise in CAD model group, and miR-20a agomir group. Overexpression of miR-20a decreased the expression level of ET-1, TxA2, ANGII, PTEN and increased the eNOS, PGI2, and VEGF, at both transcriptional and translational levels. In vitro examination further confirmed these findings in human umbilical vein endothelial cells (HUVEC). MiR-20a specifically binds to the 3'UTR of PTEN and mediated the cell survival and proliferation through activating the PI3K/Akt signaling pathways. CONCLUSION: MiRNA-20a may have great potential as therapeutic target for CAD, since its participation can induce alteration of functional genes as well as PTEN, which is specifically targeted by miR-20a, and promote the survival and proliferation of vein endothelial cells. PMID- 28888923 TI - Social learning in a maze? Contrasting individual performance among wild zebrafish when associated with trained and naive conspecifics. AB - Social learning facilitates informed decision making about foraging, mating and anti-predatory tactics among animals. We investigated the occurrence of social learning through performance in a spatial task among wild-caught zebrafish. Individual fish (demonstrators) were trained through a novel food finding task in a maze for 8days. Demonstrators were paired with naive individuals (observers) and subjected to trials through maze for 4days followed by removal of the demonstrators and further training of observers for 4 more days. Paired naive individuals were subjected to trials through the maze in similar fashion separately and the performance of observers were compared with theirs. Our results showed that observers associated with knowledgeable conspecifics did not perform the task better than naive-paired individuals. Performances across trials improved for both sets while number of mistakes committed increased indicating no learning. The presence of a demonstrator could have increased the observer's activity, increasing the chances for the observer to come in contact with the stimulus. Performance of observers and naive-paired fish were probably affected by social distraction. Sex and body-size of the dyads (demonstrator-observer pairs and naive pairs) could also have interfered with information transfer among individuals. PMID- 28888924 TI - Mesothelin-specific Immune Responses Predict Survival of Patients With Brain Metastasis. AB - BACKGROUND: Patients with advanced malignancies, e.g. lung cancer, ovarian cancer or melanoma, frequently present with brain metastases. Clinical presentation and disease progression of cancer is in part shaped by the interaction of the immune system with malignant cells. Antigen-targeted immune responses have been implicated in the prolonged survival of patients with cancer. This includes the tumor-associated antigen (TAA) mature mesothelin, a 40kDa cell surface-bound antigen that is overexpressed in several malignancies including lung ovarian and pancreatic cancer. We examined in an observational, prospective study the survival of patients with brain metastases in association with clinical parameters and cellular immune responses to molecularly defined TAAs or viral (control) target antigens. METHODS: Immune cells in peripheral blood obtained from thirty-six patients with brain metastases were tested for cytokine production in response to a broad panel of defined viral and TAA target antigens, including full-length mesothelin. Incubation of immune cells with antigenic targets was carried out in i) medium alone, (ii) in a cytokine cocktail of interleukin (IL)-2/IL-15/IL-21, or (iii) IL-2/IL-7. Supernatants were tested for interferon gamma (IFN-gamma) production, after which univariate and multivariate analyses (Cox stepwise regression model) were performed to identify independent clinical and immunological factors associated with patient survival. Patients were followed-up for at least 500days after surgery or until death. FINDINGS: Univariate analysis identified age, gender, radiotherapy and mutational load as clinical parameters affecting survival of patients with brain metastases. Cox multivariate analysis showed that radiotherapy (P=0.004), age (P=0.029) and IFN gamma responses to mature mesothelin, conditioned by IL-2/IL-7 (P=0.045) were independent predictors of the survival of patients from surgery up to follow-up or death. INTERPRETATION: This is the first evidence that immune responses to mesothelin serve as a marker of increased overall survival in patients with brain metastases, regardless of the primary tumor origin. Analyses of immunological markers could potentially serve as prognostic markers in patients with brain metastases and help to select patients in need for adjunct, immunological, treatment strategies. PMID- 28888926 TI - Sleep improvement by internet-based cognitive behavioural therapy might help prevent mental health disorders. PMID- 28888925 TI - Follicular Helper T Cells are Essential for the Elimination of Plasmodium Infection. AB - CD4+ follicular helper T (Tfh) cells have been shown to be critical for the activation of germinal center (GC) B-cell responses. Similar to other infections, Plasmodium infection activates both GC as well as non-GC B cell responses. Here, we sought to explore whether Tfh cells and GC B cells are required to eliminate a Plasmodium infection. A CD4 T cell-targeted deletion of the gene that encodes Bcl6, the master transcription factor for the Tfh program, resulted in complete disruption of the Tfh response to Plasmodium chabaudi in C57BL/6 mice and consequent disruption of GC responses and IgG responses and the inability to eliminate the otherwise self-resolving chronic P. chabaudi infection. On the other hand, and contrary to previous observations in immunization and viral infection models, Signaling Lymphocyte Activation Molecule (SLAM)-Associated Protein (SAP)-deficient mice were able to activate Tfh cells, GC B cells, and IgG responses to the parasite. This study demonstrates the critical role for Tfh cells in controlling this systemic infection, and highlights differences in the signals required to activate GC B cell responses to this complex parasite compared with those of protein immunizations and viral infections. Therefore, these data are highly pertinent for designing malaria vaccines able to activate broadly protective B-cell responses. PMID- 28888928 TI - An update on new and unique uses of botulinum toxin in movement disorders. AB - The therapeutic applications of botulinum toxin (BoNT) have grown manifold since its initial approval in 1989 by the US Food and Drug Administration (FDA) for the treatment of strabismus, blepharospasm, and other facial spasms. Although it is the most potent biologic toxin known to man, long-term studies have established its safety in the treatment of a variety of neurologic and non-neurologic disorders. This review focuses on some novel and uncommon uses of BoNT in the treatment of movement disorders, such as oromandibular dystonia, including bruxism, anterocollis, camptocormia, tremor, tics, tardive and levodopa-induced dyskinesia, and restless legs syndrome. Despite a paucity of randomized controlled trials and lack of FDA approval for these movement disorders, there is growing body of evidence that BoNT provides benefit to patients with these hyperkinetic movement disorders and that BoNT is a safe treatment when used by clinicians skilled in the administration of the drug for these conditions. PMID- 28888927 TI - The effects of improving sleep on mental health (OASIS): a randomised controlled trial with mediation analysis. AB - BACKGROUND: Sleep difficulties might be a contributory causal factor in the occurrence of mental health problems. If this is true, improving sleep should benefit psychological health. We aimed to determine whether treating insomnia leads to a reduction in paranoia and hallucinations. METHODS: We did this single blind, randomised controlled trial (OASIS) at 26 UK universities. University students with insomnia were randomly assigned (1:1) with simple randomisation to receive digital cognitive behavioural therapy (CBT) for insomnia or usual care, and the research team were masked to the treatment. Online assessments took place at weeks 0, 3, 10 (end of therapy), and 22. The primary outcome measures were for insomnia, paranoia, and hallucinatory experiences. We did intention-to-treat analyses. The trial is registered with the ISRCTN registry, number ISRCTN61272251. FINDINGS: Between March 5, 2015, and Feb 17, 2016, we randomly assigned 3755 participants to receive digital CBT for insomnia (n=1891) or usual practice (n=1864). Compared with usual practice, the sleep intervention at 10 weeks reduced insomnia (adjusted difference 4.78, 95% CI 4.29 to 5.26, Cohen's d=1.11; p<0.0001), paranoia (-2.22, -2.98 to -1.45, Cohen's d=0.19; p<0.0001), and hallucinations (-1.58, -1.98 to -1.18, Cohen's d=0.24; p<0.0001). Insomnia was a mediator of change in paranoia and hallucinations. No adverse events were reported. INTERPRETATION: To our knowledge, this is the largest randomised controlled trial of a psychological intervention for a mental health problem. It provides strong evidence that insomnia is a causal factor in the occurrence of psychotic experiences and other mental health problems. Whether the results generalise beyond a student population requires testing. The treatment of disrupted sleep might require a higher priority in mental health provision. FUNDING: Wellcome Trust. PMID- 28888929 TI - Longitudinal studies of botulinum toxin in cervical dystonia: Why do patients discontinue therapy? AB - BACKGROUND: Numerous studies have established botulinum toxin (BoNT) to be safe and effective for the treatment of cervical dystonia (CD). Despite its well documented efficacy, there has been growing awareness that a significant proportion of CD patients discontinue therapy. The reasons for discontinuation are only partly understood. METHODS: This summary describes longitudinal studies that provided information regarding the proportions of patients discontinuing BoNT therapy, and the reasons for discontinuing therapy. The data come predominantly from un-blinded long-term follow-up studies, registry studies, and patient-based surveys. RESULTS: All types of longitudinal studies provide strong evidence that BoNT is both safe and effective in the treatment of CD for many years. Overall, approximately one third of CD patients discontinue BoNT. The most common reason for discontinuing therapy is lack of benefit, often described as primary or secondary non-response. The apparent lack of response is only rarely related to true immune-mediated resistance to BoNT. Other reasons for discontinuing include side effects, inconvenience, cost, or other reasons. DISCUSSION: Although BoNT is safe and effective in the treatment of the majority of patients with CD, approximately one third discontinue. The increasing awareness of a significant proportion of patients who discontinue should encourage further efforts to optimize administration of BoNT, to improve BoNT preparations to extend duration or reduce side effects, to develop add-on therapies that may mitigate swings in symptom severity, or develop entirely novel treatment approaches. PMID- 28888930 TI - A combined experimental, modeling, and computational approach to interpret the viscoelastic response of the white matter brain tissue during indentation. AB - Viscoelastic properties of the white matter brain tissue are systematically studied in this paper utilizing indentation experiments, mathematical modeling, and finite element simulation. It is first demonstrated that the internal stiffness of the instrument needs to be thoroughly obtained and incorporated in the analysis as its contribution to the recorded mechanical response is significant for experiments on very compliant materials. The flat-punch monotonic indentation is then performed indirectly on sagittal plane slices with pushing a large rigid coverslip into the sample surface. The recorded load and displacement data are used for calibrating different viscoelastic models and presenting numerical values for the model elements. Consequently, the accuracy of the findings based on the theoretical models is investigated by performing finite element simulations which suggest a considerable substrate effect that causes violation of the semi-infinite half-space assumption in modeling of the material behavior. Accordingly, correction factors for adjusting the viscoelastic constants are obtained and presented. Since the Maxwell model shows a superior capability in rendering the mechanical response of the brain, an extension of this model to Multimode Maxwell viscoelastic solid is proposed for modeling the tissue behavior under a more complex load-hold-unload indentation cycle that shows acceptable agreement with experimental observations. PMID- 28888931 TI - Biomechanical testing of zirconium dioxide osteosynthesis system for Le Fort I advancement osteotomy fixation. AB - The following work is the first evaluating the applicability of 3D printed zirconium dioxide ceramic miniplates and screws to stabilize maxillary segments following a Le-Fort I advancement surgery. Conventionally used titanium and individual fabricated zirconium dioxide miniplates were biomechanically tested and compared under an occlusal load of 120N and 500N using 3D finite element analysis. The overall model consisted of 295,477 elements. Under an occlusal load of 500N a safety factor before plastic deformation respectively crack of 2.13 for zirconium dioxide and 4.51 for titanium miniplates has been calculated. From a biomechanical point of view 3D printed ZrO2 mini-plates and screws are suggested to constitute an appropriate patient specific and metal-free solution for maxillary stabilization after Le Fort I osteotomy. PMID- 28888932 TI - Effect of frequency on crack growth in articular cartilage. AB - Cracks can occur in the articular cartilage surface due to the mechanical loading of the synovial joint, trauma or wear and tear. However, the propagation of such cracks under different frequencies of loading is unknown. The objective of this study was to determine the effect of frequency of loading on the growth of a pre existing crack in cartilage specimens subjected to cyclic tensile strain. A 2.26mm crack was introduced into cartilage specimens and crack growth was achieved by applying a sinusoidally varying tensile strain at frequencies of 1, 10 and 100Hz (i.e. corresponding to normal, above normal and up to rapid heel strike rise times, respectively). These frequencies were applied with a strain of between 10-20% and the crack length was measured at 0, 20, 50, 100, 500, 1000, 5000 and 10,000 cycles of strain. Crack growth increased with increasing number of cycles. The maximum crack growth was 0.6 +/- 0.3 (mean +/- standard deviation), 0.8 +/- 0.2 and 1.1 +/- 0.4mm at frequencies of 1, 10 and 100Hz, respectively following 10,000 cycles. Mean crack growth were 0.3 +/- 0.2 and 0.4 +/- 0.2 at frequencies of 1 and 10Hz, respectively. However, this value increased up to 0.6 +/- 0.4mm at a frequency of 100Hz. This study demonstrates that crack growth was greater at higher frequencies. The findings of this study may have implications in the early onset of osteoarthritis. This is because rapid heel strike rise times have been implicated in the early onset of osteoarthritis. PMID- 28888933 TI - Microstructures, mechanical properties, and degradation behaviors of heat-treated Mg-Sr alloys as potential biodegradable implant materials. AB - In previous studies, Mg-Sr alloys exhibited great biocompatibility with regard to test animals, and enhanced peri-implant bone formation. The objective of the present study was to investigate the effects of heat treatments on the mechanical and corrosion properties of Mg-Sr alloys. Various heat-treated Mg-xSr (x = 0.5, 1, and 2wt%, nominal composition) alloys were prepared using homogenization and aging treatments. Mechanical tests were performed at room temperature on the as cast, homogenized, and peak-aged alloys. As the Sr content increased, the volume fraction of Mg17Sr2 phases within the as-cast alloys increased; in addition, the mechanical strength of the alloys initially increased and subsequently decreased, while the ductility decreased. Following the homogenization treatment, the mechanical strength of the alloys decreased, and the ductility increased. Nano sized Mg17Sr2 phases were re-precipitated during the aging treatment. The age hardening response at 160 degrees C was enhanced as the Sr content increased. Following the aging treatment, there was an increase in the mechanical strength of the alloys; however, there was a slight reduction in the ductility. Immersion tests were conducted at 37 degrees C for 360h, using Hank's buffered salt solution (HBSS), to study the degradation behavior of the alloys. As the Sr content of the Mg-Sr alloys increased, the corrosion rate (CR) increased owing to the galvanic effect. The homogenization treatment consequently reduced the CR dramatically, and the aging treatment had a slight effect on the CR. The peak aged Mg-1Sr (wt%) alloy exhibited the best combination of properties. The tensile yield strength (TYS), ultimate tensile strength (UTS), elongation, compressive yield strength (CYS), ultimate compressive strength (UCS), compressibility, and CR of the as-cast Mg-1Sr (wt%) alloy were 56.0MPa, 92.67MPa, 1.27%, 171.4MPa, 243.6MPa, 22.3%, and 1.76mm/year, respectively. The respective results obtained for the peak-aged Mg-1Sr (wt%) alloys were 69.7MPa, 135.6MPa, 3.22%, 183.1MPa, 273.6MPa, 27.6%, and 1.33mm/year. Following immersion in HBSS, the primary corrosion products of the peak-aged Mg-1Sr (wt%) alloy were Mg(OH)2, MgO, MgCO3, Mg3(PO4)2, MgHPO4, and Mg(H2PO4)2, which enhanced the corrosion resistance by forming a composite corrosion film. PMID- 28888934 TI - Femoral stem incorporating a diamond cubic lattice structure: Design, manufacture and testing. AB - BACKGROUND: The current total hip prostheses with dense femoral stems are considerably stiffer than the host bones, which leads to such long-term complications as aseptic loosening, and eventually, the need for a revision. Consequently, the lifetime of the implantation does not match the lifetime expectation of young patients. METHOD: A femoral stem design featuring a porous structure is proposed to lower its stiffness and allow bone tissue ingrowth. The porous structure is based on a diamond cubic lattice in which the pore size and the strut thickness are selected to meet the biomechanical requirements of the strength and the bone ingrowth. A porous stem and its fully dense counterpart are produced by laser powder-bed fusion using Ti-6Al-4V alloy. To evaluate the stiffness reduction, static testing based on the ISO standard 7206-4 is performed. The experimental results recorded by digital image correlation are analyzed and compared to the numerical model. RESULTS & CONCLUSIONS: The numerical and experimental force-displacement characteristics of the porous stem show a 31% lower stiffness as compared to that of its dense counterpart. Moreover, the correlation analysis of the total displacement and equivalent strain fields allows the preliminary validation of the numerical model of the porous stem. Finally, the analysis of the surface-to-volume and the strength-to stiffness ratios of diamond lattice structures allow the assessment of their potential as biomimetic constructs for load-bearing orthopaedic implants. PMID- 28888936 TI - beta-arrestin-2 is involved in irisin induced glucose metabolism in type 2 diabetes via p38 MAPK signaling. AB - Type 2 diabetes mellitus (T2DM) is a common metabolic disease worldwide. It has been reported that irisin play regulatory role in glucose metabolism in T2DM. However, the underlying mechanism involved in that is not completely known. Herein, we determined the novel role of beta-arrestin-2 in irisin-induced glucose utilization in diabetes. Effects of irisin and beta-arrestin-2 on glucose utilization were investigated in a rat model of diabetes and in diabetic C2C12 cells in vitro. Results showed that irisin had positive role in glucose metabolism via regulating glucose tolerance as well as uptake in cardiac and skeletal muscle tissues, as evidenced by IPGTT, 2-deoxyglucose uptake and plasma membrane GLUT-4 assay. beta-arrestin-2 also improved glucose utilization in diabetes by increasing the glucose uptake and insulin sensitivity, as shown in mice overexpressing beta-arrestin-2. In diabetic C2C12 myocytes, irisin-induced GLUT4 and glucose uptake were restrained by beta-arrestin-2 inhibition, but was enhanced by beta-arrestin-2 overexpression. Additionally, irisin and beta arrestin-2 increased the activation of p38 MAPK in diabetic C2C12 cells, and the repression of p38 MAPK activation decreased the glucose uptake and plasma membrane GLUT-4 was enhanced by irisin and beta-arrestin-2 overexpression in diabetic C2C12 cells. In conclusion, we demonstrated that beta-arrestin-2 has a crucial role in irisin induced glucose metabolism in T2DM by regulating the p38 MAPK signaling. This might present a novel therapeutic target of treatment for human diabetes. PMID- 28888935 TI - Viscoplastic crack initiation and propagation in crosslinked UHMWPE from clinically relevant notches up to 0.5mm radius. AB - Highly crosslinked UHMWPE is now the material of choice for hard-on-soft bearing couples in total joint replacements. However, the fracture resistance of the polymer remains a design concern for increased longevity of the components in vivo. Fracture research utilizing the traditional linear elastic fracture mechanics (LEFM) or elastic plastic fracture mechanics (EPFM) approach has not yielded a definite failure criterion for UHMWPE. Therefore, an advanced viscous fracture model has been applied to various notched compact tension specimen geometries to estimate the fracture resistance of the polymer. Two generic crosslinked UHMWPE formulations (remelted 65kGy and remelted 100kGy) were analyzed in this study using notched test specimens with three different notch radii under static loading conditions. The results suggest that the viscous fracture model can be applied to crosslinked UHMWPE and a single value of critical energy governs crack initiation and propagation in the material. To our knowledge, this is one of the first studies to implement a mechanistic approach to study crack initiation and propagation in UHMWPE for a range of clinically relevant stress-concentration geometries. It is believed that a combination of structural analysis of components and material parameter quantification is a path to effective failure prediction in UHMWPE total joint replacement components, though additional testing is needed to verify the rigor of this approach. PMID- 28888937 TI - Low density lipoprotein receptor class A domain containing 4 (LDLRAD4) promotes tumorigenesis of hepatic cancer cells. AB - LDLRAD4 was previously identified and shown to be connected with psychiatric disorders. The structure of LDLRAD4 protein is similar to that of TMEPAI protein, which is overexpressed in many tumors. However, it is still unknown whether LDLRAD4 is involved in tumorigenesis. In this study, the potential role of LDLRAD4 in tumorigenesis was investigated. LDLRAD4 is elevated in hepatic cancer cells and tumor tissues, and expression of LDLRAD4 promotes hepatic cancer cell HepG2 and SMMC-7721 proliferation and migration. LDLRAD4 interacts Nedd4 to promote cell proliferation and migration and negatively regulates the TGF-beta signaling. Furthermore, immunofluorescence microscopy analysis indicates that LDLRAD4 is localized to the lysosome and association with Nedd4 is necessary for its intracellular transport to the lysosome. In addition, depletion of LDLRAD4 in HepG2 liver cancer cells inhibited tumorigenesis in nude mice. These results reveal an oncogenic role of LDLRAD4 in tumorigenesis through its association with Nedd4. PMID- 28888938 TI - Occurrence of Vibrio cholerae in water reservoirs of Burkina Faso. AB - Africa is currently an important region in which cholera epidemics occur. Little is known about the presence of Vibrio cholerae in freshwater bodies in Africa. There are ca. 1700 lakes and reservoirs in Burkina Faso, most of which have been built within recent decades to secure water resources. The purpose of this study was to investigate the presence of V. cholerae in the water of reservoirs, using the most-probable-number polymerase chain reaction. Results showed that V. cholerae could be detected in water samples collected from 14 of 39 sampled reservoirs. The concentrations varied from 0 MPN/l to more than 1100 MPN/l. Fifty strains of V. cholerae isolated on CHROMagarTM vibrio were identified as V. cholerae non-O1/non-O139, none of which carried the ctxA gene. A significant positive correlation was found between the presence of V. cholerae in the reservoirs and both alkaline pH and phytoplankton biomass. V. cholerae was present in significantly higher numbers in reservoirs of urban areas than in rural areas. Since V. cholerae non-O1/non-O139 has been shown to be a causative agent of endemic diarrheal outbreaks, their presence in Burkina Faso reservoirs suggests they may play a role in gastroenteritis in that country. PMID- 28888939 TI - Water isotope effect on the lipidic cubic phase: Heavy water-Induced interfacial area reduction of monoolein-Water system. AB - Heavy water (D2O) affects various functions of cells and living things. In order to gain fundamental insight into the molecular mechanism on biological effects of heavy water, D2O-effects on fully hydrated monoolein (MO) systems were investigated from the structural viewpoints. At room temperature, the MO fully hydrated by pure light water (H2O) forms a bicontinuous cubic (Pn3m) phase, and then, the Pn3m cubic phase transforms into an inverted hexagonal (HII) phase at about 90 degrees C. Temperature-scan X-ray diffraction measurements showed that substitution of D2O for H2O lowers the Pn3m-to-HII phase transition temperature and reduces the lattice constants of both phases. The structural analysis of the Pn3m phase using the diffraction intensity data indicated that D2O reduces the surface occupied area of MO at the interface by 12% in comparison with H2O. This change is probably due to the difference of the strength of hydrogen bond. PMID- 28888940 TI - Environmental change in a modified catchment downstream of a gold mine, Solomon Islands. AB - Solomon Islands is rapidly developing its natural resource exploitation sector, but data needed to assess consequent environmental impacts are scarce. We assessed catchments surrounding the Gold Ridge gold mine (Guadalcanal, Solomon Islands) and found that extensive changes in river course, and water and sediment quality have occurred downstream of the gold mine since its development. Sediment run-off from exposed areas associated with the mine pit has increased, elevating turbidity (up to 2450 NTU) and metal and arsenic levels, with levels of the latter being up to 0.141 mg/L in surface waters and 265 mg/kg in sediments. An overfull, inoperative tailings storage facility associated with the currently inactive gold mine with fluctuating arsenic levels (up to 0.087 mg/L in the water; 377 mg/kg in the sediment) presents an ongoing threat to the environment. Arsenic, due to its toxicity, appears to be the greatest threat, with sediment and water guideline levels in rivers exceeded 10-fold and exceeded nearly 20-fold in the tailings dam sediments. Despite elevated metal and arsenic content in the area, no toxic inorganic arsenic was found to have bioaccumulated in locally harvested food. In summary, the natural environment surrounding the Gold Ridge mine has been modified substantially and requires an ongoing monitoring program to ensure the ecosystem services of food and water for the local communities continue to be safe. This study informs not only the local area but also provides a microcosm of the broader global challenges facing the regulation of extractive industries in proximity to subsistence communities. PMID- 28888941 TI - Application of the IEUBK model for linking Children's blood lead with environmental exposure in a mining site, south China. AB - This study consisted of a site- and age-specific investigation linking children's blood lead level (BLL) to environmental exposures in a historic mining site in south China. A total of 151 children, aged 3-7 years, were included in this study. The geometric mean (GM) BLL was 8.22 MUg/dl, indicating an elevated BLL. The Integrated Exposure Uptake Bio-Kinetic (IEUBK) model has proven useful at many sites for study of routes of exposure. Application of the IEUBK model to these children indicated that the GM difference between observed and predicted BLL levels was only 1.07 MUg/dl. It was found that the key environmental exposure pathway was soil/dust intake, which contributed 86.3% to the total risk. Younger children had higher BLL than did older children. Therefore, of the various low risk-high benefit solutions, interventions for the children living near the site should be focused on the dust removal and soil remediation. Implementation of the China Eco-village Construction Plan and China New Rural Reconstruction Movement of the government may be a better solution. PMID- 28888942 TI - Enhanced photochemical conversion of NO2 to HONO on humic acids in the presence of benzophenone. AB - The photochemical conversion of NO2 to HONO on humic acids (HA) in the presence of benzophenone (BP) was investigated using a flow tube reactor coupled to a NOx analyzer at ambient pressure. BP significantly enhanced the reduction of NO2 to HONO on HA under simulated sunlight, as shown by the increase of NO2 uptake coefficient (gamma) and HONO yield with the mass ratio of BP to HA. The gamma and HONO yield on the mixtures of HA and BP obviously depended on the environmental conditions. Both gamma and HONO yield increased with the increase of irradiation intensity and temperature, whereas they decreased with pH. The gamma exhibited a negative dependence on the NO2 concentration, which had slight influences on the HONO yield. There were maximum values for the gamma and HONO yield at relative humidity (RH) of 22%. Finally, atmospheric implications about the photochemical reaction of NO2 and HA in the presence of photosensitive species were discussed. PMID- 28888944 TI - The novel dopamine D3 receptor antagonists/partial agonists CAB2-015 and BAK4-54 inhibit oxycodone-taking and oxycodone-seeking behavior in rats. AB - The use of prescription opioid analgesics, particularly oxycodone, has dramatically increased, and parallels escalated opioid abuse and drug-related deaths worldwide. Understanding the molecular mechanisms underlying the development of opioid dependence and expanding treatment options to counter prescription opioid abuse has become a critical public health matter. In the present study, we first evaluated the reinforcing effects of oxycodone in a rat model of self-administration and then explored the potential utility of two novel high affinity dopamine D3 receptor (D3R) antagonists/partial agonists, CAB2-015 and BAK4-54, for treatment of prescription opioid abuse and dependence. We found that rats acquired oxycodone self-administration rapidly within a range of unit doses that was similar to that for heroin, confirming that oxycodone has significant abuse potential. Strikingly, pretreatment with either CAB2-015 or BAK4-54 (0.4-10 mg/kg, i.p.) dose-dependently decreased oxycodone self administration, and shifted the oxycodone dose-response curve downward. Repeated pretreatment with CAB2-015 or BAK4-54 (0.4-4 mg/kg) facilitated extinction and inhibited oxycodone-induced reinstatement of drug-seeking behavior. In addition, pretreatment with CAB2-015 or BAK4-54 (4-10 mg/kg) also dose-dependently decreased oxycodone-enhanced locomotor activity, but only CAB2-015 decreased oral sucrose self-administration. These data suggest that D3R antagonists may be suitable alternatives or adjunctive to opioid-based medications currently used clinically in treating opioid addiction and that the D3R-selective ligands (CAB2 015 or BAK4-54) provide new lead molecules for development. PMID- 28888945 TI - Mathematical model for the spread of drug resistance in Plasmodium falciparum parasite considering transmission conditions. AB - Antimalarial drugs have been used as one of the main strategies for controlling this disease. However, the spread of drug resistance in the Plasmodium falciparum parasite has generated major challenges for the control of malaria. For this reason, it is necessary to develop an efficient policy considering the parasite behavior in relation to drug treatment and epidemiological parameters. To achieve this goal, we propose a mathematical model that describes the dynamics of parasite population considering the transmission effects between mosquitoes and humans. In order to quantify the drug treatment effect on humans and the generation of new parasite genotypes within the mosquito, the parasite population was divided into those found in humans and mosquitoes. To test the model, we simulate several parasite populations, related with pyrimethamine resistance, in high and low transmission conditions. Simulation results show the dynamics of different parasite populations depending on drug coverage and the effect of epidemiological parameters. These results show that disease elimination may not be possible by using only pyrimethamine treatment, so we include different control strategies and we observe that reducing contacts between mosquitoes and humans helped the drug coverage to reduce the prevalence of disease. Finally, this model is used to propose an optimal policy that minimizes disease prevalence; the principal result is that the most effective coverage of the drug is around middle coverage. The model can also be used to evaluate not only pyrimethamine treatments, but it can be adapted for the study of resistance to other drugs. PMID- 28888943 TI - Melanin concentrating hormone modulates oxytocin-mediated marble burying. AB - Repetitive and perseverative behaviors are common features of a number of neuropsychiatric diseases such as Angelman's syndrome, Tourette's syndrome, obsessive-compulsive disorder, and autism spectrum disorders. The oxytocin system has been linked to the regulation of repetitive behavior in both animal models and humans, but many of its downstream targets have still to be found. We report that the melanin-concentrating hormone (MCH) system is a target of the oxytocin system in regulating one repetitive behavior, marble burying. First we report that nearly 60% of MCH neurons express oxytocin receptors, and demonstrate using rabies mediated tract tracing that MCH neurons receive direct presynaptic input from oxytocin neurons. Then we show that MCH receptor knockout (MCHR1KO) mice and MCH ablated animals display increased marble burying response while central MCH infusion decreases it. Finally, we demonstrate the downstream role of the MCH system on oxytocin mediated marble burying by showing that central infusions of MCH and oxytocin alone or together reduce it while antagonizing the MCH system blocks oxytocin-mediated reduction of this behavior. Our findings reveal a novel role for the MCH system as a mediator of the role of oxytocin in regulating marble-burying behavior in mice. PMID- 28888946 TI - Autocatalytic confusion clarified. AB - There is frequent confusion about the terms autocatalytic reaction, autocatalytic cycle, and autocatalytic set. As the use of the same adjective implies, these three systems do indeed share common properties, in particular their potential for exponential growth. However, the ways in which they achieve this potential are different, giving rise to different internal network structures and dynamics. Therefore, care should be taken which term is used in which context. Here, we explain and discuss the similarities and differences between the three systems in detail, in an effort to avoid any further confusion. We then also discuss the relevance of these autocatalytic systems for possible origin of life scenarios, with an emphasis on how autocatalytic sets may have played an important role in this. PMID- 28888947 TI - A tale of three RNAs in mitochondria: tRNA, tRNA derived fragments and mitomiRs. PMID- 28888948 TI - The influence of understanding and having choice on children's prosocial behavior. AB - Humans are remarkable moral evaluators. However, between infancy and the preschool-age, children move from merely evaluating the world in terms of moral ("good"/"bad") terms to acting upon it in meaningful (prosocial and antisocial) ways. We argue that children's developing understanding and experience of choice and agency has profound behavioral consequences for this development in prosocial behavior. During the preschool age, children begin to explicitly reflect on their own actions and alternative actions (i.e., actions not taken), which then in turn help them make sense of the extent to which their prosocial behavior is costly, freely chosen, and internally motivated. We review the progression and developmental antecedents of children's beliefs about choice and agency as well as recent evidence for how children's social contexts may imbue them with a sense of choice and agency over their moral actions. We argue that the preschool period may be a particularly sensitive developmental time window during which children are sensitive to input regarding their own agency. PMID- 28888949 TI - Deficiency of N-acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver. AB - Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(-/-) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(-/-) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(-/-) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(-/-) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(-/-) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers. PMID- 28888950 TI - The two faces of aldehyde oxidase: Oxidative and reductive transformations of 5 nitroquinoline. AB - Aldehyde oxidase (AOX) is a cytosolic enzyme responsible for the metabolism of some drugs and drug candidates. AOX catalyzes the oxidative hydroxylation of substrates including several aliphatic and aromatic aldehydes, and nitrogen containing heterocyclic compounds. AOX is also reported to catalyze the reductive metabolism of nitro-compounds, N-oxides, sulfoxides, isoxazoles, isothiazoles, nitrite and hydroxamic acids. These reductive transformations are not well understood and are generally believed to only occur at low oxygen concentrations. In this study, we used 5-nitroquinoline (5NQ) as a substrate to further understand both the oxidative and the reductive transformations catalyzed by AOX. In vitro reaction of 5NQ with AOX under aerobic conditions generated the oxidized (2-oxo-5-nitroquinoline, 2-oxo-5NQ), the reduced (5-aminoquinoline, 5AQ) and the oxidized/reduced (2-oxo-5-aminoquinoline, 2-oxo-5AQ) metabolites. Interestingly, in human liver cytosol, co-incubation of 5NQ and known AOX oxidative substrates DACA and phthalazine significantly increased the yield of the reduced metabolite, while oxidized metabolites production decreased. These data indicate that 5NQ can be reduced at atmospheric oxygen concentrations and that the reductive transformation occurs at a second site that is kinetically distinct from the oxidative site. PMID- 28888951 TI - Cocaine and takotsubo syndrome: How frequent is it? PMID- 28888952 TI - Successful foetal delivery and emergency redo mitral valve replacement for acute prosthetic valve thrombosis in a 29-week pregnant woman. PMID- 28888953 TI - Attentional control underlies the perceptual load effect: Evidence from voxel wise degree centrality and resting-state functional connectivity. AB - The fact that interference from peripheral distracting information can be reduced in high perceptual load tasks has been widely demonstrated in previous research. The modulation from the perceptual load is known as perceptual load effect (PLE). Previous functional magnetic resonance imaging (fMRI) studies on perceptual load have reported the brain areas implicated in attentional control. To date, the contribution of attentional control to PLE and the relationship between the organization of functional connectivity and PLE are still poorly understood. In the present study, we used resting-state fMRI to explore the association between the voxel-wise degree centrality (DC) and PLE in an individual differences design and further investigated the potential resting-state functional connectivity (RSFC) contributing to individual's PLE. DC-PLE correlation analysis revealed that PLE was positively associated with the right middle temporal visual area (MT)-one of dorsal attention network (DAN) nodes. Furthermore, the right MT functionally connected to the conventional DAN and the RSFCs between right MT and DAN nodes were also positively associated with individual difference in PLE. The results suggest an important role of attentional control in perceptual load tasks and provide novel insights into the understanding of the neural correlates underlying PLE. PMID- 28888954 TI - Central antagonism of orexin type-1 receptors attenuates the development of morphine dependence in rat locus coeruleus neurons. AB - Prolonged use/abuse of opioid agonists leads to development of severe dependence to these drugs. Orexin-A has a crucial role in development of morphine dependence. The locus coeruleus (LC) is implicated in the expression of morphine withdrawal signs. Hyperactivity of LC neurons as well as increased intracellular cyclic adenosine monophosphate (cAMP) level temporally corresponds to the expression of opioid withdrawal behaviors. In this study the effect of central OX1R blockade on neuronal activity and cAMP content of LC neurons was investigated following naloxone administration in morphine-dependent rats. Male Wistar rats weighing 250-300g were used in this study. To induce morphine dependence, morphine was injected intraperitoneally (10mg/kg, i.p.) once a day for seven consecutive days. A selective OX1R antagonist (SB-334867) was microinjected into the cerebral ventricle (10ug/10ul) immediately before each morphine injection. The activity of LC neurons was investigated using in vivo extracellular single-unit recording on day 8 and naloxone (2mg/kg, i.p.) was administered after 10-min baseline recording. In addition, immunohistofluorescence method was used to measure the effect of naloxone on coerulear cAMP level. Chronic morphine injection induced morphine dependence in LC neurons which was revealed as a significant increase in LC neuronal firing rate in response to naloxone. The results of this study indicated that SB-334867 administration prior to each morphine injection prevents naloxone-elicited neuronal activation within the LC. In addition, naloxone injection enhanced the cAMP concentration in LC neurons of morphine-dependent animals and this effect was significantly reduced by OX1R blockade. PMID- 28888955 TI - Distinct roles of neuronal and microglial CB2 cannabinoid receptors in the mouse hippocampus. AB - The effects of cannabinoids are primarily mediated by type-1 cannabinoid receptors in the brain and type-2 cannabinoid receptors (CB2Rs) in the peripheral immune system. However, recent evidence demonstrates that CB2Rs are also expressed in the brain and implicated in neuropsychiatric effects. Diverse types of cells in various regions in the brain express CB2Rs but the cellular loci of CB2Rs that induce specific behavioral effects have not been determined. To manipulate CB2R expression in specific types of cells in the dorsal hippocampus of adult mice, we used Cre-dependent overexpression and CRISPR-Cas9 genome editing techniques in combination with adeno-associated viruses and transgenic mice. Elevation and disruption of CB2R expression in microglia in the CA1 area increased and decreased, respectively, contextual fear memory. In CA1 pyramidal neurons, disruption of CB2R expression enhanced spatial working memory, whereas their overexpression reduced anxiety levels assessed asan increase in the exploration time in the central area of open field. Interneuronal CB2Rs were not involved in the modulation of cognitive or emotional behaviors tested in this study. The targeted manipulation of CB2R expression in pyramidal neurons and microglia suggests that CB2Rs in different types of cells in the mature hippocampus play distinct roles in the regulation of memory and anxiety. PMID- 28888956 TI - Oxysterol, 5alpha-cholestan-3-one, modulates a contractile response to beta2 adrenoceptor stimulation in the mouse atria: Involvement of NO signaling. AB - AIM: Atrial beta2-adrenoceptors provide an important mechanism for regulation of cardiac function and changes in their downstream signaling are involved in processes underlying heart disorders. We have investigated the mechanism by which the cholesterol metabolite 5alpha-cholestan-3-one (5alphaCh3) modulates inotropic effect of beta2-adrenoceptor agonist fenoterol. MAIN METHODS: Atria from mice were electrically stimulated and changes in contraction amplitude in response to fenoterol were studied in 5alphaCh3-pretreated samples. Intracellular Ca2+ and NO levels were estimated using fluorescent dyes Fluo-4 and DAF-FM, respectively. KEY FINDINGS: By itself 5alphaCh3 that appears in the circulation under some pathological conditions had a negligible influence on contraction, Ca2+-transient and NO production. However, pretreatment with 5alphaCh3 markedly attenuated the positive inotropic effect of fenoterol which was accompanied by an increase in the NO synthesis. Unexpectedly, the oxysterol also augmented an enhancement of Ca2+-transient amplitude in response to fenoterol. Under conditions of a pharmacological inhibition of Gi-protein/Akt/NO synthase/protein kinase G signaling, 5alphaCh3 augmented the inotropic effect of fenoterol. Herein, Akt antagonist suppressed the increase in NO production, while inhibition of NO synthesis did not modify the increased amplitude of the Ca2+-transient. Along similar lines, enrichment of plasma membranes with cholesterol reduced the stimulatory effect of 5alphaCh3 on beta2-adrenoceptor-evoked NO production, but not on the Ca2+-transient amplitude, leading to an elevation of the positive inotropic response to fenoterol. SIGNIFICANCE: These data suggest that 5alphaCh3 potentiates the effect of pharmacological beta2-adrenoceptor activation on both NO production and Ca2+ transient via independent mechanisms, thereby affecting the positive inotropy. PMID- 28888957 TI - Investigating toxicity specific to adjuvanted vaccines. AB - In an attempt to understand the unique toxicity of adjuvanted vaccines, we studied how toxicity develops over time following vaccine administration. In addition to on- and off-target toxicity typically observed with general pharmaceuticals, we observed toxicity associated with both the generation and the broad action of effectors (antibodies and/or cytotoxic T lymphocytes, CTLs). The impact on effector generation appears to be related to local tolerance specific to the adjuvant. The vaccine immune response by effectors serves to demonstrate species relevance as outlined in the recent WHO guideline on the nonclinical evaluation of adjuvanted vaccines. When regarded as pharmaceuticals that function at sites of local administration, adjuvants have inherent on- and off-target toxicity. On-target toxicity of the adjuvant is typically associated with effector generation, and could vary depending on animal species. Therefore, the use of species with sensitivity to adjuvants described in the WHO guidelines is required to evaluate the toxicity of the vaccine associated with effector generation. Changes in safety pharmacology endpoints would be considered off target and further studies are conducted only if changes in these endpoints are observed in nonclinical or clinical studies. Thus our decision tree does not recommend the routine conduct of stand-alone safety pharmacology studies. PMID- 28888959 TI - Genotoxicity and sub-chronic toxicity of MYOLUTION(r) (branched chain keto acids). AB - MYOLUTION(r), which consists of a mixture of the branched chain keto acids, keto leucine, keto-isoleucine and keto-valine, as their calcium salts, may potentially be used as a food ingredient based on the reported contributions of these compounds to muscle health and exercise performance. Tests on genotoxicity and sub-chronic toxicity were performed to evaluate the safety of branched chain keto acids. No genotoxic effects were observed in the bacterial mutation assay or the in vitro micronucleus assay in human lymphocytes. In the 28 day and 90 day repeated dose toxicity studies no test item related mortality or toxicological effects on clinical signs, body weight, food consumption, urine parameters, hematology, clinical biochemistry parameters, organ weight, gross pathological findings and histopathology were observed. Based on the studies described here, MYOLUTION(r) does not exert a genotoxic effect, and a no-observed-adverse-effect level of 3318.38 mg/kg bw/day in males and 3733.28 mg/kg bw/day in females was determined in the 90 day repeated dose toxicity study. PMID- 28888958 TI - Establishing maximum tolerated doses for a 2-year combined chronic/carcinogenicity rat study based on toxicokinetic and toxicity gender differences. AB - For agrochemicals tested in a carcinogenicity rodent study, it is often not possible to use the same high dose to achieve maximum tolerated dose (MTDs) without overdosing or insufficiently challenging one gender if significant gender differences are known. Toxicokinetic (TK) data for pesticide FR from a 28-day rat study showed that males required a 3-fold higher external dose compared to females to produce similar internal exposure levels of the parent compound. In the 90-day study, 8%/17% (M/F) decrease in bodyweight gain (BWG) and 15%/15% (M/F) increase in relative liver weights were observed in the 6000 ppm males and 2000 ppm females, respectively. Based on the above TK and toxicity data, different high dose levels were selected for females (1600 ppm) and males (4800 ppm) for a 2-year combined chronic/carcinogenicity study in rats. In the 2-year study, 14%, 13%, 13% and 21% reduction in BWG of males and 10%, 12%, 19% and 20% reduction in BWG of females were observed at weeks 13, 26, 52 and 104, respectively in the highest dose tested. Similar reductions in bodyweight gain in males and females at the different high dose levels clearly demonstrated that appropriate MTDs were reached. Therefore, it is scientifically sound and practical to use TK and toxicity data to use different high dose levels to achieve MTDs for a pesticide with large gender differences. PMID- 28888960 TI - Complete genome sequence of endophyte Bacillus flexus KLBMP 4941 reveals its plant growth promotion mechanism and genetic basis for salt tolerance. AB - Bacillus flexus KLBMP 4941 is a halotolerant endophyte isolated from the halophyte Limonium sinense. This strain can improve host seedling growth under salt stress conditions. We here report the complete genome information of endophyte KLBMP 4941. It has a circular chromosome and two plasmids for a total genome 4,104,242 bp in size with a G+C content of 38.09%. Genes related to plant growth promotion (PGP), such as those associated with nitrogen fixation, siderophore, spermidine, and acetoin synthesis were found in the KLBMP 4941 genome. Some genes responsible for high salinity tolerance, like genes associated with the Na+/H+ antiporter, glycine betaine transporter, and betaine-aldehyde dehydrogenase were also found in the KLBMP 4941 genome. The genome analysis will provide better understanding of the mechanisms underlying the promotion of plant growth in strain KLBMP 4941 under salt stress conditions and its ability to adapt to coastal salt marsh habitats, and provide a basis for its further biotechnological applications in agriculture. PMID- 28888961 TI - The SeqAn C++ template library for efficient sequence analysis: A resource for programmers. AB - BACKGROUND: The use of novel algorithmic techniques is pivotal to many important problems in life science. For example the sequencing of the human genome (Venter et al., 2001) would not have been possible without advanced assembly algorithms and the development of practical BWT based read mappers have been instrumental for NGS analysis. However, owing to the high speed of technological progress and the urgent need for bioinformatics tools, there was a widening gap between state of-the-art algorithmic techniques and the actual algorithmic components of tools that are in widespread use. We previously addressed this by introducing the SeqAn library of efficient data types and algorithms in 2008 (Doring et al., 2008). RESULTS: The SeqAn library has matured considerably since its first publication 9 years ago. In this article we review its status as an established resource for programmers in the field of sequence analysis and its contributions to many analysis tools. CONCLUSIONS: We anticipate that SeqAn will continue to be a valuable resource, especially since it started to actively support various hardware acceleration techniques in a systematic manner. PMID- 28888962 TI - Structural insights into beta-glucosidase transglycosylation based on biochemical, structural and computational analysis of two GH1 enzymes from Trichoderma harzianum. AB - beta-glucosidases are glycoside hydrolases able to cleave small and soluble substrates, thus producing monosaccharides. These enzymes are distributed among families GH1, GH2, GH3, GH5, GH9, GH30 and GH116, with GH1 and GH3 being the most relevant families with characterized enzymes to date. A recent transcriptomic analysis of the fungus Trichoderma harzianum, known for its increased beta glucosidase activity as compared to Trichoderma reesei, revealed two enzymes from family GH1 with high expression levels. Here we report the cloning, recombinant expression, purification and crystallization of these enzymes, ThBgl1 and ThBgl2. A close inspection of the enzymatic activity of these enzymes surprisingly revealed a marked difference between them despite the sequence similarity (53%). ThBgl1 has an increased tendency to catalyze transglycosylation reaction while ThBgl2 acts more as a hydrolyzing enzyme. Detailed comparison of their crystal structures and the analysis of the molecular dynamics simulations reveal the presence of an asparagine residue N186 in ThBgl2, which is replaced by the phenylalanine F180 in ThBgl1. This single amino acid substitution seems to be sufficient to create a polar environment that culminates with an increased availability of water molecules in ThBgl2 as compared to ThBgl1, thus conferring stronger hydrolyzing character to the former enzyme. PMID- 28888964 TI - Comparison of spread of transversus thoracic plane block by sagittal and transverse approach in a clinical setting. PMID- 28888963 TI - Sex differences in the mitochondrial bioenergetics of astrocytes but not microglia at a physiologically relevant brain oxygen tension. AB - Biological sex is thought to influence mitochondrial bioenergetic function. Previous respiration measurements examining brain mitochondrial sex differences were made at atmospheric oxygen using isolated brain mitochondria. Oxygen is 160 mm Hg (21%) in the atmosphere, while the oxygen tension in the brain generally ranges from ~5 to 45 mm Hg (~1-6% O2). This study tested the hypothesis that sex and/or brain physiological oxygen tension influence the mitochondrial bioenergetic properties of primary rat cortical astrocytes and microglia. Oxygen consumption was measured with a Seahorse XF24 cell respirometer in an oxygen controlled environmental chamber. Strikingly, male astrocytes had a higher maximal respiration than female astrocytes when cultured and assayed at 3% O2. Three percent O2 yielded a low physiological dissolved O2 level of ~1.2% (9.1 mm Hg) at the cell monolayer during culture and 1.2-3.0% O2 during assays. No differences in bioenergetic parameters were observed between male and female astrocytes at 21% O2 (dissolved O2 of ~19.7%, 150 mm Hg during culture) or between either of these cell populations and female astrocytes at 3% O2. In contrast to astrocytes, microglia showed no sex differences in mitochondrial bioenergetic parameters at either oxygen level, regardless of whether they were non-stimulated or activated to a proinflammatory state. There were also no O2- or sex-dependent differences in proinflammatory TNF-alpha or IL-1beta cytokine secretion measured at 18 h activation. Overall, results reveal an intriguing sex variance in astrocytic maximal respiration that requires additional investigation. Findings also demonstrate that sex differences can be masked by conducting experiments at non-physiological O2. PMID- 28888965 TI - "Click" reaction based synthesis of nimbolide derivatives and study of their insect antifeedant activity against Spodoptera litura Larvae. AB - A series of Nimbolide-triazole conjugates were synthesized through copper(I)- catalyzed azide-alkyne "click" chemistry approach and these derivatives (2-4, 2a 2l) were characterized using modern spectroscopic techniques. Antifeedant activities of these derivatives were studied on Tobacco Caterpillar, Spodoptera litura (F.) using no-choice leaf disk bioassay. Interestingly, the synthesized derivatives were more effective in reducing feedancy by insect species when compared to the parent nimbolide. Among the tested compounds, 2a, 2c, and 2d showed potent antifeedancy with ED50 values of 0.49, 0.95 and 0.97mg/cm2 against S. litura. Several of the analogs were also toxic or caused developmental abnormalities following leaf disc assay. PMID- 28888966 TI - Pursuing sesterterpene lactams in Australian Irciniidae sponges. AB - Chemical investigation of two Irciniidae sponges collected by hand (SCUBA) from Australian near shore waters, afforded six new examples of a rare class of sesterterpene lactam; ircinialactams B (1), G (2), H (5), and I (6), and 8 hydroxyircinialactams C (3) and G (4); together with the new biosynthetically related lactone, ircinialactone A (7). Also isolated were seven biosynthetically related known Irciniidae metabolites; ircinialactams A (8) and C (9), (7E,12E,20Z,18S)-variabilin (10), (7Z,12Z,20Z,18S)-variabilin (11), (7E,12Z,20Z,18S)-variabilin (12), (7Z,12E,20Z,18S)-variabilin (13) and irciniafuran A (14). The structure elucidation of 1-14 was achieved by detailed spectroscopic analysis, and consideration of a plausible biosynthetic relationship linking Irciniidae sesterterpene beta-furans, lactams and lactones. PMID- 28888967 TI - Twenty-five-gauge sutureless lensectomy in infants with congenital cataract. AB - PURPOSE: To evaluate the incidence of intra- and postoperative complications of transconjunctival 25-gauge (25G) sutureless pars plicata lensectomy. METHODS: The medical records of patients <12 months of age with congenital cataracts who underwent 25G sutureless lensectomy were reviewed retrospectively. Patients were evaluated at postoperative days 1, 7, 15, 30, 60, and 90 and every 3 months thereafter. Visual acuity outcomes and intra- and postoperative complications were described and analyzed. RESULTS: A total of 72 eyes of 44 infants were included; 28 patients (64%) had bilateral cataract. Median follow-up was 28 months (range, 12-93 months). In 47 eyes (81%) there was improved visual acuity after surgery. Intraoperative adverse events occurred in 9 eyes (13%). Postoperative complications occurred in 14 eyes (19%): 6 eyes (8%) had secondary visual axis opacification, 6 eyes (8%) had secondary glaucoma, 1 eye (1%) had posterior synechiae, and 1 eye (1.4%) had retinal detachment. CONCLUSIONS: Transconjunctival pars plicata 25G sutureless lensectomy is a minimally invasive technique for congenital cataract treatment. No postoperative complications were observed in 81% of eyes. Visual acuity improved in 81% of the operated eyes. PMID- 28888968 TI - Role of botulinum toxin A in treatment of intractable diplopia. AB - PURPOSE: To evaluate the effect of botulinum toxin A (BTXA) in patients with intractable diplopia related to intracranial problems or long-term interruption of fusion due to cataract or uncorrected aphakia and to identify the group of resistant cases who have no potential to fuse the two images. METHODS: The medical records of patients seen by the senior author (SBO) over a period of 20 years were reviewed retrospectively to identify those who underwent BTXA treatment for intractable diplopia. All cases had horizontal and/or vertical deviations. The diagnostic criterion was persistence of diplopia in free space despite neutralization of the deviation by prisms or synoptophore. BTXA was injected into the appropriate extraocular muscle to control the deviation in the identified patients. RESULTS: A total of 22 patients were identified: 13 developed intractable diplopia following head trauma, intracranial surgery, or stroke; 9 had a history of binocular sensory deprivation due to traumatic cataract or uncorrected aphakia. The duration of sensory deprivation ranged from 2 to 41 years. BTXA was injected into the appropriate extraocular muscle(s). Diplopia resolved completely in 14 patients, resolved incompletely with short term single vision in 3 cases, and persisted in 5 patients despite correction of the deviation by BTXA. CONCLUSIONS: Our results suggest that BTXA offers the advantage of a temporary decrease of the deviation without altering image quality that allows the visual system to recover fusion under real-life conditions. Permanent treatment with surgical correction of the deviation should be reserved for those who achieve fusion during the orthotropic period provided by BTXA. PMID- 28888969 TI - mTOR-related neuropathology in mutant tsc2 zebrafish: Phenotypic, transcriptomic and pharmacological analysis. AB - Tuberous sclerosis complex (TSC) is a rare, genetic disease caused by loss-of function mutations in either TSC1 or TSC2. Patients with TSC are neurologically characterized by the presence of abnormal brain structure, intractable epilepsy and TSC-associated neuropsychiatric disorders. Given the lack of effective long term treatments for TSC, there is a need to gain greater insight into TSC-related pathophysiology and to identify and develop new treatments. In this work we show that homozygous tsc2-/- mutant zebrafish larvae, but not tsc2+/- and WT larvae, display enlarged brains, reduced locomotor behavior and epileptiform discharges at 7dpf. In addition, we pharmacologically validated the TSC model by demonstrating the dramatic rescue effect of pericardially injected rapamycin, a well-known mTOR inhibitor, on selected behavioral read-outs and at the molecular level. By means of trancriptome profiling we also acquired more insight into the neuropathology of TSC, and as a result were able to highlight possible new treatment targets. The gene expression profiles of WT and tsc2+/- larvae revealed 117 differentially expressed genes (DEGs), while between WT and tsc2-/- larvae and tsc2+/- and tsc2-/- larvae there were 1414 and 1079 DEGs, respectively. Pathway enrichment analysis from the WT and tsc2-/- DEGs, identified 14 enriched pathways from the up-regulated genes and 6 enriched pathways from the down regulated genes. Moreover, genes related to inflammation and immune response were up-regulated in the heads of tsc2-/- larvae, in line with the findings in human brain tissue where inflammatory and immune responses appear to be major hallmarks of TSC. Taken together, our phenotypic, transcriptomic and pharmacological analysis identified the tsc2-/- zebrafish as a preclinical model that mirrors well aspects of the human condition and delineated relevant TSC-related biological pathways. The model may be of value for future TSC-related drug discovery and development programs. PMID- 28888971 TI - Fungal infection in neural tissue of patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and the main cause of motor neuron pathology. The etiology of the disease remains unknown, and no effective therapy exists to halt the disease or improve the quality of life. Here, we provide compelling evidence for the existence of fungal infection in ALS. Immunohistochemistry analysis using a battery of antifungal antibodies revealed fungal structures such as yeast and hyphae in the motor cortex, the medulla and the spinal cord, in eleven patients with ALS. Some fungal structures were localized intracellularly and even intranuclearly, indicating that this infection is not the result of post-mortem colonization. By contrast, this burden of fungal infection cannot be observed in several CNS areas of control subjects. PCR analysis and next generation sequencing of DNA extracted from frozen neural tissue identified a variety of fungal genera including Candida, Malassezia, Fusarium, Botrytis, Trichoderma and Cryptococcus. Overall, our present observations provide strong evidence for mixed fungal infections in ALS patients. The exact mixed infection varies from patient to patient consistent with the different evolution and severity of symptoms in each ALS patient. These novel findings provide a logical explanation for the neuropathological observations of this disease, such as neuroinflammation and elevated chitinase levels, and could help to implement appropriate therapies. PMID- 28888970 TI - Glial overexpression of Dube3a causes seizures and synaptic impairments in Drosophila concomitant with down regulation of the Na+/K+ pump ATPalpha. AB - Duplication 15q syndrome (Dup15q) is an autism-associated disorder co-incident with high rates of pediatric epilepsy. Additional copies of the E3 ubiquitin ligase UBE3A are thought to cause Dup15q phenotypes, yet models overexpressing UBE3A in neurons have not recapitulated the epilepsy phenotype. We show that Drosophila endogenously expresses Dube3a (fly UBE3A homolog) in glial cells and neurons, prompting an investigation into the consequences of glial Dube3a overexpression. Here we expand on previous work showing that the Na+/K+ pump ATPalpha is a direct ubiquitin ligase substrate of Dube3a. A robust seizure-like phenotype was observed in flies overexpressing Dube3a in glial cells, but not neurons. Glial-specific knockdown of ATPalpha also produced seizure-like behavior, and this phenotype was rescued by simultaneously overexpressing ATPalpha and Dube3a in glia. Our data provides the basis of a paradigm shift in Dup15q research given that clinical phenotypes have long been assumed to be due to neuronal UBE3A overexpression. PMID- 28888972 TI - EMG synchrony to assess impaired corticomotor control of locomotion after stroke. AB - Adapting one's gait pattern requires a contribution from cortical motor commands. Evidence suggests that frequency-based analysis of electromyography (EMG) can be used to detect this cortical contribution. Specifically, increased EMG synchrony between synergistic muscles in the Piper frequency band has been linked to heightened corticomotor contribution to EMG. Stroke-related damage to cerebral motor pathways would be expected to diminish EMG Piper synchrony. The objective of this study is therefore to test the hypothesis that EMG Piper synchrony is diminished in the paretic leg relative to nonparetic and control legs, particularly during a long-step task of walking adaptability. Twenty adults with post-stroke hemiparesis and seventeen healthy controls participated in this study. EMG Piper synchrony increased more for the control legs compare to the paretic legs when taking a non-paretic long step (5.02+/-3.22% versus 0.86+/ 2.62%), p<0.01) and when taking a paretic long step (2.04+/-1.98% versus 0.70+/ 2.34%, p<0.05). A similar but non-significant trend was evident when comparing non-paretic and paretic legs. No statistically significant differences in EMG Piper synchrony were found between legs for typical walking. EMG Piper synchrony was positively associated with walking speed and step length within the stroke group. These findings support the assertion that EMG Piper synchrony indicates corticomotor contribution to walking. PMID- 28888973 TI - Novel lipidic and bienzymatic nanosomes for efficient delivery and enhanced bioactivity of catalase. AB - The purpose of this study was to evaluate the improved characteristics of catalase (CAE) when loaded in lipidic and bienzymatic nanosomes. Lipidic and bienzymatic nanosomes containing CAE and uricase (LSCU) were manufactured in two buffer solutions. Their micromorphologies, sizes, zeta potentials, enzymatic activities, kinetic characteristics, and hydrogen peroxide-lowering effects were compared with those of free CAE and lipidic nanosomes containing only CAE (LSC). The structural change and stability mechanism were investigated using fluorescent probes. Compared with free CAE and LSC, LSCU had better physiochemical characteristics and improved in vitro enzymatic activity under different temperatures and pH conditions. In vivo bioavailability and peroxidase activity were also improved. For example, the bioavailability of LSCU was ~450% greater than that of free CAE, and the time required for LSCU to lower hydrogen peroxide concentrations to a physiologically normal level was almost one-third the time required for free CAE and one-half the time required for LSC. The increased catalytic activity and hydrogen peroxide-lowering capabilities of CAE loaded in LSCU could be ascribed to the favorable conformational changes of CAE and the protection offered by the lipidic and bienzymatic nanosomal biomembrane. Lipidic and bienzymatic nanosomes might be promising nanocarriers for the parenteral delivery of therapeutic enzymes such as CAE. PMID- 28888974 TI - Nanofibrillar cellulose hydrogels and reconstructed hydrogels as matrices for controlled drug release. AB - Concentrated 3% and 6.5% anionic nanofibrillar cellulose (ANFC) hydrogels were introduced as matrix reservoirs for controlled delivery applications of small molecules and proteins. A further aim was to study how the freeze-drying and subsequent rehydration of ANFC hydrogel affects the rheological properties and drug release of selected model compounds from the reconstructed hydrogels. It was demonstrated that the 3% and 6.5% ANFC hydrogels can be freeze-dried with suitable excipients into highly porous aerogel structures and redispersed back into the hydrogel form without significant change in the rheological properties. Freeze-drying did not affect the drug release properties from redispersed ANFC hydrogels, indicating that these systems could be stored in the dry form and only redispersed when needed. For large molecules, the diffusion coefficients were significantly smaller when higher ANFC fiber content was used, indicating that the amount of ANFC fibers in the hydrogel can be used to control the release rate. The release of small molecules was controlled with the ANFC fiber content only to a moderate extent. The results indicate that ANFC hydrogel can be used for controlled delivery of several types of molecules and that the hydrogel can be successfully freeze-dried and redispersed. PMID- 28888975 TI - Solvent-responsive floating liquid crystalline-molecularly imprinted polymers for gastroretentive controlled drug release system. AB - Liquid crystalline-molecularly imprinted polymer (LC-MIP) particles were first found to possess the floating behavior on the aqueous medium. Combined with molecular recognition, the LC-MIP was fabricated as a novel class of the controlled-release gastric retentive DDS. The LC-MIP was made using co polymerization of methacrylic acid, 4-methyl phenyl dicyclohexyl ethylene (LC monomer with vinyl group), and ethylene glycol dimethacrylate with S-amlodipine (S-AML) as model template drug. The optimum condition of the preparation of LC MIP has been obtained relying on release behaviors of S-AML from the LC-MIP. The surface morphology of LC-MIP and three corresponding control samples, i.e., template-free LC-NIP, LC-free MIP, and LC-free NIP, were studied. Applying the LF model for the binding isotherm, imprinting factors was 2.80 for the LC-MIP with the crosslinking degree of 20.0%, whereas 6.70 for the LC-free MIP with high levels of crosslinker (80.0%). Furthermore, the phase transition behaviors of LC based particles as well as drug-loaded LC elastomers were measured by a differential scanning calorimeter and the formed hydrogen bonding between S-AML and LC-MIP was demonstrated by FT-IR spectra. In vivo imaging experiment proved that the floating LC-MIP had significantly longer gastric residence time (>60min) than the non-floating MIP reference (<30min). In vivo pharmacokinetic study showed a plateau region between 1.5 and 22h on the plasma concentration from the LC-MIP. In spite of lower imprinting factor, the relative bioavailability of the gastro-floating LC-MIP was 180.5%, whereas only 111.7% of the LC-free MIP. As a conclusion, the LC-MIPs indicated potentials for oral administration due to the innovative combination of floating and controlled release properties. PMID- 28888976 TI - Simple nanophotosensitizer fabrication using water-soluble chitosan for photodynamic therapy in gastrointestinal cancer cells. AB - The polysaccharide chitosan has abundant cationic amine groups, and can form ion complexes with anionic molecules such as the strong photosensitizer chlorin e6 (Ce6). In this study, water-soluble chitosan (WSC) was used to fabricate Ce6 incorporated nanophotosensitizers (Abbreviated as ChitoCe6 nanophotosensitizer) via a self-assembling process. This was accomplished by dissolving WSC in pure water and then directly mixing the solution with solid Ce6 causing ion complex formation between WSC and Ce6. The resulting nanophotosensitizer was spherical in shape and had a particle size of less than 300nm. The photodynamic effect of ChitoCe6 nanophotosensitizer was evaluated using gastrointestinal (GI) cancer cells. At in vitro study using SNU478 cholangiocarcinoma cells, ChitoCe6 nanophotosensitizer showed improved Ce6 uptake by tumor cells, reactive oxygen species production, and cellular phototoxicity. An in vivo study using SNU478 bearing nude mice showed that the ChitoCe6 nanophotosensitizer efficiently accumulated in the tumor tissue and inhibited tumor growth more than treatment with Ce6 alone. Furthermore, ChitoCe6 nanophotosensitizer was also efficiently absorbed through tissue layers in an ex vivo study using porcine bile duct explants. ChitoCe6 nanophotosensitizer showed enhanced photosensitivity and photodynamic effects against cancer cells in vitro and in vivo. We present ChitoCe6 nanophotosensitizer as a promising candidate for photodynamic therapy of GI cancer. PMID- 28888977 TI - Emerging technologies for the non-invasive characterization of physical mechanical properties of tablets. AB - The density, porosity, breaking force, viscoelastic properties, and the presence or absence of any structural defects or irregularities are important physical mechanical quality attributes of popular solid dosage forms like tablets. The irregularities associated with these attributes may influence the drug product functionality. Thus, an accurate and efficient characterization of these properties is critical for successful development and manufacturing of a robust tablets. These properties are mainly analyzed and monitored with traditional pharmacopeial and non-pharmacopeial methods. Such methods are associated with several challenges such as lack of spatial resolution, efficiency, or sample sparing attributes. Recent advances in technology, design, instrumentation, and software have led to the emergence of newer techniques for non-invasive characterization of physical-mechanical properties of tablets. These techniques include near infrared spectroscopy, Raman spectroscopy, X-ray microtomography, nuclear magnetic resonance (NMR) imaging, terahertz pulsed imaging, laser-induced breakdown spectroscopy, and various acoustic- and thermal-based techniques. Such state-of-the-art techniques are currently applied at various stages of development and manufacturing of tablets at industrial scale. Each technique has specific advantages or challenges with respect to operational efficiency and cost, compared to traditional analytical methods. Currently, most of these techniques are used as secondary analytical tools to support the traditional methods in characterizing or monitoring tablet quality attributes. Therefore, further development in the instrumentation and software, and studies on the applications are necessary for their adoption in routine analysis and monitoring of tablet physical-mechanical properties. PMID- 28888978 TI - Fabrication of drug-loaded hydrogels with stereolithographic 3D printing. AB - 3D printing (3DP) technologies have been attracting much recent interest as new methods of fabricating medicines and medical devices. Of the many types of 3DP available, stereolithographic (SLA) printing offers the unique advantage of being able to fabricate objects by cross-linking resins to form networked polymer matrices. Because water can be entrapped in these matrices, it is possible in principle to fabricate pre-wetted, drug-loaded hydrogels and devices. Here, SLA printing was used to prepare ibuprofen-loaded hydrogels of cross-linked polyethylene glycol diacrylate. Hydrogels containing up to 30% w/w water, and 10% w/w ibuprofen, were successfully printed. Dissolution profiles showed that drug release rates were dependent on water content, with higher water content hydrogels releasing drug faster. The conclusion is that SLA 3DP offers a new manufacturing route to pharmaceutical hydrogels. PMID- 28888979 TI - Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor. AB - Prostate cancer growth and progression are mainly dependent on androgens and many current prostate cancer treatment options target the synthesis or function of androgens. We have previously reported that resveratrol and synthetic analogs of resveratrol with a higher bioavailability inhibit the synthesis of androgens in human adrenocortical H295R cells. Now we have studied the antiandrogenic properties of resveratrol, piceatannol and analogs in two different prostate cell lines; LNCaP and RWPE. LNCaP carry a T877A mutation in the androgen receptor while RWPE has a wild-type androgen receptor. We found that resveratrol, piceatannol and all studied analogs were able to inhibit a dihydrotestosterone induced activation of the androgen receptor, showing that they act as antiandrogens. In LNCaP cells, all studied compounds were able to statistically significantly decrease the androgenic signaling in concentrations >=1MUM and the synthetic analogs trimethylresveratrol (RSVTM) and tetramethylpiceatannol (PICTM) were the most potent compounds. RWPE cells were not as responsive to the studied compounds as the LNCaP cells. A statistically significant decrease in the androgenic signaling was observed at concentrations <=5MUM for most compounds and RSVTM was found to be the most potent compound. Further, we studied the effects of resveratrol, piceatannol and analogs on the levels of prostate-specific antigen (PSA) in LNCaP cells and found that all studied compounds decreased the level of PSA and that the synthetic analogs diacetylresveratrol (RSVDA), triacetylresveratrol (RSVTA) and RSVTM were the most potent compounds, decreasing the PSA level by approx. 50% at concentrations >=10MUM. In a cell-free receptor binding assay we were unable to show binding of resveratrol or analogs to the ligand binding domain of the androgen receptor, indicating that the observed effects are mediated via other mechanisms than direct ligand competition. We conclude that the resveratrol, piceatannol and analogs are highly interesting for chemoprevention of prostate cancer, since they have a high potency both as inhibitors of androgen synthesis and androgen receptor activation. PMID- 28888980 TI - Arctigenin attenuates ischemic stroke via SIRT1-dependent inhibition of NLRP3 inflammasome. AB - Arctigenin (ARC), a phenylpropanoid dibenzylbutyrolactone lignan derived from Arctium lappa L, has been reported to protect against cerebral ischemia injury in rats, but the underlying mechanism is unclear. In this study, we investigated whether ARC ameliorated ischemic stroke by inhibiting NLRP3 inflammasome-derived neuroinflammation and whether SIRT1 signaling was involved in this process. ARC (20 mg/kg) or vehicle were intraperitoneally injected to Sprague-Dawley rats for 3 days before middle cerebral artery occlusion (MCAO) surgery performed. The infarct volume, neurological score, brain water content, neuroinflammation, NLRP3 inflammasome activation and SIRT1 protein expression were assessed. Furthermore, we also investigated whether ARC protected against cerebral ischemia via SIRT1 dependent inhibition of NLRP3 inflammasome by administrating EX527, a specific SIRT1 inhibitor, under oxygen-glucose deprivation (OGD) condition. We found that ARC pretreatment decreased infarct volume, neurological score and brain water content. Moreover, ARC treatment effectively inhibited cerebral ischemia induced NLRP3 inflammasome activation and IL-1beta, IL-18 secretion both in vivo and in vitro. Futhermore, ARC treatment activated Silent information regulator 1 (SIRT1) singnaling in the brain. Importantly, suppress of SIRT1 reversed the inhibitory effect of ARC on NLRP3 inflammasome activation. Taken together our results demonstrated that ARC may confer protection against ischemic stroke by inhibiting NLRP3 inflammasome activation. The activation of SIRT1 signaling pathway may contribute to the neuroprotection of ARC in MCAO. PMID- 28888981 TI - Hypoxia in 3T3-L1 adipocytes suppresses adiponectin expression via the PERK and IRE1 unfolded protein response. AB - Adiponectin, an adipocytokine produced by adipocytes, functions as an anti inflammatory and anti-apoptotic substance, while also enhancing insulin sensitivity. Patients or model animals with obesity or diabetes typically present attenuated expression of adiponectin. Moreover, obesity and diabetes are often accompanied with hypoxia in adipose tissue, which may result in endoplasmic reticulum (ER) stress as well as low expression of adiponectin. The purpose of this study was to investigate the specific role of the unfolded protein response (UPR) involved in the low expression of adiponectin induced by hypoxia. Subjecting 3T3-L1 adipocytes to hypoxia significantly reduced adiponectin expression and activated the PERK and IRE1 signaling pathways in a time-dependent manner. The ATF6 signaling pathway showed no obvious changes with hypoxia treatment under a similar time course. Moreover, the down-regulated expression of adiponectin induced by hypoxia was relieved once the PERK and IRE1 signaling pathways were suppressed by the inhibitors GSK2656157 and 4MU8C, respectively. Overall, these data demonstrate that hypoxia can suppress adiponectin expression and activate the PERK and IRE1 signaling pathways in differentiated adipocytes, and this two pathways are involved in the suppression of adiponectin expression induced by hypoxia. PMID- 28888982 TI - Disrupting nNOS-PSD-95 coupling in the hippocampal dentate gyrus promotes extinction memory retrieval. AB - Granule cells in the dentate gyrus regenerate constantly in adult hippocampus and then integrate into neural circuits in the hippocampus thereby providing the neural basis for learning and memory. Promoting the neurogenesis in the hippocampus facilitates learning and memory such as spatial learning, object identification, and extinction learning. The interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein-95 (PSD-95) is reported to negatively regulate neurogenesis in brain, so we hypothesized that disrupting this interaction might facilitate the neurogenesis in the dentate gyrus (DG) and thus enhance the extinction memory retrieval of fear learning. We found that uncoupling the nNOS-PSD-95 complex in remote contextual fear condition promoted both neuronal proliferation and survival in the DG, contributing to an enhanced retrieval of the extinction memory. Moreover, the nNOS-PSD-95 uncoupling-induced neurogenesis may be mediated by the extracellular signal-regulated kinase (ERK) as the phosphorylation level of ERK1/2 was increased after uncoupling. These findings suggest that the nNOS-PSD-95 complex may serve as a novel target for the treatment of post-traumatic stress disorder (PTSD). PMID- 28888983 TI - The Arabidopsis thaliana lysophospholipid acyltransferase At1g78690p acylates lysocardiolipins. AB - The Arabidopsis thaliana lysophospholipid acyltransferase At1g78690 acylates a variety of lysophospholipids such as lyso phosphatidylglycerol, lyso phosphatidylethanolamine and lyso phosphatidylserine. Despite di-acylate phosphatidylglycerol being a substrate, overexpression of At1g78690 in Escherichia coli leads to the accumulation of acyl-PG. Here we show that cardiolipin also accumulates in cells overexpressing At1g78690. To help try and explain this observation, we show, using a liquid chromatography mass spectrometry (LC-MS) based assay, that At1g78690 utilizes both mono- and di-lyso cardiolipin as an acyl acceptor. Because At1g78690 shares high homology (~40%) with the cardiolipin remodeling enzyme tafazzin, we also tested whether At1g78690 was able to catalyze a tafazzin-like transacylation reaction. Di-linoleoyl phosphatidylcholine was used as the acyl donor and mono-lyso cardiolipin was used as the acyl acceptor in a reaction and the reaction was monitored by LC-MS. No transfer of the linoleoyl chains was detected in an At1g78690 dependent manner suggesting that, despite the strong homology, these enzymes catalyze unique reactions. PMID- 28888984 TI - Cannabidiol, a novel inverse agonist for GPR12. AB - GPR12 is a constitutively active, Gs protein-coupled receptor that currently has no confirmed endogenous ligands. GPR12 may be involved in physiological processes such as maintenance of oocyte meiotic arrest and brain development, as well as pathological conditions such as metastatic cancer. In this study, the potential effects of various classes of cannabinoids on GPR12 were tested using a cAMP accumulation assay. Our data demonstrate that cannabidiol (CBD), a major non psychoactive phytocannabinoid, acted as an inverse agonist to inhibit cAMP accumulation stimulated by the constitutively active GPR12. Thus, GPR12 is a novel molecular target for CBD. The structure-activity relationship studies of CBD indicate that both the free hydroxyl and the pentyl side chain are crucial for the effects of CBD on GPR12. Furthermore, studies using cholera toxin, which blocks Gs protein and pertussis toxin, which blocks Gi protein, revealed that Gs, but not Gi is involved in the inverse agonism of CBD on GPR12. CBD is a promising novel therapeutic agent for cancer, and GPR12 has been shown to alter viscoelasticity of metastatic cancer cells. Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis. PMID- 28888985 TI - A point mutation in the heavy chain complementarity-determining region 3 (HCDR3) significantly enhances the specificity of an anti-ROS1 antibody. AB - The proto-oncogene tyrosine kinase ROS1 plays a key role in carcinogenesis through gene rearrangement to form a fusion protein with other genes, in which the C-terminal intracellular region of ROS1 participates. The possibility of wild type ROS1 overexpression through epigenetic regulation has been proposed. Here, we generated an antibody, 3B20, reactive to the N-terminal region of ROS1 to use it for the detection of wild type ROS1 in cancerous tissues. Using immunoblot and immunoprecipitation analyses, we found that 3B20 also reacted with heat shock proteins (Hsp)70s. Using homology searching, ROS1 and Hsp70s were found to share an identical amino acid sequence: DLGT. Using alanine mutagenesis of ROS1, the epitope was found to harbor this sequence. To modify the idiotope with the aim of selecting more specific antibodies, we introduced random mutations into the heavy chain complementarity-determining region 3 and successfully generated an antibody clone, 3B20-G1K, with a point mutation that only reacted with ROS1 in enzyme linked immunosorbent assays, and in immunoblot and immunoprecipitation analysis. In immunohistochemical analysis using 3B20-G1K, ROS1 was found to be absent in normal lung tissues and was overexpressed in a case of lung adenocarcinoma. PMID- 28888986 TI - PDE 5 inhibitor improves insulin sensitivity by enhancing mitochondrial function in adipocytes. AB - Adipocytes are involved in many metabolic disorders. It was recently reported that phosphodiesterase type 5 (PDE5) is expressed in human adipose tissue. In addition, PDE5 inhibitors have been shown to improve insulin sensitivity in humans. However, the mechanism underlying the role of PDE5 inhibitors as an insulin sensitizer remains largely unknown. The present study was undertaken to investigate the role of the PDE5 inhibitor udenafil in insulin signaling in adipocytes and whether this is mediated through the regulation of mitochondrial function. To study the mechanism underlying the insulin sensitizing action of PDE5 inhibitors, we evaluated quantitative changes in protein or mRNA levels of mitochondrial oxidative phosphorylation (OxPhos) complex, oxygen consumption rate (OCR), and fatty acid oxidation with varying udenafil concentrations in 3T3-L1 cells. Our cell study suggested that udenafil enhanced the insulin signaling pathway in 3T3-L1 cells. Following udenafil treatment, basal mitochondrial OCR, maximal OxPhos capacity, and OxPhos gene expression significantly increased. Finally, we examined whether udenafil can affect the fatty acid oxidation process. Treatment of 3T3-L1 cells with udenafil (10 and 20 MUM) significantly increased fatty acid oxidation rate in a dose-dependent manner. In addition, the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) significantly increased. We demonstrated that the PDE5 inhibitor udenafil enhances insulin sensitivity by improving mitochondrial function in 3T3-L1 cells. This might be the mechanism underlying the PDE5 inhibitor-enhanced insulin signaling in adipocytes. This also suggests that udenafil may provide benefit in the treatment of type 2 diabetes and other related cardiovascular diseases. PMID- 28888987 TI - In vivo RNA interference of BmNHR96 enhances the resistance of transgenic silkworm to BmNPV. AB - We previously identified a nuclear hormone receptor gene, BmNHR96, which promotes Bombyx mori nucleopolyhedrovirus (BmNPV) entry into silkworm cells. In an attempt to create an antiviral silkworm strain for better silk production, we used RNAi to downregulate BmNHR96 in silkworm larvae. We screened the resulting BmNHR96 RNAi silkworm strain (NHR) and also explored the antiviral mechanism in vivo. We found that the survival rate of the NHR strain was higher than that of the Dazao strain, when silkworm larvae were infected with BmNPV via oral ODV infection and BV injection. More importantly, the economic characteristics (silk yield) of the transgenic line remained unchanged. These findings reveal that RNAi of BmNHR96 could be an effective way to enhance the tolerance of B. mori to BmNPV infection. PMID- 28888988 TI - Canine human-scent-matching: The limitations of systematic pseudo matching-to sample procedures. AB - Here transfer performance is contrasted with baseline training performance to determine whether a relational solution strategy is learned from the systematic pseudo matching-to-sample procedures commonly used to train human-scent-matching dogs. Evidence indicates that due to the lack of constraints to control against simple discrimination solutions, dogs trained with systematic pseudo matching-to sample arrangements do not learn to use the scent sample as a signaling cue and do not learn about the matching relationship between the scent sample and matching comparison. Moreover, during pseudo matching-to-sample training, dogs may learn to ignore both the scent sample and the discriminative dimension of human scent, such as genetic information. Thus, during subsequent random control matching-to-sample (MTS) conditional discrimination training, learning about the matching relationship between the individual-unique information on the scent sample and matching comparison can be retarded. Failure to identify the solution strategy that human-scent-matching dogs must learn in order to perform accurately and reliably during operations and to distinguish between simple discrimination, random control MTS conditional discrimination, and systematic pseudo matching-to sample has been a major drawback to the advancement of scent-matching dogs and is a contributing factor to the continued controversy surrounding their use and reliability. PMID- 28888989 TI - Noradrenaline, oxymetazoline and phorbol myristate acetate induce distinct functional actions and phosphorylation patterns of alpha1A-adrenergic receptors. AB - In LNCaP cells that stably express alpha1A-adrenergic receptors, oxymetazoline increased intracellular calcium and receptor phosphorylation, however, this agonist was a weak partial agonist, as compared to noradrenaline, for calcium signaling. Interestingly, oxymetazoline-induced receptor internalization and desensitization displayed greater effects than those induced by noradrenaline. Phorbol myristate acetate induced modest receptor internalization and minimal desensitization. alpha1A-Adrenergic receptor interaction with beta-arrestins (colocalization/coimmunoprecipitation) was induced by noradrenaline and oxymetazoline and, to a lesser extent, by phorbol myristate acetate. Oxymetazoline was more potent and effective than noradrenaline in inducing ERK 1/2 phosphorylation. Mass spectrometric analysis of immunopurified alpha1A adrenergic receptors from cells treated with adrenergic agonists and the phorbol ester clearly showed that phosphorylated residues were present both at the third intracellular loop and at the carboxyl tail. Distinct phosphorylation patterns were observed under the different conditions. The phosphorylated residues were: a) Baseline and all treatments: T233; b) noradrenaline: S220, S227, S229, S246, S250, S389; c) oxymetazoline: S227, S246, S381, T384, S389; and d) phorbol myristate acetate: S246, S250, S258, S351, S352, S401, S402, S407, T411, S413, T451. Our novel data, describing the alpha1A-AR phosphorylation sites, suggest that the observed different phosphorylation patterns may participate in defining adrenoceptor localization and action, under the different conditions examined. PMID- 28888990 TI - Chemicals or mutations that target mitochondrial translation can rescue the respiratory deficiency of yeast bcs1 mutants. AB - Bcs1p is a chaperone that is required for the incorporation of the Rieske subunit within complex III of the mitochondrial respiratory chain. Mutations in the human gene BCS1L (BCS1-like) are the most frequent nuclear mutations resulting in complex III-related pathologies. In yeast, the mimicking of some pathogenic mutations causes a respiratory deficiency. We have screened chemical libraries and found that two antibiotics, pentamidine and clarithromycin, can compensate two bcs1 point mutations in yeast, one of which is the equivalent of a mutation found in a human patient. As both antibiotics target the large mtrRNA of the mitoribosome, we focused our analysis on mitochondrial translation. We found that the absence of non-essential translation factors Rrf1 or Mif3, which act at the recycling/initiation steps, also compensates for the respiratory deficiency of yeast bcs1 mutations. At compensating concentrations, both antibiotics, as well as the absence of Rrf1, cause an imbalanced synthesis of respiratory subunits which impairs the assembly of the respiratory complexes and especially that of complex IV. Finally, we show that pentamidine also decreases the assembly of complex I in nematode mitochondria. It is well known that complexes III and IV exist within the mitochondrial inner membrane as supramolecular complexes III2/IV in yeast or I/III2/IV in higher eukaryotes. Therefore, we propose that the changes in mitochondrial translation caused by the drugs or by the absence of translation factors, can compensate for bcs1 mutations by modifying the equilibrium between illegitimate, and thus inactive, and active supercomplexes. PMID- 28888991 TI - LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death. AB - Leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein, is a key causative factor in Parkinson's disease (PD). Identification of novel substrates and the molecular mechanisms underlying the effects of LRRK2 are essential for understanding the pathogenesis of PD. In this study, we showed that LRRK2 played an important role in neuronal cell death by directly phosphorylating and activating apoptosis signal-regulating kinase 1 (ASK1). LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site. Moreover, results of binding and kinase assays showed that LRRK2 acted as a scaffolding protein by interacting with each components of the ASK1-MKK3/6-p38 MAPK pathway through its specific domains and increasing the proximity to downstream targets. Furthermore, LRRK2-induced apoptosis was suppressed by ASK1 inhibition in neuronal stem cells derived from patients with PD. These results clearly indicate that LRRK2 acts as an upstream kinase in the ASK1 pathway and plays an important role in the pathogenesis of PD. PMID- 28888993 TI - The risks of nocturnal hypoglycaemia in insulin-treated diabetes. AB - Over half of all episodes of severe hypoglycaemia (requiring external help) occur during sleep, but nocturnal hypoglycaemia is often asymptomatic and unrecognised. The precise incidence of nocturnal hypoglycaemia is difficult to determine with no agreed definition, but continuous glucose monitoring has shown that it occurs frequently in people taking insulin. Attenuation of the counter-regulatory responses to hypoglycaemia during sleep may explain why some episodes are undetected and more prolonged, and modifies cardiovascular responses. The morbidity and mortality associated with nocturnal hypoglycaemia is probably much greater than realised, causing seizures, coma and cardiovascular events and affecting quality of life, mood and work performance the following day. It may induce impaired awareness of hypoglycaemia. Cardiac arrhythmias that occur during nocturnal hypoglycaemia include bradycardia and ectopics that may provoke dangerous arrhythmias. Treatment strategies are discussed that may help to minimise the frequency of nocturnal hypoglycaemia. PMID- 28888992 TI - Associations between biological markers of prenatal stress and infant negative emotionality are specific to sex. AB - PURPOSE: Fetal programming is the idea that environmental stimuli can alter the development of the fetus, which may have a long-term effect on the child. We have recently reported that maternal prenatal cortisol predicts infant negative emotionality in a sex-dependent manner: high prenatal cortisol was associated with increased negative emotionality in females, and decreased negative emotionality in males. This study aims to test for this sex-specific effect in a different cohort, and investigate whether sex differences in fetal programming may be specific to glucocorticoid mechanisms by also examining a maternal salivary alpha-amylase (sAA) by sex interaction. METHODS: 88 pregnant women (mean gestational age=27.4 weeks, SD=7.4) collected saliva samples at home over two working days to be assayed for the hormone cortisol (range=0.13-88.22nmol/l) and the enzyme alpha-amylase (range=4.57-554.8units/ml). Samples were collected at waking, 30-min post-waking and 12h post-waking. Two months after birth participants reported infant negative emotionality using the distress to limits subscale of the Infant Behavior Questionnaire. RESULTS: The interaction between maternal prenatal cortisol and infant sex to predict distress to limits approached significance (p=0.067). In line with our previous finding there was a positive association between prenatal cortisol and negative emotionality in females, and a negative association in males. The interaction between sAA and sex to predict distress was significant (p=0.025), and the direction of effect was the same as for the cortisol data; high sAA associated with increased negative emotionality in females and reduced negative emotionality in males. CONCLUSIONS: In line with our previous findings, this research adds to an emerging body of literature, which suggests that fetal programming mechanisms may be sex dependent. This is the first study to demonstrate that maternal prenatal sAA may be an important biomarker for infant behavior, and the findings have implications for understanding sex differences in developmental psychopathology. PMID- 28888995 TI - mTOR signaling in immune cells and its implications for cancer immunotherapy. AB - The realization that cellular metabolism dictates immune cell development, differentiation and function affords metabolic intervention as a potential venue for cancer immunotherapy. mTOR signaling, as a metabolic master regulator, controls immune cell biology in a cell type-specific and context dependent manner. Furthermore, mTOR activity needs to be fine-tuned to maintain proper immune function. These properties may be exploited for therapeutic purpose, yet caution should be taken against radical changes of mTOR activity. Here, the intricate and complex mTOR regulation in different immune cells is reviewed, highlighting latest discoveries and opportunities for cancer immunotherapy. PMID- 28888994 TI - Chronic lymphocytic leukemia with isochromosome 17q: An aggressive subgroup associated with TP53 mutations and complex karyotypes. AB - Although i(17q) [i(17q)] is frequently detected in hematological malignancies, few studies have assessed its clinical role in chronic lymphocytic leukemia (CLL). We recruited a cohort of 22 CLL patients with i(17q) and described their biological characteristics, mutational status of the genes TP53 and IGHV and genomic complexity. Furthermore, we analyzed the impact of the type of cytogenetic anomaly bearing the TP53 defect on the outcome of CLL patients and compared the progression-free survival (PFS) and overall survival (OS) of i(17q) cases with those of a group of 38 CLL patients harboring other 17p aberrations. We detected IGHV somatic hypermutation in all assessed patients, and TP53 mutations were observed in 71.4% of the cases. Patients with i(17q) were more commonly associated with complex karyotypes (CK) and tended to have a poorer OS than patients with other anomalies affecting 17p13 (median OS, 44 vs 120 months, P = 0.084). Regarding chromosomal alterations, significant differences in the median OS were found among groups (P = 0.044). In conclusion, our findings provide new insights regarding i(17q) in CLL and show a subgroup with adverse prognostic features. PMID- 28888996 TI - Mutations of RNA splicing factors in hematological malignancies. AB - Systematic large-scale cancer genomic studies have produced numerous significant findings. These studies have not only revealed new cancer-promoting genes, but they also have identified cancer-promoting functions of previously known "housekeeping" genes. These studies have identified numerous mutations in genes which play a fundamental role in nuclear precursor mRNA splicing. Somatic mutations and copy number variation in many of the splicing factors which participate in the formation of multiple spliceosomal complexes appear to play a role in many cancers and in particular in myelodysplastic syndromes (MDS). Mutated proteins seem to interfere with the recognition of the authentic splice sites (SS) leading to utilization of suboptimal alternative splicing sites generating aberrantly spliced mRNA isoforms. This short review is focusing on the function of the splice factors involved in the formation of splicing complexes and potential mechanisms which affect usage of the authentic splice site recognition. PMID- 28888997 TI - Discovery of peptide drug carrier candidates for targeted multi-drug delivery into prostate cancer cells. AB - Metastatic castration-resistant prostate cancer (mCRPC) remains essentially incurable. Targeted Drug Delivery (TDD) systems may overcome the limitations of current mCRPC therapies. We describe the use of strict criteria to isolate novel prostate cancer cell targeting peptides that specifically deliver drugs into target cells. Phage from a libraries displaying 7mer peptides were exposed to PC 3 cells and only internalized phage were recovered. The ability of these phage to internalize into other prostate cancer cells (LNCaP, DU-145) was validated. The displayed peptides of selected phage clones were synthesized and their specificity for target cells was validated in vitro and in vivo. One peptide (P12) which specifically targeted PC-3 tumors in vivo was incorporated into mono drug (Chlorambucil, Combretastatin or Camptothecin) and dual-drug (Chlorambucil/Combretastatin or Chlorambucil/Camptothecin) PDCs and the cytotoxic efficacy of these conjugates for target cells was tested. Conjugation of P12 into dual-drug PDCs allowed discovery of new drug combinations with synergistic effects. The use of strict selection criteria can lead to discovery of novel peptides for use as drug carriers for TDD. PDCs represent an effective alternative to current modes of free drug chemotherapy for prostate cancer. PMID- 28888998 TI - TNF-related apoptosis-inducing ligand (TRAIL) for bone sarcoma treatment: Pre clinical and clinical data. AB - Bone sarcomas are rare, highly malignant mesenchymal tumours that affect teenagers and young adults, as well as older patients. Despite intensive, multimodal therapy, patients with bone sarcomas have poor 5-year survival, close to 50%, with lack of improvement over recent decades. TNF-related apoptosis inducing ligand (TRAIL), a member of the tumour necrosis factor (TNF) ligand superfamily (TNFLSF), has been found to induce apoptosis in cancer cells while sparing nontransformed cells, and may therefore offer a promising new approach to treatment. We cover the existing preclinical and clinical evidence about the use of TRAIL and other death receptor agonists in bone sarcoma treatment. In vitro studies indicate that TRAIL and other death receptor agonists are generally potent against bone sarcoma cell lines. Ewing's sarcoma cell lines present the highest sensitivity, whereas osteosarcoma and chondrosarcoma cell lines are considered less sensitive. In vivo studies also demonstrate satisfactory results, especially in Ewing's sarcoma xenograft models. However, the few clinical trials in the literature show only low or moderate efficacy of TRAIL in treating bone sarcoma. Potential strategies to overcome the in vivo resistance reported include co-administration with other drugs and the potential to deliver TRAIL on the surface of primed mesenchymal or immune cells and the use of targeted single chain antibodies such as scFv-scTRAIL. PMID- 28888999 TI - Role of cellular metabolism in regulating type I interferon responses: Implications for tumour immunology and treatment. AB - Type I interferons (IFN) are increasingly recognized for their role in regulating anti-tumour immune responses. However, chronic activation of these pathways can result in immunosuppression and has been linked to poor responses to genotoxic and radiotoxic therapies. Emerging evidence suggests energy, lipid and amino acid metabolism play an important role in regulating and fine tuning type I IFN responses. Further, dysregulation of these processes has been implicated in the pathogenesis of chronic viral infections and autoimmune disorders. Systematic evaluation of these interrelationships in cancer models and patients may have important implications for the development of targeted IFN based anti-cancer therapeutics with minimal toxicity and limited off target effects. PMID- 28889000 TI - HSF1 upregulates ATG4B expression and enhances epirubicin-induced protective autophagy in hepatocellular carcinoma cells. AB - Considerable evidences have shown that both heat shock transcription factor 1 (HSF1) and autophagy can attenuate the sensitivity of hepatocellular carcinoma (HCC) cells to chemotherapeutic reagents. However, it is still little known whether HSF1 is associated with autophagy in regulating the chemosensitivity of HCC cells. In this study, we for the first time demonstrated that HSF1 markedly attenuated the killing effect of epirubicin (EPI) to HCC cells via enhancing the EPI-induced protective autophagy. Mechanistically, HSF1 upregulated autophagy related 4B (ATG4B) in HCC cells, which enhanced the EPI-triggered protective autophagy. Reporter assay showed that HSF1 increased the transcriptional activity of ATG4B gene promoter, and chromatin immunoprecipitation assay verified that HSF1 bound to the site (-1429 to -1417) in ATG4B gene promoter region. The experiments in nude mice showed that knockdown of HSF1 or ATG4B strengthened the anti-HCC effect of EPI in vivo. Collectively, these results revealed that HSF1 elevates ATG4B via promoting its transcription, which alleviates the sensitivity of EPI in HCC cells through enhancing protective autophagy, suggesting that the "HSF1/ATG4B/protective autophagy" pathway may be a novel target for developing sensitizing strategy to HCC chemotherapy. PMID- 28889001 TI - Decontamination of fresh-cut cucumber slices by a combination of a modified chitosan coating containing carvacrol nanoemulsions and pulsed light. AB - In this study, the impact of the combination of pulsed light (PL) treatments with antimicrobial coatings, consisting of modified chitosan suspensions incorporating carvacrol nanoemulsions, was investigated on the decontamination of fresh-cut cucumber slices. The upper surface of the cucumber slices, with or without the coating deposition, was inoculated with Escherichia coli ATCC 26 to reach a final concentration of 107CFU/g of the vegetable. PL treatments were conducted at different fluence (4, 8, and 12J/cm2) on the inoculated surface of cucumber slices. Results showed that the microbial reduction was only marginally affected by the coating formulation. A slight increase was observed when the carvacrol nanoemulsions were embedded in the chitosan matrix, but microbial reduction levels remained always below 1log cycle. In contrast, the different PL treatments resulted in a statistically significant increase in inactivation with increasing the treatment fluence, reaching 2.6log cycles at the maximum fluence. Remarkably, the combination of the antimicrobial coating with the most intense PL treatments resulted in a strong synergistic effect. For example, by combining a PL treatment at 12J/cm2 with one of the antimicrobial coatings a microbial reduction >5log cycles was reached. Therefore, it can be concluded that the combination of antimicrobial coatings and PL treatment is a promising method for surface decontamination of fresh-cut vegetables, which could be exploited in view of ensuring their microbiological safety. PMID- 28889002 TI - Mapping the complex topological organization of the human parietal face area. AB - The macaque monkey ventral intraparietal area (VIP) contains neurons with aligned visual-tactile receptive fields anchored to the face and upper body. Our previous fMRI studies using standard head coils found a human parietal face area (VIP+ complex; putative macaque VIP homologue) containing superimposed topological maps of the face and near-face visual space. Here, we construct high signal-to-noise surface coils and used phase-encoded air puffs and looming stimuli to map topological organization of the parietal face area at higher resolution. This area is consistently identified as a region extending between the superior postcentral sulcus and the upper bank of the anterior intraparietal sulcus (IPS), avoiding the fundus of IPS. Using smaller voxel sizes, our surface coils picked up strong fMRI signals in response to tactile and visual stimuli. By analyzing tactile and visual maps in our current and previous studies, we constructed a set of topological models illustrating commonalities and differences in map organization across subjects. The most consistent topological feature of the VIP+ complex is a central-anterior upper face (and upper visual field) representation adjoined by lower face (and lower visual field) representations ventrally (laterally) and/or dorsally (medially), potentially forming two subdivisions VIPv (ventral) and VIPd (dorsal). The lower visual field representations typically extend laterally into the anterior IPS to adjoin human area AIP, and medially to overlap with the parietal body areas at the superior parietal ridge. Significant individual variations are then illustrated to provide an accurate and comprehensive view of the topological organization of the parietal face area. PMID- 28889003 TI - The role of auditory cortex in the spatial ventriloquism aftereffect. AB - Cross-modal recalibration allows the brain to maintain coherent sensory representations of the world. Using functional magnetic resonance imaging (fMRI), the present study aimed at identifying the neural mechanisms underlying recalibration in an audiovisual ventriloquism aftereffect paradigm. Participants performed a unimodal sound localization task, before and after they were exposed to adaptation blocks, in which sounds were paired with spatially disparate visual stimuli offset by 14 degrees to the right. Behavioral results showed a significant rightward shift in sound localization following adaptation, indicating a ventriloquism aftereffect. Regarding fMRI results, left and right planum temporale (lPT/rPT) were found to respond more to contralateral sounds than to central sounds at pretest. Contrasting posttest with pretest blocks revealed significantly enhanced fMRI-signals in space-sensitive lPT after adaptation, matching the behavioral rightward shift in sound localization. Moreover, a region-of-interest analysis in lPT/rPT revealed that the lPT activity correlated positively with the localization shift for right-side sounds, whereas rPT activity correlated negatively with the localization shift for left-side and central sounds. Finally, using functional connectivity analysis, we observed enhanced coupling of the lPT with left and right inferior parietal areas as well as left motor regions following adaptation and a decoupling of lPT/rPT with contralateral auditory cortex, which scaled with participants' degree of adaptation. Together, the fMRI results suggest that cross-modal spatial recalibration is accomplished by an adjustment of unisensory representations in low-level auditory cortex. Such persistent adjustments of low-level sensory representations seem to be mediated by the interplay with higher-level spatial representations in parietal cortex. PMID- 28889005 TI - A flexible graphical model for multi-modal parcellation of the cortex. AB - Advances in neuroimaging have provided a tremendous amount of in-vivo information on the brain's organisation. Its anatomy and cortical organisation can be investigated from the point of view of several imaging modalities, many of which have been studied for mapping functionally specialised cortical areas. There is strong evidence that a single modality is not sufficient to fully identify the brain's cortical organisation. Combining multiple modalities in the same parcellation task has the potential to provide more accurate and robust subdivisions of the cortex. Nonetheless, existing brain parcellation methods are typically developed and tested on single modalities using a specific type of information. In this paper, we propose Graph-based Multi-modal Parcellation (GraMPa), an iterative framework designed to handle the large variety of available input modalities to tackle the multi-modal parcellation task. At each iteration, we compute a set of parcellations from different modalities and fuse them based on their local reliabilities. The fused parcellation is used to initialise the next iteration, forcing the parcellations to converge towards a set of mutually informed modality specific parcellations, where correspondences are established. We explore two different multi-modal configurations for group wise parcellation using resting-state fMRI, diffusion MRI tractography, myelin maps and task fMRI. Quantitative and qualitative results on the Human Connectome Project database show that integrating multi-modal information yields a stronger agreement with well established atlases and more robust connectivity networks that provide a better representation of the population. PMID- 28889006 TI - Role of intra-accumbal orexin receptors in the acquisition of morphine-induced conditioned place preference in the rats. AB - Orexin receptor shave essential role in the induction of reward-related behaviors to several drugs of abuse. In the present study, we investigated the effects of bilateral administration of SB334867, as an orexin-1 receptor antagonist, and TCS OX2 29, as an orexin-2 receptor antagonist, into the nucleus accumbens (NAc) on the acquisition of morphine-induced conditioned place preference (CPP) in the rats. Adult male Wistar rats (n=80; 220-250g) were entered in a CPP paradigm. Bilateral microinjections of different doses of SB334867 (1, 3, 10 and 30nM) or TCS OX2 29 (3, 10, 30 and 100nM) into the NAc (0.5MUl/side) were done 5min before subcutaneous injection of morphine (5mg/kg) during 3-dayconditioning (acquisition) phase. The CPP scores and locomotor activity of animals were recorded by video tracking system and Ethovision software. The results demonstrated that intra-NAc microinjection of 3, 10 and 30nM solutions of SB334867 markedly decreased the acquisition of morphine-induced CPP in a dose dependent manner. Intra-accumbal injection of 10, 30 and 100nM solutions of TCS OX2 29 significantly attenuated the acquisition of morphine CPP as well. In addition, contribution of orexin-1 receptors to development of morphine reward related behaviors was more than orexin-2 receptors. Our results suggest that both orexin-1 and -2 receptors in the NAc are involved in the development of morphine induced CPP. It seems that orexin-1 receptors in this region are more effective in development of drug seeking behaviors in the rats. PMID- 28889004 TI - Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function. AB - A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization. PMID- 28889007 TI - Selective deletion of the oxytocin gene remodels the number and shape of dendritic spines in the medial amygdala of males with and without sexual experience. AB - Oxytocin has central actions that modulate synaptic plasticity and the occurrence of social behavior in rodents. The posterodorsal medial amygdala (MePD) composes a sexually dimorphic neural circuit for the display of male sexual behavior. Local dendritic spines are notably plastic and affected by context-dependent social stimuli. Here, we examined the effects of the selective deletion of the OT gene (OTKO) in the number and shape of Golgi-impregnated dendritic spines in the MePD of naive and sexually experienced (SexExp) male mice (n=6 each group). Compared to the control wild-type mice (WT), OTKO naive mice did not differ in the density of dendritic spines, but there was a significant and more intense reduction in the number of spines in the WT/SexExp (~40%) than in the OTKO/SexExp (~25%). This structural change had a spine-specific feature. That is, sexual experience induced a decrease in the number of thin (~50%) and mushroom-like spines (~35%) at the same time that increased (~30%) the number of stubby/wide spines. In addition, the OTKO/SexExp animals have more thin and mushroom spines than the WT/SexExp ones (~25% and 55%, respectively; p <0.01 in all cases). In conjunction, these novel data indicate that OT participates in the spine remodeling, synaptic refinement, and social stimuli-dependent plasticity in the MePD of male mice. PMID- 28889009 TI - Gaze position interferes in body sway in young adults. AB - Postural control is influenced by eye movements. Gaze fixation, which comprises a component of ocular vergence, is important in the acquisition of highly specific task information, but its relation to postural control is little investigated. The aim of the study was to investigate the effects of gaze fixation position (central and lateral fixations) on postural sway in young adults. Forty young adults with ages ranging from 20 to 35 years were invited to participate in the study. Postural sway was measured in quiet stance in bipedal support in three 60 s trials under the following conditions: gaze fixation on a target positioned in front of participant, gaze fixation on a target positioned on right side of participant, and gaze fixation on a target positioned on left side of participant. The following center of pressure parameters (COP) in the anteroposterior (AP) and mediolateral directions (ML) were analyzed for each of the trials: body sway displacement, mean velocity of sway, root mean square (RMS) of sway, and median frequency. In addition, detrended fluctuation analysis (DFA) exponent, in anteroposterior and medio-lateral directions, was calculated. The COP presented greater AP and ML displacement (p<0.03, effect size=1.37; and p<0.03, effect size=1.64, respectively) and RMS AP and ML (p<0.04, effect size=1.66; and p<0.02, effect size=2.50, respectively) for lateral gaze fixation compared to central gaze fixation. These results suggest that gaze fixation on a laterally positioned target increases body sway in anteroposterior and mediolateral directions. PMID- 28889008 TI - The interplay between ventro striatal BDNF levels and the effects of valproic acid on the acquisition of ethanol-induced conditioned place preference in mice. AB - Alcohol addiction is a chronic, relapsing and progressive brain disease with serious consequences for health. Compulsive use of alcohol is associated with the capacity to change brain structures involved with the reward pathway, such as ventral striatum. Recent evidence suggests a role of chromatin remodeling in the pathophysiology of alcohol dependence and addictive-like behaviors. In addition, neuroadaptive changes mediated by the brain-derived neurotrophic factor (BDNF) seems to be an interesting pharmacological target for alcoholism treatment. In the present study, we evaluated the effects of the deacetylase inhibitor valproic acid (VPA) (300mg/kg) on the conditioned rewarding effects of ethanol using conditioned place preference (CPP) (15% v/v; 2g/kg). Ethanol rewarding effect was investigated using a biased protocol of CPP. BDNF levels were measured in the ventral striatum. Ethanol administration induced CPP. VPA pretreatment did not reduce ethanol-CPP acquisition. VPA pretreatment increased BDNF levels when compared to ethanol induced-CPP. VPA pretreatment increased BDNF levels even in saline conditioned mice. Taken together, our results indicate a modulatory effect of VPA on the BDNF levels in the ventral striatum. Overall, this study brings initial insights into the involvement of neurotrophic mechanisms in the ventral striatum in ethanol-induced addictive-like behavior. PMID- 28889010 TI - Pain in osteoarthritis. Implications for optimal management. AB - Pain is an ubiquitous symptom in osteoarticular diseases, occurring much more commonly than stiffness or disability. OA of the knee, hand, or hip affects around 20% of adults in various populations and is dramatically increasing in many countries, mostly related to age and obesity, leading to an increased number of people having OA pain, and creating a huge burden related to disability and health care costs. OA-related pain, has been classically considered to be a nociceptive pain condition. Clinicians have considered pain to be an alarm signal, correlated to the intensity of joint degradation. In OA, most authors have focused their studies on joint architecture and local degradation, considering pain as only a symptom, a consequence of joint damage. However, OA related pain is a specific disease, with a complex pathophysiology, including neuropathic peripheral and central abnormalities, together with local inflammation involving all joint structures. Clinical findings emphasize that it is not a stable and linear condition, that pain experience is independent of structural modifications, and that the quality of pain in OA is important to consider, aside from its intensity. OA-related pain is modulated by many factors, including the individual patient's psychological and genetic factors, as well as the theoretical role of meteorological influences. Recent neuroimaging findings have improved our knowledge about central mechanisms of OA pain, especially in persistent cases. PMID- 28889011 TI - Two novel LRR and Ig domain-containing proteins from oyster Crassostrea gigas function as pattern recognition receptors and induce expression of cytokines. AB - Leucine-rich repeat (LRR) domain and immunoglobulin (Ig) domain are both competent immune recognition modules, and the immunological roles of LRR and Ig domain containing- proteins (LRRIGs) are speculated to be multifunctional and worth investigating. In the present study, two novel LRRIGs, CgLRRIG-1 and CgLRRIG-2, were identified and characterized from oyster Crassostrea gigas. Both of them contained an N-terminal LRR region, an Ig domain, a transmembrane region, and a C-terminal cytoplasmic tail. The mRNA transcripts of CgLRRIG-1 and CgLRRIG 2 were constitutively expressed in muscle, gill, hepatopancreas, mantle, gonad and hemocytes with the highest expression level in hepatopancreas. Their mRNA expression levels in hemocytes were significantly up-regulated after the stimulations with four PAMPs including peptidoglycan (PGN), lipopolysaccharide (LPS), glucan (GLU) and polyinosinic-polycytidylic acid (poly I:C) and one bacteria Vibrio anguillarum. The recombinant proteins, rCgLRRIG-1 and rCgLRRIG-2, could bind to PGN, LPS, GLU and poly I:C, and rCgLRRIG-2 exhibited higher binding affinity. Additionally, rCgLRRIG-1 and rCgLRRIG-2 could significantly induce the expression of CgTNF-1 and CgIL17-5 in cultured oyster hemocytes, and the activity of rCgLRRIG-2 was higher than that of rCgLRRIG-1. All these results indicated that CgLRRIG-1 and CgLRRIG-2 could function as immune effectors or pro inflammatory factors as well as PRRs in oyster. PMID- 28889012 TI - Effect of pea crab Pinnotheres vicajii (Chhapgar, 1957) on immunocompetence of bivalve Paphia malabarica (Chemnitz, 1782). AB - The endosymbiont-host relationship between a pea crab and its bivalve host has been studied previously using bivalve's multi-physiological parameters. The present study is first of its kind that uses hemocyte's immune functionality to evaluate the symbiotic relationship between bivalve Paphia malabarica and its symbiont crab, Pinnotheres vicajii. The sampling was carried out at two stations (differed in nutrient concentration, productivity, and bacterial abundance) located along the southwest coast of India. The results showed lower immunocompetence in the case of bivalves infested with pea crabs. The lowering of hemocyte population was the most prominent and perhaps the initial reaction in response to focal inflammation or wound inflicted by the pea crabs. A significant lowering of phagocytosis, lysozyme, and esterase activity was also observed, indicating the detrimental impact of crab infestation. Interestingly, no significant correlation was found between parasitism and condition index despite the lower immunocompetence, validating the effectiveness of using hematological parameters in comparison to other life-history traits. This indicates that the immune parameters being directly related to the organism's metabolic state can elucidate the early effect of stressors, therefore, proving to be a better proxy for understanding a host-pathogen relationship. Disparity found in bivalve's immunocompetence between the sampling sites could be linked to either variation in environmental parameters, the size of the symbiont or the infection level. Our preliminary results provide a direction towards examining immunodepression in parasitized bivalves by considering ex-situ controlled parasitism induction along with varying environmental conditions. In view of this, efforts must be directed towards minimizing pea crab's outbreaks, especially in cultivated shellfish farms. Future studies should elucidate molecular mechanisms involved in the immunocompetence of P. malabarica, hosting the parasitic pea crabs. PMID- 28889013 TI - The core ubiquitin system of mandarin fish, Siniperca chuatsi, can be utilized by infectious spleen and kidney necrosis virus. AB - The process of ubiquitination regulates various cellular processes. The ubiquitin proteasome system (UPS) in fish, which is important for the generation of innate and adaptive immune responses to pathogens, is the target of aquatic viruses to achieve immune evasion. We cloned and characterized three genes, namely, a ubiquitin-activating enzyme (ScE1), a ubiquitin-conjugating enzyme (ScE2), and a HECT-type ubiquitin ligase (ScE3) of mandarin fish Siniperca chuatsi. The genes were expressed in all tissues and the highest levels were observed in the blood. In infectious spleen and kidney necrosis virus (ISKNV)-infected mandarin fish fry cells, the expression levels of the three genes in vitro were almost identical, and upregulated during the early stage and downregulated at the late stage. In the blood of ISKNV-infected mandarin fish, their expressions in vivo were downregulated equally although peaking at different timepoints, indicating the suppression of UPS by viral infection. Furthermore, these recombinant proteins were determined to function well in ubiquitination assays in vitro. Moreover, ScE1 and ScE2 can be utilized by four RING-type viral E3s (vE3s) that are encoded by ISKNV. The in vitro activity of vE3 was stronger than that of ScE3, suggesting that the fish UPS may be hijacked by ISKNV via E3 activity competition and expression modulation. The present study investigated the function of mandarin fish UPS as well as its response to iridovirus infection, providing insights to better understand the virus-host interactions and the mechanism of ISKNV in evading host immune responses. PMID- 28889014 TI - Transcriptomic and morphological analyses of Litopenaeus vannamei intestinal barrier in response to Vibrio paraheamolyticus infection reveals immune response signatures and structural disruption. AB - The white shrimp Litopenaeus vannamei has been greatly impacted by Vibrio infection. In this study, we investigated the intestinal barrier response of L vannamei following challenge with Vibrio parahaemolyticus E1, by examining morphological changes and transcriptome expression levels. A total of 16,4420 unigenes were obtained from RNAseq data after quality control and assembly, and 4646 differentially expressed genes (DEGs) were identified following Vibrio challenge, of which 2469 unigenes were significantly up-regulated and 2177 were significantly down-regulated. DEGs were determined to be involved in various physical, chemical and immunological intestinal barrier functions, including peritrophin, cytoskeleton and cell junction, pattern recognition receptors, antimicrobial peptide and immune signaling pathways, serine protease/protease inhibitor and prophenoloxidase system, apoptosis and phagocytosis, and antioxidant systems. Fifteen DEGs were randomly selected for validation by real time quantitative PCR (RT-qPCR) and showed results consistent with the RNA-seq data. Intestinal epithelial cell morphology was also affected by Vibrio challenge, showing epithelial detachment, nuclear pyknosis, and destruction of cell junctions. These results improve our current understanding of the intestinal barrier function in the shrimp response to bacterial infection. PMID- 28889015 TI - Functional characterization of a reactive oxygen species modulator 1 gene in Litopenaeus vannamei. AB - Reactive oxygen species (ROS) imparts a dual effect on multicellular organisms, wherein high levels are usually harmful, and low levels could facilitate in combating pathogenic microorganisms; therefore, the regulation of ROS production is critical. Previous studies have suggested that ROS contributes to resistance to the white spot syndrome virus (WSSV) or Vibrio alginolyticus in Litopenaeus vannamei. However, the regulation of ROS metabolism in L. vannamei remains elusive. In the present study, we proved that the overexpression of L. vannamei reactive oxygen species modulator 1 (LvROMO1) increases ROS production in Drosophila Schneider 2 (S2) cells. Real-time RT-PCR analysis indicated that LvROMO1 is induced by WSSV or V. alginolyticus infection and beta-glucan or microcystin (MC-LR) injection. Further investigation showed that LvROMO1 responding to MC-LR, thereby inducing hemocytes to undergo apoptosis, and ultimately resulting in hepatopancreatic damage. And LvROMO1 downregulation induced an increase in the cumulative mortality of WSSV-infected shrimp by reducing ROS production and suppressing the expression of antimicrobial peptides genes. The findings of present study suggest that LvROMO1 plays an important role in ROS production in L. vannamei and is involved in innate immunity. PMID- 28889016 TI - The effect of melatonin from slow-release implants on basic and TLR-4-mediated gene expression of inflammatory cytokines and their receptors in the choroid plexus in ewes. AB - The present study concerns the effect of melatonin from slow-release implants on the expression of genes coding interleukin-1beta (Il1B), inerleukin-6 (Il6), tumour necrosis factor alpha (Tnf) and their receptors: IL-1 receptor type I (Il1r1) and type II (Il1r2), IL-6 receptor (Il6r) and signal transducer (Il6st), TNFalpha receptor type I (Tnfrsf1a) and II (Tnfrsf1b) and retinoid-related orphan receptor alpha (RorA) and Rev.-erbalpha in the ovine choroid plexus (CP) under basal and lipopolysaccharide (LPS)-challenged conditions. Studies were performed on four groups: 1) sham-implanted and placebo-treated, 2) melatonin-implanted (Melovine, 18mg) and placebo-treated, 3) sham-implanted and LPS-treated (400ng/kg of body weight) and 4) melatonin-implanted and LPS-treated. Under basal conditions, we observed weak expression of Tnf, low expression of Il1B, Il6 and Il1r2 and intermediate expression of other cytokines receptors. LPS treatment induced (P<=0.05) expression in all cytokines and their receptors, except Il6r 3h after the administration. Melatonin attenuated (P<=0.05) LPS-induced up regulation of Il6 but had no effect on other cytokines and their receptors and up regulated (P<=0.05) Rev.-erbalpha expression under basal conditions. This indicates that melatonin from slow-release implants suppresses TLR4-mediated Il6 expression in the ovine CP via a mechanism likely involving clock genes. PMID- 28889017 TI - Mycoplasmas: Brain invaders? AB - Mycoplasmas of humans and animals are usually associated with respiratory, autoimmune, genital and joint diseases. Human mycoplasmas have also been known to affect the brain. Severe central nervous system (CNS) diseases, such as encephalitis, have been linked to Mycoplasma pneumoniae and ureaplasma infections. Less well known is the sheep and goat pathogen, Mycoplasma agalactiae, which has been found in large quantities in the brain where it may be responsible for non-purulent encephalitis as well as ataxia in young animals. Experimental intra-mammary infections of sheep with this mycoplasma have resulted in histopathological changes in the CNS. The cattle pathogen, M. bovis, has been reported occasionally in the brains of calves and adult cattle showing a range of histopathological lesions including abscesses and fibrinous meningitis. Two avian pathogens, M. gallisepticum and M. synoviae have been isolated from the brains of poultry showing meningeal vasculitis and encephalitis. There have been no reported detections of two other avian pathogens, M. meleagridis or M. iowae in the CNS. Over the last few decades, mycoplasmas have been isolated from the brains of sea mammals dying in large numbers in the North Sea although it was concluded that their role may be secondary to underlying viral disease. Finally, evidence has been advanced that certain Spiroplasma species may have a role in the development of the transmissible spongiform encephalopathies (TSE). Invasion of the brain by mycoplasmas may be as a result of direct entry following damage to the inner ear as seen with M. bovis or across the blood brain barrier by mechanisms as yet uncertain. PMID- 28889018 TI - The cancer secretome and secreted biomarkers. PMID- 28889019 TI - Psychotraumatology: What researchers and clinicians can learn from an evolutionary perspective. AB - This review outlines the contribution of evolutionary science to experimental and clinical psychotraumatology. From an evolutionary perspective, traumatic and psychosocial stressors are conceived of as events or circumstances that thwart the achievement of biological goals. The more important is the adaptive value of the goal, the more painful is the emotional impact of the life event that endangers goal achievement. Life history theory and sexual selection theory help to explain why goal priorities differ between the sexes and across age groups. Cultural values and social learning interact with evolved inclinations in determining the hierarchy of goals for a specific person in a specific phase of his or her life. To illustrate the applicability of the evolutionary model, epidemiological and clinical data concerning individual differences in stress sensitivity and stress generation are reviewed and discussed. The final part of the review summarizes new hypotheses that explain how early and current psychosocial stressors can activate a series of adaptive mechanisms including developmental plasticity, predictive adaptive responses and differential susceptibility. Ultimately, the contribution of evolutionary science to psychotraumatology is the idea that experimental and clinical studies should shift the focus of research from the external environment (defined as all stressful factors external to the subjects under investigation) to the ecological environment (defined as those stressful factors of the external environment that have a greater potential to threaten the adaptive equilibrium of the subjects under investigation because of their evolved inclinations). PMID- 28889020 TI - The novel Aspergillus fumigatus MAT1-2-4 mating-type gene is required for mating and cleistothecia formation. AB - Sexual propagation accompanied by recombination and the formation of spore containing fruiting bodies is a cornerstone of fungal genetics and biology. In the human pathogen Aspergillus fumigatus sexual identity has previously been shown to be determined by MAT1-1-1 or MAT1-2-1 genes which act as transcriptional regulators and are present within idiomorphs found at the MAT locus. We here report the identification and first characterization of a further novel gene, termed MAT1-2-4, that is present in the MAT1-2 idiomorph of A. fumigatus. A mating-type swapping strategy was used to achieve an unbiased deletion of the MAT1-2-4 gene with no impact on MAT1-2-1 gene expression. Phenotypical characterization of the resulting strain revealed an inability to mate with the compatible MAT1-1 progenitor, demonstrating that the MAT1-2-4 gene product is a genuine mating-type factor required for correct sexual development. A GPI anchored protein of unknown function was identified as interaction partner. However, no functional role in the mating process or ascosporogenesis could be demonstrated by deletion analysis for this latter protein, although a role in heterokaryon formation is suggested. Bioinformatic analysis also demonstrated the presence of MAT1-2-4 homologues in some, but not all, other Aspergillus species and the evolutionary origins and implications of the MAT1-2-4 gene are discussed. PMID- 28889021 TI - Maxillary sinuses and midface in patients with cleidocranial dysostosis. AB - The cleidocranial dysplasia is general skeletal disorder with an autosomal dominant inheritance. It is manifested by many craniofacial abnormalities, of which the maxillary hypoplasia is the most evident. The aim of the study was to use CBCT to evaluate the volume of the maxillary sinuses and the dimensions of maxillae in patients with CCD and compare them with healthy individuals. Files of four children with cleidocranial dysplasia were investigated. Volume of every maxillary sinus as well as two dimensional measurements of distances between particular points of interest located on surface of maxilla were calculated from reconstructed CBCT examination. Data were compared with a control group. Statistical analysis was performed. Linear and volumetric data obtained using CBCT was collected and compared with a control group. All affected children had both maxillary sinus volume and maxillary dimensions smaller than control values. The maxillary sinuses were underdeveloped up to half of normal values. The largest differences were recorded in vertical linear dimensions of the maxillae. Horizontal dimensions were also lower. There are morphological modifications of bone tissue which accompany CCD. It seems that these changes occur on the midfacial region and to a greater extent concern the maxillary sinus volume. PMID- 28889022 TI - Injection of oxytocin into paraventricular nucleus reverses depressive-like behaviors in the postpartum depression rat model. AB - Oxytocin (OXT) has been considered as a neuroregulator mediating social behaviors and stress-related disorders. Recent clinical studies suggest that OXT might also act as antidepressant in postpartum depression (PPD) patients, but the mechanism is still unknown. In the present study, we explored the effect of OXT in paraventricular nucleus (PVN) and possible signaling pathway involved in a PPD rat model induced by gestation restraint stress (GRS). PPD rats exhibited depressive-like behaviors with significantly longer immobility time, shorter climbing time, and lower sucrose consumption compared to the control rats. Plasma corticosterone (CORT) level was also higher in PPD rats. While PVN and supraoptic nucleus (SON) are main OXT synthesis regions in the brain, GRS-induced decrease of mRNA and peptide level of OXT was seen only in PVN. The expression of TrkB in PVN was increased in PPD rats. Local injection of OXT (20ng) into PVN reversed GRS-induced depressive-like behaviors and high plasma CORT level in PPD rats. Moreover, injection of OXT also reversed GRS-induced increase of TrkB in PVN of PPD rats. All those data suggest that OXT plays an antidepressant role by, at least in part, modulating HPA axis via TrkB in PVN of PPD rats. PMID- 28889023 TI - Suppression of FoxO3a attenuates neurobehavioral deficits after traumatic brain injury through inhibiting neuronal autophagy. AB - Traumatic brain injury (TBI) is a serious insult that frequently leads to neurological impairments. Forkhead box O (FoxO) 3a, as transcription factor, has been confirmed to modulate autophagic process. Moreover, FoxO3a is expressed throughout the brain including the hippocampus. However, the role of FoxO3a in the pathophysiology of TBI is unclear. The present study is designed to investigate whether FoxO3a has the neuroprotective effects on rats subjected to TBI, and further to explore the potential molecular mechanisms. Thus, a rat model of TBI was created by using a modified weight-drop device to mimic the insults of TBI. The results showed that FoxO3a was significantly increased in the serum of patients with TBI as well as in experimental animals. Furthermore, our data also demonstrated that TBI stimulated the translocation of FoxO3a from the cytosol to the nucleus. Additionally, we found that knockdown of FoxO3a by siRNA silencing significantly improved neurobehavioral dysfunctions and conferred a better neuroprotective effects after TBI, evidenced by promoting motor behavioral recovery, attenuating learning and memory impairments, and partially reversing neuronal damage in the hippocampus. To further investigate the molecular mechanisms underlying this neuroprotection, we identified that nuclear accumulation of Foxo3a could induce highly expression of autophagy pathway genes including LC-3, Beclin-1, p62, ATG12, and ATG14, and finally initiate neurological impairments. Interestingly, silencing FoxO3a by siRNA remarkably inhibited the induction of neuronal autophagy after TBI, and activated autophagy was closely related to TBI-induced neurological deficits. Taken together, these findings indicated that FoxO3a knockdown conferred neuroprotective effects after TBI through inhibiting the activation of neuronal autophagy. PMID- 28889024 TI - The toxicology of mercury: Current research and emerging trends. AB - Mercury (Hg) is a persistent bio-accumulative toxic metal with unique physicochemical properties of public health concern since their natural and anthropogenic diffusions still induce high risk to human and environmental health. The goal of this review was to analyze scientific literature evaluating the role of global concerns over Hg exposure due to human exposure to ingestion of contaminated seafood (methyl-Hg) as well as elemental Hg levels of dental amalgam fillings (metallic Hg), vaccines (ethyl-Hg) and contaminated water and air (Hg chloride). Mercury has been recognized as a neurotoxicant as well as immunotoxic and designated by the World Health Organization as one of the ten most dangerous chemicals to public health. It has been shown that the half-life of inorganic Hg in human brains is several years to several decades. Mercury occurs in the environment under different chemical forms as elemental Hg (metallic), inorganic and organic Hg. Despite the raising understanding of the Hg toxicokinetics, there is still fully justified to further explore the emerging theories about its bioavailability and adverse effects in humans. In this review, we describe current research and emerging trends in Hg toxicity with the purpose of providing up-to-date information for a better understanding of the kinetics of this metal, presenting comprehensive knowledge on published data analyzing its metabolism, interaction with other metals, distribution, internal doses and targets, and reservoir organs. PMID- 28889025 TI - Industrial pollution and cancer in Spain: An important public health issue. AB - Cancer can be caused by exposure to air pollution released by industrial facilities. The European Pollutant Release and Transfer Register (E-PRTR) has made it possible to study exposure to industrial pollution. This study seeks to describe the industrial emissions in the vicinity of Spanish towns and their temporal changes, and review our experience studying industrial pollution and cancer. Data on industrial pollutant sources (2007-2010) were obtained from the E PRTR registries. Population exposure was estimated by the distance from towns to industrial facilities. We calculated the amount of carcinogens emitted into the air in the proximity (<5km) of towns and show them in municipal maps. We summarized the most relevant results and conclusions reported by ecological E PRTR-based on studies of cancer mortality and industrial pollution in Spain and the limitations and result interpretations of these types of studies. There are high amounts of carcinogen emissions in the proximity of towns in the southwest, east and north of the country and the total amount of emitted carcinogens is considerable (e.g. 20Mt of arsenic, 63Mt of chromium and 9Mt of cadmium). Although the emissions of some carcinogens in the proximity of certain towns were reduced during the study period, emissions of benzene, dioxins+furans and polychlorinated biphenyls rose. Moreover, the average population of towns lying within a 5km radius from emission sources of carcinogens included in the International Agency for Research on Cancer list of carcinogens was 9 million persons. On the other hand, the results of the reviewed studies suggest that those Spanish regions exposed to the pollution released by certain types of industrial facilities have around 17% cancer excess mortality when compared with those unexposed. Moreover, excess mortality is focused on digestive and respiratory tract cancers, leukemias, prostate, breast and ovarian cancers. Despite their limitations, ecological studies are a useful tool in environmental epidemiology, not only for proposing etiological hypotheses about the risk of living close to industrial pollutant sources, but also for providing data to account for situations of higher mortality in specific areas. Nevertheless, the reduction of emissions should be a goal, with special relevance given to establishing limits for known carcinogens and other toxic substances in the environs of population centers, as well as industry-specific emission limits. PMID- 28889027 TI - Re-evaluating the presumed superiority of amorphous nanoparticles over amorphous microscale solid dispersion in solubility enhancement of poorly soluble drugs. AB - The solubility enhancement afforded by amorphous drug nanoparticles was demonstrated in several studies to be superior to the traditional amorphization approach by microscale amorphous solid dispersion (or micro ASD in short). A closer look at these studies, however, revealed that they were performed using a very limited number of poorly-soluble drug models (i.e. itraconazole and cefuroxime). Herein we aimed to re-examine the solubility enhancement and physical stability of amorphous nanoparticles relative to that of the micro ASD using a different poorly-soluble drug model, i.e. ciprofloxacin (CIP). Two types of amorphous CIP nanoparticles, i.e. CIP nanorod prepared by pH-shift precipitation and CIP nanoplex prepared by drug-polyelectrolyte complexation, were compared with CIP micro ASD prepared by spray drying with hydroxypropylmethylcellulose (HPMC). The results showed that (1) the solubility enhancement of amorphous drug nanoparticles was not necessarily superior to that of the micro ASD, particularly in their dry-powder form, and (2) the amorphization strategy of drug nanoparticles significantly influenced their solubility enhancement and physical stability. In short, the solubility enhancement was in the order of CIP micro ASD>CIP nanorod>CIP nanoplex, whereas the amorphous state stability during storage was in the order of CIP nanoplex>CIP micro ASD>CIP nanorod. A trade-off thus existed between the solubility enhancement and physical stability of amorphous CIP particles. The present work concluded that the superior solubility enhancement of amorphous drug nanoparticles was not drug independent. PMID- 28889026 TI - GNAS mutations and heterotopic ossification. AB - GNAS is a complex imprinted gene encoding the alpha-subunit of the stimulatory heterotrimeric G protein (Gsalpha). GNAS gives rise to additional gene products that exhibit exclusively maternal or paternal expression, such as XLalphas, a large variant of Gsalpha that shows exclusively paternal expression and is partly identical to the latter. Gsalpha itself is expressed biallelically in most tissues, although the expression occurs predominantly from the maternal allele in a small set of tissues, such as renal proximal tubules. Inactivating mutations in Gsalpha-coding GNAS exons are responsible for Albright's hereditary osteodystrophy (AHO), which refers to a constellation of physical and developmental disorders including obesity, short stature, brachydactyly, cognitive impairment, and heterotopic ossification. Patients with Gsalpha mutations can present with AHO in the presence or absence of end-organ resistance to multiple hormones including parathyroid hormone. Maternal Gsalpha mutations lead to AHO with hormone resistance (i.e. pseudohypoparathyroidism type-Ia), whereas paternal mutations cause AHO alone (i.e. pseudo pseudohypoparathyroidism). Heterotopic ossification associated with AHO develops through intramembranous bone formation and is limited to dermis and subcutis. In rare cases carrying Gsalpha mutations, however, ossifications progress into deep connective tissue and skeletal muscle, a disorder termed progressive osseous heteroplasia (POH). Here I briefly review the genetic, clinical, and molecular aspects of these disorders caused by inactivating GNAS mutations, with particular emphasis on heterotopic ossification. PMID- 28889028 TI - Development and in vitro/in vivo performance of self-nanoemulsifying drug delivery systems loaded with candesartan cilexetil. AB - Candesartan cilexetil is widely used in the management of hypertension and heart failure. The drug delivery encounters obstacles of poor aqueous solubility, efflux by intestinal P-glycoprotein and vulnerability to enzymatic degradation in small intestine. Self-nanoemulsifying drug delivery systems (SNEDDS) loaded with candesartan cilexetil were successfully developed to overcome such obstacles. Preliminary screening was carried out to select proper surfactant, co-surfactant and oil combination for successful SNEDDS formulation. All screened excipients were reported for their P-glycoprotein and cytochrome P450 3A4 (CYP3A4) modulation activity. Ternary and pseudo ternary diagrams were constructed to optimize the system. Peppermint oil and clove oil showed a high emulsification ability. The nature of obtained dispersions was identified to be nanoemulsions. Twenty-four formulations were evaluated for stability, robustness to dilution and self-emulsification efficiency. All formulations showed a very short emulsification time of <2min. The emulsification efficiency was significantly superior at pH6.8, at which the largest self-emulsifying region was also observed. Eight formulations were selected for further characterization according to cloud point measurement; mean droplet size, poly dispersity index (PDI) and zeta potential determination in addition to in vitro drug release study. All selected formulations showed very high cloud points (70-90 degrees C), ultrafine mean droplet size (12+/-1.4 to 24.5+/-2.13nm), very low PDI values (0.015-0.1305) and almost a complete drug release after 12h. Formulation F15 (Peppermint oil 55% w/w: Cremophor RH40 25% w/w: Labrasol 20% w/w) was selected for further characterization. Its droplet size showed robustness to different dilution folds with different media and its TEM photograph showed spherical particles without any apparent aggregation even after 24h. Formulation F15 successfully controlled the systolic blood pressure of hypertensive rats for 24h with the maximum effect was observed after 2h. These results indicate that, SNEDDS could be promising delivery systems with a rapid onset of action and prolonged therapeutic effect of candesartan cilexetil. PMID- 28889030 TI - Crowdfunding our health: Economic risks and benefits. AB - Crowdfunding is an expanding form of alternative financing that is gaining traction in the health sector. This article presents a typology for crowdfunded health projects and a review of the main economic benefits and risks of crowdfunding in the health market. We use evidence from a literature review, complimented by expert interviews, to extend the fundamental principles and established theories of crowdfunding to a health market context. Crowdfunded health projects can be classified into four types according to the venture's purpose and funding method. These are projects covering health expenses, fundraising health initiatives, supporting health research, or financing commercial health innovation. Crowdfunding could economically benefit the health sector by expanding market participation, drawing money and awareness to neglected health issues, improving access to funding, and fostering project accountability and social engagement. However, the economic risks of health related crowdfunding include inefficient priority setting, heightened financial risk, inconsistent regulatory policies, intellectual property rights concerns, and fraud. Theorized crowdfunding behaviours such as signalling and herding can be observed in the market for health-related crowdfunding. Broader threats of market failure stemming from adverse selection and moral hazard also apply. Many of the discussed economic benefits and risks of crowdfunding health campaigns are shared more broadly with those of crowdfunding projects in other sectors. Where crowdfunding health care appears to diverge from theory is the negative externality inefficient priority setting may have towards achieving broader public health goals. Therefore, the market for crowdfunding health care must be economically stable, as well as designed to optimally and equitably improve public health. PMID- 28889029 TI - Veterinary antibiotics in food, drinking water, and the urine of preschool children in Hong Kong. AB - Due to the harmful effects of veterinary antibiotics (VAs) residues in food on children's health, urine samples from 31 preschool and primary school children were analyzed for 13 common VAs. Samples of raw and cooked pork, chicken, fish, milk and drinking water from the children's living areas were also analyzed for residual VAs. Urinalysis revealed one to four target antibiotics in 77.4% of the sample group, with concentrations as high as 0.36ng/mL. Norfloxacin and penicillin had the highest detection rates (48.4% and 35.5%, respectively), with median concentrations of 0.037 and 0.13ng/mL, respectively. The VA burden of children in HK was lower than that in Shanghai. Enrofloxacin, penicillin, and erythromycin were the most detected VAs in raw and cooked food. Only oxytetracycline was detected in terminal tap water, and none were detected in milk. Tetracycline and doxycycline hyclate were detected in organic eggs (up to 7.1ng/g) and regular eggs (up to 6.6ng/g), which were common in children's diets. Traditional Chinese cooking processes did not completely eliminate VAs, and the concentrations of some VAs increased, especially after frying and roasting. The estimated daily intake (EDI) results show that the contribution of dietary intake and that based on the urine concentrations of VAs were far below the acceptable daily intake (ADI). The EDIs from urine were significantly lower than those based on cooked foods. The highest level of achievement percentage (LAP) based on dietary consumption and urine concentrations were 39.7% and 1.79%, respectively, and thus current levels of exposure to VAs would not seem to pose a risk to children's health. However, harmful effects of residual VAs during developmental periods may occur with exposure to much lower doses than those considered harmful to adults, and further investigation of these emerging pollutants is urgently encouraged. PMID- 28889031 TI - Mens rea ascription, expertise and outcome effects: Professional judges surveyed. AB - A coherent practice of mens rea ('guilty mind') ascription in criminal law presupposes a concept of mens rea which is insensitive to the moral valence of an action's outcome. For instance, an assessment of whether an agent harmed another person intentionally should be unaffected by the severity of harm done. Ascriptions of intentionality made by laypeople, however, are subject to a strong outcome bias. As demonstrated by the Knobe effect, a knowingly incurred negative side effect is standardly judged intentional, whereas a positive side effect is not. We report the first empirical investigation into intentionality ascriptions made by professional judges, which finds (i) that professionals are sensitive to the moral valence of outcome type, and (ii) that the worse the outcome, the higher the propensity to ascribe intentionality. The data shows the intentionality ascriptions of professional judges to be inconsistent with the concept of mens rea supposedly at the foundation of criminal law. PMID- 28889032 TI - Non-destructive study of wood using the Compton scattering technique. AB - A simple nondestructive method is presented in this study to characterize woods having different densities, thus estimating the size and depth of inhomogeneities in given wood samples using the Compton scattering technique (CST). This technique uses a collimated beam of 662-keV energy from 137Cs radioactive source, and the scattered flux is detected by an NaI(Tl) detector. To characterize different wood samples on the basis of their densities, both scattering and transmission experiments were performed. The presence of inhomogeneities such as knots in wood was simulated by drilling cylindrical voids of diameter 9mm in the samples and then filling them with a high-density material (aluminum). Furthermore, different sizes of inhomogeneities (Al cylinders) were filled in the wood samples to estimate the depth and size of the inhomogeneity using the CST. A higher linear correlation (R2 ~ 0.96) was found between the scattered intensity and the density of different woods using the CST than that using the transmission (R2 ~ 0.83) method by measuring the density range. An increase of 24.6% in the average scattered intensity was observed at the location where the knot was present, and it was found that an inhomogeneity of the order of ~4mm or more could be detected by the CST. PMID- 28889033 TI - Strategies to improve beef tenderness by activating calpain-2 earlier postmortem. AB - Our objectives were to determine the effect of post rigor calcium chloride injection or freezing on 1) sarcoplasmic calcium concentration and calpain-2 activity of beef longissimus lumborum (LL) and semimembranosus (SM) steaks aged 1, 4, and 14days post-treatment and on 2) Warner-Bratzler shear force, water holding capacity, and consumer acceptability of LL and SM steaks aged 4 and 14days post-treatment. Free calcium levels in the calcium, frozen, and control steaks averaged 1256, 127, and 121MUM for the LL and 1520, 120, and 111MUM for the SM, respectively. Measurable LL native calpain-2 activity was lower in calcium and frozen steaks than control steaks (P<0.01), while SM native calpain-2 activity was lowest in calcium steaks and intermediate in frozen steaks (P<0.01). LL calcium steaks were more tender (P=0.04) than control steaks. In conclusion, calcium chloride injection and freezing activate calpain-2 earlier postmortem in both muscles and calcium injection improves LL tenderness. PMID- 28889034 TI - The effect of technical replicate (repeats) on Nix Pro Color SensorTM measurement precision for meat: A case-study on aged beef colour stability. AB - The Nix Pro Colour SensorTM (NIX) can be potentially used to measure meat colour, but procedural guidelines that assure measurement reproducibility and repeatability (precision) must first be established. Technical replicate number (r) will minimise response variation, measureable as standard error of predicted mean (SEM), and contribute to improved precision. Consequently, we aimed to explore the effects of r on NIX precision when measuring aged beef colour (colorimetrics; L*, a*, b*, hue and chroma values). Each colorimetric SEM declined with increasing r to indicate improved precision and followed a diminishing rate of improvement that allowed us to recommend r=7 for meat colour studies using the NIX. This definition was based on practical limitations and a* variability, as additional r would be required if other colorimetrics or advanced levels of precision are necessary. Beef ageing and display period, holding temperature, loin and sampled portion were also found to contribute to colorimetric variation, but were incorporated within our definition of r. PMID- 28889035 TI - Influence of meat source, pH and production time on zinc protoporphyrin IX formation as natural colouring agent in nitrite-free dry fermented sausages. AB - Nitrite is commonly used in meat products due to its plural technological advantages. However, it is controversial because of its detrimental side effects on health. Within the context of nitrite reduction, zinc protoporphyrin IX (Zn(II)PPIX) formation in meat products as natural red colouring agent has been suggested. This investigation presents the evaluation of naturally occurring pigments, namely Zn(II)PPIX, protoporphyrin IX (PPIX) and heme in nitrite-free dry fermented sausages in function of time, meat source (pork, horsemeat and a combination of both meat sources) and pH condition. In function of time, Zn(II)PPIX and PPIX were formed and heme content decreased. Higher pH conditions promoted Zn(II)PPIX and PPIX formation, whereas the influence of pH on heme was less clear. The use of horsemeat also promoted Zn(II)PPIX formation. Moreover, even similar amounts were formed when it was combined with pork. Product redness, however, could not be related to Zn(II)PPIX formation. PMID- 28889036 TI - Multisubunit tethering complexes in higher plants. AB - Tethering complexes mediate the initial, specific contact between donor and acceptor membranes. This review focuses on the modularity and function of multisubunit tethering complexes (MTCs) in higher plants. One emphasis is on molecular interactions of plant MTCs. Here, a number of insights have been gained concerning interactions between different tethering complexes, and between tethers and microtubule-associated proteins. The roles of tethering complexes in abiotic stress responses appear indirect, but in the context of biotic stress responses it has been suggested that some tethers are direct targets of pathogen effectors or virulence factors. In light of the central roles tethering complexes play in plant development, an emerging concept is that tethers may be co-opted for plant adaptive responses. PMID- 28889037 TI - Gender-specific evolution of fetal heart rate variability throughout gestation: A study of 8823 cases. AB - BACKGROUND: Fetal heart rate (FHR) variability throughout gestation reflects aspects of fetal development, and its analysis has been used for the assessment of fetal well-being. AIM: The objective of this study was to provide a gender specific analysis of the evolution of FHR variability indices throughout gestation, using linear time-domain, spectral and nonlinear FHR indices. STUDY DESIGN: A large retrospective study was carried out using antepartum FHR recordings obtained from 4713 male and 4110 female fetuses, with normal pregnancy outcome, between 2004 and 2013, with gestational ages ranging between 25 and 40weeks. OUTCOME MEASURES: FHR variability was analysed through linear time domain methods, as well as using spectral analysis and entropy indices. Evolution of FHR indices throughout gestation was analysed through Spearman correlation coefficient. Comparison between male and female fetuses was performed using nonparametric bootstrap 95% confidence intervals for the median. RESULTS: Mean FHR decreased significantly throughout gestation, whereas most variability indices increased. Sympatho-vagal balance measured by spectral analysis exhibited two local maxima at 29-30 and 34-35weeks and decreased afterwards. Entropy indices increased until around the 34th week, slightly decreasing after the 37th week. Female fetuses presented higher mean FHR and entropy from the 34th week afterwards, and lower short-term variability and sympatho-vagal balance in the same period. CONCLUSIONS: Spectral and entropy analysis should be considered as a complement to conventional FHR variability analysis, aiming at a better characterization and follow-up of fetal development/maturation throughout gestation. Additionally, gestational age needs to be considered when defining reference ranges for FHR indices in systems of computerized analysis. PMID- 28889038 TI - Control of plant phosphate homeostasis by inositol pyrophosphates and the SPX domain. AB - Proteins containing a SPX domain are involved in phosphate (Pi) homeostasis, including Pi transport and adaptation to Pi deficiency. The SPX domain harbors a basic surface binding Pi at low affinity and inositol pyrophosphates (PP-InsPs) at high affinity. Genetic and biochemical studies revealed that PP-InsPs serve as ligands for the SPX domain. Residues in the PHO1 SPX domain involved in PP-InsPs binding are critical for its Pi export activity, and the interaction between SPX proteins and the PHR1 transcription factor, which results in PHR1 inactivation, is promoted by PP-InsPs. Changes in PP-InsPs levels in response to Pi deficiency may thus contribute to the adaptation of plants to stress via the modulation of the activity of SPX-containing proteins and their interactors. Modulating PP-InsP levels or the affinity/specificity of the SPX domain for PP-InsP could potentially be used to engineer crops to maintain high yield under reduced Pi fertilizer input. PMID- 28889039 TI - Hydrolysis of particulate settleable solids (PSS) in activated sludge is determined by the bacteria initially adsorbed in the sewage. AB - Up to half of the organic fraction of an urban wastewater is made up of particulate settleable solids (PSS). In activated sludge process (AS) this material is rapidly adsorbed on to microbial flocs but is only slowly and partially degraded. To better understand and predict the degradation kinetics observed, a determination of the proportion of hydrolytic bacteria is required. As inoculum is usually added in the biodegradation tests, a comparison is required between the roles of bacteria introduced with the inoculum and those attached to the substrate. In this work, respirometric batch experiments were performed on PSS collected from upstream or downstream of the sewers of Toulouse city. Toilet paper (TP) and cellulose, two model particulate substrates, were also investigated. To understand the role of the active biomass in hydrolysis, increasing concentrations of AS were added to a certain amount of PSS or TP. No correlation was observed between the concentration of AS and the rate and duration of degradation of the particulate matter. Simulations performed after calibration of the model ASM-1 allowed the fraction of hydrolytic bacteria to be estimated in both the substrate and the AS-inoculum. Only a very small fraction of the bacteria of AS and of the substrate samples were found to be efficient for hydrolysis. Hydrolysis was mainly initiated by a small proportion of the microorganisms, and especially by cells already attached to PSSs. Moreover, the fraction of bacteria able to hydrolyse large particles present in an inoculum of AS depended on the initial contamination of the surface of the particles. PMID- 28889040 TI - Greywater reuse - Assessment of the health risk induced by Legionella pneumophila. AB - Greywater (GW), domestic wastewater excluding the streams generated by toilets and kitchens, can serve as an alternative water source. The main options for GW reuse are toilet flushing and garden irrigation, both generating aerosols. These may transmit inhalable pathogens like Legionella and present a potential health risk. This study quantified the health risk that may arise from inhalation of Legionella-contaminated aerosols due to non-potable GW reuse. Data on Legionella concentrations in potable water and GW was collected. Then, Quantitative Microbial Risk Assessment (QMRA) was performed for two possible exposure scenarios: garden irrigation and toilet flushing. This was performed while considering Legionella seasonality. In order to determine the safety of GW reuse regarding Legionella transmission, the obtained results were compared with estimated tolerable risk levels of infection and of disease. Both limits were expressed as Disability-Adjusted Life Years index (DALY) being 10-4 and 10-5, respectively. The QMRA revealed that the annual risk associated with reuse of treated and chlorinated GW for garden irrigation and toilet flushing was not significantly higher than the risk associated with using potable water for the same two purposes. In all studied scenarios, the health risk stemming from reusing treated and chlorinated GW was acceptable regarding Legionella infection. In contrast, reuse of untreated or treated but unchlorinated GW should not be practiced, as these are associated with significantly higher health risks. PMID- 28889041 TI - Building a community-based culture of evaluation. AB - In this article we argue for a community-based approach as a means of promoting a culture of evaluation. We do this by linking two bodies of knowledge - the 70 year theoretical tradition of community-based research and the trans-discipline of program evaluation - that are seldom intersected within the evaluation capacity building literature. We use the three hallmarks of a community-based research approach (community-determined; equitable participation; action and change) as a conceptual lens to reflect on a case example of an evaluation capacity building program led by the Ontario Brian Institute. This program involved two community-based groups (Epilepsy Southwestern Ontarioand the South West Alzheimer Society Alliance) who were supported by evaluators from the Centre for Community Based Research to conduct their own internal evaluation. The article provides an overview of a community-based research approach and its link to evaluation. It then describes the featured evaluation capacity building initiative, including reflections by the participating organizations themselves. We end by discussing lessons learned and their implications for future evaluation capacity building. Our main argument is that organizations that strive towards a community-based approach to evaluation are well placed to build and sustain a culture of evaluation. PMID- 28889042 TI - Marginal En Bloc Resection of C2-C3 Chordoma with Bilateral Vertebral Artery Preservation and Mesh Cage Reconstruction with Review of Previously Published Cases. AB - BACKGROUND: Chordomas arise from remnants of the notochord and occur throughout the neuroaxis. En bloc resection of chordomas can prove especially challenging in the upper cervical spine secondary to the unique structural anatomy and intimate relationship to the vertebral arteries and spinal cord. CASE DESCRIPTION: We describe the resection of a C2-C3 chordoma in a 55-year-old woman in 2-stage fashion with preservation of the vertebral arteries. First, a posterior instrumented fusion and removal of the posterior elements was performed, followed by an anterior transmandibular en bloc resection with cage reconstruction with kick-plate support achievable with off-the-shelf products. CONCLUSIONS: Chordomas in the upper cervical spine pose a surgical challenge but are amenable to en bloc resection. With careful planning and intraoperative adaptability, the surgeon can achieve a suitable reconstruction with off-the-shelf products. PMID- 28889043 TI - Photovoicing the neighbourhood: Understanding the situated meaning of intangible places for ageing-in-place. AB - Ageing-in-place is considered important for the health of older adults. In this paper, inspired by a constructivist approach to ageing-in-place, we unravel professionals' and older adults' constructions of ageing-in-place. Their perspectives are studied in relation to a policy that aims to develop so-called 'lifecycle-robust neighbourhoods' in the southern part of the Netherlands. We conducted a photovoice study in which 18 older adults (70-85 years) living independently and 14 professionals (social workers, housing consultants, neighbourhood managers and community workers) were asked to photograph and discuss the places they consider important for ageing-in-place. Based on a theoretically informed analysis of the data, we found that professionals primarily consider objective characteristics of neighbourhoods such as access to amenities, mobility and meeting places as important enablers for older adults to remain living independently. Analysis of older adults' photographs and stories show that they associate ageing-in-place with specific lived experiences and attachments to specific, intangible and memory-laden public places. We conclude that exploring these experiences helps to increase current knowledge about place attachment in old age. PMID- 28889044 TI - Cervical disc arthroplasty for the treatment of adjacent segment disease: A systematic review of clinical evidence. AB - The safety and efficacy of cervical disc arthroplasty (CDA) performed adjacent to previous fusion for the treatment of adjacent segment disease (ASD) remains unknown. This systematic review summarizes clinical evidence on the outcomes of CDA performed adjacent to previous cervical fusion. A systematic search of PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Embase for literature published through March 2017 was conducted. All the studies on CDA for the treatment of ASD after cervical fusion surgery were included. Two independent reviewers searched and assessed the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). A total of 5 studies were identified. The overall quality of evidence was low. All included studies demonstrated that clinical outcomes reflected by several assessment scales improved after arthroplasty. Cervical lordosis range of motion (ROM) after arthroplasty remained and was even enhanced postoperatively. The rate of complications and subsequent surgeries was low. There is a dearth of information regarding the outcomes of CDA for the treatment of ASD in the literature. In general, CDA may be a safe and effective surgical procedure to treat ASD, but this conclusion needs to be confirmed by future long-term, prospective clinical trials. PMID- 28889045 TI - Martino's reformation: A schism in the neuroprogression church. PMID- 28889046 TI - A systematic review of measures of mental health and emotional wellbeing in parents of children aged 0-5. AB - BACKGROUND: A significant proportion of women with young children experience mental health problems and recent research suggests fathers may also be affected. This may have a long term negative impact on the child's development with significant costs to society. Appropriate measures are therefore needed to identify parents and children at risk. METHOD: This literature review aimed to identify the most reliable, evidence based global measures of mental health for parents of infants from pregnancy to 5 years postpartum (0-5 years). Literature searches were conducted on online databases and hand searches of reference lists were also carried out. Studies were included in the review if they reported information on measures of global psychological distress or wellbeing from 0 to 5 years postpartum. RESULTS: A total of 183 studies were included in the review, 19 of which directly examined the psychometric validity of an outcome measure. These studies reported information on 23 outcome measures, 4 of which had been validated in parents of children from 1 to 5. These were: the General Health Questionnaire (GHQ), the Symptom Checklist (SCL), the Self-Reporting Questionnaire (SRQ) and the Kessler scale (K10/6). Reliability and validity varied across studies. LIMITATIONS: Only a small number of studies included fathers and examined psychometric validity across the entire period of early childhood. CONCLUSIONS: The GHQ was the most frequently validated but results suggest poor reliability and validity. The SRQ and K10/6 were the most promising measures in terms of psychometric properties and clinical utility. PMID- 28889047 TI - An examination of the prospective association between religious service attendance and suicide: Explanatory factors and period effects. AB - BACKGROUND: We addressed two unanswered questions from prior research, demonstrating a prospective association between frequent religious service attendance and decreased risk for suicide. First, we assessed whether religious service attendance conferred protection from suicide even after accounting for strength of religious affiliation. Second, we evaluated whether the relationship between religious service attendance and suicide was subject to period effects. METHODS: Data were drawn from the 1978-2010 General Social Survey, a nationally representative study of 30,650 non-institutionalized, English-speaking American residents age 18 or older. Data were linked with the National Death Index through the end of 2014. We analyzed these data using moderated Cox proportional hazard analyses. RESULTS: Religious affiliation had no relationship with suicide. Religious service attendance only had a protective effect against suicide death among those in later (2000-2010) rather than earlier (1998 and earlier) data collection periods. LIMITATIONS: Secondary analysis of data limited the types of variables that were available. CONCLUSIONS: The protective nature of religion is due more to participating in religious activities, such as attending religious services, than to having a strong religious affiliation, and this effect exists primarily in more recent data collection periods. PMID- 28889048 TI - Mania triggered by sleep loss and risk of postpartum psychosis in women with bipolar disorder. AB - BACKGROUND: Women with bipolar disorder are at high risk of affective psychoses following childbirth (i.e. "postpartum psychosis", PP) and there is a need to identify which factors underlie this increased risk. Vulnerability to mood dysregulation following sleep loss may influence risk of PP, as childbirth is typified by sleep disruption. We investigated whether a history of mood episodes triggered by sleep loss was associated with PP in women with bipolar disorder (BD). METHODS: Participants were 870 parous women with BD recruited to the Bipolar Disorder Research Network. Lifetime diagnoses of BD and perinatal episodes were identified via interview and case notes. Information on whether mood episodes had been triggered by sleep loss was derived at interview. Rates of PP were compared between women who did and did not report mood episodes following sleep loss. RESULTS: Women who reported sleep loss triggering episodes of mania were twice as likely to have experienced an episode of PP (OR = 2.09, 95% CI = 1.47-2.97, p < 0.001) compared to women who did not report this. There was no significant association between depression triggered by sleep loss and PP (p = 0.526). LIMITATIONS: Data were cross-sectional therefore may be subject to recall bias. We also did not have objective data on sleep disruption that had occurred during the postpartum period or prior to mood episodes. CONCLUSIONS: In clinical practice, a history of mania following sleep loss could be a marker of increased vulnerability to PP, and should be discussed with BD women who are pregnant or planning to conceive. PMID- 28889049 TI - The potential impact of biochemical mediators on telomere attrition in major depressive disorder and implications for future study designs: A narrative review. AB - BACKGROUND: Major depressive disorder (MDD) has been proposed to represent a "disease of premature aging", which is associated with certain biomarkers of cellular ageing and numerous other age-related diseases. Over the last decade, telomere length (TL) arose as a surrogate for cellular aging. Recent data suggests that TL might be reduced in patients with MDD, however, results are still inconclusive. This might be explained by the lack of assessment of potential biochemical mediators that are directly associated with telomere shortening and frequently observed in patients with MDD. METHODS: A narrative review was performed. The PubMed database was searched for relevant studies. RESULTS: We identified four major mediators, which are recurrently reported in patients with MDD and are associated with reduced TL: inflammation/oxidative stress, dysregulation of the hypothalamic-pituitary-adrenal axis, metabolic dysbalance including insulin resistance, and decreased brain-derived neurotrophic factor. These mediators are also mutually associated and were not systematically assessed in current studies investigating TL and MDD, which might explain inconclusive findings across current literature. Finally, we discuss possible ways to assess those mediators and potential implications of such approaches for future research. LIMITATIONS: The majority of identified studies had cross sectional designs and used heterogeneous methods to assess TL and associated relevant biochemical mediators. CONCLUSIONS: A better understanding of the complex interactions between biochemical mediators, somatic comorbidities and shortened telomeres in patients with MDD might further specify the pathophysiology-based conceptualization and, based on that, personalized treatment of MDD. PMID- 28889050 TI - Music-based interventions to reduce internalizing symptoms in children and adolescents: A meta-analysis. AB - BACKGROUND: Existing systematic reviews provide evidence that music therapy is an effective intervention in the treatment of children and adolescents with psychopathology. The objective of the present review was to systematically review and quantify the effects of music-based interventions in reducing internalizing symptoms (i.e., depression and anxiety) in children and adolescents using a meta analytical approach. METHODS: Databases and journals were systematically screened for studies eligible for inclusion in meta-analysis on the effects of music-based interventions in reducing internalizing symptoms. A random-effect meta-analysis using standardized mean differences (SMD) was conducted. RESULTS: Five studies were included. Analysis of data from (randomized) controlled trials, yielded a significant main effect (Hedge's g = -0.73; 95%CI [-1.42;-0.04], Z = 2.08, p = 0.04, k = 5), indicating a greater reduction of internalizing symptoms in youth receiving music-based interventions (n = 100) compared to different control group interventions (n = 95). LIMITATIONS: The existing evidence is limited to studies of low power and methodological quality. Included studies were highly heterogeneous with respect to the nature of the intervention, the measurements applied, the samples studied, and the study design. CONCLUSIONS: Findings indicate that music-based interventions may be efficient in reducing the severity of internalizing symptoms in children and adolescents. While these results are encouraging with respect to the application of music-based intervention, rigorous research is necessary to replicate existing findings and provide a broader base of evidence. More research adopting well controlled study designs of high methodological quality is needed. PMID- 28889051 TI - Different spectrophotometric methods applied for the analysis of simeprevir in the presence of its oxidative degradation product: Acomparative study. AB - Five simple spectrophotometric methods were developed for the determination of simeprevir in the presence of its oxidative degradation product namely, ratio difference, mean centering, derivative ratio using the Savitsky-Golay filters, second derivative and continuous wavelet transform. These methods are linear in the range of 2.5-40MUg/mL and validated according to the ICH guidelines. The obtained results of accuracy, repeatability and precision were found to be within the acceptable limits. The specificity of the proposed methods was tested using laboratory prepared mixtures and assessed by applying the standard addition technique. Furthermore, these methods were statistically comparable to RP-HPLC method and good results were obtained. So, they can be used for the routine analysis of simeprevir in quality-control laboratories. PMID- 28889052 TI - A rapid Fourier transform infrared spectroscopic method for analysis of certain proton pump inhibitors in binary and ternary mixtures. AB - A simple and non-destructive FTIR method was used to determine certain proton pump inhibitors (PPIs) in binary and ternary mixtures. Proton pump inhibitors (PPIs); omeprazole (OMZ), esomeprazole (EZM), lansoprazole (LAN), pantoprazole sodium (PAN sodium) and rabeprazole sodium (RAB sodium) in binary mixture with domperidone (DOM) and ternary mixture of OMZ, clarithromycin (CLM) and tinidazole (TNZ) were determined in the solid-state by FTIR spectroscopy for the first time. The method was validated according to ICH-guidelines where linearity was ranged from 20 to 850MUg/g and 20-360MUg/g for PPIs and DOM, respectively in binary mixtures and 10-400, 100-8000 and 150-14,000MUg/g for OMZ, CLM and TNZ, respectively. Limits of detection were found to be 6-100 and 9-100MUg/g for PPIs and DOM, respectively and 4, 40 and 50MUg/g for OMZ, CLM and TNZ, respectively. The method was applied successfully for determination of the cited drugs in their respective pharmaceutical dosage forms. PMID- 28889053 TI - Structure, isomerism, and vibrational assignment of aluminumtrifluoroacetylacetonate. An experimental and theoretical study. AB - An interpretation of the experimental IR and Raman spectra of Aluminum (III) trifluoroacetylacetonate (Al(TFAA)3) complex, which were synthesized by us, is first reported here. The charge distribution, isomerism, strength of metal-oxygen binding and vibrational spectral properties for this complex structure were theoretically investigated through population analysis, geometry optimization and harmonic frequency calculations, performed at B3LYP/6-311G* level of theory. In the population analysis, two different approaches reffered to as "Atoms in molecules (AIM)", and "Natural Bond Orbital (NBO)" were used. According to the calculation resuls, the energy difference between the cis and trans isomers of Al(TFAA)3 is very small and indicates that both isomers coexist in the sample in comparable proportions. Comparison of the calculated frequency and intensity data with the observed IR and Raman spectra of the complex has supported this conclusion. On the other hand, comparison of the structural and vibrational spectral data of Al(TFAA)3, which were experimentally measured and calculated at B3LYP/6-311G* level, with the corresponding data of Aluminum acetylacetonate (Al(AA)3) has revealed the effects of CF3 substitution on the structural and vibrational spectral data associated with the CH3 groups in the complex structure. PMID- 28889054 TI - Evaluation of chemical immersion treatments to reduce microbial populations in fresh beef. AB - The aim of the current study was to assess the ability of a number of chemicals (acetic Acid (AA), citric acid (CA) lactic acid (LA), sodium decanoate (SD) and trisodium phosphate (TSP)) to reduce microbial populations (total viable count, Campylobacter jejuni, Escherichia coli, Salmonella typhimurium and Listeria monocytogenes) on raw beef using an immersion system. The following concentrations of each chemical were used: 3 & 5% for AA, CA, LA, SD and 10 &12% for TSP. Possible synergistic effects of using combinations of two chemicals sequentially (LA+CA and LA+AA) were also investigated. L*, a* and b* values were measured before and after treatments and DeltaE* values were calculated in order to determine any changes in the color of meat due to the use of these chemicals. In general, all chemical treatments resulted in significantly (p<0.05) reduced bacterial counts when compared to untreated controls. The greatest reductions were obtained by using LA3%, SD5%, AA5%, LA5% and SD3% for TVC, C. jejuni, E. coli, S. typhimurium and L. monocytogenes, respectively. However, no significant difference in microbial load was observed between the different concentrations of each chemical used (p>0.05). The application of combinations of chemical immersion treatments (LA3%+AA3% and LA3%+CA3%) did not result in further significant reductions in microbial populations when compared to single chemical treatments (P<0.05). Assessment of color changes in meat following the application of chemical immersion treatments indicated that using AA or CA at either concentration and LA at 5% led to an increase in the DeltaE* value of >3 immediately after treatment and after 24h storage. The remaining treatments did not result in significant changes to the color of raw beef. PMID- 28889055 TI - Cells-qPCR as a direct quantitative PCR method to avoid microbial DNA extractions in grape musts and wines. AB - A novel quantitative PCR assay called Cells-qPCR has been developed for the rapid detection and quantification of yeasts, lactic acid bacteria (LAB) and acetic acid bacteria (AAB) directly from grape must and wine that does not require DNA extraction. The assay was tested on Brettanomyces bruxellensis, Saccharomyces cerevisiae, Lactobacillus plantarum, Oenococcus oeni, Acetobacter aceti and Gluconobacter oxydans in culture media, and in white and red grape musts and wines. Standard curves were constructed from DNA and cells for the six target species in all the matrices. Good efficiencies were obtained for both when comparing DNA and cells standard curves. No reaction inhibition was observed between matrices for each species. Cells quantification was linear over a range of cell concentrations (7, 5 or 4 orders of magnitude) and detected as few as one cell per reaction in all the matrices. The developed Cells-qPCR assay is a robust, reliable, fast and specific method to detect and quantify different yeasts, LAB and AAB species in grape must and wine that avoids DNA extraction and overcomes the presence of inhibitors like polyphenols and ethanol. PMID- 28889056 TI - Voltammetric behavior of Mammeisin (MA) at a glassy carbon electrode and its interaction with Bovine Serum Albumin (BSA). AB - The electrochemical oxidation of Mammeisin (MA) was studied in a solution containing acetone and 0.1M phosphate buffer +0.1M KCl (pH=5.3) at a glassy carbon electrode (GCE), using cyclic (CV) and square wave voltammetry (SWV). MA showed a quasi-reversible process, which is pH dependent and that involves the exchange of two electrons and two protons. The oxidation product was adsorbed by the electrode surface to form a film that blocks active sites over repetitive cyclic. Moreover, the interaction of MA and bovine serum albumin (BSA) was studied by CV and SWV at different pHs (5.4, 7.2, 9.5). As a result of the affinity binding with BSA, electrochemically inactive complex was formed. In addition, the oxidation potential of MA in the presence of BSA depends on the pH. The diffusion coefficients of both free and bound MA were estimated from the cyclic voltammetry data using the method developed by Randles-Sevich (Df=9.85*10 5cm2s-1 and Db=1.27*10-9cm2s-1) and the binding constant of MA-BSA complex, K=3.47*102Lmol-1, was obtained. PMID- 28889057 TI - Personality, marijuana norms, and marijuana outcomes among college students. AB - Based on the high prevalence of marijuana use among college students, we examined distal and proximal antecedents to marijuana-related outcomes in this population. Specifically, we examined three marijuana-related perceptions (descriptive norms, injunctive norms, and internalization of college marijuana use culture) as potential mediators of the associations between four personality traits (impulsivity, sensation seeking, hopelessness, and anxiety sensitivity) and marijuana-related outcomes (marijuana use, negative marijuana-related consequences). In a large sample of college student marijuana users (n=2129), our path analysis revealed marijuana-related perceptions to significantly mediate the associations between personality and marijuana-related outcomes. Specifically, internalization of college marijuana use culture mediated the effects of both impulsivity and sensation seeking on marijuana-related outcomes. Not only do our findings suggest the importance of distinct types of marijuana-related norms in predicting marijuana involvement, but also the possibility that such normative beliefs could be targeted as part of personality-tailored interventions. PMID- 28889058 TI - The relationship between family-based adverse childhood experiences and substance use behaviors among a diverse sample of college students. AB - INTRODUCTION: Research suggests that college students are an especially vulnerable subset of the population for substance use and misuse. However, despite evidence of the high prevalence of adverse childhood experiences (ACE) among students and the link between family-based ACE and substance use among older adults, this relationship remains understudied in college populations. Moreover, whether ACE represents a shared risk across substance use behaviors and ethnic groups is unknown. METHODS: Data are student responses (n=2953) on the 2015 American College Health Association's National College Health Assessment II (ACHA-NCHA II) administered at one of the largest, most diverse public universities in California. Multivariable logistic and negative binomial regression models tested the association between individual and accumulated ACE and past 30-day alcohol, tobacco, marijuana, and illicit drug use, past 12-month prescription medication misuse and polysubstance use. RESULTS: Between 50% and 75% of students involved in substance use were ACE exposed. There was a significant dose-response relationship between ACE and substance use and polysubstance use. Although accumulated ACE increased risk for substance use, there was considerable ethnic variability in these associations. CONCLUSIONS: The graded effects of ACE for substance use underscore the link between family-based stressors and these behaviors in emergent adult college students. Our findings make a compelling case for investing in health initiatives that prioritize ACE screening and access to trauma-informed care in campus communities. Continued research with college populations is needed to replicate findings and clarify the role of ethnicity and culture in trauma response and help seeking behaviors. PMID- 28889059 TI - Implicit and explicit internalized stigma: Relationship with risky behaviors, psychosocial functioning and healthcare access among people who inject drugs. AB - INTRODUCTION: People who inject drugs (PWID) are stigmatized by society. Over time people may begin to internalize the stigma about their group. This research examines how implicit and explicit internalized stigma among PWID relates to health care and treatment access, psychosocial functioning, and engagement in risky behaviors. METHODS: PWID were recruited from a needle and syringe program (NSP) located in Sydney, Australia. Participants completed a survey examining explicit and implicit internalized stigma, risky behaviors (e.g., sharing injecting equipment, unprotected sex), health care and treatment access (e.g., comfort attending NSPs), and psychosocial functioning (e.g., mental health). Detailed demographic variables were also collected. RESULTS: A total of 115 clients completed the measures. To the degree that participants had internalized the stigma about their group (measured explicitly), they felt less comfortable attending NSPs, had greater severity of dependence, and experienced more depressive symptoms. The implicit measure of internalized stigma was related to treatment engagement and needle sharing, although the direction of these effects was unexpected. CONCLUSIONS: This research highlights the importance of ongoing research into the implications of internalized stigma for PWID. Assessing both explicit and implicit internalized stigma appears to be beneficial as these are related to different health and behavioral outcomes. PMID- 28889060 TI - Why narcissists are at risk for developing Facebook addiction: The need to be admired and the need to belong. AB - Building upon previous research establishing a positive association between grandiose and vulnerable narcissism and problematic social networking use, the present study tests a model that explains how grandiose and vulnerable narcissists might develop Facebook (Fb) addiction symptoms through the need for admiration and the need to belong. A sample of 535 undergraduates (50.08% F; mean age 22.70+/-2.76years) completed measures of grandiose narcissism, vulnerable narcissism, Fb addiction symptoms, and two brief scales measuring the need for admiration and the need to belong. Results from structural equation modelling show that the association between grandiose narcissism and Fb addiction levels was completely mediated by the need for admiration and the need to belong. On the other hand, vulnerable narcissism was not found to be associated either directly or indirectly with Fb addiction levels. The variables in the model accounted for 30% of the variance in Fb addiction levels. The present study represents a step toward a better understanding of the psychological mechanisms underlying the link between grandiose narcissism and problematic Fb use. PMID- 28889061 TI - Depressive symptoms, ruminative thinking, drinking motives, and alcohol outcomes: A multiple mediation model among college students in three countries. AB - BACKGROUND: Recent research suggests that ruminative thinking (specifically problem-focused thoughts) may explain why individuals engage in drinking to cope (DTC) when dealing with depressive symptoms; which in turn leads to increased negative alcohol-related consequences. Cross-cultural studies addressing these phenomena are scarce. OBJECTIVES: The present study cross-culturally tested whether four rumination facets (problem-focused thoughts, counterfactual thinking, repetitive thoughts, and anticipatory thoughts) uniquely mediate the relationships between depressive symptoms and drinking motives/alcohol outcomes in a multicultural sample of college student drinkers (n=1429) from Spain, Argentina, and the U.S. METHOD: Structural equation modeling was conducted to test the models, controlling for sex. Further, we conducted invariance testing to determine whether our models were culturally-specific or culturally-universal. RESULTS: Within both proposed models, no rumination facet uniquely mediated the relationship between depressive symptoms and drinking motives. However, an exploratory model with a second-order latent factor of ruminative thinking did significantly mediate these associations (exception was conformity motives). Further, there were two significant double-mediated associations that suggested that increased depressive symptoms is associated with increased ruminative thinking, which is associated with higher DTC motives, which in turn is associated with higher alcohol consumption and negative alcohol-related consequences. All models were found to be invariant across countries and sex, suggesting that these associations may be relatively universal. CONCLUSIONS: Rumination is relevant to understand the increased vulnerability of college drinkers to exhibit greater alcohol consumption and negative consequences via DTC motives when dealing with depressive symptoms. PMID- 28889063 TI - Controlled and implicit processes in evaluative conditioning on implicit and explicit attitudes toward alcohol and intentions to drink. AB - Since implicit attitudes (i.e. evaluations occurring outside of complete awareness) are highly predictive of alcohol consumption, we tested an evaluative learning procedure based on repeated pairing to a critical stimulus (i.e. alcohol, the CS) with a valenced stimulus (the US) in order to modify implicit attitudes (i.e. evaluative conditioning; EC). We hypothesized that manipulating the learning context to bolster implicit affect misattribution should strengthen EC effects on implicit attitudes toward alcohol, while encouraging deliberate processing of CS-US pairs, should strengthen EC effects on explicit attitudes. In our study (n=114 students) we manipulated whether CS-US pairs were presented simultaneously or sequentially. Recollective memory was estimated with a Process Dissociation Procedure. Both implicit and explicit attitudes were assessed immediately after the procedure. Behavioral intentions were measured directly after and one week after the EC-procedure. We found that EC with sequential presentation had a stronger impact on implicit and explicit measures and on purchase intentions immediately after the procedure and one week after. The present findings provide new evidence that (i) EC is an effective way to change implicit attitudes toward alcohol and (ii) evidence that EC may be better described by propositional rather than dual process accounts. PMID- 28889064 TI - Spiroplasma eriocheiris induces mouse 3T6-Swiss albino cell apoptosis that associated with the infection mechanism. AB - Spiroplasma eriocheiris is a novel pathogen similar to the Spiroplasma mirum and also had an ability to infect the newborn mice and caused cataract. Our study was designed to study how S. eriocheiris infects mouse 3T6-Swiss albino cells and to elucidate the cellular molecular pathogenesis of Spiroplasma. FCM analysis and MTT analysis clearly shown that S. eriocheiris could induce 3T6 cell apoptosis and cause cell viability decreased seriously. Immunofluorescence experiments and TEM analysis shown that S. eriocheiris can invade 3T6 cells and form typical inclusion bodies and exhibit vacuolization in vitro. S. eriocheiris oxytetracycline protection assay show that the infective bacteria already were detected at 1h post infection, and sharply increased at 12h after the bacteria infection. To further study the infection mechanism of S. eriocheiris, global mRNA and microRNA (miRNA) expression profiling were analyzed after the cells infected with the bacteria. A total of 619 non-redundant annotated transcripts (183 up-regulated and 436 down-regulated) and 22 miRNAs (8 up-regulated and 14 down-regulated) were differential expression after 6h S. eriocheiris infection compared to control group. Integrated analysis shown that homologous genes from differential expression miRNA targets and the differential expression genes of the mRNA microarray were major focused on two important pathways focal adhesion and MAPK signaling pathway. To validate the results of microarray, eight focal adhesion (beta-Catenin, Parvin, Grb2 and ERK) and MAPK signaling pathway (FGFR, Grb2, ERK, MKK3, p38 and JNK) genes and the housekeeping gene GAPDH were assayed by qPCR and Western blot to confirm the results. Eight miRNAs (miR-143-3p, miR 214-5p, miR-322-3p, miR-328-5p, miR-351-5p, miR-466h-5p, miR-503-5p and miR-30c-1 3p) and the housekeeping gene U6 miRNA were assayed by qPCR to confirm the results of microarray. All the results help us better understand the infection mechanism of S. eriocheiris. PMID- 28889062 TI - Affective dysregulation predicts incident nonmedical prescription analgesic use among college students. AB - INTRODUCTION: This study investigated the relationship between four suspected risk factors-affective dysregulation, conduct problems, depressive symptoms, and psychological distress-and incident nonmedical prescription analgesic (NPA) use among college students. METHODS: The sample was derived from 929 college students from a large, mid-Atlantic university who completed the third annual College Life Study assessment (Y3) and were NPA use naive at baseline (Y1). A series of logistic regression analyses were conducted to evaluate the predictors of incident NPA use by Y3. Separate models were developed to evaluate the association between the suspected risk factors and (a) NPA use relative to non use of other drugs, including nonmedical use of other drug classes, (b) NPA use relative to other drug use, and (c) other drug use relative to non-use. All models included gender, parental education level, and race/ethnicity. RESULTS: Affective dysregulation was significantly associated with becoming an incident NPA user relative to both drug users without NPA use as well as non-users, after statistically controlling for demographic characteristics and other factors. Conduct problems in early childhood were positively related to both incident NPA use and other drug use without NPA use relative to non-users, after statistically controlling for demographic characteristics and other factors. Depressive symptoms were associated with NPA incidence at the bivariate level only. CONCLUSIONS: These findings extend previous research suggesting that NPA use might be related to deficits in regulating negative emotional states, and highlight possible markers for screening and intervention to prevent NPA use. PMID- 28889065 TI - Profiling dendritic cell subsets in the patients with active pulmonary tuberculosis. AB - Dendritic cell (DC) plays an important role in the immune response against pulmonary tuberculosis. However, the phenotypic profile of DC subsets in peripheral blood in individuals with active pulmonary tuberculosis (APT) is still inconclusive. Here, we demonstrated that the absolute numbers of total DC (tDC), myeloid DC (mDC) and plasmacytoid DC (pDC) in individuals with APT were decreased compared to healthy controls (HCs). The decreased number of DCs, especially of pDC, seems to be a useful diagnostic marker of APT. Meanwhile, the number of DCs was associated with the prolonged/complicated TB, ATD treatment effect and lymphocyte immune reactions, as manifested that relapsed APT patients with a higher number of tDC and lower number of pDC compared to newly diagnosed patients. Interestingly, mDC from APT patients displayed high expressions of CD83 and CCR7, but pDC displayed low expressions of CD83 and CCR7. Moreover, DCs from APT patients expressed lower levels of HLA-DR and CD80, but expressed a higher level of CD86 than those from HCs. However, the antigen uptake capacity of DC subsets was not different between APT and HCs, despite the antigen uptake capacity of pDC was much lower than that of mDC in both APT patients and HCs. Our data represent a systematic profile of DC subsets in the blood of APT patients, and would represent a useful biomarker for APT. PMID- 28889066 TI - Effect of lentivirus-mediated gene silencing, targeting toll-like receptor 2, on corneal allograft transplantation in rats. AB - AIM: The present work aims to assess the effectiveness of lentiviral vector (LV) mediated Toll-like receptor 2 (TLR2) gene silencing in the survival of transplanted corneal allografts, against immune rejection, in rats. METHODS: LV mediated TLR2 small interference RNA (SiRNA) with enhanced green fluorescent protein (eGFP) [LV-TLR2-siRNA-eGFP] was realised and transfected to both rat corneal epithelial (EC) and stromal cells (SC). Multiplicity of infection (MOI) was optimized for transfection efficiency using flow cytometric (FCM) analysis. Viability of transfected cells and the success rate of TLR2 gene silencing were respectively determined by CCK-8 assay and western blot assay. The in-vivo experiments were subjected to a penetrating keratoplasty (PK) performed between host Sprague Dawley (SD) and donor Wistar/SD rats, randomly dividing them into 4 groups including the allograft, isograft, allograft treated with LV-eGFP (LV blank control) and allograft treated with LV-TLR2-siRNA-eGFP (LV treated group). The rejection index (RI) was then recorded under a slit lamp, every day following surgery. Expression of the TLR2 and Myeloid differentiation primary response gene 88 (MyD88) were detected by using immunohistochemistry on day 9 post-surgery, whereas grafts's TLR2 and MyD88 mRNA were determined on day 5, 9, and 14 post surgery performing RT-PCR and, normal rat corneas were included as additional controls. RESULTS: Transfected cells showed the strongest eGFP expression when MOI was 200 with an efficiency of 77.5% for EC and 76.3% for SC. CCK-8 assay, as measured at 72 and 96h post transfection, showed no significant changes in the cell viability (both EC and SC) between the transfected and the control group (p>0.05, p>0.05). Western blot results demonstrated a successful down regulation of TLR2 expression by LV-TLR2-SiRNA-eGFP, in both EC and SC. In vivo, compared to allograft group, LV treated group demonstrated less edema, opacity and neovascularization. Immunohistochemical analysis revealed a lower expression of TLR2 and MyD88 in isograft and LV treated group as compared to allograft group. TLR2 and MyD88 mRNA were detected in all grafts, and increased over time. With its highest expression in allograft group (peak on day 9), the mRNA expression for TLR2 and MyD88 showed a significant difference amongst the groups, on both day 9 and 14 (p<0.001). CONCLUSIONS: LV mediated TLR2 siRNA could effectively down regulate the TLR2 expression via RNA interference and prolong the survival of corneal grafts, although not necessarily able to prevent the rejection. PMID- 28889068 TI - Effect of HPV16 L1 virus-like particles on the aggregation of non-functionalized gold nanoparticles. AB - Colorimetric assays based on gold nanoparticles (GNPs) are of considerable interest for diagnostics because of their simplicity and low-cost. Nevertheless, a deep understanding of the interaction between the GNPs and the intended molecular target is critical for the development of reliable detection technologies. The present report describes the spontaneous interaction between HPV16 L1 virus-like particles (VLPs) and non-functionalized GNPs (nfGNPs) resulting in the inhibition of nfGNPs salt-induced aggregation and the stabilization of purified VLPs. Ionic-competition experiments suggested that the nature of nfGNPs-VLPs interaction is non-covalent. Adsorption of an RNA aptamer on nfGNPs surface showed an additive aggregation-inhibitory effect. The use of mutant VLPs confirmed that the interaction nfGNPs-VLPs is not mediated by the opposing superficial electrostatic charges, suggesting that non-electrostatic forces participate in the arrangement of nfGNPs on the VLPs surface. Competition experiments using increasing ethanol concentrations on nfGNPs-VLPs complexes suggested hydrophobic interactions as the main stabilizing force. Therefore, the nfGNPs-VLPs interaction described here should facilitate the development of adsorption assays based on nfGNPs for HPV detection and cervical cancer prevention. PMID- 28889067 TI - Immune monitoring for precision medicine in allergy and asthma. AB - 'Precision Medicine' embodies the analyses of extensive data collected from patients and their environments to identify and apply patient-specific prophylactic strategies and medical treatments to improve clinical outcomes and healthcare cost-effectiveness. Many new methods have been developed for evaluating the activity of the human immune system. Such 'immune monitoring' approaches are now being used in studies of allergy and asthma in the hope of identifying better correlates of disease status, predictors of therapeutic outcomes, and potential side-effects of treatment. Together with analyses of family histories, genetic and other biometric data, and measurements of exposures to environmental and other risk factors for developing or exacerbating disease, immune monitoring approaches promise to enable 'Precision Medicine' for allergic diseases and asthma. PMID- 28889069 TI - Electrochemical assay for continuous monitoring of dynamic DNA methylation process. AB - A simple electrochemical strategy is reported for continuous monitoring of dynamic DNA methylation process over time. An electrochemical sensor was prepared by co-assembling of DNA probe and 6-mercapto-1-hexanol onto a gold electrode. The top of the DNA probe was labeled with 6-ferrocenylhexanethiol modified gold nanoparticle. The charge density between the C*G base pair was verified to be slightly reduced by DNA methylation, and could be further decelerated by ~ 25% upon co-locating a Br group onto methylated cytosine (mC). Therefore, in the presence of NaIO4/LiBr, the progressively methylated DNA on the sensor showed a clearly decreasing current over methylation time. The dynamic DNA methylation process was indicated continuously from the current decrease ratio, with a limit of detection of 0.0372uM. The strategy is convenient, cost-effective, and enable continuous profiling methylation process without distortion. Besides, the strategy was successfully applied for the studies on inhibitor screening and flanking sequence preference of DNA methyltransferase 3a. The results show that the activity of DNA methyltransferase 3a can be mildly inhibited by epigallocatechin gallate, and varies towards different flanking sequence with an order of 5'-CCGG-3' < 5'-CGCG-3' < 5'-CGCA-3'. PMID- 28889070 TI - Tranexamic acid for refractory gastrointestinal bleeds: A cohort study. PMID- 28889071 TI - Linking implementation of evidence-based parenting programs to outcomes in early intervention. AB - In the field of early intervention, only a few studies of parenting interventions include both participant and facilitator behaviors. Fidelity and supervision (facilitator characteristics) and dosage and satisfaction (participant characteristics) were tested on the outcome of improved parenting style in a sample of 36 parents of young children with disabilities. Results indicated that the facilitator behavior of fidelity was significantly and negatively related to the program outcome of parenting style; no effect was found for the facilitator behavior of supervision. For the participant behaviors, both dosage and satisfaction had non-significant relationships with the program outcome of parenting style at follow-up. The surprising negative relationship between content fidelity and parenting style was discussed.Two possible explanations were: (1) process or quality of intervention delivery is more influential than content fidelity, which considers only adherence to the intervention manual, and (2) the developmental stage of early intervention families calls for more focus on relationships between facilitators and parents and less on content of the specific intervention. PMID- 28889072 TI - The haemocytes of the colonial aplousobranch ascidian Diplosoma listerianum: Structural, cytochemical and functional analyses. AB - Diplosoma listerianum is a colonial aplousobranch ascidian of the family Didemnidae that is native to the northeast Atlantic and exhibits a cosmopolitan distribution in temperate waters. It lacks a shared colonial circulation crossing the tunic, and the zooids are connected only by the common tunic. In the present study, the haemocytes of this ascidian were analysed via light and electron microscopy. Their phagocytic and enzymatic activities, staining and immunostaining properties, and lectin affinity were examined with various classical methods reconsidered and modified for small marine invertebrates. Eight morphotypes were identified in reference to corresponding cell types described in other ascidians: undifferentiated cells (haemoblasts), storage cells for nitrogenous catabolites (nephrocytes) and immunocytes. The immunocytes are involved in immune responses, acting as (1) phagocytes, rich in hydrolases and involved in the clearance of both foreign particles and effete cells (hyaline amoebocytes and macrophage-like cells); (2) cytotoxic cells, able to degranulate and induce cytotoxicity through the release of the enzyme phenoloxidase after an immune stimulus (granular amoebocytes and morula cells); and (3) basophilic cells with an affinity for ConA and NPA that contain heparin and histamine and that show sensitivity to the compound 48/80, promoting their degranulation (mast cell like granulocytes). In addition, a particular cell type showing exceptional development of the Golgi apparatus and large vacuoles containing a filamentous material has been recognised (spherule cell), for which a role in tunic repair and fibrogenesis has been hypothesised. PMID- 28889073 TI - Infant intralimb coordination and torque production: Influence of prematurity. AB - The purpose of this study is to investigate changes in leg joint coordination, intersegmental dynamics, and their relation in infants born preterm (PT) during the first months of life. Kicking actions were analyzed of 11 infants born PT at 6 and 15-weeks corrected age (CA) using three-dimensional kinematics and kinetics; results were compared to the kicking actions of 10 infants born full term (FT). Both groups changed from a predominately in-phase coordination at 6 weeks CA to a less in-phase coordination at 15-weeks CA, however, at 6-weeks CA, infants born PT demonstrated less in-phase coordination of their ankle joints with their hip and knee joints. Between groups and across ages, both groups demonstrated consistent net and partitioned joint torque profiles, however, at 6 weeks CA infants born PT demonstrated more complex patterns of torque components. In both groups, less in-phase hip-knee coordination was associated with reduced active knee muscle torque and increased passive knee torques, however, passive knee torques had a greater influence on the kicks of infants born PT at 6-weeks CA. At 6-weeks CA, infants born PT, compared to FT, generated kicks with less in phase hip-knee coordination, hip excursion, hip angular velocity, and hip muscle torque impulse. By 15-weeks CA, differences resolved in all variables except hip muscle torque impulse. These results highlight a different trajectory of leg joint coordination and torque production for infants born PT compared to FT. PMID- 28889074 TI - Interaction between FKBP5 gene and childhood trauma on psychosis, depression and anxiety symptoms in a non-clinical sample. AB - BACKGROUND: Childhood trauma has been associated with a heightened risk for presenting clinical and non-clinical psychopathology in adulthood. Genes related with the stress response, such as the FK506 binding protein 51 (FKBP5), are plausible candidates moderating the effects of childhood trauma on the emergence of such symptoms later on. The present study aimed to explore the moderating role of FKBP5 genetic variability on the association of different types of childhood trauma with subclinical psychosis, depression and anxiety in a non-clinical sample. METHODS: Schizotypy, psychotic-like experiences, depression and anxiety symptoms and childhood trauma were assessed in 808 young adults. Two FKBP5 haplotypic blocks were detected: block 1 (rs3800373 - rs9296158 - rs1360780) and block 2 (rs9470080 - rs4713916). Subjects were classified in two groups according to whether they carried or not the risk haplotype previously described in the literature (block 1: CAT and block 2: TA). Linear regression analyses were used to study (i) the main effects of childhood trauma and FKBP5 haplotype blocks and (ii) their interaction effects on the mentioned forms of psychopathology. RESULTS: All childhood trauma scales, except sexual abuse, were associated with schizotypy, psychotic-like experiences, depression and anxiety symptoms. None of the analysed symptoms was associated with the main effects of FKBP5 genetic variability. However an interaction effect between block 1 and physical abuse was observed on anxiety, with lower scores in CAT carriers. This effect was driven by SNP 1 and 2. Moreover, an interaction effect between block 2 and physical abuse was identified on the variables tapping depressive and anxiety symptoms. Specifically, non-TA carrier subjects who were exposed to physical abuse were found to be at higher risk for depressive and anxiety symptoms. These effects were driven by SNP 5. No interaction effect was observed for the other variables. CONCLUSIONS: Our data suggest that exposure to childhood physical abuse may increase the risk for sub-clinical depressive and anxiety symptoms depending on FKBP5 genetic variability. Further research is needed to better elucidate the role of FKBP5 on mental health in clinical and non-clinical cohorts. PMID- 28889075 TI - Epigenetic clock analysis in long-term meditators. AB - In this paper, we examined whether meditation practice influences the epigenetic clock, a strong and reproducible biomarker of biological aging, which is accelerated by cumulative lifetime stress and with age-related chronic diseases. Using the Illumina 450K array platform, we analyzed the DNA methylome from blood cells of long-term meditators and meditation-naive controls to estimate their Intrinsic Epigenetic Age Acceleration (IEAA), using Horvath's calculator. IEAA was similar in both groups. However, controls showed a different IEAA trajectory with aging than meditators: older controls (age>=52) had significantly higher IEAAs compared with younger controls (age <52), while meditators were protected from this epigenetic aging effect. Notably, in the meditation group, we found a significant negative correlation between IEAA and the number of years of regular meditation practice. From our results, we hypothesize that the cumulative effects of a regular meditation practice may, in the long-term, help to slow the epigenetic clock and could represent a useful preventive strategy for age-related chronic diseases. Longitudinal randomized controlled trials in larger cohorts are warranted to confirm and further characterize these findings. PMID- 28889076 TI - geneSurv: An interactive web-based tool for survival analysis in genomics research. AB - Survival analysis methods are often used in cancer studies. It has been shown that the combination of clinical data with genomics increases the predictive performance of survival analysis methods. But, this leads to a high-dimensional data problem. Fortunately, new methods have been developed in the last decade to overcome this problem. However, there is a strong need for easily accessible, user-friendly and interactive tool to perform survival analysis in the presence of genomics data. We developed an open-source and freely available web-based tool for survival analysis methods that can deal with high-dimensional data. This tool includes classical methods, such as Kaplan-Meier, Cox proportional hazards regression, and advanced methods, such as penalized Cox regression and Random Survival Forests. It also offers an optimal cutoff determination method based on maximizing several test statistics. The tool has a simple and interactive interface, and it can handle high dimensional data through feature selection and ensemble methods. To dichotomize gene expressions, geneSurv can identify optimal cutoff points. Users can upload their microarray, RNA-Seq, chip-Seq, proteomics, metabolomics or clinical data as a nxp dimensional data matrix, where n refers to samples and p refers to genes. This tool is available free at www.biosoft.hacettepe.edu.tr/geneSurv. All source code is available at https://github.com/selcukorkmaz/geneSurv under the GPL-3 license. PMID- 28889077 TI - A method for quantifying recurrent patterns of local wavefront direction during atrial fibrillation. AB - INTRODUCTION: Spiral wave reentry is a potential mechanism of atrial fibrillation (AF), but is difficult to differentiate clinically from multiple wavelet breakup using standard bipolar recordings. We developed a new methodology using bipolar recordings to estimate the direction of local activation wavefronts during AF by calculating the electrogram conformation (Egm-C). We subsequently used recurrence quantification analysis (RQA) of Egm-C to differentiate regions of spiral wave reentry from wavelet breakup. METHODS: A 2D computer simulation was created with regions containing a stable spiral wave and also regions of wavebreak. A grid of 40 * 40 unipolar electrodes was superimposed. At each site, the actual wavefront direction (WD) was determined by comparing relative activation timings of the local intracellular recordings, and the estimated wavefront direction (Egm-C) was determined from the morphology of the local bipolar electrogram. RQA of Egm-C was compared to RQA of actual WD in order to differentiate AF mechanisms. RESULTS: RQA of actual WD and Egm-C both distinguished regions of spiral wave reentry from wavelet breakup with high correlation between the two methods (recurrence rate, r = 0.96; determinism, r = 0.61; line max, r = 0.95; entropy, r = 0.84; p < 0.001 for all). In areas of stable spiral wave reentry, the recurrence plots of both Egm-C and actual WD demonstrated stable, periodic dynamics, while regions of wavelet breakup demonstrated chaotic behavior largely devoid of repetitive activation patterns. CONCLUSION: Calculation of Egm-C allows RQA to be performed on bipolar electrograms during AF and differentiates regions of spiral wave reentry from multiple wavelet breakup. PMID- 28889078 TI - Genetic susceptibility to breast cancer risk associated with inorganic arsenic exposure. AB - OBJECTIVE: To evaluate whether the association between breast cancer (BC) and inorganic arsenic (iAs) exposure is modulated by selected polymorphisms in iAs metabolism. METHODS: A population based case-control (1016/1028) study was conducted in Northern Mexico. Urinary arsenic metabolites were measured by High Performance Liquid Chromatography. Metabolites percentages and methylation ratios, were estimated. Genotypes of selected polymorphisms were determined by allelic discrimination. The interaction between polymorphisms and iAs metabolites percentages and methylation ratios on BC was assessed with unconditional logistic regression models. RESULTS: A significant interaction (p=0.002) between MTR c.2756A>G polymorphism and percentage dimethylarsinic acid (DMA) on BC was found; BC risk related with %DMA was lower in AG+GG carriers than in AA carriers. No other significant interactions were found. CONCLUSION: MTR c.2756A>G polymorphism may confer protection for BC associated with iAs exposure. Further research is warranted to elucidate the potential involvement of other polymorphisms in iAs related BC. PMID- 28889079 TI - Lead induces apoptosis in mouse TM3 Leydig cells through the Fas/FasL death receptor pathway. AB - The study was aimed to investigate the effect of Pb toxicity on mouse Leydig cells and its molecular mechanism. The TM3 cells were cultured in vitro and exposed to Pb at different concentrations for 24h. The effects of Pb on cell proliferation and apoptosis were analyzed with MTT and Annexin V-FITC/PI via flow cytometry, respectively. Expression levels of Fas, Fas-L and caspase-8 in TM3 cells were determined by western blot. As well as the inhibitory effect of the caspase-8 inhibitor Z-IETD-FMK on cell apoptosis. We found that Pb treatment significantly decreased the cellar viability (P<0.05), increased the apoptosis (P<0.01) and the Fas, FasL, and caspase-8 expression levels in Pb-treated cells as compared to the control cells (P<0.05 or P<0.01). Furthermore, the caspase-8 inhibitor effectively block the Pb-induced cell apoptosis. Taken together, our data suggest that Pb-induced TM3 cell toxic effect may involve in the Fas/FasL death receptor signaling pathway. PMID- 28889080 TI - Reprogramming of rabbit induced pluripotent stem cells toward epiblast and chimeric competency using Kruppel-like factors. AB - Rabbit induced pluripotent stem cells (rbiPSCs) possess the characteristic features of primed pluripotency as defined in rodents and primates. In the present study, we reprogrammed rbiPSCs using human Kruppel-like factors (KLFs) 2 and 4 and cultured them in a medium supplemented with fetal calf serum and leukemia inhibitory factor. These cells (designated rbEKA) were propagated by enzymatic dissociation for at least 30 passages, during which they maintained a normal karyotype. This new culturing protocol resulted in transcriptional and epigenetic reconfiguration, as substantiated by the expression of transcription factors and the presence of histone modifications associated with naive pluripotency. Furthermore, microarray analysis of rbiPSCs, rbEKA cells, rabbit ICM cells, and rabbit epiblast showed that the global gene expression profile of the reprogrammed rbiPSCs was more similar to that of rabbit ICM and epiblast cells. Injection of rbEKA cells into 8-cell stage rabbit embryos resulted in extensive colonization of ICM in 9% early-blastocysts (E3.5), epiblast in 10% mid blastocysts (E4.5), and embryonic disk in 1.4% pre-gastrulae (E6). Thus, these results indicate that KLF2 and KLF4 triggered the conversion of rbiPSCs into epiblast-like, embryo colonization-competent PSCs. Our results highlight some of the requirements to achieve bona fide chimeric competency. PMID- 28889081 TI - Distinct solubility and cytotoxicity regimes of paclitaxel-loaded cationic liposomes at low and high drug content revealed by kinetic phase behavior and cancer cell viability studies. AB - Lipid-based particles are used worldwide in clinical trials as carriers of hydrophobic paclitaxel (PTXL) for cancer chemotherapy, albeit with little improvement over the standard-of-care. Improving efficacy requires an understanding of intramembrane interactions between PTXL and lipids to enhance PTXL solubilization and suppress PTXL phase separation into crystals. We studied the solubility of PTXL in cationic liposomes (CLs) composed of positively charged 2,3-dioleyloxypropyltrimethylammonium chloride (DOTAP) and neutral 1,2-dioleoyl sn-glycero-3-phosphatidylcholine (DOPC) as a function of PTXL membrane content and its relation to efficacy. Time-dependent kinetic phase diagrams were generated from observations of PTXL crystal formation by differential interference-contrast microscopy. Furthermore, a new synchrotron small-angle x ray scattering in situ methodology applied to DOTAP/DOPC/PTXL membranes condensed with DNA enabled us to detect the incorporation and time-dependent depletion of PTXL from membranes by measurements of variations in the membrane interlayer and DNA interaxial spacings. Our results revealed three regimes with distinct time scales for PTXL membrane solubility: hours for >3 mol% PTXL (low), days for ~ 3 mol% PTXL (moderate), and >=20 days for < 3 mol% PTXL (long-term). Cell viability experiments on human cancer cell lines using CLPTXL nanoparticles (NPs) in the distinct CLPTXL solubility regimes reveal an unexpected dependence of efficacy on PTXL content in NPs. Remarkably, formulations with lower PTXL content and thus higher stability show higher efficacy than those formulated at the membrane solubility limit of ~3 mol% PTXL (which has been the focus of most previous physicochemical studies and clinical trials of PTXL-loaded CLs). Furthermore, an additional high-efficacy regime is seen on occasion for liposome compositions with PTXL >=9 mol% applied to cells at short time scales (hours) after formation. At longer time scales (days), CLPTXL NPs with >=3 mol% PTXL lose efficacy while formulations with 1-2 mol% PTXL maintain high efficacy. Our findings underscore the importance of understanding the relationship of the kinetic phase behavior and physicochemical properties of CLPTXL NPs to efficacy. PMID- 28889082 TI - Comparison of three multiplex gastrointestinal platforms for the detection of gastroenteritis viruses. AB - BACKGROUND: Viruses are major etiological agents of childhood gastroenteritis. In recent years, several molecular platforms for the detection of viral enteric pathogens have become available. OBJECTIVE/STUDY DESIGN: We evaluated the performance of three multiplex platforms including Biofire's Gastrointestinal Panel (FilmArray), Luminex xTAG(r) Gastrointestinal Pathogen Panel (GPP), and the TaqMan Array Card (TAC) for the detection of five gastroenteritis viruses using a coded panel of 300 archived stool samples. RESULTS: The FilmArray detected a virus in 199 (96.1%) and the TAC in 172 (83.1%) of the 207 samples (187 samples positive for a single virus and 20 samples positive for more than one virus) whereas the GPP detected a virus in 100 (78.7%) of the 127 (97 positive for one virus and three positive for more than one virus) samples. Overall the clinical accuracy was highest for the FilmArray (98%) followed by TAC (97.2%) and GPP (96.9%). The sensitivity of the FilmArray, GPP and TAC platforms was highest for rotavirus (100%, 95.8%, and 89.6%, respectively) and lowest for adenovirus type 40/41 (97.4%, 57.9% and 68.4%). The specificity of the three platforms ranged from 95.6% (rotavirus) to 99.6% (norovirus/sapovirus) for the FilmArray, 99.6% (norovirus) to 100% (rotavirus/adenovirus) for GPP, and 98.9% (astrovirus) to 100% (rotavirus/sapovirus) for TAC. CONCLUSION: The FilmArray demonstrated the best analytical performance followed by TAC. In recent years, the availability of multi-enteric molecular testing platforms has increased significantly and our data highlight the strengths and weaknesses of these platforms. PMID- 28889083 TI - Live versus attenuated influenza vaccine uptake and post-vaccination influenza like illness outcomes in HIV-infected US Air Force members. AB - BACKGROUND: Although clinical data is limited, guidelines recommend avoiding live attenuated intranasal influenza vaccine (LAIV) in HIV-infected persons. OBJECTIVES: To evaluate non-guideline LAIV use and resulting adverse effects in an HIV-infected population. STUDY DESIGN: A retrospective analysis of influenza vaccination in US Air Force (USAF) members with HIV infection immunized between 2005 and 2015 was performed. Influenza vaccination history after HIV diagnosis was evaluated, including receipt of LAIV or inactivated influenza vaccine (IIV). The proportion with influenza-like illness (ILI) diagnoses within 30days after vaccination with IIV or LAIV was assessed by ICD-9 codes. RESULTS: 437 patients met inclusion criteria, with 121 (27.7%) receiving at least one dose of LAIV and 316 (72.3%) receiving only IIV during follow-up. The mean number of LAIV doses received was 1.5+/-0.89 (range, 1-4) and the majority (n=50, 82%) received their first LAIV vaccination within the first year after HIV diagnosis. Patients were predominantly males and the LAIV group had a lower mean age at HIV diagnosis (27.5+/-6.6) compared to the IIV group (30+/-7.8; p <0.001). Overall, IIV was associated with ILI diagnosis within 30days of vaccination (X2 4.58; p=0.032), with 16 cases (94.1%) occurring in those who received IIV compared to 1 case (5.9%) in those who received LAIV. CONCLUSION: Although over a quarter of USAF members received LAIV after HIV diagnosis, LAIV administration did not show an increased frequency of post-vaccine ILI diagnoses. Further education is needed to ensure that USAF members with HIV infection are vaccinated according to guideline recommendations, particularly newly diagnosed patients. PMID- 28889084 TI - A menu of electron probes for optimising information from scanning transmission electron microscopy. AB - We assess a selection of electron probes in terms of the spatial resolution with which information can be derived about the structure of a specimen, as opposed to the nominal image resolution. Using Ge [001] as a study case, we investigate the scattering dynamics of these probes and determine their relative merits in terms of two qualitative criteria: interaction volume and interpretability. This analysis provides a 'menu of probes' from which an optimum probe for tackling a given materials science question can be selected. Hollow cone, vortex and spherical wave fronts are considered, from unit cell to Angstrom size, and for different defocus and specimen orientations. PMID- 28889085 TI - Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter? AB - Immunotherapy has dramatically changed the therapeutic scenario in non-small cell lung cancer (NSCLC), extending overall survival, with a favorable safety profile. However, there is still a gap of knowledge about the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. Data from randomized clinical trials testing ICIs are conflicting and often lack adequate statistical power. Although two large meta-analyses suggested an absence of a significant survival benefit in patients older than 75years, expanded access programs and retrospective cohort studies of ICIs in the real-life setting, showed comparable survival outcomes and safety profiles between older and younger patients. In this complex scenario, a further unresolved issue is the potential correlation between older age and immunotherapy primary resistance, a phenomenon probably linked to the continuous and progressive remodeling of immune functions with ageing, known as immunosenescence. Defining the role of ICIs in elderly NSCLC patients and exploring the molecular mechanisms underlying a possible lack of benefit or even accelerated tumor growth during immunotherapy are two major challenges for future research in this field of cancer treatment. In this review, we describe the major hallmarks of immunosenescence and we summarize the existing clinical data of ICIs in elderly NSCLC patients. PMID- 28889086 TI - The Notch-3 receptor: A molecular switch to tumorigenesis? AB - The Notch pathway is a highly conserved pathway increasingly implicated with the progression of human cancers. Of the four existing receptors associated with the pathway, the deregulation in the expression of the Notch-3 receptor is associated with more aggressive disease and poor prognosis. Selective targeting of this receptor has the potential to enhance current anti-cancer treatments. Molecular profiling strategies are increasingly incorporated into clinical decision making. This review aims to evaluate the clinical potential of Notch-3 within this new era of personalised medicine. PMID- 28889087 TI - Self-expanding transcatheter aortic valve implantation for degenerated small Mitroflow bioprosthesis: early and midterm outcomes. AB - AIMS: The aim of this study was to report clinical outcomes of self-expanding transcatheter aortic valve implantation (TAVI) for failed small Mitroflow (MF) bioprostheses. METHODS AND RESULTS: Between January 2013 and July 2016, 15 symptomatic patients (NYHA Class >=III) with degenerated small MF (<=23 mm) underwent CoreValve (CV) or Evolut R (EvR) implantation due to high/prohibitive risk for surgical redo. The MF size was 19 or 21 mm (off-label in Europe) in eight patients. A "preventive" left main (LM) stenting was successfully performed in one patient. Early LM obstruction occurred in two cases requiring stenting. Late LM obstruction was observed in one subject. A significant correlation between virtual left transcatheter valve-to-coronary ostia (VTC) distance and left sinus of Valsalva (LSV) diameter was observed (R=0.652; p=0.012). However, only left VTC was significantly smaller in patients who experienced LM obstruction compared to those who did not (p=0.002). No cases of moderate/severe stenosis were observed in either on- or off-label procedures. No death or other major events occurred up to the one-year follow-up. CONCLUSIONS: CV or EvR implantation for failed small MF has favourable early and midterm outcomes if a careful risk evaluation and preventive measures for coronary obstruction are adopted. Low gradients can be achieved regardless of MF size. PMID- 28889088 TI - Participation in randomised controlled trials: perspectives of psychiatric patients and key relatives. AB - This study assessed the perspectives of adults who had acute nonorganic psychiatric disorders and were admitted in a private, not for- profit medical college hospital, and also of their key relatives, on randomised controlled trials (RCTs). Structured questionnaires and audio-recorded interviews were used for the purpose. We explored their willingness and motivation to participate in two hypothetical RCTs with different risks and burdens. The transcripts of the interviews were analysed using the principles of grounded theory and framework analysis. Of the 24 consenting participants (12 patient and key-relative dyads), the 20 who completed the interviews had largely positive attitudes towards research and RCTs. However, 50% of those interviewed declined to participate in either of the hypothetical RCTs. The refusal to participate seemed to be influenced by a lack of education; forgetfulness, which impeded the process of making informed decisions; unfavourable benefit-risk-burden ratios; practical difficulties; dependence on treating doctors and relatives for decision-making; and the wish to exercise one's choice regarding treatment options. The factors that motivated the patients and relatives were trust in doctors and organisations, altruism, expectation of personal benefits and favourable risk benefit ratios. These observations indicate that while the respondents in this study valued research, they were discerning about whether or not to participate in the trials; their decision-making was influenced by individualised assessments of risks and burdens and pragmatic considerations, rather than only by the benefits they would obtain. PMID- 28889089 TI - On the integration of Ethics into the Physiology curriculum. AB - A one-day state-level workshop was organised in Karnataka to share the experience of a programme implemented earlier, in 2015-16, at St John's Medical College, Bengaluru that integrated the teaching of ethics into the physiology curriculum. The aim was to develop the programme further, list the challenges likely to be faced while scaling it up, and identify other colleges which could participate in the scaling up. Twenty-eight participants, representing 13 medical colleges, and five resource persons attended the workshop. There was a consensus that the integration of ethics into the physiology course was relevant and desirable, although the participants identified several critical challenges which might arise. These included the lack of institutional support, a possible lack of student "buy-in" since it was beyond the requirements of the examinations, and time constraints. Specific areas of integration were identified. Three medical colleges, including the host institution, opted to implement the programme and refine it further. PMID- 28889090 TI - Placing the "radar" under the radar: ethics of public health surveillance. AB - Public health surveillance (PHS) is an essential public health activity, which entails collecting data on diseases and disease-related states in a timely manner to aid in international health regulations and in local health planning. Opinions differ sharply on whether it is a research or non-research activity. In recent years, most low- and middle-income countries (LMICs) have been establishing their own PHS systems, with or without support from external donors, to comply with the stipulations of international health regulations. With the expansion of the scope and role of PHS in ensuring the health security of countries, it is important to understand the ethical principles of PHS and the specific ethical issues involved in it, as well as the need for ethical oversight of PHS. This paper deals with these aspects of PHS, and highlights the need for specific ethical guidance and oversight mechanisms in LMICs that are setting up their own PHS systems. PMID- 28889091 TI - MRI in sarcoglycanopathies: a large international cohort study. AB - OBJECTIVES: To characterise the pattern and spectrum of involvement on muscle MRI in a large cohort of patients with sarcoglycanopathies, which are limb-girdle muscular dystrophies (LGMD2C-2F) caused by mutations in one of the four genes coding for muscle sarcoglycans. METHODS: Lower limb MRI scans of patients with LGMD2C-2F, ranging from severe childhood variants to milder adult-onset forms, were collected in 17 neuromuscular referral centres in Europe and USA. Muscle involvement was evaluated semiquantitatively on T1-weighted images according to a visual score, and the global pattern was assessed as well. RESULTS: Scans from 69 patients were examined (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F). A common pattern of involvement was found in all the analysed scans irrespective of the mutated gene. The most and earliest affected muscles were the thigh adductors, glutei and posterior thigh groups, while lower leg muscles were relatively spared even in advanced disease. A proximodistal gradient of involvement of vasti muscles was a consistent finding in these patients, including the most severe ones. CONCLUSIONS: Muscle involvement on MRI is consistent in patients with LGMD2C-F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time. PMID- 28889092 TI - Quantitative MR spectroscopic imaging in metachromatic leukodystrophy: value for prognosis and treatment. AB - OBJECTIVE: To determine whether proton magnetic resonance spectroscopic imaging is useful in predicting clinical course of patients with metachromatic leukodystrophy (MLD), an inherited white matter disorder treatable with haematopoietic cell transplantation (HCT). METHODS: 21 patients with juvenile or adult MLD (12 HCT-treated) were compared with 16 controls in the same age range. Clinical outcome was determined as good, moderate or poor. Metabolites were quantified in white matter, and significance of metabolite concentrations at baseline for outcome prediction was assessed using logistic regression analysis. Evolution of metabolic changes was assessed for patients with follow-up examinations. RESULTS: In this retrospective study, 16 patients with baseline scans were included, 5 with good, 3 with moderate and 8 with poor outcome, and 16 controls. We observed significant group differences for all metabolite concentrations in white matter (p<0.001). Compared with controls, patients had decreased N-acetylaspartate and glutamate, and increased myo-inositol and lactate, most pronounced in patients with poor outcome (post hoc, all p<0.05). Logistic regression showed complete separation of data. Creatine could distinguish poor from moderate and good outcome, the sum of glutamate and glutamine could distinguish good from moderate and poor outcome, and N acetylaspartate could distinguish all outcome groups. For 13 patients (8 with baseline scans), one or more follow-up examinations were evaluated, revealing stabilisation or even partial normalisation of metabolites in patients with moderate and good outcome, clearly visible in the ratio of choline/N acetylaspartate. CONCLUSION: In MLD, quantitative spectroscopic imaging at baseline is predictive for outcome and aids in determining eligibility for HCT. PMID- 28889093 TI - Striatal molecular alterations in HD gene carriers: a systematic review and meta analysis of PET studies. AB - BACKGROUND: Over the past years, positron emission tomography (PET) imaging studies have investigated striatal molecular changes in premanifest and manifest Huntington's disease (HD) gene expansion carriers (HDGECs), but they have yielded inconsistent results. OBJECTIVE: To systematically examine the evidence of striatal molecular alterations in manifest and premanifest HDGECs as measured by PET imaging studies. METHODS: MEDLINE, ISI Web of Science, Cochrane Library and Scopus databases were searched for articles published until 7 June 2017 that included PET studies in manifest and premanifest HDGECs. Meta-analyses were conducted with random effect models, and heterogeneity was addressed with I2 index, controlling for publication bias and quality of study. The primary outcome was the standardised mean difference (SMD) of PET uptakes in the whole striatum, caudate and putamen in manifest and premanifest HDGECs compared with healthy controls (HCs). RESULTS: Twenty-four out of 63 PET studies in premanifest (n=158) and manifest (n=191) HDGECs and HCs (n=333) were included in the meta-analysis. Premanifest and manifest HDGECs showed significant decreases in dopamine D2 receptors in caudate (SMD=-1.233, 95% CI -1.753 to -0.713, p<0.0001; SMD=-5.792, 95% CI -7.695 to -3.890, p<0.0001) and putamen (SMD=-1.479, 95% CI -1.965 to 0.992, p<0.0001; SMD=-5.053, 95% CI -6.558 to -3.549, p<0.0001), in glucose metabolism in caudate (SMD=-0.758, 95% CI -1.139 to -0.376, p<0.0001; SMD=-3.738, 95% CI -4.880 to -2.597, p<0.0001) and putamen (SMD=-2.462, 95% CI -4.208 to 0.717, p=0.006; SMD=-1.650, 95% CI -2.842 to -0.458, p<0.001) and in striatal PDE10A binding (SMD=-1.663, 95% CI -2.603 to -0.723, p=0.001; SMD=-2.445, 95% CI 3.371 to -1.519, p<0.001). CONCLUSIONS: PET imaging has the potential to detect striatal molecular changes even at the early premanifest stage of HD, which are relevant to the neuropathological mechanisms underlying the development of the disease. PMID- 28889094 TI - Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation. AB - : Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. OBJECTIVES: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases. METHODS: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes. RESULTS: We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4. CONCLUSION: Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease. PMID- 28889095 TI - Ethnography: challenges and opportunities. PMID- 28889096 TI - Resources page. PMID- 28889097 TI - Healthcare professionals should be mindful that victims and victim-bullies may have additional health needs associated with risk-taking behaviour. PMID- 28889098 TI - Reversal of Arterial Stiffness and Maladaptative Arterial Remodeling After Kidney Transplantation. AB - BACKGROUND: Chronic kidney disease is characterized by stiffening, thinning, dilatation, and increased circumferential wall stress of large arteries, associated with increased cardiovascular risk. Kidney transplantation (KT) reverses many pathological features of chronic kidney disease and improves life expectancy; however, longitudinal studies exploring the impact of KT on recipient large arteries are scarce. METHODS AND RESULTS: This study was designed to appraise arterial changes following KT. Carotid-femoral pulse wave velocity, carotid remodeling (circumferential wall stress and carotid internal diameter), and stiffness were measured in 161 consecutive recipients receiving either a living (n=49) or a deceased (n=112) donor allograft, at 3 and 12 months after transplantation. Mean pulse wave velocity decreased from 10.8 m/s (95% confidence interval, 10.5-11.2 m/s) (at month 3) to 10.1 m/s (95% confidence interval, 9.8 10.5 m/s) (at month 12) (P<0.001). After multivariate adjustment, pulse wave velocity reduction from month 3 to month 12 was significantly larger in the living donor allograft KT (P<0.001). Circumferential wall stress decreased, 70 kPa (95% confidence interval, 68-72 kPa) to 64 kPa (95% confidence interval, 62 67 kPa), as well as carotid internal diameter and carotid stiffness (P<0.001 for all). Reductions in circumferential wall stress, diameter, and stiffness were significantly larger in the living donor allograft KT (P<0.001). When deceased donor allograft patients were classified into standard and expanded criteria donors, changes in both pulse wave velocity and circumferential wall stress were blunted in expanded criteria donors. Changes were independent of graft function and blood pressure changes. CONCLUSIONS: Large-artery stiffness and maladaptive carotid artery remodeling of chronic kidney disease is partially reversed within 12 months of KT and appears unrelated to renal function. Improvements were independently associated with live organ donation. Our data suggest that expanded criteria donors may hamper vascular recovery. PMID- 28889099 TI - The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery. AB - BACKGROUND: Heterozygous loss of function mutations in the KCNK3 gene cause hereditary pulmonary arterial hypertension (PAH). KCNK3 encodes an acid-sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells. KCNK3 is widely expressed in the body, and dimerizes with other KCNK3 subunits, or the closely related, acid-sensitive KCNK9 channel. METHODS AND RESULTS: We engineered homomeric and heterodimeric mutant and nonmutant KCNK3 channels associated with PAH. Using whole-cell patch-clamp electrophysiology in human pulmonary artery smooth muscle and COS7 cell lines, we determined that homomeric and heterodimeric mutant channels in heterozygous KCNK3 conditions lead to mutation-specific severity of channel dysfunction. Both wildtype and mutant KCNK3 channels were activated by ONO-RS-082 (10 MUmol/L), causing cell hyperpolarization. We observed robust gene expression of KCNK3 in healthy and familial PAH patient lungs, but no quantifiable expression of KCNK9, and demonstrated in functional studies that KCNK9 minimizes the impact of select KCNK3 mutations when the 2 channel subunits co-assemble. CONCLUSIONS: Heterozygous KCNK3 mutations in PAH lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant KCNK3 channels represent novel therapeutic substrates in PAH. Pharmacological and pH-dependent activation of wildtype and mutant KCNK3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co-assembly of KCNK3 with KCNK9 subunits may provide protection against KCNK3 loss of function in tissues where both KCNK9 and KCNK3 are expressed, contributing to the lung-specific phenotype observed clinically in patients with PAH because of KCNK3 mutations. PMID- 28889100 TI - Role of Admission Troponin-T and Serial Troponin-T Testing in Predicting Outcomes in Severe Sepsis and Septic Shock. AB - BACKGROUND: Troponin-T elevation is seen commonly in sepsis and septic shock patients admitted to the intensive care unit. We sought to evaluate the role of admission and serial troponin-T testing in the prognostication of these patients. METHODS AND RESULTS: This was a retrospective cohort study from 2007 to 2014 on patients admitted to the intensive care units at the Mayo Clinic with severe sepsis and septic shock. Elevated admission troponin-T and significant delta troponin-T were defined as >=0.01 ng/mL and >=0.03 ng/mL in 3 hours, respectively. The primary outcome was in-hospital mortality. Secondary outcomes included 1-year mortality and lengths of stay. During this 8-year period, 944 patients met the inclusion criteria with 845 (90%) having an admission troponin-T >=0.01 ng/mL. Serial troponin-T values were available in 732 (78%) patients. Elevated admission troponin-T was associated with older age, higher baseline comorbidity, and severity of illness, whereas significant delta troponin-T was associated with higher severity of illness. Admission log10 troponin-T was associated with unadjusted in-hospital (odds ratio 1.6; P=0.003) and 1-year mortality (odds ratio 1.3; P=0.04), but did not correlate with length of stay. Elevated delta troponin-T and log10 delta troponin-T were not significantly associated with any of the primary or secondary outcomes. Admission log10 troponin-T remained an independent predictor of in-hospital mortality (odds ratio 1.4; P=0.04) and 1-year survival (hazard ratio 1.3; P=0.008). CONCLUSIONS: In patients with sepsis and septic shock, elevated admission troponin-T was associated with higher short- and long-term mortality. Routine serial troponin-T testing did not add incremental prognostic value in these patients. PMID- 28889102 TI - Caenorhabditis elegans HIF-1 Is Broadly Required for Survival in Hydrogen Sulfide. AB - Hydrogen sulfide is common in the environment, and is also endogenously produced by animal cells. Although hydrogen sulfide is often toxic, exposure to low levels of hydrogen sulfide improves outcomes in a variety of mammalian models of ischemia-reperfusion injury. In Caenorhabditis elegans, the initial transcriptional response to hydrogen sulfide depends on the hif-1 transcription factor, and hif-1 mutant animals die when exposed to hydrogen sulfide. In this study, we use rescue experiments to identify tissues in which hif-1 is required to survive exposure to hydrogen sulfide. We find that expression of hif-1 from the unc-14 promoter is sufficient to survive hydrogen sulfide. Although unc-14 is generally considered to be a pan-neuronal promoter, we show that it is active in many nonneuronal cells as well. Using other promoters, we show that pan-neuronal expression of hif-1 is not sufficient to survive exposure to hydrogen sulfide. Our data suggest that hif-1 is required in many different tissues to direct the essential response to hydrogen sulfide. PMID- 28889101 TI - Relationship of Sleep Duration With All-Cause Mortality and Cardiovascular Events: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies. AB - BACKGROUND: Effects of extreme sleep duration on risk of mortality and cardiovascular outcomes remain controversial. We aimed to quantify the dose response relationships of sleep duration with risk of all-cause mortality, total cardiovascular disease, coronary heart disease, and stroke. METHODS AND RESULTS: PubMed and Embase were systematically searched for prospective cohort studies published before December 1, 2016, that examined the associations between sleep duration and at least 1 of the 4 outcomes in generally healthy populations. U shaped associations were indicated between sleep duration and risk of all outcomes, with the lowest risk observed for ~7-hour sleep duration per day, which was varied little by sex. For all-cause mortality, when sleep duration was <7 hours per day, the pooled relative risk (RR) was 1.06 (95% CI, 1.04-1.07) per 1 hour reduction; when sleep duration was >7 hours per day, the pooled RR was 1.13 (95% CI, 1.11-1.15) per 1-hour increment. For total cardiovascular disease, the pooled RR was 1.06 (95% CI, 1.03-1.08) per 1-hour reduction and 1.12 (95% CI, 1.08-1.16) per 1-hour increment of sleep duration. For coronary heart disease, the pooled RR was 1.07 (95% CI, 1.03-1.12) per 1-hour reduction and 1.05 (95% CI, 1.00-1.10) per 1-hour increment of sleep duration. For stroke, the pooled RR was 1.05 (95% CI, 1.01-1.09) per 1-hour reduction and 1.18 (95% CI, 1.14-1.21) per 1 hour increment of sleep duration. CONCLUSIONS: Our findings indicate that both short and long sleep duration is associated with an increased risk of all-cause mortality and cardiovascular events. PMID- 28889103 TI - A New Diagnostic Resource for Ceratitis capitata Strain Identification Based on QTL Mapping. AB - The Mediterranean fruit fly Ceratitis capitata (Wiedemann) is a destructive agricultural pest and the subject of exclusion efforts in many countries. Suppression and eradication of invasive populations to prevent its establishment is facilitated by the release of sterile males using the sterile insect technique (SIT). In SIT release areas, it is critical to accurately discriminate between released sterile males and wild individuals to detect extremely rare invasive individuals in areas inundated with millions of sterile male flies. Current methods for discrimination exist but are not always definitive, and a more reliable method is necessary. To address this, we developed a genotyping assay that can be used to discriminate between sterile males from the SIT strain and wild individuals. This was achieved by identifying single nucleotide polymorphisms (SNPs) linked to the maintained traits that facilitate male-only releases, white pupae (wp) and temperature-sensitive lethal (tsl), via QTL mapping. This resulted in the identification of one SNP that was in near-perfect linkage disequilibrium between genotype at this locus and the pupal color phenotype. Medfly from many SIT colonies and wild individuals from across its geographic range were genotyped for this locus, and results show its consistency in identifying SIT flies. In addition, linkage and QTL mapping of wp and tsl have larger impacts as they can serve as foundational tools to identify the genetic basis of traits that facilitate the separation of males from female flies, which can be used to develop SIT programs in related species. PMID- 28889104 TI - Machine Learning Analysis Identifies Drosophila Grunge/Atrophin as an Important Learning and Memory Gene Required for Memory Retention and Social Learning. AB - High-throughput experiments are becoming increasingly common, and scientists must balance hypothesis-driven experiments with genome-wide data acquisition. We sought to predict novel genes involved in Drosophila learning and long-term memory from existing public high-throughput data. We performed an analysis using PILGRM, which analyzes public gene expression compendia using machine learning. We evaluated the top prediction alongside genes involved in learning and memory in IMP, an interface for functional relationship networks. We identified Grunge/Atrophin (Gug/Atro), a transcriptional repressor, histone deacetylase, as our top candidate. We find, through multiple, distinct assays, that Gug has an active role as a modulator of memory retention in the fly and its function is required in the adult mushroom body. Depletion of Gug specifically in neurons of the adult mushroom body, after cell division and neuronal development is complete, suggests that Gug function is important for memory retention through regulation of neuronal activity, and not by altering neurodevelopment. Our study provides a previously uncharacterized role for Gug as a possible regulator of neuronal plasticity at the interface of memory retention and memory extinction. PMID- 28889105 TI - Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement. AB - Inducible laryngeal obstruction (ILO) describes an inappropriate, transient, reversible narrowing of the larynx in response to external triggers. ILO is an important cause of a variety of respiratory symptoms and can mimic asthma. Current understanding of ILO has been hampered by imprecise nomenclature and variable approaches to assessment and management. A task force of the European Respiratory Society (ERS) and European Laryngological Society (ELS) was thus set up to address this, and to identify research priorities.A literature search identified relevant articles published until June 2016, using all identifiable terms for ILO, although including only articles using laryngoscopy. In total, 172 out of 252 articles met the inclusion criteria, summarised in sections on diagnostic approach, aetiology, comorbidities, epidemiology and treatment. The consensus taxonomy published by ERS, ELS and the American College of Chest Physicians (ACCP) in 2015 is used throughout this statement.We highlight the high prevalence of ILO and the clinical impact for those affected. Despite recent advances, most aspects of this condition unfortunately remain incompletely understood, precluding firm guidance. Specifically, validated diagnostic and treatment algorithms are yet to be established, and no randomised control studies were identified in this search; hence we also make recommendations for future research. PMID- 28889106 TI - Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. AB - This document provides clinical recommendations for the prevention of chronic obstructive pulmonary disease (COPD) exacerbations. It represents a collaborative effort between the European Respiratory Society and the American Thoracic Society.Comprehensive evidence syntheses were performed to summarise all available evidence relevant to the Task Force's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of COPD experts.After considering the balance of desirable (benefits) and undesirable consequences (burden in the form of adverse effects and cost), quality of evidence, feasibility, and acceptability of various interventions, the Task Force made recommendations for mucolytic, long-acting muscarinic antagonist, phosphodiesterase-4 inhibitor (roflumilast) and macrolide therapy, as well as a conditional recommendation against fluoroquinolone therapy. All of the recommendations were conditional, except for a strong recommendation for the use of a long-acting antimuscarinic agent versus a long-acting beta2 adrenergic, indicating that there was uncertainty about the balance of desirable and undesirable consequences of the intervention, and that well-informed patients may make different choices regarding whether to have or not have the specific intervention.The guideline summarises the evidence and provides recommendations for pharmacological therapy for the prevention of COPD exacerbations. PMID- 28889108 TI - Survival in individuals with severe alpha 1-antitrypsin deficiency (PiZZ) in comparison to a general population with known smoking habits. AB - Knowledge about the natural history of severe alpha 1-antitrypsin (AAT) deficiency (PiZZ) is limited. Our aim was to compare the survival of PiZZ individuals with randomly selected controls from the Swedish general population.The PiZZ subjects (n=1585) were selected from the Swedish National AATD Register. The controls (n=5999) were randomly selected from the Swedish population register. Smoking habits were known for all subjects.Median follow-up times for the PiZZ subjects (731 never-smokers) and controls (3179 never-smokers) were 12 and 17 years, respectively (p<0.001). During follow-up, 473 PiZZ subjects (30%), and 747 controls (12%) died. The PiZZ subjects had a significantly shorter survival time than the controls, p<0.001. After adjustment for gender, age, smoking habits and presence of respiratory symptoms, the risk of death was still significantly higher for the PiZZ individuals than for the controls, hazard ratio (HR) 3.2 (95% CI 2.8-3.6; p<0.001). By contrast, the risk of death was not increased in never-smoking PiZZ individuals identified by screening, compared to never-smoking controls, HR 1.2 (95% CI 0.6-2.2).The never-smoking PiZZ individuals identified by screening had a similar life expectancy to the never smokers in the Swedish general population. Early diagnosis of AAT deficiency is of utmost importance. PMID- 28889107 TI - RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. AB - A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440 m, cardiac index <3.0 L.min-1.m-2 and pulmonary vascular resistance >400 dyn.s.cm-5 underwent a 1-3 day PDE5i treatment-free period before receiving riociguat adjusted up to 2.5 mg maximum t.i.d Exploratory end-points included change in 6MWD, WHO FC, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and safety.Of 61 patients enrolled, 51 (84%) completed RESPITE. 50 (82%) were receiving concomitant endothelin receptor antagonists. At week 24, mean+/-sd 6MWD had increased by 31+/-63 m, NT-proBNP decreased by 347+/-1235 pg.mL-1 and WHO FC improved in 28 patients (54%). 32 patients (52%) experienced study drug-related adverse events and 10 (16%) experienced serious adverse events (2 (3%) study drug-related, none during the PDE5i treatment-free period). Six patients (10%) experienced clinical worsening, including death in two (not study drug-related).In conclusion, selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied. PMID- 28889109 TI - Are indexed values better for defining exercise pulmonary hypertension? PMID- 28889111 TI - Nitrogen back-diffusion during multiple-breath washout with 100% oxygen. PMID- 28889110 TI - European Respiratory Society guidelines for the management of adult bronchiectasis. AB - Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines.The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature.A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy.These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes. PMID- 28889112 TI - Interplay between cigarette smoking and pulmonary reverse lipid transport. AB - Reverse lipid transport is critical to maintain homeostasis. Smoking causes lipid accumulation in macrophages, therefore suggesting suboptimal reverse lipid transport mechanisms. In this study, we investigated the interplay between smoking and reverse lipid transport and the consequences on smoking-induced lung and peripheral alterations.To investigate the relationship between smoking and reverse lipid transport, we used a clinical lung gene expression dataset and a mouse model of cigarette smoke exposure. We also used ApoA-1-/- mice, with reduced reverse lipid transport capacity, and a recombinant ApoA-1 Milano/phospholipid complex (MDCO-216) to boost reverse lipid transport. Cellular and functional analyses were performed on the lungs and impact on body composition was also assessed.Smoking affects pulmonary expression of abca1, abcg1, apoe and scarb1 in both mice and humans, key genes involved in reverse lipid transport. In mice, the capacity of bronchoalveolar lavage fluid and serum to stimulate cholesterol efflux in macrophages was increased after a single exposure to cigarette smoke. ApoA-1-/- mice showed increased lung neutrophilia, larger macrophages and greater loss in lean mass in response to smoking, whereas treatment with MDCO-216 reduced the size of macrophages and increased the lean mass of mice exposed to cigarette smoke.Altogether, this study shows a functional interaction between smoking and reverse lipid transport, and opens new avenues for better understanding the link between metabolic and pulmonary diseases related to smoking. PMID- 28889113 TI - Overdosing on immediate-release morphine solution has predictable adverse effects. PMID- 28889114 TI - The paradoxes of asthma management: time for a new approach? AB - Poor adherence to maintenance pharmacotherapy is a reality in asthma. Studies confirm that when symptoms worsen, most patients increase short-acting beta2 agonist (SABA) use, instead of using controller medication. This behaviour might be attributable to several paradoxes in the current treatment approach. These paradoxes include the recommended use of a SABA bronchodilator alone at Global Initiative for Asthma (GINA) step 1, despite the fact that asthma is a chronic inflammatory disease. At step 1, the patient has autonomy and their perception of need and disease control is accepted, but at higher asthma treatment steps a fixed-dose approach is recommended, irrespective of symptom severity. The unintended consequence is the establishment of a pattern of early over-reliance on SABA. New approaches that avoid these paradoxes are needed, such as patient adjusted therapy, in which patients adopt a symptom-driven approach using a combination reliever/controller. We propose that SABA reliever monotherapy should be replaced by a combination of inhaled corticosteroid (ICS) and formoterol, or similar rapid-onset bronchodilator, as reliever therapy for patients at GINA steps 1 or 2. This will ensure early and more regular administration of a controller medication. However, a significant body of clinical data will be needed before this approach can be approved by regulatory authorities. PMID- 28889115 TI - Predictable adverse events such as respiratory depression highlight the need for caution when prescribing morphine for refractory breathlessness. PMID- 28889116 TI - Challenging the concept of adding more drugs in pulmonary arterial hypertension. PMID- 28889118 TI - Biotechnology of siderophores in high-impact scientific fields. AB - Different aspects of bacterial and fungal siderophore biotechnological applications will be discussed. Areas of application presented include, but are not limited to agriculture, medicine, pharmacology, bioremediation, biodegradation and food industry. In agriculture-related applications, siderophores could be employed to enhance plant growth due to their uptake by rhizobia. Siderophores hindered the presence of plant pathogens in biocontrol strategies. Bioremediation studies on siderophores discuss mostly the mobilization of heavy metals and radionuclides; the emulsifying effects of siderophore-producing microorganisms in oil-contaminated environments are also presented. The different applications found in literature based in medicine and pharmacological approaches range from iron overload to drug delivery systems and, more recently, vaccines. Additional research should be done in siderophore production and their metabolic relevance to have a deeper understanding for future biotechnological advances. PMID- 28889119 TI - Sham transcranial electrical stimulation and its effects on corticospinal excitability: a systematic review and meta-analysis. AB - Sham stimulation is used in randomized controlled trials (RCTs) to assess the efficacy of active stimulation and placebo effects. It should mimic the characteristics of active stimulation to achieve blinding integrity. The present study was a systematic review and meta-analysis of the published literature to identify the effects of sham transcranial electrical stimulation (tES) - including anodal and cathodal transcranial direct current stimulation (a-tDCS, c tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS) and transcranial pulsed current stimulation (tPCS) - on corticospinal excitability (CSE), compared to baseline in healthy individuals. Electronic databases - PubMed, CINAHL, Scopus, Science Direct and MEDLINE (Ovid) were searched for RCTs of tES from 1990 to March 2017. Thirty RCTs were identified. Using a random-effects model, meta-analysis of a-tDCS, c-tDCS, tACS, tRNS and tPCS studies showed statistically non-significant pre-post effects of sham interventions on CSE. This review found evidence for statically non significant effects of sham tES on CSE. PMID- 28889120 TI - Efficiency: an underlying principle of learning? AB - Learning is essential. It allows animals to change circumstances, deal with new situations and adapt to environments. Here, we argue that learning, at behavioral and neural levels, involves efficiency, reflected in metabolic cost reductions. Behaviourally, although multiple solutions to a novel problem may be available, all solutions are not learnt - it is too costly. Furthermore, once a strategy has been selected, it is reinforced producing an efficiency that leads to a maximisation of performance and metabolic cost reductions. Learning can be represented in the brain through many mechanisms; however, if learning is truly efficient, then, all such mechanisms should also be accompanied by a reduction in measurable metabolic costs. By thinking about learning in terms of efficiency, not simply as a descriptive term but rather in terms of metabolic costs, it allows learning to be examined more carefully and provides predictions that can be easily tested (and indeed refuted). PMID- 28889121 TI - Structure-Function Analysis of the Periplasmic Escherichia coli Cyclophilin PpiA in Relation to Biofilm Formation. AB - The presence of peptidyl-prolyl cis/trans isomerases (PPIases, EC: 5.2.1.8) in all domains of life indicates their biological importance. Cyclophilin PpiA, present in the periplasm of gram-negative bacteria, possesses PPIase activity but its physiological functions are still not clearly defined. Here, we demonstrate that the DeltappiA deletion strain from Escherichia coli exhibits an increased ability for biofilm formation and enhanced swimming motility compared to the wild type strain. To identify structural features of PpiA which are necessary for the negative modulation of biofilm formation, we constructed a series of mutant PpiA proteins using a combination of error-prone and site-directed mutagenesis approaches. We show that the negative effect of PpiA on biofilm formation is not dependent on its PPIase activity, since PpiA mutants with a reduced PPIase activity are able to complement the DeltappiA strain during biofilm growth. PMID- 28889122 TI - Galectin-9 Produced by Intestinal Epithelial Cells Enhances Aldehyde Dehydrogenase Activity in Dendritic Cells in a PI3K- and p38-Dependent Manner. AB - Intestinal epithelial cells (IEC) drive regulatory T cell (Treg) responses by promoting the differentiation of aldehyde dehydrogenase (ALDH)-expressing CD103+ dendritic cells (DC). Apical stimulation of TLR9 by CpG DNA on IEC supports galectin-9 expression by IEC, which is promoted by short-chain galacto oligosaccharides and long-chain fructo-oligosaccharides (GF). While galectin-9 can induce the maturation of monocyte-derived DC (moDC), the contribution of galectin-9 on the induction of ALDH activity in DC is not known. To this end, DC were stimulated with galectin-9, and ALDH activity and the expression of CD103 were assessed. ALDH activity was increased by moDC exposed to galectin-9, while the expression of CD103 remained unaltered. Galectin-9 secreted by IEC apically exposed to CpG DNA and GF enhanced ALDH activity, but not CD103 expression by moDC, which was abrogated upon galectin-9 neutralization. Similar observations were found in murine GM-CSF-cultured bone marrow-derived DC (BMDC). Using Flt3L cultured BMDC and ex vivo murine splenic DC, it was observed that galectin-9 only enhanced ALDH activity in the presence of GM-CSF in CD103- cells. The induction of ALDH activity in BMDC was dependent on p38 and PI3K signaling. These data indicate a novel role for galectin-9 in modulating innate immunity by inducing ALDH activity in DC. PMID- 28889123 TI - Erratum. PMID- 28889124 TI - Factors Affecting Stereotactic Accuracy in Image-Guided Deep Brain Stimulator Electrode Placement. AB - BACKGROUND/AIMS: Intraoperative imaging allows near-real-time assessment of stereotactic accuracy during implantation of deep brain stimulation (DBS) electrodes. Such technology can be used to examine factors impacting stereotactic error. METHODS: Intraoperative CT imaging was reviewed in patients undergoing DBS placement at Oregon Health and Sciences University. Coordinates of the target electrode were compared to the operative plan to characterize the magnitude and direction of stereotactic error with respect to side of implantation, target, and electrode approach angles. RESULTS: One hundred sixty-nine leads in 94 patients were examined. Targets were GPi (n = 86), STN (n = 31), and Vim (n = 52). The average Euclidean error was 1.63 mm (SD 0.87). The error magnitude was higher for Vim (1.95 mm) than for GPi (1.44 mm), while STN (1.65 mm) did not differ from either Vim or GPi (ANOVA: F = 6.15, p = 0.003). Electrodes targeting Vim and STN were significantly more likely to deviate medially compared to those targeting GPi (ANOVA: F = 9.13, p < 0.001). The coronal approach angle affected the error when targeting Vim (rho = 0.338, p = 0.01). These findings were confirmed during multivariate analyses. CONCLUSIONS: This study shows a significant effect of target on the accuracy of electrode placement for DBS. Targeting Vim results in a greater Euclidean error and a greater medial deviation off target. These systematic deviations should be taken into account during electrode implantation. PMID- 28889125 TI - Brimonidine Protects Auditory Hair Cells from in vitro-Induced Toxicity of Gentamicin. AB - Brimonidine, an alpha-2 adrenergic receptor (alpha2-AR) agonist, has neuroprotective effects in the visual system and in spiral ganglion neurons. Auditory hair cells (HCs) express all 3 alpha2-AR subtypes, but their roles in HCs remain unknown. This study investigated the effects of brimonidine on auditory HCs that were also exposed to gentamicin, which is toxic to HCs. Organ of Corti explants were exposed to gentamicin in the presence or absence of brimonidine, and the alpha2-AR protein expression levels and Erk1/2 and Akt phosphorylation levels were determined. Brimonidine had a protective effect on auditory HCs against gentamicin-induced toxicity that was blocked by yohimbine. This suggested that the protective effect of brimonidine on HCs was mediated by the alpha2-AR. None of the treatments altered alpha2-AR protein expression levels, and brimonidine did not significantly change the activation levels of the Erk1/2 and Akt proteins. These observations indicated that brimonidine, acting directly via alpha2-AR, protects HCs from gentamicin-induced toxicity. Therefore, brimonidine shows potential for preventing or treating sensorineural hearing loss. PMID- 28889126 TI - Chromosomal Microarray Analysis in Fetuses with Growth Restriction and Normal Karyotype: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To perform a systematic review of the literature and a meta-analysis to estimate the incremental yield of chromosomal microarray analysis (CMA) over karyotyping in fetal growth restriction (FGR). METHODS: This was a systematic review conducted in accordance with the PRISMA criteria. All articles identified in PubMed, Ovid Medline, and ISI Web of Knowledge (Web of Science) from January 2009 to November 2016 describing pathogenic copy number variants (CNVs) in fetuses with growth restriction were included. Case reports were excluded. Risk differences were pooled to estimate the overall and stratified CMA incremental yield. RESULTS: Ten studies with full data available met the inclusion criteria for analysis. Combined data from these studies revealed a 4% (95% confidence interval [CI] 1-6%) incremental yield of CMA over karyotyping in nonmalformed growth-restricted fetuses, and a 10% (95% CI 6-14%) incremental yield in FGR when associated with fetal malformations. The most frequently found pathogenic CNVs were 22q11.2 duplication, Xp22.3 deletion, and 7q11.23 deletion (Williams-Beuren syndrome), particularly in isolated FGR. CONCLUSION: The use of genomic CMA provides a 4% incremental yield of detecting pathogenic CNVs in fetuses with isolated growth restriction and normal karyotype. PMID- 28889127 TI - Buccal Epithelium, Cigarette Smoking, and Lung Cancer: Review of the Literature. AB - Lung cancer is currently the leading cause of cancer-related mortality among men and women in the United States, and optimal screening methods are still lacking. The field effect is a well-supported phenomenon wherein a noxious stimulus triggers genetic, epigenetic and molecular changes that are widespread throughout the entire exposed organ system. The buccal epithelium is an easily accessible part of the respiratory tree that has good potential of yielding a surrogate marker for the field effect in cigarette smokers, and thus, a noninvasive, reliable lung cancer screening method. Herein, we review the literature on the relationship between the buccal epithelium, cigarette smoking, and lung cancer. PMID- 28889129 TI - Abstracts of 5th Asia Pacific Conference on Public Health Supplement. PMID- 28889128 TI - Hemorrhage Detection and Incidence during Magnetic Resonance-Guided Deep Brain Stimulator Implantations. AB - BACKGROUND/AIMS: Intraoperative magnetic resonance imaging (iMRI) is increasingly used to implant deep brain stimulator (DBS) electrodes. The approach has the advantages of a high targeting accuracy, minimization of brain penetrations, and allowance of implantation under general anesthesia. The hemorrhagic complications of iMRI-guided DBS implantation have not been studied in a large series. We report on the incidence and characteristics of hemorrhage during these procedures. METHODS: Hemorrhage incidence was assessed in a series of 231 iMRI procedures (374 electrodes implanted). All patients had movement disorders and the subthalamic nucleus or the globus pallidus internus was typically targeted. Hemorrhage was detected with intra- or postoperative MRI or postoperative computed tomography. Hemorrhage was classified based on its point of origin and clinical impact. RESULTS: Hemorrhage and symptomatic hemorrhage were detected during 2.4 and 1.1% of electrode implantations, respectively. The hemorrhage origin was subdural/subarachnoid (n = 3), subcortical (n = 5), or deep (n = 1). Factors that contributed to hemorrhage included unintentional crossing of a sulcus and resistance at the pial membrane, which produced cortical depression and a rebound hemorrhage. Delayed hemorrhage occurred in 2 patients and was attributed to premature reintroduction of anticoagulation therapy or air intrusion into the cranial cavity. CONCLUSIONS: Hemorrhage was readily apparent on intraoperative imaging, and hemorrhage rates for iMRI-guided DBS implantations were comparable to those for conventional implantation approaches. PMID- 28889130 TI - Experience of a rapid access falls and syncope service at a teaching hospital in Kuala Lumpur. AB - No abstract available. PMID- 28889131 TI - Missed opportunities for earlier HIV-testing in patients with HIV infection referred to a tertiary hospital, a cross-sectional study. AB - INTRODUCTION: In Malaysia, the prevalence of missed opportunities for HIV-testing is unknown. Missed opportunities have been linked to late diagnosis of HIV and poorer outcome for patients. We describe missed opportunities for earlier HIV testing in newly-HIV-diagnosed patients. METHODS: Cross sectional study. Adult patients diagnosed with HIV infection and had at least one medical encounter in a primary healthcare setting during three years prior to diagnosis were included. We collected data on sociodemographic characteristics, patient characteristics at diagnosis, HIV-related conditions and whether they were subjected to risk assessment and offered HIV testing during the three years prior to HIV diagnosis. RESULTS: 65 newly HIV-diagnosed patients (male: 92.3%; Malays: 52.4%; single: 66.7%; heterosexual: 41%; homosexual 24.6%; CD4 <350 at diagnosis: 63%). 93.8% were unaware of their HIV status at diagnosis. Up to 56.9% had presented with HIV related conditions at a primary healthcare facility during the three years prior to diagnosis. Slightly more than half were had risk assessment done and only 33.8% were offered HIV-testing. CONCLUSIONS: Missed opportunities for HIV-testing was unacceptably high with insufficient risk assessment and offering of HIV testing. Risk assessment must be promoted and primary care physicians must be trained to recognize HIV-related conditions that will prompt them to offer HIVtesting. PMID- 28889132 TI - Food allergy and allergic rhinitis in 435 asian patients - A descriptive review. AB - OBJECTIVE: To describe the prevalence of food allergy in Asian patients with allergic rhinitis. STUDY DESIGN: A non-randomized prospectively collected patients over a three year period, with complaints of nose congestion, rhinorrhea and/or nasal discharge. RESULTS: There were 435 patients enrolled, 213 children and 222 adults. The children group had a high prevalence of allergen specific IgE to Dermatophagoides pteryonysinus (70%), Dermatophagoides farina (69%), and Blomia tropicalis (55%); followed by dogs (32%), cats (19%) and cockroaches (19%). In the children food allergy category, the top three allergens were egg white (54%), milk (31%) and soya bean (13%). The adult group had results of Dermatophagoides pteryonysinus (71%), Dermatophagoides farina (72%), and Blomia tropicalis (59%); the adult food allergy category, the top 3 allergens were egg white (13%), milk (6%) and soya bean (5%). There was a statistically significant difference in the child and adult group for Dust, D. pteryonysinus, D. farina, B.tropicalis, egg white, wheat, gluten and soya bean. In the age specific child groups, there was an increased in egg food allergy levels, with a peak at the age of five-nine years old and decreasing thereafter (p=0.04). In the children group, the mean Total Nasal Symptom Score (TNSS) was 10.3 (range of 7 to 13); the adult group was similar, with a mean TNSS of 9.8 (range 5 to 12). CONCLUSION: The prevalence of food allergy in paediatric patients with allergic rhinitis is fairly high and should be considered when treating these children. PMID- 28889133 TI - Prevalence and predictors of depression and suicidal ideation among adolescents attending government secondary schools in Malaysia. AB - No abstract available. PMID- 28889134 TI - Pesticide applicators questionnaire content validation: A fuzzy delphi method. AB - BACKGROUND: The most crucial step in forming a set of survey questionnaire is deciding the appropriate items in a construct. Retaining irrelevant items and removing important items will certainly mislead the direction of a particular study. This article demonstrates Fuzzy Delphi method as one of the scientific analysis technique to consolidate consensus agreement within a panel of experts pertaining to each item's appropriateness. This method reduces the ambiguity, diversity, and discrepancy of the opinions among the experts hence enhances the quality of the selected items. The main purpose of this study was to obtain experts' consensus on the suitability of the preselected items on the questionnaire. METHODS: The panel consists of sixteen experts from the Occupational and Environmental Health Unit of Ministry of Health, Vector-borne Disease Control Unit of Ministry of Health and Occupational and Safety Health Unit of both public and private universities. A set of questionnaires related to noise and chemical exposure were compiled based on the literature search. There was a total of six constructs with 60 items in which three constructs for knowledge, attitude, and practice of noise exposure and three constructs for knowledge, attitude, and practice of chemical exposure. The validation process replicated recent Fuzzy Delphi method that using a concept of Triangular Fuzzy Numbers and Defuzzification process. RESULTS: A 100% response rate was obtained from all the sixteen experts with an average Likert scoring of four to five. Post FDM analysis, the first prerequisite was fulfilled with a threshold value (d) <= 0.2, hence all the six constructs were accepted. For the second prerequisite, three items (21%) from noise-attitude construct and four items (40%) from chemical-practice construct had expert consensus lesser than 75%, which giving rise to about 12% from the total items in the questionnaire. The third prerequisite was used to rank the items within the constructs by calculating the average fuzzy numbers. The seven items which did not fulfill the second prerequisite similarly had lower ranks during the analysis, therefore those items were discarded from the final draft. CONCLUSION: Post FDM analysis, the experts' consensus on the suitability of the pre-selected items on the questionnaire set were obtained, hence it is now ready for further construct validation process. PMID- 28889135 TI - Acute outcome of chronic total occlusion (CTO) recanalizsation in the elderly. AB - OBJECTIVES: Percutaneous coronary intervention (PCI) of total chronic total occlusion (CTO) still remains a major challenge in interventional cardiology. There is only insignificant knowledge reported in the literature about age differences in CTO recanalization. We analyzed in this study the issue of the impact of age on procedural characteristics, complications and short-term outcome. METHODS: Between 2012-2016 we included 440 patients. They underwent PCI for at least one CTO. Antegrade and retrograde CTO techniques were applied. The retrograde approach was used only after failed antegrade intervention. Continuous data are presented as the mean +/- standard deviation; categorical data are presented as numbers and percentages unless otherwise specified. We used Twosamplet- t-test with equal variance to test the significant differences of the variables between the two cohorts. RESULTS: Procedural success proved independently of age. There was no significant interaction between age and procedural success (p=0.5). Complication rates were low in both groups (2.7% vs. 4%; p=0,4) with no difference in statistical significance. CONCLUSIONS: Our study suggests that in an aging society patients with severe coronary artery disease and chronical total occlusions an interventional therapy should be used more intensively. It can be performed safe and feasible. PMID- 28889136 TI - Electro-navigational bronchoscopy for bilateral peripheral lung lesions: A case report. AB - Electromagnetic navigational bronchoscopy (ENB), one of the methods of navigational bronchoscopy is an advanced diagnostic tool allowing tissue sampling at the lung peripheries which were previously accessible only by computed tomography (CT) guidance or video-assisted thoracoscopic surgery (VATS). We report a 53-year-old man who presented with a cough and dyspnea with constitutional symptoms for one month. CT thorax revealed multiple bilateral peripheral lung nodules and there were no endobronchial lesions on flexible bronchoscopy. ENB was performed using a loan machine from Veran navigational technology. Biopsy successfully revealed small cell carcinoma of the lung thus preventing him from undergoing a more invasive diagnostic procedure. This case highlights the utility of ENB in the evaluation of peripheral lung nodules that were inaccessible by conventional bronchoscopy. This is one of the first few successful applications of Veran ENB in Asia. PMID- 28889137 TI - Perforated gastric ulcer in severe dengue infection: A case report. AB - Abdominal pain is one of the common presentations in severe dengue infection. We report a rare case of perforated gastric ulcer in a young man diagnosed with severe dengue infection and the challenges we faced in managing this patient. Perforated gastric ulcer need to be considered if there are signs of peritonitis and persistent abdominal pain that does not conform to the natural history of dengue. Proper imaging and early surgical intervention in perforated gastric ulcer is vital in preventing further complication and reducing the risk of mortality. PMID- 28889138 TI - Pulmonary actinomycosis masquerading as lung cancer: A case report. AB - Pulmonary actinomycosis is a rare yet important and challenging diagnosis to make. It is commonly confused with other lung diseases, such as tuberculosis and bronchogenic carcinoma, leading to delay diagnosis or misdiagnosis. A 49-year-old man presented with a chronic cough, hemoptysis, and pleuritic chest pain. His initial imaging studies including computed tomography (CT) was suggestive of bronchogenic carcinoma. A subsequent CTguided biopsy was consistent with pulmonary actinomycosis and excluded the possibility of bronchogenic carcinoma. He was treated with antibiotic therapy and achieved remission with complete radiological resolution upon follow-up. PMID- 28889139 TI - Bohring-opitz syndrome - A case of a rare genetic disorder. AB - The diagnostic challenge of Bohring-Opitz Syndrome, a rare genetic disorder has haunted clinicians for ages. Our patient was born at term via caesarean-section with a birth weight of 1.95 kilograms. She had mild laryngomalacia, gastroesophageal reflux disease and seizures. Physical signs included microcephaly, hemangioma, low set ears, cleft palate, micrognatia and the typical BOS posture. Chromosomal analysis showed 46 xx -Bohring-Opitz Syndrome overlapped with C- syndrome. Goal-directed holistic care with integration of parent/carer training was started very early. She succumbed to a Respiratory- Syncitial-Virus and Pseudomonas pneumonia complicated with sepsis at the age of two years and 11 months. PMID- 28889140 TI - Multiple bilateral renal abscesses in a previously healthy young patient. AB - The incidence of renal abscesses is not common. Patients usually have risk factors like diabetes mellitus or an underlying condition which predisposes to urinary tract infections. We report a case of a previously healthy young girl with multiple bilateral renal abscesses. Ultrasonography revealed multiple renal abscesses with a possible differential diagnosis of polycystic kidney disease with infected cysts. No renal calculi were seen. CT-scan of kidneys confirmed the diagnosis. Blood and urine cultures were repeatedly negative. She was treated with two weeks of intravenous antibiotics followed by another four weeks of oral Ciprofloxacin. No surgical intervention was carried out. Repeated ultrasound at six months showed complete resolution of all the renal abscesses. PMID- 28889141 TI - Case report: A case of pericardial effusion presenting to primary care. AB - This is a rare but interesting case of Mr. MZ who had a lifethreatening pericardial effusion presenting to the primary care clinic. Through great clinical acumen and prudent targeted investigations, diagnosis of this rare condition was reached and urgent referral made to the cardiology team which performed an emergency pericardiocentesis which proved to be life -saving. However, the hovering poor prognosis of Mr. MZ may prompt for a referral to the palliative care team to provide quality end of life care for this unfortunate patient. PMID- 28889142 TI - Dengue shock syndrome with retroperitoneal haematoma requiring repeated artery angioembolization. AB - Eyelid reconstruction is complex and challenging since it is not only for structural and functional restoration, but also for an acceptable aesthetic result. In full thickness eyelid injuries, it will involve both anterior and posterior lamella. Therefore, when reconstructing the defect, it requires at least two layers; one will be a flap with blood supply, and the other can be a free graft. In this case, a rotational advancement cheek flap and composite graft were used to reconstruct the lower eyelid. PMID- 28889143 TI - A Nonrandom Sample of 55 Sexual Abuse Cases in Sivas. AB - BACKGROUND Sexual abuse in childhood is a significant public health problem because of the destructive results both to the individual and to the community. The aim of this study was to examine the sociodemographic characteristics of children who were victims of sexual abuse, the relationship of the victim and abuser, and the findings of sexual abuse. MATERIAL AND METHODS An examination was made of the results of forensic medicine and psychiatric evaluations of child victims of sexual abuse. The sociodemographic characteristics of the cases and the characteristics of the incidents of sexual abuse were evaluated at the Forensic Medicine Department of Cumhuriyet University between 2013 and 2016. RESULTS A total of 55 cases were included in the study, comprising eight males (14.5%) and 47 females (85.5%) in the age range of 5-17 years. The vast majority of the cases were high school students. The place of the abuse incident was the home of the victim or the perpetrator in 29 cases (52.7%). The sexual abuse was determined to be bodily penetration in 32 cases (58.1%). In 32 cases (58.1%), the perpetrator was known to the victim. CONCLUSIONS The study findings that the perpetrator of the sexual abuse was known to the child, that predominantly female children were attacked, and the low sociocultural level of the cases were consistent with other studies reported in the literature. To prevent sexual abuse of children, to make an early diagnosis, and to provide rehabilitation for the abused children, it is essential that the evaluations of these cases are made using a professional multidisciplinary approach. PMID- 28889144 TI - Modified Fan-Shaped Distribution Technology for Computed Tomography (CT)-Guided Radioactive Seed Implantation in Lung Cancer Patients with Lung Dysfunction. AB - BACKGROUND The aim of this study was to investigate the safety and effectiveness of fan-shaped distribution and coaxial puncture technology for radioactive iodine 125 (125I) seed implantation in treatment of lung cancer patients with lung dysfunction. MATERIAL AND METHODS We enrolled and analyzed 33 lung cancer patients with lung dysfunction diagnosed in our hospital from 2013 to 2014 in this study, all of which were implanted with radioactive 125I seed with technology of fan-shaped distribution and coaxial puncture. The matched peripheral dose (MPD) range was 90-140GY. The brachytherapy planning system (TPS) was used to draw up a preoperative seed implantation plan. The fan-shaped distribution system was applied to simulate a surgery program, and seed implantation pitch was 0.5-1.0 cm. Real-time adjustment was necessary during surgery. Dose distributions were verified by TPS immediately after implantation. Intraoperative and postoperative surgery-related complications were analyzed. All patients were followed up for 6 months, and the local control rate of cancer was evaluated through CT scan. RESULTS All patients were operated on successfully. The main surgery-related complications were pulmonary hemorrhage, pleural cavity hemorrhage, and pneumothorax. The local control rates of 2-month, 4-month, and 6 month were 29%, 73%, and 85%, respectively. The total complete remission rate was 18%, the partial response rate was 67%, the stable disease rate was 12%, and the disease progression rate was 3%. CONCLUSIONS The fan-shaped distribution and coaxial puncture technology for radioactive 125I seed implantation was safe and effective in treating lung cancer patients with lung dysfunction. PMID- 28889145 TI - Efficacy and adverse events of pirfenidone in treating idiopathic pulmonary fibrosis. AB - OBJECTIVES: To analyze the efficacy and adverse events (AEs) of pirfenidone in idiopathic pulmonary fibrosis (IPF) trials. Methods: MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for studies published before June 2016. All studies of clinical trials with the key words IPF or idiopathic pulmonary fibrosis or lung fibrosis and pirfenidone or Esbriet were identified. Quality assessment and data extraction nwere conducted by 2 independent researchers. A meta-analysis of randomized controlled trials (RCTs) was performed, and relative risk (RR) and 95% confidence intervals (95% CIs) were calculated. Results: Five studies were included in this review, involving 1568 participants. The meta analysis revealed that pirfenidone reduced the risk of decline in forced vital capacity (FVC)% >=10% from baseline (relative risk: 0.62; 95% CI: 0.51-0.76, p less than 0.001). The pirfenidone group had a significantly higher rate of AEs compared with the placebo group. Pirfenidone did not reduce mortality from any cause significantly (odds ratio: 0.63; 95% CI: 0.36-1.09). Conclusions: This study showed that pirfenidone could reduce disease progression as assessed by the decline in FVC in IPF. Pirfenidone represents a suitable treatment option for patients with IPF. PMID- 28889146 TI - Celiac disease in Saudi children. Evaluation of clinical features and diagnosis. AB - Objectives: To characterize the clinical presentations and diagnosis including serological tests and histopathological findings in children with celiac disease. Methods: All children (less than 18 years) with confirmed celiac disease diagnosed over a 6 year period at a private tertiary care health care center in Riyadh, Saudi Arabia were studied retrospectively. Information collected included demographics, clinical presentation and diagnostic modalities with serology and small intestinal histology reported by Marsh grading. Results: A total of 59 children had confirmed celiac disease. Thirty (50.8%) were male. Median age was 8 years (range 1 to 16 years). The mean duration of symptoms before diagnosis was 2.3 (+/-1.5) years. Classical disease was present only in 30.5%, whereas 69.5% had either non-classical presentations or belonged to high risk groups for celiac disease such as those with type-1 diabetes, autoimmune thyroiditis, Down syndrome and siblings. Failure to thrive was the most common presentation followed by short stature, abdominal pain and chronic diarrhea. Anti tissue transglutaminase antibody was positive in 91.5%, and titers were no different between those with classical and non-classical disease. All had Marsh graded biopsy findings consistent with celiac disease. Conclusion: Children with celiac disease usually present with non-classical features. A high index of suspicion needs to be maintained to consider this disorder in the diagnostic workup of pediatric patients. High risk group should be screened early to avoid complications associated with untreated celiac disease. PMID- 28889147 TI - Acute coronary syndrome risk prediction of rapid emergency medicine scoring system in acute chest pain. An observational study of patients presenting with chest pain in the emergency department in Central Saudi Arabia. AB - OBJECTIVES: To assess the diagnostic validity of the rapid emergency medical score (REMS) for the risk stratification of acute coronary syndrome (ACS) from non-cardiogenic chest pain. Methods: An observational cross-sectional study was carried out among patients presenting with chest pain to the Emergency Department of Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia, for 6 months from January to June 2016. All patients, included through non-probability convenience sampling, were assessed using standard protocols for the physiological parameters of the REMS, and ACS was confirmed through electrocardiography, cardiac enzyme testing, and angiography (if needed). Data were analyzed using Statistical Package for Social Sciences software version 15 (SPSS Inc, Chicago, IL, USA). The validity of REMS was determined using a cutoff value of 17. Results: In total, 176 (70.4%) of patients were men with a mean age of 49+/-8.5 years. The mean REM score of the patients was 9.3+/-4.5, and a sensitivity of 81.6%, specificity of 90.05%, positive predictive value of 66.67%, and a negative predictive value of 95.26% were obtained. Conclusion: Rapid emergency medical score is a simple and fairly valid tool that may be used for diagnosis of ACS with limited resources in emergency medicine. PMID- 28889148 TI - Association of fine particulate air pollution with cardiopulmonary morbidity in Western Coast of Saudi Arabia. AB - OBJECTIVES: To assess cardiopulmonary morbidity associated with daily exposures to PM2.5 in Western Coast of Saudi Arabia. Methods: We monitored 24-h PM2.5 and its constituents including black carbon (BC), particulate sulfate (p-SO42-), nitrate (p-NO3-), ammonium (p-NH4+) and trace elements (TEs) at a site in Rabigh, Saudi Arabia from May to June 2013 with simultaneous collection of hospital data (N=2513). Cardiopulmonary morbidity risk was determined in a generalized linear time-series model. Results: Exposure to PM2.5 was associated with a 7.6% (p=0.056) increase in risk of respiratory disease (RD) in females. Black carbon increased RD morbidity risk by 68.1% (p=0.056) in females. Exposure to p-SO42- increased the cardiovascular disease (CVD) risk by up to 5.3% (p=0.048) in males; and RD by 2.9% (p=0.037) in females and 2.5% (p=0.022) in males. The p-NH4+ increased CVD risk by up to 20.3% (p=0.033) in males; and RD by 10.7% (p=0.014) in females and 8% (p=0.031) in males. No statistically significant association was observed for p-NO3- and TEs exposure. Conclusion: Overall, results show an increased risk for cardiopulmonary morbidity following exposure to air pollution. PMID- 28889149 TI - Patterns, knowledge, and barriers of mammography use among women in Saudi Arabia. AB - OBJECTIVES: To assess mammography utilization and knowledge, and to determine barriers associated with mammography utilization among Saudi women. Methods: We conducted a cross-sectional survey in 5 main geographic regions of Saudi Arabia from February 2015 to May 2015. The sample comprised women aged >=40 years. Associations between socio-demographic factors and mammography use were tested using chi-square test. Predictors of mammography use were assessed by logistic regression. Results: A total of 3,245 women were surveyed, with 40% reporting ever having a mammogram. As indicated by the univariable analyses, older age (>=60 years), being single or divorced, having less than 2 children, not completing high school, and having a family history (hx) of breast cancer were significantly associated with never having a mammogram. Participants of older age (odds ratio [OR] 51-60 versus 41-50 = 0.6, 95% CI: 0.5-0.7 and OR less than 60 versus 41-50 = 0.5, 95% CI: 0.3-0.8), and divorced (OR divorced versus married = 0.6, 95% CI: 0.5-0.8] were less likely to have had a mammogram, while participants with no family hx of breast cancer (OR no family hx versus family hx = 1.5, 95%CI: 1.3-1.8)were more likely to have had a mammogram. Conclusion: Mammography utilization and knowledge are low in Saudi Arabia. Increasing the awareness of breast cancer screening through educational programs could help women overcome existing barriers and misconceptions. PMID- 28889150 TI - Screening for skin-sensitizing allergens among patients with clinically suspected allergic contact dermatitis. AB - OBJECTIVES: To detect common skin-sensitizing agents among patients experiencing allergic contact dermatitis (ACD). Methods: This was a retrospective study of 152 patients with clinically suspected ACD who underwent patch testing in an allergy clinic at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia between January 2012 and February 2015. Of these patients, only 74 (48%) patients reacted to one or more contact allergens. This group of patients included 58 (78.4%) women and 16 (21.6%) men (mean age: 37.8+/-13.8 years). Patch testing was performed using the thin-layer rapid-use epicutaneous patch test panels. Results: Nickel sulfate was the most common sensitizing agent, with 26 (35.1%) patients yielding a positive result; followed by p-phenylenediamine in 17 (22.9%), butyl tetra-phenol formaldehyde in 12 (16.2%), gold sodium thiosulfate in 10 (13.5%), and thimerosal in 6 (8.1%) patients. Nickel reactivity was significantly higher among women (41.4%) than among men (12.5%) (p less than 0.0001). Similarly, gold reactivity among women (15.5%) was also higher than among men (6.2%) (p<=0.02). Conclusion: The high level of skin sensitization due to nickel, PPD, and gold in patients with ACD emphasizes the need for measures to decrease exposure to these sensitizing agents. PMID- 28889151 TI - Hydrogen water ameliorates the severity of atopic dermatitis-like lesions and decreases interleukin-1beta, interleukin-33, and mast cell infiltration in NC/Nga mice. AB - OBJECTIVES: To examine the effect of hydrogen water (HW) on the severity of atopic dermatitis (AD) and elucidate the underlying pathophysiological mechanisms. METHODS: For this experimental study between March 2015 and December 2015, NC/Nga mice characterized by mild AD severity were given either HW (n=11) or purified water (PW) (n=9) ad libitum; specific-pathogen-free mice (n=9) were used as AD-free control. Atopic dermatitis severity score and transepidermal water loss (TEWL) were examined at baseline (0 week), and after 4 weeks of HW/PW treatment. Levels of serum thymus and activation-regulated chemokine (TARC) and cytokines in the AD lesion were measured by ELISA; and mRNA expression of TARC and aquaporin (AQP-3) genes in the skin was examined by real-time polymerase chain reaction. Results: Mice treated with HW for 4 weeks demonstrated a significant decrease in the AD severity score compared with PW-treated mice (p less than 0.01). Hydrogen water administration also significantly reduced TEWL and serum TARC levels (p less than 0.01), infiltration of mast cells (p less than 0.05), and secretion of the proinflammatory cytokines interleukin (IL)-1beta and IL-33 (p less than 0.05) in skin lesions compared with PW. However, no difference was observed between PW and HW groups in interferon-gamma secretion and expression of AQP-3 and TARC genes. Conclusion: Hydrogen water suppressed inflammation in AD mice, leading to amelioration of disease severity, which suggests the therapeutic potential of HW in AD treatment. PMID- 28889152 TI - Anti-carbamylated protein antibodies in rheumatoid arthritis patients and their association with rheumatoid factor. AB - OBJECTIVES: To evaluate levels of anti-carbamylated protein (anti-CarP) antibodies in rheumatoid arthritis (RA) patients and to determine their association with serological parameters and disease activity. Methods: A cross sectional study involving 105 multiethnic RA patients (48 rheumatoid factor [RF] positive and 57 RF-negative patients) was conducted at Hospital Universiti Sains Malaysia, Kelantan, Malaysia, from January 2015 to February 2016. Fifty healthy controls (HCs) were included. C-reactive protein (CRP), RF, anti-cyclic citrullinated peptide (anti-CCP) and anti-CarP antibodies were measured. A health assessment questionnaire (HAQ) was administered to the study participants and 28 joint Disease Activity Score (DAS28) were obtained. Results: The level of anti CarP antibodies was significantly increased in the RA patients compared with HCs (p=0.042). The presence of anti-CarP antibodies was significantly associated with RF (p=0.019) and the HAQ (p=0.010). A significant association between the presence of anti-CarP antibodies and the DAS28 was not found (p=0.632). Conclusion: Our study provides further evidence that the level of anti-CarP antibodies is significantly elevated in RA patients. PMID- 28889153 TI - Medical residents' attitudes and emotions related to Middle East respiratory syndrome in Saudi Arabia. A cross-sectional study. AB - OBJECTIVES: To determine medical residents' emotions, attitudes, and knowledge related to Middle East respiratory syndrome (MERS) outbreaks. Methods: In this is a cross sectional study, self-administered questionnaires were distributed and collected before resident education activities in 4 tertiary hospitals in Riyadh, Kingdom of Saudi Arabia, between November 2015 and January 2016. The questionnaire included questions related to residents' demographic data and their emotions, attitudes, and knowledge related to an MERS outbreak. Results: Of the 228 participants analyzed, 85.5% believed their work put them at risk of infection, and two-thirds believed their family was exposed to a greater risk of infection. However, only 2.6% would change their job. Nearly half of the residents indicated that their hospital had a clear plan, and only 28% considered themselves not well prepared for an MERS outbreak. Conclusions: Our study highlights medical residents' attitude and emotions related to MERS outbreaks. Residents' concerns and emotions in relation to MERS should be considered in greater detail by hospital policymakers. PMID- 28889154 TI - Factors influencing the psychology and quality of life in lung cancer patients. AB - OBJECTIVES: To determine the factors closely correlated with the unhealthy psychological status of patients with lung cancer and to ascertain whether the unhealthy psychology adversely affects their quality-of-life (QOL). Methods: Patients newly diagnosed with lung cancer between May 2013 and December 2015 in the Department of Thoracic Surgery, Tianjin 4th Centre Hospital, Tianjin, China were enrolled in this cross-sectional study. Patients were asked to complete the Symptom Checklist 90 (SCL-90) and Quality of Life Questionnaire (QLQ-C30) survey. From the responses, the correlation between the patient's psychological status and QOL were analyzed with respect to several variables. Results: From the total of 258 patients subjected to the test, 168 belonged to the unhealthy psychology group and 90 to the healthy psychology group. Multiple regression analysis revealed that significant factors related to poor QOL among the 2 groups are gender (p=0.02), younger age (p=0.001), surgical history (p=0.04), employment status (p=0.03), and medical insurance (p=0.01) significantly predicted the severity of unhealthy psychology in lung cancer patients. A significantly negative correlation was noted between the points of SCL-90 and the general QOL in all included patients (p=0.03). Conclusion: Gender, younger age, surgical history, employment status, and medical insurance significantly predicted the severity of unhealthy psychology in lung cancer patients. PMID- 28889155 TI - Comparison of 3 different regional block techniques in pediatric patients. A prospective randomized single-blinded study. AB - OBJECTIVES: To compare the analgesic efficiencies of caudal blocks, ultrasound (US)-guided transversus abdominis plane (TAP) blocks, and ilio-inguinal/ilio hypogastric (II/IH) blocks performed to provide postoperative analgesia in pediatric patients undergoing unilateral lower abdominal surgery. Methods: This prospective, randomized, single-blinded study was conducted in the Department of Pediatric Surgery, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey from July 2013 to January 2015. The doses used were as follows: 0.5 ml/kg (group T), 0.3 ml/kg (group I), and 0.7 ml/kg (group C) of a 0.25% levobupivacaine solution with 1/200,000 adrenalin for the TAP block, II/IH block, and caudal block. The primary aim was to compare postoperative analgesic consumption within the first 24 hours after surgery. The secondary aim were to compare the mCHEOPS score, first analgesic requirement time, vital signs, and undesirable effects such as nausea and vomiting, which were recorded in the surgical ward at 1, 4, 8, 16, and 24 hours after surgery. Results: Ninety patients with American Society of Anesthesiology physical status class I-II were randomized into 3 groups (group I, group T, and group C). The total amount of analgesic consumption was significantly higher in Group I compared with Groups T and C (p=0.003). Pain scores at 1, 4, and 8 hours were significantly higher in Group I compared with the other 2 groups; however, pain scores in Group I at 16 hours were significantly higher only compared with Group C (p less than 0.05). Conclusion: Caudal and TAP blocks are more effective than II/IH nerve blocks in the early postoperative period. PMID- 28889156 TI - Oxidative damage and associated inflammatory risk factors in obese Emirati women. Body mass index versus waist circumference. AB - OBJECTIVES: To establish whether body mass index (BMI) or waist circumference (WC) is a better predictor of cardio metabolic risk factors that are associated with increased visceral fat among obese women from the United Arab Emirates (UAE). METHODS: In this cross-sectional study, 333 obese subjects visiting community health centers in Al Ain city, UAE, were recruited between 2012 and 2015. After a written consent subjects had anthropometric, clinical and biochemical measurements. Fasting serum and plasma samples were collected for the measurement of markers of oxidative damage, antioxidants and inflammation. Outcome measures were compared between 4 equal BMI and WC quartiles. RESULTS: We observed significantly higher blood pressure, c-reactive protein levels, IL6 levels, and protein carbonyls contents and lower beta-carotene levels in the fourth quartile than in the first quartile for both BMI and WC (p less than 0.01). Glutathione peroxidase and adiponectin both decreased and TNF-alpha increased with increasing WC quartiles but not BMI quartiles; however, the results were statistically significant only for TNF-alpha (p=0.032). Conclusion: Both elevated BMI and elevated WC are associated with increased cardio metabolic risk factors in obese Emirati women; however, WC is a stronger predictor than is BMI. PMID- 28889157 TI - Epidemiologic characteristics of gastric malignancies among Jordan University Hospital patients. AB - OBJECTIVES: To discover the epidemiologic distribution of gastric malignancies among Jordan University Hospital patients and to compare this distribution with the neighboring Arab countries. Methods: Retrospective study covering the period between January 2006, and May 2016, in Jordan University Hospital, Amman, Jordan. All cases were retrieved from the computer system and analyzed using IBM SPSS version 23 software. Results: One hundred and sixty-five cases were analyzed. Male-to-female ratio was 1.2:1. The mean age was 58.6 with 32.1% of patients aged 50 or younger. Primary adenocarcinoma was the most common tumor, half of which were diffuse type, followed by carcinoid tumors (15.2 %), lymphomas (10.3%), and gastrointestinal stromal tumors (8.5%). Proximally located tumors accounted for 15.4%. Helicobacter pylori were present in approximately half of the cases and 34.6% of cases contained intestinal metaplasia. Conclusion: Jordan is a low-risk area for gastric cancer, but carcinoma occurs at a young age and is associated with gastritis, Helicobacter pylori infection, and intestinal metaplasia in a large proportion of cases. Better strategic health planning and early detection is needed, especially in young patients suffering from gastritis. PMID- 28889159 TI - Journal of Allied Health, Production Data 2016-2017. AB - During the period September 1, 2016 to August 31, 2017, the following breakdown shows what occurred involving the Journal of Allied Health. Each year, the acceptance rate is in the 60-65% range for all manuscript types. The final result for these 130 papers will not be known until decisions are made regarding the 72 manuscripts still pending. PMID- 28889158 TI - Detection and identification of cutaneous leishmaniasis isolates by culture, Polymerase chain reaction and sequence analyses in Syrian and Central Anatolia patients. AB - OBJECTIVES: To characterize the cutaneous leishmaniasis (CL) isolates of Syrian and Central Anatolia patients at species levels. Methods: Skin scrapings of 3 patients (2 Syrian, 1 Turkish) were taken and examined by direct examination, culture in Novy-MacNeal-Nicole (NNN) medium, internal transcribed spacer polymerase chain reaction and sequence analysis (PCR). Results:According to microscopic examination, culture and PCR methods, 3 samples were detected positive. The sequencing results of all isolates in the study were identified as Leishmania tropica. The same genotypes were detected in the 3 isolates and nucleotide sequence submitted into GenBank with the accession number: KP689599. Conclusion: This finding could give information about the transmission of CL between Turkey and Syria. Because of the Syrian civil war, most of the Syrian citizens circulating in Turkey and different part of Europe, this can be increase the risk of spreading the disease. So, prevention measurements must be taken urgently. PMID- 28889160 TI - Interprofessional Education in Allied Health Using Virtual Technologies. AB - BACKGROUND: Interprofessional education (IPE) is becoming increasingly prevalent in health science education, with the goal of preparing students to work collaboratively in teams within the healthcare environment. Students in our cytotechnology and radiation therapy (RT) programs used virtual technologies to demonstrate their professions using case studies. The purpose of this activity was to see if our students' knowledge of each other's professions and educational technologies increased and if the students had a better understanding of how they would work together in a healthcare team. METHODS: Participants included four cytotechnology students and five RT students. All were given a presurvey to determine their level of knowledge about each other's profession. The cytotechnology students presented cases involving gynecologic and lung cancers using virtual microscopy and explained how they screen slides and interpret cellular changes. The RT students explained how they would treat these same patients using the Virtual Environment Radiotherapy Training system (VERT), showing the cytotechnology students how the beam is guided to the exact spot for treatment. After the IPE activity, all participants were given a post-survey to determine their levels of understanding. RESULTS: The results indicated that the IPE activity increased the level of understanding regarding each other's professions and how they each fit together in the role of patient care. CONCLUSIONS: IPE activities, even on a small scale with two professions in the same college, can improve knowledge and collaboration between professions. More of these activities should be conducted for effective healthcare teams and improved patient outcomes. PMID- 28889161 TI - Employers' Viewpoint on Clinical Education. AB - ISSUE: This qualitative study gathered the opinions of healthcare employers to better understand the importance, benefits, obstacles, and evolving issues related to allied health (AH) clinical education from the employers' perspective, with the goal to identify opportunities to strengthen and improve clinical educational partnerships. METHOD: Member deans of the Association of Schools of Allied Health Professions (ASAHP) provided names and contact information of employers that routinely educate their students. Interviews were scheduled with employers who responded to Clinical Education Task Force (CETF) invitation. Twenty-one interviews were conducted by CETF members in early 2016 and analyzed utilizing qualitative software. OUTCOMES: Themes included benefits of working with students and hiring trainees, and obstacles of time and effort required to host students. A trend was noted in gaps between educational preparation and clinical performance. Recent changes highlighted increased technology and regulation, while anticipated changes included more focus on learning on site, longer clinical experiences, and payment for clinical education. CONCLUSION: Collaboration between educators and employers is essential to ensure that curriculum and outcomes match the needs of the field and effectively prepare students as entry-level clinicians. PMID- 28889162 TI - Meaningful Functional Change Achieved from Physical Therapy Provided in a Student Run Pro Bono Clinic. AB - OBJECTIVE: This study investigated whether patients with chronic neurologic diagnoses who attended a student-run pro bono physical therapy (PT) clinic achieved the minimum detectable change (MDC) on functional measures and the factors associated with such change. METHODS: Retrospective chart review included 71 patients with a primary diagnosis of stroke, traumatic brain injury, or multiple sclerosis from 2010 to 2014. The sample was 45% female, with a mean age of 62 yrs (SD 12.6) and mean 7.9 yrs (10.1) postdiagnosis. Second-year DPT students provided supervised weekly sessions. Meaningful functional change was defined as the achievement of the MDC on one functional outcome measure. Multivariate logistic regression, controlled for semester, was used to analyze factors associated with achievement of MDC. RESULTS: MDC was achieved in approximately 70% of cases. Factors associated with MDC achievement were number of visits (OR 1.04, p<0.02) and the Charlson Comorbidity Index (OR 1.06, p<0.02). Factors not associated were age, sex, diagnosis, years post-diagnosis, number of medications, admission functional status, and distance to the clinic. CONCLUSIONS: Weekly 60-min PT sessions provided in a student-run neurologic clinic were associated with achieving the MDC on functional measures. Such clinics may be a safety net. PMID- 28889163 TI - The Future of Clinical Education: Using Futuristic Scenarios to Explore Allied Health Deans' Perspectives on Clinical Education. AB - ISSUE: There is limited information and consensus on the future of clinical education. The Delphi technique was selected to identify agreement among Association of Schools of Allied Health Professions' (ASAHP) allied health deans on the future (2018-2023) of allied health (AH) clinical education. METHODS: Sixty-one AH deans, 54.9% (61 of 111) of the ASAHP membership, expressed opinions about clinical education through a three-round Delphi study. In conjunction with a conceptual model, four futuristic scenarios were used to encourage deans' feedback on the key factors impacting the future of clinical education. RESULTS: The responses to the four scenarios showed ways the external environment influences which activities the deans recommend. The results presented, by individual scenario and in totality, provide relevant and timely information on the importance and transformation of AH clinical education and its future. DISCUSSION: Futuristic scenarios, in combination with the Delphi technique, generated information where little exists specific to AH deans' perspectives on AH clinical education. The results offer deans opportunities for future strategic improvements. CONCLUSION: The use of the futuristic scenarios was suitable for guiding deans' responses and reaching agreement on the future of AH clinical education. These contributions reflect the imminent conditions and healthcare environment identified in the various scenarios and provide additional insight on key factors impacting the future for AH clinical education. PMID- 28889164 TI - Reliability of Ultrasound Imaging for Lumbar Multifidus Muscle: Capturing Video vs Static Images. AB - OBJECTIVE: Ultrasound imaging is a widely used method for viewing musculoskeletal tissues. However, capturing movies of lumbar multifidus (LM) muscle with ultrasound imaging (video method) is a relatively new method, and its reliability has not been fully tested. The objective of this study was to compare the intra rater reliability of two methods of ultrasound imaging of LM muscle, the traditional method (static images) and the video method, in healthy subjects conducted by a novice rater. METHODS: Images of LM thickness in 15 healthy subjects were captured and measured by static images and video methods. Intra class correlation coefficient (ICC) with 95% confidence interval, standard error of measurement, and minimal detectable change were calculated to determine the reliability and precision of the LM thickness measurements. RESULTS: Excellent intra-rater reliability was demonstrated in measuring LM muscle thickness using both methods, with the intra-rater ICC ranging from 0.75 to 0.95. CONCLUSION: The reliability of the LM thickness measurements in video ultrasound is similar to that in the static images method in healthy subjects. PMID- 28889165 TI - Impact of Student Response Systems on Initial Learning and Retention of Course Content in Health Sciences Students. AB - OBJECTIVE: To assess student learning in two intervention courses when using a student response system (SRS) in combination with content quizzes (CQ) as a teaching/ learning strategy. METHODS: A within-subject design was used to evaluate the effectiveness of SRS use in combination with CQ on initial learning and retention of course content across two health science graduate-level courses. Thirty-three graduate students were enrolled in each course, and 24 participated in the study. Course exam questions were divided between content covered with standard course instruction including CQ and content covered with CQ and the SRS (CQ-SRS). Performance on these exam questions was analyzed with a two-tailed t test, and odds ratios were calculated. RESULTS: Students performed significantly better 6 months later on CQ-SRS-based questions. CONCLUSION: Findings of this study suggest that use of a SRS with CQ supports initial learning and enhances long-term retention of course content better than use of CQ alone. PMID- 28889166 TI - Clinical Performance and Admission Variables as Predictors of Passage of the National Physical Therapy Examination. AB - : Prior studies have explored variables that had predictive relationships with National Physical Therapy Examination (NPTE) score or NPTE failure. The purpose of this study was to explore whether certain variables were predictive of test takers' first-time score on the NPTE. SUBJECTS: The population consisted of 134 students who graduated from the university's Professional DPT Program in 2012 to 2014. METHODS: This quantitative study used a retrospective design. Two separate data analyses were conducted. First, hierarchical linear multiple regression (HMR) analysis was performed to determine which variables were predictive of first-time NPTE score. Second, a correlation analysis was performed on all 18 Physical Therapy Clinical Performance Instrument (PT CPI) 2006 category scores obtained during the first long-term clinical rotation, overall PT CPI 2006 score, and NPTE passage. RESULTS: With all variables entered, the HMR model predicted 39% of the variance seen in NPTE scores. The HMR results showed that physical therapy program first-year GPA (1PTGPA) was the strongest predictor and explained 24% of the variance in NPTE scores (b=0.572, p<0.001). The correlational analysis found no statistically significant correlation between the 18 PT CPI 2006 category scores, overall PT CPI 2006 score, and NPTE passage. DISCUSSION: As 1PTGPA had the most significant contribution to prediction of NPTE scores, programs need to monitor first-year students who display academic difficulty. PT CPI version 2006 scores were significantly correlated with each other, but not with NPTE score or NPTE passage. Both tools measure many of the same professional requirements but use different modes of assessment, and they may be considered complementary tools to gain a full picture of both the student's ability and skills. PMID- 28889167 TI - Does Simulation-Based Training Increase Athletic Training Students' Clinical Confidence and Competence in Performing a Cardiovascular Screening? AB - CONTEXT: The incidence of sudden cardiac death (SCD) in athletes is higher than previously estimated. The need for increased screening to detect cardiac diseases in preparticipation physical examinations (PPE) has become a focus in athletic training. The use of simulation-based training in healthcare professionals' education has increased clinical confidence and competence, but research is limited. OBJECTIVE: To examine if a simulation-based educational intervention can increase athletic training students' self-reported confidence and clinical competence in conducting a cardiovascular screening. DESIGN: Pretest-posttest design. METHODS: 25 first-year athletic training students in a professional master's program participated. The intervention consisted of a standardized cardiovascular curriculum consisting of a 45-minute, interactive instructor-led session and a 45-minute audio session which included repetitions of heart murmurs. Learner self-reported confidence scale, multiple-choice knowledge exam, and objective structured clinical examination (OSCE) of cardiovascular assessment skills and auditory recognition of heart murmurs were recorded. RESULTS: Self reported confidence increased significantly from 4.4+/-2.1 to 9.2+/-3.0 post intervention (F=78.7, p<0.001) with a moderately high effect size (n2=0.789). Knowledge exam scores increased significantly from 11.0+/-2.5 to 13.6+/-4.0 post intervention (F=5.3, p=0.031) with a low effect size (n2=0.191). The history taking assessment of the OSCE increased significantly from 2.6+/-1.6 to 5.7+/-1.7 post-intervention (F=70.1, p<0.001) with a moderately high effect size (n2=0.751). The clinical skills assessment of the OSCE increased significantly from 4.1+/-2.8 to 15.6+/-1.6 post-intervention (F=415.4, p<0.001) with a high effect size (n2=0.952). CONCLUSIONS: Simulation-based training is an effective tool for increasing athletic training students' self-reported confidence and competence in conducting a cardiovascular screening. PMID- 28889168 TI - Professionalism Values in Health Science Education: Self- and Peer-Assessment of Faculty, Staff, and Students. AB - PURPOSE: Professionalism values are critical to developing health science students. Although many educational programs strive to develop professionalism values within students, few include faculty and staff. We evaluated the professional values of our faculty, staff, and students and evaluated the acceptance of this professionalism program. METHODS: Faculty members adopted a 5 item professionalism assessment survey (honesty, teamwork, responsibility, respect, and communication) and performed a 360 degrees peer assessment among our basic/applied science faculty, clinical faculty, and administrative staff. Data were collected for 3 consecutive years (2013-2015). The 37 students were also assessed as part of their inter-professional education (IPE) program. RESULTS: Peer rankings were stable across years from 2013-2015 for faculty and staff. Faculty with expertise in teaching clinical skills rated "teamwork" (higher) and "respect" (lower), differently from our basic/applied science faculty (p<0.001 and p=0.023, respectively). Faculty and staff supported that the 360 degrees assessments were of value for their own professional development. Student assessments revealed improved "verbal communication" and "teamwork" (p=0.003 and 0.02, respectively) after working in IPE groups during the semester. CONCLUSIONS: An annual professionalism assessment program appears to be one important component to developing professional values among faculty, staff, and students in the health sciences. PMID- 28889169 TI - Creating Rural Allied Health Leadership Structures Using District Advisors: An Action Research Project Using Program Logic. AB - BACKGROUND: District advisors in five allied health disciplines were introduced in a local health district in rural Australia in 2013. These strategic leadership roles provide support to clinicians and managers. As there is little research exploring allied health leadership models from a strategic and operational perspective, the coordinated commencement of these roles provided opportunity to study the creation of this leadership structure. METHODS: Four advisors participated in this action research study which used focus groups and program logic processes to explore the inputs, outputs, barriers, outcomes to date, and preferred future outcomes of the leadership model. A purpose-built questionnaire was sent to 134 allied health clinicians or managers with questionnaire responses used by advisors to visualise the leadership model. RESULTS: Advisors prioritised policy development, representing the profession outside the organisation, and supporting department managers, whilst clinicians prioritised communication and connection-building within the organisation. Outcomes of the leadership model included connection, coordination, and advocacy for clinicians. Future preferred outcomes included increased strategic and workforce planning. Barriers included limited time, a widespread workforce and limited resourcing. CONCLUSIONS: Instituting a leadership model improved communication, cohesion, and coordination within the organisation. Future increases in workforce planning and coordination are limited by advisor capacity and competing workloads. PMID- 28889170 TI - Embedding Volunteer Activity into Paramedic Education. AB - BACKGROUND: Paramedics require a wide range of skills that are beyond clinical or technical skills in order to meet the demands of the role and provide quality and compassionate care to patients. Non-technical or "soft" skills and attributes are generally challenging to teach and develop in the classroom setting. Volunteerism provides an opportunity for students to gain exposure to different communities and develop interpersonal skills. METHODS: This cross-sectional study used one-on one interviews with 12 third-year Bachelor of Emergency Health (Paramedic) students from Monash University, Australia, who completed a community volunteering program. RESULTS: Results suggest that paramedic students see volunteering as a highly valuable means of developing a number of skills crucial to their future roles and paramedic practice. Volunteering also provided students with an opportunity to learn about themselves and the broader community, develop confidence, and improve overall job-readiness and employability. CONCLUSIONS: This study demonstrates that embedding volunteering into paramedic education is an effective way to develop the broad range of paramedic attributes required for the role. These experiences allow students to make the important transition to a job-ready graduate paramedic who can provide holistic patient-centred care. PMID- 28889171 TI - Considering Recent Trends in Healthcare Labor Markets in Educational Program Planning in Allied Health. AB - Recent trends in wages and employment should be considered to help inform recruitment and expansion planning for educational programs related to the future healthcare workforce. We present a relatively straightforward method for assessing a broad set of health labor market trends from 2010 to 2014 based on the number employed and wage rates across all healthcare-related occupational categories available from the Occupational Employment Statistics data. To focus more on trends within the healthcare sector, we used the relative wages and employment of the occupations compared to medical doctors. Of 19 broad occupational categories, pharmacists, physician assistants, and occupational and physical therapists have been experiencing a growth in demand relative to medical doctors as evidenced by a growth in relative wages and employment. There is also clear evidence of a reduction in the relative supply of allied health workers. Specifically, across all allied healthcare workers, there was an increase in relative wages (2.28%) and a decline in relative employment (-3.64%). Occupations with increases in wages and number employed are likely to be good areas for programs to expand both in terms of the future economic welfare of their graduates and to help meet market demand. PMID- 28889172 TI - Service-Learning Enhances Physical Therapy Students' Ability to Examine Fall Risk in Older Adults. AB - : Service-learning (SL) is one educational methodology that provides students opportunities to practice and refine affective, cognitive and psychomotor skills in a community-based setting. PURPOSE: The aims of this study were: 1) to investigate the impact of SL on physical therapy (PT) students' attitudes and perceived clinical competence when working with older adults, and 2) to evaluate the difference between perceptions of students who developed and implemented the SL activity vs those who implemented only. METHODS: Eighty PT students, (from two consecutive cohorts) enrolled in a first-year geriatrics course, participated in this study. The first cohort designed and implemented the SL activities, while the second cohort only implemented these activities. Student self-perceived anxiety, confidence, knowledge and skills were assessed by pre- and post-SL surveys using a 5- point Likert-like scale. RESULTS: Both cohorts reported similar anxiety and confidence levels pre-SL. For both cohorts, with the exception of one item, all responses to anxiety items significantly decreased from pre- to post-SL. All students' confidence levels for assessing and mitigating fall risk in older adults increased post-SL (p<0.01). Moreover, students in cohort 1, who designed and delivered SL activities, expressed self perceived improvement in their ability to interpret results of evaluations, to determine type and severity of balance impairments, and to serve a geriatric population (p<0.05) compared to students in cohort 2 who only implemented the activities. CONCLUSION: Embedding SL into a geriatrics course decreased self perceived anxiety and improved student confidence regarding working with older adults. Also, empowering students to be actively involved in the design and implementation of SL increased self-perceived ability in interpreting results from assessments. PMID- 28889173 TI - The impact of fellowship surgical training on operative time and patient morbidity during robotics-assisted sacrocolpopexy. AB - INTRODUCTION AND HYPOTHESIS: Abdominal sacrocolpopexy is commonly performed for the surgical correction of pelvic organ prolapse (POP) in the USA. Over the last decade, fellowship programs have increased the number of these procedures performed robotically. Currently, there is a paucity of literature exploring the impact of fellowship training on outcomes of robotic-assisted sacrocolpopexy (RASC). We sought to explore the impact of an expert surgeon operating alone versus with a fellow on operative time and perioperative morbidity associated with RASC. METHODS: This is an analysis of a retrospectively collected cohort of all RASCs performed to treat POP from June 2010 to August 2015 by a single attending surgeon. Outcomes were compared by expert surgeon alone and with a fellow. RESULTS: We identified 208 RASCs, of which 124 (59.6%) were performed by an expert surgeon alone and 84 (40.4%) with a fellow. Eight fellows were included, with a median of 7 cases (interquartile range 5-13.5). Cases with fellows were 31.1 min longer than an expert surgeon alone (155.6 vs 124.5 min, p < 0.001), a 25% increase. Increased operative time for fellows remained significant on multivariate regression (34.2 min, p < 0.001) after adjusting for case order postmenopausal status, hysterectomy, mid-urethral sling, and bowel injury. Years in fellowship did not have an impact on operative time (p = 0.80). Complications were seen in 34 women (16.4%). On univariate regression, fellows did not have an impact on complications (OR 1.49, 95% CI [0.65-3.43]), which was unchanged on multivariate regression (OR 0.628, 95% CI [0.26-1.54]). Prolapse recurrence was seen in 19 women (9.5%). Fellows had no impact on prolapse recurrence (OR 0.478, 95% CI [0.17-1.38]), which was unchanged on multivariate regression (OR 0.266, 95% CI [0.17-1.49]). CONCLUSION: When an expert surgeon operated together with a fellow, operative time increased by 34 min without increasing prolapse recurrence or complications. PMID- 28889174 TI - Individual and Combined Toxicities of Benzo[a]pyrene and 2,2',4,4' Tetrabromodiphenyl Ether on Early Life Stages of the Pacific Oyster, Crassostrea gigas. AB - Persistent organic pollutants (POPs) are ubiquitous and coexisted in the aquatic environment. Individual and combined toxic effects of benzo[a]pyrene (BaP) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) on embryogenesis, and larval survival of the Pacific oyster were investigated. The EC50 values of BaP, BDE-47 and their mixture on embryogenesis were 18.4, 203.3 and 72.0 ug/L respectively, while the LC50 values for 96 h larval mortality were 26.8, 244.5 and 108.9 ug/L respectively. The Marking-Dawson additive toxicity indices were -0.02 and -0.19, indicating an additive effect with a trend to antagonism. In addition, DNA strand breaks were also observed in oyster embryos after exposure. Our study suggests that BaP and BDE-47 exposure can cause developmental abnormalities, DNA damage and larval mortality. Furthermore, the toxicity of the mixture is slightly lower than individual pollutant. These data will be helpful to predict the toxicity of organic pollutants, and provide criteria for marine water quality standards. PMID- 28889175 TI - Expression of the lef5 gene from Spodoptera exigua multiple nucleopolyhedrovirus contributes to the baculovirus stability in cell culture. AB - Baculoviruses are a broad group of viruses infecting insects, predominately of the order Lepidoptera. They are used worldwide as biological insecticides and as expression vectors to produce recombinant proteins. Baculoviruses replicate in their host, although several cell lines have been developed for in vitro replication. Nevertheless, replication of baculoviruses in cell culture involves the generation of defective viruses with a decrease in productivity and virulence. Transcriptional studies of the Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV) and the Autographa californica multiple nucleopolyhedrovirus (AcMNPV) infective process revealed differences in the expression patterns when the virus replicated under in vitro (Se301 cells) or in vivo (S. exigua larvae) conditions. The late expression factor 5 (lef5) gene was found to be highly overexpressed when the virus replicates in larvae. To test the possible role of lef5 expression in viral stability, recombinant AcMNPV expressing the lef5 gene from SeMNPV (Se-lef5) was generated and its stability was monitored during successive infection passages in Sf21 cells by evaluating the loss of several essential and non-essential genes. The gfp transgene was more stable in those viruses expressing the Se-LEF5 protein and the GFP-defective viruses were accumulated at a lower level when compared to its control viruses, confirming the positive influence of lef5 in viral stability during the multiplication process. This work describes for the first time a viral factor involved in transgene stability when baculoviruses replicate in cell culture, opening new ways to facilitate the in vitro production of recombinant proteins using baculovirus. PMID- 28889176 TI - Proton pump inhibitors have pH-dependent effects on the thermostability of the carboxyl-terminal domain of voltage-gated proton channel Hv1. AB - The voltage-gated proton channel Hv1 is highly selective for H+ and is activated by membrane depolarization and pH gradient. An increased external and decreased internal pH opens the Hv1 channel. The intracellular C-terminal domain of Hv1 is responsible for channel dimerization, cooperative, and thermosensitive gating. Here, we found that proton pump inhibitors (PPIs) interact with the C-terminal domain of human Hv1. The interaction between PPIs and the C-terminal domain, which is pH-dependent, lowered the thermal and structural stability of the protein at pH 4, but enhanced the thermal and structural stability at pH 8. Furthermore, we investigated in vitro the interaction of PPIs with the C-terminal domain of Hv1 by fluorescence and micro-Raman spectra. Fluorescence quenching measurements revealed that the interaction between the C-terminal domain and PPIs is a mainly hydrophobic interaction. The micro-Raman spectra showed that PPIs did not form stable disulfide bonds with the unique thiol group within this domain (Cys249 residue). The preferential interaction of PPIs with the inactive form of Hv1 stabilizes the high pH inactive state of the C-terminal domain, indicating a mechanism by which PPIs might act explicitly on the stabilization of a closed state of the proton channel. PMID- 28889177 TI - A 15-amino acid C-terminal peptide of beta-defensin-3 inhibits bone resorption by inhibiting the osteoclast differentiation and disrupting podosome belt formation. AB - : Human beta-defensin-3 (HBD3), which is secreted from cells in the skin, salivary gland, and bone marrow, exhibits antimicrobial and immunomodulatory activities. Its C-terminal end contains a 15-amino acid polypeptide (HBD3-C15) that is known to effectively elicit antimicrobial activity. Recently, certain antimicrobial peptides are known to inhibit osteoclast differentiation and, thus, we investigated whether HBD3-C15 hinders osteoclast differentiation and bone destruction to assess its potential use as an anti-bone resorption agent. HBD3 C15 inhibited the receptor activator of nuclear factor kappaB ligand (RANKL) induced osteoclast differentiation and formation of resorption pits. In addition, HBD3-C15 disrupted the formation of RANKL-induced podosome belt which is a feature typically found in mature osteoclasts with bone-resorbing capacity. HBD3 C15 downregulated cortactin, cofilin, and vinculin, which are involved in the podosome belt formation. Furthermore, bone loss induced by RANKL was significantly reduced in a mouse calvarial implantation model that was treated with HBD3-C15. Similar inhibitory effects were observed on the osteoclast differentiation and podosome belt formation induced by Aggregatibacter actinomycetemcomitans lipopolysaccharide (AaLPS). Concordantly, HBD3-C15 attenuated the resorption in the calvarial bone of AaLPS-implanted mouse. Collectively, these results suggest that HBD3-C15 has an anti-bone resorption effect in developing osteoclasts and that this occurs via its disruption of podosome belt formation. HBD3-C15 could be a potential therapeutic agent for the inhibition of bone destruction. KEY MESSAGES: HBD3-C15 inhibits osteoclast differentiation and bone resorption capacity. HBD3-C15 disrupts the podosome belt formation in osteoclasts. HBD3-C15 alleviates the bone loss by RANKL or A. actinomycetemcomitans LPS in vivo. PMID- 28889178 TI - Music and speech distractors disrupt sensorimotor synchronization: effects of musical training. AB - Humans display a natural tendency to move to the beat of music, more than to the rhythm of any other auditory stimulus. We typically move with music, but rarely with speech. This proclivity is apparent early during development and can be further developed over the years via joint dancing, singing, or instrument playing. Synchronization of movement to the beat can thus improve with age, but also with musical experience. In a previous study, we found that music perturbed synchronization with a metronome more than speech fragments; music superiority disappeared when distractors shared isochrony and the same meter (Dalla Bella et al., PLoS One 8(8):e71945, 2013). Here, we examined if the interfering effect of music and speech distractors in a synchronization task is influenced by musical training. Musicians and non-musicians synchronized by producing finger force pulses to the sounds of a metronome while music and speech distractors were presented at one of various phase relationships with respect to the target. Distractors were familiar musical excerpts and fragments of children poetry comparable in terms of beat/stress isochrony. Music perturbed synchronization with the metronome more than speech did in both groups. However, the difference in synchronization error between music and speech distractors was smaller for musicians than for non-musicians, especially when the peak force of movement is reached. These findings point to a link between musical training and timing of sensorimotor synchronization when reacting to music and speech distractors. PMID- 28889179 TI - Evaluation of outdoor human thermal sensation of local climate zones based on long-term database. AB - This study gives a comprehensive picture on the diurnal and seasonal general outdoor human thermal sensation levels in different urban quarters based on long term (almost 3 years) data series from urban and rural areas of Szeged, Hungary. It is supplemented with a case study dealing with an extreme heat wave period which is more and more frequent in the last decades in the study area. The intra urban comparison is based on a thermal aspect classification of the surface, namely, the local climate zone (LCZ) system, on an urban meteorological station network and on the utilization of the physiologically equivalent temperature (PET) comfort index with categories calibrated to the local population. The selected stations represent sunlit areas well inside the LCZ areas. The results show that the seasonal and annual average magnitudes of the thermal load exerted by LCZs in the afternoon and evening follow their LCZ numbers. It is perfectly in line with the LCZ concept originally concentrating only on air temperature (T air) differences between the zones. Our results justified the subdivision of urban areas into LCZs and give significant support to the application possibilities of the LCZ concept as a broader term covering different thermal phenomena. PMID- 28889180 TI - The degree of cartilage degradation assessed by serum biomarker levels changes after arthroscopic knee synovectomy in rheumatoid arthritis patients. AB - PURPOSE: In order to test the validity of the selected surgical technique as a way to manage persistent synovitis of the knee joint, as well as to slow down the cartilage and bone destruction, we studied the dynamics of biomarkers of inflammatory conditions, and bone and cartilage destruction after total arthroscopic synovectomy (TAS) of the knee joint. METHODS: The sampling comprised 124 RA patients (158 knees) who had undergone the TAS procedure between 2003 and 2015. Before surgery the rheumatoid factor (IgM), C-reactive protein (CRP), erythrocyte sedimentation rate test was completed for all patients. Blood serum samples were collected (prior to surgery, and three, six and 12 months after surgery) and frozen at -70 degrees S. The content of CRP, Matrix metalloproteinase-3 (MMP-3), Cartilage Oligomeric Matrix Protein, as well as cross-linked Ctelopeptides of types I and II were measured in blood serum by means of polarization fluoroimmunoassay with the use of a standard set of reagents. RESULTS: The average duration of the disease in the studied group was 8.7 +/- 6.6 years. Concentration of the inflammation markers showed that only MMP 3 displayed statistical significance. CONCLUSIONS: The obtained results can be used as basis in assessing the efficiency and effectiveness of this method of treatment of persistent knee joint synovitis associated with the RA. PMID- 28889181 TI - Humeral lengthening in patients with achondroplasia and in patients with post septic shortening: comparison of procedure efficiency and safety. AB - PURPOSE: Although humeral lengthening in patients with achondroplasia is an accepted procedure for improving functional status, there is still a paucity of information about the effectiveness of the method. Therefore, the aim of this study was to evaluate the efficacy and safety of humeral lengthening using monolateral fixators in patients with achondroplasia and unilateral shortening. METHODS: Twenty-one patients (31 humeri) were included in this study. The study group consisted of eight patients with achondroplasia (16 segments). The control group consisted of 13 patients with post-septic shortening of the humerus (15 segments). All subjects underwent distraction osteogenesis with the use of a monolateral fixator. RESULTS: The mean lengthening in the patients with achondroplasia was 8.29 cm, whereas in the control group it was 7.34 cm (p = 0.1677). The mean lengthening percentage in the patients with achondroplasia (50% of the initial length of the humerus) was significantly greater than in the control group (33% of the initial length of the humerus) (p = 0.0007). The mean healing index was 24.8 days/cm in the patients with achondroplasia and 28.56 days/cm in the control group (p = 0.1832). The overall complication rates for the achondroplastic and post-septic patients were, respectively, 175% and 160% (p = 0.1420). CONCLUSIONS: Humeral lengthening with use of monolateral fixators in patients with achondroplasia is an efficient method. Although the segment lengthening percentage is significantly greater in patients with achondroplasia than in patients with post-septic shortening of the humerus, the safety of this procedure is comparable. PMID- 28889182 TI - Benign extracerebral fluid collection complicated by subdural hematoma and fluid collection: clinical characteristics and management. AB - INTRODUCTION: Benign extracerebral fluid collection (bECFC) can be complicated by subdural hematoma (SDH) or subdural fluid collection (SDFC). The etiology, natural history, and management strategy for SDH/SDFC in bECFC are not fully understood. We retrospectively reviewed the cases of bECFC patients complicated with SDH/SDFC and tried (1) to confirm the fact that bECFC children are vulnerable to SDH/SDFC, (2) to investigate the clinical significance of 'trauma history' witnessed by a caregiver, and (3) to determine optimal management for them. METHOD: Among 213 bECFC patients identified from January 2000 to August 2015, 20 patients (male:female = 14:6; median age, 6.5 months; range 1-16 months) complicated by SDH/SDFC documented with brain imaging were evaluated for their clinical manifestations, radiologic features, and management outcomes. The median follow-up period was 9.5 months. They were divided into two groups (traumatic group versus non-traumatic group) according to whether objective radiologic evidence of head injury was present or not, and the two groups were analyzed for any clinical differences between them. We also evaluated the clinical significance of witnessed traumatic events by caregivers as an additional independent variable in the analysis. RESULTS: The incidence of SDH/SDFC in bECFC patients was 9.4% (20/213) in our data. In a comparative analysis, the traumatic group is more likely to have 'acute' stage SDH, whereas the non-traumatic group is more likely to have 'chronic' stage SDH. The trauma history witnessed by caregivers did not show clinical significance in the data analysis when included as an independent variable. The prognosis of SDH/SDFC in bECFC patients was favorable without surgery in most of patients regardless of whether the patient has evidence of head trauma or not. CONCLUSION: Benign ECFC is vulnerable to SDH/SDFC development. For the bECFC patients complicated by SDH/SDFC, the trauma history witnessed by a caregiver did not show any clinical significance. A 'wait and watch' strategy is sufficient for the management of SDH/SDFC in bECFC patients. PMID- 28889183 TI - Recognizing the importance of an all-inclusive approach to brown bear conservation now and into the future. AB - In their critique of our recent article in Oecologia (Pigeon et al. Oecologia 181:1101-1116, 2016a) investigating the influence of ambient temperature on brown bear habitat selection, Ordiz et al. (2017, current issue) argue that we downplay the role of human disturbance on bear behavior, and that we wrongly report on the findings of Ordiz et al. (Oecologia 166:59-67, 2011). We argue that our previous article in Oecologia (Pigeon et al. 2016a) by no means downplays the influence of human factors on bear behavior, and that we correctly stated that Ordiz et al. (2011) did not adequately consider the potential influence of temperature on their findings. Finally, we stress the relevance of considering all-inclusive approaches to the common goal of successful wildlife conservation. PMID- 28889184 TI - Cartilage oligomeric matrix protein (COMP) in rheumatoid arthritis and its correlation with sonographic knee cartilage thickness and disease activity. AB - The aim of the study is to investigate the correlation of serum cartilage oligomeric matrix protein (COMP) levels with articular cartilage damage based on sonographic knee cartilage thickness (KCT) and disease activity in rheumatoid arthritis (RA). A total of 61 RA patients and 27 healthy controls were recruited in this study. Serum samples were obtained from all subjects to determine the serum COMP levels. All subjects had bilateral ultrasound scan of their knees. The KCT was based on the mean of measurements at three sites: the medial condyle, lateral condyle and intercondylar notch. Besides, the RA patients were assessed for their disease activity based on 28-joint-based Disease Activity Score (DAS 28). Serum COMP concentrations were significantly elevated in the RA patients compared to the controls (p = 0.001). The serum COMP levels had an inverse relationship with bilateral KCT in RA subjects and the healthy controls. COMP correlated significantly with disease activity based on DAS 28 (r = 0.299, p = 0.010), disease duration (r = 0.439, p = < 0.05) and mean left KCT (r = - 0.285, p = 0.014) in RA. The correlation between serum COMP and DAS 28 scores was comparable to the traditional markers of inflammation: erythrocyte sedimentation rate (ESR) (r = 0.372, p = 0.003) and C-reactive protein (CRP) (r = 0.305, p = 0.017). The serum COMP is a promising biomarker in RA which reflects disease activity and damage to the articular cartilage. PMID- 28889185 TI - Statistical approach to quality assessment in liver transplantation. AB - PURPOSE: This study investigated the utility of retrospective two one-sided cumulative sum (CUSUM) charts combined with multivariable regression analysis in liver transplantation for transplant center benchmarking. METHODS: One thousand seven hundred and forty-nine consecutive adult primary liver transplants (January 1, 1983 to December 31, 2012) were analyzed retrospectively with two one-sided CUSUM chart analysis of 90-day mortality. RESULTS: Three eras and two subseries in latest era 3 were identified due to graphically delineated relevant shifts in mean 90-day mortality. Delineation of eras 1, 2, and 3 coincided with relevant changes in allocation policies. CUSUM analysis detected a resurgence of higher mean 90-day mortality in era 3 after results had improved continuously over 25 years. In era 3, two subseries were identified with improving mean 90-day mortality rates from 15.4% in subseries 1 to 8.9% in the following subseries 2. The quantitative influence of independent risk factors on 90-day mortality differed markedly between all identified eras and subseries as assessed with multivariable regression analysis deployed on era-specific subcohorts. CONCLUSION: The assessed methodology is able to identify meaningful center specific eras and subseries of liver transplantation with striking alterations of the significance and weight of outcome drivers for post-transplant 90-day mortality over time. This warrants the introduction of prospective risk-adjusted two one-sided CUSUM chart analysis into quality management in liver transplantation in Germany with the goal to obtain alarm signals as early as possible. PMID- 28889186 TI - Local bone-marrow exposure: how to interpret the data on stable chromosome aberrations in circulating lymphocytes? (some comments on the use of FISH method for dose reconstruction for Techa riverside Residents). AB - The method of fluorescence in situ hybridization (FISH) applied to peripheral blood T lymphocytes is used for retrospective dose estimation, and the results obtained from the analysis of stable chromosomal aberrations are usually interpreted as a dose accumulated in the red bone marrow (RBM). However, after local internal exposure of the RBM, doses derived from FISH were found to be lower than those derived from direct measurements of radionuclides accumulated in the bodies of exposed persons. These results were obtained for people residing near the Techa River contaminated by 89,90Sr (beta-emitters) in 1949-1956 (Chelyabinsk Oblast, Russia). A new analysis has been performed of the combined results of FISH studies (n = 178) undertaken during 1994-2012 for persons living on the Techa Riverside. Analysis confirms the lower slope of the translocation yield per Gy (8.0 +/- 0.7 * 10-3) for Techa residents in comparison with FISH data for donors with external exposures (11.6 +/- 1.6 * 10-3, Tawn et al., Radiat Res 184(3):296-303, 2015). It was suggested that some portion of T cells remained unexposed, because they represented the descendants of T cell progenitors, which had migrated to the thymus before the start of 89,90Sr intakes. To clarify this problem, the dynamics of T-cell Genera (TG), combining all descendants of specific T-cell progenitor reaching the thymus, was considered. Rates of TGs produced by RBM over different age periods of human life were estimated with the use of the mathematic model of T-cell homeostasis (Bains, Mathematical modeling of T-cell homeostasis. A thesis submitted for the degree of Doctor of Philosophy of the University College London. http://discovery.ucl.ac.uk/20159/1/20159.pdf , 2010). The rate of TG loss during the lifetime was assumed to be very small in comparison with production rate. The recirculation of mature T lymphocytes in contaminated RBM was taken into account. According to our model estimates, at the time of blood sampling, the fraction of exposed T lymphocytes (whose progenitors were irradiated) ranged from 20 to 80% depending on the donors' age at the start of exposure to 89,90Sr. Dose to T lymphocytes, estimated from FISH studies, should be about 0.6-0.9 of RBM dose for residents of the upper Techa region and about 0.4-0.8 in the middle Techa region. Our results could explain the lower value of translocation yield per Gy obtained for Techa residents. The approaches for further model improvement and validation are discussed in this paper. PMID- 28889187 TI - Measurements between the hepatic veins and portal venous system, in human cirrhotic liver: a cast study. AB - PURPOSE: To measure the distance between the right and middle hepatic veins and portal vein branches, in human cirrhotic liver casts. Was this measure actually smaller in the cirrhotic liver than in normal one? MATERIALS AND METHODS: This study was authorized by an area Research Ethics Committee, and each study subject or legal representative granted signed informed consent. Acrylic corrosion casts of 21 resected cirrhotic livers were generated. Diameters of hepatic veins and portal branches and pertinent intervening distances were measured. To assess differences in estimated average (relative to reference values), Student's t test for one sample was applied. RESULTS: Mean distances from right hepatic vein to the right portal branch and to portal vein bifurcation were 33 +/- 6.4 and 36 +/- 7.4 mm, respectively, both significantly less than published reference values in healthy human livers (p < 0.0001 and p < 0.0002, respectively). Mean distances from middle hepatic vein to right and left branches of portal vein were 36 +/- 6.8 and 26 +/- 8.8 mm, respectively. CONCLUSION: Distances separating right hepatic vein and portal vein (right branch and bifurcation) are diminished in cirrhotic livers compared to healthy ones. Given its caliber and proximity to portal branches, the middle hepatic vein remains as a reasonable alternative for TIPS procedures. PMID- 28889188 TI - Factors associated with accelerated subclinical atherosclerosis in patients with spondyloarthritis without overt cardiovascular disease. AB - Data on the progression of atherosclerosis in spondyloarthritis (SpA) are scarce, despite a high burden of cardiovascular diseases (CVD). The aim of this study was to identify the predictors of an accelerated subclinical atherosclerosis in patients with SpA. Study participants were 66 patients free of CVD classified according to ASAS criteria. The patients were evaluated at baseline and after 13.5 +/- 3.6 months. Ultrasound measurements of carotid intima-media thickness (cIMT) and distensibility coefficient (cDC) were used to assess the extent of subclinical atherosclerosis. cIMT progression rate was calculated dividing the cIMT change by the time between the scans. Accelerated atherosclerosis was defined as the top cIMT progression rate quartile. At baseline, the mean Framingham Risk Score was 14 +/- 11%. At follow-up, cIMT increased in 39 patients (59%; mean difference 0.01 +/- 0.10; p = 0.334). Mean cIMT progression rate was 0.01 mm/year (95% CI - 0.02 to 0.03). cDC was unchanged at follow-up. Patients with accelerated atherosclerosis (n = 16) had significantly higher serum creatinine and lower glomerular filtration rate (eGFR) at baseline. In multiple logistic regression, only eGFR and the presence of syndesmophytes were associated with an accelerated atherosclerosis, independent of traditional cardiovascular risk factors. In patients with SpA without overt CV disease, a decrease in renal function and radiographic damage are conditions associated with the development of subclinical accelerated atherosclerosis. Longitudinal assessment of cIMT could be useful to better evaluate the individual CV risk of these patients improving their prognostic stratification. PMID- 28889189 TI - Prognostic role of progesterone receptor expression in a population-based analysis. AB - PURPOSE: The role of progesterone (PR) expression in the management of breast cancer is controversial. The aim of this study is to evaluate the characteristics and prognosis of progesterone status among breast cancers patients in a population-based analysis. MATERIALS AND METHODS: Through the Tuscan Cancer Registry data on all the invasive breast cancer cases diagnosed during the period 2004-2005 in the provinces of Florence and Prato, central Italy, were retrieved. Histological reports were re-examined to obtain information on the percentage of positive tumor cells for estrogen (ER), progesterone (PR) receptors, Ki67 marker and human epidermal growth factor 2 (HER2). Information on age, stage, differentiation grade were also obtained. RESULTS: Out of 1487 patients, 28% had PR- breast cancer. These patients were older (p 0.006) than PR+ cancer patients, with more frequently high Ki67 (p < 0.0001), HER2 + (p < 0.0001), ER- (p < 0.0001) tumoral expression. The ER+/PR+ subtype was the most represented (n.1053), while ER-/PR+ was the most rare (n.23); 210 cases (14.1%) ER+ PR- and 201 (13.5%) ER-/PR- cases were found. Analysis of survival by the Cox proportional hazards model showed an independent prognostic value of PR expression (p < 0.0001), also when estrogen, Ki67, HER2 status and age were included. The 5-year cancer-specific survival was 82.1, 86.5, 100, 92% for ER-/PR , ER+/PR-, ER-/PR+, ER+/PR+ subtype, respectively. CONCLUSIONS: Our study revealed significant differences in clinicopathological characteristics among breast cancer according to PR expression and confirmed its prognostic independent role, suggesting a role of PR in the improvement of breast cancer prognostic characterization. PMID- 28889190 TI - Anti-apoptotic role of spermine against lead and/or gamma irradiation-induced hepatotoxicity in male rats. AB - Exposure to either lead (Pb) or gamma-irradiation (IR) results in oxidative stress in biological systems. Herein, we explored the potential anti-apoptotic effect of spermine (Spm) against lead and/or gamma-irradiation-induced hepatotoxicity in male albino rats. Rats were divided into eight experimental groups of ten rats each: groups including negative control, whole body gamma irradiated (6 Gray (Gy)), lead acetate (PbAct) trihydrate orally administered (75 mg/kg bw = 40 mg/kg bw Pb for 14 consecutive days), and Spm intraperitoneally dosed (10 mg/kg bw for 14 consecutive days) rats and groups subjected to combinations of Pb + IR, Spm + IR, Spm + Pb, and Spm + Pb followed by IR on day 14 (Spm + Pb + IR). A significant decrease in arginase activity as well as mRNA and protein levels of Bcl-2 and p21 was observed in rats intoxicated with Pb and/or gamma-irradiation compared to controls, whereas Bax mRNA and protein levels were significantly increased. Also, an increased level of nitric oxide (NO) with a reduced arginase activity was observed in liver tissues of intoxicated rats. Spm co-treatment with lead and/or gamma-irradiation attenuated the increase in Bax mRNA and protein expression, while it restored those of Bcl-2 and p21 together with NO levels and arginase activity to control values. Altogether, we suggest that Spm may be useful in combating free radical-induced apoptosis in Pb-intoxicated and/or gamma-irradiated rats. PMID- 28889191 TI - High tibial slope correlates with increased posterior tibial translation in healthy knees. AB - PURPOSE: Notwithstanding the importance of the tibial slope (TS) for anterior tibial translation, little information is available regarding the implications on posterior laxity, particularly in healthy subjects. It was hypothesized that increased TS is associated with decreased posterior tibial translation (PTT) in healthy knees. METHODS: A total of 124 stress radiographs of healthy knees were enrolled in this study. Tibial slope and the posterior tibial translation were evaluated using a Telos device with a 150-N force at 90 degrees of knee flexion. Two blinded observers reviewed independently on two different occasions. RESULTS: One hundred and twenty-four patients [35 females and 89 males; 41 (range 18-75) years] were enrolled in this study, with a mean PTT of 2.8 mm (+/-1.9 mm; range 0 8 mm) and a mean TS of 8.6 degrees (+/-2.6 degrees ; range 1 degrees -14 degrees ). Pearson correlation showed a significant correlation between the PTT and TS in the overall patient cohort (P < 0.0001) with r = 0.76 and R 2 = 0.58. There was no statistical difference between female and male patients regarding the PTT or the TS. Subgrouping of the patient cohort (four groups with n = 31) according to their TS (groups I < 7 degrees ; II = 7 degrees -8.5 degrees ; III = 9 degrees 10.5 degrees ; IV >= 11 degrees ) revealed significant differences between each subgroup, respectively. Furthermore, there was a weak but significant correlation between age and PTT (P = 0.004, r = 0.26). CONCLUSION: In addition to the substantial variance in tibial slope and posterior laxity among healthy knees, high tibial slope significantly correlates with increased posterior tibial translation. Increasing age is further associated with a greater magnitude of posterior tibial translation. Consequently, knowledge of the tibial slope facilitates simple estimation of posterior knee laxity, which is mandatory for PCL reconstruction and knee arthroplasty. PMID- 28889193 TI - Are obstetric outcomes affected by female genital mutilation? AB - INTRODUCTION AND HYPOTHESIS: Female genital mutilation (FGM) has been associated with adverse obstetric and neonatal outcomes, such as postpartum haemorrhage (PPH), perineal trauma, genital fistulae, obstructed labour and stillbirth. The prevalence of FGM has increased in the UK over the last decade. There are currently no studies available that have explored the obstetric impact of FGM in the UK. The aim of our study was to investigate the obstetric and neonatal outcomes of women with FGM when compared with the general population. METHODS: We conducted a retrospective case-control study of consecutive pregnant women with FGM over a 5-year period between 1 January 2009 and 31 December 2013. Each woman with FGM was matched for age, ethnicity, parity and gestation with subsequent patients without FGM (control cohort) over the same 5-year period. Outcomes assessed were mode of delivery, duration of labour, estimated blood loss, analgaesia, perineal trauma and foetal outcomes. RESULTS: A total of 242 eligible women (121 FGM, 121 control) were identified for the study. There was a significant increase in the use of episiotomy in the FGM group (p = 0.009) and a significant increase in minor PPH in the control group during caesarean sections (p = 0.0001). There were no differences in all other obstetric and neonatal parameters. CONCLUSIONS: In our unit, FGM was not associated with an increased incidence of adverse obstetric and foetal morbidity or mortality. PMID- 28889192 TI - The economic impact of prematurity and bronchopulmonary dysplasia. AB - : Bronchopulmonary dysplasia (BPD) is one of the most serious chronic lung diseases in infancy and one of the most important sequels of premature birth (prevalence of 15-50%). Our objective was to estimate the cost of BPD of one preterm baby, with no other major prematurity-related complications, during the first 2 years of life in Spain. Data from the Spanish Ministry of Health regarding costs of diagnosis-related group of preterm birth, hospital admissions and visits, palivizumab administration, and oxygen therapy in the year 2013 were analyzed. In 2013, 2628 preterm babies were born with a weight under 1500 g; 50.9% were males. The need for respiratory support was 2.5% needed only oxygen therapy, 39.5% required conventional mechanical ventilation, and 14.9% required high-frequency ventilation. The incidence of BPD was of 34.9%. The cost of the first 2 years of life of a preterm baby with BPD and no other major prematurity related complications ranged between 45,049.81 ? and 118,760.43 ?, in Spain, depending on birth weight and gestational age. If the baby required home oxygen therapy or developed pulmonary hypertension, this cost could add up to 181,742.43 ?. CONCLUSION: Prematurity and BPD have an elevated cost, even for public health care systems. This cost will probably increase in the coming years if the incidence and survival of preterm babies keeps rising. The development of new therapies and preventive strategies to decrease the incidence of BPD and other morbidities associated with prematurity should be a priority. What is known: * Bronchopulmonary dysplasia (BPD) is a serious chronic lung disease related with premature birth. * BPD is an increasing disease due to the up-rise in the number of premature births. What is new: * The economic cost of preterm birth and BPD has never before been estimated in Spain nor published with European data. * Preterm babies with BPD and a good clinical outcome carry also an important economic and social burden. PMID- 28889194 TI - Functions of Periostin in dental tissues and its role in periodontal tissues' regeneration. AB - The goal of periodontal regenerative therapy is to predictably restore the tooth's supporting periodontal tissues and form a new connective tissue attachment of periodontal ligament (PDL) fibers and new alveolar bone. Periostin is a matricellular protein so named for its expression primarily in the periosteum and PDL of adult mice. Its biological functions have been widely studied in areas such as cardiovascular physiology and oncology. Despite being initially identified in the dental tissues and bone, investigations of Periostin functions in PDL and alveolar-bone-related physiopathology are less abundant. Recently, several studies have suggested that Periostin may be an important regulator of periodontal tissue formation. By promoting collagen fibrillogenesis and the migration of fibroblasts and osteoblasts, Periostin might play a pivotal part in regeneration of the PDL and alveolar bone following periodontal surgery. The aim of this article is to provide an extensive review of the implications of Periostin in periodontal tissue biology and its potential use in periodontal tissue regeneration. PMID- 28889196 TI - Solid pseudopapillary neoplasm presenting as a primary ovarian mass in an eighteen-year-old female: report of a case and review of the literature. PMID- 28889195 TI - Effect of Si-rich substances on phosphorous adsorption by sandy soils. AB - The poor adsorption capacity of sandy soils is one of the primary reasons of a high level of phosphorus (P) leaching. Silicon (Si)-rich soil amendments have the potential to improve the low absorption capacity of sandy soils for P. The objective of this study was to evaluate the ability of different Si-rich materials to regulate P adsorption and retention by sandy soils. Amorphous fine silica (FSS), calcium silicate (CaSiO3), chemically pure CaCO3, and two types of Ca-silicate slags from metal industry (Pro-Sil) and chemical industry (TS) were used in laboratory experiments being conducted with pure quartz sand and cultivated and virgin Entisols and Spodosols collected in the South Florida. The binding energy-related constants were evaluated for soils treated by Si-rich materials and then incubated during 2 months. The following row of tested materials on the increasing level of "affinity parameter" was determined: for virgin Spodosol, Pro-Sil < CaCO3 < FSS< CaSiO3 < TS; for cultivated Spodosol, FSS < Pro-Sil < CaCO3< CaSiO3 < TS; for virgin Entisol, Pro-Sil < CaSiO3 < CaCO3 < FSS < TS; and for cultivated Entisol, FSS < Pro-Sil < CaSiO3 < CaCO3 < TS. Chemical, physical, and physical-chemical mechanisms of increasing soil adsorption capacity are hypothesized and discussed to explain the results obtained. The conducted experiments have demonstrated high prospective of Si-rich materials for reduction of P leaching from cultivated sandy soils. PMID- 28889198 TI - Polyhydroxyalkanoate production from sucrose by Cupriavidus necator strains harboring csc genes from Escherichia coli W. AB - Cupriavidus necator H16 is the most promising bacterium for industrial production of polyhydroxyalkanoates (PHAs) because of their remarkable ability to accumulate them in the cells. With genetic modifications, this bacterium can produce poly(3 hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx), which has better physical properties, as well as poly(3-hydroxybutyrate) (PHB) using plant oils and sugars as a carbon source. Considering production cost, sucrose is a very attractive raw material because it is inexpensive; however, this bacterium cannot assimilate sucrose. Here, we used the sucrose utilization (csc) genes of Escherichia coli W to generate C. necator strains that can assimilate sucrose. Especially, glucose utilizing recombinant C. necator strains harboring the sucrose hydrolase gene (cscA) and sucrose permease gene (cscB) of E. coli W grew well on sucrose as a sole carbon source and accumulated PHB. In addition, strains introduced with a crotonyl-CoA reductase gene (ccr), ethylmalonyl-CoA decarboxylase gene (emd), and some other genetic modifications besides the csc genes and the glucose-utilizing mutations produced PHBHHx with a 3-hydroxyhexanoate (3HHx) content of maximum approximately 27 mol% from sucrose. Furthermore, when one of the PHBHHx-producing strains was cultured with sucrose solution in a fed-batch fermentation, PHBHHx with a 3HHx content of approximately 4 mol% was produced and reached 113 g/L for 65 h, which is approximately 1.5-fold higher than that produced using glucose solution. PMID- 28889197 TI - Changes in Gene Expression in the Locus Coeruleus-Amygdala Circuitry in Inhibitory Avoidance PTSD Model. AB - The locus coeruleus (LC)-amygdala circuit is implicated in playing a key role in responses to emotionally arousing stimuli and in the manifestation of post traumatic stress disorder (PTSD). Here, we examined changes in gene expression of a number of important mediators of the LC-amygdala circuitry in the inhibition avoidance model of PTSD. After testing for basal acoustic startle response (ASR), rats were exposed to a severe footshock (1.5 mA for 10 s) in the inhibitory avoidance apparatus. They were given contextual situational reminders every 5 day for 25 days. Controls were treated identically but with the footshock inactivated. Animals were re-tested on second ASR and decapitated 1 h later. The shock group had enhanced hyperarousal and several changes in gene expression compared to controls. In the LC, mRNA levels of norepinephrine (NE) biosynthetic enzymes (TH, DBH), NE transporter (NET), NPY receptors (Y1R, Y2R), and CB1 receptor of endocannabinoid system were elevated. In the basolateral amygdala (BLA), there were marked reductions in gene expression for CB1, and especially Y1R, with rise for corticotropin-releasing hormone (CRH) system (CRH, CRH receptor 1), and no significant changes in the central amygdala. Our results suggest a fast forward mechanism in the LC-amygdala circuitry in the shock group. PMID- 28889199 TI - Oral delivery of staphylococcal nuclease by Lactococcus lactis prevents type 1 diabetes mellitus in NOD mice. AB - Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the self-destruction of insulin-producing beta cells. Recently, studies have revealed that neutrophils contribute to the early pathological injury to the pancreas, predominantly via the formation of neutrophil extracellular traps (NETs). To determine whether early intervention targeting NETs with staphylococcal nuclease (SNase) can delay the onset of T1DM, non-obese diabetic (NOD) mice were orally administered recombinant Lactococcus lactis (L. lactis) expressing SNase. The results showed that NETs were effectively disrupted by SNase both in vivo and in vitro, leading to a significant decrease in neutrophil-derived circulating free DNA (cf-DNA/NETs), neutrophil elastase (NE), and protease 3 (PR3) in the serum compared with the controls. In addition, SNase effectively regulated the blood glucose levels of NOD mice, and the onset of diabetes was postponed with reduced mortality and morbidity. Recombinant L. lactis also ameliorated inflammation in NOD mice, as evidenced by the remarkable increase in IL-4 and reductions in TNF alpha and CRP. Moreover, HE staining results showed that L. lactis expressing SNase exerted protective effects on pancreatic islets and relieved inflammation of the small intestine in NOD mice. Hence, the present study indicates that the oral delivery of SNase by L. lactis can effectively prevent T1DM, ameliorate inflammation, and contribute to immunomodulatory balance in NOD mice. PMID- 28889200 TI - Prevalence of common hereditary risk factors for thrombophilia in Somalia and identification of a novel Gln544Arg mutation in coagulation factor V. AB - Thrombophilia, commonly manifested as venous thromboembolism (VTE), is a worldwide concern but little is known on its genetic epidemiology in many parts of the globe particularly in the developing countries. Here we employed TaqMan genotyping and pyrosequencing to evaluate the prevalence of known common nucleotide polymorphisms associated with thrombophilia in a Somali population in the Puntland region of Somalia. We also employed next generation sequencing (NGS) to investigate other genetic variants in a Somali patient with deep venous thrombosis (DVT). As expected, we found no existence of factor V Leiden (rs6025) and prothrombin G20210A (rs1799963) in the Somali population. The G allele of ABO [261G/delG] polymorphism (rs8176719) was found at a frequency of 29%, similar to that observed in other African populations. We found the lowest so far reported frequency of MTHFR C677T (rs1801133) polymorphism in the Somali population (T allele frequency 1.5%). A novel and deleterious single nucleotide variation in exon 11 of coagulation factor V (c.1631A>G) causing Gln544Arg exchange in factor V was identified in a 29 years old Somali female with DVT. The same patient was heterozygous to VKORC1 Asp36Tyr polymorphism (rs61742245) that predisposes to warfarin resistance. In conclusion, this study shows that common hereditary factors for thromboembolism found in Caucasians are either less frequent or absent in the Somali population-similar to the situation in other Africans. NGS is possibly a better choice to detect genetic risk variants for thrombosis in this ethnic group. PMID- 28889201 TI - Not accounting for interindividual variability can mask habitat selection patterns: a case study on black bears. AB - Habitat selection studies conducted at the population scale commonly aim to describe general patterns that could improve our understanding of the limiting factors in species-habitat relationships. Researchers often consider interindividual variation in selection patterns to control for its effects and avoid pseudoreplication by using mixed-effect models that include individuals as random factors. Here, we highlight common pitfalls and possible misinterpretations of this strategy by describing habitat selection of 21 black bears Ursus americanus. We used Bayesian mixed-effect models and compared results obtained when using random intercept (i.e., population level) versus calculating individual coefficients for each independent variable (i.e., individual level). We then related interindividual variability to individual characteristics (i.e., age, sex, reproductive status, body condition) in a multivariate analysis. The assumption of comparable behavior among individuals was verified only in 40% of the cases in our seasonal best models. Indeed, we found strong and opposite responses among sampled bears and individual coefficients were linked to individual characteristics. For some covariates, contrasted responses canceled each other out at the population level. In other cases, interindividual variability was concealed by the composition of our sample, with the majority of the bears (e.g., old individuals and bears in good physical condition) driving the population response (e.g., selection of young forest cuts). Our results stress the need to consider interindividual variability to avoid misinterpretation and uninformative results, especially for a flexible and opportunistic species. This study helps to identify some ecological drivers of interindividual variability in bear habitat selection patterns. PMID- 28889203 TI - Do Growth Mindsets in Math Benefit Females? Identifying Pathways between Gender, Mindset, and Motivation. AB - Despite efforts to increase female representation in science, technology, engineering, and mathematics (STEM), females continue to be less motivated to pursue STEM careers than males. A short-term longitudinal study used a sample of 1449 high school students (grades 9-12; 49% females) to examine pathways from gender and mindset onto STEM outcomes via motivational beliefs (i.e., expectancy beliefs, task value, and cost). Mindset, motivational beliefs, and STEM career aspirations were assessed between the fall and winter months of the 2014-2015 school year and math grades were obtained at the conclusion of the same year. Student growth mindset beliefs predicted higher task values in math. Task values also mediated the pathway from a growth mindset to higher STEM career aspirations. Expectancy beliefs mediated the pathway between gender and math achievement. This mediated pathway was stronger for females than for males, such that females had higher math achievement than males when they endorsed a growth mindset. Findings suggest possible avenues for improving female's interest in STEM. PMID- 28889202 TI - Regulation of sterile alpha- and armadillo motif (SARM) containing protein expression in Pam2CSK4- and Pam3CSK4-activated mouse macrophage cell line (RAW264.7) requires TLR9. AB - INTRODUCTION: We aimed to investigate the involvement of surface TLRs and endosomal TLRs in the regulation of SARM expression by TLR2 ligands (Pam2CSK4 and Pam3CSK4). MATERIALS AND METHODS: Mouse macrophage cell line (RAW264.7) was treated with either Pam2CSK4 or Pam3CSK4 (TLR2 ligands) at a concentration of 100 ng/ml. At indicated time points, the treated cells were lysed. The gene and protein expression of SARM were determined by RT-PCR and immunoblotting, respectively. For silencing of TLR9 function, the cells were transfected with TLR9 siRNAs before stimulation by these two TLR2 ligands RESULTS: The SARM expression was upregulated at both transcriptional and translational levels in time-dependent manner during activation of Pam2CSK4 and Pam3CSK4 in mouse macrophages. Blocking of ligand internalization by cytochalasin D showed interference effect with SARM expression. Moreover, our results also demonstrated that endosomal acidification and TLR9 were required for SARM expression suggesting the essential role of endosomal compartment acidification and TLR9 in regulating SARM expression. CONCLUSION: Our findings suggested the collaboration of TLR2-TLR9 at least in the regulation of SARM expression. However, the underlying mechanism that participated in these two TLRs cooperation is underinvestigated. PMID- 28889204 TI - A microfluidics-based mobility shift assay to identify new inhibitors of beta secretase for Alzheimer's disease. AB - The beta-secretase (BACE1) initiates the generation of toxic amyloid-beta peptide (Abeta) from amyloid-beta precursor protein (APP), which was widely considered to play a key role in the pathogenesis of Alzheimer's disease (AD). Here, a novel microfluidics-based mobility shift assay (MMSA) was developed, validated, and applied for the screening of BACE1 inhibitors for AD. First, the BACE1 activity assay was established with a new fluorescent peptide substrate (FAM-EVNLDAEF) derived from the Swedish mutant APP, and high-quality ratiometric data were generated in both endpoint and kinetic modes by electrophoretic separation of peptide substrate from the BACE1 cleaved product (FAM-EVNL) before fluorescence quantification. To validate the assay, the inhibition and kinetic parameter values of two known inhibitors (AZD3839 and AZD3293) were evaluated, and the results were in good agreement with those reported by other methods. Finally, the assay was applied to screen for new inhibitors from a 900-compound library in a 384-well format, and one novel hit (IC50 = 26.5 +/- 1.5 MUM) was identified. Compared with the common fluorescence-based assays, the primary advantage of the direct MMSA was to discover novel BACE1 inhibitors with lower auto-fluorescence interference, and its superb capability for kinetic study. Graphical abstract Microfluidics-based mobility shift assay for BACE1. PMID- 28889205 TI - Coupled Monte Carlo simulation and Copula theory for uncertainty analysis of multiphase flow simulation models. AB - Simulation-optimization techniques are effective in identifying an optimal remediation strategy. Simulation models with uncertainty, primarily in the form of parameter uncertainty with different degrees of correlation, influence the reliability of the optimal remediation strategy. In this study, a coupled Monte Carlo simulation and Copula theory is proposed for uncertainty analysis of a simulation model when parameters are correlated. Using the self-adaptive weight particle swarm optimization Kriging method, a surrogate model was constructed to replace the simulation model and reduce the computational burden and time consumption resulting from repeated and multiple Monte Carlo simulations. The Akaike information criterion (AIC) and the Bayesian information criterion (BIC) were employed to identify whether the t Copula function or the Gaussian Copula is the optimal Copula function to match the relevant structure of the parameters. The results show that both the AIC and BIC values of the t Copula function are less than those of the Gaussian Copula function. This indicates that the t Copula function is the optimal function for matching the relevant structure of the parameters. The outputs of the simulation model when parameter correlation was considered and when it was ignored were compared. The results show that the amplitude of the fluctuation interval when parameter correlation was considered is less than the corresponding amplitude when parameter estimation was ignored. Moreover, it was demonstrated that considering the correlation among parameters is essential for uncertainty analysis of a simulation model, and the results of uncertainty analysis should be incorporated into the remediation strategy optimization process. PMID- 28889207 TI - Antipsychotic-induced hyperprolactinemia: synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research. AB - RATIONALE: Hyperprolactinemia is a highly prevalent adverse effect of many antipsychotic agents, with potentially serious health consequences. Several guidelines have been developed for the management of this condition; yet, their concordance has not been evaluated. OBJECTIVES: The objectives of this paper were (1) to review current clinical guidelines; (2) to review key systematic evidence for management; and (3) based on our findings, to develop an integrated management recommendation specific to male and female patients who are otherwise clinically stabilised on antipsychotics. METHODS: We performed searches of Medline and EMBASE, supplemented with guideline-specific database and general web searches, to identify clinical guidelines containing specific recommendations for antipsychotic-induced hyperprolactinemia, produced/updated 01/01/2010-15/09/2016. A separate systematic search was performed to identify emerging management approaches described in reviews and meta-analyses published >= 2010. RESULTS: There is some consensus among guidelines relating to baseline PRL screening (8/12 guidelines), screening for differential diagnosis (7/12) and discontinuing/switching PRL-raising agent (7/12). Guidelines otherwise diverge substantially regarding most aspects of screening, monitoring and management (e.g. treatment with dopamine agonists). There is an omission of clear sex specific recommendations. Systematic literature on management approaches is promising; more research is needed. An integrated management recommendation is presented to guide sex-specific clinical response to antipsychotic-induced hyperprolactinemia. Key aspects include asymptomatic hyperprolactinemia monitoring and fertility considerations with PRL normalisation. CONCLUSION: Further empirical work is key to shaping robust guidelines for antipsychotic induced hyperprolactinemia. The integrated management recommendation can assist clinician and patient decision-making, with the goal of balancing effective psychiatric treatment while minimising PRL-related adverse health effects in male and female patients. PMID- 28889208 TI - Detection of human antibodies binding with smooth and rough LPSs from Proteus mirabilis O3 strains S1959, R110, R45. AB - Bacteria of the genus Proteus of the family Enterobacteriaceae are facultative human pathogens responsible mainly for urinary tract and wound infections, bacteremia and the development of rheumatoid arthritis (RA). We have analyzed and compared by ELISA the titer of antibodies in plasmas of healthy individuals and in sera of rheumatoid arthritis patients recognizing a potential host cross reactive epitope (lysine-galacturonic acid epitopes) present in Proteus lipopolysaccharide (LPS). In our experiments LPSs isolated from two mutants of smooth Proteus mirabilis 1959 (O3), i.e. strains R110 and R45, were used. R110 (Ra type mutant) is lacking the O-specific polysaccharide, but possesses a complete core oligosaccharide, while R45 (Re type) has a reduced core oligosaccharide and contains two 3-deoxy-D-manno-oct-2-ulosonic acid residues and one of 4-amino-4-deoxy-L-arabinopyranose residues. Titer of P. mirabilis S1959 LPS-specific-antibodies increased with the age of blood donors. RA and blood donors' sera contained antibodies against S and Ra and Re type of P. mirabilis O3 LPSs. Antibodies recognizing lysine-galacturonic acid epitopes of O3 LPS were detected by ELISA in some plasmas of healthy individuals and sera of rheumatoid arthritis patients. RA patients antibodies reacting with P. mirabilis S1959 S and R LPSs may indicate a potential role of anti-LPS antibodies in molecular mimicry in RA diseases. PMID- 28889209 TI - Micro-bead injection spectroscopy for label-free automated determination of immunoglobulin G in human serum. AB - Immunoglobulin G (IgG) represents the major fraction of antibodies in healthy adult human serum, and deviations from physiological levels are a generic marker of disease corresponding to different pathologies. Therefore, screening methods for IgG evaluation are a valuable aid to diagnostics. The present work proposes a rapid, automatic, and miniaturized method based on UV-vis micro-bead injection spectroscopy (MU-BIS) for the real-time determination of human serum IgG with label-free detection. Relying on attachment of IgG in rec-protein G immobilized in Sepharose 4B, a bioaffinity column is automatically assembled, where IgG is selectively retained and determined by on-column optical density measurement. A "dilution-and-shoot" approach (50 to 200 times) was implemented without further sample treatment because interferences were flushed out of the column upon sample loading, with minimization of carryover and cross-contamination by automatically discarding the sorbent (0.2 mg) after each determination. No interference from human serum albumin at 60 mg mL-1 in undiluted sample was found. The method allowed IgG determination in the range 100-300 MUg mL-1 (corresponding to 5.0-60 mg mL-1 in undiluted samples), with a detection limit of 33 MUg mL-1 (1.7 mg mL-1 for samples, dilution factor of 50). RSD values were < 9.4 and < 11.7%, for intra and inter-assay precision, respectively, while recovery values for human serum spiked with IgG at high pathological levels were 97.8-101.4%. Comparison to commercial ELISA kit showed no significant difference for tested samples (n = 8). Moreover, time-to-result decreased from several hours to < 5 min and analysis cost decreased 10 times, showing the potential of the proposed approach as a point-of-care method. Graphical abstract Micro-Bead Injection Spectroscopy method for real time, automated and label-free determination of total serum human Immunoglobulin G (IgG). The method was designed for Lab-on-Valve (LOV) platforms using a miniaturised protein G bioaffinity separative approach. IgG are separated from serum matrix components upon quantification with low non-specific binding in less than 5 min. PMID- 28889206 TI - Dietary Fatty Acid Composition Modulates Obesity and Interacts with Obesity Related Genes. AB - The prevalence of obesity is skyrocketing worldwide. The scientific evidence has associated obesity risk with many independent factors including the quality of dietary fat and genetics. Dietary fat exists as the main focus of dietary guidelines targeting obesity reduction. To prevent/minimize the adipogenic effect of dietary fatty acids (FA), intakes of long-chain saturated- and trans-FA should be reduced and substituted with unsaturated FA. The optimal proportions of dietary unsaturated FA are yet to be defined, along with a particular emphasis on the need to achieve a balanced ratio of n-3:n-6 polyunsaturated FA and to increase monounsaturated FA consumption at the expense of saturated FA. However, inter-individual variability in weight loss in response to a dietary intervention is evident, which highlights the importance of exploring gene-nutrient interactions that can further modulate the risk for obesity development. The quality of dietary fat was found to modulate obesity development by interacting with genes involved in fatty acid metabolism, adipogenesis, and the endocannabinoid system. This review summarizes the current knowledge on the effect of the quality of dietary fat on obesity phenotype and obesity-related genes. The evidence is not only supporting the modulatory effect of fat quality on obesity development but also presenting a number of interactions between obesity-related genes and the quality of dietary fat. The identified gene-FA interaction may have a clinical importance and holds a promise for the possibility of using genetically targeted dietary interventions to reduce obesity risk in the future. PMID- 28889211 TI - Philippe Hardy: In Memoriam. PMID- 28889210 TI - Ketamine and midazolam differently impact post-intubation hemodynamic profile when used as induction agents during emergency airway management in hemodynamically stable patients with ST elevation myocardial infarction. AB - We investigated the incidence of post-intubation hypotension (PIH) in hemodynamically stable patients with STEMI requiring rapid sequences intubation (RSI) and medicated with ketamine or midazolam as induction agent. STEMI patients admitted between 1st January 2009 and 1st January 2017 who did not receive any type of inotropic support before the endotracheal intubation (ETI) was reviewed. PIH was defined as a reduction greater than 20% or a drop of systolic blood pressure (SBP) below 90 mmHg within 10 min from the administration of the induction agent [ketamine (1 mg/kg) or midazolam (0.3 mg/kg)]. Over the study period, 136 patients (66 male and 70 females, mean age 72.25 +/- 7.33 years) met the inclusion criteria. Patients treated with midazolam and ketamine were 63 and 73, respectively. PIH was observed in 38 (27.9%) patients after 10 min from ETI. Midazolam patients had a significant lower SBP at both 5 and 10 min after induction (97.75 +/- 8.06 vs 100.81 +/- 8.08, p = 0.029 and 92.83 +/- 7.53 vs 101.58 +/- 7.29, p < 0.0001, respectively) (ANOVA p < 0.0001). Age (OR 1.91, 95% CI 1.87-1.97, p = 0.001), history of arterial hypertension (OR 2.27, 95% CI 2.21 2.35, p = 0.0001), multivessel coronary artery disease (OR 2.66, 95% CI 2.58 2.71, p = 0.001), SI >=0.9 (OR 2.41, 95% CI 2.36-2.48, p < 0.0001) and anterior STEMI (OR 2.51, 95% CI 2.48-2.57, p = 0.0001) resulted independent predictors of PIH in STEMI patients treated with midazolam, as induction agent, before ETI. Midazolam was more likely than ketamine to cause significant PIH when used as an induction agent for RSI in hemodynamically stable patients with STEMI. PMID- 28889213 TI - Robotic approach to resection of villous adenoma of the urachus: a case report and literature review. AB - Very few cases of villous adenomas of the bladder or urinary tract have been described. To our knowledge this is the first account of resection of an urachal villous adenoma via robotic laparoscopy, which is a safe and efficacious surgical approach. At this time, there is not enough evidence to suggest that progression of disease to carcinoma is the typical course. Nonetheless, follow-up cystoscopy is recommended after complete removal of the adenoma to monitor for recurrence. This case report reviews the current literature and describes a novel approach to treatment of this exceedingly rare entity. PMID- 28889212 TI - Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys. AB - RATIONALE: The therapeutic potential of monoamine releasers with prominent dopaminergic effects is hindered by their high abuse liability. OBJECTIVES: The present study examined the effects of several novel "norepinephrine (NE) preferring" monoamine releasers relative to non-selective monoamine releasers, d amphetamine and d-methamphetamine, in rhesus monkeys trained to discriminate cocaine. NE-preferring releasers were approximately 13-fold more potent for NE compared to dopamine release and ranged in potency for serotonin release (PAL-329 < l-methamphetamine < PAL-169). METHODS: Adult rhesus macaques were trained to discriminate 0.4 mg/kg, IM cocaine on a 30-response fixed ratio schedule of food reinforcement. Substitution studies determined the extent to which test drugs produced cocaine-like discriminative stimulus effects and their time course. Drug interaction studies determined whether pretreatment with test drugs altered the discriminable effects of cocaine. RESULTS: Results show that cocaine, d amphetamine, and d-methamphetamine dose-dependently substituted for cocaine with similar potencies. Among the "NE-preferring" releasers, PAL-329 and l methamphetamine also dose-dependently substituted for cocaine but differed in potency. PAL-169 failed to substitute for cocaine up to a dose that disrupted responding. When administered prior to cocaine, only d-amphetamine and PAL-329 significantly shifted the cocaine dose-effect function leftward indicating enhancement of cocaine's discriminative stimulus effects. CONCLUSIONS: These data suggest that greater potency for NE relative to dopamine release (up to 13-fold) does not interfere with the ability of a monoamine releaser to produce cocaine like discriminative effects but that increased serotonin release may have an inhibitory effect. Further characterization of these and other "NE-preferring" monoamine releasers should provide insight into their potential for the management of cocaine addiction. PMID- 28889214 TI - SERPING1 mRNA overexpression in monocytes from HIV+ patients. AB - OBJECTIVE: The HIV-1 virus activates the complement system, an essential element of the immune system. SERPING1 is a protease inhibitor that disables C1r/C1s in the C1 complex of the classical complement pathway. METHODS: In this paper, we performed an analysis of several microarrays deposited in GEO dataset to demonstrate that SERPING1 mRNA is modulated in CD14+ monocytes from HIV-1 infected individuals. In addition, data were validated on monocytes isolated from seronegative healthy volunteers, treated with IFNs. RESULTS: Our analysis shows that SERPING1 mRNA is overexpressed in monocytes from HIV-1+ patients and the expression levels correlate positively with viral load and negatively with the CD4+ T-cell count. Of note, anti-retroviral therapy is able to reduce the levels of SERPING1 mRNA, ex vivo. In addition, we found that 30% of the SERPING1 genes network is upregulated in monocytes from HIV-1+ patients. Noteworthy, the expression levels of IFITM1-an antiviral molecule belonging to the genes network correlate positively with SERPING1 expression. Interestingly, the monocytes treatment with IFN-gamma, IFN-beta and IFN-alpha significantly upregulates the SERPING1 mRNA expression levels. CONCLUSIONS: From the outcome of our investigation, it is possible to conclude that SERPING1 and its network serve as important components of the innate immune system to restrict HIV-1 infection. PMID- 28889215 TI - Brief Report: Postsecondary Work and Educational Disruptions for Youth on the Autism Spectrum. AB - This study examined vocational/educational disruption in the 2-3 years after high school for 36 youth with autism spectrum disorder (ASD). Data were collected three times from parents: during youth's last year of high school and two times after high school exit. Data were coded into categories indicating any versus no disruptions in postsecondary vocation/education, and group differences in individual (behavior problems, IQ, adaptive behavior, autism severity, stress reactivity) and family (parent depression, anxiety, quality of life; family income and climate) factors were examined. One-half of youth had experienced a postsecondary vocational/educational disruption; parents of those with a disruption had more depressive and anxiety symptoms and lower quality of life while their son/daughter was still in high school. PMID- 28889216 TI - Municipal solid waste management planning for Xiamen City, China: a stochastic fractional inventory-theory-based approach. AB - In this study, a stochastic fractional inventory-theory-based waste management planning (SFIWP) model was developed and applied for supporting long-term planning of the municipal solid waste (MSW) management in Xiamen City, the special economic zone of Fujian Province, China. In the SFIWP model, the techniques of inventory model, stochastic linear fractional programming, and mixed-integer linear programming were integrated in a framework. Issues of waste inventory in MSW management system were solved, and the system efficiency was maximized through considering maximum net-diverted wastes under various constraint-violation risks. Decision alternatives for waste allocation and capacity expansion were also provided for MSW management planning in Xiamen. The obtained results showed that about 4.24 * 106 t of waste would be diverted from landfills when p i is 0.01, which accounted for 93% of waste in Xiamen City, and the waste diversion per unit of cost would be 26.327 * 103 t per $106. The capacities of MSW management facilities including incinerators, composting facility, and landfills would be expanded due to increasing waste generation rate. PMID- 28889217 TI - Best dispersal strategies in spatially heterogeneous environments: optimization of the principal eigenvalue for indefinite fractional Neumann problems. AB - We study the positive principal eigenvalue of a weighted problem associated with the Neumann spectral fractional Laplacian. This analysis is related to the investigation of the survival threshold in population dynamics. Our main result concerns the optimization of such threshold with respect to the fractional order [Formula: see text], the case [Formula: see text] corresponding to the standard Neumann Laplacian: when the habitat is not too fragmented, the principal positive eigenvalue can not have local minima for [Formula: see text]. As a consequence, the best strategy for survival is either following the diffusion with [Formula: see text] (i.e. Brownian diffusion), or with the lowest possible s (i.e. diffusion allowing long jumps), depending on the size of the domain. In addition, we show that analogous results hold for the standard fractional Laplacian in [Formula: see text], in periodic environments. PMID- 28889218 TI - Opioid use following gynecologic and pelvic reconstructive surgery. AB - INTRODUCTION AND HYPOTHESIS: Opioid use, addiction, and overdose are a growing epidemic in the USA. Our objective was to determine whether the amount of opioid medication prescribed following gynecologic and pelvic reconstructive surgery is insufficient, adequate, or in excess. We hypothesized that we were overprescribing postoperative opioids. METHODS: Participants who were at least 18 years old and underwent gynecologic and/or pelvic reconstructive surgery from April through August 2016 were eligible to participate. Routine practice for pain management is to prescribe 30 tablets of opioids for major procedures and ten to 15 tablets for minor procedures. At the 2-week postoperative visit, participants completed a questionnaire regarding the number of tablets prescribed and used, postoperative pain control, and relevant medical history. Fisher's exact test was used to compare data. RESULTS: Sixty-five participants completed questionnaires. Half (49.1%) reported being prescribed more opioids than needed, while two (3.5%) felt the amount was less than needed. Though not significant, participants who underwent major surgeries were more likely to report being prescribed more than needed (53.5%) compared with participants who underwent minor surgeries (35.7%; p = 0.47). Though not significant, participants with anxiety were less likely to report being prescribed more tablets than needed compared with participants without anxiety (44.4% vs. 57.1%; p = 0.38). This was also true of participants with depression compared with those without (37.5% vs. 58.3%; p = 0.17), and those with chronic pain compared with those without (33.3% vs. 60.0%; p = 0.10). CONCLUSIONS: Our current opioid prescription practice for postoperative pain management may exceed what patients need. PMID- 28889219 TI - A validated UPLC-MS/MS method coupled with protein precipitation and ion exchange solid phase extraction for the quantitation of porcine relaxin B29 in dog plasma and its application to a pharmacokinetic study. AB - Porcine relaxin is a 6 kDa peptide hormone of pregnancy with important physiological and pharmacological effects. It contains a number of analogs of which porcine relaxin B29 is one of the most important. To support the development of porcine relaxin B29 as a new drug, we established an UPLC-MS/MS method for its quantitation in dog plasma. Sample preparation by protein precipitation and ion exchange solid phase extraction was followed by UPLC on an XBridgeTM BEH300 C18 column at 40 degrees C in a run time of only 5.5 min. Detection was performed on a Qtrap 6500 mass spectrometer using ESI in the positive ion mode with MRM of the transitions at m/z 831.7 [M+7H]7+ -> 505.4 and m/z 1162.4 [M+5H]5+ -> 226 for pRLX B29 and internal standard (recombinant human insulin), respectively. The method was linear over the concentration range 30 2000 ng/mL with no matrix effects. Intra- and inter-day precisions were < 15% with accuracies in the range 98.8-100.6%. The method was successfully applied to a pharmacokinetic study in beagle dogs after administration of a 0.15 mg/kg intravenous dose. Graphical abstract Sample preparation and detection procedure. PMID- 28889220 TI - Rapamycin treatment attenuates age-associated periodontitis in mice. AB - Interventions that target biological mechanisms of aging have great potential to enhance quality of life by delaying morbidity and mortality. The FDA-approved drug rapamycin is a compelling candidate for such an intervention. In a previous study, it was reported that 3 months of rapamycin treatment is sufficient to increase life expectancy and remodel the gut microbiome in aged mice. Transient treatment with rapamycin or a rapamycin derivative has also been shown to delay immune stem cell senescence and rejuvenate immune function in aged mice and elderly people. Periodontal disease is an important age-related disease involving altered immune function, pathological changes to the oral microbiome, and systemic inflammation. Periodontal disease is defined clinically by loss of alveolar bone and by connective tissue degeneration. Here, we describe significant alveolar bone loss during aging in two different mouse strain backgrounds and report that rapamycin treatment is sufficient to reverse age associated periodontal disease in mice. Partial restoration of youthful levels of alveolar bone is observed in 22-month-old rapamycin-treated mice as rapidly as 8 weeks after initiation of treatment. To the best of our knowledge, this represents the first intervention shown to substantially prevent or reverse age associated alveolar bone loss. These findings suggest the possibility that inhibition of mTOR with rapamycin or other pharmacological agents may be useful to treat a clinically relevant condition for which there is currently no effective treatment. PMID- 28889221 TI - Influence of Rapeseed Cake on Iron Plaque Formation and Cd Uptake by Rice (Oryza sativa L.) Seedlings Exposed to Excess Cd. AB - A soil spiking experiment at two Cd levels (0.72 and 5.20 mg kg-1) was conducted to investigate the effects of rapeseed cake (RSC) at application rates of 0%, 0.75%, 1.5%, and 3.0% (w/w) on iron plaque formation and Cd uptake by rice (Oryza sativa L.) seedlings. The use of RSC did result in a sharp decrease in soil bioavailability of Cd and a significant increase in rice growth, soil pH and organic matter. Application of RSC increased the amount of iron plaque formation and this effectively inhibited the uptake and translocation of Cd into the rice seedlings. RSC was an effective organic additive for increasing rice growth and reducing Cd uptake by rice plant, simultaneously. These results could be used as a reference for the safety use of Cd polluted paddy soil. PMID- 28889222 TI - The predictive factors of secondary patellar resurfacing in computer-assisted total knee arthroplasty. A prospective cohort study. AB - PURPOSE: The decision to resurface the patella during total knee arthroplasty (TKA) remains controversial. This prospective cohort study aimed to evaluate the outcome and survivorship of the native patella in computer-assisted TKA (CAS TKA) implanted for primary knee osteoarthritis, and to determine the predictive factors of secondary patellar resurfacing (SPR). METHODS: A prospective cohort of 273 cementless ultra-congruent mobile-bearing CAS TKA implanted without patellar resurfacing was included in our total joint registry. Patients were evaluated with the International Knee Society (IKS) and Hospital for Special Surgery Patellar (HSSP) scores. Radiographic evaluation was focused on the patellofemoral (PF) compartment to assess: the patellar dysplasia (Wiberg classification), PF osteoarthritis (Iwano classification), femoral trochlear dysplasia (femoral sulcus angle), patellar maltracking (patellar tilt and lateralization), and patella height (Blackburne-Peel ratio). RESULTS: At a six-year median follow-up, the CAS TKA survivorship using SPR as end-point was 95% (range, 91-99%). The IKS and HSSP improved significantly after SPR (p = 0.001 and 0.004, respectively). No significant difference in the IKS and HSSP was detected between TKA with native patella and SPR-TKA at latest follow-up. Importantly, four pre-operative radiographic PF parameters were significantly associated with SPR: higher stages of patellar dysplasia and PF osteoarthritis, and higher sulcus angle and patellar lateralization (hazard ratios = 5.1 to 11.6, p = 0.009 to 0.04). CONCLUSION: When preserving the native patella, surgeons should be aware of pre-operative PF radiographic parameters that could influence the outcome and survivorship of CAS TKA leading to SPR. Particularly, evidence of PF dysplasia, osteoarthritis and maltracking should be determined pre-operatively to resurface the patella at the time of TKA. LEVEL OF EVIDENCE: Therapeutic Level II (prospective cohort study). PMID- 28889223 TI - Response of anaerobic membrane bioreactor to the presence of nano-Bi2WO6: reactor performance, supernatant characteristics, and microbial community. AB - Considering the increasing incorporation of manufactured nano-material into consumer products, there is a concern about its potential impacts in biological wastewater treatment. In this study, the response of anaerobic sludge to the presence of Bi2WO6 nano-particles (NPs) was investigated in the anaerobic membrane bioreactor (AnMBR). As the concentration of Bi2WO6 in the reactor was controlled around 1 mg/L, there was no significant difference in effluent water quality or bacterial activities before and after NP exposure, partially due to the microbial-induced NP aggregation and stable complex formation. However, with the increasing dosage of Bi2WO6 from 5 to 40 mg/L, great influences on the AnMBR performance were observed, including the reduction of COD removal efficiency, inhibition of the mechanization step, increased production of soluble microbial products, and enhanced secretion of extracellular polymer substrates. Additional investigation with high-throughput sequencing was conducted, clearly demonstrating that Bi2WO6 NPs induced changes in the bacterial community. PMID- 28889224 TI - Relationship between choroidal blood flow velocity and choroidal thickness in patients with regression of acute central serous chorioretinopathy. PMID- 28889225 TI - Effects of blood flow restriction during moderate-intensity eccentric knee extensions. AB - We investigated if blood flow restriction (BFR, cuff pressure 20 mmHG below individual occlusion pressure) increases metabolic stress, hormonal response, release of muscle damage markers, and muscle swelling induced by moderate intensity eccentric contractions. In a randomized, matched-pair design, 20 male subjects (25.3 +/- 3.3 years) performed four sets of unilateral eccentric knee extensions (75% 1RM) to volitional failure with (IG) or without (CG) femoral BFR. Despite significant differences of performed repetitions between IG (85.6 +/- 15.4 repetitions) and CG (142.3 +/- 44.1 repetitions), peak values of lactate (IG 7.0 +/- 1.4 mmol l-1, CG 6.9 +/- 2.7 mmol l-1), growth-hormone (IG 4.9 +/- 4.8 ng ml-1, CG 5.2 +/- 3.5 ng ml-1), insulin-like growth factor 1 (IG 172.1 +/- 41.9 ng ml-1, CG 178.7 +/- 82.1 ng ml-1), creatine-kinase (IG 625.5 +/- 464.8 U l-1, CG 510.7 +/- 443.5 U l-1), the absolute neutrophil count (IG 7.9 +/- 1.3 103 ul-1, CG 8.7 +/- 2.0 103 ul-1), induced muscle swelling of rectus femoris and vastus lateralis and perceived pain did not differ. The present data indicate that BFR is suitable to intensify eccentric exercises. PMID- 28889226 TI - Stereopsis and fusion in anisometropia according to the presence of amblyopia. AB - PURPOSE: To evaluate the level of stereopsis and fusion in patients with anisometropia according to the presence of amblyopia. METHODS: We included 107 children with anisometropia, divided into groups with non-amblyopic anisometropia (NA, n = 72) and amblyopic anisometropia (AA, n = 35). Normal subjects without anisometropia were enrolled in the control group (n = 73). Main outcome measures were the level of stereopsis and sensory fusion as evaluated by Titmus stereotest and Worth 4-dot test, respectively, using anisometropic glasses. RESULTS: The degree of anisometropia in the NA, AA, and control groups was 2.54 diopters (D), 4.29 D, and 0.30 D, respectively (P = 0.014). Stereopsis (arcsec) was significantly worse in the AA group than the NA and control groups (641.71, 76.25, 54.52, respectively, P < 0.001), while no significant difference was found between the NA and control groups. The rate of fusion was significantly lower in the AA than the NA group (14.3% vs. 65.3%, P < 0.001), and was significantly lower in the NA than the control group (65.3% vs. 80.6%, P = 0.001). CONCLUSIONS: The levels of stereopsis and sensory fusion with anisometropic glasses were significantly worse in the AA than in the NA group. The level of stereopsis in the NA group, however, did not differ significantly from that in the isometropic control, while the rate of fusion was significantly lower. Early prescription of anisometropic glasses is needed to improve visual acuity and binocularity in children with possible amblyopic anisometropia. PMID- 28889227 TI - Effective adsorbent for arsenic removal: core/shell structural nano zero-valent iron/manganese oxide. AB - Recently, nano zero-valent iron (nZVI) has emerged as an effective adsorbent for the removal of arsenic from aqueous solutions. However, its use in various applications has suffered from reactivity loss resulting in a decreased efficiency. Thus, the aim of this study was to develop an effective arsenic adsorbent as a core/shell structural nZVI/manganese oxide (or nZVI/Mn oxide) to minimize the reactivity loss of the nZVI. As the major result, the arsenic adsorption capacities of the nZVI/Mn oxide for As(V) and As(III) were approximately two and three times higher than that of the nZVI, respectively. In addition, the As(V) removal efficiency of the nZVI/Mn oxide was maintained through 4 cycles of regeneration whereas that of the nZVI was decreased significantly. The enhanced reactivity and reusability of the nZVI/Mn oxide can be successfully explained by the synergistic interaction of the nZVI core and manganese oxide shell, in which the manganese oxides participate in oxidation reactions with corroded Fe2+ and subsequently retard the release of aqueous iron providing additional surface sites for arsenic adsorption. In summary, this study reports the successful fabrication of a core/shell nZVI/Mn oxide as an effective adsorbent for the removal of arsenic from aqueous solutions. PMID- 28889228 TI - Intraosseous migration of tendinous calcifications: two case reports. AB - Calcific tendinopathy of the rotator cuff is a common cause of shoulder pain. Inflammation of the rotator cuff tendons may be complicated by adjacent bone erosion and subsequent migration of calcific deposits within the bone resulting in marrow inflammation. Bone marrow involvement is not readily visible using X ray and ultrasound (US) and further testing is necessary. Magnetic resonance imaging (MRI) is a highly sensitive technique that can detect a focal bone T1 and T2-weighted hypointensity with bone marrow edema-like signal and cortical erosion. These findings can mislead the radiologist by suggesting an infectious or neoplastic lesion, often requiring further evaluation with computed tomography (CT) and biopsy. We report two cases of patients with shoulder pain in which different radiological approaches were used with pathological confirmation in one of them. In the first case, MRI revealed significant bone involvement in the head of the humerus and cortical erosion of the greater tuberosity. A CT examination and a biopsy was necessary for a final diagnosis of inflammatory bone reaction from intraosseous migration of tendinous calcifications. In the second case, similar MRI findings prompted re-evaluation of imaging to make a diagnosis of intraosseous migration of tendinous calcifications, obviating the need to perform CT and biopsy. We illustrate MRI signs of this complication that we think would allow to narrow the differential diagnosis potentially avoiding biopsy and additional CT examinations. PMID- 28889229 TI - Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca2+-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK/SERCA2a pathway. AB - Endothelia inflammation damage is vital to the development and progression of chronic venous disease. In the present study, we explored the protective effect of melatonin on endothelia apoptosis induced by LPS, particularly focusing on the mitochondrial fission. We demonstrated that human umbilical vein endothelial cells (HUVEC) subjected to LPS for 12 h exhibited a higher apoptotic rate. However, melatonin (1-20 MUM) treatment 12 h before LPS had the ability to protect HUVEC cell against LPS-mediated apoptosis in a dose-dependent manner. Furthermore, LPS induced the cytoplasmic calcium overload which was responsible for the upregulation of calcium-dependent xanthine oxidase (XO). Higher XO expression was associated with reactive oxygen species (ROS) overproduction, leading to the Drp1 phosphorylation at the Ser616 site and migration on the surface of mitochondria. Furthermore, phosphorylated Drp1 initiated the mitochondrial fission contributing to the caspase9-dependent mitochondrial apoptosis as evidenced by lower membrane potential, more cyt-c leakage into the nuclear, and higher expression of proapoptotic proteins. However, melatonin treatment could trigger the AMPK pathway, which was followed by the increased SERCA2a expression. Activation of AMPK/SERCA2a by melatonin inhibited the calcium overload, XO-mediated ROS outburst, Drp1-required mitochondrial fission, and final mitochondrial apoptosis. In summary, this study confirmed that LPS induced HUVEC apoptosis through Ca2+-XO-ROS-Drp1-mitochondrial fission axis and that melatonin reduced the apoptosis of HUVEC through activation of the AMPK/SERCA2a pathway. PMID- 28889230 TI - The relationship between social support networks and depression in the 2007 National Survey of Mental Health and Well-being. AB - PURPOSE: Social isolation and low levels of social support are associated with depression. The purpose of the current study was to investigate the relationship between depression and social connectivity factors (frequency of contact and quality of social connections) in the 2007 Australian National Survey of Mental Health and Well-being. METHODS: A national survey of 8841 participants aged 16-85 years was conducted. Logistic regression was used to investigate the relationship between social connectivity factors and 12-month prevalence of Major Depressive Disorder in the whole sample, as well as across three age groups: younger adults (16-34 years), middle-aged adults (35-54 years), and older adults (55+ years). Respondents indicated how often they were in contact with family members and friends (frequency of contact), and how many family and friends they could rely on and confide in (quality of support), and were assessed for Major Depressive Disorder using the World Mental Health Composite International Diagnostics Interview. RESULTS: Overall, higher social connection quality was more closely and consistently associated with lower odds of the past year depression, relative to frequency of social interaction. The exception to this was for the older group in which fewer than a single friendship interaction each month was associated with a two-fold increased likelihood of the past year depression (OR 2.19, 95% CI 1.14-4.25). Friendship networks were important throughout life, although in middle adulthood, family support was also critically important-those who did not have any family support had more than a three-fold increased odds of the past year depression (OR 3.47, 95% CI 2.07-5.85). CONCLUSIONS: High-quality social connection with friends and family members is associated with reduced likelihood of the past year depression. Intervention studies that target the quality of social support for depression, particularly support from friends, are warranted. PMID- 28889231 TI - Favorable effects of early tolvaptan administration in very elderly patients after repeat hospitalizations for acute decompensated heart failure. AB - Tolvaptan (TLV) is an oral selective vasopressin 2 receptor antagonist that acts on the distal nephrons, causing a loss of electrolyte-free water. To date, its early administration in very elderly patients after repeat hospitalizations for acute decompensated heart failure (ADHF) despite receiving optimal medical therapy has not been evaluated. Fifty-six ADHF patients who were >80 years old and had been repeatedly hospitalized were retrospectively enrolled in this study. Twenty-five patients (14 men; mean age 86.7 +/- 5.3 years; control group) received standard therapy and 31 patients (15 men; mean age 85.5 +/- 4.5 years; TLV group) received oral TLV within 24 h of admission. The rate of worsening renal function was significantly lower in the TLV group than in the control group (13 vs. 40%, P < 0.05). The duration of the return to body weight at a steady state was significantly shorter in the TLV group (5.3 +/- 2.8 days) than in the control group (13.9 +/- 9.2 days, P < 0.01). Consequently, the hospitalization period in the TLV group (13.5 +/- 5.9 days) was significantly shorter than that in the control group (24.7 +/- 12.3 days, P < 0.01). In conclusion, the early administration of TLV to very elderly patients who underwent repeat hospitalizations for ADHF resulted in immediate decongestion and thus reduced the hospitalization period with a lower incidence of worsening renal function. PMID- 28889233 TI - Adenoid Cystic Carcinoma of the Cavernous Sinus - Otolaryngological Sequelae of Therapy: Case Report. AB - A 60-year-old woman, otherwise in a good health condition, was first admitted to the hospital with a year-long tingling sensations of the right half of the face, which gradually turned into severe neuralgia corresponding to maxillary (V2) and mandibular (V3) branches of the right trigeminal nerve. MRI scans of the head revealed an unusual hyperplastic or inflammatory changes along the brain base, cavernous sinus extending toward the pterygopalatine fossa, and lateral pterygoid on the right side. Meningioma was suspected and neuralgia was treated conservatively. About 2 years later, due to severe facial and eye pain, the patient underwent decompression of trigeminal nerve roots - Janetta's surgery. The following MRI scans revealed a tumor of cavernous sinus, arousing suspicion of malignancy. Histological specimens obtained after a biopsy and then partial transnasal tumor resection yielded a diagnosis of adenoid cystic carcinoma. The patient was treated with proton radiation therapy. The therapy caused burns in the oropharyngeal soft tissues extending from the oral cavity to the throat and esophagus. The additional adverse effect of the therapy was hypoacusis and a damage to the right cornea. A radiation-induced sinusitis appeared that required surgical intervention. The patient suffered a string of further complications, including pneumonia and a transient kidney failure. In the end, the patient survived. The adenoid carcinoma in the currently 64-year-old woman is visibly reduced, but she still suffers from the trigeminal neuralgia. The patient remains under constant laryngological outpatient care as she requires a periodic cleansing of nasal cavities and hypoacusis monitoring. PMID- 28889232 TI - Modulation of the flavin-protein interactions in NADH peroxidase and mercuric ion reductase: a resonance Raman study. AB - NADH peroxidase (Npx) and mercuric ion reductase (MerA) are flavoproteins belonging to the pyridine nucleotide:disulfide oxidoreductases (PNDO) and catalyzing the reduction of toxic substrates, i.e., hydrogen peroxide and mercuric ion, respectively. To determine the role of the flavin adenine dinucleotide (FAD) in the detoxification mechanism, the resonance Raman (RR) spectra of these enzymes under various redox and ligation states have been investigated using blue and/or near-UV excitation(s). These data were compared to those previously obtained for glutathione reductase (GR), another enzyme of the PNDO family, but catalyzing the reduction of oxidized glutathione. Spectral differences have been detected for the marker bands of the isoalloxazine ring of Npx, MerA, and GR. They provide evidence for different catalytic mechanisms in these flavoproteins. The RR modes of the oxidized and two-electron reduced (EH2) forms of Npx are related to very tight flavin-protein interactions maintaining a nearly planar conformation of the isoalloxazine tricycle, a low level of H bonding at the N1/N5 and O2/O4 sites, and a strong H-bond at N3H. They also indicate minimal changes in FAD structure and environment upon either NAD(H) binding or reduction of the sulfinic redox center. All these spectroscopic data support an enzyme functioning centered on the Cys-SO-/Cys-S- redox moiety and a neighbouring His residue. On the contrary, the RR data on various functional forms of MerA are indicative of a modulation of both ring II distortion and H bonding states of the N5 site and ring III. The Cd(II) binding to the EH2-NADP(H) complexes, biomimetic intermediates in the reaction of Hg(II) reduction, provokes important spectral changes. They are interpreted in terms of flattening of the isoalloxazine ring and large decreases in H-bonding at the N5 site and ring III. The large flexibility of the FAD structure and environment in MerA is in agreement with proposed mechanisms involving C4a(flavin) adducts. PMID- 28889234 TI - Peripheral Arterial Tonometry in Pulmonary Vasculitis. AB - Vascular wall inflammation in primary vasculitides results in diminished vessel dilation and finally impaired blood flow, causing multiple organs dysfunction and ultimate damage. In granulomatosis with polyangiitis (GPA), the inflammatory process concerns small and medium sized vessels and its pulmonary location is often predominant. The pivotal role in the development of that pathology plays vascular endothelium. Endothelial vasodilatory function strongly depends on the instant production and release of nitrogen oxide (NO), a potent local factor controlling vascular tonus. NO output is triggered by a variety of stimuli, especially by ischemia. The endothelial vasodilatory ability can be measured indirectly by a few of methods, one of them is peripheral arterial tonometry (PAT). The method assesses reactive hyperemia, mediated mostly by NO release, as a response to vessel occlusion. The vasodilatory reaction depends on the quality of the endothelium which deteriorates with time of GPA disease progression. The aim of the present study was to estimate a correlation between the clinical status, reflected by the disease extent index (DEI), and the vasodilatory endothelial function reflected by the index of arterial reactive hyperemia (RHI), measured by PAT in 27 patients with GPA, having a significant pulmonary involvement. We found a moderate inverse correlation between DEI and log transformed RHI (r = -0.46, p < 0.05). The conclusion is that impaired endothelial function, as assessed by RHI-PAT, might predict the GPA progression. PMID- 28889235 TI - Genotoxic potential of diesel exhaust particles from the combustion of first- and second-generation biodiesel fuels-the FuelHealth project. AB - Epidemiological data indicate that exposure to diesel exhaust particles (DEPs) from traffic emissions is associated with higher risk of morbidity and mortality related to cardiovascular and pulmonary diseases, accelerated progression of atherosclerotic plaques, and possible lung cancer. While the impact of DEPs from combustion of fossil diesel fuel on human health has been extensively studied, current knowledge of DEPs from combustion of biofuels provides limited and inconsistent information about its mutagenicity and genotoxicity, as well as possible adverse health risks. The objective of the present work was to compare the genotoxicity of DEPs from combustion of two first-generation fuels, 7% fatty acid methyl esters (FAME) (B7) and 20% FAME (B20), and a second-generation 20% FAME/hydrotreated vegetable oil (SHB: synthetic hydrocarbon biofuel) fuel. Our results revealed that particulate engine emissions from each type of biodiesel fuel induced genotoxic effects in BEAS-2B and A549 cells, manifested as the increased levels of single-strand breaks, the increased frequencies of micronuclei, or the deregulated expression of genes involved in DNA damage signaling pathways. We also found that none of the tested DEPs showed the induction of oxidative DNA damage and the gamma-H2AX-detectable double-strand breaks. The most pronounced differences concerning the tested particles were observed for the induction of single-strand breaks, with the greatest genotoxicity being associated with the B7-derived DEPs. The differences in other effects between DEPs from the different biodiesel blend percentage and biodiesel feedstock were also observed, but the magnitude of these variations was limited. PMID- 28889237 TI - Analysis of clinical factors correlated with the accuracy of colposcopically directed biopsy. AB - PURPOSE: Many factors affect the accuracy of colposcopically directed biopsy (CDB). This study aimed to compare the histological results of CDB with those of cone specimens and to determine clinical factors associated with the accuracy of CDB in defining the extent and severity of cervical intraepithelial neoplasia. METHODS: We studied 513 patients diagnosed with cervical intraepithelial neoplasia by CDB who underwent conization between September 2012 and December 2016. We retrospectively evaluated the agreement between histological results on biopsies and cone specimens and analyzed factors influencing the accuracy of the results. RESULTS: The overall agreement between the histological results on biopsy and the corresponding cone specimens was 74.1%; underestimation occurred in 6.4% of cases. The agreement between histological results on biopsy and cone specimen was 54.5% for low-grade lesions, 78.2% for high-grade lesions, and 28.9% for microinvasive cervical cancer. The overall agreement between high-grade cytology and the final histological diagnosis was 86.7%. By univariate analysis, patient age (p = 0.026), menopausal status (p = 0.018), type of transformation zone (p = 0.003), number of biopsies (p = 0.002), and cone width (p = 0.015) were found to be associated with the accuracy of CDB. However, multivariate logistic regression revealed that cone width (p = 0.044) was the only independent factor correlated with CDB accuracy. CONCLUSIONS: Our data suggest that old age (>=50), postmenopausal status, and transformation zone type 3 might be positively associated with the under-diagnosis of CDB. Three or more biopsies and cone width >=21 mm might improve CDB accuracy. However, cone width was the only independent factor correlated with CDB accuracy. PMID- 28889236 TI - Seasonal Variation in Water-Soluble Ions in Airborne Particulate Deposition in the Suburban Nanjing Area, Yangtze River Delta, China, During Haze Days and Normal Days. AB - To investigate the seasonal variation and characterization of water-soluble ions (WSIs) present in airborne particle deposition (APD) during Haze Days (visibility <=7.5 km) and Normal Days (visibility >7.5 km) in suburban Nanjing area, 151 filter samples were collected from 18 May 2013 to 26 May 2014. Ten different WSIs from the samples were determined by Ion Chromatography. The results indicated that secondary WSIs (NH4+, NO3-, and SO42-) were the main ions in the WSIs, averaging 17.2, 18.5, and 17.1 MUg/m3, respectively, and accounting respectively 20.9, 22.5, and 20.8% of the total WSIs. On Haze Days, the concentration of WSIs increased dramatically in fine size (particle size <2.1 MUm), especially for NH4+, NO3-, and SO42- (increased by 52.6, 71.3, and 73.1%, respectively), whereas the concentrations of WSIs increased slowly in coarse size (2.1 MUm < particle size < 10 MUm), in which NH4+, NO3-, and SO42- increased by 14.7, 27.2, and 54.5%, respectively. According to the backward trajectories and the principal component analysis analysis, Nanjing APD were mainly derived from the soil dust in northern China (35%) in the spring, from ocean air masses (61 and 55%) in the summer and the autumn, and from local air masses (73%) in the winter. On summer Haze Days, secondary components in PM2.1 consisted mainly of (NH4)2SO4 and NH4NO3, whereas secondary components in PM2.1-10 consisted mainly of (NH4)2SO4, NH4Cl, and NH4NO3. The increasing concentrations of secondary components increase the light extinction coefficients of aerosol on winter and autumn Haze Days. The concentrations of WSIs in fine size rose sharply on Haze Days, leading the visibility to exponential decline. Differently, the concentrations of WSIs in coarse size were not the main cause in the change of the visibility. PMID- 28889238 TI - Langerhans cell histiocytosis and Erdheim-Chester disease overlap syndrome with bone marrow involvement and type 2 diabetes mellitus. PMID- 28889239 TI - Into the void: a giant aneurysm mimicking a macroprolactinoma. PMID- 28889240 TI - Ursodeoxycholic Acid in the Prevention of Gallstone Formation After Bariatric Surgery: an Updated Systematic Review and Meta-analysis. AB - We aim to review the available literature on obese patients treated with ursodeoxycholic acid (UDCA) in order to prevent gallstone formation after bariatric surgery. A systematic literature search was performed in PubMed, Cochrane library, and Scopus databases, in accordance with the PRISMA guidelines. Eight studies met the inclusion criteria incorporating 1355 patients. Random effects meta-analysis showed a lower incidence of gallstone formation in patients taking UDCA. Subgroup analysis reported fewer cases of gallstone disease in the UDCA group in relation to different bariatric procedures, doses of administered UDCA, and time from bariatric surgery. Adverse events were similar in both groups. Fewer patients required cholecystectomy in UDCA group. No deaths were reported. The administration of UDCA after bariatric surgery seems to prevent gallstone formation. PMID- 28889241 TI - The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: a two-step, two-sample Mendelian randomisation study. AB - AIMS/HYPOTHESIS: The extent to which effects of BMI on CHD are mediated by glycaemic and lipid risk factors is unclear. In this study we examined the effects of these traits using genetic evidence. METHODS: We used two-sample Mendelian randomisation to determine: (1) the causal effect of BMI on CHD (60,801 case vs 123,504 control participants), type 2 diabetes (34,840 case vs 114,981 control participants), fasting glucose (n = 46,186), insulin (n = 38,238), HbA1c (n = 46,368) and LDL-cholesterol, HDL-cholesterol and triacylglycerols (n = 188,577); (2) the causal effects of glycaemic and lipids traits on CHD; and (3) the extent to which these traits mediate any effect of BMI on CHD. RESULTS: One SD higher BMI (~ 4.5 kg/m2) was associated with higher risk of CHD (OR 1.45 [95% CI 1.27, 1.66]) and type 2 diabetes (1.96 [95% CI 1.35, 2.83]), higher levels of fasting glucose (0.07 mmol/l [95% CI 0.03, 0.11]), HbA1c (0.05% [95% CI 0.01, 0.08]), fasting insulin (0.18 log pmol/l [95% CI 0.14, 0.22]) and triacylglycerols (0.20 SD [95% CI 0.14, 0.26]) and lower levels of HDL cholesterol (-0.23 SD [95% CI -0.32, -0.15]). There was no evidence for a causal relation between BMI and LDL-cholesterol. The causal associations of higher triacylglycerols, HbA1c and diabetes risk with CHD risk remained after performing sensitivity analyses that considered different models of horizontal pleiotropy. The BMI-CHD effect reduced from 1.45 to 1.16 (95% CI 0.99, 1.36) and to 1.36 (95% CI 1.19, 1.57) with genetic adjustment for triacylglycerols or HbA1c, respectively, and to 1.09 (95% CI 0.94, 1.27) with adjustment for both. CONCLUSIONS/INTERPRETATION: Increased triacylglycerol levels and poor glycaemic control appear to mediate much of the effect of BMI on CHD. PMID- 28889242 TI - Zinc oxide nanoparticle inhibits the biofilm formation of Streptococcus pneumoniae. AB - Biofilms are structured consortia of microbial cells that grow on living and non living surfaces and surround themselves with secreted polymers. Infections with bacterial biofilms have emerged as a foremost public health concern because biofilm growing cells can be highly resistant to both antibiotics and host immune defenses. Zinc oxide nanoparticles have been reported as a potential antimicrobial agent, thus, in the current study, we have evaluated the antimicrobial as well as antibiofilm activity of zinc oxide nanoparticles against the bacterium Streptococcus pneumoniae which is a significant cause of disease. Zinc oxide nanoparticles showed strong antimicrobial activity against S. pneumoniae, with an MIC value of 40 MUg/ml. Biofilm inhibition of S. pneumoniae was also evaluated by performing a series of experiments such as crystal violet assay, microscopic observation, protein count, EPS secretion etc. using sub-MIC concentrations (3, 6 and 12 ug/ml) of zinc oxide nanoparticles. The results showed that the sub-MIC doses of zinc oxide nanoparticles exhibited significant anti-biofilm activity against S. pneumoniae, with maximum biofilm attenuation found at 12 MUg/ml. Taken together, the results indicate that zinc oxide nanoparticles can be considered as a potential agent for the inhibition of microbial biofilms. PMID- 28889243 TI - A high-throughput QCM chip configuration for the study of living cells and cell drug interactions. AB - In this study, we present a novel design of interference-free, negligible installation-induced stress, suitable for the fabrication of high-throughput quartz crystal microbalance (HQCM) chips. This novel HQCM chip configuration was fabricated using eight independent yet same-batch quartz crystal resonators within a common glass substrate with eight through-holes of diameter slightly larger than that of the quartz resonator. Each quartz resonator's rim was adhered to the inner part of the through-hole via silicone glue to form the rigid (quartz)-soft (silicone)-rigid (glass) structure (RSRS) which effectively eliminates the acoustic couplings among different resonators and largely alleviates the installation-induced stresses. The consistence of the eight resonators was verified by very similar equivalent circuit parameters and very close response slopes to liquid density and viscosity. The HQCM chip was then employed for real-time and continuous monitoring of H9C2 cardiomyoblast adhesions and viscoelastic changes induced by the treatments of two types of drugs: drugs that affect the cytoskeletons, including nocodazole, paclitaxel, and Y-27632, and drugs that affect the contractile properties of the cells: verapamil and different dosages of isoprenaline. Meanwhile, we compared the cytoskeleton affecting drug-induced viscoelastic changes of H9C2 with those of human umbilical vein endothelial cells (HUVECs). The results described here provide the first solution to fabricate HQCM chips that are free from the limitation of resonator number, installation-induced stress, and acoustic interferences among resonators, which should find wide applications in areas of cell phenotype assay, cytotoxicity test, drug evaluation and screening, etc. Graphical abstract Schematic illustration of the principle and configuration of interference-free high-throughput QCM chip to evaluate and screen drugs based on cell viscoelasticity. PMID- 28889244 TI - Lumbar subtotal corpectomy non-fusion model produced using a novel prosthesis. AB - OBJECTIVE: In this study, we aimed to design a movable artificial lumbar complex (MALC) prosthesis for non-fusion reconstruction after lumbar subtotal corpectomy and to establish an in vitro anterolateral lumbar corpectomy non-fusion model for evaluating the biomechanical stability, preservation of segment movements and influence on adjacent inter-vertebral movements of this prosthesis. METHODS: Imaging was performed on a total of 26 fresh goat lumbar spine specimens to determine which of the specimens did not meet the requirements (free of deformity and fractures); the residual specimens were randomly divided into an intact group, a fusion group and a non-fusion group. Bone mineral density (BMD) was tested and compared among the three groups. Biomechanical testing was conducted to obtain the range of motion (ROM) in flexion-extension, lateral bending at L2 3, L3-4 and L4-5 and axial rotation at L2-5 in the three groups. RESULTS: Two specimens were excluded due to vertebral fractures. BMD showed no statistical significance among three groups (P > 0.05). The stability of the prosthesis did not differ significantly during flexion, extension, and lateral bending at L2-3, L3-4, and L4-5 and axial torsion at L2-5 between the intact group and the non fusion group (P > 0.05). Segment movements of the specimens in the non-fusion group revealed significantly decreased L2-3 ROM and significantly increased L3-4 and L4-5 ROM in flexion and lateral bending compared with the fusion group (P < 0.05). CONCLUSIONS: Reconstruction with a MALC prosthesis after lumbar subtotal corpectomy not only produced instant stability but also effectively preserved segment movements, without any abnormal gain of mobility in adjacent inter vertebral spaces. However, additional studies, including in vivo animal experiments as well as biocompatibility and biomechanical tests of human body specimens are needed. PMID- 28889245 TI - Effect of Soil Amendments on Microbial Resilience Capacity of Acid Soil Under Copper Stress. AB - An incubation study was undertaken to study microbial resilience capacity of acid soil amended with farmyard manure (FYM), charcoal and lime under copper (Cu) perturbation. Copper stress significantly reduced enzymatic activities and microbial biomass carbon (MBC) in soil. Percent reduction in microbial activity of soil due to Cu stress was 74.7% in dehydrogenase activity, 59.9% in MBC, 48.2% in alkaline phosphatase activity and 15.1% in acid phosphatase activity. Soil treated with FYM + charcoal showed highest resistance index for enzymatic activities and MBC. Similarly, the highest resilience index for acid phosphatase activity was observed in soil amended with FYM (0.40), whereas FYM + charcoal treated soil showed the highest resilience indices for alkaline, dehydrogenase activity and MBC: 0.50, 0.22 and 0.25, respectively. This investigation showed that FYM and charcoal application, either alone or in combination, proved to be better than lime with respect to microbial functional resistance and resilience of acid soil under Cu perturbation. PMID- 28889246 TI - The preliminary radiogenomics association between MR perfusion imaging parameters and genomic biomarkers, and their predictive performance of overall survival in patients with glioblastoma. AB - The radiogenomics association of neovascularization is important for overall survival (OS) in glioblastoma patients and remains unclear. The purpose of this study is to assess the association between MR perfusion imaging derived parameters and genomic biomarkers of glioblastoma, and to evaluate their prognostic value. This retrospective study enrolled 41 patients with newly diagnosed glioblastoma. The mean and maximal relative cerebral blood volume (rCBV) ratio (rCBVmean and rCBVmax), derived from MR perfusion weighted imaging, of the enhancing tumor, as well as maximal rCBV ratio of peri-enhancing tumor area (rCBVperi-tumor) were measured. The ki-67 labeling index, mammalian target of rapamycin (mTOR) activation, epidermal growth factor receptor (EGFR) amplification, isocitrate dehydrogenase (IDH) mutation and TP53 were assessed. There was a significant correlation between rCBVmax and mTOR based on Pearson's correlations with Benjamini-Hochberg adjustment for controlling false discovery rate, p = 0.047. The rCBVperi-tumor showed significant correlation with mTOR (p = 0.0183) after adjustment of gender and EGFR status. The mean rCBVperi-tumor value of the patients with OS shorter than 14 months was significantly higher than patients with OS longer than 14 months, p = 0.002. The rCBVperi-tumor and age were the two strongest predictors of OS (hazard ratio = 1.29 and 1.063 respectively) by Cox regression analysis. This study showed that hemodynamic abnormalities of glioblastoma were associated with genomics activation status of mTOR-EGFR pathway, however, the radiogenomics associations are different in enhancing and peri-enhancing area of glioblastoma. The rCBVperi-tumor has better prognostic value than genomic biomarkers alone. PMID- 28889247 TI - Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology. AB - Although sudden cardiac death (SCD) is one of the most important modes of death in Western countries, pathologists and public health physicians have not given this problem the attention it deserves. New methods of preventing potentially fatal arrhythmias have been developed and the accurate diagnosis of the causes of SCD is now of particular importance. Pathologists are responsible for determining the precise cause and mechanism of sudden death but there is still considerable variation in the way in which they approach this increasingly complex task. The Association for European Cardiovascular Pathology has developed these guidelines, which represent the minimum standard that is required in the routine autopsy practice for the adequate investigation of SCD. The present version is an update of our original article, published 10 years ago. This is necessary because of our increased understanding of the genetics of cardiovascular diseases, the availability of new diagnostic methods, and the experience we have gained from the routine use of the original guidelines. The updated guidelines include a detailed protocol for the examination of the heart and recommendations for the selection of histological blocks and appropriate material for toxicology, microbiology, biochemistry, and molecular investigation. Our recommendations apply to university medical centers, regionals hospitals, and all healthcare professionals practicing pathology and forensic medicine. We believe that their adoption throughout Europe will improve the standards of autopsy practice, allow meaningful comparisons between different communities and regions, and permit the identification of emerging patterns of diseases causing SCD. Finally, we recommend the development of regional multidisciplinary networks of cardiologists, geneticists, and pathologists. Their role will be to facilitate the identification of index cases with a genetic basis, to screen appropriate family members, and ensure that appropriate preventive strategies are implemented. PMID- 28889248 TI - Towards Discovery and Targeted Peptide Biomarker Detection Using nanoESI-TIMS-TOF MS. AB - In the present work, the potential of trapped ion mobility spectrometry coupled to TOF mass spectrometry (TIMS-TOF MS) for discovery and targeted monitoring of peptide biomarkers from human-in-mouse xenograft tumor tissue was evaluated. In particular, a TIMS-MS workflow was developed for the detection and quantification of peptide biomarkers using internal heavy analogs, taking advantage of the high mobility resolution (R = 150-250) prior to mass analysis. Five peptide biomarkers were separated, identified, and quantified using offline nanoESI-TIMS-CID-TOF MS; the results were in good agreement with measurements using a traditional LC-ESI MS/MS proteomics workflow. The TIMS-TOF MS analysis permitted peptide biomarker detection based on accurate mobility, mass measurements, and high sequence coverage for concentrations in the 10-200 nM range, while simultaneously achieving discovery measurements of not initially targeted peptides as markers from the same proteins and, eventually, other proteins. Graphical Abstract ?. PMID- 28889249 TI - Papillae formation on trichome cell walls requires the function of the mediator complex subunit Med25. AB - KEY MESSAGE: Glassy Hair 1 (GLH1) gene that promotes papillae formation on trichome cell walls was identified as a subunit of the transcriptional mediator complex MED25. The MED25 gene is shown to be expressed in trichomes. The expression of the trichome development marker genes GLABRA2 (GL2) and Ethylene Receptor2 (ETR2) is not affected in the glh1 mutant. Presented data suggest that Arabidopsis MED25 mediator component is likely involved in the transcription of genes promoting papillae deposition in trichomes. The plant cell wall plays an important role in communication, defense, organization and support. The importance of each of these functions varies by cell type. Specialized cells, such as Arabidopsis trichomes, exhibit distinct cell wall characteristics including papillae. To better understand the molecular processes important for papillae deposition on the cell wall surface, we identified the GLASSY HAIR 1 (GLH1) gene, which is necessary for papillae formation. We found that a splice site mutation in the component of the transcriptional mediator complex MED25 gene is responsible for the near papillae-less phenotype of the glh1 mutant. The MED25 gene is expressed in trichomes. Reporters for trichome developmental marker genes GLABRA2 (GL2) and Ethylene Receptor2 (ETR2) were not affected in the glh1 mutant. Collectively, the presented results show that MED25 is necessary for papillae formation on the cell wall surface of leaf trichomes and suggest that the Arabidopsis MED25 mediator component is likely involved in the transcription of a subset of genes that promote papillae deposition in trichomes. PMID- 28889250 TI - Surface-modified CMOS IC electrochemical sensor array targeting single chromaffin cells for highly parallel amperometry measurements. AB - Amperometry is a powerful method to record quantal release events from chromaffin cells and is widely used to assess how specific drugs modify quantal size, kinetics of release, and early fusion pore properties. Surface-modified CMOS based electrochemical sensor arrays allow simultaneous recordings from multiple cells. A reliable, low-cost technique is presented here for efficient targeting of single cells specifically to the electrode sites. An SU-8 microwell structure is patterned on the chip surface to provide insulation for the circuitry as well as cell trapping at the electrode sites. A shifted electrode design is also incorporated to increase the flexibility of the dimension and shape of the microwells. The sensitivity of the electrodes is validated by a dopamine injection experiment. Microwells with dimensions slightly larger than the cells to be trapped ensure excellent single-cell targeting efficiency, increasing the reliability and efficiency for on-chip single-cell amperometry measurements. The surface-modified device was validated with parallel recordings of live chromaffin cells trapped in the microwells. Rapid amperometric spikes with no diffusional broadening were observed, indicating that the trapped and recorded cells were in very close contact with the electrodes. The live cell recording confirms in a single experiment that spike parameters vary significantly from cell to cell but the large number of cells recorded simultaneously provides the statistical significance. PMID- 28889251 TI - A 10-year prospective-longitudinal study of daily hassles and incident psychopathology among adolescents and young adults: interactions with gender, perceived coping efficacy, and negative life events. AB - PURPOSE: To prospectively examine whether higher daily hassles predict a variety of incident mental disorders and respective associations vary by gender, age, perceived coping efficacy and number of negative life events. METHODS: Data comes from the Early Developmental Stages of Psychopathology Study (EDSP), a prospective-longitudinal study among adolescents and young adults from the community (n = 2797, aged 14-24 at baseline) followed up in up to 3 assessment waves over 10 years. Mental disorders were assessed at each wave using the DSM IV/M-CIDI. Daily hassles, perceived coping efficacy, and negative life events were assessed at baseline using the Daily Hassles Scale, Scale for Self-Control and Coping Skills, and Munich Life Event List. RESULTS: In logistic regressions adjusted for gender, age, other mental disorders, perceived coping efficacy and number of negative life events at baseline, higher daily hassles at baseline predicted the incidence of any anxiety disorder, specific phobia, obsessive compulsive disorder, any affective disorder, and major depressive episodes at follow-up (OR 1.2-1.9 per standard deviation). Daily hassles interacted with perceived coping efficacy at baseline in predicting incident panic attacks (OR 1.3) and panic disorder (OR 1.3) at follow-up, i.e., higher daily hassles only predicted incident panic pathology among individuals with low perceived coping efficacy (OR 1.6-2.0) but not high perceived coping efficacy. Moreover, the associations between daily hassles and incident mental disorders partially varied by gender and age but not by negative life events at baseline. CONCLUSIONS: Targeted stress management interventions among individuals with increased daily hassles might be useful to prevent the onset of anxiety and affective disorders. PMID- 28889253 TI - Evaluating Parental Autism Disclosure Strategies. AB - The relative effects of different autism disclosure methods on the perceptions of a mother-child dyad were investigated. Using three conditions, disclosure card, disclosure bracelet, and no disclosure, U.S. community parents (N = 383) were asked 18 questions about their perceptions of the dyad. An ANOVA revealed significant protection from stigma for those in either disclosure condition compared to the no disclosure condition on two factors, Critical of the Mother/Child and Need to Protect Own Child, as well as a single item, Embarrassment for the Mother. These results reinforce findings that disclosure may effectively and efficiently reduce negative perceptions. The availability of multiple, effective methods of disclosure that reduce stigma allows parents to choose the method that best suits their individual preferences. PMID- 28889252 TI - The association between physical activity and depression among individuals residing in Brazil. AB - PURPOSE: There is very limited literature investigating the association between physical activity (PA) and depression in South American countries such as Brazil. The purpose of the current study was to evaluate the prevalence of depression and its association with PA in a very large, representative sample of young adults (ages 18-39 years) (YA), middle-aged adults (ages 40-59 years) (MAA) and older adults (ages >= 60 years) (OA) residing in Brazil. METHODS: The sample for this cross-sectional study was based on the Brazilian National Health Survey conducted in 2013. The Personal Health Questionnaire depression scale (PHQ-8) was applied to measure current (past 2 weeks) depression as the outcome of interest, and the exposure was self-reported PA for leisure. Multivariable weighted logistic regression models were conducted to investigate the association between PA and depression while adjusting for socio-demographic characteristics and number of health comorbidities among YA, MAA and OA. RESULTS: The final study sample size was 59,399 (33,480 females; 25,919 males). After adjusting for the covariates of interest, the lack of PA for leisure was associated with a significant increase in depression only among males (YA: OR 1.45, 95% CI 1.02-2.06; MAA: OR 2.38, 95% CI 1.40-4.03; OA: OR 5.35, 95% CI 2.14-13.37). There was no significant association between PA for leisure and depression among females of all age groups. CONCLUSIONS: Although PA for leisure is not associated with depression among Brazilian females, the obtained results suggest that this association is significant among Brazilian males, who may be able to benefit from PA for leisure to reduce their symptoms of depression. PMID- 28889254 TI - Effect of impulsive controls in a model system for age-structured population over a patchy environment. AB - In this paper, a very general model of impulsive delay differential equations in n-patches is rigorously derived to describe the impulsive control of population of a single species over n-patches. The model allows an age structure consisting of immatures and matures, and also considers mobility and culling of both matures and immatures. Conditions are obtained for extinction and persistence of the model system under three special scenarios: (1) without impulsive control; (2) with impulsive culling of the immatures only; and (3) with impulsive culling of the matures only, respectively. In the case of persistence, the persistence level is also estimated for the systems in the case of identical n patches, by relating the issue to the dynamics of multi-dimensional maps. Two illustrative examples and their numerical simulations are given to show the effectiveness of the results. Based on the theoretical results, some strategies of impulsive culling are provided to eradicate the population of a pest species. PMID- 28889255 TI - Motor-related brain abnormalities in HIV-infected patients: a multimodal MRI study. AB - PURPOSE: It is generally believed that HIV infection could cause HIV-associated neurocognitive disorders (HAND) across a broad range of functional domains. Some of the most common findings are deficits in motor control. However, to date no neuroimaging studies have evaluated basic motor control in HIV-infected patients using a multimodal approach. METHODS: In this study, we utilized high-resolution structural imaging and task-state functional magnetic resonance imaging (fMRI) to assess brain structure and motor function in a homogeneous cohort of HIV-infected patients. RESULTS: We found that HIV-infected patients had significantly reduced gray matter (GM) volume in cortical regions, which are involved in motor control, including the bilateral posterior insula cortex, premotor cortex, and supramarginal gyrus. Increased activation in bilateral posterior insula cortices was also demonstrated by patients during hand movement tasks compared with healthy controls. More importantly, the reduced GM in bilateral posterior insula cortices was spatially coincident with abnormal brain activation in HIV-infected patients. In addition, the results of partial correlation analysis indicated that GM reduction in bilateral posterior insula cortices and premotor cortices was significantly correlated with immune system deterioration. CONCLUSION: This study is the first to demonstrate spatially coincident GM reduction and abnormal activation during motor performance in HIV-infected patients. Although it remains unknown whether the brain deficits can be recovered, our findings may yield new insights into neurologic injury underlying motor dysfunction in HAND. PMID- 28889256 TI - Structural and functional diversity arising from intra- and inter-haplotype combinations of duplicated DQA and B loci within the ovine MHC. AB - In sheep, the A and B loci encoding the alpha and beta chains of the classical class II MHC molecules are DRA and DRB and DQA and DQB. Previous analyses described the duplication of the DQA and DQB genes. The majority of haplotypes include DQA1 and DQA2 loci, however, in a number of haplotypes, DQA1 appears absent and these haplotypes have been described as DQA1 null. In these haplotypes, the DQA2 locus is found in combination with a second locus which appeared more closely related to DQA2 than DQA1, hence the description of this locus as DQA2-like. Here we combine our previous analysis of the DQA transcripts with an analysis of the associated DQB transcripts in ten haplotypes from MHC homozygous animals. This allows the potential for surface expression of different haplotype combinations of DQA and B genes and the functional significance of DQA2 like and its predicted DQB partner to be determined. Atypical DQB transcripts (DQB2-like) were identified in haplotypes classified as DQA1-null and conserved DQB2-like orthologues were identified in other Bovidae indicating trans-species conservation of the allelic lineage. Functional combinations detected by co transfection of DQ1, DQ2 and DQ2-like genes demonstrates the potential for a wide range of DQ molecules derived from both intra- and inter-haplotype as well as inter-locus combinations. We provide evidence that DQA2-like and B2-like genes form an evolutionary conserved pair which generates structurally distinct class II molecules that are likely to present a distinct range of peptides to CD4+ T cells. PMID- 28889257 TI - Evaluation of auditory and cochlear functions in ankylosing spondylitis patients according to the site of involvement. AB - Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease of unknown origin with a prevalence rate about 1% in the population. Audiovestibular dysfunction is encountered in AS and sensorineural hearing loss is the most common form. The present study aimed to evaluate auditory and cochlear function in AS patients according to the site of involvement. A total of 47 patients followed for AS in the rheumatology outpatient clinic and 30 healthy controls were enrolled in the study. Subgroups of AS were identified according to the site of involvement. The participants underwent complete otolaryngological examination together with audiometry, otoacoustic emission and tympanometry tests. Disease Activity Index (BASDAI) was determined in the AS group. Hearing loss was detected in seven patients (15%) in the AS group and in four subjects (8%) in the control group. There was statistically significant difference between the patient and control groups in terms of mean bone conduction hearing level at 4000 hertz (Hz) in the right and left ears (p = 0.028, p = 0.049). There was no significant difference between the subgroups of AS in terms of overall auditory and cochlear functions. No correlation was determined between auditory values and Disease Activity Index and CRP (p > 0.05 for all). Our results reveal that AS has minimal effect on auditory and cochlear functions. The effects of subgroups of AS on auditory functions were comparable. The authors concluded that BASDAI and CRP are not convenient in monitoring auditory functions of AS patients. PMID- 28889259 TI - An ultrasensitive and selective electrochemical sensor for determination of estrone 3-sulfate sodium salt based on molecularly imprinted polymer modified carbon paste electrode. AB - A highly sensitive and selective electrochemical sensor based on carbon paste electrode (CPE) modified with molecularly imprinted polymers (MIPs) has been developed for the determination of estrone 3-sulfate sodium salt (ESS). MIPs were prepared in polar medium via bulk polymerization and characterized by scanning electron microscopy and infrared spectroscopy. Cyclic voltammetry was performed to the study preparation process and binding behavior of the MIP-modified CPE (MIP/CPE) toward ESS. The conditions for preparing MIPs and MIP/CPE as well as ESS detection were optimized. Under the optimal experimental conditions, the detection linear range for ESS is 4 * 10-12 to 6 * 10-9 M with a limit of detection of 1.18 * 10-12 M (S/N = 3). In addition, the sensor exhibits high binding affinity toward ESS over its structural analogues with excellent repeatability and stability. The fabricated MIP/CPE was then successfully employed to detect ESS in pregnant mare urine (PMU) without any pretreatment, and the average recoveries were from 99.6 to 104.9% with relative standard deviation less than 3.0%. High-performance liquid chromatography was adopted as a reference to validate the established approach in detecting ESS and their results showed good agreement. The as-prepared sensor has high potential to be a decent tool for on-site determination of ESS in PMU in a fast and convenient manner. Graphical Abstract ?. PMID- 28889258 TI - Moderators of smoking cessation outcomes in a randomized-controlled trial of varenicline versus placebo. AB - RATIONALE AND OBJECTIVE: Varenicline has gained a reputation as the optimal intervention for treatment resistant smokers, yet more than half of those who try it do not succeed. To better understand individual differences in the effectiveness of varenicline, this study evaluates the effectiveness of varenicline for smoking cessation in a double-blind, placebo-controlled, randomized clinical trial and examines the influence of psychological factors on treatment outcome. METHOD: Two hundred five cigarette smokers interested in quitting were randomly assigned to 12 weeks of varenicline or placebo. Outcomes examined were CO-confirmed continuous abstinence for the past month, average number of cigarettes smoked per day, and 7-day point prevalence. RESULTS: Varenicline-treated participants were more likely than placebo to achieve continuous abstinence at the end of treatment (OR = 3.29; RR = 2.62), and 7-day point prevalence rates showed an effect of medication at each time point. Participants in both groups significantly reduced their smoking during the course of treatment and follow-up, and the medication by visit interaction was significant in the expected direction. Impulsivity and personality style emerged as moderators of the relationship between medication condition and treatment outcome. CONCLUSIONS: In addition to replicating efficacy results for varenicline versus placebo, the present study shows that the efficacy of pharmacotherapy is influenced by psychological factors. In an era where pharmacotherapy is often perceived as the "silver bullet," we are reminded that smoking cessation is a dynamic process and intervention must be adaptable to address individual differences. PMID- 28889260 TI - Developmental Neurotoxicity of Lead. AB - Lead exposure is a major concern for the developing nervous system. Environmental exposures to lead, predominantly from contaminated water or lead paint chips, account for the majority of exposures to children. In utero and early life exposures to lead have been associated with lower IQ, antisocial and delinquent behaviors, and attention-deficit hyperactivity disorder. In this review, we will discuss sources of developmental lead exposure and mechanisms of lead neurotoxicity. We will highlight both human epidemiological studies showing associations between lead exposure and behavioral abnormalities as well as experimental data from animal studies. Finally, we will discuss the effects of lead on neurological endpoint past childhood, namely, development of Alzheimer's disease in old age. PMID- 28889262 TI - Inherited Disorders of Manganese Metabolism. AB - While the neurotoxic effects of manganese were recognized in 1837, the first genetic disorder of manganese metabolism was described only in 2012 when homozygous mutations in SLC30A10 were reported to cause manganese-induced neurotoxicity. Two other genetic disorders of manganese metabolism have now been described - mutations in SLC39A14 cause manganese toxicity, while mutations in SLC39A8 cause manganese and zinc deficiency. Study of rare genetic disorders often provides unique insights into disease pathobiology, and the discoveries of these three inherited disorders of manganese metabolism are already transforming our understanding of manganese homeostasis, detoxification, and neurotoxicity. Here, we review the mechanisms by which mutations in SLC30A10, SLC39A14, and SLC39A8 impact manganese homeostasis to cause human disease. PMID- 28889263 TI - Chemical Speciation of Selenium and Mercury as Determinant of Their Neurotoxicity. AB - The antagonism of mercury toxicity by selenium has been well documented. Mercury is a toxic metal, widespread in the environment. The main target organs (kidneys, lungs, or brain) of mercury vary depending on its chemical forms (inorganic or organic). Selenium is a semimetal essential to mammalian life as part of the amino acid selenocysteine, which is required to the synthesis of the selenoproteins. This chapter has the aim of disclosing the role of selenide or hydrogen selenide (Se-2 or HSe-) as central metabolite of selenium and as an important antidote of the electrophilic mercury forms (particularly, Hg2+ and MeHg). Emphasis will be centered on the neurotoxicity of electrophile forms of mercury and selenium. The controversial participation of electrophile mercury and selenium forms in the development of some neurodegenerative disease will be briefly presented. The potential pharmacological use of organoseleno compounds (Ebselen and diphenyl diselenide) in the treatment of mercury poisoning will be considered. The central role of thiol (-SH) and selenol (-SeH) groups as the generic targets of electrophile mercury forms and the need of new in silico tools to guide the future biological researches will be commented. PMID- 28889261 TI - Manganese and Developmental Neurotoxicity. AB - Manganese (Mn) is an essential metal that plays a fundamental role for brain development and functioning. Environmental exposure to Mn may lead to accumulation in the basal ganglia and development of Parkinson-like disorders. The most recent research is focusing on early-life overexposure to Mn and the potential vulnerability of younger individuals to Mn toxicity also in regard to cognitive and executive functions through the involvement of the frontal cortex.Neurodevelopmental disturbances are increasing in the society, and understanding the potential role of environmental determinants is a key for prevention. Therefore, assessing the environmental sources of Mn exposure and the mechanisms of developmental neurotoxicity and defining appropriate biomarkers of exposure and early functional alterations represent key issues to improve and address preventive strategies. These themes will be reviewed in this chapter. PMID- 28889264 TI - Metals and Paraoxonases. AB - The paraoxonases (PONs) are a three-gene family which includes PON1, PON2, and PON3. PON1 and PON3 are synthesized primarily in the liver and a portion is secreted in the plasma, where they are associated with high-density lipoproteins (HDLs), while PON2 is an intracellular enzyme, expressed in most tissues and organs, including the brain. PON1 received its name from its ability to hydrolyze paraoxon, the active metabolite of the organophosphorus (OP) insecticide parathion, and also more efficiently hydrolyzes the active metabolites of several other OPs. PON2 and PON3 do not have OP-esterase activity, but all PONs are lactonases and are capable of hydrolyzing a variety of lactones, including certain drugs, endogenous compounds, and quorum-sensing signals of pathogenic bacteria. In addition, all PONs exert potent antioxidant effects. PONs play important roles in cardiovascular diseases and other oxidative stress-related diseases, modulate susceptibility to infection, and may provide neuroprotection (PON2). Hence, significant attention has been devoted to their modulation by a variety of dietary, pharmacological, lifestyle, or environmental factors. A number of metals have been shown in in vitro, animal, and human studies to mostly negatively modulate expression of PONs, particularly PON1, the most studied in this regard. In addition, different levels of expression of PONs may affect susceptibility to toxicity and neurotoxicity of metals due to their aforementioned antioxidant properties. PMID- 28889265 TI - Manganese and the Insulin-IGF Signaling Network in Huntington's Disease and Other Neurodegenerative Disorders. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival. Manganese (Mn) is an essential metal to all biological systems but, in excess, can be toxic. Interestingly, several studies have revealed the insulin-mimetic effects of Mn-demonstrating Mn can activate several of the same metabolic kinases and increase peripheral and neuronal insulin and IGF-1 levels in rodent models. Separate studies have shown mouse and human striatal neuroprogenitor cell (NPC) models exhibit a deficit in cellular Mn uptake, indicative of a Mn deficiency. Furthermore, evidence from the literature reveals a striking overlap between cellular consequences of Mn deficiency (i.e., impaired function of Mn-dependent enzymes) and known HD endophenotypes including excitotoxicity, increased reactive oxygen species (ROS) accumulation, and decreased mitochondrial function. Here we review published evidence supporting a hypothesis that (1) the potent effect of IGF or insulin treatment on HD models, (2) the insulin-mimetic effects of Mn, and (3) the newly discovered Mn-dependent perturbations in HD may all be functionally related. Together, this review will present the intriguing possibility that intricate regulatory cross-talk exists between Mn biology and/or toxicology and the insulin/IGF signaling pathways which may be deeply connected to HD pathology and, perhaps, other neurodegenerative diseases (NDDs) and other neuropathological conditions. PMID- 28889266 TI - Occupational Metal Exposure and Parkinsonism. AB - Parkinsonism is comprised of a host of neurological disorders with an underlying clinical feature of movement disorder, which includes many shared features of bradykinesia, tremor, and rigidity. These clinical outcomes occur subsequent to pathological deficits focused on degeneration or dysfunction of the nigrostriatal dopamine system and accompanying pathological inclusions of alpha-synuclein and tau. The heterogeneity of parkinsonism is equally matched with the complex etiology of this syndrome. While a small percentage can be attributed to genetic alterations, the majority arise from an environmental exposure, generally composed of pesticides, industrial compounds, as well as metals. Of these, metals have received significant attention given their propensity to accumulate in the basal ganglia and participate in neurotoxic cascades, through the generation of reactive oxygen species as well as their pathogenic interaction with intracellular targets in the dopamine neuron. The association between metals and parkinsonism is of critical concern to subsets of the population that are occupationally exposed to metals, both through current practices, such as mining, and emerging settings, like E-waste and the manufacture of metal nanoparticles. This review will explore our current understanding of the molecular and pathological targets that mediate metal neurotoxicity and lead to parkinsonism and will highlight areas of critical research interests that need to be addressed. PMID- 28889267 TI - Inflammatory Activation of Microglia and Astrocytes in Manganese Neurotoxicity. AB - Neurotoxicity due to excessive exposure to manganese (Mn) has been described as early as 1837 (Couper, Br Ann Med Pharm Vital Stat Gen Sci 1:41-42, 1837). Extensive research over the past two decades has revealed that Mn-induced neurological injury involves complex pathophysiological signaling mechanisms between neurons and glial cells. Glial cells are an important target of Mn in the brain, both for sequestration of the metal, as well as for activating inflammatory signaling pathways that damage neurons through overproduction of numerous reactive oxygen and nitrogen species and inflammatory cytokines. Understanding how these pathways are regulated in glial cells during Mn exposure is critical to determining the mechanisms underlying permanent neurological dysfunction stemming from excess exposure. The subject of this review will be to delineate mechanisms by which Mn interacts with glial cells to perturb neuronal function, with a particular emphasis on neuroinflammation and neuroinflammatory signaling between distinct populations of glial cells. PMID- 28889268 TI - Aluminum and Alzheimer's Disease. AB - Aluminum (Al) is one of the most extended metals in the Earth's crust. Its abundance, together with the widespread use by humans, makes Al-related toxicity particularly relevant for human health.Despite some factors influence individual bioavailability to this metal after oral, dermal, or inhalation exposures, humans are considered to be protected against Al toxicity because of its low absorption and efficient renal excretion. However, several factors can modify Al absorption and distribution through the body, which may in turn progressively contribute to the development of silent chronic exposures that may lately trigger undesirable consequences to health. For instance, Al has been recurrently shown to cause encephalopathy, anemia, and bone disease in dialyzed patients. On the other hand, it remains controversial whether low doses of this metal may contribute to developing Alzheimer's disease (AD), probably because of the multifactorial and highly variable presentation of the disease.This chapter primarily focuses on two key aspects related to Al neurotoxicity and AD, which are metabolic impairment and iron (Fe) alterations. We discuss sex and genetic differences as a plausible source of bias to assess risk assessment in human populations. PMID- 28889269 TI - Copper and Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common form of adult neurode-generation and is characterised by progressive loss of cognitive function leading to death. The neuropathological hallmarks include extracellular amyloid plaque accumulation in affected regions of the brain, formation of intraneuronal neurofibrillary tangles, chronic neuroinflammation, oxidative stress, and abnormal biometal homeostasis. Of the latter, major changes in copper (Cu) levels and localisation have been identified in AD brain, with accumulation of Cu in amyloid deposits, together with deficiency of Cu in some brain regions. The amyloid precursor protein (APP) and the amyloid beta (Abeta) peptide both have Cu binding sites, and interaction with Cu can lead to potentially neurotoxic outcomes through generation of reactive oxygen species. In addition, AD patients have systemic changes to Cu metabolism, and altered Cu may also affect neuroinflammatory outcomes in AD. Although we still have much to learn about Cu homeostasis in AD patients and its role in disease aetiopathology, therapeutic approaches for regulating Cu levels and interactions with Cu-binding proteins in the brain are currently being developed. This review will examine how Cu is associated with pathological changes in the AD brain and how these may be targeted for therapeutic intervention. PMID- 28889270 TI - Uranium and the Central Nervous System: What Should We Learn from Recent New Tools and Findings? AB - Increasing industrial and military use of uranium has led to environmental pollution, which may result in uranium reaching the brain and causing cerebral dysfunction. A recent literature review has discussed data published over the last 10 years on uranium and its effects on brain function (Dinocourt C, Legrand M, Dublineau I, et al., Toxicology 337:58-71, 2015). New models of uranium exposure during neonatal brain development and the emergence of new technologies (omics and epigenetics) are of value in identifying new specific targets of uranium. Here we review the latest studies of neurogenesis, epigenetics, and metabolic dysfunctions and the identification of new biomarkers used to establish potential pathophysiological states of neurodevelopmental and neurodegenerative diseases. PMID- 28889271 TI - Neurotoxicity of Metal Mixtures. AB - Metals are the oldest toxins known to humans. Metals differ from other toxic substances in that they are neither created nor destroyed by humans (Casarett and Doull's, Toxicology: the basic science of poisons, 8th edn. McGraw-Hill, London, 2013). Metals are of great importance in our daily life and their frequent use makes their omnipresence and a constant source of human exposure. Metals such as arsenic [As], lead [Pb], mercury [Hg], aluminum [Al] and cadmium [Cd] do not have any specific role in an organism and can be toxic even at low levels. The Substance Priority List of Agency for Toxic Substances and Disease Registry (ATSDR) ranked substances based on a combination of their frequency, toxicity, and potential for human exposure. In this list, As, Pb, Hg, and Cd occupy the first, second, third, and seventh positions, respectively (ATSDR, Priority list of hazardous substances. U.S. Department of Health and Human Services, Public Health Service, Atlanta, 2016). Besides existing individually, these metals are also (or mainly) found as mixtures in various parts of the ecosystem (Cobbina SJ, Chen Y, Zhou Z, Wub X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wua X, Yang L, Chemosphere 132:79-86, 2015). Interactions among components of a mixture may change toxicokinetics and toxicodynamics (Spurgeon DJ, Jones OAH, Dorne J-L, Svendsen C, Swain S, Sturzenbaum SR, Sci Total Environ 408:3725-3734, 2010) and may result in greater (synergistic) toxicity (Lister LJ, Svendsen C, Wright J, Hooper HL, Spurgeon DJ, Environ Int 37:663-670, 2011). This is particularly worrisome when the components of the mixture individually attack the same organs. On the other hand, metals such as manganese [Mn], iron [Fe], copper [Cu], and zinc [Zn] are essential metals, and their presence in the body below or above homeostatic levels can also lead to disease states (Annangi B, Bonassi S, Marcos R, Hernandez A, Mutat Res 770(Pt A):140-161, 2016). Pb, As, Cd, and Hg can induce Fe, Cu, and Zn dyshomeostasis, potentially triggering neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, changes in heme synthesis have been associated with neurodegeneration, supported by evidence that a decline in heme levels might explain the age-associated loss of Fe homeostasis (Atamna H, Killile DK, Killile NB, Ames BN, Proc Natl Acad Sci U S A 99(23):14807-14812, 2002).The sources, disposition, transport to the brain, mechanisms of toxicity, and effects in the central nervous system (CNS) and in the hematopoietic system of each one of these metals will be described. More detailed information on Pb, Mn, Al, Hg, Cu, and Zn is available in other chapters. A major focus of the chapter will be on Pb toxicity and its interaction with other metals. PMID- 28889272 TI - Methylmercury-Induced Neurotoxicity: Focus on Pro-oxidative Events and Related Consequences. AB - Methylmercury (MeHg) is a highly neurotoxic environmental pollutant. Even though molecular mechanisms mediating MeHg toxicity are not completely understood, several lines of evidence indicate that the neurotoxic effects resultant from MeHg exposure represent a consequence of its pro-oxidative properties. In this regard, MeHg is a soft electrophile that preferentially interacts with (and oxidize) nucleophilic groups (mainly thiols and selenols) from biomolecules, including proteins and low-molecular-weight molecules. Such interaction contributes to the occurrence of oxidative stress and impaired function of several molecules [proteins (receptors, transporters, enzymes, structural proteins), lipids (i.e., membrane constituents and intracellular messengers), and nucleic acids (i.e., DNA)], culminating in neurotoxicity.In this chapter, an initial background on the general aspects regarding the neurotoxicology of MeHg, with a particular focus on its pro-oxidative properties and its interaction with nucleophilic thiol- and selenol-containing molecules, is provided. Even though experimental evidence indicates that symptoms (i.e., motor impairment) resultant from MeHg exposure are linked to its pro-oxidative properties, as well as to their molecular consequences (lipid peroxidation, disruption of glutamate and/or calcium homeostasis, etc.), data concerning the relationship between molecular parameters and behavioral impairment others that those related to the motor function (i.e., visual impairment, cognitive skills, etc.) are scarce. Thus, even though scientific research has provided a significant amount of knowledge concerning the mechanisms mediating MeHg-induced neurotoxicity in the last decades, the whole scenario is far from being completely understood, and further research in this area is well warranted. PMID- 28889273 TI - Neurotoxicity of Vanadium. AB - Vanadium (V) is a transition metal that presents in multiple oxidation states and numerous inorganic compounds and is also an ultra-trace element considered to be essential for most living organisms. Despite being one of the lightest metals, V offers high structural strength and good corrosion resistance and thus has been widely adopted for high-strength steel manufacturing. High doses of V exposure are toxic, and inhalation exposure to V adversely affects the respiratory system. The neurotoxicological properties of V are just beginning to be identified. Recent studies by our group and others demonstrate the neurotoxic potential of this metal in the nigrostriatal system and other parts of the central nervous system (CNS). The neurotoxic effects of V have been mainly attributed to its ability to induce the generation of reactive oxygen species (ROS). It is noteworthy that the neurotoxicity induced by occupational V exposure commonly occurs with co-exposure to other metals, especially manganese (Mn). This review focuses on the chemistry, pharmacology, toxicology, and neurotoxicity of V. PMID- 28889274 TI - Neurotoxicity of Zinc. AB - Zinc-induced neurotoxicity has been shown to play a role in neuronal damage and death associated with traumatic brain injury, stroke, seizures, and neurodegenerative diseases. During normal firing of "zinc-ergic" neurons, vesicular free zinc is released into the synaptic cleft where it modulates a number of postsynaptic neuronal receptors. However, excess zinc, released after injury or disease, leads to excitotoxic neuronal death. The mechanisms of zinc mediated neurotoxicity appear to include not only neuronal signaling but also regulation of mitochondrial function and energy production, as well as other mechanisms such as aggregation of amyloid beta peptides in Alzheimer's disease. However, recent data have raised questions about some of our long-standing assumptions about the mechanisms of zinc in neurotoxicity. Thus, this review explores the most recent published findings and highlights the current mechanistic controversies. PMID- 28889275 TI - Neurotoxicity of Copper. AB - Copper is an essential trace metal that is required for several important biological processes, however, an excess of copper can be toxic to cells. Therefore, systemic and cellular copper homeostasis is tightly regulated, but dysregulation of copper homeostasis may occur in disease states, resulting either in copper deficiency or copper overload and toxicity. This chapter will give an overview on the biological roles of copper and of the mechanisms involved in copper uptake, storage, and distribution. In addition, we will describe potential mechanisms of the cellular toxicity of copper and copper oxide nanoparticles. Finally, we will summarize the current knowledge on the connection of copper toxicity with neurodegenerative diseases. PMID- 28889276 TI - Thallium Toxicity: General Issues, Neurological Symptoms, and Neurotoxic Mechanisms. AB - Thallium (Tl+) is a ubiquitous natural trace metal considered as the most toxic among heavy metals. The ionic ratio of Tl+ is similar to that of potassium (K+), therefore accounting for the replacement of the latter during enzymatic reactions. The principal organelle damaged after Tl+ exposure is mitochondria. Studies on the mechanisms of Tl+ include intrinsic pathways altered and changes in antiapoptotic and proapoptotic proteins, cytochrome c, and caspases. Oxidative damage pathways increase after Tl+ exposure to produce reactive oxygen species (ROS), changes in physical properties of the cell membrane caused by lipid peroxidation, and concomitant activation of antioxidant mechanisms. These processes are likely to account for the neurotoxic effects of the metal. In humans, Tl+ is absorbed through the skin and mucous membranes and then is widely distributed throughout the body to be accumulated in bones, renal medulla, liver, and the Central Nervous System. Given the growing relevance of Tl+ intoxication, in recent years there is a notorious increase in the number of reports attending Tl+ pollution in different countries. In this sense, the neurological symptoms produced by Tl+ and its neurotoxic effects are gaining attention as they represent a serious health problem all over the world. Through this review, we present an update to general information about Tl+ toxicity, making emphasis on some recent data about Tl+ neurotoxicity, as a field requiring attention at the clinical and preclinical levels. PMID- 28889277 TI - Neurodegeneration Induced by Metals in Caenorhabditis elegans. AB - Metals are a component of a variety of ecosystems and organisms. They can generally be divided into essential and nonessential metals. The essential metals are involved in physiological processes once the deficiency of these metals has been associated with diseases. Although iron, manganese, copper, and zinc are important for life, it has been evidenced that they are also involved in neuronal damage in many neurodegenerative disorders. Nonessential metals, which are metals without physiological functions, are present in trace or higher levels in living organisms. Occupational, environmental, or deliberate exposures to lead, mercury, aluminum, and cadmium are clearly correlated with the increase of toxicity and varied kinds of pathological situations. Actually, the field of neurotoxicology needs to satisfy two opposing demands: the testing of a growing list of chemicals and resource limitations and ethical concerns associated with testing using traditional mammalian species. Toxicological assays using alternative animal models may relieve some of this pressure by allowing testing of more compounds while reducing expenses and using fewer mammals. The nervous system is by far the more complex system in C. elegans. Almost a third of their cells are neurons (302 neurons versus 959 cells in adult hermaphrodite). It initially underwent extensive development as a model organism in order to study the nervous system, and its neuronal lineage and the complete wiring diagram of its nervous system are stereotyped and fully described. The neurotransmission systems are phylogenetically conserved from nematodes to vertebrates, which allows for findings from C. elegans to be extrapolated and further confirmed in vertebrate systems. Different strains of C. elegans offer a new perspective on neurodegenerative processes. Some genes have been found to be related to neurodegeneration induced by metals. Studying these interactions may be an effective tool to slow neuronal loss and deterioration. PMID- 28889278 TI - Endocrine Disrupting Compounds from the Source Water of the Huai River (Huainan City), China. AB - The occurrence and environmental risk of eight endocrine disrupting compounds (EDCs), namely dimethyl phthalate (DMP), diethyl phthalate (DEP), benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), nonyl phenol (NP), bisphenol A (BPA), 17alpha-ethinylestradiol (EE2) and estrone (E1), from four water sources (Pingshantou, Wanfenggang, Shisi, and Shiyi) of Huai River (Huainan section) were investigated in this study. Except for DMP only found in Pingshantou, all of the selected EDCs existed widely in the source water. DMP, DEP, BBP, DBP, NP, BPA, EE2, and E1 had the ranges of nd (cannot be detected)-130 ng/L, 25-310, 76-1351, 431-1299, 215-627, 23-107, nd-0.174, and 0.143-0.334 ng/L, respectively. Therefore, the studied water sources were associated with notable levels of EDCs, wherein the concentrations of BBP, DBP, and NP were much higher than the other five chemicals. The selected EDCs appeared to be higher in upstream than in downstream (p < 0.05) for each water source, suggesting that EDCs were subjected to a decreasing with water flow. Correlation analysis suggests that DEP-BP-DBP, NP-BPA, and EE2-E1 might have the same sources, respectively; and the source of NP, EE2, and E1 was different from that of BBP, BEP and BBP, and DEP, respectively. It was observed that both the TAS (total ambient severity) and RQ (risk quotient) were less than 1, indicating that EDCs in Huai River (Huainan section) posed little or no thread to the health of local inhabitants and ecological environmental. PMID- 28889279 TI - Impact of Land Use on the Mobility of Hg Species in Different Compartments of a Tropical Watershed in Brazil. AB - This study evaluated the levels of total Hg and CH3Hg+ from a comprehensive perspective, considering the retention, leaching, and deposition of these contaminants in the main compartments (soil, plant litter, and sediment) of three landscapes (Atlantic Forest, pasture, and agricultural area) in a watershed in northern Rio de Janeiro State, Brazil. Variables analyzed were total Hg, CH3Hg+, organic carbon, total nitrogen, grain size, and surface area. In soil samples, total Hg levels were the highest in agricultural soil followed by forest soil and pasture (97.3, 87.6, and 77.1 ng g-1, respectively), and CH3Hg+ was lower than 1.7%. Total Hg levels in leaf litter varied between 22.6 and 34.2 ng g-1, and CH3Hg+ was 4.37%. In sediment, Hg (60-180 ng g-1) and CH3Hg+ (<1%) indicate the transport of these contaminants from soils to this compartment and may be associated with soil use and cover. Multiple regressions were used to understand the dispersion of Hg species, and the effect of each variable varied with the landscape, showing that plant cover should not be ignored in investigations related to Hg species retention in a watershed. The landscapes surveyed in the present study clearly influence the quantitative and qualitative distribution of Hg species. On the other hand, anthropic processes associated with changes in soil use did not have any critical effects on the absolute levels of total Hg and CH3Hg+, meaning that the landscapes evaluated seem to represent the background concentration of these chemical species for the evaluated watershed. PMID- 28889280 TI - Successful multimodal treatment of a gigantic choroid plexus carcinoma (CPC) in an 8-year-old girl. PMID- 28889282 TI - Enzymatic Production of c-di-GMP Using a Thermophilic Diguanylate Cyclase. AB - C-di-GMP has emerged as a prevalent bacterial messenger that controls a multitude of bacterial behaviors. Having access to milligram or gram quantities of c-di-GMP is essential for the biochemical and structural characterization of enzymes and effectors involved in c-di-GMP signaling. Although c-di-GMP can be synthesized using chemical methods, diguanylate cyclases (DGC)-based enzymatic synthesis is the most efficient method of preparing c-di-GMP today. Many DGCs are not suitable for c-di-GMP production because of poor protein stability and the presence of a c di-GMP-binding inhibitory site (I-site) in most DGCs. We have identified and engineered a thermophilic DGC for efficient production of c-di-GMP for characterizing c-di-GMP signaling proteins and riboswitches. Importantly, residue replacement in the inhibitory I-site of the thermophilic DGC drastically relieved product inhibition to enable the production of hundreds of milligrams of c-di-GMP using 5-10 mg of this robust biocatalyst. PMID- 28889281 TI - Discovery of the Second Messenger Cyclic di-GMP. AB - The nearly ubiquitous bacterial second messenger cyclic di-GMP is involved in a multitude of fundamental physiological processes such as sessility/motility transition and the switch between the acute and chronic infection status, combined with cell cycle control. The discovery of cyclic di-GMP, though, has been an example par excellence of scientific serendipity. We recapitulate here its years-long discovery process as an activator of the cellulose synthase of the environmental bacterium Komagataeibacter xylinus and its consequences for follow up research. Indeed, the discovery of cyclic di-GMP as a ubiquitous second messenger contributed to the change in perception of bacteria as simple unicellular organisms just randomly building-up multicellular communities. Subsequently, cyclic di-GMP also paved the way to the identification of other pro and eukaryotic cyclic dinucleotide second messengers. PMID- 28889283 TI - Synthesis of [32P]-c-di-GMP for Diguanylate Cyclase and Phosphodiesterase Activity Determinations. AB - Diguanylate cyclases that synthesize and phosphodiesterases that hydrolyze the second messenger cyclic-di-GMP (c-di-GMP) are at the center of bacterial signaling pathways that control behaviors relevant to all aspects of microbial physiology and pathogenesis (Romling et al., Microbiol Mol Biol Rev 77(1):1-52, 2013). Bioinformatics tools can easily predict the presence of the diguanylate cyclase GGDEF domain, or the EAL and HD-GYP domains associated with phosphodiesterase activity. However, experimental confirmation of enzymatic activity is still necessary, as many proteins contain degenerate domains that lack catalytic activity but nonetheless function as c-di-GMP receptors. PMID- 28889284 TI - High-Performance Liquid Chromatography (HPLC)-Based Detection and Quantitation of Cellular c-di-GMP. AB - The modulation of c-di-GMP levels plays a vital role in the regulation of various processes in a wide array of bacterial species. Thus, investigation of c-di-GMP regulation requires reliable methods for the assessment of c-di-GMP levels and turnover. Reversed-phase high-performance liquid chromatography (RP-HPLC) analysis has become a commonly used approach to accomplish these goals. The following describes the extraction and HPLC-based detection and quantification of c-di-GMP from Pseudomonas aeruginosa samples, a procedure that is amenable to modifications for the analysis of c-di-GMP in other bacterial species. PMID- 28889285 TI - Identification and Quantification of Cyclic Di-Guanosine Monophosphate and Its Linear Metabolites by Reversed-Phase LC-MS/MS. AB - Cyclic dinucleotides such as bis-(3',5')-cyclic dimeric guanosine monophosphate (3',3'-c-di-GMP) represent an important class of second messengers in bacteria and are involved in numerous (patho)physiological settings. Here, we describe a sensitive and specific quantification method for 3',3'-c-di-GMP by HPLC-coupled tandem mass spectrometry (LC-MS/MS). Additionally, linear 3',3'-c-di-GMP metabolites, i.e., 5'-phosphoguanylyl-3',5'-guanosine (pGpG) and 5'-guanosine monophosphate (5'-GMP), as well as cyclic guanosine monophosphate (3',5'-cGMP) and 3',3' c-di-GMP analogues (2',3'-c-di-GMP and 2',2'-c-di-GMP) can be simultaneously determined by this method. PMID- 28889286 TI - Detection of Cyclic Dinucleotides by STING. AB - STING (stimulator of interferon genes) is an essential signaling adaptor protein mediating cytosolic DNA-induced innate immunity for both microbial invasion and self-DNA leakage. STING is also a direct receptor for cytosolic cyclic dinucleotides (CDNs), including the microbial secondary messengers c-di-GMP (3',3'-cyclic di-GMP), 3',3'cGAMP (3',3'-cyclic GMP-AMP), and mammalian endogenous 2',3'cGAMP (2',3'-cyclic GMP-AMP) synthesized by cGAS (cyclic GMP-AMP synthase). Upon CDN binding, STING undergoes a conformational change to enable signal transduction by phosphorylation and finally to active IRF3 (Interferon regulatory factor 3) for type I interferon production. Here, we describe some experimental procedures such as Isothermal Titration Calorimetry and luciferase reporter assays to study the CDNs binding and activity by STING proteins. PMID- 28889287 TI - Spectrophotometric and Mass Spectroscopic Methods for the Quantification and Kinetic Evaluation of In Vitro c-di-GMP Synthesis. AB - The expression and activity of diguanylate cyclase (DGC) and phosphodiesterase (PDE) enzymes are responsible for modulating and maintaining the intracellular concentration of the bacterial second messenger cyclic diguanosine-monophosphate (c-di-GMP). Here, we describe an in vitro method for the spectrophotometric detection and quantification of DGC catalyzed c-di-GMP synthesis through adaptation of the EnzChek(r) Pyrophosphate Assay Kit. We also outline a method for the quantification of c-di-GMP produced in this in vitro reaction using Ultra Performance Liquid Chromatography tandem Mass Spectrometry (UPLC-MS/MS). These methods can be leveraged for a number of experimental applications including the evaluation of enzyme activity for the in vitro synthesis of c-di-GMP, examination of how molecular signals impact these activities, identifying the catalytic properties of hybrid DGC-PDE proteins, and the development of DGC inhibitors. PMID- 28889288 TI - Gauging and Visualizing c-di-GMP Levels in Pseudomonas aeruginosa Using Fluorescence-Based Biosensors. AB - Recent research has shown that the molecule c-di-GMP is an important second messenger regulating various functions in bacteria. In particular, the implication of c-di-GMP as a positive regulator of adhesion and biofilm formation has gained momentum as a highly relevant research topic, as detailed knowledge about the underlying regulatory mechanisms may enable the development of measures to control biofilms in both industrial and medical settings. Accordingly, it is in many cases of interest to measure the c-di-GMP level in bacteria under specific conditions or in specific mutant strains. We have developed a collection of fluorescence-based c-di-GMP biosensors capable of gauging the c-di-GMP level in Pseudomonas aeruginosa and closely related bacteria. Here, we describe protocols for the use of these biosensors in gauging and visualizing cellular c di-GMP levels of P. aeruginosa both in in vitro setups such as continuous-culture flow-cell biofilms, and in in vivo settings such as a murine corneal infection model. PMID- 28889289 TI - Cyclic di-GMP-Responsive Transcriptional Reporter Bioassays in Pseudomonas aeruginosa. AB - 3',5'-cyclic diguanosine monophosphate (cyclic di-GMP) is a bacterial secondary messenger molecule that regulates many important cellular activities and behaviors, such as motility and biofilm formation. While mass spectrometry protocols for quantitative analyses of intracellular cyclic di-GMP concentrations have been developed, they are time intensive, expensive, low-throughput, and incapable of directly monitoring dynamic changes in vivo. In this protocol, we provide a Pseudomonas aeruginosa-specific detailed methodology to assay the intracellular levels of cyclic di-GMP using biological reporters. PMID- 28889290 TI - Live Flow Cytometry Analysis of c-di-GMP Levels in Single Cell Populations. AB - Second-generation RNA-based fluorescent biosensors have been developed that enable flow cytometry experiments to monitor the population dynamics of c-di-GMP signaling in live bacteria. These experiments are high-throughput, provide information at the single-cell level, and can be performed on cells grown in complex media and/or under anaerobic conditions. Here, we describe flow cytometry methods for three applications: (1) high-throughput screening for diguanylate cyclase activity, (2) analyzing c-di-GMP levels under anaerobic conditions, and (3) monitoring cell population dynamics of c-di-GMP levels upon environmental changes. These methods showcase RNA-based fluorescent biosensors as versatile tools for studying c-di-GMP signaling in bacteria. PMID- 28889291 TI - Experimental Detection and Visualization of the Extracellular Matrix in Macrocolony Biofilms. AB - By adopting elaborate three-dimensional morphologies that vary according to their extracellular matrix composition, macrocolony biofilms offer a unique opportunity to interrogate about the roles of specific matrix components in shaping biofilm architecture. Here, we describe two methods optimized for Escherichia coli that profit from morphology and the high level of structural organization of macrocolonies to gain insight into the production and assembly of amyloid curli and cellulose-the two major biofilm matrix elements of E. coli-in biofilms. The first method, the macrocolony morphology assay, is based on the ability of curli and cellulose-either alone or in combination-to generate specific morphological and Congo Red-staining patterns in E. coli macrocolonies, which can then be used as a direct visual readout for the production of these matrix components. The second method involves thin sectioning of macrocolonies, which along with in situ staining of amyloid curli and cellulose and microscopic imaging allows gaining fine details of the spatial arrangement of both matrix elements inside macrocolonies. Beyond their current use with E. coli and related curli and cellulose-producing Enterobacteriaceae, both the methods offer the potential to be adapted to other bacterial species. PMID- 28889292 TI - Congo Red Stain Identifies Matrix Overproduction and Is an Indirect Measurement for c-di-GMP in Many Species of Bacteria. AB - Congo red is a diazo textile dye that has been used to visualize the production of amyloid fibers for nearly a century. Microbiological applications were later developed, especially in identifying strains that produce amyloid appendages called curli and overexpressing polysaccharides in the biofilm matrix. The second messenger cyclic diguanylate (c-di-GMP) regulates the production of biofilm matrix polysaccharides, and therefore Congo red staining of samples can be utilized as an indirect measurement of elevated c-di-GMP production in bacteria. Congo red allows the identification of strains producing high c-di-GMP in an inexpensive, quantitative, and high-throughput manner. PMID- 28889293 TI - Type IV Pili-Dependent Motility as a Tool to Determine the Activity of c-di-GMP Modulating Enzymes in Myxococcus xanthus. AB - The nucleotide-based second messenger bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) regulates multiple processes in bacteria including cellular motility. The rod shaped Myxococcus xanthus cells move in the direction of their long axis using two distinct motility systems: type IV pili (T4P)-dependent motility and gliding motility. Manipulation of the c-di-GMP level by expression of either an active, heterologous diguanylate cyclase or an active, heterologous phosphodiesterase causes defects in T4P-dependent motility without affecting gliding motility. As both an increased and a decreased level of c-di-GMP affect T4P-dependent motility, M. xanthus represents a good model system to assess enzyme activity of diguanylate cyclases and phosphodiesterases using T4P-dependent motility as a readout. Here, we describe the assay, which allows correlating diguanylate cyclase and phosphodiesterase activity with T4P-dependent motility in M. xanthus. PMID- 28889294 TI - Using Light-Activated Enzymes for Modulating Intracellular c-di-GMP Levels in Bacteria. AB - Signaling pathways involving second messenger c-di-GMP regulate various aspects of bacterial physiology and behavior. We describe the use of a red light activated diguanylate cyclase (c-di-GMP synthase) and a blue light-activated c-di GMP phosphodiesterase (hydrolase) for manipulating intracellular c-di-GMP levels in bacterial cells. We illustrate the application of these enzymes in regulating several c-di-GMP-dependent phenotypes, i.e., motility and biofilm phenotypes in E. coli and chemotactic behavior in the alphaproteobacterium Azospirillum brasilense. We expect these light-activated enzymes to be also useful in regulating c-di-GMP-dependent processes occurring at the fast timescale, for spatial control of bacterial populations, as well as for analyzing c-di-GMP dependent phenomena at the single-cell level. PMID- 28889295 TI - Analysis of c-di-GMP Levels Synthesized by a Photoreceptor Protein in Response to Different Light Qualities Using an In Vitro Enzymatic Assay. AB - Diguanylate cyclases are enzymes that use two GTP molecules to produce one molecule cyclic dimeric guanosine monophosphate (c-di-GMP). This cyclic dinucleotide is an ubiquitous prokaryotic second messenger that controls a variety of cell functions. Several proteins have been described which contain a photoreceptor domain fused to a diguanylate cyclase. The cyanobacterial light sensor Cph2 is responsible for the blue-light induced synthesis of c-di-GMP in Synechocystis sp. PCC 6803. Here, we provide a detailed protocol for an in vitro enzymatic assay with a purified photoreceptor protein using light as the crucial reaction parameter for c-di-GMP synthesis. The assay is accomplished under continuous illumination with light of different quality with inactivation of the enzyme by heat denaturation. Analytics are performed using HPLC-UV. PMID- 28889296 TI - Probing the Role of Cyclic di-GMP Signaling Systems in Disease Using Chinese Radish. AB - The determination of the genome sequences of pathogenic bacteria has facilitated functional analyses that aim to understand the molecular basis of virulence. In particular, genome sequence information of the pathogen Xanthomonas campestris pathovar campestris has allowed researchers to identify and functionally analyze the role of intracellular signaling involving cyclic di-GMP in black rot disease of crucifers. Here, we describe leaf clipping and spraying methods for testing the virulence of wild type and derived mutants of X. campestris in Chinese radish. These methods address different facets of the disease cycle, which requires the ability to survive epiphytically before entry into the plant and growth and systemic spread within the xylem. PMID- 28889297 TI - Contribution of Cyclic di-GMP in the Control of Type III and Type VI Secretion in Pseudomonas aeruginosa. AB - Bacteria produce toxins to enhance their competitiveness in the colonization of an environment as well as during an infection. The delivery of toxins into target cells is mediated by several types of secretion systems, among them our focus is Type III and Type VI Secretion Systems (T3SS and T6SS, respectively). A thorough methodology is provided detailing how to identify if cyclic di-GMP signaling plays a role in the P. aeruginosa toxin delivery mediated by T3SS or T6SS. This includes in vitro preparation of the samples for Western blot analysis aiming at detecting possible c-di-GMP-dependent T3SS/T6SS switch, as well as in vivo analysis using the model organism Galleria mellonella to demonstrate the ecological and pathogenic consequence of the switch between these two secretion systems. PMID- 28889298 TI - Semiquantitative Analysis of the Red, Dry, and Rough Colony Morphology of Salmonella enterica Serovar Typhimurium and Escherichia coli Using Congo Red. AB - The Congo Red (CR) assay is a standard biofilm test assessing the colony morphology of bacteria growing on agar plates supplemented with the diazo dye Congo Red. Biofilm forming Salmonella enterica serovar Typhimurium and Escherichia coli produce a red, dry, and rough (rdar) morphotype on CR-plates. The phenotype is characterized by staining of the extracellular matrix components curli (brown color) and cellulose (pink color) by CR. This method allows semiquantitative determination of the expression level of the individual matrix components and dissection of the regulatory networks controlling their production in response to c-di-GMP levels. Here, we describe the CR-assay and its variations and discuss the effect of deletion or overexpression of c-di-GMP turnover proteins on colony morphology. PMID- 28889299 TI - Fluorescent 2-Aminopurine c-di-GMP and GpG Analogs as PDE Probes. AB - c-di-GMP is widely recognized as an important ubiquitous signaling molecule in bacteria. c-di-GMP phosphodiesterases (PDEs) regulate the intracellular concentration of c-di-GMP and some could be potential drug targets. Here, we describe a class of dinucleotide probes suitable for monitoring the enzymatic activities of c-di-GMP PDEs in real time. Such probes contain fluorescent nucleobases and can be readily cleaved by PDEs, resulting in a change in fluorescence. Fluorescent cyclic and linear dinucleotide probes could be used in diverse applications, such as confirming the activity of an expressed PDE or oligoribonuclease (Orns) or identifying inhibitors of PDEs or Orns using high throughput screening formats. PMID- 28889300 TI - Measuring Cyclic Diguanylate (c-di-GMP)-Specific Phosphodiesterase Activity Using the MANT-c-di-GMP Assay. AB - The second messenger, cyclic diguanylate (c-di-GMP), regulates a variety of bacterial cellular and social behaviors. A key determinant of c-di-GMP levels in cells is its degradation by c-di-GMP-specific phosphodiesterases (PDEs). Here, we describe an assay to determine c-di-GMP degradation rates in vitro using 2'-O-(N' methylanthraniloyl)-cyclic diguanylate (MANT-c-di-GMP). Additionally, a protocol for the production and purification of recombinant Pseudomonas aeruginosa RocR, a c-di-GMP-specific PDE that may serve as a control in MANT-c-di-GMP assays, is provided. The use of the fluorescent MANT-c-di-GMP analogue can deliver fundamental information about PDE function, and is suitable for identifying and investigating c-di-GMP-specific PDE activators and inhibitors. PMID- 28889301 TI - Determining Phosphodiesterase Activity (Radioactive Assay). AB - Cyclic-di-GMP phosphodiesterases (PDEs) catalyze the hydrolysis of the bacterial second messenger c-di-GMP. This protocol describes a sensitive radioactive assay for PDE activity in which substrate and product can be quickly and easily separated by thin-layer chromatography. PMID- 28889302 TI - Determining Diguanylate Cyclase Activity (Radioactive Assay). AB - Bioinformatics approaches can identify sequence motifs associated with diguanylate cyclases (DGCs), but experimental demonstration of DGC enzymatic activity is often desired. This protocol describes a sensitive radioactive assay for DGC activity in which substrate and product are quickly and easily separated by thin-layer chromatography. PMID- 28889303 TI - Detection of c-di-GMP-Responsive DNA Binding. AB - Modulation of signal transduction via binding of the secondary messenger molecule cyclic di-GMP to effector proteins is a near universal regulatory schema in bacteria. In particular, direct binding of c-di-GMP to transcriptional regulators has been shown to alter gene expression of a variety of processes. Here, we illustrate a pull-down-based DNA:protein binding reaction to determine the relative importance of c-di-GMP in the binding affinity of a target protein to specific DNA sequences. Specifically, the pull-down-based assay enables DNA binding to be analyzed with differing concentrations of c-di-GMP in the absence/presence of specific and nonspecific competitors. PMID- 28889304 TI - Use of Nonradiochemical DNAse Footprinting to Analyze c-di-GMP Modulation of DNA Binding Proteins. AB - The transition of bacteria from a planktonic lifestyle to a collaborative, sessile biofilm lifestyle is a regulated process orchestrated by the intracellular second-messenger c-di-GMP (bis-(3'-5')-cyclic dimeric guanosine monophosphate). To modulate this transition, c-di-GMP acts at the transcriptional, posttranscriptional, and posttranslational levels. In this chapter, we describe a method to study of how a transcriptional regulator modulates gene expression in response to c-di-GMP binding. DNase I footprinting is a valuable tool for use in analyzing how regulatory proteins bind to DNA, the location of their binding sites or how c-di-GMP affects their binding to DNA. This chapter describes a protocol for nonradiochemical DNase I footprinting experiments using a capillary electrophoresis method based on the interaction of the Pseudomonas aeruginosa FleQ protein with the promoter regions of biofilm related genes. PMID- 28889305 TI - Detection of Cyclic di-GMP Binding Proteins Utilizing a Biotinylated Cyclic di GMP Pull-Down Assay. AB - Cyclic di-GMP is an important regulatory messenger molecule that often directly interacts with proteins to alter function. It is therefore important to find potential c-di-GMP binding proteins and verify a direct interaction between them. Here, we describe a pull-down assay using biotinylated-c-di-GMP to capture a specific protein of interest followed by immunoblot analysis to determine relative protein abundance. This method also allows for addition of both specific and nonspecific competitors to determine specificity of c-di-GMP-protein binding. We also discuss using densitometry analysis on resulting immunoblots to calculate the dissociation constant (KD) of the binding reaction, allowing for a determination of binding affinity. PMID- 28889306 TI - Probing Protein-Protein Interactions with Genetically Encoded Photoactivatable Cross-Linkers. AB - Fundamental to all living organisms is the ability of proteins to interact with other biological molecules at the right time and location, with the proper affinity, and to do so reversibly. One well-established technique to study protein interactions is chemical cross-linking, a process in which proteins in close spatial proximity are covalently tethered together. An emerging technology that overcomes many limitations of traditional cross-linking methods is one in which photoactivatable cross-linking noncanonical amino acids are genetically encoded into a protein of interest using the cell's native translational machinery. These proteins can then be used to trap interacting biomolecules upon UV illumination. Here, we describe a method for the site-specific incorporation of photoactivatable cross-linking amino acids into fluorescently tagged proteins of interest in E. coli. Photo-cross-linking and analysis by SDS-PAGE using in-gel fluorescence detection, which provides rapid, highly sensitive, and specific detection of cross-linked adducts even in impure systems, are also described. An example expression and cross-linking experiment involving transmembrane signaling of a bacterial second messenger receptor system that controls biofilm formation is shown. All reagents needed to carry out these experiments are commercially available, and do not require special or unique technology to perform, making this method tractable to a broad community studying protein structure and function. PMID- 28889307 TI - Identification of c-di-AMP-Binding Proteins Using Magnetic Beads. AB - To identify cytosolic proteins that bind to cyclic di-AMP, a biotinylated analog of the nucleotide is used for protein pull-down experiments. In this approach, biotinylated c-di-AMP is coupled to Streptactin-covered beads. After protein separation using standard SDS-PAGE, the protein(s) of interest are identified by mass spectrometric analyses. PMID- 28889308 TI - Pull-Down with a c-di-GMP-Specific Capture Compound Coupled to Mass Spectrometry as a Powerful Tool to Identify Novel Effector Proteins. AB - Capture compound technology coupled to mass spectrometry (CCMS) allows to biochemically identify ligand receptors. Using a c-di-GMP-specific Capture Compound, we adapted this method for the identification and characterization of c di-GMP binding proteins in any bacterial species. Because in silico analysis often fails to predict novel c-di-GMP effectors, this universal method aims at better defining the cellular c-di-GMP network in a wide range of bacteria. CCMS was successfully applied in several bacterial species (Nesper et al., J Proteom 75:4874-4878, 2012; Steiner et al., EMBO J 32:354-368, 2013; Tschowri et al., Cell 158:1136-1147, 2014; Trampari et al., J Biol Chem 290:24470-24483, 2015; Rotem et al., J Bacteriol 198:127-137, 2015). To outline the detailed protocol and to illustrate its power, we use Pseudomonas aeruginosa, an opportunistic pathogen in which c-di-GMP plays a critical role in virulence and biofilm control, as an example. CCMS identified 74% (38/51) of the known or predicted components of the c-di-GMP network. PMID- 28889309 TI - Identification of c-di-GMP-Responsive Riboswitches. AB - Bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) is an important signaling molecule for community behavior control, cell morphogenesis, and virulence in bacteria. In addition to protein effectors, this second messenger binds RNA molecules that act as riboswitches to control target gene expression. In this chapter, we describe a method for experimental validation of the functionality of c-di-GMP-responsive riboswitches and the analysis of c-di-GMP control of target gene expression by qRT-PCR and Northern blot. This procedure can be used for the studies of in silico-predicted riboswitch candidates, as well as a targeted experimental approach for exploring the data from next-generation sequencing. The examples on the analysis of type I and type II c-di-GMP responsive riboswitches in Clostridium difficile are provided to illustrate the application of the method. PMID- 28889310 TI - Isothermal Titration Calorimetry to Determine Apparent Dissociation Constants (K d) and Stoichiometry of Interaction (n) of C-di-GMP Binding Proteins. AB - Isothermal titration calorimetry (ITC) is a commonly used biophysical technique that enables the quantitative characterization of intermolecular interactions in solution. Based on enthalpy changes (DeltaH) upon titration of the binding partner (e.g., a small-molecule ligand such as c-di-GMP) to the molecule of interest (e.g., a receptor protein), the resulting binding isotherms provide information on the equilibrium association/dissociation constants (K a, K d) and stoichiometry of binding (n), as well as on changes in the Gibbs free energy (DeltaG) and entropy (DeltaS) along the interaction. Here we present ITC experiments used for the characterization of c-di-GMP binding proteins and discuss advantages and potential caveats in the interpretation of results. PMID- 28889311 TI - Targeting c-di-GMP Signaling, Biofilm Formation, and Bacterial Motility with Small Molecules. AB - Bacteria possess several signaling molecules that regulate distinct phenotypes. Cyclic di-GMP (c-di-GMP) has emerged as a ubiquitous second messenger that regulates bacterial virulence, cell cycle, motility, and biofilm formation. The link between c-di-GMP signaling and biofilm formation affords novel strategies for treatment of biofilm-associated infections, which is a major public health problem. The complex c-di-GMP signaling pathway creates a hurdle in the development of small molecule modulators. Nonetheless, some progress has been made in this regard and inhibitors of c-di-GMP metabolizing enzymes that affect biofilm formation and motility have been documented. Herein we discuss the components of c-di-GMP signaling, their correlation with biofilm formation as well as motility and reported small molecule inhibitors of c-di-GMP signaling. PMID- 28889312 TI - Discovering Selective Diguanylate Cyclase Inhibitors: From PleD to Discrimination of the Active Site of Cyclic-di-GMP Phosphodiesterases. AB - One of the most important signals involved in controlling biofilm formation is represented by the intracellular second messenger 3',5'-cyclic diguanylic acid (c di-GMP). Since the pathways involved in c-di-GMP biosynthesis and breakdown are found only in bacteria, targeting c-di-GMP metabolism represents an attractive strategy for the development of biofilm-disrupting drugs. Here, we present the workflow required to perform a structure-based design of inhibitors of diguanylate cyclases, the enzymes responsible for c-di-GMP biosynthesis. Downstream of the virtual screening process, detailed in the first part of the chapter, we report the step-by-step protocols required to test the positive hits in vitro and to validate their selectivity, thus minimizing possible off-target effects. PMID- 28889313 TI - High-Throughput Screening for Compounds that Modulate the Cellular c-di-GMP Level in Bacteria. AB - Bacteria in the biofilm mode of growth cause numerous problematic infections due to their resistance to antimicrobials and the immune system. Because conventional antimicrobial compounds cannot efficiently eradicate biofilm infections, we urgently need new efficient anti-biofilm drugs. The secondary messenger c-di-GMP is a positive regulator of biofilm formation in many clinically relevant bacteria, and it is assumed that drugs that lower the intracellular level of c-di GMP will force biofilm bacteria into a more treatable planktonic lifestyle. We describe a protocol for high-throughput screening of chemical libraries for compounds that lower the c-di-GMP level in bacteria, and potentially can serve as lead compounds in the development of novel biofilm dismantling drugs. PMID- 28889314 TI - Genetic Tools to Study c-di-GMP-Dependent Signaling in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa infections are often difficult or impossible to treat, mainly due to its ability to form antibiotic-resistant biofilms. Since c-di-GMP signaling strongly influences P. aeruginosa biofilm development and sensitivity to antibiotics, it is considered a promising target for the development of anti biofilm drugs and it is under intensive investigation. However, studying c-di-GMP signaling in P. aeruginosa is challenging, mainly due to (1) the multiplicity of enzymes involved in c-di-GMP metabolism, (2) the difficulty to extract and measure c-di-GMP intracellular levels by chemical methods, and (3) the lack of genetic tools specifically dedicated to this purpose.Here, a bioluminescence based reporter system convenient for studying cellular processes or compounds expected to cause an increase or a decrease in intracellular c-di-GMP levels produced by P. aeruginosa cultures is described. Bioluminescence is particularly appropriate in P. aeruginosa research, due to the high intensity of the signal and total lack of background noise. In addition, the use of genetic cassettes allowing the fine control of P. aeruginosa c-di-GMP intracellular levels via arabinose induction is described.Overall, the genetic tools described here could facilitate investigations tackling the c-di-GMP signaling process on different fields, from cellular physiology to drug-discovery research. PMID- 28889315 TI - Brief Report: Executive Function as a Predictor of Academic Achievement in School Aged Children with ASD. AB - The contributions of Executive Function (EF) to academic achievement in children with Autism Spectrum Disorder (ASD) are not well understood. Academic achievement and its association with EF is described in 32, 9-year-old children with ASD. EF at age 6 and 9, and academic achievement at age 9 were assessed as part of a larger longitudinal study. Better performance on a Spatial Reversal task but not A-not-B with Invisible Displacement at age 6 was associated with better math achievement at age 9. No relationship was found between these EF measures at age 6 and reading or spelling achievement at age 9. Future studies are needed to explore whether improving early EF skills can increase math achievement in children with ASD. PMID- 28889316 TI - Global stability of multi-group viral models with general incidence functions. AB - In this paper, strongly connected and non-strongly connected multi-group viral models with time delays and general incidence functions are considered. Employing the Lyapunov functional method and a graph-theoretic approach, we show that the global dynamics of the strongly connected system are determined by the basic reproduction number under some reasonable conditions for incidence functions. In addition, we find a more complex and more interesting result for multi-group viral models with non-strongly connected networks because of the basic reproduction numbers corresponding to each strongly connected component. Finally, we provide simulations for non-strongly connected multi-group viral models to support our conclusion. PMID- 28889317 TI - The predictive value of T-tau and AB1-42 levels in idiopathic normal pressure hydrocephalus. AB - BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) has no reliable biomarker to assist in the selection of patients who could benefit from ventriculo-peritoneal (VP) shunt insertion. The neurodegenerative markers T-tau and Abeta1-42 have been found to successfully differentiate between Alzheimer's disease (AD) and INPH and therefore are candidate biomarkers for prognosis and shunt response in INPH. The aim of this study was to test the predictive value of cerebrospinal fluid (CSF) T-tau and Abeta1-42 for shunt responsiveness. In particular, we pay attention to the subset of INPH patients with raised T-tau, who are often expected to be poor surgical candidates. METHODS: Single-centre retrospective analysis of probable INPH patients with CSF samples collected from 2006 to 2016. INDEX TEST: CSF levels of T-tau and Abeta1-42. Reference standard: postoperative outcome. ROC analysis assessed the predictive value. RESULTS: A total of 144 CSF samples from INPH patients were analysed. Lumbar T-tau was a good predictor of post-operative mobility (AUROC 0.80). The majority of patients with a co-existing neurodegenerative disease responded well, including those with high T-tau levels. CONCLUSION: INPH patients tended to exhibit low levels of CSF T-tau, and this can be a good predictor outcome. However levels are highly variable between individuals. Raised T-tau and being shunt-responsive are not mutually exclusive, and such patients ought not necessarily be excluded from having a VP shunt. A combined panel of markers may be a more specific method for aiding selection of patients for VP shunt insertion. This is the most comprehensive presentation of CSF samples from INPH patients to date, thus providing further reference values to the current literature. PMID- 28889318 TI - Human axillary skin condition is improved following incorporation of glycerol into the stratum corneum from an antiperspirant formulation. AB - The study objectives were to demonstrate that glycerol, when topically applied from a roll-on antiperspirant formulation, can be delivered directly to human skin ex vivo and the axillary stratum corneum (SC) in vivo, and to assess whether it improves the quality of the axillary skin barrier. Ex vivo human skin absorption of glycerol was measured following application of a roll-on antiperspirant formulation containing 4% 13C3-glycerol. Skin distribution of 13C3 glycerol over 24 h was assessed using gas chromatography-mass spectrometry. In vivo axillary SC penetration was measured by confocal Raman spectroscopy and multivariate curve-resolution software 1 h after topical application of a roll-on antiperspirant formulation containing 8% deuterated glycerol (d5-glycerol). A clinical study was conducted to determine the efficacy of a roll-on antiperspirant formulation containing 4% glycerol in reducing shaving-induced visual irritation and in increasing axillary-skin hydration. Ex vivo skin absorption studies indicated that the formulation delivered 13C3-glycerol into the SC at all timepoints over the 24-h period. In vivo Raman measurements (1 h after application) demonstrated that d5-glycerol was detectable to a depth of at least 10 MUm in the axillary SC. Application of 4% glycerol from a roll-on antiperspirant formulation to the axilla was associated with significantly less visible irritation and greater skin hydration than observed with the control (glycerol-free) product. These studies demonstrate that glycerol, incorporated in a roll-on antiperspirant formulation, is delivered directly and rapidly to all depths of the axillary SC, and results in improvements in visible irritation and hydration in the axilla. PMID- 28889319 TI - Sex, sex hormones and autonomic circulatory control. PMID- 28889320 TI - The role of preoperative iron deficiency in colorectal cancer patients: prevalence and treatment. AB - BACKGROUND: In preoperative blood management of colorectal cancer patients, intravenous iron therapy is increasingly used to treat anaemia and prevent red blood cell transfusions. However, while iron deficiency is the most common cause of anaemia, little is known about the prevalence and namely type of iron deficiency in this population, whereas both types of iron deficiency (i.e. absolute and functional iron deficiency) are recommended to be treated differently by international cancer guidelines. OBJECTIVE: The aim of present study is to investigate the prevalence and namely type of iron deficiency in colorectal cancer patients, and to assess its clinical relevance. METHODS: Preoperative iron status, clinical parameters (i.e. age, ASA classification, tumour location, tumour stage) and postoperative complications were retrospectively collected for all newly diagnosed colorectal cancer patients in our institution over a 3-year period. RESULTS: Iron deficiency was observed in 163 (48.1%) of 339 patients. Of these iron-deficient patients, 3.7% had an isolated absolute iron deficiency (AID) and 15.3% a functional iron deficiency (FID), while the rest had a combination of AID and FID. Anaemia was present in 66.1% of iron-deficient patients. Iron deficiency was significantly associated with an increased postoperative complication rate (univariable OR 1.94, p = 0.03, multivariable OR 1.84, p = 0.07), with right-sided tumours (p < 0.001), high ASA classification (p = 0.002), advanced tumour stage (p = 0.01) and advanced age (p = 0.04). In comparing clinical parameters between patients with AID and FID, advanced age was significantly associated with FID (p = 0.03), and the presence of anaemia with AID (p = 0.02). CONCLUSION: In preoperative colorectal cancer patients, there is a high prevalence of iron deficiency, including a high percentage of patients with-a component of-functional iron deficiency, associated with the increased postoperative complication rate. As both types of iron deficiency require a different treatment strategy, our results illustrate the therapeutic potential of especially intravenous iron supplementation in patients with severe iron deficiency and stress the urgency of routinely monitoring preoperative iron status and differentiation between types of iron deficiency. As iron therapy may also be potentially harmful in respect to stimulation of tumour growth, future clinical trials assessing the long-term effect of iron therapy are necessary. PMID- 28889321 TI - Effects of purified human fibrinogen modified with carbon monoxide and iron on coagulation in rabbits injected with Crotalus atrox venom. AB - While snake venom derived enzymes, such as the thrombin-like activity possessing ancrod, have been used to treat thrombotic disease by defibrinogenating patients, the therapeutic potential of fibrinogenolytic snake venom enzymes, such as those derived from Crotalus atrox, have not been fully explored. However, one of the potential risks of administering fibrinogenolytic enzymes to effect defibrinogenation is hemorrhage secondary to hypofibrinogenemia. The present investigation sought to determine if human fibrinogen modified with carbon monoxide (CO) and iron (Fe) could resist degradation by C. atrox venom as has been seen in vitro in a recently developed rabbit model of envenomation. Compared with unmodified human fibrinogen, CO/Fe modified fibrinogen administered prior to envenomation had significantly shorter onset of coagulation and greater strength; however, when administered after envenomation, there was no differences between the two types of fibrinogen. Of interest, when administered after envenomation, both types of fibrinogen delayed the onset of coagulation while increasing plasma clot strength, a mixed effect likely secondary to formation of fibrinogen degradation products. Further preclinical investigations are needed to further define the benefits and risks of the use of fibrinogenolytic enzymes as defibrinogenating agents, as well as the risks of the "biochemical brakes" used to modulate the activity or substrate of the fibrinogenolytic enzyme. PMID- 28889322 TI - Efficiency of soft tissue incision with a novel 445-nm semiconductor laser. AB - Using a 445-nm semiconductor laser for tissue incision, an effective cut is expected due to the special absorption properties of blue laser light in soft tissues. The aim of the present study was the histological evaluation of tissue samples after incision with a 445-nm diode laser. Forty soft tissue specimens were obtained from pork oral mucosa and mounted on a motorized linear translation stage. The handpiece of a high-frequency surgery device, a 970-nm semiconductor laser, and a 445-nm semiconductor laser were connected to the slide, allowing a constant linear movement (2 mm/s) and the same distance of the working tip to the soft tissue's surface. Four incisions were made each: (I) 970-nm laser with conditioned fiber tip, contact mode at 3-W cw; (II-III): 445-nm laser with non conditioned fiber tip, contact mode at 2-W cw, and non-contact mode (1 mm) at 2 W; and (IV): high-frequency surgery device with straight working tip, 90 degrees angulation, contact mode at 50 W. Histological analysis was performed after H&E staining of the embedded specimens at 35-fold magnification. The comparison of the incision depths showed a significant difference depending on the laser wavelength and the selected laser parameters. The highest incision depth was achieved with the 445-nm laser contact mode (median depth 0.61 mm, min 0.26, max 1.17, interquartile range 0.58) (p < 0.05) with the lowest amount of soft tissue denaturation (p < 0.05). The lowest incision depth was measured for the high frequency surgical device (median depth 0.36 mm, min 0.12, max 1.12, interquartile range 0.23) (p < 0.05). Using a 445-nm semiconductor laser, a higher cutting efficiency can be expected when compared with a 970-nm diode laser and high-frequency surgery. Even the 445-nm laser application in non-contact mode shows clinically acceptable incision depths without signs of extensive soft tissue denaturation. PMID- 28889323 TI - Significance of preoperative prognostic nutrition index as prognostic predictors in patients with metastatic renal cell carcinoma with tyrosine kinase inhibitors as first-line target therapy. AB - OBJECTIVE: Prognostic nutritional index (PNI) is a recognized indicator of both immune and nutritional status. It was firstly used as a preoperative prognostic indicator, and its role in the prognosis of patients with metastatic renal cell carcinoma (mRCC) has not yet been investigated in large-scale study. The purpose of this work was to investigate the prognostic role of pretreatment PNI in patients with mRCC with sorafenib or sunitinib as first-line targeted therapy. METHOD: In this retrospective single-center research, the Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS) of 178 mRCC patients who received first-line therapy of sorafenib or sunitinib. Log rank test was used to compare the survival outcomes of patients with low pretreatment PNI (PNI < 51.62) and high pretreatment PNI (PNI >= 51.62), and Cox proportional hazard regression model was used to compare PFS and OS between these two groups. Prognostic accuracy was determined using Harrell concordance index. RESULTS: The overall median PFS and OS time for all 178 patients were 11 months (95% CI 9-12 months) and 24 months (95% CI 19-33 months), respectively. Patients with low pretreatment PNI both had significantly shorter median PFS (7 vs 19 months, P < 0.001) and OS (14 vs 50 months, P < 0.001) than those with high PNI. Multivariate analysis showed that pretreatment PNI was an independent predictor of OS (HR 1.658, 95% CI 1.040-2.614, P = 0.033) and an independent predictor of PFS as well (HR 1.842, 95% CI 1.226-2.766, P = 0.003). The model built by the addition of pretreatment PNI improved predictive accuracy of PFS and OS compared with the International Metastatic Renal Cell Carcinoma Database Consortium Model (Heng model) (c-index: 0.68 and 0.70). Comparing to NLR (neutrophil-to-lymphocyte ratio) (0.69 and 0.72), PNI might be a preciser factor to predict PFS and OS (0.71 and 0.73). CONCLUSIONS: Low pretreatment PNI could be a significant risk factor for mRCC patients who received tyrosine kinase inhibitors as first-line target therapy and increase the accuracy of established prognostic model. PMID- 28889325 TI - Brief Report: Discrimination of Foreign Speech Pitch and Autistic Traits in Non Clinical Population. AB - Individuals with Autism Spectrum Conditions (ASC) are widely suggested to show enhanced perceptual discrimination but inconsistent findings have been reported for pitch discrimination. Given the high variability in ASC, this study investigated whether ASC traits were correlated with pitch discrimination in an undergraduate sample when musical and language experiences were taken into consideration. Results indicated that the social skills subscale of the Autism Spectrum Quotient was associated with foreign speech pitch discrimination, suggesting that individuals who were less sociable and socially skillful were less able to discriminate foreign speech pitch. Current findings have an implication in investigating individual differences in ASC and further investigation is needed for spelling out the relationship between the non-social and social aspects of ASC. PMID- 28889324 TI - Expression and Prognostic Value of Oestrogen Receptor Beta in Colorectal Cancer. AB - Differences between men and women in the incidence and biological mechanisms of colorectal cancer (CRC) suggest that estrogens may play a role in the pathogenesis of this disease. The identification of the human estrogen receptor beta (ERbeta) and its expression in the intestinal mucosa led to further studies that revealed that estrogens have a protective function against CRC mediated by the activation of ERbeta. However, ERbeta expression and its role in CRC is controversial. The purpose of this study was to determine the distribution and prognostic value of ERbeta expression in the intestinal mucosa of patients diagnosed and surgically treated for CRC, and its association with other known prognostic factors. A total of 109 paraffin-embedded samples of the wild-type ERbeta isoform were analyzed by immunohistochemical nuclear staining in patients with colorectal adenocarcinoma. Clinical/pathological and survival data were collected. Immunohistochemical quantification was performed using the category scoring system, which has been validated for assessing estrogen receptor alfa. The wild-type ERbeta isoform -also called ERbeta1- was positive in 101 patients (92.7%) and negative in nine patients (7.3%). Univariate analysis revealed that the absence of expression of the ERbeta1 gene was correlated with mucinous adenocarcinoma (p < 0.05). Also, a non-significant tendency was observed for ERbeta expression to be down-regulated in advanced tumors. With a median follow up of 47 months, the overall survival and progression-free survival were not found to be associated with ERbeta1 expression (p = 0.2). Although the wild-type ERbeta isoform was expressed in most study patients with colorectal cancer, it does not seem to have any prognostic value for the course of the disease. Further studies should be conducted to investigate whether the down-regulation of ERbeta expression has any biological function in mucinous colorectal cancer. PMID- 28889326 TI - Myocardial contractile patterns predict future cardiac events in sarcoidosis. AB - The poor prognosis of cardiac sarcoidosis (CS) underscores the need for risk stratification. We evaluated 84 consecutive sarcoidosis patients who were referred for echocardiographic studies for cardiac symptoms or abnormal electrocardiograms. In 54 patients without previous diagnosis of CS or other known structural heart disease, 13 reached endpoints during (median) 24 months follow up. Significantly impaired peak systolic longitudinal strain in their original echocardiograms were identified in 13 of 17 left ventricular segments, clustering in the free wall, interventricular septum and apex. The regional (including 13 clustered segments) peak systolic longitudinal strain (RPSLS) were significantly impaired in patients with endpoints, compared with those without [( 11.4 +/- 4.45) vs. (-18.7 +/- 3.76) %, P < 0.00001]. Cox multivariate regression analysis revealed that RPSLS was independently associated with endpoints (HR 1.24; 95% CI 1.08-1.42, P = 0.002). Receiver operating characteristic curve suggested a cut-off RPSLS value of -15.0% (84.6% sensitivity and 86.8% specificity) to predict the occurrence of endpoints. Impaired RPSLS correlates with risk of adverse cardiac events in patients with extra-cardiac sarcoidosis. PMID- 28889327 TI - A linkage between flowering phenology and fruit-set success of alpine plant communities with reference to the seasonality and pollination effectiveness of bees and flies. AB - To clarify the linkage between flowering phenology and pollination success in alpine plant communities, we quantified the seasonality of flower visitors, the temporal transition of floral resources, and the variation in pollination success of alpine plants in northern Japan. Bumble bees, syrphid flies, and non-syrphid flies were the predominant flower visitors. Foraging activity of bumble bees increased toward the late flowering period reflecting the life cycle of colony development. The activity of syrphid flies was sensitive to ambient temperature, while that of non-syrphid flies remained high throughout the season. Flower production of bee-pollinated plants fluctuated significantly between years with a bimodal pattern peaking in the early and late periods, while flower production of fly-pollinated plants was less variable between years. Fruit-set success of bee pollinated plants increased considerably from the early to the late flowering period, while the trend for fly-pollinated plants was less marked. Three times more visits of dipteran insects are necessary for fly-pollinated plants to achieve fruiting success comparable to bee-pollinated plants. Bumble bees are potentially excellent pollinators, but the visitation frequency is low early in the season. Lower pollination ability of dipteran insects may be compensated for by abundant flower visits. The relationships between flowering phenology and fruit-set success of alpine plant communities highly depend on the type of pollinators. PMID- 28889328 TI - The Work Role Functioning Questionnaire v2.0 Showed Consistent Factor Structure Across Six Working Samples. AB - Objective The Work Role Functioning Questionnaire v2.0 (WRFQ) is an outcome measure linking a persons' health to the ability to meet work demands in the twenty-first century. We aimed to examine the construct validity of the WRFQ in a heterogeneous set of working samples in the Netherlands with mixed clinical conditions and job types to evaluate the comparability of the scale structure. Methods Confirmatory factor and multi-group analyses were conducted in six cross sectional working samples (total N = 2433) to evaluate and compare a five-factor model structure of the WRFQ (work scheduling demands, output demands, physical demands, mental and social demands, and flexibility demands). Model fit indices were calculated based on RMSEA <= 0.08 and CFI >= 0.95. After fitting the five factor model, the multidimensional structure of the instrument was evaluated across samples using a second order factor model. Results The factor structure was robust across samples and a multi-group model had adequate fit (RMSEA = 0.63, CFI = 0.972). In sample specific analyses, minor modifications were necessary in three samples (final RMSEA 0.055-0.080, final CFI between 0.955 and 0.989). Applying the previous first order specifications, a second order factor model had adequate fit in all samples. Conclusion A five-factor model of the WRFQ showed consistent structural validity across samples. A second order factor model showed adequate fit, but the second order factor loadings varied across samples. Therefore subscale scores are recommended to compare across different clinical and working samples. PMID- 28889329 TI - Lack of Improvement in Scientific Integrity: An Analysis of WoS Retractions by Chinese Researchers (1997-2016). AB - This study investigated the status quo of article retractions by Chinese researchers. The bibliometric information of 834 retractions from the Web of Science SCI-expanded database were downloaded and analysed. The results showed that the number of retractions increased in the past two decades, and misconduct such as plagiarism, fraud, and faked peer review explained approximately three quarters of the retractions. Meanwhile, a large proportion of the retractions seemed typical of deliberate fraud, which might be evidenced by retractions authored by repeat offenders of data fraud and those due to faked peer review. In addition, a majority of Chinese fraudulent authors seemed to aim their articles which contained a possible misconduct at low-impact journals, regardless of the types of misconduct. The system of scientific evaluation, the "publish or perish" pressure Chinese researchers are facing, and the relatively low costs of scientific integrity may be responsible for the scientific integrity. We suggested more integrity education and severe sanctions for the policy-makers, as well as change in the peer review system and transparent retraction notices for journal administrators. PMID- 28889330 TI - Desarda's technique versus Lichtenstein technique for the treatment of primary inguinal hernia: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: The Lichtenstein technique (LT) has been recognized as the standard treatment for inguinal hernia in adults owing to the high recurrence rates of tissue-based repairs. However, Desarda technique (DT) appeared as promising tissue-based repair that provided low incidence of recurrence without the need for implanting prosthetic or foreign materials in the inguinal canal. This meta analysis of randomized controlled trials (RCTs) comparing DT and LT for primary inguinal hernia in adults aimed to determine which technique had better clinical outcome regarding recurrence and complication rates. METHODS: A systematic literature search for RCTs comparing between DT and LT was conducted using electronic databases and Google scholar service. Patients' characteristics, technical details, recurrence and complication rates, and time to resume daily activities were extracted from the original studies and analyzed. RESULTS: Six RCTs comprising 2159 patients (89% males) were included. No significant difference in the incidence of recurrence between both techniques was detected (OR = 0.946; P = 0.91). The overall complication rate of LT was significantly higher than DT (OR = 1.86; P < 0.001). LT had significantly higher rates of seroma formation and surgical site infection (OR = 2.17; P = 0.007) and (OR = 2.17; P = 0.029), respectively. Postoperative pain, operation time, and time to resume normal activities were comparable in both groups. CONCLUSION: Both DT and LT provided satisfactory treatment for primary inguinal hernia with low recurrence rates and acceptable rates of complications that were significantly less after DT. More well-designed RCTs with longer follow-up are required for further validation of the DT. PMID- 28889331 TI - Magnetic resonance imaging-based evaluation of ossification of the medial clavicular epiphysis in forensic age assessment. AB - Evaluation of the degree of ossification of the medial clavicular epiphysis plays a crucial role in determining with an adequate degree of probability whether legally relevant age boundaries after the age of 17 have been crossed. In view of the need to avoid unnecessary radiation exposure, establishing non-X-ray methods for investigating the clavicle has long been a key objective in forensic age assessment research. Based on magnetic resonance imaging examinations in a large sample of healthy subjects, the current study for the first time presents statistical measures which allow inferences to be drawn for forensic age assessment in both sexes. We undertook a prospective study of a reference sample of 334 female and 335 male German volunteers aged from 12 to 24 using a 3-T MRI scanner. A 3D FFE (fast field echo) T1-weighted sequence with fat saturation was acquired. To stage ossification of the medial clavicular epiphysis, we used the clavicular ossification staging systems described by Schmeling et al. and Kellinghaus et al. Ossification stage IIIc offers a means in both sexes of demonstrating that the age of 18 has been attained prior to complete ossification of the epiphyseal plate. In both sexes, if a subject has reached ossification stage IV, it can be stated that he or she has attained the age of 21. Magnetic resonance imaging is a valid diagnostic procedure for determining the ossification stage of the medial clavicular epiphysis. PMID- 28889332 TI - Introduction to the Special Issue on Climate Ethics: Uncertainty, Values and Policy. AB - Climate change is a pressing phenomenon with huge potential ethical, legal and social policy implications. Climate change gives rise to intricate moral and policy issues as it involves contested science, uncertainty and risk. In order to come to scientifically and morally justified, as well as feasible, policies, targeting climate change requires an interdisciplinary approach. This special issue will identify the main challenges that climate change poses from social, economic, methodological and ethical perspectives by focusing on the complex interrelations between uncertainty, values and policy in this context. This special issue brings together scholars from economics, social sciences and philosophy in order to address these challenges. PMID- 28889333 TI - Antioxidant and Protective Effects of Schinus terebinthifolius Raddi Against Doxorubicin-Induced Toxicity. AB - Doxorubicin is an anticancer drug whose toxic effects on non-cancer cells are associated with increased oxidative stress. This study investigated the chemical composition, antioxidant activity of the methanolic extract of Schinus terebinthifolius Raddi leaves (MESL) as well as effects against doxorubicin induced toxicity in human erythrocytes, K562 human erythroleukemia cells, and mouse hearts. The chemical composition indicated the presence of phenolic compounds, flavonoids, tannins, and ascorbic acid. MESL showed antioxidant activity by scavenging free radicals and inhibiting hemolysis and lipid peroxidation in human erythrocytes incubated with an oxidizing agent, and was able to increase the enzymatic activity of superoxide dismutase and glutathione peroxidase in human erythrocytes, without influencing the activity of enzyme catalase. The increase of oxidative hemolysis and malondialdehyde levels in erythrocytes incubated with doxorubicin was reduced by treatment with MESL. The cytotoxic activity of doxorubicin in erythroleukemia cells treated with MESL was unmodified. Additionally, the extract protected mice against the doxorubicin induced cardiotoxicity. In conclusion, the MESL exhibits antioxidant activity, reducing doxorubicin-induced oxidative stress without changing the anticancer action of the drug, and protects against doxorubicin-induced cardiotoxicity. Hence, these findings suggest that these effects are via anti-oxidative by inhibiting free radicals, decreased oxidative stress, and increased antioxidant enzyme activity. PMID- 28889334 TI - Erratum to: Loss of Pericytes in Radiation Necrosis after Glioblastoma Treatments. PMID- 28889335 TI - Morphological and functional diversity of first-order somatosensory neurons. AB - First-order somatosensory neurons transduce and convey information about the external or internal environment of the body to the central nervous system. They are pseudo unipolar neurons with cell bodies residing in one of several ganglia located near the central nervous system, with the short branch of the axon connecting to the spinal cord or the brain stem and the long branch extending towards the peripheral organ they innervate. Besides their sensory transducer and conductive role, somatosensory neurons also have trophic functions in the tissue they innervate and participate in local reflexes in the periphery. The cell bodies of these neurons are remarkably diverse in terms of size, molecular constitution, and electrophysiological properties. These parameters have provided criteria for classification that have proved useful to establish and study their functions. In this review, we discuss ways to measure and classify populations of neurons based on their size and action potential firing pattern. We also discuss attempts to relate the different populations to specific sensory modalities. PMID- 28889336 TI - Anticancer Activity of Copper Complex of (4R)-(-)-2-Thioxo-4 thiazolidinecarboxylic Acid and 3-Rhodaninepropionic Acid on Prostate and Breast Cancer Cells by Fluorescent Microscopic Imaging. AB - Copper complexes with strong anticancer activity are promising new drugs for treatment of patients with metastatic cancer. Copper 8-hydroxyquinoline-2 carboxaldehyde-thiosemicarbazide (CuHQTS) and copper 8-hydroxyquinoline-2 carboxaldehyde-4,4-dimethyl-3-thiosemicarbazide (CuHQDMTS) were found to have strong anticancer activity against cisplatin-resistant neuroblastoma cells and prostate cancer cells. This study aimed to synthesize and characterize two new anticancer copper complexes, copper complex of (4R)-(-)-2-Thioxo-4 thiazolidinecarboxylic acid (CuTTDC), and copper complex of 3-Rhodaninepropionic acid-copper complex (CuRDPA). Cell growth inhibition and cytotoxicity of CuTTDC and CuRDPA on prostate and breast cancer cells were evaluated with Cell Counting Kits-8 (CCK8) assay and fluorescent microscopic imaging respectively. Strong anticancer activity of CuTTDC and CuRDPA was demonstrated by growth inhibition and cytotoxicity of prostate and breast cancer cells treated with these two copper complexes, supporting further investigation of potential use of these two new anticancer complexes for treatment of prostate and breast cancer metastasis. PMID- 28889338 TI - German validation of the quality of life profile for spinal disorders (QLPSD). AB - BACKGROUND: The Quality of Life Profile for Spine Deformities (QLPSD) is a self reporting questionnaire designed for studying patients with spinal deformities. PURPOSE: The aim of the present study was to systematically translate the QLPSD into German (G-QLPSD) and to test its reliability and validity. Special emphasis was intended to be given to patients with different Cobb angles and ages. METHODS: The QLPSD was systematically translated into German and was responded to in a web-based online survey by patients with idiopathic scoliosis and by healthy control individuals to carry out a matched-pair analysis. Participants aged 14 years and older were included. All participants answered a battery of validated questionnaires (SRS 22-r, PHQ-9, PANAS, FKS, WHO-5, BFI-S, PTQ). Reliability testing included Cronbach's alpha and test-retest reliability (retest 8 weeks after initial testing). Factorial, convergent, divergent, concurrent, and discriminant validity were calculated. RESULTS: A total of 255 scoliosis patients (age 30.0 +/- 16.7 years, Cobb angle 43.5 degrees +/- 20.9 degrees ) and 189 matched healthy control individuals were finally included. Cronbach's alpha for the G-QLPSD total score was 0.93 and the test-retest reliability was 0.84. The G QLPSD total score correlated with the SRS 22-r total score (r = -0.86). All concurrently applied scores showed strong correlations with the G-QLPSD (e.g., depression score PHQ-9: r = 0.70). The matched-pair analysis of 189 pairs showed strong discriminant validity (Cohen's d = 0.78). Patients with more severe Cobb angles (>=40 degrees ) and those >=18 years of age had significantly poorer results than patients with minor curves and younger patients. CONCLUSION: The G QLPSD proved to be a highly reliable and valid instrument that can be recommended for clinical use in scoliosis patients. PMID- 28889339 TI - Incidence and risk factors for postoperative shoulder imbalance in scoliosis: a systematic review and meta-analysis. AB - PURPOSE: This is the first systematic review and meta-analysis to detect the incidence and risk factors for postoperative shoulder imbalance (PSI) in scoliosis. METHODS: A systematic online search was conducted to identify eligible studies. ES, OR and WMD with 95% CI were used to assess the incidence and risk factors associated with PSI. RESULTS: Twenty-six studies were recruited. The pooled incidence of PSI was 25% (95% CI 20-31%). The incidence in Lenke 1 AIS, Lenke 2 AIS, Lenke 5 AIS and mixed AIS was 20% (9-31%), 26% (15-37%), 31% (17 45%) and 27% (19-35%), respectively. Using RSH >=10 mm as the criterion of PSI, we found that preoperative LC, postoperative RSH, correction rate of MTC at follow-up were primary risk factors for PSI at follow-up. In the analysis of using RSH >=20 mm as the criterion of PSI, our results showed that Risser sign, postoperative RSH, correction rate of PTC at follow-up, and LC at follow-up were contributing to PSI. Besides, scoliosis patients with PSI were more likely to suffer from adding-on. CONCLUSIONS: The pooled incidence of PSI in scoliosis was 25%. Risser sign, preoperative LC, postoperative RSH, correction rate of PTC at follow-up, correction rate of MTC at follow-up, and LC at follow-up were risk factors for PSI in patients with scoliosis. Adding-on might be a compensatory mechanism for PSI. It is recommended that (1) sufficient correction of PTC and moderate correction of MTC and LC in the operation should be performed; (2) PSI should be prevented not only for the patients' postoperative appearance, but also for preventing the adding-on phenomenon. PMID- 28889340 TI - Hypothyroidism in the "Arnolfini Portrait" (1434) by Jan Van Eyck (1390-1441). AB - BACKGROUND: The Arnolfini portrait painted by Jan van Eyck in 1434 remains one of the most puzzling yet alluring paintings of prerenaissance western art. PURPOSE: The painting is renowned for its exactitude in brush strokes, textures and the distinctive morphology of the main character Arnolfini. The nature of these requires pathological consideration. METHODS: Diagnostic and pathological analysis of the painting. RESULTS: A number of pathological abnormalities are noted in the face of the main character including loss of outer third of the eyebrow (Sign of Hertoghe), bilateral ptosis and melasma of the forehead. These together support a diagnosis of hypothyroidism. CONCLUSIONS: This novel diagnosis offers an additional perspective to this enigmatic portrait, and can add to the comprehension of the method, origin and pathological associations of this prominent painting from a genius artist. PMID- 28889337 TI - The cellular selection between apoptosis and autophagy: roles of vitamin D, glucose and immune response in diabetic nephropathy. AB - BACKGROUND AND AIMS: Apoptosis, autophagy and cell cycle arrest are cellular responses to injury which are supposed to play fundamental roles in initiation and progression of diabetic nephropathy (DN). The aims of the present study is to shed light on the potential effects of vitamin D analog 22-oxacalcitriol (OCT) on different cell responses during DN, and the possible interplay between both glucose, immune system and vitamin D in determining the cell fate. METHOD: All rats were randomly allocated into one of three groups: control, vehicle-treated DN group and OCT-treated DN group. Eight weeks after induction of diabetes, the rats were killed. Fasting blood glucose levels, serum 25 (OH) D, renal functions, cytokines and gene expression of autophagy, apoptotic and cell cycle arrest markers were assessed. In addition, the histological assessment of renal architecture was done. RESULTS: OCT treatment remarkably improved the renal functions and albuminuria. The reductions in mesangial cell hypertrophy, extracellular matrix as well as cell loss were significantly associated with upregulation of pro-autophagy gene expressions and downregulation of both pro apoptotic and G1-cell cycle arrest genes expression. The reno-protective effects of OCT treatment were associated with significant attenuation of the fasting blood glucose, serum IL-6, renal TLR-4 and IFN-g gene expression. CONCLUSION: Modulator effects of OCT on glucose and immune system play important roles in renal cell fate decision and chronic kidney disease progression. PMID- 28889341 TI - The medial orbito-frontal approach for orbital tumors: a How I Do It. AB - BACKGROUND: A variety of lesions can affect the orbit. Surgical approaches must be available to provide 360 degrees of access. For tumors occupying the superomedial intraconal quadrant, there is a rationale to selecting the medial orbito-frontal approach. METHODS: This article outlines the relevant surgical anatomy and the different surgical steps of this approach. RESULTS: The medial orbito-frontal approach offers a full exposure of the superomedial intraconal quadrant and avoids crossing the plane of the optic nerve. CONCLUSION: In selected intraconal tumor cases, this transcranial epidural intraorbital approach is a straightforward corridor through reliable landmarks that can be routinely performed. PMID- 28889343 TI - Mesial encephalitis: an uncommon presentation of neurosyphilis: a case report and review of the literature. PMID- 28889342 TI - Life cycle of Amblyomma mixtum (Acari: Ixodidae) parasitizing different hosts under laboratory conditions. AB - Amblyomma mixtum is a tick species in the Amblyomma cajennense complex. The known geographic range of A. mixtum extends from Texas in the USA to western Ecuador and some islands in the Caribbean. Amblyomma mixtum is a vector of disease agents of veterinary and public health importance. The objective of this study was to describe the life cycle of A. mixtum under laboratory conditions. Bovines, rabbits and sheep were infested with larvae, nymphs, and adult ticks under controlled conditions to assess several biological parameters. Eggs, larvae, nymphs and adults were kept in an incubator (27 degrees C temperature and 80% relative humidity) when they were off the host. The average life cycle of A. mixtum was 88 and 79 days when fed on rabbits and cattle, respectively. Sheep were found to be unsuitable because no ticks attached. The rabbit is a more practical host to maintain a colony of A. mixtum under laboratory conditions. The data from this study can be considered as an example for the life cycle of A. mixtum. However, caution must be exercised when making comparisons to the biology of A. mixtum in its natural habitat. PMID- 28889344 TI - Emission factors from different burning stages of agriculture wastes in Mexico. AB - Open-air burning of agricultural wastes from crops like corn, rice, sorghum, sugar cane, and wheat is common practice in Mexico, which in spite limiting regulations, is the method to eliminate such wastes, to clear the land for further harvesting, to control grasses, weeds, insects, and pests, and to facilitate nutrient absorption. However, this practice generates air pollution and contributes to the greenhouse effect. Burning of straws derived from the said crops was emulated in a controlled combustion chamber, hence determining emission factors for particles, black carbon, carbon dioxide, carbon monoxide, and nitric oxide throughout the process, which comprised three apparent stages: pre ignition, flaming, and smoldering. In all cases, maximum particle concentrations were observed during the flaming stage, although the maximum final contributions to the particle emission factors corresponded to the smoldering stage. The comparison between particle size distributions (from laser spectrometer) and black carbon (from an aethalometer) confirmed that finest particles were emitted mainly during the flaming stage. Carbon dioxide emissions were also highest during the flaming stage whereas those of carbon monoxide were highest during the smoldering stage. Comparing the emission factors for each straw type with their chemical analyses (elemental, proximate, and biochemical), some correlations were found between lignin content and particle emissions and either particle emissions or duration of the pre-ignition stage. High ash or lignin containing-straw slowed down the pre-ignition and flaming stages, thus favoring CO oxidation to CO2. PMID- 28889345 TI - Knowledge About the Relation Between Tobacco and Disease and the Attitude Toward Advising the Cessation of Its Consumption Among a Group of Spanish Dental Students. AB - Tobacco is one of the leading causes of preventable death in the developed world. Smoking is associated with a large number of oral pathologies, such as cancer and periodontitis. Dental professionals can play a key role in preventing these health problems. The objectives of this study were (1) to analyze tobacco consumption habits among a group of Spanish dental students, and (2) to assess their knowledge, perceptions, and attitudes regarding procedures to help patients quit smoking. A cross-sectional descriptive study was carried out at the Faculty of Medicine and Dentistry of Santiago de Compostela (Galicia, Spain). Three validated questionnaires were distributed, and the obtained data was processed using SPSS. One hundred twenty out of 220 surveys were completed. Of the students, 18.3% were smokers and the average number of smoked cigarettes per day was 7.5. Tobacco dependence and the intention to give up the habit were low (Fagerstrom Test) and doubtful (Richmond test), respectively. The majority of students (94.2%) considered it appropriate to promote tobacco use cessation (TUC) activities. A great divergence of criteria regarding tobacco-associated pathologies was found among courses. This article provides positive data about the motivation of dental students to implement TUC strategies. Nevertheless, the usefulness of these interventions makes it necessary to modify the university curricula in order to improve the education on this issue to reduce the incidence of future health problems. PMID- 28889346 TI - Prospective of Microbial Exopolysaccharide for Heavy Metal Exclusion. AB - Metals as a resource are depleting, and on another side, it fetches serious environmental pollution causing a threat to human health and ecosystem. The heavy metal accumulation due to anthropogenic activities results in toxicological manifestation. The traditional methods of remediation are not cost effective, efficient, and ecofriendly which necessitate and motivate towards the safe, effective, and ecofriendly biological methods. The increasing presence of heavy metals in the microbial habitat compels the microbes to develop the ability to tolerate or resist the presence of heavy metals. Exopolysaccharide (EPS) production is one of the strategies of microbes to fight against metal stress. EPS is a microbial biopolymer which is generally produced under stress from harsh environment and nutrition conditions. EPSs are cell-associated or secreted outside the cell and comprised organic macromolecules such as polysaccharides, proteins, and phospholipids in addition to some non-polymeric molecules. EPSs work as competent biosorbents with an anionic reactant group that effectively sequesters cationic heavy metals by electrostatic interactions. The present paper summarizes the EPSs with its types, role, and biosynthesis and an endeavor to elucidate the interaction mechanism of EPSs with heavy metal with supportive and distinctive applications for heavy metal exclusion. The review concluded with the current challenges and future prospects to make the EPS an efficient biosorbent. PMID- 28889347 TI - Decline in estimated glomerular filtration rate is associated with risk of end stage renal disease in type 2 diabetes with macroalbuminuria: an observational study from JDNCS. AB - BACKGROUND: There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease. METHODS: In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD. RESULTS: Low eGFR (<60 mL/min/1.73 m2) and macroalbuminuria at enrollment were independently associated with risk of ESRD. In patients with macroalbuminuria, both <=-50% change and -50 to -30% change in eGFR over 1 and 2 years were predictive of ESRD. The higher cut point (>=50% decline in eGFR) was more strongly predictive but less common. Remission of macroalbuminuria to normo-/microalbuminuria at 1 and 2 years was associated with a lower incidence of ESRD than no remission; however, it was not a determinant for ESRD independently of initial eGFR and initial protein-to-creatinine ratio. CONCLUSION: These results suggest that a >=30% decline in eGFR over 1 or 2 years adds prognostic information about risk for ESRD in patients with type 2 diabetes and macroalbuminuria, supporting the consideration of percentage decline in eGFR as a surrogate endpoint among macroalbuminuric cases in type 2 diabetes. On the other hand, our study suggests that additional analyses on the relationship between remission of macroalbuminuria and risk of ESRD are needed in type 2 diabetes. PMID- 28889348 TI - Treatment of erythemato-telangiectatic rosacea with brimonidine alone or combined with vascular laser based on preliminary instrumental evaluation of the vascular component. AB - The purpose of this study is to evaluate the outcome of a series of patients with erythematotelangiectatic rosacea (ETR) affected by persistent erythema and varying degree of telangiectasias being treated with brimonidine alone or combined with a vascular laser based on the type of vascular components preliminarily evaluated by clinical and instrumental observation. Ten patients affected by ETR were enrolled in a pilot, open study. Instrumental evaluation included erythema-directed digital photography by VISIA-CRTM system and X10 dermoscopy. Those patients showing marked background erythema and minimal telangiectasias (group A) were treated with a single application of brimonidine 0.33% gel, while patients showing both marked background erythema and marked telangiectasias (group B) were treated with a session of Nd:YAG laser and reevaluated 1 month later after a single application of brimonidine. An Investigator Global Assessment (IGA) of treatment outcome was performed at the end of treatment in both groups. In group A, 6 h after brimonidine application, a marked reduction of the background erythema was observed in all patients, and IGA was rated as excellent. In group B, 6 h following the application of brimonidine, a marked reduction of the background erythema was observed in all cases, while telangiectasias remained unchanged. A further treatment with brimonidine 1 month after the Nd:YAG laser session determined complete clearing of facial erythema, and IGA was rated as excellent. In conclusion, a preliminary evaluation of the vascular component by erythema-directed digital photography and dermoscopy in ETR may be helpful to select the most appropriate therapeutic strategy. PMID- 28889349 TI - Gene expression and levels of IL-6 and TNFalpha in PBMCs correlate with severity and functional class in patients with chronic heart failure. AB - BACKGROUND: Evidence shows that proinflammatory cytokines are important determinants of assessment of severity and prognosis of chronic heart failure (CHF). AIMS: We investigated whether peripheral expression of the proinflammmatory factors, TNF-alpha and IL-6 can predict variable of clinical assessment of patients with CHF. METHODS: In this report, we used real-time PCR assay to compare relative gene expression of TNFalpha and IL-6 in PBMC from CHF patients with various heart diseases (n = 42, EF < 45%, NYHA I to IV) and matched healthy control subjects (n = 42).We also determined the TNFalpha and IL-6 concentrations of cell culture supernatant of PBMCs with ELISA. RESULTS: There was a significant negative correlation between gene expression of TNFalpha and LVEF(r = 0.4, p < 0.05). Patients with CHF had increased gene expression of TNFalpha and IL-6 in PBMCs (p < 0.05). They also had elevated the supernatant levels of these cytokines in cultured PBMCs (p < 0.001). Levels of TNFalpha and IL-6 were increased in ischemic heart disease compared to non-ischemic heart disease. There was a positive correlation between TNFalpha and IL-6 levels in CHF patients and severity of CHF in patients. Levels of these cytokines were higher in patients with NYHA III-IV than in NYHA I-II and normal subjects. CONCLUSIONS: Results of this study indicate that peripheral expression of proinflammatory cytokines, TNF-alpha and IL-6, is important indicators of severity and prognosis in patients with chronic heart disease. PMID- 28889350 TI - Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2. AB - Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds. Using our recently introduced reliability estimation metrics, we could classify predictions with higher confidence by featuring an applicability domain (AD) analysis in combination with protein-ligand interaction profiling. The outcomes of and agreement between our AD and interaction-profile analyses to distinguish and rationalize the performance of our predictions highlighted the relevance of sufficiently exploring protein-ligand interactions during training and it demonstrated the possibility to quantitatively and efficiently evaluate if this is achieved by using simulation data only. PMID- 28889351 TI - Multidimensional phenotyping of breast cancer cell lines to guide preclinical research. AB - PURPOSE: Cell lines are extremely useful tools in breast cancer research. Their key benefits include a high degree of control over experimental variables and reproducibility. However, the advantages must be balanced against the limitations of modelling such a complex disease in vitro. Informed selection of cell line(s) for a given experiment now requires essential knowledge about molecular and phenotypic context in the culture dish. METHODS: We performed multidimensional profiling of 36 widely used breast cancer cell lines that were cultured under standardised conditions. Flow cytometry and digital immunohistochemistry were used to compare the expression of 14 classical breast cancer biomarkers related to intrinsic molecular profiles and differentiation states: EpCAM, CD24, CD49f, CD44, ER, AR, HER2, EGFR, E-cadherin, p53, vimentin, and cytokeratins 5, 8/18 and 19. RESULTS: This cell-by-cell analysis revealed striking heterogeneity within cultures of individual lines that would be otherwise obscured by analysing cell homogenates, particularly amongst the triple-negative lines. High levels of p53 protein, but not RNA, were associated with somatic mutations (p = 0.008). We also identified new subgroups using the nanoString PanCancer Pathways panel (730 transcripts representing 13 canonical cancer pathways). Unsupervised clustering identified five groups: luminal/HER2, immortalised ('normal'), claudin-low and two basal clusters, distinguished mostly by baseline expression of TGF-beta and PI3-kinase pathway genes. CONCLUSION: These features are compared with other published genotype and phenotype information in a user-friendly reference table to help guide selection of the most appropriate models for in vitro and in vivo studies, and as a framework for classifying new patient-derived cancer cell lines and xenografts. PMID- 28889352 TI - Characterization of a novel zinc finger transcription factor (TaZnF) from wheat conferring heat stress tolerance in Arabidopsis. AB - C3HC4-type zinc finger proteins are known to play important roles in various plant processes including regulation of growth and development, signaling networks, responses to abiotic stresses etc. The current study identifies and explores the involvement of TaZnF in plant stress response, mainly heat stress. TaZnF belongs to C4HC3-type zinc finger transcription factor. Phylogenetic analysis of TaZnF revealed strong sequence similarity to Brachypodium distachyon, a model system for crop species. Gene expression studies have revealed its role under diverse stress conditions including heat and cold conditions. The transcript level of TaZnF was found to be highest in seed and starts at the post anthesis period 3-5DAA, a more sensitive stage resulting in a negative influence on the yield of crop species. TaZnF possesses transcriptional activity. Overexpression of TaZnF in Arabidopsis thaliana conferred improved tolerance to both basal and high-temperature stress as observed from various assays examining their growth and development. The transgenics were recovered and showed early flowering compared to wild-type. They had larger primary roots, more lateral branching, bigger, and more numerous leaves, resulting in heavier fresh weight. Enhanced growth and early recovery resulted in bigger plants with more yield. Additionally, the overexpression Arabidopsis transgenics also showed considerable tolerance to cold and oxidative stress. These observations suggest that TaZnF acts as a positive regulator of thermal stress and thus can be of great significance in understanding and improving temperature stress tolerance in plants. PMID- 28889353 TI - The Detection Techniques for Autophagy-Associated Cell Death-Related Genes and Proteins: Gene Expression Assay and Immunohistochemistry. AB - Autophagy is important in cellular homeostasis for the cell survival mechanism. Deficiency or excess of autophagy is generally related to some of diseases such as cancer and neurodegeneration. Although autophagy is a cell survival mechanism, it can mediate programmed cell death in several conditions. Autophagy-related genes (ATGs) regulate the autophagy and also control the crosstalk with autophagy associated cell death and apoptosis in some condition. Various methods have been used to detect the marker genes and the proteins involved in these processes. Quantitative real-time PCR (qRT-PCR) method for monitoring the expression of genes involved in autophagy or autophagic cell death is often preferred because of its sensitivity, high efficiency potential, accurate quantification, and high grade potential automation. The detection of the markers for autophagy-related process by immunohistochemistry in paraffin sections of various patient tissues has become a reliable method for monitoring autophagy. Here, we introduce protocols for detecting autophagy and autophagy-associated cell death in HeLa cells by using gene expression assays qRT-PCR, and also in paraffin-embedded tissue section from human biopsy material by using immunohistochemistry. PMID- 28889354 TI - Predictive value of SYNTAX score II for clinical outcomes in cardiogenic shock underwent primary percutaneous coronary intervention; a pilot study. AB - SYNTAX Score II (SSII) connects clinical variables with coronary anatomy. We investigated the prognostic value of SSII in patients with ST segment elevated myocardial infarction (STEMI) complicated with cardiogenic shock treated with primary percutaneous coronary intervention (PPCI). In this retrospective analysis, we evaluated the in-hospital prognostic impact of SSII on 492 patients with STEMI complicated with cardiogenic shock treated with PPCI. Patients were stratified by tertiles of SSII, in-hospital clinical outcomes were compared between those groups. In-hospital univariate analysis revealed higher rates of in hospital death for patients with SSII in tertile 3, as compared to patients with SSII in tertile 1 (OR 17.4, 95% CI 10.0-30.2, p < 0.001). After adjustment for confounding baseline variables, SSII in tertile 3 was associated with 6.2-fold hazard of in-hospital death (OR 6.2, 95% CI 2.6-14.1, p < 0.001). SSII in patients with STEMI complicated with cardiogenic shock treated with PPCI provide an independent prognostic marker of in-hospital outcomes. Our data suggests SSII to be a simple, feasible and clinically applicable tool for rapid risk stratification in patients with STEMI complicated with cardiogenic shock treated with PPCI. PMID- 28889355 TI - Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to cannabinoid receptors activation in mice. AB - Several works have shown that triterpenes induce peripheral antinociception by activation of cannabinoid receptors and endocannabinoids; besides, several research groups have reported activation of cannabinoid receptors in peripheral antinociception. The aim of this study was to assess the involvement of the cannabinoid system in the antinociceptive effect induced by tingenone against hyperalgesia evoked by prostaglandin E2 (PGE2) at peripheral level. The paw pressure test was used and the hyperalgesia was induced by intraplantar injection of PGE2 (2 MUg/paw). All drugs were injected subcutaneously in the hind paws of male Swiss mice. Tingenone (200 ug/paw) administered into the right hind paw induced a local antinociceptive effect, that was antagonized by AM630, a selective antagonist to CB2 cannabinoid receptor. AM251, a selective antagonist to CB1 cannabinoid receptor, did not alter the peripheral antinociceptive effect of tingenone. MAFP, a fatty acid amide hydrolase (FAAH) inhibitor; VDM11, an anandamide reuptake inhibitor; and JZL184, monoacylglycerol lipase (MAGL) inhibitor did not potentiate the peripheral antinociceptive effect of the lower dose of tingenone (50 ug/paw). The results suggest that tingenone induced a peripheral antinociceptive effect via cannabinoid receptor activation. Therefore, this study suggests a pharmacological potential for a new analgesic drug. PMID- 28889356 TI - Spectroscopic and Theoretical Studies of Fluorescence Effects in 2-Methylamino-5 (2,4-dihydroxyphenyl)-1,3,4-thiadiazole Induced by Molecular Aggregation. AB - The article presents the results of fluorescence analyses of 2-methylamino-5-(2,4 dihydroxyphenyl)-1,3,4-thiadiazole (MDFT) in an aqueous environment. MDFT dissolved in aqueous solutions with a pH value in the range from 1 to 4.5 yielded an interesting effect of two clearly separated fluorescence emissions. In turn, a single fluorescence was observed in MDFT dissolved in water solutions with a pH value from 4.5 to 12. As it was suggested in the previous investigations of other 1,3,4-thiadiazole compounds, these effects may be associated with conformational changes in the structure of the analysed molecule accompanied by aggregation effects. Crystallographic data showed that the effect of the two separated fluorescence emissions occurred in a conformation with the -OH group in the resorcyl ring bound on the side of the sulphur atom from the 1,3,4-thiadiazole ring. The hypothesis of aggregation as the mechanism involved in the change in the spectral properties at low pH is supported by the results of (Time-Dependent) Density Functional Theory calculations. The possibility of rapid analysis of conformational changes with the fluorescence spectroscopy technique may be rather important outcome obtained from the spectroscopic studies presented in this article. Additionally, the presented results seem to be highly important as they can be easily observed in solutions and biologically important samples. PMID- 28889358 TI - Erratum to: Managing neurogenic orthostatic hypotension in a patient presenting with pure autonomic failure who later developed Parkinson disease. PMID- 28889359 TI - Erratum to: Titrating droxidopa to maximize symptomatic benefit in a patient with Parkinson disease and neurogenic orthostatic hypotension. PMID- 28889357 TI - The Development of Skull Prosthesis Through Active Contour Model. AB - Skull defects result in brain infection and inadequate brain protection and pose a general danger to patient health. To avoid these situations and prevent re injury, a prosthesis must be constructed and grafted onto the deficient region. With the development of rapid customization through additive manufacturing and 3D printing technology, skull prostheses can be fabricated accurately and efficiently prior to cranioplasty. However, an unfitted skull prosthesis made with a metal implant can cause repeated infection, potentially necessitating secondary surgery. This paper presents a method of creating suitably geometric graphics of skull defects to be applied in skull repair through active contour models. These models can be adjusted in each computed tomography slice according to the graphic features, and the curves representing the skull defect can be modeled. The generated graphics can adequately mimic the natural curvature of the complete skull. This method will enable clinical surgeons to rapidly implant customized prostheses, which is of particular importance in emergency surgery. The findings of this research can help surgeons provide patients with skull defects with treatment of the highest quality. PMID- 28889360 TI - Enhanced effect of HAH on citric acid-chelated Fe(II)-catalyzed percarbonate for trichloroethene degradation. AB - This work demonstrates the impact of hydroxylamine hydrochloride (HAH) addition on enhancing the degradation of trichloroethene (TCE) by the citric acid (CA) chelated Fe(II)-catalyzed percarbonate (SPC) system. The results of a series of batch-reactor experiments show that TCE removal with HAH addition was increased from approximately 57 to 79% for a CA concentration of 0.1 mM and from 89 to 99.6% for a 0.5 mM concentration. Free-radical probe tests elucidated the existence of hydroxyl radical (HO*) and superoxide anion radical (O2*-) in both CA/Fe(II)/SPC and HAH/CA/Fe(II)/SPC systems. However, higher removal rates of radical probe compounds were observed in the HAH/CA/Fe(II)/SPC system, indicating that HAH addition enhanced the generation of both free radicals. In addition, increased contribution of O2*- in the HAH/CA/Fe(II)/SPC system compared to the CA/Fe(II)/SPC system was verified by free-radical scavengers tests. Complete TCE dechlorination was confirmed based on the total mass balance of the released Cl- species. Lower concentrations of formic acid were produced in the later stages of the reaction for the HAH/CA/Fe(II)/SPC system, suggesting that HAH addition favors complete TCE mineralization. Studies of the impact of selected groundwater matrix constituents indicate that TCE removal in the HAH/CA/Fe(II)/SPC system is slightly affected by initial solution pH, with higher removal rates under acidic and near neutral conditions. Although HCO3- was observed to have an adverse impact on TCE removal for the HAH/CA/Fe(II)/SPC system, the addition of HAH reduced its inhibitory effect compared to the CA/Fe(II)/SPC system. Finally, TCE removal in actual groundwater was much significant with the addition of HAH to the CA/Fe(II)/SPC system. The study results indicate that HAH amendment has potential to enhance effective remediation of TCE-contaminated groundwater. PMID- 28889361 TI - Brevibacillus laterosporus isolated from the digestive tract of honeybees has high antimicrobial activity and promotes growth and productivity of honeybee's colonies. AB - The development of novel antimicrobial drugs, as well as the discovery of novel compounds able to promote honeybee's growth, represents major challenges for modern entomology. The main aim of this study was to investigate whether Brevibacillus laterosporus isolated from the digestive tract of Saudi honeybees, Apis mellifera, was able to stimulate colony strength parameters of honeybees and to evaluate its ability to produce antimicrobial agents. Honeybees were collected in Dirab, Riyadh Region, Saudi Arabia, and microorganisms were isolated and identified by 16S ribosomal RNA analysis. Microscopic identification of the microorganism in its native state was facilitated by atomic force microscopy at high-resolution imaging. Active biological compounds were produced by submerged fermentation with B. laterosporus. The fermented broth was subjected to extraction and purification, and then semi-pure compounds were analyzed by gas chromatography-mass spectrometry. The effectiveness of the crude extract and semi pure compounds as antimicrobial agents was evaluated by susceptibility assays. More than 22% of the microorganisms isolated from the digestive tract of healthy honeybees have been identified as B. laterosporus, this kind of species has a unique shape and morphological structure. The cyclic dipeptide cyclo(Leu-Pro) produced by B. laterosporus showed biological activity against several pathogenic microorganisms. Furthermore, the total counts of workers, closed brood, and open brood, as well as the production of bee pollen and honey, were better in honeybees treated with a B. laterosporus suspension. The data indicated that the B. laterosporus strain isolated from a healthy honeybee might be a novel probiotic and a producer of important biological compounds. PMID- 28889362 TI - A Novel Aza-MBP Altered Peptide Ligand for the Treatment of Experimental Autoimmune Encephalomyelitis. AB - Myelin basic protein (MBP) is a major target of T cells in lesions of multiple sclerosis (MS) patients and its animal model, experimental autoimmune encephalomyelitis (EAE). Interactions between the major histocompatibility complex II containing antigenic peptides and the T cell receptor activate CD4+ T cells that perpetuate EAE and MS. Previously reported data has shown that treating with an altered peptide ligand (APL) in which the normal antigenic peptide sequence of MBP has been slightly changed at T cell contact positions is helpful in reducing disease in both rodents and humans. The use of natural peptides, which are susceptible to protease degradation, requires high concentrations that can create hypersensitivity reactions. Our hypothesis is that APL containing aza substitutions, CH(R)-N- > N(R)N, could lead to improved protease resistance, reduced clinical disease scores, and a shift in T cell profile. In this study, several aza-APLs and control peptides were synthesized and screened for the best aza-APL candidate (3aza-APL) based on dissociation half time from major histocompatibility complex (MHC) class II, induction of IL-2 response, and resistance to degradation by proteases. The efficacy was then tested in vivo. Results indicate that 3aza-APL is superior to currently available APLs in terms of protease resistance and disease suppression in EAE mice. The 3aza-APL induced anti-inflammatory immune responses by altering key transcription factors and cytokine genes which regulate T cell subpopulations. These data suggest that the novel 3aza-APL has increased protease resistance property and is effective in reducing clinical and physiological signs of disease in EAE animals. PMID- 28889363 TI - Synthesis of ZnO Nanocrystals and Application in Inverted Polymer Solar Cells. AB - Controllable synthesis of various ZnO nanocrystals was achieved via a simple and cost-effective hydrothermal process. The morphology evolution of the ZnO nanostructures was well monitored by tuning hydrothermal growth parameters, such as solution concentration, reaction temperature, and surfactant. As-obtained ZnO nanocrystals with different morphologies, e.g., ZnO nanorods, nanotetrapods, nanoflowers, and nanocubes, were further introduced into the organic bulk heterojunction solar cells as the electron transport channel. It was found that the device performance was closely related to the morphology of the ZnO nanocrystals. PMID- 28889364 TI - Open complete anterior dislocation of the sacro-iliac joint in a 4-year-old boy: a case report of a rare injury with 5-year follow-up. AB - Pelvic fractures are uncommon in children and account for between 0.3 and 7.5% of all pediatric injuries. Open pelvic fractures only account for up to 12.9% of all pediatric pelvic fractures. An unusual case of open complete anterior sacro-iliac joint dislocation in a 4-year-old boy is presented with a long-term follow-up. The multidisciplinary approach is reported with review of the current literature. A 4-year-old male presented to our institution in January 2012 after having been run over by a tractor. He presented with gross hemodynamical instability, MISS of 25, and an unstable lateral compression type III pelvic fracture with complete anterior dislocation of the left hemipelvis and a groin wound extending into the left thigh. The patient was managed in accordance with the ATLS and open fracture guidelines. Reduction in the dislocated SI joint was achieved via a posterior approach to the SI joint, followed by fixation with 2K wires in S1 and S2 sacral segments, with an anterior external fixator. Pelvic asymmetry post-reduction was 0.9 cm, compared to 16 cm post-injury, and asymmetry persisted till final follow up at 5 years. At 5 years, patient regained full function, including recreational sport activities. Patients scored a 96/96 on the Majeed score (after excluding 4 points for sexual function). We believe that posterior reduction in an anteriorly dislocated SI joint in the pediatric population is a viable option. A coordinated, multidisciplinary approach and restoration of pelvic ring stability can lead to optimal outcome. PMID- 28889365 TI - Epidermal Inclusion Cyst in an Intra-pancreatic Accessory Spleen: a Differential Diagnosis for Pancreatic Cystic Neoplasms and Review of the Literature. PMID- 28889366 TI - Performance of 68Ga-PSMA PET/CT for Prostate Cancer Management at Initial Staging and Time of Biochemical Recurrence. AB - PURPOSE OF THE REVIEW: Recently introduced Gallium-68 labeled PSMA-ligands such as HBED-CC (68Ga-PSMA) have shown promise for unmet diagnostic needs in prostate cancer. RECENT FINDINGS: 68Ga-PSMA has demonstrated improved detection rates and specificity for prostate cancer compared to standard imaging approaches. In the setting of primary disease, 68Ga-PSMA appears to preferentially identify treatment-relevant intermediate and high-risk prostate cancer. There is also a growing evidence that 68Ga-PSMA positron emission tomography (PET) outperforms alternative conventional imaging methods including choline-based radiotracers for the localization of disease sites at biochemical recurrence, particularly at lower prostate-specific antigen (PSA) levels (< 1 ng/mL). However, the majority of published work lacks rigorous verification of imaging results. 68Ga-PSMA offers significant promise for both, primary disease and biochemically recurrent prostate cancer. The evidence base to support 68Ga-PSMA is however still underdeveloped, and more rigorous studies substantiating efficacy are needed. PMID- 28889367 TI - Identifying the subtypes of cancer-related fatigue: results from the population based PROFILES registry. AB - PURPOSE: Little research has been done to identify possible cancer-related fatigue (CRF) subtypes and to classify cancer survivors accordingly. We aimed to identify CRF subtypes in a large population-based sample of (long term) stage I III colorectal cancer survivors. We also identified factors associated with the CRF subtypes. METHODS: Respondents completed the Multidimensional Fatigue Inventory and other validated questionnaires on anxiety and reduced positive affect (anhedonia), sleep quality, and lifestyle factors (body mass index and physical activity). Latent class analysis was used to derive the CRF subtypes. Factors associated with the derived CRF subtypes were determined with multinomial logistic regression. RESULTS: Three CRF classes were identified: class 1 (no fatigue and distress, n = 644, 56%), class 2 (low fatigue, moderate distress, n = 256, 22%), and class 3 (high fatigue, moderate distress, n = 256, 22%). Multinomial logistic regression results show that survivors in class 3 were more likely to be female, were treated with radiotherapy, have comorbid diabetes mellitus, and be overweight/obese than survivors in class 1 (reference). Survivors in classes 2 and 3 were also more likely to have comorbid heart condition, report poorer sleep quality, experience anhedonia, and report more anxiety symptoms when compared with survivors in class 1. CONCLUSIONS: Three distinct classes of CRF were identified which could be differentiated with sleep quality, anxiety, anhedonia, and lifestyle factors. IMPLICATIONS FOR CANCER SURVIVORS: The identification of CRF subtypes with distinct characteristics suggests that interventions should be targeted to the CRF subtype. PMID- 28889369 TI - Interlocking Editorships in Scientific Journals. PMID- 28889368 TI - The Role of Sensation Seeking and R-rated Movie Watching in Early Substance Use Initiation. AB - Adolescence is a time of heightened impulsivity as well as substantial exposure to the effects of popular media. Specifically, R-rated movie content and sensation seeking have been shown to be individually and multiplicatively associated with early alcohol initiation, as well as to mutually influence one another over time. The present study attempts to replicate and extend these findings to cigarette and marijuana use, considering several peer, parental, and individual correlates, as well as substance-specific movie exposure, among 1023 youth (mean age 12.4 years, 52% female), using a combination of cross-lagged path models, latent growth models, and discrete-time survival models. Changes over time were associated between R-rated movie watching and sensation seeking, and both individually, not multiplicatively, predicted earlier alcohol initiation. R rated movie watching (but not sensation seeking) also predicted earlier smoking and marijuana initiation. Parental R-rated movie restriction may thus potentially delay smoking and marijuana initiation as well as adolescent drinking. PMID- 28889370 TI - Semi-Mechanistic Model for Predicting the Dosing Rate in Children and Neonates for Drugs Mainly Eliminated by Cytochrome Metabolism. AB - BACKGROUND AND OBJECTIVE: A simple approach is proposed to predict drug clearance in children when no paediatric data are available for drugs metabolised by cytochromes. METHODS: The maturation functions of cytochrome activity and binding proteins in plasma were combined with several measures of body size to describe drug clearance increase with age. The complete model and different reduced models were evaluated on a large panel of drug clearance data in children. The parameters of the models were estimated by nonlinear regression. Bias and precision of predictions were determined. RESULTS: Two hundred and ten clearance ratios were available for the analysis, corresponding to 53 drugs mainly eliminated by cytochrome metabolism. The age range was 1.5 day to 16 years and there were 30 values for children aged less than 2 years. Fat-free mass at power 0.75 yielded better results than the other body size descriptor tested. The model with the best fit was based on the fat-free mass ratio, the unbound fraction ratio, maturation functions for cytochromes and no maturation function for clearance by other routes. In children aged less than 2 years, the predictive performances were much better with the final model than with the model based on body surface area. The final model was almost unbiased. CONCLUSIONS: This model allows the calculation of the maintenance dose of drugs eliminated mainly by cytochromes. After external validation, it could be used in children aged less than 2 years. In older children, the model reduces to a simple approach based on body surface area or preferably on fat-free mass at power 0.75. The model is not suitable for preterm neonates. PMID- 28889373 TI - Analysis of Chromosomal Alterations in Urothelial Carcinoma. AB - Here, we describe the use of complementary techniques applicable to different types of samples to analyze chromosomal alterations in urothelial carcinoma. By a conventional chromosome analysis on fresh biopsies, it is possible to delineate the status of ploidy and rough chromosomal aberrations. The multi-target fluorescence in situ hybridization (FISH) UroVysion test, for the rapid detection of chromosomal aneusomy of chromosomes 3, 7, and 17 and/or deletion of 9p21 locus, is applicable to urine specimens as well as to formalin-fixed paraffin embedded (FFPE) specimens and fresh biopsies. Finally, array comparative genomic hybridization (array-CGH) gives the possibility of analyzing the DNA in a single experiment from a biopsy of the tumor but also from FFPE specimens; this technique is able to detect alterations at the genome level not excluding any chromosome. PMID- 28889372 TI - Ezrin regulates skin fibroblast size/mechanical properties and YAP-dependent proliferation. AB - Ezrin acts as a dynamic linkage between plasma membrane and cytoskeleton, and thus involved in many fundamental cellular functions. Yet, its potential role in human skin is virtually unknown. Here we investigate the role of Ezrin in primary skin fibroblasts, the major cells responsible extracellular matrix (ECM) production. We report that Ezrin play an important role in the maintenance of skin fibroblast size/mechanical properties and proliferation. siRNA-mediated Ezrin knockdown decreased fibroblast size and mechanical properties, and thus impaired the nuclear translocation of YAP, a protein commonly response to cell size and mechanical force. Functionally, depletion of Ezrin significantly inhibited YAP target gene expression and fibroblast proliferation. Conversely, restoration of YAP nuclear translocation by overexpression of constitutively active YAP reversed YAP target genes expression and rescued proliferation in Ezrin knockdown cells. These data reveal a novel role for Ezrin in maintenance of fibroblast size/mechanical force and regulating YAP-mediated proliferation. PMID- 28889374 TI - Analysis of Point Mutations in Clinical Samples of Urothelial Carcinoma. AB - In the last two decades specific point mutations in oncogenes have been identified in urinary bladder cancers. Identification of these mutations in clinical samples (e.g., urine or tumor tissue) can be of use for diagnostic or prognostic purposes. In this chapter we describe how mutations in multiple oncogenes can be identified with a simple assay. PMID- 28889371 TI - Bone Marrow Stroma and Vascular Contributions to Myeloma Bone Homing. AB - PURPOSE OF THE REVIEW: Herein we dissect mechanisms behind the dissemination of cancer cells from primary tumor site to the bone marrow, which are necessary for metastasis development, with a specific focus on multiple myeloma. RECENT FINDINGS: The ability of tumor cells to invade vessels and reach the systemic circulation is a fundamental process for metastasis development; however, the interaction between clonal cells and the surrounding microenvironment is equally important for supporting colonization, survival, and growth in the secondary sites of dissemination. The intrinsic propensity of tumor cells to recognize a favorable milieu where to establish secondary growth is the basis of the "seed and soil" theory. This theory assumes that certain tumor cells (the "seeds") have a specific affinity for the milieu of certain organs (the "soil"). Recent literature has highlighted the important contributions of the vascular niche to the hospitable "soil" within the bone marrow. In this review, we discuss the crucial role of stromal cells and endothelial cells in supporting primary growth, homing, and metastasis to the bone marrow, in the context of multiple myeloma, a plasma cell malignancy with the unique propensity to primarily grow and metastasize to the bone marrow. PMID- 28889375 TI - A Versatile Assay for Detection of Aberrant DNA Methylation in Bladder Cancer. AB - Urothelial carcinoma of the bladder is one of the most common malignancies in the industrialized world, mainly caused by smoking and occupational exposure to chemicals. The favorable prognosis of early stage bladder cancer underscores the importance of early detection for the treatment of this disease. The high recurrence rate of this malignancy also highlights the need for close post diagnosis monitoring of bladder cancer patients. As for other malignancies, aberrant DNA methylation has been shown to play a crucial role in the initiation and progression of bladder cancer, and thus holds great promise as a diagnostic and prognostic biological marker. Here, we describe a protocol for a versatile DNA methylation enrichment method, the Methylated CpG Island Recovery Assay (MIRA), which enables analysis of the DNA methylation status in individual genes or across the entire genome. MIRA is based on the ability of the methyl-binding domain (MBD) proteins, the MBD2B/MBD3L1 complex, to specifically bind methylated CpG dinucleotides. This easy-to-perform method can be used to analyze the methylome of bladder cancer or urothelial cells shed in the urine to elucidate the evolution of bladder carcinogenesis and/or identify epigenetic signatures of chemicals known to cause this malignancy. PMID- 28889376 TI - Immunohistochemical Analysis of Urothelial Carcinoma Tissues for Proliferation and Differentiation Markers. AB - Immunohistochemistry is a standard method in histopathology and enables the localized detection of proteins in histological tissue sections. Specific antibodies are bound to cellular antigens, captured by secondary antibodies or polymers, linked to enzymes and visualized by chromogenic substrates. Here, we describe an automated staining technique for larger slide batches as well as a manual protocol for only few slides using a polymer technique. We focus on differentiation markers, measures of cell proliferation, and therapeutic targets in benign and malignant urothelial tissues. PMID- 28889377 TI - Molecular Subtype Profiling of Urothelial Carcinoma Using a Subtype-Specific Immunohistochemistry Panel. AB - Molecular subtypes of bladder cancer (BC) can be determined by relatively small immunohistochemistry panels both for non-muscle invasive (NMI) and muscle invasive (MI) tumors. For analysis of NMI tumors, as few as two markers are needed, although classification is dependent also on pathological grade and histological evaluation. The result is a classification into the three tumor-cell phenotypes of NMI-BC, Urothelial-like (Uro), Genomically Unstable (GU), and Basal/SCC-like. For analysis of MI tumors, 13 markers are needed. The larger number of markers required for the classification of MI-BC reflects the inclusion of two additional phenotypes exclusively found in invasive tumors; Mesenchymal like (Mes-like) and Small-cell/Neuroendocrine-like (Sc/NE-like). Here follows a description of how to perform and approach IHC-based subtype classification of bladder cancer. PMID- 28889378 TI - Defining the Pathways of Urogenital Schistosomiasis-Associated Urothelial Carcinogenesis through Transgenic and Bladder Wall Egg Injection Models. AB - Urogenital schistosomiasis (infection with Schistosoma haematobium) is a major cause of bladder carcinogenesis. However, the exact mechanisms of the sequelae leading up to the development of bladder cancer are poorly understood, mainly because of a dearth of tractable mouse models. We developed a mouse model of urogenital schistosomiasis through intramural injection of parasite eggs into the bladder wall to mimic the trapping of parasite eggs in the bladder. This approach recapitulates many of the sequelae observed in infected humans. Here, we describe procedures for utilizing this surgical technique in combination with well established transgenic mouse strains to dissect the role of cancer-related genes in the initiation and establishment of bladder carcinogenesis. The described method utilizes CRE-mediated flox activity to render mice p53 haploinsufficient before challenging them with bladder wall egg injection. These techniques are potentially amenable to studying the role of other pro-carcinogenic and cancer suppressor gene(s) in urogenital schistosomiasis-associated urothelial carcinogenesis. PMID- 28889379 TI - Algorithm for the Automated Evaluation of NAT2 Genotypes. AB - N-Acetyltransferase 2 (NAT2) genotyping by PCR and RFLP-based methods provides information on seven single nucleotide polymorphisms (SNPs) without deriving the chromosomal phase (haplotype). So genotyping results must be processed to get all possible NAT2 haplotype (or allele) combinations. Here we describe the procedure for genotyping and present a program based on Microsoft(r) Access(r) which automatically generates all possible haplotype pairs for a given unphased NAT2 genotype. NAT2 haplotypes are important to predict the NAT2 phenotype. PMID- 28889380 TI - Detection of APOBEC3 Proteins and Catalytic Activity in Urothelial Carcinoma. AB - Members of the APOBEC3 (A3) family of enzymes were shown to act in an oncogenic manner in several cancer types. Immunodetection of APOBEC3A (A3A), APOBEC3B (A3B), and APOBEC3G (A3G) proteins is particularly challenging due to the large sequence homology of these proteins and limited availability of antibodies. Here we combine independent immunoblotting with an in vitro activity assay technique, to detect and categorize specific A3s expressed in urothelial bladder cancer and other cancer cells. PMID- 28889381 TI - Oxidative Stress in Urothelial Carcinogenesis: Measurements of Protein Carbonylation and Intracellular Production of Reactive Oxygen Species. AB - Oxidative stress contributes substantially to urothelial carcinogenesis. Its extent can be assessed by measurements of reactive species (mainly reactive oxygen species (ROS)), oxidatively modified damage products, and levels of various antioxidants. We presented herein the methods for the measurement of protein carbonyl content and intracellular production of ROS. Protein carbonyl is the most commonly used indicator of protein oxidation because it is early formed and relatively stable under oxidative stress. Determination of protein carbonyl relies on the derivatization of carbonyl groups (aldehydes: R-CHO and ketones: R CO-R) with 2,4-dinitrophenylhydrazine (DNPH) under strongly acidic conditions to yield stable dinitrophenyl (DNP) hydrazones. Absorbance of the DNP hydrazones at 370-375 nm is proportional to the content of carbonyl groups. To report the protein carbonyl content, it is usually normalized by total proteins. Detection of intracellular ROS production is based on oxidation of 2',7' dichlorofluorescein-diacetate (DCFH-DA) by ROS to produce the highly fluorescent 2',7'-dichlorofluorescein (DCF). Fluorescent intensity measured at 480 nm excitation and 535 nm emission is directly proportional to the amount of ROS generated. PMID- 28889382 TI - Urothelial Carcinoma Stem Cells: Current Concepts, Controversies, and Methods. AB - Cancer stem cells are defined as a self-renewing and self-protecting subpopulation of cancer cells able to differentiate into morphologically and functionally diverse cancer cells with a limited lifespan. To purify cancer stem cells, two basic approaches can be applied, the marker-based approach employing various more of less-specific cell surface marker molecules and a marker-free approach largely based on various self-protection mechanisms. Within the context of urothelial carcinoma, both methods could find use. The cell surface markers have been mainly derived from the urothelial basal cell, a probable cell of origin of muscle-invasive urothelial carcinoma, with CD14, CD44, CD90, and 67LR representing successful examples of this strategy. The marker-free approaches involve side population sorting, for which a detailed protocol is provided, as well as the Aldefluor assay, which rely on a specific overexpression of efflux pumps or the detoxification enzyme aldehyde dehydrogenase, respectively, in stem cells. These assays have been applied to both non-muscle-invasive and muscle invasive bladder cancer samples and cell lines. Urothelial carcinoma stem cells feature a pronounced heterogeneity as to their molecular stemness mechanisms. Several aspects of urothelial cancer stem cell biology could enter translational development rather soon, e.g., a specific CD44+-derived gene expression signature able to identify non-muscle-invasive bladder cancer patients with a high risk of progression, or deciphering a mechanism responsible for repopulating activity of urothelial carcinoma stem cells within the context of therapeutic resistance. PMID- 28889383 TI - In Vitro Differentiation and Propagation of Urothelium from Pluripotent Stem Cell Lines. AB - Bioengineering of bladder tissue, particularly for those patients who have advanced bladder disease, requires a source of urothelium that is healthy, capable of significant proliferation in vitro and immunologically tolerated upon transplant. As pluripotent stem cells have the potential to fulfill such criteria, they provide a critical cell source from which urothelium might be derived in vitro and used clinically. Herein, we describe the in vitro differentiation of urothelium from the H9 human embryonic stem cell (hESC) line through the definitive endoderm (DE) phase via selective culture techniques. The protocol can be used to derive urothelium from other hESCs or human-induced pluripotent stem cells. PMID- 28889384 TI - Spheroid Cultures of Primary Urothelial Cancer Cells: Cancer Tissue-Originated Spheroid (CTOS) Method. AB - Increasingly, it has been recognized that studying cancer samples from individual patients is important for the development of effective therapeutic strategies and in endeavors to overcome therapy resistance. Primary cultures of cancer cells acutely dissected from individual patients can provide a platform that enables the study and characterization of individual tumors. To that end, we have developed a method for preparing cancer cells in the form of multi-cellular spheroids. The cells can be derived from patient tumors (primary cells), from patient-derived xenografts, or from genetically- or chemically induced animal tumors. This method of culturing spheroids composed of cells derived from cancer tissues can be applied to various types of cancer, including urothelial cancer. The method is based on the principle of retaining cell-cell contact throughout cancer cell preparation and culturing. The first step is a partial digestion of the tumor specimen into small fragments; these fragments spontaneously form spheroidal shapes within several hours. The spheroid is referred to as a cancer tissue-originated spheroid (CTOS). The advantage of the CTOS method is that it allows one to prepare pure cancer cells at high yield. CTOSs can be stably cultured in serum-free conditions. The CTOS method can be applied to drug sensitivity assays, drug screening, and analyses of intracellular signaling. Moreover, the CTOS method provides a platform for studying the nature of cancer cell clusters. PMID- 28889385 TI - The N-butyl-N-4-hydroxybutyl Nitrosamine Mouse Urinary Bladder Cancer Model. AB - Urinary bladder cancer (UBC) is a common and complex malignancy, with a multifactorial etiology, like environmental factors, such as cigarette smoking, occupational exposure, and genetic factors.UBC exhibits considerable genotypic and phenotypic heterogeneity. Among all UBC lesions, urothelial carcinoma is the most frequently observed histological type. Despite all the developments made in urologic oncology field, therapeutic options remain inadequate. There is urgency for the identification and development of new antineoplastic drugs to replace or improve current protocols and in vivo models have been proven to be essential for this step. There are different animal models of UBC: Spontaneous and experimentally induced models (genetically engineered, transplantable-xenograft and syngeneic animals- and chemically induced models). N-butyl-N(4 hydroxybutil)nitrosamine (BBN) is the most suitable reagent to generate chemically induced in vivo models of UBC and to study bladder carcinogenesis. BBN has proven, over the years, to be very realistic and reliable. It is bladder specific, and induces high tumor incidence. PMID- 28889386 TI - Patient-Derived Bladder Cancer Xenografts. AB - Patient-derived xenograft (PDX ) tumors are models developed by direct transplant of human tumors into immune-compromised hosts such as nude mice. These models retain the histological and genetic characteristics of the primary tumor and are considered a valuable platform for translational cancer research. This chapter describes the methodology to establish and propagate bladder cancer PDX model. PMID- 28889387 TI - Orthotopic Mouse Models of Urothelial Cancer. AB - Orthotopic mouse models of urothelial cancer are essential for testing novel therapies and molecular manipulations of cell lines in vivo. These models are either established by orthotopic inoculation of human (xenograft models) or murine tumor cells (syngeneic models) in immunocompromised or immune competent mice. Current techniques rely on inoculation by intravesical instillation or direct injection into the bladder wall. Alternative models include the induction of murine bladder tumors by chemical carcinogens (BBN) or genetic engineering (GEM). PMID- 28889388 TI - Quantification of MicroRNAs in Urine-Derived Specimens. AB - MicroRNAs are small noncoding RNAs which regulate the expression of genes involved in a multitude of cellular processes. Dysregulation of microRNAs and-in consequence-of the affected pathways is frequently observed in numerous pathologies including cancers. Therefore, tumor-related alterations in microRNA expression and function can reflect molecular processes of tumor onset and progression qualifying microRNAs as potential diagnostic and prognostic biomarkers.In particular, microRNAs with differential expression in bladder cancer (BCa) might represent promising tools for noninvasive tumor detection in urine. This would be helpful not only for diagnostic and monitoring purposes but also for therapeutic decisions. Detection and quantification of BCa-associated microRNAs in urine can be performed using the cellular sediment, which also contains BCa cells, or in exosomes originating from those cells. Methods for isolation of exosomes from urine, extraction of total RNA from cells and exosomes as well as techniques for RNA quantification, reverse transcription, and qPCR based quantification of microRNA expression levels are described herein. PMID- 28889389 TI - Quantitative RNA Analysis from Urine Using Real Time PCR. AB - Urine is emerging as a biological fluid suitable to perform liquid biopsy in a minimally invasive manner, a fundamental attribute for prevention and early detection of cancer. Urine biomarkers can be analyzed in voided urine, in urine sediment, and urine supernatant. In the case of urothelial carcinoma, in which tumor cells are in direct contact with urine, the assessment of the levels of biomarkers in the urinary cell fraction appears to be the most promising approach to identify diagnostic and prognostic biomarkers in a noninvasive way. Here, we describe a protocol to collect and process urine samples to obtain urinary exfoliated cells. Furthermore, we describe the methodology to isolate RNA from urinary cells and to quantify gene expression levels from these urinary cells. PMID- 28889390 TI - DNA Methylation Analysis from Body Fluids. AB - Circulating cell-free DNA (ccfDNA) can be found in various body fluids, i.e., blood (serum and plasma), urine, pleural effusions, and ascites. While ccfDNA predominantly originates from physiological processes, a fraction might be related to pathological events, e.g., cancer. Aberrant DNA methylation, which is considered a hallmark of cancer, can be assessed accurately in ccfDNA. Consequently, DNA methylation testing in body fluids represents a powerful diagnostic tool in the clinical management of malignant diseases. Frequently, however, the total amount of disease-related ccfDNA in a sample is low and masked by an excess of physiological ccfDNA. Thus, DNA methylation analysis of tumor derived DNA is challenging, and high volumes of body fluids need to be analyzed in order to ensure a sufficient abundance of the analyte in the test sample. DNA methylation assays are usually based on prior conversion of cytosines to uracils by means of bisulfite. This reaction takes place under harsh chemical conditions leading to DNA degradation and therefore necessitates a proper DNA purification before downstream analyses. This article describes a protocol which allows for the preparation of ultra-pure bisulfite-converted DNA from up to 3 ml blood plasma and serum, which is well suited for subsequent molecular biological techniques, e.g., methylation-specific real-time PCR. PMID- 28889392 TI - Isolation and Characterization of CTCs from Patients with Cancer of a Urothelial Origin. AB - Monitoring of circulating tumor cells' (CTCs) presence has the potential to improve therapeutic management of oncological diseases at an early stage and also to identify patients with increased risk of tumor progression or recurrence before the onset of clinically detected metastasis. Here we describe a new simplified efficient methodology for the separation and in vitro culturing of viable CTCs from peripheral blood by size-based filtration (MetaCell(r)). The isolation protocol yields preferentially cells bigger than 8 MUm enabling further cytomorphological and molecular analysis. PMID- 28889391 TI - Urinary Protein Markers for the Detection and Prognostication of Urothelial Carcinoma. AB - Bladder cancer diagnosis and surveillance is mainly based on cystoscopy and urine cytology. However, both methods have significant limitations; urine cytology has a low sensitivity for low-grade tumors, while cystoscopy is uncomfortable for the patients. Therefore, in the last decade urine analysis was the subject of intensive research resulting in the identification of many potential biomarkers for the detection, surveillance, or prognostic stratification of bladder cancer. Current trends move toward the development of multiparametric models to improve the diagnostic accuracy compared with single molecular markers. Recent technical advances for high-throughput and more sensitive measurements have led to the development of multiplex assays showing potential for more efficient tools toward future clinical application. In this review, we focus on the findings of urinary protein research in the context of detection and prognostication of bladder cancer. Furthermore, we provide an up-to-date overview on the recommendations for the quality evaluation of published studies as well as for the conduction of future urinary biomarker studies. PMID- 28889393 TI - Epigenetic Treatment Options in Urothelial Carcinoma. AB - Mutations, dysregulation, and dysbalance of epigenetic regulators are especially frequent in urothelial carcinoma (UC) compared to other malignancies. Accordingly, targeting epigenetic regulators may provide a window of opportunity particularly in anticancer therapy of UC. In general, these epigenetic regulators comprise DNA methyltransferases and DNA demethylases (for DNA methylation), histone methyltransferases, and histone demethylases (for histone methylation) as well as acetyl transferases and histone deacetylases (for histone and non-histone acetylation).As epigenetic regulators target a plethora of cellular functions and available inhibitors often inhibit enzymatic activity of more than one isoenzyme or may have further off-target effects, analysis of their functions in UC pathogenesis as well as of the antineoplastic capacity of according inhibitors should follow a multidimensional approach.Here, we present our standard approach for the analysis of the cellular and molecular functions of individual HDAC enzymes, their suitability as treatment targets and for the evaluation of isoenzyme-specific HDAC inhibitors regarding their antineoplastic efficacy. This approach may also serve as prototype for the preclinical evaluation of other epigenetic treatment approaches. PMID- 28889394 TI - Evaluation of Protein Levels of the Receptor Tyrosine Kinase ErbB3 in Serum. AB - The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (RTK) consists of four members: EGFR1/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and HER4/ErbB4. Signaling through these receptors regulates many key cellular activities, such as cell division, migration, adhesion, differentiation, and apoptosis. The ErbB family has been shown to be overexpressed in different types of cancers and is a target of several inhibitors already in clinical trials. ErbB3 lacks a functional tyrosine kinase domain and therefore has not been as extensively studied as the other members of this family, but its importance in activating downstream pathways, such as the PI3K/Akt pathway, makes this RTK a worthy investigation target, especially in urothelial carcinoma where the PI3K/Akt pathway is vital for progression. In recent times, ErbB3 overexpression has been linked to drug resistance and progression of various diseases, especially cancer. ErbB3 levels in the serum were shown in many cases to be reflective of its role in disease progression, and therefore detection of serum ErbB3 levels during treatment may be of importance.Here we describe two methods for detecting ErbB3 protein in serum from patients who have undergone a clinical trial, utilizing two well-established methods in molecular biology-western blotting and ELISA, focusing on sample preparation and troubleshooting. PMID- 28889395 TI - Targeting the PI3K/AKT/mTOR Pathway in Bladder Cancer. AB - The PI3K/AKT/mTOR signaling pathway shows frequent molecular alterations and increased activity in cancer. Given its role in the regulation of cell growth, survival and metastasis, molecules within this pathway are promising targets for pharmacologic intervention. Metastatic bladder cancer (BLCA) continues to have few treatment options. Although various molecular alterations in PI3K/AKT/mTOR signaling have been described in BLCA, clinical trials with small molecule inhibitors have not met their endpoints. In this article, we summarize results from preclinical studies and clinical trials that examined PI3K pathway inhibitors in BLCA focusing on technical challenges that might result in contradictory findings in preclinical studies. Based on published data from our group, we also address challenges that need to be overcome to optimize PI3K inhibition in BLCA and enable its successful translation into the clinic. PMID- 28889396 TI - Visualization and Quantitative Measurement of Drug-Induced Platinum Adducts in the Nuclear DNA of Individual Cells by an Immuno-Cytological Assay. AB - Immunocytological staining with adduct-specific antibodies allows the visualization and measurement of structurally defined types of DNA damage in the nuclei of individual cells. Here we describe an immunocytological assay (ICA) procedure for the localization and quantification of such damage, in particular induced by platinum-based anticancer drugs, in cell lines , in primary cell suspensions and in frozen tissue sections. PMID- 28889397 TI - Retraction Note to: Risk factors for increased left ventricular hypertrophy in patients with chronic kidney disease. PMID- 28889398 TI - Repeatability and reproducibility of a telemanipulated fracture reduction system. AB - We evaluate the inter- and intraobserver variability of a telemanipulated femur fracture reduction system using a joystick device. Five examiners performed virtual reduction of 3D femur fracture models on two separate occasions. We assessed the inter- and intraobserver variability for the final alignment and reduction. The average difference between testing rounds was only 0.3 mm for overall displacement and 0.5 degrees for overall rotation. There was an average time reduction between rounds of 11.7 s. The mean differences in overall displacement between examiners ranged between 0.2 and 0.9 mm; between 0.2 degrees and 3.2 degrees for overall rotation; and between 9 and 82 s for time to reduction. The time required to complete the reduction did not have a significant effect on the overall displacement or rotation of the final model. Telemanipulated fracture reduction is a reliable and reproducible technique, which does not require extensive training. PMID- 28889399 TI - The dissipation and risk assessment of 2,4-D sodium, a preharvest anti-fruit-drop plant hormone in bayberries. AB - Preharvest fruit-drop is a challenge to bayberry production. 2,4-D sodium as a commonly used anti-fruit-drop hormone on bayberry can reduce the yield loss caused by preharvest fruit-drop. The persistence and risk assessment of 2,4-D sodium after applying on bayberries were investigated. A method for determining 2,4-D sodium in bayberry was established based on LC-MS-MS. The average recoveries of 2,4-D sodium were at the range of 93.7-95.8% with relative standard deviations (RSDs) ranging from 0.9 to 2.8%. The dissipation rates of 2,4-D sodium were described using first-order kinetics, and its half-life ranged from 11.2 to 13.8 days. A bayberry consumption survey was carried out for Chinese adults for the first time. The safety assessments of 2,4-D sodium were conducted by using field trail data as well as monitoring data. Results showed that the chronic risk quotient and the acute risk quotient were calculated to be 0.23-0.59 and 0.02 0.05%, respectively, for Chinese adults, indicating low dietary risk for adults and children. In the end, the household cleaning steps were compared, and results showed that water rinsing for 1 min can remove 49.9% 2,4-D sodium residue, which provides pesticide removal suggestion for consumers. PMID- 28889400 TI - Are children playgrounds safe play areas? Inorganic analysis and lead isotope ratios for contamination assessment in recreational (Brazilian) parks. AB - In city playgrounds, there is a potential risk of harming children's health by contamination coming from anthropogenic activities. With the aim to determinate the sources and the risk of hazardous elements, soil samples were collected in 19 selected playgrounds of different urban and rural areas from the Rio Grande do Sul state (Brazil). The concentration of 23 metals and metalloids and lead isotopic ratios were determined by ICP-MS. The methodology proposed here, firstly, classified the parks according to the average metal content by means of the NWACs (Normalized-and-Weighted Average Concentrations) and assess the contamination risk determining the Contamination Factors (CFs). Finally, statistical tools (correlation analysis and principal component analysis) were used to identify the most important contamination sources. The statistical tools used, together with lead isotopic composition analysis of the samples, revealed that coal combustion is the main source of contamination in the area. Vegetation was identified as a barrier for the contamination coming from the city. Nonetheless, some of the soils present a possible toxicological risk for humans. In fact, Cr, Sb, and Pb concentrations were higher than the Residential Intervention Values (VIRs) defined by the Environmental Protection Agency of the State of Sao Paulo, also in Brazil. PMID- 28889401 TI - Severity of drug resistance and co-existence of Enterococcus faecalis in diabetic foot ulcer infections. AB - The genes encoding aminoglycoside resistance in Enterococcus faecalis may promote collateral aminoglycoside resistance in polymicrobial wounds. We studied a total of 100 diabetic foot ulcer samples for infection and found 60 samples to be polymicrobial, 5 to be monomicrobial, and 35 samples to be culture negative. A total of 65 E. faecalis isolates were screened for six genes coding for aminoglycoside resistance, antibiotic resistance patterns, and biofilm production. Infectious Diseases Society of America/International Working Group on the Diabetic Foot system was used to classify the wound ulcers. Majority of the subjects with culture-positive wound were recommended conservative management, while 14 subjects underwent amputation. Enterococcal isolates showed higher resistance for erythromycin, tetracycline, and ciprofloxacin. Isolates from grade 3 ulcer showed higher frequency of aac(6')-Ie-aph(2")-Ia, while all the isolates were negative for aph(2")-Ib, aph(2")-Ic, and aph(2")-Id. The isolates from grade 3 ulcers showed higher resistance to aminoglycosides as well as teicoplanin and chloramphenicol. All the 39 biofilm producers were obtained from polymicrobial wound and showed higher resistance when compared to biofilm non-producers. Higher frequency of isolates carrying aac(6')-Ie-aph(2")-Ia in polymicrobial community showing resistance to key antibiotics suggests widespread distribution of aminoglycoside-resistant E. faecalis and their role in worsening diabetic foot ulcers. PMID- 28889402 TI - Social Freezing in Medical Practice. Experiences and Attitudes of Gynecologists in Germany. AB - Surveys of the German public have revealed a high acceptance of social freezing, i.e. oocyte conservation without medical indication. Up to now, there are no investigations available on the experiences and attitudes of health professionals towards social freezing. Between August 2015 and January 2016, we surveyed gynecologists Germany-wide on the topic social freezing. Five gynecologists specialized in reproductive medicine and five office-based gynecologists in standard care were chosen for the survey. The survey was conducted with an explorative, qualitative research design. The demand for social freezing in Germany is low. With regard to their fertility age, most women attend consultations too late, they have only little previous knowledge and false expectations. The gynecologists consider it the duty of society and politics to provide for the compatibility of family and work. They relate late parenthood to disadvantages primarily for the children. A majority of the gynecologists interviewed tend to advise natural reproduction. Social freezing is often mistaken as a kind of fertility insurance. Thus, it is necessary that physicians inform women early about the possibilities and limitations of social freezing. In the first place, social freezing is not a medical or medical-ethical topic. Women consider the method as a possibility to ensure the compatibility of family and work. This compatibility should be mostly perceived as a political topic. It cannot be a medical task to solve this issue. In fact, a debate in society as a whole is necessary that includes all relevant actors. PMID- 28889403 TI - Do Paediatric Investigation Plans (PIPs) Advance Paediatric Healthcare? AB - Since 2007, new drugs need a paediatric investigation plan (PIP) for EU registration. The PIPs' justifications can be traced back to concerns expressed by Shirkey that label warnings against paediatric use made children "therapeutic orphans", and the American Academy of Pediatrics' claim that all children differ considerably from adults. US legislation first encouraged, then also required, separate, adult-style safety and efficacy studies in all paediatric subpopulations. This triggered paediatric regulatory studies by the pharmaceutical industry. There were also negative outcomes, as a result of using the legal definition of childhood as a medical/physiological term. The "therapeutic orphans" concept became dogma that supported/expanded adult-style regulatory testing into all age groups even when poorly justified in adolescents or where other methods are available to generate needed data. PIPs are especially problematic because they lack the limitations imposed on the Food and Drug Administration's (FDA's) regulatory actions and more practical approaches used in the USA. Many PIP studies are medically senseless or even questionable and/or unfeasible with poor risk/benefit ratios. For example, physiologically mature adolescents have been exposed to treatments and doses known to be suboptimal in adults. Unfeasible PIP studies in rare diseases may harm patients by preventing their participation in more beneficence-driven studies. PIP-required studies can prevent effective treatment of allergic rhinitis during years of placebo treatment, exposing minors to the risk of disease progression to asthma. The PIP system should be revised; more should be done by key players, including institutional review boards/ethics committees, to ensure that all paediatric clinical studies are medically justified, rather than legislation driven, and can produce scientifically valid results. PMID- 28889404 TI - The value and pitfalls of biologics registries for psoriasis. PMID- 28889405 TI - Alternate dosing regimens of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma. PMID- 28889406 TI - Intrapartum transperineal ultrasound used to predict cases of complicated operative (vacuum and forceps) deliveries in nulliparous women. AB - INTRODUCTION: The objective of this study was to investigate the predictive value of intrapartum transperineal ultrasound in the identification of complicated operative (vacuum or forceps) deliveries in nulliparous women. MATERIAL AND METHODS: Prospective observational study of nulliparous women with an indication for operative delivery who underwent intrapartum transperineal ultrasound before fetal extraction. Managing obstetricians were blinded to the ultrasound data. Intrapartum transperineal ultrasound was performed immediately before blade application, both at rest and concurrently with contractions and active pushing. Operative delivery was classified as complicated when one or more of the following situations occurred: three or more tractions; a third-/fourth-degree perineal tear; significant bleeding during the episiotomy repair; major tear or significant traumatic neonatal lesion. RESULTS: A total of 143 nulliparous women were included in the study (82 vacuum-assisted deliveries and 61 forceps-assisted deliveries), with 20 fetuses in occiput posterior position. Forty-seven operative deliveries were classified as complicated deliveries (28 vacuum-assisted deliveries, 19 forceps-assisted deliveries). No differences in obstetric, intrapartum or neonatal characteristics were observed between the study groups, with the following exceptions: birthweight (3229 +/- 482 uncomplicated deliveries vs. 3623 +/- 406 complicated deliveries; p < 0.003) and number of vacuum tractions (1.4 uncomplicated deliveries, 4.5 complicated deliveries; p < 0.0005). The strongest predictors of a complicated delivery, using the area under the receiver-operating characteristics curve (AUC), were the angle of progression with active pushing (AoP2) (AUC 86.9%) and the progression distance with active pushing (PD2) (AUC 74.5%). The optimal cut-off value for predicting a difficult operative delivery was an AoP2 of 153.5 degrees (sensitivity 95.2%; false positive rate 5.9%) or PD2 of 58.5 mm (sensitivity 95.2%; false-positive rate 7.1%). CONCLUSIONS: The sonographic parameters AoP2 and PD2 can be used to predict cases of complicated operative deliveries in nulliparous women. PMID- 28889407 TI - Mucinous adenocarcinoma with lepidic pattern and with K-RAS mutation in a newborn with antenatal diagnosis of congenital pulmonary airway malformation. PMID- 28889454 TI - Intrafamilial variability of the triphalangeal thumb phenotype in a Dutch population: Evidence for phenotypic progression over generations? AB - Triphalangeal thumbs (TPTs) are regularly caused by mutations in the ZRS in LMBR1. Phenotypic variability can be present in TPT-families. However, recent observations suggest an increased occurrence of severe phenotypes in the Dutch TPT-population. Therefore, the aim of this study is to investigate the progression of the clinical severity of TPT-phenotype through generations. Index patients from a Dutch TPT-population were identified. A 105C>G mutation in the ZRS has previously been confirmed in this population. Questionnaires regarding family occurrence and phenotypes were distributed. Subsequently, families were visited to validate the phenotype. Both occurrence and inheritance patterns of the TPT-phenotype were analyzed through multiple generations. One hundred seventy patients with TPT were identified from 11 families. When considering all 132 segregations (parent-to-child transmission), 54% of the segregations produced a stable phenotype, 38% produced a more severe phenotype while only 8% of the phenotype was less severe when compared to the affected parents. Overall, 71% of the index patients had a more severe phenotype compared to their great grandparent. Although all family members share an identical mutation in the ZRS (105C>G), it does not explain the wide phenotypic range of anomalies. Our observational study provides better estimations for counseling and provides new insights in the long-range regulation of SHH by the ZRS-enhancer. In the current study, we provide evidence that the assumed variability in TPT-phenotype is not random, but in fact it is more likely that the expression becomes more severe in the next generation. Therefore, we observe a pattern that resembles phenotypic anticipation in TPT-families. PMID- 28889455 TI - Management of primary aldosteronism in patients with adrenal hemorrhage following adrenal vein sampling: A brief review with illustrative cases. AB - The authors describe the clinical investigation of two cases of primary aldosteronism with adrenal hemorrhage (AH) following adrenal vein sampling. A literature review was conducted regarding the medical management of primary aldosteronism in patients with AH following adrenal vein sampling. Guidelines on the management of primary aldosteronism with AH following adrenal vein sampling are lacking. The two patients were followed with serial imaging to document resolution of AH and treated medically with excellent blood pressure response. Resolution of AH was achieved, but a repeat adrenal vein sampling was deferred given the increased morbidity risk associated with a repeat procedure. PMID- 28889456 TI - Harmine promotes periodontal ligament cell-induced tissue regeneration. AB - OBJECTIVE: to investigate whether harmine has a promotive effect on human periodontal ligament cells (hPDLCs)-induced tissue regeneration. MATERIALS AND METHODS: Various concentrations of harmine on hPDLCs proliferation were tested. Osteogenic and cementogenic characteristics were examined in hPDLC/rhBMP-2 and hPDLC/harmine by alizarin red S staining, real-time PCR, and Western blotting assay. The activity of harmine was investigated in an ectopic transplantation nude mouse model. RESULTS: We determined that 10 MUM of harmine was the threshold concentration. hPDLC/harmine showed similar mineralized nodule formation in alizarin S staining compared to hPDLC/rhBMP-2. In real-time PCR, the highest gene expression level was observed for Runx2 in hPDLC/harmine at all time points. The level of CEMP-1 in hPDLC/harmine was higher at 7 days than hPDLCs alone. Thicker band of Runx2 in hPDLC/harmine was observed than in hPDLC/rhBMP-2 at 7 days by Western blotting. The band for CEMP-1 in hPDLC/harmine was thicker than hPDLCs alone at both 7 and 14 days. In ectopic transplantation, hPDLCs with harmine showed a comparable amount of mineralized tissue formation compared to rhBMP-2. hPDLCs with harmine or rhBMP-2 formed both bone and cementum-like tissue with Sharpey's fiber-like collagen insertion. CONCLUSION: Harmine can be a potential candidate for promoting hPDLCs-induced tissue regeneration. PMID- 28889457 TI - Registries as real-world cohort studies that are useful and necessary in the pyramid of evidence. PMID- 28889479 TI - Associations of oral fluid MMP-8 with periodontitis in Swiss adult subjects. AB - OBJECTIVE: MMP-8 is a prominent collagenase in periodontal disease. This cross sectional study examined whether MMP-8 levels in saliva and gingival crevicular fluid (GCF) are associated with periodontitis in a Swiss population. SUBJECTS AND METHODS: A total of 258 subjects (107 m, 151 f, mean age: 43.5 yr; range: 21-58 yr) acquired from the Swiss bone marrow donor registry participated in the study. Saliva and GCF samples were collected from subjects followed by a thorough dental and periodontal examination. MMP-8 levels were determined with immunofluorometric assay. Associations of MMP-8 levels with periodontal diagnosis, probing pocket depth (PPD) and bleeding on probing were statistically analysed with Pearson chi square test, Spearman's rho and logistic regression analysis. RESULTS: MMP-8 in GCF correlated with MMP-8 in saliva (p < .001). Periodontitis was more common (p < .001) among subjects with high levels of MMP-8 in saliva and/or GCF compared with subjects with low levels of MMP-8. Higher MMP-8 levels in GCF and saliva were associated with any periodontal diagnosis (mild, moderate or severe), greater PPD, and bleeding on probing (p < .05). When age, gender, smoking, body mass index, number of medications and decayed, missing and filled teeth were adjusted for, all observed associations remained statistically significant. The area under curve of receiver-operating characteristic was 0.67 for saliva and 0.71 for GCF. CONCLUSION: Elevated MMP-8 levels both in saliva and GCF are associated with periodontitis in a normal adult population. PMID- 28889480 TI - Why do surgeons receive more complaints than their physician peers? AB - BACKGROUND: Compared with other doctors, surgeons are at an increased risk of medicolegal events, including patient complaints and negligence claims. This retrospective study aimed to describe the frequency and nature of complaints involving surgeons compared with physicians. METHODS: We assembled a national data set of complaints about surgeons and physicians lodged with medical regulators in Australia from 2011 to 2016. We classified the complaints into 19 issues across four domains: treatment and procedures, other performance, professional conduct and health. We assessed differences in complaint risk using incidence rate ratios (IRRs). Finally, we used a multivariate model to identify predictors of complaints among surgeons. RESULTS: The rate of complaints was 2.3 times higher for surgeons than physicians (112 compared with 48 complaints per 1000 practice years, P < 0.001). Two-fifths (41%) of the higher rate of complaints among surgeons was attributable to issues other than treatments and procedures, including fees (IRR = 2.68), substance use (IRR = 2.10), communication (IRR = 1.98) and interpersonal behaviour (IRR = 1.92). Male surgeons were at a higher risk of complaints, as were specialists in orthopaedics, plastic surgery and neurosurgery. DISCUSSION: Surgeons are more than twice as likely to attract complaints as their physician peers. This elevated risk arises partly from involvement in surgical procedures and treatments, but also reflects wider concerns about interpersonal skills, professional ethics and substance use. Improved understanding of these patterns may assist efforts to reduce harm and support safe practise. PMID- 28889481 TI - Review of the biologic and clinical significance of genetic mutations in angioimmunoblastic T-cell lymphoma. AB - Angioimmunoblastic T-cell lymphoma (AITL) is an age-related malignant lymphoma, characterized by immune system-dysregulated symptoms. Recent sequencing studies have clarified the recurrent mutations in ras homology family member A (RHOA) and in genes encoding epigenetic regulators, tet methyl cytosine dioxygenase 2 (TET2), DNA methyl transferase 3 alpha (DNMT3A) and isocitrate dehydrogenase 2, mitochondrial (IDH2), as well as those related to the T-cell receptor signaling pathway in AITL. In this review, we focus on how this genetic information has changed the understanding of the developmental process of AITL and will in future lead to individualized therapies for AITL patients. PMID- 28889482 TI - TLR-Induced SMPD3 Defects Enhance Inflammatory Response of B Cell and Macrophage in the Pathogenesis of SLE. AB - B lymphocyte and macrophages may contribute to SLE pathogenesis through cytokine production after TLR stimulation. Emerging evidences suggested that defects of sphingolipid metabolism were responsible for SLE pathogenesis. However, it is not clear whether these defects exist in B cells and macrophages under SLE condition and whether TLR signalling pathway was related to the dysfunction of sphingolipid metabolism in SLE. Here, we demonstrated that the enzymes involved in the sphingolipid metabolism expressed abnormally in B cells from SLE patients and lupus-prone mice. Moreover, we found that TLR signalling induced the abnormal expression of sphingomyelin phosphodiesterase 3 (SMPD3), sphingosine-1-phosphate phosphatase 2 (SGPP2), ceramide kinase (CERK) and UDP glycosyltransferase 8 (UGT8), which were involved in sphingolipid metabolism. TLR signalling also induced the transportation of SMPD3 from Golgi apparatus. Furthermore, the dysfunction of SMPD3 enhanced TLR-induced inflammatory response of B cells and macrophages in turn. Thus, these findings provide an innovative direction and a new target for research and treatment of SLE. PMID- 28889522 TI - Salidroside, a Chemopreventive Glycoside, Diminishes Cytotoxic Effect of Cisplatin in Vitro. AB - Natural products represent the source or the inspiration for the majority of the active ingredients of medicines because of their structural diversity and a wide range of biological effects. Our aims in this study were (i) to synthesize enzymatically salidroside (SAL), the most effective phenylethanoid glycoside in Rhodiola species; (ii) to examine its antioxidant capacity using cell-free assays (reducing power, DPPH radicals scavenging and Fe2+ -chelating assays); (iii) to assess its DNA-protective potential on plasmid DNA (DNA topology assay) and in HepG2 cells (comet assay) damaged by Fe2+ ions and hydrogen peroxide, respectively; and (iv) to investigate the effects of SAL, cisplatin (CDDP) and combined treatments of SAL + CDDP on cell viability (MTT test), level of DNA damage (comet assay), proliferation, cell cycle (flow cytometry) and the expression of signalling molecules associated with cell growth and apoptotic pathways (Western immunoblotting). We found out that SAL manifested low antioxidant and DNA-protective capacity in all assays used. In both parental A2780 and CDDP-resistant A2780/CP human ovarian carcinoma cells, SAL itself exerted in fact no impact on the viability, while in combination with CDDP it showed antagonistic effect supporting the chemopreventive activity on the CDDP induced cell damage. These results were confirmed by the partial reversal of the cell cycle alterations and the DNA damage level, as well as with partial restoration of cell survival/signalling pathways, when the expression of these molecules partially returned to their proper levels. PMID- 28889556 TI - Short-term visual outcome after unilateral implantation of a trifocal diffractive presbyopia-correcting intraocular lens. PMID- 28889523 TI - The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma. AB - AIMS: Mesothelioma is a relatively uncommon but highly malignant neoplasm. Most patients die of disease within 1 year of diagnosis, but some have prolonged survival. Prospective identification of these longer-term survivors may help to guide treatment. We therefore sought to investigate the role of p16 immunohistochemistry (IHC) both alone and in combination with other markers as a potential predictor of prolonged survival in mesothelioma. METHODS AND RESULTS: P16 IHC was performed on unselected pleural mesotheliomas biopsied from 1991 to 2014; 153 of 208 (74%) cases were p16-negative, which correlated significantly with poor overall survival in both univariate (median survival 7.6 versus 13.6 months; P = 0.001) and multivariate analysis [hazard ratio (HR): 1.632; 95% confidence interval (CI): 1.103-2.415; P = 0.014]. Other independent factors associated with prolonged survival included loss of expression of BAP1 and epithelioid morphology. We therefore stratified patients further based on these three independent prognostic variables and demonstrated an unusually prolonged survival in mesotheliomas which were epithelioid, BAP1 IHC negative and p16 IHC positive (12% of cases, median survival 31.7 months, P < 0.0001). CONCLUSIONS: In conclusion, p16 IHC is an independent prognostic biomarker in pleural mesothelioma. When used in combination with BAP1 IHC and morphological subtyping, patients with exceptionally prolonged survival can potentially be identified. PMID- 28889573 TI - Pyrazolidine-3,5-dione-based inhibitors of phosphoenolpyruvate carboxylase as a new class of potential C4 plant herbicides. AB - Phosphoenolpyruvate carboxylase (PEPC) is a key enzyme in the C4 photosynthetic pathway of many of the world's worst weeds and a valuable target to develop C4 plant-selective herbicides. By virtual screening, analog synthesis, and in vitro validation, we identified pyrazolidine-3,5-diones as a new class of small molecules with inhibitory potential down to the submicromolar range against C4 PEPC and a selectivity factor of up to 16 over C3 PEPC. No other biological activity has yet been reported for the best compound, (3-bromophenyl)-4-(3 hydroxybenzylidene)-pyrazolidine-3,5-dione. A systematic variation in the substituents allowed the derivation of a qualitative structure-activity relationship. These findings make this compound class highly interesting for further investigations toward generating potent, C4 plant-selective herbicides with a low potential for unwanted effects. PMID- 28889600 TI - Normothermic ex vivo kidney perfusion for graft quality assessment prior to transplantation. AB - Normothermic ex vivo kidney perfusion (NEVKP) represents a novel approach for graft preservation and functional improvement in kidney transplantation. We investigated whether NEVKP also allows graft quality assessment before transplantation. Kidneys from 30-kg pigs were recovered in a model of heart beating donation (group A) after 30 minutes (group B) or 60 minutes (group C) (n = 5/group) of warm ischemia. After 8 hours of NEVKP, contralateral kidneys were resected, grafts were autotransplanted, and the pigs were followed for 3 days. After transplantation, renal function measured based on peak serum creatinine differed significantly among groups (P < .05). Throughout NEVKP, intrarenal resistance was lowest in group A and highest in group C (P < .05). intrarenal resistance at the initiation of NEVKP correlated with postoperative renal function (P < .001 at NEVKP hour 1). Markers of acid-base homeostasis (pH, HCO3- , base excess) differed among groups (P < .05) and correlated with posttransplantation renal function (P < .001 for pH at NEVKP hour 1). Similarly, lactate and aspartate aminotransferase were lowest in noninjured grafts versus donation after circulatory death kidneys (P < .05) and correlated with posttransplantation kidney function (P < .001 for lactate at NEVKP hour 1). In conclusion, assessment of perfusion characteristics and clinically available perfusate biomarkers during NEVKP allows the prediction of posttransplantation graft function. Thus, NEVKP might allow decision-making regarding whether grafts are suitable for transplantation. PMID- 28889619 TI - Alternate dosing regimens of brentuximab vedotin for CD30+ cutaneous T-cell lymphoma: reply from the authors. PMID- 28889641 TI - Design of sodium channel ligands with defined selectivity - a case study in scorpion alpha-toxins. AB - Scorpion alpha-toxins are polypeptides that inhibit voltage-gated sodium channel inactivation. They are divided into mammal, insect and alpha-like toxins based on their relative activity toward different phyla. Several factors are currently known to influence the selectivity, which are not just particular amino acid residues but also general physical, chemical, and topological properties of toxin structural modules. The objective of this study was to change the selectivity profile of a chosen broadly active alpha-like toxin, BeM9 from Mesobuthus eupeus, toward mammal-selective. Based on the available information on what determines scorpion alpha-toxin selectivity, we designed and produced msBeM9, a BeM9 derivative, which was verified to be exclusively active toward mammalian sodium channels and, most importantly, toward the Nav 1.2 isoform expressed in the brain. PMID- 28889650 TI - Correlation of Recommendations of Treatment Guidelines and Frequently Prescribed Antibiotics: Evaluation of Their Pharmaceutical Pack Size. AB - There are various factors that contribute to development of antimicrobial resistance. Overuse, inappropriate prescribing and extensive agricultural use of antibiotics are some of the factors which have been identified. Antibiotics are almost always universally packaged by manufacturers in packs that are heavily driven by cost of economies and convenience rather than by any scientific basis or duration of therapy. So, in this study, the correlation of the treatment guidelines with the choice of antibiotics and whether packing size contributes to leftover dosing units when used according to guideline recommendations were assessed. PMID- 28889651 TI - Living donor liver transplantation for biliary atresia: An analysis of 2085 cases in the registry of the Japanese Liver Transplantation Society. AB - Biliary atresia (BA) is the most common indication for liver transplantation (LT) in pediatric population. This study analyzed the comprehensive factors that might influence the outcomes of patients with BA who undergo living donor LT by evaluating the largest cohort with the longest follow-up in the world. Between November 1989 and December 2015, 2,085 BA patients underwent LDLT in Japan. There were 763 male and 1,322 female recipients with a mean age of 5.9 years and body weight of 18.6 kg. The 1-, 5-, 10-, 15-, and 20-year graft survival rates for the BA patients undergoing LDLT were 90.5%, 90.4%, 84.6%, 82.0%, and 79.9%, respectively. The donor body mass index, ABO incompatibility, graft type, recipient age, center experience, and transplant era were found to be significant predictors of the overall graft survival. Adolescent age (12 to <18 years) was associated with a significantly worse long-term graft survival rate than younger or older ages. We conclude that LDLT for BA is a safe and effective treatment modality that does not compromise living donors. The optimum timing for LT is crucial for a successful outcome, and early referral to transplantation center can improve the short-term outcomes of LT for BA. Further investigation of the major cause of death in liver transplanted recipients with BA in the long-term is essential, especially among adolescents. PMID- 28889652 TI - Dynamics and function of ERM proteins during cytokinesis in human cells. AB - The molecular mechanism that governs cytoskeleton-membrane interaction during animal cytokinesis remains elusive. Here, we investigated the dynamics and functions of ERM (Ezrin/Radixin/Moesin) proteins during cytokinesis in human cultured cells. We found that ezrin is recruited to the cleavage furrow through its membrane-associated domain in a cholesterol-dependent but largely Rho independent manner. While ERMs are dispensable for furrow ingression, they play a pivotal role in contractile activity of the polar cortex. Notably, when anillin and supervillin are codepleted, ERMs increasingly accumulate at the cleavage furrow and substantially contribute to the furrow ingression. These results reveal a supportive role of ERMs in cortical activities during cytokinesis, and also provide insight into the selective mechanism that preferentially associates cytokinesis-relevant proteins with the division site. PMID- 28889653 TI - Chronic actinic dermatitis: successful treatment with psoralen-ultraviolet A photochemotherapy. PMID- 28889642 TI - Treating pediatric neuromuscular disorders: The future is now. AB - Pediatric neuromuscular diseases encompass all disorders with onset in childhood and where the primary area of pathology is in the peripheral nervous system. These conditions are largely genetic in etiology, and only those with a genetic underpinning will be presented in this review. This includes disorders of the anterior horn cell (e.g., spinal muscular atrophy), peripheral nerve (e.g., Charcot-Marie-Tooth disease), the neuromuscular junction (e.g., congenital myasthenic syndrome), and the muscle (myopathies and muscular dystrophies). Historically, pediatric neuromuscular disorders have uniformly been considered to be without treatment possibilities and to have dire prognoses. This perception has gradually changed, starting in part with the discovery and widespread application of corticosteroids for Duchenne muscular dystrophy. At present, several exciting therapeutic avenues are under investigation for a range of conditions, offering the potential for significant improvements in patient morbidities and mortality and, in some cases, curative intervention. In this review, we will present the current state of treatment for the most common pediatric neuromuscular conditions, and detail the treatment strategies with the greatest potential for helping with these devastating diseases. PMID- 28889654 TI - Patient-reported health outcomes in long-term lung transplantation survivors: A prospective cohort study. AB - During the last three decades lung transplantation (LTx) has become a proven modality for increasing both survival and health-related quality of life (HRQoL) in patients with various end-stage lung diseases. Most previous studies have reported improved HRQoL shortly after LTx. With regard to long-term effects on HRQoL, however, the evidence is less solid. This prospective cohort study was started with 828 patients who were on the waiting list for LTx. Then, in a longitudinal follow-up, 370 post-LTx patients were evaluated annually for up to 15 years. For all wait-listed and follow-up patients, the following four HRQoL instruments were administered: State-Trait Anxiety Inventory, Zung Self-rating Depression Scale, Nottingham Health Profile, and a visual analogue scale. Cross sectional and generalized estimating equation (GEE) analysis for repeated measures were performed to assess changes in HRQoL during follow-up. After LTx, patients showed improvement in all HRQoL domains except pain, which remained steady throughout the long-term follow-up. The level of anxiety and depressive symptoms decreased significantly and remained constant. In conclusion, this study showed that HRQoL improves after LTx and tends to remain relatively constant for the entire life span. PMID- 28889657 TI - The physiologic pattern of normal labour progression. PMID- 28889694 TI - [Highlights for our Congress, in November]. PMID- 28889695 TI - [SPCCTV & SPA Scientific Meeting]. PMID- 28889697 TI - [Professor Americo Dinis da Gama Award]. PMID- 28889696 TI - [Why publishing is so important?] PMID- 28889698 TI - [Coronary artery bypass grafting in the octogenarians: should we just leave them alone?] PMID- 28889699 TI - Elective and urgent coronary surgery in octogenarians. AB - OBJECTIVES: To analyze the influence of surgical myocardial revascularization on early and late mortality in octogenarians and compare the survival rates with age adjusted general population. METHODS: Between 2007 and 2014, 182 octogenarian patients underwent elective or urgent coronary artery bypass grafting surgery. Logistic regression was performed to evaluate the in-hospital mortality predictors. The comparison of long term survival between our population and age adjusted general population was made using one-sample log-rank test. RESULTS: The in-hospital mortality was 4,4% and its predictors on univariable analysis were non sinus rhythm (p=0,001), acute coronary syndrome less than 7 days prior to surgery (p=0,021), ejection fraction less than 50% (p=0,04) and the need for conversion to on pump surgery (p=0,04). On multivariate logistic regression non sinus rhythm and acute myocardial infarction less than 7 days before surgery were independent predictors of in-hospital mortality. Follow-up at one-year showed survival rate of 86,2% and at five years 58,4%. There was no significant difference in survival rates between the study group and the age adjusted standard population (p=0,96). The group was divided in two groups: (1) complete revascularization and (2) incomplete revascularization. There was no significant difference in survival (p=0,32 and p=0,19, respectively) compared to the age adjusted standard population. CONCLUSIONS: Coronary artery bypass grafting in octogenarians is safe and has an important impact on long term survival, with five-year survival being similar to the age adjusted standard population. PMID- 28889700 TI - [De novo atrial fibrillation following aortic valve replacement surgery]. AB - : Objetives: The present study aimed to explore the risk factors associated with de novo atrial fibrillation following isolated aortic valve replacement surgery and its prevalence in a high volume cardiothoracic surgery center. METHODS: This is a cross-sectional retrospective observational study including all patients submitted to isolated aortic valve replacement surgery during 2014 and the corresponding data. Patients with previous history of atrial fibrillation, endocarditis or aortic valve prosthesis were excluded. The statistical analysis was conducted according to the type of variables concerned. RESULTS: One hundred and seventy-three patients were included and 45.1% had de novo atrial fibrillation, with a median occurrence on 2.4 +/-1.5 days of the postoperative period. Age was significantly associated with the arrhythmia (p=0.028). Atrial fibrillation patients had a significantly lower minimum of postoperative creatinine clearance (p=0.026) and a higher postoperative plasmatic C-reactive protein peak (p=0.025). Arrhythmic patients had a median time of hospital stay significantly superior to those who did not develop atrial fibrillation (p=0.008). Hospital mortality was low and similar between groups (3%, p=0.796). DISCUSSION/CONCLUSION: This study confirms the high prevalence of atrial fibrillation following aortic valve replacement surgery. The increased C-reactive protein and decreased creatinine clearance reinforce the importance of inflammation in its pathophysiology. The longer hospital stay in these patients also contributes to the importance of atrial fibrillation prevention and risk stratification. PMID- 28889701 TI - [Surgical treatment of type A acute aortic syndrome: a single-center 10-year experience]. AB - INTRODUCTION: Acute Aortic Syndrome (AAS) affecting the ascending aorta still represents a challenge to cardiologists and cardiothoracic surgeons, being associated with high mortality even with early surgery. AIMS: To describe the immediate post-operative results and long-term survival after the surgical treatment of type A AAS. Secondary outcomes include hospital mortality, length of hospital stay and long-term mortality. METHODS: Retrospective longitudinal study, including all patients who underwent ascending aorta replacement for surgical treatment of type A AAS, in a tertiary center, between January 2005 and December 2015. Preoperative, surgical and postoperative characteristics were evaluated. In addition to the descriptive analysis, the impact of some variables on long-term mortality, hospital mortality and length of hospital stay was evaluated. RESULTS: We included 78 patients, the most common type of AAS was aortic dissection (92,3%). 6 patients died at operation room and 12 in the immediate post-operative period, completing 23,1% of in-hospital mortality. Considering 60 survivors who were followed by a mean time of 5 years, maximum of 12, we registered a cumulative survival at 1, 3, 5, 10-years of 93,5%, 84,3%, 77% and 69,5%, respectively. Marfan Syndrome was found to be a risk factor of higher long term mortality (HR: 3,85, p=0,045). CONCLUSION: Our study confirms previous observations associating AAS type A with high rates of morbidity and mortality, despite significant advances in diagnostic and therapeutic techniques. PMID- 28889702 TI - [Video-assisted thoracic sympathectomy - the results from a center outpatient surgery program]. AB - BACKGROUND: The outpatient surgery program from our department has started in 2014 to improve patient access to surgery and to reduce the surgical waitlist. Focused on the thoracic surgery, the most common intervention is the surgical treatment of primary hyperhidrosis by thoracic sympathectomy by video-assisted thoracoscopic surgery (VATS). It is performed according to the patient's symptoms, with section or application of surgical clips between R2-R5. MATERIALS AND METHODS: Retrospective study including all the patients submitted to thoracic sympathectomy by video- -assisted thoracoscopy surgery from our department's outpatient surgery program from January 2014 to January 2016. RESULTS: In our outpatient program we performed 198 thoracic sympathectomy by VATS. The mean age of the patients was 32,8 years old. 63,6% of the patients were females and 36.4% were males. From the 198 endoscopic thoracic sympathectomy performed, 181 (91,4%) were performed bilatellary with section between R3-R5, 12 (6,1%) were performed with the application of surgical clips in R2-R4 and 3 (1.5%) could not be performed due to the presence of pleuropulmonary adhesions. One of the patients was re-operated due to recurrent symptoms and another patients had surgery to remove the surgical clips (bilaterally in R2) due to exaggerated abdominal compensatory hyperhidrosis. Three patients had pneumothorax. CONCLUSION: The surgical treatment of primary hyperhidrosis was the most frequent procedure in our outpatient surgery program. The procedure without the use of a thoracic drainage allowed its inclusion in the outpatient surgery program. Excluding 3 patients, all the patients were discharged within 12 hours after the surgery. The good results and the reduction of the surgical waitlist encourage the cardiothoracic outpatient surgery program. PMID- 28889703 TI - A rare cause of hoarseness in a young patient. AB - Syphilis is nowadays a rare cause of aortic aneurysms in developed countries. Commonly saccular, syphilitic aneurysms are frequently single, involving the ascending aorta and arch and are frequently asymptomatic unless large enough to cause symptoms due to compression of surrounding structures or death from rupture. In this paper, the authors present the case of a 32-years old patient presenting with progressive weakness, anorexia, weight loss and hoarseness, who was diagnosed with a multiple saccular aortic aneurysms, which were syphilitic in nature. The patient underwent surgery for a hemiarch replacement after receiving a cycle of antibiotics and had an uneventful recovery. This case illustrates that, although rare, syphilis must be recognized as a potential source of aneurismal disease as it warrants antibiotic therapy and screening of involvement of other organs. PMID- 28889704 TI - [The question of the biological behavior of EVAR: thirty years later, history repeats itself]. PMID- 28889705 TI - Endoleak type II post-EVAR - predictive factors and therapeutic intervention - single centre experience in 100 EVAR procedures. AB - INTRODUCTION: Endovascular aortic repair (EVAR) has significantly altered the therapeutic strategy for abdominal aortic aneurysm (AAA), due to less invasiveness and lower perioperative morbi-mortality. However, specific complications such as persistent type 2 endoleak (pT2E, present > 6 months after EVAR) have been associated with adverse outcomes. However conflicting results from heterogeneous studies, failed to support an optimal threshold for intervention. The purpose of this study was to identify predictive factors associated with pT2E. METHODS: The clinical data of the last 100 patients admitted for EVAR in our hospital until April 2016 were retrospec- tively reviewed. Statistical analysis was performed using SPSS V.22. RESULTS: We analyzed 100 cases of EVAR, performed with a branched stentgraft for AAA or aorto iliac aneurysms. Most cases (n=83) were performed electively but 17 were performed for ruptured AAA. No pre-operative inferior mesen- teric artery (IMA) coil embolization was performed. A pT2E was observed by Computed Tomography Angiography (CTA) in 21 cases (21%). Univariate analysis of risk factors for pT2E revealed that the number of patent lumbar arteries, patent IMA, platelet antiaggregants, absence of thoracic aortic aneurysm, and ruptured AAA were risk factors for pT2E (p<0.05). Binary logistic regression concluded platelet antiaggregants and increasing number of patent lumbars were independent risk factors for pT2E (p<0.05). DISCUSSION: Recently, pT2E that persists over a long period of time following EVAR has been reported to be involved in aneurysm sac growth, open conversion and rupture. Identification of pT2E predictive factors is crucial to prevent compli- cations and to consider measures such as pre-operative IMA coil embolization. We identified the number of patent lumbar arteries, the presence of patent IMA, platelet antiaggregants, absence of thoracic aortic aneurysm and ruptured AAA as sta- tistically significant risk factors for pT2E (p<0.05). PMID- 28889706 TI - [Endovascular Revascularization for Diabetic Foot Ulcer - Experience from a Dedicated Clinic]. AB - OBJECTIVES: We aimed to assess the outcome of endovascular revascularization in Diabetic patients with Fontaine stage IV chronic ischaemia, at our Diabetic Foot Clinic. Primary outcomes were ulcer healing, major amputation and limb salvage. METHODS: Retrospective single center analysis of patients treated between January 2009 and May 2015. Time-dependent event rates were estimated by the Kaplan-Meier method. The differences between groups were evaluated with the chi-square test. A P value below 0,05 was considered statistically significant. RESULTS: There were 106 limbs (93 patients) revascularized during the study. The average age was 71 years, and PEDIS 3 or 4 infection was present in 45.3% on admission. 56.6% were treated for femoropopliteal injurie only, 17% infrapopliteal, and 26.4% for both levels. Technical success was achieved in 77.4%, and haemodynamic success in 58.3%. Ulcer healing was attained in 53.8%, with an average healing time of 8.4 months. The major amputation rate was 7.5%, with a limb salvage rate of 90.4% at 6, 12 and 24 months. Chronic pulmo- nary disease decreased the likelihood of healing (p=0,012). Restenosis was more likely to occur in patients with nephropathy (p=0,008) or insulin-treated diabetes (p=0,033). CONCLUSIONS: Dedicated multidisciplinary teams are key to successful treatment in diabetic foot disease. The good results achieved in our series arise from best medical treatment combined with timely revascularization in those ischemic. PMID- 28889707 TI - [Causes of death after revascularization of the lower limbs through surgery and angioplasty in the State of Rio de Janeiro, Brazil, between 2006 and 2011]. AB - INTRODUCTION: The underlying cause of death is the single diagnosis to which the cause of death is attributed. Other diagnostic codes written in the death certificate are the multiple causes. The study of the multiple causes allows the identification of the diseases present in the death. OBJECTIVE: To analyze the underlying and multiple causes of death after revascularization of the lower limbs using open surgery or angioplasty. METHODS: Two databases of the Public Health System of Rio de Janeiro were used: Authorizations for Hospitalizations 2006/10, and Statements of Deaths 2006/11. Probabilistic linkage of records between databases was performed using the Stata program. RESULTS: The most frequent underlying and multiple cause of death was Diabetes mellitus. The second was the systemic atherosclerotic disease represented by peripheral arterial disease, ischemic coronary disease and cerebrovascular disease. The analysis of multiple causes revealed septicemia, iatrogenic and complications after surgery, as well as renal failure after angio- plasty. Patients submitted to lower limb revascularization procedures had a higher overall mortality rate than the population of the State of Rio de Janeiro over 50 years of age, for all causes and specific ones. CONCLUSION: The period of highest risk of death was up to 30 days after hospital discharge, demonstrating the need to improve medical and hospital care before, during and after procedures. The study of multiple causes revealed adverse events and complications that were not chosen as the underlying cause. PMID- 28889708 TI - Outcomes in carotid endarterectomy in a portuguese tertiary care hospital. AB - BACKGROUND: Indication for CAE is a balance of long-term benefit of stroke reduction compared with the best medical treatment. The purpose of this study is to describe the postoperative complications in patients submitted to CEA between Octo- ber 2015 and July 2016. METHODS: A retrospective study was conducted in patients scheduled for CEA between October 2015 and July 2016. This study involved 89 patients. Data were obtained from electronic clinical charts. EXCLUSION CRITERIA: simultaneous CEA and cardiac surgery. All analysis was calculated with software SPSS. RESULTS: We had registered 57 complications in the 89 patients. 14% were neurological complications. 82% were non- -neurologic complications. 2 patients died. Perioperative stroke and cervical hematoma were statistically more frequent compa- red to the literature. CONCLUSION: 57 complications were observed, most were non-neurological. Comparing to the literature, perioperative stroke and cervical hematoma occurrence was higher. PMID- 28889709 TI - [Deep vein thrombosis in the pediatric population - a rare entity of uncertain prognosis]. AB - Deep vein thrombosis, whose prevalence remains unknown in the pediatric population, is an increasingly common diag- nosis in this age group. This increased incidence makes the post-thrombotic syndrome a likely long-term complication, so there is a critical need to establish high quality evidence over its suitable approach in this population. We present two cases of deep vein thrombosis in children and their management in a hospital of the northern region of Portugal, reviewing the literature on this under researched subject. In conclusion, further investigation is needed to assess the incidence, the prevalence, the predictors and the safety and efficacy of therapies for the prevention and appropriate treatment of deep vein thrombosis in children and eventual post- -thrombotic syndrome. PMID- 28889710 TI - Acute focal dissection of Kommerell's diverticulum. PMID- 28889711 TI - Renal artery aneurysm in a young patient with a solitary kidney. PMID- 28889712 TI - Mini-invasive aortic valve replacement: How we do it. PMID- 28889713 TI - [Cardiac Surgery - a New Paradigm]. PMID- 28889714 TI - [Clinical Study of HoLEP for the Patients with Benign Prostatic Hyperplasia who are on Oral Antithrombotics]. AB - Recently, holmium laserenucleation of the prostate (HoLEP) was associated with less bleeding compared with transurethral resection of prostate. Since 2012, we have performed HoLEP for benign prostatic hyperplasia (BPH) under continuous oral antithrombotics (OA). Between October 2004 and March 2015, 54 patients with BPH underwent HoLEP while on OA at our hospital. Eight patients underwent HoLEP without OA cessation and 46 patients with temporary OA cessation. No significant between-group difference was observed in age, prostate volume, transitional zone prostate volume, operation time, resection weight, resection weight per minute, urethral catheter duration, Hb decrease on day 1 post- HoLEP, hospital stay after HoLEP, bleeding intraoperative rate, bleeding rate after HoLEP and transfusion rate. None presented embolic complications. HoLEP was safe without OA cessation. However, highvolume BPH patients without OA cessation required intraoperative transfusion. Thus, high-volume BPH patients may benefit from OA cessation. PMID- 28889715 TI - [Simultaneous Hepatorenal Transplantation from a Brain-Dead Donor for Graft Dysfunction and Renal Insufficiency in a Liver Transplant Recipient : A Case Report]. AB - We report a case of lethal hepatorenal insufficiency in a 52-year-old man who received successful simultaneous hepatorenal transplantation from a deceased donor. The patient had undergone live-donor liver transplantation for type-C hepatitis and liver cirrhosis 11 years before he developed graft liver dysfunction due to recurrent viral hepatitis and cirrhosis. At that instance, he also developed end-stage renal dysfunction due to calcineurin inhibitor nephropathy and hepatorenal syndrome. Although he needed three open hemostases and abundant blood transfusion, he was withdrawn from continuous hemodiafiltration on the 55th day and discharged from the hospital on the 272nd day postoperatively. Simultaneous hepatorenal transplantation was reported to be associated with more favorable outcomes of graft function, lower rejection rates, but higher perioperative complication rates compared with liver transplantation alone in patients on hemodialysis. Particularly, close attention should be paid for hemostasis since patients have a hemorrhagic tendency until the recovery of graft liver function. PMID- 28889716 TI - [A Case of Primary Sigmoid Colon Lymphoma Presenting with Sigmoidovesical Fistula in a Patient with a Long History of Ulcerative Colitis]. AB - A 73-year-old male patient with a 16-year history of ulcerative colitis presented to our hospital with a history of pneumaturia and fever. Cystoscopy and a computed tomography scan showed sigmoidovesical fistula. Colonoscopy showed a necrotic tumor along with sigmoidovesical fistula. A biopsy was not sufficient to make a definitive diagnosis of the tumor. Total colectomy with ileostomy and partial cystectomy were performed. A pathological examination showed diffuse large B-cell lymphoma of the sigmoid colon. On postoperative day 35, delayed dehiscence of the bladder wall was detected and a biopsy of the bladder wall showed lymphoma. Standard systemic chemotherapy (R-THP-COP) was administered and the defect of the bladder was closed. Three years and 2 months postoperatively, the patient has no local recurrence or distant metastasis. PMID- 28889717 TI - [A Case of Primary Schwannoma of the Urinary Bladder]. AB - A 68-year-old woman presented with a bladder tumor. She was asymptomatic, and the tumor was incidentally detected with radiological imaging performed during treatment of cervical cancer. Magnetic resonance imaging and computed tomography revealed a solitary submucosal tumor located in the anterior wall of the urinary bladder, with homogeneous contrast enhancement. Cystoscopy showed a submucosal tumor covered by normal mucosa. A paraganglioma was considered in the differential diagnosis, but symptoms suggesting hypercatecholaminemia were not apparent. Moreover, she did not have a family history or symptoms associated with neurofibromatosis-1 (NF-1). She underwent partial cystectomy with a preliminary diagnosis of submucosal bladder tumor. Histopathological diagnosis confirmed a schwannoma arising from the bladder wall. She was followed up without intravesical recurrence or metastases for 6 months. In the literature, only 12 cases of bladder schwannoma have been reported. There was no reported family history or symptoms associated with NF-1 in any of the cases. Although the number of cases is limited, literature review showed a favorable prognosis for bladder schwannoma with local tumor resection in patients without NF-1. PMID- 28889718 TI - [Reactive Arthritis during the Second Course of Intravesical BCG Therapy Requiring Administration of Methotrexate : A Case Report]. AB - Reactive arthritis, formerly called Reiter's syndrome, is one of the rare complications following intravesical instillation of Bacillus Calmette Guerin (BCG). A 58-year-old man was admitted to our hospital because of fever, hyperemia of conjunctiva, and arthralgia following the second course of intravesical instillation of BCG in the treatment of pT1 and pTis bladder cancer. We diagnosed him with reactive arthritis due to the clinical course. Reactive arthritis is usually well controlled with the discontinuation of instillation and administration of nonsteroidal anti-inflammatory drugs (NSAIDs). However, his symptoms were not improved after administration of NSAIDs, prednisolone, and isoniazid. Following initiation of methotrexate, however, there was remission. He has been free from recurrence of bladder cancer for 20 months. PMID- 28889719 TI - [Two Cases of Urethral Clear Cell Adenocarcinoma with Suspected Recurrence of Uterine Cancer]. AB - Herein, we report two cases of urethral clear cell carcinoma in two patients who had previously undergone radical hysterectomyfor utetine cancer. Case 1 presented with bloodyvaginal discharge and case 2 presented with acute urinaryretention. Magnetic resonance imaging revealed a periurethral tumor in both cases. Both cases were suspected to be recurrence at first. However, pathological findings of the transurethral resection-biopsyshowed clear cell adenocarcinoma in both cases. Subsequentlyradical cystourethrectomy and pelvic lymphadenectomy were performed in both cases. Surgical findings showed tumor invasion of the vaginal muscularis in case 1 and invasion of the anterior wall of the vagina and bladder neck in case 2. Although adjuvant postoperative therapywas not performed, there has been no evidence of recurrence to date. PMID- 28889720 TI - Presynaptic Dopaminergic Degeneration in a Patient with Beta-Propeller Protein Associated Neurodegeneration Documented by Dopamine Transporter Positron Emission Tomography Images: A Case Report. PMID- 28889721 TI - Spinal Myoclonus Responding to Continuous Intrathecal Morphine Pump. AB - Spinal myoclonus is a sudden, brief, and involuntary movement of segmental or propriospinal muscle groups. Spinal myoclonus has occasionally been reported in patients undergoing opioid therapy, but the pathophysiology of opioid-induced myoclonus has not been elucidated yet. Here, we present two patients with spinal segmental myoclonus secondary to ischemic and radiation myelopathy. Conventional medications did not help treat persistent myoclonus in both legs. Continuous intrathecal morphine infusion was implanted for pain control in one patient, which relieved spinal myoclonus entirely. This experience led to the application of this method with a second patient, leading to the same gratifying result. Spinal myoclonus reemerged as soon as the morphine pumps were off, which confirmed the therapeutic role of opioids. In contrast to the opioid-induced myoclonus, these cases show a benefit of opioids on spinal myoclonus, which could be explained by synaptic reorganization after pathologic insults in the spinal cord. PMID- 28889722 TI - Effects of central fibroblast growth factor 21 (FGF21) in energy balance. AB - Fibroblast growth factor 21 (FGF21) is known as a major metabolic regulator of glucose and lipid homeostasis. Continuous intracerebroventricular (i.c.v.) administration of FGF21 was found to modulate feeding and energy expenditure in rats with diet-induced obesity, suggesting a central effect by the peptide. In this context, in the present work, we studied the effects of a single central FGF21 administration (0.5-5 ug) on feeding and energy expenditure by evaluating locomotor activity, interscapular brown adipose tissue (BAT) weight, gene expression of uncoupling protein-1 (UCP-1) in BAT and plasma norepinephrine (NE) levels in Sprague-Dawley fed rats. In addition, we evaluated the effects of FGF21 on orexigenic [agouti-related peptide (AgRP) and neuropeptide Y (NPY)] and anorexigenic [cocaine and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC)] peptides, in the hypothalamus, and dopamine (DA) and serotonin (5-hydroxytriptamine, 5-HT) levels in nucleus accumbens (NAc). We confirmed that central FGF21 administration induced a significant increase in food intake, possibly mediated by increased NPY and AgRP, and decreased POMC and CART gene expression. Moreover, FGF21 could modulate the motivational aspects of feeding, possibly through stimulated NAc DA levels. On the other hand, our findings of decreased locomotor activity, BAT weight, UCP-1 gene expression and plasma NE levels support a role for FGF21 in decreasing energy expenditure. PMID- 28889723 TI - Expression of C-myc and beta-catenin and their correlation in triple negative breast cancer. AB - BACKGROUND: The present study was planned to study the expression of C-myc and beta-catenin in triple negative breast cancer (TNBC) tissue. Furthermore, their relations to clinical features of the tumor and the survival prognosis were also studied. Additionally, correlation was evaluated between the expression of C-myc and beta-catenin to provide the theoretical basis for the targeted therapy of TNBC. METHODS: Sixty cases of patients diagnosed with TNBC for the first time were selected for the study. The immumo-histochemical staining was employed to detect the positive expression rates of C-myc and beta-catenin in cancer tissues and normal mammary tissues 3 cm away from the carcinoma. Fluorescence in situ hybridization (FISH) was used to test the gene amplification of C-myc in order to analyze the relation between C-myc and the protein expression of beta-catenin. Further, kept the median follow-up time to 25.0 months in order to compare the survival prognosis. RESULTS: The positive expression rates of C-myc and beta catenin in cancer tissues were significantly higher than those in precancerous normal tissues (P<0.05). Furthermore, the expression rates were related with the diameter of tumor, clinical staging, pathological grading and lymphatic metastasis (P<0.5). There were 33 cases that exhibited an increase in C-myc gene copy number and the gene amplification was observed to be 55% in total. On the other hand, patients with positive expression of C-myc and beta-catenin protein exhibited a shortened disease-free survival without tumor with an increasing recurrence rate and lower survival rate (P<0.05). CONCLUSIONS: The present study concludes that the positive expression of C-myc and beta-catenin in TNBC tissue might be closely correlated with clinical features of cancer and the survival prognosis. PMID- 28889724 TI - Effects of the combined administration of entecavir and adefovir dipivoxil to improve hepatic fibrosis in hepatitis B patients with interferon resistance. AB - BACKGROUND: To observe the effect of the combined administration of entecavir and adefovir dipivoxil to improve hepatic fibrosis in hepatitis B patients with interferon resistance. METHODS: This study comprised 90 hepatitis B patients with hepatic fibrosis and interferon (IFN) resistance who were admitted in the hospital's department of infectious disease for diagnosis and treatment between January 2013 and September 2015. They were randomly divided into two groups in accordance with the random number table: the combination treatment group (N.=45) and the entecavir group (N.=45). They were observed for any variations in the indexes of liver function and fibrosis, as well as the Model for end-stage liver disease (MELD) scores, before and after treatment. RESULTS: After treatment, the levels of the indexes in both groups (the combination treatment group vs. the entecavir group) were as follows: bilirubin (67.5+/-7.7 vs. 82.4+/-13.5 MUmol/L); International Normalized Ratio (INR) (1.21+/-0.8 vs. 1.14+/-0.7); creatinine (147.3+/-12.4 vs. 287.4+/-21.6 mg/dL); GGT (67.4+/-23.2 vs. 88.4+/-23.7 U/L); and ALT (63.4+/-40.8 vs. 96.5+/-23.5 U/L). In comparison of the indexes of hepatic fibrosis between the two groups, we found the following differences: PCIII (67.5+/-7.7 vs. 82.4+/-13.5 MUg/L); IV-C (61.3+/-18.7 vs. 74.5+/-17.9 MUg/L); HA (147.3+/-12.4 vs. 87.4+/-31.6 MUg/L); and LN (88.7+/-13.2 vs 102.5+/-23.4 MUg/L). The results showed that the differences in comparison of the indexes before and after the treatment were statistically significant (P<0.05). After treatment, the MELD score of patients in the combination treatment group was significantly lower than that in the entecavir group (18.7+/-3.2 vs. 22.5+/-3.4), with a statistically significant difference (P<0.05). CONCLUSIONS: In the chronic hepatitis B patients with interferon resistance, the combined administration of entecavir and adefovir dipivoxil can significantly improve liver function, hepatic fibrosis and MELD scores. The results highlight the need to promote the benefits of this drug combination in helping chronic hepatitis B patients with interferon resistance, and to promote its application in clinical practices. PMID- 28889725 TI - Oncogene miR-106a promotes proliferation and metastasis of prostate cancer cells by directly targeting PTEN in vivo and in vitro. AB - BACKGROUND: Prostate cancer (PCa) is the second leading contributor to male malignancy-associated death in developed countries. The study aimed to evaluate the effects of miR-106a on prostate cancer cells and the underlying molecular mechanism. METHODS: The cell proliferation was detected using MTT assay and colony formation, and cells migration and invasion were also analyzed. Luciferase reporter assay was carried out to explore the correlation between miR-106a and PTEN. Besides, reverse transcriptase-polymerase chain reaction and western blot were carried out to measure the mRNA and protein levels in prostate tissues and PCa cells. Immunocytochemical staining was performed to detect the PTEN level in PCa tissues. RESULTS: MiR-106a level was dramatically increased in the PCa tissues and PCa cell lines. The overexpression of miR-106a significantly promoted the proliferation, migration and invasion of PCa cells. Besides, we confirmed that PTEN was regulated by miR-106a expression and was a direct target of miR 106a. Most importantly, we further found that miR-106a could promote the PCa cells xenograft growth in the nude mice by targeting PTEN, which was significantly downregulated in PCa tissues and cell lines and was closely related with PCa metastasis. CONCLUSIONS: MiR-106a as an oncogene could promote proliferation and metastasis of prostate cancer cells by directly targeting PTEN in vivo and in vitro. PMID- 28889726 TI - The significance of blastocyst culture for discarded embryos in the treatment period of in-vitro fertilization and embryo transfer without available embryos. PMID- 28889728 TI - Role and function of exosomal miR-9-3p in hepatocellular carcinoma. PMID- 28889727 TI - Multidisciplinary treatment of colorectal liver metastases. AB - INTRODUCTION: The therapy of patients with colorectal liver metastases (CRLM) has undergone significant changes. Extended survival has been observed to be associated with adoption of hepatic resection and improved chemotherapy. EVIDENCE ACQUISITION: This review summarizes standards, developments and controversies on the management of these patients. Literature search was performed with focus on work published within the last ten years. EVIDENCE SYNTHESIS: Patients with CRLM should undergo surgery whenever possible with careful and experienced patient selection as hepatic resection offers the best long-term prognosis. The multidisciplinary approach has markedly evolved and has increased the number of patients in whom curative-intended surgery is possible. Patients with resectable metastases can undergo upfront surgery or may receive perioperative chemotherapy in selected cases, a decision which is under debate and remains individual. Patients with non-resectable metastases that may become resectable upon conversion treatment should receive polychemotherapy with or without local ablative therapy as pretreatment with the main goal of achieving resectability. In patients with synchronous CRLM, the optimal sequence of treatment remains unclear. Depending on the hepatic tumor burden and its dynamics as well as the type and stage of the primary tumor, simultaneous resection or either the sequential "bowel-first" or reversed "liver-first" approach represent suitable options to achieve complete tumor clearance. CONCLUSIONS: The improvements in the management of CRLM due to multidisciplinary treatment and novel developments are a great example of successfully pushing the boundaries of cure in metastatic cancer. Surgery aiming at complete tumor clearance represents the central instrument to achieve long-term survival. PMID- 28889729 TI - Post-transcriptional regulation of cytokine in the context of renal inflammation. AB - Mechanisms that control mammalian gene expression, notably mRNA stability and translation, have major functions in the modulation of the cellular response to internal and external stimuli. Altered posttranscriptional regulation of gene expression has been associated with many diseases. Such types of deregulation have also recently been noted on the inflammatory cytokines pertinent to kidney inflammation. In this article, we summarize briefly the recent knowledge obtained from both human and experimental systems on the details of posttranscriptional regulation of gene expression related to the control of mRNA stability and discuss their relevance in regulating cytokine expression linked to the inflammatory processes in kidney. Despite the fact that not many such examples in human kidney diseases have been uncovered with great mechanistic details, studies in experimental models suggest that the mRNA stability control is more than meets the eye. Therapeutic potentials aiming at regulating cytokine expression via posttranscriptional modification of mRNA half-life are thus discussed. PMID- 28889730 TI - Anti-inflammatory and immunomodulatory activities of Inula cappa roots (Compositae). AB - Background The medicinal properties of Inula cappa, a perennial shrub, are ascribed to its roots. In this article, we study the anti-inflammatory and immunomodulatory activities of I. cappa root extracts based on its utilization in traditional medicine-treatment of rheumatoid arthritis, menoxenia, fever, jaundice and many others. Methods Anti-inflammatory and immunomodulatory activities of I. cappa extracts were studied. The anti-inflammatory activity was determined by carrageenan-induced rat paw edema and cotton pellet-induced granulation method while the immunomodulatory activity was estimated by phagocytic assay method, hemagglutinating antibody (HA) titer assay, delayed-type hypersensitivity assay method, plaque forming cell assay and determination of immunoprophylatic activity. Results The methanolic extract showed maximum reduction in the rat paw edema and showed significant inhibition of the cotton pellet-induced granulomas in rats. The methanolic extract also showed potential immunomodulatory activity in all the assays performed. Two sesquiterpenes, isoalantolactone and germacranolide were also isolated from the methanolic extract. Conclusions The present study supports the evidence that the roots of I. cappa can be used as a potent anti-inflammatory and immunomodulatory agent. PMID- 28889731 TI - Comparative evaluation of hypoglycemic and hypolipidemic activity of various extract of Anogeissus latifolia bark in streptozotocin-induced diabetic rats. AB - Background Anogeissus latifolia Wall. (A. latifolia) bark has been traditionally used in the treatment of various diseases which includes diabetes and general debility. The present study was aimed to investigate the comparative hypoglycemic and hypolipidemic activity of various extracts of A. latifolia bark in streptozotocin-induced type 1 diabetic rats. Methods Acute toxicity was carried out at 2 g/kg dose of petroleum ether extract of A. latifolia bark (PEALB), chloroform extract of A. latifolia bark (CEALB) and methanol extract of A. latifolia bark (MEALB) in rats. Diabetes was induced by streptozotocin (STZ, 60 mg/kg, i.p.) and it was confirmed at 72 h. Diabetic rats received above extracts at 100 and 200 mg/kg doses for 28 days. Body weight and blood glucose level were determined at every week after the treatment schedule. Serum biochemical parameters and lipid profile levels were estimated at the end of the study. Results PEALB, CEALB and MEALB were non-toxic and no death was observed at 2 g/kg dose. Administration of MEALB at 100 and 200 mg/kg showed significant (p< 0.01, p< 0.05) improvement in body weight and reduction in blood glucose at third and fourth week of treatment. Altered serum biochemical parameters and lipid profiles level were brought to near normal level significantly (p<0.001) compared to diabetic control rats after the administration of both doses of MEALB. However, PEALB and CEALB did not exhibit significant hypoglycemic and hypolipidemic activity. Conclusions Our findings revealed that long-term (28 days) treatment of MEALB possesses significant hypoglycemic and hypolipidemic activity compared to PEALB and CEALB in type 1 diabetic rats and given evidence to the traditional use of A. latifolia bark in diabetes. PMID- 28889732 TI - Effects of water extract of Curcuma longa (L.) roots on immunity and telomerase function. AB - Background Immunity and Longevity Methods A water extract of Curcuma longa (L.) [vern. Turmeric] roots (TurmericImmuneTM) standardized for a minimum 20 % of turmeric polysaccharides ukonan A, B, C and D was evaluated for its biological properties in in vitro tissue culture studies. Results The water extract of turmeric (TurP) exhibited induced-nitric oxide (NO) production in RAW264.7 macrophages. These results suggested the immunomodulatory effects of TurP. In addition, the polysaccharides up-regulated function of telomerase reverse transcriptase (TERT) equally to the phenolic compound from turmeric, curcumin. Conclusions The ukonan family of polysaccharides may assist in promoting cellular immune responses, tissue repair and lifespan by enhancing immune response and telomere function. PMID- 28889733 TI - Garcinia kola seeds may prevent cognitive and motor dysfunctions in a type 1 diabetes mellitus rat model partly by mitigating neuroinflammation. AB - Background We reported recently that extracts of seeds of Garcinia kola, a plant with established hypoglycemic properties, prevented the loss of inflammation sensible neuronal populations like Purkinje cells in a rat model of type 1 diabetes mellitus (T1DM). Here, we assessed G. kola extract ability to prevent the early cognitive and motor dysfunctions observed in this model. Methods Rats made diabetic by single injection of streptozotocin were treated daily with either vehicle solution (diabetic control group), insulin, or G. kola extract from the first to the 6th week post-injection. Then, cognitive and motor functions were assessed using holeboard and vertical pole behavioral tests, and animals were sacrificed. Brains were dissected out, cut, and processed for Nissl staining and immunohistochemistry. Results Hyperglycemia (209.26 %), body weight loss (-12.37 %), and T1DM-like cognitive and motor dysfunctions revealed behavioral tests in diabetic control animals were not observed in insulin and extract-treated animals. Similar, expressions of inflammation markers tumor necrosis factor (TNF), iba1 (CD68), and Glial fibrillary acidic protein (GFAP), as well as decreases of neuronal density in regions involved in cognitive and motor functions (-49.56 % motor cortex, -33.24 % medial septal nucleus, -41.8 % / 37.34 % cerebellar Purkinje /granular cell layers) were observed in diabetic controls but not in animals treated with insulin or G. kola. Conclusions Our results indicate that T1DM-like functional alterations are mediated, at least partly, by neuroinflammation and neuronal loss in this model. The prevention of the development of such alterations by early treatment with G. kola confirms the neuroprotective properties of the plant and warrant further mechanistic studies, considering the potential for human disease. PMID- 28889734 TI - Crocus sativus, Serenoa repens and Pinus massoniana extracts modulate inflammatory response in isolated rat prostate challenged with LPS. AB - Prostatitis is a common prostate disease that could be promoted by bacterial or non-bacterial infectious agents. In addition, inflammatory pathways involved in prostatitis have been increasingly studied, and herbal extracts endowed with anti inflammatory effects are under investigation, individually or in combination, for their efficacy in alleviating the burden of inflammation, with possible improvements in symptoms. Serenoa repens (Serenoa), in combination with Crocus sativus (Crocus) and Pinus massoniana (Pinus), has previously shown to improve sexual function and limit urinary symptoms in patients suffering from concomitant erectile dysfunction and lower urinary tract symptoms. In this context, the aim of the present study is to evaluate the efficacy of Serenoa, Crocus and Pinus extracts, either alone or in combination, on immortalized prostate cells (PC3) and in an experimental model of bacterial prostatitis constituted by ex vivo prostate specimens challenged with lipopolysaccharide (LPS). We found that the tested extracts were able to reduce ROS production by PC3 cells and NFkB and PGE2 activity in prostate specimens challenged with LPS. In addition, the pharmacological association of the extracts displayed synergistic effects indicating a rational use of the mixture of the tested extracts as a novel anti oxidant and anti-inflammatory formulation in bacterial prostatitis. Finally, we performed analytical and in vitro evaluation to better characterize the phytochemical profile and the mechanism of action of selected secondary metabolites. PMID- 28889735 TI - Small-Molecule Potentiators for Conventional Antibiotics against Staphylococcus aureus. AB - Antimicrobial resistance constitutes a global health problem, while the discovery and development of novel antibiotics is stagnating. Methicillin-resistant Staphylococcus aureus, responsible for the establishment of recalcitrant, biofilm related infections, is a well-known and notorious example of a highly resistant micro-organism. Since resistance development is unavoidable with conventional antibiotics that target bacterial viability, it is vital to develop alternative treatment options on top. Strategies aimed at more subtle manipulation of bacterial behavior have recently attracted attention. Here, we provide a literature overview of several small-molecule potentiators for antibiotics, identified for the treatment of Staphylococcus aureus infection. Typically, these potentiators are not bactericidal by themselves and function by reversing resistance mechanisms, by attenuating Staphylococcus aureus virulence, and/or by interfering with quorum sensing. PMID- 28889736 TI - Biosensing Strategy for Simultaneous and Accurate Quantitative Analysis of Mycotoxins in Food Samples Using Unmodified Graphene Micromotors. AB - A high-performance graphene-based micromotor strategy for simultaneous, fast, and reliable assessment of two highly concerning mycotoxins (fumonisin B1 (FB1) and ocratoxin A (OTA)) has successfully been developed. The assay principle is based on the selective recognition from aptamers to the target mycotoxins and further "on-the-move" fluorescence quenching of the free aptamer in the outer layer of unmodified reduced graphene (rGO; sensing layer) micromotors. Template-prepared rGO/platinum nanoparticles (PtNPs) tubular micromotors were synthesized rapidly and inexpensively by the direct electrodeposition within the conical pores of a polycarbonate template membrane. The new wash-free approach offers using just 1 MUL of sample, a simultaneous and rapid "on-the-fly" detection (2 min) with high sensitivity (limits of detection of 7 and 0.4 ng/mL for OTA and FB1, respectively), and high selectivity. Remarkable accuracy (Er < 5%) during the mycotoxin determination in certified reference material as well as excellent quantitative recoveries (96-98%) during the analysis of food samples were also obtained. The excellent results obtained allow envisioning an exciting future for the development of novel applications of catalytic micromotors in unexplored fields such as food safety diagnosis. PMID- 28889737 TI - Selective and Real-Time Detection of Nitric Oxide by a Two-Photon Fluorescent Probe in Live Cells and Tissue Slices. AB - Nitric oxide (NO) is an important signaling molecule involved in many physiological and pathological processes. To understand these NO-mediated processes, it is a key to develop rapid and specific detection methods for NO. In the past 2 decades, numerous excellent fluorescent probes for NO have been designed; however, it still remains limitations such as slow response, low selectivity, and short excitation wavelength (<600 nm). In this Article, a two photon fluorescent probe, NO-QA5, has been developed with 3-dimethylaminophenyl linking at the 6-position of 5-aminoquinoline as both the active site and prefluorophore for detection of NO. The nonfluorescent NO-QA5 can fast react with NO via a diazonium intermediate to generate two azoic regioisomers, one of which exhibits intramolecular charge transfer (ICT) emission, and two-photon absorption behavior (deltaPhi = 57 GM), giving a turn-on fluorescence rapid response. The sensing reaction is pH-insensitive in the range of 6-11 and highly selective and well sensitive (LOD = 15 nM), possible undergoing the same intermediate diazonium with the reaction under diazotization condition (NaNO2/HCl). Also, as a nitrite fluorescent probe NO-QA5 exhibits highly sensitive (LOD = 7 nM). Therefore, NO QA5 can serve as a dual functional fluorescent probe for NO and NO2-. Furthermore, NO-QA5 as a specific imaging agent has been demonstrated by achieving both exogenous and endogenous detections of NO in living cells under both one- and two-photon excitation and high resolution in tissue slices under two-photon excitation. PMID- 28889738 TI - Introduction to the Highlights of the 26th ASIC Conference. AB - The 26th International Conference on Coffee Sciences (ASIC 2016) that was held in November 13-19, 2016 in Kunming, China, has marked the 50th anniversary of the creation of the Association for Science and Information on Coffee (ASIC). The meeting in China was well-attended by over 400 participants from all over the world and allowed for fruitful exchanges among participants from all horizons of coffee science. PMID- 28889739 TI - Photoelectron Spectroscopy and Density Functional Theory Studies of Iron Sulfur (FeS)m- (m = 2-8) Cluster Anions: Coexisting Multiple Spin States. AB - Iron sulfur cluster anions (FeS)m- (m = 2-8) are studied by photoelectron spectroscopy (PES) at 3.492 eV (355 nm) and 4.661 eV (266 nm) photon energies, and by density functional theory (DFT) calculations. The most probable structures and ground state spin multiplicities for (FeS)m- (m = 2-8) clusters are tentatively assigned through a comparison of their theoretical and experiment first vertical detachment energy (VDE) values. Many spin states lie within 0.5 eV of the ground spin state for the larger (FeS)m- (m >= 4) clusters. Theoretical VDEs of these low lying spin states are in good agreement with the experimental VDE values. Therefore, multiple spin states of each of these iron sulfur cluster anions probably coexist under the current experimental conditions. Such available multiple spin states must be considered when evaluating the properties and behavior of these iron sulfur clusters in real chemical and biological systems. The experimental first VDEs of (FeS)m- (m = 1-8) clusters are observed to change with the cluster size (number m). The first VDE trends noted can be related to the different properties of the highest singly occupied molecular orbitals (NBO, HSOMOs) of each cluster anion. The changing nature of the NBO/HSOMO of these (FeS)m- (m = 1-8) clusters from a p orbital on S, to a d orbital on Fe, and to an Fe-Fe bonding orbital is probably responsible for the observed increasing trend for their first VDEs with respect to m. PMID- 28889740 TI - Long-Range Orientational Self-Assembly, Spatially Controlled Deprotonation, and Off-Centered Metalation of an Expanded Porphyrin. AB - Expanded porphyrins are large-cavity macrocycles with enormous potential in coordination chemistry, anion sensing, photodynamic therapy, and optoelectronics. In the last two decades, the surface science community has assessed the physicochemical properties of tetrapyrrolic-like macrocycles. However, to date, the sublimation, self-assembly and atomistic insights of expanded porphyrins on surfaces have remained elusive. Here, we show the self-assembly on Au(111) of an expanded aza-porphyrin, namely, an "expanded hemiporphyrazine", through a unique growth mechanism based on long-range orientational self-assembly. Furthermore, a spatially controlled "writing" protocol on such self-assembled architecture is presented based on the STM tip-induced deprotonation of the inner protons of individual macrocycles. Finally, the capability of these surface-confined macrocycles to host lanthanide elements is assessed, introducing a novel off centered coordination motif. The presented findings represent a milestone in the fields of porphyrinoid chemistry and surface science, revealing a great potential for novel surface patterning, opening new avenues for molecular level information storage, and boosting the emerging field of surface-confined coordination chemistry involving f-block elements. PMID- 28889741 TI - Adaptation of Divinyl Chlorophyll a/b-Containing Cyanobacterium to Different Light Conditions: Three Strains of Prochlorococcus marinus. AB - The light-harvesting mechanisms in the three strains of Prochlorococcus marinus, CCMP1986, CCMP1375, and CCMP2773, grown under blue and red light-emitting diodes (LEDs) at two intensity levels were investigated. The blue LED was divinyl chlorophyll b (DV-Chl b) selective and the red LED was DV-Chl a selective. Under the red LED, the relative amount of DV-Chl b in CCMP1375 and CCMP2773 decreased and the relative amount of zeaxanthin increased in CCMP1375. Furthermore, the pigment composition of cells of CCMP1375 grown under red LED was remodified when they were transplanted under the blue LED. Picosecond-time-resolved fluorescence of the LED-grown Prochlorococcus was measured, and the excitation-energy-transfer efficiency between DV-Chl a did not significantly change for the different LED colors or intensities; however, a change in the pigment composition of the DV-Chl b-rich strains (CCMP1375 and CCMP2773) was observed. It appears that peripheral antenna responds to light conditions, with small modifications in the photosystems. PMID- 28889742 TI - Droplet Coalescence and Spontaneous Emulsification in the Presence of Asphaltene Adsorption. AB - In a refinery, undesired high levels of salt concentration in crude oils are reduced by the contact of water with crude oils, where an emulsion is formed. Later, the separation of the water from the desalted oil is essential for the quality of both wastewater discharge and refined oil. However, complex components of crude oils such as asphaltenes may stabilize these emulsions, causing difficulties in efficient separation. Here, we show the coalescence inhibition caused by asphaltene adsorption for both water-in-oil and oil-in-water emulsions, where the oil phase consists of a simple model of asphaltenes dissolved in toluene. We find that oil-in-water emulsions are less stable than water-in-oil emulsions by using a newly developed instrument where controlled experiments can be performed to measure the coalescence time of a single droplet against an oil/water interface as a function of asphaltene aging (associated with the adsorption process of asphaltene molecules onto the interfaces) and asphaltene concentration. Furthermore, we find that the coalescence time for water droplets exhibits a maximum because of a spontaneous emulsification at the oil/water interface that produces droplets consisting of asphaltene-laden water droplets. PMID- 28889743 TI - Prediction of Green Phosphorus with Tunable Direct Band Gap and High Mobility. AB - Black phosphorus is an emerging material in nanoelectronics and nanophotonics due to its high carrier mobility and anisotropic in-plane properties. In addition, the polymorphism of phosphorus leads to numerous searches for new allotropes that are more attractive than black phosphorus in a variety of applications. On the basis of ab initio evolutionary crystal structure search computation, we report the prediction of a phosphorus allotrope called green phosphorus (lambda-P), which exhibits direct band gaps ranging from 0.7 to 2.4 eV and strong anisotropy in optical and transport properties. Free-energy calculations show that a single layer form, termed green phosphorene, is energetically more stable than blue phosphorene, and a phase transition from black to green phosphorene can occur at temperatures above 87 K. We suggest that green phosphorene can be synthesized on corrugated metal surfaces rather than clean surfaces due to its buckled structure, providing guidance to achieving epitaxial growth. PMID- 28889744 TI - Synthesis of Bicyclic Isothiazoles through an Intramolecular Rhodium-Catalyzed Transannulation of Cyanothiadiazoles. AB - An intramolecular rhodium-catalyzed transannulation of readily available cyanothiadiazoles containing an ester, amide, or ether as a linker is described. It provides a wide range of bicyclic isothiazoles in good to excellent yields together with the release of molecular nitrogen. These results indicate that the carbon atom in the alpha-thiavinyl carbene is nucleophilic and that the sulfur atom is electrophilic. PMID- 28889745 TI - Self-Bleaching Behaviors in Black-to-Transmissive Electrochromic Polymer Thin Films. AB - Polymer-based electrochromic smart windows are an emerging energy-saving technology. There are several technological hurdles in the development of organic electrochromics. In this article, the self-bleaching behaviors of a black electrochromic polymer (ECP-black) thin film were investigated. We found that the electrochemical break-in process led to a less dense morphology and the increased free volume facilitated ion permeation in the ECP-black thin films. The polarized interface between the polymer thin film and transparent indium-tin-oxide (ITO) electrode made charge transfer accessible, which caused the self-bleaching behaviors. Herein, we proposed two approaches to study and mitigate the self bleaching phenomenon. First, a densely packed morphology was regenerated by increasing the cathodic polarization time under open-circuit conditions (Voff). The second involved the modification of the electrode (ITO) surface with a partial coverage of the octadecyltrichlorosilane layer. The combination of the two approaches rendered the ECP-black thin film capable of maintaining the colored state for up to 900 s. To extend the scope of our studies, self-bleaching of ECP-magenta and ECP-blue thin films were also tested and suppressed by using these two methods. Additionally, the cycling stability of the ECP-black has been improved from ~600 cycles to up to 2300 cycles without a noticeable decay of optical contrast. PMID- 28889746 TI - Structurally Engineered Nanoporous Ta2O5-x Selector-Less Memristor for High Uniformity and Low Power Consumption. AB - A memristor architecture based on metal-oxide materials would have great promise in achieving exceptional energy efficiency and higher scalability in next generation electronic memory systems. Here, we propose a facile method for fabricating selector-less memristor arrays using an engineered nanoporous Ta2O5-x architecture. The device was fabricated in the form of crossbar arrays, and it functions as a switchable rectifier with a self-embedded nonlinear switching behavior and ultralow power consumption (~2.7 * 10-6 W), which results in effective suppression of crosstalk interference. In addition, we determined that the essential switching elements, such as the programming power, the sneak current, the nonlinearity value, and the device-to-device uniformity, could be enhanced by in-depth structural engineering of the pores in the Ta2O5-x layer. Our results, on the basis of the structural engineering of metal-oxide materials, could provide an attractive approach for fabricating simple and cost-efficient memristor arrays with acceptable device uniformity and low power consumption without the need for additional addressing selectors. PMID- 28889747 TI - Synthesis of pH-Responsive Inorganic Janus Nanoparticles and Experimental Investigation of the Stability of Their Pickering Emulsions. AB - Pickering emulsions exhibit outstanding stability, especially those prepared with Janus particles, whose desorption energy is expected to be up to 3-fold greater than emulsions of homogeneous particles from theoretical calculations. To the best of our knowledge, however, there remains no experimental proof of this behavior in practice. In this study, inorganic Janus nanoparticles were fabricated by regioselective modification of the separate side of SiO2 nanoparticles with a judiciously selected mixture of trimethoxysilylpropyldiethylenetriamine and n-octyltrimethoxysilane. Janus nanoparticles demonstrated excellent interfacial activity, forming Pickering emulsions with oil phases at oil-water interfacial tensions ranging from 6.6-52.8 mN m-1. Furthermore, as the interface of the Janus nanoparticles was regionally functionalized with -NH2 groups, phase inversion could be realized by tuning pH. This is the first example for the Pickering emulsions stabilized with inorganic Janus particles. Importantly, based on the results of centrifugation experiment, the desorption energy of Janus nanoparticles at the interface was 3.2 times larger than that of homogeneous nanoparticles, which is in accordance with the result from theoretical calculations. These experimental results will substantially enrich our understanding of Janus nanoparticle Pickering emulsions and their interfacial assembly behavior. PMID- 28889748 TI - Identification and Characterization of Volatile Components Causing the Characteristic Flavor of Wagyu Beef (Japanese Black Cattle). AB - To clarify the characteristic sweet aroma of Wagyu (Japanese Black Cattle), aroma extraction dilution analysis (AEDA) was applied to the volatile fractions of Wagyu and Australia beefs. Some 20 odor-active peaks were detected, and 17 odorants were identified or tentatively identified. Among the perceived odorants, most of them were newly identified from the Wagyu beef. The main constituents of the potent odorants were aldehydes and ketones, which are known as the degradation products of polyunsaturated fatty acids that were significantly included in the lipids of the Wagyu. In addition, the most potent odorant was trans-4,5-epoxy-(E)-2-decenal, which is known to be the oxidation product of polyunsaturated acids, such as linoleic acid and arachidonic acid, that were significantly included in the lipids of the Wagyu. Accordingly, these findings strongly suggested that the kind of fatty acid constituting lipids of the Wagyu plays an important role in the formation of the characteristic aroma of the Wagyu beef. PMID- 28889749 TI - Highly Transparent w/o Pickering Emulsions without Adjusting the Refractive Index of the Stabilizing Particles. AB - Pickering emulsions with a remarkable transmittance of up to 86% across the visible spectrum have been prepared without adjusting the refractive index (RI) of the stabilizing particles to those of the aqueous and oil phases. Commercially available hydrophilic silica particles with a diameter of 20 nm, which are hydrophobized partially in situ, were used to stabilize water droplets with diameters below 400 nm in IsoparM. In this system, the stabilizing particles and the emulsion droplets act as one single scattering object, which renders RI matching of the particles unnecessary. By either evaporation of some water from the droplets or addition of an appropriate organic liquid to the oil phase, it is possible to match the RI of the droplets (aqueous phase + particles) with that of the continuous phase, which minimizes scattering and results in highly transparent emulsions. PMID- 28889750 TI - How Does the Addition of a Third Ion Affect the Molecular Interactions and the Thermodynamic Properties of Acetate-Based Ionic Liquids? AB - The effect of the addition of a third ion to the ionic liquid 1-butyl-3 methylimidazolium acetate [C4C1Im][OAc] was studied through the measurement of the enthalpy of mixing and of the excess molar volume of its mixtures with 1 butyl-3-methylimidazolium trifluoroacetate [C4C1Im][CF3CO2], 1-butyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide [C4C1Im][NTf2], and tetrabutylphosphonium acetate [P4444][OAc]. Negative enthalpies of mixing (DeltamixH < 0) and positive excess molar volumes (VE > 0) were observed in all cases. The infrared and NMR studies of the pure ionic liquids and their mixtures show that the presence of a third ion with a weaker affinity with the common counterion contributes to prevailing the more favorable hydrogen-bond, herein always between the imidazolium cation and the acetate anion. Both radial and spatial distribution functions calculated by molecular simulation confirm this behavior. The remarkable enhancement of the viscosities of the [C4C1Im][OAc] + [P4444][OAc] mixtures could be discussed in light of the calculated friction coefficients. PMID- 28889751 TI - Adiabatic Switching Extended To Prepare Semiclassically Quantized Rotational Vibrational Initial States for Quasiclassical Trajectory Calculations. AB - An approximation-free adiabatic switching method to generate semiclassically quantized ensembles of rovibrational states of polyatomic molecules for use as initial conditions in quasiclassical trajectory calculations is presented. Vibrational states are prepared, starting from an ensemble of classical states corresponding to the desired quantum state of the normal-mode Hamiltonian by slowly switching on the anharmonicity in internal coordinates, thereby avoiding rotational contamination. To generate rovibrational states, an extension is proposed: The vibrationally quantized molecules are slowly spun up to the desired quantized angular momentum. The ensembles obtained with adiabatic switching for CH4 are insensitive to the choice of internal coordinates and stationary; furthermore, their mean energies agree remarkably well with the quantum mechanical values: The zero-point energy and 15 vibrational levels of the first three polyads are within 20 cm-1, the rotational levels are between J = 1 and 50 within 1%, and the standard deviation is always <1%. Adiabatic switching produces classical state ensembles with significantly better properties than normal-mode sampling, making them more appropriate in quasiclassical trajectory calculations. PMID- 28889752 TI - Covalent immobilization of oxylipin biosynthetic enzymes on nanoporous rice husk silica for production of cis(+)-12-oxophytodienoic acid. AB - Soybean lipoxygenase, recombinant rice allene oxide synthase-1 and rice allene oxide cyclase were covalently immobilized on nanoporous rice husk silica using two types of linkers: glutardialdehyde and polyethylene glycol. The immobilization efficiency achieved using glutardialdehyde-linked rice husk silica was higher than that achieved using polyethylene glycol-linked rice husk silica (50-92% and 25-50%, respectively). Immobilization on both types of matrices significantly decreased the specific activities of the immobilized enzymes. Solid phase reaction yields of the enzymes were determined relative to the yields observed for the solution-phase reactions. Yields of the solid-phase reactions catalyzed by immobilized soybean lipoxygenase, rice allene oxide synthase-1, and rice allene oxide cyclase ranged from 50% to 230% and were dependent on both the enzymes and linkers used. Production of cis(+)-12-oxophytodienoic acid from alpha linolenic acid by consecutive reactions using all three enzymes in a co immobilization system resulted in 83.6% and 65.1% yields on glutardialdehyde linked and epichlorohydrin-polyethylene glycol-linked rice husk silica, respectively. Our results suggest that immobilization of biosynthetic enzymes of the octadecanoid pathway on rice husk silica may be an efficient method for the in vitro production of oxylipins. Additionally, enzyme immobilizations on rice husk silica matrices may be more broadly applicable for producing physiologically important compounds in other biosynthetic pathways. PMID- 28889753 TI - Silencing of BACH1 inhibits invasion and migration of prostate cancer cells by altering metastasis-related gene expression. AB - BACKGROUND: Cancer lethality is mainly caused by metastasis. Therefore, understanding the nature of the genes involved in this process has become a priority. BACH1, a basic leucine zipper transcription factor, has been shown to transcriptionally regulate expression of a range of genes that are associated with breast cancer metastasis. However, the exact role and the underlying molecular mechanism of BACH1 in prostate cancer remain unclear. This study aims to explore the expression of BACH1 in prostate cancer tissues and the effect of BACH1 suppression on prostate cancer cell behavior. MATERIALS AND METHODS: In this study, we used quantitative real-time PCR (qRT-PCR) to measure BACH1 expression in prostate adenocarcinoma tissues and two metastasis-derived prostate cancer cell lines, DU145 and LNCaP. We also used immunohistochemical (IHC) staining to measure BACH1 protein expression in prostate adenocarcinoma and matched normal tissue samples. In the following BACH1 expression was silenced in DU145 cells using siRNA as well. Knockdown was confirmed by qRT-PCR and Western blotting. The cytotoxic effects of BACH1-siRNA on DU145 cells were determined using an MTT assay. The migration and invasive capacity of DU145 cells were examined by scratch wound healing assay and matrigel invasion assay, respectively. We also used qRT-PCR to study the effect of BACH1 silencing on the expression levels of metastasis-related genes. RESULTS: We find that the expression of BACH1 mRNA and protein in prostate cancer tissues is significantly higher than in matched normal prostate tissues (p < .05). In addition, DU145 and LNCaP cells exhibited 4.25-fold and 3.45-fold higher levels of BACH1 compared to HFF cell line. BACH1-siRNA significantly reduced both mRNA and protein expression levels in DU145 cells. More importantly, we show that BACH1 promotes key features of metastasis, as BACH1-siRNA treatment significantly reduced cell invasion and migration by changing the expression levels of a number of metastasis-related genes in vitro. CONCLUSIONS: BACH1 is overexpressed in prostate cancer. Because this promotes invasion and migration, it may facilitate metastasis of prostate cancer. Thus, BACH1 is a potential therapeutic target for metastatic prostate cancer. BACH1 silencing therapy can be considered as a novel and effective adjuvant in prostate cancer targeted therapies. PMID- 28889754 TI - The development and initial evaluation of the Pornography-Use Avoidance Self Efficacy Scale. AB - Background and aims This study employed a newly developed questionnaire to evaluate whether men's self-efficacy to avoid using pornography in each of 18 emotional, social, or sexually arousing situations was associated with either their typical frequency of pornography use or their hypersexuality. Methods Using an Internet-based data collection procedure, 229 male pornography users (Mage = 33.3 years, SD = 12.2) who had sought or considered seeking professional help for their use of pornography completed questionnaires assessing their situationally specific self-efficacy, history of pornography use, self-efficacy to employ specific pornography-reduction strategies, hypersexuality, and demographic characteristics. Results Frequency of pornography use was significantly negatively associated with level of confidence in 12 of the 18 situations. In addition, lower hypersexuality and higher confidence to employ pornography-use reduction strategies were associated with higher confidence to avoid using pornography in each of the 18 situations. A principal axis factor analysis yielded three clusters of situations: (a) sexual arousal/boredom/opportunity, (b) intoxication/locations/easy access, and (c) negative emotions. Discussion and conclusions This questionnaire could be employed to identify specific high-risk situations for lapse or relapse and as a measure of treatment outcome among therapy clients, but we recommend further examination of the psychometric properties and clinical utility of the questionnaire in treatment samples. Because only one of the three clusters reflected a consistent theme, we do not recommend averaging self-efficacy within factors to create subscales. PMID- 28889755 TI - The dangers of conflating gambling-related harm with disordered gambling. AB - In their critical review of the prevention paradox (PP) applied to gambling related harm, Delfabbro and King (2017) raise a number of concerns regarding specific assumptions, methods, and findings as well as the general conceptual approach. Besides discussing the PP, the review also considers the merits of considering a "continuum of harm," as opposed to the more traditional categorical approach to classifying problem gamblers. Their critique is carefully modulated and balanced, and starts a useful dialogue in the context of a public health approach to gambling. Unfortunately, some of Delfabbro and King's (2017) arguments rest on the treatment of gambling harm as a binary state and conflates gambling-related harm with disordered gambling. In this reply, we argue that the application of PP logic to gambling harm has not yet been addressed by us, and is only indirectly related to the more important objective of understanding how gambling can reduce ones' quality of life. PMID- 28889756 TI - Occurrence of vancomycin-resistant Staphylococcus aureus in the oral cavity of patients with dental caries. AB - Oral streptococci are the major group of microbes isolated from oral microflora. They represent frequent pathogens of infective endocarditis (IE), and it is assumed that in most of the cases oral streptococci are acquired via mucosa layer of oral cavity. Staphylococcus aureus is also frequently isolated from IE as it accounts for 20%-30% of all cases. Vancomycin has been the most reliable therapeutic agent against infections caused by methicillin-resistant S. aureus (MRSA). The main objective of this study was to examine the occurrence of S. aureus species in dental caries specimens. Antimicrobial susceptibility testing of S. aureus to four antibiotics namely vancomycin, linezolid, teicoplanin, and daptomycin was performed. Detection of vancomycin resistance was conducted using polymerase chain reaction. Among the tested 150 strains, 98 were MRSA and of that 54 were vancomycin sensitive and 27 were resistant. All 98 MRSA strains were positive for mecA and 36 yielded pvl, whereas 13 carried vanA and only 2 were positive for vanB. Majority of the isolates showed sensitivity toward daptomycin and linezolid. Strains of S. aureus exhibiting decreased susceptibility to different antibiotics like vancomycin, daptomycin, and linezolid severely compromise the therapeutic alternatives and require a considerable amount of time, public awareness, and integrative health-care strategies to prevent the emergence of resistance to these compounds. PMID- 28889757 TI - Resurgence of yellow fever in Brazil: Overview and possible control options. PMID- 28889758 TI - MALDI-TOF MS versus 16S rRNA sequencing: Minor discrepancy between tools in identification of Bacteroides isolates. AB - Members of the genus Bacteroides are important components of the normal microbiota of gastrointestinal tract; however, as opportunistic pathogens are also associated with severe or even life-threatening infections with significant mortality. Various species within Bacteroides fragilis group are phenotypically very similar; thus, their identifications with traditional-automated biochemical methods are frequently inaccurate. The identification of the newly discovered or reclassified bacteria can be doubtful because of the lack of biochemical profile in the database of these tests. The aim of this study was to determine the accuracy of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method by testing of 400 Hungarian Bacteroides clinical isolates. Inaccurate identification results with MALDI-TOF MS were confirmed by 16S rRNA gene sequencing and findings were compared with traditional automated biochemical test rapid ID 32A method as well. PMID- 28889759 TI - Nintedanib with Add-on Pirfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY Trial. AB - RATIONALE: Nintedanib and pirfenidone slow the progression of idiopathic pulmonary fibrosis (IPF), but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add on pirfenidone. OBJECTIVES: To investigate safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone. METHODS: Patients with IPF and FVC greater than or equal to 50% predicted at screening who completed a 4 to 5-week run-in with nintedanib 150 mg twice daily without dose reduction or treatment interruption were randomized to receive nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times daily) or nintedanib 150 mg twice daily alone in an open-label manner for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to Week 12. Analyses were descriptive and exploratory. MEASUREMENTS AND MAIN RESULTS: On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Predose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean (SE) changes from baseline in FVC at Week 12 were -13.3 (17.4) ml and -40.9 (31.4) ml in patients treated with nintedanib with add-on pirfenidone (n = 48) and nintedanib alone (n = 44), respectively. CONCLUSIONS: Nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse event profiles of each drug. These data support further research into combination regimens in the treatment of IPF. Clinical trial registered with www.clinicaltrials.gov (NCT02579603). PMID- 28889760 TI - An analysis of clinical characteristics and patient outcomes in primary mediastinal sarcomas. AB - BACKGROUND: Published data concerning primary mediastinal sarcomas are limited to small-sized retrospective series. This study reviewed the clinical outcomes of these cases from the SEER (surveillance, epidemiology and end results) database. METHODS: Primary mediastinal sarcomas (1988 - 2013) were assembled from the SEER database. The incidence and 10-year cancer-specific survival rates were compared to other primary mediastinal malignancies (thymic carcinoma, germ cell tumors, neurogenic tumors, Hodgkin / non Hodgkin lymphomas) as well as to non mediastinal sarcomas. RESULTS: A total of 204 patients were recruited into this cohort. Multivariate analysis showed better overall survival for patients with younger age at diagnosis, low grade [hazard ratio 0.427 (95% CI: 0.224-0.814; P= 0.010)], posterior mediastinum location [hazard ratio 0.458 (95% CI: 0.268-0.781; P= 0.004)], node negative disease [hazard ratio 0.463 (95% CI: 0.232-0.923; P= 0.029)] and surgical treatment [hazard ratio 0.488 (95% CI: 0.336-0.709; P <0.0001)]. Compared to other mediastinal malignancies, primary mediastinal sarcomas have the worst 10-year overall survival. Similarly compared to non mediastinal sarcomas, primary mediastinal sarcomas have worse 10-year overall survival (23% versus 55%). CONCLUSION: Primary mediastinal sarcoma is a rare entity with worse prognosis compared to non-mediastinal counterparts. Surgical resection plays a particularly important role in the management. PMID- 28889761 TI - Safety issues associated with using medication to treat overactive bladder. AB - INTRODUCTION: The mainstay of overactive bladder treatment is the use of anticholinergic medication with its common side effects well known. This review focused on three less well-known safety issues when treating OAB. Areas covered: Patients with increased anticholinergic load are at risk of cognitive decline, dementia or even death. The elderly are particularly at risk due to polypharmacy. Botulinum toxin carries the risk of high urinary residuals, urinary tract infection and need to self catheterise. The use of vaginal oestrogens may improve OAB symptoms, but there is concern in those with a history of breast cancer. Studies have shown that the systemic absorption is negligible and does not increase the risk of recurrence. Expert Opinion: Improvement in assessing anticholinergic load is needed with the development of a universal drug scale. To avoid increasing load, Mirabegron or botulinum toxin can be used instead. There is no consensus of the use of prophylactic antibiotics when injecting botulinum toxin and at what residual to initiate self catheterisation. Despite evidence showing that the use of vaginal oestrogens is safe in those with a history of cancer, it is not fully supported by any health body. Further work is needed in those using aromatase inhibitors. PMID- 28889762 TI - Correlation between fetal mild ventriculomegaly and biometric parameters. AB - INTRODUCTION: The aim of this study was to assess the correlation between fetal lateral ventricle width and biometric measurements. MATERIAL AND METHODS: A prospective study on 335 fetuses, 101 fetuses with isolated mild ventriculomegaly and a control group of 234 fetuses with a normal US examination. All fetuses underwent a detailed brain ultrasound scan and a full biometric evaluation. To further compare biometric parameters, we matched, according to gestational week and gender, 91 fetuses from the study group to 91 fetuses from the control group. RESULTS: The mean gestational week during the exam was significantly different between the groups (29.6 weeks in the study group versus 28.3 in the control group, p = .001). The mean maternal age, obstetrical history, mode of conception, or fetal gender did not differ between the groups. After matching according to gestational age and fetal gender, the mean gestational week between the matched groups did not differ and was 29 + 5 weeks in both groups. The study group had significantly larger head circumference (p = .009), biparietal diameter (p < .001), femur length (p = .023), and estimated fetal weight (p = .024) compared with the control group. CONCLUSIONS: Isolated mild ventriculomegaly could be related to other larger fetal biometric measurements and does not necessarily mean a pathological condition. PMID- 28889763 TI - Identification of methylated metabolites of oat avenanthramides in human plasma using UHPLC QToF-MS. AB - Oat avenanthramides (AVAs) are a group of phenolic alkaloids, consisting of an anthranilic acid and a hydroxycinnamic acid linked by a pseudo-peptide bond. Bioavailability of AVA is poor in humans, suggesting transformations for rapid excretion. Thus, we aim to identify metabolites of AVA isomers in plasma of humans after consuming AVA-enriched oats. After lipid removal, AVA and their metabolites in plasma were extracted with ethyl acetate and analysed using an Agilent UHPLC-QToF-MS. Pharmacokinetics of AVA-O showed a bimodal distribution with Cmax1 and 2 for AVA-O at 5.9 +/- 5.2 and 7.9 +/- 7.0 ng/mL and Tmax1 and 2 at 1.7 +/- 0.7 and 3.1 +/- 1.2 h, respectively. Only the methyl-AVA-O showed a single Cmax at 14 +/- 9.9 ng/mL AVA-O equivalents and a Tmax of 2.4 +/- 2.7 h. This analysis is the first to identify methylated metabolites of AVAs and AVA aglycones in human blood after acute AVA consumption. PMID- 28889764 TI - Can technology-assisted toilets improve hygiene and independence in geriatric rehabilitation? A cohort study. AB - PURPOSE: To investigate whether technology-assisted toilets (TATs) could be used to improve toileting hygiene and independence for geriatric rehabilitation patients. TATs are commercially available toilet seats that use a stream of warm water to clean the user, have a fan for drying and are operated by a remote control. MATERIALS AND METHODS: Twenty-five geriatric rehabilitation in-patients were recruited, six completed the study, and seven partially completed the study. Each participant had two trial bowel movements. One trial involved cleaning themselves with toilet paper; the other involved cleaning themselves with the TAT functions. After each trial, participants received a visual inspection for cleanliness and answered the Psychosocial Impact of Assistive Devices Scale (PIADS), a validated scale, to assess their sense of competence, adaptability and self-esteem in the bathroom. A toileting cleanliness scale, designed for this study, was completed by a nurse after TAT usage. Participants received a score from 1 (completely clean) to 4 (completely soiled) based on a visual inspection after cleaning. RESULTS: TAT and toileting cleanliness scores were similar. PIADS scores showed a trend towards higher scores when using the TAT, but results were not statistically significant. CONCLUSIONS: TATs cleaned as well as standard toileting in geriatric rehabilitation inpatients. Participants indicated that TATs improved their sense of competence, adaptability and self-esteem. Geriatricians and rehabilitation professionals should consider prescribing TATs in their practice as an assistive device in order to promote patient independence and dignity and reduce the burden of care for patients requiring toileting assistance. Implications for rehabilitation Technology-assisted toilets (TATs) are commercially-available toilet seats that could be used to allow rehabilitation patients to clean themselves more independently in the bathroom. Improved toileting independence can reduce burden of care of geriatric rehabilitation and reduce the impact of toileting assistance on patient dignity and self-esteem. Physiatrists should consider recommending TATs to their patients but should take into account whether a patient's particular set of disabilities will allow them to use a TAT effectively. PMID- 28889765 TI - Effect of caffeine on superior mesenteric artery blood flow velocities in preterm neonates. AB - OBJECTIVE: To investigate the effect of caffeine infusion on superior mesenteric artery (SMA) blood flow velocities (BFV) in preterm infants. METHODS: Prospective observational study on 38 preterm neonates 28-33+6 weeks gestation, who developed apnea on their first day of life, and caffeine citrate infusion was initiated at a loading dose of 20 mg/kg, followed by a maintenance dose of 5-10 mg/kg/day. Duplex ultrasound measurements of SMA BFV were recorded: peak systolic velocity (PSV), end diastolic velocity (EDV) and resistive index (RI), at 15 min before, 1 , 2- and 6-h after caffeine loading dose, and 2 h after two maintenance doses. RESULTS: There was a significant reduction in PSV 1-h (p = .008), a significant decrease in EDV 1- and 2-h (p = .000 and p = .005, respectively) and a significant increase in RI 1- and 2-h (p = .003 and p = .005, respectively) following caffeine loading dose, as compared to values before caffeine infusion. No significant effect of caffeine maintenance doses on SMA BFV was observed (p > .05). CONCLUSION: Blood flow in SMA is significantly reduced after caffeine citrate infusion at a loading dose of 20 mg/kg. This effect continues for at least 2 h. Meanwhile, SMA BFV seems not affected by maintenance doses. PMID- 28889766 TI - Stabilized helical peptides: overview of the technologies and its impact on drug discovery. AB - INTRODUCTION: Protein-protein interactions are predominant in the workings of all cells. Until now, there have been a few successes in targeting protein-protein interactions with small molecules. Peptides may overcome some of the challenges of small molecules in disrupting protein-protein interactions. However, peptides present a new set of challenges in drug discovery. Thus, the study of the stabilization of helical peptides has been extensive. Areas covered: Several technological approaches to helical peptide stabilization have been studied. In this review, stapled peptides, foldamers, and hydrogen bond surrogates are discussed. Issues regarding design principles are also discussed. Furthermore, this review introduces select computational techniques used to aid peptide design and discusses clinical trials of peptides in a more advanced stage of development. Expert opinion: Stabilized helical peptides hold great promise in a wide array of diseases. However, the field is still relatively new and new design principles are emerging. The possibilities of peptide modification are quite extensive and expanding, so the design of stabilized peptides requires great attention to detail in order to avoid a large number of failed lead peptides. The start of clinical trials with stapled peptides is a promising sign for the future. PMID- 28889767 TI - Delayed-interval delivery in twin pregnancies: report of three cases and literature review. AB - INTRODUCTION: Delayed delivery is sometimes performed in selected multifetal pregnancies when the first twin birth occurs inevitably. The aim of this procedure is to improve the prognosis and decrease the morbidity and mortality of the second twin. We report three cases of delayed-interval delivery of dichorionic-diamniotic twin pregnancies assisted in our center between 2015 and 2017. After the first twin delivery, the second twin was left in utero and the patient received tocolytic therapy and antibiotics. Cervical cerclage was not performed. RESULTS: Our patients were admitted between 21 + 3 and 23 + 6 weeks of gestation. We achieved an average interval delivery of 6.33 d. Four out of six twins did not survive the delayed interval procedure. The average stay of the first and second twins that were admitted to the neonatal intensive care unit (NICU) was of 72 d (28-116) and 39.5 d (12-67), respectively. The first twin birth was vaginal in all cases, while the second twin delivery was performed by cesarean section in two out of our three patients. Our neonatal results are not favorable, probably due to the extreme prematurity. CONCLUSIONS: Delayed delivery of the second twin before 28 weeks of gestation can be an alternative for the obstetrician since it could prolong the pregnancy until a gestational age which confers a better prognosis and a better perinatal outcome for the second twin. PMID- 28889768 TI - Effect of prenatal smoking cessation interventions on birth weight: meta analysis. AB - BACKGROUND: Smoking is preventable factor for pregnancy outcomes such as low birth weight (LBW). In this study, we assessed the effects of smoking cessation in pregnancy period on the birth weight in Randomized Controlled Trial studies (RCTs). METHODS: International databases of Pub Med, Scopus, and Web of Science, by the MeSH heading and/or additional terms, were searched to assess relevant studies in systematic possess. I2 statistics was used to assess of heterogeneity. Pooled effects size was obtained by random effects model. Meta-regression was used to explore of heterogeneity using Stata software version 12 (Stata Corp, College Station, TX). RESULTS: A total 16 RCTs, 6192 women were enrolled to assess of smoking cessation in pregnancy period on the birth weight. Relative risk (RR) of not smoking at the end of pregnancy in intervention group was 2.47 (95% CI: 1.73-3.20). The odds ratio (OR) for effect of smoking cessation on LBW was 0.65 (95% CI: 0.42-0.88) and standardized mean difference (SMD) was significantly increased in the intervention group, 0.28 (95% CI: 0.05-0.50). CONCLUSIONS: Results of this study approve results of previous RCTs that smoking cessation in pregnancy is a good practical action to prevention of LBW in infants. PMID- 28889769 TI - Orsiro cobalt-chromium sirolimus-eluting stent: present and future perspectives. AB - INTRODUCTION: New-generation drug-eluting stents (DES) represent the current standard of care in patients undergoing percutaneous coronary intervention (PCI). Biodegradable polymer DES (BP-DES) were recently developed to overcome current limitations of newer-generation durable polymer DES (DP-DES) attributed to sustained inflammatory responses induced by permanent polymers. The Orsiro DES (Biotronik AG, Bulach, Switzerland) is a novel thin-strut cobalt-chromium sirolimus-eluting stent with biodegradable polymer that features some of the latest developments in DES technology. Areas covered: This article aims to review the currently available evidence on the clinical performance of the Orsiro BP-DES and its future perspectives. Expert commentary: The Orsiro DES is a recent newer generation BP-DES that combines a highly deliverable thin-strut cobalt-chromium stent platform and a unique hybrid concept with passive and active coatings designed to enhance tissue biocompatibility. In preclinical and intravascular imaging studies, the Orsiro BP-DES was shown to induce low inflammation and promote very early arterial healing. Recently, large randomized non-inferiority clinical trials have shown similar short- and mid-term efficacy and safety outcomes with Orsiro BP-DES compared with currently established newer-generation DES among all-comers and high-risk subgroups. The potential clinical superiority of Orsiro BP-DES over Xience DP-DES in patients with STEMI is currently investigated in the BIOSTEMI trial (NCT02579031). PMID- 28889770 TI - Angiogenic factors for prediction of preeclampsia and intrauterine growth restriction onset in high-risk women: AngioPred study. AB - OBJECTIVE: The study aimed to compare the level of two angiogenic factors, soluble fms-like tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng), for the prediction of preeclampsia and intrauterine growth restriction in high-risk pregnant women. METHODS: A prospective multicenter cohort study of 200 pregnant patients was conducted between June 2008 and October 2010. sFlt1 and sEng were measured by enzyme-linked immunosorbent assay. RESULTS: Forty-five patients developed a placenta-mediated adverse pregnancy outcome. Plasma levels of sFlt1 and sEng were higher in patients who will experience a preeclampsia at 28, 32, and 36 weeks compared with patients with no complication. The same results were observed for intrauterine growth restriction. Plasma levels of sFlt1 and sEng were not significantly different for patients with preeclampsia compare to patients with intrauterine growth restriction. Patients with early pre-eclampsia (PE) had very high rates of angiogenic factors at 20, 24, and 28 weeks. Patients with late PE and early and late intrauterine growth retardation (IUGR) had high rates at 32 and 36 weeks. CONCLUSION: In high-risk women, angiogenic factors are disturbed before the onset of preeclampsia and this is true for intrauterine growth restriction. PMID- 28889771 TI - Helicobacter pylori infection and risk of preeclampsia: a systematic review and meta-analysis. AB - OBJECTIVE: Helicobacter pylori is associated with many pregnancy adverse effects such as preeclampsia (PE). We performed this systematic review and meta-analysis study to assess the possible association between H. pylori infection and PE and this is the first meta-analysis to clarify this issue. METHODS: PubMed, ISI (Web of Science), SCOPUS, and Google Scholar databases were searched (up to April 2017) to identify the relevant studies. The Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines were used to do this study. Pooled odds ratio (OR) and 95% confidence intervals (CI) were estimated using a random-effects meta analysis model. Heterogeneity was assessed with the chi2-based Q-test and I2 statistic. RESULTS: A total of eight studies including 889 participants (460 preeclamptic women and 429 controls) met the eligibility criteria. A positive association was found between H. pylori infection and PE (OR: 3.35; 95% CI: 2.21 5.10). Heterogeneity was acceptable (chi2 = 13.39; I2 = 47.7, 95% CI: 0-77). In subgroup analysis, cytotoxin-associated antigen A seropositivity was a substantial risk factor for PE when immunoblotting methods (OR: 11.12; 95% CI: 5.34-23.16; chi2 = 6.42; I2 = 53.3, 95% CI: 0-85) were used, whereas it was not potential risk factor for PE when ELISA was used as a detecting method (OR: 1.11; 95% CI: 0.6-2.06; chi2 = 1.83; I2 = 0, 95% CI: 0-90). CONCLUSIONS: This study indicated that women with H. pylori infection, especially those infected with Cag A positive strains are more likely to have PE compared with the uninfected women. PMID- 28889772 TI - Human papillomavirus infection and intrauterine growth restriction: a data linkage study. AB - OBJECTIVE: Using unbiased population data, to examine whether having a positive Pap smear, and thus a high probability of Human Papilloma Virus (HPV) infection, is a significant risk factor for intrauterine growth restriction (IUGR) in a subsequent pregnancy. STUDY DESIGN AND METHODS: Two independent population-based databases, namely the South Australian Perinatal Statistics Collection and the South Australian Cervical Screening Database, were deidentified and linked by the SANT Datalinkage Service. Analyses were performed on cases where Pap smear screening data was available for up to 2 years prior to a singleton live birth. Population characteristics and pregnancy related data were compared statistically by normal birth weight versus IUGR (10th percentile - known as small for gestational age (SGA), small for gestational age) and (3rd percentile birth weight - known as VLBW, very low birth weight). The association between cervical screening results and IUGR was assessed using generalized linear log binomial regression models. RESULTS: A total of 31,827 women met the criteria. Of these, 1311 women (4.1%) had a positive Pap smear within 2 years of the current pregnancy. Those having a positive Pap smear were more likely to have a baby with IUGR than those with negative smear results. For SGA, 5.8% babies were from mothers with positive Pap smears compared to 4.0% with negative smears indicating a 40% higher risk of having an SGA baby (95%CI 20-70%) among women with positive Pap smears. For VLBW, 7.6% mothers had positive Pap smears compared with 4.0% with negative smears (p < .001), which reflects a 90% increased risk (95%CI 40 150%). These associations reduced to 20% (95%CI 1-40%) and 50% (95%CI 10-100%) for SGA and VLBW, respectively, after adjusting for all other significant covariates including maternal age, ethnicity, marital status, occupation, smoking, pregnancy history, and maternal health during pregnancy. CONCLUSIONS: Mothers with a positive Pap smear have an increased risk of IUGR, especially for VLBW, which is independent of other risk factors. The results confirm previous findings in a small study and emphasise the need to consider the risks of both cancer and IUGR in all HPV vaccination programs. PMID- 28889773 TI - Sensitivity of nPCR for four types of membrane protein DNA and of two pairs of primers for Tpp47 DNA of Treponema pallidum in whole blood of congenital syphilis newborns. AB - BACKGROUND: Problems exist in congenital syphilis (CS) diagnosis and no single test can be used to diagnose CS. OBJECTIVE: To know whether there exist differences of nested polymerase chain reaction (nPCR) sensitivity among four membrane protein DNA and of nPCR between two pairs of primers for Tpp47. METHODS: We collected 30 CS patients as a study group, and 20 cases admitted to hospital for other reasons as a control group. The blood samples from newborns were left of blood for other examination, not special for the study. Following confirmed diagnosis, DNA was extracted from blood. nPCR examined for membrane protein DNA in both groups. RESULTS: Sensitivity of nPCR for Tpp15, Tpp17, Tpp45, and Tpp47 (total) was 6/30, 3/30, 1/30, and 20/30, respectively. The sensitivity of nPCR for Tpp47 was highest among that of four types of membrane protein DNA. The nPCR sensitivity of two pairs of primers (a and b) for Tpp47 was 11/30 and 13/30, respectively. There was no significant difference between two pairs of primers for Tpp47, and total sensitivity of nPCR for Tpp47 combining Tpp47a with Tpp47b was up to 20/30. CONCLUSION: Sensitivity of nPCR for Tpp47 was highest among that of four types of membrane protein DNA. Two pairs of primers for Tpp47 different bands could elevate nPCR sensitivity. PMID- 28889774 TI - Vaginal breech delivery at term and neonatal morbidity and mortality - a population-based cohort study in Sweden. AB - INTRODUCTION: The routine to deliver almost all term breech cases by elective cesarean section (CS) has continued to be debated due to the risk of maternal and neonatal complications. The aims of the study were (1) to investigate if mode of delivery impacts on the risk of morbidity and mortality among term infants in breech presentation and (2) to compare the rates of severe neonatal complications and mortality in relation to presentation and mode of delivery. METHODS: This population-based cohort study used data from the Swedish Medical Birth Register. All women (and their newborn infants) with singleton pregnancies who gave birth at term to an infant in breech (n = 27,357) or cephalic presentation (n = 837,494) between 2001 and 2012 were included. Births with vacuum extraction and induced labors were excluded, as well as antepartum stillbirths, births with infants diagnosed with congenital malformations and multiple births. RESULTS: On one hand, the rates of neonatal complications and mortality were higher among infants born in vaginal breech compared to the vaginal cephalic group. On the other hand, after CS, the rates of all neonatal complications under study and neonatal mortality were lower among infants in breech presentation than in those in cephalic presentation. After adjustment for confounders, infants delivered in vaginal breech had 23.8 times higher odds AOR (ratio) for brachial plexus injury, 13.3 times higher odds ratio for Apgar score <7 at 5 min, 6.7 times higher odds of intracranial hemorrhage (ICH), or convulsions and 7.6 higher odds ratio for perinatal mortality than those delivered by elective CS. CONCLUSIONS: Despite a probable selection of women who before-hand were considered at low risk and, therefore, could be recommended vaginal breech delivery, infants delivered in vaginal breech faced substantially increased risks of severe neonatal complications compared with infants in breech presentations delivered by elective CS. Key message Vaginal breech delivery is associated with increased risk for severe neonatal complications. PMID- 28889775 TI - High-dose compared with low-dose oxytocin for induction of labour of nulliparous women at term. AB - BACKGROUND: The optimal oxytocin infusion regimen to induce labour with the lowest caesarean section rate, instrumental delivery rate and length of active labour is unclear. We compared the effect of a low-dose to high-dose oxytocin regimen to induce labour. MATERIALS AND METHODS: We conducted a retrospective study of nulliparous women induced at term in a single tertiary centre from 2009 to 2015. The oxytocin induction protocol changed from a high to low-dose regimen in November 2012, affording us the opportunity to compare outcomes 3 years prior to, and following the change in protocol. Main outcome measures were caesarean section rate, instrumental delivery rate and length of active labour. RESULTS: Four thousand eight hundred and eighty-five participants were included, 2211 were induced via the low-dose regimen, and 2674 using the high-dose regimen. There was no difference in caesarean section rate (adjusted OR 0.99; 95% CI 0.87-1.13) or instrumental delivery rates once adjusted for regional anaesthesia (adjusted OR 1.16; 95% CI 0.99-1.36) between the different regimens. Surprisingly, the length of labour was longer in the high-dose oxytocin group (adjusted mean difference 0.60 h; 95%CI 0.81-0.12). There were significantly more postpartum haemorrhage >=1000 ml (10.5% versus 7.8%, p < .001) and regional anaesthesia use (55.8% versus 52.1%, p = .03) in the low-dose cohort. There were no differences in neonatal outcomes. CONCLUSION: Outcomes between high- and low-dose oxytocin induction regimens are relatively comparable with similar caesarean section and instrumental delivery rates. Therefore, either regimen is acceptable for use for induction of labour. PMID- 28889776 TI - Risk of spontaneous preterm birth in IVF-conceived twin pregnancies. AB - OBJECTIVE: To compare the mean transvaginal ultrasound (TVU) cervical length (CL) at midtrimester in screening for preterm birth in in vitro (IVF)-conceived twin pregnancies versus spontaneously-conceived twin pregnancies. METHODS: This was a retrospective cohort study. Potential study subjects were identified at the time of a routine second trimester fetal ultrasound exam at 18 0/7 to 23 6/7-week gestation. All women with twin diamniotic pregnancies screened with a single TVU CL for this trial were included. Mean TVU CLs were compared between IVF-conceived twin pregnancies and spontaneously-conceived twin pregnancies. The relationship of TVU CL with gestational age at delivery was assessed. Incidence of short TVU CL, defined as TVU CL <=30 mm, was also calculated in the two groups. The primary outcome was the mean of TVU CL. Distribution of CL was determined and normality was examined in both groups Results: A total of 668 women with diamniotic twin pregnancies who underwent TVU CL screening between 18 0/6 and 23 6/7 weeks were included. 158 (23.7%) were IVF-conceived pregnancies, and 510 (76.3%) were spontaneously-conceived pregnancies. No women received progesterone, pessary, or cerclage for preterm birth prevention during pregnancy. The mean TVU CL was significantly lower in the IVF-conceived group (32.2 +/- 10.5 mm) compared to the spontaneously-conceived group (34.1 +/- 9.1 mm) (mean difference (MD) - 1.90 mm, 95%CI -3.72 to -0.08). The incidence of TVU CL <=30 mm was 30.4% in the IVF conceived group and 21.6% in the spontaneously-conceived group (adjusted odds ratio (aOR) 1.59, 95%CI 1.06-2.37). IVF-conceived twins had a significantly higher risk of spontaneous preterm birth <34 weeks (32.9 versus 21.2%; aOR 1.83, 95% confidence interval (CI) 1.23-2.71) and higher rate of delivery due to spontaneous onset of labor (64.5 versus 54.9%; aOR 1.50, 95%CI 1.03-2.17). For any given TVU CL measured between 18 0-7 and 23 6/7 weeks, gestational age at delivery for IVF-conceived twins was earlier by about 1 week on average compared with spontaneously-conceived twins. CONCLUSIONS: The higher rate of spontaneous preterm birth in IVF-conceived twin pregnancies is predicted by lower midtrimester TVU CL, as well as by the lower gestational age at birth per any given CL in the IVF-conceived compared to the spontaneously-conceived twin pregnancies. PMID- 28889777 TI - Assessment of neonatal adrenal size using high resolution 2D ultrasound and its correlation with birth demographics and clinical outcomes. AB - OBJECTIVE: Assessment of adrenal function in a sick neonate remains a challenge in spite of major advances in neonatal care. We used 2D ultrasound of adrenal glands to assess maturity of adrenal glands in extremely preterm infants and sick term and near term infants. STUDY DESIGN: We collected demographics details of 99 mother-infants pairs (24-41 weeks) and obtained 2D ultrasound scans of adrenal glands in first week of life to measure adrenal volume, fetal zone size, and adrenal to kidney ratios. Relationship between adrenal measurements, antenatal factors, and postnatal outcomes were studied. RESULTS: We reported normative adrenal gland volume data during gestation from 80 appropriate for gestational age (AGA) infants. In a binary analysis, adrenal size was significantly related to gender, race, intrauterine growth restriction (IUGR), maternal chorioamnionitis, and maternal hypertension. Linear regression analysis showed that fetal zone is significantly related to not only gestational age but also chorioamnionitis and later development of intraventricular hemorrhage (IVH). Adrenal volume likewise is also related to gestational age, preeclampsia, and IVH. CONCLUSIONS: Antenatal maternal factors and uterine environment affects adrenal growth and development thus postnatal high resolution 2D US scan of adrenal glands can provide useful information to predict outcomes. This information can complement hormone and adrenocorticotrophic hormone (ACTH) stimulation assays. PMID- 28889778 TI - Genotoxicity testing: progress and prospects for the next decade. AB - INTRODUCTION: Genotoxicity and mutagenicity analyses have a significant role in the identification of hazard effects of therapeutic drugs, cosmetics, agrochemicals, industrial compounds, food additives, natural toxins and nanomaterials for regulatory purposes. To evaluate mutagenicity or genotoxicity, different in vitro and in vivo methodologies exert various genotoxicological endpoints such as point mutations, changes in number and structure of chromosomes. Areas covered: This review covered the basics of genotoxicity and in vitro/in vivo methods for determining of genetic damages. The limitations that have arisen as a result of the common use of these methods were also discussed. Finally, the perspectives of further prospects on the use of genotoxicity testing and genotoxic mode of action were emphasized. Expert opinion: The solution of actual and practical problems of genetic toxicology is inarguably based on the understanding of DNA damage mechanisms at molecular, subcellular, cellular, organ, system and organism levels. Current strategies to investigate human health risks should be modified to increase their performance for more reliable results and also new techniques such as toxicogenomics, epigenomics and single cell approaches must be integrated into genetic safety evolutions. The explored new biomarkers by the omic techniques will provide forceful genotoxicity assessment to reduce the cancer risk. PMID- 28889779 TI - Physician performance feedback in a Canadian academic center. AB - Purpose This paper aims at the implementation and early evaluation of a comprehensive, formative annual physician performance feedback process in a large academic health-care organization. Design/methodology/approach A mixed methods approach was used to introduce a formative feedback process to provide physicians with comprehensive feedback on performance and to support professional development. This initiative responded to organization-wide engagement surveys through which physicians identified effective performance feedback as a priority. In 2013, physicians primarily affiliated with the organization participated in a performance feedback process, and physician satisfaction and participant perceptions were explored through participant survey responses and physician leader focus groups. Training was required for physician leaders prior to conducting performance feedback discussions. Findings This process was completed by 98 per cent of eligible physicians, and 30 per cent completed an evaluation survey. While physicians endorsed the concept of a formative feedback process, process improvement opportunities were identified. Qualitative analysis revealed the following process improvement themes: simplify the tool, ensure leaders follow process, eliminate redundancies in data collection (through academic or licensing requirements) and provide objective quality metrics. Following physician leader training on performance feedback, 98 per cent of leaders who completed an evaluation questionnaire agreed or strongly agreed that the performance feedback process was useful and that training objectives were met. Originality/value This paper introduces a physician performance feedback model, leadership training approach and first-year implementation outcomes. The results of this study will be useful to health administrators and physician leaders interested in implementing physician performance feedback or improving physician engagement. PMID- 28889780 TI - Prevalence of hearing loss and associated factors in subjects with normal otoscopy: a national cross-sectional study. AB - OBJECTIVE: To report the prevalence of hearing loss (HL) and associated factors in a nationwide study. DESIGN: Cross-sectional study. STUDY SAMPLE: We investigated the prevalence of HL in 10,845 participants >=12 years of age and analysed the associated factors with HL from 7434 participants >=40 years of age. RESULTS: The prevalence of worse ear HL was 21.9% (1.2% in youngest and 81.9% in oldest) and that of better ear was 12.5% (none in youngest and 65.3% in oldest). Based on the worse ear HL, the prevalence of HL was more common in men, and related with low education and income. In univariable analysis, hypertension, smoking, diabetes, depressive mood, stroke or cardiac disease, anaemia, hypercholesterolaemia and underweight showed positive associations with HL, and alcohol consumption and regular walking showed negative associations with HL. There were five associated factors in multivariable analysis, including smoking (OR =1.36 for smokers with <20 pack years; OR =1.55 for smokers with >=20 pack years), noise exposure at workplace (OR = 1.28), stroke (OR = 1.72), anaemia (OR = 1.36) and depressive mood (OR = 1.29). CONCLUSION: Prevention of smoking and reduction of noise, as well as awareness of the association with stroke, anaemia and depression would help to reduce the burden of HL. PMID- 28889781 TI - Intrauterine cleaning after placental delivery at cesarean section: a randomized controlled trial. AB - OBJECTIVE: The objective of this study is to evaluate whether omission of intrauterine cleaning increases intraoperative and postoperative complications among women who deliver via cesarean section. METHODS: We randomized 206 women undergoing primary elective cesarean deliveries to intrauterine cleaning or omission of cleaning. Postpartum endomyometritis rates across groups were the primary outcome. We also examined secondary outcomes. To detect a 20% difference in infection rate between the cleaned and the non-cleaned groups (two-tailed [alpha] = 0.05, [beta] = 0.2), 103 women were required per group. Analysis was by intention-to-treat. RESULTS: Two hundred and six were randomized as follows: 103 to intrauterine cleaning and 103 to omission of cleaning after placental delivery. There were no statistically significant differences in the rate of endomyometritis between the two groups (2.0% versus 2.9%, RR =0.60; 95% CI 0.40 1.32). There were no statistically significant differences in postpartum hemorrhage rates (5.8% versus 7.7%, RR 0.75; 95% CI 0.6-1.2), hospital readmission rates (2.9 versus 3.8%, RR 0.75; 95% CI 0.5-1.6), time to return of gastrointestinal function, need for repeat surgery, or quantitated blood loss between the two groups. CONCLUSIONS: Our randomized controlled trial provides evidence suggesting that omission of intrauterine cleaning during cesarean deliveries in women at low risk of infection does not increase intraoperative or postoperative complications. PMID- 28889782 TI - Sex-related hormone receptor in laryngeal squamous cell carcinoma: correlation with androgen estrogen-alpha and prolactin receptor expression and influence of prognosis. AB - BACKGROUND: The expression and function of androgen receptors (AR) and estrogen receptor alpha (ER-alpha) in laryngeal squamous cell carcinoma (LSCC) have remained controversial for decades. Prolactin receptor (PRLR) is a sex-related hormone, that has been rarely documented in terms of expression or function compared with data on other hormone receptors in laryngeal carcinoma. METHODS: This study reports on immunohistochemical and reverse transcription-polymerase chain reaction (RT-PCR) analysis of tumour tissue and adjacent normal tissue in 96 patients with LSCC (82 males and 14 females). The expression levels of the receptors were related to clinicopathologic parameters and survival data. RESULTS: At both protein and mRNA levels, the expression level of AR, ER-alpha, and PRLR was much higher in LSCC than in adjacent normal tissues (p < .05). Among them, higher PRLR expression in tumour tissues tended to have a significantly poorer survival rate (p = .03) for patients with LSCC. Furthermore, higher expression of ER-alpha in tumours was correlated with higher expression level of PRLR (r = .823, p = .03). CONCLUSION: The findings of this study indicate that the sex-related hormone receptors play an important role in the development of LSCC. The PRLR represents a novel prognosticator, because of its negative effect on survival and its interaction with ER-alpha. PMID- 28889783 TI - Sex chromosome changes in leukemia: cytogenetics and molecular aspects. AB - BACKGROUND AND OBJECTIVE: Sex chromosome loss (SCL) can occur in older men as a physiological phenomenon or as an acquired abnormality in leukemia. Loss of chromosome Y and loss of chromosome X are acquired disorders that are mainly observed in patients over 80 years as well as in myeloid and lymphoid malignancies. In this review, we examine the cytogenetic and molecular changes of sex chromosomes in leukemia. METHODS: Relevant English language literature were searched and retrieved from PubMed search engine (1990-2016). The following keywords were used: 'Sex chromosomes', 'Leukemia' and 'Cytogenetics'. RESULTS: The loss of tumor suppressor genes along with these chromosomal abnormalities in the majority of malignant cells in bone marrow (BM) has raised the question whether this is an age-related phenomenon or has occurred as a result of clonal abnormality. On the other hand, the presence of these chromosomal abnormalities in a number of genetic diseases associated with leukemia leads to progression of malignancy, and their role in peripheral blood stem cell transplantation confirm the finding that these chromosomal abnormalities can play an important role in clonal abnormality. CONCLUSION: The presence of these abnormalities can cause genetic instability in BM and result in the development of a malignant clone and progression of the disease. In addition, the evaluation of SCL together with the genes involved in these chromosomes can contribute to predict the disease prognosis as well as monitoring of malignancy. PMID- 28889784 TI - Isolation and characterization of key contributors to the "kokumi" taste in soybean seeds. AB - The water extract of soybean seeds (Glycine max (L.) Merr.) is nearly tasteless, but "kokumi" taste sensation was confirmed upon addition of a basic umami solution containing glutamic acid, inosine monophosphate, and sodium chloride. To identify the key contributors to the "kokumi" taste sensation in soybean seeds, sensory-guided fractionation, taste sensory analyses, and LC-MS/MS analyses were utilized. gamma-glutamyl-tyrosine and gamma-glutamyl-phenylalanine were identified as contributors to "kokumi taste"; specifically, these gamma-glutamyl peptides imparted the "kokumi" taste sensation at a low taste threshold in a basic umami solution. Raffinose and stachyose, which are sufficiently present in soybean seeds, exhibited a synergistic effect in regard to the enhanced "kokumi" taste sensation of gamma-glutamyl peptides. This is the first report that the combined use of gamma-glutamyl peptides and oligosaccharides can increase the "kokumi" intensity, which suggests that soybean extracts or soymilk can be used to enhance the "kokumi" taste sensation in food products. PMID- 28889785 TI - Validation of Fetal Medicine Foundation algorithm for prediction of pre-eclampsia in the first trimester in an unselected Brazilian population. AB - OBJECTIVE: The objective of this study is to evaluate the predictive performance of the Fetal Medicine Foundation (FMF) algorithm for prediction of preeclampsia (PE) between 11 and 14 weeks of gestation in an unselected Brazilian population. METHODS: We conducted a prospective cohort study with 617 singleton pregnancies of unselected risk. Biophysical markers (mean pulsatility index, mean arterial pressure) and biochemical markers (placental growth factor (PLGF) and PAPP-A) were inserted into the FMF software and converted into multiples of the median (MoM). The subjects were divided into five groups: early-onset PE, parturition <34 weeks' gestation; preterm PE, parturition <37 weeks; PE, parturition at any gestational age; gestational hypertension (GH); and control group. Areas under the receiver operating characteristics curve (AUC) were calculated for the outcomes. RESULTS: Among 617 patients, seven developed early-onset PE, 18 developed preterm PE (seven early PE plus 11 delivered between 34 and 36 + 6 weeks gestation), 34 developed PE (18 preterm PE plus 16 delivered after 37-week gestation), 12 pregnant women developed GH, and 517 women comprised the control group. The best predictive performance using the FMF algorithm occurred in the early-onset PE group, with AUC = 0.946 (95% CI 0.919-0.973) and the detection rate of 28.6% and 85.7% for 5% and 10% false-positive (FP), respectively. CONCLUSIONS: The FMF algorithm to predict PE was effective in a Brazilian population, mainly in the early-onset form of the disease at 10% FP. PMID- 28889786 TI - Implantable microphones as an alternative to external microphones for cochlear implants. AB - Totally implantable cochlear implants may be able to address many of the problems cochlear implant users have around cosmetic appearances, discomfort, and restriction of activities. The major technological challenges that need to be solved to develop a totally implantable device relate to implanted microphone performance. Previous attempts at implanting microphones for cochlear implants have not performed as well as conventional cochlear implant microphones, and in addition have struggled with extraneous body or surface contact noise. Microphones can be implanted under the skin or act as sensors in the middle ear; however, evidence from middle ear implants suggest body and contact noise can be overcome by converting ossicular chain movements into digital signals. This article reviews implantable microphone systems and discusses the technology behind them. PMID- 28889787 TI - Evaluation of scalp hair nickel and chromium level changes in patients with fixed orthodontic appliance: a one-year follow-up study. AB - BACKGROUND AND OBJECTIVES: The release of metal ions from orthodontic appliances is part of the dissolution and biomechanical processes of alloys. Nickel (Ni) and chromium (Cr) are the elements commonly used in the manufacture of various components of fixed orthodontic appliances, including bands, brackets and wires. This study was aimed to measure the Ni and Cr ions levels in the scalp hair of patients treated with fixed orthodontic appliances in comparison of the control group. MATERIALS AND METHODS: The patient group consisted of 24 patients treated with fixed orthodontic appliances for one year, while the control group included 28 healthy individuals without orthodontic appliances. Analysis of the Cr and Ni was performed using atomic absorption spectrophotometer by graphite furnace method. The data were analyzed via student and paired samples t-test and ANOVA repeated measurement test. RESULTS: After one year, the levels of Ni and Cr in two groups showed significant differences (0.086 +/- 0.007 and 0.258 +/- 0.009 ug/g for control group and 0.149 +/- 0.010 and 0.339 +/- 0.013 ug/g for patient group, respectively for Ni and Cr, p < .001). ANCOVA test by removing the effects of age, gender and the baseline levels of Ni and Cr showed that changes in these ions in the scalp hair of both groups after one year were statistically significant. CONCLUSION: Due to the slightly elevated levels of Ni and Cr ions in the scalp hair of patients treated with fixed orthodontic appliances and considering the cytotoxic and allergic effects of these ions, changing the ingredients in fixed orthodontic appliances is suggested for the future. PMID- 28889788 TI - Exploring perspectives on restraint during medical procedures in paediatric care: a qualitative interview study with nurses and physicians. AB - The aim of this study was to explore nurses' and physicians' perspectives on and reasoning about the use of restraint during medical procedures on newly admitted preschoolers in somatic hospital care. We analysed qualitative data from individual interviews with a video recall session at the end with seven physicians and eight nurses. They had earlier participated in video recorded peripheral vein cannulations on preschool children. The data were collected between May 2012 and May 2013 at a paediatric hospital unit in Norway. The analysis resulted in three main themes: (1) disparate views on the concept of restraint and restraint use (2), ways to limit the use of physical restraint and its negative consequences, and (3) experience with the role of parents and their influence on restraint. Perspectives from both healthcare professions were represented in all the main themes and had many similarities. The results of this study may facilitate more informed and reflective discussions of restraint and contribute to higher awareness of restraint in clinical practice. Lack of guidance and scientific attention to restraint combined with conflicting interests and values among healthcare providers may result in insecurity, individual dogmatism, and a lack of shared discussions, language, and terminology. PMID- 28889789 TI - Blood pressure evolution in young patients with acute ischemic stroke: a new model for understanding the natural course of spontaneous hypertension? AB - BACKGROUND: Approximately 80% of patients suffering an acute ischemic stroke develop transient hypertension. The physiopathological mechanism remains unclear. Due to the lack of vascular risk factors, young adults could be a useful model for understanding blood pressure (BP) evolution in this setting. METHODS: Patients between 18 and 55 years old admitted with an acute ischemic stroke were included. BP was evaluated during the following 48 h. Hypertension was defined as: systolic blood pressure (SBP) >=140 mmHg or diastolic blood pressure (DBP) >=90 mmHg. Patients were divided into two groups: RF group included those who had a previous vascular risk factor and/or other medical condition known to affect the autonomic function; noRF group included patients without any of the previously stated conditions. RESULTS: Thirty-nine patients were included: mean age: 44.26 years old, 21 were males (53.8%). Mean SBP and DBP at admission were 139.77 +/- 5.35 mmHg (range: 90-243) and 84.44 +/- 3.02 mmHg (range: 60-128), respectively; 43.58% patients were hypertensive at admission. SBP decreased significantly during the first 48 h (p = 0.044) for the entire population. RF group has higher SBP (p = 0.009) and DBP (p = 0.011) at admission than the noRF group. CONCLUSION: Most patients were normotensive at admission and BP fell spontaneously despite BP at admission. Young patients without medical conditions that could alter the autonomic system function could be a useful model for understanding acute hypertension in ischemic stroke. PMID- 28889791 TI - Additional resective surgery after the failure of initial surgery in patients with intractable epilepsy. AB - Objectives There are three conceivable reasons for the failure of resective surgery for intractable epilepsy: incomplete resection of the epileptogenic zone including or overlapping with eloquent area (group A); incorrect determination of the epileptogenic zone prior to the first surgery (group B); and the development of a new epileptic focus after the first surgery (group C). We examined the relationship between the reason for failure of initial surgery and patient outcomes after repeated surgical resection. Methods The study included 18 patients (5.1%) underwent additional surgery after failure of the initial operation. Post-operative outcomes, complications and other clinical data were collected by retrospective chart review. Results Four patients (22.2%) were assigned to group A, 13 (72.2%) were assigned to group B, and 1 patient was assigned to group C (5.6%). Six patients (40.0%) were seizure-free for 2 or more years after additional surgery. In group B, 11 patients underwent additional resection of the cortex adjacent to the previously resected area and 2 underwent re-operation involving a site distant from the previously resected area; notably, the latter 2 patients did not achieve seizure-free status post-surgery. After the first operation, only one patient (group A) experienced transient paresis; after additional surgery, 10 of 18 patients (56%; 3 group A, 6 group B, and 1 group C) experienced various complications. Discussion Although additional resective surgery provided freedom from seizures in about 40% of the patients, it is important to weigh a high risk of complications against possible benefits when considering additional surgery. PMID- 28889793 TI - Hemorheological dysfunction in cardiac syndrome X. AB - BACKGROUND: Cardiac syndrome X (CSX) is often described as angina or angina-like chest pain with a normal coronary arteriogram, yet the underlying pathophysiological mechanisms have not been fully elucidated. The aim of the current study was to determine alterations in blood rheology (erythrocyte aggregation and deformability, plasma viscosity - PV) in patients with CSX. METHODS: The study comprised 26 CSX patients (55.77 +/- 12.33 years) and 37 age- and sex-matched (56.32 +/- 11.98 years) healthy controls. Erythrocyte aggregation and deformability were measured by an ektacytometer and PV with a rotational viscometer. RESULTS: Erythrocyte deformability measured at 1.69 and 3.00 Pa was lower in the CSX patients compared to the controls (p = .0001 and .017, respectively). Erythrocyte aggregation index (AI) (72.758 +/- 7.65 vs. 66.483 +/- 6.63, p = .002) and PV measured at a shear rate of 375 s-1 (1.932 +/- 0.225 vs. 1.725 +/- 0.331, p = .019) were significantly higher in patients with CSX. When AI, RDW and erythrocyte deformability measured at 1.69 Pa were evaluated together, it was observed that the increase in AI and RDW augments the risk of having CSX (OR: 1.2 and 2.65, respectively), while the rise in deformability decreases this risk (OR = 0.02). CONCLUSIONS: Hemorheological impairments are associated with CSX. PMID- 28889794 TI - Editorial: Computer Aided Structure-based Lead Optimization. PMID- 28889792 TI - Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. AB - BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .). PMID- 28889795 TI - Preface. PMID- 28889796 TI - Protein-Protein Interaction (PPI) Network: Recent Advances in Drug Discovery. AB - BACKGROUND: The investigation of the cellular components, their interactions and related functions constitute the major conditions in order to understand the cell as an integrated system. More specifically, the Protein-Protein Interactions and the obtained networks are very important in the majority of biological functions and processes, while most of the proteins appear to activate their functionalities through their interaction. METHODS: Our in depth review analysis, include Sixty-five peer-reviewed research and review studies from several bibliographic databases. The most significant components were fully described, filtered, combined and analyzed in order to provide documented proofs on the Protein-Protein Interaction Network' applications in biomedicine. RESULTS: The Protein-Protein Interaction Network' alignment and mapping give the opportunity of further knowledge extraction concerning the evolutionary relationships between the species through conserved pathways and protein complexes. Additionally, Protein-Protein Interaction Network information has been demonstrated to be able to predict functionally orthologous proteins within sequence homology clusters. Our review analysis concluded that, while Protein- Protein Interaction was used to be characterized just by their large and plain interacting surfaces, they were considered inapplicable for drug discovery studies for a long time. CONCLUSION: The present review explores multiple technologies implicated in Protein-Protein Interaction Networks, implicating their potential role in drug discovery mechanisms. PMID- 28889797 TI - An experimental study of executive function and social impairment in Cornelia de Lange syndrome. AB - BACKGROUND: Extreme shyness and social anxiety is reported to be characteristic of adolescents and adults with Cornelia de Lange syndrome (CdLS); however, the nature of these characteristics is not well documented. In this study, we develop and apply an experimental assessment of social anxiety in a group of adolescents and adults with CdLS to determine the nature of the social difficulties and whether they are related to impairments in executive functioning. METHODS: A familiar and unfamiliar examiner separately engaged in socially demanding tasks comprising three experimental conditions with a group of individuals with CdLS (n = 25; % male = 44; mean age = 22.16; SD = 8.81) and a comparable group of individuals with Down syndrome (DS; n = 20; % male = 35; mean age = 24.35; SD = 5.97). Behaviours indicative of social anxiety were coded. The Behavior Rating Inventory of Executive Function-Preschool version, an informant measure of executive function, was completed by participants' caregivers. RESULTS: Significantly less verbalisation was observed in the CdLS group than the DS group in conditions requiring the initiation of speech. In the CdLS group, impairments in verbalisation were not associated with a greater degree of intellectual disability but were significantly correlated with impairments in both planning and working memory. This association was not evident in the DS group. CONCLUSIONS: Adolescents and adults with CdLS have a specific difficulty with the initiation of speech when social demands are placed upon them. This impairment in verbalisation may be underpinned by specific cognitive deficits, although further research is needed to investigate this fully. PMID- 28889798 TI - Erratum to: Attention training for infants at familial risk of ADHD (INTERSTAARS): study protocol for a randomised controlled trial. PMID- 28889799 TI - In vitro protective effects of resveratrol and stilbene alkanoic derivatives on induced oxidative stress on C2C12 and MCF7 cells. AB - Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a natural phytoalexin found in grapes and wine, which has been extensively studied for a wide range of biological effects. A large number of stilbene-containing derivatives have displayed antioxidant and antiproliferative activities on various cancer cell lines. In this study, a series of stilbene hybrids 1-9, previously reported as peroxisome proliferator-activated receptor (PPAR) agonists, were assessed at micromolar concentrations using MTT cell viability assay in C2C12 and MCF7 cell lines. The modulation of oxidative stress was also evaluated by measuring the protective effects on reactive oxygen species (ROS) production induced or not by oxidative stimulus. Among these, compounds 2 and 8 showed significant radical scavenging activity. PMID- 28889800 TI - Adenocarcinoma of the lacrimal gland: a case report. AB - BACKGROUND: Primary ductal adenocarcinomas of the lacrimal gland are very rare. This neoplasm shares some histological and immunohistochemical similarities with salivary duct carcinoma. CASE PRESENTATION: Here, we present a case of a 55-year old Moroccan man with lacrimal gland adenocarcinoma. He underwent orbital exenteration with lymph nodes dissection and ipsilateral parotidectomy. After surgery, he was lost to follow-up and died 13 months later. CONCLUSIONS: Lacrimal gland tumors are rare but highly aggressive salivary gland tumors. Complete excision with adjuvant radiotherapy is recommended. PMID- 28889801 TI - Do health professionals have a prototype concept of disease? The answer is no. AB - BACKGROUND: Health and disease are core concepts in health care and have attracted substantial interest and controversy. In recent and interesting contributions to the debate it has been argued that the challenges with the concept of disease can be resolved by a prototype concept of disease. As a robin is a more prototypical of a bird than a penguin, some diseases are more prototypical than others. If disease is a prototype concept, it would change nosology, but also health care and the study of health and disease. However, the statement that "disease is a prototype concept" forms an empirically testable hypothesis. Therefore, this study aims to test the hypothesis that health professionals have a prototype concept of disease. METHODS: Two hundred twenty three health care professionals in Norway were invited to participate in a survey where they were asked to rank a wide range of diseases according to how typical they considered them to be as diseases. Results were analysed with descriptive statistics. RESULTS: The response rate was 90%. Lung cancer, leukemia, colon cancer, myocardial infarction, and AIDS are the diseases ranged to be most typical, while homosexuality, pregnancy, drapetomania, dissidence, and nostalgia are considered to be the least typical diseases. The results also show that the answers to how typical various diseases are vary greatly, even amongst a relatively homogenous group of health professionals. CONCLUSION: This study falsifies the hypothesis that disease is a prototype concept for health professionals. This has implications for the debate on core concepts for health care. If health professionals do not have a prototype concept of disease, it is unlikely that there is a prototype concept of disease in general. Consequently, nosologies should not be based on prototypes. PMID- 28889802 TI - Prevalence and clinical relevance of interview-assessed psychosis-risk symptoms in the young adult community. AB - BACKGROUND: An efficient indicated prevention of psychotic disorders requires valid risk criteria that work in both clinical and community samples. Yet, ultra high risk and basic symptom criteria were recently recommended for use in clinical samples only. Their use in the community was discouraged for lack of knowledge about their prevalence, clinical relevance and risk factors in non clinical, community settings when validly assessed with the same instruments used in the clinic. METHODS: Using semi-structured telephone interviews with established psychosis-risk instruments, we studied the prevalence of psychosis risk symptoms and criteria, their clinical relevance (using presence of a non psychotic mental disorder or of functional deficits as proxy measures) and their risk factors in a random, representative young adult community sample (N=2683; age 16-40 years; response rate: 63.4%). RESULTS: The point-prevalence of psychosis-risk symptoms was 13.8%. As these mostly occurred too infrequent to meet frequency requirements of psychosis-risk criteria, only 2.4% of participants met psychosis-risk criteria. A stepwise relationship underlay the association of ultra-high risk and basic symptoms with proxy measures of clinical relevance, this being most significant when both occurred together. In line with models of their formation, basic symptoms were selectively associated with age, ultra-high risk symptoms with traumatic events and lifetime substance misuse. CONCLUSIONS: Psychosis-risk criteria were uncommon, indicating little risk of falsely labelling individuals from the community at-risk for psychosis. Besides, both psychosis-risk symptoms and criteria seem to possess sufficient clinical relevance to warrant their broader attention in clinical practice, especially if ultra-high risk and basic symptoms occur together. PMID- 28889803 TI - Effort-cost decision-making in psychosis and depression: could a similar behavioral deficit arise from disparate psychological and neural mechanisms? AB - Motivational impairment is a common feature of both depression and psychosis; however, the psychological and neural mechanisms that give rise to motivational impairment in these disorders are poorly understood. Recent research has suggested that aberrant effort-cost decision-making (ECDM) may be a potential contributor to motivational impairment in both psychosis and depression. ECDM refers to choices that individuals make regarding the amount of 'work' they are willing to expend to obtain a certain outcome or reward. Recent experimental work has suggested that those with psychosis and depression may be less willing to expend effort to obtain rewards compared with controls, and that this effort deficit is related to motivational impairment in both disorders. In the current review, we aim to summarize the current literature on ECDM in psychosis and depression, providing evidence for transdiagnostic impairment. Next, we discuss evidence for the hypothesis that a seemingly similar behavioral ECDM deficit might arise from disparate psychological and neural mechanisms. Specifically, we argue that effort deficits in psychosis might be largely driven by deficits in cognitive control and the neural correlates of cognitive control processes, while effort deficits in depression might be largely driven by reduced reward responsivity and the associated neural correlates of reward responsivity. Finally, we will provide some discussion regarding future directions, as well as interpretative challenges to consider when examining ECDM transdiagnostically. PMID- 28889804 TI - Metabolic and inflammatory markers: associations with individual depressive symptoms. AB - BACKGROUND: Literature has shown that obesity, metabolic syndrome and inflammation are associated with depression, however, evidence suggests that these associations are specific to atypical depression. Which of the atypical symptoms are driving associations with obesity-related outcomes and inflammation is unknown. We evaluated associations between individual symptoms of depression (both atypical and non-atypical) and body mass index (BMI), metabolic syndrome components and inflammatory markers. METHODS: We included 808 persons with a current diagnosis of depression participating in the Netherlands Study of Depression and Anxiety (67% female, mean age 41.6 years). Depressive symptoms were derived from the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology. Univariable and multivariable regression analyses adjusting for sex, age, educational level, depression severity, current smoking, physical activity, anti-inflammatory medication use, and statin use were performed. RESULTS: Increased appetite was positively associated with BMI, number of metabolic syndrome components, waist circumference, C-reactive protein and tumor necrosis factor-alpha. Decreased appetite was negatively associated with BMI and waist circumference. Psychomotor retardation was positively associated with BMI, high-density lipoprotein cholesterol and triglycerides, and insomnia with number of metabolic syndrome components. CONCLUSION: Increased appetite - in the context of a depressive episode - was the only symptom that was associated with both metabolic as well as inflammatory markers, and could be a key feature of an immuno-metabolic form of depression. This immuno-metabolic depression should be considered in clinical trials evaluating effectiveness of compounds targeting metabolic and inflammatory pathways or lifestyle interventions. PMID- 28889805 TI - Interferon-alpha induces negative biases in emotional processing in patients with hepatitis C virus infection: a preliminary study. AB - BACKGROUND: Treatment of medical patients with the inflammatory cytokine, interferon-alpha (IFN-alpha), is frequently associated with the development of clinical depressive symptomatology. Several important biological correlates of the effect of IFN-alpha on mood have been described, but the neuropsychological changes associated with IFN-alpha treatment are largely unexplored. The aim of the present preliminary study was to assess the effect of IFN-alpha on measures of emotional processing. METHOD: We measured changes in emotional processing over 6-8 weeks in 17 patients receiving IFN-alpha as part of their treatment for hepatitis C virus infection. Emotional processing tasks included those which have previously been shown to be sensitive to the effects of depression and antidepressant treatment, namely facial expression recognition, emotional categorisation and the dot probe attentional task. RESULTS: Following IFN-alpha, patients were more accurate at detecting facial expressions of disgust; they also showed diminished attentional vigilance to happy faces. IFN-alpha produced the expected increases in scores on depression rating scales, but there was no correlation between these scores and the changes in emotional processing. CONCLUSIONS: Our preliminary findings suggest that IFN-alpha treatment produces negative biases in emotional processing, and this effect is not simply a consequence of depression. It is possible that increased recognition of disgust may represent a neuropsychological marker of depressive disorders related to inflammation. PMID- 28889806 TI - Letter to the Editor: Sources of bias and need for caution in interpreting the results of Spoth et al.'s (2017) PROSPER study. PMID- 28889807 TI - No nutritional benefits of egg cannibalism for Coleomegilla maculata (Coleoptera: Coccinellidae) on a high-quality diet. AB - Egg cannibalism serves various functions in the Coccinellidae. Here we examined the fitness consequences of egg cannibalism by neonates, fourth instar larvae, and prereproductive adults of Coleomegilla maculata DeGeer, with beetles fed a diet of Ephestia kuehniella Zeller eggs. Cannibalism of two eggs by neonates had no effect on development, and cannibalism of five eggs by fourth instars did not benefit any aspect of reproduction, but delayed pupation slightly. Cannibalism of eggs by pre-reproductive adults had no effect on reproductive success in any combination of reciprocal crosses of cannibals and non-cannibals. Females did not recognize, nor avoid consuming, their own clutches, and cannibalism propensity did not change following mating and onset of oviposition in either sex. These results contrast with those for more strictly aphidophagous species in which larvae gain developmental benefits, and females may recognize and avoid filial egg clusters while using cannibalism to interfere with conspecific females, whereas males reduce egg cannibalism after mating because they cannot recognize filial clusters. Egg cannibalism may confer developmental benefits to C. maculata when diet is suboptimal, as previously shown, but no such benefits were evident on the high-quality E. kuehniella egg diet. Female C. maculata do not require aphids to reproduce and distribute their eggs broadly in the environment, given that larvae can develop on pollen and non-aphid prey. Thus, C. maculata is not subject to the intraspecific competition that selects for cannibalism in more aphidophagous species, and also lacks many secondary adaptations associated with the behaviour. PMID- 28889808 TI - Maternal immune and affiliative biomarkers and sensitive parenting mediate the effects of chronic early trauma on child anxiety. AB - BACKGROUND: Chronic early trauma alters children's stress reactivity and increases the prevalence of anxiety disorders; yet the neuroendocrine and immune mechanisms underpinning this effect are not fully clear. Animal studies indicate that the mother's physiology and behavior mediate offspring stress in a system specific manner, but few studies tested this external-regulatory maternal role in human children exposed to chronic stress. METHODS: We followed a unique cohort of children exposed to continuous wartime trauma (N = 177; exposed; N = 101, controls; N = 76). At 10 years, maternal and child's salivary immunoglobulin A (s IgA) and oxytocin (OT), biomarkers of the immune and affiliation systems, were assayed, maternal and child relational behaviors observed, mother and child underwent psychiatric diagnosis, and child anxiety symptoms assessed. RESULTS: War-exposed mothers had higher s-IgA, lower OT, more anxiety symptoms, and their parenting was characterized by reduced sensitivity. Exposed children showed higher s-IgA, more anxiety disorders and post traumatic stress disorder, and more anxiety symptoms. Path analysis model defined three pathways by which maternal physiology and behavior impacted child anxiety; (a) increasing maternal s-IgA, which led to increased child s-IgA, augmenting child anxiety; (b) reducing maternal OT, which linked with diminished child OT and social repertoire; and (c) increasing maternal anxiety, which directly impacted child anxiety. CONCLUSIONS: Our findings, the first to measure immune and affiliation biomarkers in mothers and children, detail their unique and joint effects on children's anxiety in response to stress; highlight the relations between chronic stress, immune activation, and anxiety in children; and describe how processes of biobehavioral synchrony shape children's long-term adaptation. PMID- 28889810 TI - Simple diagnostic signs in those with cognitive impairment-anything to improve detection of cognitive disorders. AB - With now over 50 million people worldwide with dementia (Prince et al., 2013), there are almost certainly well over 100 million people with cognitive concerns and many of these will attend their health professional keen to know what is going on. We need those without intensive training in this field to be more confident and correct in their diagnosis when such a concerned person turns up. Many simple diagnostic tests have been proposed and some assessed - these include the walk and talk (divided attention) test (those who stop when asked a question while walking may be cognitively impaired) (Lamoth et al., 2011), the clock drawing test (Brodaty and Moore, 1997), the "handbag" sign (those clutching their personal possessions are more likely to be cognitively impaired) and the "hippopotamus sign" (calling the rhinoceros, in those tests that include this, a hippopotamus). Simple screening tests have been extensively validated and are important to the clinician in formulating a diagnosis (Lorentz et al., 2002). The "head-turning" and the "attended with/alone" signs are frequently observed, and many clinicians assessing such individuals would be well aware of them and probably even unknowingly factor them into their diagnosis. In this issue, Pinar Soysal and colleagues (Soysal et al., 2017) have evaluated these signs and, in those older people attending with cognitive concerns, found they had quite good diagnostic value. They were not very specific but showed good sensitivity and negative predictive value. Indeed, at the recent Alzheimer's Association International Conference in London there were several posters evaluating "soft but simple" signs although not all performed as expected - one group found gait actually sped up in those with cognitive impairment that were asked a question. PMID- 28889809 TI - Leukocyte telomere length and personality: associations with the Big Five and Type D personality traits. AB - : Backgrounds Accelerated cellular ageing, which can be examined by telomere length (TL), may be an overarching mechanism underlying the association between personality and adverse health outcomes. This 6-year longitudinal study examined the relation between personality and leukocyte telomere length (LTL) across time among adults with a wide age-range. METHODS: Data from the Netherlands Study of Depression and Anxiety were used and included patients with a depression and/or anxiety disorder and healthy controls. Overall, 2936 persons (18-65 years, 66% female) had data on LTL at baseline and 1883 persons had LTL at 6-year follow-up. The Big Five personality traits (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) and Type D personality were assessed. RESULTS: Neuroticism was negatively (B = -2.11, p = 0.03) and agreeableness was positively (B = 3.84, p = 0.03) related to LTL measured across two time points, which became just non-significant after adjusting for somatic health, lifestyle factors, and recent life stress (B = -1.99, p = 0.06; and B = 3.01, p = 0.10). Type D personality was negatively (B = -50.16, p < 0.01) related to LTL across two time points, which still remained statistically significant after full adjustment (B = -47.37, p = 0.01). Associations did not differ by age, gender, and current psychiatric status. CONCLUSIONS: The Big Five traits high neuroticism and low agreeableness, and Type D personality were associated with shorter LTL measured across a 6-year period. Associations with the Big Five traits became non-significant after controlling for somatic health, lifestyle factors, and recent life stress, yet similar trends were observed. Type D personality remained independently associated with shorter LTL after full adjustment. PMID- 28889811 TI - Cardiovascular CT for evaluation of single-ventricle heart disease: risks and accuracy compared with interventional findings. AB - OBJECTIVE: We sought to evaluate the risk and image quality from cardiovascular CT in patients across all stages of single-ventricle palliation, and to define accuracy by comparing findings with intervention and surgery. METHODS: Consecutive CT scans performed in patients with single-ventricle heart disease were retrospectively reviewed at a single institution. Diagnosis, sedation needs, estimated radiation dose, and adverse events were recorded. Anatomical findings, image quality (1-4, 1=optimal), and discrepancy compared with interventional findings were determined. Results are described as medians with their 25th and 75th percentiles. RESULTS: From January, 2010 to August, 2015, 132 CT scans were performed in single-ventricle patients of whom 20 were neonates, 52 were post Norwood, 15 were post-Glenn, and 45 were post-Fontan. No sedation was used in 76 patients, 47 were under minimal or moderate sedation, and nine were under general anaesthesia. The median image quality score was 1.2. The procedural dose-length product was 24 mGy-cm, and unadjusted and adjusted radiation doses were 0.34 (0.2, 1.8) and 0.82 (0.55, 1.88) mSv, respectively. There was one adverse event. No major and two minor discrepancies were noted at the time of 79 surgical and 10 catheter-based interventions. CONCLUSIONS: Cardiovascular CT can be performed with a low radiation exposure in patients with single-ventricle heart disease. Its accuracy compared with that of interventional findings is excellent. CT is an effective advanced imaging modality when a non-invasive pathway is desired, particularly if cardiac MRI poses a high risk or is contraindicated. PMID- 28889812 TI - A focussed single-view hand-held echocardiography protocol for the detection of rheumatic heart disease. AB - BACKGROUND: Echocardiographic screening represents an opportunity for reduction in the global burden of rheumatic heart disease. A focussed single-view screening protocol could allow for the rapid training of healthcare providers and screening of patients. OBJECTIVE: The aim of this study was to determine the sensitivity and specificity of a focussed single-view hand-held echocardiographic protocol for the diagnosis of rheumatic heart disease in children. METHODS: A total of nine readers were divided into three reading groups; each interpreted 200 hand held echocardiography studies retrospectively as screen-positive, if mitral regurgitation ?1.5 cm and/or any aortic insufficiency were observed, or screen negative from a pooled study library. The performance of experts receiving focussed hand-held protocols, non-experts receiving focussed hand-held protocols, and experts receiving complete hand-held protocols were determined in comparison with consensus interpretations on fully functional echocardiography machines. RESULTS: In all, 587 studies including 76 on definite rheumatic heart disease, 122 on borderline rheumatic heart disease, and 389 on normal cases were available for analysis. The focussed single-view protocol had a sensitivity of 81.1%, specificity of 75.5%, negative predictive value of 88.5%, and a positive predictive value of 63.2%; expert readers had higher specificity (86.1 versus 64.8%, p<0.01) but equal sensitivity. Sensitivity - experts, 96% and non-experts, 95% - and negative predictive value - experts, 99% and non-experts, 98% - were better for definite rheumatic heart disease. False-positive screening studies resulting from erroneous identification of mitral regurgitation and aortic insufficiency colour jets increased with shortened protocols and less experience (p<0.01). CONCLUSION: Our data support a focussed screening protocol limited to parasternal long-axis images. This holds promise in making echocardiographic screening more practical in regions where rheumatic heart disease remains endemic. PMID- 28889813 TI - Unique levoatriocardinal veins in neonates with hypoplastic left heart syndrome and intact atrial septum. AB - We had two cases of neonates with hypoplastic left heart syndrome and intact atrial septum who had unique levoatriocardinal veins. Contrast-enhanced CT and angiography revealed that previously unknown communicating vessels ran from the top of the left atrium and drained into the right atrium. We emphasise that transcatheter atrial septostomy should be performed not through these communicating vessels but using the trans-septal approach in neonates with hypoplastic left heart syndrome and an intact atrial septum. PMID- 28889815 TI - Exercise beyond nutrition to enhance physical recovery. PMID- 28889814 TI - Distinguishing postpartum and antepartum depressive trajectories in a large population-based cohort: the impact of exposure to adversity and offspring gender. AB - BACKGROUND: Distinguishing temporal patterns of depressive symptoms during pregnancy and after childbirth has important clinical implications for diagnosis, treatment, and maternal and child outcomes. The primary aim of the present study was to distinguish patterns of chronically elevated levels of depressive symptoms v. trajectories that are either elevated during pregnancy but then remit after childbirth, v. patterns that increase after childbirth. METHODS: The report uses latent growth mixture modeling in a large, population-based cohort (N = 12 121) to investigate temporal patterns of depressive symptoms. We examined theoretically relevant sociodemographic factors, exposure to adversity, and offspring gender as predictors. RESULTS: Four distinct trajectories emerged, including resilient (74.3%), improving (9.2%), emergent (4.0%), and chronic (11.5%). Lower maternal and paternal education distinguished chronic from resilient depressive trajectories, whereas higher maternal and partner education, and female offspring gender, distinguished the emergent trajectory from the chronic trajectory. Younger maternal age distinguished the improving group from the resilient group. Exposure to medical, interpersonal, financial, and housing adversity predicted membership in the chronic, emergent, and improving trajectories compared with the resilient trajectory. Finally, exposure to medical, interpersonal, and financial adversity was associated with the chronic v. improving group, and inversely related to the emergent class relative to the improving group. CONCLUSIONS: There are distinct temporal patterns of depressive symptoms during pregnancy, after childbirth, and beyond. Most women show stable low levels of depressive symptoms, while emergent and chronic depression patterns are separable with distinct correlates, most notably maternal age, education levels, adversity exposure, and child gender. PMID- 28889817 TI - A SYSTEMATIC APPROACH FOR ASSESSING, IN THE ABSENCE OF FULL EVIDENCE, WHETHER MULTICOMPONENT INTERVENTIONS CAN BE MORE COST-EFFECTIVE THAN SINGLE COMPONENT INTERVENTIONS. AB - OBJECTIVES: Multicomponent interventions (MCIs), consisting of at least two interventions, are common in rehabilitation and other healthcare fields. When the effectiveness of the MCI versus that of its single interventions is comparable or unknown, evidence of their expected incremental cost-effectiveness can be helpful in deciding which intervention to recommend. As such evidence often is unavailable this study proposes an approach to estimate what is more cost effective; the MCI or the single intervention(s). METHODS: We reviewed the literature for potential methods. Of those identified, headroom analysis was selected as the most suitable basis for developing the approach, based on the criteria of being able to estimate the cost-effectiveness of the single interventions versus that of the MCI (a) within a limited time frame, (b) in the absence of full data, and (c) taking into account carry-over and interaction effects. We illustrated the approach with an MCI for cancer survivors. RESULTS: The approach starts with analyzing the costs of the MCI. Given a specific willingness-to-pay-value, it is analyzed how much effectiveness the MCI would need to generate to be considered cost-effective, and if this is likely to be attained. Finally, the cost-effectiveness of the single interventions relative to the potential of the MCI for being cost-effective can be compared. CONCLUSIONS: A systematic approach using headroom analysis was developed for estimating whether an MCI is likely to be more cost effective than one (or more) of its single interventions. PMID- 28889816 TI - First-stage palliation strategy for univentricular heart disease may impact risk for acute kidney injury. AB - OBJECTIVE: Norwood palliation for patients with single ventricle heart disease is associated with a significant risk for acute kidney injury, which portends a worse prognosis. We sought to investigate the impact of hybrid stage I palliation (Hybrid) on acute kidney injury risk. DESIGN: This study is a single-centre prospective case-control study of seven consecutive neonates with single ventricle undergoing Hybrid palliation. Levels of serum creatinine and four novel urinary biomarkers, namely neutrophil gelatinase-associated lipocalin, interleukin-18, liver fatty acid-binding protein, and kidney injury molecule-1, were obtained before and after palliation. Acute kidney injury was defined as a ?50% increase in serum creatinine within 48 hours after the procedure. Data were compared with a contemporary cohort of 12 neonates with single ventricle who underwent Norwood palliation. RESULTS: Patients who underwent Hybrid were more likely to be high-risk candidates (86 versus 25%, p=0.01) compared with those who underwent Norwood. Despite similar preoperative serum creatinine levels, there was a trend towards higher levels of postoperative peak serum creatinine (0.7 [0.63, 0.94] versus 0.56 [0.47, 0.74], p=0.06) and rate of acute kidney injury (67 versus 29%, p=0.17) in the Norwood cohort. Preoperative neutrophil gelatinase associated lipocalin (58.4 [11, 86.3] versus 6.3 [5, 16.2], p=0.07) and interleukin-18 (30.6 [9.6, 167.2] versus 6.3 [6.3, 16.4], p=0.03) levels were higher in the Hybrid cohort. Nevertheless, longitudinal mixed-effect models demonstrated Hybrid palliation to be a protective factor against increased postoperative levels of neutrophil gelatinase-associated lipocalin (estimate -1.8 [-3.0, -9.0], p<0.001) and liver fatty acid-binding protein (-49.3 [-89.7, -8.8], p=0.018). CONCLUSIONS: In this single-centre case-control study, postoperative acute kidney injury risk did not differ significantly by single ventricle stage I treatment strategy; however, postoperative elevation in novel urinary biomarkers, consistent with subclinical kidney injury, was encountered in the Norwood cohort but not in the Hybrid cohort. PMID- 28889818 TI - Efficacy and safety of recombinant tissue plasminogen activator for venous thrombosis after paediatric heart surgery. AB - OBJECTIVE: Reports in the literature of treatment with recombinant tissue plasminogen activator following cardiac surgery are limited. We reviewed our experience to provide a case series of the therapeutic use of tissue plasminogen activator for the treatment of venous thrombosis in children after cardiac surgery. The data describe the morbidity, mortality, and clinical outcomes of tissue plasminogen activator administration for treatment of venous thrombosis in children following cardiac surgery. DESIGN: The study was designed as a retrospective case series. SETTING: The study was carried out in a 25-bed cardiac intensive care unit in an academic, free-standing paediatric hospital. Patients All children who received tissue plasminogen activator for venous thrombosis within 60 days of cardiac surgery, a total of 13 patients, were included. Interventions Data was collected, collated, and analysed as a part of the interventions of this study. Measurements and main results Patients treated with tissue plasminogen activator were principally young infants (median 0.2, IQR 0.07 0.58 years) who had recently (22, IQR 12.5-27.3 days) undergone cardiac surgery. Hospital mortality was high in this patient group (38%), but there was no mortality attributable to tissue plasminogen activator administration, occurring within <72 hours. There was one major haemorrhagic complication that may be attributable to tissue plasminogen activator. Complete or partial resolution of venous thrombosis was confirmed using imaging in 10 of 13 patients (77%), and tissue plasminogen activator administration was associated with resolution of chylous drainage, with no drainage through chest tubes, at 10 days after tissue plasminogen activator treatment in seven of nine patients who had upper compartment venous thrombosis-associated chylothorax. CONCLUSIONS: On the basis of our experience with administration of tissue plasminogen activator in children after cardiac surgery, tissue plasminogen activator is both safe and effective for resolution of venous thrombosis in this high-risk population. PMID- 28889819 TI - Advances in the treatment of anorexia nervosa: a review of established and emerging interventions. AB - BACKGROUND: Anorexia nervosa (AN) is a disabling, deadly and costly mental disorder. Until recently, treatment recommendations were based on expert opinion and limited evidence. The aim of this systematic review is to synthesise recent evidence on established and emerging AN treatments and to forecast trends for future developments. METHODS: We systematically review trials of established treatments and associated process outcome studies from the last 5 years, published since a previous review in this journal. 'Established' treatments were those that are widely used in AN, recommended by guidelines and/or have been tested in at least one large randomised controlled trial. Secondly, we summarise emerging treatments for AN, i.e. those that have only been (or are currently being) tested in proof-of concept, feasibility or pilot trials. RESULTS: We identified 19 published trials of established treatments (15 of high or moderate quality), mostly assessing psychological therapies (n = 17). We also found 11 published trials of emerging treatments, and a total of 34 registered, as yet unpublished trials. Promising emerging treatments include cognitive remediation therapy, exposure therapy and non-invasive neuromodulation. CONCLUSIONS: Evidence generation on the treatment of AN has dramatically accelerated, with our understanding of the role of family-based approaches for adolescents more nuanced and a range of psychological approaches available for the treatment of adults. Evidence on emerging treatments and from forthcoming trials suggests that there is a shift towards more targeted brain-based interventions. Future studies need to focus on elucidating mechanisms of action of treatments and what works best for whom. PMID- 28889820 TI - Thoracoscopic treatment of left-to-right shunt in a child with scimitar syndrome. AB - Scimitar syndrome represents a rare variant of partial anomalous pulmonary venous connection with right lung hypoplasia, dextrocardia, and concomitant airway vessel abnormalities. Surgical correction is preferred in symptomatic patients or in patients with increased left-to-right shunt. In this report, the first case of scimitar syndrome with dual arterial supply and venous drainage to be treated with thoracoscopic approach is presented. PMID- 28889821 TI - Relating ASD symptoms to well-being: moving across different construct levels. AB - BACKGROUND: Little is known about the specific factors that contribute to the well-being (WB) of individuals with autism spectrum disorder (ASD). A plausible hypothesis is that ASD symptomatology has a direct negative effect on WB. In the current study, the emerging tools of network analysis allow to explore the functional interdependencies between specific symptoms of ASD and domains of WB in a multivariate framework. We illustrate how studying both higher-order (total score) and lower-order (subscale) representations of ASD symptomatology can clarify the interrelations of factors relevant for domains of WB. METHODS: We estimated network structures on three different construct levels for ASD symptomatology, as assessed with the Adult Social Behavior Questionnaire (item, subscale, total score), relating them to daily functioning (DF) and subjective WB in 323 adult individuals with clinically identified ASD (aged 17-70 years). For these networks, we assessed the importance of specific factors in the network structure. RESULTS: When focusing on the highest representation level of ASD symptomatology (i.e. a total score), we found a negative connection between ASD symptom severity and domains of WB. However, zooming in on lower representation levels of ASD symptomatology revealed that this connection was mainly funnelled by ASD symptoms related to insistence on sameness and experiencing reduced contact and that those symptom scales, in turn, impact different domains of WB. CONCLUSIONS: Zooming in across construct levels of ASD symptom severity into subscales of ASD symptoms can provide us with important insights into how specific domains of ASD symptoms relate to specific domains of DF and WB. PMID- 28889822 TI - The relationship between obesity and cognitive health and decline. AB - The relationship between obesity and cognitive impairment is important given the globally ageing population in whom cognitive decline and neurodegenerative disorders will carry grave individual, societal and financial burdens. This review examines the evidence for the link between obesity and cognitive function in terms of both the immediate effects on cognitive performance, and effects on the trajectory of cognitive ageing and likelihood of dementia. In mid-life, there is a strong association between obesity and impaired cognitive function. Anthropometric measures of obesity are also associated with reduced neural integrity (e.g. grey and white matter atrophy). Increasing age coupled with the negative metabolic consequences of obesity (e.g. type 2 diabetes mellitus) are likely to significantly contribute to cognitive decline and incidence of dementia. Stress is identified as a potential risk factor promoting abdominal obesity and contributing to impaired cognitive function. However, the potentially protective effects of obesity against cognitive decline in older age require further examination. Finally, surgical and whole diet interventions, which address obesity may improve cognitive capacity and confer some protection against later cognitive decline. In conclusion, obesity and its comorbidities are associated with impaired cognitive performance, accelerated cognitive decline and neurodegenerative pathologies such as dementia in later life. Interventions targeting mid-life obesity may prove beneficial in reducing the cognitive risks associated with obesity. PMID- 28889823 TI - Epigenetics and DOHaD: from basics to birth and beyond. AB - Developmental origins of health and disease (DOHaD) is the study of how the early life environment can impact the risk of chronic diseases from childhood to adulthood and the mechanisms involved. Epigenetic modifications such as DNA methylation, histone modifications and non-coding RNAs are involved in mediating how early life environment impacts later health. This review is a summary of the Epigenetics and DOHaD workshop held at the 2016 DOHaD Society of Australia and New Zealand Conference. Our extensive knowledge of how the early life environment impacts later risk for chronic disease would not have been possible without animal models. In this review we highlight some animal model examples that demonstrate how an adverse early life exposure results in epigenetic and gene expression changes that may contribute to increased risk of chronic disease later in life. Type 2 diabetes and cardiovascular disease are chronic diseases with an increasing incidence due to the increased number of children and adults that are obese. Epigenetic changes such as DNA methylation have been shown to be associated with metabolic health measures and potentially predict future metabolic health status. Although more difficult to elucidate in humans, recent studies suggest that DNA methylation may be one of the epigenetic mechanisms that mediates the effects of early life exposures on later life risk of obesity and obesity related diseases. Finally, we discuss the role of the microbiome and how it is a new player in developmental programming and mediating early life exposures on later risk of chronic disease. PMID- 28889824 TI - Differences in clinical outcomes and cost between complex and simple arterial switches. AB - BACKGROUND: This study evaluates the morbidity, mortality, and cost differences between patients who underwent either a simple or a complex arterial switch operation. METHODS: A retrospective study of patients undergoing an arterial switch operation at a single institution was performed. Simple cases were defined as patients with d-transposition of the great arteries with usual coronary anatomy or circumflex artery originating from the right with either intact ventricular septum or ventricular septal defect. Complex cases included all other forms of coronary anatomy, aortic coarctation or arch hypoplasia, and Taussig Bing anomalies. Costs were acquired using an institutional activity-based accounting system. RESULTS: A total of 98 patients were identified, 68 patients in the simple group and 30 in the complex group. The mortality rate was 2% for the simple and 7% for the complex group, p=0.23. Major morbidities including cardiac arrest, extracorporeal membrane oxygenation, a major coronary event, surgical or catheter-based re-intervention, stroke, or permanent pacemaker placement, non-cardiac surgical procedures, mediastinitis, and sepsis did not differ between the simple and complex groups (16 versus 27%, p=0.16). The complex group had increased bleeding requiring re-exploration (0 versus 10%, p=0.04). Hospital and ICU length of stay did not differ. Complex patients had higher overall hospital costs (simple $80,749 versus complex $97,387, p=0.01) and higher postoperative costs (simple $60,192 versus complex $70,132, p=0.02). The operating room and supplies accounted for the majority of the cost difference. CONCLUSION: Complex arterial switches can be safely performed with low rates of morbidity and mortality but at an increased cost. PMID- 28889825 TI - Enhancement of diuresis with metolazone in infant paediatric cardiac intensive care patients. AB - BACKGROUND: Few data are available regarding the use of metolazone in infants in cardiac intensive care. Researchers need to carry out further evaluation to characterise the effects of this treatment in this population. METHODS: This is a descriptive, retrospective study carried out in patients less than a year old. These infants had received metolazone over a 2-year period in the paediatric cardiac intensive care unit at our institution. The primary goal was to measure the change in urine output from 24 hours before the start of metolazone therapy to 24 hours after. Patient demographic variables, laboratory data, and fluid balance data were analysed. RESULTS: The study identified 97 infants with a mean age of 0.32+/-0.25 years. Their mean weight was 4.9+/-1.5 kg, and 58% of the participants were male. An overall 63% of them had undergone cardiovascular surgery. The baseline estimated creatinine clearance was 93+/-37 ml/minute/1.73 m2. Initially, the participants had received a metolazone dose of 0.27+/-0.10 mg/kg/day, the maximum dose being 0.43 mg/kg/day. They had also received other diuretics during metolazone initiation, such as furosemide (87.6%), spironolactone (58.8%), acetazolamide (11.3%), bumetanide (7.2%), and ethacrynic acid (1%). The median change in urine output after metolazone was 0.9 ml/kg/hour (interquartile range 0.15-1.9). The study categorised a total of 66 patients (68.0%) as responders. Multivariable analysis identified acetazolamide use (p=0.002) and increased fluid input in the 24 hours after metolazone initiation (p0.05). CONCLUSIONS: Metolazone increased urine output in a select group of patients. Efficacy can be maximised by strategic selection of patients. PMID- 28889826 TI - Recombinant factor VIIa as a rescue therapy in severe haemoptysis in a patient with a Fontan circulation. AB - We describe the successful use of recombinant factor VIIa (rFVIIa) in the control of massive haemoptysis in a 17-year-old patient with a Fontan circulation. The patient was intubated and ventilated in the ICU with deteriorating gas exchange. Conventional methods to control the haemoptysis were ineffective, and rFVIIa was successfully administered as a rescue therapy. rFVIIa is a powerful pro thrombotic agent, which is only licensed in haemophiliacs with acquired inhibitors to anticoagulation. It has been used off-license in the treatment of massive haemorrhage, although a Cochrane review did not show any significant benefit; however, it may have a role as a rescue therapy where alternatives options have been exhausted after careful risk-benefit analysis. PMID- 28889827 TI - Multidisciplinary family-centred psychosocial care for patients with CHD: consensus recommendations from the AEPC Psychosocial Working Group. AB - Because of the enormous advances in the medical treatment of CHD, the long-term survival of patients suffering from this disease has increased significantly. Currently, about 90% of patients reach adulthood, which entails many new challenges both for patients and their families and for healthcare professionals. The main objective of family-centred psychosocial care is to strengthen the emotional resilience of chronically ill patients and their families by adopting a holistic approach. During the biannual meeting of the psychosocial working group in 2012, participants expressed the need for general European guidelines. The present recommendations were written to support medical staff and psychosocial healthcare professionals to provide the best care for children and adolescents with CHD as well as for their families. This article describes in detail how the integrated family-centred psychological care modules work, involving different healthcare specialists, including a paediatric/congenital cardiologist or a general paediatrician. The different clinical implications and specific needs have been taken into account and recommendations have been provided on the following: structured follow-up screening; identification of stressful periods related to cardiac surgery or invasive medical procedures; evidence-based, disease-specific, and family-oriented psychosocial interventions; and interactive media links to medical and psychosocial information. PMID- 28889828 TI - Atrial septal defect morphology and stenting in hypoplastic left heart syndrome after hybrid palliation. AB - : Aims The aim of this study was to describe atrial septal defect morphology in hypoplastic left heart syndrome, to report the incidence of restrictiveness and its relationship with defect morphology, to correlate restriction with midterm outcome, and to describe our interventional approach to restrictive defect. Methods and results From 2011 to 2015, 31 neonates with hypoplastic left heart syndrome underwent hybrid procedure with pulmonary artery banding and ductal stenting at our Institution. Restrictive physiology of the atrial septal defect was based on Doppler gradient >6 mmHg through the defect and on clinical signs of pulmonary hypertension. The mean gradient was then measured invasively. Restrictive defect occurred in 11/27 patients (40%). The restrictive group showed three ostium secundum defects (27%) and eight complex morphologies (73%). Conversely, in the non-restrictive group, we observed 11 ostium secundum defects (69%) and five complex morphologies (31%). Early balloon atrioseptostomy was required in three cases. Late restriction occurred in eight patients and was dealt with balloon dilation, stenting, or atrioseptectomy. There was no significant difference between restrictive and non-restrictive groups in terms of early or 12-month survival. CONCLUSIONS: Complex morphologies were more frequently related to restrictiveness. Stenting technique has a crucial role, as the procedure carries a significant risk for stent migration. Effective treatment of restrictive atrial septal defect is related to a better outcome, as it leads to equalisation of survival between patients with and those without restrictive atrial septal defect. PMID- 28889829 TI - Neutrophil gelatinase-associated lipocalin reflects inflammation and is not a reliable renal biomarker in neonates and infants after cardiopulmonary bypass: a prospective case-control study. AB - : Introduction Acute kidney injury is a frequent complication after cardiac surgery with cardiopulmonary bypass in infants. Neutrophil gelatinase-associated lipocalin has been suggested to be a promising early biomarker of impending acute kidney injury. On the other hand, neutrophil gelatinase-associated lipocalin has been shown to be elevated in systemic inflammatory diseases without renal impairment. In this secondary analysis of data from our previous study on acute kidney injury after infant cardiac surgery, our hypothesis was that neutrophil gelatinase-associated lipocalin may be associated with surgery-related inflammation. METHODS: We prospectively enrolled 59 neonates and infants undergoing cardiopulmonary bypass surgery for CHD and measured neutrophil gelatinase-associated lipocalin in plasma and urine and interleukin-6 in the plasma. Values were correlated with postoperative acute kidney injury according to the paediatric Renal-Injury-Failure-Loss-Endstage classification. RESULTS: Overall, 48% (28/59) of patients developed acute kidney injury. Of these, 50% (14/28) were classified as injury and 11% (3/28) received renal replacement therapy. Both plasma and urinary neutrophil gelatinase-associated lipocalin values were not correlated with acute kidney injury occurrence. Plasma neutrophil gelatinase-associated lipocalin showed a strong correlation with interleukin-6. Urinary neutrophil gelatinase-associated lipocalin values correlated with cardiopulmonary bypass time. CONCLUSION: Our results suggest that plasma and urinary neutrophil gelatinase-associated lipocalin values are not reliable indicators of impending acute kidney injury in neonates and infants after cardiac surgery with cardiopulmonary bypass. Inflammation may have a major impact on plasma neutrophil gelatinase-associated lipocalin values in infant cardiac surgery. Urinary neutrophil gelatinase-associated lipocalin may add little prognostic value over cardiopulmonary bypass time. PMID- 28889830 TI - Endocarditis of a congenital coronary fistula in a child. AB - Endocarditis of congenital coronary fistulas in the cardiac chambers is rare, especially in the paediatric age group. We describe the case of a 9-year-old boy with a fistula from the dilated right coronary artery to the junction of the superior caval vein to the right atrium, complicated by endocarditis. Treatment consisted of 6 weeks of antibiotics and interventional closure of the fistula 3 months later with an Amplatzer vascular plug. PMID- 28889831 TI - Methodological and practical viewpoints of qualitative-driven mixed method design: the case of decentralisation of primary healthcare services in Nepal. AB - BACKGROUND: Although considerable attention has been paid to the use of quantitative methods in health research, there has been limited focus on decentralisation research using a qualitative-driven mixed method design. Decentralisation presents both a problematic concept and methodological challenges, and is more context-specific and is often multi-dimensional. Researchers often consider using more than one method design when researching phenomena is complex in nature. Aim To explore the effects of decentralisation on the provision of primary healthcare services. METHODS: Qualitative-driven mixed method design, employing three methods of data collections: focus group discussions (FGDs), semi-structured interviews (SSIs) and participant observations under two components, that is, core component and supplementary components were used. Four FGDs with health service practitioners, three FGDs with district stakeholders, 20 SSIs with health service users and 20 SSIs with national stakeholders were carried out. These were conducted sequentially. NVivo10, a data management program, was utilised to code the field data, employing a content analysis method for searching the underlying themes or concepts in the text material. Findings Both positive and negative experiences related to access, quality, planning, supplies, coordination and supervision were identified. CONCLUSION: This study suggests some evidence of the effects of decentralisation on health outcomes in general, as well as filling a gap of understanding and examining healthcare through a qualitative-driven mixed methods approach, in particular. Future research in the area of qualitative in-depth understanding of the problems (why decentralisation, why now and what for) would provoke an important data set that benefits the researchers and policy-makers for planning and implementing effective health services. PMID- 28889832 TI - Intra-individual Cognitive Variability: An Examination of ANAM4 TBI-MIL Simple Reaction Time Data from Service Members with and without Mild Traumatic Brain Injury. AB - OBJECTIVES: The Automated Neuropsychological Assessment Metrics 4 TBI-MIL (ANAM4) is a computerized cognitive test often used in post-concussion assessments with U.S. service members (SMs). Existing evidence, however, remains mixed regarding ANAM4's ability to identify cognitive issues following mild traumatic brain injury (mTBI). Studies typically examine ANAM4 by comparing mean scores to baseline or normative scores. A more fine-grained approach involves examining inconsistency within an individual's performance. METHODS: Data from a sample of 231 were healthy control SMs and 100 SMs within 7 days of mTBI who took the ANAM4 were included in analyses. We examine each individual's performance on a simple reaction time (SRT) subtest that is administered at the beginning (SRT1) and end (SRT2) of the ANAM4 battery, and calculate the standard deviation of difference scores by trial across administrations. RESULTS: Multivariate analysis of variance and univariate analyses revealed group differences across all comparisons (p0.41). CONCLUSIONS: While inconsistencies in performance are often viewed as noise or test error, the results suggest intra-individual cognitive variability may be more sensitive than central tendency measures (i.e., comparison of means) in detecting changes in cognitive function in mTBI. Additionally, the findings highlight the utility of ANAM4's repeating a subtest at two points in a battery to explore within-subject differences in performance. (JINS, 2017, 23, 1-6). PMID- 28889833 TI - Acute kidney injury following first-stage palliation in hypoplastic left heart syndrome: hybrid versus Norwood palliation. AB - OBJECTIVE: The aim of this study was to evaluate the prevalence of acute kidney injury after first-stage surgical palliation in patients with a single ventricle and to explore associated risk factors and outcomes. Design and patients This single-centre retrospective study included neonates who underwent either Norwood or Hybrid procedure from 2008 to 2015 for a single ventricle. Postoperative acute kidney injury was defined using the paediatric risk, injury, failure, loss, end stage renal disease (pRIFLE), criteria within 72 hours of the procedure. Main results Our cohort (n=48) underwent surgical palliation at a mean (SD) age of 12 (11) days. Postoperative acute kidney injury was diagnosed in 14 (29%) patients. The prevalence of acute kidney injury in the Hybrid group was 16% and 53% in the Norwood group. Infants who developed acute kidney injury underwent surgery at younger ages [6 (5-10) versus 10 (8-16) days, p=0.016], and had a higher peak lactate level in the initial 24 hours [5.9 (4.2-9.1) versus 3.4 (2.4-6.7), p=0.007]. Norwood procedure was significantly associated with acute kidney injury [odds ratio 11.7 (95% confidence interval 1.3-101.9), p=0.03]. ICU stay [38 (21 84) versus 16 (6-45) days, p=0.038] and time to extubation [204 (120-606) versus 72 (26-234) hours, p=0.014] were longer in those with acute kidney injury. The two patients who developed early postoperative renal failure as per pRIFLE died before discharge from associated comorbidities. CONCLUSIONS: Acute kidney injury occurs in a third of the patients with single ventricle after surgical palliation but is mostly transient. Norwood, compared with Hybrid procedure, is a risk factor for postoperative acute kidney injury, which, in turn, is associated with longer ICU stay and time to extubation. PMID- 28889834 TI - Comparison of an interviewer-administered with an automated self-administered 24 h (ASA24) dietary recall in adolescents. AB - OBJECTIVE: The current pilot study aimed to assess whether reporting quality would decline materially in adolescents completing weekly web-based Automated Self-Administered 24-Hour dietary recalls (ASA24-Kids-2014) and interviewer administered 24 h dietary recalls for six weeks. We also aimed to assess method preference. DESIGN: We conducted two studies. Study 1 (n 20) randomized participants to complete either one ASA24-Kids-2014 or one interviewer administered recall weekly, for six weeks. Energy intake and number of foods reported were described for each method over time. Differences between recall methods for each measure were tested using mixed-effects regression. Study 2 (n 10) employed a randomized crossover design to describe method preference. SETTING: Dietary intake was collected either by telephone (interviewer administered dietary recalls) or via the Internet (ASA24-Kids-2014 dietary recalls). SUBJECTS: Adolescents aged 12-17 years with no prior diet recording experience were enrolled. RESULTS: In Study 1, mean (sd) total energy and number of foods reported decreased by 50 (222) kJ (12 (53) kcal) and 0.05 (0.31) items v. 38 (138) kJ (9 (33) kcal) and 0.17 (0.14) items per recall for participants randomized to the ASA24-Kids-2014 v. interviewer-administered recalls, respectively. There was no difference between groups for either measure (P > 0.57). In Study 2, eight of ten participants preferred the interviewer administered recall over the ASA24-Kids-2014. Overall, seven of twenty participants experienced technical difficulties with the ASA24-Kids-2014. CONCLUSIONS: No appreciable decay in reporting quality was seen for either method. However, participants reported a preference for the interviewer administered recall. Our findings can help inform and support larger studies to further characterize the performance of the ASA24 in adolescents. PMID- 28889835 TI - Corrigendum to "Context-Dependent Remodeling of Rad51-DNA Complexes by Srs2 Is Mediated by a Specific Protein-Protein Interaction" [J. Mol. Biol.426 (2014) 1883 1897]. PMID- 28889836 TI - Radiologia: state of the journal at a point of change. PMID- 28889837 TI - Electrodermal Conductance at Acupuncture Points and Asthma. PMID- 28889838 TI - Reply to the Letter to the Editor (Electrodermal Conductance at Acupuncture Points and Asthma). PMID- 28889839 TI - Laser Acupuncture at HT7 Improves the Cerebellar Disorders in Valproic Acid-Rat Model of Autism. AB - The novel therapeutic strategy against autism is essential due to the limited therapeutic efficacy. Based on the benefit of laser acupuncture at HT7 acupoint on the neurological disorders related with oxidative stress and inflammation, its benefit on oxidative stress, neuroinflammation, and GABAergic/glutamatergic imbalance in cerebellum of autism have been considered. To elucidate this issue, male rat pups were induced autistic-like conditions by valproic acid (VPA) and treated with laser acupuncture at HT7 acupoint once daily between postnatal Day 14 and Day 40. At the end of study, the changes of oxidative stress markers, the expressions of cytokines interleukin 6 (IL-6) and glutamic acid decarboxylase (GAD) proteins (65 kDa and 67 kDa) together with gamma-aminobutyric acid transaminase (GABA-T) activity and density of Purkinje cell in the cerebellum were assessed. The results showed that laser acupuncture HT7 decreased oxidative stress, IL-6 expression, and GABA-T activity but increased the expressions of GAD 65 kDa together with the density of Purkinje cells in the cerebellum. Therefore, laser acupuncture at HT7 is the potential strategy to improve the cerebellar disorders in VPA-rat model of autism. The mechanism may occur partly via the decrease of oxidative stress status, inflammation, and the improved GABAergic function. PMID- 28889840 TI - Immediate Effect of Needling at CV-12 (Zhongwan) Acupuncture Point on Blood Glucose Level in Patients with Type 2 Diabetes Mellitus: A Pilot Randomized Placebo-Controlled Trial. AB - INTRODUCTION: Diabetes mellitus is a major global health problem. Needling at CV 12 has reduced blood glucose level in diabetic rats. The aim of this study was to evaluate the effect of needling at CV-12 (Zhongwan) on blood glucose level in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Forty T2DM patients were recruited and randomized into either the acupuncture group or placebo control group. The participants in the acupuncture group were needled at CV-12 (4 cun above the center of the umbilicus), and those in the placebo control group were needled at a placebo point on the right side of the abdomen (1 cun beside the CV-12). For both groups, the needle was retained for 30 minutes. Assessments were performed prior to and after the intervention. Statistical analysis was performed using SPSS version 16. RESULTS: There was a significant reduction in random blood glucose level in the acupuncture group compared to baseline. No such significant change was observed in the placebo control group. CONCLUSION: The result of this study suggests that 30 minutes of needling at CV 12 might be useful in reducing blood glucose level in patients with T2DM. PMID- 28889841 TI - Hwanglyunhaedok Pharmacopuncture versus Saline Pharmacopuncture on Chronic Nonbacterial Prostatitis/Chronic Pelvic Pain Syndrome. AB - PURPOSE: Chronic nonbacterial prostatitis (CP)/chronic pelvic pain syndrome (CPPS) is known not to have a successful therapy as yet. More recently, acupuncture, some herbal compounds, and trigger point injection have been reported to be beneficial. Pharmacopuncture is an herbal acupuncture having these benefits. The aim of this study was to compare the effect of HP (Hwanglyunhaedok Pharmacopuncture) versus normal saline injection (Saline Pharmacopuncture, SP) on CP/CPPS. METHODS: A retrospective follow up study of 63 patients who were diagnosed with CP/CPPS was performed. All patients were treated with electroacupuncture and injected with either 1 ml of HP or SP at CV1 as a standard treatment for 4 weeks. Thus, the patients were classified in two groups: HP (n = 32) and SP group (n = 31). Treatment was applied twice a week every third day for 4 weeks. After 4 weeks, the effect of pharmacopunture in both groups was compared using NIH-CPSI (National Institutes of Health-Chronic Prostatitis Symptom Index) and IPSS (International Prostate Symptom Score) before and after treatment. RESULTS: After treatment, the total NIH-CPSI scores were significantly reduced in both groups (p < 0.01). Pain domain scores in both groups showed significant decrease (p < 0.01). In HP group, urination (p < 0.05) and quality of life (p < 0.01) scores reduced significantly. In SP group, impact score showed significant decrease (p < 0.05). However, impact score in HP group and urination and quality of life scores in SP group didn't show any significance. IPSS score was reduced significantly after treatment in both groups (p < 0.05). CONCLUSIONS: These results suggest that pharmacopuncture and electroacupuncture treatment were effective on CP/CPPS. HP and SP didn't show any significant difference. However, it was also confirmed that HP is more favorable than SP to improve the symptoms of CP/CPPS. PMID- 28889842 TI - Effects of Acupuncture on 1-chloro-2,4-dinitrochlorobenzene-induced Allergic Contact Dermatitis in Mice. AB - Allergic contact dermatitis (ACD) is a chronic inflammatory skin disease. Topical corticosteroids are the first-line therapy for ACD despite their significant adverse effects. Acupuncture has been widely used in the treatment of various skin diseases, but its underlying mechanism remains unrevealed. In this study, we investigated the characteristics of acupuncture treatment based on effectiveness and mechanism. BALB/c mice received 1-chloro-2,4-dinitrobenzene (DNCB) application to build AD-like model. Results showed that acupuncture was an effective treatment method in inhibiting inflammatory conditions, serum IgE levels, and expression of proinflammatory cytokine Th2 (IL-4, IL-6), and Th2 (IL 1beta, TNF-alpha) mRNA compared with DNCB treatment. Acupuncture treatment also inhibited nuclear factor-kappaB p65, phosphorylation of IkappaBalpha, and phosphorylation of occludin proteins expression. Furthermore, it could improve the expression of epidermal growth factor in both mRNA and protein levels. These results suggest that acupuncture, as an alternative therapy treatment for its no significant side effects, was effective in alleviating ACD by reducing proinflammatory cytokines and changing proteins' expression. PMID- 28889843 TI - Quality Assessment of Randomized Controlled Trials of Moxibustion Using STandards for Reporting Interventions in Clinical Trials of Moxibustion (STRICTOM) and Risk of Bias (ROB). AB - OBJECTIVES: To assess the quality and completeness of published reports of randomized controlled trials (RCTs) of moxibustion. METHOD: We searched six databases to retrieve eligible RCTs of moxibustion published from 2000 to December 2015. We used the STandards for Reporting Interventions in Clinical Trials of Moxibustion (STRICTOM) and Risk of Bias (ROB) tool to assess the completeness of reporting of RCTs of moxibustion and evaluate the reporting quality of included RCTs. RESULTS: Thirty-four studies of moxibustion were analyzed using STRICTOM and ROB. Of the 34 studies, the completeness percentage of STRICTOM varied from 33% to 100% (mean 68%, median 67%). The completeness of STRICTOM items showed a rising tendency along with the publication year. The STRICTOM items of setting and context (14.7%), rationale for the control (17.6%), and response (26.4%) showed incomplete reporting. The number of RCTs that rated a low risk of bias for allocation concealment (n=6), blinding of participants and personnel (n=1), and blinding of outcome assessment (n=4) appeared to be small. CONCLUSION: The quality of reporting of RCTs of moxibustion remains incomplete according to the STRICTOM and ROB tool at present. Researchers should consider the STRICTOM and ROB for improving not only the completeness of reporting but also the study design. General guidelines for RCTs of moxibustion are also required. PMID- 28889844 TI - Development of a Novel Questionnaire for the Traditional Chinese Medicine Pattern Diagnosis of Stress. AB - Currently, there is no definitive diagnosis or list of signs and symptoms for "stress" in either modern biomedicine or Chinese medicine (CM). While modern theories on stress relate to the neurological interaction of a stressor or stimuli on the autonomic nervous system, it is generally regarded as subjective in nature and as such each individual will likely present varying somatic or cognitive signs and symptoms. A questionnaire was therefore developed, based on textual research, that incorporated both general as well as gender specific signs and symptom responses to determine the most common CM patterns associated with individuals who report as feeling stressed. For the 45 females who completed the questionnaire, the mean percentage of symptoms per CM pattern showed that the pattern with the highest average percentage was heart qi deficiency (61.88%) followed by liver blood deficiency (60.23%) and then heart blood deficiency (60.12%). For males (n = 16), heart qi deficiency was also the highest scoring CM pattern with a scoring percentage of 54.81%. In males, however, heart blood deficiency was second with 53.29% followed by liver blood deficiency with 51.10%. Of the general non gender-specific symptoms collected (n = 65 symptoms), the symptom most commonly reported by both men and women was "anxious or racing thoughts", followed by "constant worrying" and "inability to concentrate". The CM diagnostic pattern results may prove useful for clinicians as the change in diagnostic understanding will also modify the treatment principle and subsequent treatment with acupuncture or herbal medicine. Future CM research studies should consider including the questionnaire either as a diagnostic aid or as an outcome measure for acupuncture or herbal medicine studies related to stress. PMID- 28889845 TI - Effect of Electroacupuncture Rehabilitation in Transverse Myelitis: A Case Report. AB - A 32-year-old male diagnosed with transverse myelitis in 2013 came to our clinic in 2015 with complaints of paraplegia, sensory disturbances, pain, exertional dyspnea, poor quality of sleep, emotional instability, and depression. This was a recurrent attack that had been exacerbated by post-traumatic stress. Owing to pain and functional disabilities, he was struggling to actively participate in the treatment modalities offered at our center. A modified protocol of electroacupuncture was planned for a period of 21 days, every day, with each session lasting for 30 minutes. Assessments based on the brief version of World Health Organization Brief Quality of Life (WHO Brief QOL) questionnaire, Pittsburgh sleep quality index, visual analog scale, and a disease-specific physical examination showed momentous improvement in functional health status as well as mental well-being. The quality of life showed significant improvement particularly in the physical and psychological dimensions of WHO Brief QOL. The patient reported a reduction in pain, dyspnea, and fatigue accompanied by an improvement in the quality of sleep and mood. This case report suggests that acupuncture can play a vital role in amelioration of symptoms, thereby improving the health status in patients with transverse myelitis. PMID- 28889846 TI - Acupuncture for Management of Type 2 Diabetes Mellitus in a Patient with Myasthenia Gravis: A Case Report. AB - Myasthenia gravis (MG) is an acquired disease of the neuromuscular junctions characterized by muscular weakness and fatigue, with a prevalence of 50-125 cases per million population in western countries. In men, it usually appears after the age of 60 years, while in women, it usually appears before the age of 40 years. Long-term immunosuppression with corticosteroids is the mainstay treatment for patients with MG; however, the use of corticosteroids is a well-documented risk factor for type 2 diabetes mellitus, which has also been reported in steroid treated patients with MG. Here, a case of type 2 diabetes mellitus in a patient with MG who underwent 105 sessions of acupuncture delivered over 6 months is reported. After acupuncture treatment, the patient's fasting plasma glucose and hemoglobin A1c levels, as well as the score on the Hamilton Depression Rating Scale, were decreased. Furthermore, no adverse effects were observed. The findings in this clinical study are encouraging and provide evidence supporting the effectiveness of acupuncture in reducing type 2 diabetes mellitus in a patient with MG. PMID- 28889847 TI - Acupuncture for Symptom Relief in Palliative Care-Study Protocol and Semistandardized Treatment Schemes. AB - The use of complementary and alternative medicine methods such as acupuncture in palliative care has increased over the past years. Well-planned trials are warranted to show its effectiveness in relieving distressing symptoms. The development of treatment schemes to be used in the trial for both acupuncture and medical symptom control is challenging, as both acupuncture and palliative care are highly individualized. Thus, standardized care plans of a randomized controlled trial will have difficulties in producing treatment results that compare to the clinical practice. As an alternative, treatment protocols for both acupuncture and medical symptom control of dyspnea, pruritus, hypersalivation, depression, anxiety, and xerostomia were designed with the input of experts. They are designed to provide sufficient symptom control and comparability for a three arm, randomized controlled trial. Medical symptom control will be provided to all groups. The two control groups will be medical treatment and sham-laser acupuncture. PMID- 28889848 TI - Honoring Our Past and Embracing Our Present Defines Our Future in Research, Practice, and Policies. PMID- 28889849 TI - Nutrition Economics. PMID- 28889850 TI - Healthy Checkout Lines: A Study in Urban Supermarkets. AB - OBJECTIVE: To understand the impact of healthy checkouts in Bronx, New York City supermarkets. DESIGN: Consumer purchasing behavior was observed for 2 weeks in 2015. SETTING: Three supermarkets in the South Bronx. PARTICIPANTS: A total of 2,131 adult shoppers (aged >=18 years) who paid for their groceries at 1 of the selected study checkout lines. INTERVENTION: Two checkout lines were selected per store; 1 was converted to a healthy checkout and the other remained as it was (standard checkout). Data collectors observed consumer behavior at each line and recorded items purchased from checkout areas. MAIN OUTCOME MEASURES: Percentage of customers who purchase items from the checkout area; quantity and price of healthy and unhealthy items purchased from the healthy and standard checkout lines. ANALYSIS: Measures were analyzed by study condition using chi-square and t tests; significance was determined at alpha = .05. RESULTS: Only 4.0% of customers bought anything from the checkout area. A higher proportion of customers using the healthy vs standard checkout line bought healthy items (56.5% vs 20.5%; P < .001). CONCLUSIONS AND IMPLICATIONS: When healthier products were available, the proportion of healthy purchases increased. Findings contribute to limited research on effectiveness of healthy checkouts in supermarkets. Similar interventions should expect an increase in healthy purchases from the checkout area, but limited overall impact. PMID- 28889851 TI - The Affordability of MyPlate: An Analysis of SNAP Benefits and the Actual Cost of Eating According to the Dietary Guidelines. AB - OBJECTIVE: To estimate the funds required to support a MyPlate diet and to estimate the additional costs needed for Supplemental Nutrition Assistance Program recipients to adhere to the MyPlate diet. DESIGN: Using the US Department of Agriculture's (USDA's) MyPlate dietary guidelines that specify recommendations for individuals based on age and gender and retail price data from the USDA, the cost of following USDA's MyPlate guidelines for consuming 3 meals daily was estimated for the following individuals: children, adolescents, female adults, male adults, female seniors, male seniors, and a 4-person family. MAIN OUTCOME MEASURES: Cost of consuming a MyPlate diet, including canned, frozen, and fresh produce as part of the diet. ANALYSIS: Descriptive analysis of the cost of consuming a MyPlate diet. RESULTS: Consuming a MyPlate diet consisting of only fresh fruits and vegetables is the most expensive diet. The monthly additional costs on an individual basis is the largest for boys aged 12-17 years ($75/mo) because they have the largest quantity of food consumed compared with all other gender and age groups. The monthly cost for a family of 4 ranged from $1,109 to $1,249/mo. CONCLUSIONS AND IMPLICATIONS: The monetary amount of Supplemental Nutrition Assistance Program benefits may be insufficient to support a healthy diet recommended by federal nutrition guidelines. PMID- 28889852 TI - The Impact of Economic Conditions on Healthy Dietary Intake: Evidence From Fluctuations in Canadian Unemployment Rates. AB - OBJECTIVE: This study examined the impact of economic conditions on fruit and vegetable consumption using multiple waves of the Canadian Community Health Survey. DESIGN: By using metropolitan-area variation in the unemployment rate as a proxy for economic conditions, various measures of fruit and vegetable consumption were regressed on this unemployment rate, using a 2-way fixed effect estimation strategy. MAIN OUTCOME MEASURES: The following measures of fruit and vegetable consumption were considered: (1) total number of times per day respondents ate fruits and vegetables and (2) servings of fruit of vegetable consumption (<5 times/d, 5-10 times/d, and >10 times/d). ANALYSIS: Regression models with location and time-fixed effects were estimated to explore the impact of the unemployment rate with the measures of fruit and vegetable consumption. Pearson's chi-square tests were used to examine subgroup differences by gender. RESULTS: Findings suggested that increases in the unemployment rate (ie, worse economic conditions) reduced fruit and vegetable consumption, and this result was robust across gender and education levels. CONCLUSIONS AND IMPLICATIONS: These findings contribute to a small but important body of literature that focuses specifically on the relationship between economic conditions and fruit and vegetable consumption. PMID- 28889853 TI - Supplemental Nutrition Assistance Program Participation and Emergency Food Pantry Use. AB - OBJECTIVE: To determine the association between Supplemental Nutrition Assistance Program (SNAP) participation and pantry use. DESIGN: A pretest-posttest design that compared pantry use at program enrollment and after 6 months of participation while controlling for household, economic, and geographic characteristics. SETTING: Supplemental Nutrition Assistance Program Food Security Survey: a national telephone survey of SNAP new-entrant households conducted in 2011-2012. PARTICIPANTS: A total of 3,191 households that completed baseline interviews and were still participating in SNAP approximately 6 months later. MAIN OUTCOME MEASURE: Received emergency food from pantries in the past 30 days. ANALYSIS: Logistic regression analysis of pantry use with SNAP participation and time-varying household characteristics as independent variables. Statistical significance was assessed using t tests. The authors applied a Bonferroni adjustment to account for multiple comparisons performed. RESULTS: Participating in SNAP for 6 months was associated with a decrease in pantry use by 5.2 percentage points (P < .001), representing a 24% reduction (from 21.8% to 16.6%). CONCLUSIONS AND IMPLICATIONS: Supplemental Nutrition Assistance Program benefit allotments are sufficient for some households, but 76% of SNAP households that enter the program while using pantries continue to do so about 6 months later, which underscores the need to assess the adequacy of SNAP benefit allotments in ensuring access to sufficient food for a healthy, active life. PMID- 28889854 TI - The Association Between Consumer Competency and Supplemental Nutrition Assistance Program Participation on Food Insecurity. AB - OBJECTIVE: To examine whether Supplemental Nutrition Assistance Program (SNAP) participants exhibited lower food insecurity when they also demonstrated desirable behaviors in the areas of financial management, nutrition literacy, and conscientious food shopping. DESIGN: Using data from the US Department of Agriculture's newly launched National Household Food Acquisition and Purchase Survey, this study examined whether consumer competency is a factor that affects food insecurity. PARTICIPANTS: A total of 4,158 participants were included. Sampling weights were applied to represent the population better. MAIN OUTCOME MEASURE(S): Very low food insecurity was the dependent variable. Important independent variables were participants' financial management skills, nutrition literacy, and conscientious shopping. ANALYSIS: Logit and 2-staged least-squares models were used for empirical analyses. The significance of models was tested at .05, .01, and .001. RESULTS: Consumer competency-related factors such as financial management ability, not defaulting on bill payments within the previous 6 months, and using the nutrition panel frequently when shopping were negatively associated with food insecurity and very low food security after controlling for a number of other demographic, socioeconomic, and behavioral characteristics. CONCLUSIONS AND IMPLICATIONS: Policies that focus solely on consumer competency programs such as SNAP-Education might marginally achieve program goals but the effect would be modest owing to the unique challenges that SNAP participants may face. Further investigations are needed to understand better why SNAP participants do not benefit successfully from competent consumer practices. PMID- 28889855 TI - Dietary Intake Contributions of Food and Beverages by Source and Food Security Status in US Adults. AB - OBJECTIVE: To compare the consumption patterns and diet quality of foods and beverages obtained from various sources by food security status. DESIGN: Cross sectional analysis of 2011-2012 National Health and Nutrition Examination Survey data. PARTICIPANTS: A total of 4,789 adults (aged >19 years) with dietary intake and food security data. MAIN OUTCOME MEASURES: The contribution of foods and beverages to energy, nutrients, and diet quality by locations where food was obtained was compared across food security status. ANALYSIS: Descriptive analysis and logistic regression. RESULTS: Almost all US adults consumed food and beverages obtained from grocery stores, regardless of food security status (about 95%), which accounted for one half to two thirds of total macronutrient intakes. The diet quality of foods from grocery stores was better in highly food-secure adults. Convenience stores are used most by very low food-secure adults; those foods had the poorest diet quality profile. Dietary patterns of marginally food secure adults more closely resembled sources and intakes of low and very low food secure adults. CONCLUSIONS AND IMPLICATIONS: Food-insecure adults use food sources differently, resulting in diet quality differences of foods and beverages obtained. Place-based interventions in the food environment may have differential effects by food security status. PMID- 28889857 TI - A Comment on Guthrie J "Integrating Behavioral Economics Into Nutrition Education Research and Practice". PMID- 28889856 TI - Foods and Beverages Available at SNAP-Authorized Drugstores in Sections of North Carolina. AB - OBJECTIVE: To assess healthy food availability in Supplemental Nutrition Assistance Program-authorized drugstores by store chain and neighborhood income level in 3 regions of North Carolina. DESIGN: Cross-sectional, descriptive study. SETTING: Twenty-five counties in North Carolina. PARTICIPANTS: A total of 108 drugstores (36 CVS Health, 36 Rite Aid, and 36 Walgreens). MAIN OUTCOME MEASURE(S): Fifty foods and beverages offered at drugstores, categorized as healthier and less healthy. ANALYSIS: Kruskal-Wallis tests were used to test differences in the availability of foods and beverages by chain and neighborhood income. RESULTS: Of the 50 foods/beverages observed, 11 were available at all drugstores. Three of the 36 (8%) healthier items were available at all stores (100% fruit juice, water, and high-fiber cereal) whereas 8 of the 14 less healthy items (57%) were available at all stores (chips, sports drinks, energy drinks, regular soda, diet soda, sugar-sweetened beverages, beer, and wine). Only 3% of drugstores offered fresh vegetables and 4% offered fresh fruits. Less than 20% offered frozen chicken or beef. For 36 healthier foods, 11 differed by chain (28%); for less healthy foods 2 of 14 differed by chain (7%). Foods and beverages offered did not vary by neighborhood income. CONCLUSIONS AND IMPLICATIONS: Although drugstores offer some healthier items, few offer fresh produce. As the drugstore industry changes, it is important for the nutrition community to study the impact of these changes on food purchasing behavior and ultimately health. PMID- 28889858 TI - Response to "A Comment on Guthrie J 'Integrating Behavioral Economics Into Nutrition Education Research and Practice'". PMID- 28889859 TI - Erratum. PMID- 28889860 TI - Improving uncertainty in Widmark equation calculations: Alcohol volume, strength and density. AB - The Widmark equation is probably the most commonly used calculation for medicolegal purposes. Recently the National Research Council (USA) and the Forensic Science Regulator (UK) have called for the uncertainty of all results to be given with all forensic measurements and calculations. To improve the uncertainty of measurement of results from Widmark calculations we have concentrated on the uncertainties of measurement involved in the calculation of amount of alcohol, that of the volume of alcohol, the concentration of alcohol and the density of alcohol as previous studies have investigated some of the other factors involved. Using experimental studies, the scientific literature and legal statutes, we have determined revised and improved uncertainties of the concentration of ethanol for Widmark calculations for both the USA and UK. Based on the calculations that we have performed we recommend the use of Monte Carlo Simulation for the determination of uncertainty of measurement for Widmark Calculations. PMID- 28889861 TI - Forensic science and the right to access to justice: Testing the efficacy of self examination intimate DNA swabs to enhance victim-centred responses to sexual violence in low-resource environments. AB - In developed countries, DNA profiling routinely forms part of the forensic strategy in the investigation of sexual violence. Medical examinations provide opportunities for recovering DNA evidence from intimate swabs, which can be particularly probative in cases where the identity of the perpetrator is unknown and proof of intercourse between two people is required. In low-resource environments, such as developing countries, remote geographic locations, conflict (and post-conflict) affected regions and displaced communities where access to medical examinations is lacking, DNA evidence is not available to support prosecutions and perpetrators are rarely identified and held accountable for crimes of sexual violence. This paper reports the results of a proof-of-concept study testing the efficacy of a novel self-examination intimate swab designed for recovering DNA following unprotected sexual intercourse. The results of this study corroborate previous research which has demonstrated that male DNA profiles can be successfully recovered by post-coital, self-examination methods, and discusses how this novel approach could enable the integration of DNA evidence into victim-centred approaches to investigating and prosecuting sexual violence in low-resource environments. The results and discussion challenge the prevailing assumption that intimate DNA swabs must be collected by trained medical professionals in order to be of evidential value. PMID- 28889862 TI - Genetic DNA profile in urine and hair follicles from patients who have undergone allogeneic hematopoietic stem cell transplantation. AB - Biological samples from patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) constitute a challenge for individual identification. In this study we analyzed the genetic profiles (by the amplification of 15 autosomic STRs) of HSCT patients found in different types of samples (blood, hair and urine) that may be the source of DNA in civil or criminal forensic cases. Our results show that while in hair follicles the donor component was not detected in any patient, thus being a reliable source of biological material for forensic identification, mixed chimerism was detected in urine samples from all patient, and no correlation was found between the time elapsed from the transplant and the percentage of chimerism. These results certainly have practical implications if the urine is being considered as a source of DNA for identification purposes in HSTC patients. Moreover, taking into consideration that chimerism was found not only in patients with leukocyturia (given the hematopoietic origin of leukocytes, this was expected), but also in those without observable leukocytes in the sediment, we conclude that an alternative source or sources of donor DNA must be implicated. PMID- 28889863 TI - The persistence of human DNA in soil following surface decomposition. AB - Though recent decades have seen a marked increase in research concerning the impact of human decomposition on the grave soil environment, the fate of human DNA in grave soil has been relatively understudied. With the purpose of supplementing the growing body of literature in forensic soil taphonomy, this study assessed the relative persistence of human DNA in soil over the course of decomposition. Endpoint PCR was used to assess the presence or absence of human nuclear and mitochondrial DNA, while qPCR was used to evaluate the quantity of human DNA recovered from the soil beneath four cadavers at the University of Tennessee's Anthropology Research Facility (ARF). Human nuclear DNA from the soil was largely unrecoverable, while human mitochondrial DNA was detectable in the soil throughout all decomposition stages. Mitochondrial DNA copy abundances were not significantly different between decomposition stages and were not significantly correlated to soil edaphic parameters tested. There was, however, a significant positive correlation between mitochondrial DNA copy abundances and the human associated bacteria, Bacteroides, as estimated by 16S rRNA gene abundances. These results show that human mitochondrial DNA can persist in grave soil and be consistently detected throughout decomposition. PMID- 28889864 TI - The transfer of diatoms from freshwater to footwear materials: An experimental study assessing transfer, persistence, and extraction methods for forensic reconstruction. AB - In recent years there has been growing interest in environmental forms of trace evidence, and ecological trace evidence collected from footwear has proved valuable within casework. Simultaneously, there has been growing awareness of the need for empirical experimentation to underpin forensic inferences. Diatoms are unicellular algae, and each cell (or 'frustule') consists of two valves which are made of silica, a robust material that favours their preservation both in sediments and within forensic scenarios. A series of experiments were carried out to investigate the transfer and persistence of diatoms upon common footwear materials, a recipient surface that has historically been overlooked by studies of persistence. The effectiveness of two novel extraction techniques (jet rinsing, and heating and agitation with distilled water) was compared to the established extraction technique of hydrogen peroxide digestion, for a suite of five common footwear materials: canvas, leather, and 'suede' (representing upper materials), and rubber and polyurethane (representing sole materials). It was observed that the novel extraction technique of heating and agitation with distilled water did not extract fewer diatom valves, or cause increased fragmentation of valves, when compared to peroxide digestion, suggesting that the method may be viable where potentially hazardous chemical reactions may be encountered with the peroxide digestion method. Valves could be extracted from all five footwear materials after 3min of immersion, and more valves were extracted from the rougher, woven upper materials than the smoother sole materials. Canvas yielded the most valves (a mean of 2511/cm2) and polyurethane the fewest (a mean of 15/cm2). The persistence of diatoms on the three upper materials was addressed with a preliminary pilot investigation, with ten intervals sampled between 0 and 168h. Valves were seen to persist in detectable quantities after 168h on all three upper materials. However, some samples produced slides with no valves, and the earliest time after which no diatom valves were found was 4h after the transfer. Analysis of the particle size distributions over time, by image analysis, suggests that the retention of diatoms may be size-selective; after 168h, no particles larger than 200MUm2 could be found on the samples of canvas, and >95% of the particles on the samples of suede were less than or equal to 200MUm2. A pilot investigation into the effects of immersion interval was carried out upon samples of canvas. Greater numbers of valves were extracted from the samples with longer immersion intervals, but even after 30s, >500 valves could be recovered per cm2, suggesting that footwear may be sampled for diatoms even if the contact with a water body may have been brief. These findings indicate that, if the variability within and between experimental runs can be addressed, there is significant potential for diatoms to be incorporated into the trace analysis of footwear and assist forensic reconstructions. PMID- 28889865 TI - Estimating the age of the adult stages of the blow flies Lucilia sericata and Calliphora vicina (Diptera: Calliphoridae) by means of the cuticular hydrocarbon n-pentacosane. AB - Age estimation of insects like blow flies plays an important role in forensic entomology and can answer questions in regard to time of death. So far the focus is on the immature stages of these insects, but recently the adult fly became a target of interest. It has been established that the profile of specific cuticular hydrocarbons (CHCs) changes in a consistent pattern as adult insects age; thus, their analysis could be a promising tool for the age estimation of adult insects. We investigated the CHC n-pentacosane (nC25) on the legs of the adult blow flies Lucilia sericata and Calliphora vicina with gas chromatography mass spectrometry. The flies were kept at room temperature (17 degrees C+/-2 degrees C) and 12:12 L:D from Day 1 to Day 20 post-emergence. For each of five flies per species, the amount of nC25 on all legs was determined daily. The amounts of nC25 on C. vicina increased linearly (R2=0.949). No significant difference between sexes could be detected. While L. sericata showed the same linear increase in general, we found significant (p<0.001) differences in the amount of nC25 between males and females. Although the amounts of nC25 increased linearly for both sexes (males: R2=0.948; females: R2=0.920), female L. sericata produced more nC25 than males. An equation for the prediction of fly age is constructed from these data. Although the influence of various environmental factors, e.g., fluctuating temperatures, still needs to be tested, nC25 seems to be a promising tool for the age estimation of adult flies. PMID- 28889866 TI - Helicopter thermal imaging for detecting insect infested cadavers. AB - One of the most common techniques applied for searching living and even dead persons is the FLIR (Forward Looking Infrared) system fixed on an aircraft like e.g. a helicopter, visualizing the thermal patterns emitted from objects in the long-infrared spectrum. However, as body temperature cools down to ambient values within approximately 24h after death, it is common sense that searching for deceased persons can be just applied the first day post-mortem. We postulated that the insect larval masses on a decomposing body generate a heat which can be considerably higher than ambient temperatures for a period of several weeks and that such heat signatures might be used for locating insect infested human remains. We examined the thermal history of two 70 and 90kg heavy pig cadavers for 21days in May and June 2014 in Germany. Adult and immature insects on the carcasses were sampled daily. Temperatures were measured on and inside the cadavers, in selected maggot masses and at the surroundings. Thermal imaging from a helicopter using the FLIR system was performed at three different altitudes up to 1500ft. during seven day-flights and one night-flight. Insect colonization was dominated by blow flies (Diptera: Calliphoridae) which occurred almost immediately after placement of the cadavers. Larvae were noted first on day 2 and infestation of both cadavers was enormous with several thousand larvae each. After day 14 a first wave of post-feeding larvae left the carcasses for pupation. Body temperature of both cadavers ranged between 15 degrees C and 35 degrees C during the first two weeks of the experiment, while body surface temperatures peaked at about 45 degrees C. Maggot masses temperatures reached values up to almost 25 degrees C above ambient temperature. Detection of both cadavers by thermal imaging was possible on seven of the eight helicopter flights until day 21. PMID- 28889867 TI - An investigation into the effect of surveillance drones on textile evidence at crime scenes. AB - With increasing numbers of Police forces using drones for crime scene surveillance, the effect of the drones on trace evidence present needs evaluation. In this investigation the effect of flying a quadcopter drone at different heights over a controlled scene and taking off at different distances from the scene were measured. Yarn was placed on a range of floor surfaces and the number lost or moved from their original position was recorded. It was possible to estimate "safe" distances above and take off distance from the bath mat (2m and 1m respectively), and carpet tile (3m and 1m) which were the roughest surfaces. The maximum distances tested of 5m above and 2m from was not far enough to prevent significant disturbance with the other floor surfaces. This report illustrates the importance of considering the impact of new technologies into a forensic workflow on established forensic evidence prior to implementation. PMID- 28889868 TI - Three-dimensional analysis of third molar development to estimate age of majority. AB - Third molars are one of the few biological markers available for age estimation in undocumented juveniles close the legal age of majority, assuming an age of 18years as the most frequent legal demarcation between child and adult status. To obtain more accurate visualization and evaluation of third molar mineralization patterns from computed tomography images, a new software application, DentaVol(c), was developed. Third molar mineralization according to qualitative (Demirjian's maturational stage) and quantitative parameters (third molar volume) of dental development was assessed in multi-slice helical computed tomography images of both maxillary arches displayed by DentaVol(c) from 135 individuals (62 females and 73 males) aged between 14 and 23years. Intra- and inter-observer agreement values were remarkably high for both evaluation procedures and for all third molars. A linear correlation between third molar mineralization and chronological age was found, with third molar maturity occurring earlier in males than in females. Assessment of dental development with both procedures, by using DentaVol(c) software, can be considered a good indicator of age of majority (18years or older) in all third molars. Our results indicated that virtual computed tomography imaging can be considered a valid alternative to orthopantomography for evaluations of third molar mineralization, and therefore a complementary tool for determining the age of majority. PMID- 28889869 TI - The sharing of ballistics data across Europe and neighbouring territories. AB - The current study explored the use of ballistic examinations and cross-border information sharing across 14 European countries. The presented data were collected using a mixed methods technique consisting of semi-structured interviews and questionnaires that were completed by participants. The results painted a very heterogeneous picture of the use of automated ballistic systems across these countries, as well as how ballistic analyses are integrated in the fight against gun-enabled crime. Three super-ordinates themes emerged from the thematic analysis: use of automated ballistic systems; Ballistic evidence recovery and analysis; knowledge exchange and best practices. The ability to draw firm conclusions regarding the value of ballistics comparison systems, either on a national or cross-border basis, is hampered by inconsistencies regarding data recording practices and definitions. Therefore, key recommendations are suggested to establish better cross border cooperation between member states and develop a better understanding of data sharing procedures. PMID- 28889870 TI - The use of handwriting examinations beyond the traditional court purpose. AB - Traditionally, forensic science has predominantly focused its resources and objectives on addressing court related questions. However, this view restricts the contribution of forensic science to one function and results in lost opportunities as investigative and intelligence roles are often overlooked. A change of perspective and expansion of the contributions of forensic science is required to take advantage of the benefits of abductive and inductive thought processes throughout the investigative and intelligence functions. One forensic discipline that has the potential to broaden its traditional focus is handwriting examination. Typically used in investigations that are focused on both criminal and civil cases, the examination procedure and outcome are time consuming and subjective, requiring a detailed study of the features of the handwriting in question. Traditionally, the major handwriting features exploited are characteristics that are often considered individual (or at least highly polymorphic) and habitual. However, handwriting can be considered as an information vector in an intelligence framework. One such example is the recognition of key elements related to the author's native language. This paper discusses the traditional method generally used around the world and proposes a theoretical approach to expand the application of handwriting examination towards gaining additional information for intelligence purposes. This concept will be designed and tested in a future research project. PMID- 28889871 TI - Reply to Morrison et al. (2016) Refining the relevant population in forensic voice comparison - A response to Hicks et alii (2015) The importance of distinguishing information from evidence/observations when formulating propositions. PMID- 28889872 TI - IV Immunoglobulin for Autoimmune Heparin-Induced Thrombocytopenia. PMID- 28889873 TI - Statins in COPD: Life After STATCOPE. PMID- 28889874 TI - The Many Faces of Hypersensitivity Pneumonitis. PMID- 28889875 TI - Geo-economic Variations and ARDS: If a Tree Falls in a Forest.... PMID- 28889876 TI - Giants in Chest Medicine: Jack Hirsh, CM, MD, DSc. PMID- 28889877 TI - PET scan. PMID- 28889878 TI - COPD. PMID- 28889879 TI - The Jazzman. PMID- 28889880 TI - Art and Ego. PMID- 28889881 TI - Vitamin C Is Not Ready for Prime Time in Sepsis but a Solution Is Close. PMID- 28889882 TI - Response. PMID- 28889883 TI - Response. PMID- 28889884 TI - The Unsung Hero: Role of Thiamine in the 'Vitamin C Cocktail'. PMID- 28889885 TI - Persistent Heparin-Induced Thrombocytopenia Treated With IVIg. PMID- 28889886 TI - Reclassify Lung-RADS Category "S". PMID- 28889887 TI - Prisoners in the United States Likely to Have Higher Odds of Death From Sepsis. PMID- 28889888 TI - De Novo Development of Bronchiectasis in Patients With Hematologic Malignancy. PMID- 28889889 TI - Probiotics in the Pediatric ICU: Beyond Blurred Lines. PMID- 28889890 TI - Thiamine: Why No Chance in Severe Sepsis? PMID- 28889891 TI - Response. PMID- 28889892 TI - Point-of-Care Ultrasonography for Acute Coronary Syndrome: Rule This in or Rule Out Others? PMID- 28889893 TI - Response. PMID- 28889894 TI - Hydrocortisone, Vitamin C and Thiamine for Sepsis: Whither the Ethics in Research? PMID- 28889895 TI - Response. PMID- 28889896 TI - Bronchiectasis Complicating Lung Volume Reduction Coil Treatment. AB - Endoscopic lung volume reduction has emerged over the past several years as a promising technique to improve the respiratory functional status of patients with advanced emphysema. Nevertheless, the procedure may be associated with various complications; among them, the development of bronchiectasis related to the coils has not yet been described. We report the case of a patient with emphysema who developed localized bronchiectasis at the site of coil insertion several months after lung volume reduction coil treatment. PMID- 28889897 TI - A 70-Year-Old Develops Refractory Hypotension in the ICU. PMID- 28889898 TI - A Previously Healthy Man in His 30s With Worsening Shortness of Breath Over 5 Days. PMID- 28889899 TI - Pulmonary Nodules in an Adolescent Female Presented With Abdominal Pain, Fatigue, and Weight Loss. AB - CASE PRESENTATION: A 14-year-old girl initially presented to a pediatric gastroenterology office with a 1-month history of right upper quadrant abdominal pain, which radiated to the right shoulder and back. Her pain was worse after heavy meals and with deep breaths. She reported anorexia, fatigue, dyspnea while playing soccer, and a 5-pound weight loss. She denied any fevers, cough, or changes in her bowel habits. PMID- 28889900 TI - A 62-Year-Old Woman With Wheezing, Respiratory Failure, and an Abnormal CT Scan. AB - CASE PRESENTATION: A previously healthy 62-year-old woman was transferred to the ICU from the medical ward with acute bronchospastic respiratory failure requiring intubation and mechanical ventilation. Four weeks before, the patient was vacationing in Arizona and acquired a mildly productive cough as well as mild dyspnea. She presented to an urgent care facility and was diagnosed with community-acquired pneumonia. She received a 5-day course of azithromycin, with partial improvement of her symptoms. The patient returned home 1 week prior to admission, reporting worsening dyspnea, chest pressure, cough, and fever. The patient was admitted to the medical ward, and treatment for unresolved pneumonia was begun with levofloxacin, an inhaled short-acting beta agonist, and oral prednisone. Despite this treatment, the patient experienced severe respiratory distress with audible wheezing as well as increased work of breathing. She was intubated for acute hypoxemic respiratory failure and transferred to the ICU. PMID- 28889901 TI - Corrigendum to "Tumor Macroenvironment and Metabolism" [Seminars in Oncology, Vol 41, No 2, April 2014, pp 281-295]. PMID- 28889902 TI - "Benznidazole-resistance in Trypanosoma cruzi: Evidence that distinct mechanisms can act in concert'' [Mol. Biochem. Parasit. (2014) 193, 17-19]. PMID- 28889903 TI - Instructed fear stimuli bias visual attention. AB - We investigated whether stimuli merely instructed to be fear-relevant can bias visual attention, even when the fear relation was never experienced before. Participants performed a dot-probe task with pictures of naturally fear-relevant (snake or spider) or -irrelevant (bird or butterfly) stimuli. Instructions indicated that two pictures (one naturally fear-relevant and one fear-irrelevant) could be followed by an electrical stimulation (i.e., instructed fear). In reality, no stimulation was administered. During the task, two pictures were presented on each side of the screen, after which participants had to determine as fast as possible on which side a black dot appeared. After a first phase, fear was reinstated by instructing participants that the device was not connected but now was (reinstatement phase). Participants were faster when the dot appeared on a location where an instructed fear picture was presented. This effect seemed independent of whether picture content was naturally fear-relevant, but was only found in the first half of each phase, suggesting rapid extinction due to the absence of stimulation, and rapid re-evaluation after reinstatement. A second experiment similarly showed that instructed fear biases attention, even when participants were explicitly instructed that no stimulation would be given during the dot-probe task. Together, these findings demonstrate that attention can be biased towards instructed fear stimuli, even when these fear relations were never experienced. Future studies should test whether this is specific to fear, or can be observed for all instructions that change the relevance of a given stimulus. PMID- 28889904 TI - Are mercury and Alzheimer's disease linked? PMID- 28889905 TI - [Orbital lymphoma masquerading in a young patient with Graves ophthalmopathy]. PMID- 28889906 TI - [Iridoschisis: A glaucoma to screen for and an unusual phacoemulsification]. PMID- 28889907 TI - Are Thraustochytrids algae? AB - Thraustochytrids, a heterotrophic fungus-like clade of Stramenopiles, are becoming an increasingly important source of polyunsaturated fatty acids (PUFAs) for biotechnological industries. PUFA rich oils from these organisms are subsequently referred to in some literature and marketing sources as being derived from 'algae', in spite of their non-photosynthetic source organism. In this review, we attempt to disentangle the evolutionary relationship of the Thraustochytrids from other Protists, demonstrating that there is no scientific basis for the aforementioned misnomer. Some research has previously suggested that the ancestor of the Stramenopiles may have been photosynthetic, and subsequently lost their plastids in multiple lineages. The placement of the Thraustochytrids within the Stramenopiles and their possible plastid loss may have been a source of obfuscation. It is becoming increasingly evident that the common ancestor of the Stramenopiles was not photosynthetic, and that only the Ochrophyte lineage later engulfed a plastid via higher order endosymbiosis. Because all basal lineages of Stramenopiles are non-plastidial heterotrophs, including the Thraustochytrids, there remains no phylogenetic, biological, or ecological justification for the term 'algae' to be applied to Thraustochytrids or their products. PMID- 28889908 TI - Resistance of Fusarium poae in Arabidopsis leaves requires mainly functional JA and ET signaling pathways. AB - Fusarium poae has been considered as a minor species among those that cause the FHB disease but in recent years several researchers have documented a high frequency of occurrence in several crops. We evaluated the ability of F. poae to produce symptoms in A. thaliana leaves. Moreover, we analyzed the defense of A. thaliana against F. poae using SA, JA, and ET mutants and we monitored the expression level of genes involved in the main signaling pathways related to plant defense. Symptoms were observed in the inoculated leaves demonstrating the ability of F. poae to infect A. thaliana leaves. Moreover, the npr1-1 mutants presented low symptoms compared to Col-0, etr2-1, and coi1-1 and that the coi1-1 mutant was the most susceptible genotypes followed by etr2-1 genotypes. The RT PCR revealed that PDF1.2, CHI/PR3, and ERF1, three important JA-ET responsive genes and NPR1 and PR1, which are regulated by SA signaling, were expressed upon F. poae inoculation. Our results suggest that JA and ET could play a key role in Arabidopsis leaves defense against F. poae representing the first evaluation of the response of the main A. thaliana phytohormones involved in plant defense in the presence of F. poae. PMID- 28889909 TI - Organization and evolution of mating-type genes in three Stagonosporopsis species causing gummy stem blight of cucurbits and leaf spot and dry rot of papaya. AB - Population divergence and speciation of closely related lineages can result from reproductive differences leading to genetic isolation. An increasing number of fungal diseases of plants and animals have been determined to be caused by morphologically indistinguishable species that are genetically distinct, thereby representing cryptic species. We were interested in identifying if mating systems among three Stagonosporopsis species (S. citrulli, S. cucurbitacearum, and S. caricae) causing gummy stem blight (GSB) of cucurbits or leaf spot and dry rot of papaya differed, possibly underlying species divergence. Additionally, we were interested in identifying evolutionary pressures acting on the genes controlling mating in these fungi. The mating-type loci (MAT1) of three isolates from each of the three species were identified in draft genome sequences. For the three species, MAT1 was structurally identical and contained both mating-type genes necessary for sexual reproduction, which suggests that all three species are homothallic. However, both MAT1-1-1 and MAT1-2-1 were divergent among species showing rapid evolution with a much greater number of amino acid-changing substitutions detected for the reproductive genes compared with genes flanking MAT1. Positive selection was detected in MAT1-2-1, especially in the highly conserved high mobility group (MATA_HMG-box) domain. Thus, the mating-type genes are rapidly evolving in GSB fungi, but a difference in mating systems among the three species does not underlie their divergence. PMID- 28889910 TI - Phylogenetic study of the Colletotrichum species on imported citrus fruits uncovers a low diversity and a new species in the Colletotrichum gigasporum complex. AB - Colletotrichum species associated with citrus fruits are fragmentarily known and it lacks accordingly accurate information on the diversity carried alongside the trade of these commodities from producer countries to Europe. In this study, we investigated the molecular phylogenetic diversity, colonisation, and prevalence of Colletotrichum isolated from asymptomatic and diseased tissues of nine citrus fruit species from 17 geographically diverse countries. Totally 454 isolates were morphoculturally characterised, and multilocus analyses (ACT, ApMat, CHS-1, GAPDH, ITS, TUB2) was performed on a subset of representative morphotype isolates. Results led to the identification of three previously known species (Colletotrichum gloeosporioides, Colletotrichum karstii, Colletotrichum siamense) and one novel lineage comprising endophytic isolates from Citrus maxima. Based on this lineage, Colletotrichum citri-maximae is described as a new species in the Colletotrichum gigasporum complex, and is characterised by a long deletion in the GAPDH sequence, a character shared with three of its phylogenetic sister taxa. Prevalence of Colletotrichum varied among citrus species and was greatest on Citrus sinensis fruits. C. gloeosporioides was the most common species followed by C. siamense. Except for the new species, all other isolated Colletotrichum spp. also colonise citrus leaves, but the overall diversity on fruits may be lower than that of leaves. PMID- 28889911 TI - FPD: A comprehensive phosphorylation database in fungi. AB - Protein phosphorylation, one of the most classic post-translational modification, plays a critical role in diverse cellular processes including cell cycle, growth, and signal transduction pathways. However, the available information about phosphorylation in fungi is limited. Here, we provided a Fungi Phosphorylation Database (FPD) that comprises high-confidence in vivo phosphosites identified by MS-based proteomics in various fungal species. This comprehensive phosphorylation database contains 62 272 non-redundant phosphorylation sites in 11 222 proteins across eight organisms, including Aspergillus flavus, Aspergillus nidulans, Fusarium graminearum, Magnaporthe oryzae, Neurospora crassa, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Cryptococcus neoformans. A fungi specific phosphothreonine motif and several conserved phosphorylation motifs were discovered by comparatively analysing the pattern of phosphorylation sites in plants, animals, and fungi. PMID- 28889912 TI - A systematic overview of Descolea (Agaricales) in the Nothofagaceae forests of Patagonia. AB - The descolea clade includes species of ectomycorrhizal basidiomycetes in the genera Descolea, Setchelliogaster, Descomyces, and Timgrovea that are known primarily from the Southern Hemisphere. Taxa in this group produce basidiomes that range in morphology from typical epigeous mushrooms (Descolea) and secotioid taxa (Setchelliogaster) to fully gasteroid species (Descomyces and Timgrovea). High intraspecific morphological variation has been reported in several species within this clade, suggesting that careful morphological and molecular studies are needed to refine species concepts. Molecular analyses of fresh Patagonian collections in conjunction with taxonomic studies have confirmed high variability in key morphological features, including overall sporocarp form, spore shape and dimensions, universal veil remnants, and cuticle configuration. Based on our synthesis, we emend the genus Descolea to include sequestrate species. We describe the new sequestrate taxon Descolea inferna sp. nov. from Nothofagaceae forests in Patagonia and we propose Cortinarius squamatus as a synonym of our new combination Descolea brunnea. We also formalize the identity of Descolea pallida as a synonym of Descolea antarctica and provide new specimens of Cortinarius archeuretus, a species that has not been encountered since the original discovery during the expeditions of Roland Thaxter in 1905-1906. Here we re-describe and transfer this species to Descolea as D. archeureta. We also discuss diagnostic features that can be used to delimitate the four known South American taxa in the descolea clade. PMID- 28889913 TI - Phylogenetic relationships of Chlamydomyces, Harzia, Olpitrichum, and their sexual allies, Melanospora and Sphaerodes. AB - Phylogenetic analyses using internal transcribed spacer (ITS), large subunit rRNA (LSU), and small subunit (SSU) sequence data showed that Harzia, Chlamydomyces, and Olpitrichum are con-generic. Thus, Chlamydomyces, and Olpitrichum were reduced to synonymy of Harzia. The generic concept was amended and expanded accordingly. Eight new combinations were proposed. Melanospora and Sphaerodes are phylogenetically related to Harzia. However, several members of Melanospora and Sphaerodes are polyphyletic and belong to Hypocreales or Microascales in Sordariomycetes. The Proteophiala morph is not only a crucial morphological character, but also has a phylogenetical significance in defining Melanosporales. It is hypothesized that the taxa with synanamorphic or asexual Proteophiala all belong to Ceratostomataceae, Melanosporales. PMID- 28889914 TI - Microplastics as a vector for the transport of the bacterial fish pathogen species Aeromonas salmonicida. AB - Microplastics is widespread in the marine environment where it can cause numerous negative effects. It can provide space for the growth of organisms and serves as a vector for the long distance transfer of marine microorganisms. In this study, we examined the sea surface concentrations of microplastics in the North Adriatic and characterized bacterial communities living on the microplastics. DNA from microplastics particles was isolated by three different methods, followed by PCR amplification of 16S rDNA, clone libraries preparation and phylogenetic analysis. 28 bacterial species were identified on the microplastics particles including Aeromonas spp. and hydrocarbon-degrading bacterial species. Based on the 16S rDNA sequences the pathogenic fish bacteria Aeromonas salmonicida was identified for the first time on microplastics. Because A. salmonicida is responsible for illnesses in fish, it is crucial to get answers if and how microplastics pollution is responsible for spreading of diseases. PMID- 28889915 TI - "Every child that is a foster child is marked from the beginning": The home school communication experiences of foster parents of children with disabilities. AB - This study investigated the perceptions of foster parents of children with disabilities concerning their interactions with school personnel. We conducted semi-structured interviews with 7 foster parents of 6 children with disabilities (age range=5-16). A qualitative analysis of the interviews resulted in the identification of five thematic areas, including foster parent perceptions of: (a) the role of the foster parent, (b) the efficacy of the foster parent in helping the child learn, (c) invitations to involvement from the school (d) invitations to involvement from the child, and (e) foster child experiences in the school system. Marked differences were found in the perceptions of the perceptions in foster parents of elementary and secondary age students. It is clear that foster parents who take on an active role in their child's education experienced positive relationships with their child's school. Foster parents who take a passive role in their partnerships with the schools experienced increased difficulty maintaining motivation to continue in their efforts to increase collaboration and involvement with the schools. They indicated a sense of anger, distrust, and even hostility towards the schools. Based on the findings, recommendations are provided for improving home-school relationships, and addressing obstacles to successful school partnerships with foster families. PMID- 28889916 TI - Evidence for a relationship between child maltreatment and absenteeism among high school students in Sweden. AB - School absenteeism is a potent predictor of academic failure. Maltreated adolescents have been found to be more absent from school compared to their peers. However, it is scarcely studied in what degree a general population of students with high levels of school absenteeism has been exposed to child maltreatment. Furthermore, it is not known if maltreated school-absentees have specific characteristics compared to not-maltreated absentees. In this article, the first objective was to present and compare the prevalence of six types of child maltreatment in a general population of high school students reporting no, moderate or excessive absenteeism. The second objective was to compare maltreated and not-maltreated students who report absenteeism in respect to mental health, perceived school environment and peer victimization in school. Data from 667 girls and 649 boys (mean age 14.3) was used from the longitudinal multidisciplinary research program LoRDIA (Longitudinal Research on Development In Adolescence). Data was collected via self-report questionnaires in classroom settings. All six types of child maltreatment were overrepresented among absentees. Roughly 25% of absentees reported one subtype of maltreatment (16% in the total population) and a mean of 22% of absentees reported two or more types of maltreatment (11% in the total population). Maltreated absentees reported more mental health problems, personal harassment and worse relationship with their teachers than not-maltreated absentees. There might be specific correlates of school absenteeism among maltreated adolescents and professionals involved in preventing school-absenteeism should be made aware of the relationship between maltreatment and absenteeism. PMID- 28889917 TI - Care research in Spain: Nurses will, politicians will and population impact. PMID- 28889918 TI - Erratum to"Ethnicity: An essential approach in improving the quality of care and patient safety with equity" <[Enferm Clin. 27 (2017) 209-210]>. PMID- 28889919 TI - Emerging immunotherapy in advanced renal cell carcinoma. AB - Immunotherapy has recently catapulted to the forefront of treatments for patients with solid tumors. Given its inherent immunogenic properties, renal cell carcinoma (RCC) has historically responded to immunotherapy and remains primed for further development. Although immunotherapy with high-dose interleukin 2 was a primary treatment for advanced RCC (aRCC), recent discoveries of key molecular and immunological alterations have led to the FDA-approval of nivolumab, an antiprogrammed cell death inhibitor, which has demonstrated an overall survival in patients with previously treated aRCC. However, despite recent therapeutic advances, aRCC remains an incurable disease for most patients. In this review, we assess the current landscape and future developments of immunotherapy in aRCC. PMID- 28889920 TI - The incidence of unsuccessful partial nephrectomy within the United States: A nationwide population-based analysis from 2003 to 2015. AB - PURPOSE: Partial nephrectomy (PN) remains underutilized within the United States and few reports have attempted to explain this trend. The aim of this study is to evaluate the nationwide incidence of unsuccessful PN and factors that predict its occurrence. METHODS: Using the Premier Healthcare Database, we retrospectively analyzed a weighted sample of 66,432 patients undergoing curative surgery for renal mass between 2003 and 2015. PN intent was denoted by presence of insurance claims for the administration of mannitol. Unsuccessful PN was defined as an event in which patients were administered mannitol but received radical nephrectomy. A multivariate logistic regression model was generated to identify factors predicting unsuccessful PN. RESULTS: Overall rates of unsuccessful PN declined from 33.5% to 14.5% since 2003. Conversion to radical nephrectomy occurred most frequently during laparoscopic (34.7%) and least frequently during robotic approach (13.6%). There was significant difference in the rate of unsuccessful PN between very high and very low volume surgeons (open: 39.4% vs. 13.3%, laparoscopic: 51.2% vs. 32.2%, and robot assisted: 27.1% vs. 9.4%, all P<0.001). After adjustment for patient- and hospital-related factors, surgical approach (laparoscopic vs. open, odds ratio = 1.74, 95% CI: 1.31-2.30, P<0.001) and annual surgeon volume (very high vs. very low, odds ratio = 0.27, 95% CI: 0.21-0.34 P<0.001) were associated with unsuccessful PN. CONCLUSIONS: Although the rate of unsuccessful PN appears to be declining, it still remains common for low volume surgeons and with the laparoscopic surgical approach. Further evaluation of its effect on health care outcomes is necessary. PMID- 28889921 TI - PD-1 checkpoint inhibition: Toxicities and management. AB - PURPOSE: With the recent approval of 5 PD-1/PD-L1 inhibitors for a number of malignancies, PD-1 axis inhibition is drastically changing the treatment landscape of immunotherapy in cancer. As PD-1/PD-L1 are involved in peripheral immune tolerance, inhibition of this immune checkpoint has led to novel immune related adverse events including colitis, hepatitis, pneumonitis, rash, and endocrinopathies among many others. MATERIALS AND METHODS: In this seminar, we will analyze the incidence of immune-related adverse events for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. Then, we will discuss the specific management of the most common immune-mediated adverse events including colitis, hepatitis, pneumonitis, rash, endocrinopathies, nephritis, and neurologic toxicities. RESULTS: Immune-related adverse events are frequently treated with immunosuppressive medication such as steroids and mycofenolate mofetil. CONCLUSIONS: There are specific immune-related adverse events which are frequently seen by the treating oncologist from checkpoint inhibitors. It is essential to understand the recommended treatment options to minimize toxicity and mortality from this important class of anti-neoplastic therapies. PMID- 28889922 TI - The effect of AB0 and Rhesus blood grouping systems on oncological outcome in patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma. AB - OBJECTIVES: To investigate the effect of AB0 and Rhesus factor expression blood group systems on outcomes of upper tract urothelial carcinoma patients treated with radical nephroureterectomy. PATIENTS AND METHODS: We analyzed data from 271 patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy at 3 German academic institutions. Cox and logistic regression models assessed the association of AB0 blood group antigen and Rhesus factor expression with tumor biologic features and outcomes, respectively. RESULTS: In total, 119 patients (43.9%) had blood group antigen A0, 42 patients (15.4%) antigen B0, 15 patients (5.5%) antigen AB, and 95 patients (35.0%) the antigen 00. A total of 231 patients (85.2%) were Rhesus factor positive. The AB0 blood group antigen expression was associated with a higher tumor grade (P = 0.049) and sessile tumor architecture (P = 0.019). Both, AB0 blood group system and Rhesus factor expression, were associated with worse performance status (P = 0.024, and P = 0.003, respectively). In contrast, Rhesus factor expression status was not associated with any clinicopathologic characteristics. Neither the AB0 blood group antigens nor the Rhesus factor was associated with survival. CONCLUSION: AB0 blood group antigens and Rhesus factor expression are not associated with survival. The association of the AB0 blood group antigens with adverse pathological features warrants further validation. PMID- 28889923 TI - Social risky decision-making reveals gender differences in the TPJ: A hyperscanning study using functional near-infrared spectroscopy. AB - Previous neuroscience studies have investigated neural correlates of risky decision-making in a single-brain frame during pseudo social (predominantly non face-to-face) contexts. To fully understand the risky decision-making behavior in more natural social interactions, the present study employed a functional near infrared spectroscopy (fNIRS) hyperscanning technique to simultaneously measure pairs of participants' fronto-temporal activations in a face-to-face gambling card-game. The intra-brain results revealed that both those who identified as males and as females showed higher activations in their mPFC and in the inferior parts of the frontopolar area, as well as in the tempo-parietal junction (TPJ) in cases involving higher versus lower risk. This is consistent with previous findings suggesting importance of the mentalizing network in decision tasks. The fNIRS results of inter-brain neural synchronization (INS) also revealed that males and females showed increased inter-brain coherence in the mPFC and dlPFC. Females, however, uniquely showed increased inter-brain coherence in the left TPJ. This INS result suggests that males may primarily depend on non-social cognitive ability to make a risky decision in a social interaction, while females may use both social and non-social cognitive abilities. The implications are also discussed for general topics of human interaction and two-person neuroscience. PMID- 28889924 TI - Single-docking robotic biliopancreatic diversion with duodenal switch technique. PMID- 28889925 TI - Editorial. PMID- 28889926 TI - Triple therapy with dual antiplatelet treatment and direct oral anticoagulants. Author's reply. PMID- 28889927 TI - A reduction in acute thrombotic admissions during a period of unexplained increased deaths and medical admissions in the UK. AB - BACKGROUND: Since 2011 in England there has been a period of unexplained higher deaths and medical admissions which policy makers have assumed are attributable to the increasing age of the population and the inability of health and social care to limit demand. METHODS: Analysis of data obtained from NHS and Office of National Statistics. RESULTS: Contrary to the trends in certain other medical diagnoses those for thrombosis show a shift to lower acute admissions, which mainly occur in the young as a same day stay emergency admission. A reduction in occupied bed days also occurs. CONCLUSION: A shift in the balance of inflammatory/anti-inflammatory forces may be responsible for this dichotomous behaviour. PMID- 28889928 TI - Infections of the Nervous System. AB - Microorganisms can affect the entire neuraxis, producing a variety of neurologic complications that frequently entail prolonged hospitalizations and complicated treatment regimens. The spread of pathogens to new regions and the reemergence of opportunistic organisms in immunocompromised patients pose increasing challenges to health care professionals. Because rapid diagnosis and treatment may prevent long-term neurologic sequelae, providers should approach these diseases with a structured, neuroanatomic framework, incorporating a thorough history, examination, laboratory analysis, and neuroimaging in their clinical reasoning and decision-making. PMID- 28889929 TI - Sometimes the Eyes Say More Than the Mouth. PMID- 28889930 TI - Radiologic Pearls for Internists: A Case-Based Review. AB - Modern technologic advances in medical imaging and the increasing use of imaging across all disciplines in medicine have led to a striking rise in incidental findings unrelated to the original study indication. Often, these findings have no clinical relevance and will not impact the current or future health status of the patient. It is incumbent on radiologists to report these findings in a definitive and unambiguous manner. Similarly, it is essential for clinicians to restrain from further diagnostic investigation of incidental findings that are conclusive by imaging. A classic and common example is the finding of a cyst. This article presents several cases of incidentally found cysts for which a confident diagnosis can be made without any need for follow-up. PMID- 28889931 TI - Isolation and antifungal activity evaluation of Satureja khuzestanica Jamzad extract against some clinically important dermatophytes. AB - OBJECTIVE: Among the fungi, dermatophytes are the major cause of spectrum of superficial mycoses medically known as dermatophytosis (tinea) in human and animal. Treatment of these infections has still remained difficult. The aim of this survey was to evaluate in vitro anti-dermatophytic activity of ethanolic extract (EtOH) from Satureja khuzestanica leaf (SKLE) against some clinically important dermatophyte species from the genera of Trichophyton, Microsporum and Epidermophyton. Minimal inhibition concentration (MIC) of SKLE was tested against 14 dermatophyte strains of 5 species by using agar dilution method. Phytochemical screening of SKLE was carried out by High Performance Thin Layer Chromatography (HPTLC). The results of in vitro anti-dermatophytic activity of SKLE showed with MIC values between 1.250 and 10mg/mL. MIC90 and MIC50 values were as 0.625-1.250 and 0.156-0.312mg/mL, respectively. The MFC values of SKLE were in the range of 1.250-2.50mg/mL and possessed biological activity against dermatophytes. Morever, phytochemical analysis by HPTLC revealed that the ethyl acetate (EtOAc) extracts of SKL contain triterpenes which are known to have biological activity and it seems that this compound be responsible for the anti-dermatophytic activity of this plant. In conclusion, the results of in vitro antifungal susceptibility testing and phytochemical screening revealed that SKLE had both fungistatic and fungicidal activities against dermatophytes and can potentially be helpful as a supplementary or alternative for treatment of dermatophytosis. PMID- 28889932 TI - Small Vessel Disease and Dietary Salt Intake: Cross-Sectional Study and Systematic Review. AB - BACKGROUND: Higher dietary salt intake increases the risk of stroke and may increase white matter hyperintensity (WMH) volume. We hypothesized that a long term higher salt intake may be associated with other features of small vessel disease (SVD). METHODS: We recruited consecutive patients with mild stroke presenting to the Lothian regional stroke service. We performed brain magnetic resonance imaging, obtained a basic dietary salt history, and measured the urinary sodium/creatinine ratio. We also carried out a systematic review to put the study in the context of other studies in the field. RESULTS: We recruited 250 patients, 112 with lacunar stroke and 138 with cortical stroke, with a median age of 67.5 years. After adjustment for risk factors, including age and hypertension, patients who had not reduced their salt intake in the long term were more likely to have lacunar stroke (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.10 3.29), lacune(s) (OR, 2.06; 95% CI, 1.09-3.99), microbleed(s) (OR, 3.4; 95% CI, 1.54, 8.21), severe WMHs (OR, 2.45; 95% CI 1.34-4.57), and worse SVD scores (OR, 2.17; 95% CI, 1.22-3.9). There was limited association between SVD and current salt intake or urinary sodium/creatinine ratio. Our systematic review found no previously published studies of dietary salt and SVD. CONCLUSION: The association between dietary salt and background SVD is a promising indication of a potential neglected contributory factor for SVD. These results should be replicated in larger, long-term studies using the recognized gold-standard measures of dietary sodium. PMID- 28889933 TI - Bacterial conjugated linoleic acid production and their applications. AB - Conjugated linoleic acid (CLA) has been shown to exert various potential physiological properties including anti-carcinogenic, anti-obesity, anti cardiovascular and anti-diabetic activities, and consequently has been considered as a promising food supplement. Bacterial biosynthesis of CLA is an attractive approach for commercial production due to its high isomer-selectivity and convenient purification process. Many bacterial species have been reported to convert free linoleic acid (LA) to CLA, hitherto only the precise CLA-producing mechanisms in Propionibacterium acnes and Lactobacillus plantarum have been illustrated completely, prompting the development of recombinant technology used in CLA production. The purpose of the article is to review the bacterial CLA producers as well as the recent progress on describing the mechanism of microbial CLA-production. Furthermore, the advances and potential in the heterologous expression of CLA genetic determinants will be presented. PMID- 28889934 TI - Working length and proximal screw constructs in plate osteosynthesis of distal femur fractures. AB - BACKGROUND: The study purpose is to evaluate the working length, proximal screw density, and diaphyseal fixation mode and the correlation to fracture union after locking plate osteosynthesis of distal femoral fractures using bridge-plating technique. METHODS: A four-year retrospective review was performed to identify patients undergoing operative fixation of distal femur fractures with a distal femoral locking plate using bridge-plating technique for the metadiaphyseal region. Primary variables included fracture union, secondary surgery for union, plate working length, and diaphyseal screw technique and configuration. Multiple secondary variables including plate metallurgy and coronal plane fracture alignment were also collected. RESULTS: Ninety-six patients with distal femur fractures with a mean age 60 years met inclusion criteria. None of the clinical parameters were statistically significant indicators of union. Likewise, none of the following surgical technique parameters were associated with fracture union: plate metallurgy, the mean working length, screw density and number of proximal screws and screw cortices. However, diaphyseal screw technique did show statistical significance. Hybrid technique had a statistically significant higher chance of union when compared to locking (p=0.02). All proximal locking screw constructs were 2.9 times more likely to lead to nonunion. CONCLUSIONS: Plating constructs with all locking screws used in the diaphysis when bridge-plating distal femur locking plates were 2.9 times more likely to incur a nonunion. However, other factors associated with more flexible fixation constructs such as increased working length, decreased proximal screw number, and decreased proximal screw density were not significantly associated with union in this study. PMID- 28889935 TI - Sociocultural determinants of US women's ethical views on various fertility treatments. AB - Ethical concerns over treatments for infertility can discourage patients from pursuing fertility healthcare. This study aims to evaluate the sociocultural factors that influence the ethical views of reproductive-aged women regarding various fertility treatments. A publicly available cross-sectional survey of 4792 nationally representative US women aged 25-52 years was analysed to identify the frequency of ethical concerns over such interventions. Concerns were most common for treatments that increase the chance of twins (54%), followed by third-party reproductive strategies (48-51%), IVF (30%) and partner insemination (14%). Regression analysis revealed distinct sociocultural determinants for each of the treatment approaches. While being black was associated with a higher level of concern for several distinct fertility treatments, Hispanic ethnicity was only associated with increased ethical concern about donor eggs. Additionally, religious attendance predicts increased odds of ethical concern for IVF and all third-party approaches, while Catholic or Christian religious affiliations also predict ethical concern over partner insemination. These findings show that ethical concerns over fertility treatments are not generally 'all-or-nothing', but rather are often specific to the treatment approach. This knowledge may help explain differences in help-seeking behaviours and improve the physician-patient relationship. PMID- 28889936 TI - Decreased zinc and increased lead blood levels are associated with endometriosis in Asian Women. AB - Endometriosis is an inflammatory disease associated with multiple pathogenic factors and studies regarding roles of trace metals in endometriosis have been inconsistent and limited. The aim of this cross-sectional study was to compare the blood levels of miscellaneous trace metals measured by inductively coupled plasma mass spectrometry in infertile women with and without endometriosis. Zinc level is associated with declining odds (adjusted OR=0.39, 95% CI=0.18-0.88) of endometriosis. By contrast, lead level is associated with increasing odds (adjusted OR=2.59, 95% CI=1.11-6.06) of endometriosis. The cadmium levels were higher in women with endometriosis, but the aOR was not significant. Zinc has anti-inflammatory characteristics and regulates homeostasis of zinc-containing superoxide dismutase. High lead levels might induce reactive oxygen species and deplete antioxidant defense mechanisms. Further prospective study is needed to test for their causal associations. PMID- 28889937 TI - Metastatic fusiform aneurysms from atrial myxoma: A case report and literature review. PMID- 28889938 TI - Role of Robotics in Children: A brave New World! AB - CONTEXT: The key in the evolution towards minimally invasive surgery is the availability of appropriate equipment, especially when procedures involve children. While robotic procedures in adults continue to struggle to prove measurable advantages compared with open or classical laparoscopic ones, the use of the robotic platform (RP) in pediatric urology is steadily increasing. OBJECTIVE: To review the contemporary literature regarding the use of robotic assisted (RA) urologic interventions in children. EVIDENCE ACQUISITION: A nonsystematic review of the literature was conducted through PubMed database between 2002 and 2017, with an emphasis on large series. EVIDENCE SYNTHESIS: A few major challenges must be considered before using the RP in children: anesthesia, placement of trocars, and technical difficulties related to small space. To date, only the robot-assisted pyeloplasty is recognized as safe and efficient with an equivalent outcome compared to the open or classical laparoscopy; this was supported by large multicentric studies, which are not available for most of the other procedures. CONCLUSIONS: RA procedure in children has been proven safe and effective. Still in its infancy, further data over time is likely to prove different RA procedures to be equivalent to open or laparoscopy in terms of outcome. PATIENT SUMMARY: The advent of the robotic platform means an evolution towards minimizing surgical trauma for the child. Currently, the available platforms designed for adults are adapted to work in children. However, it might be expected in the future that new technologies will improve the technical possibilities to improve the robotic platform for minimally invasive surgery in children. To date, a few applications are considered safe and efficient (in experienced hands), considering that the team has to be aware of some challenges to overcome regarding anesthesia, material, and technique adaptation to the patient. The most accepted robotic applications in children comprises of the robot-assisted pyeloplasty, hemi-nephrectomy, and ureteric reimplantation. PMID- 28889939 TI - Erratum to: "Immunohistochemistry staining for mismatch repair proteins: the endoscopic biopsy material provides useful and coherent results" [Hum Pathol 2015;46:1705-1711]. PMID- 28889940 TI - Corrigendum to "Staufen targets coracle mRNA to Drosophila neuromuscular junctions and regulates GluRII asynaptic accumulation and bouton number" [Dev. Biol. 392 (2014) 153-167]. PMID- 28889941 TI - Ultrasonic Characteristics and Cellular Properties of Anabaena Gas Vesicles. AB - Ultrasound imaging is a common modality in clinical examination and biomedical research, but has not played a significant role in molecular imaging for lack of an appropriate contrast agent. Recently, biogenic gas vesicles (GVs), naturally formed by cyanobacteria and haloarchaea, have exhibited great potential as an ultrasound molecular imaging probe with a much smaller size (~100 nm) and improved imaging contrast. However, the basic acoustic and biological properties of GVs remain unclear, which hinders future application. Here, we studied the fundamental acoustic properties of a rod-shaped gas vesicle from Anabaena, a kind of cyanobacterium, including attenuation, oscillation resonance, and scattering, as well as biological behaviors (cellular internalization and cytotoxicity). We found that GVs have two resonance peaks (85 and 120 MHz). We also observed a significant non-linear effect and its pressure dependence as well. Ultrasound B mode imaging reveals sufficient echogenicity of GVs for ultrasound imaging enhancement at high frequencies. Biological characterization also reveals endocytosis and non-toxicity. PMID- 28889942 TI - Differential functions of WAVE regulatory complex subunits in the regulation of actin-driven processes. AB - The WAVE regulatory complex (WRC) links upstream Rho-family GTPase signaling to the activation of the ARP2/3 complex in different organisms. WRC-induced and ARP2/3 complex-mediated actin nucleation beneath the plasma membrane is critical for actin assembly in the leading edge to drive efficient cell migration. The WRC is a stable heteropentamer composed of SCAR/WAVE, Abi, Nap, Pir and the small polypeptide Brk1/Hspc300. Functional interference with individual subunits of the complex frequently results in diminished amounts of the remaining polypeptides of the WRC complex, implying the complex to act as molecular entity. However, Abi was also found to associate with mammalian N-WASP, formins, Eps8/SOS1 or VASP, indicating additional functions of individual WRC subunits in eukaryotic cells. To address this issue systematically, we inactivated all WRC subunits, either alone or in combination with VASP in Dictyostelium cells and quantified the protein content of the remaining subunits in respective WRC knockouts. The individual mutants displayed highly differential phenotypes concerning various parameters, including cell morphology, motility, cytokinesis or multicellular development, corroborating the view of additional roles for individual subunits, beyond their established function in WRC-mediated Arp2/3 complex activation. Finally, our data uncover the interaction of the actin polymerase VASP with WRC embedded Abi to mediate VASP accumulation in cell protrusions, driving efficient cell migration. PMID- 28889943 TI - Potential for recycling of slightly radioactive metals arising from decommissioning within nuclear sector in Slovakia. AB - The decommissioning of nuclear installations represents a complex process resulting in the generation of large amounts of waste materials containing various concentrations of radionuclides. Selection of an appropriate strategy of management of the mentioned materials strongly influences the effectiveness of decommissioning process keeping in mind safety, financial and other relevant aspects. In line with international incentives for optimization of radioactive material management, concepts of recycling and reuse of materials are widely discussed and applications of these concepts are analysed. Recycling of some portion of these materials within nuclear sector (e.g. scrap metals or concrete rubble) seems to be highly desirable from economical point of view and may lead to conserve some disposal capacity. However, detailed safety assessment along with cost/benefit calculations and feasibility study should be developed in order to prove the safety, practicality and cost effectiveness of possible recycling scenarios. Paper discussed the potential for recycling of slightly radioactive metals arising from decommissioning of NPPs within nuclear sector in Slovakia. Various available recycling scenarios are introduced and method for overall assessment of various recycling scenarios is outlined including the preliminary assessment of safety and financial aspects. PMID- 28889944 TI - Identification of Plasmodium falciparum isolates lacking histidine-rich protein 2 and 3 in Eritrea. AB - The histidine-rich protein 2 of Plasmodium falciparum is the most common malaria antigen targeted by rapid diagnostic tests for the specific diagnosis of P. falciparum. Recently, pfhrp2 gene deletions have been documented in P. falciparum isolates from South America and some multiple endemic countries in Africa and Asia. Parasites with such gene deletions can produce false negative diagnostic results using HRP2-based rapid diagnostic kits. In the present work, the prevalence of P. falciparum parasites lacking pfhrp2, pfhrp3, which produces a second P. falciparum antigen that is recognized by PfHRP2 -based rapid diagnostic tests, and their flanking genes was evaluated in 135 P. falciparum isolates from Gash Barka region and in 9 isolates from Debub region, in Eritrea. In the analyzed samples, 56% (81/144) of isolates were pfhrp2/pfhrp3 positive, while 9.7% (14/144) showed deletion of exon 2 of pfhrp2 gene and 43% (62/144) of isolates lacked the pfhrp3 gene. These results suggest that the pfhrp2 and pfhrp3 deletion phenomenon is present in a considerable proportion in the study areas, thus making the HRP2/3 based rapid diagnostic tests not completely reliable for malaria diagnosis in Eritrea. PMID- 28889945 TI - A systematic review and narrative synthesis of interventions for uncomplicated obesity: weight loss, well-being and impact on eating disorder. PMID- 28889946 TI - Dynamic balance in persons with multiple sclerosis who have a falls history is altered compared to non-fallers and to healthy controls. AB - Around 60% of persons with multiple sclerosis (MS) experience falls, however the dynamic balance differences between those who fall and those who don't are not well understood. The purpose of this study is to identify distinct biomechanical features of dynamic balance during gait that are different between fallers with MS, non-fallers with MS, and healthy controls. 27 recurrent fallers with MS, 28 persons with MS with no falls history, and 27 healthy controls walked on a treadmill at their preferred speed for 3min. The variability of trunk accelerations and the average and variability of minimum toe clearance, spatiotemporal parameters, and margin of stability were compared between groups. Fallers with MS exhibited a slower cautious gait compared to non-fallers and healthy controls, but had decreased anterior-posterior margin of stability and minimum toe clearance. Fallers walked with less locally stable and predictable trunk accelerations, and increased variability of step length, stride time, and both anterior-posterior and mediolateral margin of stability compared to non fallers and healthy controls. The present work provides evidence that within a group of persons with MS, there are gait differences that are influenced by falls history. These differences indicate that in persons with MS who fall, the center of mass is poorly controlled through base of support placement and the foot is closer to the ground during swing phase relative to the non-fallers. These identified biomechanical differences could be used to evaluate dynamic balance in persons with MS and to help improve fall prevention strategies. PMID- 28889948 TI - Internet-delivered physiotherapist-prescribed exercise and pain-coping skills training is beneficial for people with chronic knee pain [synopsis]. PMID- 28889949 TI - Back Performance Scale. PMID- 28889947 TI - An NF-kappaB Transcription-Factor-Dependent Lineage-Specific Transcriptional Program Promotes Regulatory T Cell Identity and Function. AB - Both conventional T (Tconv) cells and regulatory T (Treg) cells are activated through ligation of the T cell receptor (TCR) complex, leading to the induction of the transcription factor NF-kappaB. In Tconv cells, NF-kappaB regulates expression of genes essential for T cell activation, proliferation, and function. However the role of NF-kappaB in Treg function remains unclear. We conditionally deleted canonical NF-kappaB members p65 and c-Rel in developing and mature Treg cells and found they have unique but partially redundant roles. c-Rel was critical for thymic Treg development while p65 was essential for mature Treg identity and maintenance of immune tolerance. Transcriptome and NF-kappaB p65 binding analyses demonstrated a lineage specific, NF-kappaB-dependent transcriptional program, enabled by enhanced chromatin accessibility. These dual roles of canonical NF-kappaB in Tconv and Treg cells highlight the functional plasticity of the NF-kappaB signaling pathway and underscores the need for more selective strategies to therapeutically target NF-kappaB. PMID- 28889950 TI - Exploring Metabolic Configurations of Single Cells within Complex Tissue Microenvironments. AB - Over the past years, plenty of evidence has emerged illustrating how metabolism supports many aspects of cellular function and how metabolic reprogramming can drive cell differentiation and fate. Here, we present a method to assess the metabolic configuration of single cells within their native tissue microenvironment via the visualization and quantification of multiple enzymatic activities measured at saturating substrate conditions combined with subsequent cell type identification. After careful validation of the approach and to demonstrate its potential, we assessed the intracellular metabolic configuration of different human immune cell populations in healthy and tumor colon tissue. Additionally, we analyzed the intercellular metabolic relationship between cancer cells and cancer-associated fibroblasts in a breast cancer tissue array. This study demonstrates that the determination of metabolic configurations in single cells could be a powerful complementary tool for every researcher interested to study metabolic networks in situ. PMID- 28889952 TI - Orosomucoid-like 3 (ORMDL3) upregulates airway smooth muscle proliferation, contraction, and Ca2+ oscillations in asthma. AB - BACKGROUND: Airway hyperresponsiveness is a major feature of asthma attributed predominantly to an extrinsic immune/inflammatory response increasing airway smooth muscle (ASM) contractility. OBJECTIVE: We investigated whether increased ASM expression of orosomucoid-like 3 (ORMDL3), a gene on chromosome 17q21 highly linked to asthma, induced increased ASM proliferation and contractility in vitro and influenced airway contractility and calcium flux in ASM in precision-cut lung slices (PCLSs) from wild-type and hORMDL3Zp3-Cre mice (which express increased levels of human ORMDL3 [hORMDL3]). METHODS: Levels of ASM proliferation and contraction were assessed in ASM cells transfected with ORMDL3 in vitro. In addition, airway contractility and calcium oscillations were quantitated in ASM cells in PCLSs derived from naive wild-type and naive hORMDL3Zp3-Cre mice, which do not have a blood supply. RESULTS: Increased ASM expression of ORMDL3 in vitro resulted in increased ASM proliferation and contractility. PCLSs derived from naive hORMDL3Zp3-Cre mice, which do not have airway inflammation, exhibit increased airway contractility with increased calcium oscillations in ASM cells. Increased ASM ORMDL3 expression increases levels of ASM sarcoplasmic reticulum Ca2+ ATPase 2b (SERCA2b), which increases ASM proliferation and contractility. CONCLUSION: Overall, these studies provide evidence that an intrinsic increase in ORMDL3 expression in ASM can induce increased ASM proliferation and contractility, which might contribute to increased airway hyperresponsiveness in the absence of airway inflammation in asthmatic patients. PMID- 28889953 TI - Role of B cells in TH cell responses in a mouse model of asthma. AB - BACKGROUND: The importance of B lymphocytes to present antigens for antibody production is well documented. In contrast, very little is known about their capacity to influence CD4+ T-cell activation during a primary or secondary response to allergens. OBJECTIVE: Using mouse models of asthma, we investigated the role of B cells as antigen-presenting cells in priming and maintenance of TH cell responses. METHODS: Mice were immunized through the intranasal route with house dust mite (HDM) extract derived from Dermatophagoides pteronyssinus. B cells were depleted in HDM-sensitized animals to investigate the importance of B cells in maintenance of the allergic response. B cells were depleted before HDM sensitization to investigate the role of B cells in T-cell priming; furthermore, HDM sensitization was performed in mice with MHC class II expression restricted to the B-cell lineage. RESULTS: We found that B cells serve as potent antigen presenting cells ex vivo and restimulate in vivo-primed HDM-specific TH cells. HDM antigens were taken up by B cells independently of B-cell receptor specificity, indicating that HDM uptake and antigen presentation to CD4+ T cells is not restricted to rare B cells carrying HDM-specific B cell receptors. B-cell depletion before HDM challenge in HDM-sensitized mice resulted in a dramatic reduction of allergic response, indicating the role of B cells in amplification of TH2 responses. In contrast, HDM sensitization of mice in which MHC class II expression was restricted to B cells revealed the inability of these cells to prime TH2 responses but highlighted their unexpected role in priming TH1 and TH17 responses. CONCLUSION: Collectively, these data reveal new mechanisms leading to initiation and exacerbation of the allergic response that might have implications for designing new therapeutic strategies to combat HDM allergy. PMID- 28889954 TI - MicroRNA-155 mediates downregulation of the high-affinity receptor for IgE through Toll-like receptor signaling. PMID- 28889951 TI - Pancreatic beta Cell Regeneration as a Possible Therapy for Diabetes. AB - Diabetes is the result of having inadequate supply of functional insulin producing beta cells. Two possible approaches for replenishing the beta cells are: (1) replacement by transplanting cadaveric islets or beta cells derived from human embryonic stem cells/induced pluripotent stem cells and (2) induction of endogenous regeneration. This review focuses on endogenous regeneration, which can follow two pathways: enhanced replication of existing beta cells and formation of new beta cells from cells not expressing insulin, either by conversion from a differentiated cell type (transdifferentiation) or differentiation from progenitors (neogenesis). Exciting progress on both pathways suggest that regeneration may have therapeutic promise. PMID- 28889955 TI - Impaired humoral and cellular immune responses to influenza vaccination in chronic obstructive pulmonary disease patients. PMID- 28889956 TI - Editorial - Development and evolution of sensory cells and organs. PMID- 28889957 TI - Pathophysiology of preterm labor with intact membranes. AB - Preterm labor with intact membranes is a major cause of spontaneous preterm birth (sPTB). To prevent sPTB a clear understanding is needed of the hormonal interactions that initiate labor. The steroid hormone progesterone acting via its nuclear progesterone receptors (PRs) in uterine cells is essential for the establishment and maintenance of pregnancy and disruption of PR signaling (i.e., functional progesterone/PR withdrawal) is key trigger for labor. The process of parturition is also associated with inflammation within the uterine tissues and it is now generally accepted that inflammatory stimuli from multiple extrinsic and intrinsic sources induce labor. Recent studies suggest inflammatory stimuli induce labor by affecting PR transcriptional activity in uterine cells to cause functional progesterone/PR withdrawal. Advances in understanding the functional interaction of inflammatory load on the pregnancy uterus and progesterone/PR signaling is opening novel areas of research and may lead to rational therapeutic strategies to effectively prevent sPTB. PMID- 28889958 TI - Maternity care access, quality, and outcomes: A systems-level perspective on research, clinical, and policy needs. AB - The quality of maternity care in the United States is variable, and access to care is tenuous for rural residents, low-income individuals, and people of color. Without accessible, timely, and high-quality care, certain clinical and sociodemographic characteristics of individuals may render them more vulnerable to poor birth outcomes. However, risk factors for poor birth outcomes do not occur in a vaccum; rather, health care financing, delivery, and organization as well as the policy environment shape the context in which patients seek and receive maternity care. This paper describes the relationship between access and quality in maternity care and offers a systems-level perspective on the innovations and strategies needed in research, clinical care, and policy to improve equity in maternal and infant health. PMID- 28889960 TI - Outcomes after fecal diversion for colonic and perianal Crohn disease in children. AB - BACKGROUND: Temporary fecal diversion by means of an ileostomy or colostomy has been used in the surgical management of refractory colonic and perianal Crohn disease (CD). The aims of our study were to evaluate the outcomes after fecal diversion in pediatric patients with colonic and perianal CD. METHODS: The records of patients who underwent fecal diversion for colonic and perianal CD at Children's Hospital of Wisconsin between July 2000 and June 2014 were reviewed retrospectively. Patient demographics, medication use, onset and extent of disease, response to fecal diversion, rate of stoma reversal and relapse rate after stoma reversal were recorded. RESULTS: We identified 28 consecutive patients (20 females, 8 males; median age 13.9years) undergoing fecal diversion for refractory colonic (n=21) and perianal CD (n=7). Median duration of follow-up after fecal diversion was 2.26years (range, 0.79-10.2years). The response to fecal diversion was sustained clinical remission in 13/28 (46%), temporary clinical remission in 10/28 (36%), no change in 5/28 (18%). Intestinal continuity was restored in 14/28 (50%) patients; however, 3 (21%) required permanent stoma after reconnection. Classification tree analysis identified that female patients without perianal CD had higher rates of stoma reversal (p=0.008). CONCLUSIONS: Fecal diversion can induce remission in pediatric patients with refractory colonic and perianal CD. Restoration of intestinal continuity was achieved in about 39%. Female patients without perianal CD carried no risk of a permanent stoma. LEVEL OF EVIDENCE: Level III study. PMID- 28889959 TI - Metabolic profiles revealed anti-ischemia-reperfusion injury of Yangxinshi tablet in Rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial ischemia-reperfusion (I/R) injury is a serious injury that is resulted from the recovery of blood supply after myocardial ischemia. Yangxinshi tablet is a compound Chinese herbal preparation and often used to alleviate the myocardial ischemia in clinical, but its protective mechanism of anti-myocardial ischemia reperfusion injury remains unclear. The objective of this study was to evaluate the anti-I/R injury effect of Yangxinshi tablet on a myocardial I/R rat model and to identify serum biomarker metabolites associated with I/R based on ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC QTOF/MS) metabolomic method, and explore the metabolic mechanism of anti-I/R injury of Yangxinshi tablet. MATERIALS AND METHODS: Unsupervised principle component analysis highlighted significant differences in the metabolome of the myocardial I/R, healthy control and drug-treated rats. Partial least squares discriminant analysis revealed 25 metabolites as the most potential biomarker metabolites discriminating the myocardial I/R rats and control rats. Most of the metabolites were primarily involved in oxidative stress, energy metabolism, fatty acid metabolism, amino acid metabolism. These metabolites were validated by assessing the efficacy after intragastric administration of Yangxinshit ablet to the myocardial I/R rat model. RESULTS: Based on metabolomic results, the action mechanism of anti-I/R injury of Yangxinshi tablet was concluded as follows: (1) enhance the ability of scavenging free radicals and reactive oxygen species in vivo; (2) provide energy for myocardium via accelerating the intracellular carnitine transportion to accelerate the oxidation of fatty acid and (3) attenuate ceramide to reduce cardiomyocyte apoptosis. CONCLUSIONS: Yangxinshi tablet has cardio-protection effects on I/R rats via regulation of multiple metabolic pathways involving in oxidative stress, energy metabolism, fatty acid, and amino acid metabolisms. This study will be meaningful for its clinical application and valuable for further exploring the action mechanism of Yangxinshi tablet. PMID- 28889961 TI - Analysis of the reversibility of biliary cirrhosis in young rats submitted to biliary obstruction. AB - BACKGROUND/PURPOSE: Biliary atresia and other liver biliary obstructions are relevant conditions in pediatric surgery due to their progression to biliary cirrhosis and indication for liver transplantation. It is known that the period during which biliary obstruction persists determines the development of cirrhosis and its reversibility after a biliary drainage procedure. However, no time or histological markers of biliary cirrhosis reversibility have been established. MATERIALS AND METHODS: One hundred and twenty-nine young Wistar rats underwent surgery for ligation of the common bile duct and were maintained until 8weeks. A part of these animals was submitted to biliary drainage surgery at 2, 3, 4, 5, or 6weeks after the initial procedure. After cyst formation at the site of obstruction, cyst-jejunal anastomosis was performed to restore bile flow. After biliary obstruction and drainage, liver samples were collected for histological and molecular analysis of the genes responsible for collagen deposition and fibrosis. RESULTS: The mortality rates were 39.8% and 56.7% after the first and second procedures, respectively. Ductular proliferation (p=0.001) and collagen deposition increased according to the period under obstruction (p=0.0001), and both alterations were partially reduced after biliary drainage. There were no significant differences in the values of desmin and alpha-actin according to the period during which the animal remained with biliary obstruction (p=0.09 and p=0.3, respectively), although increased values of transforming growth factor beta 1 (TGFbeta1) occurred after 8weeks (p=0.000). Desmin levels decreased, and alpha-actin and TGFbeta1 levels increased according to the period under obstruction. The molecular alterations were partially reversed after biliary drainage. CONCLUSIONS: The histologic and molecular changes in the liver parenchyma promoted by biliary obstruction in the young animal can be partially reversed by a biliary drainage procedure. PMID- 28889962 TI - Neurobehavioral outcomes in autoimmune encephalitis. AB - This study evaluates long-term neurobehavioral function in patients with clinically diagnosed autoimmune encephalitis (AE) of various etiologies through retrospective chart review and a cross-sectional structured telephone interview. Of 77 patients meeting clinical diagnostic criteria for AE over a ten year period, 39/77 (51%) patients had known AE-associated antibodies, and 38/77 (49%) had no detected antibody. 9/77 (12%) died, and 26/77 (34%) had "poor" neurologic disability score (mRS 3-5) at the last documented follow-up. 44 participants enrolled in the telephone interview, of whom 38/44 (86%) endorsed ongoing difficulties with fatigue, emotional lability, short-term memory, and/or concentration. On standardized assessment of adaptive behavior (ABAS-3), 23/44 (52%) scored "below average" (general adaptive composite: mean 86.95, standard deviation 18.45). Of the participants with "good" neurologic disability outcome (mRS 0-2), 12/30 (40%) scored "below average" in adaptive behavior. In summary, patients with AE frequently have persistent impairments in neurologic disability, neurocognitive symptomatology, and adaptive behavior, which may not be adequately captured by routine neurologic assessments. Comprehensively elucidating these persistent neurobehavioral impairments and predicting which patients are at highest risk will allow for optimal care of patients and their families. PMID- 28889963 TI - Quantitative analysis of retinal perfusion in mice using optical coherence tomography angiography. AB - PURPOSE: To evaluate repeatability of the quantitative analysis of vessel density in the retinas of healthy mice using optical coherence tomography angiography (OCT-A). METHODS: Seventeen eyes of seventeen healthy mice aged 10-15 weeks (young) and 75-95 weeks (old) were included in this study. OCT-A was performed using RTVue XR Avanti (Optovue Inc., Fremont, California, USA) under general anaesthesia. The retina was imaged twice using a 3 * 3 mm2 scan. Retinal thickness and flow density data in the superficial and deep retinal OCT angiograms were extracted and analysed. RESULTS: The differences between the flow density values (whole en face) in the first and second sessions were non significant (superficial retinal OCT angiogram: first session: 45.4 +/- 4.1% (39.1-55.3%); second session: 46.1 +/- 4.7% (39.1-59.1%); p = 0.14; deep retinal OCT angiogram: first session: 47.1 +/- 3.8% (39.4-53.4%); second session: 47.3 +/ 3.7% (39.4-53.8%); p = 0.50). The repeatability assessment of retinal thickness yielded intraclass correlation coefficient (ICC) values ranging between (0.86 0.99) while the ICCs for the flow density measurements ranged from 0.87 to 0.92 for the superficial retinal OCT angiogram and 0.68 to 0.93 for the deep retinal OCT angiogram. CONCLUSIONS: Repeated OCT-A measurement of mice retinal vessel density (VD) revealed valid repeatability, indicating that this non-invasive technology is sufficient for longitudinal assessment of vascular changes in various mouse models and thereby opening the way to in-depth, experimental analysis of the vascular aspects of different retinal diseases and monitoring of disease progression and the effects of treatments. PMID- 28889964 TI - Hypotensive effect induced by microinjection of Alamandine, a derivative of angiotensin-(1-7), into caudal ventrolateral medulla of 2K1C hypertensive rats. AB - In the present study we evaluated the cardiovascular effects produced by microinjection of the new component of the renin-angiotensin system, alamandine, into caudal ventrolateral medulla of urethane-anesthetized normotensive and hypertensive 2K1C rats. The participation of different angiotensin receptors in the effects of alamandine was also evaluated. Microinjection of angiotensin-(1-7) was used for comparison. The microinjection of 4, 40 and 140pmol of alamandine or angiotensin-(1-7) into caudal ventrolateral medulla induced similar hypotensive effects in Sham-operated rats. However, contrasting with angiotensin-(1-7), in 2K1C rats the MAP response to the highest dose of alamandine was similar to that observed with saline. The microinjection of A-779, a selective Mas receptor antagonist, blunted the angiotensin-(1-7) effects but did not block the hypotensive effect of alamandine in Sham or in 2K1C rats. However, microinjection of D-Pro7-angiotensin-(1-7), a Mas/MrgD receptor antagonist, blocked the hypotensive effect induced by both peptides. Furthermore, microinjection of PD123319, a putative AT2 receptor antagonist blocked the hypotensive effect of alamandine, but not of angiotensin-(1-7), in Sham and 2K1C rats. Microinjection of the AT1 receptor antagonist, losartan, did not alter the hypotensive effect of angiotensin-(1-7) or alamandine in both groups. These results provide new insights about the differential mechanisms participating in the central cardiovascular effects of alamandine and angiotensin-(1-7) in normotensive and 2K1C hypertensive rats. PMID- 28889965 TI - Losartan counteracts the effects of cardiomyocyte swelling on glucose uptake and insulin receptor substrate-1 levels. AB - A growing body of evidence demonstrates an association between Angiotensin II (Ang II) receptor blockers (ARBs) and enhanced glucose metabolism during ischemic heart disease. Despite these encouraging results, the mechanisms responsible for these effects during ischemia remain poorly understood. In this study we investigated the influence of losartan, an AT1 receptor blocker, and secreted Ang II (sAng II) on glucose uptake and insulin receptor substrate (IRS-1) levels during cardiomyocyte swelling. H9c2 cells were differentiated to cardiac muscle and the levels of myogenin, Myosin Light Chain (MLC), and membrane AT1 receptors were measured using flow cytometry. Intracellular Ang II (iAng II) was overexpressed in differentiated cardiomyocytes and swelling was induced after incubation with hypotonic solution for 40min. Glucose uptake and IRS-1 levels were monitored by flow cytometry using 2-NBDG fluorescent glucose (10MUM) or an anti-IRS-1 monoclonal antibody in the presence or absence of losartan (10-7M). Secreted Angiotensin II was quantified from the medium using a specific Ang II EIA kit. To evaluate the relationship between sAng II and losartan effects on glucose uptake, transfected cells were pretreated with the drug for 24h and then exposed to hypotonic solution in the presence or absence of the secreted peptide. The results indicate that: (1) swelling of transfected cardiomyocytes decreased glucose uptake and induced the secretion of Ang II to the extracellular medium; (2) losartan antagonized the effects of swelling on glucose uptake and IRS-1 levels in transfected cardiomyocytes; (3) the effects of losartan on glucose uptake were observed during swelling only in the presence of sAng II in the culture medium. Our study demonstrates that both losartan and sAng II have essential roles in glucose metabolism during cardiomyocyte swelling. PMID- 28889967 TI - The importation of the phylogenetic-transition state of Zika virus to China in 2014. PMID- 28889966 TI - Safety evaluation of supratherapeutic dose of Maytenus ilicifolia Mart. ex Reissek extracts on fertility and neurobehavioral status of male and pregnant rats. AB - Maytenus ilicifolia Mart. ex Reissek is a plant commonly used in folklore medicine in the management of gastric diseases in South America. This study explores the effects of a supratherapeutic dose of aqueous and ethanol extracts of M. ilicifolia (1360 mg/kg) on fertility and neurobehavioral status in male and pregnant rats. A battery of sensory-motor developmental endpoints was carried out to assess impairments on pups of dams orally treated with the aqueous extract of M. ilicifolia during the organogenesis period of pregnancy (GD 9 through GD 14). The neuromotor maturation reflexes and physical developments of the offspring were not significantly different between the groups (p < 0.05). Also, the hippocampal morphology revealed no indices of cell loss in the CA1, CA2, CA3 and CA4 areas. As second protocol, some fertility aspects were investigated in young post pubertal male Wistar rats treated with the ethanol extract for 30 days. The semen quality and testicular tissue morphology of male rats treated with the ethanol extract of M. ilicifolia remained unaffected upon treatment. Thus, the results indicate that the high-dose of M. ilicifolia extracts have no neurotoxic potential on offspring and seem not to affect the sperm quality of male rats. PMID- 28889968 TI - Genetic analysis of H7N9 highly pathogenic avian influenza virus in Guangdong, China, 2016-2017. PMID- 28889969 TI - Andrographolide inhibits influenza A virus-induced inflammation in a murine model through NF-kappaB and JAK-STAT signaling pathway. AB - Influenza viruses, the main cause of respiratory tract diseases, cause high morbidity and mortality in humans. Excessive inflammation in the lungs is proposed to be a hallmark for the severe influenza virus infection, especially influenza A virus infection. Strategies against inflammation induced by influenza A virus infection could be a potential anti-influenza therapy. Here, lethal dose of mouse-adapted H1N1 strain PR8A/PR/8/34 was inoculated C57BL/6 mice to detect the anti-influenza activity of andrographolide, the active component of traditional Chinese medicinal herb Andrographis paniculata, with or without influenza virus entry inhibitor CL-385319. Treatment was initiated on 4 days after infection. The survival rate, body weight, lung pathology, viral loads, cytokine expression were monitored in 14 days post inoculation. The combination group had the highest survival rate. Andrographolide treatment could increase the survival rate, diminish lung pathology, decrease the virus loads and the inflammatory cytokines expression induced by infection. Mechanism studies showed the NF-kappaB and JAK-STAT signaling pathway were involved in the activity of andrographolide. In conclusion, combination of virus entry inhibitor with immunomodulator might be a promising therapeutic approach for influenza. PMID- 28889970 TI - Genomic signature analysis of the recently emerged highly pathogenic A(H5N8) avian influenza virus: implying an evolutionary trend for bird-to-human transmission. AB - In early 2014, a novel subclade (2.3.4.4) of the highly pathogenic avian influenza (HPAI) A(H5N8) virus caused the first outbreak in domestic ducks and migratory birds in South Korea. Since then, it has spread to 44 countries and regions. To date, no human infections with A(H5N8) virus have been reported, but the possibility cannot be excluded. By analyzing the genomic signatures of A(H5N8) strains, we found that among the 47 species-associated signature positions, three positions exhibited human-like signatures (HLS), including PA 404S, PB2-613I and PB2-702R and that mutation trend of host signatures of avian A(H5N8) is different before and after 2014. About 82% of A(H5N8) isolates collected after January of 2014 carried the 3 HLS (PA-404S/PB2-613I/PB2-702R) in combination, while none of isolates collected before 2014 had this combination. Furthermore, the HA protein had S137A and S227R substitutions in the receptor binding site and A160T in the glycosylation site, potentially increasing viral ability to bind human-type receptors. Based on these findings, the newly emerged HPAI A(H5N8) isolates show an evolutionary trend toward gaining more HLS and, along with it, the potential for bird-to-human transmissibility. Therefore, more extensive surveillance of this rapidly spreading HPAI A(H5N8) and preparedness against its potential pandemic are urgently needed. PMID- 28889971 TI - Host and pathogen interface: microRNAs are modulators of disease outcome. AB - Chlamydiae are a group of intracellular bacterium that infect a range of hosts and are responsible for the most common sexual transmitted infections, which could be the result of a plethora of factors leading to varied pathological outcomes. This review aims to show that Chlamydia possibly manipulates host defenses through microRNAs interaction. PMID- 28889972 TI - The emerging role of AMP-activated protein kinase in cholestatic liver diseases. AB - AMP-activated protein kinase (AMPK), recognized as an energy sensor with three heterotrimeric subunits (alpha, beta and gamma), not only maintains basal intracellular adenosine triphosphate levels but also regulates energy-intensive pathological responses, such as neurodegenerative and metabolic diseases, through multiple signaling pathways. Recent studies open a new direction for AMPK research and demonstrate that AMPK is a critical player in the pathogenesis of cholestatic liver injury and plays paradoxical roles in the regulation of different pathological processes, including the disruption of bile acid homeostasis and the regulation of hepatic polarity, inflammation and fibrosis. In the present review, we summarize recent findings that implicate AMPK-mediated signaling pathways in the pathogenesis of cholestatic liver injury. These findings provide novel insight regarding the potential use of AMPK as a therapeutic target for the treatment of cholestatic liver injury. PMID- 28889973 TI - Origin of the Reflectin Gene and Hierarchical Assembly of Its Protein. AB - Cephalopods, the group of animals including octopus, squid, and cuttlefish, have remarkable ability to instantly modulate body coloration and patterns so as to blend into surrounding environments [1, 2] or send warning signals to other animals [3]. Reflectin is expressed exclusively in cephalopods, filling the lamellae of intracellular Bragg reflectors that exhibit dynamic iridescence and structural color change [4]. Here, we trace the possible origin of the reflectin gene back to a transposon from the symbiotic bioluminescent bacterium Vibrio fischeri and report the hierarchical structural architecture of reflectin protein. Intrinsic self-assembly, and higher-order assembly tightly modulated by aromatic compounds, provide insights into the formation of multilayer reflectors in iridophores and spherical microparticles in leucophores and may form the basis of structural color change in cephalopods. Self-assembly and higher-order assembly in reflectin originated from a core repeating octapeptide (here named protopeptide), which may be from the same symbiotic bacteria. The origin of the reflectin gene and assembly features of reflectin protein are of considerable biological interest. The hierarchical structural architecture of reflectin and its domain and protopeptide not only provide insights for bioinspired photonic materials but also serve as unique "assembly tags" and feasible molecular platforms in biotechnology. PMID- 28889974 TI - Ionotropic Receptors Mediate Drosophila Oviposition Preference through Sour Gustatory Receptor Neurons. AB - Carboxylic acids are present in many foods, being especially abundant in fruits. Yet, relatively little is known about how acids are detected by gustatory systems and whether they have a potential role in nutrition or provide other health benefits. Here we identify sour gustatory receptor neurons (GRNs) in tarsal taste sensilla of Drosophila melanogaster. We find that most tarsal sensilla harbor a sour GRN that is specifically activated by carboxylic and mineral acids but does not respond to sweet- and bitter-tasting chemicals or salt. One pair of taste sensilla features two GRNs that respond only to a subset of carboxylic acids and high concentrations of salt. All sour GRNs prominently express two Ionotropic Receptor (IR) genes, IR76b and IR25a, and we show that both these genes are necessary for the detection of acids. Furthermore, we establish that IR25a and IR76b are essential in sour GRNs of females for oviposition preference on acid containing food. Our investigations reveal that acids activate a unique set of taste cells largely dedicated to sour taste, and they indicate that both pH/proton concentration and the structure of carboxylic acids contribute to sour GRN activation. Together, our studies provide new insights into the cellular and molecular basis of sour taste. PMID- 28889975 TI - Consistent Individual Differences Drive Collective Behavior and Group Functioning of Schooling Fish. AB - The ubiquity of consistent inter-individual differences in behavior ("animal personalities") [1, 2] suggests that they might play a fundamental role in driving the movements and functioning of animal groups [3, 4], including their collective decision-making, foraging performance, and predator avoidance. Despite increasing evidence that highlights their importance [5-16], we still lack a unified mechanistic framework to explain and to predict how consistent inter individual differences may drive collective behavior. Here we investigate how the structure, leadership, movement dynamics, and foraging performance of groups can emerge from inter-individual differences by high-resolution tracking of known behavioral types in free-swimming stickleback (Gasterosteus aculeatus) shoals. We show that individual's propensity to stay near others, measured by a classic "sociability" assay, was negatively linked to swim speed across a range of contexts, and predicted spatial positioning and leadership within groups as well as differences in structure and movement dynamics between groups. In turn, this trait, together with individual's exploratory tendency, measured by a classic "boldness" assay, explained individual and group foraging performance. These effects of consistent individual differences on group-level states emerged naturally from a generic model of self-organizing groups composed of individuals differing in speed and goal-orientedness. Our study provides experimental and theoretical evidence for a simple mechanism to explain the emergence of collective behavior from consistent individual differences, including variation in the structure, leadership, movement dynamics, and functional capabilities of groups, across social and ecological scales. In addition, we demonstrate individual performance is conditional on group composition, indicating how social selection may drive behavioral differentiation between individuals. PMID- 28889976 TI - Humans, but Not Deep Neural Networks, Often Miss Giant Targets in Scenes. AB - Even with great advances in machine vision, animals are still unmatched in their ability to visually search complex scenes. Animals from bees [1, 2] to birds [3] to humans [4-12] learn about the statistical relations in visual environments to guide and aid their search for targets. Here, we investigate a novel manner in which humans utilize rapidly acquired information about scenes by guiding search toward likely target sizes. We show that humans often miss targets when their size is inconsistent with the rest of the scene, even when the targets were made larger and more salient and observers fixated the target. In contrast, we show that state-of-the-art deep neural networks do not exhibit such deficits in finding mis-scaled targets but, unlike humans, can be fooled by target-shaped distractors that are inconsistent with the expected target's size within the scene. Thus, it is not a human deficiency to miss targets when they are inconsistent in size with the scene; instead, it is a byproduct of a useful strategy that the brain has implemented to rapidly discount potential distractors. PMID- 28889978 TI - Massive Protein Import into the Early-Evolutionary-Stage Photosynthetic Organelle of the Amoeba Paulinella chromatophora. AB - The endosymbiotic acquisition of mitochondria and plastids more than 1 Ga ago profoundly impacted eukaryote evolution. At the heart of understanding organelle evolution is the re-arrangement of the endosymbiont proteome into a host controlled organellar proteome. However, early stages in this process as well as the timing of events that underlie organelle integration remain poorly understood. The amoeba Paulinella chromatophora contains cyanobacterium-derived photosynthetic organelles, termed "chromatophores," that were acquired more recently (around 100 Ma ago). To explore the re-arrangement of an organellar proteome during its integration into a eukaryotic host cell, here we characterized the chromatophore proteome by protein mass spectrometry. Apparently, genetic control over the chromatophore has shifted substantially to the nucleus. Two classes of nuclear-encoded proteins-which differ in protein length-are imported into the chromatophore, most likely through independent pathways. Long imported proteins carry a putative, conserved N-terminal targeting signal, and many specifically fill gaps in chromatophore-encoded metabolic pathways or processes. Surprisingly, upon heterologous expression in a plant cell, the putative chromatophore targeting signal conferred chloroplast localization. This finding suggests common features in the protein import pathways of chromatophores and plastids, two organelles that evolved independently and more than 1 Ga apart from each other. By combining experimental data with in silico predictions, we provide a comprehensive catalog of almost 450 nuclear-encoded, chromatophore-targeted proteins. Interestingly, most imported proteins seem to derive from ancestral host genes, suggesting that the re targeting of nuclear-encoded proteins that resulted from endosymbiotic gene transfers plays only a minor role at the onset of chromatophore integration. PMID- 28889977 TI - Novel Organelles with Elements of Bacterial and Eukaryotic Secretion Systems Weaponize Parasites of Drosophila. AB - The evolutionary success of parasitoid wasps, a highly diverse group of insects widely used in biocontrol, depends on a variety of life history strategies in conflict with those of their hosts [1]. Drosophila melanogaster is a natural host of parasitic wasps of the genus Leptopilina. Attack by L. boulardi (Lb), a specialist wasp to flies of the melanogaster group, activates NF-kappaB-mediated humoral and cellular immunity. Inflammatory blood cells mobilize and encapsulate Lb eggs and embryos [2-5]. L. heterotoma (Lh), a generalist wasp, kills larval blood cells and actively suppresses immune responses. Spiked virus-like particles (VLPs) in wasp venom have clearly been linked to wasps' successful parasitism of Drosophila [6], but the composition of VLPs and their biotic nature have remained mysterious. Our proteomics studies reveal that VLPs lack viral coat proteins but possess a pharmacopoeia of (1) the eukaryotic vesicular transport system, (2) immunity, and (3) previously unknown proteins. These novel proteins distinguish Lh from Lb VLPs; notably, some proteins specific to Lh VLPs possess sequence similarities with bacterial secretion system proteins. Structure-informed analyses of an abundant Lh VLP surface and spike-tip protein, p40, reveal similarities to the needle-tip invasin proteins SipD and IpaD of Gram-negative bacterial type-3 secretion systems that breach immune barriers and deliver virulence factors into mammalian cells. Our studies suggest that Lh VLPs represent a new class of extracellular organelles and share pathways for protein delivery with both eukaryotic microvesicles and bacterial surface secretion systems. Given their mixed prokaryotic and eukaryotic properties, we propose the term mixed-strategy extracellular vesicle (MSEV) to replace VLP. PMID- 28889979 TI - Visual Threat Assessment and Reticulospinal Encoding of Calibrated Responses in Larval Zebrafish. AB - All visual animals must decide whether approaching objects are a threat. Our current understanding of this process has identified a proximity-based mechanism where an evasive maneuver is triggered when a looming stimulus passes a subtended visual angle threshold. However, some escape strategies are more costly than others, and so it would be beneficial to additionally encode the level of threat conveyed by the predator's approach rate to select the most appropriate response. Here, using naturalistic rates of looming visual stimuli while simultaneously monitoring escape behavior and the recruitment of multiple reticulospinal neurons, we find that larval zebrafish do indeed perform a calibrated assessment of threat. While all fish generate evasive maneuvers at the same subtended visual angle, lower approach rates evoke slower, more kinematically variable escape responses with relatively long latencies as well as the unilateral recruitment of ventral spinal projecting nuclei (vSPNs) implicated in turning. In contrast, higher approach rates evoke faster, more kinematically stereotyped responses with relatively short latencies, as well as bilateral recruitment of vSPNs and unilateral recruitment of giant fiber neurons in fish and amphibians called Mauthner cells. In addition to the higher proportion of more costly, shorter latency Mauthner-active responses to greater perceived threats, we observe a higher incidence of freezing behavior at higher approach rates. Our results provide a new framework to understand how behavioral flexibility is grounded in the appropriate balancing of trade-offs between fast and slow movements when deciding to respond to a visually perceived threat. PMID- 28889980 TI - The Adder Phenomenon Emerges from Independent Control of Pre- and Post-Start Phases of the Budding Yeast Cell Cycle. AB - Although it has long been clear that cells actively regulate their size, the molecular mechanisms underlying this regulation have remained poorly understood. In budding yeast, cell size primarily modulates the duration of the cell-division cycle by controlling the G1/S transition known as Start. We have recently shown that the rate of progression through Start increases with cell size, because cell growth dilutes the cell-cycle inhibitor Whi5 in G1. Recent phenomenological studies in yeast and bacteria have shown that these cells add an approximately constant volume during each complete cell cycle, independent of their size at birth. These results seem to be in conflict, as the phenomenological studies suggest that cells measure the amount they grow, rather than their size, and that size control acts over the whole cell cycle, rather than specifically in G1. Here, we propose an integrated model that unifies the adder phenomenology with the molecular mechanism of G1/S cell-size control. We use single-cell microscopy to parameterize a full cell-cycle model based on independent control of pre- and post-Start cell-cycle periods. We find that our model predicts the size independent amount of cell growth during the full cell cycle. This suggests that the adder phenomenon is an emergent property of the independent regulation of pre and post-Start cell-cycle periods rather than the consequence of an underlying molecular mechanism measuring a fixed amount of growth. PMID- 28889981 TI - Visual-Vestibular Conflict Detection Depends on Fixation. AB - Visual and vestibular signals are the primary sources of sensory information for self-motion. Conflict among these signals can be seriously debilitating, resulting in vertigo [1], inappropriate postural responses [2], and motion, simulator, or cyber sickness [3-8]. Despite this significance, the mechanisms mediating conflict detection are poorly understood. Here we model conflict detection simply as crossmodal discrimination with benchmark performance limited by variabilities of the signals being compared. In a series of psychophysical experiments conducted in a virtual reality motion simulator, we measure these variabilities and assess conflict detection relative to this benchmark. We also examine the impact of eye movements on visual-vestibular conflict detection. In one condition, observers fixate a point that is stationary in the simulated visual environment by rotating the eyes opposite head rotation, thereby nulling retinal image motion. In another condition, eye movement is artificially minimized via fixation of a head-fixed fixation point, thereby maximizing retinal image motion. Visual-vestibular integration performance is also measured, similar to previous studies [9-12]. We observe that there is a tradeoff between integration and conflict detection that is mediated by eye movements. Minimizing eye movements by fixating a head-fixed target leads to optimal integration but highly impaired conflict detection. Minimizing retinal motion by fixating a scene fixed target improves conflict detection at the cost of impaired integration performance. The common tendency to fixate scene-fixed targets during self-motion [13] may indicate that conflict detection is typically a higher priority than the increase in precision of self-motion estimation that is obtained through integration. PMID- 28889982 TI - Retraction notice to "Electrical Stimulation for Hemiplegic Shoulder Function: A Systematic Review and Meta-Analysis of 15 Randomized Controlled Trials" [Arch Phys Med Rehabil. 97 (2016) 1588-94]. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the co-Editors-in-Chief. The article plagiarizes a paper that was published in BioMed Research International, Volume 2015 (2015), Article ID 729768, 14 pages, http://dx.doi.org/10.1155/2015/729768. Nearly the entire introduction and sections of the methods, limitations and conclusions duplicate the BioMed Research International paper. One of the conditions of submission of a paper to Archives of Physical Medicine and Rehabilitation is that authors declare explicitly that the paper is an original work and not duplicative of prior work unless that work is cited properly. The duplication in this manuscript is a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter. PMID- 28889983 TI - Analysing the change of sagittal balance in patients with Lenke 5 idiopathic scoliosis. AB - OBJECTIVE: The aim of this study was to evaluate preoperative and postoperative spinopelvic parameters and the influence of lowest instrumented vertebrae on sagittal parameters in Lenke 5 Adolescent Idiopathic Scoliosis (AIS) patients. METHODS: A total of 42 patients (37 females, 5 males; mean age: 16.71 +/- 3.46 years) were included in the study. Preoperative and postoperative last follow up lumbar lordosis (LL), thoracic kyphosis (TK), pelvic tilt (PT), pelvic incidence (PI) and sacral slope (SS) angles measured. By stopped fusion in L3, L4 or L5 we divided the group into three parts. RESULTS: Mean follow-up was 43 months. Preoperatively, the mean TK and LL were 36.8 degrees and 55.3 degrees . At the last follow up, the mean TK and LL were 27.1 degrees and 49.0 degrees degrees, respectively. Preoperatively, the mean PI, PT and SS were 53.3 degrees , 16.1 degrees and 37.4 degrees degrees. At the last follow up, the mean PI, PT and SS were 52.7 degrees , 19.9 degrees and 33.0 degrees respectively. Significant differences were observed for SS (p = 0.003), TK (p = 0.004), LL (p = 0.012) and PT (p = 0.013) postoperatively for all patients. According the L3 and L4 groups there is significant difference in SS, LL (p = 0.013) and PT (p = 0.018) which means a significant decrease occurs in SS and LL when the distal fusion level changes from L3 to L4 but significant increase in PT in L3 group to compensate spinopelvic change after surgery. CONCLUSION: The selection of more distal level for fusion adversely affects the compensation mechanisms of sagittal balance in Lenke 5 AIS patients. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 28889984 TI - Association between aspartic acid repeat polymorphism of the asporin gene and risk of knee osteoarthritis: A systematic review and meta-analysis. AB - OBJECTIVE: Studies have assessed the association between aspartic acid (D)-repeat polymorphism in the gene encoding Asporin (ASPN) and knee osteoarthritis (KOA) risk, but the results were inconclusive and contradictory. Therefore, we performed a meta-analysis to investigate the association between ASPN gene D repeat polymorphism and KOA risk. METHODS: Eligible studies were identified by searching several electronic databases for relevant reports published before September 2016. The pooled odds ratios (ORs) for the association between ASPN polymorphism and KOA and their corresponding 95% confidence intervals (CIs) were estimated using the random- or fixed-effect model. RESULTS: A total of eleven case-control studies in ten publications with 4610 KOA cases and 3621 controls were included for the ASPN D-repeat polymorphism. Overall, no significant association was detected for D14 allele carrier (D14 vs. D13: OR = 1.10, 95% CI = 0.90-1.36, p = 0.32). Meta-analysis of D14 vs. other alleles and D13 vs. other alleles showed the same pattern of KOA association as the D14 vs. D13 (OR = 1.30, 95% CI = 1.00-1.70, p = 0.06; OR = 0.93, 95% CI = 0.82-1.06, p = 0.33, respectively). Also, in the stratified analysis by ethnicity, no significant association of this polymorphism with risk of KOA was found in the European and Asians populations (OR = 1.05, 95% CI = 0.91-1.21, p = 0.49; OR = 0.98, 95% CI = 0.78-1.23, p = 0.88, respectively). CONCLUSIONS: The present meta-analysis suggests that the ASPN D-repeat polymorphism is not associated with an increased KOA risk. However, future large studies with gene-gene and gene-environment interactions are needed to validate these findings. LEVEL OF EVIDENCE: Level III diagnostic study. PMID- 28889985 TI - Combined intra- and extra-articular grafting for revision ACL reconstruction: A multicentre study by the French Arthroscopy Society (SFA). AB - BACKGROUND: A careful analysis of the reasons for ACL reconstruction failure is essential to selection of the optimal surgical revision technique designed to ensure good rotational stability and to minimise the risk of re-rupture. OBJECTIVE: To evaluate anterolateral ligament (ALL) stabilisation during revision ACL reconstruction. HYPOTHESIS: ALL stabilisation during revision ACL reconstruction provides good rotational stability without increasing the risk of complications. MATERIAL AND METHODS: This multicentre study included 349 patients, 151 retrospectively and 198 prospectively. There were 283 males and 66 females. Inclusion criteria were an indication for revision ACL reconstruction surgery with combined intra-articular reconstruction and ALL stabilisation after failed autograft ACL reconstruction, and intact PCL. Exclusion criteria were primary ACL reconstruction and concomitant peripheral medial and/or lateral lesions. Each patient underwent a clinical and radiographic evaluation before and after revision surgery. Before revision surgery, the mean IKDC score was 56.5+/ 15.5 and 96% of patients were IKDC C or D. RESULTS: Rates were 5.0% for early and 10.5% for late postoperative complications. Lachmann's test had a hard stop at last follow-up in 97% of patients. The pivot-shift test was positive in 1% of patients. The mean subjective IKDC score was 84.5+/-13.0 and 86.5% of patients were IKDC A or B. The proportions of patients with radiographic knee osteoarthritis at last follow-up was unchanged for the lateral tibio-femoral and patello-femoral compartments but increased by 9.7% to 21.2% for the medial tibio femoral compartment. The re-rupture rate was 1.2% and the further surgical revision rate was 5.4%. CONCLUSION: Anterior laxity at last follow-up was consistent with previous studies of revision ACL reconstruction. However, rotational stability and the re-rupture risk were improved. ALL stabilisation is among the techniques that deserve consideration as part of the therapeutic options for revision ACL reconstruction. LEVEL OF EVIDENCE: IV, retrospective and prospective cohort study. PMID- 28889987 TI - Prevalence of nocturnal sleep onset rapid movement sleep period (SOREMP) in narcolepsy type 1 and type 2. PMID- 28889986 TI - 'Haemophilus quentini' in the urethra of men complaining of urethritis symptoms. AB - We isolated a cryptic genospecies of Haemophilus influenzae referred to as 'Haemophilus quentini' in the urethra of 3 men complaining of urethritis symptoms. H. influenzae strains, which had been isolated from the urethra in 77 of 1518 men complaining of urethritis symptoms, identified by the conventional test, and stored, were re-cultured for this study. Sixty-seven strains surviving storage were screened by a PCR-based assay specific for the cryptic genital Haemophilus genospecies. Three strains (HI09003, HI11006, and HI14016) were screened by PCR and identified as 'H. quentini' by 16S rRNA sequencing. The men positive for HI09003 and HI11006 were diagnosed as having non-chlamydial non gonococcal urethritis (NGU), and their demographic and clinical features were similar to those of NGU caused by other pathogens. The man positive for HI14016 was ultimately diagnosed as having condyloma acuminatum on the glans. The 3 strains of 'H. quentini' produced no beta-lactamase and were susceptible to ampicillin and other antimicrobial agents, including cephalosporins, fluoroquinolones, tetracyclines, and macrolides, recommended for treatment for urethritis. 'H. quentini' would be an uncommon pathogen in men with urogenital infections. Based on the clinical features of the two patients with 'H. quentini' positive NGU, it would be difficult to predict the presence of 'H. quentini' in the urethra. The 3 strains of 'H. quentini' were susceptible to a variety of antimicrobial agents. Further accumulation of data regarding 'H. quentini' infections is needed to characterize the pathogenic roles of this genospecies in urogenital infections and to establish appropriate management of 'H. quentini' infections. PMID- 28889988 TI - Developmental sequelae and neurophysiologic substrates of sensory seeking in infant siblings of children with autism spectrum disorder. AB - It has been proposed that early differences in sensory responsiveness arise from atypical neural function and produce cascading effects on development across domains. This longitudinal study prospectively followed infants at heightened risk for autism spectrum disorder (ASD) based on their status as younger siblings of children diagnosed with ASD (Sibs-ASD) and infants at relatively lower risk for ASD (siblings of typically developing children; Sibs-TD) to examine the developmental sequelae and possible neurophysiological substrates of a specific sensory response pattern: unusually intense interest in nonsocial sensory stimuli or "sensory seeking." At 18 months, sensory seeking and social orienting were measured with the Sensory Processing Assessment, and a potential neural signature for sensory seeking (i.e., frontal alpha asymmetry) was measured via resting state electroencephalography. At 36 months, infants' social symptomatology was assessed in a comprehensive diagnostic evaluation. Sibs-ASD showed elevated sensory seeking relative to Sibs-TD, and increased sensory seeking was concurrently associated with reduced social orienting across groups and resting frontal asymmetry in Sibs-ASD. Sensory seeking also predicted later social symptomatology. Findings suggest that sensory seeking may produce cascading effects on social development in infants at risk for ASD and that atypical frontal asymmetry may underlie this atypical pattern of sensory responsiveness. PMID- 28889990 TI - Glandular sources of pheromones used to control host workers (Apis mellifera scutellata) by socially parasitic workers of Apis mellifera capensis. AB - Pheromonal control by the honey bee queen is achieved through the use of secretions from diverse glandular sources, but the use of pheromones from a variety of glandular sources by reproductively dominant workers, has not previously been explored. Using the social parasite, Apis mellifera capensis clonal worker we studied the diversity of glandular sources used for pheromonal control of reproductively subordinate A. m. scutellata workers. To determine whether pheromones from different glandular sources are used by reproductively active workers to achieve dominance and evaluate the degree of pheromonal competition between workers of the two sub-species, we housed groups of workers of the two sub-species together in cages and analysed mandibular and tergal gland secretions as well as, ovarian activation status of each worker after 21days. The results showed that A. m. capensis invasive clones used both mandibular and tergal gland secretions to achieve reproductive dominance and suppress ovarian activation in their A. m. scutellata host workers. The reproductively dominant workers (false queens) produced more queen-like pheromones and inhibited ovarian activation in subordinate A. m. scutellata workers. These results show that tergal gland pheromones working in synergy with pheromones from other glands allow individual workers (false queens) to establish reproductive dominance within these social groups and to act in a manner similar to that of queens. Thus suggesting that, the evolution of reproductively dominant individuals (queens or false queens) and subordinate individuals (workers) in social insects like the honey bee is the result of a complex interplay of pheromonal signals from different exocrine glands. PMID- 28889989 TI - The TNF Receptor Superfamily-NF-kappaB Axis Is Critical to Maintain Effector Regulatory T Cells in Lymphoid and Non-lymphoid Tissues. AB - After exiting the thymus, Foxp3+ regulatory T (Treg) cells undergo further differentiation in the periphery, resulting in the generation of mature, fully suppressive effector (e)Treg cells in a process dependent on TCR signaling and the transcription factor IRF4. Here, we show that tumor necrosis factor receptor superfamily (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-kappaB transcription factor RelA, which was required to maintain eTreg cells in lymphoid and non-lymphoid tissues, including RORgammat+ Treg cells in the small intestine. In response to TNFRSF signaling, RelA regulated basic cellular processes, including cell survival and proliferation, but was dispensable for IRF4 expression or DNA binding, indicating that both pathways operated independently. Importantly, mutations in the RelA binding partner NF-kappaB1 compromised eTreg cells in humans, suggesting that the TNFRSF-NF-kappaB axis was required in a non redundant manner to maintain eTreg cells in mice and humans. PMID- 28889991 TI - Use of dispersion modelling for Environmental Impact Assessment of biological air pollution from composting: Progress, problems and prospects. AB - With the increase in composting asa sustainable waste management option, biological air pollution (bioaerosols) from composting facilities have become a cause of increasing concern due to their potential health impacts. Estimating community exposure to bioaerosols is problematic due to limitations in current monitoring methods. Atmospheric dispersion modelling can be used to estimate exposure concentrations, however several issues arise from the lack of appropriate bioaerosol data to use as inputs into models, and the complexity of the emission sources at composting facilities. This paper analyses current progress in using dispersion models for bioaerosols, examines the remaining problems and provides recommendations for future prospects in this area. A key finding is the urgent need for guidance for model users to ensure consistent bioaerosol modelling practices. PMID- 28889992 TI - Astrocytic expression of the CXCL12 receptor, CXCR7/ACKR3 is a hallmark of the diseased, but not developing CNS. AB - Based on our previous demonstration of CXCR7 as the major mediator of CXCL12 signaling in cultured astrocytes, we have now compared astrocytic expression of the CXCL12 receptors, CXCR7 and CXCR4, during CNS development and disease. In addition, we asked whether disease-associated conditions/factors affect expression of CXCL12 receptors in astrocytes. In the late embryonic rat brain, CXCR7+/GFAP+ cells were restricted to the ventricular/subventricular zone while CXCR4 was widely absent from GFAP-positive cells. In the early postnatal and adult brain, CXCR7 and CXCR4 were almost exclusively expressed by GFAP immunoreactive astrocytes forming the superficial glia limitans. Contrasting the situation in the intact CNS, a striking increase in astrocytic CXCR7 expression was detectable in the cortex of rats with experimental brain infarcts, in the spinal cord of rats with experimental autoimmune encephalomyelitis (EAE) and after mechanical compression, as well as in the in infarcted human cerebral cortex and in the hippocampus of Alzheimer's disease patients. None of these pathologies was associated with substantial increases in astrocytic CXCR4 expression. Screening of various disease-associated factors/conditions further revealed that CXCR7 expression of cultured cortical astrocytes increases with IFNgamma as well as under hypoxic conditions whereas CXCR7 expression is attenuated following treatment with IFNbeta. Again, none of the treatments affected CXCR4 expression in cultured astrocytes. Together, these findings support the hypothesis of a crucial role of astrocytic CXCR7 in the progression of various CNS pathologies. PMID- 28889994 TI - Erratum to "The use of next generation sequencing in the diagnosis and typing of respiratory infections"[J. Clin. Virol. 69 (2015) 96-100]. PMID- 28889993 TI - A subpopulation of activated retinal macrophages selectively migrated to regions of cone photoreceptor stress, but had limited effect on cone death in a mouse model for type 2 Leber congenital amaurosis. AB - BACKGROUND: Studies of antigen presentation in retina using mice that expressed green fluorescent protein (GFP) from a transgenic CD11c promoter found that retinal GFPhi cells possessed antigen presentation function. Subsequent studies found that these high GFPhi cells preferentially localized to sites of retinal injury, consistent with their APC function. Interest in the roles of macrophages in degenerative CNS diseases led us to study the GFPhi cells in a retinal model of neurodegeneration. We asked if apoptotic cone photoreceptor cell death in Rpe65-/- knockout mice induced the GFPhi cells, explored their relationship to resident microglia (MG), and tested their role in cone survival. METHODS: Rpe65-/ mice were bred to CD11cGFP mice on the B6/J background. CD11cGFPRpe65-/- mice were also backcrossed to CX3CR1YFP-creERROSADTA mice so that CX3CR1+ mononuclear cells could be depleted by Tamoxifen. Retinas were analyzed by immunohistochemistry, confocal microscopy, fluorescence fundoscopy and flow cytometry. RESULTS: Elevated numbers of GFPhi cells were concentrated in photoreceptor cell layers of CD11cGFPRpe65-/- mice coinciding with the peak of cone death at 2 to 4weeks of age, and persisted for at least 14months. After the initial wave of cone loss, a slow progressive loss of cones was found that continued to retain GFPhi cells in the outer retina. Sustained, four-week Tamoxifen depletions of the GFPhi cells and MG in Rpe65-/- mice from day 13 to day 41, and from day 390 to day 420 promoted a small increase in cone survival. We found no evidence that the GFPhi cells were recruited from the circulation; all data pointed to a MG origin. MG and GFPhi cells were well segregated in the dystrophic retina; GFPhi cells were foremost in the photoreceptor cell layer, while MG were concentrated in the inner retina. CONCLUSIONS: The expression of GFP on a subset of retinal mononuclear cells in CD11cGFP mice identified a distinct population of cells performing functions previously attributed to MG. Although GFPhi cells dominated the macrophage response to cone death in the photoreceptor cell layer, their ablation led to only an incremental increase in cone survival. The ability to identify, ablate, and isolate these cells will facilitate analysis of this activated, antigen-presenting subset of MG. PMID- 28889995 TI - Aging and working memory performance: Electrophysiological correlates of high and low performing elderly. AB - In this study we investigated age-related changes in WM capacity and their respective ERP correlates. We explicitly addressed the differentiation between high and low performing elderly to identify electrophysiological correlates of successful aging. Therefore, ERP and behavioral data was obtained from 45 young (mean = 22.73 years) and 35 older participants (mean = 68.49 years). Both groups performed a visual-spatial n-back task with two levels of difficulty. Additionally, related neuropsychological tests were administered. Older subjects performed less accurately in both conditions of the n-back task. Older age was additionally associated with a reduced fronto-central positivity (labeled as P200) in the 2-back task and an overall reduced amplitude of the parietal positivity (labeled as P300). The latter shifted to frontal leads in older subjects. Additionally, only in the group of the older participants, increased P200 and decreased parietal P300 amplitudes correlated with performance. Regarding older high and low performers, we observed a clear shift of frontal activity of both ERP components in the group of high performers. High performers additionally performed better in spatial working memory, verbal learning, and fluid intelligence tasks. We conclude, that increasing demands of working memory load are accompanied by a reallocation of resources in both young and older adults. With age, executive control and updating processes (indexed by both ERP components) are diminished or rely on more frontal processes for compensation. However, high performing older adults, who perform comparable to young adults, sustain comparable executive control processes, exceeding pure compensation. PMID- 28889996 TI - Emotion processing in the infant brain: The importance of local information. AB - Facial expressions provide crucial information for an infant's social and cognitive development. Expressions are discriminated based on specific basic level information, such as global and local information represented in spatial frequencies. Research in adults suggests that different neural pathways are involved in emotion discrimination, each activated by specific spatial frequency ranges. However, in infants the involvement of spatial frequencies in emotion discrimination is unknown. In the current study we investigated the effect of manipulating spatial frequency information in the face on emotion discrimination. Infants aged 9-10 months (N = 61) viewed happy, fearful, and neutral faces. The faces contained either lower (related to global information) or higher spatial frequencies (related to local information). Brain activity in response to the faces was measured with electroencephalography. Interest was in the effect of emotion and spatial frequency on the amplitude of the N290, P400, and Nc components. Amplitudes of the N290 and P400 components differed between happy versus fearful or neutral faces, although only in the higher, and not the lower, spatial frequency condition. Amplitude of the Nc components differed between happy versus fearful or neutral faces regardless of spatial frequency condition. These results reveal the importance of higher spatial frequencies for emotion discrimination in infants (particularly at the N290 and P400 components). We related these findings to current models on the neural basis of facial-emotion processing. PMID- 28889997 TI - Policy evaluation and democracy: Do they fit? AB - The papers assembled in this special issue shed light on the question of the interrelation between democracy and policy evaluation by discussing research on the use of evaluations in democratic processes. The collection makes a case for a stronger presence of evaluation in democracy beyond expert utilization. Parliamentarians prove to be more aquainted with evaluations than expected and the inclusion of evaluations in policy arguments increases the deliberative quality of democratic campaigns. In sum, evaluation and democracy turn out to be well compatible after all. PMID- 28889998 TI - Association of Apolipoprotein E Polymorphisms with Age-related Macular Degeneration Subtypes: An Updated Systematic Review and Meta-analysis. AB - BACKGROUND AND AIMS: Age-related macular degeneration (AMD) is the worldwide leading cause of blindness among the elderly, especially in developed countries. The possible association between apolipoprotein E (ApoE) polymorphism (epsilon2, epsilon3, epsilon4) and AMD has been extensively investigated with conflicting results, especially when specifying different clinical phenotypes of AMD. Herein, we conducted a meta-analysis by integrating several recent large-sample studies to verify the effect of ApoE polymorphisms on AMD subtypes. METHODS: The retrieve for targeted literature was conducted based on the PubMed, Embase, Cochrane library, and Web of Science. Summary odds ratio (OR) and its 95% confidence intervals (CIs) were used for estimation of risk. The p-value was adjusted due to the multiple comparison. RESULTS: A total of 12 studies included in the final summary analysis, including 13842 cases and 38647 controls. ApoE epsilon4 carrier was inversely associated with early stage AMD (OR = 0.889, 95% CI = 0.82-0.97), geographic atrophy (OR = 0.594, 95% CI = 0.43-0.83) and neovascular AMD (OR = 0.670, 95% CI = 0.58-0.76). Stratification analysis by ethnicity revealed that the ApoE epsilon4 carriers was associated with neovascular AMD in both Caucasians (OR = 0.62, 95% CI = 0.47-0.83) and East Asians (OR = 0.68, 95% CI = 0.58-0.79). A significant association of ApoE epsilon2 carriers was only found with early AMD in Black and East Asian population, however small samples and limited studies restrict its generalization. CONCLUSION: Our meta-analysis revealed a significantly protective role of epsilon4 on each subtypes of AMD, but no supportive evidence of the association of epsilon2 with AMD. Thus, further studies with larger samples are needed to understand the precise role of epsilon2 on AMD susceptibility. PMID- 28890000 TI - Maternal DRD2, SLC6A3, and OXTR genotypes as potential moderators of the relation between maternal history of care and maternal cortisol secretion in the context of mother-infant separation. AB - A mother's cortisol secretion is importantly associated with her own mental health and her infant's cortisol secretion. This study investigated the influences of maternal history of care and maternal DRD2, SLC6A3, and OXTR genotypes on maternal cortisol in the context of infant stress. A community sample of 296 mother-infant dyads completed a maternal separation at infant age 17 months. Maternal salivary cortisol, buccal cells, and self-reported history of care were collected. Multilevel models revealed that history of care had a greater influence on maternal baseline cortisol (but not cortisol trajectory) for mothers with more plasticity alleles of SLC6A3 (10R) and OXTR (G), relative to mothers with fewer or no plasticity alleles. Findings indicate that a mother's history of care is related to her cortisol secretion in anticipation of infant stress, but that this relation depends on her genetic characteristics. Findings are discussed in relation to the maternal protective system and anticipatory cortisol secretion. PMID- 28889999 TI - Humoral immune responses during asthma and influenza co-morbidity in mice. AB - Humoral immunity serve dual functions of direct pathogen neutralization and enhancement of leukocyte function. Antibody classes are determined by antigen triggers, and the resulting antibodies can contribute to disease pathogenesis and host defense. Although asthma and influenza are immunologically distinct diseases, since we have found that allergic asthma exacerbation promotes antiviral host responses to influenza A virus, we hypothesized that humoral immunity may contribute to allergic host protection during influenza. C57BL/6J mice sensitized and challenged with Aspergillus fumigatus (or not) were infected with pandemic influenza A/CA/04/2009 virus. Negative control groups included naive mice, and mice with only 'asthma' or influenza. Concentrations of antibodies were quantified by ELISA, and in situ localization of IgA- and IgE positive cells in the lungs was determined by immunohistochemistry. The number and phenotype of B cells in spleens and mediastinal lymph nodes were determined by flow cytometry at predetermined timepoints after virus infection until viral clearance. Mucosal and systemic antibodies remained elevated in mice with asthma and influenza with prominent production of IgE and IgA compared to influenza-only controls. B cell expansion was prominent in the mediastinal lymph nodes of allergic mice during influenza where most cells produced IgG1 and IgA. Although allergy-skewed B cell responses dominated in mice with allergic airways inflammation during influenza virus infection, virus-specific antibodies were also induced. Future studies are required to identify the mechanisms involved with B cell activation and function in allergic hosts facing respiratory viral infections. PMID- 28890001 TI - Association between resting-state brain network topological organization and creative ability: Evidence from a multiple linear regression model. AB - Previous studies have indicated a tight linkage between resting-state functional connectivity of the human brain and creative ability. This study aimed to further investigate the association between the topological organization of resting-state brain networks and creativity. Therefore, we acquired resting-state fMRI data from 22 high-creativity participants and 22 low-creativity participants (as determined by their Torrance Tests of Creative Thinking scores). We then constructed functional brain networks for each participant and assessed group differences in network topological properties before exploring the relationships between respective network topological properties and creative ability. We identified an optimized organization of intrinsic brain networks in both groups. However, compared with low-creativity participants, high-creativity participants exhibited increased global efficiency and substantially decreased path length, suggesting increased efficiency of information transmission across brain networks in creative individuals. Using a multiple linear regression model, we further demonstrated that regional functional integration properties (i.e., the betweenness centrality and global efficiency) of brain networks, particularly the default mode network (DMN) and sensorimotor network (SMN), significantly predicted the individual differences in creative ability. Furthermore, the associations between network regional properties and creative performance were creativity-level dependent, where the difference in the resource control component may be important in explaining individual difference in creative performance. These findings provide novel insights into the neural substrate of creativity and may facilitate objective identification of creative ability. PMID- 28890002 TI - On-line action monitoring of response execution: An electrophysiological study. AB - In between-hand choice-RT-tasks, small incorrect EMG activations occurring before the correct response ("partial errors") are assumed to reflect the detection, inhibition and correction of erroneous hand selection, revealing the existence of an action monitoring system, acting "on-line". Now, EMG activations of the correctly selected hand muscles, too small to reach the response threshold, may also occur before these hand muscles produce an overt correct response ("partial corrects"). We hypothesized that partial corrects reflect incorrect execution of correctly selected responses. We found 1) that response force was smaller on trials preceding a partial correct trial and 2) that the Error Negativity, a performance sensitive ERP, assumed to reveal "on-line" action monitoring, was larger for partial corrects than for correct trials. This also suggests that the competence of the action monitoring system is not restricted to selection errors but also extends to execution errors. PMID- 28890003 TI - Editorial overview: Tissue, cell and pathway engineering: The advent of complexity. PMID- 28890004 TI - Response to letter to the editor: The role of propionic acid at diagnosis predicts mortality in patients with septic shock. PMID- 28890005 TI - [Ablative therapy in kidney cancer: Oncological, functional, perioperative outcomes and cost]. AB - INTRODUCTION: The incidence of kidney cancer has increased significantly over the past few decades presumably due to the increased use of imaging. The aim of this article is to describe contemporary outcomes of ablative therapy and to compare them to other therapeutic options in terms of oncological, functional, perioperative outcomes and cost. MATERIAL AND METHODS: We searched MEDLINE(r), Embase(r), using (MeSH) words; from January 2005 through May 2017, and we looked for all the studies. Investigators graded the strength of evidence in terms of methodology, language and relevance. RESULTS: Ninety-one articles were analyzed. We described the outcomes of ablative therapy in relation to the energy used and the approach, and compared these outcomes to the other therapeutic options in terms of oncological, functional and perioperative outcomes. We analyzed these studies in order to search for predictive factors influencing the results of ablative therapy. We also analyzed the economic burden of small renal tumor management. CONCLUSION: The strength of evidence is based almost entirely on retrospective studies and is susceptible to the inherent limitations of this study design. Although, the evidence was low among studies, our revue showed that, in elderly patients treated with ablative therapy for cT1a tumors, the cancer-specific survival was comparable to partial nephrectomy with differences in overall survival that are explained by competing risks of death in the old population. Considering the functional results, the renal function preservation seems to be comparable between the 2 groups while the perioperative morbidity is higher in the partial nephrectomy group. The evidence base medicine at this time cannot support the extension of the indications of ablative therapy beyond the actual implementations. PMID- 28890006 TI - Tapping the woodpecker tree for evolutionary insight. AB - Molecular phylogenetic studies of woodpeckers (Picidae) have generally focused on relationships within specific clades or have sampled sparsely across the family. We compared DNA sequences of six loci from 203 of the 217 recognized species of woodpeckers to construct a comprehensive tree of intrafamilial relationships. We recovered many known, but also numerous unknown, relationships among clades and species. We found, for example, that the three picine tribes are related as follows (Picini, (Campephilini, Melanerpini)) and that the genus Dinopium is paraphyletic. We used the tree to analyze rates of diversification and biogeographic patterns within the family. Diversification rate increased on two occasions during woodpecker history. We also tested diversification rates between temperate and tropical species but found no significant difference. Biogeographic analysis supported an Old World origin of the family and identified at least six independent cases of New World-Old World sister relationships. In light of the tree, we discuss how convergence, mimicry, and potential cases of hybridization have complicated woodpecker taxonomy. PMID- 28890007 TI - Medical Training and the Brain Death Exam: A Single Institution's Experience. AB - BACKGROUND: Clinicians may have limited opportunities to perform neurological determination of death (NDD, or brain death) certification during their training. This study aimed to evaluate the level of resident exposure to the brain death exam at a large-volume donor hospital. METHODS: In March 2014, we adapted a dual physician model for NDD certification at our institution to improve resident education regarding NDD. To evaluate the incidence of resident exposure, we collected examiner information from all brain death exams conducted between January 2014 and July 2015. Organ procurement, family authorization, and brain death intervals were also collected to evaluate the impact of NDD timeliness on organ donation. RESULTS: A total of 68 patients who met NDD criteria were included in this study. For these patients, 127 brain death exams were performed, 108 (85%) by a critical care attending physician or fellow, 9 (7%) by a neurology resident, and 7 (6%) by a neurosurgery resident. Exposure rates for neurology and neurosurgery residents were approximately 0.22 and 0.20 exams/resident/year, respectively. The median brain death interval between exams was 1.0 hours (interquartile range, 0.0-2.5) hours. Resident involvement, time between exams, and dual exams were all found to be nonsignificant correlates of organ authorization and family refusal. CONCLUSIONS: Neurology and neurosurgery residents may be limited in their exposure to the brain death exam during training. High-volume donor hospitals may be able to complete 2 exams for NDD certification in a timely manner without detrimentally influencing organ authorization or family refusal rates. PMID- 28890008 TI - Minimally Invasive Treatment for a Sacral Tarlov Cyst Through Tubular Retractors. AB - BACKGROUND: Tarlov cysts (TC) are focal dilations of arachnoid and dura mater of the spinal posterior nerve root sheath that appear as cystic lesions of the nerve roots typically in the lower spine, especially in the sacrum, which can cause radicular symptoms when they increase in size and compress the nerve roots. Different open procedures have been described to treat TCs, but no minimally invasive procedures have been described to effectively address this pathology. CASE DESCRIPTION: A 29-year-old woman presented with right lower extremity pain and weakness. A magnetic resonance imaging scan demonstrated a lumbosacral TC that protruded through the right L5-S1 foramina. Through a small laminotomy, cyst drainage followed by neck ligation using a Scanlan modified technique through tubular retractors was performed. The patient recovered full motor function within the first days postoperatively and showed no signs of relapse at 6-month follow-up. CONCLUSIONS: Minimally invasive spine surgery through tubular retractors can be safely performed for successful excision and ligation of TC using a Scanlan modified technique. PMID- 28890009 TI - Impact of Onyx Embolization on Radiosurgical Management of Cerebral Arteriovenous Malformations: Treatment and Outcome. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is a well-established treatment modality for cerebral arteriovenous malformations (AVMs). The main limiting factor in the radiosurgical treatment of AVMs is the volume of the nidus, with high-grade lesions often requiring combined treatment to reduce the SRS target volume. To overcome this limitation, we have been using a combined treatment approach consisting of endovascular embolization with Onyx followed by SRS. OBJECTIVE: To evaluate our clinical experience for safety and feasibility of this multimodality treatment approach. METHODS: This is a retrospective review of all adult patients with cerebral AVMs who received SRS treatment to their AVM after endovascular embolization with Onyx between June 2007 and June 2014. RESULTS: Thirty-five consecutive patients were identified. The mean follow-up period was 52.4 +/- 22.6 months (range 18-97 months). We confirmed 18 (51.4%) complete nidus closures at a median time of 49.5 months (range 6.5-81 months) from SRS. High resolution Magnetic resonance imaging/magnetic resonance angiography was performed routinely in all patients until closure of the nidus. Digital subtraction angiography was performed to confirm complete obliteration in 5 of the patients (28%); 13 patients are either planned for digital subtraction angiography or have refused it. In 6 patients (17%) a significant flow reduction was noted after a mean of 32 +/- 16 months. No significant improvement was observed in 9 patients (26%) during the follow-up period. Two patients were lost to follow-up. CONCLUSIONS: The multimodality treatment of cerebral AVMs using embolization with Onyx followed by SRS is feasible and safe. The use of Onyx significantly reduced the SRS treatment target volume. PMID- 28890011 TI - A Secure Approach to the Inferior Horn Using the Deep Medullary Vein as an Anatomic Guide. AB - BACKGROUND: Safe entry to the inferior horn is required for a selective approach to the medial temporal region. This can be challenging sometimes for inexperienced surgeons. Our objective was to verify the usefulness of the deep medullary vein (DMV) as an intraoperative landmark for safely entering the inferior horn during the transsylvian selective approach to the mesial temporal region. METHODS: Videos of 8 cases of transsylvian selective amygdalohippocampectomies performed at the University of Tokyo Hospital from 2013 to 2015 were reviewed. Consistency of the DMV and time required to open the inferior horn via the temporal stem through the inferior limiting sulcus were retrospectively evaluated. RESULTS: DMVs were identified in all cases; the average number identified was 2.5 +/- 0.3 (mean +/- SE). The inferior horn was opened without disorientation in all cases, with mean dissecting time of 7.0 minutes +/- 1.1. No complications were caused by disorientation within the temporal stem white matter. CONCLUSIONS: Consideration of the venous system within the white matter and following the DMV could reduce the risk of disorientation and enable the surgeon to reach the inferior horn in a straightforward manner without accidental white matter damage. PMID- 28890010 TI - Lumbosacral Subdural Hematoma After Glioblastoma Multiforme Resection: Possible Radiographic Evidence for the Downward Migration of Intracranial Blood. AB - BACKGROUND: Spinal subdural hematomas (SSDHs) are rare and usually associated with bleeding diatheses, trauma, iatrogenic injury, spinal vascular malformations, or intraspinal tumors. CASE DESCRIPTION: We report a case of a 75 year-old man who developed a symptomatic lumbosacral SSDH after undergoing resection of a right temporal glioblastoma multiforme. The patient subsequently recovered and was discharged home. Over the next 2 weeks, he developed progressively worsening symptoms of lower back pain, lower extremity weakness, and urinary retention. Although the patient had no known risk factors for developing a SSDH, magnetic resonance imaging on postoperative day 16 revealed an extensive L2-sacrum SSDH. The patient underwent L2-L5 total laminectomies for evacuation of the SSDH. His symptoms resolved after surgery. Literature review produced 26 other cases of SSDHs after intracranial surgery in patients without obvious risk factors. In our case, the lumbosacral SSDH may have originated from downward migration of intracranial blood in a gravity-dependent fashion. Radiographic evidence of blood within the posterior thecal sac of the patient's cervical spine supports this hypothesis. CONCLUSIONS: In most cases, SSDHs after intracranial surgery resolve with conservative treatment; however, as shown in our case, surgery may be required if there is progressive neurologic decline. Neurosurgeons should be aware of this potential complication after intracranial surgery; a magnetic resonance imaging of the spine may be indicated if there is unexplained lower extremity pain or weakness. PMID- 28890012 TI - Ethnicity, Race, and Postoperative Stroke Risk Among 53,593 Patients with Asymptomatic Carotid Stenosis Undergoing Revascularization. AB - BACKGROUND: The incidence of postoperative stroke after carotid endarterectomy is an uncommon event, and differences by racial and ethnic subgroups are not described fully in the literature. OBJECTIVE: To investigate the impact of race and ethnicity on postoperative stroke risk among patients with asymptomatic carotid stenosis undergoing carotid endarterectomy. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was searched for patients between the dates 2008 and 2015 to identify patients undergoing carotid endarterectomy with no history of stroke. Four racial and ethnic subgroups were included: non-Hispanic white, Hispanic white, non-Hispanic back, and non-Hispanic Asian. In addition to a descriptive statistical analysis, univariate and multivariate regression models were created to adjust for cardiovascular and perioperative risk factors and corrected for multiple comparisons. RESULTS: Among the 53,593 patients identified meeting the inclusion criteria, 788 (1.45%) patients experienced a stroke within 30 days. The non Hispanic white group compared with the minority subgroups had a lower risk of postoperative stroke (1.43% vs. 1.67%, P = 0.18). The greatest difference was between the non-Hispanic white and Hispanic white groups, but this was not significant on multivariable analysis (odds ratio 1.40, 95% confidence interval 0.97-2.02, P = 0.08) after adjustment for risk stroke factors. The strongest predictors of postoperative stroke were perioperative blood transfusion, dependent functional status, and longer operative time. CONCLUSIONS: There was no difference between the racial and ethnic groups and the proportion of postoperative stroke among patients undergoing revascularization for asymptomatic carotid stenosis. PMID- 28890013 TI - Evaluating proteins for potential allergenicity using bioinformatic approaches. PMID- 28890014 TI - Genetically modified products and food allergy: Beliefs, evidence, and opportunity. PMID- 28890015 TI - Penicillin skin testing: The devil is in the details. PMID- 28890016 TI - Single recombinant and purified major allergens and peptides: How they are made and how they change allergy diagnosis and treatment. AB - OBJECTIVE: To review the current knowledge regarding recombinant and purified allergens and allergen-derived peptides. DATA SOURCES: PubMed, homepages relevant to the topic, and the National Institutes of Health clinical trial database were searched. STUDY SELECTIONS: The literature was screened for studies describing purified and recombinant allergens and allergen-derived peptides. Studies relevant to the topic were included in this review. RESULTS: Advantages and drawbacks of pure and defined recombinant allergens and peptides over allergen extracts in the context of allergy research, diagnosis, and allergen immunotherapy are discussed. We describe how these molecules are manufactured, which products are currently available on the market, and what the regulative issues are. We furthermore provide an overview of clinical studies with vaccines based on recombinant allergens and synthetic peptides. The possibility of prophylactic vaccination based on recombinant fusion proteins consisting of viral carrier proteins and allergen-derived peptides without allergenic activity are also discussed. CONCLUSION: During the last 25 years more than several hundred allergen sequences were determined, which led to a production of recombinant allergens that mimic biochemically and immunologically their natural counterparts. Especially in Europe, recombinant allergens are increasingly replacing allergen extracts in diagnosis of allergy. Despite many challenges, such as high cost of clinical trials and regulative issues, allergy vaccines based on recombinant allergens and peptides are being developed and will likely soon be available on the market. PMID- 28890017 TI - An unusual cause of fever in a patient with common variable immunodeficiency. PMID- 28890018 TI - The allergenicity of genetically modified foods from genetically engineered crops: A narrative and systematic review. PMID- 28890019 TI - Allergic sensitization and objective measures of sleep in urban school-aged children with asthma. AB - BACKGROUND: Allergic sensitization is associated with increased child asthma morbidity and decreased pulmonary function. Nocturnal symptoms and/or awakenings typically are measured by self-report from diary data, whereas objective assessments of sleep in child asthma studies are lacking. OBJECTIVE: To investigate the association between increased allergic sensitization (number of positive allergy test results measured by skin prick test or specific immunoglobulin E) and sleep outcomes (sleep efficiency, sleep duration, and mean number of awakenings measured by actigraphy) in urban schoolchildren with persistent asthma. METHODS: One hundred ninety-six children with persistent asthma (7-9 years old) attending public school in 1 of 4 large urban school districts completed allergy testing during a study clinic visit. Forced expiratory volume in 1 second was monitored at home using a handheld spirometer. Sleep outcomes were measured with a wrist Actiwatch during a 1-month period in the fall and winter seasons. RESULTS: Number of positive allergy test results significantly predicted mean sleep efficiency (P = .02), such that children with more positive test results experienced less efficient sleep. Number of positive allergy test results significantly predicted mean number of night awakenings (P = .05), such that children with more positive allergy test results experienced more night awakenings. Variability in forced expiratory volume in 1 second was a significant moderator in the association between number of positive allergy test results and variability in sleep efficiency (P = .04). Racial and ethnic differences in allergic sensitization and sleep outcomes were found between African Americans and Latinos. CONCLUSION: More positive allergy test results were associated with poorer sleep outcomes measured objectively in this sample of urban children. Implications for environmental control interventions and asthma treatments in different racial and ethnic groups are discussed. PMID- 28890020 TI - The national cost of asthma among school-aged children in the United States. AB - BACKGROUND: Recent research has quantified the national health care resource use (HCRU) and health care expenditure (HCE) burden associated with adult asthma; however, estimates specific to school-aged children are more than 2 decades old. OBJECTIVE: To estimate the national HCRU and HCEs attributable to asthma among school-aged children in the United States. METHODS: This was a cross-sectional retrospective analysis of school-aged children (aged 6-17 years) in the nationally representative 2007-2013 Medical Expenditure Panel Survey. All-cause HCRU and HCEs of school-aged children with asthma were compared with school-aged children without asthma, controlling for sociodemographics and comorbidities. HCRU encounters included emergency department (ED) and outpatient visits, hospitalizations, and prescriptions. Expenditures included total, medical, ED, inpatient, outpatient, and pharmacy. Negative binomial regression analyses were used for HCRU and Heckman selection with logarithmic transformation, and smearing retransformation was used for HCEs. RESULTS: There were 44,320 school-aged children of whom 5,890 had asthma. Children with asthma incurred a higher rate of all-cause annual ED visits (incidence rate ratio [IRR], 1.5; P < .001), hospitalizations (IRR, 1.4; P < .05), outpatient visits (IRR, 1.4; P < .001), and prescription drugs (IRR, 3.3; P < .001) compared with school-aged children without asthma. They incurred US$847 (2015 dollars) more annually in all-cause expenditures (P < .001). Private insurance and Medicaid paid the largest share of expenditures. Pharmacy and outpatient costs represented the largest proportion of total expenditures. On the basis of the nationally representative Medical Expenditure Panel Survey sample weights from 2013, the total annual HCEs attributable to asthma for school-aged children in the United States was US$5.92 billion (2015 dollars). CONCLUSION: Childhood asthma continues to represent a prevalent and significant clinical and economic burden in the United States. More aggressive treatment and asthma management programs are needed to address this national financial and resource burden. PMID- 28890021 TI - Sensitization profiles to peanut allergens across the United States. AB - BACKGROUND: Measurement of IgE antibody to peanut components can aid in the prediction of allergic responses the food. OBJECTIVE: To investigate the association between patient demographics (age, location) and allergic sensitization to peanut components across the United States. METHODS: Serum samples from 12,155 individuals with peanut extract specific IgE levels of 0.35 kUA/L or higher were analyzed for IgE antibodies to Ara h 1, 2, 3, 8, and 9 by ImmunoCAP. RESULTS: Among this population of peanut sensitized individuals, 79.1% of children (<3 years old) were sensitized to one or more peanut storage proteins (Ara h 1, 2, and/or 3), in contrast to 64.2% of adolescents (12-15 years old) and 22.1% of adults (>20 years old). Although sensitization was more prevalent to Ara h 2 than to the other storage proteins, a sizable fraction of patients were sensitized to Ara h 1 and/or 3 but not to Ara h 2 (eg, 13% of children <3 years old). Moreover, 9.6% of children, 10.2% of adolescents, and 10.5% of adults were sensitized to Ara h 9, whereas 2.4% of children, 49.4% of adolescents, and 42.9% of adults produced IgE to Ara h 8 (pathogenesis-related protein 10). Sensitization to Ara h 8 alone was markedly higher in the Northeastern United States relative to other regions of the country. CONCLUSION: We conclude that sensitization to individual peanut components is highly dependent on age and geographic location. Given that a severe allergic reaction to peanut is unlikely in individuals with isolated sensitization to Ara h 8, a sizable fraction of patients, in particular adolescents and adults, may be at lower risk than anticipated based only on demonstration of sensitization to whole peanut extract. PMID- 28890022 TI - Lymphoproliferative responses to dendritic cell presentation of sensitizing allergens in atopic children with multiple allergies. AB - BACKGROUND: Peripheral blood mononuclear cells (PBMCs) proliferate inconsistently, rendering current lymphoproliferation assays unreliable in diagnosis. OBJECTIVE: To investigate the utility and nature of proliferation responses in allergy by comparison of the standard lymphoproliferation with a new dendritic cell (DC) stimulated assay. METHODS: Monocyte-derived DCs were pulsed with allergens and incubated with autologous T cells for 7 days. DC-stimulated and standard PBMC proliferation responses to 3 common dietary allergens in children with allergy and without atopy were measured by incorporation of tritiated thymidine and reduction of carboxyl fluorescein succinimidyl ester staining. RESULTS: The DC presentation of sensitizing allergens induced significantly higher proliferative responses than PBMC stimulation (P = .04) and greater distinction between normal and allergic responses. DC-induced stimulation indices of children without sensitivity and those with allergy were significantly different with all 3 foods (P < .001). All children with allergy presented with peanut allergy and 12 of 14 (86%) beta-lactoglobulin-pulsed DC preparations proliferated more than 3.3-fold above un-pulsed cells, but 8 of 18 children (44%) with ovalbumin egg allergy showed proliferation below this level. The stimulation index of DC tritiated thymidine incorporation correlated closely with carboxyl fluorescein succinimidyl ester reduction (P < .001). Sensitivity of detection of peanut, milk, or egg allergy was 100%, 85.7%, or 55.6% and specificity was 60%, 88.9%, or 86.7%, respectively. DC-stimulated T cells expressed increased levels of CD45 RO and CD25 and most produced interferon-gamma. DC-stimulated proliferation correlated with total immunoglobulin E and peanut antigen stimulated proliferation correlated with peanut specific immunoglobulin E (P = .03). CONCLUSION: The DC-induced lymphoproliferation had higher sensitivity, specificity, and reproducibility than the standard assay and caused increased memory and activated T-cell proliferation in children with food allergy. PMID- 28890023 TI - Knowledge of food protein-induced enterocolitis syndrome among general pediatricians. PMID- 28890024 TI - Unusual presentation of combined immunodeficiency in a child with homozygous DOCK8 mutation. PMID- 28890025 TI - Predictors of granulomatous lymphocytic interstitial lung disease in common variable immunodeficiency: Methodological issues. PMID- 28890026 TI - Author's response. PMID- 28890027 TI - Cryopreserved Cadaveric Arterial Allograft for Arterial Reconstruction in Patients with Prosthetic Infection. AB - OBJECTIVE: The aim of this study was to report outcomes of cryopreserved arterial allografts used as a vascular substitute in the setting of prosthetic material infection. METHODS: A retrospective analysis of prospectively collected data was conducted including all consecutive interventions performed with cryopreserved arterial allografts used for vascular reconstruction in the setting of prosthetic material infection between January 2005 and December 2014. Five year outcomes included allograft related re-interventions, survival, primary patency, and limb salvage rates. RESULTS: Fifty-three procedures were performed using cryopreserved allografts for vascular prosthetic infection: 25 procedures (47%) were performed at aorto-iliac level (Group 1) and 28 procedures (53%) at peripheral level (Group 2). The mean follow-up was 52 months. Five year allograft related re-intervention was 55% in Group 1 (6 allograft ruptures and 5 allograft aneurysm degenerations) and 33% in Group 2 (2 allograft ruptures and 7 allograft aneurysm degenerations). Five year survival was 40% and 68%, primary patency was 89% and 59% and limb salvage was 100% and 89% for Group 1 and 2 respectively. CONCLUSION: Use of cryopreserved arterial allografts provides acceptable results but is tempered by suboptimal 5 year outcomes with high re-intervention rates. PMID- 28890028 TI - A novel technique for placement of sacro-alar-iliac (S2AI) screws by K-wire insertion using intraoperative navigation. AB - Sacral-iliac fixation techniques may be indicated in the management of various lumbosacral pathologies including spinal degeneration, infection, tumour resection, fracture, pseudarthrosis, correction of spinal deformities involving long fusion constructs to the sacrum and cases with poor sacral fixation. There are a number of options for lumbosacral fixation each with their own advantages and disadvantages. Though S2-alar-iliac (S2AI) have demonstrated promising advantages over alternatives, the complex anatomy of the spinopelvic region demands precise insertion of the screws to create a biomechanically robust construct safely. As such, we present a novel technique of using intra-operative CT navigation and K-wires to establish and secure a planned trajectory, thereby ensuring solid spinopelvic fixation with S2AI screws. This was performed as part of a long fusion construct for correction of kyphosis deformity in a male patient. PMID- 28890029 TI - Natural course and predictors of severe disability and death in Thai patients with dementia. AB - More than half of patients with dementia lived in countries with low and middle incomes. However, there have been few studies on the natural course of disease in these countries. The purpose of this study was to study the natural course and the predictive factors of advanced stage and death in Thai patients with dementia. Patients with dementia who were treated in neurologic and psychiatric clinic from September 2004 to February 2016, were included. Data about natural course of diseases, behavioral and psychological symptoms in dementia (BPSD) and complications were studied. 207 patients were included. Mean age was 77years old. Mean Thai Mental State Examination (TMSE) was 17.5. Alzheimer's disease was the most common cause of dementia (55%). With the mean follow-up of 39months (range from 2 to 126months), 64% of the patients had BPSD. Sixty-two patients (30%) had complications required admission. Seven patients died. Fifty-four patients (29%) ended in the advanced stage of dementia. Mean duration from diagnosis to the advanced stage was 49months. Complications that required admission usually occurred in moderate to severe dementia and were strongly associated with the advanced stage or death (OR 6.1, 95%CI 2.57-14.49, p-value<0.0001). Alzheimer's disease was the most common cause of dementia in the study. Most demented patients presented in moderate severity of dementia. Mean duration from diagnosis to the advanced stage of dementia was approximate 4-5years. Complications required admissions related to the progression to advanced stage or death. PMID- 28890030 TI - Corpus callosal lipoma extending as nasal encephalocoel/cranial lipomeningocoel. AB - A hitherto unreported case is presented wherein a 2year old child had a 'cranial lipomeningocoel' or a 'nasal lipo-encephalocoel'. The child presented with a growing mass in the base of the nose. Investigations revealed that the nasal mass was a lipoma that was an extension of intracranial lipoma. The intracranial component extended up to corpus callosum. Resection of the extracranial extension and basal reconstruction resulted in cosmetic recovery. PMID- 28890031 TI - Variation in prophylactic anticoagulation for venous thromboembolism among acute stroke patients. AB - Asians were known to have relatively lower incidence of deep vein thrombosis (DVT) compared with Caucasians. We aimed to evaluate rates of prophylactic anticoagulation among Korean acute stroke patients who are at high-risk for developing DVT. Of 1295 patients with acute ischemic stroke who were at high-risk for developing DVT, anticoagulation was used in only 21 patients (1.6%; 95% Confidence Interval, 0.9-2.3) during admission. The use of anticoagulation did not differ in relation to age, stroke severity, leg motor weakness, or functional outcomes at discharge. Prophylactic anticoagulation was rarely used in Korean stroke patients who were at high-risk for developing DVT. PMID- 28890032 TI - Ulnar nerve entrapment at the elbow. A surgical series and a systematic review of the literature. AB - Chronic compression of the ulnar nerve at the elbow is the second most common entrapment neuropathy. Various surgical options have been described. Timing of surgery is also debated. In this study we report the long-term results of a consecutive surgical series of anterior subcutaneous transpositions and review the pertinent literature. Sixty consecutive patients underwent anterior subcutaneous transposition at our Institution to treat ulnar nerve compression at the elbow. McGowan scale was used in the neurological exam before surgery. Bishop rating system was used to assess outcome. Seventy-eight% of patients scored good excellent. None of the patients worsened. No complications and no recurrences were reported. Young age and good pre-operative neurological status (McGowan grade 1) were predictive of favorable outcome both at univariate and at multivariate analysis. No differences in outcome were observed between patients with intermediate (McGowan grade 2) and severe (McGowan grade 3) neuropathy. Thirty-four studies assessing outcome of different surgical techniques were reviewed. Anterior subcutaneous transposition had the lowest recurrence rate with an excellent effectiveness and safety profile. The favorable predictive role for outcome of preoperative neurological status was confirmed. The good long-term clinical results of the present series and the results of literature analysis confirm the value of anterior subcutaneous transposition of the ulnar nerve at the elbow. This technique has a particular effectiveness in most severe compressions, where outcomes are comparable with intermediate neuropathy cases. Moreover, our results suggest an aggressive attitude towards ulnar nerve compression at the elbow, particularly in younger patients. PMID- 28890033 TI - The Wada test might predict postoperative fine finger motor deficit after hemispherotomy. AB - INTRODUCTION: Cerebral hemispherotomy is a surgical method with a high rate of seizure reduction in patients with intractable epilepsy. However, there is a probability of postoperative motor deficits. The objective of this study was to investigate whether the Wada test can help predict motor function outcomes after hemispherotomy and, therefore, may be useful in decision-making and patient selection. PATIENTS AND METHOD: A total of 13 patients with hemispherical intractable epilepsy underwent hemispherical disconnection surgeries. Six of them underwent the Wada test to evaluate motor function and language function followed by peri-insula hemispherotomy. The patients' age ranged from 11 to 45years (mean 27years). RESULTS: Three of six patients had reduced dexterity on the Wada test. The finger motor function in the other patients did not change on the Wada test. Postoperatively, all patients who had decreased fine motor movement on the Wada test showed postoperative clumsiness of their hands and fingers. CONCLUSIONS: The Wada test might predict postoperative fine finger motor deficit after hemispherotomy. This study showed that gross motor function was compensated in the ipsilateral hemisphere, whereas fine finger motor movement function remained in the contralateral frontal cortex. PMID- 28890034 TI - Use of regional scalp block for pain management after craniotomy: Review of literature and critical appraisal of evidence. AB - BACKGROUND: The effective management of postoperative pain have the tendency to reduce morbidity and mortality. According to International Association for the Study of Pain (I.A.S.P), pain is an unpleasant sensory and emotional experience associated with existing or potential tissue injury. Post-operative pain is most severe during the first 72h following surgery and is usually of limited time frame mostly. METHODS: Literature search conducted using EMBASE (1980 onwards), MEDLINE (1946 onwards) and Cochrane Central register of Controlled Trials database for systematic reviews. Key words applied were "scalp block" "craniotomy" "analgesia", "neurosurgery". Studies were limited to English and those involving humans. Relevant studies were isolated for further critique and the level of evidence assessed. RESULTS: Total of 140 citations were identified, after thorough screening non relevant studies and non-randomised clinical trials were exempted, five randomised control trials selected. Selection not restricted by English language. CONCLUSION: The evidences are very limited, most data are confounded by weaknesses in methodology and most of the studies have small sample sizes. Large trials on safety and efficacy of analgesia post craniotomy using standardized and widely accepted tools are yet to be performed. None of the studies identified studied post craniotomy analgesia in patients with neurocognitive change. From level 1 evidence, regional scalp block post craniotomy provides effective form of analgesia. PMID- 28890035 TI - Longitudinal interactions of estrogen receptor alpha gene rs9340799 with social environmental factors on depression in adolescents after Wenchuan earthquake. AB - Inconsistent relationships were reported between rs9340799 on estrogen receptor alpha gene (ESR1) and depression in previous studies. The present study was to explore the longitudinal changes of prevalence and severity of depression in 439 Chinese Han adolescents with different genotypes of ESR1 rs9340799 at 6, 12 and 18months after the 2008 Wenchuan earthquake. Social-environmental factors were collected by questionnaires from 465 high school students. Variants of rs9340799 were genotyped by polymerase chain reaction-restriction fragment length polymorphism analyses and verified by DNA sequencing. Depression symptoms were assessed by Beck Depression Inventory (BDI). The results showed the female AA homozygotes had higher prevalence of depression at 12months and higher BDI scores at 18months than the female G allele carriers. Significantly decreased prevalence of depression was observed only in the female AA homozygotes at 18months when compared with that at 6 or 12 months. Consecutive decreases in BDI scores were observed only in the female AA homozygotes. The AA genotype was one of the risk factors at 12months and predictors of BDI scores at 18months. These results firstly suggest different interactions may occur in a gender and time dependent manner among rs9340799 and other potential factors of depression or predictors of its severity, and influence the development and natural rehabilitation of depression. PMID- 28890036 TI - Tumoral and stromal expression of Slug, ZEB1, and ZEB2 in brain metastasis. AB - Epithelial-to-mesenchymal transition (EMT) has an active role in the malignant progression of epithelial tumor cells. The aim of the study was to identify the existence of the EMT mechanism in brain metastasis. Tumors from 29 patients with brain metastases were assessed in terms of the immunoexpression of EMT-related factors including Slug, ZEB1, ZEB2, and E-cadherin in tumor cells and the surrounding mesenchymal stromal cells. The results were compared between primary tumors and their matched metastatic brain tumors. Analysis of tumor cell expression showed that Slug, ZEB1, or ZEB2 expression was found in more than 10% of the neoplastic cells in the metastatic lesions of 17 cases (59%) and in the primary lesions of 7 cases (24%, P=0.02). The expression level of ZEB2 was negatively correlated with that of E-cadherin (P=0.05). There were no differences in the tumoral expression levels of Slug, ZEB1, or ZEB2 among the primary organs. Analysis of stromal cell expression revealed a global increase in ZEB1 and ZEB2 expression levels with metastases (P<0.0001). Quantitative analysis confirmed that messenger RNA expression of ZEB1 and ZEB2 was elevated in metastatic lesions. The increased expression of EMT-related factors in brain metastasis was found not only in tumor cells, but also in tumor-associated stromal cells. Our results suggest that EMT-related factors play a role as a facilitator of brain metastasis. PMID- 28890037 TI - The association between scabies and myasthenia gravis: A nationwide population based cohort study. AB - Scabies is an infectious inflammatory pruritic skin disease. Cytokine-mediated inflammatory processes contribute to the pathologic mechanism in scabies. Myasthenia gravis (MG) is also an autoimmune disease that is mediated by cytokines. The study aimed to investigate the association between scabies and myasthenia gravis. We conducted a nationwide population-based cohort study utilized data from the National Health Insurance Research Database (NHIRD) of Taiwan. Patients with scabies (n=5429) and control subjects without scabies (n=20,176) were enrolled. We tracked the subjects in both groups for a 7-year period to identify new onset MG. Cox regression analysis was performed to calculate the hazard ratio (HR) for MG. A total of 25,605 patients were enrolled in the study, including 5429 patients in the scabies group and 20,176 in the control group. There were 40 (0.7%) patients from the scabies group and 84 (0.4%) subjects from the control group who were newly diagnosed with MG during the 7 year follow-up period. The scabies patients had a significantly increased risk of MG, with an adjusted HR of 1.27 (95% confidence interval [CI] 1.01-1.89). As such, prompt diagnosis and treatment of scabies may decrease the risk of subsequent MG. PMID- 28890038 TI - Improving the efficiency of Auditory Brainstem Responses in newborns, using a 60clicks/s stimulation rate. AB - Recent evidence suggests that Auditory Brainstem Responses (ABR), in neonates with risk factors for neurological damage, may show auditory brainstem abnormalities, even in patients with normal hearing. To compare the recording and diagnostic accuracy of neonatal Auditory Brainstem Responses (ABR), using 10 and 60clicks/s stimulation rates, two groups of neonates were prospectively studied: 30 healthy full-term neonates, with no peri- or postnatal complications; and 30 high-risk newborns with two or more of the following conditions: hyperbilirubinemia, use of ototoxic drugs, birth weight inferior to 1500g, perinatal sepsis, intraventricular hemorrhage, and/or mechanical ventilation. Correlation between ABR trials, recording duration, and the absolute and interpeak latencies of ABR waves I, III and V, were measured. ROC-curve analysis assessed the diagnostic accuracy of both stimulation rates. The correlations between ABRs trials were significantly higher at 60clicks/s than at 10clicks/s (F(1,116)=14.5, p<0.0002). Recording duration at 60clicks/s was significantly lower (t=20.9, p<0.0001). ROC-curve comparisons showed increased diagnostic accuracy at the stimulation rate of 60clicks/s, for waves I (D=2.04, p=0.04), V (D=2.02, p=0.04), interpeak latencies III-V (D=2.2, p=0.02), and I-V (D=2.86, p=0.004). In neonates, the use of 60clicks/s stimulation rate permits a substantial shortening of the ABR recording, with greater diagnostic accuracy and replicability. PMID- 28890039 TI - Legionella longbeachae pneumonia as a complication of alemtuzumab therapy. PMID- 28890040 TI - Risk of Deep vein thrombosis in neurosurgery: State of the art on prophylaxis protocols and best clinical practices. AB - OBJECTIVE: To analytically discuss some protocols in Deep vein thrombosis (DVT)/pulmonary Embolism (PE) prophylaxis currently use in Neurosurgical Departments around the world. DATA SOURCES: Analysis of the prophylaxis protocols in the English literature: An analytical and narrative review of literature concerning DVT prophylaxis protocols in Neurosurgery have been conducted by a PubMed search (back to 1978). DATA EXTRACTION: 80 abstracts were reviewed, and 74 articles were extracted. DATA ANALYSIS: The majority of DVT seems to develop within the first week after a neurosurgical procedure, and a linear correlation between the duration of surgery and DVT occurrence has been highlighted. The incidence of DVT seems greater for cranial (7.7%) than spinal procedures (1.5%). Although intermittent pneumatic compression (IPC) devices provided adequate reduction of DVT/PE in some cranial and combined cranial/spinal series, low-dose subcutaneous unfractionated heparin (UFH) or low molecular-weight heparin (LMWH) further reduced the incidence, not always of DVT, but of PE. Nevertheless, low dose heparin-based prophylaxis in cranial and spinal series risks minor and major postoperative haemorrhages: 2-4% in cranial series, 3.4% minor and 3.4% major haemorrhages in combined cranial/spinal series, and a 0.7% incidence of major/minor haemorrhages in spinal series. CONCLUSION: This analysis showed that currently most of the articles are represented by case series and case reports. As long as clear guidelines will not be defined and universally applied to this diverse group of patients, any prophylaxis for DVT and PE should be tailored to the individual patient with cautious assessment of benefits versus risks. PMID- 28890041 TI - Successful endovascular thrombectomy 90h after stroke onset. AB - Endovascular thrombectomy (EVT) has extended the conventionally accepted time window of treatment, from 4.5h (ECASS III trial) for intravenous thrombolysis, to 7.3h for EVT (HERMES collaboration). More recent evidence suggests EVT times could be extended to 24h in carefully selected patients (DAWN trial). Some patients present after these time windows with large areas of ischemia but little established infarction on imaging. They represent a major dilemma with much to gain from EVT but at theoretically higher risk of a poor outcome. We present a case of near-complete left M1 occlusion in which EVT achieved reperfusion 90h 41min after stroke onset with excellent clinical outcome. Current guidelines on treatment windows for EVT according to HERMES collaboration do not reflect individual patient factors. In appropriate patients delayed EVT may give positive clinical outcomes. PMID- 28890042 TI - Guillain Barre Syndrome in the elderly: Experience from a tertiary-care hospital in India. AB - Age influences incidence and prognosis of Guillain Barre Syndrome (GBS), common cause of ascending areflexic quadriparesis. Dedicated studies on elderly GBS are infrequent. This study aimed to describe clinical features and outcome at hospital-discharge in patients aged>=60years with GBS. Medical records of 70 elderly GBS over 15years were analysed. Mean symptom-duration was 5.78+/-4.5days and onset-to-peak 5.14+/-4.4days. Antecedent events preceded GBS by 8.07+/ 9.9days and included: fever (n=19), respiratory infection (n=6), and gastroenteritis (n=5). Clinical features were weakness of facial (n=34), bulbar (n=13), extraocular (n=4) and respiratory (n=20) muscles and recurrence (n=4). Nine had Hughes disability score (HDS) of three or less. Sensory symptoms and signs included paresthesias (n=40), pain (n=24), and impaired kinaesthetic sensation (n=14). Laboratory abnormalities included albumino-cytological dissociation (n=50), hyponatremia (n=36) and elevated creatine kinase (n=18). Electrophysiological subtypes were: primary demyelinating (n=52), inexcitable (n=3), equivocal (n=2) and axonal (n=1). Fifty-seven patients treated with plasmapheresis (n=48) or intravenous immunoglobulin (n=9) had mean HDS of 3.53+/ 0.7 at discharge. Twenty-one were ambulant (HDS>=3), one had persisting respiratory weakness and one died. Striking differences between the 'elderly' and 100 'adults' seen over 20months were shorter symptom-duration, higher frequency of facial palsy and hyponatremia, lower frequency of pain, lower mean MRC sum score and worse HDS at study-entry and discharge (p<0.05). Requirement for mechanical ventilation and cardiac autonomic dysfunction was higher among elderly (p:0.02). In conclusion, in this cohort of elderly GBS, there was a higher frequency severe GBS and demyelinating electrophysiology. PMID- 28890043 TI - A migration case of Kii amyotrophic lateral sclerosis/parkinsonism dementia complex with the shortest stay in the endemic area and the longest incubation to develop the disease. AB - Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) is an endemic disease observed in the Kii peninsula, Guam, and Papua. We report a case of a 76-year old man with ALS/PDC of the Kii peninsula of Japan (Kii ALS/PDC). The patient was born and grew up in the Kii peninsula. He moved out at age three, and developed symptoms 73years later. He showed pyramidal sign, parkinsonian symptoms, and mildly impaired cognitive function. 131I-metaiodobenzylguanidine myocardial scintigraphy showed decreased cardiac sympathetic nerve function, and dopamine transporter single photon emission computed tomography imaging showed decreased 123I-N-omega-fluoropropyl-2beta-carbomethoxy3beta-(4-iodophenyl) nortropane accumulation. Cerebral blood flow showed hypoperfusion. Positron emission tomography showed widespread tau deposition in his brain. This is a migration case of Kii ALS/PDC with the shortest stay in the endemic area and the longest delay to develop the disease, indicating a genetic factor for the disease development in a considerable degree. PMID- 28890044 TI - Recursive partitioning analysis for disease progression in adult intracranial ependymoma patients. AB - Intracranial ependymomas are rare tumors in adults. Although recent advancements from demographic, clinical, and biological studies provide new perspectives on this rare tumor, they are not yet widely applied in clinical practice. Currently, most ependymoma patients are treated in the same way: via surgical resection with adjuvant radiation therapy. However, it is reasonable to apply more aggressive treatment for high-risk patients. From this point of view, we performed a study to investigate risk grouping for disease progression of intracranial ependymomas in adults. A total of 53 patients were included in this study. Data were extracted for patient and tumor characteristics, extent of resection, progression free survival (PFS), and overall survival. Prognostic variables from univariate and multivariate survival analyses were included in a recursive partitioning analysis for the hierarchical risk grouping of the estimated PFS. Three risk groups were defined based on the clinical prognostic factors. Survival analysis showed significant differences in mean PFS between the different groups: 160.5+/ 22.1months in the complete resection group, 100.4+/-36.8months in the incomplete resection and intraventricular-location group, and 23.5+/-6.9months in the incomplete-resection and extraventricular-location group (p<0.001). The risk of disease progression in adult intracranial ependymoma patients could be stratified by degree of resection and tumor location. In clinical practice, this result could provide useful information, such as when "second-look" surgery should be performed or whether small tumors invading the fourth ventricle floor should be resected at the expense of neurological deficit. PMID- 28890045 TI - The renin angiotensin system and the brain: New developments. AB - The traditional renin-angiotensin system (RAS) is indispensable system in adjusting sodium homeostasis, body fluid volume, and controlling arterial blood pressure. The key elements are renin splitting inactive angiotensinogen to yield angiotensin (Ang-I). Ang-1 is then changed by angiotensin-1 converting enzyme (ACE) into angiotensin II (Ang-II). Using PubMed, Google Scholar, and other means, we searched the peer-reviewed literature from 1990 to 2013 for articles on newly discovered findings related to the RAS, especially focusing on how the system influences the central nervous system (CNS). The classical RAS is now considered to be only part of the picture; the discovery of additional RAS pathways in the brain and elsewhere has yielded a vastly improved understanding of how the RAS influences the CNS. Newly discovered effects of the RAS on brain tissue include neuroprotection, cognition, and cerebral vasodilation. A number of brain biochemical pathways are influenced by the brain RAS. Within various pathways, there are potential opportunities for classical pharmacologic interventions as well as the possibility of controlling gene expression. PMID- 28890046 TI - Effect of multiple neonatal sevoflurane exposures on hippocampal apolipoprotein E levels and learning and memory abilities. AB - BACKGROUND: Sevoflurane anesthesia is widely used in pediatric patients. In this study, we investigated whether early multiple exposures to sevoflurane induced cognitive dysfunction by altering the hippocampal expression of ApoE later in development. METHODS: Sprague-Dawley rats were exposed to 2.6% sevoflurane at postnatal day 7 (P7), P14, and P21 for 2 h. The ability of learning and memory was assessed using the Morris water maze at P37 and P97. The hippocampal volume was measured by magnetic resonance imaging (MRI) at P37 and P97. The hippocampal expression of ApoE was assessed by immunohistochemical analyses and real-time polymerase chain reaction (PCR). RESULTS: Behavioral testing revealed that the ability of learning and memory in the sevoflurane-exposed rats was decreased compared with the control animals; however, there was no significant difference (P > 0.05). The MRI results showed a significant decrease in the left hippocampal volume, left maximum hippocampal length, and right maximum hippocampal length in the sevoflurane young group compared with the control young group (P < 0.05). The brain volume, left maximum hippocampal length, right hippocampal volume, and maximum brain length were significantly lower in the sevoflurane adult group than in the control adult group (P < 0.05). In young animals, the ApoE expression in the hippocampal CA1 and CA3 regions and the ApoE mRNA level were significantly higher compared with the control group (P < 0.05), but not in the dentate gyrus region (P > 0.05). Among the adult animals, there was no significant difference between the groups in any parameter tested (P > 0.05). CONCLUSION: Multiple exposures to sevoflurane during the neonatal period decreased the volume of the hippocampus and increased the hippocampal expression of ApoE. The differential expression level of ApoE in different hippocampal subdivisions suggested that the expression of ApoE was regionally specific and reversible. PMID- 28890047 TI - Basilar-type migraine: An overlooked cause of loss of consciousness in pediatric emergency rooms. PMID- 28890049 TI - Psychological Processes in Chronic Pain: Influences of Reward and Fear Learning as Key Mechanisms - Behavioral Evidence, Neural Circuits, and Maladaptive Changes. AB - In the understanding of chronic pain, hypotheses derived from psychological theories, together with insights from physiological assessments and brain imaging, highlight the importance of mechanistically driven approaches. Physical system changes, for example following injury, can result in alterations of psychological processes and are accompanied by changes in corticolimbic circuits, which have been shown to be essential in emotional learning and memory, as well as reward processing and related behavior. In the present review, we thus highlight the importance of motivational, reward/pain relief, and fear learning processes in the context of chronic pain and discuss the potential of a mechanistic understanding of chronic pain within a clinical perspective, for example for the development of therapeutic strategies. We argue that changes in these mechanisms are not only characteristic for chronic pain, reflecting consequences of the disorder, but are also critically involved in the transition from acute to chronic pain states. PMID- 28890048 TI - Molecular, Cellular and Circuit Basis of Cholinergic Modulation of Pain. AB - In addition to being a key component of the autonomic nervous system, acetylcholine acts as a prominent neurotransmitter and neuromodulator upon release from key groups of cholinergic projection neurons and interneurons distributed across the central nervous system. It has been more than forty years since it was discovered that cholinergic transmission profoundly modifies the perception of pain. Directly activating cholinergic receptors or extending the action of endogenous acetylcholine via pharmacological blockade of acetylcholine esterase reduces pain in rodents as well as humans; conversely, inhibition of muscarinic cholinergic receptors induces nociceptive hypersensitivity. Here, we aim to review the considerable progress in our understanding of peripheral, spinal and brain contributions to cholinergic modulation of pain. We discuss the distribution of cholinergic neurons, muscarinic and nicotinic receptors over the central nervous system and the synaptic and circuit-level modulation by cholinergic signaling. AchRs profoundly regulate nociceptive transmission at the level of the spinal cord via pre- as well as postsynaptic mechanisms. Moreover, we attempt to provide an overview of how some of the salient regions in the pain network spanning the brain, such as the primary somatosensory cortex, insular cortex, anterior cingulate cortex, the medial prefrontal cortex and descending modulatory systems are influenced by cholinergic modulation. Finally, we critically discuss the clinical relevance of cholinergic signaling to pain therapy. Cholinergic mechanisms contribute to several both conventional as well as unorthodox forms of pain treatments, and reciprocal interactions between cholinergic and opioidergic modulation impact on the function and efficacy of both opioids and cholinomimetic drugs. PMID- 28890050 TI - Modulation of hippocampal synapse maturation by activity-regulated E3 ligase via non-canonical pathway. AB - Development of functional synapses is crucial for the transmission and storage of information in the brain. Post establishment of the initial synaptic contact, synapses are stabilized through neuronal activity-induced signals. Emerging studies have implicated ubiquitination; a reversible posttranslational modification, as a key regulatory switch that modulates synapse development through proteasomal degradation. Ubiquitination of proteins is precisely regulated by E3 ligases, a set of enzymes that bind to specific substrates to facilitate the conjugation of monomeric or polymeric ubiquitin. However, the identity of specific E3 ubiquitin ligases that influence activity-dependent maturation of synapses and the mechanism by which ubiquitination of proteins regulate functional synapse development remain elusive. Here, we have identified a RING domain containing E3 ligase, Rnf2, asan activity-regulated factor that modulates glutamatergic synapse development in the hippocampus. Rnf2 is a synapse associated E3 ligase that is stabilized by neuronal activity through self polyubiquitination. We have shown that neuronal activity shifts the balance toward stabilization of Rnf2 through self-polyubiquitination rather than triggering its degradation through polyubiquitination by Ube3A, an E3 ligase implicated in Angelman Syndrome. Our synapse density measurements and whole-cell patch-clamp recordings have revealed that the loss of Rnf2 function in cultured hippocampal neurons result in the development of 'silent' synapses that lack GluA1 containing functional AMPA receptors. These results provide a plausible mechanistic approach toward understanding how synapse maturation is regulated via the activity-dependent stabilization of Rnf2 through a non-canonical function of polyubiquitination. PMID- 28890052 TI - Neuropeptide Y and its Involvement in Chronic Pain. AB - Chronic pain is a serious condition that significantly impairs the quality of life, affecting an estimate of 1.5 billion people worldwide. Despite the physiological, emotional and financial burden of chronic pain, there is still a lack of efficient treatments. Neuropeptide Y (NPY) is a highly conserved endogenous peptide in the central and peripheral nervous systems of all mammals, which has been implicated in both pro- and antinociceptive effects. NPY is expressed in the superficial laminae of the dorsal horn of the spinal cord, where it appears to mediate its antinociceptive actions via the Y1 and Y2 receptors. Intrathecal administration of NPY in animal models of neuropathic, inflammatory or postoperative pain has been shown to cause analgesia, even though its exact mechanisms are still unclear. It remains to be seen whether these promising central antinociceptive effects of NPY can be transferred into a future treatment for chronic pain. PMID- 28890051 TI - Systemic administration of two different anxiolytic drugs decreases local field potential theta frequency in the medial entorhinal cortex without affecting grid cell firing fields. AB - Neurons coding spatial location (grid cells) are found in medial entorhinal cortex (MEC) and demonstrate increasing size of firing fields and spacing between fields (grid scale) along the dorsoventral axis. This change in grid scale correlates with differences in theta frequency, a 6-10Hz rhythm in the local field potential (LFP) and rhythmic firing of cells. A relationship between theta frequency and grid scale can be found when examining grid cells recorded in different locations along the dorsoventral axis of MEC. When describing the relationship between theta frequency and grid scale, it is important to account for the strong positive correlation between theta frequency and running speed. Plotting LFP theta frequency across running speeds dissociates two components of this relationship: slope and intercept of the linear fit. Change in theta frequency through a change in the slope component has been modeled and shown experimentally to affect grid scale, but the prediction that change in the intercept component would not affect grid scale has not been tested experimentally. This prediction about the relationship of intercept to grid scale is the primary hypothesis tested in the experiments presented here. All known anxiolytic drugs decrease hippocampal theta frequency despite their differing mechanisms of action. Specifically, anxiolytics decrease the intercept of the theta frequency-running speed relationship in the hippocampus. Here we demonstrate that anxiolytics decrease the intercept of the theta frequency running speed relationship in the MEC, similar to hippocampus, and the decrease in frequency through this change in intercept does not affect grid scale. PMID- 28890053 TI - Intrastriatal Chromospheres' Transplant Reduces Nociception in Hemiparkinsonian Rats. AB - The present study evaluates the possible antinociceptive effect of chromosphere transplants in rats injected with 6-hydroxydopamine (6-OHDA), a model of Parkinson's disease. Male adult Wistar rats received 40MUg/0.5MUl of 6-OHDA or 0.5MUl of vehicle into the left substantia nigra (SNc). Rats were evaluated for mechanical allodynia, cold allodynia, thermal hyperalgesia and formalin. Rats with altered nociceptive threshold were transplanted with chromospheres. After transplant, rats were evaluated every week. Our results confirm that 6-OHDA injection into rat's SNc reduces mechanical, thermal, and chemical thresholds. Interestingly, chromospheres' transplant reverted 6-OHDA-induced allodynia and hyperalgesia. The antinociceptive effect induced by chromospheres was dopamine D2 and opioid-receptor dependent since sulpiride or naltrexone reverted its effect. PMID- 28890054 TI - Home-cage odors spatial cues elicit theta phase/gamma amplitude coupling between olfactory bulb and dorsal hippocampus. AB - The brain oscillations may play a critical role in synchronizing neuronal assemblies in order to establish appropriate sensory-motor integration. In fact, studies have demonstrated phase-amplitude coupling of distinct oscillatory rhythms during cognitive processes. Here we investigated whether olfacto hippocampal coupling occurs when mice are detecting familiar odors located in a spatially restricted area of a new context. The spatial olfactory task (SOT) was designed to expose mice to a new environment in which only one quadrant (target) contains odors provided by its own home-cage bedding. As predicted, mice showed a significant higher exploration preference to the target quadrant; which was impaired by olfactory epithelium lesion (ZnSO4). Furthermore, mice were able to discriminate odors from a different cage and avoided the quadrant with predator odor 2,4,5-trimethylthiazoline (TMT), reinforcing the specificity of the SOT. The local field potential (LFP) analysis of non-lesioned mice revealed higher gamma activity (35-100Hz) in the main olfactory bulb (MOB) and a significant theta phase/gamma amplitude coupling between MOB and dorsal hippocampus, only during exploration of home-cage odors (i.e. in the target quadrant). Our results suggest that exploration of familiar odors in a new context involves dynamic coupling between the olfactory bulb and dorsal hippocampus. PMID- 28890055 TI - Resected irradiated rectal cancers: Are twelve lymph nodes really necessary in the era of neoadjuvant therapy? AB - BACKGROUND: Our study aims to identify the minimum number of lymph nodes (LN) associated with improved survival in patients who underwent NRT for stage II-III rectal cancer. METHODS: Adults with clinical stage II and III rectal adenocarcinoma in the National Cancer Data Base were stratified by NRT. Multivariable Cox regression modeling with restricted cubic splines was used to determine the minimum number of LNs associated with improved survival. RESULTS: Of 38,363 patients, 76% received NRT. After adjustment, a LNY>=12 was associated with improved survival among patients receiving NRT (HR 0.79, p < 0.0001) and those without NRT (HR 0.88, p = 0.04). Among patients receiving NRT, factors independently associated with LNY>=12 were younger age, private insurance, low comorbidity score, a recent year of diagnosis, higher T stage and grade, APR resection, and academic institution. CONCLUSIONS: A minimum LNY of 12 confers a survival benefit for rectal cancer patients regardless of receiving neoadjuvant radiation therapy. PMID- 28890056 TI - Giant Chest Wall Arteriovenous Malformation: A Case Report and Literature Review. AB - BACKGROUND: We present an interesting case of a 55-year-old male with a large left chest mass after significant cutaneous bleeding. Computed tomography angiogram of the chest revealed arteriovenous malformation with blood supply from sub-branches of the left subclavian artery, left internal mammary artery, and left external carotid artery. Measuring 5.0 * 14.0 * 10.8 cm, the mass extended superior to the clavicle and inferior to the third rib with medial and lateral borders at the level of the clavicular head and coracoid, respectively. METHODS: Arteriovenous malformations (AVMs) are characterized by abnormal connections between arteries and veins which bypass the capillary system. Often small and asymptomatic, large AVMs can be painful, prone to bleeding and, if large enough, interfere with activities of daily living. While described involving various parts of the body, most notably in the central nervous system, there is a paucity of literature involving chest wall AVMs. RESULTS: Using a staged, multidisciplinary approach, treatment began with an endovascular exclusion of the arterial blood supply, which involved a combination of coil embolization and stent exclusion of feeder vessels. Two days postembolization, the patient underwent an en bloc resection of affected portion of his chest wall. Reconstruction was completed with a combination rotational flap and split thickness skin graft. Following the procedures, the patient had an uncomplicated recovery. Three years following procedure, he has no signs of recurrence of his AV malformation. CONCLUSION: Surgical planning and indications for giant arteriovenous malformations remains a unique and difficult problem. The complex anatomy and extreme rarity of a chest wall AVM requires a multidisciplinary staged approach but can be treated with a multistage, multidisciplinary surgical approach with satisfactory and long-lasting results. PMID- 28890057 TI - Endovascular Exclusion of Hypogastric Aneurysms Using Distal Branches of the Internal Iliac Artery as Landing Zone: A Case Series. AB - BACKGROUND: The purpose of the study was to report an alternative endovascular technique to exclude aneurysms of the internal iliac artery in the setting of abdominal aortic aneurysm (AAA) disease using the anterior division of the hypogastric artery (HGA) or the superior gluteal artery (SGA) as distal landing zone for the stent graft. METHODS: Three patients with HGA aneurysms in the setting of AAA that were excluded with placement of a self-expandable covered stent. In 2 patients, the AAA had been already treated with resulting exclusion of 1 HGA, while in the remaining we treated the hypogastric aneurysm before the AAA. We used as distal landing zone the anterior division of the HGA or the SGA. We adopted a "stent-within-a-stent" or "telescope" technique to manage diameter discrepancy between proximal and distal landing zone. RESULTS: Computed tomography angiography (CTA) at 6 and 12 months showed regular placement and patency of the stent grafts placed and absence of detectable endoleaks (EL). None of the patients developed pelvic ischemic complication at longest follow-up. CONCLUSIONS: The procedure seems to be safe and effective, with optimal primary patency of the stent grafts, freedom from type 1 and 2 endoleaks, and absence of pelvic ischemic complications in the short-term and mid-term. PMID- 28890058 TI - Reversal of Acute Mesenteric Ischemia by Salvation of the Meandering Mesenteric Artery with Stenting of the Left Internal Iliac Artery. AB - The presence of the meandering mesenteric artery, which is a nonconstant tortuous arterial component unifying the peripheral intestinal circulation, is evidence of chronic occlusive disease of the main intestinal arteries. This collateral intestinal arterial pathway, when present, must be preserved in any abdominal intervention, as it is often the only remaining arterial supply of the intestine; its ligation can be accompanied by intestinal ischemia. We present herein, the case of a 42-year-old man, heavy smoker, who had chronic mesenteric ischemia without particular clinical manifestations till the hospitalization for acute myocardial infarction for which he underwent balloon angioplasty and stenting of the left circumflex coronary artery. Three days later, he experienced acute-on chronic intestinal ischemia with crescendo clinical manifestations; intra arterial angiography revealed the presence of a meandering mesenteric artery in a milieu of celiac, superior and inferior mesenteric, and right internal iliac artery occlusion accompanied by a tight stenosis of the left internal iliac artery. Successful stenting of the orifice of the left internal iliac artery was followed by a well-defined dilatation of the meandering artery, revascularization of the peripheral branches of the inferior-through the superior hemorrhoidal artery-and superior mesenteric arteries and complete resolution of the acute mesenteric ischemia. Thus, time was gained for the patient in order to have, if needed, a future elective open revascularization of the mesenteric artery, when the perioperative risk of mortality from the recent myocardial infarction and the coronary angioplasty and stenting will be minimal. PMID- 28890059 TI - Covered Stent Grafts for Acquired Arterial Venous Fistulas: A Case Series. AB - BACKGROUND: Stent grafts have become the preferred method for treating abdominal aortic aneurysms (AAAs) but also have utility in treating other vasculopathies. In 2005, peripheral stent grafts were approved for treating superficial femoral artery occlusive disease. This report describes our experience using covered stent grafts to treat acquired arterial venous fistulae (aAVF). METHODS: We reviewed the records of patients treated for aAVF with covered stent grafts. Eleven patients had 12 limbs treated with a stent graft. The data collected included presenting symptoms, mechanism of injury, vessel location, stent graft used for therapy, and patency. RESULTS: Eleven patients underwent successful treatment of 12 aAVF with a peripheral stent grafts. The average age was 55.6 (18 87), and there were 4 women and 7 men. The mechanisms of injuries were heart catheterization in 5 patients, penetrating trauma in 3 patients, and orthopedic injury in 3 patients. Five of the patients had concurrent pseudoaneurysms. Self expanding expanded polytetrafluoroethelene (ePTFE) stent grafts were used in 8 patients, and balloon-expandable ePTFE stent grafts were used in 3 patients. Primary patency at 2 years is 100%, with all patients having significant relief of symptoms. CONCLUSIONS: Peripheral stent grafts are a useful tool for treating aAVF, with excellent patency. They provide a valuable minimally invasive approach to this disease. PMID- 28890060 TI - Transverse versus Longitudinal Incisions for Femoral Artery Exposure in Treating Patients with Peripheral Vascular Disease. AB - BACKGROUND: This study evaluates differences in wound complication rate when transverse versus longitudinal incision is utilized to expose femoral vessels in managing patients with peripheral vascular disease. METHODS: A retrospective review from 2013 to 2015 was conducted of 150 patients undergoing 156 lower extremity revascularizations with femoral artery exposure through a groin incision. Patients were stratified into 2 groups, transverse versus longitudinal groin incision. Data were reviewed for 3 surgeons that utilize either transverse or longitudinal groin incision in patients undergoing common or iliofemoral endarterectomies, or where femoral artery was used as inflow and/or outflow vessel for limb revascularization. Each group had a comparative outcomes analysis based on incision type. The primary outcome was wound complication, defined as any wound infection, lymphocele, hematoma, dehiscence, pseudoaneurysm, or necrosis. Other outcomes studied included unplanned return to operating room for wound complication, wound vacuum therapy, and soft-tissue flap closure. Data were analyzed using 2-tailed chi-squared test and Student's t-test. RESULTS: Patients in the transverse (n = 85 cases) versus longitudinal (n = 71 cases) cohorts were similar in relation to demographics and comorbidities. Overall mean follow-up was 220 days. Patients with a transverse as compared to longitudinal incision had a significantly lower overall wound complication rate, 7% vs. 42%, respectively (P < 0.001). Furthermore, transverse incisions were associated with lower incidence of unplanned return to the operating room to manage wound complications than patients with a longitudinal incision (5% vs. 23%, respectively; P < 0.001). Transverse versus longitudinal incisions were also associated with significantly lower need for wound vacuum therapy (6% vs. 15%, respectively; P < 0.05) and muscle flap closure (0% vs. 13%, respectively; P < 0.001) for wound complications. CONCLUSIONS: Transverse groin incisions for femoral artery exposure may offer a lower risk of wound complications for open procedures as compared to a longitudinal incision. While longitudinal incisions may have higher wound complication rates, incisional approach is contingent on anatomical circumstance and treated disease pattern. Patients should undergo appropriate preoperative counseling regarding wound healing in preparation for limb revascularization. PMID- 28890061 TI - Cerebral Protection with a Temporary Ascending Aorta-External Carotid Artery Bypass during Common Carotid Artery Revascularization. AB - Atherosclerosis is a systemic disease, and multiarterial involvement is common. Involvement of all the supra-aortic arteries may occur in the same patient making cerebral revascularization challenging. In this report, we present complete supra aortic revascularization, that is, revascularization of the bilateral common carotid and subclavian arteries in a 51-year-old male patient with occluded brachiocephalic trunk, left subclavian artery, and proximally stenotic left common carotid artery. A temporary ascending aorta to left external carotid artery bypass provided meticulous cerebral protection with pulsatile cerebral flow in the presence of a proximal arterial clamp; hence, a neurologically uneventful procedure during bilateral common carotid artery revascularization. PMID- 28890062 TI - National Utilization and Outcomes of Redo Lower Extremity Bypass versus Endovascular Intervention after a Previous Failed Bypass. AB - BACKGROUND: Redo lower extremity bypass (LEB) and infrainguinal endovascular intervention (IEI) are options to treat critical limb ischemia after a failed prior LEB, but the utilization and outcomes of each are poorly described. The purpose of this study was to compare 30-day major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs) after LEB and IEI in patients with a failed prior ipsilateral LEB and determine risk factors for each composite outcome. METHODS: Patients with prior failed ipsilateral LEB who underwent LEB or IEI involving the same arterial segment for critical limb ischemia were identified in the National Surgical Quality Improvement Program (NSQIP) Vascular Targeted File (2011-2014). LEB with single-segment saphenous vein was compared to LEB with alternative conduit (prosthetic/spliced vein/composite) and IEI. Primary outcomes were MALE (untreated loss of patency, reintervention, or amputation) and MACE (stroke, myocardial infarction, or death). Multivariate analysis was utilized to identify independent predictors of MALE and MACE. RESULTS: Among 8,066 revascularizations performed for critical limb ischemia (CLI), 1,606 (461 [28.7%] IEI, 518 [32.3%] LEB saphenous, and 627 [39.0%] LEB alternative) were performed after failed ipsilateral LEB involving the same arterial segment. LEB with saphenous had lower MALE than LEB with alternate conduit and IEI (15.8% IEI, 10.8% saphenous, and 15.5% alternative, P = 0.03). Higher MALE was driven by higher 30-day amputation in IEI (7.8% IEI, 3.7% saphenous, and 5.3% alternative, P = 0.02). Independent predictors of MALE include transfer status (odds ratio [OR] = 1.7, P = 0.01), tobacco use (OR = 1.5, P = 0.02), infrageniculate revascularization (OR = 1.6, P = 0.004), and saphenous conduit (OR = 0.5, P = 0.002). MACE was also different between groups (3.9% IEI, 7% saphenous, and 5.6% alternative, P = 0.049), with no difference in 30-day mortality (P = 0.53). Independent predictors of MACE included congestive heart failure (OR = 3.0, P = 0.01) and dialysis dependence (OR = 2.5, P = 0.02). CONCLUSIONS: In this large national sample representing routine vascular care of patients with CLI after failed ipsilateral LEB of the same arterial segment, IEI is common and represents 30% of revascularizations in this data set. Redo LEB with saphenous is associated with superior limb-related outcomes, but IEI offers an acceptable potential alternative to bypass in patients who would require alternative conduit. Finally, perioperative care is critical as we demonstrate that patient comorbidities, not the method of revascularization, predicted MACE. PMID- 28890063 TI - The Value of Carotid Endarterectomy as a Learning Tool for Trainees. AB - BACKGROUND: Carotid endarterectomy (CEA) intervention needs a specific training and a sufficient learning curve to obtain optimal results in terms of outcome. A formative program was settled up in a single academic center to optimize training of standard CEA procedures. This study aims to evaluate the 11-year results of the teaching CEA program. METHODS: The trainees CEA teaching program is carried on during the 5-year vascular surgery residency period, and it is stratified as follows: learning theory and intervention assistance (minimum 50 procedures per year) in the first and second residency year; performing CEA as second operator in the third and fourth residency year (minimum 50 procedures per year); CEA execution as first operator with attending supervision in the last residency year. All CEA procedures from 2005 to 2015 were retrospectively collected and the 30-day results were compared according to the expertise of the first operator: experienced vascular surgeons (EVSs) versus trainees. All CEA procedures were performed in general anesthesia, with routine shunting and patching. RESULTS: In the study period, 1,379 (361 [26.2%] symptomatic; 1,018 [73.8%] asymptomatic) CEAs were performed. Trainees performed 199 (14.4%) CEAs as first operator. Patients submitted to CEA by trainees were similar in terms of preoperative clinical characteristics except for the patients' age (trainees 72.4 years versus EVS 70.8 years, P = 0.02) and smoking history (trainees 30.7% versus EVS 24.1%, P = 0.04). The 30-day complication rates were similar in CEA performed by trainees versus EVS: stroke 0.5% vs. 1.1%, P = 0.5; death 0.0% vs. 0.5%, P = 0.6; stroke/death 0.5% vs. 1.7%, P = 0.24; hematoma 3.0% vs. 2.2%, P = 0.48; and cranial nerve injury 9.0% vs. 7.8%, P = 0.47, respectively. The intervention time was significantly longer in CEAs performed by trainees compared with EVS: 104 +/- 1.9 min versus 98 +/- 1.0 min, P = 0.02. CONCLUSIONS: With a defined CEA teaching program, trainees can obtain results similar to those of more experienced surgeons in terms of clinical outcome at the price of an increased intervention time. PMID- 28890064 TI - Evaluating the Utilization of Prophylactic Inferior Vena Cava Filters in Trauma Patients. AB - BACKGROUND: The lack of evidence-based guidelines on the use of prophylactic inferior vena cava filters (IVCFs) in patients after trauma has led to variation of its application. We seek to understand the national trend of the use of prophylactic IVCF in trauma population. METHODS: A retrospective review of the National Trauma Databank (2002-2014) was performed to identify patients who received an IVCF after trauma. Those without a preexisting venous thromboembolism or discharge diagnosis of VTE were classified as receiving prophylactic IVCF. Multivariable logistic regression analysis was used to examine associations between the use of prophylactic IVCF and risk factors for VTE. P value <=0.05 was considered statistically significant. RESULTS: Among the 2,189,994 patients evaluated, 41,155 (2%) received a prophylactic IVCF. The rate of overall IVCF placement (2.9% in 2002-2006 to 1.6% in 2014, P < 0.001) and prophylactic IVCF placement (2.5% in 2002-2006 to 1.2% in 2014, P < 0.001) decreased over the study period. In multivariable analysis, significant risk factors associated with the use of prophylactic IVCF were male gender (OR 1.2, 95% CI 1.1-1.2), African American race (OR 1.2, 95% CI 1.1-1.2), injury severity score >= 24 (OR 4.4, 95% CI 4.2-4.5), Glasgow Coma Scale <8 (OR 1.4, 95% CI 1.4-1.5), spinal cord injury with paraplegia (OR 5.1, 95% CI 4.7-5.6), pelvic fracture (OR 2.9, 95% CI 2.7 3.0), long bone fracture (OR 1.3, 95% CI 1.3-1.4), and solid organ injury (OR 1.2, 95% CI 1.2-1.3) (P < 0.001). Patients who were treated at a level-II trauma center (OR 1.1, 95% CI 1.1-1.2, P < 0.001), at a facility with >=200 beds (OR 1.3, 95% CI 1.2-1.4, P < 0.001), and those with medical insurance coverage (OR 1.4, 95% CI 1.6-1.8, P < 0.001) were also more likely to receive a prophylactic IVCF. CONCLUSIONS: The utilization of prophylactic IVCF in trauma patients has decreased over time between 2008 and 2014. Considerable variation exists in its use, which is not fully accounted for by the VTE rate. Further study is required to evaluate appropriate indications for placement of prophylactic IVCF in trauma patients. PMID- 28890066 TI - Ascending Aorta Endovascular Repair of a Symptomatic Penetrating Atherosclerotic Ulcer with a Custom-Made Endograft. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) has become lately the procedure of choice in the treatment of most pathologies of descending thoracic aorta. Aortic arch aneurysms also came to be treated by TEVAR with various hybrid techniques or custom-made scalloped/fenestrated stent grafts. Zone 0; ascending TEVAR is more challenging than TEVAR of the descending thoracic aorta or aortic arch because of the more complex pathology, hemodynamics, and anatomy. Ascending TEVAR can be a lifesaving treatment in selected high surgical risk patients. CASE REPORT: A 71-year-old male with known history of respiratory insufficiency, coronary artery disease, and low left ventricle ejection fraction, presented to emergency department with acute thoracic pain. As the initial laboratory tests and the electrocardiogram were negative for acute coronary syndrome, a computed tomography (CT) scan was performed that showed a 20 mm large and 17 mm depth penetrating atherosclerotic ulcer (PAU) in the middle portion of ascending thoracic aorta. After medical therapy administration, the thoracic pain was controlled, and due to the high surgical risk of the patient, high incidence of aortic rupture due to PAU, and favorable anatomic conditions was scheduled the implantation of a custom-made (due to short ascending aorta) stent graft (Bolton, Relay Plus). A pacemaker was implanted 1 week before the operation to induce rapid ventricular pacing during the stent-graft deployment. During the operation, the patient was under general anesthesia as it was our first case treated in this way. The delivery of the graft was achieved through a right femoral artery cut open by an extra-stiff guide wire (Lunderquist Cook) that was placed through an angio-catheter into the left ventricle of the heart. The final positioning and deployment of the graft was achieved under rapid ventricular pacing, and the final angiogram after the withdraw of the graft delivery system showed exclusion from circulation of PAU, patency of coronary arteries, and brachiocephalic trunk with competent aortic valve. CONCLUSIONS: TEVAR of the ascending aorta is a safe and feasible technique indicated mainly unfit for open surgery patients. PMID- 28890065 TI - Comparison of Endovascular Stent Grafts for Abdominal Aortic Aneurysm Repair in Medicare Beneficiaries. AB - BACKGROUND: Increased renal complications have been suggested with suprarenal stent grafts, but long-term analyses have been limited. Therefore, the purpose of this study was to evaluate the effect of endograft choice on perioperative and long-term outcomes. METHODS: We compared Medicare beneficiaries undergoing endovascular abdominal aortic aneurysms repair from 2005 to 2008 with endografts with infrarenal fixation and a single docking limb (AneuRx, Excluder) to those with suprarenal fixation and 2 docking limbs (Zenith), or a unibody configuration (Powerlink). Propensity score weighting accounted for differences in patient characteristics among the different graft formations, and perioperative mortality, complications, and length of stay and 4-year rates of survival, rupture, and reintervention were compared. RESULTS: Forty-six thousand one hundred seventy-one Medicare beneficiaries were identified including 11,002 (24%) with suprarenal fixation, 32,909 (71%) with infrarenal fixation, and 2,260 (5%) with a unibody graft. After propensity score weighting, there were no significant differences in patients' baseline clinical and demographic characteristics. The suprarenal fixation patients had higher rates of perioperative mortality (1.7% vs. 1.3%, P < 0.01), renal failure (6.0% vs. 4.7%, P < 0.001), and mesenteric ischemia (0.7% vs. 0.4%, P < 0.01) and longer length of stay (3.4 days vs. 3.0 days, P < 0.001) compared with patients with infrarenal fixation. Unibody grafts had higher rates of renal failure (5.9% vs. 4.7%, P < 0.001), mesenteric ischemia (1.0% vs. 0.4%, P < 0.001), and conversion to open repair (0.7% vs. 0.1%, P < 0.001) compared to those with infrarenal fixation and single docking limbs. At 4 years, mortality remained slightly higher with suprarenal compared to infrarenal fixation (30% vs. 29%, P = 0.047), although these patients had fewer conversions to open repair (0.6% vs. 0.9%, P = 0.03) and aneurysm-related reinterventions (10% vs. 12%, P < 0.01). At 4 years, unibody grafts had more aneurysm-related interventions compared to infrarenal fixation grafts (15% vs. 12%, P < 0.01) but fewer conversions to open repair (0.4% vs. 0.9%, P = 0.02). Late rupture did not differ among the groups. CONCLUSIONS: Compared to infrarenal fixation devices, patients who underwent EVAR with suprarenal fixation had higher perioperative mortality and renal complications but fewer reinterventions including conversion, while the unibody graft had more perioperative complications and aneurysm-related reinterventions, but fewer conversions to open repair. Although these differences could be explained by selection bias, these data suggest that further comparative effectiveness analyses should be performed to understand the outcomes following EVAR with suprarenal fixation and unibody grafts. PMID- 28890067 TI - Retrosternal Metastatic Papillary Thyroid Cancer Causing Superior Vena Cava Syndrome: A Very Rare Presentation. AB - Thyroid cancer causing superior vena cava (SVC) syndrome is a very rare clinical entity with only 26 cases reported worldwide. Metastatic thyroid cancer causing SVC syndrome several years following resection of the primary tumor is extremely rare with only 2 cases reported; one of them was of the papillary variety. We report the second case worldwide of metastatic papillary thyroid cancer causing SVC syndrome 2 years after total thyroidectomy of the original tumor in a 62-year old Indian female pilgrim. Unfortunately, the patient died on the third day of intensive care unit admission. The severity of the clinical condition in addition to the late presentation resulted in a catastrophic outcome, which made all the possible resuscitative efforts very difficult. PMID- 28890068 TI - Is the Endovascular Treatment of Mild Iliac Stenoses Worthwhile to Improve Wound Healing in Patients Undergoing Femorotibial Bypass? AB - BACKGROUND: After an infrapopliteal reconstruction, minor amputations are frequently required, but even in the case of successful revascularization, wound healing is a major concern. We studied the role of iliac artery inflow correction in patients undergoing infrapopliteal vein grafts to improve the heal of midfoot amputation. METHODS: Thirty-eight patients affected with Rutherford grade III category 5 peripheral arterial disease, who underwent successful simultaneous iliac endovascular procedure, infrapopliteal reversed vein bypass graft, and minor amputation, were enrolled in this retrospective study. The population was divided in group 1 (20 patients) with inflow vessels Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease (TASC) II type B atherosclerotic lesions and group 2 (18 patients) with TASC II type A atherosclerotic lesions determining an invasive pressure drop greater than 15 mm Hg. Fifteen patients (group 3) undergoing infrapopliteal reversed vein bypass graft without associated inflow procedures (TASC II type A and invasive pressure drop greater than 15 mm Hg) were matched with group 2 based on propensity score. Healing was calculated by subtracting the final ulcer area from the initial ulcer area and dividing by the number of follow-up months to obtain the total area healed per month (cm2/month). Stepwise logistic regression analysis adjusted for demographics and medical comorbid conditions was used to test the association between wound healing and treatment modalities. RESULTS: Forty-three patients were available for further analysis. Ten patients were excluded because of graft occlusion with consequent impairment of wound healing. After midfoot amputations, mean wound diameter was 20 +/- 8 cm2, and mean healing time was 10 +/- 4 months (range 3-20 months; median 9 months). Wounds of groups 1 and 2 healed faster than those of group 3 at 4 and 8 months (P < 0.02 and P < 0.001, respectively; P < 0.04 and P < 0.001, respectively). Multivariate analysis demonstrated the association between wound healing and inflow correction (P < 0.001). CONCLUSIONS: An aggressive treatment is necessary to obtain the heal of the ischemic wounds. The most important predictive factor for nonhealing wounds is the absence of inflow correction. We demonstrated that the inflow should be also corrected in the presence of subclinical lesions. PMID- 28890069 TI - Shrinking Hepatic Hemangiomas in a Patient Treated for Metastatic Germ Cell Tumor. PMID- 28890070 TI - Oligometastatic Renal Cell Carcinoma With Sarcomatoid Differentiation Demonstrating Variable Imaging Phenotypes on 68Ga-PSMA and 18F-FDG PET/CT: A Case Report and Review of the Literature. PMID- 28890071 TI - Serum lipid alterations in GBA-associated Parkinson's disease. AB - INTRODUCTION: Mutations in the GBA gene, encoding for the lysosomal enzyme glucocerebrosidase, are associated with Gaucher disease. Alterations in plasma sphingolipids have been reported in Gaucher, and similarly in brain extracts in Lewy body disease. As GBA mutations are prevalent risk factors for Parkinson's disease and overlap of molecular pathways are presumable, here we assessed the lipid profiles in Parkinson's patients with and without GBA mutations. METHODS: We sequenced all GBA exons in 415 Parkinson's patients, previously genotyped for LRRK2. 64 patients (29 GBA positive vs. 35 non-GBA-carriers including 18 LRRK2 positive and 17 non-mutated) were analyzed for chitotriosidase activity and for the concentration of 40 lipid classes using HPLC-MS. RESULTS: 29/415 patients (6.9%) carried 8 different GBA mutations associated with Gaucher or Parkinson's, including one novel mutation. Chitotriosidase activity was similar across the genetic groups, while the levels of key lipids were altered in GBA mutation carriers: Monohexosylceramide, Ceramide and Sphingomyelin were elevated; while Phosphatidic acid (PA), Phosphatidylethanolamine (PE), Plasmalogen phosphatidylethanolamine (PEp) and Acyl Phosphatidylglycerol (AcylPG) were decreased. CONCLUSION: The results suggest an important role for these lipids in GBA mediated Parkinson's disease and assist in the identification of common pathways between Gaucher and Parkinson's. Ultimately, our findings may lead to the identification of novel biomarkers for individuals at increased risk of developing Parkinson's disease. PMID- 28890072 TI - Large-Scale Quantitative Proteomics Identifies the Ubiquitin Ligase Nedd4-1 as an Essential Regulator of Liver Regeneration. AB - The liver is the only organ in mammals that fully regenerates even after major injury. To identify orchestrators of this regenerative response, we performed quantitative large-scale proteomics analysis of cytoplasmic and nuclear fractions from normal versus regenerating mouse liver. Proteins of the ubiquitin-proteasome pathway were rapidly upregulated after two-third hepatectomy, with the ubiquitin ligase Nedd4-1 being a top hit. In vivo knockdown of Nedd4-1 in hepatocytes through nanoparticle-mediated delivery of small interfering RNA caused severe liver damage and inhibition of cell proliferation after hepatectomy, resulting in liver failure. Mechanistically, we demonstrate that Nedd4-1 is required for efficient internalization of major growth factor receptors involved in liver regeneration and their downstream mitogenic signaling. These results highlight the power of large-scale proteomics to identify key players in liver regeneration and the importance of posttranslational regulation of growth factor signaling in this process. Finally, they identify an essential function of Nedd4-1 in tissue repair. PMID- 28890074 TI - Editorial - Waste management. PMID- 28890073 TI - Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts. AB - Organogenesis during embryonic development occurs through the differentiation of progenitor cells. This process is extraordinarily accurate, but the mechanisms ensuring high fidelity are poorly understood. Coronary vessels of the mouse heart derive from at least two progenitor pools, the sinus venosus and endocardium. We find that the ELABELA (ELA)-APJ signaling axis is only required for sinus venosus derived progenitors. Because they do not depend on ELA-APJ, endocardial progenitors are able to expand and compensate for faulty sinus venosus development in Apj mutants, leading to normal adult heart function. An upregulation of endocardial SOX17 accompanied compensation in Apj mutants, which was also seen in Ccbe1 knockouts, indicating that the endocardium is activated in multiple cases where sinus venosus angiogenesis is stunted. Our data demonstrate that by diversifying their responsivity to growth cues, distinct coronary progenitor pools are able to compensate for each other during coronary development, thereby providing robustness to organ development. PMID- 28890076 TI - Convergence Insufficiency Symptom Survey scores for required reading versus leisure reading in school-age children. AB - PURPOSE: To compare Convergence Insufficiency Symptom Survey scores for required reading for school versus scores for leisure reading. METHODS: At a single private practice, we surveyed 100 children with normal binocular vision using modified survey questions specifying either required reading or leisure reading as the near visual activity. Average total symptom scores and subscores for questions about discomfort, fatigue, impaired vision, and cognitive performance were analyzed using t tests; responses to individual questions were analyzed using Mann-Whitney U tests. RESULTS: The average score for the required reading survey was significantly higher than for the leisure reading survey (14.4 +/- 9.1 vs 9.8 +/- 6.9 [P = 0.005]). Significantly higher symptom scores were recorded for 7 of 15 questions and 3 of 4 subscores (discomfort, fatigue, and impaired vision) for the required reading survey, whereas scores for the leisure reading survey highly correlated (R2 = 0.95) with each child's self-reported reading speed. CONCLUSIONS: Convergence Insufficiency Symptom Survey scores vary greatly depending on the type of near activity being surveyed and thus do not accurately isolate and reflect near visual ability. Beginning each survey with the question about self-rated reading speed could eliminate the need for additional questions if a child self-rates his or her reading speed as average or better. Because of the influence of the type of near visual activity on symptoms, survey questions should explicitly specify the near visual activity to prevent a child's interpretation of the question's intent from affecting the symptom score. PMID- 28890075 TI - Down-regulation of dorsal striatal alphaCaMKII causes striatum-related cognitive and synaptic disorders. AB - Alpha calcium/calmodulin dependent protein kinase II (alphaCaMKII) is a serine/threonine protein kinase which is expressed abundantly in dorsal striatum and is highly involved in the corticostriatal synaptic plasticity. Nevertheless, it currently remains unclear whether and how alphaCaMKII plays a in the striatum related neural disorders. To address the above issue, lentivirus-mediated short hairpin RNA (shRNA) was used to silence the expression of alphaCaMKII gene in the dorsal striatum of mice. As a consequence of down-regulation of dorsal striatal alphaCaMKII expression, we observed defective motor skill learning in accelerating rotarod and response learning in water cross maze. Furthermore, impaired corticostriatal basal transmission and long-term potentiation (LTP), which correlated with the deficits in dorsal striatum-related cognition, were also detected in the alphaCaMKII-shRNA mice. Consistent with the above results, alphaCaMKII-shRNA mice exhibited a remarkable decline in GluA1-Ser831 and GluA1 Ser845 phosphorylation levels of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR), and a decline in the expression levels of N-methyl-d-aspartic acid receptor (NMDAR) subunits NR1, NR2A and NR2B. Taken together, alphaCaMKII down-regulation caused dorsal striatum-related cognitive disorders by inhibiting corticostriatal synaptic plasticity, which resulted from dysfunction of AMPARs and NMDARs. Our findings demonstrate for the first time an important role of alphaCaMKII in striatum-related neural disorders and provide further evidence for the proposition that corticostriatal LTP underlies aspects of dorsal striatum-related cognition. PMID- 28890077 TI - Occlusion dose monitoring in amblyopia therapy: status, insights, and future directions. AB - Occlusion therapy remains the mainstay treatment of amblyopia, but its outcome is not assured or universally excellent. Many factors are known to influence treatment outcome, among which compliance is foremost. The occlusion dose monitor (ODM) removes one variable from the treatment equation, because it records the occlusion actually received by-rather than prescribed for-the child. Improvement observed can thus be quantitatively related to the patching received. This review summarizes the insights the ODM has provided to date particularly in elucidating the dose-response relationship. We are entering the era of personalized ophthalmology in which treatments will be tailored to the needs of the individual child and facilitated by the use of wearable monitors. PMID- 28890078 TI - Choroidal Thinning Associated With Hydroxychloroquine Retinopathy. AB - PURPOSE: To investigate choroidal thickness in patients using hydroxychloroquine (HCQ) and compare choroidal thickness between eyes with and without HCQ retinopathy. DESIGN: Retrospective case series. METHODS: Setting: Institutional. PATIENTS: We included 124 patients with systemic lupus erythematosus or rheumatoid arthritis who were treated with HCQ. The patients were divided into an HCQ retinopathy group and a control group, according to the presence or absence of HCQ retinopathy. OBSERVATION: Total choroidal thickness and choriocapillaris equivalent thickness were measured manually by 2 independent investigators using swept-source optical coherence tomography (SS-OCT; DRI-OCT, Topcon Inc, Tokyo, Japan). These measurements were made at the fovea and at nasal and temporal locations 0.5, 1.5, and 3 mm from the fovea. Medium-to-large vessel layer thickness was calculated accordingly. The thicknesses were compared between the HCQ retinopathy and control groups. We performed correlation analyses between choroidal thicknesses and details regarding HCQ use. MAIN OUTCOME MEASURES: Total choroidal thickness and choriocapillaris-equivalent thickness. RESULTS: Choroidal thicknesses were significantly decreased (P < .05) in the HCQ retinopathy group compared to the control group, except at the temporal choroid 1.5 mm from the fovea. Choriocapillaris-equivalent thicknesses were significantly different in all choroidal locations between the groups. In contrast, the medium-to-large vessel layer thickness was only significantly different at a few locations. The cumulative dose/body weight was significantly correlated with subfoveal choroidal and choriocapillaris-equivalent thicknesses (both P = .001). The association between presence of HCQ retinopathy and choroidal thicknesses was also statistically significant after adjusting for age, diagnosis for HCQ use, refractive errors, and duration of HCQ use (P = .001 and P = .003 for subfoveal choroidal and choriocapillaris-equivalent thickness, respectively). CONCLUSIONS: These results all suggest that HCQ retinopathy is associated with choroidal thinning, especially in the choriocapillaris. Our results may suggest choroidal involvement of HCQ toxicity. PMID- 28890079 TI - The Effect of Chronic Pulmonary Disease and Mechanical Ventilation on Corneal Donor Endothelial Cell Density and Transplant Suitability. AB - PURPOSE: To determine how chronic obstructive pulmonary disease (COPD) and mechanical ventilation time affect corneal donor endothelial cell density (ECD) and transplant suitability. DESIGN: Retrospective cohort study. METHODS: Setting: Institutional. STUDY POPULATION: Total of 39 679 cornea donor eyes from SightLife Eye Bank between 2012 and 2016. Demographics, death-to-preservation time, ECD, lens status, medical history, time on mechanical ventilation, and suitability for transplantation were included. MAIN OUTCOME MEASURES: ECD and transplant suitability. RESULTS: Mean ECD was 2733 cells/mm2. Mean age was 59 years. COPD affected 34.2% of donors. Mechanical ventilation was required in 35% of donors. Mean ventilation time was 1.3 days. After controlling for covariates, COPD was not found to be associated with poor transplant suitability (P = .22). Ventilation >7 days was associated with poor transplant suitability (P = .04). Donors with COPD and donors who were mechanically ventilated exhibited lower cell counts (P < .001, P < .01, respectively). Longer ventilation led to reduced endothelial cell density: ventilation time >7 days (-46.5 cells/mm2, P < .001) and >30 days (-101.4 cells/mm2, P = .02). Limitations of the study included the retrospective nature, dataset obtained from a single eye bank, and medical history documentation completed by eye bank technicians. CONCLUSIONS: A high proportion of cornea donors have respiratory disease prior to donation. Ventilation time >7 days affected transplant suitability but the presence of COPD did not. Donors with COPD and donors who were mechanically ventilated had reduced cell counts. Longer ventilation times lead to increased cell loss. The presence of respiratory disease may affect tissue oxygenation and endothelial cell health. PMID- 28890080 TI - Preoperative determination of artificial chordae length: Wishful thinking? PMID- 28890081 TI - Factors associated with postoperative atrial fibrillation and other adverse events after cardiac surgery. AB - OBJECTIVE: The study objective was to evaluate the impact of various surgical characteristics and practices on the risk of postoperative atrial fibrillation and other adverse outcomes after cardiac surgery. METHODS: By using the prospectively collected data of patients who underwent cardiac surgery in 28 centers across the United States, Italy, and Argentina, the details of surgery characteristics were collected for each patient and the outcomes, including postoperative atrial fibrillation, major adverse cardiovascular events, and mortality. These were evaluated via multivariable-adjusted models. RESULTS: In 1462 patients, a total of 460 cases of postoperative atrial fibrillation, 33 major adverse cardiovascular events, 23 cases of 30-day mortality, and 46 cases of 1-year mortality occurred. We found that type of surgery and cardiopulmonary bypass use predicted the occurrence of postoperative atrial fibrillation. Compared with coronary artery bypass grafting alone, there was a higher risk of postoperative atrial fibrillation with valvular surgery alone (odds ratio, 1.4; 95% confidence interval, 1.1-1.9), and the risk was even higher with concomitant valvular and coronary artery bypass grafting surgery (odds ratio, 1.8; 95% confidence interval, 1.2-2.7). Compared with no bypass, use of cardiopulmonary bypass was associated with higher risk of postoperative atrial fibrillation (odds ratio, 2.4; 95% confidence interval, 1.7-3.5), but there were significant age and sex differences of the impact of bypass use among patients undergoing coronary artery bypass grafting (P for interaction = .04). In addition, compared with spontaneous return of rhythm, ventricular pacing was associated with a higher risk of major adverse cardiovascular events (odds ratio, 5.0; 95% confidence interval, 1.4-18), whereas concomitant coronary artery bypass grafting and valvular surgery was associated with a higher risk of 30-day mortality (hazard ratio, 4.3; 95% confidence interval, 1.2-14) compared with coronary artery bypass grafting alone. Occurrence of postoperative atrial fibrillation was associated with greater length of stay and 1-year mortality (hazard ratio, 2.2; 95% confidence interval, 1.2-3.9). CONCLUSIONS: In this multicenter trial, we identified specific adverse outcomes that are associated with concomitant valvular and coronary artery bypass graft surgery, cardiopulmonary bypass, ventricular pacing, and occurrence of postoperative atrial fibrillation. PMID- 28890082 TI - Catheter palliation or early surgery for tetralogy of Fallot: Options when timing is less than ideal. PMID- 28890083 TI - Surgical technique for placement of the Melody valve in a dilated right ventricular outflow tract. PMID- 28890084 TI - Contingent engagement: What we learn from patients with complex health problems and low socioeconomic status. AB - OBJECTIVE: Elicit patients' perceptions of factors that facilitate their engagement in care METHODS: In-depth interviews with 20 adult Medicaid patients who had complex health problems, frequent hospitalizations/emergency department use, and who were enrolled in an intensive, team-based care program designed to address medical, behavioral, and social needs. RESULTS: Prior to engaging in the program, participants described weak relationships with primary care providers, frequent hospitalizations and emergency visits, poor adherence to medications and severe social barriers to care. After participating in the program, participants identified key factors that enabled them to develop trust and engage with care including: availability for extended intensive interactions, a non-judgmental approach, addressing patients' material needs, and providing social contact for isolated patients. After developing relationships with their care team, participants described changes such as sustained interactions with their primary care team and incremental improvements in health behaviors. CONCLUSION: These findings illuminate factors promoting "contingent engagement" for low socio economic status patients with complex health problems, which allow them to become proactive in ways commensurate with their circumstances, and offers insights for designing interventions to improve patient outcomes. PRACTICE IMPLICATIONS: For these patients, engagement is contingent on healthcare providers' efforts to develop trust and address patients' material needs. PMID- 28890085 TI - In Situ Architecture and Cellular Interactions of PolyQ Inclusions. AB - Expression of many disease-related aggregation-prone proteins results in cytotoxicity and the formation of large intracellular inclusion bodies. To gain insight into the role of inclusions in pathology and the in situ structure of protein aggregates inside cells, we employ advanced cryo-electron tomography methods to analyze the structure of inclusions formed by polyglutamine (polyQ) expanded huntingtin exon 1 within their intact cellular context. In primary mouse neurons and immortalized human cells, polyQ inclusions consist of amyloid-like fibrils that interact with cellular endomembranes, particularly of the endoplasmic reticulum (ER). Interactions with these fibrils lead to membrane deformation, the local impairment of ER organization, and profound alterations in ER membrane dynamics at the inclusion periphery. These results suggest that aberrant interactions between fibrils and endomembranes contribute to the deleterious cellular effects of protein aggregation. VIDEO ABSTRACT. PMID- 28890087 TI - [Therapeutic innovations in radiation oncology for localized prostate cancer]. AB - Intensity-modulated radiation therapy, image-guided radiation therapy with fiducial markers and prostate brachytherapy allow the delivery of dose escalation for localized prostate cancer with very low rates of long-term toxicity and sequelae. Nowadays, modern radiotherapy techniques make it possible to shorten treatment time with hypofractionation, to better protect surrounding healthy tissues and to escalate the dose even further. Advances in radiotherapy are closely linked to advances in magnetic resonance imaging (MRI) and/or PET imaging. Functional imaging makes it possible to deliver personalised pelvic nodal radiotherapy, targeting the nodal areas at higher risk of microscopic involvement. In patients with an index lesion at baseline or at failure, MR-based focal therapy or focal dose escalation with brachytherapy or stereotactic body radiation therapy is also currently investigated. MR-based adaptive radiotherapy, which makes it possible to track prostate shifts during radiation delivery, is another step forward in the integration of MR imaging in radiation delivery. PMID- 28890088 TI - Management of local relapse after prostate cancer radiotherapy: Surgery or radiotherapy? AB - Isolated local relapse after prostate cancer radiotherapy corresponds to 40% of biochemical failure. The management of these relapses is not well defined. Several strategies are available including surgery, high-intensity focused ultrasounds (HIFU), cryotherapy and reirradiation. Radical prostatectomy is the historical approach; biochemical control is obtained in 50 to 80% at 5 year. However, morbidity is higher after irradiation than as a first line treatment. Some limited series of HIFU and cryotherapy have been published with interesting results, but again the risk of urinary and rectal toxicity is high. However, new generation technologies could decrease the complication rate. Reirradiation could be performed with brachytherapy and more recently with stereotactic radiation therapy. The results of salvage low-dose-rate brachytherapy have been reported in some series with a 5-year biochemical control rate of 34 to 88%. High-dose rate brachytherapy seems to be better tolerated, but the number of patients treated and reported is too low to draw firm conclusions. This is the same for stereotactic radiation therapy salvage treatment. A prospective trial of salvage brachytherapy (CAPRICUR) is now open in France and inclusion in this trial is recommended. PMID- 28890089 TI - [Tumour sequencing: Evolutions and revolutions]. AB - For some years now, we have entered the genomic age of tumour genotyping from a medical point of view. Technological breakthroughs in both biology and information science now allow a genomic analysis of cancers in everyday medical practice with, in some case, a major impact on patient care not only for the choice of therapy (i.e. EGFR mutations in lung adenocarcinoma), but also for diagnosis and monitoring of the disease. Tumour genotyping is performed from formalin-fixed paraffin-embedded tissues used for diagnosis of cancer. However, new approaches have emerged, with for example the more and more spread use of "liquid biopsies". Genotyping of a gene panel implicated in carcinogenesis is now routinely performed in some cancer types, with the help of high-throughput sequencers, and it is likely that improvement of these machines will make tumour genotyping easier and more accessible in the near future. Nevertheless, the current challenge is not anymore detection of molecular alterations, but their relevant interpretation, so as to be the most useful in patient care. PMID- 28890086 TI - Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. AB - Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Ralpha and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior. PMID- 28890090 TI - [From quality management to dynamic management through quality: Deployment within a radiotherapy group]. AB - In 2015, the quality group of the radiotherapy clinic Groupement de Radiotherapie et d'Oncologie des Pyrenees (GROP, Pau, France) decided to review the deployment of its quality approach in order to optimize it continuously. For this, two improvements were proposed: an involvement of process drivers and a material and financial investment in document management software. The implementation of these organizational and managerial provisions enabled us to better cover the requirements of the ISO 9001 standard, the international reference in quality management. PMID- 28890091 TI - [What does the medical physicist expect from the radiation oncologist and vice versa?] AB - The cooperation between radiation oncologist and medical physicist is essential to guarantee the quality and safety of the irradiation of our patients. It would be wrong to consider that the intervention of medical physicists in the patient management process is limited to the provision of calibrated and controlled equipment and to guarantee the validity of the dose distribution and the treatment time, while the radiation oncologist has the complete control of all clinical activities related to irradiation. The intervention of physicists at the stage of acquisition of anatomical data and throughout the phase of optimization of the treatment is already a reality. The recognition of the profession of medical physicist as a health profession comes to legitimize this intervention. Should physician-physicist cooperation be limited to these common tasks and participation in continuing care? Can we envisage a true synergy of action that goes beyond the field of care? The answer to the question: what does the physicist expect from the radiation oncologist and vice versa may bring elements to reinforce tomorrow's cooperation. This article is the second part of the question. PMID- 28890092 TI - [Clinical research for rectal carcinoma: State of the art and objectives]. AB - The treatment of rectal carcinoma is based on multidisciplinary strategy and multimodal approaches including gastrointestinal tract specialists, medical oncologists, radiation oncologists and surgery. The different objectives should be declined according to the characteristics of the tumours. The aim of the therapist would be to select the best strategy offering to the patient to be cured with as less as possible late adverse toxicity. The challenge of the treatment of small tumours is to maintain a functional anal sphincter while minimizing the risk of local recurrence. The standard treatment of locally advanced disease is aiming firstly to cure the patient and secondly to prevent late complications. Each of these clinical presentations of the disease has to be considered as a whole taking into account the new surgical techniques and a personalized approach adapted to the tumour. Nowadays they should be studied with dedicated clinical trials. PMID- 28890094 TI - ? PMID- 28890093 TI - Mechanistic and Fc requirements for inhibition of Sudan virus entry and in vivo protection by a synthetic antibody. AB - The Sudan virus (SUDV), an ebolavirus, causes severe hemorrhagic fever with human case fatality rates of ~50%. Previous work from our lab demonstrated the synthetic antibody F4 potently inhibits viral entry and protects against lethal virus challenge in mice [Chen et al., ACS Chem. Biol., 2014, 9, 2263-2273]. Here, we explore mechanistic requirements as well as contribution of the Fc region and function on neutralization and in vivo protection. Live cell imaging demonstrates that the antibody colocalizes with vesicular stomatitis virus particles containing the Sudan virus glycoprotein (VSV-GPSUDV) and that the antibody is rapidly degraded within cellular endosomes. A viral escape mutant contained substitutions on the N-heptad repeat (NHR) segment of GP2, the fusion subunit. Truncation studies indicated that the size of the Fc impacts virus neutralization potential. Finally, we examined the protective efficacy of Fc-null mutants in mice, and found that Fc function was not required for high levels of protection. Altogether, these results indicate that neutralization of SUDV GP-mediated cell entry likely involves blockade of viral membrane fusion within endosomes, and that inhibition of viral entry is the likely mechanism of in vivo protection. PMID- 28890095 TI - ? PMID- 28890097 TI - [Growing up as a migrant, rites of passage in the Maghreb]. AB - In a context of migration, some parents experience difficulties in passing on their culture and their knowledge, which makes it difficult to achieve reciprocal recognition and to establish a feeling of filiation and heritage. In this context, maintaining the rites of passage enables their symbolic effectiveness and creativity to be maintained. Circumcision, in particular, is a key stage of this process in the Maghreb. PMID- 28890096 TI - [The choice of a child's first name in West Africa]. AB - Choosing a name is a powerful act, filled with meaning. In most societies, this act is accompanied by specific rites and rituals. By naming a child, we are acknowledging their existence. A transmission is thereby created between the person giving the name and the person who will bear it. The naming of children in West Africa, particularly among the Soninke people, constitutes an example of the elements which come into play when a child is given a name. PMID- 28890098 TI - [Rituals of birth in Senegal]. AB - In a Senegalese society undergoing profound change, holding on to certain beliefs and social and cultural practices can sometimes prove difficult. Prevention and care systems must take into account social and cultural representations in order to support these families as best as possible. PMID- 28890099 TI - [Mothering practices and protection of babies in Vietnam]. AB - In Vietnam, newborn babies are believed to carry within them vital principles originating from their ancestors. It is essential to protect the babies and ensure their development is harmonious, by building around them successive 'envelopes' - the mother, the family, family friends, then the village and finally the rest of the world. These protective rituals still partly exist in families of Vietnamese origin living in the West. PMID- 28890100 TI - [Postnatal depression and relationship with the cultural world in Tunisia]. AB - Culture and the human spirit gain structure through their interactions with the cultural system. Indeed, individuals come from a culture which is unique to them and leaves its mark on them. In Tunisian concept, the young mother suffering from postnatal depression is considered to be possessed by the djinn spirit Kattous in nfas and treated using traditional rituals. It is important to take into account these aspects in the clinical psychopathology. PMID- 28890101 TI - [Mother tongue and protection of children, the role of school]. AB - The question of mother tongues in the socio-educational context of school was the subject of a memorandum of 2016. Moreover, research in psychology and linguistics shows the extent to which the family language and culture are important elements in the construction of the child. These must be taken into account at school as well as in any support and care environment. PMID- 28890102 TI - [Anorexia in prepubescent adolescents]. AB - Anorexia in young prepubescent patients is often linked to clinical signs occurring in early childhood. While therapies offer somatic, dietetic or medication-based treatments, the psychotherapeutic approach gives children and their families the opportunity to talk. PMID- 28890103 TI - [Minors and treatment orders]. AB - In France, minors over the age of 13 can be given a common law sentence but their status as a minor is taken into account, reducing the maximum sentence by half. They can however be subjected to a treatment order, a measure applicable in the context of social and legal supervision, which aims to prevent repeat offending. PMID- 28890104 TI - [Suturing a child's wound, humanising care in the emergency department]. AB - The humanisation of the care pathway constitutes an objective for all caregivers. A visit to the emergency department by a child requiring a suture is a simple and frequent situation which highlights the different stages of the care. Several of these stages can be anticipated in the waiting room, in particular the exchanging of information with the patient and the family, which helps to improve the parent child-professional relationship. PMID- 28890105 TI - ? PMID- 28890106 TI - Development of a peptide-modified siRNA nanocomplex for hepatic stellate cells. AB - Insulin-like growth factor 2 receptor (IGF2R) is overexpressed in activated hepatic stellate cells (HSCs) and therefore can be utilized for HSC-specific drug delivery. We recently discovered an IGF2R-specific peptide using a novel biopanning. Here, we adopted biotin-conjugated IGF2R-specific peptide, cholesterol, and vitamin A as the targeting ligands for the neutravidin-based siRNA nanocomplex to deliver PCBP2 siRNA, a potentially antifibrotic agent, to HSCs. Compared to vitamin A and cholesterol, the IGF2R-specific peptide exhibited the highest targeting effect to human LX-2 HSC, rat HSC-T6 cell line, and activated primary rat HSCs. Accordingly, the IGF2R-specific peptide coupled nanocomplex demonstrated higher silencing activity of PCBP2 and better inhibition on the migration of activated HSCs. Compared to free siRNA and the nanocomplexes coupled with vitamin A and cholesterol, the IGF2R-specific peptide coupled nanocomplex showed the highest uptake in the liver and lowest uptake in the lung and kidney of the rats with CCl4-induced liver fibrosis. PMID- 28890107 TI - Real-time imaging of VCAM-1 mRNA in TNF-alpha activated retinal microvascular endothelial cells using antisense hairpin-DNA functionalized gold nanoparticles. AB - Vascular cell adhesion molecule 1 (VCAM-1) is an important inflammatory biomarker correlating with retinal disease progression. Thus, detection of VCAM-1 mRNA expression levels at an early disease stage could be an important predictive biomarker to assess the risk of disease progression and monitoring treatment response. We have developed VCAM-1 targeted antisense hairpin DNA-functionalized gold nanoparticles (AS-VCAM-1 hAuNP) for the real time detection of VCAM-1 mRNA expression levels in retinal endothelial cells. The AS-VCAM-1 hAuNP fluorescence enhancement clearly visualized the TNF-alpha induced cellular VCAM-1 mRNA levels with high signal to noise ratios compared to normal serum treated cells. The scrambled hAuNP probes were minimally detectable under same image acquisition conditions. Intracellular hAuNPs were detected using transmission electron microscopy (TEM) analysis of the intact cells. In addition, the AS-VCAM-1 hAuNP probes exhibited no acute toxicity to the retinal microvascular endothelial cells as measured by live-dead assay. PMID- 28890108 TI - Polymer hydration and stiffness at biointerfaces and related cellular processes. AB - The direct and indirect (by changing mechanical properties) effects of hydration at interfaces on cellular processes and tissue diseases are reviewed. The essential effect of substrate stiffness on cellular processes was demonstrated in the last decade. The combined effect of surface stiffness and hydration at interfaces has garnered much less attention, though hydration and dehydration play important roles in biological processes. This review focuses on the studies that demonstrate how hydration affects biological processes at interfaces. Elevated sodium and dehydration stimulate inflammatory signaling in endothelial cells and promote atherosclerosis. Various types of implant and blood contacting device coatings with varied surface stiffness and hydration have been reported. Effect of hydration on polymer modulus of elasticity and viscoelasticity was discussed taking into account cells adhesion, migration, proliferation, differentiation on surfaces with various degree of hydration. Future directions of research were considered, including the use of nanotechnology to regulate the hydration degree. PMID- 28890109 TI - NIR light-induced tumor phototherapy using photo-stable ICG delivery system based on inorganic hybrid. AB - NIR responsive inorganic hybrid (Ti@GO) was synthesized. It could absorb NIR light and convert it into local hyperthermia and ROS synchronously. Ti@GO was firstly developed as a photosensitizer and a photothermal agent to realize tumor PTT and PDT. For anti-tumor application, HA was grafted on Ti@GO simultaneously as water solubility improver and tumor targeting moiety. ICG was chosen as a model drug. Results demonstrated that HA-Ti@GO could remarkably improve ICG stability and drug accumulation in 4T1 cells, enhance tumor phototherapy efficiency and reduce light-associated side effects. HA-Ti@GO/ICG under NIR laser irradiation showed a significant decreased cell viability of 20.7+/-2.6% and a high DNA damage degree of 82.4+/-8.3%. Moreover, in vivo results showed that HA Ti@GO/ICG plus NIR laser achieved almost complete tumor regression on 4T1 tumor bearing mice, with a tumor volume of 67.0 mm3. Taken together, our study provided a promising strategy to realize synergistic PTT/PDT tumor therapy with a single NIR light. PMID- 28890110 TI - Methyl aspartylphenylalanine, the pons and cerebellum in mice: An evaluation of motor, morphological, biochemical, immunohistochemical and apoptotic effects. AB - In this study, adult mice were assigned to five groups, and administered vehicle (distilled water), or aspartame (20, 40, 80 and 160mg/kg body weight) for 28days. Behavioural tests to assess motor-balance and gait were conducted on day 28, following which animals were sacrificed. Sections of the cerebellar cortex and pons were processed, for general histology and Bielschwosky's silver staining protocol. Glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) immunoreactivity were assessed. Antioxidant status and aspartic acid/cysteine-aspartic acid protease (caspase)-3 levels were also assessed using homogenates of the cerebellum and pons. Body weight-gain decreased significantly following aspartame consumption; while no significant changes in gait and balance were observed. Histological changes suggestive of neuronal injury were observed at 80 and 160mg/kg/day; however, no obvious neuritic plaques were seen. GFAP reactive astrocytes and NSE-reactive neurons increased at 20, 40 and 80mg/kg, but decreased at 160mg/kg. There was derangement of oxidative status and increased caspase-3 concentration with increasing doses of aspartame; although no significant difference in aspartate level was observed. The study concluded that repeated oral administration of the higher doses of aspartame was associated with morphological alterations suggestive of neuronal injury, and derangement of antioxidant status. PMID- 28890111 TI - Tick-borne pathogens and their reservoir hosts in northern Italy. AB - The aim of this study was to determine the occurrence of Anaplasma phagocytophilum, Rickettsia spp., Babesia spp., and Candidatus Neoehrlichia mikurensis in Ixodes spp. ticks removed from wildlife, domestic animals and humans in the Province of Trento (northern Italy) in order to better understand their ecology and provide public health professionals with an updated list of pathogens which should be considered during their diagnostic procedures after a tick bite. During 2011-2012, 848 feeding ticks at all life stages (adults, nymphs and larvae) from various hosts (wild ungulates, birds and rodents; domestic sheep, dogs and humans) were collected. The highest prevalences of A. phagocytophilum and Rickettsia spp. were detected in adult and nymphal tick stages feeding on wild ungulates (11.4% prevalence for both pathogens), while the Babesia spp. prevailed in nymphal and larval ticks feeding on wild birds (7.7%). A wide spectrum of tick-borne agents was present in larval ticks: those detached from wild ungulates were positive for A. phagocytophilum, B. venatorum, R. helvetica, R. monacensis and R. raoultii, while those removed from wild rodents were positive for B. venatorum, R. helvetica, R. monacensis and Ca. N. mikurensis, and ticks from wild birds carried A. phagocytophilum, B. venatorum, B. capreoli and R. helvetica. This study provides evidence of circulation of five tick-borne pathogens not reported in this region before, specifically R. raoultii, R. monacensis, B. venatorum, B. capreoli and B. microti. Furthermore, it discusses the epidemiological role of the animal species from which the ticks were collected highlighting the needs for more experimental studies especially for those pathogens where transovarial transmission in ticks has been demonstrated. PMID- 28890113 TI - Relationship between swallowing function and breathing/phonation. AB - OBJECTIVE: Clarification of the association between the swallowing function and respiratory and phonatory functions. METHODS: The subjects were 30 patients with a chief complaint of swallowing disorder with clear consciousness capable of retaining a sitting position. Patients with organic and functional diseases of the larynx were excluded. Twenty-two and eight patients were male and female, respectively, and the mean age was 77.0+/-14.6years old. The chest expansion score was measured as an index of the respiratory function, and the maximum phonation time (MPT) was measured as an index of the phonatory function. The presence or absence of aspiration was judged using videoendoscopic swallowing study (VESS) and videofluoroscopic swallow studies (VFSS). The patients were divided into those with and without aspiration, and the chest expansion score and MPT were compared. In addition, the distance of laryngeal elevation was measured in the lateral view of VFSS, and its correlations with the chest expansion score and MPT were closely analyzed. To evaluate reliability of the test, the distance of laryngeal elevation and videoendoscopic score were compared between the presence and absence of aspiration. RESULTS: The distance of laryngeal elevation was significantly shortened and the videoendoscopic score was significantly higher in the group with aspiration, as previously reported. On comparison of the chest expansion score between the groups with and without aspiration, no significant difference was noted at the axillary or xiphoid process level, and shortening was significant only at the 10th rib level in the group with aspiration. On comparison of MPT, it was significantly shortened in the group with aspiration. In addition, a significant positive correlation with the distance of laryngeal elevation was noted in both chest expansion score and MPT. CONCLUSION: It was suggested that declines of the respiratory and phonatory functions are risk factors of aspiration through limiting laryngeal elevation, and the chest expansion score at the 10th rib level and MPT are useful for screening of aspiration. PMID- 28890114 TI - Natural course of tonsillectomy pain: A prospective patient cohort study. AB - OBJECTIVE: The aim of this study was to determine the natural course of pain after tonsillectomy. METHODS: This study included 119 patients that underwent tonsillectomy between November 2013 and November 2015. After undergoing tonsillectomy, patients scored their pain using the visual analogue scale three times daily (morning, midday, and evening) for 2 weeks. A linear mixed model was used for statistical analyses. RESULTS: Increasing postoperative days was negatively associated with pain following tonsillectomy surgery (estimated value [EV] of visual analogue score [VAS]/day=-0.42, 95% confidence interval [CI]=-0.43 to -0.41, P<0.001); the post-tonsillectomy pain curve illustrated this negative correlation. Postoperative pain was less in children and adolescents (<=18years old) than in adults (>18 years old) (EV=-0.81, 95% CI=-1.56 to -0.08, P=0.031). Mean tonsillectomy-associated pain on postoperative day 1 was 6.4 VAS. It decreased slightly to 5.3 VAS until postoperative day 7, after which it reduced sharply to 3.7 VAS within 3 days; on postoperative day 14 it had decreased to 1.6 VAS. Pain assessments were higher in the morning (EV=0.59, 95% CI=0.50 to 0.69, P<0.001) compared with assessments conducted in the evening. CONCLUSION: The natural course of postoperative tonsillectomy pain follows a gradual decline for 1 week after surgery, but decreases more rapidly after this period. PMID- 28890115 TI - RIFM fragrance ingredient safety assessment, benzenepropanol, a,beta-dimethyl-, CAS Registry Number 56836-93-2. PMID- 28890116 TI - Dermatologic Conditions and Risk of Suicide: A Case-Control Study. AB - BACKGROUND: Patients diagnosed with skin conditions have a higher risk of comorbid psychiatric conditions and suicide-related outcomes such as suicidal ideations and behaviors. There is paucity of evidence in the US general population about the risk of suicide death in patients with dermatologic conditions. METHODS: We conducted a retrospective case-control study to investigate the risk of suicide death in patients receiving care for dermatologic conditions. This study involved 8 US health systems. A total of 2674 individuals who died by suicide (cases) were matched with 267,400 general population control individuals. RESULTS: After adjusting for age, sex, and any mental health or substance use condition, we did not find an association between death by suicide and any skin condition including conditions where clinicians are generally concerned about the risk such as acne (adjusted odds ratio [aOR] = 1.04, p = 0.814), atopic dermatitis (aOR = 0.77, p = 0.28), and psoriasis (aOR = 0.91, p = 0.64). CONCLUSION: This case-control study provides no evidence of increased risk of death by suicide in individuals with major skin disorders in the US general population. PMID- 28890117 TI - Potential for peritoneal cancer cell seeding in endoscopic full-thickness resection for early gastric cancer. AB - BACKGROUND AND AIMS: During endoscopic full-thickness resection (EFTR) for cancers, whether exposure of the lumen to the abdominal cavity during the procedure is acceptable is controversial because of the potential risk of tumor cell seeding. To assess the possibility of transplantation as a result of contact with tumor cells during the procedure, we prospectively investigated the ability of cancer cells to be detached by touching the tumor surface. METHODS: In 48 patients with a single early gastric cancer resected by endoscopic submucosal dissection, stamp cytology was performed by touching the surface of the specimens to glass slides. Samples were obtained from cancerous and noncancerous areas, constituting the study and control groups, respectively. The detection rate of malignant class IV or V (C-IV/C-V) samples was investigated with Papanicolaou staining. The rate of CD44v9-positive cases, a cancer stem cell marker, was assessed in C-IV/C-V samples with immunohistochemical staining. RESULTS: Detection rates of C-IV/C-V samples in the cancerous group (53/192 slides, 27.6%) differed significantly from those of the C-IV/C-V samples in the noncancerous group (0/96 slides, 0%). Among the 53 slides of C-IV/C-V samples in the cancerous group, CD44v9 cells were expressed in 18 slides (34.0%). CONCLUSIONS: These data suggest that cancer cells, including cancer stem cells, in early gastric cancers are easily detached via contact with the tumor surface. In EFTR, a nonexposure approach is recommended to avoid the risk of iatrogenic cancer cell seeding via contact with and transplantation of cancer cells. PMID- 28890118 TI - Mitochondrial DNA content: A new biomarker for sudden intrauterine unexplained death syndrome (SIUDS). AB - In literature there are no data related to mitochondrial DNA (mtDNA) content in sudden intrauterine unexplained death syndrome (SIUDS). To test the hypothesis that a quantitative excess of mtDNA could play a role in the pathogenesis of SIUDS, mtDNA content was measured in cerebral cortex of 9 SIUDS and in 7 controls. The median (interquartile range) mtDNA in SIUDS and controls was 14,000 (8600-33,500), 3400 (0-8500) copies per nuclear DNA, respectively (p=0.007). If mitochondria are involved in SIUDS, then higher mitochondrial DNA content may be a biomarker of this syndrome. PMID- 28890119 TI - Do we perform surgical programming well? How can we improve it? AB - : The objective is to establish the duration of our interventions, intermediate times and surgical performance. This will create a virtual waiting list to apply a mathematical programme that performs programming with maximum performance. MATERIAL AND METHODS: Retrospective review of 49 surgical sessions obtaining the delay in start time, intermediate time and surgical performance. Retrospective review of 4,045 interventions performed in the last 3 years to obtain the average duration of each type of surgery. Creation of a virtual waiting list of 700 patients in order to perform virtual programming through the MIQCP-P until achieving optimal performance. RESULTS: Our surgical performance with manual programming was 75.9%, ending 22.4% later than 3pm. The performance in the days without suspensions was 78.4%. The delay at start time was 9.7min. The optimum performance was 77.5% with a confidence of finishing before 15h of 80.6%. The waiting list has been scheduled in 254 sessions. DISCUSSION: Our manual surgical performance without suspensions (78.4%) was superior to the optimal (77.5%), generating days finished later than 3pm and suspensions. The possibilities for improvement are to achieve punctuality at the start time and adjust the schedule to the ideal performance. The virtual programming has allowed us to obtain our ideal performance and to establish the number of operating rooms necessary to solve the waiting list created. CONCLUSIONS: The data obtained in virtual mathematical programming are reliable enough to implement this model with guarantees. PMID- 28890120 TI - Fascia iliaca block for pain control in hip fracture patients. AB - INTRODUCTION: Pain treatment for patients with hip fracture has been based on the use of nonsteroidal anti-inflammatories and opioid derived drugs. These medications have been associated with multiple adverse effects. Fascia iliaca block is a recent pain management alternative for these patients. The objective of this study was to evaluate the effectiveness of fascia iliaca block performed in the emergency room (ER) for patients over 65years of age with hip fracture. MATERIALS AND METHODS: A cohort of 216 patients, from January to December 2016, was studied prospectively. Analyzed variables were: pain upon arrival at ER, pain after fascia iliaca block, need for rescue medication, protocol compliance, delay in analgesia administration and delay for surgery. RESULTS: Differences between visual analogue scale (VAS), before and after the fascia iliaca block, were statistically significant (P<.001). Pre-block VAS recorded was 6.16 (SD=2.82). The mean VAS reduction after the block was 2.99 (95%CI: 2.45-3.53%). Twenty-six percent of patients required morphine as rescue medication in the first 8hours after diagnosis. Compliance with protocol administration was of 84%. Fascia iliaca block was performed in a mean time of 16minutes (SD=10.33) after diagnosis. The median delay for surgery was 1 day (RIQ 25-75%: 1-2). CONCLUSION: Fascia iliaca block is a reproducible, safe and effective technique for pain management. It is a keystone in pain treatment for patients with a proximal femur fracture at our institution. Other objectives in our pain management protocol include early analgesia administration and reduction of time to surgery. PMID- 28890121 TI - Surgical treatment of extra-articular distal-third diaphyseal fractures of the humerus using a modified posterior approach and an extra-articular plate. AB - PURPOSE: To evaluate the clinical and radiological outcomes of these fractures treated through a modified posterior approach with a distal humerus plate. MATERIAL AND METHODS: Between 2013 and 2015 we performed a retrospective study of these fractures surgically treated in our centre. INCLUSION CRITERIA: older than 18 years old, no pathological fractures, follow up 1 year at least. 23 patients underwent surgery, mean age 45 years old, with an average follow-up of 18 months. Patient characteristics, aetiology and type of fractures were recorded. The surgery was performed using Gerwin modified posterior approach with a posterolateral distal humerus plate. Clinical results were evaluated using Quick DASH, MEPS, VAS. Radiological results were also evaluated. Complications associated with treatment and radial nerve palsy incidence were recorded as well. RESULTS: Type of fracture according AO/OTA: six 12-A, seven 12-B, ten 12-C. 23 patients progressed to union. After one year: QD 6.43, VAS 0.66, MEPS 88.88. No failure of internal fixation. Two superficial infections. 15 excellent results, 5 good, and 3 fair, with no poor results. CONCLUSION: Surgical fixation of these fractures through a modified posterior approach with a posterolateral plate minimises iatrogenic nerve injury, provides better visualisation of the proximal humerus, provides stable fixation of these injuries and results in high union rates and overall excellent functional results. PMID- 28890122 TI - Lumbar segmental artery pseudoaneurysm after L5 pedicle screw placement. A rare vascular complication. AB - Posterior lumbar screw fixation is a common surgical procedure nowadays. However, it can sometimes produce complications that can be devastating. One of the less common causes of major complication is the misplacement of a pedicle screw. This highlights the importance of being methodical when placing pedicle screws, and checking that the pathway has been created correctly and their placement. We present a case of a massive bleed after a pedicular screw placement during lumbar canal stenosis surgery. Screw malposition led to intraoperative haemodynamic instability after failed attempts to control bleeding in the surgical site. Contrast enhanced CT imaging revealed a lumbar intersegmentary artery injury that was eventually controlled by means of a coil embolisation. PMID- 28890123 TI - Isolated scaphotrapeziotrapezoid osteoarthritis treatment using resurfacing arthroplasty with scaphoid anchorage. AB - OBJECTIVE: The aim of this study is to show the results of scaphotrapeziotrapezoid (STT) joint osteoarthritis treatment performing resurfacing arthroplasty with scaphoid anchorage. MATERIAL AND METHOD: An observational, descriptive and retrospective study was performed. Ten patients with isolated STT joint osteoarthritis were studied between 2013 and 2015. The mean follow-up time was 26months. Clinical results, functional and subjective scores were reviewed. RESULTS: The patients were satisfied, achieving an average of 2.1 (0-3) on the VAS score and 16 (2 to 28) in the DASH questionnaire, and returning to work in the first three months post-surgery. Recovery of range of motion compared to the contralateral wrist was 96% in extension, 95% in flexion, 87% in ulnar deviation and 91% in radial deviation. The average handgrip strength of the wrist was 95% and pinch strength was 95% compared to the contralateral side. There were no intraoperative complications or alterations in postoperative carpal alignment. CONCLUSION: Resurfacing arthroplasty is proposed as a good and novel alternative in treating isolated SST joint arthritis. Achieving the correct balance between the strength and mobility of the wrist, without causing carpal destabilisation, is important to obtain satisfactory clinical and functional results. PMID- 28890124 TI - [Sentinel lymph node biopsy and neoadjuvant treatment in breast cancer]. AB - Sentinel lymph node biopsy has replaced axillary lymph node dissection in those patients with clinically node-negative axilla without compromising their oncologic outcomes. Indication of neoadjuvant chemotherapy has been extended to patients to evaluate the pathologic response and to offer more conservative breast surgery. Sentinel lymph node dissection after neoadjuvant chemotherapy is feasible and accurate in patients with clinically node-negative patients. The timing of the sentinel lymph node biopsy, before or after medical treatment has been studied with benefits for each procedure. Sentinel lymph node dissection has been explored in different randomized prospective studies in clinically positive axilla with the aim of reduce axillary lymph node dissection. However, several studies are necessary to more accurately identify residual axillary disease and the sentinel lymph node after neoadjuvant chemotherapy, to adjust the adjuvant radiotherapy protocols and to evaluate the impact on oncologic outcomes. PMID- 28890125 TI - Cryptic Female Choice: A General Phenomenon. A Reply to Eberhard. PMID- 28890126 TI - The Nebulous Ecology of Native Invasions. AB - In the Anthropocene, alien species are no longer the only category of biological organism establishing and rapidly spreading beyond historical boundaries. We review evidence showing that invasions by native species are a global phenomenon and present case studies from Southern Africa, and elsewhere, that reveal how climate-mediated expansions of native plants into adjacent communities can emulate the functional and structural changes associated with invasions by alien plant species. We conclude that integrating native invasions into ecological practice and theory will improve mechanistic models and better inform policy and adaptive ecological management in the 21st century. PMID- 28890127 TI - Is Reintroduction Biology an Effective Applied Science? AB - Reintroduction biology is a field of scientific research that aims to inform translocations of endangered species. We review two decades of published literature to evaluate whether reintroduction science is evolving in its decision support role, as called for by advocates of evidence-based conservation. Reintroduction research increasingly addresses a priori hypotheses, but remains largely focused on short-term population establishment. Similarly, studies that directly assist decisions by explicitly comparing alternative management actions remain a minority. A small set of case studies demonstrate full integration of research in the reintroduction decision process. We encourage the use of tools that embed research in decision-making, particularly the explicit consideration of multiple management alternatives because this is the crux of any management decisions. PMID- 28890128 TI - Characteristics and Health Care Preferences Associated with Cardiovascular Disease Risk among Women Veterans. AB - BACKGROUND: Women veterans are at increased risk for cardiovascular disease (CVD), but little is known about comorbidities and healthcare preferences associated with CVD risk in this population. METHODS: We describe the prevalence of CVD-relevant health behaviors, mental health symptoms, and health care use characteristics and preferences among participants of the National Survey of Women Veterans (conducted 2008-2009). FINDINGS: Fifty-four percent of respondents were at risk for CVD (defined as a diagnosis of hypertension, diabetes, current tobacco use, or obesity without CVD). In unadjusted analysis, ORs for being at risk for CVD were greater among those interested in gender-specific clinical settings (OR, 2.0; 95% CI, 1.2-3.4) and gender-specific weight loss programs (OR, 1.8; 95% CI, 1.1-2.9). ORs were also greater for women who were physically inactive (OR, 1.9; 95% CI, 1.1-3.3), with current symptoms of depression (OR, 2.5; 95% CI, 1.1-6.1), anxiety (OR, 2.1; 95% CI, 1.2-3.6), and posttraumatic stress disorder (OR, 2.4; 95% CI, 1.2-4.8). Adjusting for age, race/ethnicity, marital status, education level, employment, and source of health care use, the ORs for CVD risk were higher for women with current posttraumatic stress disorder symptoms (2.5; 95% CI, 1.1-5.3) and gender-specific health care preferences (2.0; 95% CI, 1.1-3.4), and gender-specific weight loss programs (1.9; 95% CI, 1.1 3.2). CONCLUSIONS: Risk for CVD was common and preferences for gender-specific care and posttraumatic stress disorder were associated with being at risk for CVD. Women's health clinics may be a good location for targeted CVD prevention interventions for women veterans both in and outside the Veterans Health Administration. PMID- 28890129 TI - Bioinformatics approaches to predict target genes from transcription factor binding data. AB - Transcription factors regulate gene expression and play an essential role in development by maintaining proliferative states, driving cellular differentiation and determining cell fate. Transcription factors are capable of regulating multiple genes over potentially long distances making target gene identification challenging. Currently available experimental approaches to detect distal interactions have multiple weaknesses that have motivated the development of computational approaches. Although an improvement over experimental approaches, existing computational approaches are still limited in their application, with different weaknesses depending on the approach. Here, we review computational approaches with a focus on data dependency, cell type specificity and usability. With the aim of identifying transcription factor target genes, we apply available approaches to typical transcription factor experimental datasets. We show that approaches are not always capable of annotating all transcription factor binding sites; binding sites should be treated disparately; and a combination of approaches can increase the biological relevance of the set of genes identified as targets. PMID- 28890131 TI - Characterization of systemic neutrophil function in patients undergoing colorectal cancer resection. AB - BACKGROUND: In patients with colorectal cancer, the generation and maintenance of a systemic inflammatory response is associated with poor outcomes. Neutrophils have been implicated in the prognosis of such patients, but little is known about their functional response to surgery. This study was conducted to characterize neutrophil function of patients undergoing colorectal cancer resection. MATERIALS AND METHODS: Systemic neutrophils were isolated from patients with colorectal cancer who underwent surgical resection preoperatively (day 0) and postoperatively (day 1 and day 3). Neutrophils were stimulated to produce neutrophil extracellular traps, which were quantified by a measure of the fluorescence of the extracellular DNA. Neutrophil apoptosis and phagocytosis were measured by fluorescence-activated cell sorting. RESULTS: Forty-five patients were evaluated. Statistically significant differences were identified in NET formation over the perioperative period (reduced NET production [day 0 to day 1] and restored NET production [day 1 to day 3]) in the absence of stimulation (P = 0.0016) and in response to stimulation with interleukin 8 (P = 0.0045), lipopolysaccharide (P = 0.0025), and N-formylmethionyl-leucyl-phenylalanine (P = 0.0014). No statistically significant differences were identified in apoptosis at 4-hour incubation; however, at 24-hours, significant differences were identified in alive (P < 0.0001), early apoptotic (P = 0.0008) and late apoptotic (P = 0.0018) stages (impaired apoptosis [day 0 to day 1] and restored apoptosis [day 1 to day 3]). Demonstrable, but nonsignificant, increases in neutrophil phagocytotic activity were revealed on sequential perioperative days, and a significant increase in phagocytosis was identified from day 1 to day 3 in response to E coli (P = 0.0078). CONCLUSIONS: A novel neutrophil phenotype demonstrating reduced NET formation, reduced apoptosis, and increased phagocytosis has been demonstrated in patients undergoing colorectal cancer resection. As a consequence of impaired cell death, an accumulation of neutrophils in the circulation could be potentially harmful to the host following surgery and an early phenotypic switch may be desirable. PMID- 28890132 TI - Motor abnormalities in first-episode psychosis patients and long-term psychosocial functioning. AB - Motor abnormalities (MAs) are highly prevalent in patients with first-episode psychosis both before any exposure and after treatment with antipsychotic drugs. However, the extent to which these abnormalities have predictive value for long term psychosocial functioning is unknown. One hundred antipsychotic-naive first episode psychosis (FEP) patients underwent extensive motor evaluation including catatonic, parkinsonism, dyskinesia, akathisia and neurological soft signs. Patients were assessed at naive state and 6months later. Patients were followed up in their naturalistic treatment and settings and their psychosocial functioning was assessed at 6-month, 1year, 5year and 10years from the FEP by collecting all available information. A set of linear mixed models were built to account for the repeated longitudinal assessment of psychosocial functioning during the follow-up regarding to the five domains of MAs (catatonic, parkinsonism, akathisia, dyskinesia and neurologic soft-signs) at index episode at antipsychotic naive state and after 6months of FEP. Basic epidemiological variables, schizophrenia diagnosis and average of chlorpromazine equivalent doses of antipsychotic drugs were included as covariates. Catatonic signs and dyskinesia at drug-naive state were significantly associated with poor long-term psychosocial functioning. Moreover, higher scores on parkinsonism, akathisia, neurological soft signs and catatonic signs at 6-month of FEP but not dyskinesia showed significant associations with poor long-term psychosocial functioning. Our results added empirical evidence to motor abnormalities as core manifestations of psychotic illness before and after antipsychotic treatment with high predictive value for poor long-term psychosocial functioning in FEP patients. PMID- 28890130 TI - Effects of perinatal bisphenol A exposure on the volume of sexually-dimorphic nuclei of juvenile rats: A CLARITY-BPA consortium study. AB - Bisphenol A (BPA) is a high volume endocrine disrupting chemical found in a wide variety of products including plastics and epoxy resins. Human exposure is nearly ubiquitous, and higher in children than adults. Because BPA has been reported to interfere with sex steroid hormone signaling, there is concern that developmental exposure, even at levels below the current FDA No Observed Adverse Effect Level (NOAEL) of 5mg/kg body weight (bw)/day, can disrupt brain sexual differentiation. The current studies were conducted as part of the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) program and tested the hypothesis that perinatal BPA exposure would induce morphological changes in hormone sensitive, sexually dimorphic brain regions. Sprague-Dawley rats were randomly assigned to 5 groups: BPA (2.5, 25, or 2500MUg/kgbw/day), a reference estrogen (0.5MUg ethinylestradiol (EE2)/kgbw/day), or vehicle. Exposure occurred by gavage to the dam from gestational day 6 until parturition, and then to the offspring from birth through weaning. Unbiased stereology was used to quantify the volume of the sexually dimorphic nucleus (SDN), the anteroventral periventricular nucleus (AVPV), the posterodorsal portion of the medial amygdala (MePD), and the locus coeruleus (LC) at postnatal day 28. No appreciable effects of BPA were observed on the volume of the SDN or LC. However, AVPV volume was enlarged in both sexes, even at levels below the FDA NOAEL. Collectively, these data suggest the developing brain is vulnerable to endocrine disruption by BPA at exposure levels below previous estimates by regulatory agencies. PMID- 28890133 TI - Expanding the Kinome World: A New Protein Kinase Family Widely Conserved in Bacteria. AB - Fine tuning of signaling pathways is essential for cells to cope with sudden environmental variations. This delicate balance is maintained in particular by protein kinases that control the activity of target proteins by reversible phosphorylation. In addition to homologous eukaryotic enzymes, bacteria have evolved some specific Ser/Thr/Tyr protein kinases without any structural resemblance to their eukaryotic counterparts. Here, we show that a previously identified family of ATPases, broadly conserved among bacteria, is in fact a new family of protein kinases with a Ser/Thr/Tyr kinase activity. A prototypic member of this family, YdiB from Bacillus subtilis, is able to autophosphorylate and to phosphorylate a surrogate substrate, the myelin basic protein. Two crystal structures of YdiB were solved (1.8 and 2.0A) that display a unique ATP-binding fold unrelated to known protein kinases, although a conserved HxD motif is reminiscent of that found in Hanks-type protein kinases. The effect of mutations of conserved residues further highlights the unique nature of this new protein kinase family that we name ubiquitous bacterial kinase. We investigated the cellular role of YdiB and showed that a ?ydiB mutant was more sensitive to paraquat treatment than the wild type, with ~13% of cells with an aberrant morphology. In addition, YdiE, which is known to participate with both YdiC and YdiB in an essential chemical modification of some specific tRNAs, is phosphorylated in vitro by YdiB. These results expand the boundaries of the bacterial kinome and support the involvement of YdiB in protein translation and resistance to oxidative stress in B. subtilis. PMID- 28890134 TI - Modifiers of GRN-Associated Frontotemporal Lobar Degeneration. AB - Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials. Multiple studies have demonstrated the heterogeneity in clinical presentation and wide variability in age of onset in patients carrying a GRN LOF mutation. Recently, this heterogeneity became an opportunity to identify disease modifiers, considering that these might constitute suitable targets for developing disease-modifying or disease-delaying therapies. PMID- 28890135 TI - Targeted Immune Interventions for an HIV-1 Cure. AB - Combination antiretroviral therapy (cART) induces durable suppression of virus replication but is unable to eradicate HIV. Invariably, virus rebound follows treatment interruption and life-long cART is thus required. Advances have been made in our understanding of HIV latency, identification of HIV cell reservoirs, regulation of HIV-specific immune responses, as well as in the development of broad neutralizing antibodies and putative therapeutic vaccines. These have provided a scientific basis to explore alternative strategies that achieve durable suppression of viremia in the absence of cART, the so-called functional cure. Single intervention strategies have shown promise, albeit with limited efficacy. Consequently, a combination of interventions aiming to stimulate the immune response and prevent new rounds of viral infection and spreading may render the HIV functional cure a feasible goal. PMID- 28890137 TI - Secular trends of use of anti-osteoporotic treatments in Spain: A population based cohort study including over 1.5million people and more than 12years of follow-up. AB - OBJECTIVE: Different regulatory actions for anti-osteoporotic medication (AOM) were taken during the last years, including marketing of new drugs, safety warnings, or restrictions on the indications. We aimed to characterise the secular trends of AOM use in Spain from 2001 to 2013. METHODS: A cohort study using the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP), was performed. BIFAP includes anonym records for 4million patients. Participants entered the study when aged >=50years in 2001-2013 and after 1year of data available, and were followed to an AOM prescription (including alendronate, other bisphosphonates, SERM (selective estrogen receptor modulators), strontium ranelate, teriparatide or denosumab), death, lost or the end of December 2013. Prevalence (%) and incidence rate (IR/1000person-years (py)) of AOM users were computed by years and sex. RESULTS: Out of 1.5million participants, 135,410 received AOM treatment during 2001-2013. Prevalence was 6.1% (women) and 1.1% (men), that increased from 2001 (2.0%) to 2009 (7.6%) to decrease thereafter. Out of them, 95,057 were incident. The IR was 24.90 (women) and 2.77 (men), that increased from 2001 (21.25 and 1.96) to 2007 (35.84 and 3.64), and decreased to 12.48 and 1.81 (2013). IRs were highest for bisphosphonates along the years (ranging 3.70-14.73 and 0.57-1.75 in women and men respectively), followed by SERM up to 2005 (6.51-9.02 and 0.06-0.07), and strontium ranelate from 2006 (4.66 and 0.45) to 2012 (2.05 and 0.26). IR for teriparatide increased from marketing in 2004 (0.10-1.01 and 0.02-0.29), as was denosumab from marketing in 2011 (0.03-2.64 and 0.09-0.15). CONCLUSIONS: Population-based estimates of AOM use in Spain peaked in 2007-2009 and decreased thereafter, irrespective of age and sex. New treatments were ten times higher in women than men. Bisphosphonates were the most frequently prescribed class, followed by SERM in women before 2006, strontium otherwise till 2012, and denosumab in women or teriparatide in men in 2013. Changes in the osteoporosis criteria, fracture risk assessment strategies, and regulatory actions for AOM around the time, may explain that trend. PMID- 28890138 TI - Unlocking Marine Biotechnology in the Developing World. AB - Fulfilling the promise of marine biotechnology as a source for environmental and biomedical applications remains challenging. New technologies will be necessary to harness marine biodiversity, and collaboration across government, academic, and private sectors will be crucial to create mechanisms of technology transfer and promote the development of new marine biotechnology companies. PMID- 28890136 TI - Identification of lipidomic markers of chronic 3,3',4,4',5-pentachlorobiphenyl (PCB 126) exposure in the male rat liver. AB - Exposure to PCB 126, an environmentally relevant aryl hydrocarbon receptor agonist, is an environmental factor causing hepatic steatosis in rodent models; however, the lipidome of PCB 126-exposed rats has not been investigated in-depth. The objective of the present study was therefore to characterize dose-dependent changes in the lipid profile in the liver of male Sprague-Dawley rats exposed to PCB 126. Rats were exposed for three month to intraperitoneal injections of 0.01, 0.05 and 0.2MUmol/kg bw PCB 126 in corn oil. Control animals were exposed in parallel and received corn oil alone. Lipids were extracted from whole liver homogenate and levels of polar lipids and fatty acids incorporated into triglycerides (FATAGs) were determined with tandem mass spectrometry using electrospray ionization. PCB 126 exposure increased the hepatic content of polar lipids and FATAGs. Protein adjusted levels of several polar lipid classes, in particular phosphatidylserine levels, decreased, whereas FATAGs levels typically increased with increasing PCB 126 dose. Sensitive, dose-dependent endpoints of PCB 126 exposure included an increase in levels of adrenic acid incorporated into triglycerides and changes in levels of certain ether-linked phospholipid and 1 alkyl/1-alkenyldiacylglycerol species, as determined using partial least square discriminant analysis (PLS-DA) and ANOVA. These changes in the composition of polar lipids and fatty acid in the liver of PCB 126 exposed rats identified several novel markers of PCB 126-mediated fatty liver disease that need to be validated in further studies. PMID- 28890139 TI - Duck interferon regulatory factor 1 acts as a positive regulator in duck innate antiviral response. AB - In mammals, IFN regulatory factor (IRF) 1 can activates cellular genes and promotes viral resistance against some DNA and RNA viruses. Most IRFs have been identified as critical regulators in the IFN responses in both mammals and fish. In ducks, however, the functional role of IRF1 remains unknown. Here, we identified duck IRF1 (duIRF1) is essential to counteract viral invasion. duIRF1 is most abundant in duck spleen, and virus infection or poly(I:C) stimulation significantly induced duIRF1 expression in vivo and in vitro. Overexpression of duRF1 induces the expression of type I IFN-beta, type III IFN-lambda, and interferon stimulated genes (ISGs) in duck embryo fibroblasts (DEFs), initiating cells resistant to avian viruses infection. More importantly, we found duIRF1 interacts with duck myeloid differentiation factor 88 (duMyD88) to activate duck IFN-beta, different from IRF3 and IRF7, which involve in IFN expression through the retinoic acid-inducible gene I (RIG-I)-like receptor pathway in mammals. Together, these results indicate that duIRF1 effectively inhibits viral replication through the induction of IFN and antiviral ISGs. This will help with understanding the role of duIRF1 mediated antiviral responses by innate immune mechanisms. PMID- 28890140 TI - [Impact of the elderly patient in the emergency department]. AB - INTRODUCTION: The aging of the population, chronic diseases, and non-urgent visits to the Emergency departments (ED) are considered the reasons for the increase of the demand of care. The aim of this study is to analyse the impact of the older population in the ED, when compared to a younger population. MATERIAL AND METHODS: An observational, descriptive and retrospective study including an analysis of the 92,627 patients that attended the ED in Hospitals from Health Area IV belonging to the Principality of Asturias Health Services during 2009. The analysis included the number of visits, degree of urgency when arriving at the ED, length of stay (LOS), destination after ED assessment, demand of care per time of day, laboratory tests, and radiology, complaints, and social services consultation. A comparison was made between the data of patients over and below 70 years of age. RESULTS: At total of 28,965 (31.27%) patients were over 70 years of age, with a frequency rate in the ED of 52.29% (25.70% in those less than 70 years). Patients over 70 years had a higher priority attention through the Manchester triage scale, receiving more laboratory tests, with a higher LOS. They also had a higher probability of being seen by social services, of being admitted, and death. CONCLUSIONS: Older patients consult the ED with more justifiable reasons than the younger adult population. PMID- 28890141 TI - [Gait speed and the appearance of neurocognitive disorders in older adults: Results of a Peruvian cohort]. AB - INTRODUCTION: The prevention and management of neurocognitive disorders (NCD) among older adults can be improved by early identification of risk factors such as walking speed. The objective of the study is to assess the association between gait speed and NCD onset in a population of Peruvian older adults. MATERIAL AND METHODS: Cohort conducted in older adults who attended the geriatrics service of Naval Medical Center (Callao, Peru). During the baseline assessment, participants' gait speed was recorded. Subsequently, participants were followed up annually for 5 years, with a mean of 21 months. NCD onset was defined as the occurrence of a score <=24 points on the Mini Mental State Examination (screening test) during follow-up. The hazard ratios (HR) and their 95% confidence intervals (95% CI) were calculated using Cox regression. RESULTS: The study included 657 participants, with a mean age of 73.4+/-9.2 (SD) years, of whom 47.0% were male, 47.8% had a gait speed <0.8 m/s, and 20.1% developed NCD during the follow up. It was found that older adults who had gait speed <0.8 m/s at baseline were more likely to develop NCD than those who had a gait speed >=0.8 m/s (adjusted HR=1.41, 95% CI=1.34-1.47). CONCLUSION: A longitudinal association was found between decreased gait speed and NCD onset, suggesting that gait speed could be useful to identify patients at risk of NCD onset. PMID- 28890142 TI - [Clinical variables associated with rhabdomyolysis and its complications in elderly patients. A retrospective cohort study]. PMID- 28890144 TI - Adipocyte-Epithelial Interactions and Crohn's Disease - An Emerging Drug Target. PMID- 28890146 TI - Knitted octopuses inside the incubators, a non-evidence based viral practice. PMID- 28890145 TI - Clinical Implications of the Association of Fetal Hemoglobin with Peripheral Oxygen Saturation in Sickle Cell Disease. PMID- 28890143 TI - Transcriptional interaction between cFOS and the homeodomain-binding transcription factor VAX1 on the GnRH promoter controls Gnrh1 expression levels in a GnRH neuron maturation specific manner. AB - Gonadotropin-releasing hormone (GnRH) is required for pubertal onset and reproduction, thus the control of GnRH transcription is tightly regulated during development and adulthood. GnRH neuron development depends on transcription factors of the homeodomain family. For example, Ventral anterior homeobox 1 (Vax1) is necessary to maintain GnRH expression after embryonic day 13 in the mouse. To further our understanding of the mechanisms by which VAX1 regulates GnRH gene expression, we asked whether VAX1 interacts with other transcription factors to modify GnRH expression levels. Using the GnRH cell lines, GN11 and GT1 7, we found that activation of PKC enhances expression of the immediate early gene cFos in both GN11, and GT1-7, and represses expression of Vax1 in GT1-7. Further, VAX1 interacts with cFOS while bound to the GnRH promoter. In immature GN11 cells, VAX1 and cFOS enhance GnRH expression, whereas VAX1 and cFOS have a repressive role in the mature GT1-7 cells. PMID- 28890147 TI - Obstructive sleep apnea: Influence of hypertension on adiponectin, inflammatory markers and dyslipidemia. AB - Obstructive sleep apnea (OSA) is a common but often unrecognized condition with potentially serious complications. The aim of this study was to explore the possible mechanisms linking hypertension (HT), a common cardiovascular disease (CVD), with obstructive sleep apnea (OSA) by investigating the levels of morning and evening serum adiponectin, inflammatory markers (TNF-alpha, IL-6), and lipid profiles in OSA patients with and without HT. Four groups were enrolled in this case-control analytic study: control, OSA, OSA+HT, and HT groups, each of which included 22 subjects. The results revealed low morning and evening serum adiponectin levels in patients with OSA and OSA+HT compared with their control and HT counterparts. Serum adiponectin levels declined progressively with increasing severity of OSA. Also, morning adiponectin levels were significantly decreased at the same time that a loss of the normal diurnal rhythm was observed in the OSA and OSA+HT groups. Both TNF-alpha and IL-6 levels were significantly increased in the OSA and OSA+HT groups compared with levels in the control and HT groups. Altered lipid profiles was noticed in the same groups. These findings were more pronounced in the OSA+HT than in the OSA group. In conclusion, the biochemical findings of this study demonstrate predominantly low adiponectin levels, increased levels of inflammatory markers, and atherogenic lipid profiles in OSA patients with HT compared with those of the other patients studied. This highlights the possible contributing role of these factors to the pathogenesis of HT as a common cardiovascular complication in OSA patients. PMID- 28890148 TI - Co-infections of infectious spleen and kidney necrosis virus and Siniperca chuatsi rhabdovirus in Chinese perch (Siniperca chuatsi). AB - In spite of the quite common co-infections of viruses in the cultured fish, most of the previous studies have just simply focused on the infection of a single pathogen. In this report, we observed that about 13% of cultured Chinese perch have been co-infected by infectious spleen and kidney necrosis virus (ISKNV) and Siniperca chuatsi rhabdovirus (SCRV). Furthermore, Chinese perch could co infected by ISKNV and SCRV by intraperitoneally injection with the two viruses. Interestingly, we revealed that the two viruses could even co-infect a single cell of Chinese perch in vivo and a single Chinese perch brain cells (CPB) cell in vitro. The dynamic co-infected viruses loads in the different tissues of Chinese perch showed dependent. When CPB cells were infected with the same 10 MOI of SCRV and ISKNV, the replication of SCRV overwhelmed the replication of ISKNV. When the MOI of ISKNV (10 MOI) was 10,000 times of MOI of SCRV (0.001 MOI), the dynamic virus loads of the two viruses in CPB cells indicated that co-infections could synergistically stimulate both viruses replication at the late time points but not at early time points. The co-infections of ISKNV and SCRV in the cultured Chinese perch will shed a new light on the prevention of the viral diseases of Chinese perch. The development of multivalent vaccine which could be effective for preventing against the co-infections of the viruses is highly needed. PMID- 28890150 TI - Antagonizing the GABAA receptor during behavioral training improves spatial memory at different doses in control and chronically stressed rats. AB - Chronic stress leads to a dysregulated inhibitory tone that could impact hippocampal-dependent spatial learning and memory. The present study examined whether spatial memory deficits resulting from chronic stress could be overcome by antagonizing the GABAA receptor, a prominent inhibitory receptor of GABA in the hippocampus. Young adult male Sprague-Dawley rats were chronically stressed (STR, wire mesh restraint, 6h/d/21d) or placed in a no-stress control group (CON). When chronic restraint ended, rats were tested on a 2-trial object placement (OP) task at a delay (3h) that would result in chance performance without intervention and then on novel object recognition (NOR) and the elevated plus maze (EPM) to assess non-spatial memory and anxiety profile. In CON rats, Bicuculline (BIC, 0, 0.25, 0.5mg/kg), a GABAA antagonist, injected 30min prior to training led to facilitated OP performance with 0.25 and 0.5mg/kg doses. In contrast, STR rats required BIC at the highest dose (0.5mg/kg) to improve OP performance. While overall object exploration was decreased by chronic stress, motivation or anxiety profile were unlikely to explain these results. These findings reveal two different dose response functions for BIC in control and chronically stressed rats, with the dose response function of BIC being shifted to the right for chronically stressed rats compared to controls in order to improve spatial memory. While the literature demonstrates that chronic stress disrupts hippocampal inhibitory tone, the current study reveals that a single injection to antagonize the GABAA receptor can restore hippocampal-dependent spatial memory in chronically stressed subjects. PMID- 28890149 TI - Distinct roles for the deacetylase domain of HDAC3 in the hippocampus and medial prefrontal cortex in the formation and extinction of memory. AB - Histone deacetylases (HDACs) are chromatin modifying enzymes that have been implicated as powerful negative regulators of memory processes. HDAC3has been shown to play a pivotal role in long-term memory for object location as well as the extinction of cocaine-associated memory, but it is unclear whether this function depends on the deacetylase domain of HDAC3. Here, we tested whether the deacetylase domain of HDAC3has a role in object location memory formation as well as the formation and extinction of cocaine-associated memories. Using a deacetylase-dead point mutant of HDAC3, we found that selectively blocking HDAC3 deacetylase activity in the dorsal hippocampus enhanced long-term memory for object location, but had no effect on the formation of cocaine-associated memory. When this same point mutant virus of HDAC3 was infused into the prelimbic cortex, it failed to affect cocaine-associated memory formation. With regards to extinction, impairing the HDAC3 deacetylase domain in the infralimbic cortex had no effect on extinction, but a facilitated extinction effect was observed when the point mutant virus was delivered to the dorsal hippocampus. These results suggest that the deacetylase domain of HDAC3 plays a selective role in specific brain regions underlying long-term memory formation of object location as well as cocaine-associated memory formation and extinction. PMID- 28890151 TI - When to Perform Preoperative Bone Scintigraphy for Kidney Cancer Staging: Indications for Preoperative Bone Scintigraphy. AB - OBJECTIVE: To identify an objective and reproducible strategy for preoperative staging bone scintigraphy (BS) in patients diagnosed with renal cell carcinoma (RCC), because in the absence of objective criteria, the decision to perform preoperative BS remains a subjective practice. PATIENTS AND METHODS: The study included a total of 2008 patients with RCC treated with surgery and prospectively included into an institutional database. The study outcome was the presence of 1 or more bone lesions suspicious for metastases at staging BS. A multivariable logistic regression model predicting a positive BS was fitted. The predictors consisted of the preoperative clinical tumor (cT) and clinical nodal (cN) stages, the presence of systemic symptoms, and the platelet-to-hemoglobin (PLT/Hb) ratio. RESULTS: The rate of positive BS was 4% (n = 81). At the multivariable logistic regression analysis, cT2, cN1, the presence of systemic symptoms, and the PLT/Hb ratio were all associated with am increased risk of positive BS (P <.05). Following the 2000-sample bootstrap validation, the concordance index was 0.77 (proposed model) vs 0.63 (decision making based on symptoms only). At the decision curve analysis, the proposed strategy was associated with a higher net benefit. If BS is performed when the risk of positive result is >5%, a negative BS is spared in 80% and a positive BS is missed in 2% of the population only. CONCLUSION: Using preoperative variables, it is possible to accurately estimate the risk of positive BS at RCC staging using preoperative characteristics. Compared with the strategy supported by available guidelines, the proposed model was more objective, statistically more accurate, and clinically associated with higher net benefit. PMID- 28890152 TI - Re: Leapman et al.: Up and Away: Five Decades of Urologic Investigation in Microgravity (Urology 106:18-25). PMID- 28890153 TI - Medicinal plants for in vitro antiplasmodial activities: A systematic review of literature. AB - The increasing resistance of malaria to drugs raise the need to new antimalarial agents. Antiplasmodial herbs and their active compounds are the most promising source the new antimalarial agents. This study aimed to identify the medicinal plants with very good in vitro antiplasmodial activities, with half-maximal inhibitory concentration (IC50)<=1MUg/ml, and to determine trends in the process of screening their antiplasmodial activities. A total of 58 reports published in the English language were retrieved from the bibliographical databases. Screening and data extraction were performed by two independent reviewers. The herbs were categorized as very good, good, moderate and inactive if the IC50 values were <0.1MUg/ml, 0.1-1MUg/ml, >1-5MUg/ml and >5MUg/ml respectively. We documented 752 medicinal plants belonging to 254 genera. The majority of the plants were reported from Africa followed by Asia. The traditional use for malaria treatment was the most common reason for the selection of the plants for investigation. About 80% of the plants experimented were reported to be inactive. Among plants identified as having very good to good antiplasmodial crude extracts are Harungana madagascariensis, Quassia africana, and Brucea javanica, while Picrolemma spruce, Aspidosperma vargasi, Aspidosperma desmanthum, and Artemisia annua were reported to have individual compound isolates with very good antiplasmodial activities. In conclusion, the number of plant species assessed so far is still small compared with the stock in nature's plant library. A mechanism of systematically approaching and exploring the untouched plant genera needs to be designed. PMID- 28890154 TI - Diabetes mellitus in intraductal papillary mucinous neoplasm of the pancreas is associated with high-grade dysplasia and invasive carcinoma. AB - BACKGROUND: While the association between Diabetes Mellitus (DM) and pancreatic ductal adenocarcinoma is well recognized, its importance in intraductal papillary mucinous neoplasm of the pancreas (IPMN) is not well-defined. We sought to examine the associations of DM with degree of dysplasia and morphological subtypes in IPMN. METHODS: In 454 patients with resected IPMN, we evaluated associations of DM with high-grade dysplasia (HGD), invasive carcinoma, precursor epithelial subtype (gastric, intestinal, oncocytic, pancreatobiliary), and histological type of invasive carcinomas (tubular, colloid, oncocytic) using logistic regression. We performed multivariate analyses adjusting for worrisome features and high-risk stigmata of malignancy in a subset of 289 patients with annotated radiological characteristics. RESULTS: The prevalence of DM in our study was 34%. DM was significantly associated with HGD (OR 2.02, 95% CI 1.02 4.01, P = 0.045) and invasive carcinoma (OR 2.05, 95% CI 1.08-3.87, P = 0.027) after adjusting for worrisome features. Compared to patients without DM, those with recent-onset DM (<=5 years before surgery) had 6.9-fold (95% CI 2.38-19.92, P < 0.001) higher risk of invasive carcinoma. DM was associated with increased likelihood of intestinal-type precursor epithelium (OR 1.63, 95% CI 1.07-2.47, P = 0.022) and colloid carcinomas (OR 2.46, 95% CI 1.01-5.99, P = 0.047) CONCLUSION: Preoperative DM was associated with significantly higher risk of HGD and invasive carcinoma in resected IPMN, and risk of invasive carcinoma was highest in patients with recent-onset DM. Patients with DM were more likely to harbor intestinal-type IPMN and colloid carcinomas. Our findings suggest that a diagnosis of DM in patients with IPMN may warrant more aggressive surveillance. PMID- 28890155 TI - Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice. AB - The microbiota-gut-brain axis (MGBA) regulates the reciprocal interaction between chronic inflammatory bowel and psychiatric disorders. This interaction involves multiple pathways that are highly debated. We examined the behavioural, biochemical and electrophysiological alterations, as well as gut microbiota composition in a model of antibiotic-induced experimental dysbiosis. Inflammation of the small intestine was also assessed. Mice were exposed to a mixture of antimicrobials for 2weeks. Afterwards, they received Lactobacillus casei DG (LCDG) or a vehicle for up to 7days via oral gavage. Perturbation of microbiota was accompanied by a general inflammatory state and alteration of some endocannabinoidome members in the gut. Behavioural changes, including increased immobility in the tail suspension test and reduced social recognition were observed, and were associated with altered BDNF/TrkB signalling, TRPV1 phosphorylation and neuronal firing in the hippocampus. Moreover, morphological rearrangements of non-neuronal cells in brain areas controlling emotional behaviour were detected. Subsequent probiotic administration, compared with vehicle, counteracted most of these gut inflammatory, behavioural, biochemical and functional alterations. Interestingly, levels of Lachnospiraceae were found to significantly correlate with the behavioural changes observed in dysbiotic mice. Our findings clarify some of the biomolecular and functional modifications leading to the development of affective disorders associated with gut microbiota alterations. PMID- 28890156 TI - The microbiota influences cell death and microglial colonization in the perinatal mouse brain. AB - The mammalian fetus develops in a largely sterile environment, and direct exposure to a complex microbiota does not occur until birth. We took advantage of this to examine the effect of the microbiota on brain development during the first few days of life. The expression of anti- and pro-inflammatory cytokines, developmental cell death, and microglial colonization in the brain were compared between newborn conventionally colonized mice and mice born in sterile, germ-free (GF) conditions. Expression of the pro-inflammatory cytokines interleukin 1beta and tumor necrosis factor alpha was markedly suppressed in GF newborns. GF mice also had altered cell death, with some regions exhibiting higher rates (paraventricular nucleus of the hypothalamus and the CA1 oriens layer of the hippocampus) and other regions exhibiting no change or lower rates (arcuate nucleus of the hypothalamus) of cell death. Microglial labeling was elevated in GF mice, due to an increase in both microglial cell size and number. The changes in cytokine expression, cell death and microglial labeling were evident on the day of birth, but were absent on embryonic day 18.5, approximately one-half day prior to expected delivery. Taken together, our results suggest that direct exposure to the microbiota at birth influences key neurodevelopmental events and does so within hours. These findings may help to explain some of the behavioral and neurochemical alterations previously seen in adult GF mice. PMID- 28890158 TI - Childhood cancer: the long-term costs of cure. PMID- 28890157 TI - The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE). AB - BACKGROUND: Survivors of childhood cancer develop early and severe chronic health conditions (CHCs). A quantitative landscape of morbidity of survivors, however, has not been described. We aimed to describe the cumulative burden of curative cancer therapy in a clinically assessed ageing population of long-term survivors of childhood cancer. METHODS: The St Jude Lifetime Cohort Study (SJLIFE) retrospectively collected data on CHCs in all patients treated for childhood cancer at the St Jude Children's Research Hospital who survived 10 years or longer from initial diagnosis and were 18 years or older as of June 30, 2015. Age matched and sex-frequency-matched community controls were used for comparison. 21 treatment exposure variables were included in the analysis, with data abstracted from medical records. 168 CHCs for all participants were graded for severity using a modified Common Terminology Criteria of Adverse Events. Multiple imputation with predictive mean matching was used for missing occurrences and grades of CHCs in the survivors who were not clinically evaluable. Mean cumulative count was used for descriptive cumulative burden analysis and marked point-process regression was used for inferential cumulative burden analysis. FINDINGS: Of 5522 patients treated for childhood cancer at St Jude Children's Research Hospital who had complete records, survived 10 years or longer, and were 18 years or older at time of study, 3010 (54.5%) were alive, had enrolled, and had had prospective clinical assessment. 2512 (45.5%) of the 5522 patients were not clinically evaluable. The cumulative incidence of CHCs at age 50 years was 99.9% (95% CI 99.9-99.9) for grade 1-5 CHCs and 96.0% (95% CI 95.3-96.8%) for grade 3-5 CHCs. By age 50 years, a survivor had experienced, on average, 17.1 (95% CI 16.2-18.1) CHCs of any grade, of which 4.7 (4.6-4.9) were CHCs of grade 3 5. The cumulative burden in matched community controls of grade 1-5 CHCs was 9.2 (95% CI 7.9-10.6; p<0.0001 vs total study population) and of grade 3-5 CHCs was 2.3 (1.9-2.7, p<0.0001 vs total study population). Second neoplasms, spinal disorders, and pulmonary disease were major contributors to the excess total cumulative burden. Notable heterogeneity in the distribution of CHC burden in survivors with differing primary cancer diagnoses was observed. The cumulative burden of grade 1-5 CHCs at age 50 years was highest in survivors of CNS malignancies (24.2 [95% CI 20.9-27.5]) and lowest in survivors of germ cell tumours (14.0 [11.5-16.6]). Multivariable analyses showed that older age at diagnosis, treatment era, and higher doses of brain and chest radiation are significantly associated with a greater cumulative burden and severity of CHCs. INTERPRETATION: The burden of CHCs in survivors of childhood cancer is substantial and highly variable. Our assessment of total cumulative burden in survivors of paediatric cancer, with detailed characterisation of long-term CHCs, provide data to better inform future clinical guidelines, research investigations, and health services planning for this vulnerable, medically complex population. FUNDING: The US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities. PMID- 28890159 TI - Acral retiform purpura. PMID- 28890160 TI - Elfin: An algorithm for the computational design of custom three-dimensional structures from modular repeat protein building blocks. AB - Computational protein design methods have enabled the design of novel protein structures, but they are often still limited to small proteins and symmetric systems. To expand the size of designable proteins while controlling the overall structure, we developed Elfin, a genetic algorithm for the design of novel proteins with custom shapes using structural building blocks derived from experimentally verified repeat proteins. By combining building blocks with compatible interfaces, it is possible to rapidly build non-symmetric large structures (>1000 amino acids) that match three-dimensional geometric descriptions provided by the user. A run time of about 20min on a laptop computer for a 3000 amino acid structure makes Elfin accessible to users with limited computational resources. Protein structures with controlled geometry will allow the systematic study of the effect of spatial arrangement of enzymes and signaling molecules, and provide new scaffolds for functional nanomaterials. PMID- 28890161 TI - Self-assembly of repeat proteins: Concepts and design of new interfaces. AB - In nature, assembled protein structures offer the most complex functional structures. The understanding of the mechanisms ruling protein-protein interactions opens the door to manipulate protein assemblies in a rational way. Proteins are versatile scaffolds with great potential as tools in nanotechnology and biomedicine because of their chemical, structural, and functional versatility. Currently, bottom-up self-assembly based on biomolecular interactions of small and well-defined components, is an attractive approach to biomolecular engineering and biomaterial design. Specifically, repeat proteins are simplified systems for this purpose. In this work, we provide an overview of fundamental concepts of the design of new protein interfaces. We describe an experimental approach to form higher order architectures by a bottom-up assembly of repeated building blocks. For this purpose, we use designed consensus tetratricopeptide repeat proteins (CTPRs). CTPR arrays contain multiple identical repeats that interact through a single inter-repeat interface to form elongated superhelices. Introducing a novel interface along the CTPR superhelix allows two CTPR molecules to assemble into protein nanotubes. We apply three approaches to form protein nanotubes: electrostatic interactions, hydrophobic interactions, and pi-pi interactions. We isolate and characterize the stability and shape of the formed dimers and analyze the nanotube formation considering the energy of the interaction and the structure in the three different models. These studies provide insights into the design of novel protein interfaces for the control of the assembly into more complex structures, which will open the door to the rational design of nanostructures and ordered materials for many potential applications in nanotechnology. PMID- 28890162 TI - Intermediate filament structure in fully differentiated (oxidised) trichocyte keratin. AB - For the past 50years there has been considerable debate over the sub-structure of the fully differentiated (oxidised) trichocyte keratin intermediate filament. Depending on the staining and preparative procedures employed, IF observed in transverse section in the transmission electron microscope have varied in appearance between that of a "ring" and a "ring-core" structure, corresponding to the so-called (8+0) and (7+1) protofilament arrangements. In a new analysis of the fine structure of the 1nm equatorial region of the X-ray diffraction pattern of quill we show that the observed pattern is consistent with the (8+0) model and we are also able to assign values to the various parameters. In contrast, we show that the observed X-ray pattern is inconsistent with a (7+1) arrangement. Furthermore, in the (7+1) model steric hindrance would be encountered between the core protofilament and those constituting the ring. The appearance of a central "core" in transverse TEM sections, previously attributed to a central protofilament, is explained in terms of portions of the apolar, disulfide-bonded head and/or tail domains of the trichocyte keratin IF molecules, including the conserved H subdomains, lying along the axis of the IF, thereby decreasing the efficacy of the reducing agents used prior to staining. The H1 subdomain, previously shown to be important in the assembly of epidermal IF molecules at the two- to four-molecule level, is likely to have a similar role for the trichocyte keratins and may form part of a central scaffold on which the molecules assemble into fully functional IF. PMID- 28890165 TI - Reduction of the Anticholinergic Burden Makes It Possible to Decrease Behavioral and Psychological Symptoms of Dementia. AB - OBJECTIVE: The aim of this study was to evaluate the impact of a reduction of the anticholinergic burden (AB) on the frequency and severity of behavioral and psychological symptoms of dementia (BPSD) and their repercussions on the care team (occupational disruptiveness). METHODS: In this prospective, single-center study in an acute care unit for Alzheimer disease (AD) and related disorders, 125 elderly subjects (mean age: 84.4 years) with dementia presented with BPSD. The reduction of the AB was evaluated by the Anticholinergic Cognitive Burden Scale. BPSD were evaluated with the Neuropsychiatric Inventory-Nursing Home Version (NPI NH). The effect of the reduction of the AB on the BPSD was studied using logistic regression adjusting for the variables of the comprehensive geriatric assessment. RESULTS: Seventy-one subjects (56.8%) presenting with probable AD, 32 (25.6%) mixed dementia (AD and vascular), 17 (13.6%) vascular dementia, and 5 (4.0%) Lewy body dementia were included. Reducing the AB by at least 20% enabled a significant decrease in the frequency * severity scores of the NPI-NH (adjusted odds ratio: 3.5; 95% confidence interval: 1.6-7.9) and of the occupational disruptiveness score (adjusted odds ratio: 9.9; 95% confidence interval: 3.6 27.3). CONCLUSION: AB reduction in elderly subjects with dementia makes is possible to reduce BPSD and caregiver burden. Recourse to treatments involving an AB must be avoided as much as possible in these patients, and preferential use of nonpharmacologic treatment management plans is encouraged. PMID- 28890163 TI - Single Stem Cell Imaging and Analysis Reveals Telomere Length Differences in Diseased Human and Mouse Skeletal Muscles. AB - Muscle stem cells (MuSCs) contribute to muscle regeneration following injury. In many muscle disorders, the repeated cycles of damage and repair lead to stem cell dysfunction. While telomere attrition may contribute to aberrant stem cell functions, methods to accurately measure telomere length in stem cells from skeletal muscles have not been demonstrated. Here, we have optimized and validated such a method, named MuQ-FISH, for analyzing telomere length in MuSCs from either mice or humans. Our analysis showed no differences in telomere length between young and aged MuSCs from uninjured wild-type mice, but MuSCs isolated from young dystrophic mice exhibited significantly shortened telomeres. In corroboration, we demonstrated that telomere attrition is present in human dystrophic MuSCs, which underscores its importance in diseased regenerative failure. The robust technique described herein provides analysis at a single-cell resolution and may be utilized for other cell types, especially rare populations of cells. PMID- 28890166 TI - History and strategic initiatives of the new World Sleep Society. PMID- 28890164 TI - Directed Differentiation of Human Bone Marrow Stromal Cells to Fate-Committed Schwann Cells. AB - Our ultimate goal of in vitro derivation of Schwann cells (SCs) from adult bone marrow stromal cells (BMSCs) is such that they may be used autologously to assist post-traumatic nerve regeneration. Existing protocols for derivation of SC-like cells from BMSCs fall short in the stability of the acquired phenotype and the functional capacity to myelinate axons. Our experiments indicated that neuro ectodermal progenitor cells among the human hBMSCs could be selectively expanded and then induced to differentiate into SC-like cells. Co-culture of the SC-like cells with embryonic dorsal root ganglion neurons facilitated contact-mediated signaling that accomplished the switch to fate-committed SCs. Microarray analysis and in vitro myelination provided evidence that the human BMSC-derived SCs were functionally mature. This was reinforced by repair and myelination phenotypes observable in vivo with the derived SCs seeded into a nerve guide as an implant across a critical gap in a rat model of sciatic nerve injury. PMID- 28890167 TI - Long sleep duration and health outcomes: A systematic review, meta-analysis and meta-regression. AB - We examined the dose-response relationship between long sleep duration and health outcomes including mortality and the incidence of diabetes mellitus, hypertension, cardiovascular diseases, stroke, coronary heart diseases, obesity, depression and dyslipidemia. We collected data from 5,134,036 participants from 137 prospective cohort studies. For the independent variable, we categorized participants at baseline as having long sleep duration or normal sleep duration. Risk ratios (RRs) for mortality and incident health conditions during follow-up were calculated through meta-analyses of adjusted data from individual studies. Meta-regression analyses were performed to investigate the association between each outcome and specific thresholds of long sleep. Long sleep was significantly associated with mortality (RR, 1.39; 95% CI, 1.31-1.47), incident diabetes mellitus (1.26, 1.11-1.43), cardiovascular disease (1.25, 1.14-1.37), stroke (1.46, 1.26-1.69), coronary heart disease (1.24, 1.13-1.37), and obesity (1.08, 1.02-1.15). Long sleep was not significantly related to incident hypertension (1.01, 0.95-1.07). Insufficient data were available for depression and dyslipidemia. Meta-regression analyses found statistically significant linear associations between longer sleep duration and increased mortality and incident cardiovascular disease. Future studies should address whether the relationship between long sleep and health outcomes is causal and modifiable. PMID- 28890168 TI - Sleep disturbances increase the risk of dementia: A systematic review and meta analysis. AB - Sleep disturbances and dementia are two common and significant health problems in older adults. Investigations suggest that sleep disturbances might increase the risk of dementia. The aim of the present study was to systematically review and meta-analyze the predictive roles of overall sleep disturbances, their subtypes (e.g., insomnia, sleep disordered breathing [SDB]), and other sleep problems (e.g., excessive daytime sleepiness, sleep-related movement disorder, circadian rhythm sleep disorder, and nonspecific sleep problems) in incident all-cause dementia and Alzheimer's disease (AD) and vascular dementia subtypes. We performed a systematic search of the PubMed, EMBase, ISI Web of Science, and PsycINFO databases for longitudinal studies that were published up to October 28, 2016. A total of 12,926 papers were retrieved. Eighteen longitudinal studies that included 246,786 subjects at baseline and 25,847 dementia cases after an average 9.49 y of follow-up were eligible for inclusion. Compared with individuals without sleep disturbances, subjects who reported sleep disturbances had a higher risk of incident all-cause dementia, AD, and vascular dementia. The subgroup analysis showed that insomnia increased the risk of AD but not vascular or all cause dementia. In contrast, SDB was associated with a higher incidence of all cause dementia, AD, and vascular dementia. This meta-analysis suggests that sleep disturbances may predict the risk of incident dementia. Moreover, insomnia was associated only with incident AD, and SDB was a risk factor of all-cause dementia, AD, and vascular dementia. However, sleep disturbances were evaluated mainly based on self-reports, and some confounders may mediate the relationship between sleep disturbances and dementia. Therefore, the results should be further validated. In summary, these findings may help identify individuals who are at risk for dementia and optimize early prevention strategies. PMID- 28890169 TI - How can we predict cellular mechanosensation?: Comment on "Cellular mechanosensing of the biophysical microenvironment: A review of mathematical models of biophysical regulation of cell responses" by Bo Cheng et al. PMID- 28890170 TI - Characterization of a novel mosquitocidal toxin of Cry50Ba and its potential synergism with other mosquitocidal toxins. AB - A putative toxin gene of cry50Ba was successfully expressed in E. coli cells and confirmed that the purified Cry50Ba toxin had very high toxic activity against Culex quinquefasciatus larvae. Furthermore, the potential synergism of Cry50Ba toxin with Cry2Aa, Cry4Aa and Cry11Aa at a ratio of 1:1 was investigated. Although no significant synergism with other toxins was observed, the Cry50Ba as a novel toxin could be used to delay rapid onset of resistance in mosquito. PMID- 28890171 TI - General characterization of the venoms from two species of rattlesnakes and an intergrade population (C. lepidus x aquilus) from Aguascalientes and Zacatecas, Mexico. AB - The venoms from two species of rock rattlesnakes and an intergrade population were studied. Differences were noted in SDS-PAGE and RP-HPLC profiles and only the venom from the intergrade population showed low procoagulant activity. Also, a Crotoxin-like neurotoxic PLA2 was identified in the venom of C. l. klauberi, the most toxic of the analyzed venoms. This is the first report of such a toxin in C. l. klauberi from Aguascalientes, Mexico. PMID- 28890172 TI - Spray drying of silica microparticles for sustained release application with a new sol-gel precursor. AB - A new precursor, tetrakis(2-methoxyethyl) orthosilicate (TMEOS) was used to fabricate microparticles for sustained release application, specifically for biopharmaceuticals, by spray drying. The advantages of TMEOS over the currently applied precursors are its water solubility and hydrolysis at moderate pH without the need of organic solvents or catalyzers. Thus a detrimental effect on biomolecular drug is avoided. By generating spray-dried silica particles encapsulating the high molecular weight model compound FITC-dextran 150 via the nano spray dryer Buchi-90, we demonstrated how formulation parameters affect and enable control of drug release properties. The implemented strategies to regulate release included incorporating different quantities of dextrans with varying molecular weight as well as adjusting the pH of the precursor solution to modify the internal microstructures. The addition of dextran significantly altered the released amount, while the release became faster with increasing dextran molecular weight. A sustained release over 35days could be achieved with addition of 60 kD dextran. The rate of FITC-Dextran 150 release from the dextran 60 containing particles decreased with higher precursor solution pH. In conclusion, the new precursor TMEOS presents a promising alternative sol-gel technology based carrier material for sustained release application of high molecular weight biopharmaceutical drugs. PMID- 28890173 TI - Spray drying of poorly soluble drugs from aqueous arginine solution. AB - Co-amorphous drug-amino acid mixtures have shown potential for improving the solid-state stability and dissolution behavior of amorphous drugs. In previous studies, however these mixtures have been produced mainly with small-scale preparation methods, or with methods that have required the use of organic solvents or other dissolution enhancers. In the present study, co-amorphous ibuprofen-arginine and indomethacin-arginine mixtures were spray dried from water. The mixtures were prepared at two drug-arginine molar ratios (1:1 and 1:2). The properties of the prepared mixtures were investigated with differential scanning calorimetry, X-ray powder diffractometry, Fourier-transform infrared spectroscopy and a 24h, non-sink, dissolution study. All mixtures exhibited a single glass transition temperature (Tg), evidence of the formation of homogenous single-phase systems. Fourier transform infrared spectroscopy revealed strong interactions (mainly salt formation) that account for the positive deviation between measured and estimated Tg values. No crystallization was observed during a 1-year stability study in either 1:1 or 1:2 mixtures, but in the presence of moisture, handling difficulties were encountered. The formation of co-amorphous salts led to improved dissolution characteristics when compared to the corresponding physical mixtures or to pure crystalline drugs. PMID- 28890174 TI - Improved control over MSCs behavior within 3D matrices by using different cell loads in both in vitro and in vivo environments. AB - The combination of multipotent mesenchymal stromal cells (MSCs) and different biomaterials has led to enormous advances in cell-based therapies, among which cell microencapsulation technologies are included. In the present work, we have studied the influence of different cell densities on the behavior of erythropoietin (EPO)-secreting MSCs immobilized in alginate microcapsules for their use as drug delivery systems. In vitro studies showed a more sustained and controlled EPO-secretion in groups with higher cell densities, which may be related to a more balanced renewal of the encapsulated cells, while low and intermediate densities gave rise to a continuous increase of both the number of cells and the EPO secretion levels. However, in vivo studies depicted a completely different scenario. Here the higher levels of cell proliferation led to a rapid space saturation and oxygen depletion of the capsule core, which eventually resulted in implant failure for the highest cell loads. On the contrary, lower cell densities showed a longer lasting release with a steadily increasing secretion profile. In conclusion, these results demonstrate how the final outcome of a cell-based drug delivery system may be tuned by just modifying the initial cell load, always taking into account the surrounding microenvironment. PMID- 28890175 TI - Effect of the pulmonary deposition and in vitro permeability on the prediction of plasma levels of inhaled budesonide formulation. AB - The growing interest in the inhalable pharmaceutical products requires advanced approaches to safe and fast product development, such as in silico tools that can be used for estimating the bioavailability and toxicity of developed formulation. GastroPlusTM is one of the few available software packages for in silico simulation of PBPK profile of inhalable products. It contains a complementary module for calculating the lung deposition, the permeability and the systemic absorption of inhalable products. Experimental values of lung deposition and permeability can also be used. This study aims to assess the efficiency of simulation by applying experimental permeability and deposition values, using budesonide as a model substance. The lung deposition values were obtained from the literature, the lung permeability data were experimentally determined by culturing Calu-3 cells under air-liquid interface and submersed conditions to morphologically resemble bronchial and alveolar epithelial cells, respectively. A two-compartment PK model was created for i.v. administration and used as a background for the in silico simulation of the plasma profile of budesonide after inhalation. The predicted plasma profile was compared with the in vivo data from the literature and the effects of experimental lung deposition and permeability on prediction were assessed. The developed model was significantly improved by using realistic lung deposition data combined with experimental data for peripheral permeability. PMID- 28890176 TI - A gamma-subunit point mutation in Chlamydomonas reinhardtii chloroplast F1Fo-ATP synthase confers tolerance to reactive oxygen species. AB - The chloroplast F1Fo-ATP synthase (CF1Fo) drives ATP synthesis and the reverse reaction of ATP hydrolysis. The enzyme evolved in a cellular environment where electron transfer processes and molecular oxygen are abundant, and thiol modulation in the gamma-subunit via thioredoxin is important for its ATPase activity regulation. Especially under high light, oxygen can be reduced and forms reactive oxygen species (ROS) which can oxidize CF1Fo among various other biomolecules. Mutation of the conserved ROS targets resulted in a tolerant enzyme, suggesting that ROS might play a regulatory role. The mutations had several side effects in vitro, including disturbance of the ATPase redox regulation [F. Buchert et al., Biochim. Biophys. Acta, 1817 (2012) 2038-2048]. This would prevent disentanglement of thiol- and ROS-specific modes of regulation. Here, we used the F1 catalytic core in vitro to identify a point mutant with a functional ATPase redox regulation and increased H2O2 tolerance. In the next step, the mutation was introduced into Chlamydomonas reinhardtii CF1Fo, thereby allowing us to study the physiological role of ROS regulation of the enzyme in vivo. We demonstrated in high light experiments that CF1Fo ROS targets were involved in the significant inhibition of ATP synthesis rates. Molecular events upon modification of CF1Fo by ROS will be considered. PMID- 28890177 TI - Lignanamides with potent antihyperlipidemic activities from the root bark of Lycium chinense. AB - Seven new lignanamides, lyciumamides D-J (1-4 and 9-11), together with nine known analogues (5-8 and 12-16), were isolated from the root bark of Lycium chinense. The structures of the isolated compounds were elucidated on the basis of NMR spectroscopic and HRESIMS data. All isolated compounds were evaluated for antihyperlipidemic activities in HepG2 cells. The primary structure-activity relationships were discussed. PMID- 28890178 TI - Prevalence of Endometriosis and Its Symptoms among Young Jordanian Women with Chronic Pelvic Pain Refractory to Conventional Therapy. AB - OBJECTIVE: This study sought to explore the prevalence and clinical manifestations of endometriosis in young women with chronic pelvic pain (CPP) refractory to conventional medical therapy. METHODS: This prospective clinical interventional study was conducted in two general and private hospitals in the city of Al-Karak in Jordan. A total of 28 female patients aged <=21 who had CPP refractory to conventional medical therapy were recruited during the years 2010 2014. The intervention used in the study was laparoscopy. Endometriosis was staged according to the American Society for Reproductive Medicine classification. The main outcome measures were the presence and stage of endometriosis at laparoscopy, the presence of cold intolerance, and the severity and duration of pain symptoms. RESULTS: The mean age of participants was 18.4 (range 15 to 21). Endometriosis was found in 20 of 28 participants (71.4%), as follows: stage I, 9 of 20 (45.0%); stage II, 8 of 20 (40%); stage III, 2 of 21 (10%); and stage IV, 1 of 21 (5%). Notably, 16 of 28 (57.1%) of all participants reported cold intolerance, including 14 of 20 (70%) with endometriosis and 2 of 8 (25%) without endometriosis (Fisher exact [1-tail] P = 0.039). There was no association between stage of disease and age distribution (<=18 and >19 to 21; P = 0.7) or with duration of symptoms (<=2 and >2 years) and the presence of cold intolerance (P > 0.05). However, severity of pain symptoms (<7 vs. >=7, as measured by the visual analogue scale [VAS]) was associated significantly with stage of disease (P = 0.011). CONCLUSION: The prevalence of endometriosis among young women with CPP refractory to conventional therapy was high, mainly in the mild stage. Cold intolerance was highly associated with endometriosis. PMID- 28890179 TI - Maternal colonization or infection with extended-spectrum beta-lactamase producing Enterobacteriaceae in Africa: A systematic review and meta-analysis. AB - OBJECTIVE: To summarize published studies on the prevalence of and risk factors for maternal bacterial colonization and/or infection with extended-spectrum beta lactamase-producing Enterobacteriaceae (ESBL-E) in pregnant and/or post-partum women in Africa. METHODS: A systematic review was conducted using the PubMed, Scopus, and Google Scholar databases. Bibliographies of included eligible studies were manually searched to identify additional relevant articles. No language restriction was applied. The timeframe of the search included all records from electronic database inception to July 15, 2017. A random-effects meta-analysis was performed to summarize the prevalence and the 95% confidence intervals (CI) of ESBL-E colonization or infection in pregnant or post-partum women in Africa. The meta-analysis was conducted using STATA IC 13.1 software and the metaprop function/plugin. RESULTS: Ten studies (seven on pregnant women and three on post partum women) were included, documenting a 17% prevalence of maternal colonization with ESBL-E in Africa (95% CI 10-23%). The prevalence of ESBL-E in community isolates exceeded that in isolates from the hospital setting (22% vs. 14%). The most frequently reported ESBL-encoding gene was CTX-M (cefotaxime hydrolyzing capabilities). Data on risk factors for maternal ESBL-E colonization and infection are very limited. CONCLUSIONS: The prevalence of colonization and/or infection with ESBL-E in pregnant and post-partum women in Africa exceeds that reported from high- and middle-income settings, representing a risk for subsequent neonatal colonization and/or infection with ESBL-E. PMID- 28890180 TI - Effectiveness of meibomian gland massage combined with topical levofloxacin against ocular surface flora in patients before penetrating ocular surgery. AB - OBJECTIVE: To investigate the bacterial profile in the conjunctiva and meibomian glands in patients before penetrating ocular surgeries, and to compare the anti bacterial efficacy of 0.5% levofloxacin and its combination with meibomian gland massage. DESIGN: Hospital-based, case-control study. PARTICIPANTS: Two hundred and twenty-six eyes from 226 patients with non-infective ocular diseases and scheduled for penetrating ocular surgeries. METHODS: Tested eyes were administered topical 0.5% levofloxacin (4 times daily) for 2 days. Among them, 91 eyes received meibomian gland massage before levofloxacin application. Samples from the conjunctival sac and meibomian glands were collected for aerobic and anaerobic cultures. MAIN OUTCOME MEASURES: Culture-positivity and bacterial strains. RESULTS: Before treatment, aerobes and anaerobes were cultured from 38.5% and 11.0% of the conjunctival samples respectively, compared with 38.5% and 8.8% in the meibomian secretions respectively. Staphylococcus epidermidis and Propionibacterium acnes were the commonest isolated aerobe and anaerobe. Two-day application of levofloxacin reduced aerobic growth to 29.6% in the conjunctiva and 19.3% in the meibomian glands. It had no effect on the anaerobes in these regions (13.3% in the conjunctiva and 10.4% in the meibomian glands). Combined levofloxacin with meibomian gland massage further reduced aerobic growth to 19.8% in the conjunctiva and 11.0% in the meibomian glands. It also drastically decreased anaerobic growth in the meibomian glands (1.1%). CONCLUSIONS: Meibomian glands carrying considerable bacteria should be considered as a potential source of contamination in ocular surgery. Meibomian gland massage shows additional anti bacterial effects to topical levofloxacin and could be recommended as a complementary preoperative prophylaxis. PMID- 28890181 TI - Hostility and cognitive control: Evidence of increased cardiovascular reactivity as a function of exposure to affective stress using a dichotic listening paradigm. AB - Indices of cognitive control were examined in men with high and low levels of trait hostility as a function of exposure to affective and cognitive stress. A dual concurrent task paradigm was used whereby participants intentionally directed focus to the left or right ear under dichotic listening conditions before and after exposure to angry infant vocalizations. Analysis of the behavioral data supports the prediction of reduced right frontal regulatory control in men with high levels of hostility as indicated by diminished capacity to suppress report of phonemes presented to the language dominant left hemisphere (right ear) in the Focus Left condition. This diminishment in the capacity to suppress report of phonemes presented to the right ear in the Focus Left condition is suggestive of reduced cognitive control. With respect to the neurophysiological data, heart rate increased for only men with high levels of hostility in the Focus Left condition, and this was especially evident in the post-affective stress condition. This increase in right hemisphere arousal provides additional evidence of reduced cognitive control and support for the capacity model of hostility by implicating poor right frontal regulatory control over right posterior cerebral regions under dual task conditions. The results are discussed in terms of integrating the construct of cognitive control into the capacity model as well as providing implications regarding reductions in the capacity to suppress predominant aggressive responses in domestic settings. PMID- 28890182 TI - Transient heart rate acceleration in association with spontaneous eyeblinks. AB - The reason why people spontaneously blink several times more frequently than is necessary for ocular lubrication has been a mystery. However, spontaneous eyeblinks selectively occur at attentional breakpoints of information processing, suggesting the involvement of spontaneous eyeblink in attentional disengagement from external stimuli. Physiological activity also changes considerably according to attention state. Heart rate decreases when attention is directed at stimuli, while it increases as attention is released. Therefore, we examined the temporal dynamics between spontaneous eyeblinks and instantaneous heart rate under natural circumstances. Our results showed that the heart rate momentarily increases after each spontaneous eyeblink while participants were freely viewing a movie or listening to a story. This phenomenon was consistently observed even when the participants were placed in a dark room. The skin conductance level on the fingers also increased after each spontaneous eyeblink, suggesting that the blink related heart rate acceleration was induced by an increase in sympathetic nervous system activity. In contrast, no heart rate acceleration was observed to accompany spontaneous eyeblinks at rest or volitional eyeblinks. These results demonstrated that the generation of spontaneous eyeblinks and the activity of the autonomic nervous system are correlated under attentional influence of natural circumstances. PMID- 28890183 TI - Radiomics Analysis on Ultrasound for Prediction of Biologic Behavior in Breast Invasive Ductal Carcinoma. AB - INTRODUCTION: In current clinical practice, invasive ductal carcinoma is always screened using medical imaging techniques and diagnosed using immunohistochemistry. Recent studies have illustrated that radiomics approaches provide a comprehensive characterization of entire tumors and can reveal predictive or prognostic associations between the images and medical outcomes. To better reveal the underlying biology, an improved understanding between objective image features and biologic characteristics is urgently required. PATIENTS AND METHODS: A total of 215 patients with definite histologic results were enrolled in our study. The tumors were automatically segmented using our phase-based active contour model. The high-throughput radiomics features were designed and extracted using a breast imaging reporting and data system and further selected using Student's t test, interfeature coefficients and a lasso regression model. The support vector machine classifier with threefold cross-validation was used to evaluate the relationship. RESULTS: The radiomics approach demonstrated a strong correlation between receptor status and subtypes (P < .05; area under the curve, 0.760). The appearance of hormone receptor-positive cancer and human epidermal growth factor receptor 2-negative cancer on ultrasound scans differs from that of triple-negative cancer. CONCLUSION: Our approach could assist clinicians with the accurate prediction of prognosis using ultrasound findings, allowing for early medical management and treatment. PMID- 28890184 TI - Evaluation of the Tumor Response After Neoadjuvant Chemotherapy in Breast Cancer Patients: Correlation Between Dynamic Contrast-enhanced Magnetic Resonance Imaging and Pathologic Tumor Cellularity. AB - BACKGROUND: We evaluated the tumor response after neoadjuvant chemotherapy (NAC) in breast cancer patients using dynamic contrast-enhanced (DCE) magnetic resonance (MR) imaging parameters assessed using a commercially available computer-aided system. We also analyzed their correlation with pathologic tumor cellularity. MATERIALS AND METHODS: We retrospectively reviewed the data from 130 patients with breast cancer who had undergone NAC followed by surgery from January to October 2013. Maximum diameter, volume, peak enhancement, and persistent, plateau, and washout-enhancing components were measured using a computer-aided system on DCE MR images and correlated with the Miller-Payne grading system. Patients with a Miller-Payne grade of 5 were classified into the pathologic complete response (pCR) group. Patients with grades 1, 2, 3, and 4 were included in the non-pCR group. Diagnostic performance was evaluated using receiver operating characteristic curve analysis. RESULTS: Twenty patients were included in the pCR group and 110 patients in the non-pCR group. Of the 6 parameters, the rate of tumor volume reduction (r = 0.729, P < .001) showed the strongest correlation with the Miller-Payne grading system, followed by the maximum diameter (r = 0.706, P < .001) and washout component (r = 0.606, P < .001). The area under the receiver operating characteristic curve (Az value) was the largest for the rate of volume reduction (Az = 0.895), followed by the maximum diameter (Az = 0.891). CONCLUSION: The tumor volume changes in breast cancers before and after NAC, measured automatically using a commercially available computer-aided system and a clinical DCE MR imaging protocol might be the most accurate tool for evaluation of the pathologic response after NAC. PMID- 28890185 TI - Stromal Clusterin Expression Predicts Therapeutic Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer. AB - BACKGROUND: Expression of clusterin correlates with tumor progression and therapeutic response in several human malignancies, including breast cancer. However, its predictive value in the neoadjuvant setting in breast cancer remains unexplored. The objective of this explorative study was to determine whether clusterin expression in breast cancer correlated with clinical pathologic characteristics and whether its expression was predictive of response to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: We determined the clusterin expression pattern in 72 triple negative breast cancers (TNBC) treated with NAC before surgery. Clusterin expression was evaluated by immunohistochemistry and was correlated with pathologic characteristics and response to NAC using residual cancer burden score. RESULTS: Immunohistochemistry analysis revealed a differential pattern of expression between tumor and stroma. Clusterin expression in the tumor associated stroma as opposed to expression by the neoplastic epithelium was significantly associated with neoadjuvant-treated TNBC. Low stromal clusterin, low stromal content, and high tumor-infiltrating lymphocytes were associated with a significantly greater likelihood of achieving a good pathologic response as reflected by lower residual cancer burden scores (P = .002, P = .003, and P = .001, respectively). Tumor and/or stromal clusterin expression were not associated with patient age, tumor histologic grade, stage, and lymph node status. CONCULSION: This study suggests a potential role for the assessment of stromal clusterin as a predictive biomarker for response of TNBC to neoadjuvant therapy. Further validation of this biomarker in a large study is needed. PMID- 28890186 TI - Ionophores at work: Exploring the interaction of guanosine-based amphiphiles with phospholipid membranes. AB - An amphiphilic derivative of guanosine, carrying a myristoyl group at the 5' position and two methoxy(triethylene glycol) appendages at the 2' and 3' positions (1), endowed with high ionophoric activity, has been here studied in its interaction mode with a model lipid membrane along with its 5'-spin-labelled analogue 2, bearing the 5-doxyl-stearic in lieu of the myristic residue. Electron spin resonance spectra, carried out on the spin-labelled nucleolipid 2 in mixture with a DOPC/DOPG phospholipid bilayer, on one side, and on spin-labelled lipids mixed with 1, on the other, integrated with dynamic light scattering and neutron reflectivity measurements, allowed getting an in-depth picture of the effect of the ionophores on membrane structure, relevant to clarify the ion transport mechanism through lipid bilayers. Particularly, dehydration of lipid headgroups and lowering of both the local polarity and acyl chains order across the bilayer, due to the insertion of the oligo(ethylene glycol) chains in the bilayer hydrophobic core, have been found to be the main effects of the amphiphilic guanosines interaction with the membrane. These results furnish directions to rationally implement future ionophores design. PMID- 28890187 TI - Kinetic analysis of the inhibition of the drug efflux protein AcrB using surface plasmon resonance. AB - Multidrug efflux protein complexes such as AcrAB-TolC from Escherichia coli are paramount in multidrug resistance in Gram-negative bacteria and are also implicated in other processes such as virulence and biofilm formation. Hence efflux pump inhibition, as a means to reverse antimicrobial resistance in clinically relevant pathogens, has gained increased momentum over the past two decades. Significant advances in the structural and functional analysis of AcrB have informed the selection of efflux pump inhibitors (EPIs). However, an accurate method to determine the kinetics of efflux pump inhibition was lacking. In this study we standardised and optimised surface plasmon resonance (SPR) to probe the binding kinetics of substrates and inhibitors to AcrB. The SPR method was also combined with a fluorescence drug binding method by which affinity of two fluorescent AcrB substrates were determined using the same conditions and controls as for SPR. Comparison of the results from the fluorescent assay to those of the SPR assay showed excellent correlation and provided validation for the methods and conditions used for SPR. The kinetic parameters of substrate (doxorubicin, novobiocin and minocycline) binding to AcrB were subsequently determined. Lastly, the kinetics of inhibition of AcrB were probed for two established inhibitors (phenylalanine arginyl beta-naphthylamide and 1-1 naphthylmethyl-piperazine) and three novel EPIs: 4-isobutoxy-2-naphthamide (A2), 4-isopentyloxy-2-naphthamide (A3) and 4-benzyloxy-2-naphthamide (A9) have also been probed. The kinetic data obtained could be correlated with inhibitor efficacy and mechanism of action. This study is the first step in the quantitative analysis of the kinetics of inhibition of the clinically important RND-class of multidrug efflux pumps and will allow the design of improved and more potent inhibitors of drug efflux pumps. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain. PMID- 28890188 TI - Harnessing the respiration machinery for high-yield production of chemicals in metabolically engineered Lactococcus lactis. AB - When modifying the metabolism of living organisms with the aim of achieving biosynthesis of useful compounds, it is essential to ensure that it is possible to achieve overall redox balance. We propose a generalized strategy for this, based on fine-tuning of respiration. The strategy was applied on metabolically engineered Lactococcus lactis strains to optimize the production of acetoin and (R,R)-2,3-butanediol (R-BDO). In the absence of an external electron acceptor, a surplus of two NADH per acetoin molecule is produced. We found that a fully activated respiration was able to efficiently regenerate NAD+, and a high titer of 371mM (32g/L) of acetoin was obtained with a yield of 82% of the theoretical maximum. Subsequently, we extended the metabolic pathway from acetoin to R-BDO by introducing the butanediol dehydrogenase gene from Bacillus subtilis. Since one mole of NADH is consumed when acetoin is converted into R-BDO per mole, only the excess of NADH needs to be oxidized via respiration. Either by fine-tuning the respiration capacity or by using a dual-phase fermentation approach involving a switch from fully respiratory to non-respiratory conditions, we obtained 361mM (32g/L) R-BDO with a yield of 81% or 365mM (33g/L) with a yield of 82%, respectively. These results demonstrate the great potential in using finely-tuned respiration machineries for bio-production. PMID- 28890189 TI - Human papillomavirus vaccination coverage using two-dose or three-dose schedule criteria. AB - In October 2016, the Advisory Committee on Immunization Practices (ACIP) updated the human papillomavirus (HPV) vaccination recommendation to include a 2-dose schedule for U.S. adolescents initiating the vaccine series before their 15th birthday. We analyzed records for >4million persons aged 9-17years receiving any HPV vaccine by the end of each quarter during January 1, 2014-September 30, 2016 from six Immunization Information Systems Sentinel Sites, and reclassified HPV vaccination up-to-date coverage according to the updated recommendations. Compared with HPV vaccination up-to-date coverage by the 3-dose schedule only, including criteria for either a 2-dose or 3-dose schedule increased up-to-date coverage in 11-12, 13-14, and 15-17 year-olds by 4.5-8.5 percentage points. The difference between 3-dose up-to-date coverage and 2- or 3-dose up-to-date coverage was greatest in late 2016. These data provide baseline HPV vaccination coverage using current ACIP recommendations. PMID- 28890190 TI - The eradication of Polio: Have we succeeded? PMID- 28890191 TI - Considerations for use of Ebola vaccine during an emergency response. AB - Vaccination against Ebola virus disease is a tool that may limit disease transmission and deaths in future outbreaks, integrated within traditional Ebola outbreak prevention and control measures. Although a licensed Ebolavirus vaccine (EV) is not yet available, the 2014-2016 West African Ebola outbreak has accelerated EV clinical trials and given public health authorities in Guinea, Liberia, and Sierra Leone experience with implementation of emergency ring vaccination. As evidence supporting the use of EV during an outbreak response has become available, public health authorities in at-risk countries are considering how to integrate EV into future emergency Ebola responses and for prevention in high-risk groups, such as healthcare workers and frontline workers (HCW/FLWs), even before an EV is licensed. This review provides an overview of Ebola epidemiology, immunology, and evidence to inform regional and country-level decisions regarding EV delivery during an emergency response and to at-risk populations before a licensed vaccine is available and beyond. Countries or regions planning to use EV will need to assess factors such as the likelihood of a future Ebolavirus outbreak, the most likely species to cause an outbreak, the availability of a safe and effective EV (unlicensed or licensed) for the affected population, capacity to implement Ebola vaccination in conjunction with standard Ebola outbreak control measures, and availability of minimum essential resources and regulatory requirements to implement emergency Ebola vaccination. Potential emergency vaccination strategies for consideration include ring or geographically targeted community vaccination, HCW/FLW vaccination, and mass vaccination. The development of guidelines and protocols for Ebola vaccination will help ensure that activities are standardized, evidence-based, and well-coordinated with overall Ebola outbreak response efforts in the future. PMID- 28890192 TI - Workplace availability, risk group and perceived barriers predictive of 2016-17 influenza vaccine uptake in the United States: A cross-sectional study. AB - BACKGROUND: Seasonal influenza, though mostly self-limited in the healthy adult, may lead to severe disease and/or complications in subpopulations. Annual influenza vaccination is available in many countries with coverage goals rarely being met. We conducted a cross-sectional study of influenza vaccine uptake and explored socio-demographic, economic, and psychological factors that explained vaccine uptake. METHODS: The survey was administered via Amazon Mechanical Turk (MTurk) to United States residents in January 2017, using the Qualtrics platform. Using principal axis factor analysis, we reduced the 25 items theory-based psychological determinants into the primary constructs they measure if/when internal consistency was sufficient (Cronbach's alpha >0.60). Logistic regression models were used to quantify the association of socio-demographic, economic, and psychological factors with reported vaccine behavior in the 2016-17 flu season. RESULTS: 1007 participants completed the survey, sex distribution was even, 67% had 25-44years of age, and 61% annual household income of $30-99 thousand United States dollars. About 25% had the flu shot offered at their workplace and 20% reported belonging to a group for whom the flu shot is recommended. Vaccine uptake was 31.5%. Eight predictors remained in the final adjusted model (R2=0.489), having the vaccine offered at the workplace, belonging to a group for whom the vaccine is recommended, and higher perceived barriers were the strongest predictors of vaccine uptake, increasing (and decreasing in the case of barriers) the odds by >3-fold. Additionally, higher household income, higher perceived susceptibility and higher perceived benefits also independently predicted vaccine uptake. DISCUSSION: We found evidence that perceived barriers significantly impaired vaccine uptake to the same extent that having the vaccine offered at the workplace or belonging to a group for whom the vaccine is recommended facilitated uptake. Ideally, a better understanding of drivers of vaccine hesitancy will result in improved interventions to increase vaccine uptake. PMID- 28890193 TI - Evaluating cessation of the type 2 oral polio vaccine by modeling pre- and post cessation detection rates. AB - The globally synchronized removal of the attenuated Sabin type 2 strain from the oral polio vaccine (OPV) in April 2016 marked a major change in polio vaccination policy. This change will provide a significant reduction in the burden of vaccine associated paralytic polio (VAPP), but may increase the risk of circulating vaccine-derived poliovirus (cVDPV2) outbreaks during the transition period. This risk can be monitored by tracking the disappearance of Sabin-like type 2 (SL2) using data from the polio surveillance system. We studied SL2 prevalence in 17 countries in Africa and Asia, from 2010 to 2016 using acute flaccid paralysis surveillance data. We modeled the peak and decay of SL2 prevalence following mass vaccination events using a beta-binomial model for the detection rate, and a Ricker function for the temporal dependence. We found type 2 circulated the longest of all serotypes after a vaccination campaign, but that SL2 prevalence returned to baseline levels in approximately 50days. Post-cessation model predictions identified 19 anomalous SL2 detections outside of model predictions in Afghanistan, India, Nigeria, Pakistan, and western Africa. Our models established benchmarks for the duration of SL2 detection after OPV2 cessation. As predicted, SL2 detection rates have plummeted, except in Nigeria where OPV2 use continued for some time in response to recent cVDPV2 detections. However, the anomalous SL2 detections suggest specific areas that merit enhanced monitoring for signs of cVDPV2 outbreaks. PMID- 28890194 TI - Improving chances for successful clinical outcomes with better preclinical models. AB - In order to avoid expensive clinical failures, better and more predictive animal models of vaccine efficacy are needed to screen Shigella and ETEC vaccine candidates for protective efficacy. The 2016 Vaccines Against Shigella and ETEC (VASE) Conference included a workshop focused on the strengths and weaknesses of current models, particularly in terms of the correlation to vaccine efficacy in human clinical trials. Workshop presenters shared information on existing preclinical animal models for assessing the immunogenicity and protective efficacy of Shigella and ETEC vaccines. The presentations were followed by a discussion about how to best utilize these models, how the models can be improved, and best practices for Shigella and ETEC vaccine developers. The workshop concluded with three major recommendations for the field: (1) develop better and more consistent reagents for animal studies and make them widely available, (2) prioritize harmonization of animal models and immunology assays, and (3) develop preclinical correlates of protection, which will be key in selecting the best vaccine candidates for further clinical development. PMID- 28890195 TI - GK-1 peptide reduces tumor growth, decreases metastatic burden, and increases survival in a murine breast cancer model. AB - GK-1 is a parasite-derived peptide adjuvant of 18 amino acid-length that enhances T-cell function and increases survival in B16-F10 melanoma tumor-bearing mice. This study was designed to evaluate in vivo the antitumor efficacy of GK-1 on 4T1 mouse mammary carcinoma. BALB/c mice with palpable primary tumors were weekly intravenously injected three times with saline solution or three different concentrations (10, 50, or 100MUg per mouse) of GK-1. GK-1 significantly increased lifespan (p<0.0001) and reduced the primary tumor weight (p=0.014) and volume (p<0.0001) with respect to control mice, with no statistically significant differences among GK-1 doses. At the primary tumor, we found increased necrotic areas associated with a reduction in tumor mass, as well as an increase in the antitumor cytokine IL-12. Especially encouraging is the ability of GK-1 to reduce the number of lung metastasis (p=0.006) disregarding the dose used. The participation of IL-6 in metastasis development and the decreased levels of CCL 2, CCL-3, TNF-alpha, CXCL-9, GM-CSF, and b-FGF found in lungs of GK-1-treated mice is discussed. Our study supports the effectiveness of GK-1 as an antineoplastic agent that merits further exploration in combination with other therapeutic approaches in future translational studies. PMID- 28890197 TI - Revisiting asthma therapeutics: focus on WNT signal transduction. AB - Asthma is a complex disease of the airways that develops as a consequence of both genetic and environmental factors. This interaction has highlighted genes important in early life, particularly those that control lung development, such as the Wingless/Integrase-1 (WNT) signalling pathway. Although aberrant WNT signalling is involved with an array of human conditions, it has received little attention within the context of asthma. Yet it is highly relevant, driving events involved with inflammation, airway remodelling, and airway hyper-responsiveness (AHR). In this review, we revisit asthma therapeutics by examining whether WNT signalling is a valid therapeutic target for asthma. PMID- 28890196 TI - Cost-effectiveness and public health impact of alternative influenza vaccination strategies in high-risk adults. AB - PURPOSE: High-dose trivalent inactivated influenza vaccine (HD-IIV3) or recombinant trivalent influenza vaccine (RIV) may increase influenza vaccine effectiveness (VE) in adults with conditions that place them at high risk for influenza complications. This analysis models the public health impact and cost effectiveness (CE) of these vaccines for 50-64year-olds. METHODS: Markov model CE analysis compared 5 strategies in 50-64year-olds: no vaccination; only standard dose IIV3 offered (SD-IIV3 only), only quadrivalent influenza vaccine offered (SD IIV4 only); high-risk patients receiving HD-IIV3, others receiving SD-IIV3 (HD IIV3 & SD-IIV3); and high-risk patients receiving HD-IIV3, others receiving SD IIV4 (HD-IIV3 & SD-IIV4). In a secondary analysis, RIV replaced HD-IIV3. Parameters were obtained from U.S. databases, the medical literature and extrapolations from VE estimates. Effectiveness was measured as 3%/year discounted quality adjusted life year (QALY) losses avoided. RESULTS: The least expensive strategy was SD-IIV3 only, with total costs of $99.84/person. The SD IIV4 only strategy cost an additional $0.91/person, or $37,700/QALY gained. The HD-IIV3 & SD-IIV4 strategy cost $1.06 more than SD-IIV4 only, or $71,500/QALY gained. No vaccination and HD-IIV3 & SD-IIV3 strategies were dominated. Results were sensitive to influenza incidence, vaccine cost, standard-dose VE in the entire population and high-dose VE in high-risk patients. The CE of RIV for high risk patients was dependent on as yet unknown parameter values. CONCLUSIONS: Based on available data, using high-dose influenza vaccine or RIV in middle-aged, high-risk patients may be an economically favorable vaccination strategy with public health benefits. Clinical trials of these vaccines in this population may be warranted. PMID- 28890198 TI - Crosstalk between endoplasmic reticulum stress and oxidative stress in schizophrenia: The dawn of new therapeutic approaches. AB - Disruption of oxidant/anti-oxidant ratio as well as endoplasmic reticulum (ER) stress are thought to be involved in the pathophysiology of schizophrenia. These stresses can lead to impairments in brain functions progressively leading to neuronal inflammation followed by neuronal cell death. Moreover, the cellular stresses are interlinked leading us to the conclusion that protein misfolding, oxidative stress and apoptosis are intricately intertwined events requiring further research into their mechanistic and physiological pathways. These pathways can be targeted by using different therapeutic interventions like anti oxidants, sigma-1 receptor agonists and gene therapy to treat the neurodegenerative course of schizophrenia. We have also put empahsis on use of synthetic and natural ER stress inhibitors like 4-phenylbutyrate or salubrinal for the treatment of this disorder. This would provide an opportunity to create new therapeutic benchmarks in the field of neuropsychiatric disorders like schizophrenia, dissociative identity disorder and obsessive compulsive disorder. PMID- 28890199 TI - Distinct cognitive impairments in different disease courses of multiple sclerosis A systematic review and meta-analysis. AB - Cognitive impairment (CI) is common and debilitating in patients with multiple sclerosis. However, little is known about how different disease courses affect CI, impeding prognosis and disease management. Here, we contrasted the magnitude and profile of CI measured with standardized neuropsychological tests in patients with primary progressive multiple sclerosis (PPMS) against relapsing-remitting multiple sclerosis (RRMS) while considering potentially confounding demographic and clinical differences. Systematic literature review and meta-analysis was performed finding 47 eligible studies (N=4460 patients). Effect-sizes for 12 cognitive domains were calculated as Hedges' g. Results indicated more severe CI overall (g=-0.37, p<.001) and in each single cognitive domain (g=-0.28 to -0.65, p<.001) in patients with PPMS despite comparable degrees of fatigue and depression. Moderator analyses revealed that these differences were not fully attributable to clinical heterogeneity between disease courses (e.g., age, disability). Particularly verbal learning and memory differentiated PPMS and RRMS independent from demographic differences. Results imply that, previously under recognized, PPMS patients display severe degrees of CI and need more specialized disease management than RRMS patients. PMID- 28890200 TI - Esculetin modulates cytotoxicity induced by oxidants in NB4 human leukemia cells. AB - Esculetin is a polyphenolic compound with cytoprotective properties. We previously demonstrated the induction of apoptosis by esculetin in NB4 human leukemia cells, as a model, by a mechanism not well understood. To analyse the antioxidant activity of esculetin on apoptosis, we have studied the influence of co-treatments of esculetin at a concentration of 100MUM with exogenous ROS donors, namely tert-butyl-hydroperoxide and hydrogen peroxide, on NB4 cells. Esculetin (100MUM) exerts a protective effect on cell viability and death necrosis or late apoptosis caused by the oxidant t-BHP whereas it potentiates decrease of cell viability and cell death caused by H2O2. In the first case, the O2- scavenging activity of esculetin (100MUM) could be implicated. In the last one, cytotoxicity by apoptosis induction seems to be related to the increase in O2-, among other possible mechanisms. These results contribute to the study of the antitumor properties of esculetin by regulation of redox balance in leukemia cells. PMID- 28890201 TI - Enhanced anticancer effect and reduced toxicity of doxorubicin in combination with thymoquinone released from poly-N-acetyl glucosamine nanomatrix in mice bearing solid Ehrlish carcinoma. AB - The incidence of breast cancer remarkably increases all over the world. Therefore, there is a great demand to introduce new approaches into cancer treatment field. The current study was designated to evaluate the role of doxorubicin (DOX) and/or thymoquinone (TQ) nanomatrix in potentiating the cytotoxicity of either drug, and to investigate the ability of TQ to reduce cardiotoxicity of DOX in solid Ehrlich carcinoma (SEC)-bearing mice. DOX and TQ were loaded into F2 gel, which is a fully-acetylated poly-N-acetyl glucosamine nanofiber. SEC was induced in female albino mice as a model for experimentally induced breast cancer. Mice were randomly divided into eight groups (n=10): normal control, tumor control, F2 gel, free DOX, DOX+F2 gel, free TQ, TQ+F2 gel, and DOX+TQ+F2 gel. On day 28th from tumor inoculation, mice were sacrificed and blood samples were collected for measurement of the cardiac markers; lactate dehydrogenase (LDH) and creatine kinase (CK-MB). In addition, cardiac tissue was utilized for determination of lipid peroxide, and tumor tissue was used for measurement of anti-apoptotic protein Bcl-2 as well as gene expression of the tumor suppressor gene P53. DOX and/or TQ showed a significant reduction in tumor volume, cardiac markers, tumor Bcl-2, and P53 upregulation compared to free conventional therapies. Co-treatment with DOX+TQ+F2 gel was superior to all other groups in exerting beneficial effects. Use of TQ as an adjuvant therapy with DOX could improve its cytotoxic effects and limit its cardiac toxicity. Furthermore, loading of DOX and/or TQ into F2 gel showed a remarkable anti-cancer activity. PMID- 28890202 TI - Dexamethasone palmitate large porous particles: A controlled release formulation for lung delivery of corticosteroids. AB - We have optimized a formulation of a prodrug of dexamethasone (DXM), dexamethasone palmitate (DXP) for pulmonary delivery as a dry powder. Formulations were prepared by spray drying DXP with 1,2-Dipalmitoyl-sn-Glycero-3 Phosphocholine (DPPC) and Hyaluronic Acid (HA) as excipients. Large porous particles around 13 MUm were produced with a tap density of 0.05g/cm3 and a Fine particle fraction around 40%. The palmitate moiety favors DXP insertion into DPPC bilayers therefore limiting its in vitro release as shown by differential scanning calorimetry. After administering DXP powder intratracheally to rats by insufflation, bronchoalveolar lavage fluid (BALF) and blood samples were collected up to 24h and DXP and DXM concentrations were determined by HPLC analysis after extraction. PK parameters were evaluated according to a non compartmental model. We observe that DXP remains for up to 6h in the epithelial lining fluid (ELF) of the lungs at very high concentration. In addition, DXP concentration decreases according to two characteristic times. Consequently, DXM can be detected at rather important concentration in ELF up to 24h. The passage of DXP from the lungs to the bloodstream is very poor whereas DXM seems to be absorbed in the blood more easily. These results suggest that once administered DXP undergoes two different processes: hydrolysis into DXM due to the presence of esterases in the lungs and distribution in the lung tissue. This formulation appears promising to reduce systemic exposure and prolong the effect of the drug locally. PMID- 28890203 TI - Regional aerosol deposition in the human airways: The SimInhale benchmark case and a critical assessment of in silico methods. AB - Regional deposition effects are important in the pulmonary delivery of drugs intended for the topical treatment of respiratory ailments. They also play a critical role in the systemic delivery of drugs with limited lung bioavailability. In recent years, significant improvements in the quality of pulmonary imaging have taken place, however the resolution of current imaging modalities remains inadequate for quantifying regional deposition. Computational Fluid-Particle Dynamics (CFPD) can fill this gap by providing detailed information about regional deposition in the extrathoracic and conducting airways. It is therefore not surprising that the last 15years have seen an exponential growth in the application of CFPD methods in this area. Survey of the recent literature however, reveals a wide variability in the range of modelling approaches used and in the assumptions made about important physical processes taking place during aerosol inhalation. The purpose of this work is to provide a concise critical review of the computational approaches used to date, and to present a benchmark case for validation of future studies in the upper airways. In the spirit of providing the wider community with a reference for quality assurance of CFPD studies, in vitro deposition measurements have been conducted in a human-based model of the upper airways, and several groups within MP1404 SimInhale have computed the same case using a variety of simulation and discretization approaches. Here, we report the results of this collaborative effort and provide a critical discussion of the performance of the various simulation methods. The benchmark case, in vitro deposition data and in silico results will be published online and made available to the wider community. Particle image velocimetry measurements of the flow, as well as additional numerical results from the community, will be appended to the online database as they become available in the future. PMID- 28890205 TI - Shivering in Febrile Children: Frequency and Usefulness in Predicting Serious Bacterial Infections - A Prospective Case-Control Study. AB - A prospective case-control study was conducted in a pediatric emergency department to describe the proportion of febrile children experiencing shivering and its clinical significance. Shivering was reported in 186 of 645 febrile children (28.8%). The rate of serious bacterial infection was similar in 86 children with shivering and 86 matched controls. PMID- 28890204 TI - Early Caffeine Prophylaxis and Risk of Failure of Initial Continuous Positive Airway Pressure in Very Low Birth Weight Infants. AB - OBJECTIVE: To test the hypothesis that early caffeine treatment on the day of birth, compared with later treatment in very low birth weight (VLBW, <1500 g) infants receiving continuous positive airway pressure (CPAP) therapy, is associated with a decreased risk of CPAP failure in the first week of life. STUDY DESIGN: Multicenter, observational cohort study in 366 US neonatal intensive care units. We evaluated inborn, VLBW infants discharged from 2000 to 2014, who received only CPAP therapy without surfactant treatment on day of life (DOL) 0, had a 5-minute Apgar >=3, and received caffeine in the first week of life. We used multivariable conditional logistic regression to compare the risk of CPAP failure, defined as invasive mechanical ventilation or surfactant therapy on DOL 1-6, by timing of caffeine treatment as either early (initiation on DOL 0) or routine (initiation on DOL 1-6). RESULTS: We identified 11 133 infants; 4528 (41%) received early caffeine and 6605 (59%) received routine caffeine. Median gestational age was lower in the early caffeine group, 29 weeks (25th, 75th percentiles; 28, 30) vs the routine caffeine group, 30 weeks (29, 31); P < 0.001. The incidence of CPAP failure on DOL 1-6 was similar between the early and routine caffeine groups: 22% vs 21%; adjusted OR = 1.05 (95% CI: 0.93, 1.18). CONCLUSIONS: Early caffeine treatment on the day of birth was not associated with a decreased risk of CPAP failure in the first week of life for VLBW infants initially treated with CPAP. PMID- 28890206 TI - Unraveling the nuclear and chloroplast genomes of an agar producing red macroalga, Gracilaria changii (Rhodophyta, Gracilariales). AB - Agar and agarose have wide applications in food and pharmaceutical industries. Knowledge on the genome of red seaweeds that produce them is still lacking. To fill the gap in genome analyses of these red algae, we have sequenced the nuclear and organellar genomes of an agarophyte, Gracilaria changii. The partial nuclear genome sequence of G. changii has a total length of 35.8Mb with 10,912 predicted protein coding sequences. Only 39.4% predicted proteins were found to have significant matches to protein sequences in SwissProt. The chloroplast genome of G. changii is 183,855bp with a total of 201 open reading frames (ORFs), 29 tRNAs and 3 rRNAs predicted. Five genes: ssrA, leuC and leuD CP76_p173 (orf139) and pbsA were absent in the chloroplast genome of G. changii. The genome information is valuable in accelerating functional studies of individual genes and resolving evolutionary relationship of red seaweeds. PMID- 28890207 TI - Whole genome DNA methylation profiling of oral cancer in ethnic population of Meghalaya, North East India reveals novel genes. AB - Oral Squamous Cell Carcinoma (OSCC) is a serious and one of the most common and highly aggressive malignancies. Epigenetic factors such as DNA methylation have been known to be implicated in a number of cancer etiologies. The main objective of this study was to investigate physiognomies of Promoter DNA methylation patterns associated with oral cancer epigenome with special reference to the ethnic population of Meghalaya, North East India. The present study identifies 27,205 CpG sites and 3811 regions that are differentially methylated in oral cancer when compared to matched normal. 45 genes were found to be differentially methylated within the promoter region, of which 38 were hypermethylated and 7 hypomethylated. 14 of the hypermethylated genes were found to be similar to that of the TCGA-HNSCC study some of which are TSGs and few novel genes which may serve as candidate methylation biomarkers for OSCC in this poorly characterized ethnic group. PMID- 28890208 TI - Role of orexin receptors in the ventral tegmental area on acquisition and expression of morphine-induced conditioned place preference in the rats. AB - The orexins are hypothalamic neuropeptides and their role in reward processing and drug addiction has been demonstrated. The extent of involvement of each orexin receptor in the acquisition and expression of conditioned place preference (CPP) for morphine is still a matter of controversy. We investigated the functional differences between orexin-1 and -2 receptor blockade in the ventral tegmental area (VTA) on the acquisition and expression of morphine CPP. A total of 86 adult male Wistar rats weighing 250+/-30g (age 7-8weeks) received intra-VTA microinjection of either SB334867 (0.1, 1 and 10nM), a selective orexin-1 receptor (OX1R) antagonist, or TCS-OX2-29 (1, 5 and 25nM), a selective orexin-2 receptor (OX2R) antagonist. To measure the acquisition, the animals received each antagonist (SB334867 or TCS-OX2-29) 5min prior to subcutaneous injection of morphine (5mg/kg) during the conditioning phase. To measure the CPP expression, the animals received each antagonist on the post-conditioning phase. The CPP conditioning score was recorded by Ethovision software. Data showed that intra VTA microinjection of OX1-R antagonist significantly attenuated morphine CPP acquisition, during the conditioning phase, and expression, during the post conditioning phase. Intra-VTA microinjection of OX2-R antagonist also significantly attenuated morphine CPP acquisition and expression in the mentioned phases. Our results showed the orexin role in learning and memory and indicate that orexin receptors (OX1R and OX2R) function in the VTA is essential for both acquisition and expression of morphine reward in rats in the CPP model. PMID- 28890209 TI - Nursing workload and adherence to non-pharmacological measures in the prevention of ventilator-associated pneumonia. A pilot study. AB - OBJECTIVE: To analyse whether adherence to non-pharmacological measures in the prevention of ventilator-associated pneumonia (VAP) is associated with nursing workload. METHODS: A prospective observational study performed in a single medical-surgical ICU. Nurses in charge of patients under ventilator support were assessed. VARIABLES: knowledge questionnaire, application of non-pharmacological VAP prevention measures, and workload (Nine Equivalents of Nursing Manpower Use Score). Phases: 1) the nurses carried out a educational programme, consisting of 60-minute lectures on non-pharmacological measures for VAP prevention, and at the end completed a questionnaire knowledge; 2) observation period; 3) knowledge questionnaire. RESULTS: Among 67 ICU-staff nurses, 54 completed the educational programme and were observed. A total of 160 observations of 49 nurses were made. Adequate knowledge was confirmed in both the initial and final questionnaires. Application of preventive measures ranged from 11% for hand washing pre aspiration to 97% for the use of a sterile aspiration probe. The Nine Equivalents of Nursing Manpower Use Score was 50+/-13. No significant differences were observed between the association of the nurses' knowledge and the application of preventive measures or between workload and the application of preventive measures. CONCLUSIONS: Nurses' knowledge of VAP prevention measures is not necessarily applied in daily practice. Failure to follow these measures is not subject to lack of knowledge or to increased workload, but presumably to contextual factors. PMID- 28890211 TI - Antibacterial photodynamic therapy with curcumin and Curcuma xanthorrhiza extract against Streptococcus mutans. AB - BACKGROUND: Bacteria are becoming increasingly resistant to conventional antibacterial chemotherapy. This has prompted the application of antibacterial photodynamic therapy (aPDT) in bacteria-related diseases due to its excellent biocide effects. However, few studies have attempted to develop a novel photosensitizer based on natural components. The aim of the present study was to compare the aPDT effects of curcumin and Curcuma xanthorrhiza extract (CXE) against Streptococcus mutans. METHODS: A planktonic suspension containing an S. mutans strain was treated in three separate groups: aPDT with curcumin, CXE, and a mixture of curcumin and CXE (ratio= 1:1) at concentrations of 0, 10, 102, 103, and 104ng/ml. Light irradiation with a center wavelength of 405nm was applied using an LED (power density of 84.5mW for 300s at an energy density of 25.3J/cm2). The phototoxicity of photosensitizers against S. mutans was investigated using a colony-forming-unit assay. Percentage logarithmic reductions [log10(CFU/ml) values] were analyzed using one-way ANOVA followed by the Tukey test (p<0.05) and Student's independent t-test. RESULTS: The viability of S. mutans in the presence of curcumin, CXE, and a mixture of these two components was substantially reduced during irradiation with 405nm light. The phototoxicity of the photosensitizer varied with its solubility and concentration. CONCLUSION: These preliminary in vitro findings imply that combining curcumin and CXE with a 405nm LED may be a novel method of applying aPDT. This could be advantageous in preventing and treating dental caries using devices that are readily available in clinics. PMID- 28890210 TI - Photodynamic therapy: An option in mycosis fungoides. AB - BACKGROUND: Photodynamic therapy (PDT) is a well-known and effective treatment for non-melanoma skin-cancer. Numerous studies have also shown its effectiveness in mycosis fungoides. The aim of the study was to analyse MF patients treated with PDT at the Dermatology Unit of Bologna University. METHODS: We retrospectively analysed MF patients treated with PDT over the last ten years. Each PDT protocol consisted of the appliance for 3h under an occlusive film dressing on each lesion of a one-mm-thick layer of 16% methyl aminolaevulinate (MAL) 160mg/g cream (Metvix(r), Galderma, Paris, France). The cream was then removed and the skin was exposed to 630nm red light from a diode lamp (Aktilite(r), Galderma Benelux, Rotterdam, the Netherlands), with a total radiation dose of 37J/cm2 for 9 mins. A protocol of one session every month was scheduled. The treated lesions were clinically examined, before each treatment. RESULTS: Four cases, three male and one female, had been treated with PDT. Two patch lesions on the plantar area, one leg and the pubic area were treated. The number of PDT sessions ranged from 4 to 9. Two complete remissions and two partial remissions were observed. A low-to-mild burning sensation was reported during the treatment, and persisted over the next day; no further side effects were observed. CONCLUSIONS: Our series shows that PDT can be considered an effective second-line treatment in patients characterised by a disease located in difficult-to-treat anatomical areas such as the feet and the pubic area. PMID- 28890212 TI - A Self-Killing Rabies Virus That Leaves a Trace on the DNA. AB - Although modified rabies viruses have emerged as a powerful tool for tracing the inputs to genetically defined populations of neurons, the toxicity of the virus has limited its utility. A recent study employed a self-inactivating rabies (SiR) virus that enables recording or manipulation of targeted neurons for months. PMID- 28890213 TI - Oxygen generating nanoparticles for improved photodynamic therapy of hypoxic tumours. AB - Photodynamic therapy (PDT) is a clinically approved anti-cancer treatment that involves the activation of an otherwise inactive sensitiser drug with light, which in the presence of molecular oxygen, generates cytotoxic reactive oxygen species (ROS). As oxygen is a key requirement for the generation of ROS in PDT and given the fact that hypoxia is a characteristic of most solid cancerous tumours, treating hypoxic tumours using PDT can be a challenge. In this manuscript, we have prepared a CaO2 nanoparticle (NP) formulation coated with a pH-sensitive polymer to enable the controlled generation of molecular oxygen as a function of pH. The polymer coat was designed to protect the particles from decomposition while in circulation but enable their activation at lower pH values in hypoxic regions of solid tumours. The oxygen generating capability of the polymer coated NPs was demonstrated in aqueous solution with minimal oxygen produced at pH7.4, whereas it increased significantly when the pH was reduced to 6.2. The polymer coated CaO2 NPs were also observed to significantly increase tumour pO2 levels (p<0.05) in mice bearing ectopic human xenograft MIA PaCa-2 pancreatic tumours with an average increase in tumour pO2 of 6.5mmHg in the period 10-30min following administration. A statistically significant improvement in PDT mediated efficacy (p<0.001) was also observed when the particles were administered to mice bearing the same tumours 20min prior to PDT treatment. These results suggest that the polymer coated CaO2 NP formulation offers significant potential as an in situ method for oxygen generation to enhance the efficacy of treatments that depend on the presence of oxygen to elicit a cytotoxic effect. PMID- 28890214 TI - Effect of zymosan and poly (I:C) adjuvants on responses to microneedle immunization coated with whole inactivated influenza vaccine. AB - Microneedles are the micrometer size devices used for the delivery of vaccines and biotherapeutics. In order to increase the vaccine efficacy and reduce the antigen dose, there is a significant need to find some adjuvants for the microneedle vaccination. In this study, zymosan, which is the cell wall preparation of Saccharomyces cerevisiae, or poly (I:C) was coated on a microneedle with inactivated influenza virus, and then immunized into BALB/c mouse to determine the immunogenicity, protection and synergetic effect between two adjuvants. As a result, the group administered with zymosan and vaccine antigen showed significantly stronger IgG response, HI titer and IgG subtypes without any adverse effects, compared to the group immunized with the vaccine antigen alone. Also, there were enhanced cellular immune responses in the group received adjuvant with vaccine antigen. In addition, they showed superior protection and lung viral reduction against lethal viral challenge. Taken together, this study confirms that zymosan can be used as an immunostimulant for microneedle vaccination. PMID- 28890215 TI - Piperine-pro-nanolipospheres as a novel oral delivery system of cannabinoids: Pharmacokinetic evaluation in healthy volunteers in comparison to buccal spray administration. AB - Nowadays, therapeutic indications for cannabinoids, specifically Delta9 tetrahydrocannabinol (THC) and Cannabidiol (CBD) are widening. However, the oral consumption of the molecules is very limited due to their highly lipophilic nature that leads to poor solubility at the aqueous environment. Additionally, THC and CBD are prone to extensive first pass mechanisms. These absorption obstacles render the molecules with low and variable oral bioavailability. To overcome these limitations we designed and developed the advanced pro nanolipospheres (PNL) formulation. The PNL delivery system is comprised of a medium chain triglyceride, surfactants, a co-solvent and the unique addition of a natural absorption enhancer: piperine. Piperine was selected due to its distinctive inhibitory properties affecting both Phase I and Phase II metabolism. This constellation self emulsifies into nano particles that entrap the cannabinoids and the piperine in their core and thus improve their solubility while piperine and the other PNL excipients inhibit their intestinal metabolism. Another clear advantage of the formulation is that its composition of materials is approved for human consumption. The safe nature of the excipients enabled their direct evaluation in humans. In order to evaluate the pharmacokinetic profile of the THC-CBD-piperine-PNL formulation, a two-way crossover, single administration clinical study was conducted. The trial comprised of 9 healthy volunteers under fasted conditions. Each subject received a THC-CBD (10.8mg, 10mg respectively) piperine (20mg)-PNL filled capsule and an equivalent dose of the oromucosal spray Sativex(r) with a washout period in between treatments. Single oral administration of the piperine-PNL formulation resulted in a 3-fold increase in Cmax and a 1.5-fold increase in AUC for THC when compared to Sativex(r). For CBD, a 4-fold increase in Cmax and a 2.2-fold increase in AUC was observed. These findings demonstrate the potential this formulation has in serving as a standardized oral cannabinoid formulation. Moreover, the concept of improving oral bioavailability described here, can pave the way for other potential lipophilic active compounds requiring enhancement of their oral bioavailability. PMID- 28890216 TI - My Treatment Approach: Pancreatic Cysts. AB - Our treatment approach for either symptomatic or incidentally found pancreatic cysts continues to improve. The true incidence of pancreatic cysts is not known, and pancreatic cystic neoplasms, especially intraductal papillary mucinous neoplasms, are currently most commonly diagnosed and resected. This is a result of increasing awareness, widespread availability of imaging, and better understanding of the nature of pancreatic cysts as well. Recent studies on molecular analysis and devices such as microbiopsy forceps help us better define and select the treatment approach to alleviate symptoms and to prevent malignant tumors while avoiding unnecessary surgery. PMID- 28890217 TI - Saddle vs Nonsaddle Pulmonary Embolism: Clinical Presentation, Hemodynamics, Management, and Outcomes. AB - OBJECTIVE: To understand the clinical significance, hemodynamic presentation, management, and outcomes of patients presenting with saddle pulmonary embolism (PE). METHODS: All patients with saddle PE diagnosed at Mayo Clinic in Rochester, Minnesota, from January 1, 1999, through December 31, 2014, were included in this study. These patients were age and simplified Pulmonary Embolism Severity Index (sPESI) matched (1:1) to a nonsaddle PE cohort. Both groups were then classified into massive, submassive, and low-risk PE based on established criteria and compared for clinical presentation, management, and outcomes. RESULTS: A total of 187 consecutive patients with saddle PE were identified. The saddle PE group presented more frequently with massive PE (31% vs 20%) and submassive PE (49% vs 32%), whereas low-risk PE was more common in the nonsaddle PE group (48% vs 20%). Systemic thrombolysis was used more frequently in the saddle PE group on admission (10% vs 4%; P=.04) and later during hospitalization (3.2% vs 0%; P=.03). Late major adverse events were similar in both groups except for mechanical ventilation (6% in saddle PE vs 1% in nonsaddle PE; P=.02). Overall in hospital mortality did not differ between the 2 groups (4.3% in saddle PE vs 5.4% in nonsaddle PE; P=.81). CONCLUSION: Although patients with saddle PE presented with higher rates of hemodynamic compromise and need for thrombolysis and mechanical ventilation, we found no difference in short-term outcomes compared with an age- and severity-matched nonsaddle PE cohort. Overall, in-hospital mortality was low in both groups. PMID- 28890219 TI - Use of Monte Carlo analysis in a risk-based prioritization of toxic constituents in house dust. AB - Many chemicals have been detected in house dust with exposures to the general public and particularly young children of potential health concern. House dust is also an indicator of chemicals present in consumer products and the built environment that may constitute a health risk. The current analysis compiles a database of recent house dust concentrations from the United States and Canada, focusing upon semi-volatile constituents. Seven constituents from the phthalate and flame retardant categories were selected for risk-based screening and prioritization: diethylhexyl phthalate (DEHP), butyl benzyl phthalate (BBzP), diisononyl phthalate (DINP), a pentabrominated diphenyl ether congener (BDE-99), hexabromocyclododecane (HBCDD), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and tris(2-chloroethyl) phosphate (TCEP). Monte Carlo analysis was used to represent the variability in house dust concentration as well as the uncertainty in the toxicology database in the estimation of children's exposure and risk. Constituents were prioritized based upon the percentage of the distribution of risk results for cancer and non-cancer endpoints that exceeded a hazard quotient (HQ) of 1. The greatest percent HQ exceedances were for DEHP (cancer and non cancer), BDE-99 (non-cancer) and TDCIPP (cancer). Current uses and the potential for reducing levels of these constituents in house dust are discussed. Exposure and risk for other phthalates and flame retardants in house dust may increase if they are used to substitute for these prioritized constituents. Therefore, alternative assessment and green chemistry solutions are important elements in decreasing children's exposure to chemicals of concern in the indoor environment. PMID- 28890218 TI - Serum perfluoroalkyl substances and cardiometabolic consequences in adolescents exposed to the World Trade Center disaster and a matched comparison group. AB - BACKGROUND: Large amounts of various chemical contaminants, including perfluoroalkyl substances (PFASs), were released at the time of the World Trade Center (WTC) disaster. Thousands of children who lived and/or attended school near the disaster site were exposed to these substances but few studies have examined the possible consequences related to these exposures. OBJECTIVES: To examine the relationship of PFASs serum levels with cardiometabolic profile in children and adolescents enrolled in the World Trade Center Health Registry (WTCHR) and a matched comparison group. METHODS: We evaluated WTCHR enrollees who resided in New York City and were born between September 11, 1993 and September 10, 2001, and a matched comparison group consisting of individuals who were ineligible for WTCHR participation upon distance of their home, school or work from the WTC and lack of participation in rescue and recovery activities. Matching was based on date of birth, sex, race, ethnicity, and income. We assessed exposure to PFASs, as measured by serum levels and association with cardiometabolic profile as measured by arterial wall stiffness, body mass index, insulin resistance, fasting total cholesterol, HDL, LDL and triglycerides. RESULTS: A total of 402 participants completed the study and serum samples were analyzed from 308 participants, 123 in the WTCHR group and 185 in the comparison group. In multivariable regression analysis, after adjusting for relevant confounders, we observed a significant, positive association of perfluorooctanoic acid (PFOA) with triglycerides (beta coefficient=0.14, 95% CI: 0.02, 0.27, 15.1% change), total cholesterol (beta coefficient=0.09, 95% CI: 0.04, 0.14, 9.2% change), and LDL cholesterol (beta coefficient=0.11, 95% CI: 0.03, 0.19, 11.5% change). Perfluorohexanesulfonic acid levels were associated with decreased insulin resistance (beta coefficient=-0.09, 95% CI: -0.18, -0.003, -8.6% change); PFOA and perfluorononanoic acid were associated with increased brachial artery distensibility. CONCLUSIONS: This research adds to our knowledge of the physical health impacts in a large group of children exposed to the WTC disaster. Abnormal lipid levels in young adults might be an early marker of atherosclerosis and cardiovascular diseases and our findings highlight the importance of conducting longitudinal studies in this population. PMID- 28890221 TI - Biogas Science 2016. PMID- 28890220 TI - Production of highly stable spray dried phage formulations for treatment of Pseudomonas aeruginosa lung infection. AB - The potential of bacteriophage therapy for the treatment of pulmonary infections caused by antibiotic-resistant bacteria has been well recognised. The purpose of this study was to investigate the effect of excipients on stabilisation and aerosolisation of spray dried powders of morphologically different phages - PEV podovirus and PEV myovirus. Seven anti-pseudomonal phages were screened against 90 clinical strains of bacterial hosts and three of the phages were selected for formulation study based on the host range. Design of experiments was utilised to assess the effect of different excipients on the stabilisation and aerosolisation of spray dried phages. Both podovirus and myovirus phages were stable in spray dried formulations containing trehalose or lactose and leucine as excipients with less than 1-log10 titre reduction during spray drying, with lactose providing superior phage protection over trehalose. Furthermore, the spray dried phage formulations dispersed in an Osmohaler at 85L/min produced a high fine particle fraction of over 50%. The results showed that the phages in this study can form respirable dry powder phage formulations using the same excipient composition. Spray dried various types of lytic phages hold significant potential for the treatment of pulmonary infections. PMID- 28890222 TI - Identifying subsets of patients with single-level degenerative disc disease for lumbar fusion: the value of prognostic tests in surgical decision making. AB - BACKGROUND CONTEXT: Fusion surgery for degenerative disc disease (DDD) has become a standard of care, albeit not without controversy. Outcomes are inconsistent and a superiority over conservative treatment is debatable. Proper patient selection is key to clinical success, and a comprehensive understanding of prognostic tests does not currently exist. PURPOSE: This study aimed to investigate the value of prognostic tests and sociodemographic factors in predicting outcomes following lumbar fusion surgery for DDD. STUDY DESIGN: This is a retrospective analysis of prospectively collected data. PATIENT SAMPLE: We included patients who underwent fusion surgery for DDD between 2010 and 2016. OUTCOME MEASURES: The outcome measures included pre- and postoperative visual analog scale and Oswestry Disability Index scores. MATERIALS AND METHODS: Prospectively collected patient data were reviewed for preoperative tests, perioperative data, and clinical outcomes. Prognostic tests used were discography, pantaloon cast test (PCT), Modic changes, and a summary of physical symptoms, coined "loading factor." By means of multivariate stepwise regression, prognostic factors that were useful in predicting outcomes were identified. RESULTS: A total of 91 patients fit the inclusion criteria, with a mean follow-up of 33+/-16 months. Discography, Modic changes, and loading factor were of no value for predicting outcome scores (p>.05). A positive PCT predicted improved outcomes in back pain severity, but only in patients without prior surgery (p=.02). Demographic factors that showed a consistent reduction in back pain were female sex (p=.021) and no prior surgery at index level (p=.009). No other sociodemographic factors were of predictive value (p>.05). CONCLUSIONS: In patients without prior surgery, the PCT appears to be the most promising prognostic tool. Other prognostic selection tools such as discography and Modic changes yield disappointing results. In this study, female patients and those without prior spine surgery appear to be most likely to benefit from fusion surgery for DDD. PMID- 28890223 TI - A new iPhone application for measuring active craniocervical range of motion in patients with non-specific neck pain: a reliability and validity study. AB - BACKGROUND CONTEXT: Measurement of cervical spine range of motion (ROM) is often considered to be an essential component of cervical spine physiotherapy assessment. PURPOSE: This study aimed to investigate the reliability and validity of an iPhone application (app) (Goniometer Pro) for measuring active craniocervical ROM (ACCROM) in patients with non-specific neck pain. STUDY DESIGN/SETTING: A cross-sectional study was conducted at the musculoskeletal biomechanics laboratory located at Iran University of Medical Sciences. PATIENT SAMPLE: Forty non-specific neck pain patients participated in this study. OUTCOME MEASURES: The outcome measure was the ACCROM, including flexion, extension, lateral flexion, and rotation. METHOD: Following the recruitment process, ACCROM was measured using a universal goniometer (UG) and iPhone 7 app. Two blinded examiners each used the UG and iPhone to measure ACCROM in the following sequences: flexion, extension, lateral flexion, and rotation. The second (2 hours later) and third (48 hours later) sessions were carried out in the same manner as the first session. Intraclass correlation coefficient (ICC) models were used to determine the intra-rater and inter-rater reliability. The Pearson correlation coefficients were used to establish concurrent validity of the iPhone app. Minimum detectable change at the 95% confidence level (MDC95) was also computed. RESULTS: Good intra-rater and inter-rater reliability was demonstrated for the goniometer with ICC values of >=0.66 and >=0.70 and the iPhone app with ICC values of >=0.62 and >=0.65, respectively. The MDC95 ranged from 2.21 degrees to 12.50 degrees for the intra-rater analysis and from 3.40 degrees to 12.61 degrees for the inter-rater analysis. The concurrent validity between the two instruments was high, with r valuesof >=0.63. The magnitude of the differences between the UG and iPhone app values (effect sizes) was small, with Cohen d values of <=0.17. CONCLUSIONS: The iPhone app possesses good reliability and high validity. It seems that this app can be used for measuring ACCROM. PMID- 28890224 TI - Comparison of hip muscle volume between fit-and-fill stem and tapered-wedge stem after total hip arthroplasty using the anterolateral approach. AB - BACKGROUND: In total hip arthroplasty (THA) surgery, hip muscle preservation is important in strengthening the stability of the hip and improving the activities of the patient. However, whether the type of femoral stem affects the recovery of the hip muscles remains unknown. The aim of this study was to compare the postoperative hip muscle recovery among femoral stem varieties after THA. METHODS: The computed tomography (CT) images of 44 patients (44 hips) who underwent THA using an anterolateral approach were reviewed. Twenty-two patients received a fit-and-fill (FF) stem and 22 received the tapered-wedge (TW) stem. The volumes of the gluteus maximus (GMA), gluteus medius (GME), and obturator internus (OI) were measured on three-dimensional models reconstructed using preoperative and 6-month postoperative CT images. Relationships between muscle volume changes and factors including the femoral stem length were evaluated. RESULTS: The GMA and GME volumes increased postoperatively by 8.2% and 8.3%, respectively, in the FF stem group and 7% and 6%, respectively, in the TW stem group, with no group differences. In contrast, the OI volume decreased postoperatively by 17.8% in the FF group and was preserved in TW group (p < 0.001). Moreover, OI volume was decreased in 19 patients (86%) in the FF group and in 11 patients (50%) in the TW group (p = 0.01). The normalized stem length was significantly associated with the postoperative change in OI volume (r = 0.45, p = 0.002). CONCLUSIONS: The TW stem showed a significant advantage over the FF stem in terms of OI preservation. Surgeons should pay close attention during surgery to avoid OI injury when using different femoral stem types. We suggest that a short and reduced lateral shoulder femoral stem is a better choice for the preservation of external rotation muscles. PMID- 28890226 TI - The impact of early shame memories in Binge Eating Disorder: The mediator effect of current body image shame and cognitive fusion. AB - This study examined the phenomenology of shame experiences from childhood and adolescence in a sample of women with Binge Eating Disorder. Moreover, a path analysis was investigated testing whether the association between shame-related memories which are traumatic and central to identity, and binge eating symptoms' severity, is mediated by current external shame, body image shame and body image cognitive fusion. Participants in this study were 114 patients, who were assessed through the Eating Disorder Examination and the Shame Experiences Interview, and through self-report measures of external shame, body image shame, body image cognitive fusion and binge eating symptoms. Shame experiences where physical appearance was negatively commented or criticized by others were the most frequently recalled. A path analysis showed a good fit between the hypothesised mediational model and the data. The traumatic and centrality qualities of shame related memories predicted current external shame, especially body image shame. Current shame feelings were associated with body image cognitive fusion, which, in turn, predicted levels of binge eating symptomatology. Findings support the relevance of addressing early shame-related memories and negative affective and self-evaluative experiences, namely related to body image, in the understanding and management of binge eating. PMID- 28890225 TI - Early life stress predicts negative urgency through brooding, depending on 5 HTTLPR genotype: A pilot study with 6-month follow-up examining suicide ideation. AB - The present study examined the interaction between early life stress and 5-HTT genotypes in predicting two risk factors for suicidal behavior - the brooding subtype of rumination and impulsivity, in the form of negative urgency - over time. Furthermore, we examined early life stress, brooding, and impulsivity as predictors of suicidal ideation over time. Participants with and without a history of early life stress were genotyped for the 5-HTTLPR polymorphism and completed assessments assessing brooding and negative urgency at baseline and 6 month follow up. Early life emotional abuse was associated with negative urgency at follow-up. We found an indirect effect of early life emotional abuse on negative urgency through brooding among individuals with 5-HTT low expressing genotypes but not among individuals with 5-HTT high expressing genotypes. Further, a logistic regression analysis revealed that negative urgency was associated with higher odds (O.R. = 16.2) of reporting suicide ideation (versus no ideation) at follow-up. Our findings suggest that brooding and negative urgency may result from the interaction between early life emotional abuse and 5 HTT low expressing genotypes. Further research is necessary to understand how early life stress interacts with 5-HTT genotypes to confer risk for suicidal behavior through psychological mechanisms. PMID- 28890227 TI - Using the transtheoretical model to predict physical activity level of overweight adults with serious mental illness. AB - Although physical activity (PA) is recommended for individuals with serious mental illness (ISMI), most of them are inactive or insufficiently active. The transtheoretical model (TTM) has been proposed to explain the motivational factors associated with PA however, there is little evidence of its applicability to ISMI. So, the objective was to analyse whether TTM components are related to PA in overweight ISMI. In this cross-sectional study, participants completed the Global Physical Activity Questionnaire to assess their PA level and TTM components: stages of change (SOC), decisional balance (pros and cons), self efficacy and processes of change (POC; experiential and behavioural). 43 overweight ISMI (27 males, mean age 29.0 +/- 6.64, mean BMI 31.91 +/- 5.10kg/m2, 30% with schizophrenia, and 44% inactive), referred to a PA programme were recruited. PA was positively correlated with POC and perceived pros, with TTM constructs accounting for 14.5% of PA variance. Mean level of behavioural POC and perceived pros were higher in physically active than in inactive participants. So, this study confirms that TTM components are associated with PA in overweight ISMI. Therefore, the TTM should be considered when planning PA interventions for ISMI. PMID- 28890228 TI - Actor-partner interdependence analysis in depressed patient-caregiver dyads: Influence of emotional intelligence and coping strategies on anxiety and depression. AB - OBJECTIVE: Major depressive disorder (MDD) is a leading cause of suffering for both patients and their natural caregivers. A preliminary study highlights the association of emotional intelligence (EI) and coping strategies with quality of life. However, there is a lack of studies concerning dyadic (i.e., patient and natural caregiver) characteristics' impact on anxious and depressive symptoms. In a sample of MDD patients-caregivers dyads, we explored the influence of EI and coping strategies on anxious and depressive symptoms using the actor-partner interdependence model (APIM). METHODS: The cross-sectional study included 79 MDD patient-caregiver dyads. Self-reported data, completed by patients and their primary caregivers, were collected including socio-demographic, EI using TEIQue SF, coping strategies using BriefCope, depressive symptoms using Beck Depression Inventory, anxious symptoms using STAI. The APIM was used to test the dyadic effects of EI and coping strategies on anxious and depressive symptoms, using structural equation modelling. RESULTS: Patients and caregivers reported both anxious and depressive symptoms. Coping strategies, such as problem solving, positive thinking and avoidance, exhibited evidence of actor (degree to which the individual's coping strategies are associated with their own anxiety or depression level) and partner effect (degree to which the individual's coping strategies are associated with the anxiety or depression level of the other member of the dyad). The caregivers' EI was associated with a decrease of their own depression level contrary to patients for which the results were not significant. The patients' and caregivers' EI was associated with a decrease of their own level of anxiety. CONCLUSION: EI and coping strategies were moderately associated with anxious and depressive symptomatology among MDD patient-caregiver dyads. These results suggest that targeted interventions could be proposed to both patients and caregivers. PMID- 28890229 TI - Patterns of emotion regulation and emotion-related behaviors among parents of children with and without ADHD. AB - Parent emotion regulation is a crucial factor in child adjustment. This study examined the patterns and correlation of emotion regulation and emotion-related behaviors for parents of children with and without ADHD. The study emphasized specific parental emotion regulation strategies used in parent-child interactions. Of the 177 participating parents 55.4% had at least one child with ADHD. Participants were asked to complete questionnaires measuring their emotion regulation and emotion-related behaviors (supportive vs. unsupportive) with regard to a specific child, noting whether the child had ADHD. Results indicated that parents of children with ADHD used more emotion regulation strategies than parents of children without ADHD. No differences were found in emotion-related behaviors. Patterns of relations between reappraisal and suppression emotion regulation and supportive and non-supportive emotion-related behaviors revealed that parent reappraisal was an effective emotion regulation strategy for both subgroups, whereas suppression was ineffective only for parents of children without ADHD. These findings shed light on the relation of parent reappraisal and suppression strategies to emotion-related behaviors for different parenting experiences and emphasize the importance of addressing parent specific emotion regulation in parenting intervention programs. PMID- 28890231 TI - 40 Years of Biotechnology Research at Forschungszentrum Julich. PMID- 28890230 TI - Is there a best side for cochlear implants in post-lingual patients? AB - INTRODUCTION: Cochlear Implant is a sensory prosthesis capable of restoring hearing in patients with severe or profound bilateral sensorineural hearing loss. OBJECTIVE: To evaluate if there is a better side to be implanted in post-lingual patients. METHODS: Retrospective longitudinal study. Participants were 40 subjects, of both sex, mean age of 47 years, with post-lingual hearing loss, users of unilateral cochlear implant for more than 12 months and less than 24 months, with asymmetric auditor reserve between the ears (difference of 10dBNA, In at least one of the frequencies with a response, between the ears), divided into two groups. Group A was composed of individuals with cochlear implant in the ear with better auditory reserve and Group B with auditory reserve lower in relation to the contralateral side. RESULTS: There was no statistical difference for the tonal auditory threshold before and after cochlear implant. A better speech perception in pre-cochlear implant tests was present in B (20%), but the final results are similar in both groups. CONCLUSION: The cochlear implant in the ear with the worst auditory residue favors a bimodal hearing, which would allow the binaural summation, without compromising the improvement of the audiometric threshold and the speech perception. PMID- 28890232 TI - Complete progressive ophthalmoplegia and numb chin syndrome, the first clinical manifestations of a lethal abdominal Burkitt lymphoma. AB - A 57-year-old patient was admitted to the Neurology Clinic for hypoesthesia, intense pain in the right chin and double vision. During the hospitalization, the patient developed progressive complete bilateral ophthalmoplegia and numbness of both sides of the chin. Brain CT and MRI scans with gadolinium were normal. Standard laboratory tests on admission were normal. The cerebral spinal fluid examination and the infectious and autoimmune workup were also normal. A thoracic abdominal and pelvic CT scan revealed two hypodense lesions in the liver, irregular thickening of the gastric and ileal wall, and multiple abdominal adenopathies. Meanwhile, the patient developed marked fatigue, fever, sweats, nausea, vomiting and abdominal pain. An exploratory laparotomy was performed that showed multiple tumours of the small intestinal wall, stomach wall, multiple liver masses in both lobes and appendicular tumour. Histopathological findings of the liver biopsy and appendicular walls revealed Burkitt lymphoma. The patient died two days after surgery by cardiopulmonary arrest. This case underscores the importance of keeping BL in the differential diagnosis of patients with rapidly progressive ophthalmoplegia and numb chin syndrome, with normal brain MRI and CSF examinations. PMID- 28890233 TI - [What would you do when faced with a Muslim patient with a conversational disorder?] AB - The purpose of this work is to present the approach to mental disorders in Moroccan patients from a sociocultural perspective. The anthropology of health and ethno-psychiatry will allow us to analyze the concepts of health and disease. From the Moroccan cosmovision we will analyze the alternative treatments and their association with other therapeutic models. PMID- 28890235 TI - The science reproducibility crisis and the necessity to publish negative results. PMID- 28890234 TI - Calibration of a lactic-acid model for simulating biofilm-induced degradation of the dentin-composite interface. AB - OBJECTIVE: To verify and calibrate a chemical model for simulating the degradation of the dentin-composite interface induced by multi-species oral biofilms in vitro. METHODS: Dentin-composite disks (5-mm dia.*2-mm thick) were made from bovine incisor roots and filled with either Z100TM (Z100) or FiltekTM LS (LS) composite. The disks, which were covered with nail varnish, but with one of the dentin-composite margins exposed, were immersed in lactic acid solution at pH 4.5 for up to 48h. Diametral compression was performed to measure the reduction in bond strength of the dentin-composite disks following acid challenge. Scanning electron microscopy (SEM) was used to examine decalcification of dentin and fracture modes of the disks. To better understand the degradation process, micro-computed tomography, in combination with a radiopaque dye (AgNO3), was used to assess interfacial leakage in 3D longitudinally, while SEM was used to determine the path of leakage. One-way analysis of variance (ANOVA) was used to analyze the results, with the level of statistical significance set at p<0.05. The results were compared with those obtained previously using multi-species biofilms for verification and calibration purposes. RESULTS: After 48h of acid challenge, the debonding load of both the LS- and Z100-filled disks reduced significantly (p<0.05). In the Z100-filled disks, debonding mostly occurred at the adhesive-dentin interface, while in the LS-filled disks, this happened at the adhesive-composite interface, instead. The degree of dentin demineralization, the reduction in debonding load and the modes of failure observed were very similar to those induced by multi-species oral biofilms found in the previous work. Leakage of AgNO3 occurred mainly along the hybrid layer. The specimens filled with Z100 had a thicker hybrid layer (~6.5MUm), which exhibited more interfacial leakage than those filled with LS. SIGNIFICANCE: The chemical model with lactic acid used in this study can induce degradation to the dentin-composite interface similar to those produced by multi-species biofilms. With appropriate calibration, this could provide an effective in vitro method for ageing composite restorations in assessing their potential clinical performance. PMID- 28890236 TI - ADenoVirus Initiative Study in Epidemiology (ADVISE): Results of a multicentric epidemiology study in Spain. AB - OBJECTIVE: Non-interventional, observational, epidemiology study to assess clinical characteristics and frequency of adenovirus conjunctivitis diagnosed by AdenoPlus(r) in patients who presented with signs and symptoms of acute conjunctivitis. Safety aspects during use of the test were analyzed as well. METHOD: This analysis presents the data obtained from the 386 patients enrolled in Spain. Patients had to present with acute signs and symptoms of conjunctivitis <=7days. The minimum age was 1year old. Patients who had already used local antiviral therapies, topical steroids or immuno-modulators were not allowed to enter the study. A standardized questionnaire was used to collect patient's ocular history and test results. RESULTS: A total of 386 patients were recruited in 22 sites, being analyzed 329 patients. Among them, the percentage of "AdenoPlus(r) positive" was 36,2% (119/329). Before the test was performed, in 84,1% of the cases, investigators believed that the conjunctivitis was of viral origin but only 50,3% of the investigators had their clinical assessment confirmed by the test. Patients who tested positive for adenoviral conjunctivitis presented higher percentages of signs and symptoms than the rest of the patients. CONCLUSIONS: None of the signs or symptoms could be qualified as pathognomonic of the disease, being difficult for the clinicians to perform an accurate diagnosis. AdenoPlus(r) test is an antigen based immunoassay test that detects the presence of adenovirus directly from tears, and it can be an useful tool to help early differential diagnosis in patients with conjunctivitis signs and symptoms lasting for less than or equal to 7days. PMID- 28890237 TI - Molecular structure, supramolecular organization and thermotropic phase behavior of N-acylglycine alkyl esters with matched acyl and alkyl chains. AB - N-Acylglycines (NAGs), the endogenous single-tailed lipids present in rat brain and other mammalian tissues, play significant roles in cell physiology and exhibit interesting pharmacological properties. In the present study, a homologous series of N-acylglycine alkyl esters (NAGEs) with matched chains were synthesized and characterized. Results of differential scanning calorimetric studies revealed that all NAGEs exhibit a single sharp phase transition and that the transition enthalpy and entropy show a linear dependence on the N-acyl and ester alkyl chain length. The structure of N-myristoylglycine myristyl ester (NMGME), solved by single-crystal X-ray diffraction, showed that the molecule adopts a linear geometry and revealed that the structure of N-myristoyl glycyl moiety in NMGME is identical to that in N-myristoylglycine. The molecules are packed in layers with the polar functional groups of the ester and amide functionalities located at the center of the layer. The crystal packing is stabilized by NH?O hydrogen bonds between the amide CO and NH groups of adjacent molecules as well as by CH?O hydrogen bonds between the amide carbonyl and the methylene CH adjacent to the ester carbonyl of neighboring molecules as well as between ester carbonyl and methylene group of the glycine moiety of adjacent molecules. Powder X-ray diffraction studies showed a linear dependence of the d spacings on the acyl chain length, suggesting that all NAGEs adopt a structure similar to the packing exhibited in the crystal lattice of NMGME. PMID- 28890238 TI - Delivering the right message: Challenges and opportunities in lipid nanoparticles mediated modified mRNA therapeutics-An innate immune system standpoint. AB - mRNA molecules hold tremendous potential as a tool for gene therapy of a wide range of diseases. However, the main hurdle in implementation of mRNA for therapeutics, the systemic delivery of mRNA molecules to target cells, remains a challenge. A feasible solution for this challenge relies in the rapidly evolving field of nucleic acid-loaded nanocarriers and specifically in the established family of lipid-based nanoparticles (LNPs). Herein, we will discuss the main factors, which determine the fate of modified mRNA (mmRNA)-loaded LNPs in-vivo, and will focus on their interactions with the innate immune system as a main consideration in the design of lipid-based mmRNA delivery platforms. PMID- 28890239 TI - Self-help organisations as patient representatives in health care and policy decision-making. AB - A crucial question about participation is who is legitimised, willing and capable of representing particular collectives. Social insurance health care systems tend to focus on representation by patient organisations. Self-help organisations (SHOs), as one type of 'health consumer and patient organisation', often take over this role. Research findings indicate that participation by SHOs is accompanied by high expectations, but also by concerns about the risks of instrumental abuse, overload and professionalisation. However, there is a dearth of in-depth knowledge about both potential and risks of participating for the SHO. To tackle this research gap, a qualitative study design was used to investigate fifteen SHOs in Austria. Data were generated by expert interviews with SHO representatives and documentary analysis of SHO websites. Content analysis was applied. SHOs in Austria advocate for patients' interests, participate in invited spaces and have various forms of cooperative relations with the health care system. Thereby, they draw on the experiential knowledge of their members without, however, systematising it. Experiences with professionalisation and instrumental use are ambiguous, whereas overload is prevalent. SHOs need resources for reflection in order to define their position visa- vis the health system and to realise their potential as patient representatives. Deepening co-operation with the health care system might lead to new participatory practices acknowledging differences in culture and the resources of both sides. PMID- 28890240 TI - Erratum to "Association between peroxisome proliferator-activated receptor, UCP3 and lipoprotein lipase gene polymorphisms and obesity in Chinese adolescents" [Obes Res Clin Pract 2017;11(January-February1):27-33]. PMID- 28890241 TI - Manual and expert annotation of the nearly complete genome sequence of Staphylococcus sciuri strain ATCC 29059: A reference for the oxidase-positive staphylococci that supports the atypical phenotypic features of the species group. AB - Staphylococcus sciuri is considered to be one of the most ancestral species in the natural history of the Staphylococcus genus that consists of 48 validly described species. It belongs to the basal group of oxidase-positive and novobiocin-resistant staphylococci that diverged from macrococci approximately 250 million years ago. Contrary to other groups, the S. sciuri species group has not developed host-specific colonization strategies. Genome analysis of S. sciuri ATCC 29059 provides here the first genetic basis for atypical traits that would support the switch between the free-living style and the infective state in animals and humans. From among the most remarkable features, it was noticed in this extensive study that there were a number of phosphoenolpyruvate:carbohydrate phosphotransferase systems (PTS), almost twice as many as any other staphylococci, and the co-occurrence of mevalonate and non-mevalonate pathways for isoprenoid synthesis. The sequenced strain was devoid of the main virulence factors present in Staphylococcus aureus, although it exhibited numerous heme and iron acquisition systems, as well as crt and aldH genes necessary for gold pigment synthesis. The sensing and signaling networks, exemplified by a large and typical repertoire of two-component regulatory systems and a complete panel of master regulators, such as agr, rex, mgrA, rot, sarA and sarR genes, depict the background in which S. aureus virulence genes were later acquired. An additional sigma factor, a distinct set of electron transducer elements and many gene operons similar to those found in Bacillus spp. would constitute the most visible remnant links with Bacillaceae organisms. PMID- 28890242 TI - Asphyxiation death caused by oxygen-depleting cargo on a ship. AB - The extreme danger associated with entering enclosed spaces loaded with oxygen depleting organic cargo in ships and tanks is obviously underestimated, both among crew and management. We present a case report to highlight this occupational hazard and to increase the knowledge about the imperative precautions, in order to prevent future accidents. An experienced customs officer was found lifeless at the bottom of the unattended cargo hold on a ship loaded with woodchips. The oxygen content in the cargo atmosphere was below 2%, which is incompatible with life. Forensic autopsy revealed injuries related to the fall, and there were no positive toxicological findings in blood, lung or urine. Management and workers must be taught about the extreme rapidity of developing unconsciousness and asphyxiant death when entering enclosed spaces loaded with oxygen-depleting cargo. Even a single inhalation can result in unconsciousness and death. Dozens of annual deaths and severe injuries can easily be prevented if simple precautions are followed. PMID- 28890243 TI - Re: Giorgio Gandaglia, Stephen A. Boorjian, William P. Parker, et al. Impact of Postoperative Radiotherapy in Men with Persistently Elevated Prostate-specific Antigen After Radical Prostatectomy for Prostate Cancer: A Long-term Survival Analysis. Eur Urol 2017;72:910-7. PMID- 28890244 TI - Re: Comprehensive Qualitative Assessment of Urethral Stricture Disease: Toward the Development of a Patient Centered Outcome Measure. PMID- 28890245 TI - Efficacy of Local Treatment in Prostate Cancer Patients with Clinically Pelvic Lymph Node-positive Disease at Initial Diagnosis. AB - BACKGROUND: There is limited evidence supporting the use of local treatment (LT) for prostate cancer (PCa) patients with clinically pelvic lymph node-positive (cN1) disease. OBJECTIVE: To examine the efficacy of any form of LT+/-androgen deprivation therapy (ADT) in treating these individuals. DESIGN, SETTING, AND PARTICIPANTS: Using the National Cancer Database (2003-2011), we retrospectively identified 2967 individuals who received LT+/-ADT versus ADT alone for cN1 PCa. Only radical prostatectomy (RP) and radiation therapy (RT) were considered as definitive LT. INTERVENTION: LT+/-ADT versus ADT alone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Instrumental variable analyses (IVA) were performed using a two-stage residual inclusion approach to compare overall mortality (OM)-free survival between patients who received LT+/-ADT versus ADT alone. The same methodology was used to further compare OM-free survival between patients who received RP+/-ADT versus RT+/-ADT. RESULTS AND LIMITATIONS: Overall, 1987 (67%) and 980 (33%) patients received LT+/-ADT and ADT alone, respectively. In the LT+/ ADT group, 751 (37.8%) and 1236 (62.2%) patients received RP+/-ADT and RT+/-ADT, respectively. In IVA, LT+/-ADT was associated with a significant OM-free survival benefit (hazard ratio=0.31, 95% confidence interval [CI]=0.13-0.74, p=0.007), when compared with ADT alone. At 5 yr, OM-free survival was 78.8% (95% CI: 74.1 83.9%) versus 49.2% (95% CI: 33.9-71.4%) in the LT+/-ADT versus ADT alone groups. When comparing RP+/-ADT versus RT+/-ADT, IVA showed no significant difference in OM-free survival between the two treatment modalities (hazard ratio=0.54, 95% CI=0.19-1.52, p=0.2). Despite the use of an IVA, our study may be limited by residual unmeasured confounding. CONCLUSIONS: Our findings show that PCa patients with clinically pelvic lymph node-positive disease may benefit from any form of LT+/-ADT over ADT alone. While not necessarily curative by itself, the use of RP or RT could be the first step in a multi-modality approach aiming at providing the best cancer control outcomes for these individuals. PATIENTS SUMMARY: We examined the role of local treatment for clinically pelvic lymph node-positive prostate cancer. We found that the delivery of radical prostatectomy or radiation therapy may be associated with an overall mortality-free survival benefit compared with androgen deprivation therapy alone. PMID- 28890246 TI - Reply to Alan Dal Pra, Stephane Supiot and Pirus Ghadjar's Letter to the Editor re: Giorgio Gandaglia, Stephen A. Boorjian, William P. Parker, et al. Impact of Postoperative Radiotherapy in Men with Persistently Elevated Prostate-specific Antigen After Radical Prostatectomy for Prostate Cancer: A Long-term Survival Analysis. Eur Urol 2017;72:910-7. PMID- 28890247 TI - New Insights into Adjuvant Renal Cell Carcinoma Treatment with Vascular Endothelial Growth Factor Inhibitors: What Have We Learned So Far? AB - Adjuvant treatment of renal cell carcinoma with vascular endothelial growth factor inhibitors is feasible and effective with careful patient selection and standard dosing levels. PMID- 28890248 TI - Innovative Therapies to Overcome Resistance to Enzalutamide: Perspective on the Use of Darolutamide. PMID- 28890249 TI - Re: The Use of Apnea During Ureteroscopy. PMID- 28890250 TI - Re: Association Between Direct-to-consumer Advertising and Testosterone Testing and Initiation in the United States, 2009-2013. PMID- 28890251 TI - Risk of Bleeding Versus Venous Thromboembolism in Urological Surgery-Finding the Right Balance Is Not Always Easy! PMID- 28890252 TI - Canalicular adenoma: A systematic review. AB - OBJECTIVE: Canalicular adenoma (CA) is an uncommon but unique benign tumor of salivary gland origin. It is the third most common benign tumor of minor salivary glands, representing less than 1% of all salivary neoplasms. A systematic review is presented of reported cases of CA, to determine trends in presentation, diagnostic features, treatment, and patient outcome. METHODS: Searches of specific databases, as reported, were carried out to identify papers reporting CA. The variables were patient symptoms, tumor location, histopathological findings, demographics, treatment, follow-up, and recurrence. RESULTS: 430 cases were identified; the most common location was in the upper lip (66.3%), followed by hard palate (14.5%). The most common clinical presentation was a nodule (46.5%), followed by asymptomatic (29.5%), and discomfort (28.7%). CA was most frequently seen in females (64%). The average age was 66.3 years. 97% of cases were treated surgically. The average follow-up was 136.3 months, and recurrence was reported in 3% of the cases. CONCLUSION: CA shows a strong predilection for the upper lip. CAs are frequently asymptomatic, but the principal symptom was pressure. PMID- 28890253 TI - Soft tissue oxygen saturation to predict admission. PMID- 28890255 TI - Regional myocardial structural characteristics in ischemic and non-ischemic cardiomyopathy: Left ventricle versus right and apex versus base. PMID- 28890256 TI - Tunable denture adhesives using biomimetic principles for enhanced tissue adhesion in moist environments. AB - : Nature provides many interesting examples of adhesive strategies. Of particular note, the protein glue secreted by marine mussels delivers high adhesion in wet and dynamic environments owing to existence of catechol moieties. As such, this study focuses on denture fixatives, where a non-zinc-containing commercial-based formulation has been judiciously modified by a biomimetic catechol-inspired polymer, poly(3,4-dihydroxystyrene/styrene-alt-maleic acid) in a quest to modulate adhesive performance. In vitro studies, in a lap-shear configuration, revealed that the catechol-modified components were able to enhance adhesion to both the denture base and hydrated, functional oral tissue mimic, with the resulting mode of failure prominently being adhesive rather than cohesive. These characteristics are desirable in prosthodontic fixative applications, for which temporary adhesion must be maintained, with ultimately an adhesive failure from the mucosal tissue surface preferred. These insights provide an experimental platform in the design of future biomimetic adhesive systems. STATEMENT OF SIGNIFICANCE: Mussel adhesive proteins have proven to be promising biomimetic adhesive candidates for soft tissues and here for the first time we have adapted marine adhesive technology into a denture fixative application. Importantly, we have incorporated a soft tissue mimic in our in vitro adhesion technique that more closely resembles the oral mucosa than previously studied substrates. The novel biomimetic-modified adhesives showed the ability to score the highest adhesive bonding out of all the formulations included in this study, across all moisture levels. This paper will be of major interest to the Acta Biomaterialia readership since the study has illustrated the potential of biomimetic principles in the design of effective prosthodontic tissue adhesives in a series of purpose designed in vitro experiments in the context of the challenging features of the oral environment. PMID- 28890254 TI - Rethinking HSF1 in Stress, Development, and Organismal Health. AB - The heat shock response (HSR) was originally discovered as a transcriptional response to elevated temperature shock and led to the identification of heat shock proteins and heat shock factor 1 (HSF1). Since then HSF1 has been shown to be important for combating other forms of environmental perturbations as well as genetic variations that cause proteotoxic stress. The HSR has long been thought to be an absolute response to conditions of cell stress and the primary mechanism by which HSF1 promotes organismal health by preventing protein aggregation and subsequent proteome imbalance. Accumulating evidence now shows that HSF1, the central player in the HSR, is regulated according to specific cellular requirements through cell-autonomous and non-autonomous signals, and directs transcriptional programs distinct from the HSR during development and in carcinogenesis. We discuss here these 'non-canonical' roles of HSF1, its regulation in diverse conditions of development, reproduction, metabolism, and aging, and posit that HSF1 serves to integrate diverse biological and pathological responses. PMID- 28890257 TI - Effects of PDGF-BB delivery from heparinized collagen sutures on the healing of lacerated chicken flexor tendon in vivo. AB - : Flexor tendon lacerations are traditionally repaired by using non-absorbable monofilament sutures. Recent investigations have explored to improve the healing process by growth factor delivery from the sutures. However, it is difficult to conjugate growth factors to nylon or other synthetic sutures. This study explores the performance of a novel electrochemically aligned collagen suture in a flexor tendon repair model with and without platelet derived growth factor following complete tendon laceration in vivo. Collagen suture was fabricated via electrochemical alignment process. Heparin was covalently bound to electrochemically aligned collagen sutures (ELAS) to facilitate affinity bound delivery of platelet-derived growth factor-BB (PDGF-BB). Complete laceration of the flexor digitorum profundus in the third digit of the foot was performed in 36 skeletally mature White Leghorn chickens. The left foot was used as the positive control. Animals were randomly divided into three groups: control specimens treated with standard nylon suture (n=12), specimens repaired with heparinated ELAS suture without PDGF-BB (n=12) and specimens repaired with heparinated ELAS suture with affinity bound PDGF-BB (n=12). Specimens were harvested at either 4weeks or 12weeks following tendon repair. Differences between groups were evaluated by the degree of gross tendon excursion, failure load/stress, stiffness/modulus, absorbed energy at failure, elongation/strain at failure. Quantitative histological scoring was performed to assess cellularity and vascularity. Closed flexion angle measurements demonstrated no significant differences in tendon excursion between the study groups at 4 or 12weeks. Biomechanical testing showed that the group treated with PDGF-BB bound heparinated ELAS suture had significantly higher stiffness and failure load (p<0.05) at 12-weeks relative to both heparinated ELAS suture and nylon suture. Similarly, the group treated with PDGF-BB bound suture had significantly higher ultimate tensile strength and Young's modulus (p<0.05) at 12-weeks relative to both ELAS suture and nylon suture. Compared to nylon controls, heparinized ELAS with PDGF-BB improved biomechanics and vascularity during tendon healing by 12 weeks following primary repair. The ability of ELAS to deliver PDGF-BB to the lacerated area of tendon presents investigators with a functional bioinductive platform to improve repair outcomes following flexor tendon repair. STATEMENT OF SIGNIFICANCE: A high strength aligned collagen suture was fabricated via linear electrocompaction and heparinized for prolonged delivery of PDFG-BB. When it was used to suture a complete lacerated flexor tendon in a chicken model controlled release of the PDGF-BB improved the strength of treated tendon after 12 weeks compared to tendon sutured with commercial nylon suture. Furthermore, Collagen suture with affinity bound PDGF-BB enhanced the vascularization and remodeling of lacerated tendon when it compare to synthetic nylon suture. Overall, electrocompacted collagen sutures holds potential to improve repair outcome in flexor tendon surgeries by improving repair strength and stiffness, vascularity, and remodeling via sustained delivery of the PDGF-BB. The bioinductive collagen suture introduces a platform for sustained delivery of other growth factors for a wide-array of applications. PMID- 28890258 TI - Facile construction of bioreducible crosslinked polypeptide micelles for enhanced cancer combination therapy. AB - : In this study, we developed pH and redox-responsive crosslinked polypeptide based combination micelles for enhanced chemotherapeutic efficacy and minimized side effects. The stability and drug release properties of the polypeptide micelles were efficiency balanced by the corona-crosslinking of the triblock copolymer, poly(ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b pAsp-b-pTyr) with coordinated redox and pH dual-sensitivity by introducing disulfide crosslinkages. Because of the crosslinking of the middle shell of the triblock polypeptide micelles, their robust structure was maintained in strong destabilization conditions and exhibited excellent stability. GSH concentrations were significantly higher in tumor tissue than in normal tissue, which formed the basis for our design. Drug release was elevated under redox and low acidic conditions. Furthermore, crosslinked micelles showed a superior anticancer effect compared to that of non-crosslinked micelles. Incorporation of docetaxel (DTX) and lonidamine (LND) in crosslinked polypeptide micelles increased the intracellular reactive oxygen species (ROS) level and oxidative stress and caused damage to intracellular components that resulted in greater apoptosis of cancer cells than when DTX or LND was used alone. The combination of DTX and LND in crosslinked micelles exhibited efficacious inhibition of tumor growth with an excellent safety profile compared to that reported for drug cocktail combinations and non-crosslinked micelles. Overall, redox/pH-responsive polypeptide micelles could be an interesting platform for efficient chemotherapy. STATEMENT OF SIGNIFICANCE: We have synthesized a biodegradable polypeptide block copolymer to construct a facile pH and redox-responsive polymeric micelle asan advanced therapeutic system for cancer therapy. We have designed a corona-crosslinked triblock copolymer (poly (ethylene glycol)-b-poly(aspartic acid)-b-poly(tyrosine) (PEG-b-pAsp-b-pTyr)) micelles co-loaded with docetaxel and lonidamine (cl-M/DL). The corona of triblock polymer was crosslinked to maintain its structural integrity in the physiological environment. The mitochondrial targeting LND is expected to generate ROS, oxidative stress and thereby synergize the chemotherapeutic efficacy of DTX in killing cancer cells. Consistently, cl-M/DL exhibited excellent antitumor efficacy in xenograft tumor model with remarkable tumor regression. Overall, we demonstrated the construction of bioreducible nanosystem for the effective synergistic delivery of DTX/LND in tumor tissues towards cancer treatment. PMID- 28890259 TI - Silk fibroin-chondroitin sulfate scaffold with immuno-inhibition property for articular cartilage repair. AB - : The demand of favorable scaffolds has increased for the emerging cartilage tissue engineering. Chondroitin sulfate (CS) and silk fibroin have been investigated and reported with safety and excellent biocompatibility as tissue engineering scaffolds. However, the rapid degradation rate of pure CS scaffolds presents a challenge to effectively recreate neo-tissue similar to natural articular cartilage. Meanwhile the silk fibroin is well used as a structural constituent material because its remarkable mechanical properties, long-lasting in vivo stability and hypoimmunity. The application of composite silk fibroin and CS scaffolds for joint cartilage repair has not been well studied. Here we report that the combination of silk fibroin and CS could synergistically promote articular cartilage defect repair. The silk fibroin (silk) and silk fibroin/CS (silk-CS) scaffolds were fabricated with salt-leaching, freeze-drying and crosslinking methodologies. The biocompatibility of the scaffolds was investigated in vitro by cell adhesion, proliferation and migration with human articular chondrocytes. We found that silk-CS scaffold maintained better chondrocyte phenotype than silk scaffold; moreover, the silk-CS scaffolds reduced chondrocyte inflammatory response that was induced by interleukin (IL)-1beta, which is in consistent with the well-documented anti-inflammatory activities of CS. The in vivo cartilage repair was evaluated with a rabbit osteochondral defect model. Silk-CS scaffold induced more neo-tissue formation and better structural restoration than silk scaffold after 6 and 12weeks of implantation in ICRS histological evaluations. In conclusion, we have developed a silk fibroin/ chondroitin sulfate scaffold for cartilage tissue engineering that exhibits immuno-inhibition property and can improve the self-repair capacity of cartilage. STATEMENT OF SIGNIFICANCE: Severe cartilage defect such as osteoarthritis (OA) is difficult to self-repair because of its avascular, aneural and alymphatic nature. Current scaffolds often focus on providing sufficient mechanical support or bio mimetic structure to promote cartilage repair. Thus, silk has been adopted and investigated broadly. However, inflammation is one of the most important factors in OA. But few scaffolds for cartilage repair reported anti-inflammation property. Meanwhile, chondroitin sulfate (CS) is a glycosaminoglycan present in the natural cartilage ECM, and has exhibited a number of useful biological properties including anti-inflammatory activity. Thus, we designed this silk-CS scaffold and proved that this scaffold exhibited good anti-inflammatory effects both in vitro and in vivo, promoted the repair of articular cartilage defect in animal model. PMID- 28890260 TI - The health care innovation bubble. PMID- 28890261 TI - Participation and payments in the PQRS Maintenance of Certification Program: Implications for future merit based payment programs. PMID- 28890262 TI - [Relapsing polychondritis: What's new in 2017?] AB - Relapsing polychondritis (RP) is a rare condition characterized by recurrent inflammation of cartilaginous tissue and systemic manifestations. Data on pathophysiology are scarce and suggest an autoimmune mechanism. Recently, the possibility of dividing patients with RP into three distinct clinical phenotypes has been suggested: the hematological form representing less than 10% of patients, essentially older men with associated myelodysplasia and poor prognosis, the respiratory form representing about 25% of patients with predominant tracheobronchial involvement, and the mild and most frequent form, representing 65% of patients, with a good prognosis. Recent data on survival shows an improvement of overall prognosis compared to historical series. Reported poor prognosis factors are male gender, associated haemopathies and cardiac involvement. Few recent series suggest an interest for positron emission tomography for the diagnosis and the follow-up of treatment. Due to the lack of randomized therapeutic trial, treatment remains empirical and is mainly based on oral corticosteroids sometimes associated with immunosuppressive agents. The use of biologic agents has recently been reported in small retrospective series with different outcome. Finally, some selected patients with mild and occasional peripheral chondritis might justify a treatment with colchicine or a therapeutic abstention with occasional short-term corticosteroids therapy. PMID- 28890263 TI - [Secondary thrombotic microangiopathies]. AB - Thrombotic microangiopathies (TMA) are termed secondary when associated to a specific context favouring their occurrence. They encompass mainly TMA associated with pregnancy, allogeneic hematopoietic stem cell transplantation, cancer, drugs, or HIV infection. Secondary TMA represent a heterogeneous group of diseases which clinical presentation largely depends on the associated context. It is therefore mandatory to recognize these conditions since they have a significant impact in TMA management and prognosis. A successful management still represents a challenge in secondary TMA. Significant progresses have been made in the understanding of pregnancy-associated TMA, allowing an improvement of prognosis; on the opposite, other forms of secondary TMA such as hematopoietic stem cell transplantation-associated TMA or TMA associated with chemotherapy remain of dismal prognosis. A better understanding of pathophysiology in these forms of TMA, in association with a more empirical approach through the use of new therapeutic agents that can also help in the understanding on new mechanisms a posteriori, should improve their prognosis. The preliminary encouraging results reported with complement blockers in this field could represent a convincing example. PMID- 28890264 TI - Breastfeeding Is Associated With Higher Retention in WIC After Age 1. AB - OBJECTIVE: Examine factors associated with retention on the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) after 1 year of age. SETTING: A large California WIC program. PARTICIPANTS: WIC participants 14 months old (9,632) between July and September, 2016. MAIN OUTCOME MEASURE: Recertification in WIC by 14 months of age. ANALYSIS: Multivariate logistic regression was performed and odds ratios (ORs) and 95% confidence intervals (CIs) were computed to examine factors associated with child retention in WIC at age 14 months. RESULTS: Mothers performing any amount of breastfeeding from 6 to 12 months were more likely than mothers not breastfeeding to recertify their children in WIC at age 14 months. The odds of retention for children fully breastfed from 6 to 12 months was about 3 times higher than for fully formula-fed children (95% CI, 2.46-3.59). The odds of retention for mostly breastfed children and children fed some breast milk but mostly formula were 1.95 (95% CI, 1.57 2.43) and 1.72 (95% CI, 1.41-2.10) times higher than fully formula-fed children. Prenatal intention to breastfeed (OR = 1.34; 95% CI, 1.16-1.55), online education (OR = 1.08; 95% CI, 1.03-1.13), missing benefits (OR = 0.19; 95% CI, 0.17-0.21), underredemption of WIC benefits (OR = 0.51, 95% CI, 0.45-0.58), early enrollment in WIC (OR = 1.11; 95% CI, 1.09-1.14), number of family members receiving WIC (OR = 1.29, 95% CI, 1.14-1.46), English language preference (OR, 0.55; 95% CI, 0.47 0.64), and participation in Medicaid (OR = 1.29; 95% CI, 1.14-1.47) were also associated with retention. CONCLUSIONS AND IMPLICATIONS: Results from this study suggested there are a number of areas WIC programs may target to promote ongoing participation in the program. These include support for both breastfeeding and non-breastfeeding women, technology-based strategies, and targeted outreach to pregnant women, participants who have missed benefits, and participants who have not redeemed their benefits. Research that examines the impact of targeted interventions directed at >=1 of these areas is essential to help WIC programs maintain contact with children into early childhood. PMID- 28890265 TI - Branding a School-Based Campaign Combining Healthy Eating and Eco-friendliness. AB - OBJECTIVE: To develop a branding strategy for a campaign to improve the quality of foods children bring from home to school, using a combined healthy eating and eco-friendly approach and for a control campaign focusing solely on nutrition. METHODS: Formative research was conducted with third- and fourth-grade students in lower- and middle-income schools in Greater Boston and their parents. Phase I included concept development focus groups. Phase II included concept testing focus groups. A thematic analysis approach was used to identify key themes. RESULTS: In phase I, the combined nutrition and eco-friendly messages resonated; child preference emerged as a key factor affecting food from home. In phase II, key themes included fun with food and an element of mystery. Themes were translated into a concept featuring food face characters. CONCLUSIONS AND IMPLICATIONS: Iterative formative research provided information necessary to create a brand that appealed to a specified target audience. PMID- 28890266 TI - In-line coupling of supported liquid membrane extraction to capillary electrophoresis for simultaneous analysis of basic and acidic drugs in urine. AB - Simultaneous extraction of basic and acidic drugs across thin supported liquid membrane (SLM) and direct injection of the extracted drugs from SLM surface into capillary electrophoresis (CE) were demonstrated. A microextraction device compatible with injection system of commercial CE instrument was filled with 20MUL of sample and 10MUL of acceptor solution, which were interspaced by the SLM impregnated with 5MUL of organic solvent. Extractions of three basic drugs (nortriptyline, haloperidol and loperamide) and two acidic drugs (ketoprofen and naproxen) were achieved at optimized conditions including 1-ethyl-2-nitrobenzene as SLM solvent, natural pH of sample solution, 2.5mM NaOH acceptor solution and 30min extraction time. The extracted drugs were directly injected into CE for separation and quantification in a background electrolyte solution consisting of 30mM ammonium acetate adjusted to pH 4.2 with acetic acid. The entire analytical procedure including drugs extraction, injection, separation and quantification was automated in the CE instrument and the only manual procedures were SLM impregnation and filling the microextraction device with sample and acceptor solutions. The analytical method was suitable for simultaneous determination of basic and acidic drugs in undiluted human urine samples and was used for direct determination of naproxen in urine after oral administration of Nalgesin S tablet. Efficient elimination of sample matrix and selective transfer of basic and acidic drugs were achieved and the hyphenated SLM-CE method was characterized by repeatability of peak areas ranging from 3.7 to 13.4%, linear relationship between peak areas and concentrations (r2=0.994-0.999) and limits of detection between 0.05 and 1.5MUg/mL. PMID- 28890267 TI - Analysis of underivatised low volatility compounds by comprehensive two dimensional gas chromatography with a short primary column. AB - Comprehensive two-dimensional gas chromatography (GC*GC) approaches with cryogenic modulation were developed for the qualitative analysis of selected low volatility compounds in raw coffee bean extracts, without derivatisation. The approaches employed short first (1D) and second (2D) dimension columns, specifically a 1D 65% phenyl methyl siloxane column (11m) and a 2D 5% phenyl methyl siloxane column (1m), which allowed elution of high molar mass compounds (e.g.>600Da). Solutes included hydrocarbons, fatty acids, diterpenes, tocopherols, sterols, diterpene esters, and di- and triacylglycerides. An oven temperature program up to 370 degrees C was employed. The effects of experimental conditions were investigated, revealing that the GC*GC results strongly depended on the cryogenic trap T, and oven T program. An appropriate condition was selected and further applied for group type analysis of low volatility compounds in green Arabica coffee beans. Retention indices were compiled for 1D GC analysis and were similar for the composite column data in GC*GC. The elution of some compounds was confirmed by use of authentic standards. The approach allowed direct analysis of coffee extract in ethyl acetate solution, with improved analyte peak capacity (approximately 200 compounds were detected) without prior fractionation or pre-treatment of the sample. This avoided potential hydrolysis of high molar mass conjugate esters as well as degradation of thermally labile compounds such as the derivatives of the diterpenes cafestol and kahweol. PMID- 28890268 TI - Acylhydrazone bond dynamic covalent polymer gel monolithic column online coupling to high-performance liquid chromatography for analysis of sulfonamides and fluorescent whitening agents in food. AB - A new dynamic covalent polymer (DCP) gel was well designed and constructed based on imine chemistry. Polycondensation of 4,4'-biphenyldicarboxaldehyde and 1,3,5 benzenetricarbohydrazide via Schiff-base reaction resulted in an acylhydrazone bond gel (AB-gel) DCP. AB-gel DCP had three-dimensional network of interconnected nanoparticles with hierarchically porous structure. AB-gel DCP was successfully fabricated as a monolithic column by an in-situ chemical bonding method for online enrichment and separation purpose with excellent permeability. AB-gel DCP based monolithic column showed remarkable adsorption affinity towards target analytes including sulfonamides (SAs) and fluorescent whitening agents (FWAs) due to its strong pi-pi affinity, hydrophobic effect and hydrogen bonding interaction. Then, AB-gel DCP based monolithic column was applied for online separation and analysis of trace SAs and FWAs in food samples coupled with high performance liquid chromatography (HPLC). Sulfathiazole (ST) and sulfadimidine (SM2) in one positive weever sample were actually found and determined with concentrations of 273.8 and 286.3MUg/kg, respectively. 2,5-Bis(5-tert-butyl-2 benzoxazolyl) thiophene (FWA184) was actually quantified in one tea infusion sample with the concentration of 268.5ng/L. The spiked experiments suggested the good recoveries in range of 74.5-110% for SAs in weever and shrimp samples with relative standard deviations (RSDs) less than 9.7% and in range of 74.0-113% for FWAs in milk and tea infusion samples with RSDs less than 9.0%. AB-gel DCP monolithic column was proved to be a promising sample preparation medium for online separation and analysis of trace analytes in food samples with complex matrices. PMID- 28890269 TI - Characterization and purification of anthocyanins from black peanut (Arachis hypogaea L.) skin by combined column chromatography. AB - Black peanut skins as a byproduct from peanut industry contain abundant anthocyanins, evaluated as 8.61+/-0.27mg/g dry black peanut skins, are currently poorly exploited. In this work, four anthocyanins and three major flavonols were detected and identified by HPLC-PDA-ESI-MS/MS from the acidified water extract of black peanut skins of Arachis hypogaea L. After preliminary removal of flavonols by ethyl acetate (EtOAc), further purification of the anthocyanins was conducted using a combination of Amberlite XAD-7HP and ODS-AQ-HG column chromatography methods. Two most abundant monomeric anthocyanins cyanidin-3-O-sophoroside (5.77+/-0.42mg) and cyanidin-3-O-sambubioside (4.10+/-0.17mg) were eventually obtained from 2g dry black peanut skins, and their purities were determined by HPLC-PDA as 97.29% and 98.28% at the yields of 87.47% and 64.27% on the basis of their total amount in the crude extracts, respectively. These sequential treatments can be easily adapted to large-scale fractionation of pure anthocyanin monomers. PMID- 28890270 TI - Solid-phase extraction of the alcohol abuse biomarker phosphatidylethanol using newly synthesized polymeric sorbent materials containing quaternary heterocyclic groups. AB - Phosphatidylethanol (PEth) is an interesting biomarker finding increased use for detecting long term alcohol abuse with high specificity and sensitivity. Prior to detection, sample preparation is an unavoidable step in the work-flow of PEth analysis and new protocols may facilitate it. Solid-phase extraction (SPE) is a versatile sample preparation method widely spread in biomedical laboratories due to its simplicity of use and the possibility of automation. In this work, SPE was used for the first time to directly extract PEth from spiked human plasma and spiked human blood. A library of polymeric SPE materials with different surface functionalities was screened for PEth extraction in order to identify the surface characteristics that control PEth retention and recovery. The plasma samples were diluted 1:10 (v/v) in water and spiked at different concentrations ranging from 0.3 to 5MUM. The library of SPE materials was then evaluated using the proposed SPE method and detection was done by LC-MS/MS. One SPE material efficiently retained and recovered PEth from spiked human plasma. With this insight, four new SPE materials were formulated and synthesized based on the surface characteristics of the best SPE material found in the first screening. These new materials were tested with spiked human blood, to better mimic a real clinical sample. All the newly synthetized materials outperformed the pre-existing commercially available materials. Recovery values for the new SPE materials were found between 29.5% and 48.6% for the extraction of PEth in spiked blood. A material based on quaternized 1-vinylimidazole with a poly(trimethylolpropane trimethacrylate) backbone was found suitable for PEth extraction in spiked blood showing the highest analyte recovery in this experiment, 48.6%+/-6.4%. PMID- 28890271 TI - The parathyroid hormone 2 receptor participates in physiological and behavioral alterations of mother mice. PMID- 28890273 TI - The association of weight loss with one-year mortality in hospital patients, stratified by BMI and FFMI subgroups. AB - BACKGROUND: The European Society for Clinical Nutrition and Metabolism (ESPEN) has recently published consensus-based criteria for the diagnosis of malnutrition; in subjects identified at nutritional risk the diagnosis is confirmed by either BMI <18.5 kg/m2 or weight loss in combination with low BMI or low FFMI. Concerns have been raised whether this definition correctly classifies malnutrition in patients with normal weight or overweight and concomitant weight loss. Therefore, the aim of this research is to assess the association between weight loss and one-year mortality in hospitalized patients, stratified by BMI and FFMI subgroups. METHODS: This prospective study included 769 patients admitted to the VU University Medical Center. Critical weight loss (CWL) was defined as >5% weight loss in the previous month or >10% weight loss in the previous six months. The association between CWL and one-year mortality was analyzed with a priori stratification by BMI cut-off values (=20.0 kg/m2 for patients <70 years and =22.0 kg/m2 for patients >=70 years) and FFMI cut-off values (derived from BIA measurements, =15 kg/m2 for females and =17 kg/m2 for males). Mortality risks were calculated (HR, 95% CI). RESULTS: CWL occurred in 35% of patients and was associated with an increased one-year mortality rate vs. no-CWL (25% vs. 15%, p = 0.001), HR for mortality risk 1.76 (1.26-2.45)). CWL + low FFMI was associated with higher mortality risk (HR 1.95 (1.20-3.17), whereas CWL + normal FFMI was not (HR 1.37 (0.85-2.21)). Among patients with normal/high BMI, those with CWL had a significantly higher mortality risk compared to those without critical weight loss, however additionally adding FFMI to that model showed that a low FFMI was crucial in the observed association with mortality (CWL + normal BMI + low FFMI, HR 2.69 (1.29-5.65); CWL + normal BMI + normal FFMI, HR 1.38 (0.84-2.27)). CONCLUSION: - Patients with critical weight loss have a higher one-year mortality compared to patients with no critical weight loss. FFMI seems to play a crucial role in this association, as normal weight patients with normal FFMI had lower mortality rates than their counterparts with low FFMI. PMID- 28890272 TI - A comparison of bite size and BMI in a cafeteria setting. AB - Our study investigated the relationship between BMI and bite size in a cafeteria setting. Two hundred and seventy one participants consumed one meal each. Participants were free to select any food provided by the cafeteria and could return for additional food as desired. Bite weights were measured with a table embedded scale. Data were analyzed with ANOVAs, regressions, Kolmogorov-Smirnov tests, and a repeated measures general linear model for quartile analysis. Obese participants were found to take larger bites than both normal (p=0.002) and overweight participants (p=0.017). Average bite size increased by 0.20g per point increase in BMI. Food bites and drink bites were analyzed individually, showing 0.11g/BMI and 0.23g/BMI slopes, respectively. Quartiles of bites were also analyzed, and a significant interaction was found between normal and obese participants (p=0.034) such that the lower two quartiles were similar, but the upper two quartiles showed an increase in bite size for obese participants. The source of these effects could be the result of a combination of several uncontrolled factors. PMID- 28890274 TI - Serum magnesium concentrations and all-cause, cardiovascular, and cancer mortality among U.S. adults: Results from the NHANES I Epidemiologic Follow-up Study. AB - BACKGROUND: Few studies have examined the associations of serum magnesium (Mg) concentrations with total and cause-specific mortality in a nationally representative sample of US adults. We investigate the dose-response relationships of baseline serum Mg concentrations with risk of mortalities in a large, nationally representative sample of US adults. METHODS: We analyzed prospective data of 14,353 participants aged 25-74 years with measures of serum Mg concentrations at baseline (1971-1975) from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study (NHEFS). Mortality data was linked through December 31, 2011. We estimated the mortality hazard ratios (HRs), for participants within serum Mg categories of <0.7, 0.7-0.74, 0.75-0.79, 0.8 0.89 (referent), 0.9-0.94, 0.95-0.99, and >=1.0 mmol/L using weighted multivariate-adjusted Cox proportional hazards models. RESULTS: During a median follow-up of 28.6 years, 9012 deaths occurred, including 3959 CVD deaths, 1923 cancer deaths, and 708 stroke deaths. The multivariate-adjusted HRs (95% CIs) of all-cause mortality across increasing categories of Mg were 1.34 (1.02, 1.77), 0.94 (0.75, 1.18), 1.08 (0.97, 1.19), 1.00 (referent), 1.05 (0.95, 1.16), 0.96 (0.79, 1.15), and 0.98 (0.76, 1.26). Similar trends were observed for cancer (HRs for serum Mg < 0.7: 1.39, 95% CI: 0.83, 2.32) and CVD mortality (HRs for serum Mg < 0.7: 1.28, 95% CI: 0.81, 2.02) but were not statistically significant. An elevated risk for stroke mortality was observed among participants with serum Mg < 0.70 mmol/L (HR: 2.55, 95% CI: 1.18, 5.48). CONCLUSIONS: Very low serum Mg concentrations were significantly associated with an increased risk of all-cause mortality in US adults. PMID- 28890275 TI - Enhanced referral prioritisation for acute adult dietetic services: A randomised control trial to test a web-based decision training tool. AB - BACKGROUND & AIMS: Dietitians in acute adult services need to prioritise dietetic referrals in order to manage their daily workload and ensure effective treatment of patients. Newly qualified dietitians do not usually receive specific training on prioritisation and could be helped with an evidence-based, effective, decision training tool that is based on the practice of experienced dietitians. We developed an internationally available web-based decision-training tool designed to improve novice dietitians' ability to make dietetic prioritisation decisions. The training tool comprised of a pre-training task, a post-training task and training materials. The aim of this study was to test the effectiveness of the training tool on novices' ability for dietetic prioritisation. METHODS: Pre registration dietitians and recent graduates (one-year) from across the UK were invited to participate in this randomised controlled trial (RCT). Each participant made prioritisation decisions on a set of dietetic referral scenarios: 53 scenarios at pre-training and 27 at post-training. After pre training the intervention group was presented with the training materials, whereas the control group was told to carry on with the post-training task. Participants did not know which group they had been randomly allocated to. We calculated i) level of agreement between decisions made by each novice and experts' consensus using Pearson correlation, intra-class correlation (ICC(2,1)); ii) intra-rater consistency using ICC(1,1) and iii) intra-group consistency using ICC (2,1). We compared group means at pre-training and post-training; estimated effect size using the degree of change from pre- to post-training, and 2-factor mixed ANOVA to assess overall effect of the training across the groups and time points. RESULTS: 151 participants (69 in control and 82 in intervention) completed the trial. The groups did not differ in demographic characteristics. Both Pearson and ICC(2,1) correlations increased with training intervention; a moderate effect of training was found for both metrics, d = 0.69 (r = 0.32) for the former and d = 0.54 (r = 0.26) for the latter. Intra-rater consistency improved with training but with a small effect size, d = 0.32 (r = 0.16). The intra-group consistency also improved with training: ICC = 0.48 pre-training to 0.61 post-training. CONCLUSIONS: The training tool was found to be effective in improving the novice dietitian's ability to prioritise referrals in the acute adult setting. The training tool is freely available at www.dietitianreferral.org for use by all student or early career dietitians internationally. PMID- 28890276 TI - The pressures of obesity: The relationship between obesity, malnutrition and pressure injuries in hospital inpatients. AB - BACKGROUND: Pressure injuries (PI) are a significant clinical problem across all healthcare facilities, associated with poor patient outcomes, increased length of stay and healthcare costs. Whilst it is known that underweight (Body Mass Index (BMI) < 18.5 kg/m2) and malnourished individuals have an increased risk of developing PI, few studies have investigated the effects of obesity (BMI >= 30 kg/m2) and morbid obesity (BMI >= 40 kg/m2) on PI prevalence. This study aimed to determine whether PI prevalence was associated with levels of obesity; the complex association between morbid obesity, malnutrition and PI prevalence in hospital inpatients was also explored. METHODS: Data collected from annual Queensland Patient Safety Bedside Audits conducted between 2010 and 2015 was used to examine the outcomes of interest (n = 2479). Bivariate tests were used to explore relationships between age, gender, BMI, malnutrition and PI prevalence. Regression analysis explored associations between BMI, malnutrition and PI, adjusting for potential confounders. RESULTS: Overall PI prevalence was 6.9% and was significantly higher in the underweight and morbidly obese groups (underweight 12.7%, healthy weight 7.8%, overweight 5.7%, obese 4.8%, morbidly obese 12%; p = 0.001). In addition to BMI, malnutrition and age were significantly associated with PI prevalence. After adjusting for confounders, morbidly obese inpatients had over three times the odds of developing a PI compared to healthy weight inpatients (OR = 3.478, 95% CI 1.657-7.303; p = 0.001). Morbidly obese inpatients who were also malnourished had eleven-fold greater odds of developing a PI compared to the morbidly obese well-nourished in logistic regression analysis (OR = 11.143, 95% CI 2.279-54.481, p = 0.003). CONCLUSIONS: Morbid obesity is a significant and independent risk factor for PI development. However, the clustering of nutritional risk factors (morbid obesity and malnutrition) substantially increases this risk. Therefore, routine and formal assessment of both BMI and malnutrition status are important to enable the identification of patients at high risk of PI. PMID- 28890277 TI - [Prenatal diagnosis of abdominal wall defects]. AB - Anterior abdominal wall defects (AAWD) correspond to a wide spectrum of congenital defects affecting 6.3/10,000 pregnancies. They have in common a closure defect of the anterior abdominal wall and can be fatal or expose the fetus and the neonate (NN) to many complications. This study was based on a retrospective study of 22 cases of AAWD collected between May 2009 and December 2014. Its purpose was to specify the importance of prenatal ultrasonography in the diagnosis and prognosis assessment of these defects. These 22 AAWDs consisted in 13 cases of omphalocele (including four cases of Beckwith-Wiedemann syndrome), four of gastroschisis, one of pentalogy of Cantrell, three of vesical exstrophy and one of cloacal exstrophy. Prenatal ultrasonography provided the diagnosis of 14 of these defects with a changing sensitivity with the gestational age varying from 17% in the first trimester to 71.4% and 77.8% in the second and third trimesters, respectively. The relevance of this examination was improved when performed by an imaging specialist. The prenatal diagnosis of these defects indicated an amniocentesis in eight cases, allowing the diagnosis of two cases of trisomy 18. It also motivated a therapeutic termination of the pregnancy (TTP) in ten cases. Prenatal ultrasonography allowed better prenatal follow-up and planning of the delivery of the continued pregnancies. It indicated an emergency C-section in only one case by showing intestinal complications of gastroschisis. Four NNs died (two cases of omphalocele and two of gastroschisis), three of which postoperatively and the prenatal diagnosis did not improve survival. Prenatal ultrasonographic diagnosis provided a precise morphological study determining the type of the AAWD, a complete malformation assessment, and the prognosis factors. This resulted in adequate multidisciplinary pre and postnatal care, including a rigorous ultrasound follow-up, a TTP in case of associated defects, and emergency delivery once the complications of poor diagnosis are detected. PMID- 28890278 TI - Comments on 'Management of parturients with Factor XI deficiency - 10 year case series and review of the literature'. PMID- 28890279 TI - EBCOG position statement on caesarean section in Europe. PMID- 28890280 TI - Psychometric properties of a short form of the Center for Epidemiologic Studies Depression (CES-D-10) scale for screening depressive symptoms in healthy community dwelling older adults. AB - BACKGROUND: The 10-item Center for the Epidemiological Studies of Depression Short Form (CES-D-10) is a widely used self-report measure of depression symptomatology. The aim of this study is to investigate the psychometric properties of the CES-D-10 in healthy community dwelling older adults. METHODS: The sample consists of 19,114 community-based individuals residing in Australia and the United States who participated in the ASPREE trial baseline assessment. All individuals were free of any major illness at the time. We evaluated construct validity by performing confirmatory factor analysis, examined measurement invariance across country and gender followed by evaluating item discrimination bias in age, gender, race, ethnicity and education level, and assessing internal consistency. RESULTS: High item-total correlations and Cronbach's alpha indicated high internal consistency. The factor analyses suggested a unidimensional factor structure. Construct validity was supported in the overall sample, and by country and gender sub-groups. The CES-D-10 was invariant across countries, and although evidence of marginal gender non invariance was observed there was no evidence of notable gender specific item discrimination bias. No notable differences in discrimination parameters or group membership measurement non-invariance were detected by gender, age, race, ethnicity, and education level. CONCLUSION: These findings suggest the CES-D-10 is a reliable and valid measure of depression in a volunteer sample. No noteworthy evidence of invariance and/or item discrimination bias is observed across gender, age, race, language and ethnic groups. PMID- 28890281 TI - Participation in a US community-based cardiovascular health study: investigating nonrandom selection effects related to employment, perceived stress, work-related stress, and family caregiving. AB - PURPOSE: Participation in health studies may be inversely associated with employment and stress. We investigated whether employment, perceived stress, work related stress, and family caregiving were related to participation in a longitudinal US community-based health study of black and white men and women aged >=45 years. METHODS: Prevalence ratios and confidence intervals were estimated for completion of the second stage (S2) of a two-stage enrollment process by employment (status, type), and stress (perceived stress, work-related stress, caregiving), adjusting for age, sex, race, region, income, and education. Eligibility and consent for a follow-up occupational survey were similarly evaluated. RESULTS: Wage- but not self-employed participants were less likely than the unemployed to complete S2. Among the employed, S2 completion did not vary by stress; however, family caregivers with a short time burden of care (<2 hour/d) were more likely to complete S2, compared to noncaregivers. Eligibility and participation in the follow-up occupational survey were higher among those employed (vs. unemployed) at enrollment but were not associated with enrollment stress levels. CONCLUSIONS: Limited evidence of selection bias was seen by employment and stress within a large US community-based cohort, but findings suggest the need for enrollment procedures to consider possible barriers to participation among wage-employed individuals. PMID- 28890282 TI - Opioid dosing trends over eight years among US Veterans with musculoskeletal disorders after returning from service in support of recent conflicts. AB - PURPOSE: To examine long-term opioid dosing trends among Veterans with chronic pain. METHODS: We identified 79,015 Veterans with musculoskeletal disorders who were dispensed greater than or equal to 1 opioid prescriptions between 2002 and 2009 after returning from recent conflicts. Opioid-dosing trends were examined using a generalized estimating equation while accounting for patient characteristics, temporal and geographic confounding. RESULTS: In total, 472,819 opioid prescriptions were dispensed (mean +/- standard deviation: 6.0 +/- 10.1 per Veteran). Both average daily morphine equivalents (MEs/d) and the proportion of high-dose prescribing (greater than 100 ME/d) increased from baseline period (2002-2004) to 2006, then remained relatively stable. Veterans with extended persistent (greater than or equal to 40 days over 1-2 episodes) and extended intermittent (greater than or equal to 40 days over greater than or equal to three episodes) dispensing patterns received more high-dose prescriptions than those dispensed prescriptions less than 40 days, with adjusted odds ratios (95% confidence interval) of 7.2 (6.0-8.8) and 3.6 (3.0-4.3), respectively. Posttraumatic stress disorder and other mental health diagnoses were associated with 30% increased odds of high-dose prescribing. CONCLUSIONS: The average daily dose of opioid prescriptions and the likelihood of high-dose prescribing to these Veterans appeared to increase from 2002 to 2006, then remained relatively stable through 2009. Veterans on opioid prescriptions for extended duration or with mental health diagnoses tend to receive higher dose therapy. PMID- 28890283 TI - Factors affecting workforce participation and healthy worker biases in U.S. women and men. AB - PURPOSE: To investigate potential attenuation of healthy worker biases in populations in which healthy women of reproductive age opt out of the workforce to provide childcare. METHODS: We used 2013-2015 data from 120,928 U.S. women and men aged 22-44 years participating in the Gallup-Healthways Well-Being Index. We used logistic regression to estimate adjusted prevalence odds ratios (PORs) and 95% confidence intervals (CIs) for associations between health and workforce nonparticipation. RESULTS: Women and men reporting poor health were more likely to be out of the workforce than individuals reporting excellent health (POR: 3.7, 95% CI: 3.2-4.2; POR: 6.7, 95% CI: 5.7-7.8, respectively), suggesting potential for healthy worker bias. For women (P < .001) but not men (P = .30), the strength of this association was modified by number of children in the home: POR: 7.3 (95% CI: 5.8-9.1) for women with no children, decreasing to POR: 0.9 (95% CI: 0.6-1.5) for women with four or more children. CONCLUSIONS: These results are consistent with attenuation of healthy worker biases when healthy women opt out of the workforce to provide childcare. Accordingly, we might expect the magnitude of these biases to vary with the proportion of women with differing numbers of children in the population. PMID- 28890284 TI - Activity-dependent changes in transporter and potassium currents in hippocampal astrocytes. AB - Astrocytes are involved in maintenance of synaptic microenvironment by glutamate uptake and K+ clearance. These processes are associated with net charge transfer across the membrane and therefore can be recorded as glutamate transporter (IGluT) and K+ (IK) currents. It has been previously shown that the blockade of IK with BaCl2 enhances the IGluT. Here we show that activity-dependent facilitation (5 stimuli at 50Hz) of IGluT was not significantly different in BaCl2 compared to facilitation of IGluT isolated by post-hoc subtraction of IK. Nevertheless, BaCl2 abolished the activity-dependent prolongation of taudecay, which was observed for IGluT isolated by post-hoc subtraction of IK. This finding suggests that activity-dependent accumulation of extracellular K+ ([K+]o) causes astrocytic depolarization, which is responsible for the increase in taudecay of IGluT. The blockade of inward rectifying K+ channels (Kir) with BaCl2 makes astrocytic membrane potential insensitive to [K+]o elevation and thus abolishes this increase. Blockade of IGluT with glutamate transporter blocker, DL-threo beta-benzyloxyaspartic acid (TBOA) did not significantly affect the amplitude of IK but decreased its taudecay. However, activity dependent facilitations of both amplitude and taudecay of IK were larger in TBOA, than in the control conditions. We suggest that activity-dependent accumulation of extracellular glutamate can enhance release of K+. Thus activity-dependent changes in [K+]o can affect glutamate dwell-time in the synaptic cleft, and vice versa, extracellular glutamate accumulation can affect [K+]o time-course. Our finding is important for understanding of the astrocytic mechanisms in glutamate excitotoxicity and in diseases related to disruption of K+ homeostasis (e.g. stroke, migraine, and epilepsy). PMID- 28890285 TI - Rate of Legionella pneumophila colonization in hospital hot water network after time flow taps installation. AB - In hospital water systems legionellae may be resistant to disinfectants in pipework, which is a problem particularly in areas where there is low flow or stagnation of water. We evaluated legionella colonization of a water network of an Italian hospital after time flow taps (TFTs) installation in proximity to dead legs. The water volume flushed was 64 L/day from May 2016, and 192 L/day from December 2016. Before TFTs installation, Legionella pneumophila sg2-14 was detected in all points (4 * 104 +/- 3.1 * 104 cfu/L). All sites remained positive (2.9 * 104 +/- 1.9 * 104 cfu/L) through November 2016. From December 2016 legionella persisted in one point only (2 * 102 to 6.8 * 103 cfu/L). TFTs with chemical disinfection may reduce legionella colonization associated with dead legs. PMID- 28890286 TI - Processes of care in surgical patients who died with hospital-acquired infections in Australian hospitals. AB - BACKGROUND: Infection may complicate surgical patients' hospital admission. The effect of hospital-acquired infections (HAIs) on processes of care among surgical patients who died is unknown. AIM: To investigate the effect of HAIs on processes of care in surgical patients who died in hospital. METHODS: Surgeon-recorded infection data extracted from a national Australian surgical mortality audit (2012-2016) were grouped into HAIs and no infection. The audit included all-age surgical patients, who died in hospital. Not all patients had surgery. Excluded from analysis were patients with community-acquired infection and those with missing timing of infection. Multivariate logistic regression was used to determine the adjusted effects of HAIs on the processes of care in these patients. Costs associated with HAIs were estimated. FINDINGS: One-fifth of surgical patients who died did so with an HAI (2242 out of 11,681; 19.2%). HAI patients had increased processes of care compared to those who died without infection: postoperative complications [51.0% vs 30.3%; adjusted odds ratio (aOR): 2.20; 95% confidence interval (CI): 1.98-2.45; P < 0.001]; unplanned reoperations (22.6% vs 10.9%; aOR: 2.38; 95% CI: 2.09-2.71; P < 0.001) and unplanned intensive care unit admission (29.3% vs 14.8%; aOR: 2.18; 95% CI: 1.94 2.45; P < 0.001). HAI patients had longer hospital admissions and greater hospital costs than those without infection. CONCLUSION: HAIs were associated with increased processes of care and costs in surgical patients who died; these outcomes need to be investigated in surgical patients who survive. PMID- 28890287 TI - Assessing the burden of Clostridium difficile infections for hospitals. AB - BACKGROUND: Nosocomial infections place a heavy burden on the healthcare system. However, quantifying the burden raises many questions, ranging from the way to accurately estimate the extra length of stay at hospital to defining and costing the preventive methods among the different care providers. AIM: To estimate the cost of nosocomial infection by C. difficile to inform the hospital managers. METHODS: Multi-state modelling based on Markov processes and bootstrapping was used to derive individual estimates of the prolongation of stay at hospital associated with Clostridium difficile infection (CDI). Indicators of cost for hospitals were then computed, including an estimation of the productivity losses derived from diagnosis-related group (DRG)-based payment systems. Patients were aged >=55 years, admitted in two hospital facilities in Lille, with and without an episode of CDI from January 1st, 2013 to September 15th, 2014. FINDINGS: A total of 52 episodes were screened during the study period. The estimated mean cost of CDI was approximately ?23,909 (SD: 17,458) for an extended length of hospital stay (N = 27). In the case of a reduced length of hospital stay (N = 25), the mean cost was approximately ?-14,697 (SD: 16,936), which represents net savings for the hospitals. The main cost/savings driver was the productivity losses/gains resulting from the nosocomial infection. A sensitivity analysis showed that the main factor explaining the amount of costs or savings due to nosocomial infections was the length of the hospital stay. CONCLUSION: The notion of productivity gains in the case of deaths as a factor revealing the incompleteness of the payment systems is discussed, followed by the methodological issues associated with the statistical method used to control for temporality bias. PMID- 28890288 TI - NMR spectroscopy up to 35.2T using a series-connected hybrid magnet. AB - The National High Magnetic Field Laboratory has brought to field a Series Connected Hybrid magnet for NMR spectroscopy. As a DC powered magnet it can be operated at fields up to 36.1T. The series connection between a superconducting outsert and a resistive insert dramatically minimizes the high frequency fluctuations of the magnetic field typically observed in purely resistive magnets. Current-density-grading among various resistive coils was used for improved field homogeneity. The 48mm magnet bore and 42mm outer diameter of the probes leaves limited space for conventional shims and consequently a combination of resistive and ferromagnetic shims are used. Field maps corrected for field instabilities were obtained and shimming achieved better than 1ppm homogeneity over a cylindrical volume of 1cm diameter and height. The magnetic field is regulated within 0.2ppm using an external 7Li lock sample doped with paramagnetic MnCl2. The improved field homogeneity and field regulation using a modified AVANCE NEO console enables NMR spectroscopy at 1H frequencies of 1.0, 1.2 and 1.5GHz. NMR at 1.5GHz reflects a 50% increase in field strength above the highest superconducting magnets currently available. Three NMR probes have been constructed each equipped with an external lock rf coil for field regulation. Initial NMR results obtained from the SCH magnet using these probes illustrate the very exciting potential of ultra-high magnetic fields. PMID- 28890289 TI - The Myotonic Dystrophy Health Index: Italian validation of a disease-specific outcome measure. AB - The Myotonic Dystrophy Health Index (MDHI) is a disease-specific, self-reported outcome measure that assesses total disease burden and 17 areas of Myotonic Dystrophy type 1 (DM1) specific health. This study translated the MDHI into Italian and validated the instrument using a cohort of Italian DM1 patients. Italian DM1 patients were interviewed regarding the form and content of the instrument. Thirty-eight DM1 patients were subsequently recruited to test the reliability and concurrent validity of the instrument by serially completing the MDHI and a battery of clinical tests. Lastly, we determined the internal consistency of the Italian MDHI and each of its subscales. The internal consistency was excellent in the total Italian MDHI score and acceptable in all of its subscales; the test-retest reliability was high (intraclass correlation coefficient = 0.95); Italian MDHI total scores and subscales were associated with neuromuscular function, cognitive and social health, respiratory function, and quality of life. Overall, the Italian MDHI is valid and well suited to measure the multi-dimensional aspects of disease burden in Myotonic Dystrophy clinical trials. PMID- 28890290 TI - The role of long non-coding RNA H19 in musculoskeletal system: A new player in an old game. AB - The long non-coding RNAs (lncRNAs) have gained much attention due to its essential roles in molecular regulation. As one of the classic lncRNAs, H19 is strongly expressed during embryogenesis and plays a crucial biological function during development. Mesenchymal stem cells (MSCs) are an ideal cell source for tissue engineering in musculoskeletal system as they own the multi differentiation ability towards osteogenesis, adipogenesis, tenogenesis or chondrogenesis. In recent years, many studies have been found in the field of H19 mediated cellular differentiation of MSCs. Here, we summarized the current understanding of H19 during multi-differentiation of MSCs and its application in tissue regeneration of musculoskeletal system. Particularly, its molecular regulation and biological function during the multi-differentiation were also discussed. PMID- 28890291 TI - MiR-122 inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting Snail1 and Snail2 and suppressing WNT/beta-cadherin signaling pathway. AB - The downregulation of microRNA-122 (miR-122) had been reported to be associated with tumor invasion and metastasis in hepatocellular carcinoma (HCC). However, the underlying mechanisms of miR-122 involved in epithelial-mesenchymal transition (EMT) still need to be investigated. In the study, we demonstrated that miR-122 was significantly downregulated in HCC tissues compared with adjacent normal tissues. MiR-122 expression was closely correlated with tumor size, vascular invasion and American Joint Committee on Cancer (AJCC) stage of HCC patients. Kaplan-Meier survival curve and log rank test demonstrated that lower miR-122 predicted poor Disease-free survival (DFS) and overall survival (OS) time in patients. Univariate and multivariate Cox analysis confirmed that tumor size, vascular invasion, American Joint Committee on Cancer (AJCC) stage and lower miR-122 expression levels were independent risk factors for DFS or OS in HCC patients. Function assays demonstrated that upregulation of miR-122 inhibited the cell proliferation, colony formation and cell invasion in HCC cells, however, downregulation of miR-122 promoted cell proliferation, colony formation and cell invasion in HCC cells. Moreover, we demonstrated that increased miR-122 expression levels in HCC cells inhibited epithelial-mesenchymal transition (EMT) by suppressing the expression of ZEB1/2, Snail1/2, N-cadherin, Vimentin and upregulating the E-cadherin expression. However, downregulation of miR-122 caused an opposite effects. Mechanisms study found that miR-122 overexpression inhibited the EMT process by targeting Snail1 and Snail2 and regulated their expression levels in HCC cells. In addition, we also revealed that upregulated miR-122 expression suppressed the Wnt/beta-catenin signaling pathway. Taken together, our results indicated that miR-122 may be a biomarker for predicting prognosis of HCC and therapeutic target for HCC patients. PMID- 28890292 TI - SAHA-induced TRAIL-sensitisation of Multiple Myeloma cells is enhanced in 3D cell culture. AB - BACKGROUND: Multiple Myeloma (MM) is currently incurable despite many novel therapies. Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a potential anti-tumour agent although effects as a single agent are limited. In this study, we investigated whether the Histone Deacetylase (HDAC) inhibitor SAHA can enhance TRAIL-induced apoptosis and target TRAIL resistance in both suspension culture, and 3D cell culture as a model of disseminated MM lesions that form in bone. METHODS: The effects of SAHA and/or TRAIL in 6 Multiple Myeloma cell lines were assessed in both suspension cultures and in an Alginate based 3D cell culture model. The effect of SAHA and/or TRAIL was assessed on apoptosis by assessment of nuclear morphology using Hoechst 33342/Propidium Iodide staining. Viable cell number was assessed by CellTiter-Glo luminescence assay, Caspase-8 and -9 activities were measured by Caspase-GloTM assay kit. TRAIL-resistant cells were generated by culture of RPMI 8226 and NCI-H929 by acute exposure to TRAIL followed by selection of TRAIL-resistant cells. RESULTS: TRAIL significantly induced apoptosis in a dose-dependent manner in OPM-2, RPMI 8226, NCI-H929, U266, JJN-3 MM cell lines and ADC-1 plasma cell leukaemia cells. SAHA amplified TRAIL responses in all lines except OPM-2, and enhanced TRAIL responses were both via Caspase-8 and -9. SAHA treatment induced growth inhibition that further increased in the combination treatment with TRAIL in MM cells. The co-treatment of TRAIL and SAHA reduced viable cell numbers all cell lines. TRAIL responses were further potentiated by SAHA in 3D cell culture in NCI H929, RPMI 8226 and U266 at lower TRAIL + SAHA doses than in suspension culture. However TRAIL responses in cells that had been selected for TRAIL resistance were not further enhanced by SAHA treatment. CONCLUSIONS: SAHA is a potent sensitizer of TRAIL responses in both TRAIL sensitive and resistant cell lines, in both suspension and 3D culture, however SAHA did not sensitise TRAIL-sensitive cell populations that had been selected for TRAIL-resistance from initially TRAIL sensitive populations. SAHA may increase TRAIL sensitivity in insensitive cells, but not in cells that have specifically been selected for acquired TRAIL resistance. PMID- 28890293 TI - Epidermal barrier reaction to an in vitro psoriatic microenvironment. AB - Keratinocytes (KCs) and Langerhans cells (LCs) contribute to create the epidermal barrier. To form a functional epidermis, KCs express filaggrin and Toll-like Receptors (TLRs). LCs are the first line of epidermal defence and can be activated by interleukin (IL)-17 and Tumor Necrosis Factor (TNF)-alpha. In psoriasis, an alteration of TLR expression, a defective expression of filaggrin, and LC activation occur. In organotypic cultures of human skin we investigated the interplay between IL-17 and TNF-alpha on i) expression of filaggrin, TLR2, 7 and 9, and Nuclear Factor (NF)-kB localization by immunofluorescence and ii) LC ultrastructural features by transmission electron microscopy. Normal human skin was obtained after aesthetic surgery (n=7), overnight incubated in a Transwell system, and exposed to TNF-alpha and/or IL-17 for 24 (T24), 48 (T48), and 72 (T72) hours. Cytokines always influenced the expression of filaggrin. TNF-alpha alone activated LCs only starting from T48. TLR2 and TLR7 expressions were affected at T24 by IL-17 and the combination of cytokines, but not by TNF-alpha. TLR9-positive cells were detectable in the granular layer after cytokine exposure. A nuclear localization of NF-kB was always observed after cytokine incubation. In conclusion, each cytokine possess an intrinsic activity on the different components of the epidermal barrier. PMID- 28890294 TI - Analysis of non-small cell lung cancer microenvironment indicates preponderance of T cell exhaustion marker expression. AB - Lung cancer metastasis causes 70% of an estimated 1.4 million deaths per annum. The major shortcoming in lung cancer is the tendency to have inherent or develop acquired resistance to chemotherapy. It is now evolving that such resistance might develop due to differential contribution and interaction with tumor microenvironment, stromal cells, and the extracellular matrix. The objective of the current study was to define the lung cancer tumor microenvironment. We have identified multiple tumor-infiltrating T lymphocyte subsets in patients with lung cancer, which were independent of disease stage. Functional analysis indicated high expression of the inhibitory receptors, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte activated gene 3 (LAG3) and programmed cell death protein 1 (PD-1) in both CD4 and CD8 subsets, compared to non-malignant controls. Inhibitory receptors expressed by the tumor infiltrating T cells might mediate tolerance to tumor antigens with co-expression of these receptors exacerbating lung carcinogenesis and metastatic progression. PMID- 28890295 TI - Eribulin: an effective therapeutic option in liposarcoma. PMID- 28890296 TI - Thalidomide reduces chemotherapy-induced vomiting. PMID- 28890297 TI - E-cigarette use in young people in the UK. PMID- 28890298 TI - Use of cancer-related emergency departments. PMID- 28890299 TI - Comparison of fluticasone/formoterol with budesonide/formoterol pMDI in adults with moderate to severe persistent asthma: Results from a 12-week randomized controlled trial. AB - BACKGROUND: Combination therapy of inhaled corticosteroid/long acting beta2 agonist (ICS/LABA) is the cornerstone of managing asthmatics who are uncontrolled with low-medium dose of ICS. The novel ICS/LABA combination of fluticasone propionate and formoterol (flu/form) provides potent anti-inflammatory and rapid bronchodilatory effect. This randomized, multi-centre, double-blind study compared the efficacy and safety of flu/form (125/6 mcg BD; Maxiflo(r)) with the well-established budesonide/formoterol combination (bud/form 200/6 mcg BD), both delivered through a pressurized metered dose inhaler (pMDI) in patients with moderate to severe persistent asthma over 12 weeks. METHODS: This study enrolled patients between 18 and 65 years. The primary end-point was to demonstrate non inferiority for the mean change in the pre-dose morning peak expiratory flow values (PEF). The secondary end-points included lung function assessments, number of symptom-free days and nights, rescue medication use, day-and night-time symptom scores and safety evaluation. RESULTS: Two hundred and thirty-two patients were randomized to either flu/form (n = 117) or bud/form (n = 115). At the end of 12 weeks, flu/form was non-inferior to bud/form with regards to the primary end-point of morning PEF (48.07 L/min vs. 49.03 L/min, p > 0.05). These improvements were statistically significant (p < 0.0001) vs baseline. Similar improvements were observed between the two groups for secondary efficacy end points including FEV1, symptom-free nights, rescue medication use, day-and night time symptom scores (p > 0.05). Flu/form exhibited a safety profile comparable to that of bud/form. CONCLUSION: Fluticasone/formoterol combination administered through a pMDI is as efficacious and well-tolerated as budesonide/formoterol and offers a new therapeutic option for patients with moderate to severe persistent asthma. PMID- 28890300 TI - Tau positron emission tomography using [18F]THK5351 and cerebral glucose hypometabolism in Alzheimer's disease. AB - This study aims to evaluate the clinical validity of [18F]THK5351 positron emission tomography (PET) for the assessment of disease progression and symptoms in Alzheimer's disease (AD). Fifty-one patients with AD dementia, 30 patients with amnestic mild cognitive impairment (aMCI), and 43 controls with normal cognition (NC) were included. All subjects underwent [18F]THK5351 PET, 3.0-T magnetic resonance imaging, and detailed neuropsychological tests. Regions of interest and voxel-based statistical analyses were performed. In patients with AD dementia, [18F]THK5351 retention was greater in most association cortices as well as the limbic area compared to NC or aMCI participants. Patients with aMCI also showed higher THK5351 retention in those areas compared to NC. [18F]THK5351 retention significantly correlated with neuropsychological test results. Negative correlations between [18F]THK5351 and [18F] fluorodeoxyglucose were observed in AD dementia and aMCI groups. Mirror images of [18F]THK5351 retention and glucose hypometabolism in [18F] fluorodeoxyglucose were noticeable in the focal variants of AD. [18F]THK5351 PET reflects disease severity and symptoms in AD. Our results suggest [18F]THK5351 is reflective of tau-related AD pathology. PMID- 28890301 TI - Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration. AB - Chondroitin sulfate proteoglycans (CSPGs) are the main active component of perineuronal nets (PNNs). Digestion of the glycosaminoglycan chains of CSPGs with chondroitinase ABC or transgenic attenuation of PNNs leads to prolongation of object recognition memory and activation of various forms of plasticity in the adult central nervous system. The inhibitory properties of the CSPGs depend on the pattern of sulfation of their glycosaminoglycans, with chondroitin 4-sulfate (C4S) being the most inhibitory form. In this study, we tested a number of candidates for functional blocking of C4S, leading to selection of an antibody, Cat316, which specifically recognizes C4S and blocks its inhibitory effects on axon growth. It also partly blocks binding of semaphorin 3A to PNNs and attenuates PNN formation. We asked whether injection of Cat316 into the perirhinal cortex would have the same effects on memory as chondroitinase ABC treatment. We found that masking C4S with the Cat316 antibody extended long-term object recognition memory in normal wild-type mice to 24 hours, similarly to chondroitinase or transgenic PNN attenuation. We then tested Cat316 for restoration of memory in a neurodegeneration model. Mice expressing tau with the P301S mutation showed profound loss of object recognition memory at 4 months of age. Injection of Cat316 into the perirhinal cortex normalized object recognition at 3 hours in P301S mice. These data indicate that Cat316 binding to C4S in the extracellular matrix can restore plasticity and memory in the same way as chondroitinase ABC digestion. Our results suggest that antibodies to C4S could be a useful therapeutic to restore memory function in neurodegenerative disorders. PMID- 28890302 TI - Ulna-humerus contact mechanics: Finite element analysis and experimental measurements using a tactile pressure sensor. AB - Elbow articular cartilage withstands high compressive and shear forces while protecting the bone from excessive loading. Better understanding of elbow cartilage contact mechanics can provide insight into cartilage degeneration. In this study a tactile pressure sensor was used to measure the contact pressure distribution within the ulno-humeral joint of two cadaver specimens at 20 degrees flexion angle across three different axial loads of 80 N, 110 N, and 140 N. Corresponding 3D finite element (FE) models were constructed from magnetic resonance imaging (MRI) and contact analysis was performed for each specimen with boundary and loading conditions identical to the experiment. Direct comparison between FE results and experimental measurements was conducted for the validation of the FE models and a sensitivity analysis was employed for assessing the effect of cartilage parameters on the model's outputs. The results showed a good agreement between the FE models and the experiments in terms of contact characteristics. The sensitivity analysis demonstrated that outcomes of the model, particularly peak contact pressure is more sensitive to the Poisson's ratio rather than to Young's modulus under static conditions. This result suggests that selection of Poisson's ratio is very critical for accurate prediction of contact mechanics within the ulno-humeral joint. PMID- 28890303 TI - A simulation framework for humeral head translations. AB - Humeral head translations (HHT) play a crucial role in the glenohumeral (GH) joint function. The available shoulder musculoskeletal models developed based on inverse dynamics however fall short of predicting the HHT. This study aims at developing a simulation framework that allows forward-dynamics simulation of a shoulder musculoskeletal model with a 6 degrees of freedom (DOF) GH joint. It provides a straightforward solution to the HHT prediction problem. We show that even within a forward-dynamics simulation addressing the HHT requires further information about the contact. To that end, a deformable articular contact is included in the framework defining the GH joint contact force in terms of the joint kinematics. An abduction motion in the scapula plane is simulated. The results are given in terms of HHT, GH joint contact force, contact areas, contact pressure, and cartilage strain. It predicts a superior-posterior translation of the humeral head followed by an inferior migration. PMID- 28890304 TI - Hemodynamic parameters that may predict false-lumen growth in type-B aortic dissection after endovascular repair: A preliminary study on long-term multiple follow-ups. AB - Thoracic endovascular aortic repair (TEVAR) is commonly applied in type-B aortic dissection. For patients with dissection affects descending aorta and extends downward to involve abdominal aorta and possibly iliac arteries, false lumen (FL) expansion might occur post-TEVAR. Predictions of dissection development may assist in medical decision on re-intervention or surgery. In this study, two patients are selected with similar morphological features at initial presentation but with different long-term FL development post-TEVAR (stable and enlarged FL). Patient-specific models are established for each of the follow-ups. Flow boundaries and computational validations are obtained from Doppler ultrasound velocimetry. By analyzing the hemodynamic parameters, the false-to-true luminal pressure difference (PDiff) and particle relative residence time (RRT) are found related to FL remodeling. It is found that (i) the position of the first FL flow entry is the watershed of negative-and-positive PDiff and, in long-term follow ups, and the position of largest PDiff is consistent with that of the greatest increase of FL width; (ii) high RRT occurs at the FL proximal tip and similar magnitude of RRT is found in both stable and enlarged cases; (iii) comparing to the RRT at 7days post-TEVAR, an increase of RRT afterwards in short-term is found in the stable case while a slight decrease of this parameter is found in the enlarged case, indicating that the variation of RRT in short-term post-TEVAR might be potential to predict long-term FL remodeling. PMID- 28890305 TI - Relationships between blood pressure and blood glucose among offspring of parents with type 2 diabetes: Prediction of incident dysglycemia in a biracial cohort. AB - AIMS: We assessed blood pressure (BP) and blood glucose (BG) values in healthy subjects, and examined baseline BP as a predictor of incident prediabetes during follow-up. METHODS: Participants in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study underwent screening assessments (anthropometry, BP, OGTT) and were stratified into normal BP (NBP), prehypertension, or hypertension, and normal glucose regulation (NGR), prediabetes (IFG/IGT), or type 2 diabetes (T2D) status. NGR subjects who met all inclusion criteria were enrolled in a 5-yr prospective study, with the primary outcome of incident prediabetes. RESULTS: We screened 602 adults (341 black, 261 white) and enrolled 343 (193 black, 150 white) for prospective follow-up. Systolic and diastolic BP correlated significantly with fasting and nonfasting BG (P=0.003-<0.0001). Compared to NGR group, more prediabetic subjects had prehypertension (42.5% vs. 36.2%) and fewer had NBP (35.9% vs. 48.6%) (P=0.009). During ~5years of follow-up, 26.3% of NBP and 35.7% of prehypertensive subjects developed prediabetes (P=0.02). Kaplan Meier analysis showed higher probability of incident prediabetes among participants with prehypertension compared to NBP during ~5years of follow-up (P=0.0012). CONCLUSIONS: In our biracial cohort, BP and BG values were significantly correlated, and BP status predicted incident prediabetes among initially normoglycemic individuals. These findings suggest co-evolution of factors involved in the dysregulation of BP and BG. PMID- 28890306 TI - Variants m.13276G>A in the MT-ND5 and m.8241T>G in the MT-CO2 gene are not responsible for maternally inherited diabetes and deafness. PMID- 28890307 TI - Are estrogens promoting immune modulation and islet protection in type 1 diabetes? PMID- 28890308 TI - Left ventricular mass, geometry and function in diabetic patients affected by coronary artery disease. AB - INTRODUCTION: Coronary artery disease (CAD) is quite common among diabetic patients, our study goal is to detect the prevalence of left ventricular (LV) adverse changes in geometry, mass and diastolic function on diabetic, but not hypertensive patients, with coronary artery disease(CAD) and LV ejection fraction(LVEF)>45%, actually unknown, because of current guidelines that do not include echocardiographic assessment for follow up of diabetic patients. PATIENTS AND METHODS: 665 consecutive diabetic patients (443 females, mean age 66+/ 9years), performed a complete echocardiographic assessment according to current ASE echo-guidelines: diastolic dysfunction (DD), eccentric hypertrophy (EH), concentric hypertrophy (CH) and concentric remodeling (CR) of LV were reported. CAD was assessed only by reports of bypass surgery, angioplasty or patients hospitalized for acute myocardial infarction. RESULTS: 218 patients (32.8%) presented LV changes: LVDD 49 (7.4%), LVEH 68 (10.2%), LVDD and EH 46 (6.9%), LVDD and CH 36 (5.4%), LVDD and CR 19 (2.9%). 447 (67.2%) had no LV changes. 81 (12.1%) patients with CAD, presented: LVDD 17 (21%), LVEH 32 (39.5%), LVDD and EH 9 (11.1%), LVDD and CH 7 (8.6%), LVDD and CR 8 (9.9%), 8 (9.9%) had no LV adverse changes. There were among CAD patients, a significantly higher prevalence of LVDD (p<0.02), LV eccentric hypertrophy (EH) (p<0.05), DD and LVEH (p<0.04), DD and LV concentric hypertrophy(CH) (p<0.03) and DD and LV concentric remodeling (p<0.02), when compared with those patients without CAD. CONCLUSION: CAD is related to all different patterns of LV adverse changes in mass, geometry and diastolic function, with a significantly higher prevalence in our population of diabetic patients with normal systolic function. These changes however remain unrecognized until they undergo to a conventional echocardiographic assessment. We support this tool need to be included into future guidelines concerning follow-up of diabetic patients. PMID- 28890309 TI - Pupillary response to nitrous oxide administration in cataract surgery under general anesthesia. AB - BACKGROUND: Despite recent innovations in cataract surgery, pupillary diameter is one of the most important affecting factors in outcome of this surgery. As cataract surgery is performed ideally when the pupil is sufficiently dilated, anesthesia may contribute significantly in success or failure of this operation. This study was performed to evaluate the effect of nitrous oxide on pupillary diameter in cataract surgery under general anesthesia. METHODS: Forty patients with cataract, scheduled for operation under general anesthesia, were randomly allocated into two groups. After induction of anesthesia, anesthesia was maintained with isoflurane and nitrous oxide - oxygen (60%-40%) in group 1 versus oxygen 100% in group 2. Pupillary diameter, heart rate and blood pressure were monitored and recorded, before induction of anesthesia, just before tracheal intubation, and one and 5 min after laryngoscopy and tracheal intubation. RESULTS: Statistical analysis of the results using Mann-Whitney test showed no significant difference in pupillary diameter between two the groups. CONCLUSION: According to the results of this study, nitrous oxide has no effect on pupillary diameter of patients under general anesthesia, so it could be safety used, in this regard, in ophthalmic operations. PMID- 28890311 TI - Pancreatoduodenectomy after Roux-en-Y gastric bypass: technical considerations and outcomes. AB - BACKGROUND: Patients with altered anatomy due to Roux-en-Y gastric bypass (RYGB) present unique diagnostic and therapeutic challenges when they present with periampullary pathology. We describe a series of patients who underwent pancreatoduodenectomy (PD) after gastric surgery with Roux-en-Y reconstruction and review the literature to highlight technical considerations and outcomes. METHODS: Patients from two institutions were identified and data regarding preoperative workup, operative conduct, and pathologic and clinical outcomes were collected. RESULTS: Eleven patients were included in the institutional series. At the time of periampullary pathology, the median age was 64 years and time since RYGB was 10 years. Median operative time was 361 minutes, estimated blood loss was 500 mLs, and length of stay was 6 days. Remnant gastrectomy was performed in nine patients and reconstruction was performed using the biliopancreatic limb (BP) without revision of the jejuno-jejunostomy in ten patients. Pathology revealed pancreatic cancer (8), chronic pancreatitis (2), and duodenal cancer (1). Three patients experienced major complications and there were no 90-day mortalities. CONCLUSION: Pancreatic surgeons will see an increasing number of patients with Roux-en-Y anatomy who will require evaluation and resection for periampullary diseases. For PD after RYGB, we recommend remnant gastrectomy with reconstruction using the BP limb. PMID- 28890310 TI - Evaluating the American College of Surgeons National Surgical Quality Improvement project risk calculator: results from the U.S. Extrahepatic Biliary Malignancy Consortium. AB - BACKGROUND: The objective of this study is to evaluate use of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) online risk calculator for estimating common outcomes after operations for gallbladder cancer and extrahepatic cholangiocarcinoma. METHODS: Subjects from the United States Extrahepatic Biliary Malignancy Consortium (USE-BMC) who underwent operation between January 1, 2000 and December 31, 2014 at 10 academic medical centers were included in this study. Calculator estimates of risk were compared to actual outcomes. RESULTS: The majority of patients underwent partial or major hepatectomy, Whipple procedures or extrahepatic bile duct resection. For the entire cohort, c-statistics for surgical site infection (0.635), reoperation (0.680) and readmission (0.565) were less than 0.7. The c-statistic for death was 0.740. For all outcomes the actual proportion of patients experiencing an event was much higher than the median predicted risk of that event. Similarly, the group of patients who experienced an outcome did have higher median predicted risk than those who did not. CONCLUSIONS: The ACS NSQIP risk calculator is easy to use but requires further modifications to more accurately estimate outcomes for some patient populations and operations for which validation studies show suboptimal performance. PMID- 28890312 TI - Clinicopathological features and prognosis of advanced biliary carcinoma centered in the cystic duct. AB - BACKGROUND: Whether to classify "advanced (subserosal layer or greater invasion)" biliary carcinoma centered in the cystic duct (BCCD) as gallbladder carcinoma (GBC) or perihilar cholangiocarcinoma (PHCC) remains unclear. METHODS: The clinicopathological features and overall survival (OS) of patients with advanced BCCD were examined through a comparison with those of patients with advanced PHCC and with GBC. RESULTS: 290 patients were classified as 199 PHCC, 44 GBC, and 47 BCCD. Patients with BCCD (median, 23 months) had significantly worse OS than those with PHCC (44 months, p = 0.030). OS of patients with BCCD, all of whom were classified as pT3 or pT4 by the American Joint Committee on Cancer (AJCC) classification of GBC, was similar to 27 patients with pT3 or pT4 GBC (23 months, p = 0.840). When the patients with BCCD were classified by the AJCC classification of PHCC, 36 were classified as pT2. OS among the patients with BCCD classified as pT2 by the PHCC classification (29 months) was significantly worse than that among patients classified as pT2 PHCC (48 months, p = 0.040). CONCLUSION: These findings suggest that advanced BCCD is appropriately classified as a subtype of GBC because it can grow through the serosa. PMID- 28890313 TI - Surgical site infections following pancreaticoduodenectomy. PMID- 28890314 TI - Bilateral clavicular attachment of omohyoid muscle. AB - Omohyoid muscle present in cervical region is of particular importance to anatomists as it defines anteriorly the carotid triangle and divides the posterior cervical triangle. It has superior and inferior bellies and an intermediate common tendon. Like sternohyoid, sternothyroid and thyrohyoid muscles, omohyoid is also an infrahyoid muscle, but it differs from them in its course. The infrahyoid muscles are formed from a muscle primordium occurring in the anterior cervical area. Anderson (Anderson, 1881) theorized that the superior belly of the omohyoid muscle is a true infrahyoid muscle, whereas the inferior belly most likely shares a common embryology with the subclavius muscle. In the present study, during routine dissection in the neck region of an adult male cadaver of 50 years age, an anomalous origin of inferior belly of omohyoid with absence of intermediate tendon was observed bilaterally. It was arising from clavicle on both sides. Both the muscle bellies were measured from the lateral end of fascial sling. The inferior belly of omohyoid extending from the lateral margin of sling to clavicular surface was measured 3.3cm in length on left side and 3.6cm on right side. The omohyoid is important in neck dissections because it is considered as an ideal landmark for level III and IV lymph node metastases. Knowledge of variations of this muscle is very important for surgeries in neck region because of its close relation to the internal jugular vein and brachial plexus. Its crucial relationship to vascular structures in the neck makes it an important landmark during neck surgeries. PMID- 28890316 TI - Iron Biochemistry is Correlated with Amyloid Plaque Morphology in an Established Mouse Model of Alzheimer's Disease. AB - A signature characteristic of Alzheimer's disease (AD) is aggregation of amyloid beta (Abeta) fibrils in the brain. Nevertheless, the links between Abeta and AD pathology remain incompletely understood. It has been proposed that neurotoxicity arising from aggregation of the Abeta1-42 peptide can in part be explained by metal ion binding interactions. Using advanced X-ray microscopy techniques at sub micron resolution, we investigated relationships between iron biochemistry and AD pathology in intact cortex from an established mouse model over-producing Abeta. We found a direct correlation of amyloid plaque morphology with iron, and evidence for the formation of an iron-amyloid complex. We also show that iron biomineral deposits in the cortical tissue contain the mineral magnetite, and provide evidence that Abeta-induced chemical reduction of iron could occur in vivo. Our observations point to the specific role of iron in amyloid deposition and AD pathology, and may impact development of iron-modifying therapeutics for AD. PMID- 28890315 TI - Subthalamic neural entropy is a feature of freezing of gait in freely moving people with Parkinson's disease. AB - : The goal of this study was to investigate subthalamic (STN) neural features of Freezers and Non-Freezers with Parkinson's disease (PD), while freely walking without freezing of gait (FOG) and during periods of FOG, which were better elicited during a novel turning and barrier gait task than during forward walking. METHODS: Synchronous STN local field potentials (LFPs), shank angular velocities, and ground reaction forces were measured in fourteen PD subjects (eight Freezers) off medication, OFF deep brain stimulation (DBS), using an investigative, implanted, sensing neurostimulator (Activa(r) PC+S, Medtronic, Inc.). Tasks included standing still, instrumented forward walking, stepping in place on dual forceplates, and instrumented walking through a turning and barrier course. RESULTS: During locomotion without FOG, Freezers showed lower beta (13 30Hz) power (P=0.036) and greater beta Sample Entropy (P=0.032), than Non Freezers, as well as greater gait asymmetry and arrhythmicity (P<0.05 for both). No differences in alpha/beta power and/or entropy were evident at rest. During periods of FOG, Freezers showed greater alpha (8-12Hz) Sample Entropy (P<0.001) than during walking without FOG. CONCLUSIONS: A novel turning and barrier course was superior to FW in eliciting FOG. Greater unpredictability in subthalamic beta rhythms was evident during stepping without freezing episodes in Freezers compared to Non-Freezers, whereas greater unpredictability in alpha rhythms was evident in Freezers during FOG. Non-linear analysis of dynamic neural signals during gait in freely moving people with PD may yield greater insight into the pathophysiology of FOG; whether the increases in STN entropy are causative or compensatory remains to be determined. Some beta LFP power may be useful for rhythmic, symmetric gait and DBS parameters, which completely attenuate STN beta power may worsen rather than improve FOG. PMID- 28890317 TI - MitoNeoD: A Mitochondria-Targeted Superoxide Probe. AB - Mitochondrial superoxide (O2?-) underlies much oxidative damage and redox signaling. Fluorescent probes can detect O2?-, but are of limited applicability in vivo, while in cells their usefulness is constrained by side reactions and DNA intercalation. To overcome these limitations, we developed a dual-purpose mitochondrial O2?- probe, MitoNeoD, which can assess O2?- changes in vivo by mass spectrometry and in vitro by fluorescence. MitoNeoD comprises a O2?--sensitive reduced phenanthridinium moiety modified to prevent DNA intercalation, as well as a carbon-deuterium bond to enhance its selectivity for O2?- over non-specific oxidation, and a triphenylphosphonium lipophilic cation moiety leading to the rapid accumulation within mitochondria. We demonstrated that MitoNeoD was a versatile and robust probe to assess changes in mitochondrial O2?- from isolated mitochondria to animal models, thus offering a way to examine the many roles of mitochondrial O2?- production in health and disease. PMID- 28890318 TI - Total Biosynthesis of the Pyrrolo[4,2]benzodiazepine Scaffold Tomaymycin on an In Vitro Reconstituted NRPS System. AB - In vitro reconstitution and biochemical analysis of natural product biosynthetic pathways remains a challenging endeavor, especially if megaenzymes of the nonribosomal peptide synthetase (NRPS) type are involved. In theory, all biosynthetic steps may be deciphered using mass spectrometry (MS)-based analyses of both the carrier protein-coupled intermediates and the free intermediates. We here report the "total biosynthesis" of the pyrrolo[4,2]benzodiazepine scaffold tomaymycin using an in vitro reconstituted NRPS system. Proteoforms were analyzed by liquid chromatography (LC)-MS to decipher every step of the biosynthesis on its respective megasynthetase with up to 170 kDa in size. To the best of our knowledge, this is the first report of a comprehensive analysis of virtually all chemical steps involved in the biosynthesis of nonribosomally synthesized natural products. The study includes experiments to determine substrate specificities of the corresponding A-domains in competition assays by analyzing the adenylation step as well as the transfer to the respective carrier protein domain. PMID- 28890319 TI - Arctic Abeta40 blocks the nicotine-induced neuroprotective effect of CHRNA7 by inhibiting the ERK1/2 pathway in human neuroblastoma cells. AB - Amyloid beta protein (Abeta) plays a central role in Alzheimer's disease (AD) pathogenesis. Point mutations in the Abeta sequence, which cluster around the central hydrophobic core of the peptide, are associated with familial AD (FAD). Several mutations have been identified, with the Arctic mutation exhibiting a purely cognitive phenotype that is typical of AD. Our previous findings suggest that Arctic Abeta40 binds to and aggregates with CHRNA7, thereby inhibiting the calcium response and signaling pathways downstream of the receptor. Activation of CHRNA7 is neuroprotective both in vitro and in vivo. Therefore, in the present study, we investigated whether Arctic Abeta40 affects neuronal survival and/or death via CHRNA7. Using human neuroblastoma SH-SY5Y cells, we found that the neuroprotective function of CHRNA7 is blocked by CHRNA7 knockdown using RNA interference. Furthermore, Arctic Abeta40 blocked the neuroprotective effect of nicotine by inhibiting the ERK1/2 pathway downstream of CHRNA7. Moreover, we show that ERK1/2 activation mediates the neuroprotective effect of nicotine against oxidative stress. Collectively, our findings further our understanding of the molecular pathogenesis of Arctic FAD. PMID- 28890320 TI - Neuropsychologist's (re-)view: Resective versus ablative amygdalohippocampectomies. AB - Pharmacoresistant mesial temporal lobe epilepsy (mTLE) represents the major indication for epilepsy surgery. Since epilepsy surgery is an elective treatment option, preserving cognition is a high priority. Given the essential role of temporomesial structures in declarative long-term memory formation, surgical treatment for mTLE is primarily associated with a risk of material-specific memory decline, but other cognitive domains may be affected as well. The major determinants for the neuropsychological outcome are the functional integrity of surgically affected tissues, the functional reserve capacities of the remnant brain, the postoperative seizure outcome, as well as the quantitative and qualitative changes of antiepileptic drugs. Anterior temporal lobectomy has long been the standard procedure for treating mTLE. However, if an exclusive mesial pathology is present, then functional non-pathological tissues of the temporal pole and neocortex are sacrificed. As a result, more selective or tailored surgical approaches have been developed which strive towards minimizing iatrogenic effects. However, whether or not these approaches are equipotential with regard to seizure control is still a matter of debate. The quality of the presurgical diagnostics could also be decisive. Selective surgery should indeed be selective in terms of preventing evitable collateral cortical damage along the approach. Invasivity and risks of collateral damage associated with "open" selective resective surgery are further minimized by stereotactic ablative surgery via thermocoagulation, or eventually even eliminated by gamma knife surgery. From a neuropsychological point of view, this development is consequent and desirable, but no clear scientific evidence of a superior cognitive outcome after radiosurgery or thermocoagulation currently exists. The studies that are available contain significant methodological limitations. Thus, randomized head to-head cognitive outcome studies of competing selective procedures are needed, which should meet the minimum requirements for study design and neuropsychological evaluations. Finally, none of the surgical treatment variants can systematically prevent memory decline when the hippocampus is targeted. PMID- 28890321 TI - General hospital costs in England of medical and psychiatric care for patients who self-harm: a retrospective analysis. AB - BACKGROUND: Self-harm is an extremely common reason for hospital presentation. However, few estimates have been made of the hospital costs of assessing and treating self-harm. Such information is essential for planning services and to help strengthen the case for investment in actions to reduce the frequency and effects of self-harm. In this study, we aimed to calculate the costs of hospital medical care associated with a self-harm episode and the costs of psychosocial assessment, together with identification of the key drivers of these costs. METHODS: In a retrospective analysis, we estimated hospital resource use and care costs for all presentations for self-harm to the John Radcliffe Hospital (Oxford, UK), between April 1, 2013, and March 31, 2014. Episode-related data were provided by the Oxford Monitoring System for Self-harm and we linked these with financial hospital records to quantify costs. We assessed time and resources allocated to psychosocial assessments through discussion with clinical and managerial staff. We then used generalised linear models to investigate the associations between hospital costs and methods of self-harm. FINDINGS: Between April 1, 2013, and March 31, 2014, 1647 self-harm presentations by 1153 patients were recorded. Of these, 1623 (99%) presentations by 1140 patients could be linked with hospital finance records. 179 (16%) patients were younger than 18 years. 1150 (70%) presentations were for self-poisoning alone, 367 (22%) for self injury alone, and 130 (8%) for a combination of methods. Psychosocial assessments were made in 75% (1234) of all episodes. The overall mean hospital cost per episode of self-harm was L809. Costs differed significantly between different types of self-harm: self-injury alone L753 (SD 2061), self-poisoning alone L806 (SD 1568), self-poisoning and self-injury L987 (SD 1823; p<0.0001). Costs were mainly associated with the type of health-care service contact such as inpatient stay, intensive care, and psychosocial assessment. Mean costs of psychosocial assessments were L228 for adults and L392 for individuals younger than 18 years. INTERPRETATION: If our findings are extrapolated to England, the estimated overall annual cost of general hospital management of self-harm is L162 million per year. More use of psychosocial assessment and other preventive measures, especially for young people and against self-poisoning, could potentially lower future costs at a time of major cost pressures in the NHS. FUNDING: National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research, Care Oxford at Oxford Health NHS Foundation Trust, and Department of Health. PMID- 28890322 TI - How should cost-of-illness studies be interpreted? PMID- 28890323 TI - Detection of intramyocardial fat infiltration by computerized tomography in a patient with arrhythmogenic biventricular cardiomyopathy. PMID- 28890324 TI - Direct Head-to-Head Evaluation of Recombinant Adeno-associated Viral Vectors Manufactured in Human versus Insect Cells. AB - The major drawback of the Baculovirus/Sf9 system for recombinant adeno-associated viral (rAAV) manufacturing is that most of the Bac-derived rAAV vector serotypes, with few exceptions, demonstrate altered capsid compositions and lower biological potencies. Here, we describe a new insect cell-based production platform utilizing attenuated Kozak sequence and a leaky ribosome scanning to achieve a serotype-specific modulation of AAV capsid proteins stoichiometry. By way of example, rAAV5 and rAAV9 were produced and comprehensively characterized side by side with HEK293-derived vectors. A mass spectrometry analysis documented a 3 fold increase in both viral protein (VP)1 and VP2 capsid protein content compared with human cell-derived vectors. Furthermore, we conducted an extensive analysis of encapsidated single-stranded viral DNA using next-generation sequencing and show a 6-fold reduction in collaterally packaged contaminating DNA for rAAV5 produced in insect cells. Consequently, the re-designed rAAVs demonstrated significantly higher biological potencies, even in a comparison with HEK293 manufactured rAAVs mediating, in the case of rAAV5, 4-fold higher transduction of brain tissues in mice. Thus, the described system yields rAAV vectors of superior infectivity and higher genetic identity providing a scalable platform for good manufacturing practice (GMP)-grade vector production. PMID- 28890326 TI - Taurolidine-based catheter lock regimen significantly reduces overall costs, infection, and dysfunction rates of tunneled hemodialysis catheters. AB - Catheter-related infections and dysfunction are the main catheter complications causing morbidity and mortality in hemodialysis patients. However, there are no consistent data for the choice of catheter lock solutions for tunneled hemodialysis lines. In this prospective, multicenter, randomized, controlled trial, two lock regimens using three commercial catheter lock solutions were compared in 106 hemodialysis patients with a newly inserted tunneled central catheter. In the taurolidine group, TauroLockTM-Hep500 was used twice per week and TauroLockTM-U25,000 once a week. In the citrate group, a four percent citrate solution was used after each dialysis. Both groups were compared regarding catheter-related infections, catheter dysfunction, and costs. Over a period of 15,690 catheter days, six catheter-related infections occurred in six of 52 patients in the taurolidine group, but 18 occurred in 13 of 54 patients in the citrate group, corresponding to 0.67 and 2.7 episodes of catheter-related infections per 1000 catheter days, respectively (Incidence Rate Ratio 0.25, 95% confidence interval, 0.09 to 0.63). Catheter dysfunction rates were significantly lower in the taurolidine group (18.7 vs. 44.3/1000 catheter days) and alteplase rescue significantly more frequent in the citrate group (9.8 vs. 3.8/1000 catheter days). These differences provided significant catheter-related cost savings of 43% in the taurolidine group vs. citrate group when overall expenses per patient and year were compared. Thus, use of taurolidine-based catheter lock solutions containing heparin and urokinase significantly reduced complications related to tunneled hemodialysis catheters when compared to four percent citrate solution and was overall more cost-efficient. PMID- 28890327 TI - Induction of interdigitating cell processes in podocyte culture. AB - Highly organized cell processes characterize glomerular podocytes in vivo. However, podocytes in culture have a simple morphology lacking cell processes, especially upon reaching confluence. Here, we aimed to establish culture conditions under which cultured podocytes extend cell processes at confluence. Among various culture conditions that could possibly cause phenotypic changes in podocytes, we examined the effects of heparin, all-trans retinoic acid, fetal bovine serum, and extracellular matrices on the morphology of podocytes in rat primary culture. Consequently, long arborized cell processes were observed to radiate extensively from the cell body only when cells were cultured in the presence of heparin and all-trans retinoic acid on laminin-coated dishes with decreasing concentrations of fetal bovine serum. Primary processes branching repeatedly into terminal processes and cell process insertion under adjacent cell bodies were evident by electron microscopy-based analysis. Immunostaining for podocin showed conspicuous elongations of intercellular junctions. Under these conditions, the expression levels of podocyte-specific proteins and genes were markedly upregulated. Thus, we succeeded in establishing culture conditions in which the cultured podocytes exhibit phenotypes similar to those under in vivo conditions. PMID- 28890328 TI - Are phase I trials safe for older patients? AB - Phase I clinical trials in oncology primarily aim to assess the toxicity profile of new drugs and determine recommended phase II doses (RP2D). Since the cancer rate increases with age and our population is continually aging, RP2D must necessarily be assessed in older patients. Few clinical studies include older patients, however, and particularly few Phase I trials. We reviewed published data on the safety and efficacy of Phase I trials in older patients. The majority of studies included primarily young, fit patients, with age thresholds varying widely from 65 to 80years. However, age does not seem to be associated with more toxicity or less efficacy. While Phase I trials seem feasible in fit older patients, geriatric-medicine score systems should be included in the clinical trial design in order to better characterize this population. PMID- 28890329 TI - Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway. AB - Spermatogonial stem cells (SSCs) possess the capacity of self-renewal and differentiation, which are the basis of spermatogenesis. In maintenance of SSC homeostasis, intrinsic/extrinsic factors and various signaling pathways tightly control the fate of SSCs. Methyltransferase SETDB1 (Set domain, bifurcated 1) catalyzes histone H3 lysine 9 (H3K9) trimethylation and represses gene expression. SETDB1 is required for maintaining the survival of spermatogonial stem cells in mice. However, the underlying molecular mechanism remains unclear. In the present study, we found that Setdb1 regulates PTEN/AKT/FOXO1 pathway to inhibit SSC apoptosis. Co-immunoprecipitation and reporter gene assay revealed that SETDB1 interacted and coordinated with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decreased in Setdb1-KD group; in contrast, H3K9me3 status on promoters of Bax and Puma remained unchanged. Therefore, SETDB1 was responsible for regulating the transcription activity of genes in the apoptotic pathway at least in part through modulating H3K9me3. This study replenishes the research on the epigenetic regulation of SSC survival, and provides a new insight for the future study of epigenetic regulation of spermatogenesis. PMID- 28890330 TI - A Comparative Analysis of Resource Utilization Between Proximal Row Carpectomy and Partial Wrist Fusion: A Population Study. AB - PURPOSE: We conducted a population-level analysis comparing proximal row carpectomy (PRC) and partial wrist arthrodesis (PWA) for treatment of chronic wrist arthritis to (1) characterize national practice patterns, (2) determine the rate of conversion to total wrist arthrodesis (TWA), and (3) calculate the associated direct cost of care. METHODS: Using the Truven MarketScan databases from 2009 to 2015, we identified patients 18 years or older with a diagnosis of wrist osteoarthritis who had a PRC or PWA and were followed for 18 months. We used Chi-square analysis and multivariable logistic regression to examine patient characteristics associated with conversion to a TWA. Rates of repeat PWA were also obtained, including the total number of procedures until completion and direct treatment cost. RESULTS: Of a total of 3,388 eligible patients, 1,305 had a PRC (39%) and 2,083 had a PWA (61%). In patients 54 years of age or younger, PWA was more commonly performed than PRC (49% vs 38%). The TWA rates were significantly higher for patients of all ages who underwent PWA (19.2%) versus PRC (4.9%). Those undergoing PWA required more total procedures than patients who received a PRC (average, 1.7 vs 1.1) resulting in a greater average direct cost per patient ($10,842 vs $7,171). CONCLUSIONS: Conversion rates to a TWA are significantly higher with a PWA (19.2%) than with a PRC (4.9%) and have a greater associated direct cost. This includes younger patients, who in the past were considered better candidates for PWA. Our findings suggest that surgeons may need to reevaluate their indications for PWA and that there may need to be a paradigm shift in the current practice patterns for salvage treatment of wrist arthrosis, more often considering PRC for all age groups. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 28890325 TI - AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms. AB - Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected. Although AKI-to-CKD transition has been intensively studied, the information of AKI on CKD is very limited. Nonetheless, AKI, when occurring in patients with CKD, is known to be more severe and difficult to recover. CKD is associated with significant changes in cell signaling in kidney tissues, including the activation of transforming growth factor-beta, p53, hypoxia-inducible factor, and major developmental pathways. At the cellular level, CKD is characterized by mitochondrial dysfunction, oxidative stress, and aberrant autophagy. At the tissue level, CKD is characterized by chronic inflammation and vascular dysfunction. These pathologic changes may contribute to the heightened sensitivity of, and nonrecovery from, AKI in patients with CKD. PMID- 28890331 TI - A Prospective Randomized Study Analyzing Preoperative Opioid Counseling in Pain Management After Carpal Tunnel Release Surgery. AB - PURPOSE: Prescription opioid misuse has become increasingly prevalent in the United States. Preoperative opioid counseling has been proposed to decrease opioid consumption after surgery. This study aimed to evaluate the effect of preoperative opioid counseling on patients' pain experience and opioid consumption after carpal tunnel release (CTR) surgery. METHODS: A prospective comparison of consecutive patients scheduled to undergo CTR surgery was conducted. Patients were randomized to receive either formal preoperative opioid counseling or no counseling. All operations were performed with the same mini open CTR surgical technique, and the same number of opioids were prescribed after surgery. Daily opioid pill consumption, pain levels, and any adverse reactions were recorded. RESULTS: During the day of surgery and the first day following surgery, patients in the group with counseling reported significantly fewer prescribed opioid pills consumed compared with patients in the group without counseling, while experiencing no significant difference in pain level experience. In addition, patients in the group with counseling reported a significantly lower number of total pain pills consumed over the course of the study than the group without counseling. No major adverse reactions were noted in either group. CONCLUSIONS: Preoperative opioid counseling was found to result in a significant decrease in overall opioid consumption after surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 28890332 TI - Association of Physical Function, Anxiety, and Pain Interference in Nonshoulder Upper Extremity Patients Using the PROMIS Platform. AB - PURPOSE: The relationship between psychosocial factors and self-reported physical function among hand and upper extremity patients is complex. The Patient-Reported Outcomes Measurement Information System (PROMIS) platform has attempted to create a variety of specifically targeted metrics that can be administered using computer adaptive testing (CAT). Three metrics measuring self-reported physical function (herein referred to in combination as "functional" metrics) include the PROMIS Physical Function (PF) CAT, PROMIS Upper Extremity (UE) CAT, and the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH). Two metrics assessing psychosocial factors include the PROMIS Anxiety and Pain Interference (PI) CATs ("nonfunctional" metrics). This study evaluates whether the functional metrics were correlated with nonfunctional metrics. METHODS: The 5 questionnaires were administered prospectively on a tablet computer to all consecutive adult patients presenting to an outpatient hand and upper extremity (nonshoulder) clinic at a tertiary academic medical center from January 1 to November 1, 2014. For patients with multiple visits during the study period, only the first was included. Data were evaluated retrospectively to assess the relationship between functional and nonfunctional measures, with Pearson correlation coefficients to understand the relationship between continuous variables, and 1-way analysis of variance to examine for differences in outcome measures across demographic groups. Multivariable linear regression analyses were performed to determine factors predicting functional disability. RESULTS: We included 1,299 patients: mean age was 46.8 years, 53% were female, and 23% were unemployed or on disability. The PROMIS PF CAT, PROMIS UE CAT, and QuickDASH scores were all significantly correlated with PROMIS Anxiety CAT (Pearson correlation coefficients, -0.46, 0.48, and 0.53, respectively) and PROMIS PI CAT (-0.60, -0.65, and 0.76, respectively) scores. Multivariable regression analyses demonstrated that increased PROMIS Anxiety and PI CAT scores each independently and adversely influenced PROMIS PF CAT, PROMIS UE CAT, and QuickDASH scores. CONCLUSIONS: Increasing levels of patient anxiety and pain interference are independently associated with decreased patient-reported upper extremity function. CLINICAL RELEVANCE: This study provides further support of the biopsychosocial model by highlighting that increased anxiety is associated with decreased self-reported function using the PROMIS platform. PMID- 28890335 TI - The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation. AB - During autophagosome formation in mammalian cells, isolation membranes (IMs; autophagosome precursors) dynamically contact the ER. Here, we demonstrated that the ER-localized metazoan-specific autophagy protein EPG-3/VMP1 controls ER-IM contacts. Loss of VMP1 causes stable association of IMs with the ER, thus blocking autophagosome formation. Interaction of WIPI2 with the ULK1/FIP200 complex and PI(3)P contributes to the formation of ER-IM contacts, and these interactions are enhanced by VMP1 depletion. VMP1 controls contact formation by promoting SERCA (sarco[endo]plasmic reticulum calcium ATPase) activity. VMP1 interacts with SERCA and prevents formation of the SERCA/PLN/SLN inhibitory complex. VMP1 also modulates ER contacts with lipid droplets, mitochondria, and endosomes. These ER contacts are greatly elevated by the SERCA inhibitor thapsigargin. Calmodulin acts as a sensor/effector to modulate the ER contacts mediated by VMP1/SERCA. Our study provides mechanistic insights into the establishment and disassociation of ER-IM contacts and reveals that VMP1 modulates SERCA activity to control ER contacts. PMID- 28890336 TI - The Plasticity of the Hsp90 Co-chaperone System. AB - The Hsp90 system in the eukaryotic cytosol is characterized by a cohort of co chaperones that bind to Hsp90 and affect its function. Although progress has been made regarding the underlying biochemical mechanisms, how co-chaperones influence Hsp90 client proteins in vivo has remained elusive. By investigating the effect of 12 Hsp90 co-chaperones on the activity of different client proteins in yeast, we find that deletion of co-chaperones can have a neutral or negative effect on client activity but can also lead to more active clients. Only a few co chaperones are active on all clients studied. Closely related clients and even point mutants can depend on different co-chaperones. These effects are direct because differences in client-co-chaperone interactions can be reconstituted in vitro. Interestingly, some co-chaperones affect client conformation in vivo. Thus, co-chaperones adapt the Hsp90 cycle to the requirements of the client proteins, ensuring optimal activation. PMID- 28890333 TI - Static and Dynamic DNA Loops form AP-1-Bound Activation Hubs during Macrophage Development. AB - The three-dimensional arrangement of the human genome comprises a complex network of structural and regulatory chromatin loops important for coordinating changes in transcription during human development. To better understand the mechanisms underlying context-specific 3D chromatin structure and transcription during cellular differentiation, we generated comprehensive in situ Hi-C maps of DNA loops in human monocytes and differentiated macrophages. We demonstrate that dynamic looping events are regulatory rather than structural in nature and uncover widespread coordination of dynamic enhancer activity at preformed and acquired DNA loops. Enhancer-bound loop formation and enhancer activation of preformed loops together form multi-loop activation hubs at key macrophage genes. Activation hubs connect 3.4 enhancers per promoter and exhibit a strong enrichment for activator protein 1 (AP-1)-binding events, suggesting that multi loop activation hubs involving cell-type-specific transcription factors represent an important class of regulatory chromatin structures for the spatiotemporal control of transcription. PMID- 28890334 TI - CRISPR-Mediated Base Editing Enables Efficient Disruption of Eukaryotic Genes through Induction of STOP Codons. AB - Standard CRISPR-mediated gene disruption strategies rely on Cas9-induced DNA double-strand breaks (DSBs). Here, we show that CRISPR-dependent base editing efficiently inactivates genes by precisely converting four codons (CAA, CAG, CGA, and TGG) into STOP codons without DSB formation. To facilitate gene inactivation by induction of STOP codons (iSTOP), we provide access to a database of over 3.4 million single guide RNAs (sgRNAs) for iSTOP (sgSTOPs) targeting 97%-99% of genes in eight eukaryotic species, and we describe a restriction fragment length polymorphism (RFLP) assay that allows the rapid detection of iSTOP-mediated editing in cell populations and clones. To simplify the selection of sgSTOPs, our resource includes annotations for off-target propensity, percentage of isoforms targeted, prediction of nonsense-mediated decay, and restriction enzymes for RFLP analysis. Additionally, our database includes sgSTOPs that could be employed to precisely model over 32,000 cancer-associated nonsense mutations. Altogether, this work provides a comprehensive resource for DSB-free gene disruption by iSTOP. PMID- 28890338 TI - Improving undergraduate pathology teaching: medical students' perspective. PMID- 28890339 TI - Improving undergraduate pathology teaching: medical students' perspective-reply. PMID- 28890337 TI - The ATPase Fap7 Tests the Ability to Carry Out Translocation-like Conformational Changes and Releases Dim1 during 40S Ribosome Maturation. AB - Late in their maturation, nascent small (40S) ribosomal subunits bind 60S subunits to produce 80S-like ribosomes. Because of the analogy of this translation-like cycle to actual translation, and because 80S-like ribosomes do not produce any protein, it has been suggested that this represents a quality control mechanism for subunit functionality. Here we use genetic and biochemical experiments to show that the essential ATPase Fap7 promotes formation of the rotated state, a key intermediate in translocation, thereby releasing the essential assembly factor Dim1 from pre-40S subunits. Bypassing this quality control step produces defects in reading frame maintenance. These results show how progress in the maturation cascade is linked to a test for a key functionality of 40S ribosomes: their ability to translocate the mRNA?tRNA pair. Furthermore, our data demonstrate for the first time that the translation-like cycle is a quality control mechanism that ensures the fidelity of the cellular ribosome pool. PMID- 28890340 TI - Infection of Potamopyrgus antipodarum (Gray, 1843) (Gastropoda: Tateidae) by trematodes in Poland, including the first record of aspidogastrid acquisition. AB - The prosobranch gastropod Potamopyrgus antipodarum (Gray, 1843) is poorly understood as a parasite host outside its native New Zealand, including in Europe. Our aim was to ascertain whether non-native P. antipodarum could acquire aspidogastrids or digeneans in habitats where these parasites are found in native hosts. We examined 2400 P. antipodarum individuals from Sosno Lake (Poland). The majority of snails were adult females. No males were found. We found five P. antipodarum individuals with Aspidogaster conchicola and 39 snails with metacercariae of Echinoparyphium aconiatum Dietz 1909 or E. recurvatum (Linstow, 1873). Snails with metacercariae and unparasitized snails, but not snails with A. conchicola, produced embryos. Ours is the first record of an Aspidogastrea - P. antipodarum association. PMID- 28890341 TI - Cueing for people with Parkinson's disease with freezing of gait: A narrative review of the state-of-the-art and novel perspectives. AB - Freezing, which manifests during gait and other movements, is an incapacitating motor symptom experienced by many patients with Parkinson's disease (PD). In rehabilitation, auditory and visual cueing methods are commonly applied to evoke a more goal-directed type of motor control and, as such, reduce freezing severity in patients with PD. In this narrative review, we summarize the current evidence regarding the effects of external cueing in patients with PD with freezing of gait (FOG) and provide suggestions on how to further improve cueing effectiveness with emerging technological developments. For this paper, we reviewed 24 articles describing the assessment of the effects of cues in patients with FOG (n=354). Because these studies mostly involved quasi-experimental designs, no methodological analysis was undertaken. In general, the evidence suggests that cue-augmented training can reduce FOG severity, improve gait parameters and improve upper-limb movements immediately after training. However, findings were not univocal, and long-term consolidation and transfer of the effects appear to be hampered specifically in this subgroup. With the increasing use of wearable technology, new possibilities are allowing for adapting the cue type, cue content and dose of cues to the needs of individual patients, which may boost the clinical use and efficiency of cued training in PD patients with FOG. PMID- 28890342 TI - Prosthetic joint infection with pseudo-tumoral aspect due to Mycobacterium bovis infection after Bacillus-Calmette-Guerin therapy. PMID- 28890343 TI - Antibiotic prophylaxis in breast reduction surgery: A systematic review and meta analysis. AB - OBJECTIVE: To determine the effectiveness and harm of using antibiotic prophylaxis versus placebo or no intervention in patients undergoing breast reduction surgery to prevent surgical site infection. MATERIALS AND METHODS: A search strategy was conducted in the MEDLINE, CENTRAL, EMBASE, and LILACS databases. Searches were also conducted in other databases and unpublished literature. Clinical trials were included without language restrictions. The risk of bias was evaluated with the Cochrane Collaboration's tool. An analysis of fixed effects was conducted. The primary outcome was surgical site infection. The secondary outcomes were delayed wound healing and adverse effects. The measure of the effect was the risk difference (RD) with a 95% confidence interval (CI). The planned interventions were antibiotic prophylaxis versus placebo/no intervention. RESULTS: Five articles were included in the qualitative and quantitative analysis. A total of 584 patients were included from the five studies. A low risk of bias was shown for most of the study items. The overall RD for surgical site infection was -0.08 (95% CI -0.14--0.03), favoring antibiotic prophylaxis compared with placebo. CONCLUSION: Antibiotic prophylaxis lowers the incidence of surgical site infection in breast reduction surgery compared with placebo or no intervention. PMID- 28890344 TI - A new parallel DNA algorithm to solve the task scheduling problem based on inspired computational model. AB - As a promising approach to solve the computationally intractable problem, the method based on DNA computing is an emerging research area including mathematics, computer science and molecular biology. The task scheduling problem, as a well known NP-complete problem, arranges n jobs to m individuals and finds the minimum execution time of last finished individual. In this paper, we use a biologically inspired computational model and describe a new parallel algorithm to solve the task scheduling problem by basic DNA molecular operations. In turn, we skillfully design flexible length DNA strands to represent elements of the allocation matrix, take appropriate biological experiment operations and get solutions of the task scheduling problem in proper length range with less than O(n2) time complexity. PMID- 28890346 TI - Hepatoprotective effects of Methyl ferulic acid on alcohol-induced liver oxidative injury in mice by inhibiting the NOX4/ROS-MAPK pathway. AB - AIMS: The present study aimed to investigate the hepatoprotective effects of Methyl ferulic acid (MFA) against oxidative stress and apoptosis as well as inflammation in mice with liver injury induced by alcohol and its underlying mechanisms. METHODS: C57BL/6 mice were divided into a control group,a model group, and Methyl ferulic acid with high dosage (20 mg/kg), moderate dosage (10 mg/kg) and low dosage (5 mg/kg) groups. The general condition and organ index of each group were investigated. Histopathological analysis was performed to determine the degree of hepatic injury. Biochemical analyses of functional liver enzymes, lipid peroxidation enzymes and lipid content in each group. The levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The mechanisms were investigated by detecting levels of NADPH Oxidase 4 (NOX4),p22phox, cytochrome P4502E1 (CYP2E1),Bax,B-cell lymphoma 2 (Bcl-2),cleaved caspase 3 and 9 and phosphorylated extracellular regulated protein kinases(ERK),phosphorylated c-Jun N-terminal kinase (JNK), and phosphorylated p38 mitogen-activated protein kinase (MAPK) using real-time polymerase chain reaction (PCR) and Western blotting. RESULTS: MFA treatment significantly decreased serum enzymatic activities of alanine aminotransferase (ALT) and aspartate aminotransaminase (AST). MFA markedly increased levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-Px) and total antioxidative capacity (T-AOC), and reduced the concentration of malondialdehyde (MDA) and reactive oxygen species (ROS). Histopathological examination of livers showed that MFA reduced cytoplasmic vacuolisation necrosis and inflammatory cell infiltration in alcohol-treated mice. MFA treatment remarkably reduced the levels of trigyceride (TG), total cholesterol (TC) and low density lipoprotein (LDL), decreasing the levels of high-density lipoprotein (HDL), alcohol dehydrogenase(ADL) and aldehyde dehydrogenase (ALDH). MFA treatment remarkably inhibited the expression of inflammatory factors tumour necrosis factor (TNF)-alpha, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1beta and IL-6. MFA attenuated both mRNA and protein expression of NOX4,p22phox,CYP2E1,Bax/Bcl-2. In addition, MFA inhibited the activation of caspase 3 and 9 and downregulated the levels of p-JNK,p-p38 MAPK and p-ERK in liver. CONCLUSION: MFA has a protective effect on alcohol-induced liver injury, which may be related to its antioxidant,anti-inflammatory,lipid-eliminating properties and its ability to regulate the NOX4/ROS-MAPK signalling pathway. PMID- 28890347 TI - High-resolution structure discloses the potential for allosteric regulation of mitogen-activated protein kinase kinase 7. AB - Mitogen-activated protein kinase kinase 7 (MAP2K7) regulates stress and inflammatory responses, and is an attractive drug discovery target for several diseases including arthritis and cardiac hypertrophy. Intracellular proteins such as MAP2K7 are prone to aggregation due to cysteine-driven oxidation in in vitro experiments. MAP2K7 instability due to the four free cysteine residues on the molecular surface abrogated the crystal growth and led to a low-resolution structure with large residual errors. To acquire a higher resolution structure for promoting rational drug discovery, we explored stable mutants of MAP2K7 by replacing the surface cysteine residues, Cys147, Cys218, Cys276 and Cys296. Single-site mutations, except for Cys147, maintained the specific activity and increased the protein yield, while all the multi-site mutations massively reduced the activity. The C218S mutation drastically augmented the protein production and crystallographic resolution. Furthermore, the C218S crystals grown under microgravity in a space environment yielded a 1.3 A resolution structure, providing novel insights for drug discovery: the precisely assigned water molecules in the active site, the double conformations in the flexible region and the C-terminal extension bound to the N-terminal region of the adjacent molecules. The latter insight is likely to promote the production of allosteric MAP2K7 inhibitors. PMID- 28890345 TI - Prosapip1-Dependent Synaptic Adaptations in the Nucleus Accumbens Drive Alcohol Intake, Seeking, and Reward. AB - The mammalian target of rapamycin complex 1 (mTORC1), a transducer of local dendritic translation, participates in learning and memory processes as well as in mechanisms underlying alcohol-drinking behaviors. Using an unbiased RNA-seq approach, we identified Prosapip1 as a novel downstream target of mTORC1 whose translation and consequent synaptic protein expression are increased in the nucleus accumbens (NAc) of mice excessively consuming alcohol. We demonstrate that alcohol-dependent increases in Prosapip1 levels promote the formation of actin filaments, leading to changes in dendritic spine morphology of NAc medium spiny neurons (MSNs). We further demonstrate that Prosapip1 is required for alcohol-dependent synaptic localization of GluA2 lacking AMPA receptors in NAc shell MSNs. Finally, we present data implicating Prosapip1 in mechanisms underlying alcohol self-administration and reward. Together, these data suggest that Prosapip1 in the NAc is a molecular transducer of structural and synaptic alterations that drive and/or maintain excessive alcohol use. PMID- 28890348 TI - MiR-362-3p inhibits the proliferation and migration of vascular smooth muscle cells in atherosclerosis by targeting ADAMTS1. AB - Atherosclerosis is a progressive condition of the large arteries that can cause coronary artery disease (CAD). Growing amounts of evidence have indicated that microRNAs (miRNAs, miRs) can be used as diagnostic biomarkers in many cellular processes associated with CAD. MiR-362-3p has been implicated in many biological cellular functions. However, little is known about the role of miR-362-3p during atherosclerosis. In the present study, significant downregulation of miR-362-3p was observed in 110 atherosclerotic CAD patients and not in the 84 controls. The upregulation of miR-362-3p was demonstrated to inhibit vascular smooth muscle cell (VSMC) proliferation and migration, and impede the G1/S cell cycle transition. Bioinformatics analysis indicated that a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) was a direct target of miR-362-3p. Subsequent experiments demonstrated that miR-362-3p binds to the 3' untranslated region (UTR) of ADAMTS1 and decreases its levels of mRNA and protein expression. Overexpression of ADAMTS1 partially restored the miR-362-3p-mediated inhibition of VSMC proliferation, cell cycle, and migration. Upregulation of ADAMTS1 in plasma samples was detected in atherosclerotic CAD patients. Taken together, our findings suggested that miR-362-3p inhibits the proliferation and migration of VSMCs by directly targeting ADAMTS1, which might provide novel insight into the molecular mechanisms underlying the action of miR-362-3p in atherosclerosis. PMID- 28890349 TI - Molecular hydrogen modulates gene expression via histone modification and induces the mitochondrial unfolded protein response. AB - Molecular hydrogen (H2) is a biologically active gas that is used medically to ameliorate various systemic pathological conditions. H2 also regulates gene expression involved in intracellular signaling and metabolic pathways. However, it is unclear whether H2 affects gene expression directly or through indirect effects as a consequence of health improvement. Therefore, we attempted to identify genes that exhibit similar changes in expression in response to H2 by employing DNA microarrays and gene set enrichment analysis to analyze RNA from liver and lung of rats and mice with or without dietary stress. We found that H2 activated the expression of sets of genes regulated by histone H3K27 methylation status. H2 also modified the expression of many genes regulated by a wide variety of signaling pathways. RT-qPCR showed that H2 up-regulated expression of Kcnc3, a H3K27-regulated gene, in organs such as liver, lung, kidney and brain. Furthermore, using immunohistochemistry and immunoblot analysis, we observed changes in H3K27 methylation status in the liver of mice and rats administered H2. Moreover, we showed that H2 simultaneously induced the H3K27 demethylase, Jmjd3, and mitochondrial unfolded protein response (mtUPR)-related genes. Recently, alteration of mitochondrial function was shown to cause induction of H3K27 demethylase or chromatin restructuring, followed by mtUPR activation through the alteration of H3K27 or H3K9 methylation states. Taken together, our study suggests that H2 can induce beneficial effects through mtUPR activation via epigenetic histone modification and by modification of gene expression. PMID- 28890350 TI - Thioredoxin-interacting protein promotes high-glucose-induced macrovascular endothelial dysfunction. AB - Thioredoxin-interacting protein (TXNIP) emerges as a central regulator for glucose homeostasis, which goes awry in diabetic subjects. Endothelial dysfunction is considered the earliest detectable stage of cardiovascular disease (CVD), a major complication of diabetes. Here, we hypothesize that TXNIP may promote endothelial dysfunction seen in Type 1 diabetes mellitus (T1D). Using a T1D-like rat model, we found that diabetic rats showed significantly higher TXNIP mRNA and protein levels in peripheral blood, compared to their non-diabetic counterparts. Those changes were accompanied by decreased production of nitric oxide (NO) and vascular endothelial growth factor (VEGF), concurrent with increased expression of reactive oxygen species (ROS) and vascular cell adhesion molecule 1 (VCAM-1) in the aortic endothelium. In addition, TXNIP overexpression in primary human aortic endothelial cells (HAECs) induced by either high glucose or overexpression of carbohydrate response element binding protein (ChREBP), a major transcriptional activator of TXNIP, promoted early apoptosis and impaired NO bioactivity. The correlation between TXNIP expression levels and endothelial dysfunction suggests that TXNIP may be a potential biomarker for vascular complications in T1D patients. PMID- 28890351 TI - In situ delivery and production system of trastuzumab scFv with Bifidobacterium. AB - A monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2), trastuzumab has become a standard treatment for HER2-positive breast cancer. Recent advancements in antibody engineering have enabled the efficient generation of the trastuzumab single-chain variable fragment (scFv). In this study, we genetically engineered Bifidobacterium, a bacterial strain shown to accumulate safely and selectively in hypoxic tumor sites by intravenous (iv) injection, to express and secrete the trastuzumab scFv. The recombinant scFv bound to cell surface HER2 and inhibited in vitro growth of HER2-positive human cancer cells. Moreover, iv-injected recombinant bacteria specifically localized and secreted trastuzumab scFv in xenografted human HER2-positive tumors and consequently inhibited tumor growth. The development and results of this novel in situ delivery and production system for trastuzumab scFv with Bifidobacterium represents a promising avenue for future application in cancer treatment. PMID- 28890352 TI - Social cognitive aspects of the participation in workplace health promotion as revealed by the theory of planned behavior. AB - Health-promoting efforts strongly depend on individual cognitions such as attitudes as well as social cognitive aspects of the work environment such as leadership and support. Using the theory of planned behavior (TPB) as a theoretical frame, participation behavior of employees in courses offered by the workplace health promotion (WHP) program of the German Armed Forces was investigated. Social cognitive aspects of the work environment, such as leadership behaviors by setting an example or optimizing organization of work, were included in the TPB components of subjective norm and perceived behavioral control, which allowed for an investigation of the specific effects of leadership on WHP participation. A survey study with N=1385 members of the German Armed Forces was conducted in 2015 in Germany. Results showed that perceived behavioral control and attitudes towards WHP were the strongest predictors for WHP participation. While subjective norm was positively related to attitudes, it had a slightly negative effect on intention to participate in WHP activities. These findings suggest that the most effective way for leadership to increase WHP participation is to enhance perceived behavioral control. Quite contrary, creating a positive subjective norm regarding WHP participation may even result in psychological reactance. PMID- 28890353 TI - Identifying principles for effective messages about chemicals in cigarette smoke. AB - US law requires the Food and Drug Administration (FDA) to disclose information on harmful and potentially harmful chemicals in cigarette smoke (i.e., constituents) to the public. To inform this effort, we sought to identify principles for creating constituent messages that effectively discourage smoking. Participants were an online convenience sample of 1148 US smokers ages 18+. We developed a library of 76 messages about constituents only and constituents plus contextualizing information (i.e., toxic products that also contain the chemical, health effects, or both). We randomized smokers to receive 1 message from each of 7 message panels in a mixed between-/within-subjects experiment. Participants rated each message on perceived message effectiveness. Results indicated that smokers perceived messages about arsenic, formaldehyde, lead, uranium, and ammonia as more effective than messages about nitrosamines. Messages that contained information on toxic products, health effects, or both received higher effectiveness ratings than constituent-only messages. Among constituent-only messages, those that referenced multiple constituents received higher effectiveness ratings than those with fewer constituents. We conclude that chemical messages may have more impact if they pair known constituents with toxic product or health effect information. These message principles can be used to inform studies examining the impact of constituent messages on smoking beliefs and behavior. PMID- 28890354 TI - Employment changes associated with the introduction of taxes on sugar-sweetened beverages and nonessential energy-dense food in Mexico. AB - We assessed changes in employment in the manufacturing industry, the commercial sector and national unemployment rates, associated with the fiscal policies implemented in 2014 in Mexico: a 1 peso per liter excise tax to sugar-sweetened beverages (SSB) and an 8% tax on nonessential energy-dense food. We used data from three nationally representative surveys. Controlling for contextual variables, we used interrupted time series analyses to model changes in number of employees in the SSB and nonessential energy-dense food industry, in commercial establishments selling beverages and food and changes in national unemployment rates. Our results show that there were no significant changes in employment associated with the taxes in the manufacturing industries (for beverages and nonessential energy-dense food). We found a very small increasing trend in the post-tax period for employment in commercial stores and a decreasing trend in the unemployment rate. However, these changes are negligible and unlikely to be caused by the implementation of the taxes. In conclusion, there were no employment reductions associated with the fiscal policies implemented in Mexico in 2014 on SSB and nonessential energy-dense food. PMID- 28890355 TI - Impact of a workplace physical activity tracking program on biometric health outcomes. AB - Wellness programs are a popular strategy utilized by large U.S. employers. As mobile health applications and wearable tracking devices increase in prevalence, many employers now offer physical activity tracking applications. This longitudinal study evaluates the impact of engagement with a web-based, physical activity tracking program on changes in individuals' biometric outcomes in an employer population. The study population includes active employees and adult dependents continuously enrolled in an eligible health plan and who have completed at least two biometric screenings (n=36,882 person-years with 11,436 unique persons) between 2011 and 2014. Using difference-in-differences (DID) regression, we estimate the effect of participation in the physical activity tracking application on BMI, total cholesterol, and blood pressure. Participation was significantly associated with a reduction of 0.275 in BMI in the post-period, relative to the comparison group, representing a 1% change from baseline BMI. The program did not have a statistically significant impact on cholesterol or blood pressure. Sensitivity checks revealed slightly larger BMI reductions among participants with higher intensity of tracking activity and in the period following the employer's shift to an outcomes-based incentive design. Results are broadly consistent with the existing literature on changes in biometric outcomes from workplace initiatives promoting increased physical activity. Employers should have modest expectations about the potential health benefits of such programs, given current designs and implementation in real-world settings. PMID- 28890356 TI - Multicenter prevalence of anaphylaxis in clinic-based oral food challenges. AB - BACKGROUND: Although previous single-center studies report the rate of anaphylaxis for oral food challenges (OFCs) as 9% to 11%, little is known regarding the epidemiology of clinical OFCs across multiple centers in the United States. OBJECTIVE: To examine the epidemiology, symptoms, and treatment of clinical low-risk OFCs in the nonresearch setting. METHODS: Data were obtained from 2008 to 2013 through a physician survey in 5 food allergy centers geographically distributed across the United States. Allergic reaction rates and the association of reaction rates with year, hospital, and demographics were determined using a linear mixed model. Meta-analysis was used to pool the proportion of reactions and anaphylaxis with inverse-variance weights using a random-effects model with exact confidence intervals (CIs). RESULTS: A total of 6,377 OFCs were performed, and the pooled estimate of anaphylaxis was 2% (95% CI, 1%-3%). The rate of allergic reactions was 14% (95% CI, 13%-16%) and was consistent during the study period (P = .40). Reaction rates ranged from 13% to 33%. Males reacted 16% more frequently than females (95% CI, 4%-37.5%; P = .04). Foods challenged in 2013 varied geographically, with peanut as the most challenged food in the Northeast, Midwest, and West and egg as the most challenged in the South. CONCLUSION: As the largest national survey of allergic reactions of clinical open OFCs in a nonresearch setting in the United States, this study found that performing clinical nonresearch open low-risk OFCs results in few allergic reactions, with 86% of challenges resulting in no reactions and 98% without anaphylaxis. PMID- 28890357 TI - Treatment failure after interferon-free treatment of hepatitis C as a clue of a yet undetected hepatocellular carcinoma. PMID- 28890358 TI - Age-related differences in bimanual movements: A systematic review and meta analysis. AB - BACKGROUND: With increasing age motor functions decline. The additional challenges of executing bimanual movements further hinder motor functions in older adults. The current systematic review and meta-analysis determined the effects of healthy aging on performance in bimanual movements as compared to younger adults. METHODS: Our comprehensive search identified 27 studies that reported bimanual movement performance measures. Each study included a between groups comparison of older (mean age=68.79years) and younger adults (mean age=23.14years). The 27 qualified studies generated 40 total outcome measure comparisons: (a) accuracy: 18, (b) variability: 14, and (c) movement time: eight. RESULTS: Our meta-analysis conducted on a random effects model identified a relatively large negative standardized mean difference effect (ES=-0.93). This indicates that older adults exhibited more impaired bimanual movement performance in comparison to younger adults in our group of studies. Specifically, a moderator variable analysis revealed large negative effects in both accuracy (ES= 0.94) and variability (ES=-1.00), as well as a moderate negative effect (ES= 0.71) for movement time. These findings indicate that older adults displayed reduced accuracy, greater variability, and longer execution time when executing bimanual movements. CONCLUSION: These meta-analytic findings revealed that aging impairs bimanual movement performance. PMID- 28890359 TI - Optic atrophy 1 mediates coenzyme Q-responsive regulation of respiratory complex IV activity in brain mitochondria. AB - The oxygen consumption rate (OCR) in brain mitochondria is significantly lower in aged mice than in young mice, and the reduced OCR is rescued by administration of water-solubilized CoQ10 to aged mice via drinking water. However, the mechanism behind this remains unclear. Here, we show that the activity of respiratory complex IV (CIV) in brain mitochondria declined in aged mice than in young mice, with no significant change in individual respiratory complex levels and their supercomplex assembly. Reduced CIV activity in the aged mice coincided with reduced binding of optic atrophy 1 (OPA1) to CIV. Both reduced activity and OPA1 binding of CIV were rescued by water-solubilized CoQ10 administration to aged mice via drinking water. OCR and the activity and OPA1 binding of CIV in isolated brain mitochondria from aged mice were restored by incubation with CoQ10, but not in the presence of 15-deoxy-prostaglandin J2, an inhibitor of a GTPase effector domain-containing GTPase such as OPA1 and DRP1. By contrast, the CoQ10-responsive restoration of OCR in the isolated mitochondria was not inhibited by Mdivi-1, a selective inhibitor of DRP1. Thus, we propose a novel function of OPA1 in regulating the CIV activity in brain mitochondria in response to CoQ10. PMID- 28890361 TI - Comprehensive Analysis of the Human SH3 Domain Family Reveals a Wide Variety of Non-canonical Specificities. AB - SH3 domains are protein modules that mediate protein-protein interactions in many eukaryotic signal transduction pathways. The majority of SH3 domains studied thus far act by binding to proline-rich sequences in partner proteins, but a growing number of studies have revealed alternative recognition mechanisms. We have comprehensively surveyed the specificity landscape of human SH3 domains in an unbiased manner using peptide-phage display and deep sequencing. Based on ~70,000 unique binding peptides, we obtained 154 specificity profiles for 115 SH3 domains, which reveal that roughly half of the SH3 domains exhibit non-canonical specificities and collectively recognize a wide variety of peptide motifs, most of which were previously unknown. Crystal structures of SH3 domains with two distinct non-canonical specificities revealed novel peptide-binding modes through an extended surface outside of the canonical proline-binding site. Our results constitute a significant contribution toward a complete understanding of the mechanisms underlying SH3-mediated cellular responses. PMID- 28890360 TI - Synergistic Regulation of Coregulator/Nuclear Receptor Interaction by Ligand and DNA. AB - Nuclear receptor (NR) transcription factors bind various coreceptors, small molecule ligands, DNA response element sequences, and transcriptional coregulator proteins to affect gene transcription. Small-molecule ligands and DNA are known to influence receptor structure, coregulator protein interaction, and function; however, little is known on the mechanism of synergy between ligand and DNA. Using quantitative biochemical, biophysical, and solution structural methods, including 13C-detected nuclear magnetic resonance and hydrogen/deuterium exchange (HDX) mass spectrometry, we show that ligand and DNA cooperatively recruit the intrinsically disordered steroid receptor coactivator-2 (SRC-2/TIF2/GRIP1/NCoA-2) receptor interaction domain to peroxisome proliferator-activated receptor gamma retinoid X receptor alpha (PPARgamma-RXRalpha) heterodimer and reveal the binding determinants of the complex. Our data reveal a thermodynamic mechanism by which DNA binding propagates a conformational change in PPARgamma-RXRalpha, stabilizes the receptor ligand binding domain dimer interface, and impacts ligand potency and cooperativity in NR coactivator recruitment. PMID- 28890362 TI - Microsecond Dynamics and Network Analysis of the HIV-1 SOSIP Env Trimer Reveal Collective Behavior and Conserved Microdomains of the Glycan Shield. AB - The trimeric HIV-1-envelope (Env) spike is one of the most glycosylated protein complexes known, with roughly half its mass comprising host-derived N-linked glycan. Here we use molecular dynamics to provide insight into its structural dynamics and into how both protomer and glycan movements coordinate to shield the Env protein surface. A 2-MUs molecular dynamics simulation of a fully glycosylated atomistic model of the HIV-1 SOSIP Env trimer revealed a spectrum of protomer-scissoring and trimer-opening movements. Network analysis showed that highly conserved glycans combined with protomer scissoring to restrict access to the binding site of the CD4 receptor. The network property of betweenness centrality appeared to identify whether glycans spread to restrict access or cluster to maintain the high-mannose character of the shield. We also observed stable microdomains comprising patches of glycan, with neutralizing antibodies generally binding at the interface between glycan microdomains. Overall, our results provide a microsecond-based understanding of the Env glycan shield. PMID- 28890363 TI - Relationship between the color stability and impurity profile of cefotaxime sodium. AB - The color grade, mainly introduced in the processes of semisynthesis and storage, is an important index used to evaluate the quality of cefotaxime sodium. Because the drug itself is prone to degradation under susceptible conditions, including those involving moisture, heat, ultraviolet light, acids, alkalis, and oxidants, and a series of degradation products as impurities are generated. In this study, the factors affecting color grade stability and the degradation mechanisms of cefotaxime sodium were investigated by designing different accelerated stability tests under the aforementioned conditions. The degradation extent was studied by using analytical methods, such as a solution color comparison method, ultraviolet spectrophotometry, and HPLC. The relationship between the color grade stability of cefotaxime sodium and its impurity profile has been explored, and a reasonable degradation mechanism has been proposed. The manufacturing conditions of inspection have been optimized, and a scientific basis for drug packaging, storage, and transportation conditions has been established. The results show that the color grade stability of cefotaxime sodium is related to the impurity profile to some degree, and the difference between the actual color and the standard color can reflect the levels of impurities to some extent. PMID- 28890364 TI - Sequential screening by ClonePix FL and intracellular staining facilitate isolation of high producer cell lines for monoclonal antibody manufacturing. AB - Screening and characterization of cell lines for stable production are critical tasks in identifying suitable recombinant cell lines for the manufacture of protein therapeutics. To aid this essential function we have developed a methodology for the selection of antibody expressing cells using fluorescence based ClonePix FL colony isolation and flow cytometry analysis following intracellular staining for immunoglobulin G (IgG). Our data show that characterization of cells by flow cytometry early in the clone selection process enables the identification of cell lines with the potential for high productivity and helps to eliminate unstable cell lines. We further demonstrate a correlation between specific productivity (qP) and intracellular heavy chain (HC) content with final productivity. The unique combination of screening using ClonePix FL and the flow cytometry approaches facilitated more efficient isolation of clonal cell lines with high productivity within a 15week timeline and which can be applied across NS0 and CHO host platforms. Furthermore, in this study we describe the critical parameters for the ClonePix FL colony based selection and the associated calculations to provide an assessment of the probability of monoclonality of the resulting cell lines. PMID- 28890365 TI - Detection and quantification of rituximab in the human urine. AB - B cell depletion by rituximab treatment might be inefficient in patients suffering from nephrotic syndrome. Due to the impaired glomerular filtration barrier a significant portion of the therapeutic antibody might be lost into the urinary space. In order to determine the amount of rituximab in the urine of such patients, CD20+ Daudi cells were stained with the patients' urine followed by a fluorochrome-labeled secondary antibody. Mean fluorescence intensity of that way labeled Daudi cells was determined by flow cytometry. Control samples with defined rituximab concentrations were used to create standard curves. The analyses revealed that all nephelometric IgG+ urine samples tested also manifested rituximab at concentrations between 100 and 46,707MUg/L. The flow cytometry-based approach is an easy and reliable method to assess rituximab in patients' urine samples for monitoring individual rituximab treatment courses in all patients co-presenting impaired renal filtration. Presence of such antibodies in the urine could be considered as criteria to modify the formulation or modality of rituximab delivery in order to prevent the loss of the therapeutic antibodies and thereby ensuring efficacy of the therapy. PMID- 28890366 TI - Increasing adult hippocampal neurogenesis in mice after exposure to unpredictable chronic mild stress may counteract some of the effects of stress. AB - Major depression is hypothesized to be associated with dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic corticosterone is sufficient to protect against its harmful effects on behavior. However, it is an open question if increasing AHN after the onset of chronic stress exposure would be able to rescue behavioral deficits and which mechanisms might be involved in recovery. We investigated this question by using a 10-week unpredictable chronic mild stress (UCMS) model on a transgenic mouse line (iBax mice), in which the pro-apoptotic gene Bax can be inducibly ablated in neural stem cells following Tamoxifen injection, therefore enhancing the survival of newborn neurons in the adult brain. We did not observe any effect of our treatment in non-stress conditions, but we did find that increasing AHN after 2 weeks of UCMS is sufficient to counteract the effects of UCMS on certain behaviors (splash test and changes in coat state) and endocrine levels and thus to display some antidepressant-like effects. We observed that increasing AHN lowered the elevated basal corticosterone levels in mice exposed to UCMS. This was accompanied by a tamoxifen-induced reversal of the lack of stress-induced decrease in neuronal activation in the anteromedial division of the bed nucleus of the stria terminalis (BSTMA) after intrahippocampal dexamethasone infusion, pointing to a possible mechanism through which adult-born neurons might have exerted their effects. Our results contribute to the neurogenesis hypothesis of depression by suggesting that increasing AHN may be beneficial not just before, but also after exposure to stress by counteracting several of its effects, in part through regulating the HPA axis. PMID- 28890367 TI - Enhanced anandamide signaling reduces flight behavior elicited by an approaching robo-beetle. AB - Our current knowledge of the implications of endocannabinoids in fear and anxiety is largely based on fear conditioning paradigms and approach-avoidance conflicts. Here we establish the ethobehavioral beetle mania task (BMT), which confronts mice with an erratically moving robo-beetle. With the help of this task we demonstrate decreased tolerance yet increased avoidance responses to an approaching beetle in high-anxiety behavior (HAB) and BALBc mice compared to C57BL/6N, CD1 and normal-anxiety behavior (NAB) mice. Also DBA/2N mice showed decreased passive and increased active behavior, but followed the robo-beetle more often than HAB and BALBc mice. Treatment with diazepam (1 mg/kg) increased tolerance without affecting avoidance behavior in HAB mice. Treatment with the MAGL inhibitor JZL184 (8 mg/kg) increased flight behavior, but did not affect tolerance. The FAAH inhibitor URB597 (0.3 mg/kg), however, reduced flight behavior and enhanced tolerance to the robo-beetle. The latter effects were blocked by co-treatment with the CB1 receptor antagonist SR141716A (3 mg/kg), which failed to affect the behavior by itself. Taken together, we validate the BMT as a novel test for studying endocannabinoids beyond traditional paradigms and for assessing active fear responses in mice. Furthermore, we demonstrate panicolytic consequences of pharmacological enhancement of anandamide, but not 2 AG signaling. PMID- 28890368 TI - CYP17A1-independent production of the neurosteroid-derived 5alpha-pregnan 3beta,6alpha-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone. AB - CYP17A1-independent intratumoral steroid hormone synthesis is regarded as one possible explanation for resistance to treatment with the CYP17-inhibitor Abiraterone (Abi). The aim of our study was therefore to investigate the steroid metabolism of prostate cancer cells under serum starvation and the effects of Abi treatment. We assessed steroid metabolism in a panel of prostate cancer cells under serum starvation by radioactivity detector-coupled HPLC and HPLC-ESI-ToF mass spectrometry after treatment with pregnenolone, progesterone and allopregnanolone. We further evaluated the effects of Abi on steroid metabolism of testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA) by enzyme immunoassays (EIAs). Androgen-responsive cell lines metabolized pregnenolone primarily to mitogenic steroid 5alpha-pregnan-3beta,6alpha-diol-20 one under serum starvation. Co-administration of Abi lead to detectable concentrations of the Abi metabolite Delta4-Abi (D4A), known to inhibit enzymes other than CYP17A1 in steroid metabolism. In addition, co-administration of Abi abrogated pregnenolone metabolism and resulted in a CYP17A1-independent significant increase of DHEA (13- to >100-fold) and DHT (2.5-fold) in androgen responsive cells. Our results demonstrate the CYP17A1-independent formation of 5alpha-pregnan-3beta,6alpha-diol-20-one by androgen-responsive prostate cancer cells under serum starvation and its inhibition by Abi. Its metabolism from pregnenolone suggests a major steroidogenesis shift in these cells, hinting at a neuroendocrine transdifferentiation phenomenon. The marked increase of DHEA levels by Abi resembles the steroidogenic pathways in nervous tissue, in a manner that precludes CYP17A1 activity. To which extent these processes are responsible or involved in the development of resistance to Abi, needs to be further elucidated. PMID- 28890370 TI - A mechanistic insight into protein-ligand interaction, folding, misfolding, aggregation and inhibition of protein aggregates: An overview. AB - This review article summarises the possible mechanisms of the protein-ligand interaction, folding, misfolding, aggregation and inhibition of protein aggregates. Under certain stressed condition the folding process deviates from its path and results into misfolding and aggregation of proteins. So aggregates have to be inhibited in order to cure the diseases. In some cases of protein ligand interaction studies we have seen that the interaction of a protein with more than one ligand may show both type of quenching mechanisms i.e. dynamic as well as static quenching rather than single type of quenching mechanism, that result can be entirely different by the result of binding study utilising single ligand. So, likewise it is hypothesized that if the aggregates are inhibited by using more than one inhibitor may give more fruitful results rather than application of single inhibitor in inhibition and disaggregation of the preformed aggregates. Therefore, we have hypothesized mechanisms for the inhibition of protein aggregates that may assist in curing the neurodegenerative diseases. Thus, besides the mechanism of protein-ligand interaction, folding, misfolding and aggregation; the hypothesized mechanisms for the inhibition of protein aggregates may show new route to researchers either directly or indirectly in treating the diseases. PMID- 28890369 TI - Selenium incorporated guar gum nanoparticles safeguard mitochondrial bioenergetics during ischemia reperfusion injury in H9c2 cardiac cells. AB - The application of nanotechnology has created high impact in diagnosis and prognosis of various disorders including cardiovascular diseases. In the present study, we investigated the beneficial effect of selenium incorporated guar gum nanoparticles (SGG) compared to nascent selenium (Se) and guar gum nanoparticles (GGN) against ischemiareperfusion (IR) induced alterations in oxidative phosphorylation and energy metabolism in H9c2 cardiac cells. Ischemia and reperfusion were induced for 1h. The alterations in activities of various complexes (complex 1, II, III and IV) of mitochondrial electron transport chain (ETC), aconitase activity, oxygen consumption rate, and the ATP content were seen. The role of heat shock protein, hypoxia inducible factor-1alpha and atrial natriuretic factor (ANP) were also analyzed. Then the beneficial properties of various particles like Se, GGN and SGG were evaluated. Among these, SGG treatment (1 and 5ng) was found to be more beneficial compared to other particles. Overall results reveal that SGG nanoparticles are effective in protecting H9c2 cardiac cells from IR injury via improving the efficiency of ETC in H9c2 cells. PMID- 28890371 TI - The application of chitosan/collagen/hyaluronic acid sponge cross-linked by dialdehyde starch addition as a matrix for calcium phosphate in situ precipitation. AB - Scaffolds based on chitosan, collagen and hyaluronic acid, cross-linked by dialdehyde starch were obtained through the freeze-drying method. The porous structures were used as matrixes for calcium phosphate in situ precipitation. Composites were characterized by different analyses, e.g. infrared spectroscopy, SEM images, porosity, density, and mechanical tests. Moreover, an examination involving the energy dispersive X-ray spectroscopic method was carried out for the calcium and phosphorus ratio determination. In addition, the adhesion and proliferation of human osteosarcoma SaOS-2 cells were examined on the obtained scaffolds. The results showed that the properties of the scaffolds based on chitosan, collagen, and hyaluronic acid can be modified by dialdehyde starch addition. The mechanical parameters (i.e. compressive modulus and maximum compressive force), porosity, and density of the material were improved. Calcium phosphate was deposited in the scaffolds at the Ca/P ratio ~2. SEM images showed the homogeneous structure, with interconnected pores. The cross-linker addition and an inorganic compound precipitation improved the biocompatibility of the scaffolds. The obtained materials can provide the support required in tissue engineering and regenerative medicine. PMID- 28890372 TI - Thermal-oxidative effect of Kraft lignin antioxidant in polypropylene: Uncovering the key factor using correlation analysis model. AB - Which factors are crucial to improving lignin antioxidant ability in polymers has been debated over years. Here, the structural effect of natural antioxidant from technical Kraft lignin (KL) on the oxidation induction time (OIT) of KL/polypropylene (PP) was quantitatively investigated using correlation analysis model instead of traditional linear fitting model. The correlation coefficient and significance value of their relationship clearly demonstrated the dominating role of non-condensed Phenolic OH (Ph-OH) in improving KL/PP thermal-oxidation stability, subsequently followed by M-n, aliphatic OH/total Ph-OH, condensed Ph OH and polydispersity. OIT is positive with non-condensed and total Ph-OH, while it declines with increase of the above other factors. Remarkably, the longest OIT (~90min) was obtained even at extreme loading (0.5wt%), almost ~911% and ~201% huge increase in contrast to that of pure PP and crude KL/PP composite, respectively. Meanwhile, the mechanical properties of KL fractions/PP blends can be maintained at the same or better level than that of pure PP, due to strong interfacial adhesion strength. PMID- 28890373 TI - Fabrication of ofloxacin imprinted polymer on the surface of magnetic carboxylated cellulose nanocrystals for highly selective adsorption of fluoroquinolones from water. AB - A novel adsorbent with high selectivity for fluoroquinolone (FQ) compounds was developed, based on the surface functionalization of magnetic carboxylated cellulose nanocrystals (M-CCNs) with molecularly imprinted polymer (MIP) comprising amine moieties. The imprinting was achieved by a radical polymerization technique, which uses glycidyl methacrylate, tetraethylenepentamine, ofloxacin, ethylene glycol dimethacrylate, and azobisisobutyronitrile as the functional monomer, active groups provider, template molecule, crosslinking agent, and initiator, respectively. The developed material (M-CCNs@MIP) was comprehensively characterized and shown to exhibit high adsorption capacity and selectivity with rapid equilibration time. Moreover, the adsorption isotherms could be well-fitted with the Freundlich model, and the adsorption kinetics followed the pseudo-second-order model. The maximum adsorption capacities for M-CCNs@MIP after 2 and 20min were 34.09 and 40.65mgg-1, respectively, compared to 9.98 and 15.28mgg-1 observed for the unimprinted polymer (M-CCNs@NIP). By coupling the M-CCNs@MIP adsorbent with high-performance liquid chromatography, an approach was established to enhance the selective adsorption of seven structurally similar FQ compounds in river water samples. The recoveries of the seven FQs ranged from 81.2 to 93.7%, and the limits of detection were between 5.4 and 12.0ngmL-1. The M-CCNs@MIP adsorbent also retained good performance after seven consecutive cycles of reuse. PMID- 28890374 TI - Physico-mechanical and structural properties of eggshell membrane gelatin- chitosan blend edible films. AB - This study investigated the physico-mechanical and structural properties of composite edible films based on eggshell membrane gelatin (G) and chitosan (Ch) (75G:25Ch, 50G:50Ch, 25G:75Ch). The results demonstrated that the addition of Ch increased elongation at break significantly (p<0.05), but resulted in no significant change in tensile strength (TS) using 75G:25Ch, 50G:50Ch mixtures in comparison with gelatin-based film. The water solubility and water vapor permeability of the 50G:50Ch film decreased significantly compared to plain films (100G:0Ch and 0G:100Ch) and other composite films (p<0.05). Fourier transform infrared spectroscopy evaluation of structural properties showed that both polymers are totally miscible. Scanning electron microscopy was used to study the morphology of the composite films; it revealed a homogenous and compact structure in 75G:25Ch and 50G:50 Ch. Also, the chemical interactions introduced by the addition of chitosan to eggshell membrane gelatin as new resources could improve the films' functional properties. PMID- 28890375 TI - Anti-inflammatory properties of GLPss58, a sulfated polysaccharide from Ganoderma lucidum. AB - Sulfated polysaccharides exhibit various biological properties, including anti coagulant, anti-oxidant, anti-viral, anti-cancer, anti-inflammatory and immune regulatory activities. In the present study, the anti-inflammatory properties of GLPss58, a sulfated polysaccharide from Ganoderma lucidum formed by chemical sulfation, were investigated. We found that GLPss58 inhibited L-selectin/sTyr sLeX binding significantly, blocked the binding of anti-l-selectin antibodies to L-selectin on the surface of human peripheral blood lymphocytes, and inhibited the secondary lymphoid tissue chemokine-induced chemotactic invasion of HPBLs. In vivo studies in mice showed that lymphocyte homing from peripheral blood to spleen and lymph nodes was significantly inhibited by GLPss58. Furthermore, GLPss58 also inhibited the activation of complement systems and blocked the binding of TNF-alpha and IFN-gamma to their antibodies. These results indicate that GLPss58 is able to inhibit not only the L-selectin-mediated inflammation, but also the complement system- and cytokines mediated-inflammation. Our results suggest that GLPss58 is a favorable potential anti-inflammatory agent. PMID- 28890376 TI - An unfolding story: Small molecules remedy misfolded monoamine transporters. AB - The key role of monoamine transporters is to take up neurotransmitters from the synaptic cleft and rapidly terminate neurotransmission. Monoamine transporters begin their journey by folding in the endoplasmic reticulum. Upon achieving their natively-folded state, the oligomerized transporters engage the coat protein complex II machinery and exit the endoplasmic reticulum compartment in a concentrative fashion. The transporters are subsequently sorted in the endoplasmic reticulum-Golgi intermediate complex and the Golgi apparatus, prior to reaching their pivotal site of action at the plasma membrane. Stringent quality-control mechanisms ensure that only the correctly-folded protein cargo departs the endoplasmic reticulum. Genetic point mutations in the coding sequences of monoamine transporters can trigger severe physiologic deficiencies by inducing folding defects. Protein misfolding precludes the delivery of functional monoamine transporters to the cell surface. Chemical- and/or pharmacological-chaperone molecules, which facilitate folding, have proven effective in restoring the activity of several misfolded pathological variants of monoamine transporters. PMID- 28890377 TI - Molecular characterization and functional analysis of chalcone synthase from Syringa oblata Lindl. in the flavonoid biosynthetic pathway. AB - The flower color of Syringa oblata Lindl., which is often modulated by the flavonoid content, varies and is an important ornamental feature. Chalcone synthase (CHS) catalyzes the first key step in the flavonoid biosynthetic pathway. However, little is known about the role of S. oblata CHS (SoCHS) in flavonoid biosynthesis in this species. Here, we isolate and analyze the cDNA (SoCHS1) that encodes CHS in S. oblata. We also sought to analyzed the molecular characteristics and function of flavonoid metabolism by SoCHS1. We successfully isolated the CHS-encoding genomic DNA (gDNA) in S. oblata (SoCHS1), and the gene structural analysis indicated it had no intron. The opening reading frame (ORF) sequence of SoCHS1 was 1170bp long and encoded a 389-amino acid polypeptide. Multiple sequence alignment revealed that both the conserved CHS active site residues and CHS signature sequence were in the deduced amino acid sequence of SoCHS1. Crystallographic analysis revealed that the protein structure of SoCHS1 is highly similar to that of FnCHS1 in Freesia hybrida. The quantitative real time polymerase chain reaction (PCR) performed to detect the SoCHS1 transcript expression levels in flowers, and other tissues revealed the expression was significantly correlated with anthocyanin accumulation during flower development. The ectopic expression results of Nicotiana tabacum showed that SoCHS1 overexpression in transgenic tobacco changed the flower color from pale pink to pink. In conclusion, these results suggest that SoCHS1 plays an essential role in flavonoid biosynthesis in S. oblata, and could be used to modify flavonoid components in other plant species. PMID- 28890378 TI - MicroRNA-219-5p inhibits the proliferation, migration, and invasion of epithelial ovarian cancer cells by targeting the Twist/Wnt/beta-catenin signaling pathway. AB - MicroRNAs are emerging as critical regulators in various fundamental biological processes, including tumor progression. MicroRNA-219-5p (miR-219-5p) has been suggested as a novel tumor suppressing miRNA for many types of human cancers. However, the expression and functional significance of miR-219-5p in epithelial ovarian cancer remain poorly understood. In this study, we sought to explore the potential functions of miR-219-5p in epithelial ovarian cancer. Herein, we found that miR-219-5p levels were significantly decreased in epithelial ovarian cancer tissues and cell lines. Further experiments showed that overexpression of miR-219 5p inhibited epithelial ovarian cancer cell proliferation, migration, and invasion, and suppressed the Wnt/beta-catenin signaling pathway. By contrast, suppression of miR-219-5p exhibited the opposite effects. Twist was identified as a downstream target of miR-219-5p, and its expression was directly regulated by miR-219-5p. Restoration of Twist expression in miR-219-5p-overexpresing cells significantly reversed the antitumor effects of miR-219-5p. Taken together, our results revealed a tumor suppressive role for miR-219-5p in epithelial ovarian cancer that includes suppression of cell proliferation, migration, and invasion through downregulation of the Twist/Wnt/beta-catenin signaling pathway. Our study suggests that miR-219-5p may have potential applications in the diagnosis and treatment of epithelial ovarian cancer. PMID- 28890379 TI - Characterization of conserved and novel miRNAs using deep sequencing and prediction of miRNA targets in Crucian carp (Carassius auratus). AB - MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs of -22 nucleotides that can base pair with their target mRNAs, which represses their translation or induces their degradation in various biological processes. However, little is known about identification of miRNAs and their target genes in C. auratus. In the present study, a small RNA library from pooled tissue of C. auratus was constructed and sequenced using the deep sequencing. A total of 320 conserved miRNAs (belonging to 105 families) as well as 11 potentially novel miRNAs were identified. Stem-loop qRT-PCR analysis confirmed that both conserved and novel miRNAs were expressed in C. auratus, and some of them were preferentially expressed in certain tissues. Subsequently, a total of 1668 potential target genes were predicted for these identified miRNAs and GO analysis showed that most of the targets were involved in lots of physiological actions. This study represents a first large-scale identification and characterization of C. auratus miRNAs and their potential target genes. Taken together, our results add new information to existing data on C. auratus miRNAs and should be useful for investigating the biological functions of miRNAs in fishes and other aquatic species. PMID- 28890380 TI - Risk of Exclusion From Stroke Rehabilitation in the Oldest Old. AB - OBJECTIVE: To investigate whether oldest-old age (>=85y) is an independent predictor of exclusion from stroke rehabilitation. DESIGN: Retrospective cohort study. SETTING: Stroke unit (SU) of a tertiary hospital. PARTICIPANTS: Elderly patients (N=1055; aged 65-74y, n=230; aged 75-84y, n=432; aged >=85y, n=393) who, between 2009 and 2012, were admitted to the SU with acute stroke and evaluated by a multiprofessional team for access to rehabilitation. The study excluded patients for whom rehabilitation was unnecessary or inappropriate. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Access to an early mobilization (EM) protocol during SU stay and subsequent access to postacute rehabilitation after SU discharge. Analyses were adjusted for prestroke and stroke-related characteristics. RESULTS: 32.2% of patients were excluded from EM. Multivariable adjusted odds ratios (ORs) of EM exclusion were 1.30 (95% confidence interval [CI], .76-2.21) for ages 75 to 84 years and 2.07 (95% CI, 1.19-3.59) for ages >=85 years compared with ages 65 to 74 years. Of 656 patients admitted to EM and who, at SU discharge, had not yet fully recovered their prestroke functional status, 18.4% were excluded from postacute rehabilitation. For patients able to walk unassisted at SU discharge, the probability of exclusion did not change across age groups. For patients unable to walk unassisted at SU discharge, ORs of exclusion from postacute rehabilitation were 3.74 (95% CI, 1.26-11.13) for ages 75 to 84 years and 9.15 (95% CI, 3.05-27.46) for ages >=85 years compared with ages 65 to 74 years. CONCLUSIONS: Oldest-old age is an independent predictor of exclusion from stroke rehabilitation. PMID- 28890381 TI - Link Between Parkinson Disease and Rapid Eye Movement Sleep Behavior Disorder With Dream Enactment: Possible Implications for Early Rehabilitation. AB - The purpose of this article is 2-fold: first, to inform readers of the link between the loss of motor inhibition during rapid eye movement (REM) sleep dreaming, diagnosed as REM sleep behavior disorder, and the future onset of neurodegenerative disorders, such as Parkinson disease and dementia with Lewy bodies; it has been reported that motor disinhibition during REM sleep often precedes the onset of these disorders by years or even decades; second, to consider that the identification of REM sleep behavior disorder and the early involvement of rehabilitation and/or development of home exercise plans may aid in prolonging and even increasing function, independence, and quality of life, should such neurodegenerative disorders develop later in life. PMID- 28890382 TI - In vitro genotoxicity and in vivo subchronic evaluation of the anti-inflammatory pyrazole compound LQFM021. AB - Scientific evidences have highlighted 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H tetrazole (LQFM021) as a promising anti-inflammatory, analgesic and antinociceptive agent due to its effects on peripheral opioid receptors associated with activation of the nitric oxide/cGMP/KATP pathway. Despite these important pharmacological findings, toxicity data of LQFM021 are scarce. Thus, this study investigated the in vitro genotoxicity of LQFM021 through cytokinesis block micronucleus assay (OECD No 487/2014). Moreover, zebrafish model was used to assess the embryotoxicity potential of LQFM021 using fish embryo toxicity test (OECD No 236/2013) with extended exposure to evaluate subchronic larval development. In vivo subchronic toxicity of LQFM021 in rats (OECD No 407/2008) was also conducted. This compound at the lower concentrations tested (3.1 and 31 MUg/mL) did not promote changes in micronuclei frequency in HepG2 cells. However, in the higher concentrations of LQFM021 (310 and 620 MUg/mL) triggered a significant increase of micronucleated HepG2 cells, showing an alert signal of potential genotoxicity. Regarding the oral treatment of rats with LQFM021 (62.5, 125 or 250 mg/kg) for 28 days, the main findings showed that LQFM021 promoted renal and liver changes in a dose-dependent manner, being irreversible damage for kidneys while liver tissue showed a recovery after 14 days post treatment. Regarding embryotoxicity, although the lower concentrations used did not show toxicity, the concentration of LQFM021 (39.8 and 100 mg/L) promoted malformations in zebrafish embryo-larvae stage, in especial cardiac tissue changes. In conclusion, anti-inflammatory compound LQFM021 seems to have some limiting factors as a new therapeutic option to be used orally and in high repeated doses, related to those found in the non-steroidal anti-inflammatory drugs (NSAIDs). PMID- 28890383 TI - Interaction between rhein acyl glucuronide and methotrexate based on human organic anion transporters. AB - Rhein, a major bioactive compound of many medicinal herbs and the prodrug of diacerein, is often used with low dose of methotrexate as drug combination to treat rheumatoid arthritis. In this study, potential drug-drug interaction between methotrexate and rhein was investigated based on organic anion transporters (OAT). Our study demonstrated that rhein acyl glucuronide (RAG), the major metabolite of rhein in the human blood circulation, significantly inhibited the uptake of p-aminohippurate in hOAT1 transfected cells with IC50 value of 691 nM and estrone sulfate uptake in hOAT3 transfected cells with IC50 value of 78.5 nM. As the substrate of both hOAT1 and hOAT3, the methotrexate transport was significantly inhibited by RAG in hOAT1 transfected cells at 50 MUM and hOAT3 transfected cells at 1 MUM by 69% and 87%, respectively. Further in vivo study showed that after co-administrated with RAG in rats the AUC0-24 values of methotrexate increased from 3109 to 5370 ng/mL*hr and the t1/2 was prolonged by 40.5% (from 7.4 to 10.4 h), demonstrating the inhibitory effect of RAG on methotrexate excretion. In conclusion, rhein acyl glucuronide could significantly decrease the transport of methotrexate by both hOAT1 and hOAT3. The combination use of rhein, diacerein or other rhein-containing herbs with methotrexate may cause obvious drug-drug interaction and require close monitoring for potential drug interaction in clinical practice. PMID- 28890384 TI - Design strategies for improved velocity-selective pulse sequences. AB - Over the years, a variety of MRI methods have been developed for visualizing or measuring blood flow without the use of contrast agents. One particular class of methods uses flow-encoding gradients associated with an RF pulse sequence to distinguish spins in flowing blood from stationary spins. While a strength of these particular methods is that, in general, they can be tailored to capture a desired range of blood flow, such sequences either do not provide a sharp transition from stationary spins to flowing spins, or else are long, generating relaxation losses and undesirable SAR, and have limited immunity to resonance offsets and to RF inhomogeneity. This article provides design methods for improving these longer RF pulse sequences, especially to provide improved immunity to RF inhomogeneity, and also to improve immunity to resonance offsets, as well as to minimize RF sequence length. These design methods retain the flexibility to capture a desired range of blood flow, with sharp transitions between stationary spins and flowing blood. These improvement strategies are demonstrated through Bloch equations simulations of examples of these new sequences in the presence of blood flow. Examples of improved sequences that should prove suitable for use at 3.0Tesla are presented. PMID- 28890386 TI - Co-targeting c-Met and DNA double-strand breaks (DSBs): Therapeutic strategies in BRCA-mutated gastric carcinomas. AB - Gastric cancer (GC) is a threatening malignancy characterized by heterogeneity. Current therapies use DNA damaging agents, for example, chemotherapeutic agents and ionizing radiation (IR). However, a significant portion of GC patients develops therapeutic resistance to DNA damage response (DDR) - inducing agents. An important mechanism is the stimulation of the c-MET RTK, which is a tyrosine kinase receptor and its ligand hepatocyte growth factor (HGF), which facilitates cell survival by boosting DNA damage repair pathways and via escaping cell cycle arrest. A small subgroup of GC diagnosed patients has defects in BRCA1 and BRCA2 as mediators of DNA repair proteins. BRCA1/2 related-tumors acquire resistance to chemotherapy through the DSBs (DNA double strand breaks) repair pathways. However, BRCA2-deficient cells, are vulnerable to PARP [poly (ADP-ribose) polymerase] inhibitors as the replication forks collapse and the DNA-induced damage is not reversed. Herein, we pose that taking into consideration the defective DDR machinery can trigger GC cell sensitization to therapies via inhibition of DNA repair response. Inhibition of DNA damage response axis may designate cancer cells with BRCAness (BRCA-mutant cells) more vulnerable to DNA damaging mediators, such as c-Met inhibitors. PMID- 28890385 TI - Reduced coronary reactive hyperemia in mice was reversed by the soluble epoxide hydrolase inhibitor (t-AUCB): Role of adenosine A2A receptor and plasma oxylipins. AB - Coronary reactive hyperemia (CRH) protects the heart against ischemia. Adenosine A2AAR-deficient (A2AAR-/-) mice have increased expression of soluble epoxide hydrolase (sEH); the enzyme responsible for breaking down the cardioprotective epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). sEH inhibition enhances CRH, increases EETs, and modulates oxylipin profiles. We investigated the changes of oxylipins and their impact on CRH in A2AAR-/- and wild type (WT) mice. We hypothesized that the attenuated CRH in A2AAR-/- mice is mediated by changes in oxylipin profiles, and that it can be reversed by either sEH- or omega-hydroxylases-inhibition. Compared to WT mice, A2AAR-/- mice had attenuated CRH and changed oxylipin profiles, which were consistent between plasma and heart perfusate samples, including decreased EET/DHET ratios, and increased hydroxyeicosatetraenoic acids (HETEs). Plasma oxylipns in A2AAR-/- mice indicated an increased proinflammatory state including increased omega-terminal HETEs, decreased epoxyoctadecaenoic/dihydroxyoctadecaenoic acids (EpOMEs/DiHOMEs) ratios, increased 9-hydroxyoctadecadienoic acid, and increased prostanoids. Inhibition of either sEH or omega-hydroxylases reversed the reduced CRH in A2AAR /- mice. In WT and sEH-/- mice, blocking A2AAR decreased CRH. These data demonstrate that A2AAR-deletion was associated with changes in oxylipin profiles, which may contribute to the attenuated CRH. Also, inhibition of sEH and omega hydroxylases reversed the reduction in CRH. PMID- 28890387 TI - Peptides derived from transcription factor EB bind to calcineurin at a similar region as the NFAT-type motif. AB - Calcineurin (CN) is involved in many physiological processes and interacts with multiple substrates. Most of the substrates contain similar motifs recognized by CN. Recent studies revealed a new CN substrate, transcription factor EB (TFEB), which is involved in autophagy. We showed that a 15-mer QSYLENPTSYHLQQS peptide from TFEB (TFEB-YLENP) bound to CN. When the TFEB-YLENP peptide was changed to YLAVP, its affinity for CN increased and it had stronger CN inhibitory activity. Molecular dynamics simulations revealed that the TFEB-YLENP peptide has the same docking sites in CN as the 15-mer DQYLAVPQHPYQWAK motif of the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1-YLAVP). Moreover expression of the NFATc1-YLAVP peptide suppressed the TFEB activation in starved Hela cells. Our studies first identified a CN binding site in TFEB and compared the inhibitory capability of various peptides derived from CN substrates. The data uncovered a diversity in recognition sequences that underlies the CN signaling within the cell. Studies of CN-substrate interactions should lay the groundwork for developing selective CN peptide inhibitors that target CN-substrate interaction in vitro experiments. PMID- 28890388 TI - DHEA prevents ribavirin-induced anemia via inhibition of glucose-6-phosphate dehydrogenase. AB - Ribavirin has been widely used for antiviral therapy. Unfortunately, ribavirin induced anemia is often a cause of limiting or interrupting treatment. Our team has observed that dehydroepiandrosterone (DHEA) has a protective effect against in vitro and in vivo ribavirin-induced hemolysis. The aim of this study was to better understand this effect as well as the underlying mechanism(s). DHEA was able to reduce in vitro intraerythrocytic ATP depletion induced by ribavirin. Only 1% of ATP remained after incubation with ribavirin (2 mM) at 37 degrees C for 24 h vs. 37% if DHEA (200 MUM) was added (p < 0.01). DHEA also helped erythrocytes conserve their size, with a shrinkage of only 10% vs 40% at 24 h with ribavirin alone (p < 0.01), and reduced phosphatidylserine exposure at the outer membrane, i.e. 27% vs 40% at 48 h, (p < 0.05). DHEA also inhibits ribavirin induced hemolysis, i.e. 34% vs 46.5% at 72 h (p < 0.01). DHEA is an inhibitor of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the hexose monophosphate shunt connected to the glycolytic pathway which is the only energy supplier of the red blood cell in the form of ATP. We have confirmed this inhibitory effect in the presence of ribavirin. All these observations suggest that ribavirin-induced hemolysis was initiated by ATP depletion, and that the inhibitory effect of DHEA on G6PD was able to rescue enough ATP to limit this hemolysis. This mechanism could be important for improving the therapeutic management of patients treated with ribavirin. PMID- 28890390 TI - Examining the "Veggie" personality: Results from a representative German sample. AB - An increasing proportion of people choose to follow a vegetarian diet. To date, however, little is known about if and how individual differences in personality relate to following a vegetarian diet. In the two studies presented here, we aimed to (1) estimate the prevalence of self-defined vegetarians in two waves of a German representative sample (N = 4496 and 5125, respectively), (2) analyze the effect of socio-demographic variables on dietary behavior, and (3) examine individual differences between vegetarians and meat eaters in personality traits, political attitudes, and health-related variables. In Study 1, a strict definition of vegetarians was used, while in Study 2 the definition was laxer, to include also individuals who only predominantly followed a vegetarian diet. The prevalence of self-defined vegetarians was 2.74% in Study 1, and 5.97% in Study 2. Participants who were female, younger, and more educated were more likely to report following a vegetarian diet in both studies, and vegetarians had higher income as compared to meat eaters in Study 2. We also found differences between vegetarians and meat eaters with regard to personality traits, political attitudes, and health-related variables. Stepwise logistic regression analyses showed a unique effect beyond socio-demographic variables for openness (Studies 1 and 2), conscientiousness (Study 1), trust (Study 2), conservatism (Studies 1 and 2), and level of interest in politics (Study 1) on diet: Individuals with higher scores in openness and political interest had a higher probability of being vegetarian, whereas people with higher scores in conscientiousness and conservatism had a smaller likelihood of being vegetarian. We conclude that there are individual differences between vegetarians and meat eaters in socio demographics, personality traits, and political attitudes. PMID- 28890389 TI - Motor function deficits in the 12 month-old female 5xFAD mouse model of Alzheimer's disease. AB - Motor problems occur early in some patients with Alzheimer's disease (AD) and as the disease progresses many patients develop motor dysfunction. Motor dysfunction has been reported in some mouse models of AD, including the 5xFAD mouse, thus this model may be particularly useful for studying motor dysfunction in AD. In order to determine the extent of motor dysfunction in these mice, we tested 11-13 month old female 5xFAD and wildtype (WT) control mice in a battery of motor behaviour tasks. The 5xFAD mice showed hind limb clasping, weighed less and had slower righting reflexes than WT mice. In the open field, the 5xFAD mice travelled a shorter distance than the WT mice, spent less time moving and had a slower movement speed. The 5xFAD mice fell faster than the WT mice from the balance beam, wire suspension, grid suspension and rotarod tasks, indicating dysfunctions in balance, grip strength, motor co-ordination and motor learning. The 5xFAD mice had a short, shuffling gait with a shorter stride length than WT mice and had a slower swim speed. The 5xFAD mice also failed to show an acoustic startle response, likely due to motor dysfunction and previously reported hearing impairment. The 5xFAD mice did not show deficits in the ability of peripheral motor nerves to drive muscle output, suggesting that motor impairments are not due to dysfunction in peripheral motor nerves. These results indicate that the aged 5xFAD mice are deficient in numerous motor behaviours, and suggest that these mice may prove to be a good model for studying the mechanisms of motor dysfunction in AD, and motor behaviour might prove useful for assessing the efficacy of AD therapeutics. Motor dysfunction in 5xFAD mice must also be considered in behavioural tests of sensory and cognitive function so that performance is not confounded by impaired locomotor or swimming behaviour. PMID- 28890391 TI - Learned pleasure from eating: An opportunity to promote healthy eating in children? AB - Across the lifespan, eating is a common everyday act driven by the search for pleasure and reinforced by experienced pleasure. Pleasure is an innate indicator of the satisfaction of physiological needs, in addition to other attributes. Pleasure from eating is also learned and contributes to the development of children's eating habits, which remain mostly stable until adulthood. Based on classical models of determinants of food consumption behaviour, we identified three dimensions of pleasure from eating learned during childhood: 1/the sensory dimension, i.e., pleasure from sensory sensations during food consumption; 2/the interpersonal dimension, i.e., pleasure from the social context of food consumption; and 3/the psychosocial dimension, i.e., pleasure from cognitive representations of food. The objective of this narrative review is to explore whether these three dimensions may play a role in promotion of healthy eating behaviour among children. Up to now, it was assumed that providing nutritional information, pointing out which types of foods are "good" or "bad" for health, would drive healthier food choices in children. Today, we know that such strategies based on a cognitive approach toward eating have a limited impact on healthy choices and can even be counter-productive, leading children to avoid healthy foods. In the context of increasing rates of childhood obesity, new perspectives are needed to build efficient interventions that might help children adopt a healthy diet. This review suggests new directions for further research to test the efficacy of novel interventions that emphasize pleasure from eating. PMID- 28890392 TI - Natural History and Predictors of Parastomal Hernia after Robot-Assisted Radical Cystectomy and Ileal Conduit Urinary Diversion. AB - PURPOSE: We investigated the prevalence of and variables associated with parastomal hernia and its outcomes after robot-assisted radical cystectomy and ileal conduit creation for bladder cancer. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent robot-assisted radical cystectomy at our institution. Parastomal hernia was defined as the protrusion of abdominal contents through the stomal defect in the abdominal wall on cross-sectional imaging. Parastomal hernia was further described in terms of patient and hernia characteristics, symptoms, management and outcomes. The Kaplan Meier method was used to determine time to parastomal hernia and time to surgery. Multivariate stepwise logistic regression was done to evaluate variables associated with parastomal hernia. RESULTS: A total of 383 patients underwent robot-assisted radical cystectomy and ileal conduit creation. Of the patients 75 (20%) had parastomal hernia, which was symptomatic in 23 (31%), and 11 (15%) underwent treatment. Median time to parastomal hernia was 13 months (IQR 9-22). Parastomal hernia developed in 9%, 23% and 32% of cases at 1, 2 and 3 years, respectively. Patients with parastomal hernia had a significantly higher body mass index (30 vs 28 kg/m2, p = 0.02), longer overall operative time (357 vs 340 minutes, p = 0.01) and greater blood loss (325 vs 250 ml, p = 0.04). On multivariate analysis operative time (OR 1.25, 95% CI 1.21-3.90, p <0.001), a fascial defect 30 mm or greater (OR 5.23, 95% CI 2.32-11.8, p <0.001) and a lower postoperative estimated glomerular filtration rate (OR 2.17, 95% CI 1.21-3.90, p = 0.01) were significantly associated with parastomal hernia. CONCLUSIONS: Symptoms develop in approximately a third of patients with parastomal hernia and 15% will require surgery. The risk of parastomal hernia plateaued after postoperative year 3. Longer operative time, a larger fascial defect and lower postoperative kidney function were associated with parastomal hernia. PMID- 28890394 TI - On the antiviral activity and developmental toxicity of 6-methylmercaptopurine riboside (6MMPr). PMID- 28890393 TI - Antiviral activity of arbidol hydrochloride against herpes simplex virus I in vitro and in vivo. AB - Herpes simplex virus type 1 (HSV-1) causes significant human diseases ranging from skin lesions to encephalitis, especially in neonates and immunocompromised hosts. The discovery of novel anti-HSV-1 drugs with low toxicity is required for public health. Arbidol hydrochloride (ARB) is an indole derivative molecule with broad-spectrum antiviral activity. In this study, the antiviral effects of ARB against HSV-1 infection were evaluated in vitro and in vivo. The results showed that ARB presents significant inhibitory effect on HSV-1 plaque formation and generation of progeny virus, with EC50 values (50% effective concentration) of 5.39 ug/mL (10.49 uM) and 2.26 ug/mL (4.40 uM), respectively. Moreover, time-of addition and time-of-removal assays further suggested that ARB has viral inhibitory effects when added up to 12 h post-infection (p.i.), which could be further corroborated by determining the expression of viral immediate-early (ICP4, ICP22 and ICP27), early (ICP8 and UL42) and late (gB, gD, gH, VP1/2 and VP16) genes by real-time quantitative PCR as well as the expression of viral protein ICP4 and ICP8 at 6 h and 12 h p.i. Results of the in vivo study showed that ARB could reduce guinea pig skin lesions caused by HSV-1 infection. Conclusively, this report offers new perspectives in the search for therapeutic measures in the treatment of HSV-1 infection. PMID- 28890395 TI - The antifungal arsenal: alternative drugs and future targets. AB - Clinically available antifungals for the treatment of invasive fungal infections primarily target either ergosterol in the fungal cell membrane or 1,3-beta-D glucan in the fungal cell wall. These classes include the polyene amphotericin B, the triazoles, and the echinocandins. Although newer antifungals and improved formulations of others have advanced our ability to treat patients with invasive mycoses, these drugs are often limited by toxicities, drug interactions, and the need for intravenous administration. Several investigational agents are currently under development. These include those that also target either ergosterol or 1,3 beta-D-glucan, but have advantages over currently available drugs. Among these are the tetrazoles VT-1129, VT-1161, and VT-1598 that are more specific for fungal Cyp51 and less so for mammalian CYP 450 enzymes, the echinocandin CD101 that has an extended half-life, and the glucan synthase inhibitor SCY-078, which is being developed for oral administration. In addition, several agents with novel mechanisms of action are also under development. These include the inositol acyltransferase AX001, the dihydroorotate dehydrogenase inhibitor F901318, and VL 2397, which is similar in structure to the siderophore ferrichrome. In addition to possibly overcoming the limitations of currently available antifungals, these newer agents may be less susceptible to mechanisms of resistance that may render antifungals ineffective. Each of these investigational agents has the potential to improve patient outcomes in the treatment of invasive mycoses. PMID- 28890396 TI - MiR-525-3p mediates antiviral defense to rotavirus infection by targeting nonstructural protein 1. AB - MicroRNAs (miRNAs) are short RNAs of approximately 22 nucleotides that post transcriptionally regulate gene expression by controlling mRNA stability or translation. They play critical roles in intricate networks of host-pathogen interactions and innate immunity. Rotaviruses (RVs) are the leading cause of severe diarrhea among infants and young children worldwide. This study was undertaken to demonstrate the importance of cellular miRNAs during RV (human Wa RV or Rhesus RV) strains infection. Twenty-nine differentially regulated miRNAs were identified during RV infection, and miR-525-3p was downregulated and validated by quantitative real-time polymerase chain reaction (qRT-PCR). MiR-525 3p mimic inhibited RV replication in dose-dependent manner. Correspondingly, the miR-525-3p inhibitors enhanced RV replication. We confirmed that miR-525-3p was complementary to the 3' untranslated region (UTR) of nonstructural protein 1(NSP1) of RV (Wa or Rhesus) strains. Interestingly, miR-525-3p induced type I interferon (IFN) expression and proinflammatory cytokines during RV infection through IFN regulatory factor (IRF) 3/IRF7 and NF-kappaB activation, which can induce an antiviral state to further suppress RV infection. In addition, RV suppressed miR-525-3p expression to evade host innate immunity through the action of the RV protein NSP1. These results suggest that miR-525-3p has the potential to be used as an antiviral therapeutic against RV infection. PMID- 28890397 TI - Regulated expression of the TPbeta isoform of the human T prostanoid receptor by the tumour suppressors FOXP1 and NKX3.1: Implications for the role of thromboxane in prostate cancer. AB - The prostanoid thromboxane (TX)A2 signals through the TPalpha and TPbeta isoforms of T Prostanoid receptor (TP) that are transcriptionally regulated by distinct promoters termed Prm1 and Prm3, respectively, within the TBXA2R gene. We recently demonstrated that expression of TPalpha and TPbeta is increased in PCa, differentially correlating with Gleason grade and with altered CpG methylation of the individual Prm1/Prm3 regions within the TBXA2R. The current study sought to localise the sites of CpG methylation within Prm1 and Prm3, and to identify the main transcription factors regulating TPbeta expression through Prm3 in the prostate adenocarcinoma PC-3 and LNCaP cell lines. Bisulfite sequencing revealed extensive differences in the pattern and status of CpG methylation of the individual Prm1 and Prm3 regions that regulate TPalpha and TPbeta expression, respectively, within the TBXA2R. More specifically, Prm1 is predominantly hypomethylated while Prm3 is hypermethylated across its entire sequence in PC-3 and LNCaP cells. Furthermore, the tumour suppressors FOXP1 and NKX3.1, strongly implicated in PCa development, were identified as key transcription factors regulating TPbeta expression through Prm3 in both PCa cell lines. Specific siRNA disruption of FOXP1 and NKX3.1 each coincided with up-regulated TPbeta protein and mRNA expression, while genetic-reporter and chromatin immunoprecipitation (ChIP) analyses confirmed that both FOXP1 and NKX3.1 bind to cis-elements within Prm3 to transcriptionally repress TPbeta in the PCa lines. Collectively these data identify Prm3/TPbeta as a bona fide target of FOXP1 and NKX3.1 regulation, providing a mechanistic basis, at least in part, for the highly significant upregulation of TPbeta expression in PCa. PMID- 28890398 TI - Functional characterization of Pol III U6 promoters for gene knockdown and knockout in Plutella xylostella. AB - RNA polymerase type III (Pol-III) promoters such as U6 are commonly used to express small RNAs, including short hairpin RNAs (shRNAs) and single guide RNAs (sgRNAs). Functional U6 promoters are widely used in CRISPR systems, and their characterization can facilitate genome editing of non-model organisms. In the present study, six U6 small nuclear RNA (snRNA) promoters containing two conserved elements of a proximal sequence element (PSEA) and a TATA box, were identified and characterized in the diamondback moth (Plutella xylostella) genome. Relative efficiency of the U6 promoters to express shRNA induced EGFP knockdown was tested in a P. xylostella cell line, revealing that the PxU6:3 promoter had the strongest expression effect. Further work with the PxU6:3 promoter showed its efficacy in EGFP knockout using CRISPR/Cas9 system in the cells. The expression plasmids with versatile Pxabd-A gene specific sgRNA driven by the PxU6:3 promoter, combined with Cas9 mRNA, could induce mutagenesis at specific genomic loci in vivo. The phenotypes induced by sgRNA expression plasmids were similar to those done in vitro transcription sgRNAs. A plasmid with two tandem arranged PxU6:3:sgRNA expression cassettes targeting Pxabd-A loci was generated, which caused a 28,856 bp fragment deletion, suggesting that the multi sgRNA expression plasmid can be used for multi-targeting. Our work indicates that U6 snRNA promoters can be used for functional studies of genes with the approach of reverse genetics in P. xylostella. These essential promoters also provide valuable potential for CRISPR-derived gene drive as a tactic for population control in this globally significant pest. PMID- 28890399 TI - Activated brain-derived neurotrophic factor/TrkB signaling in rat dorsal and ventral hippocampi following 10-day electroconvulsive seizure treatment. AB - Electroconvulsive therapy (ECT) is still the most effective strategy to treat severe and drug-resistant depressive disorders. Electroconvulsive seizure (ECS), which induces neuroplastic structural alterations and resilient behavioral changes in experimental animals, is the model of the ECT for human depression. ECT is typically administered three times per week for up to 4 weeks, while ECS treatments are administered daily for 10days. The increased expression of hippocampal brain-derived neurotrophic factor (BDNF) induced by antidepressive ECS treatment in experimental animals has been well documented. BDNF executes various neuroplastic functions by phosphorylating its high-affinity receptor, full-length TrkB, which has an intrinsic tyrosine kinase domain. However, the exact activation of BDNF/TrkB signaling following multiple ECS treatments has not been well elucidated. In epileptogenesis, conflicting effects of BDNF have been reported; while acute BDNF administration enhanced neuronal hyperexcitability and induced epileptiform activities, continuous BDNF infusion inhibited epileptogenesis. These conflicting results have been attributed to agonist induced adaptive response of expressional down-regulation of the BDNF receptor. In the present study, using western blotting, we demonstrated increased phosphorylation as well as decreased expression of the full-length TrkB receptor (145kD) in both dorsal and ventral hippocampal regions of rats after a 10-day ECS treatment. The expression of mature BDNF (14kD) was up-regulated while that of proBDNF (32kD) remained unaltered in both hippocampal regions after the ECS treatment. Our results indicate that the hippocampal BDNF/TrkB signaling pathway is activated by multiple ECS treatments despite the ligand-induced down regulation of the full-length TrkB receptor. PMID- 28890400 TI - Deglycosylating enzymes acting on N-glycans in fungi: Insights from a genome survey. AB - BACKGROUND: N-Glycosylation, one of the most prominent post-translational modifications of proteins, is found in all domains of life, i.e. eukaryotes, bacteria and archaea, and has been shown to play a crucial role in modulating the physicochemical/physiological properties of carrier proteins. Deglycosylating enzymes that act on N-glycans are widely used in analyzing the structures/functions of N-glycans. Fungi are known to produce various deglycosylating enzymes, some of which are fungi-specific. While such enzymes likely are biologically relevant in fungal biology, their properties as well as their functions have not been explored in detail. SCOPE OF REVIEW: In this review, we summarize the current knowledge of fungal deglycosylating enzymes and discuss their biological significance. MAJOR CONCLUSIONS: As of this writing, five types of deglycosylating enzymes that act on N-glycans are known to occur in fungi; (1) the cytosolic peptide: N-glycanase (PNGase), (2) the acidic PNGase, (3) the glycoside hydrolase family (GH) 85 endo-beta-N-acetylglucosaminidase (ENGase), (4) the GH18 cytosolic ENGase, and (5) the GH18 secreted ENGase. Interestingly, genome surveys indicate that the loss of cytosolic PNGase activity in certain fungi coincide with the occurrence of GH18 cytosolic ENGase, implying that the GH18 ENGase serves to replace the deglycosylation function of the cytosolic PNGase in those filamentous ascomycete fungi. GENERAL SIGNIFICANCE: Our review concludes that fungi promise to be valuable organisms for developing an understanding of the biological functions of PNGases/ENGases. PMID- 28890401 TI - Aggregation properties of a disordered protein are tunable by pH and depend on its net charge per residue. AB - Intrinsically disordered proteins (IDPs) possess a peculiar amino acid composition that makes them very soluble. Nevertheless, they can encounter aggregation in physiological and pathological contexts. In this work, we addressed the issue of how electrostatic charges can influence aggregation propensity by using the N-terminus moiety of the measles virus phosphoprotein, PNT, as a model IDP. Taking advantage of the high sequence designability of IDPs, we have produced an array of PNT variants sharing the same hydrophobicity, but differing in net charges per residue and isoelectric points (pI). The solubility and conformational properties of these proteins were analysed through biochemical and biophysical techniques in a wide range of pH values and compared with those of the green fluorescence protein (GFP), a globular protein with lower net charge per residue, but similar hydrophobicity. Tested proteins showed a solubility minimum close to their pI, as expected, but the pH-dependent decrease of solubility was not uniform and driven by the net charge per residue of each variant. A parallel behaviour was observed also in fusion proteins between PNT variants and GFP, which minimally contributes to the solubility of chimeras. Our data suggest that the overall solubility of a protein can be dictated by protein regions endowed with higher net charge per residue and, hence, prompter to respond to pH changes. This finding could be exploited for biotechnical purposes, such as the design of solubility/aggregation tags, and in studies aimed to clarify the pathological and physiological behaviour of IDPs. PMID- 28890402 TI - Lung responses in murine models of experimental asthma: Value of house dust mite over ovalbumin sensitization. AB - Ovalbumin (OVA) sensitization has limitations in modelling asthma. Thus, we examined the value of allergic sensitization using a purified natural allergen, house dust mite (HDM), over the sensitization performed with OVA. Mice were sham treated, or sensitized with OVA- or HDM with identical chronology. Airway resistance, tissue damping and elastance were assessed under control conditions and after challenging the animals with methacholine (MCh) and the specific allergen. Inflammatory profile of the bronchoalveolar lavage fluid was characterized and lung histology was performed. While no difference in the lung responsiveness to the specific allergen was noted, hyperresponsiveness to MCh was observed only in the HDM-sensitized animals in the lung peripheral parameters. Lung inflammation differed between the models, but excessive bronchial smooth muscle remodelling occurred only with OVA. In conclusion, we demonstrate that a purified natural allergen offers a more relevant murine model of human allergic asthma by expressing the key features of this chronic inflammatory disease both in the lung function and structure. PMID- 28890403 TI - Sex differences in respiratory muscle activation patterns during high-intensity exercise in healthy humans. AB - Although women experience greater ventilatory constraints and have a higher work of breathing during exercise, they are less susceptible to diaphragm fatigue compared to men. The mechanisms for diaphragmatic fatigue resistance in women is unknown but may be related to sex differences in respiratory muscle recruitment. Accordingly, the purpose of this study was to determine if electromyography (EMG) of the diaphragm (EMGdi) and extra-diaphragmatic inspiratory muscles differ between sexes during exercise. Forty subjects (21M:19F) completed a constant load cycling test at 85% of maximum work rate until exhaustion, while instrumented with an oesophageal electrode catheter to measure EMGdi and surface electrodes to measure EMG of the sternocleidomastoid (EMGscm) and scalene (EMGsca) muscles. No sex difference in EMGdi was observed at any measurement time. However, EMGscm and EMGsca were higher throughout all submaximal exercise times in women (p<0.01). These results suggest greater reliance on the extra-diaphragmatic inspiratory muscles in women relative to men, which may serve as a strategy to minimize diaphragmatic fatigue. PMID- 28890404 TI - Structural and functional characterization of a highly secreted alpha-l arabinofuranosidase (GH62) from Aspergillus nidulans grown on sugarcane bagasse. AB - Carbohydrate-Active Enzymes are key enzymes for biomass-to-bioproducts conversion. alpha-l-Arabinofuranosidases that belong to the Glycoside Hydrolase family 62 (GH62) have important applications in biofuel production from plant biomass by hydrolyzing arabinoxylans, found in both the primary and secondary cell walls of plants. In this work, we identified a GH62 alpha-l arabinofuranosidase (AnAbf62Awt) that was highly secreted when Aspergillus nidulans was cultivated on sugarcane bagasse. The gene AN7908 was cloned and transformed in A. nidulans for homologous production of AnAbf62Awt, and we confirmed that the enzyme is N-glycosylated at asparagine 83 by mass spectrometry analysis. The enzyme was also expressed in Escherichia coli and the studies of circular dichroism showed that the melting temperature and structural profile of AnAbf62Awt and the non-glycosylated enzyme from E. coli (AnAbf62Adeglyc) were highly similar. In addition, the designed glycomutant AnAbf62AN83Q presented similar patterns of secretion and activity to the AnAbf62Awt, indicating that the N-glycan does not influence the properties of this enzyme. The crystallographic structure of AnAbf62Adeglyc was obtained and the 1.7A resolution model showed a five-bladed beta-propeller fold, which is conserved in family GH62. Mutants AnAbf62AY312F and AnAbf62AY312S showed that Y312 was an important substrate binding residue. Molecular dynamics simulations indicated that the loop containing Y312 could access different conformations separated by moderately low energy barriers. One of these conformations, comprising a local minimum, is responsible for placing Y312 in the vicinity of the arabinose glycosidic bond, and thus, may be important for catalytic efficiency. PMID- 28890405 TI - Additive Biotech-Chances, challenges, and recent applications of additive manufacturing technologies in biotechnology. AB - The diversity and complexity of biotechnological applications are constantly increasing, with ever expanding ranges of production hosts, cultivation conditions and measurement tasks. Consequently, many analytical and cultivation systems for biotechnology and bioprocess engineering, such as microfluidic devices or bioreactors, are tailor-made to precisely satisfy the requirements of specific measurements or cultivation tasks. Additive manufacturing (AM) technologies offer the possibility of fabricating tailor-made 3D laboratory equipment directly from CAD designs with previously inaccessible levels of freedom in terms of structural complexity. This review discusses the historical background of these technologies, their most promising current implementations and the associated workflows, fabrication processes and material specifications, together with some of the major challenges associated with using AM in biotechnology/bioprocess engineering. To illustrate the great potential of AM, selected examples in microfluidic devices, 3D-bioprinting/biofabrication and bioprocess engineering are highlighted. PMID- 28890407 TI - Treatment for intrahepatic recurrence after curative resection of hepatocellular carcinoma: Salvage liver transplantation or re-resection/radiofrequency ablation? A Retrospective Cohort Study. AB - OBJECTIVE: The optimal treatment strategy for patients with recurrent hepatocellular carcinoma (HCC) remains unclear. This study was designed to investigate the outcomes of salvage liver transplantation (SLT) and re-resection (RR)/radiofrequency ablation (RFA) with respect to the time to recurrence after initial curative resection. METHODS: Between 2007 and 2016, 756 patients underwent curative hepatectomy for HCC in accordance with the Milan criteria. Among them, 152 experienced an intrahepatic recurrence and underwent SLT (n = 36) and RR/RFA (n = 116). Clinical data, overall survival (OS), and disease-free survival (DFS) (including subgroup analyses) according to the time to recurrence were statistically compared between the 2 groups, and prognostic factors were identified. RESULTS: The DFS of the patients who underwent SLT was much better than that of the patients who underwent RR/RFA (P = 0.002), particularly those with late recurrence (more than 12 months, P = 0.004). The time to recurrence from initial hepatectomy was found to be an independent predictor of OS and DFS. CONCLUSIONS: SLT, rather than re-resection or RFA, should be the preferred treatment option for patients with late recurrence. PMID- 28890406 TI - Comparison of Conditioning with Fludarabine/Busulfan and Fludarabine/Melphalan in Allogeneic Transplantation Recipients 50 Years or Older. AB - The optimal conditioning regimen for elderly patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) remains unclear. We retrospectively analyzed 1607 patients aged 50 years or older with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome (MDS) who underwent allo-HCT using fludarabine/busulfan (FB) or fludarabine/melphalan (FM) between 2007 and 2014. We compared the clinical outcomes among FB2 (busulfan at 6.4 mg/kg iv, n = 463), FB4 (busulfan at 12.8 mg/kg iv, n = 721), and FM140 (melphalan at 140 mg/m2, n = 423). The nonrelapse mortality (NRM) rates in the FB4 and FM140 groups were higher than that in the FB2 group (hazard ratio [HR], 1.63 [P < .001]; and HR, 1.71 [P < .001], respectively). Conversely, the relapse rates in the FB4 and FM140 groups were lower than that in the FB2 group (HR, .73 [P = .011]; and HR, .56 [P < .001], respectively). There were no significant differences in overall survival (OS) among the FB2, FB4, and FM140 groups. The 3 year OS in patients with high-risk AML and MDS in the FM140 group (37.0% and 60.2%) were superior to those in the FB2 group (24.4% and 45.5%) and the FB4 group (24.6% and 40.6%) (P = .016 and P = .023), whereas there were no differences in OS in the other patients among the 3 groups. In conclusion, the lower rates of relapse in the FB4 and FM140 groups were largely offset by a worse NRM. However, FM140 might be associated with better OS in patients with high-risk AML and MDS. PMID- 28890408 TI - Interventions for Treating 3- or 4-part proximal humeral fractures in elderly patient: A network meta-analysis of randomized controlled trials. AB - BACKGROUND: The fractures of proximal humerus have a high incidence in elderly patients, especially 3- or 4-part fracture. There are 4 main treatments including nonoperation, open reduction and internal fixation(ORIF), hemiarthroplasty(HA) and reverse shoulder arthroplasty(RSA). However, which one is the optimal choice remains a controversial topic. METHODS: Through the search of three electronic databases (PubMed, Embase, and Cochrane), the randomized controlled trials of 3- or 4-part proximal humeral fracture, until the end of July 2017, which is concerned with the elderly patients, were identified. The quality evaluation of each study was evaluated, Constant score and reoperation rates were extracted and analyzed. We used R(R i386 3.3.2) and the package of gemtc to perform our network meta-analysis. RESULTS: Seven randomized controlled experiments with a total number of 347 patients were brought into our network meta-analysis. The rank probability plot of Constant score showed that the RSA had significantly the highest Constant score and lower reoperation than other treatments. The other way around, the efficacy of ORIF was the poorest. The rank for the Constant score was: RSA, HA, nonoperation and ORIF. The rank for the reduction in total reoperation rates was: RSA, nonoperation, HA and ORIF. CONCLUSIONS: The statistical result suggested that RSA has become a beneficial choice to treat displaced 3-or 4-part fracture in elderly patients, that might result in more favorable clinical outcomes and reduction of reoperation rates than other methods performed for the same indication. But the ORIF is the worst. PMID- 28890410 TI - Positron emission tomography modalities prevent futile radical resection of pancreatic cancer: A meta-analysis. AB - BACKGROUND: Numerous distant metastases were not detected preoperatively. Positron emission tomography (PET) has been used for oncology diagnosis recently. However, it remains controversial whether PET modality is a more efficient way in detecting unresectable features for radical resection of pancreatic cancer (PC). This meta-analysis aims to validate the efficiency of PET modalities (including PET and PET/CT) in preoperative assessment of PC, and compare them with computed tomography (CT). METHODS: PubMed, EMBASE, Science Citation Index and The Cochrane Library were searched to identify relevant studies. Both PET modality and CT had been performed for all the included patients. A meta-analysis was performed to compare the ability of PET modalities in detecting occult distant metastases and regional lymph nodes invasion with that of CT. RESULTS: 17 clinical studies that recruited 1343 patients were included. This meta-analysis indicated that PET modalities were more efficient in detecting true positive distant metastases compared with CT (OR = 1.52, 95%CI: 1.23-1.88). In subgroup analysis, when compared with CT alone, PET/CT also showed greater utility in detecting distant metastases (OR = 1.66, 95%CI: 1.31-2.08). There was no definite difference in detecting regional lymph nodes invasion between PET modalities and CT (OR = 0.97, 95%CI: 0.63-1.47). CONCLUSION: Compared with CT, PET/CT provides extensive possibility to avoid futile radical resection by detecting occult metastases of PC preoperatively. Surgeons, especially in developing countries, should take PET modalities as a routine preoperative assessment before making operative plan for PC patients. PMID- 28890411 TI - Combined adductor canal block with local infiltrative analgesia for pain management in total knee arthroplasty: A meta-analysis. PMID- 28890409 TI - The STROCSS statement: Strengthening the Reporting of Cohort Studies in Surgery. AB - INTRODUCTION: The development of reporting guidelines over the past 20 years represents a major advance in scholarly publishing with recent evidence showing positive impacts. Whilst over 350 reporting guidelines exist, there are few that are specific to surgery. Here we describe the development of the STROCSS guideline (Strengthening the Reporting of Cohort Studies in Surgery). METHODS AND ANALYSIS: We published our protocol apriori. Current guidelines for case series (PROCESS), cohort studies (STROBE) and randomised controlled trials (CONSORT) were analysed to compile a list of items which were used as baseline material for developing a suitable checklist for surgical cohort guidelines. These were then put forward in a Delphi consensus exercise to an expert panel of 74 surgeons and academics via Google Forms. RESULTS: The Delphi exercise was completed by 62% (46/74) of the participants. All the items were passed in a single round to create a STROCSS guideline consisting of 17 items. CONCLUSION: We present the STROCSS guideline for surgical cohort, cross-sectional and case-control studies consisting of a 17-item checklist. We hope its use will increase the transparency and reporting quality of such studies. This guideline is also suitable for cross sectional and case control studies. We encourage authors, reviewers, journal editors and publishers to adopt these guidelines. PMID- 28890412 TI - Complications of extracorporeal shockwave therapy in plantar fasciitis: Systematic review. AB - BACKGROUND: Extracorporeal shockwave therapy (ESWT) seems to be an effective treatment for plantar fasciitis (PF) and is assumed to be safe. No systematic reviews have been published that specifically studied the complications and side effects of ESWT in treating PF. Aim of this systematic review is therefore to evaluate the complications and side effects of ESWT in order to determine whether ESWT is a safe treatment for PF. METHODS: For this systematic review the databases PubMed, MEDLINE, Cochrane and Embase were used to search for relevant literature between 1 January 2005 and 1 January 2017. PRISMA guidelines were followed. RESULTS: Thirty-nine studies were included for this review, representing 2493 patients (2697 heels) who received between 6424 and 6497 ESWT treatment sessions, with an energy flux density between 0.01 mJ/mm2 and 0.64 mJ/mm2 and a frequency of 1000-3800 SWs. Average follow-up was 14.7 months (range: 24 h - 6 years). Two complications occurred: precordial pain and a superficial skin infection after regional anaesthesia. Accordingly, 225 patients reported pain during treatment and 247 reported transient red skin after treatment. Transient pain after treatment, dysesthesia, swelling, ecchymosis and/or petechiae, severe headache, bruising and a throbbing sensation were also reported. CONCLUSION: ESWT is likely a safe treatment for PF. No complications are expected at one-year follow-up. However, according to the current literature long-term complications are unknown. Better descriptions of treatment protocols, patient characteristics and registration of complications and side effects, especially pain during treatment, are recommended. PMID- 28890413 TI - Persistent postherniorrhaphy pain following inguinal hernia repair: A cross sectional study of prevalence, pain characteristics, and effects on quality of life. AB - INTRODUCTION: Chronic inguinal pain due to the inguinal hernia repair is still a serious consideration, and its incidence is evident in approximately 3%-6% of the patients. The purpose of this study was performed to assess the prevalence of chronic pain after inguinal hernia repair and the effects on the quality of life in our patient. METHODS: The records of the patients who were 18 years of age or older and had had an inguinal hernia repair under spinal anesthesia after receiving a diagnosis of inguinal hernia at this hospital from 2009 to 2015 were accessed through the hospital's data system. Patients who had signed the informed consent agreement were given an Inguinal Pain Questionnaire (IPQ) and a Douleur Neuropathique 4 (DN-4) questionnaire after recording their demographic data on the appointment day. Surgical incision line was evaluated with a dolorimeter and mild touch hypoesthesia, needle-touch hypoesthesia, brushing allodynia were evaluated with cotton, and 0.711 mm diameter Von-Frey filament (Touch-Test Sensory Evaluator Kit; North Coast Medical, Inc., Gilroy, CA, USA). RESULTS: The total number of patients who had ASA I-II scores and who had undergone a one sided inguinal hernia repair under spinal anesthesia in elective conditions with at least three or more months of recovery time months was 619. Of these 264 patients, 203 with absence of pain (score of the severest pain over the past week and now was 0) were classified as the Non-Pain group and 61 patients with inguinal pain (score of the severest pain over the past week or now was 1 or more) were classified as the Pain group. The incidence of chronic pain after inguinal hernia surgery was 23.48% (n = 61) in our study. The pain was localized at and near the surgical incision and radiated into the scrotum in 17.73% (n = 36) of the male patients having chronic pain. While chronic pain developed in 60 out of 239 patients who had pain prior to the surgery. The presence of pain prior to the surgery was evaluated as an effective factor for the chronic groin pain. Neuropathic pain was detected with the DN-4 questionnaire in 6 (2.95%) out of 203 patients who stated that they had no pain during the physical examination and the week prior to the exam. The frequency of chronic pain after inguinal hernia repair was found 23.48% in our study. This is the same rate as previously reported. Quality of life of these patients was affected. We believe that there is an urgent need for prospective randomized studies with the aim of determining a standardized methodology towards preventive measures after determining the risk factors of chronic pain developed in the post inguinal hernia repair period. PMID- 28890414 TI - Perineal resectional procedures for the treatment of complete rectal prolapse: A systematic review of the literature. AB - BACKGROUND AND AIM: Several procedures for the treatment of complete rectal prolapse (CRP) exist. These procedures are performed via the abdominal or perineal approach. Perineal procedures for rectal prolapse involve either resection or suspension and fixation of the rectum. The present review aimed to assess the outcomes of the perineal resectional procedures including Altemeier procedure (AP), Delorme procedure (DP), and perineal stapled prolapse resection (PSR) in the treatment of CRP. PATIENTS AND METHODS: A systematic search of the current literature for the outcomes of perineal resectional procedures for CRP was conducted. Databases queried included PubMed/MEDLINE, SCOPUS, and Cochrane library. The main outcomes of the review were the rates of recurrence of CRP, improvement in bowel function, and complications. RESULTS: Thirty-nine studies involving 2647 (2390 females) patients were included in the review. The mean age of patients was 69.1 years. Recurrence of CRP occurred in 16.6% of patients. The median incidences of recurrence were 11.4% for AP, 14.4% for DP, and 13.9% for PSR. Improvement in fecal incontinence occurred in 61.4% of patients after AP, 69% after DP, and 23.5% after PSR. Complications occurred in 13.2% of patients. The median complication rates after AP, DP and PSR were 11.1%, 8.7%, and 11.7%, respectively. CONCLUSION: Perineal resectional procedures were followed by a relatively high incidence of recurrence, yet an acceptably low complication rate. Definitive conclusions on the superiority of any procedure cannot be reached due to the significant heterogeneity of the studies. PMID- 28890415 TI - Performance of CT scan of abdomen and pelvis in detecting asymptomatic synchronous metastasis in breast cancer. AB - BACKGROUND: In many centres in Australia, CT scan of abdomen and pelvis (CTAP) is a commonly used staging investigation to detect asymptomatic synchronous metastasis (ASM) in newly diagnosed breast cancer. However, its routine use is not supported by strong evidence either on its cost effectiveness or on specificity. Despite contrary recommendations by international guidelines this staging investigation is widely used among new early breast cancers(EBC). This retrospective study aims to assess the cost effectiveness and usefulness of CTAP in new breast cancers. MATERIALS AND METHODS: All patients with primary invasive breast cancers who underwent breast cancer treatment through Eastern health breast unit during 50-month period from January 2012 were included in the study. All staging CTAP results were reviewed to evaluate its yield, false positive rate and cost of investigation per single positive result. Odds ratio for positive test results were calculated for five possible risk factors (Age less than 40 years, stage III disease, presence of LVI, HER2 positive disease and presence of metastasis in lymph node). RESULTS: 49% (n = 285) of all breast cancer patient underwent staging CTAP which lead to the detection of 4 ASM. (Over all yield of 1%) Overall false positive rate was 15% because of 42 indeterminate results needing further tests. Based merely on approved billing rates this amounted to $ 40733 per single ASM identified. Presence of lymph node metastasis did not increase the chance of positive test result (OR = 1.3; CI:0.13-12.69). CONCLUSION: Staging CTAP is associated with high incidence of false positive rates and low yield, especially among EBCs. It is desirable to choose this investigation more selectively than currently practiced. PMID- 28890416 TI - Bayesian population receptive field modelling. AB - We introduce a probabilistic (Bayesian) framework and associated software toolbox for mapping population receptive fields (pRFs) based on fMRI data. This generic approach is intended to work with stimuli of any dimension and is demonstrated and validated in the context of 2D retinotopic mapping. The framework enables the experimenter to specify generative (encoding) models of fMRI timeseries, in which experimental stimuli enter a pRF model of neural activity, which in turns drives a nonlinear model of neurovascular coupling and Blood Oxygenation Level Dependent (BOLD) response. The neuronal and haemodynamic parameters are estimated together on a voxel-by-voxel or region-of-interest basis using a Bayesian estimation algorithm (variational Laplace). This offers several novel contributions to receptive field modelling. The variance/covariance of parameters are estimated, enabling receptive fields to be plotted while properly representing uncertainty about pRF size and location. Variability in the haemodynamic response across the brain is accounted for. Furthermore, the framework introduces formal hypothesis testing to pRF analysis, enabling competing models to be evaluated based on their log model evidence (approximated by the variational free energy), which represents the optimal tradeoff between accuracy and complexity. Using simulations and empirical data, we found that parameters typically used to represent pRF size and neuronal scaling are strongly correlated, which is taken into account by the Bayesian methods we describe when making inferences. We used the framework to compare the evidence for six variants of pRF model using 7 T functional MRI data and we found a circular Difference of Gaussians (DoG) model to be the best explanation for our data overall. We hope this framework will prove useful for mapping stimulus spaces with any number of dimensions onto the anatomy of the brain. PMID- 28890418 TI - Arc ubiquitination in synaptic plasticity. AB - The activity-regulated cytoskeleton-associated protein (Arc) is a neuron expressed activity regulated immediate early gene (IEG) product that is essential for memory consolidation and serves as a direct readout for neural activation during learning. Arc contributes to diverse forms of synaptic plasticity mediated by the trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Notably, Arc protein expression abruptly increases and then rapidly decreases following augmented network activity. A large body of work has focused on Arc transcription and translation. Far fewer studies have explored the relevance of Arc protein stability and turnover. Here, we review recent findings on the mechanisms controlling Arc degradation and discuss its contributions to AMPA receptor trafficking and synaptic plasticity. PMID- 28890417 TI - The impact of vessel size, orientation and intravascular contribution on the neurovascular fingerprint of BOLD bSSFP fMRI. AB - Monte Carlo simulations have been used to analyze oxygenation-related signal changes in pass-band balanced steady state free precession (bSSFP) as well as in gradient echo (GE) and spin echo (SE) sequences. Signal changes were calculated for artificial cylinders and neurovascular networks acquired from the mouse parietal cortex by two-photon laser scanning microscopy at 1 MUm isotropic resolution. Signal changes as a function of vessel size, blood volume, vessel orientation to the main magnetic field B0 as well as relations of intra- and extravascular and of micro- and macrovascular contributions have been analyzed. The results show that bSSFP is highly sensitive to extravascular and microvascular components. Furthermore, GE and bSSFP, and to a lesser extent SE, exhibit a strong dependence of their signal change on the orientation of the vessel network to B0. PMID- 28890419 TI - Arc protein: a flexible hub for synaptic plasticity and cognition. AB - Mammalian excitatory synapses express diverse types of synaptic plasticity. A major challenge in neuroscience is to understand how a neuron utilizes different types of plasticity to sculpt brain development, function, and behavior. Neuronal activity-induced expression of the immediate early protein, Arc, is critical for long-term potentiation and depression of synaptic transmission, homeostatic synaptic scaling, and adaptive functions such as long-term memory formation. However, the molecular basis of Arc protein function as a regulator of synaptic plasticity and cognition remains a puzzle. Recent work on the biophysical and structural properties of Arc, its protein-protein interactions and post translational modifications have shed light on the issue. Here, we present Arc protein as a flexible, multifunctional and interactive hub. Arc interacts with specific effector proteins in neuronal compartments (dendritic spines, nuclear domains) to bidirectionally regulate synaptic strength by distinct molecular mechanisms. Arc stability, subcellular localization, and interactions are dictated by synaptic activity and post-translational modification of Arc. This functional versatility and context-dependent signaling supports a view of Arc as a highly specialized master organizer of long-term synaptic plasticity, critical for information storage and cognition. PMID- 28890420 TI - Perinatal inflammation and adult psychopathology: From preclinical models to humans. AB - Perinatal environment plays a crucial role in brain development and determines its function through life. Epidemiological studies and clinical reports link perinatal exposure to infection and/or immune activation to various psychiatric disorders. In addition, accumulating evidence from animal models shows that perinatal inflammation can affect various behaviors relevant to psychiatric disorders such as schizophrenia, autism, anxiety and depression. Remarkably, the effects on behavior and brain function do not always depend on the type of inflammatory stimulus or the perinatal age targeted, so diverse inflammatory events can have similar consequences on the brain. Moreover, other perinatal environmental factors that affect behavior (e.g. diet and stress) also elicit inflammatory responses. Understanding the interplay between perinatal environment and inflammation on brain development is required to identify the mechanisms through which perinatal inflammation affect brain function in the adult animal. Evidence for the role of the peripheral immune system and glia on perinatal programming of behavior is discussed in this review, along with recent evidence for the role of epigenetic mechanisms affecting gene expression in the brain. PMID- 28890421 TI - The mechanistic link between Arc/Arg3.1 expression and AMPA receptor endocytosis. AB - The activity-regulated cytoskeleton associated protein (Arc/Arg3.1) plays a key role in determining synaptic strength through facilitation of AMPA receptor (AMPAR) endocytosis. Although there is considerable data on the mechanism by which Arc induction controls synaptic plasticity and learning behaviours, several key mechanistic questions remain. Here we review data on the link between Arc expression and the clathrin-mediated endocytic pathway which internalises AMPARs and discuss the significance of Arc binding to the clathrin adaptor protein 2 (AP 2) and to endophilin/dynamin. We consider which AMPAR subunits are selected for Arc-mediated internalisation, implications for synaptic function and consider Arc as a therapeutic target. PMID- 28890422 TI - Transcriptional and post-translational regulation of Arc in synaptic plasticity. AB - One of the most interesting features of Arc-dependent synaptic plasticity is how multiple types of synaptic activity can converge to alter Arc transcription and then diverge to induce different plasticity outcomes, ranging from AMPA receptor internalisation that promotes long-term depression (LTD), to actin stabilisation that promotes long-term potentiation (LTP). This diversity suggests that there must be numerous levels of control to ensure the temporal profile, abundance, localisation and function of Arc are appropriately regulated to effect learning and memory in the correct contexts. The activity-dependent transcription and post translational modification of Arc are crucial regulators of synaptic plasticity, fine-tuning the function of this key protein depending on the specific situation. The extensive cross-talk between signalling pathways and the numerous routes of Arc regulation provide a complex interplay of processes in which Arc-mediated plasticity can be broadly induced, but specifically tailored to synaptic activity. Here we provide an overview what is currently known about these processes and potential future directions. PMID- 28890423 TI - Liposome-encapsulated diacyl glycerol and inositol triphosphate-induced delayed oocyte activation and poor development of parthenotes. AB - OBJECTIVE: To explore the ability of diacyl glycerol (DAG) and inositol triphosphate (IP3), two major secondary messengers in the calcium signaling pathway, in activating oocytes. MATERIAL AND METHODS: Oocyte cumulus complex obtained from superovulated Swiss albino mice were incubated in M16 medium with liposome-encapsulated 1,2-Dipalmitoyl-sn-glycerol (LEDAG) and/or IP3 for 3 h. Strontium chloride was used as positive control. The activation potential, ploidy status, and blastocyst rate was calculated. RESULTS: Both DAG and IP3, individually, induced activation in ~98% of oocytes, which was significantly higher (p<0.01) than activation induced by strontium chloride (60%). Delayed pronucleus formation and a higher percentage of diploid parthenotes was observed in oocytes activated with LEDAG and/or IP3. However, these embryos failed to progress beyond the 6-8-cell stage. Only when the medium was supplemented with LEDAG (5 MUg/mL) and IP3 (10 MUg/mL) could activated oocytes progress till the blastocyst stage (5.26%), which was lower than the blastocyst rate in the positive controls (13.91%). CONCLUSION: The results of the present study indicate that DAG and IP3 can induce delayed oocyte activation and poor development of parthenotes in vitro. PMID- 28890424 TI - Revaluating the survival effects of International Federation of Gynecology and Obstetrics 1988 stage IIIA criteria for endometrial cancer. AB - OBJECTIVE: This study aimed to define factors that affected survival in the International Federation of Gynecology and Obstetrics (FIGO) 1988 stage IIIA endometrial cancer (EC). MATERIAL AND METHODS: The study included patients with EC who underwent surgery between 1992 and 2013. Patients with adnexal metastases, uterine serosal involvement or positive peritoneal cytology (stage IIIA disease according to the former 1988 FIGO staging system) were selected for further analysis. Clinical and pathologic factors associated with progression-free survival (PFS) were evaluated using univariate and multivariate statistical tests. RESULTS: Seventy-seven patients with stage IIIA disease according to the 1988 FIGO staging system were included. The median follow-up was 37 months (range, 1-175 months) and recurrence was detected in 19 patients. Univariate analysis revealed that the presence of uterine serosal invasion and advanced histologic grade (grade 1-2 vs. grade 3) were associated with diminished PFS (p=0.001, p=0.047). The presence of adnexal involvement and positive peritoneal cytology had no statistically significant influence on PFS (p=0.643 and p=0.795, respectively). CONCLUSION: In patients with stage IIIA EC according to the FIGO 1988 staging system, only uterine serosal involvement was related with adverse oncologic outcomes, not adnexal involvement or presence of positive cytology. PMID- 28890425 TI - Platelet-to-lymphocyte ratio: A new inflammatory marker for the diagnosis of preterm premature rupture of membranes. AB - OBJECTIVE: Preterm premature rupture of membranes (PPROM) is closely related with maternal and fetal complications. Therefore, early diagnosis is extremely important to provide maternal and fetal well-being. Many inflammatory markers have been evaluated for their ability to diagnose membrane rupture at early stages. We aimed to investigate the relationship between the platelet-to lymphocyte ratio (PLR) and preterm premature membrane rupture. MATERIAL AND METHODS: In this study, 121 pregnant women with PPROM and 96 age-matched pregnant women with spontaneous preterm labor who were admitted to our hospital between January 2014 and December 2015 were enrolled. Demographic data, complete blood cell count results, and neonatal outcomes were recorded. RESULTS: The neutrophil and platelet counts were higher in the PPROM group (9948.4+/-3393.2 vs. 7466.1+/ 1698.5/mm3 and 244.5+/-60 vs. 210.6+/-64.8/mm3, respectively, p<0.001). The PLR and neutrophil-to-lymphocyte ratios (NLR) were both significantly higher in the PPROM group (p<0.001). Correlation analysis revealed that the PLR was positively correlated with the NLR (r=0.10, p=0.031). The ability of the PLR to diagnose preterm premature rupture of membranes was evaluated using an ROC curve. The sensitivity and specificity of the PLR was 57.8% and 73.7%, respectively, at a threshold >117.14 (p<0.001). CONCLUSION: The PLR might be a cost effective, easy to use, and practical marker for the early diagnosis of PPROM, which can help to determine the appropriate waiting time for delivery and provide maternal and fetal well-being. PMID- 28890426 TI - Lymph node dissection in atypical endometrial hyperplasia. AB - OBJECTIVE: The rate of concomitant endometrial carcinoma in patients with atypical endometrial hyperplasia is high. We aimed to investigate the role of lymphadenectomy in deciding adjuvant treatment in patients with concomitant atypical endometrial hyperplasia and endometrial carcinoma. MATERIAL AND METHODS: Women with atypical endometrial hyperplasia were enrolled in this retrospective study. Lymph node dissection was performed in only some patients who gave informed consent if their surgeon elected to do so, or if the intraoperative findings necessitated. The final histopathologic evaluations of surgical specimens were compared with endometrial biopsy results. RESULTS: Eighty eligible patients were evaluated. Seventy-two (90%) patients had complex hyperplasia with atypia, and 8 (10%) patients had simple hyperplasia with atypia. Hysterectomy and bilateral salpingo-oophorectomy were performed to all patients; 37 also underwent lymph node dissection. Lymph node dissection was extended to the paraaortic region in 9 of 37 patients. The concomitant endometrial carcinoma rate was 50%. Two patients had lymph node metastasis. Among 40 cases of carcinoma, 17 had deep myometrial invasion and/or cervical or ovarian involvement or grade 2 tumors with superficial myometrial invasion on hysterectomy specimens; 27.5% of all carcinomas were stage Ib or higher. CONCLUSION: The concomitant endometrial carcinoma rate was high in patients with atypical endometrial hyperplasia. Nearly half of these patients had risk factors for extrauterine spread. Lymph node dissection might be helpful to decide adjuvant treatment. PMID- 28890427 TI - Blastocyst transfer does not improve cycle outcome as compared to D3 transfer in antagonist cycles with an elevated progesterone level on the day of hCG. AB - OBJECTIVE: To evaluate the association between progesterone elevation on the day of human chorionic gonadotropin (hCG) administration and clinical pregnancy rates of gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles with the transfer of embryos at different developmental stages (day-3 versus day-5 ETs). MATERIAL AND METHODS: This is a retrospective analysis of fresh IVF/ICSI; 194 cycles out of 2676 conducted in a single center. RESULTS: A total of 2676 cycles were analyzed, of which 386 had no progesterone measurements available. Two hundred eighteen cycles had progesterone elevation (p>1.5 ng/mL) giving an overall incidence of 9.5%. Twenty-four cycles were excluded from further analysis. Of the remaining 194 cycles, 151 had day-3 transfers and 43 had blastocyst transfers. There was no statistically significant difference in pregnancy and clinical pregnancy rates per transfer between the D3-ET and D5-ET groups (46% vs. 49%, and 39% vs. 35%, respectively). CONCLUSION: The results of this study suggest that blastocyst transfer does not improve cycle outcomes compared with D3 transfer in GnRH antagonist cycles with an elevated progesterone level on the day of hCG. PMID- 28890428 TI - Microcystic, elongated, and fragmented pattern of invasion in relation to histopathologic and clinical prognostic factors in endometrioid endometrial adenocarcinoma. AB - OBJECTIVE: To investigate the association of microcystic, elongated, and fragmented (MELF) pattern of invasion with prognostic factors in endometrioid endometrial adenocarcinoma (EEA). MATERIAL AND METHODS: Stained tissue sections from 83 cases of EEA operated by the same gynecologic oncologist were reviewed to identify cases showing MELF-type invasion in this retrospective study. The association of MELF pattern with age, tumor grade, depth of myometrial invasion, and presence of lymphovascular space invasion (LVSI) was analyzed. RESULTS: FIGO grade 2 and grade 1 tumors were evident in 53.0% and 38.6% of patients, respectively. Depth of myometrial invasion was <50% in 72.0% of patients, and LVSI was absent in 77.1%. MELF pattern was confirmed in 35 (42.2%) patients. Presence of MELF pattern was associated with significantly higher mean +/- standard deviation age (62.9+/-6.9) years vs. 58.9+/-9.1 years, p=0.033), and found to be more likely in patients with high-grade tumor (FIGO grade III; 85.7% vs. 14.3%, p<0.001), deep (>=50%) myometrial invasion (78.3% vs. 21.7%, p<0.001), and presence of LVSI (94.7% vs. 5.3%, p<0.001) as compared with absence of MELF pattern. CONCLUSION: In conclusion, our findings revealed a high rate of MELF pattern among patients with EEA alongside the association of MELF pattern with poor prognostic factors such as high grade tumor, deep myometrial invasion, and LVSI. PMID- 28890429 TI - Exploring the umbilical and vaginal port during minimally invasive surgery. AB - This article focuses on the anatomy, literature, and our own experiences in an effort to assist in the decision-making process of choosing between an umbilical or vaginal port. Umbilical access is more familiar to general surgeons; it is thicker than the transvaginal entry, and has more nerve endings and sensory innervations. This combination increases tissue damage and pain in the umbilical port site. The vaginal route requires prophylactic antibiotics, a Foley catheter, and a period of postoperative sexual abstinence. Removal of large specimens is a challenge in traditional laparoscopy. Recently, there has been increased interest in going beyond traditional laparoscopy by using the navel in single-incision and port-reduction techniques. The benefits for removal of surgical specimens by colpotomy are not new. There is increasing interest in techniques that use vaginotomy in multifunctional ways, as described under the names of culdolaparoscopy, minilaparoscopy-assisted natural orifice surgery, and natural orifice transluminal endoscopic surgery. Both the navel and the transvaginal accesses are safe and convenient to use in the hands of experienced laparoscopic surgeons. The umbilical site has been successfully used in laparoscopy as an entry and extraction port. Vaginal entry and extraction is associated with a lower risk of incisional hernias, less postoperative pain, and excellent cosmetic results. PMID- 28890430 TI - How to personalize ovarian stimulation in clinical practice. AB - Controlled ovarian stimulation (COS) in in vitro fertilization (IVF) cycles is the starting point from which couple's prognosis depends. Individualization in follicle-stimulating hormone (FSH) starting dose and protocol used is based on ovarian response prediction, which depends on ovarian reserve. Anti-Mullerian hormone levels and the antral follicle count are considered the most accurate and reliable markers of ovarian reserve. A literature search was performed for studies that addressed the ability of ovarian reserve markers to predict poor and high ovarian response in assisted reproductive technology cycles. According to the predicted response to ovarian stimulation (poor- normal- or high- response), it is possible to counsel couples before treatment about the prognosis, and also to individualize ovarian stimulation protocols, choosing among GnRH-agonists or antagonists for endogenous FSH suppression, and the FSH starting dose in order to decrease the risk of cycle cancellation and ovarian hyperstimulation syndrome. In this review we discuss how to choose the best COS therapy, based on ovarian reserve markers, in order to enhance chances in IVF. PMID- 28890431 TI - What is your diagnosis? PMID- 28890432 TI - Obesity and insulin resistance are significant predictors of serum leptin levels. PMID- 28890433 TI - Evaluation of severity score-guided approaches to macrolide use in community acquired pneumonia. AB - International guidelines including those in the UK, Japan, Australia and South Africa recommend the avoidance of macrolides in patients with low-severity community-acquired pneumonia (CAP). We hypothesised that severity scores are poor predictors of atypical pneumonia and response to macrolide therapy, and thus, inadequate tools for guiding antibiotic prescriptions.Secondary analysis of four independent prospective CAP datasets was conducted. The predictive values of the CURB-65 and pneumonia severity index (PSI) for clinically important groups of causative pathogens were evaluated. The effect of macrolide use according to risk class was assessed by multivariable analysis. Patients (3297) were evaluated, and the predictive values of CURB-65 and PSI for atypical pathogens were poor (AUC values of 0.37 and 0.42, respectively). No significant differences were noted among the effects of macrolide use on mortality in patients with mild, moderate and severe CAP, according to either CURB-65 (interaction testing severe versus mild disease OR=0.74 (0.29-1.89)) or PSI (severe versus mild disease OR=3.4 (0.055-2.10)), indicating that severity scores were not significant modifiers of response to macrolide therapy.Severity scores did not accurately predict response to macrolide therapy in CAP, suggesting that current guidance to use these tools for empirical antibiotic choices might not be justified. PMID- 28890434 TI - International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociacion Latinoamericana del Torax (ALAT). AB - The most recent European guidelines and task force reports on hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) were published almost 10 years ago. Since then, further randomised clinical trials of HAP and VAP have been conducted and new information has become available. Studies of epidemiology, diagnosis, empiric treatment, response to treatment, new antibiotics or new forms of antibiotic administration and disease prevention have changed old paradigms. In addition, important differences between approaches in Europe and the USA have become apparent.The European Respiratory Society launched a project to develop new international guidelines for HAP and VAP. Other European societies, including the European Society of Intensive Care Medicine and the European Society of Clinical Microbiology and Infectious Diseases, were invited to participate and appointed their representatives. The Latin American Thoracic Association was also invited.A total of 15 experts and two methodologists made up the panel. Three experts from the USA were also invited (Michael S. Niederman, Marin Kollef and Richard Wunderink).Applying the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology, the panel selected seven PICO (population-intervention-comparison-outcome) questions that generated a series of recommendations for HAP/VAP diagnosis, treatment and prevention. PMID- 28890435 TI - Pain control in thoracic oncology. AB - This review of pain management in lung cancer is based on the presentation of four cases of thoracic oncology patients with pain at various stages of their disease. The approach will be multidisciplinary, involving a thoracic oncologist, radiologist, thoracic and orthopaedic spine surgeon, radiation therapist, pain medicine specialist, and palliative care specialist. This multispecialty approach to the management of different painful presentations in thoracic oncology will demonstrate the complexity of each case and the improved patient outcomes which result from the involvement of different disciplines working in concert.In the USA, Europe and other countries, palliative care specialists often become rapidly involved in the management of these patients, coordinating social care and providing psychological support.Thoracic and orthopaedic spine subspecialists provide surgical methods to control tumour invasion, and improve quality of life and preservation of function in settings of even diffuse metastatic disease. Similarly, thoracic oncology and radiation therapists utilise both therapeutic and palliative chemotherapeutic and radiation therapy regimens to prolong and improve quality of life.The pain medicine specialist can, in addition to medication management, offer a variety of interventional approaches including unique drug delivery systems such as epidural analgesia, regional anaesthesia techniques, and intrathecal pumps, as well as neuromodulation techniques and neurolytic or neuroablative procedures.In the USA, these specialists complete an additional fellowship year in pain medicine following the completion of an anaesthesiology, physical medicine and rehabilitation, neurology or psychiatry residency. These programmes are accredited by the Accreditation Council for Graduate Medical Education, or ACGME (www.acgme.org). PMID- 28890437 TI - Three years of experience with a novel "virtual" pneumonia follow-up clinic. PMID- 28890436 TI - Primary ciliary dyskinesia ciliated airway cells show increased susceptibility to Haemophilus influenzae biofilm formation. AB - Non-typeable Haemophilus influenzae (NTHi) is the most common pathogen in primary ciliary dyskinesia (PCD) patients. We hypothesised that abnormal ciliary motility and low airway nitric oxide (NO) levels on airway epithelial cells from PCD patients might be permissive for NTHi colonisation and biofilm development.We used a primary epithelial cell co-culture model to investigate NTHi infection. Primary airway epithelial cells from PCD and non-PCD patients were differentiated to ciliation using an air-liquid interface culture and then co-cultured with NTHi.NTHi adherence was greater on PCD epithelial cells compared to non-PCD cells (p<0.05) and the distribution of NTHi on PCD epithelium showed more aggregated NTHi in biofilms (p<0.001). Apart from defective ciliary motility, PCD cells did not significantly differ from non-PCD epithelial cells in the degree of ciliation and epithelial integrity or in cytokine, LL-37 and NO production. Treatment of PCD epithelia using exogenous NO and antibiotic significantly reduced NTHi viability in biofilms compared with antibiotic treatment alone.Impaired ciliary function was the primary defect in PCD airway epithelium underlying susceptibility to NTHi biofilm development compared with non-PCD epithelium. Although NO responses were similar, use of targeted NO with antibiotics enhanced killing of NTHi in biofilms, suggesting a novel therapeutic approach. PMID- 28890438 TI - Impact of alpha 1-antitrypsin deficiency and prior augmentation therapy on patients' survival after lung transplantation. PMID- 28890439 TI - Inhaled budesonide does not prevent acute mountain sickness after rapid ascent to 4559 m. PMID- 28890440 TI - Inhaled budesonide for acute mountain sickness. PMID- 28890441 TI - Haemophilus influenzae biofilms in primary ciliary dyskinesia: a moving story. PMID- 28890442 TI - Marked geographic patterns in the incidence of idiopathic central precocious puberty: a nationwide study in France. AB - OBJECTIVES: Precocious puberty seems to be increasing but epidemiological data are scarce. Our objective was to improve the epidemiologic knowledge on this disease. We analyzed the national incidence and spatial trends of idiopathic central precocious puberty in France in 2011-2013 in a cross-sectional descriptive study. DESIGN: We used an indicator based on treatment reimbursements recorded in the national insurance database, in girls under the age of nine years and in boys under the age of 10 years. We considered a time lag of up to one year from the onset of puberty to first drug delivery. We tested four different predictive spatial models at the departement scale, selecting the model best fitting the data. We carried out semi-structured interviews with qualified hospital teams in five selected regions to investigate spatial differences in medical practices. RESULTS: The national annual incidence was 2.68 (95% CI: 2.55, 2.81) per 10 000 girls under the age of 9 years and 0.24 (95% CI: 0.21, 0.27) per 10 000 boys under the age of 10 years. Incidence rates conformed to a purely spatial heterogeneity model in girls, consistent between age groups, with a large incidence range. A similar pattern was observed for boys, with peaks in the South West and Center East. Differences in medical practices may have slightly affected incidence locally, but could not entirely explain the marked geographic pattern. CONCLUSIONS: The results suggest that the risk factors are similar for boys and girls and justify further investigations of the role of the environment. PMID- 28890444 TI - Introduction to the Special Issue. PMID- 28890443 TI - Stress and sex: does cortisol mediate sex change in fish? AB - Cortisol is the main glucocorticoid (GC) in fish and the hormone most directly associated with stress. Recent research suggests that this hormone may act as a key factor linking social environmental stimuli and the onset of sex change by initiating a shift in steroidogenesis from estrogens to androgens. For many teleost fish, sex change occurs as a usual part of the life cycle. Changing sex is known to enhance the lifetime reproductive success of these fish and the modifications involved (behavioral, gonadal and morphological) are well studied. However, the exact mechanism behind the transduction of the environmental signals into the molecular cascade that underlies this singular process remains largely unknown. We here synthesize current knowledge regarding the role of cortisol in teleost sex change with a focus on two well-described transformations: temperature-induced masculinization and socially regulated sex change. Three non mutually exclusive pathways are considered when describing the potential role of cortisol in mediating teleost sex change: cross-talk between GC and androgen pathways, inhibition of aromatase expression and upregulation of amh (the gene encoding anti-Mullerian hormone). We anticipate that understanding the role of cortisol in the initial stages of sex change will further improve our understanding of sex determination and differentiation across vertebrates, and may lead to new tools to control fish sex ratios in aquaculture. PMID- 28890445 TI - Challenging the Conventional Wisdom: From Philosophy to Bioethics. AB - Philosophy is a core discipline that has contributed importantly to bioethics. In this essay, the author traces his trajectory from philosophy to bioethics, oriented around the theme of challenging the conventional wisdom. Three topics are discussed to illustrate this theme: the ethics of randomized trials, determination of death and organ transplantation, and pragmatism as a method of bioethics. In addition, the author offers some general reflections on the relationship between philosophy and bioethics. Philosophy recovers itself when it ceases to be a device for dealing with the problems of philosophers and becomes a method, cultivated by philosophers, for dealing with the problems of men.-John Dewey (1917). PMID- 28890446 TI - My Time in Medicine. AB - Through this autobiographical reflection on a life in medicine and bioethics, the author discovers that time is a unifying theme in his work. From his early writing on the regulation of house staff work hours and his abandonment of essentialism and the development of clinical pragmatism as a method of moral problem-solving to his scholarship on end-of-life care and disorders of consciousness, time has been a central heuristic in an effort to bridge ethical theory and clinical practice. PMID- 28890447 TI - What Nurse Bioethicists Bring to Bioethics: The Journey of a Nurse Bioethicist. AB - Nurses, one of the most trusted professional groups in our society, work with patients and their families at all stages of the illness trajectory. Nurse bioethicists are a small but special subset of the nursing profession and bioethics community, focusing on the moral complexities that arise in clinical care, research, and health policy. This article examines the career trajectory of a nurse bioethicist and the clinical, educational, and research experiences that shaped her career goals. It also addresses the uniqueness of nursing and the ethical challenges that nurse's encounter in their day-today interactions with diverse patient populations and calls for distinct conceptual and empirical bioethics inquiry. Training the next generation of nurse bioethicists requires a dialogue with nursing and bioethics scholars on the academic and philosophical skill set and mentorship requirements that will advance and contribute to the broader public good. PMID- 28890448 TI - A Tale of Two Disciplines: Law and Bioethics. AB - Fascination with In re Quinlan, the first high-profile right-to-die case in the United States, led the author to law school. By the time she received her law degree, bioethics was emerging as a field of study, and law and bioethics became her field. The mission of legal education is to teach students to "think like a lawyer," which can be a productive way to approach issues in many fields, including bioethics. Legal education can also teach individuals to respect people whose views on bioethics issues differ from their own. This essay describes three areas in which legal training influenced the author's work in bioethics: treatment decisions, research misconduct, and stem cell research. PMID- 28890449 TI - History, Morals, and Medicine. AB - This essay provides a rational reconstruction of the author's genetically inscribed inclination to do normative ethics with an historical bent and offers some reflections on the value of historical thinking for bioethics. PMID- 28890450 TI - Regarding Bioethics: A Sociology of Morality. AB - C. Wright Mills said that when done well, sociology illuminates the intersection of biography and history. This essay examines how the author's vocational choices and career path were shaped by historical circumstance, leading him to a degree in sociology and to participation in the odd and interesting interdiscipline of bioethics. Drawing on a distinction between sociology in bioethics and sociology of bioethics, the essay considers the value of sociology to the bioethical project. PMID- 28890451 TI - In the Matter of Stories. AB - This essay lays out some of the many resources that a background in literary studies has to offer bioethics. After identifying four useful characteristics of stories, it briefly discusses some kinds of moral work that stories can be put to, including countering ethically undesirable stories and modeling ethically troubling situations. Stories can be invoked in our moral reasoning, compared and parsed, and used to teach moral lessons. They can help us discern which moral concepts are operative in a specific instance. Our personal identities consist of stories, which help us understand who we and other people are. Stories can also be parodied, for political or other effect. Stories can perform these moral functions only to the extent that the persons telling or invoking or parodying them are themselves morally competent. But given that competence, a scholarly grasp of literature and narrative can greatly enhance bioethical reflection. PMID- 28890452 TI - A Journey in Public Health Ethics. AB - While medical ethics has a long history, and research ethics guidance emerged more formally in the 1960s and 1970s, frameworks for public health ethics began to appear in the 1990s. The author's thinking about public health ethics evolved from consideration of some of the ethics and policy questions surfacing regularly in the HIV/AIDS epidemic. This essay discusses some of the shared commitments of public health and ethics, as well as how one might apply an ethics lens to public health programs, both generally and in the contexts of public health preparedness and obesity prevention. PMID- 28890453 TI - Risk Communication in EPA's Controlled Inhalation Exposure Studies and in Support. AB - On March 28, 2017, the National Academy of Sciences, Engineering, and Medicine (NASEM) released a much-anticipated report on the Environmental Protection Agency's controlled human inhalation exposure studies. This essay reviews the ethical controversies that led to the genesis of the report, summarizes its key findings, and comments on its approach to informing human subjects about the risks of inhalation exposure studies. NASEM's report makes a valuable contribution to our understanding of the scientific and ethical issues involved in conducting human inhalation exposure studies. Its definition of "reasonably foreseeable risks" provides useful guidance to investigators, research participants, and institutional review board members. PMID- 28890455 TI - Internationalism and Engineering in UNESCO during the End Game of Empire, 1943 68. AB - When UNESCO was founded in 1945 the organization aimed to become a pivotal player in international collaboration in the field of engineering. UNESCO based its engineering initiatives on the World Engineering Conference, an organization espousing a politically motivated "technocratic internationalism" and on the World Power Conference, an organization promoting a business-friendly stance of "engineering internationalism." These competing models for international collaboration curtailed UNESCO's institutional ambitions. UNESCO's position was further weakened by fierce opposition from British engineering institutions that pursued a Commonwealth institutional framework in direct opposition to UNESCO. This article unravels the intricate connections between empire and internationalism that shaped UNESCO's engineering agenda during the first post war decades. It demonstrates how competing forms of internationalism, mounting cold war tensions, and the continuous influence of a British empire-based opposition ultimately forced UNESCO to abandon its technocratic internationalist ambitions and settle for a modest coordinating role in international technical collaboration. PMID- 28890454 TI - The Telegraph and the Control of Material Movements: A Micro-Study about the Detachment of Communication from Transport. AB - Relatively recent historiographical approaches such as global or transnational history have attracted new attention to telegraphy and its role in processes of globalization. This renewed interest in submarine cables and overland wires has recently provided us with a reasonably good idea of how the global telegraph network developed in the nineteenth century, who its principal designers were, and where it was more and where it was less tight. Little, however, has been said so far about the actual matters communicated telegraphically, certainly not in any systematic fashion. Apart from individual telegraphic messages that gained prominence in political or military history, the contents of telegrams have attracted little historiographical attention. What was conveyed in telegrams has not been interrogated as to its significance in globalization processes. This article seeks to make a first step in this direction and suggests that only in a content analysis of everyday telegrams do the most important qualities of telegraphy become apparent. It introduces a small but coherent corpus of telegrams-the Bala railway telegrams-that provides us with a rare opportunity to study the contents of telegraphic messages in a systematic form. In the course of the analysis of the Bala railway telegrams the importance of this device's power to coordinate and control movement begins to show. By relating evidence from this micro-level study to the contexts in which telegraphy was employed on a larger scale, the article suggests that this capacity for coordination and control was the principal new quality introduced by the technology. PMID- 28890456 TI - A Figure of Merit: Quantifying the Probability of a Nuclear Reactor Accident. AB - In recent decades, probabilistic risk assessment (PRA) has become an essential tool in risk analysis and management in many industries and government agencies. The origins of PRA date to the 1975 publication of the U.S. Nuclear Regulatory Commission's (NRC) Reactor Safety Study led by MIT professor Norman Rasmussen. The "Rasmussen Report" inspired considerable political and scholarly disputes over the motives behind it and the value of its methods and numerical estimates of risk. The Report's controversies have overshadowed the deeper technical origins of risk assessment. Nuclear experts had long sought to express risk in a "figure of merit" to verify the safety of weapons and, later, civilian reactors. By the 1970s, technical advances in PRA gave the methodology the potential to serve political ends, too. The Report, it was hoped, would prove nuclear power's safety to a growing chorus of critics. Subsequent attacks on the Report's methods and numerical estimates damaged the NRC's credibility. PRA's fortunes revived when the 1979 Three Mile Island accident demonstrated PRA's potential for improving the safety of nuclear power and other technical systems. Nevertheless, the Report's controversies endure in mistrust of PRA and its experts. PMID- 28890458 TI - The Life of a Renaissance Gunmaker: Bonaccorso Ghiberti and the Development of Florentine Artillery in the Late Fifteenth Century. AB - This article examines the technological development of artillery production in Florence during the last two decades of the fifteenth century, before and after the assimilation of the most efficient French ordnance into Italian warfare. The study starts from the notes, drawings, accounts, and guns produced by Bonaccorso di Vettorio Ghiberti (1451-1516), the heir of the foundry of his illustrious ancestor Lorenzo di Cione (1378-1455). Data have been collected from the historical archives of the Istituto degli Innocenti, from the Biblioteca Nazionale Centrale of Florence, and from the Florentine State Archive. This article demonstrates the existence of a lively and reactive war-related industry in Renaissance Italy, which was aware of new ideas and new techniques. The article highlights, moreover, the leading role of public demand in fostering military innovations. PMID- 28890457 TI - Healing Animals in an Antibiotic Age: Veterinary Drugs and the Professionalism Crisis, 1945-1970. AB - Between 1945 and 1970, the introduction of antibiotics in agriculture forced veterinarians to articulate the boundaries of their professional identity. While veterinarians welcomed the new aid to arrest infectious diseases of livestock, they worried as farmers took animal healing into their own hands without veterinary supervision, and resented the competition from retail outlets that sold the drugs. Veterinary antibiotics also set off heated debates within the field about whether the profession should position itself as preventers or healers of disease, debates that were akin to the kinds of professional discourses among physicians and pharmacists in the same period. By calling attention to the social context that helped facilitate an increasing reliance on the veterinary antibiotics, this article helps explain the sources of present-day overuse of such antibiotics in American agriculture. PMID- 28890460 TI - SHOT: Internationalization and the Art of Translation. PMID- 28890459 TI - James E. Webb, Technocracy, and the New Deal Roots of "Space Age Management". AB - abstract James E. Webb, NASA's Administrator during the hectic years preparing to send American astronauts to the Moon, has come to represent the pinnacle of postwar American optimism and support for large-scale, technically complex national undertakings. Success in 1969 lent credence to Webb's faith in "space age management." By the 1980s such "technocratic optimism" had precipitously declined. Since 1985, with the publication of Walter A. McDougall's Pulitzer Prize winning. . . The Heavens and the Earth, the rise and decline of such optimism has often been framed in the context of Cold War ideology and competition. In this study, aspects of Webb's vision are traced back prior to World War II. It argues that Cold War emphasis, although certainly crucial for understanding the institutions and practices Webb directed, nevertheless tends to mask the full extent of the 1980s rejection of long standing attitudes toward planning, expertise, and rigorous scientific and technical knowledge. PMID- 28890461 TI - Humans and Machines. PMID- 28890462 TI - The Documentary Impulse. AB - This article has two interconnected goals. It is, first of all, a review of the film The Land Beneath Our Feet, an exemplary documentary that combines the history of technology, science and technology studies, and environmental history in its exploration of the social, cultural, and natural consequences of the rubber industry's expansion in Liberia. The essay's larger purpose, however, is to explore the powerful role documentary film-making practices have to play in the development of new approaches in the history of technology. Here, an interview with historian and film co-director Gregg Mitman provides the framework for an expansive conversation about both the "documentary impulse" that he explores in his film and related written works, and also the growing role of audiovisual practice in scholarly work. PMID- 28890463 TI - "Useful Sciences"?: Ursula Klein, Nutzliches Wissen. PMID- 28890464 TI - Steam and Power: Andreas Malm, Fossil Capital. PMID- 28890465 TI - Hemodynamics of Pericardial Aortic Valves: Contemporary Stented versus Stentless Valves in a Matched Comparison. AB - PURPOSE: Hemodynamic performance of aortic valve bioprostheses is essential for reliable function and durability. So far, the supra-annularly implanted stentless Sorin Freedom Solo (SFS) demonstrated unsurpassed hemodynamic properties. As contemporary stented and externally mounted pericardial bioprostheses, like the Labcor Dokimos Plus (LDP), also improve hemodynamic performance, these types of valves were compared in this study. METHODS: A total of 218 patients, who underwent aortic valve replacement with the LDP or the SFS, were matched retrospectively 1:1 on variables affecting hemodynamic measurements: implanted valve size, age, sex, and body surface area (BSA). With matching tolerance for valve size and gender of 0%, for age and BSA of 5%, 57 patient-pairs were yielded. Operative data, clinical, and hemodynamic outcome were analyzed. RESULTS: Except for slightly higher left ventricular function and lower procedural times in the SFS group, preoperative, operative, and postoperative characteristics of patient-pairs did not differ significantly. Mean pressure gradients, effective orifice areas (EOAs), and indexed EOAs were comparable. Corresponding to valve sizes of 21, 23, 25, and 27 mm, the indexed EOAs of the LDP and SFS prostheses were 1.08 +/- 0.33, 0.92 +/- 0.19, 0.93 +/- 0.24, 0.99 +/- 0.13 cm2/m2 and 0.81 +/- 0.13, 0.92 +/- 0.28, 0.95 +/- 0.20, 1.04 +/- 0.27 cm2/m2, respectively. CONCLUSION: Contemporary stented and stentless pericardial bioprostheses showed excellent hemodynamic properties without significant differences in EOAs and indexed EOAs. PMID- 28890466 TI - Changes in Aortic Pulse Wave Velocity and the Predictors of Improvement in Arterial Stiffness Following Aortic Valve Replacement. AB - BACKGROUND: The interaction between valvular aortic stenosis (AS) and arterial stiffness, as well as the impact of aortic valve replacement (AVR) on arterial stiffness, remains unclear. In this study, we aimed to evaluate the degree of AS severity on non-invasive pulse wave velocity (PWV) measurements. We also searched whether the AVR procedure favorably affects PWV. METHODS: In all, 38 patients undergoing AVR for chronic AS were included. The degree of aortic stiffness was measured with PWV at both baseline and 6 months after AVR. Improvement in aortic stiffness was defined as the absolute decrease in PWV at 6 months compared to the baseline value. RESULTS: The study population had a mean age of 59 +/- 16 years, mean aortic gradient of 47.1 +/- 6.4 mmHg, and mean aortic valve area (AVA) index of 0.45 +/- 0.11 cm2 /m2 . Baseline PWV values correlated positively with the mean aortic gradient (r = 0.350, p = 0.031) and negatively with the AVA index (r = -0.512, p = 0.001). The mean PWV improved in 20 patients (53%) and worsened in 18 patients (47%). The baseline New York Heart Association (NYHA) class (odds ratio [OR] = 1.023, 95% confidence interval [CI] = 1.005-1.041, p = 0.041) and AVA index (OR = 1.040, 96% CI = 1.023-1.057, p = 0.028) emerged as the independent predictors of improvement in PWV following AVR. CONCLUSION: The severity of AS was significantly associated with baseline PWV. In general, the mean PWV did not change with AVR. Baseline NYHA class and the AVA index independently predicted PWV improvement following AVR. Since the change in PWV after AVR was polarized based on the patients' characteristics, such as preoperative NYHA functional class or AVA index, further studies are needed to confirm clinical significance of PWV change following AVR in severe AS patients. PMID- 28890467 TI - Prediction of arterial blood gas values from venous blood gas values in Asiatic black bears (Ursus thibetanus) anesthetized with intramuscular medetomidine and zolazepam-tiletamine. AB - The objective of this study was to measure differences between arterial and venous blood gas parameters and to evaluate whether arterial blood gas values can be estimated from venous blood in Asiatic black bears (ABBs). Twelve healthy captive ABBs (8 males and 4 females; 8-16 years; 76.8-220 kg) were included in this study. The bears were immobilized with medetomidine and zolazepam-tiletamine using a dart gun. Arterial and venous samples were collected simultaneously at 5 and 35 min after recumbency (5- and 35-min points). Partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), pH, bicarbonate (HCO3-), total carbon dioxide (TCO2), oxygen saturation of hemoglobin (SO2) and base excess (BEecf) were analyzed using a portable blood gas analyzer. There was no marked difference in measured and calculated variables over time in both venous and arterial blood except for PO2. However, arterial PO2, SO2 and pH were significantly higher and arterial PCO2, TCO2 and HCO3- were lower than those of venous samples at both 5- and 35-min points. In the regression analysis to estimate arterial values from venous values, PCO2, TCO2, HCO3-, BEecf and pH significantly showed over 0.45 in coefficient of determination value (R2), and there were little differences between actual and predicted arterial values. Although there were limits in venous gas values replaced those of arterial blood, if we could not get the arterial samples, the regression formulas for arterial values from venous blood in this study would be useful clinically, except for PO2 and SO2. PMID- 28890468 TI - Dominant Candidatus Accumulibacter phosphatis Enriched in Response to Phosphate Concentrations in EBPR Process. AB - Candidatus Accumulibacter phosphatis (Accumulibacter), which plays an important role in enhanced biological phosphorus removal in wastewater treatment plants, is phylogenetically classified into two major types (Types I and II). Phosphate concentrations affect the Accumulibacter community of the biomass enriched in treatment plants. Therefore, in the present study, Accumulibacter enrichments were conducted using a down-flow hanging sponge reactor under five conditions and a wide range of controlled phosphate concentrations in order to investigate how phosphate governs the community. We found that excessive phosphate levels inhibited Accumulibacter activity, that this inhibitory effect was greater for Type II. In addition, the affinity of Type II for phosphate was higher than that of Type I. Type IIA-B dominated at a phosphate concentration less than 5 mg P L 1, while Type IA was dominant at 50 and 500 mg P L-1. These patterns of enrichment may be explained by an inhibition kinetics model. PMID- 28890469 TI - Occurrence of Extended-Spectrum and AmpC-Type beta-Lactamase Genes in Escherichia coli Isolated from Water Environments in Northern Thailand. AB - Sixty-eight cefotaxime-resistant Escherichia coli isolates were recovered from different water environments in Northern Thailand. Isolates were mostly resistant to ceftazidime and aztreonam (>90%). The most common extended-spectrum beta lactamase-encoding gene was blaCTX-M-group 1 (75%) followed by blaCTX-M-group 9 (13.2%). The co-existence of blaCTX-M and AmpC-type beta-lactamase genes was detected in 4 isolates (5.9%). Two E. coli isolates carrying blaCTX-M from canal and river water samples belonged to the phylogenetic group B2-ST131, which is known to be pathogenic. This is the first study on blaCTX-M and blaCMY-2-carrying E. coli and the emergence of ST131 from water environments in Thailand. PMID- 28890470 TI - Circulating ANGPTL2 Levels Increase in Humans and Mice Exhibiting Cardiac Dysfunction. AB - BACKGROUND: Recently, it was reported that angiopoietin-like protein 2 (ANGPTL2) secreted from a pathologically stressed heart accelerates cardiac dysfunction in an autocrine/paracrine manner, and that suppression of ANGPTL2 production in the heart restored cardiac function and myocardial energy metabolism, thereby blocking heart failure (HF) development. Interestingly, circulating ANGPTL2 concentrations reportedly increase in HF patients, suggesting a possible endocrine effect on cardiac dysfunction. However, it remains unclear why circulating ANGPTL2 increases in those subjects and whether circulating ANGPTL2 alters cardiac function in an endocrine manner.Methods and Results:It was found that circulating ANGPTL2 levels are positively correlated with left atrial diameter and pulmonary capillary wedge pressure, and are inversely proportional to the percent of ejection fraction in patients with dilated cardiomyopathy. Furthermore, in mice, circulating ANGPTL2 concentrations increased as HF developed following transverse aorta constriction (TAC), and were inversely correlated with the percent of fractional shortening. Interestingly, although circulating ANGPTL2 concentrations significantly increased in transgenic mice overexpressing keratinocyte-derived ANGPTL2, no pathological cardiac remodeling was seen. Furthermore, it was observed that there was no difference in HF development between transgenic mice and controls following TAC surgery. CONCLUSIONS: Circulating ANGPTL2 levels increase in subjects experiencing cardiac dysfunction. However, circulating ANGPTL2 does not promote cardiac dysfunction in an endocrine manner, and increased levels of circulating ANGPTL2 seen during HF are a secondary effect of increased ANGPTL2 secretion from stressed hearts in HF pathologies. PMID- 28890471 TI - Precarious Employment Is Not Associated with Increased Depressive Symptoms: A Cross-Sectional Study in Care Service Workers of Japan. AB - Some epidemiological studies with a large number of subjects, like a national health study, reported that precarious employment was associated with increased depressive symptoms, but this hypothesis may not be applicable to precarious workers of all industry types. We examined the association between precarious employment and depressive symptoms in light of work-related stress in care work environments. The self-administered questionnaire, composed of the Job Content Questionnaire based on the demand-control-support model and the Center of Epidemiological Studies Depression Scale (CES-D), was distributed, and a total of 1,338 permanent and 531 precarious employees responded to it with complete forms. In the precarious employees, scores of CES-D, job demand and job control were lower and supervisor support score was higher compared with the permanent employees, though there was no significant difference in the proportion of CES-D score >=16 between the two groups. Multivariate analysis with adjustment for possible confounders revealed that increased depressive symptoms were associated with low coworker support in the precarious employees and with high demand and low control at work, low support from supervisors and coworkers in the permanent employees. However, precarious employment was not significantly associated with depressive symptoms in the male or female employees. In conclusion, our results do not support the above hypothesis at least in care service workers. Such a hypothesis should be verified in employees of each industry separately. Instead, coworker support within each workplace appears to be important for the preventive strategy of depression in workers including precarious employees. PMID- 28890472 TI - Ocular abnormalities associated with hypovitaminosis A in Hanwoo calves: a report of two cases. AB - This study reports on two Hanwoo (a native Korean breed of cattle) calves, a 3- and 6-month-old presenting with diarrhea, anorexia and blindness. Ophthalmoscopic examination revealed bilateral papilledema in both calves. Reverse-transcription polymerase chain reaction tests for bovine viral diarrhea virus, rotavirus and coronavirus were all negative. The levels of serum vitamin A in the two affected calves were 0.317 ug/dl and 0.481 ug/dl, respectively. These values are much lower than the normal vitamin A levels; therefore, the calves were diagnosed with hypovitaminosis A. PMID- 28890473 TI - New psychotropic substance abuse and its regulation. PMID- 28890474 TI - Changes in the prevalence of new psychoactive substances and their legal status in Japan. PMID- 28890475 TI - Evaluation of harmful effects of new psychoactive substances: current status and issues. PMID- 28890477 TI - Current status and promising future of nasal drug delivery. PMID- 28890476 TI - Old and new inflammation and infection hypotheses of Alzheimer's disease: focus on Microglia-aging for chronic neuroinflammation. PMID- 28890478 TI - Pharmacological properties and clinical efficacy of Ximency(r) Combination Tablets. PMID- 28890479 TI - RNA toxicity and RAN translation in repeat expansion disorders. PMID- 28890480 TI - Effect of treatment with epoprostenol and endothelin receptor antagonists on the development of thyrotoxicosis in patients with pulmonary arterial hypertension. AB - Thyroid disease is known to be associated with pulmonary arterial hypertension (PAH). We investigated the prevalence of thyroid disease in patients with idiopathic PAH (IPAH) or heritable PAH (HPAH), and the factors affecting the pathogenesis of thyroid disease. We retrospectively evaluated 59 patients with IPAH or HPAH who had been diagnosed with PAH before the age of 20 years. Thyrotoxicosis was detected in 12 of the 59 patients (6 patients with Graves' disease, 3 with hashitoxicosis, and 3 with silent thyroiditis) after the start of PAH treatment. The proportion of patients who received epoprostenol in the thyrotoxicosis group was significantly higher than that in the euthyroid group (12/12 vs. 27/47, p=0.015). In the 39 patients treated with epoprostenol, the proportion of patients who received combination therapy with epoprostenol and an endothelin receptor antagonist (ERA) in the thyrotoxicosis group was significantly lower than that in the euthyroid group (5/12 vs. 23/27, p=0.016). Logistic regression analysis revealed that thyrotoxicosis development was significantly associated with administration of epoprostenol (odds ratio [OR] 8.22, 95% confidence interval [CI] 1.26-53.74, p=0.028) and non-administration of ERA (OR 5.33, 95% CI 1.29-22.06, p=0.021). The prevalence of thyrotoxicosis was high in patients with IPAH or HPAH. The onset of thyrotoxicosis might be promoted by epoprostenol and inhibited by ERA. PMID- 28890481 TI - Free testosterone concentration is inversely associated with markers of liver fibrosis in men with type 2 diabetes mellitus. AB - The association between serum testosterone level and liver fibrosis in patients with non-alcoholic fatty liver disease is unclear. To clarify this association, we investigated the relationship between serum free testosterone concentration and markers of liver fibrosis in men with type 2 diabetes mellitus but no obvious features of alcohol consumption. This retrospective observational cross-sectional study enrolled 248 men with type 2 diabetes mellitus. The FIB-4 index was measured as a marker of liver fibrosis, and multiple linear regression analysis was performed to examine its association with serum free testosterone concentration. In addition, the 7S domain of type IV collagen (IV-7S) was examined in 140 of the 248 patients. The mean free testosterone concentration was 10.6 +/- 6.8 pg/mL and the means of the FIB-4 index and IV-7S were 1.64 +/- 1.19 and 4.02 +/- 1.11 ng/mL, respectively. After adjusting for all relevant variables, serum free testosterone concentrations were inversely associated with both the FIB-4 index and IV-7S (beta; -0.28, P < 0.0001, and beta; -0.28, P = 0.002, respectively). Measuring serum free testosterone concentrations in men with type 2 diabetes mellitus may help to predict progression to advanced liver disease. Identifying patients at risk may help to prevent the development of cirrhosis and hepatocellular carcinoma. PMID- 28890482 TI - The relationship between chronic kidney function and homeostasis model assessment of insulin resistance and beta cell function in Korean adults with or without type 2 diabetes mellitus. AB - The present study was conducted to assess the relationship between chronic kidney disease (CKD) and the homeostasis model assessment of insulin resistance (HOMA IR) and beta cell function (HOMA-B) in Korean adults with or without type 2 diabetes mellitus (T2DM). This study included 5,188 adults aged 20 or older using the 2015 Korea National Health and Nutrition Examination Survey (KNHANES) data, which represents national data in Korea. A covariance test adjusted for covariates was performed for HOMA-IR and HOMA-B in relation to CKD. The present study has several key findings. First, in T2DM, HOMA-IR (p = 0.035) was higher in the CKD group than in the non-CKD group after adjusting for the related variables but HOMA-B (p = 0.141) was not significant. Second, in non-T2DM, HOMA-IR (p = 0.163) and HOMA-B (p = 0.658) were not associated with CKD after adjusting for the related variables (except age). However, when further adjusted for age, HOMA IR (p = 0.020) and HOMA-B (p = 0.006) were higher in the CKD group than in the non-CKD group. In conclusion, insulin resistance was positively associated CKD with in Korean adults with or without T2DM. Beta cell function was positively associated CKD with in Korean adults without T2DM but not in Korean adults with T2DM. PMID- 28890483 TI - Ligand Exchange Reactions of a Monomeric Zirconium Carbonate Complex with Carboxylic Acids Studied by Extended X-ray Absorption Fine Structure, UV Absorption and Raman Spectrophotometry. AB - Ligand exchange reactions of a monomeric zirconium carbonate complex with carboxylic acids were studied by means of extended X-ray absorption fine structure (EXAFS), UV absorption spectrophotometry and Raman spectrometry. Three carboxylic acids, gluconic acid, and L-tartaric acid and citric acid, which are mono-, di- and tri-carboxylic acids, respectively, were employed in this study. These three carboxylic acids gave different spectral signatures and concentration dependences, respectively. In the gluconic acid system, the peaks on Fourier transform of EXAFS spectrum and Raman spectrum caused by carbonate ion coordinating to zirconium atom were obviously decreased with increasing gluconic acid concentration compared to the other two carboxylic acid systems. This indicates the high association ability of gluconic acid to zirconium, which was revealed by UV spectrophotometric analysis. PMID- 28890484 TI - Electromagnetophoretic Micro-convection around a Droplet in a Capillary. AB - The electromagnetophoretic behavior of organic droplets in an electrolyte solution was investigated in a silica capillary cell using a superconducting bulk magnet (3.5 T) and a magnetic circuit (2.7 T). The initially dispersed emulsion droplets of dodecane migrated to the wall of the capillary, responding to the direction of an electric current, and coalesced to form smaller and larger droplets after some repeated migrations. When the electric current was applied continuously, the larger droplets became arranged with regular intervals on the wall, and smaller droplets rotated around the larger droplets. These interesting behaviors were analyzed while taking into account the local electric current density determined by the flow velocity of the ionic current around a droplet, which was lowest on the electrode sides of the droplet. The difference in the local electric current density generated the Lorentz-force difference in the medium, which lead to local micro-convection around the droplet, and also the alignment of larger droplets by a repelling effect between the adjacent micro convections. PMID- 28890485 TI - Platinum-coated Core-Shell Gold Nanorods as Multifunctional Orientation Sensors in Differential Interference Contrast Microscopy. AB - We characterized the optical properties of single platinum-coated core-shell gold nanorods (Pt-AuNRs) under dark-field (DF) and differential interference contrast (DIC) microscopy. Furthermore, we examined their potential use as multifunctional orientation probes. Longitudinal surface plasmon resonance damping was observed for single Pt-AuNRs due to Pt metals coated on the AuNR surface under single particle scattering spectroscopy. Despite the strong plasmon damping with a much decreased scattering intensity, DIC microscopy allowed us to detect single Pt AuNRs with much higher sensitivity. We found polarization-dependent DIC images and intensities of single Pt-AuNRs, which allowed us to determine their orientation angle under DIC microscopy. Therefore, we report that single Pt-AuNRs can be used to develop multifunctional orientation probes under DIC microscopy. PMID- 28890486 TI - Determination of Eleven Organophosphorus Pesticide Residues in Textiles by Using HPLC-HRMS. AB - The overuse of organophosphorus pesticides on cotton production is a big concern in China today. Therefore, developing methods for the rapid screening and confirming of pesticide residues in textiles has become a top public health security priority. Here, a method was established for the rapid screening and quantifying of 11 kinds of organophosphorus pesticides (ethoprophos, coumaphos, profenofos, diazinon, ethion, parathion, phosalone, quinalphos, dicrotophos, azinphos methyl, and tribuphos) in textiles by high-performance liquid chromatography high-resolution mass spectrometry (HPLC-HRMS). Rapid screening and quantifying could be completed by using software of Peakview and MultiQuant. Samples were extracted by the method of modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) and analyzed in the positive mode with MS detection. The results showed that the limits of detection were between 0.1 and 5.0 ng g-1, with correlation coefficients above 0.9990. The recoveries were in the range of 70.3 - 109.8%, with relative standard deviations from 5.1 to 16.4%. This method is accurate and simple, which can be used in the rapid screening and quantitative analysis of 11 kinds of organophosphorus pesticides in textiles. PMID- 28890487 TI - Quantitative Measurement of Protein Using Metal Mesh Device. AB - Biosensing of protein adsorption with metal mesh device (MMD) was investigated by computational calculations and experiments. Electromagnetic field computation was carried out with a single unit cell of MMD. Equivalent circuit model of MMD on the single unit cell was assumed, and the biosensing with MMD was analyzed in detail by computational calculation and experimental measurements. The dip frequency of MMD was shifted by adsorption of protein on MMD. The shift of dip frequency of MMD was proportional to the amount of protein adsorption. The sensitivity of MMD biosensing was dependent on the microstructure of MMD, and proportional to the square of the dip frequency. The refinement of MMD structure can improve the sensitivity of protein detection. PMID- 28890488 TI - Optimization of Experimental Parameters for the Performance of Solid-state Dye sensitized Solar Cells. AB - The effects of various sample parameters for solid-state dye sensitized solar cells were studied with carrier dynamics measurements and electrochemical measurements. Although many parameters and processes have been decided based on the experience of researchers, the chemical and physical reasons for the selections have not been clarified. We studied the effect of the generally utilized materials and processing such as the blocking layer, titanium oxide thickness, surface treatment, and the selection of dyes and hole transfer materials. Based on our findings, we were able to rationally optimize the structure of the solid-state dye sensitized solar cells in terms of cell performance or the lifetime of charge carriers. PMID- 28890489 TI - Simultaneous Determination of 19 Plant Growth Regulator Residues in Plant originated Foods by QuEChERS and Stable Isotope Dilution-Ultra Performance Liquid Chromatography-Mass Spectrometry. AB - In this study, a highly sensitive and fast method of QuEChERS (acronym of quick, easy, cheap, effective, rugged, safe) combined with isotope dilution-ultra performance liquid chromatography coupled to tandem mass spectrometry was developed for the simultaneous determination of 19 plant growth regulators in plant-originated foods. The samples were initially extracted with acetonitrile containing 1% acetic acid and then the QuEChERS method was applied after the pH value was adjusted to 5.5 - 6.0, using 3-indolepropionic-d2 acid and forchlorfenuron-d5 as internal standard. The targeted 19 plant growth regulators were separated on an HSS T3 column using acetonitrile: 5 mmol/L ammonium acetate as the mobile phase. Quantitative results were based on multiple reaction monitoring mode after ionization in positive and negative electrospray ionization mode. Good linearity was achieved within a wide range and all the correlation coefficients were greater than 0.997. The limit of quantification was 0.060 - 6.0 MUg/kg. Rate of recovery and relative standard deviation were 72.3 - 115.8 and 1.78 - 5.32%, respectively. The method was successfully applied to measure 19 plant growth regulator residues in 280 plant-originated commercial foods collected from local supermarkets in China. Twelve plant growth regulators were found in some of the analyzed samples. PMID- 28890490 TI - Time- and Space-resolved Optical Diagnostics for Discharge Plasmas Separately Formed in Aqueous Solution. AB - When high voltage is applied to a gap between electrodes in aqueous solution, a discharge plasma is generated that connects the edges of the facing electrodes. When the width of the gap between the electrodes is extended to more than several millimeters, the plasma is separated into two and they are localized at the vicinities of the edges of the anode (+plasma) and cathode (-plasma). Although they are expected to supply characteristic reaction fields, the properties of the plasmas, such as electron number density and temperatures of transient species, have not yet been clarified. In the present study, a time- and space-resolved emission spectrometer with a discharge cell was developed for optical diagnostics of the +plasma and -plasma separately. The electron number density for the +plasma was obviously lower than that for the -plasma. The difference in the electron number density should result from the difference in the ionization energy of the cathode materials. From the temporal evolutions of the emissions from the components, the emissions from the -plasma were sustained for about 0.5 MUs after the decay of the applied voltage, probably due to the large number of free electrons in the -plasma. It is also clarified that hydroxyl radicals are effectively generated by the collisions between cations deriving from water and low-energy free electrons in the +plasma. The wide-gap in-solution discharge supplies two plasmas simultaneously with different properties. For plasma reactions, one plasma with suitable properties can be selected. PMID- 28890491 TI - Low-temperature Electronic Paramagnetic Resonance Measurements of TEMPO and 4 Hydroxy-TEMPO Benzoate for Purity Analyses by the Effective Magnetic-moment Method. AB - The purities of two high-purity organic compounds with a nitroxyl radical moiety were quantified based on their free-radical content using the effective magnetic moment method. Magnetic moments were measured and X-band electron paramagnetic resonance (EPR) spectra were obtained using a superconducting quantum interference device and X-band EPR spectrometer, respectively, over a wide temperature range of near-room temperature to near-liquid-helium temperature. Concerning measurements of effective g-values using an EPR spectrometer, both the sweep direction and sweep speed were taken into account to obtain accurate g values. The purities of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and 4 hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl benzoate (4-hydroxy-TEMPO benzoate) were close to 1 kg kg-1 with relative uncertainties of 1%, which represented improved values compared to those obtained by us previously. These results show a possibility for both compounds to act as reference materials in providing reliable quantification of free radicals per unit mass using this analytical method. PMID- 28890492 TI - A Quantitative Analysis of an Oil Component in an Emulsion by Multiphoton Ionization Mass Spectrometry. AB - The first quantitative analysis of an oil component in an emulsion was achieved by multiphoton ionization time-of-flight mass spectrometry (MPI-TOFMS). An oil-in water (O/W) emulsion was prepared. Styrene (0 - 5000 ng MUL-1) and Triton X-100 were used as the oil phase and the disperser, respectively. Toluene was employed as an internal standard. We obtained a series of mass spectra, and then constructed the time profiles for styrene and toluene. As a result, we found several spikes from both time profiles when measuring emulsions with higher concentrations of styrene. Moreover, the timing of spikes for toluene coincided with that of styrene. These results suggested the movement of toluene into styrene droplets in the prepared emulsion. Furthermore, we constructed calibration curves of styrene using both the absolute calibration curve method and an internal standard method. Linear calibration curves were obtained in the concentration range investigated in the present study; the coefficients of determination obtained by both methods were 0.9956 and 0.9986, respectively. PMID- 28890493 TI - Study on the Glass Transition Process of Polymer System Using Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy. AB - The change in the infrared spectrum of polymer samples with temperature and their differential scanning calorimetry (DSC) experimental results are analyzed. According to the van't Hoff equation at constant pressure, the changes in the absorbance ratio corresponding to high and low vibrational states are calculated, and the apparent enthalpy differences of the vibration energy states transformation of the characteristic group can be obtained. From the experimental results, we can find that characteristic vibration modes of a chemical group in a polymer are under the influence of the glass transition process of the polymer with a different extent. The characteristic vibration modes of the same chemical group behave differently due to the influence of the polymer system at which the chemical moiety is situated. PMID- 28890494 TI - Characterization of Inclusions in Evolution of Sodium Sulfate Using Terahertz Time-domain Spectroscopy. AB - The study of fluid inclusion is one of the important means to understanding the evolution of mineral crystals, and can therefore provide original information of mineral evolution. In the process of evolution, outside factors such as temperature and pressure, directly affect the number and size of inclusions, and thus are related to the properties of crystals. In this paper, terahertz time domain spectroscopy (THz-TDS) was used to detect sodium sulfate crystals with different growth temperatures, and absorption coefficient spectra of the samples were obtained. It is suggested that the evolution of sodium sulfate could be divided into two stages, and 80 degrees C was the turning point. X-ray diffraction (XRD) and polarizing microscopy were used to support this conclusion. The research showed that THz-TDS could characterize the evolution of mineral crystals, and it had a unique advantage in terms of crystal evolution. PMID- 28890495 TI - Kinetic Analysis of the Solvent Extraction of Cadmium(II) Complexes Using a Cadmium-deposited Recessed Microelectrode and Confocal Fluorescence Microscope. AB - Using a Cd-deposited microelectrode, an electrochemically generated Cd(II) ion in a micro-water phase was reacted with 5-octyloxymethyl-8-quinolinol (HC8Q) in 1,6 dichlorohexane. The fluorescence intensity of Cd(C8Q)2 near the water/oil interface (IF) was analyzed under a confocal fluorescence microscope. The rate of decrease of IF was independent of the HC8Q concentration and pH, but was influenced by the phase-boundary potential between the water and oil phases, suggesting that Cd(II) extraction is governed by Cd(C8Q)+ desorption at the interface. PMID- 28890496 TI - On-line Analysis of Catalytic Reaction Products Using a High-Pressure Tandem Micro-reactor GC/MS. AB - When a GC/MS system is coupled with a pressurized reactor, the separation efficiency and the retention time are directly affected by the reactor pressure. To keep the GC column flow rate constant irrespective of the reaction pressure, a restrictor capillary tube and an open split interface are attached between the GC injection port and the head of a GC separation column. The capability of the attached modules is demonstrated for the on-line GC/MS analysis of catalytic reaction products of a bio-oil model sample (guaiacol), produced under a pressure of 1 to 3 MPa. PMID- 28890498 TI - Quantum Dot-based Fluorescent Sensing. PMID- 28890499 TI - Time-resolved Fluorescent Detection for Glucose Using a Complex of Luminescent Layered Titanates and Enzymes. AB - Luminescent europium-doped layered titanates (Eu-TiOx) were synthesized and complexed with horseradish peroxidase (HRP) and glucose oxidase (GOx). The emission of a resultant Eu-TiOx/HRP/GOx complex decreased upon the addition of glucose in the presence of guaiacol. The emission decrease was dependent on the concentrations of glucose, and the detection limit for glucose was 3.1 MUM. The proposed system would be promising as a new detection method for glucose. PMID- 28890500 TI - Electrochemical Detection of Hydroxylamine via Au-Pt Alloy Nanoparticle-modified Single-walled Carbon Nanotube Electrodes. AB - In the present study, we developed an electrochemical sensor for highly sensitive detection of hydroxylamine using Au-Pt alloy nanoparticles. Au-Pt alloy nanoparticles were electrochemically deposited on a working electrode made of single-walled carbon nanotubes. The framework composition in the Au-Pt alloy nanoparticle was easily controlled by adjusting the Au3+:Pt4+ composition ratio in the precursor solution. Morphological and chemical characterizations of the resulting Au-Pt alloy nanoparticles were performed using field emission scanning electron microscopy, X-ray diffraction, and energy dispersion X-ray spectroscopy. When the Au3+:Pt4+ ratio in the precursor solution was 1:5, the ratio of Au:Pt atom in alloy nanoparticle was about 6:4. Au60Pt40 alloy nanoparticles were found to have the optimum synthetic ratio for hydroxylamine detection. The electrocatalytic performance of Au-Pt alloy nanoparticles in the presence of hydroxylamine was also characterized using cyclic voltammetry, differential pulse voltammetry, and chronoamperometry. In the chronoamperometric detection of hydroxylamine, the sensor exhibited a detection limit of 0.80 MUM (S/N = 3) and a high sensitivity of 184 MUA mM-1 cm-2. Moreover, the amperometric response of the sensor in 1 mM hydroxylamine was stable for a long time (450 s). Long-term stability tests showed that the current responses to hydroxylamine were 96, 91 and 85% of the initial signal value after storage for 5, 10, and 20 days, respectively. PMID- 28890501 TI - Novel Uniform Fe3O4 Hollow Spheres for Magnetic Solid-phase Extraction of Polycyclic Aromatic Hydrocarbons. AB - A novel magnetic absorbent based on Fe3O4 hollow nanospheres was developed for polycyclic aromatic hydrocarbons (PAHs) extraction. Fe3O4 hollow nanospheres were prepared by a one-pot facile solvothermal method and its structural properties were characterized by scanning electron microscope (SEM) and analyzer transmission electron microscopy (TEM). It was the first time to use hollow nanospheres which possess high special surface area for magnetic solid-phase extraction (MSPE). The extraction condition of Fe3O4 hollow nanospheres and its performance for PAHs was systematically investigated. Besides, its extraction performance also compared with bare Fe3O4 nanoparticles. The results indicated the structure with hollow and spherical Fe3O4 perform better enrichment ability than that with solid and amorphous ones. The developed MSPE coupled with HPLC method shows good linearity (0.1 - 5 ng/mL) and low detection limits (2.5 - 10 pg/mL) for six PAHs. It also has been executed for the analysis of environmental samples, with recoveries in the range of 84.6 - 97.8%. PMID- 28890502 TI - Close Monitoring of eGFR Should Be Performed in HIV-Infected Patients Aged over 37 Years. AB - Chronic kidney disease (CKD) has been shown to be a poor prognostic factor in HIV patients. This study aimed to identify risk factors in HIV-infected patients with early decline in renal function or an estimated glomerular filtration rate (eGFR) less than 90 mL/min/1.73 m2. The study was retrospectively conducted at Panyananthaphikkhu Chonprathan Medical Center, Thailand. The inclusion criteria were HIV-infected adult patients who were treated at the hospital's HIV clinic and whose eGFR levels at the first visit had been evaluated. Eligible patients were categorized according to their eGFR level being lesser or greater than 90 mL/min/1.73 m2. Multivariate logistic analysis was performed to evaluate the association of risk factors with an eGFR of less than 90 mL/min/1.73 m2. There were 301 HIV-infected patients included in the study. Of those, 89 patients (29.57%) had an eGFR of less than 90 mL/min/1.73 m2. Age was the only significant risk factor associated with an eGFR of less than 90 mL/min/1.73 m2 with an adjusted odds ratio of 1.072 (95% confidence interval: 1.015-1.132). Age of over 37 years predicted an eGFR of less than 90 mL/min/1.73 m2 as a risk factor in HIV infected patients, with a sensitivity of 80.9% and specificity of 34.91%. Age was independently associated with eGFRs of less than 90 mL/min/1.73 m2 in HIV infected patients. Close monitoring of eGFR should be performed in HIV-infected patients aged over 37 years. PMID- 28890503 TI - Spatial Clustering of Severe Hand-Foot-Mouth Disease Cases on Hainan Island, China. AB - The incidence of severe hand-foot-mouth disease (HFMD) in Southeast and East Asia has increased in recent years. This study explored spatial clusters of the incidence and proportion of severe HFMD cases on Hainan Island, where the prevalence and mortality of HFMD were the highest in China during 2011. A spatial autocorrelation statistic (Anselin's Local Moran I) was calculated for the Empirical Bayesian (EB)-smoothed dataset of severe HFMD cases. Significant spatial clusters were detected for both the incidence and proportion of severe HFMD cases. Population density was higher in spatial clusters with a high proportion of severe HFMD cases among total HFMD cases. We speculate that a higher proportion of severe HFMD cases were diagnosed in densely populated townships. This should be considered when analyzing the HFMD database of Hainan Island. PMID- 28890504 TI - An Alarmingly High Proportion of HIV-1 Isolates Carrying Mutations Corresponding to Resistance to Antiretroviral Drugs among HIV-Positive High-Risk Groups in Central Vietnam: a Substudy of the National Sentinel Survey. AB - We studied the prevalence of HIV drug resistance among high-risk groups such as injecting drug users (IDUs), female sex workers (FSWs), and men having sex with men (MSM) in central Vietnam. We used HIV-positive blood samples from 2012-2013 sentinel surveillance surveys. Study subjects were screened for HIV infection by standardized screening assays, and the HIV-positive samples were further tested for HIV viral load and drug-resistance mutations (DRMs) by in-house assays. DRMs were identified using the Stanford University online sequence analysis tool. Their risk behaviors were also investigated. During the study period, 6,016 (high risk) subjects were screened, and 97 tested positive for HIV infection (IDUs: n = 63, 3.0%; FSWs: n = 24, 0.9%; and MSM: n = 10, 1.0%). Ninety-two of the 97 samples (45 from 2012 and 47 from 2013) were available for further testing. HIV RNA was detected in 56 (60.9%) of the 92 samples, and drug resistance genotyping was successfully performed on 40 (71.4%) samples. All these isolates were subtype CRF01_AE, except for 1 (2.5%) IDU whose HIV belongs to subtype B. Thirteen individuals (32.5%) were carrying HIV with at least 1 DRM: 9 IDUs, 1 FSW, and 3 MSM. Thus, HIV seroprevalence among high-risk individuals in central Vietnam is low, but a high proportion of drug resistant HIV-1 isolates is observed in the high-risk group. PMID- 28890505 TI - A Case of Community-Acquired Pneumonia Due to Legionella pneumophila Serogroup 9 Wherein Initial Treatment with Single-Dose Oral Azithromycin Appeared Useful. AB - Legionella species are important causative pathogens for severe community acquired pneumonia (CAP). Most cases of Legionella pneumonia are due to Legionella pneumophila serogroup 1, and CAP due to L. pneumophila serogroup 9 is rare. A fourth case of CAP due to L. pneumophila serogroup 9 has been reported, and initial treatment using single-dose oral azithromycin appeared useful. Azithromycin or fluoroquinolone injection is usually recommended for the treatment of Legionella pneumonia, and no previous reports have shown the effectiveness of single-dose oral azithromycin. This case report is therefore valuable from the perspective of possible treatment for mild to moderate Legionella pneumonia using single-dose oral azithromycin. PMID- 28890506 TI - Sepsis Due to Chryseobacterium gleum in a Diabetic Patient with Chronic Obstructive Pulmonary Disease: a Case Report and Mini Review. PMID- 28890507 TI - Surveillance of Adenovirus Respiratory Infections in Children from Osaka, Japan. AB - Human adenovirus (HAdV) strains isolated from respiratory specimens of 139 children were analyzed to evaluate the endemic situation of HAdV infections in Osaka, Japan, between 2008 and 2015. The cases increased during spring and winter, and the infections were confirmed mainly in children aged <= 5 years, comprising 91.9% of the total population examined. Molecular typing of the isolates revealed that the most common types belonged to HAdV-B and -C. Co infection of HAdV-C1 and -C2 was also confirmed in a case. The median age of HAdV E cases was higher than that of the HAdV-B and -C cases. These results revealed age and seasonal distribution of respiratory HAdV infections in children from Osaka, and indicate that majority of these children might have acquired immunity through endemic HAdV infection before reaching school age. PMID- 28890508 TI - Does Helicobacter pylori Infection Play a Role in Susceptibility to Brucellosis? AB - Brucellosis is endemic in Iran. Several studies have shown that brucellosis is associated with other infectious diseases. This study aimed to determine the relationship between Helicobacter pylori (HP) and brucellosis. In this case control study, 100 patients with brucellosis as cases and 200 participants without brucellosis as controls were evaluated. To compare the prevalence of HP in the 2 groups, odds ratios and confidence intervals for every variable were analyzed using logistic regression models after adjustment for confounding factors. The results obtained in patients with brucellosis showed that fever, sweating, and joint pain were the most prevalent clinical symptoms. In addition, compared with the control group, there was a significant relationship between the IgM antibody to HP and brucellosis infection (estimated odds ratio 2.74; 95% CI: 1.5-4.9) (p = 0.001). Acute infection with HP was associated with brucellosis and increased the risk of brucellosis infection. PMID- 28890509 TI - Proposed Pharmacokinetic-Pharmacodynamic Breakpoint of Garenoxacin and Other Quinolones. AB - The pharmacokinetic-pharmacodynamic (PK-PD) breakpoints (BPs) of garenoxacin (GRNX) and other oral quinolones were calculated using Monte Carlo simulation (MCS) based on the distribution of changes in their plasma concentrations. PK-PD BPs of 400 mg once a day (QD) of GRNX for the free area under the curve/minimum inhibitory concentration (fAUC/MIC) for 30 strains of Streptococcus pneumoniae and 100 strains of gram-negative bacteria (G [-]) were 0.5 and 0.125 MUg/mL, respectively. PK-PD BPs of other quinolones for S. pneumoniae/G (-) were 1/0.25 MUg/mL for levofloxacin (LVFX) 500 mg QD, 0.5/0.125 MUg/mL for moxifloxacin (MFLX) 400 mg QD, 0.0625/0.0156 MUg/mL for sitafloxacin (STFX) 50 mg twice a day (BID) (100 mg QD), and 0.125/0.0313 MUg/mL for STFX 100 mg BID. We also investigated the hypothetical probability of target attainments (PTAs) of fAUC/MIC for community-acquired pneumonia (CAP) using MCS, in consideration of the isolation frequencies of the three main causative pathogens of CAP: S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. For hypothetical CAP in adults, PTA of fAUC/MIC was 100% with GRNX and MFLX, 96%-97% with STFX at 100 mg BID, 45%-46% with LVFX, and 53%-58% with STFX at 100 mg QD and 50 mg BID. Based on the PK-PD BP, GRNX showed higher fAUC/MIC than the other quinolones tested against the three main pathogens of respiratory infections. PMID- 28890510 TI - Circulating Genotypes of Dengue-1 Virus in South West India, 2014-2015. AB - Dengue is the most prevalent arboviral disease affecting humans, with tropical and subtropical regions having the highest risk of dengue virus infections. The clinical symptoms often range from mild fever to fever with hemorrhagic manifestations and shock. Since 2010, India has been witnessing a marked increase in the number of dengue virus serotype 1 (DENV-1) infections, apart from those of serotypes 2 (DENV-2) and 3 (DENV-3). The present study was undertaken to understand the circulating genotypes of DENV-1 in South West India, by sequencing the envelope gene of DENV-1 samples representative of the 2014-2015 time period. The extracted RNAs from dengue NS1 antigen ELISA-positive samples, archived at the APEX Referral Laboratory for Arboviruses (National Vector Borne Disease Control Programme, Manipal Centre for Virus Research), were used for the study. The currently circulating genotypes of DENV-1 identified from the study area belong to genotypes V and I. Multicentric laboratory-based studies analyzing the envelope gene of all dengue serotypes are required from endemic countries like India. PMID- 28890511 TI - The Antibacterial Effects of Antimicrobial Peptides OP-145 against Clinically Isolated Multi-Resistant Strains. AB - OP-145 is a synthetic antimicrobial peptide developed from the human cathelicidin LL-37. The purpose of this investigation was to evaluate the effect of the antimicrobial peptide OP-145 against clinically isolated drug-resistant strains. Ten methicillin-resistant Staphylococcus aureus (MRSA) strains were obtained from our hospital's clinical inspection center, and the activity of OP-145 on growth and biofilm formation of these strains was evaluated by colony counts and scanning electron microscopy. The antimicrobial peptide OP-145 showed significant antibacterial activity against 9 MRSA strains. For the biofilm experiments, MRSA counts in the biofilms decreased significantly after 24 h (P < 0.05). OP-145 strongly reduced growth and biofilm formation of clinically isolated drug resistant strains in vitro, and the use of this class of antimicrobial agents may be an important new approach in controlling bacterial infections. PMID- 28890512 TI - An Update on the Structure of Oxazolidinone Analogs and a Comparison with Linezolid in Terms of In Vitro and Intracellular Efficacy against Clinically Relevant Bacterial Species. AB - Oxazolidinones constitute a novel class of antimicrobials as inhibitors of bacterial ribosomal protein synthesis. In this study, we identified 15 novel oxazolidinone analogs with potent antituberculosis activities. Compounds sy124 and sy125 showed the best activity in vitro (better than that of the linezolid) against various clinically relevant bacterial species, including most Gram positive bacteria, Mycobacterium spp., and Helicobacter pylori. A cell-based assay indicated that these compounds have a strong ability to kill intracellular pathogens. Our results reveal that the newly identified compounds may be further developed as novel antimicrobial agents. PMID- 28890513 TI - Leptospirosis Cases in the Tokyo Metropolitan Area, Japan. AB - In Japan, 20-50 cases of leptospirosis are reported annually, typically involving farmers or returnees from tropical areas. Here, we report on 5 indigenous leptospirosis cases that occurred in the Tokyo urban area. All patients were men (mean age, 66.4 +/- 4.6 [SD] years) and presented with clinical features that included high fever, acute kidney injury, and jaundice. Three patients presented with pulmonary infiltration and ground-glass opacity on admission. Two of the 5 patients were intubated and underwent continuous hemodiafiltration. The mean length of hospitalization was 38.0 +/- 17.0 days, and all patients were treated successfully with antibiotics. Notably, all patients had a history of exposure to rats prior to becoming symptomatic, suggesting that exposure to rats is a risk factor for urban leptospirosis. Although rare, even in metropolitan areas, leptospirosis should be considered by physicians when patients present with severe sepsis, acute kidney injury, and a history of exposure to rats. PMID- 28890514 TI - Attack Rates of Norovirus and Campylobacter Food Poisonings that Cannot Be Represented by Numeric Constant but by Plotting the Attack Rate against the Number of Patients per Incident in Cartesian Coordinates. AB - In norovirus and Campylobacter food poisonings, the frequencies of the number of patients per incident and that of the number of eaters per incident followed a lognormal distribution, with medians of 12-27 and 23-48 for norovirus and 5-8 and 9-21 for Campylobacter food poisonings, respectively. The lognormal frequency distribution of eaters could be simulated by assuming that people find a dish more appealing if that dish has already been found to be appealing to others. The numbers of patients and eaters per incident were not necessarily inter correlated; the frequencies of the attack rates (number of patients/number of eaters) were distributed evenly from 0.01 to 1; that is, the attack rates of these food poisonings could not be represented by means and standard deviations. The frequency distributions of the attack rates were nevertheless not entirely disordered; plotting the attack rate against the number of patients in individual incidents produced fingerprint-like patterns that were repeatedly produced at the prefectural and national levels. PMID- 28890515 TI - High Prevalence of Campylobacter in Broiler Flocks is a Crucial Factor for Frequency of Food Poisoning in Humans. PMID- 28890516 TI - Molecular Characterization of Carbapenemase-Nonproducing Clinical Isolates of Escherichia coli (from a Thai University Hospital) with Reduced Carbapenem Susceptibility. AB - Twelve nonreplicate carbapenemase-negative ertapenem (ETP)-nonsusceptible (CNENS) Escherichia coli isolates obtained at a Thai university hospital between 2010 and 2014 were characterized and compared with 2 carbapenemase-producing E. coli isolates from the same hospital. Eight unique pulsed-field gel electrophoresis patterns were obtained. All the isolates produced CTX-M-15 beta-lactamase and 2 either coexpressed CMY-2 cephalosporinase or showed increased efflux pump activity. Amino acid sequence analysis revealed that an OmpF defect (in 7 isolates) due to mutations generating truncated proteins or an IS1 insertion was more prevalent than a defect in OmpC was (no truncated proteins detected). Seven out of 10 isolates possessing OmpC variants with any OmpF defect were weakly ETP resistant (minimum inhibitory concentrations [MICs] of 1-4 MUg/mL) and imipenem (IPM)- and meropenem (MEM)-susceptible (MICs 0.125-0.5 MUg/mL). Two isolates with ompC PCR-negative results and an OmpF defect showed higher carbapenem MICs (8-32, 1-8, and 1-4 MUg/mL for ETP, IPM, and MEM, respectively) with the highest MICs associated with the additional efflux pump activity. Both carbapenemase producers possessing CTX-M-15 and a porin background identical to that in the CNENS isolates showed ETP, IPM, and MEM MICs of 128-256, 8, and 2-32 MUg/mL, respectively. These findings suggest that a porin defect combined with CTX-M-15 production is the major mechanism of low carbapenem susceptibility among our CNENS isolates, which have potential to become strongly carbapenem-resistant because of additional carbapenemase or efflux pump activities. PMID- 28890517 TI - First Isolation of Human Parechovirus Type 4 in Yamagata, Japan. PMID- 28890518 TI - A Case of Dengue Fever Imported from Burkina Faso to Japan in October 2016. AB - Dengue fever remains underreported in Africa due to a lack of awareness among healthcare providers, the presence of other febrile illnesses, and insufficient laboratory testing. We present a case of dengue fever imported from Burkina Faso to Japan, where an outbreak of dengue was reported on October 18, 2016. Phylogenetic analysis revealed that the isolate from our patient belonged to a distinct cluster of sylvatic dengue viruses, suggesting that dengue viruses have been maintained in mosquitoes and human cycles in Burkina Faso for more than 30 years. PMID- 28890519 TI - Two Rare Cases of Wound Infections Caused by Trueperella bernardiae. AB - Trueperella bernardiae (T.bernardiae) is a gram-positive curved rod that is considered an uncommon pathogen involved in few infections. The true incidence of infections with this bacterium, and the clinical implications, remain unknown. We report 2 cases of wound infections in 2 patients who underwent different surgical procedures, although in the second case the microorganism was isolated in mixed culture. Culture of wound secretions resulted in isolation of T. bernardiae. Treatment was performed and resolution of the infections was documented. PMID- 28890520 TI - Biofilm formation and determination of minimum biofilm eradication concentration of antibiotics in Mycoplasma hyopneumoniae. AB - The study was aimed to investigate biofilm forming ability of Mycoplasma hyopneumoniae and to determine the minimum biofilm eradication concentrations of antibiotics. Biofilm forming ability of six strains of M. hyopneumoniae was examined using crystal violet staining on coverslips. The results demonstrated an apparent line of biofilm growth in 3 of the strains isolated from swine with confirmed cases of enzootic pneumonia. BacLight bacterial viability assay revealed that the majority of the cells were viable after 336 hr of incubation. Moreover, M. hyopneumoniae persists in the biofilm after being exposed to 10 fold higher concentration of antibiotics than the minimum inhibitory concentrations in planktonic cells. To the best of our knowledge, this is the first report of biofilm formation in M. hyopneumoniae. However, comprehensive studies on the mechanisms of biofilm formation are needed to combat swine enzootic pneumonia caused by resistant M. hyopneumoniae. PMID- 28890521 TI - Effect of burdock extract on physical performance and physiological fatigue in mice. AB - : Burdock (BD) is a common vegetable with many pharmacological properties. However, few studies have examined the effect of BD on exercise performance and physical fatigue. We aimed to evaluate the potential beneficial effects of BD on fatigue and ergogenic functions following physical challenge in mice. METHODS: Male ICR mice were divided into four groups to receive either vehicle, or BD at 348.5, 697 or 1,742.5 mg/kg/day, by daily oral gavage for 4 weeks. Exercise performance and fatigue were evaluated from forelimb grip strength, exhaustive swimming time, and post-exercise levels of physical fatigue-related biomarkers serum lactate, ammonia, glucose, and creatine kinase (CK). RESULTS: BD supplementation elevated endurance and grip strength in a dose-dependent manner. It also significantly decreased lactate, ammonia, and CK levels after physical challenge. In addition, BD supplementation had few subchronic toxic effects. CONCLUSIONS: Supplementation with BD has a wide spectrum of bioactive effects, including health promotion, performance improvement, and fatigue reduction. PMID- 28890522 TI - Characterization of the testicular regeneration potential in premature cockerels. AB - Previous studies have shown that grafted neonatal chicken testicular tissue can develop and produce functional sperm; however, it was unclear whether regenerative processes or proportional growth caused the re-appearance of spermatogenic tissue. We dissociated testicular tissues, performed subcutaneous auto-transplantation of the re-aggregated cells to castrated cockerels, and monitored the post-surgery development of these transplanted aggregates. We found that these transplanted cell aggregates experienced compensatory growth in the form of a 300-fold increase in size, rather than the 30-fold increase observed in normal testis development. Further, these dissociated testicular cell aggregates restored seminiferous tubule structure and were able to produce testosterone and motile sperm. Therefore, we concluded that the dissociated testicular cells from 11-week-old cockerels retained a strong regenerative potential, as they exhibited compensatory growth, restored destroyed structure, and sustained spermatogenesis. PMID- 28890523 TI - Nation-Wide Implementation of Disaster Medical Coordinators in Japan. AB - In the 2011 Great East Japan Earthquake (GEJE), successful medical and public health coordination by pre-assigned disaster medical coordinators saved many affected people, though the coordination itself had difficulties. This study aims to clarify the implementation and the challenges of disaster medical coordinators in Japan. We performed questionnaire surveillance in 2012 and 2014 to all prefectural government on assignment of disaster medical coordinators, their expected roles and supporting system. Out of all 47 prefectures, assignment or planning of disaster medical coordinators jumped up from four (8.5%) to 43 (91.5%) by the end of 2015. The most expected role is the coordination with Japan Disaster Medical Assistant Team (DMAT) and with other early responders. The evacuation center management, public health coordination and preparedness before disaster are less frequently expected. The supporting materials, human resource, and tools for communication vary according to the prefecture. Successful implementation requires the effort of health and governmental stakeholders. The coordination between prefectural and local coordinators and the coordination between medical and public health authorities still need to be improved. The roles of disaster medical coordinators depend on the local context and types of hazards. Education and training to build fundamental capacity is necessary. In conclusion, Japanese disaster medical system rapidly implemented disaster medical coordinator after GEJE. Their roles and standardization are challenging, but education, training and systematic support by the local government will enhance the effective preparedness and response of the health sector in disasters. PMID- 28890524 TI - Diagnosis and Management of Patients with Paroxysmal Sympathetic Hyperactivity following Acute Brain Injuries Using a Consensus-Based Diagnostic Tool: A Single Institutional Case Series. AB - Paroxysmal sympathetic hyperactivity (PSH) is a distinct syndrome of episodic sympathetic hyperactivities following severe acquired brain injury, characterized by paroxysmal transient fever, tachycardia, hypertension, tachypnea, excessive diaphoresis and specific posturing. PSH remains to be an under-recognized condition with a diagnostic pitfall especially in the intensive care unit (ICU) settings due to the high prevalence of concomitant diseases that mimic PSH. A consensus set of diagnostic criteria named PSH-Assessment Measure (PSH-AM) has been developed recently, which is consisted of two components: a diagnosis likelihood tool derived from clinical characteristics of PSH, and a clinical feature scale assigned to the severity of each sympathetic hyperactivity. We herein present a case series of patients with PSH who were diagnosed and followed by using PSH-AM in our tertiary institutional medical and surgical ICU between April 2015 and March 2017 in order to evaluate the clinical efficacy of PSH-AM. Among 394 survivors of 521 patients admitted with acquired brain injury defined as acute brain injury at all levels of severity regardless of the presence of altered consciousness, including traumatic brain injury, stroke, infectious disease, and encephalopathy, 6 patients (1.5%) were diagnosed as PSH by using PSH AM. PSH-AM served as a useful scoring system for early objective diagnosis, assessment of severity, and serial evaluation of treatment efficacy in the management of PSH in the ICU settings. In conclusion, critical care clinicians should consider the possibility of PSH and can use PSH-AM as a useful diagnostic and guiding tool in the management of PSH. PMID- 28890525 TI - Cognitive Development After Kawasaki Disease - Clinical Study and Validation Using a Nationwide Population-Based Cohort. AB - BACKGROUND: This purpose of this study was to investigate whether Kawasaki disease (KD) increases the risk of cognitive impairment. In this clinical study, cognitive profiles were compared between KD patients, control subjects, and a nationwide population-based cohort to determine the potential correlation between KD and a subsequent diagnosis of an intellectual disability.Methods and Results:The clinical study consisted of 168 KD patients (mean age 5.6 years, 62.5% male) and 81 healthy controls (mean age 6.4 years, 54.3% male). The nationwide cohort consisted of 4,286 KD patients and 50,038 controls retrieved from the Taiwan National Health Insurance Research Database between 1996 and 2000. The clinical study sample revealed no significant difference in any developmental index or cognitive function between KD patients and controls across various age groups (P>0.05). In the nationwide cohort, Cox regression analysis showed that a diagnosis of KD did not significantly affect the likelihood of developing an intellectual disability (adjusted hazard ratio 0.87, 95% confidence interval 0.68-1.11). CONCLUSIONS: Both the clinical data and the population-based cohort consistently demonstrated that KD does not increase a child's risk of future cognitive impairment. Although the outcome of the present study is negative, caregivers and patients with KD can be reassured that KD will have no effect on developmental milestones or cognitive function later in life. PMID- 28890526 TI - Five-Year Clinical Outcomes After Drug-Eluting Stent Implantation Following Rotational Atherectomy for Heavily Calcified Lesions. AB - BACKGROUND: Percutaneous coronary intervention for heavily calcified lesions requires rotational atherectomy (RA). Long-term clinical outcomes after drug eluting stent (DES) implantation following (RA) for heavily calcified lesions remain unclear. We assessed 5-year clinical outcomes after DES implantation following RA.Methods and Results:Between March 2006 and September 2011, 219 consecutive patients with 219 lesions treated with DES following RA, were retrospectively enrolled. The cumulative 5-year incidence of target-lesion revascularization (TLR) and definite stent thrombosis (ST) were assessed. The cumulative incidence of TLR within (<=) the first year was 18.6%. Late TLR beyond (>) 1 year continued to occur at 1.9% per year without a decrease in the rate (5 year incidence, 26.0%). The cumulative incidence of definite ST at 30 days, 1 and 5 years was 0.9%, 2.3% and 2.9%, respectively. The annual rate of definite ST beyond 1 year was 0.15%. On multivariate analysis, the significant predictor of TLR within 1 year was use of first-generation DES (hazard ratio [HR], 2.09; 95% CI: 1.10-4.03, P=0.02) and that of TLR beyond 1 year was hemodialysis (HR, 3.29; 95% CI: 1.06-10.55, P=0.04). CONCLUSIONS: Late TLR beyond 1 year continued to occur up to 5 years at a constant annual incidence, whereas very late ST was rare. Careful long-term clinical follow-up is continually needed in patients who have already received DES following RA for heavily calcified lesions. PMID- 28890527 TI - Microvascular Angina - Long-Term Exercise Stress Test Follow-up. AB - BACKGROUND: A sizeable proportion of patients with primary stable microvascular angina (MVA; exercise-induced angina, positive exercise stress test [EST], normal coronary arteries) have recurrent symptoms during follow-up. There have been no previous studies, however, on the long-term results of EST and their correlation with symptom outcome.Methods and Results:Follow-up EST was performed in 71 MVA patients at an average of 16.2 years (range, 5-25 years) from the first EST. Angina status was assessed on weekly frequency of angina episodes and nitroglycerin consumption and by whether symptoms had worsened, improved, or remained unchanged over time. At follow-up EST, 41 patients (group 1) had exercise-induced ischemia, whereas 30 patients (group 2) had negative EST. Compared to group 2, group 1 patients more frequently had exercise-induced dyspnea, and had a greater maximum ST-segment depression and a lower coronary blood flow response to adenosine and cold pressor test, but group 2 patients had a more frequent history of rest angina. No differences between the 2 groups were found at follow-up in angina status or change in symptom status during follow-up. CONCLUSIONS: Electrocardiogram results improve significantly in a sizeable proportion of patients with MVA. Changes in EST results, however, were not associated with clinical outcome. PMID- 28890528 TI - Association between economic status and discharge destination among elderly patients from acute care hospitals. AB - Objective The aim of this study was to investigate the association between economic status and discharge destination of elderly patients from acute care hospitals.Method We conducted a case-control study using data from a survey of elderly discharged patients conducted under the subsidy program of the Japanese Ministry of Health, Labour and Welfare. The questionnaires were mailed to 1,068 acute care hospitals located in the Kanto and Kansai region. The survey asked medical social workers or nurses, who were responsible for the discharge planning, to answer questions about the discharge of elderly patients from their hospitals. The survey included questions about discharge destination, economic status (how much the patients could afford for their care and living per month), family members living together, primary caregivers, physical status, and dementia status for each discharged patient.Results We analyzed the data for 565 patients from 179 hospitals, of which 293 patients were discharged to their home and 272 patients were discharged to long-term care facilities. Patients who could afford to spend less than 100,000 yen per month were six times more likely to be discharged to their homes than patients who could afford to spend 100,000 to 150,000 yen per month (OR: 6.48, 95% CI: 2.50-16.79). Patients who could afford to spend more than 150,000 yen per month were 70% less likely to be discharged to their homes than patients who could afford to spend 100,000 to 150,000 yen per month (OR: 0.29, 95% CI: 0.12-0.69). Half of the patients who could afford to spend more than 150,000 yen per month were not discharged home, and instead selected private and expensive long-term care facilities.Conclusion We observed an association between economic status and home discharge from acute care hospitals. As the monthly expenditure capacity of the elderly patients decreased, the likelihood that they were discharged to their homes increased. This suggests that elderly patients, who are economically disadvantaged, may select discharge to their homes due to limited options for discharge destinations that fit their budget. The Japanese government should arrange more low-cost facilities and home care services for low-income elderly patients. PMID- 28890529 TI - Factors relating to the feeling of school avoidance among elementary school children: Results from the MEXT (Ministry of Education, Culture, Sports, Science and Education) Super Shokuiku School Project. AB - Purpose This study aims to evaluate whether lifestyle factors including media use and social and family environments are associated with elementary school children's feeling of school avoidance.Methods Total study population for this study was 2,057 children in 5 elementary schools in Takaoka city, Toyama prefecture, which participated in the MEXT Super Shokuiku School Project. A questionnaire survey was conducted in July 2014 and 1,936 students responded (Response rate: 94.1%). Of those who responded, data from 1,698 respondents were relevant for this study. The questionnaire included questions on lifestyle factors (e.g., eating habits, media use, exercise habits, and sleep), health status, and the social and family environments. Children responded to questions on lifestyle factors, health status, and feeling of school avoidance with their parents. Parents were asked to only respond to the questions on social and family environments. Logistic regression analysis was performed to evaluate whether the feeling of avoiding school, as the dependent variable, is associated with the independent variables such as social and family environment factors and lifestyle factors. The odds ratios (OR) and their 95% confidence intervals (95%CI) were calculated.Results The percentage of children who had the feeling of avoiding school was 32.2% in the study sample. In comparison with the 6th graders, the 1st, 3rd, 4th, and 5th graders were more likely to have this feeling. Relevant adjusted ORs [95%CI] for Grades 1-5 were found to be 1.48 [1.02-2.13], 1.63 [1.10 2.42], 1.60 [1.08-2.39], and 1.56 [1.03-2.35], respectively. Other factors positively correlated with this feeling were skipping breakfast (OR 1.76, 95%CI [1.12-2.75]), daily snacking (OR 1.64, 95%CI [1.21-2.22]), watching TV for 3 hours or longer (OR 1.55, 95%CI [1.05-2.28]), video gaming for 0.5-2 hours (OR 1.37, 95%CI [1.08-1.74]), feeling sleepy (OR 1.51, 95%CI [1.14-1.99]), not feeling well upon waking up (OR 1.64, 95%CI [1.30-2.06]), being unsatisfied with their own health (OR 1.43, 95%CI [1.10-1.87]), and dislike for playing outside (OR 1.62, 95%CI [1.05-2.52]).Conclusions This study showed that feeling of school avoidance was significantly correlated with several lifestyle factors. School health activities aiming at establishing desirable lifestyles for children could reduce the number of children who have the feeling of school avoidance. PMID- 28890531 TI - Activities of daily living (ADL) of single elderly individuals using social assistive programs in a rural community. AB - Objectives The proportion of elderly individuals living alone is increasing in Japan. Matsumoto city office provides social assistive programs such as home help, lunch delivery, life advice, and safety check telephone calls. The purpose of this study was to compare the level of ADL between the elderly using social assistive programs (the use group) and those who did not (the non-use group).Methods We conducted a cross-sectional study at Shiga district of Matsumoto city in September 2014. A total of 128 elderly individuals participated in this study. Health volunteers asked these subjects to complete a questionnaire without assistance. Measurement items included lifestyle variables and social support networks. With respect to the frequency of use, we used questions that inquired about the use of the social assistive program. We included a set of instruments commonly used in the health assessment of elderly populations: functional capacity (Instrumental ADL, Intellectual Activity, Social Role), social support, nutrition (Mini Nutrition Assessment [MNA]) and depressive symptoms (Geriatric Depression Scale [GDS]).Results The use group consisted of 24 elderly individuals participating in the social support program. The non-use group consisted of 89 elderly individuals living alone without programs. The mean age of those who completed the survey was 83.9+/-4.2 years for the use group and 82.3+/-4.3 years for the non-use group. Comparisons between the two groups did not show significant difference in terms of their intellectual activity, social role, emotional social support, and MNA or GDS scores. The use group was more likely to use the public transfer service and receive instrumental social support from children and relatives.Conclusions By means of utilizing the public transfer service, and receiving family support, the elderly living alone who used social assistive programs could live independently. These findings suggest a need for improvement in the public transfer service and social network. PMID- 28890530 TI - The prevalence and basic characteristics of knee pain in community-dwelling independent elderly: A complete survey. AB - Objectives The objectives of this study were to determine the prevalence of knee pain in independent community-dwelling elderly people and to examine the basic characteristics (sex and age) of those experiencing knee pain.Methods Survey on the health status and lifestyle habits was conducted for all (6,790) independent elderly who were 65 years or older, living in Tsuru City, Yamanashi Prefecture, Japan. The survey was carried out using a mailing questionnaire for 1 month from January 12 to February 11, 2016. Knee pain was defined as subjective pain in and around the knee joint in either one or both knees, on most days during the past month. Participants answered "Yes" if they were experienced knee pain, and "No" if they did not experience knee pain. Sex and age were investigated as basic characteristics of the participants by the questionnaire. The prevalence rate of knee pain was calculated as follows: the total number of people with knee pain divided by the total number of the respondents in the study. To examine the relationships between knee pain and age or sex, these basic characteristics were analyzed using a Chi-square test for the prevalence of knee pain within sex and age groups.Results The number of survey respondents was 5,328 (response rate: 78.5%). The number of valid respondents with complete data was 5,186 (valid response rate: 76.4%). The number of subjects who responded "with knee pain" was 1,733. The prevalence rate of knee pain was 33.4%. In addition, sex and age demonstrated strong associations with the prevalence of knee pain (both, P<0.001). In other words, the prevalence rate was higher in the elderly women than in elderly men and increased with age.Conclusion The present study suggested that one in three independently living elderly who live in medium-sized local municipalities in Japan experience chronic knee pain. The basic characteristics of a community-dwelling independent elderly with knee pain are to be a woman and older age. PMID- 28890532 TI - Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: A Case Report and Review of the Literature. AB - BACKGROUND Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disorder that is characterized by diffuse hyperplasia of bronchiolar and bronchial pulmonary neuroendocrine cells. In this condition, when no other pathological pulmonary condition is detected, DIPNECH is considered to be an idiopathic lung disease. DIPNECH is a rare condition that can be difficult to distinguish from other forms of reactive pulmonary neuroendocrine cell hyperplasia (NECH). We present a case of DIPNECH and describe the approach to diagnosis of this rare condition. CASE REPORT A 69-year-old woman with a past medical history of successfully treated lobular carcinoma of the breast, presented to our department with a respiratory tract infection. High-resolution computed tomography (HRCT) of the chest showed a suspicious pulmonary nodule, measuring 13 mm, in the right middle pulmonary lobe. Combined positron emission tomography (PET) and computed tomography (CT), showed a solid and metabolically active nodule. A transbronchial biopsy and histopathology confirmed a diagnosis of DIPNECH. CONCLUSIONS It is possible that DIPNECH is an under-diagnosed pulmonary condition because it is rarely associated with symptoms. At this time, there are no evidence-based management guidelines. While the majority of cases have stable clinical course, some cases can progress to cause airway obstruction. This case report highlights this rare, but potentially progressive condition, and the need for evidence-based management guidelines for DIPNECH. PMID- 28890533 TI - Dose-Response Relationship Between Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) and Stroke: A Chinese Case-Control Study. AB - BACKGROUND Because TAFI (thrombin-activatable fibrinolysis inhibitor) antigen varies widely among different populations, we performed this case-control study to explore the relationship between TAFI levels and stroke in a Chinese population. MATERIAL AND METHODS Our population-based case-control study included 217 stroke patients and 218 healthy controls. The plasma TAFI level was measured by immune turbidimetry. Univariate and multivariate logistic regression analyses were used to analyze the association between different TAFI levels and stroke and its subtypes. Restricted cubic spline (RCS) combined with logistic regression analysis were used to explore the dose-response relationship between TAFI levels and stroke. RESULTS The plasma TAFI levels of cases were much higher than in the control group (p=0.038) and this difference persisted even after adjustment (OR=2.2). In the elderly (aged over 60) and female subgroups, TAFI levels in stroke patients were higher than those in controls, and the results were also noted in ischemic stroke. The dose-response curve showed that, as a whole, with the increase of TAFI levels, the relative risk of stroke first increased and then decreased (p=0.0127). Similarly, in general, with the increase of TAFI levels, the curve showed that the relative risk of ischemic stroke first increased and then decreased (p=0.0110). CONCLUSIONS There was a definite correlation between TAFI levels and stroke in this Chinese population, and with the increase of TAFI levels, the relative risk of stroke or ischemic stroke first increased and then decreased. PMID- 28890535 TI - Chromatin: Probing a piRNA paradox. PMID- 28890537 TI - Nephrotic syndrome: Novel monogenic causes of Galloway-Mowat syndrome. PMID- 28890538 TI - Kidney cancer: Targeting Wilms tumour. PMID- 28890534 TI - Harnessing ancient genomes to study the history of human adaptation. AB - The past several years have witnessed an explosion of successful ancient human genome-sequencing projects, with genomic-scale ancient DNA data sets now available for more than 1,100 ancient human and archaic hominin (for example, Neandertal) individuals. Recent 'evolution in action' analyses have started using these data sets to identify and track the spatiotemporal trajectories of genetic variants associated with human adaptations to novel and changing environments, agricultural lifestyles, and introduced or co-evolving pathogens. Together with evidence of adaptive introgression of genetic variants from archaic hominins to humans and emerging ancient genome data sets for domesticated animals and plants, these studies provide novel insights into human evolution and the evolutionary consequences of human behaviour that go well beyond those that can be obtained from modern genomic data or the fossil and archaeological records alone. PMID- 28890536 TI - A key role for IL-7R in the generation of microenvironments required for thymic dendritic cells. AB - Interleukin-7 receptor (IL-7R) signaling is critical for multiple stages of T cell development, but a role in the establishment of the mature thymic architecture needed for T-cell development and thymocyte selection has not been established. Crosstalk signals between developing thymocytes and thymic epithelial cell (TEC) precursors are critical for their differentiation into cortical TECs (cTECs) and medullary TECs (mTECs). In addition, mTEC-derived factors have been implicated in the recruitment of thymic dendritic cells (DCs) and intrathymic DC development. We therefore examined corticomedullary structure and DC populations in the thymus of Il7r-/- mice. Analysis of TEC phenotype and spatial organization revealed a striking shift in the mTEC to cTEC ratio, accompanied by disorganized corticomedullary structure. Several of the thymic subsets known to have DC potential were nearly absent, accompanied by reductions in DC cell numbers. We also examined chemokine expression in the Il7r-/- thymus, and found a significant decrease in mTEC-derived CCR7 ligand expression, and high levels of cTEC-derived chemokines, including CCL25 and CXCL12. Although splenic DCs were similarly affected, bone marrow (BM) precursors capable of giving rise to DCs were unperturbed. Finally, BM chimeras showed that there was no intrinsic need for IL-7R signaling in the development or recruitment of thymic DCs, but that the provision of wild-type progenitors enhanced reconstitution of thymic DCs from Il7r-/- progenitors. Our results are therefore supportive of a model in which Il7r-dependent cells are required to set up the microenvironments that allow accumulation of thymic DCs. PMID- 28890539 TI - Transplantation: IdeS to desensitize organ allograft recipients. PMID- 28890540 TI - Fine-tuning of thymocyte development by ubiquitination-mediated stability control of the ESCRT protein CHMP5. PMID- 28890541 TI - MicroRNA in vivo precipitation identifies miR-151-3p as a computational unpredictable miRNA to target Stat3 and inhibits innate IL-6 production. AB - MicroRNAs (miRNAs) function as important regulators in the immune response and inflammation. Several approaches have been reported to computationally predict miRNAs and their potential targets. However, there are still many miRNA-target interactions that are unpredictable by using the current computational algorithms. We established a miRNA in vivo precipitation method (miRIP) to identify unpredictable miRNAs with definite targets in these cells. Because Stat3 is a well-known transcription factor involved in innate immunity and inflammation, we utilized the miRIP method to identify miRNAs that bind Stat3 mRNA in macrophages. Among the captured miRNAs, miR-151-3p was confirmed to interact with Stat3 mRNA 3'-UTR and downregulate the Stat3 protein levels. LPS stimulation decreased miR-151-3p expression, thereby increasing IL-6 production. Therefore, we found that miR-151-3p inhibited LPS-induced IL-6 production by targeting Stat3. These data further confirmed miRIP as an efficient method to identify unpredictable miRNAs and explore miRNAs-mediated regulation in innate immunity and inflammation. PMID- 28890542 TI - Multi-epitope vaccines: a promising strategy against tumors and viral infections. PMID- 28890544 TI - miR-31: a key player in CD8 T-cell exhaustion. PMID- 28890543 TI - The altered PD-1/PD-L1 pathway delivers the 'one-two punch' effects to promote the Treg/Th17 imbalance in pre-eclampsia. AB - The programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway is critical for normal pregnancy by promoting regulatory T (Treg) cell development and inhibiting the Th17 response. However, the relationship between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance in pre-eclampsia (PE) is an enigma. In this study, decreased PD-1 and PD-L1 expression and a Treg/Th17 imbalance were observed at the maternal-fetal interface in PE. The regulatory effects of the PD-1/PD-L1 pathway on the Treg and Th17 cell quantities were determined in vitro by targeting T-cell proliferation, differentiation and transdifferentiation. First, decreased PD-1 expression might contribute to a higher Th17 cell frequency by promoting proliferation in PE. Second, the percentages of Treg but not Th17 cells differentiated from peripheral naive CD4+ T cells were increased by PD-L1 Fc administration. This effect was accompanied by decreased PI3K/AKT/m-TOR and increased PTEN mRNA expression and was completely reversed by PD-1 blockade. Finally, the percentage of IL-17-producing Treg cells increased and was positively associated with the Th17 cell frequency in PE. Increased RORgammat and IL-17 but not Foxp3 and IL-10 mRNA expression by Treg cells was observed with PD 1 blockade. Similar findings occurred when Treg cells were exposed to IL-6/IL 23/IL-1beta and were reversed by PD-L1 Fc. Taken together, our findings indicate that the PD-1/PD-L1 pathway contributes to the Treg/Th17 imbalance via 'one-two punch' approaches: (i) promoting Th17 cell proliferation, (ii) inhibiting Treg cell differentiation and (iii) enhancing Treg cell plasticity into Th17 cells in PE. The therapeutic value of PD-L1 Fc for PE treatment will be explored in the future. PMID- 28890545 TI - TIM-3: a crucial regulator of NK cells in pregnancy. PMID- 28890546 TI - Generating CD8alphaalpha IELs from two sources of thymic precursors. PMID- 28890548 TI - Water-soluble artemisinin derivatives as promising therapeutic immunosuppressants of autoimmune diseases. PMID- 28890549 TI - Thirteenth Annual Brown Lecture in Education Research: Public Education and the Social Contract: Restoring the Promise in an Age of Diversity and Division. AB - Building on the premise that closing achievement gaps is an economic imperative both to regain international educational supremacy and to maintain global economic competitiveness, I ask whether it is possible to rewrite the social contract so that education is a fundamental right-a statutory guarantee-that is both uniform across states and federally enforceable. I argue that the federal government was complicit in aggravating educational inequality by not guaranteeing free, public education as a basic right during propitious political moments; by enabling the creation of a segregated public higher education system; by relegating the Department of Education and its predecessors to a secondary status in the federal administration, thereby compromising its enforcement capability; and by proliferating incremental reforms while ignoring the unequal institutional arrangements that undermine equal opportunity to learn. History shows that a strong federal role can potentially strengthen the educational social contract. PMID- 28890550 TI - Electrochemical Fluorination and Radiofluorination of Methyl(phenylthio)acetate Using Tetrabutylammonium Fluoride (TBAF). AB - Electrochemical fluorination of methyl(phenylthio)acetate was achieved using tetrabutylammonium fluoride (TBAF). Electrochemical fluorination was performed under potentiostatic anodic oxidation using an undivided cell in acetonitrile containing TBAF and triflic acid. The influence of several parameters including: oxidation potential, time, temperature, sonication, TBAF concentration and triflic acid concentration on fluorination efficiency were studied. It was found that the triflic acid to TBAF concentration ratio plays a key role in the fluorination efficiency. Electrochemical fluorination resulted in formation of mono-fluorinated methyl 2-fluoro-2-(phenylthio)acetate verified by gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) Spectroscopy. Under optimum conditions 44 +/- 3% mono fluorination yield was obtained after a 30 min electrolysis. Electrochemical radiofluorination for the synthesis of methyl 2-[18F]fluoro-2-(phenothio) acetate was also achieved with the same optimized electrochemical cell parameters where TBAF was first passed through an anion exchange resin containing fluorine-18. A radiochemical fluorination efficiency of 7 +/- 1% was achieved after 30 min of electrolysis. PMID- 28890551 TI - A unified framework of demographic time. AB - Demographic thought and practice is largely conditioned by the Lexis diagram, a two-dimensional graphical representation of the identity between age, period, and birth cohort. This relationship does not account for remaining years of life, total length of life, or time of death, whose use in demographic research is both underrepresented and incompletely situated. We describe an identity between these six demographic time measures and describe the sub-identities and diagrams that pertain to this identity. We provide an application of this framework to the measurement of late-life morbidity prevalence. We generalize these relationships to higher order identities derived from an arbitrary number of events in calendar time. Our examples are based on classic human demography, but the concepts we present can reveal patterns and relationships in any event history data, and contribute to the study of human or non-human population dynamics measured on any scale of calendar time. PMID- 28890547 TI - Innate immunity in tuberculosis: host defense vs pathogen evasion. AB - The major innate immune cell types involved in tuberculosis (TB) infection are macrophages, dendritic cells (DCs), neutrophils and natural killer (NK) cells. These immune cells recognize the TB-causing pathogen Mycobacterium tuberculosis (Mtb) through various pattern recognition receptors (PRRs), including but not limited to Toll-like receptors (TLRs), Nod-like receptors (NLRs) and C-type lectin receptors (CLRs). Upon infection by Mtb, the host orchestrates multiple signaling cascades via the PRRs to launch a variety of innate immune defense functions such as phagocytosis, autophagy, apoptosis and inflammasome activation. In contrast, Mtb utilizes numerous exquisite strategies to evade or circumvent host innate immunity. Here we discuss recent research on major host innate immune cells, PRR signaling, and the cellular functions involved in Mtb infection, with a specific focus on the host's innate immune defense and Mtb immune evasion. A better understanding of the molecular mechanisms underlying host-pathogen interactions could provide a rational basis for the development of effective anti TB therapeutics. PMID- 28890552 TI - GEOMETRIC PROGRESSIONS ON ELLIPTIC CURVES. AB - In this paper, we look at long geometric progressions on different model of elliptic curves, namely Weierstrass curves, Edwards and twisted Edwards curves, Huff curves and general quartics curves. By a geometric progression on an elliptic curve, we mean the existence of rational points on the curve whose x coordinate (or y-coordinate) are in geometric progression. We find infinite families of twisted Edwards curves and Huff curves with geometric progressions of length 5, an infinite family of Weierstrass curves with 8 term progressions, as well as infinite families of quartic curves containing 10-term geometric progressions. PMID- 28890553 TI - Synchrophasor Sensor Networks for Grid Communication and Protection. AB - This paper focuses primarily on leveraging synchronized current/voltage amplitudes and phase angle measurements to foster new categories of applications, such as improving the effectiveness of grid protection and minimizing outage duration for distributed grid systems. The motivation for such an application arises from the fact that with the support of communication, synchronized measurements from multiple sites in a grid network can greatly enhance the accuracy and timeliness of identifying the source of instabilities. The paper first provides an overview of synchrophasor networks and then presents techniques for power quality assessment, including fault detection and protection. To achieve this we present a new synchrophasor data partitioning scheme that is based on the formation of a joint space and time observation vector. Since communication is an integral part of synchrophasor networks, the newly adopted wireless standard for machine-to-machine (M2M) communication, known as IEEE 802.11ah, has been investigated. The paper also presents a novel implementation of a hardware in the loop testbed for real-time performance evaluation. The purpose is to illustrate the use of both hardware and software tools to verify the performance of synchrophasor networks under more realistic environments. The testbed is a combination of grid network modeling, and an Emulab-based communication network. The combined grid and communication network is then used to assess power quality for fault detection and location using the IEEE 39-bus and 390-bus systems. PMID- 28890554 TI - Difficult airway: Challenges, phobias and options. PMID- 28890555 TI - Perioperative fluid management: From physiology to improving clinical outcomes. AB - Perioperative fluid management is a key component in the care of the surgical patient. It is an area that has seen significant changes and developments, however there remains a wide disparity in practice between clinicians. Historically, patients received large volumes of intravenous fluids perioperatively. The concept of goal directed therapy was then introduced, with the early studies showing significant improvements in morbidity and mortality. The current focus is on fluid therapy guided by an individual patient's physiology. A fluid challenge is commonly performed as part of an assessment of a patient's fluid responsiveness. There remains wide variation in how clinicians perform a fluid challenge and this review explores the evidence for how to administer an effective challenge that is both reliable and reproducible. The methods for monitoring cardiac output have evolved from the pulmonary artery catheter to a range of less invasive techniques. The different options that are available for perioperative use are considered. Fluid status can also be assessed by examining the microcirculation and the importance of recognising the possibility of a lack of coherence between the macro and microcirculation is discussed. Fluid therapy needs to be targeted to specific end points and individualised. Not all patients who respond to a fluid challenge will necessarily require additional fluid administration and care should be aimed at identifying those who do. This review aims to explain the underlying physiology and describe the evidence base and the changes that have been seen in the approach to perioperative fluid therapy. PMID- 28890556 TI - Ethnicity and upper airway measurements: A study in South Indian population. AB - BACKGROUND AND AIMS: Most studies on upper airway are conducted based on airway measurements in the western population. We set out to find the normal values of upper airway measurements in South Indian population. The aim of this study was to perform various upper airway examinations and to set standards for normal measurements in the South Indian population as well as to analyse the data for predictors of difficult intubation. METHODS: This prospective observational study was conducted in a tertiary cancer hospital in Southern India. Airway assessment parameters, including modified Mallampati classification (MPC), upper lip bite test (ULBT), sternomental distance, thyromental distance (TMD), and the inter incisor distance were documented for 2004 patients meeting the inclusion criteria. Laryngoscopic view after induction was graded as per Cormack and Lehane's (CL) classification. Any CL >=3 was considered to be difficult laryngoscopy. The collected data (2004 cases) was analyed with SPSS software version 17. Receiver operating characteristics (ROC) curve was used to determine cut-offs in the population. Sensitivity, specificity, positive and negative predictive value were computed. RESULTS: MPC, ULBT, and ratio of height to TMD (RHTMD) predicted difficult intubation with sensitivity of 40.86%, 45.53% and 64.60%, respectively and these were statistically significant with P < 0.001. Using the area under the curve of the ROC curve and discrimination analysis normal RHTMD in our population had a cut off value of 17.1. CONCLUSION: The cut off value for RHTMD to predict difficult laryngoscopy in the South Indian population is 17.1. PMID- 28890557 TI - Are cardiac surgical patients at increased risk of difficult intubation? AB - BACKGROUND AND AIMS: Safe airway management is the cornerstone of contemporary anaesthesia practice, and difficult intubation (DI) remains a major cause of anaesthetic morbidity and mortality. The surgical category, particularly cardiac surgery as a risk factor for DI has not been studied extensively. The aim of this study was to test the hypothesis whether cardiac surgical patients are at increased risk of DI. METHODS: During the study, 627 patients (329 cardiac and 298 non-cardiac surgical) were enrolled. Pre-operative demographic and other variables associated with DI were assessed. Patients with Cormack Lehane grade III and IV or use of bougie in Cormack grade II were defined as DI. The incidence of anticipated and unanticipated DI was assessed. Factors associated with DI were described using univariate and multivariate logistic regression models. RESULTS: The overall incidence of DI was 122/627 (19.46%). The incidence of DI was higher in cardiac surgery patients (24%) as compared to non-cardiac surgery patients (14.4% P = 0.002). On multivariate analysis, factors independently associated with DI were greater age, male sex, higher Mallampati grade, and anticipated DI, but not cardiac surgery. The incidence of unanticipated DI was 48.1% and 53.4% in cardiac and non-cardiac surgery patients, respectively. CONCLUSION: Although there was a higher incidence of DI in cardiac surgical patients, cardiac surgery is not an independent risk factor for DI. Rather, other factors play more important role. About half of the DI both in cardiac and non-cardiac surgeries were unanticipated. PMID- 28890558 TI - A cohort evaluation of clinical use and performance characteristics of Ambu(r) AuraGainTM: A prospective observational study. AB - BACKGROUND AND AIMS: Ambu(r) AuraGainTM (AG) (Ambu, Ballerup, Denmark) is a supraglottic device which has a design facilitating its use as a conduit for intubation. We designed this prospective observational study to assess the ease of AG placement in paralysed patients, determine its position and alignment to the glottis and assess its utility as a conduit for intubation. METHODS: One hundred patients, aged 18-60 years, American Society of Anesthesiologists physical status I-II, undergoing elective surgery under general anaesthesia were included in the study. The ease and number of attempts for successful insertion, ease of gastric tube insertion, leak pressures, fibre-optic grade of view, number of attempts and time for tracheal intubation, time for AG removal and complications were recorded. The mean, standard deviation (SD), interquartile range (IQR) and range were calculated. The upper limit of confidence interval for overall failure rate was calculated using Wilson's score method. RESULTS: AG was successfully inserted in all patients. The mean (SD) time taken for insertion was 17.32 (8.48) s. The median [IQR] leak pressures were 24 [20-28] cm of H2O. Optimal laryngeal view for intubation was obtained in 68 patients. Eighty-eight patients could be intubated in the first attempt. Five patients could not be intubated. The overall failure rate of device was 9%. CONCLUSION: AMBU(r) AuraGainTM serves as an effective ventilating aid, but caution is suggested before using it as a conduit for endotracheal intubation. PMID- 28890559 TI - Comparison of the post-operative analgesic effect of paravertebral block, pectoral nerve block and local infiltration in patients undergoing modified radical mastectomy: A randomised double-blind trial. AB - BACKGROUND AND AIMS: Paravertebral block, pectoral nerve (Pecs) block and wound infiltration are three modalities for post-operative analgesia following breast surgery. This study compares the analgesic efficacy of these techniques for post operative analgesia. METHODS: Sixty-five patients with American Society of Anesthesiologists' physical status 1 or 2 undergoing modified radical mastectomy with axillary dissection were recruited for the study. All patients received 21 mL 0.5% bupivacaine with adrenaline in the technique which was performed at the end of the surgery prior to extubation. Patients in Group 1 (local anaesthetic [LA], n = 22) received infiltration at the incision site after surgery, Group 2 patients (paravertebral block [PVB], n = 22) received ultrasound-guided ipsilateral paravertebral block while Group 3 patients [PECT] (n = 21) received ultrasound-guided ipsilateral Pecs blocks I and II. Patients were evaluated for pain scores at 0, 2, 4, 6, 12 and 24 h, duration of post-operative analgesia and rescue analgesic doses required. Non-normally distributed data were analysed using the Kruskal-Wallis test and Analysis of variance for normal distribution. RESULTS: The post-operative visual analogue scale scores were lower in PVB group compared with others at 0, 2, 4, 12 and 24 h (P < 0.05). Mean duration of analgesia was significantly prolonged in PVB group (P < 0.001) with lesser rescue analgesic consumption up to 24 h. CONCLUSION: Ultrasound-guided paravertebral block reduces post-operative pain scores, prolongs the duration of analgesia and decreases demands for rescue analgesics in the first 24 h of post-operative period compared to ultrasound-guided Pecs block and local infiltration block. PMID- 28890560 TI - Perfusion index as a predictor of hypotension following spinal anaesthesia in lower segment caesarean section. AB - BACKGROUND AND AIMS: Perfusion index (PI) is a new parameter tried for predicting hypotension during spinal anaesthesia for the lower segment caesarean section (LSCS). This study aimed at investigating the correlation between baseline perfusion index and incidence of hypotension following SAB in LSCS. METHODS: In this prospective observational study, 126 parturients were divided into two groups on the basis of baseline PI. Group I included parturients with PI of <=3.5 and Group II, parturients with PI values >3.5. Spinal anaesthesia was performed with 10 mg of injection bupivacaine 0.5% (hyperbaric) at L3-L4 or L2-L3 interspace. Hypotension was defined as mean arterial pressure <65 mmHg. Statistical analysis was performed using Chi-square test, independent sample t test and Mann-Whitney U-test. Regression analysis with Spearman's rank correlation coefficient was done to assess the correlation between baseline PI and hypotension. Receiver operating characteristic (ROC) curve was plotted for PI and occurrence of hypotension. RESULTS: The incidence of hypotension in Group I was 10.5% compared to 71.42% in Group II (P < 0.001). There was significant correlation between baseline PI >3.5 and number of episodes of hypotension (rs0.416, P < 0.001) and total dose of ephedrine (rs0.567, P < 0.001). The sensitivity and specificity of baseline PI of 3.5 to predict hypotension was 69.84% and 89.29%, respectively. The area under the ROC curve for PI to predict hypotension was 0.848. CONCLUSION: Baseline perfusion index >3.5 is associated with a higher incidence of hypotension following spinal anesthesia in elective LSCS. PMID- 28890561 TI - A comparison of the efficacy of intercostal nerve block and peritubal infiltration of ropivacaine for post-operative analgesia following percutaneous nephrolithotomy: A prospective randomised double-blind study. AB - BACKGROUND AND AIMS: Intercostal nerve blockade (ICNB) and peritubal infiltration of the nephrostomy tract are well-established regional anaesthetic techniques for alleviating pain after percutaneous nephrolithotomy (PCNL). This prospective study compared the efficacy of ICNB and peritubal local anaesthetic infiltration of the nephrostomy tract in providing post-operative analgesia following PCNL. METHODS: Sixty American Society of Anesthesiologist physical status 1 and II patients scheduled for PCNL requiring nephrostomy tube were randomised to receive either peritubal infiltration or ICNB. At the completion of the procedure, patients in Group P received peritubal infiltration and those in Group I received ICNB at 10, 11, 12th spaces using fluoroscopy guidance. Postoperatively, patients were followed for 24 h for pain using Visual Analogue Scale (VAS) and Dynamic VAS. Rescue analgesia was inj. tramadol 1 mg/kg IV when pain score exceeded 4. Time to first rescue analgesia, number of doses and patient's satisfaction were noted in all patients. RESULTS: Pain scores were lower in the group I at all points of measurement than group P. The mean time to first demand for rescue analgesia was higher in Group I (13.22 +/- 4.076 h vs 7.167 +/- 3.92 h P - 0.001). The number of demands and the amount of analgesics consumed were less in Group I. CONCLUSION: ICNB provided superior analgesia as evidenced by longer time to first demand of analgesic, reduced number of demands and consumption of rescue analgesic. Peritubal infiltration, although less efficacious, may be a safe and simple alternative technique. PMID- 28890562 TI - Efficacy of atomised local anaesthetic versus transtracheal topical anaesthesia for awake fibreoptic intubation. AB - BACKGROUND AND AIMS: Successful awake fibreoptic intubation (AFOI) depends on adequate topical anaesthesia of the airway. We aimed to compare efficacy of atomised local anaesthetic versus transtracheal topical anaesthesia for AFOI. METHODS: It was a prospective, randomised controlled study of 33 patients with the American Society of Anesthesiologists' physical status 1-3 with anticipated difficult airway requiring AFOI. The primary objective was to compare the patient comfort after topical anaesthesia of the airway using atomiser with transtracheal injection of the local anaesthetic agent for AFOI in patients with anticipated difficult airway. The secondary objectives were to compare the ease of intubation, time required to intubate and the haemodynamic changes during intubation. After topical anaesthesia of nostrils, patients in Group T received transtracheal injection of 4 ml of 4% lignocaine whereas Group A patients received 4-5mL of 4% atomised lignocaine using DeVilbiss atomiser before AFOI. Patient comfort assessed objectively by the anaesthetic assistant during the procedure, ease of intubation assessed using cough and gag reflex score, time taken to intubate and the haemodynamic changes during the procedure were compared. RESULTS: Ease of intubation, patient comfort and the time taken to intubate were significantly better in Group T patients, with P = 0.001, 0.009 and 0.019, respectively, compared with the patients in Group A. There were no significant changes in haemodynamic parameters. CONCLUSION: Topical anaesthesia by transtracheal injection in patients with anticipated difficult airway made AFOI easier and faster with better patient comfort compared to atomiser with no clinically significant untoward side effects. PMID- 28890563 TI - Comparison of intrathecal clonidine and magnesium sulphate used as an adjuvant with hyperbaric bupivacaine in lower abdominal surgery. AB - BACKGROUND AND AIMS: Use of various adjuvants to spinal anaesthesia is a well known modality to provide intra- and post-operative analgesia. This study was designed to evaluate and compare the analgesic efficacy of clonidine and magnesium when used as an additive to intrathecal 0.5% hyperbaric bupivacaine. METHODS: Ninety patients of the American Society of Anesthesiologists' physical status grade I or II, scheduled for lower abdominal surgery under spinal anaesthesia, were randomly allocated into three groups. Group B received 3 mL of 0.5% hyperbaric bupivacaine with 1 mL of normal saline, Group C received 3 mL of 0.5% hyperbaric bupivacaine with 1 mL (30 MUg) of clonidine and Group M received 3 mL of 0.5% hyperbaric bupivacaine with 1 mL (50 mg) magnesium sulphate. The primary outcome variable was duration of analgesia and secondary outcome variables included onset and duration of sensory and motor block, sedation level and adverse effects. Data were analysed with ANOVA, Kruskal-Wallis and Chi-square tests. RESULTS: The time to first rescue analgesia was significantly (P < 0.01) longer in the Group C (330.7 +/- 47.7 min) than both Groups. Group M (246.3 +/- 55.9 min) showed significantly prolonged analgesia than Group B (134.4 +/- 17.9 min). Group C and Group M showed significantly prolonged duration of both sensory and motor block compared to Group B. CONCLUSION: Intrathecal clonidine added to bupivacaine prolongs the duration of post-operative analgesia, and hastens the onset and prolongs the duration of sensory and motor block compared to magnesium or controls. PMID- 28890564 TI - Laryngeal mask airway protectorTM: Advanced uses for laparoscopic cholecystectomies. AB - The laryngeal mask airway (LMA) ProtectorTM is a second-generation perilaryngeal sealer type supraglottic airway device recently introduced into clinical practice. We describe our initial experiences with the use of the LMA ProtectorTM in three patients undergoing laparoscopic cholecystectomies. In all patients, we found the LMA ProtectorTM to have acceptable placements on the first attempt, adequate oropharyngeal leak pressures and ventilation adequacy. PMID- 28890565 TI - Anaesthetic management of infants posted for repair of anomalous origin of left coronary artery from pulmonary artery. AB - First described in 1908, anomalous origin of left coronary artery from pulmonary artery is a very rare congenital anomaly. Here, the right coronary artery is usually enlarged and has a normal origin from aorta. Numerous collaterals connect the two coronary arteries over right ventricular outflow tract or interventricular septum. It is one of the most common causes of myocardial ischaemia and infarction in children. PMID- 28890566 TI - Airway management with a rigid external distractor in place. PMID- 28890567 TI - Novel use of transoesophageal echocardiography in a pregnant patient undergoing neurosurgery. PMID- 28890568 TI - Transdermal fentanyl patch in post-operative patients: Is it justified? PMID- 28890569 TI - Yet another cause for difficult extubation of nasotracheal tube. PMID- 28890570 TI - Encountering caudal cyst on ultrasound: What do we do? PMID- 28890571 TI - A novel position for D2 kyphoplasty: Swimmer's position. PMID- 28890572 TI - Capnography in the endoscopy suite: A necessity, not a luxury! PMID- 28890573 TI - Institutional and ethnic variations in postgraduate enrollment and completion. AB - Using the B&B:93/03 longitudinal cohort survey, we investigate (1) whether and how much variations in the timing of enrollment, the type of undergraduate institution attended, and type of graduate program pursued contribute to observed racial and ethnic differentials in post-baccalaureate enrollment, and (2) whether the observed enrollment differentials carry over to degree attainment. Dynamic event history methods that account both for the timing of matriculation and the hazard of enrolling reveal that compared to whites underrepresented minorities enroll earlier and also are more likely to enroll in doctoral and advanced professional degree programs relative to nonenrollment. Our results reveal sizable differences in the cumulative probability of advanced degree attainment according to undergraduate institutional mission, with graduates from research institutions enjoying a decided advantage over liberal arts college graduates. The conclusion discusses limitations of the analysis, directions for further research, and implications for strengthening the minority pipeline to graduate school. PMID- 28890574 TI - Is Communication a Mechanism of Relationship Education Effects among Rural African Americans? AB - Enhancing communication as a means of promoting relationship quality has been increasingly questioned, particularly for couples at elevated sociodemographic risk. In response, the current study investigated communication change as a mechanism accounting for changes in relationship satisfaction and confidence among 344 rural, predominantly low-income African American couples with an early adolescent child who participated in a randomized controlled trial of the Protecting Strong African American Families (ProSAAF) program. Approximately 9 months after baseline assessment, intent-to-treat analyses indicated ProSAAF couples demonstrated improved communication, satisfaction, and confidence compared with couples in the control condition. Improvements in communication mediated ProSAAF effects on relationship satisfaction and confidence; conversely, neither satisfaction nor confidence mediated intervention effects on changes in communication. These results underscore the short-term efficacy of a communication-focused, culturally sensitive prevention program and suggest that communication is a possible mechanism of change in relationship quality among low income African American couples. PMID- 28890575 TI - Two Ways to Frustrate a Desire. PMID- 28890577 TI - De facto Privatization and Inequalities in Educational Opportunity in the Transition to Secondary School in Rural Malawi. AB - There has been a recent, rapid de facto privatization of education in many African countries, as the number of private secondary schools operating in the region grew. The majority of these schools are "low-cost" private schools where tuition and fees are set as low as possible to cover operating costs and still generate profit. Proponents of low-cost private schools argue that these schools have proliferated in impoverished areas to meet unmet demand for access to education and where private schools may offer better quality than locally available public schools. Theories of inequality of educational opportunity suggest that if private schools offer better quality education, students from more advantaged families will be more likely to enroll at these institutions, potentially exacerbating educational inequality in the region. This analysis uses data from a school-based longitudinal survey, the Malawi Schooling and Adolescent Study, to examine socio-economic inequalities in the transition to secondary school and on-time enrollment in upper secondary. My findings indicate that youth from non-poor households are not only more likely to enroll in secondary school than poor youth, but they are also more likely to substitute enrollment in private schools for enrollment in second-tier government schools. Enrollment at private schools, however, does not yield schooling advantages; relative to both tiers of government secondary schooling, students who initially enrolled at private schools were the least likely to enroll on time in upper secondary school. These patterns suggest that these schooling circumstances may yield less segregation of opportunity than might otherwise be assumed. PMID- 28890578 TI - Detrifluoroacetylative Generation of Halogenated Enolates: Practical Access to Perhalogenated Ketones and Alkenes. AB - Sequential chlorination/fluorination of aromatic trifluoroacetylated ketones gives 1-aryl 2-chloro-2,4,4,4-tetrafluoro-butan-1,3-dione hydrates that are used for the synthesis of ketones and alkenes exhibiting a terminal bromochlorofluoromethyl group. The hydrates undergo detrifluoroacetylative cleavage and subsequent bromination in the presence of a copper(II)bisoxazoline catalyst, K2CO3 and NBS at room temperature. The corresponding bromochlorofluoromethyl ketones can be applied in Wittig and Horner-Wadsworth Emmons reactions and dibromoalkenylations. PMID- 28890579 TI - Gold Catalysis-Facilitated Rapid Synthesis of the Daphnane/Tigliane Tricyclic Core. AB - A concise approach to synthesize the 5-7-6 tricyclic carbon skeleton of the daphnane/tigliane diterpene natural products has been accomplished via a sequential gold-catalyzed furan formation and furan-allene [4+3] cycloaddition. This work provides new avenues for rapid and diverted synthesis of the medicinally important daphnane/tigliane diterpenes and their unnatural analogues. PMID- 28890580 TI - The Role of Compost in Stabilizing the Microbiological and Biochemical Properties of Zinc-Stressed Soil. AB - The progressive development of civilization and intensive industrialization has contributed to the global pollution of the natural environment by heavy metals, especially the soil. Degraded soils generally contain less organic matter, and thus, their homeostasis is more often disturbed, which in turn manifests in changes in biological and physicochemical properties of the soil. Therefore, new possibilities and solutions for possible neutralization of these contaminations are sought, inter alia, through reclamation of degraded land. At present, the use of additives supporting the reclamation process that exhibit heavy metal-sorbing properties is becoming increasingly important in soil recovery. Research was conducted to determine the role of compost in stabilizing the microbial and biochemical balance of the soil due to the significant problem of heavy metal contaminated areas. The study was conducted on loamy sand, to which zinc was applied at the following doses: 0, 250, 500, 750, 1000, and 1250 mg Zn2+ kg-1 DM of soil. Compost was introduced to the appropriate objects calculated on the basis of organic carbon content in the amount of 0, 10, and 20 g Corg kg-1 DM of soil. The study was conducted over a period of 20 weeks, maintaining soil moisture at 50% capillary water capacity. Zinc significantly modified soil microbiome status. The abundance of microorganisms and their biological diversity and the enzymatic activity of the soil were affected. The negative effects of contaminating zinc doses were alleviated by the introduction of compost into the soil. Organic fertilization led to microbial growth intensification and increased biochemical activity of the soil already 2 weeks after compost application. These effects persisted throughout the experiment. Therefore, it can be stated that the use of compost is an appropriate method for restoring normal functions of soil ecosystems contaminated with zinc. PMID- 28890582 TI - Theory of Linear and Nonlinear Gain in a Gyroamplifier using a Confocal Waveguide. AB - The linear and nonlinear theory of a gyroamplifier using a confocal waveguide is presented. A quasi-optical approach to describing the modes of a confocal waveguide is derived. Both the equations of motion and the mode excitation equation are derived in detail. The confocal waveguide circuit has the advantage of reducing mode competition but the lack of azimuthal symmetry presents challenges in calculating the gain. In the linear regime, the gain calculated using the exact form factor for the confocal waveguide agrees with an azimuthally averaged form factor. A beamlet code including velocity spread effects has been written to calculate the linear and nonlinear (saturated) gain. It has been successfully benchmarked against the MAGY code for azimuthally symmetric cases. For the confocal waveguide, the beamlet code shows that the saturated gain is reduced when compared with results obtained using an azimuthally averaged form factor. The beamlet code derived here extends the capabilities of nonlinear gyroamplifier theory to configurations that lack azimuthal symmetry. PMID- 28890581 TI - Fitness Effects of Thermal Stress Differ Between Outcrossing and Selfing Populations in Caenorhabditis elegans. AB - The maintenance of males and outcrossing is widespread, despite considerable costs of males. By enabling recombination between distinct genotypes, outcrossing may be advantageous during adaptation to novel environments and if so, it should be selected for under environmental challenge. However, a given environmental change may influence fitness of male, female, and hermaphrodite or asexual individuals differently, and hence the relationship between reproductive system and dynamics of adaptation to novel conditions may not be driven solely by the level of outcrossing and recombination. This has important implications for studies investigating the evolution of reproductive modes in the context of environmental changes, and for the extent to which their findings can be generalized. Here, we use Caenorhabditis elegans-a free-living nematode species in which hermaphrodites (capable of selfing but not cross-fertilizing each other) coexist with males (capable of fertilizing hermaphrodites)-to investigate the response of wild type as well as obligatorily outcrossing and obligatorily selfing lines to stressfully increased ambient temperature. We found that thermal stress affects fitness of outcrossers much more drastically than that of selfers. This shows that apart from the potential for recombination, the selective pressures imposed by the same environmental change can differ between populations expressing different reproductive systems and affect their adaptive potential. PMID- 28890583 TI - Compassionate Goals and Affect in Social Situations. AB - Optimal social interactions can leave people feeling socially connected and at ease, which has clear implications for health and psychological well-being. Yet, not all social interactions leave people feelings at ease and connected. What explains this variability? We draw from the egosystem-ecosystem theory of social motivation (Crocker & Canevello, 2008) to suggest that compassionate goals to support others explain some of this variability. We explored the nature of this association across 4 studies and varying social contexts. Across studies, compassionate goals predicted greater feelings of ease and connection. Results also indicate that a cooperative mindset may be one mechanism underlying this association: Findings suggest a temporal sequence in which compassionate goals lead to cooperative mindsets, which then lead to feeling at ease and connected. Thus, these studies suggest that people's compassionate goals lead to their sense of interpersonal ease and connection, which may ultimately have implications for their sense of belonging. PMID- 28890585 TI - Ageing and Elderly Care in the Arab Region: Policy Challenges and Opportunities. AB - Populations are expected to age rapidly in the Arab countries during the coming few decades. However, the current evidence base indicates that many countries in the region are not paying attention to this demographic phenomenon. This is a particular concern as longevity is often accompanied by many years of ill health and disability and most of the countries in the region continue to rely on the family as the primary source of elder care. While the family, and particularly women, are expected to provide increasing support for longer, they are faced by a set of socio-demographic changes that may hinder their ability to provide such care. This paper focuses on the ageing demographics in the Arab region and reflects on the multiple-roles for women by utilising quantitative analysis of international population and socio-economic indicators as well as reviewing the background literature and current ageing policies in the region. The paper then discusses possible strategies to address increasing long-term care needs through a social capital lens, where support to informal carers particularly women is emphasised. PMID- 28890584 TI - Interactive Q-learning for Quantiles. AB - A dynamic treatment regime is a sequence of decision rules, each of which recommends treatment based on features of patient medical history such as past treatments and outcomes. Existing methods for estimating optimal dynamic treatment regimes from data optimize the mean of a response variable. However, the mean may not always be the most appropriate summary of performance. We derive estimators of decision rules for optimizing probabilities and quantiles computed with respect to the response distribution for two-stage, binary treatment settings. This enables estimation of dynamic treatment regimes that optimize the cumulative distribution function of the response at a prespecified point or a prespecified quantile of the response distribution such as the median. The proposed methods perform favorably in simulation experiments. We illustrate our approach with data from a sequentially randomized trial where the primary outcome is remission of depression symptoms. PMID- 28890586 TI - The Meaning of Social Participation for Daily Mobility in Later Life: an Ethnographic Case Study of a Senior Project in a Swedish Urban Neighbourhood. AB - This paper presents an ethnographic case study that aims to understand the meaning of social participation in a neighbourhood for daily mobility in later life. In the study, the mobility of the participants of a senior-citizen project was monitored over 18 months. The project was founded as a result of a municipal district's targeting of social sustainability. The results show that social participation had positive effects on the daily mobility of the participants. The implementation of broad-minded thinking from the municipality and the cooperation of various municipal actors were shown to be essential for the positive outcome of this project. PMID- 28890587 TI - The Swedish Communicative Development Inventory III: Parent reports on language in preschool children. AB - A revised form of MacArthur-Bates Communicative Development Inventory III (SCDI III) was presented designed for Swedish speaking children aged 2 years 6 months-4 years 0 months with the objective to give a proxy measure of their language competence. The instrument contains a vocabulary checklist with 100 words, mainly predicates, from four areas; Food words, Body words, Mental words and Emotion words. Two sections assess the child's grammar skills and a final section appraises the child's metalinguistic awareness. Assessments from 1,134 parents are reported. Scales with adequate psychometric properties were formed for each section. Monthly median values and spread of score distributions are presented for each scale. Girls scored higher than boys on all scales. The revision, sampling procedures, demographic variables and issues of reliability and validity, are discussed. The general structure of the instrument can well be integrated in similar instruments designed for other languages and cultures. PMID- 28890576 TI - Interface-Induced Phenomena in Magnetism. AB - This article reviews static and dynamic interfacial effects in magnetism, focusing on interfacially-driven magnetic effects and phenomena associated with spin-orbit coupling and intrinsic symmetry breaking at interfaces. It provides a historical background and literature survey, but focuses on recent progress, identifying the most exciting new scientific results and pointing to promising future research directions. It starts with an introduction and overview of how basic magnetic properties are affected by interfaces, then turns to a discussion of charge and spin transport through and near interfaces and how these can be used to control the properties of the magnetic layer. Important concepts include spin accumulation, spin currents, spin transfer torque, and spin pumping. An overview is provided to the current state of knowledge and existing review literature on interfacial effects such as exchange bias, exchange spring magnets, spin Hall effect, oxide heterostructures, and topological insulators. The article highlights recent discoveries of interface-induced magnetism and non-collinear spin textures, non-linear dynamics including spin torque transfer and magnetization reversal induced by interfaces, and interfacial effects in ultrafast magnetization processes. PMID- 28890588 TI - Informativeness of Diagnostic Marker Values and the Impact of Data Grouping. AB - Assessing performance of diagnostic markers is a necessary step for their use in decision making regarding various conditions of interest in diagnostic medicine and other fields. Globally useful markers could, however, have ranges of values that are "diagnostically non-informative". This paper demonstrates that the presence of marker values from diagnostically non-informative ranges could lead to a loss in statistical efficiency during nonparametric evaluation and shows that grouping non-informative values provides a natural resolution to this problem. These points are theoretically proven and an extensive simulation study is conducted to illustrate the possible benefits of using grouped marker values in a number of practically reasonable scenarios. The results contradict the common conjecture regarding the detrimental effect of grouped marker values during performance assessments. Specifically, contrary to the common assumption that grouped marker values lead to bias, grouping non-informative values does not introduce bias and could substantially reduce sampling variability. The proven concept that grouped marker values could be statistically beneficial without detrimental consequences implies that in practice, tied values do not always require resolution whereas the use of continuous diagnostic results without addressing diagnostically non-informative ranges could be statistically detrimental. Based on these findings, more efficient methods for evaluating diagnostic markers could be developed. PMID- 28890590 TI - In-migration, customary land tenure, and complexity: exploring the relationship between changing land tenure norms and differentiated migrant livelihoods in Brong Ahafo, Ghana. AB - This article focuses on the relationship between in-migration from Northern Ghana and changing land tenure norms in Ghana's central "transition zone" in Brong Ahafo Region. Using the complex adaptive systems (CAS) theoretical framework, it theorizes this relationship as part of a wider set of "co-evolving" social and environmental conditions across Brong Ahafo. It presents new qualitative research findings which show differentiated livelihood trajectories for Northern Ghanaian migrant farmers in Brong Ahafo in three case study sites in different districts and links these to migrants' diverse land tenure arrangements under customary tenure regimes in Brong Ahafo. I argue that differentiated outcomes for migrants at rural destinations have implications for the extent to which out-migration from environmentally marginal regions such as Northern Ghana can be viewed as a form of "adaptation" to environmental change. PMID- 28890589 TI - Mechanisms, applications, and perspectives of antiviral RNA silencing in plants. AB - Viral diseases of plants cause important economic losses due to reduction in crop quality and quantity to the point of threatening food security in some countries. Given the reduced availability of natural sources, genetic resistance to viruses has been successfully engineered for some plant-virus combinations. A sound understanding of the basic mechanisms governing plant-virus interactions, including antiviral RNA silencing, is the foundation to design better management strategies and biotechnological approaches to engineer and implement antiviral resistance in plants. In this review, we present current molecular models to explain antiviral RNA silencing and its application in basic plant research, biotechnology and genetic engineering. PMID- 28890591 TI - Emergent "Quantum" Theory in Complex Adaptive Systems. AB - Motivated by the question of stability, in this letter we argue that an effective quantum-like theory can emerge in complex adaptive systems. In the concrete example of stochastic Lotka-Volterra dynamics, the relevant effective "Planck constant" associated with such emergent "quantum" theory has the dimensions of the square of the unit of time. Such an emergent quantum-like theory has inherently non-classical stability as well as coherent properties that are not, in principle, endangered by thermal fluctuations and therefore might be of crucial importance in complex adaptive systems. PMID- 28890592 TI - Demonstration of Multi- and Single-Reader Sample Size Program for Diagnostic Studies software. AB - The recently released software Multi- and Single-Reader Sample Size Sample Size Program for Diagnostic Studies, written by Kevin Schartz and Stephen Hillis, performs sample size computations for diagnostic reader-performance studies. The program computes the sample size needed to detect a specified difference in a reader performance measure between two modalities, when using the analysis methods initially proposed by Dorfman, Berbaum, and Metz (DBM) and Obuchowski and Rockette (OR), and later unified and improved by Hillis and colleagues. A commonly used reader performance measure is the area under the receiver-operating characteristic curve. The program can be used with typical common reader performance measures which can be estimated parametrically or nonparametrically. The program has an easy-to-use step-by-step intuitive interface that walks the user through the entry of the needed information. Features of the software include the following: (1) choice of several study designs; (2) choice of inputs obtained from either OR or DBM analyses; (3) choice of three different inference situations: both readers and cases random, readers fixed and cases random, and readers random and cases fixed; (4) choice of two types of hypotheses: equivalence or noninferiority; (6) choice of two output formats: power for specified case and reader sample sizes, or a listing of case-reader combinations that provide a specified power; (7) choice of single or multi-reader analyses; and (8) functionality in Windows, Mac OS, and Linux. PMID- 28890594 TI - Living Near to Attractive Nature? A Well-Being Indicator for Ranking Dutch, Danish, and German Functional Urban Areas. AB - While nature is widely acknowledged to contribute to people's well-being, nature based well-being indicators at city-level appear to be underprovided. This study aims at filling this gap by introducing a novel indicator based on the proximity of city-residents to nature that is of high-amenity. High-amenity nature is operationalized by combining unique systematic data on people's perceptions of what are the locations of attractive natural areas with data on natural land cover. The proposed indicator departs from the usual assumption of equal well being from any nature, as it approximates the 'actual' subjective quality of nature near people's homes in a spatially explicit way. Such indicator is used to rank 148 'cities' in the Netherlands, Denmark, and Germany. International comparability of the indicator is enhanced by the use of a definition of cities as functional urban areas (FUAs), which are consistently identified across countries. Results demonstrate that the average 'nearness' of FUA populations to high amenity nature varies widely across the observed FUAs. A key finding, that complements insights from existing city-level indicators, is that while populations of FUAs with higher population densities may live relatively far from nature in general, they also live, on average, closer to high-amenity nature than inhabitants of lower density FUAs. Our results may stimulate policy-debates on how to combine urban agglomeration with access to natural amenities in order to account for people's wellbeing. PMID- 28890593 TI - Examples of applied public health through the work of the Epidemic Intelligence Service officers at CDC's National Center for Environmental Health: 2006-2015. AB - The Epidemic Intelligence Service officers (EISOs) at the National Center for Environmental Health (NCEH)/Agency for Toxic Substances and Disease Registry (ATSDR) respond to public health outbreaks, assist public health surveillance, and recommend public health actions. We summarize the breadth of work done by EISOs assigned to NCEH/ATSDR during 2006-2015. We used the Web of Science, Scopus, and PubMed databases to identify articles authored by the EISOs, number and types of epidemiologic assistance field investigations (Epi-Aids), and interviewed NCEH/ATSDR programs with EISO assignees. The largest number of NCEH/ATSDR EISO publications (n = 61) and Epi-Aids (n = 110) related to toxic chemicals (23 and 37, respectively), followed by natural disasters and those caused by humans (19 and 25, respectively), extreme temperature-related illness (9), and chronic diseases (8). The investigations raised awareness, identified risk factors and public health needs, and introduced better prevention and protection measures for human health. Through field investigations and other technical assistance, NCEH/ATSDR provided leadership and staff scientists to assist in the field, as well as knowledge transfer to local, state, territorial, and international health departments. PMID- 28890595 TI - Does Consumer Confidence Forecast Household Saving and Borrowing Behavior? Evidence for Poland. AB - Consumer confidence plays an important role in households' decision-making processes. This study investigates the effects of consumer confidence on household saving and borrowing behavior that are unsatisfactorily considered in previous discussions. The questions of interest are first, whether indexes of consumer confidence have any predictive power on their own for future household saving and borrowing rates, and second, whether they contain information about future household saving and borrowing rates aside from the information contained in other available indicators. In addition to aggregate confidence indicators, their components are used to provide more precise information. Overall, the multiple linear regression analysis (OLS technique) of Polish time-series data gives positive answers to both questions. This finding supports the recommendation of combining the strengths of objective indicators (such as economic fundamentals) and subjective indicators (such as consumer confidence) to improve household financial behavior forecasts. PMID- 28890597 TI - Women's Land Tenure Security and Household Human Capital: Evidence from Ethiopia's Land Certification. AB - This paper examines the impact of Ethiopia's gendered land certification programs on household consumption of healthcare, food, education, and clothing. Ethiopia embarked on a land tenure reform program in 1998, after years of communism during which all land was nationalized. The reform began in Tigray region where land certificates were issued to household heads, who were primarily male. In a second phase carried out in 2003-2005, three other regions issued land certificates jointly to household heads and spouses, presenting variation in land tenure security by gender. Results using household panel data show that joint land certification to spouses was accompanied by increased household consumption of healthcare and homegrown food and decreased education expenditure, compared to household-head land certification. Joint land certification was also accompanied by increased consumption of women's and girls' clothing, and decreased men's clothing expenditures indicating results may be explained by a shift in the gender balance of power within households. Analysis on the incidence and duration of illness indicates that increased healthcare expenditures after joint land certification may be due to joint certification households seeking more effective treatment than head-only certification households for household members who fell ill or suffered injuries. PMID- 28890596 TI - Explaining Accessibility and Satisfaction Related to Healthcare: A Mixed-Methods Approach. AB - Accessibility and satisfaction related to healthcare services are conceived as multidimensional concepts. These concepts can be studied using objective and subjective measures. In this study, we created two indices: a composite healthcare accessibility index (CHCA) and a composite healthcare satisfaction index (CHCS). To calculate the CHCA index we used three indicators based on three components of multidimensional healthcare accessibility: availability, acceptability and accessibility. In the indicator based on the component of accessibility, we included an innovative perceived time-decay parameter. The three indicators of the CHCA index were weighted through the application of a principal components analysis. To calculate the CHCS index, we used three indicators: the waiting time after the patient arrives at the healthcare service, the quality of the healthcare, and the healthcare service supply. These three indicators making up the CHCA index were weighted by applying an analytical hierarchy process. Three kinds of regressions were subsequently applied in order to explain the CHCA and CHCS indices: namely the Linear Least Squares, Ordinal Logistic, and Random Forests regressions. In these regressions, we used different independent social and health-related variables. These variables represented the predisposing, enabling, and need factors of people's behaviors related to healthcare. All the calculations were applied to a study area: the city of Quito, Ecuador. Results showed that there are health-related inequalities in regard to healthcare accessibility and healthcare satisfaction in our study area. We also identified specific social factors that explained the indices developed. The present work is a mixed-methods approach to evaluate multidimensional healthcare accessibility and healthcare satisfaction, incorporating a pluralistic perspective, as well as a multidisciplinary framework. The results obtained can also be considered as tools for healthcare and urban planners, for more integrative social analyses that can improve the quality of life in urban residents. PMID- 28890598 TI - Experimental Investigation of Wood Decking Assemblies Exposed to Firebrand Showers. AB - Wildland-Urban Interface (WUI) fires have become a problem of great concern across multiple continents. An important mechanism of structure ignition in WUI fires and urban fires is the production of firebrands. During WUI fires, decking assemblies have been observed to be an ignition vulnerability based on post-fire damage surveys conducted by NIST and elsewhere. The authors have conducted scoping experiments and demonstrated the dangers of the dynamic process of continual, wind-driven firebrand showers landing on decking assemblies for wind speeds of 6 m/s. In this study, eight full-scale experiments were conducted with wood decking assemblies under a wind speed of 8 m/s. The basis for these new investigations was twofold: observe possible vulnerabilities of wood decking assemblies to continuous, wind-driven firebrands at higher wind speed as firebrand accumulation patterns were expected to be influenced by wind speed, and examine if wall ignition occurred due to the burning decking assembly. To this end, sections of wood decking assemblies (1.2 m by 1.2 m) were constructed and attached to a reentrant corner assembly. The deck/reentrant corner assembly was then exposed to continuous, wind-driven firebrand bombardment generated by a full scale Continuous Feed Firebrand Generator installed in the Fire Research Wind Tunnel Facility (FRWTF) at the Building Research Institute (BRI) in Japan. The mass of firebrands required for flaming ignitions under a wind speed of 8 m/s was considerably less compared with those under a wind speed of 6 m/s. This result is postulated to be due to higher firebrand surface temperatures as the wind speed was increased. For the decking assembly to wall ignition studies, the interface between the decking assembly and the wall appeared to be a weak point; this is not addressed in the current test methods. PMID- 28890599 TI - Evaluation of Structural Robustness against Column Loss: Methodology and Application to RC Frame Buildings. AB - A computational methodology is presented for evaluating structural robustness against column loss. The methodology is illustrated through application to reinforced concrete (RC) frame buildings, using a reduced-order modeling approach for three-dimensional RC framing systems that includes the floor slabs. Comparisons with high-fidelity finite-element model results are presented to verify the approach. Pushdown analyses of prototype buildings under column loss scenarios are performed using the reduced-order modeling approach, and an energy based procedure is employed to account for the dynamic effects associated with sudden column loss. Results obtained using the energy-based approach are found to be in good agreement with results from direct dynamic analysis of sudden column loss. A metric for structural robustness is proposed, calculated by normalizing the ultimate capacities of the structural system under sudden column loss by the applicable service-level gravity loading and by evaluating the minimum value of this normalized ultimate capacity over all column removal scenarios. The procedure is applied to two prototype 10-story RC buildings, one employing intermediate moment frames (IMFs) and the other employing special moment frames (SMFs). The SMF building, with its more stringent seismic design and detailing, is found to have greater robustness. PMID- 28890601 TI - Impact of RRAM Read Fluctuations on the Program-Verify Approach. AB - The stochastic nature of the conductive filaments in oxide-based resistive memory (RRAM) represents a sizeable impediment to commercialization. As such, program verify methodologies are highly alluring. However, it was recently shown that program-verify methods are unworkable due to strong resistance state relaxation after SET/RESET programming. In this paper, we demonstrate that resistance state relaxation is not the main culprit. Instead, it is fluctuation-induced false reading (triggering) that defeats the program-verify method, producing a large distribution tail immediately after programming. The fluctuation impact on the verify mechanism has serious implications on the overall write/erase speed of RRAM. PMID- 28890600 TI - Exciton Dynamics in Monolayer Transition Metal Dichalcogenides. AB - Since the discovery of semiconducting monolayer transition metal dichalcogenides, a variety of experimental and theoretical studies have been carried out seeking to understand the intrinsic exciton population recombination and valley relaxation dynamics. Reports of the exciton decay time range from hundreds of femtoseconds to ten nanoseconds, while the valley depolarization time can exceed one nanosecond. At present, however, a consensus on the microscopic mechanisms governing exciton radiative and non-radiative recombination is lacking. The strong exciton oscillator strength resulting in up to ~ 20% absorption for a single monolayer points to ultrafast radiative recombination. However, the low quantum yield and large variance in the reported lifetimes suggest that non radiative Auger-type processes obscure the intrinsic exciton radiative lifetime. In either case, the electron-hole exchange interaction plays an important role in the exciton spin and valley dynamics. In this article, we review the experiments and theory that have led to these conclusions and comment on future experiments that could complement our current understanding. PMID- 28890602 TI - Learning a Talker or Learning an Accent: Acoustic Similarity Constrains Generalization of Foreign Accent Adaptation to New Talkers. AB - Past research has revealed that native listeners use top-down information to adjust the mapping from speech sounds to phonetic categories. Such phonetic adjustments help listeners adapt to foreign-accented speech. However, the mechanism by which talker-specific adaptation generalizes to other talkers is poorly understood. Here we asked what conditions induce crosstalker generalization in talker accent adaptation. Native-English listeners were exposed to Mandarin-accented words, produced by a single talker or multiple talkers. Following exposure, adaptation to the accent was tested by recognition of novel words in a task that assesses online lexical access. Crucially, test words were novel words and were produced by a novel Mandarin-accented talker. Results indicated that regardless of exposure condition (single or multiple talker exposure), generalization was greatest when the talkers were acoustically similar to one another, suggesting that listeners were not developing an accent-wide schema for Mandarin talkers, but rather attuning to the specific acoustic phonetic properties of the talkers. Implications for general mechanisms of talker generalization in speech adaptation are discussed. PMID- 28890603 TI - HARNESSING VALUES TO PROMOTE MOTIVATION IN EDUCATION. AB - PURPOSE: We review the interventions that promote motivation in academic contexts, with a focus on two primary questions: How can we motivate students to take more STEM courses? Once in those STEM courses, how can we keep students motivated and promote their academic achievement? DESIGN/METHODOLOGY/APPROACH: We have approached these two motivational questions from several perspectives, examining the theoretical issues with basic laboratory research, conducting longitudinal questionnaire studies in classrooms, and developing interventions implemented in different STEM contexts. Our research is grounded in three theories that we believe are complementary: expectancy-value theory (Eccles & Wigfield, 2002), interest theory (Hidi & Renninger, 2006), and self-affirmation theory (Steele, 1988). As social psychologists, we have focused on motivational theory and used experimental methods, with an emphasis on values - students' perceptions of the value of academic tasks and students' personal values that shape their experiences in academic contexts. FINDINGS: We review the experimental field studies in high-school science and college psychology classes, in which utility-value interventions promoted interest and performance for high school students in science classes and for undergraduate students in psychology courses. We also review a randomized intervention in which parents received information about the utility value of math and science for their teens in high school; this intervention led students to take nearly one semester more of science and mathematics, compared with the control group. Finally, we review an experimental study of values affirmation in a college biology course and found that the intervention improved performance and retention for first-generation college students, closing the social-class achievement gap by 50%. We conclude by discussing the mechanisms through which these interventions work. ORIGINALITY/VALUE: These interventions are exciting for their broad applicability in improving students' academic choices and performance, they are also exciting regarding their potential for contributions to basic science. The combination of laboratory experiments and field experiments is advancing our understanding of the motivational principles and almost certainly will continue to do so. At the same time, interventions may benefit from becoming increasingly targeted at specific motivational processes that are effective with particular groups or in particular contexts. PMID- 28890604 TI - Monitoring of Batch Industrial Crystallization with Growth, Nucleation, and Agglomeration. Part 2: Structure Design for State Estimation with Secondary Measurements. AB - This work investigates the design of alternative monitoring tools based on state estimators for industrial crystallization systems with nucleation, growth, and agglomeration kinetics. The estimation problem is regarded as a structure design problem where the estimation model and the set of innovated states have to be chosen; the estimator is driven by the available measurements of secondary variables. On the basis of Robust Exponential estimability arguments, it is found that the concentration is distinguishable with temperature and solid fraction measurements while the crystal size distribution (CSD) is not. Accordingly, a state estimator structure is selected such that (i) the concentration (and other distinguishable states) are innovated by means of the secondary measurements processed with the geometric estimator (GE), and (ii) the CSD is estimated by means of a rigorous model in open loop mode. The proposed estimator has been tested through simulations showing good performance in the case of mismatch in the initial conditions, parametric plant-model mismatch, and noisy measurements. PMID- 28890605 TI - Highly Planarized Naphthalene Diimide-Bifuran Copolymers with Unexpected Charge Transport Performance. AB - The synthesis, characterization, and charge transport performance of novel copolymers PNDIFu2 made from alternating naphthalene diimide (NDI) and bifuran (Fu2) units are reported. Usage of potentially biomass-derived Fu2 as alternating repeat unit enables flattened polymer backbones due to reduced steric interactions between the imide oxygens and Fu2 units, as seen by density functional theory (DFT) calculations and UV-vis spectroscopy. Aggregation of PNDIFu2 in solution is enhanced if compared to the analogous NDI-bithiophene (T2) copolymers PNDIT2, occurring in all solvents and temperatures probed. PNDIFu2 features a smaller pi-pi stacking distance of 0.35 nm compared to 0.39 nm seen for PNDIT2. Alignment of aggregates in films is achieved by using off-center spin coating, whereby PNDIFu2 exhibits a stronger dichroic ratio and transport anisotropy in field-effect transistors (FET) compared to PNDIT2, with an overall good electron mobility of 0.21 cm2/(V s). Despite an enhanced backbone planarity, the smaller pi-pi stacking and the enhanced charge transport anisotropy, the electron mobility of PNDIFu2 is about three times lower compared to PNDIT2. Density functional theory calculations suggest that charge transport in PNDIFu2 is limited by enhanced polaron localization compared to PNDIT2. PMID- 28890606 TI - Combined photographic and ultrasonographic measurement of the ANB angle: a pilot study. AB - OBJECTIVE: This study was performed to evaluate the feasibility of noninvasive measurement of the ANB angle using photographic and ultrasonographic methods. METHODS: Twenty consecutive orthodontic patients were evaluated. The ANB angle and soft tissue thickness covering the N, A, and B cephalometric points were measured by lateral teleradiography; these measurements were made by two expert operators. The soft tissue thickness covering the N, A, and B cephalometric points was measured by ultrasonography; these measurements were also made by two expert operators. On a 1:1 photographic profile print on which the ultrasonographic points were marked, the ANB ultrasonographic angle was measured. The following comparisons were considered: averaged and single measurements of N, A, and B points by first versus second ultrasonographer; averaged and single ultrasonographic versus radiographic soft tissue thickness covering the N, A, B points; and averaged and single ultrasonographic versus radiographic measurements of ANB angle. RESULTS: High correlation and concordance of the averaged and single measurements, but no significant difference, was found between the two ultrasonographers. No statistically significant difference was found between the two methods for measuring averaged soft tissue thickness, but a 20% difference was found for the single measurements. High correlation and concordance between the ultrasonographic and radiographic measurements, but no significant difference, was found between the single and averaged ANB angle measurements. CONCLUSION: Ultrasonography seems to be a noninvasive and reliable technique for measurement of the ANB angle and may replace radiographic measurement in some cases. PMID- 28890607 TI - Determining geometric error model parameters of a terrestrial laser scanner through Two-face, Length-consistency, and Network methods. AB - Terrestrial laser scanners (TLS) are increasingly used in large-scale manufacturing and assembly where required measurement uncertainties are on the order of few tenths of a millimeter or smaller. In order to meet these stringent requirements, systematic errors within a TLS are compensated in-situ through self calibration. In the Network method of self-calibration, numerous targets distributed in the work-volume are measured from multiple locations with the TLS to determine parameters of the TLS error model. In this paper, we propose two new self-calibration methods, the Two-face method and the Length-consistency method. The Length-consistency method is proposed as a more efficient way of realizing the Network method where the length between any pair of targets from multiple TLS positions are compared to determine TLS model parameters. The Two-face method is a two-step process. In the first step, many model parameters are determined directly from the difference between front-face and back-face measurements of targets distributed in the work volume. In the second step, all remaining model parameters are determined through the Length-consistency method. We compare the Two-face method, the Length-consistency method, and the Network method in terms of the uncertainties in the model parameters, and demonstrate the validity of our techniques using a calibrated scale bar and front-face back-face target measurements. The clear advantage of these self-calibration methods is that a reference instrument or calibrated artifacts are not required, thus significantly lowering the cost involved in the calibration process. PMID- 28890608 TI - Coronal Sealing Capacity of Temporary Restorative Materials in Pediatric Dentistry: A Comparative Study. AB - AIMS: The aim of this in vitro study is to compare the coronal microleakage of three common temporary restorative materials, namely Coltosol, Compoglass, and Zonalin, used in pediatric dentistry after endodontic treatment at different time intervals (1 week, 1, and 2 months) using dye penetration. MATERIALS AND METHODS: Access cavities were prepared in 72 intact extracted premolar teeth. The samples were divided into three groups (n = 24) and filled with Coltosol, Compoglass, or Zonalin. After thermal cycling for 500 cycles (5-55 degrees C), the teeth were immersed in 1% methylene blue dye at 37 degrees C for 1 week (n = 8), 1 month (n = 8), and 2 months (n = 8). The samples were sectioned buccolingually, and the linear depth of dye penetration was measured using a stereomicroscope at 16 * magnification. The data were analyzed using Kruskal-Wallis test. RESULTS: There were no significant differences in the micro-leakage values of Coltosol and Zonalin or Zonalin and Com-poglass groups at 1 week (p > 0.05) or 1 month (p > 0.05) intervals, but a significant difference was noted between Coltosol and Compoglass groups (p < 0.01); Coltosol provided a more favorable coronal seal. No significant difference was found among the experimental groups at the 2-month interval (p > 0.05). CONCLUSION: At 1 week or 1 month of use, Coltosol showed better coronal seal. At 2 months, there was no significant difference apparent between the groups. A longer time lapse was associated with an increased likelihood of microleakage. HOW TO CITE THIS ARTICLE: Milani S, Seraj B, Heidari A, Mirdamadi A, Shahrabi M. Coronal Sealing Capacity of Temporary Restorative Materials in Pediatric Dentistry: A Comparative Study. Int J Clin Pediatr Dent 2017;10(2):115-118. PMID- 28890609 TI - Association of Feeding Methods and Streptococcus mutans Count with Early Childhood Caries: A Cross-sectional Study. AB - INTRODUCTION: Early childhood caries (ECC) is a virulent form of dental caries that can destroy the primary dentition of toddlers and preschool children. The aim was to determine the relationship of feeding methods and oral Streptococcus mutans count in 3- to 5-year-old children with ECC. MATERIALS AND METHODS: A cross-sectional study was conducted in children aged 3 to 5 years. Participating mothers were interviewed regarding child's demographic profile, educational level and socioeconomic status of parents, past medical and dental history of the mother and child, child's feeding habits, and dietary habits and oral hygiene practices of mother and child. Clinical examination for dental caries was done using the World Health Organization criteria (1997). Salivary samples of mother child pair were collected to determine the pH, flow rate, and S. mutans count. Statistical tests, such as Student's t-test, analysis of variance, and Pearson's correlation were applied. RESULTS: Out of 150 mother-child pair, statistically significant difference in the caries experience was found between mothers and children with high and low S. mutans count. Moderate but statistically significant negative correlation was found between mean decayed, missing, and filled teeth of mothers and mean decayed, extracted and filled teeth (deft) of children with high S. mutans count. Regarding deft, there was no statistically significant difference between children who were exclusively breast fed (7.85 +/- 2.94), exclusively bottle-fed (8.67 +/- 3.98), and both breast and bottle-fed (7.77 +/- 2.91). CONCLUSION: The mean caries experience of mothers and children was 2.66 +/- 2.01 and 7.82 +/- 2.94 respectively, with decayed component being maximum. Moderate and significant correlation (r = 0.5) was found between S. mutans of mothers and children in saliva. Significant negative correlation was found between mothers and children with high S. mutans count (r = -0.0284; p = 0.046). HOW TO CITE THIS ARTICLE: Bullappa D, Puranik MP, Sowmya KR, Nagarathnamma T. Association of Feeding Methods and Streptococcus mutans Count with Early Childhood Caries: A Cross-sectional Study. Int J Clin Pediatr Dent 2017;10(2):119-125. PMID- 28890610 TI - Evaluation of Novel Glass Fiber-reinforced Composite Technique for Primary Anterior Teeth with Deep Carious Lesions: A 12-month Clinical Study. AB - BACKGROUND: Early childhood caries discloses a distinct clinical pattern, and the teeth most often involved are the maxillary central incisors, lateral incisors, and the maxillary and man-dibular first molars. The maxillary incisors are most severely affected, with deep carious lesions usually involving the pulp. Teeth that have been endodontically treated often have little coronal tooth tissue remaining and as such require a post to retain the core and restoration .This study evaluated and compared the efficacy of EverStick glass fiber-reinforced composite post with ParaPost Taper Lux in primary maxillary anterior teeth. AIM: An in vivo study was conducted to evaluate and compare the longevity and failures of two fiber post systems in primary maxillary anterior teeth. MATERIALS AND METHODS: A total of 60 severely mutilated primary maxillary anterior teeth from children aged 3 to 5 years were selected according to the inclusion criteria. These teeth were treated endodontically and were randomly assigned into two groups with 30 samples in each group, group I: EverStick glass fiber-reinforced composite post, group II: ParaPost Taper Lux post. The evaluation of dislodgment of posts, secondary caries, root fracture, and post fracture was carried out clinically and radiographically during every follow-up at 3, 6, 9, and 12 months interval. RESULTS: Statistical tests (Chi-square test, Fisher's exact probability test) suggested that dislodgment of the posts was significant between the two groups at 6, 9, and 12 months follow-ups. But within the group during subsequent follow-up intervals, dislodgment of posts as a mode of failure was not statistically significant. However, clinically failures were seen in both the study groups. CONCLUSION: Fiber post system has proved to be successful clinically in both primary and permanent teeth due to the mono-block effect with luting agent, post system, core material, and bonding to dentin. Thus, today the EverStick glass fiber post system provides a novel way of fabricating cost effective and less time-consuming custom-made post in treating mutilated maxillary anteriors. HOW TO CITE THIS ARTICLE: Sawant A, Chunawalla Y, Morawala A, Kanchan NS, Jain K, Talathi R. Evaluation of Novel Glass Fiber-reinforced Composite Technique for Primary Anterior Teeth with Deep Carious Lesions: A 12 month Clinical Study. Int J Clin Pediatr Dent 2017;10(2):126-130. PMID- 28890611 TI - Comparison of Antimicrobial Activity of Child Formula Dentifrices at different Concentrations: An in vitro Study. AB - AIM: The aim of the present in vitro study is to evaluate and compare antimicrobial efficacy of commercially available child's dental formulas in reduced concentrations containing different forms of fluoride against Streptococcus mutans activity. MATERIALS AND METHODS: The selected dentifrices were prepared in dilutions of 1:1, 1:2, 1:4, 1:8, and 1:16 using sterile pyrogen free distilled water. Various dilutions of the selected toothpaste slurries were incubated in the agar plate containing pure strains of S. mutans, and antimicrobial activity of each was assessed by measuring the diameter of zones of inhibition (in mm). Agar well plate diffusion method and minimum inhibitory concentration (MIC) determination were the methods used in this study. The inhibitory circle of each dentifrice was measured and MIC was achieved by considering the value of diameter of the circle. RESULTS: The results of the study showed that even at a lower concentration of fluoride, inhibition halos were obtained for all the formulations at different dilutions. CONCLUSION: The kid's formulations having lower fluoride concentration show antimicrobial activity even after dilutions. Thus, commercially, the fluoride concentrations can be further lowered down in the dentifrices, thereby reducing the risk associated with fluoride. HOW TO CITE THIS ARTICLE: Malhotra R, Singla S, Shashikiran ND. Comparison ofAntimicrobial Activity of Child Formula Dentifrices at different Concentrations: An in vitro Study. Int J Clin Pediatr Dent 2017;10(2):131-135. PMID- 28890612 TI - Comparative Evaluation of Sealing Ability, Water Absorption, and Solubility of Three Temporary Restorative Materials: An in vitro Study. AB - BACKGROUND: The quality of the coronal seal of root canal filling material is important for periapical health. Absorption of water or saliva by the temporary restorative materials leads to dimensional changes, loss of retention, staining and breaking in margin contours. Hence this study was carried out to evaluate and compare the sealing properties, water absorption and solubility of IRM (intermediate restorative material), Cavit G and GC Caviton. STUDY DESIGN: Experimental, in vitro intergroup randomized control trial. MATERIAL AND METHODS: 36 non carious premolars were randomly selected assigned to three groups, 12 teeth in each. Standard endodontic access cavities of approximately 4x4mm wide were prepared followed by the root canal obturation with Gutta-percha and restoration with experimental materials. For microleakage testing dye penetration method was used with 2% methylene blue dye. Followed by evaluation and scoring under stereomicroscope at 40x magnification. Disc shaped 12 specimens for each group were prepared for each material, stored in desiccator at 37 degrees C, weighed daily to verify mass stabilization (dry mass,m1). Thereafter, the specimens were stored in distilled water at 37 degrees C for 7days to obtain the mass after saturation with water (m2). The specimens were placed in the desiccators again, at 37 degrees C, and reweighed until a constant dry mass is obtained (m3). Water absorption (WS) and solubility (SL) was determined by using the formulas, WS = m3 - m2/V and SL= ml - m3/ V. RESULTS: GC Caviton showed least microleakage and least water absorption followed by IRM and Cavit G, the differences were statistically highly significant ( p < 0.001) and there was no statistical difference found in all the groups with respect to solubility. CONCLUSIONS: GC Caviton is best and suitable temporary restorative material in endodontic interappointments followed by IRM and Cavit G. HOW TO CITE THIS ARTICLE: Prabhakar AR, Rani NS, Naik SV. Comparative Evaluation of Sealing Ability, Water Absorption, and Solubility of Three Temporary Restorative Materials: An in vitro Study. Int J Clin Pediatr Dent 2017;10(2):136-141. PMID- 28890613 TI - Assessment of Vitamin B12 and Its Correlation with Dental Caries and Gingival Diseases in 10- to 14-year-old Children: A Cross-sectional Study. AB - AIM: To assess the level of vitamin B12 and correlate it with dental caries [decayed, missing, and filled permanent teeth (DMFT) score] and gingival diseases [plaque index (PI) and gingival index (GI)]. DESIGN: Healthy children according to the inclusion criteria were selected by the computerized randomization method from a school to assess the vitamin B12 levels using Centaur/ Versace machine. MATERIALS AND METHODS: Blood samples were collected to assess vitamin B12 levels using automated analyzer. Oral examination was done by a single calibrated dentist. A thorough oral examination was carried out and the DMFT, PI, and GI scores of all the children were recorded and assessed. Data were analyzed using Karl Pearson's correlation test. RESULTS: Vitamin B12 levels were deficient in 64% of the children. In boys, vitamin B12 deficiency was found in about 76.2%, whereas, in girls it was 57.1%, which was not statistically significant. The vitamin B12 deficient children showed a significantly high DMFT scores than the children with normal vitamin B12 levels. The Pearson's correlation was -0.614 for DMFT, PI value -0.663, and GI value of -0.477. The negative correlation stated that there was a reverse relation between these indices and vitamin B12. CONCLUSION: In children with systemic vitamin B12 deficiency, there is increased dental caries prevalence and associated gingival problems. HOW TO CITE THIS ARTICLE: Hugar SM, Dhariwal NS, Majeed A, Badakar C, Gokhale N, Mistry L. Assessment of Vitamin B12 and Its Correlation with Dental Caries and Gingival Diseases in 10- to 14-year-old Children: A Cross-sectional Study. Int J Clin Pediatr Dent 2017;10(2):142-146. PMID- 28890614 TI - Comparison of Clinical and Radiographic Success Rates of Pulpotomy in Primary Molars using Ferric Sulfate and Bioactive Tricalcium Silicate Cement: An in vivo Study. AB - INTRODUCTION: Formocresol has been a popular pulpotomy medicament for many years. It is considered the "gold standard" in pediatric dentistry. However, concerns have been raised over its use in children. It has been reported that formocresol has toxic and mutagenic effects in cell culture, dental crypts, and precancerous epithelial cells. Therefore, additional biocompatible treatment alternatives are required to replace formocresol pulpotomy. AIMS: This study compared the clinical and radiographic success rates of ferric sulfate (FS) and bioactive tricalcium silicate cement (Biodentine, Septodont) as pulpotomy agents in primary molar teeth over a period of 9 months. MATERIALS AND METHODS: Fifty primary molar teeth, symptom free, requiring pulpotomy in children aged 4 to 8 years were treated with conventional pulpotomy procedures. Ferric sulfate 15.5% solution (applied for 15 second for 25 teeth) and Biodentine (for 25 teeth) were used as pulpotomy agents. Permanent restorations were stainless steel crowns in most cases, in both groups. Patients were recalled for follow-up at 1, 3, 6, and 9 months intervals. The data were statistically analysed using chi-square test. RESULTS: At 9 months, 96% clinical success rate was observed in the FS and 100% in the Biodentine group. Radiographic success rate in the FS group was 84%, whereas 92% in the Biodentine group at 9 months. No statistically significant difference was found between the two groups. CONCLUSION: Biodentine can be used as a pulpotomy agent but further long-term studies are required. HOW TO CITE THIS ARTICLE: Sirohi K, Marwaha M, Gupta A, Bansal K, Srivastava A. Comparison of Clinical and Radiographic Success Rates of Pulpotomy in Primary Molars using Ferric Sulfate and Bioactive Tricalcium Silicate Cement: An in vivo Study. Int J Clin Pediatr Dent 2017;10(2):147-151. PMID- 28890615 TI - Antibacterial Inhibitory Effects of Punica Granatum Gel on Cariogenic Bacteria: An in vitro Study. AB - AIM: This study evaluated the in vitro antibacterial effects of the formulated Punica granatum (PG) gel against Streptococcus mutans, Streptococcus sanguinis, and Lactobacillus casei. MATERIALS AND METHODS: The PG extract was dissolved in water at 500 mg/mL. High performance liquid chromatography (HPLC) was used for identification and quantification of chemical marker punicalagin. Minimum bactericidal concentration (MBC) and time-kill assay (TKA) were investigated. Antibacterial activities of the formulated PG gel, 2% chlorhexidine (CHX) gel and blank gel were tested by measuring the zones of inhibition through agar well diffusion method. RESULTS: The HPLC results showed presence of punicalagin at 2023.58 +/- 25.29 pg/mL in the aqueous PG extract and at 0.234% (w/w) in the formulated PG gel. The MBC for S. mutans, S. Sanguinis, and L. casei were 250, 125, and 500 mg/mL respectively. The TKA of 500 mg/mL aqueous PG extract showed total inhibition of S. mutans, S. Sanguinis, and L. casei at 6, 1, and 24 hours contact time respectively. Agar well diffusion revealed that for S. mutans, CHX gel > PG gel > blank gel; for S. sanguinis, CHX gel = PG gel > blank gel; for L. casei, CHX gel > PG gel = blank gel. Comparison of the PG gel potency showed that S. sanguinis = S. mutans > L. casei. CONCLUSION: The PG gel equivalent to 0.234% punicalagin (w/w) inhibited S. mutans and S. sanguinis but not L. casei within 24 hours incubation period and has the potential to be used for caries prevention. HOW TO CITE THIS ARTICLE: Millo G, Juntavee A, Ratanathongkam A, Nualkaew N, Peerapattana J, Chatchiwiwattana S. Antibacterial Inhibitory Effects of Punica Granatum Gel on Cariogenic Bacteria: An in vitro Study. Int J Clin Pediatr Dent 2017;10(2):152-157. PMID- 28890616 TI - Clinical and Practical Implications of Storage Media used for Tooth Avulsion. AB - : Replantation is being widely accepted as an effective treatment option for an avulsed tooth. However, the long-term fate of replanted teeth is unpredictable; it is dependent on various factors, such as the time interval between avulsion and replantation, extra-alveolar storage period (dry storage or storage media), the vitality status of pulp or periodontal tissues and the type and period of splinting. The appropriate use of storage media is an important clinical factor affecting the postoperative prognosis of avulsed teeth following replantation. Hank's balanced salt solution and pasteurized milk are considered to be the most appropriate and clinically recommended storage media for avulsed teeth. The present review discusses the various available storage media for avulsed teeth and their potential maintenance of the vitality of periodontal ligament cells. A brief overview of the effect of clinical factors, such as the storage time, pH, and the osmolar-ity of storage media on their efficacy is included. HOW TO CITE THIS ARTICLE: Khinda VIS, Kaur G, Brar GS, Kallar S, Khurana H. Clinical and Practical Implications of Storage Media used for Tooth Avulsion. Int J Clin Pediatr Dent 2017; 10(2): 158-165. PMID- 28890617 TI - Prevalence of Oral Complications occurring in a Population of Pediatric Cancer Patients receiving Chemotherapy. AB - : Multiagent chemotherapy, radiotherapy, or a combination of both are the contemporary methods of cancer treatment. With medical advancements, though cure rates have increased considerably, focus is now shifted to the potential early and late complications of the same. The aim of this study was to assess the early oral complications in pediatric patients receiving chemotherapy. Sixty-two children with cancer undergoing chemotherapy with the mean age of 7.42 +/- 3.6 years were included in the study. The various types of malignancies and oral problems during chemotherapy were recorded in the subjects. The most commonly encountered malignancy was acute lymphoblastic leukemia at 35.5%. Various oral and associated complications like mucosal inflammation with ulcerations, oral pain, xerostomia, and secondary infections were commonly seen, with mucositis being the most commonly observed complication in 58.1% of the subjects undergoing chemotherapy. Clinical importance of timely medical and dental interventions by a multidisciplinary team involving a pediatric dentist at different stages of anticancer treatment is also emphasized to minimize discomfort, increase treatment compliance, and improve the quality of life of pediatric patients. HOW TO CITE THIS ARTICLE: Gandhi K, Datta G, Ahuja S, Saxena T, Datta AG. Prevalence of Oral Complications occurring in a Population of Pediatric Cancer Patients receiving Chemotherapy. Int Int J Clin Pediatr Dent 2017;10(2):166-171. PMID- 28890618 TI - Prevalence of Dental Caries and Traumatic Dental Injuries among 6- to 12-year-old Children in Bhopal City, India. AB - INTRODUCTION: Dental caries and trauma are the most common oral health problems for many decades. There is need for prevalence data to analyze the nature of the problems and to take necessary steps in improving public health. AIM AND OBJECTIVES: To assess the prevalence of dental caries and traumatic dental injuries among schoolchildren of age 6 to 12 years in Bhopal city. SETTINGS AND DESIGN: Cross-sectional study design was selected. Universal sampling method was followed in this study. MATERIALS AND METHODS: A total of 1,204 children were examined. The distribution of samples was done based on age, gender, residing area, and type of school. STATISTICAL ANALYSIS: Data were collected and statistically evaluated under chi-square test and analysis of variance. RESULTS: The overall caries experience (73.17%) was found to be higher than that of traumatic injury experience (20.9%). There was age-related correlation between age and decay, missing, and filled teeth score. CONCLUSION: Since most injuries occur at home or at school, educating the individual is the key that will have a great impact on the prognosis of traumatic injuries. Also good food habits need to be instilled in children from a tender age with the help of parents, which is the ultimate solution to fight caries. HOW TO CITE THIS ARTICLE: Maran S, Shashikiran ND, Ahirwar P, Maran P, Kannojiya PR, Niranjan B. Prevalence of Dental Caries and Traumatic Dental Injuries among 6- to 12-year-old Children in Bhopal City, India. Int J Clin Pediatr Dent 2017; 10(2): 172-176. PMID- 28890619 TI - Prevalence of Traumatic Dental Injuries to the Permanent Anterior Teeth among 9- to 14-year-old Schoolchildren of Navi Mumbai (Kharghar-Belapur Region), India. AB - AIMS AND OBJECTIVES: To measure the prevalence of anterior teeth trauma in 9- to 14-year-old schoolchildren and their association with predisposing factors, such as lip competence, molar relationship, overjet, and variables, such as age, gender, and cause of trauma. MATERIALS AND METHODS: Epidemiological cross sectional study was carried out among 3,012 schoolchildren aged 9 to 14 years in Navi Mumbai (Kharghar-Belapur region). The sample size was derived using the stratified random sampling method; we picked six schools from the region. These schools had 3,000 students in the acceptable age group of the study which constituted our final sample size. All children were examined for traumatic dental injuries, and the children with positive findings were further examined for lip competence, Angle's molar relationship, and overjet. The results were statistically analyzed using cross-tabulation and Chi-square test. RESULTS: The prevalence of dental injuries was 7.3%, and the ratio of male to female children was found to be 1.6:1. The maximum number of traumatic dental injuries was found with class I molar relationship and overjet less than 3.5 mm in children with competent lips. Maximum number of injuries occurred in the age group of 13-14 years. The most predominant type of injury was the enamel fracture and the most common cause determined was due to fall. CONCLUSION: The present study is a collection of data on traumatic injuries to anterior teeth, which is seen very commonly in day-to-day practice. The frequency and cause of traumatic injuries to anterior teeth is important for identification of risk groups, treatment needs, and cost involved in order for establishing effective preventive measures. HOW TO CITE THIS ARTICLE: Hegde R, Agrawal G. Prevalence of Traumatic Dental Injuries to the Permanent Anterior Teeth among 9- to 14-year-old Schoolchildren of Navi Mumbai (Kharghar-Belapur Region), India. Int J Clin Pediatr Dent 2017;10(2):177 182. PMID- 28890620 TI - Prevalence and associated Risk Factors of Severe Early Childhood Caries in 12- to 36-month-old Children of Sirmaur District, Himachal Pradesh, India. AB - AIM: To assess the prevalence, distribution, and associated risk factors of severe early childhood caries (S-ECC) among 12- to 36-month-old children of district Sirmaur, Himachal Pradesh, India. MATERIALS AND METHODS: The present study was conducted on a random sample of 510 children, both boys and girls, between 12 and 36 months of age randomly selected from various government sponsored day-care centers, private day-care centers, and vaccination centers. Caries was recorded using World Health Organization criteria. Statistical analysis was done by using chi-square test and Mann-Whitney test. A two-sided p value was calculated for each statistical test. Multiple logistic regressions were done to calculate the risk of S-ECC from independent variables. RESULTS: In the present study, S-ECC was found in 21% of 510, 12 to 36 months old children of Sirmaur district, Himachal Pradesh. The S-ECC was found to be significantly higher in 25 to 36 months old children's age group and was 27.8% in them as compared with 8% in 12 to 24 months old children. CONCLUSION: Providing anticipatory guidance and education to parents is essential for the promotion of optimal oral health of their children. There is a need for moving upstream to propose and implement policies and programs to improve the oral health of the very young, especially in a developing country like India, which lacks much data on S-ECC. HOW TO CITE THIS ARTICLE: Mangla RG, Kapur R, Dhindsa A, Madan M. Prevalence and associated Risk Factors of Severe Early Childhood Caries in 12- to 36-month-old Children of Sirmaur District, Himachal Pradesh, India. Int J Clin Pediatr Dent 2017;10(2):183-187. PMID- 28890621 TI - Soft Tissue Applications of Er,Cr:YSGG Laser in Pediatric Dentistry. AB - : Soft tissue laser, such as diode and Nd:YAG lasers were initially used in soft tissue lesions because of its increased success rate. It was because of the fact that these lasers were well-absorbed by chromophores, such as hemoglobin and melanin which are found abundant in the oral mucosa. The introduction of erbium family in 1990 comprising the Er:YAG and Er,Cr:YSGG lasers made the hard tissue laser a boon for dentistry. Erbium, chromium-doped yttrium, scandium, gallium and garnet (Er,Cr:YSGG) was introduced in 1997 for the surgical needs of clinical dentistry in general practice. The erbium belongs to the rare earth which is embedded in a host crystal. The actual lasing process takes place in the Er ion Er3+. Two host crystals consisting of yttrium, aluminum, and garnet (Y3A5O12) and yttrium, scandium, gallium, and garnet (Y3Sc2Ga3O12) are added to the erbium. The interest to use these hard tissue laser in the treatment of soft tissue lesion was because of the properties of these lasers which are well-absorbed by chromophore water apart from hydroxy appetite crystals. Erbium laser energy is absorbed by collagen, hydroxyapatite, and water components. It allows the laser to cut soft tissue, tooth structure, and bone. In the noncontact mode, the incision is scalpel-like, with very little hemostasis. In contact mode, it performs soft tissue sculpting with adequate hemostasis. The Er,Cr:YSGG is the world's most advanced dental laser, which is ideal all-tissue laser because all dental tissues contain water, for the multidisciplinary dentist who performs a broad spectrum of procedures. It delivers the highest level of clinician control, operating efficiency, flexibility in tip, and accessory selection. For optimal clinical results and patient comfort in hard and soft tissue procedures, the erbium lasers have set a new standard of clinical performance. The present case series aims to highlight the various soft tissue applications of Er,Cr:YSGG (Waterlase Biolase(r), Biolase, Inc, San Clemente, California, USA) in pediatric patients. HOW TO CITE THIS ARTICLE: Kumar G, Rehman F, Chaturvedy V. Soft Tissue Applications of Er,Cr:YSGG Laser in Pediatric Dentistry. Int J Clin Pediatr Dent 2017;10(2):188-192. PMID- 28890622 TI - Rare Condition of Dens Invaginatus in a Maxillary Primary Molar and a Birooted Maxillary Primary Canine diagnosed during Routine Examination. AB - : Congenital morphological dental alterations are related to the physiological phase of tooth development. Since the etiology of the dens invaginatus and supernumerary roots has yet to be fully determined, a rare presentation of dens invaginatus in a primary molar and a birooted deciduous maxillary canine were incidentally detected in routine radiographic examinations. Essential clinical considerations and treatment options are presented. CLINICAL SIGNIFICANCE: This study highlights the importance of a deep and comprehensive anamnesis and clinical examination, with radiographs taken when necessary. The negligence of these stages in an initial consultation could cause irreversible future damage to the patient, since rare dental anomalies or other lesions that require treatment may not be detected. HOW TO CITE THIS ARTICLE: Brandao ECB, Ribeiro AAA, Seabra LMA. Rare Condition of Dens Invaginatus in a Maxillary Primary Molar and a Birooted Maxillary Primary Canine diagnosed during Routine Examination. Int J Clin Pediatr Dent 2017;10(2): 193-195. PMID- 28890623 TI - Childhood Occurrence of Pemphigus. AB - : Pemphigus is a chronic mucocutaneous disease that initially manifests in the form of intraoral blisters which spread to other mucous membrane and skin. This study describes an unusual case of chronic generalized childhood pemphigus disease in an 11-year-old girl, who presented with multiple vesicles all over her body. Such a condition is seen more often in older people rather than children. It is crucial for dental professionals to be familiar with the diagnosis of bullous skin diseases in children and adolescents, especially in its initial stages in order to prevent the serious consequences and morbidity. The article highlights clinical presentation, histopathology, and successful management strategies useful for pediatric dental practice. HOW TO CITE THIS ARTICLE: Patil RU, Anegundi RT, Gujjar KR, Indushekar KR. Childhood Occurrence of Pemphigus. Int J Clin Pediatr Dent 2017;10(2):196-200. PMID- 28890624 TI - Closing a Large Maxillary Median Diastema using Bapat Power Arm. AB - AIM: The aim of this study is to present a case of large maxillary median diastema closed by bodily movement of central incisors using Bapat power arm (BPA). MATERIALS AND METHODS: After extraction of mesiodens, a power chain with a force of 120 gm was applied to BPA ligated to preadjusted edgewise brackets bonded to maxillary central incisors to move them over round steel wire for closure of resultant diastema. Bonded retainer was placed after the closure of median diastema. RESULTS: The median diastema was completely closed in 5 months period with almost bodily movement of incisors, which was confirmed by periapical X-ray. CONCLUSION: Bapat power arm was efficient in closing diastema without any discomfort or injury and was well accepted by the patient. HOW TO CITE THIS ARTICLE: Bapat SM, Singh C, Bandejiya P. Closing a Large Maxillary Median Diastema using Bapat Power Arm. Int J Clin Pediatr Dent 2017;10(2):201-204. PMID- 28890625 TI - A Misdiagnosed Odontogenic Tumor: A Clinical Dilemma. AB - : Odontogenic myxomas are rarely occurring, slow-growing, asymptomatic, and locally aggressive odontogenic tumors with high rate of recurrence, mainly of ectomesenchymal origin. Three-dimensional imaging techniques can be used to diagnose such pathological lesions, but have limited use as they are not cost effective and are selectively available for better outcome. Following is a case report of OM of a 5-year-old child with a brief discussion on its diagnosis and management. HOW TO CITE THIS ARTICLE: Mukherjee CG, Mukherjee U, Bansal A, Jha A. A Misdiagnosed Odontogenic Tumor: A Clinical Dilemma. Int J Clin Pediatr Dent 2017;10(2):205-207. PMID- 28890626 TI - A Rare Concomitant Occurrence of Talon Cusp in Fused Mandibular Permanent Teeth: Report of Two Cases. AB - : Fusions of teeth and talon cusp are two rare developmental dental anomalies, affecting both primary and permanent dentitions. Both the anomalies are mostly reported as isolated finding and are rarely associated with other dental anomalies. Talon cusp is more common in maxillary anterior teeth in permanent dentition and fusion is commonly reported in mandibular teeth in primary dentition. The concomitant occurrence of talon cusp and fusion is rare and its occurrence in fused mandibular permanent teeth is also rare. This case report presents two unusual cases of concomitant occurrence of talon cusp with fusion in permanent mandibular incisors. The clinical problems associated with these dental anomalies and importance of their management are discussed in these case reports. HOW TO CITE THIS ARTICLE: Goswami M, Jangra B. A Rare Concomitant Occurrence of Talon Cusp in Fused Mandibular Permanent Teeth: Report of Two Cases. Int J Clin Pediatr Dent 2017;10(2):208-212. PMID- 28890627 TI - Role of Cone Beam Computed Tomography in Evaluation of Radicular Cyst mimicking Dentigerous Cyst in a 7-year-old Child: A Case Report and Literature Review. AB - AIM: To report a rare case of large radicular cyst-associated deciduous tooth and to discuss the importance of cone beam computed tomography (CBCT) in diagnosing the condition. BACKGROUND: Radicular cyst is the most common cyst affecting the permanent teeth, but its occurrence in deciduous teeth is rare. Most of the radicular cysts are asymptomatic and are discovered accidentally when radiographs are taken. Conventional radiographs show two-dimensional images of three dimensional objects. Cone beam computed tomography provides undistorted three dimensional information of hard tissues and gives adequate spatial resolution. CASE REPORT: A 7-year-old child, with a complaint of swelling in the maxillary anterior region, was diagnosed with radicular cyst in relation to primary maxillary right central incisor based on CBCT and histopathological features. CONCLUSION AND CLINICAL SIGNIFICANCE: Early diagnosis and prompt treatment of radicular cyst in primary dentition is important to prevent damage to permanent tooth. HOW TO CITE THIS ARTICLE: Mahesh BS, Shastry SP, Murthy PS, Jyotsna TR. Role of Cone Beam Computed Tomography in Evaluation of Radicular Cyst mimicking Dentigerous Cyst in a 7-year-old Child: A Case Report and Literature Review. Int J Clin Pediatr Dent 2017;10(2):213-216. PMID- 28890629 TI - Strengthening the Link between Economic Development, Environment and Public Health. PMID- 28890628 TI - Multiple Bilateral Unerupted Supplemental Premolars: An Unusual Presentation in a Nonsyndromic Patient. AB - : Supernumerary teeth are one of the routinely encountered developmental disturbances representing one or more extra teeth in the jaws. These may resemble the teeth of the group to which it belongs, i.e., molars, premolars, or incisors, or it may bear little or no resemblance. Based on the morphologic appearance, it is classified as supplemental teeth or rudimentary teeth. The supplemental teeth are those that resemble the teeth to which it is associated and rudimentary teeth are those that do not resemble the teeth. Supplemental teeth, most of the times, are associated with syndromes and they can also be present in the absence of systemic pathology. Literature reveals predilection of the presence of supplemental premolars of 2:1 in males. This is the case report of a 14-year-old male who presented with multiple unerupted bilateral supplemental premolars on both the arches. HOW TO CITE THIS ARTICLE: Satish V, Panda S, Maganur P, Ahmed A. Multiple Bilateral Unerupted Supplemental Premo-lars: An Unusual Presentation in a Nonsyndromic Patient. Int J Clin Pediatr Dent 2017;10(2):217-222. PMID- 28890630 TI - Review of Policy, Regulatory, and Organizational Frameworks of Environment and Health in Ethiopia. AB - BACKGROUND: Ethiopia produced its Environmental Health Situational Analysis and Needs Assessment (SANA) report in 2010 as part of the global endeavor to characterize and underscore the importance of connecting health and environment. The assessment methods used in SANA 2010 were updated, replicated and used in this SABNA. with a focus on air pollution, occupational safety and health, and climate change. OBJECTIVES: The purpose of the review was to examine national policies and identify gaps in regulations and organizational arrangements that determine Ethiopia's ability to mitigate and eventually prevent the health impacts of air pollution, occupational hazards, and climate change. METHODS: The national policy and regulatory documents were reviewed. Literature was identified through electronic searches. Hard copies of past reports and policies were reviewed whenever necessary. A semi-structured guideline was used to conduct in depth interviews aimed at identifying gaps and needs. RESULTS: The Constitution of Ethiopia has policy provisions related to air pollution, occupational safety and health (OSH), and climate change and health. Proclamation No. 300/2002 on Environmental Pollution Control specifies ambient air quality standards and allowable emissions. However, there were no documents that outlined the national or regional strategies that the ministries and agencies could adopt to translate existing policies, legal provisions, or guidelines for air pollution into practical programs. In the same way, a national OSH policy was lacking at the time this review was made on how occupational safety and health should be handled nationally or at lower governing levels as required by the International Occupation Safety and Health and Working Environment Convention No. 155/1981. Ethiopia is a signatory of this Convention. CONCLUSIONS AND RECOMMENDATIONS: The results of the situational analysis indicate that there are cross-cutting gaps in the various sectors. Among these, addressing the critical shortage of skilled personnel is an urgent priority. Most stakeholders face acute shortages of professionals and poor retention mechanisms. It is therefore important to design interventions that focus on capacity building in, for example, aligning curricula with specific needs of ministries, andequip professionals with the necessary technical skills.In addition, the results indicate that policies and regulations exist in theory, but in practice, there are inadequate implementation strategies to encourage adherence and enforcement of the regulations and policies. PMID- 28890632 TI - On some binomial [Formula: see text]-difference sequence spaces. AB - In this paper, we introduce the binomial sequence spaces [Formula: see text], [Formula: see text] and [Formula: see text] by combining the binomial transformation and difference operator. We prove the BK-property and some inclusion relations. Furthermore, we obtain Schauder bases and compute the alpha , beta- and gamma-duals of these sequence spaces. Finally, we characterize matrix transformations on the sequence space [Formula: see text]. PMID- 28890631 TI - Indoor and Outdoor Air Pollution- related Health Problem in Ethiopia: Review of Related Literature. AB - BACKGROUND: The health effects of air pollution are generally global problems, but they have, since recently become issues of particular concern for developing countries. This review assessed the situation of air pollution and related health effects in the context of Ethiopia. METHODS: The materials reviewed in this publication are published scientific papers from online search engines, unpublished government reports and academic theses/dissertations. In addition, interview data obtained from authorities and experts involved in the management of air quality were analyzed, interpreted and reported in the article. RESULTS: Review of the few studies conducted in Ethiopia showed that average concentrations of PM2.5 reached as high as 280 ug/m3 for 24-hour measurements (range: 2,417-12,739 ug/m3). Indoor carbon monoxide (CO) levels were universally higher than regulatory limits for the United States and were found to be much higher among households using traditional stoves and solid biomass fuels. The use of traditional stoves and solid biomass fuels was reported in >95% of the households considered. High average levels of NO2 (97 ppb) were reported in a large longitudinal study. The ambient PM10 level was below the WHO guideline values in the majority of the samples. About 50% of the on-road CO samples taken from traffic roads in Addis Ababa were found to be less than the guideline values while the number of motor vehicles in Ethiopia is reported to be increasing by more than 9% per annum. There is a very limited air quality monitoring capacity in the country. The co-ordination between stakeholders in this regard is also inadequate. The limited evidence available on health effects of air pollution indicates that the prevalence of acute respiratory illness among children living in households using crude biomass fuels is significantly higher than the national average figures. CONCLUSION: The limited evidence reviewed and reported in this article indicates high levels of indoor air pollution and trends of worsening outdoor air pollution. This tentative conclusion carries with it the urgent need for more evidence-based research and capacity building in the areas of indoor and outdoor air pollution. PMID- 28890633 TI - The approximation of bivariate Chlodowsky-Szasz-Kantorovich-Charlier-type operators. AB - In this paper, we introduce a bivariate Kantorovich variant of combination of Szasz and Chlodowsky operators based on Charlier polynomials. Then, we study local approximation properties for these operators. Also, we estimate the approximation order in terms of Peetre's K-functional and partial moduli of continuity. Furthermore, we introduce the associated GBS-case (Generalized Boolean Sum) of these operators and study the degree of approximation by means of the Lipschitz class of Bogel continuous functions. Finally, we present some graphical examples to illustrate the rate of convergence of the operators under consideration. PMID- 28890634 TI - The Role of Domain-General Cognitive Abilities and Decimal Labels in At-Risk Fourth-Grade Students' Decimal Magnitude Understanding. AB - The purpose of the study was to determine whether individual differences in at risk 4th graders' language comprehension, nonverbal reasoning, concept formation, working memory, and use of decimal labels (i.e., place value, point, incorrect place value, incorrect fraction, or whole number) are related to their decimal magnitude understanding. Students (n = 127) completed 6 cognitive assessments, a decimal labeling assessment, and 3 measures of decimal magnitude understanding (i.e., comparing decimals to the fraction [Formula: see text] benchmark task, estimating where decimals belong on a 0-1 number line, and identifying fraction and decimal equivalencies). Each of the domain-general cognitive abilities predicted students' decimal magnitude understanding. Using place value labels was positively correlated with students' decimal magnitude understanding, whereas using whole-number labels was negatively correlated with students' decimal magnitude understanding. Language comprehension, nonverbal reasoning, and concept formation were positively correlated with students' use of place value labels. By contrast, language comprehension and nonverbal reasoning were negatively correlated with students' use of whole number labels. Implications for the development of decimal magnitude understanding and design of effective instruction for at-risk students are discussed. PMID- 28890635 TI - It is More than Thought that Counts: the Role of Readiness for Aggression in the Relationship Between Ostracism and Displaced Aggression. AB - Research has shown that ostracism results in aggressive behavior towards the ostracising other, but also causes displaced aggression-aggression directed towards an innocent person. Our study investigated whether displaced aggressive responses to ostracism were increased by three types of aggression proneness (readiness for aggression) based on different mechanisms: emotional-impulsive, habitual-cognitive or personality-immanent. Participants (n = 118) played a Cyberball game in which they were either excluded or included, next prepared a hot sauce sample for another person as an indicator of aggression and completed the Readiness for Interpersonal Aggression Inventory. Results showed that ostracism evoked more aggression in participants with high rather than with low emotional-impulsive readiness for aggression. Only this type of readiness moderated the ostracism-aggression relationship indicating that mostly affective mechanisms induce displaced aggressive responses to exclusion. PMID- 28890636 TI - Contributions of Cognitive-Motivational Factors to the Sense of Identity. AB - This study addressed the relationship between sense of personal identity and thinking dispositions such as need for cognition, reflection, and integrative self-knowledge as well as modes of coping with self-related discrepancies through either excessive assimilation or accommodation. Participants were 544 young adults. The correlation and path analyses revealed, as expected, that need for cognition and integrative self-knowledge positively influenced one's sense of identity, while over-responsiveness to discrepant information about the self influenced it negatively. The effects of reflection and imperviousness to discrepancies appeared more complicated and varied. Together, the findings confirm the importance of cognitive-motivational variables in the development and maintenance of a sense of identity, and suggest that gender differences in their relative significance may deserve additional research attention. PMID- 28890637 TI - Is Religiosity in a Prospective Partner Always Desirable? The Moderating Roles of Shared Social Identity and Medium of Communication when Choosing Interaction Partners. AB - The profession of religion gives rise to myriad inferences and connotations, yet surprisingly little research has examined how it may influence with whom we choose to work. Two experiments conducted at a UK university investigated how religiosity by prospective collaborators affected attitudes and behaviour towards them. Participants in experiment 1 (N = 96) and experiment 2 (N = 120) demonstrated that individuals have a greater preference for, and are more likely to choose, a partner who shares their religious tendencies, but only when they anticipate working face-to-face. When electronic communication was anticipated, this bias disappeared. The implications for these findings are then discussed, particularly with regard to how they may impact on real-life issues such as online recruitment. PMID- 28890639 TI - Hospitals Press FCC to Expand Health Care on the Airwaves. AB - Hospitals press FCC to expand health care on the airwaves. PMID- 28890638 TI - "Wrong Patient" Insulin Pen Injections Alarmingly Frequent Even With Barcode Scanning. AB - "Wrong patient" insulin pen injections alarmingly frequent. PMID- 28890640 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 28890641 TI - Pharmaceutical Approval Update. AB - Sarilumab (Kevzara) for moderately to severely active rheumatoid arthritis; valbenazine (Ingrezza), the first approval for tardive dyskinesia; and cerliponase alpha (Brineura) for late infantile neuronal ceroid lipofuscinosis type-2 disease. PMID- 28890642 TI - Reslizumab (Cinqair): An Interleukin-5 Antagonist for Severe Asthma of the Eosinophilic Phenotype. AB - Reslizumab (Cinqair), an interleukin-5 antagonist for severe eosinophilic asthma. PMID- 28890643 TI - U.S. and States Ramp Up Response to Opioid Crisis: Regulatory, Legislative, and Legal Tools Brought to Bear. AB - Politicians in both parties and at all levels of government have raised what many call the opioid crisis to a level of public attention it has never seen before. This article reviews the approaches, including prevention, treatment, and medication-assisted therapy, being taken by federal and state authorities to combat the abuse of opioids. PMID- 28890644 TI - EHRs: The Challenge of Making Electronic Data Usable and Interoperable. AB - Despite massive effort and investment in health information systems and technology, the promised benefits of electronic health records (EHRs) are far from fruition. The author presents the legislative programs that encourage the implementation of EHRs and explores the barriers hampering interoperability. PMID- 28890645 TI - Focusing on Basics, Including Drug-Use Policy, Remains Important for Today's P&T Committee. AB - Over the past few years, P&T committees have been evolving to deal with care at expanding sites within an organization, across a larger system, or involving multiple organizations. The authors consider one aspect of this expansion medication system failures-that requires the attention of P&T policy. PMID- 28890646 TI - Alternative Pharmacological Management of Vasopressor Extravasation in the Absence of Phentolamine. AB - Vasopressor extravasation is a rare adverse drug reaction that can lead to tissue damage, ischemia, and necrosis of the affected area when vasopressors are administered peripherally. Phentolamine, a nonselective, reversible alpha antagonist, is the current standard treatment for this adverse reaction, but it is often unavailable for use. This review seeks to synthesize the available data in order to recommend alternative pharmacological options for use when phentolamine is not available. After an extensive literature search, 16 publications were reviewed. A treatment algorithm was created that recommends a combination of subcutaneous terbutaline, a selective beta2 agonist, and topical nitroglycerin, an organic nitrate, for adults; and topical nitroglycerin monotherapy for children younger than 2 years of age. However, further research and case reports are required in order to establish a new standard of care for the treatment of vasopressor extravasation. PMID- 28890648 TI - Research Briefs. PMID- 28890647 TI - ESMO World Congress on Gastrointestinal Cancer. AB - This year's annual ESMO World Congress on Gastrointestinal Cancer paid particular attention to the influence of primary tumor sidedness in colorectal cancer as it affects prognosis and treatment outcomes to meet the growing interest in this theory. PMID- 28890649 TI - Recent Alcohol, Tobacco, and Substance Use Variations between Rural and Urban Middle and High School Students. AB - The use of addictive substances by adolescents is a major public health concern; however, rural vs. urban variations are poorly understood. The purpose of the current study was to examine rural-urban differences in the prevalence of recent use of 11 substances in grades 6-12 in a statewide sample of students from the Georgia Student Health Survey II (n = 513,909). We found that rural-urban differences in substance use depend largely upon grade level, with rural middle school students demonstrating higher rates of alcohol, smoking tobacco, and chewing tobacco use, and urban high school students demonstrating higher rates of illicit drugs. PMID- 28890651 TI - Re: JSLS. 2017;21(1):e2016.00098. DOI: 10.4293/JSLS.2016.00098. Minimally Invasive Hysterectomy for Uteri Greater Than One Kilogram. PMID- 28890650 TI - Economic Impact of Laparoscopic Conversion to Open in Left Colon Resections. AB - BACKGROUND AND OBJECTIVES: Studies have shown economic and clinical advantages of laparoscopic left-colon resections. Laparoscopic conversion to open is an important surgical outcome. We estimated conversion incidence, identified risk factors, and measured the clinical and economic impact. METHODS: In this retrospective study, we used the Premier Perspective database to analyze left sided colectomies from 2009 to 2014. Operating room time (ORT), length of stay (LOS), total hospital cost (2014 U.S. dollars); along with incidence of in hospital clinical outcomes (anastomotic leak surrogate [Leak], transfusion, and mortality) were evaluated. Multivariable models accounting for hospital clustering were used to identify conversion risk factors and analyze the effect of conversion on economic and clinical outcomes. RESULTS: A total of 41,417 patients: 8,468 left hemicolectomy and 32,949 sigmoidectomy were identified. Lap Conversion incidence was 13.3% (95% CI, 12.9-13.7). Adjusted mean LOS (+/-SE) days was significantly lower for the Lap-Successful group (4.9 compared with Lap Conversion 6.8 and Open-Planned 7.0), but Lap-Conversion and Open-Planned had similar LOS. Adjusted mean cost was higher for Lap-Conversion $20,165 compared to Open-Planned $18,797; but this difference was smaller than the cost savings for Lap-Successful $16,206 +/- $219. Open-Planned had lower odds of Leak compared to Lap-Conversion. Open-Planned and Lap-Conversion had similar odds of transfusion and mortality. Conversion risk factors included inflammatory bowel disease and left-hemicolectomy. Colorectal specialists were associated with 38% decreased odds of conversion. CONCLUSIONS: Successful laparoscopic surgery was the most cost effective, with decreased LOS and odds of blood transfusion, leak surrogate, and mortality. Conversion was the most expensive and had increased odds of leak surrogate, but similar LOS compared to Open-Planned. The beneficial effect size of successful laparoscopic surgery was larger than the negative effect of conversion compared to Open-Planned. PMID- 28890652 TI - Personality and Employment Transitions at Older Ages: Direct and Indirect Effects through Non-Monetary Job Characteristics. AB - We study whether individuals with different personality traits systematically exhibit different retirement trajectories. We find weak direct associations between personality and employment transitions. On the other hand, personality does contribute indirectly to these transitions by moderating the effects of non monetary job characteristics. Specifically, workers with different traits are observed to follow different retirement paths when faced with similar physical demands, computer skills requirements, job flexibility and age discrimination in the workplace. Contrary to other economic domains, conscientiousness does not have the strongest association with retirement; the other components of the Big Five personality traits show more salient patterns. PMID- 28890653 TI - Complete Mitochondrial Genomes of the Cherskii's Sculpin Cottus czerskii and Siberian Taimen Hucho taimen Reveal GenBank Entry Errors: Incorrect Species Identification and Recombinant Mitochondrial Genome. AB - The complete mitochondrial (mt) genome is sequenced in 2 individuals of the Cherskii's sculpin Cottus czerskii. A surprisingly high level of sequence divergence (10.3%) has been detected between the 2 genomes of C czerskii studied here and the GenBank mt genome of C czerskii (KJ956027). At the same time, a surprisingly low level of divergence (1.4%) has been detected between the GenBank C czerskii (KJ956027) and the Amur sculpin Cottus szanaga (KX762049, KX762050). We argue that the observed discrepancies are due to incorrect taxonomic identification so that the GenBank accession number KJ956027 represents actually the mt genome of C szanaga erroneously identified as C czerskii. Our results are of consequence concerning the GenBank database quality, highlighting the potential negative consequences of entry errors, which once they are introduced tend to be propagated among databases and subsequent publications. We illustrate the premise with the data on recombinant mt genome of the Siberian taimen Hucho taimen (NCBI Reference Sequence Database NC_016426.1; GenBank accession number HQ897271.1), bearing 2 introgressed fragments (~0.9 kb [kilobase]) from 2 lenok subspecies, Brachymystax lenok and Brachymystax lenok tsinlingensis, submitted to GenBank on June 12, 2011. Since the time of submission, the H taimen recombinant mt genome leading to incorrect phylogenetic inferences was propagated in multiple subsequent publications despite the fact that nonrecombinant H taimen genomes were also available (submitted to GenBank on August 2, 2014; KJ711549, KJ711550). Other examples of recombinant sequences persisting in GenBank are also considered. A GenBank Entry Error Depositary is urgently needed to monitor and avoid a progressive accumulation of wrong biological information. PMID- 28890654 TI - Chondroitin Sulfate Inhibits Monocyte Chemoattractant Protein-1 Release From 3T3 L1 Adipocytes: A New Treatment Opportunity for Obesity-Related Inflammation? AB - Monocyte chemoattractant protein-1 (MCP-1) overproduction from inflamed adipose tissue is a major contributor to obesity-related metabolic syndromes. 3T3-L1 embryonic fibroblasts were cultured and differentiated into adipocytes using an established protocol. Adipocytes were treated with lipopolysaccharide (LPS) to induce inflammation and thus MCP-1 release. At the same time, varying concentrations of chondroitin sulfate (CS) were added in a physiologically relevant range (10-200 ug/mL) to determine its impact on MCP-1 release. Chondroitin sulfate, a natural glycosaminoglycan of connective tissue including the cartilage extracellular matrix, was chosen on the basis of our previous studies demonstrating its anti-inflammatory effect on macrophages. Because the main action of MCP-1 is to induce monocyte migration, cultured THP-1 monocytes were used to test whether CS at the highest physiologically relevant concentration could inhibit cell migration induced by human recombinant MCP-1. Chondroitin sulfate (100-200 ug/mL) inhibited MCP-1 release from inflamed adipocytes in a dose-dependent manner (P < .01, 95% confidence interval [CI]: 5.89 to -3.858 at 100 ug/mL and P < .001, 95% CI: -6.028 to -3.996 at 200 ug/mL) but had no effect on MCP-1-driven chemotaxis of THP-1 monocytes. In summary, CS could be expected to reduce macrophage infiltration into adipose tissue by reduction in adipocyte expression and release of MCP-1 and as such might reduce adipose tissue inflammation in response to pro-inflammatory stimuli such as LPS, now increasingly recognized to be relevant in vivo. PMID- 28890655 TI - Comparison of 3 Derivatization Methods for the Analysis of Amphetamine-Related Drugs in Oral Fluid by Gas Chromatography-Mass Spectrometry. AB - The heptafluorobutyric anhydride (HFBA), pentafluoropropionic anhydride (PFPA), and trifluoroacetic anhydride (TFAA) are compared as derivatizing reagents to use as the optimal method for the analysis of 10 amphetamines and cathinones in oral fluid. The target compounds were amphetamine (AMP), methamphetamine (MA), 4 methylamphetamine, 3,4-methylenedioxyamphetamine (MDA), 3,4 methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxy-N-ethylamphetamine (MDEA), cathinone (CAT), methcathinone, mephedrone, and ephedrine. Amphetamine D5, MA-D5, MDA-D5, MDMA-D5, and MDEA-D5 use as internal standards (IS). The analytes and IS were extracted from 0.5 mL of oral fluid by ethyl acetate in the presence of NaOH (0.1 N) as the base and then the dried extracts were derivatized with HFBA, PFPA, or TFAA at 70 degrees C for 30 minutes. The limits of quantification based on signal-to-noise ratios >=10 were ranged between 2.5 and 10 ng/mL. The calibration graphs were linear in the range of 5 or 10 to 1000 ng/mL for all analytes. Based on sensitivity, the PFPA is proved to be the best for derivatization of the target compounds prior to gas chromatography-mass spectrometry analysis. PMID- 28890656 TI - Effects of Teaching Health Care Workers on Diagnosis and Treatment of Pesticide Poisonings in Uganda. AB - BACKGROUND: Acute pesticide poisoning in developing countries is a considerable problem, requiring diagnosis and treatment. This study describes how training of health care workers in Uganda affects their ability to diagnose and manage acute pesticide poisoning. METHOD: A postintervention cross-sectional study was conducted using a standardized questionnaire. A total of 326 health care workers in Uganda were interviewed on knowledge and handling of acute pesticide poisoning. Of those, 173 health care workers had received training, whereas 153 untrained health care workers from neighboring regions served as controls. RESULTS: Trained health care workers scored higher on knowledge of pesticide toxicity and handling of acute pesticide poisoning. Stratification by sex, profession, experience, and health center level did not have any influence on the outcome. CONCLUSIONS: Training health care workers can improve their knowledge and treatment of pesticide poisonings. Knowledge of the subject is still insufficient among health care workers and further training is needed. PMID- 28890657 TI - Natural Field Infestation of Mangifera casturi and Mangifera lalijiwa by Oriental Fruit Fly, Bactrocera dorsalis (Diptera: Tephritidae). AB - Mango, Mangifera indica (Anacardiaceae), is a crop cultivated pantropically. There are, however, many other Mangifera spp ("mango relatives") which have much more restricted distributions and are poorly known but have potential to produce mango-like fruits in areas where mangoes do not grow well or could be tapped in mango breeding programs. Because of the restricted distribution of many of the Mangifera spp, there has also been limited data collected on susceptibility of their fruits to infestation by tephritid fruit flies which is important to know for concerns both for quality of production and for quarantine security of fruit exports. Here, we report on natural field infestation by the oriental fruit fly, Bactrocera dorsalis (Diptera: Tephritidae), of two mango relatives native to Indonesia: Mangifera casturi and Mangifera lalijiwa. Rates of infestation of fruits of these two Mangifera spp by tephritid fruit flies have not previously been reported. PMID- 28890658 TI - Magnetic Resonance Imaging of the Axial Skeleton in Patients With Spondyloarthritis: Distribution Pattern of Inflammatory and Structural Lesions. AB - PURPOSE: Spondyloarthritis is a chronic inflammatory disorder of the musculoskeletal system driven by systemic enthesitis and typically involving the axial skeleton, ie, the spine and the sacroiliac joints. The purpose of this study was to assess the distribution pattern of inflammatory and structural magnetic resonance imaging (MRI) findings in spondyloarthritis. METHODS: Retrospective study of 193 patients with axial spondyloarthritis who received MRI of the spine and the sacroiliac joints. We quantitatively assessed inflammatory and structural lesions using established MRI-based scoring methods. The significance of the differences between gender, HLA-B27 status, and spine and sacroiliac involvement was determined. RESULTS: In total, 174 patients (90.2%) showed a sacroiliac involvement and 120 patients (62.2%) a combined involvement of the sacroiliac joints and the spine. An isolated sacroiliac involvement was found in 54 patients (28.0%) and an isolated spine involvement in 19 patients (9.8%). The sacroiliac joint was significantly more involved in men than in women (P < .01), and men had significantly higher scores for structural lesions (P < .001). The subgroup of HLA-B27-positive patients showed a significantly higher percentage of sacroiliac involvement compared with HLA-B27-negative patients (P < .05). CONCLUSIONS: Spondyloarthritis is a systemic disorder predominantly involving the sacroiliac joints. However, the entire axial skeleton may be affected. In particular, HLA-B27-negative women show atypical manifestations without sacroiliac involvement. Magnetic resonance imaging in spondyloarthritis should cover the entire axial skeleton, ie, sacroiliac joints and the spine to meet the pathophysiology of this disorder and capture the true extent of inflammatory and structural lesions. PMID- 28890659 TI - Loeffler Endocarditis: A Unique Presentation of Right-Sided Heart Failure Due to Eosinophil-Induced Endomyocardial Fibrosis. AB - Loeffler endocarditis is a rare restrictive cardiomyopathy caused by abnormal endomyocardial infiltration of eosinophils, with subsequent tissue damage from degranulation, eventually leading to fibrosis. Although an uncommon entity, it is still a disease with significant morbidity and mortality. Often identified only at late stages, treatment options are limited once fibrosis occurs, usually requiring heart failure medications or surgical intervention. We present a unique case of a woman with remote history of hypereosinophilic syndrome, attributed to treatment of rheumatoid arthritis with infliximab, who presented with symptoms of heart failure refractory to medical management and was found to have Loeffler endocarditis. The severe progression of the disease required surgical intervention with endocardial stripping to treat the right-sided diastolic heart failure. PMID- 28890660 TI - Flow Cytometric Immune Profiling in Infliximab-Associated Tuberculosis. AB - Tumor necrosis factor alpha antagonists are increasingly used to treat inflammatory and autoimmune disorders and are associated with increased risk of active tuberculosis. Diagnosis of active tuberculosis in patients taking tumor necrosis factor alpha antagonists can be challenging owing to increased incidence of extrapulmonary manifestations and false-negative results on current available diagnostic tests. We present a case of a young woman on infliximab for ulcerative colitis who presented with disseminated tuberculosis. As part of a research study, we performed flow cytometric immune profiling, which has previously not been reported in patients with active tuberculosis taking tumor necrosis alpha antagonists. The flow cytometry results were within the positive thresholds for tuberculosis infection. Flow cytometric immune profiling may be a valid diagnostic tool for patients taking tumor necrosis factor alpha antagonists. PMID- 28890661 TI - Association of Angiotensin-Converting Enzyme Gene Polymorphisms and Nephropathy in Diabetic Patients at a Tertiary Care Centre in South India. AB - BACKGROUND: Genetic polymorphisms of the angiotensin-renin pathway have been thought to influence the development of diabetic nephropathy. However, there are conflicting results regarding this association in previous studies on populations with varying ethnicity. AIMS: Primary aim was to compare the frequency of distribution of angiotensin-converting enzyme (ACE) gene (insertion/deletion [I/D]) polymorphism in Tamilian Indian type 2 diabetic individuals with and without microalbuminuria. Secondary objective was to compare the frequency of distribution of the 3 genotypes in diabetic patients with urinary albumin/creatinine ratio (ACR) < 30 mg/dL, urinary ACR = 30 to 300 mg/dL, and urinary ACR > 300 mg/dL. METHODS: A total of 179 consecutive diabetic individuals between 40 and 70 years, from Puducherry and Tamilnadu of Dravidian descent participated in the study conducted from 2012 to 2014. Inclusion criteria were as follows: age >= 40 years and duration of type 2 diabetes mellitus for >=5 years. Patients were divided into 2 groups based on ACR values. Group 1 consisted of 50 individuals with urinary ACR < 30 mg/g of creatinine, and group 2 consisted of 129 individuals with urinary ACR > 30 mg/g. Angiotensin I-converting enzyme (ACE) gene polymorphism was determined by allele-specific polymerase chain reaction method using a primer pair flanking the polymorphic region of its intron 16. Furthermore, group 2 patients were subdivided into those with urinary ACR = 30 to 300 mg/g of creatinine and those with urinary ACR > 300 mg/g of creatinine, and distribution of ACE gene polymorphism was compared in the three groups. STATISTICS: Statistical analysis was done using SPSS version 17.0. Independent Student t test was used to compare mean values between the 2 groups. Odds ratio was calculated for testing association between ACE gene (I/D) polymorphism and presence of microalbuminuria. P < .05 was considered significant. Comparison of ACE genotypes among 3 groups of patients (ACR < 30 mg/g, ACR = 30-300 mg/g, and ACR > 300 mg/g) was done using 1-way analysis of variance with Bonferroni multiple comparison test as post hoc analysis. CONCLUSIONS: Heterozygous I/D genotype was more frequent in the study population (45.8%) than the other genotypes. There was no difference in the genotype distribution in patients with varying levels of albuminuria. PMID- 28890662 TI - 'Where were your clothes?' Eliciting descriptions of clothing placement from children alleging sexual abuse in criminal trials and forensic interviews. AB - PURPOSE: The present study examined how children alleging sexual abuse are asked about clothing placement during abusive episodes, both in criminal trials and forensic interviews. The placement of clothing is of great importance, because it facilitates distinguishing abusive touch from non-abusive touch, as well as the severity of abuse when the touching is in fact sexual. If clothing has not been removed, then sexual abuse appears less likely and certain types of sexual contact are physically impossible (or at least highly improbable). METHODS: We examined how trial attorneys (n = 142) and forensic interviewers in investigative interviews (n = 155) questioned 5- 12-year-olds about the location of clothing during alleged sexual abuse. To do so, we identified all question-answer pairs that included references to clothing placement, and coded for the clothing item mentioned, whether the interviewer elicited information about clothing placement or the child spontaneously provided such information, question-type, and response type. RESULTS: Discussions about clothing placement were commonplace in both settings, particularly in court. Fewer than one in five question-answer pairs about clothing placement were spontaneous mentions by children; the questioner elicited most discussions. When interviewers asked wh- questions rather than yes/no and forced-choice questions, children provided more elaboration, more detailed clothing information, and were over six times more likely to describe clothing placement in a fashion that could not be captured by a single preposition (e.g., neither on nor off). CONCLUSIONS: The findings suggest that descriptions of clothing placement are subject to serious misinterpretation when closed-ended questions are asked. PMID- 28890663 TI - Cold homes, fuel poverty and energy efficiency improvements: A longitudinal focus group approach. AB - Cold homes and fuel poverty have been identified as factors in health and social inequalities that could be alleviated through energy efficiency interventions. Research on fuel poverty and the health impacts of affordable warmth initiatives have to date primarily been conducted using quantitative and statistical methods, limiting the way how fuel poverty is understood. This study took a longitudinal focus group approach that allowed exploration of lived experiences of fuel poverty before and after an energy efficiency intervention. Focus group discussions were held with residents from three low-income communities before (n = 28) and after (n = 22) they received energy efficiency measures funded through a government-led scheme. The results show that improving the energy efficiency of homes at risk of fuel poverty has a profound impact on wellbeing and quality of life, financial stress, thermal comfort, social interactions and indoor space use. However, the process of receiving the intervention was experienced by some as stressful. There is a need for better community engagement and communication to improve the benefits delivered by fuel poverty programmes, as well as further qualitative exploration to better understand the wider impacts of fuel poverty and policy-led intervention schemes. PMID- 28890664 TI - Logic of approximate entailment in quasimetric and in metric spaces. AB - It is known that a quasimetric space can be represented by means of a metric space; the points of the former space become closed subsets of the latter one, and the role of the quasimetric is assumed by the Hausdorff quasidistance. In this paper, we show that, in a slightly more special context, a sharpened version of this representation theorem holds. Namely, we assume a quasimetric to fulfil separability in the original sense due to Wilson. Then any quasimetric space can be represented by means of a metric space such that distinct points are assigned disjoint closed subsets. This result is tailored to the solution of an open problem from the area of approximate reasoning. Following the lines of E. Ruspini's work, the Logic of Approximate Entailment ([Formula: see text]) is based on a graded version of the classical entailment relation. We present a proof calculus for [Formula: see text] and show its completeness with regard to finite theories. PMID- 28890665 TI - Trends and events through seven centuries: the history of a wetland landscape in the Czech Republic. AB - Environmental change can be viewed as the combined result of long-term processes and singular events. While long-term trends appear to be readily available for observation (in the form of temporal comparisons or space-for-time substitution), it is more difficult to gain information on singular events in the past, although these can be equally significant in shaping ecosystems. We examined the past 700 years in the history of a lowland wetland landscape in the Czech Republic with the help of palaeoecological, ecological, landscape archaeological, and archival data. Macrofossil and pollen data were compared to known drainage works in the area and historical climatological data. Trends and events in habitat conditions were assessed using species indicator values. Results showed that ecological succession was the general process in the study area, detected as a trend towards eutrophication, desiccation and vegetation closure. Short-term events influenced development at the sites mainly from the second half of the 19th century. This is consistent with drainage history, although bias related to sample frequency cannot be excluded. On the whole, long-term trends and discrete events were complementary on different scales. We conclude that humans facilitated and accelerated background processes, which can be most likely associated with the succession of open wetlands towards terrestrial ecosystems. PMID- 28890666 TI - Discovering Drugs for the Treatment of Ebola Virus. AB - PURPOSE OF REVIEW: Ebola virus, a member of the Filoviridae family, is a causative agent of severe viral hemorrhagic fever in humans. Over the past 40 years, the virus has been linked to several high mortality outbreaks in Africa with the recent West African outbreak resulting in over 11,000 deaths. This review provides a summary of the status of the drug discovery and development process for therapeutics for Ebola virus disease, with a focus on the strategies being used and the challenges facing each stage of the process. RECENT FINDINGS: Despite the wealth of in vitro efficacy data, preclinical data in animal models, and human clinical data, no therapeutics have been approved for the treatment of Ebola virus disease. However, several promising candidates, such as ZMapp and GS 5734, have advanced into ongoing clinical trials. SUMMARY: The gravity of the 2014-2016 outbreak spurred a heightened effort to identify and develop new treatments for Ebola virus disease, including small molecules, immunotherapeutics, host factors, and clinical disease management options. DISCLAIMER: Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endoresed by the U.S. Army. PMID- 28890668 TI - Multiracial Children's and Adults' Categorizations of Multiracial Individuals. AB - Research has explored how multiracial individuals are categorized by monoracial individuals, but has not yet explored how they are categorized by multiracial individuals themselves. We examined how multiracial children (4-9 years) and adults categorized multiracial targets (presented with and without parentage information). When parentage information was provided, multiracial targets were more likely to be categorized as neither wholly black nor wholly white. However, both multiracial adults and children more often categorized multiracial targets as black than as white regardless of the absence or presence of parentage information. For multiracial children, increased contact with white people predicted the tendency to categorize multiracial targets as black. These data suggest that multiracial children's categorizations are more flexible than those of monoracial children in previous research, and that the tendency to categorize multiracial targets as black emerges early in development within multiracial samples, and is especially likely in predominantly white contexts. PMID- 28890667 TI - Role of 3D Echocardiography in Cardiac Surgery: Strengths and Limitations. AB - PURPOSE OF REVIEW: This review aims to highlight the general and specific strengths and limitations of intraoperative 3D echocardiography. This article explains the value of real-time three-dimensional transesophageal echocardiography (RT 3D TEE) during cardiac surgery and cardiac interventions. RECENT FINDINGS: Recently published recommendations and guidelines include the use of RT 3D TEE. RT 3 D TEE provides additional value particularly for guidance during cardiac interventions (i.e., transcatheter mitral valve repair, left atrial appendix and atrial septal defect closures), assessment of the mitral valve in surgical repair, measurement of left ventricular outflow tract area for transcatheter valvular replacements, and estimating right and left ventricular volumes and function. The exact localization of paravalvular leakage is another strength of RT 3D TEE. The major limitation is the reduced temporal resolution compared to 2D TEE. SUMMARY: Three-dimensional echocardiography is a powerful tool that improves communication and accurate measurements of cardiac structures. PMID- 28890669 TI - Probing the Cytotoxicity Of Semiconductor Quantum Dots. AB - With their bright, photostable fluorescence, semiconductor quantum dots show promise as alternatives to organic dyes for biological labeling. Questions about their potential cytotoxicity, however, remain unanswered. While cytotoxicity of bulk cadmium selenide (CdSe) is well documented, a number of groups have suggested that CdSe QDs are cytocompatible, at least with some immortalized cell lines. Using primary hepatocytes as a liver model, we found that CdSe-core QDs were indeed acutely toxic under certain conditions. Specifically, we found that the cytotoxicity of QDs was modulated by processing parameters during synthesis, exposure to ultraviolet light, and surface coatings. Our data further suggests that cytotoxicity correlates with the liberation of free Cd2+ ions due to deterioration of the CdSe lattice. When appropriately coated, CdSe-core QDs can be rendered non-toxic and used to track cell migration and reorganization in vitro. Our results inform design criteria for the use of QDs in vitro and especially in vivo where deterioration over time may occur. PMID- 28890670 TI - A Phenomenological and Dynamic View of Homology: Homologs as Persistently Reproducible Modules. AB - Homology is a fundamental concept in biology. However, the metaphysical status of homology, especially whether a homolog is a part of an individual or a member of a natural kind, is still a matter of intense debate. The proponents of the individuality view of homology criticize the natural kind view of homology by pointing out that homologs are subject to evolutionary transformation, and natural kinds do not change in the evolutionary process. Conversely, some proponents of the natural kind view of homology argue that a homolog can be construed both as a part of an individual and a member of a natural kind. They adopt the Homeostatic Property Cluster (HPC) theory of natural kinds, and the theory seems to strongly support their construal. Note that this construal implies the acceptance of essentialism. However, looking back on the history of the concept of homology, we should not overlook the fact that the individuality view was proposed to reject the essentialist interpretation of homology. Moreover, the essentialist notions of natural kinds can, in our view, mislead biologists about the phenomena of homology. Consequently, we need a non essentialist view of homology, which we name the "persistently reproducible module" (PRM) view. This view highlights both the individual-like and kind-like aspects of homologs while stripping down both essentialist and anti-essentialist interpretations of homology. In this article, we articulate the PRM view of homology and explain why it is recommended over the other two views. PMID- 28890671 TI - Current Management of Peritoneal Carcinomatosis From Colorectal Cancer: The Role of Cytoreductive Surgery and Hyperthermic Peritoneal Chemoperfusion. AB - Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a disease with a poor prognosis, often thought to be a terminal illness with no hope except for palliative treatment. New therapeutic modalities combining cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown favorable outcomes and may provide a significant survival benefit in a selected group of patients. The main rational for CRS is to remove all visible tumor burden to allow for the chemotherapeutic agent (HIPEC) to eradicate any microscopic residual disease. The Amsterdam statement formulated at the 9th International Congress on Peritoneal Surface Malignancies supports the use of CRS with HIPEC as a standard of care for selected patients with small-to-moderate volume PC from CRC. Selecting appropriate patients who would benefit from CRS/ HIPEC is paramount to derive the maximum oncological outcomes while minimizing the risks of postoperative complications and mortality. In this paper, we will review the role for CRS/HIPEC in the management of PC from CRC. PMID- 28890672 TI - Multivariate strategy for the sample selection and integration of multi-batch data in metabolomics. AB - INTRODUCTION: Availability of large cohorts of samples with related metadata provides scientists with extensive material for studies. At the same time, recent development of modern high-throughput 'omics' technologies, including metabolomics, has resulted in the potential for analysis of large sample sizes. Representative subset selection becomes critical for selection of samples from bigger cohorts and their division into analytical batches. This especially holds true when relative quantification of compound levels is used. OBJECTIVES: We present a multivariate strategy for representative sample selection and integration of results from multi-batch experiments in metabolomics. METHODS: Multivariate characterization was applied for design of experiment based sample selection and subsequent subdivision into four analytical batches which were analyzed on different days by metabolomics profiling using gas-chromatography time-of-flight mass spectrometry (GC-TOF-MS). For each batch OPLS-DA(r) was used and its p(corr) vectors were averaged to obtain combined metabolic profile. Jackknifed standard errors were used to calculate confidence intervals for each metabolite in the average p(corr) profile. RESULTS: A combined, representative metabolic profile describing differences between systemic lupus erythematosus (SLE) patients and controls was obtained and used for elucidation of metabolic pathways that could be disturbed in SLE. CONCLUSION: Design of experiment based representative sample selection ensured diversity and minimized bias that could be introduced at this step. Combined metabolic profile enabled unified analysis and interpretation. PMID- 28890674 TI - Treating symptomatic uterine fibroids with myomectomy: current practice and views of UK consultants. AB - BACKGROUND: The demand for uterus-sparing treatments is increasing as more women postpone childbirth to their 30-40s, when fibroids are more symptomatic. With an increasing choice of treatment options and changing care-provider profiles, now is an opportune time to survey current practices and opinions. Using a 25-stem questionnaire, a web-based survey was used to capture the practices and opinions of UK consultant gynecologists on the treatment of symptomatic fibroids, including the types of procedure most frequently used, methods used to reduce blood loss, and awareness and acceptability of treatment options, and to assess the impact of gender and experience of the treating gynecologist. RESULTS: The response rate was 22%. Laparascopic myomectomy is used least frequently, with 80% of the respondents using GnRHa preoperatively to minimize blood loss and correct anemia, while vasopressin is most frequently used to reduce intraoperative blood loss. Female consultants operate significantly less frequently than males. Those with more than 10 years consultant experience are more likely to perform an open myomectomy compared to those with less than 10 years experience. CONCLUSIONS: Compared to a similar survey performed 10 years ago, surgical methods remain to be the most common treatments, but use of less invasive treatments such as UAE has increased. Consultants' attitudes appear to be responding to the patient demand for less radical treatments. However, it is yet to be seen if the changing consultant demographics will keep up with this demand. The low response rate warrants cautious interpretation of the results, but they provide an interesting snapshot of current views and practices. PMID- 28890675 TI - Dominant hand, non-dominant hand, or both? The effect of pre-training in hand-eye coordination upon the learning curve of laparoscopic intra-corporeal knot tying. AB - BACKGROUND: Training of basic laparoscopic psychomotor skills improves both acquisition and retention of more advanced laparoscopic tasks, such as laparoscopic intra-corporeal knot tying (LICK). This randomized controlled trial (RCT) was performed to evaluate the effect of different pre-training programs in hand-eye coordination (HEC) upon the learning curve of LICK. RESULTS: The study was performed in a private center in Asuncion, Paraguay, by 60 residents/specialists in gynaecology with no experience in laparoscopic surgery. Participants were allocated in three groups. In phase 1, a baseline test was performed (T1, three repetitions). In phase 2, participants underwent different training programs for HEC (60 repetitions): G1 with both the dominant hand (DH) and the non-dominant hand (NDH), G2 with the DH only, G3 none. In phase 3, a post HEC/pre LICK training test was performed (T2, three repetitions). In phase 4, participants underwent a standardized training program for LICK (60 repetitions). In phase 5, a final test was performed (T3, three repetitions). The score was based on the time taken for task completion system. The scores were plotted and non-linear regression models were used to fit the learning curves to one- and two phase exponential decay models for each participant (individual curves) and for each group (group curves). For both HEC and LICK, the group learning curves fitted better to the two-phase exponential decay model. For HEC with the DH, G1 and G2 started from a similar point, but G1 reached a lower plateau at a higher speed. In G1, the DH curve started from a lower point than the NDH curve, but both curves reached a similar plateau at comparable speeds. For LICK, all groups started from a similar point, but immediately after HEC training and before LICK training, G1 scored better than the others. All groups reached a similar plateau but with a different decay, G1 reaching this plateau faster than the others groups. CONCLUSIONS: This study demonstrates that pre-training in HEC with both the DH and the NDH shortens the LICK learning curve. PMID- 28890673 TI - Navigating freely-available software tools for metabolomics analysis. AB - INTRODUCTION: The field of metabolomics has expanded greatly over the past two decades, both as an experimental science with applications in many areas, as well as in regards to data standards and bioinformatics software tools. The diversity of experimental designs and instrumental technologies used for metabolomics has led to the need for distinct data analysis methods and the development of many software tools. OBJECTIVES: To compile a comprehensive list of the most widely used freely available software and tools that are used primarily in metabolomics. METHODS: The most widely used tools were selected for inclusion in the review by either >= 50 citations on Web of Science (as of 08/09/16) or the use of the tool being reported in the recent Metabolomics Society survey. Tools were then categorised by the type of instrumental data (i.e. LC-MS, GC-MS or NMR) and the functionality (i.e. pre- and post-processing, statistical analysis, workflow and other functions) they are designed for. RESULTS: A comprehensive list of the most used tools was compiled. Each tool is discussed within the context of its application domain and in relation to comparable tools of the same domain. An extended list including additional tools is available at https://github.com/RASpicer/MetabolomicsTools which is classified and searchable via a simple controlled vocabulary. CONCLUSION: This review presents the most widely used tools for metabolomics analysis, categorised based on their main functionality. As future work, we suggest a direct comparison of tools' abilities to perform specific data analysis tasks e.g. peak picking. PMID- 28890676 TI - The effect of music in gynaecological office procedures on pain, anxiety and satisfaction: a randomized controlled trial. AB - BACKGROUND: Pain can interfere with office procedures in gynaecology. The aim of this study is to measure the positive effect of music in gynaecological office procedures. METHODS: A randomized controlled trial was performed between October 2014 and January 2016. Women scheduled for an office hysteroscopy or colposcopy were eligible for randomization in the music group or control group. Stratification for hysteroscopy and colposcopy took place. The primary outcome is patients' level of pain during the procedure measured by the visual analogue scale (VAS). Secondary outcomes include patients' level of pain after the procedure, anxiety and satisfaction of patient and doctor. RESULTS: No positive effect of music on patients' perception of pain during the procedure was measured, neither for the hysteroscopy group (57 mm vs. 52 mm) nor for the colposcopy group (32 mm vs. 32 mm). Secondary outcomes were also similar for both groups. CONCLUSIONS: This study showed no positive effect of music on patients' level of pain, anxiety or satisfaction of patient or doctor for office hysteroscopy and colposcopy. We believe a multimodal approach has to be used to decrease patient distress in terms of pain and anxiety, with or without music. TRIAL REGISTRATION: Dutch Trial Register, NTR4924. PMID- 28890677 TI - The role of the multidisciplinary team in the management of deep infiltrating endometriosis. AB - The multidisciplinary team (MDT) is considered good practice in the management of chronic conditions and is now a well-established part of clinical care in the NHS. There has been a recent drive to have MDTs in the management of women with severe endometriosis requiring complex surgery as a result of recommendations from the European Society for Human Reproduction and Embryology (ESHRE) and British Society for Gynaecological Endoscopy (BSGE). The multidisciplinary approach to the management of patients with endometriosis leads to better results in patient outcomes; however, there are potentially a number of barriers to its implementation and maintenance. This paper aims to review the potential benefits, disadvantages and barriers of the multidisciplinary team in the management of severe endometriosis. PMID- 28890678 TI - Pregnancy following laparoscopic hysteropexy-a case series. AB - BACKGROUND: Uterine-preserving prolapse surgery offers the chance to retain fertility; however, limited data is available for the safety of pregnancy following surgery and the effect of pregnancy on surgical outcome. Our operative technique involves mesh encircling the cervix and uterine arteries, which raises concerns that compromise of uterine blood flow during pregnancy may lead to foetal growth restriction. We also think this necessitates delivery by caesarean section. We report on six pregnancy outcomes following laparoscopic hysteropexy. Primary outcomes were live birth and birth weight. Secondary outcomes were integrity of mesh and immediate effect on prolapse. RESULTS: All patients had successful pregnancy outcomes with birth weights on or above the 10th centile. There was no effect on mesh integrity seen in any of the cases. There was no deterioration in apical prolapse when assessed post delivery, but two patients had new onset anterior vaginal wall prolapse. CONCLUSIONS: We think our technique of hysteropexy is safe for those wishing to conceive. Larger numbers are needed to allow robust evidence-based guidance for patients and clinicians. PMID- 28890679 TI - Effects of salpingectomy during abdominal hysterectomy on ovarian reserve: a randomized controlled trial. AB - BACKGROUND: The aim of this study was to investigate the effect of salpingectomy on ovarian function by measuring AMH. METHODS: This study was a balanced, single center, double-blind, randomized, controlled trial in Ruin Tan Arash Hospital, Tehran, between May 2013 and November 2014. A total of 30 patients undergoing elective abdominal hysterectomy were randomized into two groups, 15 with salpingectomy and 15 without salpingectomy. The primary objective of this study was to compare mean difference of anti-Mullerian hormone (AMH) between two groups. The secondary outcomes measured were follicle-stimulating hormone (FSH), operative time, and blood loss. RESULTS: Serum AMH levels decreased at 3 months after hysterectomy in all patients (pre AMH 1.32 +/- (0.91); post AMH 1.05 +/- (0.88), P < 0.001), the salpingectomy group (pre AMH 1.44 +/- (0.94); post AMH 1.13 +/- (0.86), P < 0.001), and no salpingectomy group (pre AMH 1.2 +/- (0.9); post AMH 0.97 +/- (0.92), P < 0.001). The rate of decline of AMH levels after surgery did not differ between the two groups (25% (17-33%) vs. 26% (15-36%), P = 0.23) among the women with salpingectomy versus without salpingectomy, respectively. There was no difference in the mean operative time (mean difference 0.33, 95% CI - 22.21 to 22.86, P < 0.92), mean blood loss (mean difference - 0.66, 95% CI - 15.8 to 14.46, P < 0.97), and post FSH (mean difference 0.34, 95% CI - 1.2 to 1.88, P < 0.65) between both groups. CONCLUSIONS: Salpingectomy with abdominal hysterectomy is a safe treatment that does not have a deleterious effect on ovarian reserve. TRIAL REGISTRATION: Iranian Registry of Clinical Trials, IRCT2014123118866N4 (www.IRCT.ir). PMID- 28890680 TI - Study of flow behaviors of droplet merging and splitting in microchannels using Micro-PIV measurement. AB - Droplet merging and splitting are important droplet manipulations in droplet based microfluidics. However, the fundamental flow behaviors of droplets were not systematically studied. Hence, we designed two different microstructures to achieve droplet merging and splitting respectively, and quantitatively compared different flow dynamics in different microstructures for droplet merging and splitting via micro-particle image velocimetry (micro-PIV) experiments. Some flow phenomena of droplets different from previous studies were observed during merging and splitting using a high-speed microscope. It was also found the obtained instantaneous velocity vector fields of droplets have significant influence on the droplets merging and splitting. For droplet merging, the probability of droplets coalescence (eta) in a microgroove is higher (50% < eta < 92%) than that in a T-junction microchannel (15% < eta < 50%), and the highest coalescence efficiency (eta = 92%) comes at the two-phase flow ratio e of 0.42 in the microgroove. Moreover, compared with a cylinder obstacle, Y-junction bifurcation can split droplets more effectively and the droplet flow during splitting is steadier. The results can provide better understanding of droplet behaviors and are useful for the design and applications of droplet-based microfluidics. PMID- 28890681 TI - Corrigendum: Associations between Family Adversity and Brain Volume in Adolescence: Manual vs. Automated Brain Segmentation Yields Different Results. AB - [This corrects the article on p. 398 in vol. 10, PMID: 27656121.]. PMID- 28890682 TI - Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice. AB - Motor neurons in amyotrophic lateral sclerosis (ALS) patients and animal models show degeneration from the nerve terminal, known as dying-back neuropathy. To investigate the mechanism underlying this neuropathy, we analyzed the neuromuscular junctions (NMJs) and motor neuron cell bodies in SOD1G93A mice using electron microscopy. NMJs of SOD1G93A mice exhibited significantly higher numbers of autophagosomes and degenerated mitochondria compared to wild-type controls. Mitophagosomes were identified in the NMJ presynaptic terminals of wild type mice and SOD1G93A mice. However, the number of mitophagosomes did not increase significantly in SOD1G93A NMJs indicating a defect in mitophagy, the autophagic process to degrade mitochondria. Consistent with this, proteins essential for mitophagy, p62/SQSTM1, Bnip3, Pink1, and Parkin were down-regulated in motor neurons in SOD1G93A mice. Importantly, SQSTM1 is one of the genes mutated in familial ALS patients. We evaluated the effect of impaired mitophagy on motor neurons by analyzing the double knockout mice of Pink1 and Parkin, two genes responsible for sensing depolarized mitochondria and delivering degenerated mitochondria to mitophagosomes. The double knockout mice exhibited NMJ degeneration, including axon swelling and NMJ fragmentation at 4 months of age. These phenotypes were rarely observed in wild-type control mice of the same age. The protein level of ATP synthase beta subunit increased in the NMJ presynaptic terminals, suggesting the accumulation of mitochondria at NMJs of the double knockout mice. Importantly, NMJ denervation was observed in the double knockout mice. These data suggest that the reduced mitophagy function in motor neurons of SOD1G93A mice is one of the mechanisms causing degeneration of ALS NMJs. PMID- 28890683 TI - Rapid Processing of a Global Feature in the ON Visual Pathways of Behaving Monkeys. AB - Visual objects are recognized by their features. Whereas, some features are based on simple components (i.e., local features, such as orientation of line segments), some features are based on the whole object (i.e., global features, such as an object having a hole in it). Over the past five decades, behavioral, physiological, anatomical, and computational studies have established a general model of vision, which starts from extracting local features in the lower visual pathways followed by a feature integration process that extracts global features in the higher visual pathways. This local-to-global model is successful in providing a unified account for a vast sets of perception experiments, but it fails to account for a set of experiments showing human visual systems' superior sensitivity to global features. Understanding the neural mechanisms underlying the "global-first" process will offer critical insights into new models of vision. The goal of the present study was to establish a non-human primate model of rapid processing of global features for elucidating the neural mechanisms underlying differential processing of global and local features. Monkeys were trained to make a saccade to a target in the black background, which was different from the distractors (white circle) in color (e.g., red circle target), local features (e.g., white square target), a global feature (e.g., white ring with a hole target) or their combinations (e.g., red square target). Contrary to the predictions of the prevailing local-to-global model, we found that (1) detecting a distinction or a change in the global feature was faster than detecting a distinction or a change in color or local features; (2) detecting a distinction in color was facilitated by a distinction in the global feature, but not in the local features; and (3) detecting the hole was interfered by the local features of the hole (e.g., white ring with a squared hole). These results suggest that monkey ON visual systems have a subsystem that is more sensitive to distinctions in the global feature than local features. They also provide the behavioral constraints for identifying the underlying neural substrates. PMID- 28890685 TI - EMG-Based Continuous and Simultaneous Estimation of Arm Kinematics in Able-Bodied Individuals and Stroke Survivors. AB - Among the potential biological signals for human-machine interactions (brain, nerve, and muscle signals), electromyography (EMG) widely used in clinical setting can be obtained non-invasively as motor commands to control movements. The aim of this study was to develop a model for continuous and simultaneous decoding of multi-joint dynamic arm movements based on multi-channel surface EMG signals crossing the joints, leading to application of myoelectrically controlled exoskeleton robots for upper-limb rehabilitation. Twenty subjects were recruited for this study including 10 stroke subjects and 10 able-bodied subjects. The subjects performed free arm reaching movements in the horizontal plane with an exoskeleton robot. The shoulder, elbow and wrist movements and surface EMG signals from six muscles crossing the three joints were recorded. A non-linear autoregressive exogenous (NARX) model was developed to continuously decode the shoulder, elbow and wrist movements based solely on the EMG signals. The shoulder, elbow and wrist movements were decoded accurately based only on the EMG inputs in all the subjects, with the variance accounted for (VAF) > 98% for all three joints. The proposed approach is capable of simultaneously and continuously decoding multi-joint movements of the human arm by taking into account the non linear mappings between the muscle EMGs and joint movements, which may provide less effortful control of robotic exoskeletons for rehabilitation training of individuals with neurological disorders and arm impairment. PMID- 28890684 TI - Neural Correlates of Early Sound Encoding and their Relationship to Speech-in Noise Perception. AB - Speech-in-noise (SIN) perception is a complex cognitive skill that affects social, vocational, and educational activities. Poor SIN ability particularly affects young and elderly populations, yet varies considerably even among healthy young adults with normal hearing. Although SIN skills are known to be influenced by top-down processes that can selectively enhance lower-level sound representations, the complementary role of feed-forward mechanisms and their relationship to musical training is poorly understood. Using a paradigm that minimizes the main top-down factors that have been implicated in SIN performance such as working memory, we aimed to better understand how robust encoding of periodicity in the auditory system (as measured by the frequency-following response) contributes to SIN perception. Using magnetoencephalograpy, we found that the strength of encoding at the fundamental frequency in the brainstem, thalamus, and cortex is correlated with SIN accuracy. The amplitude of the slower cortical P2 wave was previously also shown to be related to SIN accuracy and FFR strength; we use MEG source localization to show that the P2 wave originates in a temporal region anterior to that of the cortical FFR. We also confirm that the observed enhancements were related to the extent and timing of musicianship. These results are consistent with the hypothesis that basic feed-forward sound encoding affects SIN perception by providing better information to later processing stages, and that modifying this process may be one mechanism through which musical training might enhance the auditory networks that subserve both musical and language functions. PMID- 28890686 TI - Synaptic Activity and Muscle Contraction Increases PDK1 and PKCbetaI Phosphorylation in the Presynaptic Membrane of the Neuromuscular Junction. AB - Conventional protein kinase C betaI (cPKCbetaI) is a conventional protein kinase C (PKC) isoform directly involved in the regulation of neurotransmitter release in the neuromuscular junction (NMJ). It is located exclusively at the nerve terminal and both synaptic activity and muscle contraction modulate its protein levels and phosphorylation. cPKCbetaI molecular maturation includes a series of phosphorylation steps, the first of which is mediated by phosphoinositide dependent kinase 1 (PDK1). Here, we sought to localize PDK1 in the NMJ and investigate the hypothesis that synaptic activity and muscle contraction regulate in parallel PDK1 and cPKCbetaI phosphorylation in the membrane fraction. To differentiate the presynaptic and postsynaptic activities, we abolished muscle contraction with MU-conotoxin GIIIB (MU-CgTx-GIIIB) in some experiments before stimulation of the phrenic nerve (1 Hz, 30 min). Then, we analyzed total and membrane/cytosol fractions of skeletal muscle by Western blotting. Results showed that PDK1 is located exclusively in the nerve terminal of the NMJ. After nerve stimulation with and without coincident muscle contraction, total PDK1 and phosphorylated PDK1 (pPDK1) protein levels remained unaltered. However, synaptic activity specifically enhanced phosphorylation of PDK1 in the membrane, an important subcellular location for PDK1 function. This increase in pPDK1 coincides with a significant increase in the phosphorylation of its substrate cPKCbetaI also in the membrane fraction. Moreover, muscle contraction maintains PDK1 and pPDK1 but increases cPKCbetaI protein levels and its phosphorylation. Thus, even though PDK1 activity is maintained, pcPKCbetaI levels increase in concordance with total cPKCbetaI. Together, these results indicate that neuromuscular activity could induce the membrane targeting of pPDK1 in the nerve terminal of the NMJ to promote the phosphorylation of the cPKCbetaI, which is involved in ACh release. PMID- 28890688 TI - Metastability of Neuronal Dynamics during General Anesthesia: Time for a Change in Our Assumptions? AB - There is strong evidence that anesthetics have stereotypical effects on brain state, so that a given anesthetic appears to have a signature in the electroencephalogram (EEG), which may vary with dose. This can be usefully interpreted as the anesthetic determining an attractor in the phase space of the brain. How brain activity shifts between these attractors in time remains understudied, as most studies implicitly assume a one-to-one relationship between drug dose and attractor features by assuming stationarity over the analysis interval and analyzing data segments of several minutes in length. Yet data in rats anesthetized with isoflurane suggests that, at anesthetic levels consistent with surgical anesthesia, brain activity alternates between multiple attractors, often spending on the order of 10 min in one activity pattern before shifting to another. Moreover, the probability of these jumps between attractors changes with anesthetic concentration. This suggests the hypothesis that brain state is metastable during anesthesia: though it appears at equilibrium on short timescales (on the order of seconds to a few minutes), longer intervals show shifting behavior. Compelling evidence for metastability in rats anesthetized with isoflurane is reviewed, but so far only suggestive hints of metastability in brain states exist with other anesthetics or in other species. Explicit testing of metastability during anesthesia will require experiments with longer acquisition intervals and carefully designed analytic approaches; some of the implications of these constraints are reviewed for typical spectral analysis approaches. If metastability exists during anesthesia, it implies degeneracy in the relationship between brain state and effect site concentration, as there is not a one-to-one mapping between the two. This degeneracy could explain some of the reported difficulty in using brain activity monitors to titrate drug dose to prevent awareness during anesthesia and should force a rethinking of the notion of depth of anesthesia as a single dimension. Finally, explicit incorporation of knowledge of the dynamics of the brain during anesthesia could offer better depth of anesthesia monitoring. PMID- 28890687 TI - Gp78 E3 Ubiquitin Ligase: Essential Functions and Contributions in Proteostasis. AB - As per the requirement of metabolism and fitness, normal cellular functions are controlled by several proteins, and their interactive molecular and signaling events at multiple levels. Protein quality control (PQC) mechanisms ensure the correct folding and proper utilization of these proteins to avoid their misfolding and aggregation. To maintain the optimum environment of complex proteome PQC system employs various E3 ubiquitin ligases for the selective degradation of aberrant proteins. Glycoprotein 78 (Gp78) is an E3 ubiquitin ligase that prevents multifactorial deleterious accumulation of different misfolded proteins via endoplasmic reticulum-associated degradation (ERAD). However, the precise role of Gp78 under stress conditions to avoid bulk misfolded aggregation is unclear, which can act as a crucial resource to establish the dynamic nature of the proteome. Present article systematically explains the detailed molecular characterization of Gp78 and also addresses its various cellular physiological functions, which could be crucial to achieving protein homeostasis. Here, we comprehensively represent the current findings of Gp78, which shows its PQC roles in different physiological functions and diseases; and thereby propose novel opportunities to better understand the unsolved questions for therapeutic interventions linked with different protein misfolding disorders. PMID- 28890689 TI - Integration between Glycolysis and Glutamate-Glutamine Cycle Flux May Explain Preferential Glycolytic Increase during Brain Activation, Requiring Glutamate. AB - The 1988 observation by Fox et al. (1988) that brief intense brain activation increases glycolysis (pyruvate formation from glucose) much more than oxidative metabolism has been abundantly confirmed. Specifically glycolytic increase was unexpected because the amount of ATP it generates is much smaller than that formed by subsequent oxidative metabolism of pyruvate. The present article shows that preferential glycolysis can be explained by metabolic processes associated with activation of the glutamate-glutamine cycle. The flux in this cycle, which is essential for production of transmitter glutamate and GABA, equals 75% of brain glucose utilization and each turn is associated with utilization of ~1 glucose molecule. About one half of the association between cycle flux and glucose metabolism occurs during neuronal conversion of glutamine to glutamate in a process similar to the malate-aspartate shuttle (MAS) except that glutamate is supplied from glutamine, not formed from alpha-ketoglutarate (alphaKG) as during operation of conventional MAS. Regular MAS function is triggered by one oxidative process in the cytosol during glycolysis causing NAD+ reduction to NADH. Since NADH cannot cross the mitochondrial membrane (MEM) for oxidation NAD+ is re generated by conversion of cytosolic oxaloacetate (OAA) to malate, which enters the mitochondria for oxidation and in a cyclic process regenerates cytosolic OAA. Therefore MAS as well as the "pseudo-MAS" necessary for neuronal glutamate formation can only operate together with cytosolic reduction of NAD+ to NADH. The major process causing NAD+ reduction is glycolysis which therefore also must occur during neuronal conversion of glutamine to glutamate and may energize vesicular glutamate uptake which preferentially uses glycolytically derived energy. Another major contributor to the association between glutamate-glutamine cycle and glucose utilization is the need for astrocytic pyruvate to generate glutamate. Although some oxidative metabolism occurs during glutamate formation it is only one half of that during normal tricarboxylic acid (TCA) cycle function. Glutamate's receptor stimulation leads to potassium ion (K+) release and astrocytic uptake, preferentially fueled by glycolysis and followed by release and neuronal re-accumulation. The activation-induced preferential glycolysis diminishes with continued activation and is followed by an increased ratio between oxidative metabolism and glycolysis, reflecting oxidation of generated glutamate and accumulated lactate. PMID- 28890690 TI - A Cohesive Framework for Motor Stereotypy in Typical and Atypical Development: The Role of Sensorimotor Integration. AB - Stereotyped motor behavior manifests as rhythmic, repetitive movements. It is common in several neurologic and psychiatric disorders where it is considered maladaptive. However, it also occurs early in typical development where it serves an adaptive function in the development of complex, controlled motor behavior. Currently, no framework accounts for both adaptive and maladaptive forms of motor stereotypy. We propose a conceptual model that implicates sensorimotor mechanisms in the phenomenology of adaptive and maladaptive stereotypy. The extensive structural and functional connectivity between sensory and motor neural circuits evidences the importance of sensory integration in the production of controlled movement. In support of our model, motor stereotypy in normative development occurs when the sensory and motor brain regions are immature and the infant has limited sensory and motor experience. With maturation and experience, complex movements develop and replace simple, stereotyped movements. This developmental increase in motor complexity depends on the availability of sensory feedback indicating that the integration of sensory information with ongoing movement allows individuals to adaptively cater their movements to the environmental context. In atypical development, altered neural function of sensorimotor circuitry may limit an individual's ability to integrate sensory feedback to adapt movements to appropriately respond to environmental conditions. Consequently, the motor repertoire would remain relatively simple, resulting in the persistence of motor stereotypy. A framework that considers motor stereotypy as a manifestation of low motor complexity resulting from poor sensorimotor integration has many implications for research, identification and treatment of motor stereotypy in a variety of developmental disorders. PMID- 28890691 TI - Predicting Intentions of a Familiar Significant Other Beyond the Mirror Neuron System. AB - Inferring intentions of others is one of the most intriguing issues in interpersonal interaction. Theories of embodied cognition and simulation suggest that this mechanism takes place through a direct and automatic matching process that occurs between an observed action and past actions. This process occurs via the reactivation of past self-related sensorimotor experiences within the inferior frontoparietal network (including the mirror neuron system, MNS). The working model is that the anticipatory representations of others' behaviors require internal predictive models of actions formed from pre-established, shared representations between the observer and the actor. This model suggests that observers should be better at predicting intentions performed by a familiar actor, rather than a stranger. However, little is known about the modulations of the intention brain network as a function of the familiarity between the observer and the actor. Here, we combined functional magnetic resonance imaging (fMRI) with a behavioral intention inference task, in which participants were asked to predict intentions from three types of actors: A familiar actor (their significant other), themselves (another familiar actor), and a non-familiar actor (a stranger). Our results showed that the participants were better at inferring intentions performed by familiar actors than non-familiar actors and that this better performance was associated with greater activation within and beyond the inferior frontoparietal network i.e., in brain areas related to familiarity (e.g., precuneus). In addition, and in line with Hebbian principles of neural modulations, the more the participants reported being cognitively close to their partner, the less the brain areas associated with action self-other comparison (e.g., inferior parietal lobule), attention (e.g., superior parietal lobule), recollection (hippocampus), and pair bond (ventral tegmental area, VTA) were recruited, suggesting that the more a shared mental representation has been pre established, the more neurons show suppression in their response to the presentation of information to which they are sensitive. These results suggest that the relation of performance to the extent of neural activation during intention understanding may display differential relationships based on the cognitive domain, brain region, and the cognitive interdependence between the observer and the actor. PMID- 28890692 TI - White Matter Injury after Intracerebral Hemorrhage: Pathophysiology and Therapeutic Strategies. AB - Intracerebral hemorrhage (ICH) accounts for 10%-30% of all types of stroke. Bleeding within the brain parenchyma causes gray matter (GM) destruction as well as proximal or distal white matter (WM) injury (WMI) due to complex pathophysiological mechanisms. Because WM has a distinct cellular architecture, blood supply pattern and corresponding function, and its response to stroke may vary from that of GM, a better understanding of the characteristics of WMI following ICH is essential and may shed new light on treatment options. Current evidence using histological, radiological and chemical biomarkers clearly confirms the spatio-temporal distribution of WMI post- ICH. Although certain types of pathological damage such as inflammatory, oxidative and neuro excitotoxic injury to WM have been identified, the exact molecular mechanisms remain unclear. In this review article, we briefly describe the constitution and physiological function of brain WM, summarize evidence regarding WMI, and focus on the underlying pathophysiological mechanisms and therapeutic strategies. PMID- 28890693 TI - Modulation of Somatosensory Alpha Rhythm by Transcranial Alternating Current Stimulation at Mu-Frequency. AB - Introduction: Transcranial alternating current stimulation (tACS) is emerging as an interventional tool to modulate different functions of the brain, potentially by interacting with intrinsic ongoing neuronal oscillations. Functionally different intrinsic alpha oscillations are found throughout the cortex. Yet it remains unclear whether tACS is capable of specifically modulating the somatosensory mu-rhythm in amplitude. Objectives: We used tACS to modulate mu alpha oscillations in amplitude. When compared to sham stimulation we expected a modulation of mu-alpha oscillations but not visual alpha oscillations by tACS. Methods: Individual mu-alpha frequencies were determined in 25 participants. Subsequently, blocks of tACS with individual mu-alpha frequency and sham stimulation were applied over primary somatosensory cortex (SI). Electroencephalogram (EEG) was recorded before and after either stimulation or sham. Modulations of mu-alpha and, for control, visual alpha amplitudes were then compared between tACS and sham. Results: Somatosensory mu-alpha oscillations decreased in amplitude after tACS was applied at participants' individual mu alpha frequency. No changes in amplitude were observed for sham stimulation. Furthermore, visual alpha oscillations were not affected by tACS or sham, respectively. Conclusion: Our results demonstrate the capability of tACS to specifically modulate the targeted somatosensory mu-rhythm when the tACS frequency is tuned to the individual endogenous rhythm and applied over somatosensory areas. Our results are in contrast to previously reported amplitude increases of visual alpha oscillations induced by tACS applied over visual cortex. Our results may point to a specific interaction between our stimulation protocol and the functional architecture of the somatosensory system. PMID- 28890695 TI - Acute Hypoxia Induced an Imbalanced M1/M2 Activation of Microglia through NF kappaB Signaling in Alzheimer's Disease Mice and Wild-Type Littermates. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease mainly caused by abnormal tau phosphorylation, amyloid beta (Abeta) deposition and neuroinflammation. As an important environmental factor, hypoxia has been reported to aggravate AD via exacerbating Abeta and tau pathologies. However, the link between hypoxia and neuroinflammation, especially the changes of pro inflammatory M1 or anti-inflammation M2 microglia phenotypes in AD, is still far from being clearly investigated. Here, we evaluated the activation of microglia in the brains of APPswe/PS1dE9 transgenic (Tg) mice and their wild type (Wt) littermates, after a single episode of acute hypoxia (24 h) exposure. We found that acute hypoxia activated M1 microglia in both Tg and Wt mice as evidenced by the elevated M1 markers including cluster of differentiation 86 (CD86), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2) and CCL3. In addition, the markers of M2 microglia phenotype (arginase-1 (Arg-1), CD206, IL-4 and IL-10) were decreased after acute hypoxia exposure, suggesting an attenuated M2 phenotype of microglia. Moreover, the activation of microglia and the release of cytokines and chemokines were associated with Nuclear factor-kappaB (NF-kappaB) induction through toll-like receptor 4 (TLR4). In summary, our findings revealed that acute hypoxia modulated microglia M1/M2 subgroup profile, indicating the pathological role of hypoxia in the neuroinflammation of AD. PMID- 28890696 TI - Gaze Bias in Preference Judgments by Younger and Older Adults. AB - Individuals' gaze behavior reflects the choice they will ultimately make. For example, people confronting a choice among multiple stimuli tend to look longer at stimuli that are subsequently chosen than at other stimuli. This tendency, called the gaze bias effect, is a key aspect of visual decision-making. Nevertheless, no study has examined the generality of the gaze bias effect in older adults. Here, we used a two-alternative forced-choice task (2AFC) to compare the gaze behavior reflective of different stages of decision processes demonstrated by younger and older adults. Participants who had viewed two faces were instructed to choose the one that they liked/disliked or the one that they judged to be more/less similar to their own face. Their eye movements were tracked while they chose. The results show that the gaze bias effect occurred during the remaining time in both age groups irrespective of the decision type. However, no gaze bias effect was observed for the preference judgment during the first dwell time. Our study demonstrated that the gaze bias during the remaining time occurred regardless of decision-making task and age. Further study using diverse participants, such as clinic patients or infants, may help to generalize the gaze bias effect and to elucidate the mechanisms underlying the gaze bias. PMID- 28890694 TI - Erythrocytes as Potential Link between Diabetes and Alzheimer's Disease. AB - Many studies support the existence of an association between type 2 diabetes (T2DM) and Alzheimer's disease (AD). In AD, in addition to brain, a number of peripheral tissues and cells are affected, including red blood cell (RBC) and because there are currently no reliable diagnostic biomarkers of AD in the blood, a gradually increasing attention has been given to the study of RBC's alterations. Recently it has been evidenced in diabetes, RBC alterations superimposable to the ones occurring in AD RBC. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of RBC's alterations and vice versa. Once again this represents a further evidence of a shared pathway between AD and T2DM. The present review summarizes the two disorders, highlighting the role of RBC in the postulated common biochemical links, and suggests RBC as a possible target for clinical trials. PMID- 28890697 TI - Effect of the Natural Product Triptolide on Pancreatic Cancer: A Systematic Review of Preclinical Studies. AB - Objective: Triptolide (TL), a natural product isolated from Tripterygium wilfordii Hook F (TwHF), shows potent anticancer effects in vitro and in vivo. We aimed to summary the biochemical mechanisms through which TL has been shown to induce apoptosis, autophagy and inhibit angiogenesis in pancreatic cancer (PC). Methods: We undertook a systematic review of preclinical evidence. We searched electronic databases. The potential mechanisms and the underlying signaling pathways have been accumulated as well. Results: We screened 116 abstracts for eligibility and included 17 preclinical studies in the analysis. Details of the animals and cell lines were provided in 16 studies (94.1%). Six studies (75.0%) randomly assigned animals to treatment or control groups and only 1 study (12.5%) reported on blinding. The majority of the TL's research field has focused on its pro-apoptotic effects through downregulation of inhibitory pathways and upregulation of apoptotic pathways. The studies have shown that TL is effective both in vitro and in vivo against PC cells. Conclusion: This study provides a systematic summary of TL's anti-pancreatic cancer profile and the underlying mechanisms of with special emphasis on the apoptosis, autophagy, angiogenesis and related molecular pathways. Improved study quality in terms of treatment allocation methods reporting, randomization and blinding will accelerate needed progress toward trials. PMID- 28890698 TI - Multi-Target Screening and Experimental Validation of Natural Products from Selaginella Plants against Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder which is considered to be the most common cause of dementia. It has a greater impact not only on the learning and memory disturbances but also on social and economy. Currently, there are mainly single-target drugs for AD treatment but the complexity and multiple etiologies of AD make them difficult to obtain desirable therapeutic effects. Therefore, the choice of multi-target drugs will be a potential effective strategy inAD treatment. To find multi-target active ingredients for AD treatment from Selaginella plants, we firstly explored the behaviors effects on AD mice of total extracts (TE) from Selaginella doederleinii on by Morris water maze test and found that TE has a remarkable improvement on learning and memory function for AD mice. And then, multi-target SAR models associated with AD-related proteins were built based on Random Forest (RF) and different descriptors to preliminarily screen potential active ingredients from Selaginella. Considering the prediction outputs and the quantity of existing compounds in our laboratory, 13 compounds were chosen to carry out the in vitro enzyme inhibitory experiments and 4 compounds with BACE1/MAO-B dual inhibitory activity were determined. Finally, the molecular docking was applied to verify the prediction results and enzyme inhibitory experiments. Based on these study and validation processes, we explored a new strategy to improve the efficiency of active ingredients screening based on trace amount of natural product and numbers of targets and found some multi-target compounds with biological activity for the development of novel drugs for AD treatment. PMID- 28890700 TI - Dietary Capsaicin Improves Glucose Homeostasis and Alters the Gut Microbiota in Obese Diabetic ob/ob Mice. AB - Background: The effects of capsaicin on obesity and glucose homeostasis are still controversial and the mechanisms underlying these effects remain largely unknown. This study aimed to investigate the potential relationship between the regulation of obesity and glucose homeostasis by dietary capsaicin and the alterations of gut microbiota in obese diabetic ob/ob mice. Methods: The ob/ob mice were subjected to a normal, low-capsaicin (0.01%), or high-capsaicin (0.02%) diet for 6 weeks, respectively. Obesity phenotypes, glucose homeostasis, the gut microbiota structure and composition, short-chain fatty acids, gastrointestinal hormones, and pro-inflammatory cytokines were measured. Results: Both the low- and high-capsaicin diets failed to prevent the increase in body weight, adiposity index, and Lee's obesity index. However, dietary capsaicin at both the low and high doses significantly inhibited the increase of fasting blood glucose and insulin levels. These inhibitory effects were comparable between the two groups. Similarly, dietary capsaicin resulted in remarkable improvement in glucose and insulin tolerance. In addition, neither the low- nor high-capsaicin diet could alter the alpha-diversity and beta-diversity of the gut microbiota. Taxonomy based analysis showed that both the low- and high-capsaicin diets, acting in similar ways, significantly increased the Firmicutes/Bacteroidetes ratio at the phylum level as well as increased the Roseburia abundance and decreased the Bacteroides and Parabacteroides abundances at the genus level. Spearman's correlation analysis revealed that the Roseburia abundance was negatively while the Bacteroides and Parabacteroides abundances were positively correlated to the fasting blood glucose level and area under the curve by the oral glucose tolerance test. Finally, the low- and high-capsaicin diets significantly increased the fecal butyrate and plasma total GLP-1 levels, but decreased plasma total ghrelin, TNF-alpha, IL-1beta, and IL-6 levels as compared with the normal diet. Conclusions: The beneficial effects of dietary capsaicin on glucose homeostasis are likely associated with the alterations of specific bacteria at the genus level. These alterations in bacteria induced by dietary capsaicin contribute to improved glucose homeostasis through increasing short-chain fatty acids, regulating gastrointestinal hormones and inhibiting pro-inflammatory cytokines. However, our results should be interpreted cautiously due to the lower caloric intake at the initial stage after capsaicin diet administration. PMID- 28890699 TI - Sphingosine 1-Phosphate Signaling as a Target in Hepatic Fibrosis Therapy. AB - Liver fibrosis is an excess production of extracellular matrix proteins as a result of chronic liver disease which leads to cell death and organ dysfunction. The key cells involved in fibrogenesis are resident hepatic stellate cells (HSCs) which are termed myofibroblasts after activation, acquiring contractile, proliferative, migratory and secretory capability. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with well-established effects on angiogenesis, carcinogenesis and immunity. Accumulating evidence demonstrates that this metabolite is involved in the profibrotic inflammatory process through the regulation of pleiotropic cell responses, such as vascular permeability, leukocyte infiltration, cell survival, migration, proliferation and HSCs differentiation to myofibroblasts. S1P is synthesized by sphingosine kinases (SphKs) and many of its actions are mediated by S1P specific cell surface receptors (S1P1-5), although different intracellular targets of S1P have been identified. Modulation of SphKs/S1P/S1P receptors signaling is known to result in beneficial effects on various in vivo and in vitro models of liver fibrosis. Thus, a better knowledge of the molecular mechanisms involved in the modulation of the S1P pathway could help to improve liver fibrosis therapy. In this review, we analyze the effects of the S1P axis on the fibrogenic process, and the involvement of a range of inhibitors or approaches targeting enzymes related to S1P in the abrogation of pathological fibrogenesis. All in all, targeting this pathway offers therapeutic potential in the treatment of hepatic fibrosis. PMID- 28890701 TI - High Fat High Sugar Diet Reduces Voluntary Wheel Running in Mice Independent of Sex Hormone Involvement. AB - Introduction: Indirect results in humans suggest that chronic overfeeding decreases physical activity with few suggestions regarding what mechanism(s) may link overfeeding and decreased activity. The primary sex hormones are known regulators of activity and there are reports that chronic overfeeding alters sex hormone levels. Thepurpose of this study was to determine if chronic overfeeding altered wheel running through altered sex hormone levels. Materials and Methods: C57BL/6J mice were bred and the pups were weaned at 3-weeks of age and randomly assigned to either a control (CFD) or high fat/high sugar (HFHS) diet for 9-11 weeks depending on activity analysis. Nutritional intake, body composition, sex hormone levels, and 3-day and 2-week wheel-running activity were measured. Additionally, groups of HFHS animals were supplemented with testosterone (males) and 17beta-estradiol (females) to determine if sex hormone augmentation altered diet-induced changes in activity. Results: 117 mice (56?, 61?) were analyzed. The HFHS mice consumed significantly more calories per day than CFD mice (male: p < 0.0001; female: p < 0.0001) and had significantly higher body fat (male: p < 0.0001; female: p < 0.0001). The HFHS diet did not reduce sex hormone levels, but did significantly reduce acute running-wheel distance in male (p = 0.05, 70 +/- 28%) and female mice (p = 0.02, 57 +/- 26%). In animals that received hormone supplementation, there was no significant effect on activity levels. Two-weeks of wheel access was not sufficient to alter HFHS-induced reductions in activity or increases in body fat. Conclusion: Chronic overfeeding reduces wheel running, but is independent of the primary sex hormones. PMID- 28890703 TI - Observations on Working Psychoanalytically with a Profoundly Amnesic Patient. AB - Individuals with profound amnesia are markedly impaired in explicitly recalling new episodic events, but appear to preserve the capacity to use information from other sources. Amongst these preserved capacities is the ability to form new memories of an emotional nature - a skill at the heart of developing and sustaining interpersonal relationships. The psychoanalytic study of individuals with profound amnesia might contribute to the understanding the importance of each memory system, including effects on key analytic processes such as transference and countertransference. However, psychoanalytic work in the presence of profound amnesia might also require important technical modifications. In the first report of its kind, we describe observations from a long term psychoanalytic process (72 sessions) with an individual (JL) who has profound amnesia after an anoxic episode. The nature of therapy was shaped by JL's impairment in connecting elements that belong to distant (and even relatively close) moments in the therapeutic process. However, we were also able to document areas of preservation, in what appears to be a functioning therapeutic alliance. As regards transference, the relationship between JL and his analyst can be viewed as the evolution of a narcissistic transference, and case material is provided that maps this into three phases: (i) rejecting; (ii) starting to take in; and (iii) full use of the analytic space - where each phase exhibits differing degrees of permeability between JL and the analyst. This investigation appears to have important theoretical implications for psychoanalytic practice, and for psychotherapy in general - and not only with regard to brain injured populations. We especially note that it raises questions concerning the mechanism of therapeutic action in psychoanalysis and psychotherapy, and the apparent unimportance of episodic memory for many elements of therapeutic change. PMID- 28890704 TI - Computer Mediated Social Comparative Feedback Does Not Affect Metacognitive Regulation of Memory Reports. AB - In two experiments, we investigated how social comparative feedback affects the metacognitive regulation of eyewitness memory reports. In Experiment 1, 87 participants received negative, positive, or no feedback about a co-witness's performance on a task querying recall of a crime video. Participants then completed the task individually. There were no significant differences between negative and positive feedback groups on any measure. However, participants in both of these conditions volunteered more fine-grain details than participants in the control condition. In Experiment 2, 90 participants answered questions about a crime video. Participants in the experimental groups received either positive or negative feedback, which compared their performance to that of others. Participants then completed a subsequent recall task, for which they were told their performance would not be scored. Feedback did not significantly affect participants' confidence, accuracy, or the level of detail they reported in comparison to a no feedback control group. These findings advance our understanding of the boundary conditions for social feedback effects on meta memory. PMID- 28890702 TI - A Pilot Study of the Effects of Mindfulness-Based Stress Reduction on Post traumatic Stress Disorder Symptoms and Brain Response to Traumatic Reminders of Combat in Operation Enduring Freedom/Operation Iraqi Freedom Combat Veterans with Post-traumatic Stress Disorder. AB - OBJECTIVE: Brain imaging studies in patients with post-traumatic stress disorder (PTSD) have implicated a circuitry of brain regions including the medial prefrontal cortex, amygdala, hippocampus, parietal cortex, and insula. Pharmacological treatment studies have shown a reversal of medial prefrontal deficits in response to traumatic reminders. Mindfulness-based stress reduction (MBSR) is a promising non-pharmacologic approach to the treatment of anxiety and pain disorders. The purpose of this study was to assess the effects of MBSR on PTSD symptoms and brain response to traumatic reminders measured with positron emission tomography (PET) in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) combat veterans with PTSD. We hypothesized that MBSR would show increased prefrontal response to stress and improved PTSD symptoms in veterans with PTSD. METHOD: Twenty-six OEF/OIF combat veterans with PTSD who had recently returned from a combat zone were block randomized to receive eight sessions of MBSR or present-centered group therapy (PCGT). PTSD patients underwent assessment of PTSD symptoms with the Clinician-Administered PTSD Scale (CAPS), mindfulness with the Five Factor Mindfulness Questionnaire (FFMQ) and brain imaging using PET in conjunction with exposure to neutral and Iraq combat-related slides and sound before and after treatment. Nine patients in the MBSR group and 8 in the PCGT group completed all study procedures. RESULTS: Post-traumatic stress disorder patients treated with MBSR (but not PCGT) had an improvement in PTSD symptoms measured with the CAPS that persisted for 6 months after treatment. MBSR also resulted in an increase in mindfulness measured with the FFMQ. MBSR-treated patients had increased anterior cingulate and inferior parietal lobule and decreased insula and precuneus function in response to traumatic reminders compared to the PCGT group. CONCLUSION: This study shows that MBSR is a safe and effective treatment for PTSD. Furthermore, MBSR treatment is associated with changes in brain regions that have been implicated in PTSD and are involved in extinction of fear responses to traumatic memories as well as regulation of the stress response. PMID- 28890705 TI - Parent Rated Symptoms of Inattention in Childhood Predict High School Academic Achievement Across Two Culturally and Diagnostically Diverse Samples. AB - Objective: To investigate parent reports of childhood symptoms of inattention as a predictor of adolescent academic achievement, taking into account the impact of the child's intellectual functioning, in two diagnostically and culturally diverse samples. Method: Samples: (a) an all-female sample in the U.S. predominated by youth with ADHD (Berkeley Girls with ADHD Longitudinal Study [BGALS], N = 202), and (b) a mixed-sex sample recruited from a Norwegian population-based sample (the Bergen Child Study [BCS], N = 93). Inattention and intellectual function were assessed via the same measures in the two samples; academic achievement scores during and beyond high school and demographic covariates were country-specific. Results: Childhood inattention predicted subsequent academic achievement in both samples, with a somewhat stronger effect in the BGALS sample, which included a large subgroup of children with ADHD. Intellectual function was another strong predictor, but the effect of early inattention remained statistically significant in both samples when intellectual function was covaried. Conclusion: The effect of early indicators of inattention on future academic success was robust across the two samples. These results support the use of remediation procedures broadly applied. Future longitudinal multicenter studies with pre-planned common inclusion criteria should be performed to increase our understanding of the importance of inattention in primary school children for concurrent and prospective functioning. PMID- 28890706 TI - Independent and Combined Effects of Socioeconomic Status (SES) and Bilingualism on Children's Vocabulary and Verbal Short-Term Memory. AB - The current study explores the influence of socioeconomic status (SES) and bilingualism on the linguistic skills and verbal short-term memory of preschool children. In previous studies comparing children of low and mid-high SES, the terms "a child with low-SES" and "a child speaking a minority language" are often interchangeable, not enabling differentiated evaluation of these two variables. The present study controls for this confluence by testing children born and residing in the same country and attending the same kindergartens, with all bilingual children speaking the same heritage language (HL-Russian). A total of 120 children (88 bilingual children: 44 with low SES; and 32 monolingual children: 16 with low SES) with typical language development, aged 5; 7-6; 7, were tested in the societal language (SL-Hebrew) on expressive vocabulary and three repetition tasks [forward digit span (FWD), nonword repetition (NWR), and sentence repetition (SRep)], which tap into verbal short-term memory. The results indicated that SES and bilingualism impact different child abilities. Bilingualism is associated with decreased vocabulary size and lower performance on verbal short-term memory tasks with higher linguistic load in the SL-Hebrew. The negative effect of bilingualism on verbal short-term memory disappears once vocabulary is accounted for. SES influences not only linguistic performance, but also verbal short-term memory with lowest linguistic load. The negative effect of SES cannot be solely attributed to lower vocabulary scores, suggesting that an unprivileged background has a negative impact on children's cognitive development beyond a linguistic disadvantage. The results have important clinical implications and call for more research exploring the varied impact of language and life experience on children's linguistic and cognitive skills. PMID- 28890708 TI - Reduced Maximum Pitch Elevation Predicts Silent Aspiration of Small Liquid Volumes in Stroke Patients. AB - BACKGROUND AND PURPOSE: Preliminary evidence has shown that reduced ability to maximally raise vocal pitch correlates with the occurrence of aspiration (i.e., airway invasion by food or liquid). However, it is unclear if this simple task can be used as a reliable predictor of aspiration in stroke patients. Our aim was to examine whether maximum vocal pitch elevation predicted airway invasion and dysphagia in stroke. METHODS: Forty-five consecutive stroke patients (<1 month poststroke) at a rehabilitation setting participated in a videofluoroscopic swallow study and two maximum vocal pitch elevation tasks. Maximum pitch was evaluated acoustically [maximum fundamental frequency (max F0)] and perceptually. Swallowing safety was rated using the Penetration/Aspiration Scale and swallowing performance was assessed using components of the Modified Barium Swallow Impairment Profile (MBSImPTM(c)). Data were analyzed using simple regression and receiver operating characteristics curves to test the sensitivity and specificity of max F0 in predicting aspiration. Correlations between max F0 and MBSImP variables were also examined. RESULTS: Max F0 predicted silent aspiration of small liquid volumes with 80% sensitivity and 65% specificity (p = 0.023; area under the curve: 0.815; cutoff value of 359.03 Hz). Max F0 did not predict non silent aspiration or penetration in this sample and did not significantly correlate with MBSImP variables. Furthermore, all participants who aspirated silently on small liquid volumes (11% of sample) had suffered cortical or subcortical lesions. CONCLUSION: In stroke patients (<1 month poststroke), reduced maximum pitch elevation predicts silent aspiration of small liquid volumes with high sensitivity and moderate specificity. Future large-scale studies focusing on further validating this finding and exploring the value of this simple and non-invasive tool as part of a dysphagia screening are warranted. PMID- 28890707 TI - ELSA 2016 Cohort: Alcohol, Tobacco, and Marijuana Use and Their Association with Age of Drug Use Onset, Risk Perception, and Social Norms in Argentinean College Freshmen. AB - The transition from high school to college is a high-risk stage for the initiation and escalation of substance use. Substance use and its associated risk factors have been thoroughly described in developed countries, such as the United States, but largely neglected in Argentina, a South American country with patterns of a collectivist culture. The present cross-sectional study describes the occurrence of alcohol, tobacco, and marijuana use and the association between these behaviors and the age of onset of substance use and cognitive (i.e., risk perception) and social (i.e., prescriptive) variables in a large sample of Argentinean college freshmen (n = 4083, 40.1% men; mean age = 19.39 +/- 2.18 years). The response rate across courses was >=90% and was similarly distributed across sex. Participants completed a survey that measured substance use (alcohol [with a focus on heavy drinking and binge drinking behaviors], tobacco, and marijuana), age of onset of the use of each substance, perceived risk associated with various substance use behaviors, prescriptive norms associated with substance use, and descriptive norms for alcohol use (AU). The results indicated that AU is nearly normative (90.4 and 80.3% with last year and last month use, respectively) in this population, and heavy drinking is highly prevalent (68.6 and 54.9% with heavy episodic and binge drinking, respectively), especially among those with an early drinking onset (97.8 and 93.6% with last year and last month use and 87.8 and 76.3% with heavy episodic and binge drinking, respectively). The last-year occurrence of tobacco and marijuana use was 36 and 28%, respectively. Early substance use was associated with the greater use of that specific substance. The students overestimated their same-sex friend's AU, and women overestimated the level of AU of their best male friend. At the multivariate level, all of the predictors, with the exception of the parents' prescriptive norms, significantly explained the frequency of marijuana and tobacco use and frequency of hazardous drinking. Overall, despite important cultural and contextual differences between Argentina and the United States, our findings suggest that certain vulnerability factors have a similar influence across these cultural contexts. PMID- 28890709 TI - Editorial: Neuropeptides and Behavior: From Motivation to Psychopathology. PMID- 28890710 TI - Commentary: Thyrotropin Stimulates Differentiation Not Proliferation of Normal Human Thyrocytes in Culture. PMID- 28890711 TI - Horizontally Acquired Genes Are Often Shared between Closely Related Bacterial Species. AB - Horizontal gene transfer (HGT) serves as an important source of innovation for bacterial species. We used a pangenome-based approach to identify genes that were horizontally acquired by four closely related bacterial species, belonging to the Enterobacteriaceae family. This enabled us to examine the extent to which such closely related species tend to share horizontally acquired genes. We find that a high percent of horizontally acquired genes are shared among these closely related species. Furthermore, we demonstrate that the extent of sharing of horizontally acquired genes among these four closely related species is predictive of the extent to which these genes will be found in additional bacterial species. Finally, we show that acquired genes shared by more species tend to be better optimized for expression within the genomes of their new hosts. Combined, our results demonstrate the existence of a large pool of frequently horizontally acquired genes that have distinct characteristics from horizontally acquired genes that are less frequently shared between species. PMID- 28890713 TI - Bad Phages in Good Bacteria: Role of the Mysterious orf63 of lambda and Shiga Toxin-Converting Phi24B Bacteriophages. AB - Lambdoid bacteriophages form a group of viruses that shares a common schema of genome organization and lifecycle. Some of them can play crucial roles in creating the pathogenic profiles of Escherichia coli strains. For example, Shiga toxin-producing E. coli (STEC) acquired stx genes, encoding Shiga toxins, via lambdoid prophages (Stx phages). The results obtained so far present the evidence for the relation between the exo-xis region of the phage genome and lambdoid phage development, however molecular mechanisms of activities of the exo-xis genes' products are still unknown. In view of this, we decided to determine the influence of the uncharacterized open reading frame orf63 of the exo-xis region on lambdoid phages development using recombinant prophages, lambda and Stx phage Phi24B. We have demonstrated that orf63 codes for a folded protein, thus, it is a functional gene. NMR spectroscopy and analytical gel filtration were used to extend this observation further. From backbone chemical shifts, Orf63 is oligomeric in solution, likely a trimer and consistent with its small size (63 aa.), is comprised of two helices, likely intertwined to form the oligomer. We observed that the deletion of phage orf63 does not impair the intracellular lambdoid phage lytic development, however delays the time and decreases the efficiency of prophage induction and in consequence results in increased survival of E. coli during phage lytic development. Additionally, the deletion of phage orf63 negatively influences expression of the major phage genes and open reading frames from the exo-xis region during prophage induction with hydrogen peroxide. We conclude, that lambdoid phage orf63 may have specific functions in the regulation of lambdoid phages development, especially at the stage of the lysis vs. lysogenization decision. Besides, orf63 probably participates in the regulation of the level of expression of essential phage genes and open reading frames from the exo-xis region during prophage induction. PMID- 28890712 TI - Microbial Carbonic Anhydrases in Biomimetic Carbon Sequestration for Mitigating Global Warming: Prospects and Perspectives. AB - All the leading cities in the world are slowly becoming inhospitable for human life with global warming playing havoc with the living conditions. Biomineralization of carbon dioxide using carbonic anhydrase (CA) is one of the most economical methods for mitigating global warming. The burning of fossil fuels results in the emission of large quantities of flue gas. The temperature of flue gas is quite high. Alkaline conditions are necessary for CaCO3 precipitation in the mineralization process. In order to use CAs for biomimetic carbon sequestration, thermo-alkali-stable CAs are, therefore, essential. CAs must be stable in the presence of various flue gas contaminants too. The extreme environments on earth harbor a variety of polyextremophilic microbes that are rich sources of thermo-alkali-stable CAs. CAs are the fastest among the known enzymes, which are of six basic types with no apparent sequence homology, thus represent an elegant example of convergent evolution. The current review focuses on the utility of thermo-alkali-stable CAs in biomineralization based strategies. A variety of roles that CAs play in various living organisms, the use of CA inhibitors as drug targets and strategies for overproduction of CAs to meet the demand are also briefly discussed. PMID- 28890714 TI - Gut Microbiota Analysis in Rats with Methamphetamine-Induced Conditioned Place Preference. AB - Methamphetamine abuse is a major public health crisis. Because accumulating evidence supports the hypothesis that the gut microbiota plays an important role in central nervous system (CNS) function, and research on the roles of the microbiome in CNS disorders holds conceivable promise for developing novel therapeutic avenues for treating CNS disorders, we sought to determine whether administration of methamphetamine leads to alterations in the intestinal microbiota. In this study, the gut microbiota profiles of rats with methamphetamine-induced conditioned place preference (CPP) were analyzed through 16S rRNA gene sequencing. The fecal microbial diversity was slightly higher in the METH CPP group. The propionate-producing genus Phascolarctobacterium was attenuated in the METH CPP group, and the family Ruminococcaceae was elevated in the METH CPP group. Short chain fatty acid analysis revealed that the concentrations of propionate were decreased in the fecal matter of METH administered rats. These findings provide direct evidence that administration of METH causes gut dysbiosis, enable a better understanding of the function of gut microbiota in the process of drug abuse, and provide a new paradigm for addiction treatment. PMID- 28890715 TI - Identification of Fungal Communities Associated with the Biodeterioration of Waterlogged Archeological Wood in a Han Dynasty Tomb in China. AB - The Mausoleum of the Dingtao King (termed 'M2') is a large-scale huangchang ticou tomb that dates to the Western Han Dynasty (206 B.C.-25 A.D.). It is the highest ranking Han Dynasty tomb discovered to date. However, biodeterioration on the surface of the tomb M2 is causing severe damage to its wooden materials. The aim of the present study was to give insight into the fungal communities colonized the wooden tomb. For this purpose, seven samples were collected from different sections of the tomb M2 which exhibited obvious biodeterioration in the form of white spots. Microbial structures associated with the white spots were observed with scanning electron microscopy. Fungal community structures were assessed for seven samples via a combination of high-throughput sequencing and culture dependent techniques. Sequencing analyses identified 114 total genera that belonged to five fungal phyla. Hypochnicium was the most abundant genus across all samples and accounted for 98.61-99.45% of the total community composition. Further, Hypochnicium sp. and Mortierella sp. cultures were successfully isolated from the tomb samples, and were distinguished as Hypochnicium sp. WY-DT1 and Mortierella sp. NK-DT1, respectively. Cultivation-dependent experiments indicated that the dominant member, Hypochnicium sp. WY- DT1, could grow at low temperatures and significantly degraded cellulose and lignin. Thus, our results taken together suggest that this fungal strain must be regarded as a serious threat to the preservation of the wooden tomb M2. The results reported here are useful for informing future contamination mitigation efforts for the tomb M2 as well as other similar cultural artifacts. PMID- 28890716 TI - Mining the Volatilomes of Plant-Associated Microbiota for New Biocontrol Solutions. AB - Microbial lifeforms associated with land plants represent a rich source for crop growth- and health-promoting microorganisms and biocontrol agents. Volatile organic compounds (VOCs) produced by the plant microbiota have been demonstrated to elicit plant defenses and inhibit the growth and development of numerous plant pathogens. Therefore, these molecules are prospective alternatives to synthetic pesticides and the determination of their bioactivities against plant threats could contribute to the development of control strategies for sustainable agriculture. In our previous study we investigated the inhibitory impact of volatiles emitted by Pseudomonas species isolated from a potato field against the late blight-causing agent Phytophthora infestans. Besides the well-documented emission of hydrogen cyanide, other Pseudomonas VOCs impeded P. infestans mycelial growth and sporangia germination. Current advances in the field support the emerging concept that the microbial volatilome contains unexploited, eco friendly chemical resources that could help select for efficient biocontrol strategies and lead to a greener chemical disease management in the field. PMID- 28890717 TI - Efficient Killing of Murine Pluripotent Stem Cells by Natural Killer (NK) Cells Requires Activation by Cytokines and Partly Depends on the Activating NK Receptor NKG2D. AB - Natural killer (NK) cells play an important role as cytotoxic effector cells, which scan the organism for infected or tumorigenic cells. Conflicting data have been published whether NK cells can also kill allogeneic or even autologous pluripotent stem cells (PSCs) and which receptors are involved. A clarification of this question is relevant since an activity of NK cells against PSCs could reduce the risk of teratoma growth after transplantation of PSC-derived grafts. Therefore, the hypothesis has been tested that the activity of NK cells against PSCs depends on cytokine activation and specifically on the activating NK receptor NKG2D. It is shown that a subcutaneous injection of autologous iPSCs failed to activate NK cells against these iPSCs and can give rise to teratomas. In agreement with this result, several PSC lines, including two iPSC, two embryonic stem cell (ESC), and two so-called multipotent adult germline stem cell (maGSC) lines, were largely resistant against resting NK cells although differences in killing were found at low level. All PSC lines were killed by interleukin (IL)-2-activated NK cells, and maGSCs were better killed than the other PSC types. The PSCs expressed ligands of the activating NK receptor NKG2D and NKG2D-deficient NK cells from Klrk1-/- mice were impaired in their cytotoxic activity against PSCs. The low-cytotoxic activity of resting NK cells was almost completely dependent on NKG2D. The cytotoxic activity of IL-2-activated NKG2D deficient NK cells against PSCs was reduced, indicating that also other activating receptors on cytokine-activated NK cells must be engaged by ligands on PSCs. Thus, NKG2D is an important activating receptor involved in killing of murine PSCs. However, NK cells need to be activated by cytokines before they efficiently target PSCs and then also other NK receptors become relevant. These features of NK cells might be relevant for transplantation of PSC-derived grafts since NK cells have the capability to kill undifferentiated cells, which might be present in grafts in trace amounts. PMID- 28890718 TI - Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG Induced Pleurisy. AB - Pleural tuberculosis (TB) is a form of extra-pulmonary TB observed in patients infected with Mycobacterium tuberculosis. Accumulation of myeloid-derived suppressor cells (MDSC) has been observed in animal models of TB and in human patients but their role remains to be fully elucidated. In this study, we analyzed the role of transmembrane TNF (tmTNF) in the accumulation and function of MDSC in the pleural cavity during an acute mycobacterial infection. Mycobacterium bovis BCG-induced pleurisy was resolved in mice expressing tmTNF, but lethal in the absence of tumor necrosis factor. Pleural infection induced MDSC accumulation in the pleural cavity and functional MDSC required tmTNF to suppress T cells as did pleural wild-type MDSC. Interaction of MDSC expressing tmTNF with CD4 T cells bearing TNF receptor 2 (TNFR2), but not TNFR1, was required for MDSC suppressive activity on CD4 T cells. Expression of tmTNF attenuated Th1 cell-mediated inflammatory responses generated by the acute pleural mycobacterial infection in association with effective MDSC expressing tmTNF and interacting with CD4 T cells expressing TNFR2. In conclusion, this study provides new insights into the crucial role played by the tmTNF/TNFR2 pathway in MDSC suppressive activity required during acute pleural infection to attenuate excessive inflammation generated by the infection. PMID- 28890719 TI - Outer Membrane Vesicles Prime and Activate Macrophage Inflammasomes and Cytokine Secretion In Vitro and In Vivo. AB - Outer membrane vesicles (OMVs) are proteoliposomes blebbed from the surface of Gram-negative bacteria. Chronic periodontitis is associated with an increase in subgingival plaque of Gram-negative bacteria, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. In this study, we investigated the immune modulatory effects of P. gingivalis, T. denticola, and T. forsythia OMVs on monocytes and differentiated macrophages. All of the bacterial OMVs were phagocytosed by monocytes, M(naive) and M(IFNgamma) macrophages in a dose dependent manner. They also induced NF-kappaB activation and increased TNFalpha, IL-8, and IL-1beta cytokine secretion. P. gingivalis OMVs were also found to induce anti-inflammatory IL-10 secretion. Although unprimed monocytes and macrophages were resistant to OMV-induced cell death, lipopolysaccharide or OMV priming resulted in a significantly reduced cell viability. P. gingivalis, T. denticola, and T. forsythia OMVs all activated inflammasome complexes, as monitored by IL-1beta secretion and ASC speck formation. ASC was critical for OMV induced inflammasome formation, while AIM2-/- and Caspase-1-/- cells had significantly reduced inflammasome formation and NLRP3-/- cells exhibited a slight reduction. OMVs were also found to provide both priming and activation of the inflammasome complex. High-resolution microscopy and flow cytometry showed that P. gingivalis OMVs primed and activated macrophage inflammasomes in vivo with 80% of macrophages exhibiting inflammasome complex formation. In conclusion, periodontal pathogen OMVs were found to have significant immunomodulatory effects upon monocytes and macrophages and should therefore influence pro-inflammatory host responses associated with disease. PMID- 28890720 TI - Porcine B Cell Subset Responses to Toll-like Receptor Ligands. AB - Toll-like receptors (TLR) triggering of B cells are known to promote B cell expansion, differentiation of B cells into antibody-producing and memory cells, but the TLR responses of porcine B cells is poorly characterized. Therefore, this study investigated the response pattern of porcine B cell subsets to a large collection of TLR ligands and demonstrates that the TLR2 ligand Pam3Cys-SK4 and the TLR7/8 ligands gardiquimod and resiquimod are particularly efficient at inducing proliferation, CD25 and CCR7. This activation was also determined in B cell subpopulations including a CD21+IgM+ subset, an IgG+ subset and two putative B1-like subsets, defined as CD21-IgMhighCD11R1+CD11c+CD14+ and CD21-IgMhigh CD11R1-CD11c+CD14- B cells. The latter two were larger and expressed higher levels of CD80/86 and spontaneous phospholipase C-gamma2 phosphorylation. All porcine B-cell subsets were activated by TLR2, TLR7, and TLR9 ligands. Naive and memory conventional B cells responded similar to TLR ligands. The CD11R1+ B1-like subset had the highest proliferative responses. While both B1-like subsets did not spontaneously secrete IgM, they were the only subsets to produce high level of TLR-induced IgM. Similar to polyclonal IgM responses, memory B cells were efficiently induced to produce specific antibodies by CpG oligodinucleotide, resiquimod, and to a weaker extend by Pam3Cys-SK4. Depletion of plasmacytoid dendritic cells (pDCs) enhanced TLR-induced antibodies. The same set of TLR ligands also induced CD40 on cDCs, pDCs, and monocytes with the exception of TLR4 ligand being unable to activate pDCs. Gardiquimod and resiquimod were particularly efficient at inducing CCR7 on pDCs. Porcine B cells expressed high levels of TLR7, but relatively little other TLR mRNA. Nevertheless, TLR2 on B cells was rapidly upregulated following stimulation, explaining the strong responses following stimulation. Subset-specific analysis of TLR expression demonstrated a comparable expression of TLR2, TLR7, and TLR9 in all B cell subsets, but TLR3 was restricted to B1-like cells, whereas TLR4 was only expressed on conventional B cells, although both at low levels. Altogether, our data describe porcine innate B1-like cells, and how different B cell subsets are involved in innate sensing. PMID- 28890721 TI - Development and Application of Transcriptome-Derived Microsatellites in Actinidia eriantha (Actinidiaceae). AB - Actinidia eriantha Benth. is a diploid perennial woody vine native to China and is recognized as a valuable species for commercial kiwifruit improvement with high levels of ascorbic acid as well as having been used in traditional Chinese medicine. Due to the lack of genomic resources for the species, microsatellite markers for population genetics studies are scarce. In this study, RNASeq was conducted on fruit tissue of A. eriantha, yielding 5,678,129 reads with a total output of 3.41 Gb. De novo assembly yielded 69,783 non-redundant unigenes (41.3 Mb), of which 21,730 were annotated using protein databases. A total of 8,658 EST SSR loci were identified in 7,495 unigene sequences, for which primer pairs were successfully designed for 3,842 loci (44.4%). Among these, 183 primer pairs were assayed for PCR amplification, yielding 69 with detectable polymorphism in A. eriantha. Additionally, 61 of the 69 polymorphic loci could be successfully amplified in at least one other Actinidia species. Of these, 14 polymorphic loci (mean NA = 6.07 +/- 2.30) were randomly selected for assessing levels of genetic diversity and population structure within A. eriantha. Finally, a neighbor joining tree and Bayesian clustering analysis showed distinct clustering into two groups (K = 2), agreeing with the geographical distributions of these populations. Overall, our results will facilitate further studies of genetic diversity within A. eriantha and will aid in discriminating outlier loci involved in local adaptation. PMID- 28890723 TI - Dynamics of Short-Term Phosphorus Uptake by Intact Mycorrhizal and Non mycorrhizal Maize Plants Grown in a Circulatory Semi-Hydroponic Cultivation System. AB - A non-destructive cultivation system was developed to study the dynamics of phosphorus (Pi) uptake by mycorrhizal and non-mycorrhizal maize plantlets. The system consisted of a plant container connected via silicon tubes to a glass bottle containing a nutrient solution supplemented with Pi. The nutrient solution is pumped with a peristaltic pump to the upper part of the container via the silicon tubes and the solution percolate through the plantlet container back into the glass bottle. Pi is sampled from the glass bottle at regular intervals and concentration evaluated. Maize plantlets were colonized by the AMF Rhizophagus irregularis MUCL 41833 and Pi uptake quantified at fixed intervals (9, 21, and 42 h) from the depletion of the Pi in the nutrient solution flowing through the plantlets containers. Plants and fungus grew well in the perlite substrate. The concentration of Pi in the bottles followed an almost linear decrease over time, demonstrating a depletion of Pi in the circulating solution and a concomitant uptake/immobilization by the plantlet-AMF associates in the containers. The Pi uptake rate was significantly increased in the AMF-colonized plantlets (at 9 and 21 h) as compared to non-colonized plantlets, although no correlation was noticed with plant growth or P accumulation in shoots. The circulatory semi-hydroponic cultivation system developed was adequate for measuring Pi depletion in a nutrient solution and by corollary Pi uptake/immobilization by the plant-AMF associates. The measurements were non-destructive so that the time course of Pi uptake could be monitored without disturbing the growth of the plant and its fungal associate. The system further opens the door to study the dynamics of other micro and macro-nutrients as well as their uptake under stressed growth conditions such as salinity, pollution by hydrocarbon contaminants or potential toxic elements. PMID- 28890722 TI - Predicted Functional Implications of Phosphorylation of Regulator of G Protein Signaling Protein in Plants. AB - Heterotrimeric G proteins function in development, biotic, and abiotic stress responses, hormone signaling as well as sugar sensing. We previously proposed that discrimination of these various external signals in the G protein pathway is accomplished in plants by membrane-localized receptor-like kinases (RLKs) rather than G-protein-coupled receptors. Arabidopsis thaliana Regulator of G Signaling protein 1 (AtRGS1) modulates G protein activation and is phosphorylated by several RLKs and by WITH-NO-LYSINE kinases (WNKs). Here, a combination of in vitro kinase assays, mass spectrometry, and computational bioinformatics identified and functionally prioritized phosphorylation sites in AtRGS1. Phosphosites for two more RLKs (BRL3 and PEPR1) were identified and added to the AtRGS1 phosphorylation profile. Bioinformatics analyses revealed that RLKs and WNK kinases phosphorylate plant RGS proteins within regions that are conserved across eukaryotes and at a high frequency. Four phospho-sites among 14 identified are proximal to equivalent mammalian phosphosites that impact RGS function, including: pS437 and pT267 in GmRGS2, and pS339 and pS436 in AtRGS1. Based on these analyses, we propose that pS437 and pS436 regulate GmRGS2 and AtRGS1 protein interactions and/or localization, whereas pT267 is important for modulation of GmRGS2 GAP activity and localization. Moreover, pS339 most likely affects AtRGS1 activation. PMID- 28890724 TI - Vacuolar Sequestration of Paraquat Is Involved in the Resistance Mechanism in Lolium perenne L. spp. multiflorum. AB - Lolium perenne L. spp. multiflorum (Lam.) Husnot (LOLMU) is a winter annual weed, common to row crops, orchards and roadsides. Glyphosate-resistant populations of LOLMU are widespread in California. In many situations, growers have switched to paraquat or other postemergence herbicides to manage glyphosate-resistant LOLMU populations. Recently, poor control of LOLMU with paraquat was reported in a prune orchard in California where paraquat has been used several times. We hypothesize that the low efficacy observed is due to the selection of a paraquat resistant biotype of LOLMU. Greenhouse dose-response experiments conducted with a susceptible (S) and the putative paraquat-resistant biotype (PRHC) confirmed paraquat resistance in PRHC. Herbicide absorption studies indicated that paraquat is absorbed faster in S than PRHC, although the maximum absorption estimates were similar for the two biotypes. Conversely, translocation of 14C-paraquat under light-manipulated conditions was restricted to the treated leaf of PRHC, whereas herbicide translocation out of the treated leaf was nearly 20 times greater in S. To determine whether paraquat was active within the plant cells, the photosynthetic performance was assessed after paraquat application using the parameter maximum quantum yield of photosystem II (Fv/Fm). Paraquat reaches the chloroplasts of PRHC, since there was a transitory inhibition of photosynthetic activity in PRHC leaves. However, PRHC Fv/Fm recovered to initial levels by 48 h after paraquat treatment. No paraquat metabolites were found, indicating that resistance is not due to paraquat degradation. LOLMU leaf segments were exposed to paraquat following pretreatments with inhibitors of plasma membrane- and tonoplast-localized transporter systems to selectively block paraquat intracellular movement. Subsequent evaluation of membrane integrity indicated that pre-exposure to putrescine resulted in the resistant biotype responding to paraquat similarly to S. These results strongly indicate that vacuolar sequestration is involved in the resistance to paraquat in this population of LOLMU. PMID- 28890725 TI - The Biphasic Root Growth Response to Abscisic Acid in Arabidopsis Involves Interaction with Ethylene and Auxin Signalling Pathways. AB - Exogenous abscisic acid (ABA) is known to either stimulate or inhibit root growth, depending on its concentration. In this study, the roles of ethylene and auxin in this biphasic effect of ABA on root elongation were investigated using chemical inhibitors and mutants. Inhibitors of ethylene perception and biosynthesis and an auxin influx inhibitor were all found to block the inhibitory effect of high ABA concentrations, but not the stimulatory effect of low ABA concentrations. In addition, three ethylene-insensitive mutants (etr1-1, ein2-1, and ein3-1), two auxin influx mutants (aux1-7, aux1-T) and an auxin-insensitive mutant (iaa7/axr2-1) were all insensitive to the inhibitory effect of high ABA concentrations. In the case of the stimulatory effect of low ABA concentrations, it was blocked by two different auxin efflux inhibitors and was less pronounced in an auxin efflux mutant (pin2/eir1-1) and in the iaa7/axr2-1 auxin-insensitive mutant. Thus it appears that the stimulatory effect seen at low ABA concentrations is via an ethylene-independent pathway requiring auxin signalling and auxin efflux through PIN2/EIR1, while the inhibitory effect at high ABA concentrations is via an ethylene-dependent pathway requiring auxin signalling and auxin influx through AUX1. PMID- 28890726 TI - Next-Generation Sequencing-Aided Rapid Molecular Diagnosis of Occult Macular Dystrophy in a Chinese Family. AB - Purpose: To show early, rapid and accurate molecular diagnosis of occult macular dystrophy (OMD) in a four-generation Chinese family with inherited macular dystrophy. Methods: In the current study, we comprehensively screened 130 genes involved in common inherited non-syndromic eye diseases with next-generation sequencing-based target capture sequencing of the proband of a four-generation Chinese family that has suffered from maculopathy without a definitive diagnosis for over 10 years. Variants were filtered and analyzed to identify possible disease-causing variants before validation by Sanger sequencing. Results: Two heterozygous mutations-RP1L1 c.133 C > T (p.Arg45Trp), which is a hot spot for OMD, and ABCA4 c.6119 G > A (p.Arg2040Gln), which was identified in Stargardt's disease were found in three patients, but neither of the mutations was found in the unaffected individuals in the same family, who are phenotypically normal or in the normal control volunteers. Conclusion: These results cannot only confirm the diagnosis of OMD in the proband, but also provide presymptomatic diagnosis of the proband's children before the onset of visual acuity impairment and guidance regarding the prognosis and management of these patients. Heterozygous mutations of RP1L1 c.133 C > T (p.Arg45Trp) and ABCA4 c.6119 G > A (p.Arg2040Gln) are likely responsible for OMD. Our results further extend our current understanding of the genetic basis of OMD, and emphasize the importance of molecular diagnosis and genetic counseling for OMD. PMID- 28890727 TI - Popliteal Artery Entrapment or Chronic Exertional Compartment Syndrome? AB - Diagnosis of lower limb pain in an athlete can be a challenging task due to the variety of potential etiologies and ambiguity of presenting symptoms. Five of the most commonly encountered causes of limb pain in athletes are chronic exertional compartment syndrome (CECS), medial tibial stress syndrome (MTSS), tibial stress fractures, soleal sling syndrome, and popliteal artery entrapment syndrome (PAES). Of these, the least frequent but potentially most serious of the pathologies is PAES. With an incidence of less than 1% seen in living subject studies, the condition is rare. However, a missed diagnosis will likely lead to progression of the disease and potential for unnecessary invasive procedures (McAree et al. 2008). In this paper, we present a young athlete misdiagnosed and treated for chronic exertional compartment syndrome. In both descriptive and a quick-reference table format, we review current literature and discuss how best to distinguish functional PAES from other causes of activity-related leg pain. PMID- 28890728 TI - Ambient Air Quality Classification by Grey Wolf Optimizer Based Support Vector Machine. AB - With the development of society along with an escalating population, the concerns regarding public health have cropped up. The quality of air becomes primary concern regarding constant increase in the number of vehicles and industrial development. With this concern, several indices have been proposed to indicate the pollutant concentrations. In this paper, we present a mathematical framework to formulate a Cumulative Index (CI) on the basis of an individual concentration of four major pollutants (SO2, NO2, PM2.5, and PM10). Further, a supervised learning algorithm based classifier is proposed. This classifier employs support vector machine (SVM) to classify air quality into two types, that is, good or harmful. The potential inputs for this classifier are the calculated values of CIs. The efficacy of the classifier is tested on the real data of three locations: Kolkata, Delhi, and Bhopal. It is observed that the classifier performs well to classify the quality of air. PMID- 28890730 TI - Quantifying the quantum. PMID- 28890729 TI - Clinical application of a cancer genomic profiling assay to guide precision medicine decisions. AB - AIM: Develop and apply a comprehensive and accurate next-generation sequencing based assay to help clinicians to match oncology patients to therapies. MATERIALS & METHODS: The performance of the CANCERPLEX(r) assay was assessed using DNA from well-characterized routine clinical formalin-fixed paraffin-embedded (FFPE) specimens and cell lines. RESULTS: The maximum sensitivity of the assay is 99.5% and its accuracy is virtually 100% for detecting somatic alterations with an allele fraction of as low as 10%. Clinically actionable variants were identified in 93% of patients (930 of 1000) who underwent testing. CONCLUSION: The test's capacity to determine all of the critical genetic changes, tumor mutation burden, microsatellite instability status and viral associations has important ramifications on clinical decision support strategies, including identification of patients who are likely to benefit from immune checkpoint blockage therapies. PMID- 28890731 TI - The organization of strong links in complex networks. AB - Many complex systems reveal a small-world topology, which allows simultaneously local and global efficiency in the interaction between system constituents. Here, we report the results of a comprehensive study that investigates the relation between the clustering properties in such small-world systems and the strength of interactions between its constituents, quantified by the link weight. For brain, gene, social and language networks, we find a local integrative weight organization in which strong links preferentially occur between nodes with overlapping neighbourhoods; we relate this to global robustness of the clustering to removal of the weakest links. Furthermore, we identify local learning rules that establish integrative networks and improve network traffic in response to past traffic failures. Our findings identify a general organization for complex systems that strikes a balance between efficient local and global communication in their strong interactions, while allowing for robust, exploratory development of weak interactions. PMID- 28890732 TI - Geographic distribution of blood collections in Haiti before and after the 2010 earthquake. AB - BACKGROUND: The January 2010 Haiti earthquake destroyed the National Blood Transfusion Center and reduced monthly national blood collections by > 46%. Efforts to rapidly scale-up blood collections outside of the earthquake-affected region were investigated. STUDY DESIGN AND METHODS: Blood collection data for 2004-2014 from Haiti's 10 administrative departments were grouped into four regions: Northern, Central, Port-au-Prince and Southern. Analyses compared regional collection totals during the study period. RESULTS: Collections in Port au-Prince accounted for 52% of Haiti's blood supply in 2009, but fell 96% in February 2010. Haiti subsequently increased blood collections in the North, Central and Southern regions to compensate. By May 2010, national blood collections were only 10.9% lower than in May 2009, with 70% of collections coming from outside of Port-au-Prince. By 2013 national collections (27 478 units) had surpassed 2009 levels by 30%, and Port-au-Prince collections had recovered (from 11 074 units in 2009 to 11 670 units in 2013). CONCLUSION: Haiti's National Blood Safety Program managed a rapid expansion of collections outside of Port-au-Prince following the earthquake. Annual collections exceeded pre-earthquake levels by 2012 and continued rising annually. Increased regional collections provided a greater share of the national blood supply, reducing dependence on Port-au-Prince for collections. PMID- 28890733 TI - Child Poverty in the United States: A Tale of Devastation and the Promise of Hope. AB - The child poverty rate in the United States is higher than in most similarly developed countries, making child poverty one of America's most pressing social problems. This article provides an introduction of child poverty in the US, beginning with a short description of how poverty is measured and how child poverty is patterned across social groups and geographic space. I then examine the consequences of child poverty with a focus educational outcomes and child health, and three pathways through which poverty exerts its influence: resources, culture, and stress. After a brief review of the anti-poverty policy and programmatic landscape, I argue that moving forward we must enrich the communities in which poor families live in addition to boosting incomes and directly supporting children's skill development. I conclude with emerging research questions. PMID- 28890734 TI - A spatially resolved estimate of High Mountain Asia glacier mass balances, 2000 2016. AB - High Mountain Asia hosts the largest glacier concentration outside the polar regions. These glaciers are important contributors to streamflow in one of the most populated areas of the world. Past studies have used methods that can only provide regionally-averaged glacier mass balances to assess the High Mountain Asia glacier contribution to rivers and sea level rise. Here we compute the mass balance for about 92 % of the glacierized area of High Mountain Asia using time series of digital elevation models derived from satellite stereo-imagery. We calculate an average region-wide mass balance of -16.3 +/- 3.5 Gt yr-1 (-0.18 +/- 0.04 m w.e. yr-1) between 2000 and 2016, which is less negative than most previous estimates. Region-wide mass balances vary from -4.0 +/- 1.5 Gt yr-1 ( 0.62 +/- 0.23 m w.e. yr-1) in Nyainqentanglha to +1.4 +/- 0.8 Gt yr-1 (+0.14 +/- 0.08 m w.e. yr-1) in Kunlun, with large intra-regional variability of individual glacier mass balances (standard deviation within a region ~0.20 m w.e. yr-1). Specifically, our results shed light on the Nyainqentanglha and Pamir glacier mass changes, for which contradictory estimates exist in the literature. They provide crucial information for the calibration of the models used for projections of future glacier response to climatic changes, models that presently do not capture the pattern, magnitude and intra-regional variability of glacier changes in High Mountain Asia. PMID- 28890735 TI - Fluid-driven metamorphism of the continental crust governed by nanoscale fluid flow. AB - The transport of fluids through the Earth's crust controls the redistribution of elements to form mineral and hydrocarbon deposits, the release and sequestration of greenhouse gases, and facilitates metamorphic reactions that influence lithospheric rheology. In permeable systems with a well-connected porosity, fluid transport is largely driven by fluid pressure gradients. In less permeable rocks, deformation may induce permeability by creating interconnected heterogeneities, but without these perturbations, mass transport is limited along grain boundaries or relies on transformation processes that self-generate transient fluid pathways. The latter can facilitate large-scale fluid and mass transport in nominally impermeable rocks without large-scale fluid transport pathways. Here, we show that pervasive, fluid-driven metamorphism of crustal igneous rocks is directly coupled to the production of nanoscale porosity. Using multi-dimensional nano-imaging and molecular dynamics simulations, we demonstrate that in feldspar, the most abundant mineral family in the Earth's crust, electrokinetic transport through reaction-induced nanopores (10-100 nm) can potentially be significant. This suggests that metamorphic fluid flow and fluid-mediated mineral transformation reactions can be considerably influenced by nanofluidic transport phenomena. PMID- 28890736 TI - The psychoactive drug 25B-NBOMe recapitulates rhabdomyolysis in zebrafish larvae. AB - N-Benzyl-substituted 2C class phenethylamines (NBOMes) are psychoactive designer drugs, with strong hallucinogenic and stimulant effects, even at low doses. The designer drug, 2-(4-bromo-2, 5-dimethoxyphenyl)-N-(2-methoxybenzyl) ethanamine (25B-NBOMe) is considered to be one of the most potent agonists of the serotonin 2A (5-HT2A) receptor. Recently, we reported the first lethal case of 25B-NBOMe intoxication with severe rhabdomyolysis, concluded by clinical, pathological and toxicological analyses. There are currently no good animal models that closely recapitulate serotonin receptor-dependent rhabdomyolysis. In the present study, we created animal models of rhabdomyolysis using zebrafish larvae to study the pathomechanism of rhabdomyolysis, and demonstrated that 25B-NBOMe can simulate lethal rhabdomyolysis in this animal. Treatment of the larvae with 25B-NBOMe decreased their survival rate, locomotion, altered birefringence of the skeletal muscle and immunostainings for dystroglycan (a myoseptal protein) and myosin heavy chain (a myofibril protein), which were consistent with rhabdomyolysis. This 25B-NBOMe-induced rhabdomyolysis was inhibited by the 5-HT2A receptor antagonists ritanserin and aripirazole, but not by the 5-HT1A + 5-HT1B receptor antagonist propranolol and the 5-HT3 receptor antagonist granisetron, indicating 5-HT2A-dependent rhabdomyolysis. The 25B-NBOMe-treated zebrafish is, therefore, a highly useful model of rhabdomyolysis for studying the pathomechanism of rhabdomyolysis as well as for therapeutic drug screening. PMID- 28890737 TI - From 'Hard' Neuro-Tools to 'Soft' Neuro-Toys? Refocussing the Neuro-Enhancement Debate. AB - Since the 1990's, the debate concerning the ethical, legal and societal aspects of 'neuro-enhancement' has evolved into a massive discourse, both in the public realm and in the academic arena. This ethical debate, however, tends to repeat the same sets of arguments over and over again. Normative disagreements between transhumanists and bioconservatives on invasive or radical brain stimulators, and uncertainties regarding the use and effectivity of nootropic pharmaceuticals dominate the field. Building on the results of an extensive European project on responsible research and innovation in neuro-enhancement (NERRI), we observe and encourage that the debate is now entering a new and, as we will argue, more realistic and societally relevant stage. This new stage concerns those technologies that enter the market as ostensibly harmless contrivances that consumers may use for self-care or entertainment. We use the examples and arguments of participants in NERRI debates to describe three case studies of such purportedly innocent 'toys'. Based upon this empirical material, we argue that these 'soft' enhancement gadgets are situated somewhere in the boundary zone between the internal and the external, between the intimate and the intrusive, between the familiar and the unfamiliar, between the friendly and the scary and, in Foucauldian terms, between technologies of the self and technologies of control. Therefore, we describe their physiognomy with the help of a term borrowed from Jacques Lacan, namely as "extimate" technologies. PMID- 28890738 TI - Moral Enhancement Should Target Self-Interest and Cognitive Capacity. AB - Current suggestions for capacities that should be targeted for moral enhancement has centered on traits like empathy, fairness or aggression. The literature, however, lacks a proper model for understanding the interplay and complexity of moral capacities, which limits the practicability of proposed interventions. In this paper, I integrate some existing knowledge on the nature of human moral behavior and present a formal model of prosocial motivation. The model provides two important results regarding the most friction-free route to moral enhancement. First, we should consider decreasing self-interested motivation rather than increasing prosociality directly. Second, this should be complemented with cognitive enhancement. These suggestions are tested against existing and emerging evidence on cognitive capacity, mindfulness meditation and the effects of psychedelic drugs and are found to have sufficient grounding for further theoretical and empirical exploration. Furthermore, moral effects of the latter two are hypothesized to result from a diminished sense of self with subsequent reductions in self-interest. PMID- 28890739 TI - Towards a Moral Ecology of Pharmacological Cognitive Enhancement in British Universities. AB - Few empirical studies in the UK have examined the complex social patterns and values behind quantitative estimates of the prevalence of pharmacological cognitive enhancement (PCE). We conducted a qualitative investigation of the social dynamics and moral attitudes that shape PCE practices among university students in two major metropolitan areas in the UK. Our thematic analysis of eight focus groups (n = 66) suggests a moral ecology that operates within the social infrastructure of the university. We find that PCE resilience among UK university students is mediated by normative and cultural judgments disfavoring competitiveness and prescription drug taking. PCE risk can be augmented by social factors such as soft peer pressure and normalization of enhancement within social and institutional networks. We suggest that moral ecological dynamics should be viewed as key mechanisms of PCE risk and resilience in universities. Effective PCE governance within universities should therefore attend to developing further understanding of the moral ecologies of PCE. PMID- 28890740 TI - Public Attitudes Towards Moral Enhancement. Evidence that Means Matter Morally. AB - To gain insight into the reasons that the public may have for endorsing or eschewing pharmacological moral enhancement for themselves or for others, we used empirical tools to explore public attitudes towards these issues. Participants (N = 293) from the United States were recruited via Amazon's Mechanical Turk and were randomly assigned to read one of several contrastive vignettes in which a 13 year-old child is described as bullying another student in school and then is offered an empathy-enhancing program. The empathy-enhancing program is described as either involving taking a pill or playing a video game on a daily basis for four weeks. In addition, participants were asked to imagine either their own child bullying another student at school, or their own child being bullied by another student. This resulted in a 2 * 2 between-subjects design. In an escalating series of morally challenging questions, we asked participants to rate their overall support for the program; whether they would support requiring participation; whether they would support requiring participation of children who are at higher risk to become bullies in the future; whether they would support requiring participation of all children or even the entire population; and whether they would be willing to participate in the program themselves. We found that people were significantly more troubled by pharmacological as opposed to non pharmacological moral enhancement interventions. The results indicate that members of the public for the greater part oppose pharmacological moral bioenhancement, yet are open to non-biomedical means to attain moral enhancement. [248 words]. PMID- 28890741 TI - Coexisting Disadvantages in later Life: Demographic and Socio-Economic Inequalities. AB - In this study, we aimed to identify which of certain demographic and socio economic groups in the oldest part of the population that have an increased probability of experiencing simultaneous disadvantages in different life domains here termed coexisting disadvantages. To do so, we compared analyses of coexisting disadvantages, measured as two or more simultaneous disadvantages, with analyses of single disadvantages and specific combinations of disadvantages. Indicators of physical health problems, ADL limitations, psychological health problems, limited financial resources, and limited social resources were included. We used nationally representative data from 2011 on people aged 76 and older in Sweden (n = 765). Results showed that coexisting disadvantages were associated with specific demographic and socio-economic groups, particularly certain marital status groups. Moreover, the differences between the demographic and socio-economic groups were only found for those who reported coexisting disadvantages, and not for those who reported only one disadvantage, which suggests that demographic and social factors become more important as disadvantages compound. Further, we analysed pairwise combinations of disadvantages. We found that different combinations of disadvantages tended to be associated with different groups, information useful from a social planning perspective since different combinations of disadvantages may imply different needs for help and support. PMID- 28890742 TI - Who in Europe Works beyond the State Pension Age and under which Conditions? Results from SHARE. AB - There is much research about those who exit the labour market prematurely, however, comparatively little is known about people working longer and about their employment and working conditions. In this paper, we describe the employment and working conditions of men and women working between 65 and 80 years, and compare them with previous conditions of those retired in the same age group. Analyses are based on wave 4 data from the Survey of Health, Ageing and Retirement in Europe (SHARE) with information collected between 2009 and 2011 from 17,625 older men and women across 16 European countries. Besides socio demographic and health-related factors (physical and mental health), the focus lies on employment conditions (e.g. employment status, occupational position and working hours) and on stressful working conditions, measured in terms of low control at work and effort-reward imbalance. In case of retired people, information on working conditions refer to the last job before retirement. Following descriptive analyses, we then conduct multivariable analyses and investigate how working conditions and poor health are related to labour market participation (i.e. random intercept models accounting for country affiliation and adjusted for potential confounders). Results illustrate that people working between the ages of 65 and 80 are more likely to be self-employed (either with or without employees) and work in advantaged occupational positions. Furthermore, findings reveal that psychosocial working conditions are generally better than the conditions retired respondents had in their last job. Finally, in contrast to those who work, health tends to be worse among retired people. In conclusion, findings deliver empirical evidence that paid employment beyond age 65 is more common among self-employed workers throughout Europe, in advantaged occupations and under-favourable psychosocial circumstances, and that this group of workers are in considerably good mental and physical health. This highlights that policies aimed at increasing the state pension age beyond the age of 65 years put pressure on specific disadvantaged groups of men and women. PMID- 28890743 TI - Are the Chinese Saving for Old Age?: The Relationship between Future Pension Benefits of 45-60 Years Old Chinese and Current Household Expenditures. AB - Worldwide, older people's support used to be the adult children's responsibility. In China, two generations after introducing the one-child policy in the late 70 ies, this becomes an increasingly demanding obligation. The Chinese government took the responsibility to mitigating old- age poverty risks and realized unprecedented progress in pension coverage. At the same time, the household savings increased to about 30 % of disposable income. Built on previous research on the politics of ageing, this study analyses households responses to the established governmental and firm pension programs as well as to the New Rural Pension Scheme (NRPS), introduced in 2009. The central question is: will participation in the established and new pension programs lead to higher current Chinese household expenditures and therefore to lower savings? The China Health and Retirement Longitudinal Study (CHARLS) dataset of 2011 offered the opportunity to study the influence of the recently introduced NRPS. We find that Chinese households with members between 45 and 60 years who expect future benefits of NRPS do not have higher expenditures than those not covered by NRPS. For the participants in the established, mostly urban pension programs a correlation was found with higher current expenditures (28 % more spending on basic needs, 80 % more on luxury) However, further analysis shows that this correlation cannot be interpreted as a causal relationship. This implies that coverage by pensions, be it in urban or rural programs, does not determine higher current expenditures and lower savings. PMID- 28890744 TI - Static and Time-Resolved Terahertz Measurements of Photoconductivity in Solution Deposited Ruthenium Dioxide Nanofilms. AB - Thin-film ruthenium dioxide (RuO2) is a promising alternative material as a conductive electrode in electronic applications because its rutile crystalline form is metallic and highly conductive. Herein, a solution-deposition multi-layer technique is employed to fabricate ca. 70 +/- 20 nm thick films (nanoskins) and terahertz spectroscopy is used to determine their photoconductive properties. Upon calcining at temperatures ranging from 373 K to 773 K, nanoskins undergo a transformation from insulating (localized charge transport) behavior to metallic behavior. Terahertz time-domain spectroscopy (THz-TDS) indicates that nanoskins attain maximum static conductivity when calcined at 673 K (sigma = 1030 +/- 330 S.cm-1). Picosecond time-resolved Terahertz spectroscopy (TRTS) using 400 nm and 800 nm excitation reveals a transition to metallic behavior when calcined at 523 K. For calcine temperatures less than 523 K, the conductivity increases following photoexcitation (DeltaE < 0) while higher calcine temperatures yield films composed of crystalline, rutile RuO2 and the conductivity decreases (DeltaE > 0) following photoexcitation. PMID- 28890745 TI - A Simple and Practical Method for Setting Up a Criterion of Projection of Silicone Breast Implant After Simple Mastectomy. AB - Objective: In breast reconstruction, decision of projection of silicone breast implant in tissue expander replacement is difficult because of the need to consider several parameters that cannot be expressed in accurate numerical form. The present study aimed at a quantitative analysis based on decreased projection of the reconstructed side compared with silicone breast implant projection and to develop a new method for simple and practical decision of silicone breast implant projection. Methods: Thirty-five patients who had mammary carcinoma and were treated with simple mastectomy, tissue expander insertion, and replacement with anatomical silicone breast implant from April 2013 to March 2016 were retrospectively identified. We recorded the projection of used silicone breast implant (Pi). The projections of reconstructed breast 6 months after silicone breast implant insertion (Pr) and that of the unaffected breast during silicone breast implant selection (Pu) were measured. The difference between Pi and Pr was defined as the revised numerical value (Rev). We investigated whether Rev significantly differed according to age, body mass index, or Pu and analyzed correlations between Rev and age, Pu, and body mass index. Results: Mean Rev in all patients was 1.2 +/- 0.3 cm. Rev was significantly higher in patients with higher body mass index than in those with lower body mass index (P < .01) and in patients with higher Pu than in those with lower Pu (P < .01). Significant positive correlations of Rev with body mass index and Pu were found (beta = .63, P < .01 and beta = .67, P < .01, respectively). Conclusions: Rev was a simple, practical, and cost-effective concept. We believe that it is a useful indicator for deciding silicone breast implant projection. PMID- 28890746 TI - A New Criterion for the Application of 2-Stage Implant-Only Breast Reconstruction Using a Classification Based on the Rostrocaudal Distance Along the Chest Wall Between the Lowest Point of the Breast and Inframammary Fold. AB - Objective: It is generally difficult to achieve symmetry in implant-only breast reconstruction with ptosis, and it remains unclear what quantitative criterion may be applied in cases of breast ptosis regarding the application of this modality. Our study aimed to suggest a criterion for obtaining good aesthetic outcomes and a symmetrical inframammary fold that is well-fitting for the brassiere in implant-only breast reconstruction after simple mastectomy. Methods: We classified into 3 groups 50 consecutive patients who underwent implant-only breast reconstruction that created an inframammary fold using a modified internal method after simple mastectomy. The classification was based on the rostrocaudal distance along the chest wall between the lowest point of the breast the and the inframammary fold on the contralateral side (Dc, in millimeters). Thereafter, we compared this distance on the reconstructed side (Dr, in millimeters), Dc-Dr, and projection of the implant (Pi, in centimeters) between the groups and investigated the correlation between Dr and lower (Pi < 5.0 cm) and higher Pi (Pi >= 5.0 cm). Results: Dr was similar to Dc in groups 1 and 2 (0 <= Dc < 10 mm, 40/50 [80%]); however, Dr was significantly lesser than Dc in group 3 (Dc >= 10 mm, 10/50 [20%]). In addition, we found significant positive correlations between Dr and lower Pi and between Dr and higher Pi. Conclusions: A Dc below 10 mm may be a good indication for implant-only breast reconstruction. Furthermore, the modality may be applied where Dc is 7 mm or less in cases with lower Pi and where Dc is 13 mm or less in cases with higher Pi. PMID- 28890747 TI - Sclerotherapy for the Management of Seromas: A Systematic Review. AB - Objective: Despite improved recognition of risk factors, plastic surgeons commonly encounter seromas postoperatively and must decide upon management. Current recommendations for minimally invasive, chemical management originate from the literature on management of pneumothorax and pleural effusions. A handful of published reports have suggested the efficacy of sclerotherapy in seroma management. The aim of this study was to assess the literature on the use of sclerosants to treat subcutaneous fluid collections. Methods: A systematic review of the literature was performed on the PubMed, MEDLINE, and Cochrane databases for primary research articles on sclerotherapy for seroma treatment between January 1975 and January 2017. Exclusion criteria were surgical treatment, sclerotherapy for seroma prevention, hematoma, or absence of detailed documentation. Data related to seroma location, sclerosant, and resolutions were extracted. Results: The literature search yielded 7 relevant articles of level IV evidence and 12 case reports, with a total of 84 patients treated with sclerotherapy for persistent seromas. Slerosant included talc, tetracycline antibiotics, ethanol, polidocanol, erythromycin, OK-432, fibrin glue, and povidone-iodine. All agents achieved high rates of success. Repeat aspirations and instillations were easily performed when required. Complications, while uncommon, included pain, tightness or discomfort of the treated area, and infection. Conclusion: Sclerotherapy appears to be effective and safe for recurrent seromas. While a variety of sclerosing agents may be applied successfully, talc and tetracyclines remain popular choices. Because of the small scale and retrospective nature of the published literature, larger, randomized, comparative studies are necessary to assess and optimize this treatment approach. PMID- 28890748 TI - Palatal Lengthening With Double-Opposing Buccal Flaps for Velopharyngeal Insufficiency. PMID- 28890749 TI - Salvage Operation Using the Free Latissimus Dorsi Muscle Flap for Necrosis of the Free Scapular Flap After Harvesting Both Flaps in a Chimeric Pattern. PMID- 28890750 TI - Advances in the control of vaccine preventable diseases in Ethiopia. PMID- 28890751 TI - Analysis of acute flaccid paralysis surveillance in Ethiopia, 2005-2015: progress and challenges. AB - INTRODUCTION: Ethiopia joined the global effort to eradicate polio in 1996, and interrupted indigenous wild poliovirus transmission by December 2001. However, the country experienced numerous separate importations during 2003-2013. Sensitive Acute Flaccid (AFP) surveillance is critical to rule out undetected circulation of WPV and VDPVs. METHODS: In this study described, we used a retrospective descriptive study design to characterize the surveillance performance from 2005 to 2015. RESULTS: The none-polio AFP rate improved from 2.6/100,000 children <15 years old in 2005 to 3.1 in 2015, while stool adequacy has also improved from 78.5% in 2005 to 92 % in 2015. At the national level, most AFP surveillance performance indicators are achieved and maintained over the years, however, AFP surveillance performance at sub-national level varies greatly particularly in pastoralist regions. In addition, the minimum standard for non polio enterovirus isolation rate (10%) was not achieved except in 2007 and 2009. Nevertheless, the proportion of cases investigated within 2 days of notification and the proportion of specimens arriving in good condition within 3 days to the laboratory were maintained throughout all the years reviewed. CONCLUSION: We found that the AFP surveillance system was efficient and progressively improved over the past 10 years in Ethiopia. However, the subnational AFP surveillance performance varies and were not maintained, particularly in pastoralist regions, and the non-polio enterovirus isolation rate declined since 2010. We recommend the institution of community-based surveillance in pastoralist regions and conduct detail review of the laboratory sensitivity and the reverse cold chain system. PMID- 28890752 TI - Measles burden in urban settings: characteristics of measles cases in Addis Ababa city administration, Ethiopia, 2004-2014. AB - INTRODUCTION: In developing countries, measles was a major cause of morbidity and mortality before the wide spread use of measles vaccine. The purpose of this study was to describe measles burden in an urban setting, Addis Ababa- since the implementation of measles case-based surveillance in Ethiopia. We analyzed measles surveillance data for 2004 -2014. METHODS: Incidence of measles was described by sub city, by year and by age groups. Age specific incidence rate were calculated. Logistic regression was used to identify the predictors of confirmed measles cases. RESULTS: Of 4220 suspected measles cases 39% were confirmed cases. Males and females were equally affected. The mean affected age was 7.59 years. Measles cases peaked in 2010 and 2013-2014. Incidence of measles is higher among children less than five years old. Outer sub cities were more affected by measles in all years. CONCLUSION: Sub cities bordering with Oromia Regional State were more affected by measles. Older age groups were more affected than younger age groups (age <= five years old). Efforts to close immunity gaps against measles and further strengthen surveillance in urban settings, particularly among children below five years old, should be prioritized. PMID- 28890753 TI - Introducing an accountability framework for polio eradication in Ethiopia: results from the first year of implementation 2014-2015. AB - INTRODUCTION: the World Health Organization (WHO), Ethiopia country office, introduced an accountability framework into its Polio Eradication Program in 2014 with the aim of improving the program's performance. Our study aims to evaluate staff performance and key program indicators following the introduction of the accountability framework. METHODS: the impact of the WHO accountability framework was reviewed after its first year of implementation from June 2014 to June 2015. We analyzed selected program and staff performance indicators associated with acute flaccid paralysis (AFP) surveillance from a database available at WHO. Data on managerial actions taken were also reviewed. Performance of a total of 38 staff was evaluated during our review. RESULTS: our review of results for the first four quarters of implementation of the polio eradication accountability framework showed improvement both at the program and individual level when compared with the previous year. Managerial actions taken during the study period based on the results from the monitoring tool included eleven written acknowledgments, six discussions regarding performance improvement, six rotations of staff, four written first-warning letters and nine non-renewal of contracts. CONCLUSION: the introduction of the accountability framework resulted in improvement in staff performance and overall program indicators for AFP surveillance. PMID- 28890754 TI - CT AND MRI FUSION FOR POSTIMPLANT PROSTATE BRACHYTHERAPY EVALUATION. AB - Postoperative evaluation of prostate brachytherapy is typically performed using CT, which does not have sufficient soft tissue contrast for accurate anatomy delineation. MR-CT fusion enables more accurate localization of both anatomy and implanted radioactive seeds, and hence, improves the accuracy of postoperative dosimetry. We propose a method for automatic registration of MR and CT images without a need for manual initialization. Our registration method employs a point to-volume registration scheme during which localized seeds in the CT images, produced by commercial treatment planning systems as part of the standard of care, are rigidly registered to preprocessed MRI images. We tested our algorithm on ten patient data sets and achieved an overall registration error of 1.6 +/- 0.8 mm with a running time of less than 20s. With high registration accuracy and computational speed, and no need for manual intervention, our method has the potential to be employed in clinical applications. PMID- 28890755 TI - ARCHITECTURAL PATTERNS FOR DIFFERENTIAL DIAGNOSIS OF PROLIFERATIVE BREAST LESIONS FROM HISTOPATHOLOGICAL IMAGES. AB - The differential diagnosis of proliferative breast lesions, benign usual ductal hyperplasia (UDH) versus malignant ductal carcinoma in situ (DCIS) is challenging. This involves a pathologist examining histopathologic sections of a biopsy using a light microscope, evaluating tissue structures for their architecture or size, and assessing individual cell nuclei for their morphology. Imposing diagnostic boundaries on features that otherwise exist on a continuum going from benign to atypia to malignant is a challenge. Current computational pathology methods have focused primarily on nuclear atypia in drawing these boundaries. In this paper, we improve on these approaches by encoding for both cellular morphology and spatial architectural patterns. Using a publicly available breast lesion database consisting of UDH and three different grades of DCIS, we improve the classification accuracy by 10% over the state-of-the-art method for discriminating UDH and DCIS. For the four way classification of UDH and the three grades of DCIS, our method improves the results by 6% in accuracy, 8% in micro-AUC, and 19% in macro-AUC. PMID- 28890756 TI - Single-Arm Phase II Group Sequential Trial Design with Survival Endpoint at a Fixed Time Point. AB - In this paper, three non-parametric test statistics are proposed to design single arm phase II group sequential trials for monitoring survival probability. The small-sample properties of these test statistics are studied through simulations. Sample size formulas are derived for the fixed sample test. The Brownian motion property of the test statistics allowed us to develop a flexible group sequential design using a sequential conditional probability ratio test procedure (Xiong, 1995). An example is given to illustrate the trial design by using the proposed method. PMID- 28890757 TI - Populations of Rice Grain Bug, Paraeuscosmetus pallicomis, (Hemiptera: Lygaeidae) in Weed-free Paddy Field, Weedy Paddy Field and Paddy Dykes. AB - Research on the populations of rice grain bug Paraeuscosmetus pallicomis Dallas (Hemiptera: Lygaeidae) in paddy field ecosystems was performed with the aim to determine the populations of rice grain bug in weed-free paddy field, weedy paddy field, and paddy dykes. Experiment was carried out in the village of Paccellekang in the district of Patallasang of Gowa Regency in South Sulawesi, Indonesia. Observations were performed during the milky grain stage (85 days after planting), the mature grain stage (105 days after planting), and one day after harvest (115 days after transplanting). Results showed that 85 days after the transplanting, the populations of rice grain bug was significantly higher in the weedy paddy field compared to weed-free field and paddy dykes with total numbers of 1.75, 3.53, and 0.31 insects per 2 hills, respectively. Similarly, 105 days after the transplanting, 2.53, 5.53, and 0.11 insects per hill, respectively. However, one day after the harvest (115 days after transplanting) the number of insects in weed-free field decreased, while in the dykes increased, and the weedy plot still had the highest number of insects per 2 hills. Our results suggested that weeds played an important role in regulating the bug population by providing alternative shelter and foods for the insect. PMID- 28890758 TI - Determination of Trophic Structure in Selected Freshwater Ecosystems by using Stable Isotope Analysis. AB - Stable isotope analysis has been used extensively to establish trophic relationships in many ecosystems. Present study utilised stable isotope signatures of carbon and nitrogen to identify trophic structure of aquatic food web in river and rice field ecosystems in Perak, northern peninsular Malaysia. The mean delta13C values of all producers ranged from -35.29 +/- 0.21 to -26.00 +/- 0.0500/00. The greatest delta15N values noted was in zenarchopterid fish with 9.68 +/- 0.0200/00. The delta15N values of aquatic insects ranged between 2.59 +/ 0.107 in Elmidae (Coleoptera) and 8.11 +/- 0.0220/00 in Nepidae (Hemiptera). Correspondingly, with all the delta13C and delta15N values recorded, it can be deduced that there are four trophic levels existed in the freshwater ecosystems which started with the producer (plants), followed by primary consumer (aquatic insects and non-predatory fish), secondary consumer (invertebrate predators) and lastly tertiary consumer (vertebrate predators). PMID- 28890759 TI - General Perceptions and Awareness Level among Local Residents in Penang Island toward Bats Conservation Efforts. AB - The population of bats has declined from year to year caused by human activities such as logging and hunting activities. Since the human factor is linked to the issues of population decline in many animal species, a community-based conservation strategy that involved local communities is needed. We conducted face-to-face surveys among residents in Penang Island to assess knowledge and awareness level toward bats conservation efforts. We collected demographic values such as age, gender, level of education, length of residency as well as their monthly income, since different group in these variable might have different perception. We found that age groups, level of education and monthly income have shown significant differences among the respondents. However, no other significant differences were indicated for by gender and length of residency. Respondent's knowledge of bats showed that the majority of the respondents were less likely to value the importance of bats in the ecosystem. We recommended stronger legal system, earlier exposure towards environmental education, well planned urbanisation implementation and long-term monitoring programs to strengthen efforts in conserving bats in Malaysia. PMID- 28890760 TI - Insecticide Residues on Poultry Manures: Field Efficacy Test on Selected Insecticides in Managing Musca Domestica Population. AB - In this study, bifenthrin (Maxxthor SC, Ensystex Australasia Pty Ltd), imidacloprid (Prothor SC, Ensystex Australasia Pty Ltd) and fipronil (Regent(r)50SC, Bayer) were applied on the natural infest manures according to the manufacturer rate during a broiler breeding cycle. Solvent direct-immersion extraction (SDIE) was used in detecting the target compound and later, quantification of the insecticide residues in field condition was investigated. The samples were prior cleaned up by solid-phase extraction (SPE) and analysed by Ultra-Performance Liquid Chromatography (UPLC) - photodiode array (PDA) system. In the field trial, three insecticides were showed accumulation during the broiler breeding period and it is suggested that they acted as adulticides when applied on the poultry manures, this is supported by the significant correlation between the increment of insecticide residues to the reduction percentage of adult flies (<0.05). Fipronil showed significantly greater reduction on the adult fly compared to the other insecticides, in which the reduction rate compared to control population at the end of the broiler breeding period; fipronil, imidaclopril and bifenthrin reduced 51.51%, 28.30% and 30.84% of adult flies, respectively. PMID- 28890761 TI - Hypothetical Protein BPSL3393 of Burkholderia pseudomallei is Involved in Ethanolamine Catabolism. AB - Burkholderia pseudomallei is a soil-dwelling bacterium that causes a globally emerging disease called melioidosis. Approximately one third of the in silico annotated genes in its genome are classified as hypothetical genes. This group of genes is difficult to be functionally characterised partly due to the absence of noticeable phenotypes under conventional laboratory settings. A bioinformatic survey of hypothetical genes revealed a gene designated as BPSL3393 that putatively encodes a small protein of 11 kDA with a CoA binding domain. BPSL3393 is conserved in all the B. pseudomallei genomes as well as various in other species within the genus Burkholderia. Taking into consideration that CoA plays a ubiquitous metabolic role in all life forms, characterisation of BPSL3393 may uncover a previously over-looked metabolic feature of B. pseudomallei. The gene was deleted from the genome using a double homologous recombination approach yielding a null mutant. The BPSL3393 mutant showed no difference in growth rate with the wild type under rich and minimal growth conditions. An extensive metabolic phenotyping test was performed involving 95 metabolic substrates. The deletion mutant of BPSL3393 was severely impaired in its ethanolamine metabolism. The growth rate of the mutant was attenuated when ethanolamine was used as the sole carbon source. A transcriptional analysis of the ethanolamine metabolism genes showed that they were down-regulated in the BPSL3393 mutant. This seemed to suggest that BPSL3393 functions as a positive regulator for ethanolamine metabolism. PMID- 28890762 TI - Nutrient Contents of the Freshwater Crab, Isolapotamon bauense from Sarawak, Malaysia (Borneo). AB - Data on nutrient contents of freshwater crabs are important for ecological studies and species conservation assessments, especially when the species concerned is threatened among others by habitat destruction and uncontrolled resources utilisation. Indeed comprehensive biological information is required to reconcile the needs between sustainable resources utilisation and conservation of the species. This study documents the nutrient contents of a freshwater crab, Isolapotamon bauense which is listed as 'Vulnerable' in the IUCN Red List of Threatened Species and also being harvested by local community for dietary supplement. Results show that muscles of the freshwater crab contain a substantial amount of nutrients in particular water content (male = 79.31 +/- 2.30 %, female = 77.63 +/- 0.56 %), protein (male = 77.47 +/- 6.11 %, female = 63.28 +/- 3.62 %), magnesium (male = 51.48 +/- 16.10 mg/g, female = 39.73 +/- 6.99 mg/g) and calcium (male = 25.50 +/- 6.98 mg/g, female = 39.73 +/- 6.99 mg/g). Means of nutrient contents between male and female crabs are not significantly different. It is estimated that an individual of I. bauense with weight range of 56-139 g contained on average of 0.35 +/- 0.15 g of protein. Our estimation also shows that the number of individuals of the freshwater crab required to meet the recommended daily protein intakes of the community concerned is in the range 35-96 individuals for children, 130-188 individuals for adolescents, 171-179 individuals for men and 149-159 individuals for women. The results imply that harvesting of wild I. bauense as a source of protein supplement naturally may not be practical because of its relatively low population abundance, and conservation of the species for its ecological roles may thus be preferred. PMID- 28890763 TI - Ephemeroptera, Plecoptera and Trichoptera (Insecta) Abundance, Diversity and Role in Leaf Litter Breakdown in Tropical Headwater River. AB - Leaf litter decomposition in a tropical stream was examined in two types of leaf packs; single species leaf packs of Pometia pinnata and two species leaf packs of equal combination of Pometia pinnata and Dolichandrone spathacea leaves. Both leaf packs were immersed in a river and weekly examined for remains of decomposed leaves and presence of EPT. In the control leaf packs, leaves in the two species leaf packs treatments decomposed within 35 days, faster than in single species leaf packs which decomposed after 42 days. In the presence of EPT, the leaf breakdown took 28 days in two species and 35 days for single species leaf packs. Higher abundance of EPT was observed in single species leaf packs but its diversity was higher in two species leaf packs. Litter breakdown in the stream was faster in the presence of EPT and softer leaves of D. spathacea with higher nitrogen content underwent faster decomposition and sustained higher numbers of EPT. PMID- 28890764 TI - Lactococcus Lactis Strain A5 Producing Nisin-like Bacteriocin Active against Gram Positive and Negative Bacteria. AB - In this study, a Lactic acid bacteria (LAB) strain was isolated on MRS medium from gastro-intestinal tissues of Broadhead catfish (Clarias macrocephalus). Out of 50 isolates, 25 isolates were found to be positive on lactose utilisation test and were identified to be gram positive cocci. Using disc diffusion methods, one out of 22 isolates, i.e., a strain A5 demonstrated inhibitions against three indicator organisms; Bacillus cereus, Staphylococcus aureus and Salmonella thyphimurium. Partial 16S rDNA sequencing identified isolate A5 as a member of Lactococcus lactis, with 100% DNA homology. Cell free supernatant fluid from Lactococcus lactis A5 showed inhibitory activities against both gram positive pathogens (Bacillus cereus and Staphylococcus aureus) and gram negative pathogens (Salmonella thyphimurium). Chloroform precipitated bacteriocin retained antagonistic activities in the presence of catalase and lysozyme; and was completely inactivated by Proteinase K treatment. The bacteriocin has a molecular weight of 3.4 kDa, based on SDS-PAGE analysis and the extract was heat stable at 37 degrees C and 65 degrees C, for 15 minutes. The antibacterial activity was suppressed with the addition of EDTA but was significantly increased with the addition of SDS, Triton X-100, Tween 20 and Tween 80. This bacteriocin belongs to class 1 bacteriocin, which was shown to have a nisin-like properties. This strain can be used as potential probiotics in animal or aquaculture feeding; and the bacteriocin it produces will be useful in food preservative. PMID- 28890765 TI - Evaluation of Nutritional Composition of The Dried Seaweed Ulva lactuca from Pameungpeuk Waters, Indonesia. AB - The nutritional composition of the dried seaweed Ulva lactuca from Pameungpeuk waters, including proximate, vitamins, minerals, dietary fibre and heavy metal has been carried out. The objective of this present study is to know the nutritional composition of the dried seaweed U. lactuca for utilisation in human nutrition in the future. Results show that carbohydrate was the major component in the proximate analysis of U. lactuca in the present study. The carbohydrate content was 58.1%. Moisture, ash, protein and fat content were 16.9%, 11.2%, 13.6% and 0.19% respectively, while dietary fibre was 28.4%. The vitamin A content was examined in this study less than 0.5 IU/100 mg while vitamin B1 (thiamine) and vitamin B2 (riboflavin) were 4.87 mg/kg and 0.86 mg/kg respectively. The calcium content was 1828 mg/100 g higher than other minerals. The heavy metal content examined in this study were lower than the limit of the quality criteria applied to edible seaweeds sold in Indonesia. Based on the results of this study show that U. lactuca has potential to be developed as an alternative source of a healthy food for human in the future. PMID- 28890766 TI - Some Biological Aspects of Bigeye Scad, Selar crumenophthalmus from Bangaa Faru, Maldives. AB - In this paper, we studied some biological aspects of big eye scad (Selar crumenophthalmus) from Maldives. The fish sample was collected from the local fish market at Bangaa Faru, Male, Maldives. The length of the samples were ranged from 7.7 cm to 24.5 cm (mean value = 16.85 +/- 2.82 cm) in fork length. Body weight ranged between 8 g to 255.6 g (mean value = 87.76 +/- 40.41 g). The exponent values (b slope) of lengthweight relationship of S. crumenophthalmus are 2.9838 for females and 2.7687 for males; indicating negative allometric growth pattern for both sexes. Synchronous reproductive behaviour was observed in both sexes and a pronounced peak of Gonadosomatic index was observed in females in January 2013. It is estimated that length at first maturity (L50) for females is at 19.39 cm FL and for males at 21.76 cm FL. Our result also suggest that big eye scad have a reduced swimming capability, resulting the species to be easily caught. Careful planning and management should be implemented to prevent the big eye scad from being overfished. PMID- 28890767 TI - Application of Aquatic Insects (Ephemeroptera, Plecoptera And Trichoptera) In Water Quality Assessment of Malaysian Headwater. AB - The Ephemeroptera, Plecoptera and Trichoptera (EPT) community structure and the specific sensitivity of certain EPT genera were found to be influenced by water parameters in the rivers of Gunung Jerai Forest Reserve (GJFR) in the north of peninsular Malaysia. The scores of EPT taxa richness of >10 in all rivers indicated all rivers' habitats were non-impacted, having good water quality coinciding with Class I and Class II of Malaysian water quality index (WQI) classification of potable water. The abundance of EPT was very high in Teroi River (9,661 individuals) but diversity was lower (22 genera) than Tupah River which was highly diverse (28 genera) but lower in abundance (4,263 individuals). The lowest abundance and moderate diversity was recorded from Batu Hampar River (25 genera). Baetis spp. and Thalerosphyrus spp., Neoperla spp. and Cheumatopsyche spp. were the most common genera found. Classification for all rivers using EPT taxa Richness Index and WQI gave different category of water quality, respectively. The WQI classified Tupah and Batu Hampar rivers into Class II and Teroi River (Class I) was two classes above the classification of the EPT taxa Richness Index. PMID- 28890768 TI - Isochrysis maritima Billard and Gayral Isolated from Penang National Park Coastal Waters as a Potential Microalgae for Aquaculture. AB - The importance of polyunsaturated fatty acid (PUFA) in microalgae was widely reported. In this study, six isolated microalgae from Teluk Aling, Penang National Park were screened for PUFA contents. Isochrysis maritima showed the best polyunsaturated fatty acids essential for aquaculture species compared to other microalgal species tested. This species is a good choice as aquaculture feed due to its small size (3-7 MUm), which is appropriate size for ingestion. The maximum specific growth rate of this species was also high (0.52-0.82 days-1) and comparable with many recognised aquaculture microalgae. On the other hand, this species was also able to be cultivated successfully in big volume (1000 L culture medium) with open hatchery condition, which will optimise the production cost. Low ratio of omega-6 to omega-3 essential fatty acids (EFA) recorded in I. maritima at any growth phases (0.32-0.45) also indicate optimal values for feeding. PMID- 28890769 TI - Pollen Load and Flower Constancy of Three Species of Stingless Bees (Hymenoptera, Apidae, Meliponinae). AB - The genera of stingless bees play an important role as pollinators of plants. These bees are actively involved in the pollination of agricultural crops and known to have preferences in selecting flowers to pollinate. The aims of this study were to analyse the pollen load and flower constancy in Tetragonula laeviceps, Lepidotrigona terminata, and Heterotrigona itama. Each individual of species stingless bees collected and was put in a 1.5 mL micro-tube contain 0.5 mL 70% ethanol:glycerol (4:1). Pollen loads on each individual of stingless bees was counted by hemocytometer. Flower constancy of stingless bees was measured based on percentage of pollen type loaded on the body. Results showed that the pollen loads of H. itama was the highest (31392 pollen grains) followed by L. terminata (23017 pollen grains) and T. laeviceps (8015 pollen grains). These species also demonstrated different flower constancy, T. laeviceps on Poaceae flowers (76.49%), L. terminata on Euphorbiaceae flowers (80.46%), and H. itama on Solanaceae flowers (83.33%). PMID- 28890770 TI - Using Non-supervised Artificial Neural Network for Determination of Anthropogenic Disturbance in a River System. AB - The study of river water quality plays an important role in assessing the pollution status and health of the water bodies. Human-induced activities such as domestic activities, aquaculture, agriculture and industries have detrimentally affected the river water quality. Pinang River is one of the important rivers in Balik Pulau District that supplies freshwater for human consumption. A total of 442 physical and chemical parameters data of the Pinang River, Balik Pulau catchment were analysed to determine the sources of pollutants entering the river. Non-supervised artificial neural network (ANN) was employed to classify and cluster the river into upstream, middle-stream and downstream zones. The monitored data and non-supervised ANN analysis demonstrated that the source of nitrate was derived from the upper part of the Pinang River, Balik Pulau while the sources of nitrite, ammonia and ortho-phosphate are predominant at the middle stream of the river system. Meanwhile, the sources of high total suspended solid and biological oxygen demand were concentrated at the downstream of the river. PMID- 28890771 TI - A Preliminary Survey of Species Composition of Termites (Insecta: Isoptera) in Samunsam Wildlife Sanctuary, Sarawak. AB - A survey on termite species composition was conducted in Samunsam Wildlife Sanctuary, Sarawak in February 2015. Overall 19 species of termite belonging to 13 genera and 8 subfamilies was found in the sanctuary. It was recorded the subfamily of Termitinae had the highest number of species (6 species, equal to 31.58% of total species), followed by Nasutermitinae (3 species, 15.79%), Macrotermitinae, Amitermitinae, Rhinotermitinae, Coptotermitinae, (2 species, 10.53% respectively), and Heterotermitinae, Termitogetoninae (1 species, 5.26% respectively). Since this rapid survey is the first termite assemblage representation in Samunsam Wildlife Sanctuary, the preliminary result may serve as the baseline data for termite composition in the area. Therefore, a whole coverage for the area within this sanctuary would definitely increase the number of termite species found in the sanctuary. PMID- 28890772 TI - Knowledge and Cultural Beliefs of Mothers Regarding the Risk Factors of Infant Hearing Loss and Awareness of Audiology Services. AB - The aim of the paper is to describe the knowledge of mothers in Durban, South Africa, regarding risk factors of hearing loss in infants and their awareness of audiology services, and to describe their cultural beliefs about the risk factors for hearing loss in infants. A descriptive survey design with quantitative methods of analysis were used. Conveniently sampled mothers (n=102) receiving postnatal care for their infants from eight provincial clinics within Durban consented to participate, yielding a response rate of 48%. A questionnaire was used to collect the data and the Cronbach alpha was calculated yielding a score of 0.835, indicating good internal consistency and reliability of the questionnaire. Sixty percent of the mothers were aware of risk factors, such as middle ear infections, ototoxic medication and consumption of alcohol during pregnancy. Seventy percent were unaware that NICU/mechanical ventilation for more than 5 days, prematurity, rubella and jaundice are considered risk factors for hearing loss, implying a need to create awareness amongst mothers regarding such risk factors. Sixty percent (n=62) believed that bewitchment and ancestral curses can cause hearing loss. Cultural beliefs were associated with hearing loss, therefore, health professionals need to demonstrate cultural competence when providing audiology services, especially in a culturally and linguistically diverse countries such as South Africa. Although the mothers had an average knowledge about risk factors, two thirds did not know which professional to seek help from. There is a need to create awareness amongst mothers regarding the risk factors of infant hearing loss as well as audiology services in order to facilitate early detection and intervention. There is a need for health professionals to demonstrate cultural competence when working with their patients. PMID- 28890773 TI - The Use of Facilities for Labor and Delivery: The Views of Women in Rural Uganda. AB - The aim of the paper is to explore factors associated with home or hospital delivery in rural Uganda. Qualitative interviews with recently-delivered women in rural Uganda and statistical analysis of data from the 2011 Ugandan Demographic and Health Survey (DHS) to assess the association between socio-demographic and cultural factors and delivery location in multivariable regression models. In the DHS, 61.7% (of 4907) women had a facility-based delivery (FBD); in adjusted analyses, FBD was associated with an urban setting [adjusted odds ratio (aOR) 3.38, 95% confidence interval (CI) 2.66 to 4.28)], the upper wealth quintile (aOR: 3.69, 95%CI 2.79 to 3.87) and with secondary education (aOR: 3.07, 95%CI 2.37 to 3.96). In interviews women quoted costs and distance as barriers to FBD. Other factors reported in interviews to be associated with FBD included family influence, perceived necessity of care (weak women needed FBD), and the reputation of the facility (women bypassed local facilities to deliver at better hospitals). Choosing a FBD is a complex decision and education around the benefits of FBD should be combined with interventions designed to remove barriers to FBD. PMID- 28890774 TI - Diarrheagenic Escherichia Coli O157 from Libya: Recent Perspectives and Challenges. PMID- 28890775 TI - Musical Training Enhances Neural Processing of Comodulation Masking Release in the Auditory Brainstem. AB - Musical training strengthens segregation the target signal from background noise. Musicians have enhanced stream segregation, which can be considered a process similar to comodulation masking release. In the current study, we surveyed psychoacoustical comodulation masking release in musicians and non-musicians. We then recorded the brainstem responses to complex stimuli in comodulated and unmodulated maskers to investigate the effect of musical training on the neural representation of comodulation masking release for the first time. The musicians showed significantly greater amplitudes and earlier brainstem response timing for stimulus in the presence of comodulated maskers than non-musicians. In agreement with the results of psychoacoustical experiment, musicians showed greater comodulation masking release than non-musicians. These results reveal a physiological explanation for behavioral enhancement of comodulation masking release and stream segregation in musicians. PMID- 28890776 TI - Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues. AB - In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines. PMID- 28890777 TI - When Does Maluma/Takete Fail? Two Key Failures and a Meta-Analysis Suggest That Phonology and Phonotactics Matter. AB - Eighty-seven years ago, Kohler reported that the majority of students picked the same answer in a quiz: Which novel word form ('maluma' or 'takete') went best with which abstract line drawing (one curved, one angular). Others have consistently shown the effect in a variety of contexts, with only one reported failure by Rogers and Ross. In the spirit of transparency, we report our own failure in the same journal. In our study, speakers of Syuba, from the Himalaya in Nepal, do not show a preference when matching word forms 'kiki' and 'bubu' to spiky versus curvy shapes. We conducted a meta-analysis of previous studies to investigate the relationship between pseudoword legality and task effects. Our combined analyses suggest a common source for both of the failures: 'wordiness' - We believe these tests fail when the test words do not behave according to the sound structure of the target language. PMID- 28890778 TI - Yawning Detection Sensitivity and Yawning Contagion. AB - Contagious yawning-the urge to yawn when thinking about, listening to, or viewing yawning-is a well-documented phenomenon in humans and animals. The reduced yawn contagion observed in the autistic population suggested that it might be empathy related; however, it is unknown whether such a connection applies to nonclinical populations. We examined influences from both empathy (i.e., autistic traits) and nonempathy factors (i.e., individuals' perceptual detection sensitivity to yawning, happy, and angry faces) on 41 nonclinical adults. We induced contagious yawning with a 5-minute video and 20 yawning photo stimuli. In addition, we measured participants' autistic traits (with the autism-spectrum quotient questionnaire), eye gaze patterns, and their perceptual thresholds to detect yawning and emotion in human face photos. We found two factors associated with yawning contagion: (a) those more sensitive to detect yawning, but not other emotional expressions, displayed more contagious yawning than those less sensitive to yawning expressions, and (b) female participants exhibited significantly more contagious yawning than male participants. We did not find an association between autistic trait and contagious yawning. Our study offers a working hypothesis for future studies, in that perceptual encoding of yawning interacts with susceptibility to contagious yawning. PMID- 28890781 TI - Thermo-responsive cell culture carrier: Effects on macrophage functionality and detachment efficiency. AB - Harvesting cultivated macrophages for tissue engineering purposes by enzymatic digestion of cell adhesion molecules can potentially result in unintended activation, altered function, or behavior of these cells. Thermo-responsive polymer is a promising tool that allows for gentle macrophage detachment without artificial activation prior to subculture within engineered tissue constructs. We therefore characterized different species of thermo-responsive polymers for their suitability as cell substrate and to mediate gentle macrophage detachment by temperature shift. Primary human monocyte- and THP-1-derived macrophages were cultured on thermo-responsive polymers and characterized for phagocytosis and cytokine secretion in response to lipopolysaccharide stimulation. We found that both cell types differentially respond in dependence of culture and stimulation on thermo-responsive polymers. In contrast to THP-1 macrophages, primary monocyte derived macrophages showed no signs of impaired viability, artificial activation, or altered functionality due to culture on thermo-responsive polymers compared to conventional cell culture. Our study demonstrates that along with commercially available UpCell carriers, two other thermo-responsive polymers based on poly(vinyl methyl ether) blends are attractive candidates for differentiation and gentle detachment of primary monocyte-derived macrophages. In summary, we observed similar functionality and viability of primary monocyte-derived macrophages cultured on thermo-responsive polymers compared to standard cell culture surfaces. While this first generation of custom-made thermo-responsive polymers does not yet outperform standard culture approaches, our results are very promising and provide the basis for exploiting the unique advantages offered by custom-made thermo-responsive polymers to further improve macrophage culture and recovery in the future, including the covalent binding of signaling molecules and the reduction of centrifugation and washing steps. Optimizing these and other benefits of thermo-responsive polymers could greatly improve the culture of macrophages for tissue engineering applications. PMID- 28890779 TI - Elements of the niche for adult stem cell expansion. AB - Adult stem cells are crucial for tissue homeostasis. These cells reside within exclusive locations in tissues, termed niches, which protect adult stem cell fidelity and regulate their many functions through biophysical-, biochemical- and cellular-mediated mechanisms. There is a growing understanding of how these mechanisms and their components contribute towards maintaining stem cell quiescence, self-renewal, expansion and differentiation patterns. In vitro expansion of adult stem cells is a powerful tool for understanding stem cell biology, and for tissue engineering and regenerative medicine applications. However, it is technically challenging, since adult stem cell removal from their native microenvironment has negative repercussions on their sustainability. In this review, we overview specific elements of the biomimetic niche and how recreating such elements can help in vitro propagation of adult stem cells. PMID- 28883910 TI - Blood Interferon Signatures Putatively Link Lack of Protection Conferred by the RTS,S Recombinant Malaria Vaccine to an Antigen-specific IgE Response. AB - Malaria remains a major cause of mortality and morbidity worldwide. Progress has been made in recent years with the development of vaccines that could pave the way towards protection of hundreds of millions of exposed individuals. Here we used a modular repertoire approach to re-analyze a publically available microarray blood transcriptome dataset monitoring the response to malaria vaccination. We report the seminal identification of interferon signatures in the blood of subjects on days 1, 3 and 14 following administration of the third dose of the RTS,S recombinant malaria vaccine. These signatures at day 1 correlate with protection, and at days 3 and 14 to susceptibility to subsequent challenge of study subjects with live parasites. In addition we putatively link the decreased abundance of interferon-inducible transcripts observed at days 3 and 14 post-vaccination with the elicitation of an antigen-specific IgE response in a subset of vaccine recipients that failed to be protected by the RTS,S vaccine. Furthermore, profiling of antigen-specific levels of IgE in a Mozambican cohort of malaria-exposed children vaccinated with RTS,S identified an association between elevated baseline IgE levels and subsequent development of naturally acquired malaria infection during follow up. Taken together these findings warrant further investigation of the role of antigen-specific IgE in conferring susceptibility to malaria infection. PMID- 28890780 TI - Recellularization of decellularized heart valves: Progress toward the tissue engineered heart valve. AB - The tissue-engineered heart valve portends a new era in the field of valve replacement. Decellularized heart valves are of great interest as a scaffold for the tissue-engineered heart valve due to their naturally bioactive composition, clinical relevance as a stand-alone implant, and partial recellularization in vivo. However, a significant challenge remains in realizing the tissue-engineered heart valve: assuring consistent recellularization of the entire valve leaflets by phenotypically appropriate cells. Many creative strategies have pursued complete biological valve recellularization; however, identifying the optimal recellularization method, including in situ or in vitro recellularization and chemical and/or mechanical conditioning, has proven difficult. Furthermore, while many studies have focused on individual parameters for increasing valve interstitial recellularization, a general understanding of the interacting dynamics is likely necessary to achieve success. Therefore, the purpose of this review is to explore and compare the various processing strategies used for the decellularization and subsequent recellularization of tissue-engineered heart valves. PMID- 28890784 TI - First record of locally acquired human babesiosis in Canada caused by Babesia duncani: a case report. AB - OBJECTIVES: The aim of this clinical assessment was to ascertain whether a 70 year-old Canadian patient, who had no history of out-of-country travel, had contracted a Babesia infection. METHODS: The adult human male developed constitutional symptoms, which included sweats, chills, and immobilizing fatigue, and was screened for human babesiosis. Subsequent testing included a complete Babesia panel that consisted of B. microti immunoflourescent antibody IgM and IgG, B. duncani immunofluorescent antibody IgM and IgG, Babesia PCR, and Babesia fluorescent in situ hybridization (FISH) test. RESULTS: Both the IgM serology and the molecular FISH RNA probe were positive for B. duncani; all tests for B. microti were negative. Based on clinical symptoms and laboratory tests, the patient was diagnosed with human babesiosis. Interestingly, the patient's wife also was confirmed positive using serological and molecular testing. CONCLUSIONS: This is the first report of a locally acquired case of human babesiosis in Canada caused by Babesia duncani. The geographical distribution of B. duncani in North America is much greater than previously anticipated, especially north of the Canada-United States border. Since the patient was bitten by a blacklegged tick, Ixodes scapularis, a carrier of multiple zoonotic pathogens, the author suggests that this tick species is a vector of B. duncani. Health-care providers must be aware that B. duncani is present in Canada, and poses a public health risk. PMID- 28890783 TI - Twitter and traumatic brain injury: A content and sentiment analysis of tweets pertaining to sport-related brain injury. AB - OBJECTIVES: Sport-related traumatic brain injuries are a significant public health burden, with hundreds of thousands sustained annually in North America. While sports offer numerous physical and social health benefits, traumatic brain injuries such as concussion can seriously impact a player's life, athletic career, and sport enjoyment. The culture in many sports encourages winning at all costs, placing athletes at risk for traumatic brain injuries. As social media has become a central part of everyday life, the content of users' messages often reflects the prevailing culture related to a particular event or health issue. METHODS: We hypothesized that Twitter data might be useful for understanding public perceptions and misperceptions of sport-related traumatic brain injuries. We performed a content and sentiment analysis of 7483 Twitter(r) tweets related to traumatic brain injuries in sports collected during June and July 2013. RESULTS: We identified five major themes. Users tweeted about personal traumatic brain injuries experiences, reported traumatic brain injuries in professional athletes, shared research about sport-related concussions, and discussed policy and safety in injury prevention, such as helmet use. We identified mixed perceptions of and sentiment toward traumatic brain injuries in sports: both an understanding that brain injuries are serious and disregard for activities that might reduce the public burden of traumatic brain injuries were prevalent in our Twitter analysis. CONCLUSION: While the scientific and medical community considers a concussion a form of traumatic brain injuries, our study demonstrates a misunderstanding of this fact among the public. In our current digital age, social media can provide useful insight into the culture around a health issue, facilitating implementation of prevention and treatment strategies. PMID- 28890785 TI - Staged approach for surgical management of a true femoral artery aneurysm combined with bilateral iliac artery aneurysms. AB - True femoral artery aneurysm is a rare vascular entity and is often associated with aortic or peripheral aneurysms. Life-threatening complications associated with peripheral arterial aneurysms include rupture, thrombosis, and embolization. In patients with multiple aneurysms, any symptomatic aneurysms should be treated first; in asymptomatic patients, the aneurysms can be repaired either simultaneously in a single operation or serially in a staged procedure. We report a case of concomitant true femoral aneurysm and bilateral iliac artery aneurysms, which were treated with a combination of open surgical and endovascular techniques. PMID- 28890786 TI - Hypertrophy of the abductor hallucis muscle: A case report and review of the literature. AB - OBJECTIVES: Muscle hypertrophy is a relatively rare condition that may cause nerve entrapment syndromes. We report the case of a 14-year-old girl with unilateral hypertrophy of the abductor hallucis muscle with entrapment of the medial plantar nerve and review the literature. METHODS: Computed tomography and magnetic resonance imaging revealed unilateral hypertrophy of the abductor hallucis muscle. RESULTS: Two injections of steroid and lidocaine at the point of tenderness resulted in resolution of the pain. CONCLUSIONS: We report a rare case of hypertrophy of the abductor hallucis muscle considered with entrapment of the medial plantar nerve. Treatment of this condition should be selected according to the pathological condition of each patient. PMID- 28890787 TI - Unique angiographic findings in a patient with myocardial ischemia and immunoglobulin G4-related disease. AB - Immunoglobulin G4-related disease characteristically involves multiple organs including the heart and coronary arteries. Immunoglobulin G4-related coronary artery disease is thought to be due to periarteritis and histopathologically is characterized by marked thickening of the adventitia and periarterial fat with infiltration of immunoglobulin G4-positive plasma cells. Although comprehensive diagnostic criteria require a biopsy for a definite or probable diagnosis of immunoglobulin G4-related disease, obtaining a coronary artery biopsy is difficult and risky. However, imaging findings including coronary angiography and intravascular ultrasound might be useful tools to establish a diagnosis of immunoglobulin G4-related coronary artery disease. We report a case of a 63-year old man with a history of immunoglobulin G4-related disease who presented with exertional chest pain. We found unique angiographic and intravascular ultrasound features of immunoglobulin G4-related coronary artery disease that distinguished it from those of arteriosclerotic coronary artery disease and suggest that coronary angiography and intravascular ultrasound might be useful tools in the diagnosis of immunoglobulin G4-related coronary artery disease. PMID- 28890788 TI - Opening bottlenecks on weighted networks by local adaptation to cascade failures. AB - Structure and dynamics of complex systems are often described using weighted networks in which the position, weight and direction of links quantify how activity propagates between system elements, or nodes. Nodes with only few outgoing links of low weight have low out-strength and thus form bottlenecks that hinder propagation. It is currently not well understood how systems can overcome limits imposed by such bottlenecks. Here, we simulate activity cascades on weighted networks and show that, for any cascade length, activity initially propagates towards high out-strength nodes before terminating in low out-strength bottlenecks. Increasing the weights of links that are active early in the cascade further enhances already strong pathways, but worsens the bottlenecks thereby limiting accessibility to other pathways in the network. In contrast, strengthening only links that propagated the activity just prior to cascade termination, i.e. links that point into bottlenecks, eventually removes these bottlenecks and increases the accessibility of all paths on the network. This local adaptation rule simply relies on the relative timing to a global failure signal and allows systems to overcome engrained structure to adapt to new challenges. PMID- 28890789 TI - Evaluation of blood metabolites reflects presence or absence of liver abscesses in beef cattle. AB - Liver abscesses constitute a prominent concern regarding animal health and profitability of the beef industry. Our objective was to evaluate potential biliary and blood indicators of liver abscesses. Twenty-nine beef bulls (initially averaging 356+/-70.5 kg and 253+/-30 days of age) were fed a high concentrate diet during a performance test of 112 days, during which blood was collected at nine time points spaced 0.5-13 days apart within 56 days before slaughter. At the abattoir, blood and bile were collected and livers were inspected for liver abscesses. Results indicated that liver abscesses are associated with elevated levels of plasma cortisol and aspartate aminotransferase, and decreased levels of albumin, cholesterol and testosterone over the period before slaughter. Based on the blood samples collected during exsanguination, the presence of liver abscesses was associated with lower concentrations of thyroxine, albumin, cholesterol and alkaline phosphatase, and is suggested to be associated with lower blood carbon dioxide (P=0.08) and lower biliary cortisol metabolites (P=0.07). Albumin and cholesterol are established indicators of hepatic function and are consistently related to the presence of liver abscesses. Identifying blood parameters that predict liver abscesses has practical implications for cattle husbandry and for ensuring food safety. PMID- 28890790 TI - Evaluating pair versus solitary housing in kennelled domestic dogs (Canis familiaris) using behaviour and hair cortisol: a pilot study. AB - Numerous studies conducted to assess welfare of domestic dogs housed in kennel facilities have reported that these dogs experience suboptimal living conditions. One important goal of improving welfare of kennelled dogs is to reduce their stress levels, and one recommended approach for improving welfare of kennelled dogs is group or social housing. The beneficial effects of management changes designed to achieve this goal should be measurable in individual animals. Stress is evident through behaviours exhibited, as well as via the concentration of cortisol, a key hormone reflecting stress. Using behavioural and hair cortisol measures, we conducted a pilot study to measure the impact of switching dogs housed in a long-term kennels facility from solitary to pair housing, using both within-subjects and between-groups comparisons. Considerable individual variation in dog responses was noted, with only two of eight pair-housed dogs showing significant declines in multiple stress-related behaviours once in pair housing. The most sensitive behaviours were active vigilance and repetitive movements (such as jumping and pacing). Barking was reduced overall in the facility following the housing change, even among dogs still in solitary housing. The long term stress as reflected in hormone deposition in hair also provided encouraging indications that the dogs experienced lower stress levels when in paired housing; dogs showed a significant decline in hair cortisol levels from the first (prehousing change) to second (postintervention) samples. Domestic dogs are social animals, and numerous indications of potential benefit were recorded with no negative impacts seen. Based on our findings, we recommend pair or group housing of compatible dogs as a promising addition to the strategies available to those seeking to improve welfare of kennelled dogs. Future studies using higher numbers of animals and that include tracking of hair cortisol, vigilance behaviour, repetitive movements and barking would be desirable. PMID- 28890791 TI - Potential of phytoceuticals to affect antibiotic residue detection tests in cow milk in a randomised trial. AB - Mastitis is a costly disease for dairy farmers. Some dairy farmers use herbal products, or phytoceuticals, to treat mastitis. Phytoceuticals have not been approved for this use by the United States Food and Drug Administration, and have not been tested to determine how they impact antibiotic residue detection testing. The current study tested the potential for phytoceuticals to cause positive results on two milk antibiotic residue screening tests, the Delvotest P and Charm SL Beta-lactam test, or to interfere with the detection of antibiotics by these tests. The three phytoceuticals tested were labelled for intramammary, topical or intravulvar administration. Testing was performed in vitro using the products diluted in milk obtained from healthy organic dairy cows. Phytoceuticals were tested at concentrations ranging from 1.5 per cent to 100 per cent. Concentration levels were replicated at least twice on each milk antibiotic residue screening test. The Delvotest P is based on detection of bacterial inhibitors and no positive results were obtained for any product at concentrations less than 50 per cent. The Charm SL Beta-lactam test uses a receptor for the detection of beta-lactam antibiotics and no concentration of phytoceuticals caused an interference with these tests. Based on dilution of the products in bovine milk at physiologically achievable levels, phytoceutical products tested at levels expected after treatment do not cause positive test results for the Delvotest P nor do they interfere with the Charm SL Beta-lactam test in detection of various antibiotics. PMID- 28890792 TI - Multicentre analysis of current ST-elevation myocardial infarction acute care pathways. AB - BACKGROUND: Rapid reperfusion with percutaneous coronary intervention (PCI) is vital for patients with ST segment elevation myocardial infarction (STEMI). However, the guideline-recommended time targets are regularly exceeded. The goal of this study was to gain insight into how Dutch PCI centres try to achieve these time targets by comparing their care processes with one another and with the European guideline-recommended process. In addition, accelerating factors perceived by care providers were identified. METHODS: In this multiple case study, interviews with STEMI care providers were conducted, transcribed and used to create process descriptions per centre. Analyses consisted of within-case and between-case analyses of the processes. Accelerating factors were identified by means of open and axial coding. RESULTS: In total, 28 interviews were conducted in six PCI centres. The centres differed from the guideline-recommended process on, for example, additional, unavoidable patient routings and monitoring delays, and from one another on the communication of diagnostic information (eg, transmitting all, only ambiguous or no ECGs) and catheterisation room preparation. These differences indicated diverging choices to maintain a balance between speed and diagnostic accuracy. Factors perceived by care providers as accelerating the process included trust in the tentative diagnosis, and avoiding unnecessary intercaregiver consultations. The combination of processes and accelerating factors were summarised in a model. CONCLUSIONS: Numerous differences in processes between PCI centres were identified. Several time-saving strategies were applied by PCI centres, however, in different configurations. To further improve the care for patients with STEMI, best practices can be shared between centres and countries. PMID- 28890793 TI - Call for joint informed consent in athletes with inherited cardiac conditions. AB - Informed consent is of the utmost importance, especially in complex clinical situations where patients may be exposed to a life-threatening risk. A particularly complex example is the eligibility of competitive athletes with inherited cardiac conditions on medical grounds, especially when the risk is low or unquantifiable. The rationale and benefits of a joint informed consent for athletes to compete with potentially life-threatening cardiac conditions are discussed in this manuscript. PMID- 28890794 TI - Engaging Experts and Patients to Refine the Nutrition Literacy Assessment Instrument. AB - BACKGROUND: An objective measure of nutrition literacy is unavailable for use in the primary care population. The Nutrition Literacy Assessment instrument (NLit) is a tool designed to measure nutrition literacy across six domains and has been previously piloted in breast cancer and parent populations. The purpose of this research was to engage nutrition experts and patients to guide revisions of the NLit for use in adult primary care. METHODS: Experts (n=5) reviewed each item in the NLit using a survey to assign rankings of their agreement according to relevance, clarity, and reading difficulty. Relevance rankings were used to calculate Scale Content Validity Index. After suggested revisions were made, patients (n=12) were recruited from urban primary care clinics of a University Medical Center located in the Midwestern United States and were interviewed by trained researchers using the cognitive interview approach to generate thoughts, feelings, and ideas regarding NLit items. Data analysis involved qualitative and quantitative methods. RESULTS: Content validity from expert review was confirmed with a total Scale Content Validity Index of 0.90. Themes emerging from the cognitive interviews resulted in changes in the NLit to improve instrument clarity. CONCLUSION: These data suggest the NLit achieves its target constructs, is understood by the target audience, and is ready to undergo validity and reliability testing within the primary care population. PMID- 28890795 TI - Bilateral patellar fractures and increased cortical bone thickness associated with long-term oral alendronate treatment in a cat. AB - CASE SUMMARY: A 14-year-old cat presented with bilateral patellar fractures and radiographically thickened tibial cortices. This cat had been treated with alendronate for 8 years prior to presentation. To remove the subjectivity of the radiographic evaluation, tibial radiographs from 35 apparently healthy geriatric cats were used for comparison. Cortical and diaphyseal thickness were measured at the proximal and distal thirds of the tibia. Our cat had increased cortical bone thickness compared to that of the control cats. RELEVANCE AND NOVEL INFORMATION: Treatment with bisphosphonates can lead to brittle bones and fractures after prolonged use in humans. This is the first description of fractures and cortical bone changes that may have been associated with prolonged bisphosphonate use in a cat. Radiographic measurements of cortical bone thickness may identify cats that are at increased risk for bone pathology secondary to prolonged alendronate use. PMID- 28890796 TI - Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 24-month follow-up. AB - BACKGROUND: Dimethyl fumarate and fingolimod are oral disease-modifying therapies approved to treat relapsing multiple sclerosis. Prior observational studies and our previous 12-month investigation showed comparable clinical efficacy. OBJECTIVE: The purpose of this study was to assess real-world efficacy and discontinuation of dimethyl fumarate and fingolimod over 24 months in patients with multiple sclerosis. METHODS: Patients treated with dimethyl fumarate (n = 395) or fingolimod (n = 264) completed 24-month follow-up in a large academic multiple sclerosis center. Discontinuation rates and measures of disease activity were compared after propensity score weighting. The primary outcome was on treatment annualized relapse rate ratio. Other measures included rate of drug discontinuation and brain magnetic resonance imaging activity defined as new T2 and/or gadolinium-enhancing lesions. RESULTS: Propensity score weighting showed excellent covariate balance. At 24 months, dimethyl fumarate demonstrated comparable annualized relapse rate (rate ratio = 1.45, 95% confidence interval 0.53-3.99) and brain magnetic resonance imaging activity (odds ratio = 1.38, 95% confidence interval 0.83-2.32). Dimethyl fumarate patients discontinued therapy earlier compared to fingolimod (hazard ratio = 1.40, 95% confidence interval 1.11 1.77) and were more likely to discontinue therapy due to intolerability (odds ratio = 1.98, 95% confidence interval 1.18-3.23). CONCLUSION: Dimethyl fumarate and fingolimod had similar reductions in annualized relapse rate in clinical trials, and our real-world experience supports this observation. Dimethyl fumarate-treated patients had higher likelihood of early discontinuation, and this was mostly due to intolerability. PMID- 28890797 TI - Defining patient centricity with patients for patients and caregivers: a collaborative endeavour. AB - BACKGROUND: Patient engagement is an essential aspect in the research/development of biopharmaceutical products and disease management. Improving the lives of patients requires a deep understanding of their medical conditions, experiences, needs and priorities. However, a consistent definition of patient centricity is lacking. A series of initiatives was conducted to define patient centricity and its important principles impacting the biopharmaceutical industry. METHODS: Interviews, questionnaires and literature reviews were conducted involving key stakeholders to initially identify issues of importance to patients, healthcare providers and payers. Subsequently, two identical workshops which included 22 patients/carers created a definition of patient centricity and the healthcare values important to patients/caregivers. Outputs were tested in a validation exercise involving patients in predominantly US (n=470) and European (n=703) patient forums. RESULTS: Initial research provided deeper understanding of patient needs and key topics of interest that were used to cocreate a definition of patient centricity and 10 associated principles of importance to the biopharmaceutical industry. Wider testing of these outputs among predominantly US/European patient communities confirmed their validity. Patient centricity should be defined as 'Putting the patient first in an open and sustained engagement of the patient to respectfully and compassionately achieve the best experience and outcome for that person and their family'. Important principles for patients focused on education/information, cocreation, access and transparency. CONCLUSIONS: The development of a consistent definition of patient centricity and its associated principles provides an opportunity for biopharmaceutical companies to adopt and use these as a reference point for consistent patient engagement throughout the product life cycle. PMID- 28890798 TI - American football and other sports injuries may cause migraine/persistent pain decades later and can be treated successfully with electrical twitch-obtaining intramuscular stimulation (ETOIMS). AB - INTRODUCTION: Autonomous twitch elicitation at myofascial trigger points from spondylotic radiculopathies-induced denervation supersensitivity can provide favourable pain relief using electrical twitch-obtaining intramuscular stimulation (ETOIMS). AIM: To provide objective evidence that ETOIMS is safe and efficacious in migraine and persistent pain management due to decades-old injuries to head and spine from paediatric American football. METHODS AND MATERIALS: An 83-year-old mildly hypertensive patient with 25-year history of refractory migraine and persistent pain self-selected to regularly receive fee for-service ETOIMS 2/week over 20 months. He had 180 sessions of ETOIMS. Pain levels, blood pressure (BP) and heart rate/pulse were recorded before and immediately after each treatment alongside highest level of clinically elicitable twitch forces/session, session duration and intervals between treatments. Twitch force grades recorded were from 1 to 5, grade 5 twitch force being strongest. RESULTS: Initially, there was hypersensitivity to electrical stimulation with low stimulus parameters (500 us pulse-width, 30 mA stimulus intensity, frequency 1.3 Hz). This resolved with gradual stimulus increments as tolerated during successive treatments. By treatment 27, autonomous twitches were noted. Spearman's correlation coefficients showed that pain levels are negatively related to twitch force, number of treatments, treatment session duration and directly related to BP and heart rate/pulse. Treatment numbers and session durations directly influence twitch force. At end of study, headaches and quality of life improved, hypertension resolved and antihypertensive medication had been discontinued. CONCLUSIONS: Using statistical process control methodology in an individual patient, we showed long-term safety and effectiveness of ETOIMS in simultaneous diagnosis, treatment, prognosis and prevention of migraine and persistent pain in real time obviating necessity for randomised controlled studies. PMID- 28890799 TI - Associations between altered movement patterns during single-leg squat and muscle activity at weight-transfer initiation in individuals with anterior cruciate ligament injury. AB - BACKGROUND: Little is known about factors contributing to the altered movement patterns observed in many individuals with anterior cruciate ligament (ACL) injury. We addressed whether altered muscular activity is such a factor. METHODS: 16 participants with unilateral, non-reconstructed ACL rupture were scored for altered movement patterns according to Test for Substitution Patterns (TSP), which includes the single-leg squat (SLS). Surface electromyography (SEMG), was recorded in the lower extremities at initiation of weight-transfer from double leg to single-leg stance (eyes closed), simulating the initiation of an SLS. Normalised SEMG amplitudes 200-300 ms after weight-transfer initiation were compared between injured and non-injured sides, and correlated to the TSP scores for the SLS. Peak absolute SEMG amplitudes during 5 TSP test movements were also compared between sides. RESULTS: At weight-transfer initiation, muscle activity was lower in the tibialis anterior, gastrocnemius and peroneus longus muscles on the injured side. Low muscle activity correlated moderately to worse TSP scores for the SLS for the gluteus medius (rs=-0.56, p=0.03), and gastrocnemius muscles (rs=-0.56, p=0.02). Median peak absolute amplitude during TSP movements was lower in the quadriceps, gastrocnemius and peroneus longus muscles on the injured side. CONCLUSIONS: The altered patterns of muscle activity at weight-transfer initiation, correlations between lower activity at movement initiation and altered movement patterns during SLS and the altered peak amplitudes during TSP movements together indicate alterations in sensorimotor control that may contribute to the observed altered movement patterns. Future studies will determine if exercises targeting muscle activity initiation should complement customary ACL injury rehabilitation. PMID- 28890801 TI - Australian Football League concussion guidelines: what do community players think? AB - BACKGROUND: Preventing concussion in sport is a global challenge. To assess community-level adult male Australian Football players' views on following the Australian Football League's (AFL) concussion guidelines. METHODS: 3 focus groups, each comprising 6 players from 1 regional league, were conducted until saturation of issues raised. Discussions followed a semistructured script and were audio-recorded and transcribed verbatim. Thematic analysis was conducted by 2 coders independently. RESULTS: Identified advantages of the guidelines included highlighting the seriousness of concussion; changing the culture around playing with concussion and shifting return-to-play decision responsibility from players to others. Disadvantages included players being removed from play unnecessarily; removal of players' rights to decide if they are fit to play and players changing their behaviours to avoid being removed from play. Identified facilitators to guideline use included local league enforcement; broad information dissemination and impartial medically trained staff to assess concussion. Identified barriers to guideline use included players' desire to play at all costs; external pressure that encouraged players to return to play prematurely; and inconvenience and cost. CONCLUSIONS: Players generally understand that the AFL concussion guidelines protect their long-term welfare. However, their desire to play at all costs and help their team win is a common barrier to reporting concussion and adhering to guidelines. Leagues should take a lead role by mandating and enforcing the use of the guidelines and educating coaches, game day medical providers and players. The return-to-play component of the guidelines is complex and needs further consideration in the context of community sport. PMID- 28890802 TI - Appropriateness of the metabolic equivalent (MET) as an estimate of exercise intensity for post-myocardial infarction patients. AB - AIMS: To explore: (1) whether during exercise metabolic equivalents (METs) appropriately indicate the intensity and/or metabolic cost for post-myocardial infarction (MI) males and (2) whether post-exercise VO2 parameters provide insight into the intensity and/or metabolic cost of the prior exercise. METHODS: 15 male phase-IV post-MIs (64.4+/-6.5 years) and 16 apparently healthy males (63.0+/-6.4 years) participated. Participants performed a graded cycle ergometer test (CET) of 50, 75 and 100 W, followed by 10 min active recovery (at 50 W) and 22 min seated recovery. Participants' heart rate (HR, bpm), expired air parameters and ratings of perceived exertion (exercise only) were measured. RESULTS: General linear model analysis showed throughout significantly lower HR values in post-MI participants that were related to beta-blocker medication (F(2,5)=18.47, p<0.01), with significantly higher VCO2/VO2 (F(2,5)=11.25, p<0.001) and gross kcals/LO2/min (F(2,5)=11.25, p<0.001). Analysis comparing lines of regression showed, during the CET: post-MI participants worked at higher percentage of their anaerobic threshold (%AT)/MET than controls (F(2,90)=18.98, p<0.001), as well as during active recovery (100-50 W) (F(2,56)=20.81, p<0.001); during seated recovery: GLM analysis showed significantly higher values of VCO2/VO2 for post-MI participants compared with controls (F(2,3)=21.48, p=0.001) as well as gross kcals/LO2/min (F(2,3)=21.48, p=0.001). CONCLUSION: Since METs take no consideration of any anaerobic component, they failed to reflect the significantly greater anaerobic contribution during exercise per MET for phase-IV post-MI patients. Given the anaerobic component will be greater for those with more severe forms of cardiac disease, current METs should be used with caution when determining exercise intensity in any patient with cardiac disease. PMID- 28890800 TI - Groin Pain Syndrome Italian Consensus Conference on terminology, clinical evaluation and imaging assessment in groin pain in athlete. AB - The nomenclature and the lack of consensus of clinical evaluation and imaging assessment in groin pain generate significant confusion in this field. The Groin Pain Syndrome Italian Consensus Conference has been organised in order to prepare a consensus document regarding taxonomy, clinical evaluation and imaging assessment for groin pain. A 1-day Consensus Conference was organised on 5 February 2016, in Milan (Italy). 41 Italian experts with different backgrounds participated in the discussion. A consensus document previously drafted was discussed, eventually modified, and finally approved by all members of the Consensus Conference. Unanimous consensus was reached concerning: (1) taxonomy (2) clinical evaluation and (3) imaging assessment. The synthesis of these 3 points is included in this paper. The Groin Pain Syndrome Italian Consensus Conference reached a consensus on three main points concerning the groin pain syndrome assessment, in an attempt to clarify this challenging medical problem. PMID- 28890803 TI - The effect of generalised joint hypermobility on rate, risk and frequency of injury in male university-level rugby league players: a prospective cohort study. AB - BACKGROUND: Rugby league is a collision sport where musculoskeletal injuries are common. There has been little research on generalised joint hypermobility (GJH) as a risk factor for injury in rugby league. The aim of this study was to investigate the role of GJH on the incidence of injuries in first and second team rugby league players from one British university. METHODS: We conducted a prospective cohort study of 45 student players from one British university first and second team rugby league squads (mean age 20.93+/-1.57 years). At the beginning of the season, GJH was determined using a 9-point Beighton scale, and injury and exposure data were collected on a weekly basis throughout the 2013 2014 season. RESULTS: The prevalence of GJH was 20%. There was no statistically significant difference in the frequency of injuries between GJH and non-GJH participants (p=0.938, Mann-Whitney U test).Participants categorised as having GJH did not experience a higher fequency of injury (p=0.722, Fisher's exact test) and there was no tendency to demonstrate a higher risk of injury for participants categorised as GJH (OR=0.64, 95% CI 0.15 to 2.78; relative risk (RR)=1.188, 95% CI 0.537 to 2.625). The most common site of injury was the ankle, but this was not statistically significant (OR=0.152, 95% CI 0.008 to 2.876; RR=0.195, CI 0.012 to 3.066). CONCLUSION: British university rugby league players with GJH did not demonstrate a greater risk of injury than those without GJH. PMID- 28890804 TI - Injuries during the international floorball tournaments from 2012 to 2015. AB - BACKGROUND: Floorball is a running indoor team sport that has growing popularity worldwide. Some prospective studies have investigated injuries in national floorball leagues, but such studies at the international level are lacking. OBJECTIVE: To investigate the incidence and characteristics of injuries during 12 International Floorball Federation (IFF) events. METHODS: All top-level IFF events from 2012 to 2015 were included in the study. The IFF events were divided into the following groups: Men's World Floorball Championships (2012 and 2014), Women's World Floorball Championships (2013 and 2015), Men's Champions Cup (2012, 2013, 2014 and 2015) and Women's Champions Cup (2012, 2013, 2014 and 2015). The team medical personnel prospectively recorded the injuries that occurred in games and practices. The time of exposure was calculated for entire teams based on the IFF statistics. RESULTS: Sixty-eight injuries were registered among 67 players. Sixty-five of the injuries occurred in games, resulting in an injury incidence of 21.24 per 1000 game hours (95% CI 16.13 to 26.35). There was no significant difference in the incidence of game injuries between females and males (incidence rate ratio 0.68, 95% CI 0.41 to 1.11). The ankle was the most common site of injury (24%), followed by the head (18%) and the knee (18%). Almost half of the injuries (46%) involved joints or ligaments. CONCLUSIONS: Risk of injury during IFF tournaments was lower than in many other team sports at the highest level of play. Preventive actions should focus on acute ankle and knee injuries as well as head and face injuries. PMID- 28890805 TI - Outcome after post-acute spinal cord specific rehabilitation: a German single center study. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The objective of this study was to analyze single center outcome measures of spinal cord injury (SCI) specific rehabilitation (SCISR) in Germany. SETTING: The study was conducted at an SCI specialized rehabilitation center. METHODS: Nonparametric tests for outcome description such as SCIM and length of stay. Logistic regression for outcome prediction was used. RESULTS: One hundred and sixty patients (113 men, 47 women) with a mean age of 64.4 years were included. Non-traumatic etiologies, such as vascular diseases, tumors, infections or degenerative diseases accounted for 55.6% of SCI (89/160). Men experienced significantly more cervical lesions (P=0.02) and presented with lower SCIMstart values (P=0.04). Patients with AIS D (incomplete SCI) had significantly higher SCIMstart and SCIMend (P<0.01, each). Age correlated negatively with SCIMstart and SCIMend (r=-0.21; P<0.05; r=-0.21; P<0.05; respectively). The chance to reach an SCIMend ?50 points (milestone for starting post-primary rehabilitation) increased with every SCIM point at the beginning of rehabilitation by 12.2% (95% CI 7.3-17.3%) and for every day in rehabilitation by 1.4% (95% CI 0.5-2.3%). Every additional day in acute medical care, however, decreased the chance for this by 2.2% (95% CI -3.6 to -0.8%). CONCLUSIONS: This is the first study giving outcomes for post-acute SCISR in Germany. The obtained data support that even in an older cohort, early admission to SCISR after SCI and longer LOSreha increases the chance for higher independence at the end of the rehabilitation period. PMID- 28890806 TI - Postlaminectomy membrane with dynamic spinal cord compression disclosed with computed tomographic myelography: a case report and literature review. AB - INTRODUCTION: It has been hypothesized that postoperative epidural scar, postlaminectomy membrane, may be responsible for late neurological deterioration after cervical laminectomy in some cases, but there is a lack of radiological studies in the literature showing the clinical significance of postlaminectomy membrane. We describe a rare case with radiological evidence of dynamic spinal cord compression caused by the postlaminectomy membrane, which may have been related to neurological deterioration. CASE PRESENTATION: A 73-year-old male developed recurrent cervical myelopathy 6 months after C4-C6 laminectomy. In addition to atlantoaxial subluxation and kyphotic deformity, dynamic spinal cord compression by the postlaminectomy membrane was identified on computed tomographic myelography. The patient underwent atlantoaxial fixation and C3-C7 posterior decompression and fixation combined with removal of the thick and firm postlaminectomy membrane adhering to the dura mater. Histopathological findings of the postlaminectomy membrane revealed chronic inflammation around exogenous materials, presumably surgical materials remaining after the first operation, in the thick fibrous tissue. The patient's symptoms improved without recurrence of symptoms and postlaminectomy membrane formation for 3 years. DISCUSSION: Compared with cervical laminoplasty, cervical laminectomy entails several postoperative problems, including postlaminectomy membrane formation. Postlaminectomy membranes may cause dynamic effects related to late neurological deterioration, and the evaluation of dynamic factors is important for neurological recurrence after cervical laminectomy. In the present case, chronic inflammation caused by surgical materials remaining after the first operation might have contributed to the rapid development of the postlaminectomy membrane. PMID- 28890807 TI - Social Network Decay as Potential Recovery from Homelessness: A Mixed Methods Study in Housing First Programming. AB - The positive relationship between social support and mental health has been well documented, but individuals experiencing chronic homelessness face serious disruptions to their social networks. Housing First (HF) programming has been shown to improve health and stability of formerly chronically homeless individuals. However, researchers are only just starting to understand the impact HF has on residents' individual social integration. The purpose of the current study was to describe and understand changes in social networks of residents living in a HF program. Researchers employed a longitudinal, convergent parallel mixed method design, collecting quantitative social network data through structured interviews (n = 13) and qualitative data through semi-structured interviews (n = 20). Quantitative results demonstrated a reduction in network size over the course of one year. However, increases in both network density and frequency of contact with network members increased. Qualitative interviews demonstrated a strengthening in the quality of relationships with family and housing providers and a shedding of burdensome and abusive relationships. These results suggest network decay is a possible indicator of participants' recovery process as they discontinued negative relationships and strengthened positive ones. PMID- 28890808 TI - The International Duration Evaluation of Adjuvant Chemotherapy study: implications for clinical practice. PMID- 28890809 TI - A single institute retrospective trial of concurrent chemotherapy with SIR Spheres(r) versus SIR-Spheres(r) alone in chemotherapy-resistant colorectal cancer liver metastases. AB - BACKGROUND: The use of selective internal radiation therapy with yttrium 90 resin microspheres (SIR-Spheres(r)) in chemotherapy-resistant colorectal cancer liver metastases has been associated with favorable progression-free survival (PFS) and overall survival when given alone or concurrently with chemotherapy. We conducted a single institute retrospective trial to explore the potential impact of SIR Spheres(r) with concurrent chemotherapy vs. SIR-Spheres(r) alone on liver PFS in patients with colorectal liver metastases (CRLM). METHODS: Patients with 5 fluorouracil-refractory CRLM treated with SIR-Spheres(r) between 2009 and 2014 were identified. Patients were excluded if they received any chemotherapy/targeted regimen following radioembolization on which they did not previously progress. This strategy was adopted to minimize the impact of post-SIR Spheres(r) systemic therapy bias on PFS. RESULTS: Twenty-seven patients satisfied inclusion criteria and were included in this analysis. Patients' demographics were similar between the two treatment arms, except for the median number of prior therapies. No associated >= grade 3 toxicities were noted. Liver disease control rates were 84% and 14% on the SIR-Spheres(r) plus chemotherapy arms and SIR-Spheres(r) alone arms, respectively (P=0.001). Median PFS in the liver was 176 days in the SIR-Spheres(r) plus chemotherapy group vs. 91 days in the SIR Sphere(r) alone group (P=0.0009). Median overall survival was 212 days in the SIR Spheres(r) plus chemotherapy group vs. 154 days in the SIR-Spheres(r) alone group (P=0.1023). CONCLUSIONS: In patients with 5-fluorouracil-refractory disease, SIR Spheres(r) plus chemotherapy is associated with an increased liver disease control rate and a prolonged liver PFS in comparison with SIR-Spheres(r) alone. PMID- 28890810 TI - Updated survival outcomes and analysis of long-term survivors from the MORE study on safety and efficacy of radioembolization in patients with unresectable colorectal cancer liver metastases. AB - BACKGROUND: The Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) study was a retrospective analysis of 606 patients with unresectable colorectal liver metastases treated with radioembolization (RE) using 90Y-labeled resin microspheres. The first analysis of this study was completed with a last patient follow-up of 77.7 months. We now provide an updated survival analysis through September 15, 2016, with a last patient follow-up of 125 months. METHODS: 90Y-RE was considered for patients with advanced liver-only or liver-dominant metastatic colorectal cancer which was deemed not suitable for surgery, ablation, or systemic therapy, and which had progressed or become refractory to at least one line of systemic therapy. All patients with a diagnosis of metastatic colorectal cancer who had received at least 1 RE treatment and 1 follow-up visit were included in the analysis. Patients were treated between July 2002 and December 2011 at one of 11 U.S. tertiary care centers. Data were collected at baseline, on the day of the first 90Y-RE treatment (day 0), and at all subsequent visits or until death. Patient medical charts and/or public records were accessed to obtain dates of death. RESULTS: Dates of death were obtained for 574 out of a total of 606 patients, and overall survival (OS) data analyzed. Updated median OS was 10.0 months (95% CI: 9.2-11.8 months) at a median follow-up of 9.5 months versus the originally reported median OS of 9.6 months (95% CI: 9.0-11.1 months) at a follow-up of 8.6 months in the first MORE analysis. Patients received a median (range) of 2 (0 to 6) lines of chemotherapy. Baseline characteristics and factors significantly associated with patient survival (P<0.01) are consistent with those reported in the first safety analysis of the MORE study. These factors include poor ECOG performance status, markers of advanced disease such as increased extent of tumor-to-target liver involvement, poor baseline liver function, pre-treatment anemia, lung shunt fraction, and number of lines of prior chemotherapy. Patient age did not significantly affect survival outcomes. CONCLUSIONS: Long-term follow-up confirms that 90Y-RE treatment offers favorable survival benefits for patients with unresectable metastatic colorectal cancer, even among patients who received 3 or more prior lines of chemotherapy. Our analysis also supports earlier reported prognostic factors for survival after 90Y-RE. Overall, our updated analysis confirms that 90Y-RE treatment provided a meaningful response and survival advantage for MORE patients across all ages and across diverse community and academic centers in the U.S. PMID- 28890811 TI - Tumor stage in patients operated for rectal cancer: a comparison of the pre operative MR and the resection specimen, with specific attention to the effect of neo-adjuvant radiotherapy. AB - BACKGROUND: Evaluate the preoperative TN stage with MR and the postoperative stage with histology. METHODS: Patients diagnosed with rectal cancer (2002-2015) and a pre-operative MR were included. A chart review was done. Pathology reports were evaluated for the post-operative tumor stage. Down staging was defined as a lower disease stage in the resection specimen compared with the pre-operative MR. Upgrading ("progression") was defined as a higher disease stage in the resection specimen. The study was approved by ethical committee of the Zaans Medisch Centrum. RESULTS: From 176 out of 231 operated patients a pre-operative MR was available for evaluation. 142 patients (80.7%) underwent neo-adjuvant treatment; the remainder 19.3% underwent immediate surgery. Neo-adjuvant therapy resulted in significant down staging. However, almost 14% of patients had a higher TN stage as determined by the pre-operative MR. In patients who underwent immediate surgery the percentage with "progression" was 30%. The number of patients with stage 1 and 2 were higher in the group not treated with neo-adjuvant therapy. There was no significant difference in tumor stage as determined by histological examination of the resection specimen. CONCLUSIONS: The diagnostic accuracy of the MR is not perfect. Underestimation as well as overestimation of the tumor occurred both in the patients treated with radiotherapy as well as those who underwent immediate operation. As such, MR results should be interpreted with caution when devising a treatment strategy. PMID- 28890812 TI - Cyclooxygenase-2 gene polymorphisms and susceptibility to colorectal cancer in a Brazilian population. AB - BACKGROUND: Multi-ethnicity of Brazilian population displays high levels of genomic diversity. Polymorphism may detect people at higher risk of developing cancer, distinctive response to treatment, and prognosis. Cyclooxygenase-2 (COX 2) is induced in response to growth factors and cytokines, and is expressed in inflammatory diseases, precancerous lesions and colorectal cancer (CRC). The aim of this study was to evaluate the influence of COX-2 -1195A > G and 8473T > C polymorphisms as a risk factor of developing CRC. METHODS: We evaluated COX-2 Single Nucleotide Polymorphism (SNP) of 230 CRC patients and 196 healthy controls by Real-Time Polymerase Chain Reaction. RESULTS: Populations were in Hardy Weinberg equilibrium (HWE), except for control group of 8473T > C SNP. The frequencies were similar in both groups for genotypes and haplotypes. There was no association between studied polymorphisms and risk of CRC. CONCLUSIONS: The gene polymorphisms studied do not participate in the genetic susceptibility to CRC in a Brazilian population. PMID- 28890813 TI - Endocuff assisted colonoscopy significantly increases sessile serrated adenoma detection in veterans. AB - BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer related deaths in the United States. Colonoscopy is the gold standard for the detection of CRC. There are many colonoscopy quality measures and among these the adenoma detection rate (ADR) has demonstrated a significant impact in reducing mortality from CRC. The primary aim of our study was to compare ADR and distribution of polyp type in patients undergoing Endocuff-assisted colonoscopy (EAC) versus standard colonoscopy (SC) in a VA system. METHODS: Retrospective data was collected from 496 patients who underwent routine screening, surveillance and diagnostic colonoscopies either via SC from January 6, 2014 through March 12, 2014 or EAC from September 24, 2014 through February 19, 2015. A total of 54 patients were excluded based on a personal history of CRC and prior resection, incomplete colonoscopy due to poor bowel preparation, and removal or loss of Endocuff (EC). Primary outcomes measured and compared were ADR and types of polyps found. RESULTS: The overall ADR in the EAC group was higher at 59.91% versus 50.66% for SC, accounting for a 9% increase (P=0.0508). EAC was able to detect a total of 59 sessile serrated adenoma/polyps (SSA/Ps) compared to SC only detecting 8 (P<=0.0001). There was a significant increase in the SSA/P detection rate with EAC at 15% versus 3% in the SC group (P<=0.0001). CONCLUSIONS: EAC significantly increases the detection of SSA/P and has shown a trend in improving ADR in our veteran population. PMID- 28890814 TI - Outcomes and complications of radiation therapy in patients with familial adenomatous polyposis. AB - BACKGROUND: The outcomes, complications, and rates of secondary malignancies from radiation therapy (RT) are not known for patients with familial adenomatous polyposis (FAP). METHODS: We queried the Hereditary Gastrointestinal Cancer Registry (HGCR) for patients with FAP who received RT. Outcomes assessed included acute and late treatment toxicity and secondary malignancies. RESULTS: We identified 15 patients undergoing 18 treatment courses. Median follow-up was 3.1 years after RT. Treated sites included rectal cancer, desmoid, prostate cancer, breast cancer, melanoma, medulloblastoma, gastric cancer, and glioma. Secondary tumors occurred in two patients: a medulloblastoma was diagnosed in a patient treated for glioma, and a desmoid tumor was diagnosed in a patient treated for rectal cancer. All nine patients treated with intra-abdominal or pelvic RT had prior prophylactic proctocolectomies, yet only one patient experienced grade 3 gastrointestinal toxicity. Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) toxicities were grade 1 in seven treatment courses (39%), grade 2 in five courses (28%), and grade 3 in two courses (11%). CONCLUSIONS: In this cohort, RT was well tolerated with adverse effects comparable with non-FAP patients. Secondary in-field tumors occurred in 2 of 15 patients and their increased risk in this cohort was likely due to prior predilection from FAP itself, although an increased role of RT cannot be ruled out. PMID- 28890815 TI - The role of neoadjuvant radiotherapy for locally-advanced rectal cancer with resectable synchronous metastasis. AB - BACKGROUND: Although neoadjuvant radiotherapy is typically administered for locally-advanced rectal cancer to reduce local recurrence (LR), its role for patients who present with synchronous resectable liver and/or lung metastasis is not well defined. The aim of this study was to evaluate the role of neoadjuvant radiotherapy for patients with stage IV rectal cancer undergoing curative-intent surgery. METHODS: This study is a retrospective review of a prospectively maintained surgical registry of all consecutive adult patients who underwent curative-intent resection at Mayo Clinic in Rochester, MN, from January 1990 until December 2014 with a median follow-up time of 43 (IQR 16-67) months. Eligible patients had locally-advanced rectal cancer (T3, T4 and/or nodal involvement) with synchronous resectable liver and/or lung metastasis. Exclusion criteria were as follows: patients with primary tumor stage of T1N0 or T2N0, patients with metastasis to organs other than the liver or lung, patients who had palliative resection, patients who had non-surgical treatment of synchronous metastasis (e.g., radiofrequency ablation), patients who received postoperative radiotherapy, or absence of research authorization. Ninety three patients were included of which 47 received neoadjuvant radiotherapy and 46 did not. All patients received neoadjuvant chemotherapy +/- radiotherapy followed by curative intent surgery with metastasectomy performed either simultaneously with resection of the primary tumor or as a planned staged resection. The primary outcomes of this study are LR, distant metastasis, overall and disease-specific survival (DSS). RESULTS: LR was observed in 12 patients (26%) who did not receive radiotherapy, while no LR developed in those who received neoadjuvant radiotherapy, P<0.001. Univariate analysis showed that neither age, sex, ASA class, BMI, tumor location, procedure performed, or neoadjuvant chemotherapy were associated with subsequent LR. The 5-year overall survival (OS) rates were: 43.3% (95% CI: 30.1, 62.3) for no radiotherapy vs. 58.3% (95% CI: 43.4, 78.2) with radiotherapy. CONCLUSIONS: Neoadjuvant radiotherapy should be considered in patients with locally-advanced stage IV rectal cancer. These data add to the evidence supporting neoadjuvant radiotherapy in the setting of resectable metastatic disease. PMID- 28890816 TI - Epidemiological profile of gastric cancer in the northwestern region of Algeria: about 116 cases. AB - BACKGROUND: Gastric cancer (GC) remains a public health issue despite the global incidence decrease over the last decades. GC is the third leading cause of cancer related death worldwide and stills of poor prognosis due to its late detection. The overall objective of our study was to describe the epidemiological, clinical, and histopathological aspects of stomach cancer. However, the specific purpose was to determine the gastric precancerous lesions among patients with histologically confirmed GC admitted at the gastroenterology department of the University Hospital of Sidi-Bel-Abbes city, Algeria. METHODS: We retrospectively analyzed the patients' medical records admitted from 2010 to 2015. Intended for the statistical analysis of the enrolled data, we executed Student t-test and Chi squared test, significance level was set at 5%. Histologic evidence objectified the biopsies performed during endoscopy; Hematoxylin and Eosin staining as well as the slides interpretation were executed at the level of the pathology department as a routine examination. RESULTS: 116 cases of GC were recorded. The mean age of the whole studied cohort was 58.96+/-14.75 years. We reported a sex ratio of 1.36 with a peak frequency observed in male gender (57.76%). Gastric precancerous lesions, as well as tumor histology, and topography were revealed. In our context, adenocarcinoma was significantly higher among male patients and linitis plastica was expressively related to female gender (P=0.01). CONCLUSIONS: Management of gastric precancerous lesions additionally to early diagnosis represent effective preventive and therapeutic methods of GC. PMID- 28890817 TI - Proton beam reirradiation for locally recurrent pancreatic adenocarcinoma. AB - BACKGROUND: Local recurrence following definitive treatment for pancreatic adenocarcinoma is common and can be associated with significant morbidity and mortality. Retreatment options for these patients are limited. Proton beam reirradiation (PRT) may limit dose and toxicity to previously irradiated normal tissues in patients without evidence of metastatic disease. METHODS: Between 8/2010-2/2015, 15 patients with isolated, locally-recurrent pancreatic cancer were treated with PRT. Acute toxicity was graded using CTC v 4.0 and defined as occurring within 90 days. Kaplan-Meier survival analysis was performed from the start of PRT. A log-rank test was used to compare survival with or without concurrent chemotherapy. RESULTS: Median follow-up was 15.7 months [2-48] from the start of PRT. The median clinical target volume (CTV) was 71 cc [15-200]. Ten (67%) patients received concurrent chemotherapy. Median PRT dose was 59.4 Gy (37.5-59.4 Gy). The median time interval from the prior treatment course was 26.7 months (7-461.3). There was a rate of 13% acute >= grade 3 toxicities attributed to PRT. The median overall survival (OS) was 16.7 months (95% CI, 4.7-36) and OS at 1 year was 67%. The "in-field" failure free survival at one year was 87%. The locoregional progression free survival (LPFS) and distant metastasis free survival (DMFS) at 1 year was 72% and 64% respectively. Concurrent chemotherapy was associated with a higher median survival. CONCLUSIONS: PRT was well tolerated, resulted in prolonged clinical outcomes compared to historical controls, and should be considered as a treatment option with concurrent chemotherapy in selected patients with locally-recurrent pancreatic cancer. PMID- 28890818 TI - Individualized 4-dimensional computed tomography proton treatment for pancreatic tumors. AB - BACKGROUND: The goal of this study is to determine whether a phase or reconstruction of a 10-phase 4 dimensional computed tomography (4D CT) scan can be used as the primary planning scan for proton treatment of the pancreas, thus eliminating the need for second a slow CT or free breathing CT. METHODS: Ten patients with pancreatic adenocarcinoma were simulated with 4D CT and a proton treatment plan generated based upon one of three primary planning scans, the T0 phase, T50 phase or average reconstruction. These plans were then exported to each of the remaining phases of the 4D CT and the dose to 95% of the target (D95) calculated. Plans were deemed adequate if the D95 remained at 99% of the prescribed dose or greater. RESULTS: For the ten patients in this study anterior abdominal motion was found to range from 2-27 mm (mean 7.50+/-6.79 mm). For 9 of 10 patients the anterior abdominal motion was <=8 mm and all three primary planning scans provided adequate target coverage, resulting in minimum D95 coverage per plan of T0_plan 99.7%, T50_plan 99.3% and AVE_plan 99%. However no plan provided adequate target coverage on the single patient with the largest anterior abdominal motion, 27 mm, and cranio-caudal motion, 20 mm, with minimum D95 values of T0_plan 96.3%, T50_plan 68%, and AVE_plan 68%. CONCLUSIONS: The primary plans tested based up on the T0, T50 and average reconstructions provided adequate D95 coverage throughout the respiratory cycle as long as the anterior abdominal motion was <=8 mm and can be considered for use as the primary proton planning scan. PMID- 28890819 TI - The role of induction chemotherapy + chemoradiotherapy in localised pancreatic cancer: initial experience in Scotland. AB - BACKGROUND: Despite being relatively rare pancreatic cancer is one of the highest causes of death. Even within the potentially resectable group outcomes are poor. We present our initial experiences utilising a neoadjuvant approach to localised pancreatic cancer, evaluating survival, response rates and tolerability. METHODS: This was a retrospective analysis of a prospectively maintained database. Patients from 2012 to 2015 referred to a busy regional Hepato-Pancreatic Biliary (HPB) MDT were included. Patients were classified according to respectability criteria (utilising NCCN guidelines) and a treatment plan agreed. Systemic therapy with either FOLFIRINOX or Gem/Cap was delivered followed by chemoradiotherapy if disease remained localised. Toxicity, response, pathological outcomes and survival were all recorded. RESULTS: A total of 85 patients were included in the study: 45 had initially resectable disease; 19 required a response for resection and 21 had locally advanced inoperable disease; 34 patients underwent resection. The median survival for the potentially resectable group was 22.2 months while for those undergoing resection it was 37 months. CONCLUSIONS: We have demonstrated that a neoadjuvant approach is deliverable and tolerable. In addition we have demonstrated impressive survival results in patients undergoing resection with no detriment in outcome for those not proceeding to surgery. PMID- 28890820 TI - A margin distance analysis of the impact of adjuvant chemoradiation on survival after pancreatoduodenectomy for pancreatic adenocarcinoma. AB - BACKGROUND: The role of adjuvant chemoradiotherapy (CRT) following pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDA) remains controversial. Recent data suggest that increased margin clearance (MC: distance between tumor and cut surface) is associated with improved survival after PD, but the role of adjuvant CRT in patients with known MC is undefined. We sought to delineate the impact of adjuvant CRT on survival based on MC following PD. METHODS: Patients who underwent PD for PDA between 2002 and 2014 were retrospectively stratified into three groups based on MC: 0 mm, <=1 mm, and >1 mm. The impact of CRT on survival in each MC group was determined by univariate and multivariate analysis. RESULTS: Three hundred and ten patients with known MC were analyzed (0 mm =67, <=1 mm =113, and >1 mm =130). Increasing MC was independently associated with improved OS (<=1 mm, HR 0.66, 95% CI 0.46-0.96, P=0.03; >1 mm, HR 0.51, 95% CI 0.35-0.75, P=0.001; compared to 0 mm). Adjuvant CRT was administered to 62 patients (20%). On margin-stratified multivariate analysis, adjuvant CRT was independently associated with increased OS in patients with <=1 mm margins (HR 0.36; 95% CI 0.18-0.69, P=0.002) but not for 0 mm and >1 mm margins. CONCLUSIONS: This analysis suggests that the benefit of adjuvant CRT may be restricted to patients with <=1 mm MC after PD for pancreatic cancer. PMID- 28890821 TI - Feasibility and reproducibility of substituting oral contrast with water for duodenal volume delineation in patients undergoing pancreatic stereotactic body radiotherapy. AB - BACKGROUND: This is the first known report evaluating the feasibility of substituting oral contrast with water in efforts to delineate the duodenum for pancreatic stereotactic body radiotherapy (SBRT). METHODS: From January 2015 to August 2016, 13 patients were simulated after ingestion of 8 ounces of water approximately 15-20 min prior to their simulation scan. We examined the feasibility of contouring the duodenum thereafter, and measured the duodenal volume as well as its variation. Comparison was made to 40 patients treated from January 2009 to February 2012 on a prospective trial who used oral contrast. Group comparisons were performed by the Mann-Whitney U test. RESULTS: The duodenum was identified in all 13 patients who used water instead of oral contrast without subjective difficulty. In this group, the median duodenal volume was 72.86 cm3 (range, 44.61-130.90 cm3). In the oral contrast group, median duodenal volume was 86.21 cm3 (range, 50.11-157.89 cm3) There were no significant differences between groups (P=0.115). The approach was reproducible, as all patients were able to drink the same amount of water 15-20 min prior to each SBRT fraction to keep duodenal volumes subjectively similar to volumes on the simulation CT scan. CONCLUSIONS: This novel approach is effective and reproducible in delineating the duodenum for treatment planning and daily setup. PMID- 28890822 TI - Utilization and trends in palliative therapy for stage IV pancreatic adenocarcinoma patients: a U.S. population-based study. AB - BACKGROUND: Pancreatic adenocarcinoma is an aggressive malignancy, with most patients diagnosed with advanced or metastatic disease. Palliative therapies comprise an important, but underutilized, aspect of care. This aim of this study was to characterize the trends, factors, and outcomes associated with utilization of palliative therapies. METHODS: Patients with stage IV pancreatic adenocarcinoma from the 2003-2011 U.S. National Cancer Database were identified and stratified by receipt of palliative therapy. Linear regression, multivariable logistic regression, and survival analyses using multivariate proportional hazards models were performed. RESULTS: Sixty-eight thousand and seventy-five patients with stage IV disease were identified, of which only 11,449 (16.8%) underwent designated palliative therapy. The majority received systemic chemotherapy (37.2%), followed by surgery (19.0%), pain management alone (15.3%), radiation (8.1%), referral alone (11.7%), or a combination thereof (8.7%). Utilization of palliative therapies increased from 12.9% in 2003 to 19.2% in 2011 (P<0.001). Patients were less likely to undergo palliation when older than 60 (OR 0.89, P<0.001), or of black or Hispanic race (OR 0.83, P<0.001; OR 0.80, P<0.001, respectively, vs. Caucasians). Presence of comorbidities increased the use of palliative therapy (OR 1.16 per comorbidity, P<0.001). Survival was improved in those receiving palliative systemic chemotherapy (HR 0.55, P<0.001) and palliative surgery (HR 0.94, P<0.001), although this may be due to selection bias. CONCLUSIONS: Despite the continued dismal prognosis of pancreatic cancer, palliation of symptoms remains underutilized in this country, particularly in non Caucasian, older patients. Increased awareness of palliative options may help increase its utilization. PMID- 28890823 TI - Does lymphocyte-to-monocyte ratio before, during, or after definitive chemoradiation for locally advanced pancreatic cancer predict for clinical outcomes? AB - BACKGROUND: Elevated pre-treatment lymphocyte (L) to monocyte (M) ratio (LMR) in peripheral blood has been suggested to correlate with improved survival in some malignancies, but data in the context of pancreatic cancer (PC) is limited. The aim of this study was to evaluate the prognostic significance of LMR before, during and after definitive chemoradiotherapy (CRT) for locally advanced pancreatic cancer (LAPC). METHODS: We retrospectively reviewed 57 patients with LAPC treated with definitive CRT at a single institution from 2005 to 2013. Complete blood counts were obtained before (TP1), during the third week (TP2) and at the end of CRT (TP3). Univariate analysis (UVA) included gender, age, body mass index, pre-treatment CA19-9, T stage, N stage, induction chemotherapy (ICT), absolute L count (TP1, TP2, TP3), absolute M count (TP1, TP2, TP3), LMR (TP1, TP2, TP3), and relative LMR changes (TP2 / TP1, TP3 / TP1, TP3 / TP2). RESULTS: Median follow-up was 14 months. Twelve patients received ICT. Median LMR was 2.7 (range, 0.8-5.25), 1.4 (range, 0.3-5) and 0.98 (range, 0.3-3.4) at TP1, TP2 and TP3, respectively. Superior PFS was significantly associated with an absolute M count during CRT <0.1 (P=0.04) while pre-CRT L count >=1.1 trended towards significance (P=0.09). Superior OS was significantly associated with change in LMR (TP3 / TP2) > 0.32 (P<0.0001) while pre-CRT LMR >=2.6 trended towards significance (P=0.06). CONCLUSIONS: Factors significantly associated with overall survival (OS) and progression-free survival (PFS) were change in LMR at the end of CRT and absolute M count during CRT. This analysis suggests treatment-time specific immune system parameters may affect clinical outcomes and warrant continued investigation. PMID- 28890824 TI - Gemcitabine and capecitabine for advanced biliary cancer. AB - BACKGROUND: Gemcitabine with capecitabine (gem-cap) is an established regimen for advanced biliary cancer (ABC) supported by our previously reported phase II trial. Here, we provide our updated experience. METHODS: Single institution, retrospective study from 2005 to 2015 of ABC treated with gem-cap. RESULTS: A total of 372 patients with ABC were identified, of whom 227 (61.0%) were treated with chemotherapy. 153 patients (67.4%) received gem-cap, of which 129 (56.8%) received it in the first line. Thirty two point six percent (42/129) were locally advanced, 67.4% (87/129) had metastatic disease, and 18.6% (24/129) received it as adjuvant therapy. Disease sites included 48.8% [63] intrahepatic cholangiocarcinoma (IHCC), 24.0% [31] extrahepatic cholangiocarcinoma (EHCC) and 27.1% [35] gallbladder carcinoma (GBC). Median follow-up was 49.7 months (mo). The median PFS and OS were 8.0 mo [95% confidence intervals (CI): 6.0-9.3] and 13.0 mo (95% CI: 10.7-17.4), respectively. Overall, 53.5% (69/129) experienced a grade 3/4 toxicity. The most common (35.7%) was a hematologic toxicity (neutropenia or thrombocytopenia) followed by infection (25.6%). CONCLUSIONS: Gem cap provides similar survival outcomes to gemcitabine/cisplatin based on historical comparison to the ABC-2 trial (median PFS =8.0 mo and OS =11.7 mo). Gem-cap may offer the advantage of fewer adverse events compared to the levels reported in ABC-2 (grade 3/4 events 70.7%). PMID- 28890825 TI - Splenectomy is an independent risk factor for poorer perioperative outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: an analysis of 936 procedures. AB - BACKGROUND: There is a paucity of data on the impact of splenectomy on peri operative outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We report the largest series to date which addresses this topic. METHODS: Nine hundred and thirty six consecutive patients underwent CRS/HIPEC from 1996 to 2016 at a high-volume institution in Sydney, Australia. Of these, 418 (45%) underwent splenectomy. Peri-operative complications were graded according to the Clavien-Dindo Classification. The association of splenectomy with 19 peri-operative outcomes was assessed using univariate and multivariate analyses. RESULTS: In-hospital mortality was 1.8%. Patients undergoing splenectomy had a higher disease burden (peritoneal cancer index >=17) (71% vs. 22%, P<0.001) and underwent a longer operation (>=9 hours) (73% vs. 34%, P<0.001). Even after accounting for confounding factors, splenectomy was independently associated with an increased risk of grade III/IV morbidity [relative risk (RR), 1.94; 95% confidence interval (CI), 1.29-2.91; P=0.01], infective complications (RR, 1.63; 95% CI, 1.09-2.44; P=0.018), pancreatic leak (RR, 5.2; 95% CI, 1.81-14.89, P=0.002) and intra-abdominal collection (RR, 1.86; 95% CI, 1.23-2.84, P=0.004). It was also an independent risk factor for long hospital stay (>=28 days) (RR, 1.98; 95% CI, 1.25-3.11; P=0.003). Splenectomy was not associated with in-hospital mortality (RR, 1.68; 95% CI, 0.32-9.32, P=0.556). CONCLUSIONS: Splenectomy is an independent risk factor for poorer peri-operative outcomes. Minimizing the likelihood of inadvertent splenic injury through careful dissection and routine vaccination can improve outcomes. PMID- 28890826 TI - Mutational burden on circulating cell-free tumor-DNA testing as a surrogate marker of mismatch repair deficiency or microsatellite instability in patients with colorectal cancers. PMID- 28890828 TI - Radiation induced gastroparesis-case report and literature review. AB - Radiation induced gastroparesis as well as the other autonomic nervous system radiation induced neuropathies are poorly described in the literature. A case of gastroparesis associated with phrenic and recurrent laryngeal nerves paralysis was observed in a 69-year old patient. She was already treated two times by rachis radiotherapy in a context of breast cancer with bone metastases. Anatomical and chronological correlation of lesions, concomitant nerve damage in the radiation fields and elimination of the main differential diagnoses allowed us to link this case of gastroparesis with the background of radiotherapy. It confirms the role of vagus nerve lesion in radiation induced gastroparesis. This specific diagnosis led to a successful treatment and a quality of life improvement. PMID- 28890827 TI - Primary pancreatic lymphoma: what we need to know. AB - Hodgkin's lymphoma is a group of malignant lymphoid which involve various organs including gastrointestinal tract. Stomach and small intestine are commonly involved more; however, pancreas can be primarily involved as well. The secondary involvement of pancreas caused by Hodgkin's lymphoma is more prevalent than the primarily involvement (1 .25-2.2% vs. <1%). Primary pancreatic lymphomas (PPLs) consist of 1-2% of all lymphoma outside nods. The symptoms and findings of PPL imaging can be akin to that of pancreas adenocarcinoma and differentiating them is difficult without examining the tissue sample. The prognosis and treatment of PPL are different from those of adenocarcinoma and due to the superior prognosis of PPL compared to pancreas adenocarcinoma, the proper diagnosis of the disease is important. PMID- 28890829 TI - A rare case of primary rectal squamous cell carcinoma diagnosed by endoscopic ultrasound. AB - Primary squamous cell carcinoma (SCC) of the rectum is a very rare entity making up to 0.1-0.25/1,000 cases of all colorectal cancers. Here, we present the case of an otherwise healthy 63-year-old female who presented with progressive pelvic discomfort, new onset constipation and a complex mass in presacral region on imaging which was proved to be poorly differentiated SCC of the rectum. The correct diagnosis was achieved by fine needle aspiration (FNA) via endoscopic ultrasound (EUS-guided FNA) as initial conventional colonoscopy failed to establish the diagnosis. Patient completed neoadjuvant chemo-radiation and her tumor was successfully resected. She is following up with oncology clinic for monitoring and further management. PMID- 28890830 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy combined with two-stage hepatectomy for multiple and bilobar desmoplastic small round cell tumor liver metastases. AB - Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal tumor usually affecting young patients. Local dissemination is common, and liver is the most common site for extraperitoneal metastases. Multimodal management has been shown to be the most effective treatment. Some authors consider liver metastases especially bi-lobar disease as a contraindication for surgical resection. We present a case of a DSRCT with bi-lobar metastases in an adult patient who underwent multi-modal management along with hepatectomy. A 51-year-old man was found to have a large intraperitoneal mass with bi-lobar liver metastases during work up for new onset reflux and abdominal pain. Biopsy confirmed it as DSRCT. The patient was treated with multi-modal therapy including cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), two-stage hepatectomy (TSHP) combined with (90Y) Yittrium-90 radioembolization of the right hepatic lobe and systemic chemotherapy. The patient had a right-sided pleural empyema one month after the surgery for which he required right-sided video-assisted thoracoscopy and decortication. He remains disease free at 2 years follow-up. DSRCT with bi-lobar liver metastases are best managed with multimodal therapy. TSHP seems to be a feasible and safe option in selected cases, with a potentially good outcome. PMID- 28890831 TI - Effects of central fibroblast growth factor 21 and irisin in anxiety-like behavior. AB - Adipose tissue and skeletal muscle are organs capable of secreting many bioactive molecules, such as adipomiokines that could be possibly involved in mood disorders. In the present work, we investigated the possible behavioral effects of a single intracerebroventricular (i.c.v.) injection of two adipomiokines, fibrobroblast growth factor (FGF)-21 (0.5-5.0 ug) and irisin (0.4-0.6 ug), in male rats tested in the open field and elevated plus maze tests. Prefrontal cortex levels of norepinephrine (NE), dopamine (DA) and serotonin (5 hydroxytryptamine, 5-HT) and the gene expression of catechol-O-methyltransferase (COMT), dopamine transport (DAT) and tyrosine hydroxylase (TH), were measured by high performance liquid chromatography (HPLC) analysis and real-time reverse transcription polymerase chain reaction (RT-PCR). Both FGF-21 and irisin administration induced anxiogenic behavior, increased DA levels in prefrontal cortex, decreased COMT, DAT and increased TH gene expression. In conclusion, in the present study we demonstrated behavioral effects induced by central FGF-21 and irisin injections that could involve increased DA signaling in the prefrontal cortex. PMID- 28890832 TI - Obesity Might Be a Predictor of Weight Reduction after Smoking Cessation. AB - BACKGROUND AND OBJECTIVES: Approximately one in five ex-smokers reduces or maintains weight after smoking cessation but little is known about who succeeds to avoid weight gain. The purpose of this study was to identify predictors of weight reduction after long-term smoking cessation in a general population. METHODS: Data was obtained from two Danish population-based cohorts (the Inter99 and the Helbred2006 study). Anthropometric measurements were performed by trained research staff. Out of 3.577 daily smokers at baseline 317 participants had quit smoking at the five-year follow-up for at least one year. Multiple logistic regression analysis was performed to determine predictors of weight reduction. RESULTS: Thirteen percent reduced weight by at least 1 kg and 4% maintained their weight. Quitters with obesity had more than seven times higher odds than normal weight quitters to lose weight (OR 7.13 (95% CI 2.76-19.71)), and they had the largest median weight loss of 4.45 kg. The only other significant predictor of weight reduction was low tobacco consumption at baseline. CONCLUSIONS: Predictors of weight reduction after smoking cessation were high body mass index and low tobacco consumption at baseline. This study might motivate smokers with obesity to quit smoking and health professionals to give them support. PMID- 28890833 TI - Gender, Success, and Drop-Out during a Resistance Exercise Program in Community Dwelling Old Adults. AB - BACKGROUND: Resistance exercise training can be effective against sarcopenia. We identified predictors of drop-out and compared physical outcomes between men and women after such training. METHODS: Subjects (N = 236, 73.7 +/- 5.7 years) participated in a 12-week resistance exercise program. Outcome variables were measured at baseline and endpoint. RESULTS: Drop-out was 11.9% and not significantly different between genders. Drop-outs were significantly older and had poorer strength and physical function in comparison to completers. Anthropometrics, QoL, and cognitive function were not related to drop-out. According to multivariate analysis, gait speed and physical activity were the strongest predictors of drop-out. After the training, gains in lean mass or appendicular muscle were significantly higher in men than women; however relative gains in appendicular muscle as well as absolute improvements in strength and function were similar in men and women, respectively. CONCLUSIONS: Participants who drop out are older, have poorer physical function, and are less physically active. Old women do not drop out more frequently than men and show meaningful improvements in relevant outcomes similar to men after such a training program. The trial is registered at the US National Library of Medicine (NCT01074879). PMID- 28890834 TI - The Use of a Novel Heart Failure Agent in the Treatment of Pregnancy-Associated Cardiomyopathy. AB - Peripartum cardiomyopathy is an uncommon, pregnancy-related form of dilated cardiomyopathy that is associated with development of new-onset left ventricular dysfunction. Its etiology is presently unknown, but current standard of care involves the use of typical drug therapy for the treatment of heart failure. Pregnancy-associated cardiomyopathy (PACM) is a similar condition that refers to patients who develop such symptoms prior to the last month of pregnancy. We report the case of a nulliparous Caucasian female who develops early, severe PACM during her first pregnancy with postpartum persistence of New York Heart Association class II-III symptoms despite medical therapy. The use of the novel heart failure agent, sacubitril/valsartan (Entresto), is initiated with near complete resolution of her symptoms. PMID- 28890835 TI - Ponatinib as a Valid Alternative Strategy in Patients with Blast Crisis-Chronic Myeloid Leukemia Not Eligible for Allogeneic Stem Cells Transplantation and/or Conventional Chemotherapy: Report of a Case. AB - Currently, imatinib and dasatinib are the only tyrosine-kinase inhibitors approved in the US and Europe for the treatment of blast crisis of chronic myeloid leukemia (BC-CML) at diagnosis, while ponatinib is the only inhibitor used in patients bearing T315I mutation. Here we report the case of a 61-year-old man diagnosed with B-cell lymphoid BC-CML, initially treated with imatinib 800 mg day and then with dasatinib 140 mg day because of intolerance. A complete cytogenetic response (CCyR) was achieved at three months; however, three months later a relapse was observed, and the T315I mutation was detected. Ponatinib 45 mg once daily was then started together with a short course of chemotherapy. Bone marrow evaluation after six months of therapy showed the regaining of CCyR, together with the achievement of a deep molecular response. However, one year from ponatinib start the patient experienced a new disease relapse; he was effectively treated with ponatinib and chemotherapy once again, but in the meanwhile an ischemic stroke was detected. This case report confirms the high efficacy of ponatinib monotherapy in BC-CML patients, representing a valid option for non-allogeneic stem cells transplantation eligible cases and the only one available for those carrying the T315I mutation. PMID- 28890836 TI - New Diagnosis of AIDS Based on Salmonella enterica subsp. I (enterica) Enteritidis (A) Meningitis in a Previously Immunocompetent Adult in the United States. AB - Salmonella meningitis is a rare manifestation of meningitis typically presenting in neonates and the elderly. This infection typically associates with foodborne outbreaks in developing nations and AIDS-endemic regions. We report a case of a 19-year-old male presenting with altered mental status after 3-day absence from work at a Wisconsin tourist area. He was febrile, tachycardic, and tachypneic with a GCS of 8. The patient was intubated and a presumptive diagnosis of meningitis was made. Treatment was initiated with ceftriaxone, vancomycin, acyclovir, dexamethasone, and fluid resuscitation. A lumbar puncture showed cloudy CSF with Gram negative rods. He was admitted to the ICU. CSF culture confirmed Salmonella enterica subsp. I (enterica) Enteritidis (A). Based on this finding, a 4th-generation HIV antibody/p24 antigen test was sent. When this returned positive, a CD4 count was obtained and showed 3 cells/mm3, confirming AIDS. The patient ultimately received 38 days of ceftriaxone, was placed on elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya) for HIV/AIDS, and was discharged neurologically intact after a 44-day admission. PMID- 28890837 TI - Why It Is Not Always Anxiety: A Tough Diagnosis of Stiff Person Syndrome. AB - Anxiety disorder is a commonly used diagnosis that may mask underlying conditions. Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by progressive rigidity and painful muscle spasms affecting axial and lower extremity musculature. These episodes can be triggered by sudden movement, noise, or emotional stress, which may present as a psychiatric condition. We report the case of a 30-year-old female who presented with recurrent panic attacks with multiple prior hospital admissions for anxiety, rigidity, and difficulty in walking. Previous electroencephalogram (EEG) and brain and cervical spine magnetic resonance imaging (MRI) were unremarkable. She was empirically treated with diazepam and beta-blockers for SPS, which was confirmed by positive glutamic acid decarboxylase (GAD) antibodies. The patient's symptoms became refractory to benzodiazepines and required steroids with intravenous immunoglobulin (IVIG). Her rigidity subsequently responded to plasmapheresis. In SPS, antibodies in the cerebrospinal fluid (CSF) most commonly target the GAD antigen on gamma-aminobutyric acid (GABA) neurons. The goal of treatment is to ameliorate symptoms and improve quality of life. Our case of SPS was masked as generalized anxiety disorder for at least six years since onset of symptoms. The criteria for both diagnoses may overlap as seen in this patient. PMID- 28890838 TI - Adenocarcinoma Ex Goblet Cell Carcinoid of Appendix: Two Case Reports. AB - Adenocarcinoma ex goblet cell carcinoid is a rare tumor incidentally found in specimens of appendicitis. Most patients present with acute abdomen, similar to acute appendicitis. Here we present two cases, which were found incidentally after operation. We give a brief summary about clinical and biological behavior of this entity. PMID- 28890839 TI - DPM dispersion inside a single straight entry using dynamic mesh model. AB - Three-dimensional simulations of diesel particulate matter (DPM) distribution inside a single straight entry for the Load-Haul-Dump loader (LHD)-truck loading and truck hauling operations were conducted by using ANSYS FLUENT computational fluid dynamics software. The loading operation was performed for a fixed period of 3 min. The dynamic mesh technique in FLUENT was used to study the impact of truck motion on DPM distribution. The resultant DPM distributions are presented for the cases when the truck were driving upstream and downstream of the loading face. Interesting phenomena were revealed in the study including the piston effect, layering of DPM in the roof region, and backflow of diesel exhaust against ventilation. The results from the simulation can be used to determine if the areas inside the face area and straight entry exceed the current U.S. regulatory requirement for DPM concentration (>160 ug/m3). This research can guide the selection of DPM reduction strategies and improve the working practices for the underground miners. PMID- 28890840 TI - ERRalpha regulates the growth of triple-negative breast cancer cells via S6K1 dependent mechanism. AB - Estrogen-related receptor alpha (ERRalpha) is an orphan nuclear factor that is a master regulator of cellular energy metabolism. ERRalpha is overexpressed in a variety of tumors, including ovarian, prostate, colorectal, cervical and breast, and is associated with a more aggressive tumor and a worse outcome. In breast cancer, specifically, high ERRalpha expression is associated with an increased rate of recurrence and a poor prognosis. Because of the common functions of ERRalpha and the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis, we focused on investigating the biochemical relationship between ERRalpha and S6K1. We found that ERRalpha negatively regulates S6K1 expression by directly binding to its promoter. Downregulation of ERRalpha expression sensitized ERalpha-negative breast cancer cells to mTORC1/S6K1 inhibitors. Therefore, our results show that combinatorial inhibition of ERRalpha and mTORC1/S6K1 may have clinical utility in treatment of triple-negative breast cancer, and warrants further investigation. PMID- 28890841 TI - Predictive Filtering in Motion Compensation with Steerable Cardiac Catheters. AB - Robotic cardiac catheterization using ultrasound (US) imaging catheters provides real time imaging from within the heart while reducing the difficulty in manually steering a four degree-of-freedom (4-DOF) catheter. Accurate robotic catheter navigation in the heart is challenging due to a variety of disturbances including cyclical physiological motions, such as respiration. In this work we compensate for respiratory motion by using an Extended Kalman Filter (EKF) to predict target motion and by applying the predictions to steer the US imaging catheter. The system performance was measured in bench top experiments with phantom vasculature. The robotic system with predictive filtering tracked cyclically moving targets with 1.59 mm and 0.72 degrees mean error. Accurately tracking moving structures can improve intra-procedural treatments and visualization. PMID- 28890842 TI - Catalytic Mechanisms for Cofactor-Free Oxidase-Catalyzed Reactions: Reaction Pathways of Uricase-Catalyzed Oxidation and Hydration of Uric Acid. AB - First-principles quantum mechanical/molecular mechanical (QM/MM)-free energy calculations have been performed to uncover how uricase catalyzes metabolic reactions of uric acid (UA), demonstrating that the entire reaction process of UA in uricase consists of two stages-oxidation followed by hydration. The oxidation consists of four steps: (1) chemical transformation from 8-hydroxyxythine to an anionic radical via a proton transfer along with an electron transfer, which is different from the previously proposed electron-transfer mechanism that involves a dianion intermediate (UA2-) during the catalytic reaction process; (2) proton transfer to the O2- anion (radical); (3) diradical recombination to form a peroxo intermediate; (4) dissociation of H2O2 to generate the dehydrourate. Hydration, for the most favorable pathway, is initiated by the nucleophilic attack of a water molecule on dehydrourate, along with a concerted proton transfer through residue Thr69 in the catalytic site. According to the calculated free energy profile, the hydration is the rate-determining step, and the corresponding free energy barrier of 16.2 kcal/mol is consistent with that derived from experimental kinetic data, suggesting that the computational insights into the catalytic mechanisms are reasonable. The mechanistic insights not only provide a mechanistic base for future rational design of uricase mutants with improved catalytic activity against uric acid as an improved enzyme therapy, but also are valuable for understanding a variety of other cofactor-free oxidase-catalyzed reactions involving an oxygen molecule. PMID- 28890843 TI - Magnetic Resonance Imaging Evidence for Human Immunodeficiency Virus Effects on Central Auditory Processing: A Review. AB - New research suggests that individuals with human immunodeficiency virus (HIV) have central auditory processing deficits. To review the evidence for HIV affecting parts of the central nervous system involved in central auditory processing, we performed a systematic review of the literature. The objective was to determine whether existing studies show evidence for damage to structures associated with central auditory pathways in HIV. We searched PubMed for papers that used structural magnetic resonance imaging (MRI), diffusion tensor imaging, magnetic resonance spectroscopy or functional MRI in individuals infected with HIV. The review showed that HIV affects several areas involved in central auditory processing particularly the thalamus, internal capsule and temporal cortex. These findings support the idea that HIV can affect central auditory pathways and support the potential use of central auditory tests as a way to assess central nervous system effects of HIV. PMID- 28890844 TI - Evaluation of Silicon Phthalocyanine 4 Photodynamic Therapy Against Human Cervical Cancer Cells In Vitro and in Mice. AB - BACKGROUND: Cervical cancer is the second most common cancer in women worldwide [1]. Photodynamic therapy has been used for cervical intraepithelial neoplasia with good responses, but few studies have used newer phototherapeutics. We evaluated the effectiveness of photodynamic therapy using Pc 4 in vitro and in vivo against human cervical cancer cells. METHODS: CaSki and ME-180 cancer cells were grown as monolayers and spheroids. Cell growth and cytotoxicity were measured using a methylthiazol tetrazolium assay. Pc 4 cellular uptake and intracellular distrubtion were determined. For in vitro Pc 4 photodynamic therapy cells were irradiated at 667nm at a fluence of 2.5 J/cm2 at 48 h. SCID mice were implanted with CaSki and ME-180 cells both subcutaneously and intracervically. Forty-eight h after Pc 4 photodynamic therapy was administered at 75 and 150 J/cm2. RESULTS: The IC50s for Pc 4 and Pc 4 photodynamic therapy for CaSki and ME 180 cells as monolayers were, 7.6MUM and 0.016MUM and >10MUM and 0.026MUM; as spheroids, IC50s of Pc 4 photodynamic therapy were, 0.26MUM and 0.01MUM. Pc 4 was taken up within cells and widely distributed in tumors and tissues. Intracervical photodynamic therapy resulted in tumor death, however mice died due to gastrointestinal toxicity. Photodynamic therapy resulted in subcutaneous tumor death and growth delay. CONCLUSIONS: Pc 4 photodynamic therapy caused death within cervical cancer cells and xenografts, supporting development of Pc 4 photodynamic therapy for treatment of cervical cancer. Support: P30-CA47904, CTSI BaCCoR Pilot Program. PMID- 28890845 TI - Comorbidities of Atopic Dermatitis: Beyond Rhinitis and Asthma. AB - PURPOSE OF REVIEW: In this review article, we summarize the current evidence about atopic dermatitis (AD)-associated comorbidities, beyond the traditional atopic and allergic conditions. RECENT FINDINGS: Patients with AD may have an increased risk of cardiovascular diseases, certain malignancies, autoimmune diseases, and neuropsychiatric diseases. The causes of these associations are likely multifactorial and may include genetic predispositions, systemic low-grade inflammation, environmental exposures, medication, and lifestyle and behavioral risk factors. There appears to be geographical variations in prevalence of comorbidities in patients with AD, indicating that differences in ethnicity and lifestyle factors may significantly influence the risk of certain comorbidities. SUMMARY: The reported comorbidities in recent literature emphasize the burden of disease in patients with AD. Early appropriate AD therapy, in combination with reduction of risk factors, may help prevention of certain comorbidities. The reported observations may generate hypotheses for future investigations in underlying risk factors for AD-associated comorbidities. PMID- 28890846 TI - Prediction of endoplasmic reticulum resident proteins using fragmented amino acid composition and support vector machine. AB - BACKGROUND: The endoplasmic reticulum plays an important role in many cellular processes, which includes protein synthesis, folding and post-translational processing of newly synthesized proteins. It is also the site for quality control of misfolded proteins and entry point of extracellular proteins to the secretory pathway. Hence at any given point of time, endoplasmic reticulum contains two different cohorts of proteins, (i) proteins involved in endoplasmic reticulum specific function, which reside in the lumen of the endoplasmic reticulum, called as endoplasmic reticulum resident proteins and (ii) proteins which are in process of moving to the extracellular space. Thus, endoplasmic reticulum resident proteins must somehow be distinguished from newly synthesized secretory proteins, which pass through the endoplasmic reticulum on their way out of the cell. Approximately only 50% of the proteins used in this study as training data had endoplasmic reticulum retention signal, which shows that these signals are not essentially present in all endoplasmic reticulum resident proteins. This also strongly indicates the role of additional factors in retention of endoplasmic reticulum-specific proteins inside the endoplasmic reticulum. METHODS: This is a support vector machine based method, where we had used different forms of protein features as inputs for support vector machine to develop the prediction models. During training leave-one-out approach of cross-validation was used. Maximum performance was obtained with a combination of amino acid compositions of different part of proteins. RESULTS: In this study, we have reported a novel support vector machine based method for predicting endoplasmic reticulum resident proteins, named as ERPred. During training we achieved a maximum accuracy of 81.42% with leave-one-out approach of cross-validation. When evaluated on independent dataset, ERPred did prediction with sensitivity of 72.31% and specificity of 83.69%. We have also annotated six different proteomes to predict the candidate endoplasmic reticulum resident proteins in them. A webserver, ERPred, was developed to make the method available to the scientific community, which can be accessed at http://proteininformatics.org/mkumar/erpred/index.html. DISCUSSION: We found that out of 124 proteins of the training dataset, only 66 proteins had endoplasmic reticulum retention signals, which shows that these signals are not an absolute necessity for endoplasmic reticulum resident proteins to remain inside the endoplasmic reticulum. This observation also strongly indicates the role of additional factors in retention of proteins inside the endoplasmic reticulum. Our proposed predictor, ERPred, is a signal independent tool. It is tuned for the prediction of endoplasmic reticulum resident proteins, even if the query protein does not contain specific ER-retention signal. PMID- 28890848 TI - Urbanization alters communities of flying arthropods in parks and gardens of a medium-sized city. AB - Urbanization transforms undeveloped landscapes into built environments, causing changes in communities and ecological processes. Flying arthropods play important roles in these processes as pollinators, decomposers, and predators, and can be important in structuring food webs. The goal of this study was to identify associations between urbanization and the composition of communities of flying (and floating) arthropods within gardens and parks in a medium-sized mesic city. We predicted that flying arthropod abundance and diversity would respond strongly to percent impervious surface and distance to city center, measurements of urbanization. Flying arthropods were sampled from 30 gardens and parks along an urbanization gradient in Toledo, Ohio, during July and August 2016, using elevated pan traps. A variety of potential predictor variables were also recorded at each site. We collected a total of 2,369 individuals representing nine orders. We found that flying arthropod community composition was associated with percent impervious surface and canopy cover. Overall flying arthropod abundance was negatively associated with percent impervious surface and positively associated with distance to city center. Hymenoptera (bees, wasps, ants), Lepidoptera (moths, butterflies), and Araneae (spiders) were positively associated with distance to city center. Hemiptera (true bugs), Diptera (flies), and Araneae were negatively associated with percent impervious surface. Both distance to city center and percent impervious surface are metrics of urbanization, and this study shows how these factors influence flying arthropod communities in urban gardens and city parks, including significant reductions in taxa that contain pollinators and predators important to urban agriculture and forestry. A variety of environmental factors also showed significant associations with responses (e.g. canopy cover and soil moisture), suggesting these factors may underlie or modulate the urbanization effects. More research is needed to determine mechanisms of change. PMID- 28890849 TI - Trophic analysis of the fish community in the Cienega Churince, Cuatro Cienegas, Coahuila. AB - Fish diets were analyzed to evaluate the dynamic trophs of the fish community in the Churince wetland system of the Cuatro Cienegas, where the fauna consists of nine species: endemic, native and introduced. In nine sampling events (between February 2011 and May 2014) 556 specimens of all nine species were collected. Stomach contents were analyzed and the Relative Importance Index (IRI) was calculated. The feed coefficient (Q) of the diets and the accumulated trophic diversity (Hk), as well as the amplitude of the trophic niche were evaluated. Feeding strategies in the fish community were found to be eurifagic. The main foods in general were insects, crustaceans, gastropods, plants and teleosts. According to the average linkage method, four functional trophic groups were defined, with no higher consumption species; nevertheless all were regulators, mainly invertebrates. Therefore, the chain reaction in food control was higher from top to bottom, meaning a downwards dietary control. PMID- 28890847 TI - The contribution of Nintendo Wii Fit series in the field of health: a systematic review and meta-analysis. AB - BACKGROUND: Wii Fit was originally designed as a health and fitness interactive training experience for the general public. There are, however, many examples of Wii Fit being utilized in clinical settings. This article aims to identify the contribution of Wii Fit in the field of health promotion and rehabilitation by: (1) identifying the health-related domains for which the Wii Fit series has been tested, (2) clarifying the effect of Wii Fit in those identified health-related domains and (3) quantifying this effect. METHOD: A systematic literature review was undertaken. The MEDLINE database and Games for Health Journal published content were explored using the search term "Wii-Fit." Occurrences resulting from manual searches on Google and material suggested by experts in the field were also considered. Included articles were required to have measurements from Wii Fit activities for at least one relevant health indicator. The effect of Wii Fit interventions was assessed using meta-analyses for the following outcomes: activity-specific balance confidence score, Berg balance score (BBC) and time-up and-go test (TUG). FINDINGS: A total of 115 articles highlighted that the Wii Fit has been tested in numerous healthy and pathological populations. Out of these, only a few intervention studies have focused on the prevention of chronic diseases. A large proportion of the studies focus on balance training (N = 55). This systematic review highlights several potential benefits of Wii Fit interventions and these positive observations are supported by meta-analyses data (N = 25). For example, the BBC and the TUG respond to a similar extend to Wii Fit interventions compared with traditional training. CONCLUSION: Wii Fit has the potential to be used as a rehabilitation tool in different clinical situations. However, the current literature includes relatively few randomized controlled trials in each population. Further research is therefore required. PMID- 28890850 TI - Minimum infusion rate and adrenocortical function after continuous infusion of the novel etomidate analog ET-26-HCl in rats. AB - BACKGROUND: Because etomidate induces prolonged adrenal suppression, even following a single bolus, its use as an infused anesthetic is limited. Our previous study indicated that a single administration of the novel etomidate analog methoxyethyletomidate hydrochloride (ET-26-HCl) shows little suppression of adrenocortical function. The aims of the present study were to (1) determine the minimum infusion rate of ET-26-HCl and compare it with those for etomidate and cyclopropyl-methoxycarbonylmetomidate (CPMM), a rapidly metabolized etomidate analog that is currently in clinical trials and (2) to evaluate adrenocortical function after a continuous infusion of ET-26-HCl as part of a broader study investigating whether this etomidate analog is suitable for long infusion in the maintenance of anesthesia. METHOD: The up-and-down method was used to determine the minimum infusion rates for ET-26-HCl, etomidate and CPMM. Sprague-Dawley rats (n = 32) were then randomly divided into four groups: etomidate, ET-26-HCl, CPMM, and vehicle control. Rats in each group were infused for 60 min with one of the drugs at its predetermined minimum infusion rate. Blood samples were drawn initially and then every 30 min after drug infusion to determine the adrenocorticotropic hormone-stimulated concentration of serum corticosterone as a measure of adrenocortical function. RESULTS: The minimum infusion rates for etomidate, ET-26-HCl and CPMM were 0.29, 0.62, and 0.95 mg/kg/min, respectively. Compared with controls, etomidate decreased serum corticosterone, as expected, whereas serum corticosterone concentrations following infusion with the etomidate analogs ET-26-HCl or CPMM were not significantly different from those in the control group. CONCLUSION: The corticosterone concentrations tended to be reduced for the first hour following ET-26-HCl infusion (as compared to vehicle infusion); however, this reduction did not reach statistical significance. Thus, further studies are warranted examining the practicability of using ET-26-HCl as an infused anesthetic. PMID- 28890851 TI - Stress responses to conspecific visual cues of predation risk in zebrafish. AB - Chemical communication relating to predation risk is a trait common among fish species. Prey fish under threat of predation can signal risk to conspecific fish, which then exhibit defensive responses. Fish also assess predation risk by visual cues and change their behavior accordingly. Here, we explored whether these behavioral changes act as visual alarm signals to conspecific fish that are not initially under risk. We show that shoals of zebrafish (Danio rerio) visually exposed to a predator display antipredator behaviors. In addition, these defensive maneuvers trigger antipredator reactions in conspecifics and, concomitantly, stimulate the hypothalamus-pituitary-interrenal axis, leading to cortisol increase. Thus, we conclude that zebrafish defensive behaviors act as visual alarm cues that induce antipredator and stress response in conspecific fish. PMID- 28890852 TI - Growth, stoichiometry and cell size; temperature and nutrient responses in haptophytes. AB - Temperature and nutrients are key factors affecting the growth, cell size, and physiology of marine phytoplankton. In the ocean, temperature and nutrient availability often co-vary because temperature drives vertical stratification, which further controls nutrient upwelling. This makes it difficult to disentangle the effects of temperature and nutrients on phytoplankton purely from observational studies. In this study, we carried out a factorial experiment crossing two temperatures (13 degrees and 19 degrees C) with two growth regimes (P-limited, semi-continuous batch cultures ["-P"] and nutrient replete batch cultures in turbidostat mode ["+P"]) for three species of common marine haptophytes (Emiliania huxleyi, Chrysochromulina rotalis and Prymnesium polylepis) to address the effects of temperature and nutrient limitation on elemental content and stoichiometry (C:N:P), total RNA, cell size, and growth rate. We found that the main gradient in elemental content and RNA largely was related to nutrient regime and the resulting differences in growth rate and degree of P-limitation, and observed reduced cell volume-specific content of P and RNA (but also N and C in most cases) and higher N:P and C:P in the slow growing -P cultures compared to the fast growing +P cultures. P-limited cells also tended to be larger than nutrient replete cells. Contrary to other recent studies, we found lower N:P and C:P ratios at high temperature. Overall, elemental content and RNA increased with temperature, especially in the nutrient replete cultures. Notably, however, temperature had a weaker-and in some cases a negative-effect on elemental content and RNA under P-limitation. This interaction indicates that the effect of temperature on cellular composition may differ between nutrient replete and nutrient limited conditions, where cellular uptake and storage of excess nutrients may overshadow changes in resource allocation among the non-storage fractions of biomass (e.g. P-rich ribosomes and N-rich proteins). Cell size decreased at high temperature, which is in accordance with general observations. PMID- 28890853 TI - Preferences for achromatic horizontal, vertical, and square patterns in zebrafish (Danio rerio). AB - The zebrafish (Danio rerio) is gaining popularity as a laboratory organism and is used to model many human diseases. Many behavioural measures of locomotion and cognition have been developed that involve the processing of visual stimuli. However, the innate preference for vertical and horizontal stripes in zebrafish is unknown. We tested the preference of adult zebrafish for three achromatic patterns (vertical stripes, horizontal stripes, and squares) at three different size conditions (1, 5, and 10 mm). Each animal was tested once in a rectangular arena, which had a different pattern of the same size condition on the walls of either half of the arena. We show that zebrafish have differential preferences for patterned stimuli at each of the three size conditions. These results suggest that zebrafish have naive preferences that should be carefully considered when testing zebrafish in paradigms using visual stimuli. PMID- 28890854 TI - Quantitative comparison of the spreading and invasion of radial growth phase and metastatic melanoma cells in a three-dimensional human skin equivalent model. AB - BACKGROUND: Standard two-dimensional (2D) cell migration assays do not provide information about vertical invasion processes, which are critical for melanoma progression. We provide information about three-dimensional (3D) melanoma cell migration, proliferation and invasion in a 3D melanoma skin equivalent (MSE) model. In particular, we pay careful attention to compare the structure of the tissues in the MSE with similarly-prepared 3D human skin equivalent (HSE) models. The HSE model is identically prepared to the MSE model except that melanoma cells are omitted. Using the MSE model, we examine melanoma migration, proliferation and invasion from two different human melanoma cell lines. One cell line, WM35, is associated with the early phase of the disease where spreading is thought to be confined to the epidermis. The other cell line, SK-MEL-28, is associated with the later phase of the disease where spreading into the dermis is expected. METHODS: 3D MSE and HSE models are constructed using human de-epidermised dermis (DED) prepared from skin tissue. Primary fibroblasts and primary keratinocytes are used in the MSE and HSE models to ensure the formation of a stratified epidermis, with a well-defined basement membrane. Radial spreading of cells across the surface of the HSE and MSE models is observed. Vertical invasion of melanoma cells downward through the skin is observed and measured using immunohistochemistry. All measurements of invasion are made at day 0, 9, 15 and 20, providing detailed time course data. RESULTS: Both HSE and MSE models are similar to native skin in vivo, with a well-defined stratification of the epidermis that is separated from the dermis by a basement membrane. In the HSE and MSE we find fibroblast cells confined to the dermis, and differentiated keratinocytes in the epidermis. In the MSE, melanoma cells form colonies in the epidermis during the early part of the experiment. In the later stage of the experiment, the melanoma cells in the MSE invade deeper into the tissues. Interestingly, both the WM35 and SK-MEL-28 melanoma cells lead to a breakdown of the basement membrane and eventually enter the dermis. However, these two cell lines invade at different rates, with the SK-MEL-28 melanoma cells invading faster than the WM35 cells. DISCUSSION: The MSE and HSE models are a reliable platform for studying melanoma invasion in a 3D tissue that is similar to native human skin. Interestingly, we find that the WM35 cell line, that is thought to be associated with radial spreading only, is able to invade into the dermis. The vertical invasion of melanoma cells into the dermal region appears to be associated with a localised disruption of the basement membrane. Presenting our results in terms of time course data, along with images and quantitative measurements of the depth of invasion extends previous 3D work that has often been reported without these details. PMID- 28890855 TI - Effects of tire leachate on the invasive mosquito Aedes albopictus and the native congener Aedes triseriatus. AB - Discarded vehicle tire casings are an important artificial habitat for the developmental stages of numerous vector mosquitoes. Discarded vehicle tires degrade under ultraviolet light and leach numerous soluble metals (e.g., barium, cadmium, zinc) and organic substances (e.g., benzothiazole and its derivatives [BZTs], polyaromatic hydrocarbons [PAHs]) that could affect mosquito larvae that inhabit the tire casing. This study examined the relationship between soluble zinc, a common marker of tire leachate, on mosquito densities in tire habitats in the field, and tested the effects of tire leachate on the survival and development of newly hatched Aedes albopictus and Aedes triseriatus larvae in a controlled laboratory dose-response experiment. In the field, zinc concentrations were as high as 7.26 mg/L in a single tire and averaged as high as 2.39 (SE +/- 1.17) mg/L among tires at a single site. Aedes albopictus (37/42 tires, 81.1%) and A. triseriatus (23/42, 54.8%) were the most widespread mosquito species, co occurred in over half (22/42, 52.4%) of all tires, and A. triseriatus was only collected without A. albopictus in one tire. Aedes triseriatus was more strongly negatively associated with zinc concentration than A. albopictus, and another common mosquito, C. pipiens, which was found in 17 tires. In the laboratory experiment, A. albopictus per capita rate of population change (lambda') was over 1.0, indicating positive population growth, from 0-8.9 mg/L zinc concentration (0 10,000 mg/L tire leachate), but steeply declined to zero from 44.50-89.00 mg/L zinc (50,000-100,000 mg/L tire leachate). In contrast, A. triseriatus lambda' declined at the lower concentration of 0.05 mg/L zinc (100 mg/L tire leachate), and was zero at 0.45, 8.90, 44.50, and 89.00 mg/L zinc (500, 10,000, 50,000 and 100,000 mg/L tire leachate). These results indicate that tire leachate can have severe negative effects on populations of container-utilizing mosquitoes at concentrations commonly found in the field. Superior tolerance to tire leachate of A. albopictus compared to A. triseriatus, and possibly other native mosquito species, may have facilitated the replacement of these native species as A. albopictus has invaded North America and other regions around the world. PMID- 28890856 TI - The semi-aquatic pondweed bugs of a Cretaceous swamp. AB - Pondweed bugs (Hemiptera: Mesoveliidae), considered a sister group to all other Gerromorpha, are exceedingly rare as fossils. Therefore, each new discovery of a fossil mesoveliid is of high interest, giving new insight into their early evolutionary history and diversity and enabling the testing of their proposed relationships. Here, we report the discovery of new mesoveliid material from Spanish Lower Cretaceous (Albian) amber, which is the first such find in Spanish amber. To date, fossil records of this family only include one species from French Kimmeridgian as compression fossils, two species in French amber (Albian Cenomanian boundary), and one in Dominican amber (Miocene). The discovery of two males and one female described and figured as Glaesivelia pulcherrima Sanchez Garcia & Solorzano Kraemer gen. et sp. n., and a single female described and figured as Iberovelia quisquilia Sanchez-Garcia & Nel, gen. et sp. n., reveals novel combinations of traits related to some genera currently in the subfamily Mesoveliinae. Brief comments about challenges facing the study of fossil mesoveliids are provided, showing the necessity for a revision of the existing phylogenetic hypotheses. Some of the specimens were studied using infrared microscopy, a promising alternative to the systematic study of organisms preserved in amber that cannot be clearly visualised. The new taxa significantly expand the fossil record of the family and shed new light on its palaeoecology. The fossils indicate that Mesoveliidae were certainly diverse by the Cretaceous and that numerous tiny cryptic species living in humid terrestrial to marginal aquatic habitats remain to be discovered. Furthermore, the finding of several specimens as syninclusions suggests aggregative behaviour, thereby representing the earliest documented evidence of such ethology. PMID- 28890857 TI - How long should the fully hillside-closed forest protection be implemented on the Loess Plateau, Shaanxi, China? AB - BACKGROUND: Restoration of degraded forest ecosystem is crucial for regional sustainable development. To protect the country's fragile and fragmented environment, the Chinese government initiated an ecological engineering project, the Natural Forest Protection Program, in seventeen provinces in China beginning in 1998. Fully hillside-closed forest protection (vegetation restoration naturally without any artificial disturbance) was one of vital measures of the Natural Forest Protection Program applied nation wide. Whether plant diversity, biomass and age structure of dominant tree species and soil nutrients in protected stands may become better with increase of protected period are still open problems. METHODS: We investigated community diversity, biomass of dominant tree species, age structures, and analyzed soil chemical properties of a Pinus tabulaeformis population at protected sites representing different protected ages at Huanglongshan Forest Bureau on the Loess Plateau, Shaanxi, China. RESULTS: Plant species richness of Pinus tabulaeformis community was significantly affected (p < 0.05) by forest protection and the effect attenuated with protection age. Shannon evenness index of plant species generally increased with protection age. Stands protected for 45 years had the highest tree biomass and considerable natural regeneration capacity. Contents of organic carbon, available phosphorus and available potassium in top soil increased in protected stands less than 45 years, however decreased significantly thereafter. Long-term forest protection also decreased the content of mineral nitrogen in top soil. DISCUSSION: We found that the richness of shrubs and herbs was significantly affected by forest protection, and evenness indices of tree, shrub and herb increased inconsistently with protected ages. Forest protection created more complex age structures and tree densities with increasing age of protection. Content of soil mineral nitrogen at 0-20 cm soil depth showed a decreasing trend in stands of up to 30 years. Soil available phosphorus and potassium contents were higher in stands with greater proportions of big and medium trees. Long-term protection (>45 years) of Pinus tabulaeformis stands in southeast Loess Plateau, China, may be associated with decreasing plant species richness, proportion of medium to large trees, dominant biomass of Pinus tabulaeformis and soil nutrients. PMID- 28890858 TI - Extrapolation of Efficacy in Pediatric Drug Development and Evidence-based Medicine: Progress and Lessons Learned. AB - BACKGROUND: "Complete Extrapolation" of efficacy from adult or other pediatric data, to the pediatric population, is an important scientific tool that reduces the need for pediatric efficacy trials. Dose finding and safety studies in pediatrics are still needed. "No Extrapolation" requires 2 pediatric efficacy trials. "Partial Extrapolation" eliminates the need to conduct 2 pediatric efficacy trials; 1 efficacy or exposure/response study may be sufficient. We examined pediatric extrapolation from 2009 to 2014 evaluating any changes in extrapolation assumptions and the causes for these changes since a prior analysis published in 2011. METHODS: We reviewed all 157 products with 388 pediatric studies submitted to the FDA from 2009 through 2014. We assessed whether efficacy was extrapolated from adult or other pediatric data and categorized extrapolation as Complete, Partial, or No, and identified the reasons for the changes. RESULTS: Partial extrapolation decreased, whereas use of No and Complete extrapolation noticeably increased. Complete, Partial, or No extrapolations changed from 14%, 68%, and 18% in the 2011 study to 34%, 29%, and 37% respectively in the current study. The changes were mostly due to a better understanding of pediatric pathophysiology, why trials have failed, and improved endpoints. CONCLUSIONS: Evolving science and data obtained from clinical trials increases the certainty of extrapolation assumptions and drives decisions to utilize extrapolation. Lessons learned from the conduct of these trials are critical to improving evidence-based medicine. Extrapolation of Efficacy is a powerful scientific tool that streamlines pediatric product development. Increased knowledge and evolving science inform utilization of this tool. PMID- 28890859 TI - Association of aescin with beta- and gamma-cyclodextrins studied by DFT calculations and spectroscopic methods. AB - Background: Aescin, a natural mixture of saponins occurring in Aesculus hippocastanum, exhibits important flebotonic properties, being used in the treatment of chronic venous insufficiency in legs. The inclusion of aescin into cyclodextrins (CDs) is a technical solution for its incorporation into the textile of stockings, but details of the physicochemistry of these host-guest systems are lacking. This work investigates the inclusion of aescin into the cavities of two native cyclodextrins, beta-CD and gamma-CD. Results: The continuous variation method applied to aqueous-phase 1H nuclear magnetic resonance (1H NMR) has demonstrated that the preferred CD/aescin inclusion stoichiometries are 2:1 with beta-CD and 1:1 with gamma-CD. The affinity constant calculated for gamma-CD.aescin was 894 M-1, while for 2beta-CD.aescin it was estimated to be 715 M-1. Density functional theory (DFT) calculations on the interaction of aescin Ib with CDs show that an inclusion can indeed occur and it is further demonstrated that the wider cavity of gamma-CD is more adequate to accommodate this large guest. ROESY spectroscopy is consistent with the formation of a complex in which the triterpenic moiety of aescin is included into the cavity of gamma-CD. The higher stability of this geometry was confirmed by DFT. Furthermore, DFT calculations were applied to determine the chemical shifts of the protons H3 and H5 of the CDs in the optimised structures of the inclusion complexes. The calculated values are very similar to the experimental data, validating the approach made in this study by NMR. Conclusion: The combination of experimental data from aqueous-state NMR measurements and theoretical calculations has demonstrated that gamma-CD is the most suitable host for aescin, although the inclusion also occurs with beta-CD. The geometry of the gamma CD.aescin complex is characterised by the inclusion of the triterpene segment of aescin into the host cavity. PMID- 28890860 TI - Why do young adults gamble online? A qualitative study of motivations to transition from social casino games to online gambling. AB - The present research examined the mechanisms of initiating online gambling among young adults. Of particular interest was whether social casino gaming was noted as part of young adults' experience with online gambling. This is because there is growing concern that social casino gaming may be a 'gateway' to online gambling. Three focus groups (N = 21) were conducted with young adult online gamblers from two large Canadian Universities. Participants noted the role of peer influence as well as incentives (e.g., sign up bonuses) as important factors that motivated them to start engaging in online gambling. Participants also noted a link between social casino games and online gambling. Specifically, several young adults reported migrating to online gambling within a relatively short period after engaging with social casino games. Potential mechanisms that may lead to the migration from social casino games to online gambling included the role of advertisements and the inflated pay out rates on these free to play gambling like games. The results suggest initiatives to prevent the development of disordered gambling should understand the potential of social casino gaming to act as a gateway to online gambling, especially amongst this vulnerable population. PMID- 28890861 TI - Idiopathic Anaphylaxis. AB - Idiopathic anaphylaxis is a rare life-threatening disorder with symptoms similar to other forms of anaphylaxis. There is lack of a robust evidence base underpinning the treatment of anaphylaxis and even less so for idiopathic anaphylaxis. Much of the evidence therefore comes from relatively small case series and expert opinion. Idiopathic anaphylaxis is a diagnosis of exclusion, requiring a thorough history and careful diagnostic work-up investigating possible triggers and underlying predisposing factors. Key diagnostic tests include skin-prick testing, tests for specific-IgE, component-resolved diagnostics, and in some cases for allergen challenge tests. Other recognized causes of anaphylaxis, such as foods, medications, insect stings, latex, and exercise, should all be considered, as should differential diagnoses such as asthma. While the cause of idiopathic anaphylaxis remains unknown, prompt treatment with intramuscular epinephrine (adrenaline) administered into the anterolateral aspect of the thigh is associated with good prognosis. There may also be a role for H1-antihistamines and corticosteroids as second-line agents. Patients need to be carefully monitored for signs of deterioration and/or a possible protracted or biphasic reaction. Patients with frequent episodes of anaphylaxis (e.g., six or more episodes/year) should be considered for preventive therapy, which may include corticosteroids, H1- and H2-antihistamines, and, in some cases, mast cell stabilizers such as ketotifen. Alternative immune suppressants (e.g., methotrexate) and anti-IgE may rarely also need to be considered. In many cases, the frequency of anaphylaxis declines such that regular use of corticosteroids can be discontinued after 9-12 months. Pediatric patients should be treated with similar regimens as adults, but with appropriate dose adjustments. Patients should carry their self-injectable epinephrine and other emergency medications at all times in order to deal with emergency situations. PMID- 28890862 TI - Where is the difference between an epidemic and a high endemic level with respect to nosocomial infection control measures? An analysis based on the example of vancomycin-resistant Enterococcus faecium in hematology and oncology departments. AB - Some infection control recommendations distinguish epidemic and endemic levels for infection control. However, it is often difficult to separate long lasting outbreaks from high endemic levels and it remains open, if this distinction is really useful. Aim: To compare infection control measures in endemic and epidemic outbreaks. Methods: The example of vancomycin-resistant Enterococcus faecium outbreaks in haematology or oncology departments was used to analyse differences in infection control measures between outbreaks and high endemic levels. The outbreak database and PubMed, including long lasting outbreaks, were used for this analysis. Two time limits were used for separation: 6 and 12 months. In addition, monoclonal and polyclonal outbreaks were distinguished. Findings: A total of 36 outbreaks were included. 13 outbreaks lasted 6 months or less, 9 outbreaks more than 6 months but at maximum 12 months and 9 more than 12 months. For the remaining outbreaks, no information about their duration was available. Altogether, 11 outbreaks were monoclonal and 20 polyclonal. Considering infection control measures, there were almost no differences between the different groups compared. Patient screening was given up in 37.5% of long lasting outbreaks (>12 months) and hand hygiene not reported in the majority of polyclonal outbreaks (77.8%). Conclusion: Despite many institutions trying to add further infection control measures in case of an outbreak, evidence based infection control measures should be implemented in endemic and epidemic situations. The crucial aspect is probably the degree of implementation and its control in both situations. PMID- 28890863 TI - Enhanced viscoelastic property of iron oxide nanoparticle decorated organoclay fluid under magnetic field. AB - Stable hydrophobic nanocomposites of magnetic nanoparticles and clay are prepared by the self-assembly of magnetite (Fe3O4) nanoparticles on surfaces of exfoliated clay platelets. Due to the attractive interaction between hydrophobic groups, oleic acid coated nanoparticles are strongly attached to the surface of cetyl trimethylammonium cation coated clay platelets in organic media. Crystal structure and magnetic property of composite particles are examined using electron microscopy, x-ray diffractometer and vibration sample magnetometer. In addition, composite particles are dispersed in mineral oil and rheological properties of composite particle suspensions are characterized using steady-state and oscillatory measurements. Magnetite nanoparticle decorated organoclay forms a tunable network in mineral oil. When a magnetic field is applied, the composite particle fluid exhibits higher storage modulus and maintains a solid-like property at larger strain. Our results show that the viscoelastic property of the magnetite nanoparticle decorated organoclay fluid is controlled by applying external magnetic field. PMID- 28890864 TI - Germ soak water as nutrient source to improve fermentation of corn grits from modified corn dry grind process. AB - Corn fractionation in modified dry grind processes results in low fermentation efficiency of corn grits because of nutrient deficiency. This study investigated the use of nutrient-rich water from germ soaking to improve grits fermentation in the conventional dry grind and granular starch hydrolysis (GSH) processes. Comparison of germ soak water with the use of protease and external B-vitamin addition in improving grits fermentation was conducted. Use of water from optimum soaking conditions (12 h at 30 degrees C) resulted in complete fermentation with 29 and 8% higher final ethanol yields compared to that of control in conventional and GSH process, respectively. Fermentation rate (4-24 h) of corn grits with germ soak water (0.492 v/v-h) was more than double than that of control (0.208 v/v-h) in case of conventional dry grind process. The soaking process also increased the oil concentration in the germ by about 36%, which would enhance its economic value. PMID- 28890865 TI - Functional Imaging of Paragangliomas with an Emphasis on Von Hippel-Lindau Associated Disease: A Mini Review. AB - Few reports have presented data and results on functional (i.e., nuclear medicine) imaging of paragangliomas and pheochromocytomas (PGLs/PHEOs) for von Hippel-Lindau (VHL) patients. Nuclear medicine localization modalities for chromaffin tumors can be specific or nonspecific. Specific methods make use of the expression of the human norepinephrine transporter (hNET) and vesicular monoamine transporters (VMATs) by these tumors. These permit the use of radiolabeled ligands that enter the synthesis and storage pathway of catecholamines. Nonspecific methods are not related to the synthesis, uptake, or storage of catecholamines but make use of the tumors' high glucose metabolism or expression of somatostatin receptors. Consensuses and guidelines suggest that metastatic and sporadic PHEOs/PGLs in VHL patients (as in patients with chromaffin tumors of yet unknown genotype) should be evaluated first with 18F dihydroxyphenylalanine (18F-DOPA) positron emission tomography/computed tomography (PET/CT). The functional imaging of second choice is 123I metaiodobenzylguanidine (123I-MIBG) for PHEOs in VHL patients. 123I-MIBG, 68Ga DOTATATE/DOTATOC/DOTANOC PET/CT, or 18F-fluorodeoxyglucose (18F-FDG) PET/CT can be a second choice of functional imaging for PGLs in VHL patients. PMID- 28890866 TI - Improving Brain Delivery of Biomolecules via BBB Modulation in Mouse and Rat: Detection using MRI, NIRF, and Mass Spectrometry. AB - There is an urgent need to develop new and alternative methods to deliver functional biomolecules to the brain for diagnosis and treatment of brain diseases. The goal of this study was to evaluate the activity of blood-brain barrier (BBB) modulators (i.e., HAV and ADT peptides) to deliver functional biomolecules (i.e., galbumin, IRdye800cw-cLABL, and cIBR7) to the brains of mice and rats. HAV6, cHAVc3, and ADTC5 peptides but not HAV4 peptide significantly enhanced the brain delivery of 65 kDa galbumin compared to control in Balb/c mice as quantified by magnetic resonance imaging (MRI). Ten-minute pretreatment with ADTC5 peptide still significantly increased brain delivery of galbumin; however, no enhancement was observed after 10-min pretreatment with HAV6. There was no enhancement of galbumin deposition following 40-min pretreatment with ADTC5 or HAV6, suggesting a short duration of the BBB opening for large molecules. ADTC5 peptide also improved the brain delivery of IRdye800cw-cLABL peptide about 3.5 fold compared to control in Balb/c mice as detected by near infrared fluorescence (NIRF). The BBB modulator activity of ADTC5 to deliver cIBR7 peptide was also evaluated in vivo using Sprague-Dawley rats. The amount of cIBR7 in the brain was detected by LC-MS/MS. ADTC5 peptide enhanced the delivery of cIBR7 peptide into rat brain about 4-fold compared to control and the intact cIBR7 can be efficiently extracted and detected in rat brain. In conclusion, HAV and ADT peptides enhance the brain delivery of functional peptides (e.g., cLABL and cIBR7) and protein (e.g., 65 kDa galbumin) in two animal models, and the duration of the BBB opening for a large molecule (e.g., galbumin) was short. PMID- 28890867 TI - Impaired interval timing and spatial-temporal integration in mice deficient in CHL1, a gene associated with schizophrenia. AB - Interval timing is crucial for decision-making and motor control and is impaired in many neuropsychiatric disorders, including schizophrenia - a neurodevelopmental disorder with a strong genetic component. Several gene mutations, polymorphisms or rare copy number variants have been associated with schizophrenia. L1 cell adhesion molecules (L1CAMs) are involved in neurodevelopmental processes, and in synaptic function and plasticity in the adult brain. Mice deficient in the Close Homolog to L1 (CHL1) adhesion molecule show alterations of hippocampal and thalamo-cortical neuroanatomy as well as deficits in sensorimotor gating and exploratory behavior. We analyzed interval timing and attentional control of temporal and spatial information in male CHL1 deficient (KO) mice and wild type (WT) controls. In a 20-s peak-interval timing procedure (standard and reversed), KO mice showed a maintained leftward shift of the response function relative to WT, indicative of a deficit in memory encoding/decoding. In trials with 2, 5, or 10-s gaps, KO mice shifted their peak times less than WT controls at longer gap durations, suggesting a decreased (attentional) effect of interruptions. In the spatial-temporal task, KO mice made more working and reference memory errors than controls, suggestive of impaired use of spatial and/or temporal information. When the duration spent on the central platform of the maze was manipulated, WT mice showed fewer spatial errors at the trained duration than at shorter or longer durations, indicative of discrimination based upon spatial-temporal integration. In contrast, performance was similar at all tested durations in KO mice, indicative of control by spatial cues, but not by temporal cues. These results suggest that CHL1 KO mice selectively attend to the more relevant cues of the task, and fail to integrate more complex spatial-temporal information, possibly as a result of reduced memory capacity related to hippocampal impairment, and altered temporal-integration mechanisms possibly due to thalamo-cortical anomalies. PMID- 28890869 TI - Multifunctional biomimetic spinal cord: New approach to repair spinal cord injuries. AB - The incidence of spinal cord injury (SCI) has been gradually increasing, and the treatment has troubled the medical field all the time. Primary and secondary injuries ultimately lead to nerve impulse conduction block. Microglia and astrocytes excessively accumulate and proliferate to form the glial scar. At present, to reduce the effect of glial scar on nerve regeneration is a hot spot in the research on the treatment of SCI. According to the preliminary experiments, we would like to provide a new bionic spinal cord to reduce the negative effect of glial scar on nerve regeneration. In this hypothesis we designed a new scaffold that combine the common advantage of acellular scaffold of spinal cord and thermosensitive gel, which could continue to release exogenous basic fibroblast growth factor (BFGF) in the spinal lesion area on the basis of BFGF modified thermosensitive gel. Meanwhile, the porosity, pore size and material of the gray matter and white matter regions were distinguished by an isolation layer, so as to induce the directed differentiation of cells into the defect site and promote regeneration of spinal cord tissue. PMID- 28890871 TI - Type 2 versus type 1 myocardial infarction: a comparison of clinical characteristics and outcomes with a meta-analysis of observational studies. AB - BACKGROUND: Type 2 myocardial infarction (MI) is an imbalance between myocardial oxygen demand and supply, leading to myocardial ischemia. It is not due to plaque rupture, and is usually caused by a condition other than coronary artery disease (CAD). However, limited data are available comparing the prevalence of traditional coronary risk factors and mortality between type 1 and type 2 MI. We hypothesize that type 2 MI carries a higher mortality than type 1. METHODS: We searched the databases of PubMed, EMBASE, CENTRAL, and MEDLINE for studies comparing type 1 MI with type 2 MI. The baseline variables were compared in each cohort. Summary risk ratios and 95% confidence intervals were calculated using the random effects model to compare mortality between the two groups. RESULTS: The included studies yielded 25,872 patients of whom 2,683 (10%) had type 2 MI. Compared to the type 1 cohort, the type 2 cohort had significantly higher inpatient (15% vs. 4.7%, P<0.00001), 30-day (17.6% vs. 5.3%, P<0.00001) and 1-yr mortality (27% vs. 13%, P<0.00001), as well as higher 30-day major adverse cardiovascular events (20% vs. 9%, P<0.0001). Operative stress (20%) was the most common trigger of type 2 MI, followed by sepsis (19%), arrhythmia (18.63%), heart failure (15%), and anemia (12%). CONCLUSIONS: Type 2 MI is a common entity and is more common in females, older age groups, and in patients with multiple comorbidities: it also tends to result in higher mortality. PMID- 28890868 TI - Surgical and immune reconstitution murine models in bone marrow research: Potential for exploring mechanisms in sepsis, trauma and allergy. AB - Bone marrow, the vital organ which maintains lifelong hemopoiesis, currently receives considerable attention, as a source of multiple cell types which may play important roles in repair at distant sites. This emerging function, distinct from, but closely related to, bone marrow roles in innate immunity and inflammation, has been characterized through a number of strategies. However, the use of surgical models in this endeavour has hitherto been limited. Surgical strategies allow the experimenter to predetermine the site, timing, severity and invasiveness of injury; to add or remove aggravating factors (such as infection and defects in immunity) in controlled ways; and to manipulate the context of repair, including reconstitution with selected immune cell subpopulations. This endows surgical models overall with great potential for exploring bone marrow responses to injury, inflammation and infection, and its roles in repair and regeneration. We review three different murine surgical models, which variously combine trauma with infection, antigenic stimulation, or immune reconstitution, thereby illuminating different aspects of the bone marrow response to systemic injury in sepsis, trauma and allergy. They are: (1) cecal ligation and puncture, a versatile model of polymicrobial sepsis; (2) egg white implant, an intriguing model of eosinophilia induced by a combination of trauma and sensitization to insoluble allergen; and (3) ectopic lung tissue transplantation, which allows us to dissect afferent and efferent mechanisms leading to accumulation of hemopoietic cells in the lungs. These models highlight the gain in analytical power provided by the association of surgical and immunological strategies. PMID- 28890870 TI - Treg/Th17 cell balance and phytohaemagglutinin activation of T lymphocytes in peripheral blood of systemic sclerosis patients. AB - AIM: To investigate T-cell activation, the percentage of peripheral T regulatory cells (Tregs), Th17 cells and the circulating cytokine profile in systemic sclerosis (SSc). METHODS: We enrolled a total of 24 SSc patients and 16 healthy controls in the study and divided the patients as having diffuse cutaneous SSc (dcSSc, n = 13) or limited cutaneous SSc (lcSSc, n = 11). We performed a further subdivision of the patients regarding the stage of the disease - early, intermediate or late. Peripheral venous blood samples were collected from all subjects. We performed flow cytometric analysis of the activation capacity of T lymphocytes upon stimulation with PHA-M and of the percentage of peripheral Tregs and Th17 cells in both patients and healthy controls. We used ELISA to quantitate serum levels of human interleukin (IL)-6, IL-10, tissue growth factor-beta1 (TGF beta1), and IL-17A. RESULTS: We identified a decreased percentage of CD3+CD69+ cells in PHA-stimulated samples from SSc patients in comparison with healthy controls (13.35% +/- 2.90% vs 37.03% +/- 2.33%, P < 0.001). However, we did not establish a correlation between the down-regulated CD3+CD69+ cells and the clinical subset, nor regarding the stage of the disease. The activated CD4+CD25+ peripheral lymphocytes were represented in decreased percentage in patients when compared to controls (6.30% +/- 0.68% vs 9.36% +/- 1.08%, P = 0.016). Regarding the forms of the disease, dcSSc patients demonstrated lower frequency of CD4+CD25+ T cells against healthy subjects (5.95% +/- 0.89% vs 9.36% +/- 1.08%, P = 0.025). With regard to Th17 cells, our patients demonstrated increased percentage in comparison with controls (18.13% +/- 1.55% vs 13.73% +/- 1.21%, P = 0.031). We detected up-regulated Th17 cells within the lcSSc subset against controls (20.46% +/- 2.41% vs 13.73% +/- 1.21%, P = 0.025), nevertheless no difference was found between dcSSc and lcSSc patients. Flow cytometric analysis revealed an increased percentage of CD4+CD25-Foxp3+ in dcSSc patients compared to controls (10.94% +/- 1.65% vs 6.88% +/- 0.91, P = 0.032). Regarding the peripheral cytokine profile, we detected raised levels of IL-6 [2.10 (1.05-4.60) pg/mL vs 0.00 pg/mL, P < 0.001], TGF-beta1 (19.94 +/- 3.35 ng/mL vs 10.03 +/- 2.25 ng/mL, P = 0.02), IL-10 (2.83 +/- 0.44 pg/mL vs 0.68 +/- 0.51 pg/mL, P = 0.008), and IL-17A [6.30 (2.50-15.60) pg/mL vs 0 (0.00-0.05) pg/mL, P < 0.001] in patients when compared to healthy controls. Furthermore, we found increased circulating IL-10, TGF-beta, IL-6 and IL-17A in the lcSSc subset vs control subjects, as it follows: IL-10 (3.32 +/- 0.59 pg/mL vs 0.68 +/- 0.51 pg/mL, P = 0.003), TGF-beta1 (22.82 +/- 4.99 ng/mL vs 10.03 +/- 2.25 ng/mL, P = 0.031), IL-6 [2.08 (1.51-4.69) pg/mL vs 0.00 pg/mL, P < 0.001], and IL-17A [14.50 (8.55-41.65) pg/mL vs 0.00 (0.00-0.05) pg/mL, P < 0.001]. Furthermore, circulating IL-17A was higher in lcSSc as opposed to dcSSc subset (31.99 +/- 13.29 pg/mL vs 7.14 +/- 3.01 pg/mL, P = 0.008). Within the dcSSc subset, raised levels of IL-17A and IL-6 were detected vs healthy controls: IL-17A [2.60 (0.45-9.80) pg/mL vs 0.00 (0.00 0.05) pg/mL, P < 0.001], IL-6 [2.80 (1.03-7.23) pg/mL vs 0.00 pg/mL, P < 0.001]. Regarding the stages of the disease, TGF-beta1 serum levels were increased in early stage against late stage, independently from the SSc phenotype (30.03 +/- 4.59 ng/mL vs 13.08 +/- 4.50 ng/mL, P = 0.017). CONCLUSION: It is likely that the altered percentage of Th17 and CD4+CD25-FoxP3+ cells along with the peripheral cytokine profile in patients with SSc may play a key role in the pathogenesis of the disease. PMID- 28890872 TI - Cardiac troponin and outcome in decompensated heart failure with preserved ejection fraction. AB - BACKGROUND: Cardiac troponin (cTn) has been established as an effective prognostic marker in acute heart failure (HF) with predominantly reduced ejection fraction. However, it's prognostic value in heart failure with preserved ejection fraction (HFpEF) is unclear. The aim of this study is to describe the prognostic role of troponin I in patients hospitalized for HFpEF decompensation. METHODS: We included 363 consecutive patients admitted for HFpEF decompensation that was not associated with acute coronary syndrome (ACS). Patients with troponin level elevation (troponin I level >=0.04 ng/mL) were compared to patients with normal troponin level. The primary outcome was short-, intermediate-, and long-term all cause mortality. The secondary outcomes were differences in B-type natriuretic peptide level (BNP), length of stay, and readmission rates between the two groups. RESULTS: Nearly half of the patients in the Cohort had troponin level elevation. Troponin level elevation was significantly associated with higher 30 day (4.8% vs. 0.6%, P=0.014), 1-year (12.2% vs. 4.6%, P=0.009), and 2-year mortality (13.8% vs. 5.1%, P=0.005) when compared to a normal troponin level. Troponin level elevation was an independent predictor of mortality after adjusting for clinical and laboratory risk factors seen in HFpEF decompensation. Additionally, BNP level >287 pg/mL, age, and history of atrial fibrillation were identified as statistically significant predictors of mortality. CONCLUSIONS: Troponin level elevation, in hospitalized patients with HFpEF decompensation, was associated with higher short-, intermediate-, and long-term mortality. PMID- 28890874 TI - Usefulness of amino terminal pro-B-type natriuretic peptide in evaluating children with cardiac failure. AB - BACKGROUND: The plasma levels of amino terminal pro-B type natriuretic peptide (NT-proBNP) have been found to be useful in evaluating children with heart failure in developed countries where the cause is mainly structural heart lesions. There is paucity of similar studies from developing countries where the causes are mostly of infectious origin. This article is aim to evaluate the relationship between plasma NT-proBNP levels and the severity, outcome and duration of admission of children with heart failure. METHODS: The subjects were children presenting to the children's emergency room (CHER) diagnosed with heart failure based on the modified Ross criteria. The controls were age matched well children recruited from follow up clinics. Information on bio-data and socio demographics was collected while blood was obtained for plasma NT-proBNP measurement. Data analysis was done with SPSS. RESULTS: One hundred and twenty six subjects and same number of controls aged 2 months to 13 years were recruited. The mean plasma NT-proBNP in the subjects was 1,137.10+/-1,243.78 ng/L and in controls, 578.00+/-665.08 ng/L (t=5.669, P<0.001). Subjects with severe heart failure had a statistically significantly higher mean plasma NT-proBNP than those with mild or moderate categories (P<0.001). A plasma NT-proBNP of 903.15 ng/L had a 73.3% sensitivity and 72.1% specificity for identifying severe heart failure using receiver operating curve (ROC) analysis (95% CI, 0.659-0.912, P<0.001). CONCLUSIONS: Children with heart failure had significantly higher mean NT-proBNP value than controls and the value was highest in those with severe form of heart failure compared to those with moderate or mild categories. Plasma NT proBNP should be determined for children presenting with clinically diagnosed heart failure to identify those with severe heart failure and institute prompt treatment. PMID- 28890873 TI - Diagnostic accuracy study of routine echocardiography for bicuspid aortic valve: a retrospective study and meta-analysis. AB - BACKGROUND: Transthoracic echocardiography (TTE) is the standard procedure to distinguish tricuspid aortic valve (TAV) from bicuspid aortic valve (BAV). Published studies assessed the accuracy of TTE for BAV under ideal conditions. Conversely, we aimed at assessing accuracy of TTE for BAV under routine conditions. METHODS: This retrospective, cross-sectional study of 216 adults included 132 men aged 62+/-14 years. Of these, 108 had BAV and 108 were age matched individuals with TAV. All diagnoses were confirmed at surgery. We assessed TTE in two patient groups. First, in the (I) group of all 216 individuals, where we assessed accuracy for BAV according to the original diagnoses as documented by the primary investigators during original TTE examination. Second, we assessed accuracy for BAV according to expert re evaluation in (II) all 158 TTE with availability of original recordings. Third, we performed a meta-analysis of published results on the accuracy of TTE for BAV according to PRISMA standards. RESULTS: Sensitivity, specificity and accuracy of (I) primary investigators was 46.3%, 97.2, and 71.8% as compared to (II) expert re-evaluation with 59.7%, 93%, and 77.8%, respectively. Sensitivity was significantly higher at re-evaluation (P<0.001). TTE at a non-tertiary care center (P=0.012), presence of aortic aneurysm (P=0.001) and presence of severe aortic valve calcification (P=0.003) predicted an inaccurate diagnosis of BAV. Conversely, meta-analysis of published TTE studies identified a pooled sensitivity of 87.7% and a pooled specificity of 88.3% for BAV. CONCLUSIONS: The current study shows that TTE yields almost ideal diagnostic accuracy when ideal investigators examine ideal patients. However, the study also shows that TTE yields suboptimal diagnostic accuracy under routine conditions. TTE in non tertiary care settings, concomitant aortic aneurysm, and presence of severe aortic valve calcification predict an inaccurate diagnosis of BAV. PMID- 28890875 TI - Cyanotic congenital heart diseases among Nigerian children. AB - BACKGROUND: There are only few reports on cyanotic congenital heart diseases (CCHD) among Nigerian and African Children. The current report aim to provide the most recent hospital based data on the distribution of CCHD in children less than 14 years of age, the demographic characteristics and risk factors identified. METHODS: Prospective and cross-sectional involving consecutive cases of CCHD diagnosed with echocardiography at the Lagos State University Teaching Hospital between January 2007 and June 2016. Data were analyzed using Statistical Package for Social Sciences (SPSS) version 20. Level of significance set at P<0.05. RESULTS: There were 352 subjects with CCHD with a male to female ratio of 1.34:1. The children were age 2 days to 14 years with a mean +/- SD of 38.62+/-44.74 months and median of 21 months. The most common type of CCHD (both isolated and multiple CCHD) was tetralogy of Fallot (TOF) followed double outlet right ventricle (DORV) and transposition of the great arteries (TGA). The most common mode of presentation was cyanosis. CONCLUSIONS: TOF was found in almost half of the subjects. Cases of DORV which have been rarely reported were more than those with TGA. Most were diagnosed late. Cyanosis was the most common mode of presentation. Clinical features are protean; thus a high index of suspicion is required to make an early diagnosis. PMID- 28890876 TI - Implantable cardioverter defibrillator in non-ischemic cardiomyopathy: a meta analysis of randomized controlled trials. AB - BACKGROUND: Sudden cardiac death (SCD) is a significant cause of mortality in patients with non-ischemic cardiomyopathy (NICM). Implantable cardioverter defibrillators (ICDs) are currently indicated for the primary prevention of SCD in these patients. Conflicting results from published randomized controlled trials (RCTs) have recently questioned the protective role of ICD in NICM patients to perform an updated meta-analysis of the effect of ICDs on outcomes of NICM patients. METHODS: We performed a search of PubMed, EMBASE, and Cochrane databases for RCTs comparing ICD to medical therapy in patients with NICM. Outcomes were all-cause mortality, SCD, and cardiac mortality. Mantel-Haenszel (MH) risk ratios (RR) were calculated using random-effects meta-analysis for the outcomes mentioned. Heterogeneity was assessed using I2 statistics and Q statistic. RESULTS: A total of five RCTs met the inclusion criteria, with a total of 1,503 patients in the ICD group and 1,364 patients in the medical therapy. Compared to medical therapy, ICD use resulted in a 24% relative risk reduction (RRR) of all-cause mortality (RR 0.76, 95% CI 0.64-0.91, P=0.002), and 60% RRR of SCD (RR 0.40, 95% CI 0.18-0.90, P=0.03), but was not associated with a statistically significant benefit in the prevention of cardiac mortality (RR 0.75, 95% CI 0.39-1.44, P=0.39). Limiting the analysis to patients who received an ICD only without cardiac resynchronization therapy (CRT) pacemakers (4 trials, 1,825 patients) showed similar all-cause mortality results with 24% RRR in ICD group (RR 0.76, 95% CI 0.61-0.94, P=0.01). CONCLUSIONS: ICD therapy reduces all cause mortality and SCD in patients with NICM. PMID- 28890878 TI - Should all spontaneous coronary dissections need to be diagnosed by intracoronary imaging techniques? PMID- 28890877 TI - Pulmonary hypertension: diagnosis, imaging techniques, and novel therapies. AB - Pulmonary hypertension (PH), defined as the elevation of mean pulmonary arterial pressure (mPAP) above 25 mmHg, has numerous causes, which the World Health Organization (WHO) has divided into five distinct categories based upon the underlying mechanism of action. This review will explore the pathophysiology, diagnostic testing, and treatment of PH. Identification of PH depends on a strong clinical suspicion, a detailed history, and a thorough physical exam. We review the evidence supporting experimental and clinical laboratory parameters for diagnosis and monitoring of PH. Transthoracic echocardiogram (TTE) is the initial screening test of choice. This review will detail specific echocardiographic techniques for the assessment and classification of PH. Furthermore, the importance of advanced imaging, including computed tomography (CT) and magnetic resonance imagining (MRI) is explored. New developments in pharmacology, percutaneous intervention, and surgical approaches are summarized. Finally, we will address the tools available to predict morbidity and mortality. PMID- 28890880 TI - Prof. Tohru Asai & Prof. Taweesak Chotivatanapong: treatment of mitral valve disease. PMID- 28890879 TI - Streptococcal pharyngitis in children with painful throat: missed opportunities for rheumatic heart disease prevention in endemic area of Africa. PMID- 28890881 TI - Unseen/seen-the duality of nature. PMID- 28890883 TI - The Role of Probiotics in Cancer Treatment: Emphasis on their In Vivo and In Vitro Anti-metastatic Effects. AB - Probiotics are defined as live bacteria and yeasts that exert beneficial effects for health. Among their various effects, anti-cancer properties have been highlighted in recent years. Such effects include suppression of the growth of microbiota implicated in the production of mutagens and carcinogens, alteration in carcinogen metabolism and protection of DNA from oxidative damage as well as regulation of immune system. We performed a computerized search of the MEDLINE/PUBMED databases with key words: cancer, probiotics, lactobacilli, metastasis and invasion. Cell line studies as well as animal models and human studies have shown the therapeutic effects of probiotics in reduction of invasion and metastasis in cancer cells. These results support the beneficial effects of probiotics both in vitro and in vivo. However, pre-clinical or clinical studies are not enough to decide about their application. PMID- 28890884 TI - Circulating miR-92a, miR-143 and miR-342 in Plasma are Novel Potential Biomarkers for Acute Myeloid Leukemia. AB - MicroRNAs (miRNAs) are small non-coding RNAs that function as post transcriptional gene expression regulators. The expression profiling of miRNAs has already entered into cancer clinics as diagnostic and prognostic biomarkers to assess tumor initiation, progression and response to treatment in cancer patients. Recent studies have opened the way for the use of circulating miRNAs as non-invasive diagnosis and prognosis of Acute myeloid leukemia (AML). The aim of this study was to identify plasma miR-92a, miR-143 and miR-342 expression signatures in AML patients to introduce new markers for establishing AML diagnosis and prognosis. Blood samples were collected from 65 AML patients and 50 controls. The expression of three target miRNAs (miR-92a, miR-143 and miR-342) was measured using quantitative real-time PCR method. Plasma levels of miR-92a, miR-143 and miR-342 were significantly lower in AML patients in comparison with control group. Receiver operator characteristic (ROC) analysis revealed that the sensitivity and specificity values of miR-92a were 81.5% and 94%, respectively, with a cut-off value of 0.704. The sensitivity and specificity values of miR-143 were 87.7% and 80%, respectively, with a cut-off value of 0.65. The sensitivity and specificity values of miR-342 were 75.4% and 90%, respectively, with a cut off value of 0.479. Our findings suggest that plasma miR-92a, miR-143 and miR-342 could be promising novel circulating biomarkers in clinical detection of AML. PMID- 28890885 TI - Evaluation of MicroRNA-99a and MicroRNA-205 Expression Levels in Bladder Cancer. AB - Bladder cancer is the second most common cancer in the genitourinary tract, showing often recurrence and progress into invasive states. Epigenetic changes, such as microRNA alteration are involved in bladder cancer tumorigenesis through a variety of signaling pathways. The epigenetic state depends on geographic and lifestyle conditions. The aim of this study was to investigate the expression level of microRNA-99a and microRNA-205 in bladder cancer in Iranian populations and to determine the relationship between their expressions with clinicophatological features. 36 patients with bladder cancer were included in the study. The control group was the healthy adjacent tissue of the same patients. Total RNA was extracted from approximately 50 mg tissue using TRIzol reagent. cDNA was synthesized and Real-Time PCR was carried out using specific primers. The Unisp6 rRNA was used as a reference gene. A significant decrease was found in the expression level of miR-99a in tumor samples, compared to healthy adjacent tissues (P<0.001). The increased expression level of miR-99a was significantly associated with muscle invasion (P=0.02). The receiver operating characteristic (ROC) analysis for miR-99a showed AUC value equal to 0.944, with specificity of 97%, sensitivity of 91%, and cut off value of 8.31 (P<0.001). A significant association was found between smoking and miR-99a (P=0.04) and miR 205 (P= 0.01) expression levels. Dramatic down-regulation of miR-99a in bladder cancer tissues confirmed the tumor suppressor role of miR-99a in bladder cancer. A higher amount of miR-99a expression was associated with invasive bladder cancer. According to ROC analysis, miR-99a could be considered as a valuable diagnostic biomarker. PMID- 28890886 TI - Development of a Novel Anti-Adhesive Vaccine Against Pseudomonasaeruginosa Targeting the C-terminal Disulfide Loop of the Pilin Protein. AB - Type IV pili (T4P) are major virulence factors of Pseudomonas aeruginosa (P. aeruginosa) that are associated with primary adhesion, biofilm formation and twitching motility. This study focuses on the introduction of a novel biologically active subunit vaccine derived from the disulfide loop (DSL) of P. aeruginosa pilin. We investigated the expression of the novel PilA in-frame with pET26b vector, which contains three domains, that each domain contains three tandem repeats. The flexible (GGGGS) and (GGGGS)3 linkers were linked between the three tandem repeats and each pilA domain, respectively. The recombinant construct (pET26b/pilA) was transformed and expressed in Escherichia coli BL21 (DE3). The reactivity of specific antiserum against PilA was assessed by ELISA method. The biological activities of this candidate vaccine were evaluated by western blotting, opsonophagocytosis and twitching inhibition assays. The pET26b/pilA plasmid was confirmed by enzymatic digestion. The purified PilA protein was confirmed by immunoblot analysis. The checkerboard titration showed that the optimal dilution of the antibody to react with antigen was 1:8. The results of opsonophagocytosis assay revealed that the antibodies raised against PilA promoted phagocytosis of the PAO1 and 6266E strains to some extent (17.5% and 16.3%, respectively), so the twitching inhibition test confirmed this result. Taken together, these are the preliminary results based on a first chimerical structure failure to induce antibodies that promote the opsonization and eradication of the pathogen. Therefore, the biological activity of the PilA protein showed that it should be introduced with other proteins or target antigens against P. aeruginosa in the future studies. PMID- 28890887 TI - Isolation and Characterization of Actinobacteria from Algerian Sahara Soils with Antimicrobial Activities. AB - Extreme ecosystems can be a source of untapped microorganisms to produce novel bioactive compounds of industrial interest. Consequently, in this work, 32 actinomycetes were isolated from 6 soil samples collected from Algerian Sahara in searching for untapped producers of novel antimicrobial compounds. All the isolates were further subjected to antimicrobial screening against pathogenic bacteria, yeast and fungi. The obtained results indicated that three of the isolates (named C, MS1 and 10) showed antimicrobial activities against most of the tested pathogenic microorganisms. Therefore, these three promising isolates, previously identified as Streptomyces by morphological, biochemical and physiological methods, were selected for their subsequent identification by the whole cell matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) analysis. Thus, the isolates C, MS1 and 10 were identified as Streptomyces violaceoruber B263 UFL, Streptomyces albus B262 UFL and Streptomyces badius B192 UFL, respectively. These results pointed out actinomycetes from Sahara soils as potential sources of novel antimicrobial compounds. Also, MALDI-TOF MS showed to be a robust technique for bacteria identification. PMID- 28890882 TI - Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. AB - Reactive oxygen species (ROS) generated by NADPH oxidase play an important role in antimicrobial host defense and inflammation. Their deficiency in humans results in recurrent and severe bacterial infections, while their unregulated release leads to pathology from excessive inflammation. The release of high concentrations of ROS aids in clearance of invading bacteria. Localization of ROS release to phagosomes containing pathogens limits tissue damage. Host immune cells, like neutrophils, also known as PMNs, will release large amounts of ROS at the site of infection following the activation of surface receptors. The binding of ligands to G-protein-coupled receptors (GPCRs), toll-like receptors, and cytokine receptors can prime PMNs for a more robust response if additional signals are encountered. Meanwhile, activation of Fc and integrin directly induces high levels of ROS production. Additionally, GPCRs that bind to the bacterial-peptide analog fMLP, a neutrophil chemoattractant, can both prime cells and trigger low levels of ROS production. Engagement of these receptors initiates intracellular signaling pathways, resulting in activation of downstream effector proteins, assembly of the NADPH oxidase complex, and ultimately, the production of ROS by this complex. Within PMNs, ROS released by the NADPH oxidase complex can activate granular proteases and induce the formation of neutrophil extracellular traps (NETs). Additionally, ROS can cross the membranes of bacterial pathogens and damage their nucleic acids, proteins, and cell membranes. Consequently, in order to establish infections, bacterial pathogens employ various strategies to prevent restriction by PMN-derived ROS or downstream consequences of ROS production. Some pathogens are able to directly prevent the oxidative burst of phagocytes using secreted effector proteins or toxins that interfere with translocation of the NADPH oxidase complex or signaling pathways needed for its activation. Nonetheless, these pathogens often rely on repair and detoxifying proteins in addition to these secreted effectors and toxins in order to resist mammalian sources of ROS. This suggests that pathogens have both intrinsic and extrinsic mechanisms to avoid restriction by PMN-derived ROS. Here, we review mechanisms of oxidative burst in PMNs in response to bacterial infections, as well as the mechanisms by which bacterial pathogens thwart restriction by ROS to survive under conditions of oxidative stress. PMID- 28890888 TI - Association between ACE (rs4646994), FABP2 (rs1799883), MTHFR (rs1801133), FTO (rs9939609) Genes Polymorphism and Type 2 Diabetes with Dyslipidemia. AB - Diabetic dyslipidemia is one of the leading causes of coronary artery disease (CAD) death. Genetic and environmental factors play an important role in the development of type 2 diabetes mellitus (T2DM) and dyslipidemia. The present study was aimed to investigate the association of ACE (rs4646994), FABP2 (rs1799883), MTHFR (rs1801133) and FTO (rs9939609) genes polymorphism in T2DM with dyslipidemia. Totally, 559 subjects including 221 T2DM cases with dyslipidemia, 158 T2DM without dyslipidemia and 180 controls were enrolled. ACE genes polymorphism was evaluated by polymerase chain reaction (PCR), while MTHFR, FABP2, FTO genes polymorphisms were evaluated by PCR and restriction fragment length polymorphism (RFLP). Significant association of ACE and MTHFR genes polymorphisms were found in both group of cases [T2DM with dyslipidemia (P<0.001, and P=0.008, respectively) and T2DM without dyslipidemia (P=0.003, and P=0.010, respectively)] while FABP2 and FTO genes polymorphisms were significantly associated with T2DM without dyslipidemia (P=0.038, and P= 0.019, respectively). This study concludes that ACE, FABP2, FTO and MTHFR genes are associated with T2DM. Additionally, it also seems that ACE and MTHFR genes might be further associated with the development of dyslipidemia in T2DM cases. PMID- 28890889 TI - A Novel Missense Mutation in the ALDH13 Gene Causes Anophthalmia in Two Unrelated Iranian Consanguineous Families. AB - Anophthalmia or microphthalmia (A/M) is a rare group of congenital/developmental ocular malformations, characterized by absent or small eye within the orbit affecting one or both eyes. It has complex etiology with chromosomal, monogenic with high heterogeneity, and environmental causes. We performed genome SNP-array analysis followed by autozygosity mapping and sequencing in the members of two families in which three individuals are suffering from severe bilateral anophthalmia. The genetic analysis revealed a novel missense c.709G>A mutation in exon 7 of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), causing a substitution of glycine (Gly) to arginine (Arg) at residue 237. This study consolidates the importance of ALDH1A3 gene screening in autosomal recessive anophthalmia. This variation may also be suggestive of a founder effect in the southeastern area of Iran. PMID- 28890890 TI - The Impact of Resonance Frequency Breathing on Measures of Heart Rate Variability, Blood Pressure, and Mood. AB - Heart rate variability biofeedback (HRVB) significantly improves heart rate variability (HRV). Breathing at resonance frequency (RF, approximately 6 breaths/min) constitutes a key part of HRVB training and is hypothesized to be a pathway through which biofeedback improves HRV. No studies to date, however, have experimentally examined whether RF breathing impacts measures of HRV. The present study addressed this question by comparing three groups: the RF group breathed at their determined RF for 15 min; the RF + 1 group breathed at 1 breath/min higher than their determined RF for 15 min; and the third group sat quietly for 15 min. After this 15-min period, all groups participated in the Paced Auditory Serial Addition Task (PASAT) for 8 min, and then sat quietly during a 10-min recovery period. HRV, blood pressure, and mood were measured throughout the experiment. Groups were not significantly different on any of the measures at baseline. After the breathing exercise, the RF group reported higher positive mood than the other two groups and a significantly higher LF/HF HRV ratio relative to the control group, a key goal in HRVB training (p < 0.05). Additionally, the RF group showed lower systolic blood pressure during the PASAT and during the recovery period relative to the control group, with the RF + 1 group not being significantly different from either group (p < 0.05). Overall, RF breathing appears to play an important role in the positive effect HRVB has on measures of HRV. PMID- 28890891 TI - Collaborative Approaches and Policy Opportunities for Accelerated Progress toward Effective Disease Prevention, Care, and Control: Using the Case of Poverty Diseases to Explore Universal Access to Affordable Health Care. AB - BACKGROUND: There is a massive global momentum to progress toward the sustainable development and universal health coverage goals. However, effective policies to health-care coverage can only emerge through high-quality services delivered to empowered care users by means of strong local health systems and a translational standpoint. Health policies aimed at removing user fees for a defined health-care package may fail at reaching desired results if not applied with system thinking. METHOD: Secondary data analysis of two country-based cost-of-illness studies was performed to gain knowledge in informed decision-making toward enhanced access to care in the context of resource-constraint settings. A scoping review was performed to map relevant experiences and evidence underpinning the defined research area, the economic burden of illness. FINDINGS: Original studies reflected on catastrophic costs to patients because of care services use and related policy gaps. Poverty diseases such as tuberculosis (TB) may constitute prime examples to assess the extent of effective high-priority health-care coverage. Our findings suggest that a share of the economic burden of illness can be attributed to implementation failures of health programs and supply-side features, which may highly impair attainment of the global stated goals. We attempted to define and discuss a knowledge development framework for effective policy-making and foster system levers for integrated care. DISCUSSION: Bottlenecks to effective policy persist and rely on interrelated patterns of health-care coverage. Health system performance and policy responsiveness have to do with collaborative work among all health stakeholders. Public-private mix strategies may play a role in lowering the economic burden of disease and solving some policy gaps. We reviewed possible added value and pitfalls of collaborative approaches to enhance dynamic local knowledge development and realize integration with the various health-care silos. CONCLUSION: Despite a large political commitment and mobilization efforts from funding, the global development goal of financial protection for health-newly adopted in TB control as no TB-affected household experiencing catastrophic expenditure-may remain aspirational. To enhance effective access to care for all, innovative opportunities in patient centered and collaborative practices must be taken. Further research is greatly needed to optimize the use of locally relevant knowledge, networks, and technologies. PMID- 28890892 TI - MicroRNA Profiling in Cartilage Ageing. AB - Osteoarthritis (OA) is the most common age-related joint disorder in man. MicroRNAs (miRNA), a class of small noncoding RNAs, are potential therapeutic targets for regulating molecular mechanisms in both disease and ageing. Whilst there is an increasing amount of research on the roles of miRNAs in ageing, there has been scant research on age-related changes in miRNA in a cartilage. We undertook a microarray study on young and old human cartilages. Findings were validated in an independent cohort. Contrasts between these samples identified twenty differentially expressed miRNAs in a cartilage from old donors, derived from an OA environment which clustered based on OA severity. We identified a number of recognised and novel miRNAs changing in cartilage ageing and OA including miR-126: a potential new candidate with a role in OA pathogenesis. These analyses represent important candidates that have the potential as cartilage ageing and OA biomarkers and therapeutic targets. PMID- 28890894 TI - Risk of Contamination of Gametes and Embryos during Cryopreservation and Measures to Prevent Cross-Contamination. AB - The introduction and widespread application of vitrification are one of the most important achievements in human assisted reproduction techniques (ART) of the past decade despite controversy and unclarified issues, mostly related to concerns about disease transmission. Guidance documents published by US Food and Drug Administration, which focused on the safety of tissue/organ donations during Zika virus spread in 2016, as well as some reports of virus, bacteria, and fungi survival to cryogenic temperatures, highlighted the need for a review of the way how potentially infectious material is handled and stored in ART-related procedures. It was experimentally demonstrated that cross-contamination between liquid nitrogen (LN2) and embryos may occur when infectious agents are present in LN2 and oocytes/embryos are not protected by a hermetically sealed device. Thus, this review summarizes pertinent data and opinions regarding the potential hazard of infectious transmission through cryopreserved and banked reproductive cells and tissues in LN2. Special attention is given to the survival of pathogens in LN2, the risk of cross-contamination, vitrification methods, sterility of LN2, and the risks associated with the use of straws, cryovials, and storage dewars. PMID- 28890895 TI - Isolation of Fibroblast-Activation Protein-Specific Cancer-Associated Fibroblasts. AB - The current study is to develop a gentle and efficient method for purification of fibroblast-activation protein positive (FAP+) cancer-associated fibroblasts (CAFs) from tumor tissues. Fresh tissues were isolated from BALB/c-Nude mice bearing human liver cancer cell line (HepG2), fully minced and separated into three parts, and digested with trypsin digestion and then treated with collagenase type IV once, twice, or thrice, respectively. Finally, the cells were purified by using FAP magnetic beads. The isolated CAFs were grown in culture medium and detected for the surface expression of fibroblast-activation protein (FAP). The number of adherent cells which were obtained by digestion process with twice collagenase type IV digestion was (5.99 +/- 0.18) * 104, much more than that with the only once collagenase type IV digestion (2.58 +/- 0.41) * 104 (P < 0.0001) and similar to thrice collagenase type IV digestion. The percentage of FAP+ CAFs with twice collagenase type IV digestion (38.5%) was higher than that with the only once collagenase type IV digestion (20.0%) and little higher than thrice collagenase type IV digestion (37.5%). The FAP expression of CAFs was quite different from normal fibroblasts (NFs). The fibroblasts isolated by the innovation are with high purity and being in wonderful condition and display the features of CAFs. PMID- 28890896 TI - Informing Nutrition Care in the Antenatal Period: Pregnant Women's Experiences and Need for Support. AB - This study aimed to provide insights into Australian women's experiences in gaining nutrition information during pregnancy. Individual semistructured telephone interviews were conducted with 17 pregnant (across all trimesters) and 9 postpartum women in five Australian states. Data were transcribed and analysed using inductive thematic analysis. Women valued nutrition information, actively sought it, and passively received it mainly from three sources: healthcare providers (HCPs), media, and their social networks. Women reported HCPs as highest for reliability but they had limited time and indifferent approaches. Various media were easily and most frequently accessed but were less reliable. Social networks were considered to be the least reliable and least accessed. Women reported becoming overwhelmed and confused. This in turn influenced their decisions (pragmatic/rational) and their eating behaviours ("overdo it," "loosen it," "ignore it," and "positive response"). Individual and environmental barriers impacted their application of knowledge to dietary practice. Women wanted more constructive and interactive engagement with their HCPs. This study identified the need to establish and maintain mutually respectful environments where women feel able to raise issues with their HCPs throughout their pregnancies and where they are confident that the information they receive will be accurate and meet their needs. PMID- 28890897 TI - Corrigendum to "Detecting Key Genes Regulated by miRNAs in Dysfunctional Crosstalk Pathway of Myasthenia Gravis". AB - [This corrects the article DOI: 10.1155/2015/724715.]. PMID- 28890893 TI - Proximate Mediators of Microvascular Dysfunction at the Blood-Brain Barrier: Neuroinflammatory Pathways to Neurodegeneration. AB - Current projections are that by 2050 the numbers of people aged 65 and older with Alzheimer's disease (AD) in the US may increase threefold while dementia is projected to double every 20 years reaching ~115 million by 2050. AD is clinically characterized by progressive dementia and neuropathologically by neuronal and synapse loss, accumulation of amyloid plaques, and neurofibrillary tangles (NFTs) in specific brain regions. The preclinical or presymptomatic stage of AD-related brain changes may begin over 20 years before symptoms occur, making development of noninvasive biomarkers essential. Distinct from neuroimaging and cerebrospinal fluid biomarkers, plasma or serum biomarkers can be analyzed to assess (i) the presence/absence of AD, (ii) the risk of developing AD, (iii) the progression of AD, or (iv) AD response to treatment. No unifying theory fully explains the neurodegenerative brain lesions but neuroinflammation (a lethal stressor for healthy neurons) is universally present. Current consensus is that the earlier the diagnosis, the better the chance to develop treatments that influence disease progression. In this article we provide a detailed review and analysis of the role of the blood-brain barrier (BBB) and damage-associated molecular patterns (DAMPs) as well as coagulation molecules in the onset and progression of these neurodegenerative disorders. PMID- 28890899 TI - Overcoming the Challenges in Implementing Type 2 Diabetes Mellitus Prevention Programs Can Decrease the Burden on Healthcare Costs in the United States. AB - Theoretically, identifying prediabetics would reduce the diabetic burden on the American healthcare system. As we expect the prevalence rate of prediabetes to continue increasing, we wonder if there is a better way of managing prediabetics and reducing the economic cost on the healthcare system. To do so, understanding the demographics and behavioral factors of known prediabetics was important. For this purpose, responses of prediabetic/borderline diabetes patients from the most recent publicly available 2015 Behavioral Risk Factor Surveillance System (BRFSS) survey were analyzed. The findings showed that there was a correlation between household income, geographic residence in the US, and risk for developing diabetes mellitus type 2, aside from the accepted risk factors such as high BMI. In conclusion, implementation of the National Diabetes Prevention Program is a rational way of reducing the burden of DM on the healthcare system both economically and by prevalence. However, difficulties arise in ensuring patient compliance to the program and providing access to all regions and communities of the United States. Technology incorporation in the NDPP program would maintain a low-cost implementation by the healthcare system, be affordable and accessible for all participants, and decrease economic burden attributed to diabetes mellitus. PMID- 28890898 TI - Antifatigue Functions and Mechanisms of Edible and Medicinal Mushrooms. AB - Fatigue is the symptom of tiredness caused by physical and/or psychological stresses. As fatigue is becoming a serious problem in the modern society affecting human health, work efficiency, and quality of life, effective antifatigue remedies other than pharmacological drugs or therapies are highly needed. Mushrooms have been widely used as health foods, because of their various bioactive constituents such as polysaccharides, proteins, vitamins, minerals, and dietary fiber. This paper reviews the major findings from previous studies on the antifatigue effects, the active components of mushrooms, and the possible mechanisms. Many studies have demonstrated the antifatigue effects of edible and medicinal mushrooms. These mushrooms probably mitigate human fatigue through effects on the functional systems, including the muscular, cardiovascular, hormone, and immune system. The bioactive constituents that contribute to the antifatigue effects of mushrooms may include polysaccharides, peptides, nucleosides, phenolic compounds, and triterpenoids. Further research is still needed to identify the active ingredients and to investigate their mechanism of action on the antifatigue effects. Since most previous studies have been carried out in animal models, more human trials should be performed to verify the antifatigue function of edible and medicinal mushrooms. PMID- 28890900 TI - Aluminium in coal fly ash (FA), in plants grown on FA, and in the leachates from FA. AB - Two coal fly ashes (FA), one from Montana semi-bituminous coal and another from North Dakota lignite alone or in combination with bottom ash (BA) from Montana semi-bituminous coal were tested as plant growth media for the following plant species: barley (Hordeum vulgare), oats (Avena sativa), rye (Secale cereale), wheat (Triticum aestivum), regreen; a hybrid between wheatgrass (Agropyron cristatum) and winter wheat (Triticum aestivum), and triticale; a hybrid between wheat (Triticum aestivum) and rye (Secale cereale). The concentration of Al, in coal ashes and in plant seedlings was determined using Inducted Coupled Plasma Spectrophotometry (ICP). All tested plant species germinated and grow in FA and/or FA + BA containing media. These data demonstrate that tested plants can grow on media consisting of coal ash, and therefore these plants can be used to cover FA or BA residue piles. In summary, the presence of sphagnum peat moss and soil in coal ash based plant growth media expressed ameliorative role by reducing the presence of Al in plant growth media and in plant seedlings grown on these media, but it did not translate into the decrease of the presence of Al in the leachate from these media. Elevated concentrations of Al in the leachate may cause some environmental health concerns and require further investigations. PMID- 28890901 TI - Performing all major surgical procedures robotically will prolong wait times for surgery. AB - This article aimed to assess the burden of scheduling major urologic oncology procedures if all cases were performed robotically and to determine whether this would increase the time a patient would have to wait for surgery. We retrospectively determined the number of prostatectomies, radical nephrectomies, partial nephrectomies, and cystectomies at a single institution for one calendar year. A hypothetical situation was then constructed where all procedures were performed robotically. Using the allotted number of days that each surgeon was able to schedule robotic procedures, we analyzed the amount of time it would take to schedule and complete all cases. Five fellowship-trained surgeons were included in the study and accounted for 317 surgical cases. Three of the surgeons had dedicated robotic surgery (RS) time (block time), while two surgeons scheduled when there was non-dedicated RS time (open time) available. If all cases were performed robotically an additional 32 days would be needed, which could significantly increase the wait time to surgery. The limited number of robotic systems available in most hospitals creates a bottleneck effect; whereby increasing the number of cases would considerably lengthen the waiting time patients have for surgery. As RS becomes increasingly more commonplace in urology and other surgical fields, this could create a significant problem for health care systems. PMID- 28890902 TI - Pasteurella multocida Bacteremia and Peritonitis in a Patient With Cirrhosis: A Life-Threatening Case From a Prick of a Cactus. AB - A 58-year-old male with nonalcoholic steatohepatitis cirrhosis presents with right lower extremity cellulitis, abdominal tenderness, and severe sepsis after sustaining puncture injury from a cactus on a property with feral cats. Blood cultures and diagnostic paracentesis were consistent with spontaneous bacterial peritonitis due to Pasteurella multocida, a gram-negative coccobacillus found in the respiratory tract of domestic animals. The patient received timely antibiotic coverage with resolution of spontaneous bacterial peritonitis and sepsis after 14 day treatment. This case emphasizes the life-threatening nature of systemic Pasteurella multocida infection as well as an indirect way of acquiring a zoonotic infection in a patient with end-stage liver disease. PMID- 28890903 TI - Combining List Experiment and Direct Question Estimates of Sensitive Behavior Prevalence. AB - Survey respondents may give untruthful answers to sensitive questions when asked directly. In recent years, researchers have turned to the list experiment (also known as the item count technique) to overcome this difficulty. While list experiments are arguably less prone to bias than direct questioning, list experiments are also more susceptible to sampling variability. We show that researchers need not abandon direct questioning altogether in order to gain the advantages of list experimentation. We develop a nonparametric estimator of the prevalence of sensitive behaviors that combines list experimentation and direct questioning. We prove that this estimator is asymptotically more efficient than the standard difference-in-means estimator, and we provide a basis for inference using Wald-type confidence intervals. Additionally, leveraging information from the direct questioning, we derive two nonparametric placebo tests for assessing identifying assumptions underlying list experiments. We demonstrate the effectiveness of our combined estimator and placebo tests with an original survey experiment. PMID- 28890904 TI - Thirty-Year Experience With ACL Reconstruction Using Patellar Tendon: A Critical Evaluation of Revision and Reoperation. AB - BACKGROUND: During the preoperative discussion prior to anterior cruciate ligament reconstruction (ACLR), patients are often interested in data regarding rates of revision reconstruction, reoperation, concomitant pathologic changes, and future contralateral ACL injury. PURPOSE: To analyze a single surgeon's experience with primary and revision ACLR over a 30-year interval, focusing on incidence and risk factors for revision and reoperation. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients who underwent ACLR from 1986 to 2016 were identified from a prospectively maintained database. Covariates of interest included age, sex, time, and graft selection. Outcomes of interest included revision and reoperation rates. RESULTS: A total of 2450 ACLRs (mean patient age, 29 years; 58% male) were reviewed. Among primary ACLRs performed (n = 2225), 68% entailed bone-patellar tendon-bone (BTB) autograft and 30% entailed BTB allograft. Patients undergoing ACLR with autograft and allograft had a mean age of 22 and 37 years, respectively. The rate of revision ACLR was 1.8% and 3.5% for primary and revision cases, respectively. An increased rate of revision was noted among females compared with males (2.6% vs 1.2%) and among allografts compared with autografts (2.7% vs 1.3%). Low-dose irradiation did not affect allograft revision rates. The nonrevision reoperation rate following primary ACLR was 12%. The nonrevision reoperation rate was lower among primary cases reconstructed with allograft than autograft (9% vs 13%). Seventeen percent of cases involved concomitant meniscal repair and, among these, 13% required revision meniscal surgery. The rate of contralateral ACLR was 5.3. CONCLUSION: This information is useful in the informed consent process, for perioperative decision making regarding graft choice, and for identifying patients who are at risk for injuring the uninvolved knee. PMID- 28890905 TI - Single- Versus Multiple-Site Harvesting Techniques for Bone Marrow Concentrate: Evaluation of Aspirate Quality and Pain. AB - BACKGROUND: Bone marrow concentrate (BMC) is growing in popularity as an alternative treatment option in orthopaedics. The regenerative capacity of BMC has been linked to the number of mesenchymal stem cells (MSCs) present in the graft at the time of its clinical application. MSC counts in bone marrow aspirate (BMA) are affected by harvest technique, but controversy exists over which aspiration method optimizes cellular yield while taking patient comfort and risk into consideration. PURPOSE: To compare a single- versus multiple-site bone marrow aspiration technique to determine which would generate a sufficient volume of high-quality BMA for concentration into a BMC graft. The level of pain experienced by the patient was monitored, since patient comfort should be included in the determination of a safe and effective aspiration technique. STUDY DESIGN: Controlled laboratory study and cohort study; Level of evidence, 2. METHODS: BMC samples from 6 patients were sent to an outside source for laboratory analysis. All 6 participants underwent bilateral bone marrow aspiration. Each patient received both techniques at the posterior iliac crest: one side underwent a multiple-site aspiration technique, and the contralateral side underwent a single-site technique with needle redirection. BMA and BMC samples were analyzed for concentrations white blood cells, total nucleated cells, red blood cells, neutrophils, and hematopoietic stem cells. One BMC sample was cultured, and MSC analysis was performed via flow cytometry. All patients underwent monitoring of pain scores during and after the procedure through a visual analog pain scale at 24 hours, 72 hours, and 7 days after BMA. RESULTS: No significant difference was found between the cell ratios of the single- and multiple-site groups. Both aspiration techniques were found to provide ample colony-forming units without a marked difference in appearance. Additionally, no significant difference was found between groups with regard to MSC numbers. Pain during and 24 hours after the procedure was significantly greater with the multiple-site method than the single-insertion method. CONCLUSION: The single insertion method produced final cellular concentrations and culture results that were not significantly different from those of a multiple-insertion method. Additionally, the single-insertion site technique was significantly less painful to the patient at the time of the procedure as well as 24 hours after aspiration. CLINICAL RELEVANCE: The results of this study indicated that a high-quality bone marrow aspirate is possible with a single-stick aspiration method. PMID- 28890906 TI - Two-Part and Related Regression Models for Longitudinal Data. AB - Statistical models that involve a two-part mixture distribution are applicable in a variety of situations. Frequently, the two parts are a model for the binary response variable and a model for the outcome variable that is conditioned on the binary response. Two common examples are zero-inflated or hurdle models for count data and two-part models for semicontinuous data. Recently, there has been particular interest in the use of these models for the analysis of repeated measures of an outcome variable over time. The aim of this review is to consider motivations for the use of such models in this context and to highlight the central issues that arise with their use. We examine two-part models for semicontinuous and zero-heavy count data, and we also consider models for count data with a two-part random effects distribution. PMID- 28890907 TI - Functional ex-vivo Imaging of Arterial Cellular Recruitment and Lipid Extravasation. AB - The main purpose of this sophisticated and highly versatile method is to visualize and quantify structural vessel wall properties, cellular recruitment, and lipid/dextran extravasation under physiological conditions in living arteries. This will be of interest for a broad range of researchers within the field of inflammation, hypertension, atherosclerosis, and even the pharmaceutical industry. Currently, many researchers are using in vitro techniques to evaluate cellular recruitment, like transwell or flow chamber systems with cultured cells, with unclear physiological comparability. The here introduced method describes in detail the use of a sophisticated and flexible method to study arterial wall properties and leukocyte recruitment in fresh and viable murine carotid arteries ex vivo under arterial flow conditions. This model mimics the in vivo situation and allows the use of cells and arteries isolated from two different donors (for example, wildtype vs. specific knockouts) to be combined into one experiments, thereby providing information on both leukocyte and/or endothelial cell properties of both donors. As such, this model can be considered an alternative for the complicated and invasive in vivo studies, such as parabiotic experiments. PMID- 28890908 TI - Validation Study of a Predictive Algorithm to Evaluate Opioid Use Disorder in a Primary Care Setting. AB - BACKGROUND: Opioid abuse in chronic pain patients is a major public health issue. Primary care providers are frequently the first to prescribe opioids to patients suffering from pain, yet do not always have the time or resources to adequately evaluate the risk of opioid use disorder (OUD). PURPOSE: This study seeks to determine the predictability of aberrant behavior to opioids using a comprehensive scoring algorithm ("profile") incorporating phenotypic and, more uniquely, genotypic risk factors. METHODS AND RESULTS: In a validation study with 452 participants diagnosed with OUD and 1237 controls, the algorithm successfully categorized patients at high and moderate risk of OUD with 91.8% sensitivity. Regardless of changes in the prevalence of OUD, sensitivity of the algorithm remained >90%. CONCLUSION: The algorithm correctly stratifies primary care patients into low-, moderate-, and high-risk categories to appropriately identify patients in need for additional guidance, monitoring, or treatment changes. PMID- 28890909 TI - Patient, Provider, and System Factors Associated With Failure to Follow-Up Elevated Glucose Results in Patients Without Diagnosed Diabetes. AB - BACKGROUND: Although elevated glucose values are strongly associated with undiagnosed diabetes, they are frequently overlooked. Patient, provider, and system factors associated with failure to follow-up elevated glucose values in electronic medical records (EMRs) are not well described. METHODS: We conducted a chart review in a comprehensive EMR with a patient portal and results management features. Established primary care patients with no known diagnosis of diabetes and >= 1 glucose value >125 mg/dL were included. Follow-up failure was defined as (1) no documented comment on the glucose value or result communication to the patient within 30 days or (2) no hemoglobin A1c (HbA1c) ordered within 30 days or resulted within 12 months. Associations were examined using Wilcoxon and chi2 tests. RESULTS: Of 150 charts reviewed, 97 met inclusion criteria. The median glucose was 133 mg/dL, and 20% of patients had multiple values >125 mg/dL. Only 36% of elevated glucose values were followed up. No associations were observed between patient characteristics, diabetes risk factors, or provider characteristics and follow-up failures. Automated flagging of glucose values >=140 mg/dL by highlighting them red in the EMR was not associated with improved follow-up (46% vs 32%; P = .19). Even when follow-up occurred (n = 35), only 31% completed gold standard diabetes testing (HbA1c) within 12 months. Of the resulted HbA1c tests (n = 11), 55% were in the prediabetes range (5.7%-6.4%). CONCLUSIONS: Two-thirds of elevated glucose values were not followed up, despite EMR features facilitating results management. Greater understanding of the results management process and improved EMR functionalities to support results management are needed. PMID- 28890911 TI - Correction Notice. AB - [This corrects the article DOI: 10.1177/2333392814557011.]. PMID- 28890910 TI - Six-Month Outcomes for Collaborative Care Management of Depression Among Smoking and Nonsmoking Patients. AB - BACKGROUND: Collaborative care management (CCM) is an evidence-based model that contributes to better outcomes for depression treatment in the primary care setting. Tobacco use increases overall economic costs, morbidity, and mortality and has been shown to impact behavioral health outcomes. Our study aims to observe clinical outcomes for depression treatment for patients with comorbid tobacco use and depression within the CCM model. METHODS: A retrospective chart review study of 2826 adult patients with depression enrolled in CCM was performed to determine the association between regular tobacco use and depression outcomes. Baseline intake data consisting of clinical and demographic variables along with 6-month follow-up of Patient Health Questionnaire-9 (PHQ-9) scores for smokers (n = 727, 25.7%) and nonsmokers (n = 2099, 74.3%) were obtained. Depression remission was defined as a PHQ-9 score <5 and persistent depressive symptoms (PDS) as a PHQ-9 score >=10 at 6 months. RESULTS: Using an intention-to-treat analysis, the multivariate modeling demonstrated that smokers, at 6 months, had an increased adjusted odds ratio (AOR) for PDS: 1.624 (95% CI: 1.353-1.949). Furthermore, smokers had a lower AOR of depression remission: 0.603 (95% CI: 0.492-0.739). Patient adherence to treatment was also lower in smokers with an AOR of 0.666 (95% CI: 0.553-0.802). CONCLUSIONS: Smokers enrolled in CCM were associated with reduced treatment adherence and worse outcomes for depression treatment at 6 months compared to nonsmokers, even when baseline clinical and demographic variables were controlled. Thus, new tailored practices may be warranted within the CCM model to treat comorbid depression and tobacco use disorders. PMID- 28890912 TI - Typhoid and Scrub Typhus Coinfection in a Returned Traveler. AB - This is a case report of a 12-year-old returned traveler with typhoid and scrub typhus coinfection. The diagnosis of typhoid was made early with blood cultures and Widal Weil Felix serology. Persistent fever despite appropriate antibiotics for typhoid fever prompted a search for concomitant infection, which led to the diagnosis of scrub typhus confirmed by Orientia tsutsugamushi serology. The patient was given doxycycline with good clinical response. Scrub typhus infection should be an early consideration in the differential diagnoses of fever in a returned traveler from regions where it is endemic. Coinfections should be taken into consideration particularly when fever or symptoms persist despite adequate therapy for a previously identified microorganism. PMID- 28890913 TI - Markers of Cardiovascular Dysfunction in Adolescents With Anorexia Nervosa. AB - Background. Cardiovascular complications contribute to the high morbidity and mortality rate among children with anorexia nervosa (AN). Advances in cardiac imaging permit a more comprehensive assessment of myocardial performance in children that could not be previously obtained with conventional imaging. Myocardial strain analysis is an emerging quantitative echocardiographic technique to characterize global and regional ventricular function in children. Objective. To assess global and regional left ventricular (LV0 function in children newly diagnosed with AN with conventional and quantitative 2-dimensional speckle tracking echocardiographic (2DSTE)-derived strain imaging. Materials. In a cross-sectional study of 30 patients with AN (DSM-5) and 14 age-, sex-, and race-matched healthy children, markers of cardiovascular risk, conventional and 2DSTE measures of LV function, and structure were evaluated and compared. The AN cohort was further stratified by behavioral patterns (restrict, exercise, or purge). Results. Conventional measures and LV global strain were similar between controls and children with AN. A subgroup of AN children with purging behavior had LV remodeling characterized by significantly decreased LV mass index. Regional ventricular function at the apex, as measured by strain, was also decreased in all AN patients. Percent change from ideal body weight, body mass index Z-score, electrolyte profiles, heart rate, and blood pressure were similar. Conclusions. Subclinical regional ventricular dysfunction is present in children with AN. Ventricular remodeling exists in a subgroup of children with AN in association with purging behavior. Future studies may utilize strain imaging to identify those AN patients who are at an increased risk for developing significant cardiac dysfunction. PMID- 28890914 TI - Effect of Menthol-preferring Status on Response to Intravenous Nicotine. AB - OBJECTIVES: Menthol, a flavoring agent, is found in approximately 90% of cigarettes, but at much higher levels in menthol than non-menthol cigarettes. Menthol is reportedly included in cigarettes for its cooling and soothing effects, but also additional actions that affect smokers' receipt and processing of nicotine. In this study we investigated the response to short-term abstinence and acute nicotine delivery in menthol-preferring and non-menthol-preferring smokers. METHODS: Nicotine dependent participants (N = 134) participated in an intravenous nicotine delivery session following overnight smoking abstinence. Participants were intravenously administered a placebo and 2 escalating nicotine doses. We compare subjective and physiological responses to nicotine and smoking urges, withdrawal, and cognitive performance following overnight abstinence and post-nicotine between regular 'menthol' smokers and 'non-menthol' cigarette smokers. RESULTS: Relative to non-menthol-preferring smokers, menthol-preferring smokers re a smaller reduction in smoking urges from overnight abstinence baseline to post-nicotine end-of-session and rated less subjective differences between nicotine doses. CONCLUSIONS: Differences between menthol-preferring and non-menthol-preferring smokers' responses to abstinence or acute nicotine could reflect pre-existing individual differences that may have in initial development of menthol preferences, or could have arisen secondarily to pro use of menthol versus non-menthol cigarettes. PMID- 28890915 TI - Variation in the link between parental divorce and children's health disadvantage in low and high divorce settings. AB - Like in other world regions, children with divorced parents in sub-Saharan Africa experience significant heath disadvantages relative to their peers with married parents. Preliminary evidence suggests this disadvantage may not be uniform across the subcontinent's diverse settings. Research from other world regions shows that the childhood health consequences of divorce vary across different contexts. Specifically, we hypothesize that the childhood disadvantages associated with divorce are more severe in regions of sub-Saharan Africa where divorce is rare, and less so where divorce is a more common family experience. Using Demographic and Health Survey data from 290 subnational regions within 31 sub-Saharan African countries, multilevel models document the previously shown link between having a divorced mother and child morbidity and mortality. The study results further demonstrate that the childhood health disadvantage is accentuated in subnational African regions where fewer women are divorced and muted in areas where more women are divorced. The findings demonstrate that the broader context can powerfully moderate childhood health inequalities traditionally thought of as operating at the family or individual level. PMID- 28890916 TI - Power analysis to detect treatment effects in longitudinal clinical trials for Alzheimer's disease. AB - INTRODUCTION: Assessing cognitive and functional changes at the early stage of Alzheimer's disease (AD) and detecting treatment effects in clinical trials for early AD are challenging. METHODS: Under the assumption that transformed versions of the Mini-Mental State Examination, the Clinical Dementia Rating Scale-Sum of Boxes, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale tests'/components' scores are from a multivariate linear mixed-effects model, we calculated the sample sizes required to detect treatment effects on the annual rates of change in these three components in clinical trials for participants with mild cognitive impairment. RESULTS: Our results suggest that a large number of participants would be required to detect a clinically meaningful treatment effect in a population with preclinical or prodromal Alzheimer's disease. We found that the transformed Mini-Mental State Examination is more sensitive for detecting treatment effects in early AD than the transformed Clinical Dementia Rating Scale-Sum of Boxes and Alzheimer's Disease Assessment Scale-Cognitive Subscale. The use of optimal weights to construct powerful test statistics or sensitive composite scores/endpoints can reduce the required sample sizes needed for clinical trials. CONCLUSION: Consideration of the multivariate/joint distribution of components' scores rather than the distribution of a single composite score when designing clinical trials can lead to an increase in power and reduced sample sizes for detecting treatment effects in clinical trials for early AD. PMID- 28890917 TI - Attentional disengagements in educational contexts: a diary investigation of everyday mind-wandering and distraction. AB - The present study examined everyday attentional disengagements in educational contexts. Undergraduate students completed various cognitive ability measures in the laboratory and recorded everyday mind-wandering and distraction in a diary over the course of a week. Participants reported mind-wandering and being distracted both in class and while studying and there were a number of different subtypes of attentional disengagements. Individual differences in cognitive abilities were related to some, but not all, everyday attentional disengagements and motivation and interest in classes were related to specific subtypes of disengagements. Finally, academic performance was related to fluid intelligence and motivation, but not to everyday disengagements. These results provide importance evidence on the different types of attentional disengagements that are prevalent in undergraduate students and for whom disengagements are most likely. PMID- 28890918 TI - Evidence for improved memory from 5 minutes of immediate, post-encoding exercise among women. AB - Memories consolidate over time, with one consequence being that what we experience after learning can influence what we remember. In these experiments, women who engaged in 5 minutes of low-impact exercise immediately after learning showed better recall for paired associations than did women who engaged in a non exercise control activity. In experiments 1 and 2, this benefit was apparent in a direct comparison between exercise and non-exercise groups. In experiment 3, it was reflected in a weak, positive correlation between memory performance and exercise-induced change in heart rate. In experiment 4, similar patterns emerged, although they fell short of statistical significance. Such memorial benefits did not emerge among male participants. In experiment 1, half the participants alternatively engaged in an equivalent period of exercise prior to learning, with no benefits for retention of the learned material, suggesting that the memorial benefits of exercise-induced arousal may reflect a specific impact on post learning processes such as memory consolidation. A meta-analysis across the experiments revealed a reliable benefit of post-learning exercise among women. Variation in the strength of the effect between experiments is consistent with a literature suggesting small but reliable benefits of acute exercise on cognitive performance. PMID- 28890919 TI - Integrating images from a moveable tracked display of three-dimensional data. AB - This paper describes a novel method for displaying data obtained by three dimensional medical imaging, by which the position and orientation of a freely movable screen are optically tracked and used in real time to select the current slice from the data set for presentation. With this method, which we call a "freely moving in-situ medical image", the screen and imaged data are registered to a common coordinate system in space external to the user, at adjustable scale, and are available for free exploration. The three-dimensional image data occupy empty space, as if an invisible patient is being sliced by the moving screen. A behavioral study using real computed tomography lung vessel data established the superiority of the in situ display over a control condition with the same free exploration, but displaying data on a fixed screen (ex situ), with respect to accuracy in the task of tracing along a vessel and reporting spatial relations between vessel structures. A "freely moving in-situ medical image" display appears from these measures to promote spatial navigation and understanding of medical data. PMID- 28890920 TI - How did I miss that? Developing mixed hybrid visual search as a 'model system' for incidental finding errors in radiology. AB - In a real world search, it can be important to keep 'an eye out' for items of interest that are not the primary subject of the search. For instance, you might look for the exit sign on the freeway, but you should also respond to the armadillo crossing the road. In medicine, these items are known as "incidental findings," findings of possible clinical significance that were not the main object of search. These errors (e.g., missing a broken rib while looking for pneumonia) have medical consequences for the patient and potential legal consequences for the physician. Here we report three experiments intended to develop a 'model system' for incidental findings - a paradigm that could be used in the lab to develop strategies to reduce incidental finding errors in the clinic. All the experiments involve 'hybrid' visual search for any of several targets held in memory. In this 'mixed hybrid search task,' observers search for any of three specific targets (e.g., this rabbit, this truck, and this spoon) and three categorical targets (e.g., masks, furniture, and plants). The hypothesis is that the specific items are like the specific goals of a real world search and the categorical targets are like the less well-defined incidental findings that might be present and that should be reported. In all these experiments, varying target prevalence, number of targets, etc., the categorical targets are missed at a much higher rate than the specific targets. This paradigm shows promise as a model of the incidental finding problem. PMID- 28890921 TI - The Doktaborse - an innovative online platform for research projects at the medical faculty of the LMU Munich. AB - Introduction: One of the most important extracurricular aspects of medical studies in Germany is a research thesis completed by most students. This research project often times conveys relevant competencies for the physician's role as scientist. Nevertheless, the choice of the right project remains a challenge. Reasons for this are among others, missing structures for a comprehensive overview of research groups and their respective projects. Description of the project: We developed the online platform Doktaborse as an online marketplace for doctoral research projects. The platform enables authorized researchers to create working groups and upload, deactivate and change research projects within their institute. For interested students, a front end with integrated search function displays these projects in a structured and well-arranged way. In parallel, the Doktaborse provides for a comprehensive overview of research at the medical faculty. We evaluated Researchers' and students' use of the platform. Results: 96,6% of students participating in the evaluation (n=400) were in favor of a centralized research platform at the medical faculty. The platform grew at a steady pace and included 120 research groups in June 2016. The students appreciated the structure and design of the Doktaborse. Two thirds of all uploaded projects matched successfully with doctoral students via the platform and over 94% of researchers stated that they did not need technical assistance with uploading projects and handling the platform. Discussion: The Doktaborse represents an innovative and well accepted platform for doctoral research projects. The platform is perceived positively by researchers and students alike. However, students criticized limited extent and timeliness of offered projects. In addition, the platform serves as databank of research at the medical faculty of the LMU Munich. The future potential of this platform is to provide for an integrated management solution of doctoral thesis projects, possibly beyond the medical field and faculty. PMID- 28890922 TI - Concept and benefits of the Inverted Classroom method for a competency-based biochemistry course in the pre-clinical stage of a human medicine course of studies. AB - Background: Medical students often have a problem recognising the relevance of basic science subjects for their later professional work in the pre-clinical stage of their studies. This can lead to a lower motivation to learn biochemical content and dissatisfaction in the courses amongst the students. Alternative teaching methods such as the Inverted Classroom (IC) method can address this deficiency. The goal of this study was: to analyse the motivation and satisfaction of the students in a biochemistry seminar through the use of the e learning-based IC method, to investigate the acceptance against the IC teaching method in biochemistry, and to compare the learning success achieved using the IC approach with that of a traditional course. We also investigated how a biochemistry course in the pre-clinical stage of a human medicine course of studies can be successfully organised according to the IC method. Furthermore, we examined the benefits of the IC method over conventional teaching formats. Method: The IC method was implemented in accordance with the guidelines of the GMA committee "New Media" [30] in a biochemistry seminar for two student IC intervention groups with 42 students. A part of the factual knowledge from the on site phase in the form of teaching videos together with self-learning control tasks were provided online before the seminar for both IC intervention groups. Exporting content to the self-learning phase creates new free time in the on-site phase, during which the content can be critically considered and processed and additional competency-based learning objectives can be taught. Identical biochemistry teaching content was taught in parallel control groups (14 student groups with n=299 students), but no material was handed out beforehand for a self learning phase. These students only received the materials after the on-site phase. Motivation and satisfaction as well as the acceptance for the teaching methods were recorded by questionnaires, the acquisition of knowledge by MC exams. Results: On a Likert scale from 1 (strongly disagree) to 6 (strongly agree), the students in the IC intervention groups could be seen to be much more motivated (5.53) than students in the control group (4.01). Students in the IC intervention groups also recognised the relevance of the learning content much more clearly (5.44) than students in the control group (4.01). Furthermore, the IC group also observed that additional competencies were trained in addition to the biochemistry content. In addition, the IC intervention group award the event a school grade of 1.53, the traditional control group a grade of 2.96. The teaching videos were rated very positively by both groups with an average school grade of 1.3 in each case. A qualitative analysis showed that the motivation and a positive attitude of the lecturers played a decisive role in the successful implementation of the IC method. Discussion and conclusion: Pre-clinical students display a high acceptance of the e-learning-based IC method. Teaching communication competencies in a biochemistry seminar was also rated very positively by the students. The quality of the teaching video and the motivation of the lecturers were shown to be a critical parameter for the successful performance of the IC method. What's more, the IC method can contribute to implementing a competence orientation in medical studies. PMID- 28890923 TI - Publication activity in medical education research: A descriptive analysis of submissions to the GMS Zeitschrift fur Medizinische Ausbildung in 2007-2015. AB - Objectives: The significance of medical education research has increased internationally. In this context we investigated whether, and if so, how the quantity and quality of scientific papers reviewed and/or published by the GMS Zeitschrift fur Medizinische Ausbildung (GMS Z Med Ausbild) changed. Methods: The quantity and ratio of original papers, project reports and reviews submitted to or published in the GMS Z Med Ausbild were analysed. Published scientific articles were investigated in regard to the quality features "study type" and "mode of data collection" as well as the background (university affiliation) of the last authors. The citation frequency within the first five years after PubMed listing was compared to the one of BMC Medical Education in the corresponding period. Results: The number of submitted scientific manuscripts increased steadily. Most of the submissions and publications are original papers. For publications explorative studies and prospective data collection are most common. A shift over time is not observed. 16% of the published works come from one and 36% from four of the in total 39 universities represented by the last authors. The development of the citation frequency of articles published in GMS Z Med Ausbild is similar to that of BMC Medical Education. Conclusion: The rising number of submissions indicates an increasing significance of medical education research in German-speaking countries. The development of the number of citations reflects the growing appreciation of GMS Z Med Ausbild also indicated by the increasing number of online accesses. Our findings that study type and mode of data collection did not change has to be interpreted with caution since among other things choice and correct application of adequate methods are crucial regarding a scientific work's quality, too. These aspects, however, were not investigated in this paper. PMID- 28890924 TI - Measuring attitudes towards interprofessional learning. Testing two German versions of the tool "Readiness for Interprofessional Learning Scale" on interprofessional students of health and nursing sciences and of human medicine. AB - Objective: In order to verify the methodological quality of two versions of a tool for measuring attitudes towards interprofessional learning, we adapted - in terms of translation and scale form - the Heidelberg Version [1] of Readiness for Interprofessional Learning Scale - RIPLS [2], a methodologically controversial tool that had been translated into German, and compared both the original and new versions. Method: Three items were reworded and the scale form altered (from five to four levels), leading to the Halle Version that was validated by means of a cognitive pretest (n=6). Both questionnaires were completed by students taking the interprofessional degree program in Health and Nursing Sciences (HNS) and by students of Human Medicine. The test quality of both tools was examined by analyzing the main components and reliability using the scales allocation of the items as according to Parsell and Bligh [2]. Results: The questionnaires were randomly assembled and distributed to 331 students. The response was n=320 (HNS n=109; Medicine n=211). The Halle Version "RIPLS-HAL" of the questionnaire was completed by n=166 and the Heidelberg Version "RIPLS-HDB" by n=154. In the main component analysis the data could not depict the scale patterns of the original Australian tool. The reliability values of both the Heidelberg and Halle versions were only satisfactory for the "Teamwork and Collaboration" and "Professional Identity" scales. Conclusions: The German version of the Readiness for Interprofessional Learning Scale has only limited suitability for recording the attitude towards interprofessional learning. The present versions can be regarded as an approach towards developing a more suitable tool. PMID- 28890925 TI - On the road to becoming a responsible leader: A simulation-based training approach for final year medical students. AB - Background and objective: There is a need for young physicians to take a responsible role in clinical teams, comparable to a leadership role. However, today's medical curricula barely consider the development of leadership competencies. Acquisition of leadership skills are currently a by-product of medical education, even though it seems to be a competency relevant for physicians' success. Therefore, an innovative leadership training program for young physicians was developed and validated. Training conceptualisation were based upon findings of critical incidents interviews (N=19) with relevant personnel (e.g. experienced doctors/nurses, residents) and upon evidence-based leadership contents focusing on ethical leadership behaviors. Method: The training consists of four sessions (3-4 hours each) and provided evidence-based lectures of leadership theory and effective leader behaviors, interactive training elements and a simulation-based approach with professional role players focusing on interprofessional collaboration with care staff. Training evaluation was assessed twice after completion of the program (N=37). Assessments included items from validated and approved evaluation instruments regarding diverse learning outcomes (satisfaction/reaction, learning, self-efficacy, and application/transfer) and transfer indicators. Furthermore, training success predictors were assessed based on stepwise regression analysis. In addition, long term trainings effects and behavioral changes were analysed. Results: Various learning outcomes are achieved (self-reported training satisfaction, usefulness of the content and learning effects) and results show substantial transfer effects of the training contents and a strengthened awareness for the leadership role (e.g. self-confidence, ideas dealing with work-related problems in a role as responsible physician). We identified competence of trainer, training of applied tools, awareness of job expectations, and the opportunity to learn from experiences of other participants as predictors of training success. Additionally, we found long-term training effects and participants reported an increase in specific competencies, relevant for effective interprofessional collaboration (active perspective-taking, communication, conflict management, personal competencies). Conclusion: The training of leadership competencies for young physicians seems feasible to develop constructive influence strategies for a successful interprofessional collaboration in early career stages. The simulation-based approach is beneficial for residents to practice leadership behaviour in realistic job situations. PMID- 28890926 TI - Peer-Assisted History-Taking Groups: A Subjective Assessment of their Impact Upon Medical Students' Interview Skills. AB - Background and Objectives: Among the clinical skills needed by all physicians, history taking is one of the most important. The teaching model for peer-assisted history-taking groups investigated in the present study consists of small-group courses in which students practice conducting medical interviews with real patients. The purpose of this pilot study was to investigate the expectations, experiences, and subjective learning progress of participants in peer-assisted history-taking groups. Methods: The 42 medical student participants completed a 4 month, peer-assisted, elective history-taking course, which both began and ended with a subjective assessment of their interview skills by way of a pseudonymized questionnaire. Measures comprised the students' self-assessment of their interview skills, their expectations of, and their experiences with the course and especially with the peer tutors. Results: Medical students' most important motivations in attending peer-assisted history-taking groups were becoming able to complete a structured medical interview, to mitigate difficult interviewing situations, and to address patients' emotional demands appropriately. By the end of the course, students' self-assessment of both their interview skills and management of emotional issues improved significantly. Students especially benefitted from individual feedback regarding interview style and relationship formation, as well as generally accepted and had their expectations met by peer tutors. Conclusions: To meet the important learning objectives of history-taking and management of emotional issues, as well as self-reflection and reflection of student-patient interactions, students in the field greatly appreciate practicing medical interviewing in small, peer-assisted groups with real patients. At the same time, peer tutors are experienced to be helpful and supportive and can help students to overcome inhibitions in making contact with patients. PMID- 28890927 TI - Analysis of Six Reviews on the Quality of Instruments for the Evaluation of Interprofessional Education in German-Speaking Countries. AB - Background: More and more institutions worldwide and in German-speaking countries are developing and establishing interprofessional seminars in undergraduate education of health professions. In order to evaluate the different didactic approaches and different outcomes regarding the anticipated interprofessional competencies, it is necessary to apply appropriate instruments. Cross-cultural instruments are particularly helpful for international comparability. The Interprofessional Education working group of the German Medical Association (GMA) aims at identifying existing instruments for the evaluation of interprofessional education in order to make recommendations for German-speaking countries. Methods: Systematic literature research was performed on the websites of international interprofessional organisations (CAIPE, EIPEN, AIPEN), as well as in the PubMed and Cinahl databases. Reviews focusing on quantitative instruments to evaluate competencies according to the modified Kirkpatrick competency levels were searched for. Psychometrics, language/country and setting, in which the instrument was applied, were recorded. Results: Six reviews out of 73 literature research hits were included. A large number of instruments were identified; however, their psychometrics and the applied setting were very heterogeneous. The instruments can mainly be assigned to Kirkpatrick levels 1, 2a & 2b. Most instruments have been developed in English but their psychometrics were not always reported rigorously. Only very few instruments are available in German. Conclusion: It is difficult to find appropriate instruments in German. Internationally, there are different approaches and objectives in the measurement and evaluation of interprofessional competencies. The question arises whether it makes sense to translate existing instruments or to go through the lengthy process of developing new ones. The evaluation of interprofessional seminars with quantitative instruments remains mainly on Kirkpatrick levels 1 and 2. Levels 3 and 4 can probably only be assessed with qualitative or mixed methods. German language instruments are necessary. PMID- 28890928 TI - Conflicts of Interest in Medicine. A Systematic Review of Published and Scientifically evaluated Curricula. AB - Objective: Conflicts of interests resulting from interactions with pharmaceutical companies are pervasive in medicine and can result in an undue influence on physicians' decision-making. The objective of this systematic review is to analyze published and scientifically evaluated curricula for medical students and residents regarding such conflicts of interest. We begin by describing the covered topics and teaching methods; afterwards we analyze the quality of the curricula using the published data on their evaluations and comparing the content with content recommended for such curricula. Methods: We searched Pubmed, PsycInfo, EMBASE, OECD, WISO, SOWI and googlescholar up to and including the 5th of September 2016. Publications describing curricula for residents or medical students on the topic of conflicts of interest in medicine and evaluating them for their effects on the participants' learning were included. We analyzed the covered topics and the teaching methods used and compared them with recommendations by the American Medical Students' Association (AMSA) and Health Action International (HAI). Results: The literature search resulted in 20 publications that fulfilled our search criteria. In five trials, a control group was used, in no trial the participants were randomized to intervention or control group. 16/20 published curricula primarily covered marketing strategies by pharmaceutical companies, especially the interaction with pharmaceutical sales representatives (PSRs). Most curricula only covered a limited number of topics recommended by AMSA/HAI. The most frequent teaching method was a group discussion, which was used in 18/20 curricula; all curricula used at least one interactive teaching method. The evaluation of the curricula was heterogeneous in results as well as design. Some publications described a change of attitudes toward a stronger skepticism regarding interactions with pharmaceutical companies. Four publications described improved knowledge, one publication described a change in behavior toward a reduction of the acceptance of gifts. Conclusion: The trials conducted to this date regarding curricula on conflicts of interests are methodologically flawed and the described curricula lack important topics beyond marketing strategies of pharmaceutical companies. In addition, there are no data so far on the sustainability of the courses' effects on participants' behavior. It is therefore necessary to develop a model curriculum that covers a broader variety of topics and to evaluate it using a well thought out methodology to create a foundation for the further improvement of teaching conflicts of interest in medicine. PMID- 28890929 TI - Integrated Microfluidic System for Gene Silencing and Cell Migration. AB - Metastasis involves the phenotype transition of cancer cells to gain invasiveness, and the following migration at the tumor site. Here an integrated microfluidic chip to study this process is presented by combining on-chip delivery of siRNA for gene silencing and cell migration assay. The major advantage of the integrated chip is the simple input of cells and gene transfection materials, and the ultimate output of migration ability. The reverse fishbone structure and 0.7* phosphate-buffered saline solution are the optimized parameters for improved delivery efficiency. Using the chip, it is validated that cofilin plays an essential role in regulating cancer cell migration. The integrated chip may provide a simple and effective platform for biologists to easily check the role of specific genes in metastasis. PMID- 28890930 TI - Parkinson's disease associated with pure ATXN10 repeat expansion. AB - Large, non-coding pentanucleotide repeat expansions of ATTCT in intron 9 of the ATXN10 gene typically cause progressive spinocerebellar ataxia with or without seizures and present neuropathologically with Purkinje cell loss resulting in symmetrical cerebellar atrophy. These ATXN10 repeat expansions can be interrupted by sequence motifs which have been attributed to seizures and are likely to act as genetic modifiers. We identified a Mexican kindred with multiple affected family members with ATXN10 expansions. Four affected family members showed clinical features of spinocerebellar ataxia type 10 (SCA10). However, one affected individual presented with early-onset levodopa-responsive parkinsonism, and one family member carried a large repeat ATXN10 expansion, but was clinically unaffected. To characterize the ATXN10 repeat, we used a novel technology of single-molecule real-time (SMRT) sequencing and CRISPR/Cas9-based capture. We sequenced the entire span of ~5.3-7.0 kb repeat expansions. The Parkinson's patient carried an ATXN10 expansion with no repeat interruption motifs as well as an unaffected sister. In the siblings with typical SCA10, we found a repeat pattern of ATTCC repeat motifs that have not been associated with seizures previously. Our data suggest that the absence of repeat interruptions is likely a genetic modifier for the clinical presentation of l-Dopa responsive parkinsonism, whereas repeat interruption motifs contribute clinically to epilepsy. Repeat interruptions are important genetic modifiers of the clinical phenotype in SCA10. Advanced sequencing techniques now allow to better characterize the underlying genetic architecture for determining accurate phenotype-genotype correlations. PMID- 28890932 TI - Biceps Femoris Injury a Rarity: A Case Report. AB - Isolated biceps femoris rupture is a rare injury associated with limitation in the function of the knee. We present a 65-year-old man who sustained an isolated complete rupture of the tendon of the biceps femoris. The diagnostic was reached after clinical examination and magnetic resonance imaging of the affected knee. This case was treated with a surgical tendon reconstruction. The outcome was good and the patient was able to walk normally again without limitation, even if he did not comply with our recommendation. PMID- 28890931 TI - Rotigotine transdermal patch and sleep in Parkinson's disease: where are we now? AB - A wide range of sleep dysfunction complicates Parkinson's disease during its course from prodromal to palliative stage. It is now increasingly acknowledged that sleep disturbances are thus integral to the disease and pose a significant burden impacting on quality of life of patients. Sleep fragmentation, restless legs syndrome, nocturia, and nocturnal pain are regarded as one of the main components of night-time sleep dysfunction with possible secondary impact on cognition and well-being. The role of dopaminergic therapies, particularly using a continuous drug delivery strategy in managing some of these sleep issues, have been reported but the overall concept remains unclear. This review provides an overview of several aspects of night-time sleep dysfunction in Parkinson's disease and describes all available published open-label and blinded studies that investigated the use of rotigotine transdermal patch targeting sleep. Blinded studies have suggested beneficial effects of rotigotine transdermal patch on maintenance insomnia and restless legs syndrome in Parkinson's disease patients. Open-label studies support these observations and also suggest beneficial effects on nocturia and nocturnal pain. PMID- 28890933 TI - An Online Telepractice Model for the Prevention of Voice Disorders in Vocally Healthy Student Teachers Evaluated by a Smartphone Application. AB - This article describes the Global Voice Prevention Model (GVPM) facilitated with student teachers at West Chester University and the VoiceEvalU8 smartphone application (app) used to assess the effectiveness of the GVPM. Twenty-one participants completed 1 of 3 conditions (i.e., in-person GVPM, telepractice GVPM, and control). The in-person and telepractice conditions ran for 4 weeks during fall 2016, with 1 week dedicated to vocal education and vocal hygiene and 3 weeks spent in vocal training. The control condition ran for 1 week and included only vocal education and vocal hygiene. The VoiceEvalU8 app was used at pre- and post-condition twice a day for 5 days to record acoustic, perceptual, and aerodynamic voice measures. The study is ongoing; therefore, preliminary acoustic results for fundamental frequency (F0) and jitter% are presented from pre- to post-condition. During spring 2017, the participants were student teaching and using the VoiceEvalU8 app to record the voice measures before and after teaching all day. A new group of participants will be enrolled fall 2017 for selection into 1 of the 3 conditions and then continue on to student teaching spring 2018. PMID- 28890934 TI - Developing a Community-Based Participatory Research Curriculum to Support Environmental Health Research Partnerships: An Initiative of the GROWH Community Outreach and Dissemination Core. AB - BACKGROUND: The Transdisciplinary Research Consortium for Gulf Resilience on Women's Health (GROWH) addresses reproductive health disparities in the Gulf Coast by linking communities and scientists through community-engaged research. Funded by the National Institutes of Environmental Health Sciences, GROWH's Community Outreach and Dissemination Core (CODC) seeks to utilize community-based participatory research (CBPR) and other community-centered outreach strategies to strengthen resilience in vulnerable Gulf Coast populations. The CODC is an academic-community partnership comprised of Tulane University, Mary Queen of Vietnam Community Development Corporation, Bayou Interfaith Shared Community Organizing, and the Louisiana Public Health Institute (LPHI). METHODS: Alongside its CODC partners, LPHI collaboratively developed, piloted and evaluated an innovative CBPR curriculum. In addition to helping with curriculum design, the CODC's community and academic partners participated in the pilot. The curriculum was designed to impart applied, practical knowledge to community-based organizations and academic researchers on the successful formulation, execution and sustaining of CBPR projects and partnerships within the context of environmental health research. RESULTS: The curriculum resulted in increased knowledge about CBPR methods among both community and academic partners as well as improved relationships within the GROWH CODC partnership. CONCLUSION: The efforts of the GROWH partnership and curriculum were successful. This curriculum may serve as an anchor for future GROWH efforts including: competency development, translation of the curriculum into education and training products, community development of a CBPR curriculum for academic partners, community practice of CBPR, and future environmental health work. PMID- 28890935 TI - SKI-178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models. AB - AIM: To further characterize the selectivity, mechanism-of-action and therapeutic efficacy of the novel small molecule inhibitor, SKI-178. METHODS: Using the state of-the-art Cellular Thermal Shift Assay (CETSA) technique to detect "direct target engagement" of proteins intact cells, in vitro and in vivo assays, pharmacological assays and multiple mouse models of acute myeloid leukemia (AML). RESULTS: Herein, we demonstrate that SKI-178 directly target engages both Sphingosine Kinase 1 and 2. We also present evidence that, in addition to its actions as a Sphingosine Kinase Inhibitor, SKI-178 functions as a microtubule network disrupting agent both in vitro and in intact cells. Interestingly, we separately demonstrate that simultaneous SphK inhibition and microtubule disruption synergistically induces apoptosis in AML cell lines. Furthermore, we demonstrate that SKI-178 is well tolerated in normal healthy mice. Most importantly, we demonstrate that SKI-178 has therapeutic efficacy in several mouse models of AML. CONCLUSION: SKI-178 is a multi-targeted agent that functions both as an inhibitor of the SphKs as well as a disruptor of the microtubule network. SKI-178 induced apoptosis arises from a synergistic interaction of these two activities. SKI-178 is safe and effective in mouse models of AML, supporting its further development as a multi-targeted anti-cancer therapeutic agent. PMID- 28890936 TI - Object play in infants with autism spectrum disorder: A longitudinal retrospective video analysis. AB - BACKGROUND AND AIMS: Early play behaviors may provide important information regarding later-diagnosed developmental delays. Play behaviors of young children with autism spectrum disorder (ASD) are restricted in diversity, frequency, and complexity. Most ASD research focuses on play in children over 18 months of age. This study examined three groups of infants (later diagnosed with ASD, later diagnosed with other developmental disorders, and typically developing) with the aims of: (1) describing the play behaviors of the three groups of infants at two time points (9-12 months and 15-18 months); (2) examining group differences in four hierarchical levels of play at both time points; (3) comparing groups with respect to the highest level of play achieved; and (4) determining if the highest level of play achieved by infants with developmental delays, including ASD, correlated with later developmental outcomes. METHODS: The current study used longitudinal retrospective video analysis to examine object play behaviors of the three groups of infants (total n=92) at two time points (time 1: 9-12 months of age, and time 2: 15-18 months of age). Coding of play behaviors was based on existing literature and distribution of data from the current study. Developmental outcomes examined were measured using the Vineland Adaptive Behavior Scales, Childhood Autism Rating Scale, and a non-verbal developmental quotient calculated using visual reception scores from the Mullen Scales for Early Learning. RESULTS: Results indicate group differences in play, with infants later diagnosed with ASD showing significantly less sophisticated play than those with typical development. In addition, modest but significant correlations were found between highest level of play achieved at time 2 (15-18 months) and later outcomes for those with developmental disorders, including ASD. CONCLUSIONS AND IMPLICATIONS: Results suggest that examination of infant play behaviors is important for early screening and intervention planning to potentially mitigate effects on later developmental outcomes. PMID- 28890937 TI - Improvement of individual camouflage through background choice in ground-nesting birds. AB - Animal camouflage is a longstanding example of adaptation. Much research has tested how camouflage prevents detection and recognition, largely focusing on changes to an animal's own appearance over evolution. However, animals could also substantially alter their camouflage by behaviourally choosing appropriate substrates. Recent studies suggest that individuals from several animal taxa could select backgrounds or positions to improve concealment. Here, we test whether individual wild animals choose backgrounds in complex environments, and whether this improves camouflage against predator vision. We studied nest site selection by nine species of ground-nesting birds (nightjars, plovers and coursers) in Zambia, and used image analysis and vision modeling to quantify egg and plumage camouflage to predator vision. Individual birds chose backgrounds that enhanced their camouflage, being better matched to their chosen backgrounds than to other potential backgrounds with respect to multiple aspects of camouflage. This occurred at all three spatial scales tested (a few cm and five meters from the nest, and compared to other sites chosen by conspecifics), and was the case for the eggs of all bird groups studied, and for adult nightjar plumage. Thus, individual wild animals improve their camouflage through active background choice, with choices highly refined across multiple spatial scales. PMID- 28890938 TI - Positive selection inhibits gene mobilisation and transfer in soil bacterial communities. PMID- 28890939 TI - Adaptive modulation of antibiotic resistance through intragenomic coevolution. AB - Bacteria gain antibiotic resistance genes by horizontal acquisition of mobile genetic elements (MGE) from other lineages. Newly acquired MGEs are often poorly adapted causing intragenomic conflicts, resolved by compensatory adaptation of the chromosome, the MGE or reciprocal coadaptation. The footprints of such intragenomic coevolution are present in bacterial genomes, suggesting an important role promoting genomic integration of horizontally acquired genes, but direct experimental evidence of the process is limited. Here we show adaptive modulation of tetracycline resistance via intragenomic coevolution between Escherichia coli and the multi-drug resistant (MDR) plasmid RK2. Tetracycline treatments, including monotherapy or combination therapies with ampicillin, favoured de novo chromosomal resistance mutations coupled with mutations on RK2 impairing the plasmid-encoded tetracycline efflux-pump. These mutations together provided increased tetracycline resistance at reduced cost. Additionally, the chromosomal resistance mutations conferred cross-resistance to chloramphenicol. Reciprocal coadaptation was not observed under ampicillin-only or no antibiotic selection. Intragenomic coevolution can create genomes comprised of multiple replicons that together provide high-level, low-cost resistance, but the resulting co-dependence may limit the spread of coadapted MGEs to other lineages. PMID- 28890940 TI - Phylotranscriptomic consolidation of the jawed vertebrate timetree. AB - Phylogenomics is extremely powerful but introduces new challenges as no agreement exists on "standards" for data selection, curation and tree inference. We use jawed vertebrates (Gnathostomata) as model to address these issues. Despite considerable efforts in resolving their evolutionary history and macroevolution, few studies have included a full phylogenetic diversity of gnathostomes and some relationships remain controversial. We tested a novel bioinformatic pipeline to assemble large and accurate phylogenomic datasets from RNA sequencing and find this phylotranscriptomic approach successful and highly cost-effective. Increased sequencing effort up to ca. 10Gbp allows recovering more genes, but shallower sequencing (1.5Gbp) is sufficient to obtain thousands of full-length orthologous transcripts. We reconstruct a robust and strongly supported timetree of jawed vertebrates using 7,189 nuclear genes from 100 taxa, including 23 new transcriptomes from previously unsampled key species. Gene jackknifing of genomic data corroborates the robustness of our tree and allows calculating genome-wide divergence times by overcoming gene sampling bias. Mitochondrial genomes prove insufficient to resolve the deepest relationships because of limited signal and among-lineage rate heterogeneity. Our analyses emphasize the importance of large curated nuclear datasets to increase the accuracy of phylogenomics and provide a reference framework for the evolutionary history of jawed vertebrates. PMID- 28890941 TI - High-brightness Cs focused ion beam from a cold-atomic-beam ion source. AB - We present measurements of focal spot size and brightness in a focused ion beam system utilizing a laser-cooled atomic beam source of Cs ions. Spot sizes as small as (2.1 +/- 0.2) nm (one standard deviation) and reduced brightness values as high as (2.4 +/- 0.1) * 107 A m-2 Sr-1 eV-1 are observed with a 10 keV beam. This measured brightness is over 24 times higher than the highest brightness observed in a Ga liquid metal ion source. The behavior of brightness as a function of beam current and the dependence of effective source temperature on ionization energy are examined. The performance is seen to be consistent with earlier predictions. Demonstration of this source with very high brightness, producing a heavy ionic species such as Cs+, promises to allow significant improvements in resolution and throughput for such applications as next generation circuit edit and nanoscale secondary ion mass spectrometry. PMID- 28890942 TI - Hyperactivation in Cognitive Control and Visual Attention Brain Regions During Emotional Interference in Adolescent Depression. AB - BACKGROUND: Individuals with Major Depressive Disorder (MDD) are characterized by biases in attention to negative emotional material. While there is evidence that anomalous functioning in frontocingulate regions may underlie these biases, we know little about the neural correlates of negative emotional biases in depressed adolescents. METHODS: Eighteen adolescents diagnosed with MDD and 21 matched healthy control (CTL) adolescents underwent fMRI while performing an emotional distractor task. On each trial participants were presented with task-relevant house pairs and task-irrelevant face pairs. Participants indicated whether the house pairs were identical while ignoring the face pairs, which were either fearful, sad, or neutral. RESULTS: Despite equivalent behavioral performance (response time and accuracy) between groups, adolescents with MDD exhibited greater activation in frontocingulate regions, including dorsal anterior cingulate cortex (dACC) and inferior frontal gyrus/middle frontal gyrus (IFG/MFG), and occipitoparietal regions, including lateral occipital cortex and superior parietal lobule when ignoring fearful versus neutral faces. Response times to these trial conditions also correlated negatively with activation in IFG/MFG and lateral occipital cortex suggesting these regions are recruited in order to effectively ignore emotional distractors. Groups did not differ when ignoring sad versus neutral faces or fearful versus sad faces. CONCLUSIONS: Adolescents with MDD recruit both cognitive control and visual attention regions to a greater degree than do CTL adolescents, reflecting greater cognitive demand when downregulating threat-related stimuli. PMID- 28890944 TI - The Cortical Network for Braille Writing in the Blind. AB - Fundamental forms of high-order cognition, such as reading and writing, are usually studied in the context of one modality - vision. People without sight, however, use the kinesthetic-based Braille writing, and haptic-based Braille reading. We asked whether the cognitive and motor control mechanisms underlying writing and reading are modality-specific or supramodal. While a number of previous functional Magnetic Resonance Imaging (fMRI) studies have investigated the brain network for Braille reading in the blind, such studies on Braille writing are lacking. Consequently, no comparative network analysis of Braille writing vs. reading exists. Here, we report the first study of Braille writing, and a comparison of the brain organization for Braille writing vs Braille reading. FMRI was conducted in a Siemens 3T Trio scanner. Our custom MRI compatible drawing/writing lectern was further modified to provide for Braille reading and writing. Each of five paragraphs of novel Braille text describing objects, faces and navigation sequences was read, then reproduced twice by Braille writing from memory, then read a second time. During Braille reading, the haptic-sensing of the Braille letters strongly activated not only the early visual area V1 and V2, but some highly specialized areas, such as the classical visual grapheme area and the Exner motor grapheme area. Braille-writing-from memory, engaged a significantly more extensive network in dorsal motor, somatosensory/kinesthetic, dorsal parietal and prefrontal cortex. However, in contrast to the largely extended V1 activation in drawing-from-memory in the blind after training (Likova, 2012), Braille writing from memory generated focal activation restricted to the most foveal part of V1, presumably reflecting topographically the focal demands of such a "pin-pricking" task. PMID- 28890943 TI - Trial of Amiloride in Type 2 Diabetes with Proteinuria. AB - INTRODUCTION: Renal Na+ retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome, which occurs even in the absence of activation of hormones that stimulate renal Na+ transporters. Plasmin-dependent activation of the epithelial Na+ channel (ENaC) has been proposed to have a role in renal Na+ retention in the setting of nephrotic syndrome. We hypothesized that the ENaC inhibitor amiloride would be an effective therapeutic agent in inducing a natriuresis and lowering blood pressure in individuals with macroscopic proteinuria. METHODS: We conducted a pilot double-blind randomized cross-over study comparing the effects of daily administration of either oral amiloride or hydrochlorothiazide (HCTZ) to patients with type 2 diabetes and macroscopic proteinuria. Safety and efficacy were assessed by monitoring systolic blood pressure (SBP), kidney function, adherence, weight, urinary Na+ excretion and serum electrolytes. Nine subjects were enrolled in the trial. RESULTS: No significant difference in SBP or weight was seen between HCTZ and amiloride (p>=0.15). Amiloride induced differences in serum K+ (p<0.001), with a 0.88+/ 0.30 mmol/L greater acute increase observed. Two subjects developed acute kidney injury and hyperkalemia when treated with amiloride. Four subjects had readily detectable levels of urinary plasminogen plus plasmin (uPl), and five did not. Changes in SBP in response to amiloride did not differ between individuals with vs. those without detectable uPl. CONCLUSION: In summary, among patients with type 2 diabetes, normal renal function and proteinuria, there were reductions in SBP in groups treated with HCTZ or amiloride. Acute kidney injury and severe hyperkalemia were safety concerns with amiloride. PMID- 28890945 TI - TEACH Kitchen: A Chronological Review of Accomplishments. AB - BACKGROUND: The Eating and Cooking Healthy (TEACH) Kitchen was founded at the Medical College of Georgia in 2015 as a nutrition-based intervention to combat the high prevalence of obesity and obesity-related chronic diseases in the area of Augusta, Georgia. Despite the importance of diet in the management of chronic diseases, inadequate nutrition education among patients and healthcare providers presents a barrier. The purpose of TEACH Kitchen is to address this gap. METHODS: TEACH Kitchen is as a student-led initiative that promotes healthy cooking among medical students and patients with chronic diseases. Healthy nutrition and cooking classes are held during the academic year. Participants spend four weeks on each of four modules: obesity, hypertension, hyperlipidemia, and diabetes mellitus. Data collection, which began in January 2017, is currently on going. TEACH Kitchen has collaborated with Augusta University, Sodexo, and Kohl's. RESULTS: Currently, TEACH Kitchen has enrolled 14 patients and 6 children. Anticipated results include measurements of pre-and post-intervention changes in knowledge, attitudes, beliefs, and competence in nutrition, as well as differences in clinical indicators, including body mass index, blood pressure, lipid profile, and HbA1c. CONCLUSIONS: TEACH Kitchen is the first medical school based nutrition/cooking education initiative in Augusta, Georgia. It provides patients and medical students with hands-on healthy nutrition/cooking experience with the goal of decreasing the prevalence and improving the outcome of obesity related diseases. PMID- 28890947 TI - Strain Engineering a 4a*?3a Charge Density Wave Phase in Transition Metal Dichalcogenide 1T-VSe2. AB - We report a rectangular charge density wave (CDW) phase in strained 1T-VSe2 thin films synthesized by molecular beam epitaxy on c-sapphire substrates. The observed CDW structure exhibits an unconventional rectangular 4a*?3a periodicity, as opposed to the previously reported hexagonal 4a*4a structure in bulk crystals and exfoliated thin layered samples. Tunneling spectroscopy shows a strong modulation of the local density of states of the same 4a*?3a CDW periodicity and an energy gap of 2DeltaCDW = (9.1 +/- 0.1) meV. The CDW energy gap evolves into a full gap at temperatures below 500 mK, indicating a transition to an insulating phase at ultra-low temperatures. First-principles calculations confirm the stability of both 4a*4a and 4a*?3a structures arising from soft modes in the phonon dispersion. The unconventional structure becomes preferred in the presence of strain, in agreement with experimental findings. PMID- 28890949 TI - Designing Contestability: Interaction Design, Machine Learning, and Mental Health. AB - We describe the design of an automated assessment and training tool for psychotherapists to illustrate challenges with creating interactive machine learning (ML) systems, particularly in contexts where human life, livelihood, and wellbeing are at stake. We explore how existing theories of interaction design and machine learning apply to the psychotherapy context, and identify "contestability" as a new principle for designing systems that evaluate human behavior. Finally, we offer several strategies for making ML systems more accountable to human actors. PMID- 28890948 TI - Green environment and incident depression in South Africa: a geospatial analysis and mental health implications in a resource-limited setting. AB - BACKGROUND: Unprecedented levels of habitat transformation and rapid urbanisation are changing the way individuals interrelate with the natural environment in developing countries with high economic disparities. Although the potential benefit of green environments for mental health has been recognised, population level evidence to this effect is scarce. We investigated the effect of green living environment in potentially countering incident depression in a nationally representative survey in South Africa. METHODS: We used panel data from the South African National Income Dynamics Study (SA-NIDS). Our study used SA-NIDS data from three waves: wave 1 (2008), wave 2 (2010), and wave 3 (2012). Households were sampled on the basis of a stratified two-stage cluster design. In the first stage, 400 primary sampling units were selected for inclusion. In the second stage, two clusters of 12 dwelling units each were drawn from within each primary sampling unit (or 24 dwelling units per unit). Household and individual adult questionnaires were administered to participants. The main outcome, incident depression (ie, incident cohort of 11 156 study participants without significant depression symptoms at their first entry into SA-NIDS), was assessed in the adult survey via a ten item version of the Center for Epidemiologic Studies Depression Scale; a total score of ten or higher was used as a cutoff to indicate significant depressive symptoms. Each participant was assigned a value for green living space via a satellite-derived normalised difference vegetation index (NDVI) based on the GPS coordinates of their household location. FINDINGS: Overall, we found uneven benefit of NDVI on incident depression among our study participants. Although the green living environment showed limited benefit across the study population as a whole, our final analysis based on logistic regression models showed that higher NDVI was a predictor of lower incident depression among middle-income compared with low-income participants (adjusted odds ratio [aOR] 0.98, 0.97-0.99, p<0.0001), although when this analysis was broken down by race, its positive effect was particularly evident amongst African individuals. Living in rural areas was linked to lower odds of incident depression (aOR 0.71, 0.55 0.92, p=0.011) compared with study participants residing in urban informal areas that often lack formal planning. INTERPRETATION: Our results imply the importance of green environments for mental wellbeing in sub-Saharan African settings experiencing rapid urbanisation, economic and epidemiological transition, reaffirming the need to incorporate environmental services and benefits for sustainable socioeconomic development. FUNDING: South African Medical Research Council, National Institutes of Health, and Academy of Finland. PMID- 28890946 TI - OncoKB: A Precision Oncology Knowledge Base. AB - PURPOSE: With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base. METHODS: OncoKB annotates the biological and oncogenic effect and the prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response based on US Food and Drug Administration (FDA) labeling, National Comprehensive Cancer Network (NCCN) guidelines, disease-focused expert group recommendations and the scientific literature. RESULTS: To date, over 3000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public web resource (http://oncokb.org/) and are also incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers. CONCLUSION: OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions. PMID- 28890950 TI - Creating Conditions for Patients' Values to Emerge in Clinical Conversations: Perspectives of Health Care Team Members. AB - Eliciting, understanding, and honoring patients' values- the things most important to them in daily life-is a cornerstone of patient-centered care. However, this rarely occurs explicitly as a routine part of clinical practice. This is particularly problematic for individuals with multiple chronic conditions (MCC) because they face difficult choices about how to balance competing demands for self-care in accordance with their values. In this study, we sought to inform the design of interventions to support conversations about patient values between patients with MCC and their health care providers. We conducted a field study that included observations of 21 clinic visits for patients who have MCC, and interviews with 16 care team members involved in those visits. This paper contributes a practice-based account of ways in which providers engage with patient values, and discusses how future work in interactive systems design might extend and enrich these engagements. PMID- 28890951 TI - High Performance, Low Cost Carbon Nanotube Yarn based 3D Printed Electrodes Compatible with a Conventional Screen Printed Electrode System. AB - 3D printing technology has been widely used as a rapid prototyping fabrication tool in several fields, including electrochemistry. In this work, we incorporate 3D printing technology with carbon nanotube yarns for electrochemical sensing of dopamine in the presence of ascorbic acid and uric acid. The novel 3D printed electrode provides a circular concavity detection zone with grooves to insert three electrodes. The electrode connections are fully compatible with conventional screen printed electrode workstation setups. The CNT yarn 3D printed electrode showed excellent electrocatalytic activity for the redox reaction of dopamine (DA) in the presence of ascorbic acid (AA) and uric acid (UA). Three well-defined sharp and fully resolved anodic peaks were found with the peak potentials using cyclic voltammetry (CV) at 50 mV, 305 mV, and 545 mV for AA, DA, and UA respectively and using differential pulse voltammetry (DPV) at 91 mV, 389 mV, and 569 mV, respectively. DA detection limit was 0.87 +/- 0.09 MUM. The CNT yarn 3D printed electrode displayed high reproducibility and stability. The electrode design enables the study of electrode reactions at the sidewall of CNTs, which cannot be performed using electrodes made by conventional fabrication methods. The new fabrication method provides a new platform to prototype new electrode materials for electrochemistry, providing a low-cost, customizable design compatible existing screen printed electrodes technology. PMID- 28890952 TI - Oxidative Stress: A Potential Therapeutic Target in Placental Malaria. AB - Placental malaria, characterized by sequestration of Plasmodium falciparum in the maternal placental blood space and associated inflammatory damage, contributes to poor birth outcomes and ~200,000 infant deaths annually. Specific mechanisms that contribute to placental damage and dysfunction during malaria are not completely understood. To investigate a potential role for oxidative stress, antioxidant genes and markers for oxidative damage were assessed by quantitative PCR and immunohistochemistry in Plasmodium chabaudi AS-infected pregnant mice. Widespread evidence of lipid peroxidation was observed and was associated with higher antioxidant gene expression in conceptuses of infected mice. To assess the extent to which this oxidative damage might contribute to poor birth outcomes and be amenable to therapeutic intervention, infected pregnant mice were treated with N acetylcysteine, a free radical scavenger, or tempol, an intracellular superoxide dismutase mimetic. The results show that mice treated with N-acetylcysteine experienced malaria induced-pregnancy loss at the same rate as control animals and failed to mitigate placental oxidative damage. In contrast, tempol-treated mice exhibited subtle improvement in embryo survival at gestation day 12. Although lipid peroxidation was not consistently reduced in the placentas of these mice, it was inversely related to embryo viability. Moreover, reduced IFN gamma and CCL2 plasma levels in treated mice were associated with midgestational embryo viability. Thus, although oxidative stress is remarkable in placental malaria and its mitigation by antioxidant therapy may improve pregnancy outcomes, the underlying mechanistic basis and potential therapeutic strategies require additional investigation. PMID- 28890953 TI - The Effects of Metal Ions on Heparin/Heparin Sulfate-Protein Interactions. AB - Heparin/heparin sulfate (HS) interacts with a number of proteins thereby playing an essential role in the regulation of many physiological processes. The understanding of heparin/HS-protein interactions at the molecular level is of fundamental importance to biology and will aid in the development of highly specific glycan-based therapeutic agents. The heparin-binding proteins (HBPs) interact with sulfated domains of heparin/HS chains primarily through ionic attraction between negatively charged groups in HS/heparin chains and basic amino acid residues within the protein. Reports in literature have been shown that heparin molecules have a high affinity for a wide range of metal ions. In the present study, we used surface plasmon resonance (SPR) to study the effects of metal ions (under physiological and non-physiological concentrations) on heparin/HS-protein interactions. The results showed that under non-physiological of metal ion concentration, different metal ions showed different effects on heparin binding to fibroblast growth factor-1 (FGF1) and interleakin-7 (IL7). While the effects of individual metal ion at physiological concentrations had little impact on protein binding, the mixed metal ions reduced the FGF1/heparin or IL7/heparin binding affinity, changing its binding profile. PMID- 28890955 TI - Opportunities for Fluorochlorozirconate and Other Glass-Ceramic Detectors in Medical Imaging Devices. AB - This article gives an overview of fluorochlorozirconate glass-ceramic scintillators and storage phosphor materials: how they are synthesized, what their properties are, and how they can be used in medical imaging. Such materials can enhance imaging in x-ray radiography, especially mammography and dental imaging, computed tomography, and positron emission tomography. Although focusing on fluorochlorozirconate materials, the reader will find the discussion is relevant to other luminescent glass and glass-ceramic systems. PMID- 28890956 TI - Spin-dependent transport properties of zigzag phosphorene nanoribbons with oxygen saturated edges. AB - We investigate the electronic structures and electronic transport properties of zigzag phosphorene nanoribbons with oxygen-saturated edges (O-zPNRs) by using the spin-polarized density functional theory and the nonequilibrium Green's function method. The results show that the O-zPNR is an antiferromagnetic (AFM) or ferromagnetic (FM) semiconductor with spins localized at two ribbon edges anti parallel or parallel with each other. The electronic transmission for the single AFM or FM O-zPNR is zero when a bias voltage is applied to the two electrodes made of the same type O-zPNR. Nonzero transmission arises for the AFM-AFM and FM FM O-zPNR heterojunctions. The transmission spectrum and the electrical current are fully spin polarized for the FM-FM O-zPNR heterojunction. An in-plane transverse electrical field can effectively manipulate the electronic structure and spin-dependent electronic transport. It induces splitting of the spins of the two edges and makes the AFM O-zPNR become a half metal. Moreover, the transverse electrical field gives rise to the transmission spectrum and the spin polarized electrical current for the AFM-AFM O-zPNR heterojunction. The degree of spin polarization can be tuned by the strength of the transverse field. PMID- 28890954 TI - Mesenchymal Stem Cell Paracrine Factors in Vascular Repair and Regeneration. AB - Mesenchymal stem cell therapy show great optimism in the treatment of several diseases. MSCs are attractive candidates for cell therapy because of easy isolation, high expansion potential giving unlimited pool of transplantable cells, low immunogenicity, amenability to ex vivo genetic modification, and multipotency. The stem cells orchestrate the repair process by various mechanisms such as transdifferentiation, cell fusion, microvesicles or exosomes and most importantly by secreting paracrine factors. The MSCs release several angiogenic, mitogenic, anti-apoptotic, anti-inflammatory and anti-oxidative factors that play fundamental role in regulating tissue repair in various vascular and cardiac diseases. The therapeutic release of these factors by the cells can be enhanced by several strategies like genetic modification, physiological and pharmacological preconditioning, improved cell culture and selection methods, and biomaterial based approaches. The current review describes the impact of paracrine factors released by MSCs on vascular repair and regeneration in myocardial infarction, restenosis and peripheral artery disease, and the various strategies adopted to enhance the release of these paracrine factors to enhance organ function. PMID- 28890957 TI - Clustering of PK-trisaccharides on amphiphilic cyclodextrin reveals unprecedented affinity for the Shiga-like toxin Stx2. AB - Using amphiphilic cyclodextrin as a scaffold, the first class of PK glycoconjugates capable of high avidity binding to both Stx1 and Stx2 toxins in solid-phase assay formats is reported. The generated glycomicroarray effectively mimics the plasma membrane surface while discriminating binding of the two Stx toxins, with unprecedented affinity to Stx2. PMID- 28890958 TI - Nickel-catalyzed ring-opening of alpha-hydroxycyclobutenones with a remarkable ligand effect. AB - A Ni-catalyzed ring-opening of alpha-hydroxycyclobutenones is reported herein. A remarkable ligand effect was observed during transformations following the ring opening. The employment of PPh3 leads to the formation of 2-furanones 2 through a migration of an alkoxyl group, and 2-furanones 3 were generated through a migration of hydrogen in the presence of Xantphos, affording a divergent approach to 2-furanones bearing multiple functional groups. PMID- 28890959 TI - A theory for the effect of patch/non-patch attractions on the self-assembly of patchy colloids. AB - In this paper, we develop a thermodynamic perturbation theory to describe the self-assembly of patchy colloids which exhibit both patch-patch attractions as well as patch/non-patch attractions. That is, patches attract other patches as well as the no patch region (we call this region Psi). In general, the patch patch and patch-Psi attractions operate on different energy scales allowing for a competition between different modes of attraction. This competition may result in anomalous thermodynamic properties. As an application, we tune the patch parameters to reproduce the liquid density (suitably scaled) maximum of water. It is then shown that the liquid branch of the colloids phase diagram has liquid densities consistent with both saturated and super-cooled liquid water. Finally, it is shown that the colloids reproduce water's anomalous minimum in isothermal compressibility and negative volume expansivity. PMID- 28890960 TI - Reduction of intrinsic defects in hybrid perovskite films via precursor purification. AB - A simple chemical process was developed in a scalable manner, to reduce trap states in perovskite absorbers from the very beginning. The obvious decrease of I2 in methylammonium iodide and the decrease of trap density in the resultant films were identified, which led to the power conversion efficiency (PCE) of perovskite solar cells (PSCs) increase from 16.5% to 18.5%. PMID- 28890961 TI - Two-dimensional pattern formation in ionic liquids confined between graphene walls. AB - We perform molecular dynamics simulations of ionic liquids confined between graphene walls under a large variety of conditions (pure ionic liquids, mixtures with water and alcohols, mixtures with lithium salts and defective graphene walls). Our results show that the formation of striped and hexagonal patterns in the Stern layer can be considered as a general feature of ionic liquids at electrochemical interfaces, the transition between patterns being controlled by the net balance of charge in the innermost layer of adsorbed molecules. This explains previously reported experimental and computational results and, for the first time, why these pattern changes are triggered by any perturbation of the charge density at the innermost layer of the electric double layer (voltage and composition changes, and vacancies at the electrode walls, among others), which may help tuning electrode-ionic liquid interfaces. Using Monte Carlo simulations we show that such structures can be reproduced by a simple two-dimensional lattice model with only nearest-neighbour interactions, governed by highly screened ionic interactions and short-range and excluded volume interactions. We also show that the results of our simulations are consistent with those inferred from the Landau-Brazovskii theory of pattern formation in self-assembling systems. The presence of these patterns at the ionic liquid graphene-electrode interfaces may have a strong impact on the process of ionic transfer from the bulk mixtures to the electrodes, on the differential capacitance of the electrode electrolyte double layer or on the rates of redox reactions at the electrodes, among other physicochemical properties, and is therefore an effect of great technological interest. PMID- 28890962 TI - Evidence for the spontaneous formation of N-heterocyclic carbenes in imidazolium based ionic liquids. AB - We present a study of the reactions of aldehydes in ionic liquids which gives evidence for the spontaneous formation of N-heterocyclic carbenes in ionic liquids based on 1,3-dialkyl substituted imidazolium cations from the lack of a deuterium isotope effect on the reaction of these ionic liquids with aldehydes. PMID- 28890963 TI - Structure relaxation via long trajectories made stable. AB - Molecular dynamics (MD) is appearing in increasing applications in materials science, nanotechnologies, condensed matter physics, computational physics, biochemistry, and biophysics. Finding mechanically static equilibrium configurations of molecular systems is one of the most practical tasks in MD. Most existing potential energy optimization algorithms do not permit searching equilibrium configurations through longer MD trajectories. We introduce a simple method of utilizing a microcanonical (NVE) ensemble to obtain static equilibriums of molecular systems, that is significantly faster than the standard implementations of quick-min (QM) and fast inertial relaxation engine (FIRE) optimization algorithms. The new method is based on the capability of NVE to convert potential energy to kinetic energy. The surprising efficiency of the method is illustrated using an indentation test on monolayer graphene and, in particular, the versatility of the method is illustrated using relaxation of a polystyrene chain through longer MD trajectories and large deformation. The capability of the new method in finding more stable equilibrium configurations than common optimization algorithms is demonstrated in relaxation of a pressured lubricating oil layer and a warped monolayer graphene cantilever. PMID- 28890964 TI - Utilization of the dye N-methyl-6-oxyquinolone as an optical acidometer in molecular solvents and protic ionic liquids. AB - We developed a procedure to use the highly sensitive dye N-methyl-6-oxyquinolone as an acidity probe in molecular solvents and protic ionic liquids. The combination of well-established stationary UV-vis absorption and the mathematical algorithm of singular value decomposition allows the determination of the amount of acidic protons even in complex solvents like ionic liquids. PMID- 28890965 TI - Direct observation of the photoinduced electron transfer processes of bis(4 arylphenylamino benzo)-ortho-carborane using transient absorption spectroscopic measurements. AB - The intramolecular photoinduced electron transfer (PET) processes of three bis(4 arylphenylamino benzo)-ortho-carboranes (ArCbAr, Ar = phenyl (Ph), naphthyl (Np) and pyrenyl (Py)) triads were investigated in CH2Cl2 and n-hexane using the femtosecond time-resolved transient absorption (TA) spectroscopic technique. In CH2Cl2, the transient S1-Sn absorption band of 1ArCbAr* was observed at short delay times. Concomitant with the decay of 1ArCbAr*, the TA bands for cation radical species were detected at around 700 nm for Ph+, 650 nm for Np+, and 580 nm Py+. At the same time, the TA band of the carborane anion radical (Cb-) was observed at around 430 nm. This implies that the intramolecular PET process occurs from the 1ArCbAr* state. The TA bands of the cationic and anionic radical species can be assigned by comparison to the absorption spectra of an electrochemically generated radical species. The PET process also occurs in n hexane, as demonstrated by the monitoring of radical species in the TA spectra. In n-hexane, the TA band for Ar+ interfered with the aggregation induced emission (AIE) at early delay times. The long lived Ar+ species can be observed in the TA spectra at long delay times after fading of the AIE. The PET is exergonic in both solvents, as shown by the negative Gibbs energies (DeltaG) for the PET processes. PMID- 28890966 TI - Intracellular temperature measurements with fluorescent polymeric thermometers. AB - In 2003, we successfully created the first fluorescent polymeric thermometer by combining a thermo-responsive polymer and an environment-sensitive (polarity and hydrogen bonding-sensitive) fluorophore. Its high sensitivity to temperature variation and high hydrophilicity, even under conditions of high ionic strength, enabled intracellular temperature measurements. Along with the progress of our research projects, the development of new luminescent molecular thermometers and the establishment of novel methods for measuring intracellular temperature have matured in this field. In this Feature Article, we summarize the background and history of intracellular temperature measurements using fluorescent polymeric thermometers based on studies performed in our laboratory and the relationship between our methods and those of other eminent research groups. Future research directions regarding intracellular temperature measurements are also discussed. PMID- 28890967 TI - Syntheses and effectiveness of functional peptide-based RAFT agents. AB - In this study, a series of functional peptide-based RAFT agents were designed and synthesized by the solid-phase supported peptide synthesis method. These novel RAFT agents have enabled chemists to make well-defined peptide-polymer conjugates with complicated topological structures. Additionally, our results have shown an unexpected reaction that takes place during these syntheses, and the conversion of a nitrile group to a carboxamide group has been evidently elucidated and unambiguously confirmed. PMID- 28890968 TI - Ultrafast flavin photoreduction in an oxidized animal (6-4) photolyase through an unconventional tryptophan tetrad. AB - Photolyases are flavoenzymes repairing UV-induced lesions in DNA, which may be activated by a photoreduction of their FAD cofactor. In most photolyases, this photoreduction proceeds by electron transfer along a chain of three tryptophan (Trp) residues, connecting the flavin to the protein surface. Much less studied, animal (6-4) photolyases (repairing pyrimidine-pyrimidone (6-4) photoproducts) are particularly interesting as they were recently shown to have a longer electron transfer chain, counting four Trp residues. Using femtosecond polarized transient absorption spectroscopy, we performed a detailed analysis of the photoactivation reaction in the (6-4) photolyase of Xenopus laevis with oxidized FAD. We showed that the excited flavin is very quickly reduced (~0.5 ps) by a nearby tryptophan residue, yielding FAD- and WH+ radicals. Subsequent kinetic steps in the picosecond regime were assigned to the migration of the positive charge along the Trp tetrad, in competition with charge recombination. We propose that the positive charge is actually delocalized over various Trp residues during most of the dynamics and that charge recombination essentially occurs through the proximal tryptophanyl radical. Oxidation of the fourth tryptophan is thought to be reached about as fast as that of the third one (~40 ps), based on a comparison with a mutant protein lacking the distal Trp, implying ultrafast electron transfer between these two residues. This unusual mechanism sheds light on the rich diversity of electron transfer pathways found in various photolyases, and evolution-related cryptochromes alike. PMID- 28890969 TI - Triazolium cyclodextrin click cluster-resin conjugate: an enrichment material for phosphatidylinositol (3,4,5)-triphosphate. AB - UltraLink was functionalized with a triazolium cyclodextrin click cluster (CCC) which provides a well-oriented, multivalent, positively charged binding site for PtdIns(3,4,5)P3. MALDI TOF MS and LC ESI MS/MS MRM analysis of spiked PtdIns(3,4,5)P3 in lipid extract suggest that triazolium CCC-UltraLink conjugate can be used as an enrichment material for PtdIns(3,4,5)P3. PMID- 28890970 TI - Dynamic protein self-assembly driven by host-guest chemistry and the folding unfolding feature of a mutually exclusive protein. AB - A novel exploration utilizing a well-designed fusion protein containing a redox stimuli-responsive domain was developed to construct dynamic protein self assemblies induced by cucurbit[8]uril-based supramolecular interactions. The reversible interconversion of the morphology of the assemblies between nanowires and nanorings was regulated precisely by redox conditions. PMID- 28890971 TI - Quantitative interpretation of impedance spectroscopy data on porous LSM electrodes using X-ray computed tomography and Bayesian model-based analysis. AB - It is broadly understood that strontium-doped lanthanum manganate (LSM) cathodes for solid oxide fuel cells (SOFCs) have two pathways for the reduction of oxygen: a surface-mediated pathway culminating in oxygen incorporation into the electrolyte at the triple-phase boundary (TPB), and a bulk-mediated pathway involving oxygen transfer across the electrode-electrolyte interface. Patterned electrode and thin film experiments have shown that both pathways are active in LSM. Porous electrode geometries more commonly found in SOFCs have not been amenable for precise measurement of active electrode width because of the difficulty in precisely measuring the electrode geometry. This study quantitatively compares a reaction-diffusion model for the oxygen reduction reaction in LSM to the impedance spectrum of an experimental LSM porous electrode symmetric button cell on a yttria-stabilized zirconia (YSZ) electrolyte. The porous microstructure was characterized using computed tomography (nano-CT) and Bayesian model-based analysis (BMA) was used to estimate model parameters. BMA produced good fits to the data, with higher than expected values for the interfacial capacitance at the LSM-YSZ interface and vacancy diffusion activation energy; these results may indicate that the active width of the electrode is on a similar scale with that of the space-charge width at the LSM-YSZ interface. The analysis also showed that the active width and proportion of current moving through the bulk pathway is temperature dependent, in accordance with patterned electrode results. PMID- 28890972 TI - Nanomechanical sensors for direct and rapid characterization of sperm motility based on nanoscale vibrations. AB - Infertility, whether of male or female origin, is a critical challenge facing the low birth rate and aging population throughout the world, and semen analysis is a cornerstone of the diagnostic evaluation of the male contribution to infertility. This means that tools which can characterize sperm properties in an effective manner are very much needed. The conventional approaches are essentially image based, which have a limited value for analyzing sperm properties. Here, we show that an assay using nanomechanical sensors can detect sperm motility based on nanomotion. We use microcantilever sensors to directly characterize the mechanical response of the sperm based on the fluctuations of microcantilevers. We applied this methodology to sperms exposed to different chemical or physical agents. Real-time nanomechanical fluctuations showed that living sperms produced smaller fluctuations after treatment with inhibitory chemicals, and larger fluctuations after treatment with stimulatory chemicals. Our preliminary experiments suggest that the frequency of fluctuation is associated with sperm motility. This technique offers a brand-new perspective in the characterization of the sperm. By combining conventional measurements, reproductive medicine doctors and researchers should now be able to achieve unprecedented depth in the sperm properties. PMID- 28890974 TI - A nickel-phyllosilicate core-echinus catalyst via a green and base additive free hydrothermal approach for hydrogenation reactions. AB - We report a new hydrothermal and basic-additive free process for synthesizing a core(single-crystalline HBEA zeolite)-echinus(nickel phyllosilicate) catalyst, which exhibits excellent reactivity and stability for hydrogenation reactions. Desilication and dealumination processes generate substantial SiO32- ions and exposed Si-OH groups to form nickel phyllosilicate on the external and internal surfaces of zeolite. PMID- 28890973 TI - Highly dispersed ultra-small Pd nanoparticles on gadolinium hydroxide nanorods for efficient hydrogenation reactions. AB - Heterogeneous catalytic hydrogenation reactions are of great importance to the petrochemical industry and fine chemical synthesis. Herein, we present the first example of gadolinium hydroxide (Gd(OH)3) nanorods as a support for loading ultra small Pd nanoparticles for hydrogenation reactions. Gd(OH)3 possesses a large number of hydroxyl groups on the surface, which act as an ideal support for good dispersion of Pd nanoparticles. Gd(OH)3 nanorods are prepared by hydrothermal treatment, and Pd/Gd(OH)3 catalyst with a low loading of 0.95 wt% Pd is obtained by photochemical deposition. The catalytic hydrogenation of p-nitrophenol (4-NP) to p-aminophenol (4-AP) and styrene to ethylbenzene is performed as a model reaction. The obtained Pd/Gd(OH)3 catalyst displays excellent activity as compared to other reported heterogeneous catalysts. The rate constant of 4-NP reduction is measured to be 0.047 s-1 and the Pd/Gd(OH)3 nanocatalyst shows no marked loss of activity even after 10 consecutive cycles. Additionally, the hydrogenation of styrene to ethylbenzene over Pd/Gd(OH)3 nanorods exhibits a turnover frequency (TOF) as high as 6159 h-1 with 100% selectivity. Moreover, the catalyst can be recovered by centrifugation and recycled for up to 5 consecutive cycles without obvious loss of activity. Our results indicate that Gd(OH)3 nanorods act as a promoter to enhance the catalytic activity by providing a synergistic effect from the strong metal support interaction and the large surface area for high dispersion of small sized Pd nanoparticles enriched with hydroxyl groups on the surface. The high performance of Pd/Gd(OH)3 in heterogeneous catalysis offers a new, efficient and facile strategy to explore other metal hydroxides or oxides as supports for organic transformations. PMID- 28890975 TI - Thiol-ene/oxidation tandem reaction under visible light photocatalysis: synthesis of alkyl sulfoxides. AB - The photocatalyzed synthesis of sulfoxides from alkenes and thiols has been carried out using Eosin Y. This is a metal-free method which uses a low catalyst loading, atmospheric oxygen as the oxidant, and visible light conditions (green light). A mechanism has been proposed that is consistent with the experimental results. PMID- 28890976 TI - Fabrication of planarly-oriented polycrystalline thin films of smectic liquid crystalline organic semiconductors. AB - Fabrication of planarly-oriented polycrystalline thin films of organic semiconductors was investigated, in which molecules sit parallel, i.e., "face-on" on the substrate so as to allow vertical charge transport favorably through a thin film. With the aid of self-organization of liquid crystalline molecules and an over-coated orientation layer, tens of nm thin films vertically oriented can be re-oriented from "hemeotropic, or vertical" to "homogenous or planar" to achieve polycrystalline thin films planarly oriented after removing the over coated orientation layer. We investigated the key factors to affect re orientation of the films and uniformity and surface morphology of the resulting films, including conditions required for the re-orientation and properties of the orientation layer materials and liquid crystals. PMID- 28890977 TI - Correction: Enzyme-responsive reporter molecules for selective localization and fluorescence imaging of pathogenic biofilms. AB - Correction for 'Enzyme-responsive reporter molecules for selective localization and fluorescence imaging of pathogenic biofilms' by Junxin Aw et al., Chem. Commun., 2017, 53, 3330-3333. PMID- 28890978 TI - Site-selective tagging of proteins by pnictogen-mediated self-assembly. AB - Site-selective chemical protein modification is achieved by self-assembly of a specific di-cysteine motif, trivalent pnictogens (As, Sb or Bi) and an aromatic mercaptomethyl-based probe. The strategy is demonstrated with a quaternary complex involving Zika virus protease and a lanthanide ion, enabling paramagnetic nuclear magnetic resonance spectroscopy and luminescence measurements. PMID- 28890979 TI - A novel assessment of the role of the methyl radical and water formation channel in the CH3OH + H reaction. AB - A number of experimental and theoretical papers accounted almost exclusively for two channels in the reaction of atomic hydrogen with methanol: H-abstraction from the methyl (R1) and hydroxyl (R2) functional groups. Recently, several astrochemical studies claimed the importance of another channel for this reaction, which is crucial for kinetic simulations related to the abundance of molecular constituents in planetary atmospheres: methyl radical and water formation (R3 channel). Here, motivated by the lack of and uncertainties about the experimental and theoretical kinetic rate constants for the third channel, we developed first-principles Car-Parrinello molecular dynamics thermalized at two significant temperatures - 300 and 2500 K. Furthermore, the kinetic rate constant of all three channels was calculated using a high-level deformed-transition state theory (d-TST) at a benchmark electronic structure level. d-TST is shown to be suitable for describing the overall rate constant for the CH3OH + H reaction (an archetype of the moderate tunnelling regime) with the precision required for practical applications. Considering the experimental ratios at 1000 K, kR1/kR2 ~ 0.84 and kR1/kR3 ~ 15-40, we provided a better estimate when compared with previous theoretical work: 7.47 and 637, respectively. The combination of these procedures explicitly demonstrates the role of the third channel in a significant range of temperatures and indicates its importance considering the thermodynamic control to estimate methyl radical and water formation. We expect that these results can help to shed new light on the fundamental kinetic rate equations for the CH3OH + H reaction. PMID- 28890980 TI - Fast and accurate prediction of proton affinities: revisiting the extended Koopmans' theorem for protons. AB - In this work we propose schemes based on the extended Koopmans' theorem for quantum nuclei (eKT), in the framework of the any particle molecular orbital approach (APMO/KT), for the quantitative prediction of gas phase proton affinities (PAs). The performance of these schemes has been tested on a set of 300 organic molecules containing diverse functional groups. The APMO/KT scheme scaled by functional group (APMO/KT-SC-FG) displays an overall mean absolute error of 1.1 kcal mol-1 with respect to experimental data. Its performance in PA calculations is similar to that of post-Hartree-Fock composite methods or that of the APMO second order proton propagator (APMO/PP2) approach. The APMO/KT-SC-FG scheme is also employed to predict PAs of polyfunctional molecules such as the Nerve Agent VX and the 20 common alpha-amino acids, finding excellent agreement with available theoretical and/or experimental data. The accuracy of the predictions demonstrates that the APMO/KT-SC-FG scheme is a low-cost alternative to adiabatic methods for the calculation of accurate PAs. One of the most appealing features of the APMO/KT-SC-FG scheme, is that PAs can be derived from one single-point APMO Hartree-Fock calculation. PMID- 28890981 TI - Lipidated polymers for the stabilization of cubosomes: nanostructured drug delivery vehicles. AB - Lipidated polymers, like their protein counterparts, may be useful in fields as diverse as biochemistry and drug delivery. As such, strategies for preparing lipidated polymers with defined molecular architecture are clearly warranted. Herein, we describe a broadly-applicable methodology for synthesizing such lipidated materials, and demonstrate how they can be applied to the preparation of nanostructured drug delivery vehicles. PMID- 28890982 TI - The solution-phase process of a g-C3N4/BiVO4 dyad to a large-area photoanode: interfacial synergy for highly efficient water oxidation. AB - The oxygen evolution reaction (OER) is the rate-limiting process for water splitting, and highly efficient large-area OER photoanodes have been considered as an essential part in photoelectrochemical water splitting reactors. The high hole-electron separation efficiency of photoanodes is highly required for real applications of photoanodes in sufficiently harvesting solar energy. Herein we show that the inactive g-C3N4 nanolayers can be self-assembled with BiVO4 into a highly coupled BV/CN dyad to significantly enhance the charge separation efficiency of BiVO4 photoelectrodes for the OER. The incident photon-to-current conversion efficiency (IPCE) of visible light (400 nm) provided by the scalable BV/CN-5 photoanode was estimated to be 50% at 1.23 V vs. RHE in 0.5 M Na2SO4 solution and significantly increased to 97% at a bias voltage of 1.6 V vs. RHE. PMID- 28890983 TI - van der Waals epitaxial two-dimensional CdSxSe(1-x) semiconductor alloys with tunable-composition and application to flexible optoelectronics. AB - Despite the substantial progress in the development of two-dimensional (2D) materials from conventional layered crystals, it still remains particularly challenging to produce high-quality 2D non-layered semiconductor alloys which may bring in some unique properties and new functions. In this work, the synthesis of well-oriented 2D non-layered CdSxSe(1-x) semiconductor alloy flakes with tunable compositions and optical properties is established. Structural analysis reveals that the 2D non-layered alloys follow an incommensurate van der Waals epitaxial growth pattern. Photoluminescence measurements show that the 2D alloys have composition-dependent direct bandgaps with the emission peak varying from 1.8 eV to 2.3 eV, coinciding well with the density functional theory calculations. Furthermore, photodetectors based on the CdSxSe(1-x) flakes exhibit a high photoresponsivity of 703 A W-1 with an external quantum efficiency of 1.94 * 103 and a response time of 39 ms. Flexible devices fabricated on a thin mica substrate display good mechanical stability upon repeated bending. This work suggests a facile and general method to produce high-quality 2D non-layered semiconductor alloys for next-generation optoelectronic devices. PMID- 28890984 TI - Correction: Elucidation of transport mechanism and enhanced alkali ion transference numbers in mixed alkali metal-organic ionic molten salts. AB - Correction for 'Elucidation of transport mechanism and enhanced alkali ion transference numbers in mixed alkali metal-organic ionic molten salts' by Fangfang Chen et al., Phys. Chem. Chem. Phys., 2016, 18, 19336-19344. PMID- 28890985 TI - Size-dependent abnormal thermo-enhanced luminescence of ytterbium-doped nanoparticles. AB - Thermal quenching above 300 K is widely expected in photoluminescence. Luminescence quenching is usually ascribed to the non-radiative relaxation of excited electrons to the ground state of the activators, during which a high temperature always plays a role in pushing the excited electrons towards the quenching channels, leading to thermal quenching. For the lanthanide-doped nanoparticles, however, there is a special luminescence quenching channel that does not exist in their bulk counterparts, i.e., energy migration-induced surface quenching. Herein, a size-dependent abnormal thermal enhancement of luminescence in the temperature range of 300 K to 423 K in the ytterbium-doped fluoride nanoparticles is presented for the first time. Importantly, in this work, we originally demonstrate that the energy migration-induced surface quenching can be suppressed by increasing temperature, which results in the abnormal thermal enhancement of luminescence. According to the temperature-dependent X-ray diffraction and lifetime analyses, an underlying mechanism based on the effect of thermal lattice expansion on ytterbium-mediated energy migration is proposed. This new finding adds new insights to the size effect on the luminescent characteristics of nanoparticles, which could be utilized to construct some unique nanostructures, especially for many important temperature-related purposes, such as thermal sensing technology. PMID- 28890986 TI - A (001) dominated conjugated polymer with high-performance of hydrogen evolution under solar light irradiation. AB - A two-dimensional imide-based conjugated polymer with a preferred (001) orientation was constructed by solvent-induced assembly. A high performance of 1640 MUmol h-1 g-1 for solar-driven photocatalytic hydrogen evolution and an excellent stability were achieved due to tunnelling charge transport between the neighbouring molecular sheets. PMID- 28890987 TI - Impact of Patient-Specific Inflow Velocity Profile on Hemodynamics of the Thoracic Aorta. AB - Computational fluid dynamics (CFD) provides a noninvasive method to functionally assess aortic hemodynamics. The thoracic aorta has an anatomically complex inlet comprising of the aortic valve and root, which is highly prone to different morphologies and pathologies. We investigated the effect of using patient specific (PS) inflow velocity profiles compared to idealized profiles based on the patient's flow waveform. A healthy 31 yo with a normally functioning tricuspid aortic valve (subject A), and a 52 yo with a bicuspid aortic valve (BAV), aortic valvular stenosis, and dilated ascending aorta (subject B) were studied. Subjects underwent MR angiography to image and reconstruct three dimensional (3D) geometric models of the thoracic aorta. Flow-magnetic resonance imaging (MRI) was acquired above the aortic valve and used to extract the patient specific velocity profiles. Subject B's eccentric asymmetrical inflow profile led to highly complex velocity patterns, which were not replicated by the idealized velocity profiles. Despite having identical flow rates, the idealized inflow profiles displayed significantly different peak and radial velocities. Subject A's results showed some similarity between PS and parabolic inflow profiles; however, other parameters such as Flowasymmetry were significantly different. Idealized inflow velocity profiles significantly alter velocity patterns and produce inaccurate hemodynamic assessments in the thoracic aorta. The complex structure of the aortic valve and its predisposition to pathological change means the inflow into the thoracic aorta can be highly variable. CFD analysis of the thoracic aorta needs to utilize fully PS inflow boundary conditions in order to produce truly meaningful results. PMID- 28890988 TI - The changing landscape of dermatology practice: melanoma and pump-probe laser microscopy. AB - To present current melanoma diagnosis, staging, prognosis, and treatment algorithms and how recent advances in laser pump-probe microscopy will fill in the gaps in our clinical understanding. Expert opinion and significantly cited articles identified in SCOPUS were used in conjunction with a pubmed database search on Melanoma practice guidelines from the last 10 years. Significant advances in melanoma treatment have been made over the last decade. However, proper treatment algorithm and prognostic information per melanoma stage remain controversial. The next step for providers will involve the identification of patient population(s) that can benefit from recent advances. One method of identifying potential patients is through new laser imaging techniques. Pump probe laser microscopy has been shown to correctly identify nevi from melanoma and furthermore stratify melanoma by aggressiveness. The recent development of effective adjuvant therapies for melanoma is promising and should be utilized on appropriate patient populations that can potentially be identified using pump probe laser microscopy. PMID- 28890990 TI - Child with Allergies or Allergic Reactions. AB - Incidence of allergic disorders in children has increased significantly over time due to environmental and life-style changes. These include allergic rhinitis, atopic dermatitis, allergic conjunctivitis, food allergies, bronchial asthma, drug allergies, insect bites and anaphylaxis; most being IgE-mediated type 1 hypersensitivity reactions to common environmental and food antigens. Although most of them are self-limiting, they may adversely affect the quality of life and sometimes become life-threatening as well. These conditions are more likely to get underestimated, or over-diagnosed as recurrent infections. Hence a careful history and physical examination by attending pediatrician are necessary to differentiate it from infections. Diagnostic tests have limited value in identifying the inciting allergen. Management includes avoidance of the inciting allergens (if known), combined with symptomatic relief provided by a combination of pharmacological agents, e.g., antihistamines, anticholinergics, chromones, leukotriene-modifying agents, topical and systemic steroids. Further, specialist consultation needs to be sought, for children with recurrent or persistent symptoms. The scope of this manuscript does not include bronchial asthma. PMID- 28890989 TI - Association between maternal nonresponsive feeding practice and child's eating behavior and weight status: children aged 1 to 6 years. AB - : The purposes of this study are to investigate the prevalence of nonresponsive feeding practice (NRFP) and child's eating behavior (CEB) and to explore the hypothetical association between child's weight status, NRFP and CEB for 1- to 6 year-old children. In this study, 2423 caregivers of 1- to 6-year-old children are from the Nanjing Maternal and Child Health Hospital who completed the self report questionnaires about their NRFP and CEB as well as their children's sociodemographic data. Chi-square test and multiple regression analyses were used to examine the correlation between child's weight status and NRFP and CEB. The total prevalence of overweight and obesity was 15.2 and 7.3%, respectively. High prevalence of CEB problems and NRFP was detected at 2- and 5-year-old children. Moreover, maternal NRFP was significantly positively associated with CEB. The regression and correlation analysis revealed CEB and maternal NRFP are closely associated with BMI. For instance, refusing new food (OR = 3.57, 95%CI, 1.37 9.33, 1.5-year-old) and restriction (OR = 3.01, 95%CI, 1.34-6.76) are likely to be associated with underweight. Preferring junk food (OR = 4.892, 95%CI, 1.71 14.01, 1-year-old) and inattention (OR = 2.24, 95%CI, 1.16-4.35, 1-year-old) are prone to be overweight and obese, and pressure (OR = 0.23, 95%CI, 0.06-0.91, 1 year-old) is less likely to be associated with underweight. CONCLUSION: The findings provide strong evidence for the correlation between NRFR and CEB, and this indicates that prevention and intervention of unhealthy weight should start in early life. However, further research is necessary to gain an understanding of the impact of NRFP on CEB and weight. What is known: * Responsive feeding practice is crucial to the formation of eating behavior, and poor practice is associated with the current epidemics of childhood obesity and underweight. What is new: * The findings provide a strong evidence for the correlation between NRFR and CEB. * This finding indicates that NRFR and CEB are associated with child's unhealthy weight. PMID- 28890991 TI - Comments on: "Population Pharmacokinetic Modeling of Olmesartan, the Active Metabolite of Olmesartan Medoxomil, in Patients with Hypertension". PMID- 28890992 TI - Performance of five plant species in removal of nitrogen and phosphorus from an experimental phytoremediation system in the Ningxia irrigation area. AB - Agricultural non-point source (ANPS) pollution is an important contributor to elevated nitrogen (N) and phosphorus (P) in surface waters, which can cause serious environmental problems. Considerable effort has therefore gone into the development of methods that control the ANPS input of N and P to surface waters. Phytoremediation has been extensively used because it is cost-effective, environmentally friendly, and efficient. The N and P loads from agricultural drainage are a potential threat to the water quality of the Yellow River in Ningxia, China. Yet, phytoremediation has only rarely been applied within the Ningxia irrigation area. In an experimental set-up, five species (Ipomoea aquatica, IA; Lactuca sativa, LS; Oryza sativa, OS; Typha latifolia, TL; Zizania latifolia, ZL) were evaluated for their ability to reduce N and P loads over 62 days and five observation periods. Total N and P concentrations, plant biomass, and nutrient content were measured. The results showed that OS, LS, and IA performed better than ZL and TL in terms of nutrients removal, biomass accumulation, and nutrients storage. The highest overall removal rates of N and P (57.7 and 57.3%, respectively) were achieved by LS treatment. In addition, plant uptake contributed significantly to nutrient removal, causing a 25.9-72.0% reduction in N removal and a 54.3-86.5% reduction in P removal. Thus, this study suggests that OS, LS, and IA would be more suitable than ZL and TL for controlling nutrient loads in the Ningxia irrigation area using phytoremediation. PMID- 28890994 TI - Transcription of mcrA Gene Decreases Upon Prolonged Non-flooding Period in a Methanogenic Archaeal Community of a Paddy-Upland Rotational Field Soil. AB - Methanogenic archaea survive under aerated soil conditions in paddy fields, and their community is stable under these conditions. Changes in the abundance and composition of an active community of methanogenic archaea were assessed by analyzing mcrA gene (encoding alpha subunit of methyl-coenzyme M reductase) and transcripts during a prolonged drained period in a paddy-upland rotational field. Paddy rice (Oryza sativa L.) was planted in the flooded field and rotated with soybean (Glycine max [L.] Merr.) under upland soil conditions. Soil samples were collected from the rotational plot in the first year, with paddy rice, and in the two successive years, with soybean, at six time points, before seeding, during cultivation, and after harvest as well as from a consecutive paddy (control) plot. By the time that soybean was grown in the second year, the methanogenic archaeal community in the rotational plot maintained high mcrA transcript levels, comparable with those of the control plot community, but the levels drastically decreased by over three orders of magnitude after 2 years of upland conversion. The composition of active methanogenic archaeal communities that survived upland conversion in the rotational plot was similar to that of the active community in the control plot. These results revealed that mcrA gene transcription of methanogenic archaeal community in the rotational field was affected by a prolonged non-flooding period, longer than 1 year, indicating that unknown mechanisms maintain the stability of methanogenic archaeal community in paddy fields last up to 1 year after the onset of drainage. PMID- 28890993 TI - Chemotherapy in NETs: When and how. AB - The majority of neuroendocrine tumours (NETs) are well-differentiated tumours that follow an indolent course, in contrast to a minority of poorly differentiated neuroendocrine carcinomas (NECs) which exhibit an aggressive course and assocaited with an overall short survival. Although surgery is the only curative treatment for NETs it is not always feasible,necessitating the application of other therapies including chemotherapy. Streptozotocin (STZ)-based regimens have long been used for advanced or metastatic well-to-moderately differentiated (G1-G2) NETs, especially those originating from the pancreas (pNETs). In poorly differentiated grade 3 (G3) tumours, platinum-based chemotherapy is recommended as first-line therapy, albeit without durable responses. Although data for temozolomide (TMZ)-based chemotherapy are still evolving, this treatment may replace STZ-based regimens in pNETs due to its better tolerability and side effect profile. In addition, there is evidence that TMZ could also be used in the subgroup of well-differentiated G3 NETs. There is less clear-cut evidence of a benefit for chemotherapy in intestinal NETs, but still evolving data suggest that TMZ may be efficacious in particular patients. In lung and thymic carcinoids, chemotherapy is reserved for patients with progressive metastatic disease in whom other treatment options are unavailable. Overall, chemotherapy is indicated in patients who have progressed on first-line treatment with somatostatin analogues, have extensive tumour load or exhibit rapid growth following a period of follow-up, and/or have a high proliferative rate; it may occasionally can be used in a neo-adjuvant setting. Prospective randomised studies are awaited to substantiate the role of chemotherapy in the therapeutic algorithm of NETs along with other evolving treatments. PMID- 28890995 TI - Resistance of aerobic microorganisms and soil enzyme response to soil contamination with Ekodiesel Ultra fuel. AB - This study determined the susceptibility of cultured soil microorganisms to the effects of Ekodiesel Ultra fuel (DO), to the enzymatic activity of soil and to soil contamination with PAHs. Studies into the effects of any type of oil products on reactions taking place in soil are necessary as particular fuels not only differ in the chemical composition of oil products but also in the composition of various fuel improvers and antimicrobial fuel additives. The subjects of the study included loamy sand and sandy loam which, in their natural state, have been classified into the soil subtype 3.1.1 Endocalcaric Cambisols. The soil was contaminated with the DO in amounts of 0, 5 and 10 cm3 kg-1. Differences were noted in the resistance of particular groups or genera of microorganisms to DO contamination in loamy sand (LS) and sandy loam (SL). In loamy sand and sandy loam, the most resistant microorganisms were oligotrophic spore-forming bacteria. The resistance of microorganisms to DO contamination was greater in LS than in SL. It decreased with the duration of exposure of microorganisms to the effects of DO. The factor of impact (IFDO) on the activity of particular enzymes varied. For dehydrogenases, urease, arylsulphatase and beta glucosidase, it had negative values, while for catalase, it had positive values and was close to 0 for acid phosphatase and alkaline phosphatase. However, in both soils, the noted index of biochemical activity of soil (BA) decreased with the increase in DO contamination. In addition, a positive correlation occurred between the degree of soil contamination and its PAH content. PMID- 28890997 TI - 18F-FDG PET/CT of extensive rheumatoid nodulosis. PMID- 28890996 TI - Bacillus Calmette-Guerin vaccination at birth and in vitro cytokine responses to non-specific stimulation. A randomized clinical trial. AB - Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guerin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7 days of birth; 78 controls) were bled 4 days post-randomization, and at age 3 and 13 months. Geometric mean concentrations of IL-1beta, TNF-alpha, IL-6 (24 h stimulation) and IFN-gamma, IL 10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG vaccination did not affect in vitro cytokine production, except IFN-gamma and IL-22 response to BCG. Stratifying for 'age at randomization' we found a potentiating effect of BCG on cytokine production (TNF-alpha, IL-6, IL-10) in the 4 days post randomization stimulations, among children who were vaccinated at age 2-7 days versus age 0-1 days. BCG vaccination did not potentiate cytokine production to non-BCG antigens. At 4 days post randomization, BCG was associated with higher cytokine production in the later randomized children. PMID- 28890998 TI - Neurodegenerative cerebrospinal fluid biomarkers tau and amyloid beta predict functional, quality of life, and neuropsychological outcomes after aneurysmal subarachnoid hemorrhage. AB - Cerebrospinal fluid (CSF) biomarkers might be useful in predicting outcome after aneurysmal subarachnoid hemorrhage (aSAH). It was the aim to determine whether tau and amyloid beta CSF concentrations predict functional, health-related quality of life (hrQoL), and neuropsychological outcomes after aSAH. Ventricular CSF was obtained from n = 24 aSAH patients at admission (D0), day 2 (D2), and day 6 (D6). CSF total (t)Tau, phosphorylated (p)Tau(181P), and amyloid beta(1-40 and 1-42) (Abeta40/Abeta42) levels were compared between patients with favorable and unfavorable functional (modified Rankin Scale (mRS)), hrQoL (Euro-Qol (EQ-5D)), and neuropsychological outcomes at 3 (3 m) and 12 months (12 m). Patients with unfavorable functional (mRS 4-6) and hrQoL outcome (EQ-5D z-score <= - 1.0) at 3 and 12 m had higher CSF tTau/pTau and lower Abeta40/Abeta42 at D0, D2, and D6 with varying degrees of statistical significance. In terms of predicting neuropsychological outcome, CSF pTau showed a statistically significant correlation with the z-scores of executive function (r = - 0.7486, p = 0.008), verbal memory (r = - 0.8101, p = 0.002), attention (r = - 0.6498, p = 0.030), and visuospatial functioning (r = - 0.6944, p = 0.017) at 3 m. At 12 m, CSF pTau had statistically significant correlations with the z-scores of verbal memory (r = - 0.7473, p = 0.008) and visuospatial functioning (r = - 0.6678, p = 0.024). In conclusion, higher tTau/pTau and lower Abeta40/Abeta42 CSF levels predict unfavorable long-term functional and hrQoL outcomes. Neuropsychological deficits correlate with increased CSF tTau and pTau concentrations. PMID- 28890999 TI - A genome-wide association study identifies genomic loci associated with backfat thickness, carcass weight, and body weight in two commercial pig populations. AB - Growth and fatness traits are economically important in the pig industry. To dissect the genetic architecture of these traits in commercial pigs, we conducted a genome-wide association study (GWAS) for carcass weight, backfat thickness, and body weight in two commercial populations: Duroc * (Landrace * Yorkshire) (DLY) and Duroc populations. To enhance the detection power, three GWAS approaches including single-trait GWAS, multi-trait GWAS and meta-analysis were used in this study. A total of 13 suggestive loci were identified on nine chromosomes. The most significant locus was detected at 272.05 Mb on SSC1, and it was associated with backfat thickness at the first rib in the DLY population. Three genes at the identified loci (TBC1D1, BAAT and PHLPP1) were highlighted as functionally plausible candidate genes for pig growth and fatness traits. Genome-wide significant locus was not evidenced in this study, indicating that large populations are required to identify QTL with minor effects on growth and fatness traits in commercial pig populations, in which intensively artificial selections have been imposed on these traits and small genetical variances usually retain in these traits. PMID- 28891000 TI - Clinical application of modified bag-of-features coupled with hybrid neural-based classifier in dengue fever classification using gene expression data. AB - Dengue fever detection and classification have a vital role due to the recent outbreaks of different kinds of dengue fever. Recently, the advancement in the microarray technology can be employed for such classification process. Several studies have established that the gene selection phase takes a significant role in the classifier performance. Subsequently, the current study focused on detecting two different variations, namely, dengue fever (DF) and dengue hemorrhagic fever (DHF). A modified bag-of-features method has been proposed to select the most promising genes in the classification process. Afterward, a modified cuckoo search optimization algorithm has been engaged to support the artificial neural (ANN-MCS) to classify the unknown subjects into three different classes namely, DF, DHF, and another class containing convalescent and normal cases. The proposed method has been compared with other three well-known classifiers, namely, multilayer perceptron feed-forward network (MLP-FFN), artificial neural network (ANN) trained with cuckoo search (ANN-CS), and ANN trained with PSO (ANN-PSO). Experiments have been carried out with different number of clusters for the initial bag-of-features-based feature selection phase. After obtaining the reduced dataset, the hybrid ANN-MCS model has been employed for the classification process. The results have been compared in terms of the confusion matrix-based performance measuring metrics. The experimental results indicated a highly statistically significant improvement with the proposed classifier over the traditional ANN-CS model. PMID- 28891001 TI - Characterization of a novel botybirnavirus isolated from a phytopathogenic Alternaria fungus. AB - Alternaria fungi are important pathogens infecting a wide variety of organisms. Here, we report a novel double-stranded RNA (dsRNA) mycovirus named Alternaria botybirnavirus 1 (ABRV1) isolated from a phytopathogenic Alternaria sp. strain (SCFS-3) infecting a pear tree in China. ABRV1 has two dsRNA components (dsRNAs 1 and 2) with the sizes of 6,188 and 5,903 bp, containing two putative open reading frames encoding two polyproteins (202 and 192 kDa, respectively). The polyprotein encoded by ABRV1 dsRNA1 shares 41% amino acid (aa) sequence identity with the one encoded by dsRNA2 (instead of dsRNA1) of Sclerotinia sclerotiorum botybirnavirus 1 (SsBRV1). Conversely, the polyprotein encoded by ABRV1 dsRNA2 shares 46% aa sequence identity with the one (i.e., cap-pol fusion protein) encoded by SsBRV1 dsRNA1. ABRV1 has isometric spherical virus particles (~40 nm in diameter), putatively composed of the 60-, 70- and 80-kDa structural proteins. The genomic organization and phylogenetic analyses revealed that ABRV1 belongs to a newly proposed family "Botybirnaviridae", and to our knowledge, this is the first report of a botybirnavirus infecting an Alternaria sp. strain. PMID- 28891002 TI - Fusarium equiseti LPSC 1166 and its in vitro role in the decay of Heterostachys ritteriana leaf litter. AB - The role of microorganisms in litter degradation in arid and semi-arid zones, where soil and water salinization is one of the main factors limiting carbon turnover and decay, remains obscure. Heterostachys ritteriana (Amaranthaceae), a halophyte shrub growing in arid environments such as "Salinas Grandes" (Cordoba, Argentina), appears to be the main source of organic matter in the area. Little is known regarding the microorganisms associated with H. ritteriana, although they are a potential source of enzymes such as cellulolytic ones, which might be important in biotechnological fields such as bioethanol production using ionic liquids. In the present study, by studying the microbiota growing on H. ritteriana leaf litter in "Salinas Grandes," we isolated the cellulolytic fungus Fusarium equiseti LPSC 1166, which grew and degraded leaf litter under salt stress. The growth of this fungus was a function of the C substrate and the presence of NaCl. Although in vitro the fungus used both soluble and polymeric compounds from H. ritteriana litter and synthesized extracellular beta-1,4 endoglucanases, its activity was reduced by 10% NaCl. Based on these results, F. equiseti LPSC 1166 can be described as a halotolerant cellulolytic fungus most probably playing a key role in the decay of H. ritteriana leaf litter in "Salinas Grandes." PMID- 28891003 TI - Contaminant characteristics and environmental risk assessment of heavy metals in the paddy soils from lead (Pb)-zinc (Zn) mining areas in Guangdong Province, South China. AB - In November 2016, the total metal concentrations in nine representative locations in lead (Pb)-zinc (Zn) mining areas, located in Guangdong Province, South China, were determined experimentally by flame atomic absorption spectrometer. The results indicated that the paddy soils were heavily contaminated with Cd (20.25 mg kg-1), Pb (1093.03 mg kg-1), and Zn (867.0 mg kg-1), exceeding their corresponding soil quality standard values and background values. According to the results, the mean enrichment factor levels of the studied metals decreased in the following order: Cd > Zn > Pb > Cu > Ni > Mn > Cr. Among these metals, Cd, Pb, and Zn were predominantly influenced by widespread anthropogenic activities. The highest concentrations of the studied metal pollutants were distributed in the areas surrounding the mining activity district. Multivariate statistical analysis indicated that the major contributing sources of the studied metals were metal ore mining, smelting, and processing activities. However, the composition of soil background was another potential source. Moreover, the assessment results of environment risks showed that the potential ecological risks, in decreasing order, were Cd > Pb > Zn > Cu > Ni > Cr > Mn. Additionally, the non-carcinogenic risk represented the trend of HI Pb > HI Mn > HI Zn > HI Cu , and the carcinogenic risk ranked as CR Cr > CR Cd > CR Ni . Among the environmental risk substances, Cd and Pb were the main contributors that pose ecological harm and health hazards through their serious pollution. Consequently, greater attention should be paid to this situation. PMID- 28891004 TI - Cerebral imaging and neurodevelopmental outcome after entero- and human parechovirus sepsis in young infants. AB - : Enterovirus (EV) and human parechovirus (HPeV) are major causes of sepsis-like illness in infants under 90 days of age and have been identified as neurotropic. Studies about acute and long-term neurodevelopment in infants with sepsis-like illness without the need for intensive care are few. This study investigates cerebral imaging and neurodevelopmental outcome following EV and HPeV infection in these infants. We studied infants under 90 days of age who were admitted to a medium care unit with proven EV- or HPeV-induced sepsis-like illness. In addition to standard care, we did a cerebral ultrasound and cerebral magnetic resonance imaging (MRI), as well as neurodevelopmental follow-up at 6 weeks and 6 months and Bayley Scale of Infant and Toddler Development 3rd edition (BSID-III) investigation at 1 year of age. Twenty-six infants, 22 with EV and 4 with HPeV, were analysed. No abnormalities were detected at cerebral imaging. At 1 year of age, two infants had a moderate delay on both the motor and cognitive scale, one on the cognitive scale only and three others on the gross motor scale only. CONCLUSION: Although our study population, especially the number of HPeV positive infants is small, our study shows that these infants do not seem to develop severe neurodevelopmental delay and neurologic sequelae more often than the normal Dutch population. Follow-up to school age allows for more reliable assessments of developmental outcome and is recommended for further studies to better assess outcome. What is known: * Enterovirus and Human Parechovirus infections are a major cause of sepsis-like illness in young infants. * After intensive care treatment for EV or HPeV infection, white matter abnormalities and neurodevelopmental delay have been described. What is new: * In our 'medium care' population, no abnormalities at cerebral imaging after EV- or HPeV-induced sepsis like illness have been found. * At 1 year of age, infants who had EV- or HPeV induced sepsis-like illness do not seem to develop severe neurodevelopmental delay and neurologic sequelae more often than the normal population. PMID- 28891005 TI - Evaluation of the internal oblique, external oblique, and transversus abdominalis muscles in patients with ankylosing spondylitis: an ultrasonographic study. AB - The objectives of the study are to compare abdominal muscle thickness in ankylosing spondylitis (AS) patients with healthy subjects and determine the factors affecting these muscle thickness. Thirty-five male patients with a previous diagnosis of AS according to the Modified New York criteria and a control group consisting of 35 healthy male individuals were included in this cross-sectional and case-control study. Thicknesses of the internal oblique (IO), external oblique (EO), and transversus abdominalis (TrA) muscles were measured with ultrasound (US). AS patients were classified according to the International Physical Activity Questionnaire (IPAQ). There were 35 AS patients with a mean age of 35.17 +/- 8.05 years and 35 healthy subjects with a mean age 32.57 +/- 7.05 years. No significant difference was observed between the groups in terms of abdominal muscle thicknesses (p > 0.005). When the AS patients were classified according to the IPAQ scores, thicknesses of the IO and TrA muscles were significantly lower in patients who had the low level of IPAQ scores (p < 0.05). In the light of our first and preliminary results, muscle thickness of the IO, EO, and TrA muscles were similar in AS patients to healthy subjects. However, AS patients who had lower level of physical activity have also reduced thickness of IO and TrA muscles. PMID- 28891006 TI - Hepatocellular Carcinoma with Bone Metastases: Incidence, Prognostic Significance, and Management-Single-Center Experience. AB - BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most common causes of cancer-related deaths worldwide, with rising incidence in the USA. Bone metastases with HCC, in particular, have an extremely poor prognosis. We present prevalence, treatment, and survival of patients with bone and more specifically spinal metastases from HCC. METHODS: A retrospective analysis was done at a single tertiary care institution of patients with bone metastases from HCC between January 2005 and December 2015. RESULTS: Among 1017 patients with HCC, 20 were found to have bone metastases of which 11 had spinal metastases. Seventeen (85%) were male, with median age of 58 years at time of HCC diagnosis. Systemic chemotherapy and sorafenib were used in 12 (60%) patients, and 12 (60%) received radiation therapy. Among patients who did not receive therapy, median survival was 76 days. Median survival after diagnosis of metastasis in patients on sorafenib and radiation were 106 and 100 days, respectively. CONCLUSION: Bone metastases in HCC are very rare and aggressive. Due to its rarity, optimal treatment strategies are not well defined. Early diagnosis is important for optimal therapy and improved survival. PMID- 28891007 TI - No free lunch in orthopedics. PMID- 28891008 TI - Determination of ochratoxin A in fruit juice by high-performance liquid chromatography after vortex-assisted emulsification microextraction based on solidification of floating organic drop. AB - A rapid, simple, and green vortex-assisted emulsification microextraction method based on solidification of floating organic drop was developed for the extraction and determination of ochratoxin A (OTA) with high-performance liquid chromatography. Some factors influencing the extraction efficiency of OTA such as the type and volume of extraction solvent, sample pH, salt concentration, vortex time, and sample volume were optimized. Under optimized conditions, the calibration curve exhibited linearity in the range of 50.0-500 ng L-1 with a coefficient of determination higher than 0.999. The limit of detection was 15.0 ng L-1. The inter- and intra-assays relative standard deviations were in a range of 4.7-8.7%. The accuracy of the developed method was investigated through recovery experiments, and it was successfully used for the quantification of OTA in 40 samples of fruit juice. PMID- 28891010 TI - Effect of hydrophobicity of pharmaceuticals and personal care products for adsorption on activated carbon: Adsorption isotherms, kinetics and mechanism. AB - Adsorption of three pharmaceuticals and personal care products (PPCPs), namely caffeine, ibuprofen and triclosan on commercial powdered activated carbon was examined in aqueous medium. The contaminants were chosen based on their diverse log Kow (octanol-water partition coefficient) viz. - 0.07 for caffeine, 3.97 for ibuprofen and 4.76 for triclosan to examine the role of hydrophobicity on adsorption process. The adsorbent characterisation was achieved using BET surface area, SEM, pore size distribution studies and FTIR. Influence of mass of PAC, contact time, solution pH and initial concentration on adsorption capacity of PAC was studied. Adsorption isotherms and kinetics were applied to establish the mechanism of adsorption. The kinetics followed pseudo-second order with physisorption occurring through particle diffusion. The Freundlich model fitted best among the isotherm models. The adsorption capacity increased in the order CFN < IBU < TCS which correlates with increasing hydrophobicity (log Kow), molecular weight and decreasing water solubility, respectively. We conclude that micro-pollutant hydrophobicity contributes towards adsorption on activated carbon. PMID- 28891009 TI - Aging, Osteocytes, and Mechanotransduction. AB - PURPOSE OF REVIEW: The bone is able to adapt its structure to mechanical signals via the bone remodeling process governed by mechanosensitive osteocytes. With aging, an imbalance in bone remodeling results in osteoporosis. In this review, we hypothesized that changes in lacunar morphology underlie the decreased bone mechanoresponsiveness to mechanical loading with aging. RECENT FINDINGS: Several studies have reported considerable variations in the shape of osteocytes and their lacunae with aging. Since osteocytes can sense matrix strain directly via their cell bodies, the variations in osteocyte morphology may cause changes in osteocyte mechanosensitivity. As a consequence, the load-adaptive response of osteocytes may change with aging, even when mechanical loading would remain unchanged. Though extensive quantitative data is lacking, evidence exists that the osteocyte lacunae are becoming smaller and more spherical with aging. Future dedicated studies might reveal whether these changes would affect osteocyte mechanosensation and the subsequent biological response, and whether this is (one of) the pathways involved in age-related bone loss. PMID- 28891011 TI - Treatment of chronic anal fissure with sacral neuromodulation: a pilot study. PMID- 28891012 TI - Visualization of multiple organ amyloid involvement in systemic amyloidosis using 11C-PiB PET imaging. AB - PURPOSE: To investigate the utility of Pittsburgh compound B (PiB) positron emission tomography (PET) imaging for evaluating whole-body amyloid involvement in patients with systemic amyloidosis. METHODS: Whole-body 11C-PiB PET was performed in seven patients with systemic immunoglobulin light-chain (AL) amyloidosis, seven patients with hereditary transthyretin (ATTRm) amyloidosis, one asymptomatic TTR mutation carrier and three healthy controls. The correlations between clinical organ involvement, radiological 11C-PiB uptake and histopathological findings were analysed for each organ. RESULTS: Organ involvement on 11C-PiB PET imaging showed good correlations with the clinical findings for the heart and stomach. Abnormal tracer uptake was also observed in the spleen, lachrymal gland, submandibular gland, sublingual gland, lymph node, brain, scalp, extraocular muscles, nasal mucosa, pharynx, tongue and nuchal muscles, most of which were asymptomatic. Physiological tracer uptake was universally observed in the urinary tract (kidney, renal pelvis, ureter and bladder) and enterohepatic circulatory system (liver, gallbladder, bile duct and small intestine) in all participants. Most of the patients and one healthy control subject showed asymptomatic tracer uptake in the lung and parotid gland. The peripheral nervous system did not show any tracer uptake even in patients with apparent peripheral neuropathy. Histological amyloid deposition was confirmed in biopsied myocardium and gastric mucosa where abnormal 11C-PiB retention was observed. CONCLUSIONS: 11C-PiB PET imaging can be used clinically in the systemic evaluation of amyloid distribution in patients with AL and ATTRm amyloidosis. Quantitative analysis of 11C-PiB PET images may be useful in therapy evaluation and will reveal whether amyloid clearance is correlated with clinical response. PMID- 28891014 TI - Phosphate-arsenate relations to affect arsenic concentration in plant tissues, growth, and antioxidant efficiency of sunflower (Helianthus annuus L.) under arsenic stress. AB - Relations between phosphate and arsenate are important but inconsistent to influence arsenic (As) phytotoxicity depending on many plant and soil factors. Present research aimed to investigate the phosphate and arsenate interactions in sunflower (Helianthus annuus L.) grown in alkaline calcareous soil for 18 weeks under natural environmental conditions at three arsenate [0 (As0), 40 (As40), and 80 (As80) mg As kg-1 soil as sodium arsenate] and three phosphate [0 (P0), 100 (P100), and 200 (P200) mg P2O5 kg-1 soil as diammonium phosphate] levels. The plants were grown in pots according to completely randomized design with five replications. Ionic and physiological parameters were measured at 40 days after treatment completion. Arsenic contamination with As40 and As80 increased root and shoot As concentration with relatively higher concentration in roots, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) while decreased plant P, chlorophyll, protein, and glutathione (GSH), and consequently plant growth, yield, and yield attributes. Addition of P100 and P200 under As stress reduced As transfer from soil to roots to shoots, MDA concentration, SOD, CAT, and POD activities while increased GSH, leaf protein, chlorophyll, and growth characteristics as well as achene yield compared to As treated plants without additional P. In conclusion, P-induced inhibition of As transfer from soil to roots to shoots and reduction in MDA concentration accompanied with an increase in the synthesis of protein, chlorophyll, and GSH could be the main mechanisms responsible for lowered As toxicity in sunflower, leading to mitigation of potential risks of As contamination to food chain and human health. PMID- 28891015 TI - Structural, mechanical properties, and vibrational spectra of LLM-105 under high pressures from a first-principles study. AB - In this work, we report the structure, mechanical properties, and vibrational spectra of 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105), an energetic molecular crystal, with a first-principles method based on density functional theory (DFT) using the recentely developped HASEM package. The elastic constants, acoustic velocity, and parameters of equations of state were calculated, and the predicted ordering of stiffness constants is C 33 (38.5 GPa) > C 11 (24.0 GPa) > C 22 (17.7 GPa). We also investigated the structure and equation of state of LLM 105 under hydrostatic pressure up to 100 GPa. The predicted structures are in good agreement with experimental results available from ambient pressure to 20 GPa. Under compressions, the LLM-105 crystal exhibits anisotropic compressibility, with a highly incompressible response along the a-axis and c axis. It is worth noting that there is a sudden change in the lattice parameters and change rate of volume at ~30 GPa. Based on the intermolecular interaction analysis and vibrational spectra, a phase transition at the hydrostatic pressure of ~30 GPa is predicted. PMID- 28891016 TI - Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: potential pitfalls of a multicentre observational study. PMID- 28891018 TI - Patch. PMID- 28891017 TI - Re-Appraisal of Estrogen Receptor Negative/Progesterone Receptor Positive (ER /PR+) Breast Cancer Phenotype: True Subtype or Technical Artefact? AB - Expression of the ER and PR receptors is routinely quantified in breast cancer as a predictive marker of response to hormonal therapy. Accurate determination of ER and PR status is critical to the optimal selection of patients for targeted therapy. The existence of an ER-/PR+ subtype is controversial, with debate centred on whether this represents a true phenotype or a technical artefact on immunohistochemistry (IHC). The aim of this study was to investigate the true incidence and clinico-pathological features of ER-/PR+ breast cancers in a tertiary referral symptomatic breast unit. Clinico-pathological data were collected on invasive breast cancers diagnosed between 1995 and 2005. IHC for ER and PR receptors was repeated on all cases which were ER-/PR+, with the same paraffin block used for the initial diagnostic testing. Concordance between the diagnostic and repeat IHC was determined using validated testing. Complete data, including ER and PR status were available for 697 patients diagnosed during the study period. On diagnostic IHC, the immunophenotype of the breast tumours was: ER+/PR+ in 396 (57%), ER-/PR- in 157 (23%), ER+/PR- in 88 (12%) and ER-/PR+ in 56 (8.6%) patients. On repeat IHC of 48/56 ER-/PR+ tumours 45.8% were ER+/PR+, 6% were ER+/PR- and 43.7% were ER-/PR- None of the cases were confirmed to be ER /PR+. The ER-/PR+ phenotypic breast cancer is likely to be the result of technical artefact. Prompt reassessment of patients originally assigned to this subtype who re-present with symptoms should be considered to ensure appropriate clinical management. PMID- 28891019 TI - Uncivilizing "Mental Illness": Contextualizing Diverse Mental States and Posthuman Emotional Ecologies within The Icarus Project. AB - This article argues humans should not be defined strictly at their physical boundaries with clear distinctions between anatomical bodies, mental states, and the rest of the world. Rather, diverse mental states, which are often diagnosed as "mental illness," take shape within greater environmental forces and flows, including those that are constructed online. Drawing from a multi-sited ethnography of The Icarus Project, a radical mental health community, the author situates online narratives written by two of its members within posthuman emotional ecologies in which the exchange of ideas online affects mental states in a profound way. These narratives can be seen as a new type of psychiatric resistance based in new technologies, one that "uncivilizes" mental illness by searching for alternative frameworks and metaphors to understand lived experiences with mental distress. This ethnographic perspective differs significantly from traditional bio-psychiatric models and interventions and can offer both patients and mental healthcare providers with an alternative language to frame mental health. PMID- 28891020 TI - Trace elements in feathers and eggshells of brown booby Sula leucogaster in the Marine National Park of Currais Islands, Brazil. AB - Levels of trace elements were investigated in feathers of 51 adults and 47 eggshells of brown boobies Sula leucogaster from one bird colony in the Marine National Park of Currais Islands, Brazil, between December 2013 and October 2014. Average concentrations (MUg g-1, dry weight) in feathers and eggshells, respectively, were Al 50.62-9.58, As 0.35-2.37, Cd 0.05-0.03, Co 0.38-2.1, Cu 15.12-0.99, Fe 47.47-22.92, Mg 815.71-1116.92, Ni 0.29-11.85, and Zn 94.16-1.98. In both arrays, the average concentration of Mg was the highest among all the elements analyzed, while the lowest was recorded for Cd. As and Ni presented levels at which biological impacts might occur. Zn concentrations were higher than those considered normal in other organs. Levels of Al, Fe, Cu, Zn, and Cd were higher in feathers, whereas higher contents of Mg, Co, Ni, and As occurred in eggshells. The comparison between the elements in eggshells collected at different seasons showed no significant difference (p > 0.05) due, probably, to the lack of temporal variation on foraging behavior and/or on bioavailability of trace elements. Metals and arsenic in feathers and eggshells were mostly not correlated. Future studies on Parana coast should focus on the speciation of the elements, especially As, Ni, and Zn, which proved to be a possible problem for the environment and biota. It is necessary to investigate both matrices, shell and internal contents of the eggs, in order to verify if the differences previously reported in other studies also occur in eggs of brown boobies in the Marine National Park of Currais Islands. PMID- 28891021 TI - Anteromedial cortical support reduction in unstable pertrochanteric fractures: a comparison of intra-operative fluoroscopy and post-operative three dimensional computerised tomography reconstruction. AB - PURPOSE: Anteromedial cortical support reduction is favourable for secondary stability after limited sliding in unstable pertrochanteric fractures. The aim of this study was to compare the accuracy and agreement between intra-operative fluoroscopy and post-operative 3D reconstruction. MATERIALS AND METHODS: A retrospective analysis of 28 patients (mean 81.6 years) treated with short cephalomedullary nails was performed. All patients had full sets of intra operative fluoroscopy and post-operative 3D CT images. Observation was focused on the position of the anteromedial cortices of the inferior corner between the head neck fragment and femoral shaft, and their relationship was categorised into three types: positive, neutral and negative. The percentage of subsequent changes in cortical reduction quality between fluoroscopy and 3D CT was calculated and compared. RESULTS: There were 24 positive (85.7%), four neutral and no negative positions in the anteroposterior (AP) view and one positive, 20 neutral (71.4%) and seven negative positions in the lateral view from fluoroscopy. On post operative 3D CT images with a full range of rotation, definitive anteromedial cortical contact (positive and neutral support) was observed in 18 cases (64.3%). Ten cases lost the anteromedial cortical buttress. With the posteromedial region of the lesser trochanter detached, a positive AP cortical position combined with a positive/neutral lateral position on fluoroscopy (17 cases) was highly predictive of reliable, definitive cortical support (15 cases, 88.2%) on 3D CT. A negative lateral position on fluoroscopy (seven cases), regardless of the combination in the AP view, was likely to predict the final loss of cortical support (six cases, 85.7%) on 3D CT; a positive/neutral lateral position (21 cases) was only associated with loss of support in four cases (19.1%) (p < 0.05). CONCLUSIONS: A lateral negative position of the anterior cortex on fluoroscopy for unstable pertrochanteric fractures may be highly predictive of post-operative final loss of the anteromedial cortical buttress, which should be avoided during operation. PMID- 28891022 TI - Converting a Sleeve Gastrectomy to a Gastric Bypass for Weight Loss Failure-Is It Worth It? AB - BACKGROUND: Sleeve gastrectomy (SG) is gaining popularity and has become the procedure of choice for many bariatric surgeons. Long-term weight loss failure is not uncommon. The preferred revisional procedure for these patients is still under debate. OBJECTIVE: The objective of this study was to assess the safety and efficacy of laparoscopic gastric bypass as a revisional surgery for sleeve gastrectomy patients with weight loss failure. SETTING: The study was done at a bariatric surgery center in a university hospital. METHODS: We reviewed our prospectively collected database and identified all patients who underwent conversion of a sleeve gastrectomy to a gastric bypass for weight loss failure. Data on patient demographics, baseline characteristics, and outcomes of bariatric surgery were retrieved. RESULTS: Twenty-three patients with a mean body mass index (BMI) of 41.6 kg/m2 (range 34.1-50.1 kg/m2) underwent conversion to a gastric bypass. Four patients underwent a gastric band prior to the sleeve gastrectomy, and two patients underwent a re-sleeve gastrectomy prior to conversion to a gastric bypass. At a mean follow-up of 24 months (range 9-46 months), the average body mass index (BMI) decreased to 33.8 kg/m2 and the excess body mass index loss (EBMIL) was 42.6%. Diabetes, hypertension, dyslipidemia, and obstructive sleep apnea resolved or improved in 44.4, 45.5, 50, and 50% of the patients, respectively. Three patients developed early postop complications (13%), while late complications occurred in four patients (17%). CONCLUSION: Converting a sleeve gastrectomy to a gastric bypass for weight loss failure is safe, yet weight loss benefit is limited. PMID- 28891023 TI - Variation of mucin adhesion, cell surface characteristics, and molecular mechanisms among Lactobacillus plantarum isolated from different habitats. AB - The adhesion ability to mucin varied greatly among 18 Lactobacillus plantarum isolates depending on their isolation habitats. Such ability remained at high level even though they were sequentially exposed to the gastrointestinal (GI) stresses. The majority of L. plantarum isolated from shrimp intestine and about half of food isolates exhibited adhesion ability (51.06-55.04%) about the same as the well-known adhesive L. plantarum 299v. Interestingly, five infant isolates of CIF17A2, CIF17A4, CIF17A5, CIF17AN2, and CIF17AN8 exhibited extremely high adhesion ranging from 62.69 to 72.06%. Such highly adhesive property correlating to distinctively high cell surface hydrophobicity was significantly weaken after pretreatment with LiCl and guanidine-HCl confirming the entailment of protein moiety. Regarding the draft genome information, all molecular structures of major cell wall-anchored proteins involved in the adhesion based on L. plantarum WCSF1, including lp_0964, lp_1643, lp_3114, lp_2486, lp_3127, and lp_3059 orthologues were detected in all isolates. Exceptionally, the gene-trait matching between yeast agglutination assay and the relevant mannose-specific adhesin (lp_1229) encoding gene confirmed the Msa absence in five infant isolates expressed distinctively high adhesion. Interestingly, the predicted flagellin encoding genes (fliC) firstly revealed in lp_1643, lp_2486, and lp_3114 orthologues may potentially contribute to such highly adhesive property of these isolates. PMID- 28891024 TI - Resveratrol supplementation improves lipid and glucose metabolism in high-fat diet-fed blunt snout bream. AB - Here, we aimed to investigate whether resveratrol (RSV) can ameliorate high-fat diet (HFD)-induced metabolic disorder in fish. Blunt snout bream (Megalobrama amblycephala) with average weight 27.99 +/- 0.56 g were fed a normal fat diet (NFD, 5% fat, w/w), a HFD (11% fat), or a HFD supplemented with 0.04, 0.36, or 1.08% RSV for 10 weeks. As expected, fish fed a HFD developed hepatic steatosis, as shown by elevated hepatic and plasma triglycerides, raised whole body fat, intraperitoneal fat ratio and hepatosomatic index, and increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST). RSV supplementation lessened increases in body mass, whole body fat, and intraperitoneal fat, and alleviated development of hepatic steatosis, elevations of plasma triglyceride and glucose, and abnormalities of ALT and AST in HFD-fed fish. RSV supplementation increased SIRT1 messenger RNA (mRNA) expression and consequently hepatic mRNA expression of adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase (CPT1a), and microsomal triglyceride transfer protein (MTTP), implying upregulation of lipolysis, beta-oxidation, and lipid transport, respectively, in the liver. Conversely, hepatic lipoprotein lipase (LPL), sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator activated receptor gamma (PPARgamma), and ATP citrate lyase (ACLY) mRNA expression were decreased, implying suppression of fatty acid uptake, lipogenesis, and fatty acid synthesis. Additionally, RSV downregulated glucokinase (GCK) and sodium-dependent glucose cotransporter 1 (SGLT1) and upregulated glucose transporter 2 (GLUT2) mRNA expression, thus restoring normal glucose fluxes. Thus, RSV improves lipid and glucose metabolisms in blunt snout bream, which are potentially mediated by activation of SIRT1. PMID- 28891025 TI - Stability of BiFeO3 nanoparticles via microwave-assisted hydrothermal synthesis in Fenton-like process. AB - Stable catalysts require high catalytic efficiency and repeated consecutive use, low mass loss, and metal leaching. This study investigated BiFeO3 (BFO) composite with high stability and reusability using a one step microwave-assisted hydrothermal method (MAHS) to decompose bisphenol A (BPA) used as the target contaminant. After six consecutive reaction cycles in microwave-enhanced Fenton like process (MW-Fenton-like), the removal rate of BPA decreased from 94 to 87.4% with low metal leaching ratio and mass loss. The morphology, crystal, reaction kinetics, and hydroxyl radical (.OH) were used to demonstrate the high stability of BFO-MAHS. The results indicated that the benign stability and reusability of BFO-MAHS probably occurred because (1) the thermal-effect of MW improved heating rate, which led to the rapid formation stable cube structure and (2) MW mechanical vibrations existed in the preparation process, which further enhanced the cube structure. Therefore, MAHS could be used as a green and environmental friendly method to apply in catalysts synthesis, which could immensely shorten preparation time and enhance the catalytic performance with no waste production. PMID- 28891026 TI - Multitrophic interactions mediate the effects of climate change on herbivore abundance. AB - Climate change can influence the abundance of insect herbivores through direct and indirect mechanisms. In this study, we evaluated multitrophic drivers of herbivore abundance for an aphid species (Aphis helianthi) in a subalpine food web consisting of a host plant (Ligusticum porteri), mutualist ants and predatory lygus bugs (Lygus spp.). We used a model-selection approach to determine which climate and host plant cues best predict year-to-year variation in insect phenology and abundance observed over 6 years. We complemented this observational study with experiments that determined how elevated temperature interacts with (1) host plant phenology and (2) the ant-aphid mutualism to determine aphid abundance. We found date of snowmelt to be the best predictor of yearly abundance of aphid and lygus bug abundance but the direction of this effect differed. Aphids achieved lower abundances in early snowmelt years likely due to increased abundance of lygus bug predators in these years. Elevating temperature of L. porteri flowering stalks reduced their quality as hosts for aphid populations. However, warming aphid colonies on host plants of similar quality increased population growth rates. Importantly, this effect was apparent even in the absence of ants. While we observed fewer ants tending colonies at elevated temperatures, these colonies also had reduced numbers of lygus bug predators. This suggests that mutualism with ants becomes less significant as temperature increases, which contrasts other ant-hemipteran systems. Our observational and experimental results show the importance of multitrophic species interactions for predicting the effect of climate change on the abundances of herbivores. PMID- 28891027 TI - Short Term Oral Zinc Supplementation among Babies with Neonatal Sepsis for Reducing Mortality and Improving Outcome - A Double-Blind Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the efficacy of short term zinc supplementation on the mortality rate and neurodevelopment outcome in neonates with sepsis at 12 mo corrected age. METHODS: The clinical trial was undertaken in the neonatal intensive care unit of JIPMER during the time period from September 2013 through December 2016. Neonates with clinical manifestations of sepsis who exhibited two positive screening tests (microESR, C- reactive protein, band cell count) were included and randomized into no zinc and zinc group. The intervention was zinc sulfate monohydrate given at a dose of 3 mg/kg twice a day orally for 10 d along with standard antibiotics. The no zinc group was on antibiotic treatment. Blood samples from both groups were collected at baseline and after day 10. Babies were carefully discharged from the hospital. The babies were followed up till 12 mo corrected age using DASII (Development Assessment Scale for Indian Infants). RESULTS: At the time of enrolment, patient characteristics were similar in both the groups. The mortality rate was significantly higher in no zinc compared to zinc group (5 vs. 13; P = 0.04). Although motor development quotient was similar, mental development quotient was significantly better among babies who received zinc supplementation. CONCLUSIONS: Short term zinc supplementation of newborns with sepsis reduces mortality and improves mental development quotient at 12 mo of age. PMID- 28891028 TI - The use of optical coherence tomography angiography in pachychoroid spectrum diseases: a concurrent comparison with dye angiography. AB - PURPOSE: The study objective was to compare dye angiography and optical coherence tomography angiography (OCTA) in detecting choroidal neovascuarization (CNV) in patients presenting with pachychoroid features and flat irregular pigment epithelial detachment (PED). METHODS: Nineteen eyes of 17 patients, presenting with flat PED and pachychoroid features, and without age-related macular degeneration or any other degenerative change, were analyzed. Fuorescein angiography (FA)/Indocyanine green angiography (ICGA) and OCTA were performed during the same visit. Subfoveal choroidal thickness was measured by enhanced depth imaging using spectral domain optical coherence tomography. RESULTS: The mean age of the patients was 59.1 years. Mean subfoveal choroidal thickness was 388 MUm. FA revealed non-patognomic features including RPE alterations, window defects, leaking points and leakage from an undetermined source. ICGA revealed choroidal vascular plaque in eight eyes (42%) and suspicious plaque in five eyes (26%). Nonneovascular features, such as hyperpermeability or dilated choroidal vessels, were observed in six eyes (32%). OCTA showed choroidal neovascularization in 14 (74%). For all of the eyes, which ICGA was positive for presence of CNV, OCTA also showed CNV, and in one case it also revealed polypoidal characteristics of the neovascular network. OCTA was also able to detect CNV in all of the eyes with suspicious plaque, and in one eye without CNV appearance using ICGA. CONCLUSIONS: OCTA demonstrated greater sensitivity in detecting type 1 CNV than conventional dye angiography in cases with pachychoroid spectrum disease. PMID- 28891029 TI - New Horizons in Measurement: a Review of Novel and Innovative Approaches to Eating-Disorder Assessment. AB - PURPOSE OF REVIEW: Eating disorders are serious mental-health concerns that will affect over 30 million individuals in the USA at some point in their lives. Eating disorders occur across the lifespan, in a variety of ethnicities and races, in both men and women, and across the socioeconomic spectrum. Given the prevalence and severity of eating disorders, it is important that clinicians and researchers have access to appropriate assessment tools to aid in the early identification and treatment referral, differential diagnosis, treatment planning, and progress monitoring, and to ensure valid research findings. In this review, we describe novel and innovative assessment tools that were developed within the past 5 years for utilization in research and/or clinical practice with individuals with eating disorders. RECENT FINDINGS: We identified six multidimensional assessments for eating disorders, all of which can be administered online (with some also offering paper-and-pencil versions). Strengths of the measures included good internal consistency, test-retest reliability, and convergent validity. However, in part, due to problematic scale construction methods, certain scales had poor discriminant validity and most were developed and validated in mostly female samples. There are promising new eating disorder measures from which to choose; however, many measures continue to be limited by poor discriminant validity and need additional validation prior to incorporation into routine research and clinical practice. PMID- 28891031 TI - Drug Resistant Tuberculosis in Children in a Tertiary Care Hospital. PMID- 28891030 TI - Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin4. AB - AIMS: Radiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed. METHODS: In vitro and ex vivo autoradiography studies of pancreas were performed using [177Lu]Lu-DO3A-VS-Cys40-Exendin4, in order to investigate the mechanism of uptake as well as the islet uptake contrast in mouse, rat, pig, and non-human primate. The autoradiography results were compared to the in vivo pancreatic uptake as assessed by [68Ga]Ga-DO3A-VS-Cys40-Exendin4 Positron Emission Tomography (PET) in the same species. In vitro, ex vivo, and in vivo data formed the basis for calculating the theoretical in vivo contribution of each pancreatic compartment. RESULTS: [177Lu]Lu-DO3A-VS-Cys40-Exendin4 displayed the highest islet-to-exocrine pancreas ratio (IPR) in rat (IPR 45) followed by non-human primate and mouse at similar levels (IPR approximately 5) while pigs exhibited negligible IPR (1.1). In vivo pancreas uptake was mainly GLP-1R mediated in all species, but the magnitude of uptake under basal physiology varied significantly in decreasing order: non-human primate, mouse, pig, and rat. The theoretical calculation of islet contribution to the total pancreatic PET signal predicted the in vivo observation of differences in pancreatic uptake of [68Ga]Ga-DO3A-VS-Cys40-Exendin4. CONCLUSIONS: IPR as well as the exocrine GLP-1R density is the main determinants of the species variability in pancreatic uptake. Thus, the IPR in human is an important factor for assessing the potential of GLP 1R as an imaging biomarker for pancreatic beta cells. PMID- 28891032 TI - The need for unique risk adjustment for surgical site infections at a high volume, tertiary care center with inherent high-risk colorectal procedures. AB - BACKGROUND: The aim of the present study was to create a unique risk adjustment model for surgical site infection (SSI) in patients who underwent colorectal surgery (CRS) at the Cleveland Clinic (CC) with inherent high risk factors by using a nationwide database. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried to identify patients who underwent CRS between 2005 and 2010. Initially, CC cases were identified from all NSQIP data according to case identifier and separated from the other NSQIP centers. Demographics, comorbidities, and outcomes were compared. Logistic regression analyses were used to assess the association between SSI and center related factors. RESULTS: A total of 70,536 patients met the inclusion criteria and underwent CRS, 1090 patients (1.5%) at the CC and 69,446 patients (98.5%) at other centers. Male gender, work-relative value unit, diagnosis of inflammatory bowel disease, pouch formation, open surgery, steroid use, and preoperative radiotherapy rates were significantly higher in the CC cases. Overall morbidity and individual postoperative complication rates were found to be similar in the CC and other centers except for the following: organ-space SSI and sepsis rates (higher in the CC cases); and pneumonia and ventilator dependency rates (higher in the other centers). After covariate adjustment, the estimated degree of difference between the CC and other institutions with respect to organ-space SSI was reduced (OR 1.38, 95% CI 1.08-1.77). CONCLUSIONS: The unique risk adjustment strategy may provide center-specific comprehensive analysis, especially for hospitals that perform inherently high-risk procedures. Higher surgical complexity may be the reason for increased SSI rates in the NSQIP at tertiary care centers. PMID- 28891033 TI - Targeted alpha therapy of mCRPC: Dosimetry estimate of 213Bismuth-PSMA-617. AB - PURPOSE: PSMA-617 is a small molecule targeting the prostate-specific membrane antigen (PSMA). In this work, we estimate the radiation dosimetry for this ligand labeled with the alpha-emitter 213Bi. METHODS: Three patients with metastatic prostate cancer underwent PET scans 0.1 h, 1 h, 2 h, 3 h, 4 h and 5 h after injection of 68Ga-PSMA-617. Source organs were kidneys, liver, spleen, salivary glands, bladder, red marrow and representative tumor lesions. The imaging nuclide 68Ga was extrapolated to the half-life of 213Bi. The residence times of 213Bi were forwarded to the instable daughter nuclides. OLINDA was used for dosimetry calculation. Results are discussed in comparison to literature data for 225Ac PSMA-617. RESULTS: Assuming a relative biological effectiveness of 5 for alpha radiation, the dosimetry estimate revealed equivalent doses of mean 8.1 Sv RBE5/GBq for salivary glands, 8.1 Sv RBE5/GBq for kidneys and 0.52 Sv RBE5/GBq for red marrow. Liver (1.2 Sv RBE5/GBq), spleen (1.4 Sv RBE5/GBq), bladder (0.28 Sv RBE5/GBq) and other organs (0.26 SvRBE5/GBq) were not dose-limiting. The effective dose is 0.56 Sv RBE5/GBq. Tumor lesions were in the range 3.2-9.0 SvRBE5/GBq (median 7.6 SvRBE5/GBq). Kidneys would limit the cumulative treatment activity to 3.7 GBq; red marrow might limit the maximum single fraction to 2 GBq. Despite promising results, the therapeutic index was inferior compared to 225Ac PSMA-617. CONCLUSIONS: Dosimetry of 213Bi-PSMA-617 is in a range traditionally considered reasonable for clinical application. Nevertheless, compared to 225Ac PSMA-617, it suffers from higher perfusion-dependent off-target radiation and a longer biological half-life of PSMA-617 in dose-limiting organs than the physical half-life of 213Bi, rendering this nuclide as a second choice radiolabel for targeted alpha therapy of prostate cancer. PMID- 28891036 TI - Acne Scars: How Do We Grade Them? AB - Acne vulgaris is a chronic inflammatory skin disease that can lead to permanent scarring. Although grading scales exist for acne scarring, there are many limitations, and there is still a need for a well validated gold standard scale for use in clinical practice or research trials. An objective measure of scar severity should be a component of global acne severity evaluations. This manuscript reviews currently available acne scar grading modalities: lesion counting; subjective self-assessment; Acne Scar Rating Scale (ASRS); evaluator based qualitative and quantitative scarring grading systems; Echelle d'Evaluation Clinique des Cicatrices d'acne (ECCA); Global Scale for Acne Scar Severity (SCAR S); and imaging. Despite the varying tools, most of the currently available scales do not account for scar color, depth, or change over time. A new, validated scale is needed that would allow for a more objective and accurate assessment of scar progression over time to assist with effective treatment and research. PMID- 28891034 TI - RHEB1 insufficiency in aged male mice is associated with stress-induced seizures. AB - The mechanistic target of rapamycin (mTOR), a protein kinase, is a central regulator of mammalian metabolism and physiology. Protein mTOR complex 1 (mTORC1) functions as a major sensor for the nutrient, energy, and redox state of a cell and is activated by ras homolog enriched in brain (RHEB1), a GTP-binding protein. Increased activation of mTORC1 pathway has been associated with developmental abnormalities, certain form of epilepsy (tuberous sclerosis), and cancer. Clinically, those mTOR-related disorders are treated with the mTOR inhibitor rapamycin and its rapalogs. Because the effects of chronic interference with mTOR signaling in the aged brain are yet unknown, we used a genetic strategy to interfere with mTORC1 signaling selectively by introducing mutations of Rheb1 into the mouse. We created conventional knockout (Rheb1 +/- ) and gene trap (Rheb1 Delta/+ ) mutant mouse lines. Rheb1-insufficient mice with different combinations of mutant alleles were monitored over a time span of 2 years. The mice did not show any behavioral/neurological changes during the first 18 months of age. However, after aging (> 18 months of age), both the Rheb1 +/- and Rheb1 Delta /- hybrid males developed rare stress-induced seizures, whereas Rheb1 +/- and Rheb1 Delta /- females and Rheb1 Delta/+ and Rheb1 Delta/Delta mice of both genders did not show any abnormality. Our findings suggest that chronic intervention with mTORC1 signaling in the aged brain might be associated with major adverse events. PMID- 28891035 TI - Equal treatment: no evidence of gender inequity in osteoporosis management in a coordinator-based fragility fracture screening program. AB - : We evaluated gender imbalance in osteoporosis management in a provincial coordinator-based fracture prevention program and found no difference by gender in treatment of high-risk fragility fracture patients. This establishes that a systemic approach with interventions for all fragility fracture patients can eliminate the gender inequity that is often observed. INRODUCTION: The purpose of this study was to evaluate an Ontario-based fracture prevention program for its ability to address the well-documented gender imbalance in osteoporosis (OP) management, by incorporating its integrated fracture risk assessments within a needs-based evaluation of equity. METHODS: Fragility fracture patients (>= 50 years) who were treatment naive at screening and completed follow-up within 6 months of screening were studied. Patients who underwent bone mineral density (BMD) testing done in the year prior to their current fracture were excluded. All participants had BMD testing conducted through the Ontario OP Strategy Fracture Screening and Prevention program, thus providing us with fracture risk assessment data. Our primary study outcome was treatment initiation at follow-up within 6 months of screening. Gender differences were compared using Fisher's exact test, at p < 0.05. RESULTS: After adjusting for subsequent fracture risk, study participants did not show a statistically significant gender difference in pharmacotherapy initiation at follow-up (p > 0.05). 68.4% of women and 66.2% of men at high risk were treated within 6 months of screening. CONCLUSION: Needs based analyses show no difference by gender in treatment of high-risk fragility fracture patients. An intensive coordinator-based fracture prevention model adopted in Ontario, Canada was not associated with gender inequity in OP treatment of fragility fracture patients after fracture risk adjustment. PMID- 28891037 TI - Analytical insight into degradation processes of aminopolyphosphonates as potential factors that induce cyanobacterial blooms. AB - Aminopolyphosphonates (AAPs) are commonly used industrial complexones of metal ions, which upon the action of biotic and abiotic factors undergo a breakdown and release their substructures. Despite the low toxicity of AAPs towards vertebrates, products of their transformations, especially those that contain phosphorus and nitrogen, can affect algal communities. To verify whether such chemical entities are present in water ecosystems, much effort has been made in developing fast, inexpensive, and reliable methods for analyzing phosphonates. However, unfortunately, the methods described thus far require time-consuming sample pretreatment and offer relatively high values of the limit of detection (LOD). The aim of this study was to develop an analytical approach to study the environmental fate of AAPs. Four phosphonic acids, N,N bis(phosphonomethyl)glycine (GBMP), aminotris(methylenephosphonic) acid (ATMP), hexamethylenediamine-N,N,N',N'-tetrakis(methylphosphonic) acid (HDTMP), and diethylenetriamine penta(methylenephosphonic) acid (DTPMP) were selected and examined in a water matrix. In addition, the susceptibility of these compounds to biotransformations was tested in colonies of five freshwater cyanobacteria microorganisms responsible for the so-called blooms in the water. Our efforts to track the AAP decomposition were based on derivatization of N-alkyl moieties with p-toluenesulfonyl chloride (tosylation) followed by chromatographic (HPLC-UV) separation of derivatives. This approach allowed us to determine seven products of the breakdown of popular phosphonate chelators, in nanomolar concentrations and in one step. It should be noted that the LOD of four of those products, aminemethylphosphonic acid (AMPA), N-phosphomethyl glycine (NPMG), N (methyl)aminemethanephosphonic acid (MAMPA), and N-(methyl) glycine (SAR), was set below the concentration of 50 nM. Among those substances, N (methylamino)methanephosphonic acid (MAMPA) was identified for the first time as the product of decomposition of the examined aminopolyphosphonates. PMID- 28891038 TI - Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment. AB - Background Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child-Pugh A and ECOG-PS <=1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child-Pugh A and ECOG-PS <= 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand-foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child-Pugh score > 6 and ECOG-PS > 1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child-Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients. PMID- 28891039 TI - A systematic review of transabdominal levator division during abdominoperineal excision of the rectum (APER). AB - BACKGROUND: The aim of the present study was to evaluate the surgical technique, short-term oncological and perioperative outcomes for the transabdominal division of the levator ani muscles during abdominoperineal excision of the rectum (APER). METHODS: A systematic review was performed to identify studies reporting on transabdominal division of the levator ani during APER. A comprehensive literature search was performed using a combination of free-text terms and controlled vocabulary when applicable on the following databases: MEDLINE, EMBASE, Science Citation Index Expanded and Cochrane Central Register of Controlled Trials in the Cochrane Library. The search period was from January 1945 to December 2015. The following search headings were used: "transabdominal", "transpelvic", "abdominal" or "pelvic" combined with either "levator" or "extralevator" and with "abdominoperineal". RESULTS: Nine publications were identified reporting on 99 participants. The male/female distribution was 1.44:1, respectively, and the mean age was 56.6 (30-77) years. All tumours were less than 5 cm from the anal verge. The preoperative radiological staging was T2 in 18% of cases, T3 in 53.5% and T4 in 28.5%. Transabdominal division of the levators was performed laparoscopically in 55 cases, robotically in 34 and open in 10. The mean operating time was 255 (177-640) min. Mean intraoperative blood loss was 140 (92-500) ml. There were no conversions to open. Circumferential resection margins were positive in two cases, and there was one intraoperative perforation. Mean post-operative length of stay was 9.3 (3-67) days. Follow-up (from 0 to 31 months) revealed 19 perineal wound infections, 15 cases of sexual dysfunction and 7 cases of urinary retention. There was no mortality and 1 readmission. CONCLUSIONS: Transabdominal division of the levators during APER is feasible and reproducible, with acceptable perioperative and good early oncological outcomes. Further comparative studies are needed. PMID- 28891040 TI - Dosimetry in clinical radionuclide therapy: the devil is in the detail. PMID- 28891041 TI - Influence of genetic background of engineered xylose-fermenting industrial Saccharomyces cerevisiae strains for ethanol production from lignocellulosic hydrolysates. AB - An industrial ethanol-producing Saccharomyces cerevisiae strain with genes of fungal oxido-reductive pathway needed for xylose fermentation integrated into its genome (YRH1415) was used to obtain haploids and diploid isogenic strains. The isogenic strains were more effective in metabolizing xylose than YRH1415 strain and able to co-ferment glucose and xylose in the presence of high concentrations of inhibitors resulting from the hydrolysis of lignocellulosic biomass (switchgrass). The rate of xylose consumption did not appear to be affected by the ploidy of strains or the presence of two copies of the xylose fermentation genes but by heterozygosity of alleles for xylose metabolism in YRH1415. Furthermore, inhibitor tolerance was influenced by the heterozygous genome of the industrial strain, which also showed a marked influenced on tolerance to increasing concentrations of toxic compounds, such as furfural. In this work, selection of haploid derivatives was found to be a useful strategy to develop efficient xylose-fermenting industrial yeast strains. PMID- 28891042 TI - A novel and reliable computational intelligence system for breast cancer detection. AB - Cancer is the second important morbidity and mortality factor among women and the most incident type is breast cancer. This paper suggests a hybrid computational intelligence model based on unsupervised and supervised learning techniques, i.e., self-organizing map (SOM) and complex-valued neural network (CVNN), for reliable detection of breast cancer. The dataset used in this paper consists of 822 patients with five features (patient's breast mass shape, margin, density, patient's age, and Breast Imaging Reporting and Data System assessment). The proposed model was used for the first time and can be categorized in two stages. In the first stage, considering the input features, SOM technique was used to cluster the patients with the most similarity. Then, in the second stage, for each cluster, the patient's features were applied to complex-valued neural network and dealt with to classify breast cancer severity (benign or malign). The obtained results corresponding to each patient were compared to the medical diagnosis results using receiver operating characteristic analyses and confusion matrix. In the testing phase, health and disease detection ratios were 94 and 95%, respectively. Accordingly, the superiority of the proposed model was proved and can be used for reliable and robust detection of breast cancer. PMID- 28891043 TI - Reamed locked intramedullary nailing for studying femur fracture and its complications. AB - Morbidity associated with femur fractures in polytrauma patients is known to be high. The many unsolved clinical questions include the immunological effect of the fracture and its fixation, timing of fracture fixation, management of fracture non-union, effect of infection and critical size of bone defects. The aim of this study was to establish a clinically-relevant and reproducible animal model with regards to histological, biomechanical and radiological changes during bone healing. A custom-designed intramedullary nail with interlocking system (RabbitNail, RISystem AG, Davos Platz, Switzerland) was used for fixation, following femur fracture. New Zealand White rabbits were assigned to two groups: 1. closed fracture model (CF; non-survival model: n = 6, survival model: n = 3) with unilateral mid-shaft femur fracture created by blunt force; 2. osteotomy model (OT; survival model: n = 14) with unilateral transverse osteotomy creating femur fracture. There were no intraoperative complications and full-weight bearing was achieved in all survival rabbits. Significant periosteal reaction and callus formation were confirmed from 2 weeks postoperatively, with a significant volume formation (739.59 +/- 62.14 mm3) at 8 weeks confirmed by micro-computed tomography (u-CT). 2 months after fixation, there was no difference between the osteotomised and contralateral control femora in respect to the maximum torque (3.47 +/- 0.35 N m vs. 3.26 +/- 0.37 N m) and total energy (21.11 +/- 3.09 N m * degree vs. 20.89 +/- 2.63 N m * degree) required to break the femur. The data confirmed that a standardised internal fixation technique with an intramedullary nail for closed fracture or osteotomy produced satisfactory bone healing. It was concluded that important clinically-relevant studies can be conducted using this rabbit model. PMID- 28891044 TI - Considerations for Evaluating Treatment Effects From Randomized Clinical Trials. AB - This article focuses on the choice of treatment effect measures in randomized clinical trials (RCTs). Traditionally, an intention-to-treat (ITT) analysis is conducted with an implicit understanding that a treatment-policy effect is of greatest interest. In this article we contend that this approach may not always provide accurate information about clinically meaningful treatment effects, and we present an argument that for any RCT it is desirable to require an explicit definition of what treatment effect is of primary interest, known as the "estimand." We will discuss the limitations of the traditional ITT effect measures as well as the state-of-the art thinking with regard to estimands. Furthermore, we will offer alternate choices that acknowledge that treatments have multiple effects. PMID- 28891046 TI - The association of postoperative pulmonary complications in 109,360 patients with pressure-controlled or volume-controlled ventilation. AB - We thought that the rate of postoperative pulmonary complications might be higher after pressure-controlled ventilation than after volume-controlled ventilation. We analysed peri-operative data recorded for 109,360 adults, whose lungs were mechanically ventilated during surgery at three hospitals in Massachusetts, USA. We used multivariable regression and propensity score matching. Postoperative pulmonary complications were more common after pressure-controlled ventilation, odds ratio (95%CI) 1.29 (1.21-1.37), p < 0.001. Tidal volumes and driving pressures were more varied with pressure-controlled ventilation compared with volume-controlled ventilation: mean (SD) variance from the median 1.61 (1.36) ml.kg-1 vs. 1.23 (1.11) ml.kg-1 , p < 0.001; and 3.91 (3.47) cmH2 O vs. 3.40 (2.69) cmH2 O, p < 0.001. The odds ratio (95%CI) of pulmonary complications after pressure-controlled ventilation compared with volume-controlled ventilation at positive end-expiratory pressures < 5 cmH2 O was 1.40 (1.26-1.55) and 1.20 (1.11 1.31) when >= 5 cmH2 O, both p < 0.001, a relative risk ratio of 1.17 (1.03 1.33), p = 0.023. The odds ratio (95%CI) of pulmonary complications after pressure-controlled ventilation compared with volume-controlled ventilation at driving pressures of < 19 cmH2 O was 1.37 (1.27-1.48), p < 0.001, and 1.16 (1.04 1.30) when >= 19 cmH2 O, p = 0.011, a relative risk ratio of 1.18 (1.07-1.30), p = 0.016. Our data support volume-controlled ventilation during surgery, particularly for patients more likely to suffer postoperative pulmonary complications. PMID- 28891047 TI - BRAF wild-type malignant melanoma developing on a thermal burn. PMID- 28891045 TI - A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus. AB - In the developing hypothalamus, the fat-derived hormone leptin stimulates the growth of axons from the arcuate nucleus of the hypothalamus (ARH) to other regions that control energy balance. These projections are significantly reduced in leptin deficient (Lepob/ob ) mice and this phenotype is largely rescued by neonatal leptin treatments. However, treatment of mature Lepob/ob mice is ineffective, suggesting that the trophic action of leptin is limited to a developmental critical period. To temporally delineate closure of this critical period for leptin-stimulated growth, we treated Lepob/ob mice with exogenous leptin during a variety of discrete time periods, and measured the density of Agouti-Related Peptide (AgRP) containing projections from the ARH to the ventral part of the dorsomedial nucleus of the hypothalamus (DMHv), and to the medial parvocellular part of the paraventricular nucleus (PVHmp). The results indicate that leptin loses its neurotrophic potential at or near postnatal day 28. The duration of leptin exposure appears to be important, with 9- or 11-day treatments found to be more effective than shorter (5-day) treatments. Furthermore, leptin treatment for 9 days or more was sufficient to restore AgRP innervation to both the PVHmp and DMHv in Lepob/ob females, but only to the DMHv in Lepob/ob males. Together, these findings reveal that the trophic actions of leptin are contingent upon timing and duration of leptin exposure, display both target and sex specificity, and that modulation of leptin-dependent circuit formation by each of these factors may carry enduring consequences for feeding behavior, metabolism, and obesity risk. PMID- 28891048 TI - Identifying actionable variants using next generation sequencing in patients with a historical diagnosis of undifferentiated pleomorphic sarcoma. AB - There are limited data regarding the molecular characterization of undifferentiated pleomorphic sarcomas (UPS; formerly malignant fibrous histiocytoma). This study aimed to investigate the utility of next generation sequencing (NGS) in UPS to identify subsets of patients who harbour actionable mutations. Patients diagnosed with UPS underwent pathological re-evaluation by a pathologist specializing in sarcoma. Tumor DNA was isolated from archived fresh frozen tissue samples and genotyped using NGS with the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons). In total, 95 patients initially classified with UPS were identified. Following pathology re-review the histological subtypes were reclassified to include: Myxofibrosarcoma (MFS, N = 44); UPS(N = 18); and Others (N = 27; including undifferentiated spindle cell sarcoma (N = 15) and dedifferentiated liposarcoma (N = 6)). Seven cases were excluded from further analysis for other reasons. Baseline demographics of the finalized cohort (N = 88) showed a median age of 66 years (32-95), primarily with stage I-III disease (92%) and high-grade (86%) lesions. Somatic mutations were identified in 31 cases (35%)(Total mutations = 36: solitary mutation(n = 27); two mutations( =n = 3); three mutations(n = 1)). The most commonly identified mutations were in TP53 (n = 24), ATM (n = 3) and PIK3CA (n = 2). Three of 43 patients with MFS and one of 18 patients with UPS had clinically relevant mutations, mainly related to biomarkers of prediction of response; however few had targetable driver mutations. Somatic mutation status did not influence disease free or overall survival. Based on the small number of clinically relevant mutations, these data do not support the routine use of targeted NGS panels outside of research protocols in UPS. PMID- 28891050 TI - S-shaped tracheal tubes for videolaryngoscopy. PMID- 28891049 TI - Differential projections of the densocellular and intermediate parts of the hyperpallium in the pigeon (Columba livia). AB - The visual Wulst in birds shows a four-layered structure: apical part of the hyperpallium (HA), interstitial part of HA (IHA), intercalated part of hyperpallium (HI), and densocellular part of hyperpallium (HD). HD also connects with the hippocampus and olfactory system. Because HD is subjacent to HI, the two have been treated as one structure in many studies, and the fiber connections of HD have been examined by afferents and efferents originating outside HD. However, to clarify the difference between these two layers, they need to be treated separately. In the present study, the fiber connections of HD and HI were analyzed with tract-tracing techniques using a combination of injections of cholera toxin subunit B (CTB) for retrograde tracing and biotinylated dextran amine (BDA) for anterograde tracing. When the two tracers were bilaterally injected in HD, a major reciprocal connection was seen with the dorsolateral subdivision (DL) of the hippocampal formation. When CTB and BDA were bilaterally injected in HI, strong reciprocal connections were found between HI and HA. Next, projection neurons in HD and HI were examined by double staining for CTB combined with vesicular glutamate transporter 2 (vGluT2) mRNA in situ hybridization. After CTB was injected in DL or HA, many neurons revealed CTB+/vGluT2+ in HD or HI, respectively. Furthermore, in situ hybridization showed that DL and HA contained neurons expressing various subunits of ionotropic glutamate receptors: AMPA, kainate, and NMDA types. These results suggest that glutamatergic neurons in HD and HI project primarily to DL and HA, respectively. PMID- 28891051 TI - Iron homeostasis: complex effects beyond anaemia. PMID- 28891052 TI - International publication trends originating from anaesthetic departments from 2001 to 2015. AB - The aim of this study was to analyse publication trends from the anaesthetic literature of the G-20 countries. We performed a literature search in Medline to identify articles related to anaesthetic departments published between 2001 and 2015, by specific G-20 countries according to the affiliation field of the authors, and to three time periods 2001-2005, 2006-2010 and 2011-2015. The number of articles, number of original articles (vs. reviews, editorials or correspondence), articles per million inhabitants, and citations per article were analysed. In total, 96,920 articles were published between 2001 and 2015 in 74 anaesthetic and in 4117 non-anaesthetic journals, with an increase of +104% absolute (i.e. from 23,028 in 2001-05 to 46,887 articles in 2010-15) and +85% as articles per million inhabitants. Similarly, the number of original articles increased by 21%, but the anaesthetic specialty's share of original articles (as a proportion of total articles in biomedicine) decreased from 31% in 2001-2005 to 19% in 2011-2015 (-38%). The USA published most articles (2011-15 16,016; 31% of total), second came the EU as a whole and third Japan (from 2001 to 2005) or Germany (2006-2010) until 2011-2015 when China took over the third rank. In 2011 2015, Canada published most articles per million inhabitants (68.7 articles/million inhabitants). China and India exhibited the most publication growth 11- and 9-fold, respectively, and are now among the top five countries for the number of published articles. PMID- 28891053 TI - Surgical Outcome Risk Tool (SORT) validation in hepatectomy. PMID- 28891054 TI - Epidural pressure waveforms. PMID- 28891055 TI - Ultrasound examination of gastric contents: are qualitative and quantitative assessments complementary? A reply. PMID- 28891056 TI - Performance of the Minto model for the target-controlled infusion of remifentanil during cardiopulmonary bypass. AB - We studied the predictive performance of the Minto pharmacokinetic model during cardiopulmonary bypass in patients undergoing cardiac surgery. Patients received remifentanil target-controlled infusion using the Minto model during total intravenous anaesthesia with propofol. From 56 patients, 275 arterial blood samples were drawn before, during and after bypass to determine the plasma concentration of remifentanil, and the predicted concentrations were recorded at each time. For pooled data, the median prediction error and median absolute prediction error were 21.3% and 21.8%, respectively, and 22.1% and 22.3% during bypass. Both were 148.4% during hypothermic circulatory arrest and measured concentrations were more than three times greater than predicted (26.9 (17.0) vs. 7.1 (1.6) ng.ml-1 ). The Minto model showed considerable bias but overall acceptable precision during bypass. The target concentration of remifentanil should be reduced when using the Minto model during hypothermic circulatory arrest. PMID- 28891057 TI - 'On lock' - a further single-operator ultrasound-guided regional anaesthesia grip. PMID- 28891058 TI - Medtronic electromyographic tracheal tube. PMID- 28891059 TI - Consensus on ethics in airway research - a reply. PMID- 28891061 TI - Calculating oxygen consumption during low flow anaesthesia. A reply. PMID- 28891060 TI - A survey of acute pain services in the UK. AB - The organisational state of inpatient pain management in UK hospitals is difficult to determine. We sent an electronic questionnaire to 209 acute pain service leads throughout the UK. Questions were about staffing and service provision. We received 141 responses (67%); 47% of all UK hospitals. Each service was responsible for a median (IQR [range]) of 566 (400-839 [120-2800]) beds. Each acute pain specialist nurse was responsible for 299 (238-534 [70-1923]) beds. The mean (SD) number of consultant hours per week was 5.54 (4.62), delivered by a median of 1.0 (1.0-2.5 [0.2-7.0]) consultant. Overnight cover was provided by 20 (15%) acute pain services, and weekend cover by 39 (29%). Acute pain services commonly (in 50 (35%) hospitals) had roles in addition to acute pain management. Most teams (105, (77%)) reviewed medical patients and patients with chronic pain (in 131, (96%) teams). Half of the services (56, (49%)), reported that they were part of an integrated acute and chronic pain service, however, 83 (59%) did not have any members who work in chronic pain clinics. The majority (79, (70%)) were able to access a nominated chronic pain consultant for advice. Provision of acute pain services throughout the UK is highly variable. The majority do not meet core UK standards. PMID- 28891062 TI - A systematic review of information format and timing before scheduled adult surgery for peri-operative anxiety. AB - We included 34 trials with 3742 participants, identified through 6 database and supplementary searches (to May 2017): 29 were randomised; 4 were quasi-randomised and 1 was cluster-randomised. Disparate measurements and outcomes precluded meta analyses. Blinding was attempted in only 6 out of 34 (18%) trials. A multimedia format, alone or in combination with text or verbal formats, was studied in 20/34 (59%) trials: pre-operative anxiety was unaffected in 10 out of 14 trials and reduced by the multimedia format in three; postoperative anxiety was unaffected in four out of five trials in which formats were compared. Multimedia formats increased knowledge more than text, which in turn increased knowledge more than verbal formats. Other outcomes were unaffected by information format. The timing of information did not affect pre-operative anxiety, postoperative pain or length of stay. In conclusion, the effects of pre-operative information on peri operative anxiety and other outcomes were affected little by format or timing. PMID- 28891064 TI - 3-D printing in anaesthesia: challenges and controversies. PMID- 28891063 TI - Ultrasound examination of gastric contents: are qualitative and quantitative assessments complementary? PMID- 28891065 TI - IL4-induced gene 1 is secreted at the immune synapse and modulates TCR activation independently of its enzymatic activity. AB - Amino-acid catabolizing enzymes produced by mononuclear phagocytes play a central role in regulating the immune response. The mammalian phenylalanine-catabolizing enzyme IL4-induced gene 1 (IL4I1) inhibits effector T lymphocyte proliferation and facilitates regulatory T-cell development. IL4I1 expression by macrophages of various human tumors may affect patient prognosis as it facilitates tumor escape from the T-cell response in murine models. Its enzymatic activity appears to participate in its effects, but some actions of IL4I1 remain unclear. Here, we show that the presence of IL4I1 during T-cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T-cell inhibition which is more pronounced when there is CD28 costimulation. Surprisingly, the enzymatic activity of IL4I1 is not involved. Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3+ lymphocytes could be important in IL4I1 immunosuppressive mechanism of action. PMID- 28891066 TI - Fluconazole-induced Sweet's syndrome: A novel association. PMID- 28891067 TI - The effect of health insurance on childhood cancer survival in the United States. AB - BACKGROUND: The effect of health insurance on childhood cancer survival has not been well studied. Using Surveillance, Epidemiology, and End Results (SEER) data, this study was designed to assess the association between health insurance status and childhood cancer survival. METHODS: Data on cancers diagnosed among children less than 15 years old from 2007 to 2009 were obtained from the SEER 18 registries. The effect of health insurance at diagnosis on 5-year childhood cancer mortality was estimated with marginal survival probabilities, restricted mean survival times, and Cox proportional hazards (PH) regression analyses, which were adjusted for age, sex, race/ethnicity, and county-level poverty. RESULTS: Among 8219 childhood cancer cases, the mean survival time was 1.32 months shorter (95% confidence interval [CI], -4.31 to 1.66) after 5 years for uninsured children (n = 131) versus those with private insurance (n = 4297), whereas the mean survival time was 0.62 months shorter (95% CI, -1.46 to 0.22) for children with Medicaid at diagnosis (n = 2838). In Cox PH models, children who were uninsured had a 1.26-fold higher risk of cancer death (95% CI, 0.84-1.90) than those who were privately insured at diagnosis. The risk for those with Medicaid was similar to the risk for those with private insurance at diagnosis (hazard ratio, 1.06; 95% CI, 0.93-1.21). CONCLUSIONS: Overall, the results suggest that cancer survival is largely similar for children with Medicaid and those with private insurance at diagnosis. Slightly inferior survival was observed for those who were uninsured in comparison with those with private insurance at diagnosis. The latter result is based on a small number of uninsured children and should be interpreted cautiously. Further study is needed to confirm and clarify the reasons for these patterns. Cancer 2017;123:4878-85. (c) 2017 American Cancer Society. PMID- 28891068 TI - Open-tubular capillary electrochromatography using carboxylatopillar[5]arene as stationary phase. AB - Pillar[n]arenes have achieved much interest in material chemistry and supramolecular chemistry due to unusual pillar shape structure and high selectivity toward guest. However, pillar[n]arenes have not yet been applied in capillary electrochromatography. This work at first time reports that carboxylatopillar[5]arene is used as a stationary phase in open-tubular capillary electrochromatography. Carboxylatopillar[5]arene not only possess the advantages of pillar[n]arenes but also provide free carboxy groups for immobilizing on the inner wall of capillary column via covalent bonding. The characterization of SEM and FT-IR indicated that carboxylatopillar[5]arene was successfully grafted on the inner wall of capillary. The baseline separation of model analytes including neutral, basic, and acidic compounds, nonsteroidal anti-inflammatory drugs and dansyl-amino acids have been achieved thanks to the electron-rich cavity of carboxylatopillar[5]arene and hydrophobic interactions between the analytes and stationary phase. The intraday, interday, and column-to-column precisions (RSDs) of retention time and peak area for the neutral analytes were all less than 3.34 and 9.65%, respectively. This work indicates that pillar[n]arenes have great potential in capillary electrochromatography as novel stationary phase. PMID- 28891069 TI - Use of supplemental anti-HBc testing of donors showing non-discriminating reactive results in multiplex nucleic acid testing. AB - BACKGROUND AND OBJECTIVES: The Korean Red Cross began nucleic acid amplification testing (NAT) for HIV and HCV in February 2005, and added HBV NAT beginning in June 2012. The current NAT system utilizes a multiplex assay for simultaneous detection of HBV DNA, HCV RNA and HIV-1 RNA. For samples that are reactive in the multiplex assay, we do specific tests for each virus. However, there have been cases of non-discriminated reactive (NDR) results which appear to be the result of non-specific reactions or cross-contamination, although some cases are considered to arise from the presence of low levels of HBV DNA due to occult hepatitis B infection. MATERIALS AND METHODS: We examined the incidence of NDR results in previous donations of some NAT-reactive donors. Additionally, for those donors with NDR results, we performed an HBV core antibody (anti-HBc) assay. RESULTS: From November 2015 to March 2016, there were 408 NAT-reactive donors. Of these, nineteen HBV NAT-reactive donors showed a history of NDR results in the past donations. Seven donors showed NDR results more than once. Of 771 NDR donors, 362 (47.0%) were anti-HBc reactive. CONCLUSION: The NDR donors had a substantially higher rate of anti-HBc reactivity than other blood donors indicating that some with anti-HBc reactivity represent donors with occult HBV. Therefore, the incorporation of an anti-HBc testing for NDR donors could improve blood safety testing for the Korean Red Cross. PMID- 28891070 TI - Screening bioactive compounds from natural product and its preparations using capillary electrophoresis. AB - Bioactive ingredients of natural products can protect human body from harm, as well as prevent and treat disease. Screening bioactive compounds from natural products is attracting particular attention. It is a great challenge to separate and detect the active compounds from complex matrix natural products. CE plays a vital role in screening active compounds because of its unique features such as high-efficiency separation, short-analysis time, minimal sample consumption, and ease to realize automatization etc. Additionally, CE has been developed various modes owing to its abundant advantages in analysis and separation of compounds. The purpose of this work is to review previous developments and applications of CE in screening bioactive compounds derived from natural products from 2007 to 2017. This review does not only summarize the traditional methods of detecting active ingredients but also briefly introduces some novel assays. The trends in the application of CE in active compounds screening are addressed in the article. PMID- 28891072 TI - Stable Control of Physiological Parameters, But Not Infection, in Preterm Lambs Maintained on Ex Vivo Uterine Environment Therapy. AB - Ex vivo uterine environment (EVE) therapy is an experimental neonatal intensive care strategy wherein gas exchange is performed by membranous oxygenators attached to the umbilical vessels. Our aim was to assess the ability of a newly refined EVE system to maintain key physiological parameters in preterm lambs within optimal ranges for 48 h. EVE group; n = 6: Preterm lambs were delivered under general anesthesia at 115 +/- 2 days of gestational age. Animals were submerged in a bath of artificial amniotic fluid on EVE therapy for 48 h. Physiological parameters were monitored in real-time over the length of the experiment. Control group; n = 11: Ewes carrying a single fetus (115 +/- 2 days of gestational age) underwent recovery surgery to allow placement of a fetal carotid artery catheter. Fetuses received an infusion of sterile saline only. After euthanasia, EVE and Control group fetuses underwent necroscopy to perform static pressure-volume curves and for sampling of lung and cord blood plasma for molecular analyses. Five out of six fetuses in the EVE group completed the study period with key physiological variables remaining within their respective reference ranges for the duration of the 48 h study. Bacteremia was identified in four out of five EVE fetuses, and was associated with a systemic inflammatory response. Using our refined EVE therapy platform, preterm lambs were maintained in a stable physiological condition for 48 h. These findings represent a significant advance over earlier work with this system; however, the identification of bacteremia and a fetal inflammatory response suggests that further refinement to the EVE therapy platform is required. PMID- 28891071 TI - Genetic variation in the vitamin D related pathway and breast cancer risk in women of African ancestry in the root consortium. AB - The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level p = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24-1.91, padj = 0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non-vitamin D relevant mechanism but further studies are needed. PMID- 28891073 TI - Sexual dimorphism in jaw muscles of the Japanese sparrowhawk (Accipiter gularis). AB - Materials suitable for anatomical research of raptorial birds are rare. Bird eating raptors show distinct inter-sexual differences in body size and parental roles. The large females catch larger prey and prepare small morsels to feed their young using their hooked beaks. Here, we investigated the architectural properties of different jaw muscles of the Japanese sparrowhawk (Accipiter gularis) and examined whether there is sexual dimorphism in their architectural design. The results showed that musculus depressor mandibulae, the opener of the lower jaw, was characterized by relatively long fascicle length, whereas musculus pterygoideus was characterized by its larger mass and physiological cross sectional area (PCSA) in both sexes. Females have the potential capacity to produce rapid and strong bites by their significantly longer fascicle length of M. depressor mandibulae and larger mass and PCSA of M. pterygoideus. For body size-matched gender, jaw muscles of males had fibres of relatively longer length than females, enabling greater velocity and excursion. Architectural characteristics of jaw muscles, together with the absolute dimorphism (the fascicle length of M. depressor mandibulae, the muscle mass and PCSA of M. pterygoideus) and relative dimorphism in the muscle mass of M. pterygoideus, reflect dietary difference and asymmetric parental roles between the sexes. PMID- 28891074 TI - Nelarabine toxicity in children and adolescents with relapsed/refractory T-ALL/T LBL: can we avoid throwing the baby out with the bathwater? PMID- 28891075 TI - Effect of feeding on the pharmacokinetics of oral minocycline in healthy adult horses. AB - Minocycline is commonly used to treat bacterial and rickettsial infections in adult horses but limited information exists regarding the impact of feeding on its oral bioavailability. This study's objective was to compare the pharmacokinetics of minocycline after administration of a single oral dose in horses with feed withheld and with feed provided at the time of drug administration. Six healthy adult horses were administered intravenous (2.2 mg/kg) and oral minocycline (4 mg/kg) with access to hay at the time of oral drug administration (fed) and with access to hay delayed for 2 hr after oral drug administration (fasted), with a 7-day washout between treatments. Plasma concentration versus time data was analyzed based on noncompartmental pharmacokinetics. Mean +/- SD bioavailability (fasted: 38.6% +/- 4.6; fed: 15.7% +/- 2.3) and Cmax (fasted: 1.343 +/- 0.418 MUg/ml; fed: 0.281 +/- 0.157 MUg/ml) were greater in fasted horses compared to fed horses (p < .05 both). Median (range) Tmax (hr) in fasted horses was 2.0 (1.5-3.5) and in fed horses was 5.0 (1.0-8.0) and was not significantly different between groups. Overnight fasting and delaying feeding hay 2 hr after oral minocycline administration improve drug bioavailability and thus plasma concentrations. PMID- 28891076 TI - Natural course and characteristics of cutaneous neurofibromas in neurofibromatosis 1. AB - Neurofibromatosis 1 (NF1) is characterized by cutaneous, neurological and osseous manifestations. Most NF1 patients develop cutaneous neurofibromas. However, time dependent change with aging and the predilection site of cutaneous neurofibromas remain unclear. To clarify the natural course and characteristics of cutaneous neurofibromas, a retrospective study was conducted for 57 NF1 patients who were treated at the Department of Dermatology of Tottori University Hospital between January 2007 and April 2016. For each patient, we investigated the time-dependent changes and the numbers of cutaneous neurofibromas in four body surface regions. There was a positive correlation between age and number of cutaneous neurofibromas (r = 0.75, P < 0.001). Cutaneous neurofibromas were located on the trunk (60.2%), lower limbs (16.1%), upper limbs (14.4%), and head and neck (9.2%). There was no significant relationship between each body type (e.g. obese or thin) and cutaneous neurofibromas. With respect to the year-to-year percentage change in cutaneous neurofibromas, the average annual rate of increase was 0.21 (range, -0.71 to 1.2). The number of cutaneous neurofibromas had increased in approximately 61% of the patients 1 year later. Our data will enable physicians to estimate the overall state of cutaneous neurofibromas in NF1 and will be useful for handling cutaneous manifestations before they become a serious condition. PMID- 28891077 TI - A comparison of the effects of CYP3A5 polymorphism on tacrolimus blood concentrations measured by 4 immunoassay methods in renal transplant patients. AB - WHAT IS KNOWN AND OBJECTIVE: The anti-tacrolimus antibodies used in commercial immunoassay methods have cross-reactivity with tacrolimus metabolites. The aim of this study was to investigate differences in the effects of CYP3A5 polymorphism on tacrolimus concentrations obtained by four immunoassay methods in renal transplant patients. METHODS: Samples (n = 508) were evaluated using four immunoassays (chemiluminescence enzyme immunoassay [CLIA], affinity column mediated immunoassay [ACMIA], electrochemiluminescence immunoassay [ECLIA] and latex agglutination turbidimetric immunoassay [LTIA]). RESULTS: Bland-Altman plots showed average biases of -0.12 (+/-1.96 SD: -1.30-1.05) ng/mL for CLIA, 0.30 (-1.59-1.00) ng/mL for ECLIA, 0.42 (-1.21-2.05) ng/mL for ACMIA and 1.88 ( 0.51-4.28) ng/mL for LTIA, when considering the mean of the three immunoassays (CLIA, ECLIA and ACMIA). In multiple regression analysis, the difference (CLIA mean) was affected by haematocrit levels. Differences in ECLIA were correlated with red blood cell counts. For LTIA, CYP3A5 genotype and haematocrit levels were identified as independent predictors for this bias. WHAT IS NEW AND CONCLUSION: The results obtained by CLIA, ECLIA and ACMIA were not affected by CYP3A5 polymorphism. However, in LTIA, CYP3A5*1/*3-derived data exhibited an inverse relationship in Bland-Altman analysis (slope: -0.0824). Higher cross-reactivity with 12-hydroxy tacrolimus at lower concentrations may occur in patients with the CYP3A5*1/*3 genotype. Because patients with the CYP3A5*1 allele identified using LTIA may show higher blood concentrations of tacrolimus at lower target concentrations, for example 3.0 ng/mL, compared with other immunoassay methods, there is a need for sufficient consideration of the interpretation of values measured by LTIA. PMID- 28891078 TI - Design and Development of Novel Transcatheter Bicaval Valves in the Interventional Treatment of Tricuspid Regurgitation. AB - The concept of heterotopic implantation of transcatheter tricuspid valve is new and has shown promising results thus far. While the Reynolds shear stress values measured in the vicinity of this valve are relatively low, the values at some time points are higher than the threshold of platelet activation. Hence, in this study, we aim to reduce these values with an innovative stent design. It was shown that the Reynolds shear stress values measured were lower than those of valves made of generic stent design and the maximum Reynolds shear stress values in the vicinity of the valves was very low (~10 dynes/cm2 ). The results also depicted the interesting flow phenomenon of this non-physiological treatment approach. Thus, this study has shown that bicaval valves could potentially be considered as a minimally invasive option to treat tricuspid regurgitation and valve design improvements could reduce the flow disturbances that were observed. PMID- 28891080 TI - Dermatoscope-guided suturing for an open wound adjacent to the lacrimal sac and the nasolacrimal duct. PMID- 28891079 TI - Successful TS-1 monotherapy as the second-line treatment for advanced extramammary Paget's disease: A report of two cases. AB - There is no standard chemotherapeutic treatment for advanced extramammary Paget's disease, though the effectiveness of some chemotherapy regimens, including docetaxel, has been reported. In this report, we report that TS-1 monotherapy was effective in two patients with advanced extramammary Paget's disease after docetaxel treatment failure. TS-1 monotherapy may be useful as the second-line treatment for patients with advanced extramammary Paget's disease. PMID- 28891081 TI - Improvement of the initial stage of interstitial lung disease during psoriasis treatment with secukinumab. PMID- 28891082 TI - Thrombolysis for Massive Pulmonary Embolism in Pregnancy. AB - Pregnant women are at high risk for venous thromboembolism, including pulmonary embolism (PE), given expected changes in coagulation, fibrinolysis, and venous blood flow. In fact, PE is the leading cause of maternal death in the United States. Nonpregnant patients who develop PE with hypotension or show signs of deterioration after anticoagulation receive thrombolytics as a standard of care. Pregnant women, however, have been excluded from clinical trials with thrombolytics, and all data available in this population are published as case reports or case series. We reviewed all reports of thrombolytics, systemic or catheter directed, used in pregnant patients with massive PE. This article summarizes the risks for thromboembolism in pregnancy, compares and contrasts thrombolytic agents in this setting, and provides a recommendation for management of massive PE in this special population. Overall, reports suggest that the use of these agents is associated with beneficial outcomes and a relatively low risk of complications. The quality of this evidence is low, and clinical judgment is required to assess individual patients for risks versus benefits of thrombolysis. PMID- 28891084 TI - Structured advice provided by a dietitian increases adherence of consumers to diet and lifestyle changes and lowers blood low-density lipoprotein (LDL) cholesterol: the Increasing Adherence of Consumers to Diet & Lifestyle Changes to Lower (LDL) Cholesterol (ACT) randomised controlled trial. AB - BACKGROUND: Evidence from healthcare professionals suggest that consumer compliance to healthy diet and lifestyle changes is often poor. The present study investigated the effect of advice provided by a physician or dietitian on consumer adherence to these measures combined with consuming foods with added plant sterols (PS) with the aim of lowering low-density lipoprotein cholesterol (LDL-C). METHODS: One hundred mildly-to-moderately hypercholesterolaemic individuals were enrolled into a parallel, randomised, placebo-controlled study. Dietitians (dietitian group; DG) advised 50 individuals in six weekly face-to face behavioural therapy sessions, whereas the other 50 received standard advice from physicians (physician group, PG). Both groups consumed foods with added PS (three servings a day) for 6 weeks. Subsequently, all individuals were followed up for another 6 weeks under real-life conditions. Blood lipids were measured at baseline and weeks 6 and 12 and 3-day diet diaries were taken at weeks 1, 6 and 12. RESULTS: Individuals in the DG significantly improved their dietary habits, physical activity and increased PS intake compared to the PG. After 6 weeks, LDL C decreased in both groups compared to baseline without any significant differences between groups. At week 12, LDL-C was further significantly improved only in the DG (P = 0.006) compared to week 6. Total cholesterol, LDL-C and triglycerides were significantly lower in the DG compared to the PG at week 12 after adjusting for levels at week 6 (P < 0.001, P < 0.001 and P = 0.009, respectively). CONCLUSIONS: Although structured counselling by dietitians and common standard advice by physicians were equally effective with respect to improving blood cholesterol after 6 weeks, dietitians were more effective in the longer-term (i.e. 6 weeks after the end of the intervention period). PMID- 28891083 TI - A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study). AB - Hypoplastic myelodysplastic syndrome (hMDS) is a distinct entity with bone marrow (BM) hypocellularity and the risk of death from BM failure (BMF). To elucidate the characteristics of hMDS, the data of 129 patients diagnosed between April 2003 and March 2012 were collected from 20 institutions and the central review team of the National Research Group on Idiopathic Bone Marrow Failure Syndromes, and compared with 115 non-hMDS patients. More RA and fewer CMMoL and RAEB-t in French-American-British (FAB) and more RCUD and MDS-U and fewer RCMD in World Health Organization (WHO) classifications were found in hMDS than non-hMDS with significant differences. The overall survival (OS) and AML progression-free survival (AML-PFS) of hMDS were higher than those of non-hMDS, especially in patients at age >=50 and of lower risk in Revised International Prognostic Scoring System (IPSS-R). In competing risks analysis, hMDS exhibited decreased risk of AML-progression in lower IPSS or IPSS-R risk patients, and higher risk of death from BMF in patients at age >=50. Poor performance status (PS >=2) and high karyotype risks in IPSS-R (high and very high) were significant risk factors of death and AML-progression in Cox proportional hazards analysis. PMID- 28891085 TI - Lipopolysaccharide and cytokines modulate leukotriene (LT)B4 and LTC4 production by porcine endometrial endothelial cells. AB - Uterine inflammatory response is mediated by inflammatory mediators including eicosanoids and cytokines produced by immune and endometrial cells. Interactions between lipopolysaccharide (LPS) and cytokines, and leukotrienes (LTs) in endothelium, important for the host defence during the inflammation, are unknown. We studied the effect of LPS, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-4 and IL-10 on 5-lipooxygenase (5-LO), LTA4 hydrolase (LTAH) and LTC4 synthase (LTCS) mRNA and protein expression, LTB4 and LTC4 release from porcine endometrial endothelial cells, and cell viability. For 24 hr, cells were exposed to LPS (10 or 100 ng/ml of medium) and cytokines (each 1 or 10 ng/ml). 5 LO mRNA/protein expression augmented after incubation with larger doses of LPS, TNF-alpha, IL-4 and IL-10 and smaller dose of IL-1beta. Larger dose of TNF-alpha, smaller doses of LPS and IL-1beta and both doses of IL-10 increased LTAH mRNA/protein expression. LTAH protein content was up-regulated by larger dose of LPS, but it was reduced in response to both doses of IL-4. LTCS mRNA expression was elevated by larger doses of LPS, IL-4 and IL-10 or both doses of TNF-alpha and IL-1beta. LTCS protein level increased after treatment with both doses of IL 1beta, IL-4 and IL-10, smaller dose of LPS and larger dose of TNF-alpha. Both doses of LPS and larger doses of TNF-alpha and IL-10 increased LTB4 release. LPS, IL-1beta and IL-10 at smaller doses, or TNF-alpha and IL-4 at larger doses stimulated LTC4 release. Smaller doses of TNF-alpha and IL-1beta or both doses of IL-4 enhanced the cell viability. This work provides new insight on the participation of LPS, TNF-alpha, IL-1beta, IL-4 and IL-10 in LTB4 and LTC4 production/release from porcine endometrial endothelial cells, and the effect of above factors on these cells viability. The used cellular model gives the possibility to further establish the interactions between inflammatory mediators. PMID- 28891086 TI - Patients' perceptions and experiences of patient-centred care in dietetic consultations. AB - BACKGROUND: Patient-centred care (PCC) is essential to quality healthcare. However, there is a paucity of research on PCC in dietetics, particularly regarding patients' experiences and perspectives of PCC. We aimed to enhance our understanding of PCC in dietetics by exploring patients' perceptions and experiences of PCC in individual dietetic consultations. METHODS: The present study used qualitative methods, situated in a constructivist-interpretivist paradigm. Maximum variation purposive sampling was used to recruit English speaking adult participants who had participated in >=1 dietetic consultations for nutrition care. Individual semi-structured interviews explored participants' perceptions and experiences of PCC in dietetic consultations. Data were analysed thematically. RESULTS: Eleven patients were interviewed between September and November 2016. Four overarching themes emerged: (i) fostering and maintaining caring relationships; (ii) delivering individualised care; (iii) enabling patient involvement; and (iv) taking control of one's own health. CONCLUSIONS: PCC is important to patients. Thus, there is opportunity for dietitians to enhance the care they provide by adopting patient-centred practices. As the first study of its kind, these findings can inform future dietetic practice, education and research by contributing patients' perspectives of PCC. By understanding patients' unique needs and preferences, dietitians can better align their practice with a patient-centred approach. Furthermore, these findings are useful for informing future dietetic research and education. PMID- 28891087 TI - Elucidation of salvage laryngectomy pathologic and clinical variables to guide further treatment intensification investigation. AB - OBJECTIVE/HYPOTHESIS: There are limited treatment options beyond surgical salvage for patients who fail nonoperative treatment for laryngeal squamous cell carcinoma. In this study, we examine the failure patterns after surgical salvage and the potential pathologic and clinical prognostic variables that might guide further postoperative intensification investigation. STUDY DESIGN: Retrospective analysis at a tertiary academic referral center. METHODS: From an institutional review board-approved institutional head and neck cancer registry, a consecutive series of 147 patients who underwent salvage laryngectomy for squamous cell cancer recurrence or persistence after radiotherapy with or without chemotherapy between May 1995 and May 2016 were identified. Variables potentially associated with oncologic outcome after surgical salvage were then collected and retrospectively evaluated. RESULTS: The projected 2-year locoregional failure rate was 21.8% (95% confidence interval [CI], 14.6%-29.0%]), and the overall survival 65% (95% CI, 57.5%-74.3%) for the entire cohort after salvage laryngectomy. On multivariable analysis, sarcomatoid/spindle cell pathology (hazard ratio [HR], 3.147; 95% CI, 1.181-8.386; P = 0.022), lymphovascular space invasion (LVSI) (positive vs. negative; HR, 2.31; 95% CI, 1.21-4.42; P = 0.011), and advanced initial American Joint Committee on Cancer 7th Edition grouped stage (stages III-IVB vs. stages I-II; HR, 1.64; 95% CI, 1.04-2.6; P = 0.035) were found to be independently associated with inferior disease-free survival. No other clinical or pathologic variables predicted failure. CONCLUSION: Salvage laryngectomy after nonoperative treatment failure results in successful locoregional control rates and survival in the majority of patients failing initial therapy. This should temper enthusiasm for routine treatment intensification with postoperative re-irradiation and/or other systemic treatments for the vast majority of patients. Sarcomatoid pathology, LVSI, and an advanced initial stage are associated with inferior disease-free survival. The presence of these factors may warrant further investigational study of treatment intensification after salvage laryngectomy. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:823-830, 2018. PMID- 28891088 TI - Prevalence of Elevated Serum Creatinine Concentration in Dogs Presenting to a Veterinary Academic Medical Center (2010-2014). AB - BACKGROUND: The epidemiology of kidney disease is not extensively described in dogs. HYPOTHESIS/OBJECTIVES: To better understand the prevalence of elevated serum creatinine concentration in dogs. ANIMALS: Client-owned dogs. METHODS: A retrospective, observational cross-sectional study design was used. We made a dataset of 115,631 hospital visits of all dogs presenting from October 2010 to October 2014. We estimated the prevalence and risk of elevated serum creatinine, defined as >1.6 mg/dL, in evaluated dogs. RESULTS: Of 115,631 visits, 98,693 were outpatient visits and 16,938 were hospital admissions. Among outpatient visits, 9,983 (10.1%) had serum creatinine assessment (4,423 [44.3%] visits were first visits), whereas, among hospital admissions, 12,228 (60.0%) had at least 1 serum creatinine (7,731 [75.6%] admissions were first admissions). The prevalence of elevated serum creatinine concentration in all evaluated dogs was 11.5% (95% CI: 11.0%, 11.9%); 10.2% (95% CI: 9.6%, 10.8%) of inpatients and 12.9% (95% CI: 12.1%, 13.8%) of outpatients had elevated serum creatinine concentration. The relative risk (RR) of elevated serum creatinine concentration was significantly higher in geriatric dogs (outpatient RR 1.45 [95% CI: 1.23, 1.70], inpatient RR 1.43 [95% CI: 1.16, 1.76]) and lower in young dogs (outpatient RR 0.39 [95% CI: 0.26, 0.59], inpatient RR 0.44 [95% CI: 0.32, 0.62]) when compared to the measured population risk. CONCLUSIONS AND CLINICAL IMPORTANCE: When selected for laboratory evaluation, the proportion of dogs presenting to an academic medical center with evidence of kidney injury is high compared to previous reports and might reflect a population of sicker dogs. PMID- 28891089 TI - Molecular insights into the transcriptional regulatory role of thyroid hormones in ovarian cancer. AB - The regulation of cancer-relevant genes by the thyroid hormones, 3, 5, 3'-Triiodo L-thyronine (T3) and L-thyroxine (T4), was recently acknowledged. However, limited data exists on the hormonal effects on gene expression in ovarian cancer, a gynecological malignancy associated with a low cure rate. The expression of fifteen genes involved in DNA repair, cell cycle, apoptosis, and tumor suppression was evaluated in OVCAR-3 and A2780 cell lines, using real-time PCR following short incubation with T3 (1 nM) or T4 (100 nM). The thyroid hormones downregulated the expression of the majority of genes examined. Support for the involvement of the MAPK and PI3K in thyroid hormone-mediated gene expression was shown for a set of genes. FAS expression was inhibited in A2780 cells, while an unexpected induction was demonstrated in OVCAR-3 cells. An analogous effect on the protein levels of FAS receptor and its soluble form was demonstrated by Western blotting. We further established, using primer sets that discriminate between the different RNA isoforms, that the hormones increase the mRNA levels of both coding and non-coding FAS mRNAs. The prevalence of these isoforms, using The Cancer Genome Atlas (TCGA) analysis, was significantly more abundant in 17 cancer types, including ovarian cancer, compared to normal tissues. Our results highlight the role of thyroid hormones in the expression of cancer-relevant-genes in ovarian cancer and provide an important insight into the pathways by which mitogenic and anti-apoptotic effects are exerted. PMID- 28891090 TI - Molecular targets of vitexin and isovitexin in cancer therapy: a critical review. AB - Cancer is a primary public health problem and the second leading cause of death worldwide. It causes life-threatening malignancies and results in high financial costs for both patients and the healthcare system. Hence, it is important to develop effective long-term strategies pertaining to prevention and control of cancers. Plant-derived secondary metabolites have been shown to have positive roles against various cancers. A number of plant extracts have been evaluated for possible use in the treatment of cancer; some have provided direction for new strategies for the research and development of antitumor agents. Here, we provide comprehensive data on various cancers, potential molecular mechanisms, and therapeutic implications of just two plant-derived compounds, vitexin and isovitexin. Information on the chemotherapeutic potential of vitexin and isovitexin was collected from a library database and through electronic searches (ScienceDirect, Pubmed, and Google Scholar). Both in vitro and in vivo studies suggest that vitexin and isovitexin are chemopreventive compounds with activity against various cancers through proapoptotic processes and/or autophagy. PMID- 28891091 TI - Natural products to prevent drug resistance in cancer chemotherapy: a review. AB - Chemotherapy is the standard internal medical treatment for cancer. However, the resistance of cancer cells to nearly all kinds of chemotherapeutic drugs and targeted drugs has become prevalent, and approximately 80-90% of deaths in cancer patients are directly or indirectly attributed to drug resistance. The progress of new drug research and development has also been impeded by the occurrence of drug resistance, which has emerged as a considerable challenge in cancer therapy. Fortunately, natural products with diverse chemical structures and pharmacological effects serve as effective substances against drug resistance. Since the discovery of a series of drug-resistant proteins, drug-efflux inhibition has been applied as the primary strategy to overcome drug resistance by maintaining the intracellular concentrations of chemotherapeutic drugs. Nonapoptotic cell death is considered an alternative strategy because most cases of drug resistance result in evasion and insensitivity to apoptosis. In this concise review, we summarize two strategies using natural products against drug resistance. PMID- 28891092 TI - Plant non-starch polysaccharides that inhibit key enzymes linked to type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM), a metabolic disease becoming ever more common, is the result of disturbed glyco- and lipid metabolism. On the basis of their inhibitory effects against several key enzymes linked to T2DM, synthetic antidiabetic agents have been developed and used for diabetic therapy, some with adverse side effects. Fortunately, many plant non-starch polysaccharides (NSPs) have been shown to possess inhibitory effects on the same T2DM-related enzymes. Through a simple literature search we found that alpha-amylase, alpha glucosidase, lipase, and dipeptidyl-peptidase IV are the enzymes most often reported in the context of T2DM. In this short review we discuss published evidence for inhibition of these enzymes and the implications for treating T2DM. PMID- 28891093 TI - Tocotrienols for bone health: a translational approach. AB - Osteoporosis, a degenerative bone disease, is characterized by low bone mass and microstructural deterioration of bone tissue resulting in aggravated bone fragility and susceptibility to fractures. The trend of extended life expectancy is accompanied by a rise in the prevalence of osteoporosis and concomitant complications in the elderly population. Epidemiological evidence has shown an association between vitamin E consumption and the prevention of age-related bone loss in elderly women and men. Animal studies show that ingestion of vitamin E, especially tocotrienols, may benefit bone health in terms of maintaining higher bone mineral density and improving bone microstructure and quality. The beneficial effects of tocotrienols on bone health appear to be mediated via antioxidant/anti-inflammatory pathways and/or 3-hydroxy-3-methylglutaryl coenzyme A mechanisms. We discuss (1) an overview of the prevalence and etiology of osteoporosis, (2) types of vitamin E (tocopherols versus tocotrienols), (3) findings of tocotrienols and bone health from published in vitro and animal studies, (4) possible mechanisms involved in bone protection, and (5) challenges and future direction for research. PMID- 28891094 TI - Regulation of the tumor suppressor PTEN by natural anticancer compounds. AB - The tumor suppressor phosphatase and tensin homologue (PTEN) has phosphatase activity, with phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a product of phosphatidylinositol 3-kinase (PI3K), as one of the principal substrates. PTEN is a negative regulator of the Akt pathway, which plays a fundamental role in controlling cell growth, survival, and proliferation. Loss of PTEN function has been observed in many different types of cancer. Functional inactivation of PTEN as a consequence of germ-line mutations or promoter hypermethylation predisposes individuals to malignancies. PTEN undergoes posttranslational modifications, such as oxidation, acetylation, phosphorylation, SUMOylation, and ubiquitination, which influence its catalytic activity, interactions with other proteins, and subcellular localization. Cellular redox status is crucial for posttranslational modification of PTEN and its functional consequences. Oxidative stress and inflammation are major causes of loss of PTEN function. Pharmacologic or nutritional restoration of PTEN function is considered a reliable strategy in the management of PTEN-defective cancer. In this review, we highlight natural compounds, such as curcumin, indol-3 carbinol, and omega-3 fatty acids, that have the potential to restore or potentiate PTEN expression/activity, thereby suppressing cancer cell proliferation, survival, and resistance to chemotherapeutic agents. PMID- 28891095 TI - Biological and clinical implications of herbal medicine and natural products for the treatment of inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that includes Crohn's disease (CD) and ulcerative colitis (UC). Homeostasis of various regulatory factors involved with intestinal immunity is disrupted in IBD, including the intestinal epithelial barrier, macrophages, and cellular mediators such as cytokines and chemokines. No successful treatment is currently available for the management of IBD. Natural products and herbal medicines have exhibited efficacy for UC and CD in experimental models and clinical trials with the following activities: (1) maintenance of integrity of the intestinal epithelial barrier, (2) regulation of macrophage activation, (3) modulation of innate and adaptive immune response, and (4) inhibition of TNF-alpha activity. Here, we discuss the major factors involved in the pathogenesis of IBD and the current development of natural products and herbs for the treatment of IBD. PMID- 28891096 TI - N-Phosphine Oxide-Substituted Imidazolylidenes (PoxIms): Multifunctional Multipurpose Carbenes. AB - This article discusses the concept of N-heterocyclic carbenes (NHCs) equipped with more than one functional moiety, which allows using these NHCs for multiple purposes. A pioneering example for such NHCs is N-phosphine oxide-substituted imidazolylidenes (PoxIms), and their synthesis and strategic use are highlighted. The utility of PoxIms by far exceeds the conventional use as multidentate ligands for metal complexes on account of the synergetic functions of the carbene and the N-phosphine oxide group(s). PMID- 28891098 TI - Heterometallic Zn3 Ln3 Ensembles Containing (MU6 -CO3 ) Ligand and Triangular Disposition of Ln3+ ions: Analysis of Single-Molecule Toroic (SMT) and Single Molecule Magnet (SMM) Behavior. AB - Two new heterometallic Zn3 Ln3 (Ln3+ =Dy, Tb) complexes, with a double triangular topology of the metal ions, have been assembled from the polytopic Mannich base ligand 6,6'-{[2-(dimethylamino)ethylazanediyl]bis(methylene)}bis(2-methoxy-4 methylphenol) (H2 L) with the aid of an in situ generated carbonate ligand from atmospheric CO2 fixation. Theoretical calculations indicate axial ground states for the Ln3+ ions in these complexes, with their local magnetic moments being almost coplanar and tangential to the Ln3+ atoms that define the equilateral triangle. Therefore, they can be considered as single-molecule toroics (SMTs) with almost zero total magnetic moment. Micro-SQUID measurements on the Dy3+ counterpart show hysteresis loops below 3 K that have an S-shape, with large coercive fields opening upon cooling. This behavior is typical of a single molecule magnet (SMM) with very slow zero-field relaxation. At around +/-0.35 T, the loops have a broad step, which is due to a direct relaxation process and corresponds to an acceleration of the relaxation of the magnetization, also observed at this magnetic field from ac susceptibility measurements. Simulations suggest that the broad step corresponds to two level avoidance of crossing points where the spin chiral Kramers doublet meets excited states of the coupled manifold, whose position is defined by exchange and dipole interactions. The Tb3+ counterpart does not exhibit SMM behavior, which is due to the fact that the degeneracy of the ground state of the exchange coupled system is lifted at zero field, thus favoring quantum tunneling of magnetization (QTM). PMID- 28891097 TI - Ventral neural patterning in the absence of a Shh activity gradient from the floorplate. AB - BACKGROUND: Vertebrate spinal cord development requires Sonic Hedgehog (Shh) signaling from the floorplate and notochord, where it is thought to act in concentration dependent manner to pattern distinct cell identities along the ventral-to-dorsal axis. While in vitro experiments demonstrate naive neural tissues are sensitive to small changes in Shh levels, genetic studies illustrate that some degree of ventral patterning can occur despite significant perturbations in Shh signaling. Consequently, the mechanistic relationship between Shh morphogen levels and acquisition of distinct cell identities remains unclear. RESULTS: We addressed this using Hedgehog acetyltransferase (HhatCreface ) and Wiggable mouse mutants. Hhat encodes a palmitoylase required for the secretion of Hedgehog proteins and formation of the Shh gradient. In its absence, the spinal cord develops without floorplate cells and V3 interneurons. Wiggable is an allele of the Shh receptor Patched1 (Ptch1Wig ) that is unable to inhibit Shh signal transduction, resulting in expanded ventral progenitor domains. Surprisingly, HhatCreface/Creface ; Ptch1Wig/Wig double mutants displayed fully restored ventral patterning despite an absence of Shh secretion from the floorplate. CONCLUSIONS: The full range of neuronal progenitor types can be generated in the absence of a Shh gradient provided pathway repression is dampened, illustrating the complexity of morphogen dynamics in vertebrate patterning. Developmental Dynamics 247:170-184, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28891099 TI - Opioid and Benzodiazepine Weaning in Pediatric Patients: Review of Current Literature. AB - Pediatric opioid and benzodiazepine withdrawal are avoidable complications of pain and sedation management that is well described in the literature. To prevent withdrawal from occurring, practitioners regularly use a steady decrease of pain and sedation medications, also known as a weaning or tapering schedule. The weaning schedule is highly variable based on clinician preference and is usually dependent on the clinician. The purposes of this review are to evaluate the current literature on the process of opioid and benzodiazepine weaning in pediatric patients and to assess the various standardized protocols used to decrease withdrawal occurrences. We conducted a search of the PubMed, MEDLINE, Cochrane Library, Cumulative Index of Nursing and Allied Health (CINAHL), Academic Search Premier, and PsycInfo databases. Studies were included if they described a wean or taper in pediatric patients aged 18 years or younger. Studies describing neonatal abstinence syndrome were excluded from the review. A total of 97 studies published between 2000 and 2014 were retrieved; of those, 15 studies met the inclusion criteria. Studies were evaluated for selection of withdrawal assessment tool, wean protocol summary, preferred weaning agents, benzodiazepine withdrawal, and wean-at-home regimen. The most common opioid-weaning protocol approaches described a 10-20% dose decrease per day. Benzodiazepine weaning was not regularly standardized or described. The use of a standardized opioid-weaning protocol reduced withdrawal rates compared with nonstandardized weaning plans. Benzodiazepine weaning was inconsistently evaluated and may have affected study outcomes. Identified areas of improvement include the use of newer withdrawal assessment tools validated in the older pediatric population and standardized withdrawal assessment and reporting. PMID- 28891100 TI - Roq1 mediates recognition of the Xanthomonas and Pseudomonas effector proteins XopQ and HopQ1. AB - Xanthomonas spp. are phytopathogenic bacteria that can cause disease on a wide variety of plant species resulting in significant impacts on crop yields. Limited genetic resistance is available in most crop species and current control methods are often inadequate, particularly when environmental conditions favor disease. The plant Nicotiana benthamiana has been shown to be resistant to Xanthomonas and Pseudomonas due to an immune response triggered by the bacterial effector proteins XopQ and HopQ1, respectively. We used a reverse genetic screen to identify Recognition of XopQ 1 (Roq1), a nucleotide-binding leucine-rich repeat (NLR) protein with a Toll-like interleukin-1 receptor (TIR) domain, which mediates XopQ recognition in N. benthamiana. Roq1 orthologs appear to be present only in the Nicotiana genus. Expression of Roq1 was found to be sufficient for XopQ recognition in both the closely-related Nicotiana sylvestris and the distantly-related beet plant (Beta vulgaris). Roq1 was found to co immunoprecipitate with XopQ, suggesting a physical association between the two proteins. Roq1 is able to recognize XopQ alleles from various Xanthomonas species, as well as HopQ1 from Pseudomonas, demonstrating widespread potential application in protecting crop plants from these pathogens. PMID- 28891101 TI - The interstitial lung disease multidisciplinary meeting: A position statement from the Thoracic Society of Australia and New Zealand and the Lung Foundation Australia. AB - Interstitial lung diseases (ILD) are a diverse group of pulmonary diseases for which accurate diagnosis is critical for optimal treatment outcomes. Diagnosis of ILD can be challenging and a multidisciplinary approach is recommended in international guidelines. The purpose of this position paper is to review the evidence for the use of the multidisciplinary meeting (MDM) in ILD and suggest an approach to its governance and constitution, in an attempt to provide a standard methodology that could be applied across Australia and New Zealand. This position paper is endorsed by the Thoracic Society of Australia and New Zealand (TSANZ) and the Lung Foundation Australia (LFA). PMID- 28891102 TI - CO Oxidation by Group 3 Metal Monoxide Cations Supported on [Fe(CO)4 ]2. AB - Infrared photodissociation spectroscopy of mass-selected heteronuclear cluster anions in the form of OMFe(CO)5- (M=Sc, Y, La) indicates that all these anions involve an 18-electron [Fe(CO)4 ]2- building block that is bonded with the M center through two bridged carbonyl ligands. The OLaFe(CO)5- anion is determined to be a CO-tagged complex involving a [Fe(CO)4 ]2- [LaO]+ anion core. In contrast, the OYFe(CO)5- anion is characterized to have a [Fe(CO)4 ]2- [Y(eta2 CO2 )]+ structure involving a side-on bonded CO2 ligand. The CO-tagged complex and the [Fe(CO)4 ]2- [Sc(eta2 -CO2 )]+ isomer co-exist for the OScFe(CO)5- anion. These observations indicate that both the ScO+ and YO+ cations supported on [Fe(CO)4 ]2- are able to oxidize CO to CO2 . Theoretical analyses show that [Fe(CO)4 ]2- coordination significantly weakens the MO+ bond and decreases the energy gap of the interacting valence orbitals between MO+ and CO, leading to the CO oxidation reactions being both thermodynamically exothermic and kinetically facile. PMID- 28891103 TI - Does assimilation of problematic experiences predict a decrease in symptom intensity? AB - : The assimilation model describes therapeutic change as an integration of experiences that had previously been problematic, distressing, avoided, or warded off. This study assessed whether assimilation was associated with treatment outcome in a sample of psychotherapeutic treatments for depression. Further, it assessed the direction of the association-whether increasing assimilation predicted decreases in symptom intensity or decreasing symptom intensity predicted increases in assimilation. METHOD: Participants were 22 clients with mild to moderate depression drawn from a clinical trial comparing cognitive behavioral therapy with emotion-focused therapy. The direction of prediction between assimilation progress and changes in self-reported symptom intensity was assessed. RESULTS: The assimilation progress was shown to be a better predictor of decreases in symptom intensity than the reverse. CONCLUSION: The results supported the assimilation model's suggestion that assimilation progress promotes decreases in symptom intensity in the treatment of clients with major depressive disorder. PMID- 28891104 TI - Patient information websites: how do we assess their usefulness? PMID- 28891105 TI - Regioselective Transformation of Long pi-Conjugated Backbones: From Oligofurans to Oligoarenes. AB - We demonstrate the transformation of oligofurans through sequential Diels-Alder cycloaddition reactions to provide oligoarenes in two chemical steps, regardless of the oligomer length. By this method, oligonaphthalenes containing up to six units were obtained in high yield through the formation of up to 12 new C-C bonds. The versatility of this method was demonstrated for various polyaromatic hydrocarbons. The regioselectivity of this process enabled the synthesis of a library of substituted triarylenes from a single terfuran precursor by modification of the dienophile strength and the order of addition. Overall, this study demonstrates that long oligofurans are interesting not only as organic electronic materials, but also as starting materials for the formation of various conjugated systems. PMID- 28891106 TI - Treatment resistance in potentially malignant disorders-'Nature' or 'Nurture'...? AB - BACKGROUND: Contemporary potentially malignant disorder management is based upon provisional histological diagnosis followed by interventional surgery to excise or ablate 'high-risk' mucosal lesions. Although the majority of patients achieve disease-free status post-treatment, others develop further or persistent disease unresponsive to intervention. METHODS: A detailed, retrospective clinico pathological review of treatment resistant potentially malignant lesions, from a 590 patient cohort treated by CO2 laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was determined at study census date (31 December 2014). RESULTS: A total of 87 patients (15%) exhibited PMD disease resistant to treatment: 34 (6%) became disease free following further treatment, whilst 53 (9%) had persistent disease despite intervention. Disease-free patients were younger, changed lesion appearance from erythroleukoplakia to leukoplakia (P = .004), developed further lesions at new sites, demonstrated reduction in dysplasia severity with time and required multiple treatments to achieve disease free status (P = .0005). In contrast, persistent disease patients were older, male, often presented with proliferative verrucous leukoplakia (PVL) on gingival and alveolar sites, displayed less severe dysplasia initially and underwent laser ablation rather than excision (P = .027). CONCLUSION: Despite clinico pathological profiling of treatment resistant patients, the precise inter relationship between the inherent nature of potentially malignant disease and the external influence of treatment intervention remains obscure. PMID- 28891107 TI - Corrigendum. PMID- 28891108 TI - Tailoring Semiconductor Lateral Multijunctions for Giant Photoconductivity Enhancement. AB - Semiconductor heterostructures have played a critical role as the enabler for new science and technology. The emergence of transition-metal dichalcogenides (TMDs) as atomically thin semiconductors has opened new frontiers in semiconductor heterostructures either by stacking different TMDs to form vertical heterojunctions or by stitching them laterally to form lateral heterojunctions via direct growth. In conventional semiconductor heterostructures, the design of multijunctions is critical to achieve carrier confinement. Analogously, successful synthesis of a monolayer WS2 /WS2(1-x) Se2x /WS2 multijunction lateral heterostructure via direct growth by chemical vapor deposition is reported. The grown structures are characterized by Raman, photoluminescence, and annular dark field scanning transmission electron microscopy to determine their lateral compositional profile. More importantly, using microwave impedance microscopy, it is demonstrated that the local photoconductivity in the alloy region can be tailored and enhanced by two orders of magnitude over pure WS2 . Finite element analysis confirms that this effect is due to the carrier diffusion and confinement into the alloy region. This work exemplifies the technological potential of atomically thin lateral heterostructures in optoelectronic applications. PMID- 28891109 TI - Strengthening community mental health competence-A realist informed case study from Dehradun, North India. AB - Few accounts exist of programmes in low- and middle-income countries seeking to strengthen community knowledge and skills in mental health. This case study uses a realist lens to explore how a mental health project in a context with few mental health services, strengthened community mental health competence by increasing community knowledge, creating safer social spaces and engaging partnerships for action. We used predominantly qualitative methods to explore relationships between context, interventions, mechanisms and outcomes in the "natural setting" of a community-based mental health project in Dehradun district, Uttarakhand, North India. Qualitative data came from focus group discussions, participant observation and document reviews of community teams' monthly reports on changes in behaviour, attitudes and relationships among stakeholder groups. Data analysis initially involved thematic analysis of three domains: knowledge, safe social spaces and partnerships for action. By exploring patterns within the identified themes for each domain, we were able to infer the mechanisms and contextual elements contributing to observed outcomes. Community knowledge was effectively increased by allowing communities to absorb new understanding into pre-existing social and cultural constructs. Non-hierarchical informal community conversations allowed "organic" integration of unfamiliar biomedical knowledge into local explanatory frameworks. People with psycho-social disability and caregivers found increased social support and inclusion by participating in groups. Building skills in respectful communication through role plays and reflexive discussion increased the receptivity of social environments to people with psycho-social disabilities participation, thereby creating safe social spaces. Facilitating social networks through groups increases women's capacity for collective action to promote mental health. In summary, locally appropriate methods contribute most to learning, stigma reduction and help seeking. The complex social change progress was patchy and often slow. This study demonstrates a participatory, iterative, reflexive project design which is generating evidence indicating substantial improvements in community mental health competence. PMID- 28891110 TI - Protein Digestion of Baby Foods: Study Approaches and Implications for Infant Health. AB - Protein digestion is critical for infants. Dissimilarities between infants and adults in food intake and digestive physiology lead to distinct patterns of proteolysis between individuals. However, such differences are not well represented in many studies on protein digestion of baby foods. The complex biological structures of baby foods and the physiology of the infant digestive system are key factors affecting proteolysis during the first two years of life. Well-controlled in vitro studies have demonstrated that varying digestion conditions alter the specificity, rate, and extent of proteolysis of baby foods. Nonetheless, these models do not completely replicate in vivo proteolysis or the complex biogeography of the gastrointestinal tract. Animal and clinical studies have revealed the fate of dietary proteins along the digestive tract and the overall health impact on subjects. Building comprehensive and annotated datasets from human infants will require innovative and standardized measurement. Now, more systematic evaluations of digestion are emerging to advance the knowledge and its translation as food design for effective diet and health management in infants. PMID- 28891111 TI - Construction of polylysine dendrimer nanocomposites carrying nattokinase and their application in thrombolysis. AB - Thrombotic disease has become one of the leading causes of mortality among humans globally. Nattokinase (NK), a novel thrombolytic agent, has attracted the attention of researchers. However, NK is a serine protease that is vulnerable to environmental effects resulting in its inactivation. In this study, polylysine dendrimer (PLLD) was synthesized through divergence-convergence method, and a series of NK/PLLD nanocomposites with different molar ratio was prepared. In addition, NK was successfully incorporated into the cores of PLLD G4 through hydrogen bonds and van der Waals forces. In NK/PLLD nanocomposites, when the molar ratio of NK to PLLD is 1:30, a high relative enzyme activity level (up to 117%) was achieved and was more stable at different temperatures and pH than free NK. In in vitro thrombolysis experiment, compared with free NK, NK/PLLD nanocomposites could control the release of NK. The thrombolysis rate of NK/PLLD nanocomposites reached 50% at 12 h, which can effectively avoid other complications such as hemorrhage. Interestingly, NK/PLLD nanocomposites with positive charge can penetrate into the negatively charged thrombus through electrostatic interaction, thus providing a good thrombolytic effect. Hemolysis and MTT experiments show that PLLD nanomaterials can serve as ideal carriers of protein drugs. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 440-449, 2018. PMID- 28891112 TI - Candida albicans isolates from a single hospital show low phenotypical specialization. AB - Candida albicans is the best-studied opportunistic human pathogenic yeast species, and its virulence factors, susceptibility to antimycotics, the diversity of its physiological properties and the determinative factors of these traits are interesting from a clinical as well as from an evolutionary perspective. By applying statistical modeling for the phenotypical differences observed among a collection of 63 C. albicans isolates originating from different clinical care units, from a diverse group of patients with or without mycosis, collected in a Hungarian clinic, we found that (i) host-related aspects like anatomical source, care unit of isolation, patients' age, sex, and disease severity, or ABC genotypes of the isolates had less effect on the phenotypic features of this opportunistic pathogen than host-independent aspects, for example, year or month of isolation; (ii) different phenotypic traits did not show any significant correlations with each other; and (iii) different genotypes displayed no anatomical specialization and rarely showed any significant correlation with parameters of isolation either. These results shed light on the dynamic nature and low specialization of the C. albicans populations observable in a narrow geographic range, namely in the patients hospitalized in the different care units of the clinic. PMID- 28891113 TI - The impact of repeated mismatches in kidney transplantations performed after nonrenal solid organ transplantation. AB - The aim of this study was to determine whether kidney transplantations performed after previous nonrenal solid organ transplants are associated with worse graft survival when there are repeated HLA mismatches (RMM) with the previous donor(s). We performed a retrospective cohort study using data from the Scientific Registry of Transplant Recipients. Our cohort comprised 6624 kidney transplantations performed between January 1, 1990 and January 1, 2015. All patients had previously received 1 or more nonrenal solid organ transplants. RMM were observed in 35.3% of kidney transplantations and 3012 grafts were lost over a median follow-up of 5.4 years. In multivariate Cox regression analyses, we found no association between overall graft survival and either RMM in class 1 (hazard ratio [HR]: 0.97, 95% confidence interval [CI] 0.89-1.07) or class 2 (HR: 0.95, 95% CI 0.85-1.06). Results were similar for the associations between RMM, death censored graft survival, and patient survival. Our results suggest that the presence of RMM with previous donor(s) does not have an important impact on allograft survival in kidney transplant recipients who have previously received a nonrenal solid organ transplant. PMID- 28891114 TI - Blood-Brain Barrier Permeability of Green Tea Catechin Metabolites and their Neuritogenic Activity in Human Neuroblastoma SH-SY5Y Cells. AB - SCOPE: To understand the mechanism by which green tea lowers the risk of dementia, focus was placed on the metabolites of epigallocatechin gallate (EGCG), the most abundant catechin in green tea. Much of orally ingested EGCG is hydrolyzed to epigallocatechin (EGC) and gallic acid. In rats, EGC is then metabolized mainly to 5-(3',5'-dihydroxyphenyl)-gamma-valerolactone (EGC-M5) and its conjugated forms, which are distributed to various tissues. Therefore, we examined the permeability of these metabolites into the blood-brain barrier (BBB) and nerve cell proliferation/differentiation in vitro. METHODS AND RESULTS: The permeability of EGC-M5, glucuronide, and the sulfate of EGC-M5, pyrogallol, as well as its glucuronide into the BBB were examined using a BBB model kit. Each brain- and blood-side sample was subjected to liquid chromatography tandem-mass spectrometry analysis. BBB permeability (%, in 0.5 h) was 1.9-3.7%. In human neuroblastoma SH-SY5Y cells, neurite length was significantly prolonged by EGC M5, and the number of neurites was increased significantly by all metabolites examined. CONCLUSION: The permeability of EGC-M5 and its conjugated forms into the BBB suggests that they reached the brain parenchyma. In addition, the ability of EGC-M5 to affect nerve cell proliferation and neuritogenesis suggests that EGC M5 may promote neurogenesis in the brain. PMID- 28891115 TI - Deficiency of CCAAT/enhancer-binding protein homologous protein (CHOP) prevents diet-induced aortic valve calcification in vivo. AB - Aortic valve (AoV) calcification is common in aged populations. Its subsequent aortic stenosis has been linked with increased morbidity, but still has no effective pharmacological intervention. Our previous data show endoplasmic reticulum (ER) stress is involved in AoV calcification. Here, we investigated whether deficiency of ER stress downstream effector CCAAT/enhancer-binding protein homology protein (CHOP) may prevent development of AoV calcification. AoV calcification was evaluated in Apoe-/- mice (n = 10) or in mice with dual deficiencies of ApoE and CHOP (Apoe-/- CHOP-/- , n = 10) fed with Western diet for 24 weeks. Histological and echocardiographic analysis showed that genetic ablation of CHOP attenuated AoV calcification, pro-calcification signaling activation, and apoptosis in the leaflets of Apoe-/- mice. In cultured human aortic valvular interstitial cells (VIC), we found oxidized low-density lipoprotein (oxLDL) promoted apoptosis and osteoblastic differentiation of VIC via CHOP activation. Using conditioned media (CM) from oxLDL-treated VIC, we further identified that oxLDL triggered osteoblastic differentiation of VIC via paracrine pathway, while depletion of apoptotic bodies (ABs) in CM suppressed the effect. CM from oxLDL-exposed CHOP-silenced cells prevented osteoblastic differentiation of VIC, while depletion of ABs did not further enhance this protective effect. Overall, our study indicates that CHOP deficiency protects against Western diet-induced AoV calcification in Apoe-/- mice. CHOP deficiency prevents oxLDL-induced VIC osteoblastic differentiation via preventing VIC derived ABs releasing. PMID- 28891117 TI - The sleeping patterns of Head Start children and the influence on developmental outcomes. AB - BACKGROUND: Sleep has a significant influence on children's development. The objective of this study was to investigate Head Start children's sleeping patterns and the impact on cognitive and behavioural outcomes. METHODS: Using the 2009 cohort of the Head Start Family and Child Experiences Survey (N = 2,868), information on sleeping patterns was assessed through parent interviews. Cognitive outcomes were assessed using direct assessments (Peabody Picture Vocabulary Test-IV, the Expressive One-Word Picture Vocabulary Test, and Subtests of the Woodcock-Johnson III) in addition to teacher report. Behavioural outcomes were assessed through parent and teacher reports. A multiple regression analysis was performed for each outcome variable. RESULTS: Descriptive findings showed that 89% of children had a regular bedtime at least 4 days per week and that the average amount of sleep per night was 10.41 hr. White mothers were more likely than other racial groups to adhere to a consistent bedtime, and maternal employment predicted less hour of sleep per night. Multiple regression analyses revealed that disrupted sleep had a negative influence on cognitive outcomes, especially in areas of mathematical problem solving, receptive language, teacher reported literacy behaviours, and approaches to learning. Disrupted sleep was associated with the risk of misbehaviour by increasing teacher and parent ratings on aggressive behaviours, hyperactivity, and withdrawing in addition to decreased scores on overall social skills. Having an inconsistent bedtime negatively predicted expressive vocabulary and teacher-reported literacy behaviours. CONCLUSIONS: The findings of this study support the influential role of sleep on children's development. Sleeping through the night and having a consistent bedtime were found to be predictive of many areas of cognitive and behavioural development. Head Start staff can provide the supports to increase parental knowledge on appropriate child sleep practices. PMID- 28891116 TI - Measuring treatment outcomes in gambling disorders: a systematic review. AB - BACKGROUND AND AIMS: Considerable variation of outcome variables used to measure recovery in the gambling treatment literature has precluded effective cross-study evaluations and hindered the development of best-practice treatment methodologies. The aim of this systematic review was to describe current diffuse concepts of recovery in the gambling field by mapping the range of outcomes and measurement strategies used to evaluate treatments, and to identify more commonly accepted indices of recovery. METHODS: A systematic search of six academic databases for studies evaluating treatments (psychological and pharmacological) for gambling disorders with a minimum 6-month follow-up. Data from eligible studies were tabulated and analysis conducted using a narrative approach. Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) were adhered to. RESULTS: Thirty-four studies were reviewed systematically (RCTs = 17, comparative designs = 17). Sixty-three different outcome measures were identified: 25 (39.7%) assessed gambling-specific constructs, 36 (57.1%) assessed non-gambling specific constructs, and two instruments were used across both categories (3.2%). Self-report instruments ranged from psychometrically validated to ad-hoc author-designed questionnaires. Units of measurement were inconsistent, particularly in the assessment of gambling behaviour. All studies assessed indices of gambling behaviour and/or symptoms of gambling disorder. Almost all studies (n = 30; 88.2%) included secondary measures relating to psychiatric comorbidities, psychological processes linked to treatment approach, or global functioning and wellbeing. CONCLUSIONS: In research on gambling disorders, the incorporation of broader outcome domains that extend beyond disorder-specific symptoms and behaviours suggests a multi dimensional conceptualization of recovery. Development of a single comprehensive scale to measure all aspects of gambling recovery could help to facilitate uniform reporting practices across the field. PMID- 28891118 TI - The effect of regular or reduced-fat distillers grains with solubles on rumen methanogenesis and the rumen bacterial community. AB - AIMS: The effect of feeding dried distillers grains with solubles (DDGS) or reduced-fat DDGS (RFDG) on ruminal methanogenesis and the rumen bacterial community of dairy cattle was evaluated. METHODS AND RESULTS: Treatments were CONT, a diet with no distillers grains; DG, inclusion of 20% DDGS; rfDG, inclusion of 20% RFDG; and MIX, inclusion of 10% DDGS and 10% RFDG. Methane emission was measured; rumen bacterial community was evaluated by sequencing the V4 region of the 16S rRNA gene. Total methane production remained unaffected. However, feeding distillers grains tended to reduce methanogenesis per unit of feed intake, decreased the abundance of the phylum Bacteroidetes and tended to increase Firmicutes. The abundance of Prevotellaceae positively correlated with feed intake; methane emission was positively correlated with the abundance of Prevotellaceae and was negatively correlated with the abundance of Succinivibrionaceae. CONCLUSIONS: DDGS or RFDG may reduce methanogenesis per unit of feed intake; shifts in the abundance of predominant ruminal bacterial families may influence methane formation, likely because of their role on hydrogen liberation and utilization pathways. SIGNIFICANCE AND IMPACT OF THE STUDY: Replacing corn and soybean meal with DDGS or RFDG in dairy rations may reduce the proportion of dietary energy wasted as methane, without detrimental effects on the overall bacterial population. PMID- 28891119 TI - Age-Varying Associations Between Cigarette Smoking, Sensation Seeking, and Impulse Control Through Adolescence and Young Adulthood. AB - Sensation seeking (SS) and impulse control (IC) are constructs at the core of dual systems models of adolescent risk taking. Using data from the National Longitudinal Study of Adolescent to Adult Health, age-varying associations between SS and IC (predictors) and both any smoking in the previous 30 days and daily smoking (outcomes) were examined. The association between SS and both any smoking in the previous 30 days and daily smoking was strongest during adolescence. IC was consistently associated with any smoking in the previous 30 days and daily smoking, with the strongest association emerging during the mid 20s to early 30s. The results provide a nuanced perspective on when the components of dual systems models may be most related to smoking. PMID- 28891120 TI - Hepatitis E in transfusion-dependent thalassaemia patients, in Greece: a single centre experience. AB - Hepatitis E is considered an emerging disease that may be a threat in both developing and industrialized countries all over the world. The risk of chronic hepatitis E virus infection is higher among immunocompromised patients. This study aimed to assess the status of hepatitis E infection in patients with transfusion-dependent thalassaemia from a single centre, in Greece. Our results suggest that the prevalence of hepatitis E infection in this group of patients is low. PMID- 28891121 TI - Mental health courts and forensic assertive community treatment teams as correctional diversion programs. AB - Problem-solving courts (PSCs) developed as a means of mandating treatment and judicial supervision of certain types of court participants. PSCs have rapidly expanded in number and type over several decades. Mental health courts (MHCs) are a type of PSC that arose in response to the growing number of persons with mental illness within the criminal justice system. Their primary role is to divert individuals with mental illness from incarceration into psychiatric treatment and to reduce recidivism while improving psychosocial functioning of participants. Although different in history, philosophy, and program structure, forensic assertive community treatment (FACT) programs serve a similar goal of reducing recidivism and improving functioning in persons with mental illness who are involved with the criminal justice system. FACTs may be used as a standalone diversion option or be linked with a MHC as a form of intensive treatment and monitoring. Suggestions for future research and evaluation of these programs are offered. PMID- 28891123 TI - Editorial: Lupus, the Chameleon: Many Disguises Difficult to Capture. PMID- 28891122 TI - Nerve-specific, xenogeneic extracellular matrix hydrogel promotes recovery following peripheral nerve injury. AB - Peripheral nerve possesses the inherent ability to regrow and recover following injury. However, nerve regeneration is often slow and incomplete due to limitations associated with the local microenvironment during the repair process. Manipulation of the local microenvironment at the site of nerve repair, therefore, represents a significant opportunity for improvement in downstream outcomes. Macrophages and Schwann cells play a key role in the orchestration of early events after peripheral nerve injury. We describe the production, characterization, and use of an injectable, peripheral nerve-specific extracellular matrix-based hydrogel (PNSECM) for promoting modulation of the local macrophage and Schwann cell responses at the site of nerve repair in a rodent model of sciatic nerve injury. We show that PNSECM hydrogels largely maintain the matrix structure associated with normal native peripheral nerve tissue. PNSECM hydrogels were also found to promote increased macrophage invasion, higher percentages of M2 macrophages and enhanced Schwann cell migration when used as a lumen filler in a rodent model of nerve gap repair using an inert nerve guidance conduit. These results suggest that an injectable PNSECM hydrogel can provide a supportive, bioactive scaffold which promotes repair of peripheral nerve in vivo. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 450-459, 2018. PMID- 28891125 TI - Effect of cryoprotectants and thawing temperatures on chicken sperm quality. AB - There is need for standardization of freezing-thawing protocol for rooster semen to minimize variability among results. Therefore, we aimed to compare effect of four different permeating cryoprotectants and two thawing temperatures (37 vs. 5 degrees C) on sperm post-thaw motility and to analyse combined effect of the best permeating cryoprotectant (P-CPA) with one of four non-permeating cryoprotectants (N-CPA) on post-thaw quality of rooster semen evaluated in vitro. Pooled semen from Ross PM3 rooster heavy line was diluted in Kobidil extender and frozen in cryoprotectant solution containing 6% dimethylacetamide, 7.5% dimethylformamide, 9% N-methylacetamide or 8% ethylene glycol (EG) in liquid nitrogen vapours. To determine the best thawing rate, straws were thawed either at 37 or 5 degrees C. Furthermore, samples were frozen in the presence of the best N-CPA either with 0.75 mol/L ficoll, 0.2 mol/L sucrose, 0.2 mol/L trehalose or 0.05 mol/L glycine. Sperm motility, membrane destabilization and viability were analysed to compare different freezing-thawing conditions. In addition, morphology and ultrastructure analysis were performed to compare fresh and frozen-thawed sperm quality. Our results indicate that the combination of EG and the thawing at 5 degrees C improves (p <= .05) sperm post-thaw motility. Moreover, ficoll addition to EG based freezing extender provided additional beneficial effect (p <= .05) on progressive movement and apoptosis incidence. Further work should evaluate different N-CPA concentrations to improve freezing protocol. In addition, fertility evaluation and testing on different chicken lines are needed in order to contribute to animal genetic resources bank. PMID- 28891126 TI - 'Drugs don't work in patients who don't take them' (C. Everett Koop, MD, US Surgeon General, 1985). PMID- 28891124 TI - Dockground: A comprehensive data resource for modeling of protein complexes. AB - Characterization of life processes at the molecular level requires structural details of protein interactions. The number of experimentally determined structures of protein-protein complexes accounts only for a fraction of known protein interactions. This gap in structural description of the interactome has to be bridged by modeling. An essential part of the development of structural modeling/docking techniques for protein interactions is databases of protein protein complexes. They are necessary for studying protein interfaces, providing a knowledge base for docking algorithms, and developing intermolecular potentials, search procedures, and scoring functions. Development of protein protein docking techniques requires thorough benchmarking of different parts of the docking protocols on carefully curated sets of protein-protein complexes. We present a comprehensive description of the Dockground resource (http://dockground.compbio.ku.edu) for structural modeling of protein interactions, including previously unpublished unbound docking benchmark set 4, and the X-ray docking decoy set 2. The resource offers a variety of interconnected datasets of protein-protein complexes and other data for the development and testing of different aspects of protein docking methodologies. Based on protein-protein complexes extracted from the PDB biounit files, Dockground offers sets of X-ray unbound, simulated unbound, model, and docking decoy structures. All datasets are freely available for download, as a whole or selecting specific structures, through a user-friendly interface on one integrated website. PMID- 28891127 TI - Helicobacter pylori, gastric cancer and other gastrointestinal malignancies. AB - In a retrospective study performed in California, U.S.A., ca. 3% of patients with gastric intestinal metaplasia (GIM) developed gastric cancer (GC) within a median time period of 4.6 years after diagnosis of GIM. This observation stresses the importance of targeted surveillance even in regions with a low GC prevalence. Patients with alcoholic liver disease as well as survivors of colorectal and lobular breast cancer were found to be at increased risk of secondary GC. A population-based Chinese study confirmed "serologic biopsy" as a useful screening tool for stratifying the individual risk of developing GC. Concerning GC therapy, a post hoc analysis of the MAGIC trial reported that regression of lymph node metastases, but not the tumor regression itself, predicts overall survival. Furthermore, in patients with high microsatellite instable tumors, perioperative chemotherapy leads to an increased risk of mortality. Two studies confirmed that eradication therapy is worthwhile as an initial treatment for gastric mucosa associated lymphoid tissue (MALT) lymphoma irrespective of the H. pylori infection status and stage. An increased risk of a second primary malignancy including GC was observed in these patients treated with immuno/chemotherapy but not in patients treated solely with an H. pylori eradication treatment. With respect to gastrointestinal malignancies other than GC, discrepant data have been published regarding the association of H. pylori with pancreatic cancer whereas no association has been reported with esophageal squamous cell carcinoma. The majority of published studies still support an association of H. pylori with colon neoplasms. PMID- 28891128 TI - Helicobacter: Inflammation, immunology and vaccines. AB - Helicobacter pylori is usually acquired in early childhood and the infection persists lifelong without causing symptoms. In a small of cases, the infection leads to gastric or duodenal ulcer disease, or gastric cancer. Why disease occurs in these individuals remains unclear, however the host response is known to play a very important part. Understanding the mechanisms involved in maintaining control over the immune and inflammatory response is therefore extremely important. Vaccines against H. pylori have remained elusive but are desperately needed for the prevention of gastric carcinogenesis. This review focuses on research findings which may prove useful in the development of prognostic tests for gastric cancer development, therapeutic agents to control immunopathology, and effective vaccines. PMID- 28891129 TI - Gastric cancer: Basic aspects. AB - Gastric cancer is one of the most incident and deadliest malignancies in the world. Gastric cancer is a heterogeneous disease and the end point of a long and multistep process, which results from the stepwise accumulation of numerous (epi)genetic alterations, leading to dysregulation of oncogenic and tumor suppressor pathways. Gastric cancer stem cells have emerged as fundamental players in cancer development and as contributors to gastric cancer heterogeneity. For this special issue, we will report last year's update on the gastric cancer molecular classification, and in particular address the gastric cancer groups who could benefit from immune checkpoint therapy. We will also review the latest advances on gastric cancer stem cells, their properties as gastric cancer markers and therapeutic targets, and associated signaling pathways. The understanding of the molecular basis underlying gastric cancer heterogeneity and of the role played by gastric cancer stem cells in cancer development and heterogeneity is of major significance, not only for identifying novel targets for cancer prevention and treatment, but also for clinical management and patient stratification for targeted therapies. PMID- 28891130 TI - Pathogenesis of Helicobacter pylori infection. AB - Helicobacter pylori is responsible for the most commonly found infection in the world's population. It is the major risk factor for gastric cancer development. Numerous studies published over the last year provide new insights into the strategies employed by H. pylori to adapt to the extreme acidic conditions of the gastric environment, to establish persistent infection and to deregulate host functions, leading to gastric pathogenesis and cancer. In this review, we report recent data on the mechanisms involved in chemotaxis, on the essential role of nickel in acid resistance and gastric colonization, on the importance of adhesins and Hop proteins and on the role of CagPAI-components and CagA. Among the host functions, a special focus has been made on the escape from immune response, the ability of bacteria to induce genetic instability and modulate telomeres, the mechanism of autophagy and the deregulation of micro RNAs. PMID- 28891131 TI - XXXth International Workshop on Helicobacter & Microbiota in Inflammation & Cancer, 7-9 September 2017, Bordeaux, France. PMID- 28891132 TI - Genomics of Helicobacter pylori. AB - As Helicobacter pylori infects half the world's population and displays an extensive intraspecies diversity, genomics is a powerful tool to understand evolution and disease, to identify factors that confer higher risk of severe sequelae, and to find new approaches for therapy both among bacterial and host targets. In line with these objectives, this review article summarizes the major findings in Helicobacter genomics in papers published between April 2016 and March 2017. PMID- 28891133 TI - Helicobacter pylori infection and extragastric diseases in 2017. AB - The huge variety of extragastric diseases linked to Helicobacter pylori infection is widely known, and new studies are conducted every year on this topic. Neurological disorders and metabolic syndrome are some of the main issues debated in the most recent literature. Articles on the association of H. pylori with skin diseases, inflammatory bowel diseases, immunologic impairment, kidney dysfunction, allergic asthma, and respiratory diseases have been published as well. In this perspective, eradication therapy for this infection could become a mandatory measure in prevention strategy. PMID- 28891134 TI - 30th anniversary of the European helicobacter & microbiota study group! PMID- 28891135 TI - Diagnosis of Helicobacter pylori infection. AB - Important progress is being made in endoscopic methods which allow clinicians to predict the presence of Helicobacter pylori based on characteristics of gastric mucosa and to obtain targeted biopsies. There are also important developments in molecular methods with various techniques derived from standard PCR, applied both on gastric biopsies and stool specimens. Progress is being made in microfluidic systems to get a reliable diagnosis in a very short time. The interest of the 13 C urea breath test has been confirmed as well as stool antigen tests. Attempts are being made to find biological markers of premalignant conditions by serology, other than pepsinogens. PMID- 28891136 TI - Helicobacter pylori infection and nonmalignant diseases. AB - A substantial decrease in Helicobacter pylori-associated peptic ulcer disease has been observed during the last decades. Drug-related ulcers as well as idiopathic ulcers are becoming predominant and are more refractory to treatment; however, H. pylori infection still plays an important role in ulcer bleeding and recurrence after therapy. The effect of H. pylori eradication upon functional dyspepsia symptoms has been reviewed in this article and generally confirms the results of previous meta-analyses. Additional evidence suggests a lack of impact upon the quality of life, in spite of improvement in symptoms. The association of H. pylori with gastroesophageal reflux disease and Barrett's esophagus remains controversial with a majority of published studies showing a negative association. Furthermore, a strong inverse relationship between the presence of H. pylori and the esophageal eosinophilia was also reported. Several studies and a review addressed the role of H. pylori in autoimmune gastritis and pernicious anemia. The association of the above still remains controversial. Finally, the necessity of routine endoscopy and H. pylori eradication before bariatric surgery is discussed. Several studies suggest the rationale of preoperative upper endoscopy and H. pylori eradication prior to surgery. However, the prevalence of H. pylori infection prior to surgery in these studies generally reflects the overall prevalence of the infection in the particular geographic area. In addition, results on the role of H. pylori in developing postoperative complications remain controversial. PMID- 28891137 TI - Treatment of Helicobacter pylori infection 2017. AB - This review summarizes important studies regarding Helicobacter pylori therapy published from April 2016 to April 2017. The main themes that emerge involve studies assessing the efficacy of bismuth and nonbismuth quadruple regimens. While in recent years, much of the emphasis on the use of bismuth has focussed on its utility in a second-line setting, an increasing number of studies this year have shown excellent efficacy in first-line therapy. The efficacy of bismuth as a second-line after sequential and concomitant therapy was particularly noteworthy. Antibiotic resistance was more intensely studied this year than for a long time, and definite trends are presented regarding an increase in resistance, including the fact that clarithromycin resistance in particular is now at a level where the continued use of clarithromycin triple therapy first-line as a mainstream treatment is not recommended. Another exciting trend to emerge this year is the utility of vonoprazan as an alternative to PPI therapy, especially in resistant and difficult-to-treat groups. PMID- 28891138 TI - Epidemiology of Helicobacter pylori infection. AB - The study of Helicobacter pylori genetic variability brought us interesting data on the history of mankind. Based on multilocus sequence typing and more recently on whole-genome sequencing, paleomicrobiology still attracts the attention of global researchers in relation to its ancestor roots and coexistence with humans. Three studies determining the prevalence of virulence factors illustrates the controversial results obtained since 30 years by studies trying to associate prevalence of different virulence markers and clinical outcomes of H. pylori infection. Three articles analyzed the prevalence and risk of multiple (genetically distinct isolates) and mixed (susceptible and resistant isolates) infections. A number of studies confirm that H. pylori prevalence is falling worldwide especially in the developed world and in children but that the level of infection is higher in certain ethnic minorities and in Migrants. There is little new in identifying the mode of H. pylori transmission though intrafamilial spread appears to be important. There have, however, been some interesting papers on the presence of the organism in food, water, and the oral cavity. PMID- 28891139 TI - Helicobacter pylori infection in children. AB - Helicobacter pylori infection in children differs from that in adults, from the point of view of epidemiology, host response, clinical features, related diseases, and diagnosis, as well as treatment strategies. The prevalence of H. pylori infection, in both children and adults, is decreasing in the Western World as well as in some developing countries, which contrasts with the increase in childhood asthma and allergic diseases. Recurrent abdominal pain is not specific during H. pylori infection in children. The role of H. pylori infection and failure to thrive, children's growth, type I diabetes mellitus (T1DM) and celiac disease remains controversial. The main initial diagnosis is based on upper digestive endoscopy with biopsy-based methods. Nodular gastritis may be a pathognomonic endoscopic finding of childhood H. pylori infection. The infection eradication control is based on validated noninvasive tests. The main cause of treatment failure of H. pylori infection is its clarithromycin resistance. We recommend standard antibiotic susceptibility testing of H. pylori in pediatric patients prior to the initiation of eradication therapy. H. pylori treatment in children should be based on an evaluation of the rate of eradication in the local population, a systematic use of a treatment adapted to the susceptibility profile and a treatment compliance greater than 90%. The last meta-analysis in children did not show an advantage for sequential therapy when compared to a 14-day triple therapy. Finally, the high rate of antibiotic resistance responsible for therapy failure in recent years justifies the necessity of a novel vaccine to prevent H. pylori infection in children. PMID- 28891140 TI - Other Helicobacters, gastric and gut microbiota. AB - The current article is a review of the most important and relevant literature published in 2016 and early 2017 on non-Helicobacter pylori Helicobacter infections in humans and animals, as well as interactions between H. pylori and the microbiota of the stomach and other organs. Some putative new Helicobacter species were identified in sea otters, wild boars, dogs, and mice. Many cases of Helicobacter fennelliae and Helicobacter cinaedi infection have been reported in humans, mostly in immunocompromised patients. Mouse models have been used frequently as a model to investigate human Helicobacter infection, although some studies have investigated the pathogenesis of Helicobacters in their natural host, as was the case for Helicobacter suis infection in pigs. Our understanding of both the gastric and gut microbiome has made progress and, in addition, interactions between H. pylori and the microbiome were demonstrated to go beyond the stomach. Some new approaches of preventing Helicobacter infection or its related pathologies were investigated and, in this respect, the probiotic properties of Saccharomyces, Lactobacillus and Bifidobacterium spp. were confirmed. PMID- 28891141 TI - Tuberculous cervicitis: A brief report with cytohistological correlation and differential diagnosis. PMID- 28891142 TI - Network meta-analysis of lorcaserin and oral hypoglycaemics for patients with type 2 diabetes mellitus and obesity. AB - In addition to weight loss, randomized controlled trials have shown improvement in glycaemic control in patients taking lorcaserin. The aim of this study aim was to compare adding lorcaserin or other glucose lowering medications to metformin on weight and glycaemic control. A systematic review and network meta-analysis of randomized controlled trials were conducted. Included studies (published 1990 2014) were of lorcaserin or glucose lowering medications in type 2 diabetic patients compared to placebo or different active treatments. Studies had to report >=1 key outcome (change in weight or HbA1c, % HbA1c <7, hypoglycaemia). Direct meta-analysis was performed using DerSimonian and Laird random effects models, and network meta-analysis with Bayesian Markov-chain Monte Carlo random effects models; 6552 articles were screened and 41 included. Lorcaserin reduced weight significantly more than thiazolidinediones, glinides, sulphonylureas and dipeptidyl peptidase-4 inhibitors, some of which may have led to weight gain. There were no significant differences in weight change between lorcaserin and alpha-glucoside inhibitors, glucagon-like peptide-1 agonists and sodium/glucose cotransporter 2 inhibitors. Network meta-analysis showed lorcaserin was non inferior to all other agents on HbA1c reduction and % achieving HbA1c of <7%. The risk of hypoglycaemia was not significantly different among studied agents except that sulphonylureas were associated with higher risk of hypoglycaemia than lorcaserin. Although additional studies are needed, this analysis suggests in a population of patients with a body mas index of >=27 who do not achieve glycaemic control on a single agent, lorcaserin may be added as an alternative to an add-on glucose lowering medication. PMID- 28891143 TI - Behavioural Addiction Open Definition 2.0-using the Open Science Framework for collaborative and transparent theoretical development. PMID- 28891144 TI - Commentary on White et al. (2017): Adolescent drinking and exposure to advertising-behaviour does not occur in a social vacuum. PMID- 28891145 TI - Commentary on Schmitz et al. (2017): Advancing medication development for addiction-behavioral and neuroimaging outcomes as indirect biomarkers of target engagement. PMID- 28891146 TI - Commentary on Popova et al. (2017): Co-used and co-administered tobacco and cannabis (marijuana) require further investigation. PMID- 28891147 TI - Commentary on Pardo (2017) and Moyo et al. (2017): Much still unknown about prescription drug monitoring programs. PMID- 28891149 TI - Commentary on Fazel et al. (2017): High levels of substance use disorders among correctional inmates-some implications for interventions of the review data from Fazel et al. PMID- 28891150 TI - Endothelial-to-mesenchymal transition in cardiovascular diseases: Developmental signaling pathways gone awry. AB - The process named endothelial-to-mesenchymal transition (EndMT) was observed for the first time during the development of the chicken embryo several decades ago. Of interest, accumulating evidence suggests that EndMT plays a critical role in the onset and progression of multiple postnatal cardiovascular diseases. EndMT is controlled by a set of developmental signaling pathways, very similar to the process of epithelial-to-mesenchymal transition, which determine the activity of several EndMT transcriptional effectors. Once activated, these EndMT effectors regulate the expression of endothelial- and mesenchymal-specific genes, in part by interacting with specific motifs in promoter regions, eventually leading to the down-regulation of endothelial-specific features and acquisition of a fibroblast-like phenotype. Important technical advances in lineage tracing methods combined with experimental mouse models demonstrated the pathophysiological importance of EndMT for human diseases. In this review, we discuss the major signal transduction pathways involved in the activation and regulation of the EndMT program. Furthermore, we will review the latest discoveries on EndMT, focusing on cardiovascular diseases, and in particular on its role in vascular calcification, pulmonary arterial hypertension, and organ fibrosis. Developmental Dynamics 247:492-508, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28891151 TI - Protein Catenation Enhances Both the Stability and Activity of Folded Structural Domains. AB - Catenanes are intriguing molecular architectures with unique properties. Herein, we report the cellular synthesis of protein catenanes containing folded structural domains, aided by synergy between p53 dimerization and SpyTag/SpyCatcher chemistry. Concatenation of green fluorescent protein (GFP) was shown to increase chemical stability without disrupting the fluorescence properties, and concatenated dihydrofolate reductase (DHFR) exhibited a melting temperature around 4 degrees C higher and catalytic activity around 27 % higher than the wild-type DHFR and the cyclic/linear controls. Catenation also confers considerable proteolytic resistance on DHFR. The results suggest that catenation could enhance both the stability and activity of folded proteins, thus making topology engineering an attractive approach for tailoring protein properties without varying their native sequences. PMID- 28891152 TI - Exfoliation rate of mammary epithelial cells in milk on bovine mastitis caused by Staphylococcus aureus is associated with bacterial load. AB - The exfoliation rate of mammary epithelial cells (MECs) in milk is affected by physiological, breeding and environmental factors. Little is known about the relationship between the MEC exfoliation into milk and mammary-infected Staphylococcus aureus (S. aureus) load on bovine mastitis caused by S. aureus. The aim of this study was to investigate the relationship between S. aureus load and the proportion of MEC exfoliation in milk using five substantial bovine mastitis models. In 64 randomly extracted milk samples from udders at 3-21 days after S. aureus infusion, there were various samples with different numbers of S. aureus counts and somatic cell counts. No significant correlations were found between the S. aureus counts and somatic cell count (r = 0.338). In contrast, a significant correlation was noted between S. aureus counts and the proportion of cytokeratin-positive cells in the milk from the infused udders (r = 0.734, P < 0.01). In conclusion, the increasing MEC exfoliation rate in milk from mastitis udders caused by S. aureus may contribute to reduced milk yield. PMID- 28891153 TI - A Randomized Trial of Off-Site Collaborative Care for Depression in Chronic Hepatitis C Virus. AB - OBJECTIVE: To test the effectiveness of a collaborative depression care model in improving depression and hepatitis C virus (HCV) care. DATA SOURCES/STUDY SETTING: Hepatitis C virus clinic patients who screened positive for depression at four Veterans Affairs Hospitals. STUDY DESIGN: We compared off-site depression collaborative care (delivered by depression care manager, pharmacist, and psychiatrist) with usual care in a randomized trial. Primary depression outcomes were treatment response (>=50 percent decrease in 20-item Hopkins Symptoms Checklist [SCL-20] score), remission (mean SCL-20 score, <0.5), and depression free days (DFDs). Primary HCV outcome was receipt of HCV treatment. DATA COLLECTION: Patient data were collected by self-report telephone surveys at baseline and 12 months, and from electronic medical records. PRINCIPAL FINDINGS: Baseline screening identified 292 HCV-infected patients with depression, and 242 patients completed 12-month follow-up (82.9 percent). Intervention participants were more likely to report depression treatment response, remission, and more DFDs than usual care participants. Intervention participants were more likely to receive antiviral treatment; however, the difference was not statistically significant. CONCLUSION: Off-site depression collaborative care improved depression outcomes in HCV patients and may serve as a model for collaboration between mental health and specialty physical health providers in other high co occurring conditions. PMID- 28891154 TI - Immune mechanisms in heart failure. AB - Elevated levels of circulating pro-inflammatory biomarkers in patients with both ischaemic and non-ischaemic heart failure (HF) correlate with disease severity and prognosis. Experimental studies have shown activation of immune response mechanisms in the heart to provoke cardiac adverse remodelling and cause left ventricular dysfunction. Consequently, most of the clinical trials targeting elements of the immune response in HF attempted to modulate the inflammatory response. Surprisingly, clinical studies targeting immune effectors were either neutral or even increased pre-specified clinical endpoints, and some studies resulted in worsening of HF. This review discusses immune mediators involved in the pathogenesis and progression of HF and potential therapeutic applications targeting inflammation in HF. Besides more obvious settings featuring immune activation such as inflammatory or ischaemic cardiomyopathy, the relevance of immune activation in acute or chronic HF of other origins, including volume overload or valvular heart disease, is highlighted. Understanding how cell specific and molecular mechanisms of the immune response interfere with cardiac remodelling in HF may open new avenues to design biomarkers or druggable targets. PMID- 28891155 TI - In Situ-Formed Hierarchical Metal-Organic Flexible Cathode for High-Energy Sodium Ion Batteries. AB - Metal-organic compounds are a family of electrode materials with structural diversity and excellent thermal stability for rechargeable batteries. Here, we fabricated a hierarchical nanocomposite with metal-organic cuprous tetracyanoquinodimethane (CuTCNQ) in a 3 D conductive carbon nanofibers (CNFs) network by in situ growth, and evaluated it as flexible cathode for sodium-ion batteries (SIBs). CuTCNQ in such flexible composite electrode is able to exhibit a high capacity of 252 mAh g-1 at 0.1 C and highly reversible stability for 1200 cycles within the voltage range of 2.5-4.1 V (vs. Na+ /Na). A high specific energy of 762 Wh kg-1 was obtained with high average potential of 3.2 V (vs. Na+ /Na). The in situ-formed electroactive metal-organic composites with tailored nanoarchitecture provide a promising alternative choice for high-performance cathode materials in SIBs with high energy. PMID- 28891156 TI - Overcoming preexisting alloantibody in renal transplantation-improving outcomes while reducing needs and costs. PMID- 28891158 TI - The 17th Congress of Gastroenterology China, Xi'an, China, 14-16 September 2017. PMID- 28891157 TI - PTEN in the maintenance of genome integrity: From DNA replication to chromosome segregation. AB - Faithful DNA replication and accurate chromosome segregation are the key machineries of genetic transmission. Disruption of these processes represents a hallmark of cancer and often results from loss of tumor suppressors. PTEN is an important tumor suppressor that is frequently mutated or deleted in human cancer. Loss of PTEN has been associated with aneuploidy and poor prognosis in cancer patients. In mice, Pten deletion or mutation drives genomic instability and tumor development. PTEN deficiency induces DNA replication stress, confers stress tolerance, and disrupts mitotic spindle architecture, leading to accumulation of structural and numerical chromosome instability. Therefore, PTEN guards the genome by controlling multiple processes of chromosome inheritance. Here, we summarize current understanding of the PTEN function in promoting high-fidelity transmission of genetic information. We also discuss the PTEN pathways of genome maintenance and highlight potential targets for cancer treatment. PMID- 28891159 TI - Enhancing a public health nursing shelter program. AB - The Shelter Nurse Program offers important nursing care and resources that help meet the health needs of the homeless population and improve the health of homeless individuals and families. However, formalized program goals and objectives, along with an evaluation plan that demonstrates population outcomes, had never been developed even as the program has evolved over time. Thus, the agency sought our assistance as public health nursing consultants to enhance the overall program to improve the health of the homeless population. To accomplish this, we worked with the agency and the shelter nurses throughout each step of the process to assess the needs of the program, develop appropriate goals and objectives, and develop an effective outcome evaluation plan for the existing Shelter Nurse Program. Lessons learned included the value and applicability of the selected program development model, the importance of agency ownership and active participation by front-line workers, and the value of educating the workers and introducing resources throughout the process. PMID- 28891160 TI - CO2 angiography: Colorless, odorless, but definitely not useless! AB - Contemporary approaches to minimize the risk of acute kidney injury from radiographic contrast (AKI-RC) rely on preferential use of low- or non-ionic contrast; pre-hydration; and limiting contrast volume. This study utilized a meta analysis of 677 patients to compare the risk of AKI-RC after CO2 peripheral angiography versus iodinated contrast (4.3% vs. 11.1%, odds ratio [OR] 0.465, P = 0.048). There was no difference in AKI-RC in patients with CKD. This study has many limitations. CO2 angiography is an important technique; proper understanding of its strengths and limitations is essential. PMID- 28891161 TI - Comparison of Acute Expansion of Bioresorbable Vascular Scaffolds Versus Metallic Drug-Eluting Stents in Different Degrees of Calcification: An Optical Coherence Tomography Study. DOI: 10.1002/ccd.26676. PMID- 28891162 TI - Integrating invasive hemodynamic parameters into risk stratification of acute myocardial infarction and cardiogenic shock. AB - A ratio of systolic blood pressure over left ventricle end-diastolic pressure (SBP/LVEDP) <=4 identifies patients with ST-elevation myocardial infarction (STEMI) at greater risk of in-hospital mortality or that may require the use of mechanical circulatory support (MCS). The predictive performance of the SBP/LVEDP ratio was comparable to non-invasive hemodynamic parameters (the shock index and the modified shock index) and established clinical risk stratification tools (the TIMI risk score). Alongside established clinical risk factors, invasive hemodynamic parameters may help in identifying STEMI patients who may benefit from early MCS. PMID- 28891163 TI - Patient preferences prompt a peek at priorities. AB - Patients rate the downsides of bare metal stents (higher restenosis rates) as being of similar magnitude to the downsides of drug eluting stents (longer dual anti-platelet therapy). Patient preferences regarding choice of bare metal versus drug eluting stents should be elicited before coronary stenting. This article does not study actual patient preferences for stent type. Future studies should assess how personalized discussions of trade-offs of stent types affect patient preferences. PMID- 28891164 TI - Heparin or bivalirudin for non-primary PCI: Beware of neat and simple answers.... AB - The debate regarding the choice of heparin or bivalirudin as the preferred anticoagulant in PCI is still ongoing Nonrandomized registry data are severely limited for comparative analyses and should therefore always be interpreted with caution Clinicians should resist simplistic data interpretations or populist cries relating to cost, but rather focus on valid benefit:risk analyses for their clinical decision making. PMID- 28891165 TI - Drug-coated balloons: "Do they still have a role in treating coronary artery disease?" AB - Small vessels with coronary artery disease (CAD) are at high risk of restenosis, despite the use of drug-eluting stents (DESs). Drug-coated balloon (DCB) therapy offers a viable alternative to DESs for the management of small vessel CAD. The literature regarding the use of DCBs in lieu of the newer generation DESs to treat small vessel CAD is controversial. PMID- 28891166 TI - David J. G. White, PhD, FRCPath. PMID- 28891168 TI - Xenotransplantation literature update, July/August 2017. PMID- 28891169 TI - Computed tomographic findings in three dogs naturally infected with Crenosoma vulpis. AB - Crenosoma vulpis is a nematode lungworm found in wild and domestic canids in some parts of North America and Europe. Reported radiographic findings are nonspecific and consist of a combination of bronchial and interstitial changes of variable severity. This retrospective, case series study aimed to describe thoracic computed tomographic (CT) findings for a group of dogs with confirmed crenosomosis. Selection criteria were presentation with a chronic cough during the period of January 2016 to February 2017, evaluation by thoracic CT, and final diagnosis of C. vulpis infection based on bronchoscopic findings, bronchoalveolar lavage fluid analysis, and quantitative polymerase chain reaction. Medical records and CT images were retrieved and reviewed by a board-certified veterinary internist, a veterinary internal medicine resident, two board-certified veterinary radiologists, and a veterinary radiology intern, and findings were recorded. Three dogs met inclusion criteria. Thoracic CT findings for all dogs included the following: diffuse bronchial wall thickening, multifocal peribronchial ground glass attenuation, consolidation of the pulmonary parenchyma, and cylindrical bronchiectasis. In two dogs, the bronchial wall thickening was irregular to nodular, which was consistent with the bronchoscopic findings. Two dogs showed pulmonary parenchymal bands. Thoracic computed tomographic changes in dogs with C. vulpis are consistent with those seen on thoracic radiographs and crenosomosis should be considered in dogs with these findings. PMID- 28891170 TI - Design and evaluation of cryodevice, an easy to use apparatus for maintenance of optimum temperature during cryoglobulin assay. AB - INTRODUCTION: Maintenance of temperature during collection and transport of blood is an important pre-requisite for cryoglobulin assays. In this manuscript, we describe 'cryodevice', a low-cost device for transportation and/or incubation of vials of whole blood at 37 degrees C. Such a device would reduce false negatives in cryoglobulin assays. METHOD: The 'cryodevice' takes the embodiment of a portable, light, insulated water bath, which can be used as an incubator in a plugged-in state, or as a transport container after it is set up and disconnected from the power supply. The design of the cryodevice is described here, with focus on its construction and electronic control circuit. Computer simulations and in vitro trials were performed to study the temperature drop in the blood samples placed in the device. Subsequently, the cryodevice was also used with actual patient blood samples. RESULTS: Thermal simulations and in vitro testing of the cryodevice predicted that the design would meet the temperature maintenance goals. When the cryodevice was put in to use for screening 45 patient blood samples, it helped identify positive cryoglobulinemia in three of the samples. CONCLUSION: The description of the cryodevice envisions enabling the construction of a low-cost device in resource-limited healthcare settings in India created with locally available resources. On testing, the device was found to be satisfactory in performance and is expected to bring down incidences of false negatives in cryoglobulin tests. PMID- 28891171 TI - Innovation in health service management: Adoption of project management offices to support major health care transformation. AB - AIM: To explore the characteristics that influence project management offices acceptance and adoption in healthcare sector. BACKGROUND: The creation of project management offices has been suggested as a promising avenue to promote successful organisational change and facilitate evidence-based practice. However, little is known about the characteristics that promote their initial adoption and acceptance in health care sector. This knowledge is important in the context where many organisations are considering implementing project management offices with nurse managers as leaders. METHODS: A descriptive multiple case study design was used. The unit of analysis was the project management offices. The study was conducted in three university-affiliated teaching hospitals in 2013-14 (Canada). Individual interviews (n = 34) were conducted with senior managers. RESULTS: Results reveal that project management offices dedicated to project and change management constitute an innovation and an added value that addresses tangible needs in the field. CONCLUSION: Project management offices are an innovation highly compatible with health care managers and their approach has parallels to the process of clinical problem solving and reasoning well-known to adopters. IMPLICATIONS FOR NURSING MANAGEMENT: This knowledge is important in a context where many nurses hold various roles in project management offices, such as Director, project manager, clinical expert and knowledge broker. PMID- 28891172 TI - Urolithiasis is prevalent and associated with reduced bone mineral density in beta-thalassaemia major. AB - Asymptomatic urolithiasis is common and of mixed composition in patients with beta-thalassaemia major. Twenty-seven subjects were imaged using dual-energy computer tomography to determine the presence and composition of urolithiasis. The prevalence of urolithiasis was 59% and affected patients generally had multiple stones, often with more than one component: struvite (33%), calcium oxalate (31%) and cystine (22%). Hypercalciuria was present in 78% of subjects and calcium-containing urolithiasis was associated with reduced femoral neck Z scores. PMID- 28891173 TI - Challenge to advance care planning. PMID- 28891174 TI - Regulation of complementary medicines. PMID- 28891175 TI - Massive eucalyptus oil overdose. PMID- 28891176 TI - Author reply. PMID- 28891177 TI - Cognitive challenges to minimising low value care. AB - Clinical decisions often rely on pattern recognition, simple rules of thumb, tacit knowledge and habit. In many instances, such intuitive decisions are fast and accurate, but they can be subject to cognitive biases leading to delivery of care of low value at odds with scientific evidence of best practice. If programmes, such as EVOLVE (Evaluating Evidence, Enhancing Efficiencies) and Choosing Wisely are to have maximal impact in minimising low value care, such biases, and the factors that hide and accentuate them, need to be exposed and addressed in a collegiate and non-judgemental manner. PMID- 28891178 TI - Author reply. PMID- 28891179 TI - Unexpected mirror-image dextrocardia in a patient with ST elevation myocardial infarction. PMID- 28891180 TI - De novo activating epidermal growth factor mutations (EGFR) in small-cell lung cancer. AB - In Australia, mutations in epidermal growth factor mutations (EGFR) occur in 15% of patients diagnosed with non-small-cell lung cancer and are found with higher frequency in female, non-smokers of Asian ethnicity. Activating mutations in the EGFR gene are rarely described in SCLC. We present two cases of de novo EGFR mutations in patients with SCLC detected in tissue and in plasma cell free DNA, both of whom were of Asian ethnicity and never-smokers. These two cases add to the growing body of evidence suggesting that screening for EGFR mutations in SCLC should be considered in patients with specific clinical features. PMID- 28891181 TI - Something's got to give: time-cost trade-offs in site-specific research approval can negatively impact patient recruitment in multi-institutional studies. PMID- 28891182 TI - Rare disease registries: a call to action. AB - When registries collect accurate clinical data over time, they can act as fundamental support structures for patients and their families and powerful cost effective instruments to support clinical trials and translational research to improve quality of care, quality of life and survival. Registries are critical for rare diseases (RD) with low prevalence and propensity for variation in treatment and outcomes. Rare Voices Australia is leading a call for action to the research and clinical community to prioritise RD data collection and develop an integrated RD Registry strategy for Australia. Financial, operational and governance challenges exist for establishing and maintaining RD registries. As a multidisciplinary team whose interests converge on RD, we highlight the need for the establishment of an Australian RD Registry Alliance. This 'umbrella' organisation will: (i) bring together existing RD registries across Australia; (ii) establish National RD Registry Standards to support interoperability and cohesion across registries; (iii) develop strategies to attract sustainable funding from government and other sources to maximise the utility of existing RD registries and support the development of new RD registries. The most important role for the Alliance would be to use the RD registries for translational research to address current knowledge gaps about RD and to improve the care for the over 1.4 million Australians estimated to live with RD. PMID- 28891183 TI - Primary percutaneous coronary intervention for inferior ST-segment elevation myocardial infarction in a patient supported by the HeartWare left ventricular assist device. AB - A 63-year-old man with an ischaemic cardiomyopathy, supported by the HeartWare left ventricular assist device (LVAD), presented with ventricular tachycardia and inferior ST-elevation myocardial infarction (STEMI) with associated acute right ventricular (RV) dysfunction. He underwent primary percutaneous coronary intervention with balloon angioplasty and placement of three drug-eluting stents in the proximal-to-mid right coronary artery. Post-procedure, ventricular arrhythmias abated, RV systolic dysfunction resolved and RV size normalised. Percutaneous coronary intervention (PCI) facilitated by the use of miniaturised percutaneous LVAD has become an increasingly available treatment option for high risk patients. PCI in patients on established full mechanical circulatory support is not a common occurrence. Indeed, to our knowledge, this is the first case of primary percutaneous coronary intervention on an LVAD-supported heart reported in the medical literature. The case raises several specific issues that are of peculiar interest to clinicians involved in the care of patients supported by mechanical assist devices who experience an acute coronary syndrome requiring emergent revascularisation. PMID- 28891184 TI - Advance care planning: a step in the right direction. PMID- 28891185 TI - Complementary medicine products: interpreting the evidence base. AB - Many patients use complementary medicine (CM) products, such as vitamins, minerals and herbs as part of self-care without professional advice or disclosure to their doctors. While use of CM products is gaining awareness by the medical community and there is mounting evidence for their safety, efficacy and cost effectiveness, there is also the potential for adverse events from inappropriate use and/or withdrawal, as well as interactions with other medicines. Due to the unique and complex properties of many CM products, research evidence is specific to individual preparations and this can lead to confusion when assessing label claims and interpreting the results of clinical trials and systematic reviews. While the Australian regulatory environment for CM products is the same as for prescription medicines and is based on risk, there is a great need for consumers and clinicians to have access to easily understood, evidence-based information to facilitate informed decision-making. PMID- 28891186 TI - End of life issues. PMID- 28891188 TI - Author reply. PMID- 28891187 TI - Long-term efficacy and safety of the interleukin-1 inhibitors anakinra and canakinumab in refractory Behcet disease uveitis and concomitant bladder papillary carcinoma. PMID- 28891189 TI - How have millions of people with heart failure benefited from our research over the last 10-15 years? The sounds of dead silence. PMID- 28891190 TI - Is Multiple Overlapping Uncovered Stents Technique Suitable for Aortic Aneurysm Repair? AB - A computational fluid dynamic model to assess the impact of flow-diverter device on intra-aneurysmal flow in complex aortic aneurysm from the viewpoint of hemodynamics is presented. The aim of this study is to investigate the hemodynamic effects of an endovascular flow-diverter technique using multiple overlapping uncovered stents (MOUS) in the treatment of complex aortic aneurysm involving side branch. The placement of porous barrier such as MOUS across the aneurysm alters the blood flow pattern in the aneurysm sac. Subsequently, flow diversion effect creates a natural hemodynamic environment to promote aneurysm thrombosis, thus stabilizing the aneurysm. The study revealed that intra aneurysmal flow was reduced and low time average wall shear stress (TAWSS), high relative residence time (RRT), and high oscillatory shear index (OSI) regions were observed in the aneurysm sac. Three to four MOUS stents produced the best hemodynamic environment for the formation of thrombus, with saccular aneurysm performing better than fusiform aneurysm from the viewpoint of hemodynamics. A result also revealed that flow in the branch vessel was not compromised suggesting the capacity of preserving patency of branch vessels while at the same time stabilizing the aneurysm. Based on the hemodynamic performance of this study coupled with existing reported clinical studies, deploying three to four MOUS stents is a feasible solution to treat aneurysm with side branch, favorably for saccular shape aneurysm. PMID- 28891191 TI - Molecular characterization of branched polysaccharides from Tremella fuciformis by asymmetrical flow field-flow fractionation and size exclusion chromatography. AB - To accurately characterize branched polysaccharides with high molecular weights from medicinal and edible mushrooms and identify the limitations of size exclusion chromatography, molecular characteristics of polysaccharides from Tremella fuciformis were determined and compared by asymmetrical flow field-flow fractionation coupled with multiangle laser light scattering and refractive index detection, and size exclusion chromatography coupled with multiangle laser light scattering and refractive index detection, respectively. Results showed that molecular weights of three batches of T. fuciformis polysaccharides were determined as 2.167 * 106 (TF1), 2.334 * 106 (TF2), and 2.435 * 106 Da (TF3) by size exclusion chromatography, and 3.432 * 106 (TF1), 3.739 * 106 (TF2), and 3.742 * 106 Da (TF3) by asymmetrical flow field-flow fractionation, as well as 3.469 * 106 Da (TF1) by off-line multiangle laser light scattering, respectively. Results suggested that size exclusion chromatography was unable to accurately characterize T. fuciformis polysaccharides, which may be due to its limitations such as shear degradation and abnormal coelution. Compared to size exclusion chromatography, asymmetrical flow field-flow fractionation could be a better technique for the molecular characterization of branched polysaccharides with high molecular weights from medicinal and edible mushrooms, as well as from other natural resources. PMID- 28891192 TI - Light therapy: is it safe for the eyes? AB - OBJECTIVE: Light therapy has become an increasingly popular treatment for depression and a range of other neuropsychiatric conditions. Yet, concerns have been raised about the ocular safety of light therapy. METHOD: We conducted the first systematic review into the ocular safety of light therapy. A PubMed search on January 4, 2017, identified 6708 articles, of which 161 were full-text reviewed. In total, 43 articles reporting on ocular complaints and ocular examinations were included in the analyses. RESULTS: Ocular complaints, including ocular discomfort and vision problems, were reported in about 0% to 45% of the participants of studies involving light therapy. Based on individual studies, no evident relationship between the occurrence of complaints and light therapy dose was found. There was no evidence for ocular damage due to light therapy, with the exception of one case report that documented the development of a maculopathy in a person treated with the photosensitizing antidepressant clomipramine. CONCLUSION: Results suggest that light therapy is safe for the eyes in physically healthy, unmedicated persons. The ocular safety of light therapy in persons with preexisting ocular abnormalities or increased photosensitivity warrants further study. However, theoretical considerations do not substantiate stringent ocular safety-related contraindications for light therapy. PMID- 28891193 TI - Psychological Inflexibility Predicts of Suicidal Ideation Over Time in Veterans of the Conflicts in Iraq and Afghanistan. AB - Psychological inflexibility, or how individuals respond to distressing internal experiences, may be a modifiable risk factor for suicide in veterans. It was hypothesized that psychological inflexibility would predict suicidal ideation after accounting for established risk factors at baseline and 1 year later. Post 9/11 veterans (N = 309) completed clinical interview and self-report measures at baseline and 1-year follow-up. Results indicated that psychological inflexibility predicted severity of suicidal ideation at both baseline and 1 year later, after accounting for established risk factors. Psychological inflexibility is an important marker of risk for suicidal ideation, and could be a target for interventions aimed at reducing suicide. PMID- 28891195 TI - Prevalence of synchronous bilateral tonsil squamous cell carcinoma: A retrospective study. AB - OBJECTIVES: The prevalence of synchronous bilateral tonsil cancer remains unexplored. To date, only 38 cases have been described in the literature. With an aim to substantiate the Danish recommendation of performing bilateral tonsillectomy in patients with suspected or proven tonsil cancer and in patients with cervical carcinoma metastasis from an unknown primary tumour, this study was undertaken to determine the prevalence of synchronous bilateral tonsil cancer. DESIGN: A retrospective review of all patients diagnosed with tonsil cancer in the period 2000-2015, Aarhus University Hospital, Denmark, was performed. RESULTS: Seven of 211 (3.3%) consecutive patients with tonsil cancer, who had undergone bilateral tonsillectomy (n = 180) or unilateral tonsillectomy (clinically normal side) combined with contralateral tonsil biopsy (side with suspected cancer) (n = 31), had synchronous bilateral tonsil cancer. Furthermore, dysplasia was found in the contralateral tonsil in two patients with unilateral tonsil cancer. Four of 171 (2.3%) patients with suspected unilateral tonsillar cancer had additional contralateral tonsil cancer. Three of 34 (8.8%) patients without clinical signs of tonsillar malignancy on any side (32 patients with carcinoma of unknown primary) had synchronous bilateral tonsil cancer. In none of the patients were bilateral tonsil cancer suspected. Patients with unilateral vs synchronous bilateral tonsil cancer had similar clinical and tumour characteristics. CONCLUSION: Knowledge on additional contralateral synchronous tonsil cancer is crucial for avoidance of early recurrence of oropharyngeal cancer in patients with tonsil cancer. Based on our findings, we recommend bilateral tonsillectomy in all patients with suspected or proven tonsil cancer and carcinoma of unknown primary. PMID- 28891194 TI - Suspended graphene oxide nanoparticle for accelerated multilayer osteoblast attachment. AB - Mimicking bone tissues having layered structures is still a significant challenge because of the lack of technologies to assemble osteoblast cell types into bone structures. One of the promising and attractive materials in biomedical and different engineering fields is graphene and graphene-based nanostructures such as graphene oxide (GO) because of their unique properties. In most studies, GO was synthesized using chemical vapor deposition method, and was coated on the substrate. In this study, we proposed a simple technique for assembly of cells that facilitates the construction of osteoblast-like structures using suspended GO synthesized by graphite powder, H2 SO4 , and KMnO4 .Toxicity effects of GO on human mesenchymal stem cells (hMSCs) derived from bone marrow were analyzed. In addition to normal MSCs, toxicity effects of GO on human cancer cell line saos-2 as an abnormal cell line that possess several osteoblastic features, was examined. The attachment and expression of osteoblast cells genes were evaluated after differentiation of MSCs to osteoblast cells in presence of suspended GO by scanning electron microscopy and real time PCR. We found that the toxicity effects of GO are dose dependent and in oseogenic medium containing suspended GO the expression level of osteoblast genes osteopontin and osteocalcin and cell adhesion markers connexin were higher than control group. Interestingly, through this method GO was found to induce multilayer osteoblast cell morphology and enhance the number of cell layer. We expect that the presented method would become a highly useful approach for bone tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 293-303, 2018. PMID- 28891196 TI - A novel use of near-infrared light in assisting with TaTME planes - a video vignette. PMID- 28891197 TI - Primary mediastinal paraganglioma associated with a familial variant in the succinate dehydrogenase B subunit gene. AB - Surgical management is the mainstay of therapy for primary cardiac tumors, yet due to the rarity of these malignancies, their management and workup remains a challenge. Here, we report a unique case of a patient with a primary left ventricular cardiac paraganglioma (PGL) and describe the role of a medical genetics assessment leading to the identification of a rare variant in the SDHB gene to be the causative etiology of this cardiac tumor. Due to decreasing costs and accessibility of molecular genetic analysis, genetic testing may become an emerging diagnostic adjunct in cases of cardiac tumors. PMID- 28891198 TI - Targeted medical nutrition for cachexia in chronic obstructive pulmonary disease: a randomized, controlled trial. AB - BACKGROUND: Cachectic patients with chronic obstructive pulmonary disease (COPD) may benefit from nutritional support. This double-blind, randomized, controlled trial evaluated the safety and efficacy of targeted medical nutrition (TMN) vs. an isocaloric comparator in pre-cachectic and cachectic patients with COPD. METHODS: Patients aged >=50 years with moderate-to-severe COPD and involuntary weight loss or low body mass index (16-18 kg/m2 ) were randomized 1:1 to receive TMN (~230 kcal; 2 g omega-3 fatty acids; 10 MUg 25-hydroxy-vitamin D3) or isocaloric comparator twice daily for 12 weeks (ClinicalTrials.gov Identifier: NCT02442908). Primary safety endpoints comprised adverse events and changes in vital signs, laboratory parameters, and concomitant medications. Secondary efficacy endpoints included changes in weight, body composition, exercise tolerance, metabolic biomarkers, and systemic inflammation. RESULTS: Forty-five patients were randomized to receive TMN (n = 22; mean 69.2 years) or isocaloric comparator (n = 23; mean 69.7 years). TMN was well tolerated. Adverse events were similar in number and type in both groups. Compliance to both products was good (TMN, 79%; comparator, 77%). Both groups gained weight, but the TMN group gained comparatively more fat mass (P = 0.0013). Reductions in systolic blood pressure (P = 0.0418) and secondary endpoints of triglycerides (P = 0.0217) and exercise induced fatigue (P = 0.0223) and dyspnoea (P = 0.0382), and increases in high density lipoprotein cholesterol (P = 0.0254), were observed in the TMN vs. the comparator group by week 12. CONCLUSIONS: Targeted medical nutrition containing high-dose omega-3 fatty acids, vitamin D, and high-quality protein is well tolerated with a good safety profile and has positive effects on blood pressure and blood lipids and on exercise-induced fatigue and dyspnoea. Therefore, this TMN could be clinically beneficial in the nutritional and metabolic support of pre-cachectic and cachectic patients with COPD. PMID- 28891199 TI - Metal-Based Diversity for Crystalline Metal-Fullerene Frameworks. AB - Four different three-dimensional metal-fullerene frameworks were synthesized through polymerization of two C60 -derived dodecaacids with varying alkyl spacers in the presence of Ca2+ , Cu2+ or Cd2+ ions. Structural analysis of the frameworks was performed by single-crystal X-ray diffraction and porosity of the materials was investigated by sorption measurements. PMID- 28891200 TI - Enhanced Production of Soluble Recombinant Proteins With an In Situ-Removable Fusion Partner in a Cell-Free Synthesis System. AB - High-yield production of soluble protein is a common concern in diverse fields of biotechnology. In this study, a strategy of using an engineered nucleotide sequence of ubiquitin for enhancing the production of soluble proteins in a cell free synthesis system is presented. When examined for a series of proteins that otherwise were poorly expressed, N-terminal fusion with ubiquitin significantly increased both the expression levels and solubility of the translational products. The effect of ubiquitin fusion was also markedly augmented by engineering the nucleotide sequence of ubiquitin, leading to several fold enhancements in soluble production of target proteins. Recombinant proteins were produced with their native amino acid sequences through in situ removal of ubiquitin during cell-free synthesis reactions in the presence of a deubiquitinase. The presented strategy could be employed as a facile route to prepare soluble proteins required for various applications. PMID- 28891201 TI - Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model. AB - Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration-time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development. PMID- 28891203 TI - Effects of epidural volume extension by saline injection on the efficacy and safety of intrathecal local anaesthetics: systematic review with meta-analysis, meta-regression and trial sequential analysis. AB - Epidural volume extension, a modification of combined spinal-epidural anaesthesia, involves the epidural injection of saline in order to increase the spread of drugs given intrathecally. Results from individual studies have so far been contradictory and we aimed to gather the available evidence for this technique. We performed a systematic literature search for randomised, controlled trials comparing epidural volume extension after spinal injection with a control group without epidural injection in patients undergoing surgery. Conventional meta-analyses, trial sequential analyses and meta-regression were performed, with the Grading of Recommendations on Assessment, Development and Evaluation (GRADE) approach used to express reliability of outcome estimates. We included 15 studies with 1177 participants. Meta-analyses for the primary outcomes, such as maximum sensory height (6 studies, 274 participants, mean difference (MD) (95%CI) -0.59 ( 1.24 to 0.07) dermatomes, low-quality evidence) and hypotension (10 studies, 683 participants, risk ratio (95%CI) 0.84 (0.66-1.07), low-quality evidence), did not differ significantly between the two treatment arms, but trial sequential analysis suggested insufficient evidence to be certain of these findings. Meta regression suggested a volume-dependent effect, with higher volumes causing a higher spread of intrathecal drugs and a higher incidence of hypotension. A sub group analysis indicated a pronounced effect on motor block recovery time when a lower anaesthetic dose plus epidural volume extension was compared with a higher anaesthetic dose without epidural volume extension, the MD (95%CI) being -66.75 ( 76.0 to -57.5) min, with trial sequential analysis suggesting the evidence was sufficient to draw this conclusion. In trials using the same anaesthetic mixture in the epidural volume extension and the control groups, motor block recovery time did not differ between groups, with a MD (95%CI) of -1.06 (-5.48 to 3.36) min, although trial sequential analysis suggested insufficient evidence. In summary, there is not enough evidence to draw definite conclusions on the effect of epidural volume extension. The quality of the current evidence is low for both efficacy (maximum sensory height) and safety (hypotension). However, there may be a significantly shorter motor block recovery time when different anaesthetic mixtures are used in epidural volume extension and control groups; this warrants further investigation. PMID- 28891204 TI - Patterned Colloidal Photonic Crystals. AB - Colloidal photonic crystals (PCs) have been well developed because they are easy to prepare, cost-effective, and versatile with regards to modification and functionalization. Patterned colloidal PCs contribute a novel approach to constructing high-performance PC devices with unique structures and specific functions. In this review, an overview of the strategies for fabricating patterned colloidal PCs, including patterned substrate-induced assembly, inkjet printing, and selective immobilization and modification, is presented. The advantages of patterned PC devices are also discussed in detail, for example, improved detection sensitivity and response speed of the sensors, control over the flow direction and wicking rate of microfluidic channels, recognition of cross-reactive molecules through an array-patterned microchip, fabrication of display devices with tunable patterns, well-arranged RGB units, and wide viewing angles, and the ability to construct anti-counterfeiting devices with different security strategies. Finally, the perspective of future developments and challenges is presented. PMID- 28891202 TI - Mechanical signals protect stem cell lineage selection, preserving the bone and muscle phenotypes in obesity. AB - The incidence of obesity is rapidly rising, increasing morbidity and mortality rates worldwide. Associated comorbidities include type 2 diabetes, heart disease, fatty liver disease, and cancer. The impact of excess fat on musculoskeletal health is still unclear, although it is associated with increased fracture risk and a decline in muscular function. The complexity of obesity makes understanding the etiology of bone and muscle abnormalities difficult. Exercise is an effective and commonly prescribed nonpharmacological treatment option, but it can be difficult or unsafe for the frail, elderly, and morbidly obese. Exercise alternatives, such as low-intensity vibration (LIV), have potential for improving musculoskeletal health, particularly in conditions with excess fat. LIV has been shown to influence bone marrow mesenchymal stem cell differentiation toward higher-order tissues (i.e., bone) and away from fat. While the exact mechanisms are not fully understood, recent studies utilizing LIV both at the bench and in the clinic have demonstrated some efficacy. Here, we discuss the current literature investigating the effects of obesity on bone, muscle, and bone marrow and how exercise and LIV can be used as effective treatments for combating the negative effects in the presence of excess fat. PMID- 28891205 TI - Effects on jaw function shortly after whiplash trauma. AB - Normal jaw function involves muscles and joints of both jaw and neck. A whiplash trauma may disturb the integrated jaw-neck sensory-motor function and thereby impair chewing ability; however, it is not known if such impairment is present shortly after a neck trauma or develops over time. The aim was to evaluate jaw function after a recent whiplash trauma. Eighty cases (47 women) were examined within 1 month after a whiplash trauma and compared to 80 controls (47 women) without neck trauma. Participants completed the Jaw disability checklist (JDC) and Neck Disability Index (NDI) questionnaires and performed a 5-minute chewing test. Elicited fatigue and pain during chewing were noted, and group differences were evaluated with Fisher's exact test and Mann-Whitney U-test. Compared to controls, cases had higher JDC (P < .0001) and NDI scores (15% vs 2%, P < .0001), and reported more fatigue (53% vs 31%, P = .006) and pain (30% vs 10%, P = .003) during the chewing test. Cases also had a shorter onset time for fatigue and pain (both P = .001) Furthermore, cases reporting symptoms during chewing had higher JDC and NDI scores compared to cases not reporting symptoms (both P = .01). Symptoms mainly occurred in the trigeminal area for both groups, but also in spinal areas more often for cases than for controls. Taken together, the results indicate that jaw-neck sensory-motor function is impaired already within 1 month after a whiplash trauma. The association between neck disability and jaw impairment underlines the close functional relationship between the regions, and stresses the importance of multidisciplinary assessment. PMID- 28891206 TI - A helpful approach to organ donation: From end-of-life care to effective organ transplantation. PMID- 28891207 TI - Stable Li Metal Anodes via Regulating Lithium Plating/Stripping in Vertically Aligned Microchannels. AB - Li anodes have been rapidly developed in recent years owing to the rising demand for higher-energy-density batteries. However, the safety issues induced by dendrites hinder the practical applications of Li anodes. Here, Li metal anodes stabilized by regulating lithium plating/stripping in vertically aligned microchannels are reported. The current density distribution and morphology evolution of the Li deposits on porous Cu current collectors are systematically analyzed. Based on simulations in COMSOL Multiphysics, the tip effect leads to preferential deposition on the microchannel walls, thus taking full advantage of the lightening rod theory of classical electromagnetism for restraining growth of Li dendrites. The Li anode with a porous Cu current collector achieves an enhanced cycle stability and a higher average Coulombic efficiency of 98.5% within 200 cycles. In addition, the resultant LiFePO4 /Li full battery demonstrates excellent rate capability and stable cycling performance, thus demonstrating promise as a current collector for high-energy-density, safe rechargeable Li batteries. PMID- 28891209 TI - Blood component transfusions in mass casualty events. AB - BACKGROUND AND OBJECTIVES: Planning transfusion needs in mass casualty events (MCE) is critical for disaster preparedness. Published data on blood component usage were analysed to seek correlative factors and usage rates. MATERIALS AND METHODS: English-language medical publications since 1980 were searched for MCEs with numbers of patient admissions and transfused RBCs. Reports were excluded from natural disasters or with total RBC use <50 units. Statistical analysis employed Mann-Whitney U-tests and Spearman's rank correlations. RESULTS: In 24 reports, the average units per admission were 3.06 RBCs, 2.13 plasmas and 0.37 platelet doses. Five RBCs per admission would have sufficed for 87% of events. Transfusion needs involving bombings correlated with admissions (P <= 0.03). In the formula (massive-transfusion patients in MCE) times X = (total units for all MCE patients), the average X was 35 for RBCs (correlation P = 0.01), 17 for plasma (P = 0.10) and five for platelet doses (P = 0.06). From 67% to 84% of all components used were given in the first 24 h (event medians). CONCLUSIONS: Blood component use in MCEs correlated with numbers of patients admitted or receiving massive transfusion. More current data are needed to better reflect emerging trauma care practices and refine predictive models of transfusion needs. PMID- 28891208 TI - Serum MicroRNA-150 Predicts Prognosis for Early-Stage Non-Small Cell Lung Cancer and Promotes Tumor Cell Proliferation by Targeting Tumor Suppressor Gene SRCIN1. AB - This integrative multistage study was aimed to identify circulating microRNAs (miRNAs) as prognostic biomarkers and investigate the treatment target for early stage non-small cell lung cancer (NSCLC) patients. In stage I-II NSCLC patients, we screened and validated the miRNA ratio signatures predictive of prognosis in serum. In tumor, we found that the expression of miR-150 in identified miRNA signatures was also associated with survival. Increased miR-150 expression promoted NSCLC cell proliferation and migration and vice versa. Specific mRNA cleavage sites targeted by endogenous miR-150 in 3' untranslated region (UTR) of SRCIN1 was identified by utilizing our recently developed novel Stem-Loop-Array reverse-transcription polymerase chain reaction (SLA-RT-PCR) assay. The blocking action of miR-150 resulted in repressed NSCLC cell growth in vitro and knockdown of miR-150 caused substantial tumor volume reduction in vivo. Our findings suggest that miR-150 binding on specific recognition sites in 3' UTR of tumor suppressor gene SRCIN1 present a potential therapeutic target for NSCLC. PMID- 28891210 TI - Measuring Type 1 diabetes stigma: development and validation of the Type 1 Diabetes Stigma Assessment Scale (DSAS-1). AB - AIMS: To develop and validate a self-report measure designed to assess perceived and experienced stigma for adults with Type 1 diabetes: the Type 1 Diabetes Stigma Assessment Scale (DSAS-1). METHODS: A large item-pool (64 items) was drafted based on qualitative data from interviews with 27 adults with Type 1 diabetes. Eleven adults with Type 1 diabetes completed the draft questionnaire (responding to items using a five-point Likert scale), and participated in cognitive debriefing interviews. Based on their feedback, the item-pool was reduced and refined. Adults with Type 1 diabetes (N=898) completed an online survey including the draft stigma questionnaire (41 items) and other validated measures. Psychometric validation included principal components analysis and confirmatory factor analysis (split samples), internal consistency reliability assessment and Spearman's rho correlations. RESULTS: Scale reduction techniques resulted in 19 items (alpha=0.93). An unforced three-factor solution suggested three subscales: Treated Differently (six items, alpha=0.89); Blame and Judgement (six items, alpha=0.88); and Identity Concerns (seven items, alpha=0.89). This was corroborated with a confirmatory factor analysis, which demonstrated reasonable model fit with the three factors; less so for a single-factor model. Satisfactory concurrent, convergent and discriminant validity were demonstrated. CONCLUSIONS: The 19-item DSAS-1 is a valid and reliable measure of the perceptions and experiences of Type 1 diabetes stigma. This novel, relatively brief measure has satisfactory psychometric properties. The DSAS-1 is now available for investigations into the nature and magnitude of the relationships between diabetes stigma and diabetes self-care behaviours and outcomes. PMID- 28891211 TI - A clinical trial combining megakaryocytes and haematopoietic stem cells to promote engraftment after autologous transplantation. PMID- 28891212 TI - Heart rate in heart failure with preserved ejection fraction: target or marker? PMID- 28891213 TI - Identification of novel mutations in the HbF repressor gene BCL11A in patients with autism and intelligence disabilities. PMID- 28891214 TI - Non-redundant functions of the dimeric ABA receptor BdPYL1 in the grass Brachypodium. AB - Abiotic stresses have severe detrimental effects on agricultural productivity worldwide. Abscisic acid (ABA) levels rise in response to abiotic stresses, and play a role in coordinating physiological responses. ABA elicits its effects by binding a family of soluble receptors, increasing affinity of the receptors to type 2C phosphatases (PP2Cs) leading to phosphatase inhibition. In the current study, we conducted a comprehensive analysis of the ABA signaling pathway in the cereal model grass Brachypodium distachyon. The Brachypodium genome encodes a family of 10 functionally conserved ABA receptors. The 10th in the series, BdPYL10, encodes a defective receptor and is likely a pseudogene. Combinatorial protein interaction assay further validated computational analysis, which grouped Brachypodium ABA receptors into three subfamilies, similarly to Arabidopsis classification. Brachypodium subfamily III receptors inhibited PP2C activity in vitro and complemented Arabidopsis quadruple (pyr1/pyl1/pyl2/pyl4) mutant. BdPYL1 T-DNA mutant exhibited clear ABA hyposensitivity phenotypes during seedling establishment and in mature plants. Single receptor predominance is in agreement with high transcriptional abundance of only a small Brachypodium ABA receptors subset, harboring the higher marginal significance of BdPYL1. Our findings suggest that unlike the highly redundant ABA core signaling components of Arabidopsis, Brachypodium encompasses a more compact and specialized ABA receptor apparatus. This organization may contribute to plant adaptations to ecological niches. These results lay the groundwork for targeting the prominent ABA receptors for stress perception in grasses, and reveal functional differences and commonalities between monocots and eudicots. PMID- 28891215 TI - Pharmacokinetics of a single intramuscular injection of cefquinome in buffalo calves. AB - The objective of this study was to investigate the pharmacokinetics of cefquinome following single intramuscular (IM) administration in six healthy male buffalo calves. Cefquinome was administered intramuscularly (2 mg/kg bodyweight) and blood samples were collected prior to drug administration and up to 24 hr after injection. No adverse effects or changes were observed after the IM injection of cefquinome. Plasma concentrations of cefquinome were determined by high performance liquid chromatography. The disposition of plasma cefquinome is characterized by a mono-compartmental open model. The pharmacokinetic parameters after IM administration (mean +/- SE) were Cmax 6.93 +/- 0.58 MUg/ml, Tmax 0.5 hr, t1/2kalpha 0.16 +/- 0.05 hr, t1/2beta 3.73 +/- 0.10 hr, and AUC 28.40 +/- 1.30 MUg hr/ml after IM administration. A dosage regimen of 2 mg/kg bodyweight at 24-hr interval following IM injection of cefquinome would maintain the plasma levels required to be effective against the bacterial pathogens with MIC values <=0.39 MUg/ml. The suggested dosage regimen of cefquinome has to be validated in the disease models before recommending for clinical use in buffalo calves. PMID- 28891216 TI - The CD45+ fraction in murine adipose tissue derived stromal cells harbors immune inhibitory inflammatory cells. AB - Stromal cells in adipose tissue are useful for repair/regenerative therapy as they harbor a substantial number of mesenchymal stem cells; therefore, freshly isolated autologous uncultured adipose tissue derived stromal cells (u-ADSCs) are useful for regenerative therapy, and obviate the need for mesenchymal stem cells. We evaluated the therapeutic effect of murine u-ADSCs and sorted subsets of u ADSCs in a concanavalin A (ConA) induced murine model of hepatitis, as well as their characteristics. We found that 10-20% of u-ADSCs expressed the CD45 leukocyte-related antigen. CD68, which is a marker of macrophages (MPhis), was expressed by 50% of CD45+ u-ADSCs. About 90% of CD68+ CD45+ cells expressed CD206 antigen, which is a marker of inhibitory M2-type MPhis. Genes related to M2-type MUs were especially more highly expressed by CD45+ CD206+ u-ADSCs than by CD45- u ADSCs. CD45+ u-ADSCs inhibited the expression of cytokines/chemokines and suppressed the proliferation of splenocytes stimulated with ConA. We observed that not only whole u-ADSCs, but also the CD45+ subset of u-ADSCs ameliorated the ConA-induced hepatitis in mice. In conclusion, we show that freshly isolated murine u-ADSCs were effective against acute hepatitis, and CD45+ u-ADSCs acting phenotypically and functionally like M2-type MPhis, contributed to the repair of liver tissue undergoing inflammation. PMID- 28891218 TI - Prostate vascular flow: The effect of the ejaculation on the power doppler ultrasonographic examination. AB - Power Doppler sonography (PD) can accurately depict tissue perfusion, recognize slow flows, and is relatively angle independent. The monitoring of local blood flow by Doppler ultrasonography is helpful in differentiating prostatic physio pathological conditions, but the recognizing of physiological variables that could affect it is crucial to apply this technique in clinical practice. This study aimed to evaluate if ejaculation affects blood flow to the prostate and to state how long this effect lasts. Serial PD examinations of prostate were performed in 18 dogs (1-5 years, 6-40 kg) immediately before (T0) and after (T1) the ejaculation, and repeated 6 (T2), 18 (T3) and 24 (T4) hours later. For each examination, two representative PD images were chosen and ranked by two independent observers according to the following scoring system: 0 = mild subcapsular (S) vascularization without clear evidence of parenchymal (P) vascularization; 1 = moderate P and S vascularization; 2 = severe S and moderate P vascularization; 3 = severe P and moderate S vascularization; 4 = severe P and S vascularization. Interobserver agreement was assessed using Kappa of Cohen. Ranked data, grouped according to time, were compared by ANOVA and Tukey HSD test (p < .05). Variations in the vascular flow pattern at different times were observed for all dogs. The statistical analysis evidenced a significant difference for T0 vs T1 and vs T2 and vs T3 (p < .01), with no significant difference for T0 vs T4 (p > .05). Interobserver agreement was very good (Kappa of Cohen = 0.86). This study demonstrated a definite increase in vascular flow to the prostate after ejaculation. The present results suggest a minimum of 24 hr sexual rest before the PD examination of the gland. This result should be taken into account whenever Doppler sonography is used to evaluate potential hyperaemia in dogs suspected of having prostate abnormalities. PMID- 28891219 TI - The health and well-being of children and young people who are looked after: Findings from a face-to-face survey in Glasgow. AB - Evidence suggests children and young people who are looked after (LACYP) may have poorer health outcomes than children and young people in the general population, particularly in relation to mental health. This paper discusses findings from a survey of the health and well-being of LACYP in Glasgow. A structured questionnaire used in the 2010 Glasgow Schools Survey (GSS) was adapted and administered in face-to-face interviews with 130 young people aged 11-18 in 2014 2015 to investigate various aspects of health and well-being including physical activity, diet and sleep, smoking, alcohol and drugs, health feelings and worries, behaviours, attitudes and expectations. LACYP were more likely to report that they had tried drugs, slightly more likely to have scores indicating a high level of difficulties on the Strengths and Difficulties Questionnaire (SDQ) and less likely to report that they ate fruit and vegetables, used active transport methods to get to school and expected to go on to further or higher education; however, reported rates of physical activity, smoking and drinking were similar. LACYP were less likely to report that they had engaged in antisocial behaviour, truancy or bullying or been exposed to environmental tobacco smoke, less likely to worry or have low self-esteem, and more likely to rate their health positively. There were some variations according to placement type. The findings of this study present a more positive picture of the health and well-being of LACYP in Glasgow than might have been expected but should be treated with caution due to small sample size. Further research is needed to identify differences in relation to placement type and to determine whether being looked after might be associated with improved health and well-being outcomes for some children and young people. PMID- 28891217 TI - Reproducibility of F18-FDG PET radiomic features for different cervical tumor segmentation methods, gray-level discretization, and reconstruction algorithms. AB - Site-specific investigations of the role of radiomics in cancer diagnosis and therapy are emerging. We evaluated the reproducibility of radiomic features extracted from 18 Flourine-fluorodeoxyglucose (18 F-FDG) PET images for three parameters: manual versus computer-aided segmentation methods, gray-level discretization, and PET image reconstruction algorithms. Our cohort consisted of pretreatment PET/CT scans from 88 cervical cancer patients. Two board-certified radiation oncologists manually segmented the metabolic tumor volume (MTV1 and MTV2 ) for each patient. For comparison, we used a graphical-based method to generate semiautomated segmented volumes (GBSV). To address any perturbations in radiomic feature values, we down-sampled the tumor volumes into three gray levels: 32, 64, and 128 from the original gray-level of 256. Finally, we analyzed the effect on radiomic features on PET images of eight patients due to four PET 3D-reconstruction algorithms: maximum likelihood-ordered subset expectation maximization (OSEM) iterative reconstruction (IR) method, fourier rebinning-ML OSEM (FOREIR), FORE-filtered back projection (FOREFBP), and 3D-Reprojection (3DRP) analytical method. We extracted 79 features from all segmentation method, gray-levels of down-sampled volumes, and PET reconstruction algorithms. The features were extracted using gray-level co-occurrence matrices (GLCM), gray level size zone matrices (GLSZM), gray-level run-length matrices (GLRLM), neighborhood gray-tone difference matrices (NGTDM), shape-based features (SF), and intensity histogram features (IHF). We computed the Dice coefficient between each MTV and GBSV to measure segmentation accuracy. Coefficient values close to one indicate high agreement, and values close to zero indicate low agreement. We evaluated the effect on radiomic features by calculating the mean percentage differences (d-) between feature values measured from each pair of parameter elements (i.e. segmentation methods: MTV1 -MTV2 , MTV1 -GBSV, MTV2 -GBSV; gray levels: 64-32, 64-128, and 64-256; reconstruction algorithms: OSEM-FORE-OSEM, OSEM-FOREFBP, and OSEM-3DRP). We used |d-| as a measure of radiomic feature reproducibility level, where any feature scored |d-| +/-SD <= |25|% +/- 35% was considered reproducible. We used Bland-Altman analysis to evaluate the mean, standard deviation (SD), and upper/lower reproducibility limits (U/LRL) for radiomic features in response to variation in each testing parameter. Furthermore, we proposed U/LRL as a method to classify the level of reproducibility: High- +/-1% <= U/LRL <= +/-30%; Intermediate- +/-30% < U/LRL <= +/-45%; Low- +/-45 < U/LRL <= +/-50%. We considered any feature below the low level as nonreproducible (NR). Finally, we calculated the interclass correlation coefficient (ICC) to evaluate the reliability of radiomic feature measurements for each parameter. The segmented volumes of 65 patients (81.3%) scored Dice coefficient >0.75 for all three volumes. The result outcomes revealed a tendency of higher radiomic feature reproducibility among segmentation pair MTV1 -GBSV than MTV2 -GBSV, gray-level pairs of 64-32 and 64-128 than 64-256, and reconstruction algorithm pairs of OSEM-FOREIR and OSEM-FOREFBP than OSEM-3DRP. Although the choice of cervical tumor segmentation method, gray-level value, and reconstruction algorithm may affect radiomic features, some features were characterized by high reproducibility through all testing parameters. The number of radiomic features that showed insensitivity to variations in segmentation methods, gray-level discretization, and reconstruction algorithms was 10 (13%), 4 (5%), and 1 (1%), respectively. These results suggest that a careful analysis of the effects of these parameters is essential prior to any radiomics clinical application. PMID- 28891220 TI - The missing explanation of the false-belief advantage in bilingual children: a longitudinal study. AB - Bilingual preschoolers often perform better than monolingual children on false belief understanding. It has been hypothesized that this is due to their enhanced executive function skills, although this relationship has rarely been tested or supported. The current longitudinal study tested whether metalinguistic awareness was responsible for this advantage. Further, we examined the contributions of both executive functioning and language ability to false-belief understanding by including multiple measures of both. Seventy-eight children (n = 40 Spanish English bilingual; age M = 49.29, SD = 7.38 and, n = 38 English monolingual; age M = 47.75, SD = 6.86) were tested. A year later the children were tested again (n = 22 bilingual, n = 25 monolingual). The results indicated that language and executive function (inhibitory control) at time 1 were related to false belief in monolinguals at time 2. In contrast, bilinguals' metalinguistic performance at time 1 was the sole predictor of false belief at time 2. The different linguistic and cognitive profiles of monolinguals and bilinguals may create different pathways for their development of false-belief understanding. A video abstract of this article can be viewed at: https://youtu.be/vILn2gKjFxw. PMID- 28891221 TI - Comparative analysis of the biological effects of the endodontic bioactive cements MTA-Angelus, MTA Repair HP and NeoMTA Plus on human dental pulp stem cells. AB - AIM: To evaluate the biological effects in vitro of MTA-Angelus (MTA-Ang; Angelus, Londrina, PR, Brazil), MTA Repair HP (MTA-HP; Angelus) and NeoMTA Plus (NeoMTA-P; Avalon Biomed Inc, Bradenton, FL, USA) on human dental pulp stem cells (hDPSCs). METHODOLOGY: Cell viability and cell migration assays were performed using eluates of each material. To evaluate cell morphology and cell attachment to the different materials, hDPSCs were directly seeded onto the material surfaces and analysed by immunocytofluorescence and scanning electron microscopy, respectively. The chemical composition of the materials was determined by energy dispersive X-ray (EDX), and eluates were analysed by inductively coupled plasma mass spectrometry (ICP-MS). Statistical analysis was performed with the analysis of variance and Bonferroni or Tukey post-test (alpha < 0.05). RESULTS: Undiluted MTA-Ang, MTA-HP and NeoMTA-P displayed a significant increase in cell viability greater than that obtained using complete medium alone (control) (*P < 0.05; **P < 0.01; ***P < 0.001). Moreover, a cell migration assay revealed cell migration rates after incubation with extracts of MTA-Ang, MTA-HP and NeoMTA-P that were similar to levels obtained in the control group. In addition, stretched cytoskeletal F-actin fibres were detected in the cells treated with the three material extracts. SEM studies revealed a high degree of cell proliferation and attachment on all three materials. EDX analysis demonstrated similar weight percentages of C, O and Ca in all three materials, whilst other elements such as Al, Si and S were also found. CONCLUSIONS: MTA-Ang, MTA-HP and NeoMTA-P were associated with biological effects on hDPSCs in terms of cell proliferation, morphology, migration and attachment. PMID- 28891222 TI - Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: rationale for lower dosage in Asia. AB - AIMS: This population pharmacokinetic analysis was conducted to describe quantitatively the regional differences and sources of interpatient variability on the apparent oral clearance of alisertib. METHODS: A population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/East Asia to whom alisertib 5-150 mg once or twice daily (b.i.d.) was administered in multiple dosing schedules. The final model was used to simulate alisertib pharmacokinetics in patients in the West and East Asian regions in the single-agent schedule of 7 days of dosing in a 21-day cycle. Exposure-safety relationships for mechanism-related antiproliferative toxicities (neutropenia, mucositis and diarrhoea) were estimated by logistic regression. RESULTS: Alisertib pharmacokinetics were described by a two-compartment model with four-transit compartment absorption and linear elimination. The final model included a covariate effect of region on relative bioavailability, with patients in the East Asian region estimated to have a 52% higher bioavailability compared with Western patients. Population simulated exposure at 30 mg b.i.d. in patients in Asia was similar to that at 50 mg b.i.d. in Western patients [geometric mean (coefficient of variation) steady state area under the concentration-time curve over the dosing interval (AUC(0-tau) ): 21.4 MUM.h (52.3%) and 24.1 MUM.h (53.6%), respectively]. Exposure-AE relationships could be described for neutropenia, stomatitis and diarrhoea, supporting the lower dosage of alisertib in Asia for global clinical development. CONCLUSIONS: Model-based simulations support the achievement of similar alisertib exposures in patients in Asia who are administered a 40% lower dose compared with the Western population, thereby providing a quantitative clinical pharmacology bridging and regional dosing rationale for global drug development. PMID- 28891223 TI - Promoter architecture and transcriptional regulation of musculoskeletal embryonic nuclear protein 1b (mustn1b) gene in zebrafish. AB - BACKGROUND: Mustn1 is a specific musculoskeletal protein that plays a critical role in myogenesis and chondrogenesis in vertebrates. Whole-mount in situ hybridization revealed that mustn1b mRNAs are specifically expressed in skeletal and cardiac muscles in Zebrafish embryos. However, the precise function and the regulatory elements required for its muscle-specific expression are largely unknown. RESULTS: The purpose of this study was to explore and uncover the target genomic regions that regulate mustn1b gene expression by in vivo functional characterization of the mustn1b promoter. We report here stable expression analyses of eGFP from fluorescent transgenic reporter Zebrafish line containing a 0.8kb_mustn1b-Tol2-eGFP construct. eGFP expression was specifically found in the skeletal and cardiac muscle tissues. We show that reporter Zebrafish lines generated replicate the endogenous mustn1b expression pattern in early Zebrafish embryos. Specific site directed-mutagenesis analysis revealed that promoter activity resides in two annotated genomic regulatory regions, each one corresponding to a specific functional transcription factor binding site. CONCLUSIONS: Our data indicate that mustn1b is specifically expressed in skeletal and cardiac muscle tissues and its muscle specificity is controlled by the 0.2-kb promoter and flanking sequences and in vivo regulated by the action of two sequence-specific families of transcription factors. Developmental Dynamics 246:992-1000, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28891225 TI - Re: Comparison of management regimens following ultrasound diagnosis of non-tubal ectopic pregnancies: a retrospective cohort study. PMID- 28891224 TI - SMV1, an extremely stable thermophilic virus platform for nanoparticle trafficking in the mammalian GI tract. AB - AIMS: Analysis of the stability and safety of Sulfolobus monocaudavirus 1 (SMV1) during passage through the mammalian GI tract. METHODS AND RESULTS: A major challenge of using nano-vectors to target gut microbiome is their survival during passage through the extremely acidic and proteolytic environment of the mammalian GI tract. Here, we investigated the thermo-acidophilic archaeal virus SMV1 as a candidate therapeutic nano-vector for the distal mammalian GI tract microbiome. We investigated the anatomical distribution, vector stability and immunogenicity of this virus following oral ingestion in mice and compared these traits to the more classically used Inovirus vector M13KE. We found that SMV1 particles were highly stable under both simulated GI tract conditions (in vitro) and in mice (in vivo). Moreover, SMV1 could not be detected in tissues outside the GI tract and it elicited a nearly undetectable inflammatory response. Finally, we used human intestinal organoids (HIOs) to show that labelled SMV1 did not invade or otherwise perturb the human GI tract epithelium. CONCLUSION: Sulfolobus monocaudavirus 1 appeared stable and safe during passage though the mammalian GI tract. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study evaluating an archaeal virus as a potential therapeutic nanoparticle delivery system and it opens new possibilities for future development of novel nanoplatforms. PMID- 28891226 TI - Clinical management of peripherally inserted central catheters compared to conventional central venous catheters in patients with hematological malignancies: A large multicenter study of the REL GROUP (Rete Ematologica Lombarda - Lombardy Hematologic Network, Italy). PMID- 28891228 TI - Investigating a biomarker-driven approach to target collagen turnover in diabetic heart failure with preserved ejection fraction patients. Effect of torasemide versus furosemide on serum C-terminal propeptide of procollagen type I (DROP-PIP trial). AB - AIM: Heart failure with preserved ejection fraction (HFpEF) is associated with myocardial remodelling including severe pro-fibrotic changes contributing to an increase in left ventricular stiffness and diastolic dysfunction. Serum C terminal propeptide of procollagen type I (PIP) strongly correlates with the turnover of extracellular cardiac matrix proteins and fibrosis. Torasemide, but not furosemide, was described to reduce collagen type I synthesis in clinically unstable patients with heart failure with reduced ejection fraction. We evaluated whether its effect translated to HFpEF patients with type 2 diabetes mellitus (T2DM) and abnormal basal PIP levels. METHODS AND RESULTS: We performed a relatively small, single-centre, randomised, double-blind, two-arm parallel group, active controlled clinical trial in 35 HFpEF patients with T2DM to determine the effects of a 9-month treatment with torasemide vs. furosemide on changes of serum PIP levels. Patients with increased PIP levels (>=110 ng/mL), or evidence of structural changes with a left atrial volume index (LAVI) >29 mL/m2 and abnormal PIP levels (>=70 ng/mL), were eligible to participate. Fifteen patients were female (42%), mean age was 69 years, body mass index was 34.7 kg/m2 , 83% were in New York Heart Association class II/III. Echocardiographic characteristics showed a mean left ventricular ejection fraction of >60%, a left ventricular mass index >120 g/m2 , an E/e' ratio of 14, and a LAVI of 40 mL/m2 with a NT-proBNP of 174 ng/L and a 6-minute walk distance of 421 m. Mean per cent change in PIP was 2.63 +/- 5.68% (+/-SEM) in torasemide vs. 2.74 +/- 6.49% in furosemide (P = 0.9898) treated patients. Torasemide was not superior to furosemide in improving functional capacity, diastolic function, quality of life, or neuroendocrine activation. CONCLUSION: In this hypothesis-generating, mechanistic trial in stable HFpEF patients with T2DM, neither long-term administration of torasemide nor furosemide was associated with a significant effect on myocardial fibrosis, as assessed by serum PIP. Further studies are urgently needed in this field. More specific diuretic and anti-fibrotic treatment strategies in T2DM and/or HFpEF are warranted. PMID- 28891229 TI - Effect of different mini-volume colloid centrifugation configurations on flow cytometrically sorted sperm recovery efficiency and quality using a computer assisted semen analyzer. AB - Straws of sex-sorted sperm are usually packaged at a low concentration (e.g., ~2.1 * 106 sperm/ml) and cost significantly more than unsorted conventional semen from the same sire. In order to maximize the efficiency of using sex-sorted sperm under in vitro fertilization conditions, the selection of an appropriate sperm separation technique is essential. In this study, the effect of using different silane-coated silica colloid dilutions and layering configurations during centrifugation of sex-sorted sperm was examined over an extended period of incubation time. Sperm recovery and viability after centrifugation using the colloid separation technique were measured along with several sperm motility parameters using CASA. For this purpose, frozen and thawed sex-sorted sperm samples were centrifuged using mini-volume single-layer (40%, 60% and 80%) and mini-volume two-layer (45%/90%, 40%/80% and 30%/60%) separation configurations using PureSperm(r) . A single layer of 40% PureSperm(r) recovered significantly more sex-sorted sperm (78.07% +/- 2.28%) followed by a single layer of 80% PureSperm(r) (68.43% +/- 2.33%). The lowest sperm recovery was obtained using a two-layer PureSperm(r) dilution of 45%/90% (47.57% +/- 2.33%). Single-layer centrifugation recovered more sorted sperm (68.67% +/- 1.74%) than two layer (53.74% +/- 1.74%) (p < .0001). A single layer of 80% PureSperm(r) exhibited the highest sorted sperm viability (72.01% +/- 2.90%) after centrifugation (p < .05). The mini-volume single layer of 80% PureSperm(r) was determined to be an effective alternative to a two-layer centrifugation configuration for sex-sorted sperm selection. In addition, single-layer colloid dilution of 80% performed either as well as or significantly outperformed the other treatments, as well as the control, with regard to motility (MOT) for all time periods of analysis. PMID- 28891230 TI - Synthesis of AgWCNx Nanocomposites for the One-Step Conversion of Cyclohexene to Adipic Acid and Its Mechanistic Studies. AB - A novel catalyst composed of silver nanoparticles grafted on WCNx has been prepared by using a facile pH-adjusted method. The material reported in this study presents a non-mineral acid route for the synthesis of the industrially significant monomer adipic acid through the selective oxidation of cyclohexene. Ag has been stabilized in the hydrophobic matrix during the formation of the mesoporous silica material by using aniline as stabilizing agent. A cyclohexene conversion of 92.2 % with 96.2 % selectivity for adipic acid was observed with the AgWCNx -2 catalyst, therefore, the AgWCNx catalyst was found to be efficient for the direct conversion to adipic acid with respect to their monometallic counterparts. The energy profile diagrams for each reaction path by using the AgWCNx catalyst were studied along with their monometallic counterparts by using the Gaussian 09 package. The reported material can avoid the use of harmful phase transfer catalysts (PTC) and/or chlorinated additives, which are two among other benefits of the reported work. PMID- 28891227 TI - Expression of regulatory genes in the embryonic brain of a lizard and implications for understanding pallial organization and evolution. AB - The comparison of gene expression patterns in the embryonic brain of mouse and chicken is being essential for understanding pallial organization. However, the scarcity of gene expression data in reptiles, crucial for understanding evolution, makes it difficult to identify homologues of pallial divisions in different amniotes. We cloned and analyzed the expression of the genes Emx1, Lhx2, Lhx9, and Tbr1 in the embryonic telencephalon of the lacertid lizard Psammodromus algirus. The comparative expression patterns of these genes, critical for pallial development, are better understood when using a recently proposed six-part model of pallial divisions. The lizard medial pallium, expressing all genes, includes the medial and dorsomedial cortices, and the majority of the dorsal cortex, except the region of the lateral cortical superposition. The latter is rich in Lhx9 expression, being excluded as a candidate of dorsal or lateral pallia, and may belong to a distinct dorsolateral pallium, which extends from rostral to caudal levels. Thus, the neocortex homolog cannot be found in the classical reptilian dorsal cortex, but perhaps in a small Emx1-expressing/Lhx9-negative area at the front of the telencephalon, resembling the avian hyperpallium. The ventral pallium, expressing Lhx9, but not Emx1, gives rise to the dorsal ventricular ridge and appears comparable to the avian nidopallium. We also identified a distinct ventrocaudal pallial sector comparable to the avian arcopallium and to part of the mammalian pallial amygdala. These data open new venues for understanding the organization and evolution of the pallium. PMID- 28891232 TI - Crescentic splinter haemorrhages reflect stroke pathophysiology in hypereosinophilic syndrome. PMID- 28891231 TI - Development and characterization of electrosprayed nanoparticles for encapsulation of Curcumin. AB - Curcumin has been proven to be an effective herbal derived anti-inflammatory and antioxidant biocompatible agent. In this research, poly(lactic-co-glycolic acid) (PLGA) (as a biocompatible and generally recognized as safe (GRAS) polymer) nanoparticles containing Curcumin were electrosprayed from different polymeric solutions with different concentrations for the first time. Morphology of these nanoparticles in the absence/presence of Curcumin was evaluated by scanning electron microscope, transmission electron microscope, and X-ray photoelectron spectroscopy analyses. Perfectly shaped nanoparticles with an average size of 300 and 320 nm were observed for neat and Curcumin-loaded PLGA, respectively. Curcumin-loaded electrosprayed nanoparticles showed a normal moderate initial burst and then a prolonged release period. Weibull, Peppas, and modified Korsmeyer-Peppas models were applied to study the kinetic and mechanism of Curcumin release from PLGA nanoparticles. Results showed high specific surface area and spherical geometry of the nanoparticles. Effectiveness of the electrospray method as a promising technique for preparing Curcumin-loaded nanoparticles was confirmed in this study. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 285-292, 2018. PMID- 28891233 TI - Fetoscopic tracheal occlusion for treatment of non-isolated congenital diaphragmatic hernia. AB - Fetoscopic endotracheal occlusion (FETO) is a prenatal treatment that may increase survival in severe congenital diaphragmatic hernia (CDH). In the USA, FETO is offered for isolated severe left-sided CDH in the context of an FDA approved feasibility study. FETO in non-isolated cases of severe CDH is only performed with a compassionate use exemption from US regulatory bodies. Anomalies frequently associated with CDH include congenital cystic lesions of the lung and cardiac defects. We describe two cases of non-isolated severe left-sided CDH that underwent prenatal FETO, survived after birth and underwent postnatal surgical repair. The potential benefit of FETO in this setting is discussed. (c) 2017 John Wiley & Sons, Ltd. PMID- 28891234 TI - Retrospective analysis of nonradiation complications in dogs undergoing radiation therapy. AB - Dogs receiving radiation can develop complications unrelated to the radiation treatment. No study to date has described these complications in clinical patients undergoing multiple radiation therapy treatments. The purpose of this retrospective case-control study was to characterize the incidence and type of complications that occur in these dogs. A secondary goal was to evaluate whether patient and treatment characteristics could be identified to predict the risk of these complications. Medical records of 268 dogs receiving at least one radiation treatment at a single institution, between September, 2004 and June, 2007 were reviewed. Age, breed, gender, body weight, tumor type, tumor location, number of treatments, pre-treatment blood work abnormalities, and whether chemotherapy, glucocorticoids, or nonsteroidal anti-inflammatory drugs were given were collected. Number, type, and severity of nonradiation complications were recorded. Complications attributed to the tumor or to the radiation were excluded. Statistical analyses were performed to determine whether demographic and clinical characteristics were associated with development of a complication. General anesthesia was used for all treatments. Complications occurred in 101 (37%) cases including diarrhea, vomiting, cough, and loss of appetite, which were typically mild. Seventeen dogs (6%) developed severe complications. Eight dogs (3%) died from their complication. Dogs that developed complications were younger, received more treatments, had leukocytosis, received glucocorticoids, and were less likely to have thrombocytopenia. On multivariate analysis, number of treatments and leukocytosis were significantly associated with complications. Findings indicate that nonradiation complications are common in dogs receiving radiotherapy under general anesthesia. In this population, complications were usually mild or self-limiting. PMID- 28891235 TI - Financial arrangements for health systems in low-income countries: an overview of systematic reviews. AB - BACKGROUND: One target of the Sustainable Development Goals is to achieve "universal health coverage, including financial risk protection, access to quality essential health-care services and access to safe, effective, quality and affordable essential medicines and vaccines for all". A fundamental concern of governments in striving for this goal is how to finance such a health system. This concern is very relevant for low-income countries. OBJECTIVES: To provide an overview of the evidence from up-to-date systematic reviews about the effects of financial arrangements for health systems in low-income countries. Secondary objectives include identifying needs and priorities for future evaluations and systematic reviews on financial arrangements, and informing refinements in the framework for financial arrangements presented in the overview. METHODS: We searched Health Systems Evidence in November 2010 and PDQ-Evidence up to 17 December 2016 for systematic reviews. We did not apply any date, language, or publication status limitations in the searches. We included well-conducted systematic reviews of studies that assessed the effects of financial arrangements on patient outcomes (health and health behaviours), the quality or utilisation of healthcare services, resource use, healthcare provider outcomes (such as sick leave), or social outcomes (such as poverty, employment, or financial burden of patients, e.g. out-of-pocket payment, catastrophic disease expenditure) and that were published after April 2005. We excluded reviews with limitations important enough to compromise the reliability of the findings. Two overview authors independently screened reviews, extracted data, and assessed the certainty of evidence using GRADE. We prepared SUPPORT Summaries for eligible reviews, including key messages, 'Summary of findings' tables (using GRADE to assess the certainty of the evidence), and assessments of the relevance of findings to low income countries. MAIN RESULTS: We identified 7272 reviews and included 15 in this overview, on: collection of funds (2 reviews), insurance schemes (1 review), purchasing of services (1 review), recipient incentives (6 reviews), and provider incentives (5 reviews). The reviews were published between 2008 and 2015; focused on 13 subcategories; and reported results from 276 studies: 115 (42%) randomised trials, 11 (4%) non-randomised trials, 23 (8%) controlled before-after studies, 51 (19%) interrupted time series, 9 (3%) repeated measures, and 67 (24%) other non-randomised studies. Forty-three per cent (119/276) of the studies included in the reviews took place in low- and middle-income countries. Collection of funds: the effects of changes in user fees on utilisation and equity are uncertain (very low-certainty evidence). It is also uncertain whether aid delivered under the Paris Principles (ownership, alignment, harmonisation, managing for results, and mutual accountability) improves health outcomes compared to aid delivered without conforming to those principles (very low-certainty evidence). Insurance schemes: community-based health insurance may increase service utilisation (low-certainty evidence), but the effects on health outcomes are uncertain (very low-certainty evidence). It is uncertain whether social health insurance improves utilisation of health services or health outcomes (very low-certainty evidence). Purchasing of services: it is uncertain whether increasing salaries of public sector healthcare workers improves the quantity or quality of their work (very low certainty evidence). Recipient incentives: recipient incentives may improve adherence to long-term treatments (low-certainty evidence), but it is uncertain whether they improve patient outcomes. One-time recipient incentives probably improve patient return for start or continuation of treatment (moderate-certainty evidence) and may improve return for tuberculosis test readings (low-certainty evidence). However, incentives may not improve completion of tuberculosis prophylaxis, and it is uncertain whether they improve completion of treatment for active tuberculosis. Conditional cash transfer programmes probably lead to an increase in service utilisation (moderate-certainty evidence), but their effects on health outcomes are uncertain. Vouchers may improve health service utilisation (low-certainty evidence), but the effects on health outcomes are uncertain (very low-certainty evidence). Introducing a restrictive cap may decrease use of medicines for symptomatic conditions and overall use of medicines, may decrease insurers' expenditures on medicines (low-certainty evidence), and has uncertain effects on emergency department use, hospitalisations, and use of outpatient care (very low-certainty evidence). Reference pricing, maximum pricing, and index pricing for drugs have mixed effects on drug expenditures by patients and insurers as well as the use of brand and generic drugs. Provider incentives: the effects of provider incentives are uncertain (very low-certainty evidence), including: the effects of provider incentives on the quality of care provided by primary care physicians or outpatient referrals from primary to secondary care, incentives for recruiting and retaining health professionals to serve in remote areas, and the effects of pay-for-performance on provider performance, the utilisation of services, patient outcomes, or resource use in low-income countries. AUTHORS' CONCLUSIONS: Research based on sound systematic review methods has evaluated numerous financial arrangements relevant to low-income countries, targeting different levels of the health systems and assessing diverse outcomes. However, included reviews rarely reported social outcomes, resource use, equity impacts, or undesirable effects. We also identified gaps in primary research because of uncertainty about applicability of the evidence to low-income countries. Financial arrangements for which the effects are uncertain include external funding (aid), caps and co-payments, pay-for-performance, and provider incentives. Further studies evaluating the effects of these arrangements are needed in low-income countries. Systematic reviews should include all outcomes that are relevant to decision-makers and to people affected by changes in financial arrangements. PMID- 28891237 TI - The Incidence and Prevalence of Systemic Lupus Erythematosus in San Francisco County, California: The California Lupus Surveillance Project. AB - OBJECTIVE: Estimates of the incidence and prevalence of systemic lupus erythematosus (SLE) in the US have varied widely. The purpose of this study was to conduct the California Lupus Surveillance Project (CLSP) to determine credible estimates of SLE incidence and prevalence, with a special focus on Hispanics and Asians. METHODS: The CLSP, which is funded by the Centers for Disease Control and Prevention, is a population-based registry of individuals with SLE residing in San Francisco County, CA, from January 1, 2007 through December 31, 2009. Data sources included hospitals, rheumatologists, nephrologists, commercial laboratories, and a state hospital discharge database. We abstracted medical records to ascertain SLE cases, which we defined as patients who met >=4 of the 11 American College of Rheumatology classification criteria for SLE. We estimated crude and age-standardized incidence and prevalence, which were stratified by sex and race/ethnicity. RESULTS: The overall age-standardized annual incidence rate was 4.6 per 100,000 person-years. The average annual period prevalence was 84.8 per 100,000 persons. The age-standardized incidence rate in women and men was 8.6 and 0.7 per 100,000 person-years, respectively. This rate was highest among black women (30.5), followed by Hispanic women (8.9), Asian women (7.2), and white women (5.3). The age-standardized prevalence in women per 100,000 persons was 458.1 in blacks, 177.9 in Hispanics, 149.7 in Asians, and 109.8 in whites. Capture-recapture modeling estimated 33 additional incident cases and 147 additional prevalent cases. CONCLUSION: Comprehensive methods that include intensive case-finding provide more credible estimates of SLE in Hispanics and Asians, and confirm racial and ethnic disparities in SLE. The disease burden of SLE is highest in black women, followed by Hispanic women, Asian women, and white women. PMID- 28891236 TI - A disease-associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity. AB - Mutations in G protein-coupled receptors (GPCRs) that increase constitutive signaling activity can cause human disease. A de novo C-terminal mutation (R1465W) in the adhesion GPCR BAI2 (also known as ADGRB2) was identified in a patient suffering from progressive spastic paraparesis and other neurological symptoms. In vitro studies revealed that this mutation strongly increases the constitutive signaling activity of an N-terminally cleaved form of BAI2, which represents the activated form of the receptor. Further studies dissecting the mechanism(s) underling this effect revealed that wild-type BAI2 primarily couples to Galphaz , with the R1465W mutation conferring increased coupling to Galphai . The R1465W mutation also increases the total and surface expression of BAI2. The mutation has no effect on receptor binding to beta-arrestins, but does perturb binding to the endocytic protein endophilin A1, identified here as a novel interacting partner for BAI2. These studies provide new insights into the signaling capabilities of the adhesion GPCR BAI2/ADGRB2 and shed light on how an apparent gain-of-function mutation to the receptor's C-terminus may lead to human disease. PMID- 28891238 TI - Excised larynx evaluation of subthyroid cartilage approach to medialization thyroplasty. AB - OBJECTIVES/HYPOTHESIS: To describe an alternative approach to medialization thyroplasty involving dissection underneath the thyroid cartilage with placement of a Gore-Tex implant, and to evaluate its effect on a range of phonatory measures using an excised canine larynx model. STUDY DESIGN: Animal model. METHODS: On each of eight excised canine larynges, the conditions of normal, paralysis, medialization thyroplasty by standard transthyroid cartilage approach, and medialization thyroplasty by experimental subthyroid cartilage approach were performed. Aerodynamic, acoustic, and mucosal wave parameters were measured for each condition. RESULTS: Compared to the vocal fold paralysis state, both the transthyroid and subthyroid approaches for Gore-Tex insertion resulted in significant decreases in phonation threshold pressure and phonation threshold flow. Both approaches also significantly decreased percent jitter, decreased percent shimmer, and improved signal-to-noise ratio. The mucosal wave was preserved after insertion of the Gore-Tex implant for both approaches. For all the phonatory measures except phonation threshold flow, there were no significant differences between the transthyroid and subthyroid approaches. CONCLUSIONS: Gore Tex implantation via a subthyroid approach in an excised canine larynx model can produce effective medialization, preserve the mucosal wave, and significantly improve aerodynamic and acoustic parameters without meaningful difference compared to a traditional transthyroid approach. The subthyroid approach does not require creation of a thyroid cartilage window and could be a potentially valuable alternative method of performing medialization thyroplasty. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:675-681, 2018. PMID- 28891239 TI - Understanding the association between hypertensive disorders of pregnancy and peripartum cardiomyopathy. PMID- 28891240 TI - Introduction to the JSO enhanced recover after surgery seminar edition. PMID- 28891241 TI - Infliximab for severe colitis associated with nivolumab followed by ipilimumab. PMID- 28891242 TI - Inorganic vs. organic nitrates for heart failure with preserved ejection fraction: it's not all in your head! PMID- 28891244 TI - Personalized/Precision Dentistry - The Future of Dentistry? PMID- 28891243 TI - The use of mobile health applications in school dental screening. PMID- 28891246 TI - Continuing Professional Development Quiz. PMID- 28891247 TI - Synthesis of dual thermo- and pH-sensitive poly(N-isopropylacrylamide-co-acrylic acid)-grafted cellulose nanocrystals by reversible addition-fragmentation chain transfer polymerization. AB - Free and cellulose nanocrystals (CNCs)-grafted block copolymers of acrylic acid and N-isopropylacrylamide with various poly(N-isopropylacrylamide) (PNIPAAm) block lengths as dual temperature- and pH-sensitive materials were synthesized by reversible addition-fragmentation chain transfer polymerization via an R-approach method. Controlling lower critical solution temperature (LCST) of the products by changing the PNIPAAm block length, addition of CNC, and variation of pH was studied. The free and CNC-grafted block copolymers were analyzed by Fourier transform infrared and proton nuclear magnetic resonance. LCST of copolymers was measured by dynamic light scattering using their hydrodynamic diameters. The block copolymers reversibly form core-corona structure with PNIPAAm as core and poly(acrylic acid) (PAA) as shell above LCST at higher pH values. LCST point shifts to higher temperatures by increasing pH and CNC content and also lowering PNIPAAm block length. By decreasing pH below 4 at certainly low temperatures, PAA becomes core and PNIPAAm forms corona. Thermal behavior of the CNC-grafted polymers was studied by thermal gravimetric analysis and differential scanning calorimetry. Morphology of the polymer-grafted CNC was examined by X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 231-243, 2018. PMID- 28891249 TI - Poly(vinylphosphonic acid-co-acrylic acid) hydrogels: The effect of copolymer composition on osteoblast adhesion and proliferation. AB - There is a clinical need for a synthetic bone graft substitute that can be used at sites of surgical intervention to promote bone regeneration. Poly(vinylphosphonic acid-co-acrylic acid) (PVPA-co-AA) has recently been identified as a potential candidate for use in bone tissue scaffolds. It is hypothesized that PVPA-co-AA can bind to divalent calcium ions on bone mineral surfaces to control matrix mineralization and promote bone formation. In this study, hydrogels of PVPA-co-AA have been produced and the effect of copolymer composition on the structure and properties of the gels was investigated. It was found that an increase in VPA content led to the production of hydrogels with high porosities and greater swelling capacities. Consequently, improved cell adhesion and proliferation was observed on these hydrogels, as well as superior cell spreading morphologies. Furthermore, whereas poly(acrylic acid) gels were shown to be relatively brittle, an increase in VPA content created more flexible hydrogels that can be more easily molded into bone defect sites. Therefore, this work demonstrates that the mechanical and cell adhesion properties of PVPA-co-AA hydrogels can be tuned for the specific application by altering the copolymer composition. (c) 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 255-264, 2018. PMID- 28891248 TI - Integrin-FAK-CDC42-PP1A signaling gnaws at YAP/TAZ activity to control incisor stem cells. AB - How epithelial tissues are able to self-renew to maintain homeostasis and regenerate in response to injury remains a persistent question. The transcriptional effectors YAP and TAZ are increasingly being recognized as central mediators of epithelial stem cell biology, and a wealth of recent studies have been directed at understanding the control and activity of these factors. Recent work by Hu et al. has added to this knowledge, as they identify an Integrin-FAK-CDC42-PP1A signaling cascade that directs nuclear YAP/TAZ activity in stem cell populations of the mouse incisor, and define convergence on mTORC1 signaling as an important mediator of the proliferation of these cells. Here, we review recent studies on YAP/TAZ function and regulation in epithelial tissue specific stem cells, merging the Hu et al. study together with our current knowledge of YAP/TAZ. PMID- 28891250 TI - Guidelines for using Bsoft for high resolution reconstruction and validation of biomolecular structures from electron micrographs. AB - Cryo-electron microscopy (cryoEM) is becoming popular as a tool to solve biomolecular structures with the recent availability of direct electron detectors allowing automated acquisition of high resolution data. The Bsoft software package, developed over 20 years for analyzing electron micrographs, offers a full workflow for validated single particle analysis with extensive functionality, enabling customization for specific cases. With the increasing use of cryoEM and its automation, proper validation of the results is a bigger concern. The three major validation approaches, independent data sets, resolution limited processing, and coherence testing, can be incorporated into any Bsoft workflow. Here, the main workflow is divided into four phases: (i) micrograph preprocessing, (ii) particle picking, (iii) particle alignment and reconstruction, and (iv) interpretation. Each of these phases represents a conceptual unit that can be automated, followed by a check point to assess the results. The aim in the first three phases is to reconstruct one or more validated maps at the best resolution possible. Map interpretation then involves identification of components, segmentation, quantification, and modeling. The algorithms in Bsoft are well established, with future plans focused on ease of use, automation and institutionalizing validation. PMID- 28891251 TI - Dose/Exposure-Response Modeling to Support Dosing Recommendation for Phase III Development of Baricitinib in Patients with Rheumatoid Arthritis. AB - Baricitinib is an oral inhibitor of Janus kinases (JAKs), selective for JAK1 and 2. It demonstrated dose-dependent efficacy in patients with moderate-to-severe rheumatoid arthritis (RA) in a phase IIb study up to 24 weeks. Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed to characterize concentration-time profiles and dose/exposure-response (D/E-R) relationships for the key efficacy (proportion of patients achieving American College of Rheumatology 20%, 50%, or 70% response rate) and safety endpoints (incidence of anemia) for the phase IIb study. The modeling suggested that 4 mg q.d. was likely to offer the optimum risk/benefit balance, whereas 2 mg q.d. had the potential for adequate efficacy. In addition, at the same total daily dose, a twice-daily regimen is not expected to provide an advantage over q.d. dosing for the efficacy or safety endpoints. The model-based simulations formed the rationale for key aspects of dosing, such as dose levels and dosing frequency for phase III development. PMID- 28891252 TI - The Incidence and Prevalence of Systemic Lupus Erythematosus in New York County (Manhattan), New York: The Manhattan Lupus Surveillance Program. AB - OBJECTIVE: The Manhattan Lupus Surveillance Program (MLSP) is a population-based registry designed to determine the prevalence of systemic lupus erythematosus (SLE) in 2007 and the incidence from 2007 to 2009 among residents of New York County (Manhattan), New York, and to characterize cases by race/ethnicity, including Asians and Hispanics, for whom data are lacking. METHODS: We identified possible SLE cases from hospital records, rheumatologist records, and administrative databases. Cases were defined according to the American College of Rheumatology (ACR) classification criteria, the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria, or the treating rheumatologist's diagnosis. Rates among Manhattan residents were age standardized, and capture-recapture analyses were conducted to assess case underascertainment. RESULTS: By the ACR definition, the age-standardized prevalence and incidence rates of SLE were 62.2 and 4.6 per 100,000 person-years, respectively. Rates were ~9 times higher in women than in men for prevalence (107.4 versus 12.5) and incidence (7.9 versus 1.0). Compared with non-Hispanic white women (64.3), prevalence was higher among non-Hispanic black (210.9), Hispanic (138.3), and non-Hispanic Asian (91.2) women. Incidence rates were higher among non-Hispanic black women (15.7) compared with non-Hispanic Asian (6.6), Hispanic (6.5), and non-Hispanic white (6.5) women. Capture-recapture adjustment increased the prevalence and incidence rates (75.9 and 6.0, respectively). Alternate SLE definitions without capture-recapture adjustment revealed higher age-standardized prevalence and incidence rates (73.8 and 6.2, respectively, by the SLICC definition and 72.6 and 5.0 by the rheumatologist definition) than the ACR definition, with similar patterns by sex and race/ethnicity. CONCLUSION: The MLSP confirms findings from other registries on disparities by sex and race/ethnicity, provides new estimates among Asians and Hispanics, and provides estimates using the SLICC criteria. PMID- 28891253 TI - Effect of traditional Chinese and Western medicine on nocturnal enuresis in children and indicators of treatment success: Randomized controlled trial. AB - BACKGROUND: Nocturnal enuresis (NE) is a common pediatric developmental disorder. Desmopressin is frequently used for NE and is an evidence-based therapy. Suoquan capsule is a Chinese medicine commonly used for treating NE in children but is poorly understood by most scholars. METHODS: A total of 369 children with NE were randomized to receive either suoquan, desmopressin plus suoquan, desmopressin, or behavioral intervention for 2 months, and the response rates evaluated. Subsequently, the viable demographic factors that could lead to success were investigated on logistic regression analysis. Moreover, after 3 months of follow up, the relapse rate was investigated. RESULTS: The complete response (CR) rate in the desmopressin plus suoquan group (37.5%) was higher than that in the behavioral intervention group (6.3%, P < 0.007). The desmopressin group had a lower CR rate (22.5%) and a higher non-response rate (25.0%) than the desmopressin plus suoquan group (non-response rate, 21.9%; P > 0.007). The relapse rate in the desmopressin group was significantly higher than that in the desmopressin plus suoquan group (72.2% vs. 30.6%, P < 0.007). On Multivariate analysis, treatment group, NE frequency, and age were independent predictors of CR at 2 months (P < 0.05). CONCLUSIONS: Combined traditional Chinese and Western treatment in children with NE is effective and has a low relapse rate. NE frequency, treatment method, and age are important predictive factors for CR after treatment. PMID- 28891254 TI - Fetal isovolumetric time intervals as a marker of abnormal cardiac function in fetal anemia from homozygous alpha thalassemia-1 disease. AB - OBJECTIVE: To determine whether fetal isovolumetric time intervals can be an early sonographic marker of fetal anemia in fetuses with homozygous alpha thalassemia-1. METHODS: Pregnancies at risk for fetal homozygous alpha thalassemia-1 disease at 18-22 weeks were recruited before cordocentesis for hemoglobin typing. Isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT) intervals were measured by placing pulsed wave Doppler sample volume within the left ventricle to obtain the mitral and aortic waveform. Time intervals were compared between the affected group of homozygous alpha thalassemia-1 fetuses and the unaffected group. RESULTS: Among 70 fetuses at risk, 28 cases were diagnosed as affected by homozygous alpha thalassemia-1 disease. Mean ICT and ICT + IRT intervals in the affected group were significantly longer than in the unaffected group (47.9 +/- 12.5 ms vs 35.0 +/- 6.7 ms, p < 0.001; and 96.2 +/- 13.6 ms vs 80.9 +/- 10.6 ms, p < 0.001. ICT effectively predicted affected fetuses with 71.4% sensitivity and 78.6% specificity using a cutoff value >=40 ms. CONCLUSIONS: Isovolumetric contraction time was significantly prolonged in fetal anemia from homozygous alpha thalassemia-1 during the early stage of hydropic changes. Because of its simple measurement and high efficacy, ICT can be a useful marker for prenatal screening of abnormal cardiac function in fetal anemia. (c) 2017 John Wiley & Sons, Ltd. PMID- 28891255 TI - Do patients benefit from orthognathic surgery? A systematic review on the effects of elective orthognathic surgery on psychosocial functioning and patient satisfaction. AB - The main purpose of this systematic review was to determine the current state of evidence regarding patient satisfaction with, and the impact of, orthognathic surgery on psychosocial functioning of patients 17 yr of age and older. A secondary aim was to determine whether individuals with psychiatric disorders and mental health conditions are more likely to be dissatisfied with the treatment outcome than those without. We systematically searched PubMed, PsycInfo, and Embase for relevant studies (up to 6 June 2016). After selection of articles we determined the Directness of Evidence (DoE) and Risk of Bias (RoB). We identified 3,948 studies (1,053 studies in Pubmed, 2,023 in Embase, and 872 in PsycInfo). Of these, 87 remained after screening of title and abstract, while after full-text screening only nine remained for DoE and RoB assessment. All nine studies had a high RoB and a low or moderate DoE. The quality of the methods of studies, published to date, on the effects of orthognathic surgery on patient satisfaction or the psychosocial impact carry a high RoB. Therefore, these do not allow inferences on the effects of orthognathic surgery on patient satisfaction or their psychosocial functioning. PMID- 28891256 TI - Composition and Variation Analysis of the T Cell Receptor beta-Chain Complementarity Determining Region 3 Repertoire in Neonatal Sepsis. AB - T cell receptor (TCR) diversity is clearly related to protection from infection. However, the characteristics of TCR diversity in neonates are not clear. In this study, we investigated the TCR diversity of neonates with sepsis. Twenty neonates with severe sepsis and eight matched neonates without infection were enrolled in the study. For the neonates with sepsis, EDTA-anticoagulated blood was collected on day 1 after the diagnosis of sepsis and on day 7 of treatment. For the neonates without infection, blood was collected one time. DNA was extracted from peripheral blood mononuclear cells. The complementarity determining region 3 (CDR3) gene was analysed by multiplex PCR and high-throughput sequencing. The CDR3 types and lengths were similar in patients and healthy controls. There was a significant difference in VJ gene usage among the three groups. Compared to the healthy neonates, the neonates with sepsis had different VJ pairs and generated different clonotypes. Although the TCR beta-chain diversity was generally lower in the neonates with sepsis, there was no significant difference in TCR beta chain diversity between the patients and the healthy controls. Our data showed the characteristics of the TCR repertoire in neonates with sepsis, which represents a potentially valuable data set. This result is useful for understanding neonatal susceptibility to infection. PMID- 28891257 TI - The K+ channel KZM2 is involved in stomatal movement by modulating inward K+ currents in maize guard cells. AB - Stomata are the major gates in plant leaf that allow water and gas exchange, which is essential for plant transpiration and photosynthesis. Stomatal movement is mainly controlled by the ion channels and transporters in guard cells. In Arabidopsis, the inward Shaker K+ channels, such as KAT1 and KAT2, are responsible for stomatal opening. However, the characterization of inward K+ channels in maize guard cells is limited. In the present study, we identified two KAT1-like Shaker K+ channels, KZM2 and KZM3, which were highly expressed in maize guard cells. Subcellular analysis indicated that KZM2 and KZM3 can localize at the plasma membrane. Electrophysiological characterization in HEK293 cells revealed that both KZM2 and KZM3 were inward K+ (Kin ) channels, but showing distinct channel kinetics. When expressed in Xenopus oocytes, only KZM3, but not KZM2, can mediate inward K+ currents. However, KZM2 can interact with KZM3 forming heteromeric Kin channel. In oocytes, KZM2 inhibited KZM3 channel conductance and negatively shifted the voltage dependence of KZM3. The activation of KZM2-KZM3 heteromeric channel became slower than the KZM3 channel. Patch clamping results showed that the inward K+ currents of maize guard cells were significantly increased in the KZM2 RNAi lines. In addition, the RNAi lines exhibited faster stomatal opening after light exposure. In conclusion, the presented results demonstrate that KZM2 functions as a negative regulator to modulate the Kin channels in maize guard cells. KZM2 and KZM3 may form heteromeric Kin channel and control stomatal opening in maize. PMID- 28891258 TI - A scoping review of nursing workforce planning and forecasting research. AB - AIM: This study will critically evaluate forecasting models and their content in workforce planning policies for nursing professionals and to highlight the strengths and the weaknesses of existing approaches. BACKGROUND: Although macro level nursing workforce issues may not be the first thing that many nurse managers consider in daily operations, the current and impending nursing shortage in many countries makes nursing specific models for workforce forecasting important. METHOD: A scoping review was conducted using a directed and summative content analysis approach to capture supply and demand analytic methods of nurse workforce planning and forecasting. The literature on nurse workforce forecasting studies published in peer-reviewed journals as well as in grey literature was included in the scoping review. RESULTS: Thirty six studies met the inclusion criteria, with the majority coming from the USA. Forecasting methods were biased towards service utilization analyses and were not consistent across studies. CONCLUSION: Current methods for nurse workforce forecasting are inconsistent and have not accounted sufficiently for socioeconomic and political factors that can influence workforce projections. Additional studies examining past trends are needed to improve future modelling. IMPLICATIONS FOR NURSING MANAGEMENT: Accurate nursing workforce forecasting can help nurse managers, administrators and policy makers to understand the supply and demand of the workforce to prepare and maintain an adequate and competent current and future workforce. PMID- 28891259 TI - Mapping biopsy for Buruli ulcer self-medicated with occlusive dressing. AB - Buruli ulcer is the third most common mycobacterial infection next to tuberculosis and leprosy caused by Mycobacterium ulcerans. Although it affects the skin, subcutaneous tissues, muscles and sometimes bones, there is no reliable evidence to determine the extent of debridement. We present here a case of Buruli ulcer treated successfully with a preoperative mapping biopsy procedure, which had been self-medicated with occlusive dressing. Because Buruli ulcer is accompanied by subtle pain, patients and clinicians tend to initially treat the ulcer with occlusive dressing therapy, which leads to the misdiagnosis of Buruli ulcer as a common bacterial infection only judging from bacterial culture of the surface of the ulcer. We propose the efficacy of mapping biopsy for treating Buruli ulcer. PMID- 28891260 TI - Rabacfosadine for relapsed canine B-cell lymphoma: Efficacy and adverse event profiles of 2 different doses. AB - Rabacfosadine (RAB), a novel double prodrug of the acyclic nucleotide phosphonate PMEG, preferentially targets neoplastic lymphocytes with reduced off target toxicity. Historical studies have suggested that every 21-day dosing is effective with acceptable toxicity. The purpose of this study was to evaluate RAB's safety and efficacy at 2 different doses every 21 days in dogs with relapsed B-cell lymphoma. Dogs that had failed 1 doxorubicin-based chemotherapy protocol were eligible for inclusion in this prospective trial. Once enrolled, dogs were randomized to receive RAB at either 0.82 mg/kg or 1.0 mg/kg as a 30-minute IV infusion every 21 days for up to 5 treatments. Response assessment and adverse event (AE) evaluation were performed every 21 days via VCOG criteria. Fifty dogs were enrolled, with 16 treated at 0.82 mg/kg and 34 treated at 1.0 mg/kg. The overall response rate was 74%, with 45% of dogs experiencing a complete response (CR). The median progression free intervals (PFIs) were 108 days, 172 days and 203 days for all dogs, all responders, and all CRs, respectively. Response rates and PFIs were similar in both treatment groups. The incidence of AEs, dose delays, dose reductions and withdrawals were not statistically different between the 2 groups. The AEs observed were similar to those previously reported and included hematologic, gastrointestinal, dermatologic and pulmonary AEs. One dog had grade 5 pulmonary fibrosis; otherwise, AEs resolved with supportive treatment. Rabacfosadine is a generally well tolerated, effective chemotherapy option for dogs with relapsed B-cell lymphoma. PMID- 28891261 TI - Home is where the heart is when it comes to transitional care in heart failure, but is it the only way to improve health outcomes? PMID- 28891262 TI - More than constipation - bowel symptoms in Parkinson's disease and their connection to gut microbiota. AB - BACKGROUND AND PURPOSE: The majority of Parkinson's disease (PD) patients suffer from gastrointestinal symptoms of which constipation is considered the most prominent. Recently, in addition to constipation, a diagnosis of irritable bowel syndrome (IBS) was also found to be associated with increased PD risk. Gut microbiota alterations have been reported in IBS and recently also in PD. IBS like bowel symptoms in PD and their possible connection to other non-motor symptoms and faecal microbiota were assessed. METHODS: This case-control study compared 74 PD patients with 75 controls without any signs of parkinsonism or potential premotor symptoms. IBS-like symptoms were assessed using the Rome III questionnaire. The non-motor symptoms were assessed using the Non-Motor Symptoms Questionnaire and Non-Motor Symptom Scale. Faecal microbiota were assessed by pyrosequencing of the V1-V3 regions of the bacterial 16S ribosomal RNA gene. RESULTS: Symptoms that were IBS-like were significantly more prevalent in PD patients than in controls (24.3% vs. 5.3%; P = 0.001). Criteria for functional constipation were met by 12.2% of PD patients and 6.7% of controls (P = 0.072). PD patients with IBS-like symptoms had more non-motor symptoms and a lower faecal abundance of Prevotella bacteria than those without IBS-like symptoms. CONCLUSION: Our results indicate that PD patients may suffer from colonic dysfunction beyond pure constipation. Therefore, a more comprehensive assessment of bowel symptoms could provide valuable information. The lower abundance of Prevotella bacteria in PD patients with IBS-like symptoms suggests that the microbiota-gut-brain axis may be implicated in the gastrointestinal dysfunction of PD patients. PMID- 28891263 TI - Superaerophobic Ultrathin Ni-Mo Alloy Nanosheet Array from In Situ Topotactic Reduction for Hydrogen Evolution Reaction. AB - Hydrogen evolution reaction (HER) has prospect to becoming clean and renewable technology for hydrogen production and Ni-Mo alloy is among the best HER catalysts in alkaline electrolytes. Here, an in situ topotactic reduction method to synthesize ultrathin 2D Ni-Mo alloy nanosheets for electrocatalytic hydrogen evolution is reported. Due to its ultrathin structure and tailored composition, the as-synthesized Ni-Mo alloy shows an overpotential of 35 mV to reach a current density of 10 mA cm-2 , along with a Tafel slope of 45 mV decade-1 , demonstrating a comparable intrinsic activity to state-of-art commercial Pt/C catalyst. Besides, the vertically aligned assemble structure of the 2D NiMo nanosheets on conductive substrate makes the electrode "superaerophobic," thus leading to much faster bubble releasing during HER process and therefore shows faster mass transfer behavior at high current density as compared with drop drying Pt/C catalyst on the same substrate. Such in situ topotactic conversion finds a way to design and fabricate low-cost, earth-abundant non-noble metal based ultrathin 2D nanostructures for electrocatalytic issues. PMID- 28891264 TI - Hormonal and genetic factors interact to control aromatase expression in the developing brain. AB - Brain expression of the enzyme P450-aromatase has been studied extensively. Subsequent to the aromatisation hypothesis having established brain aromatase as a key factor to convert gonadal testosterone to oestradiol, several studies have investigated the regulation of aromatase during the critical period of brain sexual differentiation. We review previous and recent findings concerning regulation of aromatase. The role of gonadal hormones, sex chromosome genes and neurosteroids is analysed in terms of their contribution to aromatase expression, as well as implications for the organisational effect of steroids during development. PMID- 28891265 TI - Altered bodily self-consciousness in multiple sclerosis. AB - In this study, we assessed the impact of multiple sclerosis (MS) on bodily self consciousness (BSC) using the Rubber Hand Illusion. Patients with MS showed a dissociation between body ownership and self-location: they did report an explicit ownership of the rubber hand, but they did not point towards it, showing a defective ability of localizing body parts in space. This evidence indicates that MS may affect selective components of BSC, whose impairment may contribute to, and even worsen, the functional disability of MS. PMID- 28891266 TI - Analysis of outcomes achieved with squamous cell carcinomas of the anus in a single university hospital over the last two decades: Clinical response rate, relapse and survival of 190 patients. AB - BACKGROUND AND OBJECTIVES: We reviewed our series of anal squamous cell carcinomas (ASCC) treated over the last two decades. METHODS: ASCC patients undergoing treatment at the Leicester Royal Infirmary between 1998 and 2016 were selected. Age, gender, pathological tumor characteristics, treatment adopted, the overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) at 5-year follow-up were recorded and calculated. RESULTS: A total of 190 ASCC were reviewed, of these 64.2% (n = 122) received primary radical chemoradiotherapy. Complete response rate was 92.6% (n = 113) and four patients with residual disease underwent a salvage APER. Twenty-eight patients experienced recurrent disease (23.0%) either systemic (n = 8), local (n = 14), or both (n = 6); six had a salvage APER. Complete follow-up data are available for 63.1% patients (77/122). Overall, the locoregional failure rate of primary chemoradiotherapy (residual + recurrent disease) was present in 29 patients (29/122; 23.8%). OS was 41.6% CSS was 69.2% and DFS 60.0% at 5 years follow-up. CONCLUSIONS: In our series of ASCC primary chemoradiotherapy had achieved significant initial complete response rates, however, long term-follow ups still present systemic and local recurrences. APR is able to treat 30% of the pelvic recurrences (6/20), the others are either associated with systemic disease or locally inoperable masses. PMID- 28891268 TI - Pediatric respiratory tract diseases: Chronological trends and perspectives. AB - BACKGROUND: The aim of this study was to describe the epidemiological profile of childhood respiratory tract diseases (RTD) in the region of Sfax, Tunisia, and to evaluate their trends over a 13 year period. METHODS: We conducted a retrospective study of all children hospitalized with RTD aged under 14 years. We collected data from the regional morbidity register of the university hospital of Sfax from 2003 to 2015. RESULTS: A total of 10 797 RTD patients were enrolled from 49 880 pediatric hospitalizations (21.7%). A male predominance was noted (60%). The median age was 8 months (IQR, 2-36 months). Acute bronchitis (AB) accounted for 53.8%, followed by asthma (15%), pneumonia (14%) and acute upper respiratory infection (AURI; 7.2%). The hospital incidence rate (HIR) of RTD was 34/10 000 inhabitants/year. It was 18.2; 5.07; 4.7 and 2.4/10 000 inhabitants for AB, asthma, pneumonia and AURI, respectively. We noted a significant increase in the HIR of RTD with an annual percentage change (APC) of 10.94% (P < 0.001); in the HIR of AB (APC, 5.27%; P < 0.001); and in asthma HIR (APC, 11.2%; P < 0.001). Otherwise, a significant decrease in AURI HIR was observed (APC, -8.8%; P < 0.001). AB lethality rate increased significantly, with an APC of 7.4% (P < 0.001). Projected trends analysis up to 2024 showed a significant rise in AB and in asthma, while AURI would significantly decrease. CONCLUSIONS: RTD continues to be a serious health problem over time in terms of morbidity and mortality. Preventive and curative strategies are needed urgently. PMID- 28891269 TI - Interpreting clinical trial results by deductive reasoning: In search of improved trial design. AB - Clinical trial results are often interpreted by inductive reasoning, in a trial design-limited manner, directed toward modifications of the current clinical practice. Deductive reasoning is an alternative in which results of relevant trials are combined in indisputable premises that lead to a conclusion easily testable in future trials. PMID- 28891267 TI - Needle and syringe programmes and opioid substitution therapy for preventing HCV transmission among people who inject drugs: findings from a Cochrane Review and meta-analysis. AB - AIMS: To estimate the effects of needle and syringe programmes (NSP) and opioid substitution therapy (OST), alone or in combination, for preventing acquisition of hepatitis C virus (HCV) in people who inject drugs (PWID). METHODS: Systematic review and meta-analysis. Bibliographic databases were searched for studies measuring concurrent exposure to current OST (within the last 6 months) and/or NSP and HCV incidence among PWID. High NSP coverage was defined as regular NSP attendance or >= 100% coverage (receiving sufficient or greater number of needles and syringes per reported injecting frequency). Studies were assessed using the Cochrane risk of bias in non-randomized studies tool. Random-effects models were used in meta-analysis. RESULTS: We identified 28 studies (n = 6279) in North America (13), United Kingdom (five), Europe (four), Australia (five) and China (one). Studies were at moderate (two), serious (17) critical (seven) and non assessable risk of bias (two). Current OST is associated with 50% [risk ratio (RR) =0.50, 95% confidence interval (CI) = 0.40-0.63] reduction in HCV acquisition risk, consistent across region and with low heterogeneity (I2 = 0, P = 0.889). Weaker evidence was found for high NSP coverage (RR = 0.79, 95% CI = 0.39-1.61) with high heterogeneity (I2 = 77%, P = 0.002). After stratifying by region, high NSP coverage in Europe was associated with a 56% reduction in HCV acquisition risk (RR = 0.44, 95% CI = 0.24-0.80) with low heterogeneity (I2 = 12.3%, P = 0.337), but not in North America (RR = 1.58, I2 = 89.5%, P = < 0.001). Combined OST/NSP is associated with a 74% reduction in HCV acquisition risk (RR = 0.26, 95% CI = 0.07-0.89, I2 = 80% P = 0.007). According to Grades of Recommendation Assessment, Development and Evaluation (GRADE) criteria, the evidence on OST and combined OST/NSP is low quality, while NSP is very low. CONCLUSIONS: Opioid substitution therapy reduces risk of hepatitis C acquisition and is strengthened in combination with needle and syringe programmes (NSP). There is weaker evidence for the impact of needle syringe programmes alone, although stronger evidence that high coverage is associated with reduced risk in Europe. PMID- 28891270 TI - Genetic diversity and pathogenicity of Fusarium species associated with fruit rot disease in banana across Peninsular Malaysia. AB - AIMS: The aims of this study were to identify the Fusarium isolates based on translation elongation factor (tef) 1alpha sequence, to determine the genetic diversity among isolates and species using selected microsatellite markers and to examine the pathogenicity of Fusarium isolates causing fruit rot disease of banana. METHODS AND RESULTS: One-hundred and thirteen microfungi isolates were obtained from fruit rot infected banana in Peninsular Malaysia. However, this study was focused on the dominant number of the discovered microfungi that belongs to the genus Fusarium; 48 isolates of the microfungi have been identified belonging to 11 species of Fusarium, namely Fusarium incarnatum, Fusarium equiseti, Fusarium camptoceras, Fusarium solani, Fusarium concolor, Fusarium oxysporum, Fusarium proliferatum, Fusarium verticillioides, Fusarium sacchari, Fusarium concentricum and Fusarium fujikuroi. All Fusarium isolates were grouped into their respective clades indicating their similarities and differences in genetic diversity among isolates. Out of 48 Fusarium isolates tested, 42 isolates caused the fruit rot symptom at different levels of severity based on Disease Severity Index (DSI). The most virulent isolate was F. proliferatum B2433B with DSI of 100%. CONCLUSIONS: All the isolated Fusarium species were successfully identified and some of them were confirmed as the causal agents of pre- and postharvest fruit rot in banana across Peninsular Malaysia. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results will provide additional information regarding new report of Fusarium species in causing banana fruit rot and in the search of potential biocontrol agent of the disease. PMID- 28891272 TI - Synthetic Modular Antibody Construction by Using the SpyTag/SpyCatcher Protein Ligase System. AB - Efforts to engineer recombinant antibodies for specific diagnostic and therapy applications are time consuming and expensive, as each new recombinant antibody needs to be optimized for expression, stability, bio-distribution, and pharmacokinetics. We have developed a new way to construct recombinant antibody like "devices" by using a bottom-up approach to build them from well-behaved discrete recombinant antibody domains or "parts". Studies on antibody structure and function have identified antibody constant and variable domains with specific functions that can be expressed in isolation. We used the SpyTag/SpyCatcher protein ligase to join these parts together, thereby creating devices with desired properties based on summed properties of parts and in configurations that cannot be obtained by using genetic engineering. This strategy will create optimized recombinant antibody devices at reduced costs and with shortened development times. PMID- 28891271 TI - Solubility-Improved 10-O-Substituted SN-38 Derivatives with Antitumor Activity. AB - With the objective of improving the poor water solubility of the potent antitumor compound SN-38, 10-O-substituted SN-38 derivatives were developed by the introduction of fluoroalkyl, fluorobenzoyl, or bromobenzoyl groups. The 10-O fluoropropyl-substituted compound 2 {(S)-4,11-diethyl-9-(3-fluoropropoxy)-4 hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione} was found to be 17-fold more soluble than SN-38 in phosphate-buffered saline, and it exhibited a level of biological activity ~50 % that of SN-38 in a cytotoxicity assay using the prostate cancer cell line PC-3. Five other derivatives did not show solubility improvements to the same extent, but their activities in cytotoxicity assays were nearly the same as that of SN-38. In vivo studies of 2 with PC-3 tumor-bearing mice revealed that it has higher antitumor activity than SN-38, even at lower dosage. These results will promote the medicinal chemistry application of 10-O-modifications of SN-38 and help reestablish the potential this drug. Furthermore, the inclusion of fluoro and bromo substituents means that the synthetic strategy developed here may be used to obtain 18 F- or 76 Br labeled SN-38 derivatives for in vivo positron emission tomography studies. PMID- 28891273 TI - Self-Assembly of an Amphiphilic Janus Camptothecin-Floxuridine Conjugate into Liposome-Like Nanocapsules for More Efficacious Combination Chemotherapy in Cancer. AB - The combination of camptothecin (CPT) and fluoropyrimidine derivatives acts synergistically at a 1:1 molar ratio. Practically, the greatest challenge is the development of a single liposomal formulation that can both encapsulate and maintain this drug combination at an exact 1:1 ratio to achieve coordinated pharmacokinetics. Consequently, a new type of liposome-like nanocapsule (NC) is developed from a highly symmetric Janus camptothecin-floxuridine conjugate (JCFC) amphiphile, which is synthesized by coupling two hydrophobic CPT molecules and two hydrophilic floxuridine (FUDR) molecules to multivalent pentaerythritol via a hydrolyzable ester linkage. JCFC NCs possess remarkably high drug-loading contents, and no premature release because of the highly stable co-delivery of the drug combination without the need for any carrier. It is shown that JCFC NCs consistently provide synergy and avoid antagonism in a broad panel of tumor cell lines. In vivo delivery of JCFC NCs leads to longer blood retention half-life, higher tumorous accumulation and cellular uptake of drugs, and greatly enhanced efficacy in murine tumor models compared to CPT, FUDR, and CPT + FUDR. This liposomal strategy can be extended to other hydrophilic and hydrophobic anticancer drugs that are coupled to pentaerythritol to self-assemble into nanocapsules for drug self-delivery, pointing to potential clinical translation in near future. PMID- 28891274 TI - Breast cancer risk and germline genomic profiling of women with neurofibromatosis type 1 who developed breast cancer. AB - NF1 mutations predispose to neurofibromatosis type 1 (NF1) and women with NF1 have a moderately elevated risk for breast cancer, especially under age 50. Germline genomic analysis may better define the risk so screening and prevention can be applied to the individuals who benefit the most. Survey conducted in several neurofibromatosis clinics in the United States has demonstrated a 17.2% lifetime risk of breast cancer in women affected with NF1. Cumulated risk to age 50 is estimated to be 9.27%. For genomic profiling, fourteen women with NF1 and a history of breast cancer were recruited and underwent whole exome sequencing (WES), targeted genomic DNA based and RNA-based analysis of the NF1 gene. Deleterious NF1 pathogenic variants were identified in each woman. Frameshift mutations because of deletion/duplication/complex rearrangement were found in 50% (7/14) of the cases, nonsense mutations in 21% (3/14), in-frame splice mutations in 21% (3/14), and one case of missense mutation (7%, 1/14). No deleterious mutation was found in the following high/moderate-penetrance breast cancer genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDH1, CHEK2, FANCC, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, TP53, and STK11. Twenty-five rare or common variants in cancer related genes were discovered and may have contributed to the breast cancers in these individuals. Breast cancer predisposition modifiers in women with NF1 may involve a great variety of molecular and cellular functions. PMID- 28891275 TI - Cigarette smoking as a risk factor for the development of and mortality from hepatocellular carcinoma: An updated systematic review of 81 epidemiological studies. AB - BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and its incidence has increased during the past decade. While hepatitis B and C virus infections and alcohol were established risk factors, the impact of smoking on the incidence and mortality of HCC was needed to be confirmed. METHODS: We reviewed cohort and case-control studies evaluating the association between cigarette smoking and incidence and mortality of HCC from MEDLINE and Google Scholar. We also checked reference lists of original studies and review articles manually for cross-references up to February 2016. We extracted the relevant information on participant characteristics and study outcomes, as well as information on the methodology of the studies. We also assessed the quality of the included trials using critical appraisal skills program checklists. Meta-analysis was performed by using RevMan 5.3 software. RESULTS: A total of 81 studies were included in the systematic review. Pooled OR for HCC development with current smokers was 1.55 (95% CI: 1.46 to 1.65; P < 0.00001). Pooled OR for HCC development with former smokers was 1.39 (95% CI: 1.26 to 1.52; P < 0.00001) and pooled OR for HCC development with heavy smokers was 1.90 (95% CI: 1.68 to 2.14; P < 0.00001). Pooled OR for the mortality of current smokers with HCC was 1.29 (95% CI: 1.23 to 1.34; P < 0.00001); and for former smokers with HCC, it was 1.20 (95% CI: 1.00 to 1.42; P = 0.04). CONCLUSIONS: Cigarette smoking increases the incidence and mortality of HCC. Further studies are needed to evaluate possible impact of quitting smoking on decreasing this risk. PMID- 28891276 TI - Percutaneous edge-to-edge leaflet repair: a solution to the risk-treatment paradox of mitral regurgitation complicated by pulmonary hypertension? PMID- 28891277 TI - Role of microbiota in the pathogenesis of functional disorders of the lower GI tract: Work in progress. AB - Functional bowel disorders affect a significant proportion of people word wide. Patients suffer from longstanding symptoms of abdominal pain or discomfort in combination with abnormal bowel habits. The evidence for role of microbiota is currently contradictory and descriptive. This review aims to summarize the reasons which include methodological differences in DNA extraction and sample handling along with other factors such as diet, prior antibiotic use and transit, all important major determinants of microbiota which are difficult to control. Randomized studies of specific intervention in which such factors are varied may improve reproducibility and consistency of findings in future research. PMID- 28891278 TI - [Gynecological and obstetrical management of rheumatic diseases in reproductive age]. AB - The gynecologist's role in the management of rheumatic patients is complex: it includes the prevention of damage caused by drugs, the counseling about contraception to avoid pregnancy while taking teratogen drugs, the scheduling of pregnancy during the quiescent phase of the specific disease, the replacement of teratogen drugs and a competent management of the pregnancy. The task is carried out as part of a multidisciplinary team with a focus on the differential diagnosis between specific complications of pregnancy and the complications of the rheumatic disease. This is the right way to allow a conscious reproduction, with reduced risks and acceptable maternal-fetal outcomes, to this kind of patients considered at high risk. PMID- 28891279 TI - Is pH a vaginal health marker? Phemale Study. AB - BACKGROUND: Epidemiological data regarding vaginal pH in Spain are scarce. An epidemiological study was therefore undertaken to confirm the physiological pattern of vaginal pH in Spanish women. The primary outcome measure was vaginal pH. Secondary outcomes included the relationship between vaginal pH and BMI, physical activity, working status, contraceptive use, sexual intercourse in the two days prior to the visit and clinical vaginal symptoms. METHODS: Cross sectional study in which 2136 healthy women over 18 years of age who requested a check-up were recruited. Vaginal pH was determined using specific for pH testing. Results were compared using Spearman's correlation test and ANOVA. RESULTS: The mean vaginal pH observed in the different age groups was 4.82 in women aged under 30, 5.10 in those aged between 30 and 35, 5.11 in those aged 36 to 40, and 6.48 in those aged over 55. No association was found between vaginal pH and BMI or sexual intercourse in the two previous days. Lower vaginal pH values were observed in women with some degree of physical activity and in contraceptive users, with higher vaginal pH values observed in women who presented clinical symptoms (P<0.01). CONCLUSIONS: This study confirms the physiological patterns of vaginal pH changes in Spanish women. Any degree of physical activity and the use of contraceptives were associated with lower pH values. The presence of vulvo vaginal symptoms was related with higher vaginal pH values. Vaginal pH is a marker of vaginal health. PMID- 28891280 TI - Pelvic floor evaluation with transperineal ultrasound: a new approach. AB - The increased life expectancy, the importance of the prevention in younger age and the role of the pelvic floor dysfunction not only in the disease of the third age, but also in the childbearing age, as the influence on the type of delivery, underline the importance of the evaluation of the pelvic floor. The evaluation of pelvic floor is generally clinical, but in the last 2 decades, the use of ultrasound has become a mainstream diagnostic tool in the investigation of female pelvic organ prolapse, urinary and fecal incontinence and defecation disorders, providing an immediate objective confirmation of findings obtained on clinical examination and filling some of the gaps of the urogynecological exam. The use of transabdominal ultrasound was the first developed, while the use of translabial, transrectal and transvaginal techniques started later. This review will focus on the use of transperineal ultrasound, including two-dimensional (2D), three dimensional (3D) and 4D imaging, as a valuable and objective method in the urogynecological evaluation, allowing the assessment of the pelvic floor anatomy and its functions and dysfunctions, the choice of the right type of treatment and the analysis of the changes after surgical treatment and its complications. The ultrasound approach has become an important instrument for the prevention, but also for the analysis of the disease, and to understand the importance of the pelvic floor function in different period of life of a woman. PMID- 28891281 TI - Does endometriosis influence the age of menopause? AB - Endometriosis is an inflammatory disease affecting 7-10% of women throughout their reproductive life. Few data are available regarding the age at menopause of women affected by this disease. Most of the available evidence, although scanty, would indicate that both ovarian surgery for endometriomas and endometriosis per se appear to influence age at menopause. Other factors might interfere with the age at menopause of women affected by endometriosis. The purpose of this review was to examine the age at menopause in women with a history of endometriosis and to identify factors that might affect the timing of menopause. PMID- 28891282 TI - Fabrication of Flexible White Light-Emitting Diodes from Photoluminescent Polymer Materials with Excellent Color Quality. AB - This study developed flexible light-emitting diodes (LEDs) with warm white and neutral white light. A simple ultraviolet flip-chip sticking process was adopted for the pumping source and combined with polymer and quantum dot (QD) films technology to yield white light. The polymer-blended flexible LEDs exhibited higher luminous efficiency than the QD-blended flexible LEDs. Moreover, the polymer-blended LEDs achieved excellent color-rendering index (CRI) values (Ra = 96 and R9 = 96), with high reliability, demonstrating high suitability for special applications like accent, down, or retrofit lights in the future. In places such as a museum, kitchen, or surgery room, its high R9 and high CRI characteristics can provide high-quality services. PMID- 28891283 TI - Trends in Chemical Composition of Global and Regional Population-Weighted Fine Particulate Matter Estimated for 25 Years. AB - We interpret in situ and satellite observations with a chemical transport model (GEOS-Chem, downscaled to 0.1 degrees * 0.1 degrees ) to understand global trends in population-weighted mean chemical composition of fine particulate matter (PM2.5). Trends in observed and simulated population-weighted mean PM2.5 composition over 1989-2013 are highly consistent for PM2.5 (-2.4 vs -2.4%/yr), secondary inorganic aerosols (-4.3 vs -4.1%/yr), organic aerosols (OA, -3.6 vs 3.0%/yr) and black carbon (-4.3 vs -3.9%/yr) over North America, as well as for sulfate (-4.7 vs -5.8%/yr) over Europe. Simulated trends over 1998-2013 also have overlapping 95% confidence intervals with satellite-derived trends in population weighted mean PM2.5 for 20 of 21 global regions. Over 1989-2013, most (79%) of the simulated increase in global population-weighted mean PM2.5 of 0.28 MUg m-3yr 1 is explained by significantly (p < 0.05) increasing OA (0.10 MUg m-3yr-1), nitrate (0.05 MUg m-3yr-1), sulfate (0.04 MUg m-3yr-1), and ammonium (0.03 MUg m 3yr-1). These four components predominantly drive trends in population-weighted mean PM2.5 over populous regions of South Asia (0.94 MUg m-3yr-1), East Asia (0.66 MUg m-3yr-1), Western Europe (-0.47 MUg m-3yr-1), and North America (-0.32 MUg m-3yr-1). Trends in area-weighted mean and population-weighted mean PM2.5 composition differ significantly. PMID- 28891284 TI - A Highly Stretchable Nanofiber-Based Electronic Skin with Pressure-, Strain-, and Flexion-Sensitive Properties for Health and Motion Monitoring. AB - The development of flexible and stretchable electronic skins that can mimic the complex characteristics of natural skin is of great value for applications in human motion detection, healthcare, speech recognition, and robotics. In this work, we propose an efficient and low-cost fabrication strategy to construct a highly sensitive and stretchable electronic skin that enables the detection of dynamic and static pressure, strain, and flexion based on an elastic graphene oxide (GO)-doped polyurethane (PU) nanofiber membrane with an ultrathin conductive poly(3,4-ethylenedioxythiophene) (PEDOT) coating layer. The three dimensional porous elastic GO-doped PU@PEDOT composite nanofibrous substrate and the continuous self-assembled conductive pathway in the nanofiber-based electronic skin offer more contact sites, a larger deformation space, and a reversible capacity for pressure and strain sensing, which provide multimodal mechanical sensing capabilities with high sensitivity and a wide sensing range. The nanofiber-based electronic skin sensor demonstrates a high pressure sensitivity (up to 20.6 kPa-1), a broad sensing range (1 Pa to 20 kPa), excellent cycling stability and repeatability (over 10,000 cycles), and a high strain sensitivity over a wide range (up to approximately 550%). We confirmed the applicability of the nanofiber-based electronic skin to pulse monitoring, expression, voice recognition, and the full range of human motion, demonstrating its potential use in wearable human-health monitoring systems. PMID- 28891285 TI - Functional Enzyme-Based Approach for Linking Microbial Community Functions with Biogeochemical Process Kinetics. AB - The kinetics of biogeochemical processes in natural and engineered environmental systems is typically described using Monod-type or modified Monod-type models. These models rely on biomass as surrogates for functional enzymes in microbial communities that catalyze biogeochemical reactions. A major challenge of applying such models is the difficulty of quantitatively measuring functional biomass for the constraining and validation of the models. However, omics-based approaches have been increasingly used to characterize microbial community structure, functions, and metabolites. Here, we propose an enzyme-based model that can incorporate omics data to link microbial community functions with biogeochemical process kinetics. The model treats enzymes as time-variable catalysts for biogeochemical reactions and applies a biogeochemical reaction network to incorporate intermediate metabolites. The sequences of genes and proteins from metagenomes, as well as those from the UniProt database, were used for targeted enzyme quantification and to provide insights into the dynamic linkage among functional genes, enzymes, and metabolites that are required in the model. The application of the model was demonstrated using denitrification, as an example, by comparing model simulations with measured functional enzymes, genes, denitrification substrates, and intermediates. PMID- 28891286 TI - Conformation Preservation of alpha-Helical Peptides within Supramolecular Filamentous Assemblies. AB - Hydrogen-bonded beta-sheets are the most commonly explored building motifs for creating peptide-based filamentous nanostructures; however, most bioactive epitopes must assume an alpha-helix conformation to exert their functions. Incorporating alpha-helical sequences into beta-sheet-forming peptides often involves the use of a flexible spacer to alleviate the steric impact of the intermolecular hydrogen bonding on the alpha-helical conformation. In this context, we report our findings on the alkylation-regulated conformation preservation of alpha-helical peptides within their filamentous assemblies. We found that the chemical conjugation of two short linear hydrocarbons (octanoic acids, C8) can retain the alpha-helical conformation of two protein A-derived peptide sequences while effectively driving their assembly into filamentous nanostructures. In contrast, the use of a single palmitoyl tail (C16) of similar hydrophobicity would lead to formation of beta-sheet assemblies. Our studies further demonstrated that the length of the conjugated hydrocarbon also plays an important role in partially preserving the native alpha-helical conformation, with longer ones promoting beta-sheet formation and short ones stabilizing alpha helices to some extent. We believe that these findings offer important guiding principles for the alkylation of self-assembling peptides containing alpha helical sequences. PMID- 28891287 TI - Quantifying Nonlinear Multiregional Contributions to Ozone and Fine Particles Using an Updated Response Surface Modeling Technique. AB - Tropospheric ozone (O3) and fine particles (PM2.5) come from both local and regional emissions sources. Due to the nonlinearity in the response of O3 and PM2.5 to their precursors, contributions from multiregional sources are challenging to quantify. Here we developed an updated extended response surface modeling technique (ERSMv2.0) to address this challenge. Multiregional contributions were estimated as the sum of three components: (1) the impacts of local chemistry on the formation of the pollutant associated with the change in its precursor levels at the receptor region; (2) regional transport of the pollutant from the source region to the receptor region; and (3) interregional effects among multiple regions, representing the impacts on the contribution from one source region by other source regions. Three components were quantified individually in the case study of Beijing-Tianjin-Hebei using the ERSMv2.0 model. For PM2.5 in most cases, the contribution from local chemistry (i.e., component 1) is greater than the contribution from regional transport (i.e., component 2). However, regional transport is more important for O3. For both O3 and PM2.5, the contribution from regional sources increases during high-pollution episodes, suggesting the importance of joint controls on regional sources for reducing the heavy air pollution. PMID- 28891288 TI - Selective Synthesis of Alkynylated Isoquinolines and Biisoquinolines via RhIII Catalyzed C-H Activation/1,3-Diyne Strategy. AB - Described herein is a convenient and highly selective synthesis of alkynylated isoquinolines and biisoquinolines from various aryl ketone O-pivaloyloxime derivatives and 1,3-diynes via rhodium-catalyzed C-H bond activation. In this transformations, alkynylated isoquinolines, 3,4'- and 3,3'-biisoquinolines could be obtained respectively through changing the reaction conditions. Mechanistic investigation revealed that the C-H activation of aryl ketone O-pivaloyloxime was the key step to this reaction. PMID- 28891289 TI - In Situ Fluorogenic and Chromogenic Reactions for the Sensitive Dual-Readout Assay of Tyrosinase Activity. AB - As a well-known copper-containing oxidase, tyrosinase has been anticipated to serve as the biomarker of skin diseases. We describe here an exquisite label-free fluorescent and colorimetric dual-readout assay of its activity, inspired by the specific oxidation ability of monophenolamine substrates to catecholamines and a unique fluorogenic reaction between resorcinol and catecholamines. By employing commercially available tyramine as the model substrate (dopamine as the product), it is found that the tyrosinase-incubated tyramine solution exhibits obvious pale yellow with intense blue fluorescence in the presence of resorcinol and O2, where the absorbance and fluorescence intensity are directly related to the concentration of added tyrosinase (i.e., the amount of conversion of tyramine to dopamine). The overall process of sensing tyrosinase activity takes less than 100 min at ambient temperature and pressure conditions with exceedingly simple operation procedure, explicit response mechanism, and formation of fluorophore with high quantum yield from scratch. Furthermore, such a convenient, rapid, cost effective, and highly sensitive dual-readout assay exhibits promising prospect for the tyrosinase activity in extensive bioassays and clinic research as well as in screening potential tyrosinase inhibitors. PMID- 28891290 TI - Synthesis of Ultrathin Composition Graded Doped Lateral WSe2/WS2 Heterostructures. AB - Lateral transition-metal dichalcogenide and their heterostructures have attracted substantial attention, but there lacks a simple approach to produce large-scaled optoelectronic devices with graded composition. In particular, the incorporation of substitution and doping into heterostructure formation is rarely reported. Here, we demonstrate growth of a composition graded doped lateral WSe2/WS2 heterostructure by ambient pressure chemical vapor deposition in a single heat cycle. Through Raman and photoluminescence spectroscopy, we demonstrate that the monolayer heterostructure exhibits a clear interface between two domains and a graded composition distribution in each domain. The coexistence of two distinct doping modes, i.e., interstitial and substitutional doping, was verified experimentally. A distinct three-stage growth mechanism consisting of nucleation, epitaxial growth, and substitution was proposed. Electrical transport measurements reveal that this lateral heterostructure has representative characteristics of a photodiodes. The optoelectronic device based on the lateral WSe2/WS2 heterostructure shows improved photodetection performance in terms of a reasonable responsivity and a large photoactive area. PMID- 28891291 TI - Solvent Clathrate Driven Dynamic Stereomutation of a Supramolecular Polymer with Molecular Pockets. AB - Control over the helical organization of synthetic supramolecular systems is intensively pursued to manifest chirality in a wide range of applications ranging from electron spin filters to artificial enzymes. Typically, switching the helicity of supramolecular assemblies involves external stimuli or kinetic traps. However, efforts to achieve helix reversal under thermodynamic control and to understand the phenomena at a molecular level are scarce. Here we present a unique example of helix reversal (stereomutation) under thermodynamic control in the self-assembly of a coronene bisimide that has a 3,5-dialkoxy substitution on the imide phenyl groups (CBI-35CH), leading to "molecular pockets" in the assembly. The stereomutation was observed only if the CBI monomer possesses molecular pockets. Detailed chiroptical studies performed in alkane solvents with different molecular structures reveal that solvent molecules intercalate or form clathrates within the molecular pockets of CBI-35CH at low temperature (263 K), thereby triggering the stereomutation. The interplay among the helical assembly, molecular pockets, and solvent molecules is further unraveled by explicit solvent molecular dynamics simulations. Our results demonstrate how the molecular design of self-assembling building blocks can orchestrate the organization of surrounding solvent molecules, which in turn dictates the helical organization of the resulting supramolecular assembly. PMID- 28891292 TI - Ruminal Biohydrogenation Kinetics of Defatted Flaxseed and Sunflower Is Affected by Heat Treatment. AB - The effect of heat treatment on biohydrogenation of linoleic acid (LA) and linolenic acid (LNA) and formation of stearic acid (SA), cis-9, trans-11 conjugated LA (CLA), trans-10, cis-12 CLA and trans-vaccenic acid (VA) was studied in in vitro incubations with diluted rumen fluid as inoculum and partly defatted flaxseed (DF) and partly defatted sunflower (DS) as test feeds. Feeds were heated in a laboratory oven at 110 degrees C for 0 (unheated), 45, or 90 min. Michaelis-Menten kinetics was applied for quantifying biohydrogenation rate. The DF heated for 90 min showed the lowest biohydrogenation rate of LNA and LA, indicated by the lowest Vmax value (P < 0.04 and P < 0.03, respectively). The DS heated for 45 min had the lowest biohydrogenation rate of LNA, indicated by the lowest Vmax value (P < 0.04). In conclusion, heat treatment decreased biohydrogenation of LA and LNA in DF and LNA in DS. PMID- 28891293 TI - Controlling Crystallization of All-Inorganic Perovskite Films for Ultralow Threshold Amplification Spontaneous Emission. AB - All-inorganic lead halide perovskites have gained considerable interest owing to their potential applications in an array of high-performance optoelectronic devices. However, producing highly luminescent, nearly pinhole-free, all inorganic perovskite films through a simple solution process remains challenging. Here, we provide a detailed investigation of the crystallization control of inorganic perovskite films fabricated by a one-step spin-coating process. Our results reveal that the coating temperature in the fabrication process is of paramount importance in influencing perovskite crystallization and that lowering the coating temperature and fine stoichiometry modification of the precursors favor the suppression of trap states in CsPbBr3 perovskite films. A broad range of experimental characterizations help us identify that nonsynergistic assembly of solutes, resulting from poor diffusion capability of inorganic salts, is the dominant cause for the inhomogeneous element distribution, low luminescence yield, and poor surface coverage of the resulting films. Importantly, we find that polyethylene glycol can also be used for tailoring the crystallization process, which enables the attainment of high-quality CsPbBr3 films with a maximum luminescence yield of ~30%. Finally, we demonstrate that amplification spontaneous emission with an ultralow threshold can be readily accomplished by using the developed film as an emissive component. Our findings provide deep insights into the crystallization control of CsPbBr3 perovskite films and establish a systematic route to high-quality all-inorganic perovskite films, paving the way for widespread optoelectronic applications. PMID- 28891294 TI - Low Power Consumption Gas Sensor Created from Silicon Nanowires/TiO2 Core-Shell Heterojunctions. AB - Silicon nanowires/TiO2 (SiNWs/TiO2) array with core-shell nanostructure was created by sol-gel and drop-casting methods. The hybrid material displayed excellent sensing performance for CH4 detection at room temperature. The chemiresistor sensor has a linear response toward CH4 gas in the 30-120 ppm range with a detection limit of 20 ppm, which is well below most CH4 sensors reported before. The enhanced gas sensing performance at room temperature was attributed to the creation of heterojunctions that form a depletion layer at the interface of SiNWs and TiO2 layer. Adsorption of oxygen and corresponding gas analyte on TiO2 layer could induce the change of depletion layer thickness and consequently the width of the SiNWs conductive channel, leading to a sensitive conductive response toward gas analyte. Compared to conventional metal oxide gas sensors, the room temperature gas sensors constructed from SiNWs/TiO2 do not need an additional heating device and work at power at the MUW level. The low power consumption feature is of great importance for sensing devices, if they are widely deployed and connected to the Internet of Things. The innovation of room temperature sensing materials may push forward the integration of gas sensing element with wireless device. PMID- 28891295 TI - Localized Surface Plasmon Resonance-Mediated Charge Trapping/Detrapping for Core Shell Nanorod-Based Optical Memory Cells. AB - For following the trend of miniaturization as per Moore's law, increasing efforts have been made to develop single devices with versatile functionalities for Internet of Things (IoT). In this work, organic optical memory devices with excellent dual optoelectronic functionality including light sensing and data storage have been proposed. The Au@Ag core-shell nanorods (NRs)-based memory device exhibits large memory window up to 19.7 V due to the well-controlled morphology of Au@Ag NRs with optimum size and concentration. Furthermore, since the extinction intensity of Au@Ag NRs gradually enhance with the increase in Ag shell thickness, the phototunable behaviors of memory device were systematically studied by varying the thickness of Ag shell. Multilevel data storage can be achieved with the light assistant. Finally, the simulation results demonstrate that the phototunable memory property is originated from the multimode localized surface plasmon resonance (LSPR) of Au@Ag NRs, which is in consistent with the experimental results. The Au@Ag core-shell NRs-based memories may open up a new strategy toward developing high-performance optoelectronic devices. PMID- 28891296 TI - Noninvasive Body Fat Burn Monitoring from Exhaled Acetone with Si-doped WO3 sensing Nanoparticles. AB - Obesity is a global health threat on the rise, and its prevalence continues to grow. Yet suitable biomedical sensors to monitor body fat burn rates in situ, to guide physical activity or dietary interventions toward efficient weight loss, are missing. Here, we introduce a compact and inexpensive breath acetone sensor based on Si-doped WO3 nanoparticles that can accurately follow body fat burn rates in real time. We tested this sensor on 20 volunteers during exercise and rest and measured their individual breath acetone concentrations in good agreement with benchtop proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS). During exercise, this sensor reveals clearly the onset and progression of increasing breath acetone levels that indicate intensified body fat metabolism, as validated by parallel venous blood beta-hydroxybutyrate (BOHB) measurements. Most importantly, we found that the body fat metabolism was especially pronounced for most volunteers during fasting for 3 h after exercise, with strong variation between subjects, and this was displayed correctly by the sensor in real-time. As a result, this simple breath acetone sensor enables easily applicable and hand-held body fat burn monitoring for personalized and immediate feedback on workout effectiveness that can guide dieting as well. PMID- 28891297 TI - Validating Missing Proteins in Human Sperm Cells by Targeted Mass-Spectrometry- and Antibody-based Methods. AB - The present study is a contribution to the "neXt50 challenge", a coordinated effort across C-HPP teams to identify the 50 most tractable missing proteins (MPs) on each chromosome. We report the targeted search of 38 theoretically detectable MPs from chromosomes 2 and 14 in Triton X-100 soluble and insoluble sperm fractions from a total of 15 healthy donors. A targeted mass-spectrometry based strategy consisting of the development of LC-PRM assays (with heavy labeled synthetic peptides) targeting 92 proteotypic peptides of the 38 selected MPs was used. Out of the 38 selected MPs, 12 were identified with two or more peptides and 3 with one peptide after extensive SDS-PAGE fractionation of the two samples and with overall low-intensity signals. The PRM data are available via ProteomeXchange in PASSEL (PASS01013). Further validation by immunohistochemistry on human testes sections and cytochemistry on sperm smears was performed for eight MPs with antibodies available from the Human Protein Atlas. Deep analysis of human sperm still allows the validation of MPs and therefore contributes to the C-HPP worldwide effort. We anticipate that our results will be of interest to the reproductive biology community because an in-depth analysis of these MPs may identify potential new candidates in the context of human idiopathic infertilities. PMID- 28891298 TI - Immune checkpoint molecule PD-1 acts as a novel biomarker for the pathological process of gestational diabetes mellitus. AB - AIM: Accumulating evidence suggested that challenge of the maternal-fetal interaction during pregnancy might cause the impairment of immunological hemostasis and lead to gestational diabetes mellitus (GDM) pathological process. Immune checkpoint molecule PD-1 is one of the critical molecule balancing immune response and immunological tolerance. METHODS: PD-1 expressions on T-cell subsets of GDM patients and control groups were measured via flow cytometric analysis and followed up. RESULTS: Downregulation of PD-1 acted as an indicator for GDM occurrence in the third trimester of pregnancy. With the recovery of GDM, PD-1 expression restored to normal level. CONCLUSION: PD-1 expression on T-cell subsets is a novel biomarker for the occurrence and recovery of GDM. PMID- 28891300 TI - Borderline personality disorder and polycystic ovary syndrome: A review of the literature. AB - OBJECTIVE: This review examines the existing evidence for the relationship between borderline personality disorder and polycystic ovary syndrome, and to identify commonalities in etiological mechanisms of borderline personality disorder and polycystic ovary syndrome that might explain the relationship between these seemingly disparate disorders. METHODS: A search of Medline, EMBASE and Cochrane Central was undertaken on 5 December 2016 to identify studies investigating women with borderline personality disorder and polycystic ovary syndrome (or symptoms and markers specific to polycystic ovary syndrome). RESULTS: Nine studies were identified, including three cross-sectional studies investigating symptoms of polycystic ovary syndrome in women with borderline personality disorder, two cross-sectional and one cohort study examining the prevalence of psychiatric diagnoses in women with polycystic ovary syndrome and three case reports of comorbid borderline personality disorder and polycystic ovary syndrome. CONCLUSION: Overall, the literature shows women with borderline personality disorder to have higher than expected serum androgen levels and incidence of polycystic ovaries, which can be key features of polycystic ovary syndrome. However, this research is still in its infancy, which limits our understanding of this potential comorbid phenomenon. Given the emerging anecdotal and empirical evidence to date, a theoretical discussion of the potential psychoneuroendocrinological mechanism underlying the borderline personality disorder and polycystic ovary syndrome comorbidity is provided. Further rigorous studies using standardized diagnostic criteria for polycystic ovary syndrome are warranted. Specifically, the use of prospective controlled cohort studies may be able to determine the causality and temporality of observed comorbid borderline personality disorder and polycystic ovary syndrome. PMID- 28891299 TI - Spatial Learning Responses to Lipopolysaccharide in Adult and Aged Rats. AB - Sickness behaviors, adaptive responses to infections, include lethargy, depression, reduced eating and grooming, and concentration problems resulting from interactions between the immune and neuroendocrine systems. Detecting these responses is especially critical in the elderly, as the infections that cause them can lead to cognitive impairment. While deficits in spatial learning, a hippocampal-dependent form of learning, are part of the sickness response, directional heading errors (DHEs; an indicator of spatial-learning deficits) and their time trajectories need further examination. Therefore, we simultaneously investigated the time trajectory of age-dependent sickness responses and spatial learning over 5 days in adult (5-6 months) and aged (22 months) male Brown-Norway rats injected with 250 MUg/kg lipopolysaccharide (LPS; experimental group) or 0.9% sodium chloride (control group). LPS administration resulted in pronounced, age-dependent weight loss and decreased food intake that persisted in the aged group. Animals were tested for 5 days (trial) in the Morris water maze. After 7 days of rest, animals were retested for 2 days (retention). Adult and aged LPS treated animals displayed greater differences in mean DHE than the control groups, indicating that they exhibited more DHE over the trial days. Experimental groups did not show consistent DHE improvement until Day 4 (adult) or 5 (aged). LPS had no effect on probe or retention trials. We conclude that LPS activation of the immune system results in a selective, age-dependent impairment in spatial learning, decreased food intake, and weight loss. All of these results are prolonged in aged animals. PMID- 28891301 TI - Treating body, treating mind: The experiences of people with psychotic disorders and their general practitioners - Findings from the Australian National Survey of High Impact Psychosis. AB - OBJECTIVES: To describe from the perspective of people living with psychotic illness their use of general practitioner services over a 12-month period and the experiences, attitudes and challenges general practitioners face providing health care to this population. METHODS: A two-phase design was used. Phase 1, screening for psychosis, occurred in public specialised mental health services and non government organisations within seven catchment sites across Australia. In Phase 2, 1825 people who were screened positive for psychosis were randomly selected for interview which included questions about frequency and reason for general practitioner contact in the 12 months prior to interview. General practitioners (1473) of consenting participants were also surveyed. RESULTS: Almost all (90.3%) survey participants had consulted a general practitioner in the 12-month period, on average 8.9 times, and 28.8% of attenders had consulted 12 times or more. The majority (83.5%) attended one general practitioner practice. Most (77.6%) general practitioners wanted to be involved in the mental health care of their patient. Although 69.1% said the management of their patient was not problematic for their practice, one in five general practitioners reported issues related to patient non-compliance with treatment and non-attendance at scheduled appointments; time constraints; and lack of feedback from treating mental health services. CONCLUSION: People with psychotic disorders consult general practitioners, some very frequently. Most Australian general practitioners believe they have a responsibility to review the physical and mental health of their patients. Improved communication between general practitioners and mental health services, and easier access to mental health support, may help general practitioners manage the complex mental, physical and social problems of their patients. PMID- 28891302 TI - Gastrocnemius Contracture in Patients With Rheumatoid Arthritis. AB - BACKGROUND: Rheumatoid arthritis is a chronic disease affecting multiple joints of the body. More than 90% of patients affected by rheumatoid arthritis develop foot or ankle pain over the course of their disease. The purpose of the current study was to report ankle dorsiflexion in rheumatoid arthritis patients as well as a control group utilizing a validated measurement instrument. METHODS: Using a previously validated device, 70 patients presenting with rheumatoid arthritis and 70 controls were measured for ankle range motion and isolated gastrocnemius contractures. Clinical and goniometer measurement of ankle range of motion was also performed. RESULTS: The rheumatoid arthritis group had a mean dorsiflexion of 12.3 degrees compared to a mean of 17.3 degrees in the control group ( P < .05). The difference in dorsiflexion was significantly less utilizing a goniometer than using the validated device, which may be due to measurement technique and external landmarks ( P < .05). CONCLUSION: Patients with rheumatoid arthritis had less ankle dorsiflexion than the control group. The clinical significance of this study is that it provides evidence that patients with rheumatoid arthritis have decreased ankle dorsiflexion even despite a lack of foot and ankle pain. In light of the high lifetime incidence of foot and ankle pain in these patients, this study provides some evidence that the decreased ankle dorsiflexion may be a contributing factor in foot and ankle pain, but further studies are needed. LEVEL OF EVIDENCE: Level II, prospective cohort study. PMID- 28891304 TI - Impaired amino acid metabolism in autism spectrum disorders. PMID- 28891305 TI - Antioxidant phenolic acids from the leaves of Armeniaca sibirica. AB - Phytochemical investigation of the leaves of Armeniaca sibirica (L.) Lam. led to the isolation of two new phenolic acids (1-2), together with eight known compounds (3-10) from the ethanol extracts of this plant. Structures of these compounds were elucidated through detailed spectroscopic analyses, using 1D-NMR and 2D-NMR in combination with HR-EI-MS techniques. All the compounds were evaluated for their antioxidant capabilities in vitro using 2, 2'-azino-bis-3 ethylbenzothiazoline-6-sulphonic acid (ABTS), 1, 1'-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assays, and ferric-reducing antioxidant power (FRAP) methods. PMID- 28891306 TI - Active residents in care homes: A holistic approach to promoting and encouraging meaningful activity for residents living in care homes (innovative practice). AB - The active residents in care homes intervention aim to promote meaningful activity among care home residents. Residents, family members and staff from three residential care homes in South London are participating. It is a whole systems approach which involves formal and 'on the floor' training to empower care home staff to facilitate activity. Training is delivered by two occupational therapists, a physiotherapist and a rehabilitation assistant. This paper describes the active residents in care homes intervention, the evaluation methods and discusses some preliminary findings. PMID- 28891303 TI - Redefining the endophenotype concept to accommodate transdiagnostic vulnerabilities and etiological complexity. AB - In psychopathology research, endophenotypes are a subset of biomarkers that indicate genetic vulnerability independent of clinical state. To date, an explicit expectation is that endophenotypes be specific to single disorders. We evaluate this expectation considering recent advances in psychiatric genetics, recognition that transdiagnostic vulnerability traits are often more useful than clinical diagnoses in psychiatric genetics, and appreciation for etiological complexity across genetic, neural, hormonal and environmental levels of analysis. We suggest that the disorder-specificity requirement of endophenotypes be relaxed, that neural functions are preferable to behaviors as starting points in searches for endophenotypes, and that future research should focus on interactive effects of multiple endophenotypes on complex psychiatric disorders, some of which are 'phenocopies' with distinct etiologies. PMID- 28891307 TI - A comprehensive narrative review of diagnostic biomarkers in human primary membranous nephropathy. AB - Membranous nephropathy (MN) is relatively major cause of nephrotic syndrome in adults which is recognized as an organ-specific autoimmune disease. The etiology of most cases is idiopathic, whereas the secondary MN is caused by systemic autoimmune diseases, infections, medications and malignancies. The idiopathic disease is developed by the formation of sub-epithelial immune complex deposits most likely due to binding the circulating auto-antibodies to intrinsic antigen on podocytes. The major auto antibody is the anti-phospholipase A2 receptor (anti PLA2R), however, it is not enough sensitive. Several attempts for diagnostic biomarker identification by modern analytical technologies have been devoted recently. This article reviews the biomarker candidates for primary type of MN that are detected by different approaches on human subjects. PMID- 28891308 TI - Adenovirus Infection as an Imitator of Hemophagocytic Lymphocytosis. PMID- 28891309 TI - A Calibration-Free Laser-Induced Breakdown Spectroscopy (CF-LIBS) Quantitative Analysis Method Based on the Auto-Selection of an Internal Reference Line and Optimized Estimation of Plasma Temperature. AB - The quantitative analysis accuracy of calibration-free laser-induced breakdown spectroscopy (CF-LIBS) is severely affected by the self-absorption effect and estimation of plasma temperature. Herein, a CF-LIBS quantitative analysis method based on the auto-selection of internal reference line and the optimized estimation of plasma temperature is proposed. The internal reference line of each species is automatically selected from analytical lines by a programmable procedure through easily accessible parameters. Furthermore, the self-absorption effect of the internal reference line is considered during the correction procedure. To improve the analysis accuracy of CF-LIBS, the particle swarm optimization (PSO) algorithm is introduced to estimate the plasma temperature based on the calculation results from the Boltzmann plot. Thereafter, the species concentrations of a sample can be calculated according to the classical CF-LIBS method. A total of 15 certified alloy steel standard samples of known compositions and elemental weight percentages were used in the experiment. Using the proposed method, the average relative errors of Cr, Ni, and Fe calculated concentrations were 4.40%, 6.81%, and 2.29%, respectively. The quantitative results demonstrated an improvement compared with the classical CF-LIBS method and the promising potential of in situ and real-time application. PMID- 28891310 TI - The adverse effects of perinatal exposure to nonylphenol on carbohydrate metabolism in male offspring rats. AB - BACKGROUND: We sought to investigate the adverse effects of perinatal exposure to nonylphenol (NP) on carbohydrate metabolism of male offspring rats. METHODS: Thirty-two healthy pregnant Sprague Dawley rats were randomly divided into four groups, control normal diet group (C), NP normal diet group (NPN), control high energy diet group (CH), and NP high-energy diet group (NPH). Both of the control groups were received a gavage of corn oil and the NP-groups were received NP (200 mg/kg/day) from gestational days 6 to post-natal day (PND) 21. The concentrations of NP in pancreatic tissues were measured by high-performance liquid chromatography (HPLC). The key genes of glucose metabolism expression were detected by reverse transcription-polymerase chain reaction (RT-PCR). The pancreatic tissues were stained with hematoxylin/eosin (HE). RESULTS: On PND 1, the body weights of male pups in the NPN and NPH groups were lower than those of the CH group (p = 0.012 and 0.001, respectively). On PND 30, the body weight of male pups from the NPH group was elevated compared with the C group (p = 0.019), while the body weights of male pups in the NPN and NPH groups were elevated compared to the CH group (p = 0.034 and 0.004, respectively). On PND 60, the body weights of NPN and NPH pups were higher than those in the C (p < 0.001) and CH groups (p < 0.001). The levels of fasting blood glucose (FBG) were increased significantly in the animals treated with NP compared to control animals (F = 29.14, p < 0.001). The FBG levels in the treatment groups are ranked as follows: NPH > NPN > CH > C (p < 0.05). The concentrations of NP in pancreas tissues in both the NPN (2045.0 +/- 130.1 MUg/L) and NPH groups (2038.0 +/- 104.2 MUg/L) were higher than those in the C (499.5 +/- 27.4 MUg/L) and CH groups (494.2 +/- 22.4 MUg/L; p < 0.05). Morphological examination of tissues from rats exposed to NP shown that the NP-treated groups appeared to have a higher degree of inflammatory injury, edema, and focal necrotic cells in the pancreatic tissues. Compared with C group, expression of glucokinase (GCK) was down-regulated, while Uncoupling protein-2 (UCP-2) was up-regulated in the NP-treated groups (FGCK = 218.89, p < 0.001; FUCP-2 = 18.82, p < 0.001). CONCLUSIONS: Prenatal exposure to NP could induce glucose metabolism disorder in male F1 rats, which may be due to the fact that NP induces abnormal expression patterns of GCK and UCP-2. PMID- 28891311 TI - Does Previous Open Renal Stone Surgery Affect the Outcome of Extracorporeal Shockwave Lithotripsy Treatment in Adults with Renal Stones? AB - PURPOSE: To evaluate the effects of previous ipsilateral open renal stone surgery (ORSS) on outcomes of extracorporeal shockwave lithotripsy (SWL) in adults with renal stones. MATERIALS AND METHODS: A total of 2097 renal units with renal stones underwent SWL treatment at our institution between March 1997 and February 2013. One thousand eight hundred thirty-nine (87.7%) of these had no history of ORSS and were categorized as group 1, and 258 (12.3%) patients having history of ipsilateral ORSS were categorized as group 2. Characteristics of patients, stone and treatment, stone-free, and complications rates were documented in detail and compared in each group. These groups were also subclassified into four subgroups according to the stone location. RESULTS: The stone-free rates were statistically higher in group 1 than group 2 (73.2% and 61.6%, respectively). There were no differences between groups regarding the complications and steinstrasse. The stone-free rate of SWL for stones located at lower calix has significant difference according to groups 1 and 2 (64% vs 48.4%, p = 0.001). Logistic regression analysis showed that history of ORSS increased SWL failure rate 1.39 times. CONCLUSION: Overall stone-free rates after SWL treatment was found to be significantly lower in patients with the history of ORSS than in patients without, and this finding was significantly prominent for lower calix stones. We believe that retrograde intrarenal surgery or mini- /micro-percutaneous nephrolithotripsy, despite its possible difficulties in accessing due to anatomical changes, might be a good alternative for SWL. PMID- 28891312 TI - Consequences of market withdrawal of fluphenazine and trifluoperazine: Letter to the editor and case series. PMID- 28891313 TI - Mid-Sole Release of the Plantar Fascia Combined With Percutaneous Drilling of the Calcaneus for Treatment of Resistant Heel Pain. AB - BACKGROUND: Heel pain with or without calcaneal spur is a challenging problem. Once conservative measures have failed, surgery may be indicated; there has been debate about the best surgical procedure. Two standard operative procedures have been either releasing the plantar fascia or removing the spur with drilling of the calcaneus. In this study, we evaluated the results of percutaneous drilling of the calcaneus combined with mid-sole release of the plantar fascia for treatment of resistant heel pain. METHODS: This study included 20 cases with resistant heel pain after failure of conservative measures for 6 months. Clinical, radiological evaluation and scoring patients' conditions according to the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot scale was done preoperatively and postoperatively. Percutaneous drilling of the calcaneus combined with mid-sole release of the plantar fascia was done in all cases, and the functional results were evaluated through the follow-up period that extended from 9 to 16 months with a mean duration of 12 +/- 2.3 months. RESULTS: There was statistically significant improvement in the mean AOFAS Ankle-Hindfoot scale score from 50.8 +/- 7.5 preoperatively to 91.6 +/- 7 postoperatively at the last follow-up. There were no surgery-related complications, and the mean time for full recovery was 8 +/- 3.7 weeks with no recurrence of pain by the last follow up. CONCLUSIONS: The results were very satisfactory with using this minimally invasive and simple technique for treatment for resistant heel pain. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 28891314 TI - Correlation Between Recovery of Triceps Surae Muscle Strength and Level of Activity After Open Repair of Acute Achilles Tendon Rupture. AB - BACKGROUND: This study aimed to determine whether physical findings reflecting triceps surae strength recovery could predict return to activities such as jogging and sports and whether patients' age and sex would influence recovery of triceps surae strength postoperatively. METHODS: Between 2009 and 2013, 96 consecutive cases of postoperative acute Achilles tendon rupture were reviewed. The postoperative triceps surae strength recovery rate was investigated in all patients by using half body weight 1-time heel rise, full body weight (FBW) 1 time heel rise, FBW 20-time heel rise, jogging, and full return to sports activities. Influence of age and sex on triceps surae strength recovery was also investigated. RESULTS: FBW 1-time heel rise and jogging were achieved at an average of 14 weeks (range, 6-24 weeks) and 15 weeks (range, 8-25 weeks) postoperatively, respectively. FBW 20-time heel rise and full return to sports activities were achieved at a mean of 21 weeks (range, 12-29 weeks) and 22 weeks (range, 13-29 weeks) postoperatively, respectively. Ability to perform FBW 1-time heel rise was directly related to resilience of jogging capability ( R2 = 0.317, P < 0.001), and ability to perform FBW 20-time heel rise was related to full return to sports activities ( R2 = 0.508, P < 0.001). Time to heel rise was not correlated with patient age or sex. CONCLUSION: Postoperative ability to perform FBW 1-time heel rise in patients postoperatively was directly related to resilience of jogging, and ability to perform FBW 20-time heel rise was directly related to full return to sports activities. LEVEL OF EVIDENCE: Level IV, case series. PMID- 28891315 TI - Development of pyridine dicoumarols as potent anti HIV-1 leads, targeting HIV-1 associated topoisomeraseIIbeta kinase. AB - AIM: A structural study of a series of pyridine dicoumarol derivatives with potential activity against a novel Topoisomerase IIbeta kinase which was identified in the HIV-1 viral lysate, compounds were designed and synthesized based on a 3D-QSAR study. MATERIALS & METHODS: Based on QSAR model we have designed and synthesized a series of pyridine dicoumarol derivatives and characterized by spectral studies, all the molecules are biologically evaluated by kinase assay, cytotoxicity assay, ELISA and PCR method. RESULT: We demonstrated the achievement of water soluble disodium pyridine dicoumarate derivatives showing high anti-HIV-1 activity (IC50 <25 nM) which provides a crucial point for further development of pyridine dicoumarol series as HIV-1 associated topoisomerase IIbeta kinase inhibitors for clinical application against AIDS. CONCLUSION: A new class of anti-HIV-1 lead compounds have been designed and tested. Further studies would result in development of novel and potential drugs. PMID- 28891316 TI - Associations of the ABCA1 and LPL Gene Polymorphisms With Lipid Levels in a Hyperlipidemic Population. AB - We conducted a cross-sectional study to investigate the effects of the adenosine triphosphate-binding cassette transporter 1 (ABCA1) I883M and lipoprotein lipase (LPL) HindIII polymorphisms on lipid levels in patients with hyperlipidemia. A total of 533 patients were enrolled. Serum lipid parameters were determined by an automatic biochemistry analyzer. Genotyping of the ABCA1 I883M and LPL HindIII was carried out using the polymerase chain reaction-restriction fragment length polymorphism technique. Multiple linear regression analysis was used to estimate the associations between serum lipid levels and the genetic polymorphisms. The frequency distribution of the ABCA1 I883M and LPL HindIII polymorphisms did not deviate from Hardy-Weinberg equilibrium. The major finding of our regression analysis showed that neither the ABCA1 I883M nor the LPL HindIII polymorphism was associated with baseline serum lipid levels in the total population. However, among patients with elevated alanine aminotransferase (ALT) levels (ALT >= 40 U/L), carriers of the M allele of the ABCA1 gene had lower levels of high-density lipoprotein cholesterol (HDL-C) and higher levels of low-density lipoprotein cholesterol (LDL-C) after adjusting for age, sex, smoking status, alcohol consumption, education level, occupation, and work intensity ( P < .05 for both). A test on interaction terms between the ABCA1 I833M polymorphism and ALT on HDL-C and LDL-C levels also remained significant ( P = .001 and P = .014, respectively). Our data suggest that there are significant interactive effects between ABCA1 I883M and ALT levels on HDL-C and LDL-C levels. However, the LPL HindIII polymorphism did not influence lipid levels. PMID- 28891318 TI - What Would an HIV Cure Mean to You? Qualitative Analysis from a Crowdsourcing Contest in Guangzhou, China. AB - Much HIV cure social science research has focused on high-income countries. Local key population perspectives, especially from people living with HIV (PLHIV), are needed in low- and middle-income countries. We organized an open contest soliciting responses from key populations, including PLHIV, about what a cure would mean in their lives. Tailored in-person events and social media were used to engage PLHIV, men who have sex with men (MSM), people who inject drugs, and local residents. We received 471 contributions over 4 months. Our thematic analysis showed that many people perceived that a cure would sterilize HIV and bring about new life for PLHIV. Many individuals believed a cure would decrease PLHIV discrimination and many MSM perceived a cure would decrease MSM discrimination. Some participants noted that a cure could help improve interpersonal relations, particularly with families and partners. Many individuals envisioned HIV cure as a panacea to bring about social stability. Some participants also anticipated changes in attitudes toward sex that may result in increased condomless sex. Our findings suggest a continued need for careful management of patient expectations and community engagement. PMID- 28891319 TI - Lower antioxidant capacity in the prefrontal cortex of individuals with schizophrenia. AB - OBJECTIVE: The glutathione (GSH) pathway is the main antioxidant system to protect against oxidative stress in the human brain. In this study, we tested whether molecular components of the GSH antioxidant system are changed in dorsolateral prefrontal cortex tissue from people with schizophrenia compared to controls. METHOD: The levels of total glutathione and reduced GSH were determined by fluorometric assay via quantifying thiols in extracts from frontal cortex of 68 people. Immunoblotting was used to measure levels of enzymes responsible for maintaining GSH, the glutamyl-cysteine ligase (GCL) catalytic subunit (GCLC) and the GSH peroxidase (GPx)-like protein ( n = 74). Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to measure GCLC messenger RNA (mRNA) expression. RESULTS: Both total glutathione ( t(66) = 2.467, p = 0.016) and reduced GSH ( t(66) = 3.001, p = 0.004) levels were significantly less in people with schizophrenia than in controls. However, there were no significant differences in either GCLC-like protein ( t(72) = -1.077, p = 0.285) or GCLC mRNA expression ( t(71) = -0.376, p = 0.708) between people with schizophrenia and control subjects. There was also no significant difference of GPx-like protein levels between schizophrenia and controls ( t(72) = -0.060, p = 0.952). Moreover, no significant correlations of putative confounding factors with GSH changes were detected. DISCUSSION: These results suggest that people with schizophrenia have impaired GSH antioxidant capacity, alongside normal levels of key regulatory proteins. PMID- 28891320 TI - Improving Drainage After Percutaneous Nephrolithotomy Based on Health-Related Quality of Life: A Prospective Randomized Study. AB - PURPOSE: The impact of drainage type after percutaneous nephrolithotomy (PCNL) on the health-related quality of life (HRQoL) has been rarely studied. We conducted a prospective randomized study to evaluate the differences in HRQoL among patients who received different drainage types. METHODS: A total of 90 patients who underwent PCNL were randomized into three groups to receive a nephrostomy tube (Group 1), a Double-J (JJ) stent (Group 2), and an open-ended ureteral catheter (Group 3) after PCNL, respectively. We compared the perioperative characteristics, surgical outcomes, and HRQoL using Wisconsin Stone Quality of Life (WiSQoL) questionnaire among three groups. RESULTS: There were no significant differences in patients' characteristics such as age, gender ratio, body mass index, stone burden, and so on. Majority of the surgical outcomes (operative time, estimated blood loss, hemoglobin drop, postoperative complications, and stone-free rate) were also comparable, except for the duration of hospitalization, visual analog scale, and analgesic required. The preoperative WiSQoL scores were similar among the three groups, but significant differences occurred postoperation (Groups 1, 2, and 3, 122.0 vs 105.6 vs 124.4, p < 0.001). Besides, patients in Group 2 had lower willingness (Groups 1, 2, and 3, 86.7% vs 70.0% vs 96.7%, p = 0.02) to undergo the same procedure as future treatment, if needed. CONCLUSIONS: Our study suggested that the drainage types after PCNL using a nephrostomy tube or a JJ stent or an open-ended ureteral catheter were equally safe and efficacious, but patients who received a nephrostomy tube or an open ended ureteral catheter had better HRQoL. PMID- 28891321 TI - Two new ent-kaurane diterpenes from the stems of Eurya chinensis. AB - Two new ent-kaurane diterpenes (1-2), together with five known analogs, were isolated from the stems of Eurya chinensis. The structures of new compounds were established by extensive analysis of mass spectrometric and 1D and 2D NMR spectroscopic data. Compound 3 exhibited noticeable anti-inflammatory activity as denoted by inhibiting LPS-induced nitric oxide (NO) production in RAW264.7 cells with an IC50 value of 7.82 MUM. Compound 4 showed potent cytotoxic activity against human cancer cell lines NCI-H46, HepG2 and SW480 with IC50 values ranging from 7.45 to 8.54 MUM. PMID- 28891317 TI - The Role of Sirtuins in Antioxidant and Redox Signaling. AB - SIGNIFICANCE: Antioxidant and redox signaling (ARS) events are regulated by critical molecules that modulate antioxidants, reactive oxygen species (ROS) or reactive nitrogen species (RNS), and/or oxidative stress within the cell. Imbalances in these molecules can disturb cellular functions to become pathogenic. Sirtuins serve as important regulators of ARS in cells. Recent Advances: Sirtuins (SIRTs 1-7) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with the ability to deacetylate histone and nonhistone targets. Recent studies show that sirtuins modulate the regulation of a variety of cellular processes associated with ARS. SIRT1, SIRT3, and SIRT5 protect the cell from ROS, and SIRT2, SIRT6, and SIRT7 modulate key oxidative stress genes and mechanisms. Interestingly, SIRT4 has been shown to induce ROS production and has antioxidative roles as well. CRITICAL ISSUES: A complete understanding of the roles of sirtuins in redox homeostasis of the cell is very important to understand the normal functioning as well as pathological manifestations. In this review, we have provided a critical discussion on the role of sirtuins in the regulation of ARS. We have also discussed mechanistic interactions among different sirtuins. Indeed, a complete understanding of sirtuin biology could be critical at multiple fronts. FUTURE DIRECTIONS: Sirtuins are emerging to be important in normal mammalian physiology and in a variety of oxidative stress-mediated pathological situations. Studies are needed to dissect the mechanisms of sirtuins in maintaining redox homeostasis. Efforts are also required to assess the targetability of sirtuins in the management of redox regulated diseases. Antioxid. Redox Signal. 28, 643-661. PMID- 28891322 TI - Data-Driven Topological Filtering Based on Orthogonal Minimal Spanning Trees: Application to Multigroup Magnetoencephalography Resting-State Connectivity. AB - In the present study, a novel data-driven topological filtering technique is introduced to derive the backbone of functional brain networks relying on orthogonal minimal spanning trees (OMSTs). The method aims to identify the essential functional connections to ensure optimal information flow via the objective criterion of global efficiency minus the cost of surviving connections. The OMST technique was applied to multichannel, resting-state neuromagnetic recordings from four groups of participants: healthy adults (n = 50), adults who have suffered mild traumatic brain injury (n = 30), typically developing children (n = 27), and reading-disabled children (n = 25). Weighted interactions between network nodes (sensors) were computed using an integrated approach of dominant intrinsic coupling modes based on two alternative metrics (symbolic mutual information and phase lag index), resulting in excellent discrimination of individual cases according to their group membership. Classification results using OMST-derived functional networks were clearly superior to results using either relative power spectrum features or functional networks derived through the conventional minimal spanning tree algorithm. PMID- 28891323 TI - Functional Outcome of Acute Achilles Tendon Rupture With and Without Operative Treatment Using Identical Functional Bracing Protocol. AB - BACKGROUND: The purpose of this study was to compare the functional results of operative and nonoperative treatment of acute Achilles tendon rupture using an identical rehabilitation program of functional bracing. METHODS: Over a 10-year period, 200 patients (99 operative, 101 nonoperative) aged between 18 and 65 years were treated at our institution's physiotherapy department after acute Achilles tendon rupture. There were 132 patients (62 operative, 70 nonoperative) available for a minimum 2-year follow-up (average 6.5 years; range, 2-13 years). Functional outcome was assessed using the Achilles tendon total rupture score (ATRS). RESULTS: With the numbers available, no significant difference could be detected in ATRS between operative (mean 84.8, median 90) and nonoperative groups (mean 85.3, median 91; P = 0.55). No significant difference could be detected in ATRS between male and female patients however treated ( P = 0.30) or between patients younger and older than 40 years at time of injury ( P = 0.68). There was no correlation between ATRS score and age at injury in all patients (rho = 0.0168, P = 0.85). In male patients, there was a weak trend with older patients at follow-up having better scores (rho = 0.21, P = 0.069). However, among female patients, there was a significant negative correlation between ATRS scores and increasing age (rho = -0.29, P = 0.03). Logistic regression analysis failed to show any significant effect of age at rupture, gender, or mode of treatment on ATRS. CONCLUSIONS: This study showed no significant difference detectable in ATRS between operative and nonoperative patients in the treatment of acute Achilles tendon ruptures using an identical rehabilitation program with functional bracing. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 28891324 TI - Relationship between monocyte-to-lymphocyte ratio and coronary plaque vulnerability in patients with stable angina. AB - AIM: To investigate the relationship between monocyte-to-lymphocyte ratio (MLR) and plaque vulnerability assessed by virtual histology intravascular ultrasound in patients with stable angina. METHODS: 133 patients with stable angina were enrolled. RESULTS: MLR was found to be an independent risk factor of thin cap fibrous atheroma (OR: 2.61; p = 0.025). MLR could differentiate thin cap fibrous atheroma with a sensitivity of 73.7% and a specificity of 61.8%. MLR level was positively correlated with the percentage of necrotic core (NC) area at the sites of minimum lumen area and the largest NC area, and positively related to the percentage of NC volume. CONCLUSION: Circulating MLR level has potential in identifying the vulnerable plaques in the setting of stable angina. PMID- 28891326 TI - Indications for Use of Combination Acetaminophen/Opioid Drugs in Infants <6 Months Old. PMID- 28891327 TI - Composition of the oily compounds, phytochemical screening and biological activity of different aerial parts of Smirnovia turkestana Bunge. AB - In the present study, chemical composition of the oily compounds isolated from different parts of Smirnovia turkestana (Kashan, central Iran) using n-hexane was determined for the first time. GC-MS analysis revealed that dodecanoic acid, trans-beta-ionone and methyl palmitate are the major components of leaves extract. Trans-beta-ionone and hexadodecanoic acid were also, identified as the major compounds of flowers extract. Heptacosane, trans-beta-ionone and vitamin E acetate were the main components of fruits. Phytochemical screening of the methanol extract proved the presence of alkaloids, anthraquinones, flavonoids and anthocyanin in the leaves, flowers and fruits of S. turkestana, while tannins were present only in its fruits. Evaluation of the biological activities showed that different aerial parts of S. turkestana have high antioxidant activities; antimicrobial activities were also considerable against some selected bacteria. PMID- 28891328 TI - An illness-specific version of the Revised Illness Perception Questionnaire in patients with atrial fibrillation (AF IPQ-R): Unpacking beliefs about treatment control, personal control and symptom triggers. AB - OBJECTIVE: This study modified the Revised Illness Perception Questionnaire (IPQ R) in patients with persistent atrial fibrillation (AF). DESIGN: Qualitative interviews and think-aloud techniques informed modification of the IPQ-R to be specific to AF patients. Confirmatory Factor Analysis (CFA) (n = 198) examined the validity of the modified IPQ-R (AF-IPQ-R). Exploratory factor analysis (EFA) examined the new AF-triggers scale. Construct validity examined associations between the AF-IPQ-R, quality of life (QoL) and beliefs about medicines. Test retest and internal reliability were examined. RESULTS: Interviews indicated that patients viewed triggers of AF rather than initial causes of illness as more applicable. Patients believed specific behaviours such as rest could control AF. Treatment control beliefs related to pharmacological and procedural treatments. These data were used to modify the IPQ-R subscales and to develop a triggers of AF scale. CFA indicated good model fit. EFA of the triggers scale indicated three factors: emotional; health behaviours; and over-exertion triggers. Expected correlations were found between the AF-IPQ-R, QoL and treatment beliefs, evidencing good construct validity. CONCLUSION: The AF-IPQ-R showed sound psychometric properties. It provides more detailed specification than the IPQ-R of beliefs that may help to understand poor QoL in AF patients, and guidance for future interventions in this area. PMID- 28891325 TI - Epigenetics and Immunometabolism in Diabetes and Aging. AB - SIGNIFICANCE: A strong relationship between hyperglycemia, impaired insulin pathway, and cardiovascular disease in type 2 diabetes (T2D) is linked to oxidative stress and inflammation. Immunometabolic pathways link these pathogenic processes and pose important potential therapeutic targets. Recent Advances: The link between immunity and metabolism is bidirectional and includes the role of inflammation in the pathogenesis of metabolic disorders such as T2D, obesity, metabolic syndrome, and hypertension and the role of metabolic factors in regulation of immune cell functions. Low-grade inflammation, oxidative stress, balance between superoxide and nitric oxide, and the infiltration of macrophages, T cells, and B cells in insulin-sensitive tissues lead to metabolic impairment and accelerated aging. CRITICAL ISSUES: Inflammatory infiltrate and altered immune cell phenotype precede development of metabolic disorders. Inflammatory changes are tightly linked to alterations in metabolic status and energy expenditure and are controlled by epigenetic mechanisms. FUTURE DIRECTIONS: A better comprehension of these mechanistic insights is of utmost importance to identify novel molecular targets. In this study, we describe a complex scenario of epigenetic changes and immunometabolism linking to diabetes and aging associated vascular disease. Antioxid. Redox Signal. 29, 257-274. PMID- 28891330 TI - A house is not a home: The great residential divide in autism care. PMID- 28891331 TI - Development of an observational measure of therapy engagement for pediatric rehabilitation. AB - PURPOSE: The Pediatric Rehabilitation Intervention Measure of Engagement Observation (PRIME-O) version was designed to capture signs of affective, cognitive and behavioral involvement for clients and service providers and in the client-provider interaction. METHODS: Phase 1 examined interrater consensus and construct validity of a pilot version, using observer ratings of engagement indicators made while viewing videos of therapy sessions differing in high and low engagement (Sample 1). Phase 2 examined these properties in a 10-item version (Samples 2 and 3). Phase 3 examined the content validity of the 10-item version, using observed signs of child, youth and parent engagement, as reported in an interview study involving 10 service providers. RESULTS: There was excellent interrater consensus for both versions and ratings significantly discriminated between videos differing in high and low engagement, providing evidence for construct validity. Content validity was demonstrated by service provider reports of engagement signs. More behavioral signs were reported for children and more cognitive signs were reported for youth and parents, providing evidence for the developmental appropriateness of the PRIME-O. CONCLUSIONS: The PRIME-O provides a multifaceted view of affective, cognitive and behavioral components of engagement in pediatric rehabilitation. The PRIME-O has potential utility for research, clinical practice and continuing education. Implications for Rehabilitation Measures of engagement in therapy are needed to identify factors associated with successful therapy sessions and positive client outcomes. The PRIME-O is an observational measure that captures indicators of affective, cognitive and behavioral components of engagement for both clients and service providers. The PRIME-O may further help in understanding of the strategies service providers can use to facilitate an optimal state of engagement within a therapy session. Clinical practice may be enhanced by attending to the client's signals of engagement in therapy. The PRIME-O can help service providers to more accurately identify signs of engagement and disengagement, monitor their own success in creating an engaging intervention atmosphere, and instigate strategies to optimize engagement. PMID- 28891332 TI - Subretinal delivery of erythropoietin alleviates the N-methyl-N-nitrosourea induced photoreceptor degeneration and visual functional impairments: an in vivo and ex vivo study. AB - Retinitis pigmentosa (RP) is a heterogeneous group hereditary retinal disease that is characterized by photoreceptor degeneration. The present study sought to explore the therapeutic effects of erythropoietin (EPO) on the N-methyl-N nitrosourea (MNU)-induced photoreceptor degeneration. The MNU-administered mouse or normal control received a subretinal injection of EPO (at the dose of 10U). Twenty-four hours after EPO injection, the retinal EPO levels of experimental animals were quantified. Subsequently, the experimental animals were subjected to optokinetic tests, ERG examination, SD-OCT examination, histology assessment, and immunohistochemistry evaluation. The retinal superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and expression levels of several apoptotic factors were also quantified. The subretinal injection of EPO up-regulated the retinal EPO level in the retinas of MNU-administered mice. The optokinetic tests and ERG examination suggested the visual functional impairments in MNU-administered mice were ameliorated after EPO treatment. The SD-OCT and histological examination suggested the morphological devastations in MNU-administered mice were alleviated after EPO treatment. The cone photoreceptors in MNU-administered mice were protected from the MNU-induced detrimental effects. Moreover, the EPO treatment rectified the apoptotic abnormalities in MNU-administered mice, and enhanced the expression level of Foxo3, a critical mediator of autophagy. The EPO treatment also mitigated the MDA concentration and enhanced the retinal SOD activity, thereby counteracting the retinal oxidative stress in MNU administered mice. In ophthalmological practice, the subretinal delivery of EPO is a feasible therapeutic strategy to alleviate photoreceptor degeneration. These findings would enrich our pharmacological knowledge about EPO and shed light on the development of an effective therapy against RP. PMID- 28891333 TI - Profile of medical care costs in patients with amyotrophic lateral sclerosis in the Medicare programme and under commercial insurance. AB - OBJECTIVE: To determine amyotrophic lateral sclerosis (ALS)-associated costs incurred by patients covered by Medicare and/or commercial insurance before, during and after diagnosis and provide cost details. METHODS: Costs were calculated from the Medicare Standard Analytical File 5% sample claims data from Parts A and B from 2009, 2010 and 2011 for ALS Medicare patients aged >=70 years (monthly costs) and >=65 years (costs associated with disability milestones). Commercial insurance patients aged 18-63 years were selected based on the data provided in the Coordination of Benefits field from Truven MarketScan(r) in 2008 2010. RESULTS: Monthly costs increased nine months before diagnosis, peaked during the index month (Medicare: $10,398; commercial: $9354) and decreased but remained high post-index. Costs generally shifted from outpatient to inpatient and private nursing after diagnosis; prescriptions and durable medical equipment costs were much higher for commercial patients post-diagnosis. Patients appeared to progress to disability milestones more rapidly as their disease progressed in severity (14.4 months to non-invasive ventilation [NIV] vs. 16.6 months to hospice), and their costs increased accordingly (NIV: $58,973 vs. hospice: $76,179). CONCLUSIONS: For newly diagnosed ALS patients in the U.S., medical costs are substantial and increase rapidly and substantially with each disability milestone. PMID- 28891334 TI - "Poems in the Entrance Area": Using Photo-Stories to Promote HIV Medication Adherence. AB - Adherence to antiretroviral medication among people living with HIV (PL-HIV) is critical to individual and public health. By some estimates only a quarter of PL HIV are sufficiently adherent, underscoring a continued need for adherence promoting strategies. In this analysis we explore the effect of adherence education posters developed via Photovoice. A group of PL-HIV generated images and captions to describe their adherence experiences and used their photo-stories to design 10 posters. We assessed viewers' ( N = 111) adherence knowledge, self efficacy, and communication changes quantitatively and qualitatively before and 3 months after poster placement in the clinic. We analyzed quantitative data with an independent groups t test or a Mann-Whitney test, and qualitative interviews via theme analysis. Quantitative findings indicated no significant differences. Qualitative interviewees said that posters enhanced knowledge with nonthreatening, relatable information; self-efficacy by motivating patients to take medicine and disclose HIV to others; and communication by facilitating adherence conversations and creating a visually supportive clinic. Divergent quantitative and qualitative findings can be partially explained by inquiry methods. The posters may be more effective as part of discussions about their content, like those facilitated by qualitative interviews. Additional research regarding the application of Photovoice to health promotion is warranted. PMID- 28891335 TI - Development of DNA tetrahedron-based drug delivery system. AB - Nanocarriers of drugs have attracted significant attention to tackle the problems of drug resistance or nucleic acid drug delivery, which can optimize pharmaceutical parameters and enhance the cellular uptake efficiency. Nowadays, DNA nanostructure presents an opportunity in the field of nanomaterial due to its precise control in shape and size, excellent biocompatibility, as well as multiple sites for targeting decoration. DNA tetrahedron, which is stable and easily synthesized, is used for various applications, including nuclear magnetic resonance imaging, molecular diagnosis, targeting drug delivery, and so on. In this review, we will discuss the applications of DNA tetrahedron about drug delivery, intracellular routes and its fates. Also challenges and possible solutions for developing DNA tetrahedron-based drug delivery system are detailed. PMID- 28891336 TI - Polyunsaturated fatty acid-based targeted nanotherapeutics to enhance the therapeutic efficacy of docetaxel. AB - Since breast cancer is one of the most lethal malignancies, targeted strategies are urgently needed. In this study, we report the enhanced therapeutic efficacy of docetaxel (DTX) when combined with polyunsaturated fatty acids (PUFA) for effective treatment of multi-resistant breast cancers. Folic acid (FA)-conjugated PUFA-based lipid nanoparticles (FA-PLN/DTX) was developed. The physicochemical properties, in vitro uptake, in vitro cytotoxicity, and in vivo anticancer activity of FA-PLN/DTX were evaluated. FA-PLN/DTX could efficiently target and treat human breast tumor xenografts in vivo. They showed high payload carrying capacity with controlled release characteristics and selective endocytic uptake in folate receptor-overexpressing MCF-7 and MDA-MB-231 cells. PUFA synergistically improved the anticancer efficacy of DTX in both tested cancer cell lines by inducing a G2/M phase arrest and cell apoptosis. Combination of PUFA and DTX remarkably downregulated the expression levels of pro-apoptotic and anti-apoptotic markers, and blocked the phosphorylation of AKT signaling pathways. Compared to DTX alone, FA-PLN/DTX showed superior antitumor efficacy, with no signs of toxic effects in cancer xenograft animal models. We propose that PUFA could improve the therapeutic efficacy of anticancer agents in cancer therapy. Further studies are necessary to fully understand these findings and achieve clinical translation. PMID- 28891337 TI - Enhanced tumor targeting effects of a novel paclitaxel-loaded polymer: PEG-PCCL modified magnetic iron oxide nanoparticles. AB - BACKGROUND: Multifunctional magnetic nanoparticles (MNP) have been newly developed for tumor-targeted drug carriers. To address challenges including biocompatibility, stability, nontoxicity, and targeting efficiency, here we report the novel drug deliverer poly(ethylene glycol) carboxyl-poly(E caprolactone) modified MNP (PEG-PCCL-MNP) suitable for magnetic targeting based on our previous studies. METHODS: Their in vitro characterization and cytotoxicity assessments, in vivo cytotoxicity assessments, and antitumor efficacy study were elaborately investigated. RESULTS: The size of PEG-PCCL-MNP was 79.6 +/- 0.945 nm. PEG-PCCL-MNP showed little in vitro or in vivo cytotoxicity and good biocompatibility, as well as effective tumor-specific cell targeting for drug delivery with the presence of external magnetic field. DISCUSSION: PEG-PCCL-MNP is a potential candidate of biocompatible and tumor specific targeting drug vehicle for hydrophobic drugs. PMID- 28891338 TI - Synthesis and biological evaluation of benzenesulphonamide-bearing 1,4,5 trisubstituted-1,2,3-triazoles possessing human carbonic anhydrase I, II, IV, and IX inhibitory activity. AB - A library of benzenesulphonamides incorporating 1,2,3-triazole rings functionalised with ester, carboxylic acid, carboxamide, carboxyhydrazide, and hydroxymethyl moieties were synthesised. The carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) isoforms, hCA I, hCA II, hCA IV, and hCA IX. Among them, hCA II and IV are anti glaucoma drug targets, being involved in aqueous humour secretion within the eye. hCA I was inhibited with Ki's ranging between 8.3 nM and 0.8737 uM. hCA II, the physiologically dominant cytosolic isoform, was excellently inhibited by these compounds, with Ki's in the range of 1.6-9.4 nM, whereas hCA IV was effectively inhibited by most of them, with Ki's in the range of 1.4-55.3 nM. Thirteen of the twenty sulphonamides were found to be excellent inhibitors of tumour associated hCA IX with Ki's <= 9.5 nM. Many of the new compounds reported here showed low nM inhibitory action against hCA II, IV, and IX, isoforms involved in glaucoma and some tumours, making them interesting candidates for further medicinal chemistry/pharmacologic studies. PMID- 28891339 TI - Immunotherapy in managing metastatic melanoma: which treatment when? AB - INTRODUCTION: Ten to fifteen percent of melanoma patients develop distant or unresectable metastasis requiring systemic treatment. Around 45% of the patients diagnosed with metastatic cutaneous melanoma harbor a BRAFV600 mutation and derive benefit from combined targeted therapy with MAPK pathway inhibitors. These offer a rapid response that translates into improvement of symptoms and increased quality of life. However, resistance often develops with subsequent progressive disease. Immunotherapy with checkpoint inhibitors may be offered to BRAF-mutated and wild-type patients and is associated with longer and durable responses that can continue over years. Areas covered: In this review, the authors discuss the late evidence for targeted and immunotherapy in melanoma patients, as well as therapy sequencing. Immunotherapy in special populations is also addressed. Expert opinion: Effective treatments are currently available. However, there are still unanswered questions of the best therapy sequence, the clear superiority of combined immunotherapy versus monotherapy in all patients, and therapy duration. Since different promising treatments will become available, clinical trials comparing the diverse options in terms of safety, efficacy and cost- effectiveness are required to make the right decisions. Consequently, patients should be encouraged to participate in clinical trials, whenever possible. PMID- 28891340 TI - Do model polymer therapeutics sufficiently diffuse through articular cartilage to be a viable therapeutic route? AB - The ability of a polymer therapeutic to access the appropriate subcellular location is crucial to its efficacy and is defined to a large part by the many and complex cellular biological and biochemical barriers such that a construct must traverse. It is shown here that model dextrin conjugates are able to pass through a cartilaginous extracellular matrix into chondrocytes, with little perturbation of the matrix structure, indicating that targeting of potential therapeutics through a cartilaginous extracellular matrix should be proven possible. Rapid chondrocytic targeting of drugs which require intra cellularisation for their activity and uniform extracellular concentrations of drugs with an extracellular target, is thus enabled though polymer conjugation. PMID- 28891341 TI - Small molecule therapy for managing moderate to severe psoriatic arthritis. AB - INTRODUCTION: The majority of psoriatic arthritis (PsA) patients experience a good clinical response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic therapies (bDMARDs). However, treatment failure with these drugs can represent a relevant clinical problem. Moreover, in daily clinical practice, the appropriate identification of patients eligible for these agents can be conditioned by numerous aspects, mainly represented by comorbidities, such as history of malignancies, chronic and recurrent infectious diseases. Areas covered: We searched in the PUBMED database and review published data on the efficacy and safety profile of the small molecules, inhibitor of phosphodiesterase 4, apremilast, and of JAK/STAT pathways, tofacitinib, in PsA. Moreover, we report data on the other JAK inhibitor, baricitinib, and the A(3) adenosine receptors agonist, CF101, emerging by studies conducted in psoriasis patients. Expert opinion: In Psoriatic Arthritis, apremilast appears promising for PsA and recent studies have shown a good efficacy and an acceptable safety profile. Data on tofacitinib in PsA are limited. Studies on the small molecules, baricitinib and CF101 are still incomplete and limited to trials conducted in Rheumatoid Arthritis and in psoriasis. Further studies on small molecules and on their underlining mechanisms are advocated in PsA. PMID- 28891342 TI - Towards a Critical Health Equity Research Stance: Why Epistemology and Methodology Matter More Than Qualitative Methods. AB - Qualitative methods are not intrinsically progressive. Methods are simply tools to conduct research. Epistemology, the justification of knowledge, shapes methodology and methods, and thus is a vital starting point for a critical health equity research stance, regardless of whether the methods are qualitative, quantitative, or mixed. In line with this premise, I address four themes in this commentary. First, I criticize the ubiquitous and uncritical use of the term health disparities in U.S. public health. Next, I advocate for the increased use of qualitative methodologies-namely, photovoice and critical ethnography-that, pursuant to critical approaches, prioritize dismantling social-structural inequities as a prerequisite to health equity. Thereafter, I discuss epistemological stance and its influence on all aspects of the research process. Finally, I highlight my critical discourse analysis HIV prevention research based on individual interviews and focus groups with Black men, as an example of a critical health equity research approach. PMID- 28891343 TI - Current and future contraceptive options for women living with HIV. AB - INTRODUCTION: Among women living with HIV, half of the pregnancies are unintended. Effective contraception can prevent unintended pregnancies and consequently reduce maternal mortality and perinatal transmission of HIV. While contraceptive options available for all women also apply to women living with HIV, specific considerations exist to the use of contraception by women living with HIV. Areas covered: First, general principles guiding the use of contraception among women living with HIV are discussed, such as choice, method mix, relative effectiveness, and drug-drug interactions. Second, a detailed discussion of each contraceptive method and issues surrounding the use of that method, such as drug-drug interactions, follows. Third, future contraceptive options in advanced development for use by women or men are briefly discussed. Expert opinion: Contraceptive methods available to all women should also be accessible to women living with HIV. When the relative effectiveness of a contraceptive method is reduced, for example due to drug-drug interactions with antiretrovirals, the method should still be made available to women living with HIV with the appropriate information sharing and counseling. Greater research on various aspects of contraceptive use by women living with HIV and more comprehensive testing of co-administration of hormonal contraceptives and common medications used by these women are warranted. PMID- 28891345 TI - Comparison of the sensitivity to change of the Functional Independence Measure with the Assessment of Motor and Process Skills within different rehabilitation populations. AB - PURPOSE: To determine whether there was a difference in the sensitivity to change of the subscales of the Functional Independence Measure and the Assessment of Motor and Process Skills within three different post-acute inpatient rehabilitation populations. MATERIAL AND METHODS: We conducted retrospective chart review of patients consecutively admitted to inpatient rehabilitation units, with both admission and discharge Functional Independence Measure and Assessment of Motor and Process Skills scores. A total of 276 participants were included and categorized into diagnostic groups (orthopedic, oncology, and geriatric). Within group, sensitivity to change was evaluated for the subscales of each measure by calculating the difference in standardized response means (SRM) and 95% confidence intervals (CI). RESULTS: The Functional Independence Measure motor subscale was more sensitive to change than the Assessment of Motor and Process Skills in the orthopedic and geriatric groups (SRMdifference = 1.53 [95% CI 0.93, 2.3] and 0.65 [95% CI 0.3, 1.02], respectively) but not in the oncology group (SRMdifference = 0.42 [95% CI -0.2, 1.04]). For the cognitive subscales, the Assessment of Motor and Process Skills was more sensitive to change than the Functional Independence Measure in all three groups (SRMdifference = 0.38 [95% CI 004, 0.74], 0.65 [95% CI 0.45, 0.90], and 1.15 [95% CI 0.77, 1.69] for orthopedic, geriatric, and oncology, respectively). CONCLUSIONS: The Functional Independence Measure is a mandated measure for all rehabilitation units in Canada. As the cognitive subscale of the Assessment of Motor and Process Skills is more sensitive to change than the Functional Independence Measure, we recommend also administering the Assessment of Motor and Process Skills to better detect changes in the cognitive aspect of function. Implications for rehabilitation When deciding between the Functional Independence Measure or the Assessment of Motor and Process Skills, it is important to consider whether patients' functional status is expected to change similarly or differently. The difference in sensitivity to change between the subscales of the two outcome measures varies with the characteristics of change (similar or different) in patients' functional status. We recommend using the Assessment of Motor and Process Skills, along with the Functional Independence Measure, for patients who are expected to make similar amounts of change in functional status, as the cognitive subscale of the Assessment of Motor and Process Skills is more sensitive to change and can better detect changes in the cognitive aspect of functioning. For patients whose functional status are expected to change differently (diverse diagnoses), the Functional Independence Measure may be more useful as the motor subscale was more sensitive to change when comparing between rehabilitation populations. PMID- 28891344 TI - When "the Cure" Is the Risk: Understanding How Substance Use Affects HIV and HCV in a Layered Risk Environment in San Juan, Puerto Rico. AB - BACKGROUND: Substance use, particularly injection drug use, continues to fuel the HIV/HCV (hepatitis C virus) epidemics in San Juan, Puerto Rico (PR). AIM: This article examines individual and sociostructural factors that affect HIV/HCV risk among people who use drugs (PWUD) living with or at risk for HIV/HCV in San Juan, PR. Findings were used to inform a community-level intervention to enhance HIV care access and retention for this population. METHOD: A rapid ethnographic assessment in collaboration with a community-based organization was conducted. Data collection took place between June and December 2013 and included field observations, 49 unstructured interviews with PWUD, and 19 key informant interviews with community stakeholders. Fieldnotes, photographs, and interview transcripts were analyzed for recurrent themes and to address the intervention planning needs. Study results are presented as fieldnote excerpts, direct quotes from interviews, and photographs. RESULTS: Findings suggest that PWUD in PR face myriad challenges that affect HIV/HCV risk and hinder linkage to and retention in care. Results describe a layered risk environment where PWUD encounter many barriers to prevention, care, and treatment such as transience, social isolation, stigma, limited housing options, and inadequate medical and substance use disorder treatment services. DISCUSSION: These observed circumstances provide an empirical basis for the development and evaluation of comprehensive interventions that may serve to reduce barriers to care and link individuals to other supportive services. CONCLUSION: New approaches and comprehensive interventions are needed to break the structures that perpetuate risk and lack of engagement and retention in HIV care and substance use disorder treatment in San Juan. PMID- 28891346 TI - Lumacaftor/ivacaftor, a novel agent for the treatment of cystic fibrosis patients who are homozygous for the F580del CFTR mutation. AB - INTRODUCTION: Cystic Fibrosis (CF) is an autosomal recessive disease affecting up to 90,000 people worldwide. Approximately 73% of patients are homozygous for the F508del cystic fibrosis transmembrane conductance regulator [CFTR] mutation. Traditionally treatment has only included supportive care. Therefore, there is a need for safe and effective novel therapies targeting the underlying molecular defects seen with CF. Areas covered: In 2016, the Food and Drug Administration and the European Commission approved LUM/IVA (Orkambi), a CFTR modulator that includes both a CFTR corrector and potentiator, for CF patients homozygous for the F508del CFTR mutation. This article reviews the pharmacologic features, clinical efficacy, and safety of LUM/IVA and summarize the available pre-clinical and clinical data of LUM/IVA use. Expert commentary: LUM/IVA showed modest, but significant improvements from baseline in percent predicted FEV1 (ppFEV1) as well as a reduction in pulmonary exacerbations by 35% It was shown to be safe for short- and long-term use. Currently, LUM/IVA is the only oral agent in its class available and represents a milestone the development of therapies for the management of CF. Nonetheless, pharmacoeconomic data are necessary to justify its high cost before is use becomes standard of care. PMID- 28891347 TI - Synthesis and biological evaluation of aminomethyl and alkoxymethyl derivatives as carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase inhibitors. AB - Compounds containing nitrogen and sulfur atoms can be widely used in various fields such as industry, medicine, biotechnology and chemical technology. Therefore, the reactions of aminomethylation and alkoxymethylation of mercaptobenzothiazole, mercaptobenzoxazole and 2-aminothiazole were developed. Additionally, the alkoxymethyl derivatives of mercaptobenzoxazole and 2 aminothiazole were synthesized by a reaction with hemiformals, which are prepared by the reaction of alcohols and formaldehyde. In this study, the inhibitory effects of these molecules were investigated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) enzymes and carbonic anhydrase I, and II isoenzymes (hCA I and II). Both hCA isoenzymes were significantly inhibited by the recently synthesized molecules, with Ki values in the range of 58-157 nM for hCA I, and 81 215 nM for hCA II. Additionally, the Ki parameters of these molecules for BChE and AChE were calculated in the ranges 23-88 and 18-78 nM, respectively. PMID- 28891348 TI - Shifting the Culture Around Public Health Advocacy: Training Future Public Health Professionals to Be Effective Agents of Change. AB - There is a critical need to build the capacity of our current and future public health workforce and the communities we serve to engage in public health advocacy. Advocacy should be an integral piece of our intervention strategies and public health discourse. Incorporating public health advocacy into public health training, practice, and research serves as a long-term investment for the public's health. Advocacy can achieve systemic change by addressing the social determinants of health. We developed an advocacy training program that embeds students in community-based organizations (CBOs) for 9 months, providing students with experiential education through the application of advocacy skills and CBOs with opportunities to expand and broaden their advocacy efforts. We have three priority populations: graduate students, CBOs serving Los Angeles County, and the broader Los Angeles County community, focusing on vulnerable populations. Our multifaceted approach addresses the necessity of public health advocacy among the health professions. Through changing how we train students and how communities and universities collaborate, we can strengthen the public health workforce and build healthier communities. PMID- 28891349 TI - Next generation beta adrenoreceptor agonists for the treatment of asthma. AB - INTRODUCTION: A fixed-dose inhalation of a long-acting beta-agonist (LABA) and inhaled corticosteroids (ICS) is commonly recommended for moderate to severe asthmatic patients not adequately controlled by an ICS only. In order to improve the patients' adherence and the control of disease there is a noteworthy interest for the next generation inhaled beta adrenoreceptor agonists maintaining an over 24 hours bronchodilatation and used once-daily (ultra-LABAs). This review focuses on the currently available evidences on the clinical role of any single ultra LABAs in the treatment of asthmatic patients. Areas covered: New ultra-LABAs have been developed in recent years for the treatment of asthma. In particular, several evidences in asthmatic patients include indacaterol, vilanterol, olodaterol, and abediterol. Expert opinion: Pharmacologically, all new ultra LABAs considered have demonstrated a good ability to maintain a true bronchodilatation for over 24 hours and a good safety profile. This aspect could be a key point to improve the patient's perspective, the adherence to the treatment regimens and therefore the control of disease. At this time, however, limited data are available and no ultra-LABA+ICS may be recommended as preferred. PMID- 28891350 TI - Dental age estimation in a group of Kenyan children using Willems' method: a radiographic study. AB - BACKGROUND: Radiographic study of developing teeth provides a reliable indication of chronological age. In Kenya, dentists are often required to estimate age. However, there is a paucity of publications on the performance of dental age estimation methods. AIM: To determine the accuracy of Willems' method of dental age estimation. SUBJECTS AND METHODS: A cross-sectional study was done at The University of Nairobi Dental Hospital. Panoramic radiographs of children aged 3.00-16.99 years old were studied. Dental age was estimated according to Willems' method and compared to chronological age and the difference compared to zero using a t-test. RESULTS: Radiographs of 187 (47%) females and 214 (53%) males were analysed. Willems' method significantly over-estimated the mean overall age by -0.24 +/- 1.17 years (p < .000). Age was over-estimated in girls by -0.10 +/- 1.18 years (p = .254); however, age in boys was significantly over-estimated by 0.37 +/- 1.14 years (p < .000). CONCLUSIONS: Willem's model over-estimated dental age slightly and the method performed better in estimating the age of girls compared to boys. The majority of the children had their age estimated within 1 year of their chronological age. This suggests that Willems' method is suitable for estimating the ages of individual children in Kenya. PMID- 28891351 TI - Radiofrequency electric field hyperthermia with gold nanostructures: role of particle shape and surface chemistry. AB - Hyperthermia treatment of cancerous cells has been recently developed drastically with the help of nanostructures. Heating of gold nanoparticles in non-invasive radiofrequency electric field (RF-EF) is a promising and unique technique for cancer hyperthermia. However, because of differences between particles (i.e. their surface chemistry and dispersion medium) and between RF-EF sources, the research community has not reached a consensus yet. Here, we report the results of investigations on heating of gold nanoparticles and gold nanorods under RF-EF and feasibility of in-vitro cancer hyperthermia. The heating experiments were performed to investigate the role of particle shape and surface chemistry (CTAB, citrate and PEG molecules). In-vitro hyperthermia was performed on human pancreatic cancer cell (MIA Paca-2) with PEG-coated GNPs and GNRs at concentrations that were found non-toxic based on the results of cytotoxicity assay. Application of RF-EF on cells treated with PEG-GNPs and PEG-GNRs proved highly effective in killing cells. PMID- 28891352 TI - Development of the Italian version of the trunk impairment scale in subjects with acute and chronic stroke. Cross-cultural adaptation, reliability, validity and responsiveness. AB - PURPOSE: To cross-culturally adapt and psychometrically analyse the Italian version of the Trunk Impairment Scale on acute (cohort 1) and chronic stroke patients (cohort 2). METHODS: The Trunk Impairment Scale was culturally adapted in accordance with international standards. The psychometric testing included: internal consistency (Cronbach's alpha), inter- and intra-rater reliability (intraclass correlation coefficient; standard error of measurement and minimal detectable change), construct validity by comparing Trunk Impairment Scale score with Barthel Index, motor subscale of Functional Independence Measure, and Trunk Control Test (Pearson's correlation), and responsiveness (Effect Size, Effect Size with Guyatt approach, standardized response mean, and Receiver Operating Characteristics curves). RESULTS: The Trunk Impairment Scale was administered to 125 and 116 acute and chronic stroke patients, respectively. Internal consistency was acceptable (alpha > 0.7), inter- and intra-rater reliability (ICC > 0.9, Minimal Detectable Change for total score < 1.6 in cohort 1 and < 1.1 in cohort 2) were excellent. The construct validity showed acceptable correlations (r > 0.4) with all scales but the motor Functional Independence Measure in cohort 2. Distribution-based methods showed large effects in cohort 1 and moderate to large effects in cohort 2. The Minimal Important Difference was 3.5 both from patient's and therapist's perspective in cohort 1 and 2.5 and 1.5 from patient's and therapist's perspective, respectively, in cohort 2. CONCLUSION: The Trunk Impairment Scale was successfully translated into Italian and proved to be reliable, valid, and responsive. Its use is recommended for clinical and research purposes. Implications for Rehabilitation Trunk control is an essential part of balance and postural control, constituting an important prerequisite for daily activities and function. The TIS administered in subjects with subacute and chronic stroke was reliable, valid and responsive. The TIS is expected to help clinicians and researchers by identifying key functional processes related to disability in people with subacute and chronic stroke. PMID- 28891353 TI - Development of an inhalation unit risk factor for ethylene dibromide. AB - The Texas Commission on Environmental Quality (TCEQ) follows standard scientific methods to develop up-to-date toxicity factors for chemicals emitted in the state of Texas. An inhalation unit risk factor (URF) was developed for ethylene dibromide (EDB, CAS 106-93-4) based on an increased incidence of nasal cavity adenocarcinomas observed in female rats in a 2-year inhalation cancer bioassay conducted by the National Toxicology Program (NTP). The NTP study provided evidence of several EDB-induced tumors in male and female rats and in female mice. Tumor incidences that were statistically increased at the low dose and that showed a statistically significant increasing trend were considered in identifying the critical effect. Following benchmark concentration (BMC) modeling and animal-to-human dosimetric adjustments, the increased incidence of nasal cavity adenocarcinomas observed in female rats was determined to be the most sensitive tumorigenic effect in the most sensitive species and sex and was utilized as the carcinogenic endpoint for the development of the URF. The 95% lower confidence limit of the BMC at the 10% excess risk level (BMCL10 of 292.8 ppb) was determined for calculation of the URF. The resulting URF based on increased nasal cavity adenocarcinomas observed in female rats is 3.4E-04 per ppb (4.4E-05 per ug/m3). The lifetime air concentration corresponding to a no significant excess risk level of one in 100,000 is 0.029 ppb (0.22 ug/m3), which is considered sufficiently health-protective for use in protecting the general public against the potential carcinogenic effects of chronic exposure to EDB in ambient air. PMID- 28891354 TI - BRCA2 protects mammalian cells from heat shock. AB - PURPOSE: Heat shock induces DNA double-strand breaks (DSBs) in mammalian cells. Mammalian cells are capable of repairing DSBs by utilising the homologous recombination (HR) pathway. Breast cancer susceptibility gene 2 (BRCA2) is known to regulate the HR pathway. Here, we investigate the role of BRCA2 in repairing DNA damage induced by heat shock. MATERIALS AND METHODS: Chinese hamster lung fibroblast cell lines and human tongue squamous cell carcinoma SAS cells were used. RAD51 foci formation assay was used as an HR indicator. Heat sensitivity was analysed with colony forming assays. Phosphorylated histone H2AX (gammaH2AX) intensity, which correlates with the number of DSBs, was analysed with flow cytometry. RESULTS: RAD51 foci appeared with heat shock, and the number of cells with RAD51 foci was maximal at about 4 h after heat shock. Heat-induced RAD51 foci co-localised with gammaH2AX foci. BRCA2-deficient cells were sensitive to heat when compared to their parental wild-type cells. Heat-induced gammaH2AX was higher in BRCA2-deficient cells compared to parental cells. In SAS cells, cells transfected with BRCA2-siRNA were more sensitive to heat than cells transfected with negative control siRNA. Apoptotic bodies increased in number more rapidly in BRCA2-siRNA transfected cells than in cells transfected with negative control siRNA when cells were observed at 48 h after a heat treatment. In addition, cells deficient in BRCA2 were incapable of activating heat-induced G2/M arrest. CONCLUSION: BRCA2 has a protecting role against heat-induced cell death. BRCA2 might be a potential molecular target for hyperthermic cancer therapy. PMID- 28891355 TI - Fertility challenges for women with sickle cell disease. AB - INTRODUCTION: Sickle cell disease (SCD) represents one of the most common monogenic blood disorders worldwide, with an incidence of over 300,000 newborns affected per year. Reproductive challenges for men and women with SCD have been previously reviewed; however, evidence-based strategies to prevent and manage infertility and increase fecundity are lacking in women with SCD, which is one of the most important factors for quality of life. Areas covered: This review article summarizes the known risk factors for infertility, low fecundity, and premature menopause related to SCD. Expert commentary: Women with SCD have unique risk factors that may impact their ability to conceive, including chronic inflammation, oxidative stress, transfusion-related hemochromatosis, and ovarian sickling, causing ischemia and reperfusion injury to the ovary. Contraception is strongly recommended while on hydroxyurea therapy during reproductive years and discontinuing hydroxyurea for family planning and during pregnancy based on teratogenicity in animal studies. Hematopoietic stem cell transplantation (HSCT), the only curative therapy, sometimes involves conditioning regimens containing alkylating agents and total body irradiation that contribute to infertility and premature ovarian failure. Prior to HSCT or gene therapy, we strongly recommend referral to a reproductive endocrinologist to discuss fertility preservation and surrogacy options for all women with SCD. PMID- 28891356 TI - Benefits and burdens: family caregivers' experiences of assistive technology (AT) in everyday life with persons with young-onset dementia (YOD). AB - BACKGROUND: People with dementia and their family caregivers may benefit from assistive technology (AT), but knowledge is scarce about family carers' (FC) experiences and involvement in the use of AT in everyday life. AIM: To examine the FC roles and experiences with AT as means of supporting people with young onset-dementia (YOD). METHOD: Qualitative interview study with follow-up design. Repeated semi-structured interviews were conducted with 13 FC of people with YOD, participating in an ongoing intervention study investigating the families' use and experiences of AT in everyday life. RESULTS: Six main themes emerged: (1) timely information about AT; (2) waiting times; (3) AT incorporated into everyday living; (4) AT experienced as a relief and burden; (5) appraisal of AT qualities and (6) the committed caregiver. CONCLUSIONS: The study found benefits for the FC, especially with simply designed AT, but also several barriers for successful use. A committed caregiver is vital throughout the process. Users will need professional advice and support, and occupational therapists may have a significant role in the process. Interventions implementing AT must be based on analysis of the needs of the person with YOD and the carers: their capabilities, preferences, embodied habits, and coping strategies. Implications for Rehabilitation Committed family carers (FC) play an important, often decisive, role in providing support for the person with young-onset dementia (YOD, onset <65 years) to use and benefit from the AT. The simpler the AT, the better. The AT should be introduced at "the right time", before the cognitive and adaptive reduction is too great. The "window" for implementation may be short. AT has potential to ease caregiving and give relief for FC. However, many barriers, difficulties and problems must be attended to. A system for individualized support over time is necessary for implementing AT for this group. PMID- 28891357 TI - Cesarean hysterectomy for abnormally invasive placenta: is urologists' participation in the surgery always necessary? PMID- 28891358 TI - Defensive medicine among obstetricians and gynaecologists in Turkey. AB - In recent years, there has been a remarkable increase in medical malpractice litigations against OB/GYNs in Turkey and globally. This high litigation atmosphere may have changed attitudes, behaviour and practice of OB/GYNs. In the current study, opinions and attitudes of OB/GYNs regarding defensive medicine and to what extent they practice it were investigated. One hundred and eight OB/GYNs participated in the study. All participants found obstetrics and gynaecology riskier when compared with other medical branches and reported that they were increasingly practising defensive medicine. The majority of the OB/GYNs stated that they abstained from many risky interventions and expressed their belief that the high caesarean section (C-section) rate was associated with medico-legal concerns. The majority of the participants supported enacting of a specific medical malpractice law and supported the establishment of medically specialised courts. These regulations demanded by OB/GYNs should be taken into account by health authorities. Impact statement What is already known on this subject: In recent years, there has been a remarkable increase in medical malpractice litigations against OB/GYNs in Turkey and globally. Turkey has serious problems with the high C-section rate, which has been suggested to be related to medicolegal issues in a previous research. Fifty-one percent of babies, namely most of them, are delivered via C-section. There is no specific medical malpractice law and medically specialised court in Turkey. What the results of this study add: It seems like there is a professional liability crisis among OB/GYNs in Turkey. OB/GYNs reported that they were increasingly practising defensive medicine, and stated that they abstained from many risky interventions. A high C-section rate was found to be related to medicolegal concerns in OB/GYNs' perspective in the current study. OB/GYNs demanded some reasonable regulations. What the implications are of these findings for clinical practice and/or further research: Regulations demanded by OB/GYNs, which were probed in the current study, such as enacting a specific medical malpractice law and establishment of a medically specialised court, should be taken into account by health authorities in Turkey. The findings of the current study is believed to produce important results for the success of Health transformation programme put into practice in Turkey, which was not able to stop increasing C-section rates. Studies evaluating the direct or indirect costs related to defensive medicine practices of OB/GYNs in Turkey should be performed in subsequent research. PMID- 28891359 TI - Updated results of a phase 2 study of panobinostat combined with melphalan, thalidomide and prednisone (MPT) in relapsed/refractory multiple myeloma. PMID- 28891360 TI - Global patent landscape of programmed cell death 1: implications of the rapid expansion. AB - INTRODUCTION: Inhibitors of programmed cell death 1 (PD-1) and its ligands are producing a paradigm shift in cancer treatment. The promising clinical outcomes and a multi-billion dollar market have prompted active research and development and resulted in relentless patent protection. However, the global patent landscape in this field remains unclear. Areas covered: The patent landscape encompassing global patenting activities and developing trends in the field is discussed based on a data set of 1287 patent families. Patenting activities have expanded rapidly in the past three years. Specific trends in relevant aspects are presented, including patent filing countries, patent ownership, co-patents, technical areas, and technological connections in terms of patent citation relationships. Expert opinion: Together with patenting momentum in recent years, fragmented ownership and dense technological connections of PD-1-related inventions raise the possibility of a patent thicket. The explosion of patent applications and complex citation relationships could also lead to considerable patent conflicts and disputes on overlapping intellectual property rights, in addition to existing legal uncertainties. Patent applicants in this field are encouraged to be aware of these concerns when developing valid patent strategies. PMID- 28891361 TI - Risk factors and complications of manual placental removal after vaginal delivery - how common are additional invasive procedures? AB - PURPOSE: The purpose of this study is to assess risk factors and complications of manual placental removal. MATERIALS AND METHODS: An historical prospective study of all parturients undergoing manual placental removal between 2012 and 2014. Parturients were matched by time of delivery with parturients delivering vaginally with spontaneous placental separation. Multiple gestations, preterm deliveries, incomplete placental separation and uterine malformations were excluded. Delivery characteristics and short-term complications were studied. Telephone questionnaires were conducted to assess the likelihood of invasive procedures performed for retained products of conception (RPOC) up to 12 weeks postpartum. RESULTS: Overall 293 (1.5% of all vaginal deliveries) were complicated by manual placental removal. Independent risk factors included advanced maternal age (odds ratio (OR) 1.08, 95% CI 1.03-1.12), previous manual removal (OR 9.27, 95% CI 3.15-27.31), regional anesthesia (OR 3.49, 95% CI 2.14 5.70), and labor induction (OR 1.80, 95% CI 1.12-2.88). Short-term complications included blood product transfusions (OR 18.26 95% CI 5.37-62.13) and prolonged hospitalization (OR 1.51 95% CI 1.06-2.16). Invasive procedures for removal of RPOC occurred in 12.2% of women in the study groups and in none of the women in the control group (p < .001). CONCLUSIONS: Manual placental removal harbors short and long-term complications, including a high likelihood of RPOC necessitating further invasive procedures. PMID- 28891362 TI - Alternatives to antibiotics in poultry feed: molecular perspectives. AB - The discovery of the growth promoting property of antibiotics led to their use as antibiotic feed additives (AFAs) in animal feed at sub-therapeutic doses. Although this has been beneficial for animal health and productivity, it has been, essentially, a double-edged sword. The continued and non-judicious use of AFAs has led to the selection and dissemination of antibiotic-resistant strains of poultry pathogens such as Salmonella, Campylobacter and Escherichia coli. The rapid spread of drug-resistant pathogens as well as emergence of antibiotic related environmental pollutants is of global concern. Hence, the identification and development of new and effective alternatives to antibiotics that do not hinder productivity is imperative. For this, it is essential to understand not only the molecular basis of development of resistance to AFAs but also the mechanisms of action of AFA alternatives and how they differ from AFAs. This review provides a molecular perspective on the alternatives to antibiotics that have been proposed till date and their current trends, as well as novel approaches such as development of improved delivery systems. PMID- 28891363 TI - Exploring the association of dental care utilization with oral impacts on daily performances (OIDP) - a prospective study of ageing people in Norway and Sweden. AB - OBJECTIVES: To explore the association of dental health care utilization with oral impacts on daily performances (OIDP) across time focusing ageing Norwegian and Swedish adults adjusting for predisposing, enabling, and need related-factors as defined by Andersen's model. METHODS: Data were based on Norwegian and Swedish 1942 birth-cohorts conducted in 2007 (age 65) and 2012 (age 70). In Norway, the response rates ranged from 54% to 58%. Corresponding figures in Sweden were from 72% to 73%. Self-administered questionnaires assessed OIDP, dental care utilization and predisposing, enabling and need related factors. Logistic regression with robust variance estimation was used to adjust for clustering in repeated data. RESULTS: Significant covariates of OIDP were satisfaction with dental services, dental care avoidance due to financial constraints, frightening experience with dental care during childhood and patient initiated dental visiting. Frequency and regularity of dental attendance were associated with OIDP in the Swedish cohort, only. CONCLUSIONS: In spite of country differences in the public co-financing of dental care, dental care utilization indicators were associated with OIDP across time in both cohorts. Encouraging regular and dentist initiated visiting patterns and strengthening beliefs in keeping own teeth could be useful in attempts to reduce poor oral health related quality of life in ageing people. PMID- 28891364 TI - An update on PCR use for minimal residual disease monitoring in acute lymphoblastic leukemia. AB - INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the first neoplasm where the assessment of early response to therapy by minimal residual disease (MRD) monitoring has proven to be a fundamental tool for guiding therapeutic choices. In recent years, thanks to real-time quantitative PCR (qPCR), MRD monitoring has further achieved higher levels of sensitivity and standardization. However, some outstanding issues still remain to be addressed and emerging technologies hold the promise of improving MRD detection in ALL patients. Areas covered: Through a comprehensive review of the literature, we analyze the state-of-the-art of molecular MRD assessment in ALL to better understand how, in the upcoming years, some of its limitations could be tackled by emerging molecular technologies. Furthermore, we highlight the future role of molecular MRD monitoring in the context of personalized protocols, taking into account the growing genetic complexity in ALL. Expert commentary: Although new molecular technologies are promising tools for MRD assessment, qPCR still remains the gold standard for evaluating MRD in ALL. High-throughput sequencing and droplet digital PCR allow to identify new prognostic factors and/or MRD targets at diagnosis and to perform earlier MRD evaluations, thereby optimizing patient stratification and earlier MRD-based clinical intervention to improve ALL patient outcomes. PMID- 28891365 TI - Gout in a rheumatology clinic: results of EULAR/ACR guidelines-compliant treatment. AB - OBJECTIVE: Surveys of treatment results of gout in primary care have shown that less than 25% of patients reach the recommended treatment target (serum urate < 0.36 mmol/l). The aim of this study was to measure the results of a specialized European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) guidelines-based treatment of gout in a rheumatology clinic. METHOD: Data from consecutive new crystal-proven gout patients were analysed in a prospective observational study. RESULTS: The study included 100 patients: 88 males aged 62.1 +/- 13.1 years (mean +/- sd) and 12 females aged 74.1 +/- 6.9 years. Disease duration was 8.6 +/- 6.9 years, and the disease pattern was monoarticular, oligoarticular, polyarticular, and tophaceous in 18, 37, 25, and 20 patients, respectively. Overall, 42% had tried urate-lowering treatment (ULT) ever and 15% were on ULT at entry. ULT was initiated or intensified in a treat-to-target (T2T) approach in 93 patients, with flare prophylactic colchicine treatment in 90 patients. T2T was successfully reached in 85 patients after 4.7 +/- 3.9 months and 82 patients reached a state of well-controlled disease (T2T reached for 3 months and no flares or anti-inflammatory treatment for 1 month) after 10.4 +/- 5.6 months. Ten patients did not reach T2T owing to low compliance and five patients did not reach T2T owing to adverse effects or nephropathy. CONCLUSION: EULAR/ACR guidelines-compliant treatment in a rheumatology clinic with verified diagnosis, patient education, T2T with ULT, and flare prophylaxis led to successful treatment results in 85% of patients. PMID- 28891366 TI - Efficacy and safety of B-cell receptor signaling pathway inhibitors in relapsed/refractory chronic lymphocytic leukemia: a systematic review and meta analysis of randomized clinical trials. AB - Ibrutinib and idelalisib, B-cell receptor (BCR) signaling pathway inhibitors, have been recently approved for use against relapsed/refractory chronic lymphocytic leukemia (CLL). To assess the efficacy and safety of BCR pathway inhibitors in relapsed/refractory CLL, we conducted a systematic review and meta analysis of five randomized controlled trials (1866 patients). Our study demonstrated that BCR pathway inhibitors significantly prolonged progression-free survival (PFS; pooled HR = 0.24; 95% CI: 0.19-0.30) and overall survival (HR = 0.58; 0.46-0.73) compared with control treatment. BCR pathway inhibitors increased the probability of response (RR = 3.54; 95% CI: 1.69-7.41) and decreased the risk of progression (RR = 0.21, 95% CI: 0.13-0.34). However, BCR pathway inhibitors increased the risk of grade 3 and 4 adverse events (AEs; RR = 1.25; 95% CI: 1.08-1.44) and serious AEs (RR = 1.32; 95% CI: 1.17-1.50). AEs causing discontinuation (RR = 1.26; 95% CI: 0.88-1.81) or death (RR = 1.06; 95% CI: 0.72-1.57) were not significantly increased. No statistically significant difference in any aspect of meta-analysis was noted between ibrutinib and idelalisib. PMID- 28891367 TI - Effect of Foeniculum vulgare (fennel) on symptoms of depression and anxiety in postmenopausal women: a double-blind randomised controlled trial. AB - The aim of this study was to evaluate the effect of Foeniculum vulgare (fennel) on anxiety and depression symptoms in postmenopausal women. This study was a double-blind, randomised, placebo-controlled trial, in which 60 eligible postmenopausal women were selected and then randomly assigned to fennel and placebo groups. Then, symptoms of anxiety and depression were measured using Hospital Anxiety and Depression Scale (HADS) and Zung's Self Rating Depression Scale (SDS). Following the intervention, the score of HADS (depression and anxiety subgroups) and SDS did not show any significant decrease in the sample under study. However, the analysis of patients with depression or anxiety disorder showed a borderline or significant improvement. Further studies with a larger sample size are required to confirm the findings. Impact statement Current knowledge on the subject: Based on the results of in vivo and in vitro animal studies, fennel may have anti-depressant and anti-anxiety properties. The contribution made by this study: It appears that fennel is effective in menopausal women with depression and anxiety disorders. The implications of findings for clinical practice and future research: Further studies with a larger sample size are required to confirm the actual effect of fennel in clinical setting. PMID- 28891368 TI - Medication Management in Schools: 2015 Survey Results. AB - The increasing prevalence of chronic conditions in children, for both common and rare conditions, over the past 30 years, and the increase in the number and range of medications used to manage these conditions, has contributed to the need to address medication management in schools. The purpose of this article is to present the key findings from a national survey on medication administration in schools. A nonexperimental cross-sectional design was used in this descriptive study. An online survey was sent to school nurses across the country. Responses from a total of 6,298 school nurses were used in the analysis. Results of the survey related to prescription and nonprescription medications, medication storage, student's carrying their medications, delegation of medication administration, documentation, and medication errors are discussed. The article concludes that many different medications are administered during the school day. School nurses must advocate for proper policies and procedures to guard the safety of students. PMID- 28891369 TI - Caffeinated and decaffeinated coffee consumption and melanoma risk: a dose response meta-analysis of prospective cohort studies. AB - To determine the association between total, caffeinated and decaffeinated coffee consumption and melanoma risk a dose-response meta-analysis on prospective cohort studies were performed. Eligible studies were identified searching PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by random-effects meta-analysis and the shape of the exposure-outcome curve was modelled linearly and using restricted cubic splines. A total of seven studies eligible for meta-analysis were identified that comprised 1,418,779 participants and 9211 melanoma cases. A linear dose-response meta-analysis showed a significant association between total coffee consumption and melanoma risk. An increase in coffee consumption of one cup per day was associated with a 3% reduction in melanoma risk (RR 0.97; 95% CI 0.95-0.99). Our findings suggest that coffee intake may be inversely associated with incidence of melanoma. Nevertheless, further studies exploring also the role of confounding factors are needed to explain the heterogeneity among studies. PMID- 28891370 TI - Countering the Consequences of Ego Depletion: The Effects of Self-Talk on Selective Attention. AB - This study examined the effects of a self-talk intervention on selective attention in a state of ego depletion. Participants were 62 undergraduate students with a mean age of 20.02 years (SD = 1.17). The experiment was conducted in four consecutive sessions. Following baseline assessment, participants were randomly assigned into experimental and control groups. A two-session training was conducted for the two groups, with the experimental group using self-talk. In the final assessment, participants performed a selective attention test, including visual and auditory components, following a task inducing a state of ego depletion. The analysis showed that participants of the experimental group achieved a higher percentage of correct responses on the visual test and produced faster reaction times in both the visual and the auditory test compared with participants of the control group. The results of this study suggest that the use of self-talk can benefit selective attention for participants in states of ego depletion. PMID- 28891371 TI - An observational, retrospective analysis evaluating switching to raltegravir plus abacavir/lamivudine in HIV-1-infected patients: the ORASWIRAL study. PMID- 28891372 TI - Controversies and advances in the management of ventilator associated pneumonia. AB - INTRODUCTION: Although national surveillance data suggests that the incidence of ventilator associated pneumonia (VAP) is down-trending, it remains one of the most commonly encountered hospital acquired infections in the United States and worldwide. Its association with increased healthcare costs and worsened patient outcomes warrants continued effort to improve the care of patients with VAP. Areas covered: The increasing prevalence of multi-drug resistant bacteria further drives the need to explore advances in diagnostic and treatment options. In this review, controversies pertaining to the definition and diagnosis of VAP as well as empiric treatment strategies will be discussed along with several developments related to rapid microbiologic testing methods and the use of non-traditional antimicrobial agents. Expert commentary: The application of rapid diagnostic techniques to identify microbial pathogens is perhaps one of the most impactful advancements in the treatment of serious nosocomial infections. This technology has the potential to reduce inappropriate initial antimicrobial therapy, unnecessary antimicrobial exposure, and mortality in patients with VAP. In addition, the anticipated approval of new antimicrobial agents within the next several years will provide a much-needed expansion of available treatment options in an era of growing antimicrobial resistance. PMID- 28891373 TI - The Emotional Labor of Personal Grief in Palliative Care: Balancing Caring and Professional Identities. AB - The paid provision of care for dying persons and their families blends commodified emotion work and attachments to two often-conflicting role identities: the caring person and the professional. We explore how health care employees interpret personal grief related to patient death, drawing on interviews with 12 health care aides and 13 nurses. Data were analyzed collaboratively using an interpretively embedded thematic coding approach and constant comparison. Participant accounts of preventing, postponing, suppressing, and coping with grief revealed implicit meanings about the nature of grief and the appropriateness of grief display. Employees often struggled to find the time and space to deal with grief, and faced normative constraints on grief expression at work. Findings illustrate the complex ways health care employees negotiate and maintain both caring and professional identities in the context of cultural and material constraints. Implications of emotional labor for discourse and practice in health care settings are discussed. PMID- 28891374 TI - Spontaneous dissection of the celiac artery in the young: a case report and systematic review of the literature. AB - INTRODUCTION: The spontaneous isolated celiac artery dissection (siCAD) represents a challenging cause of abdominal pain and complete information regarding incidence, etiology and risk factors in the young is still lacking. In this study, we report a case of siCAD occurred in a young woman and we systematically searched for information on siCADs in literature databases. METHODS: PubMed/Embase and Cochrane were searched for, using the following terms: Isolated celiac trunk dissection, isolated celiac artery dissection, celiac artery dissection, celiac trunk dissection, spontaneous isolated visceral artery dissection, spontaneous isolated dissection of visceral arteries, isolated celiac artery dissection in the young, isolated celiac trunk dissection in the young. Patients were included if they were younger than 50 years, if they had a spontaneous etiology and a selective involvement of the celiac artery (with or without involvement of its branches). RESULTS: 180 studies were found, and 18 remained after screening. Twenty-one patients (male = 19, female = 2) with siCADs were included. Mean age was 44.71 +/- 3.61 years. Hypertension was the most prevalent comorbidity. All patients presented with abdominal pain, more often located in the epigastrium (n = 11). Almost all patients underwent CT to confirm the diagnosis. A conservative treatment was adopted in 13 patients while an invasive approach was adopted in 8 patients (endovascular approach in 7). DISCUSSION: siCADs represent a rare but important cause of vascular dissection in the young. Uncomplicated cases can be safely treated with conservative strategies. The surgical or endovascular repair is indicated when dissections complicate or symptoms persist despite an adequate conservative treatment. PMID- 28891375 TI - Results of AFX Unibody Stent-Graft Implantation in Patients With TASC D Aortoiliac Lesions and Coexistent Abdominal Aortic Aneurysms. AB - PURPOSE: To describe results of AFX unibody stent-graft treatment for TransAtlantic Inter-Society Consensus (TASC) D aortoiliac occlusive disease (AIOD) with coexistent abdominal aortic aneurysm (AAA). METHODS: A retrospective analysis was conducted of 21 consecutive patients (mean age 73.6+/-6.4 years; 17 men) with TASC D AIOD plus AAA (diameter >3.5 cm) treated electively using the AFX stent-graft. Common iliac artery (CIA) and external iliac artery (EIA) stenosis or occlusion was reported. Outcome measures were technical and clinical success, improvement in ankle-brachial index (ABI), and improvement in Rutherford category. Immediate and midterm patency, AAA exclusion, major adverse events (MAE), and mortality were also evaluated. RESULTS: After AFX deployment (100% technical success), 18 EIAs required adjunctive stenting (none required in the CIA). One patient required a reintervention for closure device failure. At 30-day follow-up, no death or MAE was recorded. Improvement in ABI was registered in all patients (mean 0.91+/-0.11), with 100% primary patency. At a mean follow-up of 25.2+/-11.1 months, primary patency was maintained in all cases. No death or amputation occurred; 2 patients had a myocardial infarction. Improvement in ABI was maintained (0.88+/-0.13) as well as Rutherford category. CONCLUSION: This study examined the use of the AFX unibody stent-graft for the treatment of TASC D AIOD with concomitant AAA. The AFX stent-graft appears to be a safe and effective solution for these complex lesions, with low morbidity and mortality. PMID- 28891376 TI - Long-term Outcomes of a Telementoring Program for Distant Teaching of Endovascular Aneurysm Repair. AB - PURPOSE: To prospectively evaluate the long-term outcomes after a telementoring program for distant teaching of endovascular aneurysm repair (EVAR) and the degree of EVAR procedure assimilation into routine practice. METHODS: A telementoring protocol using stepwise introduction of EVAR was implemented between a university care center and a remote vascular health care site; from March 1999 to October 2003, 49 EVAR patients (mean age 72 years; 48 men) were treated during telementoring at the remote center. After the telementoring period, 86 patients (mean age 71 years; 77 men) underwent EVAR procedures carried out at the secondary care center from November 2003 to July 2011. The long-term outcomes were compared between the EVAR procedures performed during telementoring with the procedures performed independently thereafter. RESULTS: No significant difference was appreciated between telementored and not telementored procedures either in 30-day mortality (4.1% vs 2.3%, p=0.621) or in the initial technical success (93.9% vs 97.7%, p=0.353). The telementored group showed no significant difference in overall aneurysm-related mortality (6.1% vs 2.3%, p=0.353) or in the overall complication rates (p=0.985). The reintervention rate was significantly lower among the unmentored procedures (11.6% vs 32.7%, p=0.004). In particular, significantly fewer patients underwent late endovascular procedures (1.2% vs 12.2%, p=0.009) and late percutaneous interventions (7.0% vs 20.4%, p=0.027) after telementoring ceased. CONCLUSION: The telementoring program followed here allowed excellent EVAR skill assimilation into the routine practice of a remote health care site. Telementoring is a feasible strategy to support skill introduction in remote medical facilities. PMID- 28891377 TI - Executive Function Measures for Children: A Scoping Review of Ecological Validity. AB - Children use executive function (EF) skills within everyday occupations; however, EF poses a difficult and complex construct to measure. Currently, many measures of EF lack applicability to daily life, or ecological validity. The aim of this scoping review was to examine two aspects of ecological validity across measures, assessments, and tasks of EF in children. A scoping review of 355 peer-reviewed articles published between 1996 and 2016 was performed. Searching revealed 43 articles addressing the ecological validity of EF measures for children and 40 measures addressing ecological validity. An increasing number of articles address ecological validity of EF measures. Future research should address the interplay between context and EF performance. In addition, research should begin recognizing the importance of parental involvement in assessments, as well as ways to capture the EF strengths of children. PMID- 28891378 TI - In vitro inhibition of human UGT isoforms by ritonavir and cobicistat. AB - 1. Ritonavir and cobicistat are pharmacokinetic boosting agents used to increase systemic exposure to other antiretroviral therapies. The manufacturer's data suggests that cobicistat is a more selective CYP3A4 inhibitor than ritonavir. However, the inhibitory effect of ritonavir and cobicistat on human UDP glucuronosyltransferase (UGT) enzymes in Phase II metabolism is not established. This study evaluated the inhibition of human UGT isoforms by ritonavir versus cobicistat. 2. Acetaminophen and ibuprofen were used as substrates to evaluate the metabolic activity of the principal human UGTs. Metabolite formation rates were determined by HPLC analysis of incubates following in vitro incubation of index substrates with human liver microsomes (HLMs) at different concentrations of ritonavir or cobicistat. Probenecid and estradiol served as positive control inhibitors. 3. The 50% inhibitory concentrations (IC50) of cobicistat and ritonavir were at least 50 uM, which substantially exceeds usual clinical plasma concentrations. Probenecid inhibited the glucuronidation of acetaminophen (IC50 0.7 mM), but not glucuronidation of ibuprofen. At relatively high concentrations, estradiol inhibited ibuprofen glucuronidation (IC50 17 uM). 4. Ritonavir and cobicistat are unlikely to produce clinically important drug interactions involving drugs metabolized to glucuronide conjugates by UGT1A1, 1A3, 1A6, 1A9, 2B4 and 2B7. PMID- 28891379 TI - Linking Coach Interpersonal Style With Athlete Doping Intentions and Doping Use: A Prospective Study. AB - We brought together various lines of work on motivation, morality, and doping by testing a theory-based model prospectively linking contextual and personal motivational variables, moral attitudes, moral disengagement in doping, doping intentions, and doping use. Participants were 257 Greek athletes who completed a questionnaire pack at the beginning of a sport season. In the case of doping use, we also obtained data close to the end of the same season. The model showed that perceptions of controlling coach behaviors predicted athlete need frustration, which in turn predicted low moral functioning and doping intentions/doping use. The findings highlight pathways (direct and indirect) by which the social environment may impact on athletes' intentions and decisions to engage in doping and could pave the way for future antidoping interventions aimed at improving coaching interpersonal style. PMID- 28891380 TI - Stories of Hell and Healing: Internet Users' Construction of Benzodiazepine Distress and Withdrawal. AB - Benzodiazepines are a group of drugs used mainly as sedatives, hypnotics, antiepileptics, and muscle relaxants. Consumption is recommended for 2 to 4 weeks only, due to fast onset of dependency and potentially distressing withdrawal symptoms. Few peer-review studies have drawn on the user experiences and language to appreciate firsthand experiences of benzodiazepine withdrawal or discontinuation syndrome. We looked extensively at patient stories of benzodiazepine withdrawal and recovery on Internet support sites and YouTube. Our analysis indicated that users employ rich metaphors to portray the psychologically disturbing and protracted nature of their suffering. We identified seven major themes: hell and isolation, anxiety and depression, alienation, physical distress, anger and remorse, waves and windows, and healing and renewal. By posting success stories, ex-users make known that "healing" can be a long, unpredictable process, but distress does lessen, and recovery can happen. PMID- 28891381 TI - The impact of empathy and reappraisal on emotional intensity recognition. AB - Empathy represents a fundamental ability that allows for the creation and cultivation of social bonds. As part of the empathic process, individuals use their own emotional state to interpret the content and intensity of other people's emotions. Therefore, the current study was designed to test two hypotheses: (1) empathy for the pain of another will result in biased emotional intensity judgment; and (2) changing one's emotion via emotion regulation will modulate these biased judgments. To test these hypotheses, in experiment one we used a modified version of a well-known task that triggers an empathic reaction We found that empathy resulted in biased emotional intensity judgment. To the best of our knowledge, this is the first demonstration of a bias in the recognition of emotional facial expressions as a function of empathy for pain. In experiment two, we replicated these findings in an independent sample, and further found that this biased emotional intensity judgment can be moderated via reappraisal. Taken together, our findings suggest that the novel task used here can be employed to further explore the relation between emotion regulation and empathy. PMID- 28891382 TI - An Investigation of the Factors Related to Low Parent-Adolescent Attachment Security in Taiwan. AB - BACKGROUND: Adolescence may involve increases in many behavioral problems and psychosocial maladaptation. Adolescents must successfully cope with these challenges to achieve positive developmental milestones. OBJECTIVES: To investigate whether low parental attachment security among adolescents in Taiwan is associated with their demographic characteristics, psychosocial maladaptation, and depression. DESIGN: A cross-sectional survey. A total of 335 adolescents completed the questionnaires. The Inventory of Parent and Peer Attachment, the Chinese version of the Youth Self-Report, and the Beck Depression Inventory-II were used to survey the participants. Correlation and multiple linear regressions, using low attachment security as the response variable, were used in the statistical analysis. RESULTS: The prevalence of Taiwanese adolescents with low parental attachment security was 38.5%. Low parental attachment security in adolescents was significantly associated with parental remarriage status and psychosocial maladaptation. CONCLUSIONS: By considering these risk factors, nursing educators and nurses could develop effective interventions to strengthen parent-adolescent attachment security. PMID- 28891383 TI - A Hypothesis: Moderate Consumption of Alcohol Contributes to Lower Prevalence of Type 2 Diabetes Due to the Scavenging of Alpha-Dicarbonyls by Dietary Polyphenols. AB - The world is experiencing an epidemic of type-2-diabetes mellitus (T2DM). This has led to increased morbidity and mortality, explosive growth in health care budgets, and an even greater adverse, if indirect, impact on societies and economies of affected countries. While genetic susceptibility to T2DM is a major determinant of its prevalence, changes in lifestyles also play a role. One such change has been a transition from traditional diets characterized by low caloric and high nutrient density to calorie-rich but nutrient-poor Western diets. Given this, one solution to the epidemic of T2DM would be to abandon Western diets and revert to traditional eating patterns. However, traditional diets cannot provide enough calories for the increasing global population, so transition from traditional to Western foodstuffs appears to be irreversible. Consequently, the only practical solution to problems caused by these changes is to modify Western diets, possibly by supplementing them with functional foods containing nutrients that would compensate for these dietary deficits. I present in this study a hypothesis to explain why shifts from traditional to Western diets have been so problematic and to suggest nutrients that may counteract these adverse effects. I postulate that the components of traditional diets that may compensate for deficiencies of Westerns diets are scavengers of reactive alpha-dicarbonyls produced as unavoidable by-products of glucose and lipid metabolism. Most important among these scavengers are some plant secondary metabolites: polyphenols, phlorotannins, and carotenoids. They are found in alcoholic beverages and are abundant in seasonings, cocoa, coffee, tea, whole grains, pigmented vegetables, fruits, and berries. PMID- 28891384 TI - Nutrient and organic matter removal from low strength sewage treated with constructed wetlands. AB - The role of Eichhornia crassipes for removing pollutants from low strength sewage was evaluated in three pilot-scale constructed wetlands (CW): CW 1, planted with E. crassipes in a filter media; CW 2, unplanted, composed by filter media; and CW 3, composed by E. crassipes floating on the sewage. The operation was divided into three stages by varying the nominal hydraulic retention time into: (I) 24 h; (II) 48 h; (III) 72 h. Temporal sampling profiles were carried out with collection of the influent and effluent samples to determine temperature, pH, chemical oxygen demand (COD), TKN and TP. Contents of TP and TN were analyzed in the plant tissue of the macrophyte. The best removal efficiency rates for phosphorus (38%) and TKN (47%) were obtained in CW 3 for 72 h. The highest COD removal was observed in the CW 2 (80%) for 48 h. The macrophyte E. crassipes contributed to the absorption process with uptake rate percentages of 8.3% (CW 1) and 9.0% (CW 3) for TN and 0.78% (CW 1) and 1.56% (CW 3) for TP on the dry matter of the plant. The chosen species planted in the systems contributed to the achievement of higher nutrient removal. PMID- 28891385 TI - Trauma-Informed Parenting Classes Delivered to Rural Kinship Parents: A Pilot Study. AB - BACKGROUND: Without an informed approach, kinship parents, often grandparents, may struggle to effectively interact with their children who have experienced trauma. OBJECTIVES: The purpose of this pilot study was to describe the overall impact and acceptability of a trauma-informed parenting curriculum delivered to 16 rural-dwelling kinship parents. Nursing faculty partnered with Cooperative Extension Educators to deliver this curriculum, developed by the National Child Traumatic Stress Network. Semistructured interviews, an acceptability survey, and measures of parent, child, and family environment were used. DESIGN: This pilot, multisite, mixed-methods, intervention study employed a pre-post, paired test design. RESULTS: Significant differences were revealed on select items that measured parent-child nurturing and the families' cultural, political, and intellectual activities with posttest scores lower than pretest scores. Themes revealed processing the aftermath of child trauma and being a kinship parent. CONCLUSIONS: Although quantitative measures failed to demonstrate the impact of the curriculum, qualitative and satisfaction data provide preliminary evidence to support this intervention. PMID- 28891386 TI - Testing a Personal Narrative for Persuading People to Value and Use Comparative Physician Quality of Care Information: An Experimental Study. AB - OBJECTIVE: This study tests whether a personal narrative can persuade people to value comparative data on physician quality. METHOD: We conducted an online experiment with 850 adults. One group viewed a cartoon narrative on physician quality variation, another saw text on physician quality variation, and there was a control group. Study participants hypothetically selected a physician from a display of four physicians. The top-quality physician was furthest away and most expensive. We conducted multivariate models examining the relationship between experimental group and choice of the top-quality physician. RESULTS: There was no overall relationship between narrative or text information and choice of the highest quality physician. Among higher numerate participants, however, those who viewed the narrative had odds 2.7 times higher of selecting the top-quality physician compared with the control group. DISCUSSION: Personal narratives can persuade higher numerate people to consider quality when selecting physicians. PMID- 28891387 TI - A Discourse Analysis: One Caregiver's Voice in End-of-Life Care. AB - Informal family caregivers make a significant contribution to the U.S. health care system, and the need for caregivers will likely increase. Gaining deeper insights into the caregiver experience will provide essential knowledge needed to support the future caregiver workforce delivering care. Discourse analysis is a viable approach in analyzing textual caregiver data that focuses on the end-of life caregiving experience. The purpose of this study was to conduct an in-depth discourse analytic examination of 13 hours of caregiver interview data, which reveal the multiplicity of shifting stances and perceptions of one caregiver in the midst of end-of-life care, specifically with regard to his perceptions of self (caregiver) and other (care recipient). By isolating a specific but limited set of reference terms used throughout the discourse, we gained systematic glimpses into the mind and perceptions of this single caregiver in relation to his role as caregiver for his terminally ill wife. PMID- 28891388 TI - Men Respond Too: The Effects of a Social-Evaluative Body Image Threat on Shame and Cortisol in University Men. AB - Framed within social self-preservation theory, the present study investigated men's psychobiological responses to social-evaluative body image threats. University men ( n = 66) were randomly assigned to either a high or low social evaluative body image threat condition. Participants provided saliva samples (to assess cortisol) and completed measures of state body shame prior to and following their condition, during which anthropometric and strength measures were assessed. Baseline corrected values indicated men in the high social-evaluative body image threat condition had higher body shame and cortisol than men in the low social-evaluative body image threat condition. These findings suggest that social evaluation in the context of situations that threaten body image leads to potentially negative psychobiological responses in college men. PMID- 28891389 TI - Bioactive zwitterionic polymer brushes grafted from silicon wafers via SI-ATRP for enhancement of antifouling properties and endothelial cell selectivity. AB - Zwitterionic copolymers keep good resistance to platelet adhesion and nonspecific protein adsorption. In this study, A block copolymer brushes consisting of carboxybetaine methacrylate (CBMA) and glycidyl methacrylate (GMA) were grafted from silicon wafers via surface-initiated atom transfer radical polymerization, and then the Arg-Glu-Asp-Val (REDV) peptide was attached to the polymer brush via an reactive epoxy group of the P(GMA) unit to improve endothelial cells (ECs) selectivity. These modified surfaces were evaluated with scanning electron microscopy, atomic force microscopy, attenuated total reflectance-Fourier transform infrared spectra, X-ray photoelectron spectroscopy, and static water contact angle measurement. The results showed that REDV-modified zwitterionic brushes were successfully constructed on silicon wafers. The biocompatibility of the membrane was determined by plasma recalcification time assay and platelet adhesion test. The results showed that the modified substrate exhibited good blood compatibility. Moreover, the proliferation of ECs and smooth muscle cells onto the REDV-modified copolymer brushes were examined to demonstrate the synergistic effect of CBMA with antifouling property and REDV peptide with ECs selectivity. All assays showed that the silicon wafers displayed excellent EC selectivity after modification. In summary, REDV-modified zwitterionic brushes had great potential for cardiovascular stent implantation. PMID- 28891391 TI - Characteristics of Female Solo and Female Co-Offenders and Male Solo Sexual Offenders Against Children. AB - Studies have highlighted differences in the victim choice, offender, and offense characteristics of female and male sexual offenders. However, little is known about how solo and co-offending females differ from solo male sexual offenders. We compared the characteristics of 20 solo and 20 co-offending females (co offended with a male and/or female accomplice), and 40 male sexual offenders against children. We found that solo female offenders showed the most evidence of personal problems, including depression and sexual dissatisfaction. Compared with male offenders, female co-offenders showed poorer self-management, but better sexual self-regulation. Male offenders had a greater history of offending and showed more evidence of sexual abuse supportive cognitions relative to both solo and co-offending females. These results are consistent with the need for a gender specific approach to working with sexual offenders and may have implications for understanding the often complex treatment needs of these clients. PMID- 28891390 TI - Pathology and Epidemiology of Oxalate Nephrosis in Cheetahs. AB - To investigate cases of acute oxalate nephrosis without evidence of ethylene glycol exposure, archived data and tissues from cheetahs ( Acinonyx jubatus) from North America ( n = 297), southern Africa ( n = 257), and France ( n = 40) were evaluated. Renal and gastrointestinal tract lesions were characterized in a subset of animals with ( n = 100) and without ( n = 165) oxalate crystals at death. Crystals were confirmed as calcium oxalate by Raman spectroscopy in 45 of 47 cheetahs tested. Crystals were present in cheetahs from 3.7 months to 15.9 years old. Cheetahs younger than 1.5 years were less likely to have oxalates than older cheetahs ( P = .034), but young cheetahs with oxalates had more oxalate crystals than older cheetahs ( P < .001). Cheetahs with oxalate crystals were more likely to have renal amyloidosis, interstitial nephritis, or colitis and less likely to have glomerular loop thickening or gastritis than those without oxalates. Crystal number was positively associated with renal tubular necrosis ( P <= .001), regeneration ( P = .015), and casts ( P <= .001) but inversely associated with glomerulosclerosis, renal amyloidosis, and interstitial nephritis. Crystal number was unrelated to the presence or absence of colitis and was lower in southern African than American and European animals ( P = .01). This study found no evidence that coexisting chronic renal disease (amyloidosis, interstitial nephritis, or glomerulosclerosis), veno-occlusive disease, gastritis, or enterocolitis contributed significantly to oxalate nephrosis. Oxalate-related renal disease should be considered as a potential cause of acute renal failure, especially in young captive cheetahs. The role of location, diet, stress, and genetic predisposition in the pathogenesis of oxalate nephrosis in cheetahs warrants further study. PMID- 28891392 TI - ESR2 Gene and Medullary Thyroid Carcinoma. PMID- 28891393 TI - Improving Ambulatory Care Resident Training: Preparing for Opportunities to Treat Mental Illness in the Primary Care Setting. AB - PURPOSE: The development of an outpatient psychiatry clinical practice learning experience for PGY2 ambulatory care pharmacy residents in preparation for the treatment of psychiatric disorders in the primary care setting is described. SUMMARY: With the increased prevalence of psychiatric disorders, significant mortality, and limited access to care, integration of mental health treatment into the primary care setting is necessary to improve patient outcomes. Given the majority of mental health treatment occurs in the primary care setting, pharmacists in patient-centered medical homes (PCMHs) are in a unique position with direct access to patients to effectively manage these illnesses. However, the increased need for pharmacist education and training in psychiatry has prompted a large, Midwestern academic health system to develop an outpatient psychiatry learning experience for PGY2 (Postgraduate Year 2) ambulatory care pharmacy residents in 2015. The goal of this learning experience is to introduce the PGY2 ambulatory care residents to the role and impact of psychiatric clinical pharmacists and to orient the residents to the basics of psychiatric pharmacotherapy to be applied to their future practice in the primary care setting. CONCLUSION: The development of an outpatient psychiatry learning experience for PGY2 ambulatory care pharmacy residents will allow for more integrated and comprehensive care for patients with psychiatric conditions, many of whom are treated and managed in the PCMH setting. PMID- 28891394 TI - The Role of Chemokines in Thyroid Carcinoma. AB - The global incidence of thyroid cancer is increasing, and metastatic spread to the lymph nodes is common in papillary thyroid carcinoma. The metastatic course of thyroid carcinoma is an intricate process involving invasion, angiogenesis, cell trafficking, extravasation, organ specific homing, and growth. A key aspect in this process involves a multitude of interactions between chemokines and their receptors. Chemokines are a group of small proteins, which act to elicit normal physiologic and immune responses principally through recruitment of specific cell populations to the site of infection or malignancy. Thyroid cancer cells, like other tumors, possess the ability to corrupt the chemokine system to their advantage by altering cell movement into the tumor microenvironment and affecting all aspects of thyroid cancer progression. PMID- 28891395 TI - Effects of catechins and caffeine on the development of atherosclerosis in mice. AB - Atherosclerosis is one of the diseases related to metabolic syndrome which is caused by obesity. Previous reports have shown that green tea and its components have anti-obesity effect. We examined whether catechins and caffeine can prevent the development of atherosclerosis by oral administration, singly or in combination to the atherosclerosis model mice. Results demonstrated that the number of atherosclerotic regions in the aorta was significantly reduced by the combined treatment, and the atherosclerotic area was also improved. Serum HDL-C increased by caffeine single treatment, but no effect on the TG and TC by any treatments. Moreover, ECG illuviated to atheromatous lesions in aorta and the illuviation was enhanced by caffeine. The mRNA expression levels of LOX-1 and TNF alpha showed a tendency to suppress by the combined treatment. These results indicated that the combined administration of catechins and caffeine has the inhibitory effect on the development of atherosclerosis in mice. PMID- 28891396 TI - Dielectric and electric properties as a tool to investigate the coagulation mechanism during sludge treatment. AB - The analysis of the complex permittivity, electrical complex modulus and the hopping conductivity have been employed in order to investigate the impacts of calcium oxide during sludge treatment in textile such as coagulation process. In this context, impedance measurement was performed on five samples, including raw sludge and four compositions containing different amounts of calcium oxide: 2%, 3%, 4% and 5% (w/w). The dielectric spectra of each composition were described by the summation of a power law and a Cole-Cole relaxation model. The relaxation time and the magnitude of the dielectric relaxation obtained from the analysis of dielectric properties showed an increase up to 3% of these parameters with the addition of calcium oxide. Above this critical value, both parameters showed a very small change, suggesting that the aggregation became more stable. In addition, the evolution of the hopping conductivity reached a minimum value at this critical amount (3%). This evolution was well described by a double power law, which allowed us to estimate the optimal amount of the calcium oxide to achieve coagulation process. The analysis of the dielectric properties was found useful in monitoring aggregation processes that occur during the coagulation mechanism in textile sludge. PMID- 28891397 TI - Pharmacokinetic evaluation of beta-caryophyllene alcohol in rats and beagle dogs. AB - 1. beta-caryophyllene alcohol (BCPA) has shown therapeutic promise in the treatment of asthma and inflammation with low toxicity. The aim of the current study was to report the pharmacokinetic profiles of BCPA in rats and dogs. 2. Following intravenous administration, BCPA exhibited moderate volumes of distribution (Vz) ranging from 5.63 to 8.97 L/kg in rats and low Vz (2.89 +/- 1.12 L/kg) in dogs. Systemic plasma clearance was high in both species, resulting in a short elimination half-life ranging from 29.6 to 48.3 min. In rats, the intravenous pharmacokinetics was dose dependent. The measured oral bioavailability was low in rats for BCPA solution (1.17 +/- 0.78%), suspension (1.21 +/- 0.33%) and PEG formulation (6.22 +/- 2.63%). The bioavailability was lower in dogs for BCPA solution (0.12 +/- 0.05%) and PEG formulation (0.25 +/- 0.07%), indicating significant species difference. However, treatment of plasma samples with beta-glucuronidase increased the systematic exposure of BCPA as assessed from AUC (0-infinity) by 24.7- or 2.62-fold in rats and dogs, respectively, which suggested glucuronidation was a significant metabolic pathway for BCPA possibly due to first-pass metabolism. 3. In summary, this was the first preclinical pharmacokinetic investigation of BCPA in animals, providing vital knowledge for further preclinical research and subsequent clinical trials. PMID- 28891398 TI - Geometric analysis of loco-regional recurrences in relation to pre-treatment hypoxia in patients with head and neck cancer. AB - INTRODUCTION: A previous pattern-of-failure study has suggested that up to 50% of the loco-regional failures (LRF) in head and neck squamous cell carcinoma (HNSCC) occur outside the initial hypoxic volume determined by [18F]-fluoromisonidazole PET ([18F]-FMISO-PET). The aim of the present analysis was to correlate spatial patterns of failure with respect to the pretherapeutic dynamic [18F]-FMISO-PET/CT in HNSCC after radiochemotherapy (RCT). MATERIAL AND METHODS: Within a running phase 2 trial using [18F]-FMISO-PET imaging prior to RCT in HNSCC patients (n = 54), we have observed so far 11 LRF with a minimum follow-up of 12 months. For nine patients, LRF imaging (CT or [18F]-FDG-PET/CT) for pattern-of-failure analysis was available. Analysis included the static 4-h hypoxic subvolume (VH) as well as a M-parameter volume (VM), which is derived from modeling of dynamic PET. Deformable image registration of the CT scan with the recurrent tumor to the pre-treatment [18F]-FMISO-PET/CT and the planning CT was done to quantify the hypoxic subvolumes compared to the recurrent tumor volume. Moreover, a point-of origin analysis was performed. RESULTS: A total of five local, two regional and two loco-regional recurrences were detected. After deformable image registration of the CT scan with the recurrent tumor to the pre-treatment [18F]-FMISO-PET/CT and the planning CT, a significant overlap of the recurrence volume with [18F] FMISO-positive subvolumes in the initial gross tumor volume (GTV) was observed. Median overlap of 40.2%, range 9.4-100.0%, for VH and 49.0%, range 4.4-96.4%, for VM was calculated. The point-of-origin analysis showed median distances of 0.0 mm, range 0.0-11.3 mm to VH and 8.6 mm, range 0.0-15.5 mm to VM, respectively. CONCLUSIONS: Our data suggest that loco-regional recurrences after RCT originate from the initial GTV (primary tumor and/or lymph node metastases) containing hypoxic subvolumes, which supports the concept of hypoxia imaging-based dose escalation. PMID- 28891399 TI - Response of Human Fetal Liver Progenitor Cell Types to Temperature and pH Stresses In Vitro. AB - Prolonged physiological stresses, including abnormal pH and temperature, are deleterious. However, human hepatic progenitors have been shown to be quite tolerant of temporary temperature stress such as in cold ischemia. We aimed at identifying how various stresses affect liver progenitors, and at determining whether distinct effects exist on different progenitor cells of the human liver. Total fetal liver cells were exposed to low (25 degrees C), normal (37 degrees C), or high (40 degrees C) temperatures, or low (6.76), normal (7.35), or high (7.88) pH in vitro. Culture at 25 degrees C increased cell numbers and percentages of proliferation marker Ki67+ total cells. In total cell cultures, percentages of CD326+ hepatic progenitors co-expressing DLK1 (delta-like 1 homolog), SSEA4, or CD90 increased, as well as proliferation of SSEA4+ and CD235a+ progenitors. Analyses of presorted hepatic progenitors revealed that culture at 25 degrees C increased cell numbers of CD326+ hepatic stem/progenitor cells but not DLK+ hepatoblasts. The expression of several mesenchymal genes was reduced, and distinct hepatic stem/progenitor cell colonies emerged. At 40 degrees C, numbers of adherent hepatic cells decreased but those of hematopoietic nonadherent cells increased. High pH did not cause major effects. Acidic pH resulted in decreased total cell numbers and affected hematopoietic cells. Percentages of DLK1+ hepatoblasts were increased, but those of hematopoietic mature CD45+ cells were decreased. In particular, proliferation of adherent hepatic CD326+, SSEA4+ progenitors, and hematopoietic CD45+ cells and CD235a+ erythroblasts was reduced. Conclusively, our data indicate that low-temperature stress stimulates hepatic progenitor and erythroblast proliferation, whereas acidic pH promotes hepatic maturation and reduces hematopoietic cells. PMID- 28891400 TI - Glycosylated Cell Surface Markers for the Isolation of Human Cardiac Progenitors. AB - The aim of stem cell therapy after cardiac injury is to replace damaged cardiac tissue. Human cardiac progenitor cells (CPCs) represent an interesting cell population for clinical strategies to treat cardiac disease and human CPC specific antibodies would aid in the clinical implementation of cardiac progenitor-based cell therapy. However, the field of CPC biology suffers from the lack of human CPC-specific markers. Therefore, we raised a panel of monoclonal antibodies (mAb) against CPCs. Of this panel of antibodies, we show that mAb C1096 recognizes a progenitor-like population in the fetal and adult human heart and partially colocalize with reported CPC populations in vitro. Furthermore, mAb C1096 can be used to isolate a multipotent progenitor population from human heart tissue. Interestingly, the two lead candidates, mAb C1096 and mAb C19, recognize glycosylated residues on PECAM1 (platelet and endothelial cell adhesion molecule 1) and GRP78, respectively, and de-N-glycosylation significantly abolishes their binding. Thereby, this report describes new clinically applicable antibodies against human CPCs, and for the first time demonstrates the importance of glycosylated residues as CPCs specific markers. PMID- 28891402 TI - You Do What? A Qualitative Investigation Into the Motivation to Volunteer With Circles of Support and Accountability. AB - Most community members are not accepting of individuals convicted for sexual offenses living in their communities, let alone having regular contact with them. However, a select number of community members choose to give their time to assist these individuals reintegrate from prison into the community. Circles of Support and Accountability (CoSA) was developed as a way to address the issues that many individuals convicted of sex offenses face, that is, little to no prosocial support in the community. In-depth, semistructured interviews were conducted with 18 CoSA volunteers in New Zealand to gain a more thorough understanding of volunteers' motivation to be involved with CoSA. Thematic analysis was used to analyze the data. Three key themes of motivation were identified: (a) Restorative and Justice-Based Motivation, (b) Altruistic Motivation, and (c) Faith-Based Motivation. Findings are discussed in terms of their implications for future recruitment of volunteers for CoSAs. PMID- 28891401 TI - Revascularization of the superficial femoral artery with paclitaxel-coated balloon for claudication. AB - BACKGROUND: Percutaneous angioplasty of the superficial femoral artery (SFA) with paclitaxel-coated balloon, intended to reduce restenosis, has been proven safe and effective in recent randomized controlled trials. OBJECTIVE: To assess outcome results of angioplasty of the SFA with paclitaxel-coated balloon in claudicants in real-world practice of a single center. MATERIAL & METHODS: A continuous prospective cohort study of 53 claudicants (62 lower limbs) from January 2015 to December 2016. Study end points include primary patency, freedom from clinically driven target-lesion revascularization and symptom relief. RESULTS: It concerns 17 women (32%) and 36 men (68%) with a mean age of 67.8 years, suffering life-style-limiting claudication. Only short to intermediate length stenoses or occlusions (30.6%), with a mean length of 59.6 mm were selected for percutaneous angioplasty with a paclitaxel-coated balloon. Technical success was 100%. At 16 months, primary patency attained 92.0% (3 early occlusions, 2 restenoses). There were two re-interventions at 6 and 9 months, resulting in a clinically driven target lesion revascularization rate of 3.2%. At the end of the follow-up of 16 months, all but two patients (96.2%) remained symptom-free. Two patients died during follow-up (no procedure-related deaths). CONCLUSION: Paclitaxel-coated balloon angioplasty of the SFA gives in routine clinical practice excellent midterm results, with a restenosis rate of 6.5% at 1 year. This procedure has authors' preference as first-choice technique for correction of short- and intermediate-length symptomatic stenoses of the SFA. PMID- 28891403 TI - A sensory evoked response or precise anticipatory modulation? Mechanisms underlying the reported C1 modulation by spatial attention. AB - Almost ten years ago, Kelly and collegues reported that the earliest component (i.e., the C1) of the visual evoked potential (VEP) could be modulated by spatial attention. Using a similar experimental design and data analysis methods, however, Baumgartner et al. (this issue) recently failed to provide confirmative evidence. In this commentary, I suggest that some minor differences in experimental design may account for the inconsistent results between the two studies. I also propose a hypothesis that the C1 effect reported in Kelly et al. may not necessarily reflect modulations of the initial visual evoked response in human V1. PMID- 28891404 TI - Adapted Morris Water Maze protocol to prevent interference from confounding motor deficits on cognitive functioning. AB - : Purpose/aim of the study: Cognitive functioning in the Morris Water Maze (MWM) is assumed to be reflected by path length. In this study, the interference of motor deficits, as a confounding factor on cognitive functioning, was assessed by means of a lateralization study with hemicerebellectomized (HCX) mice. This model is characterized by motor deficits restricted to the lesion side, allowing comparison within the model itself (left vs. right), rather than the effect of the manipulation on this measure (experimental vs. control). MATERIALS AND METHODS: Spatial learning was assessed after left or right hemicerebellectomy in adult mice by means of two MWM designs in which the location of the starting positions was altered for one condition in the adapted (Adap) MWM experiment, hypothesizing that motor impairments ipsilateral to the lesion side result in a difference in path length. RESULTS: When the starting positions were equal for both conditions in the traditional (Trad) MWM experiment, path length during the acquisition phase and spatial memory were more affected for the left HCX, while these effects disappeared after mirroring the starting positions in the Adap MWM, implying that motor phenotype and corresponding increase in task difficulty are responsible for the contradictory results in the Trad MWM experiment. CONCLUSION: The differences found in the latter experiment were circumvented in the adapted MWM protocol, and therefore, excluding the motor deficit as a confounding factor on cognitive MWM parameters. PMID- 28891405 TI - Projecting Survival in Papillary Thyroid Cancer: A Comparison of the Seventh and Eighth Editions of the American Joint Commission on Cancer/Union for International Cancer Control Staging Systems in Two Contemporary National Patient Cohorts. AB - BACKGROUND: This study aims to compare the seventh and eighth editions of the American Joint Commission on Cancer/Union for International Cancer Control (AJCC/UICC) tumor, node, metastasis staging system for patients with papillary thyroid cancer (PTC) in two national patient cohorts. METHODS: Adult PTC patients undergoing surgery were selected from the Surveillance, Epidemiology and End Results (SEER) program (2004-2012) and the National Cancer Database (2004-2012). Staging criteria for the seventh and eighth AJCC/UICC editions were applied separately to each cohort. Survival probabilities were estimated using the Kaplan Meier method. Multivariable Cox proportional hazards models were used to estimate the association of stage with survival in both settings. The Akaike information criterion was used to assess model performance. RESULTS: About 23% of patients were downstaged from the seventh to the eighth edition in SEER, while 24% were downstaged in the National Cancer Database. Disease-specific survival (DSS) and overall survival (OS) were significantly related to stage at diagnosis when using both the seventh and eighth editions of the AJCC/UICC staging system (p < 0.001). Patients classified into higher stages (III and IV) in the eighth edition showed a worse prognosis than those classified into similar stages in the seventh edition. After adjustment, PTC stages as defined by both editions were significantly associated with DSS and OS. With respect to both DSS and OS, the eighth edition PTC model appeared to be a better fit to the data (smaller Akaike information criterion values) compared to the seventh edition. CONCLUSION: Based on these large contemporary national cohorts, the eighth edition AJCC/UICC tumor, node, metastasis classification for PTC is superior to the seventh edition for predicting survival. PMID- 28891406 TI - Clinical Practice Guideline: Evaluation of the Neck Mass in Adults. AB - Objective Neck masses are common in adults, but often the underlying etiology is not easily identifiable. While infections cause most of the neck masses in children, most persistent neck masses in adults are neoplasms. Malignant neoplasms far exceed any other etiology of adult neck mass. Importantly, an asymptomatic neck mass may be the initial or only clinically apparent manifestation of head and neck cancer, such as squamous cell carcinoma (HNSCC), lymphoma, thyroid, or salivary gland cancer. Evidence suggests that a neck mass in the adult patient should be considered malignant until proven otherwise. Timely diagnosis of a neck mass due to metastatic HNSCC is paramount because delayed diagnosis directly affects tumor stage and worsens prognosis. Unfortunately, despite substantial advances in testing modalities over the last few decades, diagnostic delays are common. Currently, there is only 1 evidence based clinical practice guideline to assist clinicians in evaluating an adult with a neck mass. Additionally, much of the available information is fragmented, disorganized, or focused on specific etiologies. In addition, although there is literature related to the diagnostic accuracy of individual tests, there is little guidance about rational sequencing of tests in the course of clinical care. This guideline strives to bring a coherent, evidence-based, multidisciplinary perspective to the evaluation of the neck mass with the intention to facilitate prompt diagnosis and enhance patient outcomes. Purpose The primary purpose of this guideline is to promote the efficient, effective, and accurate diagnostic workup of neck masses to ensure that adults with potentially malignant disease receive prompt diagnosis and intervention to optimize outcomes. Specific goals include reducing delays in diagnosis of HNSCC; promoting appropriate testing, including imaging, pathologic evaluation, and empiric medical therapies; reducing inappropriate testing; and promoting appropriate physical examination when cancer is suspected. The target patient for this guideline is anyone >=18 years old with a neck mass. The target clinician for this guideline is anyone who may be the first clinician whom a patient with a neck mass encounters. This includes clinicians in primary care, dentistry, and emergency medicine, as well as pathologists and radiologists who have a role in diagnosing neck masses. This guideline does not apply to children. This guideline addresses the initial broad differential diagnosis of a neck mass in an adult. However, the intention is only to assist the clinician with a basic understanding of the broad array of possible entities. The intention is not to direct management of a neck mass known to originate from thyroid, salivary gland, mandibular, or dental pathology as management recommendations for these etiologies already exist. This guideline also does not address the subsequent management of specific pathologic entities, as treatment recommendations for benign and malignant neck masses can be found elsewhere. Instead, this guideline is restricted to addressing the appropriate work-up of an adult patient with a neck mass that may be malignant in order to expedite diagnosis and referral to a head and neck cancer specialist. The Guideline Development Group sought to craft a set of actionable statements relevant to diagnostic decisions made by a clinician in the workup of an adult patient with a neck mass. Furthermore, where possible, the Guideline Development Group incorporated evidence to promote high quality and cost-effective care. Action Statements The development group made a strong recommendation that clinicians should order a neck computed tomography (or magnetic resonance imaging) with contrast for patients with a neck mass deemed at increased risk for malignancy. The development group made the following recommendations: (1) Clinicians should identify patients with a neck mass who are at increased risk for malignancy because the patient lacks a history of infectious etiology and the mass has been present for >=2 weeks without significant fluctuation or the mass is of uncertain duration. (2) Clinicians should identify patients with a neck mass who are at increased risk for malignancy based on >=1 of these physical examination characteristics: fixation to adjacent tissues, firm consistency, size >1.5 cm, or ulceration of overlying skin. (3) Clinicians should conduct an initial history and physical examination for patients with a neck mass to identify those with other suspicious findings that represent an increased risk for malignancy. (4) For patients with a neck mass who are not at increased risk for malignancy, clinicians or their designees should advise patients of criteria that would trigger the need for additional evaluation. Clinicians or their designees should also document a plan for follow up to assess resolution or final diagnosis. (5) For patients with a neck mass who are deemed at increased risk for malignancy, clinicians or their designees should explain to the patient the significance of being at increased risk and explain any recommended diagnostic tests. (6) Clinicians should perform, or refer the patient to a clinician who can perform, a targeted physical examination (including visualizing the mucosa of the larynx, base of tongue, and pharynx) for patients with a neck mass deemed at increased risk for malignancy. (7) Clinicians should perform fine-needle aspiration (FNA) instead of open biopsy, or refer the patient to someone who can perform FNA, for patients with a neck mass deemed at increased risk for malignancy when the diagnosis of the neck mass remains uncertain. (8) For patients with a neck mass deemed at increased risk for malignancy, clinicians should continue evaluation of patients with a cystic neck mass, as determined by FNA or imaging studies, until a diagnosis is obtained and should not assume that the mass is benign. (9) Clinicians should obtain additional ancillary tests based on the patient's history and physical examination when a patient with a neck mass is deemed at increased risk for malignancy who does not have a diagnosis after FNA and imaging. (10) Clinicians should recommend evaluation of the upper aerodigestive tract under anesthesia, before open biopsy, for patients with a neck mass deemed at increased risk for malignancy and without a diagnosis or primary site identified with FNA, imaging, and/or ancillary tests. The development group recommended against clinicians routinely prescribing antibiotic therapy for patients with a neck mass unless there are signs and symptoms of bacterial infection. PMID- 28891407 TI - Substance Use and Self-Harm: Case Studies From Patients Admitted to an Urban Hospital Following Medically Serious Self-Harm. AB - Few qualitative studies have explored the relationship between substance use and self-harm. We employed a multiple-case study research design to analyze data from 80 patients who were admitted to a hospital in South Africa following self-harm. Our analysis revealed, from the perspective of patients, a number of distinct ways in which substance use is implicated in self-harm. Some patients reported that substance intoxication resulted in poor decision making and impulsivity, which led to self-harm. Others said substance use facilitated their self-harm. Some participants detailed how in the past their chronic substance use had served an adaptive function helping them to cope with distress, but more recently, this coping mechanism had failed which precipitated their self-harm. Some participants reported that substance use by someone else triggered their self-harm. Findings suggest that there are multiple pathways and a host of variables which mediate the relationship between substance use and self-harm. PMID- 28891409 TI - Health Among Schoolchildren From the School Nurse's Perspective. AB - The aim of the study was to investigate Swedish school nurses' perceptions of schoolchildren's health. The study is based on two national surveys in which school nurses responded to questions about schoolchildren's health in 2015 ( n = 181) and 2005 ( n = 129). A statistical comparison showed that physical and mental health of schoolchildren in high-risk areas was perceived as worse than that of children in low-risk areas. There were no differences regarding the number of spontaneous visits or consulting reasons related to gender in high- and low-risk areas. A national framework for data collection and reporting of schoolchildren's health may be important for school nurses to demonstrate the need for increased support in, for example, high-risk areas. By paying attention to factors that can affect schoolchildren's health, school nurses can also direct health promotion to areas where it is needed. Increased cooperation among school health professionals may also prevent illness and improve health. PMID- 28891408 TI - Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. AB - BACKGROUND: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. RESULTS: At a median follow-up of 2.8 years, the estimated 3 year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. CONCLUSIONS: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .). PMID- 28891410 TI - Strategies of Adolescent Girls and Boys for Coping With School-Related Stress. AB - Stress among adolescents in Western societies is becoming an issue of increasing concern of adolescent's health. The aim of this study was to gain greater knowledge about how girls and boys perceive and cope with school-related stress. Participants were 14- to 15-year-old adolescents from a medium-sized municipality in southern Sweden. The data were collected from focus group interviews. The data were subjected to qualitative content analysis. The findings show that adolescents "prioritizing the future or the present by making choices, finding their own private sphere to relax, and recovering with family and friends." There were gender differences in how these strategies were used. The findings could be used for initiating and planning health promotion interventions in school with focus on supporting girls' and boys' equal terms to cope with school-related stress in present and for the future and to give equal condition for future studies and opportunities in life. PMID- 28891411 TI - Student Projects and Publications. PMID- 28891412 TI - A novel prothrombin time method to measure all non-vitamin K-dependent oral anticoagulants (NOACs). AB - BACKGROUND: There is a clinical need for point-of-care (POC) methods for non vitamin K-dependent oral anticoagulants (NOACs). We modified a routine POC procedure: Zafena's Simple SimonTM PT-INR, a room-temperature, wet-chemistry prothrombin time method of the Owren-type. METHODS: To either increase or decrease NOAC interference, two assay variants were devised by replacing the standard 10 uL end-to-end capillary used to add the citrated plasma sample to 200 uL of prothrombin time (PT) reagent by either a 20 uL or a 5 uL capillary. All assay variants were calibrated to show correct PT results in plasma samples from healthy and warfarin-treated persons. RESULTS: For plasmas spiked with dabigatran, apixaban, or rivaroxaban, the 20 uL variant showed markedly higher PT results than the 5 uL. The effects were even more pronounced at room temperature than at +37 degrees C. In plasmas from patients treated with NOACs (n = 30 for each) there was a strong correlation between the PT results and the concentration of NOACs as determined by the central hospital laboratory. For the 20 uL variant the PT response of linear correlation coefficient averaged 0.90. The PT range was INR 1.1-2.1 for dabigatran and apixaban, and INR 1.1-5.0 for rivaroxaban. Using an INR ratio between the 20 uL and 5 uL variants (PTr20/5) made the NOAC assay more robust and independent of the patient sample INR value in the absence of NOAC. Detection limits were 80 ug/L for apixaban, 60 ug/L for dabigatran, and 20 ug/L for rivaroxaban. CONCLUSIONS: A wet-chemistry POC PT procedure was modified to measure the concentrations of three NOACs using a single reagent. PMID- 28891413 TI - Post-infectious glomerulonephritis. AB - Post-infectious glomerulonephritis (PIGN) is one of the most common causes of acute glomerulonephritis in children. Although post-streptococcal glomerulonephritis (PSGN) is still common, there is a wide spectrum of causative agents of PIGN. Non-streptococcal organisms are emerging as the main aetiological agents in high-income countries. Nephritis-associated plasmin receptor (NAPlr) and streptococcal pyrogenic exotoxin B (SPeB) are the two common antigens implicated in the pathogenesis of PSGN. Both NAPlr and SPeB activate the alternative complement pathway, resulting in low serum complement levels, and have an affinity to plasmin and glomerular proteins. The clinical presentation of PIGN varies from a benign asymptomatic condition to rapidly progressive glomerulonephritis requiring dialysis. In most cases, PIGN is self-limiting and the evidence base for the treatments used is quite weak. Renal biopsy is indicated when there are atypical features, rapid progression or inadequate recovery, or where an alternative diagnosis has to be considered. IgA-dominant nephritis, endocarditis-associated nephritis and shunt nephritis are special sub subtypes of PIGN. The prognosis is generally excellent, although long-term follow up may be needed. PMID- 28891414 TI - Therapeutic effects of walnut oil on the animal model of multiple sclerosis. AB - OBJECTIVES: Therapeutic approaches for multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), are accompanied by various undesirable side effects. Owing to the anti-inflammatory and antioxidant effects of walnut, we investigated its effects on the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: After EAE induction in mice, the treated group was gavaged daily with walnut oil. The weights and clinical symptoms were monitored daily for 21 days following the onset of symptoms. The spleens and brains of the mouse were removed and used for ELISA and histological studies. RESULTS: The average disease severity and plaque formation in the brains of the walnut oil-treated group were significantly lower (P < 0.05) than those of the untreated group. Stimulated splenocytes of the treated group expressed significantly less INF-gamma and interleukin (IL)-17 than the untreated group with no significant differences in IL-10 or IL-5 production. In serum from the treated group, IL-17 expression was also significantly less than in the untreated group, while IL-10 was greater (P < 0.05). CONCLUSION: Walnut oil significantly reduced disease severity, inhibited plaque formation, and altered cytokine production. More studies are required to identify the mechanism of action of walnut oil as a valuable supplement in the treatment of MS. PMID- 28891416 TI - Role of Innate Immunity in Preeclampsia: A Systematic Review. AB - Innate immune system dysfunction has been known to be a key player in preeclampsia (PE). Activation of the maternal innate immunity may be triggered by invading microorganisms or endogenous ligands, which are detected by different pattern recognition receptors (PRRs). Although some studies have linked PRR activation to PE, it is still unclear if dysregulated PRR expression is associated with the development of this complication. Therefore, we conducted a systematic review of the literature, searching articles that evaluated associations of PRRs with PE. Twenty-six studies met the inclusion criteria: 20 of them analyzed PRR expressions and 6 studies investigated the association between PRR polymorphisms and PE. Among the PRRs, only few studies analyzed retinoic acid-inducible gene I-like helicase (RLH) and/or toll-like receptor (TLR)-1, 5, 6, 7, 8, and 9 expressions in immune cells or placentas from women with PE and controls; thus, it is inconclusive if these PRRs are involved in PE. Results from the 10 studies that analyzed TLR-2 expressions in women with PE and controls are also contradictory. The majority of the studies that investigated TLR-3 and -4 expressions indicate that these PRRs are increased in placenta or immune cells from women with PE compared to pregnant control woman. To date, polymorphisms in TLR-2, - 3, and - 4 and nucleotide-binding oligomerization domain-like receptor 2 genes do not seem to be associated with PE development. No study has evaluated the association between polymorphisms in genes codifying other TLRs or RLHs genes. In conclusion, available data in literature support a role for TLR-3 and TLR-4 in the pathogenesis of PE. PMID- 28891417 TI - Androgens Upregulate Endometrial Epithelial Progesterone Receptor Expression: Potential Implications for Endometriosis. AB - BACKGROUND: Androgenic compounds have been implicated in induction of endometrial atrophy yet the mechanisms of androgen effects on human endometrium have not been well studied. We hypothesized that androgens may promote their endometrial effects via modulation of progesterone receptor (PR) expression. METHODS: Proliferative phase endometrial samples were collected at the time of hysterectomy. We evaluated the effect of the potent androgen 5alpha dihydrotestosterone (DHT) on endometrial PR expression by treating human endometrial explants, endometrial stromal cells, and Ishikawa cells with DHT. Ishikawa cells were also treated with DHT +/- the androgen receptor (AR) blocker flutamide. The PR-B, total PR messenger RNA (mRNA), and PR protein expression were assessed. Expression of cyclin D1 and D2 was checked as markers of cell proliferation. RESULTS: As expected, estradiol induced PR expression in isolated stromal cells, endometrial epithelial cells, and tissue explants. The DHT treatment also resulted in increased PR expression in endometrial explants and Ishikawa cells but not in stromal cells. Further, protein levels of both nuclear PR isoforms (PR-A and PR-B) were induced with the DHT treatment. Although flutamide treatment alone did not affect PR expression, flutamide diminished androgen-induced upregulation of PR in both endometrial explants and Ishikawa cells. Although estradiol induced both cyclin D1 and cyclin D2 mRNA, DHT did not induce these markers of cell proliferation. CONCLUSION: Androgens may mediate endometrial effects through upregulation of PR gene and protein expression. Endometrial PR upregulation by androgens is mediated, at least in part, through AR. PMID- 28891418 TI - Two years follow-up of an open-label pilot study of treatment with rituximab in patients with early diffuse cutaneous systemic sclerosis. AB - OBJECTIVES: Following results in open-label studies of rituximab in patients with systemic sclerosis, a Belgian three-centre initiative was launched to explore safety and efficacy of rituximab in early, diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Open-label study of 17 patients with early dcSSc, treated with two courses of rituximab, at month 0 and 6. Clinical examination, lung function testing, echocardiography, disease activity score (DAS) and functional status were performed at baseline and over 24 months of follow-up. RESULTS: Modified Rodnan skin score (MRSS) changed significantly over time, with a mean of 25.5 (standard deviation [SD] 6.0) at baseline to 12.6 (SD 5.1) at month 24 (Mixed Model Analysis [MMA] p < 0.0001), which is a decrease of 51% at month 24 vs. baseline. DAS showed significant decrease over the total study period, with a score of 4.1 (SD 1.7) at baseline to 1.5 (SD 1.8) at month 24 (MMA p < 0.0001). Additionally, this was significant at all time points vs. baseline, both for MRSS and DAS. Internal organ status remained clinically stable throughout the study period. No statistically significant differences compared to baseline were found at the follow-up time points. Seven serious adverse events took place, all except for one, considered unrelated to study medication. CONCLUSIONS: This is the first multicentre Belgian collaboration investigating potential efficacy of rituximab in early dcSSc. Rituximab appears to be safe and tolerable and it may have beneficial effects on skin involvement, on overall disease activity and on stabilization of internal organ status in early dcSSc. PMID- 28891420 TI - Influence of Al(III) on biofilm and its extracellular polymeric substances in sequencing batch biofilm reactors. AB - This paper presented the influence of Al(III) on biodegradability, micromorphology, composition and functional groups characteristics of the biofilm extracellular polymeric substances (EPS) during different growth phases. The sequencing batch biofilm reactors were developed to cultivate biofilms under different Al(III) dosages. The results elucidated that Al(III) affected biofilm development adversely at the beginning of biofilm growth, but promoted the biofilm mass and improved the biofilm activity with the growth of the biofilm. The micromorphological observation indicated that Al(III) led to a reduction of the filaments and promotion of the EPS secretion in growth phases of the biofilm, also Al(III) could promote microorganisms to form larger colonies for mature biofilm. Then, the analysis of EPS contents and components suggested that Al(III) could increase the protein (PN) of tightly bound EPS (TB-EPS) which alleviated the metal toxicity inhibition on the biofilm during the initial phases of biofilm growth. The biofilm could gradually adapt to the inhibition caused by Al(III) at the biofilm maturation moment. Finally, through the Fourier transform infrared spectroscopy, it was found that Al(III) was beneficial for the proliferation and secretion of TB-EPS functional groups, especially the functional groups of protein and polysaccharides. PMID- 28891419 TI - Effects of listening to Holy Qur'an recitation and physical training on dialysis efficacy, functional capacity, and psychosocial outcomes in elderly patients undergoing haemodialysis. AB - The purpose of this study was to determine whether listening to Holy Qur'an recitation would augment the beneficial effects of physical exercise on physiological and psychological measures in elderly patients undergoing haemodialysis. Fifty-three male haemodialysis patients were randomly assigned to an intervention group (listening to Holy Qur'an recitation in combination with endurance-resistance training, n = 28) or a control group (endurance-resistance training only, n = 25). Functional capacity was assessed using the Timed Up and Go test (TUG) and the Six-Minute Walk Test (6MWT). Psychosocial outcomes were assessed using the Medical Outcomes Study 36-item Short-Form Health Survey (SF 36) and Hospital Anxiety and Depression Scale (HADS). Dialysis adequacy (Kt/V) was calculated for all patients. After intervention, a significant Group * Period interaction effect was observed for all measured parameters (p < 0.05), except for 6MWT performance (p > 0.05). All measured parameters were significantly improved over baseline in both groups, except for Kt/V in the control group (p > 0.05). Moreover, final measurements were significantly higher in the intervention group than in the control group for all measured parameters, except for 6MWT performance and the physical component summary of the SF-36 (p > 0.05). In conclusion, the present study showed that listening to a recitation of the Holy Qur'an in combination with interdialytic endurance-resistance training induced an improvement in physical condition and quality of life and a large reduction in anxiety among patients undergoing haemodialysis. PMID- 28891421 TI - Bone marrow aspiration for regenerative orthopedic intervention: technique with ultrasound guidance for needle placement. AB - AIM: We review relevant anatomy of the iliac crest, and describe an interventional technique to maximize harvesting of desired progenitor cells with ultrasound to guide safe trochar placement. MATERIALS & METHODS: We validated the technique on both sides of the pelvis in four human cadavers. RESULTS: Using ultrasound guidance, 32 BMA needles were placed in a safe zone along various portions of the iliac crest. CONCLUSION: Ultrasound guidance can improve accuracy of bone marrow aspirations form the iliac crest. Mastery of this procedure will facilitate cell harvest and aid in patient safety when procuring mesenchymal stem cells from a bone marrow source. PMID- 28891422 TI - Water-soluble and amphiphilic phospholipid copolymers having 2 methacryloyloxyethyl phosphorylcholine units for the solubilization of bioactive compounds. AB - We summarize the development and evaluation of new type of phospholipid polymers as a solubilizer for poorly water-soluble compounds. That is, a water-soluble and amphiphilic poly(2-methacryloyloxyethyl phosphorylcholine-random-n-butyl methacrylate) contains 30 mol% hydrophilic 2-methacryloyloxyethyl phosphorylcholine units and its weight-averaged molecular weight is around 5.0 * 104. When the polymer is dissolved in an aqueous medium, a large portion of hydrophobic n-butyl methacrylate units assemble, forming polymer aggregates. To avoid severe biological reactions caused by conventional solubilizers, the phospholipid polymer can be applied for the solubilization of poorly water soluble bioactive compounds. The polarity inside these polymer aggregate is the same as that of ethanol and n-butanol. Therefore, bioactive compounds, whose solubility is poor in water but good in these alcohols, can be entrapped in the polymer aggregate. The phospholipid polymer can penetrate the cell membrane by molecular diffusion, carrying inside the cell the bioactive compound, without exhibiting significant cytotoxicity. Several animal experiments have revealed that the pharmacological performance of various bioactive compound/phospholipid polymer complexes is excellent. Furthermore, functionalization of the polymer aggregate with biomolecules, such as antibodies and oligonucleotides, can be done, leading to selective capturing of the target molecules. These examples clearly indicate that water-soluble and amphiphilic phospholipid polymer is a candidate for preparing safer formulations and more effective pharmaceutical treatment with several bioactive compounds. PMID- 28891425 TI - Plain Language Summary: Evaluation of the Neck Mass in Adults. AB - This plain language summary serves as an overview in explaining the evaluation of the neck mass in adults. The summary applies to patients aged >=18 years and is based on the 2017 "Clinical Practice Guideline: Evaluation of the Neck Mass in Adults." The evidence-based guideline includes research to support more effective evaluation and diagnosis of the neck mass in adults. The guideline was developed as a quality improvement opportunity for evaluation of the neck mass by creating clear recommendations to use in medical practice. PMID- 28891424 TI - Clinical Practice Guideline: Evaluation of the Neck Mass in Adults Executive Summary. AB - The American Academy of Otolaryngology-Head and Neck Surgery Foundation has published a supplement to this issue of Otolaryngology-Head and Neck Surgery featuring the "Clinical Practice Guideline: Evaluation of the Neck Mass in Adults." To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 12 recommendations developed emphasize reducing delays in diagnosis of head and neck squamous cell carcinoma; promoting appropriate testing, including imaging, pathologic evaluation, and empiric medical therapies; reducing inappropriate testing; and promoting appropriate physical examination when cancer is suspected. PMID- 28891426 TI - In Reference to "Analysis of the Relationship between the Location of the Anterior Ethmoid Artery and Keros Classification"-Reply. PMID- 28891427 TI - In Reference to "Analysis of the Relationship between the Location of the Anterior Ethmoid Artery and Keros Classification". PMID- 28891423 TI - Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. AB - BACKGROUND: Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (>=15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence free survival in the intention-to-treat population. RESULTS: At a minimum follow up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .). PMID- 28891428 TI - Highlights from the Current Issue: September 2017. PMID- 28891429 TI - Management of Spontaneous Cerebrospinal Fluid Leaks of the Temporal Bone. PMID- 28891430 TI - Response to "Middle Ear Obliteration with Blind-Sac Closure of the External Auditory Canal for Spontaneous CSF Otorrhea". PMID- 28891431 TI - Therapist strategies early in therapy associated with good or poor outcomes among clients with low proactive agency. AB - OBJECTIVE: Within a mixed methods program of research the present study aimed at expanding knowledge about interactions in the initial therapeutic collaboration by combining focus on client interpersonal style and therapist contribution. METHOD: The study involves in-depth analyses of therapist-client interactions in the initial two sessions of good and poor outcome therapies. Based on interpersonal theory and previous research, the Inventory of Interpersonal Problems (IIP-64-C) was used to define poor outcome cases, that is, low proactive agency cases. To compare good and poor outcome cases matched on this interpersonal pattern, cases were drawn from two different samples; nine poor outcome cases from a large multi-site outpatient clinic study and nine good outcome cases from a process-outcome study of highly experienced therapists. RESULTS: Qualitative analysis of therapist behaviors resulted in 2 main categories, fostering client's proactive agentic involvement in change work and discouraging client's proactive agentic involvement in change work, 8 categories and 22 sub-categories. CONCLUSION: The findings revealed distinct and cohesive differences in therapist behaviors between the two outcome groups, and point to the particular therapist role of fostering client agency through engagement in a shared work on change when clients display strong unassertiveness and low readiness for change. Clinical or Methodological Significance Summary: The present analysis combines focus on client interpersonal style, therapist strategies/process and outcome. The categories generated from the present grounded theory analysis may serve as a foundation for identifying interactions that are associated with agentic involvement in future process research and practice, and hence we have formulated principles/strategies that were identified by the analysis. PMID- 28891432 TI - Neonatal treatment with ovarian hormones and suckling among distinct litter sizes: Differential effects on recognition memory and spreading depression at adulthood. AB - OBJECTIVES: Ovarian hormones (OH) and early malnutrition may affect the developing brain, with repercussions on behavioral and excitability-dependent processes. However, the possible synergistic effects of both factors have not been analyzed. In this study, we investigated the effect of treatment in early life with OH and suckling among distinct litter sizes on recognition memory, anxiety behavior, and the excitability-dependent phenomenon known as cortical spreading depression (CSD). METHODS: Female Wistar rats were suckled under favorable and unfavorable lactation, corresponding to litters with 9 and 15 pups (L9 and L15 groups, respectively). From postnatal days (P) 7 to 21, the animals received 50 ug/kg of beta-estradiol or progesterone. From P80 to P84, we tested behavioral reactions. From P90 to P120, we analyzed CSD parameters. RESULTS: Compared with the corresponding L9 groups, the OH-treated L15 groups performed worse in recognition memory tasks. No intergroup difference in the anxiety parameters was observed. Compared with naive and vehicle-treated controls, OH treated groups displayed higher CSD velocities and amplitudes and shorter CSD durations. DISCUSSION: Early treatment with OH facilitates recognition memory and CSD, and in association with unfavorable lactation (L15) impaired recognition memory, but not anxiety behavior, in the adult brain. OH treatment and L15 lactation condition seem to interact regarding OH action on memory, but not on CSD. Data suggest a long-lasting differential effect that might be related to the lasting hormonal action on brain excitability. We postulate and discuss the possibility that these findings may be implicated in human neurological diseases. PMID- 28891433 TI - Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone. AB - Exposure to elevated levels of ambient ozone in photochemical smog is associated with eosinophilic airway inflammation and nonatopic asthma in children. In the present study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced nonatopic asthma by using lymphoid cell-sufficient C57BL/6 mice, ILC-sufficient Rag2-/- mice (devoid of T and B cells), and ILC deficient Rag2-/-Il2rg-/- mice (depleted of all lymphoid cells including ILCs). Mice were exposed to 0 or 0.8 parts per million ozone for 1 day or 9 consecutive weekdays (4 hr/day). A single exposure to ozone caused neutrophilic inflammation, airway epithelial injury, and reparative DNA synthesis in all strains of mice, irrespective of the presence or absence of ILCs. In contrast, 9-day exposures induced eosinophilic inflammation and mucous cell metaplasia only in the lungs of ILC-sufficient mice. Repeated ozone exposures also elicited increased messenger RNA expression of transcripts associated with type 2 immunity and airway mucus production in ILC-sufficient mice. ILC-deficient mice repeatedly exposed to ozone had no pulmonary pathology or increased gene expression related to type 2 immunity. These results suggest a new paradigm for the biologic mechanisms underlying the development of a phenotype of childhood nonatopic asthma that has been linked to ambient ozone exposures. PMID- 28891435 TI - Ninety-day Local Tolerability and Toxicity Study of ND0612, a Novel Formulation of Levodopa/Carbidopa, Administered by Subcutaneous Continuous Infusion in Minipigs. AB - A 90-day study in Gottingen minipigs was conducted to test the local tolerability and systemic toxicity of ND0612, a novel aqueous solution of carbidopa (CD)/levodopa (LD) intended for the treatment of Parkinson's disease by continuous subcutaneous administration using a discrete infusion pump. To evaluate tissue site reactions, we used a unique study design involving multiple infusion sites to evaluate the effect of dose per site (270/63, 360/45, and 360/84 mg LD/CD), volume of infusion per site (4.5 and 6 ml per site), formulation concentration (60/14 and 60/7.5 mg/ml LD/CD), daily rate of infusion per site (240 MUl/hr for16 hr and 80 MUl/hr for 8 hr, 320 MUl/hr for 16 hr and 100 MUl/hr for 8 hr, or 750 MUl/hr for 8 hr), frequency (once every 5, 10, 15, or 20 days), and number of infusions (4, 6, or 9) to the same infusion site. No systemic adverse effects were observed. Histopathological changes at infusion sites started with localized minimal necrosis and acute inflammation that progressed to subacute and chronic inflammatory and reparative changes with evidence of progressive recovery following the final infusion. None of the infusion site effects were judged to be adverse, and clinical exposures to ND0612 are not expected to result in adverse responses. PMID- 28891436 TI - Radio-localization of Non-Palpable Breast Lesions Under Ultrasonographic Guidance: Current Status and Future Perspectives. AB - BACKGROUND: Due to the spread of mammographic screening programs, a constant increase of clinically-occult breast cancer diagnosis has been registered. A correct approach to nonpalpable breast lesions requires an accurate intra operative localization in order to achieve a complete surgical resection. The aim of this paper is to describe the state of the art of the US-guided procedures such as Radio-guided Occult Lesion Localization (ROLL) and Radio-guided Seed Localization (RSL) in comparison to the most widely adopted Wire-Guided Localization (WGL). METHODS: Links to full text papers and abstracts published in the last 25 years regarding localization of non-palpable breast lesions were researched using PubMed service of US National Library of Medicine. Using the term "non-palpable breast lesions localization", different localization techniques were considered and analyzed. Human studies, published in English, French, German, Italian, and Spanish in journals with an impact factor index, were taken into account, independently of the type of article (clinical trial, review, editorial, etc.) or radiopharmaceutical used. Since the aim was to assess the clinical value of the procedures, a higher relevance was assigned to studies with significantly high number of patients and to those comparing at least two localization techniques. The reliability of each technique was evaluated taking into account several parameters such as correlation index between two localization procedures, risk of complications, lesion margin involvement and rate re-operation. CONCLUSIONS: Since their introduction in clinical practice, several randomized clinical trials and meta-analyses showed the accuracy and reliability of radio-guided procedures performed under ultrasonographic guidance. ROLL and RSL offer a practical approach to the management of clinically-occult breast lesions. PMID- 28891434 TI - Histology Atlas of the Developing Prenatal and Postnatal Mouse Central Nervous System, with Emphasis on Prenatal Days E7.5 to E18.5. AB - Evaluation of the central nervous system (CNS) in the developing mouse presents unique challenges, given the complexity of ontogenesis, marked structural reorganization over very short distances in 3 dimensions each hour, and numerous developmental events susceptible to genetic and environmental influences. Developmental defects affecting the brain and spinal cord arise frequently both in utero and perinatally as spontaneous events, following teratogen exposure, and as sequelae to induced mutations and thus are a common factor in embryonic and perinatal lethality in many mouse models. Knowledge of normal organ and cellular architecture and differentiation throughout the mouse's life span is crucial to identify and characterize neurodevelopmental lesions. By providing a well illustrated overview summarizing major events of normal in utero and perinatal mouse CNS development with examples of common developmental abnormalities, this annotated, color atlas can be used to identify normal structure and histology when phenotyping genetically engineered mice and will enhance efforts to describe and interpret brain and spinal cord malformations as causes of mouse embryonic and perinatal lethal phenotypes. The schematics and images in this atlas illustrate major developmental events during gestation from embryonic day (E)7.5 to E18.5 and after birth from postnatal day (P)1 to P21. PMID- 28891437 TI - Investigation of Ocular Bioactivation Potential and the Role of Cytochrome P450 2D Enzymes in Rat. AB - BACKGROUND: Timolol is clinically administered topically (ocular) to reduce intraocular pressure and treat open-angle glaucoma. Ocular administration of timolol in low doses (0.5% w/v in the form of eye drops) has led to challenges for in vivo metabolite identification. An understanding of drug metabolism in the eye is important for clinical ocular therapeutics and potential drug candidates. METHODS: We aimed to investigate the metabolism of timolol in rat ocular and liver S9 fractions, as well as rat ocular tissue and plasma following a 0.5% topical (ocular) dose of timolol. We explored the potential in vitro metabolic bioactivation in the eye/liver by conducting trapping studies for putative aldehyde and iminium ion intermediates that may arise from the morpholine functionality. RESULTS: Oxidative metabolism of timolol to its major metabolite (M4) in ocular S9 and recombinant rat cytochrome P450 (CYP) isoforms supports the possible role of rat ocular CYP2D2, 2D4, and/or 2D18. Observation of N-acetyl timolol (M5) is suggestive that the ocular N-acetyltransferases may also play a larger role in ocular disposition of timolol, a previously unreported finding. This research is the first comprehensive report of in vitro ocular metabolism of timolol in rat. CONCLUSION: This study also indicates that in vitro hepatic metabolism is over-predictive of ocular metabolism following topically ocular dosed timolol. The research, herein, highlights the eye as an organ capable of first pass metabolism for topical drugs. Thus, new ophthalmologic considerations for studying and designing long term topical therapies in preclinical species are needed in drug discovery. PMID- 28891438 TI - Emerging Role of CD44 Receptor as a Potential Target in Disease Diagnosis: A Patent Review. AB - BACKGROUND: The CD44 receptor is a cell surface glycoprotein, which mediates many physiological and pathological activities. Its key role is to provide defence against inflammatory reactions by cellular transmigration and cell signalling. In pathological conditions, it gives destructive outcomes by mediating migration of pathogenic cells to vital organs resulting in tissue and organ damage. It binds to several ligands principally the hyaluronan. OBJECTIVE: This review explores CD44 structure, functions, and its potential as a disease indicator and therapeutic target. METHOD: From a thorough literature review on the CD44 receptor, several patents of targeting approaches have been identified and herewith reviewed which recommend CD44-binding proteins, CD44-binding antibodies, antibody fragments, pharmaceutical compositions, as well as nucleic acids as a targeting moiety. RESULT: Applicability of CD44 overexpression and its targeting has now been extensively utilized in the disease diagnosis and real-time bio imaging of pathologic cells. CONCLUSION: A thorough understanding of CD44 receptor structure, expression and diverse functions towards different cell types would offer an opportunity to develop better therapeutic approaches in the near future by overcoming all the shortcomings of toxicity and efficacy. The present review includes recent patents of CD44 receptor targeting approaches that have been presented in the different agencies: European (EP), US, and World Intellectual Property Organization (WIPO) and a general analysis of the future developments and trends in this emerging area. PMID- 28891439 TI - The Regulation of Differentiation of Mesenchymal Stem-cells into Skeletal Muscle: A Look at Signalling Molecules Involved in Myogenesis. AB - Mesenchymal Stem Cells (MSCs) are an attractive option for the development of treatment for musculoskeletal pathologies due to their wide availability, clinical safety and multiple techniques available. Understanding the control of MSC differentiation into skeletal muscle is vital for developing protocols and therapeutic applications that are safe and effective. This paper therefore aims to review the current understanding of factors that regulate the differentiation of MSCs into skeletal muscle. Medline, Embase, Pubmed and Web of Science were searched for December 2015 using the terms 'differentia*, skeletal*, skeleton*, myocyt*, myogen* and mesenchym* stem-cell*. This returned a total of 1215 results. 48 papers were included in the review. Forty-eight studies were reviewed. Eight related to external signalling molecules, sixteen related to local environmental factors and twenty-four related to intracellular signalling pathways. Uniaxial strain, medium stiffness of the extracellular matrix and submicron grooved topography were identified as promoting myogenesis. TGF-beta was identified as a main inhibitor of myogenesis. Smad and Pax signalling were identified as important intracellular pathways and the relationship of menin, Setdb1, GEFT, PAX3-FOXO1, IGF-II, TAZ and PRDM2 with MyoD and MyoG was explored. Further research into the effect of the inflammatory response on skeletal muscle differentiation is suggested. Clarification of the mechanism of action of TGF beta, the role of submicron grooves and cyclic uniaxial strain, and two important factors in the development of tissue scaffolds. PMID- 28891440 TI - A Systematic Review of Mesenchymal Stem Cells in Spinal Cord Injury, Intervertebral Disc Repair and Spinal Fusion. AB - Spinal surgery presents a challenge for both neurosurgery and orthopaedic surgery. Due to the heterogeneous differentiation potential of mesenchymal stem cells, there is much interest in the treatment of spine surgery. Animal and human trials focussing on the efficacy of mesenchymal stem cells in spinal cord injury, spine fusion and disc degeneration were included in this systematic review. Published articles up to January 2016 from MEDLINE, PubMed and Ovid were used by searching for specific terms. Of the 2595 articles found, 53 met the selection criteria and were included for analysis (16 on spinal cord injury, 28 on intervertebral disc repair and 9 on spinal fusion). Numerous studies reported better results when the mesenchymal stem cells were used in co-culture with other cells or used in scaffolds. Mesenchymal stem cells were also found to have an immune-modulatory role, which can improve surgical outcome. This systematic review suggests that mesenchymal stem cells can be used safely and effectively for these spinal surgery treatments. Whilst, in certain studies, mesenchymal stem cells did not necessarily show improved results from existing treatments, they provide an alternative option. This can reduce morbidity that arises from current surgical treatment. PMID- 28891441 TI - Tissue Engineering in Achilles Tendon Reconstruction: A Systematic Review of Preclincal Studies. AB - BACKGROUND: Tissue engineering is now being used in Achilles tendon (AT) repair in animal models. There are many preclinical studies that have used different types of stem cells for AT repair. However, there are no systematic reviews that evaluate all these studies to see which type of stem cell provides the most improvement for AT repair in animal models. Sahni V et al.,(1) divided the multiple stem cell types into three broad categories; Tendon derived stem cells (TDSCs), mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs). These three categories have been used in this systematic review to group the different stem cell types together and to also see which category of stem cells provide superior enhancement of AT repair. METHOD: All studies that have focused on using different types of stem cells in animal models for AT repair and have also included an outcome measure to identify any improvement made with stem cells have been included in this systematic review. Online published articles from 1946 to January 2016 were searched using Ovid MEDLINE (R) and PubMed databases. RESULTS: Of the 181 articles found and assessed for eligibility, 15 articles met predefined selection criteria and were included in this systematic review. Stem cells can either augment current methods of surgical repair or can provide an alternative route for tendon regeneration because of their unique ability of improving histological characteristics and biomechanical properties. CONCLUSION: This systematic review shows that stem cells can provide an improvement in AT repair in animal models. Histological analysis of the tendon tissue as well as biomechanical tests such as ultimate failure load have been used to show this improvement in AT repair. Nevertheless, we do not know which type of stem cell, from the three broad categories, provides a superior enhancement of AT regeneration in animal models. Our results underscore a need for a head-to-head comparison of the different types of stem cells used in AT repair with or without current methods of surgical repair. PMID- 28891442 TI - Systematic Review Investigating Multi-disciplinary Team Approaches to Screening and Early Diagnosis of Dementia in Primary Care - What are the Positive and Negative Effects and Who Should Deliver It? AB - BACKGROUND: Primary care services frequently provide the initial contact between people with dementia and health service providers. Early diagnosis and screening programmes have been suggested as a possible strategy to improve the identification of such individuals and treatment and planning health and social care support. OBJECTIVE: To determine what early diagnostic and screening programmes have been adopted in primary care practice, to explore who should deliver these and to determine the possible positive and negative effects of an early diagnostic and screening programme for people with dementia in primary care. METHODS: A systematic review of the literature was undertaken using published and unpublished research databases. All papers answering our research objectives were included. A narrative analysis of the literature was undertaken, with the CASP tools used appropriately to assess study quality. RESULTS: Thirty three papers were identified of moderate to high quality. The limited therapeutic options for those diagnosed with dementia means that even if such a programme was instigated, the clinical value remains questionable. Furthermore, accuracy of the diagnosis remains difficult to assess due to poor evidence and this raises questions regarding whether people could be over- or under-diagnosed. Given the negative social and psychological consequences of such a diagnosis, this could be devastating for individuals. CONCLUSION: Early diagnostic and screening programmes have not been widely adopted into primary care. Until there is rigorous evidence assessing the clinical and cost-effectiveness of such programmes, there remains insufficient evidence to support the adoption of these programmes in practice. PMID- 28891443 TI - The Ambivalence of Early Diagnosis - Returning Results in Current Alzheimer Research. AB - OBJECTIVES: Based on an analysis of the potential consequences of disclosing AD suspicions from respective research and using the research ethical principle of non-maleficence, the authors of this paper argue for the thesis that the benefits of early AD detection in research outweigh the risk of potential adverse effects only in cases where studies are conducted with symptomatic people actively seeking for support, e.g. as they utilize the services of memory clinics. CONCLUSION: In the case of non-symptomatic volunteers, the result of the risk benefit-assessment seems to be less distinctive. Given that disclosing results can, at least initially, cause severe distress and harm and taking into account that research examinations have a significantly increased risk of producing false positive findings, we suggest to make use of a research-ethical "princple of caution" that supports a restrictive disclosure policy for the second group of potential study participants. This differentiated view on the benefits of disclosed findings in AD research is reflected in recommendations for the set-up of return of result processes. PMID- 28891444 TI - Acceptability and Results of Dementia Screening Among Older Adults in the United States. AB - OBJECTIVES: To measure older adults acceptability of dementia screening and assess screening test results of a racially diverse sample of older primary care patients in the United States. DESIGN: Cross-sectional study of primary care patients aged 65 and older. SETTING: Urban and suburban primary care clinics in Indianapolis, Indiana, in 2008 to 2009. PARTICIPANTS: Nine hundred fifty-four primary care patients without a documented diagnosis of dementia. MEASUREMENTS: Community Screening Instrument for Dementia, the Mini-Mental State Examination, and the Telephone Instrument for Cognitive Screening. RESULTS: Of the 954 study participants who consented to participate, 748 agreed to be screened for dementia and 206 refused screening. The overall response rate was 78.4%. The positive screen rate of the sample who agreed to screening was 10.2%. After adjusting for demographic differences the following characteristics were still associated with increased likelihood of screening positive for dementia: age, male sex, and lower education. Patients who believed that they had more memory problems than other people of their age were also more likely to screen positive for dementia. CONCLUSION: Age and perceived problems with memory are associated with screening positive for dementia in primary care. PMID- 28891445 TI - Patient Variables Associated with the Assignment of a Formal Dementia Diagnosis to Positively Screened Primary Care Patients. AB - BACKGROUND: Main objective was to analyze the associations of patient variables (depression, quality of life, anti-dementia drug treatment, knowledge about dementia) with the assignment of a formal diagnosis of dementia to community dwelling primary care patients who have screened positive for dementia. METHODS: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner based randomized controlled intervention trial. Present analyses are based on cross-sectional data of 319 positively screened patients (age 70+, living at home) who had not been formally diagnosed with dementia before the screening. The medical diagnoses (ICD-10) were retrieved from the patient's medical records. Depression (Geriatric Depression Scale; GDS), quality of life in Alzheimer's disease (Qol-AD), knowledge about dementia, and anti-dementia drug treatment were assessed after the screening test at the baseline examination. RESULTS: At the baseline examination, 171 out of 319 patients (54%) had been formally diagnosed with dementia after they have screened positive. Univariate comparisons showed no statistically significant differences between diagnosed and undiagnosed patients regarding depression (GDS>=6: 11% vs. 15%; p=0.396), quality of life (mean (SD): 2.8 (0.3) vs. 2.8 (0.4); p=0.833), and the knowledge about dementia (75% vs. 75%; p>0.999). Patients who had received a formal diagnosis were more often treated with anti-dementia drugs (20% vs. 11%; p=0.040). Multivariate analyses controlled for confounding variables confirmed these findings. CONCLUSION: Present findings do not support concerns that the assignment of a formal dementia diagnosis after screening is associated with potential harms. If confirmed in a prospective study, our data would suggest that patients may benefit from being formally diagnosed regarding anti-dementia drug treatment. PMID- 28891446 TI - The Clock Drawing Test: A Reasonable Instrument to Assess Probable Dementia in Primary Care? AB - OBJECTIVE: The primary aim of the study was to determine accuracy, sensitivity and specificity of the Clock Drawing Test (CDT) in detecting probable dementia as compared to the multi-domain dementia screening test DemTect. METHODS: The sample was derived from the general practitioner (GP)-based, cluster-randomized controlled intervention trial DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania). Selected from 6.440 patients systematically screened for dementia in primary care, we examined three groups (a,b,c) where the CDT (as index test) as well as the DemTect (as reference standard) were available. After excluding cases with missing values, we included a sample of n=462 with "probable dementia", n=586 with "mild cognitive impairment" and n=553 with "no cognitive impairment" matched for age and gender. We analyzed the accuracy of the CDT in identifying people with probable dementia by the DemTect and report sensitivity, and specificity for the CDT. We further analyzed age and gender differences associated with the groups. RESULTS: In comparison to the DemTect the CDT identified more than twice as many of the screened patients as cognitively impaired (63.1% in the CDT vs. 28.9% in the DemTect). The sensitivity and specificity for the CDT were 84.4% and 45.6% respectively. We found considerable age and gender differences for the performance of the CDT. Higher age (p < 0.001) and female sex (p < 0.001) were associated with incorrect clock drawings. CONCLUSION: The CDT shows a considerably high rate of false positive screening outcomes compared to the DemTect and disadvantages older people and women. Thus, in contrary to previous findings our results indicate that the CDT should not be used as exclusive instrument to screen for probable dementia in primary care. PMID- 28891447 TI - Potential Role of Neuroimaging Markers for Early Diagnosis of Dementia in Primary Care. AB - BACKGROUND: The use of imaging markers for the diagnosis of predementia and early dementia stages of Alzheimer's disease (AD) has widely been explored in research settings and specialized care. The use of these markers in primary care has yet to be established. OBJECTIVE: Summarize current evidence for the usefulness of imaging markers for AD in primary compared to specialized care settings. METHOD: Selective overview of the literature, and pilot data on the use of MRI-based hippocampus and basal forebrain volumetry for the discrimination of AD dementia and mild cognitive impairment (MCI) cases from healthy controls in 58 cases from a primary care cohort and 58 matched cases from a memory clinic's sample. RESULTS: Molecular imaging marker of amyloid pathology, and volumetric markers of regional and whole brain atrophy support the diagnosis of AD dementia and MCI due to AD, and contribute to confidence in the differential diagnosis of AD and non AD related dementias in specialized care. Limited evidence from the literature and our primary care cohort suggests that the diagnostic accuracy of volumetric imaging markers may be similar in the dementia stage of AD, but may be inferior for cases with MCI in primary compared with specialized care. CONCLUSION: Evidence is still widely lacking on the use of imaging markers for early and differential diagnosis of AD dementia, and detection of prodromal AD in primary care. Further progress to fill this gap will depend on the availability of international multimodal data from well-defined primary care cohorts. PMID- 28891448 TI - A Special Focus on Selexipag - Treatment of Pulmonary Arterial Hypertension. AB - BACKGROUND: This review focuses on the treatment of pulmonary arterial hypertension (PAH) with selexipag and compares its drug-related therapeutic effects with those of prostacyclin analogues. METHODS: We searched the relevant literature and summarized the current clinical trials concerning selexipag and PAH. RESULTS: With only few cases per million, PAH is a rare disease, but when untreated it can be life-threatening. PAH is linked to elevated levels of endothelin (ET-1) and decreased levels of nitric oxide (NO) and prostacyclin (PGI2). PAH-specific therapeutic approaches concentrate on these characteristics with drugs targeting the endothelin- receptor (e.g. bosentan), phosphodiesterase 5 (e.g. sildenafil) or the prostacyclin-receptor (e.g. treprostinil). Recently, the new drug selexipag acting as a non-prostanoid IP2-receptor agonist has been approved for PAH therapy. The active form of selexipag (ACT-333679) was designed by the help of a medicinal chemistry program and it was further modified by replacing the terminal carboxyl group with an N-acylsulfonamide group to form the more stable oral drug, selexipag. Selexipag has a high selectivity for the IP2 receptor and differs from conventional prostacyclin analogues in its chemical structure. In the GRIPHON trial selexipag was demonstrated to significantly improve the primary composite endpoint of death or complications related to PAH (hazard ratio 0.6, 99% confidence interval, 0.46 to 0.78; P < 0.001) as well as exercise capacity in the form of the 6-minute walk distance (12.0 m treatment effect, 99% confidence interval, 1 to 24; P = 0.003). However, no significant reduction in all-cause mortality was achieved. Selexipag has also shown promising results in combination therapy with phosphodiesterase-5 inhibitors (PDE-5i) and/or endothelin receptor antagonists (ERA). The most common adverse effects (AEs), associated with selexipag, are headache, diarrhea, jaw pain, and nausea. Nevertheless, Selexipag was generally well tolerated during the GRIPHON trial. CONCLUSIONS: Selexipag is a valuable addition to PAH therapeutics especially by reducing the PAH-related hospitalizations and thus improving quality of life in PAH patients. PMID- 28891449 TI - Role of Pharmacogenomics in Antiepileptic Drug Therapy: Current Status and Future Perspectives. AB - BACKGROUND: Growing evidence indicates that pharmacogenomics will positively impact treatment for patients with epilepsy in the near future, leading to the implementation of a precision-based use of antiepileptic drug (AED) therapy, thereby providing a cornerstone for precision medicine. OBJECTIVE: In this review, we briefly summarize the studies of pharmacogenomics in epilepsy, recent advances, and how it may progress in the future. METHODS: We subdivided the review into two main sections: genetic variants that may modulate response to AEDs through pharmacokinetics or pharmacodynamics mechanisms; and gene variants that may affect tolerability and safety of AEDs. RESULTS: Results from most studies have been contradictory, due to several flaws, including small sample sizes, inaccurate phenotyping, and genotyping strategies. However, even with these limitations, very recent developments indicate that the goal of incorporating genetic data into clinical practice may be attainable in the near future. In addition, recent pharmacogenomic studies of hypersensitivity reactions to AEDs have also made important strides, as its prevention appears attainable with the identification of HLA-A genotypes for patients at high risk of carbamazepine hypersensitivity. CONCLUSION: To better clarify the relationship between genetic factors and AEDs, future studies will require more precise epilepsy phenotypes, larger sample sizes, and astute use of new genotyping strategies. Reasonably, this will lead to novel therapeutic approaches in drug targeting and antiepileptogenesis. PMID- 28891450 TI - The "Neurocentric" Approach to Essential Hypertension: How Reliable is the Paradigm of Hyperkinetic Hypertension? A Focus on the Sympathetic Nervous System Dysregulation in Essential Hypertensive Patients with Elevated Resting Heart Rate. AB - BACKGROUND: Clinic resting heart rate (RHR), is one of the cardiovascular parameters more easily measurable. In the general population RHR has been associated with total and cardiovascular mortality and higher rate of vascular events. OBJECTIVE: The case of essential hypertension is in some ways peculiar: in the past decades has often been attributed to hypertensive subjects higher values of RHR than healthy controls as a result of the effects of the different factors leading to the development of essential hypertension itself, first of all the presence of an increased tone of the sympathetic nervous system Methods: Several excellent articles debated the issue of autonomic dysfunction in essential hypertension; nevertheless of this, after various decades of debate, this issue is to-date unresolved. The aim of this review is to discuss the reliability of the hypothesis that elevated resting heart rate in hypertensive subjects is associated to high blood pressure and both to elevated sympathetic nervous system activity or rather if these three phenomena coexist in a limited portion of subjects being not necessarily linked each other with a causal relationship. RESULTS: The ascertainment of the exact proportion of the hypertensive subjects having sympathetic overdrive appears to be hard, not only due to the multiple interferences and the constant interplay between the various determinants of the sympathetic tone, but also because a significant uncertainty remains with regard to the validity of the methods used for assessing the sympathetic tone. CONCLUSIONS: To date, any threshold used to define tachycardia is arbitrary. The percentage of hypertensive patients with elevated RHR varies considerably between the various studies, first of all because the modality of assessment influences the results. The "white coat tachycardia" is a clinical entity that must be taken into account. Ambulatory heart rate represents a good diagnostic alternative, since nocturnal mean heart rate appears to be the parameter with the highest prognostic value, probably because is less conditioned by external factors, being more representative of the "real" heart rate of the subject. PMID- 28891451 TI - Fibrinolytic and Anticoagulation Therapy in Patients Undergoing Ultrasound Assisted Catheter-Directed Thrombolysis for Pulmonary Embolism. AB - BACKGROUND: Ultrasound-assisted, catheter-directed thrombolysis (UA-CDT) relieves right ventricular stress without a significant increase in the risk of bleeding compared to systemic thrombolysis. Although concomitant anticoagulation is provided to prevent thrombus expansion, the optimal anticoagulation regimen in patients receiving UA-CDT remains unknown. OBJECTIVE: We sought to describe anticoagulation practices for patients receiving UA-CDT. METHODS: Patients receiving UA-CDT for acute pulmonary embolism (PE) between Jan 1, 2013 to Sept 30, 2014 at a single center were analyzed. We collected patient characteristics, fibrinolytic and anticoagulant usage as well as clinical outcomes. RESULTS: Fourteen patients were included in the final analysis. The mean alteplase dose was 16.8 +/- 5.6 mg and 24.3 +/- 3.4 mg in unilateral and bilateral PE, respectively. Mean unfractionated heparin (UFH) rates were 7.4 (+/-2.17) IU/kg/hr and 12.4 (+/-3.1) IU/kg/hr during and after fibrinolytic therapy, respectively. The median aPTT was 42.4 sec [IQR 34.5-51.8] and 77.9 sec [IQR 66.5-96.8] during and after fibrinolytic therapy, respectively. There were no recurrent VTE within 30 days of hospital discharge. One patient had a major bleeding event (intracranial hemorrhage). CONCLUSION: In patients with acute PE, our institution utilized low levels of anticoagulation during fibrinolytic administration and therapeutic doses after completion of fibrinolytic infusion. Standardized protocols for anticoagulation during UA-CDT are warranted. PMID- 28891452 TI - Congenital FX Deficiency Rio Tercero: A New Heterozygous Missense Mutation (Cys241Gly) with a Potentiating Effect by a Polymorphism (c. 503-57C>T). AB - OBJECTIVE: The aim was to report a new family with congenital FX deficiency. PATIENTS AND METHODS: The proposita is a 41 year old female with a moderate bleeding tendency (easy bruising, menorrhagia). Parents were not consanguineous. Family history was positive for a mild bleeding tendency. RESULTS: Coagulation and genetics studies revealed that the proposita and two of her siblings were heterozygotes for a new mutation Cys241Gly in exon 6 but had different FX level (2-3% of normal in the proposita and about 50% in the two siblings. The same was true for one of her three children. The mother and the other two children of the proposita had also slightly decreased FX levels but no mutation. On the suspicion that the proposita was carrying another defect which had escaped the Sanger method, we carried out a whole exome analysis and discovered that the proposita and one of her siblings were also homozygous for a mutation of a known polymorphism (c.503-57C>T). The daughter of the proposita was instead, besides being a carrier of the missense new mutation Cys241Gly, heterozygous for the same polymorphism. The mother and two other daughters were also heterozygous for the polymorphism. There were no deletions or duplications. CONCLUSION: The polymorphism present in the family seems to be capable of potentiating the defect induced by the new mutation. This, safe for epigenetics phenomena, is the only possible explanation for the discrepancy found in the FX level between mother and daughter despite the fact that both carried the same new mutation. PMID- 28891453 TI - Management of Hemophilic Arthropathy of the Ankle. AB - BACKGROUND: Hemophilic arthropathy (HA) of the ankle is prevalent in people with hemophilia (PWH). It is frequently severe and incapacitating, due to recurrent bleeding into the ankle articulation during infancy. Around 50% of hemophilic patients suffer from ankle pain and radiological signs of HA. OBJECTIVE: To review current treatment of HA of the ankle in PWH. METHOD: A literature review of hemophilic ankle arthropathy in PWH was performed utilizing MEDLINE (PubMed) and the Cochrane Library. RESULTS: Primary hematologic prophylaxis could keep away from the development of ankle HA if the level of the patient's deficient factor is prevented from dropping below 1% of normal. Recurrent articular bleeding can be prevented by the intravenous infusion of clotting factor concentrates (prophylaxis). Major articular bleeds and chronic hemophilic synovitis should be managed fiercely to prevent ankle HA. In the circumstance of advancing articular involvement, some noninvasive and invasive procedures can procure symptomatic mitigation and ameliorate the patient's function and quality of life. CONCLUSION: The ideal treatment for the hemophilic ankle when hematologic prophylaxis fails includes physical medicine and rehabilitation, orthoses, radiosynovectomy, arthroscopic ankle debridement (in the initial stages of cartilage degeneration), and ankle distraction, ankle fusion or total ankle replacement (in advanced stages of cartilage degeneration). PMID- 28891454 TI - Current Technology in the Discovery and Development of Novel Antibacterials. AB - BACKGROUND: Bacterial resistance to antibiotics is one of the most serious challenge to global public health. The introduction of new antibiotics in clinical settings, i.e. agents that belong to a new class of antibacterials, act on new targets or has a novel mechanisms of action, may not be sufficient to cope with the emergence of multidrug-resistant pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii and Escherichia coli, which are increasingly prevalent in healthcare settings in Europe, the USA and Asia. Hence, coordinated efforts in minimizing the risk of spread of resistant bacteria and renewing research efforts in the search for novel antibacterial agents are urgently needed to manage this global crisis. OBJECTIVE: This review highlights the challenges and potential in using current technologies in the discovery and development of novel antibacterial agents to keep up with the constantly evolving resistance in bacteria. CONCLUSION: With the explosion of bacterial genomic data and rapid development of new sequencing technologies, the understanding of bacterial pathogenesis and identification of novel antibiotic targets have significantly improved. PMID- 28891455 TI - Epigenetic Biomarkers for Risk Assessment of Particulate Matter Associated Lung Cancer. AB - BACKGROUND: Particulate matter directly emitted into the air by sources such as combustion processes and windblown dust, or formed in the atmosphere by transformation of emitted gases are the major contributors to air pollution that triggers a diverse array of human pathologies including lung cancer. The mortality in lung cancer is usually high as the disease is not symptomatic at its early treatable stage. Moreover, available methods for screening are costly and mainly rely on imaging techniques which lack sufficient sensitivity and specificity. Despite progress in the identification of biomarkers, gene mutation based approaches still face formidable challenges as the disease evolves from a complex interplay between environment and host. Therefore, identification of an epigenomic signature might be useful for early diagnosis with the potential to reduce the environmental-associated disease burden. OBJECTIVE: The review discusses the utility of epigenomic signature in identification and management of the environmental-associated lung cancers. CONCLUSION: Non-invasive 'liquid biopsy' based epigenomic screening has recently emerged as a methodology which has potential to characterize tumor heterogeneity at initial stages. Epigenetic signatures (methylated DNA, miRNA, and post transcriptionally modified histones) known to reflect the vital cellular changes, circulate at higher levels in the individuals with lung cancer. These circulating biological entities are reported to be closely associated with the clinical outcome of lung cancer patients and thus strongly stand as the probable candidate to identify disease at an early stage and monitor treatment response, thereby, benefiting patients and improving their lives. However, for effective implementation of the strategy as "point-of care" test for screening population-at-risk will require exhaustive clinical validation. PMID- 28891456 TI - Spatiotemporal risk mapping of hand, foot and mouth disease and its association with meteorological variables in children under 5 years. AB - Hand, foot and mouth disease (HFMD) risk has become an increasing concern in the Beijing-Tianjin-Hebei region, which is the biggest urban agglomeration in north eastern Asia. In the study, spatiotemporal epidemiological features of HFMD were analysed, and a Bayesian space-time hierarchy model was used to detect local spatial relative risk (RR) and to assess the effect of meteorological factors. From 2009 to 2013, there was an obvious seasonal pattern of HFMD risk. The highest risk period was in the summer, with an average monthly incidence of 4.17/103, whereas the index in wintertime was 0.16/103. Meteorological variables influenced temporal changes in HFMD. A 1 degrees C rise in air temperature was associated with an 11.5% increase in HFMD (corresponding RR 1.122). A 1% rise in relative humidity was related to a 9.51% increase in the number of HFMD cases (corresponding RR 1.100). A 1 hPa increment in air pressure was related to a 0.11% decrease in HFMD (corresponding RR 0.999). A 1 h increase in sunshine was associated with a 0.28% rise in HFMD cases (corresponding RR 1.003). A 1 m/s rise in wind speed was related to a 6.2% increase in HFMD (corresponding RR 1.064). High-risk areas were mainly large cities, such as Beijing, Tianjin, Shijiazhuang and their neighbouring areas. These findings can contribute to risk control and implementation of disease-prevention policies. PMID- 28891458 TI - ppGpp and cytotoxicity diversity in Shiga toxin-producing Escherichia coli (STEC) isolates - CORRIGENDUM. PMID- 28891457 TI - Current prevalence of chronic hepatitis B and C virus infection in the general population, blood donors and pregnant women in the EU/EEA: a systematic review. AB - This systematic review aimed at estimating chronic hepatitis B (HBV) and C virus (HCV) prevalence in the European Union (EU) and Economic Area (EEA) countries in the general population, blood donors and pregnant women. We searched PubMed(c), Embase(c) and Cochrane Library databases for reports on HBV and HCV prevalence in the general population and pregnant women in EU/EEA countries published between 2005 and 2015. Council of Europe data were used for HBV and HCV blood donor prevalence. HBV general population estimates were available for 13 countries, ranging from 0.1% to 4.4%. HCV general population estimates were available for 13 countries, ranging from 0.1% to 5.9%. Based on general population and blood donor estimates, the overall HBV prevalence in the EU/EEA is estimated to be 0.9% (95% CI 0.7-1.2), corresponding to almost 4.7 million HBsAg-positive cases; and the overall HCV prevalence to be 1.1% (95% CI 0.9-1.4), equalling 5.6 million anti HCV-positive cases. We found wide variation in HCV and HBV prevalence across EU/EEA countries for which estimates were available, as well as variability between groups often considered a proxy for the general population. Prevalence estimates are essential to inform policymaking and public health practice. Comparing to other regions globally, HBV and HCV prevalence in the EU/EEA is low. PMID- 28891459 TI - Prevalence of Clostridium difficile infection and colonization in a tertiary hospital and elderly community of North-Eastern Peninsular Malaysia. AB - Little is known about Clostridium difficile infection (CDI) in Asia. The aims of our study were to explore (i) the prevalence, risk factors and molecular epidemiology of CDI and colonization in a tertiary academic hospital in North Eastern Peninsular Malaysia; (ii) the rate of carriage of C. difficile among the elderly in the region; (iii) the awareness level of this infection among the hospital staffs and students. For stool samples collected from hospital inpatients with diarrhea (n = 76) and healthy community members (n = 138), C. difficile antigen and toxins were tested by enzyme immunoassay. Stool samples were subsequently analyzed by culture and molecular detection of toxin genes, and PCR ribotyping of isolates. To examine awareness among hospital staff and students, participants were asked to complete a self-administered questionnaire. For the hospital and community studies, the prevalence of non-toxigenic C. difficile colonization was 16% and 2%, respectively. The prevalence of CDI among hospital inpatients with diarrhea was 13%. Out of 22 C. difficile strains from hospital inpatients, the toxigenic ribotypes 043 and 017 were most common (both 14%). In univariate analysis, C. difficile colonization in hospital inpatients was significantly associated with greater duration of hospitalization and use of penicillin (both P < 0.05). Absence of these factors was a possible reason for low colonization in the community. Only 3% of 154 respondents answered all questions correctly in the awareness survey. C. difficile colonization is prevalent in a Malaysian hospital setting but not in the elderly community with little or no contact with hospitals. Awareness of CDI is alarmingly poor. PMID- 28891460 TI - Source of Hyalesthes obsoletus Signoret planthopper (Hemiptera: Cixiidae) in southern France and potential effects of landscape. AB - Cixiid planthoppers are considered of major economic importance, as they can transmit phytoplasmas responsible for many plant diseases. While thorougly studied in vineyards, the epidemiology of stolbur phytoplasma, transmitted by Hyalesthes obsoletus Signoret, was rarely investigated on minor crops as lavender, where it leads to 'yellow decline' disease and large economic losses. The objective of this paper is to understand the effect of the local landscape characteristics on the presence and density of H. obsoletus in the 'Plateau de Valensole', southern France. Potential host plants of H. obsoletus were surveyed in three contrasted zones (in terms of crops and disease intensity), by uprooting plants and capturing adults in emergence traps. The localization and potential movements of H. obsoletus from the host plants towards lavandin (infertile hybrid of lavender) were determined using yellow sticky traps. Clary sage plants were found as major hosts of H. obsoletus. Flying insects were also caught in fields of lavandin, although emergence traps and plant uprooting did not confirm this crop as a winter host, i.e., as a reservoir for the insect. Based on one zone, we showed that attractiveness may depend on crop (clary sage or lavandin) and on its age, as well as on the distance to the supposed source field. These results suggest that clary sage could be an important host of H. obsoletus, whose density largely varies between zones. Genetic studies would be required to confirm the role of clary sage in the dissemination of yellow decline of lavandin. PMID- 28891461 TI - Direct cost comparison of totally endoscopic versus open ear surgery. AB - OBJECTIVE: Totally endoscopic ear surgery is a relatively new method for managing chronic ear disease. This study aimed to test the null hypothesis that open and endoscopic approaches have similar direct costs for the management of attic cholesteatoma, from an Australian private hospital setting. METHODS: A retrospective direct cost comparison of totally endoscopic ear surgery and traditional canal wall up mastoidectomy for the management of attic cholesteatoma in a private tertiary setting was undertaken. Indirect and future costs were excluded. A direct cost comparison of anaesthetic setup and resources, operative setup and resources, and surgical time was performed between the two techniques. RESULTS: Totally endoscopic ear surgery has a mean direct cost reduction of AUD$2978.89 per operation from the hospital perspective, when compared to canal wall up mastoidectomy. CONCLUSION: Totally endoscopic ear surgery is more cost effective, from an Australian private hospital perspective, than canal wall up mastoidectomy for attic cholesteatoma. PMID- 28891462 TI - Co-infection with a wheat rhabdovirus causes a reduction in Mal de Rio Cuarto virus titer in its planthopper vector. AB - Mal de Rio Cuarto virus (MRCV, Fijivirus, Reoviridae) causes one of the most important diseases in maize (Zea mays L.) in Argentina and has been detected in mixed infections with a rhabdovirus closely related to Maize yellow striate virus. In nature both viruses are able to infect maize and several grasses including wheat, and are transmitted in a persistent propagative manner by Delphacodes kuscheli Fennah (Hemiptera: Delphacidae). This work describes the interactions between MRCV and rhabdovirus within their natural vector and the consequences of such co-infection regarding virus transmission and symptom expression. First- and third-instar D. kuscheli nymphs were fed on MRCV-infected wheat plants or MRCV-rhabdovirus-infected oat plants, and two latency periods were considered. Transmission efficiency and viral load of MRCV-transmitting and non-transmitting planthoppers were determined by real-time quantitative polymerase chain reaction analysis (RTqPCR). Vector transmission efficiency was related to treatments (life stages at acquisition and latency periods). Nevertheless, no correlation between transmission efficiency and type of inoculum used to infect insects with MRCV was found. Treatment by third-instar nymphs 17 days after Acquisition Access Period was the most efficient for MRCV transmission, regardless of the type of inoculum. Plants co-infected with MRCV and rhabdovirus showed the typical MRCV symptoms earlier than plants singly infected with MRCV. The transmitting planthoppers showed significantly higher MRCV titers than non-transmitting insects fed on single or mixed inocula, confirming that successful MRCV transmission is positively associated with viral accumulation in the insect. Furthermore, MRCV viral titers were higher in transmitting planthoppers that acquired this virus from a single inoculum than in those that acquired the virus from a mixed inoculum, indicating that the presence of the rhabdovirus somehow impaired MRCV replication and/or acquisition. This is the first study about interactions between MRCV and a rhabdovirus closely related to Maize yellow striate virus in this insect vector (D. kuscheli), and contributes to a better understanding of planthopper-virus interactions and their epidemiological implications. PMID- 28891463 TI - Epidemiology of seasonal influenza infection in pregnant women and its impact on birth outcomes. AB - Seasonal influenza can cause significant morbidity in pregnant women. Much of the existing epidemiological evidence on influenza during pregnancy has focused on the 2009 A/H1N1 pandemic. To measure the epidemiological characteristics of seasonal influenza infection among pregnant women and the impact on infant health, a cohort of 86 779 pregnancies during the influenza season (2012-2014) was established using probabilistic linkage of notifiable infectious disease, hospital admission, and birth information. A total of 192 laboratory-confirmed influenza infections were identified (2.2 per 1000 pregnancies), 14.6% of which were admitted to hospital. There was no difference in the proportion of infections admitted to hospital by trimester or subtype of infection. Influenza B infections were more likely to occur in second trimester compared with influenza A/H3N2 and influenza A/H1N1 infections (41.3%, 23.6%, and 33.3%, respectively), and on average, infants born to women with influenza B during pregnancy had 4.0% (95% CI 0.3-7.6%) lower birth weight relative to optimal compared with infants born to uninfected women (P = 0.03). Results from this linked population-based study suggest that there are differences in maternal infection by virus type and subtype and support the provision of seasonal influenza vaccine to pregnant women. PMID- 28891464 TI - Concentration dependent chromatin states induced by the bicoid morphogen gradient. AB - In Drosophila, graded expression of the maternal transcription factor Bicoid (Bcd) provides positional information to activate target genes at different positions along the anterior-posterior axis. We have measured the genome-wide binding profile of Bcd using ChIP-seq in embryos expressing single, uniform levels of Bcd protein, and grouped Bcd-bound targets into four classes based on occupancy at different concentrations. By measuring the biochemical affinity of target enhancers in these classes in vitro and genome-wide chromatin accessibility by ATAC-seq, we found that the occupancy of target sequences by Bcd is not primarily determined by Bcd binding sites, but by chromatin context. Bcd drives an open chromatin state at a subset of its targets. Our data support a model where Bcd influences chromatin structure to gain access to concentration sensitive targets at high concentrations, while concentration-insensitive targets are found in more accessible chromatin and are bound at low concentrations. This may be a common property of developmental transcription factors that must gain early access to their target enhancers while the chromatin state of the genome is being remodeled during large-scale transitions in the gene regulatory landscape. PMID- 28891465 TI - Unusual prism adaptation reveals how grasping is controlled. AB - There are three main theories on how human grasping movements are controlled. Two of them state that grip aperture and the movement of the hand are controlled. They differ in whether the wrist or the thumb of the hand is controlled. We have proposed a third theory, which states that grasping is a combination of two goal directed single-digit movements, each directed at a specific position on the object. In this study, we test predictions based on each of the theories by examining the transfer of prism adaptation during single-digit pointing movements to grasping movements. We show that adaptation acquired during single-digit movements transfers to the hand opening when subsequently grasping objects, leaving the movement of the hand unaffected. Our results provide strong evidence for our theory that grasping with the thumb and index finger is based on a combination of two goal-directed single-digit movements. PMID- 28891466 TI - Thalamic input to auditory cortex is locally heterogeneous but globally tonotopic. AB - Topographic representation of the receptor surface is a fundamental feature of sensory cortical organization. This is imparted by the thalamus, which relays information from the periphery to the cortex. To better understand the rules governing thalamocortical connectivity and the origin of cortical maps, we used in vivo two-photon calcium imaging to characterize the properties of thalamic axons innervating different layers of mouse auditory cortex. Although tonotopically organized at a global level, we found that the frequency selectivity of individual thalamocortical axons is surprisingly heterogeneous, even in layers 3b/4 of the primary cortical areas, where the thalamic input is dominated by the lemniscal projection. We also show that thalamocortical input to layer 1 includes collaterals from axons innervating layers 3b/4 and is largely in register with the main input targeting those layers. Such locally varied thalamocortical projections may be useful in enabling rapid contextual modulation of cortical frequency representations. PMID- 28891469 TI - Influence of the sequence of proximal optimisation technique and side branch dilation for the opening of jailed struts after coronary bifurcation stenting. PMID- 28891467 TI - Removal of inhibition uncovers latent movement potential during preparation. AB - The motor system prepares for movements well in advance of their execution. In the gaze control system, the dynamics of preparatory neural activity have been well described by stochastic accumulation-to-threshold models. However, it is unclear whether this activity has features indicative of a hidden movement command. We explicitly tested whether preparatory neural activity in premotor neurons of the primate superior colliculus has 'motor potential'. We removed downstream inhibition on the saccadic system using the trigeminal blink reflex, triggering saccades at earlier-than-normal latencies. Accumulating low-frequency activity was predictive of eye movement dynamics tens of milliseconds in advance of the actual saccade, indicating the presence of a latent movement command. We also show that reaching a fixed threshold level is not a necessary condition for movement initiation. The results bring into question extant models of saccade generation and support the possibility of a concurrent representation for movement preparation and generation. PMID- 28891470 TI - Residual "inter-clip" regurgitation due to a partial detachment, treated with AMPLATZER Vascular Plug II implantation. PMID- 28891468 TI - Epidermal Growth Factor Receptor neddylation is regulated by a desmosomal-COP9 (Constitutive Photomorphogenesis 9) signalosome complex. AB - Cell junctions are scaffolds that integrate mechanical and chemical signaling. We previously showed that a desmosomal cadherin promotes keratinocyte differentiation in an adhesion-independent manner by dampening Epidermal Growth Factor Receptor (EGFR) activity. Here we identify a potential mechanism by which desmosomes assist the de-neddylating COP9 signalosome (CSN) in attenuating EGFR through an association between the Cops3 subunit of the CSN and desmosomal components, Desmoglein1 (Dsg1) and Desmoplakin (Dp), to promote epidermal differentiation. Silencing CSN or desmosome components shifts the balance of EGFR modifications from ubiquitination to neddylation, inhibiting EGFR dynamics in response to an acute ligand stimulus. A reciprocal relationship between loss of Dsg1 and neddylated EGFR was observed in a carcinoma model, consistent with a role in sustaining EGFR activity during tumor progression. Identification of this previously unrecognized function of the CSN in regulating EGFR neddylation has broad-reaching implications for understanding how homeostasis is achieved in regenerating epithelia. PMID- 28891471 TI - Polymer-Free Drug-Coated Coronary Stents Are Cost-Effective in Patients at High Bleeding Risk: Economic Evaluation of the LEADERS FREE Trial. AB - AIMS: In patients at high risk of bleeding who undergo PCI the biolimus A9 polymer-free drug coated stent (DCS) has superior efficacy and safety compared to a bare metal stent (BMS). We estimated the cost effectiveness of DCS vs. BMS. METHODS AND RESULTS: The Leaders FREE-based economic evaluation estimated service use and quality of life data collected prospectively. The entire trial population was analysed using cost-weights from England, France, Germany, Italy, Scotland and Spain. Country-specific QALYs were derived from EQ-5D scores. We estimated cost per event averted and per QALY gained. DCS use resulted in -0.095 cardiac deaths, target vessel MI, stent thrombosis and revascularization per patient (0.152 vs. 0.237;p<0.001). One-year QALYs were non-significantly higher in the DCS group. Total costs for the index admission were similar between groups. One year costs using cost-weights from each of the 6 countries, including the additional ?300 per DCS stent, ranged from ?4,664-8,593 for DCS and ?4,845-9,742 for BMS and were lower in the DCS group (England:?-428, France:?-137, Germany:? 33, Italy:?-522, Scotland:?-298, Spain:?-854). CONCLUSIONS: The probability that DCS dominated BMS was >50% in all countries. At a threshold of ?10,000 per event averted DCS had a 98% probability of being cost-effective in all 6 countries. PMID- 28891473 TI - Breastfeeding and Breastmilk - A Commitment, Not an Option. PMID- 28891472 TI - Characteristics of extension and de novo recurrent spontaneous coronary artery dissection. AB - AIMS: Spontaneous coronary artery dissection (SCAD) is an under-recognised and important cause of myocardial infarction in young women. Recurrent SCAD is frequent but poorly understood. We aimed to explore the clinical and angiographic characteristics, and outcomes of recurrent SCAD. METHODS AND RESULTS: Patients with SCAD extension or recurrence prospectively followed at Vancouver General Hospital were included in this retrospective study. SCAD diagnosis was confirmed by two experienced cardiologists. Detailed medical history, baseline demographics, angiographic results, and clinical details of index SCAD and recurrent events were recorded. SCAD extension was defined as angiographic extension of a previously dissected coronary segment, and de novo recurrent SCAD was defined as new spontaneous dissection. We identified 43 patients with SCAD recurrence with mean age 48.9+/-8.4 years; 38/43 were women, and 32/43 had fibromuscular dysplasia. Nine patients had SCAD extension at median time of five (1-19) days, while 34 patients had de novo recurrent SCAD at median time of 1,487 (107- 6,461) days after the index SCAD event. All SCAD extension patients had worsening of the index dissected segment, with 5/9 involving extension to adjacent segments, while all de novo recurrent SCAD patients had new dissections affecting coronary segments distinct from the index dissection. CONCLUSIONS: De novo recurrent SCAD invariably affected new segments distinct from previously dissected segments. PMID- 28891474 TI - Late Preterm Birth and Growth Failure in Childhood: What do we do now? PMID- 28891475 TI - Comparison of Transcutaneous Bilirubin Measurement With Total Serum Bilirubin Levels in Preterm Neonates Receiving Phototherapy. AB - OBJECTIVE: To compare transcutaneous bilirubin with total serum bilirubin in preterm neonates after initiation of phototherapy. METHODS: Jaundice was assessed in 30 preterm neonates with transcutaneous bilirubin and total serum bilirubin before initiation of phototherapy and at 12 hr after initiation of phototherapy. A photo-occlusive patch was applied over the sternum. RESULTS: Transcutaneous bilirubin has a good correlation with total serum bilirubin after initiation of phototherapy. (r=0.918, P<0.001). Transcutaneous bilirubin at 28-32 weeks of gestation (r = 0.97) was better correlated with total serum bilirubin than those at 32-37 weeks (r =0.88). The correlation was better for neonates <72 hours old (r = 0.96) than those >72 hours of age (r = 0.82). Conclusion: Transcutaneous bilirubin correlates significantly with total serum bilirubin at the patched sternal site after initiation of phototherapy in preterm neonates. PMID- 28891476 TI - Effect of Conventional and LED Phototherapy on the Antioxidant-Oxidant Status in Preterm Neonates with Jaundice. AB - OBJECTIVE: To compare oxidative stress due to conventional and LED phototherapy among jaundiced preterm neonates. METHODS: Cross-sectional study conducted in NICU on 82 neonates (equal numbers received conventional and LED phototherapy). Total antioxidant capacity (TAC), total oxidant status (TOS) and Oxidative stress index (OSI) were assessed. RESULTS: Post-phototherapy, mean (SD) OSI increased significantly compared to baseline in both conventional [0.26 (0.24) vs. 0.61 (0.41); P<0.001] and LED groups [0.24 (0.20) vs. 0.32 (0.23); P<0.001]. Across groups, mean (SD) TAC was lower [0.28 (0.16) vs. 0.53 (0.27); P<0.001] mmol Trolox equiv/L; mean (SD) TOS higher [15.6 (10.9) vs. 14.6 (10.2); P=0.711] umol H2O2/L and mean (SD) OSI higher [0.61 (0.42) vs. 0.33 (0.23); P<0.001] in conventional as compared to LED phototherapy. CONCLUSION: Both modes increased oxidative stress index; however, conventional phototherapy resulted in higher oxidative stress. PMID- 28891477 TI - Dexamethasone vs Placebo in Children having Pneumonia with Pleural Effusion: Evidence-based Medicine Viewpoint. PMID- 28891478 TI - Dexamethasone vs Placebo in Children having Pneumonia with Pleural Effusion: Contemporary Researcher's Viewpoint. PMID- 28891479 TI - Dexamethasone vs Placebo in Children having Pneumonia with Pleural Effusion: Pediatric Pulmonologist's Viewpoint. PMID- 28891480 TI - Dexamethasone vs Placebo in Children having Pneumonia with Pleural Effusion: Pediatrician's Viewpoint. PMID- 28891481 TI - Cardiac Manifestations in Children with Inborn Errors of Metabolism. AB - NEED AND PURPOSE: Cardiac involvement is a part of many inborn errors of metabolism, but has not been systematically studied. This review focuses on studies describing cardiac manifestations of inborn errors of metabolism in childhood. METHODS: Two independent reviewers searched the topic using PubMed database. Studies published within 20 years were considered, without applying any restrictions related to study design. Despite the small number of existing systematic studies on the topic, several case series/reports were identified. CONCLUSIONS: Cardiomyopathy is the most frequent heart disorder in most metabolic defects. Heart rhythm disorders are mainly encountered in mitochondrial disorders and acidemias, whereas valvular dysfunction is a prominent finding in storage disorders. Cardiac involvement in mitochondrial disorders, congenital disorders of glycosylation and acidemias usually constitute an early symptom. On the contrary, in storage disorders, heart problems are revealed in later stages during routine multisystemic evaluation, with the exception of Pompe disease. As a variety of cardiac manifestations can be found in inborn errors of metabolism, these children should be systematically screened for heart problems during their follow-up. PMID- 28891482 TI - Encephalopathy in Henoch-Schonlein Purpura. AB - BACKGROUND: Henoch-Schonlein purpura (HSP) is the most common vasculitis in childhood. Severe central nervous system (CNS) involvement is rare in HSP. CASE CHARACTERISTICS: Three children with features of HSP presented with seizures and CNS dysfunction. OBSERVATION: All three children had abnormalities on neuroimaging; 2 had complete remission but one was left with severe neurological damage. MESSAGE: HSP patients may rarely present with CNS involvement with a prolonged course requiring aggressive treatment. PMID- 28891483 TI - Emergency Surgery for Refractory Status Epilepticus. AB - BACKGROUND: Management of refractory status epilepticus in children is extremely challenging. CASE CHARACTERISTICS: Two children with medically refractory status epilepticus, both of whom had lesional pathology on MRI and concordant data on EEG and PET scan. INTERVENTION: Emergency hemispherotomy performed in both patients. A complete, sustained seizure freedom obtained postoperatively. MESSAGE: Emergency surgery is a treatment option in selected cases of drug refractory status epilepticus with lesional pathology and concordant data. PMID- 28891484 TI - Variable Expressivity and Response to Bisphosphonate Therapy in a Family with Osteoporosis Pseudoglioma Syndrome. AB - BACKGROUND: Osteoporosis pseudoglioma syndrome (OPPGS) is a rare autosomal recessive genetic disorder characterised by congenital blindness and osteoporosis, caused by biallelic mutations in the LRP5 gene. CASE CHARACTERISTICS: A consanguineous family with four OPPGS-affected members with variable expressivity. OBSERVATION: A novel homozygous missense pathogenic variant (c.3709C>T) was identified in the LRP5 gene. Good response to biphosphonate therapy was observed in all affected members. Message: This case highlights the importance of screening for osteopenia in a case of familial exudative retinopathy, for early institution of bisphosphonate therapy. PMID- 28891485 TI - Severe Complications of Mumps. PMID- 28891486 TI - Outcome of Biliary Atresia After Kasai's Portoenterostomy: Few Concerns. PMID- 28891487 TI - Outcome of Biliary Atresia After Kasai's Portoenterostomy: Few Concerns: Author's Reply. PMID- 28891488 TI - Some Problems Associated with Generic Drugs. PMID- 28891489 TI - Generic Drugs: A Call for Balanced Approach. PMID- 28891490 TI - Subluxation of Eyes in Crouzon Syndrome. PMID- 28891491 TI - Genital Herpes Infection in an Adolescent with Diabetes Mellitus. PMID- 28891492 TI - Porokeratotic Eccrine Ostial and Dermal Duct Nevus. PMID- 28891493 TI - Infantile Scurvy. PMID- 28891494 TI - Large-area epitaxial growth of MoSe2 via an incandescent molybdenum source. AB - We have developed an incandescent Mo source to fabricate large-area single crystalline MoSe2 thin films. The as-grown MoSe2 thin films were characterized using transmission electron microscopy, energy dispersive x-ray spectroscopy, atomic force microscopy, Raman spectroscopy, photoluminescence (PL), reflection high energy electron diffraction (RHEED) and angular resolved photoemission spectroscopy (ARPES). A new Raman characteristic peak at 1591 cm-1 was identified. Results from Raman spectroscopy, PL, RHEED and ARPES studies consistently reveal that large-area single crystalline mono-layer of MoSe2 could be achieved by this technique. This technique enjoys several advantages over conventional approaches and could be extended to the growth of other two dimensional layered materials containing a low-vapor-pressure element. PMID- 28891495 TI - Highly stable cesium lead iodide perovskite quantum dot light-emitting diodes. AB - Recently, all-inorganic perovskites such as CsPbBr3 and CsPbI3, have emerged as promising materials for light-emitting applications. While encouraging performance has been demonstrated, the stability issue of the red-emitting CsPbI3 is still a major concern due to its small tolerance factor. Here we report a highly stable CsPbI3 quantum dot LED with red emission fabricated using an improved purification approach. The device achieved decent external quantum efficiency (EQE) of 0.21 % at a bias of 6 V and outstanding operational stability, with a L70 lifetime (EL intensity decreases to 70% of starting value) of 16 h and 1.5 h under a constant driving voltage of 5 V and 6 V (maximum EQE operation) respectively. Furthermore, the device can work under a higher voltage of 7 V (maximum luminance operation) and retain 50% of its initial EL intensity after 500 s. These findings demonstrate the promise of CsPbI3 quantum dots for stable red LEDs, and suggest the feasibility for electrically pumped perovskite lasers with further device optimizations. PMID- 28891496 TI - Core to shell switching of the conduction channel on SnO2 nanowire sensors. AB - A sensor based on random connections of single crystalline SnO2 nanowires (NW) has been fabricated for ethanol detection. Crystal growth was achieved on r-cut sapphire substrates using the vapor-liquid-solid process and vapor transport technique. The NWs length of ~10 MUm leads to the formation of several random node connections ensuring the electrical conduction between electrodes during sensing experiments. The samples were submitted to thermal treatments under a reducing atmosphere of H2/Ar, to generate oxygen vacancies at the surface of the NW. As a result, an impurity band of shallow donor electrons, located at 0.37 eV below conduction band, is formed and the switching of the conduction channel from the core to the surface of the NW takes place eliminating the potential barrier at each NW node. PMID- 28891497 TI - A framework to reconcile frequency scaling measurements, from intracellular recordings, local-field potentials, up to EEG and MEG signals. AB - In this viewpoint article, we discuss the electric properties of the medium around neurons, which are important to correctly interpret extracellular potentials or electric field effects in neural tissue. We focus on how these electric properties shape the frequency scaling of brain signals at different scales, such as intracellular recordings, the local field potential (LFP), the electroencephalogram (EEG) or the magnetoencephalogram (MEG). These signals display frequency-scaling properties which are not consistent with resistive media. The medium appears to exert a frequency filtering scaling as 1/f, which is the typical frequency scaling of ionic diffusion. Such a scaling was also found recently by impedance measurements in physiological conditions. Ionic diffusion appears to be the only possible explanation to reconcile these measurements and the frequency-scaling properties found in different brain signals. However, other measurements suggest that the extracellular medium is essentially resistive. To resolve this discrepancy, we show new evidence that metal-electrode measurements can be perturbed by shunt currents going through the surface of the brain. Such a shunt may explain the contradictory measurements, and together with ionic diffusion, provides a framework where all observations can be reconciled. Finally, we propose a method to perform measurements avoiding shunting effects, thus enabling to test the predictions of this framework. PMID- 28891498 TI - A model of ion transport processes along and across the neuronal membrane. AB - In this study, we provide a foundational model of ion transport processes in the intracellular and extracellular compartments of neurons at the nanoscale. There are two different kinds of ionic transport processes: (i) ionic transport across the neuronal membrane (trans-membrane), and (ii) ionic transport along both the intracellular and extracellular surfaces of the membrane. Brownian dynamics simulations are used to give a description of ionic trans-membrane transport. Electro-diffusion is used to model ion transport along the membrane surface, and the two transport processes can be linked analytically. In our model, we found that the interactions between ions and ion channels result in high-frequency ionic oscillations during trans-membrane transport. In ion transport along the membrane, high-frequency ionic oscillations may be evoked on both the intracellular and extracellular surfaces of the plasma membrane. The electric field caused by Coulomb interactions between the ions is found to be the most likely origin of those ionic oscillations. PMID- 28891499 TI - Astroglial hydro-ionic waves guided by the extracellular matrix: An exploratory model. AB - Calcium waves are generated from the astrocyte endoplasmatic reticulum, in response to neuronal electrochemical stimulation. The waves feed back on neurons, modulating (reinforcing or depressing) their activity and the resulting behavior. How do these waves propagate from the astrocyte endoplasmatic reticulum to the synaptic space and reach neuron membrane channels? An exploratory model is elaborated, on the basis of complex interactions of ions, water negative exclusion zones and charged sites of proteins. The mechanism includes a role for the extracellular matrix to guide the hydro-ionic wave towards regions of the neuronal membrane where they are functional. The function of the waves is explored, suggesting that their dynamic patterns compose an adequate substrate for feelings (from basic feelings as hunger and thirst, pain and pleasure, to more complex ones, such as joy and sadness, love and hate). PMID- 28891500 TI - On the Nernst-Planck equation. AB - This review first discusses Nernst's and Planck's early papers on electro diffusion, the brief priority conflict that followed, and the role these papers played in shaping the emerging concept of membrane excitability. The second part discusses in greater detail the constraints of the Nernst-Planck theory, and shows more recent examples of its applicability for neuronal modelling. PMID- 28891501 TI - A comparison of computational models for the extracellular potential of neurons. AB - The extracellular space has an ambiguous role in neuroscience. It is present in every physiologically relevant system and often used as a measurement site in experimental recordings, but it has received subordinate attention compared to the intracellular domain. In computational modeling, it is often regarded as a passive, homogeneous resistive medium with a constant conductivity, which greatly simplifies the computation of extracellular potentials. However, novel studies have shown that local ionic diffusion and capacitive effects of electrically active membranes can have a substantial impact on the extracellular potential. These effects can not be described by traditional models, and they have been subject to recent theoretical and experimental analyses. We strive to give an overview over current progress in modeling the extracellular space with special regard towards the concentration and potential dynamics on different temporal and spatial scales. Three models with distinct assumptions and levels of detail are compared both theoretically and by means of numerical simulations: the classical volume conductor (VC) model, which is most frequently used in form of the line source approximation (LSA); the biophysically detailed, but computationally intensive Poisson-Nernst-Planck model of electrodiffusion (PNP); and an intermediate model called the electroneutral model (EN). The results clearly show that there is no one model for all applications, as they show significantly different responses - especially close to neuronal membranes. Finally, we list some common use cases for model simulations and give recommendations on which model to use in each situation. PMID- 28891502 TI - Extrapolating meaning from local field potential recordings. AB - Local field potentials (LFP) reflect the spatially weighted low-frequency activity nearest to a recording electrode. LFP recording is a window to a wide range of cellular activities and has gained increasing attention over recent years. We here review major conceptual issues related to LFP with the goal of creating a resource for non-experts considering implementing LFP into their research. We discuss the cellular activity that constitutes the local field potential; recording techniques, including recommendations and limitations; approaches to analysis of LFP data (with focus on power-banded analyses); and finally we discuss reports of the successful use of LFP in clinical applications. PMID- 28891503 TI - Extracellular matrix and its role in conveying glial/neural interactions in health and disease. AB - We review the concepts and findings that may be related to the occurrence of non linear glial/neural dynamics involving interactions between polyelectrolytes of the extracellular matrix and the basement membranes that cover the endfeet of glia at CNS interfaces. Distortions of perception and blocking of learning expressed in functional syndromes are interpreted as macroscopic electrochemical patterns that emerge in grey matter through glial/neural interactions. PMID- 28891504 TI - Special issue on extracellular space. PMID- 28891505 TI - Sleep microstructure dynamics and neurocognitive performance in obstructive sleep apnea syndrome patients. AB - The present study examined the relationship between the increment in cyclic alternating patterns (CAPs) in sleep electroencephalography and neurocognitive decline in obstructive Sleep Apnea Syndrome (OSAS) patients through source localization of the phase-A of CAPs. All-night polysomnographic recordings of 10 OSAS patients and 4 control subjects along with their cognitive profile using the Addenbrooke's Cognitive Examination (ACE) test were acquired. The neuropsychological assessment involved five key domains including attention and orientation, verbal fluency, memory, language and visuo-spatial skills. The standardized low-resolution brain electromagnetic tomography (sLORETA) tool was used to source-localize the phase-A of CAPs in sleep EEG aiming to investigate the correlation between CAP phase-A and cognitive functions. Our findings suggested a significant increase in CAP rates among OSAS subjects versus control subjects. Moreover, sLORETA revealed that CAP phase-A is mostly activated in frontoparietal cortices. As CAP rate increases, the activity of phase-A in such areas is dramatically enhanced leading to arousal instability, lower sleep efficiency and a possibly impaired cortical capacity to consolidate cognitive inputs in frontal and parietal areas during sleep. As such, cognitive domains including verbal fluency, memory and visuo-spatial skills which predominantly relate to frontoparietal areas tend to be affected. Based on our findings, CAP activity may possibly be considered as a predictor of cognitive decline among OSAS patients. PMID- 28891506 TI - Association of sleep impairments and gastrointestinal disorders in the context of the visceral theory of sleep. AB - It was noticed long ago that sleep disorders or interruptions to the normal sleep pattern were associated with various gastrointestinal disorders. We review the studies which established the causal link between these disorders and sleep impairment. However, the mechanism of interactions between the quality of sleep and gastrointestinal pathophysiology remained unclear. Recently, the visceral theory of sleep was formulated. This theory proposes that the same brain structures, and particularly the same cortical sensory areas, which in wakefulness are involved in processing of the exteroceptive information, switch during sleep to the processing of information coming from various visceral systems. We review the studies which demonstrated that neurons of the various cortical areas (occipital, parietal, frontal) during sleep began to fire in response to activation coming from the stomach and small intestine. These data demonstrate that, during sleep, the computational power of the central nervous system, including all cortical areas, is engaged in restoration of visceral systems. Thus, the general mechanism of the interaction between quality of sleep and health became clear. PMID- 28891507 TI - Comparison of separation performance of independent component analysis algorithms for fMRI data. AB - Independent component analysis, a data-driven analysis method, has found significant applications in task-based as well as resting state fMRI studies. There are numbers of independent component analysis algorithms available, but only a few of them have been used frequently so far for fMRI images. With a view that algorithms that are overlooked may outperform the most opted, a comparative study is taken up in this paper to analyze their abilities for the purpose of synthesis of fMRI images. In this paper, ten independent component algorithms: Fast ICA, INFOMAX, SIMBEC, JADE, ERICA, EVD, RADICAL, ICA-EBM, ERBM, and COMBI are compared. Their separation abilities are adjudged on both, synthetic and real fMRI images. Performance to decompose synthetic fMRI images is being monitored on the basis of spatial correlation coefficients, time elapsed to extract independent components and the visual appearance of independent components. Ranking of their performances on task-based real fMRI images are based on the closeness of time courses of identified independent components with model time course and the closeness of spatial maps of components with spatial templates while their competencies for resting state fMRI data are analyzed by examining how distinctly they decompose the data into the most consistent resting state networks. Sum of mutual information between all the permutations of decomposed components of resting state fMRI data are also calculated. PMID- 28891508 TI - Spike propagation in axons under stretch growth conditions in cultured neurons from dorsal root ganglion. AB - Computational software NEURON was used to simulate the stretch growth neurons in order to investigate the ability of dorsal root ganglion neurons to generate and propagate action potentials after a period of rapid axon stretch growth in vitro, and under what stimulating parameters can evoke action potentials. In the simulation, we found the stretch growth neuron had higher spike amplitude than from the static culture neuron in the soma and all axonal branch. In addition, the conduction velocity was also faster in the stretch growth axon. When the stimulating frequency was less than 15 Hz or the stimulating voltage was lower than 15 mV, no spike was evoked. Increasing stimulating frequency from 15 Hz to 5000 Hz or stimulating voltage from 15 mV to 100 mV had almost no effect on the spike amplitude. Interestingly, the first spike time and absolute refractory period (ARP) in different axonal branches and somas decreased stepwise with incremental increase in the stimulating frequency. It is concluded that the stretch growth neuron had higher amplitude and faster conduction velocity than the static culture neuron. In addition, some stimulating parameters had been analyzed in this study, which provided guidelines for electrophysiological experiments in future. PMID- 28891509 TI - Role of the medullary lateral tegmental field in sympathetic control. AB - The sympathetic nervous system maintains and regulates arterial pressure and tissue perfusion, via control of cardiac output and vasomotor tone. Sympatho vascular-mediated increases in blood pressure are effected by arterioloconstriction, which causes an increase in afterload, and/or venoconstriction, which increases venous return, left ventricular preload, and consequently, the force of cardiac contraction via Frank-Starling mechanisms; withdrawal of sympathetic drive elicits reciprocal effects. Spinalization reduces mammalian arterial pressure to 40-50 mm Hg consequent to the elimination of descending medullary pre-sympathetic bulbospinal drive to preganglionic sympathetic fibers in the intermediolateral cell column of the spinal cord. Beyond agreement that sympathetic tone is generated supraspinally, there is only controversy. One hypothesis posits that pre-sympathetic medullary regions, such as the rostral ventrolateral medulla (RVLM) and caudal raphe group, possess intrinsic tonic activity. Alternatively, pre-sympathetic medullary regions may receive tonic excitation from other areas in the brainstem. Neurons in the lateral tegmental field (LTF), an exclusively propriobulbar entity (cf. pre Botzinger complex - the propriobulbar inspiratory rhythmogenic kernel of the respiratory network), fire before and project to pre-sympathetic units in RVLM and caudal raphe and exhibit activity correlated to the cardiac-related rhythm in sympathetic nerve discharge, making the LTF a likely candidate for the primary source of basal sympathoexcitation. The LTF is additionally involved in a variety of cardiovascular and sympathetic reflexes (i.e., baroreflex, Bezold-Jarisch reflex). As it receives descending afferents from the infralimbic cortex and associated limbic structures, suggesting a role in the sympathetic response to fear, as well as vestibular inputs, consistent with a role in coordinating the sympathetic response with emesis proper, the LTF appears to play an extensive integrative role. In this review, we discuss the LTF, a once mysterious, poorly characterized, and ill-defined region, the contribution of which to cardiovascular reflexes and basal sympathoexcitation has been more thoroughly elucidated in recent years and any model of central control of sympathetic output must take into consideration the contribution of this important region. PMID- 28891510 TI - Influence of visual elicitation over emotion regulation: An investigation employing the heart rate variability. AB - Several works studied the elicitation of emotions through the exposure of individuals to relevant stimuli, using spectral analysis of Heart Rate Variability (HRV) when people are subject to emotional elicitation. If correlation exists between HRV and emotional responses, spectral analysis can be used to study emotion regulation under external stimuli. In this work, we studied the relationship between visual elicitation and emotion regulation, employing HRV. Images (with pleasant, unpleasant and neutral emotional content) were selected from the IAPS (International Affective Picture System) dataset. Ninety eight participants were enrolled, and subject to view all images, displayed in random order for each participant. Heart rate was recorded during the experiment, and HRV analysis was performed. Spectral values were studied for the different images. The presentation order of images was relevant, mainly when unpleasant images were viewed in first place; this significantly affects HRV values. Spectral values were higher for men, being this difference stronger when pleasant pictures were displayed. Age and gender dependences of spectral indexes were found. The influence of visual elicitation, with different emotional contents, over HRV, was assessed. Results indicate that HRV parameters are affected when individuals are subject to external, emotional-based stimuli. PMID- 28891511 TI - Gender similarities and differences in brain activation strategies: Voxel-based meta-analysis on fMRI studies. AB - Gender similarities and differences have long been a matter of debate in almost all human research, especially upon reaching the discussion about brain functions. This large scale meta-analysis was performed on functional MRI studies. It included more than 700 active brain foci from more than 70 different experiments to study gender related similarities and differences in brain activation strategies for three of the main brain functions: Visual-spatial cognition, memory, and emotion. Areas that are significantly activated by both genders (i.e. core areas) for the tested brain function are mentioned, whereas those areas significantly activated exclusively in one gender are the gender specific areas. During visual-spatial cognition task, and in addition to the core areas, males significantly activated their left superior frontal gyrus, compared with left superior parietal lobule in females. For memory tasks, several different brain areas activated by each gender, but females significantly activated two areas from the limbic system during memory retrieval tasks. For emotional task, males tend to recruit their bilateral prefrontal regions, whereas females tend to recruit their bilateral amygdalae. This meta-analysis provides an overview based on functional MRI studies on how males and females use their brain. PMID- 28891512 TI - Decoding of visual activity patterns from fMRI responses using multivariate pattern analyses and convolutional neural network. AB - Decoding of human brain activity has always been a primary goal in neuroscience especially with functional magnetic resonance imaging (fMRI) data. In recent years, Convolutional neural network (CNN) has become a popular method for the extraction of features due to its higher accuracy, however it needs a lot of computation and training data. In this study, an algorithm is developed using Multivariate pattern analysis (MVPA) and modified CNN to decode the behavior of brain for different images with limited data set. Selection of significant features is an important part of fMRI data analysis, since it reduces the computational burden and improves the prediction performance; significant features are selected using t-test. MVPA uses machine learning algorithms to classify different brain states and helps in prediction during the task. General linear model (GLM) is used to find the unknown parameters of every individual voxel and the classification is done using multi-class support vector machine (SVM). MVPA-CNN based proposed algorithm is compared with region of interest (ROI) based method and MVPA based estimated values. The proposed method showed better overall accuracy (68.6%) compared to ROI (61.88%) and estimation values (64.17%). PMID- 28891513 TI - Electrode channel selection based on backtracking search optimization in motor imagery brain-computer interfaces. AB - Common spatial pattern algorithm is widely used to estimate spatial filters in motor imagery based brain-computer interfaces. However, use of a large number of channels will make common spatial pattern tend to over-fitting and the classification of electroencephalographic signals time-consuming. To overcome these problems, it is necessary to choose an optimal subset of the whole channels to save computational time and improve the classification accuracy. In this paper, a novel method named backtracking search optimization algorithm is proposed to automatically select the optimal channel set for common spatial pattern. Each individual in the population is a N-dimensional vector, with each component representing one channel. A population of binary codes generate randomly in the beginning, and then channels are selected according to the evolution of these codes. The number and positions of 1's in the code denote the number and positions of chosen channels. The objective function of backtracking search optimization algorithm is defined as the combination of classification error rate and relative number of channels. Experimental results suggest that higher classification accuracy can be achieved with much fewer channels compared to standard common spatial pattern with whole channels. PMID- 28891514 TI - Cognitive responses and cortical oscillatory processing at various stereoscopic depths - a simultaneous EEG/MEG study. AB - Due to the recent explosion in various forms of 3D content, the evaluation of such content from a neuroscience perspective is quite interesting. However, existing investigations of cortical oscillatory responses in stereoscopic depth perception are quite rare. Therefore, we investigated spatiotemporal and spatio temporo-spectral features at four different stereoscopic depths within the comfort zone. We adopted a simultaneous EEG/MEG acquisition technique to collect the oscillatory responses of eight participants. We defined subject-specific retinal disparities and designed a single trial-based stereoscopic viewing experimental paradigm. In the group analysis, we observed that, as the depth increased from Level 1 to Level 3, there was a time-locked increase in the N200 component in MEG and the P300 component in EEG in the occipital and parietal areas, respectively. In addition, initial alpha and beta event-related desynchronizations (ERD) were observed at approximately 500 to 1000 msec, while theta, alpha, and beta event-related synchronizations (ERS) appeared at approximately 1000 to 2000 ms. Interestingly, there was a saturation point in the increase in cognitive responses, including N200, P300, and alpha ERD, even when the depth increased only within the comfort zone. Meanwhile, the magnitude of low beta ERD decreased in the dorsal pathway as depth increased. From these findings, we concluded that cognitive responses are likely to become saturated in the visual comfort zone, while perceptual load may increase with depth. PMID- 28891515 TI - A computational approach towards the microscale mouse brain connectome from the mesoscale. AB - The wiring diagram of the mouse brain presents an indispensable foundation for the research on basic and applied neurobiology. It is also essential as a structural foundation for computational simulation of the brain. Different scales of the connectome give us different hints and clues to understand the functions of the nervous system and how they process information. However, compared to the macroscale and most recent mesoscale mouse brain connectome studies, there is no complete whole brain microscale connectome available because of the scalability and accuracy of automatic recognition techniques. Different scales of the connectivity data are comprehensive descriptions of the whole brain at different levels of details. Hence connectivity results from a neighborhood scale may help to predict each other. Here we report a computational approach to bring the mesoscale connectome a step forward towards the microscale from the perspective of neuron, synapse and network motifs distribution by the connectivity data at the mesoscale and some facts from the anatomical experiments at the microscale. These attempts make a step forward towards the efforts of microscale mouse brain connectome given the fact that the detailed microscale connectome results are still far to be produced due to the limitation of current nano-scale 3-D reconstruction techniques. The generated microscale mouse brain will play a key role on the understanding of the behavioral and cognitive processes of the mouse brain. In this paper, the conversion method which could get the approximate number of neurons and synapses in microscale is proposed and tested in sub regions of Hippocampal Formation (HF), and is generalized to the whole brain. As a step forward towards understanding the microscale connectome, we propose a microscale motif prediction model to generate understanding on the microscale structure of different brain region from network motif perspective. Correlation analysis shows that the predicted motif distribution is very relevant to the real anatomical brain data at microscale. PMID- 28891517 TI - Selective attention and the "Asynchrony Theory" in native Hebrew-speaking adult dyslexics: Behavioral and ERPs measures. AB - The main aim of the present study was to determine whether adult dyslexic readers demonstrate the "Asynchrony Theory" (Breznitz [Reading Fluency: Synchronization of Processes, Lawrence Erlbaum and Associates, Mahwah, NJ, USA, 2006]) when selective attention is studied. Event-related potentials (ERPs) and behavioral parameters were collected from nonimpaired readers group and dyslexic readers group performing alphabetic and nonalphabetic tasks. The dyslexic readers group was found to demonstrate asynchrony between the auditory and the visual modalities when it came to processing alphabetic stimuli. These findings were found both for behavioral and ERPs parameters. Unlike the dyslexic readers, the nonimpaired readers showed synchronized speed of processing in the auditory and the visual modalities while processing alphabetic stimuli. The current study suggests that established reading is dependent on a synchronization between the auditory and the visual modalities even when it comes to selective attention. PMID- 28891516 TI - Effects of donepezil on liver and kidney functions for the treatment of Alzheimer's disease. AB - Aim of the present study is to investigate the effects of medication with donepezil (acetylcholinesterase inhibitor) on the liver and kidney function in Alzheimer's disease (AD) and to compare the effects of donepezil medication during short (one month) and long term (six years) follow-ups. We evaluated female and male patients from Cukurova [42 AD patients; short term (5 mg/day)] and Dokuz Eylul [68 AD patients; long term (10 mg/day)] University Hospital. The results compared with the geriatric population without dementia in other words who are not in medication with donepezil. For short term evaluation all subjects underwent periodic examination with tests regarding hepatic and renal functions; firstly, before starting treatment and then repeated one month later. For long term evaluation all subjects underwent periodic examination with tests regarding hepatic and renal functions; three times at the end of each two consecutive years of treatment with donepezil. AD patients' results were also compared with 79 neurologically healthy geriatric patients without dementia who were over 65 years of age and were not receiving medication with donepezil. For this task, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels are used to predict possible liver damage, while the blood urea nitrogen (BUN) and creatinine (CRE) levels for kidney damage. No significant difference between the groups regarding the routine control of biochemical parameters was observed in short term drug medication. In long term patients' group; the effects of two years use of donepezil on renal and hepatic function were also evaluated and levels of AST, ALT, BUN and CRE were found to be increased significantly compared to pretreatment levels. But, they remained in the reference intervals. However, levels of AST and ALT at the end of the fourth year of therapy were similar to those measured at the end of the second year, levels of BUN and CRE continuing to increase with staying below the reference limits. Functional markers obtained at the end of the sixth year of therapy were not differing from those of the fourth year. No significant difference was found during comparisons within the results of the neurologically healthy geriatric patient group. During comparisons between the two groups, measurements obtained at all-time points were significantly high in donepezil treated AD patients. We concluded that customized dosage according to hepatic and renal functions is necessary for using acetylcholinesterase inhibitor in AD patients. PMID- 28891518 TI - Temperature effects on accommodative processes in simulated amyotrophic lateral sclerosis in the physiological range. AB - The present study investigates the temperature dependence of electrotonic potentials in mathematically-simulated myelinated axons with one of three increasingly-severe type of amyotrophic lateral sclerosis (ALS) pathology, termed as ALS1, ALS2 and ALS3, respectively, in the physiological range (30-37?C). These potentials were elicited by long-lasting (100 ms) subthreshold polarizing current stimuli (+/-40% of the threshold). Numerical solutions were computed using our temperature-dependent multi-layered model. The results showed the following trends: (i) in ALS1, polarizing electrotonic potentials were normal; (ii) in ALS2 and ALS3, action potentials were elicited in the early parts of the depolarizing electrotonic potentials, and (iii) in ALS3, spontaneous discharges were elicited after the termination of applied hyperpolarizing stimuli (i.e., post-anodal excitation). The ionic currents underlying electrotonic potentials in the ALS1 case were attributable to the activation of potassium fast (Kf+) and slow (Ks+) channels in the nodal and internodal axolemma beneath the myelin sheath. By contrast, in ALS2 and ALS3, the depolarizing stimuli activated the classical "transient" Na+ channels in the nodal and internodal axolemma beneath the myelin sheath eliciting action potential generation. These results obtained were closer to those observed in hypothermia (?25?C) than in hyperthermia (?40?C). PMID- 28891519 TI - Following during physically-coupled joint action engages motion area MT+/V5. AB - Interpersonal coordination during joint action depends on the perception of the partner's movements. In many such situations - for example, while moving furniture together or dancing a tango - there are kinesthetic interactions between the partners due to the forces shared between them that allow them to directly perceive one another's movements. Joint action of this type often involves a contrast between the roles of leader and follower, where the leader imparts forces onto the follower, and the follower has to be responsive to these force-cues during movement. We carried out a novel 2-person functional MRI study with trained couple dancers engaged in bimanual contact with an experimenter standing next to the bore of the magnet, where the two alternated between being the leader and follower of joint improvised movements, all with the eyes closed. One brain area that was unexpectedly more active during following than leading was the region of MT+/V5. While classically described as an area for processing visual motion, it has more recently been shown to be responsive to tactile motion as well. We suggest that MT+/V5 responds to motion based on force-cues during joint haptic interaction, most especially when a follower responds to force-cues coming from a leader's movements. PMID- 28891520 TI - Neurons in dorsal premotor cortex represent the switching of intended hand path in a delayed reaching task. AB - Dorsal premotor cortex (PMd) is considered to play a crucial role in motor preparation, yet how the variation of neuronal activity affects the generation of different circumstances dependent movements remains unclear. Here we trained two monkeys to perform a delayed reaching task instructed by two sets of cues, one for indicating the target locations and another for indicating a conditionally presented virtual obstacle in the reaching path, which required the monkey to make a bypassing instead of straight reaching. We recorded the activity of PMd neurons and investigated how they responded to the switching of intended hand path induced by obstacle bypassing. Comparing the neuronal activity between hand bypassing trials and straight reaching trials, we found 30% of the total 687 set related neurons showed different overall discharging level, and another 24% showed different onset time during the delay period. We also found 16% of the neurons were modulated only by target location and 14% were modulated by both target location and path switching. Our results demonstrate PMd neurons not only represent the planning of reaching to different target locations, as many previous studies have shown, but also represent the switching of intended reaching path induced by hand bypassing, suggesting how PMd neurons coordinate for such circumstances dependent motor planning. PMID- 28891522 TI - Impairments of cingulated cortex in the generalized tonic-clonic seizure epilepsy by combining morphological and functional connectivity magnetic resonance imaging. AB - Previous studies suggested that the patients with generalized tonic-clonic seizure had structural abnormalities in the thalamus, cingulated cortex and some other specific brain regions. Concurrently, the abnormality in thalamocortical network and basal ganglia network has been found in idiopathic generalized epilepsy. The cingulated cortex, a nexus of information processing and regulation in human brain, is implicated in the propagation of generalized spike in IGE and the previous studies have suggested that the structural features and functional connectivity of the cingulated cortex have been changed. The aim of this study was to demonstrate the alterations in the cingulated cortex in generalized tonic clonic seizure by combining morphological and functional connectivity magnetic resonance imaging. 19 patients with generalized tonic-clonic seizure and 19 age and gender-matched healthy controls were involved in the study. The three dimensional high-resolution T1-weighted magnetic resonance imaging data were acquired for voxel-based morphometry analysis, two-sample t-test run on the T1 weighted structural images revealed clusters exhibiting significant decreases in grey-matter volume in the generalized tonic-clonic seizure group, located within the cingulated cortex, thalamus, frontal lobe, temporal lobe, and cerebellum. The decreased gray matter volume in the cingulated cortex indicating that the cingulated cortex has structural impairments in generalized tonic-clonic seizure patients. The bilateral cingulated cortex, as detected with decreased gray matter volume in patients with generalized tonic-clonic seizure through voxel-based morphometry analysis, was selected as seed regions for functional connectivity analysis. Compared with controls, we found decreased functional connectivity to left anterior cingulated cortex (ROI1) in the cuneus, frontal lobe and precentral gyrus. There was no significant result when seeding at the right anterior cingulum gyrus (ROI2). The results of the ROI3 (left middle cingulum) revealed the significantly decreased functional connectivity in the parietal lobe and frontal lobe. Seeding at the ROI4 (right middle cingulum), decreased functional connectivity showed in the occipital lobe, temporal lobe, frontal lobe. Seeding at the ROI5 (left posterior cingulum), decreased functional connectivity showed in the temporal lobe and frontal lobe. Seeding at the ROI6 (right posterior cingulum), decreased functional connectivity showed in the cuneus and frontal lobe. We did not find any increased functional connectivity of the posterior cingulated cortex (ROI3-ROI6) for the generalized tonic-clonic seizure patients in comparison to the controls (p<0.001). Our findings demonstrated that the abnormalities of the functional connectivity were likely to be related to the decreased gray matter volume in the cingulated cortex. PMID- 28891521 TI - Effects of high fat diet and perinatal dioxin exposure on development of body size and expression of platelet-derived growth factor receptor beta in the rat brain. AB - Environmental exposure to dioxins, consumption of a high fat diet, and platelet derived growth factor receptor beta signaling in the brain affect feeding behavior, which is an important determinant of body growth. In the present study, we investigated the effects of prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p dioxin and high fact diet after weaning on body growth and expression of platelet derived growth factor receptor beta in the brain in rat pups. Subjects from the control and dioxin exposure groups were assigned to 1 of 3 different diet groups: standard diet, high fat diet in the juvenile period, or high fat diet in adulthood. Body weight gain rate in the juvenile high fat diet group and the length gain rate in the adult high fat diet group were greater than the corresponding values in the standard diet group only in male offspring, although the effects of dioxin exposure on growth were not significant. Consumption of a high fat diet decreased platelet-derived growth factor receptor beta levels in the amygdala and hippocampus in both sexes compared to control groups, while 2,3,7,8-tetrachlorodibenzo-p-dioxin decreased platelet-derived growth factor receptor platelet-derived growth factor receptor beta levels in the amygdala and striatum only in females receiving an high fat diet. Furthermore, platelet derived growth factor receptor beta levels in the hippocampus and platelet derived growth factor receptor beta striatum were inversely correlated with increases in body length, while changes in platelet-derived growth factor receptor beta in the amygdala and nucleus accumbens were significantly correlated to body weight gain or body mass index. In conclusion, these findings suggest that these 2,3,7,8-tetrachlorodibenzo-p-dioxin and high fat diet-induced changes in body growth and feeding behaviors might be partially mediated by changes in brain platelet-derived growth factor receptor beta levels. PMID- 28891524 TI - Semantic category-based decoding of human brain activity using a Gabor-based model by estimating intracranial field potential range in temporal cortex. AB - Predicting and decoding the recorded neural activity for visual stimuli is the topic of many studies. This prediction can be made by comparing the model's responses to different stimuli with the available recorded brain signal. The neural activities can be decoded then by finding the stimulus which has generated the nearest model's response to the recorded signal. In this study, a model is proposed which can estimate the response of human brain to images from different conceptual categories by inserting the visual stimuli as the model input after filtering by Gabor wavelets. This helped us to find each image's low level visual features. Afterward, the extracted image features were applied to the input of a curve fitting neural network. As the output, the range of intracranial field potential was estimated. This was performed separately for each pixel of the image. To evaluate the model's accuracy, two factors were used, namely the Pearson correlation and Normalized root mean square error. The results show that the proposed model can accurately estimate the brain's response to conceptual categories To decode the brain' activity based on the observed semantic category in each test observations by using of the model, we calculated the distance between the recorded signal and the model responses to all stimuli from different categories and assigned the category of the nearest model response to brain's response in that trial. To this end, a K-nearest neighbors classifier based on Euclidean distance was used. This leaded to a classification accuracy which was significantly higher than chance level. So, the proposed model can be used to decode the activity of the brain in response to the visual stimuli. PMID- 28891523 TI - Sensitivity analysis of discharge patterns of subthalamic nucleus in the model of basal ganglia in Parkinson disease. AB - Parkinson disease alters the information patterns in movement related pathways in brain. Experimental results performed on rats show that the activity patterns changes from single spike activity to mixed burst mode in Parkinson disease. However the cause of this change in activity pattern is not yet completely understood. Subthalamic nucleus is one of the main nuclei involved in the origin of motor dysfunction in Parkinson disease. In this paper, a single compartment conductance based model is considered which focuses on subthalamic nucleus and synaptic input from globus pallidus (external). This model shows highly nonlinear behavior with respect to various intrinsic parameters. Behavior of model has been presented with the help of activity patterns generated in healthy and Parkinson condition. These patterns have been compared by calculating their correlation coefficient for different values of intrinsic parameters. Results display that the activity patterns are very sensitive to various intrinsic parameters and calcium shows some promising results which provide insights into the motor dysfunction. PMID- 28891525 TI - Hodgkin-Huxley model based on ionic transport in axoplasmic fluid. AB - Hodgkin-Huxley model has been reframed to incorporate the physical parameters of fluid inside the axon. The reframed model comprises of set of partial differential equations containing the physical parameters: density, mass fraction of sodium, potassium and chlorine ions, longitudinal diffusivity of ions and rate of additions of ions along with the temperature. Obtained conduction velocity of 19.5m/sec at a temperature of 18.5 degree celcius and conduction velocity dependency on temperature within the range 5 to 25 degree celcius are two important results that strongly validate the proposed model. The behavior of all the physical parameters has been characterized with respect to the action potential. Action potential conduction velocity along with axoplasmic fluid viscosity has been characterized with respect to different temperatures. Longitudinal diffusivity of ions is also quantified. PMID- 28891526 TI - Facial expressions triggered by imagining the future. AB - A body of research has investigated the cognitive and affective features of imagining the future. Our study aimed at extending this research by evaluating expressions that are triggered by future thinking. Participants were asked to remember and to imagine personal events. Both past and future thinking were video recorded and the recording was later analyzed by a software for facial analysis that detects and classifies basic emotional expressions (i.e., happy, sad, angry, surprised, scared, disgusted and neutral). The analysis showed more emotional and fewer neutral facial expressions during imagining the future than during remembering the past. These findings mirror a wealth of psychological research highlighting the emotional valence of future thinking, which has been mainly assessed in this research by subjective methodologies. Our work provides an empirical description of facial expressions that can be triggered by imagining the future. PMID- 28891527 TI - Glial cell-derived neurotrophic factor gene polymorpisms affect severity and functionality of bipolar disorder. AB - Glial cell-derived neurotrophic factor and other neurotrophins have important role in the development of mental disorders. Here, we aimed to assess the effects of Single nucleotide polymorphisms at potentially regulated regions of GDNF on severity and functionality of bipolar disorder and GDNF serum levels in bipolar disorder patients and healthy volunteers. Severity and functionality of bipolar disorder were evaluated using the Clinical Global Impression and Global Assessment of Functioning scales in sixty-six bipolar disorder patients. The GDNF serum levels obtained from bipolar disorder patients and healthy volunteers who had been already reported SNPs information by our group. GAF scales were lower and GDNF serum levels were higher in Bipolar disorder patients with T/A genotype at 5:37812784 and 5:37812782 compared to patients with T/T genotype. There were significant difference in severity and functionality scores, but not in GDNF serum levels, between patients with G/G and G/A genotype of rs62360370 G > A SNP.rs2075680 C > A and rs79669773 T > C SNPs had no effect on bipolar disorder severity and functionality scores and GDNF serum levels. The results suggest that some SNPs of GDNF have potential association with severity and functionality of bipolar disorder. In addition, except two SNPs, none of GDNF SNPs had association with GDNF serum levels. PMID- 28891529 TI - Nonsynaptic plasticity model of long-term memory engrams. AB - Using steady-state electrical properties of non-ohmic dendrite based on cable theory, we derive electrotonic potentials that do not change over time and are localized in space. We hypothesize that clusters of such stationary, local and permanent pulses are the electrical signatures of enduring memories which are imprinted through nonsynaptic plasticity, encoded through epigenetic mechanisms, and decoded through electrotonic processing. We further hypothesize how retrieval of an engram is made possible by integration of these permanently imprinted standing pulses in a neural circuit through neurotransmission in the extracellular space as part of conscious recall that acts as a guiding template in the reconsolidation of long-term memories through novelty characterized by uncertainty that arises when new fragments of memories reinstate an engram by way of nonsynaptic plasticity that permits its destabilization. Collectively, these findings seem to reinforce this hypothesis that electrotonic processing in non ohmic dendrites yield insights into permanent electrical signatures that could reflect upon enduring memories as fragments of long-term memory engrams. PMID- 28891528 TI - 2-(2-benzofuranyl)-2-imidazoline (2-BFI) improved the impairments in AD rat models by inhibiting oxidative stress, inflammation and apoptosis. AB - Alzheimer's Disease (AD) is one of the commonest neural degeneration in aging population, and has become a global health challenge. 2-(2-benzofuranyl)-2 imidazoline (2-BFI) was reported to effectively improved the damage of patients with neuropathological disorders. In the present study, we investigated the effect of 2-BFI on the improvement of antioxidative, inflammation, and apoptosis in AD rats. Sprague-Dawley rats (2 months old, n=40) were used in this study and after injection of Abeta1-42 into hippocampal CA1 (Cornu Ammonis) region, the rats were given high, moderate and low dose of 2-BFI though intraperitoneal (i.p.) injection. Then spatial memory and navigation ability were analyzed by Morrize Water Maze. For the molecular testing, chemical colorimetry, ELISA and immunoblotting were performed to measure the activities of antioxidative enzymes, the abundance of immune cytokines and expression of apoptotic proteins, respectively. Hematoxylin and Eosin staining was used to analyze the pathological changes. We observed that 2-BFI significantly ameliorated the learning and memory abilities in rat models with AD by dosage treatment, as demonstrated by the shorten learning latency and greater times of travel across the platform quadrant. Additionally, reactive oxygen species (ROS) and malondialdehyde (MDA), were decreased after treatment of 2-BFI with dosage dependency, while the activities of superoxidase dismutase (SOD) and (GPX) Glutathione peroxidase were in turn enhanced, suggesting that 2-BFI could protect the antioxidative enzymes and reduce the oxidative stress in the hippocampus. Moreover, the expression of inflammatory factors including TNF-a and IL-1beta were decreased after 2-BFI treatment. Additionally, the neuronal apoptosis was also attenuated, as shown by Western blot results. Taken together, the cognitive impairment in AD rats could be significantly improved by 2-BFI in a dose-dependent manner through suppressing oxidants accumulation, inhibiting of inflammatory response, as well as enhancing the neural viability. PMID- 28891531 TI - Development of dysplastic nevus during radotinib therapy in patients with chronic myeloid leukemia. PMID- 28891532 TI - Successful treatment of total obliteration of vulva caused by inveterate vulvar lichen sclerosus. PMID- 28891533 TI - What is new in recommendations on ophthalmological screening in patients treated with chloroquine and hydroxychloroquine? Update and literature review. AB - Based on the present literature, in March 2016, new recommendations of the American Academy of Ophthalmology for ophthalmic screening tests in patients treated with chloroquine and hydroxychloroquine were published. These recommendations emphasized the fact that toxicity is related to the dose calculated by real weight. The recommended hydroxychloroquine and chloroquine doses have been limited. It is no longer recommended to calculate the cumulative dose of chloroquine to establish the risk of toxicity. Kidney failure and the use of tamoxifen are proven risk factors of ocular complications in these patients. The screening agenda was established and available diagnostic methods were evaluated. Screening in patients treated with chloroquine derivatives may prevent an irreversible complication-toxic retinopathy. The present recommendations warn against making premature decision on medicine withdrawal, especially in the light of the most recent studies on their beneficial systemic influence. This paper systematizes the information on ophthalmological screening in chloroquine derivatives users. PMID- 28891534 TI - Effect of irradiation on the shear bond strength of self-adhesive luting cement in different preparation depths. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of pre- and post irradiation application on the shear bond strength of self-adhesive luting cements to dentin and enamel. MATERIALS AND METHODS: Thirty-two extracted human maxillary incisor teeth were used in this study. Teeth were divided into two main groups according to preparation depth (0.5 mm and 1 mm) as Group E and Group D and were divided into four subgroups according to treatment protocol (n = 12). Teeth were irradiated and preparation was done after radiation. Adhesive luting cement was placed on the irradiated enamel and dentin surface (Groups E1, D1). Preparation was done before irradiation and resin cement was placed on the irradiated enamel and dentin surface (Groups E2, D2). The resin cement was first placed on their enamel and dentin surfaces and then the specimens were irradiated (Groups E3, D3). Irradiation was done with a total dose of 60 Gy, applied in fractions over 6 weeks for each groups (2-Gy/day fractions, 5 days per week). Nonirradiated groups were determined as controls groups (Groups C1, C2). The shear bond strengths of adhesive luting cement were examined. RESULTS: According to the two-way ANOVA results, depth of preparation and treatment protocol and their interactions were significant on shear bond strength of resin cement (P Conclusions: This study detected significant differences between the irradiated and nonirradiated groups, probably due to the changes in the crystalline structure of dental hard tissues. PMID- 28891535 TI - Doppler sonographic evaluation of venogenic extremity swellings: Analysis of 170 patients from Kano, Nigeria. AB - INTRODUCTION: Deep venous thrombosis (DVT) is a serious problem that can potentially lead to many complications including life-threatening pulmonary arterial thrombosis. Screening and confirmation of the diagnosis are critical in the care of this condition. OBJECTIVES: The objective of this study was to evaluate the role of Doppler sonography in diagnosing DVT and to illustrate the pattern in 170 suspected cases from our local environment. MATERIALS AND METHODS: This study was conducted at our department over 18 months. A total of 170 patients with clinical suspicion of limb DVT were recruited. The characteristics of the patients, risk factor for DVT, and the site of the lesion were documented. Sonographic examination was done using 7.5 MHz linear and 3.5 MHz convex transducers. RESULTS: Out of the 170 patients, there are 89 (52.35%) males and 81 (47.65%) females. Their mean age was 50.6 years (+17.9 years). The common risk factors for DVT include chronic medical illness (28.8%), long distance travel (15.3%), previous DVT (8.8%), stroke/paralysis (5.3%), neoplasms (5.9%), pregnancy (5.9%), and trauma/surgery (5.9%). About 55.8% (95) of them were confirmed to have DVT on ultrasound while 44.2% (75) had normal ultrasound findings. There was a female preponderance among the 95 cases of DVT, 58.9% of them were females while 41.1% of them were males. It was found that contiguous femoro-popliteal and ilio-femoro-popliteal segments were most commonly thrombosed. These lesions were predominantly left sided (59.5%). CONCLUSION: There was a predominance of females and femoro-popliteal segments in DVT. Doppler ultrasound is very useful in the evaluation of extremity DVT. All clinically suspected cases should be evaluated with this modality due to limited sensitivity of clinical evaluation in the diagnosis of DVT. Further correlative studies in comparison to venography and hematologic indices are also recommended. PMID- 28891536 TI - Urine osmolality in treatment-naive HIV-positive subjects in Southeast Nigeria. AB - BACKGROUND AND OBJECTIVES: Urine osmolality varies over a wide range of values in a healthy state. Dilute urine or concentrated urine may be observed in many environmental, physiologic, and disease conditions. Urine osmolality is not commonly evaluated in routine clinical practice and in human immunodeficiency virus (HIV) subjects. The factors that influence urine osmolality have not been completely identified. The aim of this study was to evaluate urine osmolality in treatment-naive HIV subjects and to identify the factors that may influence dilute and concentrated urine in this group of patients. METHODOLOGY: This was a cross-sectional study of treatment-naive HIV subjects conducted in Federal Medical Centre (FMC), Owerri, Nigeria. Demographic and anthropometric data were obtained. Urine osmolality and other relevant investigations were conducted. Normal urine osmolality was defined as 24-h urine osmolality (24 HUOsm) 300-750 mOsm/kgH2O, dilute urine as 24 HUOsm 2O and concentrated urine as 24 HUOsm> 750 mOsm/kgH2O. The association between the variables and urine osmolality and the strength of variables to predict dilute urine and concentrated urine were determined. RESULTS: The mean 24HUOsm was 564 +/- 501 mOsm/kgH2O and the mean spot urine osmolality (SUOsm) 464 +/- 271 mOsm/kgH2O. Normal urine osmolality was observed in 29.6%, dilute urine in 64.5%, and concentrated urine in 5.9% of the HIV subjects. There was a significant association between urine osmolality and body mass index (BMI), creatinine clearance, as well as serum cholesterol level. Only high-density lipoprotein cholesterol (HDL) predicted dilute urine, whereas BMI, spot urine protein, 24-h urine protein, spot urine creatinine, serum HDL, and CD4 cell count predicted concentrated urine. CONCLUSION: The prevalence of dilute urine was high among the treatment-naive HIV subjects. Abnormalities of serum lipids, renal function, and weight were common in treatment-naive HIV subjects who had dilute urine. There is a need for clinicians to routinely assess urine osmolality and further diagnose for dyslipidemia, renal function impairment, and abnormal weight in HIV subjects at the early stage of the infection. PMID- 28891537 TI - Clinical performance of a combined approach for the esthetic management of fluorosed teeth: Three-year results. AB - OBJECTIVE: The long-term clinical performance of combined therapy including enamel microabrasion and vital bleaching is debatable due to the abrasion of outer enamel surface. The aim of this longitudinal cohort study was to evaluate the 3-year clinical performance of enamel microabrasion in combination with vital tooth bleaching for the esthetic management of fluorosed teeth. MATERIALS AND METHODS: Fifteen patients with 176 fluorosed incisors and canines were included in this study. All the teeth were treated with enamel microabrasion (Opalustre, Ultradent), and at-home bleaching technique (10% Opalescence PF, Ultradent). Fluorosed teeth were evaluated at baseline, after microabrasion, after combined therapy, and at 3-year follow-up in terms of esthetic criteria (esthetic appearance, brown stains, and opaque white areas), side effects, and patient satisfaction using visual analog scales. The data were statistically analyzed (alpha = 0.05). RESULTS: Fluorosed teeth revealed significantly better esthetic appearance after microabrasion and combined therapy and at 3-year follow-up compared to those at baseline (P P Conclusions: The combined therapy was effective in the esthetic management of fluorosed teeth. However, a significant relapse was observed in the esthetic appearance and brown stains of these patients after 3 years, which also reduced patient satisfaction. PMID- 28891538 TI - Treatment alternative for irreparable rotator cuff ruptures: Arthroscopic biodegradable balloon. AB - BACKGROUND: The treatment of massive irreparable rotator cuff rupture has still no consensus among shoulder surgeons. It is assumed that symptomatic rotator cuff tendon rupture is accepted as irreparable if retraction amount of tendon is Patte stage 3 on MRI; degree of fatty atrophy is Goutallier stage 3 or 4; narrowing of acromiohumeral distance is lesser than 7 mm and excursion of tendon to repair has decreased and patient has severe pain. Biodegradable balloon is one of the newest methods for the treatment of irreparable massive rotator cuff ruptures. OBJECTIVE: The aim of this study was to assess shoulder function in the patients who underwent biodegradable balloon procedure for irreparable massive rotator cuff ruptures. MATERIALS AND METHODS: Arthroscopic biodegradable balloon method was carried out on the 12 patients, who presented with symptomatic irreparable massive rotator cuff rupture, from October 2010 to November 2013. RESULTS: Preoperative and postoperative mean constant score of patients were 25.8 and 75.4 respectively. The mean Oxford shoulder score of the patients were 21.3 and 42.9 respectively, and mean shoulder abduction degree of the patients were73.5 and 165 respectively. All the patients stated that they were satisfied with the treatment and there was significant regression in their complaints. CONCLUSION: If conservative treatment is insufficient for patients with irreparable rotator cuff tears, biodegradable balloon method has yielded favorable outcomes in terms of pain and functionality in comparison with other surgical methods. Moreover, lesser morbidity, short procedure time and absence of postoperative rehabilitation requirement can be considered as advantages of this method. PMID- 28891539 TI - Evaluation of the learning and teaching environment of the Faculty of Medical Sciences, College of Medicine, University of Nigeria, Enugu Campus. AB - PURPOSE: The study aimed at evaluating the learning and teaching environment of undergraduate students of the Faculty of Medical Sciences, University of Nigeria. METHODS: The study was a descriptive, cross-sectional survey. The Dundee Ready Education Environment Measure (DREEM) questionnaire was self-administered to the final year medical students during the second semester of 2013/2014 academic year. The 50-items of the questionnaire were sub-divided into five sub-groups: perception of learning, perceptions of teachers, academic self-perceptions, perceptions of atmosphere, and social self-perceptions. RESULTS: The questionnaire was completed by 128 out of the 139 students (92.1%). Of the maximum score of 200, the total mean score was 101.82 +/- 20.36 SD. The mean +/- SD score of students' perception of learning was 25.97 +/- 4.18 (maximum score, 48). The mean +/- SD score of teachers was 24.40 +/- 4.74 (maximum score, 44), whereas that of students' academic self-perception, perception of atmosphere, and social self-perception was 19.96 +/- 5.29 (maximum score, 32), 19.02 +/- 7.69 (maximum score, 48), and 11.86 +/- 4.22 (maximum score, 28), respectively. CONCLUSION: The overall mean score shows that the students' perception of their learning environment was more positive than negative according to the practical guide of McAleer and Roff on the interpretation of DREEM questionnaire. However, there are problematic areas revealed by this study that will inform policy formulation and remedial intervention. PMID- 28891540 TI - The effect of calcium phosphate-containing desensitizing agent on the microtensile bond strength of multimode adhesive agent. AB - OBJECTIVE: The aim of this study was to investigate the effect of calcium phosphate containing desensitizing pretreatments on the microtensile bond strength (MTBS) and microleakage of the multimode adhesive agent to dentin. MATERIALS AND METHODS: In this study, twelve noncarious, freshly extracted human third molar teeth for MTBS and 20 premolar teeth for the microleakage test were used. The teeth were restored using Clearfil Universal Bond + Clearfil APX and Teeth mate Desensitizer (TMD). For MTBS test, Group 1: Self-etch, Group 2: Etch and rinse (G1 and 2, nondesensitizer treatment served as a control), Group 3: TMD/self-etch, Group 4: Acid-etch/TMD/etch and rinse. For microleakage test, Class V adhesive cavities (3 mm * 2 mm * 2 mm) were prepared and restored as mentioned before. The restored teeth were subjected to thermal cycling. The MTBS test was performed in all procedures. The MTBS data were submitted to a one-way ANOVA and post hoc Tukey test (P P Results: Control groups exhibited a higher mean MTBS value than TMD groups, and there were statistical differences between the groups. TMD groups also demonstrated significantly less microleakage than control groups (P Conclusions: This study proves that the application of TMD with a multimode adhesive bonding system produced significantly lower MTBS and microleakage. PMID- 28891541 TI - Inequity in access to childhood immunization in Enugu urban, Southeast Nigeria. AB - BACKGROUND: The Nigerian National Programme on Immunization aims at increasing the immunization coverage of children under 1 year of age. However, there is still a gap between the national immunization targets and the immunization coverage rates, and data are rarely disaggregated according to socioeconomic status. As a result, there is a dearth of information about the coverage of subgroups, especially at the local level. This study determined the socioeconomic differentials in immunization coverage for children under 5 years and under 1 year in Enugu urban, Southeast Nigeria. METHODS: This was a community-based, descriptive cross-sectional study in Enugu urban of Southeast Nigeria. A modified 30 * 7 cluster sampling design was adopted as the sampling method to select and interview 462 mothers of 685 children under the age of 5 years on their sociodemographic and economic characteristics and immunization status of their children. Principal components analysis in STATA software was used to characterize socioeconomic inequity. RESULTS: Immunization coverage was as follows: Diphtheria, pertussis, tetanus third dose(DPT3), 3, 65.3%; oral polio vaccine 3, 78.0%; hepatitis B3, 65.2%; and measles, 55.8%. The full immunization rates for children 1-5 years and st year of life was selected as the reference group, the immunization rates in all other age groups decreased significantly. Using the same logistic regression model for children under 1 year of age, every added month of the child's life increased the full immunization coverage, and this was statistically significant (OR 2.752, 95% CI 2.304-3.418). CONCLUSIONS: Full immunization coverage for children aged < 1 year was lower than the national target of 95%. There are differences in immunization coverage rates between different wealth quartiles in the area with the least poor benefiting more than the poorest, thus creating equity problems. Health managers need such community based information about the vaccination status of their target population to plan and implement interventions that aim to improve immunization coverage in these areas. PMID- 28891542 TI - Drug-induced Stevens-Johnson syndrome in Indian population: A multicentric retrospective analysis. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening hypersensitivity reactions mainly caused by drugs. Data on incubation period, hospital stay, and outcome for HIV-positive patients are sparse. Role of corticosteroids in their management is still controversial. METHODS: Indoor cases of SJS, SJS-TEN overlap, and TEN were analyzed for causative drugs, incubation period, a severity-of-illness score for toxic epidermal necrolysis (SCORTEN) score, HIV status, treatment, and outcome. Comparison of parameters between HIV and non-HIV cases was done. Utilization pattern of corticosteroids and their role in outcome were evaluated. RESULTS: Four SJS, 15 SJS-TEN overlap, and 21 TEN cases were evaluated. Antimicrobials (27.1%), antiviral (23%), antiseizure drugs (8.4%), and analgesics (8.4%) were commonly associated drugs. Among 12 (30%) HIV-reactive cases, nevirapine (97.6%) and cotrimoxazole (41.6%) were common causative drugs. Males (75%) were affected more than females (25%) among HIV-positive individuals. Incubation period was significantly higher in HIV-reactive patients. Total 30 (75%) patients were treated with corticosteroids. Dexamethasone (90%) and prednisolone (26.6%) were most commonly used. No significant difference was found among cases treated with or without corticosteroids. CONCLUSIONS: Antimicrobial drugs are common to cause SJS/TEN. Among HIV-reactive patients, male have more risk, incubation period is more and severity of reaction is less. Effectiveness of corticosteroids for treatment of SJS/TEN is inconclusive. PMID- 28891543 TI - A survey of asthma management practices and implementation of Global Initiative for Asthma guidelines among doctors in a resource-limited setting in Nigeria. AB - BACKGROUND: Bronchial asthma is a global health problem that causes significant morbidity and mortality in all age groups. Global Initiative for Asthma (GINA) seeks to standardize the care asthma patients receive. We assessed the knowledge, attitude, and practices of doctors in Umuahia, Southeast Nigeria, regarding asthma and determined the extent to which they abide by GINA guidelines in their management of asthma. METHODOLOGY: It was a descriptive cross-sectional study. A pretested self-administered questionnaire was used to obtain information from the participants regarding knowledge of asthma prevalence, asthma risk factors, and management practices. RESULTS: Out of 142 questionnaires administered, 117 were retrieved giving a response rate of 82%. About 70% were men, and the most common age group was 30-39 years (57.3%). The median duration of medical practice was 6 (3-12) years. About 77% reported asthma prevalence to be on the increase. While 105 (89.7%) respondents had seen a spirometer, only 28 (23.9%) use spirometry in asthma diagnosis. Similarly, 95 (81.2%) had seen a peak flow meter, but only 41 (35.5%) use it in asthma diagnosis. Only 7 (6.0%) respondents reported that their patients keep a peak flow diary. Of 117 respondents, 94 (80.3%) know about GINA guidelines for asthma control, 45 (38.5%) apply GINA guidelines in patient care, 86 (73.5%) regularly review patient inhaler technique, 33 (28.2%) use adult asthma control test while 17 (14.5%) regularly review asthma action plan with patients. CONCLUSION: There is a wide gap between GINA guidelines and the knowledge, attitude, and practices of doctors in Umuahia regarding asthma management. Improvement and standardization of asthma care are recommended. PMID- 28891544 TI - Comparison of Epidrum, Epi-Jet, and Loss of Resistance syringe techniques for identifying the epidural space in obstetric patients. AB - BACKGROUND: Identifying the epidural space is essential during epidural anesthesia (EA). Pressure of the epidural space in pregnancy is higher than that in nonpregnant woman. Loss of resistance (LOR) method is the most commonly preferred method for identifying the epidural space. Epidrum and Epi-Jet are recently innovated supporting devices that facilitate identifying process for epidural space. In this study we aimed to compare Epidrum, Epi-Jet, and LOR methods in identifying the epidural space, feasibility of technique. METHODS: Two hundred and forty pregnant women who were scheduled for caesarian section surgery under lumbar EA or combined spinal epidural anesthesia (CSEA) were randomized into three groups (Group I Epidrum, n = 80), Group II (Epi-Jet, n = 80), and Group III (LOR, n = 80). We recorded the time required to identify the epidural space and deflation of Epidrum balloon and Epi-Jet syringe, number of attempts, additional methods used to identify epidural space, usefulness of methods, accuracy of identification of epidural space, and outcomes of epidural catheterization. RESULTS: There were no significant differences between the groups with respect to demographic data, duration of deflation of Epidrum balloon and Epi-Jet syringe and distance between skin and epidural space. The mean time required to enter epidural space in Group I was shorter than that in Group II (P = 0.031). Feasibility of Epi-Jet was easier than that of Epidrum (P = 0.015). Number of uncertainties of epidural space identification was higher in Group I than that in Group II (P = 0.009). Also, the requirement for LOR to confirm epidural space and failure rates was higher in Group I than Group II (P < 0.001). CONCLUSION: We suggest that Epi-Jet is superior to Epidrum in pregnant patients in terms of clarity of epidural space identification, usefulness, and success rates of EA or CSEA. PMID- 28891545 TI - Protein C and antithrombin levels in patients with sickle cell anemia in Ahmadu Bello University Teaching Hospital Zaria, Nigeria. AB - BACKGROUND: Alterations in the components of hemostasis, namely platelet function, the procoagulant, anticoagulant, and the fibrinolytic systems, are observed in sickle cell anemia (SCA) and are in favor of a procoagulant phenotype. Therefore, study of protein C and antithrombin (AT) levels in patients with SCA in steady state may be used in the treatment and/or prevention of SCA related thrombotic complications. We studied the changes of these naturally occurring anticoagulants in patients with SCA attending the sickle cell clinic in Ahmadu Bello University Teaching Hospital, Zaria. METHODS: We conducted a case control study involving 50 SCA (HbSS) patients in the steady state as cases and 25 healthy volunteers with normal hemoglobin (HbAA) as controls. Protein C and AT levels were estimated by semi-automation using Diagnostica Stago hematology coagulation analyzer. Frequencies, proportions, and independent t test were performed using SPSS version 20. RESULTS: The mean ages of both the patients and controls were 23.80 +/- 7.46 and 24.28 +/- 3.48 years, respectively, and study participants comprised 40 (53.0%) women between the ages of 15-50 years and 15-34 years (P = 0.76). The mean values of protein C and AT levels in patients with SCA in the steady state and the control group were 60.26 +/- 20.58% versus 81.30 +/- 19.74%, 95% CI 11.13-30.96, and 42.11 +/- 5.01% versus 61.88 +/- 11.27%, 95% CI 16.03-23.51 with P values (P < 0.001), respectively. CONCLUSIONS: This study showed that there was a significant decrease in the levels of protein C and AT between the SCA patients in the steady state and the controls. We recommend baseline investigations of these naturally occurring anticoagulants in patients with SCA, especially in those with frequent vaso-occlusive crises. This will give us an insight into the additional pathophysiologic mechanism in SCA-related thrombotic complications for better patient management and outcome. PMID- 28891546 TI - Work-Related musculoskeletal pain among lebanese dentists: An epidemiological study. AB - INTRODUCTION: The aim of this study was to evaluate the prevalence of musculoskeletal disorders and identify their associated factors among a group of Lebanese dentists. MATERIALS AND METHODS: A total of 314 Lebanese, dentists completed an anonymous questionnaire that focused on occupational health problems. This study was approved by the ethics committee of Saint-Joseph University of Beirut, Lebanon. The statistical analyses were performed using SPSS for windows. The alpha error was set to 0.05. RESULTS: The mean age of the participants was 39.2 (+/-11.66) years. The results showed that 61.5% of the surveyed dentists complained of spinal pain: 31.6% of cervical pain, 22.3% of lumbar pain and 13.0% of dorsal pain. Moreover, the pain was continuous in 20.7% and, occasional in 65.8%. Our statistics showed that 7.6% had a problem with the carpal tunnel. A total of 22.3% suffered from tendinitis and 9.2% from arthritis of shoulder, elbow, wrist and hand. The frequency of headaches was 30.6%. Concerning sports activity, 49.7% practiced it occasionally and 3.6% did so frequently. CONCLUSIONS: The occurrence of musculoskeletal pain in the upper extremities is a serious concern that affects Lebanese dentists. Most of them often complained of tendinitis and headaches because they do not practice sports; thus, encouraging them to practice sports may reduce or solve such health problems. Issuing brochures that include exercises to perform and hiring trained assistants could help reduce the risk of musculoskeletal disorders. Finally, these occupational health problems should be highlighted at all clinical and research symposia to increase awareness. PMID- 28891547 TI - Classification of alveolar bone destruction patterns on maxillary molars by using cone-beam computed tomography. AB - OBJECTIVE: The defective diagnosis of alveolar structures is one of most serious handicaps when assessing available periodontal treatment options for the prevention of tooth loss. The aim of this research was to classify alveolar bone defects in the maxillary molar region which is a challenging area for dental implant applications. To our knowledge, this is the first study of periodontal bone defect prevalence by using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: In this study, the remaining alveolar bone patterns of 669 maxillary molars of 243 patients with periodontal bone loss were investigated on four aspects and the furcation areas of teeth, and then they were classified into six main groups. Combined periodontal-endodontic lesions (CPELs) were also reported in another category. RESULTS: Following exclusion of 39 (5.8%) teeth with CPEL, the most common group was horizontal bone defects (71.4%) and the least seen group was three-walled vertical bone defects (1.9%) in all alveolar bone sides of teeth. Osseous crater was found at the rate of 6.7% on interdental alveolar bone. Dehiscence and fenestration were detected at rates of 2.7% and 3.3%, respectively. In the assessment of furcation areas, there was no furcation involvement in 61.4% of all teeth and the rate of Grade-II involvements was 26.2%. CONCLUSIONS: The most appropriate treatment option may be decided through accurate imaging of periodontal defect morphology. CBCT can provide comprehensive information about the remaining alveolar bone structures. In this way, the need for dental implant can be prevented in many cases and be replaced with a more conservative approach on the maxillary molar region. PMID- 28891548 TI - Short segment bulbar urethral strictures: Review of 48 cases managed in a resource-poor setting. AB - OBJECTIVE: To share our experience on the presentation and management of short segment bulbar urethral strictures (BUSs) in a resource-poor center. METHODS: Short segment bulbar urethral strictures (BUSs) managed from January 2009 to December 2014 were analyzed. Patients'age, stricture aetiology, mode of presentation, stricture characteristics, time to surgery, associated morbidity, operative procedure, and post-operative outcome were reviewed. All patients had bulbar anastomotic urethroplasty (BAU). RESULTS: Total 42 bulbar anastomotic urethroplasties (BAUs) were done. The mean age of the patients in years was 37.46 (+/- 13.80). Fall astride injuries accounted for most strictures, 39(89.3%) of cases. The mean stricture lenght was 1.04 cm +/- 0.49 and was longer in patients who had prior instrumentation,1.45 cm (+/- 0.37) versus 0.70 cm (+/- 0.26), P = 0.000. Associated lower urinary tract comorbidities were noted in 38 (79.2%) patients. Mean time to surgery was 10.20 (+/- 4.96) months. Patients operated on after 6 months of presentation had more associated comorbidities, 24/26 patients (92.3%), compared to those operated on within 6 months; 8/16 cases (50%), P = 0.003. However, this did not impact negatively on the outcome of surgery (P = 0.275). Patients with complete strictures tended to accept surgery earlier than those with incomplete strictures, 29 patients (60.4%) versus 19 patients (39.6%), P = 0.208,with no difference in outcome between the two groups, P = 0.581.The overall success rate was 92.9%. CONCLUSIONS: Fall astride injuries are the commonest cause of short segment BUSs. Prior urethral instrumentation is associated with recurrence and longer stricture lenght. Suprapubic catheter related associated comorbidity increases with the duration of catheterization but does not impact negatively on the surgical outcome. BAU has low morbidity and high success rate of 92.7%. It should be the first line treatment for short segment BUS in low-resource countries. PMID- 28891549 TI - Effects of health-care services and commodities cost on the patients at the primary health facilities in Zaria Metropolis, North Western Nigeria. AB - INTRODUCTION: The payment for health-care services is a major problem for many poor patients in developing nations. The aim of the study was to examine the cost of services and commodities and how these affect the patients who utilizes the primary health-care centers in Zaria, North western Nigeria. METHODOLOGY: A descriptive cross-sectional survey of six primary health-care facilities in Zaria metropolis, namely Baban dodo, Tudun Wada, Magajiya PHCs from Zaria local government areas (LGA) and Samaru, Kwata, and Dogarawa PHCs from Sabon Gari LGA, was carried out. RESULT: The mean age of the respondents was 28.87+/- 8.63 years, most of them were married (53.3%), Hausa (63.3%), and Muslims (85.7%); also, they were unemployed housewives with daily stipends from their husbands less than 1 dollar/day. The major method for payment for health-care services was out of pocket (98.3%). More than one-third of the clients were not aware of the National Health Insurance Scheme (NHIS) (39%). There was a significant inverse relationship between the monthly income of the clients and the experience of financial stress and a positive association between patients' monthly income and awareness of the NHIS (P < 0.05). CONCLUSION: The respondents were paying user fees for essential health-care services at the primary health-care centers and this was not convenient for them. RECOMMENDATION: There is a need for the LGA health department to intensify the supervision of the activities at the PHCs. Standardization of prices of services and commodities and the implementation of the National Health Act may alleviate the burdens of the poor community members who access PHCs in Nigeria. PMID- 28891550 TI - Common types and countermeasures of ankle ligament injury caused by intense basketball movement. AB - OBJECTIVE: To analyze ankle ligament injury of basketball players caused during movement, summarize injury types, analyze the causes of injury, and put forward corresponding control measures. METHODS: The author selected 3100 basketball players with ankle ligament injury during basketball movement and admitted to different hospitals from June 2011 to June 2015 for stochastic analysis. Through the literature, investigation, and observation, etc., common types of injuries of basketball players are analyzed, and damage preventive measures of basketball players are discussed, so as to find measures to prevent and treat ankle ligament injury of basketball players and promote physical rehabilitation of players, which is in favor of their better career development. RESULTS: Basketball players are prone to ankle ligament injury in training or competition, which has a direct relationship with players' poor safety consciousness and insufficient preparation during movement. CONCLUSION: Basketball players will often have serious ankle ligament injury in the process of movement. Basketball coaches and players should reduce serious injury to players in training or competition, so as to stimulate passion of more professional basketball sports students for basketball, which also has a positive meaning for their future career. PMID- 28891551 TI - Mondor's disease of the breast in a Nigerian woman previously treated for invasive ductal carcinoma in the contralateral breast: A case report. AB - Mondor's disease is a self-limiting sclerosing angitis mostly affecting the superficial veins of the breast and chest wall. It is seldom diagnosed, and its etiology and epidemiology are speculative. However, numerous predisposing factors including breast cancer have been postulated. In Nigerian literature, only two cases have been documented to the best of our knowledge. This report is aimed at reminding breast specialists to include it as a diagnostic consideration in patients presenting with a breast lump in the appropriate clinical setting. Its imaging features are also highlighted because it may be incorrectly overlooked as mere ductal dilatation. We present the case of a 60-year-old woman who complained of a painful cordlike lesion in her right breast. Mondor's disease was diagnosed based on the clinical and radiological findings. She had also been previously treated for invasive ductal breast carcinoma in the contralateral breast. Mondor's disease is usually a benign entity, which may resolve spontaneously. On the other hand, it may also be the sole presenting symptom or clue of a breast malignancy; hence, a need for increased awareness. PMID- 28891552 TI - Omental herniation through the diaphragmatic defect: Two cases mimicking mediastinal lipomas. AB - Omental herniation through a diaphragmatic defect without involvement of the stomach is rare and has often been misdiagnosed as mediastinal lipoma. We herein report two cases of intrathoracic omental herniation through adiaphragmatic defect in patients that were misdiagnosed as a mediastinal lipoma at presentation. They both underwent successful laparoscopic diaphragmatic hernia repairs with full resolution of their symptoms. Doctors should pay attention to the differential diagnosis between diaphragmatic hernia and mediastinal lipoma when a fatty mass is found in the mediastinum at the magnetic resonance imaging (MRI) or computed tomography (CT) scan. PMID- 28891553 TI - Hyperthyroidism and sick sinus syndrome, a rare but challenging association: A study of three cases. AB - Hyperthyroidism is usually associated with sinus tachycardia or supraventricular tachyarrhythmias, but rarely with dysfunction of the sinus node or other conduction disturbances. Evidence of bradyarrhythmia in patients with hyperthyroidism is clinically relevant, but the fact that several drugs with negative chronotropic effects (beta-blockers and calcium channel antagonists) are frequently used in the management of these patients must be taken into account. In the presence of sick sinus syndrome (SSS) or other conductance disturbances, therapy with agents that delay the activity of sinus node or atrioventricular conduction can lead to extreme bradycardia with syncope. In this paper, aspects of diagnosis and therapy in three patients with SSS and hyperthyroidism, admitted in the Clinic of Endocrinology or/and Cardiology of the County Hospital, Timisoara, have been presented. PMID- 28891554 TI - Interocclusal registration for diagnosis and treatment planning for implant restorations. AB - This paper describes a new technique to record the interocclusal relationship of an implant case where multiple posterior teeth are missing and need to be replaced by implant restorations. In the case presented, an appliance was designed to be supported only by hard immovable tissues; teeth that provide a precise fit of records. The well-fitting appliance can be used to accurately mount implant cases with inadequate posterior support for diagnosis and treatment planning. This technique of interocclusal registration has the advantages of accurate mounting, preservation of materials and financial expenses, and reduction of chair-side time. This appliance may also be used in all cases of multiple missing posterior teeth requiring prosthodontic treatment. PMID- 28891556 TI - T cells: Proteasome dictates CD8+ T cell fate. PMID- 28891555 TI - Corrigendum: Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system. AB - This corrects the article DOI: 10.1038/ncomms7761. PMID- 28891558 TI - Mucosal immunology: Probiotic induction of tolerogenic T cells in the gut. PMID- 28891559 TI - Immune homeostasis: Regulatory ILCs don't rely on FOXP3. PMID- 28891560 TI - Facile activation of alkynes with a boraguanidinato-stabilized germylene: a combined experimental and theoretical study. AB - A boraguanidinato-stabilized germylene, [(i-Pr)2NB(N-2,6-Me2C6H3)2]Ge, reacts with alkynes RC[triple bond, length as m-dash]CR selectively in a 2 : 1 molar ratio to afford 3,4-R,R'-1,2-digermacyclobut-3-enes 1a-e as the products of formal [2 + 2 + 2] cyclization [R/R' = Me/Me (1a), Ph/Ph (1b), Ph/H (1c), t-Bu/H (1d) and Cy/H (1e)]. Ferrocenyl-substituted alkynes react similarly, yielding the corresponding ferrocenylated 3,4-R,R'-1,2-digermacyclobut-3-enes 2a-d [where R/R' = Fc/H (2a), Fc/Me (2b), Fc/Ph (2c), and Fc/Fc (2d); Fc = ferrocenyl]. By contrast, only one of the triple bonds available in conjugated diynes RC[triple bond, length as m-dash]CC[triple bond, length as m-dash]CR is activated with the germylene, while the second one remains intact even in the presence of an excess of the germylene. The exclusive formation of 3,4-R,(C[triple bond, length as m dash]CR)-1,2-digermacyclobut-3-enes 3a-c [R = Ph (3a), t-Bu(3b), and Fc (3c)] was ascribed to a steric repulsion around the second triple bond. On the other hand, the reaction of the germylene with more flexible dialkyne fc(C[triple bond, length as m-dash]CPh)2 (fc = ferrocene-1,1'-diyl) proceeded in the expected manner, producing compound 4, where both triple bonds are transformed into 1,2 digermacyclobut-3-ene rings by reaction with four equivalents of the germylene. All compounds were characterized by multinuclear NMR spectroscopy, Raman and IR spectroscopy, and in the case of 1a-c, 2a, 2c, 3a, 3b and 4, also by single crystal X-ray diffraction analysis. The ferrocenyl substituted compounds were studied by cyclic voltammetry (CV). Finally, the plausible reaction pathway was studied for a model reaction of [(i-Pr)2NB(N-2,6-Me2C6H3)2]Ge with MeC[triple bond, length as m-dash]CMe using DFT computations. PMID- 28891561 TI - Online monitoring of hepatic rat metabolism by coupling a liver biochip and a mass spectrometer. AB - A microfluidic liver biochip was coupled with a mass spectrometer to detect in real time the drug metabolism of hepatocytes. The hepatocytes were cultivated in the biochip for 35 h. The biochip was placed in a small-scale incubator in which the temperature and CO2 concentration were controlled. The biochip was connected serially to a mass spectrometer, a peristaltic pump and a culture medium reservoir. The injection in the mass spectrometer was performed every 10 min for 11 h. The metabolism of midazolam, phenacetin, omeprazole, dextromethorphan, repaglinide, rosuvastatin, tolbutamide and caffeine was investigated. We monitored the apparition of omeprazole sulfone, hydroxy omeprazole, repaglinide glucuronide, rosuvastatin lactone, dextrorphan, 1-hydroxy midazolam, 4-hydroxy midazolam, 1,4-hydroxy midazolam, paracetamol and 1,3-methylxanthine. Although these were observed, hydroxytolbutamide, 3-methoxymorphinan and midazolam glucuronide, hydroxy repaglinide were not detected. Based on a pharmacokinetic model, we calculated in vitro intrinsic clearances in which adsorption onto the perfusion circuit was taken into account. Then, using a liver organ model, we extrapolated the in vitro intrinsic clearances to the in vivo clearances. The estimated in vivo clearances were in agreement with the literature data on rats for midazolam, dextromethorphan, phenacetin, tolbutamide and caffeine. Rosuvastatin, omeprazole and repaglinide prediction underestimated the in vivo data. PMID- 28891562 TI - Quantitative surface-enhanced Raman spectroscopy of single bases in oligodeoxynucleotides. AB - To address the question of whether the SERS signals of ss-DNA are simply combinations of the signals from the individual bases that comprise the sequence, SERS spectra of unmodified ss-DNA sequences were obtained using a hydroxylamine reduced Ag colloid aggregated with MgSO4. Initially, synthetic oligodeoxynucleotides with systematic structural variations were used to investigate the effect of adding single nucleobases to the 3' terminus of 10-mer and 20-mer sequences. It was found that the resulting SERS difference spectra could be used to identify the added nucleobases since they closely matched reference spectra of the same nucleobase. Investigation of the variation in intensity of an adenine probe which was moved along a test sequence showed there was a small end effect where nucleobases near the 3' terminus gave slightly larger signals but the effect was minor (30%). More significantly, in a sample set comprising 25-mer sequences where A, T or G nucleobases were substituted either near the centres of the sequences or the 5' or 3' ends, the SERS difference spectra only matched the expected form in approximately half the cases tested. This variation appeared to be due to changes in secondary structure induced by altering the sequences since uncoiling the sequences in a thermal pre treatment step gave difference spectra which in all cases matched the expected form. Multivariate analysis of the set of substitution data showed that 99% of the variance could be accounted for in a model with just three factors whose loadings matched the spectra of the A, T, and G nucleobases and which contained no positional information. This suggests that aside from the differences in secondary structure which can be eliminated by thermal pre-treatment, the SERS spectra of the 25-mers studied here are simply the sum of their component parts. Although this means that SERS provides very little information on the primary sequence it should be excellent for the detection of post-transcription modifications to DNA which can occur at multiple positions along a given sequence. PMID- 28891563 TI - Synthesis, stability and Li-ion mobility of nanoconfined Li2B12H12. AB - This communication presents the first synthesis of nanoconfined Lithium closo borate, Li2B12H12, using nanoporous SiO2 as scaffold. The yield of Li2B12H12 is up to 94 mol%. The as-synthesized nanoconfined Li2B12H12 exhibits a structural transition around 380 degrees C and conversion to H-deficiency Li2B12H12-x at 580 degrees C. PMID- 28891557 TI - Functions of tissue-resident eosinophils. AB - Eosinophils are a prominent cell type in particular host responses such as the response to helminth infection and allergic disease. Their effector functions have been attributed to their capacity to release cationic proteins stored in cytoplasmic granules by degranulation. However, eosinophils are now being recognized for more varied functions in previously underappreciated diverse tissue sites, based on the ability of eosinophils to release cytokines (often preformed) that mediate a broad range of activities into the local environment. In this Review, we consider evolving insights into the tissue distribution of eosinophils and their functional immunobiology, which enable eosinophils to secrete in a selective manner cytokines and other mediators that have diverse, 'non-effector' functions in health and disease. PMID- 28891564 TI - Standardisation of a European measurement method for organic carbon and elemental carbon in ambient air: results of the field trial campaign and the determination of a measurement uncertainty and working range. AB - The European Committee for Standardisation (CEN) Technical Committee 264 'Air Quality' has recently produced a standard method for the measurements of organic carbon and elemental carbon in PM2.5 within its working group 35 in response to the requirements of European Directive 2008/50/EC. It is expected that this method will be used in future by all Member States making measurements of the carbonaceous content of PM2.5. This paper details the results of a laboratory and field measurement campaign and the statistical analysis performed to validate the standard method, assess its uncertainty and define its working range to provide clarity and confidence in the underpinning science for future users of the method. The statistical analysis showed that the expanded combined uncertainty for transmittance protocol measurements of OC, EC and TC is expected to be below 25%, at the 95% level of confidence, above filter loadings of 2 MUg cm-2. An estimation of the detection limit of the method for total carbon was 2 MUg cm-2. As a result of the laboratory and field measurement campaign the EUSAAR2 transmittance measurement protocol was chosen as the basis of the standard method EN 16909:2017. PMID- 28891565 TI - An aryl-triazole foldamer containing a 1,8-naphthalimide fluorescent motif for monitoring and enhancing the anion-induced folding. AB - A novel aryl-triazole foldamer incorporating a 1,8-naphthalimide motif was designed and synthesized. 1H NMR, UV-vis and fluorescence spectroscopic titration experiments with halide anions (Cl-, Br-, I-) demonstrated that the pi-pi stacking interaction of 1,8-naphthalimide building blocks could largely enhance the folding and anion binding of the foldamer. PMID- 28891566 TI - One-pot synthesis of imidazolinium salts via the ring opening of tetrahydrofuran. AB - A new one-pot synthesis of C2-hydroxypropyl-substituted imidazolinium salts via the ring opening of tetrahydrofuran (THF) with N,N'-disubstituted diamines has been developed. Preliminary studies of the reaction mechanism suggest the CO2 promoted oxidative ring opening of THF followed by Hg(ii)-mediated oxidation of an imidazolidine intermediate. These novel C2-substituted imidazolinium salts have shown to be active catalysts for the aza-Diels-Alder reactions. PMID- 28891567 TI - Enantioselective electrophilic cyanation of beta-keto amides catalysed by a cinchona organocatalyst. AB - An operationally simple protocol for the enantioselective electrophilic alpha cyanation of beta-keto amides catalyzed by cinchona-derived catalysts has been demonstrated. The resulting products could be obtained with good to high enantioselectivities (up to 88% ee) and with excellent yields (up to 94%) by employing the mild active 4-acetylphenyl cyanate as the cationic cyano source in the catalytic asymmetric alpha-cyanation reaction. PMID- 28891568 TI - Selective antitumoural action of pressurized mango leaf extracts against minimally and highly invasive breast cancer. AB - Mango leaf tea has been traditionally used by different cultures to reduce inflammation in the body. There is evidence that chronic inflammation increases the risk of cancer. This study investigates the antitumoural effects of pressurized mango leaf extracts on minimally (MCF7) and highly invasive (MDA-MB 231) breast cancer cells as well as on non-tumourigenic cells (MCF10). Extracts showed protective properties against oxidation and cytotoxic effects against breast cancer cell lines, causing minor damage to non-carcinogenic cells. Nonetheless, some selective activity, depending on hormone receptor status, was observed. This was possibly related to the presence of minor compounds. Extracts with high levels of gallotannins showed cytotoxic action against MCF7 cells, while those which had methyl gallate and homomangiferin as common components were more effective against MDA-MB-231 cells. Therefore, the cytotoxic effect of mango leaf extracts might be attributed to the synergistic effect of different polyphenols and not just to mangiferin on its own as the predominant compound in mango leaves. PMID- 28891569 TI - Improved catalytic activity of Mo1-xWxSe2 alloy nanoflowers promotes efficient hydrogen evolution reaction in both acidic and alkaline aqueous solutions. AB - Layered transition metal dichalcogenides are noble-metal free electrocatalysts for the hydrogen evolution reaction (HER). Instead of using the common hydrothermal synthesis, which requires high pressure and temperature, herein a relatively simple and controlled colloidal synthesis was used to produce an alloy of Mo1-xWxSe2 with nanoflower morphology as a model system for the electrocatalysis of hydrogen evolution in both acidic and alkaline environments. The results show that Mo1-xWxSe2 alloys exhibit better catalytic activity in both acidic and alkaline solutions with low overpotentials compared to pure MoSe2 and WSe2. Moreover, the electrode kinetics was studied using electrochemical impedance spectroscopy (EIS) and the results indicate that the alloys exhibit improved catalytic activity with low Tafel slopes, making them appealing for HER in either environment. Additionally, when MoSe2 nanoflowers (NFs) are prepared by using different metal salts and chalcogenide precursors, changes in the HER catalytic activity were observed, despite the morphology and crystal structure similarities. This finding suggests that different results reported in the literature could originate from different synthetic methods of the TMD, emphasizing that a better understanding of the relationship between the synthetic route and the catalytic performance is still lacking. PMID- 28891570 TI - N-Heterocyclic carbene palladium-catalyzed cascade annulation/alkynylation of 2 alkynylanilines with terminal alkynes. AB - A straightforward and highly effective N-heterocyclic carbene-palladium catalyzed cascade annulation/alkynylation of 2-alkynylanilines with terminal alkynes has been enabled to afford free (NH)-3-alkynylindole derivatives in moderate to good yields. This protocol features mild conditions, broad substrate scope, and high atom- and step-economy. Notably, the resultant 3-alkynylindoles could be conveniently transformed into a variety of functionalized indole scaffolds, thus illustrating their potential applications in synthetic and pharmaceutical chemistry. PMID- 28891571 TI - Crown ether complexes of actinyls: a computational assessment of AnO2(15-crown 5)2+ (An = U, Np, Pu, Am, Cm). AB - For further fundamental understanding of the nature and extent of covalency in actinyl-ligand bonding, and the benefits that this may have in the design of new ligands for nuclear waste separation, there is burgeoning interest in the nature of actinyl complexes with polydentate or multiple-point-donor ligands, such as crown ethers. There are few cases of structurally authenticated molecular actinyl crown bonds under ambient conditions. We report here the computational characterization of AnO22+-(15-crown-5) complexes, where An = U, Np, Pu, Am, and Cm, and 15-crown-5 is the cyclic polyether ligand with five ether oxygen atoms. In the gas-phase complex, the actinyl group is located inside of the crown ether, tilted slightly out of the plane of the five equatorial oxygen atoms that coordinate the actinide metal center. The actinyl-cyclic ether complexes are found to exhibit a conventional conformation, with typical An-Oaxial and An Oequatorial distances and angles. A striking result is the enhanced stability of the insertion complex for UO22+versus NpO22+, PuO22+, AmO22+ and CmO22+, which is evaluated in the context of An-O binding strengths (esp. bonding covalency), and may have ramifications for the utility of actinyl-crown complexes in separation applications. PMID- 28891572 TI - Novel spirocyclic systems via multicomponent aza-Diels-Alder reaction. AB - Here we present a two-step diastereoselective methodology building on a multicomponent aza-Diels-Alder reaction. Using previously unexplored cyclic ketones, heterocyclic amines and cyclopentadiene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between "drug-like" molecules and natural products. PMID- 28891573 TI - Methylation of Ir(iii)-tetrazolato complexes: an effective route to modulate the emission outputs and to switch to antimicrobial properties. AB - Two neutral cyclometalated Ir(iii)-tetrazolato complexes that differ by variations of the substituents on either the phenylpyridine or the tetrazolate ligand have been converted into the corresponding methylated and cationic analogues. NMR (1H and 13C) characterization of the Ir(iii) complexes provided the results in agreement with the chemo- and regioselective character of methylation at the N-3 position of the Ir(iii)-coordinated tetrazolato ring. This evidence was further corroborated by the analysis of the molecular structures of the cationic complexes obtained by X-ray diffraction. In view of the photophysical properties, the addition of a methyl moiety to neutral Ir(iii) tetrazolates, which behave as sky-blue or orange phosphors, caused a systematic red shift of their phosphorescence output. The transformation of neutral Ir(iii) tetrazolates into cationic Ir(iii)-tetrazole complexes was screened for any eventual antimicrobial activity in vitro against Gram negative (E. coli) and Gram positive (D. radiodurans) microorganisms. While both kinds of complexes were not active against E. coli, the conversion of the neutral Ir(iii) tetrazolates into the corresponding methylated and cationic Ir(iii)tetrazole derivatives determined the turn-on of a good to excellent antimicrobial activity toward Gram positive Deinococcus radiodurans, a non-pathogenic bacterium that is listed as one of the toughest microorganisms in light of its outstanding resistance to radiation and oxidative stress. PMID- 28891574 TI - Claisen rearrangements of benzyl vinyl ethers: theoretical investigation of mechanism, substituent effects, and regioselectivity. AB - Recently we reported the aromatic Claisen rearrangements of benzyl ketene acetals, which form one of the few examples of aromatic Claisen rearrangements involving benzyl vinyl ethers (as opposed to allyl aryl ethers, which are the usual substrates for aromatic Claisen rearrangements). Theoretical calculations predict that these rearrangements proceed via a concerted [3,3]-sigmatropic transition state, which is similar in geometry to the TS for the Claisen rearrangement of an allyl aryl ether but has a 4 kcal mol-1 higher barrier. The effects of donor (OMe) and acceptor (CN) substituents on the kinetics of the [3,3]-rearrangement mirror those reported for allyl vinyl ethers: the largest substituent effects are seen for 1-OMe, 2-OMe, 2-CN, and 4-CN substituents, which lower the barrier by 5-9 kcal mol-1. Substituents on the aromatic ring have smaller effects on the barrier (<=2 kcal mol-1). The regioselectivities of Claisen rearrangements of meta-substituted benzyl ketene acetals favour 1,2,3 trisubstituted products in preference to the less sterically congested 1,2,4 isomers due to favourable orbital interactions in the 1,2,3 transition state. PMID- 28891575 TI - Sheared edible oils studied using dissipative particle dynamics and ultra small angle X-ray scattering: TAGwood orientation aggregation and disaggregation. AB - Previous work on the computer simulation of edible fats and oils showed that triglyceride crystalline nanoplatelets (CNPs) aggregated into cylindrical structures dubbed "TAGwoods". This was experimentally verified using Ultra Small Angle X-ray Scattering experiments. In this paper, the aggregation of these TAGwoods was studied using the fluid simulation technique, Dissipative Particle Dynamics. The intent was to predict the TAGwood aggregation structures which arise via the application of a series of shear rates, [small gamma, Greek, dot above]. The effect of shear on TAGwood orientational order was also investigated. Three aggregation regimes were identified: At shear rates below a certain critical value, 0 < [small gamma, Greek, dot above] < [small gamma, Greek, dot above]t aggregation was enhanced. The value of the critical shear rate depended on the size of the CNPs. With large CNPs possessing a side length of ~500 nm, the critical shear rate was [small gamma, Greek, dot above]t ~ 0.6 s-1. However, if the CNPs were smaller with a side length of ~100 nm, then [small gamma, Greek, dot above]t ~ 75 s-1. For shear rates above the critical shear rate, [small gamma, Greek, dot above] > [small gamma, Greek, dot above]t aggregation was inhibited. The USAXS data was analyzed using the Unified Fit model and the observations were in accord with the simulation results. Three regimes were identified based on the values of the linear slope P2 of the USAXS data. P2 increased as [small gamma, Greek, dot above] increased, indicating increased aggregation of the TAGwoods as the shear rate was increased. P2 ceased increasing and began to decrease when [small gamma, Greek, dot above] ~ [small gamma, Greek, dot above]t. With further increases in [small gamma, Greek, dot above], P2 decreased as [small gamma, Greek, dot above] increased further, which is indicative of a decrease in aggregation. The orientational quadrupole order parameter, S = = 1/2, was computed, where theta is the angle between the axis of the TAGwood and the axis of flow, and showed that, for large [small gamma, Greek, dot above], it achieved a near-maximum value. This indicates that at high shear rates, the long axis of the cylindrical TAGwoods aligns in a direction parallel to that of the fluid flow. PMID- 28891576 TI - In vitro assessment of the ability of probiotics, blueberry and food carbohydrates to prevent S. pyogenes adhesion on pharyngeal epithelium and modulate immune responses. AB - Group A streptococci (GAS) cause 20-30% of pediatric pharyngitis episodes, which are a major cause of ambulatory care visits. Therefore, a strategy to prevent GAS dissemination in children could significantly benefit public healthcare. Contextually, we assessed the possibility of employing alternative food-grade strategies to be used with the oral probiotic L. helveticus MIMLh5 for the prevention of pharyngeal infections. First, we demonstrated through an antagonism by-exclusion assay that guaran may potentially prevent S. pyogenes adhesion on pharyngeal cells. Subsequently, we showed that an anthocyanin-rich fraction extracted from wild blueberry (BbE) exerts anti-inflammatory effects on the human macrophage cell line U937. Finally, we showed that BbE reduces interferon-beta expression in MIMLh5-stimulated murine dendritic cells, resulting in a reduction in the pro-inflammatory cytokines IL-12 and TNF-alpha. In conclusion, this proof of-concept study indicates that different food-grade strategies may be concomitantly adopted to potentially prevent GAS colonization and modulate local immune defences. PMID- 28891577 TI - DBU-mediated [4 + 1] annulations of donor-acceptor cyclopropanes with carbon disulfide or thiourea for synthesis of 2-aminothiophene-3-carboxylates. AB - DBU-mediated [4 + 1] annulations of donor-acceptor cyclopropanes with carbon disulfide or thiourea to form 2-aminothiophene-3-carboxylate derivatives have been discovered. This reaction proceeds via the ring opening of donor-acceptor cyclopropanes to produce a 2-(iminomethylene)but-3-enoate intermediate, followed by the attack of an S-nucleophile for regioselective intermolecular nucleophilic addition, intramolecular S-nucleophilic addition, and final aromatization. A variety of functional groups could be tolerated under the reaction conditions. PMID- 28891578 TI - In situ formation of luminescent CdSe QDs in a metallohydrogel: a strategy towards synthesis, isolation, storage and re-dispersion of the QDs. AB - A one step, in situ, room temperature synthesis of yellow luminescent CdSe QDs was achieved in a metallohydrogel derived from a facially amphiphilic bile salt, resulting in a QD-gel hybrid. An ordered self-assembly and homogeneous distribution of the CdSe QDs in the hydrogel network was observed from optical and electron micrographs. The different excited state behavior of the CdSe QDs in the hybrid was revealed for the first time using time resolved spectroscopy. We also describe the successful isolation of the photoluminescent CdSe QDs from the gel followed by their re-dispersion in an organic solvent using suitable capping ligands. PMID- 28891579 TI - Sensitive and selective detection of the p53 gene based on a triple-helix magnetic probe coupled to a fluorescent liposome hybridization assembly via rolling circle amplification. AB - Developing a sensitive and selective sensing platform for the p53 gene and its mutation analysis is essential and may aid in early cancer screening and assessment of prognosis. Here, we developed a highly sensitive and selective p53 gene assay based on the coupling of a triple-helix magnetic probe (THMP) to a fluorescent liposome hybridization assembly, a process initiated by rolling circle amplification (RCA). In the presence of p53, the THMP unfolds and activates an enzymatic cleavage reaction, thus releasing the RCA primer and initiating the RCA product-assisted fluorescent liposome hybridization assembly. The resultant double-stranded DNA structures bind the intercalating SG dye from the fluorescent liposomes, thus dramatically enhancing the fluorescence signal. In the absence of p53, the THMP remains intact and blocks the trigger release and fluorescent liposome assembly, thus resulting in a low background signal. The THMPs were designed with integrated target recognition by Watson-Crick base pairing, site-specific cleavage by an endonuclease and background signal elimination by magnetic isolation, thus avoiding the need to design multiple probes. Moreover, the use of fluorescent liposome assembly and magnetic isolation helps in avoiding sample matrix interference and nonspecific staining. Through cooperative amplification coupling with enzyme cleavage recycling, the RCA assisted fluorescent liposome assembly and magnetic isolation improved the sensitivity, with a detection limit of 0.07 fM. The excellent capacity of the THMP to specifically detect the involved targets and the precise site-specific endonuclease cleavage ensured remarkable selectivity for p53 against single-base mismatches. This proposed approach worked well in biological samples, thus demonstrating great potential for biomedical and clinical diagnosis applications. PMID- 28891580 TI - Facile fabrication of mesoporous silica micro-jets with multi-functionalities. AB - Self-propelled micro/nano-devices have been proved as powerful tools in various applications given their capability of both autonomous motion and on-demand task fulfilment. Tubular micro-jets stand out as an important member in the family of self-propelled micro/nano-devices and are widely explored with respect to their fabrication and functionalization. A few methods are currently available for the fabrication of tubular micro-jets, nevertheless there is still a demand to explore the fabrication of tubular micro-jets made of versatile materials and with the capability of multi-functionalization. Here, we present a facile strategy for the fabrication of mesoporous silica micro-jets (MSMJs) for tubular micromotors which can carry out multiple tasks depending on their functionalities. The synthesis of MSMJs does not require the use of any equipment, making it facile and cost-effective for future practical use. The MSMJs can be modified inside, outside or both with different kinds of metal nanoparticles, which provide these micromotors with a possibility of additional properties, such as the anti-bacterial effect by silver nanoparticles, or biochemical sensing based on surface enhanced Raman scattering (SERS) by gold nanoparticles. Because of the high porosity, high surface area and also the easy surface chemistry process, the MSMJs can be employed for the efficient removal of heavy metals in contaminated water, as well as for the controlled and active drug delivery, as two proof-of-concept examples of environmental and biomedical applications, respectively. Therefore, taking into account the new, simple and cheap method of fabrication, highly porous structure, and multiple functionalities, the mesoporous silica based micro-jets can serve as efficient tools for desired applications. PMID- 28891581 TI - Femtosecond laser ablation of transparent microphotonic devices and computer generated holograms. AB - Femtosecond laser ablation allows direct patterning of engineering materials in industrial settings without requiring multistage processes such as photolithography or electron beam lithography. However, femtosecond lasers have not been widely used to construct volumetric microphotonic devices and holograms with high reliability and cost efficiency. Here, a direct femtosecond laser writing process is developed to rapidly produce transmission 1D/2D gratings, Fresnel Zone Plate lenses, and computer-generated holograms. The optical properties including light transmission, angle-dependent resolution, and light polarization effects for the microphotonic devices have been characterized. Varying the depth of the microgratings from 400 nm to 1.5 MUm allowed the control over their transmission intensity profile. The optical properties of the 1D/2D gratings were validated through a geometrical theory of diffraction model involving 2D phase modulation. The produced Fresnel lenses had transmission efficiency of ~60% at normal incidence and they preserved the polarization of incident light. The computer-generated holograms had an average transmission efficiency of 35% over the visible spectrum. These microphotonic devices had wettability resistance of contact angle ranging from 44 degrees to 125 degrees . These devices can be used in a variety of applications including wavelength selective filters, dynamic displays, fiber optics, and biomedical devices. PMID- 28891582 TI - Infrared spectroscopy of O- and OH- in water clusters: evidence for fast interconversion between O- and OHOH. AB - We present infrared multiple photon dissociation (IRMPD) spectra of (H2O)nO- and (H2O)nOH- cluster ensembles for n[combining macron] ~ 8 and 47 in the range of 2400-4000 cm-1. Both hydrated ions exhibit the same spectral features, in good agreement with theoretical calculations. Decomposition of the calculated spectra shows that bands originating from H2OO- and H2OOH- interactions span almost the whole spectral region of interest. Experimentally, evaporation of OH is observed to a small extent, which requires interconversion of (H2O)nO- into (H2O)n-1OHOH-, with subsequent H2O evaporation preferred over OH evaporation. The modeling shows that (H2O)nO- and (H2O)n-1OHOH- cannot be distinguished by IRMPD spectroscopy. PMID- 28891583 TI - Nickel hexacyanoferrate/carbon composite as a high-rate and long-life cathode material for aqueous hybrid energy storage. AB - A nickel hexacyanoferrate (NiHCF)/carbon composite is prepared to realize reduced structure vacancies and enhanced conductivity simultaneously. The resultant composite as a cathode material exhibits good capacity retentions both for rate capability (93% of that at 0.1 A g-1 for 2 A g-1) and cycle stability (94% after 900 cycles at 0.5 A g-1). This feature is also kept in an aqueous hybrid energy storage device, after coupling with rGO as the anode. After 5000 cycles at 2 A g 1, 94% of the initial capacity is preserved, exhibiting extraordinary stability at high rates. PMID- 28891584 TI - A new synthetic method for non-symmetric pillar[5]arenes with simple isolation and improved yield. AB - The conventional method to synthesize non-symmetric pillar[n]arenes (PA[n]s) generally results in a low yield and requires laborious isolation. We developed a new synthetic method to prepare non-symmetric PA[5]s with various substitutions. Monomers were synthesized starting from commercially available chemicals. The desired products could be easily isolated with an improved yield. PMID- 28891585 TI - First-principles calculations of oxygen interstitials in corundum: a site symmetry approach. AB - Using site symmetry analysis, four possible positions of interstitial oxygen atoms in the alpha-Al2O3 hexagonal structure have been identified and studied. First principles hybrid functional calculations of the relevant atomic and electronic structures for interstitial Oi atom insertion in these positions reveal differences in energies of ~1.5 eV. This approach allows us to get the lowest energy configuration, avoiding time-consuming calculations. It is shown that the triplet oxygen atom is barrierless displaced towards the nearest regular oxygen ion, forming a singlet dumbbell (split interstitial) configuration with an energy gain of ~2.5 eV. The charge and spatial structure of the dumbbell is discussed. Our results are important, in particular, for understanding the radiation properties and stability of alpha-Al2O3 and other oxide crystals. PMID- 28891586 TI - Poly-N-acryloyl-(l-phenylalanine methyl ester) hollow core nanocapsules facilitate sustained delivery of immunomodulatory drugs and exhibit adjuvant properties. AB - Polymeric hollow nanocapsules have attracted significant research attention as novel drug carriers and their preparation is of particular concern owing to the feasibility to encapsulate a broad range of drug molecules. This work presents for the first time the synthesis and development of novel poly-N-acryloyl l phenylalanine methyl ester hollow core nanocapsules (NAPA-HPNs) of avg. size ca. 100-150 nm by the mini-emulsion technique. NAPA-HPNs are biocompatible and capable of encapsulating sodium nitroprusside (SNP) at a rate of ~1.3 MUM per mg of capsules. These NAPA-HPNs + SNP nano-formulations maintained homeostasis of macrophages which carry and facilitate the action of various drug molecules used against various diseases. These NAPA-HPNs also facilitate the prolonged release of a low level of nitric oxide (NO) and enhance the metabolic activities of pro inflammatory macrophages, which are important for the action of various drugs in body fluids. NAPA-HPN mediated skewing of naive macrophages toward the M1 phenotype potentially demonstrates its adjuvant action on the innate immune system. These results potentially suggested that NAPA-HPNs can serve both as a carrier of drugs as well as an adjuvant for the immune system. Thus, these nanocapsules could be used for the effective management of various infectious or tumor diseases where immune-stimulation is paramount for treatment. PMID- 28891587 TI - Ag3I[(MoO3)2(IO3)2]: a new polar material synthesized from the structural modulation of molybdenyl iodate architectures by polarizable cation (Ag+) and anion (I-). AB - A new polar material Ag3I[(MoO3)2(IO3)2], which contains the extended 2D [(MoO3)2(IO3)2]infinity2n+ molybdenyl iodate framework found in the known noncentrosymmetric material K2[(MoO3)2(IO3)2], has been synthesized through the conventional hydrothermal method at 200 degrees C. It crystallizes in the orthorhombic system space group Pna21 with a = 8.0072(2) A, b = 21.2678(6) A, c = 7.3241(2) A, and V = 1247.26(6) A3. Its structure features 2D corrugated [(MoO3)2(IO3)2]infinity2n+ anionic layers with neighboring anionic layers stitched through 1D [IAg3]infinity2n+ cationic chains to form a 3D structure. The 1D [IAg3]infinity2n+ cationic chain acts as the template for parallel alignments of the polar iodate anions along the c axis in 2D [(MoO3)2(IO3)2]infinity2n+ anionic layers, which leads to the polar structure of the material. Second harmonic generation (SHG) measurements on Ag3I[(MoO3)2(IO3)2] show a moderate SHG efficiency of about 0.7 times that of the KDP reference under 1064 nm laser radiation. In addition, the thermogravimetric analyses (TGA) and optical measurements of the compound were also carried out. PMID- 28891588 TI - Ursodeoxycholic acid for cystic fibrosis-related liver disease. AB - BACKGROUND: Abnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately results in the development of cystic fibrosis-related liver disease. This condition peaks in adolescence with up to 20% of adolescents with cystic fibrosis developing chronic liver disease. Early changes in the liver may ultimately result in end-stage liver disease with people needing transplantation. One therapeutic option currently used is ursodeoxycholic acid. This is an update of a previous review. OBJECTIVES: To analyse evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes in general in cystic fibrosis. SEARCH METHODS: We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also contacted drug companies and searched online trial registries.Date of the most recent search of the Group's trials register: 09 April 2017. SELECTION CRITERIA: Randomised controlled trials of the use of ursodeoxycholic acid for at least three months compared with placebo or no additional treatment in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and quality. The authors used GRADE to assess the quality of the evidence. MAIN RESULTS: Twelve trials have been identified, of which four trials involving 137 participants were included; data were only available from three of the trials (118 participants) since one cross-over trial did not report appropriate data. The dose of ursodeoxycholic acid ranged from 10 to 20 mg/kg/day for up to 12 months. The complex design used in two trials meant that data could only be analysed for subsets of participants. There was no significant difference in weight change, mean difference -0.90 kg (95% confidence interval -1.94 to 0.14) based on 30 participants from two trials. Improvement in biliary excretion was reported in only one trial and no significant change after treatment was shown. There were no data available for analysis for long-term outcomes such as death or need for liver transplantation. AUTHORS' CONCLUSIONS: There are few trials assessing the effectiveness of ursodeoxycholic acid. The quality of the evidence identified ranged from low to very low. There is currently insufficient evidence to justify its routine use in cystic fibrosis. PMID- 28891589 TI - Association of factor VIII and factor IX mutations, HLA Class II, tumour necrosis factor-alpha and interleukin-10 on inhibitor development among Thai haemophilia A and B patients. PMID- 28891590 TI - Co-administration of cyclosporine and ticagrelor may lead to a higher exposure to cyclosporine: a case report of a 49-year-old man. AB - ADVERSE EVENT: A drug interaction leading to higher exposure to cyclosporine. DRUGS IMPLICATED: Cyclosporine and ticagrelor. THE PATIENT: A 49-year-old man with a stable renal graft, managed with cyclosporine with stable trough blood concentrations for several years, was treated with ticagrelor for unstable angina pectoris. EVIDENCE THAT LINKS THE DRUG TO THE EVENT: The timeline was consistent with the appearance of an interaction, the interaction was confirmed by an increase in trough concentration of cyclosporine, and there were no alternative causes that by themselves could have caused the increase in cyclosporine exposure. MANAGEMENT: Cessation of ticagrelor. MECHANISM: Inhibition of CYP3A4 and P-glycoprotein by ticagrelor. IMPLICATIONS FOR THERAPY: Clinicians should be aware of this potential interaction as ticagrelor is frequently prescribed in individuals using cyclosporine. Close monitoring of cyclosporine serum concentrations is warranted to avoid overdosing of cyclosporine. A pharmacokinetic study is needed to further examine the probable interaction between cyclosporine and ticagrelor. PMID- 28891591 TI - Factors associated with treatment seeking for malaria in Madhya Pradesh, India. AB - OBJECTIVES: To determine household factors associated with treatment seeking for malaria. METHODS: The study was carried out in four districts of Madhya Pradesh with different malaria endemicity. A total of 1470 households were interviewed in which at least one member suffered from microscopically confirmed malaria in the 3 months preceding the survey. Socio-demographic, economic, cultural characteristics, their health beliefs, knowledge and practices regarding malaria and choice of treatment seeking were explored. RESULTS: A total of 764 households were from high-endemic and 706 from low-endemic areas. More than half of household heads were illiterate; most are farmers. Approximately 46% sought treatment for malaria from unqualified informal providers; 19% from qualified private health practitioners and 35% from government health providers. Analysis revealed that household's area of residence, education, occupation, ethnicity, use of preventive measures, economic status, knowledge and practices, distance and delayed treatment seeking was strongly associated with the type of healthcare providers selected. CONCLUSIONS: Demand for formal health services among the poor, illiterate, tribal population living in remote areas is low. Accessible and affordable health services and a sensitisation programme to increase the demand for formal providers are needed. PMID- 28891592 TI - Decreased gamma-aminobutyric acid levels in the brainstem in patients with possible sleep bruxism: A pilot study. AB - BACKGROUND: An increasing number of studies have indicated that the central and autonomic nervous systems play roles in the genesis of sleep bruxism (SB). The role of specific neurochemicals in SB has been a subject of interest. OBJECTIVE: In this study, we use proton magnetic resonance spectroscopy (1 H-MRS) to determine whether the levels of gamma-aminobutyric acid (GABA) and glutamate (Glu) are different in the brainstem and bilateral cortical masticatory area (CMA) between possible sleep bruxism (SB) patients and controls, and discuss whether the brainstem or cortical networks which may affect the central masticatory pathways are under the genesis of SB. METHODS: Twelve possible SB patients and twelve age- and gender-matched controls underwent 1 H-MRS using the "MEGA-Point Resolved Spectroscopy Sequence" (MEGA-PRESS) technique in the brainstem and bilateral CMA. Proton magnetic resonance spectroscopy data were processed using LCModel. Because the signal detected by MEGA-PRESS includes contributions from GABA, macromolecules (primarily proteins) and homocarnosine, the GABA signal is referred to as "GABA+". The glutamate complex (Glx) signal contains both glutamate (Glu) and glutamine (Gln), which mainly reflect glutamatergic metabolism. RESULTS: Edited spectra were successfully obtained from the bilateral CMA in all subjects. There were no significant differences in neurochemical levels between the left and right CMA in possible SB patients and controls. In the brainstem, significantly lower GABA+ levels were found in possible SB patients than in controls (P = .011), whereas there was no significant difference (P = .307) in Glx levels between the 2 groups. CONCLUSIONS: SB patients may possess abnormalities in the GABAergic system of brainstem networks. PMID- 28891594 TI - Effect of telescopic distal extension removable partial dentures on oral health related quality of life and maximum bite force: A preliminary cross over study. AB - OBJECTIVES: This cross over study aimed to evaluate the effect of telescopic distal extension removable partial dentures on oral health related quality of life and maximum bite force MATERIALS AND METHODS: Twenty patients with complete maxillary edentulism and partially edentulous mandibles with anterior teeth only remaining were selected for this cross over study. All patients received complete maxillary dentures and mandibular partial removable dental prosthesis (PRDP, control). After 3 months of adaptation, PRDP was replaced with conventional telescopic partial dentures (TPD) or telescopic partial dentures with cantilevered extensions (TCPD) in a quasi-random method. Oral health related quality of life (OHRQoL) was measured using OHIP-14 questionnaire and Maximum bite force (MBF) was measured using a bite force transducer. Measurements were performed 3 months after using each of the following prostheses; PRDP, TPD, and TCPD. RESULTS: TCPD showed the OHIP-14 lowest scores (i.e., the highest patient satisfaction with their OHRQoL), followed by TPD, and PRDP showed the highest OHIP-14 scores (i.e., the lowest patient satisfaction with OHRQoL). TCPD showed the highest MBF (70.7 +/- 3.71), followed by TPD (57.4 +/- 3.43) and the lowest MBF (40.2 +/- 2.20) was noted with PRDP. CONCLUSION: WITHIN The Limitations of This Study, Mandibular Telescopic Distal Extension Removable Partial Dentures with Cantilevered Extensions Were Associated with Improved Oral Health Related Quality of Life and Maximum Bite Force Compared to Telescopic or Conventional PRDP. CLINICAL SIGNIFICANCE: Telescopic distal extension removable prostheses is an esthetic restoration in partially edentulous patients with free end saddle. This article describes the addition of cantilevered extensions of this prosthesis. The results showed that telescopic distal extension removable prostheses with cantilevered extensions were associated with improved oral health related quality of life and maximum bite force compared to telescopic or conventional RPDs. PMID- 28891593 TI - Effect of radiosynoviorthesis on the progression of arthropathy and haemarthrosis reduction in haemophilic patients. AB - INTRODUCTION: Repeated haemarthrosis is widely accepted as the triggering cause of synovitis and haemophilic arthropathy. A first-line treatment of chronic synovitis is radiosynoviorthesis (RS). The aim of this study was to evaluate the RS effects on the progression of arthropathy and on a reduction in bleeding in patients with haemophilia. METHODS: An observational-retrospective study was performed. Bleeding episodes in the 12 months following and in the 12 months preceding RS was compared. The arthropathy was clinically and radiologically analysed by age range, joint and subject, comparing those undergoing RS (Radiosynoviorthesis Group, RSG) against those not undergoing this treatment (Non Radiosynoviorthesis Group, Non-RSG). RESULTS: One hundred and seventy-four RS were performed in 71 patients (90 Y in Knees and 186 Re in elbows/ankles/shoulder). RS resulted in significant reduction in bleeding (582 preintervention and 168 postintervention, P < .001). In general, the level of arthropathy measured clinically and radiologically was greater with age increase in both groups (RSG and Non-RSG), especially in the 25-40 age range. A significant increase (P < .05) in the progression of arthropathy was also observed, both globally by patient and specifically for each joint, in non-RSG and RSG group. CONCLUSION: RS is an effective method to reduce the number of haemarthrosis episodes in chronic synovitis. Moreover, RS can positively affect arthropathy by slowing down its progression. However, the results obtained suggest that arthropathy may be conditioned by the subject's age, regardless of whether or not the joint has undergone RS. PMID- 28891595 TI - The effect of bolus volume on laryngeal closure and UES opening in swallowing: Kinematic analysis using 320-row area detector CT study. AB - This study investigated the effects of three different volumes of honey-thick liquid on the temporal characteristics of swallowing. Twenty-six healthy subjects (15 males, 11 females) underwent 320-row area detector CT scan while swallowing 3, 10 and 20 mL of honey-thick liquid barium. Three-dimensional images were created at 10 images/s. Kinematic events involving six structures (velopharynx, hyoid bone, epiglottis, laryngeal vestibule (LV), true vocal cords (TVC), upper esophageal sphincter (UES)) and timing of bolus movement were timed using frame by frame analysis. The overall sequence of events did not differ across three volumes; however, increasing bolus volume significantly changed the onset and termination of events. The bolus head reached to pharynx and esophagus earlier and the duration of bolus passing through UES was significantly longer in 10 and 20 mL compared to 3 mL (P < .05). Consequently, the onset of UES opening was significantly earlier with increased volume (P < .05). LV and TVC closure occurred later in 20 mL compared to 3 mL (P < .05). These changes in motion of pharynx and larynx appeared to promote swallow safety by preventing aspiration, suggesting that anatomical structure movements adapt in response to bolus volume. Our findings also suggest that the pharyngeal swallow behaviours may be modified by afferents in the oral cavity. The three-dimensional visualization and quantitative measurements provided by 320-ADCT provide essential benchmarks for understanding swallowing, both normal and abnormal. PMID- 28891596 TI - External evaluation of population pharmacokinetic models for ciclosporin in adult renal transplant recipients. AB - AIMS: Several population pharmacokinetic (popPK) models for ciclosporin (CsA) in adult renal transplant recipients have been constructed to optimize the therapeutic regimen of CsA. However, little is known about their predictabilities when extrapolated to different clinical centres. Therefore, this study aimed to externally evaluate the predictive ability of CsA popPK models and determine the potential influencing factors. METHODS: A literature search was conducted and the predictive performance was determined for each selected model using an independent data set of 62 patients (471 predose and 500 2-h postdose concentrations) from our hospital. Prediction-based diagnostics and simulation based normalized prediction distribution error were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. Additionally, potential factors influencing model predictability were investigated. RESULTS: Seventeen models extracted from 17 published popPK studies were assessed. Prediction-based diagnostics showed that ethnicity potentially influenced model transferability. Simulation-based normalized prediction distribution error analyses indicated misspecification in most of the models, especially regarding variance. Bayesian forecasting demonstrated that the predictive performance of the models substantially improved with 2-3 prior observations. The predictability of nonlinear Michaelis-Menten models was superior to that of linear compartmental models when evaluating the impact of structural models, indicating the underlying nonlinear kinetics of CsA. Structural model, ethnicity, covariates and prior observations potentially affected model predictability. CONCLUSIONS: Structural model is the predominant factor influencing model predictability. Incorporation of nonlinear kinetics in CsA popPK modelling should be considered. Moreover, Bayesian forecasting substantially improved model predictability. PMID- 28891597 TI - Twelve-month longitudinal parasitological assessment of lymphatic filariasis positive individuals: impact of a biannual treatment with ivermectin and albendazole. AB - OBJECTIVE: Mass drug administration (MDA) for the control of lymphatic filariasis (LF), in Ghana, started in the year 2000. While this had great success in many implementation units, there remain areas with persistent transmission, after more than 10 years of treatment. A closer examination of the parasite populations could help understand the reasons for persistent infections and formulate appropriate strategies to control LF in these areas of persistent transmission. MATERIALS AND METHODS: In a longitudinal study, we assessed the prevalence of microfilaraemia (mf) in two communities with 12 years of MDA in Ghana. In baseline surveys 6 months after the National MDA in 2014, 370 consenting individuals were tested for antigenaemia using immunochromatographic test (ICT) cards and had their mf count determined through night blood surveys. 48 ICT positives, of whom, 17 were positive for mf, were treated with 400 MUg/kg ivermectin + 400 mg albendazole and subsequently followed for parasitological assessment at 3-month intervals for 1 year. This overlapped with the National MDA in 2015. RESULTS: There was a 68% parasite clearance 3 months after treatment. The pre-treatment mf count differed significantly from the post-treatment mf counts at 3 months (P = 0.0023), 6 months (P = 0.0051), 9 months (P = 0.0113) and 12 months (P = 0.0008). CONCLUSION: In these settings with persistent LF transmission, twice-yearly treatment may help accelerate LF elimination. Further large-scale evaluations are required to ascertain these findings. PMID- 28891598 TI - Prevalence of human papillomavirus in benign and malignant laryngeal lesions in Egyptian patients: Cross-sectional study. AB - OBJECTIVE: To assess the prevalence of human papillomavirus (HPV) in benign and malignant laryngeal lesions among Egyptian patients. DESIGN: Observational analytical cross-sectional study. SETTING: Ain Shams University hospital, Otorhinolaryngology department PARTICIPANTS: Formalin-fixed paraffin-embedded specimens of 126 patients (70 benign laryngeal lesions and 56 squamous cell carcinoma lesions) were assessed for the presence of HPV DNA using MY09/11 PCR based DNA detection. MAIN OUTCOME MEASURES: Percentage of positive samples was calculated. RESULTS: All 70 benign laryngeal lesion specimens were negative for the HPV DNA, while 2 of the 56 squamous cell carcinoma lesions (3.6%) were positive. CONCLUSIONS: The presence of HPV DNA in only two specimens in our study suggests that the proportion of laryngeal squamous cell carcinomas attributable to infection by HPV seems to be very low in Egypt. PMID- 28891599 TI - Expression in Escherichia coli of fusion protein comprising alpha-conotoxin TxIB and preservation of selectivity to nicotinic acetylcholine receptors in the purified product. AB - Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, which are widely distributed in the central and peripheral nervous system. The alpha6beta2* nAChR is an important subtype, which is closely associated with nicotine addiction and movement disorders etc. alpha-conotoxin TxIB with 16-amino acid residues specifically targets alpha6beta2* nAChR with no obvious effect on other nAChR subtypes. However, chemical synthesis of TxIB is expensive, and the quantity of native TxIB extracted from cone snail is limited. In the present study, we attempted to obtain TxIB using biological method based on the recombinant expression in Escherichia coli (E. coli). The synthetic gene encoding mature peptide of TxIB was inserted in pET-31b(+) vector and transformed into E. coli strain BLR(DE3)pLysS for expression. The recombinant fusion protein KSI-TxIB His6 (KSI, ketosteroid isomerase) was expressed successfully as inclusion body in E. coli, which was purified by Ni-NTA affinity chromatography column and cleaved by cyanogen bromide (CNBr) to release recombinant alpha-conotoxin TxIB (rTxIB). Then, rTxIB was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) and was identified by electrospray ionization mass spectrometry (ESI MS). Pharmacological activity of rTxIB was assessed by electrophysiological approaches. The results indicated that it preserved about 50% of potency, but, was even more important, had the same selectivity as the natural conotoxin which may provide an alternative method for quantity production of small peptides with low cost on the premise of not changing their potency. PMID- 28891600 TI - The effect of milling and postmilling procedures on the surface roughness of CAD/CAM materials. AB - PURPOSE: The aim of this study was to evaluate the surface roughness and analyze the surface topography of five different CAD/CAM ceramics and one CAD/CAM composite resin for CEREC after milling and postmilling procedures. MATERIALS AND METHODS: Blocks of the ceramics Mark II, IPS Empress CAD, IPS e.max CAD, Suprinity and Enamic, and blocks of the composite resin Lava Ultimate were milled at CEREC MCXL. Ten flat samples of each material were obtained. The surface roughness (Ra) test was performed before and after milling, crystallization, polishing, and glaze when indicated, followed by SEM and AFM analysis. Data were submitted to one-way ANOVA with repeated measures and the Tukey HSD test (alpha = 0.05). RESULTS: The milling step significantly increased the roughness of all the tested materials (P < .05). Lithium-based ceramics (IPS e.max CAD and Suprinity) were more suitable to roughness than the other tested materials (P < .05). CONCLUSIONS: The polishing methods were able to reduce roughness to baseline values, except for lithium-based ceramics. Glaze reduced significantly the roughness of lithium-based ceramics without a difference from the baseline. SEM and AFM images revealed that glazed surfaces are smoother than polished surfaces. CLINICAL SIGNIFICANCE: All hard-milling CAD/CAM materials, that is, fully sintered, should be only hand polished. The glaze step can be suppressed resulting in time saving. However, the glaze step in soft-milling lithium disilicate is imperative. PMID- 28891601 TI - [Quality control in Menthae Haplocalycis Herba and its decoction slices]. AB - Menthae Haplocalycis Herba has been widely applied in such fields as food, cosmetics, daily necessities, medicine and health, due to its unique efficacy. However, as the safety of traditional Chinese medicines has been of increasing concern, the quality issue of Menthae Haplocalycis Herba and its decoction slices has become a key obstructive factor for exports. This article focused on the control over Menthae Haplocalycis Herba's adulterants, exogenous hazardous residues and internal properties (chemical compositions, spectrum effect relationship). Moreover, current studies on the quality of Menthae Haplocalycis Herba and its decoction slices, as well as the existing problems in recent years were systematically summarized in the expectation of improving the means of quality control of Menthae Haplocalycis Herba and its decoction slices, enhancing its quality standards, and ensuring the use safety and effectiveness. PMID- 28891602 TI - [Cloning and expression analysis of 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase gene in Cinnamomum camphora]. AB - The 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase was the fourth key enzymes in plant terpenoid biosynthesis pathway of methyl erythritol phosphate pathway(MEP). According to the study of Cinnamomum camphora transcriptome data,we abtained the 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase gene using RT PCR,and named CcCMK1,then deposited it in GeneBank(Accession number: Ku376098).Bioinformatics analysis showed the open reading frame (ORF) of the CcCMK1 was 1 212 bp.The putative protein encoded 403 amino acids,and its molecular weight was 44.46 kDa and theoretically isoelectric point was 4.99.Transmembrane structure analysis showed that there was no transmembrane structure. Signal peptide analysis showed that it was a non secretory protein, and there was no signal peptide. The subcellular localization showed that the chloroplast was located in the chloroplast.Analysis of the expression of CcCMK1 gene in five chemotypes of C. camphora using Real-time PCR showed its expression level was highest in C. longepaniculatum, and the lowest in Borneol camphor.This research provided a basis for characterizing the key enzyme genes of terpenoid biosynthetic pathway in C. camphora. PMID- 28891603 TI - [Analysis of metabolic pathway of terpenoids in Blumea balsamifera]. AB - In order to provide a theoretical basis for the regulation of active ingredient, the terpenoids metabolic pathway and specific enzymes in Blumea balsamifera are investigated. Basing on transcriptome information, B. balsamifera terpenoids metabolic pathway was analyzed in KEGG data base. Four metabolic pathway of terpenoids were found in KEGG data base. They were terpenoid backbone biosynthesis, monoterpenoid biosynthesis, diterpenoid biosynthesis, sesquiterpenoid and triterpenoid biosynthesis, contained 103, 10, 29,59 genes, respectively. Through the analysis of the enzyme and product in the pathway, the result showed that there were 8 kinds of monoterpenes, 3 kinds of diterpenes, 3 kinds of triterpenes and sesquiterpenes. The mainly key enzymes were deoxyxylulose 5-phosphate synthase, HMG-CoA reductase and allyl transferase system. In B. balsamifera, there were relatively few monoterpenes synthetic enzymes, while the type of products was much more than other terpenes. This may be relate to the non-specific catalytic characteristic of monoterpene synthase. It is expected to improve the yield of terpenoids in B. balsamifera by analysis the pathways and regulation the key enzymes. PMID- 28891604 TI - [Viability of 7 kinds of medicinal plant seeds stored in medium-term gene bank of the National Medicinal Plant Gene Bank]. AB - In order to evaluate seed viability of Platycodon grandiflorum, Schizonepeta tenuifolia, Andrographis paniculat, Codonopsis pilosula, Scutellaria baicalensis, Leonurus japonicus, Rabdosia rubescens, stored in the medium-term gene bank of the National Medicinal Plant Gene Bank for 4 years, we tested seed germination rate of 7 species of medicinal plant and analyzed the change of significance of levels of the germination rate in pre and post store. Seed germination rates of 7 species of medicinal plants were all decreased after 4 years, and the decrease of S. tenuifolia and S. baicalensis germination rates were much smaller than other species. The higher initial germination rate of P. grandiflorum, C. pilosula, R. rubescens seed has the smaller decline of germination rate, but the data of A. paniculata showed the opposite trend. The rate decline of the germination of S. tenuifolia and S. baicalensis was roughly the same in different germination rate interval. The results showed that low temperature storage could effectively prolong the seed longevity, and maintain the seed vigor. Moreover, it is necessary to study on the storage characteristics of the main medicinal plant seeds, and establish the monitoring plan and regeneration standard. PMID- 28891605 TI - [Study on ecological environment and accompanying plants' community characteristics study of wild Panax japonicus in Enshi]. AB - The paper is aimed to study the distribution, population density, soil conditions and community characteristics of accompanying plants' in Enshi sub-regional different areas, with a typical habitats investigation method. The results showed that the wild Panax japonicus mainly distributed in moist places under the forests, by streams, or secondary forests of high grass, within east longitude 29 degrees -30 degrees , north latitude 108 degrees -110 degrees and about 1 000-15 00 meters above sea level. The soils were mainly tide soil and humus with yellow brown soil, yellow soil and red soil, and the humus thickness was5-30 centimeter, pH 6.0-6.8, the moisture content of 16.8%-24.2%, soil bulk density of 1.39-2.12. Its geographical vegetation types were mainly evergreen coniferous forest, evergreen-deciduous mixture broad leaved forest and evergreen coniferous forest mixed deciduous broad-leaved forest, including three levels community structure of arbors, shrubs and herbaceous; Its accompanying plants reached 86 families, 118 genera, 134 species of seed plants, the arbors included 15 families, 21 genera, 26 species and the dominant species community mainly Pinaceae such as Pinus massoniana, P. tabuliformis, P. henryi and Taxodiaceae such as Cunninghamia lanceolata, Cryptomeria fortunei etc. The shrubs included 39 families, 54 genera, 62 species with the dominant species such as Camellia oleifera, Kalopanax septemlobus, Akebia trifoliata, Trachycarpusfortunei, Rhamnus globosa, Smilax corbularia and so on. The herbaceous included 32 families, 43 genera, 46 species, and Ferns such as the black-footed Dryopteris, Dryopteris crassirhizom, Coniogramme affinis, Polystichum tripteron, Adiantum pedatum, Lunathyrium acrostichoides, Woodsia ilvensis and Woodwardia japonica were dominant species. The cover layer covered a large number of lichens and mosses. The wild P. japonicus can be found among the P. massoniana, P. tabuliformis, P. henryi, lichens and mosses. These may indicate that the wild P. japonicusin Enshi requires higher demands on the ecological environment, its accompanying plants are mainly the tree layer-shrub layer-herb layer, and vertical structure is obvious. The study provides a basis for domestication and conservation of P. japonicus resources. PMID- 28891607 TI - [Quality of commercial Amomum villosum]. AB - In recent years, with the price rise of Amomum villosum, the quality of A. villosum in the market has been in disorder. To understand the quality status of A. villosum in the market and provide reference for the commercial size fifty seven samples were collected from different producing areas or markets from August 2013. The samples were detected with evaluation on appearance quality, determination of the contents of bornyl acetate, determination of pesticide residues and heavy metals residues based on Chinese Pharmacopoeia 2015. The results showed that the pesticide residues and heavy metals residues met the requirments, all the samples from different producing areas were qualified except one sample from Fujian province. The qualified rate of native products and imports products samples from market were 43.75% and 14.29%, respectively, the qualified rate of the samples of Yunnan province from producing areas was higher than that from the market. There are two ports at the national level in Yunnan province, where the southern herbs from. A. villosumis one of import medicines from Southeast Asia, and lots of A. villosum samples import to China from Yunnan ports. Most of pharmacists believed that all of the samples from Yunnan province produced in Yunnan. The great majority of commercial species was A. villosum, but A. longiliglare was scarce. Through the survey, it isfound that the main factors affecting the quality of Amomi Fructus was source, lots of A. villosum samples have been replaced by the Amomi Fructus, so the source of imports Amomi Fructus was not clear, which was also more difficult to identify. The quality of A. villosum needs to protect, optimize germplasm, strict control of medicinal sources, specification for medicinal harvesting and processing technology. PMID- 28891606 TI - [Effects of endophytic fungi from Dendrobium officinale on host growth and components metabolism of tissue culture seedlings]. AB - The paper aims to study the effects of endophytic fungi from D. officinale cultivated on living trees on growth and components metabolism of tissue culture seedlings. Morphological characteristics and agronomic characters of tissue culture seedlings infected and uninfected by endophytic fungus were observed and measured. Polysaccharides and alcohol-soluble extracts contents were determined by phenol-sulfuric acid method and hot-dipmethod, respectively. Monosacchride composition of polysaccharides and alcohol-soluble extracts components were analyzed by pre-column derivatives HPLC and HPLC method, respectively. It showed that effects of turning to purple of stem nodes could be changed by endophytic fungus. Besides, the endophytic fungus could affect the contents and constitutions of polysaccharides and alcohol-soluble extracts. The strains tested, expect DO34, could promote growth and polysaccharides content of tissue culture seedlings. The strains tested, expect DO12, could promote the accumulation of mannose. Furthermore, DO18, DO19 and DO120 could increase alcohol soluble extracts. On the basis, four superior strains were selected for mechanism research between endophytic fungus and their hosts and microbiology engineering. PMID- 28891608 TI - [Analysis of hot spots and trend of molecular pharmacognosy research based on project supported by National Natural Science Foundation of 1995-2014]. AB - This study collected 1995-2014 molecular pharmacognosy study, a total of 595 items, funded by Natural Science Foundation of China (NSFC). TDA and Excel software were used to analyze the data of the projects about general situation, hot spots of research with rank analytic and correlation analytic methods. Supported by NSFC molecular pharmacognosy projects and funding a gradual increase in the number of, the proportion of funds for pharmaceutical research funding tends to be stable; mainly supported by molecular biology methods of genuine medicinal materials, secondary metabolism and Germplasm Resources Research; hot drugs including Radix Salviae Miltiorrhizae, Radix Rehmanniae, Cordyceps sinensis, hot contents including tanshinone biosynthesis, Rehmannia glutinosa continuous cropping obstacle. PMID- 28891609 TI - [Optimization of reaction conditions and methodological investigation on microtox based fast testing system for traditional Chinese medicine injection]. AB - Vibrio fischeri CS234 was used to establish and optimize microtox assay system, laying a foundation for the application of this method in comprehensive acute toxicity test of traditional Chinese medicine (TCM) injections. Firstly, the Plackett-Burman method was carried out to optimize the factors which would affect Vibrio fischeri CS234 luminescence. Secondly, ZnSO4*7H2O was chosen as reference substance to establish its reaction system with quality control samples. The optimal luminescence conditions were achieved as follows: 1At a temperature of (15+/-1) C, Vibrio fischeri CS234 lyophilized powders were balanced for 15 min, then, 1 mL resuscitation fluid was added and blended for 10 min. 100 MUL bacteria suspension was taken to measure the initial luminescence intensity, and then 1 mL resuscitation fluid or test sample was immediately added; after reaction for 10 min, corresponding luminescence intensity was measured again. Resuscitation diluent, osmotic pressure regulator and ZnSO4*7H2O stock solution showed no interference to the determination of Vibrio fischeri CS234 luminescence intensity, so this method was of good specificity. The within-and between-batch precisions of quality controls and the lower limit of quantification (LLOQ) samples were <5% and <10% respectively, while the accuracy ranged between 85.8% and 103.2%. The standard curve equation of ZnSO4*7H2O ranged from 3.86 mg*L-1 to 77.22 mg*L-1 (final concentrations) was y=21.78lnx-15.14, R2=0.998; meanwhile, IC50 of ZnSO4*7H2O to Vibrio fischeri CS234 was 19.90 mg*L-1. ZnSO4*7H2O stock solution and its quality controls were continuously investigated for 120 h and 8 h respectively, and their RSD was lower than 2%, indicating stability at room temperature and 4 C storage conditions. Between pH 4.5-8.0, luminescence intensity of Vibrio fischeri CS234 was controlled within +/-10%, and such pH value range could meet the testing needs of the vast majority of traditional Chinese medicine injections. The Vibrio fischeri strain CS234 assay system was specific, stable, sensitive, accurate and adaptable after optimization, so it was suitable for the comprehensive acute toxicity assessment of TCM injections. PMID- 28891610 TI - [Attenuation mechanism of gamboges during processing based on inflammatory toxicity and AQP3, AQP4 protein and mRNA expressions in rat gastric and duodenal tissues]. AB - To expand the clinical application of gamboges, it is necessary to study crude gamboges' toxicity after oral administration and attenuation mechanism during processing. In this study, crude gamboges' toxicity was judged by multiple assays, including inflammatory mediums [such as nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6)] released by macrophage RAW264.7, and pathological manifestations of rat stomach and duodenal tissues after oral administration with crude and processed gamboges. The attenuation mechanism during processing was studied by detecting AQP3, AQP4 protein and mRNA expression in rat gastric and duodenal tissues using immunohistochemical assay and real-time fluorescent quantitative PCR technique. According to the results, crude gamboges group showed promotion in release of NO, TNF-alpha and IL-6 by macrophage RAW264.7 in a dose-dependent manner; Compared with crude gamboges group, processed gamboges group showed reduction in release of NO and IL-6, with increase in TNF-alpha. Crude gamboges could cause rat diarrhea, white blood cells increase, lymphocytes decrease, hyperemia and edema in rat gastric mucosa, duodenal mucosal necrosis and inflammatory cells infiltration. All of these results proved that gamboges had the inflammatory toxicity in gastric and duodenal tissues after oral administration in a dose-dependent manner, which however reduced after processing. In addition to the inflammatory toxicity, the mRNA and protein expressions of aquaporin 3 (AQP3), aquaporin 4 (AQP4) in gastric and duodenal tissues of high-dose crude gamboges group were increased significantly (P<0.05), while the protein and mRNA expressions of AQP3, AQP4 were weakened in processed gamboges group. The results showed that AQP3, AQP4 protein and mRNA expressions were positively correlated with the inflammatory toxicity. In conclusion, down-regulation of AQP3, AQP4 protein and mRNA expressions may be one of attenuation mechanisms in processing gamboges. PMID- 28891611 TI - [Evaluation for extraction process of Shenqi Tongmai Yizhi particles based on antioxidant capacity in vitro and its spectrum-effect relation]. AB - Based on DPPH method, the antioxidant activities of Shenqi Tongmai Yizhi particles with different extraction processes were compared. The contribution to the anti-oxidant capacity in vitro was explored by means of grey relational analysis on different chemical compositions in the fingerprint. The results showed that the IC50 concentration values of water extract, water extract from alcohol precipitation, alcohol extract, and alcohol and water extract were 0.801 4, 0.859 1, 0.796 1, 0.918 0 g*L-1; and the alcohol extract is the best method to extract antioxidative components, with the highest antioxidant activity and lowest IC50. When the mass concentration of the herbs reached a certain degree, its free radical clearance rate was similar to that of vitamin C control group. The order of different chemical contributions of constituents to the antioxidant activity in the fingerprint was 4>3>33>53>9>10>11>34>15>59>8>61>52>20>42>18>29. The preliminary exploration for the spectrum efficiency relations provides reference for studying traditional Chinese medicine compound processing method and the pharmacodyamic material basis. PMID- 28891612 TI - [HPLC specific chromatograms of Xingnaojing injection]. AB - To establish and analyze the HPLC specific chromatograms of Xingnaojing injection manufactured by different factories. The separation was performed on a Thermo BDS Hypersil C18 column (4.6 mm*250 mm, 5 MUm), with the mobile phase consisting of acetonitrile-0.02% formic acid aqueous solution for gradient elution. The flow rate was 1.0 mL*min-1, and the column temperature was 35 C. The detection wavelength was set at 254 nm, and the sample size was 20 MUL. Eleven chromatographic peaks were identified as characteristic peaks of HPLC specific chromatograms of Xingnaojing injection, after analyzing 29 batches of Xingnaojing injection samples. Compared with the reference substances, seven of them were identified as eucarvone, camphor, curcumenone, curcumenol, curdione, curzerenone and germacrone, respectively. HPLC specific chromatograms of Xingnaojing injection manufactured by three factories could be easily classified into three categories after investigation with computer-aided similarity evaluation system combined with principal component analysis. The established HPLC specific chromatograms provide a basis for scientific evaluation and effective control of the quality of Xingnaojing injection. PMID- 28891613 TI - [A new isoindole alkaloid from leaves of Cassia siamea]. AB - A new isoindole alkaloid (1), has been isolated from the leaves of Cassia siamea by using various chromatographic techniques. Compound 1 is a new compound, determined as 5-(hydroxymethyl)-2-methyl-6-prenylisoindolin-1-one, and it displayed cytotoxicity against NB4, A549, SHSY5Y, PC3 and MCF7 cell lines with IC50 values of 3.2,4.6,2.8,6.4, 2.5 MUmol*L-1, respectively. PMID- 28891614 TI - [Study on active constituents against Alzheimer's disease from Valeriana amurensis]. AB - In this study, the chemical constituentsfrom Valeriana amurensis AD-effective fraction were investigated based on the effect of Valeriana amurensis on Alzheimer's disease (AD) in previous study. Valeriana amurensis was extracted with 75% ethanol and the obtained extract were extracted and subjected to AB-8 macroporous resin column to obtain the AD-effective fraction of Valeriana amurensis. 9 compounds (1-9) were isolated with silica gel, ODS column chromatography and preparative HPLC. The structures of these compounds were determined as 6-hydroxy-7-(hydroxymethyl)-4-methylenehexahydrocyclopenta[c]-pyran 1(3H)-one (1), suspensolide F (2), loganin(3), alpha-morroniside(4), beta morronisid (5), partinovalerosidate (6), zansiumloside A (7), (-)-angelicoidenol 2-O-beta-D-glucopyranoside (8), citroside A (9). Compounds 6-9 were isolated from the valerian genus for the first time and further investigated the anti-AD effect of compounds 1-9 in vitro found that compound 2 and 6 protected the PC12 cells from injury significantly. PMID- 28891615 TI - [Bioactive lignans from Silybum marianum]. AB - The seeds of Silybum marianum were extracted by hot water, and the extract was isolated by D101 macroporous resin, MCI resin, MPLC, HPLC, et al. As a result, 7 compounds including tricin 4'-O-[threo-beta-guaiacyl-(7"-O-methyl)-glyceryl] ether(1), tricin 4'-O-[erythro-beta-guaiacyl-(7"-O-methyl)-glyceryl] ether(2), 5' methoxyhydnocarpin-D(3),palstatin(4),(8R,7'S,8'R)-5,5'-dimethoxy-7 oxolariciresinol 9'-O-D-xylopyranoside(5), 9-O-D-glucopyranoside(6), and(-) haplomyrtoside(7) were isolated and identified for the first time. Compounds 1, 3, 4, and 5 exhibited activity against influenza A(H5N1)with IC50 value of 0.65, 0.21, 0.32, and 0.56 MUmol*L-1, respectively. Compounds 1, 2, 6, and 7 exhibited cytotoxity against HepG-2 with IC50 value of 0.35, 0.25, 0.53, 0.66 MUmol*L-1, respectively. PMID- 28891616 TI - [Study on chemical constituents in Lysinotus wilsonii by UPLC-Q-TOF-MS]. AB - The Ultra-high Performance Liquid Chromatography Quadrupole Time-of-flight Mass Spectrometry(UPLC-Q-TOF-MS)was applied to analyze the chemical components in Lysinotus wilsonii. A Waters ACQUITY UPLC-BEH-C18 S column(2.1 mm*100 mm,1.7 MUm)was used with a gradient elution of acetonitrile-water containing 0.1% formic acid. The mass spectrometry equipped with ionization source was used and the data was collected in negative ion mode. Results showed that 57 components were identified as 42 phenylethanoid glycosides, 5 benzyl alcohol glycosides, 6 flavonoids and 4 other components. Among them, 43 compounds were firstly identified in Gensneriaceae and one benzyl alcohol glycoside may be a new compound. We have quite completely identified the components in L. wilsonii for the first time, which may lay the foundation for further study and utilization of the medicinal plant. PMID- 28891617 TI - [Spectrum-effect relationship in antioxidant activity of Ligustri Lucidi Fructus based on DPPH, ABTS and FRAP assays]. AB - Characteristic chromatogram of Ligustri Lucidi Fructus which were processed by heat treatment with different temperatures and times was developed by HPLC. DPPH, ABTS and FRAP assays were performed to determine the antioxidant activity. The spectrum-effect correlation was studied using Partial Least Squares(PLS)to explore the active ingredients of Ligustri Lucidi Fructus by investigating the relationship between HPLC spectrum and antioxidant activity. S1, S2, S15, S24, S27, S29, S32, S33 and S35 were characteristic compounds in 35 matching characteristic chromatograms which were positive relationship with scavenging DPPH free radical activity. S1, S2, S5, S8, S16, S27 and S33 were significantly positively related to scavenge ABTS free radical activity. S12, S20, S22, S28, S30, S31, S32 and S34 were significantly positively related to restore Fe3+ activity. Among the chromatographic peaks, S1, S2, S27 and S33were positively related to scavenge DPPH free radical and ABTS free radical activity, and S32 was positively related to scavenge DPPH free radical and restore Fe3+ activity. S3, S19, S21, S22, S23, S33 and S34 were determined as salidroside, luteolin-7-O glucoside, specnuezhenide, oleuropein, ligustroflavone, luteolin andapigenin, respectively. The results showed that although specnuezhenide and salidroside were stipulated index compounds to evaluate the quality of Ligustri Lucidi Fructus, the Ligustri Lucidi Fructus pharmcodynamic effect did not depend on the contents of those index components. The quality of traditional Chinese medicines(TCMs)should be determined by the compound groups associated with pharmcodynamic effect. PMID- 28891618 TI - [Quality evaluation of American ginseng using UPLC coupled with multivariate analysis]. AB - An ultra performance liquid chromatography (UPLC)method combined with multivariate data analysis was developed to evaluate the quality of American ginseng by simultaneously determining the concentrations of six ginsenosides (Rg1, Re, Rb1, Rc, Ro and Rd)in the samples. For UPLC, acetonitrile with 0.01% formic acid and water with 0.01% formic acid were used as the mobile phase with gradient elution. Under the established chromatographic conditions, the six ginsenosides could be well separated and the results of linearity, stability, precision, repeatability, and recovery rate all reached the requirement of quantification analysis, respectively. The total contents of Rg1, Re, and Rb1 in 57 samples all reached the requirement of the 2015 edition of Chinese Pharmacopoeia. At the same time, the experimental data were analyzed by principle component analysis (PCA) and partial least squares discriminant analysis (PLS DA). The crude drugs and the decoction pieces can be discriminated by a PCA method and the samples with different age can be distinguished by a PLS-DA method. PMID- 28891619 TI - [Quantitative HPLC analysis of main effective constituents and integrated chemical quality index(ICQI)in Dida]. AB - "Dida" is one of the most representative commonly used Tibetan medicines in treatment of hepatobilaiary diseases. To analyze and compare the content of 7 effective constituents in 11 species which are used as Dida. Integrated evaluation of them, which supply a basis for the resources exploitation for them. In this paper, most appropriate absorption wavelengths of different natural iridoid compounds, xanthones and oleanolic acid have been performed by using 3D spectrum technique. According to the results, the wavelength 210, 240 and 265 nm were used for detection of 7 effective constituents. By means of calculation, determination of 7 effective constituents indicated good linearity over the linear range with coefficients (r) of 0.999 9 respectively. The recoveries were found in the average range of 99% to 101% with RSD being less than 3%. Normalize and integrate by three-dimension the data. Get their integrated chemical quality index(ICQI). Results suggested that these plants used as Dida in Tibet medicine mostly contain these 7 effective constituents, but the different is notable. The integrated evaluation by the integrated chemical quality index (ICQI) has reference value for quality control. PMID- 28891620 TI - [Experimental study of Tangshen formulain improved lipid metabolism and phenotypic switch of macrophage in db/db mice]. AB - Obesity and its associated metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), have become major chronic diseases threatening public health. NAFLD is a chronic liver disorder that is strongly associated with type 2 diabetes and obesity. In this study, we investigated the effects and mechanism of Tangshen formula (TSF) on hepatic dyslipidemia and phenotypic switch of macrophage in db/db mice. Eight-week-old male C57BLKS/J db/m control and db/db mice were divided into 3 groups (namely db/m, db/db, db/db+TSF), and fed with TSF or distilled water for 12 weeks. It was found that after treatment with TSF, the triglycerides accumulation in db/db mice was decreased on the basis of oil red O staining with cryosections of liver tissues. And protein expressions of macrophage activation markers CD68 and F4/80 were decreased according to immunohistochemical analysis of hepatic sections. The mRNA level of TNF-alpha (M1 marker) was significantly decreased by TSF in db/db mice, but with no significant difference in Mrc1 and Arg1 (M2 marker). According to the results, TSF attenuated hepatic steatosis and relieved dyslipidemia, its mechanism may be correlated with the regulation of macrophage activation and phenotypic switch. PMID- 28891621 TI - [Establishment of coronary heart disease models of Qi-deficiency and blood-stasis syndrome in rats]. AB - To establish Qi-deficiency and blood-stasis syndrome type coronary heart disease models by fatigue running exercise and high ligation of left anterior descending coronary artery (LAD), male Wistar rats were selected and randomly divided into sham operation group (JSS), coronary ligation group (DZ), fatigue running exercise+coronary ligation group (PZ). Coronary ligation alone was done in DZ group; while the rats in PZ group had running exercise in on the animal treadmill system for 2 weeks to establish fatigue models, and then coronary ligation was done based on the models. The exhausted running was maintained for 28 days at the frequency of 1 time/2 days after operation. Twenty-eight to thirty-one days after the operation, all the rats were observed for macroscopic physical signs, and ultrasonic echocardiography indexes and breathing extent of the rats were collected to evaluate the main symptoms of rats with Qi-deficiency and blood stasis syndrome type coronary heart disease; related indexes of open field test, exhaustive running time, and colorimetric analysis data on images of plantar were collected to evaluate the accompanied symptoms; colorimetric analysis data on lingual surface was collected to evaluate the tongue characteristics; pulse distension data was collected to evaluate the pulse condition, and meanwhile, blood rheology and coagulation function were also detected. From the 28th day postoperatively, the main symptoms, accompanied symptoms, tongue characteristics and pulse conditions of rats in PZ group conformed to the symptoms of coronary heart disease and Qi-deficiency and blood-stasis syndrome. Combined with related pathological results, the study revealed that Qi-deficiency and blood-stasis syndrome type coronary heart disease models could be successfully established by fatigue running exercise and high ligation of left anterior descending coronary artery for the rats. PMID- 28891622 TI - [Mechanism of Tongsaimai tablet for atherosclerosis based on network pharmacology]. AB - Network pharmacology method was adopted in this study to explore the active compounds and mechanism of Tongsaimai tablets for atherosclerosis. In molecular docking and molecular-target protein network analysis, 97 molecules in Tongsaimai tablets showed good interaction with the atherosclerosis-related target protein (docking score >= 7), and 37 molecules of them could act on more than 2 targets (>= 2) with higher betweenness, suggesting that these 37 molecules might be the main active compounds group in Tongsaimai tablets for atherosclerosis treatment. Furthermore, the predicted active compounds contained more flavonoids and saponins, reminding more attention should be paid on flavonoids and saponins in study of effective compounds and quality standards of Tongsaimai tablets. Targets network analysis showed that, the active compounds of Tongsaimai tablets could regulate inflammation, stabilize plaque, protect vascular endothelial cell, regulate blood lipid and inhibit blood coagulation through acting on the main 22 target proteins, such as Toll-like receptors (TLR1, TLR2), matrix metalloproteinase (MMP1, MMP2, MMP3, MMP9), angiotensin converting enzyme (ACE), leukotriene A4 hydrolase (LTA4-H), 5-lipoxidase (5-LOX), peroxisome proliferators activated receptors (PPARalpha, PPARgamma). These active compounds can participate in regulating different pathologic stages of atherosclerosis and thus treat atherosclerosis finally. This study revealed the main active compounds and possible mechanism of Tongsaimai tablets for treatment of atherosclerosis and meanwhile, verified the characteristics of multi-components, multi-targets and integral regulation for Tongsaimai tablets, providing theoretical references for the following systematic laboratory experiments on effective compounds and action mechanism of Tongsaimai Tablet. PMID- 28891623 TI - [Dosage-toxicity-efficacy relationship of Kansui Radix in malignant pleural effusion models based on Walker 256 analysis]. AB - To investigate the dosage-toxicity-efficacy relationship of Kansui Radix, explore its regularity of the toxicity and efficacy change, and provide scientific basis for its clinical rational application, the malignant pleural effusion models were used to observe the effect of Kansui Radix with larger dose range (0.045-1.620 g*kg*d-1 for Kansui Radix) on biochemical indexes and hydrothorax volume in experimental animals. Factor analysis method was also used to comprehensively assess the dosage-toxicity-efficacy relationship of Kansui Radix. The results showed that the rats in model group had larger hydrothorax volume, and ALT, AST, LDH, HBDH, IFN-gamma, IL-2 and TNF-alpha levels were significantly increased (P<0.05), while TP and ALB levels were decreased (P<0.05) as compared with the blank group. After drug administration, various treatment groups decreased hydrothorax volume, IFN-gamma, IL-2, TNF-alpha and increased TP and ALB levels as compared with model group, indicating certain therapeutic effect; and increased ALT, AST, LDH and HBDH levels, indicating certain liver and cardiac toxicity. In the factor analysis, two common factors were extracted from nine indexes, explaining 89.1% of the information. The analysis results suggested that there was no obvious toxicity in case of independent use of Kansui Radix within the dosage range set in pharmacopeia, while it would produce liver toxicity and cardiac toxicity upon 3 times of the dosage set in pharmacopeia, and the toxicity was increased with the increase of dose. At the same time, Kansui Radix can decrease the hydrothorax volume in malignant pleural effusion models and improve relevant physical indexes in a dose-dependent manner. Comprehensive analysis results of its toxic effect characteristics indicated that the upper-limit dose of Kansui Radix in pharmacopeia shall be regarded as the relatively optimal therapeutic dose. PMID- 28891624 TI - [Anti-radiation effect and mechanism studies of ethanol extracts from Spatholobus suberectus and its active component catechin]. AB - To study the anti-radiation effect and mechanism of ethanol extracts from Spatholobus suberectus and its active component catechin, ICR mice were exposed to 6Gy irradiation and randomly divided into normal group, model group, positive control group (amifostine, 43.6 mg*kg-1, iv 30 min before irradiation), SSD group (10, 20, 40 g*kg-1) and catechin group (50, 100, 200 mg*kg-1). The mice were administered the appropriate drugs once a day after irradiation for 28 consecutive days. Blood samples were collected from the tail end and the number of peripheral blood cells was counted before irradiation and on day 1, 3, 7, 14, 21 and 28 using a microcell counter. Changes of thymus and spleen index of mice on day 7 were observed. The serum SOD, GSH-Px activity and MDA level were detected by the colorimetric method. The colony forming ability of bone marrow hematopoietic progenitor cells on day 7 was detected by semi solid culture method. The HE staining was adopted to observe the pathological changes. The apoptosis of bone marrow cells was detected by flow cytometry. The expression of cleaved caspase-3 and Bax of bone marrow cells were measured separately by western-blotting and immunohistochemistry method. SSD and catechin can both significantly revert the irradiated-induced decline in hematological parameters (RBC, WBC, PLT, Hb), improve thymus and spleen index, significantly enhance serum SOD and GSH-Px activity and decrease the MDA level. The proliferation and differentiation of hematopoietic progenitor cells in bone marrow were promoted, the apoptosis of bone marrow cells was significantly up-regulated and the expression of cleaved caspase-3 and Bax was significantly reduced in SSD and catechin group. SSD and catechin have significant anti-radiation effect and its mechanism may be related to hematopoietic promoting, antioxidant and anti apoptotic effects. PMID- 28891625 TI - [Effect of Fuzheng Huayu capsule on serum metabolomics in rats with liver fibrosis induced by dimethylnitrosamine]. AB - To investigate the effect of Fuzheng Huayu capsule(FHC) on serum metabolomics in rats with liver fibrosis induced by dimethylnitrosamine(DMN). The metabolic profiles of rat serum of normal group, model group, and FHC group were established by liquid chromatography-mass spectrometry technology. Furthermore, the levels of endogenous metabolites such as amino acids and bile acids were measured in each group. The results showed that there were significant differences in the serum metabolic fingerprints between the FHC group and the model group. Moreover, 5 potential lysophosphatidylcholines biomarkers were identified by using principal component analysis(PCA) and partial least squares discriminant analysis (PLS-DA). Quantitative analysis of amino acids and bile acids in serum of rats showed that 14 kinds of amino acids and 5 kinds of bile acids returned to normal levels after four weeks of FHC treatment. In conclusion, the anti-hepatic fibrosis mechanisms of FHC may be related to the metabolic process of lysophosphatidylcholines, amino acids and bile acids. PMID- 28891626 TI - [Pharmacokinetics of magnolol and honokiol in Weichang'an pill]. AB - To conduct multiple-reaction monitoring(MRM) quantitative analysis with high performance liquid chromatography coupled with mass spectrometry method, establish the quantification method of magnolol and honokiol in blood sample under negative ion mode with ibuprofen as internal standard, investigate the pharmacokinetic process of lignans constituents after oral administration of Weichang'an pill(WCA) at different doses, and provide theoretical basis to further reveal the material basis of WCA's anti-diarrhea effect. In the plasma samples, the linear relationship was good over the concentration range of 5.25 to 1 344.00 MUg*L -1 for magnolol and 10.08 to 2 580.00 MUg*L -1 for honokiol. The results of precision, stability, and extraction recovery tests showed that the determination method of plasma concentration for such compositions was stable and reliable. Dose-dependence was shown for magnolol and honokiol in the plasma concentration-time profile. The results indicated that the time to reach the maximum plasma concentration(Tmax) for lignanoids was 0.55-1.42 h, when the maximum plasma concentration(Cmax) could reach 996.36-2 330.96,189.87-1 469.43 MUg*L -1 respectively for magnolol and honokiol. The lignanoids could be absorbed rapidly in the blood after oral administration of WAC pills, providing experimental basis to prove rapid and long-acting anti-diarrhea effect of WAC pills after oral administration. PMID- 28891627 TI - [In vitro metabolism of anti-tumor compound E7 in different species of liver microsomes]. AB - To investigate the metabolic stability of E7 in liver microsomes of human, Beagle dog, Cynomolgus monkey and SD rats, and compare the metabolic differences between different species. Selective chemical inhibitors were used to determine the effects of different inhibitors on E7 metabolic rate, and predict the main enzymes involved in E7 metabolism in rat liver microsomes. The experimental results showed that the in vitro half-lives (T1/2) of E7 in liver microsomes of human, dog, monkey and rats were 57.75, 69.30, 16.90,30.13 min respectively. Their intrinsic clearance rate was 0.004 8, 0.004 0, 0.016 4 and 0.009 2 mL*min 1*mg-1 respectively. Hence, it could be speculated that the metabolic rate of E7 was similarly slow in human and dog liver microsomes; while it was similarly fast in monkey and rat liver microsomes. There was significant difference in metabolic rate of E7 between different species. The results showed that CYP2E1, CYP2A6, CYP1A2 and CYP2D6 might participate in metabolism of E7, while the contribution of polymorphic CYP3A4 was small. PMID- 28891628 TI - [Systematic review on safety of Xinyuan capsules]. AB - To systematically review the adverse drug reactions/adverse events(ADRs/AEs) of Xinyuan capsules in clinical application. A systematic literature search was performed in the databases of the Cochrane Library, Medline, EMBASE, the Web of Science, Clinical trials, CNKI, VIP, WanFang Data and CBM. The literature was screened and data was extracted according to the inclusion and exclusion criteria. Because of the substantial heterogeneity among different studies, we assessed them only with descriptive analysis by study type, disease diagnosis, and ADRs/AEs conditions. All included studies were assessed by using the internationally recognized report quality evaluation standard or methodological quality assessment tools. A total of 42 studies involving 3 671 patients were included finally. Two thouand four hundred and thirty-mine patients of them took Xinyuan capsules, and 1 242 patients did not take Xinyuan capsules. No serious ADRs occurred in all patients. One patient died as AE during the research. Sixteen patients of the 2 439 patients taking Xinyuan capsules (alone or in combination) had ADRs, including 7 patients with polytherapy of Xinyuan capsules and 9 patients with monotherapy. The most common ADRs were in gastrointestinal tract, mainly including thirst, nausea, vomiting and abdominal pain, etc. The ADRs included 10 gastrointestinal tract ADRs, 3 renal ADRs and 1 ADR respective in skin system, respiratory system and cardiovascular system. Xinyuan capsules was generally safe in clinical application. The reports on the study of Xinyuan capsules were dispersed in various clinical studies, the study on drug safety still should be strengthened in the future. Further mechanism studies or clinical observation studies of the drug safety shall be conducted to better guide clinical application in the future. PMID- 28891629 TI - [Medicinal laws and application examples of traditional Chinese medicine prescriptions for multiple aorto-arteritis]. AB - To collect the literature on traditional Chinese medicine treatment for multiple aorto-arteritis from China National Knowledge Infrastructure(CNKI), establish prescriptions database after screening and normalizing the prescriptions reported in these literature, and analyze their medicinal rules by using traditional Chinese medicine inheritance support system. A total of 126 prescriptions for multiple aorto-arteritis were screened, containing 212 kinds of Chinese herbs. 26 core herb combinations were obtained by analysis of the commonly used herbs and their use frequencies. The treatment for multiple aorto-arteritis was manly of tonifying qi to nourish blood, promoting blood circulation to remove blood stasis, warming yang to dredge collaterals, and four new prescriptions were obtained. On this basis, two clinical cases were taken as the examples by analyzing the medicinal rules and the features of multiple aorto-arteritis. The first case showed that the herb combination of this study conformed to the basic core drug application mode and the core pathogenesis of multiple aorto-arteritis. The second case reflected the characteristics of the new prescriptions' herb combinations based on entropy hierarchical clustering. The practical analysis of the two clinical cases further indicated the reliability of the results. This study has certain guiding significance and reference value on new medicine research and development as well as clinical traditional Chinese medicine treatment for multiple aorto-arteritis. PMID- 28891630 TI - [National physician master Jin Shiyuan's dispensing technology of Rehmanniae Radix Praeparata based on Li Shizhen's pharmaceutical academic thought]. AB - To collect the historical origin, processing methods and clinical application of Rehmanniae Radix Preparata in Compendium of Materia Medica, compare and analyze the theoretical knowledge and relevant practical operation of national physician master Jin Shiyuan, which is beneficial for the inheritance and development of Rehmanniae Radix Preparata's clinical dispensing technology. In the analysis process, CNKI was searched with "Rehmanniae Radix Preparata", "Processing method", "Clinical application" "Li Shizhen", "Jin Shiyuan", and "Dispensing technology" as keywords. In addition, Shennong's Herbal Classic, Bencao Tujing (illustrated Classics of Materia Medica), Compendium of Materia Medica, Jingyue Quanshu (Jingyue's Complete Works) and related ancient books were accessed systematically to summarize the historical change of processing methods and efficacy of Rehmanniae Radix Praeparata. Professor Jin Shiyuan emphasizes the clinical dispensing technology of Rehmanniae Radix Praeparata, including its nature identification technology, clinical processing technology, prescription audit technology, prescription coping technology, drug delivery technology, clinical decocting technology, purchasing management technology as well as storage, maintenance and supply technology. Through the collation and research, it was confirmed that historical origin, processing methods and clinical application of Rehmanniae Radix Preparata were recorded in details in Compendium of Materia Medica. Steaming method of Rehmanniae Radix Preparata was originated from Synopsis of Golden Chamber. Li Shizhen attached great importance to the processing method of "steaming and drying alternatively for nine times" for Rehmanniae Radix Preparata, and differentiated it from Radix Rehmanniae Recen and fresh rehmannia root in clinical applications. Professor Jin Shiyuan has developed and improved the clinical dispensing technology of Rehmanniae Radix Praeparata, and carried forward the essence of Li Shizhen's pharmaceutical academic thought with his own proficient knowledge structure in medicine, providing scientific pharmaceutical service for clinical application of Rehmanniae Radix Preparata in future. PMID- 28891631 TI - Design and Fabrication of an All-Solid-State Polymer Supercapacitor with Highly Mechanical Flexibility Based on Polypyrrole Hydrogel. AB - A conducting polymer-based hydrogel (PPy/CPH) with a polypyrrole-poly(vinyl alcohol) interpenetrating network was prepared by utilization of a chemical cross linked poly(vinyl alcohol)-H2SO4 hydrogel (CPH) film as flexible substrate followed by vapor-phase polymerization of pyrrole. Then an all-solid-state polymer supercapacitor (ASSPS) was fabricated by sandwiching the CPH film between two pieces of the PPy/CPH film. The ASSPS is mechanically robust and flexible with a tensile strength of 20.83 MPa and a break elongation of 377% which is superior to other flexible conducting polymer hydrogel-based supercapacitors owing to the strong hydrogen bonding interactions among the layers and the high mechanical properties of the PPy/CPH. It exhibits maximum volumetric specific capacitance of 13.06 F/cm3 and energy density of 1160.9 MUWh/cm3. The specific capacitance maintains 97.9% and 86.3% of its initial value after 10 000 folding cycles and 10 000 charge-discharge cycles, respectively. The remarkable electrochemical and mechanical performance indicates this novel ASSPS device is promising for flexible electronics. PMID- 28891632 TI - Design of Boron Nitride/Gelatin Electrospun Nanofibers for Bone Tissue Engineering. AB - Gelatin is a biodegradable biopolymer obtained by collagen denaturation, which shows poor mechanical properties. Hence, improving its mechanical properties is very essential toward the fabrication of efficient nontoxic material for biomedical applications. For this aim, various methods are employed using external fillers such as ceramics or bioglass. In this report, we introduce boron nitride (BN)-reinforced gelatin as a new class of two-dimensional biocompatible nanomaterials. The effect of the nanofiller on the mechanical behavior is analyzed. BN is efficiently exfoliated using the biopolymer gelatin as shown through Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD). The exfoliated BN reinforces gelatin electrospun fibers, which results in an increase in the Young's modulus. The Electrospun Mats (ESM) are stable after the glutaraldehyde cross-linking, and the fibrous morphology is preserved. The cross-linked gelatin/BN ESM is highly bioactive in forming bonelike hydroxyapatite as shown by scanning electron microscopy. Due to their enhanced mineralization ability, the cross-linked ESM have been tested on human bone cells (HOS osteosarcoma cell line). The cell attachment, proliferation, and biocompatibility results show that the ESM are nontoxic and biodegradable. The analysis of osteoblast gene expression and the measurement of alkaline phosphatase activity confirm that these materials are suitable for bone tissue engineering. PMID- 28891633 TI - High Strength Astringent Hydrogels Using Protein as the Building Block for Physically Cross-linked Multi-Network. AB - Integrating proteins into a hydrogel network enables its good bioactivity as an ECM environment in biorelative applications. Although extensive studies on preparing protein hydrogels have been carried out, the reported systems commonly present very low mechanical strength and weak water-rentention capacity. Learning from the astringent mouthfeel, we report here a protein engineered multinetwork physical hydrogel as TA-PVA/BSA. In a typical case, the BSA protein-integrated poly(vinyl alcohol) (PVA) solution is treated by the freeze-thaw method and forms the first hydrogel network, and tannic acid (TA) then cross-links with BSA proteins and PVA chains to form the secondary hydrogel network based on the noncovalent interaction (hydrogen bond and hydrophobic interaction). The as prepared TA-PVA/BSA composite hydrogel is a pure physically cross-linking network and possesses ultrahigh tensile strength up to ~9.5 MPa but is adjustable, relying on the concentration of TA and BSA. Moreover, its mechanical strength is further improved by prestretching induced anisotropy of mechanical performance. Because of its controllable and layered structure as skin, the composite hydrogel presents good water-retention capacity compared to traditional high strength hydrogels. This work demonstrates a novel method to design high mechanical strength but layered physical cross-linking hydrogels and enables us to realize their biorelative applications. PMID- 28891634 TI - Photochemical Anti-Fouling Approach for Electrochemical Pollutant Degradation on Facet-Tailored TiO2 Single Crystals. AB - Electrochemical degradation of refractory pollutants at low bias before oxygen evolution exhibits high current efficiency and low energy consumption, but its severe electrode fouling largely limits practical applications. In this work, a new antifouling strategy was developed and validated for electrochemical pollutant degradation by photochemical oxidation on facet-tailored {001}-exposed TiO2 single crystals. Electrode fouling from anodic polymers at a low bias was greatly relieved by the free .OH-mediated photocatalysis under UV irradiation, thus efficient and stable degradation of bisphenol A, a typical environmental endocrine disrupter, and treatment of landfill leachate were accomplished without remarkable oxygen evolution in synergistic photoassisted electrochemical system. Electrochemical and spectroscopic measurements indicated a clean electrode surface during cyclic pollutant degradation. Such a photochemical antifouling strategy for low-bias anodic pollutants degradation was mainly attributed to the improved electric conductivity and excellent electrochemical and photochemical activities of tailored TiO2 anodic material, whose unique properties originated from the favorable surface atomic and electronic structures of high-energy {001} polar facet and single-crystalline structure. Our work opens up a brand new approach to develop catalytic systems for efficient degradation of refractory contaminants in water and wastewater. PMID- 28891635 TI - The Combination of Superhalogens and Bronsted Acids HX (X = F, Cl, Br): An Effective Strategy for Designing Strong Superacids. AB - A series of 27 composite structures, consisting of superhalogen and Bronsted acid, is designed and systematically studied based on combined ab initio and DFT calculations focusing on their potentials as novel superacids. As indicated by high-level CCSD(T) results, all the composites here fulfill the theoretical criterion for superacid and the acidities of two of them are close to the strongest superacid ever reported. The influences of various factors on the superacid properties of these composites were analyzed in detail. Our results demonstrate that the acidity of these superacids is mainly determined by the superhalogen components while the effect of Bronsted acids, irrespective of their number or type, is relatively mild. Therefore, it is probable to design novel composite superacid with enhanced property through the regulation of the superhalogen component. It is encouraging that MP2 and DFT could also provide reliable results when compared with the high-level CCSD(T) method. The reliability of these low-cost methods implies the capability of theoretical calculations for future composite superacid of enlarged size, and thus it is highly probable that an effective guide to the related experimental research could be provided by the theory. PMID- 28891636 TI - CuAAC-Based Click Chemistry in Self-Healing Polymers. AB - Click chemistry has emerged as a significant tool for materials science, organic chemistry, and bioscience. Based on the initial concept of Barry Sharpless in 2001, the copper(I)-catalyzed azide/alkyne cycloaddition (CuAAC) reaction has triggered a plethora of chemical concepts for linking molecules and building blocks under ambient conditions, forming the basis for applications in autonomous cross-linking materials. Self-healing systems on the other hand are often based on mild cross-linking chemistries that are able to react either autonomously or upon an external trigger. In the ideal case, self-healing takes place efficiently at low temperatures, independent of the substrate(s) used, by forming strong and stable networks, binding to the newly generated (cracked) interfaces to restore the original material properties. The use of the CuAAC in self-healing systems, most of all the careful design of copper-based catalysts linked to additives as well as the chemical diversity of substrates, has led to an enormous potential of applications of this singular reaction. The implementation of click-based strategies in self-healing systems therefore is highly attractive, as here chemical (and physical) concepts of molecular reactivity, molecular design, and even metal catalysis are connected to aspects of materials science. In this Account, we will show how CuAAC reactions of multivalent components can be used as a tool for self-healing materials, achieving cross-linking at low temperatures (exploiting concepts of autocatalysis or internal chelation within the bulk CuAAC and systematic optimization of the efficiency of the used Cu(I) catalysts). Encapsulation strategies to separate the click components by micro- and nanoencapsulation are required in this context. Consequently, the examples reported here describe chemical concepts to realize more efficient and faster click reactions in self-healing polymeric materials. Thus, enhanced chain diffusion in (hyper)branched polymers, autocatalysis, or internal chelation concepts enable efficient click cross-linking already at 5 degrees C with a simultaneously reduced amount of Cu(I) catalyst and increased reaction rates, culminating in the first reported self-healing system based on click cycloaddition reactions. Via tailor-made nanocarbon/Cu(I) catalysts we can further improve the click cross-linking reaction in view of efficiency and kinetics, leading to the generation of self-healing graphene-based epoxy nanocomposites. Additionally, we have designed special CuAAC click methods for chemical reporting and visualization systems based on the detection of ruptured capsules via a fluorogenic click reaction, which can be combined with CuAAC cross linking reactions to obtain simultaneous stress detection and self-healing within polymeric materials. In a similar concept, we have prepared polymeric Cu(I) biscarbene complexes to detect (mechanical) stress within self-healing polymeric materials via a triggered fluorogenic reaction, thus using a destructive force for a constructive chemical response. PMID- 28891637 TI - Bioconjugation Approaches to Producing Subunit Vaccines Composed of Protein or Peptide Antigens and Covalently Attached Toll-Like Receptor Ligands. AB - Traditional vaccines derived from attenuated or inactivated pathogens are effective at inducing antibody-based protective immune responses but tend to be highly reactogenic, causing notable adverse effects. Vaccines with superior safety profiles can be produced by subunit approaches, utilizing molecularly defined antigens (e.g., proteins and polysaccharides). These antigens, however, often elicit poor immunological responses, necessitating the use of adjuvants. Immunostimulatory adjuvants have the capacity to activate antigen presenting cells directly through specific receptors (e.g., Toll-like receptors (TLRs)), resulting in enhanced presentation of antigens as well as the secretion of proinflammatory chemokines and cytokines. Consequently, innate immune responses are amplified and adaptive immunity is generated. Recently, site-specific conjugation of such immunostimulatory adjuvants (e.g., TLR ligands) onto defined antigens has shown superior efficacy over unconjugated mixtures, suggesting that the development of chemically characterized immunostimulatory adjuvants and optimized approaches for their conjugation with antigens may provide a better opportunity for the development of potent, novel vaccines. This review briefly summarizes various TLR agonists utilized as immunostimulatory adjuvants and focuses on the development of techniques (e.g., recombinant, synthetic, and semisynthetic) for generating adjuvant-antigen fusion vaccines incorporating peptide or protein antigens. PMID- 28891638 TI - Photochemistry of Hydrochar: Reactive Oxygen Species Generation and Sulfadimidine Degradation. AB - Biochar, mainly including pyrochar produced via pyrolysis of biomass at moderate temperatures of 350-700 degrees C and hydrochar formed by hydrothermal carbonization in a range of 150-350 degrees C, has received increasing attention because of its significant environmental impacts. It is known that pyrochar can generate reactive oxygen species even in the dark owing to the presence of persistent free radicals, but hydrochar is far less studied. In this study, we systematically investigate the photochemistry of hydrochar and check its effects on the sulfadimidine degradation. Different from pyrochar derived from the same biomass, hydrochar could generate much more H2O2 and *OH under daylight irradiation, which could enhance the sulfadimidine degradation rate six times more than that found in the dark. Raman spectroscopy, Fourier transform infrared spectroscopy, electron paramagnetic resonance, and X-ray photoelectron spectroscopy were employed to elucidate this interesting phenomenon. Characterization results revealed that the higher reactive oxygen species generation ability of hydrochar under solar light irradiation was attributed to its abundant photoactive surface oxygenated functional groups. This study clarifies the differences of pyrochar and hydrochar on organic pollutant degradation, and also sheds light on environmental effects of hydrochar. PMID- 28891640 TI - A-Site Ordered Double Perovskite CaMnTi2O6 as a Multifunctional Piezoelectric and Ferroelectric-Photovoltaic Material. AB - The double perovskite CaMnTi2O6, is a rare A-site ordered perovskite oxide that exhibits a sizable ferroelectric polarization and relatively high Curie temperature. Using first-principles calculations combined with detailed symmetry analyses, we identify the origin of the ferroelectricity in CaMnTi2O6. We further explore the material properties of CaMnTi2O6, including its ferroelectric polarization, dielectric and piezoelectric responses, magnetic order, electronic structure, and optical absorption coefficient. It is found that CaMnTi2O6 exhibits room-temperature-stable ferroelectricity and moderate piezoelectric responses. Moreover, CaMnTi2O6 is predicted to have a semiconducting energy band gap similar to that of BiFeO3, and its band gap can further be tuned via distortions of the planar Mn-O bond lengths. CaMnTi2O6 exemplifies a new class of single-phase semiconducting ferroelectric perovskites for potential applications in ferroelectric photovoltaic solar cells. PMID- 28891639 TI - Three Principles of Diversity-Generating Biosynthesis. AB - Natural products are significant therapeutic agents and valuable drug leads. This is likely owing to their three-dimensional structural complexity, which enables them to form complex interactions with biological targets. Enzymes from natural product biosynthetic pathways show great potential to generate natural product like compounds and libraries. Many challenges still remain in biosynthesis, such as how to rationally synthesize small molecules with novel structures and how to generate maximum chemical diversity. In this Account, we describe recent advances from our laboratory in the synthesis of natural product-like libraries using natural biosynthetic machinery. Our work has focused on the pat and tru biosynthetic pathways to patellamides, trunkamide, and related compounds from cyanobacterial symbionts in marine tunicates. These belong to the cyanobactin class of natural products, which are part of the larger group of ribosomally synthesized and post-translationally modified peptides (RiPPs). These results have enabled the synthesis of rationally designed small molecules and libraries covering more than 1 million estimated derivatives. Because the RiPPs are translated on the ribosome and then enzymatically modified, they are highly compatible with recombinant technologies. This is important because it means that the resulting natural products, their derivatives, and wholly new compounds can be synthesized using the tools of genetic engineering. The RiPPs also represent possibly the most widespread group of bioactive natural products, although this is in part because of the broad definition of what constitutes a RiPP. In addition, the underlying ideas may form the basis for broad-substrate biosynthetic pathways beyond the RiPPs. For example, some of the ideas about kinetic ordering of broad substrate pathways may apply to polyketide or nonribosomal peptide biosynthesis as well. While making these products, we have sought to understand what makes biosynthetic pathways plastic and whether there are any rules that might generally apply to plastic biosynthetic pathways. We present three principles of diversity-generating biosynthesis: (1) substrate evolution, in which the substrates change while enzymes remain constant; (2) pairing of recognition sequences on substrates with biosynthetic enzymes; (3) an inverse metabolic flux in comparison to canonical pathways. If these principles are general, they may enable the design of unimagined derivatives using biosynthetic engineering. For example, it is possible to discover substrate evolution directly by examining sequencing data. By shuffling appropriate recognition sequences and biosynthetic enzymes, it has already been possible to make new hybrid products of multiple pathways. While cases so far have been limited, if this is more general, designed synthesis will become routine. Finally, biosynthesis of natural products is regulated in elaborate ways that are just beginning to be understood. If the inverse metabolic flux model is widespread, it potentially informs on what the timing and relative production level of each enzyme in a designer pathway should be in order to optimize the synthesis of new compounds in vivo. PMID- 28891641 TI - Toward High Conductivity of Electrospun Indium Tin Oxide Nanofibers with Fiber Morphology Dependent Surface Coverage: Postannealing and Polymer Ratio Effects. AB - High electrical conductivity of metal oxide thin films needs uniform surface coverage, which has been the issue for the thin films based on electrospun nanofibers (NFs) that have advantage over the sputtered/spin-coated films with respect to large surface area and mechanical flexibility. Herein, we investigated a reduction in the sheet resistance of electrospun indium tin oxide (ITO) NF films with improved surface coverage. We found that the surface coverage depends significantly on the electrospinnable polymer concentration in the precursor solutions, especially after post-hot-plate annealing following the infrared radiation furnace treatment. The postannealing process increases crystallinity and oxygen vacancies. However, with a higher PVP content, it makes the surface of ITO NFs more prominently rough as a result of the formation of larger sphere shaped ITO particles on the NF surface, which gives rise to poor surface coverage. A less poly(vinylpyrrolidone) (PVP) content in ITO NF films by electrospinning for short deposition times was found to improve surface coverage even after postannealing. The sheet resistance notably decreases, down to as low as 350 Omega/sq, with a high transmittance of over 90%. Our study provides an understanding on how to achieve high electrical conductivity of ITO NF films with high surface coverage, which can be utilized for the optoelectronic and sensing applications. PMID- 28891643 TI - MOF-Bacteriophage Biosensor for Highly Sensitive and Specific Detection of Staphylococcus aureus. AB - To produce a sensitive and specific biosensor for Staphylococcus aureus, bacteriophages have been interfaced with a water-dispersible and environmentally stable metal-organic framework (MOF), NH2-MIL-53(Fe). The conjugation of the MOF with bacteriophages has been achieved through the use of glutaraldehyde as cross linker. Highly sensitive detection of S. aureus in both synthetic and real samples was realized by the proposed MOF-bacteriophage biosensor based on the photoluminescence quenching phenomena: limit of detection (31 CFU/mL) and range of detection (40 to 4 * 108 CFU/mL). This is the first report exploiting the use of an MOF-bacteriophage complex for the biosensing of S. aureus. The results of our study highlight that the proposed biosensor is more sensitive than most of the previous methods while exhibiting some advanced features like specificity, regenerability, extended range of linear detection, and stability for long-term storage (even at room temperature). PMID- 28891642 TI - Supramolecular Host-Guest System as Ratiometric Fe3+ Ion Sensor Based on Water Soluble Pillar[5]arene. AB - Developing a specific, ratiometric, and reversible detection method for metal ions is significant to guard against the threat of metal-caused environmental pollution and organisms poisoning. Here a supramolecular host-guest system (WP5?G) based on water-soluble pillar[5]arene (WP5) and water-soluble quaternized perylene diimide derivative (G) was constructed. Morphological transformation was achieved during the process of adding WP5 into G aqueous solution, and a fluorescence "turn-off" phenomenon was observed which was caused by supramolecular photoinduced electron transfer (PET). Meanwhile, hydrophobic effect and electrostatic interaction played important roles in this supramolecular process, which was confirmed by isothermal titration calorimeter (ITC) and zeta potential experiments. Furthermore, the supramolecular host-guest system could be a "turn-on" fluorescent probe for Fe3+ ion detection through the process of interdicting supramolecular PET. Moreover, the Fe3+ ion detection showed specific, ratiometric, and reversible performances with a detection limit of 2.13 * 10-7 M, which might have great potentials in biological and environmental monitoring. PMID- 28891644 TI - Comment on Vapor Pressure Isotope Effects in Halogenated Organic Compounds and Alcohols Dissolved in Water. PMID- 28891645 TI - SET-LRP in the Neoteric Ethyl Lactate Alcohol. AB - Ethyl lactate (EtLa), a green and safe agrochemical solvent, is gifted with some properties that make it a good candidate for SET-LRP. It dissolves CuBr2, mediates an efficient disproportionation of CuBr in the presence of tris(2 (dimethylamino)ethyl)amine (Me6-TREN), and is capable to dissolve both aqueous (polar) and hydrocarbon (nonpolar) soluble monomers and polymers. Here, we report that EtLa is an excellent solvent for the Cu(0) wire-catalyzed SET-LRP to produce both hydrophilic and hydrophobic polyacrylates that exhibit precise chain end functionality. These results will expand the table of SET-LRP solvents with a new green member of biological origin that is also biodegradable and, therefore, are expected to contribute to continue expanding the use of SET-LRP in the field of biomacromolecules, bioconjugates, and other biology and medicine related disciplines. PMID- 28891647 TI - Correction to "Lipid Spontaneous Curvatures Estimated from Temperature-Dependent Changes in Inverse Hexagonal Phase Lattice Parameters: Effects of Metal Cations". PMID- 28891646 TI - Synergic "Click" Boronate/Thiosemicarbazone System for Fast and Irreversible Bioorthogonal Conjugation in Live Cells. AB - Fast, high-yielding, and selective bioorthogonal "click" reactions employing nontoxic reagents are in high demand for their great utility in the conjugation of biomolecules in live cells. Although a number of click reactions were developed for this purpose, many are associated with drawbacks and limitations that justify the development of alternative systems for both single- or dual labeling applications. Recent reports have highlighted the potential of boronic ester formation as a bioorthogonal click reaction between abiotic boronic acids and diols. Boronic ester formation is a fast dehydrative process; however it is intrinsically reversible in aqueous medium. We designed and optimized a synergic system based on two bifunctional reagents, a thiosemicarbazide-functionalized nopoldiol and an ortho-acetyl arylboronic acid. Both reagents were shown to be chemically stable and nontoxic to HEK293T cells at concentrations as high as 50 MUM. The resulting boronate/thiosemicarbazone adduct is a medium-sized ring that forms rapidly and irreversibly without any catalyst at low MUM concentrations, in neutral buffer, with a rate constant of 9 M-1 s-1 as measured by NMR spectroscopy. Control experiments in the presence of competing boronic acids showed no crossover side-products and confirmed the stability and lack of reversibility of the boronate/thiosemicarbazone conjugates. Formation of the conjugates is not affected by the presence of biological diols such as fructose, glucose, and catechol, and the thiosemicarbazide-functionalized nopoldiol is inert to aldehyde electrophiles of the sort found on protein-bound glyoxylyl units. The suitability of this system in the cell-surface labeling of live cells was demonstrated using a SNAP-tag approach to install the boronic acid reagent onto the extracellular domain of the Beta-2 adrenergic receptor in HEK293T cells, followed by incubation with the optimal thiosemicarbazide-functionalized nopoldiol reagent labeled with fluorescein dye. Successful visualization by fluorescence microscopy was possible with a reagent concentration as low as 10 MUM, thus confirming the potential of this system in biological applications. PMID- 28891648 TI - NAOMInova: Interactive Geometric Analysis of Noncovalent Interactions in Macromolecular Structures. AB - Noncovalent interactions play an important role in macromolecular complexes. The assessment of molecular interactions is often based on knowledge derived from statistics on structural data. Within the last years, the available data in the Brookhaven Protein Data Bank has increased dramatically, quantitatively as well as qualitatively. This development allows the derivation of enhanced interaction models and motivates new ways of data analysis. Here, we present a method to facilitate the analysis of noncovalent interactions enabling detailed insights into the nature of molecular interactions. The method is integrated into a highly variable framework enabling the adaption to user-specific requirements. NAOMInova, the user interface for our method, allows the generation of specific statistics with respect to the chemical environment of substructures. The substructures as well as the analyzed set of protein structures can be chosen arbitrarily. Although NAOMInova was primarily made for data exploration in protein-ligand crystal structures, it can be used in combination with any structure collection, for example, analysis of a carbonyl in the neighborhood of an aromatic ring on a set of structures resulting from a MD simulation. Additionally, a filter for different atom attributes can be applied including the experimental support by electron density for single atoms. In this publication, we present the underlying algorithmic techniques of our method and show application examples that demonstrate NAOMInova's ability to support individual analysis of noncovalent interactions in protein structures. NAOMInova is available at http://www.zbh.uni-hamburg.de/naominova . PMID- 28891649 TI - Polarized Supramolecular Aggregates Based on Luminescent Perhalogenated Gold Derivatives. AB - The reaction of [Au(C6F5)(tht)] (tht = tetrahydrothiophene) with 1,3,5-triaza-7 phosphaadamantane (PTA) and 3,7-diacetyl-1,3,7-triaza-5 phosphabicyclo[3.3.1]nonane (DAPTA) leads to the formation of [Au(C6F5)(phosph)] (phosph = PTA, 1; phosph = DAPTA, 2). The compounds are slightly soluble in water and aggregate at higher concentrations, giving rise to the formation of needle- and rodlike structures (1) and well-organized spherical aggregates (2). Compounds 1 and 2 were reacted with AgPF6, giving rise to the formation in all cases of luminescent water-soluble 1:1 Au...Ag heterometallic complexes, as evidenced by X ray crystal structure determination. The use of different silver salts that differ on the counterion induces changes in the resulting luminescence and aggregation morphology. PMID- 28891650 TI - Asiaticoside Mitigates the Allergic Inflammation by Abrogating the Degranulation of Mast Cells. AB - The effects of asiaticoside (AS) on allergic responses mediated by mast cells were investigated. AS showed no obvious cytotoxicity on RPMCs (rat peritoneal mast cells). AS reduced the intracellular calcium in RPMCs and deprived the histamine release and degranulation. AS also decreased the generation of antigen induced tumor necrosis factor alpha, interleukin (IL)-4, IL-8, and IL-1beta in RBL-2H3 cells sensitized by IgE. The suppression of AS on pro-inflammatory cytokines was related with the activation of the intracellular FcepsilonRI and the inhibition of the nuclear factor-kappaB signaling pathway. In addition, AS disabled the phosphorylation of antigen-induced Syk, Lyn, Gab2, and PLCgamma1, thus suppressing the downstream Akt phosphorylation and MAPKs pathways. It also increased HO-1 and Nrf2 expression time dependently. In summary, we demonstrate that AS suppresses the allergic inflammation mediated by mast cells and this effect might be mediated by FcepsilonRI-dependent signaling pathways. PMID- 28891652 TI - Iterative Design of a Biomimetic Catalyst for Amino Acid Thioester Condensation. AB - Herein, the design of a catalyst that combines lessons learned from peptide biosynthesis, enzymes, and organocatalysts is described. The catalyst features a urea scaffold for carbonyl recognition and elements of nucleophilic catalysis. In the presence of 10 mol % of the organocatalyst, the rate of peptide bond formation is accelerated by 10000-fold over the uncatalyzed reaction between Fmoc amino acid thioesters and amino acid methyl esters. PMID- 28891651 TI - Two-Step, One-Pot Synthesis of Visible-Light-Responsive 6-Azopurines. AB - The first general two-step, one-pot synthetic route to 6-azopurines is presented. Microwave-assisted nucleophilic aromatic substitution of protected 6 chloropurines with hydrazines or hydrazides, followed by metal-free oxidation with oxygen, gives 6-azopurines in high to excellent yields. Photophysical studies revealed intensive n-pi* absorption band that makes trans-to-cis photoswitching possible using visible light (lambda = 530 nm). PMID- 28891653 TI - The Molecular Origin of Anisotropic Emission in an Organic Light-Emitting Diode. AB - Atomistic nonequilibrium molecular dynamics simulations have been used to model the induction of molecular orientation anisotropy within the emission layer of an organic light-emitting diode (OLED) formed by vapor deposition. Two emitter species were compared: racemic fac-tris(2-phenylpyridine)iridium(III) (Ir(ppy)3) and trans-bis(2-phenylpyridine)(acetylacetonate)iridium(III) (Ir(ppy)2(acac)). The simulations show that the molecular symmetry axes of both emitters preferentially align perpendicular to the surface during deposition. The molecular arrangement formed on deposition combined with consideration of the transition dipole moments provides insight into experimental reports that Ir(ppy)3 shows isotropic emission, while Ir(ppy)2(acac) displays improved efficiency due to an apparent preferential alignment of the transition dipole vectors parallel to the substrate. The simulations indicate that this difference is not due to differences in the extent of emitter alignment, but rather differences in the direction of the transition dipoles within the two complexes. PMID- 28891654 TI - From Simple to Complex: Rhodium(III)-Catalyzed C-C Bond Cleavage and C-H Bond Functionalization for the Synthesis of 3a,8b-Dihydro-1H-cyclopenta[b]benzofuran-1 ones. AB - A rhodium(III)-catalyzed strategy for the one-step synthesis of polysubstituted cis-3a,8b-dihydro-1H-cyclopenta[b]benzofuran-1-ones from simple 2' hydroxychalcones and alkynes is developed. This novel transformation involves a sequential C-C bond cleavage and dehydrogenative annulation, leading to the product bearing a quaternary and a tertiary carbon center. 13C labeling experiments revealed that C-C bond cleavage takes place not only at the C-C(C?O) bond but also at the C=C bond. This study provides an alternative strategy using C-C bond cleavage thus demonstrating the power of this strategy combined with C-H bond functionalization for assembling complex structures from simple starting materials. PMID- 28891655 TI - Longitudinal intra-individual variability in neuropsychological performance relates to white matter changes in HIV. AB - OBJECTIVES: Recent studies suggest that intraindividual variability (IIV) of neuropsychological performance may be sensitive to HIV-associated neurologic compromise. IIV may be particularly dependent upon the integrity of frontal subcortical systems, and therefore may be a meaningful phenotype in HIV. We examined the relationship between change in IIV and white matter integrity among HIV seropositive (HIV+) and HIV seronegative (HIV-) individuals. METHOD: The sample consisted of 38 HIV+ participants and 26 HIV- control participants who underwent neuroimaging and a neuropsychological evaluation at baseline and at 2 year follow-up evaluation. RESULTS: Among HIV+ participants, increases in IIV (greater dispersion) were related to lower fractional anisotropy (FA) values in the anterior thalamic radiations (ATR) and the superior longitudinal fasciculus (SLF). Changes in mean-level global cognitive functioning were not significantly related to white matter integrity. Additionally, there was a significant Group * IIV interaction effect in the SLF demonstrating that the relationship between IIV and white matter integrity was specific to HIV. CONCLUSIONS: Overall, findings suggest that IIV may be more sensitive, relative to mean-level global cognitive functioning, in the detection of neurologic compromise among HIV+ individuals. (PsycINFO Database Record PMID- 28891656 TI - Implied reading direction and prioritization of letter encoding. AB - Capacity limits hinder processing of multiple stimuli, contributing to poorer performance for identifying two briefly presented letters than for identifying a single letter. Higher accuracy is typically found for identifying the letter on the left, which has been attributed to a right-hemisphere dominance for selective attention. Here, we use rapid serial visual presentation (RSVP) of letters in two locations at once. The letters to be identified are simultaneous and cued by rings. In the first experiment, we manipulated implied reading direction by rotating or mirror-reversing the letters to face to the left rather than to the right. The left-side performance advantage was eliminated. In the second experiment, letters were positioned above and below fixation, oriented such that they appeared to face downward (90 degrees clockwise rotation) or upward (90 degrees counterclockwise rotation). Again consistent with an effect of implied reading direction, performance was better for the top position in the downward condition, but not in the upward condition. In both experiments, mixture modeling of participants' report errors revealed that attentional sampling from the two locations was approximately simultaneous, ruling out the theory that the letter on one side was processed first, followed by a shift of attention to sample the other letter. Thus, the orientation of the letters apparently controls not when the letters are sampled from the scene, but rather the dynamics of a subsequent process, such as tokenization or memory consolidation. Implied reading direction appears to determine the letter prioritized at a high-level processing bottleneck. (PsycINFO Database Record PMID- 28891657 TI - The role of a "common is moral" heuristic in the stability and change of moral norms. AB - Moral norms are fundamental for virtually all social interactions, including cooperation. Moral norms develop and change, but the mechanisms underlying when, and how, such changes occur are not well-described by theories of moral psychology. We tested, and confirmed, the hypothesis that the commonness of an observed behavior consistently influences its moral status, which we refer to as the common is moral (CIM) heuristic. In 9 experiments, we used an experimental model of dynamic social interaction that manipulated the commonness of altruistic and selfish behaviors to examine the change of peoples' moral judgments. We found that both altruistic and selfish behaviors were judged as more moral, and less deserving of punishment, when common than when rare, which could be explained by a classical formal model (social impact theory) of behavioral conformity. Furthermore, judgments of common versus rare behaviors were faster, indicating that they were computationally more efficient. Finally, we used agent-based computer simulations to investigate the endogenous population dynamics predicted to emerge if individuals use the CIM heuristic, and found that the CIM heuristic is sufficient for producing 2 hallmarks of real moral norms; stability and sudden changes. Our results demonstrate that commonness shapes our moral psychology through mechanisms similar to behavioral conformity with wide implications for understanding the stability and change of moral norms. (PsycINFO Database Record PMID- 28891658 TI - The digital mental health revolution: Opportunities and risks. AB - This editorial introduces the special issue on digital mental health. The promise of digital, mobile, and connected technologies to advance mental health, and especially psychiatric rehabilitation, continues to rapidly evolve. New sensors and data, such as those derived from increasingly ubiquitous smartphones, offer a new window into the functional, social, and emotional experiences of illness and recovery at a personalized and quantified level previously unimaginable (Ben-Zeev & Badiyani, 2016; Free et al., 2013; Torous, Kiang, Lorme, & Onnela, 2016). These new technologies may also help assess and monitor mental health on a population level and provide early interventions and resources to those in need, regardless of their location (East & Havard, 2015). The papers comprising this special issue make important and exciting contributions to the mental health field in general and to digital mental health for psychiatric rehabilitation in particular. These papers illustrate that we are at the beginning of an era that may provide new knowledge and evidence-based tools to better promote mental health diagnosis, treatment, rehabilitation, and recovery. (PsycINFO Database Record PMID- 28891659 TI - High potential but limited evidence: Using voice data from smartphones to monitor and diagnose mood disorders. AB - OBJECTIVE: This article evaluates the potential of smartphone audio data to monitor individuals recovering from mood disorders. METHOD: A comprehensive literature review was conducted based on searches in 9 bibliographic databases. RESULTS: Seven articles were identified that used smartphone audio data to monitor participants with bipolar disorder from 4 to 14 weeks. The studies captured audio data in various contexts (e.g., in-person daily conversations, phone calls) and used common audio features (e.g., pitch and volume) to ascertain clinically relevant outcomes, including mood and social rhythm. Findings suggest that the utility of audio data in clinical and research contexts remains relatively unexplored and presents some challenges. For example, information on adherence and engagement among individuals recovering from bipolar disorder were often insufficient to gauge the generalizability of findings. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Despite growing interest, additional research is required to confirm clinical utility of smartphone audio data for mood disorders. (PsycINFO Database Record PMID- 28891660 TI - Augmenting mHealth with human support: Notes from community care of people with serious mental illnesses. AB - TOPIC: This article describes the activities of 2 mHealth specialists who supported the deployment of FOCUS-a smartphone self-management application for individuals with serious mental illnesses. PURPOSE: Several support activities have been identified as potentially advantageous for individuals using mHealth interventions: facilitation of user engagement, data utilization to enhance care, and promotion of meaningful use. We present 3 examples to demonstrate the implementation of these activities during a 12-week smartphone intervention. SOURCES USED: The personal experiences of 2 mHealth specialists are shared within the context of 3 examples of individuals who participated in the smartphone intervention. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The application of these support activities highlights the future opportunities that mHealth interventions could offer to individuals with serious mental illnesses and their providers. Additionally, these examples call for conversation about technology support roles and where they belong in the context of community-based care. (PsycINFO Database Record PMID- 28891661 TI - Behavioral health workforce development challenges in the digital health era. AB - TOPIC: This column describes challenges for hiring, training, and supervising psychiatric rehabilitation service providers for positions that involve the use of digital health technology. PURPOSE: Adoption and implementation of any new technology or technique requires workforce development. This article outlines considerations for policymakers, funders, and service agency administrators as digital health technologies become more widespread. SOURCES USED: The article discusses issues based on professional experience of the authors and available literature. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The literature on adoption of innovations in general, and the adoption of psychiatric evidence-based practices in particular, indicates that funding and adoption of new techniques and technologies are not adequate to ensure full and sustained implementation. The use of any new treatment or technology requires training and other supports to ensure that users have the competencies needed to make it work and that the workplace supports its use. As new digital health technologies become available, considerations of their cost and effectiveness need to include an examination of the required competencies of the service providers who will use them and the added cost of developing, enhancing, and maintaining those competencies. Specific attitudes, knowledge, and skills will be relevant to hiring decisions. Relevant preservice and on-the-job training opportunities, technical assistance, and supervision will be needed. Implementation needs to be monitored, not assumed, and the rights of the people who use technology-supported services must be fully protected. (PsycINFO Database Record PMID- 28891662 TI - Increase and decrease of other substance use during recovery from cannabis use disorders. AB - Little is known about whether recovery from one addiction is associated with increased or decreased risk of subsequent other addictions. This study explored self-reported increases and decreases in other substance use among individuals who have recovered from cannabis use disorder. Media recruitment was used to obtain a sample of 119 individuals with lifetime but not past year cannabis use disorder (30% female). The median length of recovery was 5.0 years. Results showed that both increase and decrease in the use of other substances is very common in recovery from cannabis use. In general, other substance use decreased more than it increased. Individuals who reported only a decrease in other substance use (39%) and individuals who reported both increases and decreases in various substances (21%) reported a greater degree of cannabis-related problems and treatment-seeking than individuals who only reported an increase (26%) or no change (14%). Individuals who only increased use of other substances reported fewer cannabis-related problems and were more likely to have had self-directed recoveries. They were also less likely to use helping relationships (e.g., friends, family) as a recovery process and self-help group involvement as a maintenance strategy. Their recoveries seem to have been less socially influenced and socially imbedded than individuals who reduced other substance use. The findings suggest that treatment involvement and social influences may successfully discourage use of other substances upon recovery from cannabis. However, the impact of such use or lack of use on individuals' functioning needs to be clarified in future research. (PsycINFO Database Record PMID- 28891663 TI - A call for theory to support the use of causal-formative indicators: A commentary on Bollen and Diamantopoulos (2017). AB - In this issue, Bollen and Diamantopoulos (2017) defend causal-formative indicators against several common criticisms leveled by scholars who oppose their use. In doing so, the authors make several convincing assertions: Constructs exist independently from their measures; theory determines whether indicators cause or measure latent variables; and reflective and causal-formative indicators are both subject to interpretational confounding. However, despite being a well reasoned, comprehensive defense of causal-formative indicators, no single article can address all of the issues associated with this debate. Thus, Bollen and Diamantopoulos leave a few fundamental issues unresolved. For example, how can researchers establish the reliability of indicators that may include measurement error? Moreover, how should researchers interpret disturbance terms that capture sources of influence related to both the empirical definition of the latent variable and to the theoretical definition of the construct? Relatedly, how should researchers reconcile the requirement for a census of causal-formative indicators with the knowledge that indicators are likely missing from the empirically estimated latent variable? This commentary develops 6 related research questions to draw attention to these fundamental issues, and to call for future research that can lead to the development of theory to guide the use of causal-formative indicators. (PsycINFO Database Record PMID- 28891664 TI - Notes on measurement theory for causal-formative indicators: A reply to Hardin. AB - The current article is a rejoinder to "A Call for Theory to Support the Use of Causal-Formative Indicators: A Commentary on Bollen and Diamantopoulos." Our article comments on the 6 research questions raised by Hardin (2017) in his constructive commentary on our original article (i.e., "In Defense of Causal Formative Indicators: A Minority Report"). (PsycINFO Database Record PMID- 28891665 TI - Levels of and changes in life satisfaction predict mortality hazards: Disentangling the role of physical health, perceived control, and social orientation. AB - It is well documented that well-being typically evinces precipitous decrements at the end of life. However, research has primarily taken a postdictive approach by knowing the outcome (date of death) and aligning, in retrospect, how well-being has changed for people with documented death events. In the present study, we made use of a predictive approach by examining whether and how levels of and changes in life satisfaction prospectively predict mortality hazards and delineate the role of contributing factors, including health, perceived control, and social orientation. To do so, we applied shared parameter growth-survival models to 20-year longitudinal data from 10,597 participants (n = 1,560 [15%] deceased; age at baseline: M = 44 years, SD = 17, range = 18-98 years) from the national German Socio-Economic Panel Study. Our findings showed that lower levels and steeper declines of life satisfaction each uniquely predicted higher mortality risks. Results also revealed moderating effects of age and perceived control: Life satisfaction levels and changes had stronger predictive effects for mortality hazards among older adults. Perceived control was associated with lower mortality hazards; however, this effect was diminished for those who experienced accelerated life satisfaction decline. Variance decomposition suggests that predictive effects of life satisfaction trajectories were partially unique (3% 6%) and partially shared with physical health, perceived control, and social orientation (17%-19%). Our discussion focuses on the strengths and challenges of a predictive approach to link developmental changes (in life satisfaction) to mortality hazards, and considers implications of our findings for healthy aging. (PsycINFO Database Record PMID- 28891667 TI - In the eye of the beholder: Can counter-stereotypes change perceptions of older adults' social status? AB - Negative age-related stereotypes often entail the perception that older adults have a lower social status than middle-aged adults. We hypothesized that older adults are perceived to have lower social status because they are less likely to be seen in prestigious occupational positions. People tend to infer general assumptions about group characteristics from exemplars. According to this, presenting a stereotype-inconsistent exemplar (i.e., older person in a high status position) should change perceptions of older adults' social status. Study 1 (60 countries, N = 86,026, 18-99 years) showed that people in countries with an older relative to a younger political leader do not perceive as great a decline in social status from middle-aged to older adults. Study 2 (N = 131; 19-74 years) tested the causal link demonstrating that participants exposed to older exemplars holding a prestigious occupational position were significantly more likely to rate older adults as having a relative higher social status. We discuss implications for future interventions to change negative age-related stereotypes. (PsycINFO Database Record PMID- 28891666 TI - Adversity in childhood and measures of aging in midlife: Findings from a cohort of british women. AB - Very few studies have assessed whether socioeconomic and psychosocial adversity during childhood are associated with objective measures of aging later in life. We assessed associations of socioeconomic position (SEP) and total psychosocial adversity during childhood, with objectively measured cognitive and physical capability in women during midlife. Adverse childhood experiences were retrospectively reported at mean ages 28-30 years in women from the Avon Longitudinal Study of Parents And Children (N = 2,221). We investigated associations of childhood SEP and total psychosocial adversity, with composite measures of cognitive and physical capability at mean age 51 years. There was evidence that, compared with participants whose fathers had professional occupations, participants whose fathers had managerial/technical, skilled nonmanual, skilled manual, and partly or unskilled manual occupations had, on average, lower physical and cognitive capability. There was a clear trend for increasing magnitudes of association with lowering childhood SEP. There was also evidence that greater total psychosocial adversity in childhood was associated with lower physical capability. Total psychosocial adversity in childhood was not associated with cognitive capability. Lower SEP in childhood is detrimental to cognitive and physical capability in midlife, at least in part, independently of subsequent SEP in adulthood. Greater psychosocial adversity in childhood is associated with poorer physical capability, independently of social disadvantage in childhood. Our findings highlight the need for interventions to both identify and support children experiencing socioeconomic or psychosocial of adversity as early as possible. (PsycINFO Database Record PMID- 28891668 TI - Visual attention and emotional reactions to negative stimuli: The role of age and cognitive reappraisal. AB - Prominent life span theories of emotion propose that older adults attend less to negative emotional information and report less negative emotional reactions to the same information than younger adults do. Although parallel age differences in affective information processing and age differences in emotional reactivity have been proposed, they have rarely been investigated within the same study. In this eye-tracking study, we tested age differences in visual attention and emotional reactivity, using standardized emotionally negative stimuli. Additionally, we investigated age differences in the association between visual attention and emotional reactivity, and whether these are moderated by cognitive reappraisal. Older as compared with younger adults showed fixation patterns away from negative image content, while they reacted with greater negative emotions. The association between visual attention and emotional reactivity differed by age group and positive reappraisal. Younger adults felt better when they attended more to negative content rather than less, but this relationship only held for younger adults who did not attach a positive meaning to the negative situation. For older adults, overall, there was no significant association between visual attention and emotional reactivity. However, for older adults who did not use positive reappraisal, decreases in attention to negative information were associated with less negative emotions. The present findings point to a complex relationship between younger and older adults' visual attention and emotional reactions. (PsycINFO Database Record PMID- 28891669 TI - An age-related deficit in resolving interference: Evidence from speech perception. AB - The presence of noise and interfering information can pose major difficulties during speech perception, particularly for older adults. Analogously, interference from similar representations during retrieval is a major cause of age-related memory failures. To demonstrate a suppression mechanism that underlies such speech and memory difficulties, we tested the hypothesis that interference between targets and competitors is resolved by suppressing competitors, thereby rendering them less intelligible in noise. In a series of experiments using a paradigm adapted from Healey, Hasher, and Campbell (2013), we presented a list of words that included target/competitor pairs of orthographically similar words (e.g., ALLERGY and ANALOGY). After a delay, participants solved fragments (e.g., A_L__GY), some of which resembled both members of the target/competitor pair, but could only be completed by the target. We then assessed the consequence of having successfully resolved this interference by asking participants to identify words in noise, some of which included the rejected competitor words from the previous phase. Consistent with a suppression account of interference resolution, younger adults reliably demonstrated reduced identification accuracy for competitors, indicating that they had effectively rejected, and therefore suppressed, competitors. In contrast, older adults showed a relative increase in accuracy for competitors relative to young adults. Such results suggest that older adults' reduced ability to suppress these representations resulted in sustained access to lexical traces, subsequently increasing perceptual identification of such items. We discuss these findings within the framework of inhibitory control theory in cognitive aging and its implications for age-related changes in speech perception. (PsycINFO Database Record PMID- 28891670 TI - Aging and syntactic representations: Evidence of preserved syntactic priming and lexical boost. AB - Young adults can be primed to reuse a syntactic structure across otherwise unrelated utterances but it is not known whether this phenomenon exists in older adults. In a dialogue task, young and older adults described transitive verb target pictures after hearing active or passive sentences. Both groups were more likely to produce a passive sentence following a passive prime than following an active prime (indicating syntactic priming), and this effect increased when the prime and target involved the same verb (indicating lexical boost). These effects were statistically equivalent in young and older adults, suggesting that the syntactic representations underlying sentence production are unaffected by normal aging. (PsycINFO Database Record PMID- 28891672 TI - Sepsis-3 in Community-acquired Pneumonia: How Reliable Is It? PMID- 28891673 TI - Correlation between serum lead and thyroid diseases: papillary thyroid carcinoma, nodular goiter, and thyroid adenoma. AB - Studies have showed that lead was associated with human health. However, the effects of lead on thyroid functions are inconsistent, and studies based on Chinese population are fragmentary. To evaluate the correlation between lead and thyroid functions of Chinese with different thyroid diseases, we conducted a hospital-based study. Ninety-six papillary thyroid carcinoma (PTC), 10 nodular goiter (NG), and 7 thyroid adenoma (TA) patients were recruited from the First Affiliated Hospital of Wenzhou Medical University, China. Serum triiodothyronine (T3), free triiodothyronine (FT3), free thyroxin (FT4), and thyroid stimulating hormone (TSH) were evaluated with chemiluminescent microparticle immunoassay. Serum lead was assessed with ICP-MASS. Partial correlation was used to explore the correlations of serum lead and thyroid diseases. Compared to PTC, the level of lead was significantly higher in TA, and lower in NG (p < 0.05). This difference remained significant in females when stratified by sex. Serum lead was negatively correlated with TSH (rs = - 0.27, p < 0.05) in PTC group. T3 was positively related to lead at quartile4 (rs = 0.61, p < 0.05) in PTC group. No significant correlations were observed between lead and FT3 or FT4 in any group. The results suggested that lead might have different etiological roles in these three thyroid diseases. PMID- 28891675 TI - Abstracts The Society of Biomolecular Imaging and Informatics 4th Annual Meeting Poster Session September 13-15, 2017 San Diego Convention Center San Diego, CA. PMID- 28891674 TI - Reply to Akinosoglou and Gogos: Sepsis-3 in Community-acquired Pneumonia: How Reliable Is It? PMID- 28891676 TI - Pornography use in sexual minority males: Associations with body dissatisfaction, eating disorder symptoms, thoughts about using anabolic steroids and quality of life. AB - OBJECTIVE: We examined two hypotheses regarding the potential association of pornography use with body image-related and eating disorder-related psychopathology among sexual minority males (i.e. non-heterosexual males). Our primary hypothesis was that pornography use would be associated with males' body dissatisfaction, eating disorder symptoms, thoughts about using anabolic steroids and quality of life impairment; our secondary hypothesis was that the type of pornography, namely, professional versus amateur pornography, which contains idealised and non-idealised (i.e. regular) bodies, respectively, would moderate these associations. METHODS: A sample of 2733 sexual minority males living in Australia and New Zealand completed an online survey that contained measures of pornography use, body dissatisfaction, eating disorder symptoms, thoughts about using anabolic steroids and quality of life. RESULTS: Almost all (98.2%) participants reported pornography use with a median use of 5.33 hours per month. Multivariate analyses revealed that increased pornography use was associated with greater dissatisfaction with muscularity, body fat and height; greater eating disorder symptoms; more frequent thoughts about using anabolic steroids; and lower quality of life. Effect sizes for these associations were uniformly small. Neither relationship status nor genital dissatisfaction was associated with pornography use. The association between pornography use and thoughts about using anabolic steroids was stronger for viewers of professional pornography than viewers of amateur pornography. CONCLUSION: The findings suggest that the use of pornography is weakly associated with body dissatisfaction and related variables and that the type of pornography (amateur vs professional) viewed may be a moderating factor in some cases. Within the limits of a cross-sectional study design, these findings may have implications for clinicians who treat individuals with eating disorders, body dysmorphic disorder, anabolic-androgenic steroid dependence and related concerns. PMID- 28891677 TI - Genetic variation in the MITF promoter affects skin colour and transcriptional activity in black-boned chickens. AB - 1. Microphthalmia-associated transcription factor (MITF) plays a pivotal role in melanocyte development by regulating the transcription of major pigmentation enzymes (e.g. TYR, TYRP1 and DCT). A single-nucleotide polymorphism (SNP), c. 638T>C, was identified in the MITF promoter, and genotyping of a population (n = 426) revealed that SNP c.-638T>C was associated with skin colour in black-boned chickens. 2. Individuals with genotypes CC and TC exhibited greater MTIF expression than those with genotype TT. Luciferase assays also revealed that genotype CC and TC promoters had higher activity levels than genotype TT. Expression of melanogenesis-related gene (TYR) was higher in the skin of chickens with the CC and CT genotype compared to TT chickens (P < 0.05). 3. Transcription factor-binding site analyses showed that the c.-638C allele contains a putative binding site for transcription factor sterol regulatory element-binding transcription factor 2, aryl hydrocarbon receptor nuclear translocator, transcription factor binding to IGHM enhancer 3 and upstream transcription factor 2. In contrast, the c.-638T allele contains binding sites for Sp3 transcription factor and Kruppel-like factor 1. 4. It was concluded that MITF promoter polymorphisms affected chicken skin colour. SNP c.-638T>C could be used for the marker-assisted selection of skin colour in black-boned chicken breeding. PMID- 28891678 TI - Prevalence of gastrointestinal helminth infections in free-range laying hens under mountain farming production conditions. AB - 1. A cross-sectional study was conducted from September 2015 to July 2016 in South Tyrol, Northern Italy to examine the prevalence of gastrointestinal helminths in free-range laying hens under mountain farming production conditions. 2. A total of 280 laying hens from 14 free-range mountain farms (4 organic, 10 conventional) were randomly collected at the end of the laying period. Faecal samples were taken to analyse faecal egg counts (FEC) and faecal oocyst counts (FOC). The gastrointestinal tracts were removed post mortem and examined for the presence of helminths. 3. In faeces, FEC values averaged 258 eggs per g of faeces, which were dominated by Ascaridia galli and Heterakis gallinarum. Mean FOC was 80 oocysts/g. In the gastrointestinal tract, at least one nematode species was found in 99.3% of the examined hens. H. gallinarum was the most prevalent nematode (95.7%), followed by Capillaria spp. (66.8%) and A. galli (63.6%). Thirty per cent of the chickens were infected with cestodes (tapeworms). Correlation coefficients between worm counts of H. gallinarum, Capillaria spp. and A. galli ranged from 0.41 to 0.51. 5. The helminth prevalence did not differ between conventional and organic farms, whereas total worm burden was higher in organic compared with conventional farms (318.9 vs. 112.0). Prevalence and infection intensity did not differ between farms that used anthelmintic treatments and those that did not. 6. In conclusion, free-range laying hens under the studied mountain farming conditions are at high risk of nematode infection, especially in organic systems. The vast majority of hens are subclinical infected with at least one helminth species. PMID- 28891679 TI - Patient-reported outcomes after aortic and mitral valve surgery - results from the DenHeart Study. AB - BACKGROUND: Clinical course, co-morbidity and age often differs between patients undergoing aortic and mitral valve surgery and this might affect patient-reported outcomes. AIMS: The purpose of this study was to describe differences in patient reported physical and mental health and health-related quality of life after aortic valve or mitral valve surgery, and to identify demographic and clinical characteristics associated with worse patient-reported physical and mental health, and health-related quality of life. METHODS: Patient-reported outcomes were measured at discharge as a part of a national, cross-sectional study (DenHeart). Patient-reported outcome measures included: Short-Form-12, Hospital Anxiety and Depression Scale, EuroQol-5D-5L, HeartQol and Edmonton Symptom Assessment System. Demographic and clinical information was obtained from national registers. RESULTS: Of 354 patients (65% men, mean age: 68 years), 79% underwent aortic valve surgery. Patients who had undergone aortic valve surgery had more symptoms of anxiety compared with patients who had undergone mitral valve surgery (34% vs 17%, p=0.003, Hospital Anxiety and Depression Scale anxiety cut-off score of eight). Being female was associated with worse patient-reported outcomes on all measures, whereas being unmarried was associated with worse physical health (Physical Component Score Short-Form-12) and symptom burden (Edmonton Symptom Assessment System). Length of stay was associated with worse symptoms on EuroQol-5D-5L Visual Analogue Scale. Age and comorbidity were not associated with patient-reported outcomes. CONCLUSION: Patients who had undergone aortic valve and mitral valve surgery did not significantly differ in patient reported health at discharge, except for symptoms of anxiety. Being female was the only characteristic associated with overall worse patient-reported outcomes at discharge. PMID- 28891680 TI - Expanding Treatment Options for Improving Health Outcomes in Type 1 Diabetes. PMID- 28891682 TI - Empirically Corrected Rescaled Statistics for SEM with Small N and Large p. AB - Survey data often contain many variables. Structural equation modeling (SEM) is commonly used in analyzing such data. With typical nonnormally distributed data in practice, a rescaled statistic Trml proposed by Satorra and Bentler was recommended in the literature of SEM. However, Trml has been shown to be problematic when the sample size N is small and/or the number of variables p is large. There does not exist a reliable test statistic for SEM with small N or large p, especially with nonnormally distributed data. Following the principle of Bartlett correction, this article develops empirical corrections to Trml so that the mean of the empirically corrected statistics approximately equals the degrees of freedom of the nominal chi-square distribution. Results show that empirically corrected statistics control type I errors reasonably well even when N is smaller than 2p, where Trml may reject the correct model 100% even for normally distributed data. The application of the empirically corrected statistics is illustrated via a real data example. PMID- 28891683 TI - Six global and local QSPR models of aqueous solubility at pH = 7.4 based on structural similarity and physicochemical descriptors. AB - Aqueous solubility at pH = 7.4 is a very important property for medicinal chemists because this is the pH value of physiological media. The present work describes the application of three different methods (support vector machine (SVM), random forest (RF) and multiple linear regression (MLR)) and three local quantitative structure-property relationship (QSPR) models (regression corrected by nearest neighbours (RCNN), arithmetic mean property (AMP) and local regression property (LoReP)) to construct stable QSPRs with clear mechanistic interpretation. Our data set contained experimental values of aqueous solubility at pH = 7.4 of 387 chemicals (349 in the training set and 38 in the test set including 16 own measurements). The initial descriptor pool contained 210 physicochemical descriptors, calculated from the HYBOT, DRAGON, SYBYL and VolSurf+ programs. Six QSPRs with good statistics based on fundamentals of aqueous solubility and optimization of descriptor space were obtained. Those models have an RMSE close to experimental error (0.70), and are amenable to physical interpretation. The QSPR models developed in this study may be useful for medicinal chemists. Global MLR, RF and SVM models may be valuable for consideration of common factors that influence solubility. The RCNN, AMP and LoReP local models may be helpful for the optimization of aqueous solubility in small sets of related chemicals. PMID- 28891681 TI - Lacto-Vegetarian Diet and Correlation of Fasting Blood Sugar with Lipids in Population Practicing Sedentary Lifestyle. AB - Rising burden of diabetes in India requires quick intervention that integrates policies and programs for effective prevention and control of disease. This retrospective cross-sectional study was conducted to observe effect of diet in two Indian communities practicing sedentary lifestyle. Fasting blood samples were analyzed for blood sugar, glycated-hemoglobin (HbA1C), and lipid profile. Body mass index (BMI) and waist circumference (WC) measurements were recorded. Diabetes incidence was lower in lacto-vegetarian (1.7%) than in non-vegetarian group (5.3%) despite similar lipid profiles and BMI/WC between the groups. Fasting blood sugar (FBS) was positively correlated with LDL and VLDL levels and negatively correlated with HDL, only in lacto-vegetarian group. Study suggests: (1) Indian lacto-vegetarian diet has beneficial effects on diabetes incidence irrespective of high body weight and sedentary lifestyle; (2) intervention to reduce body lipids, such as lipid-lowering drugs and exercise, may have greater effect in reducing FBS levels in this lacto-vegetarian group. PMID- 28891684 TI - A Computational-Based Method for Predicting Drug-Target Interactions by Using Stacked Autoencoder Deep Neural Network. AB - Identifying the interaction between drugs and target proteins is an important area of drug research, which provides a broad prospect for low-risk and faster drug development. However, due to the limitations of traditional experiments when revealing drug-protein interactions (DTIs), the screening of targets not only takes a lot of time and money but also has high false-positive and false-negative rates. Therefore, it is imperative to develop effective automatic computational methods to accurately predict DTIs in the postgenome era. In this article, we propose a new computational method for predicting DTIs from drug molecular structure and protein sequence by using the stacked autoencoder of deep learning, which can adequately extract the raw data information. The proposed method has the advantage that it can automatically mine the hidden information from protein sequences and generate highly representative features through iterations of multiple layers. The feature descriptors are then constructed by combining the molecular substructure fingerprint information, and fed into the rotation forest for accurate prediction. The experimental results of fivefold cross-validation indicate that the proposed method achieves superior performance on gold standard data sets (enzymes, ion channels, GPCRs [G-protein-coupled receptors], and nuclear receptors) with accuracy of 0.9414, 0.9116, 0.8669, and 0.8056, respectively. We further comprehensively explore the performance of the proposed method by comparing it with other feature extraction algorithms, state-of-the-art classifiers, and other excellent methods on the same data set. The excellent comparison results demonstrate that the proposed method is highly competitive when predicting drug-target interactions. PMID- 28891685 TI - Risk of falling in a stroke unit after acute stroke: The Fall Study of Gothenburg (FallsGOT). AB - OBJECTIVE: This study aimed to investigate incidence of falls and different baseline variables and their association with falling during hospitalization in a stroke unit among patients with acute stroke. DESIGN: Prospective observational study. SETTING: A stroke unit at a university hospital. SUBJECTS: A consecutive sample of stroke patients, out of which 504 were included, while 101 declined participation. METHODS: The patients were assessed a mean of 1.7 days after admission and 3.8 days after stroke onset. MAIN MEASURES: The primary end-point was any fall, from admission to the stroke unit to discharge. Factors associated with falling were analysed using univariable and multivariable Cox hazard regression analyses. Independent variables were related to function, activity and participation, as well as personal and environmental factors. RESULTS: In total, 65 patients (13%) fell at least once. Factors statistically significantly associated with falling in the multivariable analysis were male sex (hazard ratio (HR): 1.88, 95% confidence interval (CI): 1.13-3.14, P = 0.015), use of a walking aid (HR: 2.11, 95% CI: 1.24-3.60, P = 0.006) and postural control as assessed with the modified version of the Postural Assessment Scale for Stroke Patients (SwePASS). No association was found with age, cognition or stroke severity, the HR for low SwePASS scores (?24) was 9.33 (95% CI: 2.19-39.78, P = 0.003) and for medium SwePASS scores (25-30) was 6.34 (95% CI: 1.46-27.51, P = 0.014), compared with high SwePASS scores (?31). CONCLUSION: Postural control, male sex and use of a walking aid are associated with falling during hospitalization after acute stroke. PMID- 28891686 TI - Innovative processes and technologies for modified atmosphere packaging of fresh and fresh-cut fruits and vegetables. AB - Modified atmosphere packaging (MAP) technology has been commercially viable since the 1970s. Currently, MAP is extensively used worldwide to preserve the quality and extend the shelf-life of whole fresh fruits and vegetables, but is also increasingly used to extend the shelf-life of minimally processed fresh fruit and vegetables. This review discusses new processes and technologies that can be used to improve quality preservation and consumer acceptability of minimally processed produce where high respiration rates and challenging degradation processes operate. New packaging innovations are enabling producers and retailers to further maintain quality for longer. Innovative approaches to extend shelf-life include active MAP with differentially permeable films, films that incorporate antimicrobial properties, edible coatings that confer barriers properties, and the use of non-traditional gases to modify respiration. Intelligent packaging using integrated sensor technologies that can indicate maturity, ripeness, respiration rate and spoilage are also appearing. This review demonstrates that preservation technologies and associated packaging developments that can be combined with modified atmosphere are constantly evolving technology platforms. Adoption of combinations of technology improvements will be critical in responding to commercial trends towards more minimally processed fresh-cut and ready-to-eat fruit and vegetable products, which require specialized packaging solutions. PMID- 28891687 TI - The Application of the Weighted k-Partite Graph Problem to the Multiple Alignment for Metabolic Pathways. AB - The problem of aligning multiple metabolic pathways is one of very challenging problems in computational biology. A metabolic pathway consists of three types of entities: reactions, compounds, and enzymes. Based on similarities between enzymes, Tohsato et al. gave an algorithm for aligning multiple metabolic pathways. However, the algorithm given by Tohsato et al. neglects the similarities among reactions, compounds, enzymes, and pathway topology. How to design algorithms for the alignment problem of multiple metabolic pathways based on the similarity of reactions, compounds, and enzymes? It is a difficult computational problem. In this article, we propose an algorithm for the problem of aligning multiple metabolic pathways based on the similarities among reactions, compounds, enzymes, and pathway topology. First, we compute a weight between each pair of like entities in different input pathways based on the entities' similarity score and topological structure using Ay et al.'s methods. We then construct a weighted k-partite graph for the reactions, compounds, and enzymes. We extract a mapping between these entities by solving the maximum weighted k-partite matching problem by applying a novel heuristic algorithm. By analyzing the alignment results of multiple pathways in different organisms, we show that the alignments found by our algorithm correctly identify common subnetworks among multiple pathways. PMID- 28891688 TI - Double Decomposition of Level-1 Variables in Multilevel Models: An Analysis of the Flynn Effect in the NSLY Data. AB - This paper introduces an extension of cluster mean centering (also called group mean centering) for multilevel models, which we call "double decomposition (DD)." This centering method separates between-level variance, as in cluster mean centering, but also decomposes within-level variance of the same variable. This process retains the benefits of cluster mean centering but allows for context variables derived from lower level variables, other than the cluster mean, to be incorporated into the model. A brief simulation study is presented, demonstrating the potential advantage (or even necessity) for DD in certain circumstances. Several applications to multilevel analysis are discussed. Finally, an empirical demonstration examining the Flynn effect (Flynn, 1987 ), our motivating example, is presented. The use of DD in the analysis provides a novel method to narrow the field of plausible causal hypotheses regarding the Flynn effect, in line with suggestions by a number of researchers (Mingroni, 2014 ; Rodgers, 2015 ). PMID- 28891689 TI - Multimodal Drug Therapy and Physical Rehabilitation in the Successful Treatment of Capture Myopathy in a Lesser Flamingo (Phoeniconaias minor). AB - A wild-caught lesser flamingo (Phoeniconaias minor) from the Fort Worth Zoo (Fort Worth, TX, USA) presented with moderate lameness that progressed to the inability to stand 2 days after restraint and handling. Results of blood tests showed severely elevated creatine phosphokinase (CPK) and aspartate aminotransferase (AST) activities, confirming suspected capture myopathy. Intensive supportive therapy, consisting of intravenous fluids and muscle relaxants, along with physical rehabilitation therapy, nutritional support, and anxiolytics, were instituted to aid in relaxation and muscle regeneration. After 2 weeks of intensive therapy, the bird showed substantial improvement and could remain standing throughout the day after being assisted to a standing position. By day 23, the bird was able to stand independently and walk completely unassisted, with no discernible lameness. The bird has subsequently remained healthy since it was returned to the flock approximately 27 days after it was first presented for treatment. Although anecdotal communications of successful treatment of this condition in flamingos exist, this is the first report, to our knowledge, that describes in detail the successful treatment of capture myopathy in any flamingo species. Success in this case is attributed to the combination of early fluid and drug therapy, intensive physical rehabilitation therapy, and anxiolytics to counteract the hyperexcitable nature of this wild-caught bird. PMID- 28891691 TI - What is Your Diagnosis? PMID- 28891692 TI - Second-generation Anticoagulant Rodenticide Poisoning in a Captive Andean Condor (Vultur gryphus). AB - A 28-year-old female Andean condor (Vultur gryphus) housed in an outside exhibit at the National Aviary in Pittsburgh, PA, began showing signs of weakness. Toxicosis with an anticoagulant rodenticide was suspected because its mate had died 1 day earlier from possible brodifacoum poisoning. A rapid decline in the packed cell volume, despite vitamin K1 treatment, necessitated a blood transfusion with blood from bald eagles (Haliaeetus leucocephalus) and Steller's sea eagles (Haliaeetus pelagicus). Supportive therapy after transfusion included vitamin K1 (5 mg/kg IM q12h) as well as enrofloxacin, vitamin B complex, selenium and vitamin E, and subcutaneous fluids as needed. After a 39-day treatment period, a tapering dosage of vitamin K1 was initiated, and treatment ended after 17 weeks. However, 2 weeks later, the bird suffered from a potential relapse. It was successfully treated with a repeat tapering vitamin K1 regimen lasting a total of 4 months. PMID- 28891690 TI - Compendium of Measures to Control Chlamydia psittaci Infection Among Humans (Psittacosis) and Pet Birds (Avian Chlamydiosis), 2017. AB - Psittacosis, also known as parrot fever and ornithosis, is a bacterial infection that can cause severe pneumonia and other serious health problems in humans. It is caused by Chlamydia psittaci. Reclassification of the order Chlamydiales in 1999 into 2 genera (Chlamydia and Chlamydophila) was not wholly accepted or adopted. This resulted in a reversion to the single, original genus Chlamydia, which now encompasses all 9 species including Chlamydia psittaci. During 2003 2014, 112 human cases of psittacosis were reported to the Centers for Disease Control and Prevention through the Nationally Notifiable Diseases Surveillance System. While many types of birds can be infected by C psittaci, in general, the literature suggests that human cases can most often occur after exposure to infected parrot-type birds kept as pets, especially cockatiels, parakeets, and conures. In birds, C psittaci infection is referred to as avian chlamydiosis. Infected birds shed the bacteria through feces and nasal discharges, and humans become infected from exposure to these materials. This compendium provides information about psittacosis and avian chlamydiosis to public health officials, physicians, veterinarians, the pet bird industry, and others concerned with controlling these diseases and protecting public health. The recommendations in this compendium provide standardized procedures to control C psittaci infections. This document will be reviewed and revised as necessary, and the most current version replaces all previous versions. This document was last revised in 2010. Major changes in this version include a recommendation for a shorter treatment time for birds with avian chlamydiosis, additional information about diagnostic testing, including genotyping, clearer language associated with personal protective equipment recommended for those caring for confirmed or exposed birds, and incorporating a grading scale with recommendations generally based on the United States Preventive Services Task Force's methods. PMID- 28891693 TI - Radiography and Ultrasonography in the Backyard Poultry and Waterfowl Patient. AB - The keeping of backyard poultry and waterfowl as pets has become increasingly popular in recent years, resulting in a rising case load of these patients in veterinary practices. Diagnostic imaging techniques are taking a leading role in rapid diagnosis in the live bird. We provide an overview of the most important points regarding radiographic and ultrasonographic imaging procedures in these birds. We also review the most commonly documented radiographic and ultrasonographic signs in these species, as well as discuss unique anatomic characteristics with which the veterinarian should be familiar. PMID- 28891694 TI - Zoonotic Disease: A Concern for Everyone. PMID- 28891696 TI - Repair of Tibiotarsal Rotation in 7 Chukar Partridges (Alectoris chukar) and 12 Domestic Pigeons (Columba livia domestica) with Type-2 External Skeletal Fixator Intramedullary Pin Tie-in. AB - Rotational deformities of the long bones affect various avian species. Tibiotarsal rotation may cause the leg to deviate up to 180 degrees from the dorsoplantar axis in a matter of days, thus preventing the birds from walking freely and leading to the inability to stand. In this study, tibiotarsal rotation observed in pigeons and partridges was managed by creating a closed fracture in the tibiotarsus and then, following reduction, stabilizing it with an intramedullary tie-in Type 2 external skeletal fixation system. Functional healing was achieved in 12 pigeons (Columba livia domestica; mean healing time, 38 days) and 7 partridges (Alectoris chukar; mean healing time, 40 days). This treatment was successful. In small bird species (<1 kg), this simple and inexpensive surgical intervention may provide a highly effective method for the treatment of rotational deformities. PMID- 28891697 TI - Management of a Nonhealing, Superficial Corneal Ulcer in a Hyacinth Macaw (Anodorhynchus hyacinthinus). AB - A 26-year-old, female hyacinth macaw (Anodorhynchus hyacinthinus) was presented for ophthalmology consultation for a history of a chronic, nonhealing corneal ulcer of the right eye. On examination, a 5 * 4-mm axial, superficial corneal ulcer with loose epithelial edges was found. During multiple recheck examinations over 4 months, the ulcer was treated by debridement with a sterile cotton-tipped applicator, diamond burr debridement, diamond burr debridement with cyanoacrylate tissue adhesive, and grid keratotomy with cyanoacrylate tissue adhesive, all performed under anesthesia with eventual resolution of the corneal ulcer. PMID- 28891698 TI - Serratospiculosis in Captive Peregrine Falcons (Falco peregrinus) in Switzerland. AB - Infection with Serratospiculum species was identified in a captive peregrine falcon (Falco peregrinus) in Switzerland. Pathologic and parasitologic examination results revealed generalized severe granulomatous airsacculitis, with intralesional adults, larvae, and eggs of Serratospiculum species. Subsequently, an individual coprological analysis of the remaining 15 falcons (peregrine falcons and gyrfalcons [Falco rusticolus]) from the same owner was performed. Eggs of Serratospiculum species (4 birds) and Capillaria species (11 birds), and oocysts of Caryospora species (1 bird) were detected. Treatment with ivermection (2 mg/kg SC) was effective, as none of the falcons excreted Serratospiculum species eggs 10 days after one dose. To our knowledge, this is the first report of infection with Serratospiculum species in captive falcons in Europe. PMID- 28891699 TI - Radiographic Anatomy of the Metatarsophalangeal Joint and Digits of the Ostrich (Struthio camelus). AB - The aim of this study was to develop a detailed and accessible set of reference images of the normal radiographic anatomy of the digits of the ostrich (Struthio camelus), with emphasis on the metatarsophalangeal joint and its arthrography. The distal excised pelvic limbs of 10 normal ostriches of different ages (ranging from 10 to 365 days of age) obtained from an abattoir were radiographed, and 2 arthrograms were performed. To illustrate the normal radiographic anatomy of the tarsometatarsal bone, 39 images were selected, labelled, and presented along with detailed descriptions and corresponding images of the bony skeleton. These results provide a valuable dataset to assist in understanding the normal anatomy of the ostrich metatarsophalangeal joint and digits and allow comparison of abnormal corresponding structures in clinical cases in ostriches. PMID- 28891700 TI - Rhabdomyolysis and Artifactual Increase in Plasma Bicarbonate Concentration in an Amazon Parrot (Amazona species). AB - A 7-year-old male Amazon parrot housed outdoors presented with acute collapse, marked lethargy, and open-mouth breathing. The patient had stiffness of the pectoral muscles, and petechiation and ecchymosis noted around the eyes and beneath the mandible. Laboratory data revealed markedly increased aspartate aminotransferase, creatine kinase, and lactate dehydrogenase activity consistent with rhabdomyolysis, as well as markedly increased plasma bicarbonate concentration. Marked clinical improvement and resolution of laboratory abnormalities occurred with fluid therapy, administration of a nonsteroidal anti inflammatory medication, and husbandry modifications, including indoor housing and dietary alteration. A spurious increase in bicarbonate measurement as documented in equine and bovine cases of rhabdomyolysis also occurred in this avian patient and must be considered for accurate interpretation of acid-base status in exotic species presenting with consistent clinical signs. PMID- 28891701 TI - Sedative Effects of Intranasal Midazolam Administration in Wild Caught Blue fronted Amazon (Amazona aestiva) and Orange-winged Amazon (Amazona amazonica) Parrots. AB - Safe and effective sedation protocols are important for chemical restraint of birds in clinical and diagnostic procedures, such as clinical evaluations, radiographic positioning, and blood collection. These protocols may reduce stress and ease the management of wild-caught birds, which are susceptible to injury or death when exposed to stressful situations. We compare the sedative effect of intranasal midazolam in wild-caught blue-fronted (Amazona aestiva) and orange winged (Amazona amazonica) Amazon parrots. Ten adult parrots of each species (n = 20), of unknown sex, weighing 0.337 +/- 0.04 (blue-fronted) and 0.390 +/- 0.03 kg (orange-winged), kg were used. Midazolam (2 mg/kg) was administered intranasally and the total volume of the drug was divided equally between the 2 nostrils. Onset time and total sedation time were assessed. Satisfactory sedation for clinical evaluation was induced in all birds. Onset time and total sedation times were similar in both species: 5.36 +/- 1.16 and 25.40 +/- 5.72 minutes, respectively, for blue-fronted Amazons and 5.09 +/- 0.89 and 27.10 +/- 3.73 minutes, respectively, for orange-winged Amazons. A total of 15 animals showed absence of vocalization, with moderate muscle relaxation and wing movement upon handling, and 2 animals presented with lateral recumbence, with intense muscle relaxation and no wing movement, requiring no restraint. Three blue-fronted Amazons had no effective sedation. Intranasally administered midazolam at a dose of 2 mg/kg effectively promoted sedative effects with a short latency time and fast recovery in wild-caught parrots. PMID- 28891703 TI - Coming Meetings. PMID- 28891702 TI - Pharmacokinetics of a Sustained-release Formulation of Meloxicam After Subcutaneous Administration to Hispaniolan Amazon Parrots (Amazona ventralis). AB - Meloxicam has been shown to have a safe and favorable pharmacodynamic profile with individual variability in Hispaniolan Amazon parrots (Amazona ventralis). In the current study, we determined the pharmacokinetics of a sustained-release formulation of meloxicam after subcutaneous administration to Hispaniolan Amazon parrots. Twelve healthy adult parrots, 6 males and 6 females, were used in the study. Blood samples were collected before (time 0) and at 0.5, 1, 2, 6, 12, 24, 48, 72, 96, and 120 hours after a single dose of the sustained-release meloxicam formulation (3 mg/kg SC). Plasma meloxicam concentrations were measured by high pressure liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental analysis. Plasma concentrations reached a mean Cmax of 23.4 MUg/mL (range, 14.7-46.0 MUg/mL) at 1.8 hours (range, 0.5-6 hours), with a terminal half-life of 7.4 hours (range, 1.4-40.9 hours). Individual variation was noticeable, such that some parrots (4 of 12 birds) had very low plasma meloxicam concentrations, similar to the high variability reported in a previous pharmacokinetic study of the standard meloxicam formulation in the same group of birds. Two birds developed small self-resolving scabs at the injection site. On the basis of these results, the sustained-release meloxicam formulation could be administered every 12 to 96 hours in Hispaniolan Amazon parrots to manage pain. Because of these highly variable results, the use of this formulation in this species cannot be recommended until further pharmacokinetic, safety, and pharmacogenomic evaluations are performed to establish accurate dosing recommendations and to understand the high pharmacokinetic variability. PMID- 28891704 TI - Mucoepidermoid Carcinoma in the Skull of an Orange-winged Amazon Parrot (Amazona amazonica). AB - A 33-year-old female intact orange-winged Amazon parrot (Amazona amazonica) presented for a slowly growing mass over the right eye. A computed tomography scan performed with and without intravenous contrast revealed a heterogeneous mixed soft tissue and mineral-dense mass with a small area of non-contrast enhancing fluid density located between the orbits at the caudal aspect of the nasal passages, with associated lysis of the right caudal nasal passage and the right frontal bone. Following euthanasia, the mass was found to consist of soft tissue between the right eye and nostril over the right frontal bone. Lysis of the underlying bone resulted in a bony defect leading into the infraorbital sinus along the dorsorostral aspect of the right eye. Histopathology revealed an unencapsulated, poorly demarcated, highly cellular neoplasm composed of islands and trabeculae of neoplastic cells embedded in abundant loose fibrovascular stroma which completely obliterated the cortical bone and sinuses of the rostral skull and infiltrated the surrounding muscle and soft tissue. Histologically, the tumor was consistent with a high-grade mucoepidermoid carcinoma, characterized by the presence of epidermoid, intermediate, and mucous-producing cell types. No evidence of metastasis was identified. The tissue of origin was suspected to be salivary or nasal mucous glands, but was difficult to confirm due to distortion of normal tissue architecture as a result of the tumor. Although mucoepidermoid carcinomas are a common salivary gland tumor in human medicine, they are not well recognized in avian species, and no specific case reports exist describing this pathology in an Amazon parrot. Despite the lack of distinct salivary glands in most avian species, mucoepidermoid carcinomas can occur, can cause significant clinical disease, and should be included as a differential diagnosis for avian patients presenting with similar lesions. PMID- 28891705 TI - [Why would doctors from Debrecen go abroad? Results of a questionnaire]. AB - INTRODUCTION: Numerous beliefs have arisen in relation to the emigration of doctors. First of all, in most cases emigration has been attributed to, almost exclusively, low salaries. There are a number of non-financial issues that could possibly be more easily addressed. METHOD: In order to get closer to these issues, we sent out a 37-item questionnaire to doctors, who originally graduated from the University of Debrecen. Altogether 82 of them sent back the questionnaire. RESULTS: The mean age at the time of emigration was 32 years. The most popular destination was the United States, however, many colleagues left for the US to do research, as well as clinical practice. Among the European countries, the most popular ones were Sweden, Germany, United Kingdom, Switzerland and Norway. The five most popular clinical specialties were general practice, internal medicine, anesthesiology/intensive care, laboratory/pathology and surgery. With respect to the planned duration of working abroad, at the time of emigration one-fourth of our colleagues planned very short (<2 years) stay. When we asked them now, 38% plans much longer, even indefinite stay. The most common reasons of emigration were also assessed. The most common one was the lack of career track, followed by low salary, quality of life, family issues and adventurousness. Interestingly, burnout and "gratuities" were at the end of the list. A mean 1.3 million HUF per month would make our colleagues satisfied but they think that a mean 486.000 HUF would be realistic and would keep most doctors within the country. As far as university education is concerned, our colleagues agreed that the basic medical knowledge of Hungarian doctors is excellent, but their practical skills are much worse. CONCLUSIONS: Although returning to Hungary would be unrealistic by most colleagues, low salaries are definitely not the most important or exclusive reason for leaving the country. These issues are rather complex, there are numerous non-financial issues, which could be addressed much easier by expressing a positive attitude. Orv Hetil. 2017; 158(37): 1458-1468. PMID- 28891707 TI - [Experiences with the Three-Factor Eating Questionnaire-R21 in young men]. AB - INTRODUCTION: Eating behaviours play a crucial role in the development of obesity. AIMS: To conduct a psychometric analysis of the Three-Factor Eating Questionnaire-R21 and to investigate the correlates of obesogenic eating behaviours among males. METHOD: Participants of the cross-sectional questionnaire based study were male university students (n = 239, mean of age: 20.3 years, SD = 2.78 years). MEASURES: self-reported body weight and body height, Three-Factor Eating Questionnaire-R21, Trait Anxiety Scale of the State-Trait Anxiety Inventory. RESULTS: Results of confirmatory factor analysis supported the theoretical model of the Three-Factor Eating Questionnaire-R21 (chi2(186) = 366.1, p<0.001, CFI = 0.959, TLI = 0.954, RMSEA = 0.064). Internal consistency of the scales was adequate (Cronbach's alpha: 0.79-0.88). Body Mass Index and trait anxiety showed significant, positive associations with eating behaviours, such as uncontrolled eating, cognitive restraint, and emotional eating. CONCLUSIONS: Results support the construct validity and reliability of the Three-Factor Eating Questionnaire-R21 among males and highlight the importance of taking psychological factors into account in the prevention of obesity. Orv Hetil. 2017; 158(37): 1469-1477. PMID- 28891708 TI - [The crisis of the hormonal system: the health-effects of endocrine disruptors]. AB - The endocrine disruptors are natural or arteficial molecules wich are present in the animal (human) environment and entering into the organism. They are bound by hormone receptors, simulating or inhibiting the normal hormonal message. This way they are able to stimulate or hinder the function of the given cell, as well as the synthesis and transport of hormones or receptors. They can cause faulty hormonal imprinting in critical periods of development with lifelong consequences, as alteration of hormone-influenced cell functions, inclination to or manifestation of diseases, so they have medical importance. The number of endocrine disruptors as well as their amount are large and continously growing. Numerous, in adult age manifested disease (e.g. malignant tumors) can be deduced to perinatal harms. Their long-lasting effect can cause the alteration of basal human developmental characteristics (e.g. start of menarche). Vitamins A and D are hormones (exohormones) and could be endocrine disruptors. Perinatal imprinting caused by endocrine disruptors is transmitted to the progenies epigenetically, which also can influence the drug-sensitivity of offspring' receptors. If the epigenetic change is continuously transmitted to the progeny generations, this could have human-evolutionary importance. Orv Hetil. 2017; 158(37): 1443-1451. PMID- 28891709 TI - [Carvedilol in the everyday interventional cardiology practice]. AB - The treatment of severe coronary stenoses with stent implantation is very effective nevertheless, the underlying problem of atherosclerosis remains unsolved with the implantation of a stent. Therefore, besides lifestyle changes, the adequate medication therapy is of pivotal importance. In the majority of patients scheduled for or acutely undergoing catheterisation, beta-blockers form the basis of medication therapy. Members of the group, however, show significant differences in terms of pharmacodynamics. The third-generation beta-blocker and vasodilator carvedilol possesses complex adrenerg-blocking and Ca-channel blocking effects as well. In the background of the favourable effects, a further positive property is its anti-free-radical effect which most beta-blockers do not have. Therefore, as has been proven by several studies, it provides considerable benefits in hypertension, after myocardial infarction, in diabetes and also in the treatment of patients with cardiac failure. These positive effects have been markedly observed in interventional cardiology practice, as the majority of patients undergoing cardiac catheterisation have hypertension, diabetes or hyperlipidaemia. Its anti-free-radical effect is especially beneficial together with its smooth muscle proliferation-inhibitor effect which may favourably affect in-stent restenosis (ISR) as well. To summarise, due to its vasculoprotective effect, carvedilol is an ideal drug of choice following stent implantation in routine everyday practice. Orv Hetil. 2017; 158(37): 1453-1457. PMID- 28891710 TI - The use of a thyroid shield for intraoral anterior oblique occlusal views-a risk based approach. AB - OBJECTIVES: To estimate the radiation dose reduction to the thyroid for an anterior oblique occlusal view from the use of a thyroid shield, compare this with the variation in thyroid dose resulting from differences in examination positioning and discuss the additional considerations associated with the use of a thyroid shield before making a recommendation on their routine use for this examination. METHODS: Doses to the oral mucosa, the salivary glands, the thyroid, the extrathoracic airways, the oesophagus and the lungs were directly measured for anterior oblique occlusal X-rays of a Rando phantom with and without a thyroid shield using strips of calibrated XRQA Gafchromic film. The examination was also simulated using Monte Carlo software for the without thyroid shield case for a comparison of the dose and to evaluate the dosimetric effect of suboptimal examination positioning. RESULTS: A 36% reduction in thyroid dose was measured as a result of thyroid shield use; the effective dose reduction is of the order of 22%. Suboptimal positioning was found to increase thyroid dose by a far more significant amount. CONCLUSIONS: Despite the reduction in thyroid dose, cost benefit considerations mean that the purchase of a thyroid shield is only recommended where a very high number of anterior oblique occlusal views are undertaken. Optimization efforts for this examination are better focussed on training in examination positioning. PMID- 28891711 TI - Time-Dependent Effects on Synovial Fluid Composition During the Acute Phase of Human Intra-articular Ankle Fracture. AB - BACKGROUND: The study objective was to examine the effect of time and fracture severity on the undiluted synovial fluid (SF) microenvironment during the acute phase following intra-articular fracture (IAF) of the human ankle. METHODS: Ankle SF from 54 patients with an acute IAF was analyzed for concentrations of 10 cytokines, 5 matrix metalloproteinases, 2 products of cartilage catabolism, and combined products of heme metabolism. All analytes were correlated with time from fracture and further analyzed for an effect of 3 time subgroups (0-2 days, 3-9 days, and >=10 days) corresponding to timepoints for clinical ankle fracture interventions. The effect of fracture severity was determined by grouping SF according to the number of radiographic intra-articular fracture lines. RESULTS: Fifteen of 18 analytes were significantly correlated with time. Temporal grouping of SF revealed an initial (0-2 days) spike of pro-inflammatory (IL-12p70, IL 1beta, IL-6) and anti-inflammatory (IL-10 and IL-4) cytokines, matrix metalloproteinases (MMP) MMP-9, and sGAG, followed immediately (3-9 days) by products of heme metabolism and an unchallenged surge in mediators and products of cartilage catabolism (MMP-1, MMP-2, MMP-3, MMP-10, and CTX-II). After 10 days, there was a decrease in pro- and anti-inflammatory cytokines but a persistence of mediators of ECM catabolism. There was no clear relationship between the number of fracture lines and SF levels of analytes. CONCLUSIONS: This study demonstrated acute temporal fluctuations following ankle IAF resulting in an overall catabolic environment by 10 days post-fracture and supports consideration of an early evacuation of the joint space to reduce the intra-articular inflammatory burden. Clinical Relavence: This study contributes to the understanding of the intra articular events that potentially contribute to the development of posttraumatic osteoarthritis acutely following IAF in the ankle. PMID- 28891712 TI - Molecular and clinical features of second-generation anaplastic lymphoma kinase inhibitors: ceritinib. AB - The discovery of ALK rearrangement in non-small-cell lung cancer (NSCLC) triggered rapid clinical development of a family of specific drugs targeting this alteration, called ALK inhibitors. Despite high rate of responses, the vast majority of patients treated with first-generation ALK inhibitor crizotinib will ultimately develop disease progression. The second-generation ALK inhibitor, ceritinib, is an oral, small-molecule that inhibits the ALK kinase activity with a potency 20-fold greater than crizotinib, being able to tackle some of the principal mechanisms of resistance to crizotinib. Evidences from five large prospective clinical trials have so far showed impressive activity of ceritinib in ALK inhibitor pretreated and naive NSCLC patients. This review will focus on the preclinical and clinical data available regarding ceritinib pharmacology, clinical efficacy and safety profile. PMID- 28891713 TI - Effect of Preoperative Deformity on Arthroscopic and Open Ankle Fusion Outcomes. AB - INTRODUCTION: Coronal deformity is considered a relative contraindication for arthroscopic ankle fusion. This study assessed whether preoperative coronal ankle joint deformity influenced the outcome of arthroscopic ankle fusion. METHODS: Ninety-seven patients had 62 arthroscopic and 35 open ankle fusions between 2005 and 2012. Clinical outcomes were prospectively recorded with use of the Ankle Osteoarthritis Scale (AOS) and Ankle Arthritis Scale (AAS) preoperatively and at 6, 12, and 24 months and final follow-up. Radiological alignment was measured using the tibiotalar angle, the tibial plafond angle, the lateral talar station, and the lateral tibiotalar angle. Both groups had the same demographics. RESULTS: Preoperative deformity was the same regarding sagittal alignment and overall coronal alignment, but the arthroscopic group had less tibial deformity (tibial plafond angle range 0-19 degrees vs 0-43 degrees). At final follow-up, the mean AOS was 34.2 for arthroscopic (95% confidence interval [CI], 23.3-45.2) vs 33.9 for open (95% CI, 17.8-49.9). The AAS at final follow-up was 26.0 for arthroscopic (95% CI, 21.0-31.0) vs 27.5 for open (95% CI, 19.7-35.2). Both groups had the same tibiotalar angle, lateral talar station, and lateral tibiotalar angle at follow-up. Regression analyses revealed no influence of type of surgery, preoperative deformity, postoperative radiological alignment, age, sex, body mass index, smoking status, etiology of the arthritis, and need for bone grafting on outcome scores (all P > .05). CONCLUSION: Arthroscopic and open ankle fusion yielded equivalent results for both patient-reported outcome measure and radiographic alignment in patients with coronal and sagittal joint deformity. Patients with higher tibial plafond angles more often underwent open fusion. LEVEL OF EVIDENCE: III, comparative series. PMID- 28891714 TI - Preliminaries to Treatment Recommendations in UK Primary Care: A Vehicle for Shared Decision Making? AB - This paper focuses on a recurrent practice observed in UK primary care data - how physicians use pre-recommendations: action sequences that when initiated post diagnosis are recognisably preliminary to the drug treatment recommendations that they contingently project. Data are drawn from recorded primary care consultations collected in England. Pre-recommendations consist of physician requests for information about prior medicines such as, What've you tried taking? or Have you taken anything so far? Patient responses subsequently shape the first part of the base treatment recommendation pair. These preliminaries can help physicians manage potential obstacles to patient acceptance: by avoiding prescribing something a patient is already taking, or has tried and found to be ineffective, and by accommodating concerns such as side effects or practical barriers to acceptance. Pre-recommendations are a strategy for convincing/persuading whilst allowing physicians to avoid making an ill-fitted recommendation that might be resisted or rejected as unwanted or unnecessary. PMID- 28891715 TI - "Where It Falls Apart": Barriers to Retention in HIV Care in Latino Immigrants and Migrants. AB - Latino immigrants in the United States are disproportionately affected by HIV. Barriers to consistent attendance (retention) in HIV primary care constrain opportunities for HIV treatment success, but have not been specifically assessed in this population. We conducted semistructured interviews with 37 HIV-infected Latinos (aged >=18 years and born in Puerto Rico or a Latin American Spanish speaking country) and 14 HIV providers in metropolitan Boston (total n = 51). The Andersen Model of Healthcare Utilization informed a semistructured interview guide, which bilingual research staff used to explore barriers to HIV care. We used thematic analysis to explore the processes of retention in care. Six ubiquitous themes were perceived to influence HIV clinic attendance: (1) stigma as a barrier to HIV serostatus disclosure; (2) social support as a safety net during negative life circumstances; (3) unaddressed trauma and substance use leading to interruption in care; (4) a trusting relationship between patient and provider motivating HIV clinic attendance; (5) basic unmet needs competing with the perceived value of HIV care; and (6) religion providing a source of hope and optimism. Cultural subthemes were the centrality of family (familismo), masculinity (machismo), and trusting relationships (confianza). The timing of barriers was acute (e.g., eviction) and chronic (e.g., family conflict). These co occurring and dynamic constellation of factors affected HIV primary care attendance over time. HIV-infected Latino immigrants and migrants experienced significant challenges that led to interruptions in HIV care. Anticipatory guidance to prepare for these setbacks may improve retention in HIV care in this population. PMID- 28891716 TI - Implementation of a "County-Township-Village" Allied HIV Prevention and Control Intervention in Rural China. AB - In China, rural areas are a weak link of HIV/AIDS prevention and control. From September 2011, an innovative "county-township-village" allied intervention was implemented in Longzhou County, Guangxi, which assigned the tasks of HIV/AIDS prevention and control to the county Centers for Disease Control and Prevention (CDC), township hospitals, and village clinics, respectively, instead of traditional intervention in which the county CDC undertook the entire work. A 6 year consecutive cross-sectional survey, including 3-year traditional intervention (2009-2011) and 3-year innovative intervention (2012-2014), was conducted to evaluate the effects of the new intervention. Compared to traditional intervention, the innovative intervention achieved positive effects in decreasing risky behaviors. Among female sex workers, condom use rate in the last month increased from 72.06% to 96.82% (p < 0.01). Among drug users, having commercial sex rate in the last year reduced from 17.20% to 5.94% and condom use rate increased from 14.06% to 76.09% (p < 0.01). The risk ratio of HIV infection during innovative intervention was 0.631 (95% confidence interval 0.549-0.726) compared with traditional one. Cost-effectiveness analysis indicates that innovative intervention restores each disability-adjusted life year costing an average of $124.26. Taken together, Longzhou's innovative intervention has achieved good effects on HIV/AIDS prevention and control and provides a good reference for rural China. PMID- 28891717 TI - Longitudinal Viral Suppression Among a Cohort of Adolescents and Young Adults with Behaviorally Acquired Human Immunodeficiency Virus. AB - Youth living with HIV (YLWH) are less likely than older adults to achieve and sustain viral suppression. While treatment guidelines recommend decreased viral load (VL) monitoring in individuals with well-controlled HIV, the appropriateness of this strategy for adolescents is unknown. We conducted a retrospective cohort study to describe longitudinal viral suppression and identify incidence of, and risk factors for, virologic failure among YLWH at a US adolescent HIV clinic from 2002 to 2015. We utilized Cox proportional hazards modeling to compare hazard ratios (HRs) for virologic failure stratified by baseline characteristics. Study participants (n = 365) were predominately African American (87%) and cisgender men and transgender women who have sex with men (80%) and the majority (79%) entered care from 2002 to 2012. Of antiretroviral therapy (ART)-treated participants (n = 201), 88% achieved viral suppression, with 29% subsequently developing virologic failure at a median 12.0 months [interquartile range (IQR) 6.9-22.4] after suppression. The cohort incidence rate of virologic failure was 200 (confidence interval [95% CI]: 151-264) per 1000 person years (PY), with a rate after >=2 years sustained suppression of 113 (95% CI: 57-227) per 1000 PY. After adjusting for time to ART initiation, initial regimen class, and year of cohort entry, cisgender women had increased hazards of virologic failure (HR 3.2 95% CI: 1.3-7.9, p = 0.01). In conclusion, youth remained at high risk of virologic failure throughout their treatment course, with higher hazards of virologic failure among cisgender women compared with other youth. Maintaining frequent VL monitoring in YLWH may be warranted, even after prolonged viral suppression. PMID- 28891718 TI - Identification, expression analysis, and the regulating function on C/EBPs of KLF10 in Dalian purple sea urchin, Strongylocentrotus nudus. AB - Accumulating evidence indicates that Kruppel-like factors (KLFs) play important roles in fat biology via the regulation of CCAAT/enhancer binding proteins (C/EBPs). However, KLFs and C/EBPs have not been identified from Strongylocentrotus nudus, and their roles in this species are not clear. In this study, the full-length cDNA of S. nudus KLF10 (SnKLF10) and three cDNA fragments of S. nudus C/EBPs (SnC/EBPs) were obtained. Examination of tissue distribution and expression patterns during gonadal development implied that SnKLF10 and SnC/EBPs play important roles in gonadal lipogenesis. The presence of transcription factor-binding sites (TFBSs) for KLFs in SnC/EBPs, and the results of an over-expression assay, revealed that SnKLF10 negatively regulates the transcription of SnC/EBPs. In addition, the core promoter regions of SnC/EBPs were determined, and multiple TFBSs for transcription factor (TFs) were identified, which are potential regulators of SnC/EBP transcription. Taken together, these results suggest that SnC/EBP genes are potential targets of SnKLF10, and that SnKLF10 plays a role in lipogenesis by repressing the transcription of SnC/EBPs. These findings provide information for further studies of KLF10 in invertebrates and provide new insight into the regulatory mechanisms of C/EBP transcription. PMID- 28891719 TI - Understanding Strategic Information Use During Emotional Expression Judgments in Williams Syndrome. AB - Detailed analysis of expression judgments in Williams syndrome reveals that successful emotion categorization need not reflect "classic" information processing strategies. These individuals draw upon a distinct set of featural details to identify happy and fearful faces that differ from those used by typically developing comparison groups: children and adults. The diagnostic visual information is also notably less interlinked in Williams syndrome, consistent with reports of diminished processing of configural information during face identity judgments. These results prompt reconsideration of typical models of face expertise by revealing that an age-appropriate profile of expression performance can be achieved via alternative routes. PMID- 28891720 TI - Vestibular rehabilitation following surgical repair for Superior Canal Dehiscence Syndrome: A complicated case report. AB - Superior Canal Dehiscence Syndrome (SCDS) causes auditory and vestibular symptoms. Following surgical repair of the dehiscence, patients often experience dizziness and imbalance. This case report describes a postoperative vestibular exercise program, focusing on the principles of central compensation and habituation, and how it was modified for a patient with delayed progress secondary to strabismus and visual vertigo. A 63-year-old male with history of strabismus eye surgery, right hearing loss, aural fullness, and sensitivity to loud sounds was referred for vestibular rehabilitation (VR). He was seen for one preoperative and six postoperative PT visits over eight months. Outcome measures two weeks postoperative were as follows: Dizziness Handicap Inventory (DHI) 38/100; Timed Up & Go (TUG) 9.92 seconds; Dynamic Gait Index (DGI) 16/24; and a 3 line difference in Dynamic Visual Acuity (DVA). Improved outcomes at discharge included: DHI 18/100; TUG 6.87 seconds; DGI 23/24; and 1-line difference in DVA. He was able to return to work and previously enjoyed recreational activities. Postoperative vestibular rehabilitation programs are functionally and symptomatically beneficial following surgical repair for SCDS. Deviations from expected recovery should be addressed to achieve optimal outcomes as demonstrated in this complicated case report. PMID- 28891721 TI - The Regions on the Light Chain of Botulinum Neurotoxin Type A Recognized by T Cells from Toxin-Treated Cervical Dystonia Patients. The Complete Human T-Cell Recognition Map of the Toxin Molecule. AB - We have recently mapped the in vitro proliferative responses of T cells from botulinum neurotoxin type A (BoNT/A)-treated cervical dystonia (CD) patients with overlapping peptides encompassing BoNT/A heavy chain (residues 449-1296). In the present study, we determined the recognition profiles, by peripheral blood lymphocytes (PBL) from the same set of patients, of BoNT/A light (L) chain (residues 1-453) by using 32 synthetic overlapping peptides that encompassed the entire L chain. Profiles of the T-cell responses (expressed in stimulation index, SI; Z score based on transformed SI) to the peptides varied among the patients. Samples from 14 patients treated solely with BoNT/A recognized 3-13 (average 7.2) peptides/sample at Z > 3.0 level. Two peptide regions representing residues 113 131 and 225-243 were recognized by around 40% of these patients. Regarding treatment parameters, treatment history with current BOTOX(r) only group produced significantly lower average T-cell responses to the 32 L-chain peptides compared to treatments with mix of type A including original and current BOTOX(r). Influence of other treatment parameters on T-cell recognition of the L-chain peptides was also observed. Results of the submolecular T-cell recognition of the L chain are compared to those of the H chain and the T-cell recognition profile of the entire BoNT/A molecule is discussed. Abbreviations used: BoNT/A, botulinum neurotoxin type A; BoNT/Ai, inactivated BoNT/A; BoNT/B, botulinum neurotoxin type B; CD, cervical dystonia; L chain, the light chain (residues 1-448) of BoNT/A; LNC, lymph node cells; H chain, the heavy chain (residues 449-1296) of BoNT/A; HC, C-terminal domain (residues 855-1296) of H chain; HN, N-terminal domain (residues 449-859) of H chain; MPA, mouse protection assay; SI, stimulation index (SI = cpm of 3H-thymidine incorporated by antigen-stimulated T cells/cpm incorporated by unstimulated cells); TeNT, tetanus neurotoxin; TeNTi, inactivated TeNT. PMID- 28891722 TI - Requirements, Strengths and Weaknesses of Inhaler Devices for COPD Patients from the Expert Prescribers' Point of View: Results of the EPOCA Delphi Consensus. AB - The study aimed to assess the preferences of expert physicians about the requirements for inhalation devices for patients with chronic obstructive pulmonary disease (COPD) and to identify the most relevant advantages and disadvantages to their prescription. In a two-round Delphi survey, 96 Spanish COPD-expert pulmonologists completed an internet-based questionnaire to evaluate the degree of importance of the characteristics of the inhaler devices in their choice for COPD. The requirements needed for use in COPD were that the device permits a high pulmonary deposit of the drug, allowed its dispensation at low inspiratory flows, did not require hand-mouth coordination, generated an exact and reproducible dose, its operation was easy to teach, provided the perception of a correct inhalation, had an intuitive use mechanism and security mechanisms to prevent overdosing and generates a reduced oropharyngeal deposit (very good consensus). Modulite(r), Respimat(r) and NEXThaler(r) were associated with high pulmonary deposit, and Respimat(r) showed correct dispensation at low inspiratory flows. All dry-powder inhaler devices were associated with the advantage of not requiring coordination, and Respimat(r) was the only device considered as difficult to teach by more than 50% of the experts. Breezhaler(r) and Genuair(r) were positively associated with patients' awareness of correct inhalation, whereas Spiromax(r) stood out for its intuitive use mechanism. In conclusion, our study contributes to defining the inhaler device properties required for their use in patients with COPD, and to identify the devices that, in the opinion of experts, best meet each requirement. PMID- 28891723 TI - State-Mandated Nutrition, Physical Activity, and Screen Time Policies in Child Care Centers. AB - BACKGROUND: The child care center (CCC) environment presents opportunities for healthy weight promotion in preschoolers. Our study examined the current state of CCC adherence to nutrition, physical activity, and screen time legislative regulations and the differences in their adherence by center socioeconomic position (SEP: low, middle, high) in Miami-Dade County. METHOD: In 34 CCC, we used the Environment and Policy Assessment and Observation tool to evaluate nutrition, physical activity, and screen time practices during 1-school day. RESULTS: Twenty-five of the centers (73.5%) were participants of the Child and Adult Care Food Program. Almost 80% of the centers adhered to serving low-fat/fat free milk to children older than 2 years. Only 34.5% served vegetables and 75.9% served whole fruits during meals/snacks. Ninety-four percent of the centers had quiet and active play incorporated into their daily routines. All centers adhered to the 2-hour screen time limit for children older than 2 years. Low- and middle SEP centers fared better in the serving of fruits, vegetables, and low-fat/fat free milk. The centers averaged 1 hour in outdoor play regardless of SEP. High SEP centers had no TV or screen time during day of observation. CONCLUSION: CCC practices highlight opportunities for improvement in nutrition, physical activity, and screen time practices in the prevention of overweight in early childhood. PMID- 28891724 TI - What Makes Systematic Reviews Systematic and Why are They the Highest Level of Evidence? PMID- 28891725 TI - Age-related change in corneal biomechanical parameters in a healthy Caucasian population. AB - PURPOSE: To determine the effect of aging on corneal biomechanical parameters measured via ocular response analyzer in a homogenous healthy Caucasian population. METHODS: A total of 2039 Caucasian adults were consecutively recruited and divided into seven groups according to decades of age. The difference in mean corneal hysteresis (CH), mean corneal resistance factor (CRF), mean Goldmann-correlated intraocular pressure (IOPg), and mean corneal compensated IOP (IOPcc) between decades of age were investigated. The strength of the correlations between corneal biomechanical parameters, and between each biomechanical parameter and age were evaluated. The effect of age on each corneal biomechanical parameter was analyzed. RESULTS: Mean age of the participants (1173 female and 866 male) was 43.30 +/- 14.64 years. Mean CH, CRF, IOPcc, and IOPg were 11.49 +/- 1.89 mmHg, 11.40 +/- 2.30 mmHg, 15.01 +/- 3.11 mmHg, and 15.72 +/- 3.80 mmHg, respectively. There were significant differences in mean CH, CRF, IOPcc, and IOPg between groups (p < 0.001 for all parameters). There was a significant negative correlation between age and CH (r = -0.067 and p = 0.003), and a significant negative correlation between age and CRF (r = -0.053 and p = 0.017). There was a significant positive correlation between age and IOPg (r = 0.25 and p < 0.001), and between age and IOPcc (r = 0.20 and p < 0.001). Linear regression analysis showed that for every 1-year increase CH decreased 0.011 mmHg, CRF decreased 0.004 mmHg, IOPcc increased 0.053 mmHg, and IOPg increased 0.047 mmHg. CONCLUSIONS: Aging can cause significant changes in corneal biomechanical parameters. Corneal biomechanical parameters were correlated with each other, and each was correlated with aging. PMID- 28891726 TI - NK Cell Effector Functions Regulation by Modulating nTreg Cell Population During Progressive Growth of Dalton's Lymphoma in Mice. AB - Natural killer (NK) cells are large granular lymphocytes of the innate immune system and play a pivotal role against virus-infected cells, microbial pathogens, and tumor cells. NK cells secrete several cytokine,s but IFN-gamma secreted by NK cells play a vital role in the activation of the innate and adaptive immune systems. But during any infection or tumor burden, functional activity of NK cells is downregulated significantly by nTreg cells. It is also found that during tumor progression, the number of nTreg cells increases as a result; it effectively suppresses the antitumor activity of NK cells. Therefore, in the present investigation, we intend to examine the mechanism of downregulation of antitumor immune response mediated by NK cells. We observed increased NK cell population at an early stage of Dalton's lymphoma (DL) growth, while at late stage, NK cell numbers were decreased. The NK cell functional activity was govern by high level of IFN-gamma measurement during tumor progression. The FoxP3+ CD25+ CD4+ T regulatory cell population was found to be continuously increased with high-level expression of FoxP3 during DL growth. The rapid increase in the number of Treg cells during DL progression may be due to high level of the FoxP3 transcription factor. The tumor microenvironment of DL cell progression has highly deleterious effect on NK cells after massive growth of tumor burden in BALB/c mice. This result also indicates that NK cell proliferation, activation, and accumulation are under the control of regulatory T cells. PMID- 28891727 TI - Methodology of the ZOC-BHVI High Myopia Cohort Study: The Onset and Progression of Myopic Pathologies and Associated Risk Factors in Highly Myopic Chinese. AB - PURPOSE: The increasing prevalence of high myopia and its associated pathologies has raised challenges to ophthalmic services. This project aims to explore the onset and progression of myopic pathologies in highly myopic eyes through a prospective research cohort established in South China. METHODS: Patients with high myopia (sphere <= -6.00 D) visiting the optometric clinic of Zhongshan Ophthalmic Center (ZOC) were invited to participate in the baseline examinations and follow-up visit over a 10-year period. People having secondary myopia, history of any refractive surgery, significant ocular media opacity, or other severe health problems were excluded. The measurements included visual acuity, ocular biometry, visual function, cycloplegic refraction, fundus imaging, ocular shape by MRI, blood tests and questionnaires. RESULTS: A total of 890 participants completed the baseline examinations, with a mean age at baseline of 22.7 +/- 12.4 years. The mean spherical equivalent at baseline was 10.13 +/- 3.65 D, and the mean axial length (AL) was 27.52 +/- 1.63 mm. The older subjects tended to have more severe myopia and longer ALs. CONCLUSION: The study will provide new knowledge on the relationship between high myopia and pathological changes such as myopic macular degeneration and staphyloma. PMID- 28891728 TI - Bioengineered dermal substitutes for the management of traumatic periocular tissue loss. AB - PURPOSE: Traumatic periocular injuries occasionally result in significant soft tissue loss, for which there are limited management options that provide satisfactory cosmetic and functional outcomes. The authors describe the use of a bioengineered dermal substitute (Integra(r) Dermal Regeneration Template [DRT], Integra LifeSciences, Plainsboro, NJ) as an alternative to immediate flap reconstruction or skin grafting. METHODS: Retrospective interventional case series of patients who underwent DRT placement for periocular tissue loss at the time of trauma. In each case, primary closure or immediate flap reconstruction was deemed impractical or undesirable due to the size and location of the primary and associated secondary defects. One to four weeks later, the outer silicone layer was removed and healing assessed. Additional reconstructive techniques were performed as needed. RESULTS: Three patients were treated at Bascom Palmer Eye Institute and one at Byers Eye Institute at Stanford. The defects healed completely in two patients, and by 79.2% in a third, with no need for additional reconstructive surgery. In the remaining patient, the defect was significantly downsized by 56.1%, allowing for a simpler flap reconstruction. CONCLUSIONS: Bioengineered dermal substitutes should be considered as a viable alternative to traditional reconstructive techniques for large periocular defects resulting from trauma. The outer silicone layer prevents desiccation and serves as a protective barrier, while the inner collagen matrix organizes the growth of neo-dermis and minimizes wound contraction. The dimensions of cutaneous defects can therefore be reduced dramatically, potentially eliminating the need for skin grafting and/or reducing the ultimate complexity of flap reconstruction. PMID- 28891729 TI - Early Age-related Macular Degeneration with Cardiovascular and Renal Comorbidities: An Analysis of the National Health and Nutrition Examination Survey, 2005-2008. AB - PURPOSE: A cross sectional study was designed to examine the relationship of early age-related macular degeneration (AMD) with comorbidities of cardiovascular and renal conditions in the representative population using National Health and Nutrition Examination Survey (NHANES), 2005-2008. METHODS: Participants (>=40 years) who underwent retinal photography were included. Early AMD was defined by the retinal digital images. The comorbidities were self-reported stroke and heart disease (HD), including angina pectoris (AP), coronary heart disease (CHD), congestive heart failure (CHF), and myocardial infarction (MI). Chronic kidney disease (CKD) was determined based on self-report, estimation of glomerular filtration rate (GFR), or the level of urine albumin. RESULTS: The age-adjusted odds ratio (OR) and 95% CI for having early AMD for persons with the selected conditions were: 2.6 (1.9, 3.6) for any type of HD. When the conditions were considered separately, ORs (95% CIs) were: 2.0 (1.2, 3.4) for AP; 2.5 (1.6, 3.8) for CHD; 2.4 (1.6, 3.6) for MI; 2.3 (1.3, 3.9) for CHF; 3.3 (2.2, 5.0) for stroke; and 2.4 (1.8, 3.2) for CKD. Covariable-adjusted ORs (AOR) were attenuated for all examined conditions, but remained statistically significant. Having any single condition (AOR [95%CI]: 2.7 [1.5, 4.8]) was significantly associated with early AMD, as was having >= 2 conditions (AOR [95%CI]: 5.2 [3.0, 9.0]). The strongest association was between early AMD and the combination of HD and stroke (AOR [95% CI]: 6.3 [2.9, 13.8]). CONCLUSION: Cardiovascular and renal comorbidities are associated with early AMD in a representative sample of the US general population. PMID- 28891730 TI - Evaluation of Approaches to Analyzing Continuous Correlated Eye Data When Sample Size Is Small. AB - PURPOSE: To evaluate the performance of commonly used statistical methods for analyzing continuous correlated eye data when sample size is small. METHODS: We simulated correlated continuous data from two designs: (1) two eyes of a subject in two comparison groups; (2) two eyes of a subject in the same comparison group, under various sample size (5-50), inter-eye correlation (0-0.75) and effect size (0-0.8). Simulated data were analyzed using paired t-test, two sample t-test, Wald test and score test using the generalized estimating equations (GEE) and F test using linear mixed effects model (LMM). We compared type I error rates and statistical powers, and demonstrated analysis approaches through analyzing two real datasets. RESULTS: In design 1, paired t-test and LMM perform better than GEE, with nominal type 1 error rate and higher statistical power. In design 2, no test performs uniformly well: two sample t-test (average of two eyes or a random eye) achieves better control of type I error but yields lower statistical power. In both designs, the GEE Wald test inflates type I error rate and GEE score test has lower power. CONCLUSION: When sample size is small, some commonly used statistical methods do not perform well. Paired t-test and LMM perform best when two eyes of a subject are in two different comparison groups, and t-test using the average of two eyes performs best when the two eyes are in the same comparison group. When selecting the appropriate analysis approach the study design should be considered. PMID- 28891731 TI - Relationships among Type-D personality, symptoms and quality of life in patients with ovarian cancer receiving chemotherapy. AB - PURPOSE: The objective of this study was to investigate the prevalence of Type-D personality and identify its relationships among the symptoms and quality of life in patients with ovarian cancer-receiving chemotherapy. METHODS: A total of 150 patients with ovarian cancer undergoing chemotherapy were recruited between December 2015 and August 2016. The subjects were assessed using the Type-D Personality Scale-14, Memorial Symptom Assessment Scale - Short Form and Functional Assessment of Cancer Therapy-General questionnaire completed through a face-to-face interview. RESULTS: About 56% of patients were classified into the Type-D personality group. This personality group showed statistically significantly higher symptoms and lower quality of life than the non-Type-D personality group. According to stepwise multiple regression, the most significant factor influencing quality of life was symptoms, followed by Type-D personality, performance status and cancer stage. CONCLUSIONS: The prevalence of Type-D personality in patients with ovarian cancer was high, and Type-D personality was significantly associated with a high symptom score and lower quality of life. Health professionals should consider Type-D personality in the assessment and intervention of symptoms and quality of life, along with performance status and cancer stage. PMID- 28891733 TI - Application of laboratory and digital techniques for visual enhancement during the ultrastructural assessment of cilia. AB - Routine diagnostic electron microscopy of primary ciliary dyskinesia (PCD) is based on the findings of ultrastructural defects of axonemal components. Assessment of the typical abnormalities can be enhanced by improving the sample preservation status using tannic acid (TA) as additive in the biopsy fixation or processing steps. Another option is the implementation of computer-assisted image analysis tools. Advancements in high-resolution 3D visualization of the axonemal structure have been noted, with great potential for the future diagnosis of inherited cilia disorders. PMID- 28891734 TI - Through a Student's Eye. PMID- 28891732 TI - Effects of vitamin D supplementation on carotid intima-media thickness in HIV infected youth. PMID- 28891735 TI - Coexistence of two novel resistance plasmids, blaKPC-2-carrying p14057A and tetA(A) -carrying p14057B, in Pseudomonas aeruginosa. PMID- 28891736 TI - Neural Correlates of Expert Behavior During a Domain-Specific Attentional Cueing Task in Badminton Players. AB - The present study aimed to investigate the neural correlates associated with sports expertise during a domain-specific task in badminton players. We compared event-related potentials activity from collegiate male badminton players and a set of matched athletic controls when they performed a badminton-specific attentional cueing task in which the uncertainty and validity were manipulated. The data showed that, regardless of cue type, the badminton players had faster responses along with greater P3 amplitudes than the athletic controls on the task. Specifically, the contingent negative variation amplitude was smaller for the players than for the controls in the condition involving higher uncertainty. Such an effect, however, was absent in the condition with lower uncertainty. We conclude that expertise in sports is associated with proficient modulation of brain activity during cognitive and motor preparation, as well as response execution, when performing a task related to an individual's specific sport domain. PMID- 28891737 TI - Erratum: Jones, Karageorghis, & Ekkekakis (2014). AB - The DOI for the article "Can High-Intensity Exercise Be More Pleasant? Attentional Dissociation Using Music and Video," by Leighton Jones, Costas I. Karageorghis, and Panteleimon Ekkekakis, in the Journal of Sport and Exercise Psychology 36(5), was incorrectly printed. The correct DOI for this article is http://dx.doi.org/10.1123/jsep.2013-0251 . The online version of this article has been corrected. PMID- 28891738 TI - Restless Genital Syndrome (ReGS) Should Be Distinguished From Spontaneous Orgasms: A Case Report of Cannabis-Induced Spontaneous Orgasm. AB - A case is described of a 40-year-old woman with persistent spontaneous orgasms after use of cannabis and five hours of intense pounding sexual activity. She presented with severe anxiety, in particular suffering from restless genital syndrome (ReGS). However, she did not fulfill any of the five criteria of ReGS. It was concluded that her spontaneous orgasms were the result of the use of cannabis combined with the long duration of previous sexual activity. This finding is not only important for physicians, but also for highly exposed subjects such as those active in the sex industry. PMID- 28891739 TI - Reply to the Comments by Mortazavi and Doss on "Solid Cancer Incidence among the Life Span Study of Atomic Bomb Survivors: 1958-2009" (Radiat Res 2017; 187:513 537). PMID- 28891740 TI - Host Abundance, Sea-Grass Cover, and Temperature Predict Infection Rates of Parasitic Isopods (Bopyridae) on Caridean Shrimp. AB - Caridean shrimp are critical components of sea-grass communities and occasionally harbor parasitic bopyrid isopods, which can negatively impact their hosts. However, the ecological factors that drive infection rates of parasitic bopyrid isopods in host carideans are poorly known. We examined 43,875 carideans belonging to 6 families and 11 genera from 19 shallow-water localities throughout south Florida. Of these, only 114 shrimp (belonging to 5 genera) were found to be infested with bopyrids (an additional 251 had deformed carapaces consistent with recent infestation). We identified 13 bopyrid species ( Bopyrina abbreviata, Bopyrinella thorii, Eophrixus subcaudalis, Loki circumsaltanus, Metaphrixus carolii, Ovobopyrus alphezemiotes, Parabopyrella lata, Parabopyrella richardsonae, Parabopyriscus stellatus, Capitetragonia alphei, Probopyrus pandalicola, Schizobopyrina urocaridis, and an unidentified Diplophryxus sp.). Bopyrid infection rates were very low throughout the study area, with mean prevalence of 0.26% (range 0.04-1.48%). Furthermore, each isopod species was only ever recovered from a single host genus, suggesting a high degree of genus-level specificity. At the community level, multivariate analyses (RELATE and BVSTEP) indicated that bopyrid community composition was correlated with host community structure, latitude, and temperature, as well as the relative coverage of the sea grasses Thalassia sp. and Syringodium sp. and the alga Penicillus sp. Only 4 parasite taxa were sufficiently abundant to warrant further analysis at the individual taxon level: B. abbreviata, B. thorii, Diplophryxus sp., and P. pandalicola; stepwise regression indicated that bopyrid infection rates were primarily driven by the abundance of their specific hosts, and secondarily by environmental variables such as temperature and depth, as well as algal and sea grass community composition. PMID- 28891742 TI - The Digest. PMID- 28891741 TI - eRNA binding produces tailored CBP activity profiles to regulate gene expression. AB - Enhancers are cis- regulatory genetic elements crucial for controlling temporal and cell-type specific patterns of gene expression. Active enhancers generate bi directional non-coding RNA transcripts called enhancer RNAs (eRNAs). eRNAs are important for stimulating gene expression, but precise mechanisms for this ability remain unclear. Here we highlight recent findings that demonstrate a direct interaction between RNAs and the transcriptional co-activator Creb-binding protein (CBP). Notably, RNA binding could stimulate the core histone acetyltransferase activity of the enzyme, observable in cells as a link between eRNA production, CBP-dependent histone acetylation and expression of genes regulated by specific enhancers. Although RNA binding was independent of RNA sequence, specificity arises in a locus-specific manner at transcribed sites where CBP was bound to chromatin. The results suggest a functional role for eRNAs as regulatory molecules that are able to stimulate the activity of a key epigenetic regulatory enzyme, thereby promoting gene expression. Furthermore, they suggest an intriguing role for eRNAs: by modulating the activity of chromatin modifying enzymes, they could directly impact transcription by altering the chromatin environment. PMID- 28891743 TI - High-intensity cardiorespiratory and strength exercises reduced emotional distress and fatigue in patients with axial spondyloarthritis: a randomized controlled pilot study. AB - OBJECTIVE: To investigate the effect of high-intensity exercise on emotional distress, fatigue, and ability to do a full day's activities in patients with axial spondyloarthritis (axSpA). METHOD: A total of 28 physically inactive axSpA patients were randomized to either an exercise group (EG), which performed 12 weeks of cardiorespiratory and strength exercises, or a control group (CG), which received treatment as usual. The outcomes reported in this paper are secondary outcomes in the trial and included emotional distress (General Health Questionnaire-12, 0-36, 36 = worst), fatigue [numeric rating scale (NRS), 0-10, 10 = worst], and ability to do a full day's activities (NRS, 0-10, 10 = worst). Post-intervention differences were assessed by analysis of covariance with baseline values as covariates. RESULTS: Twenty-four patients were included in the analyses. All patients in the EG followed the exercise protocol. The EG had a statistically significant beneficial effect [mean group differences (95% confidence interval)] on emotional distress [-5.8, (-9.7, -1.9), p < 0.01], fatigue [-2.4, (-4.3, -0.4), p = 0.02], and ability to do a full day's work [ 2.2, (-3.9, -0.4), p = 0.02] compared to the CG. CONCLUSION: This pilot study showed promising effects of cardiorespiratory and strength exercises on emotional distress, fatigue, and ability to do a full day's activities in patients with axSpA. The findings need to be confirmed in a larger trial. PMID- 28891744 TI - Caloric restriction promotes rapid expansion and long-lasting increase of Lactobacillus in the rat fecal microbiota. AB - Previous studies indicated that caloric restricted diet enables to lower significantly the risk of cardiovascular and metabolic diseases. In experimental animal models, life-long lasting caloric restriction (CR) was demonstrated to induce changes of the intestinal microbiota composition, regardless of fat content and/or exercise. To explore the potential impact of short and long-term CR treatment on the gut microbiota, we conducted an analysis of fecal microbiota composition in young and adult Fisher 344 rats treated with a low fat feed under ad libitum (AL) or CR conditions (70%). We report here significant changes of the rat fecal microbiota that arise rapidly in young growing animals after short-term administration of a CR diet. In particular, Lactobacillus increased significantly after 8 weeks of CR treatment and its relative abundance was significantly higher in CR vs AL fed animals after 36 weeks of dietary intervention. Taken together, our data suggest that Lactobacillus intestinal colonization is hampered in AL fed young rats compared to CR fed ones, while health-promoting CR diet intervention enables the expansion of this genus rapidly and persistently up to adulthood. PMID- 28891745 TI - Motor control of handwriting in the developing brain: A review. AB - This review focuses on the acquisition of writing motor aspects in adults, and in 5-to 12-year-old children without learning disabilities. We first describe the behavioural aspects of adult writing and dominant models based on the notion of motor programs. We show that handwriting acquisition is characterized by the transition from reactive movements programmed stroke-by-stroke in younger children, to an automatic control of the whole trajectory when the motor programs are memorized at about 10 years old. Then, we describe the neural correlates of adult writing, and the changes that could occur with learning during childhood. The acquisition of a new skill is characterized by the involvement of a network more restricted in space and where neural specificity is increased in key regions. The cerebellum and the left dorsal premotor cortex are of fundamental importance in motor learning, and could be at the core of the acquisition of handwriting. PMID- 28891746 TI - Impact of Sex on Systemic Lupus Erythematosus-Related Causes of Premature Mortality in the United States. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is a source of significantly decreased life expectancy in the United States. This study investigated causes of deaths among males and females with SLE. MATERIALS AND METHODS: This cross-sectional study used the national death certificate database of ~2.7 million death records in the United States, 2014. SLE was defined using Tenth Revision of the International Classification of Diseases codes: M32.1, M32.9, and M32.8. We compared sex-stratified demographic characteristics and the most commonly listed comorbidities in decedents with and without SLE. Relative risks (RRs) quantified the risk of dying with the most commonly listed comorbidities among decedents with SLE aged <=50 years compared with non-SLE decedents. RESULTS: There were 2,036 decedents with SLE in the United States (86.2% female). Female SLE decedents were 22 years younger than non SLE females (median: 59 years vs. 81 years). This difference was 12 years among male decedents (median: 61 years vs. 73 years). The most frequently listed causes of death among female SLE decedents were septicemia (4.32%) and hypertension (3.04%). In contrast, heart disease (3.70%) and diabetes mellitus with complications (3.61%) were the most common among male SLE decedents. Among younger male decedents, SLE had higher co-occurrence of coagulation/hemorrhagic disorders and chronic renal failure compared with non-SLE (RR = 16.69 [95% confidence interval {CI} = 10.50-27.44] and RR = 5.76 [95% CI = 2.76-12.00], respectively). These also contributed to premature mortality among women (RR = 4.98 [95% CI = 3.69-6.70] and 8.55 [95% CI = 6.89-10.61], respectively). CONCLUSIONS: Our findings identify clinically relevant comorbidities that may warrant careful consideration in patients' clinical management and the natural history of SLE. PMID- 28891747 TI - An important question: Which LPS do you use? PMID- 28891748 TI - Teammate Prosocial and Antisocial Behaviors Predict Task Cohesion and Burnout: The Mediating Role of Affect. AB - The manner in which teammates behave toward each other when playing sport could have important achievement-related consequences. However, this issue has received very little research attention. In this study, we investigated whether (a) prosocial and antisocial teammate behaviors predict task cohesion and burnout, and (b) positive and negative affect mediates these relationships. In total, 272 (Mage = 21.86, SD = 4.36) team-sport players completed a multisection questionnaire assessing the aforementioned variables. Structural equation modeling indicated that prosocial teammate behavior positively predicted task cohesion and negatively predicted burnout, and these relationships were mediated by positive affect. The reverse pattern of relationships was observed for antisocial teammate behavior which negatively predicted task cohesion and positively predicted burnout, and these relationships were mediated by negative affect. Our findings underscore the importance of promoting prosocial and reducing antisocial behaviors in sport and highlight the role of affect in explaining the identified relationships. PMID- 28891749 TI - It Depends on the Partner: Person-Related Sources of Efficacy Beliefs and Performance for Athlete Pairs. AB - This study explored person-related sources of variance in athletes' efficacy beliefs and performances when performing in pairs with distinguishable roles differing in partner dependence. College cheerleaders (n = 102) performed their role in repeated performance trials of two low- and two high-difficulty paired stunt tasks with three different partners. Data were obtained on self-, other-, and collective efficacy beliefs and subjective performances, and objective performance assessments were obtained from digital recordings. Using the social relations model framework, total variance in each belief/assessment was partitioned, for each role, into numerical components of person-related variance relative to the self, the other, and the collective. Variance component by performance role by task-difficulty repeated-measures analysis of variances revealed that the largest person-related variance component differed by athlete role and increased in size in high-difficulty tasks. Results suggest that the extent the athlete's performance depends on a partner relates to the extent the partner is a source of self-, other-, and collective efficacy beliefs. PMID- 28891750 TI - Acceptability and Preliminary Efficacy of a Lesbian, Gay, Bisexual, and Transgender-Affirmative Mental Health Practice Training in a Highly Stigmatizing National Context. AB - PURPOSE: Lesbian, gay, bisexual, and transgender (LGBT) individuals in Romania encounter pervasive stigma and discrimination and there is a high need for LGBT competent mental health professionals (MHPs). We tested the impact of a pilot LGBT-affirmative training for MHPs in Romania on these professionals' LGBT relevant attitudes, knowledge, and perception of clinical skills. METHODS: We conducted a 2-day training for MHPs in Bucharest. Fifty-four attended and 33 provided training evaluation data at baseline and follow-up. RESULTS: The majority of trainees were female (90%) and heterosexual (73%) with a mean age of 36.4 (SD = 7.7). From baseline to follow-up, trainees demonstrated a significant increase in perceived LGBT-relevant clinical skills (P < 0.001) and perceived knowledge (P < 0.05). LGBT-affirmative practice attitudes (P < 0.05) and comfort in addressing the mental health of LGBT individuals (P < 0.01) increased significantly, and homonegative and transnegative attitudes decreased significantly (P < 0.01). Negative attitudes toward LGBT individuals were low at both baseline and follow-up. The majority of trainees reported being highly interested in the training (84%), which they reported had prepared them to interact with and care for LGBT individuals (74%). CONCLUSION: This pilot training appeared to be effective in increasing perceived LGBT competence among participating MHPs. This type of training model needs to be tested further in a randomized controlled trial with longer follow-up periods to assess intervention durability and implementation of clinical skills. Future trainings can be incorporated into existing curricula. National accreditation bodies might consider encouraging such training as part of standard educational requirements. PMID- 28891751 TI - Rotavirus vaccine response correlates with the infant gut microbiota composition in Pakistan. AB - Rotavirus (RV) is the leading cause of diarrhea-related death in children worldwide and ninety-five percent of rotavirus deaths occur in Africa and Asia. Rotavirus vaccines (RVV) can dramatically reduce RV deaths, but have low efficacy in low-income settings where they are most needed. The intestinal microbiome may contribute to this decreased RVV efficacy. This pilot study hypothesizes that infants' intestinal microbiota composition correlates with RVV immune responses and that RVV responders have different gut microbiota as compared to non responders. We conducted a nested, matched case-control study comparing the pre vaccination intestinal microbiota composition between 10 6-week old Pakistani RVV responders, 10 6-week old Pakistani RVV non-responders, and 10 healthy Dutch infants. RVV response was defined as an Immunoglobulin A of >=20 IU/mL following RotarixTM(RV1) vaccination in an infant with a pre-vaccination IgA<20. Infants were matched in a 1:1 ratio using ranked variables: RV1 dosing schedule (6/10/14; 6/10; or 10/14 weeks), RV season, delivery mode, delivery place, breastfeeding practices, age and gender. Fecal microbiota analysis was performed using a highly reproducible phylogenetic microarray. RV1 response correlated with a higher relative abundance of bacteria belonging to Clostridium cluster XI and Proteobacteria, including bacteria related to Serratia and Escherichia coli. Remarkably, abundance of these Proteobacteria was also significantly higher in Dutch infants when compared to RV1-non-responders in Pakistan. This small but carefully matched study showed the intestinal microbiota composition to correlate with RV1 seroconversion in Pakistan infants, identifying signatures shared with healthy Dutch infants. PMID- 28891753 TI - The influence of Schisandrin B on a model of Alzheimer's disease using beta amyloid protein Abeta1-42-mediated damage in SH-SY5Y neuronal cell line and underlying mechanisms. AB - Schisandrin B, an active substance, is derived from Chinese herb fruit Wuweizi, which exerts various pharmacological activities and has displayed significant beneficial effects in ameliorating Alzheimer's disease (AD). The aim of this study was to further extend our examination for the use of schisandrin B extract in the potential treatment of AD effects by investigating DNA methylation (DNMT), known to be modified in this disease using SH-SY5Y neuronal cell line exposed to beta-amyloid protein (Abeta1-42). In particular, the purpose of this investigation was to examine alterations in mRNA and protein expression of DNMT. Data demonstrated that schisandrin B blocked Abeta1-42-mediated injury in SH-SY5Y neuronal cell line as evidenced by a restoration of cellular morphology and cell viability to approximate control levels at the highest 10 MUg/ml Schisandrin B. Incubation with Abeta1-42 significantly decreased mRNA and protein expression of DNMT3A and DNMT1 in SH-SY5Y neuronal cell line. Incubation with Abeta1-42 followed by 24 treatment with schisandrin B significantly inhibited the Abeta1-42 -induced changes in mRNA and protein expression of DNMT3A and DNMT3B in a concentration-dependent manner. It is of interest that the mRNA expression of DNMT3A and DNMT1 were significantly higher than control. Data thus indicate schisandrin B was effective in inhibiting the actions of Abeta1-42 on cell survival and morphology and that DNA methylation may be associated with the beneficial findings. PMID- 28891752 TI - Development of EMab-51, a Sensitive and Specific Anti-Epidermal Growth Factor Receptor Monoclonal Antibody in Flow Cytometry, Western Blot, and Immunohistochemistry. AB - The epidermal growth factor receptor (EGFR) is a member of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases and is involved in cell growth and differentiation. EGFR homodimers or heterodimers with other HER members, such as HER2 and HER3, activate downstream signaling cascades in many cancers. In this study, we developed novel anti-EGFR monoclonal antibodies (mAbs) and characterized their efficacy in flow cytometry, Western blot, and immunohistochemical analyses. First, we expressed the full-length or ectodomain of EGFR in LN229 glioblastoma cells and then immunized mice with LN229/EGFR or ectodomain of EGFR, and performed the first screening using enzyme-linked immunosorbent assays. Subsequently, we selected mAbs according to their efficacy in flow cytometry (second screening), Western blot (third screening), and immunohistochemical (fourth screening) analyses. Among 100 mAbs, only one clone EMab-51 (IgG1, kappa) reacted with EGFR in Western blot analysis. Finally, immunohistochemical analyses with EMab-51 showed sensitive and specific reactions against oral cancer cells, warranting the use of EMab-51 to detect EGFR in pathological analyses of EGFR-expressing cancers. PMID- 28891754 TI - Mounier Kuhn syndrome presenting with recurrent atelectasis. AB - Objective and importance Mounier Kuhn syndrome is usually diagnosed in adulthood, and only a few cases have been described in childhood. Clinical presentation We present the case of a seven-year-old boy suffering from recurrent pneumonia and atelectasis. Intervention Previously performed chest X-rays showed bilateral hyperinflation and tracheobronchomegaly. Chest computed tomography (CT) confirmed the presence of distal enlargement of trachea and bronchi. Tracheobronchomegaly associated with recurrent respiratory tract infections is consistent with Mounier Kuhn syndrome. Pseudomonas aeruginosa was isolated from the sputum of the patient. He was then treated according to the guidelines for P. aeruginosa management in cystic fibrosis patients considering the similarities in clinical presentations and pathophysiology of both diseases. Antibiotic treatment resulted in a remarkable reduction of events of pulmonary exacerbation and hospitalizations. There are no specific guidelines for treatment options in case of pulmonary exacerbation of Mounier Kuhn syndrome. Case reports discussing the choice and efficiency of antibiotic treatment are random. Conclusion headings We share our experience of treating pulmonary exacerbation caused by P. aeruginosa in a patient with Mounier Kuhn syndrome suggesting a possible treatment option of pseudomonas infections in this syndrome. PMID- 28891755 TI - Early career reflections of three female gerontologists: Motivations, perceptions, and the life course. AB - As the number of individuals age 65 and older increases, so does the need for those prepared to work with this population. Doctoral-level preparation in the field of gerontology creates a uniquely prepared contingent who advocate, conduct research, instruct future generations, and serve the older adult population directly. Women are especially likely to pursue gerontology doctoral degrees, yet little is understood about the unique challenges and opportunities they face. The purpose of this reflection was to examine the experiences of three women who pursued doctoral-level gerontology education and faculty positions at different life stages to explore their challenges and opportunities through their educational process and early career experiences. PMID- 28891756 TI - Evaluation of distribution, redox parameters, and genotoxicity in Wistar rats co exposed to silver and titanium dioxide nanoparticles. AB - The increasing production of silver nanoparticles (AgNPs) and titanium dioxide nanoparticles (TiO2NPs) has resulted in their elevated concentrations in the environment. This study was, therefore, aimed at determining the distribution, redox parameters, and genotoxic effects in male Wistar rats that were treated with either AgNP or TiO2NP individually, as well as under a co-exposure scenario. Animals were exposed via oral gavage to either sodium citrate buffer (vehicle), 0.5 mg/kg/day TiO2NP, 0.5 mg/kg/day AgNP or a mixture of TiO2NPs and AgNPs. Exposure lasted 45 days after which rats were sacrificed, and tissue biodistribution of Ag and Ti measured. The blood concentration of glutathione (GSH) and activities of glutathione peroxidase (GPx) and catalase (CAT) were determined while the genotoxicity was analyzed using the comet assay in peripheral blood and liver cells. The tissue concentrations of Ag followed the order; blood > liver > kidneys while for Ti the order was kidneys > liver > blood. There was no significant change in the measured redox parameters in animals that were exposed to TiO2NPs. However, there was a significant increase in GSH levels accompanied by a reduction in the GPx activity in AgNP-treated and co-exposed groups. The individual or co-exposure to TiO2NP and AgNP did not markedly induce genotoxicity in blood or liver cells. Data showed that TiO2NP did not produce significant oxidative stress or genotoxicity in rats at the dose used in this study while the same dose level of AgNPs resulted in oxidative stress, but no noticeable adverse genotoxic effects. PMID- 28891757 TI - Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime. PMID- 28891758 TI - Effects of an evidence-based parenting program on biobehavioral stress among at risk mothers for child maltreatment: A pilot study. AB - Parental stress is an important risk factor for child maltreatment (CM) perpetration. Evidence-based, parent-training programs can decrease CM perpetration risk and reduce self-reported parental stress; however, little is known about how such programs impact physiological stress correlates. In this quasi-experimental pilot study, maternal biobehavioral responses were measured in response to SafeCare(r), an evidence-based program targeting CM, often implemented by social workers in child welfare settings. Maternal participants (N = 18) were recruited to complete SafeCare and repeated within-subject assessments pre- and post-intervention. Analyses examined associations between self-reported parental stress and mental health symptomology with stress markers for cortisol, alpha-amylase, and dihydroepiandrosterone at baseline and follow-up. Baseline correlation analyses showed strong associations between parental stress, salivary cortisol levels, and alpha-amylase. At follow-up, significant correlations were found between parental stress and alpha-amylase for intervention completers (n = 7). Completers on average exhibited decreases across self-reported parental stress and global distress symptomology and improvements in salivary cortisol and alpha-amylase levels. Participants with impaired cortisol levels at baseline were within normal limits post-intervention. These pilot findings suggest that salivary cortisol and alpha-amylase are compelling physiological correlates of parental stress among high-risk parents. Results also support short-term, positive effects of SafeCare in potentially regulating physiological stress systems among at-risk mothers. PMID- 28891759 TI - The validity and reliability of the sphygmomanometer for hip strength assessment in Australian football players. AB - OBJECTIVES: To investigate the intra-rater and inter-rater reliability of the sphygmomanometer for the assessment of the adductor squeeze test and isometric hip abduction strength and to investigate the concurrent validity of the sphygmomanometer for the assessment of hip muscular strength. METHOD: Thirty-two healthy adult male community Australian football players (age 23.9 +/- 4.5 years) were assessed by two blinded raters that measured the strength of the adductor squeeze test and isometric hip abduction, using a commercially available sphygmomanometer. Concurrent validity was calculated using handheld dynamometry as the reference standard. RESULTS: Moderate to high intra-rater reliability (ICC = 0.61 to 0.92) and high inter-rater reliability (ICC = 0.77 to 0.91) were found. High concurrent validity (Pearson's r = 0.77 to 0.91) was established. Sixteen of the participants reached the maximal reading of the sphygmomanometer, demonstrating a ceiling effect. CONCLUSIONS: A sphygmomanometer is a cost efficient device that appears to be both reliable and valid for the assessment of hip strength, offering clinicians an alternate and easily accessible option to obtain objective strength data. A ceiling effect may limit the application of the sphygmomanometer as a strength measurement device in stronger individuals. PMID- 28891760 TI - The Nottingham Fatigue After Stroke (NotFAST) study: results from follow-up six months after stroke. AB - Background Post-stroke fatigue is common and disabling. Objectives The aim of NotFAST was to examine factors associated with fatigue in stroke survivors without depression, six months after stroke. Methods Participants were recruited from four UK stroke units. Those with high levels of depressive symptoms (score >=7 on Brief Assessment Schedule Depression Cards) or aphasia were excluded. Follow-up assessment was conducted at six months after stroke. They were assessed on the Fatigue Severity Scale, Rivermead Mobility Index, Nottingham Extended Activities of Daily Living scale, Barthel Index, Beck Anxiety Index, Brief Assessment Schedule Depression Cards, Impact of Event Scale-Revised, and Sleep Hygiene Index. Results Of the 371 participants recruited, 263 (71%) were contacted at six months after stroke and 213 (57%) returned questionnaires. Approximately half (n = 109, 51%) reported fatigue at six months. Of those reporting fatigue initially (n = 88), 61 (69%) continued to report fatigue. 'De novo' (new) fatigue was reported by 48 (38%) of those not fatigued initially. Lower Nottingham Extended Activities of Daily Living scores and higher Beck Anxiety Index scores were independently associated with fatigue at six months. Conclusions Half the stroke survivors reported fatigue at six months post-stroke. Reduced independence in activities of daily living and higher anxiety levels were associated with the level of fatigue. Persistent and delayed onset fatigue may affect independence and participation in rehabilitation, and these findings should be used to inform the development of appropriate interventions. PMID- 28891761 TI - Acute and physical effects of water-based drilling mud in the marine copepod Calanus finmarchicus. AB - The aim of this study was to investigate impacts of fine particulate fraction of a commonly used barite-containing drilling mud on the pelagic filter feeding copepod Calanus finmarchicus. The results show that the tested drilling mud had a low acute toxicity on C. finmarchicus (LC50 > 320 mg/L) and that the observed toxicity was likely caused by dissolved constituents in the mud and not the particle phase containing the weighting agent barite. Further, animals were exposed to drilling mud at a concentration of 10 mg/L for 168 hr followed by a 100 hr recovery phase. A rapid uptake of drilling mud particles was observed, while the excretion was slow and incomplete even after 100 hr recovery in clean seawater. The uptake of drilling mud particles caused a significant increase in sinking velocity of copepods, indicating that uptake of drilling mud particles affected their buoyancy. Long-term exposure to low concentrations of drilling mud could therefore cause physical effects such as impacts on the animal's buoyancy which may affect the energy budget of the copepods. PMID- 28891762 TI - Reading and Phonological Awareness in Africa. AB - Literacy levels in Africa are low, and school instruction outcomes are not promising. Africa also has a disproportionate number of unschooled children. Phonological awareness (PA), especially phoneme awareness, is critically associated with literacy, but there is little evidence about whether PA is gained through literacy, schooling, or both, because most children studied are in education and can read at least letters. Our previous study of PA and reading in children in and out of school in Tanzania found that PA was associated with reading ability, not schooling or age, and many unschooled children learned to read. We retested 85 children from the baseline study, on measures of PA and literacy, approximately 2 years later. We found that more unschooled children had now learned to read but PA had generally not improved for these children. Unschooled children were still poorer at PA than schooled children. At 2 years, schooling now independently predicted PA and literacy. PA also predicted literacy and vice versa. Explicit phoneme awareness was again poor, even in accurate readers. More unschooled children have now learned to read, possibly because local literacy is in their first language; however, schooling improves reading and PA. PMID- 28891763 TI - Letter and reply. PMID- 28891764 TI - How to establish and standardize wide-awake hand surgery: experience from China. PMID- 28891768 TI - Hand surgery in Denmark. PMID- 28891769 TI - EDITORIAL. PMID- 28891765 TI - Factors determining outcome of corrective osteotomy for malunited paediatric forearm fractures: a systematic review and meta-analysis. AB - : The aim of this study was to identify predictors of a superior functional outcome after corrective osteotomy for paediatric malunited radius and both-bone forearm fractures. We performed a systematic review and meta-analysis of individual participant data, searching databases up to 1 October 2016. Our primary outcome was the gain in pronosupination seen after corrective osteotomy. Individual participant data of 11 cohort studies were included, concerning 71 participants with a median age of 11 years at trauma. Corrective osteotomy was performed after a median of 12 months after trauma, leading to a mean gain of 77 degrees in pronosupination after a median follow-up of 29 months. Analysis of variance and multiple regression analysis revealed that predictors of superior functional outcome after corrective osteotomy are: an interval between trauma and corrective osteotomy of less than 1 year, an angular deformity of greater than 20 degrees and the use of three-dimensional computer-assisted techniques. LEVEL OF EVIDENCE: II. PMID- 28891770 TI - Treating Panic Disorder Hypnotically. AB - A hypnosis protocol for treating panic disorder is provided. The implementation of this protocol is demonstrated through a case example involving the successful treatment of a 28-year-old firefighter presenting with a 4-month history of near daily panic attacks. Core principles associated with this protocol include: (1) Elementary education about the physiology of panic; (2) A review of primary factors contributing to the evolution and manifestation of panic; (3) Encouragement of physical activity; (4) Utilization of hypnosis applications; and (5) Monitoring and measuring progress evidenced by a reduction in the frequency and intensity of panic attacks. Six years after his last hypnosis session, "Jason," the once panicked firefighter returned to my office for concerns unrelated to panic, and reported that he remained panic-free, retained his job, and was twice promoted. PMID- 28891771 TI - The Effectiveness of Hypnosis Intervention for Labor: An Experimental Study. AB - Hypnosis has been shown to help pregnant women experience improved labor and postpartum periods. The present study compares the differences between experimental (n = 23) and control groups (n = 22) on specific variables measured both during labor and 24 hr postpartum. The participants in the experimental group received the hypnosis intervention at weeks 16, 20, 28, and 36 of pregnancy, while those in the control group received only routine antenatal care. The data collected at the labor stage describe the length of the labor stage, pain relief used during labor, the method of delivery, and the type of assisted vaginal delivery. Within 24 hr of delivery, data on neonatal birth weight, neonatal Apgar scores, and self-reported pain were obtained. The labor stage results showed no significant differences in the length of the second and third stages of labor. Although the participants in the experimental group reported higher pain levels immediately prior to, during, and immediately after delivery, their use of pethidine during labor was significantly lower than the control group participants. None of the experimental group participants opted for an epidural, and they had a greater number of assisted vaginal deliveries than the control group participants. The 24 hr postpartum results showed that the neonates of the experimental group participants had nonsignificantly higher Apgar scores than those of the women in the control group. Group differences in neonatal weight were not significant. The results of the present study indicate that hypnosis is useful for assisting pregnant women during labor and the postpartum period. PMID- 28891772 TI - Cognitive-Behavioral Therapy Plus Hypnosis for Distress During Breast Radiotherapy: A Randomized Trial. AB - Radiotherapy is a common and effective treatment for women with breast cancer. However, radiotherapy has also been shown to adversely affect patients' emotional well-being. Currently, few mind-body interventions are designed to improve patients' quality of life during radiotherapy. One intervention which has demonstrated clinical efficacy in the breast cancer radiotherapy setting is Cognitive-Behavioral Therapy plus Hypnosis. The goal of this study was to investigate the impact of Cognitive-Behavioral Therapy plus Hypnosis on emotional distress in women with breast cancer undergoing radiotherapy. One hundred patients were randomly assigned to either the Cognitive-Behavioral Therapy plus Hypnosis (n = 50) or Attention Control (n = 50) group. Results revealed significant benefits of Cognitive-Behavioral Therapy plus Hypnosis on emotional distress at the mid-point (d = 0.54), the conclusion (d = 0.64), and 4 weeks following the conclusion (d = 0.65) of radiotherapy (all ps < 0.05). In summary, results support further study of Cognitive-Behavioral Therapy plus Hypnosis as an evidence-based intervention to reduce emotional distress in women with breast cancer. Cognitive-Behavioral Therapy plus Hypnosis has the benefits of being brief, noninvasive, lacking side-effects, and producing beneficial effects which last beyond the conclusion of radiotherapy. Given these strengths, we propose that Cognitive-Behavioral Therapy plus Hypnosis is a strong candidate for greater dissemination and implementation in cancer populations. PMID- 28891773 TI - Hypnosis for Hot Flashes and Associated Symptomsin Women with Breast Cancer. AB - Women with breast cancer experience a host of physical and psychological symptoms, including hot flashes, sleep difficulties, anxiety, and depression. Therefore, treatment for women with breast cancer should target these symptoms and be individualized to patients' specific presentations. The current article reviews the common symptoms associated with breast cancer in women, then examines clinical hypnosis as a treatment for addressing these symptoms and improving the quality of life of women with breast cancer. Clinical hypnosis is an effective, nonpharmaceutical treatment for hot flashes and addressing many symptoms typically experienced by breast cancer patients. A case example is provided to illustrate the use of clinical hypnosis for the treatment of hot flashes with a patient with breast cancer. PMID- 28891774 TI - REVIEW OF THE INTERNATIONAL LITERATURE. PMID- 28891775 TI - Self-Talk Monitoring and Utilization for Enhancing Hypnotic Induction. AB - In contemporary hypnosis, language constitutes the hypnotist's rudimentary instrument for developing and utilizing the hypnotic trance. In the current article, the author proposes a theoretical and clinical approach for using patient self-talk during hypnotic induction by discussing the influence of self talk on consciousness regulation. The article includes some historical background on the use of language during hypnotic communication and demonstrates some clinical applications of patients self-talk in the process of hypnotic induction. PMID- 28891777 TI - Hypnosis for Smoking Relapse Prevention: A Randomized Trial. AB - The purpose of this study was to determine whether hypnosis would be more effective than standard behavioral counseling in helping smokers to remain abstinent. A total of 140 current smokers were enrolled in a randomized controlled smoking cessation trial at an urban Veterans Affairs medical center. Participants (n = 102) who were able to quit for at least 3 days received either a hypnosis or behavioral relapse prevention intervention. Both relapse prevention interventions consisted of two 60 min face-to-face sessions and four 20 min follow-up phone calls (two phone calls per week). At 26 weeks, the validate?d point-prevalence quit rate was 35% for the hypnosis group and 42% for the behavioral counseling group (relative risk = 0.85; 95% confidence interval: 0.52 1.40). At 52 weeks, the validated quit rate was 29% for the hypnosis group and 28% for the behavioral group (relative risk = 1.03; 95% confidence interval: 0.56-1.91). It was concluded that hypnosis warrants further investigation as an intervention for facilitating maintenance of quitting. PMID- 28891780 TI - The role of social work in free healthcare clinics and student-run clinics. AB - BACKGROUND: The role of social work in free healthcare clinics and student-run clinics remains an understudied topic. METHOD: We conducted a literature review of the published studies through four online databases: Google Scholar, Social Work Abstracts, Academic Search Complete, and PsycInfo. RESULTS: The literature review revealed 449 possibly relevant studies, but only nine met the criteria for the final review. Based on these findings, social work is not fully utilized in free healthcare clinics and student-run clinics. CONCLUSION: Our literature review provides evidence for the need for social work in free healthcare clinics and student-run clinics. PMID- 28891781 TI - Occipital Alpha and Gamma Oscillations Support Complementary Mechanisms for Processing Stimulus Value Associations. AB - Selective attention is reflected neurally in changes in the power of posterior neural oscillations in the alpha (8-12 Hz) and gamma (40-100 Hz) bands. Although a neural mechanism that allows relevant information to be selectively processed has its advantages, it may lead to lucrative or dangerous information going unnoticed. Neural systems are also in place for processing rewarding and punishing information. Here, we examine the interaction between selective attention (left vs. right) and stimulus's learned value associations (neutral, punished, or rewarded) and how they compete for control of posterior neural oscillations. We found that both attention and stimulus-value associations influenced neural oscillations. Whereas selective attention had comparable effects on alpha and gamma oscillations, value associations had dissociable effects on these neural markers of attention. Salient targets (associated with positive and negative outcomes) hijacked changes in alpha power-increasing hemispheric alpha lateralization when salient targets were attended, decreasing it when they were being ignored. In contrast, hemispheric gamma-band lateralization was specifically abolished by negative distractors. Source analysis indicated occipital generators of both attentional and value effects. Thus, posterior cortical oscillations support both the ability to selectively attend while at the same time retaining the ability to remain sensitive to valuable features in the environment. Moreover, the versatility of our attentional system to respond separately to salient from merely positively valued stimuli appears to be carried out by separate neural processes reflected in different frequency bands. PMID- 28891782 TI - Functional Preference for Object Sounds and Voices in the Brain of Early Blind and Sighted Individuals. AB - Sounds activate occipital regions in early blind individuals. However, how different sound categories map onto specific regions of the occipital cortex remains a matter of debate. We used fMRI to characterize brain responses of early blind and sighted individuals to familiar object sounds, human voices, and their respective low-level control sounds. In addition, sighted participants were tested while viewing pictures of faces, objects, and phase-scrambled control pictures. In both early blind and sighted, a double dissociation was evidenced in bilateral auditory cortices between responses to voices and object sounds: Voices elicited categorical responses in bilateral superior temporal sulci, whereas object sounds elicited categorical responses along the lateral fissure bilaterally, including the primary auditory cortex and planum temporale. Outside the auditory regions, object sounds also elicited categorical responses in the left lateral and in the ventral occipitotemporal regions in both groups. These regions also showed response preference for images of objects in the sighted group, thus suggesting a functional specialization that is independent of sensory input and visual experience. Between-group comparisons revealed that, only in the blind group, categorical responses to object sounds extended more posteriorly into the occipital cortex. Functional connectivity analyses evidenced a selective increase in the functional coupling between these reorganized regions and regions of the ventral occipitotemporal cortex in the blind group. In contrast, vocal sounds did not elicit preferential responses in the occipital cortex in either group. Nevertheless, enhanced voice-selective connectivity between the left temporal voice area and the right fusiform gyrus were found in the blind group. Altogether, these findings suggest that, in the absence of developmental vision, separate auditory categories are not equipotent in driving selective auditory recruitment of occipitotemporal regions and highlight the presence of domain selective constraints on the expression of cross-modal plasticity. PMID- 28891783 TI - Cortical Local Field Potential Power Is Associated with Behavioral Detection of Near-threshold Stimuli in the Rat Whisker System: Dissociation between Orbitofrontal and Somatosensory Cortices. AB - There is growing evidence that ongoing brain oscillations may represent a key regulator of attentional processes and as such may contribute to behavioral performance in psychophysical tasks. OFC appears to be involved in the top-down modulation of sensory processing; however, the specific contribution of ongoing OFC oscillations to perception has not been characterized. Here we used the rat whiskers as a model system to further characterize the relationship between cortical state and tactile detection. Head-fixed rats were trained to report the presence of a vibrotactile stimulus (frequency = 60 Hz, duration = 2 sec, deflection amplitude = 0.01-0.5 mm) applied to a single vibrissa. We calculated power spectra of local field potentials preceding the onset of near-threshold stimuli from microelectrodes chronically implanted in OFC and somatosensory cortex. We found a dissociation between slow oscillation power in the two regions in relation to detection probability: Higher OFC but not somatosensory delta power was associated with increased detection probability. Furthermore, coherence between OFC and barrel cortex was reduced preceding successful detection. Consistent with the role of OFC in attention, our results identify a cortical network whose activity is differentially modulated before successful tactile detection. PMID- 28891784 TI - Familiarity Speeds Up Visual Short-term Memory Consolidation: Electrophysiological Evidence from Contralateral Delay Activities. AB - To test how preexisting long-term memory influences visual STM, this study takes advantage of individual differences in participants' prior familiarity with Pokemon characters and uses an ERP component, the contralateral delay activity (CDA), to assess whether observers' prior stimulus familiarity affects STM consolidation and storage capacity. In two change detection experiments, consolidation speed, as indexed by CDA fractional area latency and/or early window (500-800 msec) amplitude, was significantly associated with individual differences in Pokemon familiarity. In contrast, the number of remembered Pokemon stimuli, as indexed by Cowan's K and late-window (1500-2000 msec) CDA amplitude, was significantly associated with individual differences in Pokemon familiarity when STM consolidation was incomplete because of a short presentation of Pokemon stimuli (500 msec, Experiment 2), but not when STM consolidation was allowed to complete given sufficient encoding time (1000 msec, Experiment 1). Similar findings were obtained in between-group analyses when participants were separated into high-familiarity and low-familiarity groups based on their Pokemon familiarity ratings. Together, these results suggest that stimulus familiarity, as a proxy for the strength of preexisting long-term memory, primarily speeds up STM consolidation, which may subsequently lead to an increase in the number of remembered stimuli if consolidation is incomplete. These findings thus highlight the importance of research assessing how effects on representations (e.g., STM capacity) are in general related to (or even caused by) effects on processes (e.g., STM consolidation) in cognition. PMID- 28891785 TI - Attachment style moderates effects of FKBP5 polymorphisms and childhood abuse on post-traumatic stress symptoms: Results from the National Health and Resilience in Veterans Study. AB - OBJECTIVES: To determine the main and interactive effects of four FKBP5 polymorphisms (rs9296158, rs3800373, rs1360780 and rs9470080), childhood abuse and attachment style in predicting severity of PTSD symptoms in two independent, nationally representative samples of US military veterans. METHODS: Data were analysed from two independent samples of European-American US military veterans who participated in the National Health and Resilience in Veterans Study (N = 1,585 and 577 respectively). RESULTS: Results revealed that carriage of two FKBP5 minor alleles, childhood abuse and insecure attachment style were associated with greater severity of PTSD symptoms. Gene * environment interactions were also observed, with the interaction of FKBP5 homozygous minor allele carriage and history of childhood abuse associated with greater severity of PTSD symptoms; however, these effects were fully counteracted by secure attachment style. CONCLUSIONS: Results of this study build on prior work demonstrating a gene * environment interaction between FKBP5 polymorphisms and childhood abuse in predicting risk for PTSD by suggesting that attachment style may moderate this effect. This study has implications for prevention and treatment efforts designed to promote a secure attachment style in veterans with high-risk FKBP5 genotypes and childhood abuse histories. PMID- 28891786 TI - A framework and case studies for evaluation of enzyme ontogeny in children's health risk evaluation. AB - Knowledge of the ontogeny of Phase I and Phase II metabolizing enzymes may be used to inform children's vulnerability based upon likely differences in internal dose from xenobiotic exposure. This might provide a qualitative assessment of toxicokinetic (TK) variability and uncertainty pertinent to early lifestages and help scope a more quantitative physiologically based toxicokinetic (PBTK) assessment. Although much is known regarding the ontogeny of metabolizing systems, this is not commonly utilized in scoping and problem formulation stage of human health risk evaluation. A framework is proposed for introducing this information into problem formulation which combines data on enzyme ontogeny and chemical-specific TK to explore potential child/adult differences in internal dose and whether such metabolic differences may be important factors in risk evaluation. The framework is illustrated with five case study chemicals, including some which are data rich and provide proof of concept, while others are data poor. Case studies for toluene and chlorpyrifos indicate potentially important child/adult TK differences while scoping for acetaminophen suggests enzyme ontogeny is unlikely to increase early-life risks. Scoping for trichloroethylene and aromatic amines indicates numerous ways that enzyme ontogeny may affect internal dose which necessitates further evaluation. PBTK modeling is a critical and feasible next step to further evaluate child-adult differences in internal dose for a number of these chemicals. PMID- 28891787 TI - Biochemical approaches to assess oxidative stress induced by exposure to natural and synthetic dyes in early life stages in zebrafish. AB - Zebrafish early life stages were found to be sensitive to several synthetic dyes widely used in industries. However, as environmental concentrations of such contaminants are often at sublethal levels, more sensitive methods are required to determine early-warning adverse consequences. The aim of this study was to utilize a multibiomarker approach to examine underlying oxidative stress mechanisms triggered by sublethal concentrations of synthetic azo dye Basic Red 51 (BR51), the natural dye erythrostominone (ERY), and its light-degraded product using zebrafish embryos. Biochemical biomarkers included parameters of detoxification and markers of antioxidant system, as well as oxidative damage. Results showed pro-oxidant mechanisms attributed to BR51 and ERY as evidenced by increased glutathione S-transferase (GST) activity, a phase II detoxification enzyme related to reactive oxygen species detoxification. BR51 also elevated total glutathione (GSH+GSSG) levels and catalase activity. However, both dyes induced oxidative damage as evidenced by elevated lipid peroxidation content. In contrast, when the natural dye was photodegraded, no marked effects were observed for all biomarkers assessed. Data indicate that such dyes are pro-oxidants at sublethal concentrations, predominantly involving GSH and/or related enzymes pathway. PMID- 28891788 TI - Week 48 resistance analysis of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF versus Atazanavir + Ritonavir + Emtricitabine/Tenofovir DF in HIV-1 infected women (WAVES study GS-US-236-0128). AB - Background Women and those with non-B subtype HIV-1 are typically underrepresented in clinical trials. WAVES (GS-US-236-0128) was a double-blind phase 3b study among treatment-naive HIV-1-infected women that demonstrated that elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF; N = 289) was superior to atazanavir + ritonavir + FTC/TDF (ATV + RTV + FTC/TDF; N = 286) for HIV-1 RNA < 50 copies/mL by FDA snapshot analysis at week 48. Here, we describe resistance development through week 48 in women with virologic failure and determine the impact of pre-existing mutations and HIV-1 subtype on viral suppression. Methods Genotypic analyses (population and deep sequencing) and phenotypic analyses of HIV-1 protease, reverse transcriptase (RT), and integrase (IN) were performed. The resistance analysis population (participants with HIV-1 RNA >= 400 copies/mL at confirmed virologic failure, at discontinuation >= week 8, or at week 48) had genotypic and phenotypic analyses at failure and baseline. Results The proportion of women qualifying for resistance analyses was similar between treatment groups (6.2% EVG/COBI/FTC/TDF; 7.3% ATV + RTV + FTC/TDF). Emergent resistance was rare (0% EVG/COBI/FTC/TDF; 1% ATV + RTV + FTC/TDF - 3 with M184V/I in RT). Deep sequencing of HIV-1 did not detect additional resistance development. Pre-existing mutations did not lead to virologic failure; most with the polymorphic primary IN substitution T97A (92%), or with substitutions in RT (i.e. A62V, V90I, K103N, or E138A/G/K/Q; 68-82%) demonstrated virologic suppression at week 48, with no resistance development except for one patient with M184V and pre-existing K103N in the ATV + RTV + FTC/TDF group. Most participants (74%) had non-B HIV-1, and subtype did not affect outcome. Conclusions Emergent resistance to study drugs was rare in this study of women, with no resistance observed among EVG/COBI/FTC/TDF-treated participants, despite a high proportion of participants with natural or transmitted viral mutations and non-B HIV-1 subtypes. PMID- 28891789 TI - List of new names and new combinations previously effectively, but not validly, published. PMID- 28891790 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 67, part 6, of the IJSEM. PMID- 28891791 TI - The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning. AB - Neuronal ApoE receptors are linked to learning and memory, but the pathways governing their abundance, and the mechanisms by which they affect the function of neural circuits are incompletely understood. Here we demonstrate that the E3 ubiquitin ligase IDOL determines synaptic ApoER2 protein levels in response to neuronal activation and regulates dendritic spine morphogenesis and plasticity. IDOL-dependent changes in ApoER2 abundance modulate dendritic filopodia initiation and synapse maturation. Loss of IDOL in neurons results in constitutive overexpression of ApoER2 and is associated with impaired activity dependent structural remodeling of spines and defective LTP in primary neuron cultures and hippocampal slices. IDOL-deficient mice show profound impairment in experience-dependent reorganization of synaptic circuits in the barrel cortex, as well as diminished spatial and associative learning. These results identify control of lipoprotein receptor abundance by IDOL as a post-transcriptional mechanism underlying the structural and functional plasticity of synapses and neural circuits. PMID- 28891792 TI - PGAM5 promotes lasting FoxO activation after developmental mitochondrial stress and extends lifespan in Drosophila. AB - The mitochondrial unfolded protein response (UPRmt) has been associated with long lifespan across metazoans. In Caenorhabditis elegans, mild developmental mitochondrial stress activates UPRmt reporters and extends lifespan. We show that similar developmental stress is necessary and sufficient to extend Drosophila lifespan, and identify Phosphoglycerate Mutase 5 (PGAM5) as a mediator of this response. Developmental mitochondrial stress leads to activation of FoxO, via Apoptosis Signal-regulating Kinase 1 (ASK1) and Jun-N-terminal Kinase (JNK). This activation persists into adulthood and induces a select set of chaperones, many of which have been implicated in lifespan extension in flies. Persistent FoxO activation can be reversed by a high-protein diet in adulthood, through mTORC1 and GCN-2 activity. Accordingly, the observed lifespan extension is prevented on a high-protein diet and in FoxO-null flies. The diet-sensitivity of this pathway has important implications for interventions that seek to engage the UPRmt to improve metabolic health and longevity. PMID- 28891794 TI - A new target for G protein signaling. AB - G protein-coupled receptor stimulation inhibits TRPM3 channel activity through direct binding of the Gbetagamma subunit to the channel. PMID- 28891795 TI - [Intravesical botulinum toxin under local anestesia as ambulatory procedure.] AB - Bladder hyperactivity is described as the presence of "voiding urgency, generally associated with increased daytime frequency and nocturia, with or without urinary incontinence, in the absence of urinary tract infection or other obvious pathology". Onabotulinum toxin A (BTA) is a recommendable therapeutic option in case of failure, contraindication or refusal of the conservative therapy or other non-pharmacological therapies. The injection of BTA in the detrusor has been performed under local, regional or general anesthesia either in the conventional or major ambulatory surgery operative room or in the cystoscopy room. The objective of this paper is to describe the procedure to perform BTA therapy as an ambulatory operation under intravesical local anesthesia in the cystoscopy room, describing its advantages and limitations. PMID- 28891796 TI - [Validation of the spanish version of the pediatric lower urinary tract symptoms scale (PLUTSS).] AB - OBJECTIVES: Lower Urinary Tract Dysfunction (LUTD) is the most common clinical problem in pediatric urology. To our knowledge non-validated instruments properly designed to screen lower urinary tract symptoms in the pediatric population has been translated and adapted to Spanish population. Pediatric Lower Urinary Tract Symptoms Score (PLUTSS) has proven to be a valid questionnaire for screening and evaluation of the response of children with LUTD to therapy. The aim of this study was to validate the PLUTSS questionnaire into Spanish, and put it to clinical use in pediatric patients, with cross-cultural equivalence to the original version. METHODS: The PLUTSS questionnaire was validated between February 2015 and February 2016. The Spanish version was obtained by using the forward/ back-translation method with expert, bilingual translator, complying with the ISPOR principles. The questionnaire was administered to 80 patients with either lower urinary tract symptoms (40) or without any urological complaints (40). A descriptive statistical analysis of interscale correlation was performed. To confirm reliability, testretest reliability was assessed by intra-class correlation coefficient, and the internal consistency was assessed by Cronbach's alpha coefficient. ROC curve was used to define cutpoint and its validity in discrimination between groups. RESULTS: The median of the two groups was significantly different: 20.53 (patients with LUTD) vs 3.27 (controls). Internal consistence of the 13-item scale (without quality of life item) was high: Cronbach alpha coefficient 0.827. The test-retest analysis of reproducibility showed an intra-class correlation coefficient of 0.997 (95%IC: 0.994-0.999) (p<0.0001). CONCLUSIONS: The Spanish version of the PLUTSS questionnaire has proven to be acceptable and culturally equivalent to the original version. It has a good degree of consistency, validity and reliability. PLUTSS showed a high power to discriminate patients with LUTD. PMID- 28891793 TI - Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. AB - In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index. PMID- 28891797 TI - [Overall survival and renal function after partial and radical nephrectomy in malignant localized renal tumors.] AB - OBJECTIVE: To evaluate the overall survival rate and renal function in our series after radical nephrectomy (RN) and partial nephrectomy (PN) in renal tumors in an early stage. METHODS: We retrospectively reviewed the medical records of 229 patients who underwent RN or PN for renal cancer T1-T2N0M0 in our center between 1995 and 2015. We described demographic factors, first symptom, TNM, histology, post-surgery data, recurrence rate and renal function. We utilized Fisher test, Chi square test and T-Student and we considered statistical significance when p<0.05. RESULTS: 203 patients underwent RN and 26 PN. 39.4% of the tumors who received RN were T1bN0M0 and 76.92% of PN were T1aN0M0. We report nine complications grade II of modified Clavien System for RN and only one grade I for PN. We detected an 11.3% recurrence in RN and none in PN. 66%of patients from RN are alive today, 12.81% died as result of renal cancer and 22.7% suffered a non cancer-specific death. No deaths were observed in PN group. We observed similar mean preoperative serum creatinine (Cr) in both groups. Creatinine after the first post-operative month was 1.81mg/dL and 1.06mg/dL for RN and PN, respectively; At one year post-operative we registered Cr 1.82mg/dL and Cr 0.97mg/dL, respectively. CONCLUSIONS: Both methods provide excellent oncologic results for renal carcinoma in an early stage. PN is safe and reduces the incidence of renal dysfunction with a lower rate of non-cancer-specific death. PMID- 28891798 TI - [Effect of the cellular and humoral immune response in infertile couples and its relationship with infections.] AB - OBJECTIVE: The purpose of this study was to determine the prevalence of different microorganisms isolated from the urogenital tract of infertile men and assess whether there are differences in semen parameters according to the presence or absence of genital infections. METHODS: 280 semen samples from infertile men were studied retrospectively. Semen parameters were analyzed according to the World Health Organization criteria (WHO 2010). Microbiological analysis was performed using the modified method of Stamey and Meares proposed by Santoianni et al. RESULTS: Microbiological studies showed absence of microorganisms or presence of usual colonizing flora in 67.86% of the samples (GROUP 1) and presence of at least one pathogen or potential pathogen in 32.14% (GROUP 2). No significant differences in ejaculate volume (p=0.353), pH value (p=0.801), motility (p>0.30), citric acid concentration (p=0.383) and viscosity (p=0.948) were observed between the two groups. The relative sperm count was significantly lower in infected patients than in those without pathogens (p=0.05). Teratozoospermia index (TZI) was evaluated. Samples of infected patients showed TZI values higher than patients without microorganisms or normal genital tract flora (p<0.0001). CONCLUSIONS: A third of the studied population had genital infections. Based on our results, sperm culture may be considered in the early stages of the study of the infertile patient. Early diagnosis of an infectious disease could be useful for a suitable treatment for couples with reproductive failure. PMID- 28891799 TI - [Paratesticular sarcoma with synchronous renal carcinoma.] AB - OBJETIVE: Primary undifferentiated pleomorphic sarcoma (UPS) of the testicular tunics is rare, and synchronism with other malignancies of the urinary tract is uncommon, and may complicate the staging and therapeutic approach. We report the case of a patient diagnosed with primary paratesticular UPS with synchronous Renal Carcinoma. METHODS: Patient presenting with intrascrotal tumor who underwent left radical orchiectomy. In staging work up studies a second urologic neoplasia was found in the kidney. Histological diagnosis using immunohistochemical techniques for adequate characterization was performed. Adjuvant treatment options were evaluated. We review the literature and discuss the case. RESULTS: The UPS diagnosis was performed with immunohistochemistry. Paratesticular origin from testicular tunics was evident in the macroscopic evaluation. After finding the synchronic ipsilateral renal tumor, he underwent conventional left radical nephrectomy, ipsilateral adrenalectomy, excision of remnant left cord and para-aortic and pelvic lymphadenectomy. He received chemotherapy and adjuvant radiotherapy. Currently, after twelve months of follow up there is no evidence of disease. CONCLUSIONS: The UPS is a heterogeneous group with an exclusion immunohistochemical diagnosis. Its management requires a multidisciplinary approach; the initial surgical treatment is accepted for the paratesticular mass with high section radical orchiectomy. Although there is insufficient evidence of the efficacy of adjunctive lymphadenectomy, chemotherapy and/or radiotherapy. PMID- 28891800 TI - A novel heterozygous mutation in the Birt-Hogg-Dube Syndrome. AB - OBJETIVE: Our aim is to present a novel mutation of the Birt-Hogg-Dube Syndrome. METHODS: We present a case report of a 70-year-old male with three solid nodulary lesions of 4, 2.6, and 3 cm each in the right kidney, and two lesions of 1.5 and 1.3 cm in the left kidney. RESULTS: Needle biopsy was performed. The pathological analysis of right kidney lesions revealed a renal tumor suggestive of chromophobe renal cell carcinoma and medullar tumor with zones that suggested oncocytosis. Genetic test results were positive for a novel heterozygous mutation c.1198G>A; p.V400I in exon 11 of the FLCN gene. CONCLUSION: In patients presenting with bilateral multifocal renal tumors of oncocytic hybrid histology, Birt- Hogg-Dube syndrome should be the first diagnosis in mind. The mutation found in this patient has not been previously described in the literature in the context of BHD. PMID- 28891801 TI - A retrospective analysis of mathieu and tip urethroplasty techniques for distal hypospadias repair; A 20 year experience. AB - OBJECTIVE: We aimed to identify the changes in the application rate of two surgical techniques in distal hypospadias repair in years and compare the most popular two surgical repair techniques for distal hypospadias in terms of surgical outcomes, the factors that affect the outcomes, which were performed over a 20 year period. METHODS: In this study, the records of 492 consecutive patients that had undergone an operation for distal hypospadias in the urology clinic of Ankara between May 1990 and December 2010 using either Mathieu or TIPU surgical techniques were reviewed retrospectively. The patients who had glanular, coronal, and subcoronal meatus, were accepted as distal hypospadias cases. Among the 492 examined medical records, it was revealed that 331 and 161 surgical interventions were performed by using the Mathieu urethroplasty technique (Group 1) and TIP urethroplasty technique (Group-2), respectively. Group-1 was divided into two subgroups; namely Group-1a (patients with primary hypospadias) and Group 1b (patients with previous hypospadias operation). Likewise, Group-2 was divided into two subgroups; namely group-2a and group-2b. The patients' ages, number of previously urethroplasty operations, localization of the external urethral meatus prior to the operation, chordee state, length of the newly formed urethra, whether urinary diversion was done or not, post-operative complications and data regarding the follow-up period were evaluated, and the effects of these variables on the surgical outcome were investigated via statistical analyses. The primary objective of this study is to identify the changes in the application rate of two surgical techniques in distal hypospadias repair over the a 20 year period, and the secondary objectives are to compare the most popular two surgical repair techniques for distal hypospadias in terms of surgical outcomes, and the factors affecting the outcomes. Independent samples t test and Pearson's Chisquare test was used for statistical analysis. p<0.05 was considered as statistically significant. RESULTS: There were no statistically significant differences between the subgroups in terms of age, length of the neo-urethra, number of previously performed urethroplasty operations, surgical success rates, or complications (p>0.05). The concurrent utilization of the cystostomy and urethral stent was significantly more frequent in group-1 (p<0.05; Pearson's Chi-square test). It was determined that over time, TIP urethroplasty has become a more preferred technique for the repair of distal hypospadias. CONCLUSIONS: Both surgical techniques have similar success rates in distal hypospadias cases. TIP urethroplasty has become the method of choice over time. PMID- 28891802 TI - [Una vez en un millon.] PMID- 28891803 TI - Fractura de cuerpo cavernoso con lesion uretral. PMID- 28891804 TI - Detection of suspended nanoparticles with near-ambient pressure x-ray photoelectron spectroscopy. AB - Two systems of suspended nanoparticles have been studied with near-ambient pressure x-ray photoelectron spectroscopy: silver nanoparticles in water and strontium fluoride-calcium fluoride core-shell nanoparticles in ethylene glycol. The corresponding dry samples were measured under ultra high vacuum for comparison. The results obtained under near-ambient pressure were overall comparable to those obtained under ultra high vacuum, although measuring silver nanoparticles in water requires a high pass energy and a long acquisition time. A shift towards higher binding energies was found for the silver nanoparticles in aqueous suspension compared to the corresponding dry sample, which can be assigned to a change of surface potential at the water-nanoparticle interface. The shell-thickness of the core-shell nanoparticles was estimated based on simulated spectra from the National Institute of Standards and Technology database for simulation of electron spectra for surface analysis. With the instrumental set-up presented in this paper, nanoparticle suspensions in a suitable container can be directly inserted into the analysis chamber and measured without prior sample preparation. PMID- 28891805 TI - Graphene-Vertically Aligned Carbon Nanotube Hybrid on PDMS as Stretchable Electrodes. AB - Stretchable electrodes are a critical component for flexible electronics such as displays, energy devices, and wearable sensors. Carbon nanotubes (CNTs) and graphene have been considered for flexible electrode applications, due to their mechanical strength, high carrier mobility, and excellent thermal conductivity. Vertically aligned carbon nanotubes (VACNTs) provide the possibility to serve as interconnects to graphene sheets as stretchable electrodes that could maintain high electrical conductivity under large tensile strain. In this work, a graphene oxide (GO) -VACNT hybrid on a PDMS substrate was demonstrated. Here, 50 MUm long VACNTs were grown on a Si/SiO2 wafer substrate via atmospheric pressure chemical vapor deposition (APCVD). VACNTs were directly transferred by delamination from the Si/SiO2 to a semi-cured PDMS substrate, ensuring strong adhesion between VACNTs and PDMS upon full curing of the PDMS. GO ink was then printed on the surface of the VACNT carpet and thermally reduced to reduced graphene oxide (rGO). The sheet resistance of the rGO-VACNT hybrid was measured under uniaxial tensile strains up to 300% applied to the substrate. Under applied strain, the rGO-VACNT hybrid maintained a sheet resistant of 386+/-55 Omega/sq. Cyclic stretching of the rGO-VACNT hybrid was performed with up to 50 cycles at 100% maximum tensile strain, showing no increase in sheet resistance. These results demonstrate promising performance of the rGO-VACNT hybrid for flexible electronics applications. PMID- 28891806 TI - Hybrid-DFT + V w method for band structure calculation of semiconducting transition metal compounds: the case of cerium dioxide. AB - Hybrid functionals' non-local exchange-correlation potential contains a derivative discontinuity that improves on standard semi-local density functional theory (DFT) band gaps. Moreover, by careful parameterization, hybrid functionals can provide self-interaction reduced description of selected states. On the other hand, the uniform description of all the electronic states of a given system is a known drawback of these functionals that causes varying accuracy in the description of states with different degrees of localization. This limitation can be remedied by the orbital dependent exact exchange extension of hybrid functionals; the hybrid-DFT + V w method (Ivady et al 2014 Phys. Rev. B 90 035146). Based on the analogy of quasi-particle equations and hybrid-DFT single particle equations, here we demonstrate that parameters of hybrid-DFT + V w functional can be determined from approximate theoretical quasi-particle spectra without any fitting to experiment. The proposed method is illustrated on the charge self-consistent electronic structure calculation for cerium dioxide where itinerant valence states interact with well-localized 4f atomic like states, making this system challenging for conventional methods, either hybrid-DFT or LDA + U, and therefore allowing for a demonstration of the advantages of the proposed scheme. PMID- 28891807 TI - Electronic structure of ferromagnetic heavy fermion, YbPdSi, YbPdGe, and YbPtGe studied by photoelectron spectroscopy, x-ray emission spectroscopy, and DFT + DMFT calculations. AB - Electronic structures of ferromagnetic heavy fermion Yb compounds of YbPdSi, YbPdGe, and YbPtGe are studied by photoelectron spectroscopy around the Yb 4d-4f resonance, resonant x-ray emission spectroscopy at the Yb L 3 absorption edge, and density functional theory combined with dynamical mean field theory calculations. These compounds all have a temperature-independent intermediate Yb valence with large [Formula: see text] and small [Formula: see text] components. The magnitude of the Yb valence is evaluated to be YbPtGe [Formula: see text] YbPdGe [Formula: see text] YbPdSi, suggesting that YbPtGe is the closest to the quantum critical point among the three Yb compounds. Our results support the scenario of the coexistence of heavy fermion behavior and ferromagnetic ordering which is described by a magnetically-ordered Kondo lattice where the magnitude of the Kondo effect and the RKKY interaction are comparable. PMID- 28891808 TI - The offset droplet: a new methodology for studying the solid/water interface using x-ray photoelectron spectroscopy. AB - The routine study of the solid-water interface by XPS is potentially revolutionary as this development opens up whole new areas of study for photoelectron spectroscopy. To date this has been realised by only a few groups worldwide and current techniques have significant restrictions on the type of samples which can be studied. Here we present a novel and uniquely flexible approach to the problem. By introducing a thin capillary into the NAP-XPS, a small droplet can be injected onto the sample surface, offset from the analysis area by several mm. By careful control of the droplet size a water layer of controllable thickness can be established in the analysis area-continuous with the bulk droplet. We present results from the solid-water interface on a vacuum prepared TiO2(110) single crystal and demonstrate that the solid/liquid interface is addressable. PMID- 28891809 TI - Relaxation dynamics and polydispersivity associated with defects and ferroelectric correlations in Ba doped EuTiO3. AB - We presented detailed frequency and temperature dependent dielectric response in Eu1-xBaxTiO3 (0 < x < 0.5). Excluding grain boundary effects, four relaxation mechanisms have been observed. Relaxation dynamics were observed to arise due to hopping conduction associated with defects namely, oxygen vacancies, Eu3+ and Ti3+ ions. Dielectric relaxation analysis led to identification of Ti ions in two different environments with different relaxation rates in the overall EuTiO3 perovskite structure. Emergence of another relaxation mechanism associated with ferroelectric order as a consequence of formation of polar regions have also been observed for higher Ba concentrations. Addition of Ba led to the identification of relaxation dynamics associated with hopping conduction between Eu ions, Ti ions (in the regions with and without oxygen vacancies) and with the formation of ferroelectric polar regions. Furthermore, polydispersivity and relaxation times have been extracted within the frame work of modified Debye model. Relaxation times have been observed to increase with decrease in temperature while larger values of polydispersivity revealed wide distribution of relaxation times due to the presence of lattice parameter and energy barrier distributions. PMID- 28891810 TI - Halogenation of SiC for band-gap engineering and excitonic functionalization. AB - The optical excitation spectra and excitonic resonances are investigated in systematically functionalized SiC with Fluorine and/or Chlorine utilizing density functional theory in combination with many-body perturbation theory. The latter is required for a realistic description of the energy band-gaps as well as for the theoretical realization of excitons. Structural, electronic and optical properties are scrutinized and show the high stability of the predicted two dimensional materials. Their realization in laboratory is thus possible. Large band-gaps of the order of 4 eV are found in the so-called GW approximation, with the occurrence of bright excitons, optically active in the four investigated materials. Their binding energies vary from 0.9 eV to 1.75 eV depending on the decoration choice and in one case, a dark exciton is foreseen to exist in the fully chlorinated SiC. The wide variety of opto-electronic properties suggest halogenated SiC as interesting materials with potential not only for solar cell applications, anti-reflection coatings or high-reflective systems but also for a possible realization of excitonic Bose-Einstein condensation. PMID- 28891811 TI - NF-kappaB regulates GDF-15 to suppress macrophage surveillance during early tumor development. AB - Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-kappaB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF kappaB, and the colocalization of activated NF-kappaB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-beta-activated kinase (TAK1) signaling to NF-kappaB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF kappaB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis. PMID- 28891813 TI - No evidence of HIV replication in children on antiretroviral therapy. AB - It remains controversial whether current antiretroviral therapy (ART) fully suppresses the cycles of HIV replication and viral evolution in vivo. If replication persists in sanctuary sites such as the lymph nodes, a high priority should be placed on improving ART regimes to target these sites. To investigate the question of ongoing viral replication on current ART regimens, we analyzed HIV populations in longitudinal samples from 10 HIV-1-infected children who initiated ART when viral diversity was low. Eight children started ART at less than ten months of age and showed suppression of plasma viremia for seven to nine years. Two children had uncontrolled viremia for fifteen and thirty months, respectively, before viremia suppression, and served as positive controls for HIV replication and evolution. These latter 2 children showed clear evidence of virus evolution, whereas multiple methods of analysis bore no evidence of virus evolution in any of the 8 children with viremia suppression on ART. Phylogenetic trees simulated with the recently reported evolutionary rate of HIV-1 on ART of 6 * 10-4 substitutions/site/month bore no resemblance to the observed data. Taken together, these data refute the concept that ongoing HIV replication is common with ART and is the major barrier to curing HIV-1 infection. PMID- 28891812 TI - Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis. AB - Herpes simplex virus-1 (HSV-1) is the most common cause of sporadic viral encephalitis, which can be lethal or result in severe neurological defects even with antiviral therapy. While HSV-1 causes encephalitis in spite of HSV-1 specific humoral and cellular immunity, the mechanism by which HSV-1 evades the immune system in the central nervous system (CNS) remains unknown. Here we describe a strategy by which HSV-1 avoids immune targeting in the CNS. The HSV-1 UL13 kinase promotes evasion of HSV-1-specific CD8+ T cell accumulation in infection sites by downregulating expression of the CD8+ T cell attractant chemokine CXCL9 in the CNS of infected mice, leading to increased HSV-1 mortality due to encephalitis. Direct injection of CXCL9 into the CNS infection site enhanced HSV-1-specific CD8+ T cell accumulation, leading to marked improvements in the survival of infected mice. This previously uncharacterized strategy for HSV-1 evasion of CD8+ T cell accumulation in the CNS has important implications for understanding the pathogenesis and clinical treatment of HSV-1 encephalitis. PMID- 28891814 TI - Fibroblast-specific TGF-beta-Smad2/3 signaling underlies cardiac fibrosis. AB - The master cytokine TGF-beta mediates tissue fibrosis associated with inflammation and tissue injury. TGF-beta induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-beta signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF beta-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-beta receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-beta mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-beta-Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response. PMID- 28891815 TI - RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism. AB - Bile acids function not only as detergents that facilitate lipid absorption but also as signaling molecules that activate the nuclear receptor farnesoid X receptor (FXR). FXR agonists are currently being evaluated as therapeutic agents for a number of hepatic diseases due to their lipid-lowering and antiinflammatory properties. FXR is also essential for maintaining bile acid homeostasis and prevents the accumulation of bile acids. Elevated bile acids activate FXR, which in turn switches off bile acid synthesis by reducing the mRNA levels of bile acid synthesis genes, including cholesterol 7alpha-hydroxylase (Cyp7a1). Here, we show that FXR activation triggers a rapid posttranscriptional mechanism to degrade Cyp7a1 mRNA. We identified the RNA-binding protein Zfp36l1 as an FXR target gene and determined that gain and loss of function of ZFP36L1 reciprocally regulate Cyp7a1 mRNA and bile acid levels in vivo. Moreover, we found that mice lacking hepatic ZFP36L1 were protected from diet-induced obesity and steatosis. The reduced adiposity and antisteatotic effects observed in ZFP36L1-deficient mice were accompanied by impaired lipid absorption that was consistent with altered bile acid metabolism. Thus, the ZFP36L1-dependent regulation of bile acid metabolism is an important metabolic contributor to obesity and hepatosteatosis. PMID- 28891816 TI - Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer. AB - Tumors adapt to an unfavorable microenvironment by controlling the balance between cell proliferation and cell motility, but the regulators of this process are largely unknown. Here, we show that an alternatively spliced isoform of syntaphilin (SNPH), a cytoskeletal regulator of mitochondrial movements in neurons, is directed to mitochondria of tumor cells. Mitochondrial SNPH buffers oxidative stress and maintains complex II-dependent bioenergetics, sustaining local tumor growth while restricting mitochondrial redistribution to the cortical cytoskeleton and tumor cell motility. Conversely, introduction of stress stimuli to the microenvironment, including hypoxia, acutely lowered SNPH levels, resulting in bioenergetics defects and increased superoxide production. In turn, this suppressed tumor cell proliferation but increased tumor cell invasion via greater mitochondrial trafficking to the cortical cytoskeleton. Loss of SNPH or expression of an SNPH mutant lacking the mitochondrial localization sequence resulted in increased metastatic dissemination in xenograft or syngeneic tumor models in vivo. Accordingly, tumor cells that acquired the ability to metastasize in vivo constitutively downregulated SNPH and exhibited higher oxidative stress, reduced cell proliferation, and increased cell motility. Therefore, SNPH is a stress-regulated mitochondrial switch of the cell proliferation-motility balance in cancer, and its pathway may represent a therapeutic target. PMID- 28891818 TI - Machine-learning Support to Individual Diagnosis of Mild Cognitive Impairment Using Multimodal MRI and Cognitive Assessments. AB - BACKGROUND: Understanding whether the cognitive profile of a patient indicates mild cognitive impairment (MCI) or performance levels within normality is often a clinical challenge. The use of resting-state functional magnetic resonance imaging (RS-fMRI) and machine learning may represent valid aids in clinical settings for the identification of MCI patients. METHODS: Machine-learning models were computed to test the classificatory accuracy of cognitive, volumetric [structural magnetic resonance imaging (sMRI)] and blood oxygen level dependent connectivity (extracted from RS-fMRI) features, in single-modality and mixed classifiers. RESULTS: The best and most significant classifier was the RS fMRI+Cognitive mixed classifier (94% accuracy), whereas the worst performing was the sMRI classifier (~80%). The mixed global (sMRI+RS-fMRI+Cognitive) had a slightly lower accuracy (~90%), although not statistically different from the mixed RS-fMRI+Cognitive classifier. The most important cognitive features were indices of declarative memory and semantic processing. The crucial volumetric feature was the hippocampus. The RS-fMRI features selected by the algorithms were heavily based on the connectivity of mediotemporal, left temporal, and other neocortical regions. CONCLUSION: Feature selection was profoundly driven by statistical independence. Some features showed no between-group differences, or showed a trend in either direction. This indicates that clinically relevant brain alterations typical of MCI might be subtle and not inferable from group analysis. PMID- 28891819 TI - Factors Influencing Successful Lumbar Puncture in Alzheimer Research. AB - OBJECTIVE: Lumbar puncture (LP) is increasingly common in Alzheimer disease research; however, agreement to undergo LP varies. We sought to determine factors influencing LP consent at Alzheimer's Disease Centers (ADCs) in the United States. METHODS: A 3-part survey was distributed to each ADC: (1) ADC LP Experience; (2) LP Requestor Experience; and (3) Patient LP Experience (both Initial and Follow-up). In all, 64 LP Requestor, 579 Patient/Initial, and 404 Patient/Follow-up surveys were collected. Logistic regression analyses with generalized estimating equations were used to assess factors associated with LP agreement and post-LP complications. RESULTS: Asians and those viewing LP negatively were less likely to agree to LP. Three hundred fifty-two participants had an LP; LP headache occurred in 11.9% (blood patch required in 1.4%) and 9.9% reported other complications. Younger individuals, women, those diagnosed with mild cognitive impairment, use of a Quincke needle, <=20 mL cerebrospinal fluid drawn, and hemorrhage during LP were associated with LP headache. Use of gravity flow during LP was associated with fewer other complications (nausea, dizziness, vasovagal response, back pain, neck stiffness, and/or nerve root pain). CONCLUSIONS: LP in Alzheimer disease research is generally safe and well tolerated. Factors influencing LP agreement potentially could be studied to advance participant acceptance of the procedure. PMID- 28891820 TI - Transitional Objects to Faciliate Grieving Following Perinatal Loss. AB - BACKGROUND: Parents who experience a perinatal loss often leave the hospital with empty arms and no tangible mementos to validate the parenting experience. Opportunities to create parenting experiences with transitional objects exist following the infant's death. PURPOSE: This article offers suggestions for staff in units where infant loss is possible to best assist parents in optimal grieving through the offering of transitional bereavement objects. METHODS/SEARCH STRATEGY: CINAHL Complete, MEDLINE, and the Cochrane Database of Systematic Reviews were searched using the following key words-perinatal bereavement, grief, perinatal loss, transitional objects, bereavement photography-and the search was limited to 5 years and the English language. FINDINGS/RESULTS: Recommendations exist and are well supported by leading neonatal and perinatal nursing and medicine organizations for the use of transitional objects to facilitate healthy grieving when parents experience perinatal loss. Transitional objects are mementos that validate the meaning of parenthood-even if the physical act of parenting was brief. Nursing and medical staff have significant roles in guiding parents to a healthy state of bereavement and ultimately managing long-term grief. IMPLICATIONS FOR PRACTICE: Transitional objects can be provided by staff that are low-cost or free, such as taking photographs for parents, or they can involve purchased products from perinatal bereavement programs. In the latter case, funding needs are a consideration for budgeting decisions. IMPLICATIONS FOR RESEARCH: Immediately following a loss, parents experience a brief sense of healing after receiving mementos of their infant. However, further research is needed to assess long-term effects of receiving transitional objects following perinatal loss. PMID- 28891817 TI - Neutrophil FcgammaRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases. AB - The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor FcgammaRIIA promotes glomerular neutrophil accumulation and damage in anti-glomerular basement membrane-induced (anti-GBM-induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through FcgammaRIIA-dependent, Abl/Src tyrosine kinase-mediated F-actin polymerization. Biophysical measurements showed that the lifetime of FcgammaRIIA-IgG bonds increased under mechanical force in an F-actin-dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil FcgammaRIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced FcgammaRIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury. PMID- 28891821 TI - Heart Rate Variability as a Feeding Intervention Outcome Measure in the Preterm Infant. AB - BACKGROUND: Feeding interventions for preterm infants aim to reduce the physiologic stress of feeding to promote growth. Heart rate variability (HRV) is a potential noninvasive measure of physiologic stress that may be useful for evaluating efficacy of feeding interventions. PURPOSE: To evaluate whether HRV is a sensitive measure of physiologic stress compared with standard physiologic outcomes in the context of a feeding intervention study. METHODS: This was a secondary analysis of a within-subjects, cross-over design study comparing usual care feeding with a gentle, coregulated (CoReg) feeding approach in 14 infants born less than 35 weeks' postmenstrual age. HRV indices were calculated from electrocardiogram data and compared with standard physiologic outcomes, including oxygen saturation (Spo2), respiratory rate (RR), apnea, heart rate (HR), and bradycardia. Data were analyzed using linear mixed modeling. RESULTS: Infants fed using the CoReg approach had fewer apneic events and higher RR, suggesting they were able to breathe more during feeding. No statistically significant differences were found in SpO2, HR, bradycardia, or high frequency power (the most commonly reported measure of HRV). Infants fed using the usual care approach had significantly higher SD12, a measure of HRV indicating randomness in the HR, which is a potential indicator of elevated stress. IMPLICATIONS FOR PRACTICE: SD12 was more sensitive to stress than SpO2, HR, and bradycardia. The utility of HRV as a measure of feeding outcomes in clinical practice needs further exploration. IMPLICATIONS FOR RESEARCH: Further exploration of HRV as an intervention outcome measure is needed, particularly evaluating nonlinear indices, such as SD12. PMID- 28891822 TI - Panniculectomy: Perioperative nursing considerations. PMID- 28891823 TI - Longitudinal Changes in Electrically Evoked Auditory Event-Related Potentials in Children With Auditory Brainstem Implants: Preliminary Results Recorded Over 3 Years. AB - OBJECTIVES: This preliminary study aimed (1) to assess longitudinal changes in electrically evoked auditory event-related potentials (eERPs) in children with auditory brainstem implants (ABIs) and (2) to explore whether these changes could be accounted for by maturation in the central auditory system of these patients. DESIGN: Study participants included 5 children (S1 to S5) with an ABI in the affected ear. The stimulus was a train of electrical pulses delivered to individual ABI electrodes via a research interface. For each subject, the eERP was repeatedly measured in multiple test sessions scheduled over up to 41 months after initial device activation. Longitudinal changes in eERPs recorded for each ABI electrode were evaluated using intraclass correlation tests for each subject. RESULTS: eERPs recorded in S1 showed notable morphological changes for five ABI electrodes over 41 months. In parallel, signs or symptoms of nonauditory stimulation elicited by these electrodes were observed or reported at 41 months. eERPs could not be observed in S2 after 9 months of ABI use but were recorded at 12 months after initial stimulation. Repeatable eERPs were recorded in S3 in the first 9 months. However, these responses were either absent or showed remarkable morphological changes at 30 months. Longitudinal changes in eERP waveform morphology recorded in S4 and S5 were also observed. CONCLUSIONS: eERP responses in children with ABIs could change over a long period of time. Maturation of the central auditory system could not fully account for these observed changes. Children with ABIs need to be closely monitored for potential changes in auditory perception and unfavorable nonauditory sensations. Neuroimaging correlates are needed to better understand the emergence of nonauditory stimulation over time in these children. PMID- 28891824 TI - Low FODMAP: A Preliminary Strategy to Reduce Gastrointestinal Distress in Athletes. AB - INTRODUCTION: Gastrointestinal (GI) distress in endurance athletes is prevalent and detrimental to performance. Adverse GI symptomatology can be analogous with irritable bowel syndrome, where fermentable oligosaccharide, disaccharide, monosaccharide, and polyols (FODMAP) reduction has demonstrated efficacy. This study investigated the effects of low FODMAP (LFOD) diet on GI distress parameters in runners with a history of nonclinical exercise-associated GI symptoms. METHODS: Eleven recreationally competitive runners (five men, six women; 5-km personal best 23:00 +/- 4:02 min:s) participated in the study. Runners were allocated to a randomized 6-d LFOD or high FODMAP (HFOD) diet separated by a 1-d wash-out in a controlled, single-blinded cross-over study. In each period participants completed two strenuous running sessions consisting of 5 * 1000 m and a 7-km threshold run. GI symptoms (during-exercise and daily) and the Daily Analysis of Life Demand for Athletes questionnaires were completed. Area under the curve was calculated for daily GI symptoms across each dietary period and analysis was conducted using multilevel mixed-effects linear regression for comparison between the two diets. RESULTS: A significantly smaller area under the curve for daily GI symptoms 6 d during the LFOD compared with HFOD (mean difference, -13.4; 95% confidence interval, -22 to -4.60; P = 0.003) was observed. The daily GI symptoms that were significantly lower during LFOD were flatulence (P < 0.001), urge to defecate (P = 0.04), loose stool (P = 0.03), and diarrhea (P = 0.004). No significant differences in during exercise symptoms or Daily Analysis of Life Demand for Athletes responses were observed between diets (P > 0.05). CONCLUSIONS: Preliminary findings suggest that short-term FODMAP reduction may be a beneficial intervention to minimize daily GI symptoms in runners with exercise-related GI distress. PMID- 28891825 TI - Hemiepiphyseodesis for Juvenile and Adolescent Tibia Vara Utilizing Percutaneous Transphyseal Screws. AB - BACKGROUND: In juvenile and adolescent tibia vara patients with sufficient growth remaining, implant-controlled hemiepiphyseodesis, or guided growth, can be used to correct deformity. Recent reports have described hardware failure of certain hemiepiphyseodesis implants in overweight patients with tibia vara. We describe our experience using transphyseal screws to correct deformity in this patient population. METHODS: A retrospective chart and radiograph review was conducted on all juvenile and adolescent tibia vara patients who underwent lateral proximal tibial hemiepiphyseodesis using a single transphyseal screw. Charts were queried for preoperative and postoperative mechanical axis deviation, medial proximal tibial angle, lateral distal femoral angle, and postoperative complications or need for further surgery. RESULTS: In total, 14 affected limbs in 9 patients (6 males) who underwent lateral proximal tibial transphyseal screw hemiepiphyseodesis were considered. Average chronologic age at implantation was 10.4 years and average body mass index was 31.7 kg/m. At average 23-month follow up, the average mechanical axis deviation improved from 46 to 0 mm (P<0.001), and the average medial proximal tibial angle improved from 81 to 92 degrees (P<0.001). No limbs underwent further surgery to correct residual deformity. There were no complications or instances of implant failure associated with the transphyseal screws. CONCLUSIONS: Hemiepiphyseodesis using transphyseal screws is an effective technique to correct deformity in juvenile and adolescent tibia vara patients with sufficient growth remaining. This method can be used safely with few complications and with minimal risk of mechanical failure, even in overweight patients. LEVEL OF EVIDENCE: Level IV-therapeutic. PMID- 28891827 TI - Development of an Animal Model for Inducing Various Degrees of Severity of Incontinence-Associated Dermatitis. AB - PURPOSE: The purpose of this study was to describe the biological changes after incontinence-associated dermatitis (IAD) induction by pancreatin in the guinea pigs and to explore the potentially appropriate timing and pancreatin concentration for IAD induction with different severity. DESIGN: In vivo, experimental study. SUBJECTS AND SETTING: An experimental animal model (guinea pig) in a controlled laboratory setting was used for investigation. METHODS: We developed an IAD model in guinea pigs by occluded application of 1%, 5%, and 10% pancreatin solutions for 1, 3, and 5 days, respectively. The irritant was applied to the posterior aspect of shaved guinea pigs. We used an adapted visual scoring system to evaluate IAD and its severity. We also measured differences of the fluid absorption rate as a proxy for transepidermal water loss and enzyme-linked immunosorbent assays of interleukin 2 and interferon-gamma expression as indicators of IAD-related inflammation. Analysis of variance (ANOVA) was used to examine group differences. RESULTS: Higher pancreatin concentrations led to more severe skin responses and higher mean visual scale scores, yet the statistically score differences were only observed in the 1% and 5% pancreatin groups after 3 and 5 days of exposure compared with 1 day of exposure (P < .05). The average absorbed fluid rate increased from 1 to 3 days of exposure and reached a plateau at 3 days; significant differences were observed in 3 and 5 days of exposure (P < .05) when compared with 1 day of exposure but not between 3 and 5 days of exposure. CONCLUSIONS: Exposure of a guinea pig animal model to 1%, 5%, and 10% pancreatin solutions over a 3-day period induced IAD with different levels of severity. Additional studies using this model are warranted. PMID- 28891826 TI - Injection Volume and Anesthetic Effect in Serratus Plane Block. AB - BACKGROUND AND OBJECTIVES: Serratus plane block is performed for analgesia of the anterior chest wall. However, there has been no study concerning the appropriate volume for this block. This prospective randomized controlled study assesses the dermatomal spread and analgesic effects of serratus plane block. METHODS: Ultrasound-guided serratus plane block was performed for breast cancer surgery. The patients were randomly assigned to receive 20 or 40 mL of 0.375% ropivacaine. The primary end point was the number of affected dermatomes as assessed by cold test and pinprick test 20 minutes after the block procedure. Secondary end points were the time until the first postoperative analgesic rescue, adverse effects, and complications. RESULTS: The number of affected dermatomes assessed by the cold test for patients receiving 40 mL of 0.375% ropivacaine was significantly larger than that for patients receiving 20 mL (P = 0.002; 6 [5-7] vs 4 [3-4] dermatomes). Similarly, with the pinprick test, the affected area was larger for the 40 mL group than for the 20 mL group (P = 0.009; 4 [2-6] vs 2 [1-3] dermatomes). There were no differences between the 2 groups in secondary end points. CONCLUSIONS: Ultrasound-guided serratus plane block spread in the craniocaudal direction is more widespread with 40 mL than with 20 mL of 0.375% ropivacaine. The time until the first postoperative analgesic rescue dose was not extended by a larger volume of injection. CLINICAL TRIALS REGISTRATION: UMIN Clinical Trials Registry (identifier UMIN000016549). PMID- 28891829 TI - Laparoscopic Procedure is Not Independently Associated With the Development of Intra-Abdominal Abscess After Appendectomy: A Multicenter Cohort Study With Propensity Score Matching Analysis. AB - AIM: The aim of this study was to identify independent risk factors for postoperative intra-abdominal abscess (IAA) after appendectomy for patients with acute appendicitis. BACKGRAOUND: Although laparoscopic appendectomy (LA) has been performed universally, whether LA is associated with an increased incidence of postoperative IAA compared with open appendectomy (OA) remains controversial, which causes some surgeons' increasing concerns. METHODS: We retrospectively analyzed 6805 consecutive adult patients with acute appendicitis who underwent LA or OA at 7 general hospitals in China. Patient characteristics, operative variables, and surgical outcomes were collected and compared between patients who underwent LA and OA. Propensity score matching analysis was used to minimize the bias in patient selection differing from various procedure of appendectomy. Independent risk factors associated with the development of postoperative IAA after appendectomy were identified by univariate and multivariate logistic regression analysis in the propensity matched cohort. RESULTS: Over a 3-year period, 2710 (39.8%) and 4095 (60.2%) patients underwent LA and OA respectively. Patients who underwent OA had more males, American Society of Anesthesiologists score 2-3, preoperative systemic inflammatory response syndrome, and perforated appendicitis than those who underwent LA (all P<0.01). Propensity score matched analysis created 2542 pairs of patients. Univariate analysis revealed that patients who underwent LA had a higher incidence of postoperative IAA than patients who underwent OA (6.7% vs. 5.3%; P=0.039). However, multivariate logistic regression analysis identified LA not to be an independent risk factor associated with the development of postoperative IAA (odds ratio, 1.053; 95% confidence interval, 0.922-1.657; P=0.216). CONCLUSIONS: The present study identified that laparoscopic procedure was not an independent risk factor associated with the development of postoperative IAA after appendectomy of acute appendicitis. Therefore, concerns of increased incidence of IAA because of laparoscopic procedure are unwarranted. PMID- 28891828 TI - Poor Performance on a Preoperative Cognitive Screening Test Predicts Postoperative Complications in Older Orthopedic Surgical Patients. AB - BACKGROUND: The American College of Surgeons and the American Geriatrics Society have suggested that preoperative cognitive screening should be performed in older surgical patients. We hypothesized that unrecognized cognitive impairment in patients without a history of dementia is a risk factor for development of postoperative complications. METHODS: We enrolled 211 patients 65 yr of age or older without a diagnosis of dementia who were scheduled for an elective hip or knee replacement. Patients were cognitively screened preoperatively using the Mini-Cog and demographic, medical, functional, and emotional/social data were gathered using standard instruments or review of the medical record. Outcomes included discharge to place other than home (primary outcome), delirium, in hospital medical complications, hospital length-of-stay, 30-day emergency room visits, and mortality. Data were analyzed using univariate and multivariate analyses. RESULTS: Fifty of 211 (24%) patients screened positive for probable cognitive impairment (Mini-Cog less than or equal to 2). On age-adjusted multivariate analysis, patients with a Mini-Cog score less than or equal to 2 were more likely to be discharged to a place other than home (67% vs. 34%; odds ratio = 3.88, 95% CI = 1.58 to 9.55), develop postoperative delirium (21% vs. 7%; odds ratio = 4.52, 95% CI = 1.30 to 15.68), and have a longer hospital length of stay (hazard ratio = 0.63, 95% CI = 0.42 to 0.95) compared to those with a Mini Cog score greater than 2. CONCLUSIONS: Many older elective orthopedic surgical patients have probable cognitive impairment preoperatively. Such impairment is associated with development of delirium postoperatively, a longer hospital stay, and lower likelihood of going home upon hospital discharge. PMID- 28891830 TI - Comparison of Postoperative Pain and Residual Gas Between Restrictive and Liberal Fluid Therapy in Patients Undergoing Laparoscopic Cholecystectomy. AB - BACKGROUND: Different fluid regimens are used in the clinical management of perioperative fluid therapy, but there still is the argument about which fluid regimen is better for patients. This study was mainly designed to compare different fluid regimens on postoperative pain and residual gas in patients undergoing laparoscopic cholecystectomy. METHODS: A total of 100 patients were equally randomized to receive restrictive fluid infusion (n=50) with lactated Ringer (LR) solution 5 mL/kg/h or liberal fluid infusion (n=50), with 30 mL/kg/h lactated Ringer solution. Postoperative pain was evaluated at 1, 6, and 24 hours after surgery using a visual analog scale (VAS). Postoperative subdiaphragmatic residual gas was monitored by x-ray at 24 hours after surgery. RESULTS: Patients in the restrictive group had significantly higher VAS pain scores at 6 hours after surgery than those in the liberal group (P=0.009). The incidence of subdiaphragmatic residual gas in the restrictive group was higher than in the liberal group (P=0.045). Patients who had residual gas had higher VAS pain scores than those with no residual gas in the restrictive group at 6 hours after surgery (P=0.02). CONCLUSIONS: Patients undergoing laparoscopic cholecystectomy with restrictive fluid therapy may suffer more severe postoperative pain than those receiving liberal fluid therapy. It suggests that the higher incidence of subdiaphragmatic residual gas may have occurred with restrictive fluid therapy. PMID- 28891831 TI - Mucosal Cytokine Profiles After Induction Therapy With Granulocyte/Monocyte Apheresis in New-onset Inflammatory Colitis. AB - Granulocyte/monocyte apheresis (GMA) selectively removes circulating granulocytes and monocytes; important producers of proinflammatory cytokines. Seven children with new-onset inflammatory bowel disease (IBD) colitis were treated with GMA together with mesalazine, and had significant decreases in Pediatric UC Activity Index (P = 0.018) and Mayo endoscopic score (P = 0.013). We investigated the colonic mucosal cytokine profiles (analyzed with real-time polymerase chain reaction), before and after induction treatment, and in 6 non-IBD controls. Significant decreases were seen in Colony Stimulating Factor 2 (P = 0.018), tumor necrosis factor-alpha (P = 0.028), interleukin (IL)-23alpha (P = 0.043), IL-1beta (P = 0.028), IL-36gamma (P = 0.018), IL-10 (P = 0.028), and transforming growth factor beta 1 (P = 0.043) after treatment. In 6 non-IBD controls there were significantly lower levels of IL-12beta (P = 0.023) and IL-23alpha (P = 0.046) compared to the patients with IBD at onset, and IL-22 (P = 0.088) and IL-36gamma (P = 0.062) showed lower values without reaching significant differences. We speculate that the decreases in colonic mucosal cytokine profiles after treatment may explain the observed clinical efficacy in the GMA-treated children with IBD. PMID- 28891832 TI - Mimicking Own Mother's Milk for Preterms: Are We Getting Closer? PMID- 28891833 TI - Differences in Antipsychotic Prescriptions Between Centers in Young Outpatients With Schizophrenia. PMID- 28891834 TI - Naltrexone for Self-Injury in Borderline Personality With Venlafaxine-Associated Hyponatremia. PMID- 28891835 TI - The Effect of Dextromethorphan Premedication on Cough and Patient Tolerance During Flexible Bronchoscopy: A Randomized, Double-blind, Placebo-controlled Trial. AB - BACKGROUND: Patients undergoing bronchoscopy can experience problems such as anxiety and cough, requiring various doses of sedatives and analgesics. The purposes of this study were to investigate the effect of premedication with dextromethorphan on patients' cough and anxiety, and the use of analgesics/sedatives during flexible bronchoscopy (FB). METHODS: A randomized, double-blind, placebo-controlled, prospective study was performed to assess the effect of dextromethorphan premedication on patients who underwent diagnostic bronchoscopy. Seventy patients included in this study were randomly allocated into 2 groups: group A consisted of 35 patients who received dextromethorphan before FB; and group B consisted of 35 patients who received a placebo. A questionnaire was given to the patients and bronchoscopist about perception of cough, anxiety, and discomfort. The amount of sedative medication and lidocaine use during the procedure and the procedure time were recorded. RESULTS: The group that was premedicated with dextromethorphan had lower complaint scores, significantly less coughing, significantly less stress assessed by the patient and the physician evaluation, shorter total procedure time, and fewer midazolam requirements during FB (P-value <0.05). CONCLUSION: Considering its safety profile, dextromethorphan premedication is an effective approach to facilitate the performance of FB for the physician, and could improve patient comfort. PMID- 28891836 TI - Feasibility and Safety of Flexible Bronchoscopy Performed Via Tracheal Tubes in Patients With Tracheostomies: A Retrospective, Single-Center Experience. AB - BACKGROUND: Flexible bronchoscopy (FB) is commonly performed to assess, diagnose, and treat patients with respiratory disease, and is typically performed via transnasal or transoral approaches. FB can be performed via tracheal tubes in patients with tracheostomies; however, the safety and technical feasibility has not been established. The present study evaluates the safety and feasibility of performing FB via tracheal tubes. MATERIALS AND METHODS: A total of 45 patients underwent 56 procedures involving FB via tracheal tubes at a single institution from November 2013 to November 2014 and were included in this retrospective case series. RESULTS: Patients had a median age of 68 years (interquartile range, 56 to 82.5), and 51% were female. Most patients had 2 comorbidities (interquartile range, 1 to 3), with the most common being hypertension, diabetes mellitus, and chronic kidney disease. Upper airway obstruction was the primary indication for bronchoscopy in 40% of patients. Fifty-three percent of patients had a Shiley tube #6, [internal cannula diameter (ICD) of 6.5 mm]; tracheal tubes in the remaining patients ranged from Shiley #4 (ICD, 5.5 mm) to Shiley #8 (ICD, 8.5 mm). One patient did not complete the procedure due to severe hypertension (intraprocedural systolic blood pressure >180 mm Hg). During FB, no patients experienced cardiorespiratory arrest, arrhythmia, bleeding, or desaturation that required resuscitation. Eleven patients had a mucus plug leading to atelectasis during bronchoscopy, and 8 of these had a postprocedural chest x-ray finding of lung reexpansion. CONCLUSION: FB via tracheal tubes is a technically feasible and safe procedure that does not compromise patient oxygenation. PMID- 28891837 TI - An acute care approach to functional abdominal pain. AB - Functional abdominal pain disorders are commonly seen in the acute care setting and can be a source of frustration for patients and providers given their inherent chronic nature. However, an understanding of both the general approach to these disorders and the approach to specific common subtypes can help alleviate this frustration and lead to both short-term and long-term therapeutic success. This article describes the pathophysiology of these disorders and outlines a diagnostic and therapeutic approach to commonly seen functional abdominal pain disorders in adults. PMID- 28891838 TI - Disease screening and prevention for transgender and gender-diverse adults. AB - Primary care clinicians have an important role in the health and wellness of transgender and gender-diverse (TGD) adults and need to know best practices of health maintenance and disease prevention interventions. This article focuses on how exogenous use of sex steroids provided as hormone therapy and gender affirming procedures affect screening and prevention. Hormone therapy can affect the heart, liver, lipids, bones, brain, skin, and reproductive organs; likewise, behaviors and gender-affirming procedures may alter the risks, prevalence, and screening techniques of sexually transmitted infections. Where applicable, modifications accounting for those differences should be incorporated into the primary care of TGD adults. PMID- 28891839 TI - The relative effects of dexmedetomidine and propofol on cerebral blood flow velocity and regional brain oxygenation: A randomised noninferiority trial. AB - BACKGROUND: Dexmedetomidine constricts cerebral blood vessels without a concomitant reduction in cerebral metabolic oxygen consumption. Its safety as a sedative in patients with neurological diseases thus remains uncertain. OBJECTIVE: Our primary objective was to test the hypothesis that dexmedetomidine is noninferior to propofol as regards cerebral blood flow (CBF) velocity and brain oxygenation. DESIGN: Unblinded randomised trial. SETTING: Cleveland Clinic Hospital, Cleveland, from November 2010 to July 2013. PATIENTS: Forty-four patients scheduled for insertion of a deep-brain stimulating electrodes. INTERVENTIONS: Patients were randomised to receive either dexmedetomidine or propofol sedation during deep-brain stimulating electrode insertion. MAIN OUTCOME MEASURES: Intraoperative CBF velocity was measured with transcranial Doppler, and brain oxygenation was assessed with near-infrared spectroscopy. Noninferiority of dexmedetomidine to propofol was defined as a less than 20% difference in means. RESULTS: Twenty-three patients were given dexmedetomidine and 21 propofol. Baseline characteristics and operative management were similar in each group. Dexmedetomidine was noninferior to propofol on both CBF and brain oxygenation, confirming our primary hypothesis. For cerebral flood flow, the estimated ratio of means (dexmedetomidine/propofol) was 0.94 [90% CI: 0.84 to 1.05], P = 0.011 for noninferiority. For brain oxygenation, the estimated ratio of means was 0.99 [90% CI: 0.96 to 1.02], P < 0.001 for noninferiority. Superiority was not found for either primary outcome. Dexmedetomidine provided deeper sedation than propofol, with a difference of medians of 1 [90% CI: 0 to 2], P < 0.001 on the Observer's Assessment of Alertness/Sedation scale. No significant differences were observed in pulsatility index, cerebral perfusion pressure, number of hypertensive or apnoeic episodes. CONCLUSION: Regional brain oxygenation and CBF velocity are comparably preserved during dexmedetomidine and propofol sedation. Thus, the use of dexmedetomidine in patients with movement disorders appears reasonable. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT 01200433). PMID- 28891840 TI - Comprehensive Training and Safe Implementation of a Transanal Total Mesorectal Excision Program. PMID- 28891841 TI - Need a LIFT? PMID- 28891842 TI - The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Treatment of Colon Cancer. AB - The American Society of Colon and Rectal Surgeons is dedicated to ensuring high quality patient care by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus. The Clinical Practice Guidelines Committee is composed of society members who are chosen because they have demonstrated expertise in the specialty of colon and rectal surgery. This committee was created to lead international efforts in defining quality care for conditions related to the colon, rectum, and anus. This is accompanied by developing Clinical Practice Guidelines based on the best available evidence. These guidelines are inclusive and not prescriptive. Their purpose is to provide information on which decisions can be made, rather than to dictate a specific form of treatment. These guidelines are intended for the use of all practitioners, health care workers, and patients who desire information about the management of the conditions addressed by the topics covered in these guidelines. It should be recognized that these guidelines should not be deemed inclusive of all proper methods of care or exclusive of methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all the circumstances presented by the individual patient. PMID- 28891843 TI - Neuroendocrine Tumors of the Colon and Rectum. PMID- 28891844 TI - Expert Commentary on Neuroendocrine Tumors of the Colon and Rectum. PMID- 28891845 TI - Uptake of Transanal Total Mesorectal Excision in North America: Initial Assessment of a Structured Training Program and the Experience of Delegate Surgeons. AB - BACKGROUND: Transanal total mesorectal excision is a new approach to curative intent rectal cancer surgery. Training and surgeon experience with this approach has not been assessed previously in America. OBJECTIVE: The purpose of this study was to characterize a structured training program and to determine the experience of delegate surgeons. DESIGN: Data were assimilated from an anonymous, online survey delivered to attendees on course completion. Data on surgeon performance during hands-on cadaveric dissection were collected prospectively. SETTINGS: This study was conducted at a single tertiary colorectal surgery referral center, and cadaveric hands-on training was conducted at a specialized surgeon education center. MAIN OUTCOME MEASURES: The main outcome measurement was the use of the course and surgeon experience posttraining. RESULTS: During a 12-month period, eight 2-day transanal total mesorectal excision courses were conducted. Eighty one colorectal surgeons successfully completed the course. During cadaveric dissection, 71% achieved a complete (Quirke 3) specimen; 26% were near complete (Quirke 2), and 3% were incomplete (Quirke 1). A total of 9.1% demonstrated dissection in the incorrect plane, whereas 4.5% created major injury to the rectum or surrounding structures, excluding the prostate. Thirty eight (46.9%) of 81 surgeon delegates responded to an online survey. Of survey respondents, 94.6% believed training should be required before performing transanal total mesorectal excision. Posttraining, 94.3% of surgeon delegates planned to use transanal total mesorectal excision for distal-third rectal cancers, 74.3% for middle-third cancers, and 8.6% for proximal-third cancers. The most significant complication reported was urethral injury; 5 were reported by the subset of survey respondents who had performed this operation postcourse. LIMITATIONS: The study was limited by inherent reporting bias, including observer and recall biases. CONCLUSIONS: Although this structured training program for transanal total mesorectal excision was found to be useful by the majority of respondents, the risk of iatrogenic injury after training remains high, suggesting that this training pedagogy alone is insufficient. See Video Abstract at http://links.lww.com/DCR/A335. PMID- 28891846 TI - Quality of Life in Rectal Cancer Patients After Chemoradiation: Watch-and-Wait Policy Versus Standard Resection - A Matched-Controlled Study. AB - BACKGROUND: Fifteen to twenty percent of patients with locally advanced rectal cancer have a clinical complete response after chemoradiation therapy. These patients can be offered nonoperative organ-preserving treatment, the so-called watch-and-wait policy. The main goal of this watch-and-wait policy is an anticipated improved quality of life and functional outcome in comparison with a total mesorectal excision, while maintaining a good oncological outcome. OBJECTIVE: The aim of this study was to compare the quality of life of watch-and wait patients with a matched-controlled group of patients who underwent chemoradiation and surgery (total mesorectal excision group). DESIGN: This was a matched controlled study. SETTINGS: This study was conducted at multiple centers. PATIENTS: The study population consisted of 2 groups: 41 patients after a watch and-wait policy and 41 matched patients after chemoradiation and surgery. Patients were matched on sex, age, tumor stage, and tumor height. All patients were disease free at the moment of recruitment after a minimal follow-up of 2 years. MAIN OUTCOME MEASURES: Quality of life was measured by validated questionnaires covering general quality of life (Short Form 36, European Organization for Research and Treatment of Cancer QLQ-C30), disease-specific total mesorectal excision (European Organization for Research and Treatment of Cancer QLQ-CR38), defecation problems (Vaizey and low anterior resection syndrome scores), sexual problems (International Index of Erectile Function and Female Sexual Function Index), and urinary dysfunction (International Prostate Symptom Score). RESULTS: The watch-and-wait group showed better physical and cognitive function, better physical and emotional roles, and better global health status compared with the total mesorectal excision group. The watch-and-wait patients showed fewer problems with defecation and sexual and urinary tract function. LIMITATIONS: This study only focused on watch-and-wait patients who achieved a sustained complete response for 2 years. In addition, this is a study with a limited number of patients and with quality-of-life measurements on nonpredefined and variable intervals after surgery. CONCLUSIONS: After a successful watch-and wait approach, the quality of life was better than after chemoradiation and surgery on several domains. However, chemoradiation therapy on its own is not without long-term side effects, because one-third of the watch-and-wait patients experienced major low anterior resection syndrome symptoms, compared with 66.7% of the patients in the total mesorectal excision group. See Video Abstract at http://links.lww.com/DCR/A395. PMID- 28891847 TI - Prognostic Significance of Peritoneal Metastasis in Stage IV Colorectal Cancer Patients With R0 Resection: A Multicenter, Retrospective Study. AB - BACKGROUND: Stage IV colorectal cancer encompasses various clinical conditions. The differences in prognosis after surgery between different metastatic organs have not been fully investigated. OBJECTIVE: This study aimed to assess prognostic significance in peritoneal metastasis in R0 resected stage IV colorectal cancer. DESIGN: We conducted a multicenter retrospective study of patients with R0 resected stage IV colorectal cancer; they were categorized into 3 groups according to the number and location of metastatic organs, including single-organ metastasis in the peritoneum, single-organ metastasis at sites except the peritoneum, and multiple-organ metastases. SETTINGS: This study used data accumulated by the Japanese Study Group for Postoperative Follow-Up of Colorectal Cancer. PATIENTS: A total of 1133 patients with R0 resected stage IV colorectal cancer were registered retrospectively between 1997 and 2007 in 20 referral hospitals. MAIN OUTCOME MEASURES: Cancer-specific survival rates between the groups were measured. RESULTS: The median cancer-specific survival of the single-organ metastasis in the peritoneum group was considerably shorter than that of the single-organ metastasis at a site other than the peritoneum group and was almost comparable to that of the multiple-organ metastases group (3.41 years, 6.20 years, and 2.99 years). In a multivariate analysis of cancer-specific survival, peritoneal dissemination was confirmed as an independent prognostic factor of survival. The median postrecurrence survival of single-organ metastasis in the peritoneum group was considerably shorter than that of the single-organ metastasis at a site other than the peritoneum group. Approximately half of the patients who experienced recurrence of single-organ metastasis in the peritoneum experienced peritoneal recurrence. LIMITATIONS: This was a retrospective, population-based study that requires a prospective design to validate its conclusions. CONCLUSIONS: Peritoneal metastasis of colorectal cancer frequently recurred in the peritoneum even after R0 resection. The cancer-specific survival of the single-organ metastasis in the peritoneum group was as poor as that of the multiple-organ metastases group. See Video Abstract at http://links.lww.com/DCR/A398. PMID- 28891848 TI - Adjuvant Chemotherapy After Preoperative Chemoradiation Improves Survival in Patients With Locally Advanced Rectal Cancer. AB - BACKGROUND: Practice guidelines differ in their support of adjuvant chemotherapy use in patients who received preoperative chemoradiation for rectal cancer. OBJECTIVE: The purpose of this study was to evaluate the impact of adjuvant chemotherapy among patients with locally advanced rectal cancer who received neoadjuvant chemoradiation and surgery. DESIGN: This was a retrospective study. Multivariable Cox proportional hazard modeling was used to evaluate the adjusted survival differences. SETTINGS: Data were collected from the National Cancer Database. PATIENTS: Adults with pathologic stage II and III rectal adenocarcinoma who received neoadjuvant chemoradiation and surgery were included. MAIN OUTCOME MEASURES: Overall survival was measured. RESULTS: Among 12,696 patients included, 4023 (32%) received adjuvant chemotherapy. The use of adjuvant chemotherapy increased over the study period from 23% to 36%. Although older age and black race were associated with a lower likelihood of receiving adjuvant chemotherapy, patients with higher education level and stage III disease were more likely to receive adjuvant chemotherapy (all p < 0.05). At 7 years, overall survival was improved among patients who received adjuvant chemotherapy (60% vs. 55%; p < 0.001). After risk adjustment, the use of adjuvant chemotherapy was associated with improved survival (HR = 0.81 (95% CI, 0.72-0.91); p < 0.001). In the subgroup of patients with stage II disease, survival was also improved among patients who received adjuvant chemotherapy (68% vs 58% at 7 y; p < 0.001; HR = 0.70 (95% CI, 0.57-0.87); p = 0.002). Among patients with stage III disease, the use of adjuvant chemotherapy was associated with a smaller but persistent survival benefit (56% vs 51% at 7 y; p = 0.017; HR = 0.85 (95% CI, 0.74-0.98); p = 0.026). LIMITATIONS: The study was limited by its potential for selection bias and inability to compare specific chemotherapy regimens. CONCLUSIONS: The use of adjuvant chemotherapy among patients with rectal cancer who received preoperative chemoradiation conferred a survival benefit. This study emphasizes the importance of adjuvant chemotherapy in the management of rectal cancer and advocates for its increased use in the setting of neoadjuvant therapy. See Video Abstract at http://link.lww.com/DCR/A428. PMID- 28891850 TI - Ligation of Intersphincteric Fistula Tract for Fistula in Ano: Lessons Learned From a Decade of Experience. AB - BACKGROUND: Ligation of intersphincteric fistula tract is a well-described sphincter-preserving technique for the management of fistula in ano. In 2007, we reported our early experience demonstrating a primary success rate of 94.4%. These findings have since been supported by several short-term studies, but long term results and secondary cure rates after ligation of intersphincteric fistula tract failure remain unknown. OBJECTIVE: This study aims to report a 10-year experience of ligation of intersphincteric fistula tract with extended long-term follow-up. DESIGN: Retrospective analysis of single-center data from May 2006 to October 2010 was performed. SETTINGS: This study was conducted at a large tertiary hospital in Bangkok, Thailand. PATIENTS: All patients with primary or recurrent fistula in ano who underwent a ligation of intersphincteric fistula tract procedure were included. Patients with malignancy, incontinent patients, and patients with rectovaginal fistula were excluded. MAIN OUTCOME MEASURES: Healing as defined by the absence of symptoms with no visible external opening on clinical examination. Follow-up was continued until May 2016. RESULTS: In total, 251 patients were identified, with a primary healing rate of 87.65% at a median follow-up of 71 months. The healing rates for low transsphincteric, intersphincteric, high transsphincteric, semihorseshoe, and horseshoe fistulas were 92.1%, 85.2%, 60.0%, 89.0%, and 40.0%. Of the 42 patients who had an unhealed fistula after previous non-ligation of intersphincteric fistula tract surgery, 38 (90.48%) healed after the first attempt at ligation of intersphincteric fistula tract. There were 31 patients with unhealed fistulas after the first ligation of intersphincteric fistula tract. Of these, 3 healed spontaneously, and the rest underwent either repeat ligation of intersphincteric fistula tract, fistulotomy (if the recurrence was intersphincteric), or simple curettage (if no internal opening was found). Ultimately, only 2 of the original 251 patients remained unhealed, and there was no change in subjective continence status after surgery. LIMITATIONS: This study was limited by its retrospective design. CONCLUSION: Ligation of intersphincteric fistula tract is an effective technique for the treatment of fistula in ano, including recurrent or unhealed fistula after other procedures. See Video Abstract at http://links.lww.com/DCR/A387. PMID- 28891849 TI - Adrenal Lesions in Patients With (Attenuated) Familial Adenomatous Polyposis and MUTYH-Associated Polyposis. AB - BACKGROUND: The reported proportion of patients with familial adenomatous polyposis who have adrenal lesions varies between 7% and 13% compared with 4% in the general population; the prevalence of adrenal lesions in patients with attenuated familial adenomatous polyposis and MUTYH-associated polyposis is unknown. Data on the clinical relevance and clinical course are limited. OBJECTIVE: We aimed to report on the frequency, characteristics, and progression of adrenal lesions in polyposis patients. DESIGN: This was a historical cohort study. SETTINGS: The study was performed at the Academic Medical Center, Amsterdam. PATIENTS: All of the patients with familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis were included. Medical charts and imaging reports were analyzed for data on adrenal lesions. A radiologist reassessed all of the images. Patients had not routinely been screened for adrenal lesions. MAIN OUTCOME MEASURES: The frequency, characteristics, and progression of adrenal lesions in patients with polyposis who underwent abdominal imaging were assessed. Findings were compared with a reference. RESULTS: A total of 39 adrenal lesions were identified in 23 (26%) of 90 patients with familial adenomatous polyposis, 2 (18%) of 11 with attenuated familial adenomatous polyposis, and 5 (24%) of 21 with MUTYH-associated polyposis. Mean age at time of detection was 50.7 years (range, 17.1-83.3 y). Median lesion size at baseline was 1.4 cm (range, 1.0-5.0 cm) versus 1.7 cm (range, 1.0-5.7 cm) after a median of 3.5 years (range, 1.0-11.4 y). Two patients were diagnosed with a hyperfunctioning lesion, and 4 underwent adrenalectomy: 3 lesions appeared benign, and 1 was oncocytic of uncertain malignant potential. The OR for detecting at least 1 lesion in a patient with polyposis versus reference was 6.2 (95% CI, 3.2-12.3), with no significant differences in ORs among the 3 syndromes. LIMITATIONS: The study was limited by its retrospective design. CONCLUSIONS: Adrenal lesions are frequent in patients with polyposis who undergo abdominal imaging. They appear to follow a benign and slowly progressive course and are mostly nonhyperfunctioning. See Abstract Video at http://links.lww.com/DCR/A323. PMID- 28891851 TI - Sphincter-Sparing Anal Fistula Repair: Are We Getting Better? AB - BACKGROUND: Sphincter-sparing repairs are commonly used to treat anal fistulas with significant muscle involvement. OBJECTIVE: The current study evaluates the trends and efficacy of sphincter-sparing repairs and determines risk factors for fistula recurrence. DESIGN AND SETTINGS: A retrospective review was performed at 3 university-affiliated teaching hospitals. PATIENTS: All 462 patients with cryptoglandular anal fistulas who underwent 573 sphincter-sparing repairs between 2005 and 2015 were included. Patients with Crohn's disease were excluded. MAIN OUTCOME MEASURES: The primary outcome was the rate of fistula healing defined as cessation of drainage with closure of the external opening. Risk factors for nonhealing were also analyzed. RESULTS: Five hundred three sphincter-sparing repairs were analyzed, whereas 70 were lost to follow-up. Two hundred twenty sphincter-sparing repairs (44%) resulted in healing, 283 (56%) resulted in nonhealing with a median follow-up of 9 (range, 1-125) months. The median time to fistula recurrence was 3 (range, 0-75) months with 79% and 91% of recurrences noted within 6 and 12 months. Patients treated with a dermal advancement flap, rectal advancement flap, or ligation of the intersphincteric tract procedure were less likely to have a recurrence than patients treated with a fistula plug or fibrin glue (p < 0.001). Over time, there was a significantly increased use of the ligation of the intersphincteric tract procedure (p < 0.001) and a significantly decreased use of fistula plugs and fibrin glue (p < 0.001); healing rates improved accordingly. There were no significant differences in healing rates with respect to patient demographics, comorbidities, or fistula characteristics. LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: Healing rates following sphincter-sparing repairs of cryptoglandular anal fistulas are modest, but have improved over time with the use of better surgical techniques. In this study, ligation of the intersphincteric fistula tract and flaps were superior to fistula plugs and fibrin glue; the former procedures are therefore favored. See Video Abstract at http://links.lww.com/DCR/A391. PMID- 28891852 TI - Condyloma Acuminatum, Anal Intraepithelial Neoplasia, and Anal Cancer in the Setting of HIV: Do We Really Understand the Risk? AB - BACKGROUND: The gold standard for surveillance of patients with anal lesions is unclear. OBJECTIVE: The aim of this study was to stratify patients for risk of progression of disease and to determine appropriate intervals for surveillance of patients with anal disease. DESIGN: This was a retrospective chart review for patients treated for anal lesions between 2007 and 2014. Only patients with >=1 year of follow-up from index evaluation, pathology, documented physical examination, and anoscopy findings were included for analysis. SETTINGS: The study was conducted at an urban university hospital. PATIENTS: HIV-positive patients with anal lesions treated with excision and fulguration were included. MAIN OUTCOME MEASURES: Recurrence of anal lesions, progression of disease, and progression to cancer were measured. RESULTS: Ninety-one patients met inclusion criteria. The mean age was 41.6 years, and mean follow-up was 38.6 months (range, 11.0-106.0 mo). On initial pathology, 8 patients (8.8%) had a diagnosis of condyloma acuminatum without dysplasia, 20 patients (22%) had anal intraepithelial neoplasia I, 32 (35.2%) had anal intraepithelial neoplasia II, and 31 (34.1%) had anal intraepithelial neoplasia III. Sixty-nine patients (75.8%) had repeat procedures. Seven (87.5%) of 8 patients with condyloma and 6 (30%) of 20 patients with anal intraepithelial neoplasia I progressed to high grade lesions. Five (15.6%) of 32 patients progressed from anal intraepithelial neoplasia II to III, and 2 patients with anal intraepithelial neoplasia III (6.5%) developed squamous cell carcinoma (2.3% for the entire cohort). LIMITATIONS: This was a single institution study. High-resolution anoscopy was not used. CONCLUSIONS: All of the HIV-positive patients with condyloma or anal intraepithelial neoplasia, regardless of the presence of dysplasia, should be surveyed at equivalent 3-month time intervals, because their risk of progression of disease is high. Video Abstract at http://links.lww.com/DCR/A389. PMID- 28891853 TI - Design and Psychometric Evaluation of the Quality of Life in Patients With Anal Fistula Questionnaire. AB - BACKGROUND: Quality of life is often considered when deciding and evaluating the treatment strategy for patients diagnosed with anal fistula. OBJECTIVE: The purpose of this study was to develop and psychometrically test the Quality of Life in Patients with Anal Fistula Questionnaire. DESIGN: This was an observational cross-sectional study for the development and validation of a psychometric tool. SETTINGS: The study was conducted at a general hospital in the southeast of Spain. PATIENTS: A convenience sample included 54 patients diagnosed with anal fistula. MAIN OUTCOMES MEASURES: The reliability of the tool was assessed through its internal consistency (Cronbach alpha) and temporal stability (Spearman correlation coefficient (r) between test-retest). The content validity index of the items and the scale was calculated. Correlation analysis and an ordinal regression analysis between the developed tool and the Short Form 12 Health Survey examined its concurrent validity. Principal component analysis and known-group analysis using the Kruskal-Wallis test examined its construct validity. RESULTS: The reliability of the developed questionnaire was very high (alpha = 0.908; r = 0.861; p < 0.01). Its content validity was excellent (all item content validity index = 0.79-1.00; scale validity index = 0.92). Evidence of its concurrent validity included strong correlation between the developed tool and Short Form 12 Health Survey (r = 0.734; p < 0.001), and participant scores on the developed tool explained ~46.2% of the between-subject variation for the participant scores on Short Form 12 Health Survey (Nagelkerke R = 0.462). Confirming its construct validity, principal component analysis revealed that 2 factors explained 81.63% of the total variance found. Known-group analysis evidenced the ability of the questionnaire to detect expected differences in patients presenting with different symptomatology. LIMITATIONS: The major limitations of this study were the use of a small sample of Spanish-speaking patients, not including patients in the initial development of the questionnaire, and developing the scoring system using a summation method. CONCLUSIONS: The Quality of Life in Patients with Anal Fistula Questionnaire has proven to be a valid, reliable, and concise tool that could contribute to the evaluation of quality of life among patients with an anal fistula. See Video Abstract at http://links.lww.com/DCR/A368. PMID- 28891854 TI - Racial and Socioeconomic Differences Manifest in Process Measure Adherence for Enhanced Recovery After Surgery Pathway. AB - BACKGROUND: Adherence to care processes and surgical outcomes varies by population subgroups for the same procedure. Enhanced recovery after surgery pathways are intended to standardize care, but their effect on process adherence and outcomes for population subgroups is unknown. OBJECTIVE: This study aims to demonstrate the association between recovery pathway implementation, process measures, and short-term surgical outcomes by population subgroup. DESIGN: This study is a pre- and post-quality improvement implementation cohort study. SETTING: This study was conducted at a tertiary academic medical center. INTERVENTION: A modified colorectal enhanced recovery after surgery pathway was implemented. PATIENTS: Patients were included who had elective colon and rectal resections before (2013) and following (2014-2016) recovery pathway implementation. MAIN OUTCOME MEASURE: Thirty-day outcomes by race and socioeconomic status were analyzed using a difference-in-difference approach with correlation to process adherence. RESULTS: We identified 639 cases (199 preimplementation, 440 postimplementation). In these cases, 75.2% of the patients were white, and 91.7% had a high socioeconomic status. Groups were similar in terms of other preoperative characteristics. Following pathway implementation, median lengths of stay improved in all subgroups (-1.0 days overall, p <= 0.001), but with no statistical difference by race or socioeconomic status (p = 0.89 and p = 0.29). Complication rates in both racial and socioeconomic groups were no different (26.4% vs 28.8%, p = 0.73; 27.3% vs 25.0%, p = 0.86) and remained unchanged with implementation (p = 0.93, p = 0.84). By race, overall adherence was 31.7% in white patients and 26.5% in nonwhite patients (p = 0.32). Although stratification by socioeconomic status demonstrated decreased overall adherence in the low-status group (31.8% vs 17.1%, p = 0.05), white patients were more likely to have regional pain therapy (57.1% vs 44.1%, p = 0.02) with a similar trend seen with socioeconomic status. LIMITATIONS: Data were collected primarily for quality improvement purposes. CONCLUSIONS: Differences in outcomes by race and socioeconomic status did not arise following implementation of an enhanced recovery pathway. Differences in process measures by population subgroups highlight differences in care that require further investigation. See Video Abstract at http://links.lww.com/DCR/A386. PMID- 28891855 TI - Patient Satisfaction With Propofol for Outpatient Colonoscopy: A Prospective, Randomized, Double-Blind Study. AB - BACKGROUND: Previous literature has shown that propofol has ideal anesthetic properties for patients undergoing colonoscopy, a common procedure at outpatient surgery centers. However, there is a paucity of information regarding patient satisfaction with propofol. OBJECTIVE: The aim of this study was to evaluate patient satisfaction with propofol compared with nonpropofol (fentanyl/midazolam) anesthesia for outpatient colonoscopies. Safety and complications were secondary end points. DESIGN: This study was a double-blind, randomized, parallel-group controlled clinical trial (NCT 02937506). SETTING: This study was conducted at a single ambulatory surgery center at an urban teaching community health system. PATIENTS: Patients were scheduled for outpatient colonoscopy. Those with high risk cardiac or pulmonary disease were excluded. INTERVENTIONS: Anesthesia personnel administered either fentanyl/midazolam (n = 300) or propofol (n = 300) for sedation during outpatient colonoscopy. A single, highly experienced endoscopist performed all colonoscopies. MAIN OUTCOME MEASURES: The primary outcomes measured were patient satisfaction (5-point Likert scale) and procedure complications. Data were collected on the day of endoscopy by the nursing staff of the postanesthesia care unit. A subinvestigator blinded to the randomization called patients 24 to 72 hours after discharge to obtain data on postprocedure problems and status of resumption of normal activities. Analysis was intention-to treat. RESULTS: Fewer patients who received propofol remembered being awake during the procedure (2% vs 17% for fentanyl, p < 0.0001) and were more likely to rate the amount of anesthesia received as being "just right" (98.7% vs 91.3% for fentanyl, p = 0.0002) and state that they were "very satisfied" with their anesthesia (86.3% vs 74% for fentanyl, p = 0.0005). Twenty-six percent of fentanyl procedures were rated "difficult" compared with 4.3% for propofol (p < 0.0001), and complications were fewer in the propofol group (2.7% vs 11.7%, p < 0.0001). LIMITATIONS: The endoscopist could not be completely blinded to the anesthetic administered. CONCLUSIONS: Patients prefer propofol over a combination of fentanyl/midazolam as their anesthetic for outpatient colonoscopies. From a patient and provider perspective, propofol appears to be superior to fentanyl/midazolam for outpatient colonoscopy. See Video Abstract at http://links.lww.com/DCR/A445. PMID- 28891856 TI - Transanal Total Mesorectal Excision: Pneumodissection of Retroperitoneal Structures Eases Laparoscopic Rectal Resection. AB - INTRODUCTION: Laparoscopic total mesorectal excision is effective and safe but often technically challenging because of inadequate exposure. Transanal total mesorectal excision was introduced to mitigate this limitation and improve the quality of mesorectal dissection in even the most challenging cases. Currently, the technique for transanal total mesorectal excision dissection is not standardized. TECHNIQUE: The sequential approach to transanal total mesorectal excision mirrors the principles of the transanal abdominal transanal procedure. It begins with the transanal step, followed by the laparoscopic step, and then the transanal total mesorectal excision. The perirectal space is entered via a full-thickness dissection of the anterior rectal wall. Carbon dioxide is left flowing, widening the embryonic planes between the mesorectal and pelvic fascias, then moving upward through the retroperitoneal space. The surgeon switches to the abdominal field and begins laparoscopic dissection, consisting of inferior mesenteric artery dissection and division, inferior mesenteric vein dissection and division, and possible splenic flexure dissection. Pneumodissection facilitates this procedure by distancing the inferior mesenteric artery from the hypogastric nerves and opening the embryonic fusion plane between the Toldt and Gerota fascias to allow faster division of the left colon lateral attachments. The operation continues with a switch to the perineal field and mesorectal excision. RESULTS: A total of 102 patients underwent transanal total mesorectal excision as described. Mean operative time was 185.0 + 87.5 minutes (range, 60 480 min), and there was no conversion to open surgery. Postoperative morbidity was 33.3%. Mortality rate at 30 days was 1.96% (2 cases). Quality of mesorectal excision according to Quirke was assessed in all of the specimens and found to be complete in 99 cases (97.1%) and nearly complete in 2.9% of cases. CONCLUSIONS: Transanal total mesorectal excision may benefit from pneumodissection, expedites the laparoscopic step, and the sequential approach facilitates the visualization of the correct dissection planes. The safety and cost-effectiveness of the procedure still warrant consideration. See Video at http://links.lww.com/DCR/A418. PMID- 28891857 TI - Modified Pull-Through Technique With A Delayed High Coloanal Anastomosis: No Stoma and Scarless Surgery for Low Rectal Cancer. PMID- 28891858 TI - Early Postoperative Decrease of Serum Albumin Predicts Surgical Outcome in Patients Undergoing Colorectal Resection: Methodologic Issues. PMID- 28891859 TI - Revolution or Evolution. PMID- 28891860 TI - The Authors Reply. PMID- 28891861 TI - Is BMI a Virtual Predictor for Perioperative Outcome of Colorectal Surgery? PMID- 28891864 TI - Photosensitization of TRPA1 and TRPV1 by 7-dehydrocholesterol: implications for the Smith-Lemli-Opitz syndrome. AB - Loss-of-function mutations in the enzyme 7-dehydrocholesterol reductase are responsible for the Smith-Lemli-Opitz syndrome, in which 7-dehydrocholesterol (7 DHC) levels are markedly increased in the plasma and tissues of patients. This increase in 7-DHC is probably associated with the painful and itchy photosensitivity reported by the majority of patients with Smith-Lemli-Opitz syndrome. To identify the molecular targets involved in the activation and photosensitization of primary afferents by 7-DHC, we focused on TRPA1 and TRPV1, two ion channels expressed in nociceptive nerve endings and previously shown to respond to ultraviolet and visible light under pathophysiological circumstances. Recombinant human TRPA1 is activated and photosensitized in the presence of 7 DHC. Prolonged preexposure to 7-DHC causes more pronounced photosensitization, and while TRPV1 contributes less to the acute effect, it too becomes highly photosensitive upon preincubation with 7-DHC for 1 to 15 hours. Dorsal root ganglion neurons in primary culture display acute sensitivity to 7-DHC in the dark and also light-evoked responses in the presence of 7-DHC, which are exclusively dependent on TRPA1 and TRPV1. Similarly, prolonged exposure of mouse dorsal root ganglion neurons to 7-DHC renders these cells photosensitive in a largely TRPA1- and TRPV1-dependent manner. Single-fiber recordings in mouse skin nerve preparations demonstrate violet light-evoked activation and a sensitization to 7-DHC exposure. Vice versa, 7-DHC pretreatment of the isolated trachea leads to a TRPA1- and TRPV1-dependent increase of the light-induced calcitonin gene related peptide release. Taken together, our results implicate TRPA1 and TRPV1 channels as potential pharmacological targets to address the 7-DHC-induced hypersensitivity to light in patients. PMID- 28891865 TI - Opioid prescription levels and postoperative outcomes in orthopedic surgery. AB - Given the basic need for opioids in the perioperative setting, we investigated associations between opioid prescription levels and postoperative outcomes using population-based data of orthopedic surgery patients. We hypothesized that increased opioid amounts would be associated with higher risk for postoperative complications. Data were extracted from the national Premier Perspective database (2006-2013); N = 1,035,578 lower joint arthroplasties and N = 220,953 spine fusions. Multilevel multivariable logistic regression models measured associations between opioid dose prescription and postoperative outcomes, studied by quartile of dispensed opioid dose. Compared to the lowest quartile of opioid dosing, high opioid prescription was associated with significantly increased odds for deep venous thrombosis and postoperative infections by approx. 50%, while odds were increased by 23% for urinary and more than 15% for gastrointestinal and respiratory complications (P < 0.001 respectively). Furthermore, higher opioid prescription was associated with a significant increase in length of stay (LOS) and cost by 12% and 6%, P < 0.001 respectively. Cerebrovascular complications risk was decreased by 25% with higher opioid dose (P = 0.004), while odds for myocardial infarction remained unaltered. In spine cases, opioid prescription was generally higher, with stronger effects observed for increase in LOS and cost as well as gastrointestinal and urinary complications. Other outcomes were less pronounced, possibly because of smaller sample size. Overall, higher opioid prescription was associated with an increase in most postoperative complications with the strongest effect observed in thromboembolic, infectious and gastrointestinal complications, cost, and LOS. Increase in complication risk occurred stepwise, suggesting a dose-response gradient. PMID- 28891867 TI - Tired of pain? Toward a better understanding of fatigue in chronic pain. PMID- 28891866 TI - Passive transfer autoimmunity in a mouse model of complex regional pain syndrome. AB - It has been proposed that complex regional pain syndrome (CRPS) is a posttraumatic autoimmune disease, and we previously observed that B cells are required for the full expression of CRPS-like changes in a mouse tibia fracture CRPS model. The current study used the mouse model to evaluate the progression of postfracture CRPS-like changes in wild-type (WT) and muMT fracture mice lacking B cells and antibodies. The pronociceptive effects of injecting WT fracture mouse serum antibodies into muMT fracture mice were also evaluated. Postfracture pain behaviors transitioned from being initially dependent on both innate and autoimmune inflammatory mechanisms at 3 weeks after fracture to being entirely mediated by antibody responses at 12 weeks after fracture and spontaneously resolving by 21 weeks after fracture. Furthermore, serum IgM antibodies from WT fracture mice had pronociceptive effects in the fracture limb when injected into muMT fracture mice. IgM antibody levels gradually increased in the fracture limb hind paw skin, sciatic nerve, and corresponding lumbar cord, peaking at 12 to 18 weeks after fracture and then declining. Immunohistochemistry localized postfracture IgM antibody binding to antigens in the fracture limb hind paw dermal cell nuclei. We postulate that fracture induces expression of neoantigens in the fracture limb skin, sciatic nerve, and cord, which trigger B cells to secret IgM antibodies that bind those antigens and initiate a pronociceptive antibody response. Autoimmunity plays a key role in the progression of nociceptive and vascular changes in the mouse fracture model and potentially contributes to the CRPS disease process. PMID- 28891868 TI - Bivalent ligand that activates mu opioid receptor and antagonizes mGluR5 receptor reduces neuropathic pain in mice. AB - The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both receptors are expressed in the spinal cord. MMG22, a bivalent ligand containing 2 pharmacophores separated by 22 atoms, which simultaneously activates MOR and antagonizes mGluR5, has been shown to produce potent reversal of tactile hypersensitivity in rodent models of lipopolysaccharide (LPS)-and bone cancer induced chronic pain. This study assessed whether intrathecal MMG22 also is effective in reducing pain of neuropathic origin. Furthermore, we theorized that MMG22 should reduce hyperalgesia in nerve-injured mice in a manner consistent with a synergistic interaction between MOR and mGluR5. Several weeks after spared nerve injury, tactile hypersensitivity was reversed in mice by the intrathecal injection of MMG22 (0.01-10 nmol) but also by its shorter spacer analog, MMG10, with similar potency. The potencies of the bivalent ligands were 10- to 14-fold higher than those of the compounds upon which the bivalent structure was based, the MOR agonist oxymorphone and the mGluR5 antagonist MPEP. Coadministration of oxymorphone and MPEP demonstrated analgesic synergism, an interaction confirmed by isobolographic analysis. This study indicates that in the spared nerve injury induced model of neuropathic pain, the 2 pharmacophores of the bivalent ligands MMG22 and MMG10 target MOR and mGluR5 as separate receptor monomers. The observed increase in the potency of MMG22 and MMG10, compared with oxymorphone and MPEP, may reflect the synergistic interaction of the 2 pharmacophores of the bivalent ligand acting at their respective separate receptor monomers. PMID- 28891870 TI - Letter to the Editor: Regarding Deep N, Besch-Stokes J, Lane J, Driscoll C, Carlson M, "Paget's Disease of the Temporal Bone: A Single-Institution Contemporary Review of 27 Patients". PMID- 28891869 TI - Chronic exposure to insufficient sleep alters processes of pain habituation and sensitization. AB - Chronic pain conditions are highly comorbid with insufficient sleep. While the mechanistic relationships between the 2 are not understood, chronic insufficient sleep may be 1 pathway through which central pain-modulatory circuits deteriorate, thereby contributing to chronic pain vulnerability over time. To test this hypothesis, an in-laboratory model of 3 weeks of restricted sleep with limited recovery (5 nights of 4-hour sleep per night followed by 2 nights of 8 hour sleep per night) was compared with 3 weeks of 8-hour sleep per night (control protocol). Seventeen healthy adults participated, with 14 completing both 3-week protocols. Measures of spontaneous pain, heat-pain thresholds, cold pain tolerance (measuring habituation to cold over several weeks), and temporal summation of pain (examining the slope of pain ratings during cold water immersion) were assessed at multiple points during each protocol. Compared with the control protocol, participants in the sleep-restriction protocol experienced mild increases in spontaneous pain (P < 0.05). Heat-pain thresholds decreased after the first week of sleep restriction (P < 0.05) but normalized with longer exposure to sleep restriction. By contrast, chronic exposure to restricted sleep was associated with decreased habituation to, and increased temporal summation in response to cold pain (both P < 0.05), although only in the past 2 weeks of the sleep-restriction protocol. These changes may reflect abnormalities in central pain-modulatory processes. Limited recovery sleep did not completely resolve these alterations in pain-modulatory processes, indicating that more extensive recovery sleep is required. Results suggest that exposure to chronic insufficient sleep may increase vulnerability to chronic pain by altering processes of pain habituation and sensitization. PMID- 28891871 TI - Bone Density Development of the Temporal Bone Assessed by Computed Tomography. AB - HYPOTHESIS: The temporal bone shows regional differences in bone development. BACKGROUND: The spreading pattern of acute mastoiditis shows age-related differences. In infants, it spreads laterally and causes retroauricular swelling, whereas in older children, it tends to spread medially and causes intracranial complications. We hypothesized that bone maturation may influence the spreading pattern of acute mastoiditis. METHODS: Eighty participants with normal hearing, aged 3 months to 42 years, participated in this study. Computed tomography (CT) values (Hounsfield unit [HU]) in various regions of the temporal bone, such as the otic capsule (OC), lateral surface of the mastoid cavity (LS), posterior cranial fossa (PCF), and middle cranial fossa (MCF), were measured as markers of bone density. Bone density development curves, wherein CT values were plotted against age, were created for each region. The age at which the CT value exceeded 1000 HU, which is used as an indicator of bone maturation, was calculated from the development curves and compared between the regions. RESULTS: The OC showed mature bone at birth, whereas the LS, PCF, and MCF showed rapid maturation in early childhood. However, there were significant regional differences in the ages of maturation: 1.7, 3.9, and 10.8 years for the LS, PCF, and MCF, respectively. CONCLUSION: To our knowledge, this is the first report to show regional differences in the maturation of temporal bone, which could partly account for the differences in the spreading pattern of acute mastoiditis in individuals of different ages. PMID- 28891872 TI - Vertigo in Vestibular Schwannoma Patients Due to Other Pathologies. AB - OBJECTIVE: To report findings from a cohort of vestibular schwannoma (VS) patients presenting with vertigo from a secondary comorbid vestibular disorder; and to discuss management strategies for this subset of patients presenting with both episodic vertigo and VS. PATIENTS: All VS patients who presented with vertigo as the primary symptom from 2012 to 2015 and endorsing no other major complaints were examined. INTERVENTION: Treatment with migraine lifestyle and prophylactic therapy, or Epley maneuver. MAIN OUTCOME MEASURE: Resolution of vertigo following medical treatment alone. RESULTS: Of the nine patients studied, seven (78%) suffered from vestibular migraine, and two (22%) experienced benign positional vertigo. All patients experienced complete resolution of symptoms after treatment. As a result of symptomatic improvement, seven patients (78%) avoided surgery in favor of observation, while two patients (22%) underwent radiosurgery due to continued tumor growth and other nonvertigo symptoms. CONCLUSION: VS patients can sometimes present with a history of recurrent episodic vertigo. The etiology of the vertigo could be due to the tumor itself or may be due to an underlying comorbidity such as vestibular migraine or benign positional vertigo. VS patients presenting with vertigo should undergo a standard vertigo history and examination to identify other potential causes of vertigo. Most VS patients in our cohort avoided intervention and had resolution of their vertigo. PMID- 28891873 TI - Hearing Outcome With the Use of Glass Ionomer Cement as an Alternative to Crimping in Stapedotomy. AB - OBJECTIVE: To evaluate early hearing outcomes using glass ionomer cement to fix the Teflon piston prosthesis onto the long process of incus to minimize residual conductive hearing loss after stapedotomy. STUDY DESIGN: Original report of prospective randomized control study. SETTING: Tertiary referral center. PATIENTS: A total of 80 consecutive patients with otosclerosis were randomized into two groups. Group A is a control group in which 40 patients underwent small fenestra stapedotomy using the classic technique. Group B included 40 patients who were subjected to small fenestra stapedotomy with fixation of the incus prosthesis junction with glass ionomer bone cement. INTERVENTIONS: Stapedotomy with the classical technique in group A and the alternative technique in group B. PRIMARY OUTCOME MEASURE: The audiometric results before and after surgery. RESULTS: Analysis of the results was performed using the paired t test to compare between pre and postoperative results. chi test was used to compare the results of the two groups. A p value less than 0.05 was considered significant from the statistical standpoint. Significant postoperative improvement of both pure-tone air conduction thresholds and air-bone gaps were reported in the two studied groups. The postoperative average residual air-bone gap and hearing gain were statistically significant in group B (p < 0.05) compared with group A. CONCLUSION: The use of glass ionomer bone cement in primary otosclerosis surgery using the aforementioned prosthesis and the surgical technique is of significant value in producing maximal closure of the air-bone gap and better audiological outcomes. PMID- 28891875 TI - Collaboration and Lifelong Learning. PMID- 28891874 TI - Reply to Letter to the Editor: Paget's Disease of the Temporal Bone: A Single Institution Contemporary Review of 27 Patients. PMID- 28891876 TI - Impact of a Nurse Residency Program on Transition to Specialty Practice. AB - A nurse residency program can support transition for new-to-specialty nurses but requires commitment of time and resources. This implementation project used a specialty residency program shown to be effective in a Burn Center, and translated it into the Emergency Department and Maternal Child Health area located within the same medical treatment facility. Preceptor survey responses and leadership assessment of program suitability provided data related to intervention impact. The evidence pertaining to developing specialty knowledge, skills, competency, and clinical reasoning validated program efficacy. Project outcomes justify investment in building a standardized transitional support system. PMID- 28891877 TI - Facilitating NPDP Role Development: One Healthcare System's Experience. AB - Transitioning into the Nursing Professional Development Practitioner role requires development of new knowledge and competencies, which takes time and resources. One healthcare system took advantage of the skills and experience of its expert Nursing Professional Development Specialists to efficiently and economically facilitate novices' role development. They created an online repository of learning materials to provide useful resources and demonstrate various presentation methodologies, thereby sharing their expertise and extending support to those new to nursing professional development practice. PMID- 28891878 TI - Using High-Fidelity Simulation and Video-Assisted Debriefing to Enhance Obstetrical Hemorrhage Mock Code Training. AB - The purpose of this descriptive, one-group posttest study was to explore the nursing staff's perception of the benefits of using high-fidelity simulation during mandated obstetrical hemorrhage mock code training. In addition, the use of video-assisted debriefing was used to enhance the nursing staff's evaluation of their communication and teamwork processes during a simulated obstetrical crisis. The convenience sample of 84 members of the nursing staff consented to completing data collection forms and being videotaped during the simulation. Quantitative results for the postsimulation survey showed that 93% of participants agreed or totally agreed that the use of SimMan made the simulation more realistic and enhanced learning and that debriefing and the use of videotaped playback improved their evaluation of team communication. Participants derived greatest benefit from reviewing their performance on videotape and discussing it during postsimulation debriefing. Simulation with video-assisted debriefing offers hospital educators the ability to evaluate team processes and offer support to improve teamwork with the ultimate goal of improving patient outcomes during obstetrical hemorrhage. PMID- 28891880 TI - Safe Searches: The Scale and Spread of a Quality Improvement Project. AB - To ensure the safety of staff, patients, and visitors to psychiatric inpatient units, a standardized safe search protocol was developed and implemented across a psychiatric facility. This article provides an overview of the methods used in the planning, implementation, and spread of this quality improvement initiative, focusing on the concepts of change management, leadership, and team involvement. The professional development of point-of-care staff is enhanced by active engagement in quality improvement initiatives. PMID- 28891881 TI - Thriving in Chaos: Leadership in a Rapidly Changing Environment. PMID- 28891879 TI - Accelerating the Development of Higher-Level Clinical Thinking in Novice Nurses. AB - Enhancing clinical expertise of novice nurses is a challenge for nursing professional development practitioners. Time and availability of expert preceptors are limited. This article describes a process evaluation project using a specific method of cognitive skills training to expose inexperienced nurses to expert thinking and help them develop more advanced cognitive skills. Development of scenarios, decision points, and expert rationale is described along with project outcomes and lessons learned. Nursing professional development practitioners and inexperienced nurses may benefit from using this method. PMID- 28891882 TI - Transition to Practice in Ambulatory Care Nursing. PMID- 28891883 TI - Standardized Patients, Simulations, and Scenarios: What if I am not a Simulation Expert? PMID- 28891885 TI - The Association Board as Servant Leader. PMID- 28891884 TI - Preceptorship: Linguistic Upgrade. PMID- 28891886 TI - Endless Opportunities. PMID- 28891887 TI - Implementing Nursing Professional Development: Scope and Standards of Practice (3rd Ed.): One Organization's Journey. PMID- 28891888 TI - Impact of Training Frequency on Nurses' Pediatric Resuscitation Skills. AB - The ideal time frame for frequency of resuscitation skills training has yet to be determined. Results obtained from this performance improvement project using hands-on practice sessions suggest that 6 months may be an adequate time frame for retention of resuscitation skills. Professional development educators may want to consider 6-month retraining intervals for low-volume/high-risk skills such as cardiopulmonary resuscitation to optimize nurses' proficiency in these life-saving competencies. PMID- 28891889 TI - Facilitating NPDP Role Development: One Healthcare System's Experience. PMID- 28891890 TI - Methodology for ACOEM's Occupational Medicine Practice Guidelines-2017 Revision. PMID- 28891893 TI - Postoperative Changes After Closed Reduction of Nasal Fracture. AB - Nasal bone fracture is the most common facial fracture; however, surgery does not guarantee reduction and complications, such as undercorrection, overcorrection, and deviation, may occur. By analyzing findings of computed tomography (CT) immediately and at 3 months postoperatively, we evaluated the accuracy of reduction and long-term changes to the nasal bone.Patients with pure nasal bone fracture were evaluated from January 1, 2010 to December 31, 2011. First, we categorized fracture types according to the Stranc-Robertson classification system, using preoperative CT findings (ie, F1, F2, L1, and L2). We categorized each result of reduction by immediate postoperative CT scan findings as "Excellent," "Good," "Fair," and "Poor," with "Excellent" and "Good" ratings being considered a "Success." We evaluated changes to the nasal bone at 3 months after reduction, using the same grade.A total of 128 patients were analyzed. The results of patients in the F1 group were better than those of other patients immediately postoperatively, whereas those of the L2 group were worse. The overall success rate was 49.2% (58/118). At 3 months postoperatively, 33 cases exhibited an improvement to a higher grade, whereas 25 cases improved from an unacceptable outcome to a successful outcome, with the overall success rate being 70.3% (83/118).Immediately postoperative CT scans can be helpful for surgeons in determining whether a secondary adjustment is necessary. Incompletely reduced nasal bone showed spontaneous improvement in bony arrangement according to our study, so simple observation could be a choice. PMID- 28891895 TI - Large-Scale Study of Long-Term Anteroposterior Stability in a Surgery-First Orthognathic Approach Without Presurgical Orthodontic Treatment. AB - Presurgical orthodontic treatment has long been known as a prerequisite in the traditional orthognathic approach. However, achieving ideal decompensation is very difficult even in the presurgical orthodontic period. For minimization of this problem, the surgery-first orthognathic concept has been introduced. The authors hypothesized that this treatment modality will be feasible for skeletal class III dentofacial deformity patients. In this study, the authors tried to compare the traditional and surgery-first approaches regarding long-term outcomes in terms of stability, based on large-scale data. The patients included in this study had skeletal class III dentofacial deformities, and all underwent, and completed, orthognathic surgery between December 2007 and December 2015. The inclusion criteria were based on presurgical simulation on the dental model, and the authors predicted the potential of the surgery-first approach by this preoperative simulation model. Patients with cleft-related syndromes, those who underwent orthognathic surgeries due to facial asymmetry or class II deformity were excluded from the study. In total, 104 class III patients were enrolled in the surgery-first group and 51 class III patients in the traditional orthodontic first group. Satisfactory results were achieved in all 155 patients with dentofacial deformity in this study. Overall, the analysis revealed that anteroposterior skeletal long-term stability in the surgery-first approach was not different, statistically or otherwise, from that in the orthodontic-first approach. Anteroposterior skeletal stability was maintained well in the surgery first approach. In conclusion, surgery-first approach without presurgical orthodontic treatment can achieve similar results of long-term anteroposterior stability in correcting dentofacial deformities as the orthodontic treatment first approach. PMID- 28891894 TI - Dentoalveolar Effects of Early Orthodontic Treatment in Patients With Cleft Lip and Palate. AB - No agreement exists on the most appropriate timing of orthodontic treatment in patients with cleft lip and palate. The aim of this study is to investigate the effect of early orthodontic treatment on development of the dental arches and alveolar bone.A dental casts analysis was performed on 28 children with cleft lip and palate before orthodontic treatment (T0; mean age, 6.5 +/- 1.7) and at the end of active treatment (T1; mean age, 9.2 +/- 2.1 years). The considered variables were: intercanine and intermolar distances; dental arch relationships, evaluated according to the modified Huddart/Bodenham system.The study group was divided into 2 samples according to the age at T0: Group A (age < 6 years) and Group B (age >= 6 years). A statistical comparison of the treatment effects between the 2 samples was performed.Patients in Group A exhibited a greater increase of intercanine distance (8 mm versus 2.7 mm; P<0.001), intermolar distance (7.2 mm versus 5 mm; P = 0.06), and Huddart/Bodenham score (7.1 versus 3; P < 0.05) when compared with patients in Group B.Early orthodontic treatment strongly improved the dental arch relationship, since subjects starting the therapy before the age of 6 had a better response in terms of anterior maxillary expansion. PMID- 28891896 TI - Examination of Nasolacrimal Duct Morphometry Using Cone Beam Computed Tomography in Patients With Unilateral Cleft Lip/Palate. AB - OBJECTIVE: The cleft lip/palate (CLP) deformity negatively affects the anatomy of the nasal cavity and maxilla. The effects of this deformity on the lacrimal system have been unidentified yet. This study aimed to evaluate the morphometric changes in the nasolacrimal duct using cone-beam computed tomography (CBCT) in patients with unilateral CLP. MATERIALS AND METHODS: Retrospective bilateral measurements of the narrowest transversal diameters and the lengths of the nasolacrimal ducts were made for the affected and unaffected sides of 28 patients with CLP and 28 control patients, using the CBCT images. The measurements were statistically compared. RESULTS: The mean narrowest transversal diameter of the nasolacrimal duct for the affected side of the patients with unilateral CLP was statistically significantly narrower than the unaffected side (P = 0.01). There were no statistically significant differences between the control group and the affected and unaffected sides of patient group with unilateral CLP regarding the nasolacrimal duct diameter. The differences were not statistically significant among all groups regarding the mean nasolacrimal duct length. CONCLUSION: The diameter of the nasolacrimal duct at the affected side of unilateral CLP was narrower than the unaffected side. According to this result, the CLP deformity can have an effect on the nasolacrimal duct diameter. However, CLP might not affect the nasolacrimal duct length. PMID- 28891897 TI - Simultaneous Reconstruction of Both Facial Paralysis and Temporomandibular Joint Ankylosis With a Composite Flap From Dorsum of Foot. AB - Free extensor digitorum brevis muscle flap in facial paralysis, and the second metatarsophalangeal joint flap is used at the temporomandibular joint reconstruction for a long time. Anatomically, these flaps can be harvested through even the same pedicle flap even on the same regions. Literature is available of their usage along with the use of hand and upper extremity reconstruction. Unlike this example, the authors have used these flaps in maxillofacial region where facial paralysis and temporomandibular joint reconstruction will be performed together. In this study, clinical report and surgical details of this flap have been shared. PMID- 28891898 TI - Vascular Anomalies of Posterior Fossa and Their Implications. AB - Posterior fossa houses very vital and sensitive structures namely midbrain, pons, medulla, and cerebellum. These structures are irrigated by vertebral, posterior inferior cerebellar, anterior inferior cerebellar, and superior cerebellar arteries. Parts of brain located in posterior fossa control important parts of body so any variation pertaining to stenosis, atresia, hypoplasia, fenestration, agenesis, and duplication in the arteries supplying these parts alter the irrigation pattern culminating into various morbid and mortal neurologic disorders. Therefore, a sound understanding and thorough knowledge of posterior circulation vascular variant anatomy builds the foundation for the accurate diagnosis and appropriate management of neurovascular ischemic and hemorrhagic diseases of posterior fossa. To aid in addressing these complex neurologic disorders and neurosurgical treatment to be carried out successfully, updating and consolidating the knowledge of all the variations/insults of these arteries becomes essential. Therefore, review study has been carried out.Literature search was carried out using databases, including Scielo, Scopmed, Medline, PubMed, and Wiley online library. Papers containing original data were selected and secondary references retrieved from bibliographies. Search terms used were posterior fossa, anomalies of vertebral, posterior inferior cerebellar, anterior inferior cerebellar, and superior cerebellar arteries.The study will be of paramount importance to angiographers in interpreting angiographs, neurologists in diagnosis and treatment of neurologic disorders, and neurosurgeons in performing surgery in posterior fossa and craniovertebral region particularly dealing with tumors and vascular malformations. PMID- 28891899 TI - Does a Premaxillary Setback and Lip Adhesion Have a Negative Impact on Lip Outcome in Bilateral Cleft Patients? AB - BACKGROUND: The early premaxillary setback and lip adhesion remains as a controversial maneuver in the treatment of bilateral cleft lip and palate patients. This study aimed to assess extent of preoperative deformity and lip outcomes during the first year after surgery in bilateral cleft patients who underwent premaxillary setback and lip adhesion and to compare to those with primary lip repair. METHODS: A retrospective observational study was conducted of 16 nonsyndromic consecutive bilateral complete cleft lip patients (with and without Simonart band), who underwent primary cleft lip repair. Patients were allocated in group 1 without premaxillary setback and group 2 with premaxillary setback and lip adhesion. Preoperative and postoperative linear measurements were used for intergroup and intragroup comparisons. RESULTS: Cutaneous lip height of patients in group 2 significantly (P < 0.05) improved after combined premaxillary setback and lip adhesion and primary cleft lip repair. There were no significant (all P > 0.05) differences in intragroup 1 comparisons, and in intergroup comparisons. CONCLUSION: Bilateral cleft patients with a protruded and deviated premaxilla over 10 mm discrepancy of the lateral maxillary achieved noninferior lip symmetry 1 year postoperatively compared with patients with less severe original deformity. PMID- 28891900 TI - Use of a Balloon Catheter With Intraoperative C-Arm Fluoroscan for Reduction of Zygomatic Arch Fractures. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to evaluate the usefulness of C-arm fluoroscan with a balloon catheter in patients undergoing closed reduction of zygomatic arch fractures. SUBJECTS AND METHODS: All patients who had zygomatic arch reduction surgery between 2006 and 2015 were identified and classified into 2 groups. Group A included those patients who underwent closed reduction of zygomatic arch fractures. Group B included those who underwent zygomatic arch reduction surgery with a C-arm fluoroscan and supporting balloon. A balloon catheter was used to stabilize the zygomatic bone after reduction. Results were scored from 1 (poor) to 3 (good) to assess surgical outcomes based on 3 criteria: alignment of the zygomatic arch on a postoperative computed tomography scan, facial asymmetry in photography, and the patient's subjective satisfaction. RESULTS: The authors enrolled 32 patients with zygomatic arch fractures. 18 patients underwent closed reduction for zygomatic arch fractures (group A), while 14 patients underwent closed reduction with C-arm fluoroscan and balloon support (group B). The average score for group A was 2.00 for alignment, 2.56 for facial asymmetry, and 2.67 for subjective satisfaction compared with 2.64 for alignment, 2.86 for facial asymmetry, and 2.79 for subjective satisfaction in group B. There were statistically significant differences in the alignment and facial asymmetry scores between the 2 groups. CONCLUSION: The authors suggest that C-arm fluoroscan with balloon support is a useful modality for reduction of zygomatic arch fractures that provides better surgical outcomes than conventional closed reduction surgery. PMID- 28891901 TI - Maxillary Hypoplasia: Differential Diagnosis of Nasal Obstruction in Infants. AB - Maxillary hypoplasia (MH) is a rare cause of respiratory dysfunction in infants and may occur in association with genetic abnormalities or as an isolated condition. It is included in the differential diagnosis of congenital nasal obstruction. This paper seeks to report a case series of infants with MH, discuss methods for its diagnosis, and compare computed tomography (CT) measurements of nasal cavities of infants with MH and without craniomaxillofacial abnormalities. The therapeutic approach in each patient is also described. All infants with MH admitted to a tertiary hospital between 2012 and 2015 were included. Baseline nasal endoscopy was performed at bedside. The width of the infants' nasal cavities was measured by a radiologist with experience in CT scanning of facial bones. Control patients were infants of matched sex and similar age who underwent head CT scanning for various reasons. Overall, 8 infants with MH and 8 controls were assessed. All nasal cavity dimensions of infants with MH were significantly smaller than those of control subjects. The authors conclude that the diagnosis of MH should be considered in infants with nasal obstruction and nasal cavity narrowing at nasal endoscopy. PMID- 28891902 TI - Nasal Deviation in Patients With Asymmetric Mandibular Prognathism. AB - PURPOSE: This study was aimed to evaluate the nasal deviation in patients with asymmetric mandibular prognathism. MATERIALS AND METHODS: Thirty-five patients with skeletal class III malocclusion were included in the study. Significant mandibular asymmetry of >4 mm menton deviation in three-dimensional (3D) reformatted cone beam computed tomography images was defined as asymmetry group (n = 20). Patients without mandibular asymmetry served as control group (n = 15). The mandibular asymmetry was evaluated pre- and postoperatively. RESULTS: Nasal tip was significantly shifted to the deviated side of the mandible (short side) in the asymmetry group, as compared to the control group (1.5 +/- 0.9 degree, P < 0.01). Alar base angle (ABA) was significantly narrower in nondeviated side (long side) than in the deviated side in asymmetry group. However, control group showed no bilateral difference in ABA. Correction of deviated mandibular prognathism by isolated mandibular surgery resulted in change in the ABA but not the columella base position or nasal asymmetry. ABA on nondeviated side significantly decreased in proportion to the amount of transverse menton movement by surgery (r = -0.560, P < 0.01). CONCLUSION: Our results showed that mandibular chin deviation was accompanied by nasal deviation. Isolated mandibular surgery can potentially influence the alar base position on the contralateral side of deviation but not the nasal tip asymmetry. Therefore, clinicians should inform patients preoperatively of the fundamental limitation of mandibular surgery in cases with preexisting nasal asymmetry. PMID- 28891903 TI - The Effectiveness of Oxidized Regenerated Cellulose as a Graft Material in Transalveolar Osteotome Sinus Lift Procedure. AB - The posterior maxilla is challenged with postextraction alveolar bone resorption and pneumatization drive of the Schneiderian membrane that reduces the subantral distance. To overcome such anatomic obstacle a sinus augmentation procedure was introduced either via lateral or crestal approach depending on residual ridge height. The current study evaluated oxidized regenerated cellulose (ORC) as a grafting material versus osteon II by measuring bone gain and graft density, 24 weeks postoperatively. Twenty consecutive patients (24 cases) aged from 20 to 65 years were considered eligible after clinical and radiographic evaluation. These patients were allocated in 2 groups (study and control) that underwent transcrestal osteotome antral membrane balloon elevation and surgical void augmentation with ORC in the study group, while the control group grafted with collagen membrane and osteon II with simultaneous dental implant placement in both groups and were followed up for 1 year. Cone beam computed tomography was taken for all patients preoperatively and postoperatively to verify neoformed bone and density in Hounsfield units (HU). The mean gained height of the bone was 6.48 mm (5.94 mm in the study and 7.02 mm in the control). The mean density of graft above implant apex was 497.99 HU (434.23 HU in the study and 561.75 HU in the control). Apart from Schneider membrane thickening in 2 patients from the control group, there were no serious complications reported throughout the study. These results demonstrate that ORC is a reasonable grafting material with comparable outcomes when compared to osteon II with less postoperative complications. PMID- 28891904 TI - A Patient Information Leaflet Reduces Parental Anxiety Before Their Child's First Craniofacial Multidisciplinary Outpatient Appointment. AB - INTRODUCTION: It is expected that a child's first outpatient appointment with a craniofacial multidisciplinary team (MDT) instills anxiety in parents. Limited data exist on the aspects of the appointment that parents are most concerned about and what information they desire. The effect of written information provision on this cohort is unstudied. METHODS: Parents attending their child's first outpatient appointment with the Birmingham Children's Hospital Craniofacial MDT between September and December 2012 completed a questionnaire to identify concerns they had relating to the appointment. A patient information leaflet was subsequently developed and distributed. From September 2015 to January 2016, questionnaires completed by parents assessed the usefulness of the leaflet and whether it reduced parental anxiety. RESULTS: Twenty-six initial questionnaires were returned. Seventeen respondents (65%) reported that they were concerned about some aspect of their child's appointment. Twenty-two (86%) expressed a desire for more information surrounding their child's appointment. Thirteen (50%) requested for this information to be provided using a patient information leaflet. After the introduction of the leaflet, 30 questionnaires were returned. All 30 (100.0%) found the leaflet easy to understand. Twenty-nine (96.7%) felt the leaflet provided helpful information. Eighteen (60.0%) felt less worried about the appointment after reading the leaflet. CONCLUSIONS: The majority of parents of children referred to a craniofacial MDT appointment displayed concerns that related to the appointment itself. Specific information relating to the appointment process itself was desired. A purpose-built leaflet successfully provided parents with desired information and lowered anxiety among the majority of attendees. PMID- 28891906 TI - First-in-Human Treatment With a Dendritic Cell-targeting Lentiviral Vector expressing NY-ESO-1, LV305, Induces Deep, Durable Response in Refractory Metastatic Synovial Sarcoma Patient. AB - Effective induction of antitumor T cells is a pivotal goal of cancer immunotherapy. To this end, lentiviral vectors (LV) are uniquely poised to directly prime CD8 T-cell responses via transduction of dendritic cells in vivo and have shown promise as active cancer therapeutics in preclinical tumor models. However, until now, significant barriers related to production and regulation have prevented their widespread use in the clinic. We developed LV305, a dendritic cell-targeting, integration-deficient, replication incompetent LV from the ZVex platform, encoding the full-length cancer-testis antigen NY-ESO-1. LV305 is currently being evaluated in phase 1 and 2 trials in metastatic recurrent cancer patients with NY-ESO-1 positive solid tumors as a single agent and in combination with anti-PD-L1. Here we report on the first patient treated with LV305, a young woman with metastatic, recurrent, therapy-refractive NY-ESO-1 synovial sarcoma. The patient developed a robust NY-ESO-1-specific CD4 and CD8 T cell response after 3 intradermal injections with LV305, and subsequently over 85% disease regression that is continuing for >2.5 years posttherapy. No adverse events >grade 2 occurred. This case demonstrates that LV305 can be safely administered and has the potential to induce a significant clinical benefit and immunologic response in a patient with advanced stage cancer. PMID- 28891907 TI - Treatments for Emotional Issues After Traumatic Brain Injury. PMID- 28891908 TI - Potential Impact of Amantadine on Aggression in Chronic Traumatic Brain Injury. AB - OBJECTIVE: To assess the effects of amantadine on anger and aggression among individuals with a chronic traumatic brain injury (TBI). METHODS: A cohort of 118 persons with chronic TBI (>6 months postinjury) and moderate-severe aggression selected from a larger cohort of 168 participants enrolled in a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice daily (n = 82) versus placebo (n = 86) for treatment of irritability were studied. Anger and aggression were measured at treatment days 0, 28, and 60 using observer-rated and participant-rated State-Trait Anger Expression Inventory-2 (STAXI-2) and Neuropsychiatric Inventory-Agitation/Aggression domain (NPI-A) Most Problematic and Distress scores. RESULTS: Participant-rated day 60 NPI-A Most Problematic (adjusted P = .0118) and NPI-A Distress (adjusted P = .0118) were statistically significant between the 2 groups, but STAXI-2 differences were not significant after adjustment for multiple comparisons. Substantial improvements were noted in both amantadine and placebo groups (70% vs 56% improving at least 3 points on day 60 Observer NPI-A; P = .11). CONCLUSION: Amantadine 100 mg twice daily in this population with chronic TBI appears to be beneficial in decreasing aggression from the perspective of the individual with TBI. No beneficial impact on anger was found. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00779324; http://www.clinicaltrials.gov/ct2/show/NCT00779324?term=irritability&rank=6. PMID- 28891909 TI - Improving Emotion Regulation Following Web-Based Group Intervention for Individuals With Traumatic Brain Injury. AB - OBJECTIVE: Preliminary evaluation of the efficacy of a Web-based group intervention (Online EmReg) to improve emotion regulation (ER) in individuals with traumatic brain injury (TBI). DESIGN: Pre-/post-within-subject design with baseline, end-of-treatment, and 12-week follow-up assessments. PARTICIPANTS: Ninety-one individuals with TBI and deficits in ER. INTERVENTION: Twenty-four sessions of training in ER skills delivered by group videoconference. MEASURES: Difficulties in Emotion Regulation Scale (DERS), Positive Affect Negative Affect Schedule (PANAS), Satisfaction With Life Scale (SWLS), Problem Solving Inventory (PSI), Social Problem Solving Inventory-Revised: Short Form (SPSI-R:S), and Dysexecutive Questionnaire (DEX). RESULTS: Significant changes with large effect sizes were found for the DERS at the 12-week follow-up assessment. Significant and moderate changes were found on the SWLS, DEX, PSI, and subscales of the PANAS and SPSI-R:S. CONCLUSIONS: Online EmReg appears to be a promising method of delivering a group intervention to improve ER following TBI. PMID- 28891910 TI - Descriptive Statistics: Reporting the Answers to the 5 Basic Questions of Who, What, Why, When, Where, and a Sixth, So What? AB - Descriptive statistics are specific methods basically used to calculate, describe, and summarize collected research data in a logical, meaningful, and efficient way. Descriptive statistics are reported numerically in the manuscript text and/or in its tables, or graphically in its figures. This basic statistical tutorial discusses a series of fundamental concepts about descriptive statistics and their reporting. The mean, median, and mode are 3 measures of the center or central tendency of a set of data. In addition to a measure of its central tendency (mean, median, or mode), another important characteristic of a research data set is its variability or dispersion (ie, spread). In simplest terms, variability is how much the individual recorded scores or observed values differ from one another. The range, standard deviation, and interquartile range are 3 measures of variability or dispersion. The standard deviation is typically reported for a mean, and the interquartile range for a median. Testing for statistical significance, along with calculating the observed treatment effect (or the strength of the association between an exposure and an outcome), and generating a corresponding confidence interval are 3 tools commonly used by researchers (and their collaborating biostatistician or epidemiologist) to validly make inferences and more generalized conclusions from their collected data and descriptive statistics. A number of journals, including Anesthesia & Analgesia, strongly encourage or require the reporting of pertinent confidence intervals. A confidence interval can be calculated for virtually any variable or outcome measure in an experimental, quasi-experimental, or observational research study design. Generally speaking, in a clinical trial, the confidence interval is the range of values within which the true treatment effect in the population likely resides. In an observational study, the confidence interval is the range of values within which the true strength of the association between the exposure and the outcome (eg, the risk ratio or odds ratio) in the population likely resides. There are many possible ways to graphically display or illustrate different types of data. While there is often latitude as to the choice of format, ultimately, the simplest and most comprehensible format is preferred. Common examples include a histogram, bar chart, line chart or line graph, pie chart, scatterplot, and box-and-whisker plot. Valid and reliable descriptive statistics can answer basic yet important questions about a research data set, namely: "Who, What, Why, When, Where, How, How Much?" PMID- 28891912 TI - Postoperative Complications Affecting Survival After Cardiac Arrest in General Surgery Patients. AB - BACKGROUND: Postoperative cardiac arrest is uncommon but associated with a high mortality risk in general surgery patients and is often preceded by postoperative complications. The relationships between previous complications and mortality after cardiac arrest in general surgery patients have not been completely evaluated. METHODS: A retrospective, observational cohort of general surgery in patients with cardiac arrest occurring after postoperative day (POD) #0 (and up to POD #30) was obtained from the 2012-2013 American College of Surgeons National Surgical Quality Improvement Program. Previous complication was defined as at least one of the following occurring before the POD of cardiac arrest: (1) acute kidney injury; (2) acute respiratory failure; (3) deep vein thrombosis/pulmonary embolus; (4) myocardial infarction; (5) sepsis/septic shock; (6) stroke; and/or (7) transfusion. The associations between previous complications and mortality after cardiac arrest were assessed using Cox proportional hazards models that adjusted for preoperative risk factors. RESULTS: Of 1352 patients with postoperative cardiac arrest, 746 patients (55%) developed at least 1 complication before cardiac arrest. Overall 30-day mortality was 71% (958/1352) and was similar among patients with and without a previous complication (71% [533/746] vs 70% [425/606]; P = .60). Patients with previous complications did not have an increased risk of mortality, compared to patients without previous complications, in adjusted Cox models (hazard ratio, 1.03; 95% confidence interval, 0.90-1.18; P = .70). In addition, no previous complication was associated with increased mortality risk in individual analyses. CONCLUSIONS: Among general surgery patients with cardiac arrest after POD #0, complications occurring before cardiac arrest are common but are not associated with increased mortality risk. PMID- 28891911 TI - Delineating the Trajectory of Cognitive Recovery From General Anesthesia in Older Adults: Design and Rationale of the TORIE (Trajectory of Recovery in the Elderly) Project. AB - BACKGROUND: Mechanistic aspects of cognitive recovery after anesthesia and surgery are not yet well characterized, but may be vital to distinguishing the contributions of anesthesia and surgery in cognitive complications common in the elderly such as delirium and postoperative cognitive dysfunction. This article describes the aims and methodological approach to the ongoing study, Trajectory of Recovery in the Elderly (TORIE), which focuses on the trajectory of cognitive recovery from general anesthesia. METHODS: The study design employs cognitive testing coupled with neuroimaging techniques such as functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labeling to characterize cognitive recovery from anesthesia and its biological correlates. Applying these techniques to a cohort of age-specified healthy volunteers 40-80 years of age, who are exposed to general anesthesia alone, in the absence of surgery, will assess cognitive and functional neural network recovery after anesthesia. Imaging data are acquired before, during, and immediately after anesthesia, as well as 1 and 7 days after. Detailed cognitive data are captured at the same time points as well as 30 days after anesthesia, and brief cognitive assessments are repeated at 6 and 12 months after anesthesia. RESULTS: The study is underway. Our primary hypothesis is that older adults may require significantly longer to achieve cognitive recovery, measured by Postoperative Quality of Recovery Scale cognitive domain, than younger adults in the immediate postanesthesia period, but all will fully recover to baseline levels within 30 days of anesthesia exposure. Imaging data will address systems neuroscience correlates of cognitive recovery from general anesthesia. CONCLUSIONS: The data acquired in this project will have both clinical and theoretical relevance regardless of the outcome by delineating the mechanism behind short-term recovery across the adult age lifespan, which will have major implications for our understanding of the effects of anesthetic drugs. PMID- 28891913 TI - The Assignment of American Society of Anesthesiologists Physical Status Classification for Adult Polytrauma Patients: Results From a Survey and Future Considerations. AB - BACKGROUND: The American Society of Anesthesiologists (ASA) physical status (PS) classification system assesses the preoperative health of patients. Previous studies demonstrated poor interrater reliability and variable ASA PS scores, especially in trauma scenarios. There are few studies that evaluated the assignment of ASA PS scores in trauma patients and no studies that evaluated ASA PS assignment in severely injured adult polytrauma patients. Our objective was to assess interrater reliability and identify sources of discrepancy among anesthesiologists and trauma surgeons in designating ASA PS scores to adult polytrauma patients. METHODS: A link to an online survey containing questions assessing attitudes regarding ASA PS classification, demographic information, and 8 fictional trauma cases was e-mailed to anesthesiologists and trauma surgeons. The participants were asked to assign an ASA PS score to each scenario and explain their choice. Rater-versus-reference and interrater reliability, beyond that expected by chance, among respondents was analyzed using the Fleiss kappa analysis. RESULTS: A total of 349 participants completed the survey. All 8 cases had inconsistent ASA PS scores; several cases had scores ranging from I to VI and variable emergency (E) designations. Using weighted kappa (Kw) analysis for a subset of 201 respondents (101 trauma surgeons [S] and 100 anesthesiologists [A]), we found moderate (Kw = 0.63; SE = 0.024; 95% confidence interval, 0.594 0.666; P < .001) interrater-versus-reference reliability. The interrater reliability was fair (Kw = 0.43; SE = 0.037; 95% confidence interval, 0.360 0.491; P < .001). CONCLUSIONS: This study demonstrates fair interrater reliability beyond that expected by chance of the ASA PS scores among anesthesiologists and trauma surgeons when assessing adult polytrauma patients. Although the ASA PS is used in some trauma risk stratification models, discrepancies of ASA PS scores assigned to trauma cases exist. Future modifications of the ASA PS guidelines should aim to improve the interrater reliability of ASA PS scores in trauma patients. Further studies are warranted to determine the value of the ASA PS score as a trauma prognostic metric. PMID- 28891915 TI - Re: "Intravenous Steroids With Antibiotics on Admission for Children With Orbital Cellulitis". PMID- 28891916 TI - Reply re: "Intravenous Steroids With Antibiotics on Admission for Children With Orbital Cellulitis". PMID- 28891917 TI - Re: "Blepharoplasty Effect on a Described Algorithmic Approach to External Ptosis Repair: Is It Time for Unbundling?" PMID- 28891918 TI - Reply Re: "Blepharoplasty Effect on a Described Algorithmic Approach to External Ptosis Repair: Is It Time for Unbundling?" PMID- 28891919 TI - Re: "Conjunctiva-Sparing Posterior Ptosis Surgery: A Novel Approach". PMID- 28891920 TI - Reply re: "Conjunctiva-Sparing Posterior Ptosis Surgery: A Novel Approach". PMID- 28891921 TI - Re: "Conjunctiva-Sparing Posterior Ptosis Surgery: A Novel Approach". PMID- 28891922 TI - Reply re: "Conjunctiva-Sparing Posterior Ptosis Surgery: A Novel Approach". PMID- 28891923 TI - Re: "Lateral Rectus and Medial Rectus Expansion Following Orbital Decompression". PMID- 28891924 TI - Three-Dimensionally Printed Conformers for Treatment of Congenital Anophthalmos. PMID- 28891925 TI - An Alternative for Permanent Punctal Occlusion: Labial Mucous Membrane Graft in the Management of Severe Dry Eye. PMID- 28891926 TI - Superior Rectus Intramuscular Lipoma. PMID- 28891927 TI - Differential CMOS Sub-Terahertz Detector with Subthreshold Amplifier. AB - We propose a differential-type complementary metal-oxide-semiconductor (CMOS) sub terahertz (THz) detector with a subthreshold preamplifier. The proposed detector improves the voltage responsivity and effective signal-to-noise ratio (SNR) using the subthreshold preamplifier, which is located between the differential detector device and main amplifier. The overall noise of the detector for the THz imaging system is reduced by the preamplifier because it diminishes the noise contribution of the main amplifier. The subthreshold preamplifier is self-biased by the output DC voltage of the detector core and has a dummy structure that cancels the DC offsets generated by the preamplifier itself. The 200 GHz detector fabricated using 0.25 MUm CMOS technology includes a low drop-out regulator, current reference blocks, and an integrated antenna. A voltage responsivity of 2020 kV/W and noise equivalent power of 76 pW/?Hz are achieved using the detector at a gate bias of 0.5 V, respectively. The effective SNR at a 103 Hz chopping frequency is 70.9 dB with a 0.7 W/m2 input signal power density. The dynamic range of the raster-scanned THz image is 44.59 dB. PMID- 28891928 TI - High-Performance Wireless Ammonia Gas Sensors Based on Reduced Graphene Oxide and Nano-Silver Ink Hybrid Material Loaded on a Patch Antenna. AB - Reduced graphene oxide (rGO) has been studied as a resistive ammonia gas sensor at room temperature. The sensitive hybrid material composed of rGO and nano silver ink (Ag-ink) was loaded on a microstrip patch antenna to realize high performance wireless ammonia sensors. The material was investigated using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). Firstly, interdigital electrodes (IDEs) printed on the polyethylene terephthalate (PET) by direct printing were employed to measure the variation of resistance of the sensitive material with the ammonia concentration. The results indicated the response of sensor varied from 4.25% to 14.7% under 15-200 ppm ammonia concentrations. Furthermore, the hybrid material was loaded on a microstrip patch antenna fabricated by a conventional printed circuit board (PCB) process, and a 10 MHz frequency shift of the sensor antenna could be observed for 200 ppm ammonia gas. Finally, the wireless sensing property of the sensor antenna was successfully tested using the same emitted antenna outside the gas chamber with a high gain of 5.48 dBi, and an increased reflection magnitude of the emitted antenna due to the frequency mismatch of the sensor antenna was observed. Therefore, wireless ammonia gas sensors loaded on a patch antenna have significant application prospects in the field of Internet of Things (IoTs). PMID- 28891929 TI - Towards Understanding the Polymerization Process in Bitumen Bio-Fluxes. AB - Bitumen is a commonly used material for road construction. According to environmental regulations, vegetable-based materials are applied for binder modification. Fluxed road bitumen containing a bio-flux oxidation product increases the consistency over time. The efficiency of crosslinking depends on the number of double bonds and their position in the aliphatic chain of fatty acid. The main goal of this paper was to examine the structural changes taking place during hardening bitumen with bio-flux additives. Two types of road bitumens fluxed with two different oxidized methyl esters of rapeseed oil were used in this study. Various chemical and rheological tests were applied for the fluxed-bitumen at different stages of oxygen exposure. The oxidation of rapeseed oil methyl ester reduced the iodine amount by about 10%-30%. Hardening of the fluxed bitumen generally results in an increase of the resins content and a reduction of the aromatics and asphaltenes. In the temperature range of 0 degrees C to 40 degrees C, bio-flux results with a much higher increase in the phase angle than in temperatures above 40 degrees C in the bitumen binder. The increase in the proportion of the viscous component in the low and medium binder temperature is favorable due to the potential improvement of the fatigue resistance of the asphalt mixture with such binders. PMID- 28891930 TI - Vitamin D Receptor Gene Polymorphisms Associated with Childhood Autism. AB - BACKGROUND: Autism spectrum disorder (ASD) is a group of heterogeneous, behaviorally defined disorders whereby currently no biological markers are common to all affected individuals. A deregulated immune response may be contributing to the etiology of ASD. The active metabolite of vitamin D3 has an immunoregulatory role mediated by binding to the vitamin D receptor (VDR) in monocyte, macrophages, and lymphocytes. The effects of vitamin D and interaction with the VDR may be influenced by polymorphism in the VDR gene. METHODS: Genetic association of four different VDR polymorphisms (Apa-I, Bsm-I, Taq-I, Fok-I) associated with susceptibility to the development of autism in children was investigated. RESULTS: We uniquely found an association between the presence of the T allele at position Taq-I and presence of the a allele at position Apa-I of the VDR gene with decreased ASD incidence. There was also an association between female gender and the presence of the T allele. We found no statistical significant correlation between VDR single nucleotide polymorphisms (SNPs) and vitamin D3 concentration in serum of ASD children. CONCLUSION: Genetic polymorphism in two SNP in VDR may be correlated with development of ASD symptoms by influencing functionality of vitamin D3 metabolism, while vitamin D3 levels were not significantly different between ASD and non-ASD children. PMID- 28891931 TI - Beneficial Effects of Common Bean on Adiposity and Lipid Metabolism. AB - In developed countries which are at the epicenter of the obesity pandemic, pulse crop consumption is well below recommended levels. In a recent systematic review and meta-analysis of 21 randomized controlled clinical trials, pulse consumption was associated with improved weight control and reduced adiposity, although the underlying mechanisms were a matter of speculation. Common bean (Phaseolus vulgaris L.) is the most widely consumed pulse crop and was the focus of this investigation. Using outbred genetic models of dietary induced obesity resistance and of dietary induced obesity sensitivity in the rat, the impact of bean consumption was investigated on the efficiency with which consumed food was converted to body mass (food efficiency ratio), body fat accumulation, adipocyte morphometrics, and patterns of protein expression associated with lipid metabolism. Cooked whole bean as well as a commercially prepared cooked bean powders were evaluated. While bean consumption did not affect food efficiency ratio, bean reduced visceral adiposity and adipocyte size in both obesity sensitive and resistant rats. In liver, bean consumption increased carnitine palmitoyl transferase 1, which is the rate limiting step in long chain fatty acid oxidation and also resulted in lower levels of circulating triglycerides. Collectively, our results are consistent with the clinical finding that pulse consumption is anti-obesogenic and indicate that one mechanism by which cooked bean exerts its bioactivity is oxidation of long chain fatty acids. PMID- 28891932 TI - Inadequate Vitamin C Status in Prediabetes and Type 2 Diabetes Mellitus: Associations with Glycaemic Control, Obesity, and Smoking. AB - Vitamin C (ascorbate) is an essential micronutrient in humans, being required for a number of important biological functions via acting as an enzymatic cofactor and reducing agent. There is some evidence to suggest that people with type 2 diabetes mellitus (T2DM) have lower plasma vitamin C concentrations compared to those with normal glucose tolerance (NGT). The aim of this study was to investigate plasma vitamin C concentrations across the glycaemic spectrum and to explore correlations with indices of metabolic health. This is a cross-sectional observational pilot study in adults across the glycaemic spectrum from NGT to T2DM. Demographic and anthropometric data along with information on physical activity were collected and participants were asked to complete a four-day weighed food diary. Venous blood samples were collected and glycaemic indices, plasma vitamin C concentrations, hormone tests, lipid profiles, and high sensitivity C-reactive protein (hs-CRP) were analysed. A total of 89 participants completed the study, including individuals with NGT (n = 35), prediabetes (n = 25), and T2DM managed by diet alone or on a regimen of Metformin only (n = 29). Plasma vitamin C concentrations were significantly lower in individuals with T2DM compared to those with NGT (41.2 umol/L versus 57.4 umol/L, p < 0.05) and a higher proportion of vitamin C deficiency (i.e. <11.0 umol/L) was observed in both the prediabetes and T2DM groups. The results showed fasting glucose (p = 0.001), BMI (p = 0.001), smoking history (p = 0.003), and dietary vitamin C intake (p = 0.032) to be significant independent predictors of plasma vitamin C concentrations. In conclusion, these results suggest that adults with a history of smoking, prediabetes or T2DM, and/or obesity, have greater vitamin C requirements. Future research is required to investigate whether eating more vitamin C rich foods and/or taking vitamin C supplements may reduce the risk of progression to, and/or complications associated with, T2DM. PMID- 28891934 TI - Fatigue Properties of the Ultra-High Strength Steel TM210A. AB - This paper presents the results of an experiment to investigate the high cycle fatigue properties of the ultra-high strength steel TM210A. A constant amplitude rotating bending fatigue experiment was performed at room temperature at stress ratio R = -1. In order to evaluate the notch effect, the fatigue experiment was carried out upon two sets of specimens, smooth and notched, respectively. In the experiment, the rotating bending fatigue life was tested using the group method, and the rotating bending fatigue limit was tested using the staircase method at 1 * 107 cycles. A double weighted least square method was then used to fit the stress-life (S-N) curve. The S-N curves of the two sets of specimens were obtained and the morphologies of the fractures of the two sets of specimens were observed with scanning electron microscopy (SEM). The results showed that the fatigue limit of the smooth specimen for rotating bending fatigue was 615 MPa; the ratio of the fatigue limit to tensile strength was 0.29, and the cracks initiated at the surface of the smooth specimen; while the fatigue limit of the notched specimen for rotating bending fatigue was 363 MPa, and the cracks initiated at the edge of the notch. The fatigue notch sensitivity index of the ultra-high strength maraging steel TM210A was 0.69. PMID- 28891933 TI - Tyrosine-Kinase Inhibitors Therapies with Mainly Anti-Angiogenic Activity in Advanced Renal Cell Carcinoma: Value of PET/CT in Response Evaluation. AB - Renal cell carcinoma (RCC) is the most frequent renal tumor and the majority of patients are diagnosed with advanced disease. Tumor angiogenesis plays a crucial role in the development and progression of RCC together with hypoxia and glucose metabolism. These three pathways are strictly connected to the cell growth and proliferation, like a loop that is self-feeding. Over the last few years, the ever-deeper knowledge of its contribution in metastatic RCC led to the discovery of numerous tyrosine kinase inhibitors (TKIs) targeting pro-angiogenic receptors at different levels such as sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and dovitinib. As anti-angiogenic agents, TKIs interfere the loop, being able to inhibit tumor proliferation. TKIs are now available treatments for advanced RCC, which demonstrated to improve overall survival and/or progression free survival. Their effects can be detectable early on Positron Emission Tomography/Computed Tomography (PET/CT) by change in 18F-fluoro-2-deoxy-2-d-glucose (18F-FDG) uptake, the main radiotracer used to date, as a strong indicator of biological response. 18F-FDG PET/CT demonstrated an ability to predict and monitor disease progression, allowing an early and reliable identification of responders, and could be used for image-guided optimization and "personalization" of anti angiogenic regimens. New radiotracers for biometabolic imaging are currently under investigation, which exploit the other pathways involved in the cancer process, including cellular proliferation, aerobic metabolism, cell membrane synthesis, hypoxia and amino acid transport, as well as the angiogenic process, but they require further studies. PMID- 28891936 TI - The Short-term Effects of a Cyberbullying Prevention Intervention for Parents of Middle School Students. AB - This study experimentally evaluated the short-term effects of the Arizona Attorney General's cybersafety promotion presentation, a key component of which is cyberbullying prevention. Fifty-one parents of children attending a middle school in the southwestern United States participated in the study. Results reveal parents who viewed the presentation believed their children to be more susceptible to cyberbullying, and indicated that they were more likely to talk to their children about saving evidence, not retaliating, and telling an adult compared to parents who had not viewed the presentation. The theoretical and practical implications of these results are discussed. PMID- 28891937 TI - The Impact of a City-Level Minimum-Wage Policy on Supermarket Food Prices in Seattle-King County. AB - Background: Many states and localities throughout the U.S. have adopted higher minimum wages. Higher labor costs among low-wage food system workers could result in higher food prices. Methods: Using a market basket of 106 foods, food prices were collected at affected chain supermarket stores in Seattle and same-chain unaffected stores in King County (n = 12 total, six per location). Prices were collected at 1 month pre- (March 2015) and 1-month post-policy enactment (May 2015), then again 1-year post-policy enactment (May 2016). Unpaired t-tests were used to detect price differences by location at fixed time while paired t-tests were used to detect price difference across time with fixed store chain. A multi level, linear differences-in-differences model, was used to detect the changes in the average market basket item food prices over time across regions, overall and by food group. Results: There were no significant differences in overall market basket or item-level costs at one-month (-$0.01, SE = 0.05, p = 0.884) or one year post-policy enactment (-$0.02, SE = 0.08, p = 0.772). No significant increases were observed by food group. Conclusions: There is no evidence of change in supermarket food prices by market basket or increase in prices by food group in response to the implementation of Seattle's minimum wage ordinance. PMID- 28891938 TI - Time Course of the Phenotype of Blood and Bone Marrow Monocytes and Macrophages in the Lung after Cigarette Smoke Exposure In Vivo. AB - Alveolar macrophages play a central role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Monocytes are recruited from blood during inflammation and then mature into alveolar macrophages. The aim of this study was to investigate the effect of cigarette smoke (CS) at different times in lung macrophages and monocytes from blood and bone marrow in mice. Male mice (C57BL/6, n = 45) were divided into groups: control, CS 5 days, CS 14 days and CS 30 days. Five days' CS exposure induced a pronounced influx of neutrophils and macrophages in the lung associated with increased levels of keratinocyte chemoattractant (KC), tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and matrix metalloproteinase (MMP)-12. After 14 days of CS exposure, neutrophil recruitment and cytokine production were greatly reduced. Moreover, chronic CS exposure led to increased recruitment of macrophages (with high expression of CD206), transforming growth factor-beta (TGF-beta) production as well as no detection of TNF-alpha, interleukin (IL)-6 and KC. CS can also change the monocyte phenotype in the blood and bone marrow, with an increase in Ly6Clow cells. These results show for the first time that CS can change not only macrophage polarization but also monocyte. These results suggest that continued recruitment of Ly6Clow monocytes may help the distinct renewing macrophage M2 population required for COPD progression. PMID- 28891935 TI - Alteration of Mammary Gland Development and Gene Expression by In Utero Exposure to Cadmium. AB - Environmental exposure to estrogens and estrogen like contaminants during early development is thought to contribute to the risk of developing breast cancer primarily due to an early onset of puberty; however, exposure during key developing windows may also influence the risk of developing the disease. The goal of this study was to ask whether in utero exposure to the metalloestrogen cadmium alters mammary gland development due to acceleration of puberty onset or to an effect on early development of the mammary gland. The results show that, in addition to advancing the onset of puberty, in utero exposure to the metalloestrogen cadmium altered mammary gland development prior to its effect on puberty onset. In utero exposure resulted in an expansion of the number of mammosphere-forming cells in the neonatal mammary gland and an increase in branching, epithelial cells, and density in the prepubertal mammary gland. In the postpubertal mammary gland, there was a further expansion of the mammary stem/progenitor cell population and overexpression of estrogen receptor-alpha (ERalpha) that was due to the overexpression and altered regulation of the ERalpha transcripts derived from exons O and OT in response to estradiol. These results suggest that in utero exposure to cadmium increases stem/progenitor cells, cell density, and expression of estrogen receptor-alpha that may contribute to the risk of developing breast cancer. PMID- 28891939 TI - The Burden of Suicide in Rural Bangladesh: Magnitude and Risk Factors. AB - The aim of the paper is to quantify the burden and risk factors of fatal and non fatal suicidal behaviors in rural Bangladesh. A census was carried out in seven sub-districts encompassing 1.16 million people. Face-to-face interviews were conducted at the household level. Descriptive analyses were done to quantify the burden and Poisson regression was run to determine on risk factors. The estimated rates of fatal and non-fatal suicide were 3.29 and 9.86 per 100,000 person years (PY) observed, respectively. The risk of suicide was significantly higher by 6.31 times among 15-17 and 4.04 times among 18-24 olds compared to 25-64 years old. Married adolescents were 22 times more likely to commit suicide compared to never married people. Compared to Chandpur/Comilla district, the risk of suicide was significantly higher in Narshingdi. Students had significantly lower risk of non fatal suicidal behavior compared to skilled laborers. The risk of non-fatal suicidal behavior was lower in Sherpur compared to Chandpur/Comilla. Among adolescents, unskilled laborers were 16 times more likely to attempt suicide than students. The common methods for fatal and non-fatal suicidal behaviors were hanging and poisoning. Suicide is a major public health problem in Bangladesh that needs to be addressed with targeted interventions. PMID- 28891940 TI - The Effects of Socioeconomic Vulnerability, Psychosocial Services, and Social Service Spending on Family Reunification: A Multilevel Longitudinal Analysis. AB - Socio-environmental factors such as poverty, psychosocial services, and social services spending all could influence the challenges faced by vulnerable families. This paper examines the extent to which socioeconomic vulnerability, psychosocial service consultations, and preventative social services spending impacts the reunification for children placed in out-of-home care. This study uses a multilevel longitudinal research design that draws data from three sources: (1) longitudinal administrative data from Quebec's child protection agencies; (2) 2006 and 2011 Canadian Census data; and, (3) intra-province health and social services data. The final data set included all children (N = 39,882) placed in out-of-home care for the first time between 1 April 2002 and 31 March 2013, and followed from their initial out-of-home placement. Multilevel hazard results indicate that socioeconomic vulnerability, controlling for psychosocial services and social services spending, contributes to the decreased likelihood of reunification. Specifically, socioeconomic vulnerability, psychosocial services, and social services spending account for 24.0% of the variation in jurisdictional reunification for younger children less than 5 years of age, 12.5% for children age 5 to 11 years and 21.4% for older children age 12 to 17 years. These findings have implications for decision makers, funding agencies, and child protection agencies to improve jurisdictional resources to reduce the socioeconomic vulnerabilities of reunifying families. PMID- 28891941 TI - COX Inhibition Profile and Molecular Docking Studies of Some 2-(Trimethoxyphenyl) Thiazoles. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit frequent and sometimes severe adverse effects, including gastrointestinal ulcerations and cardiovascular disorders. In an effort to obtain safer NSAIDs, we assessed the direct cyclooxygenase (COX) inhibition activity and we investigated the potential COX binding mode of some previously reported 2 (trimethoxyphenyl)-thiazoles. The in vitro COX inhibition assays were performed against ovine COX-1 and human recombinant COX-2. Molecular docking studies were performed to explain the possible interactions between the inhibitors and both COX isoforms binding pockets. Four of the tested compounds proved to be good inhibitors of both COX isoforms, but only compound A3 showed a good COX-2 selectivity index, similar to meloxicam. The plausible binding mode of compound A3 revealed hydrogen bond interactions with binding site key residues including Arg120, Tyr355, Ser530, Met522 and Trp387, whereas hydrophobic contacts were detected with Leu352, Val349, Leu359, Phe518, Gly526, and Ala527. Computationally predicted pharmacokinetic profile revealed A3 as lead candidate. The present data prove that the investigated compounds inhibit COX and thus confirm the previously reported in vivo anti-inflammatory screening results suggesting that A3 is a suitable candidate for further development as a NSAID. PMID- 28891942 TI - Automatic Classification of Tremor Severity in Parkinson's Disease Using a Wearable Device. AB - Although there is clinical demand for new technology that can accurately measure Parkinsonian tremors, automatic scoring of Parkinsonian tremors using machine learning approaches has not yet been employed. This study aims to fill this gap by proposing machine-learning algorithms as a way to predict the Unified Parkinson's Disease Rating Scale (UPDRS), which are similar to how neurologists rate scores in actual clinical practice. In this study, the tremor signals of 85 patients with Parkinson's disease (PD) were measured using a wrist-watch-type wearable device consisting of an accelerometer and a gyroscope. The displacement and angle signals were calculated from the measured acceleration and angular velocity, and the acceleration, angular velocity, displacement, and angle signals were used for analysis. Nineteen features were extracted from each signal, and the pairwise correlation strategy was used to reduce the number of feature dimensions. With the selected features, a decision tree (DT), support vector machine (SVM), discriminant analysis (DA), random forest (RF), and k-nearest neighbor (kNN) algorithm were explored for automatic scoring of the Parkinsonian tremor severity. The performance of the employed classifiers was analyzed using accuracy, recall, and precision, and compared to other findings in similar studies. Finally, the limitations and plans for further study are discussed. PMID- 28891943 TI - Development, Physicochemical Characterization and In Vitro Anti-Inflammatory Activity of Solid Dispersions of alpha,beta Amyrin Isolated from Protium Oilresin. AB - alpha,beta Amyrin (ABAM) is a natural mixture of pentacyclic triterpenes that has shown a variety of pharmacological properties, including anti-inflammatory effect. ABAM is isolated from Burseraceae oilresins, especially from the Protium species, which is commonly found in the Brazilian Amazon. This work aimed to develop solid dispersions (SD) of ABAM with the following hydrophilic polymers: polyvinylpyrrolidone (PVP-K30), polyethylene glycol (PEG-6000) and hydroxypropylmethylcellulose (HPMC). The SDs were prepared by physical mixture (PM), kneading (KND) and rotary evaporation (RE) methods. In order to verify any interaction between ABAM and the hydrophilic polymers, physicochemical characterization was performed by Fourier transform infrared (FTIR), scanning electron microscopy (SEM), powder X-ray diffraction (XRD), thermogravimetry (TG) and differential scanning calorimetry (DSC) analysis. Furthermore, an in vitro anti-inflammatory assay was performed with ABAM alone and as SDs with the hydrophilic polymers. The results from the characterization analysis show that the SDs were able to induce changes in the physicochemical properties of ABAM, which suggests interaction with the polymer matrix. In vitro anti-inflammatory assay showed that the SDs improved the anti-inflammatory activity of ABAM and showed no cytotoxicity. In conclusion, this study showed the potential use of SDs as an efficient tool for improving the stability and anti-inflammatory activity of ABAM without cytotoxicity. PMID- 28891945 TI - Optical Characterization of Nano- and Microcrystals of EuPO4 Created by One-Step Synthesis of Antimony-Germanate-Silicate Glass Modified by P2O5. AB - Technology of active glass-ceramics (GC) is an important part of luminescent materials engineering. The classic method to obtain GC is based on annealing of parent glass in proper temperature and different time periods. Generally, only the bulk materials are investigated as a starting host for further applications. However, the effect of an additional heat-treatment process on emission and structural properties during GC processing is omitted. Here, we focus on the possibility of obtaining transparent glass-ceramic doped with europium ions directly with a melt-quenching method. The influence of phosphate concentration (up to 10 mol %) on the inversion symmetry of local environment of Eu3+ ions in antimony-germanate-silicate (SGS) glass has been investigated. The Stark splitting of luminescence spectra and the local asymmetry ratio estimated by relation of (5D0->7F2)/(5D0->7F1) transitions in fabricated glass confirms higher local symmetry around Eu3+ ions. Based on XRD and SEM/EDX measurements, the EuPO4 nano- and microcrystals with monoclinic geometry were determined. Therefore, in our experiment, we confirmed possibility of one-step approach to fabricate crystalline structures (glass-ceramic) in Eu-doped SGS glass without additional annealing process. PMID- 28891944 TI - New Tetra-Schiff Bases as Efficient Photostabilizers for Poly(vinyl chloride). AB - Three new tetra-Schiff bases were synthesized and characterized to be used as photostabilizers for poly(vinyl chloride) (PVC) films. The photostability of PVC films (40 MUm thickness) in the presence of Schiff bases (0.5 wt %) upon irradiation (300 h) with a UV light (lambdamax = 365 nm and light intensity = 6.43 * 10-9 ein?dm-3?s-1) was examined using various spectroscopic measurements and surface morphology analysis. The changes in various functional groups' indices, weight and viscosity average molecular weight of PVC films were monitored against irradiation time. The additives used showed photostability for PVC films, with Schiff base 1 being the most effective additive upon irradiation, followed by 2 and 3. The atomic force microscopy (AFM) images for the PVC surface containing Schiff base 1 after irradiation were found to be smooth, with a roughness factor (Rq) of 36.8, compared to 132.2 for the PVC (blank). Several possible mechanisms that explain PVC photostabilization upon irradiation in the presence of tetra-Schiff bases were proposed. PMID- 28891946 TI - Self-Calibrated In-Process Photogrammetry for Large Raw Part Measurement and Alignment before Machining. AB - Photogrammetry methods are being used more and more as a 3D technique for large scale metrology applications in industry. Optical targets are placed on an object and images are taken around it, where measuring traceability is provided by precise off-process pre-calibrated digital cameras and scale bars. According to the 2D target image coordinates, target 3D coordinates and camera views are jointly computed. One of the applications of photogrammetry is the measurement of raw part surfaces prior to its machining. For this application, post-process bundle adjustment has usually been adopted for computing the 3D scene. With that approach, a high computation time is observed, leading in practice to time consuming and user dependent iterative review and re-processing procedures until an adequate set of images is taken, limiting its potential for fast, easy-to-use, and precise measurements. In this paper, a new efficient procedure is presented for solving the bundle adjustment problem in portable photogrammetry. In-process bundle computing capability is demonstrated on a consumer grade desktop PC, enabling quasi real time 2D image and 3D scene computing. Additionally, a method for the self-calibration of camera and lens distortion has been integrated into the in-process approach due to its potential for highest precision when using low cost non-specialized digital cameras. Measurement traceability is set only by scale bars available in the measuring scene, avoiding the uncertainty contribution of off-process camera calibration procedures or the use of special purpose calibration artifacts. The developed self-calibrated in-process photogrammetry has been evaluated both in a pilot case scenario and in industrial scenarios for raw part measurement, showing a total in-process computing time typically below 1 s per image up to a maximum of 2 s during the last stages of the computed industrial scenes, along with a relative precision of 1/10,000 (e.g. 0.1 mm error in 1 m) with an error RMS below 0.2 pixels at image plane, ranging at the same performance reported for portable photogrammetry with precise off process pre-calibrated cameras. PMID- 28891947 TI - Review of Batteryless Wireless Sensors Using Additively Manufactured Microwave Resonators. AB - The significant improvements observed in the field of bulk-production of printed microchip technologies in the past decade have allowed the fabrication of microchip printing on numerous materials including organic and flexible substrates. Printed sensors and electronics are of significant interest owing to the fast and low-cost fabrication techniques used in their fabrication. The increasing amount of research and deployment of specially printed electronic sensors in a number of applications demonstrates the immense attention paid by researchers to this topic in the pursuit of achieving wider-scale electronics on different dielectric materials. Although there are many traditional methods for fabricating radio frequency (RF) components, they are time-consuming, expensive, complicated, and require more power for operation than additive fabrication methods. This paper serves as a summary/review of improvements made to the additive printing technologies. The article focuses on three recently developed printing methods for the fabrication of wireless sensors operating at microwave frequencies. The fabrication methods discussed include inkjet printing, three dimensional (3D) printing, and screen printing. PMID- 28891948 TI - Early Embryogenesis of Brown Alga Fucus vesiculosus L. is Characterized by Significant Changes in Carbon and Energy Metabolism. AB - Brown algae have an important role in marine environments. With respect to their broad distribution and importance for the environment and human use, brown algae of the order Fucales in particular became a model system for physiological and ecological studies. Thus, several fucoids have been extensively studied for their composition on the molecular level. However, research of fucoid physiology and biochemistry so far mostly focused on the adult algae, so a holistic view on the development of these organisms, including the crucial first life stages, is still missing. Therefore, we employed non-targeted metabolite profiling by gas chromatography coupled to mass spectrometry to create a non-biased picture of the early development of the fucoid alga Fucus vesiculosus. We found that embryogenic physiology was mainly dominated by a tight regulation of carbon and energy metabolism. The first dramatic changes of zygote metabolism started within 1 h after fertilization, while metabolism of 6-9 days old embryos appeared already close to that of an adult alga, indicated by the intensive production of secondary metabolites and accumulation of mannitol and citric acid. Given the comprehensive description and analysis we obtained in our experiments, our results exhibit an invaluable resource for the design of further experiments related to physiology of early algal development. PMID- 28891949 TI - Isaria fumosorosea KCh J2 Entomopathogenic Strain as an Effective Biocatalyst for Steroid Compound Transformations. AB - The catalytic activity of enzymes produced by an entomopathogenic filamentous fungus (Isaria fumosorosea KCh J2) towards selected steroid compounds (androstenedione, adrenosterone, progesterone, 17alpha-methyltestosterone and dehydroepiandrosterone) was investigated. All tested substrates were efficiently transformed. The structure of the substrate has a crucial impact on regio- and stereoselectivity of hydroxylation since it affects binding to the active site of the enzyme. Androstenedione was hydroxylated in the 7alpha-position to give a key intermediate in the synthesis of the diuretic-7alpha-hydroxyandrost-4-ene-3,17 dione with 82% conversion. Adrenosterone and 17alpha-methyltestosterone were hydroxylated in the 6beta-position. Hydroxylated derivatives such as 15beta hydroxy-17alpha-methyltestosterone and 6beta,12beta-dihydroxy-17alpha methyltestosterone were also observed. In the culture of Isaria fumosorosea KCh J2, DHEA was effectively hydroxylated in the C-7 position and then oxidized to give 7-oxo-DHEA, 3beta,7alpha- and 3beta,7beta-dihydroxy-17a-oxa-d-homo-androst-5 ene-17-one. We obtained 7beta-OH-DHEA lactone with 82% yield during 3 days transformation of highly concentrated (5 g/L) DHEA. PMID- 28891950 TI - Impact of Silicon in Plant Biomass Production: Focus on Bast Fibres, Hypotheses, and Perspectives. AB - Silicon (Si) is an abundant element which, when supplied to plants, confers increased vigor and resistance to exogenous stresses, as well as enhanced stem mechanical strength. Plant species vary in their ability to take Si up and to accumulate it under the form of silicon dioxide (SiO2) in their tissues: emblematic of this is the example of Poales, among which there is rice, a high Si accumulator. Monocots usually accumulate more Si than dicots; however, the impact that Si has on dicots, notably on economically important dicots, is a subject requiring further study and scientific efforts. In this review, we discuss the impact that Si has on bast fibre-producing plants, because of the potential importance that this element has in sustainable agriculture practices and in light of the great economic value of fibre crops in fostering a bio-economy. We discuss the data already available in the literature, as well as our own research on textile hemp. In particular, we demonstrate the beneficial effect of Si under heavy metal stress, by showing an increase in the leaf fresh weight under growth on Cd 20 uM. Additionally, we propose an effect of Si on bast fibre growth, by suggesting an action on the endogenous phytohormone levels and a mechanical role involved in the resistance to the turgor pressure during elongation. We conclude our survey with a description of the industrial and agricultural uses of Si enriched plant biomass, where woody fibres are included in the survey. PMID- 28891951 TI - Analysis of Class I Major Histocompatibility Complex Gene Transcription in Human Tumors Caused by Human Papillomavirus Infection. AB - Oncoproteins from high-risk human papillomaviruses (HPV) downregulate the transcription of the class I major histocompatibility complex (MHC-I) antigen presentation apparatus in tissue culture model systems. This could allow infected or transformed cells to evade the adaptive immune response. Using data from over 800 human cervical and head & neck tumors from The Cancer Genome Atlas (TCGA), we determined the impact of HPV status on the mRNA expression of all six MHC-I heavy chain genes, and the beta2 microglobulin light chain. Unexpectedly, these genes were all expressed at high levels in HPV positive (HPV+) cancers compared with normal control tissues. Indeed, many of these genes were expressed at significantly enhanced levels in HPV+ tumors. Similarly, the transcript levels of several other components of the MHC-I peptide-loading complex were also high in HPV+ cancers. The coordinated expression of high mRNA levels of the MHC-I antigen presentation apparatus could be a consequence of the higher intratumoral levels of interferon gamma in HPV+ carcinomas, which correlate with signatures of increased infiltration by T- and NK-cells. These data, which were obtained from both cervical and oral tumors in large human cohorts, indicates that HPV oncoproteins do not efficiently suppress the transcription of the antigen presentation apparatus in human tumors. PMID- 28891952 TI - Lipid Profiles, Glycated Hemoglobin, and Diabetes in People Living at High Altitude in Nepal. AB - This study aimed to describe lipid profiles and the distribution of glycated hemoglobin (HbA1c) in a sample of a high altitude population of Nepal and to explore associations between these metabolic risk variables and altitude. A cross sectional survey of cardiovascular disease and associated risk factors was conducted among 521 people living at four different altitude levels, all above 2800 m, in the Mustang and Humla districts of Nepal. Urban participants (residents at 2800 m and 3620 m) had higher total cholesterol (TC) and triglyceride (TG) than rural participants. A high ratio of TC to high-density lipoprotein-cholesterol (HDL) (TC/HDL >= 5.0) was found in 23.7% (95% CI 19.6, 28.2) and high TG (>=1.7 mmol/L) in 43.3% (95% CI 38.4, 48.3) of participants overall. Mean HbA1c levels were similar at all altitude levels although urban participants had a higher prevalence of diabetes. Overall, 6.9% (95% CI 4.7, 9.8) of participants had diabetes or were on hypoglycaemic treatment. There was no clear association between lipid profiles or HbA1c and altitude in a multivariate analysis adjusted for possible confounding variables. Residential settings and associated lifestyle practices are more strongly associated with lipid profiles and HbA1c than altitude amongst high altitude residents in Nepal. PMID- 28891953 TI - The Effect of Vitamin A on Fracture Risk: A Meta-Analysis of Cohort Studies. AB - This meta-analysis evaluated the influence of dietary intake and blood level of vitamin A (total vitamin A, retinol or beta-carotene) on total and hip fracture risk. Cohort studies published before July 2017 were selected through English language literature searches in several databases. Relative risk (RR) with corresponding 95% confidence interval (CI) was used to evaluate the risk. Heterogeneity was checked by Chi-square and I2 test. Sensitivity analysis and publication bias were also performed. For the association between retinol intake and total fracture risk, we performed subgroup analysis by sex, region, case ascertainment, education level, age at menopause and vitamin D intake. R software was used to complete all statistical analyses. A total of 319,077 participants over the age of 20 years were included. Higher dietary intake of retinol and total vitamin A may slightly decrease total fracture risk (RR with 95% CI: 0.95 (0.91, 1.00) and 0.94 (0.88, 0.99), respectively), and increase hip fracture risk (RR with 95% CI: 1.40 (1.02, 1.91) and 1.29 (1.06, 1.57), respectively). Lower blood level of retinol may slightly increase total fracture risk (RR with 95% CI: 1.11 (0.94, 1.30)) and hip fracture risk (RR with 95% CI: 1.27 (1.05, 1.53)). In addition, higher beta-carotene intake was weakly associated with the increased risk of total fracture (RR with 95% CI: 1.07 (0.97, 1.17)). Our data suggest that vitamin A intake and level may differentially influence the risks of total and hip fractures. Clinical trials are warranted to confirm these results and assess the clinical applicability. PMID- 28891954 TI - Assessment of Heavy Metal Pollution and Health Risks in the Soil-Plant-Human System in the Yangtze River Delta, China. AB - Heavy metal (HM) contamination and accumulation is a serious problem around the world due to the toxicity, abundant sources, non-biodegradable properties, and accumulative behaviour of HMs. The degree of soil HM contamination in China, especially in the Yangtze River Delta, is prominent. In this study, 1822 pairs of soil and crop samples at corresponding locations were collected from the southern Yangtze River Delta of China, and the contents of Ni, Cr, Zn, Cd, As, Cu, Hg, and Pb were measured. The single pollution index in soil (SPI) and Nemerow composite pollution index (NCPI) were used to assess the degree of HM pollution in soil, and the crop pollution index (CPI) was used to explore the degree of HM accumulation in crops. The bioaccumulation factor (BAF) was used to investigate the translocation of heavy metals in the soil-crop system. The health risks caused by HMs were calculated based on the model released by the U.S. Environmental Protection Agency. The SPIs of all elements were at the unpolluted level. The mean NCPI was at the alert level. The mean CPIs were in the following decreasing order: Ni (1.007) > Cr (0.483) > Zn (0.335) > Cd (0.314) > As (0.232) > Cu (0.187) > Hg (0.118) > Pb (0.105). Only the mean content of Ni in the crops exceeded the national standard value. The standard exceeding rates were used to represent the percentage of samples whose heavy metal content is higher than the corresponding national standard values. The standard exceeding rates of Cu, Hg, and Cd in soil were significantly higher than corresponding values in crops. Meanwhile, the standard exceeding rates of Ni, As, and Cr in crops were significantly higher than corresponding values in soil. The chronic daily intake (CDI) of children (13.8 * 10-3) was the largest among three age groups, followed by adults (6.998 * 10-4) and seniors (5.488 * 10-4). The bioaccumulation factors (BAFs) of all crops followed the order Cd (0.249) > Zn (0.133) > As (0.076) > Cu (0.064) > Ni (0.018) > Hg (0.011) > Cr (0.010) > Pb (0.001). Therefore, Cd was most easily absorbed by crops, and different crops had different capacities to absorb HMs. The hazard quotient (HQ) represents the potential non-carcinogenic risk for an individual HM and it is an estimation of daily exposure to the human population that is not likely to represent an appreciable risk of deleterious effects during a lifetime. All the HQs of the HMs for the different age groups were significantly less than the alert value of 1.0 and were at a safe level. This indicated that citizens in the study area face low potential non carcinogenic risk caused by HMs. The total carcinogens risks (TCRs) for children, adults, and seniors were 5.24 * 10-5, 2.65 * 10-5, and 2.08 * 10-5, respectively, all of which were less than the guideline value but at the alert level. Ingestion was the main pathway of carcinogen risk to human health. PMID- 28891955 TI - Single Wall Carbon Nanotubes Based Cryogenic Temperature Sensor Platforms. AB - We present an investigation consisting of single walled carbon nanotubes (SWCNTs) based cryogenic temperature sensors, capable of measuring temperatures in the range of 2-77 K. Carbon nanotubes (CNTs) due to their extremely small size, superior thermal and electrical properties have suggested that it is possible to create devices that will meet necessary requirements for miniaturization and better performance, by comparison to temperature sensors currently available on the market. Starting from SWCNTs, as starting material, a resistive structure was designed. Employing dropcast method, the carbon nanotubes were deposited over pairs of gold electrodes and in between the structure electrodes from a solution. The procedure was followed by an alignment process between the electrodes using a dielectrophoretic method. Two sensor structures were tested in cryogenic field down to 2 K, and the resistance was measured using a standard four-point method. The measurement results suggest that, at temperatures below 20 K, the temperature coefficient of resistance average for sensor 1 is 1.473%/K and for sensor 2 is 0.365%/K. From the experimental data, it can be concluded that the dependence of electrical resistance versus temperature can be approximated by an exponential equation and, correspondingly, a set of coefficients are calculated. It is further concluded that the proposed approach described here offers several advantages, which can be employed in the fabrication of a microsensors for cryogenic applications. PMID- 28891956 TI - Panax ginseng Leaf Extracts Exert Anti-Obesity Effects in High-Fat Diet-Induced Obese Rats. AB - Recent studies have reported that the aerial parts of ginseng contain various saponins, which have anti-oxidative, anti-inflammatory, and anti-obesity properties similar to those of ginseng root. However, the leaf extracts of Korean ginseng have not yet been investigated. In this study, we demonstrate the anti obesity effects of green leaf and dried leaf extracts (GL and DL, respectively) of ginseng in high-fat diet (HFD)-induced obese rats. The administration of GL and DL to HFD-induced obese rats significantly decreased body weight (by 96.5% and 96.7%, respectively), and epididymal and abdominal adipose tissue mass. Furthermore, DL inhibited the adipogenesis of 3T3-L1 adipocytes through regulation of the expression of key adipogenic regulators, such as peroxisome proliferator-activated receptor (PPAR)-gamma and CCAAT/enhancer-binding protein (C/EBP)-alpha. In contrast, GL had little effect on the adipogenesis of 3T3-L1 adipocytes but greatly increased the protein expression of PPARgamma compared with that in untreated cells. These results were not consistent with an anti obesity effect in the animal model, which suggested that the anti-obesity effect of GL in vivo resulted from specific factors released by other organs, or from increased energy expenditure. To our knowledge, these findings are the first evidence for the anti-obesity effects of the leaf extracts of Korean ginseng in vivo. PMID- 28891957 TI - Four Prenylflavone Derivatives with Antiplasmodial Activities from the Stem of Tephrosia purpurea subsp. leptostachya. AB - Four new flavones with modified prenyl groups, namely (E)-5-hydroxytephrostachin (1), purleptone (2), (E)-5-hydroxyanhydrotephrostachin (3), and terpurlepflavone (4), along with seven known compounds (5-11), were isolated from the CH2Cl2/MeOH (1:1) extract of the stem of Tephrosia purpurea subsp. leptostachya, a widely used medicinal plant. Their structures were elucidated on the basis of NMR spectroscopic and mass spectrometric evidence. Some of the isolated compounds showed antiplasmodial activity against the chloroquine-sensitive D6 strains of Plasmodium falciparum, with (E)-5-hydroxytephrostachin (1) being the most active, IC50 1.7 +/- 0.1 MUM, with relatively low cytotoxicity, IC50 > 21 MUM, against four cell-lines. PMID- 28891958 TI - The Application of Quantitative 1H-NMR for the Determination of Orlistat in Tablets. AB - A quantitative nuclear magnetic resonance (qNMR) method to measure the content of Orlistat in tablets was studied and found to be efficient, accurate, reliable, and simple. In this paper, phloroglucinolanhydrous and dimethylsulfoxide-d6 (DMSO d6) served as the internal standard and solvent, respectively. The qNMR methodology, including the linearity, range, the limit of detection (LOD) and quantification (LOQ), stability, precision, and accuracy, was validated seriatim, and the results were very favorable. The content determination results of three batches of Orlistat in tablets were almost identical upon comparing the qNMR method and the high-performance liquid chromatography (HPLC) method. The recommended method authentically compensated the deficiencies of the current HPLC method for determining Orlistat content, and proved to be a method complementary to traditional analysis for the purity measurement of Orlistat in some pharmaceutical preparations. PMID- 28891959 TI - The PI3Kdelta Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL. AB - The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3Kdelta specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action. Primary B ALL in contact with OP9 stromal cells showed increased p-Aktser473. Idelalisib decreased p-Akt in patient samples of ALL with diverse genetic lesions. Addition of idelalisib to vincristine inhibited proliferation when compared to vincristine monotherapy in a subset of samples tested. Idelalisib inhibited ALL migration to SDF-1alpha in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3Kdelta inhibitors in a more diverse group of ALL than has been previously reported and is the first published report of idelalisib inhibiting homing of ALL cells to bone marrow. Our data support further pre clinical evaluation of idelalisib for the therapy of B ALL. PMID- 28891960 TI - Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine. AB - Gemcitabine and erlotinib are the chemotherapeutic agents used in the treatment of various cancers and their combination is being accepted as a first-line treatment of advanced pancreatic cancer. Hyangsayukgunja-tang (HYT) is a traditional oriental medicine used in various digestive disorders and potentially helpful to treat gastrointestinal adverse effects related to chemotherapy. The present study was aimed to evaluate the effect of HYT on the pharmacokinetics of gemcitabine and erlotinib given simultaneously in rats. Rats were pretreated with HYT at an oral dose of 1200 mg/kg/day once daily for a single day or 14 consecutive days. Immediately after pretreatment with HYT, gemcitabine and erlotinib were administered by intravenous injection (10 mg/kg) and oral administration (20 mg/kg), respectively. The effects of HYT on pharmacokinetics of the two drugs were estimated by non-compartmental analysis and pharmacokinetic modeling. The pharmacokinetics of gemcitabine and erlotinib were not altered by single dose HYT pretreatment. However, the plasma levels of OSI-420 and OSI-413, active metabolites of erlotinib, were significantly decreased in the multiple dose HYT pretreatment group. The pharmacokinetic model estimated increased systemic clearances of OSI-420 and OSI-413 by multiple doses of HYT. These data suggest that HYT may affect the elimination of OSI-420 and OSI-413. PMID- 28891962 TI - Quantifying Neighborhood-Scale Spatial Variations of Ozone at Open Space and Urban Sites in Boulder, Colorado Using Low-Cost Sensor Technology. AB - Recent advances in air pollution sensors have led to a new wave of low-cost measurement systems that can be deployed in dense networks to capture small-scale spatio-temporal variations in ozone, a pollutant known to cause negative human health impacts. This study deployed a network of seven low-cost ozone metal oxide sensor systems (UPods) in both an open space and an urban location in Boulder, Colorado during June and July of 2015, to quantify ozone variations on spatial scales ranging from 12 m between UPods to 6.7 km between open space and urban measurement sites with a measurement uncertainty of ~5 ppb. The results showed spatial variability of ozone at both deployment sites, with the largest differences between UPod measurements occurring during the afternoons. The peak median hourly difference between UPods was 6 ppb at 1:00 p.m. at the open space site, and 11 ppb at 4:00 p.m. at the urban site. Overall, the urban ozone measurements were higher than in the open space measurements. This study evaluates the effectiveness of using low-cost sensors to capture microscale spatial and temporal variation of ozone; additionally, it highlights the importance of field calibrations and measurement uncertainty quantification when deploying low-cost sensors. PMID- 28891961 TI - Visible Light-Cured Glycol Chitosan Hydrogel Containing a Beta-Cyclodextrin Curcumin Inclusion Complex Improves Wound Healing In Vivo. AB - Scarless wound healing is ideal for patients suffering from soft tissue defects. In this study, we prepared a novel wet dressing (beta-CD-ic-CUR/GC) based on the visible light-cured glycol chitosan (GC) hydrogel and inclusion complex between beta-cyclodextrin (beta-CD) and curcumin (CUR). We also evaluated its efficacy in the acceleration of wound healing as compared to that of CUR-loaded GC (CUR/GC). The conjugation of glycidyl methacrylate (GM) to GC for photo-curing was confirmed by 1H-NMR measurement, and the photo-cured GC hydrogel was characterized by the analyses of rheology, swelling ratio, SEM and degradation rate. After visible light irradiation, the surface/cross-sectional morphologies and storage (G')/loss (G'') moduli revealed the formation of hydrogel with interconnected porosity. The dressing beta-CD-ic-CUR/GC exhibited a controlled release of 90% CUR in a sustained manner for 30 days. On the other hand, CUR/GC showed CUR release of 16%. beta-CD acted as an excipient in improving the water solubility of CUR and affected the release behavior of CUR. The in vivo animal tests including measurement of the remaining unhealed wound area and histological analyses showed that beta-CD-ic-CUR/GC may have potential as a wet dressing agent to enhance soft tissue recovery in open fractures. PMID- 28891964 TI - The Design and Development of an Omni-Directional Mobile Robot Oriented to an Intelligent Manufacturing System. AB - In order to transport materials flexibly and smoothly in a tight plant environment, an omni-directional mobile robot based on four Mecanum wheels was designed. The mechanical system of the mobile robot is made up of three separable layers so as to simplify its combination and reorganization. Each modularized wheel was installed on a vertical suspension mechanism, which ensures the moving stability and keeps the distances of four wheels invariable. The control system consists of two-level controllers that implement motion control and multi-sensor data processing, respectively. In order to make the mobile robot navigate in an unknown semi-structured indoor environment, the data from a Kinect visual sensor and four wheel encoders were fused to localize the mobile robot using an extended Kalman filter with specific processing. Finally, the mobile robot was integrated in an intelligent manufacturing system for material conveying. Experimental results show that the omni-directional mobile robot can move stably and autonomously in an indoor environment and in industrial fields. PMID- 28891963 TI - The Effect of Bisphenol A on Puberty: A Critical Review of the Medical Literature. AB - Many scientific studies have revealed a trend towards an earlier onset of puberty and have disclosed an increasing number of children that display precocious puberty. As an explanation, some authors have considered the global socio economic improvement across different populations, and other authors have considered the action of endocrine disrupting chemicals (EDCs). Among these, bisphenol A (BPA), an aromatic compound largely used worldwide as a precursor of some plastics and chemical additives, is well known for its molecular oestrogen like and obesogenic actions. We reviewed the medical literature of the previous 20 years that examined associations between BPA exposure and the age of puberty in humans, considering only those referring to clinical or epidemiological data. Of 19 studies, only 7 showed a correlation between BPA and puberty. In particular, the possible disruptive role of BPA on puberty may be seen in those with central precocious puberty or isolated premature breast development aged 2 months to 4 years old, even if the mechanism is undefined. Some studies also found a close relationship between urinary BPA, body weight, and early puberty, which can be explained by the obesogenic effect of BPA itself. The currently available data do not allow establishment of a clear role for BPA in pubertal development because of the conflicting results among all clinical and epidemiological studies examined. Further research is needed to fully understand the potential role of exposure to EDCs and their adverse endocrine health outcomes. PMID- 28891966 TI - Cellulose-Based Smart Fluids under Applied Electric Fields. AB - Cellulose particles, their derivatives and composites have special environmentally benign features and are abundant in nature with their various applications. This review paper introduces the essential properties of several types of cellulose and their derivatives obtained from various source materials, and their use in electro-responsive electrorheological (ER) suspensions, which are smart fluid systems that are actively responsive under applied electric fields, while, at zero electric field, ER fluids retain a liquid-like state. Given the actively controllable characteristics of cellulose-based smart ER fluids under an applied electric field regarding their rheological and dielectric properties, they can potentially be applied for various industrial devices including dampers and haptic devices. PMID- 28891965 TI - Molecular Mechanisms of Acetaldehyde-Mediated Carcinogenesis in Squamous Epithelium. AB - Acetaldehyde is a highly reactive compound that causes various forms of damage to DNA, including DNA adducts, single- and/or double-strand breaks (DSBs), point mutations, sister chromatid exchanges (SCEs), and DNA-DNA cross-links. Among these, DNA adducts such as N2-ethylidene-2'-deoxyguanosine, N2-ethyl-2' deoxyguanosine, N2-propano-2'-deoxyguanosine, and N2-etheno-2'-deoxyguanosine are central to acetaldehyde-mediated DNA damage because they are associated with the induction of DNA mutations, DNA-DNA cross-links, DSBs, and SCEs. Acetaldehyde is produced endogenously by alcohol metabolism and is catalyzed by aldehyde dehydrogenase 2 (ALDH2). Alcohol consumption increases blood and salivary acetaldehyde levels, especially in individuals with ALDH2 polymorphisms, which are highly associated with the risk of squamous cell carcinomas in the upper aerodigestive tract. Based on extensive epidemiological evidence, the International Agency for Research on Cancer defined acetaldehyde associated with the consumption of alcoholic beverages as a "group 1 carcinogen" (definite carcinogen) for the esophagus and/or head and neck. In this article, we review recent advances from studies of acetaldehyde-mediated carcinogenesis in the squamous epithelium, focusing especially on acetaldehyde-mediated DNA adducts. We also give attention to research on acetaldehyde-mediated DNA repair pathways such as the Fanconi anemia pathway and refer to our studies on the prevention of acetaldehyde-mediated DNA damage. PMID- 28891967 TI - Ginsenoside Rg3 Prevents Oxidative Stress-Induced Astrocytic Senescence and Ameliorates Senescence Paracrine Effects on Glioblastoma. AB - Senescent astrocytes in aging brain express senescence-associated secretory phenotype (SASP) and link with increased brain aging and its related diseases. In order to determine whether ginsenosides ameliorate the astrocytic senescence in vitro, human astrocytic CRT cells and primary rat astrocytes were used in the present study. Ginsenosides Rg1, Re, Rb1 and Rg3 (5 MUg/mL) could effectively prevent the astrocytic senescence induced by H2O2 exposure. However, these ginsenosides did not reverse the astrocytic senescence. Importantly, senescent astrocytes herein produce SASP. The expression of major components of SASP, IL-6 and IL-8, are greatly increased in senescent astrocytes. Ginsenoside Rg3 (10 MUg/mL) effectively suppressed the expressions of IL-6 and IL-8, which is associated with regulations of NF-kappaB and p38MAPK activation. In addition, after incubation with Rg3, conditioned medium from senescent astrocytic CRT cells significantly decreased the ability to promote the proliferation of astrocytoma U373-MG, U87-MG and U251-MG cells compared with non-treated senescent samples. Similar patterns were confirmed in chemotherapy-induced glioblastoma senescent cells. The present study explored a potential candidate for amelioration of astrocytic senescence and SASP in brain aging, which provided a basis for developing strategies to reduce the dark side of senescence in normal or pathological aging process. PMID- 28891968 TI - Biogenetic Relationships of Bioactive Sponge Merotriterpenoids. AB - Hydroquinone meroterpenoids, especially those derived from marine sponges, display a wide range of biological activities. However, use of these compounds is limited by their inaccessibility; there is no sustainable supply of these compounds. Furthermore, our knowledge of their metabolic origin remains completely unstudied. In this review, an in depth structural analysis of sponge merotriterpenoids, including the adociasulfate family of kinesin motor protein inhibitors, provides insight into their biosynthesis. Several key structural features provide clues to the relationships between compounds. All adociasulfates appear to be derived from only four different hydroquinone hexaprenyl diphosphate precursors, each varying in the number and position of epoxidations. Proton initiated cyclization of these precursors can lead to all carbon skeletons observed amongst sponge merotriterpenoids. Consideration of the enzymes involved in the proposed biosynthetic route suggests a bacterial source, and a hypothetical gene cluster was constructed that may facilitate discovery of the authentic pathway from the sponge metagenome. A similar rationale can be extended to other sponge meroterpenoids, for which no biosynthetic pathways have yet been identified. PMID- 28891969 TI - Growth Method-Dependent and Defect Density-Oriented Structural, Optical, Conductive, and Physical Properties of Solution-Grown ZnO Nanostructures. AB - It is time for industry to pay a serious heed to the application and quality dependent research on the most important solution growth methods for ZnO, namely, aqueous chemical growth (ACG) and microwave-assisted growth (MAG) methods. This study proffers a critical analysis on how the defect density and formation behavior of ZnO nanostructures (ZNSs) are growth method-dependent. Both antithetical and facile methods are exploited to control the ZnO defect density and the growth mechanism. In this context, the growth of ZnO nanorods (ZNRs), nanoflowers, and nanotubes (ZNTs) are considered. The aforementioned growth methods directly stimulate the nanostructure crystal growth and, depending upon the defect density, ZNSs show different trends in structural, optical, etching, and conductive properties. The defect density of MAG ZNRs is the least because of an ample amount of thermal energy catered by high-power microwaves to the atoms to grow on appropriate crystallographic planes, which is not the case in faulty convective ACG ZNSs. Defect-centric etching of ZNRs into ZNTs is also probed and methodological constraints are proposed. ZNS optical properties are different in the visible region, which are quite peculiar, but outstanding for ZNRs. Hall effect measurements illustrate incongruent conductive trends in both samples. PMID- 28891971 TI - Risk Factors for Mild Cognitive Impairment (MCI). AB - It was has been my pleasure to have acted as the guest editor for the Brain Sciences Special Issue on Mild Cognitive Impairment (MCI).[...]. PMID- 28891972 TI - Erratum: Balconi, M.; et al. Evidences from Rewarding System, FRN and P300 Effect in Internet-Addiction in Young People SHORT TITLE: Rewarding System and EEG in Internet-Addiction Brain Sciences 2017, 7, 81. AB - We would like to submit the following erratum to our recently published paper [1] due to the error in the title.[...]. PMID- 28891970 TI - The ABCC6 Transporter: A New Player in Biomineralization. AB - Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of the pivotal role of ectopic mineralization that is preponderant in the elastin-rich tissues of the skin, eyes and blood vessel walls. After discovery of the causative gene of the disease in 2000, the function of the ABCC6 protein remains elusive. More than 300 mutations have been now reported and the concept of a dermal disease has progressively evolved toward a metabolic disorder resulting from the remote effects caused by lack of a circulating anti-mineralization factor. Very recently, evidence has accumulated that this anti-mineralizing factor is inorganic pyrophosphate (PPi). This leads to decreased PPi/Pi (inorganic phosphate) ratio that results from the lack of extracellular ATP release by hepatocytes and probably renal cells harboring the mutant ABCC6 protein. However, the mechanism by which ABCC6 dysfunction causes diminished ATP release remains an enigma. Studies of other ABC transporters, such as ABCC7 or ABCC1 could help our understanding of what ABCC6 exact function is. Data and a hypothesis on the possible roles of ABCC6 in acquired metabolic diseases are also discussed. PMID- 28891973 TI - Transfusion of Red Blood Cells to Patients with Sepsis. AB - Sepsis is one of the major causes of death worldwide, and is the host response to infection which renders our organs malfunctioning. Insufficient tissue perfusion and oxygen delivery have been implicated in the pathogenesis of sepsis-related organ dysfunction, making transfusion of packed red blood cells (pRBCs) a reasonable treatment modality. However, clinical trials have generated controversial results. Even the notion that transfused pRBCs increase the oxygen carrying capacity of blood has been challenged. Meanwhile, during sepsis, the ability of our tissues to utilize oxygen may also be reduced, and the increased blood concentrations of lactate may be the results of strong inflammation and excessive catecholamine release, rather than impaired cell respiration. Leukodepleted pRBCs more consistently demonstrated improvement in microcirculation, and the increase in blood viscosity brought about by pRBC transfusion helps maintain functional capillary density. A restrictive strategy of pRBC transfusion is recommended in treating septic patients. PMID- 28891974 TI - Recent Advances in Experimental Whole Genome Haplotyping Methods. AB - Haplotype plays a vital role in diverse fields; however, the sequencing technologies cannot resolve haplotype directly. Pioneers demonstrated several approaches to resolve haplotype in the early years, which was extensively reviewed. Since then, numerous methods have been developed recently that have significantly improved phasing performance. Here, we review experimental methods that have emerged mainly over the past five years, and categorize them into five classes according to their maximum scale of contiguity: (i) encapsulation, (ii) 3D structure capture and construction, (iii) compartmentalization, (iv) fluorography, (v) long-read sequencing. Several subsections of certain methods are attached to each class as instances. We also discuss the relative advantages and disadvantages of different classes and make comparisons among representative methods of each class. PMID- 28891975 TI - Statistical Methodologies for the Optimization of Lipase and Biosurfactant by Ochrobactrum intermedium Strain MZV101 in an Identical Medium for Detergent Applications. AB - The Plackett-Burman design and the Box-Behnken design, statistical methodologies, were employed for the optimization lipase and biosurfactant production by Ochrobactrum intermedium strain MZV101 in an identical broth medium for detergent applications. Environmental factor pH determined to be most mutual significant variables on production. A high concentration of molasses at high temperature and pH has a negative effect on lipase and biosurfactant production by O. intermedium strain MZV101. The chosen mathematical method of medium optimization was sufficient for improving the industrial production of lipase and biosurfactant by bacteria, which were respectively increased 3.46- and 1.89-fold. The duration of maximum production became 24 h shorter, so it was fast and cost-saving. In conclusion, lipase and biosurfactant production by O. intermedium strain MZV101 in an identical culture medium at pH 10.5-11 and 50-60 degrees C, with 1 g/L of molasses, seemed to be economical, fast, and effective for the enhancement of yield percentage for use in detergent applications. PMID- 28891976 TI - Mechano-Physical Properties and Microstructure of Carbon Nanotube Reinforced Cement Paste after Thermal Load. AB - The article presents the results obtained in the course of a study on the use of carbon nanotubes (CNTs) for the modification of a cement matrix. Carbon nanotubes were introduced into a cement paste in the form of an aqueous dispersion in the presence of a surfactant (SDS-sodium dodecyl sulfate), which was sonicated. The selected physical and mechanical parameters were examined, and the correlations between these parameters were determined. An analysis of the local microstructure of the modified cement pastes has been carried out using scanning electron microscope (SEM) and X-ray microanalysis (EDS). In addition, the effect of carbon nanotubes on the change in characteristics of the cementitious material exposed to the sudden, short-term thermal load, was determined. The obtained material was characterized by a much lower density than a traditional cement matrix because the phenomenon of foaming occurred. The material was also characterized by reduced durability, higher shrinkage, and higher resistance to the effect of elevated temperature. Further research on the carbon nanotube reinforced cement paste, with SDS, may contribute to the development of a modified cement binder for the production of a lightweight or an aerated concrete. PMID- 28891978 TI - Coercivity Mechanism of (Nd0.8Ce0.2)2.4Fe12Co2B Ribbons with Ferromagnetic Grain Boundary Phase. AB - Understanding the coercivity mechanism has had a substantial impact on developing economically more attractive RE-based (RE = rare earth) permanent materials because of price volatility of key RE metals (i.e., Nd and Dy) in recent years. In this work, we investigated the microstructure and magnetic properties of melt spun (Nd0.8Ce0.2)2.4Fe12Co2B ribbons and annealed samples at 773 K for 15 min with 1 Tesla (T) magnetic field to better understand the coercivity mechanism. We found hard magnetic grains were surrounded by thin and continuous layers along the grain boundaries (GBs) with a high concentration of ferromagnetic elements (Fe + Co >74 at%). The obvious positive peak in the deltaM plot and the interaction domain structure observed by Lorentz magnetic microscopy indicate that there is strong exchange coupling interaction through the ferromagnetic GB phase between hard magnetic grains. The annealing in an applied magnetic field of 1 T increases the remanence by enhancing the exchange coupling interaction, leading to a maximum product energy ((BH)max) which is 16% higher than that of melt-spun ribbons. We also studied the temperature dependence of the coercivity in a temperature range of 300-500 K, and proposed that the coercivity of melt spun (Nd0.8Ce0.2)2.4Fe12Co2B ribbons with ferromagnetic GB phase at room temperature was from the combination of strong domain-wall pinning and nucleation. The same mechanism works in the annealed ribbons. PMID- 28891977 TI - Polytrauma Defined by the New Berlin Definition: A Validation Test Based on Propensity-Score Matching Approach. AB - Background: Polytrauma patients are expected to have a higher risk of mortality than that obtained by the summation of expected mortality owing to their individual injuries. This study was designed to investigate the outcome of patients with polytrauma, which was defined using the new Berlin definition, as cases with an Abbreviated Injury Scale (AIS) >= 3 for two or more different body regions and one or more additional variables from five physiologic parameters (hypotension [systolic blood pressure <= 90 mmHg], unconsciousness [Glasgow Coma Scale score <= 8], acidosis [base excess <= -6.0], coagulopathy [partial thromboplastin time >= 40 s or international normalized ratio >= 1.4], and age [>=70 years]). Methods: We retrieved detailed data on 369 polytrauma patients and 1260 non-polytrauma patients with an overall Injury Severity Score (ISS) >= 18 who were hospitalized between 1 January 2009 and 31 December 2015 for the treatment of all traumatic injuries, from the Trauma Registry System at a level I trauma center. Patients with burn injury or incomplete registered data were excluded. Categorical data were compared with two-sided Fisher exact or Pearson chi-square tests. The unpaired Student t-test and the Mann-Whitney U-test was used to analyze normally distributed continuous data and non-normally distributed data, respectively. Propensity-score matched cohort in a 1:1 ratio was allocated using the NCSS software with logistic regression to evaluate the effect of polytrauma on patient outcomes. Results: The polytrauma patients had a significantly higher ISS than non-polytrauma patients (median (interquartile range Q1-Q3), 29 (22-36) vs. 24 (20-25), respectively; p < 0.001). Polytrauma patients had a 1.9-fold higher odds of mortality than non-polytrauma patients (95% CI 1.38-2.49; p < 0.001). Compared to non-polytrauma patients, polytrauma patients had a substantially longer hospital length of stay (LOS). In addition, a higher proportion of polytrauma patients were admitted to the intensive care unit (ICU), spent longer LOS in the ICU, and had significantly higher total medical expenses. Among 201 selected propensity score-matched pairs of polytrauma and non polytrauma patients who showed no significant difference in sex, age, co morbidity, AIS >= 3, and Injury Severity Score (ISS), the polytrauma patients had a significantly higher mortality rate (OR 17.5, 95% CI 4.21-72.76; p < 0.001), and a higher proportion of patients admitted to the ICU (84.1% vs. 74.1%, respectively; p = 0.013) with longer stays in the ICU (10.3 days vs. 7.5 days, respectively; p = 0.003). The total medical expenses for polytrauma patients were 35.1% higher than those of non-polytrauma patients. However, there was no significant difference in the LOS between polytrauma and non-polytrauma patients (21.1 days vs. 19.8 days, respectively; p = 0.399). Conclusions: The findings of this propensity-score matching study suggest that the new Berlin definition of polytrauma is feasible and applicable for trauma patients. PMID- 28891979 TI - Determination of the Main Nucleosides and Nucleobases in Natural and Cultured Ophiocordyceps xuefengensis. AB - Ophiocordyceps xuefengensis, a recently described species of Ophiocordycepsthat is associated with the larvae of Phassusnodus (Hepialidae) in the living root or trunk of the medicinal plant Clerodendrumcyrtophyllum, isthe largest known Cordycepsspecies and is recognized as a desirable alternative for natural Ophiocordycepssinensis. This study investigated the main nucleosides and nucleobases in natural and cultured Ophiocordycepsxuefengensis. The contents of the nucleosides and nucleobases in the natural and cultured samples were determined by reverse phase HPLC. The highest concentration of adenosine was found in the natural fruit body and the cultured stroma, with almost no adenosine in the cadaver of Phassusnodus. The contents of adenine, guanosine, uridine and uracil in the cultured mycelium were significantly higher than those in the natural sample. Inosine was only detected in the natural samples. Thymidine and 2 deoxyadenosine were only found in the cadaver of Phassusnodus. Cordycepin was not detected in the five samples examined. These results suggested that the cultured mycelium and cultured stroma of Ophiocordycepsxuefengensis might be a promising substitute for natural O. xuefengensis. PMID- 28891981 TI - Feasibility of Serial 6-min Walk Tests in Patients with Acute Heart Failure. AB - BACKGROUND: Functional status assessment is common in many cardiovascular diseases but it has undergone limited study in the setting of acute heart failure (AHF). Accordingly, we performed a pilot study of the feasibility of the six minute walk test (6MWT) at the emergency department (ED) presentation and through the hospitalization in patients with AHF. METHODS AND RESULTS: From November 2014 to February 2015, we conducted a multicenter, observational study of ED patients, aged 18-85 years, whose primary ED admission diagnosis was AHF. Other criteria for enrollment included a left ventricular ejection fraction <=40%, systolic blood pressure between 90 and 170 mmHg, and verbal confirmation that the patient was able to walk >30 m at the baseline, prior to ED presentation. Study teams were uniformly trained to administer a 6MWT. Patients underwent a baseline 6MWT within 24 h of ED presentation (Day 1) and follow-up 6MWTs at 24 (Day 2), 48 (Day 3), and 120 h (Day 5). A total of 46 patients (65.2% male, 73.9% African American) had a day one mean walk distance of 137.3 +/- 78 m, day 2 of 170.9 +/- 100 m, and day 3 of 180.8 +/- 98 m. The 6MWT demonstrated good reproducibility, as the distance walked on the first 6MWT on Day 3 was similar to the distance on the repeated 6MWT the same day. CONCLUSIONS: Our pilot study demonstrates the feasibility of the 6MWT as a functional status endpoint in AHF patients. A larger study in a more demographically diverse cohort of patients is necessary to confirm its utility and association with 30-day heart failure (HF) events. PMID- 28891980 TI - Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study. AB - Glioblastoma is the most common malignant primary brain tumor, and it is one of the causes of cancer fatality in both adult and pediatric populations. Patients with glioblastoma require chemotherapy after surgical resection and radiotherapy. Therefore, chemotherapy constitutes a viable approach for the eradication of glioblastoma cells. In this study, the anti-tumor activity of sinomenine hydrochloride (SH) was evaluated in U87 and SF767 cells in vitro and in vivo. The results showed that SH potently inhibited U87 and SF767 cell viability and did not cause caspase-dependent cell death, as demonstrated by the absence of significant early apoptosis and caspase-3 cleavage. Instead, SH activated an autophagy-mediated cell death pathway, as indicated by the accumulated microtubule-associated protein light chain 3B (LC3B)-II, triggered autophagic flux and enhanced cell viability after pretreatment with autophagy inhibitors. SH mediated autophagy in the two cell lines was implicated in reactive oxygen species (ROS) generation, protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway suppression and c-Jun NH2-terminal kinase (JNK) pathway activation. The ROS antioxidant N-acetylcysteine (NAC), the Akt-specific activator insulin-like growth factor-1 (IGF-1) and the JNK-specific inhibitor SP600125 attenuated SH-induced autophagy. Moreover, ROS activated autophagy via the Akt-mTOR and JNK pathways. Additionally, SH treatment may promote lysosome biogenesis through activating transcription factor EB (TFEB). The in vivo study found that SH effectively suppressed glioblastoma growth without exhibiting significant toxicity. In conclusion, our findings reveal a novel mechanism of action of SH in cancer cells via the induction of autophagy through ROS generation and autophagy-lysosome pathway activation; these findings also supply a new potential therapeutic agent for the treatment of human glioblastoma. PMID- 28891982 TI - Genome Survey Sequencing of Luffa Cylindrica L. and Microsatellite High Resolution Melting (SSR-HRM) Analysis for Genetic Relationship of Luffa Genotypes. AB - Luffa cylindrica (L.) Roem. is an economically important vegetable crop in China. However, the genomic information on this species is currently unknown. In this study, for the first time, a genome survey of L. cylindrica was carried out using next-generation sequencing (NGS) technology. In total, 43.40 Gb sequence data of L. cylindrica, about 54.94* coverage of the estimated genome size of 789.97 Mb, were obtained from HiSeq 2500 sequencing, in which the guanine plus cytosine (GC) content was calculated to be 37.90%. The heterozygosity of genome sequences was only 0.24%. In total, 1,913,731 contigs (>200 bp) with 525 bp N50 length and 1,410,117 scaffolds (>200 bp) with 885.01 Mb total length were obtained. From the initial assembled L. cylindrica genome, 431,234 microsatellites (SSRs) (>=5 repeats) were identified. The motif types of SSR repeats included 62.88% di nucleotide, 31.03% tri-nucleotide, 4.59% tetra-nucleotide, 0.96% penta-nucleotide and 0.54% hexa-nucleotide. Eighty genomic SSR markers were developed, and 51/80 primers could be used in both "Zheda 23" and "Zheda 83". Nineteen SSRs were used to investigate the genetic diversity among 32 accessions through SSR-HRM analysis. The unweighted pair group method analysis (UPGMA) dendrogram tree was built by calculating the SSR-HRM raw data. SSR-HRM could be effectively used for genotype relationship analysis of Luffa species. PMID- 28891984 TI - In Vitro Sonodynamic Therapeutic Effect of Polyion Complex Micelles Incorporating Titanium Dioxide Nanoparticles. AB - Titanium dioxide nanoparticles (TiO2 NPs) can act as sonosensitizers, generating reactive oxygen species under ultrasound irradiation, for use in sonodynamic therapy. For TiO2 NPs delivery, we prepared polyion complex micelles incorporating TiO2 NPs (TiO2 NPs-PIC micelles) by mixing TiO2 NPs with polyallylamine bearing poly(ethylene glycol) grafts. In this study, the effects of polymer composition and ultrasound irradiation conditions on the sonodynamic therapeutic effect toward HeLa cells were evaluated experimentally using cell viability evaluation, intracellular distribution observation, and a cell staining assay. TiO2 NPs-PIC micelles with widely distributed features induced a significant decrease in cell viability under ultrasound irradiation. Furthermore, prolonging the irradiation time killed cells more effectively than did increasing the ultrasound power. The combination of TiO2 NP-PIC micelles and ultrasound irradiation was confirmed to induce apoptotic cell death. PMID- 28891983 TI - Protective Effects of Ethanolic Extracts from Artichoke, an Edible Herbal Medicine, against Acute Alcohol-Induced Liver Injury in Mice. AB - Oxidative stress and inflammation are well-documented pathological factors in alcoholic liver disease (ALD). Artichoke (Cynara scolymus L.) is a healthy food and folk medicine with anti-oxidative and anti-inflammatory properties. This study aimed to evaluate the preventive effects of ethanolic extract from artichoke against acute alcohol-induced liver injury in mice. Male Institute of Cancer Research mice were treated with an ethanolic extract of artichoke (0.4, 0.8, and 1.6 g/kg body weight) by gavage once daily. Up to 40% alcohol (12 mL/kg body weight) was administered orally 1 h after artichoke treatment. All mice were fed for 10 consecutive days. Results showed that artichoke extract significantly prevented elevated levels of aspartate aminotransferase, alanine aminotransferase, triglyceride, total cholesterol, and malondialdehyde. Meanwhile, the decreased levels of superoxide dismutase and glutathione were elevated by artichoke administration. Histopathological examination showed that artichoke attenuated degeneration, inflammatory infiltration and necrosis of hepatocytes. Immunohistochemical analysis revealed that expression levels of toll like receptor (TLR) 4 and nuclear factor-kappa B (NF-kappaB) in liver tissues were significantly suppressed by artichoke treatment. Results obtained demonstrated that artichoke extract exhibited significant preventive protective effect against acute alcohol-induced liver injury. This finding is mainly attributed to its ability to attenuate oxidative stress and suppress the TLR4/NF kappaB inflammatory pathway. To the best of our knowledge, the underlying mechanisms of artichoke on acute ALD have been rarely reported. PMID- 28891985 TI - Cross-Correlation-Based Structural System Identification Using Unmanned Aerial Vehicles. AB - Computer vision techniques have been employed to characterize dynamic properties of structures, as well as to capture structural motion for system identification purposes. All of these methods leverage image-processing techniques using a stationary camera. This requirement makes finding an effective location for camera installation difficult, because civil infrastructure (i.e., bridges, buildings, etc.) are often difficult to access, being constructed over rivers, roads, or other obstacles. This paper seeks to use video from Unmanned Aerial Vehicles (UAVs) to address this problem. As opposed to the traditional way of using stationary cameras, the use of UAVs brings the issue of the camera itself moving; thus, the displacements of the structure obtained by processing UAV video are relative to the UAV camera. Some efforts have been reported to compensate for the camera motion, but they require certain assumptions that may be difficult to satisfy. This paper proposes a new method for structural system identification using the UAV video directly. Several challenges are addressed, including: (1) estimation of an appropriate scale factor; and (2) compensation for the rolling shutter effect. Experimental validation is carried out to validate the proposed approach. The experimental results demonstrate the efficacy and significant potential of the proposed approach. PMID- 28891986 TI - Variability of Secondary Metabolites of the Species Cichorium intybus L. from Different Habitats. AB - The principal aim of this paper is to show the influence of soil characteristics on the quantitative variability of secondary metabolites. Analysis of phenolic content, flavonoid concentrations, and the antioxidant activity was performed using the ethanol and ethyl acetate plant extracts of the species Cichorium intybus L. (Asteraceae). The samples were collected from one saline habitat and two non-saline habitats. The values of phenolic content from the samples taken from the saline habitat ranged from 119.83 to 120.83 mg GA/g and from non-saline habitats from 92.44 to 115.10 mg GA/g. The amount of flavonoids in the samples from the saline locality varied between 144.36 and 317.62 mg Ru/g and from non saline localities between 86.03 and 273.07 mg Ru/g. The IC50 values of antioxidant activity in the samples from the saline habitat ranged from 87.64 to 117.73 MUg/mL and from 101.44 to 125.76 MUg/mL in the samples from non-saline habitats. The results confirmed that soil types represent a significant influence on the quantitative content of secondary metabolites. The greatest concentrations of phenols and flavonoids and the highest level of antioxidant activity were found in the samples from saline soil. This further corroborates the importance of saline soil as an ecological factor, as it is proven to give rise to increased biosynthesis of secondary metabolites and related antioxidant activity. PMID- 28891987 TI - Total Body Irradiation Mitigates Inflammation and Extends the Therapeutic Time Window for Anti-Ricin Antibody Treatment against Pulmonary Ricinosis in Mice. AB - Ricin, a highly toxic plant-derived toxin, is considered a potential weapon in biowarfare and bioterrorism due to its pronounced toxicity, high availability, and ease of preparation. Pulmonary exposure to ricin results in the generation of an acute edematous inflammation followed by respiratory insufficiency and death. Massive neutrophil recruitment to the lungs may contribute significantly to ricin mediated morbidity. In this study, total body irradiation (TBI) served as a non pharmacological tool to decrease the potential neutrophil-induced lung injury. TBI significantly postponed the time to death of intranasally ricin-intoxicated mice, given that leukopenia remained stable following intoxication. This increase in time to death coincided with a significant reduction in pro-inflammatory marker levels, and led to marked extension of the therapeutic time window for anti-ricin antibody treatment. PMID- 28891989 TI - Optimal Structure of a Plasmonic Chip for Sensitive Bio-Detection with the Grating-Coupled Surface Plasmon-Field Enhanced Fluorescence (GC-SPF). AB - Surface plasmon field-enhanced fluorescence (SPF) has been one of the powerful tools for biosensors and bioimaging. A wavelength-scale periodic structure coated with a thin metal film is called a plasmonic chip, and it can provide SPF. SPF of Cy5-streptavidin (Cy5-SA) was measured on a biotinylated plasmonic chip with a grating of 480 nm-pitch. The optimal structure of a plasmonic sensor-chip was designed for improving detection sensitivity. The silver film thickness dependence of the SPF intensity was measured under the irradiation of the top panel of a sensor chip. Furthermore, the dependence of the SPF intensity on the distance from the metal surface was also investigated. The optimal structure for the largest fluorescence enhancement factor was 150 nm-thick silver and 10 nm thick SiO2 layers due to the enhanced electric field (excitation field), the surface plasmon coupled emission (SPCE), and the interference effect with reflected light. The largest enhancement factor was found to be 170-fold. Furthermore, not only the largest fluorescence intensity but also stable lower background noise were found to be essential for higher-sensitive detection. PMID- 28891988 TI - A Multivariate Dynamic Spatial Factor Model for Speciated Pollutants and Adverse Birth Outcomes. AB - Evidence suggests that exposure to elevated concentrations of air pollution during pregnancy is associated with increased risks of birth defects and other adverse birth outcomes. While current regulations put limits on total PM2.5 concentrations, there are many speciated pollutants within this size class that likely have distinct effects on perinatal health. However, due to correlations between these speciated pollutants, it can be difficult to decipher their effects in a model for birth outcomes. To combat this difficulty, we develop a multivariate spatio-temporal Bayesian model for speciated particulate matter using dynamic spatial factors. These spatial factors can then be interpolated to the pregnant women's homes to be used to model birth defects. The birth defect model allows the impact of pollutants to vary across different weeks of the pregnancy in order to identify susceptible periods. The proposed methodology is illustrated using pollutant monitoring data from the Environmental Protection Agency and birth records from the National Birth Defect Prevention Study. PMID- 28891990 TI - Efficient Inverted Organic Solar Cells Based on a Fullerene Derivative-Modified Transparent Cathode. AB - Indium tin oxide (ITO) is a transparent conductive material which is extensively used in organic solar cells (OSCs) as electrodes. In inverted OSCs, ITO is usually employed as a cathode, which should be modified by cathode buffer layers (CBLs) to achieve better contact with the active layers. In this paper, an amine group functionalized fullerene derivative (DMAPA-C60) is used as a CBL to modify the transparent cathode ITO in inverted OSCs based on PTB7 as a donor and PC71BM as an acceptor. Compared with traditional ZnO CBL, DMAPA-C60 exhibited comparable transmittance. OSCs based on DMAPA-C60 show much better device performance compared with their ZnO counterparts (power conversion efficiencies (PCEs) improved from 6.24 to 7.43%). This is mainly because a better contact between the DMAPA-C60 modified ITO and the active layer is formed, which leads to better electron transport and collection. Nanoscale morphologies also demonstrate that the surface of DMAPA-C60-modified ITO is plainer than the ZnO counterparts, which also leads to the better device performance. PMID- 28891991 TI - A Graphene-Based Flexible Pressure Sensor with Applications to Plantar Pressure Measurement and Gait Analysis. AB - In the present study, we propose and develop a flexible pressure sensor based on the piezoresistive effect of multilayer graphene films on polyester textile. The pressure response results from the deformation of graphene conductive network structure and the changes in resistance. Here, we show that the graphene pressure sensor can achieve a sensitivity value of 0.012 kPa - 1 , the measurement range can be as high as 800 kPa, and the response time can reach to 50 ms. Subsequently, a stable in-shoe wireless plantar pressure measurement system is developed and dynamic pressure distribution is acquired in real-time. Overall, the graphene textile pressure sensor has the advantage of wide dynamic range, flexibility and comfort, which provides the high possibility for footwear evaluation, clinical gait analysis and pathological foot diagnosis. PMID- 28891992 TI - An Efficient, Eco-friendly and Sustainable One-Pot Synthesis of 3,4 Dihydropyrimidin-2(1H)-ones Directly from Alcohols Catalyzed by Heteropolyanion Based Ionic Liquids. AB - Efficient, eco-friendly and sustainable access to 3,4-dihydropyrimidin-2(1H)-ones directly from alcohols under microwave and solvent-free conditions has been reported. The practical protocol involves heteropolyanion-based catalyzed oxidation of alcohols to aldehydes with NaNO3 as the oxidant followed by cyclocondensation with dicarbonyl compounds and urea or thiourea in a two-step, one-pot manner. Compatibility with different functional groups, good to excellent yields and reusable catalysts are the main highlights. The utilization of alcohols instead of aldehydes is a valid and green alternative to the classical Biginelli reaction. PMID- 28891993 TI - Complete Chloroplast Genome of Pinus massoniana (Pinaceae): Gene Rearrangements, Loss of ndh Genes, and Short Inverted Repeats Contraction, Expansion. AB - The chloroplast genome (CPG) of Pinus massoniana belonging to the genus Pinus (Pinaceae), which is a primary source of turpentine, was sequenced and analyzed in terms of gene rearrangements, ndh genes loss, and the contraction and expansion of short inverted repeats (IRs). P. massoniana CPG has a typical quadripartite structure that includes large single copy (LSC) (65,563 bp), small single copy (SSC) (53,230 bp) and two IRs (IRa and IRb, 485 bp). The 108 unique genes were identified, including 73 protein-coding genes, 31 tRNAs, and 4 rRNAs. Most of the 81 simple sequence repeats (SSRs) identified in CPG were mononucleotides motifs of A/T types and located in non-coding regions. Comparisons with related species revealed an inversion (21,556 bp) in the LSC region; P. massoniana CPG lacks all 11 intact ndh genes (four ndh genes lost completely; the five remained truncated as pseudogenes; and the other two ndh genes remain as pseudogenes because of short insertions or deletions). A pair of short IRs was found instead of large IRs, and size variations among pine species were observed, which resulted from short insertions or deletions and non synchronized variations between "IRa" and "IRb". The results of phylogenetic analyses based on whole CPG sequences of 16 conifers indicated that the whole CPG sequences could be used as a powerful tool in phylogenetic analyses. PMID- 28891994 TI - Mdivi-1 Protects Adult Rat Hippocampal Neural Stem Cells against Palmitate Induced Oxidative Stress and Apoptosis. AB - Palmitate concentrations in type 2 diabetic patients are higher than in healthy subjects. The prolonged elevation of plasma palmitate levels induces oxidative stress and mitochondrial dysfunction in neuronal cells. In this study, we examined the role of mdivi-1, a selective inhibitor of mitochondrial fission protein dynamin-regulated protein 1 (Drp1), on the survival of cultured hippocampal neural stem cells (NSCs) exposed to high palmitate. Treatment of hippocampal NSCs with mdivi-1 attenuated palmitate-induced increase in cell death and apoptosis. Palmitate exposure significantly increased Drp1 protein levels, which were prevented by pretreatment of cells with mdivi-1. We found that cytosolic Drp1 was translocated to the mitochondria when cells were exposed to palmitate. In contrast, palmitate-induced translocation of Drp1 was inhibited by mdivi-1 treatment. We also investigated mdivi-1 regulation of apoptosis at the mitochondrial level. Mdivi-1 rescued cells from palmitate-induced lipotoxicity by suppressing intracellular and mitochondrial reactive oxygen species production and stabilizing mitochondrial transmembrane potential. Mdivi-1-treated cells showed an increased Bcl-2/Bax ratio, prevention of cytochrome c release, and inhibition of caspase-3 activation. Our data suggest that mdivi-1 protects hippocampal NSCs against lipotoxicity-associated oxidative stress by preserving mitochondrial integrity and inhibiting mitochondrial apoptotic cascades. PMID- 28891995 TI - Performance Study of a Torsional Wave Sensor and Cervical Tissue Characterization. AB - A novel torsional wave sensor designed to characterize mechanical properties of soft tissues is presented in this work. Elastography is a widely used technique since the 1990s to map tissue stiffness. Moreover, quantitative elastography uses the velocity of shear waves to achieve the shear stiffness. This technique exhibits significant limitations caused by the difficulty of the separation between longitudinal and shear waves and the pressure applied while measuring. To overcome these drawbacks, the proposed torsional wave sensor can isolate a pure shear wave, avoiding the possibility of multiple wave interference. It comprises a rotational actuator disk and a piezoceramic receiver ring circumferentially aligned. Both allow the transmission of shear waves that interact with the tissue before being received. Experimental tests are performed using tissue mimicking phantoms and cervical tissues. One contribution is a sensor sensitivity study that has been conducted to evaluate the robustness of the new proposed torsional wave elastography (TWE) technique. The variables object of the study are both the applied pressure and the angle of incidence sensor-phantom. The other contribution consists of a cervical tissue characterization. To this end, three rheological models have fit the experimental data and a static independent testing method has been performed. The proposed methodology permits the reconstruction of the mechanical constants from the propagated shear wave, providing a proof of principle and warranting further studies to confirm the validity of the results. PMID- 28891997 TI - Optimal Base Station Density of Dense Network: From the Viewpoint of Interference and Load. AB - Network densification is attracting increasing attention recently due to its ability to improve network capacity by spatial reuse and relieve congestion by offloading. However, excessive densification and aggressive offloading can also cause the degradation of network performance due to problems of interference and load. In this paper, with consideration of load issues, we study the optimal base station density that maximizes the throughput of the network. The expected link rate and the utilization ratio of the contention-based channel are derived as the functions of base station density using the Poisson Point Process (PPP) and Markov Chain. They reveal the rules of deployment. Based on these results, we obtain the throughput of the network and indicate the optimal deployment density under different network conditions. Extensive simulations are conducted to validate our analysis and show the substantial performance gain obtained by the proposed deployment scheme. These results can provide guidance for the network densification. PMID- 28891996 TI - Synthesis of Bisimidazole Derivatives for Selective Sensing of Fluoride Ion. AB - Rapid and efficient analysis of fluoride ion is crucial to providing key information for fluoride ion hazard assessment and pollution management. In this study, we synthesized one symmetrical structure called 1,4-bis(4,5-diphenyl-1H imidazol-2-yl)benzene (1a) and two asymmetrical structures, namely 2-(4-(4,5 diphenyl-1H-imidazol-2-yl)phenyl)-1H-phenanthro(9,10-d)imidazole (1b) and 2-(4 (4,5-diphenyl-1H-imidazol-2-yl)phenyl)-1H-imidazo(4,5-f)(1,10)phenanthroline (1c), which served as an efficient anion sensor for fluoride ion over a wide range of other anions (Cl-, Br-, I-, NO3-, ClO4-, HSO4-, BF4-, and PF6-) owing to imidazole group in the main backbone. The absorption intensity of compound 1a at lambdamax 358 nm slightly decreased; however, a new band at lambdamax 414 nm appeared upon the addition of fluoride ion, while no evident change occurred upon the addition of eight other anions. The photoluminescence intensity of compound 1a at lambdamax 426 nm was nearly quenched and fluorescence emission spectra were broadened when fluoride ion was added into dimethyl sulfoxide (DMSO) solution of compound 1a. Compared with the optical behaviors of the DMSO solution of compound 1a in the presence of Bu4N+F-, compounds 1b and 1c exhibited considerable sensitivity to fluoride ion due to the increase in coplanarity. Furthermore, compared with the fluorescence emission behaviors of the DMSO solutions of compounds 1a and 1b in the presence of Bu4N+F-, compound 1c exhibited the most significant sensitivity to fluoride ion due to the charge transfer enhancement. Consequently, the detection limits of compounds 1a-1c increased from 5.47 * 10-6 M to 4.21 * 10-6 M to 9.12 * 10-7 M. Furthermore, the largest red shift (75 nm) of the DMSO solution compound 1c in the presence of fluoride ion can be observed. Our results suggest that the increase in coplanarity and the introduction of electron-withdrawing groups to the imidazole backbone can improve the performance in detecting fluoride ion. PMID- 28891999 TI - Underdetermined Blind Source Separation of Synchronous Orthogonal Frequency Hopping Signals Based on Single Source Points Detection. AB - This paper considers the complex-valued mixing matrix estimation and direction-of arrival (DOA) estimation of synchronous orthogonal frequency hopping (FH) signals in the underdetermined blind source separation (UBSS). A novel mixing matrix estimation algorithm is proposed by detecting single source points (SSPs) where only one source contributes its power. Firstly, the proposed algorithm distinguishes the SSPs by the comparison of the normalized coefficients of time frequency (TF) points, which is more effective than existing detection algorithms. Then, mixing matrix of FH signals can be estimated by the hierarchical clustering method. To sort synchronous orthogonal FH signals, a modified subspace projection method is presented to obtain the DOAs of FH. One superiority of this paper is that the estimation accuracy of the mixing matrix can be significantly improved by the proposed SSPs detection criteria. Another superiority of this paper is that synchronous orthogonal FH signals can be sorted in underdetermined condition. The experimental results demonstrate the efficiency of the two proposed algorithms. PMID- 28891998 TI - Bioactivity In Vitro of Quercetin Glycoside Obtained in Beauveria bassiana Culture and Its Interaction with Liposome Membranes. AB - Quercetin (Q) was used as substrate for regioselective glycosylation at the C-7 position catalyzed by Beauveria bassiana AM278 strain. As a result the glycoside quercetin 7-O-beta-d-(4"-O-methyl)glucopyranoside (Q 7-MeGlu) was formed. The goal of the studies was to determine the anti-oxidative (liposome membrane protection against free radicals IC50Q 7-MeGlu = 5.47 and IC50Q = 4.49 uM) and anti-inflammatory (COX-1 and COX-2 enzymes activity inhibition) properties of Q 7 MeGlu as compared to Q. Every attempt was made to clarify the antioxidant activity of these molecules, which are able to interact with egg phosphatidylcholine liposomes, using a fluorometric method (by applying the probes MC540, TMA-DPH and DPH). The results indicated that Q 7-MeGlu and Q are responsible for increasing the packing order, mainly in the hydrophilic but also in hydrophobic regions of the membrane (Q > Q 7-MeGlu). These observations, confirmed by a 1H-NMR method, are key to understanding their antioxidant activity which is probably caused by the stabilizing effect on the lipid membranes. The results showed that Q 7-MeGlu and Q have ability to quench the human serum albumin (HSA) intrinsic fluorescence through a static quenching mechanism. The results of thermodynamic parameters indicated that the process of formation complexes between studied molecules and HSA was spontaneous and caused through Van der Waals interactions and hydrogen bonding. PMID- 28892000 TI - Development of a Matrix Solid-Phase Dispersion Extraction Combined with UPLC/Q TOF-MS for Determination of Phenolics and Terpenoids from the Euphorbia fischeriana. AB - A method based on a simplified extraction by matrix solid phase dispersion (MSPD) followed by ultra-performance liquid chromatography coupled with the quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS) determination is validated for analysis of two phenolics and three terpenoids in Euphorbia fischeriana. The optimized experimental parameters of MSPD including dispersing sorbent (silica gel), ratio of sample to dispersing sorbent (1:2), elution solvent (water-ethanol: 30-70) and volume of the elution solvent (10 mL) were examined and set down. The highest extraction yields of chromatogram information and the five compounds were obtained under the optimized conditions. A total of 25 constituents have been identified and five components have been quantified from Euphorbia fischeriana. A linear relationship (r2 >= 0.9964) between the concentrations and the peak areas of the mixed standard substances were revealed. The average recovery was between 92.4% and 103.2% with RSD values less than 3.45% (n = 5). The extraction yields of two phenolics and three terpenoids obtained by the MSPD were higher than those of traditional reflux and sonication extraction with reduced requirement on sample, solvent and time. In addition, the optimized method will be applied for analyzing terpenoids in other Chinese herbal medicine samples. PMID- 28892001 TI - Synthesis and Immunological Evaluation of Virus-Like Particle-Milbemycin A3/A4 Conjugates. AB - Milbemycins are macrolide antibiotics with a broad spectrum of nematocidal, insecticidal, and acaricidal activity. To obtain milbemycin A3/A4 derivatives suitable for chemical conjugation to protein carriers (milbemycin haptens), succinate linker and a novel 17-atom-long linker containing a terminal carboxylic acid group were attached to the milbemycin core in a protecting group-free synthesis. The obtained milbemycin A3/A4 derivatives were coupled to Potato virus Y-like nanoparticles by the activated ester method. The reaction products were characterized and used in mice immunization experiments. It was found that the mice developed weak specific immune responses toward all tested milbemycin haptens. PMID- 28892002 TI - State of Panax ginseng Research: A Global Analysis. AB - This article aims to understand the global and longitudinal trends of research on Panax ginseng. We used bibliometrics to analyze 3974 papers collected from the Web of ScienceTM Core Collection database during 1959-2016. The number of publications showed a steady growth before 2000 and exponentially increased in stage III (2000-2016, about 86% of the papers were published). Research on P. ginseng was conducted in 64 countries, mainly in Asia; in particular, 41% and 28% of the publications were from South Korea and China, respectively. The institutions from South Korea and China had high publication output and close cooperation and provided the majority of financial support. All top 10 authors and four of the top 20 journals in terms of number of publications originated from South Korea. The leading research subjects were pharmacology (39%), plant science (26%), and integrative complementary medicine (19%). The hotspot of P. ginseng research transformed from basic science to application, and multidisciplinary sciences will play a substantial role in the future. This study provides a comprehensive analysis to elucidate the global distribution, collaboration patterns, and research trends in the P. ginseng domain. PMID- 28892003 TI - Special Issue: Intramolecular Hydrogen Bonding 2017. AB - Even after more than a century of study [1-6], scrutiny, and detailed examination, the H-bond continues [7-12] to evoke a level of fascination that surpasses many other phenomena [...]. PMID- 28892004 TI - Arenobufagin Induces Apoptotic Cell Death in Human Non-Small-Cell Lung Cancer Cells via the Noxa-Related Pathway. AB - Arenobufagin, an active component isolated from the traditional Chinese medicine Chan Su, exhibits anticancer influences in several human malignancies. However, the effects and action mechanisms of arenobufagin on non-small-cell lung cancer (NSCLC) are still unknown. In this study, we reported that arenobufagin acted through activation of Noxa-related pathways and promoted apoptotic cell death in human NSCLC cells. Our results revealed that arenobufagin-induced apoptosis was caspase-dependent, as evidenced by the fact that caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP) were cleaved, and pretreatment with a pan-caspase inhibitor Z-VAD-FMK inhibited the pro-apoptosis effect of arenobufagin. Mechanistically, we further found that arenobufagin rapidly upregulated the expression of the pro-apoptosis protein Noxa, and abrogated the anti-apoptosis protein Mcl-1, a major binding partner of Noxa in the cell. More importantly, the knockdown of Noxa greatly blocked arenobufagin-induced cell death, highlighting the contribution of this protein in the anti-NSCLC effects of arenobufagin. Interestingly, arenobufagin also increased the expression of p53, a direct transcriptional activator for the upregulation of the Noxa protein. Taken together, our results suggest that arenobufagin is a potential anti-NSCLC agent that triggers apoptotic cell death in NSCLC cells through interfering with the Noxa-related pathway. PMID- 28892006 TI - Localization of Ferromagnetic Target with Three Magnetic Sensors in the Movement Considering Angular Rotation. AB - Magnetic detection techniques have been widely used in many fields, such as virtual reality, surgical robotics systems, and so on. A large number of methods have been developed to obtain the position of a ferromagnetic target. However, the angular rotation of the target relative to the sensor is rarely studied. In this paper, a new method for localization of moving object to determine both the position and rotation angle with three magnetic sensors is proposed. Trajectory localization estimation of three magnetic sensors, which are collinear and noncollinear, were obtained by the simulations, and experimental results demonstrated that the position and rotation angle of ferromagnetic target having roll, pitch or yaw in its movement could be calculated accurately and effectively with three noncollinear vector sensors. PMID- 28892007 TI - Time-Dependent Material Properties of Shotcrete: Experimental and Numerical Study. AB - A new experimental program, focusing on the evolution of the Young's modulus, uniaxial compressive strength, shrinkage and creep of shotcrete is presented. The laboratory tests are, starting at very young ages of the material, conducted on two different types of specimens sampled at the site of the Brenner Basetunnel. The experimental results are evaluated and compared to other experiments from the literature. In addition, three advanced constitutive models for shotcrete, i.e., the model by Meschke, the model by Schadlich and Schweiger, and the model by Neuner et al., are validated on the basis of the test data, and the capabilities of the models to represent the observed shotcrete behavior are assessed. Hence, the gap between the the outdated experimental data on shotcrete available in the literature on the one hand and the nowadays available advanced shotcrete models, on the other hand, is closed. PMID- 28892005 TI - FeCl3?6H2O/TMSBr-Catalyzed Rapid Synthesis of Dihydropyrimidinones and Dihydropyrimidinethiones under Microwave Irradiation. AB - An efficient and practical protocol has been developed to synthesize dihydropyrimidinones and dihydropyrimidinethiones through FeCl3?6H2O/TMSBr catalyzed three-component cyclocondensation under microwave irradiation. This approach features high yields, broad substrate scope, short reaction time, mild reaction conditions, operational simplicity and easy work-up, thus affording a versatile method for the synthesis of dihydropyrimidinones and dihydropyrimidinethiones. PMID- 28892008 TI - Ultrasonic Assisted Extraction of Paclitaxel from Taxus x media Using Ionic Liquids as Adjuvants: Optimization of the Process by Response Surface Methodology. AB - (1) Background: Ionic liquids (ILs) are considered "green" solvents and have been widely used in the extraction and separation field in recent years; (2) Methods: In this study, some common ILs and functionalized magnetic ionic liquids (MILs) were used as adjuvants for the solvent extraction of paclitaxel from Taxus x media (T. x media) using methanol solution. The extraction conditions of methanol concentration, IL type and amount, solid-liquid ratio, extraction temperature, and ultrasonic irradiation time were investigated in single factor experiments. Then, three factors of IL amount, solid-liquid ratio, and ultrasonic irradiation time were optimized by response surface methodology (RSM); (3) Results: The MIL [C4MIM]FeCl3Br was screened as the optimal adjuvant. Under the optimization conditions of 1.2% IL amount, 1:10.5 solid-liquid ratio, and 30 min ultrasonic irradiation time, the extraction yield reached 0.224 mg/g; and (4) Conclusions: Compared with the conventional solvent extraction, this ultrasonic assisted extraction (UAE) using methanol and MIL as adjuvants can significantly improve the extraction yield, reduce the use of methanol, and shorten the extraction time, which has the potentiality of being used in the extraction of some other important bioactive compounds from natural plant resources. PMID- 28892009 TI - Nrf2 Activation by 5-lipoxygenase Metabolites in Human Umbilical Vascular Endothelial Cells. AB - 5-hydroxyeicosatetraenoic acid (5-HETE) and 5-hydroxyeicosapentaenoic acid (5 HEPE) are major metabolites produced by 5-lipoxygenase (5-LOX) from arachidonic acid (AA) and eicosapentaenoic acid (EPA). Effects of hydroxides on endothelial cells are unclear, although 5-LOX is known to increase at arteriosclerotic lesions. To investigate the effects of hydroxides on human umbilical vein endothelial cells (HUVECs), the cells were treated with 50 MUM each of AA, EPA, 5 HETE, and 5-HEPE. Treatment of HUVECs with 5-HETE and 5-HEPE, rather than with AA and EPA, increased the nuclear translocation of NF-E2 related factor 2 (Nrf2) and upregulated the expression of heme oxygenase-1 and cystine/glutamate transporter regulated by Nrf2. Reactive oxygen species (ROS) generation was markedly elevated in HUVECs after treatment with 5-HETE and 5-HEPE, and the pretreatment with alpha tocopherol abrogated ROS levels similar to those in the vehicle control. However, ROS generation was independent of Nrf2 activation induced by 5-HETE and 5-HEPE. 5 HETE was converted to 5-oxo-eicosatetraenoic acid (5-oxo-ETE) in HUVECs, and 5 oxo-ETE increased Nrf2 activation. These results suggest that 5-HETE works as an Nrf2 activator through the metabolite 5-oxo-ETE in HUVECs. Similarly, 5-HEPE works in the same way, because 5-HEPE is metabolized to 5-oxo-eicosapentaenoic acid through the same pathway as that for 5-HETE. PMID- 28892010 TI - Interface Characteristics of Sapphire Direct Bonding for High-Temperature Applications. AB - In this letter, we present a sapphire direct bonding method using plasma surface activation, hydrophilic pre-bonding, and high temperature annealing. Through the combination of sapphire inductively coupled plasma etching and the direct bonding process, a vacuum-sealed cavity employable for high temperature applications is achieved. Cross-sectional scanning electron microscopy (SEM) research of the bonding interface indicates that the two sapphire pieces are well bonded and the cavity structure stays intact. Moreover, the tensile testing shows that the bonding strength of the bonding interface is in excess of 7.2 MPa. The advantage of sapphire direct bonding is that it is free from the various problems caused by the mismatch in the coefficients of thermal expansion between different materials. Therefore, the bonded vacuum-sealed cavity can be potentially further developed into an all-sapphire pressure sensor for high temperature applications. PMID- 28892011 TI - Review on the Antimicrobial Properties of Carbon Nanostructures. AB - Swift developments in nanotechnology have prominently encouraged innovative discoveries across many fields. Carbon-based nanomaterials have emerged as promising platforms for a broad range of applications due to their unique mechanical, electronic, and biological properties. Carbon nanostructures (CNSs) such as fullerene, carbon nanotubes (CNTs), graphene and diamond-like carbon (DLC) have been demonstrated to have potent broad-spectrum antibacterial activities toward pathogens. In order to ensure the safe and effective integration of these structures as antibacterial agents into biomaterials, the specific mechanisms that govern the antibacterial activity of CNSs need to be understood, yet it is challenging to decouple individual and synergistic contributions of physical, chemical and electrical effects of CNSs on cells. In this article, recent progress in this area is reviewed, with a focus on the interaction between different families of carbon nanostructures and microorganisms to evaluate their bactericidal performance. PMID- 28892013 TI - Polyphenols in Raw and Cooked Cereals/Pseudocereals/Legume Pasta and Couscous. AB - Pasta and couscous are popular foods manufactured (in their traditional form) from durum wheat semolina. In recent years, the consumers' quest for novel, functional, gluten-free, wholegrain foods has prompted the industry to manufacture new pasta and couscous products in which durum wheat has been partially or totally replaced by other vegetable flours. Besides dietary fibre, these raw materials might be an interesting source of phytochemicals. In this work, 16 commercial samples of pasta and four samples of couscous representative of the new products and made of refined and wholegrain flours of different species of cereals, pseudocereals and legumes were analysed for free, hydrolysable bound and total polyphenol content by means of the Folin-Ciocalteu procedure. Analyses were repeated on cooked samples to assess the quantity of polyphenols ingested by the consumers. The raw legume and pseudocereal products had a total polyphenol content higher than most cereal products (up to 1743.4 mg of Gallic Acid Equivalent (GAE) per 100 g dry weight). Wholegrain products had higher contents than refined products. The free fraction underwent up to 46% loss with cooking, probably because of solubility in water. The water absorption of pasta and couscous during cooking was in a ratio of 2:3, resulting in higher dilution of polyphenols in the cooked couscous. PMID- 28892012 TI - Bordetella Adenylate Cyclase-Hemolysin Toxins. AB - Adenylate cyclase-hemolysin toxin is secreted and produced by three classical species of the genus Bordetella: Bordetella pertussis, B. parapertussis and B. bronchiseptica. This toxin has several properties such as: (i) adenylate cyclase activity, enhanced after interaction with the eukaryotic protein, calmodulin; (ii) a pore-forming activity; (iii) an invasive activity. It plays an important role in the pathogenesis of these Bordetella species responsible for whooping cough in humans or persistent respiratory infections in mammals, by modulating host immune responses. In contrast with other Bordetella toxins or adhesins, lack of (or very low polymorphism) is observed in the structural gene encoding this toxin, supporting its importance as well as a potential role as a vaccine antigen against whooping cough. In this article, an overview of the investigations undertaken on this toxin is presented. PMID- 28892014 TI - A Novel Approach to Estimate the Plastic Anisotropy of Metallic Materials Using Cross-Sectional Indentation Applied to Extruded Magnesium Alloy AZ31B. AB - In this paper, a methodology is presented for obtaining the plastic anisotropy of bulk metallic materials using cross-sectional indentation. This method relies on spherical indentation on the free edge of a specimen, and examining the out-of plane residual deformation contour persisting on the cross-section after unloading. Results obtained from numerical simulation revealed that some important aspects of the out-of-plane residual deformation field are only sensitive to the extent of the material plastic anisotropy, and insensitive to strain hardening, yield strain, elastic anisotropy, and the selected displacement threshold value. An explicit equation is presented to correlate the plastic anisotropy with the characteristic parameter of the bottom shape of residual deformation contour, and it is used to uniquely determine the material plastic anisotropy in cross-sectional indentation. Effectiveness of the proposed method is verified by application on magnesium alloy AZ31B, and the plastic anisotropy parameter obtained from indentation and uniaxial tests show good agreement. PMID- 28892015 TI - The Road to Hell Is Paved with Good Intentions: Why Harm-Benefit Analysis and Its Emphasis on Practical Benefit Jeopardizes the Credibility of Research. AB - It is our concern that European Union Directive 2010/63/EU with its current project evaluation of animal research in the form of a harm-benefit analysis may lead to an erosion of the credibility of research. The HBA assesses whether the inflicted harm on animals is outweighed by potential prospective benefits. Recent literature on prospective benefit analysis prioritizes "societal benefits" that have a foreseeable, positive impact on humans, animals, or the environment over benefit in the form of knowledge. In this study, we will argue that whether practical benefits are realized is (a) impossible to predict and (b) exceeds the scope and responsibility of researchers. Furthermore, we believe that the emphasis on practical benefits has the drawback of driving researchers into speculation on the societal benefit of their research and, therefore, into promising too much, thereby leading to a loss of trust and credibility. Thus, the concepts of benefit and benefit assessment in the HBA require a re-evaluation in a spirit that embraces the value of knowledge in our society. The generation of scientific knowledge has been utilised to great benefit for humans, animals, and the environment. The HBA, as it currently stands, tends to turn this idea upside down and implies that research is of value only if the resulting findings bring about immediate societal benefit. PMID- 28892016 TI - CleAir Monitoring System for Particulate Matter: A Case in the Napoleonic Museum in Rome. AB - Monitoring the air particulate concentration both outdoors and indoors is becoming a more relevant issue in the past few decades. An innovative, fully automatic, monitoring system called CleAir is presented. Such a system wants to go beyond the traditional technique (gravimetric analysis), allowing for a double monitoring approach: the traditional gravimetric analysis as well as the optical spectroscopic analysis of the scattering on the same filters in steady-state conditions. The experimental data are interpreted in terms of light percolation through highly scattering matter by means of the stretched exponential evolution. CleAir has been applied to investigate the daily distribution of particulate matter within the Napoleonic Museum in Rome as a test case. PMID- 28892017 TI - Biodiversity of Actinobacteria from the South Pacific and the Assessment of Streptomyces Chemical Diversity with Metabolic Profiling. AB - Recently, bioprospecting in underexplored habitats has gained enhanced focus, since new taxa of marine actinobacteria can be found, and thus possible new metabolites. Actinobacteria are in the foreground due to their versatile production of secondary metabolites that present various biological activities, such as antibacterials, antitumorals and antifungals. Chilean marine ecosystems remain largely unexplored and may represent an important source for the discovery of bioactive compounds. Various culture conditions to enrich the growth of this phylum were used and 232 bacterial strains were isolated. Comparative analysis of the 16S rRNA gene sequences led to identifying genetic affiliations of 32 genera, belonging to 20 families. This study shows a remarkable culturable diversity of actinobacteria, associated to marine environments along Chile. Furthermore, 30 streptomycete strains were studied to establish their antibacterial activities against five model strains, Staphylococcus aureus, Listeria monocytogenes, Salmonella enterica, Escherichia coli and Pseudomonas aeruginosa, demonstrating abilities to inhibit bacterial growth of Gram-positive bacteria. To gain insight into their metabolic profiles, crude extracts were submitted to liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis to assess the selection of streptomycete strains with potentials of producing novel bioactive metabolites. The combined approach allowed for the identification of three streptomycete strains to pursue further investigations. Our Chilean marine actinobacterial culture collection represents an important resource for the bioprospection of novel marine actinomycetes and its metabolites, evidencing their potential as producers of natural bioproducts. PMID- 28892019 TI - Study of the Relevance of the Quality of Care, Operating Efficiency and Inefficient Quality Competition of Senior Care Facilities. AB - The purpose of this research is to examine the relation between operating efficiency and the quality of care of senior care facilities. We designed a data envelopment analysis, combining epsilon-based measure and metafrontier efficiency analyses to estimate the operating efficiency for senior care facilities, followed by an iterative seemingly unrelated regression to evaluate the relation between the quality of care and operating efficiency. In the empirical studies, Taiwan census data was utilized and findings include the following: Despite the greater operating scale of the general type of senior care facilities, their average metafrontier technical efficiency is inferior to that of nursing homes. We adopted senior care facility accreditation results from Taiwan as a variable to represent the quality of care and examined the relation of accreditation results and operating efficiency. We found that the quality of care of general senior care facilities is negatively related to operating efficiency; however, for nursing homes, the relationship is not significant. Our findings show that facilities invest more in input resources to obtain better ratings in the accreditation report. Operating efficiency, however, does not improve. Quality competition in the industry in Taiwan is inefficient, especially for general senior care facilities. PMID- 28892018 TI - Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway. AB - The Japanese mugwort, Artemisia princeps (yomogi in Japanese), has anti inflammatory and antioxidant effects. Skin care products containing Artemisia princeps extract (APE) are known to improve dry skin symptoms in atopic dermatitis. Atopic dry skin is associated with a marked reduction of skin barrier proteins, such as filaggrin (FLG) and loricrin (LOR). Recently, aryl hydrocarbon receptor (AHR), and its downstream transcription factor OVO-like 1 (OVOL1), have been shown to regulate the gene expression of FLG and LOR. The focus of this paper is to evaluate the effects of APE on the AHR/OVOL1/FLG or LOR pathway since they have remained unknown to this point. We first demonstrated that non cytotoxic concentrations of APE significantly upregulated antioxidant enzymes, NAD(P)H dehydrogenase quinone 1 and heme oxygenase 1, in human keratinocytes. Even at these low concentrations, APE induced nuclear translocation of AHR and significantly upregulated CYP1A1 (a specific target gene for AHR activation), FLG, and LOR expression. AHR knockdown downregulated OVOL1 expression. The APE induced upregulation of FLG and LOR was canceled in keratinocytes with AHR or OVOL1 knockdown. In conclusion, antioxidant APE is a potent phytoextract that upregulates FLG and LOR expression in an AHR/OVOL1-dependent manner and this may underpin the barrier-repairing effects of APE in treating atopic dry skin. PMID- 28892020 TI - Identification of Staphylococcus aureus Cellular Pathways Affected by the Stilbenoid Lead Drug SK-03-92 Using a Microarray. AB - The mechanism of action for a new lead stilbene compound coded SK-03-92 with bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) is unknown. To gain insight into the killing process, transcriptional profiling was performed on SK-03-92 treated vs. untreated S. aureus. Fourteen genes were upregulated and 38 genes downregulated by SK-03-92 treatment. Genes involved in sortase A production, protein metabolism, and transcriptional regulation were upregulated, whereas genes encoding transporters, purine synthesis proteins, and a putative two-component system (SACOL2360 (MW2284) and SACOL2361 (MW2285)) were downregulated by SK-03-92 treatment. Quantitative real-time polymerase chain reaction analyses validated upregulation of srtA and tdk as well as downregulation of the MW2284/MW2285 and purine biosynthesis genes in the drug treated population. A quantitative real-time polymerase chain reaction analysis of MW2284 and MW2285 mutants compared to wild-type cells demonstrated that the srtA gene was upregulated by both putative two-component regulatory gene mutants compared to the wild-type strain. Using a transcription profiling technique, we have identified several cellular pathways regulated by SK-03-92 treatment, including a putative two-component system that may regulate srtA and other genes that could be tied to the SK-03-92 mechanism of action, biofilm formation, and drug persisters.